PMID- 10391395
TI  - Effect of metformin on patients with impaired glucose tolerance.
AB  - AIMS: To evaluate the effect of metformin on glucose metabolism, insulin
      sensitivity and rate of conversion diabetes in people with impaired glucose
      tolerance (IGT). METHODS: Seventy subjects with IGT were randomized under double
      blind conditions to receive either placebo (n = 37) or metformin (n = 33) at a
      dosage of 250 mg three times daily for a duration of 12 months. Glycaemic
      control, plasma insulin and other biochemical indexes were assessed before and
      after 3, 6 and 12 months. RESULT: At 12 months the conversion rate to diabetes
      was 16.2% in the placebo group compared to 3.0% for the metformin group (P =
      0.011). Of subjects treated with metformin for 12 months, 84.9% became
      normoglycaemic compared to 51.4% of those receiving the placebo. Significant
      improvements in fasting glucose, glucose tolerance and insulin sensitivity were
      found at 12 months and at intermediate clinic assessments. CONCLUSIONS: Metformin
      can improve glucose metabolism in IGT patients and may be a treatment option in
      their management of IGT subjects.

PMID- 10391396
TI  - Comparison of effects of captopril used either alone or in combination with a
      thiazide diuretic on insulin action in hypertensive Type 2 diabetic patients: a
      double-blind crossover study.
AB  - AIMS: It has been suggested that the adverse metabolic effects of
      antihypertensive therapy offset some of the benefits of blood pressure reduction.
      It has also been suggested that angiotensin converting enzyme (ACE) inhibitors
      reduce insulin resistance and that, if used together with thiazide diuretics, the
      adverse effects of thiazides on insulin sensitivity may be eliminated. We
      examined the effects on insulin sensitivity of captopril either alone or in
      combination with bendrofluazide in 11 hypertensive Type 2 diabetic patients.
      METHODS: Insulin action was assessed using an isoglycaemic hyperinsulinaemic
      clamp in a double-blind, randomized, crossover study after a 6-week placebo run
      in and following two 12-week treatment periods with captopril (C) (100 mg) alone
      or in combination with bendrofluazide (CB) (2.5 mg). RESULTS: Blood pressure was
      lower following CB compared to C (128/82 vs. 144/ 88 mmHg; P<0.005) and both were
      lower than baseline (162/101 mmHg; P < 0.001). CB resulted in a significant
      increase in fasting plasma glucose compared to C (9.7+/-0.8 vs. 8.5+/-0.6 mmol/;
      P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia
      during hyperinsulinaemia were lower after CB compared to C (22.3+/-2.4 vs. 27.4+/
      4.2 mol x kg(-1) x min(-1); P < 0.05). Suppression of endogenous glucose
      production was reduced after CB compared to baseline (4.0+/-0.6 vs. 2.4+/-0.5 mol
      x kg(-1) x min(-1); P< 0.05). CONCLUSIONS: Combination of bendrofluazide with
      captopril lowered blood pressure but resulted in deleterious effects on insulin
      action compared to captopril alone.

PMID- 10391397
TI  - Novel surgical treatment and gastric pathology in diabetic gastroparesis.
AB  - AIMS: Observations are made on four Type 1 diabetic patients with the rare
      syndrome of intractable vomiting from confirmed gastroparesis, to determine
      whether radical surgery would alleviate their symptoms and subsequently to
      examine in detail the gastric histopathology. METHODS: The surgical approach
      consisted of an approximate 70% resection of the stomach, including the antrum
      and pylorus, with closure of the duodenum and restoration of gastrointestinal
      continuity with a 60-cm Roux-en-Y jejunal loop. Four longstanding Type 1 diabetic
      patients were examined and treated as described. They were all women in the age
      range 2741 years with grossly abnormal autonomic function tests in whom other
      causes for gastric paresis had been excluded. RESULTS: Vomiting episodes leading
      to multiple hospital admissions (6-8) in the year preceding surgery were
      eliminated in three of the four patients, while in the fourth initial success was
      followed by the need for dialysis for renal failure. Gastric histopathology
      showed evidence of smooth muscle degeneration and fibrosis, with eosinophilic
      inclusion bodies (M-bodies) which appear to be unique to this condition. The
      findings suggest the presence of a gastromyopathy. CONCLUSIONS: Satisfactory
      relief of intractable vomiting from diabetic gastroparesis was achieved by a
      novel radical surgical procedure. Histopathological findings suggest that
      gastromyopathy may contribute to the production of this syndrome.

PMID- 10391398
TI  - Plasma 1,5-anhydroglucitol concentrations are influenced by variations in the
      renal threshold for glucose.
AB  - AIMS: Measurement of serum 1,5-anhydroglucitol (1,5AG) concentrations has been
      proposed as an alternative to HbA1c as both a marker of diabetic glycaemic
      control and as a screening test for diabetes. The sugar competes with glucose for
      renal tubular reabsorption, so hyperglycaemia leads to reduced serum 1,5AG
      concentrations through increased urinary loss. This study has sought to establish
      whether plasma 1,5AG can be influenced by not only hyperglycaemia, but by
      variations in renal threshold for glucose. METHODS: Thirty-eight pregnant women
      (median age 30 years, range 20-43) found to be normoglycaemic after a 75-g
      carbohydrate load had plasma 1,5AG and urine glucose measured. RESULTS: Using
      multivariate analysis, the presence and degree of detectable glycosuria at 2 h
      post glucose load was strongly predictive of a low plasma 1,5AG concentration
      (P=0.0012) independently of fasting plasma glucose (P=0.96), 2 h glucose
      (P=0.029), subject age (P=0.97) and gestation (P=0.36). Thus, when matched for
      plasma glucose areas under the glucose load curve, 16 glycosuric subjects had
      significantly lower 1,5AG concentrations compared to 16 nonglycosuric ones
      (median 1,5AG 46 micromol/l (IQR 30-56) vs. 72 micromol/l (IQR 55-79, P=0.017).
      CONCLUSIONS: People with the same glucose tolerance may demonstrate variable
      plasma 1,5AG concentrations depending on their renal threshold for glucose. This
      inherent characteristic is likely to limit the usefulness of the test when
      monitoring or screening for diabetes.

PMID- 10391400
TI  - Enterovirus variants in the serum of children at the onset of Type 1 diabetes
      mellitus.
AB  - AIMS: This study was designed to assess further the possible links between
      enterovirus infection and Type 1 diabetes mellitus (DM). METHODS: Sera from 110
      children in the age range 0-15 years was obtained shortly after the diagnosis of
      Type 1 DM, in paediatric centres throughout the UK. They were tested for the
      presence of enteroviral sequences by the polymerase chain reaction (PCR) of the
      5' nontranslated region (5' NTR). One hundred and eighty-two controls tested were
      matched for age, geographical location and time of year. RESULTS: A significantly
      greater number of diabetic children (27% vs. 4.9%, P <0.005) had evidence of
      enteroviral RNA sequences. Proportionally, more younger children were enterovirus
      PCR positive, thus eight out of 20 children aged < or =2 years were enterovirus
      PCR positive. Sequence analysis showed that there was considerable variation in
      the sequences detected, although all appeared to be of the coxsackie/echovirus
      type. CONCLUSION: This study re-emphasizes that a link exists between enteroviral
      infection and the onset of Type 1 DM, particularly at a very early age, and
      suggests that these viruses are aetiologically important in diabetes in a
      significant proportion of children.

PMID- 10391399
TI  - Intensive lipid-lowering strategy in patients with diabetes mellitus.
AB  - AIMS: To assess the feasibility of an intensive lipid-lowering strategy in
      diabetic subjects pursuing target plasma lipid levels. METHODS: Patients with
      diabetes mellitus (DM), Type 1 or 2, with plasma lipid levels exceeding target
      values (LDL-cholesterol <2.6 mmol/l, triglycerides < 1.7 mmol/l, HDL-cholesterol
      > 0.9 mmol/l for men and > 1.1 mmol/l for women) were eligible. After 6-12 weeks
      of diet and glycaemic control, lipid-lowering medication
      (simvastatin/gemfibrozil/acipimox) was prescribed in steps of incremental dosages
      and combinations for 30 weeks. RESULTS: Of all eligible clinic patients, 25%
      initially responded and finally 12% were entered. Thirty-six patients with Type 1
      and 59 with Type 2 DM were studied. Mean baseline lipid levels in Type 1 and Type
      2 diabetic subjects were: LDL-cholesterol 3.6 and 3.7 mmol/l, triglycerides 1.7
      and 2.2 mmol/l, HDL-cholesterol for men 1.1 and 1.0 mmol/l, and for women 1.4 and
      1.2 mmol/l, respectively. All three target values were reached in 66% of the
      patients. LDL-cholesterol was reduced by 1.2 mmol/l in Type 1 and 1.3 mmol/l in
      Type 2 diabetic patients and triglycerides by 0.7 mmol/l and 1.1 mmol/l,
      respectively. HDL-cholesterol increased by 0.15 mmol/l and 0.34 mmol/l in men and
      women with Type 1 diabetes mellitus, respectively. The cholesterol-triglyceride
      ratio decreased significantly in VLDL in Type 1 diabetes and in IDL in Type 2
      diabetes and increased significantly in HDL in Type 2 DM. CONCLUSIONS: A minority
      of subjects eligible for intensive lipid lowering agreed to participate in a
      feasibility study, suggesting a potentially large compliance problem for a
      general lipid-lowering programme in a diabetes clinic. Nevertheless, intensive
      lipid lowering with drug combinations can attain the recommended target lipid
      levels in 66% of subjects with diabetes. With this strategy the plasma
      lipoprotein composition shifts towards a less atherogenic profile. Subjects with
      diabetes should therefore receive lipid-lowering therapy tailored to reach target
      levels, rather than standard dosages, in order to reduce atherogenic risk.

PMID- 10391401
TI  - Elevated plasma semicarbazide-sensitive amine oxidase (SSAO) activity in Type 2
      diabetes mellitus complicated by retinopathy.
AB  - AIMS: To measure plasma semicarbazide-sensitive amine oxidase (SSAO) activities
      and detect retinopathy in Type 2 diabetes mellitus (DM). METHODS: Cross
      sectional, population-based study of 65 diabetes patients (61 diagnosed from the
      age of 30 years) with or without retinopathy as determined by fundus photography
      in primary care. HbA1c was analysed by ion exchange chromatography on a Mono S
      for HbA1c column. SSAO activities were assayed radiometrically and formaldehyde
      albumin adducts by ELISA in plasma samples from patients and 136 healthy
      controls. RESULTS: Subjects with diabetes had higher plasma SSAO activity,
      measured as nmol benzylamine x mlplasma(-11) x h(-1)(mean 20.6), than controls
      (mean 14.3), P<0.0001; 95% confidence interval (CI) for difference 4.9-7.7. SSAO
      activity was higher in patients with retinopathy (mean 23.2) than in those
      without (mean 18.9), P=0.012; 95% CI for difference 1.0-7.5, and related to the
      HbA1c value. No statistically significant relationship between diabetes duration
      and SSAO activity was found. With HbA1c values and insulin treatment entered into
      a multiple logistic regression model, SSAO activity no longer predicted
      retinopathy, P increasing from 0.025 to 0.17. SSAO activity and the presence of
      any retinopathy were unrelated to titres of antibodies against formaldehyde
      treated human serum albumin. CONCLUSIONS: SSAO activity, earlier found to be
      elevated in Type 1 DM, is also elevated in Type 2 DM. The SSAO family of enzymes
      may be involved in the development of diabetic retinopathy, possibly by
      catalysing the formation of toxic metabolites. A potent and specific inhibitor of
      human SSAO might help prevent retinopathy in Type 1 and Type 2 DM.

PMID- 10391402
TI  - Association of plasma fibrinogen level and blood pressure with diabetic
      retinopathy, and renal complications associated with proliferative diabetic
      retinopathy, in Type 2 diabetes mellitus.
AB  - AIM: To clarify the association of several clinical parameters, including plasma
      fibrinogen level, with diabetic retinopathy in patients with Type 2 diabetes
      mellitus (DM). METHODS: A total of 294 Japanese patients with Type 2DM were
      studied; 53 patients with no diabetic retinopathy (NDR), 90 with background
      diabetic retinopathy (BDR), and 151 with proliferative diabetic retinopathy
      (PDR). Multiple logistic regression analysis was performed to assess variables
      independently associated with diabetic retinopathy in two settings: presence of
      retinopathy of any severity and presence of advanced retinopathy. RESULTS: The
      following parameters were identified as independent factors associated with the
      presence of diabetic retinopathy (NDR vs. BDR + PDR): type of therapy (P<0.0005),
      log-transformed plasma fibrinogen level (P < 0.05), mean blood pressure (P <
      0.05), and duration of diabetes (P < 0.05). The independent variables associated
      with advanced retinopathy were type of therapy (P<0.00005), age (P<0.0005) and
      nephropathy (P<0.05). Body mass index, smoking and hypertensive status, HbA1c and
      total cholesterol levels were not independently associated. CONCLUSIONS: These
      data suggest that in patients with Type 2 DM, an increased blood viscosity due to
      high fibrinogen level as well as an elevated intravessel pressure play a role in
      the development of diabetic retinopathy, and that the progression to PDR is
      influenced or accompanied by the deterioration of renal status.

PMID- 10391403
TI  - The 1997 ADA diabetes diagnostic categories: impact on employees' annual medical
      examination.

PMID- 10391404
TI  - Community-acquired pneumonia: definition, epidemiology, and outcome.
AB  - Community-acquired pneumonia does not describe pneumonia acquired in the
      community. It represents a concept about a distinct clinical syndrome in distinct
      community patients. However, considerable differences still persist in European
      as well as in American literature with regard to its exact contents, including
      the assessment of immunosuppression, aspiration, tuberculosis, postobstructive
      pneumonia, and acquisition during stays in nursing homes. The definition of
      pneumonia is also not standardized, and this may impose the greatest difficulties
      in mild courses. The incidence of pneumonia probably does not differ between
      Europe and North America. The basic microbial patterns comprise (1) Streptococcus
      pneumoniae, (2) an atypical group, (3) non-pneumococcal-non-atypical group, and
      (4) the microbiologically negative group. The relative frequency of each group is
      affected by the severity of pneumonia, age, comorbidity, season, and individual
      risk factors. Prognostic factors associated with death should be arranged
      according to a clinically meaningful concept, including the differentiation of
      basic, baseline, and evolutionary factors. This concept allows the assessment of
      prognostic factors that reflect the premorbid condition of the patient, including
      the history of pneumonia up to the time of hospital admission, the severity of
      illness at initial evaluation, and the clinical evolution since the initiation of
      antimicrobial treatment.

PMID- 10391405
TI  - Assessment of severity of community-acquired pneumonia.
AB  - Community-acquired pneumonia (CAP) is the most common serious infection
      encountered in medical practice, with 1% to 10% of patients requiring admission
      to a hospital. The mortality rate of patients admitted is considerable, ranging
      from 5% to 25%. Motivated by the results of the British Thoracic Society (BTS)
      study, different investigators have identified several risk factors associated
      with a high mortality rate. The assessment of the severity of CAP can be
      determined at three stages: (1) At home or during the general practitioner's (GP)
      consultation; (2) In the hospital outpatient clinic or emergency room; and (3) In
      the medical ward and/or intensive care unit (ICU). At stage 1, medical history,
      symptoms, and signs (respiratory rate!) seem to be relevant. However, it is not
      easy for GPs to diagnose pneumonia with any degree of certainty because of the
      limited diagnostic tools available. Once a patient is referred to a hospital
      (stage 2), factors such as clinical presentation, comorbidities, and laboratory
      and radiographic factors must be determined to identify those patients who are at
      risk. BTS criteria (respiratory rate > or =30/min, diastolic blood pressure < or
      = 60 mm Hg, blood urea nitrogen >7 mmol/L), but also other combinations of
      criteria, are associated with a multiple-fold increased risk of death. However,
      most of these prognostic models have low positive predictive value, suggesting
      that the risk of death is overestimated when these models are implemented in
      daily practice. In general, younger patients without comorbidities can be treated
      in an outpatient setting; sometimes brief inpatient observation is necessary.
      Elderly patients, especially those with comorbidities and severe illness need
      inpatient care, sometimes resulting in treatment from an ICU. Severe CAP (stage
      3) is defined as pneumonia associated with respiratory failure and/or hemodynamic
      instability requiring treatment in an ICU, and has a death rate varying from 21%
      to 54%. Pneumonia- and non-pneumonia-related complications are often observed.
      Adverse prognostic factors that have been reported in several studies are:
      advanced age, the presence of comorbidities, development of septic shock, need
      for mechanical ventilation (including use of positive end-expiratory pressure and
      FiO2 >60%), development of adult respiratory distress syndrome, progression of
      radiographic abnormalities, bacteremia (especially when due to P aeruginosa), non
      pneumonia-related complications, and inadequate antibiotic treatment. To reduce
      mortality, prospective studies focusing on adverse prognostic factors at the
      start of and during antibiotic treatment are urgently needed at all three stages.

PMID- 10391406
TI  - Microbial etiology and bacterial resistance.
AB  - The nature of the causative organisms involved in community-acquired pneumonia
      has always attracted the interest of investigators. Despite multiple studies
      using different methodological approaches, it remains a matter of controversy
      because a reliable cause cannot be obtained in a significant percentage of cases,
      even when using more sophisticated diagnostic procedures. The recent discovery of
      new pathogens such as the Legionella species or Chlamydia pneumoniae, highly
      prevalent worldwide shows the limitations of our knowledge in that field.
      Recently, common respiratory pathogens such as the pneumococcus or Haemophilus
      influenzae, among others, showed a progressive tendency to develop resistance to
      penicillins and other antibiotics. Although this phenomenon has a variable impact
      among different countries, its growing importance is changing the classical
      therapeutic approach to community-acquired pneumonia.

PMID- 10391407
TI  - Microbiological investigations.
AB  - Causative diagnosis of pneumonia is problematic. The lack of a reliable gold
      standard for diagnosis has also made the development of new diagnostic methods
      for different microbes causing pneumonia difficult. Serologic methods are
      continuously used in the diagnosis of pneumonia caused by viruses and atypical
      bacteria. However, rapid diagnostic methods are urgently needed to guide
      clinicians to choose proper antibiotic treatment because resistant bacteria are
      emerging in different parts of the world.

PMID- 10391408
TI  - In-hospital management of adults who have community-acquired pneumonia.
AB  - The initial in-hospital management of adult patients with community-acquired
      pneumonia can be divided into five major steps: an early recognition of the
      patient with presumptive pneumonia, assessment of the severity of illness,
      establishment of an etiologic diagnosis, supportive therapy, and decision
      regarding initiation of empirical therapy. In most European recommendations, the
      empirical antibiotic treatment is directed against "the most likely pathogen,"
      based on epidemiological, clinical, and laboratory data, and on the severity of
      illness. In contrast, newer North American guidelines have focused on the
      severity of illness of community-acquired pneumonia. As a consequence, the use of
      a broader initial antibiotic coverage, including extended-spectrum cephalosporins
      and combinations, seems to be more common in North America than in Europe.

PMID- 10391409
TI  - Lower respiratory tract infection and pneumonia in the community.
AB  - Community-acquired pneumonia (CAP) is common. There is no entirely satisfactory
      way of defining pneumonia using clinical criteria alone. New focal chest signs on
      examination in the presence of a systemic illness that is suggestive of a lower
      respiratory tract infection seems to be the best clinical finding that indicates
      pneumonia. Progress has been made in identifying simple clinical features that
      relate to prognosis and allow the general practitioner to decide whether care in
      the community is appropriate or hospital referral is required. Psychosocial
      factors for the patient will also remain important. Most patients who have CAP
      that is mild enough to be managed in the community will require few, if any,
      investigations. A chest radiograph is appropriate in all patients to exclude an
      underlying lung tumor. Measurement of surrogate markers of acute infection, such
      as C-reactive protein, may prove useful to the general practitioner if near
      testing were to become feasible. The antibiotic management for CAP for patients
      well enough to be managed at home can be simple and logical, providing general
      practitioners have some knowledge regarding likely pathogens and etiologic and
      epidemiological clues. Any antibiotic chosen must suppress Streptococcus
      pneumoniae, which remains the most common cause of CAP.

PMID- 10391410
TI  - Childhood community-acquired pneumonia.
AB  - Much of what we know about childhood community-acquired pneumonia in developed
      countries comes from studies in Europe, where approximately 2.5 million cases of
      childhood pneumonia occur yearly. Streptococcus pneumoniae, Mycoplasma
      pneumoniae, and respiratory syncytial virus are the most common causative agents.
      Blood culture is seldom positive and mortality is very low in developed
      countries. Tachypnea and crackles on auscultation are the major findings
      suggesting pneumonia, but their sensitivity and specificity are not high enough,
      and, if possible, a radiograph of the chest should be obtained to confirm the
      diagnosis. Recommendations for antibiotic treatment vary. Based on the etiologic
      studies we suggest macrolides as the first choice in outpatients and depending on
      the clinical picture and severity of the illness penicillin G, macrolide, or
      cefuroxime plus macrolide in hospitalized patients. The recovery of children with
      pneumonia is usually rapid and in uncomplicated cases routine follow-up
      radiographs and check-ups are unnecessary.

PMID- 10391411
TI  - Community-acquired pneumonia in the elderly.
AB  - The incidence of community-acquired pneumonia (CAP) in the elderly is higher
      compared to younger populations. In addition, pneumonia in the elderly is a life
      threatening problem. As our demographics have changed, clinicians have developed
      a heightened interest in managing pneumonia in the elderly. The development of
      pneumonia in elderly patients differs from that in younger individuals due to a
      complex array of factors. (1) The organisms involved depend on the setting in
      which the pneumonia developed: either the nonhospitalized elderly patient with
      CAP or the institutionalized patient who develops nursing-home-acquired
      pneumonia. (2) Underlying comorbid conditions commonly exist in the elderly that
      affect the etiology and outcome of pneumonia. Overall, Streptococcus pneumoniae
      and Haemophilus influenzae are still the most common etiologies of pneumonia in
      the elderly. The true role of gram-negative bacilli remains unclear although
      these micro-organisms may be more common etiologic agents in nursing-home
      pneumonia. Some recent studies from Mediterranean areas have reported high rates
      of infection by Chlamydia pneumoniae, but the real role of this micro-organism
      has to be confirmed. Another important issue is that the presenting symptoms of
      pneumonia in the elderly can be subtle and sometimes difficult to recognize.
      Fever is frequently absent, and delirium or alteration of functional physical
      capacity may be the only manifestations. Mortality in the elderly with CAP is
      higher when compared to younger populations. However, this may be explained by
      the concomitant presence of comorbid conditions more than by age per se. This
      statement has to be kept in mind when considering hospital and, particularly,
      intensive care unit admissions. Finally, antibiotic pharmacokinetics in the
      elderly populations with CAP ought to be considered to avoid frequent side
      effects and complications. Overall, antibiotic regimens in hospitalized elderly
      patients with CAP do not differ from other hospitalized CAP populations. An
      organized approach to assessing elderly patients with suspicion of pneumonia and
      an awareness of common pitfalls in the management of this pulmonary infection in
      this population are essential to improving outcomes.

PMID- 10391412
TI  - Clinical effectiveness, policies, and practices for influenza and pneumococcal
      vaccines.
AB  - Pneumococcal disease and influenza impact public health considerably. S
      pneumoniae probably accounts for almost 14,000 deaths and more than 23,000
      admissions to National Health Service hospitals per annum. Influenza epidemics
      occur frequently and unpredictably with the potential to inflict morbidity and
      mortality on a massive scale. Both diseases pose maximum risks to persons with
      underlying chronic illnesses. Assessing the effectiveness of pneumococcal and
      influenza vaccines presents complex methodological problems. However, despite
      these difficulties, a body of evidence has accumulated suggesting that
      pneumococcal vaccines offer substantial protection against both bacteremia and
      pneumonia among healthy low-risk adults, but only against bacteremia in those
      considered high-risk. There is now strong evidence that the influenza vaccine
      protects high-risk patients from both hospitalization and death. Although most
      European countries now have national guidelines for vaccination of high-risk
      patients, both vaccines remain underused in modern clinical practice mainly due
      to poor organization.

PMID- 10391413
TI  - Citalopram in the treatment of depression and other potential uses in psychiatry.
AB  - During the past decade, treatment options for depression have increased with the
      introduction of new agents. Older agents, such as tricyclic antidepressants and
      monoamine oxidase inhibitors, increase noradrenergic and serotonergic
      neurotransmission. Attempts to separate antidepressant effects from adverse
      effects led to the development of selective serotonin reuptake inhibitors
      (SSRIs). Citalopram is the newest SSRI to be marketed in the United States. Of
      all SSRIs on the market, it is the most selective for serotonin reuptake pump.
      Its efficacy in treating depression was evident in both placebo-controlled and
      comparator trials. In addition, citalopram was studied in the treatment of other
      psychiatric disorders. The agent has less inhibition of cytochrome P450 enzymes
      than other SSRIs, possibly giving it a lower potential for drug interactions.

PMID- 10391414
TI  - Bacillus anthracis: medical issues of biologic warfare.
AB  - Recent world events refocused attention on the possibility of nations engaging in
      biologic warfare, including an attack with Bacillus anthracis. The single
      available anthrax vaccine in the United States for human use, formerly known as
      MDPH-PA, has decreased ability to protect laboratory animals against virulent B.
      anthracis strains, especially compared with new vaccines being developed. Studies
      with these vaccines, however, have several shortcomings. The pathogenesis,
      diagnosis, treatment, and prophylaxis of anthrax are discussed, as well as the
      implications that an attack with B. anthracis would place on the health care
      system.

PMID- 10391415
TI  - Implications of vancomycin degradation products on therapeutic drug monitoring in
      patients with end-stage renal disease.
AB  - In renally impaired patients, vancomycin concentrations typically are maintained
      at body temperature for extended periods of time due to the drug's prolonged half
      life. Both time and increased temperature potentiate production of vancomycin
      crystalline degradation products (CDP-1). Commercially available vancomycin
      assays, such as fluorescence polarization immunoassay (FPI) and radioimmunoassay,
      cross-react with CDP-1 isomers. Overestimation of vancomycin concentrations by 40
      53% due to cross-reactivity of CDP-1 with active factor B vancomycin occurs with
      FPI. As FPI is the most common method of analyzing serum vancomycin, clinicians
      must be aware of its potential shortcomings and be prepared to alter vancomycin
      dosages in renally impaired patients. The possibility of adverse affects due to
      elevated concentrations of CDP-1 or therapeutic failures due to subtherapeutic
      levels of factor B vancomycin cannot be excluded.

PMID- 10391416
TI  - Indinavir concentrations and antiviral effect.
AB  - STUDY OBJECTIVES: To determine the variability of indinavir pharmacokinetics in
      patients attending an outpatient clinic, and to explore relationships between
      indinavir exposure and antiviral effect. DESIGN: Open, formal pharmacokinetic
      evaluation. SETTING: University-affiliated clinical research center. PATIENTS:
      Forty-three adults infected with the human immunodeficiency virus (HIV) receiving
      therapy with indinavir and concomitant nucleoside reverse transcriptase
      inhibitors. INTERVENTION: Indinavir concentrations were measured after patients
      were observed taking an 800-mg oral dose, and pharmacokinetic parameters were
      determined using a one-compartment oral absorption model. Virologic and
      pharmacologic characteristics were compared in a subset of 23 patients who were
      protease inhibitor naive before receiving indinavir. MEASUREMENTS AND MAIN
      RESULTS: Mean indinavir pharmacokinetics were similar to those reported
      previously. Significant intersubject variability in systemic exposure was
      observed in patients receiving the same dosage; the 8-hour area under the curve
      (AUC8) ranged from 5.4-68.0 microM x hour. In protease inhibitor-naive subjects,
      the indinavir AUC8 was statistically higher in those with undetectable plasma HIV
      RNA (30.7 microM x hr) versus detectable plasma HIV RNA (22.4 microM x hr,
      p=0.035). Measured concentrations 5 hours after the dose and extrapolated 8-hour
      concentrations were also significantly higher in patients with undetectable
      plasma HIV RNA (both p=0.007). CONCLUSIONS: Indinavir plasma concentrations were
      highly variable among patients receiving the same dosage. Patients with an
      undetectable plasma HIV RNA level who were protease inhibitor naive had
      statistically higher indinavir concentrations and slower oral clearance than the
      group with detectable HIV RNA. Relationships between indinavir concentrations and
      anti-HIV effect provide a basis for quantifying the pharmacologic contribution to
      the heterogeneity in therapeutic response.

PMID- 10391417
TI  - Safety and efficacy of 4-aminopyridine in humans with spinal cord injury: a long
      term, controlled trial.
AB  - STUDY OBJECTIVE: To determine the effects of the long-term administration of 4
      aminopyridine (4-AP) on sensorimotor function in humans with long-standing spinal
      cord injury (SCI). DESIGN: Randomized, open-label, active-treatment control,
      dosage-blinded study. SETTING: University-affiliated, tertiary-level care,
      Department of Veterans Affairs Medical Center. PATIENTS: Twenty-one healthy men
      and women outpatients suffering from traumatic SCI (14 tetraplegic, 7 paraplegic)
      for 2 years or more. INTERVENTIONS: Dosages of an immediate-release formulation
      of 4-AP were titrated. At 3 months, 16 subjects were receiving 4-AP 30 mg/day
      (high dose); 5 subjects were receiving 4-AP 6 mg/day (low dose) and served as an
      active-treatment control group. MEASUREMENTS AND MAIN RESULTS: Composite motor
      and sensory scores had statistically significant increases at 3 months. Maximal
      expiratory pressure, maximal inspiratory pressure, forced vital capacity, and
      forced expiratory volume in 1 second showed clinically meaningful and/or
      statistically significant increases among patients receiving 4-AP 30 mg/day.
      These subjects also had significant decreases in spasticity (modified Ashworth
      Scale). Serial biochemical profiles and electroencephalographs were unchanged
      from baseline, and no clinically significant drug toxicity was encountered.
      CONCLUSIONS: Long-term oral administration of immediate-release 4-AP was
      associated with improvement in and recovery of sensory and motor function,
      enhanced pulmonary function, and diminished spasticity in patients with long
      standing SCI. 4-Aminopyridine appears to be safe and relatively free from
      toxicity when administered orally over 3 months. Each patient who received
      immediate-release 4-AP 30 mg/day showed a response in one or more of the outcome
      measures.

PMID- 10391419
TI  - Comparison of a neural network approach with five traditional methods for
      predicting creatinine clearance in patients with human immunodeficiency virus
      infection.
AB  - STUDY OBJECTIVE: To compare the results of an artificial neural network approach
      with those of five published creatinine clearance (Cl(cr)) prediction equations
      and with the measured (true) Cl(cr) in patients infected with the human
      immunodeficiency virus (HIV). DESIGN: Six-month prospective study. SETTINGS: Two
      university medical centers. PATIENTS: Sixty-five HIV-infected patients: 18
      relatively healthy outpatients and 47 inpatients. INTERVENTIONS: All subjects had
      urine collected for 24 hours to determine Cl(cr). MEASUREMENTS AND MAIN RESULTS:
      The 16 input variables were age, ideal body weight, actual body weight, body
      surface area, height, and the following blood chemistries: sodium, potassium,
      aspartate aminotransferase, alanine aminotransferase, red blood cell count,
      platelet count, white blood cell count, glucose, serum creatinine, blood urea
      nitrogen, and albumin. The only output variable was Cl(cr). A training set of 55
      subjects was used to develop the relationship between input variables and the
      output variable. The trained neural network was then used to predict Cl(cr) of a
      validation set of 10 subjects. Mean differences between predicted Cl(cr) and
      actual Cl(cr) (bias) were 4.1, 28.7, 29.4, 26.0, 31.8, and 55.8 ml/min/1.73 m2
      for the artificial neural network, Cockcroft and Gault, Jelliffe 1, Jelliffe 2,
      Mawer et al, and Hull et al methods, respectively. CONCLUSION: The accuracy of
      predicting Cl(cr) in subjects with HIV infection by the artificial neural network
      is superior to that of the five equations that are currently used in clinical
      settings.

PMID- 10391418
TI  - Efficacy and cost of ampicillin-sulbactam and ticarcillin-clavulanate in the
      treatment of hospitalized patients with bacterial infections.
AB  - STUDY OBJECTIVE: To evaluate the efficacy and cost of treatment with two beta
      lactam/beta-lactamase-inhibitor combinations. DESIGN: Retrospective, open-label
      multicenter study. SETTING: Fifty-four hospitals across the United States.
      PATIENTS: Eight hundred ninety patients with skin and soft tissue,
      intraabdominal, gynecologic, respiratory, urinary tract, or other infections that
      required parenteral antibiotic therapy. INTERVENTION: Patients were administered
      either ampicillin-sulbactam 1.5 or 3.0 g every 6 hours or ticarcillin-clavulanate
      3.1 g every 6 hours. MEASUREMENTS AND MAIN RESULTS: The agents did not differ
      significantly in efficacy for most infections; although, ampicillin-sulbactam was
      bacteriologically superior to ticarcillin-clavulanate in the treatment of
      intraabdominal infections (p=0.0011). Costs of ampicillin-sulbactam, particularly
      the 1.5-g dose, were lower than those of ticarcillin-clavulanate for skin and
      soft tissue (p<0.001), intraabdominal (p=0.005), and respiratory tract (p<0.001)
      infections. CONCLUSION: Ampicillin-sulbactam provides effective coverage for
      patients with the above infections and is as effective as the broader-spectrum
      agent.

PMID- 10391420
TI  - Interpreting meta-analyses of pharmacologic interventions: the pitfalls and how
      to identify them.
AB  - Meta-analyses are key components of evidence-based decision making. The numbers
      of meta-analyses published in different areas of health care increased
      dramatically during the past 10 years. Many of them covered different
      pharmacologic interventions, making them useful resources to clinical
      pharmacists. Although a well-conducted meta-analysis may be valuable, a poorly
      conducted one may have false conclusions and thus incorrectly alter a clinician's
      recommendations. Several key concepts must be considered when appraising meta
      analyses of pharmacologic interventions.

PMID- 10391421
TI  - Absence of effect of stimulants on the phamacokinetics of desipramine in
      children.
AB  - We conducted a retrospective chart review to examine the pharmacokinetic
      interaction between desipramine and the stimulants methylphenidate and dexedrine
      using routinely monitored desipramine serum concentrations in children receiving
      desipramine either alone or with a stimulant. Subjects were 142 children and
      adolescents (age 6-17 yrs; 113 taking desipramine, 29 taking desipramine
      stimulants) in whom 401 dose- and weight-normalized serum concentrations were
      evaluated (333 desipramine, 68 desipramine-stimulants). Desipramine
      pharmacokinetic parameters were similar for both groups, including mean weight
      corrected dose (3.66+/-1.36 mg/kg, desipramine; 3.66+/-1.09 mg/kg, desipramine
      stimulants; p=0.97), weight- and dose-normalized serum concentrations (47.26+/
      39.26 [microg/L]/[mg/kg], desipramine, 39.02+/-19.92 [microg/L]/[mg/kg],
      desipramine-stimulants; p=0.09), and clearance (0.690+/-0.913 [L/kg]/hr,
      desipramine; 0.613+/-0.514 [L/kg]/hr, desipramine-stimulants; p=0.499). When
      stratified by age, gender, and type of stimulant, no difference was detected
      (p>0.05) between groups. Our findings indicate the absence of a clinically
      significant interaction between desipramine and stimulants.

PMID- 10391422
TI  - A urine metabolic ratio of dextromethorphan and 3-methoxymorphinan as a probe for
      CYP3A activity and prediction of cyclosporine clearance in healthy volunteers.
AB  - Dextromethorphan (DM) is metabolized in the body to dextrophan (DT) and 3
      methoxymorphinan (3-MM) by cytochrome P450 (CYP) 2D6 and 3A4, respectively, and
      cyclosporine (CsA) is a known substrate of CYP3A4. We attempted to determine if
      the urine metabolic ratio of DM:3-MM at various time intervals during 24 hours is
      predictive of CsA clearance in 11 healthy volunteers. Each subject took DM 30 mg
      orally, and serial urine samples were collected at 0-4, 4, and 4-24, and 0-24
      hours. Subjects then were randomly assigned to receive either oral microemulsion
      CsA 5 mg/kg or intravenous CsA 1.5 mg/kg in a crossover fashion in a two-sequence
      pharmacokinetic study with a wash-out period of at least 7 days. A total of 17
      blood samples were collected from each subject in the CsA pharmacokinetic study
      over 24 hours. Urinary DM, DT, and 3-MM were quantified by high-performance
      liquid chromatography (HPLC) with a fluorescence detector, and blood CsA
      concentrations were analyzed by HPLC with ultraviolet detection. All subjects
      were extensive metabolizers of CYP2D6 as determined by metabolic ratios of DM:DT
      (mean+/-SD 0.0255+/-0.048). There was no correlation between CYP2D6 and CYP3A4
      (p=0.38). The metabolic ratios of DM:3-MM in any urine samples during the 24-hour
      collection period did not predict CsA pharmacokinetics, although the 0-24 hour
      sample had an unexpected positive correlation with CsA clearance (r2 = 0.38,
      p<0.0001). The correlation was similar for metabolic ratios of DM:3-MM with
      intravenous CsA clearance (r2 = 0.5, p<0.0001). Metabolic ratios of DM:3-MM based
      on 24-hour cumulative urine collection did not appear to have clinical utility in
      predicting CYP3A activity measured by CsA clearance.

PMID- 10391423
TI  - Monitoring unfractionated heparin therapy with antifactor Xa activity results in
      fewer monitoring tests and dosage changes than monitoring with the activated
      partial thromboplastin time.
AB  - STUDY OBJECTIVE: To determine how much more costly it is to monitor
      unfractionated heparin (UFH) therapy by antifactor Xa heparin activity (HA) than
      by activated partial thromboplastin time (aPTT). DESIGN: Prospective, randomized,
      unmasked, cohort, single-center study. SETTING: A 625-bed, adults-only, private
      teaching hospital. PATIENTS: Two hundred sixty-eight patients with a variety of
      indications for UFH therapy. INTERVENTIONS: Patients were treated with UFH based
      on ideal weight (75 U/kg bolus, 20 U/kg initial infusion) and monitored by either
      HA or aPTT, MEASUREMENTS AND MAIN RESULTS: After adjusting for gender, groups
      were equivalent in patient characteristics and UFH dosage. The HA group had fewer
      monitoring tests and dosage changes/24 hours than the aPTT group. These
      reductions neutralized much of the increased cost of the HA assay itself.
      CONCLUSION: Monitoring UFH therapy over 96 hours with an HA assay costs $4.37
      more than monitoring with aPTT. This modest increase may be acceptable given
      other advantages of the HA assay.

PMID- 10391424
TI  - Staffing and the cost of clinical and hospital pharmacy services in United States
      hospitals.
AB  - A survey was mailed to pharmacy directors at all United States acute care medical
      surgical hospitals that related to staffing and cost components of hospital
      pharmacies and clinical services. Cost information was evaluated as both
      unadjusted and adjusted for severity of illness using the Health Care Financing
      Administration's Medicare case mix index (CMI). Unadjusted drug costs/occupied
      bed/year were $13,350+/-6927, a 36% increase over 1992 and a 112% increase over
      1989, with statistically significant differences observed by geographic region,
      hospital size, hospital ownership, and drug delivery system. Annual median
      pharmacist salary costs/patient associated with centrally based clinical pharmacy
      services were drug use evaluation $111, in-service education $20, drug
      information $117, poison information $24, and clinical research $35. Annual
      median pharmacist salary costs/patient associated with patient-specific clinical
      services were drug therapy monitoring $5, pharmacokinetic consultation $8,
      patient counseling $6, medical rounds $4, admission drug histories $7, and drug
      therapy protocol management (prescribing) $9. Drug costs continue to increase at
      double-digit rates. Substantial differences exist among various regions of the
      country with salary and specific cost components. Registered nursing staffing is
      increasing at twice the rate of pharmacists staffing increases.

PMID- 10391425
TI  - The ketogenic diet. Central Nervous System Practice and Research Network of the
      American College of Clinical Pharmacy.

PMID- 10391426
TI  - Outpatient self-management of warfarin therapy: a pilot study.
AB  - Self-testing and adjusting of warfarin dosages by patients is an evolving
      strategy for management of oral anticoagulation. We performed this open,
      prospective, 3-month pilot study to assess the feasibility of conducting a large,
      randomized trial comparing self-managed with physician-managed anticoagulation.
      Ten competent patients with planned anticoagulation for at least 3 months were
      provided education on warfarin therapy and trained to use an individualized
      warfarin nomogram. International normalized ratios (INRs) were determined weekly
      for 12 weeks and reported with warfarin dosages to the investigator for the first
      8 weeks only. Eight patients elected to use a home monitor (ProTime) to measure
      INRs. Patients maintained 76.5% (range 50-91.7%) of INRs within the target range.
      In 119 dosage adjustment decisions, there were only 3 errors (2.5%). No bleeding
      or thrombotic complications occurred. To confirm concordance, initial and final
      INRs were measured concurrently by the ProTime monitor and laboratory. The mean
      absolute difference for 16 paired INR determinations was 0.33 (range 0.02-0.9).
      All patients expressed satisfaction and a desire to continue with self
      management. This pilot study provides support for conducting a prospective, large
      scale, randomized trial.

PMID- 10391427
TI  - Presynaptic kainate receptors in the monkey striatum.
AB  - Although kainate has long been known as a powerful axon-sparing neurotoxin, the
      localization and functions of kainate receptors in the CNS are largely unknown.
      In the present study we examined the distribution of kainate receptor subunits in
      the monkey striatum using kainate receptor subunits GluR6/7 and kainate receptor
      subunit KA2 subunit antibodies at the electron microscope level. We found that
      kainate receptor subunits GluR6/7 immunoreactivity is expressed not only in
      neuronal perikarya and dendritic processes, but also in a large population of
      terminals which form axospinous and axodendritic asymmetric synapses. The
      ultrastructural features of these terminals resembled those of glutamatergic
      corticostriatal boutons. In contrast, very few kainate receptor subunit KA2
      containing terminals were encountered. Although the functions of these
      presynaptic kainate receptors remain to be established, the present data suggest
      the possibility that they are located to modulate the release of glutamate from
      cortical afferents in the monkey striatum, and that an abnormal regulation of
      these presynaptic receptors might be involved in the death of striatal neurons in
      Huntington's disease. Accordingly, recent findings demonstrated that the variance
      in the age of onset of Huntington's disease could be attributed to the genotype
      variation of kainate receptor subunit GluR6 in humans.

PMID- 10391428
TI  - Circadian regulation of prion protein messenger RNA in the rat forebrain: a
      widespread and synchronous rhythm.
AB  - Although the expression of the normal prion protein in the host is critical to
      the development of transmissible spongiform encephalopathies, the physiological
      role of this protein and the processes regulating its expression remain obscure.
      We now report that the messenger RNA for the prion protein is regulated in the
      rat brain in a marked circadian manner not only in the suprachiasmatic nuclei,
      the principal site for the generation of mammalian circadian rhythms, but also in
      other forebrain regions. The data show a remarkable consistency in the
      concurrence of a single peak of prion protein messenger RNA at each of the sites
      early in the animal's phase of increased locomotor activity; behavioural arousal
      does not, however, appear to affect this expression. We believe this to be the
      first study demonstrating that the expression of prion protein messenger RNA can
      change over a relatively short period in vivo. The results are discussed with
      reference to the range of recently discovered "clock-related" transcripts which
      also have widespread tissue expression; these include the messenger RNAs for D
      box binding protein and thyroid embryonic factor, transcription factors which
      bind to the prion protein promoter.

PMID- 10391429
TI  - Psychophysiological stress induces heat shock cognate protein 70 messenger RNA in
      the hippocampus of rats.
AB  - Psychophysiological stress has been shown to increase 70,000 mol. wt heat shock
      protein messenger RNAs with northern blotting in rats. However, its localization
      is unknown. With in situ hybridization, we tested our hypothesis that restraint
      water-immersion stress may induce heat shock cognate protein 70 messenger RNA
      expression simultaneously with some morphological changes selectively in the
      hippocampus of rats. Stress for 6 h significantly increased heat shock cognate
      protein 70 messenger RNAs in the hippocampus, with maximal intensity in the CA3
      subfield of the Ammon's horn and to a lesser extent in CA2. Stress for 12 h
      significantly increased heat shock cognate protein 70 messenger RNAs in the whole
      hemisphere including the cerebral cortex, the thalamus, the hypothalamus, and the
      hippocampus with the highest density in CA3. Heat shock cognate protein 70
      messenger RNA in rats with stress for 6 h followed by recovery for 6 h
      significantly increased at CA3 and CA2 compared with the controls or rats
      stressed for 6 h without recovery. No overt histological changes were detected in
      neuronal or glial cells in the slides of hematoxylin-eosin or Cresyl Violet
      staining. These results show that psychophysiological stress induces heat shock
      cognate protein 70 messenger RNA in the most stress-vulnerable brain structure,
      hippocampal CA3, probably for cytoprotection.

PMID- 10391430
TI  - In vivo induction of striatal long-term potentiation by low-frequency stimulation
      of the cerebral cortex.
AB  - Both long-term depression and long-term potentiation have been described at
      corticostriatal synapses. These long-lasting changes in synaptic strength were
      classically induced by high-frequency (100 Hz) electrical stimulations of
      cortical afferents. The purpose of the present study was to test the ability of
      corticostriatal connections to express use-dependent modifications after cortical
      stimulation applied at the frequency of synchronization of corticostriatal inputs
      observed in our in vivo preparation, i.e. the barbiturate-anesthetized rat. For
      this study we used an identified monosynaptic corticostriatal pathway, between
      the orofacial motor cortex and its target region in the striatum. Intracellular
      recording of striatal output neurons showed spontaneous large-amplitude
      oscillation-like depolarizations exhibiting a strong periodicity with a narrow
      frequency band at 5 Hz. Using the focal electroencephalogram of the cortical
      region projecting to the recorded cells, we found that membrane potential
      oscillations in striatal neurons were in phase with episodes of spontaneous
      cortical spindle waves. To determine directly the pattern of activity of
      corticostriatal neurons, we performed intracellular recordings of
      electrophysiologically identified corticostriatal neurons simultaneously with the
      corresponding surface electroencephalogram. We found that corticostriatal cells
      (n = 7) exhibited periods of spontaneous 5-Hz discharges in phase with the
      cortical spindle waves. Therefore, we have tested the effect of repetitive
      cortical stimulations at this low frequency (5 Hz, 500-1000 pulses) on the
      corticostriatal synaptic efficacy. In 62% of cases (eight of 13 neurons tested),
      this conditioning was able to produce long-term potentiation in the
      corticostriatal synaptic efficacy. The mean increase of excitatory postsynaptic
      potential amplitude ranged from 13.3% to 172% (mean = 67.3%, n = 8). These
      results provide additional support for physiological long-term potentiation at
      corticostriatal connections. Furthermore, this study demonstrates that
      corticostriatal long-term potentiation can be induced by synchronization at low
      frequency of cortical afferents. Our data support the concept that the striatal
      output neuron may operate as a coincidence detector of converging cortical
      information.

PMID- 10391431
TI  - Temporal modulation of GABA(A) receptor subunit gene expression in developing
      monkey cerebral cortex.
AB  - In situ hybridization histochemistry was used to examine the expression of 10
      GABA(A) receptor messenger RNAs corresponding to the alpha1-alpha5, beta1-beta3,
      gamma1 and gamma2 subunits in primary somatosensory and visual areas of macaque
      monkey cerebral cortex from embryonic day (E) 125 to postnatal day (P) 125.
      Results were compared with expression patterns in adults. In the sensorimotor
      cortex at E125, overall levels of all subunit transcripts were low. At E137,
      there was a major lamina-specific increase in all subunit messenger RNAs except
      gamma1. For alpha1, alpha2, alpha4, beta2, beta3 and gamma2 subunit transcripts,
      this increase was highest in areas 3a and 3b, particularly in layers III/IV and
      VI. Postnatally, there were significant decreases in all transcripts. Alpha1,
      alpha5, beta2 and gamma2 subunit transcripts, while still at significantly lower
      levels than at E137, remained expressed at levels higher than other transcripts.
      Unlike in rodents, there was no obvious "switch" in the major subunits expressed
      in fetal and adult cortex, alpha1, alpha5, beta2 and gamma2 remaining highest
      throughout. In area 17, the most prominently expressed subunits at earliest ages
      were alpha2, alpha5, beta1, beta2, beta3 and gamma2, especially in layers II/III
      and VI. At E150, expression for alpha2, alpha3, beta1 and beta3 subunit
      transcripts in these layers decreased, but levels for alpha1, alpha4, alpha5,
      beta2, gamma1 and gamma2 transcripts increased, particularly within layer IV. The
      increase at E150 was particularly marked for alpha5 transcripts, which were
      expressed at levels more than four times those of other transcripts. Alpha1,
      beta2 and gamma2 remain highest into aduthood. Fetal area 17 displayed lamina
      specific patterns of expression not found in adult animals. In particular, alpha3
      messenger RNAs were present in layer IVA and gamma1 transcripts were present in
      layer IVC at E150, despite a lack of expression in these layers in the adult.
      These data demonstrate increased expression of GABA(A) receptors during the
      period of establishment of thalamocortical and intracortical connections, and a
      temporal regulation that may be associated with the period of developmental
      plasticity.

PMID- 10391432
TI  - Synaptic and plasticity-associated proteins in anterior frontal cortex in severe
      mental illness.
AB  - Abnormalities of proteins involved in neurotransmission and neural plasticity at
      synapses are reported in schizophrenia, and may be markers of dysregulated neural
      connectivity in this illness. Studies of brain development and neural
      regeneration indicate a dynamic interplay between neural and oligodendroglial
      mechanisms in regulating synaptic plasticity and axonal sprouting. In the present
      study, markers of synapses (synaptophysin), plasticity (growth-associated protein
      43) and oligodendrocytes (myelin basic protein) were investigated in anterior
      frontal cortex homogenates from individuals with schizophrenia and depression.
      Synaptophysin immunoreactivity was reduced in schizophrenics who died of natural
      causes relative to controls. Myelin basic protein immunoreactivity was decreased
      in both schizophrenics and depressed individuals who died by suicide. Overall, no
      changes were observed in growth-associated protein-43 immunoreactivity. However,
      a slight increase in immunoreactivity in depressed suicides relative to control
      was observed. These findings support the hypothesis that synaptic abnormalities
      are a substrate for disordered connectivity in severe mental illness, and suggest
      that synaptic-oligodendroglial interactions may contribute to the mechanism of
      dysregulation in certain cases.

PMID- 10391434
TI  - The delayed effects of phencyclidine enhance amphetamine-induced behavior and
      striatal C-Fos expression in the rat.
AB  - The ability for the delayed effects of phencyclidine to model schizophrenia-like
      symptomatology was investigated by assessing the effects of phencyclidine
      pretreatment on amphetamine-induced behavior. Corresponding changes in striatal,
      nucleus accumbens and anterior cingulate cortex c-Fos induction were also
      assessed in order to test the hypothesis that alterations in the neurochemistry
      of these regions accompany phencyclidine-induced changes in amphetamine-induced
      behaviors. Rats were treated with 15.0 mg/kg phencyclidine or vehicle 24 h prior
      to behavioral testing following vehicle, 0.5, 2.5 or 5.0 mg/kg amphetamine.
      Phencyclidine pretreatment significantly increased amphetamine-induced locomotion
      and rearing in response to 0.5 mg/kg amphetamine. Likewise, phencyclidine
      pretreatment produced an increase in the number of striatal cells expressing c
      Fos following treatment with 0.5 mg/kg amphetamine. Phencyclidine pretreatment
      did not alter c-Fos induction in the nucleus accumbens, but did decrease the
      basal number of c-Fos-containing cells in the anterior cingulate cortex. While
      stereotypy rating revealed that phencyclidine pretreatment enhanced the
      behavioral response to 5.0 mg/kg amphetamine over time, no other alterations in
      behavior or c-Fos expression in response to the higher doses of amphetamine were
      induced by phencyclidine pretreatment. These data demonstrate that the delayed
      effects of a single dose of phencyclidine alter anterior cingulate cortex
      neurochemistry, and enhance the behavioral and striatal c-Fos response to a low
      dose of amphetamine. These findings suggest that the delayed effects of a single
      dose of phencyclidine may produce a reasonable animal model for schizophrenia.

PMID- 10391433
TI  - Brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5
      differentially regulate the phenotype and prevent degenerative changes in
      striatal projection neurons after excitotoxicity in vivo.
AB  - To determine whether growth factors of the neurotrophin family are able to
      regulate the phenotype of striatal projection neurons, cell lines overexpressing
      brain-derived neurotrophic factor, neurotrophin-3 or neurotrophin-4/5 were
      intrastriatally grafted. Striatal projection neurons were examined for the
      regulation of their soma areas and for the expression of glutamate decarboxylase
      67, preprotachykinin A, preproenkephalin and prodynorphin messenger RNAs by in
      situ hybridization. Brain-derived neurotrophic factor, neurotrophin-3 and
      neurotrophin-4/5 differentially regulated the soma area of projection neurons at
      different distances from the graft, but did not modify their messenger RNA
      levels. Neurotrophin-3 induced an increase in the soma area of preproenkephalin-
      and preprotachykinin A-positive neurons, brain-derived neurotrophic factor
      increased the soma area of only preprotachykinin A-positive neurons, while
      neurotrophin-4/5 did not produce any effect. Because atrophy and neuronal loss
      are hallmarks of Huntington's disease, we next examined whether neurotrophins
      prevent degenerative changes in a quinolinate model of Huntington's disease.
      Seven days after intrastriatal quinolinate injection, we observed a halo of cell
      loss around the injection sites, reduced soma area of glutamate decarboxylase 67
      , preproenkephalin- and preprotachykinin A-positive neurons bordering the lesion,
      and a decrease in the messenger RNA levels of glutamate decarboxylase 67 and
      these neuropeptides. Grafting of cell lines expressing brain-derived neurotrophic
      factor, neurotrophin-3 or neurotrophin-4/5 reduced the size of the lesion for
      preproenkephalin-, preprotachykinin- and glutamate decarboxylase 67-, but not for
      prodynorphin-positive neurons. Moreover, the three neurotrophins prevented the
      atrophy of all projection neurons, and the lesion-induced decrease in
      preproenkephalin and preprotachykinin A messenger RNA levels. We conclude that
      neurotrophins differentially regulate the phenotype of striatal projection
      neurons and prevent degenerative changes. The higher efficiency of neurotrophin-3
      suggests a potential therapeutic application of this molecule in neurological
      disorders affecting striatal projection neurons, such as Huntington's disease.

PMID- 10391435
TI  - Dexamethasone selectively suppresses microglial trophic responses to hippocampal
      deafferentation.
AB  - Hippocampal deafferentation increases the expression of insulin-like growth
      factor-1 by microglia, and of ciliary neurotrophic factor and basic fibroblast
      growth factor by astroglia in fields and periods of reactive axonal growth.
      Glucocorticoids attenuate lesion-induced hippocampal sprouting, possibly by
      reducing trophic signals that stimulate growth. With an interest in this
      hypothesis, the present studies evaluated the influence of systemic treatment
      with the synthetic glucocorticoid dexamethasone on entorhinal lesion-induced
      increases in neurotrophic factor expression in young adult rat hippocampus. Daily
      dexamethasone injections almost completely blocked increases in insulin-like
      growth factor-1 messenger RNA content, but did not perturb increases in ciliary
      neurotrophic factor or basic fibroblast growth factor messenger RNA content, in
      the deafferented dentate gyrus molecular layer. To determine if the suppression
      of insulin-like growth factor-1 expression was secondary to a general inhibition
      of microglial responses, and to identify the time period of glucocorticoid
      sensitivity, additional rats were prepared to evaluate the effects of semi
      chronic (i.e. daily) and single dexamethasone injections on microglial
      proliferation, ED-1 immunoreactivity (a marker of microglial reactivity) and
      insulin-like growth factor-1 messenger RNA expression. Semi-chronic dexamethasone
      treatment attenuated all three measures of deafferentation-induced microglial
      reactivity. However, a single dexamethasone injection given two (but not one or
      three) days postlesion inhibited deafferentation-induced increases in insulin
      like growth factor-1 messenger RNA content, without having significant effects on
      other measures. These results demonstrate that dexamethasone treatment
      preferentially suppresses microglial, as opposed to astroglial, trophic responses
      to deafferentation, and suggest that glucocorticoids attenuate reactive axonal
      sprouting by inhibiting the microglial production of insulin-like growth factor
      1.

PMID- 10391436
TI  - Effects of transient cerebral ischemia on glial fibrillary acidic protein
      phosphorylation and immunocontent in rat hippocampus.
AB  - Transient global cerebral ischemia induced in rats by four-vessel occlusion for
      20 min produced an increase in the immunocontent of glial fibrillary acidic
      protein and a protein phosphorylation response that was different in the CA1 and
      dentate gyrus areas of the hippocampus. We studied different times of reperfusion
      (one, four, seven, 14 and 30 days) and observed that the immunocontent and in
      vitro rate of phosphorylation of glial fibrillary acidic protein in the CA1
      region was significantly increased at all intervals after the ischemic insult,
      indicating that the astrocytic response was maintained for at least 30 days.
      After reperfusion for 14 days a significant increase in the ratio "in vitro
      phosphorylation rate/immunocontent" in the CA1 region was observed when compared
      to control values, to other intervals and to the dentate gyrus, suggesting a
      hyperphosphorylation of this intermediate filament protein at this interval. In
      the dentate gyrus, an area less vulnerable to the insult, labelling and
      immunocontent of glial fibrillary acidic protein were equally increased from four
      days of reperfusion and the increase remained significant until 30 days,
      confirming that neuronal death is not the only determining factor for gliosis to
      occur. In control sham-operated animals, neither the CA1 region nor the dentate
      gyrus showed significant increases in labelling or immunocontent. Changes in the
      phosphorylation of glial fibrillary acidic protein may be essential for the
      plastic response of astrocytes to neuronal damage, as neurons and astrocytes can
      act as functional units involved in homeostasis, plasticity and
      neurotransmission.

PMID- 10391437
TI  - Spatial learning deficits in rats after injection of vincristine into the dorsal
      hippocampus.
AB  - In the present study, performance in the Morris water escape task after bilateral
      lesioning of the dorsal hippocampus induced by the microtubule poison vincristine
      is discussed as a cognitive deficit model in rats. As we are especially
      interested in spontaneous or pharmacologically induced recovery processes after
      experimentally induced cognitive dysfunctions, the model should fulfil a number
      of criteria. Firstly, a clear dose-effect relationship between the dose of
      vincristine and the amount of spatial learning impairments should be present.
      Secondly, lesions must remain within the target area. Thirdly, there should be an
      observable behavioural recovery or compensation of the induced deficit. Two
      experiments evaluated the influence of the application volume (experiment 1) and
      the concentration of vincristine (experiment 2) on lesion location and size, and
      on spatial learning. The results of both experiments demonstrated that the effect
      of vincristine on the performance in the Morris water escape task seems to be
      characterized by an "all-or-none" relationship. Concentrations above a
      "threshold" value induced severe damage in the hippocampus and adjacent brain
      structures, whereas concentrations below the "threshold" value had marginal or no
      effects. The non-selective and highly toxic properties of vincristine make this
      neurotoxin an unsuitable tool for the establishment of a learning and memory
      deficit model.

PMID- 10391438
TI  - Electroshock seizures protect against apoptotic hippocampal cell death induced by
      adrenalectomy.
AB  - Seizures evoked by electroshock induce rapid changes in the expression of several
      genes in the adult brain, including those encoding for neurotrophic factors. Some
      of the neurotrophic factors induced by brief seizures such as basic fibroblast
      growth factor and nerve growth factor have been shown to have neuroprotective
      action. We reasoned therefore that these seizures may protect against neural
      injury. To test this hypothesis, we examined the effect of electroshock-induced
      seizures on the vulnerability to cell death in the hippocampus. Cell death was
      induced by adrenalectomy, which results in a highly selective apoptotic neuronal
      death in the dentate granule cell layer of the hippocampus. Daily electroshock
      seizures were administered for seven days to sham-operated and adrenalectomized
      rats. Neuronal degeneration was evaluated by the highly sensitive and reliable
      cupric-silver impregnation method. Animals experiencing electroshock seizures
      were completely protected against adrenalectomy-induced cell death, whereas
      adrenalectomized animals not exposed to electroshock seizures exhibited
      substantial neuronal cell degeneration in the dentate granule cell layer. Daily
      restraint stress did not prevent the adrenalectomy-induced neuronal death,
      indicating that the neuroprotective effect of the seizure treatment is not
      accounted for by stress. We conclude that brief controlled seizure-evoked neural
      activation may allow the sparing of otherwise vulnerable neuronal populations in
      the injured adult brain. This prompts a need to explore the possibility that
      controlled administration of electroshock seizures may have therapeutic potential
      in treating neurodegenerative disorders.

PMID- 10391439
TI  - Enhancement of glutamate release uncovers spillover-mediated transmission by N
      methyl-D-aspartate receptors in the rat hippocampus.
AB  - Properties of excitatory postsynaptic currents during increased glutamate release
      were investigated by means of a whole-cell voltage-clamp in CA1 pyramidal neurons
      of rat hippocampal slices. Enhancement of transmitter release by 50 microM 4
      aminopyridine or by elevated extracellular Ca2+ (up to 5 mM) resulted in a
      substantial increase in the peak excitatory postsynaptic current amplitude and in
      the significant stimulus-dependent prolongation of the excitatory postsynaptic
      current decay. The stronger the stimulus, the slower the excitatory postsynaptic
      current decay became. The pharmacologically isolated N-methyl-D-aspartate, but
      not alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid component of the
      excitatory postsynaptic current exhibited this phenomenon. The possible
      connection of such behaviour of the N-methyl-D-aspartate component to the loss of
      voltage control was tested in the following way: the peak of the N-methyl-D
      aspartate component was enhanced under 50 microM 4-aminopyridine and then
      returned back to the control level by a low dose of D-2-amino-5
      phosphonopentanoic acid. However, the decay of the decreased N-methyl-D-aspartate
      component remained slow suggesting another origin of the stimulus-dependent
      kinetics. Dihydrokainate, a non-competitive inhibitor of glutamate uptake, did
      not influence the kinetics of the N-methyl-D-aspartate component in control but
      induced its dramatic stimulus-dependent prolongation when applied on the
      background of a low dose of 4-aminopyridine (10 microM) which did not affect the
      decay by itself. We propose that the delayed stimulus-dependent kinetics of the N
      methyl-D-aspartate component is due to the saturation of uptake mechanisms and
      subsequent activation of extrasynaptic N-methyl-D-aspartate receptors. Our
      present observations therefore support the hypothesis that N-methyl-D-aspartate
      receptors may play a role in the cross-talk between synapses by means of the
      transmitter spillover.

PMID- 10391440
TI  - Differential increase in Fos immunoreactivity in hypothalamic and septal nuclei
      by arginine8-vasopressin and desglycinamide9-arginine8-vasopressin.
AB  - Subcutaneous or intracerebroventricular injection of either arginine8-vasopressin
      or desglycinamide9-arginine8-vasopressin has been shown to facilitate memory,
      reduce or reverse the effects of amnesic drugs, and maintain tolerance to some
      effects of ethanol. These actions of vasopressin (and, by inference, of
      desglycinamide9-arginine8-vasopressin) are mediated by vasopressin V1 receptors
      in brain, via a c-fos-dependent mechanism, but the receptors at which the
      desglycinamide analog acts have not been identified. The precise central sites
      are also not known, but evidence of several types suggested the anterior
      hypothalamus and septum as probable loci of vasopressin action. In the present
      work, this question was studied by immunocytochemistry, using antibodies against
      Fos and Fos-like proteins. The numbers of Fos-immunoreactive nuclei were counted
      in several related brain regions and structures, after administration of
      arginine8-vasopressin, des-Gly9-[Arg8]-vasopressin or saline. A subcutaneous
      injection of vasopressin, but not of saline, enhanced Fos expression in the
      paraventricular, supraoptic and suprachiasmatic nuclei of the hypothalamus, but
      the desglycinamide analog stimulated Fos expression only in the suprachiasmatic
      nucleus. Vasopressin injection significantly increased the number of Fos
      immunoreactive cells in the intermediate lateral septum, medial septum, and
      dorsal and ventral divisions of the lateral septum. In contrast, the
      desglycinamide analog increased the numbers of Fos-immunoreactive cells in the
      dorsal and intermediate portions of the lateral septum, but caused no change in
      the medial septum, and a decrease in the ventral portion of the lateral septum.
      Increased Fos expression was also found in the subfornical organ after
      subcutaneous injection of either vasopressin or the desglycinamide analog. Double
      labeling with antibodies against Fos protein and against vasopressin revealed
      that most of the vasopressin-induced Fos-immunoreactive cells in the supraoptic,
      paraventricular and suprachiasmatic hypothalamic nuclei are also vasopressin
      immunoreactive, i.e. they are vasopressin-producing neurons. These findings
      suggest that a circuit involving V1 receptors in the subfornical organ,
      connecting fibres to the suprachiasmatic nucleus, and vasopressinergic
      projections from the suprachiasmatic nucleus to the lateral septum, may play a
      central role in mediating the actions of both vasopressin and its desglycinamide
      analog in the maintenance of ethanol tolerance.

PMID- 10391441
TI  - Corticotropic-releasing hormone and serotonin interact in the human brainstem:
      behavioral implications.
AB  - The objective of this human post mortem study was to determine whether neurons
      which synthesize corticotropic-releasing hormone and serotonin form circuits
      implicated in the pathophysiology of major depression and suicide. For the first
      time, a sensitive, dual immunocytochemical procedure was used to identify
      circuits formed by corticotropic-releasing hormone-synthesizing and serotonergic
      cell groups. Corticotropic-releasing hormone-immunoreactive varicose fibers and
      puncta with morphological characteristics of terminals were labeled in the
      midline raphe, periventricular gray and pontine parabrachial complex, on single
      labeled tissues processed immunocytochemically with a rabbit antibody to
      rat/human corticotropic-releasing hormone. Presumptive synaptic interactions with
      monoaminergic neurons were demonstrated with dual labeling techniques.
      Corticotropic-releasing hormone-immunoreactive terminals apposed neuronal somata
      and primary dendrites of serotonergic neurons in the pontine raphe. Serotonergic
      neurons were immunolabeled with a mouse antibody to phenylalanine hydroxylase, an
      enzyme with substantial sequence homology to tryptophan hydroxylase. Interactions
      in the lateral parabrachial nucleus were suggested by precise overlap of
      corticotropic-releasing hormone and serotonergic terminal fields. Corticotropic
      releasing hormone projections were confirmed to noradrenergic neurons containing
      neuromelanin in the locus ceruleus. Maps of corticotropic-releasing hormone fiber
      trajectories suggest that these pathways may derive from the forebrain and,
      locally, from the human homologue of Barrington's nucleus--a neurochemically
      specialized division of the laterodorsal tegmental complex. Chemosensory
      functions were predicted by novel evidence for corticotropic-releasing hormone-
      and monoaminergic neurovascular and subependymal fiber plexuses. In conclusion,
      corticotropic-releasing hormone may influence the activity of two major
      monoaminergic cell systems implicated in the stress-diathesis model of mental
      illness, through neural and humoral mechanisms.

PMID- 10391442
TI  - The effects of radiofrequency lesion or transection of the fimbria-fornix on
      latent inhibition in the rat.
AB  - Latent inhibition consists of a decrement in conditioning to a stimulus as a
      result of its prior non-reinforced pre-exposure. Based on evidence pointing to
      the involvement of the hippocampus and the nucleus accumbens in latent inhibition
      disruption, it has been proposed that latent inhibition depends on the integrity
      of the subicular input to the nucleus accumbens. Since fibers originating in the
      subiculum and destined for the nucleus accumbens run through the fimbria-fornix,
      we assessed the effects of radiofrequency lesion or transection of the fimbria
      fornix, on latent inhibition. The effectiveness of both lesions was demonstrated
      by the total disappearance of acetylcholinesterase staining in the hippocampus
      and of retrogradely labeled cells in the hippocampus/subiculum following the
      injection of the retrograde tracer biotin-dextran amine into the shell subregion
      of the nucleus accumbens. Likewise, in accord with previously documented
      behavioral effects of lesions to the hippocampus and related structures, both
      lesions increased spontaneous activity and disrupted performance in Morris water
      maze, and the radiofrequency lesion facilitated the acquisition of two-way active
      avoidance. In spite of the above, latent inhibition remained unaffected by both
      fimbria-fornix lesions, indicating that the critical projections subserving
      latent inhibition are not those traversing the fimbria-fornix from the
      hippocampus/subiculum to the nucleus accumbens. The implications of these results
      for the neural circuitry of latent inhibition and the latent inhibition model of
      schizophrenia are discussed.

PMID- 10391443
TI  - Role of Na+/H+ exchangers, excitatory amino acid receptors and voltage-operated
      Ca2+ channels in human immunodeficiency virus type 1 gp120-mediated increases in
      intracellular Ca2+ in human neurons and astrocytes.
AB  - Human immunodeficiency virus type 1 (HIV-1) dementia is the commonest form of
      dementia in North American people less than 60 years of age. HIV-1 envelope
      glycoprotein gp120 has been implicated in the neurotoxicity observed in, and the
      pathogenesis of, HIV-1 dementia. Recombinant gp120 (gp120) was pressure-applied
      on to cultured human fetal neurons and astrocytes and, by using single-cell
      calcium imaging, we determined the mechanisms responsible for gp120-induced
      increases in the levels of intracellular calcium ([Ca2+]i). Significant dose
      related increases in [Ca2+]i were observed in neurons and astrocytes. In neurons,
      5 pM gp120 increased [Ca2+]i by 290+/-13 nM and increases of 2210+/-211 nM were
      found at 209 nM, the highest concentration of gp120 tested. The apparent EC50
      value for gp120 of 223+/-40 pM in neurons was not significantly different from
      that in astrocytes. Immunoelution of gp120 with polyclonal anti-gp120 and Ca2+
      free conditions blocked increases in [Ca2+]i by gp120. Increases in [Ca2+]i were
      significantly (P < 0.005) attenuated by the Na+/H+ exchange blocker 5-(N-methyl-N
      isobutyl)-amiloride in neurons and astrocytes. The L-type calcium channel
      blockers nimodipine, diltiazem and CdCl2 + NiCl2 significantly (P < 0.005)
      reduced increases in [Ca2+]i in neurons, but not astrocytes. Increases in [Ca2+]i
      by gp120 were not significantly affected by blockers of N-, P- and Q-type calcium
      channels. The N-methyl-D-aspartate receptor antagonists (+/-)-2-amino-5
      phosphonopentanoic acid (AP5), memantine and dizocilpine significantly (P < 0.01)
      lowered gp120-induced increases in [Ca2+]i in neurons. AP5 and memantine, but not
      dizocilpine, significantly (P < 0.01) reduced increases in [Ca2+]i by gp120 in
      astrocytes. Gp120 appears to activate astrocyte Na+/H+ exchangers to release
      glutamate and potassium and, subsequent to this, increases in [Ca2+]i in neurons
      and astrocytes result from activation of excitatory amino acid receptors on
      astrocytes and neurons, and voltage-operated calcium channels on neurons. Drugs
      that block gp120-induced changes in [Ca2+]i in neurons and astrocytes may help in
      the treatment of HIV-1 dementia.

PMID- 10391444
TI  - Overexpression of human copper/zinc superoxide dismutase in transgenic mice
      attenuates oxidative stress caused by methylenedioxymethamphetamine (Ecstasy).
AB  - Administration of 3,4-methylenedioxymethamphetamine (4 x 20 mg/kg) to non
      transgenic CD-1 mice caused marked depletion in dopamine, 3,4
      dihydroxyphenylacetic acid and 5-hydroxytryptamine in the caudate-putamen. There
      were no significant changes in serotonergic markers in the hippocampus and
      frontal cortex. Homozygous and heterozygous copper/zinc superoxide dismutase
      transgenic mice show partial protection against the toxic effects of 3,4
      methylenedioxymethamphetamine on striatal dopaminergic markers. In addition, 3,4
      methylenedioxymethamphetamine injections caused marked decreases in copper/zinc
      superoxide dismutase activity in the frontal cortex, caudate-putamen and
      hippocampus of wild-type mice. Moreover, there were concomitant 3,4
      methylenedioxymethamphetamine-induced decreases in catalase activity in the
      caudate-putamen and hippocampus, decreases in glutathione peroxidase activity in
      the frontal cortex as well as increases in lipid peroxidation in the frontal
      cortex, caudate-putamen, and hippocampus of wild-type mice. In contrast,
      administration of 3,4-methylenedioxymethamphetamine to homozygous superoxide
      dismutase transgenic mice caused no significant changes in antioxidant enzyme
      activities nor in lipid peroxidation. These results provide further
      substantiation of a role for oxygen-based radicals in 3,4
      methylenedioxymethamphetamine-induced neurotoxicity. The present data also
      suggest that free radicals generated during 3,4-methylenedioxymethamphetamine
      administration may perturb antioxidant enzymes. Consequently, there might be
      further overproduction of free radicals with associated peroxidative damage to
      cell membranes and associated terminal degeneration.

PMID- 10391445
TI  - Locus coeruleus neurons: cessation of activity during cataplexy.
AB  - Cataplexy, a symptom of narcolepsy, is a loss of muscle tone usually triggered by
      sudden, emotionally significant stimuli. We now report that locus coeruleus
      neurons cease discharge throughout cataplexy periods in canine narcoleptics.
      Locus coeruleus discharge rates during cataplexy were as low as or lower than
      those seen during rapid-eye-movement sleep. Prazosin, an alpha1 antagonist, and
      physostigmine, a cholinesterase inhibitor, both of which precipitate cataplexy,
      decreased locus coeruleus discharge rate. Our results are consistent with the
      hypothesis that locus coeruleus activity contributes to the maintenance of muscle
      tone in waking, and that reduction in locus coeruleus discharge plays a role in
      the loss of muscle tone in cataplexy and rapid-eye-movement sleep. Our results
      also show that the complete cessation of locus coeruleus activity is not
      sufficient to trigger rapid-eye-movement sleep in narcoleptics.

PMID- 10391446
TI  - Regulation of ciliary neurotrophic factor receptor alpha in sciatic motor neurons
      following axotomy.
AB  - Spinal motor neurons are one of the few classes of neurons capable of
      regenerating axons following axotomy. Injury-induced expression of neurotrophic
      factors and corresponding receptors may play an important role in this rare
      ability. A wide variety of indirect data suggests that ciliary neurotrophic
      factor receptor alpha may critically contribute to the regeneration of injured
      spinal motor neurons. We used immunohistochemistry, in situ hybridization and
      retrograde tracing techniques to study the regulation of ciliary neurotrophic
      factor receptor alpha in axotomized sciatic motor neurons. Ciliary neurotrophic
      factor receptor alpha immunoreactivity, detected with two independent antisera,
      is increased in a subpopulation of caudal sciatic motor neuron soma one, two and
      six weeks after sciatic nerve transection and reattachment, while no changes are
      detected at one day and 15 weeks post-lesion. Ciliary neurotrophic factor
      receptor alpha messenger RNA levels are augmented in the same classes of neurons
      following an identical lesion, suggesting that increased synthesis contributes,
      at least in part, to the additional ciliary neurotrophic factor receptor alpha
      protein. Separating the proximal and distal nerve stumps with a plastic barrier
      does not noticeably affect the injury-induced change in ciliary neurotrophic
      factor receptor alpha regulation, thereby indicating that this injury response is
      not dependent on signals distal to the lesion traveling retrogradely through the
      nerve or signals generated by axonal growth through the distal nerve. The
      prolonged increases in ciliary neurotrophic factor receptor alpha protein and
      messenger RNA found in regenerating sciatic motor neurons contrast with the
      responses of non-regenerating central neurons, which are reported to display, at
      most, a short-lived increase in ciliary neurotrophic factor receptor alpha
      messenger RNA expression following injury. The present data are the first to
      demonstrate, in vivo, neuronal regulation of ciliary neurotrophic factor receptor
      alpha protein in response to injury. Moreover, they suggest that the ability of a
      subpopulation of spinal motor neurons to regulate ciliary neurotrophic factor
      receptor alpha levels in response to injury may play a role in their survival and
      axonal regeneration. Consistent with such a role, we also find relatively high,
      and probably elevated, levels of ciliary neurotrophic factor receptor alpha
      immunoreactivity in regenerating axons.

PMID- 10391447
TI  - Voltage-gated proton currents in microglia of distinct morphology and functional
      state.
AB  - Whole-cell patch-clamp measurements were performed to investigate voltage-gated
      proton currents (I(PR)) in cultured murine microglia of distinct morphology and
      functional state. We studied I(PR) in ameboid microglia of untreated cultures, in
      ameboid microglia which had been activated by lipopolysaccharide, and in ramified
      microglia which had been exposed to astrocyte-conditioned medium. Proton currents
      of these three microglia populations did not differ regarding their activation
      threshold or the voltage dependence of steady-state activation. Moreover,
      pharmacological properties of I(PR) were similar: proton currents were sensitive
      to extracellularly applied Zn2+ or La3+, and could be abolished by each of those
      at a concentration of 100 microM. In the presence of extracellular Na+, I(PR) was
      decreased to a similar small extent due to activity of the Na+/H+ exchanger in
      all microglial populations. In contrast, proton currents of microglia differed
      between the three cell populations with respect to their current density and
      their time-course of activation: in comparison with untreated microglia, the
      current density of I(PR) was reduced by about 50% in microglia after their
      treatment with either lipopolysaccharide or astrocyte-conditioned medium.
      Moreover, I(PR) activated significantly more slowly in cells exposed to
      lipopolysaccharide or astrocyte-conditioned medium than in untreated cells. It
      can be concluded that the distinct H+ current characteristics of the three
      microglial populations do not correlate with the functional state of the cells.

PMID- 10391448
TI  - Peripheral inflammation increases the capsaicin sensitivity of dorsal root
      ganglion neurons in a nerve growth factor-dependent manner.
AB  - Inflammation results in a local increase in nerve growth factor production which
      potentially can modify the properties of nerve growth factor-responsive sensory
      neurons innervating the inflamed tissue. The sensitivity of primary sensory
      neurons to the neurotoxin capsaicin is regulated in vitro by nerve growth factor
      and we have now investigated the effect of complete Freund's adjuvant-induced
      inflammation on the capsaicin sensitivity of adult rat sensory neurons. Dorsal
      root ganglion neurons innervating inflamed tissue were identified in vivo by
      retrograde labelling with the dye Fast Blue. Neuronal capsaicin sensitivity was
      measured in vitro with a quantitative cobalt-uptake densitometric technique, and
      was shown to increase significantly five days after inflammation. This increase
      in sensitivity was dependent on nerve growth factor as it could be inhibited by
      systemic treatment with nerve growth factor neutralizing antibodies. The enhanced
      capsaicin sensitivity that results from Freund's adjuvant injection may
      contribute to inflammatory hyperalgesia.

PMID- 10391449
TI  - Immunohistochemical localization of a novel acidic calmodulin-binding protein,
      NAP-22, in the rat brain.
AB  - NAP-22 is a neuronal tissue-enriched acidic calmodulin-binding protein with a
      molecular mass of 22,000 and is recovered in the membrane fraction during
      biochemical fractionation. We observed the distribution pattern of this protein
      in the rat brain using an immunohistochemical method by light and electron
      microscopy. NAP-22 immunoreactivity was detected through the whole brain, and the
      most dense staining was observed in the forebrain including cerebral cortex,
      hippocampal formation, olfactory bulb, basal ganglia and thalamus.
      Immunoreactivity was distributed densely at the neuropil, whereas nerve cells and
      nerve fibres had little or no reaction. In the brain stem, immunonegative large
      nerve cell bodies were surrounded by immunopositive varicosities. In the
      cerebellar cortex, mossy fibre terminals and parallel fibres showed
      immunoreactivity, whereas Purkinje cells did not. Intracellular distribution was
      observed in the cerebral and cerebellar cortices. NAP-22 immunoreactivity was
      noted in the axon terminals, dendritic spines and thin nerve fibres. In these
      structures, reaction products were associated mainly with synaptic vesicles, pre-
      and postsynaptic membranes and microtubules. This study demonstrates that the
      immunoreactivity of NAP-22 is distributed widely in the brain, especially in the
      synapse, and suggests that this protein is involved in synaptic transmission both
      in the pre- and postsynaptic region.

PMID- 10391450
TI  - Burst firing in identified rat geniculate interneurons.
AB  - We used whole-cell patch recording to study 102 local interneurons in the rat
      dorsal lateral geniculate nucleus in vitro. Input impedance with this technique
      (607.0+/-222.4 MOhm) was far larger than that measured with sharp electrode
      techniques, suggesting that interneurons may be more electrotonically compact
      than previously believed. Consistent and robust burst firing was observed in all
      interneurons when a slight depolarizing boost was given from a potential at, or
      slightly hyperpolarized from, resting membrane potential. These bursts had some
      similarities to the low-threshold spike described previously in other thalamic
      neuron types. The bursting responses were blocked by Ni+, suggesting that the low
      threshold calcium current I(T), responsible for the low-threshold spike, was also
      involved in interneuron burst firing. Compared to the low-threshold spike of
      thalamocortical cells, however, the interneuron bursts were of relatively long
      duration and low intraburst frequency. The requirement for a depolarizing boost
      to elicit the burst is consistent with previous reports of a depolarizing shift
      of the I(T) activation curve of interneurons relative to thalamocortical cells, a
      finding we confirmed using voltage-clamp. Voltage-clamp study also revealed an
      additional long-lasting current that could be tentatively identified as the
      calcium activated non-selective cation current, I(CAN), based on reversal
      potential and on pharmacological characteristics. Computer simulation of the
      interneuron burst demonstrated that its particular morphology is likely due to
      the interaction of I(T) and I(CAN). In the slice, bursts could also be elicited
      by stimulation of the optic tract, suggesting that they may occur in response to
      natural stimulation. Synaptically triggered bursts were only partially blocked by
      Ni+, but could then be completely blocked by further addition of (+/-)-2-amino-5
      phosphonopentanoic acid. The existence of robust bursts in this cell type
      suggests an additional role for interneurons in sculpting sensory responses by
      feedforward inhibition of thalamocortical cells. The low-threshold spike is a
      mechanism whereby activity in a neuron is dependent on a prior lack of activity
      in that same neuron. Understanding of the low-threshold spike in the other major
      neuron types of the thalamus has brought many new insights into how thalamic
      oscillations might be involved in sleep and epilepsy. Our description of this
      phenomenon in the interneurons of the thalamus suggests that these network
      oscillations might be even more complicated than previously believed.

PMID- 10391451
TI  - Bcl-2, Bax and Bcl-x expression following kainic acid administration at
      convulsant doses in the rat.
AB  - Neuronal death was produced in the CA1 and CA3 areas of the hippocampus,
      amygdala, and piriform and entorhinal cortices after intraperitioneal
      administration of kainic acid at convulsant doses to adult rats. To assess the
      involvement of members of the Bcl-2 family in cell death or survival,
      immunohistochemistry, western and northern blotting to Bcl-2, Bcl-x and Bax, and
      in situ hybridization to Bax were examined at different time-points after kainic
      acid treatment. Members of the Bcl-2 family were expressed in the cytoplasm of
      pyramidal neurons in the hippocampus, and in a subset of neurons of the piriform
      and the entorhinal cortices, amygdala and neocortex in the normal adult brain.
      Dying neurons in the pyramidal cell layer of CA1 and CA3 areas, entorhinal and
      piriform cortices, and amygdala also expressed Bcl-2, Bax and Bcl-x following
      excitotoxicity, although many dying cells did not. In addition, a number of cells
      in the affected areas showed Bax immunoreactivity in their nuclei at 24-48 h
      following kainic acid administration, thus indicating Bax nuclear translocation
      in a subset of dying cells. Western blots disclosed no modifications in the
      intensity of the bands corresponding to Bcl-2, Bcl-x and Bax, between control and
      kainic acid-treated rats. No modifications in the intensity of the bcl-2
      messenger RNA band on northern blots was observed in kainic acid-treated rats.
      However, a progressive increase in the intensity of the bax messenger RNA band
      was found in kainic acid-treated rats at 6 h, 12 h and 24 h following kainic acid
      administration. Interestingly, a slight increase in Bax immunoreactivity was
      observed in the cytoplasm of neurons of the dentate gyrus at 24-48 h, a feature
      which matches the increase of bax messenger RNA in the same area, as shown by in
      situ hybridization at 12-24 h following kainic acid injection. The present
      results suggest that cell death or survival does not correlate with modifications
      of Bcl-2, Bax and Bcl-x protein, and messenger RNA expression, but rather that
      kainic acid excitotoxicity is associated with Bax translocation to the nucleus in
      a subset of dying cells.

PMID- 10391453
TI  - Endothelin converting enzyme-1-, endothelin-1-, and endothelin-3-like
      immunoreactivity in the rat brain.
AB  - Neurons likely to use endothelin as a neurotransmitter/neurohormone were mapped
      in the rat brain using polyclonal antibodies directed against endothelin
      converting enzyme-1, endothelin-1, and endothelin-3. Anti-endothelin-converting
      enzyme-1 antibodies produced the most robust staining, permitting the best
      visualization of the distribution and morphology of neurons. Labeled neurons were
      found in the dorsal thalamic nuclei and reticular thalamic nuclei, medial
      preoptic area, pontine nucleus, and locus coeruleus. Localization of endothelin
      converting enzyme-like immunoreactivity in the locus coeruleus and in the
      reticular nucleus of the thalamus suggests that endothelin is co-localized with
      norepinephrine and GABA, respectively. Additionally, endothelin-converting enzyme
      like immunoreactivity was found in the globus pallidus, septal nuclei, and in
      both the vertical and horizontal limbs of the nucleus of the diagonal band of
      Broca, and the ventrolateral area of the caudate-putamen. Strong endothelin
      converting enzyme-like immunoreactivity was found in a continuous band of
      pyramidal neurons throughout the neocortex primarily in layer V, extending into
      the cingulate gyrus and piriform cortex. Motor nuclei, including oculomotor,
      facial, and trigeminal nuclei, were also endothelin-converting enzyme
      immunoreactive. In the cerebellum, Purkinje cells were stained. Non-neuronal
      cells such as oligodendroglia, microglia, and astrocytes generally were not
      endothelin-converting enzyme-immunoreactive, although astrocytes were rarely
      stained. Endothelin-converting enzyme-, endothelin-1-, and endothelin-3-like
      immunoreactivities were generally found co-existing in given nuclei. The
      diversity of neurons immunostained for endothelin suggests multiple roles of
      endothelin in the CNS.

PMID- 10391452
TI  - Anticonvulsant actions of furosemide in vitro.
AB  - Anticonvulsant properties of furosemide have been suggested to reduce neuronal
      synchronization via its inhibitory effect on the Na+/K+/2Cl- co-transport system.
      We have studied effects of furosemide on spontaneous epileptiform activity and
      analysed effects of furosemide on amplitudes of stimulus-induced population
      spikes, on stimulus-induced K+ changes, on extracellular pH changes at rest and
      during stimulation, and on changes in the extracellular space-volume. We used
      three different in vitro models of epilepsy in the combined hippocampal
      entorhinal cortex slice preparation. Furosemide reversibly suppressed low Ca2+
      induced epileptiform activity in hippocampus proper and blocked or significantly
      reduced different types of epileptiform discharges in the low Mg2+ model and the
      4-aminopyridine model. Amplitudes of evoked field potentials underwent an initial
      slight increase followed by a significant reduction after prolonged treatment
      with furosemide. Stimulus-induced increases in extracellular potassium were also
      significantly reduced. Furosemide caused an alkaline shift at rest. Stimulus
      induced pH transients changed from a biphasic alkalotic-acidotic sequence to a
      monophasic alkalotic shift. Stimulation-induced shrinkage of extracellular space
      volume was reduced by furosemide, whereas no effect on baseline extracellular
      space-volume was seen. We conclude, that furosemide possesses strong
      anticonvulsive effects in various in vitro models of epilepsy. The anticonvulsive
      properties of furosemide cannot be explained by its effects on extracellular pH
      changes but appear in part to be mediated via a reduced excitability with
      consequent reduction of activity-induced potassium rises. Finally, partial
      inhibition of activity-induced extracellular space shrinkage may contribute to
      its anticonvulsant properties.

PMID- 10391454
TI  - Ultrastructural evidence that substance P neurons form synapses with
      noradrenergic neurons in the A7 catecholamine cell group that modulate
      nociception.
AB  - Potent antinociception can be produced by electrical stimulation of spinally
      projecting noradrenergic neurons in the A7 catecholamine cell group and this
      effect is blocked by intrathecal injection of alpha2-adrenoceptor antagonists.
      Microinjection of substance P near A7 neurons also produces antinociception that
      is blocked by intrathecal injection of alpha2-adrenoceptor antagonists. These
      observations suggest that substance P produces antinociception by activating
      noradrenergic A7 neurons. However, it is not known whether this effect of
      substance P is produced by a direct or an indirect action on A7 neurons. Although
      light microscopic studies have demonstrated the existence of both substance P
      containing axon terminals and neurokinin-1 receptors in the region of the A7 cell
      group, it is not known whether substance P terminals form synapses with
      noradrenergic A7 neurons. These experiments used double-labeling
      immunocytochemical methods and electron microscopic analysis to determine whether
      substance P-containing axons form synapses with noradrenergic neurons in the A7
      cell group. Pre-embedding immunocytochemistry, combined with light and electron
      microscopic analysis, was used to provide ultrastructural evidence for synaptic
      connections between substance P-immunoreactive terminals labeled with
      immunoperoxidase and tyrosine hydroxylase-immunoreactive A7 neurons labeled with
      silver-enhanced immunogold. Tyrosine hydroxylase labeling was found in perikarya
      and dendrites in the A7 region, and substance P labeling was found in axons and
      synaptic terminals. Substance P-labeled terminals formed asymmetric synapses with
      tyrosine hydroxylase-labeled dendrites, but only a few of these were present on
      tyrosine hydroxylase-labeled somata. Substance P-labeled terminals also formed
      asymmetric synapses with unlabeled dendrites, and many unlabeled terminals formed
      both symmetric and asymmetric synapses with tyrosine hydroxylase-labeled
      dendrites. These results demonstrate that substance P neurons form a significant
      number of synapses with the dendrites of noradrenergic A7 neurons and support the
      conclusion that microinjection of substance P in the A7 cell group produces
      antinociception by direct activation of spinally projecting noradrenergic
      neurons.

PMID- 10391455
TI  - Evidence for nitric oxide and nitric oxide synthase activity in proximal stumps
      of transected peripheral nerves.
AB  - Nitric oxide may be liberated as an inflammatory mediator within injured
      peripheral nerve trunks. We evaluated the proximal stumps of injured peripheral
      nerve stumps that later form neuromas or regenerative nerve sprouts, for evidence
      of local nitric oxide elaboration and activity. Proximal stumps were created in
      male Sprague-Dawley rats by sectioning of the sciatic nerve and resection of its
      distal portions and branches. There was striking physiological evidence of nitric
      oxide activity at the tips of 48-h and 14-day-old proximal nerve stumps. We
      detected local nitric oxide-mediated hyperemia of both extrinsic plexus and
      endoneurial microvessels that was reversible, in a dose-dependent stereospecific
      fashion, by the broad-spectrum nitric oxide synthase inhibitors, Nomega-nitro-L
      arginine-methyl ester or Nomega-nitro-L-arginine, but not by 7-nitroindazole, an
      inhibitor with relative selectivity for neuronal nitric oxide.
      Immunohistochemical studies provided evidence for the localization of nitric
      oxide generators at the same sites. In 48-h but not 14-day stumps increased
      expression of two isoforms of nitric oxide synthase was detected: endothelial
      nitric oxide and to a much lesser extent neuronal nitric oxide synthase. Both
      isoforms appeared in axonal endbulb-like profiles that co-localized with
      neurofilament immunostaining. Western immunoblots identified a band consistent
      with endothelial nitric oxide synthase expression. In 14-day stumps with early
      neuroma formation, but not 48-h stumps, there was staining for immunological
      nitric oxide synthase in some endoneurial and epineurial macrophages. Total
      nitric oxide synthase biochemical enzymatic activity, measured by labelled
      arginine to citrulline conversion, was increased in 14-day but not 48-h stumps.
      Injured peripheral nerves have evidence of early nitric oxide action, nitric
      oxide synthase expression and nitric oxide activity in proximal nerve stumps.
      Nitric oxide may have an important impact on the regenerative milieu.

PMID- 10391456
TI  - An enhanced expression of the immediate early gene, Egr-1, is associated with
      neuronal apoptosis in culture.
AB  - Cultured cerebellar granule cells grown in medium containing 10 mM K+ (K10)
      underwent apoptosis after four to five days in vitro, unless they were rescued by
      the addition of insulin-like growth factor-I. The few GABAergic neurons present
      in the cultures were more resistant to apoptotic degeneration, as indicated by
      double fluorescent staining with the chromatin dye Hoechst 33258 and with
      glutamate decarboxylase-67 antibodies. As compared with sister cultures grown in
      25 mM K+, K10 cultures showed an increased expression of the Egr-1 protein and a
      reduced expression of the Fos protein. The increase in Egr-1 was more substantial
      in granule cells than in GABAergic neurons, and was not observed in K10 cultures
      chronically exposed to insulin-like growth factor-I. To examine the temporal
      relationship between the increase in Egr-1 and the development of programmed cell
      death, we induced apoptosis in K25 cultures at six days in vitro by replacing
      their medium with serum-free K10 medium. A substantial, but transient, increase
      in Egr- expression was observed in granule cells 6 h after switching the medium,
      a time that preceded the appearance of the phenotypical markers of apoptotic
      death. An early reduction in the Fos protein was observed after switching the
      medium from K25 into serum-free K10, but also after switching the medium into
      serum-free K25, a condition which was not associated with the development of
      apoptosis nor with the increase in Egr-1. We suggest that a transient induction
      of Egr-1 contributes to the chain of events leading to the execution phase of
      neuronal apoptosis in culture.

PMID- 10391457
TI  - Involvement of axonal phospholipase A2 activity in the outgrowth of adult mouse
      sensory axons in vitro.
AB  - The effect on axonal outgrowth of inhibition of phospholipase A2 activity was
      studied in a recently developed in vitro model, where dorsal root ganglia with
      attached spinal roots and nerve stumps from young adult mice were cultured in an
      extracellular matrix material (Matrigel). The phospholipase A2 inhibitors 4
      bromophenacyl bromide and oleyloxyethyl phosphorylcholine dose-dependently
      reduced axonal outgrowth from the sciatic nerve stump. A similar inhibitory
      effect was seen when only the cut nerve end was exposed to the inhibitors in a
      compartmental culture system. The local effect of phospholipase A2 inhibition was
      further investigated on axons established in culture, using time-lapse recording.
      Exposure to phospholipase A2 inhibitors caused the retraction of filopodia
      extensions and a reduction in growth cone motility within a few minutes. After
      removal of inhibition, normal growth cone motility and axonal growth were
      regained. Nerve cell bodies and axons, in contrast to Schwann cells, showed
      immunoreactivity after staining with an antiserum against secretory phospholipase
      A2, and elevated levels of the enzyme could be detected after culture for 24 h.
      The immunoreactive protein was of approximately 170,000 molecular weight
      (phospholipase A2-170) as determined by sodium dodecyl sulphate-polyacrylamide
      gel electrophoresis and immunoblotting. The localization of phospholipase A2-170
      in axons growing into the Matrigel was also demonstrated by use of a whole-mount
      technique. The results of this study show the importance of continuous
      phospholipase A2 activity for growth cone motility and axonal outgrowth in the
      mammalian peripheral nerve, and suggest the involvement of an axonally localized
      enzyme.

PMID- 10391458
TI  - Activation of an anatomically distinct subpopulation of accessory olfactory bulb
      neurons by chemosensory stimulation.
AB  - Chemosensory cues known as pheromones play a key role in rodent reproductive
      physiology and social interactions. Pheromone molecules are detected by receptor
      cells located in the vomeronasal organ and conveyed exclusively to the accessory
      olfactory bulb, and then to limbic and hypothalamic sites for integration with
      other factors modulating reproductive physiology. We report here that
      chemosensory cues from the female mouse selectively activate a subpopulation of
      cells located in the anterior part of the accessory olfactory bulb of the male
      mouse. Exposure of male mice to female-soiled bedding resulted in a massive
      induction of c-fos expression, which was primarily confined to neurons located in
      the anterior part of the accessory olfactory bulb and was eliminated by removal
      of the vomeronasal organ. Exposure of the male to soiled bedding from a different
      stain of male mice also elevated c-fos expression, but immunoreactive cells were
      more evenly distributed along the anterior-posterior axis of the accessory
      olfactory bulb. No treatment effects were observed in the main olfactory bulb.
      Previous studies have indicated that vomeronasal receptor neurons are divided
      into two populations based on location within the organ, site of termination in
      the accessory olfactory bulb, second messenger content and putative pheromone
      receptor expression. The present study suggests that the two populations of
      vomeronasal receptor neurons detect different chemosensory stimuli. Since male
      mouse- and female mouse-specific urinary substances modulate different aspects of
      male mouse behavior, the present results suggest that anatomically segregated
      populations of vomeronasal organ receptor cells modulate distinct behavioral
      patterns.

PMID- 10391459
TI  - Episodic ataxia/myokymia mutations functionally expressed in the Shaker potassium
      channel.
AB  - Episodic ataxia type 1 is a rare, autosomal dominant neurological disorder caused
      by missense mutations of the Kv1.1 gene from the Shaker K+ channel subfamily. To
      study the functional effects of the disease-causing mutations in a robust K+
      channel background, we introduced seven different episodic ataxia type 1
      substitutions into the corresponding, conserved residues of the Shaker K+
      channel. K+ channel currents expressed in Xenopus oocytes were studied by
      electrophysiology. All episodic ataxia type 1 mutations produced functional K+
      channels. In a Shaker N-terminal deletion mutant with fast inactivation removed,
      current amplitudes were significantly reduced in channels harboring an episodic
      ataxia type 1 mutation. Six of the seven mutations also showed depolarizing
      shifts (+9 to +36 mV) in the conductance voltage dependence. One mutation (F307I)
      shifted the midpoint of the conductance-voltage relationship by 23 mV in the
      hyperpolarizing direction. Episodic ataxia type 1 mutations were also expressed
      in ShakerH4 with intact N-terminal inactivation. In this construct, current
      amplitudes for episodic ataxia type 1 mutants were not significantly different
      from wild-type channels. All mutations altered the voltage range of steady-state
      inactivation; most changes were coupled to the changes in activation gating. Some
      episodic ataxia type 1 mutants also caused significant changes in the kinetics of
      N-type (F307I, E395D) or C-type (F307I, E395D, V478A) inactivation. These results
      suggest that episodic ataxia type 1 mutations may change K+ channel function by
      two mechanisms: (i) reduced channel expression and (ii) altered channel gating.

PMID- 10391460
TI  - Cochlear and trigeminal systems contributing to the startle reflex in rats.
AB  - The startle reflex is evoked by strong acoustic or tactile stimuli, or by
      electrical stimulation of acoustic or tactile pathways. To dissociate the
      contributions of acoustic and tactile pathways, stimulating electrodes were
      placed in adjacent cochlear and trigeminal nuclei. The currents needed to evoke
      startle-like responses were an order of magnitude lower in ventral trigeminal
      sites (12-80 microA for a 0.1-ms pulse) than in cochlear nucleus sites (150-800
      microA). At low threshold sites in both areas, brief acoustic stimuli were
      followed 0-4 ms later by a single electrical pulse and the current required to
      evoke startle was measured at several interstimulus intervals. Summation between
      the acoustic and electrical stimuli for startle was strong in both cochlear and
      trigeminal sites. Collision effects were found in the anteroventral cochlear
      nucleus when the electrical stimulus followed the ipsilateral acoustic stimulus
      by 2.0 ms, suggesting that acoustic startle is mediated by axons in the
      anteroventral cochlear nucleus. Collision effects were found at 4.0 ms if the
      electrical stimulus was presented in the contralateral pontine reticular
      formation, suggesting that acoustic signals mediating startle mainly cross to the
      pontine reticular formation. Collision effects were not found in medial or
      posterior sites in the cochlear nucleus, or trigeminal sites, suggesting that the
      neurons that mediate startle in these sites do not mediate acoustic startle.
      Therefore, acoustic startle is mediated through high threshold cochlear nucleus
      sites, while low threshold sites are non-acoustic, probably as a result of
      trigeminal or vestibular stimulation.

PMID- 10391461
TI  - Ascending neural pathways in the isolated guinea-pig ileum: effect of muscarinic
      M1, M2 and M3 cholinergic antagonists.
AB  - The effect of muscarinic cholinoceptor antagonists was investigated on the
      ascending neural pathways activated by electrical stimulation in the guinea-pig
      ileum. For comparison, prejunctional and postjunctional effects of muscarinic
      cholinoceptor antagonists were also studied on circular smooth muscle. A two
      compartment (oral and anal compartments) bath was used to study the ascending
      neural pathways. These were activated by electrical field stimulation in the anal
      compartment and the resulting contraction of the intestinal circular muscle in
      the oral compartment was recorded isotonically. Pirenzepine (10-300 nM), a
      muscarinic M1 cholinoceptor antagonist, reduced the ascending neural contractions
      in a concentration-dependent fashion when applied either to the oral or anal
      compartments (11-52% and 13-55% inhibition, respectively, P < 0.05). Pirenzepine
      inhibited (31+/-7%, P < 0.05) the acetylcholine (100 nM)-induced contractions at
      a higher non-selective concentration (300 nM), while its effect on the
      electrically-induced contractions was biphasic (10 and 30nM: 8-15% increase,
      P<0.05; 100 and 300 nM: 16-28% inhibition, P<0.05). The muscarinic M2
      cholinoceptor antagonist methoctramine (3-100 nM) did not modify the contractions
      produced by 100 nM acetylcholine, electrically-induced contractions and the
      ascending neural contractions (when applied to either compartment).
      Parafluorohexahydrosiladifenidol (3-100 nM), a muscarinic M3 cholinoceptor
      antagonist, inhibited the contractions produced by 100 nM acetylcholine (19-81%
      and 15-69%), electrically-induced contractions (11-71% and 12-72%) and the
      ascending neural contractions (13-76% and 866%) when applied to the oral
      compartment, but it was without effect when applied to the anal compartment.
      These studies suggest that in the enteric ascending neural pathway, muscarinic M1
      receptors are involved in neuroneuronal transmission, muscle contraction is
      mediated by muscarinic M3 cholinergic receptors, whereas muscarinic M2 receptors
      do not seem to participate.

PMID- 10391462
TI  - Three-dimensional redox image of the normal gerbil brain.
AB  - Regional differences in the redox ratio were studied in the gerbil brain. Brains
      were frozen using an in situ funnel-freezing method, and sliced coronally for
      scanning of mitochondrial redox imaging. The relative local redox ratio of
      nicotinamide-adenosine dinucleotide to its reduced form was calculated from
      fluorescence signals of intrinsic fluorochromes, i.e. reduced nicotinamide
      adenosine dinucleotide and flavoproteins, using a high resolution fluorometer
      developed in our laboratory. Twelve consecutive coronal images were obtained from
      each of 10 gerbils. The mean value of the regional redox ratio in both the
      cerebral and cerebellar gray matter were found to be significantly lower than
      that in the cerebral and cerebellar white matter (P < 0.01, Mann-Whitney test).
      Local differences in the redox ratio were also found among subregions of gray
      matter. The redox ratio in the globus pallidus was significantly higher than
      values in other subregions of gray matter (P < 0.01, Mann-Whitney test) We
      postulate that a high concentration of the reduced form of pyridine nucleotide is
      maintained to provide redox energy for rapid turnover of ATP in the areas of high
      energy consumption.

PMID- 10391463
TI  - Increased numerical density of synapses in CA3 region of hippocampus and
      molecular layer of motor cortex after self-stimulation rewarding experience.
AB  - Self-stimulation has been considered as an intensely rewarding behavioural
      experience, being perhaps even more influential than feeding or sexual behaviour.
      Our earlier studies have demonstrated a self-stimulation rewarding experience
      induced increase in dendritic branching points, intersections and spine densities
      in CA3 hippocampal and layer V motor cortical pyramidal neurons. In the present
      study, we report self-stimulation-induced alterations in the numerical density of
      synapses in the hippocampus and motor cortex. A self-stimulation experience was
      provided 1 h daily for a period of 10 days through bipolar electrodes, implanted
      bilaterally in the lateral hypothalamus and substantia nigra-ventral tegmental
      area, stereotaxically. The results revealed a significant (P < 0.001) increase in
      the number of synapses in the CA3 region of hippocampus and the molecular layer
      of the motor cortex in self-stimulation-experienced rats. The increased synaptic
      number may be due to the activation of afferent pathways to the hippocampus and
      motor cortex following self-stimulation, which may lead to the induction of long
      term potentiation. Long-term potentiation is known to cause structural changes by
      strengthening the existing synapses or resulting in the formation of new
      synapses. These changes may be related to the improved cognitive functions
      observed in self-stimulation-experienced rats.

PMID- 10391464
TI  - Amblyopia decreases activation of the corticogeniculate pathway and visual
      thalamic reticularis in attentive rats: a 'focal attention' hypothesis.
AB  - In rats which were rendered monocular amblyopic by lid suturing one eye during a
      critical period, the intensity of neuronal activation in parts of the monocular
      segments of the striate cortex (layers 4 and 6) and lateral geniculate nucleus,
      and in the visual segment of the thalamic reticular nucleus, was determined after
      exploration of a novel-complex environment. Quantitative analysis of the number
      of Fos-labelled neurons per unit area showed that, in comparison to the
      structures contralateral to the normal eye, in the side contralateral to the
      deprived amblyopic eye there is a gradient of diminished activation. The
      strongest activation asymmetry was observed in the visual reticular segment,
      while in layers 6 and 4 of the visual cortex the activation asymmetry was less
      strong and weakest, respectively. In the lateral geniculate there was no Fos
      detectable activation asymmetry. Furthermore, there was a positive correlation
      between the time rats spent in exploration and the degree of activation asymmetry
      in the visual reticular segment. From these results it is concluded: (1)
      Activation of the visual segment of the thalamic reticular nucleus in the alert,
      attentive animal is predominantly under visual cortical control via the cortico
      reticulo-geniculate pathway originating in layer 6, because this layer showed
      activation asymmetry while the other visual input to reticularis, the geniculate,
      did not show this asymmetry. (2) Activation of the visual reticularis is a
      function of attention to the environment because its activation asymmetry was
      correlated to the amount of exploratory attentional behaviour. (3) Diminished
      activity in the cortico-reticulo-geniculate pathway originating in layer 6, and
      of visual reticularis, caused by visual deprivation during the critical period
      should be considered as additional etiological factors of the resulting
      amblyopia. The functional significance of these results is explained by a 'focal
      attention' hypothesis postulating that the observed activation of visual
      reticularis in exploring animals is necessarily a reflection of activation of the
      corticogeniculate pathway, because these axons innervate both the geniculate and
      the visual reticular segment. Mechanistically, a focus of animal's attention is
      transmitted in a top-down fashion from the extrastriate cortex, and from upper
      cortical layers, into striate cortex layer 6. In turn, activation of layer 6
      cells corresponding to attentional foci generates a core of excitation in the
      geniculate by the direct glutamatergic corticogeniculate axons, and a surround
      inhibition by the disynaptic cortico-reticulo-geniculate (ultimately GABAergic)
      pathway. In the temporal domain, in light of recent results, activation of
      thalamic reticular nucleus visual segment will contribute to the induction of
      gamma oscillations in geniculocortical pathways and in their cortical targets.
      All together, these interactions result in increased effectiveness of
      thalamocortical transmission of features from the focalized visual scene. The
      postulated attention-dependent spatiotemporal influences on thalamocortical
      transmission would be a main function of the corticothalamic pathways in the
      awake, attentive animal.

PMID- 10391465
TI  - Premature death in transgenic mice that overexpress a mutant amyloid precursor
      protein is preceded by severe neurodegeneration and apoptosis.
AB  - A mutant amyloid precursor protein (APP/RK) designed to interfere with processing
      by alpha-secretase caused a severe phenotype in transgenic mice, including
      behavioural abnormalities, i.e. neophobia, aggression, hypersensitivity to kainic
      acid, hyposensitivity to N-methyl-D-aspartate, and premature death [Moechars D.
      et al. (1996) Eur. molec. Biol. Org. J. 15, 1265-1274]. We now demonstrated that
      the APP/RK transgene did not disturb the expression of several other genes, i.e.
      endogenous amyloid precursor protein and amyloid precursor protein-like proteins,
      members of the low density lipoprotein receptor lipoprotein receptor family and
      several of their ligands, including apolipoprotein E, but expression of alpha-2
      macroglobulin was never detected. Neither amyloid deposits nor neurofibrillary
      tangles were detected in the brain of APP/RK transgenic mice, even when 15-months
      old. The tendency for seizures and hyposensitivity for N-methyl-D-aspartate was
      not due to or reflected in the distribution of the three major types of glutamate
      receptors. The major and consistent finding in transgenic APP/RK mice that died
      prematurely was extensive neurodegeneration and apoptosis, mainly in hippocampus
      and cortex, and accompanied by astrocytosis throughout the brain. Reduced
      synaptic density and dendritic damage was only observed in three transgenic mice
      that were killed shortly after positive observation of seizures. In addition, the
      distribution of cathepsin D and ubiquitin was abnormal in these mice.

PMID- 10391466
TI  - Interleukin-1beta activates forebrain glial cells and increases nitric oxide
      production and cortical glutamate and GABA release in vivo: implications for
      Alzheimer's disease.
AB  - Interleukin-1beta (10 U) was injected into the nucleus basalis of adult male
      Wistar rats. The inflammation-induced changes in glial cell morphology and
      expression of inducible nitric oxide synthase in the injected area, the release
      of acetylcholine, GABA and glutamate from the ipsilateral cortex, the production
      of nitrite levels in the injected area and ipsilateral cortex, and changes in
      motor activity were investigated. Saline-injected rats were used as control.
      Interleukin-1beta induced an activation of both microglia and astrocytes which
      was already evident 24 h after injection. Seven days after injection, many
      reactive microglial cells and astrocytes were seen in the injected area and in
      other brain regions of the same hemisphere. Microglia reaction, but not astrocyte
      activation, disappeared 30 days post-injection. Seven days after interleukin
      1beta injection, many cells immunopositive for inducible nitric oxide synthase
      were found surrounding the injection site. Inducible nitric oxide synthase
      positive cells were identified, by double staining immunohistochemistry, in the
      reactive microglial cells and, by electron microscope examination, in the
      perineuronal subpopulation of resident activated microglia. Microdialysis
      investigations revealed a transient increase in reactive nitrogen intermediates
      (at seven days post-injection), a delayed (at 30 days post-injection) increase in
      GABA and glutamate release, and no changes in acetylcholine release in the
      ipsilateral cortex in interleukin-1beta, but not saline, injected rats.
      Inhibition of inducible nitric oxide synthase expression by N(G)-nitro-L-arginine
      methyl ester administration prevented the increase in nitrogen intermediates and
      GABA release, but not in glutamate release. Our findings suggest that an
      inflammatory reaction of the basal forebrain facilitates GABA release through the
      production of nitric oxide.

PMID- 10391467
TI  - Evidence for homeostatic adjustments of rat somatosensory cortical neurons to
      changes in extracellular acetylcholine concentrations produced by iontophoretic
      administration of acetylcholine and by systemic diisopropylfluorophosphate
      treatment.
AB  - We describe the responses of single units in the awake (24 cells) or urethane
      anesthetized (37 cells) rat somatosensory cortex during repeated iontophoretic
      pulses (1.0 s, 85 nA) of acetylcholine, both before and after systemic treatment
      with the irreversible acetylcholinesterase inhibitor diisopropylfluorophosphate
      (i.p., 0.3-0.5 LD50). The time-course of the response to acetylcholine pulses
      differed among cortical neurons but was characteristic for a given cell.
      Different time-courses included monophasic excitatory or inhibitory responses,
      biphasic (excitatory-inhibitory, inhibitory-excitatory, excitatory-excitatory,
      and inhibitory-inhibitory), and triphasic (excitatory-excitatory-inhibitory,
      inhibitory-inhibitory-excitatory, and inhibitory-excitatory-inhibitory)
      responses. Although the sign and time-course of the individual responses remained
      consistent, their magnitude fluctuated across time; most cells exhibited either
      an initial increase or decrease in response magnitude followed by oscillations in
      magnitude that diminished with time, gradually approaching the original size. The
      time-course of the characteristic response to an acetylcholine pulse appeared to
      determine direction and rate of change in response magnitude with successive
      pulses of acetylcholine. Diisopropylfluorophosphate treatment, given 1 h after
      beginning repeated acetylcholine pulses, often resulted in a gradual increase in
      spontaneous activity to a slightly higher but stable level. Superimposed on this
      change in background activity, the oscillations in the response amplitude
      reappeared and then subsided in a pattern similar to the decay seen prior to
      diisopropylfluorophosphate treatment. Our results suggest that dynamic,
      homeostatic mechanisms control neuronal excitability by adjusting the balance
      between excitatory and inhibitory influences within the cortical circuitry and
      that these mechanisms are engaged by prolonged increases in extracellular
      acetylcholine levels caused by repeated pulses of acetylcholine and by
      acetylcholinesterase inhibition. However, this ability of neurons in the cortical
      neuronal network to rapidly adjust to changes in extracellular levels of
      acetylcholine questions the potential efficacy of therapeutic treatments designed
      to increase ambient levels of acetylcholine as a treatment for Alzheimer's
      disease or to enhance mechanisms of learning and memory.

PMID- 10391468
TI  - A neural network model with dopamine-like reinforcement signal that learns a
      spatial delayed response task.
AB  - This study investigated how the simulated response of dopamine neurons to reward
      related stimuli could be used as reinforcement signal for learning a spatial
      delayed response task. Spatial delayed response tasks assess the functions of
      frontal cortex and basal ganglia in short-term memory, movement preparation and
      expectation of environmental events. In these tasks, a stimulus appears for a
      short period at a particular location, and after a delay the subject moves to the
      location indicated. Dopamine neurons are activated by unpredicted rewards and
      reward-predicting stimuli, are not influenced by fully predicted rewards, and are
      depressed by omitted rewards. Thus, they appear to report an error in the
      prediction of reward, which is the crucial reinforcement term in formal learning
      theories. Theoretical studies on reinforcement learning have shown that signals
      similar to dopamine responses can be used as effective teaching signals for
      learning. A neural network model implementing the temporal difference algorithm
      was trained to perform a simulated spatial delayed response task. The
      reinforcement signal was modeled according to the basic characteristics of
      dopamine responses to novel stimuli, primary rewards and reward-predicting
      stimuli. A Critic component analogous to dopamine neurons computed a temporal
      error in the prediction of reinforcement and emitted this signal to an Actor
      component which mediated the behavioral output. The spatial delayed response task
      was learned via two subtasks introducing spatial choices and temporal delays, in
      the same manner as monkeys in the laboratory. In all three tasks, the
      reinforcement signal of the Critic developed in a similar manner to the responses
      of natural dopamine neurons in comparable learning situations, and the learning
      curves of the Actor replicated the progress of learning observed in the animals.
      Several manipulations demonstrated further the efficacy of the particular
      characteristics of the dopamine-like reinforcement signal. Omission of reward
      induced a phasic reduction of the reinforcement signal at the time of the reward
      and led to extinction of learned actions. A reinforcement signal without
      prediction error resulted in impaired learning because of perseverative errors.
      Loss of learned behavior was seen with sustained reductions of the reinforcement
      signal, a situation in general comparable to the loss of dopamine innervation in
      Parkinsonian patients and experimentally lesioned animals. The striking
      similarities in teaching signals and learning behavior between the computational
      and biological results suggest that dopamine-like reward responses may serve as
      effective teaching signals for learning behavioral tasks that are typical for
      primate cognitive behavior, such as spatial delayed responding.

PMID- 10391469
TI  - Three-dimensional distribution of nigrostriatal neurons in the rat: relation to
      the topography of striatonigral projections.
AB  - Functional regions of the rat striatum related to identified cortical territories
      were injected ionophoretically with wheat germ agglutinin coupled to horseradish
      peroxidase. Coronal serial sections were cut throughout the substantia nigra. The
      distributions of labelled striatal projections and nigrostriatal neurons were
      studied. Using software developed in our laboratory, three-dimensional
      reconstructions were calculated which confirmed and extended the organizational
      scheme of striatonigral projections already reported by our group. These
      projections were organized as a set of longitudinal lamellae spatially organized
      so as to segregate the flow of information emanating from striatal regions
      affiliated to sensorimotor and associative-limbic cortical areas. In addition,
      the relationship between the striatonigral projections and the nigrostriatal
      neurons was studied by three-dimensional reconstruction. For each striatal
      injection site, two populations of retrogradely labelled nigral neurons could be
      discriminated by their position with respect to the striatal projection field.
      The first one occupied a proximal position, in register with the labelled
      striatal projections, while the second was more distal. The populations of
      proximal neurons which innervate different functional striatal sectors were
      segregated both mediolaterally, dorsoventrally and rostrocaudally, while the
      populations of distal neurons were more scattered and showed a lesser degree of
      spatial segregation. The organization of these two populations with respect to
      the striatal projection fields suggests that the substantia nigra might control
      the flow of cortical information through the striatum via two different
      modalities, based respectively on a closed nigrostriatal loop involving the
      proximal neurons, and an open loop involving the distal ones.

PMID- 10391470
TI  - Potentiation of the D2 mutant motor phenotype in mice lacking dopamine D2 and D3
      receptors.
AB  - Within the D2-class of dopamine receptors, the D2 and D3 subtypes share the
      highest degree of similarity in their primary structure. However, the extent to
      which these two receptor subtypes have similar or different functional properties
      is unclear. The present study used gene targeting to generate mice deficient for
      D2, D3, and D2/D3 receptors. A comparative analysis of D2 and D3 single mutants
      and D2/D3 double mutants revealed that D2/D3 double mutants develop motor
      phenotypes that, although qualitatively similar to those seen in D2 single
      mutants, are significantly more severe. Furthermore, increased levels of the
      dopamine metabolites dihydroxyphenyl acetic acid and homovanillic acid are found
      in the dorsal striatum of D2 single mutants. The levels of these metabolites,
      however, are significantly higher in mice lacking D2 and D3 receptors. In
      addition, results of immunoprecipitation experiments revealed that D2 single
      mutants express higher levels of D3 receptor proteins during later stages of
      their postnatal development. These results suggest that D3 receptors compensate
      for some of the lacking D2 receptor functions and that these functional
      properties of D3 receptors, detected in mice with a D2 mutant genetic background,
      remain masked when the abundant D2 receptor is expressed.

PMID- 10391471
TI  - Different behavioral functions of dopamine in the nucleus accumbens and
      ventrolateral striatum: a microdialysis and behavioral investigation.
AB  - Three experiments were conducted to investigate the behavioral functions of
      dopamine in the nucleus accumbens and ventrolateral striatum. In the first
      experiment, dialysis probes were implanted in the nucleus accumbens or
      ventrolateral striatum of rats previously trained to respond on fixed interval
      lever pressing schedules for food reinforcement. During the dialysis test
      session, both schedule- and site-dependent effects on dopamine release were
      observed. Overall, lever pressing on a fixed interval 30-s schedule produced a
      greater increase in extracellular dopamine than did responding on a fixed
      interval 120-s schedule. The fixed interval 30-s schedule was also accompanied by
      a higher rate of lever pressing. Rats with nucleus accumbens probe placements
      showed significantly higher increases in dopamine release than rats with
      ventrolateral striatal placements. An additional dialysis experiment showed that
      baseline levels of dopamine were suppressed by 1.0 microM tetrodotoxin to a
      similar extent in the nucleus accumbens and ventrolateral striatum. In the third
      experiment, 6-hydroxydopamine was injected locally into either the nucleus
      accumbens or the ventrolateral striatum in order to deplete dopamine. Nucleus
      accumbens dopamine depletions produced only a minor decrease in operant
      responding, whereas rats with ventrolateral striatal dopamine depletions showed
      low levels of responding that differed from both the control group and from the
      group that had accumbens dopamine depletions. Thus, these results are somewhat
      paradoxical, in that the structure that showed the greatest increase in dopamine
      release (i.e. the nucleus accumbens) was also the terminal region at which
      dopamine depletions had very little effect on operant responding. Ventrolateral
      striatal dopamine appears to be largely permissive over lever pressing, in that
      normal levels of dopamine in the ventrolateral striatum are critical for
      responding, although dopamine levels do not fluctuate much during behavioral
      sessions.

PMID- 10391472
TI  - Dopamine agonist-mediated rotation in rats with unilateral nigrostriatal lesions
      is not dependent on net inhibitions of rate in basal ganglia output nuclei.
AB  - Current models of basal ganglia function predict that dopamine agonist-induced
      motor activation is mediated by decreases in basal ganglia output. This study
      examines the relationship between dopamine agonist effects on firing rate in
      basal ganglia output nuclei and rotational behavior in rats with nigrostriatal
      lesions. Extracellular single-unit activity ipsilateral to the lesion was
      recorded in awake, locally-anesthetized rats. Separate rats were used for
      behavioral experiments. Low i.v. doses of D1 agonists (SKF 38393, SKF 81297, SKF
      82958) were effective in producing rotation, yet did not change average firing
      rate in the substantia nigra pars reticulata or entopeduncular nucleus. At these
      doses, firing rate effects differed from neuron to neuron, and included
      increases, decreases, and no change. Higher i.v. doses of D1 agonists were
      effective in causing both rotation and a net decrease in rate of substantia nigra
      pars reticulata neurons. A low s.c. dose of the D1/D2 agonist apomorphine (0.05
      mg/kg) produced both rotation and a robust average decrease in firing rate in the
      substantia nigra pars reticulata, yet the onset of the net firing rate decrease
      (at 13-16 min) was greatly delayed compared to the onset of rotation (at 3 min).
      Immunostaining for the immediate-early gene Fos indicated that a low i.v. dose of
      SKF 38393 (that produced rotation but not a net decrease in firing rate in basal
      ganglia output nuclei) induced Fos-like immunoreactivity in the striatum and
      subthalamic nucleus, suggesting an activation of both inhibitory and excitatory
      afferents to the substantia nigra and entopeduncular nucleus. In addition, D1
      agonist-induced Fos expression in the striatum and subthalamic nucleus was
      equivalent in freely-moving and awake, locally-anesthetized rats. The results
      show that decreases in firing rate in basal ganglia output nuclei are not
      necessary for dopamine agonist-induced motor activation. Motor-activating actions
      of dopamine agonists may be mediated by firing rate decreases in a small
      subpopulation of output nucleus neurons, or may be mediated by other features of
      firing activity besides rate in these nuclei such as oscillatory firing pattern
      or interneuronal firing synchrony. Also, the results suggest that dopamine
      receptors in both the striatum and at extrastriatal sites (especially the
      subthalamic nucleus) are likely to be involved in dopamine agonist influences on
      firing rates in the substantia nigra pars reticulata and entopeduncular nucleus.

PMID- 10391473
TI  - Differential effects of stress on presynaptic and postsynaptic 5
      hydroxytryptamine-1A receptors in the rat brain: an in vitro electrophysiological
      study.
AB  - Extracellular and intracellular recording techniques were used to assess possible
      changes in the functional properties of 5-hydroxytryptamine-1A receptors in brain
      slices prepared from rats subjected to different stress paradigms. Whereas a 30
      min restraint stress did not alter the inhibitory influence of ipsapirone on the
      firing of serotoninergic neurons in the dorsal raphe nucleus, the same session
      followed by a 24-h isolation produced a significant decrease in the potency of
      the 5-hydroxytryptamine-1A agonist to inhibit the electrical activity of these
      cells. Similarly, exposure of the animals to novel uncontrolled environmental
      conditions for 16 h significantly reduced the potency of ipsapirone to decrease
      the firing rate of serotoninergic neurons in brain stem slices. The effects of
      the latter two stressful paradigms were observed in slices from intact rats, but
      not in those from adrenalectomized animals. Intracellular recording showed that
      exposure of the animals to novel uncontrolled environmental conditions markedly
      reduced the potency of 5-carboxamidotryptamine to hyperpolarize serotoninergic
      neurons in the dorsal raphe nucleus and to decrease the input resistance of their
      plasma membrane. In contrast, the same stressful paradigm exerted no significant
      influence on the membrane effects of this 5-hydroxytryptamine-1A agonist on
      pyramidal cells in the CA1 hippocampal area. These data show that, like the
      direct application of corticosterone on to brain slices [Laaris N. et al. (1995)
      Neuropharmacology 34, 1201-1210], the stress-induced in vivo elevation of serum
      levels of endogenous corticosterone is associated with desensitization of
      somatodendritic 5-hydroxytryptamine-1A receptors in the dorsal raphe nucleus. The
      differential changes in 5-hydroxytryptamine-1A receptor sensitivity due to stress
      in the latter area versus the hippocampus further support the idea that
      somatodendritic and postsynaptic 5-hydroxytryptamine-1A receptors are regulated
      differently in the rat brain.

PMID- 10391474
TI  - Serotonin modulates synaptic transmission in immature rat ventrolateral medulla
      neurons in vitro.
AB  - Patch-clamp recordings in whole-cell configuration were made from ventrolateral
      medulla neurons of brainstem slices from 8-12-day-old rats. 5-Hydroxytryptamine
      (3-30 microM) concentration-dependently suppressed excitatory and inhibitory
      postsynaptic currents evoked by focal stimulation. An augmentation of inhibitory
      synaptic currents by 5-hydroxytryptamine was noted in a small number of neurons.
      5-Hydroxytryptamine depressed synaptic currents with or without causing a
      significant change in holding currents and membrane conductances; the inward or
      outward currents induced by exogenously applied glutamate or GABA/glycine were
      also not significantly changed by 5-hydroxytryptamine. In paired-pulse paradigms
      designed to evaluate a presynaptic site of action, 5-hydroxytryptamine suppressed
      synaptic currents but enhanced the paired-pulse facilitation. 5-Hydroxytryptamine
      reduced the frequency of miniature excitatory postsynaptic currents without
      significantly affecting the amplitude. 5-Carboxamidotryptamine, 8-hydroxy-2(di-n
      propylamino)tetralin, sumatriptan and N-(3-trifluoromethylphenyl)piperazine which
      exhibit 5-hydroxytryptamine1 receptor agonist activity, depressed synaptic
      currents with different potencies, with 5-carboxamidotryptamine being the most
      potent. The non-selective 5-hydroxytryptamine1 receptor antagonist pindolol
      attenuated the presynaptic effect of 5-hydroxytryptamine, whereas the 5
      hydroxytryptamine1A antagonist pindobind-5-hydroxytryptamine1A and 5
      hydroxytryptamine2 receptor antagonist ketanserin were ineffective. Our results
      indicate that 5-hydroxytryptamine suppressed synaptic transmission in
      ventrolateral medulla neurons by activating presynaptic 5-hydroxytryptamine1
      receptors, probably the 5-hydroxytryptamine1B/5-hydroxytryptamine1D subtype. In
      addition, 5-hydroxytryptamine augmented inhibitory synaptic currents in a small
      number of neurons the site and mechanism of this potentiating action are not
      known.

PMID- 10391475
TI  - The effect of repeated administration of morphine, cocaine and ethanol on mu and
      delta opioid receptor density in the nucleus accumbens and striatum of the rat.
AB  - The present study was carried out to evaluate the effect of morphine, cocaine and
      ethanol on the density of opioid receptors in the nucleus accumbens and striatum
      of rat brain. The animals were injected i.p. with morphine in a single dose 20
      mg/kg, or twice daily for 10 days in increasing doses of 20-100 mg/kg. Cocaine
      was administered in a dose of 60 mg/kg/day following the "binge" paradigm, every
      hour for 3 h, one day (single treatment) or five days (chronic treatment).
      Ethanol was administered in drinking water at increasing concentrations of 1-6%
      v/v, for one month. As shown by receptor autoradiography, single morphine and
      cocaine administration did not influence the binding density of the selective
      ligand of delta2 receptors [3H]Ile5,6deltorphin b, but single administration of
      cocaine decreased binding density of a highly selective antagonist of delta
      receptors, [3H]H-Tyr-Tic psi[CH2-NH]Phe-Phe-OH. Repeated morphine administration
      decreased the receptor density after both ligands of the delta receptor in the
      nucleus accumbens after 3, 24 and 48 h, and in the striatum after 24 and 48 h.
      The density of [3H]Ile5,6deltorphin b binding remained unchanged in both
      structures following repeated cocaine administration. After repeated cocaine
      administration either no changes (3 h) or a decrease in the binding of [3H]H-Tyr
      Tic psi[CH2-NH]Phe-Phe-OH in the nucleus accumbens and striatum were observed
      after 24 and 48 h. Ethanol did not influence the binding density of [3H]H-Tyr-Tic
      psi[CH2-NH]Phe-Phe-OH and [3H]Ile5,6deltorphin b in the nucleus accumbens and
      striatum at any time-point studied. In the nucleus accumbens and striatum, no
      changes were found in the binding density of [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol
      following single or repeated morphine administration. At 3 h after single or
      repeated "binge" cocaine administration, the binding of [3H]Tyr-D-Ala-Gly-MePhe
      Gly-ol was not changed in either structure, but after 24 h the density of mu
      opioid receptors was decreased in both structures. Ethanol given to rats in
      drinking water decreased the binding of [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol at the
      time of exposure to ethanol, yet in the nucleus accumbens only. Ethanol
      withdrawal decreased the density of the mu receptor in both structures after 24,
      48 and 96 h. The above data indicate that repeated administration of morphine
      evokes a long-lasting down-regulation of the density of delta1 and delta2 opioid
      receptors, whereas cocaine affects in a similar way only the delta1 subtype in
      the nucleus accumbens, and to a lesser extent in the striatum. A long-term intake
      of ethanol solution down-regulates mu opioid receptors in both structures, but
      has no effect on any type of delta receptors. Thus changes in the particular
      opioid receptor depend on the type of drug used. Furthermore, the most profound
      changes are observed after late withdrawal, which may play some role in
      maintaining the state of dependence.

PMID- 10391476
TI  - Microinjection of morphine in the A7 catecholamine cell group produces opposing
      effects on nociception that are mediated by alpha1- and alpha2-adrenoceptors.
AB  - Stimulation of neurons in the ventromedial medulla produces antinociception in
      part by inhibiting nociceptive dorsal horn neurons. This antinociceptive effect
      is mediated in part by spinally projecting noradrenergic neurons located in the
      A7 catecholamine cell group. Methionine-enkephalin-immunoreactive neurons in the
      ventromedial medulla project to an area that includes the A7 cell group, and
      these enkephalin neurons may mediate part of the antinociception produced by
      stimulation of sites in the ventromedial medulla. This possibility was tested by
      determining the effects of microinjecting morphine near the A7 cell group on
      nociceptive foot and tail responses. Microinjection of a 3.75 nmol dose of
      morphine in the A7 region did not alter nociceptive responses, but a higher dose
      of 7.5 nmol facilitated these responses. In contrast, a higher dose of 15 nmol of
      morphine did not alter nociceptive responses. Selective alpha-adrenoceptor
      antagonists were injected intrathecally to determine whether the hyperalgesia
      produced by morphine is mediated by spinally projecting noradrenergic A7 neurons.
      Intrathecal injection of the alpha2-adrenoceptor antagonist yohimbine did not
      alter the hyperalgesic effect produced by the 7.5 nmol dose of morphine, but the
      alpha1 antagonist WB4101 reversed the hyperalgesia and produced antinociception
      that lasted for nearly 30 min. Although the 15 nmol dose of morphine did not
      alter nociceptive responses, intrathecal injection of yohimbine after the
      microinjection of morphine produced a significant facilitation of nociception,
      and intrathecal injection of WB401 produced a significant antinociceptive effect.
      Intrathecal injection of the antagonists alone did not consistently alter
      nociception. These findings, and those of published reports, suggest that
      morphine indirectly activates two populations of spinally projecting A7
      noradrenergic neurons that have opposing effects on nociception. One of these
      populations facilitates nociception by an action mediated by alpha1-adrenoceptors
      in the spinal cord dorsal horn and the other population inhibits nociception by
      an action mediated by alpha2-adrenoceptors. These results suggest that some of
      the methionine-enkephalin neurons located in the ventromedial medulla that
      project to the A7 cell group can exert bidirectional control of nociceptive
      responses.

PMID- 10391477
TI  - Distribution of the nociceptin and nocistatin precursor transcript in the mouse
      central nervous system.
AB  - The distribution of prepronociceptin messenger RNA, the recently identified
      endogenous ligand of the ORL1 receptor (opioid receptor-like-1), has been studied
      in the adult mouse central nervous system using in situ hybridization.
      Prepronociceptin is a new peptide precursor that generates, upon maturation, at
      least three bioactive peptides: nociceptin, noc2 and the recently described
      nocistatin. Considering both the density of labeled neurons per region and their
      intensity of labeling, the distribution of prepronociceptin messenger RNA
      containing neurons can be summarized as follows: the highest level of
      prepronociceptin messenger RNA expression was detected in the septohippocampal
      nucleus, bed nucleus of the stria terminalis, central amygdaloid nucleus, and in
      selective thalamic nuclei such as the parafascicular, reticular, ventral lateral
      geniculate and zona incerta. High to moderate levels of prepronociceptin
      messenger RNA expression were detected in the lateral, ventral and medial septum,
      and were evident in brainstem structures implicated in descending antinociceptive
      pathways (e.g., the gigantocellular nucleus, raphe magnus nucleus, periaqueductal
      gray matter), and also observed in association with auditory relay nuclei such as
      the inferior colliculi, lateral lemniscus nucleus, medioventral preolivary
      nucleus and lateral superior nucleus. A moderate level of prepronociceptin
      messenger RNA expression was observed in the medial preoptic nucleus,
      ventromedial preoptic nucleus, periventricular nucleus, pedonculopontine
      tegmental nucleus, solitary tract nucleus and spinal trigeminal nucleus. A weak
      level of prepronociceptin messenger RNA expression was present in some areas,
      such as the cerebral cortex, endopiriform cortex, hippocampal formation, medial
      amygdaloid nucleus, anterior hypothalamic area, medial mammillary hypothalamic
      nuclei, retrorubral field and substantia nigra pars compacta. No labeled cells
      could be found in the caudate-putamen, nucleus accumbens and ventral tegmental
      area. The present data confirm that nociceptin is expressed in a broad array of
      regions of the central nervous system. In good correlation with the presently
      known physiological actions of nociceptin, they include, amongst others, brain
      areas conveying/integrating pain and auditory sensory afferences.

PMID- 10391478
TI  - Role of apolipoprotein E and estrogen in mossy fiber sprouting in hippocampal
      slice cultures.
AB  - A role for apolipoprotein E is implicated in regeneration of synaptic circuitry
      after neural injury. The in vitro mouse organotypic hippocampal slice culture
      system shows Timm's stained mossy fiber sprouting into the dentate gyrus
      molecular layer in response to deafferentation of the entorhinal cortex. We show
      that cultures derived from apolipoprotein E knockout mice are defective in this
      sprouting response; specifically, they show no sprouting in the dorsal region of
      the dentate gyrus, yet retain sprouting in the ventral region. Dorsal but not
      ventral sprouting in cultures from C57B1/6J mice is increased 75% by treatment
      with 100 pM 17beta-estradiol; this response is blocked by both progesterone and
      tamoxifen. These results show that neuronal sprouting is increased by estrogen in
      the same region where sprouting is dependent on apolipoprotein E. Sprouting may
      be stimulated by estrogen through its up-regulation of apolipoprotein E
      expression leading to increased recycling of membrane lipids for use by sprouting
      neurons. Estrogen and apolipoprotein E may therefore interact in their modulation
      of both Alzheimer's disease risk and recovery from CNS injury.

PMID- 10391479
TI  - Expression of the transcription factor Zif268 in the visual cortex of monocularly
      deprived rats: effects of nerve growth factor.
AB  - Neurotrophins are known to be involved in experience-dependent plasticity of the
      visual cortex. Here, we have characterized in detail the effects of
      intraventricular nerve growth factor infusion in monocularly deprived rats by
      using immunostaining for the immediate-early gene product Zif268 as a marker of
      functional activity with cellular resolution. We have taken advantage of the
      rapid regulation of Zif268 by visual input to reveal the cortical units that are
      responsive to the deprived eye after a period of monocular deprivation. We found
      that responses to the deprived eye were significantly preserved in the cortex of
      monocularly deprived rats infused with nerve growth factor. The effects of nerve
      growth factor were greater for cortical cells located in deep layers and with
      more peripheral receptive fields. Results from Zif268 staining correlated very
      well with those obtained by single-cell recordings from the visual cortex. Our
      results demonstrate that exogenous nerve growth factor preserves the functional
      input from the deprived eye, enabling cortical neurons to activate immediate
      early gene expression in response to stimulation of the deprived eye.
      Furthermore, we show that the intraventricular infusion of nerve growth factor
      differentially affects the ocular dominance of cells at various depths and
      eccentricities in the developing cortex.

PMID- 10391480
TI  - Expression of nerve growth factor in astrocytes of the hippocampal CA1 area
      following transient forebrain ischemia.
AB  - We have examined by immunoassay and immunohistochemistry, the expression of nerve
      growth factor in the rat hippocampus, one to 28 days after transient forebrain
      ischemia. In the CA1 area, the overall level of nerve growth factor expression
      remained constant over the first three days of reperfusion while it increased by
      about 45% of control levels after longer postischemic periods. In contrast, a
      slight decrease in nerve growth factor levels, which was most prominent at three
      days postlesion, was observed in the other hippocampal regions.
      Immunohistochemical analysis of the distribution of nerve growth factor showed
      that its expression was up-regulated in astrocytes but not in microglia of the
      postischemic CA1 region and that the intensity and temporal profile of the
      changes in nerve growth factor immunostaining in these cells, was consistent with
      that observed in the immunoassay. Interestingly, the regulation of the nerve
      growth factor expression in reactive astrocytes of the postischemic CA1 area
      closely parallels that of kainate receptor subunits GluR5-7, raising the
      possibility of a cause-effect relationship. These results indicate that after
      ischemia nerve growth factor expression is up-regulated in reactive astrocytes
      suggesting that these cells may contribute to rescuing damaged neurons by means
      of increasing nerve growth factor production.

PMID- 10391481
TI  - Impact of neonatal kainate treatment on hippocampal insulin-like growth factor
      receptors.
AB  - The insulin-like growth factors-I and -II have neurotrophic properties and act
      through specific membrane receptors. High levels of binding sites for these
      growth factors are distributed discretely throughout the brain, being
      concentrated in the hippocampal formation. Functionally, the insulin-like growth
      factors, in addition to their growth-promoting actions, are considered to play
      important roles in normal cell functions, as well as in response to
      pharmacological or surgical manipulations. In adult rats, we have previously
      shown that systemic injection of kainate produces an overall decrease, in a time
      dependent manner, in insulin-like growth factor-I and -II receptor binding sites
      in the hippocampus [Kar S. et al. (1997) Neuroscience 80, 1041-1055]. Given the
      evidence that insulin-like growth factors play a critical role during the early
      stages of brain development, the present study is a logical extension of this
      earlier report and established the effect of neonatal kainate injection on the
      developmental profile of insulin-like growth factor receptors. We have evaluated
      the time-course alteration of these receptors following systemic injection of
      kainate to newborn rats. After injection of a sublethal dose of kainate (5 mg/kg,
      i.p.) to postnatal one-day-old pups, [125I]insulin-like growth factor-I,
      [125I]insulin-like growth factor-II and [125I]insulin binding sites were studied
      at different postnatal days (7, 14, 21, 28 and 35) using receptor
      autoradiography. In the developing hippocampus, insulin-like growth factor-I and
      insulin binding sites are concentrated primarily in the dentate gyrus and the
      CA2/CA3 subfields, whereas insulin-like growth factor-II binding is discretely
      localized to the pyramidal layer and the granular layer of the dentate gyrus.
      Following kainate injection, we observed a slight increase in insulin-like growth
      factor-I binding sites in given hippocampal subfields starting at postnatal day
      14, being significant at day 21. At later days, a progressive decrease was noted.
      This transient increase may represent an attempt for neuronal plasticity by up
      regulating receptor levels. In contrast, insulin-like growth factor-II and
      insulin receptor binding sites are found to be decreased in various regions of
      the hippocampus in kainate-treated pups. Taken together, these results provide
      further evidence for the existence and differential alterations of insulin-like
      growth factor-I, insulin-like growth factor-II and insulin receptors in the
      developing rat hippocampus following kainate-induced lesion, suggesting possible
      involvement of these growth factors in brain plasticity.

PMID- 10391482
TI  - Dopamine and serotonin interactions in the modulation of the expression of the
      immediate-early transcription factor, nerve growth factor-inducible B, in the
      striatum.
AB  - Nerve growth factor-inducible B is a closely related member of the steroid
      thyroid hormone receptor family of ligand-activated transcription factor. Recent
      evidence suggests a close relationship between nerve growth factor-inducible B
      and the dopamine system. Basal expression of messenger RNA for nerve growth
      factor-inducible B is relatively high in the striatum. The aims of the present
      study were: (i) to study the basal distribution and the modulation of striatal
      nerve growth factor-inducible B messenger RNA expression by dopamine and
      serotonin agonists, and (ii) to investigate the effects of combined
      administration of dopamine (D) and serotonin (5-HT) agonists. First, we
      investigated the effects of SKF38393 (D1), quinpirole (D2), 8-hydroxy-2-(di-n
      propylaminotetralin) (5-HT1A) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
      (5-HT2A/2C) administered alone on striatal nerve growth factor-inducible B
      messenger RNA expression. In a second series of experiments, the effects of a
      combined administration of dopamine D1 and serotonin 5-HT1A or 5-HT2A/2C agonists
      were studied. The goal of the last series of experiments was to determine the
      effects of a combined administration of the dopamine D2 agonist and either
      serotonin 5-HT1A or 5-HT2A/2C agonists. Our results show that: (i) striatal nerve
      growth factor-inducible B messenger RNA expression exhibited a lateral-medial
      gradient in drug-naive rats, (ii) quinpirole and 8-hydroxy-2-(di-n
      propylaminotetralin) administered alone induced a significant decrease in
      striatal nerve growth factor-inducible B messenger RNA expression while 1-(2,5
      dimethoxy-4-iodophenyl)-2-aminopropane significantly increased it, (iii) complex
      interactions were found when dopamine D1 and serotonin 5-HT1A or 5-HT2A/2C
      agonists were administered in combination, and (iv) combined administration of
      quinpirole and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane resulted in a
      significant decrease in nerve growth factor-inducible B expression. Taken
      together, these results demonstrate that striatal nerve growth factor-inducible B
      messenger RNA expression can be modulated by both dopamine and serotonin
      agonists. They also point out the existence of complex interactions between
      dopamine and serotonin in regard to striatal expression of the immediate-early
      transcription factor nerve growth factor-inducible B.

PMID- 10391483
TI  - Axonal transport of ribonucleoprotein particles (vaults).
AB  - RNA was previously shown to be transported into both dendritic and axonal
      compartments of nerve cells, presumably involving a ribonucleoprotein particle.
      In order to reveal potential mechanisms of transport we investigated the axonal
      transport of the major vault protein of the electric ray Torpedo marmorata. This
      protein is the major protein component of a ribonucleoprotein particle (vault)
      carrying a non-translatable RNA and has a wide distribution in the animal
      kingdom. It is highly enriched in the cholinergic electromotor neurons and
      similar in size to synaptic vesicles. The axonal transport of vaults was
      investigated by immunofluorescence, using the anti-vault protein antibody as
      marker, and cytofluorimetric scanning, and was compared to that of the synaptic
      vesicle membrane protein SV2 and of the beta-subunit of the F1-ATPase as a marker
      for mitochondria. Following a crush significant axonal accumulation of SV2
      proximal to the crush could first be observed after 1 h, that of mitochondria
      after 3 h and that of vaults after 6 h, although weekly fluorescent traces of
      accumulations of vault protein were observed in the confocal microscope as early
      as 3 h. Within the time-period investigated (up to 72 h) the accumulation of all
      markers increased continuously. Retrograde accumulations also occurred, and the
      immunofluorescence for the retrograde component, indicating recycling, was weaker
      than that for the anterograde component, suggesting that more than half of the
      vaults are degraded within the nerve terminal. High resolution immunofluorescence
      revealed a granular structure-in accordance with the biochemical characteristics
      of vaults. Of interest was the observation that the increase of vault
      immunoreactivity proximal to the crush accelerated with time after crushing,
      while that of SV2-containing particles appeared to decelerate, indicating that
      the crush procedure with time may have induced perikaryal alterations in the
      production and subsequent export to the axon of synaptic vesicles and vault
      protein. Our data show that ribonucleoprotein-immunoreactive particles can be
      actively transported within axons in situ from the soma to the nerve terminal and
      back. The results suggest that the transport of vaults is driven by fast axonal
      transport motors like the SV2-containing vesicles and mitochondria. Vaults
      exhibit an anterograde and a retrograde transport component, similar to that
      observed for the vesicular organelles carrying SV2 and for mitochondria. Although
      the function of vaults is still unknown studies of the axonal transport of this
      organelle may reveal insights into the mechanisms of cellular transport of
      ribonucleoprotein particles in general.

PMID- 10391484
TI  - Endothelin B receptor-deficient rats as a subtraction model to study the cerebral
      endothelin system.
AB  - Endothelins, due to their potent vasoactivity and mitogenicity, appear to play an
      important role in the brain, where all components of the endothelin system,
      peptides, receptors and converting enzyme, are expressed. To further elucidate
      the role of the cerebral endothelin system, astrocytes and cerebral vessels from
      sl/sl rats, devoid of functional endothelin B receptors, have been employed.
      Astrocytes from sl/sl rats display the following abnormalities as compared to
      wild-type (+/+) cells: (i) elevated basal extracellular endothelin-1 levels; (ii)
      exclusive presence of functional endothelin A receptors; (iii) increased
      extracellular endothelin-1 levels upon endothelin A receptor blockade; (iv)
      augmented basal endothelin-converting enzyme activity; (v) altered calcium
      response to endothelin-1. The basilar artery of sl/sl rats shows an enhanced
      constricting response to endothelin-1 and fails to dilate in response to
      endothelin-3, shifting the endothelin vasomotor balance to constriction. In
      conclusion, endothelin B receptors may be essential for restricting extracellular
      endothelin-1 levels in the brain, as well as for a balanced cerebral vasomotor
      action of endothelins.

PMID- 10391485
TI  - Neurokinin B receptor (NK3)-containing neurons in the paraventricular and
      supraoptic nuclei of the rat hypothalamus synthesize vasopressin and express Fos
      following intravenous injection of hypertonic saline.
AB  - Subnuclear localization of neurokinin B receptor (NK3) in the paraventricular and
      supraoptic nuclei of the hypothalamus was immunohistochemically investigated in
      the rat. In the paraventricular hypothalamic nucleus, intense neurokinin B
      receptor-like immunoreactivity was found in the posterior magnocellular part,
      moderate to weak neurokinin B receptor-like immunoreactivity was seen in the
      other parts. In the supraoptic nucleus, intense neurokinin B receptor-like
      immunoreactivity was distributed in its principal part, and a few neurons with
      neurokinin B receptor-like immunoreactivity were found in the retrochiasmatic
      part. Co-localization of neurokinin B receptor-like immunoreactivity with
      vasopressin-like immunoreactivity was examined through serial adjacent sections.
      Neurons with both neurokinin B receptor-like immunoreactivity and vasopressin
      like immunoreactivity were primarily found in the supraoptic nucleus and
      posterior magnocellular part of the pavaventricular nucleus. A small number of
      neurons with neurokinin B receptor-like immunoreactivity and vasopressin-like
      immunoreactivity were also seen in the circular nucleus and the region
      surrounding blood vessel in the anterior hypothalamus. Many neurokinin B receptor
      containing neurons in the paraventricular and supraoptic nuclei, as well as in
      circular nucleus and the region surrounding the blood vessel, expressed Fos-like
      immunoreactivity after intravenous injection of hypertonic saline. The present
      study demonstrated that a large proportion of neurokinin B receptor-like
      immunoreactive neurons in the paraventricular hypothalamic and supraoptic nuclei
      contained vasopressin-like immunoreactivity, and expressed Fos-like
      immunoreactivity after intravenous administration of hypertonic saline. The
      results suggest that neurokinin B receptor in the two nuclei may be involved in
      modulation of the release of vasopressin when the internal environment is
      disturbed.

PMID- 10391486
TI  - Rat diencephalic neurons producing melanin-concentrating hormone are influenced
      by ascending cholinergic projections.
AB  - Innervation of diencephalic neurons producing melanin-concentrating hormone by
      choline acetyltransferase-containing axons was examined using double
      immunohistochemistry. In the rostromedial zona incerta and perifornical regions
      of the lateral hypothalamic area, many choline acetyltransferase-positive fibers
      were detected in the immediate vicinity of melanin-concentrating hormone
      perikarya and their proximal dendrites. Putative contact sites were less abundant
      in the far lateral hypothalamus, and only scattered close to the third ventricle.
      After injections of the retrograde tracer FluoroGold, most of these projections
      appeared to originate in the pedunculopontine and laterodorsal tegmental nuclei.
      Finally, to determine the putative effect of acetylcholine on the melanin
      concentrating hormone neuron population, the cholinergic agonist carbachol was
      added to the medium of hypothalamic slices in culture. Using competitive reverse
      transcriptase-polymerase chain reaction, carbachol was found to induce a rapid
      increase in the melanin-concentrating hormone messenger RNA expression. This
      response was abolished by both atropine, a muscarinic antagonist, and
      hexamethonium, a nicotinic antagonist. Thus, the bulk of these results indicates
      that the diencephalic melanin-concentrating hormone neurons are targeted by
      activating ascending cholinergic projections.

PMID- 10391487
TI  - The organization of preoptic-medullary circuits in the male rat: evidence for
      interconnectivity of neural structures involved in reproductive behavior,
      antinociception and cardiovascular regulation.
AB  - The present studies used anatomical tract-tracing techniques to delineate the
      organization of pathways linking the medial preoptic area and the ventral
      medulla, two key regions involved in neuroendocrine, autonomic and sensory
      regulation. Wheatgerm agglutinin-horseradish peroxidase injections into the
      ventromedial medulla retrogradely labeled a large number of neurons in the medial
      preoptic area, including both the median and medial preoptic nuclei. The
      termination pattern of preoptic projections to the medulla was mapped using the
      anterograde tracers Phaseolus vulgaris leucoagglutinin and biotinylated dextran
      amine. Tracer injections into the preoptic area produced a dense plexus of
      labeled fibers and terminals in the ventromedial and ventrolateral pons and
      medulla. Within the caudal pons/rostral medulla, medial preoptic projections
      terminated heavily in the nucleus raphe magnus; strong anterograde labeling was
      also present in the pontine reticular field. At mid-medullary levels, labeled
      fibers focally targeted the nucleus paragigantocellularis, in addition to the
      heavy fiber labeling present in the midline raphe nuclei. By contrast, very
      little labeling was observed in the caudal third of the medulla. Experiments were
      also conducted to map the distribution of ventral pontine and medullary neurons
      that project to the medial preoptic area. Wheatgerm agglutinin-horseradish
      peroxidase injections in the preoptic area retrogradely labeled a significant
      population of neurons in the ventromedial and ventrolateral medulla. Ascending
      projections from the medulla to the preoptic area were organized along rostral
      caudal, medial-lateral gradients. In the caudal pons/rostral medulla,
      retrogradely labeled cells were aggregated along the midline raphe nuclei; no
      retrograde labeling was present laterally at this level. By contrast, in the
      caudal half of the medulla, cells retrogradely labeled from the medial preoptic
      area were concentrated as a discrete zone dorsal to the lateral reticular
      nucleus; labeled cells were not present in the ventromedial medulla at this
      level. The present findings suggest that the medial preoptic area and ventral
      midline raphe nuclei share reciprocal connections that are organized in a highly
      symmetrical fashion. By contrast, preoptic-lateral medullary pathways are not
      reciprocal. These preoptic-brainstem circuits may participate in antinociceptive,
      autonomic and reproductive behaviors.

PMID- 10391488
TI  - Effect of gonadal steroids on the oxytocin-induced excitation of neurons in the
      bed nuclei of the stria terminalis at parturition in the rat.
AB  - Experiments were undertaken to examine the role of ovarian steroids in peripartum
      programming of oxytocin sensitivity of limbic neurons implicated in oxytocin
      induced facilitation of the milk-ejection reflex. In vivo recordings of neurons
      in the bed nuclei of the stria terminalis and ventrolateral septum of pre
      parturient rats which had undergone prior ovariectomy and hysterectomy showed
      that oestradiol significantly increased the excitatory responses of bed
      nuclei/ventrolateral septum neurons to intracerebroventricular oxytocin, compared
      to oil-treated controls. Oestradiol also increased the excitation of bed nuclei
      neurons to the selective oxytocin agonist, [Thr4,Gly7]oxytocin in brain slices
      from steroid pre-treated ovariectomized hysterectomized rats, so that both the
      proportion of responsive neurons, and the magnitude of their responses were
      significantly increased. Parallel autoradiographic studies showed that oxytocin
      binding in the medial bed nuclei and ventrolateral septum was selectively
      increased following oestradiol treatment. Progesterone pre-treatment had no
      effect on either oxytocin sensitivity of bed nuclei/ventrolateral septum neurons
      recorded in vivo, or on oxytocin binding in the medial bed nuclei and
      ventrolateral septum, compared to oil-treated controls. Mean responses to
      [Thr4,Gly7]oxytocin in bed nuclei neurons recorded in slices from progesterone
      treated rats were larger than controls, but this effect was highly variable.
      These results demonstrate that oestradiol greatly enhances oxytocin receptor
      expression and sensitivity of bed nuclei/ventrolateral septum neurons to oxytocin
      over the peripartum period, consistent with involvement of this steroid in
      enhancing oxytocin regulation of neuroendocrine and behavioural adaptations
      required for lactation.

PMID- 10391489
TI  - Serotonergic input to cholinergic neurons in the substantia innominata and
      nucleus basalis magnocellularis in the rat.
AB  - The aim of the present study was to determine, at the light microscopic level,
      whether the serotonergic fibers originating from the dorsal raphe nucleus (B7),
      median raphe nucleus (B8) and ventral tegmentum (B9) make putative synaptic
      contacts with cholinergic neurons of the nucleus basalis magnocellularis and
      substantia innominata. For this purpose, we utilized: (i) the anterograde
      transport of Phaseolus vulgaris leucoagglutinin combined with choline
      acetyltransferase immunohistochemistry; (ii) choline acetyltransferase/tryptophan
      hydroxylase double immunohistochemistry; and (iii) the FluoroGold retrograde
      tracer technique combined with tryptophan hydroxylase immunohistochemistry.
      Following iontophoretic injections of Phaseolus vulgaris leucoagglutinin in the
      dorsal raphe nucleus, labeling was observed primarily in the ventral aspects of
      the nucleus basalis magnocellularis and in the intermediate region of the
      substantia innominata. When Phaseolus vulgaris leucoagglutinin was combined with
      choline acetyltransferase immunohistochemistry, a close association between the
      Phaseolus vulgaris leucoagglutinin-positive fibers and cholinergic neurons was
      observed, even though the majority of the Phaseolus vulgaris leucoagglutinin
      immunoreactive terminals seemed to establish contact with non-cholinergic
      elements. Following Phaseolus vulgaris leucoagglutinin injection in the median
      raphe nucleus, very few labeled fibers with no evident close contact with nucleus
      basalis magnocellularis and substantia innominata cholinergic neurons were
      observed. After tryptophan hydroxylase/choline acetyltransferase double
      immunohistochemistry, a plexus of serotonergic (tryptophan hydroxylase-positive)
      fibers in the vicinity of choline acetyltransferase-immunoreactive neurons of the
      substantia innominata and nucleus basalis magnocellularis was observed, and some
      serotonergic terminals have been shown to come into very close contact with the
      cholinergic cells. Most of the tryptophan hydroxylase-immunoreactive terminals
      seem to establish contacts with non-cholinergic cells. Following FluoroGold
      injection in the nucleus basalis magnocellularis and substantia innominata, the
      majority of retrogradely labeled neurons was observed mainly in the ventromedial
      cell group of the dorsal raphe nucleus. In this area, a minority of the
      FluoroGold-positive neurons was tryptophan hydroxylase immunoreactive. These
      findings show that serotonergic terminals, identified in very close association
      with the cholinergic neurons in the substantia innominata and nucleus basalis
      magnocellularis, derive primarily from the B7 serotonergic cell group of the
      dorsal raphe nucleus, and provide the neuroanatomical evidence for a direct
      functional interaction between these two neurotransmitter systems in the basal
      forebrain.

PMID- 10391490
TI  - Estrogen modulates spontaneous alternation and the cholinergic phenotype in the
      basal forebrain.
AB  - We report that a small population of neurons expresses both choline
      acetyltransferase and classical estrogen receptor immunoreactivity and they are
      found primarily in the bed nucleus of the stria terminalis. In short-term
      ovariectomized ageing mice (24 months, n = 5) there were 41.0 +/- 4.1% fewer of
      these double-labeled cells than in young (five months, n = 5) short-term
      ovariectomized C57BL/6J mice. To study cholinergic neuron estrogen
      responsiveness, young mice (n = 8) were ovariectomized at puberty (five weeks).
      After three months half of the mice (n = 4) were given physiological levels of
      17beta estradiol for 10 days. Bed nucleus double-labeled neurons increased by
      32.9% (P < or = 0.003) in the young mice given estrogen. In a gel shift assay,
      double-stranded oligonucleotides with putative estrogen response elements from
      the choline acetyltransferase gene were used as competitors against estrogen
      receptor binding to consensus estrogen response elements. A sequence with 60%
      homology to the vitellogenin estrogen response element was found to compete at
      500- and 1000-fold excess. Young mice (five months) with ovaries demonstrated
      significantly (P < or = 0.04) better performance in the spontaneous alternation T
      maze test than did old (19 month) mice with ovaries (young = 66.3 +/- 3.3%
      correct choices; vs old = 55.0 +/- 4.0% in old mice with ovaries). Young mice
      (five months old), ovariectomized for one month and treated with estrogen, showed
      significantly more spontaneous alternation than ovariectomized controls (69.1 +/-
      2.8% vs 58.3 +/- 3.9%; P < or = 0.04). Estrogen also increased spontaneous
      alternation in old, short-term ovariectomized mice (61.5 +/- 2.7% vs 48 +/- 3.3%;
      P < or = 0.005). In either young or old ovariectomized mice, estrogen increased
      spontaneous alternation to levels seen in young animals with ovaries. Estrogen
      increases the number of choline acetyltransferase-immunoreactive and choline
      acetyltransferase/estrogen receptor-immunoreactive cells in old or young mice
      lacking estrogen, and enhances working memory in old or young mice lacking
      estrogen. Our data suggest that estrogen may act at the level of the choline
      acetyltransferase gene, but in view of the limited distribution of cholinergic
      cells expressing the classical estrogen receptor, it is unlikely that these cells
      can account for a memory enhancing effect of estrogen replacement.

PMID- 10391491
TI  - PE-11, a peptide derived from chromogranin B, in the human brain.
AB  - This study was performed to investigate the distribution of chromogranin B in the
      human central nervous system. We used an antiserum raised against a synthetic
      peptide (PE-11) present in the chromogranin B molecule. PE-11-like
      immunoreactivity was characterized by molecular size exclusion and reversed-phase
      high-performance liquid chromatography. Its localization was studied using
      immunocytochemistry. Only the free peptide and an N-terminally elongated peptide
      were detected by molecular size exclusion high-performance liquid chromatography,
      indicating that proteolytic processing of chromogranin B is quite extensive. PE
      11-like immunoreactivity was present in differently shaped fibers, varicosities
      and neurons, but not in glial cells. Its density varied throughout the brain. An
      especially high density was observed in the bed nucleus of the stria terminalis,
      the central and cortical nuclei of the amygdala, the hypothalamus, the
      hippocampus, the raphe complex, the nucleus interpeduncularis, the nucleus of the
      solitary tract, and laminae I and II of the spinal cord. This study demonstrates
      a significant processing of chromogranin B and indicates that chromogranin B
      constitutes a precursor for smaller peptides which are derived by endoproteolytic
      processing. It provides the neuroanatomical basis to investigate the chromogranin
      B molecule as a widespread component of large dense-core vesicles in the human
      central nervous system.

PMID- 10391492
TI  - A study of the mechanism of the release of ATP from rat cortical astroglial cells
      evoked by activation of glutamate receptors.
AB  - Glutamate and the selective agonists at ionotropic glutamate receptors N-methyl-D
      aspartate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and
      kainate release ATP from superfused primary cultures of rat cortical astrocytes.
      The mechanism of this release was investigated. The release of ATP elicited by N
      methyl-D-aspartate and kainate was abolished or greatly reduced in the absence of
      external calcium as well as in the presence of cadmium (1 mM) and nicardipine (10
      microM). The release of ATP elicited by AMPA, in contrast, was not changed by
      these interventions. The calcium ionophore ionomycin (5 microM) released ATP in
      the presence but not in the absence of external calcium. No release was obtained
      with alpha-latrotoxin. Of several compounds tested as potential blockers of ATP
      transporters or channels only glibenclamide (100 microM) and diphenylamine-2
      carboxylate (500 microM), which block the cystic fibrosis transmembrane
      conductance regulator, caused any change: both reduced the effect of AMPA without
      changing the effects of N-methyl-D-aspartate and (only glibenclamide tested)
      kainate. Lithium (1 mM) abolished the release of ATP evoked by glutamate and AMPA
      and significantly reduced the release evoked by N-methyl-D-aspartate and kainate.
      The three glutamate receptor agonists did not increase the release of lactate
      dehydrogenase. The results confirm the previous observation that activation of N
      methyl-D-aspartate, AMPA and kainate receptors induces release of ATP from
      astrocytes in culture. Two different mechanisms seem to be involved. The N-methyl
      D-aspartate- and kainate-induced release of ATP requires an influx of calcium, is
      not due to neuron-like exocytosis, is not mediated by cystic fibrosis
      transmembrane conductance regulator or a mechanism regulated by cystic fibrosis
      transmembrane conductance regulator, and is reduced (by an unknown mechanism) but
      not abolished by lithium. The AMPA-induced release does not require extracellular
      calcium, may be mediated by cystic fibrosis transmembrane conductance regulator
      or a mechanism regulated by cystic fibrosis transmembrane conductance regulator,
      and is abolished (by an unknown mechanism) by lithium. The ability of astrocytes
      to both release ATP and respond to ATP suggests that ATP may act as an autocrine
      or paracrine messenger between these glial cells.

PMID- 10391493
TI  - Plasticity in the phenotypic expression of catecholamines and vasoactive
      intestinal peptide in adult rat superior cervical and stellate ganglia after long
      term hypoxia in vivo.
AB  - Sympathetic ganglia in the adult rat contain various populations of nerve cells
      which demonstrate plasticity with respect to their transmitter phenotype. The
      plasticity of the neuronal cell bodies and of the small intensely fluorescent
      cells in the superior cervical and stellate ganglia in response to hypoxia in
      vivo (10% O2 for seven days) was assessed by studying the expression of
      catecholamines and vasoactive intestinal peptide. The levels of norepinephrine,
      dopamine, 3,4-dihydroxyphenylacetic acid and vasoactive intestinal peptide
      immunoreactivity were determined. In addition, the density of the
      immunohistochemical staining of cells for tyrosine hydroxylase and vasoactive
      intestinal peptide was evaluated. In the intact superior cervical ganglion,
      hypoxia increased the dopamine level as well as the density of small intensely
      fluorescent cells immunolabelled for tyrosine hydroxylase and vasoactive
      intestinal peptide. In the axotomized ganglion, hypoxia elicited a twofold rise
      in the level of the vasoactive intestinal peptide as well as enhancing the
      density of neuronal cell bodies immunostained for this peptide. Thus, the effect
      of hypoxia on the expression of vasoactive intestinal peptide expression in
      neurons was dependent on neural interactions. In the intact stellate ganglion,
      hypoxia alone induced a 1.5-fold increase in the density of neuronal cell bodies
      immunostained for vasoactive intestinal peptide. Thus, ganglia-specific factors
      appeared to play a role in determining changes in neuronal phenotype in response
      to hypoxia. The present study provides evidence for the involvement of dopamine
      and vasoactive intestinal peptide in ganglionic responses to long-term hypoxia as
      well as for differential responses by the two ganglionic cell populations, i.e.
      neuronal cell bodies and small intensely fluorescent cells. Changes in the
      expression of the vasoactive intestinal peptide during long-term hypoxia may be
      of energetic, trophic and/or synaptic significance. Hypoxia may be considered to
      be a vasoactive intestinal peptide-inducing factor in sympathetic ganglia.

PMID- 10391494
TI  - Effect of 5-hydroxytryptamine infusion on microcirculation in the rabbit masseter
      muscle measured by laser-Doppler flowmetry.
AB  - The aim was to test the hypothesis that 5-hydroxytryptamine (5-HT) influences the
      microcirculation of the masseter muscle. Rabbit masseters were infused with
      increasing concentrations of 5-HT (10(-9)-10(-5) M) on the experimental side and
      with saline on the control side. The effect on microcirculatory blood flow was
      measured by laser-Doppler flowmetry. The intramuscular temperature was recorded
      to monitor the influence of tissue temperature. 5-HT infusion resulted in a
      statistically significant decrease in blood flow at the lowest concentration (10(
      9) M) (median; -11.2%: Wilcoxon signed-rank test; p<0.05). At concentrations
      greater than 10(-9) M, there was no significant change in blood flow. This study
      shows a decrease of microcirculatory blood flow in the rabbit masseter following
      5-HT infusion (10(-9) M).

PMID- 10391495
TI  - A pilot study on the effect of radiation on calmodulin in rat submandibular
      salivary glands.
AB  - Xerostomia and loss of salivary gland secretion is one of the most common
      complications of the radiation treatment of head-and-neck malignancies. The
      secretory mechanism in the salivary glands can be modulated by the concentration
      of intracellular Ca2+. Calmodulin is a calcium-binding protein that is widely
      distributed in nature and is involved in regulating intracellular calcium. In
      this study the effect of radiation on the concentration of calmodulin in rat
      salivary glands was investigated. Fourteen rats were divided into three groups:
      R1 (n = 4) and R2 (n = 5) received a single dose of 15 Gy and group C (n = 5)
      received no radiation. R1 and R2 animals were killed at weeks 2 and 10 post
      irradiation, respectively. The submandibular glands were removed, homogenized and
      their total calmodulin was determined. The mean calmodulin concentrations were
      6.4+/-1.1 microg/gland for controls, 14.1+/-3.7 microg/gland for R1 and 68.2+/
      14.4 microg/gland for R2. Kruskal-Wallis ANOVA revealed a significant increase in
      the concentration of calmodulin following irradiation (p = 0.003). The
      relationship between this increase and the loss of salivary gland function is not
      yet clear.

PMID- 10391496
TI  - Inhibitory effects of adrenaline on the release of noradrenaline from sympathetic
      nerves in human dental pulp.
AB  - The effects of adrenaline on the release of noradrenaline from sympathetic nerves
      in human dental pulp in vitro were examined. Sympathetic nerves were stimulated
      at 5 Hz for 100 sec following incubation of pulp with [3H]noradrenaline (0.6
      micromol/l). In the presence of desipramine (DMI, 0.3 micromol/l), adrenaline
      (0.1 and 1.0 micromol/l) inhibited the release of [3H]noradrenaline, an effect
      which was inhibited by the alpha2-adrenoceptor antagonist rauwolscine (0.1
      micromol/l) and by the alpha2-adrenoceptor agonist UK 14,304 (0.1 micromol/l).
      The release of [3H]noradrenaline was unaffected by adrenaline (0.001 and 0.01
      micromol/l) in the presence of DMI and DMI plus rauwolscine. Although presynaptic
      inhibitory alpha2- and facilitatory beta-adrenoceptors are present on sympathetic
      nerves in human dental pulp, these results imply that adrenaline activates only
      the inhibitory alpha2-receptors.

PMID- 10391497
TI  - Mandibular movements in response to electrical stimulation of superficial and
      deep parts of the human masseter muscle at different jaw positions.
AB  - Anatomical and electromyographical evidence suggests a compartmentalized function
      of the human jaw-closing muscles during both static and dynamic motor tasks.
      However, the voluntary nature of these tasks hampers unequivocal interpretation
      of this evidence, because it is impossible to activate voluntarily a single part
      of a muscle exclusively. Activation of discrete, localized regions can be
      accomplished with electrical stimulation. A previous study confirmed a functional
      subdivision of the temporalis muscle into at least three parts. Here, differences
      in the direction of the lower incisal-point (IP) movement in response to
      electrical stimulation of four different parts of the masseter muscle were
      examined in five healthy men. The deep masseter muscle and the anterior, middle,
      and posterior parts of the superficial masseter muscle were stimulated with
      monopolar wire electrodes in four different jaw positions (resting position; 50%
      maximum mouth opening; and 10-mm right and left lateral excursions, both with
      respect to resting position). Electrode-insertion depth was measured from
      magnetic resonance images. Movement responses to stimulation were recorded with
      the OKAS-3D jaw-movement analysis system. The variation in the direction of the
      IP movement in response to stimulation of parts of the masseter was partly
      explained by the effects of stimulus location and jaw position. The response to
      stimulation of the deep masseter was mainly laterovertically directed, whereas
      the response to stimulation of each of the superficial parts had a mainly
      anterovertical direction, the responses being most pronounced with the mandible
      in its resting position. These results provide further evidence for a functional
      subdivision of the masseter into a superficial part and a deep part, but not for
      a further subdivision of the superficial part into an anterior, middle, and
      posterior part.

PMID- 10391498
TI  - Detection of specific antibodies against human cultured chondrosarcoma (HCS-2/8)
      and osteosarcoma (Saos-2) cells in the serum of patients with osteoarthritis of
      the temporomandibular joint.
AB  - To find specific humoral antibodies in sera from patients with temporomandibular
      joint (TMJ) osteoarthritis (OA), an immortal human chondrocyte (HCS-2/8) and
      osteoblast (Saos-2) cell line derived from a chondrosarcoma and an osteosarcoma,
      respectively, were used as source proteins of human antigens. Patients with
      chronically painful TMJ OA (n = 18) but no other joints symptoms were selected
      from a consecutive series of patients with temperomandibular disorders and sex
      matched asymptomatic controls (n = 8) were also recruited. Cellular proteins of
      the HCS-2/8 and Saos-2 cells were subjected to Western blotting with the OA and
      control sera as probes. Band-recognition frequency and the peak optical density
      of the band were compared between groups by chi2 and t-tests. OA sera recognized
      various bands for the chondrocytes, and one of these (47-kDa) was specific for
      the OA sera. In two OA patients whose treatment outcome was less favorable, the
      reactivity against the 47-kDa protein was relatively high. In addition, the OA
      sera clearly cross-reacted with recombinant HSP47. Based on these findings, an
      autoimmune reaction against chondrocytes could be one of the exaggerating and/or
      perpetuating mechanisms in the pathophysiology of osteoarthritic TMJs, and the
      humoral antibody titre against the HSP47-like protein derived from the
      chondrocytes could be one of the possible markers for the prognosis of the joint
      pathology.

PMID- 10391500
TI  - Response of erupting human premolars to force application.
AB  - To test the hypothesis that human tooth eruption requires a critical time period
      during which no force is applied to the erupting tooth, the eruption of a
      maxillary second premolar in the prefunctional stage was recorded during the
      afternoon or evening hours in eight children, using an optical device based on
      the principle of Moire magnification, while intermittent loads of 300-400 mN were
      applied to the teeth. When a tooth was erupting actively, light force
      applications either had no discernible effect or decreased the eruption rate for
      2 min or less. When a tooth was intruding spontaneously rather than erupting, a
      varied response was observed, but the rate of intrusion never increased after
      force application. Often intrusion showed or halted, and especially during the
      evening, eruption was likely to occur after a force application during an initial
      period of intrusion. The conclusion is that, although light force applications
      significantly displace an erupting premolar, they have little or no effect on net
      eruption, and that a critical time period without force application is not
      necessary for eruption to occur.

PMID- 10391499
TI  - Immunofluorescence detection of cadherins in mouse tooth germs during root
      development.
AB  - The distribution of two cell-adhesion molecules, E- and P-cadherin, was studied
      in relation to morphological changes in Hertwig's epithelial root sheath Before
      root dentinogenesis had started, the root sheath expressed both cadherins. As
      dentinogenesis proceeded, the sheath fragmented and lost P-cadherin rapidly and E
      cadherin slowly, whereas the intact sheath at the apical end continued to express
      both. These results suggest that the two cadherins play a part in root as well as
      in crown development, and indicate that the decrease in the amount of these
      molecules and the fragmentation of the epithelial root sheath are interrelated.

PMID- 10391501
TI  - Finite-element morphometry of soft tissues in prepubertal Korean and European
      Americans with Class III malocclusions.
AB  - The purpose was to test the hypothesis that soft-tissue morphology differs
      consistently in people of diverse ethnic origin exhibiting Class III
      malocclusions. Lateral cephalographs of 70 Korean and 71 European-American
      children aged between 5 and 11 years were traced and 12 homologous, soft-tissue
      landmarks digitized. The total sample was subdivided into seven age- and sex
      matched groups, and Procrustes superimposition was used to generate average
      geometries scaled to an equivalent size. Statistical differences were tested by
      ANOVA. Graphical analysis using a colour-coded finite-element (FEM) program was
      used to localize differences in morphology. Procrustes' results indicated that
      the overall mean Korean and European-American soft-tissue configurations differed
      statistically (p<0.001), and this difference was also true in all seven age
      groups tested (p<0.001). On comparing mean Korean and European-American Class III
      soft-tissue configurations for local size change, FEM analysis revealed that
      whereas the Korean mental regions generally were smaller (approx. 43% on
      average), local increases in size were apparent for the lower lip (approx. 29% on
      average). For shape change, the mean Korean and European-American soft-tissue
      configurations were fairly isotropic except in the region of the columella, lower
      lip and the anterior part of the mental region. Features of the soft-tissue
      integument in individuals of diverse ethnic origins appear to be associated with
      the underlying skeletal Class III morphology.

PMID- 10391502
TI  - The effect of extracellular polysaccharides from Streptococcus mutans on the
      bactericidal activity of human neutrophils.
AB  - Extracellular polysaccharides (PS) synthesized by oral bacteria constitute one of
      their major virulence factors. The PS, synthesized from sucrose, facilitate
      adhesion and colonization by bacteria to tooth surfaces. The study was designed
      to test the effect of in situ production of extracellular PS by Streptococcus
      mutans on the bactericidal activity of human neutrophils. These effects were
      tested on bacteria pre-exposed to sucrose (PS-positive Strep. mutans) and
      compared to bacteria not exposed to sucrose (PS-negative Strep. mutans). The
      interactions between neutrophils and Strep. mutans were tested in suspension and
      on bacteria in an experimental model of dental plaque. Viability of Strep. mutans
      was measured by [3H]-thymidine incorporation into the bacteria. Degranulation of
      neutrophils was evaluated by the release of lysozyme, and the production of
      reactive oxygen products was measured by chemiluminescence. When neutrophils were
      incubated with suspended bacteria, the viability of PS-negative Strep. mutans was
      20% of that of bacteria not incubated with neutrophils (control), while the
      viability of PS-positive Strep. mutans was 40% of the control. In the
      experimental dental-plaque model, 50% of the PS-negative Strep. mutans were
      killed by neutrophils while the viability of PS-positive Strep. mutans was not
      different than of the control. Degranulation of neutrophils was not affected by
      the presence of extracellular PS of Strep. mutans. Artificial stimulation of
      neutrophils with phorbol myristate acetate also did not enhance the bactericidal
      effect of neutrophils on PS-positive Strep. mutans. However, PS-positive Strep.
      mutans elicited oxygen-reactive products from neutrophils, 2-fold less than with
      PS-negative Strep. mutans. The results indicate that in situ production of
      bacterial extracellular polysaccharides might be a major virulence factor of
      Strep. mutans, enabling PS-positive Strep. mutans in the dental-plaque biofilm to
      evade killing by human neutrophils.

PMID- 10391503
TI  - The use of polymerase chain reaction for determination of virulence factors of
      Escherichia coli strains isolated from pigs in Poland.
AB  - E. coli strains isolated from pigs with postweaning diarrhea or edema disease
      were tested by phenotypic and genotypic methods for the presence of virulence
      antigens and genes, respectively. The slide agglutination and ELISA analyses were
      used for determination of F4, F5, F6, F17, and F41 fimbriae whereas the
      prevalence of fimbrial fedA and toxin eltI, estI, estII, stx1, stx2 and stx2e
      genes were recorded by the means of PCR. Only F4 antigen (ac variant) was found
      in strains of the serogroup O149:K91 isolated from pigs with diarrhea. PCR
      analyses showed that the fedA gene encoding F18 fimbriae was present in 61.9% of
      strains isolated from pigs with diarrhea and in 84.2% of strains isolated from
      pigs with edema disease. The eltI genes encoding heat-labile toxin I (LTI) were
      present only in 9 out of 21 strains recovered from pigs with diarrhea. Shiga
      toxin 2 variant (stx2e) genes were found in six isolates from edema disease and
      also in one strain from diarrhea. The PCR test used in the study was a sensitive
      and valuable method for determination of virulence factors of E. coli strains.

PMID- 10391504
TI  - Isolation and haemolytic activity of Aeromonas species from domestic dogs and
      cats.
AB  - Rectal swabs from 120 domestic dogs and 15 domestic cats were examined for
      Aeromonas species using alkaline peptone water (pH 8.6) as the enrichment medium
      and blood agar containing 15 mg/l ampicillin as the plating medium. Aeromonads
      were isolated from 13 (10.8%) dogs and from 1 (6.7%) cat. Of the 14 aeromonads
      isolated in the present study only 9 were available for speciation and testing in
      the haemolysin assay. Of these 5 were A. sobria (including one from a cat), 2
      were A. hydrophila and 2 were A. caviae. Six were positive in the haemolysin
      assay; 4 A. sobria (one from a cat) and 2 A. hydrophila. The presence of
      haemolysin producing-Aeromonas species in the faeces of domestic dogs and cats
      may pose a public health problem for humans who come into contact with such
      animals.

PMID- 10391505
TI  - Study on the use of an enzyme-linked immunosorbent assay in determining human
      antibodies to diphtheria toxin as compared with a reference toxin neutralization
      assay.
AB  - Serum samples from 156 Greek persons were assessed by an IgG-specific enzyme
      linked immunosorbent assay (ELISA) and a reference tissue culture toxin
      neutralization (TN) assay for the quantitation of diphtheria toxin antibodies. By
      the reference method, 7.7% of the persons were susceptible to diphtheria
      (antitoxin < 0.01 IU/ml), 28.8% had basic protection (antitoxin 0.01-0.09 IU/ml)
      and 63.5% were fully protective (antitoxin > or = 0.1 IU/ ml), while the
      corresponding figures were 17.9, 36.5 and 45.5% when they were tested by the
      immunoassay. None of the samples been susceptible by the TN assay were found to
      have some protection when tested by ELISA. However, three (6.7%) of the 45
      samples showing a basic protection with TN, were fully protective when titrated
      by the immunoassay. In addition, 31 (31.3%) of the 99 samples been fully
      protective by the bioassay, were found to be either basically protective or
      susceptible by means of the ELISA. Overall, validity features of the immunoassay
      were: sensitivity 68.7%, specificity 94.7%, positive predictive value 95.8% and
      negative predictive value 63.5%. The ELISA tested in our study could be used to
      determine diphtheria antitoxin in individuals needed a booster immunization
      (susceptible or basic protective samples), although it might falsely include in
      the above categories samples that are within the fully protective levels of
      antibodies.

PMID- 10391507
TI  - Periodic reappearance of bovine herpesvirus type 4 DNA in the sera of naturally
      and experimentally infected rabbits and calves.
AB  - A BHV-4 specific nested PCR was used for the detection of viral DNA in serum
      samples of rabbits and calves. All animals were followed up for 62 days, blood
      samples were taken for PCR studies every second day. Maternal infection of calves
      resulted in the repeated regular reappearance (10-14 days) of the virus (DNA) in
      serum samples. When PCR positive five-day-old calves were infected with tissue
      culture adapted virus, the reappearance of the DNA in the serum was shown to be
      irregular, nevertheless, DNA peaks reappeared during the whole observation
      period. A PCR negative calf infected at the age of 60 days was found to possess
      viraemia until p.i.d. 32. In rabbits treated intravenously with BHV-4 the
      inoculum or a primary viraemia was detected at p.i.d. 2-3 and p.i.d. 14-16.
      Published data on human herpesviruses suggest, that the target cells might be a
      pluripotent stem cell population of the bone marrow and differentiated virus
      infected cells destroyed by the immune system might be the source of viral DNA
      detected in the serum. Frequency of DNA reappearance was depended on the age of
      the infected animals but not on the inoculated amount of BHV-4. The described
      phenomenon might be part of BHV-4 infection of very young animals.

PMID- 10391506
TI  - Detection of equine arteritis virus in semen by reverse transcriptase polymerase
      chain reaction-ELISA.
AB  - The reverse transcriptase polymerase chain reaction (RT-PCR) assay was used to
      detect Equine Arteritis Virus (EAV) in the semen of 88 horses and 2 donkeys, with
      neutralising antibodies against EAV, on the basis of the amplification of a 279
      bp long fragment located in the viral polymerase gene. The RT-PCR assay revealed
      the virus at 4 TCID50/ml in cell culture and showed a greater sensitivity (54.4%)
      than cell culture isolation (33.3%). Moreover, the two samples of donkey semen
      were found positive. The cDNAs obtained from 14 samples of horse and 2 of donkey
      semen were sequenced. Comparing the sequence of reference strain Bucyrus, the
      analysed samples were 78-100% identical and showed a 84-97% nucleotide identity
      with Bucyrus isolate. The results demonstrate high levels of genomic
      heterogeneity among the extracted RNAs, but inside the fragment amplified a well
      preserved region of 24 bp was found with only three mismatches in some samples,
      suggesting that this could be ideal as a probe for RT-PCR-ELISA. The RT-PCR-ELISA
      assay using the EAV 7 and 8 primer set, has proved to be sensitive, specific and
      above all directly applicable to semen. Additionally, the short time needed for
      the overall procedure makes this method suitable for diagnostic purposes.

PMID- 10391508
TI  - Studies on the pathogenicity of bovine herpesvirus type 5 in sheep.
AB  - Four Merino lambs were intranasally inoculated with bovine herpesvirus type 5
      (BHV-5) reference strain N569. Two lambs were mock-inoculated as negative
      controls. The virus-inoculated animals developed apathy, inappetence, rhinitis,
      nasal, ocular and genital discharge, slight diarrhea and neurological disorders,
      like tremor and salivation. BHV-5 was isolated from the nasal discharge in two of
      the animals, while the polymerase chain reaction (PCR) detected the virus in all
      the infected lambs. Two lambs died on post infection day (PID) 13, while the
      other two infected animals were euthanized on PID 15 and 30. Gross pathological
      changes were not observed, however, histopathological examinations revealed
      diffuse nonsuppurative meningo-encephalitis in all infected animals. Viral
      antigen was detected by immunohistochemistry and viral nucleic acid was revealed
      by in situ hybridization in the brain of the two lambs, which died on PID 13. The
      virus was demonstrated by virus isolation and by PCR from different organs of all
      the infected animals. Slight rise of antibodies was observed in the infected
      animals from PID 15. The results show that BHV-5 is able to cross the species
      barrier and may establish infection in sheep.

PMID- 10391509
TI  - Why screen newborns for cocaine: service patterns and social outcomes at age one
      year.
AB  - OBJECTIVE: To compare baseline characteristics, service provision, and child
      placement for infants exposed to cocaine in utero based on postnatal screening
      results. METHODS: We studied a retrospective cohort of 40 consecutive drug
      exposed, but seemingly healthy term infants who underwent urine drug screening in
      the newborn nursery of a community hospital. Using clinical and service agency
      data, two cocaine-exposed cohorts were compared (a) screen-positive at birth (n =
      22) versus (b) screen-negative at birth (n = 18). RESULTS: Both cocaine-exposed
      groups had similar infant birth weights, levels of paternal involvement, maternal
      ages, gravidity, parity, and lengths of gestation. Mothers in both groups had
      similar histories of prostitution, poor home environment, drug use, and prenatal
      drug rehabilitation. Mothers of screen-positive infants were more likely than
      mothers of screen-negative infants to have other children in foster care (27% vs.
      6%, p = .07), to have experienced previous interventions by child protective
      services (CPS) (55% vs. 17%, p < .01), to have had no prenatal care (32% vs. 6%,
      p = .09), and fewer prenatal visits (4.7 vs. 8.6, p = .02). Compared to screen
      negative infants, more screen-positive infants were referred to a high-risk
      infant tracking program (91% vs. 6%), referred to CPS (100% vs. 33%), placed
      outside the mother's home (50% vs. 22%), and had their mothers referred to drug
      rehabilitation (36% vs. 11%), (p < .01 for each). By 1 year of age, support
      services differed little between exposed cohorts. However, 6 of 22 screen
      positive infants were in foster care and 3 were placed for adoption, while only 1
      of the 18 screen-negative infants was in foster care and only 1 had been placed
      for adoption. There were no services available in this community to provide
      coordinated or comprehensive services or drug treatment specific to the needs of
      drug using mothers and drug exposed infants. CONCLUSIONS: Despite similarities
      between cocaine-exposed infants cared for in a normal newborn setting (with and
      without positive urine drug screens at birth), differences in referral services
      were noted. More striking than these differences was that services for families
      with drug-exposed infants are inadequate to even meet the needs of those families
      in our setting deemed to be at highest risk. Neonatal drug screening needs to be
      paired with effective services.

PMID- 10391510
TI  - Funding realities: child abuse diagnostic evaluations in the health care setting.
AB  - OBJECTIVE: This study examines staffing, funding sources, reimbursement, and
      financing of medically-oriented child protection teams. METHOD: A 16-item
      questionnaire on the composition, size, and services of the team, program costs,
      revenue sources, reimbursement rates, and perceptions of funding stability was
      mailed to a sample of 118 medically-oriented child protection teams. RESULTS:
      After excluding 10 programs, an overall response rate of 68% was obtained. Teams
      varied in configuration, services, charges, and funding. Over 50% identified
      funding as being important, yet, demonstrated varying levels of awareness of
      budget and reimbursement issues. Many generally relied on patient care
      reimbursement from health care and government payers. Some programs seemed to be
      doing well financially while others were struggling. Approximately one-third of
      the respondents indicated that funding was unstable. CONCLUSIONS: Many programs
      are innovatively knitting together patch-works of funding and support to serve
      children and families in need. Team leaders should increase their knowledge of
      fiscal issues in order to be effective advocates at the institutional level for
      continued team support. A potential way of accomplishing this would be to utilize
      the existing structure of a national professional association and its national
      meeting to provide a forum for relatively successful programs to showcase their
      "ideal models" of team financing.

PMID- 10391511
TI  - Worker judgements of seriousness about and reporting of suspected child
      maltreatment.
AB  - OBJECTIVE: This study examined the relationship between judgements about the
      seriousness of incidents of suspected maltreatment and the reporting of those
      incidents. METHOD: Eighty-six graduate social work students were given 12
      vignettes depicting problematic parental behaviors. Students were asked to rate
      each vignette according to how serious they perceived the parental behavior to be
      with "1" being "not serious" and "7" being "very serious." Students were also
      asked to indicate whether or not they would report the incident to child
      protective services. Data were analyzed by case and by individual. RESULTS: All
      12 vignettes were serious with mean incident ratings ranging from a low of 6.0 to
      a high of 6.9. However, not all incidents were reported with similar frequency.
      Only incidents that were collectively very serious were reported by nearly all
      respondents (Spearman rank order correlation coefficient = .94). Among worker
      characteristics, the worker's judgement of seriousness was the only predictor of
      reporting. CONCLUSION: The results suggest that beginning human service workers
      are unsure of their legal responsibility to report suspected maltreatment. The
      results also point to a need for closer collaboration between mandated reporters
      and child protective services.

PMID- 10391512
TI  - Prevalence and correlates of physical abuse in Hong Kong Chinese adolescents: a
      population-based approach.
AB  - OBJECTIVE: The objectives were to estimate the prevalence and correlates of
      physical abuse-related outcomes in the family setting in Hong Kong's adolescent
      population. METHOD: A cross-sectional study design was used. A randomly selected
      sample of 3,355 secondary school students in Kwai Tsing District of Hong Kong was
      surveyed. The response rate was 98%. RESULTS: The prevalence rates of corporal
      punishment, being beaten by parents for no apparent reason, being beaten to
      injury by family members in the past 3 months and any one of the above three were
      4.9% (95% CI, 4.2% to 5.6%), 2.0% (95% CI, 1.5% to 2.5%), 1.1% (95% CI, .98% to
      1.2%) and 6.6% (95% CI, 5.7% to 7.5%), respectively. Students who had experienced
      the above physical abuse-related outcomes were at a significant disadvantage for
      a wide range of morbidity indicators, including self-perceived bad health,
      anxiety and stress, somatic illnesses (such as asthma and epigastric pain),
      injuries and accidents, and hospitalization. They were more likely to have poor
      familial relations and coping skills, and to take up habits which potentially put
      their health at risk, such as smoking, alcohol consumption, and fighting with
      others. CONCLUSIONS: Our prevalence estimates of physical abuse in the family
      setting for a student population in Hong Kong is an improvement over previous
      local estimates of physical abuse occurrence, which were mainly based on case
      notifications and clinical samples. The results also show that the abused
      adolescents are growing up in an environment filled with physical, psychological,
      and familial adversities.

PMID- 10391513
TI  - Factors related to the reporting of childhood rape.
AB  - OBJECTIVE: The aim of this study was to examine whether there would be
      differences in reported versus unreported cases of childhood rape on incident
      characteristics including life threat, physical injury, identity of the
      perpetrator, frequency of assault(s), and rates of posttraumatic stress disorder
      or major depression. METHOD: In a telephone interview, a national probability
      sample of 4,008 (weighted) adult women was screened for a history of completed
      rape in childhood. Respondents were also assessed for DSM-III-R diagnoses of
      major depressive episode and/or posttraumatic stress disorder (PTSD). Three
      hundred forty-one (8.5%) of these women were victims of at least one rape prior
      to the age of 18, for a total of 437 completed rapes. Of these 437 rape
      incidents, 52 (11.9%) were reported to the police or other authorities. RESULTS:
      Significant differences were obtained between reported versus nonreported cases
      on incident characteristics, including life threat, physical injury, identity of
      the perpetrator. Reported cases were more likely to involve life threat and/or
      physical injury, and were more likely to have been committed by a stranger than
      nonreported cases. No significant differences between reported and nonreported
      cases were found concerning whether the rape involved a single incident versus
      series of events, or rates of PTSD or major depression. CONCLUSIONS: Findings
      suggest that different characteristics are associated with reported versus
      unreported cases of childhood rape. Since few cases of childhood rape are
      actually reported to the authorities, it appears that we may be missing valuable
      information. Implications for research and clinical intervention are discussed.

PMID- 10391514
TI  - The variability of practice in interviews used by professionals to investigate
      child sexual abuse.
AB  - OBJECTIVE: The study aimed to examine: (1) the variability of interview practice
      among professionals who interview children to investigate suspected sexual abuse;
      (2) the relationship between interview practice and respondent characteristics;
      (3) the characteristics of interviewers who used the anatomically correct dolls
      in the course of their interviews. METHOD: Sixty investigatory interviewers
      completed questionnaires focusing on professional background, training, and
      interview practice. RESULTS: Interview practice varied considerably and some
      practices were at odds with the recommendations of the literature. Most of this
      variability was not accounted for by the respondent variables examined. Where
      there was evidence for an association, the interviewers' professional background,
      number of interviews conducted in the previous year, and whether or not they used
      the anatomically correct dolls appeared to influence practice, whereas general
      training and specific training in child sexual abuse had no significant effect.
      Only a minority (36%) used the anatomically correct dolls and none of the
      interviewer characteristics evaluated differentiated them from non doll-users.
      CONCLUSIONS: In this sample interview practices varied considerably and did not
      appear to be influenced by the interviewer's specific or general training.
      Further research is needed to focus on the comparative effectiveness of different
      interview techniques and the comparative effectiveness of different training
      programs in influencing interviewing practice.

PMID- 10391515
TI  - Prevalence and risk factors for childhood sexual abuse in women: national survey
      findings.
AB  - OBJECTIVE: We interviewed a U.S. national sample of women, aged 18 years and
      older to determine the prevalence and characteristics of childhood sexual abuse.
      We also examined which family and background variables were predictive of CSA in
      this sample. METHOD: The study employed a series of detailed descriptive
      questions regarding childhood sexual experiences that were administered in a
      highly structured format by trained female interviewers. CSA prevalence rates
      were calculated using two definitions of CSA, one of which was slightly more
      inclusive. RESULTS: Prevalence rates for the more inclusive CSA definition ranged
      from 21% to 32%, depending on how respondents who provided incomplete information
      about their sexual experiences were classified. The less inclusive CSA definition
      resulted in prevalence rates ranging from 15% to 26%. Additional information
      about the types of abuse experienced, perpetrator characteristics, age at first
      abuse, and physical and affective consequences of the abusive experiences are
      reported. The risk of CSA was related to higher scores on a measure of father's
      rejection, and the interaction between parental drinking status and whether the
      respondent had lived with both parents during childhood. Further analysis of this
      interaction suggests that when respondents reported living with both biological
      parents, they were most at risk for CSA when their father was a nondrinker and
      their mother was a drinker.

PMID- 10391516
TI  - Victimization and diabetes: an exploratory study.

PMID- 10391517
TI  - Children with sexual behavior problems.

PMID- 10391518
TI  - Developmental and etiological characteristics of children with sexual behavior
      problems: treatment implications.
AB  - OBJECTIVE: Baseline data are reported on the demographics, psychological
      adjustment, victimization, and perpetration histories of 127 6- to 12-year-old
      children who have engaged in developmentally unexpected sexual behaviors.
      Information regarding the children's caregivers, and their extended families, is
      also presented. Data were collected during intake of the families into a
      longitudinal treatment outcome study. METHOD: A comprehensive battery of
      psychometric devices and a structured interview were completed with 127 children
      with sexual behavior problems and their primary caregivers at intake to a
      treatment outcome study. RESULTS: More than half of the children engaging in
      developmentally unexpected sexual behaviors had been abused both sexually and
      physically by more than two different perpetrators. One-third of the people who
      had maltreated these children were less than 18 years old. These children had
      acted out against an average of two other children. High levels of distress in
      the children and their caregivers were evident across a number of psychometric
      and historical variables. CONCLUSION: Children with sexual behavior problems
      exhibited a number of functional impairments commonly associated with
      maltreatment, including learning and psychiatric disorders. Their caregivers and
      families manifested several characteristics that deter children's recovery from
      maltreatment, including an impaired attachment between parent and child. The
      scope of the children's problems requires that treatment extend beyond the
      therapist's office to include schools and other agencies or individuals with whom
      the child and families have regular contact.

PMID- 10391519
TI  - Vectorial aspects of iron transfer in human term placenta.

PMID- 10391520
TI  - Methotrexate treatment for retained placental tissue.
AB  - Three cases of placental polyps not responding to conventional medical and
      surgical treatment are presented. In all three cases, hCG in serum was negative
      but despite this a single injection of methotrexate successfully treated the
      condition. It is suggested that methotrexate acts not only on dividing
      trophoblastic cells but also has other effects.

PMID- 10391521
TI  - Sonographic measurement of the umbilical cord and fetal anthropometric
      parameters.
AB  - OBJECTIVE: To determine reference ranges for the diameter and the cross-sectional
      area of the umbilical cord during pregnancy and to determine if umbilical cord
      morphometry is related to fetal size. METHODS: A prospective cross-sectional
      study was designed to assess the sonographic cross-sectional diameter and area of
      the umbilical cord. The sonographic umbilical cord measurements were obtained in
      a plane adjacent to the insertion of the cord into the fetal abdomen. Nomograms
      for the umbilical cord diameter and area were computed. Fetal biometry included:
      biparietal diameter, abdominal circumference, and femur length. Polynomial
      regression analysis was conducted. RESULTS: Five hundred and fifty seven patients
      were included into the study. The regression equation for the umbilical cord
      diameter (y) according to gestational age (x) was y=-10.0563+1.4265x+0.0194x2 and
      for the umbilical cord area (y') was y'=91.6-3.3x+0.03x2-0.00007x3. A significant
      relationship was found between umbilical cord measurements and fetal
      anthropometric parameters. CONCLUSION: Reference ranges for umbilical cord
      diameter and area have been generated. The sonographic diameter and cross
      sectional area of the umbilical cord increase as a function of gestational age
      and both diameter and area correlate with fetal size.

PMID- 10391522
TI  - Obstetrical outcome of pregnancy in patients with systemic Lupus erythematosus. A
      study of 60 cases.
AB  - OBJECTIVE: To analyze the course of maternal diseases and the outcome of
      pregnancy in patients with systemic Lupus Erythematosus (SLE). STUDY DESIGN:
      During a period of 11 years we prospectively followed 60 pregnancies in 46 SLE
      patients in a tertiary care center in Barcelona (Spain). The management protocol
      included: (1) planning of conception when disease was inactive; (2) frequent
      follow-up visits by an internist-obstetrician team; (3) use of sequential
      ultrasonographic, Doppler and fetal echocardiographic examinations; (4) serial
      evaluations of maternal immunological condition; and (5) low dose aspirin from 1
      month before attempting conception and throughout pregnancy was added in women
      with antiphospholipid antibodies. From 1985 until 1994 prednisone prophylaxis was
      used in all lupus patients during the last month of pregnancy and during the
      first month of the puerperium; from 1995 onwards this regime was abandoned.
      RESULTS: The mean (S.D.) age of patients was 28.6 (4.8) years (range 20 to 42)
      and the mean (S.D.) previous duration of SLE was 6.25 (4.8) years (range 0 to
      17). SLE was diagnosed during the pregnancy in two cases (3.3%) and the disease
      was active at conception in four cases (6.7%); at that time nine patients (15%)
      were taking prednisone. Antiphospholipid antibodies were positive in 16 patients
      (30.4%) and there were 10 (16.7%) pregnancies in patients having lupus
      nephropathy. There were three first-trimester miscarriages (5%) and four (6.7%)
      voluntary abortions. Obstetric complications in the remaining 53 pregnancies
      included: preterm delivery, 11 cases (20.8%); intrauterine growth retardation,
      five cases (9.4%); hypertension, 10 patients (18.9%), five of them fulfilling the
      criteria of preeclampsia; premature rupture of membranes, four patients (7.5%);
      finally, 13 neonates had a birthweight lower than 2500 g. There were 15 lupus
      flares (28.3%), giving a flare rate of 0.044 per patient/month. There were five
      neonatal deaths (perinatal mortality rate, 94 per thousand): one because of
      complete heart block, three due to severe hyaline membrane disease resulting from
      extreme prematurity and one intrauterine death in a patient having the Leiden
      mutation. CONCLUSION: Pregnancy in patients with SLE should not be regarded as an
      unacceptable high-risk condition for the mother or her baby provided that
      conception is accurately planned and patients are managed according to a careful
      multidisciplinary treatment schedule.

PMID- 10391523
TI  - Small for gestational age infant in association with maternal prothrombin gene
      variant (nt 20210A).
AB  - Most of disproportionate infants born small for gestational age (SGA) have an
      history of placental dysfunction with no explained cause. We report a case of an
      unexplained SGA infant with placental infarctions and thrombosis. Maternal
      thrombophilic disorder tests revealed that the patient was heterozygous for the
      A20210 prothrombin gene variant a newly identified thrombotic risk factor. It may
      be suggest that prothrombin gene variant, as factor V Leiden, could be a genetic
      risk factor for placental insufficiency.

PMID- 10391524
TI  - Fetal lung maturity in pregnancies complicated by insulin-dependent and
      gestational diabetes: a matched cohort study.
AB  - OBJECTIVE: To study fetal lung maturity (FLM) as determined by amniotic fluid
      (AF) tests in diabetic pregnancies (DP) under euglycemic metabolic control, in
      comparison with matched controls (C). PATIENTS AND METHODS: From 514 consecutive
      pregnancies where amniocentesis was performed for FLM assessment, we selected 45
      glycemic controlled DP. Nineteen DP were Type I (IDDM) and 26 pregnancies were
      diagnosed Type III (GDM). Cases were matched to C by therapy with
      corticosteroids, gestational age at amniocentesis, pregnancy complications other
      than diabetes and gender. FLM was determined by the shake test and lamellar
      bodies (LB) count, lecithin/sphingomyelin (L/S) ratio (planimetric and
      stechiometric) and phosphatidylglycerol presence (PG). DP were further sub
      divided according to gestational age period at amniocentesis, type of diabetes,
      associated therapy and fetal malformations. RESULTS: RDS (n=2) and neonatal wet
      lung (n=5) were diagnosed in neonates from diabetic mothers. We found no
      statistical difference when comparing FLM indices between DP and C groups: shake
      test 3.1:1+/-1.2 vs. 2.7:1+/-1.2, P<0.40; planimetric L/S 3.4+/-1.4 vs. 3.1+/
      2.0, P<0.27; stechiometric L/S 8.2+/-7.4 vs. 7.1+/-6.1, P<0.54; percentage of PG
      positivity 57% vs. 46%, P<0.13; lamellar bodies count (X10(3)/microl) 42.8+/-36.9
      vs. 41.5+/-30.4, P<0.72. No differences were found between DP and controls for
      subgroups according to gestational age, type of Diabetes (IDDM or GDM),
      congenital lesions and associated therapy. CONCLUSIONS: In euglycemic,
      metabolically controlled diabetic patients FLM is not delayed, however an
      increased risk for neonatal wet lung should be considered.

PMID- 10391525
TI  - Neonatal outcome of inborn and transported very-low-birth-weight infants:
      relevance of perinatal factors.
AB  - OBJECTIVE: To compare the neonatal outcome (survival, intraventricular hemorrhage
      and bronchopulmonary dysplasia) of inborn and outborn very-low-birth-weight
      infants accounting for sociodemographic, obstetric and perinatal variables. STUDY
      DESIGN: Ninety-one premature infants with birth weights of 750-1250 g delivered
      between 1990 and 1994 in a hospital providing neonatal intensive care were
      compared with 76 premature babies delivered in a referring hospital. In the
      statistical analysis, variables with a statistically significant association with
      the outcome variables and dissimilar distributions in the two hospitals were
      identified and entered together with the hospital of birth as explanatory
      variables in a logistic regression. RESULTS: No statistically significant
      differences between the outcome variables of the two populations examined were
      observed, whether before or after accounting for the covariates. The odds ratios
      (outborns relative to inborns) were 1.18 for mortality, 1.25 for bronchopulmonary
      dysplasia and 1.53 for severe intraventricular hemorrhage. In the multivariate
      analyses, respiratory distress syndrome was significantly associated with
      mortality; both low birth weight and the presence of respiratory distress
      syndrome were associated with the development of bronchopulmonary dysplasia; the
      evolvement of severe intraventricular hemorrhage was associated with respiratory
      distress syndrome, initial low Apgar score, advanced multiparity and delivery at
      the 28-29th week compared to the 23rd-27th week. Antenatal steroid administration
      had a protective effect. CONCLUSION: Our results concur with the notion that a
      tertiary center is the optimal location for delivery of the high risk neonate.
      Improvement in medical and nursing care prenatally and at delivery and
      transportation, including frequent administration of antenatal steroids and
      earlier administration of surfactant prior to transportation, may minimize the
      disadvantage of delivery in a referring hospital.

PMID- 10391526
TI  - Measurement of sacroiliac joint stiffness in peripartum pelvic pain patients with
      Doppler imaging of vibrations (DIV).
AB  - OBJECTIVES: The research question of the present study was: are sacroiliac joint
      stiffness levels of peripartum pelvic pain patients different from those of
      healthy subjects? STUDY DESIGN: A cross-sectional comparative sacroiliac joint
      stiffness analysis of peripartum pelvic pain patients with healthy subjects. In
      previous studies we introduced a new technique, Doppler imaging of vibrations
      (DIV), to assess sacroiliac joint stiffness using colour Doppler imaging and
      vibrations. The measurements were performed on a group of peripartum pelvic pain
      patients (n=56) and on a control group (n=52). The differences in sacroiliac
      joint stiffness between the patient group and the control group were tested
      statistically by means of the Wilcoxon's two sample test, the chi-square test and
      Student's t-tests. RESULTS: Both patients and controls displayed stiff as well as
      unstiff joints with no significant difference. There was a significant difference
      between the groups with regard to the relative difference of sacroiliac joint
      stiffness between left and right. CONCLUSIONS: A diagnostic tool which can
      possibly be developed in the future could demonstrate an objective finding among
      women with peripartum pelvic pain. DIV is easy to apply and non-invasive.
      Asymmetric stiffness of the sacroiliac joints seems to be more directly related
      to low back pain and pelvic pain, not the stiffness level of a single sacroiliac
      joint.

PMID- 10391527
TI  - Chorioamniotic membranes constitute a competent barrier to group b streptococcus
      in vitro.
AB  - OBJECTIVE: To study the penetration of group B streptococcus (GBS) through human
      chorioamniotic membranes in vitro. STUDY DESIGN: Chorioamniotic membranes from
      seventeen healthy women were mounted onto glass cylinders and placed in tissue
      culture trays constituting a two-compartment system with a maternal compartment
      internally and a fetal compartment externally. GBS from healthy pregnant women
      and from newborn babies with sepsis were added to the maternal compartment at
      densities from 10(7) to 10(9) colony forming units (cfu) per ml. RESULTS:
      Irrespective of inoculum density, GBS was not recovered from the fetal
      compartment within a 20 h incubation period. By histology, micro-colonies of GBS
      were found on the maternal surface after 8 h, but invasion of the morphologically
      intact membranes was not observed. A five log reduction in cfu occurred in the
      maternal compartment with amnion when GBS were suspended in saline. CONCLUSION:
      In this in vitro model the membranes appear to constitute an effective barrier
      against ascending infection.

PMID- 10391528
TI  - Anticoagulant therapy in pregnancy.
AB  - Anticoagulation during pregnancy should derive benefit from recent advances in
      anticoagulant therapy. Unfractionated heparin is at present the drug of choice
      for most of the indications of thromboprophylaxis as well as for acute venous
      thrombosis during pregnancy but it is likely that, in the near future, low
      molecular weight heparins will supercede this anticoagulant in many indications.
      One particular indication is mechanical heart valves that needs a high degree of
      anticoagulation. The anticoagulant of choice that carries the best efficacy-risk
      ratio in this situation seems to be oral anticoagulants. Pregnant women receiving
      anticoagulation should be considered as high-risk patients that should be managed
      in specialized centres. They are prone to bleeding complications that will mainly
      occur during delivery or in the postpartum period.

PMID- 10391529
TI  - Intake of long chain w3 polyunsaturated fatty acids during pregnancy and the
      influence of levels in the mother on newborn levels.
AB  - OBJECTIVE: To assess the relationship between the free intake of long chain w3
      polyunsaturated fatty acid (w3 LCP) during pregnancy and the levels in the mother
      with the levels in the neonate. DESIGN: Cross-sectional study. SETTING:
      University hospital. SUBJECTS: One hundred and sixty-two mother-neonate pairs
      from normal at-term pregnancies. MAIN OUTCOME MEASURE: Dietetic interview in
      order to assess the w3 LCP intake. w3 LCPs were analyzed by capillary gas
      chromatography in plasma (expressed as percentage and as total amount) and in
      erythrocyte phospholipids (expressed as percentage) from mothers and neonates.
      RESULTS: The w3 LCP intake assessed by the dietetic interview was significantly
      correlated with w3 LCP levels in the plasma of both mothers and neonates. The
      levels of w3 LCPs in mothers and neonates were significantly correlated both in
      plasma fatty acids (expressed both as a percentage and absolute values) and in
      erythrocyte phospholipids (in percentage) (r=0.49-0.22). CONCLUSION: In an
      apparently well-nourished population the w3 LCP levels of the newborn infants are
      clearly influenced by those of their mothers. The higher the levels in mothers,
      the higher those in the neonates. The w3 LCP intake assessed by an interview also
      showed a significant influence, but to a lesser extent.

PMID- 10391531
TI  - Malignant mixed mesodermal tumor arising in a benign cystic teratoma.
AB  - The occurrence of sarcoma in a benign cystic teratoma is very rare. We report the
      first poorly differentiated, malignant mixed mesodermal tumor with a component of
      rhabdomyosarcoma to arise in a benign cystic teratoma of the ovary. The tumor was
      staged as FIGO IC due to capsule invasion. Although combination chemotherapy of
      cisplatin, ifosfamide and mesna, was instituted, the disease took a rapidly
      progressive course. After an unusual metastasis to the scapula was detected, the
      patient deteriorated and died in the forth postoperative month.

PMID- 10391530
TI  - Disparity in prenatal care in Europe. Study group on barriers and incentives to
      prenatal care in Europe.
AB  - OBJECTIVE: The purpose of the study was to compare prenatal care attendance in
      European Union countries, Hungary and Norway. STUDY DESIGN: We analysed live
      births or deliveries from national registers in five countries, national surveys
      in five countries, and regional register or surveys in three countries. RESULTS:
      The frequency of no prenatal care was lower than 0.5% in 10 countries, 0.9% in
      Hungary, 2.1% in Greece and 2.6% in Portugal. Late prenatal care varied from 3.1%
      in Finland to 29.2% in Ireland. Late care among women with parity 4 and more
      varied from 7.7% in Finland to 41.5% in Hungary. Among women under 20 years old,
      late care varied from 11.8% in Finland to 39.5% in Portugal. The median number of
      prenatal visits varied from seven in Greece to 14 in Finland. CONCLUSION:
      Prenatal care attendance varies widely among European countries. Late attendance
      is frequent in many countries.

PMID- 10391532
TI  - Risk factors for pelvic endometriosis in women with pelvic pain or infertility.
      Gruppo Italiano per lo Studio dell' endometriosi.
AB  - OBJECTIVE: The objective of the study was to analyse the relationship between
      selected characteristics and risk of pelvic endometriosis. STUDY DESIGN: Eligible
      for the study were 817 women with primary or secondary infertility or pelvic pain
      requiring laparoscopy. Of these, 393 were included for infertility and 424 for
      pelvic pain. RESULTS: A total of 345 (42.2%) had a diagnosis of endometriosis and
      472 did not have the disease. Multiparous women had endometriosis less frequently
      than nulliparous, the estimated odds ratios (OR) were respectively 0.9 (95%
      confidence interval, CI, 0.5-1.6) and 0.4 (95% CI 0.2-0.7) in women reporting one
      and two or more births. In comparison with women reporting no spontaneous
      abortion, the estimated OR was 0.3 (95% CI 0.2-0.5) in those who reported > or =1
      miscarriage. In comparison with women reporting menstrual cycles lasting > or =25
      days subjects with totally irregular menstrual cycles had a reduced risk of
      endometriosis (OR 0.6, 95% CI 0.3-0.9). No significant association emerged
      between smoking, age at menarche and risk of endometriosis. CONCLUSIONS: this
      study confirms, with a different methodological approach to previously published
      studies, that multiparity, a history of abortion and lifelong irregular menstrual
      pattern decrease the risk of endometriosis in women with pelvic pain and
      infertility.

PMID- 10391533
TI  - Influence of chemotherapy on the expression of p53, HER-2/neu and proliferation
      markers in ovarian cancer.
AB  - OBJECTIVE: Mutated p53 and HER-2/neu play a role in the etiology of ovarian
      cancer. It is important to know whether the expression of these proteins is
      affected by platinum-containing chemotherapy. STUDY DESIGN: Together with the
      cell proliferation markers Ki-67 and PCNA, the expression of p53 and HER-2/neu
      was assessed before and after chemotherapy. Paraffin-embedded tumor sections from
      20 patients with ovarian cancer and four patients with benign disorders of the
      ovaries (controls) were analyzed. The expression of p53 was determined by the
      antibodies DO-1 and BP53-12. In addition to HER-2/neu and PCNA specific
      antibodies, MIB-1 was used to detect Ki-67. RESULTS: The expression of all
      markers was higher in ovarian cancer patients than in non-malignant controls. MIB
      1 showed a significant increase of expression after chemotherapy (P=0.002). HER
      2/neu, p53 and PCNA also showed a clear increase after treatment, but this was
      not statistically significant. HER-2/neu is of prognostic relevance with respect
      to the response to chemotherapy (P=0.005) and survival (P=0.0002). CONCLUSION:
      The different markers tested all increase after chemotherapy, but the differences
      are not statistically significant. Low HER-2/neu expression correlates with good
      outcome at second look.

PMID- 10391534
TI  - Long-term postmenopausal hormone replacement therapy effects on bone mass:
      differences between surgical and spontaneous patients.
AB  - BACKGROUND: Hormone Replacement Therapy (HRT) begun soon after spontaneous
      menopause or oophorectomy minimizes or even reverses the loss of bone that occurs
      normally during those years. The persistence of this HRT protective effect at
      long-term on bone density, however, is not well documented. AIM: to evaluate the
      effects of 5 years of HRT in postmenopausal women on bone mineral density of the
      lumbar spine. SUBJECTS AND METHODS: The 5-year prospective study enrolled 154
      postmenopausal women, of them 136 completed the first year and were considered
      electible to continue the follow-up. These 136 postmenopausal women were
      allocated to two groups according their origin: surgical (n=68) and spontaneous
      (n=68). HRT was prescribed and bone mineral density (BMD) was measured at the
      lumbar spine prior to commencement of therapy, and then yearly for the duration
      of the study. All patients received a continuous therapy with standard dose
      (0.625 mg/day) of conjugated equine estrogen (CEE) or 50 microg/day of 17-beta
      Estradiol in transdermal therapeutic systems (TTS). Subjects who experienced
      natural menopause also received 5 mg/day of medroxyprogesterone acetate
      sequentially added to the last 12 days of estrogen therapy. Treated groups were
      compared with two non-treated control groups (surgical n=77; spontaneous n=53).
      RESULTS: Our data showed that HRT increased the BMD of women who had experienced
      spontaneous menopause. Comparison with a control group revealed that HRT also
      protected against bone loss in women who had undergone surgical menopause.
      CONCLUSION: Long term hormone replacement therapy increases bone mineral density
      in women who have experienced natural menopause, and protects against bone loss
      in surgically postmenopausal women.

PMID- 10391535
TI  - Variations in peripheral blood levels of immunoreactive tumor necrosis factor
      alpha (TNFalpha) throughout the menstrual cycle and secretion of TNFalpha from
      the human corpus luteum.
AB  - OBJECTIVE: Several cytokines have been implicated as important mediators in the
      cyclic processes occurring in the reproductive organs. In the present study the
      peripheral blood concentrations of the cytokines interleukin(IL)-2, IL-6, and
      tumor necrosis factor (TNF) alpha, as well as the secretion of TNFalpha from the
      human corpus luteum were investigated. STUDY DESIGN: The study was undertaken at
      infertility clinics at large teaching hospitals. Eight women with unexplained
      infertility undergoing investigations with measurements of endocrine profiles
      throughout a cycle prior to IVF treatment were included in the study of blood
      concentrations of cytokines. Blood plasma were taken daily or every second day
      from a time 3-4 days before expected LH peak until menstruation. The levels of
      immunoreactive IL-2, IL-6 and TNFalpha were measured by ELISA technique and
      evaluated (repeated measures ANOVA and Scheffes test) in relation to levels on
      the day of the LH surge. To investigate a possible ovarian source of TNFalpha,
      corpus luteum (CL) tissue and cells obtained during the luteal phase from another
      group of women during abdominal surgery for benign uterine diseases, were
      cultured for 24 h to assess (ANOVA and Bonferroni test) the release of TNFalpha.
      RESULTS: There were no significant fluctuations in the levels of IL-2 and IL-6
      throughout the menstrual cycle. The concentration of TNFalpha showed significant
      fluctuations over the menstrual cycle. Compared to the values on the day of the
      LH surge, the concentrations were significantly increased during the late
      follicular phase and during the mid luteal phase. In the early luteal phase the
      levels were significantly decreased. Measurable levels of TNFalpha were found in
      the conditioned media from one out of three CL obtained from the early luteal
      phase, and in all media from CL obtained from mid- and late-luteal phases. Luteal
      cells in culture secreted TNFalpha, and the levels in the media were not
      influenced by the presence of hCG (100 IU/L). The conditioned media of luteal
      cells from late luteal phase contained higher levels than media of cells from
      early luteal phase, with the levels being higher in media of a mixture of all
      luteal cells, and large luteal cells as compared to small luteal cells.
      CONCLUSION: This study demonstrates that there are marked fluctuations of blood
      levels of TNFalpha during the menstrual cycle and that the human CL secretes
      TNFalpha, with indications of higher secretion during late luteal phase as
      compared to early luteal phase.

PMID- 10391536
TI  - The effect of testicular seminoma in semen quality.
AB  - Although male subfertility has been reported in a variety of malignancies, most
      notably testicular carcinoma, the literature that refers to semen quality in
      males with testicular seminoma is very limited. This study was designed to
      evaluate the effect of testicular seminoma in semen quality and especially in its
      three main parameters. Semen specimens from 12 men, aged 24-38 years, with
      testicular seminoma before they underwent orchidectomy and adjuvant radiotherapy
      to the ipsilateral para-aortic and pelvic lymph nodes, and from 60 fertile men,
      aged 24-44 years, were studied. The results support the view that testicular
      seminoma exerts a deleterious effect on spermatogenesis and consequently to the
      three main parameters of the semen. The mechanism though of the deleterious
      effect of seminoma on spermatogenesis remains unclear.

PMID- 10391537
TI  - Abducens nerve palsy complicating pregnancy: a case report.
AB  - We report a case presented at 38 weeks gestation with abducens nerve palsy. No
      specific pathology was found. After reviewing all the previously reported cases,
      hypertension is found to be a common factor in all cases presenting in late
      pregnancy. The clinical course is benign and all resolved after delivery.

PMID- 10391538
TI  - Pregnancy following the laparoscopic bipolar electrocoagulation of polycystic
      ovaries resistant to medicamentous ovulation induction--a case report.
AB  - The case of a primarily infertile patient with polycystic ovaries (PCOS)
      resistant to medicamentous ovulation induction is presented. The preoperative
      condition, laparoscopic ovarian drilling using an original technique of bipolar
      electrocoagulation and consecutive spontaneous pregnancy and delivery are
      described. This case suggests that bipolar forceps with jaws 1 mm wide could be a
      useful instrument for laparoscopic ovarian drilling.

PMID- 10391539
TI  - Pelvic malignant mixed mesodermal tumor of uncertain origin: a case report.
AB  - Extra-uterine, and especially extragenital, malignant mixed mesodermal tumors
      (MMMT) are very rare. A large intrapelvic tumor resected from a 56-year-old woman
      was investigated with morphological and immunohistochemical methods. A large,
      soft and fragile tumor was located in the pelvic space. The tumor showed high
      cellularity and was biphasic; it consisted of an admixture of adenocarcinoma and
      various kinds of sarcomas. The latter were comprised of high-grade endometrial
      stromal sarcoma, pleomorphic sarcoma, and chondrosarcoma. The pleomorphic sarcoma
      showed a storiform pattern. The periodic acid-Schiff-positive eosinophilic
      hyaline droplets and globules in multinucleated giant cells revealed a typical
      ring-like or peripheral staining for alpha-1-antitrypsin and alpha-1
      antichymotrypsin. We considered this case to be pelvic MMMT of uncertain origin,
      heterologous type.

PMID- 10391540
TI  - Relationship between rates and outcomes of operative treatment for lumbar disc
      herniation and spinal stenosis.
AB  - BACKGROUND: Population-based variations in rates of operations for the treatment
      of lumbar disc herniation and spinal stenosis are well known. This variability
      may occur in part because of differences in the threshold at which physicians
      recommend an operation, reflecting uncertainty about the optimum use of an
      operative procedure. To the best of our knowledge, no previous reports have
      indicated whether differences in population-based rates of operative treatment
      are associated with patient outcomes. METHODS: The Maine Lumbar Spine Study is an
      ongoing prospective study of 655 patients who had a herniated lumbar disc or
      spinal stenosis. The patients were enrolled by their physicians, who provided
      baseline demographic and treatment-related data. The patients completed baseline
      and follow-up questionnaires that focused on symptoms, function, satisfaction,
      and quality of life. Small-area variation analysis was used to develop three
      distinct so-called spine service areas in Maine. The outcomes (usually at four
      years; minimum, two years) were compared among these areas, in which a total of
      250 patients had been managed operatively and had answered questionnaires.
      RESULTS: Population-based rates of operative treatment derived from statewide
      data that had been collected over five years in the state of Maine ranged from 38
      percent below to 72 percent above the average rate in the state (a greater than
      fourfold difference). The outcomes for the patients who had been managed by
      surgeons in the lowest-rate area were superior to those for the patients in the
      two higher-rate areas. Seventy-nine percent (fifty-seven) of seventy-two patients
      in the lowest-rate area had marked or complete relief of pain in the lower
      extremity compared with 60 percent (eighteen) of thirty patients in the highest
      rate area. The improvements in the Roland disability score (p < or = 0.01),
      quality of life (p < or = 0.01), and satisfaction (p < or = 0.05) were
      significantly greater among the patients in the lowest-rate area. The patients in
      the higher-rate areas generally had less severe symptoms and findings at baseline
      than those in the lowest-rate area did. CONCLUSIONS: Higher population-based
      rates of elective spinal operations may be associated with inferior outcomes.
      This variability is possibly related to differences in physicians' preferences
      with regard to recommending an operation and in their criteria for the selection
      of patients. Physicians cannot assume that their outcomes will be the same as
      those of others, and therefore they need to evaluate their own results.

PMID- 10391541
TI  - Geographic variations in the rates of operative procedures involving the
      shoulder, including total shoulder replacement, humeral head replacement, and
      rotator cuff repair.
AB  - BACKGROUND: Although geographic variations in the rates of orthopaedic procedures
      have been well documented, considerable controversy remains regarding the factors
      that drive these variations, particularly the role of the availability of
      orthopaedic surgeons. Moreover, little attention has been specifically focused on
      variations in the rates of commonly performed shoulder procedures. METHODS: The
      current study documents state-to-state variations in the rates of total shoulder
      replacement, humeral head replacement, and rotator cuff repair and examines
      factors that might account for these variations. The regional incidences of these
      three procedures were analyzed with use of the Health Care Financing
      Administration Medicare database (MEDPAR, 1992). The rates were age-adjusted, and
      variations were measured with use of high:low ratios, variation coefficients, and
      systematic components of variation. Potential causes of variation were analyzed
      with use of Spearman and partial correlations as well as with Poisson regression.
      RESULTS: Rates for the three procedures that were studied varied from one state
      to another by as much as tenfold. Humeral head replacement had the lowest rate of
      variation according to all three measures. All three procedures were performed
      less often in states that were more densely populated. With the numbers available
      for study, no consistent, significant relationship was found between the density
      of orthopaedists and shoulder surgeons and the rates of any procedure.
      CONCLUSIONS: The striking variations that were noted for these commonly performed
      procedures showed that there is a clear need for well designed clinical research
      to further define the factors that account for the variations and to examine the
      effectiveness and appropriate indications for the procedures.

PMID- 10391542
TI  - Rates of revision knee replacement in Ontario, Canada.
AB  - BACKGROUND: The present study was designed to measure the longevity of knee
      replacements and to assess the determinants of revision knee replacements in
      order to enhance the potential for informed decision-making. METHODS: Data on all
      hospitalizations for knee replacement that occurred in Ontario, Canada, between
      April 1, 1984, and March 31, 1991, were acquired. To calculate the rates of
      revision knee replacement, two algorithms were developed: one distinguished
      primary knee replacements from revision knee replacements, and the second linked
      revision knee replacements to primary knee replacements. The Kaplan-Meier method
      was used to assess survivorship (absence of a revision) for primary knee
      replacement. A proportional-hazards regression model was estimated to assess the
      role of independent variables on the survival of primary knee replacements.
      RESULTS: During the period of the study, 7.0 percent (1301) of 18,530 knee
      replacements were classified as revisions. Significant differences were
      identified between hospitalizations for primary and revision knee replacements in
      terms of the patient and hospital characteristics. Patients who were more than
      fifty-five years old, lived in a rural area, or had a diagnosis of rheumatoid
      arthritis had a significantly (p < 0.05) longer duration before revision than did
      other patients. Primary knee replacements performed in a teaching or specialty
      hospital had a significantly (p < 0.05) shorter duration before revision than did
      those performed in a non-teaching hospital. The long-term rates of revision were
      uniformly low. Estimates of the proportion of knee replacements that would need
      to be revised within seven years ranged from a low of 4.3 percent, with use of
      the algorithm for the longest time to revision, to a high of 8.0 percent, with
      use of the algorithm for the shortest time to revision. CONCLUSIONS: Revision of
      a primary knee replacement was a rare event that depended on a patient's age,
      gender, and place of residence as well as on the hospital where the primary knee
      replacement was performed. Estimates of the rates of revision knee replacement
      after almost seven years ranged from a low of 4.3 percent to a high of 8.0
      percent.

PMID- 10391543
TI  - Excision for the treatment of periarticular ossification of the knee in patients
      who have a traumatic brain injury.
AB  - BACKGROUND: Patients who are comatose after a traumatic brain injury often have
      heterotopic periarticular ossification that can be treated with excision to
      improve the range of motion of the joint. METHODS: Areas of periarticular
      ossification were resected at an average of twenty-three months after recovery
      from a coma in seven knees of five patients who had a traumatic brain injury.
      Before the procedure, all of the knees were fixed in a flexed position that
      ranged from 10 to 40 degrees and they had a painful arc of motion that ranged
      from 20 to 70 degrees of flexion. None of the patients could walk, and some of
      them could barely sit in a wheelchair. At the end of the operation, the arc of
      motion was markedly improved in all of the knees (0 to 130 degrees in three
      knees, 0 to 120 degrees in three, and 10 to 120 degrees in one). In an attempt to
      prevent postoperative loss of motion and recurrence of the ossification,
      continuous passive motion was applied to the involved knee for six weeks before a
      full rehabilitation program was started. The latest follow-up evaluation was at
      an average of thirty-four months (range, twenty-five to sixty months). RESULTS:
      At the time of follow-up, all of the patients could walk and all of the knees
      were pain-free. One knee had an arc of flexion of 0 to 90 degrees; two, an arc of
      10 to 100 degrees; one, an arc of 5 to 110 degrees; two, an arc of 0 to 120
      degrees; and one, an arc of 0 to 130 degrees. Ossification did not recur in any
      of the knees. CONCLUSIONS: Patients with good neuromuscular control had the best
      general functional result. The routine use of a continuous-passive-motion machine
      was associated with no recurrence of ossification, and there was some late loss
      of motion after its use was discontinued.

PMID- 10391544
TI  - Osteonecrosis of the femoral head associated with pregnancy. A preliminary
      report.
AB  - BACKGROUND: Osteonecrosis is usually associated with trauma, use of
      corticosteroids, or alcohol abuse. We investigated the rare association of
      osteonecrosis of the femoral head and pregnancy, and we defined differences
      between the disorder in pregnant women and that in women of childbearing age who
      were not pregnant. The results of treatment with a free vascularized fibular
      graft were evaluated in terms of relief of pain and improvement of the Harris hip
      score after a minimum of two years of follow-up. METHODS: Thirteen women
      (seventeen hips) had the onset of pain in the hip during pregnancy or within the
      first four weeks after delivery, and the pain persisted until a diagnosis of
      osteonecrosis of the femoral head was made on the basis of magnetic resonance
      imaging. No patient had any other risk factor for this disease. Information was
      obtained by means of clinical assessment, a review of the records and
      radiographs, and a telephone survey. Eleven women (fifteen hips) were managed
      with a free vascularized fibular graft, and nine of them (eleven hips) were
      evaluated, with regard to relief of pain and the Harris hip score, at a minimum
      of two years postoperatively. RESULTS: The average age when the pain began was
      31.5 years (range, twenty-five to forty-one years). Eleven of the thirteen women
      were primigravid, and the patients typically first had the pain late in the
      second trimester or in the third trimester of pregnancy. The women tended to have
      a small body frame and a relatively large weight gain during the pregnancy. Eight
      of the thirteen patients had swelling and varicosity of the lower extremities.
      The diagnosis was delayed an average of 10.3 months, with a range of three to
      thirty months. A common misdiagnosis was transient osteoporosis of the hip during
      pregnancy. A correct diagnosis was established for all hips on the basis of the
      finding of a double-density signal on magnetic resonance imaging or evidence of
      progression of the disease on plain radiographs. According the system of Marcus
      et al., the stage at the time of diagnosis ranged from II to V. All women had
      involvement of the left hip, and four had bilateral involvement. Of the eleven
      women (fifteen hips) who were managed with a free vascularized fibular graft,
      nine noted marked or complete relief of the preoperative pain. Two hips in a
      patient who had progressive pain were treated with a total hip arthroplasty. Two
      hips (one patient) were lost to follow-up. The nine patients (eleven hips) who
      were available for follow-up at a minimum of two years had an average improvement
      in the Harris hip score of 24 points. CONCLUSIONS: Occasionally, pain in the hip
      that begins during pregnancy is caused by osteonecrosis of the femoral head. A
      high index of suspicion and use of magnetic resonance imaging may lead to an
      earlier diagnosis and a better prognosis in this population of women. In this
      study, treatment with a free vascularized fibular graft was a useful option with
      which to obviate or postpone the need for total hip arthroplasty.

PMID- 10391545
TI  - Posttraumatic tibia valga in children. A long-term follow-up note.
AB  - BACKGROUND: We reevaluated seven patients who initially had been managed
      nonoperatively because of a progressive valgus deformity that had occurred within
      approximately twelve months after satisfactory healing of a proximal tibial
      metaphyseal fracture sustained at an average age of four years (range, eleven
      months to six years and four months). All seven patients were described in a
      previous report from our institution, published in 1986. In that report,
      spontaneous improvement of the angulation was documented after an average
      duration of follow-up of thirty-nine months and nonoperative treatment of the
      deformity was recommended. METHODS: The patients were followed radiographically
      for an average of fifteen years and three months (range, ten years and four
      months to nineteen years and eleven months) after the injury. The radiographs
      were reviewed to determine the metaphyseal-diaphyseal angle, the mechanical
      tibiofemoral angle, the proximal and distal tibial remodeling angles, the limb
      length discrepancy, and the deviation of the mechanical axis of the limb from the
      center of the knee joint. Knee function was assessed with use of the rating
      system of the Cincinnati Sportsmedicine and Orthopaedic Center, and ankle
      function was assessed with use of the rating system of the American Orthopaedic
      Foot and Ankle Society. RESULTS: Every patient had spontaneous improvement of the
      metaphyseal-diaphyseal and mechanical tibiofemoral angles. Most of the correction
      occurred at the proximal part of the tibia. The mechanical axis of the limb
      remained lateral to the center of the knee joint in every patient, with an
      average deviation of fifteen millimeters (range, three to twenty-four
      millimeters). The affected tibia was longer than the contralateral tibia in every
      patient, with an average limb-length discrepancy of nine millimeters (range,
      three to eighteen millimeters). The knee score on the affected side was excellent
      for five patients and fair for two; one of the patients who had a fair score had
      had a tibial osteotomy at the age of sixteen years because of pain in the lateral
      aspect of the knee that was thought to be due to malalignment. The ankle score on
      the affected side was excellent for three patients and good for four.
      CONCLUSIONS: Spontaneous improvement of the deformity occurred in all patients
      and resulted in a clinically well aligned, asymptomatic limb in most. We believe
      that patients who have posttraumatic tibia valga should be followed through
      skeletal maturity and that operative intervention should be reserved for patients
      who have symptoms secondary to malalignment.

PMID- 10391546
TI  - Treatment of giant-cell tumors of long bones with curettage and bone-grafting.
AB  - BACKGROUND: The use of curettage, phenol, and cement is accepted by most experts
      as the best treatment for giant-cell tumor of bone. The present study was
      performed to evaluate whether equivalent results could be obtained with curettage
      with use of a high-speed burr and reconstruction of the resulting defect with
      autogenous bone graft with or without allograft bone. METHODS: The prospectively
      collected records of patients who had a giant-cell tumor of a long bone were
      reviewed to determine the rate of local recurrence after treatment with curettage
      with use of a high-speed burr and reconstruction with autogenous bone graft with
      or without allograft bone. All of the patients were followed clinically and
      radiographically, and a biopsy was performed if there were any suspicious
      changes. RESULTS: Fifty-nine patients met the criteria for inclusion in the
      study. According to the grading system of Campanacci et al., two patients (3
      percent) had a grade-I tumor, twenty-nine (49 percent) had a grade-II tumor, and
      twenty-eight (47 percent) had a grade-III tumor. Seventeen patients (29 percent)
      had a pathological fracture at the time of presentation. The mean duration of
      follow-up was eighty months (range, twenty-eight to 132 months). Seven patients
      (12 percent) had a local recurrence. Six of these seven were disease-free at the
      latest follow-up examination after at least one additional treatment with
      curettage or soft-tissue resection (one patient). One patient had resection and
      reconstruction with a prosthesis after a massive local recurrence and pulmonary
      metastases. CONCLUSIONS: Despite the high rates of recurrence reported in the
      literature after treatment of giant-cell tumor with curettage and bone-grafting,
      the results of the present study suggest that the risk of local recurrence after
      curettage with a high-speed burr and reconstruction with autogenous graft with or
      without allograft bone is similar to that observed after use of cement and other
      adjuvant treatment. It is likely that the adequacy of the removal of the tumor
      rather than the use of adjuvant modalities is what determines the risk of
      recurrence.

PMID- 10391547
TI  - Analysis of temporal wear patterns of porous-coated acetabular components:
      distinguishing between true wear and so-called bedding-in.
AB  - BACKGROUND: Standard radiographic assessment of penetration by the femoral head
      into a polyethylene liner does not enable clinicians to distinguish between the
      two processes that cause movement of the head: true wear (the removal of
      polyethylene particles) and so-called bedding-in (other factors, such as creep
      and settling-in of the liner). By analyzing radiographs made over time,
      researchers can distinguish true wear from the bedding-in process. The purpose of
      the current study was to compare the wear performance of the initial modular
      acetabular cup design (so-called first-generation components) of three different
      manufacturers with that of a so-called second-generation component made by one of
      the manufacturers. METHODS: A two-dimensional computerized radiographic method
      was used to analyze 1300 radiographs of 315 hips that were followed for 3.0 to
      10.5 years. Temporal penetration by the head in the three groups of first
      generation cups was compared with penetration in the group of second-generation
      cups. Multiple linear regression analysis was used to model penetration-versus
      time data as a line for each group. The slope of each regression line indicated
      the true rate of wear, and the intercept of the regression line indicated the
      amount of bedding-in. RESULTS: Modifications in the design of the second
      generation components, including thicker polyethylene and an improved locking
      mechanism, led to a decrease in the mean penetration by the head; however, the
      second-generation component did not have a lower true rate of wear than two of
      the first-generation components. Rather, the decreased penetration by the head
      into the second-generation component resulted from decreased bedding-in of the
      liner. CONCLUSIONS: These findings and this technique of analysis are clinically
      relevant to surgeons who evaluate polyethylene wear radiographically. First,
      penetration by the head in the early postoperative years might not be due
      entirely to abrasive wear of the polyethylene liner but, rather, to a change in
      the position of the head resulting from the bedding-in process. The inclusion of
      bedding-in in calculations of wear artificially inflates the rate of wear and may
      result in a misrepresentation of the potential risk of wear-related
      complications. This is especially true with regard to comparisons of different
      designs of modular cups, in which conformity and tolerances between the
      polyethylene liner and the metal shell can vary greatly. Second, analysis of
      penetration by the head at multiple time-intervals can be used to distinguish
      true polyethylene wear from the bedding-in process. Such an analysis allows more
      accurate determination of the true rates of wear of different designs of modular
      cups and, therefore, of potential wear-related complications.

PMID- 10391548
TI  - Comparison of fixation of the femoral component without cement and fixation with
      use of a bone-vacuum cementing technique for the prevention of fat embolism
      during total hip arthroplasty. A prospective, randomized clinical trial.
AB  - BACKGROUND: Acute hypotension, hypoxemia, cardiac arrest, and sudden death are
      well recognized complications during total hip arthroplasty, and they have been
      attributed to embolization of fat and bone marrow. An increase in intramedullary
      pressure in the femur is the most important pathogenic factor for the development
      of embolic events. Intravasation of fat, bone marrow, and bone debris during the
      implantation of a femoral component, and the embolization of these elements
      through the venous system located along the linea aspera and through the
      metaphyseal vessels, have been demonstrated experimentally and clinically. The
      purpose of the present study was to compare the effects of fixation of the
      femoral component without cement with those of fixation with a bone-vacuum
      cementing technique on the severity of embolic phenomena and cardiopulmonary
      impairment during total hip arthroplasty. Fixation with a conventional cementing
      technique was also evaluated as a control. METHODS: Sixty patients (sixty hips)
      were entered into a prospective, randomized clinical trial. The patients were
      assigned to one of three groups. Group 1 consisted of twenty patients who had the
      femoral component inserted without cement, Group 2 comprised twenty patients who
      had the component inserted with a conventional cementing technique, and Group 3
      included twenty patients who had fixation with the so-called bone-vacuum
      cementing technique. In the hips in Group 3, a suction of -800 millibars (-80,000
      pascals) was applied to a proximal drainage cannula placed along the linea aspera
      and a distal drainage cannula placed in the diaphysis in order to produce a
      vacuum in the medullary cavity of the femur during the application of cement and
      the insertion of the stem. Transesophageal echocardiography and hemodynamic and
      blood-gas analysis were performed during the operation. RESULTS: Severe embolic
      events (defined as a cascade of fine echogenic particles of less than five
      millimeters in diameter) were observed in seventeen (85 percent) of the twenty
      patients during insertion of the stem with use of a conventional cementing
      technique but in none of the patients who had the stem inserted without cement (p
      < 0.05). Insertion of the femoral component with the bone-vacuum cementing
      technique prevented embolic phenomena in all but one patient (5 percent).
      Arterial oxygen saturation decreased significantly (p < 0.05) from a mean of 99.5
      to 92.9 percent after insertion of the stem with a conventional cementing
      technique, but only slight changes were observed in the patients who had fixation
      of the component without cement and in those who were managed with the bone
      vacuum cementing technique. Intraoperative pulmonary shunt values increased a
      mean of 24 percent (p < 0.05) when the femoral component was inserted with a
      conventional cementing technique, but with the numbers available we did not
      detect a significant change in those values when the component was fixed without
      cement or when it was inserted with use of the bone-vacuum cementing technique.
      CONCLUSIONS: The present study showed that severe embolic events and
      intraoperative pulmonary impairment are common when a femoral component is fixed
      with use of a conventional cementing technique. The results clearly demonstrated
      a low risk of embolism during total hip arthroplasty when the femoral component
      was fixed without cement and when it was fixed with the bone-vacuum cementing
      technique. The ability of a patient to withstand an embolic event should be
      considered before fixation of the femoral component with use of a conventional
      cementing technique is planned.

PMID- 10391549
TI  - Catastrophic failure of a cemented, collarless, polished, tapered cobalt-chromium
      femoral stem used with impaction bone-grafting. A report of two cases.

PMID- 10391550
TI  - Long-term survival following total sacrectomy with reconstruction for the
      treatment of primary osteosarcoma of the sacrum. A case report.

PMID- 10391551
TI  - Tibial neuroma presenting as a Baker cyst. A case report.

PMID- 10391552
TI  - Interbody fusion cages in reconstructive operations on the spine.

PMID- 10391553
TI  - Stimulated Bennett fracture treated with closed reduction and percutaneous
      pinning. A biomechanical analysis of residual incongruity of the joint.

PMID- 10391554
TI  - Association between ratio of matrix metalloproteinase-1 and local recurrence,
      metastasis, and survival in human chondrosarcoma.

PMID- 10391555
TI  - Finally, good news about prostate carcinoma in African American men.

PMID- 10391556
TI  - New insights into trilateral retinoblastoma.

PMID- 10391557
TI  - Intraoperative radiation therapy to the upper mediastinum and nerve-sparing three
      field lymphadenectomy followed by external beam radiotherapy for patients with
      thoracic esophageal carcinoma.
AB  - BACKGROUND: In patients with thoracic esophageal carcinoma, radical dissection of
      the upper mediastinal lymph nodes often leads to complications such as recurrent
      laryngeal nerve palsy and subsequent pulmonary disorders. Intraoperative
      radiation therapy (IORT) to the upper mediastinum and nerve-sparing three-field
      lymphadenectomy followed by external beam radiotherapy has been developed to
      improve the locoregional control rate without resulting in these major
      postoperative complications. METHODS: Three-field lymphadenectomy, including
      cervical, mediastinal, and abdominal lymph node dissection, was performed.
      Dissection of the upper mediastinum was conservative to preserve recurrent
      laryngeal nerve function. IORT of 12-25 grays (Gy) was applied to the upper
      mediastinum. Postoperative radiation therapy (PORT) of 45 Gy in 16 fractions over
      4 weeks was applied to the entire neck and upper mediastinum using an external X
      ray beam. Between 1989-1996, 121 patients with thoracic esophageal carcinoma
      underwent surgery and received IORT, and 103 of these patients underwent PORT as
      part of their treatment schedule. RESULTS: The surgical mortality rate was 0.8%
      (1 of 121 cases). The overall 5-year survival rate was 34.4% and the cause
      specific 5-year survival rate was 54.8%. The cause specific 5-year survival rate
      for pN0 tumors was 79.4% and was 43.8% for pN1 tumors. No patients died with
      locoregional recurrence in the mediastinal lymph nodes. Recurrent laryngeal nerve
      palsy was observed in 25 patients (21%), but the palsy remained for > 1 month in
      only 13 patients (11%). Mechanical ventilation support for > 48 hours was
      required for 22 patients (18.2%). Fatal tracheal ulcers occurred in 4 of 18
      patients who received the highest IORT dose of 25 Gy. CONCLUSIONS: Three-field
      lymphadenectomy to preserve recurrent laryngeal nerves and IORT using 12-20 Gy
      followed by 45-Gy PORT effectively reduced locoregional recurrence, recurrent
      laryngeal nerve palsy, and pulmonary complications caused by radical surgical
      dissections. The minimally effective dose of IORT appears to be < or = 15 Gy, a
      factor that will be further evaluated with longer follow-up.

PMID- 10391558
TI  - K-ras and p53 mutations in the pathogenesis of classical and goblet cell
      carcinoids of the appendix.
AB  - BACKGROUND: Mutations in the K-ras oncogene and the p53 tumor suppressor gene are
      present in approximately 50% of colonic adenocarcinomas. Goblet cell carcinoids
      (GCCs) are uncommon neoplasms of the appendix that appear to be intermediate
      between carcinoid tumors and adenocarcinomas, both histologically and
      biologically. The current study was undertaken to examine the role of p53 and K
      ras mutations in the pathogenesis of GCCs and typical carcinoids (TCs) of the
      appendix. METHODS: Archival materials from 22 GCCs and 18 TCs were analyzed. K
      ras mutations in codons 12, 13, and 61 were studied by a polymerase chain
      reaction (PCR) based designed restriction fragment length polymorphism method
      using mismatched nested primers. Mutations in exons 5-8 of the p53 tumor
      suppressor gene were analyzed in 16 GCCs and 18 TCs by PCR and single-strand
      conformational polymorphism followed by direct sequencing. Immunostains for p53
      and chromogranin were performed in all cases. RESULTS: K-ras mutations and
      nuclear accumulation of p53 by immunohistochemistry were not detected in any of
      the GCCs or TCs. p53 mutations were found in 4 of 16 GCCs (25%) and 8 of 18 TCs
      (44%). Immunoreactivity for chromogranin was seen in the vast majority of GCCs
      and TCs. CONCLUSIONS: p53 mutations appear to play a role in the pathogenesis of
      some GCCs and in approximately 50% of TCs of the appendix, whereas mutations in
      the K-ras oncogene do not appear to be important in the development of these
      tumors. The minimal cytologic atypia, low incidence of metastases, and lack of K
      ras mutations in goblet cell appendiceal neoplasms suggest that they are variants
      of carcinoid tumors. Our findings lend support to the recommendation that the
      therapeutic guidelines applied to TCs of the appendix should be the same for
      GCCs.

PMID- 10391560
TI  - K-ras mutation and loss of heterozygosity of the adenomatous polyposis coli gene
      in patients with colorectal adenomas with in situ carcinoma.
AB  - BACKGROUND: The majority of colorectal carcinomas, if not all, arise from a
      benign adenoma. The DNA of the carcinomatous cells frequently has mutations in
      several genes. However, it is not exactly clear when during the neoplastic
      process each mutation develops. An adenoma with an area of in situ carcinoma
      provides an opportunity to evaluate genetic changes within a single neoplasia
      whose separate areas are comprised of both the benign adenoma as well as the
      malignant carcinoma. METHODS: Thirty-seven neoplasms with areas of both benign
      adenoma and in situ carcinoma were studied. Both portions were evaluated for loss
      of heterozygosity (LOH) of the adenomatous polyposis coli (APC) gene and for
      mutations in codons 12/13 of the K-ras oncogene using the polymerase chain
      reaction technique. RESULTS: Twenty-eight neoplasms showed no LOH in either
      portion whereas both portions of 4 neoplasms revealed a loss of heterozygosity.
      In three lesions the APC gene was normal in the adenomatous portion but LOH was
      present in the carcinomatous portion. Two neoplasms were uninformative for LOH of
      the APC gene. Thirteen neoplasms showed the wild-type pattern for the K-ras
      oncogene whereas 15 contained the identical mutation in both portions. Of the
      remaining nine neoplasms, six had a K-ras mutation in the adenomatous portion
      only and three had one pattern in the adenomatous portion and a different pattern
      in the in situ carcinoma portion. CONCLUSIONS: LOH of the APC gene is an early
      and persistent feature in the evolution of a benign colorectal adenoma into an in
      situ carcinoma. There is less consistency regarding K-ras mutations; one in five
      in situ carcinomas contains a K-ras mutation different from that observed in the
      adenomatous portion.

PMID- 10391559
TI  - Cellular immunotherapy for patients with metastatic colorectal carcinoma using
      lymph node lymphocytes localized in vivo by radiolabeled monoclonal antibody.
AB  - BACKGROUND: The authors showed previously that radiolabeled monoclonal antibody
      (MoAb) and a hand-held, gamma-detecting probe can be used to localize tumor
      reactive lymph nodes in vivo. The authors examined the feasibility, safety, and
      biologic effects of cellular immunotherapy using autologous cells expanded from
      these lymph nodes in patients with metastatic colorectal carcinoma. METHODS:
      Tumor-reactive lymph nodes containing radiolabeled MoAb were localized and
      excised from 32 patients with metastatic, unresectable colorectal carcinoma at
      laparotomy. Lymph nodes were dissociated, and cells were cultured ex vivo for 10
      14 days. Patients received a single infusion of autologous, expanded cells with
      no systemic interleukin (IL)-2. RESULTS: A mean of 1.6 x 10(10) expanded
      autologous lymph node cells were infused with toxicity limited to occasional
      fevers or chills. The cells infused predominately were activated CD3+ T-cells
      that expressed genes for IL-4, IL-5, interferon-gamma, and granulocyte-macrophage
      colony stimulating factor (GM-CSF) by using reverse transcriptase-polymerase
      chain reaction. Indium-111 labeled cells were observed to traffic initially to
      the lungs, bone marrow, liver, and spleen. One patient on study achieved a
      partial response (>80% reduction), and mixed or minor responses were noted in 4
      other patients. The responding patient's cell characteristics were notable for
      high levels of GM-CSF and IL-4 secretion on restimulation with immobilized anti
      CD3 in vitro, and biopsies of the tumor were characterized by macrophage
      infiltration. The median survival of the cell-treated group compared favorably
      with a similar group of patients who underwent radioimmunoguided surgery without
      cell treatment (12.5 months vs. 5.8 months) CONCLUSIONS: The infusion of cells
      expanded from tumor-reactive lymph nodes localized with radiolabeled MoAb in vivo
      is reproducible and safe and has biologic activity, even in the absence of
      systemic IL-2 infusion. This approach represents a novel application of MoAb
      technology, in that MoAbs are used not to diagnose or treat disease directly but
      rather to identify lymph node cells with therapeutic potential.

PMID- 10391561
TI  - The effects of supplementation with alpha-tocopherol and beta-carotene on the
      incidence and mortality of carcinoma of the pancreas in a randomized, controlled
      trial.
AB  - BACKGROUND: Dietary components may be both causal and protective in cases of
      pancreatic carcinoma, but the preventive potential of single constituents has not
      been evaluated. The authors report the effects of alpha-tocopherol and beta
      carotene supplementations on the rates of incidence of and mortality from
      pancreatic carcinoma in a randomized, controlled trial. METHODS: The 29,133
      participants in the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study
      were male smokers who were ages 50-69 years at the time they were randomized into
      1 of the following 4 intervention groups: dl-alpha-tocopherol (AT; 50 mg/day),
      beta-carotene (BC; 20 mg/day), both AT and BC, and placebo. The daily
      supplementation lasted for 5-8 years. Incident cancers were identified through
      the national Finnish Cancer Registry and death certificates of the Statistics
      Finland. Results were analyzed by supplementation with Cox regression models.
      RESULTS: Effects of both supplementations were statistically nonsignificant. The
      rate of incidence of pancreatic carcinoma was 25% lower for the men who received
      beta-carotene supplements (n = 38) compared with the rate for those who did not
      receive beta-carotene (n = 51) (95% CI, -51% to 14%). Supplementation with alpha
      tocopherol (n = 51) increased the rate of incidence by 34% (95% CI, -12% to 105%)
      compared with the rate for those who did not receive alpha-tocopherol. Mortality
      from pancreatic carcinoma during the follow-up, adjusted for stage and anatomic
      location of the tumor, was 19% (95% CI, -47% to 26%) lower among those who
      received beta-carotene and 11% (95% CI, -28% to 72%) higher among those who
      received alpha-tocopherol as compared with those who did not receive
      supplementation. CONCLUSIONS: Supplementation with beta-carotene or alpha
      tocopherol does not have a statistically significant effect on the rate of
      incidence of pancreatic carcinoma or the rate of mortality caused by this
      disease.

PMID- 10391562
TI  - Synthesis and secretion of the anticoagulant protein S and coexpression of the
      Tyro3 receptor in human lung carcinoma cells.
AB  - BACKGROUND: Protein S is a plasma protein that serves as an important cofactor
      for activated protein C in the blood anticoagulation system. Protein S also acts
      as a mitogen on distinct cell types and is a ligand for Tyro3, a member of the
      Axl family of oncogenic receptor tyrosine kinases. This lends support to the
      hypothesis that protein S might also be involved in tumor cell regulation.
      METHODS: The expression of protein S and receptor Tyro3 was examined in 22 lung
      carcinoma cell lines and normal bronchial epithelial cells by reverse
      transcriptase-polymerase chain reaction. Secreted protein S was identified by
      Western blot analysis of cell supernatants and tested in a protein S-dependent
      clotting test for anticoagulant activity. Immunohistochemistry with anti-protein
      S polyvalent antiserum was also performed on 31 primary lung carcinoma specimens.
      RESULTS: Protein S mRNA and secreted protein were found in 11 of 12 cell lines of
      nonsmall cell lung carcinoma (NSCLC) origin and in normal bronchial epithelial
      cells, but they were found in only 4 of 10 small cell lung carcinoma (SCLC) cell
      lines. The majority of lung carcinoma cell lines that expressed protein S (13 of
      15) also revealed expression of the cognate receptor, Tyro3. Protein S that was
      present in cell supernatant had anticoagulant activity comparable to that of
      plasma protein S, suggesting that it is gamma-carboxylated. In lung tumor tissue,
      protein S antigen was found in 20 of 31 cases examined, predominantly in tumors
      of the squamous cell and bronchioalveolar cell types. Protein S was found not
      only in tumor cells but also in cells of the normal bronchial epithelium, in
      alveolar macrophages, and in endothelium. CONCLUSIONS: To the authors' knowledge,
      their report is the first of the synthesis of an active anticoagulant protein in
      epithelial cells of human cancer. It suggests that protein S, by binding to a
      receptor (Tyro3), may influence local anticoagulation events or other, as yet
      unidentified, aspects of lung tumor development.

PMID- 10391563
TI  - Cryosurgical ablation of soft tissue sarcomas: a phase I trial of feasibility and
      safety.
AB  - BACKGROUND: Cryosurgery is a therapeutic method of treating neoplastic tissue by
      freezing in situ to achieve devitalization. Cell death results from exposure to
      severe cold (below -40 degrees C for at least 1 minute) as well as from the
      process of freezing and thawing, which disrupts cellular integrity. Modern
      cryosurgical technique involves insertion of hollow probes into the tumor,
      through which circulating liquid nitrogen and gaseous nitrogen can achieve tissue
      and tumor freezing and thawing for tumor control. Cryoablation is now a
      recognized approach to the treatment of various malignant tumors, and it is
      generally well tolerated. This method has been used only sporadically to date in
      the treatment of patients with soft tissue sarcomas. METHODS: The purpose of this
      study was to assess the feasibility and safety of cryosurgical ablation of soft
      tissue sarcomas utilizing a cryoprobe system. Twelve patients with soft tissue
      tumors of the extremity were included in this Institutional Review Board-approved
      protocol. Cryoablation was performed by inserting cryoprobes into the tumors,
      through which liquid nitrogen and gaseous nitrogen were pumped to achieve two
      freeze/thaw cycles. The entire process was monitored with intraoperative
      ultrasonography. All patients had subsequent resection of the residual tumor.
      Patients were monitored clinically and metabolically for toxicity. RESULTS:
      Cryoablation was successfully performed on all 12 patients. Complications
      included peripheral nerve palsy (in 3 patients) and serous wound drainage (in 3
      patients). There were no cases of wound infection, deep venous thrombosis,
      pulmonary embolism, wound dehiscence, skin slough, or metabolic abnormalities.
      All 3 cases of peripheral nerve palsy showed signs of recovery, 2 within 1 week
      and 1 within 4 months. CONCLUSIONS: Cryosurgical ablation of soft tissue sarcomas
      is technically safe and feasible. This method can be used in conjunction with
      other modalities in the treatment of patients with these tumors. The
      complications associated with cryoablation of sarcomas are minor or transient,
      and the procedure is well tolerated by patients. The role of cryosurgery in the
      management of soft tissue sarcomas needs to be elucidated as more data regarding
      its safety and effectiveness become available.

PMID- 10391564
TI  - H-ras and K-ras mutations in soft tissue sarcoma: comparative studies of sarcomas
      from Korean and American patients.
AB  - BACKGROUND: The authors' recent investigation of Korean patients with sarcoma has
      suggested that ras gene activation may play a role in oncogenesis. The authors
      attempted to extend the mutation analysis to sarcomas in American patients to
      determine whether there were racial or geographic factors relevant to the
      initiation or progression of sarcoma. METHODS: H-ras and K-ras genes were
      examined in sarcomas obtained from patients in the midwestern U. S. using the
      polymerase chain reaction technique and direct automated sequencing analysis.
      Tumors studied included 29 malignant fibrous histiocytomas, 7 liposarcomas, 5
      rhabdomyosarcomas, and 9 leiomyosarcomas. RESULTS: Of the 50 sarcomas evaluated,
      only 1 (2%) definable mutation was found; a GGC to AGC transition at codon 12 of
      H-ras was found in a rhabdomyosarcoma. None of the patients had a K-ras mutation.
      The rates of incidence of ras point mutations in these samples were much lower (H
      ras: 2%; 95% confidence interval [95% CI], 0-11.5% and K-ras: 0%) than described
      for both genes in Korean studies (H-ras: 16%; 95% CI, 5.2-26.8% and K-ras: 44%;
      95% CI, 29.5-58.5%). CONCLUSIONS: Although the reason for this discrepancy is not
      clear, there were no major differences found in histology or clinical stages.
      Based on this study of 50 sarcoma samples from American patients and the authors'
      previous study of 45 Korean tumor samples, the authors conclude that differing
      genetic and/or environmental mechanisms can affect sarcoma development or
      progression. Mutation of the H-ras and K-ras genes appears to be uncommon in
      sarcomas occurring in American patients, suggesting that the activation by point
      mutations of the H-ras and K-ras genes does not play a significant role in the
      pathogenesis or progression of sarcoma in these patients.

PMID- 10391565
TI  - Use of 5-HT3 receptor antagonists to prevent nausea and emesis caused by
      chemotherapy for patients with breast carcinoma in community practice settings.
AB  - BACKGROUND: Although 5-HT3 receptor antagonists are clinically more effective in
      controlling emesis, particularly that caused by high dose cisplatin, than
      previously available agents, they appear to be less effective against nausea.
      This report focuses on the effectiveness of these agents against nausea and
      emesis in patients receiving two moderately emetogenic combination chemotherapy
      regimens as treatment for breast carcinoma in community practice settings.
      METHODS: Six hundred ninety-two breast carcinoma patients (688 female, 4 male;
      mean age, 51 years) enrolled in a nonrandomized study completed the Morrow
      Assessment of Nausea and Emesis (MANE) following 4 consecutive chemotherapy
      treatments. The frequency, duration, and severity of postchemotherapy nausea (PN)
      and postchemotherapy emesis (PE) were compared by type of antiemetic (5-HT3
      receptor antagonist vs. other) and chemotherapy regimen (cyclophosphamide and
      doxorubicin with or without 5-fluorouracil [CA/CAF] vs. cyclophosphamide,
      methrotrexate, and 5-fluorouracil [CMF]). RESULTS: Within each regimen, the mean
      duration of PN was significantly longer for patients who received a 5-HT3
      receptor antagonist than for those who were not given an antiemetic of that type
      (CA: 40.3 hours vs. 29.6 hours, P < 0.05; CMF: 37.6 hours vs. 30.2 hours, P <
      0.05). There were no significant differences in the frequency or severity of
      nausea or in the frequency, severity, or duration of emesis by type of antiemetic
      for patients receiving either regimen. CONCLUSIONS: The results of this
      observational study suggest that 5-HT3 receptor antagonists are no more effective
      than other commonly used medications in controlling postchemotherapy nausea and
      emesis in women with breast carcinoma who are treated with moderately emetogenic
      chemotherapy in community practice settings. In fact, they may be associated with
      significant prolongation of the course of postchemotherapy nausea.

PMID- 10391566
TI  - Selective delivery of doxorubicin to patients with breast carcinoma metastases by
      stealth liposomes.
AB  - BACKGROUND: Stealth liposomes hold promise as a mode of delivering cytotoxic
      agents selectively to tumors in cancer patients. The objective of this study was
      to determine whether stealth liposomal doxorubicin accumulates selectively in
      bone metastases based on clinical material obtained from two patients with breast
      carcinoma. METHODS: Tumor tissue was obtained from two women (ages 33 years and
      41 years, respectively) with metastatic breast carcinoma who responded to
      treatment with stealth liposomal doxorubicin and later underwent a surgical
      fixation procedure to treat a pathologic fracture of the femur. Drug levels in
      the tumor and adjacent muscle were examined by high performance liquid
      chromatography analysis in both patients and by fluorescence microscopy in one of
      the patients. RESULTS: Bone tumor fragments obtained during surgery performed 6
      days after the administration of the 12th course of stealth liposomal doxorubicin
      in 1 patient and 12 days after the administration of the 16th course of stealth
      liposomal doxorubicin in the second patient had a 10-fold greater concentration
      of liposomal doxorubicin than tumor free muscle. Doxorubicin fluorescence and
      specific nuclear staining showed good colocalization, thus confirming the
      presence of the liposome-delivered drug in the nuclei of tumor cells.
      CONCLUSIONS: Using skeletal muscle as a comparator, stealth liposomal doxorubicin
      accumulates selectively in metastatic breast carcinoma cells within bone.

PMID- 10391567
TI  - Transient increases of apoptosis and Bax expression occurring during radiotherapy
      in patients with invasive cervical carcinoma.
AB  - BACKGROUND: Apoptosis plays a crucial role in radiation therapy (RT) in various
      carcinomas. This study was designed to investigate the relation between apoptosis
      and RT in invasive squamous cell carcinoma (ISCC) of the uterine cervix METHODS:
      Thirty-five specimens were obtained from 7 patients with ISCC before and during a
      fractionated RT. The occurrence of apoptosis was examined by end labeling of DNA
      gel fractionation and in situ 3' end labeling of DNA. The expression of Bax and
      Bcl-2 proteins was investigated by immunohistochemical staining. RESULTS:
      Autoradiographic analysis revealed that high molecular weight DNA was predominant
      in the untreated ISCC specimens. However, a ladder-like pattern, characteristic
      of the apoptotic breakdown of DNA, was identified at doses of 900 cGy and 1980
      cGy. At doses >1980 cGy, DNA laddering disappeared without any extensive
      smearing. Quantitative analysis of low molecular weight fragments of DNA revealed
      significant increases at doses of 900 cGy and 1980 cGy compared with those before
      RT and at doses of >1980 cGy. Labeling of DNA in situ indicated that cells
      undergoing apoptosis increased dramatically at a dose of 900 cGy. However,
      apoptotic cells decreased at a dose of 3960 cGy. In addition, a large fraction of
      tumor cells was immunonegative for Bcl-2 before and during RT. By contrast,
      immunoreactive Bax was observed intensely in many neoplastic cells at doses of
      900 cGy and 1980 cGy. CONCLUSIONS: The current investigation indicates that low
      doses of RT result in apoptotic cell death in ISCC in association with the
      increased expression of Bax but not with increased Bcl-2 expression.

PMID- 10391568
TI  - Adherence by African American men to prostate cancer education and early
      detection.
AB  - BACKGROUND: This study was designed to identify factors that predict adherence by
      African American men to prostate cancer education and early detection. METHODS:
      In the spring of 1995, the authors identified 548 African American men who were
      patients at the University Health Services of the University of Chicago, were
      ages 40-70 years, and did not have a personal history of prostate cancer.
      Baseline telephone survey data were collected from 413 men (75%). Participants
      were randomly assigned to either a minimal or an enhanced intervention group. Men
      in the former group were mailed a letter and a reminder that invited them to a
      urology clinic for prostate cancer education and early detection. Men in the
      enhanced intervention group were sent the same correspondence and were also given
      print material and telephone contacts, which were tailored to each recipient.
      RESULTS: Adherence was significantly higher (OR = 2.6, CI: 1.7-3.9) in the
      enhanced intervention group than in the minimal intervention group (51% and 29%,
      respectively). Men who were age 50 years or older (OR = 1.7, CI: 1.1-2.8), were
      married (OR = 1.8, CI: 1.2-2.9), believed that prostate cancer early detection
      examination should be performed in the absence of symptoms (OR = 2.3, CI: 1.3
      4.0), and self-reported an intention to have an early detection examination (OR =
      1.9, CI: 1.2-2.9) were also more likely to adhere. CONCLUSIONS: A tailored
      behavioral intervention can influence adherence to prostate cancer early
      detection among African American men. Individual background and cognitive and
      psychosocial characteristics may also affect behavior. Future studies should
      assess the impact of this type of intervention on cognitive and psychologic
      correlates of decision-making and behavior along the continuum of prostate cancer
      care. [See editorial on pages 1-2, this issue.]

PMID- 10391569
TI  - Quantitative assessment of bladder carcinoma by acid labile DNA assay.
AB  - BACKGROUND: Effective noninvasive methods for monitoring patients with bladder
      carcinoma and screening for bladder carcinoma that show better performance than
      the methods currently in use would be desirable for detecting urothelial
      carcinoma at an early, easily treatable stage. A rapidly hydrolyzed component of
      nuclear DNA has been described, the increase of which has been linked to
      malignancy. Quantitative determination of acid labile DNA has been applied
      successfully to detect other neoplasms. This study investigates the potential of
      this method to detect transitional cell carcinomas. METHODS: Touch imprints of
      transurethral resection material from 62 cases of nonmalignant urothelium
      (control group including reactive changes) and 94 cases of bladder carcinoma were
      analyzed. The full Feulgen hydrolysis profiles of the nonmalignant and malignant
      urothelial cells were compared by measuring the staining density of the nuclei
      using digital image analysis after various hydrolysis times. Twenty cells were
      sampled randomly from among the cells measured for calculation of the mean
      optical density (MOD). The MOD of each time was used to build the hydrolysis
      profile of a case. RESULTS: A hydrolysis time of 10 minutes was found to be the
      most discriminative between control and carcinoma cases. Applying a single
      threshold MOD value of 101 resulted in a test sensitivity of 95.7%, a specificity
      of 94.4%, a positive predictive value of 98.3%, a negative predictive value of
      95.9%, and an area under the receiver operating characteristic curve of 0.97.
      CONCLUSIONS: The results of this pilot study suggest that measurement of the
      rapidly hydrolyzed component of DNA present in the nuclei of bladder urothelium
      offers a highly sensitive and reliable supplement to the qualitative and
      subjective cytologic procedures currently in use.

PMID- 10391570
TI  - Occult primary tumors of the head and neck: lack of benefit from positron
      emission tomography imaging with 2-[F-18]fluoro-2-deoxy-D-glucose.
AB  - BACKGROUND: Patients who present with squamous cell carcinoma metastatic to
      cervical lymph nodes and no clinically apparent primary site present a
      therapeutic dilemma. Positron emission tomography imaging with 2-[F-18]fluoro-2
      deoxy-D-glucose (FDG-PET) has been shown to be useful for the examination of
      known primary tumors. This study was undertaken to determine whether FDG-PET
      imaging improves detection of occult primary tumors in patients with metastatic
      squamous cell carcinoma in the lymph nodes of the head and neck. METHODS:
      Thirteen patients with pathology proven cervical lymph node metastases from
      clinically occult primary squamous cell carcinomas were evaluated prospectively
      with FDG-PET, in addition to standard clinical and radiographic techniques, as
      part of their pretreatment diagnostic evaluation. Direct panendoscopy and biopsy
      were performed on all patients in an attempt to detect primary tumor sites and to
      characterize them histologically. RESULTS: A primary squamous cell carcinoma was
      confirmed after panendoscopy and biopsy in 3 of the 13 patients. The site of the
      primary tumor was correctly identified with FDG-PET in only one of these three
      patients. The FDG-PET study suggested a primary tumor location where no tumor was
      found in 6 of 13 patients; for 5 other of the 13 patients, the FDG-PET results
      were negative and no primary was found. No primary tumor locations were
      identified by computed tomography, magnetic resonance imaging, or direct
      panendoscopy. FDG-PET imaging correctly detected the location of the primary
      tumor in 1 patient (8%) and provided apparent false-positive results for 6 (46%)
      of the 13 patients. CONCLUSIONS: FDG-PET imaging did not significantly improve
      detection of unknown primary squamous cell carcinomas in patients with metastases
      to lymph nodes of the neck. A high percentage of results were apparent false
      positive.

PMID- 10391571
TI  - Nutritional status of children with solid tumors.
AB  - BACKGROUND: The purposes of the study were to evaluate prospectively the
      nutritional status of children with solid tumors who were receiving chemotherapy,
      to find the most sensitive parameter of protein energy malnutrition, and to
      determine whether the stage of disease and aggressiveness of chemotherapy have
      any influence on nutritional status. METHODS: Fifty patients were followed
      prospectively from the time of diagnosis throughout chemotherapy. Serum albumin,
      prealbumin, and weight were measured at the time of diagnosis and before each
      course of chemotherapy. RESULTS: At diagnosis, only 2.7% of patients had albumin
      levels < 3.5 g/dL whereas 36% had prealbumin levels below the normal limit. All
      patients showed a weight increment of 81 g/day (P = 0.0001), an albumin increment
      of 0.001 U/day (P = 0.0001), and a prealbumin increment of 0.044 U/day (P =
      0.0407). The change in prealbumin values was much more prominent (10-fold higher)
      in children age < 2 years. Changes in albumin values were not statistically
      significant by stage of disease but the increment of prealbumin did show
      statistical significance, which was most prominent in patients with Stage IV
      disease CCG (children's cancer group classification ) (P = 0.0003). The intensity
      of chemotherapy had no influence on changes in weight or albumin levels. However,
      it did influence changes in prealbumin levels, which were most pronounced in the
      group receiving high dose chemotherapy. CONCLUSIONS: Based on the results of the
      current study, the authors believe prealbumin is the most powerful test overall
      with which to evaluate the nutritional status of children with solid tumors both
      at the time of diagnosis and throughout chemotherapy.

PMID- 10391573
TI  - Trilateral retinoblastoma: is the location of the intracranial tumor important?
AB  - BACKGROUND: Trilateral retinoblastoma refers to bilateral retinoblastoma
      associated with an intracranial primitive neuroectodermal tumor in the pineal or
      suprasellar region. The purpose of this study was to review patient and tumor
      characteristics and treatment outcome in patients with trilateral retinoblastoma
      and to determine whether there is a difference in presentation or outcome
      according to the location of the intracranial tumor. METHODS: A MEDLINE search of
      all English language articles pertaining to trilateral retinoblastoma published
      between 1977-1997 was performed. A total of 94 different cases were identified
      and analyzed. RESULTS: The gender was male in 39 patients (41.5%), female in 50
      patients (53.2%), and unknown in 5 patients (5.3%). Family history for
      retinoblastoma was positive in 44 patients (46.8%), negative in 39 patients
      (41.5%), and unknown in 11 patients (11.7%). The median age at the time of
      diagnosis of retinoblastoma was 6 months. The median time interval to the
      development of an intracranial tumor from the time of diagnosis of retinoblastoma
      was 21 months. In 78 patients (83.0%) the intracranial tumor was in the pineal
      region and in 16 patients (17.0%) it was in the suprasellar region. The median
      time interval from the time of diagnosis of retinoblastoma to the development of
      a pineal region tumor was 24 months whereas the median time interval for the
      development of a suprasellar region tumor was 1 month. At 6 months after the
      diagnosis of intraocular tumors, 6 of 61 children with pineal region tumors and
      10 of 14 patients with suprasellar region tumors had developed intracranial
      disease (P = 0.005). Unilateral intraocular retinoblastoma associated with
      intracranial tumor was more likely to occur in patients with suprasellar region
      tumors than pineal region tumors (P < 0.015). The median survival after the
      diagnosis of an intracranial tumor was 6 months regardless of the location of the
      intracranial tumor. For patients who received no treatment for the intracranial
      tumor the median survival was 1 month whereas it was 8 months for those who
      received treatment. Children who were asymptomatic at the time of diagnosis of
      the intracranial tumor had a better overall survival than those who were
      symptomatic (P = 0.002). CONCLUSIONS: The prognosis of children who develop
      trilateral retinoblastoma is dismal with current treatment strategies. Tumors of
      the suprasellar region present earlier than tumors of the pineal region after the
      diagnosis of intraocular tumors. Because patients who were asymptomatic at the
      time of diagnosis of intracranial disease had a better overall survival than
      those who were symptomatic, screening for intracranial tumors may be a valuable
      strategy in the management of patients with bilateral and/or hereditary
      retinoblastoma. [See editorial on pages 3-5, this issue.]

PMID- 10391572
TI  - Outpatient treatment of fever and neutropenia for low risk pediatric cancer
      patients.
AB  - BACKGROUND: Fever and neutropenia (F&N) is a common complication of cancer
      chemotherapy. It is conveniently managed by hospitalization and empiric
      administration of parenteral antibiotics. This study attempted to determine
      whether pediatric cancer patients with F&N identified as low risk for morbidity
      and mortality by clinical criteria at the time of presentation could be treated
      safely as outpatients. METHODS: Seventy-three episodes of F&N in 41 patients were
      studied prospectively over 2 years. Eligibility criteria included age > or =2
      years, reliable caretakers, and residence within 1 hour of the hospital.
      Exclusion criteria included hemodynamic instability, dehydration, severe
      mucositis, pneumonia, leukemia/lymphoma induction therapy, bone marrow
      transplantation, or other serious comorbidity. Patients were evaluated, received
      a single dose of intravenous ceftazidime, and were observed for 3-16 hours. They
      were randomized to receive either oral ciprofloxacin or intravenous ceftazidime
      as outpatients. Patients were seen daily until they had been afebrile for at
      least 48 hours and had a rising absolute phagocyte count of >500 cells/microL.
      RESULTS: Sixty-three of 73 episodes (86%) were successfully managed on an
      outpatient basis. For 31 of 33 episodes in the ceftazidime arm, the patients
      remained outpatients, compared with 32 of 40 in the ciprofloxacin arm; this
      difference was not statistically significant. On average, patients remained
      febrile for 2.7 days and were treated for 4.7 days. Seventy-seven percent of
      episodes required no modification of initial antibiotic therapy. Of the 10
      patients who were hospitalized, 4 had prolonged fever and 3 had emesis.
      Protracted neutropenia was associated with the need for hospitalization. There
      were no deaths, intensive care unit transfers, or serious complications.
      CONCLUSIONS: Carefully selected low risk children with fever and neutropenia can
      be treated safely as outpatients. Close daily medical scrutiny is required.

PMID- 10391574
TI  - Medulloblastoma and supratentorial primitive neuroectodermal tumors: an
      institutional experience.
AB  - BACKGROUND: To the authors' knowledge there are relatively few data concerning
      supratentorial primitive neuroectodermal tumors (PNET). The authors
      retrospectively reviewed all cases of PNET of the brain treated at the study
      institution to determine whether there was a difference in presentation, overall
      survival, and recurrence-free survival with regard to tumor location
      (supratentorium vs. posterior fossa). METHODS: Between 1977-1996 33 patients with
      PNET were diagnosed and treated at 1 radiotherapy center. The median age of the
      patients was 9 years. The location of the tumor was in the posterior fossa in 25
      patients and the supratentorium in 8 patients. The tumor had spread to the
      neuraxis in six patients; four patients with disseminated neuraxis disease had a
      supratentorial PNET and two had a posterior fossa PNET. All but three patients
      received craniospinal irradiation. The primary tumor received > or = 5000
      centigray in 27 patients and chemotherapy was employed in 26 patients. The median
      follow-up was 60 months. RESULTS: The 5-year overall and recurrence-free survival
      rates for all patients were 77.2% and 79.6%, respectively. The 5-year overall
      survival rates were 86.3% for patients with medulloblastoma (posterior fossa
      PNET) and 46.9% for patients with supratentorial PNET (P = 0.01, log rank test).
      For overall survival, prognostic factors included radiotherapy dose to the
      primary site, metastases (M) status, and location of the primary tumor. The 5
      year recurrence free survival rates were 89.8% for patients with medulloblastoma
      and 46.9% for patients with supratentorial PNET (P = 0.003, log rank test). For
      recurrence free survival, prognostic factors included M status and primary tumor
      site location; radiation dose to the primary tumor site and patient gender were
      of borderline significance. In the ten patients with inadequate posterior fossa
      boost fields judged by Children's Cancer Group criteria, there were two failures,
      both of which were in the original tumor bed. CONCLUSIONS: Supratentorial PNET
      has a worse overall survival and recurrence free survival than medulloblastoma.
      There is a suggestion that radiotherapy boosts in medulloblastoma may not need to
      encompass the entire posterior fossa because posterior fossa failures primarily
      are in the tumor bed. Larger studies with longer follow-up are needed to
      determine whether craniospinal irradiation followed by a boost to the tumor bed
      is adequate for medulloblastoma patients.

PMID- 10391575
TI  - Thyroid carcinoma in children and adolescents in Ukraine after the Chernobyl
      nuclear accident: statistical data and clinicomorphologic characteristics.
AB  - BACKGROUND: The increase in the number of childhood thyroid carcinoma cases in
      Ukraine after the Chernobyl nuclear accident in 1986 prompted the development of
      a registry of thyroid carcinoma cases at the Institute of Endocrinology and
      Metabolism in Kiev. In the current study, the authors report the statistical data
      and clinicomorphologic features of the cases included in this registry. METHODS:
      To study the incidence, and age and gender distribution of thyroid carcinoma in
      Ukraine, the authors compiled complete clinical information from cases diagnosed
      and treated at the Institute of Endocrinology and Metabolism and statistical
      reports submitted to the registry from 27 regions of Ukraine. Morphologic
      features of the resected tumors were examined and were included in the database.
      RESULTS: During the 5 years preceding the Chernobyl nuclear accident, a total of
      59 cases of thyroid carcinoma were identified in the birth to 18 years age group
      (25 in children age < or = 14 years and 34 in adolescents ages 15-18 years).
      Between 1986 and 1997, the total number of thyroid carcinomas in Ukrainian
      children and adolescents was 577 (358 children and 219 adolescents).
      Morphologically, the thyroid tumors overwhelmingly were papillary carcinomas, and
      the majority of these also showed a follicular and/or solid growth pattern. Lymph
      node metastases and other extrathyroidal spread were common, thus necessitating
      total thyroidectomy and lymph node dissections in many patients. CONCLUSIONS:
      Between 1990 and 1997, a significant increase in the incidence of thyroid
      carcinoma was noted in children and adolescents in Ukraine; the group most
      affected was comprised of the individuals who were age < or = 5 years in 1986
      (the year of the Chernobyl nuclear accident). The largest number of cases
      occurred in patients living in areas of thyroid radiation doses of > or =0.50
      grays. The morphologic features of those thyroid tumors suggest that they are
      aggressive tumors with a high frequency of lymph node metastases, venous
      invasion, and extrathyroidal spread.

PMID- 10391576
TI  - A method for identifying abrupt changes in U.S. cancer mortality trends.
AB  - BACKGROUND: Summaries of trends in cancer rates evaluated over a fixed, short
      period are informative, but methods that evaluate trends over a longer time
      period, identifying when changes occur as well as the magnitude of the changes,
      can provide additional information. METHODS: Cancer mortality trends from 1973
      1995 were determined for more than 15 anatomic sites for white and black males
      and females using weighted piecewise linear regression analysis with a stepwise
      selection procedure. The dependent variable was the natural logarithm of the
      annual mortality rate, and the weight was the annual number of cancer deaths. The
      variability of estimated change points was examined by bootstrapping the
      residuals from the resulting models. RESULTS: For black males, cancer mortality
      rates declined in the 1990s due to decreases in lung, esophageal, oral cavity,
      and prostate cancer rates. However, there was no significant decline for cancer
      of the colon and rectum. For white males, cancer mortality rates declined in the
      1990s due to declines in cancer of the lung and colon/rectum since the mid-1980s
      and declines in prostate cancer in the 1990s. For black females and white
      females, total cancer mortality rates declined, but not significantly. Cancer
      rates for all sites except the lung declined significantly in the 1990s for
      white, but not black, females due to declining trends for carcinoma of the colon
      and rectum since the mid-1980s and for breast cancer in the 1990s. CONCLUSIONS: A
      method for identifying major changes in cancer trends has been developed. Trends
      for cancer of the breast and colon/rectum indicate that gaps between rates for
      blacks and whites are widening.

PMID- 10391577
TI  - The relative accuracy of the clinical estimation of the duration of life for
      patients with end of life cancer.
AB  - BACKGROUND: Although the prediction of the duration of life of patients with end
      of life cancer most often relies on the clinical estimation of survival (CES)
      made by the treating physician, the accuracy and practical value of CES remains
      controversial. METHODS: The authors prospectively evaluated the accuracy of CES
      in an inception and population-based cohort of 233 cancer patients who were seen
      at the onset of their terminal phase. They also systematically reviewed the
      literature on CES in advanced or end-stage cancer patients in MEDLINE, CANCERLIT,
      and EMBASE data bases, using two search strategies developed by a research
      librarian. RESULTS: CES had low sensitivity in detecting patients who died within
      shorter time frames (< or =2 months), and a tendency to overestimate survival was
      noted. A moderate correlation was observed between actual survival (AS) and CES
      (Pearson correlation coefficient = 0.47, intraclass correlation coefficient =
      0.46, weighted kappa coefficient = 0.42). CONCLUSIONS: Treating physicians appear
      to overestimate the duration of life of end of life ill cancer patients,
      particularly those patients who die early in the terminal phase and who may
      potentially benefit from earlier participation in palliative care programs. CES
      should be considered one of many criteria, rather than a unique criterion, by
      which to choose therapeutic intervention or health care programs for patients in
      the end of life cancer phase.

PMID- 10391578
TI  - Dynamic computed tomography predicts tumor temperature and response to
      thermoradiotherapy in superficial and subsurface tumors.
AB  - BACKGROUND: Dynamic computed tomography (CT) was performed on patients undergoing
      thermoradiotherapy for superficial or subsurface tumors, and the correlation
      between tumor enhancement and tumor temperature during hyperthermia was
      evaluated. The authors further investigated whether tumor enhancement by dynamic
      CT is predictive of tumor response to thermoradiotherapy. METHODS:
      Thermoradiotherapy was given to 26 patients. Radiotherapy consisted of 40-70
      gray. Hyperthermia was conducted over 3-5 sessions, and tumor temperature was
      measured at each session. Dynamic CT was performed prehyperthermia (within 1 week
      before the initiation of hyperthermia) and midtherapy (within 1 week after 2
      sessions of hyperthermia). RESULTS: A complete response (CR) was obtained in 11
      patients (42%) and either a partial response or no response (non-CR) in 15 (58%).
      There was no correlation between tumor enhancement obtained by prehyperthermia CT
      and tumor temperature parameters or response. However, the deltaCTmax (maximum
      increased enhancement) by prehyperthermia and midtherapy CT was 39.0 +/- 18.9 HU
      and 26.1 +/- 14.2 HU, respectively, in CR patients, and 46.4 +/- 21.1 HU and 49.6
      +/- 19.1 HU, respectively, in non-CR patients. This change in deltaCTmax at
      midtherapy was significantly different between groups (P < 0.01). The deltaCTmax
      ratio for prehyperthermia and midtherapy CT studies correlated with the average
      tumor temperature (P < 0.05). CONCLUSIONS: Tumor enhancement by prehyperthermia
      and midtherapy dynamic CT predicted tumor temperature during hyperthermia and
      response to thermoradiotherapy for superficial or subsurface malignancies.

PMID- 10391579
TI  - Second primary cancers in patients with lung carcinoma.
AB  - BACKGROUND: There are only limited population-based data available regarding the
      risk of developing a second cancer after a diagnosis of lung carcinoma. METHODS:
      Data collected from the Cancer Registry of the Swiss Canton of Vaud (comprised of
      approximately 600,000 inhabitants) were used to estimate the incidence of a
      second metachronous primary cancer following a diagnosis of lung carcinoma.
      Between 1974 and 1996, 5794 cases of lung carcinoma (occurring in 4728 males and
      1066 females) were followed actively until the end of 1996. RESULTS: One hundred
      seventy-five second primary neoplasms were registered (occurring in 146 males and
      29 females). Significant excess rates were observed for all cancer sites
      (standardized incidence ratio [SIR] = 1.2), cancers of the oral cavity and
      pharynx (SIR = 2.7), and lung (SIR = 1.7). SIRs also were above unity for cancers
      of the esophagus (SIR = 1.8), pancreas (SIR = 1.5), bladder (SIR = 1.8), kidney
      (SIR = 2.3), and the female breast (SIR = 2.0). Excess rates for all cancer sites
      together and tobacco-related neoplasms were systematically higher at a younger
      age (< 60 years). The overall cumulative risk of lung cancer was 1.8% at 5 years
      and 4.7% at 10 years and was 5% and 11%, respectively, for any tobacco-related
      tumor. The estimates were consistent for squamous cell carcinoma and
      adenocarcinoma of the lung. CONCLUSIONS: There were substantial excesses of
      second lung carcinomas as well as other major tobacco-related neoplasms, but not
      of colorectal carcinoma, prostate carcinoma, or lymphoid neoplasms after the
      diagnosis of a primary lung carcinoma. This study emphasizes the importance of
      smoking cessation even after a diagnosis of lung carcinoma.

PMID- 10391580
TI  - The changing survival of patients with mycosis fungoides: a population-based
      assessment of trends in the United States.

PMID- 10391581
TI  - A biomimetic controller for a multifinger prosthesis.
AB  - A novel controller for a multifinger hand prosthesis was developed and tested to
      measure its accuracy and performance in transducing volitional signals for
      individual "phantom" fingers. Pneumatic sensors were fabricated from open-cell
      polymeric foam, and were interposed between the prosthetic socket and superficial
      extrinsic tendons associated with individual finger flexion. Test subjects were
      prompted to move individual fingers or combinations thereof to execute either
      taps or grasps. Sensor outputs were processed by a computer that controlled
      motions of individual fingers on a mechanical prosthesis. Trials on three upper
      limb amputees showed that after brief training sessions, the TAP controller was
      effective at producing voluntary flexions of individual fingers and grasping
      motions. Signal energies were between 5 and 25 dB relative to noise from all
      sources, including adjacent sensors, indicating high degrees of both sensitivity
      and specificity for tendon-associated transduction. Finger flexions at up to
      three repetitions per second, and rhythmic tapping of sequential fingers were
      readily transduced. One amputee subject was able to play a short piano piece with
      three fingers, at approximately one-quarter normal tempo. TAP sensors responded
      linearly to graded forces from individual fingers, indicating proportional force
      control. Our results demonstrate the feasibility of restoring some degree of
      finger dexterity by noninvasive sensing of extrinsic tendons.

PMID- 10391582
TI  - Optimization and application of a wrap-spring clutch to a dynamic knee-ankle-foot
      orthosis.
AB  - A dynamic knee-brace system (DKBS) has been designed which provides stance phase
      stability and swing phase freedom. A wrap-spring clutch controls knee flexion.
      Clutch optimization was performed minimizing clutch length. Kinematic tests on a
      normal subject using the DKBS document nearly normal dynamic knee flexion during
      swing (38 degrees versus 53 degrees for normal).

PMID- 10391583
TI  - Automatic control design for a dynamic knee-brace system.
AB  - A self-contained electronically controlled dynamic knee-brace system (DKBS) has
      been designed and tested which allows knee flexion during swing phase, but
      restricts flexion during the stance phase of gait. Cardiovascular energy
      measurements indicate that DKBS use allowed a more energy efficient gait.

PMID- 10391584
TI  - Myoelectric activation pattern during gait in total knee replacement:
      relationship with kinematics, kinetics, and clinical outcome.
AB  - Gait usually presents an excellent improvement after total knee replacement.
      Nevertheless, some abnormalities persist even after a long period of time. The
      abnormal knee patterns have been attributed to several possible causes, such as
      implant geometry and surgical technique, posterior cruciate ligament
      sparing/sacrificing, preoperative "stiff-knee" pattern due to pain and altered
      biomechanics, weakness of the extensor muscles, preoperative arthritic pattern,
      proprioceptive deficiency, and multijoint degenerative involvement. Cocontraction
      of the knee flexors and extensors is a common strategy adopted to reduce strain
      and shear forces at the joint, but it increases compressive forces and joint
      loading. Even in patients with an excellent functional score, the duration of the
      implant may be compromised by an altered neuromuscular control of the knee. In
      this paper, we report a single case study carried out over two years on a patient
      that underwent total knee replacement. The aim of this work is to show that
      quantitative gait analysis is essential to augment the understanding of the
      mechanisms underlying gait, thus enabling clinicians to adapt the rehabilitation
      program to the specific patient. Although the limits of single case reports are
      obvious, we believe that this evaluation methodology could be beneficial for
      assessing the effectiveness of rehabilitation programs aimed at achieving an
      active control of the knee during gait through a correct muscular activation
      pattern.

PMID- 10391585
TI  - The effects of epimysial electrode location on phrenic nerve recruitment and the
      relation between tidal volume and interpulse interval.
AB  - Electrode location is of vital importance to diaphragm pacing devices using
      electrodes implanted on the diaphragm. Complete phrenic nerve recruitment with a
      single epimysial electrode implanted on the abdominal surface of the diaphragm
      required placement within 1 cm of the motor point. Recruitment could be increased
      further using multiple electrodes, provided the electrodes were implanted on
      opposite sides of the phrenic nerve motor point. The location of the implanted
      electrode relative to the phrenic nerve motor point also affected the relation
      between the stimulus interpulse interval (IPI) and the measured tidal volume.
      Specifically, we found that electrodes implanted lateral to the phrenic nerve
      motor point had different tidal volume--IPI relations than electrodes placed
      anterior or posterior to the motor point. We concluded that properly placed
      epimysial electrodes are required to obtain adequate phrenic nerve recruitment
      for full time ventilation and knowledge of the relative location of the electrode
      with respect to motor point is necessary to predict the tidal volume produced by
      a specific IPI.

PMID- 10391586
TI  - Evaluation of a suture electrode for direct bladder stimulation in a lower motor
      neuron lesioned animal model.
AB  - The purpose of this study was to evaluate a "suture" type electrode for direct
      bladder stimulation in an animal model of a lower motor neuron lesion. During an
      initial surgery, five male cats were instrumented under anesthesia using
      multistranded, 316 LVM, stainless-steel, wire electrodes implanted on the bladder
      wall serosa above the trigone area. Electrodes were constructed with a needle
      attached to the end that was removed after suturing the electrode in place.
      Additional instrumentation included urinary bladder catheters (tubes) for
      pressure recording and filling, and hook type electrodes for leg and pelvic floor
      electromyography recording. Chronic bladder filling and stimulation studies were
      conducted in tethered animals three to four weeks following surgery. To test
      these electrodes in a spinal cord injury model, a lower motor neuron lesion was
      performed including the sacral cord and complete nerve roots at L6 and below.
      These animals were evaluated during weeks 3 and 10 after injury. Direct bladder
      stimulation induced active contractions and voiding both before and after spinal
      cord injury. Effective stimulation parameters consisted of 40 pulses per s, 300
      micros to 1 ms pulse duration, a stimulation period from 3 to 4 s, and a
      stimulation current from 10 to 40 mA. Fluoroscopy revealed an open membranous
      urethra during stimulation and following stimulation. A small diameter penile
      urethra was observed to limit flow. Postmortem evaluation of the suture electrode
      revealed no abnormalities such as corrosion, migration into the bladder lumen or
      displacement. These findings indicate that suture electrodes are suitable and
      effective for short-term implantation in the lower motor neuron animal model.

PMID- 10391587
TI  - A new strategy for controlling the level of activation in artificially stimulated
      muscle.
AB  - Distributed stimulation of slow skeletal muscle has previously been used to
      produce smooth tetanic contractions at low stimulus rates. This involved
      distributed or interleaved stimulation of portions of the muscle with near equal
      tension contributions. Extending this to fast and mixed muscle encounters
      difficulties in getting and maintaining equal twitch responses for the portions.
      This need has now been circumvented by using distributed stimulation with unequal
      interpulse intervals. Described here is a microprocessor-based eight channel
      distributed muscle stimulator that can adjust stimulation timing to produce an
      optimally smooth tension over a range of stimulus rates even when the portions
      are unequal. This design is based on modeling results. Distributed stimulation
      experiments performed on skeletal muscle show that this method can be used to
      achieve smooth tension at physiological stimulus rates, which should reduce
      fatigue. This has important implications in functional neuromuscular stimulation
      (FNS) as well as in enabling experiments to be conducted to characterize the
      biomechanical behavior of partially activated fast and mixed muscle.

PMID- 10391588
TI  - Adaptive noncontact gesture-based system for augmentative communication.
AB  - An adaptive noncontact gesture-based system for augmentative communication is
      described. The system detects movement of any anatomical site through the
      analysis of reflected speckle. This movement is converted into two-dimensional (2
      D) cursor coordinates and an adaptive software interface provides click actions
      and decision strategies. The system requires no accessory to be placed on the
      user. The system was developed in conjunction with user groups, who participated
      in the evaluation of the system. The usability results obtained illustrate the
      utility of the system. The system also compared favorably with other interface
      solutions.

PMID- 10391589
TI  - Neurofuzzy adaptive controlling of selective stimulation for FES: a case study.
AB  - A controller was designed for the selective stimulation of the sciatic nerve with
      a multiple contact cuff electrode to generate a desired torque in the ankle joint
      of cat. The design integrates three approaches, artificial neural network (ANN)
      modeling, fuzzy logical adaptation, and geometrical mapping. The geometrical
      mapping refers to the vector transformation from the joint coordinates to the
      virtual muscle coordinates which have been conceptually developed to represent
      the major recruitment features of contact-based functional units in the physical
      plant. This method reduces the complexity of generating a data set for training
      the neural network in the feedforward path and implementing the on-line learning
      algorithm embedded in the feedback loop. The controller was evaluated by computer
      simulation with the experimental data obtained from the torque generation in five
      acute cats. The results show that the ANN-based feedforward is capable of
      predicting 65% of a given desired isometric torque, and the fuzzy logical machine
      is able to provide suitable gains for feedback modulation to reduce the error
      from 35 to 8.5% and produce a robust control.

PMID- 10391590
TI  - System identification of tendon reflex dynamics.
AB  - Patellar tendon reflexes were evaluated in 12 healthy adult subjects using
      several measures of the reflex responses and of the system input-output
      relationship. A hand-held instrumented hammer was used to tap the patellar tendon
      and to elicit the reflex response. Tendon reflex dynamics were estimated using
      the recorded tapping force (as input) and the quadriceps muscle electromyogram
      and knee joint extension torque signals (as output). A dome-shaped rubber pad was
      mounted onto the most sensitive spot on the patellar tendon, where it served as a
      tapping target, and helped to reduce the reflex variability significantly (p <
      0.01). The input-output properties of the system relating the reflex torque to
      the tapping force were characterized using several measures: the tendon reflex
      gain (Gtr), contraction rate (Rc), and half-relaxation rate (Rhr). Reflex loop
      delay (t(d)) was estimated using the delay from the onset of tapping force to the
      onset of reflex torque. We determined that these system parameters provided
      significantly more repeatable and consistent characterization of tendon reflexes
      than did reflexive torque or EMG signals alone (p < 0.025). The input-output
      relationship relating the EMG signals of the stretched muscle to the tapping
      force was also identified to help characterize neuromuscular dynamics of tendon
      reflexes. The observed sensitivity and consistency of the reflex system measures
      suggest that with appropriate simplification of the instrumentation, these
      methods may prove useful in routine clinical practice, and may allow more precise
      quantification of the tendon jerk than is currently feasible with standard
      clinical tests.

PMID- 10391591
TI  - Electronic design of a multichannel programmable implant for neuromuscular
      electrical stimulation.
AB  - An advanced stimulator for neuromuscular stimulation of spinal cord injured
      patients has been developed. The stimulator is externally controlled and powered
      by a single encoded radio frequency carrier and has four independently controlled
      bipolar stimulation channels. It offers a wide range of reprogrammability and
      flexibility, and can be used in many neuromuscular electrical stimulation
      applications. The implant system is adaptable to patient's needs and to future
      developments in stimulation algorithms by reprogramming the stimulator. The
      stimulator is capable of generating a wide range of stimulation waveforms and
      stimulation patterns and therefore is very suitable for selective nerve
      stimulation techniques. The reliability of the implant has been increased by
      using a forward error detection and correction communication protocol and by
      designing the chip for structural testability based on scan test approach.
      Implemented testability scheme makes it possible to verify the complete
      functionality of the implant before and after implantation. The stimulators
      architecture is designed to be modular and therefore its different blocks can be
      reused as standard building blocks in the design and implementation of other
      neuromuscular prostheses. Design for low-power techniques have also been employed
      to reduce power consumption of the electronic circuitry.

PMID- 10391592
TI  - Control of FES thumb force using slip information obtained from the cutaneous
      electroneurogram in quadriplegic man.
AB  - A tetraplegic volunteer was implanted with percutaneous intramuscular electrodes
      in hand and forearm muscles. Furthermore, a sensory nerve cuff electrode was
      implanted on the volar digital nerve to the radial side of the index finger
      branching off the median nerve. In laboratory experiments a stimulation system
      was used to produce a lateral grasp (key grip) while the neural activity was
      recorded with the cuff electrode. The nerve signal contained information that
      could be used to detect the occurrence of slips and further to increase
      stimulation intensity to the thumb flexor/adductor muscles to stop the slip.
      Thereby the system provided a grasp that could catch an object if it started to
      slip due to, e.g., decreasing muscle force or changes in load forces tangential
      to the surface of the object. This method enabled an automatic adjustment of the
      stimulation intensity to the lowest possible level without loosing the grip and
      without any prior knowledge about the strength of the muscles and the weight and
      surface texture of the object.

PMID- 10391593
TI  - A simple radiographic measurement method for polyethylene wear in total knee
      arthroplasty.
AB  - This study describes a new method for evaluating polyethylene wear in total knee
      arthroplasty. Since the amount of wear is dependent on a number of variables such
      as the weight and activity of the patient, it should be estimated based on in
      vivo measurements. We used a computer vision technique called three
      dimensional/two-dimensional (3-D/2-D) matching to perform in vivo assessment
      using a single-plane radiograph. Using the 3-D/2-D matching algorithm we
      estimated the 3-D position and orientation of each knee implant and then measured
      the femorotibial distance, which is defined as the shortest perpendicular
      distance from the tibial tray to the femoral component. The accuracy of the
      proposed 3-D/2-D matching method was determined by in vitro investigations. The
      worst errors in in-plane/out-of-plane translations and rotations were 0.20/1.95
      mm and 0.17/0.29 degrees, respectively. The root-mean-square error in
      femorotibial distance measurements using real polyethylene inserts was 0.04 mm.
      Results of in vivo femorotibial distance measurements are also described.

PMID- 10391595
TI  - An audio- and speech-based interface for computer-controlled scientific
      instruments.
AB  - Laboratory instruments are intrinsic to research and work in a wide array of
      scientific fields. They are used for the control of devices, data storage, and
      data analysis. The control of instruments is increasingly changing from
      independent on-instrument controls to multiple instrument integrate software
      control. Unfortunately, the graphical representation of controls and data makes
      it difficult for an individual with a visual impairment to independently operate
      laboratory instruments. Alternative interfaces have been previously developed for
      these individuals but have often proved limited in scope and accuracy, or
      otherwise expensive. The resulting inaccessibility to affordable and accurate
      scientific instrumentation, unfortunately, discourages many individuals with a
      visual impairment from entering scientific fields of research or work. This paper
      introduces an alternative interface method developed for LabVIEW, National
      Instruments' instrumentation software package. The method is specifically
      designed for individuals with visual impairments, and uses alternative navigation
      techniques as well as audio feedback. The developed user interface uses simple
      keyboard inputs to traverse through a hierarchical tree-based menu system. Speech
      and audio tones are used to alert the user to system settings and errors, as well
      as a help mechanism and data analysis tool. At this time, alternative interfaces
      have been developed for the following basic laboratory instruments: an
      oscilloscope and function/arbitrary waveform generator. The interface
      methodology, however, can be extended to include any scientific instrument that
      can be controlled by LabVIEW.

PMID- 10391594
TI  - Computer simulation and sled test validation of a powerbase wheelchair and
      occupant subjected to frontal crash conditions.
AB  - The Americans with Disabilities Act (ADA) has led to an increased number of
      wheelchair users seeking transportation services. Many of these individuals are
      unable to transfer to a vehicle and are instead required to travel seated in
      their wheelchairs. Unfortunately, wheelchairs are not typically designed with the
      same occupant protection features as motor vehicle seats, and wheelchair seated
      occupants may be at higher risk for injury in a crash. To study the effects of
      crash level forces on wheelchairs and their occupants, it is useful to simulate
      crash conditions using computer modeling. This study has used a dynamic lumped
      mass crash simulator, in combination with sled impact testing, to develop a model
      of a secured commercial powerbase and restrained occupant subjected to a 20 g/30
      mph frontal motor vehicle crash. Time histories profiles of simulation-generated
      wheelchair kinematics, occupant accelerations, tiedown forces and occupant
      restraint forces were compared to sled impact testing for model validation.
      Validation efforts for this model were compared to validation results found
      acceptable for the ISO/SAE surrogate wheelchair model. This wheelchair-occupant
      simulation model can be used to investigate wheelchair crash response or to
      evaluate the influence of various factors on occupant crash safety.

PMID- 10391596
TI  - Robotic assistance of an active upper limb exercise in neurologically impaired
      patients.
AB  - The principle of using robotic techniques to assist an active upper limb exercise
      is demonstrated in ten patients with weakness and spasticity. Using a servo motor
      to apply torque about the elbow, the mean range of active extension-flexion was
      increased in every patient. Sample kinematic and electromyographic (EMG) data are
      given.

PMID- 10391597
TI  - Perioperative cardiac arrest and resuscitation: do we know what we're doing?

PMID- 10391598
TI  - Inhalation anesthetics and Duchenne's muscular dystrophy.

PMID- 10391599
TI  - Perioperative resuscitation knowledge base.
AB  - PURPOSE: To assess the knowledge base of Canadian anesthesiologists regarding the
      management of perioperative cardiac arrest. METHODS: A random sample of 200
      Canadian Anesthesia Society members were mailed a survey composed of 10 clinical
      vignettes, each involving a special perioperative resuscitation situation, with
      six multiple choice options for optimum management. Fourteen possible "lethal
      errors" (options which are unequivocally harmful to the patient) were identified
      among the possible choices. Each question had a single correct answer and
      contributed a single point towards a possible maximum of ten. An arbitrary
      passing score of 70%, similar to the American Heart Association (AHA) standard
      for Advanced Cardiac Life Support course (ACLS), was selected. Respondents were
      asked demographic information including: time since completing residency, time
      since last ACLS course, provision of cardiac anesthesia and attitude towards
      utility of AHA protocols in anesthesia practice. RESULTS: A total of 124 surveys
      were returned. The median score was five with a range of scores from zero to
      nine. Fifty-eight (56.3%) participants chose at least one "lethal error". Only 17
      respondents (13.7%) attained the minimum score of 70% and avoided a "lethal
      error". Respondents who practiced cardiac anesthesia tended to achieve higher
      scores (P < 0.05) than generalists. All but one participant indicated that a
      Continuing Medical Education resource covering this material would be useful.
      CONCLUSIONS: This survey demonstrates a knowledge deficit concerning special
      perioperative resuscitation situations. Development of further appropriate
      research and educational material in this area is justified.

PMID- 10391600
TI  - Cost-effectiveness of prophylactic dolasetron or droperidol vs rescue therapy in
      the prevention of PONV in ambulatory gynecologic surgery.
AB  - PURPOSE: To assess the cost-effectiveness of prophylactic therapy (1.25 mg
      droperidol or 50 mg dolasetron i.v.) vs no prophylaxis (rescue therapy) for the
      prevention of post-operative nausea and vomiting (PONV) from a Canadian hospital
      perspective. METHODS:  DESIGN: A predictive decision analytic model using
      previously published clinical and economic evaluations, and costs of medical care
      in Canada. SUBJECTS: Ambulatory gynecology surgery patients. INTERVENTIONS: Three
      strategies administered prior to emergence from anesthesia were compared: 1.25 mg
      droperidol i.v., 50 mg dolasetron i.v.; and no prophylaxis (rescue therapy).
      RESULTS: The base case mean cost per patient receiving dolasetron prophylaxis was
      $28.08 CAN compared with $26.88 CAN per patient receiving droperidol prophylaxis,
      resulting in a marginal cost of $1.20 CAN. This difference translated in an
      additional cost of $12.00 CAN for the dolasetron strategy per adverse event
      avoided over the droperidol strategy. The base case mean cost per patient not
      receiving prophylaxis was $26.92 resulting in marginal costs of $1.16 CAN and
      $0.04 CAN when compared to dolasetron and droperidol, respectively. Compared with
      the no prophylaxis strategy, dolasetron prophylaxis resulted in an incremental
      cost-effectiveness ratio of $5.82 CAN per additional PONV-free patient. The mean
      costs incurred per PONV-free patient were calculated to be $48.41 for the
      dolasetron strategy, $46.34 for the droperidol strategy and $70.83 for the no
      prophylaxis strategy. CONCLUSIONS: Dolasetron and droperidol given
      intraoperatively were more cost-effective than no prophylaxis for PONV in
      patients undergoing ambulatory gynecologic surgery. The difference between the
      two agents was small and favoured droperidol. The model was robust to plausible
      changes through sensitivity analyses.

PMID- 10391601
TI  - Delayed postoperative gastric emptying following intrathecal morphine and
      intrathecal bupivacaine.
AB  - PURPOSE: A decrease in the rate of gastric emptying can delay resumption of
      enteral feeding, alter bioavailability of orally administered drugs, and result
      in larger residual gastric volumes, increasing the risk of nausea and vomiting.
      We compared the effects of 1) intrathecal bupivacaine (17.5 mg) and 2) the
      combination of intrathecal morphine (0.6 mg) and intrathecal bupivacaine (17.5
      mg) on the rate of gastric emptying in patients undergoing elective hip
      arthroplasty. METHODS: Twenty four fasting ASA 1-3 patients were randomly
      assigned, in a double blind manner, to receive intrathecal hyperbaric bupivacaine
      (17.5 mg), either alone (group 1), or followed by intrathecal morphine (0.6 mg)
      (group 2). Gastric emptying was measured (using an acetaminophen absorption
      technique), twice in each patient; preoperatively, and approximately one hour
      postoperatively. Gastric emptying parameters are: AUC (area under the plasma
      acetaminophen concentration time curve), maximum plasma acetaminophen
      concentration (Cmax), and time to Cmax (tCmax), analyzed using paired Student's t
      tests. RESULTS: Gastric emptying rates were reduced in both group 1 (AUC = 14.98
      (3.8) and 11.05 (4.6) pre- and postoperatively, respectively) and group 2 (AUC =
      13.93 (3.59) and 6.4 (3.42) pre- and postoperatively, respectively); the
      magnitude of the reduction was greater in group 2 [AUC (P = 0.04), Cmax (P =
      0.05), tCmax (P = 0.13)]. CONCLUSION: The combination of intrathecal morphine
      (0.6 mg) and intrathecal bupivacaine (17.5 mg) delays gastric emptying
      postoperatively.

PMID- 10391602
TI  - Cerebral blood flow velocity during isovolemic hemodilution and subsequent
      autologous blood retransfusion.
AB  - PURPOSE: To quantify the influence of hematocrit on cerebral blood flow velocity
      (CBFV) in healthy volunteers undergoing acute isovolemic hemodilution (HD) with
      hydroxyethyl starch 10% (HES) and subsequent autologous whole blood retransfusion
      (RT). METHODS: In 11 volunteers 20 ml x kg(-1) blood was withdrawn over 30 min
      and simultaneously replaced with HES 10%. Thirty min later, RT was started at a
      constant rate over 30 min. Recorded parameters included: CBFV pulsatility-index
      (PI) and resistance-index (RI) of the middle cerebral artery (MCA). Blood
      pressure (BP), heart rate (HR), hemoglobin (Hb), hematocrit (Hc) peripheral O2
      saturation (SpO2), P(ET)CO2, arterial oxygen content (CaO2) and cerebral arterial
      O2-transport (C(E)-DO2= CaO2 x Vm-MCA) were monitored. RESULTS: An average of
      1570 total blood was withdrawn which resulted in a decrease in Hb from 14.5 mg x
      dl(-1) to 10.3 mg x dl(-1); Hc (and CaO2) decreased from 41.8% (19.8 ml x dl(-1))
      to 29.6% (14.2 ml x dl(-1); P < 0.01). Vm-MCA increased from 61.2 cm x sec(-1) to
      77.3 cm x sec(-1) (P < 0.01). Following RT, Vm-MCA decreased again, but remained
      higher than baseline (P < 0.01). PI decreased by 13% following RT (P < 0.05).
      There were no changes in RI, HR, BP SpO2 and P(ET)CO2. Regression lines could be
      fitted between Hc and Vm-MCA, Vm-MCA and CaO2, and between Hc and C(E)DO2.
      CONCLUSIONS: Transcranial Doppler changes in blood flow velocities correlated
      with the simultaneously recorded systemic Hc and CaO2 values. We found a 2%
      increase in CBFV for each 1% decrease in Hc and CaO2.

PMID- 10391603
TI  - Comparison of the flexible and standard laryngeal mask airways.
AB  - PURPOSE: To determine mucosal pressures, ease of insertion, mask position and
      oropharyngeal leak pressures for the flexible (FLMA) and standard laryngeal mask
      airway (LMA). METHODS: Forty anesthetized, paralysed adult patients were randomly
      allocated to receive either the FLMA or LMA. Microchip sensors were attached to
      the LMA or FLMA at identical locations corresponding to the base of tongue,
      hypopharynx, lateral pharynx, oropharynx, posterior pharynx and pyriform fossa.
      Mucosal pressure, oropharyngeal leak pressure (OLP) and mask position (assessed
      fibreoptically) were recorded during inflation of the cuff from 0-40 ml in 10 ml
      increments. RESULTS: Ease of insertion and mask position were similar between
      devices. Mean OLP was higher for the LMA (22 vs 19 cm H2O), but the maximum OLP
      was similar (25 vs 24 cm H2O). Mean mucosal pressures were generally low (< 12 cm
      H2O) for both devices, but were higher for the LMA in the lateral pharynx (4 vs 1
      cm H2O) and oropharynx (13 vs 3 cm H2O) and higher in the posterior pharynx for
      the FLMA (4 vs 2 cm H2O). The OLP for both devices increased with increasing
      intracuff volume from 0-10 ml and 10-20 ml, and from 20-30 ml for the FLMA.
      CONCLUSIONS: We conclude that the LMA and FLMA perform similarly in terms of ease
      of insertion and mask position, but OLP and mucosal pressures are slightly higher
      for the LMA. Pharyngeal mucosal pressures for both devices are lower than those
      considered safe for the tracheal mucosa. The overall clinical performance between
      the two devices is similar.

PMID- 10391604
TI  - Rhabdomyolysis in association with Duchenne's muscular dystrophy.
AB  - PURPOSE: To present a case of rhabdomyolysis which developed in a child with a
      known history of Duchenne's muscular dystrophy, following an anesthetic which
      included sevoflurane. CLINICAL FEATURES: An 11 yr old boy with a known history of
      Duchenne's muscular dystrophy underwent anesthesia for strabismus repair. The
      anesthetic consisted of sevoflurane and nitrous oxide without the use of a muscle
      relaxant. His postoperative course was complicated by a complaint of heel pain
      and the development of myoglobinuria. He was treated with dantrolene sodium and
      discharged home after two days, without further complication. CONCLUSION:
      Sevoflurane anesthesia has not been shown previously to be associated with the
      development of acute rhabdomyolysis in a child with a history of Duchenne's
      muscular dystrophy. As with halothane and isoflurane, the continued use of
      sevoflurane in the presence of Duchenne's muscular dystrophy should be
      questioned.

PMID- 10391605
TI  - Factitious halothane detection during trigger-free anesthesia in a malignant
      hyperthermia susceptible patient.
AB  - PURPOSE: To discuss the problems encountered when halothane was detected in a
      presumed 'clean' patient circuit during the 'trigger-free' anesthetic management
      of a known Malignant Hyperthermia Susceptible (MHS) patient for routine
      orthopedic surgery. CLINICAL FEATURES: A 29-yr-old MHS woman had a wrist
      arthroscopy/exploration/fusion under general anesthesia. During the course of the
      'trigger-free' anesthetic the respiratory gas analyser detected end-tidal
      halothane in the patient circuit. The patient was disconnected from the circuit
      as attempts to identify the source of the readings were undertaken. After ruling
      out the presence of halothane by various clinical manoeuvre the patient was
      reconnected to the circuit without sequelae. CONCLUSION: By exclusion the problem
      was presumed to be a factitious reading resulting from the respiratory gas
      analyser incorrectly identifying patient-expired methane as halothane.

PMID- 10391607
TI  - General anesthesia with remifentanil for Cesarean section in a parturient with an
      acoustic neuroma.
AB  - PURPOSE: To describe the anesthetic management of a parturient with a large
      acoustic neuroma undergoing general anesthesia with remifentanil for Cesarean
      section. CLINICAL FEATURES: A near-term parturient presented with a large
      intracranial mass. Cesarean section under general anesthesia was elected one week
      prior to craniotomy for tumour resection. Remifentanil infusion, 0.2-1.0 microg x
      kg(-1) x min(-1), was used from induction to emergence of general anesthesia. The
      neonate was born seven minutes after the remifentanil infusion was started. She
      had normal umbilical cord pH and her Apgar scores were 7 and 8, at one and five
      minutes respectively. Although the neonate received supplemental oxygen, she did
      not require naloxone. Both mother and neonate made an uneventful recovery.
      CONCLUSION: Remifentanil was effective in producing stable hemodynamic
      conditions, without severe neonatal respiratory depression, during induction and
      maintenance of general anesthesia for a Cesarean delivery in a parturient with a
      large intracranial tumour.

PMID- 10391606
TI  - Combined lung and liver transplantation in a girl with cystic fibrosis.
AB  - PURPOSE: To describe the anesthetic considerations of a combined lung and liver
      transplant in a 14-yr-old girl with cystic fibrosis. CLINICAL FEATURES: A 14 yr
      old girl with cystic fibrosis presented for combined liver and lung
      transplantation. Anesthetic management was complex in that the pulmonary,
      hemodynamic, and hematological changes after cardiopulmonary bypass and lung
      transplantation made the management of the subsequent liver transplant unique. We
      used a moderate dose fentanyl and isoflurane anesthetic with invasive monitoring
      including a pulmonary artery catheter. Upon reperfusion of the new liver our
      patient exhibited severe pulmonary hypertension that was associated with a
      decrease in cardiac output and systemic hypotension. Utilizing a pulmonary artery
      catheter, this episode was treated with an increase of prostaglandin E1 (PGE1)
      infusion to 0.025 microg x kg(-1) x min(-1) and the initiation of 3 microg x kg(
      1) x min(-1) dobutamine. The pulmonary hypertension resolved and the cardiac
      output and blood pressure returned to baseline levels. CONCLUSION: The anesthetic
      considerations for a combined lung and liver transplant are complex because of
      the interactions and alterations in cardiovascular, pulmonary and hemostatic
      systems. The use of a pulmonary artery catheter was critical to the management of
      our patient because it allowed us to accurately treat an episode of hypotension
      occurring during liver transplantation. This episode was secondary to acute
      pulmonary hypertension which is common after pulmonary transplantation but
      unusual during liver transplantation. It is also critical that a team approach is
      used to consider all of the concerns of the multiple services managing these
      complex patients.

PMID- 10391608
TI  - The treatment of heparin resistance with Antithrombin III in cardiac surgery.
AB  - PURPOSE: To report three patients who developed heparin resistance during cardiac
      surgery which was successfully managed with 1000 U Antithrombin III (AT III).
      CLINICAL FEATURES: We observed heparin resistance prior to cardiopulmonary bypass
      (CPB) in one patient and during the CPB in two patients. In the first patient who
      was scheduled for mitral valve replacement, although heparin was administered
      sequentially up to 500 U x kg(-1) prior the CPB, the ACT value was 354 sec. After
      1,000 U ATIII were administered the ACT was 395 sec and CPB was initiated. The
      ACT remained between 496 and 599 sec throughout CPB and a total of 260 mg
      protamine sulfate was given. In the other two patients following 300 U x kg(-1)
      heparin, the ACT was up to 400 sec and CPB was initiated. During CPB, ACT were
      decreased 360 sec and 295 sec in patients II and III respectively. Although
      heparin was added 1,500 U, ACT increased to > or = 400 sec could not be achieved.
      In the second patient ATIII activity was found 10%. After the administration of
      1,000 U ATIII, ATIII activity was found to be 67% 40 min later and ACT were
      increased up to 400 sec. There was no thrombosis within the extracorporeal
      circuit, additional heparin was not required, less protamine was administered (<
      or = 3 mg x kg(-1)) and no excessive postoperative bleeding was observed in all
      patients. CONCLUSION: We recommend that AT III supplementation should be
      considered to manage heparin resistance prior or during CPB in patients
      undergoing open heart surgery.

PMID- 10391610
TI  - Propofol prevents delayed neuronal death following transient forebrain ischemia
      in gerbils.
AB  - PURPOSE: This study was conducted to ascertain whether propofol may protect
      against delayed neuronal death in the hippocampal CA1 subfield in gerbils.
      METHODS: Thirty-five gerbils were randomly assigned to five groups: Group I, the
      control group, a sham operation treated with physiological saline solution (PSS);
      Group II, ischemia/reperfusion treated with PSS; Group III, ischemia/reperfusion
      treated with 50 mg x kg(-1) propofol; Group IV, ischemia/reperfusion treated with
      100 mg x kg(-1) propofol; Group V ischemia/reperfusion treated with 150 mg x kg(
      1) propofol. Transient forebrain ischemia was induced by occluding the bilateral
      common carotid arteries for four minutes under N2O/O2/halothane anesthesia after
      administration of propofol or PSS. Five days later, histopathological changes in
      the hippocampal CA1 subfield were examined using a light microscope and
      degenerative ratio of the pyramidal cells were measured according to the
      following formula: (number of degenerative pyramidal cell/total number of
      pyramidal cells per 1 mm of hippocampal CA1 subfield) x 100. RESULTS: In group
      II, the pyramidal cells were atrophic and pycnotic; vacuolation and structural
      disruption of the radial striated zone was observed. In the other four groups,
      these changes were not observed. The degenerative ratios of pyramidal cells were
      as follows; group I: 5.9 +/- 1.9%, group II: 94.6 +/- 2.5% (P < 0.01), group III:
      10.7 +/- 1.7%, group IV: 9.7 +/- 1.8%, group V: 9.2 +/- 1.9%. CONCLUSION: This
      study suggests that propofol may prevent delayed neuronal death in the
      hippocampal CA1 subfield after cerebral ischemia/reperfusion in gerbils.

PMID- 10391609
TI  - Rats show unimpaired learning within minutes after recovery from single bolus
      propofol anesthesia.
AB  - PURPOSE: To examine the learning ability of rats shortly after recovery from a
      bolus dose of propofol by assessing learning on a swim-to-platform task. Also,
      muscarinic blockade was used as a pharmacological test of whether learning
      shortly after propofol anesthesia resembles normal learning. METHODS: Propofol
      anesthetized rats (15-20 mg x kg(-1) i.v.) were trained on a swim-to-platform
      task five to seven minutes after recovering from surgical anesthesia and tested
      two to three hours later In addition, the muscarinic antagonist scopolamine
      hydrobromide (5 mg x kg(-1) s.c.) was given to a subgroup of rats before testing.
      During 10 trials, the number of times a given rat took 10 sec or longer to locate
      and climb onto a visible platform was tabulated and counted as errors. RESULTS:
      When trained shortly after recovery from the anesthetic, propofol anesthetized
      rats made 3.2 +/- 0.4 compared with 1.0 +/- 0.1 errors in controls (P < 0.0001).
      Two to three hours later both groups performed equally well. Rats trained after
      propofol anesthesia and given scopolamine before testing made 0.7 +/- 0.5 errors
      and performed as well as normal controls, 1.2 +/- 0.2 errors when subjected to
      the same procedures without propofol anesthesia, and better than scopolamine
      treated untrained rats, 5.5 +/- 0.7 errors, (P < 0.05). CONCLUSION: Training five
      to seven minutes after recovery from propofol anesthesia resulted in normal
      retention of the swim- to-platform task. It also produced the same resistance to
      the disruptive effects of scopolamine as did training in rats that were not
      anesthetized. Thus, the ability to learn recovers rapidly after propofol
      anesthesia induced by a single intravenous bolus dose.

PMID- 10391613
TI  - New media.

PMID- 10391611
TI  - Landiolol decreases a dysrhythmogenic dose of epinephrine in dogs during
      halothane anesthesia.
AB  - PURPOSE: To examine the effect of landiolol (ONO-1101), a new ultra-short acting
      and highly selective beta blocker, on epinephrine-induced ventricular arrhythmias
      in halothane-anesthetized dogs. METHODS: We administered five different doses (0,
      0.1, 0.5, 1.0, 10 microg x kg(-1) x min(-1)) landiolol and determined the
      dysrhythmogenic dose of epinephrine (DDE), defined as the smallest dose producing
      four or more PVCs within 15 sec, at each dose of landiolol and after cessation of
      infusion. RESULTS: The control value of DDE during 1.3 MAC halothane anesthesia
      was 1.26 +/- 0.44 (mean +/- SD) microg x kg(-1) x min(-1) and the corresponding
      plasma concentration of epinephrine (PCE) was 12.2 +/- 8.3 ng x ml(-1).
      Concomitant administration of 10 microg x kg(-1) x min(-1) landiolol increased
      DDE and corresponding PCE (P < 0.05). At 30 min after cessation of landiolol
      infusion, DDE and corresponding PCE returned to the control values. CONCLUSIONS:
      Landiolol, at a dose of 10 microg x kg(-1) x min(-1), has an antiarrhythmic
      effect on epinephrine-induced ventricular arrhythmias in dogs during anesthesia
      with halothane.

PMID- 10391612
TI  - Inhaled nitric oxide does not alter pulmonary or cardiac effects of fat embolism
      in dogs after cemented arthroplasty.
AB  - PURPOSE: We examined the effect of inhaled nitric oxide (NO) on the acute
      pulmonary hypertension and right ventricular (RV) dilation after fat embolism.
      METHODS: A bilateral cemented arthroplasty (BCA), created fat embolism in 20
      dogs. In Part A, 12 dogs were randomized to an NO group (n=6, inhaled NO 40 ppm
      before BCA and throughout the study) or a control group (n=6). In Part B, a third
      group of dogs (n=8) were given NO 20-40 ppm 2-3 min after BCA when pulmonary
      artery pressure (PAP) increased. Transesophageal echocardiography (TEE) and
      invasive hemodynamic monitoring evaluated the hemodynamic response to BCA.
      Postmortem, quantitative morphometry was used to estimate the number of fat
      emboli and diameter of lung vessel occluded by fat. RESULTS: Part A: The increase
      in PAP in the NO group (16 +/- 1 to 34 +/- 9 mmHg) within three minutes of BCA
      was not different from that in the control group (14 +/- 4 to 35 +/- 9 mmHg).
      Within three minutes of BCA, TEE demonstrated RV dilation in all groups (P <
      0.05) but there was no difference in the change in RV area in the NO and control
      groups. When NO was given after BCA, no difference in PAP or RV dilation was
      noted from that in the control group. There were no differences, at post mortem,
      between the groups in the diameter of lung vessel occluded by fat CONCLUSION:
      Whether given before the embolic insult or two to three minutes after the onset
      of pulmonary hypertension, inhaled NO did not attenuate the acute pulmonary
      hypertension or RV dilation after cemented arthroplasty.

PMID- 10391614
TI  - Trachlight -- learning tips.

PMID- 10391615
TI  - Loss of resistance to saline -- does the dripping bother you?

PMID- 10391616
TI  - Transthoracic echocardiography in perioperative medicine.

PMID- 10391617
TI  - Paroxysmal sneezing during local anesthesia for ocular surgery with thiopentone
      hypnosis.

PMID- 10391618
TI  - Laryngoscopy for pediatric laryngeal mask airway insertion.

PMID- 10391619
TI  - Time-intensity trading in the late auditory evoked potential.
AB  - The present study investigated physiological correlates of the time-intensity
      trading relationship in late components (N1, P2) of the auditory evoked
      potential. Late-potential and behavioral thresholds were estimated in five normal
      hearing, young adult participants for 1000- and 4000-Hz tone bursts having
      durations of 8, 16, 32, 64, and 128 ms. The results showed that late-potential
      thresholds decreased by an average of 24 dB for 1000-Hz conditions and 18 dB for
      4000-Hz conditions. Behavioral thresholds also improved by about 22 dB and 18 dB
      for 1000-Hz and 4000-Hz conditions, respectively. The slope of improvement for
      both late-potential and behavioral thresholds was on the order of -4 to -6 dB per
      doubling of stimulus duration, depending on stimulus frequency. Stimulus duration
      also influenced latency and amplitude measures of the N1 and P2 components such
      that response latency decreased and amplitude increased as stimulus duration
      increased. The present results demonstrate a time-intensity trading relationship
      in components of the late potentials that is consistent with previous
      psychophysical and physiological data.

PMID- 10391620
TI  - Attention to facial regions in segmental and prosodic visual speech perception
      tasks.
AB  - Two experiments were conducted to test the hypothesis that visual information
      related to segmental versus prosodic aspects of speech is distributed differently
      on the face of the talker. In the first experiment, eye gaze was monitored for 12
      observers with normal hearing. Participants made decisions about segmental and
      prosodic categories for utterances presented without sound. The first experiment
      found that observers spend more time looking at and direct more gazes toward the
      upper part of the talker's face in making decisions about intonation patterns
      than about the words being spoken. The second experiment tested the Gaze
      Direction Assumption underlying Experiment 1--that is, that people direct their
      gaze to the stimulus region containing information required for their task. In
      this experiment, 18 observers with normal hearing made decisions about segmental
      and prosodic categories under conditions in which face motion was restricted to
      selected areas of the face. The results indicate that information in the upper
      part of the talker's face is more critical for intonation pattern decisions than
      for decisions about word segments or primary sentence stress, thus supporting the
      Gaze Direction Assumption. Visual speech perception proficiency requires learning
      where to direct visual attention for cues related to different aspects of speech.

PMID- 10391621
TI  - Speech perception in a communicative context: an investigation using
      question/answer pairs.
AB  - By diminishing the role of communicative context, traditional tests of speech
      perception may underestimate or misrepresent the actual speech perception
      abilities of adults with a hearing impairment. This study investigates this
      contention by devising an assessment that may better simulate some aspects of
      "real-life" speech perception. A group of 31 participants with a severe-to
      profound hearing impairment took part in a series of speech perception tests
      while wearing their hearing aids. The tests used question/answer or adjacency
      pairs, where the stimulus sentence was preceded by a question spoken by the
      participant. Four conditions were included: (a) where there was no initiating
      sentence, as in a traditional open-set speech perception test; (b) where the
      initiating question was neutral (e.g. "Why?"); (c) where there was a disruptive
      semantic relationship between the question and answer; and (d) where there was a
      strong contextual relationship between the question and answer. The time delay
      between the question and answer was also varied. Results demonstrated that in all
      conditions where there was a preceding question speech perception improved, and
      increasing the cohesion between the question and the reply improved speech
      perception scores. Additionally, time delay and the relatedness of the reply
      interacted. The effects of semantic context appeared to diminish over a 10-s
      period while other linguistic effects remained more constant. These results
      indicate the utility of simulating communicative environments within speech
      perception tests.

PMID- 10391622
TI  - Auditory sequential organization among children with and without a hearing loss.
AB  - The present investigation examined the ability of children with and without a
      hearing loss to correctly reproduce sequences of acoustic stimuli that varied in
      number, temporal spacing, and type. Forty-eight children took part in the
      investigation. They were divided into four groups: two groups of 6- and 7-year
      old children, 12 with normal hearing and 12 with a sensorineural hearing loss;
      and two groups of 9- and 10-year-old children, 12 with normal hearing and 12 with
      a sensorineural hearing loss. All of the children completed auditory temporal
      sequencing tasks with verbal (/ba/ and /da/) and nonverbal (a 1-kHz pure tone and
      a wide band noise) acoustic stimuli. For the 6- and 7-year-old children, the
      results revealed a significant difference between the children with a hearing
      loss and their peers with normal hearing for immediate recall of verbal
      sequences. There were no significant differences in performance between the
      children with a hearing loss and their peers with normal hearing on the nonverbal
      sequencing tasks or on the nonverbal and verbal memory span tasks. For the 9- and
      10-year-old children, the results did not show any significant differences in
      performance between the two groups of children for the reproduction of sequences
      containing more than two verbal or nonverbal elements nor for the auditory memory
      span task when the sequences consisted of verbal stimuli. For the recall of two
      verbal stimuli with a variable interstimulus interval (ISI) duration, the results
      showed that the children with a hearing loss experienced more difficulty than the
      children with normal hearing. Overall, the results indicated that on the auditory
      sequential organization tasks, the poorer performance of the children with a
      hearing loss is likely attributable to auditory perceptual processing deficits
      rather than to poorer short-term memory capabilities. Also, an analysis of the
      data revealed that the older children obtained significantly better results than
      the younger children on auditory sequential organization tasks.

PMID- 10391623
TI  - Effects of rate of presentation on the reception of American Sign Language.
AB  - Previous research on the visual reception of fingerspelled English suggests that
      communication rates are limited primarily by constraints on production. Studies
      of artificially accelerated fingerspelling indicate that reception of
      fingerspelled sentences is highly accurate for rates up to 2 to 3 times those
      that can be produced naturally. The current paper reports on the results of a
      comparable study of the reception of American Sign Language (ASL). Fourteen
      native deaf ASL signers participated in an experiment in which videotaped
      productions of isolated ASL signs or ASL sentences were presented at normal
      playback speed and at speeds of 2, 3, 4, and 6 times normal speed. For isolated
      signs, identification scores decreased from 95% correct to 46% correct across the
      range of rates that were tested; for sentences, the ability to identify key signs
      decreased from 88% to 19% over the range of rates tested. The results indicate a
      breakdown in processing at around 2.5-3 times the normal rate as evidenced both
      by a substantial drop in intelligibility in this region and by a shift in error
      patterns away from semantic and toward formational. These results parallel those
      obtained in previous studies of the intelligibility of the auditory reception of
      time-compressed speech and the visual reception of accelerated fingerspelling.
      Taken together, these results suggest a modality-independent upper limit to
      language processing.

PMID- 10391624
TI  - Acoustical-perceptual correlates of "whisper pitch" in synthetically generated
      vowels.
AB  - The purpose of this investigation was to clarify acoustical-perceptual
      relationships in identification of "pitch" during whispered vowel production. The
      experimenters systematically varied selected acoustic features of synthetically
      generated "whispered" vowels to control which formant frequencies were shifted
      (F1, F2, or F1&F2), the direction of formant frequency shifts (up or down), and
      the magnitude of formant frequency shifts (20 Hz, 40 Hz, 60 Hz). Two sets of
      stimuli were produced to simulate the resonance characteristics of the vowel /a/:
      one set for male talkers and one for female talkers. Ninety-four pairs of
      synthesized vowel tokens were randomly presented to 17 listeners who judged if
      the "pitch" of the second member of the pair was the same, higher, or lower than
      the "pitch" of the first member. The results showed an inverse relationship
      between the magnitude of formant frequency changes presented to the judges and
      the number of perceptual mismatches in "whisper pitch." Also, fewer mismatches in
      the identification of whisper pitch occurred when both F1 and F2 were changed
      simultaneously than when either F1 or F2 was changed individually. No differences
      were found between the perceptual responses to "male" and "female" vowel
      simulations. The primary implication of this study is that whisper pitch is more
      influenced by simultaneous changes in F1 and F2 than by changes in only one of
      the formants.

PMID- 10391625
TI  - Predicting midsagittal pharynx shape from tongue position during vowel
      production.
AB  - The shape of the pharynx has a large effect on the acoustics of vowels, but
      direct measurement of this part of the vocal tract is difficult. The present
      study examines the efficacy of inferring midsagittal pharynx shape from the
      position of the tongue, which is much more amenable to measurement. Midsagittal
      magnetic resonance (MR) images were obtained for multiple repetitions of 11
      static English vowels spoken by two subjects (one male and one female). From
      these, midsagittal widths were measured at approximately 3-mm intervals along the
      entire vocal tract. A regression analysis was then used to assess whether the
      pharyngeal widths could be predicted from the locations and width measurements
      for four positions on the tongue, namely, those likely to be the locations of a
      receiver coil for an electromagnetometer system. Predictability was quite high
      throughout the vocal tract (multiple r> 0.9), except for the extreme ends (i.e.,
      larynx and lips) and small decreases for the male subject in the uvula region.
      The residuals from this analysis showed that the accuracy of predictions was
      generally quite high, with 89.2% of errors being less than 2 mm. The extremes of
      the vocal tract, where the resolution of the MRI was poorer, accounted for much
      of the error. For languages like English, which do not use advanced tongue root
      (ATR) distinctively, the midsagittal pharynx shape of static vowels can be
      predicted with high accuracy.

PMID- 10391626
TI  - Can a model of overlapping gestures account for scanning speech patterns?
AB  - A simple acoustic model of overlapping, sliding gestures was used to evaluate
      whether coproduction was reduced for neurologic speakers with scanning speech
      patterns. F2 onset frequency was used as an acoustic measure of coproduction or
      gesture overlap. The effects of speaking rate (habitual versus fast) and
      utterance position (initial versus medial) on F2 frequency, and presumably
      gesture overlap, were examined. Regression analyses also were used to evaluate
      the extent to which across-repetition temporal variability in F2 trajectories
      could be explained as variation in coproduction for consonants and vowels. The
      lower F2 onset frequencies for disordered speakers suggested that gesture overlap
      was reduced for neurologic individuals with scanning speech. Speaking rate change
      did not influence F2 onset frequencies, and presumably gesture overlap, for
      healthy or disordered speakers. F2 onset frequency differences for utterance
      initial and -medial repetitions were interpreted to suggest reduced coproduction
      for the utterance-initial position. The utterance-position effects on F2 onset
      frequency, however, likely were complicated by position-related differences in
      articulatory scaling. The results of the regression analysis indicated that
      gesture sliding accounts, in part, for temporal variability in F2 trajectories.
      Taken together, the results of this study provide support for the idea that
      speech production theory for healthy talkers helps to account for disordered
      speech production.

PMID- 10391627
TI  - Comment on "The effect of lung volume on selected phonatory and articulatory
      variables" by Dromey and Ramig (1998)

PMID- 10391629
TI  - Application of the correct information unit analysis to the naturally occurring
      conversation of a person with aphasia.
AB  - The Correct Information Unit (CIU) analysis for measuring the communicative
      informativeness and efficiency of connected speech (Nicholas & Brookshire, 1993)
      was applied to the naturally occurring conversation of a person with moderate
      aphasia. Results indicated that, in this instance, reliable CIU measures could
      not be obtained. Intrarater reliability for CIU and %CIU was low, reaching only
      72%, and interrater reliability was never greater than 63%. However, reliability
      of word counts was good. Post hoc analysis of rater disagreements in application
      of the CIU analysis revealed that the majority (72%) resulted from
      insufficiencies in the scoring rules that were originally designed to measure
      single speaker connected discourse. Two descriptive categories of disagreements
      were identified: interpretations of informativeness and absence of rules. The
      remaining 28% of disagreements were attributable to human error in the
      application of scoring rules. Comparison of findings with previous research and
      implications for future research are discussed.

PMID- 10391628
TI  - Speech and phonological characteristics of individual children with a history of
      tracheostomy.
AB  - The present investigation studied the speech production and phonological skills
      of 6 children between the ages of 2;8 and 6;8 (years;months) who had undergone
      tracheostomy before age 8 months. Each child's speech was analyzed for size and
      composition of phonetic inventory, use of phonological processes, production of
      vowels, and production of the voicing contrast for stops. Analyses were completed
      once consistent air support for vocalization was established for each child and 3
      months after that date. This study highlights the slow development of sound
      acquisition, vowel production, and the distinction between voiced and voiceless
      stops for some, but not all, children with a history of tracheostomy. Each child
      exhibited his or her own pattern of speech production difficulties on four tasks.
      Excessive use of inappropriate phonological processes relative to age was the
      most prevalent speech production problem. Five of 6 subjects exhibited clinically
      significant use of Stridency Deletion, Liquid Deviation, and/or Cluster
      Reduction. Adjustments were noted in the speech of all subjects during a 3-month
      period.

PMID- 10391630
TI  - Bound-morpheme generalization by children with SLI: is there a functional
      relationship with accuracy of response to training targets?
AB  - We investigated whether limited bound-morpheme generalization (BMG) by preschool
      children with SLI is functionally related to limited learning of training targets
      (words, affixed forms). Thirty children with SLI and 30 age-/gender-matched
      controls participated in the study. Production probes revealed a dissociation
      between learning and generalization performance. In addition, the number of
      children who achieved criterion-level BMG increased abruptly during an additional
      instructional experience with new training targets. These findings suggest that
      positive evidence of a bound morpheme's generalizability to different vocabulary
      stems benefits BMG. Furthermore, they suggest that limited BMG reflects problems
      not with the storage or access of specific trained facts but with the extraction
      and extension of the linguistic pattern (e.g., regularity, "rule") instantiated
      in the learning targets.

PMID- 10391631
TI  - Acoustic characteristics of /s/ in adolescents.
AB  - The goal of the current study was to construct a reference database against which
      misarticulations of /s/ can be compared. Acoustic data for 26 typically speaking
      9- to 15-year-olds were examined to resolve measurement issues in acoustic
      analyses, including alternative sampling points within the /s/ frication; the
      informativeness of linear versus Bark transformations of each of the 4 spectral
      moments of /s/ (Forrest, Weismer, Milenkovic, & Dougall, 1988); and measurement
      effects associated with linguistic context, age, and sex. Analysis of the
      reference data set indicates that acoustic characterization of /s/ is
      appropriately and optimally (a) obtained from the midpoint of /s/, (b)
      represented in linear scale, (c) reflected in summary statistics for the 1 st and
      3rd spectral moments, (d) referenced to individual linguistic-phonetic contexts,
      (e) collapsed across the age range studied, and (f) described individually by
      sex.

PMID- 10391632
TI  - Grammatical morphology and the lexicon in children with specific language
      impairment.
AB  - We examined the use of grammatical morphology by preschool-age English-speaking
      children with specific language impairment (SLI) as a function of their lexical
      diversity. Relative to a group of normally developing (ND) preschoolers, these
      children's use of finite-verb morphology logged behind expectations based on the
      number of different verbs they used. Noun-related morphology fell below
      expectations based on overall lexical diversity. Differences between the ND
      children and children with SLI were also seen for the slope of the increases in
      finite-verb morphology as a function of lexical diversity, with shallower slopes
      in the SLI data. The findings of this study add to existing evidence suggesting
      that a measure of finite grammatical-morphology use has promise as a clinical
      marker of SLI in English.

PMID- 10391633
TI  - Treatment and generalization of complex sentence production in agrammatism.
AB  - The present study applies single-subject experimental design to examine (a) the
      acquisition and generalization of complex sentence production in agrammatism
      using Linguistic Specific Treatment (LST) and (b) the utility of syntactic theory
      in guiding hypotheses of treatment effects. LST trains construction and
      production of complex sentence structures. Four sentence types were selected for
      study: object clefts and object-extracted matrix and embedded questions (which
      are noncanonical with wh-movement), and embedded actives (which are canonical
      with no overt movement). All sentences contain overt material in the
      complementizer phrase (CP) of the syntactic tree. Three of five participants (1,
      2, and 3) demonstrated generalization from object cleft treatment to production
      of matrix questions. Thus, LST was effective in improving their ability to
      generate less complex sentences with wh-movement. Once production of object
      clefts and matrix questions was acquired, all 5 participants demonstrated
      generalization from treatment to improved production of embedded questions and/or
      embedded actives. This generalization involved improved ability to generate
      embedded clausal structure to form complex sentences but continuing inability to
      express overt material in CP. Finally, direct treatment for embedded questions
      did not result in accurate production of embedded actives or vice versa. There
      were no trends across participants toward improved production of morphosyntactic
      behaviors in narrative. Persons 1, 2, and 3 showed generalization to increased
      informativeness and efficiency of expression and were judged by independent
      listeners to improve in content, coherence, and fluency of spontaneous
      production. The remaining two participants showed no change or a decline in
      performance in narrative language production (4 and 5, respectively). These
      participants demonstrated more severe Broca's aphasia at pretesting compared to
      Persons 1, 2, and 3, with greater impairments in auditory comprehension, naming,
      and reading. Etiology and size of lesion did not appear to account for the
      different behavioral patterns. This study supports the use of LST, which applies
      syntactic theory to predict patterns of generalization, as an effective treatment
      approach.

PMID- 10391635
TI  - Automated grammatical tagging of child language samples.
AB  - Recent studies of the automated grammatical categorization ("tagging") of words
      using probabilistic methods have reported substantial levels of accuracy-over 95%
      agreement with manual tagging for words from a variety of texts. However, the
      texts with which this method has been tested were written by adults and edited by
      publishers. The present study examined the accuracy with which such methods could
      tag transcribed conversational language samples from 30 normally developing
      children. On a word-by-word basis, automated accuracy levels ranged from 92.9% to
      97.4%, averaging 95.1%. Accuracy at correctly tagging whole utterances was lower,
      ranging from 60.5% to 90.3%, with an average of 77.7%. Probabilistic methods of
      coding language samples hold potential as a viable tool for child language
      research. Further study and improvement of automated grammatical tagging is
      warranted and necessary before widespread use can be made of this technology.

PMID- 10391634
TI  - Syllable onsets: clusters and adjuncts in acquisition.
AB  - The Sonority Sequencing Principle is a presumed universal that governs the
      permissible sequences of consonants within syllables. In two single-subject
      experiments, we evaluated this principle as applied to the acquisition of onset
      clusters and adjuncts by children exhibiting functional phonological delays (age
      in years;months: 3;2 to 7;8). Experiment 1 tested the hypothesis that children
      abide by the Sonority Sequencing Principle in development, such that the
      occurrence and use of marked true clusters implies unmarked clusters, but not
      vice versa. This claim was validated, in part, by the gradient generalization
      learning patterns of children who were taught marked clusters. Others who were
      taught unmarked clusters exhibited limited learning characteristic of within
      class generalization, with apparent gaps in sonority sequencing. Experiment 2
      examined the role of adjunct sequences /sp, st, sk/, whose markedness status is
      questionable given their violation of the Sonority Sequencing Principle. Results
      indicated that children learned adjuncts consistent with patterns of within-class
      generalization, thereby supporting the view that these sequences are unmarked in
      structure. Experimental findings are integrated in discussion of the
      representation of onset clusters and their course of emergence in phonological
      acquisition relative to the Sonority Sequencing Principle.

PMID- 10391636
TI  - Recognition of gated words by children with specific language impairment: an
      examination of lexical mapping.
AB  - In this study we examined the lexical mapping stage of auditory word recognition
      in children with specific language impairment (SLI). Twenty-one children with
      SLI, 21 children matched for chronological age (CM), and 21 vocabulary-matched
      (VM) children participated in a forward gating task in which they listened to
      successive temporal chunks of familiar monosyllabic nouns. After each gate,
      children guessed the identity of the word and provided a confidence rating of
      their word guess. Results revealed that the children with SLI performed
      comparably to the CM and VM children on all seven dependent measures related to
      lexical mapping. The findings were interpreted to suggest that children with SLI
      and their normally developing peers demonstrate a comparable lexical mapping
      phase (i.e., acoustic-phonetic analysis) of auditory word recognition.

PMID- 10391637
TI  - Fourteen-year follow-up of children with and without speech/language impairments:
      speech/language stability and outcomes.
AB  - This report concerns the speech and language outcomes of young adults (N = 242)
      who participated in a 14-year, prospective, longitudinal study of a community
      sample of children with (n = 114) and without (n = 128) speech and/or language
      impairments. Participants were initially identified at age 5 and subsequently
      followed at ages 12 and 19. Direct assessments were conducted in multiple domains
      (communicative, cognitive, academic, behavioral, and psychiatric) at all three
      time periods. Major findings included (a) high rates of continued communication
      difficulties in those with a history of impairment; (b) considerable stability in
      language performance over time; (c) better long-term outcomes for those with
      initial speech impairments than for those with language impairments; and (d) more
      favorable prognoses for those with specific language impairments than for those
      with impairments secondary to sensory, structural, neurological, or cognitive
      deficits. These general conclusions held when either a liberal or a more
      stringent criterion for language impairment was employed. Some of these findings
      are consistent with those from earlier follow-up studies, which used less optimal
      methods. Thus, the present replication and extension of these findings with a
      sound methodology enables greater confidence in their use for prognostic,
      planning, and research purposes.

PMID- 10391638
TI  - Local norming of the test of adolescent/adult language-3 in the Ottawa Speech and
      Language Study.
AB  - The young adult norms for the Test of Adolescent/Adult Language-3 (TOAL-3; D.
      Hammill et al., 1994) are based only on individuals who pursued postsecondary
      education, a restriction that renders the norms inappropriate for many clinical
      and research purposes. This research note details the rationale, methods, and
      results of a local norming of the TOAL-3 spoken language subtests, based on
      participants from the Ottawa Speech and Language Study (C. J. Johnson et al.,
      1999). The resulting Ottawa norms represent the full range of young adult
      language abilities and, therefore, can be used with caution for some clinical and
      research purposes.

PMID- 10391639
TI  - Diagnosing diabetes mellitus - how to test, who to test, when to test.

PMID- 10391640
TI  - An evidence-based guideline for the management of heavy menstrual bleeding.
      Working Party for Guidelines for the Management of Heavy Menstrual Bleeding.
AB  - AIMS: The objective of this guideline is to provide evidence-based
      recommendations for the management of regular heavy menstrual bleeding in women
      with no detectable pathology. METHODS: A multidisciplinary working party was
      formed which met on four occasions over a 12 month period. The evidence from
      randomised controlled trials was summarised into evidence tables and guidelines
      were developed. A draft report was circulated in November 1997 prior to the final
      report which was published in July 1998. RESULTS: A diagnostic and treatment
      algorithm was produced (Figure 1) as well as a full text report. The cost of
      implementing the guideline was considered and overall net savings of $6 million
      were likely. CONCLUSIONS: An explicit evidence-based guideline on the management
      of heavy menstrual bleeding was produced. Both the Royal New Zealand College of
      Obstetricians and Gynaecologists and the Royal New Zealand College of General
      Practitioners endorsed this guideline.

PMID- 10391641
TI  - Bleeding peptic ulcers: audit of eradication treatment for H pylori.
AB  - AIMS: To determine the outcomes after presentation with bleeding peptic ulcer and
      to assess the implementation of H. pylori testing, treatment and follow-up
      testing. METHODS: Case notes and endoscopy records of patients presenting to
      Auckland Hospital between 1993-95 were reviewed. Patients were recalled for
      interview and urea breath test. RESULTS: Mean follow-up after presentation was
      three years. Eighty-nine patients were reviewed; 62% were confirmed as H. pylori
      positive, although 20% had no biopsies. H. pylori eradication treatment was given
      to 49 patients. Thirty-five patients had a definite treatment success; eight were
      failures (eradication rate of 81%) and six received treatment without proof of H.
      pylori by biopsy. Forty patients received acid suppression only. Twelve patients
      had biopsy evidence of H. pylori, and a further nine were proven H. pylori
      positive at follow-up by urea breath test (initial tests had been negative or not
      performed). Nine patients had a rebleed; seven were confirmed H pylori positive
      either at presentation, or by follow-up breath test or endoscopic biopsies.
      CONCLUSIONS: The incidence of H. pylori in patients with bleeding peptic ulcer is
      underestimated and many infected patients do not receive eradication treatment.
      Rebleeding is largely preventable if more attention is given to diagnosis and
      treatment of H. pylori and follow-up of treatment with a urea breath test.

PMID- 10391642
TI  - Malarial antibodies in Auckland blood donors.
AB  - AIM: To determine the malarial exposure characteristics of "malarial risk" blood
      donors and measure the potential infectivity of their donations using a
      commercially available malarial antibody screening kit. METHOD: Malarial risk
      donors were identified according to standard protocols, questioned as to their
      degree of exposure to malaria and blood samples were tested for malarial
      antibodies using an enzyme immunoassay kit. The kit used detects IgG antibodies
      to P. falciparum, shows 50% crossreactivity with P. vivax and some
      crossreactivity with P. ovale. Antibody positive samples were further checked by
      a direct immunochromatographic test for P. falciparum. RESULTS: We found 1.7% of
      the donors who were classified as a "malarial risk" to be positive for IgG
      malarial antibodies. None of these antibody positive samples was positive by the
      direct immunochromatographic test for P. falciparum. CONCLUSION: These results
      indicate that none of these donors tested were a risk of transmitting P.
      falciparum, the major and most serious cause of transfusion transmitted malaria.
      The introduction of malarial testing of malarial risk blood donors in Auckland,
      currently deferred for plasma donation only, could potentially recover 2300 units
      of red cells per year.

PMID- 10391643
TI  - Preventive care in Canterbury general practice.
AB  - AIMS: To describe the preventive care attitudes, beliefs, priorities and systems
      of Canterbury general practitioners, to compare their beliefs about appropriate
      care with evidence-based guidelines and to investigate possible associations
      between preventive care beliefs and attitudes, and selected practitioner
      variables. METHOD: A questionnaire was mailed to all 375 general practitioners in
      Canterbury, with a response rate of 70%. RESULTS: Respondents expressed positive
      attitudes to preventive care, their views about appropriate care corresponding
      well to United States Preventive Services Task Force recommendations. The
      responses of practitioners who had qualified more recently were closer to the
      recommendations, with these practitioners more likely to want to carry out more
      preventive care. Membership of an independent practice association or the Royal
      New Zealand College of General Practitioners was associated with more positive
      attitudes to preventive care and with believing more interventions to be
      appropriate. Relatively few preventive interventions appeared to be offered to
      patients in a systematic way. CONCLUSIONS: Canterbury general practitioners were
      well-informed about, and interested in carrying out, more preventive care.
      Preventive care delivery could be enhanced in many practices by the adoption of a
      more systematic approach.

PMID- 10391644
TI  - The New World Order revisited.

PMID- 10391645
TI  - Complications of legal termination of pregnancy.

PMID- 10391646
TI  - Complications of legal termination of pregnancy.

PMID- 10391647
TI  - Steroid confusion: another cautionary tale.

PMID- 10391648
TI  - Surgical treatment of atrial fibrillation.

PMID- 10391649
TI  - Myocardial infarction.

PMID- 10391650
TI  - Donating blood and the perceived risk of HIV infection.

PMID- 10391651
TI  - The effect of recurrent events on register-based estimates of level and trends in
      incidence of acute myocardial infarction.
AB  - Although changes in incidence of first acute myocardial infarctions (AMI) are of
      primary interest in the evaluation of preventive efforts, only few studies have
      used this measure. In the present study, the risk of recurrence over time in
      subjects with first AMI is analyzed, and the effect of inclusion of recurrent
      cases on the estimation of level and trend in the incidence of AMI is evaluated.
      The National Patient Register of Hospital Discharges and the Causes-of-Death
      Register were linked, and all cases of admission for AMI and fatal manifestation
      of the disease since 1977 and until 1992 in the Danish population were
      identified. New events occurred during the following 12 years in 46% of men and
      42% of women with their first AMI in 1980. Ninety percent of the recurrent events
      occurred during the first 5 years. Using absence of events during only 1
      preceding year as the inclusion criteria, the incidence rate would be
      overestimated by about 20%-30%. However, if the preceding event-free period was
      of the same duration throughout the study period, the trends in AMI rates were
      not altered by expanding the event-free period up to 14 years before the index
      event. Although rates of AMI based on the total number of affected persons
      without AMI in the previous year overestimate the true incidence by 20%-30%,
      trends in these rates reflect trends in rates of first events with reasonable
      accuracy.

PMID- 10391653
TI  - Hospital mortality from acute myocardial infarction has been modestly reduced
      after introduction of thrombolytics and aspirin: results from a new analytical
      approach. European Secondary Prevention Study Group.
AB  - The objective of this study was to investigate how the introduction of
      thrombolytics and aspirin has affected hospital mortality (case fatality) among
      patients with acute myocardial infarction. The study design was the application
      of the therapeutic effects found in the clinical trials in a nonselected
      myocardial infarction population characterized in detail. The study took place in
      health region 1 in Norway, population 850,000, and subjects were all patients
      hospitalized and discharged, alive or dead, with a diagnosis of acute myocardial
      infarction in the 10 hospitals in the region over a period of 2 months. The main
      outcome measures were deaths in hospital and estimation of expected hospital
      mortality without thrombolytics or aspirin, weighing and evaluating the effects
      of delay of different lengths from onset of symptoms to admission, different
      ages, and different electrocardiogram changes. We found that 32% of the patients
      received thrombolytics, and 72% received aspirin. Hospital mortality was 18.1%
      compared with 20.6% had neither of the treatments been administered, implying
      that the two regimens had reduced mortality by 12%, aspirin contributing about
      four fifths and thrombolytics one fifth. We conclude that hospital mortality in a
      nonselected myocardial infarction population has been reduced to moderate extent
      since the introduction of thrombolytics and aspirin. The effects observed in
      clinical trials are not translated into epidemiologically documented reduction in
      mortality, as the optimal conditions are found only in a proportion of the
      patient groups constituting a nonselected myocardial infarction population.

PMID- 10391652
TI  - Risk indicators for out-of-hospital cardiac arrest in patients with coronary
      artery disease.
AB  - The objective of this study was to identify risk factors for sudden cardiac
      arrest (SCA) in patients with coronary artery disease (CAD). A retrospective case
      control study was performed consisting of a group of unselected patients who had
      suffered SCA and had a clinical history of CAD, and a group of unselected age-
      and gender-matched CAD control patients living in the region of Maastricht.
      Information about previous myocardial infarction (MI), left ventricular ejection
      fraction (LVEF), hypertension, hypercholesterolemia, diabetes mellitus, smoking,
      and coffee and alcohol consumption was collected. A logistic regression model was
      fitted to all mentioned variables including age and genders. Included were 117
      SCA cases (84% men, mean age 65 years [+/-7]) and 144 control patients (83% men,
      mean age 63 years [+/-8]). Previous MI (odds ratio [OR] 4.0, 95% confidence
      interval [CI] 1.7-9.3), hypertension (OR 2.9, 95% CI 1.5-6.1), heavy coffee
      consumption (>10 cups per day) (OR 55.7, 95% CI 6.4-483), and a LVEF <40% (OR
      11.2, CI 4.4-28.5) were independent risk indicators for SCA in patients with CAD.
      Alcohol consumption (1-21 glasses per week) seemed to protect patients with CAD
      from SCA (OR 0.5, 95% CI 0.2-0.98). These observations suggest that changes in
      lifestyle factors can be of potential importance in protecting patients with CAD
      from dying suddenly.

PMID- 10391654
TI  - Perceived health over 3 years after percutaneous coronary balloon angioplasty.
AB  - The magnitude of the benefit of percutaneous transluminal coronary angioplasty
      (PTCA) in terms of quality of life depending on baseline and outcome clinical
      variables is not sufficiently understood because of the restrictive inclusion
      criteria of randomized clinical trials. The present study was designed to assess
      perceived health outcome at 3 years and its association with clinical variables
      after successful elective PTCA in a tertiary hospital throughout a prospective
      cohort study. Questionnaires were administered on the day before the procedure
      and 1 month and 3.4 years later (as mean follow-up) to 106 patients recruited
      during a 15-month period. Mean perceived health scores improved significantly for
      the population as a whole 1 month after PTCA, and improvement was maintained at
      the end of follow-up. The magnitude of the effect was different depending on
      clinical subgroups: (a) It was greatest in patients free from angina, myocardial
      infarction, or new revascularization procedures at the end of follow-up; (b) It
      was moderately reduced in patients with comorbidity; (c) Patients who reported to
      have dyspnea or angina at rest after the latest revascularization procedure did
      not improve, with poor final perceived health scores. Elective PTCA is associated
      with a significant improvement in perceived health, which varies depending on the
      clinical outcome. Comorbidity and initial perceived health influence outcome but
      do not preclude improvement.

PMID- 10391655
TI  - Development of the review quality instrument (RQI) for assessing peer reviews of
      manuscripts.
AB  - Research on the value of peer review is limited by the lack of a validated
      instrument to measure the quality of reviews. The aim of this study was to
      develop a simple, reliable, and valid scale that could be used in studies of peer
      review. A Review Quality Instrument (RQI) that assesses the extent to which a
      reviewer has commented on five aspects of a manuscript (importance of the
      research question, originality of the paper, strengths and weaknesses of the
      method, presentation, interpretation of results) and on two aspects of the review
      (constructiveness and substantiation of comments) was devised and tested. Its
      internal consistency was high (Cronbach's alpha 0.84). The mean total score
      (based on the seven items each scored on a 5-point Likert scale from 1 to 5) had
      good test-retest (Kw = 1.00) and inter-rater (Kw = 0.83) reliability. There was
      no evidence of floor or ceiling effects, construct validity was evident, and the
      respondent burden was acceptable (2-10 minutes). Although improvements to the RQI
      should be pursued, the instrument can be recommended for use in the study of peer
      review.

PMID- 10391656
TI  - Impact of study quality on outcome in placebo-controlled trials of homeopathy.
AB  - We investigated the influence of indicators of methodological quality on study
      outcome in a set of 89 placebo-controlled clinical trials of homoeopathy in three
      different ways: (1) The results of studies meeting single criteria (explicit
      statement of random allocation, allocation concealment, double-blinding,
      completeness of follow-up) of methodological quality were compared with those of
      studies not meeting the criteria in univariate and multivariate analyses; (2) The
      results of studies scoring above and below predefined scores in two quality
      assessment scales were compared; (3) Primary studies were consecutively entered
      into a cumulative meta-analysis according to the summary scores derived from the
      quality assessment scales. All analyses were performed using meta-regression
      methods. Studies that were explicitly randomized and were double-blind as well as
      studies scoring above the cut-points yielded significantly less positive results
      than studies not meeting the criteria. In the cumulative meta-analyses, there was
      a trend for increasing effect sizes when more studies with lower-quality scores
      were added. However, there was no linear relationship between quality scores and
      study outcome. We conclude that in the study set investigated, there was clear
      evidence that studies with better methodological quality tended to yield less
      positive results. Because summarizing disparate study features into a single
      score is problematic, meta-regression methods simultaneously investigating the
      influence of single study features seem the best method for investigating the
      impact of study quality on outcome.

PMID- 10391657
TI  - The effects of two aerobic training intensities on ambulatory blood pressure in
      hypertensive patients: results of a randomized trial.
AB  - The effect of different intensities of aerobic exercise on blood pressure remains
      uncertain. The goal of this trial was to compare the effect of two different
      levels of aerobic physical training on 24-hour ambulatory blood pressure. In this
      double-blind parallel-group trial, 28 sedentary hypertensive patients (mean
      diastolic blood pressure of 90 to 104 mm Hg) were randomly assigned to 10 weeks
      of physical training at 20% (Group I) or 60% (Group II) of their maximal workload
      on a cycle ergometer (mean load of 32 and 85 watts, respectively). Maximal oxygen
      consumption was estimated by the time spent on a mechanical braked Monark bicycle
      (Monark, Sao Paulo, Brazil). Indexes of physical fitness were determined by cycle
      ergometer tests before and after the experimental period. The principal outcome
      variable was mean 24-hour ambulatory blood pressure. Mean 24 hour systolic blood
      pressure fell from 137.2+/-14.9 to 135.2+/-12.7 mm Hg in Group I and from 144.4+/
      13.3 to 138.6+/-12.9 in Group II (mean between group difference of -2.1 mm Hg, P
      = 0.479, adjusted for baseline blood pressure). Mean diastolic blood pressure
      fell from 9.21+/-10.0 to 89.3+/-7.7 mm Hg in Group I and from 93.3+/-5.8 to
      90.6+/-6.8 mm Hg in Group II (mean adjusted difference of -0.06, P = 0.765).
      Nighttime blood pressure did not change in either group. Across all participants,
      a reduction in systolic blood pressure was significantly associated with improved
      physical fitness as manifest by increased physical work capacity at heart rate of
      130 bpm (PWC130), increased systolic blood pressure at PWC130, and decreased
      maximum heart rate measured during the cycle ergometer test We conclude that
      aerobic training programs at 20% and 60% of the maximum work capacity have
      similar effects on ambulatory blood pressure.

PMID- 10391658
TI  - The physical activity scale for the elderly (PASE): evidence for validity.
AB  - We assessed the validity of the Physical Activity Scale for the Elderly (PASE) in
      a sample of sedentary adults (56 men, 134 women, mean age +/- [SD] 66.5+/-5.3
      years) who volunteered to participate in a randomized controlled trial on the
      effect of aerobic conditioning on psychological function. Construct validity was
      established by correlating PASE scores with physiologic and performance
      characteristics: peak oxygen uptake, resting heart rate and blood pressure,
      percent body fat, and balance. The mean PASE scores were higher in men than in
      women (men = 145.8+/-78.0; women = 123.9+/-66.3, P<0.05), and in those age 55-64
      years compared with those age 65 years and over (55-64 = 144.2+/-75.8; 65 and
      over = 118.9+/-63.9, P<0.05). PASE scores were also significantly higher in those
      who did not report a chronic health condition (cardiovascular disease,
      hypertension, cancer, or recent surgery). PASE scores were significantly
      associated (P<0.05) with peak oxygen uptake (r = 0.20), systolic blood pressure
      (r = -0.18) and balance score (r = 0.20). No significant associations of PASE
      score and diastolic blood pressure, resting heart rate, or percent body fat were
      noted. These results provide additional evidence for the validity of the PASE as
      a measure of physical activity suitable for use in epidemiology studies on the
      association of physical activity, health, and physical function in older
      individuals.

PMID- 10391659
TI  - Convergent discriminitive, and predictive validity of the Prostate Cancer
      Specific Quality of Life Instrument (PROSQOLI) assessment and comparison with
      analogous scales from the EORTC QLQ-C30 and a trial-specific module. European
      Organisation for Research and Treatment of Cancer. Core Quality of Life
      Questionnaire.
AB  - The Prostate Cancer Specific Quality of Life Instrument (PROSQOLI) is a measure
      of health-related quality of life (HRQL) that was designed to be an outcome
      measure for clinical trials in advanced hormone-resistant prostate cancer. The
      cross-sectional validity of the PROSQOLI was assessed using baseline data from a
      randomized trial in which HRQL was also assessed with the European Organisation
      for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire
      (QLQ-C30) and a trial-specific quality of life module (QLM-P14). Convergent
      validity was assessed with the multitrait-multimethod matrix approach;
      discriminative validity was assessed according to conventional clinical criteria;
      and predictive validity was assessed by the ability to predict survival duration.
      These assessments provided strong support for the validity of all PROSQOLI scales
      except those for family/marriage relationships and passing urine; modifications
      of these two scales are under evaluation. The strength, consistency, and
      independence of the prognostic information provided by the HRQL scales were
      striking. Differences between the instruments were generally subtle. These data
      support validity of the PROSQOLI and the analogous scales from the QLQ-C30 and
      QLM-P14 in symptomatic men with advanced hormone resistant prostate cancer. The
      PROSQOLI is a short, simple, and valid measure of HRQL in this setting.

PMID- 10391660
TI  - The Marks Asthma Quality of Life Questionnaire: further validation and
      examination of responsiveness to change.
AB  - We performed analyses to examine the structure, validity, and responsiveness to
      change of the Marks Asthma Quality of Life Questionnaire (AQLQ), originally
      validated in Australia in a self-administered format, among 539 U.S. subjects
      with asthma. Subjects were interviewed twice by telephone over an 18-month
      period. Based on factor analyses, the subscale structure of the AQLQ was modified
      slightly to eliminate item overlap among subscale scores. Cross-sectionally,
      total AQLQ scores were significantly correlated in expected directions with
      baseline asthma severity scores (r = 0.58), SF-36 physical (r = -0.66) and mental
      (r = -0.40) health status scores, and pulmonary function (FEV1% predicted, r = 
      0.14). Longitudinally, changes in AQLQ total and subscale scores were
      significantly (P<0.01) associated with changes in asthma severity and both
      physical and mental status. The AQLQ, administered by telephone, appears to be
      useful for assessing changes in the impact of adult asthma.

PMID- 10391661
TI  - Alcohol and stroke: a community case-control study in Asturias, Spain.
AB  - The relationship between alcohol consumption and stroke is uncertain. Heavy
      alcohol consumption has been associated with an increased risk of stroke, while
      light drinking appears to be protective. However, the evidence is not uniform. We
      sought to examine the relationship between alcohol consumption and stroke,
      according to stroke type. We performed a population-based case-control study from
      September 1990 to December 1991. The study comprised 467 incident cases of stroke
      and 477 controls aged between 40 and 85. Case was defined following WHO criteria
      and control was randomly selected from the study base population. Alcohol
      exposure was obtained by medical interview. We found that consumption of less
      than 30 g/day of alcohol was protective against all stroke types combined, the
      multivariated adjusted odds ratio (OR) was 0.58 (95% confidence interval [CI],
      0.41-0.83). Moderate alcohol drinking is also protective against all cerebral
      infarction combined (OR = 0.53; 95% CI, 0.35-0.80) and cortical infarction (OR =
      0.40; 95% CI, 0.18-0.86). Drinking up to 30 g/day of alcohol has a borderline
      protective effect on deep cerebral infarction (OR = 0.40; 95% CI, 0.16-1.02) and
      has no effect on intracerebral hemorrhage (OR = 0.88; 95% CI, 0.44-1.74). Heavy
      alcohol drinking, over 140 g/day, is a risk factor for all stroke types combined
      (OR = 3.2; 95% CI, 1.1-9.7), all cerebral infarction combined (OR = 5.0; 95% CI,
      1.5-16.3), small deep cerebral infarction (OR = 9.7; 95% CI, 2.6-36.7),
      intracerebral hemorrhage (OR = 6.2; 95% CI, 1.3-24.0), and is marginally
      associated with superficial cerebral infarction (OR = 4.6; 95% CI, 1.0-20.6). The
      relationship between alcohol and stroke depends on the alcohol dose and the
      pathology of the disease. Atherosclerosis of the large and medium cerebral
      arteries is found mainly in superficial cerebral infarction, and this type of
      stroke shows a J-shaped relationship with alcohol similar to that found in
      coronary heart disease, suggesting that they are similar diseases. On the other
      hand, arteriosclerosis of the penetrating arteries has been found in deep
      cerebral infarction and intracerebral hemorrhage, while atherosclerosis is not
      prominent. This may explain why alcohol does not have a protective effect on
      cerebral hemorrhage whereas heavy drinking is a strong risk factor in these two
      types of stroke.

PMID- 10391662
TI  - Simultaneous screening for three correlated lipids in the VA HDL Intervention
      Trial.
AB  - We developed methodology to design the multistage lipid screen for the VA HDL
      Intervention Trial, a randomized double-blind placebo-controlled secondary
      prevention clinical trial of 2531 participants. The trial aimed to determine if
      HDL-raising therapy reduces coronary events in men with low HDL-cholesterol and
      desirable LDL-cholesterol. Joint lipid distributions for HDL-cholesterol, LDL
      cholesterol, and triglycerides were derived on the basis of estimates from
      previous studies, and simulations were performed to determine the cutpoints for
      excluding screenees for the three lipid parameters to be used at each recruitment
      stage. Operating characteristics for different screening rules are presented.
      Comparisons between the predicted and actual study recruitment results show good
      agreement in lipid characteristics and underscore the complexity of
      simultaneously screening on correlated continuous physiologic parameters such as
      lipids.

PMID- 10391664
TI  - Regulating manufacturer-affiliated communication in the information age.

PMID- 10391663
TI  - Population trends in antihypertensive drug use: results from the MONICA Augsburg
      Project 1984 to 1995.
AB  - Trends in antihypertensive drug use were assessed among 25- to 64-year-old
      participants of three independent surveys of the MONICA Augsburg region in
      1984/85, 1989/90, and in 1994/95. Despite constant prevalences of hypertension,
      the percentage of hypertensives taking medication increased over the study
      period. The latter was mainly due to significant rises in antihypertensive
      monotherapy. By contrast, the use of combination treatments with two or more
      agents remained constant; however, although combinations composed of only two
      drugs were taken more often in 1995, those with three or more agents and fixed
      dose preparations decreased substantially. Beta-blockers were most frequently,
      and with a rising tendency, taken as antihypertensive monotherapy. Newer drug
      classes like calcium channel blockers and ACE-inhibitors were introduced as
      monotherapy more hesitantly. Diuretics persisted as the basis of antihypertensive
      combination therapy. The use of combination therapies containing obsolete drugs,
      like reserpine, declined significantly with corresponding increases in drug
      combinations of, in particular, calcium channel blockers or ACE-inhibitors. We
      conclude that monotherapies account for most of the rising antihypertensive
      treatment rates and probably reflect intensified therapy of borderline
      hypertensives. The trends in antihypertensive drug classes and treatment regimens
      reflect a less rapid adoption of novel therapeutic concepts but a fairly close
      adherence to national and international guidelines.

PMID- 10391665
TI  - Development of dapsone toxicity in patients with inflammatory dermatoses:
      activity of acetylation and hydroxylation of dapsone as risk factors.
AB  - BACKGROUND: Alternative independent routes of dapsone metabolism include N
      hydroxylation to the hydroxylamine, a potentially toxic metabolite, by cytochrome
      P450 enzymes and acetylation to a nontoxic metabolite by N-acetyltransferase.
      Potentially, therefore, the relative extents of these two routes in an individual
      could determine the occurrence of adverse reaction with dapsone therapy. METHODS:
      Phenotypic activity of these two routes of metabolism was assessed in 18 patients
      receiving longterm dapsone therapy for inflammatory dermatoses and was related to
      the development of dapsone toxicity. N-Hydroxylation was assessed by the dapsone
      recovery ratio, a ratio of dapsone hydroxylamine to the sum of hydroxylamine and
      dapsone in 8-hour urine, whereas N-acetylation was assessed by the acetylation
      ratio, a ratio of monoacetyldapsone to dapsone in 8-hour plasma sample after an
      oral dose of dapsone. RESULTS: There was wide intersubject variation in both the
      acetylation ratio and the dapsone recovery ratio, but both phenotypic measures
      remained stable within individuals. The dapsone recovery ratio showed a tendency
      toward being lower in fast than in slow acetylators, but this was not
      statistically significant. There was an inverse relationship between acetylation
      and hydroxylation (r = -0.69; P < .005) at steady state that was not apparent
      after the first dose. Neurotoxicity developed in two subjects and hemolytic
      anemia developed in two subjects. Plasma levels of dapsone in these four subjects
      were similar to those in subjects who showed no toxicity. All four were slow
      acetylators and three were rapid hydroxylators, consistent with the toxic nature
      of dapsone hydroxylamine. CONCLUSIONS: These observations are consistent with
      what is known about the toxicity profile of dapsone metabolites and suggest that
      assessing N-acetylation and N-hydroxylation capacities can help to identify
      subjects at increased risk of a toxic response. This approach of assessing the
      phenotypic measures of drug-metabolizing activity to predict adverse reaction may
      also apply to other drugs with metabolic-based adverse effects.

PMID- 10391666
TI  - Theophylline pharmacokinetics are not altered by lansoprazole in CYP2C19 poor
      metabolizers.
AB  - Lansoprazole is a potent gastric proton pump inhibitor that is metabolized by
      CYP2C19 but appears to induce the activity of hepatic microsomal CYP1A2 in a
      concentration-dependent manner. Because the inducing effect appears to be a dose
      dependent phenomenon, it may be more important in poor metabolizers of CYP2C19
      who have more than four times the area under the lansoprazole plasma
      concentration-time curve (AUC) and constitute 12% to 23% of Asian populations.
      Theophylline owes a significant portion of its metabolism to CYP1A2 and can cause
      gastric acid reflux that calls for concurrent use of proton pump inhibitors. We
      conducted a prospective, randomized, subject-blind, multicenter crossover study
      of the effect of multiple high-dose oral lansoprazole (30 mg twice a day for 7
      days) on the pharmacokinetics of a single intravenous dose of theophylline (4.73
      mg/kg) in healthy volunteers characterized for CYP2C19 genotype. The study
      compared the pharmacokinetics of lansoprazole and theophylline in five white
      extensive metabolizers, six Korean extensive metabolizers, and seven poor
      metabolizers of CYP2C19. The pharmacokinetics of lansoprazole were significantly
      different among groups; AUC values were 1.55+/-0.20 microg x h/mL in white
      extensive metabolizers, 7.01+/-0.72 microg x hr/mL in Korean extensive
      metabolizers, and 14.34+/-2.60 microg x h/mL in poor metabolizers (P < .001). The
      administration of lansoprazole did not change intravenous theophylline clearance
      compared with placebo in any group, and theophylline clearance exhibited no
      correlation with AUC of lansoprazole (rs = 0.12; P > .1). These data suggest that
      usual therapeutic doses of lansoprazole have no clinically significant influence
      on the clearance of theophylline, even in poor metabolizers of CYP2C19.

PMID- 10391668
TI  - The effect of age on the pharmacokinetics and pharmacodynamics of midazolam.
AB  - OBJECTIVE: We investigated the pharmacologic properties of midazolam with special
      regard to age using the electroencephalogram (EEG) as a measure of the hypnotic
      sedative effect. METHODS: Nine younger (24 to 28 years) and nine elderly (67 to
      81 years) male volunteers received midazolam by a computer-controlled device. Two
      infusion cycles with linearly increasing target plasma levels (slope, 40
      ng/mL/min for the younger subjects; 20 ng/mL/min for the elderly subjects) were
      administered until defined end points were attained (median EEG frequency <4 Hz
      and loss of responsiveness to acoustic stimuli). An EEG was recorded to
      quantitate the hypnotic effect, relating the median frequency of the power
      spectrum to the plasma level by a sigmoid Emax model, including an effect
      compartment. Pharmacokinetic data were derived from arterial blood samples with
      use of a three-compartment model. RESULTS: The total doses needed to reach the
      defined end points were 71+/-9 mg and 35+/-6 mg for the younger and elderly
      subjects, respectively (P < .001). Pharmacokinetic parameters were similar in
      both groups (clearance, 399+/-91 and 388+/-97 mL/min; steady-state volume of
      distribution, 85+/-22 and 104 +/-11 L in young and elderly subjects,
      respectively). Pharmacodynamic data showed a large difference in half-maximum
      concentration (EC50; young subjects, 522+/-236 ng/mL; elderly subjects, 223+/-56
      ng/mL; P < .05), a steep concentration-response curve, and distinct hysteresis.
      We found much interindividual variability in the plasma concentrations necessary
      to achieve the clinical end points, regardless of age. CONCLUSIONS: These results
      suggest that the lower doses needed to reach sedation in the elderly subjects
      were attributable to a 50% decrease in EC50, not to changes in pharmacokinetics.

PMID- 10391667
TI  - Down-regulation of the pharmacokinetic-pharmacodynamic response to interleukin-12
      during long-term administration to patients with renal cell carcinoma and
      evaluation of the mechanism of this "adaptive response" in mice.
AB  - BACKGROUND: Interleukin-12 (IL-12) is a cytokine that promotes type-1 helper T
      cell responses and may have therapeutic utility in the treatment of cancer,
      asthma, and a variety of infectious diseases. METHODS: In a phase I trial,
      recombinant human IL-12 (rHuIL-12) was administered subcutaneously once a week at
      a fixed dose of 0.1 to 1.0 microg/kg to 24 patients with renal cell carcinoma. A
      similar study was later performed in mice to evaluate the mechanism of down
      regulation of pharmacokinetic-pharmacodynamic response observed in patients with
      cancer. RESULTS: Adverse events, serum IL-12 levels, and serum levels of
      interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) produced in response to
      IL- 12 were all maximum in the week after the first dose of rHuIL-12 and
      decreased after long-term administration. Similar to these results, repetitive
      subcutaneous administration of recombinant mouse IL-12 (rMoIL-12) to normal mice
      led to down-regulation of serum levels of IL-12 and IFN-gamma measured 5 hours
      after rMoIL-12 injection. Down-regulation of IL-12 serum levels was inversely
      correlated with the up-regulation of IL-12 receptor expression and may be the
      result of increased clearance of rMoIL-12 from serum by binding to lymphoid cells
      expressing increased amounts of IL-12 receptor. The down-regulation of serum IFN
      gamma levels correlated with decreased IFN-gamma messenger ribonucleic acid
      expression and may result from feedback inhibition of IL-12 signaling or from a
      more specific inhibition of IFN-gamma synthesis. CONCLUSION: Administration of
      rHuIL-12 in fixed weekly doses resulted in decreased serum levels of IL-12 and of
      IFN-gamma, a secondary cytokine believed to be critical to response of IL-12. A
      better understanding of the complex regulation of the pharmacokinetic
      pharmacodynamic response to IL-12 should facilitate the development of more
      effective dosing regimens for its use in the clinic.

PMID- 10391669
TI  - Induction of inosine monophosphate dehydrogenase activity after long-term
      treatment with mycophenolate mofetil.
AB  - OBJECTIVES: To study the pharmacologic activity of mycophenolate mofetil in
      stable kidney transplant recipients receiving mycophenolate mofetil therapy for
      different periods from 2 months to 3 years. METHODS: Seventeen patients were
      enrolled during a 9-month period. Blood samples were collected before
      administration and 1/2, 1, 2, 4, and 6 hours after administration. Mycophenolic
      acid, the active metabolite of mycophenolate mofetil, was measured in plasma with
      use of the enzyme multiplication immunoassay technique (EMIT) assay and the
      activity of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de
      novo biosynthesis of purines inhibited by mycophenolate mofetil, was determined
      in whole blood by the estimation of the 3H-release from [2,8-3H]-hypoxanthine.
      RESULTS: As the length of mycophenolate mofetil therapy increased, the inhibitory
      effect of mycophenolate mofetil on IMPDH activity was reduced (0.13+/-0.03 for
      long-term treatment versus 0.46+/-0.06 for short-term treatment; P = .0006) and a
      stimulatory effect of mycophenolate mofetil on IMPDH activity was observed
      (1.16+/-0.56 for long-term treatment, versus 0.03+/-0.01 for short-term
      treatment; P < .0001). These modifications of IMPDH activity were associated with
      fluctuations in the pharmacokinetics of mycophenolic acid. CONCLUSION: Long-term
      treatment with mycophenolate mofetil was associated with an induction of IMPDH
      activity. Such induction could be deleterious if it is followed by a restoration
      or a stimulation of the proliferative capacity of lymphocytes. These results
      strongly suggest that the place of mycophenolate mofetil in long-term treatment
      of kidney transplant patients needs to be carefully assessed.

PMID- 10391670
TI  - Effects of lisinopril administration on blood bcl-2 concentrations in patients
      with immunoglobulin A nephropathy.
AB  - We evaluated blood concentrations of bcl-2, a proto-oncogene that can inhibit
      apoptotic phenomena, in a group of patients with immunoglobulin A (IgA)
      nephropathy. Concentrations of bcl-2 were higher in patients with proteinuria
      than in those without proteinuria. A 6-month course of 5 mg/day lisinopril given
      to subjects with proteinuria significantly reduced blood bcl-2 concentrations and
      caused a reduction in proteinuria. Therefore increased blood bcl-2 concentrations
      may be considered an index of risk in subjects with IgA nephropathy, and the
      positive effects of angiotensin-converting enzyme inhibitors on proteinuria in
      patients with IgA nephropathy may be attributed, at least in part, to their
      effect on the mechanisms that regulate apoptosis. This is of fundamental
      importance in resolving glomerular hypercellularity in the course of
      glomerulonephritis.

PMID- 10391671
TI  - Cyclooxygenase-2 inhibition by rofecoxib reverses naturally occurring fever in
      humans.
AB  - Cyclooxygenase (COX) exists as constitutive (COX-1) and inducible (COX-2)
      isoforms. Nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and
      diclofenac inhibit both COX-1 and COX-2. The role of COX-2 in the genesis of
      fever in monkeys and humans was examined with use of the specific COX-2 inhibitor
      rofecoxib. Rofecoxib was administered to monkeys made febrile by 6 microg/kg
      intravenous lipopolysaccharide. Induced pyrexia was followed by oral rofecoxib (1
      or 3 mg/kg), diclofenac (3 mg/kg), or vehicle. Rofecoxib and diclofenac rapidly
      reversed the elevated temperature (P < .05 versus vehicle for 3 mg/kg rofecoxib
      and diclofenac at 70 to 90 minutes after dosing). A single-dose, parallel-group,
      double-blind randomized trial was conducted in 94 patients with fever caused by a
      viral-type illness. Mean baseline temperature was similar for all groups (-38.5
      degrees C). Patients received oral doses of 12.5 mg rofecoxib, 25 mg rofecoxib,
      400 mg ibuprofen, or placebo and the mean +/- SE change in oral temperature at 4
      hours after dosing was -0.97 degrees C +/- 0.11 degrees C, -1.19 degrees C +/-
      0.09 degrees C, -1.20 degrees C +/- 0.11 degrees C, and 0.01 C +/- 0.17 C,
      respectively (P < .001 for active treatments versus placebo). Specific inhibition
      of COX-2 by rofecoxib results in antipyretic activity in monkeys and humans
      comparable to dual COX-1/COX-2 inhibitors such as diclofenac or ibuprofen. The
      data support the hypothesis that it is the COX-2 isoform that is primarily
      involved in the genesis of fever in humans.

PMID- 10391672
TI  - Safety and efficacy of ritonavir and saquinavir in combination with zidovudine
      and lamivudine.
AB  - BACKGROUND: Ritonavir is a potent inhibitor of cytochrome P4503A4 that strongly
      increases saquinavir bioavailability. In this study we assessed the safety and
      antiretroviral efficacy of the combination of these two compounds in patients
      pretreated and receiving continued treatment with zidovudine and lamivudine who
      were protease inhibitor naive and who had a CD4 cell counts below 200/mm3.
      METHODS: In this 48-week pilot study, all patients received 600 mg ritonavir and
      400 mg saquinavir twice daily. Administration of zidovudine and lamivudine was
      continued without a change in previous doses. Viral load, CD4 cell count, and the
      emergence of resistance to the two protease inhibitors were evaluated repeatedly
      up to week 48. RESULTS: Sixteen patients were included in the study. Previous
      nucleoside analog treatment duration was 48+/-22 months (mean +/- SD). Two
      patients quit taking both protease inhibitors within 2 weeks. The ritonavir dose
      had to be reduced in 10 other patients because of side effects. Between inclusion
      and week 48, plasma viremia varied from 4.87+/-0.43 to 3.00+/-1.29 log10
      copies/mL and CD4 cell counts ranged from 98+/-61 to 250+/-139/mm3. Ten patients
      (63%) had viral loads below 200 copies/mL and 7 (44%) had viral loads below 50
      copies/mL. A single key mutation that conferred ritonavir resistance I84V and
      V82A/V developed in two patients. A mutation at codon 54 developed in another
      patient. These mutations were associated with repeated cessations of
      antiretroviral treatment. No lipodystrophy was observed. CONCLUSION: Ritonavir
      and saquinavir in combination are quite well tolerated and induce a high and
      sustained antiretroviral efficacy. A four-drug combination that includes these
      two protease inhibitors should be considered as a first line of treatment in
      patients with low CD4 cell counts.

PMID- 10391673
TI  - Quantitative characterization of therapeutic index: application of mixed-effects
      modeling to evaluate oxybutynin dose-efficacy and dose-side effect relationships.
AB  - BACKGROUND: Describing a therapeutic index for a drug is important for evaluating
      safe and effective dosage regimens. Therapeutic index can be evaluated as the
      relative position of the dose-efficacy and the dose-side effect curves.
      Oxybutynin XL (Ditropan XL), a once-daily oral controlled-release formulation for
      oxybutynin chloride, is being developed. Oxybutynin XL efficacy and side-effect
      data obtained from two parallel-group, randomized, controlled clinical trials
      were modeled to evaluate the therapeutic index. METHODS: A nonlinear mixed
      effects model was used to characterize the oxybutynin dose-efficacy and dose-dry
      mouth relationship. Weekly urge urinary incontinence episodes, the primary
      efficacy variable, is a discrete variable (counts) with only non-negative integer
      values and was therefore modeled as a Poisson variable. The probability of dry
      mouth severity (the most frequently reported side effect), assessed on a
      categorical four-point scale, was modeled with a proportional odds model. In the
      modeling process, it was assumed that the time effect was the same for the active
      and placebo treatments and that the drug effect was additive. RESULTS AND
      CONCLUSIONS: The urge urinary incontinence episodes declined log-linearly, and no
      significant difference was observed between the two formulations. However, there
      was a trend toward higher efficacy with oxybutynin XL than with immediate-release
      oxybutynin at the same dose in one study. Dose-dry mouth analysis showed that the
      probability of dry mouth with an increasing dose was significantly lower with
      oxybutynin XL than with immediate-release oxybutynin in the second study, and a
      similar trend was observed in the first study. By combining the dose-urge urinary
      incontinence and dose-dry mouth relationship, a wider therapeutic index was
      predicted for oxybutynin XL than for immediate-release oxybutynin.

PMID- 10391674
TI  - Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance
      patients: comparison of those who do and do not experience withdrawal and
      concentration-effect relationships.
AB  - OBJECTIVE: To determine plasma racemic methadone concentration-effect
      relationships for subjective and objective responses and whether pharmacokinetic
      and/or pharmacodynamic factors influence withdrawal severity. METHODS: Eighteen
      patients enrolled in a public methadone maintenance program, nine of whom
      experienced significant withdrawal, received constant doses of methadone once
      daily for at least 2 months. During an interdosing interval, 13 blood samples
      were collected to measure plasma racemic methadone concentrations (patients);
      subjective (withdrawal severity, direct opioid effects, and pain threshold) and
      objective (pupil diameter and respiratory rate) opioid effects were quantified on
      11 occasions (all participants). The sigmoid Emax model was used to relate plasma
      concentrations and effects and to calculate the slope factor (N). The rate of
      decline in plasma concentration during each hour from the peak to the trough
      concentration was calculated. RESULTS: There was an inverse relationship between
      plasma concentrations and withdrawal severity and pupil diameter, as well as a
      direct relationship with subjective opioid effects and pain threshold. The mean N
      values were 5.4+/-0.9 for withdrawal severity, 5.1+/-1.1 for subjective opioid
      effects, 1.2+/-0.1 for pupil diameter, and 2.8+/-0.7 for pain threshold.
      Withdrawal severity correlated with the maximum rate of decrease in plasma
      concentration (P < .01). There were no differences between those who reported
      significant withdrawal and those who did not with respect to mean area under the
      plasma concentration versus time curve and predose plasma concentration, but
      maximal rate of decline was greater in the former group (74.5 versus 42.1
      ng/mL/h). CONCLUSIONS: In this group of long-term methadone-maintained
      recipients, opioid responses were strongly correlated with changes in plasma
      racemic methadone concentrations. For the subjective responses, notably
      withdrawal, small changes in plasma concentrations translate into relatively
      large changes in effect; therefore, clinically important withdrawal is a
      consequence of more rapid decline in methadone concentration.

PMID- 10391675
TI  - Cell-cycle-dependent and ATM-independent expression of human Chk1 kinase.
AB  - Checkpoint genes cause cell cycle arrest when DNA is damaged or DNA replication
      is blocked. Although a human homolog of Chk1 (hChk1) has recently been reported
      to be involved in the DNA damage checkpoint through phosphorylation of Cdc25A, B,
      and C, it is not known at which phase(s) of the cell cycle hChk1 functions and
      how hChk1 causes cell cycle arrest in response to DNA damage. In the present
      study, we demonstrate that in normal human fibroblasts (MJ90), hChk1 is expressed
      specifically at the S to M phase of the cell cycle at both the RNA and protein
      levels and that it is localized to the nucleus at this time. hChk1 activity, as
      determined by phosphorylation of Cdc25C, is readily detected at the S to M phase
      of the cell cycle, and DNA damage induced by UV or ionizing radiation does not
      enhance the expression of hChk1 or its activity. Furthermore, hChk1 exists in an
      active form at the S to M phase in fibroblasts derived from patients with ataxia
      telangiectasia (AT) which lack the functional AT mutated (ATM) gene product,
      suggesting that hChk1 expression is independent of functional ATM. Taken together
      with the findings that phosphorylation of Cdc25C on serine 216 is increased at
      the S to M phase, it is suggested that at this particular phase of the cell
      cycle, even in the absence of DNA damage, hChk1 phosphorylates Cdc25C on serine
      216, which is considered to be a prerequisite for the G2/M checkpoint. Thus,
      hChk1 may play an important role in keeping Cdc25C prepared for responding to DNA
      damage by phosphorylating its serine residue at 216 during the S to M phase.

PMID- 10391676
TI  - Exon 4-encoded acidic domain in the epithelium-restricted Ets factor, ESX,
      confers potent transactivating capacity and binds to TATA-binding protein (TBP).
AB  - The Ets gene family has a complex evolutionary history with many family members
      known to regulate genetic programs essential for differentiation and development,
      and some known for their involvement in human tumorigenesis. To understand the
      biological properties associated with a recently described epithelium-restricted
      Ets factor ESX, an 11 kb fragment from the 1q32.2 genomically localized human
      gene was cloned and analysed. Upstream of the ESX promoter region in this genomic
      fragment lies the terminal exon of a newly identified gene that encodes a
      ubiquitin-conjugating enzyme variant, UEV-1. Tissues expressing ESX produce a
      primary 2.2 kb transcript along with a 4.1 kb secondary transcript arising by
      alternate poly(A) site selection and uniquely recognized by a genomic probe from
      the 3' terminal region of the 11 kb clone. Endogenous expression of ESX results
      in a 42 kDa nuclear protein having fivefold greater affinity for the chromatin
      nuclear matrix compartment as compared to other endogenous transcription factors
      like AP-2 and the homologous Ets factor, ELF-1. Exon mapping of the modular
      structure inferred from ESX cDNA and construction of GAL4(DBD)-ESX expression
      constructs were used to identify a transactivating domain encoded by exon 4
      having comparable potency to the acidic transactivation domain of the viral
      transcription factor, VP16. This exon 4-encoded 31 amino acid domain in ESX was
      shown by mutation and deletion analysis to possess a 13 residue acidic
      transactivation core which, based on modeling and circular dichroism analysis, is
      predicted to form an amphipathic alpha-helical secondary structure. Using
      recombinant GST-ESX (exon 4) fusion proteins in an in vitro pull-down assay, this
      ESX transactivation domain was shown to bind specifically to one component of the
      general transcription machinery, TATA-binding protein (TBP). Transient
      transfection experiments confirmed the ability of this TBP-binding
      transactivation domain in ESX to squelch heterologous promoters independent of
      any promoter binding as efficiently as the transactivation domain from VP16.

PMID- 10391677
TI  - SHP-2 binds to Tyr763 and Tyr1009 in the PDGF beta-receptor and mediates PDGF
      induced activation of the Ras/MAP kinase pathway and chemotaxis.
AB  - Activation of the beta-receptor for platelet-derived growth factor (PDGF) by its
      ligand leads to autophosphorylation on a number of tyrosine residues. Here we
      show that Tyr763 in the kinase insert region is a novel autophosphorylation site,
      which after phosphorylation binds the protein tyrosine phosphatase SHP-2. SHP-2
      has also previously been shown to bind to phosphorylated Tyr1009 in the PDGF beta
      receptor. Porcine aortic endothelial (PAE) cells transfected with a PDGF beta
      receptor in which Tyr763 and Tyr1009 were mutated to phenylalanine residues
      failed to associate with SHP-2 after ligand stimulation. Moreover, PDGF-BB
      induced Ras GTP-loading and Erk2 activation were severely compromised in the
      receptor mutant. Whereas the mitogenic response to PDGF-BB remained at the same
      level as in cells expressing wild-type PDGF beta-receptor, chemotaxis induced by
      PDGF-BB was significantly decreased in the case of the Y763F/Y1009F mutant cells,
      suggesting an important role for SHP-2 in chemotactic signaling.

PMID- 10391678
TI  - Tyrosine phosphorylation of C-Cbl facilitates adhesion and spreading while
      suppressing anchorage-independent growth of V-Abl-transformed NIH3T3 fibroblasts.
AB  - The protooncogenic protein c-Cbl becomes tyrosine phosphorylated in normal cells
      in response to a variety of external stimuli, as well as in cells transformed by
      oncogenic protein tyrosine kinases. Tyrosine phosphorylation of c-Cbl upregulates
      its binding to multiple crucial signaling molecules. However, the biological
      consequences of c-Cbl-mediated signaling are insufficiently understood. To
      analyse the biological functions of c-Cbl, we overexpressed wild-type c-Cbl and
      its tyrosine phosphorylation-defective mutant form in v-Abl-transformed NIH3T3
      fibroblasts. In this system, wild-type c-Cbl facilitated adhesion and spreading
      of v-Abl-transformed fibroblasts on the extracellular matrix, while reducing
      anchorage independence of these cells, as measured by their colony-forming
      efficiency in soft agar. Therefore, overexpression of wild-type c-Cbl exhibits an
      overall transformation-suppressing effect. By contrast, overexpression of a
      tyrosine phosphorylation-defective form of c-Cbl increases neither adhesion nor
      anchorage dependence of v-Abl-transformed fibroblasts. Analysis of the role of
      individual tyrosine phosphorylation sites of c-Cbl in these phenomena indicates
      that both phosphatidylinositol-3' kinase and the CrkL adaptor protein may be
      involved in the observed effects of c-Cbl. To summarize, the results presented in
      this report indicate that c-Cbl is involved in regulation of cell adhesion and
      cytoskeletal rearrangements, and that these effects of c-Cbl are dependent on its
      tyrosine phosphorylation.

PMID- 10391679
TI  - Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric
      protein.
AB  - The NPM-MLF1 chimeric protein is produced by the t(3;5)(q25.1;q34) chromosomal
      translocation, which is associated with myelodysplastic syndrome (MDS) prior to
      progression into acute myeloid leukemia (AML). Here we report that K562 human
      leukemia cells ectopically expressing NPM-MLF1, but not those with wild-type
      MLF1, were gradually eliminated from the culture by undergoing apoptosis. NIH3T3
      mouse fibroblasts engineered to overexpress NPM-MLF1 grew normally but serum
      deprivation triggered apoptotic cell death with slower kinetics than did other
      well-known apoptotic inducers such as c-Myc or E2F-1. Quantitative analysis of
      apoptotic induction confirmed that, neither NPM nor MLF1, but the NPM-MLF1 fusion
      protein was able to induce apoptosis. Analyses using a variety of deletion
      mutants of NPM-MLF1 revealed that induction of apoptosis required the N-terminal
      domain of MLF1 and the NPM domain containing nuclear localization signal and that
      removal of the NPM dimerization domain markedly impaired the ability to induce
      apoptosis. Co-expression of Bcl-2 rescued NIH3T3 fibroblasts from NPM-MLF1
      mediated cell death without affecting the expression level or the subcellular
      localization of NPM-MLF1 and enabled cells to progress into S phase in low serum.
      These findings provide an NPM-MLF1-mediated novel mechanism of apoptotic
      induction and imply that NPM-MLFI in collaboration with anti-apoptotic
      oncoproteins may play an important role in multi-step progression from MDS to
      AML.

PMID- 10391680
TI  - Cooperative activity between HER oncogenes and the tumor suppressor IRF-1 results
      in apoptosis.
AB  - The tumor suppressor transcription factor IRF-1 inhibits cell growth. In this
      report we show that IRF-1 also induces apoptosis of highly transformed and
      tumorigenic cell lines. This activity of IRF-1 is demonstrated with cell lines
      expressing HER oncogenes and an activatable IRF-1 fusion protein. Growth of cell
      lines expressing inactive HER1 is inhibited on IRF-1 activation. In contrast, the
      same cells are killed by apoptosis when HER1 and IRF-1 are activated
      simultaneously. We identified promoters stimulated synergistically by IRF-1 and
      by activated HER1. To determine the signals causing transcriptional synergism
      and/or apoptosis we tried to modulate these effects by various dominant negative
      acting proteins. Dominant negative STAT5alpha abolished both induction of
      apoptosis and transcriptional synergy of IRF-1 and HER. Thus, these results
      provide new insights into the mechanism of oncogene-dependent apoptosis induced
      by the activation of a tumor suppressor.

PMID- 10391681
TI  - JNK activation is not required for Fas-mediated apoptosis.
AB  - Fas ligation in the presence of cycloheximide induced Jun N-terminal kinase 1
      (JNK1) and JNK2 phosphorylation, caspase activation and cell death in the IL-3
      dependent cell line BAF3. Fas-mediated apoptosis was prevented by expression of
      dominant negative FADD but not inhibited by IL-3. To investigate the role of JNK
      activation in this process, we examined cells over-expressing a JNK-specific
      phosphatase M3/6. M3/6 prevented Fas stimulation of JNK, but did not affect Fas
      mediated caspase activation or cell death, demonstrating that JNK activation is
      not required for these processes.

PMID- 10391682
TI  - Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma
      cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase
      inhibitor p27/Kip1.
AB  - Interleukin-6 (IL-6)-type cytokines lead to growth arrest of human A375 melanoma
      cells. The present study demonstrates that this effect depends on the activation
      of STAT transcription factors. We observed a correlation between the extent of
      growth inhibition exerted by IL-6, IL-6 plus soluble IL-6 receptor or oncostatin
      M (OSM) and the intensities of STAT3 and STAT1 signals. A truncated chimeric
      receptor retaining only the membrane-proximal region of gp130, the common signal
      transducer of IL-6-type cytokines, did neither activate STATs nor mediate growth
      arrest of stable transfectants. These functions were restored by the addition of
      short STAT recruitment modules comprising critical tyrosine residues from gp130
      (Y767, Y814). A receptor carrying tyrosine module Y759 of gp130 effectively
      mediated activation of the phosphatase SHP-2 but did not alter cell growth.
      Overexpression of dominant negative forms of STAT3 but not STAT1 abrogated the
      inhibitory effect of OSM and IL-6 in A375 cells. In addition, we have identified
      the cyclin-dependent kinase inhibitor p27/Kipl as a novel target to be regulated
      by IL-6-type cytokines. Stimulation-dependent upregulation of p27 mRNA occurred
      STAT3-dependently. Also p27 protein accumulated which coincided with the
      disappearance of hyperphosphorylated retinoblastoma protein in three human
      melanoma cell lines sensitive to IL-6-type cytokines.

PMID- 10391684
TI  - Mutational analysis of p51A/TAp63gamma, a p53 homolog, in non-small cell lung
      cancer and breast cancer.
AB  - p51, a novel family member of human p53, is a recently identified candidate tumor
      suppressor gene mapped at chromosome 3q28. Like p53, p51 was found to activate
      p21Waf1/Cip1 and to induce apoptosis. Since the DNA loss at 3q is reported in
      several cancers including non-small cell lung cancer (NSCLC), we screened for
      mutations in p51A (TAp63gamma), an isoform of p51 with short C-terminal region,
      in 80 NSCLCs as well as 85 breast cancers by RT-PCR single strand conformation
      polymorphism (SSCP) analysis and DNA sequencing. In NSCLCs, p51 was expressed in
      most tumors at variable levels and we found three missense and one silent
      mutations: Gln31His (transactivation domain) in two tumors, Ala148Pro (DNA
      binding domain) and Leu248Leu (DNA-binding domain). In the tumor with Ala148Pro
      or the silent mutation, only the mutant gene appeared to be expressed. The
      modified FASAY method to test the ability of yeast expressing p51A cDNA to grow
      in medium lacking histidine has revealed that Ala148Pro results in a loss of
      function, while Gln31His does not. In contrast to NSCLC, no mutation was observed
      in all 85 breast cancers by the similar method. Our results suggest that, because
      of infrequent mutation, p51 may not be a Knudson type tumor suppressor in most
      NSCLCs and breast cancers. Nevertheless, in at least a part of NSCLC, p51 may
      play a certain role in carcinogenesis in a tissue-specific manner.

PMID- 10391683
TI  - Alterations of Fas (Apo-1/CD95) gene in non-small cell lung cancer.
AB  - Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling. The
      key role of the Fas system in negative growth regulation has been studied mostly
      within the immune system, and somatic mutations of Fas gene in cancer patients
      have been described solely in lymphoid-lineage malignancies. However, many non
      lymphoid tumor cells have been found to be resistant to Fas-mediated apoptosis,
      which suggests that Fas mutations, one of the possible mechanisms for Fas
      resistance, may be involved in the pathogenesis of non-lymphoid malignancies as
      well. In this study, we have analysed the entire coding region and all splice
      sites of the Fas gene for the detection of the gene mutations in 65 human non
      small cell lung cancers by polymerase chain reaction, single strand conformation
      polymorphism and DNA sequencing. Overall, five tumors (7.7%) were found to have
      the Fas mutations, which were all missense mutations. Four of the five mutations
      identified were located in the cytoplasmic region (death domain) known to be
      involved in the transduction of an apoptotic signal and one mutation was located
      in the transmembrane domain. This is the first report on the Fas gene mutations
      in non-lymphoid malignancies, and the data presented here suggests that
      alterations of the Fas gene might lead to the loss of its apoptotic function and
      contribute to the pathogenesis of some human lung cancers.

PMID- 10391685
TI  - Binding of the human T-cell leukemia virus Tax protein to the coactivator CBP
      interferes with CBP-mediated transcriptional control.
AB  - The HTLV-I oncoprotein Tax is required for high level viral transcription and is
      strongly linked to HTLV-I-associated malignant transformation. Tax stimulates
      HTLV-I transcription through high affinity binding to the KIX domain of CBP, a
      pleiotropic coactivator. Several cellular proteins, including c-jun, also bind to
      KIX and utilize CBP as a coactivator. To test whether Tax binding to KIX may
      disable cellular CBP function, we examined the potential interplay between Tax
      and c-jun for binding to KIX. We show that Tax represses the transcription
      function of c-jun in vivo and demonstrate that both transcription factors bind to
      an overlapping minimal region of KIX in vitro. c-jun binding to KIX is displaced
      by Tax, indicating that their binding is mutually exclusive and providing a
      molecular basis for the observed repression. The competition between Tax and
      cellular transcription factors for CBP represents a novel pathway for HTLV-I
      dependent deregulation of gene expression, and may have significant implications
      for cellular homeostasis and transformation in the HTLV-I infected T-cell.

PMID- 10391686
TI  - Hyperplasia in multiple smooth muscle tissues in transgenic mice expressing a
      temperature-sensitive SV40 T-antigen under the control of smooth muscle alpha
      actin regulatory sequences.
AB  - Control of smooth muscle cell (SMC) proliferation is of fundamental importance in
      the development and pathology of the vasculature. To derive vascular SMC with
      conditional inactivation of negative cell cycle regulatory proteins in the
      context of smooth muscle protein expression, a 3.4 kb fragment of the mouse SMC
      alpha-actin promoter was used to target a temperature-sensitive mutant SV40 T
      antigen (tsA58) to smooth muscle in transgenic mice. Mice with this genotype
      display a heritable phenotype of abnormal SMC proliferation in the central tail
      artery, vasa deferentia, seminal vesicles, prostate, and uterus, with the latter
      resembling uterine leiomyomatosis and prostatic hypertrophy. Neither the aorta
      nor other viscera manifested abnormal proliferation. Cultures from aorta, vas
      deferens, seminal vesicle, and kidney tissue were characterized with regard to
      protein expression, stability, and matrix remodelling capacity. The alpha-actin
      content/cell was up to 3-4-fold higher, as well as more stable than in primary
      SMC cultures, suggesting successful selection for propagation of cells expressing
      this differentiation marker. All cells displayed enhanced growth at the
      permissive temperature. As an initial functional assessment, the cells were
      compared to non-transformed mouse aortic SMC with respect to the ability to
      remodel collagen gel matrices, and demonstrated conservation of this physiologic
      function. This in vivo analysis of the SMC alpha-actin promoter supports a
      broader range of smooth muscle-directed expression activity than previously
      recognized, and establishes the feasibility of its use to direct transgene
      expression to vascular as well as genito-urinary smooth muscle. The targeted
      expression of the tsA58 T antigen has yielded transgenic animals with several
      manifestations of smooth muscle hyperplasia; these animals have in turn permitted
      the derivation of several murine SMC lines with phenotypic stability and
      conditionally-modulated proliferation. These cells will allow expansion of
      derivative transfected smooth muscle cell lines under permissive conditions, as
      well as oncogene inactivation at the restrictive temperature when desired for
      functional studies.

PMID- 10391688
TI  - p53-Dependent growth arrest and altered p53-immunoreactivity following metabolic
      labelling with 32P ortho-phosphate in human fibroblasts.
AB  - The tumour suppressor gene p53 plays a major role in the cellular response to DNA
      damage, mediating growth arrest and/or apoptosis. Phosphorylation of the protein
      occurs at numerous sites in vivo and is likely to be a major mechanism for
      modulation of its activity as a transcriptional transactivator. Not surprisingly,
      therefore, p53 has been intensively studied by 32P metabolic labelling. Here we
      show however, using normal human fibroblasts, that typical labelling conditions
      induce (i) a p53-dependent inhibition of DNA synthesis and (ii) an increase in
      the cellular content of p53 protein detectable by the phosphorylation-sensitive
      antibody DO-1 but not by antibody DO-12. These data demonstrate for the first
      time that 32P labelling is sufficient to induce a biologically-significant, p53
      mediated cellular response and strongly suggest that it perturbs the
      phosphorylation state of p53 which it is being used to measure. This highlights
      the need to re-evaluate earlier data by non-radioactive approaches using phospho
      specific antibodies.

PMID- 10391687
TI  - Mice over-expressing human O6 alkylguanine-DNA alkyltransferase selectively
      reduce O6 methylguanine mediated carcinogenic mutations to threshold levels after
      N-methyl-N-nitrosourea.
AB  - While it is well known that MNU induces thymic lymphomas in the mouse, it remains
      unclear which pre-mutagenic lesions are responsible for lymphomagenic
      transformation. One lesion thought to play a critical role is
      O6methylguanine[O6mG]which initiates G: C to A:T transition mutations in K-ras
      and other oncogenes. O6alkylguanine-DNA alkyltransferase (AGT), encoded by the
      methylguanine methyltransferase gene [MGMT], removes the methyl group thereby
      preventing the mutation from occurring. When overexpressed in the thymus, MGMT
      protects mice from MNU-induced thymic lymphomas. To determine whether MGMT
      overexpression reduced G: C to A: T mutation frequency after MNU, Big Blue lacI
      and MGMT+/Big Blue mice were treated with MNU and analysed for mutations in the
      lacI and K-ras genes. The incidence of MNU-induced lymphomas was 84% in Big Blue
      lacI mice compared to 14% in MGMT+Big Blue lacI mice. Sixty-two per cent of the
      lymphomas had a GGT to GAT activating mutation in codon 12 of K-ras consistent
      with O6mG adduct-mediated point mutagenesis. LacI mutation frequency in thymus of
      MNU treated Big Blue mice was 45-fold above background whereas it was 11-fold
      above background in MNU treated MGMT+/Big Blue mice. Most lacI mutations were G:C
      to A:T transitions, implicating O6mG even in the MGMT+mice. No mutations were
      attributable to chromosomal aberrations or rearrangements. Thus, O6mG adducts
      account for the carcinogenic effect of MNU and MGMT overexpression is selectively
      able to reduce O6methylguanine adducts below a carcinogenic threshold. Other
      adducts are mutagenic but appear to contribute much less to malignant
      transformation or oncogene activation.

PMID- 10391690
TI  - 11th International Conference on Alcohol. Liverpool, United Kingdom, 19-22 April
      1998. Abstracts.

PMID- 10391691
TI  - New issues and future legislation on biosafety.
AB  - The current debate on gene technology in Europe is reviewed with particular
      emphasis on the role of EFB and science in general. From this debate important
      lessons have been learned by scientists, industrial companies, legislators,
      parliamentarians and interest organisations. This gives confidence that the
      continued debate will eventually lead to public acceptance of gene technology
      even in the food area.

PMID- 10391689
TI  - High incidence of allelic loss on chromosome 5 and inactivation of p15INK4B and
      p16INK4A tumor suppressor genes in oxystress-induced renal cell carcinoma of
      rats.
AB  - Ferric nitrilotriacetate induces oxidative damage in renal proximal tubules, a
      consequence of Fenton-like reaction, that ultimately leads to a high incidence of
      renal cell carcinoma (RCC) in rats. In order to find common genetic alterations
      in this oxystress-induced carcinogenesis model, RCCs were produced in F1 hybrid
      rats between Wistar and Long-Evans strains and genomes were screened for loss of
      heterozygosity (LOH) with microsatellite polymorphic markers by PCR. Five
      consecutive markers on chromosome 5 (D5Mgh5, D5Mit9, D5Mgh6, D5Mit11 and D5Mit6)
      showed LOH in >40% of the RCCs. As possible candidate tumor suppressor genes on
      chromosome 5, p15INK4B and p16INK4A were investigated for genetic alteration and
      aberrant methylation by Southern blot, PCR/SSCP/ sequencing and methylation
      specific PCR. Genetic alteration (homozygous or hemizygous deletion with or
      without point mutation) or aberrant methylation were found in 30.7 and 53.8% of
      the RCC cases, respectively, which was proportionally associated with the
      histological nuclear grade and metastatic activity. Our data suggest that
      inactivation of p15 and p16 genes could be one of the major pathways responsible
      for oxystress-induced carcinogenesis.

PMID- 10391692
TI  - Chemotherapy plus radiation improves survival in patients with cervical cancer.

PMID- 10391693
TI  - The Royal College of Radiologists Clinical Oncology Information Network.
      Guidelines on the non-surgical management of lung cancer.

PMID- 10391694
TI  - Coefficient of variation of interspike intervals greater than 0.5. How and when?
AB  - Using Stein's model with and without reversal potentials, we investigated the
      mechanism of production of spike trains with a CV (ISI)(standard deviation/mean
      interspike interval) greater than 0.5, as observed in the visual cortex. When the
      attractor of the deterministic part of the dynamics is below the firing
      threshold, spike generation results primarily from random fluctuations. Using
      computer simulation for a range of membrane decay times and with other model
      parameters set to values appropriate for the visual cortex, we demonstrate that
      CV (ISI) is then usually greater than 0.5; if the attractor is above the
      threshold, spike generation is mainly due to deterministic forces, and CV (ISI)
      is then usually lower than 0.5. The critical value of the inhibitory postsynaptic
      potential (IPSP) rate at which CV (ISI) becomes greater than 0.5 is determined,
      resulting in specifications of how neurones might adjust their synaptic inputs to
      elicit irregular spike trains.

PMID- 10391695
TI  - U.S Food and Drug Administration approval of AmBisome (liposomal amphotericin B)
      for treatment of visceral leishmaniasis.

PMID- 10391696
TI  - Lack of response to short-term use of clarithromycin (BIAXIN) in multiple
      myeloma.

PMID- 10391697
TI  - Jumping translocation breakpoint regions lead to amplification of rearranged Myc.

PMID- 10391698
TI  - Relationship between levels of leptin and hemoglobin in Japanese men.

PMID- 10391699
TI  - Engraftment of ex vivo-expanded cord blood cells in NOD/SCID mice: what is the
      clinical relevance?

PMID- 10391700
TI  - Does recombinant human granulocyte colony-stimulating factor really prime marrow
      stem cells in mice and humans?

PMID- 10391701
TI  - The participation of the hemes of flavocytochrome b245 in the electron transfer
      process in NADPH oxidase.

PMID- 10391702
TI  - VIIIth International Symposium on Luminescence Spectrometry in Biomedical and
      Environmental Analysis: Detection Techniques and Applications in Chromatography
      and Capillary Electrophoresis. Canary Islands, Spain, 26-29 May 1998. Extended
      abstracts.

PMID- 10391703
TI  - Vitamin D deficiency. Groups at risk need supplementation, and milk could be
      fortified.

PMID- 10391704
TI  - Vitamin D deficiency. Guidelines are needed for treating diseases of bone
      metabolism in epilepsy.

PMID- 10391705
TI  - Fractures of the thoracolumbar spine in major trauma patients. It happened to me!

PMID- 10391706
TI  - Alcohol intake and cancer of the upper digestive tract. Confounding in such
      studies is important.

PMID- 10391707
TI  - Alcohol intake and cancer of the upper digestive tract. Such studies should be
      done in non-smokers.

PMID- 10391708
TI  - Alcohol intake and cancer of the upper digestive tract. Treating upper digestive
      tract cancers as a single entity may be misleading.

PMID- 10391709
TI  - Commentary: mix of perspectives needed in purchasing of care.

PMID- 10391711
TI  - Backdoor euthanasia. Intravenous and enteral fluids may cause rather than
      alleviate suffering.

PMID- 10391710
TI  - Antepartum risk factors for newborn encephalopathy. Inverse association of risk
      may be due to easier delivery with elective caesarean section.

PMID- 10391712
TI  - Vitamin D concentrations in Asian children living in England. Concentrations
      found may be function of analytical methodology used.

PMID- 10391713
TI  - Prediction of cardiovascular risk. Hypothesis of program is flawed.

PMID- 10391714
TI  - The evolving digital ecology.

PMID- 10391715
TI  - Enzymatic synthesis of no-carrier-added 6-[18F]fluoro-L-dopa with beta
      tyrosinase.
AB  - An enzymatic synthesis of nca 6-[18F]fluoro-L-dopa has been developed. The
      process consists of a chemical synthesis of 4-[18F]fluorocatechol and its
      enzymatic reaction with beta-tyrosinase. The 4-[18F]fluorocatechol was prepared
      by nucleophilic aromatic substitution of the NO2 group on 6-nitroveratoraldehyde
      with [K/222]+18F-, followed by decarbonylation with tris(triphenylphosphine)
      rhodium(I) chloride and hydrolysis with hydroiodic acid. By C18 Sep-Pak
      purification, 4-[18F]fluorocatechol was obtained in ethanol with a radiochemical
      yield of 9.2%. An enzymatic reaction of 4-[18F]fluorocatechol, ammonium and
      pyruvate catalyzed by beta-tyrosinase in an ethanolic Tris-HCl buffer (pH 9.0)
      containing ascorbate gave within 5 min 6-[18F]fluoro-L-dopa with an approximate
      radiochemical yield of 60% without any isomers. The deproteinized reaction
      mixture was applied to a preparative reverse phase column, and the
      radiochemically and enantiomerically pure 6-[18F]fluoro-L-dopa was obtained with
      a radiochemical yield of 2.0% based on [18F]F- (decay-corrected). The synthesis
      time was 150 min from the EOB and the specific activity was > 200 GBq/micromol.

PMID- 10391717
TI  - Presentation of confocal images.

PMID- 10391718
TI  - [Flashes of how pregnant mothers perceive pre-natal care in a university
      hospital].
AB  - This article was based on research carried out to characterize the pre- natal
      care offered to pregnant women at the outpatient unit of a university hospital.
      This qualitative study used ethnography, more precisely miniethnography. The
      methodological approach and data collection were done through participating
      observation. Results showed that pregnant in touch with health professionals are
      able to filter information and at t he same time, behave as nonparticipating
      clients, since they do not question the care offered to them even if the care is
      not good. Although women think that the care offered at this hospital is better
      than the one offered elsewhere, they admit that it does not respond successfully
      to their real expectations and needs. Generally speaking, they would like to
      receive more orientation and more personal assistance. They do not like this care
      very much mainly because of students' rotativity.

PMID- 10391716
TI  - A paper chromatographic technique for quantitative evaluation of hydrolysed and
      ionic components in 201Tl radiopharmaceuticals.
AB  - A reported paper chromatographic technique has been extended to delineate the
      hydrolysed components in 201Tl radiopharmaceuticals for the determination of
      radiochemical purity. Detailed radiochemical purity analysis of 201TlCl has been
      demonstrated using mini paper chromatographic systems. The technique is also
      useful in evaluation of the radiochemical purity of 67Ga and 111In
      radiopharmaceuticals.

PMID- 10391719
TI  - [Integrated planning in health: a possibility of participative action].
AB  - This paper intends to report an experience with the process of integrated
      planning in a Basic Health Unit at Riberiao Preto-SP. we selected as our object
      of analysis the interactions and dialogues that were expressed in the scope of
      the local health system. Therefore, we sought to consider the individual dynamics
      of this reality and the social agents involved (teachers, students, directors,
      health workers and community workers), trying to understand the communicative
      action according to HABERMAS (1989). We believe that this is an open space in the
      perspective of widening the level of integrated participation in the
      administration of public health services.

PMID- 10391720
TI  - Noninvasive screening for acute coronary syndromes.

PMID- 10391721
TI  - [Polio vaccines].

PMID- 10391722
TI  - [Furuncle].

PMID- 10391723
TI  - Irritant contact dermatitis caused by methyl iodide.

PMID- 10391724
TI  - 16th Annual Meeting of the American Society for Bariatric Surgery. San Diego,
      California, USA. June 9-12, 1999. Abstracts.

PMID- 10391725
TI  - A new aspect to the question, "How can we determine the functional viability of
      donor lungs?".

PMID- 10391726
TI  - Issues and controversies in respiratory medicine. Conference proceedings.
      Phoenix, Arizona, USA. November 20-23, 1997.

PMID- 10391727
TI  - [Unguentum lymphaticum in lymphatic diseases--current knowledge and prospects].

PMID- 10391728
TI  - Institute of Human Virology 2nd Annual Meeting. September 15-21, 1997. Abstracts.

PMID- 10391729
TI  - 9th Canadian Flow Cytometry Consensus Meeting. Mont Ste. Anne, Quebec, Canada.
      October 25-27, 1998. Abstracts.

PMID- 10391730
TI  - On "Scents and Sensitivity".

PMID- 10391731
TI  - Regional differences invalidate U.S. sperm trend conclusions.

PMID- 10391733
TI  - Garlic fights more than vampires.

PMID- 10391732
TI  - Chlorpyrifos (Dursban) and Dow employees.

PMID- 10391734
TI  - Fertilizing or contaminating?

PMID- 10391735
TI  - Environmental impacts of Hurricane Mitch.

PMID- 10391736
TI  - A focus on farming health in Iowa.

PMID- 10391737
TI  - 1st International Congress on the Sentinel Node in Diagnosis and Treatment of
      Cancer. Amsterdam, The Netherlands, April 7-10, 1999. Proceedings and abstracts.

PMID- 10391738
TI  - Image of the month. Glucagonoma syndrome.

PMID- 10391739
TI  - The epidemiology of Crohn's disease.

PMID- 10391740
TI  - NF-kappaB in IBD: does binding to DNA imply transcriptional activity?

PMID- 10391741
TI  - Balsalazide and azathiprine or 6-mercaptopurine: evidence for a potentially
      serious drug interaction.

PMID- 10391743
TI  - Perfusion techniques for determining alveolar fluid resorption rate.

PMID- 10391742
TI  - Sensitivity of urease-based test on diagnosis of Helicobacter pylori in children
      and the elderly.

PMID- 10391744
TI  - Skeletal muscle dysfunction vs. muscle disuse in patients with COPD.

PMID- 10391745
TI  - ADA advertising standards. American Dental Association.

PMID- 10391746
TI  - [On Chinese herbs neuropathy].

PMID- 10391747
TI  - Advances in the treatment of cardiovascular diseases as we approach the new
      millennium.

PMID- 10391748
TI  - [A quarter century ago: a JCC member looks back. No. 21].

PMID- 10391749
TI  - Coming to term with GABA.

PMID- 10391750
TI  - Proceedings of the Ares Serono Foundation Workshop on HIV-1 and Gametes. Siena,
      Italy, October 14-17, 1997.

PMID- 10391751
TI  - 13th Annual meeting of the Japanese Society for Immunology of Reproduction
      (JRSI). Kobe, Japan, 11-12 December 1998. Abstracts.

PMID- 10391752
TI  - OMERACT IV. Outcome Measures in Rheumatology. Cancun, Mexico, April 16-20, 1998.

PMID- 10391753
TI  - New standard of care for cervical cancer sets stage for questions.

PMID- 10391754
TI  - Does bone marrow transplantation confer a normal life span?

PMID- 10391755
TI  - The risks of lowering the cesarean-delivery rate.

PMID- 10391756
TI  - The risks of lowering the cesarean-delivery rate.

PMID- 10391758
TI  - The risks of lowering the cesarean-delivery rate.

PMID- 10391759
TI  - The risks of lowering the cesarean-delivery rate.

PMID- 10391757
TI  - The risks of lowering the cesarean-delivery rate.

PMID- 10391760
TI  - Epstein-Barr virus-associated lymphoma after treatment of macroglobulinemia with
      cladribine.

PMID- 10391761
TI  - Treating patients with severe sepsis.

PMID- 10391762
TI  - Treating patients with severe sepsis.

PMID- 10391763
TI  - Treating patients with severe sepsis.

PMID- 10391764
TI  - Horner's syndrome.

PMID- 10391765
TI  - Mechanism of intravenous immune globulin therapy.

PMID- 10391766
TI  - Who should determine when health care is medically necessary?

PMID- 10391767
TI  - Who should determine when health care is medically necessary?

PMID- 10391768
TI  - Who should determine when health care is medically necessary?

PMID- 10391769
TI  - "Tomatophagia" and iron-deficiency anemia.

PMID- 10391770
TI  - Internistendagen. Veldhoven, The Netherlands, 22-23 April 1999. Abstracts.

PMID- 10391771
TI  - European Association for Studying Regeneration Conference. Koln, Germany, 1998.
      Abstracts.

PMID- 10391772
TI  - Molecular distribution of monocarboxylic acids in Asuka carbonaceous chondrites
      from Antarctica.
AB  - Molecular distribution of low-molecular-weight monocarboxylic acids was studied
      in three CM2 Asuka carbonaceous chondrites (A-881280, A-881334 and A-881458),
      which were recovered from Antarctica by the 29th Japanese Antarctic Research
      Expedition in 1988. GC and GC/MS analyses identified more than 30 monocarboxylic
      acids in A-881458, including aliphatic and aromatic acids with various structural
      isomers. Isomeric phenolic compounds were also identified. The aliphatic
      carboxylic acids have straight-chain structures having 2 to 12 carbon atoms (C2
      to C12), and branched-chain structures (C4 to C9). The quantities of straight
      chain acids decrease logarithmically with increasing carbon number. At the same
      carbon number, a straight-chain isomer is always predominant compared to branched
      chain isomers. All of the 14 possible C4, C5 and C6 aliphatic monocarboxylic
      acids (not including optical isomers) have been identified, although all the
      isomers were not reported in Murchison and Y-791198 meteorites. Of the 17
      possible isomeric C7 acids, at least 14 isomers were tentatively identified by
      mass spectra (EI and CI mode). At C8 or above, peaks of branched-chain isomers
      become obscure, probably due to the large number of isomers and small
      concentrations. Branched-chain monocarboxylic acids over C6 have never been
      reported in Muchison. Although occurrence of aliphatic acids are similar between
      A-881458 and Murchison at C4, C5 and C6 acids, a major difference is that A
      881458 as well as Y-791198 have straight-chain predominance among isomers in
      contrast to Murchison being branched-chain predominant. In the case of isomeric
      aromatic compounds such as toluic acids and cresols, m-toluic acid and p-cresol
      are more abundant among their isomers, respectively. The molecular distribution
      may not reflect thermodynamic equilibrium but rather a kinetically controlled
      process for their formation mechanism. The other two CM2 chondrites (A-881280 and
      A-881334) were depleted in carboxylic acids in spite of similar carbon contents.
      The depletion is not due to weathering on ice, because the degrees of weathering
      are small and similar among the three chondrites. Probably those latter two
      chondrites may have been subjected to aqueous alteration or metamorphism on their
      meteorite parent bodies.

PMID- 10391773
TI  - The extraterrestrial origin of the homochirality of biomolecules--rebuttal to a
      critique.
AB  - Having concluded that abiotic terrestrial mechanisms would have been ineffectual
      for the origin of terrestrial homochirality, we have proposed an alternative
      extraterrestrial scenario involving stereoselective ultraviolet photolysis of the
      racemic constituents of interstellar grain mantles by circularly polarized
      synchrotron radiation from neutron stars, followed by terrestrial accretion of
      the resulting chiral molecules via cometary impact. Recently L. Keszthelyi (1995)
      has reviewed a number of our arguments and advanced several erroneous
      calculations and conclusions purporting to negate them. We offer here points of
      rebuttal to Keszthelyi's criticisms, and support our inferences with recent data
      regarding indigenous enantiomeric excesses of L-amino acids in the Murchison
      meteorite.

PMID- 10391774
TI  - [Zsigmond Kunewalder].

PMID- 10391775
TI  - Infant with epistaxis painted in the 1320s by Simone Martini.

PMID- 10391776
TI  - Obesitology '97. Papers presented at the conference organized by the Czech
      Society for the Study of Obesity, the J.E. Purkinje Czech Medical Society, held
      23 October 1997 at the School of Physical Education and Sports, Charles
      University, Prague 6, Vokovice.

PMID- 10391777
TI  - [Europe as a challenge].

PMID- 10391778
TI  - [Dentistry Europe-wide].

PMID- 10391780
TI  - [Drinking water with further fluorine addition. The cantonal parliamentary
      commission studies the advantages and disadvantages of drinking water
      fluoridation].

PMID- 10391779
TI  - ["The market peasant at the tooth-puller's." Christian Wilhelm Ernst Dietrich
      (after Gerrit Dou)].

PMID- 10391782
TI  - [19th Continuing Education Course. A report on the continuing education week in
      Les Diablerets, 27 February to 6 March 1999].

PMID- 10391783
TI  - NIH urged to fund centers to merge computing and biology.

PMID- 10391781
TI  - [Quality assurance in dentistry].

PMID- 10391784
TI  - Scientists block NIH plan to grant Ph.D.s.

PMID- 10391785
TI  - Elusive interferon alpha producers nailed down.

PMID- 10391786
TI  - NIH ethics office tapped for a promotion.

PMID- 10391787
TI  - No winners in patent shootout.

PMID- 10391788
TI  - From the bioweapons trenches, new tools for battling microbes.

PMID- 10391790
TI  - Religion and science.

PMID- 10391789
TI  - New clues to how neurons strengthen their connections.

PMID- 10391791
TI  - Religion and science.

PMID- 10391792
TI  - Religion and science.

PMID- 10391794
TI  - Religion and science.

PMID- 10391793
TI  - Religion and science.

PMID- 10391795
TI  - The systematics of Homo.

PMID- 10391796
TI  - Wound healing.

PMID- 10391797
TI  - Sex and repression.

PMID- 10391798
TI  - Factors affecting duodenal ulcer healing. Four double-blind trials in 193
      patients.
AB  - An analysis of four double-blind endoscopically controlled trials carried out in
      1978 -1980 is presented. Drugs utilized were (patient numbers in brackets): a new
      histamine H2-receptor antagonist ranitidine (25) v. placebo (22), the colloidal
      bismuth ulcer-coating preparation bicitropeptide (24) v. cimetidine (26), the
      tricyclic antidepressant trimipramine (20) v. placebo (19), and the disaccharide
      coating preparation sucralfate (29) v. placebo (28). Factors analysed were
      smoking, alcohol consumption, age, length of history, sex and race. The
      prevalence of smoking and alcohol use, age and length of history varied in the
      four trials. Pronouncements regarding these factors based on small trials are
      therefore unreliable. There were no overall diffeences in healing rates whether
      the patient smoked, consumed alcohol, was above or below 40 years of age, or had
      a history shorter or longer than 1 year. Comparison of drug and placebo responses
      revealed that the differences between these were most significant in: non-smokers
      (P=0,0010) compared with smokers (P=0,0288); teetotallers (P<0,005) compared with
      alcohol consumers (NS); history under 1 year (P<0,005) compared with over 1 year
      (P<0,025); males (<0,01) compared with females (NS); and Indians (P<0,005)
      compared with Blacks (NS).

PMID- 10391799
TI  - The role of laparotomy, gut manipulation and immunosuppression on bacterial
      translocation from the intestinal tract.

PMID- 10391800
TI  - Anti-HLA antibodies transduce proliferative signals in endothelial cells and
      smooth muscle cells.

PMID- 10391802
TI  - Long-term hepatocyte transplantation using three-dimensional matrices.

PMID- 10391801
TI  - Renal transplantation in patients with a vascular aortoiliac prosthesis.

PMID- 10391804
TI  - The New Public Health Challenges for the 21st Century. Proceedings of a seminar.
      Mona, Jamaica, July 1997.

PMID- 10391803
TI  - Proceedings of the 1st International Symposium on Transplant Recipient
      Compliance. Arlington, Virginia, April 3-5, 1998.

PMID- 10391805
TI  - Current awareness on yeast.

PMID- 10391806
TI  - Proceedings of the Scientific Meeting of the Collegium Oto-Rhino-Laryngologicum
      Amicitae Sacrum. Copenhagen, Denmark, August 22-26, 1998.

PMID- 10391807
TI  - [Laser photocoagulation of central retinal vein occlusion].

PMID- 10391808
TI  - Proceedings of the Middle European Meeting on Plum Pox. Smolenice, Slovakia, June
      29-July 3, 1998.

PMID- 10391809
TI  - Effect of false-positive mammograms on interval breast cancer screening in a
      health maintenance organization.
AB  - BACKGROUND: Despite the mortality benefits of breast cancer screening, not all
      women receive regular mammography. Such factors as age, socioeconomic status, and
      physician recommendation have been associated with greater use of screening.
      However, we do not know whether having an abnormal mammogram affects future
      screening. OBJECTIVE: To examine the effect of a false-positive mammogram on
      adherence to the next recommended screening mammogram. DESIGN: Prospective cohort
      study. SETTING: The breast cancer screening program at Group Health Cooperative,
      a health maintenance organization in Washington state. PATIENTS: 5059 women 40
      years of age or older with no history of breast cancer or breast surgery who had
      false-positive (n = 813) or true-negative (n = 4246) index screening mammograms
      between 1 August 1990 and 31 July 1992. MEASUREMENTS: Screening rates and odds
      ratios for recommended interval screening up to 42 months after the index
      mammogram. RESULTS: After adjustment for differences in age; previous use of
      mammography; family history of breast cancer; exogenous hormone use; and age at
      menarche, first childbirth, and menopause, women with false-positive index
      mammograms were more likely than those with true-negative index mammograms to
      obtain their next recommended screening mammogram (odds ratio, 1.21 [95% CI, 1.01
      to 1.45]). The relation between a false-positive mammogram and the likelihood of
      adherence to screening in the next recommended interval was strongest among women
      who had not previously undergone mammography (odds ratio, 1.66 [CI, 1.26 to
      2.17]). CONCLUSIONS: Having a false-positive mammogram did not adversely affect
      screening behavior in the next recommended interval. Women with false-positive
      mammograms, especially those without previous mammography, were more likely to
      return for the next scheduled screening.

PMID- 10391810
TI  - Clinical reactivation of genital herpes simplex virus infection decreases in
      frequency over time.
AB  - BACKGROUND: Visits to physicians for genital herpes simplex virus (HSV) infection
      continue to increase. Most patients with symptomatic infections have recurrences,
      but no studies of the long-term clinical course of genital herpes are available.
      OBJECTIVE: To determine whether the frequency of HSV recurrences decreases over
      time. DESIGN: Observational cohort study. SETTING: University-based research
      clinic. PATIENTS: 664 persons with genital herpes followed for at least 14
      months. MEASUREMENTS: Patients were classified as having initial or recurrent HSV
      1 or HSV-2 infection. Patient-reported recurrences and observed recurrences were
      recorded in a database; more than 12,000 recurrences were analyzed. RESULTS:
      Median recurrence rates in the first year of follow-up were one and five per year
      in patients with newly acquired HSV-1 and HSV-2 infection, respectively; second
      year rates were significantly lower in both groups. Patients presenting with
      recurrent HSV-2 infection had higher rates of recurrence in the first and second
      years and no significant decrease; significant decreases were detected with
      longer follow-up. One third of all patients experienced a decrease of two or more
      recurrences per year between years 1 and 2. Patients infected with HSV-2 who were
      followed for more than 4 years had a median decrease of two recurrences between
      years 1 and 5. However, 25% of these patients had an increase of at least one
      recurrence in year 5, illustrating the variability among HSV-infected persons.
      Decreases over time among patients who never received suppressive therapy were
      similar to decreases during untreated periods in patients who received
      suppressive therapy. CONCLUSIONS: Herpes simplex virus type 2 infection continues
      to be a chronic remitting illness. Over time, however, clinically significant
      reductions occur in a majority of patients. Physicians may wish to periodically
      assess the need for continued treatment with daily suppressive antiviral
      chemotherapy.

PMID- 10391811
TI  - Walking to work and the risk for hypertension in men: the Osaka Health Survey.
AB  - BACKGROUND: It is not known whether physical activity is effective in reducing
      the risk for hypertension. OBJECTIVE: To investigate the association of the
      duration of the walk to work and leisure-time physical activity with the risk for
      hypertension. DESIGN: Prospective cohort study. SETTING: Work site in Osaka,
      Japan. PARTICIPANTS: 6017 Japanese men 35 to 60 years of age with systolic blood
      pressure less than 140 mm Hg, diastolic blood pressure less than 90 mm Hg, normal
      glucose intolerance, and no history of hypertension or diabetes at baseline.
      MEASUREMENTS: Data on physical activity were obtained by using questionnaires.
      Blood pressure was measured by using a standard technique; a value of at least
      160/95 mm Hg was used to diagnose hypertension. RESULTS: During 59,784 person
      years of follow-up, 626 cases of hypertension were confirmed. The duration of the
      walk to work was associated with a reduction in the risk for incident
      hypertension; multivariate-adjusted relative risks were 1.00 for a walk of 10
      minutes or less (reference category), 0.88 (95% CI, 0.75 to 1.04) for an 11- to
      20-minute walk, and 0.71 (CI, 0.52 to 0.97) for a walk of 21 minutes or more (P
      for trend = 0.02). For every 26.3 men who walk more than 20 minutes to work, one
      case of hypertension will be prevented. CONCLUSIONS: Walking to work and other
      types of physical activity decreased the risk for hypertension in Japanese men.
      Regular exercise can prevent hypertension.

PMID- 10391812
TI  - Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first
      degree relatives of patients with type 2 diabetes.
AB  - BACKGROUND: Impaired ability to eliminate lipids in the postprandial state is an
      atherogenic trait associated with insulin resistance. OBJECTIVE: To assess
      insulin sensitivity and postprandial triglyceride metabolism in prediabetic
      persons. DESIGN: Cross-sectional study. SETTING: Sahlgrenska University Hospital,
      Goteborg, Sweden. PARTICIPANTS: 13 healthy, normotriglyceridemic men with two
      first-degree relatives with type 2 diabetes and 13 carefully matched controls
      without known diabetes heredity. MEASUREMENTS: Oral glucose tolerance test,
      insulin sensitivity (euglycemic clamp technique), and fasting and postprandial
      triglyceride levels after a mixed meal. RESULTS: Relatives of persons with type 2
      diabetes were insulin resistant but had normal glucose tolerance. They exhibited
      postprandial hypertriglyceridemia; the 6-hour triglyceride incremental area under
      the curve was 50% higher than that of the control group (P = 0.037). CONCLUSIONS:
      These healthy male first-degree relatives of patients with type 2 diabetes are
      insulin resistant and exhibit postprandial lipid intolerance despite having
      normal fasting triglyceride levels. These characteristics, which occur in the
      absence of glucose intolerance, are associated with an increased risk for
      macroangiopathy.

PMID- 10391814
TI  - Management of pain and spinal cord compression in patients with advanced cancer.
      ACP-ASIM End-of-life Care Consensus Panel. American College of Physicians
      American Society of Internal Medicine.
AB  - General internists often care for patients with advanced cancer. These patients
      have substantial morbidity caused by moderate to severe pain and by spinal cord
      compression. With appropriate multidisciplinary care, pain can be controlled in
      90% of patients who have advanced malignant conditions, and 90% of ambulatory
      patients with spinal cord compression can remain ambulatory. Guidelines have been
      developed for assessing and managing patients with these problems, but
      implementing the guidelines can be problematic for physicians who infrequently
      need to use them. This paper traces the last year of life of Mr. Simmons, a
      hypothetical patient who is dying of refractory prostate cancer. Mr. Simmons and
      his family interact with professionals from various disciplines during this year.
      Advance care planning is completed and activated. Practical suggestions are
      offered for assessment and treatment of all aspects of his pain, including its
      physical, psychological, social, and spiritual dimensions. The methods of pain
      relief used or discussed include nonpharmacologic techniques, nonopioid
      analgesics, opioids, adjuvant medications, radiation therapy, and
      radiopharmaceutical agents. Overcoming resistance to taking opioids; initiating,
      titrating, and changing opioid routes and agents; and preventing or relieving the
      side effects they induce are also covered. Data on assessment and treatment of
      spinal cord compression are reviewed. Physicians can use the techniques described
      to more readily implement existing guidelines and provide comfort and optimize
      quality of life for patients with advanced cancer.

PMID- 10391813
TI  - Persistence and boosting of bacille Calmette-Guerin-induced delayed-type
      hypersensitivity.
AB  - BACKGROUND: Bacille Calmette-Guerin (BCG) vaccination may induce persistent and
      booster purified protein derivative (PPD) responses that complicate tuberculosis
      screening efforts. OBJECTIVES: To investigate the effects of BCG vaccination on
      serial PPD tests and to study correlations between persistent delayed-type
      hypersensitivity and other potential surrogate markers of protective immunity.
      DESIGN: Cohort study. SETTING: Midwestern urban university. PARTICIPANTS: 69
      healthy adults. INTERVENTIONS: BCG vaccination, blood samples drawn for
      immunologic studies, and PPD tests done sequentially over 1 to 3 years.
      MEASUREMENTS: Serial PPD induration, lymphoproliferation, and interferon-gamma
      responses. RESULTS: 10% of participants (95% CI, 4% to 20%) had persistent PPD
      responses of 15 mm or greater, and 3% (CI, 0% to 10%) demonstrated PPD boosting
      of 15 mm or greater 1 to 3 years after BCG vaccination. Intradermal BCG
      vaccination induced a larger number of persistent responses that were 10 mm or
      greater than did percutaneous BCG vaccination (12 of 46 participants compared
      with 1 of 23 participants; P = 0.05). Persistent and boosted delayed-type
      hypersensitivity correlated with mycobacterial-specific lymphoproliferation and
      interferon-gamma responses. CONCLUSIONS: Previous BCG vaccination reduces the
      predictive value of serial PPD testing. The lowest PPD predictive values will
      occur in persons without known tuberculosis exposure who were vaccinated recently
      or many times with intradermal BCG. In addition, BCG-related persistence and
      boosting of delayed-type hypersensitivity responses correlate with other
      potential surrogate markers of protective mycobacterial immunity.

PMID- 10391815
TI  - Cardiogenic shock.
AB  - PURPOSE: To review the cause, epidemiology, pathophysiology, and treatment of
      cardiogenic shock. DATA SOURCES: A MEDLINE search of the English-language reports
      published between 1976 and 1998 and a manual search of bibliographies of relevant
      papers. STUDY SELECTION: Experimental, clinical, and basic research studies
      related to cardiogenic shock. DATA EXTRACTION: Data in selected articles were
      reviewed, and relevant clinical information was extracted. DATA SYNTHESIS:
      Cardiogenic shock is a state of inadequate tissue perfusion due to cardiac
      dysfunction, most commonly caused by acute myocardial infarction. Mortality rates
      for patients with cardiogenic shock remain frustratingly high, ranging from 50%
      to 80%. The pathophysiology of cardiogenic shock involves a downward spiral:
      Ischemia causes myocardial dysfunction, which, in turn, worsens ischemia. Areas
      of nonfunctional but viable (stunned or hibernating) myocardium can also
      contribute to the development of cardiogenic shock. The key to achieving a good
      outcome is an organized approach that includes rapid diagnosis and prompt
      initiation of therapy to maintain blood pressure and cardiac output. Expeditious
      coronary revascularization is crucial. When available, emergency cardiac
      catheterization and angioplasty seem to improve survival. More recent
      developments, such as placement of coronary stents and use of glycoprotein
      IIb/IIIa antagonists, are promising but have not yet been well studied in
      patients with cardiogenic shock. In hospitals without direct angioplasty
      capability, stabilization with intra-aortic balloon counterpulsation and
      thrombolysis followed by transfer to a tertiary care facility may be the best
      option. CONCLUSIONS: Improved understanding of the pathophysiology of shock and
      myocardial infarction has led to improved treatment. If cardiogenic shock is
      managed with rapid evaluation and prompt initiation of supportive measures and
      definitive therapy, outcomes can be improved.

PMID- 10391816
TI  - False-positive screening mammograms: good news, but more to do.

PMID- 10391817
TI  - Risk factors for cardiovascular disease: one down, many more to evaluate.

PMID- 10391818
TI  - The Greater Rock of Ages Baptist Church.

PMID- 10391819
TI  - Nitric oxide and impaired oxygenation before and after liver transplantation.

PMID- 10391820
TI  - Serum uric acid and risk for cardiovascular disease and death: the Framingham
      Heart Study.
AB  - BACKGROUND: Hyperuricemia is associated with risk for cardiovascular disease and
      death. However, the role of uric acid independent of established risk factors is
      uncertain. OBJECTIVE: To examine the relation of serum uric acid level to
      incident coronary heart disease, death from cardiovascular disease, and death
      from all causes. DESIGN: Community-based, prospective observational study.
      SETTING: Framingham, Massachusetts. PATIENTS: 6763 Framingham Heart Study
      participants (mean age, 47 years). MEASUREMENTS: Serum uricacid level at baseline
      (1971 to 1976); event rates per 1000 person-years by sex-specific uric acid
      quintile. RESULTS: During 117,376 person-years of follow-up, 617 coronary heart
      disease events, 429 cardiovascular disease deaths, and 1460 deaths from all
      causes occurred. In men, after adjustment for age, elevated serum uric acid level
      was not associated with increased risk for an adverse outcome. In women, after
      adjustment for age, uric acid level was predictive of coronary heart disease (P =
      0.002), death from cardiovascular disease (P = 0.009), and death from all causes
      (P = 0.03). After additional adjustment for cardiovascular disease risk factors,
      uric acid level was no longer associated with coronary heart disease, death from
      cardiovascular disease, or death from all causes. In a stepwise Cox model,
      diuretic use was identified as the covariate responsible for rendering serum uric
      acid a statistically nonsignificant predictor of outcomes. CONCLUSIONS: These
      findings indicate that uric acid does not have a causal role in the development
      of coronary heart disease, death from cardiovascular disease, or death from all
      causes. Any apparent association with these outcomes is probably due to the
      association of uric acid level with other risk factors.

PMID- 10391821
TI  - Psychotherapy for depression in diabetes.

PMID- 10391822
TI  - Psychotherapy for depression in diabetes.

PMID- 10391823
TI  - Coronary thrombolysis: a double-edged sword?

PMID- 10391824
TI  - Plasmapheresis in thyrotoxicosis.

PMID- 10391825
TI  - Elevated international normalized ratio associated with trovafloxacin.

PMID- 10391826
TI  - Tardive dyskinesia associated with olanzapine.

PMID- 10391827
TI  - Do-not-resuscitate orders in radiology departments.

PMID- 10391828
TI  - Contemplating the white coat.

PMID- 10391829
TI  - Contemplating the white coat.

PMID- 10391830
TI  - Contemplating the white coat.

PMID- 10391832
TI  - Proceedings of the 10th International Conference on Electrical Bio-Impedance.
      Barcelona, Spain, April 5-9, 1998.

PMID- 10391831
TI  - That was the century that was: historical perspectives on medical life at the fin
      de siecle.

PMID- 10391833
TI  - Proceedings of the Symposium on Renal Cancer. Tubingen, Germany, 7-10 July 1998.

PMID- 10391834
TI  - Rationale for home laundering of scrub attire.

PMID- 10391835
TI  - Using scientific principles when there is no research.

PMID- 10391836
TI  - Investigating prion diseases on the Internet.

PMID- 10391837
TI  - Inhibition of human platelet adenylate cyclase activity by adrenaline, thrombin
      and collagen: analysis and reinterpretation of experimental data.
AB  - Mathematical models based on the current understanding of stimulation and
      inhibition of adenylate cyclase (AC) activity have been developed and used to
      analyse experimental data [Farndale, Winkler, Martin and Barnes (1992) Biochem.
      J. 282, 2532] describing the inhibition of human platelet AC by collagen,
      thrombin and adrenaline. Here it has been demonstrated that neither affinities of
      receptors specific for adrenaline or thrombin nor the activity of cAMP
      phosphodiesterase are affected by collagen. Both collagen and thrombin at high
      doses act as effective inhibitors of AC activity. Inhibition of AC activity by
      collagen proceeds via two parallel pathways; the same is true for thrombin at
      moderate concentrations, and the two ligands act independently. The G-protein
      dependence of these pathways is distinct from that mediating inhibition of AC
      activity by adrenaline, i.e. Gi2. Convergence of the inhibitory pathways takes
      place at the catalytic subunit of AC.

PMID- 10391838
TI  - Genotoxicity of human milk extracts and detection of DNA damage in exfoliated
      cells recovered from breast milk.
AB  - Genotoxic agents of environmental or dietary origin may play a role in breast
      cancer initiation. The ability of extracts of human milk to cause mutations in S.
      typhimurium TA1538 and YG1019 and to induce micronuclei and DNA strand breaks in
      MCL-5 cells was investigated. Twenty samples from different donors were analysed
      and of these, 6 were adjudged to produce positive mutagenic response in one or
      both bacterial strains. The same samples also induced significant micronucleus
      formation in MCL-5 cells. In the comet assay, 13/20 samples caused DNA strand
      breaks in MCL-5 cells. Viable exfoliated breast cells were recovered from fresh
      milk samples and the ability of milk extracts to cause DNA damage in these cells
      was demonstrated. The results show that human milk can contain components capable
      of causing genotoxic damage in test systems and in human breast cells, events
      that may be significant in the initiation of breast cancer

PMID- 10391839
TI  - Cell behaviour: control and mechanism of motility. Proceedings of the 4th
      Abercrombie Conference on Cell Behaviour. Oxford, United Kingdom, 28 September-1
      October 1997.

PMID- 10391840
TI  - Special issue dedicated to Carl H. Durney.

PMID- 10391841
TI  - Evaluation of newly developed immunoperoxidase monolayer assays for detection of
      antibodies against bovine herpesvirus 4.
AB  - This study describes the evaluation of immunoperoxidase monolayer assays (IPMAs)
      for detection of antibodies against bovine herpesvirus 4 (BHV4) DN-599 or BHV4
      LVR 140 in sera of cattle. We compared the quality of these IPMAs with the
      quality of a BHV4 indirect enzyme-linked immunosorbent assay (ELISA). In
      addition, a preliminary serological survey of BHV4 antibodies was carried out to
      estimate the seroprevalence of BHV4 in Dutch cattle at different ages. The
      specificities of both BHV4 IPMAs were 1.00. The geometrical mean titers
      (detection limit) of the BHV4 IPMAs were twice as high as that of the BHV4
      indirect ELISA. In experimentally infected cattle, BHV4 antibodies were
      detectable by IPMAs 16 to 18 days postinfection, which was almost 2 weeks earlier
      than in the indirect ELISA. The reproducibility of the BHV4 DN-599 IPMA (kappaD
      value, 0.92) and of the BHV4 LVR 140 IPMA (kappaD value, 0.87) were good. For
      field sera the overall agreement between the BHV4 indirect ELISA and the two BHV4
      IPMAs, DN-599 and LVR 140, was 95 and 96%, respectively. The serological-survey
      study showed that the estimated seroprevalence of BHV4 in Dutch cattle was 16 to
      18% and that the percentage of BHV4-positive animals varied by age category
      (between 6 and 43%). In summary, the two BHV4 IPMA formats have several
      advantages that make IPMA a useful alternative to the BHV4 indirect ELISA for
      detecting BHV4 antibodies in cattle.

PMID- 10391842
TI  - Depletion of alveolar macrophages by treatment with 2-chloroadenosine aerosol.
AB  - Alveolar macrophages (AMs) are localized in the alveoli and alveolar ducts of the
      lung and are the only macrophages living in an aerobic environment. Recent
      studies have demonstrated that AMs play a central role in lung diseases, such as
      pneumonia and acute respiratory distress syndrome. It has become important to
      find a simple, effective way to eliminate AMs in order to investigate the
      function of AMs in vivo. 2-Chloroadenosine (2-CA), a purine analog, is reported
      to be selectively cytotoxic to cultured macrophages, and we hypothesized that it
      would deplete the number of AMs in the bronchoalveolar lavage fluid (BALF) of
      mice without any effect on neutrophil or lymphocyte counts. After mice had
      inhaled 1 mM aerosolized 2-CA for 2 h, AMs were found to be significantly
      depleted at 0 h [(4.42 +/- 0.16) x 10(4)/ml], 24 h [(4.17 +/- 0.89) x 10(4)/ml],
      48 h [(3.17 +/- 0.21) x 10(4)/ml], and 72 h [(5.00 +/- 0.64) x 10(4)/ml] compared
      with concentrations in untreated controls [(12.1 +/- 0.21) x 10(4)/ml].
      Neutrophil and lymphocyte counts in BALF did not change and histological changes
      in the lung were not observed after 2-CA treatment. The lung wet-to-dry weight
      ratio did not change at 0, 24, and 48 h after 2-CA aerosol application. The 2-CA
      aerosol had no effect on lung vascular permeability, as assessed by the
      intravenous administration of Evans blue, or on other phagocytes, as assessed by
      Kupffer cell counts. Our study demonstrates the efficacy of 2-CA in reducing AM
      numbers in vivo.

PMID- 10391843
TI  - Expression of Fas (CD95/APO-1) ligand by human breast cancers: significance for
      tumor immune privilege.
AB  - Breast cancers have been shown to elicit tumor-specific immune responses. As in
      other types of cancer, the antitumor immune response fails to contain breast
      tumor growth, and a reduction in both the quantity and cytotoxic effectiveness of
      tumor-infiltrating lymphocytes (TILs) is associated with a poorer prognosis. Fas
      ligand (FasL) induces apoptotic death of activated lymphocytes that express its
      cell surface receptor, FasR (CD95/APO-1). FasL-mediated apoptosis of activated
      lymphocytes contributes to normal immune downregulation through its roles in
      tolerance acquisition, immune response termination, and maintenance of immune
      privilege in the eye, testis, and fetus. In this report, we demonstrate that
      breast carcinomas express FasL. Using in situ hybridization and
      immunohistochemistry, we show that breast tumors constitutively express FasL at
      both the mRNA and protein levels, respectively. FasL expression is prevalent in
      breast cancer: 100% of breast tumors (17 of 17) were found to express FasL, and
      expression occurred over more than 50% of the tumor area in all cases. By
      immunohistochemistry, FasR was found to be coexpressed with FasL throughout large
      areas of all the breast tumors. This suggests that the tumor cells had acquired
      intracellular defects in FasL-mediated apoptotic signaling. FasL and FasR
      expression were independent of tumor type or infiltrative capacity. FasL
      expressed by tumor cells has previously been shown to kill Fas-sensitive lymphoid
      cells in vitro and has been associated with apoptosis of TILs in vivo. We
      conclude that mammary carcinomas express FasL in vivo as a potential inhibitor of
      the antitumor immune response.

PMID- 10391844
TI  - Protective effects of pertussis immunoglobulin (P-IGIV) in the aerosol challenge
      model.
AB  - Pertussis in infants is often severe, resulting in prolonged hospitalization.
      Treatment is limited to supportive care. Antibiotics do not significantly alter
      the course of the disease unless administered during the catarrhal phase.
      Therapies directed at pertussis toxin, a major virulence factor of Bordetella
      pertussis, may be beneficial. This study uses the aerosol challenge model to
      further examine the protective effects of P-IGIV, a new intravenous
      immunoglobulin product, which has high levels of pertussis toxin antibodies. P
      IGIV was prepared as a 4% immunoglobulin G (IgG) solution from the pooled donor
      plasma from donors immunized with inactivated pertussis toxoid. The IgG pertussis
      toxin antibody concentration in P-IGIV is >7-fold higher than conventional
      intravenous immunoglobulin products. In the aerosol challenge model, P-IGIV
      treated mice exhibited a dose-dependent decrease in mortality when monitored for
      28 days postchallenge. P-IGIV in doses of 2,800, 1,400, and 350 mg/kg
      significantly reduced mortality compared to saline (P < 0.01)- and human IGIV (P
      < 0.01)-treated controls. The 50% protective dose of pertussis toxin antibodies
      in P-IGIV was 147 microg/ml. Recovery of weight gain and normalization of
      leukocyte counts occurred in all P-IGIV-treated groups but did not exhibit dose
      dependent characteristics. Even after 7 days of infection, P-IGIV reversed the
      effects of pertussis in mice. This study provides further evidence that pertussis
      toxin antibodies not only play a role in passive protection but can also reverse
      symptoms of established disease in mice. We feel that P-IGIV deserves further
      evaluation in children hospitalized with severe pertussis.

PMID- 10391845
TI  - Cytokine mRNA expression in lesions in cats with chronic gingivostomatitis.
AB  - Semiquantitative reverse transcription-PCR assays were developed to measure
      feline interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-10, and IL-12 (p35 & p40);
      gamma interferon (IFN-gamma); and glyceraldehyde-3-phosphate dehydrogenase mRNA
      concentrations in biopsies of feline oral mucosa. Biopsies were collected from 30
      cats with chronic gingivostomatitis (diseased) prior to each cat receiving one of
      four treatments. In 23 cases replicate biopsies were collected 3 months after
      treatment commenced. Biopsies were also analyzed from 11 cats without clinical
      disease (nondiseased). Expression of IL-2, IL-10, IL-12 (p35 and p40), and IFN
      gamma was detected in most nondiseased biopsies, while IL-6 was detected in a
      minority, and IL-4 and IL-5 were both undetectable. Compared to nondiseased cats,
      the diseased population showed a significant increase in the relative mRNA
      expression of IL-2, IL-4, IL-6, IL-10, IL-12 (p35 and p40), and IFN-gamma. In
      contrast, IL-5 mRNA expression was unchanged and was only detected in one case.
      No significant relationship was demonstrable between the change in relative
      expression of specific cytokine mRNA and the change in clinical severity of the
      local mucosal lesions over the treatment period. The results demonstrate that the
      normal feline oral mucosa is biased towards a predominantly (Th) type 1 profile
      of cytokine expression and that during the development of lesions seen in feline
      chronic gingivostomatitis there is a shift in the cytokine profile from a type 1
      to a mixed type 1 and type 2 response.

PMID- 10391846
TI  - Serological diagnosis of human cysticercosis by use of recombinant antigens from
      Taenia solium cysticerci.
AB  - A Taenia solium metacestode cDNA expression library in the lambda ZAPII vector
      was screened with pooled sera from patients with neurocysticercosis. Sixty
      primary clones were identified and shown to belong to two classes. The clones NC
      3 and NC-9 did not reveal any significant homologies to sequences deposited in
      the databases and were further characterized. Both recombinant antigens were
      expressed as glutathione S-transferase fusion proteins and applied for
      serological diagnosis of human cysticercosis. An enzyme-linked immunosorbent
      assay was established and evaluated with 27 serum samples of La Reunion and
      Madagascar patients with cysticercosis. Diagnosis in these patients was
      established with radiological and serological procedures. For antigen NC-3 a
      sensitivity of 96.3% and a specificity of 91.5% for the serodiagnosis were
      achieved. In contrast, the sensitivity of antigen NC-9 was only 33.3%.

PMID- 10391847
TI  - Diagnosis of rickettsial diseases using samples dried on blotting paper.
AB  - The use of filter paper is an inexpensive and convenient method for collecting,
      storing, and transporting blood samples for serological studies. In addition,
      samples occupy little space and can be readily transported without refrigeration.
      Rickettsial diseases often evolve according to an epidemic mode and are now
      considered reemerging diseases, especially in developing countries, under
      conditions where fieldwork could be difficult. The suitability of collecting
      whole-blood specimens on filter paper discs for rickettsial antibody assay was
      evaluated. Dried blood specimens from 64 individuals with antibodies to Coxiella
      burnetii, Bartonella quintana, or Rickettsia conorii were tested for rickettsial
      antibodies by microimmunofluorescence. Although occasional titers were 1 or 2
      dilutions lower than those of tested serum samples, no statistically significant
      differences were observed. Among patients with negative serology, no false
      positives were found. This study demonstrated that the recovery of antibodies
      from finger-stick blood dried on filter paper after elution produces results
      comparable to those obtained by recovering antibodies from serum. Storing paper
      samples for 1 month at room temperature or at 4 degrees C did not significantly
      affect the level of antibodies recovered. This report shows the utility of this
      sample collection method in developing countries where refrigeration is not
      possible and venipuncture is problematic.

PMID- 10391848
TI  - Detection of anti-VacA antibody responses in serum and gastric juice samples
      using type s1/m1 and s2/m2 Helicobacter pylori VacA antigens.
AB  - Several different families of vacuolating toxin (vacA) alleles are present in
      Helicobacter pylori, and they encode products with differing functional
      activities. H. pylori strains containing certain types of vacA alleles have been
      associated with an increased risk for peptic ulcer disease. In this study, we
      tested serum samples and gastric juice from 19 H. pylori-negative and 39 H.
      pylori-positive patients for enzyme-linked immunosorbent assay reactivity with
      two different types of VacA antigens (types s1/m1 and s2/m2), which were purified
      from H. pylori 60190 and 86-338, respectively. Both antigens were recognized
      better by serum immunoglobulin G (IgG) from H. pylori-positive persons than by
      serum IgG from H. pylori-negative persons (P < 0.01). The s1/m1 VacA antigen was
      better recognized by sera from patients carrying vacA type s1/m1 strains than by
      sera from patients carrying vacA type s2/m2 or s1/m2 strains (P < 0.01).
      Conversely, the s2/m2 VacA antigen was better recognized by sera from patients
      carrying type s2/m2 or s1/m2 strains (P = 0.03). Serum IgG anti-VacA antibodies
      were present more frequently in patients carrying type s1/m1 strains than in
      other H. pylori-positive patients (P = 0.0002). In addition, the highest levels
      of IgA anti-VacA antibodies were detected in the gastric juice of patients
      carrying type s1/m1 strains. These data indicate that different VacA isoforms
      have distinct antigenic properties and that multiple forms of VacA elicit
      antibody responses in H. pylori-positive humans.

PMID- 10391849
TI  - CD4-positive and CD8-positive cytotoxic T lymphocytes contribute to human
      papillomavirus type 16 E6 and E7 responses.
AB  - Cytotoxic T-lymphocyte (CTL) responses to E6 and E7 were previously shown to be
      more commonly detectable in human papillomavirus type 16 (HPV-16)-positive women
      without squamous intraepithelial neoplasia (SIL) than in HPV-16-positive women
      with SIL (M. Nakagawa, D. P. Stites, S. Farhat, J. R. Sisler, B. Moss, F. Kong,
      A. B. Moscicki, and J. M. Palefsky, J. Infect. Dis. 175:927-931, 1997). The
      objective of this study was to characterize the phenotype(s) of the effector cell
      population responsible for HPV-16 E6- and E7-specific cytotoxic responses.
      Peripheral blood mononuclear cells were stimulated with HPV-16 E6 or E7 fusion
      protein. Cells from an autologous B-lymphoblastoid cell line, infected with
      vaccinia virus expressing E6 or E7, served as target cells. The effector cells
      were characterized by using natural-killer-cell removal, antibody blocking, and T
      cell subset separation. Our results suggest that both CD4 and CD8 T lymphocytes
      contribute to HPV-16 E6- and E7-specific CTL responses although their relative
      contributions vary from individual to individual. On the other hand, natural
      killer cells in the effector cell population contribute to background activities
      but not to HPV-specific responses in this assay system.

PMID- 10391850
TI  - Cell surface display of human immunodeficiency virus type 1 gp120 on Escherichia
      coli by using ice nucleation protein.
AB  - A new system designed for cell surface display of recombinant proteins on
      Escherichia coli has been evaluated for expression of eukaryotic viral proteins.
      Human immunodeficiency virus type 1 (HIV-1) gp120 was fused to the C terminus of
      ice nucleation protein (INP), an outer membrane protein of Pseudomonas syringae.
      Western blotting, immunofluorescence microscopy, fluorescence-activated cell
      sorting analysis, whole-cell enzyme-linked immunosorbent assay, and ice
      nucleation activity assay confirmed the successful expression of HIV-1 gp120 on
      the surface of Escherichia coli. This study shows that the INP system can be used
      for the expression of eukaryotic viral proteins. There is also a possibility that
      the INP system can be used as an AIDS diagnostic system, an oral vaccine delivery
      system, and an expression system for various heterologous higher-molecular-weight
      proteins.

PMID- 10391851
TI  - Immunological diagnosis of human cystic echinococcosis: utility of discriminant
      analysis applied to the enzyme-linked immunoelectrotransfer blot.
AB  - An enzyme-linked immunoelectrotransfer blot for the diagnosis of human hydatid
      disease was performed, and the different antibody responses were analyzed by a
      discriminant analysis. This multivariate technique gave us, first, a selection of
      the most important responses against Echinococcus granulosus infection and,
      second, a procedure for the classification of patients into two groups: patients
      with hydatid disease and patients without a history of hydatid disease. This
      method was applied to 67 patients, 25 with active hydatid cysts (24 hepatic and 1
      pulmonary) and 42 without a history of hydatid disease and was compared with the
      results obtained by conventional serology: indirect hemagglutination, latex
      particle agglutination, and basophil degranulation. An immunoelectrotransfer blot
      coupled to a discriminant analysis was more sensitive than conventional
      serological diagnosis and detected 100% of patients with an active hepatic
      hydatid cyst with a specificity of 100%. This method, however, failed to detect
      an uncomplicated hyaline pulmonary hydatid cyst.

PMID- 10391852
TI  - Correlation of cytokine elaboration with mononuclear cell adhesion to platelet
      storage bag plastic polymers: a pilot study.
AB  - The basis for many febrile nonhemolytic transfusion reactions associated with
      platelet transfusion therapy is cytokine elaboration and accumulation in the
      storage bag, which correlate with the leukocyte content and the length of
      platelet storage. We propose that a possible additional variable in the
      elaboration and accumulation of cytokines is the differential adhesion of
      mononuclear cells to the plastic substrate of the platelet storage bag. We
      hypothesize that mononuclear cell adhesion-induced cytokine release is greater in
      random-donor platelet bags composed of the polyolefin polymer compared to the
      single-donor apheresis platelet bags composed of the polyvinyl chloride polymer
      with the tri-(2-ethylhexyl) trimellitate (TEHTM) plasticizer. For four blood
      donors, we demonstrate preferential mononuclear cell adhesion, in vitro, to discs
      of polyolefin polymer versus discs of polyvinyl chloride polymer with the TEHTM
      plasticizer. Scanning electron microscopy corroborates this. In addition,
      proinflammatory cytokine (interleukin 1beta [IL-1beta] and tumor necrosis factor
      alpha [TNF-alpha]) levels are greater in culture wells containing discs of
      polyolefin polymer than in those containing discs of polyvinyl chloride polymer
      with the TEHTM plasticizer, and even more so in storage bags containing
      polyolefin polymer versus polyvinyl chloride polymer with the TEHTM plasticizer
      (IL-1beta, TNF-alpha, IL-6, and IL-8). This study suggests, for the first time,
      that differential plastic substrate mononuclear cell adhesion may contribute to
      cytokine release during platelet storage. This may represent an additional
      variable in the pathophysiology of febrile nonhemolytic transfusion reactions in
      patients receiving stored platelet units.

PMID- 10391853
TI  - Immunoglobulin G avidity in diagnosis of toxoplasmic lymphadenopathy and ocular
      toxoplasmosis.
AB  - Traditional serological techniques have some limitations in evaluating the
      duration of Toxoplasma gondii infection in pregnant women, patients with
      lymphadenopathy, and older children suspected of having congenital toxoplasmosis.
      In these three groups of patients, two variants of T. gondii immunoglobulin G
      (IgG) avidity tests were used: an EIA Kit (Labsystems) and a noncommercial enzyme
      linked immunosorbent assay specially elaborated in the laboratory. The avidity of
      specific IgG in sera from 23 patients with a known recently acquired infection
      (mainly pregnant women) was low (less than 30%), whereas that in sera from 19
      patients with toxoplasmic lymphadenopathy of 3 weeks to 6 months in duration
      (mean, 8.3 weeks) covered a large range (between 0.2 and 57.8%; mean, 25. 7%);
      high avidity results were observed for 10 of 19 patients (52. 6%). The large
      range of IgG avidity in patients with toxoplasmic lymphadenopathy suggests
      various durations of infection in these patients, with a tendency for a chronic
      phase of toxoplasmosis. According to the avidity marker, five patients with
      lymphadenopathy for less than 3 months did not have a recent Toxoplasma
      infection. In 6 of 19 patients with lymphadenopathy (31.6%), low IgG avidity
      values persisted until 5 months after the first serological examination. In all
      four patients with a documented chronic course of Toxoplasma infection (6 months
      to 8 years after the first positive serology), high IgG avidity values were
      observed. Among sera from 10 children and young immunocompetent adults suspected
      of having ocular reactivation of congenital toxoplasmosis, all had high IgG
      avidity values (over 40%), suggesting congenitally acquired ocular infection
      rather than noncongenital infection. In conclusion, the avidity of IgG is a
      valuable marker of recent toxoplasmosis in pregnant women, suggests the duration
      of invasion in patients with lymphadenopathy, and may be helpful for
      differentiation between reactivation of congenital infection and recently
      acquired ocular toxoplasmosis in immunocompetent patients. A low IgG avidity does
      not always identify a recent case of toxoplasmosis, but a high IgG avidity can
      exclude primary infections of less than 5 months' duration.

PMID- 10391854
TI  - Pneumococcal capsular polysaccharide preparations may contain non-C
      polysaccharide contaminants that are immunogenic.
AB  - We measured the capacity to opsonize Streptococcus pneumoniae serotype 6B and
      estimated the concentration of immunoglobulin G anti-6B capsular polysaccharide
      (PS) antibodies in 25 pre- and postimmune sera from adults immunized with a
      pneumococcal PS vaccine. We first studied two postvaccination serum samples
      displaying less opsonophagocytic capacity than expected. The majority of anti-6B
      antibodies in the two samples reacted with the capsular PSs of several unrelated
      serotypes (2, 4, 9V, 19F, and 23F) and with the lysate of noncapsulated S.
      pneumoniae bacteria but not with C-PS. The non-type-specific antibodies accounted
      for at least one-half of anti-6B antibodies in 40% of prevaccination sera and 10%
      of postvaccination sera from adults. The non-type-specific antibodies could be
      demonstrated in the enzyme-linked immunosorbent assays (ELISAs) for pneumococcal
      antibodies to other serotypes (4, 9V, 18C, 19F, and 23F). The nonspecific
      antibodies appear to bind a contaminant(s) in the current preparations of
      capsular PS. ELISA for antibodies to pneumococcal capsules may not be serotype
      specific for some samples.

PMID- 10391855
TI  - Decreased superoxide production, degranulation, tumor necrosis factor alpha
      secretion, and CD11b/CD18 receptor expression by adherent monocytes from preterm
      infants.
AB  - Preterm infants have an increased incidence of infection, which is principally
      due to deficiencies in neonatal host defense mechanisms. Monocyte adherence is
      important in localizing cells at sites of infection and is associated with
      enhanced antimicrobial functions. We isolated cord blood monocytes from preterm
      and full-term infants to study their adhesion and immune functions, including
      superoxide (O2-) generation, degranulation, and cytokine secretion and their
      adhesion receptors. O2- production and degranulation were significantly
      diminished, by 28 and 37%, respectively, in adherent monocytes from preterm
      infants compared to full-term infants (P < 0. 05); however, these differences
      were not seen in freshly isolated cells. We also observed a significant decrease
      of 35% in tumor necrosis factor alpha secretion by lipopolysaccharide-stimulated
      adherent monocytes from preterm infants compared to full-term infants (P < 0.05);
      however, this difference was not observed in interleukin-1beta or interleukin-6
      production by the monocytes. The cell surface expression of the CD11b/CD18
      adhesion receptor subunits was significantly decreased (by 60 and 52%,
      respectively) in monocytes from preterm infants compared to full-term infants (P
      < 0. 01). The cascade of the immune response to infection involves monocyte
      upregulation and adherence via CD11b/CD18 receptors followed by cell activation
      and the release of cytokines and bactericidal products. We speculate that
      monocyte adherence factors may be important in the modulation of immune responses
      in preterm infants.

PMID- 10391857
TI  - Outcomes of Bordetella infections in vaccinated children: effects of bacterial
      number in the nasopharynx and patient age.
AB  - Five outbreaks of infection (three pertussis, one parapertussis, and one mixed)
      in schools were studied prospectively. Nasopharyngeal swabs were obtained from a
      total of 697 children for culture of Bordetella organisms. Of 50 vaccinated
      children with culture-confirmed Bordetella infections (29 with pertussis and 21
      parapertussis), 40 were symptomatic and 10 remained symptom-free. Smaller numbers
      of colonies were recovered from the nasopharyngeal swabs of the asymptomatic
      children than from those of the symptomatic children. Older children had longer
      durations of illness than younger ones. Our results indicate that during
      outbreaks children who do not develop disease may have small amounts of
      Bordetella organisms in their nasopharynges and/or better immune defenses against
      the disease.

PMID- 10391856
TI  - Effects of amphetamine on development of oral candidiasis in rats.
AB  - Experiments were conducted to evaluate the effects of amphetamine (0. 4 mg/kg of
      body weight/day) on the development of oral candidiasis in Sprague-Dawley rats.
      Animals were submitted to surgical hyposalivation in order to facilitate the
      establishment and persistence of Candida albicans infection. Treatment with drugs
      (placebo or amphetamine) was initiated 7 days before C. albicans inoculation and
      lasted until the end of the experiments, day 15 postinoculation. Establishment of
      C. albicans infection was evaluated by swabbing the inoculated oral cavity with a
      sterile cotton applicator on days 2 and 15 after inoculation, followed by plating
      on YEPD (yeast extract-peptone-dextrose) agar. Tissue injury was determined by
      the quantification of the number and type (normal or abnormal) of papillae on the
      dorsal tongue per microscopic field. A semiquantitative scale was devised to
      assess the degree of colonization of the epithelium by fungal hyphae. Our results
      show that amphetamine exacerbates C. albicans infection of the tongues of rats.
      Significant increases in Candida counts, the percentage of the tongue's surface
      covered with clinical lesions, the percentage of abnormal papillae, and the
      colonization of the epithelium by fungal hyphae were found in amphetamine-treated
      rats compared to those found in the rats injected with a placebo. The last two
      parameters increased in rats treated with the placebo compared to the parameters
      of the untreated control rats.

PMID- 10391858
TI  - Effect of antiflagellar human monoclonal antibody on gut-derived Pseudomonas
      aeruginosa sepsis in mice.
AB  - We evaluated the effect of antiflagellar human monoclonal antibody on gut-derived
      Pseudomonas aeruginosa sepsis. Mice were given a suspension of P. aeruginosa
      SP10052 in their drinking water and were simultaneously treated with ampicillin
      (200 mg/kg of body weight) to disrupt the normal bacterial flora.
      Cyclophosphamide was then administered to induce leukopenia and translocation of
      the P. aeruginosa that had colonized the gastrointestinal tract, thereby
      producing gut-derived generalized sepsis. In this model, intraperitoneal
      injection of 100 microg of antiflagellar human monoclonal antibody (SC-1225) per
      mouse for 5 consecutive days significantly (P < 0.01) increased the survival rate
      compared with that for mice treated with bovine serum albumin (BSA). Treatment
      with SC-1225 significantly reduced the average number of viable bacteria in
      portal blood, liver, and heart blood compared with the average number after
      treatment with BSA. Furthermore, the presence in serum of the inflammatory
      cytokines tumor necrosis factor alpha and interleukin 6 were evaluated as markers
      of severity of infection, and the results showed that the levels of these
      cytokines in mice treated with SC-1225 were significantly decreased in comparison
      with those in BSA-treated control mice. Although there was no significant
      difference in the number of bacteria that colonized the intestine, SC-1225
      treatment significantly increased bacterial opsonophagocytosis by cultured
      peritoneal macrophages from mice with or without cyclophosphamide pretreatment.
      Our results indicate that antiflagellar human monoclonal antibody SC-1225
      protects mice against gut-derived sepsis caused by P. aeruginosa and suggest that
      such an effect is due to its opsonophagocytic activity and the reduced motility
      of the translocated bacteria once the bacteria move from the intestine into the
      bloodstream.

PMID- 10391859
TI  - Development of an antigen spot test for detection of coronavirus in bovine fecal
      samples.
AB  - We have developed a rapid and sensitive microimmunodot blot assay, the antigen
      spot test (AST), for the detection of bovine coronavirus (BCV) antigen from
      neonatal calf fecal samples. The AST procedure can be completed in 3.5 h, whereas
      the previously reported immunodot blot assays require 10 to 12 h. Ninety-six
      samples can be tested per membrane, and 10 membranes (960 samples) may be
      processed by a single technologist in 1 working day. The effects of detergents,
      oxidizing chemicals, chaotropic agents, and enzyme substrates in improving the
      sensitivity and signal-to-noise ratio of the AST were studied. Finally, the
      sensitivity and specificity of AST for the detection of BCV antigen were compared
      to those of a sandwich enzyme-linked immunosorbant assay (ELISA) and a
      hemagglutination assay (HA). Of 347 field samples tested by all three methods,
      94.2% were positive by AST, 91.4% were positive by ELISA, and 86.7% were positive
      by HA. The sensitivity of the AST was determined to be 100% compared to the
      results of the ELISA reference method. The specificity of the AST was 67%, which
      reflects a lower limit of detection of 10(4) viral particles per ml in a 10%
      fecal suspension.

PMID- 10391860
TI  - Similar humoral and cellular immunological reactivities to human herpesvirus 6 in
      patients with multiple sclerosis and controls.
AB  - Several studies have suggested an association between human herpesvirus 6 (HHV-6)
      and multiple sclerosis (MS). We have previously studied intrathecal production of
      antibody to lymphotropic herpesviruses in MS patients and the presence of human
      herpesvirus 1 to 7 DNAs in cerebrospinal fluid (CSF). In the present study anti
      HHV-6 immunoglobulin M (IgM) in serum and anti-HHV-6 IgG subclasses in serum and
      CSF were examined and the lymphoproliferative response to HHV-6 was analyzed. The
      PCR examination was refined by purifying DNA from CSF and retesting the samples
      for HHV-6 DNA. There were no statistically significant differences between the
      groups concerning IgM positivity, distribution of IgG subclasses, or
      lymphoproliferative response to HHV-6. The purification of DNA increased the
      number of PCR-positive samples from 0 of 71 to 4 of 68. The study does not give
      additional support to the possibility that HHV-6 is a common cause of MS, but a
      role for the virus in a subset of patients cannot be excluded.

PMID- 10391861
TI  - Diagnostic and prognostic potential of a competitive enzyme-linked immunosorbent
      assay for leishmaniasis in India.
AB  - A Leishmania donovani species-specific monoclonal antibody (monoclonal antibody
      D2) was evaluated for its diagnostic and prognostic potential by a competitive
      enzyme-linked immunosorbent assay (C-ELISA) in sera from Indian patients with
      visceral leishmaniasis (VL) and seven patients with post-kala-azar dermal
      leishmaniasis (PKDL). These results were compared with those obtained by
      microscopy with Giemsa-stained tissue smears and a direct enzyme-linked
      immunosorbent assay (direct ELISA) with crude parasite antigen. Of 121 patients
      with clinically diagnosed VL examined, 103 (85.1%) were positive and 11 (9.1%)
      were negative by all three methods. An additional 7 (5.8%) who were negative by
      microscopy were positive by both C-ELISA and direct ELISA. Seven PKDL patients
      were also examined and were found to be positive by all three methods. Analysis
      of the chemotherapeutic response to sodium antimony gluconate of these 110
      serologically positive VL patients showed that 57 (51.8%) were drug responsive
      and 53 (48.2%) were drug resistant. The C-ELISA with sera from 20 longitudinally
      monitored VL patients before and after chemotherapy showed a significant decrease
      in percent inhibition of monoclonal antibody D2 in drug-responsive patients.
      However, in drug-unresponsive patients, the percent inhibition of D2 was
      unchanged or was slightly increased. Our results therefore indicate (i) the
      applicability of L. donovani species-specific monoclonal antibody D2 for
      sensitive and specific serodiagnosis by C-ELISA, (ii) that the C-ELISA is more
      sensitive than microscopy, especially for early diagnosis, (iii) that L. donovani
      is still the main causative agent of VL, irrespective of the chemotherapeutic
      response, and (iv) that the C-ELISA can be used to evaluate the success of drug
      treatment.

PMID- 10391862
TI  - Evaluation of four methods for detection of immunoglobulin M antibodies to dengue
      virus.
AB  - Dengue has become hyperendemic in many islands of the Caribbean region. The
      performance in a diagnostic laboratory of four commercial assays for detection of
      immunoglobulin M (IgM) antibodies was evaluated. Sera from 62 patients with
      dengue virus infection were studied. These included 18 patients from whom dengue
      virus type 2 was isolated in a 1997 outbreak (specimens collected a mean of 14
      days after onset of symptoms), 8 patients with dengue hemorrhagic fever (mean
      time after onset, 11 days), and 36 patients in whom dengue was previously
      confirmed by serology (mean time after onset, 10 days). Thirty serum specimens
      from blood donors in a country where dengue is not endemic were used as negative
      controls. The methods evaluated were two IgM-capture enzyme-linked immunosorbent
      assays (ELISA) (MRL Diagnostics, Cypress, Calif., and PanBio, Queensland,
      Australia), a dot ELISA dipstick assay (Integrated Diagnostics, Baltimore, Md.),
      and a rapid immunochromatographic assay for dengue IgG and IgM (PanBio IC). IgG
      antibodies were also detected by an ELISA method (MRL Diagnostics). The
      sensitivities of the four assays were as follows: MRL Diagnostics IgM ELISA,
      98.4%; PanBio IgM ELISA, 85.5%; Integrated Diagnostics IgM dot ELISA, 96. 8%; and
      PanBio IC, 83.9%. The specificities of all tests were 100%. Evidence of secondary
      dengue was found in all patients with dengue hemorrhagic fever and in 83% of the
      remaining patients. The MRL Diagnostics IgM ELISA appears to be more sensitive
      than the PanBio IgM ELISA, and this may be significant when IgM titers are low,
      particularly in patients with secondary dengue infections. The dot ELISA dipstick
      assay is equally sensitive and may be more appropriate for use in laboratories
      with lower workloads.

PMID- 10391863
TI  - Identification of Bartonella-specific immunodominant antigens recognized by the
      feline humoral immune system.
AB  - The seroreactivities of both naturally and experimentally infected cats to
      Bartonella henselae was examined. Serum samples collected weekly from nine cats
      experimentally infected with B. henselae LSU16 were tested by enzyme-linked
      immunosorbent assay (ELISA) and Western blot analysis. The magnitude and isotype
      of the antibody response were investigated by ELISA. Western blot analysis
      allowed the identification of at least 24 Bartonella-specific antigens recognized
      by the cats during infection. Antibody titers to specific antigens, as determined
      by Western blot analysis, ranged from 10 to 640 and varied among the different
      antibody-antigen interactions. Absorption of sera from an experimentally infected
      cat, using whole cells and cell lysates of various Bartonella species and other
      bacteria that commonly colonize cats, supported the identification of those
      Bartonella-specific antigens recognized by the experimentally infected cats.
      Furthermore, a number of possible species- and type-specific antigens were
      identified. Finally, sera obtained from cats at local animal shelters were
      screened for the presence of antibodies directed against the Bartonella-specific
      bands identified in the experimentally infected cats. A number of Bartonella
      specific antigens have been identified to which strong antibody responses are
      generated in both experimentally and naturally infected cats, some of which may
      be useful in diagnosing species- and/or type-specific infections. In addition,
      the results from these experiments will lead to the development of monoclonal
      antibodies targeted against those genus-, species-, and type-specific antigens.

PMID- 10391864
TI  - Inhibition of cytokine gene expression by sodium salicylate in a macrophage cell
      line through an NF-kappaB-independent mechanism.
AB  - Macrophage-derived cytokines and chemokines are involved at multiple steps of
      immune and inflammatory responses, and the transcriptional factor NF-kappaB
      appears to play a pivotal role in their coordinated upregulation. The anti
      inflammatory agents salicylates have been proposed to act in part by inhibiting
      NF-kappaB. We have therefore studied the effects of sodium salicylate on
      lipopolysaccharide (LPS)-induced kappaB-binding activity and on cytokine and
      chemokine gene expression in the RAW264.7 murine macrophage cell line and
      compared them to those of an established NF-kappaB inhibitor, pyrrolidine
      dithiocarbamate (PDTC). PDTC (100 microM) completely abrogated LPS-induced kappaB
      binding activity and also profoundly inhibited the induction of interleukin
      1alpha (IL-1alpha), IL-1beta, IL-6, IL-10, granulocyte colony-stimulating factor,
      granulocyte-macrophage colony-stimulating factor, and MCP-1 and, to a lesser
      extent, leukemia inhibitory factor, RANTES, and IL-1Ra. In contrast, sodium
      salicylate (15 to 20 mM) had no effect on NF-kappaB activation but, nevertheless,
      suppressed several LPS-induced cytokine and chemokine genes to a degree similar
      to that obtained with PDTC. However, compared to PDTC, sodium salicylate caused
      significantly less inhibition of IL-1Ra and IL-10 gene expression after LPS
      stimulation. Neither LPS-induced MIP-1alpha, MIP-1beta, nor MIP-2 was
      significantly affected by PDTC or sodium salicylate, demonstrating that NF-kappaB
      is dispensable for the transcriptional regulation of these genes by LPS. In
      summary, these results suggest that both NF-kappaB-dependent and NF-kappaB
      independent pathways are necessary for the induction by LPS of a complex cytokine
      and chemokine response. In the RAW264.7 macrophage cell line,
      suprapharmacological concentrations of sodium salicylate exert a potent
      inhibitory effect on LPS-induced cytokine gene induction but appear to accomplish
      this by interfering with NF-kappaB-independent pathways of activation.

PMID- 10391865
TI  - Immunoreactivity to putative B-cell epitopes of hepatitis G virus polyprotein in
      viremic and nonviremic subjects.
AB  - The hepatitis G virus (HGV) polyprotein was scanned by computer-aided prediction
      of antigenicity to search for B-cell epitopes. Four polypeptide sequences, V37D
      (amino acids [aa] 1685 to 1721), V36S (aa 2102 to 2137), P37R (aa 2156 to 2192),
      and C40P (aa 2280 to 2319), were identified and synthesized for use in
      immunoassays. Antibodies to these peptides were searched for in a panel of 239
      serum samples, which were also tested for anti-E2 antibodies and HGV RNA.
      Furthermore, the course of HGV markers was studied prospectively in four patients
      who had been transfused with HGV RNA-positive blood. There was a negative
      association between immunoreactivity to V37D and P37R and presence of HGV RNA (2
      of 53 and 1 of 53, respectively; P < 0.05); none of the subjects with dual
      antibody positivity was HGV RNA positive. Anti-V37D and anti-P37R antibodies
      compared favorably with anti-E2 antibodies as markers of recovery from HGV
      infection. These results might be useful for the development of new, more
      sensitive diagnostic assays.

PMID- 10391866
TI  - A simple saliva-based test for detecting antibodies to human immunodeficiency
      virus.
AB  - This study was performed to determine the feasibility of using saliva as a
      diagnostic medium for the detection of antibodies to human immunodeficiency virus
      type 1 (HIV-1) and HIV-2 under nonlaboratory conditions and to evaluate the
      performance characteristics of such a test. We developed for this purpose a self
      contained kit (Saliva. Strip [ST]), which combines the collection and processing,
      as well as the analysis, of the specimen. The kit's performance was evaluated in
      a blinded study. Saliva collection was facilitated with a specially designed
      device that contains a sample adequacy indicator, and immunochromatography test
      strips were used for the analysis. A total of 1,336 matched serum and saliva
      specimens (684 reactive and 652 nonreactive specimens) were tested. We tested
      sera using an enzyme immunoassay (EIA) and a rapid strip test. Sera reactive in
      one of the assays were also analyzed by Western blotting. Sensitivity and
      specificity were 99.4 and 99.4%, respectively, for ST, 100 and 99.1%,
      respectively, for EIA, and 99.7 and 100%, respectively, for the serum strip test.
      The saliva test performed well when HIV-2-positive sera or a low-titer
      performance panel (HIV-1) of serum or plasma specimens were diluted (1:2,000) in
      nonreactive saliva. Because the methodology we present here uses a noninvasively
      obtained medium, the methodology may be suitable for use in the field where
      laboratory support and personnel are limited, such as community outreach
      programs, doctors' offices, surveillance studies, and community hospitals.

PMID- 10391867
TI  - A flow cytometric opsonophagocytic assay for measurement of functional antibodies
      elicited after vaccination with the 23-valent pneumococcal polysaccharide
      vaccine.
AB  - Opsonophagocytosis is the primary mechanism for clearance of pneumococci from the
      host, and the measurement of opsonophagocytic antibodies appears to correlate
      with vaccine-induced protection. We developed a semiautomated flow cytometric
      opsonophagocytosis assay using HL-60 granulocytes as effector cells and nonviable
      5, 6-carboxyfluorescein, succinimidyl ester-labeled Streptococcus pneumoniae
      (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) as bacterial targets. The flow
      cytometric opsonophagocytosis assay was highly reproducible (for 87% of
      repetitive assays the titers were within 1 dilution of the median titer) and
      serotype specific, with >/=97% inhibition of opsonophagocytic titer by addition
      of homologous serotype-specific polysaccharide. In general, opsonophagocytic
      titers were not significantly inhibited by the presence of either heterologous
      pneumococcal polysaccharide or penicillin in the serum. The flow cytometric assay
      could reproducibly measure functional antibody activity in prevaccination (n =
      28) and postvaccination (n = 36) serum specimens from healthy adult volunteers
      vaccinated with the 23-valent pneumococcal polysaccharide vaccine. When compared
      with a standardized manual viable opsonophagocytic assay, a high correlation (r =
      0.89; P </= 0.01) was found between the two assays for the seven serotypes
      tested. The flow cytometric assay is rapid ( approximately 4 h) with high
      throughput ( approximately 50 serum samples per day per technician) and provides
      a reproducible measurement of serotype-specific functional antibodies, making it
      a highly suitable assay for the evaluation of the immune responses elicited by
      pneumococcal vaccines.

PMID- 10391868
TI  - Significance of fatty acids in pregnancy-induced immunosuppression.
AB  - Pregnancy can exert suppressive effects on chronic inflammatory conditions. We
      have previously demonstrated a depression in polymorphonuclear leukocyte (PMN)
      respiratory burst during pregnancy which could explain this amelioration. To
      elucidate the biochemical mechanism, we have examined PMN phospholipase A2 (PLA2)
      activity and its relationship to cellular and circulating fatty acids in pregnant
      women (30 to 34 weeks) and nonpregnant controls. PMN PLA2 activity was determined
      by arachidonic acid (AA) and leukotriene B4 (LTB4) release, respiratory burst
      activity was determined by lucigenin-enhanced chemiluminescence, and total serum
      and PMN fatty acid levels were determined by gas-liquid chromatography. AA
      release was significantly reduced for pregnancy PMNs in response to N-formyl-met
      leu-phe (fMLP) under unprimed and tumor necrosis factor alpha (TNF-alpha)- or
      interleukin 8-primed conditions. Similarly, LTB4 liberation was significantly
      reduced in response to fMLP and phorbol myristate acetate in unprimed and TNF
      alpha-primed pregnancy PMNs. All major fatty acid classes were altered in the
      pregnant state. Of these differences in PMNs, oleic acid and alpha-linolenic acid
      showed a significant increase (13 and 26%, respectively) and stearic acid and AA
      showed a significant decrease (8 and 30%, respectively). The stearic acid, oleic
      acid, and AA compositions of all cells analyzed correlated with their
      corresponding changes in serum fatty acid levels. Crossover serum incubations
      modified both fatty acid profiles and the PMN respiratory burst accordingly,
      while individual fatty acid incorporation studies highlighted the importance of
      polyunsaturated fatty acids for NADPH oxidase efficiency. These findings indicate
      that the attenuation of PMN function in pregnancy may originate from a reduction
      in the available pool of cellular fatty acids. Furthermore, this reduction arises
      as a direct result of a pregnancy-induced shift in circulating fatty acids from
      polyunsaturated to monounsaturated forms.

PMID- 10391869
TI  - Pentoxifylline inhibits superantigen-induced toxic shock and cytokine release.
AB  - Tumor necrosis factor alpha (TNF-alpha) is a critical cytokine that mediates the
      toxic effects of bacterial superantigens like staphylococcal enterotoxin B (SEB)
      and toxic shock syndrome toxin 1 (TSST-1). Pentoxifylline, an anti-inflammatory
      agent that inhibits endotoxemia and lipopolysaccharide (LPS)-induced release of
      TNF-alpha, was tested for its ability to inhibit SEB- and TSST-1-induced
      activation of human peripheral blood mononuclear cells (PBMCs) in vitro and toxin
      mediated shock in mice. Stimulation of PBMCs by SEB or TSST-1 was effectively
      blocked by pentoxifylline (10 mM), as evidenced by the inhibition of TNF-alpha,
      interleukin 1beta (IL-1beta), gamma interferon (IFN-gamma), and T-cell
      proliferation. The levels of TNF-alpha, IL-1alpha, and IFN-gamma in serum after
      an SEB or TSST-1 injection were significantly lower in mice given pentoxifylline
      (5.5 mg/animal) versus control mice. Additionally, pentoxifylline diminished the
      lethal effects and temperature fluctuations elicited by SEB and TSST-1. Thus, in
      addition to treating endotoxemias, the cumulative in vitro and in vivo data
      suggest that pentoxifylline may also be useful in abrogating the ill effects of
      staphylococcal enterotoxins and TSST-1.

PMID- 10391870
TI  - Use of recombinant flagellin protein as a tracer antigen in a fluorescence
      polarization assay for diagnosis of leptospirosis.
AB  - The objective of the present study was to investigate the usefulness of a
      recombinant flagellar protein, FlaB, of Leptospira interrogans serovar pomona in
      the serodiagnosis of leptospirosis by the fluorescence polarization assay (FPA).
      The recombinant protein FlaB was purified to homogeneity by a combination of
      nickel-nitriloacetic acid agarose chromatography, electrophoresis, and
      electroelution. Purified FlaB was labeled with fluorescein isothiocyanate (FITC).
      Western blotting was performed by using bovine sera with microscopic
      agglutination test (MAT) titers of antibodies against L. interrogans serovar
      pomona and L. bergpetersenii serovars hardjo and sejroe to confirm the
      antigenicity of FlaB. Western blot analysis demonstrated that labeled as well as
      unlabeled FlaB was recognized by the positive sera tested, indicating the broad
      serovar cross-reactivity of this protein. It also indicated that labeling with
      FITC did not affect the antigenicity. By using FITC-labeled FlaB as a tracer
      antigen, a homogeneous FPA was developed to detect antileptospiral antibodies in
      bovine sera. A population of 208 MAT-positive and 208 MAT-negative serum samples
      was tested by FPA. The FPA cutoff was determined by receiver operating
      characteristic analysis. By FPA, 83. 7% of the MAT-positive serum samples were
      positive and 81.2% of the MAT-negative serum samples were negative. Compared to
      the results of MAT, the positive predictive value of FPA was 81.7% and the
      negative predictive value of FPA was 83.3%. The FPA is a simple and rapid
      technique for the detection of anti-Leptospira antibodies.

PMID- 10391871
TI  - Cellular immune responses to ESAT-6 discriminate between patients with pulmonary
      disease due to Mycobacterium avium complex and those with pulmonary disease due
      to Mycobacterium tuberculosis.
AB  - ESAT-6 (for 6-kDa early secreted antigenic target) is a secreted antigen found
      almost exclusively in organisms of the Mycobacterium tuberculosis complex. We
      compared in vitro gamma interferon (IFN-gamma) responses by peripheral blood
      mononuclear cells to this antigen in patients with pulmonary disease due to
      either Mycobacterium avium complex (MAC) or Mycobacterium tuberculosis with those
      in healthy, skin test-negative, control subjects. Significant IFN-gamma responses
      to ESAT-6 were detected in 16 (59%) of 27 M. tuberculosis pulmonary disease
      patients, 0 (0%) of 8 MAC disease patients, and 0 (0%) of 8 controls. Significant
      IFN-gamma responses to M. tuberculosis purified protein derivative were detected
      in 23 (85%) of 27 M. tuberculosis disease patients, 2 (25%) of 8 MAC disease
      patients, and 5 (63%) of 8 healthy controls. M. avium sensitin was recognized in
      24 (89%) of 27 M. tuberculosis disease patients, 4 (50%) of 8 MAC disease
      patients, and 1 (13%) of 8 controls. IFN-gamma responses to ESAT-6 are specific
      for disease due to M. tuberculosis and are not observed in patients with MAC
      disease or in healthy controls.

PMID- 10391872
TI  - Use of a monoclonal antibody against an Escherichia coli O26 surface protein for
      detection of enteropathogenic and enterohemorrhagic strains.
AB  - A monoclonal antibody (MAb) was obtained from a mouse immunized with solubilized
      outer membrane proteins extracted from a bovine enterohemorrhagic strain of
      Escherichia coli (EHEC), O26. The MAb produced a strong immunoblot reaction at
      approximately 21 kDa for an O26 strain containing the intimin gene (eae) and
      verocytotoxin (VT), but not with an O26 eae- and VT-negative strain, or O157 eae-
      and VT-positive strains. The MAb was used in a sandwich enzyme-linked
      immunosorbent assay (ELISA) format to screen strains from animal and human
      sources, and all reactive strains were characterized for the presence of eae and
      the gene encoding VT factors by PCR. The antigen was detected in a group of
      strains containing a high proportion of O26, the majority of which were eae
      positive with or without VT; these were isolated mostly from animal enteritis
      cases but included a small number of human enteric isolates. Nonreactors included
      eae-positive (with or without VT) O157 strains and one O26 strain. In a survey of
      mixed cultures from both animal and human enteric disease, ELISA-positive
      reactions were obtained from 7.1 to 11.2% of samples from bovine, porcine, ovine,
      and human sources. The two human O8 and ten animal O26 ELISA-reactive pure
      strains obtained from these samples contained six eae- and/or VT-positive
      strains; the other six strains lost their ELISA positivity following storage at 
      70 degrees C, after which none were found to contain either eae or VT factors.
      The association of the antigen detected by the MAb with significant
      enteropathogenic E. coli and EHEC virulence factors in isolates from both animal
      and human enteric infections indicates a diagnostic potential for the assay
      developed.

PMID- 10391873
TI  - Heterophile antibodies to bovine and caprine proteins causing false-positive
      human immunodeficiency virus type 1 and other enzyme-linked immunosorbent assay
      results.
AB  - Heterophile antibodies are a well-recognized cause of erroneous results in
      immunoassays. We describe here a 22-month-old child with heterophile antibodies
      reactive with bovine serum albumin and caprine proteins causing false-positive
      results to human immunodeficiency virus type 1 and other infectious serology
      testing.

PMID- 10391875
TI  - Long-term persistence of immunoglobulin A (IgA) and IgM antibodies against human
      cytomegalovirus in solid-organ transplant recipients.
AB  - The retrospective analysis of 494 solid-organ transplant recipients revealed that
      during the follow-up period (mean duration, 3.2 years) 184 (88%) of 209 anti
      human cytomegalovirus (HCMV) immunoglobulin A (IgA)-positive patients remained
      IgA positive, as did 128 (74.85%) of 171 anti-HCMV IgM-positive patients. We
      conclude that anti-HCMV IgA and IgM testing for management of clinically relevant
      HCMV infections in solid-organ transplant recipients is dispensable.

PMID- 10391874
TI  - Conservation of expression and N-terminal sequences of the Pasteurella
      haemolytica 31-kilodalton and Pasteurella trehalosi 29-kilodalton periplasmic
      iron-regulated proteins.
AB  - This study examined the conservation of expression of a 31-kDa iron-regulated
      protein by serotypes of Pasteurella haemolytica and Pasteurella trehalosi
      associated with pasteurellosis of cattle and sheep. A polyclonal antibody
      prepared against the purified 31-kDa periplasmic iron-regulated protein from P.
      haemolytica serotype A1 showed that all P. haemolytica serotypes expressed
      similar 31-kDa proteins with identical N-terminal sequences, whereas P. trehalosi
      serotypes expressed immunologically different 29-kDa proteins with a different N
      terminal sequence. Antibody to the 31-kDa iron-regulated protein was a useful
      tool to distinguish similarities and differences of the iron-regulated proteins
      of P. haemolytica and P. trehalosi.

PMID- 10391876
TI  - Total immunoglobulin E levels and dengue infection on San Andres Island,
      Colombia.
AB  - An evaluation of total immunoglobulin E (IgE) and dengue serostatus in 168
      subjects from San Andres Island, Colombia, revealed altered levels of IgE in 89%
      of the population. IgE levels were higher in patients with a history of dengue or
      with a current secondary or current primary infection than in subjects with no
      exposure (P = 0. 01). Dengue infection accounted for 23% of the variation in IgE
      levels.

PMID- 10391877
TI  - Brucella outer membrane lipoproteins share antigenic determinants with bacteria
      of the family Rhizobiaceae.
AB  - Brucellae have been reported to be phylogenetically related to bacteria of the
      family Rhizobiaceae. In the present study, we used a panel of monoclonal
      antibodies (MAbs) to Brucella outer membrane proteins (OMPs) to determine the
      presence of common OMP epitopes in some representative bacteria of this family,
      i.e., Ochrobactrum anthropi, Phyllobacterium rubiacearum, Rhizobium
      leguminosarum, and Agrobacterium tumefaciens, and also in bacteria reported to
      serologically cross-react with brucella, i.e., Yersinia enterocolitica O:9,
      Escherichia coli O:157, and Salmonella urbana. In particular, most MAbs to the
      Brucella outer membrane lipoproteins Omp10, Omp16, and Omp19 cross-reacted with
      O. anthropi and P. rubiacearum, which are actually the closest relatives of
      brucellae. Some of them also cross-reacted, but to a lower extent, with R.
      leguminosarum and A. tumefaciens. The putative Omp16 and Omp19 homologs in these
      bacteria showed the same apparent molecular masses as their Brucella
      counterparts. None of the antilipoprotein MAbs cross-reacted with Y.
      enterocolitica O:9, E. coli O:157, or S. urbana.

PMID- 10391878
TI  - A novel enzyme-linked immunosorbent assay using the recombinant Actinobacillus
      pleuropneumoniae ApxII antigen for diagnosis of pleuropneumonia in pig herds.
AB  - For the surveillance of pig herds infected with porcine pleuropneumonia, an
      enzyme-linked immunosorbent assay (ELISA) using the recombinant Actinobacillus
      pleuropneumoniae ApxII protein as species- but not serotype-specific antigen was
      developed. Using this ELISA, 243 of 400 animals from 22 A. pleuropneumoniae
      infected herds were classified as seropositive.

PMID- 10391879
TI  - Serum antibody responses to Helicobacter pylori and the cagA marker in patients
      with mucosa-associated lymphoid tissue lymphoma.
AB  - The lymphoma of the mucosa-associated lymphoid tissue (MALT) of the stomach has
      been linked to Helicobacter pylori infection, but the mechanisms involved in B
      cell proliferation remain elusive. In a search for putative H. pylori-specific
      monoclonal immunoglobulin production, an H. pylori strain was isolated from 10
      patients with MALT lymphoma and used to detect the specific serum antibody
      response to the homologous strain by immunoblotting. Moreover, the antigenicity
      of the different strains was compared by using each of the 10 sera. We found that
      the different strains induced highly variable patterns of systemic immunoglobulin
      G antibody response, although several bacterial antigens, such as the 60-kDa
      urease B, were often recognized by the different sera. The cagA marker was
      detected in the strains by PCR with specific primers and by dot blot analysis,
      and the CagA protein was found in the sera of 4 of the 10 patients by
      immunoblotting. In conclusion, MALT lymphoma patients, like other patients with
      H. pylori gastritis, exhibit a polymorphic systemic antibody response, despite an
      apparently similar antigenic profile. The CagA marker of pathogenicity is not
      associated with this disease.

PMID- 10391881
TI  - alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the
      pathogenesis of Parkinson's disease.
AB  - Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically
      characterized by the presence of intracytoplasmic Lewy bodies, the major
      components of which are filaments consisting of alpha-synuclein. Two recently
      identified point mutations in alpha-synuclein are the only known genetic causes
      of PD. alpha-Synuclein fibrils similar to the Lewy body filaments can be formed
      in vitro, and we have shown recently that both PD-linked mutations accelerate
      their formation. This study addresses the mechanism of alpha-synuclein
      aggregation: we show that (i) it is a nucleation-dependent process that can be
      seeded by aggregated alpha-synuclein functioning as nuclei, (ii) this fibril
      growth follows first-order kinetics with respect to alpha-synuclein
      concentration, and (iii) mutant alpha-synuclein can seed the aggregation of wild
      type alpha-synuclein, which leads us to predict that the Lewy bodies of familial
      PD patients with alpha-synuclein mutations will contain both, the mutant and the
      wild type protein. Finally (iv), we show that wild type and mutant forms of alpha
      synuclein do not differ in their critical concentrations. These results suggest
      that differences in aggregation kinetics of alpha-synucleins cannot be explained
      by differences in solubility but are due to different nucleation rates.
      Consequently, alpha-synuclein nucleation may be the rate-limiting step for the
      formation of Lewy body alpha-synuclein fibrils in Parkinson's disease.

PMID- 10391880
TI  - Redesignation of a purported P1.15 subtype-specific meningococcal monoclonal
      antibody as a P1.19-specific reagent.
AB  - Two reference monoclonal antibodies against the meningococcal P1.15 subtype PorA,
      MN3C5C and 2-1-P1.15, showed only partial concordant recognition of meningococcal
      isolates. Cyanogen bromide cleavage of P1.19,15 PorA, peptide mapping, and
      sequencing of porA regions demonstrated that 2-1-P1.15 was specific for subtype
      P1.19, and henceforth it is to be redesignated as 2-1-P1.19.

PMID- 10391882
TI  - The Nijmegen breakage syndrome protein is essential for Mre11 phosphorylation
      upon DNA damage.
AB  - The Nijmegen breakage syndrome (NBS), a chromosomal instability disorder, is
      characterized in part by cellular hypersensitivity to ionizing radiation. Repair
      of DNA double-strand breaks by radiation is dependent on a multifunctional
      complex containing Rad50, Mre11, and the NBS1 gene product, p95 (NBS protein,
      nibrin). The role of p95 in these repair processes is unknown. Here it is
      demonstrated that Mre11 is hyperphosphorylated in a cell cycle-independent manner
      in response to treatment of cells with genotoxic agents including gamma
      irradiation. This response is abrogated in two independently established NBS cell
      lines that have undetectable levels of the p95 protein. NBS cells are also
      deficient for radiation-induced nuclear foci containing Mre11, while those with
      Rad51 are unaffected. An analysis of the kinetic relationship between Mre11
      phosphorylation and the appearance of its radiation-induced foci indicates that
      the former precedes the latter. Together, these data suggest that specific
      phosphorylation of Mre11 is induced by DNA damage, and p95 is essential in this
      process, perhaps by recruiting specific kinases.

PMID- 10391883
TI  - Pairwise interactions between neuronal alpha7 acetylcholine receptors and alpha
      conotoxin ImI.
AB  - The present work uses alpha-conotoxin ImI (CTx ImI) to probe the neurotransmitter
      binding site of neuronal alpha7 acetylcholine receptors. We identify key residues
      in alpha7 that contribute to CTx ImI affinity, and use mutant cycles analysis to
      identify pairs of residues that stabilize the receptor-conotoxin complex. We
      first mutated key residues in the seven known loops of alpha7 that converge at
      the subunit interface to form the ligand binding site. The mutant subunits were
      expressed in 293 HEK cells, and CTx ImI binding was measured by competition
      against the initial rate of 125I-alpha-bungarotoxin binding. The results reveal a
      predominant contribution by Tyr-195 in alpha7, accompanied by smaller
      contributions by Thr-77, Tyr-93, Asn-111, Gln-117, and Trp-149. Based upon our
      previous identification of bioactive residues in CTx ImI, we measured binding of
      receptor and toxin mutations and analyzed the results using thermodynamic mutant
      cycles. The results reveal a single dominant interaction between Arg-7 of CTx ImI
      and Tyr-195 of alpha7 that anchors the toxin to the binding site. We also find
      multiple weak interactions between Asp-5 of CTx ImI and Trp-149, Tyr-151, and Gly
      153 of alpha7, and between Trp-10 of CTx ImI and Thr-77 and Asn-111 of alpha7.
      The overall results establish the orientation of CTx ImI as it bridges the
      subunit interface and demonstrate close approach of residues on opposing faces of
      the alpha7 binding site.

PMID- 10391886
TI  - On the substrate specificity of DNA methyltransferases. adenine-N6 DNA
      methyltransferases also modify cytosine residues at position N4.
AB  - Methylation of DNA is important in many organisms and essential in mammals.
      Nucleobases can be methylated at the adenine-N6, cytosine-N4, or cytosine-C5
      atoms by specific DNA methyltransferases. We show here that the M.EcoRV, M.EcoRI,
      and Escherichia coli dam methyltransferases as well as the N- and C-terminal
      domains of the M. FokI enzyme, which were formerly all classified as adenine-N6
      DNA methyltransferases, also methylate cytosine residues at position N4. Kinetic
      analyses demonstrate that the rate of methylation of cytosine residues by M.EcoRV
      and the M.FokI enzymes is reduced by only 1-2 orders of magnitude in relation to
      methylation of adenines. This result shows that although these enzymes methylate
      DNA in a sequence specific manner, they have a low substrate specificity with
      respect to the target base. This unexpected finding has implications on the
      mechanism of adenine-N6 DNA methyltransferases. Sequence comparisons suggest that
      adenine-N6 and cytosine-N4 methyltransferases have changed their reaction
      specificity at least twice during evolution, a model that becomes much more
      likely given the partial functional overlap of both enzyme types. In contrast,
      methylation of adenine residues by the cytosine-N4 methyltransferase M.BamHI was
      not detectable. On the basis of our results, we suggest that adenine-N6 and
      cytosine-N4 methyltransferases should be grouped into one enzyme family.

PMID- 10391885
TI  - Selective sensitization to tumor necrosis factor-alpha-induced apoptosis by
      blockade of NF-kappaB in primary glomerular mesangial cells.
AB  - Recent data have implicated nuclear factor kappaB (NF-kappaB) in the prevention
      of apoptosis in transformed cell lines exposed to tumor necrosis factor alpha
      (TNF-alpha). However, it is obscure whether NF-kappaB plays an anti-apoptotic
      role in nontransformed cells, and it is not clear whether NF-kappaB inhibits
      apoptosis triggered by other mediators. We investigated the effect of specific
      inhibition of NF-kappaB on cytokine-induced apoptosis of glomerular mesangial
      cells, which is important in determining the outcome of glomerulonephritis.
      Cultured rat mesangial cells were stably transfected with the dominant negative
      mutant inhibitor of NF-kappaB (IkappaBalphaM). IkappaBalphaM was resistant to
      stimulus-dependent degradation and suppressed NF-kappaB activation induced by TNF
      alpha (10 ng/ml) or IL-1beta (10 ng/ml). IkappaBalphaM significantly sensitized
      mesangial cells to TNF-alpha-induced apoptosis in a dose- and time-dependent
      manner but had no significant effects on the level of apoptosis in the presence
      of proinflammatory or apoptosis-inducing stimuli including Fas ligand, IL-1alpha,
      IL-1beta, hydrogen peroxide, lipopolysaccharide, cycloheximide, or serum
      deprivation. Moreover, IkappaBalphaM-mediated sensitization to TNF-alpha overcame
      the protective effect of mesangial cell survival factors present in serum, which
      usually inhibit killing of mesangial cells by the proapoptotic stimuli used.
      These data show that inhibition of NF-kappaB selectively sensitizes primary adult
      glomerular mesangial cells to TNF-induced apoptosis but not to other mediators of
      cell death including the Fas ligand.

PMID- 10391884
TI  - Thiols mediate superoxide-dependent NADH modification of glyceraldehyde-3
      phosphate dehydrogenase.
AB  - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is covalently modified by NAD in
      the presence of nitric oxide (NO) and dithiothreitol. Replacement of NAD with
      NADH in the presence of SIN-1 (3-morpholinosydnonimine) and dithiothreitol
      increased modification 25-fold. We now demonstrate that in contrast to NO
      mediated attachment of NAD, covalent attachment of NADH to GAPDH proceeds in the
      presence of low molecular weight thiols, independent of NO. Removal of oxygen and
      transition metal ions inhibited modification, consistent with a role for reactive
      oxygen species; inhibition by superoxide dismutase, stimulation by xanthine
      oxidase/hypoxanthine, and the lack of an effect of catalase supported the
      hypothesis that superoxide, generated from thiol oxidation, was involved.
      Electrospray mass spectrometry showed covalent linkage of the NADH molecule to
      GAPDH. Characterization of the product of phosphodiesterase cleavage demonstrated
      that linkage to GAPDH occurred through the nicotinamide of NADH. Lys-C digestion
      of GAPDH, followed by peptide isolation by high performance liquid
      chromatography, matrix-assisted laser desorption ionization time-of-flight
      analysis, and Edman sequencing, demonstrated that NADH attachment occurred at Cys
      149, the active-site thiol. This thiol linkage was stable to HgCl2. Thus, linkage
      of GAPDH to NADH, in contrast to NAD, occurs in the presence of thiol, is
      independent of NO, and is mediated by superoxide.

PMID- 10391887
TI  - Enhancement by adenosine of insulin-induced activation of phosphoinositide 3
      kinase and protein kinase B in rat adipocytes.
AB  - The role of adenosine receptor in regulation of insulin-induced activation of
      phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B was studied in
      isolated rat adipocytes. Rat adipocytes are known to spontaneously release
      adenosine, which in turn binds and stimulates the adenosine A1 receptors on the
      cells. In the present study, we observed that degradation of this adenosine by
      adenosine deaminase attenuated markedly the insulin-induced accumulation of
      phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), a product of PI 3
      kinase. p-Aminophenylacetyl xanthine amine congener (PAPA-XAC), an inhibitor of
      the adenosine A1 receptor, also inhibited the insulin-induced PtdIns(3,4,5)P3
      accumulation. When extracellular adenosine was inactivated by adenosine
      deaminase, phenylisopropyladenosine, an adenosine A1 receptor agonist,
      potentiated the insulin-induced accumulation of PtdIns(3,4,5)P3. Insulin-induced
      activation of protein kinase B, the activity of which is controlled by the lipid
      products of PI 3-kinase, was also potentiated by adenosine. Prostaglandin E2,
      another activator of a pertussis toxin-sensitive GTP-binding protein in these
      cells, potentiated the insulin actions. Thus, the receptors coupling to the GTP
      binding protein were found to positively regulate the production of
      PtdIns(3,4,5)P3, a putative second messenger for insulin actions, in
      physiological target cells of insulin.

PMID- 10391888
TI  - Integrins enhance platelet-derived growth factor (PDGF)-dependent responses by
      altering the signal relay enzymes that are recruited to the PDGF beta receptor.
AB  - Since the extracellular matrix (ECM) can promote platelet-derived growth factor
      (PDGF)-dependent responses, we hypothesized that the ECM mediates this effect by
      preventing the PDGF beta receptor (betaPDGFR) from associating with the negative
      regulator, RasGAP (the GTPase-activating protein of Ras). We found that binding
      of RasGAP to the wild-type betaPDGFR was decreased; the activation of Ras and Erk
      was enhanced, and [3H]thymidine uptake was better in cells cultured on
      fibronectin than in cells cultured on polylysine. To investigate the mechanism by
      which culturing cells on fibronectin diminished the recruitment of RasGAP to the
      betaPDGFR, we focused on SHP-2 since it dephosphorylates the betaPDGFR at the
      phosphotyrosine required for binding of RasGAP. Culturing cells on fibronectin
      increased the amount of SHP-2 that associated with the betaPDGFR. Furthermore,
      cells expressing receptor mutants that failed to associate with SHP-2 were
      insensitive to fibronectin. The ECM enhances PDGF-dependent responses by
      increasing the association of SHP-2 with the betaPDGFR, which in turn decreases
      the time that RasGAP interacts with the receptor. Thus, fibronectin changes PDGF
      dependent signaling and biological responses by altering the signal relay enzymes
      that are recruited to the receptor.

PMID- 10391889
TI  - Stress-induced stimulation of early growth response gene-1 by p38/stress
      activated protein kinase 2 is mediated by a cAMP-responsive promoter element in a
      MAPKAP kinase 2-independent manner.
AB  - The p38/stress-activated protein kinase2 (p38/SAPK2) is activated by cellular
      stress and proinflammatory cytokines. Several transcription factors have been
      reported to be regulated by p38/SAPK2, and this kinase is involved in the control
      of expression of various genes. In human Jurkat T-cells, induction of the early
      growth response gene-1 (egr-1) by anisomycin is completely inhibited by SB203580,
      a specific inhibitor of p38/SAPK2a and -b. Northern blot and reporter gene
      experiments indicate that this block is at the level of mRNA biosynthesis. Using
      mutants of the egr-1 promoter, we demonstrate that a distal cAMP-responsive
      element (CRE; nucleotides -134 to -126) is necessary to control egr-1 induction
      by p38/SAPK2. Pull-down assays indicate that phospho-CRE binding protein (CREB)
      and phospho-activating transcription factor-1 (ATF1) bind to this element in a
      p38/SAPK2-dependent manner. In response to anisomycin, two known CREB kinases
      downstream to p38/SAPK2, MAPKAP kinase 2 (MK2) and mitogen- and stress-activated
      kinase 1 (MSK1), show increased activity. However, in MK2 -/- fibroblasts derived
      from mice carrying a disruption of the MK2 gene, the phosphorylation of CREB and
      ATF1 and the expression of egr-1 reach levels comparable with wild type cells.
      This finding excludes MK2 as an involved enzyme. We conclude that egr-1 induction
      by anisomycin is mediated by p38/SAPK2 and probably by MSK1. Phosphorylated CREB
      and ATF1 then bind to the CRE of the egr-1 promoter and cause a stress-dependent
      transcriptional activation of this gene.

PMID- 10391890
TI  - Assembly and secretion of chylomicrons by differentiated Caco-2 cells. Nascent
      triglycerides and preformed phospholipids are preferentially used for lipoprotein
      assembly.
AB  - To develop a cell culture model for chyclomicron (CM) assembly, the apical media
      of differentiated Caco-2 cells were supplemented with oleic acid (OA) together
      with either albumin or taurocholate (TC). The basolateral media were subjected to
      sequential density gradient ultracentrifugations to obtain large CM, small CM,
      and very low density lipoproteins (VLDL), and the distribution of apoB in these
      fractions was quantified. In the absence of OA, apoB was secreted as VLDL/LDL
      size particles. Addition of OA (>/=0.8 mM) with TC, but not with albumin,
      resulted in the secretion of one-third of apoB as CM. Lipid analysis revealed
      that half of the secreted phospholipids (PL) and triglycerides (TG) were
      associated with CM. In CM, TG were 7-11-fold higher than PL indicating that CM
      were TG-rich particles. Secreted CM contained apoB100, apoB48, and other
      apolipoproteins. Secretion of large CM was specifically inhibited by Pluronic
      L81, a detergent known to inhibit CM secretion in animals. These studies
      demonstrate that differentiated Caco-2 cells assemble and secrete CM in a manner
      similar to enterocytes in vivo. Next, experiments were performed to identify the
      sources of lipids used for lipoprotein assembly. Cells were labeled with
      [3H]glycerol for 12 h, washed, and supplemented with OA, TC, and [14C] glycerol
      for various times to induce CM assembly and to radiolabel nascent lipids. TG and
      PL were extracted from cells and media and the association of preformed and
      nascent lipids with lipoproteins was determined. All the lipoproteins contained
      higher amounts of preformed PL compared with nascent PL. VLDL contained equal
      amounts of nascent and preformed TG, whereas CM contained higher amounts of
      nascent TG even when nascent TG constituted a small fraction of the total
      cellular pool. These studies indicate that nascent TG and preformed PL are
      preferentially used for CM assembly and provide a molecular explanation for the
      in vivo observations that the fatty acid composition of TG, but not PL, of
      secreted CM reflects the composition of dietary fat. It is proposed that in the
      intestinal cells the preformed PL from the endoplasmic reticulum bud off with
      apoB as primordial particles and the assembly of larger lipoproteins is dependent
      on the synthesis and delivery of nascent TG to these particles.

PMID- 10391891
TI  - Functional interactions between Sp1 or Sp3 and the helicase-like transcription
      factor mediate basal expression from the human plasminogen activator inhibitor-1
      gene.
AB  - Basal expression of the human plasminogen activator inhibitor-1 (PAI-1) is
      mediated by a promoter element named B box that binds the helicase-like
      transcription factor (HLTF), homologous to SNF/SWI proteins. Electrophoretic
      mobility shift assays performed on a set of B box point mutants demonstrated two
      HLTF sites flanking and partially overlapping with a GT box binding Sp1 and Sp3.
      Mutations affecting either the Sp1/Sp3 or the two HLTF sites inhibited by 6- and
      2.5-fold, respectively, transient expression in HeLa cells of a reporter gene
      fused to the PAI-1 promoter. In Sp1/Sp3-devoid insect cells, co-expression of PAI
      1-lacZ with Sp1 or Sp3 led to a 14-26-fold induction while HLTF had no effect.
      Simultaneous presence of Sp1 or Sp3 and the short HLTF form (initiating at Met
      123) provided an additional 2-3-fold synergistic activation suppressed by
      mutations that prevented HLTF binding. Moreover, a DNA-independent interaction
      between HLTFMet123 and Sp1/Sp3 was demonstrated by co-immunoprecipitation from
      HeLa cell extracts and glutathione S-transferase pull-down experiments. The
      interaction domains were mapped to the carboxyl-terminal region of each protein;
      deletion of the last 85 amino acids of HLTFMet123 abolished the synergy with Sp1.
      This is the first demonstration of a functional interaction between proteins of
      the Sp1 and SNF/SWI families.

PMID- 10391892
TI  - Activation of the cell death program by nitric oxide involves inhibition of the
      proteasome.
AB  - The ubiquitin/proteasome pathway mediates the degradation of many short-lived
      proteins that are critically involved in the regulation of cell proliferation and
      cell death, including the tumor suppressor protein p53. Accumulation of p53 and
      induction of apoptosis in RAW 264.7 macrophages in response to nitric oxide are
      well established. However, the molecular mechanisms involved in nitric oxide
      induced p53 accumulation are unknown. Here we show that, similar to nitric oxide,
      treatment of macrophages with specific proteasome inhibitors, including
      clastolactacystin-beta-lactone, induces p53 accumulation and apoptosis,
      suggesting that nitric oxide may affect the activity of the proteasome. In
      support of this hypothesis, both exposure of cells to S-nitrosoglutathione and
      stimulation of endogenous nitric oxide production by
      lipopolysaccharide/interferon-gamma treatment result in inhibition of proteasome
      activity as measured in vitro by the degradation of the proteasome-specific
      substrate succinyl-Leu-Leu-Val-Tyr-4-methylcoumarin-7-amide. Moreover, chemically
      diverse nitric oxide donors interfere with proteasome-mediated degradation of
      polyubiquitinated p53 in vitro. These data imply that nitric oxide-induced
      apoptosis and accumulation of p53 are, at least in part, mediated by inhibition
      of the proteasome.

PMID- 10391894
TI  - One-way cross-talk between p38(MAPK) and p42/44(MAPK). Inhibition of p38(MAPK)
      induces low density lipoprotein receptor expression through activation of the
      p42/44(MAPK) cascade.
AB  - In this paper, we report that SB202190 alone, a specific inhibitor of p38(MAPK),
      induces low density lipoprotein (LDL) receptor expression (6-8-fold) in a sterol
      sensitive manner in HepG2 cells. Consistent with this finding, selective
      activation of the p38(MAPK) signaling pathway by expression of MKK6b(E), a
      constitutive activator of p38(MAPK), significantly reduced LDL receptor promoter
      activity. Expression of the p38(MAPK) alpha-isoform had a similar effect, whereas
      expression of the p38(MAPK) betaII-isoform had no significant effect on LDL
      receptor promoter activity. SB202190-dependent increase in LDL receptor
      expression was accompanied by induction of p42/44(MAPK), and inhibition of this
      pathway completely prevented SB202190-induced LDL receptor expression, suggesting
      that p38(MAPK) negatively regulates the p42/44(MAPK) cascade and the responses
      mediated by this kinase. Cross-talk between these kinases appears to be one-way
      because modulation of p42/44(MAPK) activity did not affect p38(MAPK) activation
      by a variety of stress inducers. Taken together, these findings reveal a hitherto
      unrecognized one-way communication that exists between p38(MAPK) and p42/44(MAPK)
      and provide the first evidence that through the p42/44(MAPK) signaling cascade,
      the p38(MAPK) alpha-isoform negatively regulates LDL receptor expression, thus
      representing a novel mechanism of fine tuning cellular levels of cholesterol in
      response to a diverse set of environmental cues.

PMID- 10391893
TI  - Expression of factor VIII by murine liver sinusoidal endothelial cells.
AB  - Factor VIII (fVIII) is the procoagulant plasma glycoprotein that is missing or
      decreased in hemophilia A. The cellular origin of fVIII synthesis is
      controversial. Liver transplantation cures hemophilia A, demonstrating that the
      liver is a major site of fVIII synthesis. We detected fVIII mRNA in purified
      populations of murine liver sinusoidal endothelial cells (LSECs) and hepatocytes,
      but not Kupffer cells. LSECs and hepatocytes contained comparable numbers of
      fVIII mRNA (40 and 70 transcripts per cell, respectively) by quantitative
      competitive reverse transcriptase-polymerase chain reaction analysis. There was
      not detectable mRNA for factor IX, a hepatocyte marker, in the LSEC preparation,
      nor was there detectable mRNA for von Willebrand factor, an endothelial cell
      marker, in the hepatocyte preparation. This excludes the possibility that
      detectable fVIII mRNA is due to cross-contamination in the hepatocyte or LSEC
      preparations. Primary cultures of LSECs were established in which fVIII mRNA
      levels were indistinguishable from purified LSECs. LSECs secreted active fVIII
      into the culture medium. This finding represents the first demonstration of
      homologous expression of fVIII mRNA and protein in cell culture and should
      facilitate studies of fVIII gene regulation. Additionally, LSECs potentially are
      targets for a fVIII transgene during gene therapy of hemophilia A.

PMID- 10391895
TI  - Chaperone activity of DsbC.
AB  - DsbC, a periplasmic disulfide isomerase of Gram-negative bacteria, displays about
      30% of the activities of eukaryotic protein disulfide isomerase (PDI) as
      isomerase and as thiol-protein oxidoreductase. However, DsbC shows more
      pronounced chaperone activity than does PDI in promoting the in vitro
      reactivation and suppressing aggregation of denatured D-glyceraldehyde-3
      phosphate dehydrogenase (GAPDH) during refolding. Carboxymethylation of DsbC at
      Cys98 decreases its intrinsic fluorescence, deprives of its enzyme activities,
      but lowers only partly its chaperone activity in assisting GAPDH reactivation.
      Simultaneous presence of DsbC and PDI in the refolding buffer shows an additive
      effect on the reactivation of GAPDH. The assisted reactivation of GAPDH and the
      protein disulfide oxidoreductase activity of DsbC can both be inhibited by
      scrambled and S-carboxymethylated RNases, but not by shorter peptides, including
      synthetic 10- and 14-mer peptides and S-carboxymethylated insulin A chain. In
      contrast, all the three peptides and the two nonnative RNases inhibit PDI
      assisted GAPDH reactivation and the reductase activity of PDI. DsbC assists
      refolding of denatured and reduced lysozyme to a higher level than does PDI in
      phosphate buffer and does not show anti-chaperone activity in HEPES buffer. Like
      PDI, DsbC is also a disulfide isomerase with chaperone activity but may recognize
      different folding intermediates as does PDI.

PMID- 10391896
TI  - Inactivation of the inhibitory kappaB protein kinase/nuclear factor kappaB
      pathway by Par-4 expression potentiates tumor necrosis factor alpha-induced
      apoptosis.
AB  - Par-4 is a novel protein identified in cells undergoing apoptosis. The ability of
      Par-4 to promote apoptotic cell death is dependent on the binding and
      inactivation of the atypical protein kinases C (PKCs). This subfamily of kinases
      has been reported to control nuclear factor kappaB (NF-kappaB) through the
      regulation of the IkappaB kinase activity. NF-kappaB activation by tumor necrosis
      factor alpha (TNFalpha) provides a survival signal that impairs the TNFalpha
      induced apoptotic response. We show here that expression of Par-4 inhibits the
      TNFalpha-induced nuclear translocation of p65 as well as the kappaB-dependent
      promoter activity. Interestingly, Par-4 expression blocks inhibitory kappaB
      protein (IkappaB) kinase activity, which leads to the inhibition of IkappaB
      phosphorylation and degradation, in a manner that is dependent on its ability to
      inhibit lambda/iotaPKC. Of potential functional relevance, the expression of Par
      4 allows TNFalpha to induce apoptosis in NIH-3T3 cells. In addition, the down
      regulation of Par-4 levels by oncogenic Ras sensitizes cells to TNFalpha-induced
      NF-kappaB activation.

PMID- 10391897
TI  - A significant part of native gamma-aminobutyric AcidA receptors containing alpha4
      subunits do not contain gamma or delta subunits.
AB  - Using a novel antibody directed against the alpha4 subunit of gamma-aminobutyric
      acidA (GABAA) receptors, 5% of all [3H]muscimol but only about 2% of all [3H]Ro15
      4513 binding sites present in brain membrane extracts could be precipitated. This
      indicated that part of the alpha4 receptors containing [3H]muscimol binding sites
      did not contain [3H]Ro15-4513 binding sites. Immunoaffinity purification and
      Western blot analysis of alpha4 receptors demonstrated that not only alpha1,
      alpha2, alpha3, beta1, beta2, and beta3 subunits but also gamma1, gamma2, gamma3,
      and delta subunits can be colocalized with alpha4 subunits in native GABAA
      receptors. Quantification experiments, however, indicated that only 7, 33, 4, or
      7% of all alpha4 receptors contained gamma1, gamma2, gamma3, or delta subunits,
      respectively. These data not only explain the low percentage of [3H]Ro15-4513
      binding sites precipitated by the anti-alpha4 antibody but also indicate that
      approximately 50% of the alpha4 receptors did not contain gamma1, gamma2, gamma3,
      or delta subunits. These receptors, thus, either are composed of alpha4 and beta1
      3 subunits only, or additionally contain epsilon, pi, or so far unidentified
      GABAA receptor subunits.

PMID- 10391898
TI  - N-terminal tail export from the mitochondrial matrix. Adherence to the
      prokaryotic "positive-inside" rule of membrane protein topology.
AB  - Export of N-terminal tails of mitochondrial inner membrane proteins from the
      mitochondrial matrix is a membrane potential-dependent process, mediated by the
      Oxa1p translocation machinery. The hydrophilic segments of these membrane
      proteins, which undergo export, display a characteristic charge profile where
      intermembrane space-localized segments bear a net negative charge, whereas those
      remaining in the matrix have a net positive one. Using a model protein, preSu9(1
      112)-dihydrofolate reductase (DHFR), which undergoes Oxa1p-mediated N-tail
      export, we demonstrate here that the net charge of N- and C-flanking regions of
      the transmembrane domain play a critical role in determining the orientation of
      the insertion process. The N-tail must bear a net negative charge to be exported
      to the intermembrane space. Furthermore, a net positive charge of the C-terminal
      region supports this N-tail export event. These data provide experimental
      evidence that protein export in mitochondria adheres to the "positive-inside"
      rule, described for sec-independent sorting of membrane proteins in prokaryotes.
      We propose here that the importance of a charge profile reflects a need for
      specific protein-protein interactions to occur in the export reaction, presumably
      at the level of the Oxa1p export machinery.

PMID- 10391899
TI  - Acetylcholine and epibatidine binding to muscle acetylcholine receptors
      distinguish between concerted and uncoupled models.
AB  - The muscle acetylcholine receptor (AChR) has served as a prototype for
      understanding allosteric mechanisms of neurotransmitter-gated ion channels. The
      phenomenon of cooperative agonist binding is described by the model of Monod et
      al. (Monod, J., Wyman, J., and Changeux, J. P. (1965) J. Mol. Biol. 12, 88-118;
      MWC model), which requires concerted switching of the two binding sites between
      low and high affinity states. The present study examines binding of acetylcholine
      (ACh) and epibatidine, agonists with opposite selectivity for the two binding
      sites of mouse muscle AChRs. We expressed either fetal or adult AChRs in 293 HEK
      cells and measured agonist binding by competition against the initial rate of
      125I-alpha-bungarotoxin binding. We fit predictions of the MWC model to
      epibatidine and ACh binding data simultaneously, taking as constants previously
      determined parameters for agonist binding and channel gating steps, and varying
      the agonist-independent parameters. We find that the MWC model describes the
      apparent dissociation constants for both agonists but predicts Hill coefficients
      that are far too steep. An Uncoupled model, which relaxes the requirement of
      concerted state transitions, accurately describes binding of both ACh and
      epibatidine and provides parameters for agonist-independent steps consistent with
      known aspects of AChR function.

PMID- 10391900
TI  - Single strand DNA specificity analysis of human nucleoside diphosphate kinase B.
AB  - Nucleoside diphosphate kinases (NDP kinases) form a family of oligomeric enzymes
      present in all organisms. Eukaryotic NDP kinases are hexamers composed of
      identical subunits (approximately 17 kDa). A distinctive property of human NDPK-B
      encoded by the gene nm23-H2 is its ability to stimulate the gene transcription.
      This property is independent of its catalytic activity and is possibly related to
      the role of this protein in cellular events including differentiation and tumor
      metastasis. In this paper, we report the first characterization of human NDPK
      B.DNA complex formation using a filter-binding assay and fluorescence
      spectroscopy. We analyzed the binding of several oligonucleotides mimicking the
      promoter region of the c-myc oncogene including variants in sequence, structure,
      and length of both strands. We show that NDPK-B binds to single-stranded
      oligonucleotides in a nonsequence specific manner, but that it exhibits a poor
      binding activity to double-stranded oligonucleotides. This indicates that the
      specificity of recognition to DNA is a function of the structural conformation of
      DNA rather than of its specific sequence. Moreover, competition experiments
      performed with all nucleotides provide evidence for the contribution of the six
      active sites in the DNA.protein complex formation. We propose a mechanism through
      which human NDPK-B could stimulate transcription of c-myc or possibly other genes
      involved in cellular differentiation.

PMID- 10391901
TI  - Phospholipase C-beta1 directly accelerates GTP hydrolysis by Galphaq and
      acceleration is inhibited by Gbeta gamma subunits.
AB  - Phospholipase C-beta, the principal effector protein regulated by Galphaq, has
      been shown to increase the agonist-stimulated, steady-state GTPase activity of Gq
      in proteoliposomes that contain both heterotrimeric Gq and m1 muscarinic
      receptor. We now use a moderately stable complex of R183C Galphaq bound to GTP to
      show that PLC-beta1 acts directly as a GTPase-activating protein (GAP) for
      isolated Galphaq in a membrane-free system. PLC-beta1 accelerated the hydrolysis
      of GalphaqR183C.GTP up to 20-fold. The Km was 1.5 nM, which is similar both to
      the EC50 with which R183C and wild type Galphaq activate PLC-beta1 and to the
      EC50 with which PLC-beta1 acts as a Gq GAP in the vesicle-based assay. The
      Galphaq GAP activity of RGS4 can also be quantitated by this assay; it
      accelerated hydrolysis of bound GTP about 100-fold. The Gq GAP activities of both
      PLC-beta1 and RGS4 are blocked by Gbeta gamma subunits, probably by a competitive
      mechanism. These data suggest either that the Gbeta gamma subunits are not
      continuously required for receptor-catalyzed GDP/GTP exchange during steady-state
      GTP hydrolysis or that GAPs, either PLC-beta or RGS proteins, can substitute for
      Gbeta gamma in this set of reactions.

PMID- 10391902
TI  - Specific DNA recognition by F Factor TraY involves beta-sheet residues.
AB  - The F Factor TraY protein is a sequence-specific DNA-binding protein required for
      efficient conjugal transfer. Genetic and biochemical studies indicate that TraY
      has two functional roles in conjugation. TraY binds to the PY promoter to up
      regulate transcription of tra genes. TraY also binds to the plasmid origin of
      transfer (oriT), serving as an accessory protein in the nicking of F Factor in
      preparation for transfer. TraY is thought to belong to the ribbon-helix-helix
      family of transcription factors. These proteins contact DNA using residues of an
      antiparallel beta-sheet. We engineered and characterized six TraY mutants each
      having a single potential beta-sheet DNA contact residue replaced with Ala. Most
      TraY mutants had significantly reduced affinity for the TraY oriT binding site
      while possessing near wild-type stability and nonspecific DNA recognition. These
      results indicate that TraY beta-sheet residues participate in DNA recognition,
      and support inclusion of TraY in the ribbon-helix-helix family.

PMID- 10391904
TI  - Identification and expression of the TREX1 and TREX2 cDNA sequences encoding
      mammalian 3'-->5' exonucleases.
AB  - The 3'-->5' exonucleases catalyze the excision of nucleoside monophosphates from
      the 3' termini of DNA. We have identified the cDNA sequences encoding two 3'-->5'
      exonucleases (TREX1 and TREX2) from mammalian cells. The TREX1 and TREX2 proteins
      are 304 and 236 amino acids in length, respectively. Analysis of the TREX1 and
      TREX2 sequences identifies three conserved motifs that likely generate the
      exonuclease active site in these enzymes. The specific amino acids in these three
      conserved motifs suggest that these mammalian exonucleases are most closely
      related to the proofreading exonucleases of the bacterial replicative DNA
      polymerases and the RNase T enzymes. Expression of TREX1 and TREX2 in Escherichia
      coli demonstrates that these recombinant proteins are active 3'-->5'
      exonucleases. The recombinant TREX1 protein was purified, and exonuclease
      activity was measured using single-stranded, partial duplex, and mispaired
      oligonucleotide DNA substrates. The greatest activity of the TREX1 protein was
      detected using a partial duplex DNA containing five mispaired nucleotides at the
      3' terminus. No activity was detected using single-stranded RNA or an RNA-DNA
      partial duplex. Identification of the TREX1 and TREX2 cDNA sequences provides the
      genetic tools to investigate the physiological roles of these exonucleases in
      mammalian DNA replication, repair, and recombination pathways.

PMID- 10391903
TI  - Gab2, a new pleckstrin homology domain-containing adapter protein, acts to
      uncouple signaling from ERK kinase to Elk-1.
AB  - We describe a novel human adapter molecule containing a pleckstrin homolgy (PH)
      domain at the N terminus that is closely related to human Grb2-associated binder
      1, Gab1, and Drosophila daughter of sevenless. We designate this protein as Gab2.
      Northern blot analysis indicates that Gab2 is widely expressed and has an
      overlapping but distinctive expression pattern as compared with Gab1, with high
      levels of Gab2 mRNA detected in the heart, brain, placenta, spleen, ovary,
      peripheral blood leukocytes, and spinal cord. Upon tyrosine phosphorylation, Gab2
      physically interacts with Shp2 tyrosine phosphatase and Grb2 adapter protein.
      Strikingly, Gab2 has an inhibitory effect on the activation of Elk-1-dependent
      transcription triggered by a dominant active Ras mutant (RasV12) or under growth
      factor stimulation, whereas Gab1 acts to potentiate slightly the Elk-1 activity
      in the same system. In contrast to the reciprocal effects of Gab1 and Gab2 in
      mediating Elk-1 induction, these two molecules have a similar function in
      extracellular signal-regulated kinase activation induced by either oncogenic Ras
      or growth factor stimulation. Taken together, these results argue that Gab1 and
      Gab2, two closely related PH-containing adapter proteins, might have distinct
      roles in coupling cytoplasmic-nuclear signal transduction. This is the first
      evidence that an intracellular molecule with a PH domain operates as a negative
      effector in signal relay to the regulation of gene expression.

PMID- 10391905
TI  - Reactions of lipid-derived malondialdehyde with collagen.
AB  - Malondialdehyde is a product of fatty acid oxidation (e.g. from low density
      lipoprotein) implicated in the damage of proteins such as collagen in the
      cardiovascular system (Chio, K. J., and Tappel, A. L. (1969) Biochemistry 8, 2821
      2827). Its concentration is raised in diabetic subjects probably as a side effect
      of increased protein glycation. Collagen has enzyme-catalyzed cross-links formed
      between its individual molecules that are essential for maintaining the structure
      and flexibility of the collagen fiber. The cross-link dehydro
      hydroxylysinonorleucine reacts irreversibly with 10 mM malondialdehyde at least 3
      orders of magnitude faster than glucose reactions with lysine or arginine, such
      that there is little cross-link left after 1 h at 37 degrees C. Other cross-links
      and glycated elements of collagen are also vulnerable. Several possible products
      of malondialdehyde with collagen cross-links are proposed, and the potential
      involvement of collagenous histidine in these reactions is discussed. We have
      also isolated Ndelta-(2-pyrimidyl)-L-ornithine from collagenous arginine reacted
      with malondialdehyde. The yields of this product were considerably higher than
      those from model reactions, being approximately 2 molecules/collagen molecule
      after 1 day at 37 degrees C in 10 mM malondialdehyde. Collagenous lysine-derived
      malondialdehyde products may have been present but were not protected from
      protein acid hydrolysis by standard reduction techniques, thus resulting in a
      multitude of fragmented products.

PMID- 10391906
TI  - Human tryptases alpha and beta/II are functionally distinct due, in part, to a
      single amino acid difference in one of the surface loops that forms the substrate
      binding cleft.
AB  - Tryptases alpha and beta/II were expressed in insect cells to try to ascertain
      why human mast cells express these two nearly identical granule proteases. In
      contrast to that proposed by others, residue -3 in the propeptide did not appear
      to be essential for the three-dimensional folding, post-translational
      modification, and/or activation of this family of serine proteases. Both
      recombinant tryptases were functional and bound the active-site inhibitor
      diisopropyl fluorophosphate. However, they differed in their ability to cleave
      varied trypsin-susceptible chromogenic substrates. Structural modeling analyses
      revealed that tryptase alpha differs from tryptase beta/II in that it possesses
      an Asp, rather than a Gly, in one of the loops that form its substrate-binding
      cleft. A site-directed mutagenesis approach was therefore carried out to
      determine the importance of this residue. Because the D215G derivative of
      tryptase alpha exhibited potent enzymatic activity against fibrinogen and other
      tryptase beta/II-susceptible substrates, Asp215 dominantly restricts the
      substrate specificity of tryptase alpha. These data indicate for the first time
      that tryptases alpha and beta/II are functionally different human proteases.
      Moreover, the variation of just a single amino acid in the substrate-binding
      cleft of a tryptase can have profound consequences in the regulation of its
      enzymatic activity and/or substrate preference.

PMID- 10391908
TI  - Inhibition of phosphatidylcholine biosynthesis following induction of apoptosis
      in HL-60 cells.
AB  - Induction of apoptosis in HL-60 cells, using a variety of cytotoxic drugs,
      resulted, in all cases, in inhibition of CDP-choline:1, 2-diacylglycerol choline
      phosphotransferase, leading to an accumulation of its substrate, CDP-choline, and
      inhibition of phosphatidylcholine biosynthesis. Incubation of the cells with
      phosphatidylcholine reduced the number displaying an apoptotic morphology
      following drug treatment, and this was inversely related to the degree to which
      the drugs inhibited phosphatidylcholine biosynthesis. Inhibition of choline
      phosphotransferase by two of the drugs, farnesol and chelerythrine, was shown to
      be due to direct inhibition of the enzyme, while inhibition by the other drugs,
      etoposide and camptothecin, could be explained by the intracellular acidification
      that followed induction of apoptosis.

PMID- 10391907
TI  - Activation of the cAMP-specific phosphodiesterase PDE4D3 by phosphorylation.
      Identification and function of an inhibitory domain.
AB  - Splicing variants of type 4 phosphodiesterases (PDE4) are regulated by
      phosphorylation. In these proteins, a conserved region is located between the
      amino-terminal domain, which is the target for phosphorylation, and the catalytic
      domain. Previous studies have indicated that nested deletions encompassing this
      region cause an increase in catalytic activity, suggesting this domain exerts an
      inhibitory constraint on catalysis. Here, we have further investigated the
      presence and function of this domain. A time-dependent increase in hydrolytic
      activity was observed when PDE4D3 from FRTL-5 cells was incubated with the
      endoproteinase Lys-C. The activation was abolished by protease inhibitors and was
      absent when a phosphorylated enzyme was used. Western blot analysis with PDE4D
      specific antibodies indicated the Lys-C treatment separates the catalytic domain
      of PDE4D3 from the inhibitory domain. Incubation with antibodies recognizing an
      epitope within this domain caused a 3- to 4-fold increase in activity of native
      or recombinant PDE4D3. Again, PDE activation by these antibodies had properties
      similar to, and not additive with, the activation by protein kinase A
      phosphorylation. An interaction between the inhibitory domain and both regulatory
      and catalytic domains of PDE4D3 was detected by the yeast two-hybrid system.
      Mutations of Ser54 to Ala in the regulatory domain decreased or abolished this
      interaction, whereas mutations of Ser54 to the negatively charged Asp
      strengthened it. These data strongly support the hypothesis that an inhibitory
      domain is present in PDE4D and that phosphorylation of the regulatory domain
      causes activation of the enzyme by modulating the interaction between inhibitory
      and catalytic domains.

PMID- 10391909
TI  - The colonic H+,K+-ATPase functions as a Na+-dependent K+(NH4+)-ATPase in apical
      membranes from rat distal colon.
AB  - Recent studies have suggested that the colonic H+,K+-ATPase (HKalpha2) can
      secrete either Na+ or H+ in exchange for K+. If correct, this view would indicate
      that the transporter could function as either a Na+ or a H+ pump. To investigate
      this possibility a series of experiments was performed using apical membranes
      from rat colon which were enriched in colonic H+,K+-ATPase protein. An antibody
      specific for HKalpha2 was employed to determine whether HKalpha2 functions under
      physiological conditions as a Na+-dependent or Na+-independent K+-ATPase in this
      same membrane fraction. K+-ATPase activity was measured as [gamma-32P]ATP
      hydrolysis. The Na+-dependent K+-ATPase accounted for approximately 80% of
      overall K+-ATPase activity and was characterized by insensitivity to Sch-28080
      but partial sensitivity to ouabain. The Na+-independent K+-ATPase activity was
      insensitive to both Sch-28080 and ouabain. Both types of K+-ATPase activity
      substituted NH4+ for K+ in a similar manner. Furthermore, our results demonstrate
      that when incubated with native distal colon membranes, the blocking antibody
      inhibited dramatically Na+-dependent K+-ATPase activity. Therefore, these data
      demonstrate that HKalpha2 can function in native distal colon apical membranes as
      a Na+-dependent K+-ATPase. Elucidation of the role of the pump as a transporter
      of Na+ versus H+ or NH4+ versus K+ in vivo will require additional studies.

PMID- 10391910
TI  - Identification and characterization of a ran gene promoter in the protozoan
      pathogen Giardia lamblia.
AB  - The promoter elements that regulate transcription initiation in Giardia lamblia
      are poorly understood. In this report, the promoter of the Giardia ran gene was
      studied using a luciferase expression plasmid pRANluc+ to monitor transcription
      efficiency. An AT-rich sequence spanning -51/-20 relative to the translation
      start site of the ran gene was identified and was found to be required for
      efficient luciferase expression by deletion and mutation mapping of pRANluc+. The
      -51/-20 sequence was also sufficient for promoter activity as revealed from
      studies on a 32-base pair synthetic promoter derived from this region. Deletion
      mapping of the synthetic promoter revealed two minimal promoter elements, -51/-42
      and -30/-20, sufficient for 6- and 30-fold luciferase expression above
      background, respectively. The transcription start sites on luc+ messenger RNA
      were determined by the position of the synthetic promoter in the luciferase
      expression plasmids as shown by primer extension experiments. Results from
      electrophoretic mobility shift assays revealed multiple DNA-protein complexes
      upon binding of nuclear proteins with either DNA strand but not the double
      stranded DNA derived from the ran promoter. Our results delineate the first
      promoter sequence of the Giardia gene (ran), which provides an excellent model
      for future studies on transcription regulation in this protozoan parasite.

PMID- 10391911
TI  - Regulation of glycosphingolipid metabolism in liver during the acute phase
      response.
AB  - The host response to infection is associated with multiple alterations in lipid
      and lipoprotein metabolism. We have shown recently that endotoxin
      (lipopolysaccharide (LPS)) and cytokines enhance hepatic sphingolipid synthesis,
      increase the activity and mRNA levels of serine palmitoyltransferase, the first
      committed step in sphingolipid synthesis, and increase the content of
      sphingomyelin, ceramide, and glucosylceramide (GlcCer) in circulating
      lipoproteins in Syrian hamsters. Since the LPS-induced increase in GlcCer content
      of lipoproteins was far greater than that of ceramide or sphingomyelin, we have
      now examined the effect of LPS and cytokines on glycosphingolipid metabolism. LPS
      markedly increased the mRNA level of hepatic GlcCer synthase, the enzyme that
      catalyzes the first glycosylation step of glycosphingolipid synthesis. The LPS
      induced increase in GlcCer synthase mRNA levels was seen within 2 h, sustained
      for 8 h, and declined to base line by 24 h. LPS-induced increase in GlcCer
      synthase mRNA was partly accounted for by an increase in its transcription rate.
      LPS produced a 3-4-fold increase in hepatic GlcCer synthase activity and
      significantly increased the content of GlcCer (the immediate product of GlcCer
      synthase reaction) as well as ceramide trihexoside and ganglioside GM3 (products
      distal to the GlcCer synthase step) in the liver. Moreover, both tumor necrosis
      factor-alpha and interleukin-1beta, cytokines that mediate many of the metabolic
      effects of LPS, increased hepatic GlcCer synthase mRNA levels in vivo as well as
      in HepG2 cells in vitro, suggesting that these cytokines can directly stimulate
      glycosphingolipid metabolism. These results indicate that LPS and cytokines up
      regulate glycosphingolipid metabolism in vivo and in vitro. An increase in GlcCer
      synthase mRNA levels and activity leads to the increase in hepatic GlcCer content
      and may account for the increased GlcCer content in circulating lipoproteins
      during the acute phase response.

PMID- 10391912
TI  - In vivo characterization of a thioredoxin h target protein defines a new
      peroxiredoxin family.
AB  - Disruption of the two thioredoxin genes in yeast dramatically affects cell
      viability and growth. Expression of Arabidopsis thioredoxin AtTRX3 in the
      Saccharomyces thioredoxin Delta strain EMY63 restores a wild-type cell cycle, the
      ability to grow on methionine sulfoxide, and H2O2 tolerance. In order to isolate
      thioredoxin targets related to these phenotypes, we prepared a C35S (Escherichia
      coli numbering) thioredoxin mutant to stabilize the intermediate disulfide
      bridged complex and we added a polyhistidine N-terminal extension in order to
      purify the complex rapidly. Expression of this mutant thioredoxin in the wild
      type yeast induces a reduced tolerance to H2O2, but only limited change in the
      cell cycle and no change in methionine sulfoxide utilization. Expression in the
      Delta thioredoxin strain EMY63 allowed us to isolate a complex of the thioredoxin
      with YLR109, an abundant yeast protein related to PMP20, a peroxisomal protein of
      Candida. No function has so far been attributed to this protein or to the other
      numerous homologues described in plants, animals, fungi, and prokaryotes. On the
      basis of the complementation and of low similarity with peroxiredoxins, we
      produced YLR109 and one of its Arabidopsis homologues in E. coli to test their
      peroxiredoxins activity. We demonstrate that both recombinant proteins present a
      thioredoxin-dependent peroxidase activity in vitro. The possible functions of
      this new peroxiredoxin family are discussed.

PMID- 10391913
TI  - Mutational analysis of the PapB transcriptional regulator in Escherichia coli.
      Regions important for DNA binding and oligomerization.
AB  - PapB is a transcriptional regulator in the control of pap operon expression in
      Escherichia coli. There are PapB homologous proteins encoded by many fimbrial
      gene systems that are involved in the regulation of fimbriae-adhesin production,
      and previous studies suggested that PapB binds DNA through minor groove contact.
      Both deletion and alanine-scanning mutagenesis were used to identify functionally
      important regions of the PapB protein. Mutations altering Arg61 or Cys65 caused
      deficiency in DNA binding, indicating that these residues are critical for PapB
      binding to DNA. Alanine substitutions at positions 35-36, 53-56, and 74-76
      resulted in mutants that were impaired in oligomerization. All these amino acid
      residues are conserved among the PapB homologous proteins, suggesting their
      importance in the whole family of regulatory proteins. The transcriptional
      efficiency of all the mutants was clearly reduced as compared with that of wild
      type PapB. Taken together, we have localized regions in the PapB protein that are
      involved in DNA binding and oligomerization, and our results show that both
      functions are required for its activity as a transcriptional regulator.

PMID- 10391914
TI  - Activation of the phagocyte NADPH oxidase protein p47(phox). Phosphorylation
      controls SH3 domain-dependent binding to p22(phox).
AB  - Activation of phagocyte NADPH oxidase requires interaction between p47(phox) and
      p22(phox). p47(phox) in resting phagocytes does not bind p22(phox).
      Phosphorylation of serines in the p47(phox) C terminus enables binding to the
      p22(phox) C terminus by inducing a conformational change in p47(phox) that
      unmasks the SH3A domain. We report that an arginine/lysine-rich region in the
      p47(phox) C terminus binds the p47(phox) SH3 domains expressed in tandem (SH3AB)
      but does not bind the individual N-terminal SH3A and C-terminal SH3B domains.
      Peptides matching amino acids 301-320 and 314-335 of the p47(phox)
      arginine/lysine-rich region block the p47(phox) SH3AB/p22(phox) C-terminal and
      p47(phox) SH3AB/p47(phox) C-terminal binding and inhibit NADPH oxidase activity
      in vitro. Peptides with phosphoserines substituted for serines 310 and 328 do not
      block binding and are poor inhibitors of oxidase activity. Mutated full-length
      p47(phox) with aspartic acid substitutions to mimic the effects of
      phosphorylations at serines 310 and 328 bind the p22(phox) proline-rich region in
      contrast to wild-type p47(phox). We conclude that the p47(phox) SH3A domain
      binding site is blocked by an interaction between the p47(phox) SH3AB domains and
      the C-terminal arginine/lysine-rich region. Phosphorylation of serines in the
      p47(phox) C terminus disrupts this interaction leading to exposure of the SH3A
      domain, binding to p22(phox), and activation of the NADPH oxidase.

PMID- 10391915
TI  - Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy
      chain, an L-type amino acid transport activity with broad specificity for small
      and large zwitterionic amino acids.
AB  - We have identified a new human cDNA, L-amino acid transporter-2 (LAT-2), that
      induces a system L transport activity with 4F2hc (the heavy chain of the surface
      antigen 4F2, also named CD98) in oocytes. Human LAT-2 is the fourth member of the
      family of amino acid transporters that are subunits of 4F2hc. The amino acid
      transport activity induced by the co-expression of 4F2hc and LAT-2 was sodium
      independent and showed broad specificity for small and large zwitterionic amino
      acids, as well as bulky analogs (e.g. BCH (2-aminobicyclo-(2,2,1)-heptane-2
      carboxylic acid)). This transport activity was highly trans-stimulated,
      suggesting an exchanger mechanism of transport. Expression of tagged N-myc-LAT-2
      alone in oocytes did not induce amino acid transport, and the protein had an
      intracellular location. Co-expression of N-myc-LAT-2 and 4F2hc gave amino acid
      transport induction and expression of N-myc-LAT-2 at the plasma membrane of the
      oocytes. These data suggest that LAT-2 is an additional member of the family of
      4F2 light chain subunits, which associates with 4F2hc to express a system L
      transport activity with broad specificity for zwitterionic amino acids. Human LAT
      2 mRNA is expressed in kidney >>> placenta >> brain, liver > spleen, skeletal
      muscle, heart, small intestine, and lung. Human LAT-2 gene localizes at
      chromosome 14q11.2-13 (13 cR or approximately 286 kb from marker D14S1349). The
      high expression of LAT-2 mRNA in epithelial cells of proximal tubules, the
      basolateral location of 4F2hc in these cells, and the amino acid transport
      activity of LAT-2 suggest that this transporter contributes to the renal
      reabsorption of neutral amino acids in the basolateral domain of epithelial
      proximal tubule cells.

PMID- 10391916
TI  - Identification and functional characterization of a Na+-independent neutral amino
      acid transporter with broad substrate selectivity.
AB  - We have isolated a cDNA from rat small intestine that encodes a novel Na+
      independent neutral amino acid transporter with distinctive characteristics in
      substrate selectivity and transport property. The encoded protein, designated L
      type amino acid transporter-2 (LAT-2), shows amino acid sequence similarity to
      the system L Na+-independent neutral amino acid transporter LAT-1 (Kanai, Y.,
      Segawa, H., Miyamoto, K., Uchino, H., Takeda, E., and Endou, H. (1998) J. Biol.
      Chem. 273, 23629-23632) (50% identity) and the system y+L transporters y+LAT-1
      (47%) and KIAA0245/y+LAT-2 (45%) (Torrents, D., Estevez, R., Pineda, M.,
      Fernandez, E., Lloberas, J., Shi, Y.-B., Zorzano, A., and Palacin, M. (1998) J.
      Biol. Chem. 273, 32437-32445). LAT-2 is a nonglycosylated membrane protein. It
      requires 4F2 heavy chain, a type II membrane glycoprotein, for its functional
      expression in Xenopus oocytes. LAT-2-mediated transport is not dependent on Na+
      or Cl- and is inhibited by a system L-specific inhibitor, 2-aminobicyclo-(2,2,1)
      heptane-2-carboxylic acid (BCH), indicating that LAT-2 is a second isoform of the
      system L transporter. Compared with LAT-1, which prefers large neutral amino
      acids with branched or aromatic side chains, LAT-2 exhibits remarkably broad
      substrate selectivity. It transports all of the L-isomers of neutral alpha-amino
      acids. LAT-2 exhibits higher affinity (Km = 30-50 microM) to Tyr, Phe, Trp, Thr,
      Asn, Ile, Cys, Ser, Leu, Val, and Gln and relatively lower affinity (Km = 180-300
      microM) to His, Ala, Met, and Gly. In addition, LAT-2 mediates facilitated
      diffusion of substrate amino acids, as distinct from LAT-1, which mediates amino
      acid exchange. LAT-2-mediated transport is increased by lowering the pH level,
      with peak activity at pH 6.25, because of the decrease in the Km value without
      changing the Vmax value. Because of these functional properties and a high level
      of expression of LAT-2 in the small intestine, kidney, placenta, and brain, it is
      suggested that the heterodimeric complex of LAT-2 and 4F2 heavy chain is involved
      in the trans-cellular transport of neutral amino acids in epithelia and blood
      tissue barriers.

PMID- 10391917
TI  - Pleckstrin homology domains interact with filamentous actin.
AB  - A fraction of Bruton's tyrosine kinase (Btk) co-localizes with actin fibers upon
      stimulation of mast cells via the high affinity IgE receptor (FcepsilonRI). In
      this study, a molecular basis of the Btk co-localization with actin fibers is
      presented. Btk and other Tec family tyrosine kinases have a pleckstrin homology
      (PH) domain at their N termini. The PH domain is a short peptide module
      frequently found in signal-transducing proteins and cytoskeletal proteins.
      Filamentous actin (F-actin) is shown to be a novel ligand for a subset of PH
      domains, including that of Btk. The actin-binding site was mapped to a 10-residue
      region of the N-terminal region of Btk. Basic residues in this short stretch are
      demonstrated to be involved in actin binding. Isolated PH domains induced actin
      filament bundle formation. Consistent with these observations, Btk binds F-actin
      in vitro and in vivo. Wild-type Btk protein is in part translocated to the
      cytoskeleton upon FcepsilonRI cross-linking, whereas Btk containing a mutated PH
      domain is not. Phosphatidylinositol 3,4, 5-trisphosphate-mediated membrane
      translocation of Btk was enhanced in cytochalasin D-pretreated, FcepsilonRI
      stimulated mast cells. These data indicate that PH domain-mediated F-actin
      binding plays a role in Btk co-localization with actin filaments.

PMID- 10391918
TI  - Regulation of Ras.GTP loading and Ras-Raf association in neonatal rat ventricular
      myocytes by G protein-coupled receptor agonists and phorbol ester. Activation of
      the extracellular signal-regulated kinase cascade by phorbol ester is mediated by
      Ras.
AB  - The small G protein Ras has been implicated in hypertrophy of cardiac myocytes.
      We therefore examined the activation (GTP loading) of Ras by the following
      hypertrophic agonists: phorbol 12-myristate 13-acetate (PMA), endothelin-1 (ET
      1), and phenylephrine (PE). All three increased Ras.GTP loading by 10-15-fold
      (maximal in 1-2 min), as did bradykinin. Other G protein-coupled receptor
      agonists (e.g. angiotensin II, carbachol, isoproterenol) were less effective.
      Activation of Ras by PMA, ET-1, or PE was reduced by inhibition of protein kinase
      C (PKC), and that induced by ET-1 or PE was partly sensitive to pertussis toxin.
      8-(4-Chlorophenylthio)-cAMP (CPT-cAMP) did not inhibit Ras.GTP loading by PMA, ET
      1, or PE. The association of Ras with c-Raf protein was increased by PMA, ET-1,
      or PE, and this was inhibited by CPT-cAMP. However, only PMA and ET-1 increased
      Ras-associated mitogen-activated protein kinase kinase 1-activating activity, and
      this was decreased by PKC inhibition, pertussis toxin, and CPT-cAMP. PMA caused
      the rapid appearance of phosphorylated (activated) extracellular signal-regulated
      kinase in the nucleus, which was inhibited by a microinjected neutralizing anti
      Ras antibody. We conclude that PKC- and Gi-dependent mechanisms mediate the
      activation of Ras in myocytes and that Ras activation is required for stimulation
      of extracellular signal-regulated kinase by PMA.

PMID- 10391919
TI  - Cloning and characterization of a novel RING finger protein that interacts with
      class V myosins.
AB  - We have identified a novel protein (BERP) that is a specific partner for the tail
      domain of myosin V. Class V myosins are a family of molecular motors thought to
      interact via their unique C-terminal tails with specific proteins for the
      targeted transport of organelles. BERP is highly expressed in brain and contains
      an N-terminal RING finger, followed by a B-box zinc finger, a coiled-coil (RBCC
      domain), and a unique C-terminal beta-propeller domain. A yeast two-hybrid
      screening indicated that the C-terminal beta-propeller domain mediates binding to
      the tail of the class V myosin myr6 (myosin Vb). This interaction was confirmed
      by immunoprecipitation, which also demonstrated that BERP could associate with
      myosin Va, the product of the dilute gene. Like myosin Va, BERP is expressed in a
      punctate pattern in the cytoplasm as well as in the neurites and growth cones of
      PC12 cells. We also found that the RBCC domain of BERP is involved in protein
      dimerization. Stable expression of a mutant form of BERP lacking the myosin
      binding domain but containing the dimerization domain resulted in defective PC12
      cell spreading and prevented neurite outgrowth in response to nerve growth
      factor. Our studies present a novel interaction for the beta-propeller domain and
      provide evidence for a role for BERP in myosin V-mediated cargo transport.

PMID- 10391920
TI  - In vitro biosynthesis of iron-molybdenum cofactor and maturation of the nif
      encoded apodinitrogenase. Effect of substitution for NifH with site-specifically
      altered forms of NifH.
AB  - NifH has three different roles in the nitrogenase enzyme system. Apart from
      serving as the physiological electron donor to dinitrogenase, NifH is involved in
      iron-molybdenum cofactor (FeMo-co) biosynthesis and in maturation of the FeMo-co
      deficient form of apodinitrogenase to a FeMo-co-activable form (apodinitrogenase
      maturation). The exact roles of NifH in these processes are not well understood.
      In the present study, the features of NifH required for the aforementioned
      processes have been investigated by the use of site-specifically altered forms of
      the enzyme. The ability of six altered forms of NifH inactive in substrate
      reduction (K15R, D39N, D43N, L127Delta, D129E, and F135Y) to function in in vitro
      FeMo-co synthesis and apodinitrogenase maturation reactions was investigated. We
      report that the ability of NifH to bind and not hydrolyze MgATP is required for
      it to function in these processes. We also present evidence that the ability of
      NifH to function in these processes is not dictated by the properties known to be
      required for its function in electron transfer to dinitrogenase. Evidence toward
      the existence of separate, overlapping sites on NifH for each of its functions
      (substrate reduction, FeMo-co biosynthesis, and apodinitrogenase maturation) is
      presented.

PMID- 10391921
TI  - The N terminus of amphiphysin II mediates dimerization and plasma membrane
      targeting.
AB  - Amphiphysin I and II are nerve terminal-enriched proteins containing SH3 domains
      that interact with dynamin and synaptojanin. The amphiphysins may function in
      synaptic vesicle endocytosis by targeting synaptojanin and dynamin to emerging
      endocytic buds through SH3 domain-independent interactions with clathrin and AP2.
      We have recently identified and cloned several amphiphysin II splice variants
      that differentially incorporate clathrin-binding domains. To determine whether
      these domains function in membrane targeting, we used immunofluorescence to
      examine the potential localization of amphiphysin II variants to clathrin-coated
      pits on plasma membranes purified from transfected COS-7 cells. Full-length
      amphiphysin II targets to the plasma membrane where it partially co-localizes
      with clathrin. However, splice variants and deletion constructs lacking clathrin
      binding domains still target to the plasma membrane, and removal of clathrin from
      the membrane does not affect amphiphysin II distribution. Surprisingly, plasma
      membrane targeting was dependent on the presence of a 31-amino acid alternatively
      spliced sequence at the N terminus of amphiphysin II, a result confirmed using
      subcellular fractionation. In binding assays, the 31-amino acid sequence was also
      found to facilitate amphiphysin dimerization mediated through the N terminus.
      Taken together, these data support a role for the N terminus of amphiphysin II in
      membrane targeting during endocytosis.

PMID- 10391922
TI  - Oxidative stress inhibits apoptosis in human lymphoma cells.
AB  - Apoptosis and necrosis are two forms of cell death that are induced under
      different conditions and that differ in morphological and biochemical features.
      In this report, we show that, in the presence of oxidative stress, human B
      lymphoma cells are unable to undergo apoptosis and die instead by a form of
      necrosis. This was established using the chemotherapy drug VP-16 or the calcium
      ionophore A23187 to induce apoptosis in Burkitt's lymphoma cell lines and by
      measuring classical markers of apoptotic death, including cell morphology,
      annexin V binding, DNA ladder formation, and caspase activation. In the presence
      of relatively low levels of H2O2 (75-100 microM), VP-16 and A23187 were unable to
      induce apoptosis in these cells. Instead, the cells underwent non-apoptotic cell
      death with mild cytoplasmic swelling and nuclear shrinkage, similar to the death
      observed when they were treated with H2O2 alone. We found that H2O2 inhibits
      apoptosis by depleting the cells of ATP. The effects of H2O2 can be overcome by
      inhibitors of poly(ADP)-ribosylation, which also preserve cellular ATP levels,
      and can be mimicked by agents such as oligomycin, which inhibit ATP synthesis.
      The results show that oxidants can manipulate cell death pathways, diverting the
      cell away from apoptosis. The potential physiological ramifications of this
      finding will be discussed.

PMID- 10391923
TI  - The membrane association domain of RGS16 contains unique amphipathic features
      that are conserved in RGS4 and RGS5.
AB  - Regulators of G protein signaling (RGS proteins) modulate G protein-mediated
      signaling pathways by acting as GTPase-activating proteins for Gi, Gq, and G12
      alpha-subunits of heterotrimeric G proteins. Although it is known that membrane
      association is critical for the biological activities of many RGS proteins, the
      mechanism underlying this requirement remains unclear. We reported recently that
      the NH2 terminus of RGS16 is required for its function in vivo. In this study, we
      show that RGS16 lacking the NH2 terminus is no longer localized to the plasma
      membrane as is the wild type protein, suggesting that membrane association is
      important for biological function. The region of amino acids 7-32 is sufficient
      to confer the membrane-targeting activity, of which amino acids 12-30 are
      predicted to adopt an amphipathic alpha-helix. Site-directed mutagenesis
      experiments showed that the hydrophobic residues of the nonpolar face of the
      helix and the strips of positively charged side chains positioned along the
      polar/nonpolar interface of the helix are crucial for membrane association.
      Subcellular fractionation by differential centrifugation followed by conditions
      that distinguish peripheral membrane proteins from integral ones indicate that
      RGS16 is a peripheral membrane protein. We show further that RGS16 membrane
      association does not require palmitoylation. Our results, together with other
      recent findings, have defined a unique membrane association domain with
      amphipathic features. We believe that these structural features and the mechanism
      of membrane association of RGS16 are likely to apply to the homologous domains in
      RGS4 and RGS5.

PMID- 10391924
TI  - Cypher, a striated muscle-restricted PDZ and LIM domain-containing protein, binds
      to alpha-actinin-2 and protein kinase C.
AB  - We have cloned and characterized a novel striated muscle-restricted protein
      (Cypher) that has two mRNA splice variants, designated Cypher1 and Cypher2. Both
      proteins contain an amino-terminal PDZ domain. Cypher1, but not Cypher2, contains
      three carboxyl-terminal LIM domains and an amino acid repeat sequence that
      exhibits homology to a repeat sequence found in the largest subunit of RNA
      polymerase II. cypher1 and cypher2 mRNAs exhibited identical expression patterns.
      Both are exclusively expressed in cardiac and striated muscle in embryonic and
      adult stages. By biochemical assays, we have demonstrated that Cypher1 and
      Cypher2 bind to alpha-actinin-2 via their PDZ domains. This interaction has been
      further confirmed by immunohistochemical studies that demonstrated co
      localization of Cypher and alpha-actinin at the Z-lines of cardiac muscle. We
      have also found that Cypher1 binds to protein kinase C through its LIM domains.
      Phosphorylation of Cypher by protein kinase C has demonstrated the functional
      significance of this interaction. Together, our data suggest that Cypher1 may
      function as an adaptor in striated muscle to couple protein kinase C-mediated
      signaling, via its LIM domains, to the cytoskeleton (alpha-actinin-2) through its
      PDZ domain.

PMID- 10391926
TI  - A multinuclear NMR study of the active site of an endoglucanase from a strain of
      Bacillus. Use of Trp residues as structural probes.
AB  - In the hydrolytic reaction catalyzed by an endoglucanase from a Bacillus strain
      (endoglucanase K), 2 of 12 Trp residues, Trp174 and Trp243, are responsible for
      binding of the substrate and/or for the catalysis (Kawaminami, S., Ozaki, K.,
      Sumitomo, N., Hayashi, Y., Ito, S., Shimada, I., and Arata, Y. (1994) J. Biol.
      Chem. 269, 28752-28756). Here we report results of a stable isotope-aided NMR
      analysis of the active site of endoglucanase K, using Trp174 and Trp243 as
      structural probes. Hydrogen-deuterium exchange experiments performed for the NH
      protons of main and side chains of Trp residues revealed that Trp174 and Trp243
      are located in the hydrophilic and hydrophobic microenvironments in the active
      site, respectively. We also carried out pH titration experiments for indole C2
      proton resonances of Trp residues and measured the pH dependence of specific
      activities for wild-type endoglucanase K and its mutants in which Glu or Asp
      residues are replaced with their respective amide forms. On the basis of the
      results obtained from the present study, we conclude that (a) Glu130 and Asp191,
      which are in spatial proximity to Trp174 and Trp243 in the active site, play a
      crucial role in the enzymatic activity; (b) Glu130 and Asp191 interact with each
      other in the active site, leading to an increase in the pKa values to 5.5 for
      both amino acid residues; and (c) the pKa values of Glu130 and Asp191 would lead
      to an unusually narrow pH-activity profile of the endoglucanase K.

PMID- 10391925
TI  - Stimulation of a vascular smooth muscle cell NAD(P)H oxidase by thrombin.
      Evidence that p47(phox) may participate in forming this oxidase in vitro and in
      vivo.
AB  - Thrombin is a potent vascular smooth muscle cell (VSMC) mitogen. Because recent
      evidence implicates reactive oxygen intermediates (ROI) in VSMC proliferation in
      general and atherogenesis in particular, we investigated whether ROI generation
      is necessary for thrombin-induced mitogenesis. Treatment of human aortic smooth
      muscle cells with thrombin increased DNA synthesis, an effect that was
      antagonized by diphenyleneiodonium but not by other inhibitors of cellular
      oxidase systems. This effect of thrombin was accompanied by increased O-2 and
      H2O2 generation and NADH/NADPH consumption. ROI generation in response to
      thrombin pretreatment could also be blocked by diphenyleneiodonium, suggesting
      that the NAD(P)H oxidase was necessary for ROI generation and thrombin-induced
      mitogenesis. Because of observed differences between the VSMC and neutrophil
      oxidase, we examined whether the cytosolic components of the phagocytic NAD(P)H
      oxidase were present in VSMC. p47(phox) and Rac2 were present in VSMC.
      Furthermore, thrombin increased expression of p47(phox) and Rac2 and stimulated
      their translocation to the cell membrane. We examined whether p47(phox) might be
      similarly regulated in vivo in a rat aorta balloon injury model and found that
      p47(phox) protein was increased after injury. Immunocytochemistry localized
      expression of p47(phox) to the neointima and media of injured arteries. Our data
      demonstrate that generation of O-2 and H2O2 is required for thrombin-mediated
      mitogenesis in VSMC and that p47(phox) is regulated by thrombin in vitro and is
      associated with vascular lesion formation in vivo.

PMID- 10391927
TI  - Conformational changes in guanylyl cyclase-activating protein 1 (GCAP1) and its
      tryptophan mutants as a function of calcium concentration.
AB  - Guanylyl cyclase-activating proteins (GCAPs are 23-kDa Ca2+-binding proteins
      belonging to the calmodulin superfamily. Ca2+-free GCAPs are responsible for
      activation of photoreceptor guanylyl cyclase during light adaptation. In this
      study, we characterized GCAP1 mutants in which three endogenous nonessential Trp
      residues were replaced by Phe residues, eliminating intrinsic fluorescence.
      Subsequently, hydrophobic amino acids adjacent to each of the three functional
      Ca2+-binding loops were replaced by reporter Trp residues. Using fluorescence
      spectroscopy and biochemical assays, we found that binding of Ca2+ to GCAP1
      causes a major conformational change especially in the region around the EF3-hand
      motif. This transition of GCAP1 from an activator to an inhibitor of GC requires
      an activation energy Ea = 9.3 kcal/mol. When Tyr99 adjacent to the EF3-hand motif
      was replaced by Cys, a mutation linked to autosomal dominant cone dystrophy in
      humans, Cys99 is unable to stabilize the inactive GCAP1-Ca2+ complex. Stopped
      flow kinetic measurements indicated that GCAP1 rapidly loses its bound Ca2+ (k-1
      = 72 s-1 at 37 degrees C) and was estimated to associate with Ca2+ at a rate (k1
      > 2 x 10(8) M-1 s-1) close to the diffusion limit. Thus, GCAP1 displays
      thermodynamic and kinetic properties that are compatible with its involvement
      early in the phototransduction response.

PMID- 10391928
TI  - Id genes are direct targets of bone morphogenetic protein induction in embryonic
      stem cells.
AB  - Bone morphogenetic proteins (BMPs) are morphogenetic signaling molecules
      essential for embryonic patterning. To obtain molecular insight into the
      influence of BMPs on morphogenesis, we searched for new genes directly activated
      by BMP signaling. In vitro cultured mouse embryonic stem (ES) cells were used,
      cultivated in chemically defined growth medium (CDM). CDM-cultured ES cells
      responded very selectively to stimulation by various mesoderm inducers (BMP2/4,
      activin A, and basic fibroblast growth factor). BMP2/4 rapidly induced transcript
      levels of the homeobox genes Msx-1 and Msx-2 and the proto-oncogene JunB, whereas
      c-jun transcripts displayed delayed albeit prolonged increase. Using differential
      display cDNA cloning, six direct BMP target genes were identified. These include
      Id3, which showed strong mRNA induction, and the moderately induced Cyr61, DEK,
      and eIF4AII genes, as well as a gene encoding a GC-binding protein. Besides Id3,
      also the Id1 and Id2 genes were activated by BMP4 in both ES cells and a range of
      different cell lines. Id genes encode negative regulators of basic helix-loop
      helix transcription factors. In vivo we observed local ectopic expression of Id3
      and Msx-2 mRNAs in Ft/+ embryos at overlapping regions of ectopic Bmp4
      misexpression. We therefore propose that the Msx and Id genes are direct target
      genes of embryonic BMP4 signaling in vivo.

PMID- 10391930
TI  - Interplay of C1 and C2 domains of protein kinase C-alpha in its membrane binding
      and activation.
AB  - The regulatory domain of conventional protein kinase C (PKC) contains two
      membrane-targeting modules, the C2 domain that is responsible for Ca2+-dependent
      membrane binding of protein, and the C1 domain composed of two cysteine-rich zinc
      fingers (C1a and C1b) that bind diacylglycerols and phorbol esters. To understand
      the individual roles and the interplay of the C1 and C2 domains in the membrane
      binding and activation of PKC, we functionally expressed isolated C1 and C2
      domains of PKC-alpha and measured their vesicle binding and monolayer
      penetration. Results indicate that the C2 domain of PKC-alpha is responsible for
      the initial Ca2+- and phosphatidylserine-dependent electrostatic membrane binding
      of PKC-alpha, whereas the C1 domain is involved in subsequent membrane
      penetration and diacylglycerol binding, which eventually lead to enzyme
      activation. To determine the roles of individual zinc fingers in the C1 domain,
      we also mutated hydrophobic residues in the C1a (Trp58 and Phe60) and C1b (Tyr123
      and Leu125) domains of the native PKC-alpha molecule and measured the effects of
      mutations on vesicle binding, enzyme activity and monolayer penetration. Results
      show that the hydrophobic residues in the C1a domain are essential for the
      membrane penetration and activation of PKC-alpha, whereas those in the C1b domain
      are not directly involved in these processes. Based on these results in
      conjunction with our previous structure-function studies of the C2 domain
      (Medkova, M., and Cho, W. (1998) J. Biol. Chem. 273, 17544-17552), we propose a
      mechanism for the in vitro membrane binding and activation of conventional PKC
      that accounts for the temporal and spatial sequences of PKC activation.

PMID- 10391929
TI  - Regulation of angiotensin II-induced phosphorylation of STAT3 in vascular smooth
      muscle cells.
AB  - Ligand binding to the angiotensin II (Ang II) AT1 receptor on vascular smooth
      muscle cells (VSMCs) activates the Janus-activated kinase (JAK)/signal
      transducers and activators of transcription (STAT) pathway. We have shown
      previously that the JAK2 tyrosine kinase and the Src family p59 Fyn tyrosine
      kinase are required for Ang II-induced STAT1 tyrosine phosphorylation in VSMCs.
      The mitogen-activated protein kinase phosphatase, MKP-1, is required for STAT1
      tyrosine dephosphorylation. In the present study, using specific enzyme
      inhibitors and antisense oligonucleotides, we show that Ang II-induced tyrosine
      phosphorylation and nuclear translocation of STAT3 in VSMCs is mediated by p60 c
      Src, whereas tyrosine dephosphorylation is mediated by calcineurin. Calcineurin
      is activated in response to Ang II stimulation of VSMCs and is translocated to
      the nucleus. In addition, we show that Ang II-induced serine phosphorylation of
      STAT3 in VSMCs is mediated by mitogen-activated protein kinase and that
      dephosphorylation is mediated by protein phosphatase 2A (PP2A). PP2A translocates
      to the nucleus in response to Ang II stimulation of VSMCs and forms a complex
      with STAT3 in an Ang II-dependent manner.

PMID- 10391931
TI  - Architecture of the active DNA polymerase delta.proliferating cell nuclear
      antigen.template-primer complex.
AB  - The relative positions of components of the DNA-dependent DNA polymerase delta
      (pol delta).proliferating cell nuclear antigen (PCNA).DNA complex were studied.
      We have shown that pol delta incorporates nucleotides close to a template biotin
      streptavidin complex located 5' (downstream) to the replicating complex in the
      presence or absence of PCNA. PCNA-dependent synthesis catalyzed by pol delta was
      nearly totally (95%) inhibited by a biotin. streptavidin complex located at the
      3'-end of a template with a 15-mer primer (upstream of the replicating complex),
      but was only partially inhibited with a 19-mer primer. With either primer, PCNA
      independent synthesis was not affected by the biotin. streptavidin complex.
      Quantification of results with primers of varying length suggested that pol delta
      interacts with between 8 and 10 nucleotides of duplex DNA immediately proximal to
      the 3'-OH primer terminus. Using UV photocross-linking, we determined that the
      125-kDa subunit of pol delta, but not the 50-kDa subunit, interacted with a
      photosensitive residue of a substrate oligonucleotide. Interaction apparently
      takes place through the C terminus of p125. Based on these results, we conclude
      that PCNA is located "behind" pol delta in the polymerization complex during DNA
      synthesis and that only the large subunit of pol delta (two-subunit form)
      interacts directly with DNA. A detailed model of the enzymatically active complex
      is proposed.

PMID- 10391933
TI  - The catalog of human hair keratins. I. Expression of the nine type I members in
      the hair follicle.
AB  - The human type I hair keratin subfamily comprises nine individual members, which
      can be subdivided into three groups. Group A (hHa1, hHa3-I, hHa3-II, hHa4) and B
      (hHa7, hHa8) each contains structurally related hair keratins, whereas group C
      members hHa2, hHa5, and hHa6 represent structurally rather unrelated hair
      keratins. Antibodies produced against these individual hair keratins, first
      analyzed for specificity by one- dimensional Western blots of total hair
      keratins, were used to establish the two-dimensional catalog of the human type I
      hair keratin subfamily. The catalog comprises two different series of type I hair
      keratins: a strongly expressed, Coomassie-stainable series containing hair
      keratins hHa1, hHa3-I/II, hHa4, and hHa5, and a weakly expressed,
      immunodetectable series harboring hHa2, hHa6 hHa7, and hHa8. In situ
      hybridization and immunohistochemical expression studies on scalp follicles show
      that two hair keratins, hHa2 and hHa5, define the early stage of hair
      differentiation, i.e. hHa5 expression in hair matrix and hHa5/hHa2 coexpression
      in the early hair cuticle cells. Whereas cuticular differentiation proceeds
      without the expression of further type I hair keratins, matrix cells embark on
      the cortical pathway by sequentially expressing hHa1, hHa3-I/II, and hHa4, which
      are supplemented by hHa6 at an advanced stage of cortical differentiation, and
      hHa8, which is expressed heterogeneously in cortex cells. Thus, six type I hair
      keratins are involved in the terminal differentiation of anagen hairs. The
      expression of hHa7 is conspicuously different from that of the other hair
      keratins in that it does not occur in the large anagen follicles of terminal
      scalp hairs but only in central cortex cells of the rare and small follicle type
      that gives rise to vellus hairs.

PMID- 10391932
TI  - Topological localization of the carboxyl-terminal domain of RNA polymerase II in
      the initiation complex.
AB  - The carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II
      (RNAP II) functions at multiple stages of transcription and is involved in the
      coupling of transcription to pre-mRNA processing. We have used site-specific
      protein-DNA photocross-linking to determine the position of the CTD along
      promoter DNA in the transcriptional pre-initiation complex. Comparison of the
      promoter contacts made by RNAP II with or without the CTD indicate that the CTD
      approaches promoter DNA downstream of the transcriptional initiation site between
      positions +16 and +26. Incubation of pre-assembled initiation complexes with
      antibodies to the CTD prior to UV irradiation led to specific photocross-linking
      of the IgG heavy chain to nucleotide +17, indicating that the CTD is accessible
      for protein-protein interactions in a complex containing RNAP II and the general
      initiation factors. In conjunction with previously published observations, our
      structural data are fully compatible with the notion that DNA wrapping around
      RNAP II places the CTD and the RNA exit channel into juxtaposition and provide a
      rationale for contacts between the SRB-mediator complex and core RNAP II observed
      in the RNAP II holoenzyme.

PMID- 10391934
TI  - Residues in the alphaH and alphaI helices of the HIV-1 reverse transcriptase
      thumb subdomain required for the specificity of RNase H-catalyzed removal of the
      polypurine tract primer.
AB  - During retrovirus replication, reverse transcriptase (RT) must specifically
      interact with the polypurine tract (PPT) to generate and subsequently remove the
      RNA primer for plus-strand DNA synthesis. We have investigated the role that
      human immunodeficiency virus-1 RT residues in the alphaH and alphaI helices in
      the thumb subdomain play in specific RNase H cleavage at the 3'-end of the PPT;
      an in vitro assay modeling the primer removal step was used. Analysis of alanine
      scanning mutants revealed that a subgroup exhibits an unusual phenotype in which
      the PPT is cleaved up to seven bases from its 3'-end. Further analysis of alphaH
      mutants (G262A, K263A, N265A, and W266A) with changes in residues in or near a
      structural motif known as the minor groove binding track showed that the RNase H
      activity of these mutants is more dramatically affected with PPT substrates than
      with non-PPT substrates. Vertical scan mutants at position 266 were all defective
      in specific RNase H cleavage, consistent with conservation of tryptophan at this
      position among lentiviral RTs. Our results indicate that residues in the thumb
      subdomain and the minor groove binding track in particular, are crucial for
      unique interactions between RT and the PPT required for correct positioning and
      precise RNase H cleavage.

PMID- 10391935
TI  - Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin,
      a protein phosphatase-1-interacting protein.
AB  - Signaling through D2 class dopamine receptors is crucial to correct brain
      development and function, and dysfunction of this system is implicated in major
      neurological disorders such as Parkinson's disease and schizophrenia. To
      investigate potential novel mechanisms of D2 receptor regulation, the third
      cytoplasmic loop of the D2 dopamine receptor was used to screen a rat hippocampal
      yeast two-hybrid library. Spinophilin, a recently characterized F-actin and
      protein phosphatase-1-binding protein with a single PDZ domain was identified as
      a protein that specifically associates with this region of D2 receptors. A direct
      interaction between spinophilin and the D2 receptor was confirmed in vitro using
      recombinant fusion proteins. The portion of spinophilin responsible for
      interacting with the D2 third cytoplasmic loop was narrowed to a region that does
      not include the actin-binding domain, the PDZ domain, or the coiled-coil. This
      region is distinct from the site of interaction with protein phosphatase-1, and
      both D2 receptors and protein phosphatase-1 may bind spinophilin at the same
      time. The interaction is not mediated via the unique 29-amino acid insert in
      D2long; both D2long and D2short third cytoplasmic loops interact with spinophilin
      in vitro and in yeast two-hybrid assays. Expression of D2 receptors containing an
      extracellular hemagglutinin epitope in Madin-Darby canine kidney cells results in
      co-localization of receptor and endogenous spinophilin as determined by
      immunocytochemistry using antibodies directed against spinophilin and the HA tag.
      We hypothesize that spinophilin is important for establishing a signaling complex
      for dopaminergic neurotransmission through D2 receptors by linking receptors to
      downstream signaling molecules and the actin cytoskeleton.

PMID- 10391936
TI  - The myotonic dystrophy kinase-related Cdc42-binding kinase is involved in the
      regulation of neurite outgrowth in PC12 cells.
AB  - The myotonic dystrophy kinase-related Cdc42-binding kinase (MRCKalpha) has been
      implicated in the morphological activities of Cdc42 in nonneural cells. Both
      MRCKalpha and the kinase-related Rho-binding kinase (ROKalpha) are involved in
      nonmuscle myosin light-chain phosphorylation and associated actin cytoskeleton
      reorganization. We now show that in PC12 cells, overexpression of the kinase
      domain of MRCKalpha and ROKalpha resulted in retraction of neurites formed on
      nerve growth factor (NGF) treatment, as observed with RhoA. However, introduction
      of kinase-dead MRCKalpha did not result in NGF-independent neurite outgrowth as
      observed with dominant negative kinase-dead ROKalpha or the Rho inhibitor C3.
      Neurite outgrowth induced by NGF or kinase-dead ROKalpha was inhibited by
      dominant negative Cdc42(N17), Rac1(N17), and the Src homology 3 domain of c-Crk,
      indicating the participation of common downstream components. Neurite outgrowth
      induced by either agent was blocked by kinase-dead MRCKalpha lacking the p21
      binding domain or by a minimal C-terminal regulatory region consisting of the
      cysteine-rich domain/pleckstrin homology domain plus a region with homology to
      citron. The latter region alone was an effective blocker of NGF-induced
      outgrowth. These results suggest that although ROKalpha is involved in neurite
      retraction promoted by RhoA, the related MRCKalpha is conversely involved in
      neurite outgrowth promoted by Cdc42 and Rac.

PMID- 10391937
TI  - Involvement of group VI Ca2+-independent phospholipase A2 in protein kinase C
      dependent arachidonic acid liberation in zymosan-stimulated macrophage-like
      P388D1 cells.
AB  - We investigated the possible involvement of group VI Ca2+-independent
      phospholipase A2 (iPLA2) in arachidonic acid (AA) liberation in zymosan
      stimulated macrophage-like P388D1 cells. Zymosan-induced AA liberation was
      markedly inhibited by methyl arachidonoyl fluorophosphonate, a dual inhibitor of
      group IV cytosolic phospholipase A2 (cPLA2) and iPLA2. We found that a relatively
      specific iPLA2 inhibitor, bromoenol lactone, significantly decreased the zymosan
      induced AA liberation in parallel with the decrease in iPLA2 activity, without an
      effect on diacylglycerol formation. Consistent with this, attenuation of iPLA2
      activity by a group VI iPLA2 antisense oligonucleotide resulted in a decrease in
      zymosan-induced prostaglandin D2 generation. These findings suggest that zymosan
      induced AA liberation may be, at least in part, mediated by iPLA2. A protein
      kinase C (PKC) inhibitor diminished zymosan-induced AA liberation, while a PKC
      activator, phorbol 12-myristate 13-acetate (PMA), enhanced the liberation.
      Bromoenol lactone suppressed the PMA-enhanced AA liberation without any effect on
      PMA-induced PKC activation. Down-regulation of PKCalpha on prolonged exposure to
      PMA also decreased zymosan-induced AA liberation. Under these conditions, the
      remaining AA liberation was insensitive to bromoenol lactone. Furthermore, the
      PKC depletion suppressed increases in iPLA2 proteins and the activity in the
      membrane fraction of zymosan-stimulated cells. In contrast, the zymosan-induced
      increases in iPLA2 proteins and the activity in the fraction were facilitated by
      simultaneous addition of PMA. Although intracellular Ca2+ depletion prevented
      zymosan-induced AA liberation, the translocation of PKCalpha to membranes was
      also inhibited. Taken together, we propose that zymosan may stimulate iPLA2
      mediated AA liberation, probably through a PKC-dependent mechanism.

PMID- 10391938
TI  - Delta psi stimulates membrane translocation of the C-terminal part of a signal
      sequence.
AB  - For several proteins in Escherichia coli it has been shown that the protonmotive
      force (pmf) dependence of translocation can be varied with the signal sequence
      composition, suggesting an effect of the pmf on the signal sequence. To test this
      possibility, we analyzed the effect of the membrane potential on translocation of
      the signal sequence. For this purpose, a precursor peptide was used (SP+7),
      corresponding to the signal sequence of PhoE with the first seven amino acids of
      the mature part that can be processed by purified leader peptidase. Translocation
      was studied in pure lipid vesicles containing leader peptidase, with its active
      site inside the vesicles. In the presence of a positive inside Delta psi, the
      amount of processing of SP+7 was significantly higher than without a Delta psi,
      indicating that the translocation of the cleavage region is stimulated by Delta
      psi. Replacement of the helix-breaking glycine residue at position -10 in the
      signal sequence for a leucine abolished the effect of Delta psi on the
      translocation of the cleavage region. It is concluded that Delta psi directly
      acts on the wild type signal sequence by stimulating the translocation of its C
      terminus. We propose that Delta psi acts on the signal sequence by stretching it
      into a transmembrane orientation.

PMID- 10391939
TI  - Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth
      and activation of NF-kappaB require the cytoplasmic domain of the receptor but
      different downstream signaling pathways.
AB  - Receptor for advanced glycation end products (RAGE) mediates neurite outgrowth in
      vitro on amphoterin-coated substrates. Ligation of RAGE by two other ligands,
      advanced glycation end products or amyloid beta-peptide, is suggested to play a
      role in cell injury mechanisms involving cellular oxidant stress and activation
      of the transcription factor NF-kappaB. However, the RAGE signaling pathways in
      neurite outgrowth and cell injury are largely unknown. Here we show that
      transfection of RAGE to neuroblastoma cells induces extension of filopodia and
      neurites on amphoterin-coated substrates. Furthermore, ligation of RAGE in
      transfected cells enhances NF-kappaB-dependent transcription. Both the RAGE
      mediated neurite outgrowth and activation of NF-kappaB are blocked by deletion of
      the cytoplasmic domain of RAGE. Moreover, dominant negative Rac and Cdc42 but not
      dominant negative Ras inhibit the extension of neurites induced by RAGE
      amphoterin interaction. In contrast, the activation of NF-kappaB is inhibited by
      dominant negative Ras but not Rac or Cdc42. These data suggest that distinct
      signaling pathways are used by RAGE to induce neurite outgrowth and regulate gene
      expression through NF-kappaB.

PMID- 10391940
TI  - Mapping the pro-region of carboxypeptidase B by protein engineering. Cloning,
      overexpression, and mutagenesis of the porcine proenzyme.
AB  - The proteolytic processing of pancreatic procarboxypeptidase B to a mature and
      functional enzyme is much faster than that of procarboxypeptidase A1. This
      different behavior has been proposed to depend on specific conformational
      features at the region that connects the globular domain of the pro-segment to
      the enzyme and at the contacting surfaces on both moieties. A cDNA coding for
      porcine procarboxypeptidase B was cloned, sequenced, and expressed at high yield
      (250 mg/liter) in the methylotrophic yeast Pichia pastoris. To test the previous
      hypothesis, different mutants of the pro-segment at the putative tryptic targets
      in its connecting region and at some of the residues contacting the active enzyme
      were obtained. Moreover, the complete connecting region was replaced by the
      homologous sequence in procarboxypeptidase A1. The detailed study of the tryptic
      processing of the mutants shows that limited proteolysis of procarboxypeptidase B
      is a very specific process, as Arg-95 is the only residue accessible to tryptic
      attack in the proenzyme. A fast destabilization of the connecting region after
      the first tryptic cut allows subsequent proteolytic processing and the expression
      of carboxypeptidase B activity. Although all pancreatic procarboxypeptidases have
      a preformed active site, only the A forms show intrinsic activity. Mutational
      substitution of Asp-41 in the globular activation domain, located at the
      interface with the enzyme moiety, as well as removal of the adjacent 310 helix
      allow the appearance of residual activity in the mutated procarboxypeptidase B,
      indicating that the interaction of both structural elements with the enzyme
      moiety prevents the binding of substrates and promotes enzyme inhibition. In
      addition, the poor heterologous expression of such mutants indicates that the
      mutated region is important for the folding of the whole proenzyme.

PMID- 10391941
TI  - Disruption of coiled-coil domains in Fer protein-tyrosine kinase abolishes
      trimerization but not kinase activation.
AB  - The protein-tyrosine kinase Fer and the highly homologous proto-oncoprotein
      Fps/Fes are implicated in signaling from a variety of growth factor and cytokine
      receptors. Here we examine the molecular basis of Fer kinase activation with an
      emphasis on the role of oligomerization. We show that Fer forms trimers in vivo
      and that disruption of either the first or second coiled-coil domain abolishes
      oligomerization, suggesting a cooperative interaction between these two domains.
      Although Fps/Fes also forms homotypic oligomers, probably via homologous coiled
      coil domains, no heterotypic interactions were observed between Fer and Fps/Fes.
      Incorporation of catalytically inactive Fer peptides into the oligomeric complex
      caused only mild reduction of wild type Fer kinase activity, suggesting that
      kinase-inactive Fer would not behave as a potent dominant negative. Although
      oligomerization of Fer can potentiate autophosphorylation in trans at three major
      phosphorylation sites, these residues can likely also be phosphorylated in cis.
      In contrast, the testis-specific FerT isomer does not oligomerize and is able to
      autophosphorylate in cis at two of the same three residues autophosphorylated in
      Fer. These results suggest that although oligomerization potentiates
      autophosphorylation in trans, this is apparently not necessary for Fer
      activation.

PMID- 10391942
TI  - Angiotensin II negatively modulates L-type calcium channels through a pertussis
      toxin-sensitive G protein in adrenal glomerulosa cells.
AB  - In bovine adrenal glomerulosa cells, angiotensin II and extracellular K+
      stimulate aldosterone secretion in a calcium-dependent manner. In these cells,
      physiological concentrations of extracellular potassium activate both T-type (low
      threshold) and L-type (high threshold) voltage-operated calcium channels.
      Paradoxically, the cytosolic calcium response to 9 mM K+ is inhibited by
      angiotensin II. Because K+-induced calcium changes observed in the cytosol are
      almost exclusively due to L-type channel activity, we therefore studied the
      mechanisms of L-type channel regulation by angiotensin II. Using the patch-clamp
      method in its perforated patch configuration, we observed a marked inhibition (by
      63%) of L-type barium currents in response to angiotensin II. This effect of the
      hormone was completely prevented by losartan, a specific antagonist of the AT1
      receptor subtype. Moreover, this inhibition was strongly reduced when the cells
      were previously treated for 1 night with pertussis toxin. An effect of pertussis
      toxin was also observed on the modulation by angiotensin II of the K+ (9 mM)
      induced cytosolic calcium response in fura-2-loaded cells, as well as on the
      angiotensin II-induced aldosterone secretion, at both low (3 mM) and high (9 mM)
      K+ concentrations. Finally, the expression of both Go and Gi proteins in bovine
      glomerulosa cells was detected by immunoblotting. Altogether, these results
      strongly suggest that in bovine glomerulosa cells, a pertussis toxin-sensitive G
      protein is involved in the inhibition of L-type channel activity induced by
      angiotensin II.

PMID- 10391943
TI  - Molecular cloning and characterization of a novel dual specificity phosphatase,
      MKP-5.
AB  - A group of dual specificity protein phosphatases negatively regulates members of
      the mitogen-activated protein kinase (MAPK) superfamily, which consists of three
      major subfamilies, MAPK/extracellular signal-regulated kinase (ERK), stress
      activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), and p38. Nine
      members of this group of dual specificity phosphatases have previously been
      cloned. They show distinct substrate specificities for MAPKs, different tissue
      distribution and subcellular localization, and different modes of inducibility of
      their expression by extracellular stimuli. Here we have cloned and characterized
      a novel dual specificity phosphatase, which we have designated MKP-5. MKP-5 is a
      protein of 482 amino acids with a calculated molecular mass of 52.6 kDa and
      consists of 150 N-terminal amino acids of unknown function, two Cdc25 homology 2
      regions in the middle, and a C-terminal catalytic domain. MKP-5 binds to p38 and
      SAPK/JNK, but not to MAPK/ERK, and inactivates p38 and SAPK/JNK, but not
      MAPK/ERK. p38 is a preferred substrate. The subcellular localization of MKP-5 is
      unique; it is present evenly in both the cytoplasm and the nucleus. MKP-5 mRNA is
      widely expressed in various tissues and organs, and its expression in cultured
      cells is elevated by stress stimuli. These results suggest that MKP-5 is a novel
      type of dual specificity phosphatase specific for p38 and SAPK/JNK.

PMID- 10391944
TI  - Ig-hepta, a novel member of the G protein-coupled hepta-helical receptor (GPCR)
      family that has immunoglobulin-like repeats in a long N-terminal extracellular
      domain and defines a new subfamily of GPCRs.
AB  - A novel member of the G protein-coupled receptor (GPCR) family was cloned and
      characterized, which is unique, among the members, in its long extracellular
      domain comprising Ig-like repeats and in its high expression predominantly in the
      lung. The clone (Ig-Hepta) was first identified as a polymerase chain reaction
      product generated with primers designed to amplify secretin receptor family
      members including the parathyroid hormone-related peptide receptors. Analysis of
      the open reading frame of cDNAs isolated from a rat lung cDNA library indicated
      that Ig-Hepta is a protein of 1389 amino acid residues and has two Ig-like
      repeats in the N-terminal extracellular domain (exodomain) of 1053 amino acid
      residues and 7 transmembrane spans in the C-terminal region. Northern blot
      analysis revealed very high expression of its mRNA in the lung and low but
      detectable levels in the kidney and heart. The mRNA expression in the lung was
      found to be strongly induced postnatally. Biochemical analysis indicated that Ig
      Hepta is a highly glycosylated protein and exists as a disulfide-linked dimer.
      Immunohistochemistry on rat lung and kidney sections revealed dense localization
      of Ig-Hepta in alveolar walls and intercalated cells in the collecting duct,
      respectively, suggesting a role in the regulation of acid-base balance. Ig-Hepta
      defines a new subfamily of GPCRs.

PMID- 10391945
TI  - Differential IkappaB kinase activation and IkappaBalpha degradation by
      interleukin-1beta and tumor necrosis factor-alpha in human U937 monocytic cells.
      Evidence for additional regulatory steps in kappaB-dependent transcription.
AB  - The IkappaB kinases (IKKs) lie downstream of the NF-kappaB-inducing kinase (NIK)
      and activate NF-kappaB by phosphorylation of IkappaBalpha. This leads to
      IkappaBalpha degradation and release of NF-kappaB. In U937 monocytic cells,
      interleukin (IL)-1beta (1 ng/ml) and tumor necrosis factor (TNF)-alpha; 10 ng/ml)
      induced kappaB-dependent transcription equally. However, IKK activity was
      strongly induced by TNF-alpha but not by IL-1beta. This was consistent with
      IkappaBalpha phosphorylation and degradation, yet TNF-alpha-induced NF-kappaB DNA
      binding was only 30-40% greater than for IL-1beta. This was not explained by
      degradation of IkappaBbeta, IkappaBepsilon, or p105 nor nuclear translocation of
      NF-kappaB. IkappaBalpha complexes or degradation-independent release of NF
      kappaB. Dominant negative (NIK) repressed TNF-alpha and IL-1beta-induced kappaB
      dependent transcription by approximately 60% and approximately 35%, respectively.
      These data reveal an imprecise relationship between IKK activation, IkappaBalpha
      degradation, and NF-kappaB DNA binding, suggesting the existence of additional
      mechanisms that regulate NF-kappaB activation. Finally, the lack of correlation
      between DNA binding and transcriptional activation plus the fact that PP1 and
      genistein both inhibited kappaB-dependent transcription without affecting DNA
      binding activity demonstrate the existence of regulatory steps downstream of NF
      kappaB DNA binding. Therapeutically these data are important as inhibition of the
      NIK-IKK-IkappaBalpha cascade may not produce equivalent reductions in NF-kappaB
      dependent gene expression.

PMID- 10391946
TI  - Regulation of alphaA-crystallin gene expression. Lens specificity achieved
      through the differential placement of similar transcriptional control elements in
      mouse and chicken.
AB  - The lens-preferred mouse alphaA-crystallin gene contains a conserved stretch
      (proximal element 2, +24/+43) in its 5'-noncoding region that we have previously
      shown binds nuclear proteins of lens and non-lens cells. The 5'-half of this
      sequence (PE2A, +25/+32) has consensus binding sites for AP-1 and other
      transcription factors. We show here by deletion experiments that PE2A is
      important for activity of the mouse alphaA-crystallin promoter and mediates
      phorbol ester and c-Jun responsiveness of this promoter in transfected lens
      cells. In vitro protein binding studies suggest that AP-1 complexes are capable
      of binding to PE2A. Our findings suggest that PE2A plays a role in mouse alphaA
      crystallin gene expression through AP-1-mediated regulatory mechanisms. We
      propose that the mouse and chicken alphaA-crystallin genes are expressed with
      lens specificity using a similar assortment of transcription factors but with a
      different physical arrangement of their respective cis-elements within the
      promoter region. A fundamental role for AP-1 in lens-preferred expression of
      crystallin genes is consistent with the idea that a redox-sensitive mechanism is
      a selective force for recruiting lens crystallins.

PMID- 10391947
TI  - Importance of the carboxyl-terminal FTSL motif of membrane cofactor protein for
      basolateral sorting and endocytosis. Positive and negative modulation by signals
      inside and outside the cytoplasmic tail.
AB  - Membrane cofactor protein (MCP), a widely distributed complement regulatory
      protein, is expressed on the basolateral surface of polarized epithelial cells,
      and it is not endocytosed. The carboxyl-terminal tetrapeptide (FTSL) is required
      for polarized surface expression. The ability of this tetrapeptide to serve as an
      autonomous sorting signal has been analyzed by adding this sequence motif to the
      C terminus of an apical membrane protein, the influenza A virus hemagglutinin
      (HA). The recombinant protein HA-FTSL retained the apical localization of the
      parental HA protein. Substitution of the complete cytoplasmic tail of MCP for the
      cytoplasmic tail of HA resulted in the targeting of the chimeric protein (HA/MCP)
      to the basolateral surface suggesting that the carboxyl-terminal FTSL motif is a
      weak sorting signal that requires additional targeting information from the
      membrane-proximal part of the cytoplasmic tail of MCP for redirecting an apical
      protein to the basolateral membrane domain. In contrast to the native HA, the HA
      FTSL protein was subject to endocytosis. The basolateral HA/MCP was also found to
      be internalized and thus differed from the basolateral MCP. This result suggests
      that the carboxyl-terminal FTSL motif serves as an internalization signal and
      that in native MCP sorting information outside the cytoplasmic tail counteracts
      this endocytosis signal. Substitution of a tyrosine for the phenylalanine
      dramatically increased the internalization with most of the HA-YTSL protein being
      present intracellularly. Our results are consistent with the view that the
      interplay of multiple sorting signals and the modification of a well known
      targeting signal (YTSL) by amino acid exchange (FTSL) determine the constitutive
      expression of MCP on the basolateral surface of polarized epithelial cells.

PMID- 10391948
TI  - A cytoskeletal localizing domain in the cyclase-associated protein, CAP/Srv2p,
      regulates access to a distant SH3-binding site.
AB  - In the yeast, Saccharomyces cerevisiae, adenylyl cyclase consists of a 200-kDa
      catalytic subunit (CYR1) and a 70-kDa subunit (CAP/SRV2). CAP/Srv2p assists the
      small G protein Ras to activate adenylyl cyclase. CAP also regulates the
      cytoskeleton through an actin sequestering activity and is directed to cortical
      actin patches by a proline-rich SH3-binding site (P2). In this report we analyze
      the role of the actin cytoskeleton in Ras/cAMP signaling. Two alleles of CAP,
      L16P(Srv2) and R19T (SupC), first isolated in genetic screens for mutants that
      attenuate cAMP levels, reduced adenylyl cyclase binding, and cortical actin patch
      localization. A third mutation, L27F, also failed to localize but showed no loss
      of either cAMP signaling or adenylyl cyclase binding. However, all three N
      terminal mutations reduced CAP-CAP multimer formation and SH3 domain binding,
      although the SH3-binding site is about 350 amino acids away. Finally, disruption
      of the actin cytoskeleton with latrunculin-A did not affect the cAMP phenotypes
      of the hyperactive Ras2(Val19) allele. These data identify a novel region of CAP
      that controls access to the SH3-binding site and demonstrate that cytoskeletal
      localization of CAP or an intact cytoskeleton per se is not necessary for cAMP
      signaling.

PMID- 10391949
TI  - Gi proteins use a novel beta gamma- and Ras-independent pathway to activate
      extracellular signal-regulated kinase and mobilize AP-1 transcription factors in
      Jurkat T lymphocytes.
AB  - Receptors coupled to pertussis toxin (PTX)-sensitive Gi proteins regulate T
      lymphocyte cytokine secretion, proliferation, and chemotaxis, yet little is known
      about the molecular mechanisms of Gi protein signaling in mammalian lymphocytes.
      Using the Jurkat T lymphocyte cell line, we found that a stably expressed Gi
      protein-coupled receptor (the delta-opioid receptor (DOR1)) stimulates MEK-1 and
      extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) and
      transcriptional activity by an ERK target, Elk-1, via a mechanism requiring a PTX
      sensitive Gi protein. Levels of beta-adrenergic receptor kinase-1 C-terminal
      fragment that inhibited signaling by Gi protein beta gamma subunits in these
      cells had no effect on DOR1 stimulation of either MEK-1- or Elk-1-dependent
      transcription, indicating that this pathway is independent of beta gamma.
      Analysis of this betagamma-independent pathway indicates a role for a herbimycin
      A-sensitive tyrosine kinase. Unlike beta gamma-mediated pathways, the beta gamma
      independent pathway was insensitive to RasN17, inhibitors of phosphatidylinositol
      3-kinase (PI 3-kinase), and constitutive PI 3-kinase activity. The beta gamma
      independent pathway regulates downstream events, since blocking it abrogated both
      Elk-1-dependent transcription and mobilization of the mitogenic transcription
      factor, AP-1, in response to DOR1 signaling. These results characterize a novel,
      Ras- and PI 3kinase-independent pathway for ERK activation by Gi protein
      signaling that is distinct from ERK activation by beta gamma and may therefore be
      mediated by the alphai subunit.

PMID- 10391950
TI  - The mannose 6-phosphate/insulin-like growth factor-II receptor is a substrate of
      type V transforming growth factor-beta receptor.
AB  - The type V transforming growth factor beta (TGF-beta) receptor (TbetaR-V) is a
      ligand-stimulated acidotropic Ser-specific protein kinase that recognizes a motif
      of SXE/S(P)/D. This motif is present in the cytoplasmic domain of the mannose 6
      phosphate/insulin-like growth factor-II (Man-6-P/IGF-II) receptor. We have
      explored the possibility that the Man-6-P/IGF-II receptor is a substrate of
      TbetaR-V. Purified bovine Man-6-P/IGF-II receptor was phosphorylated by purified
      bovine TbetaR-V in the presence of [gamma-32P]ATP and MnCl2 with an apparent Km
      of 130 nM. TGF-beta stimulated the phosphorylation of the Man-6-P/IGF-II receptor
      at 0 degrees C in mouse L cells overexpressing the Man-6-P/IGF-II receptor and in
      wild-type mink lung epithelial (Mv1Lu cells) metabolically labeled with
      [32P]orthophosphate. The in vitro and in vivo phosphorylation of the Man-6-P/IGF
      II receptor occurred at the putative phosphorylation sites as revealed by
      phosphopeptide mapping and amino acid sequence analysis. TGF-beta stimulated Man
      6-P/IGF-II receptor-mediated uptake (approximately 2-fold after 12 h treatment)
      of exogenous beta-glucuronidase in Mv1Lu cells and type II TGF-beta receptor
      (TbetaR-II)-defective mutant cells (DR26 cells) but not in type I TGF-beta
      receptor (TbetaR-I)-defective mutant cells (R-1B cells) and human colorectal
      carcinoma cells (RII-37 cells) expressing TbetaR-I and TbetaR-II but lacking
      TbetaR-V. These results suggest the Man-6-P/IGF-II receptor serves as an in vitro
      and in vivo substrate of TbetaR-V and that both TbetaR-V and TbetaR-I may play a
      role in mediating the TGF-beta-stimulated uptake of exogenous beta-glucuronidase.

PMID- 10391951
TI  - Plant-exuded choline is used for rhizobial membrane lipid biosynthesis by
      phosphatidylcholine synthase.
AB  - Phosphatidylcholine is a major lipid of eukaryotic membranes, but found in only
      few prokaryotes. Enzymatic methylation of phosphatidylethanolamine by
      phospholipid N-methyltransferase was thought to be the only biosynthetic pathway
      to yield phosphatidylcholine in bacteria. However, mutants of the microsymbiotic
      soil bacterium Sinorhizobium (Rhizobium) meliloti, defective in phospholipid N
      methyltransferase, form phosphatidylcholine in wild type amounts when choline is
      provided in the growth medium. Here we describe a second bacterial pathway for
      phosphatidylcholine biosynthesis involving the novel enzymatic activity,
      phosphatidylcholine synthase, that forms phosphatidylcholine directly from
      choline and CDP-diacylglycerol in cell-free extracts of S. meliloti. We further
      demonstrate that roots of host plants of S. meliloti exude choline and that the
      amounts of exuded choline are sufficient to allow for maximal phosphatidylcholine
      biosynthesis in S. meliloti via the novel pathway.

PMID- 10391953
TI  - Characterization of DNA recognition by the human UV-damaged DNA-binding protein.
AB  - The UV-damaged DNA-binding (UV-DDB) protein is the major factor that binds DNA
      containing damage caused by UV radiation in mammalian cells. We have investigated
      the DNA recognition by this protein in vitro, using synthetic oligonucleotide
      duplexes and the protein purified from a HeLa cell extract. When a 32P-labeled 30
      mer duplex containing the (6-4) photoproduct at a single site was used as a
      probe, only a single complex was detected in an electrophoretic mobility shift
      assay. It was demonstrated by Western blotting that both of the subunits (p48 and
      p127) were present in this complex. Electrophoretic mobility shift assays using
      various duplexes showed that the UV-DDB protein formed a specific, high affinity
      complex with the duplex containing an abasic site analog, in addition to the (6
      4) photoproduct. By circular permutation analyses, these DNA duplexes were found
      to be bent at angles of 54 degrees and 57 degrees in the complexes with this
      protein. From the previously reported NMR studies and the fluorescence resonance
      energy transfer experiments in the present study, it can be concluded that the UV
      DDB protein binds DNA that can be bent easily at the above angle.

PMID- 10391952
TI  - Requirement for reactive oxygen species in serum-induced and platelet-derived
      growth factor-induced growth of airway smooth muscle.
AB  - Reactive oxygen species have been recently identified as important mediators of
      mitogenic signaling in a number of cell types. We therefore explored their role
      in mediating mitogenesis of airway smooth muscle. The antioxidants catalase, N
      acetylcysteine, and probucol significantly reduced proliferation in primary
      cultures of rat tracheal smooth muscle stimulated with fetal bovine serum or
      platelet-derived growth factor, without affecting cell viability or inducing
      apoptosis. N-Acetylcysteine also significantly reduced serum-stimulated elevation
      of c-Fos but did not prevent the normal mitogen-induced increase in c-fos mRNA.
      Fractionation of ribosomes by sucrose density centrifugation and subsequent dot
      blot Northern analysis revealed that antioxidants reduced incorporation of c-fos
      mRNA into the heaviest polyribosomes, suggesting redox regulation of c-fos mRNA
      translation. Serum treatment of monolayers produced a small but reproducibly
      significant rise in superoxide dismutase-inhibitable reduction of ferricytochrome
      c by myocyte monolayers. Serum-induced ferricytochrome c reduction, cellular
      proliferation, and c-Fos elevation were decreased by the flavoprotein-dependent
      enzyme inhibitor dipheyleneiodonium. Growth responses to fetal bovine serum and
      superoxide dismutase-inhibitable reduction of ferricytochrome c were not
      different between cultured tracheal myocytes from wild-type versus gp91 phagocyte
      oxidase null mice. These results suggest that mitogen stimulation of airway
      smooth muscle induces signal transduction of cell proliferation that is in part
      dependent on generation of partially reduced oxygen species, generated by an NADH
      or NADPH oxidoreductase that is different from the oxidase in phagocytic cells.

PMID- 10391954
TI  - Photocross-linking of an oriented DNA repair complex. Ku bound at a single DNA
      end.
AB  - Ku protein binds broken DNA ends, triggering a double-strand DNA break repair
      pathway. The spatial arrangement of the two Ku subunits in the initial Ku-DNA
      complex, when the Ku protein first approaches the broken DNA end, is not well
      defined. We have investigated the geometry of the complex using a novel set of
      photocross-linking probes that force Ku protein to be constrained in position and
      orientation, relative to a single free DNA end. Results suggest that this complex
      is roughly symmetric and that both Ku subunits make contact with an approximately
      equal area of the DNA. The complex has a strongly preferred orientation, with
      Ku70-DNA backbone contacts located proximal and Ku80-DNA backbone contacts
      located distal to the free end. Ku70 also contacts functional groups in the major
      groove proximal to the free end. Ku80 apparently does not make major groove
      contacts. Results are consistent with a model where the Ku70 and Ku80 subunits
      contact the major and minor grooves of DNA, respectively.

PMID- 10391955
TI  - Distribution of ARF6 between membrane and cytosol is regulated by its GTPase
      cycle.
AB  - The ADP-ribosylation factor (ARF) subfamily of small GTPases regulates
      intracellular transport. Although much is known about how ARF1 regulates
      transport in the secretory pathways, regulation of the endocytic pathways by ARF6
      remains less understood. In particular, whereas cycling of ARF1 between membrane
      and cytosol represents a major mechanism of regulating its function, this
      regulation has been questioned for ARF6. In this study, we found that ARF6 is
      distributed both on membranes and in the cytosol. Cytosolic ARF6 is recruited to
      membranes in a GTP-dependent manner that is fundamentally similar to ARF1.
      However, unlike ARF1, release of membrane-bound ARF6 to the cytosol requires
      hydrolysis of GTP that is sensitive to the level of magnesium. These findings
      suggest that the GTPase cycle of ARF6 also regulates its distribution between
      membrane and cytosol and that this form of regulation will also likely be
      important for the function of ARF6. Moreover, as ARF6 has little intrinsic
      ability to hydrolyze GTP, magnesium concentration most likely affects the release
      of membrane-bound ARF6 by altering the activity of its GTPase-activating protein.

PMID- 10391956
TI  - Helical periodicity of (PNA)2.(DNA) triplexes in strand displacement complexes.
AB  - To study the helical structure in a P-loop formed by an invasion of
      oligopyrimidine peptide nucleic acid (PNA) into DNA duplex, bent DNA fragments
      containing a homopurine.homopyrimidine sequence between two bent DNA loci were
      prepared. As the spacer DNA length between the two bent loci varied by 1 bp over
      one helical turn, the electrophoretic mobility, reflecting the overall extent of
      DNA bending, was modulated sinusoidally in non-denaturing 5% polyacrylamide gel.
      When the bent DNA fragments differing in the spacer DNA length were preincubated
      with an oligopyrimidine PNA, the gel mobilities were changed due to a P-loop
      formation. By analyzing the gel mobility data with variations of the P-loop size,
      average helical parameters at the P-loop structure were determined. (PNA)2. (DNA)
      triplex within a P-loop had the helical periodicities of 15. 6(0.2) bp per turn
      at 20 degrees C and 17.4(0.7) bp per turn at 10 degrees C. In addition, the
      results indicate that a helical unwinding by 57(7) degrees at 20 degrees C and
      37(13) degrees at 10 degrees C is present at the two junctions between a P-loop
      and its adjacent DNA duplex.

PMID- 10391957
TI  - [Diagnostic value of IgG antibody levels against 38 kDa mycobacterial antigen].
AB  - Tuberculosis diagnosis bases on clinical and radiological symptoms and
      identification of mycobacteria. Accuracy of both methods is limited. Therefore
      reliable serological test would have considerable advantage. The present study
      was aimed at evaluating IgG-mediated immune response against specific
      mycobacterial antigens 38 kDa in group of 200 patients and control subjects. Our
      material consisted of 104 tuberculosis patients, 25 with sarcoidosis, 24 with
      lung cancer, 13 with bacterial or fungal pulmonary infection, 8 with
      mycobacterial infections other than tuberculosis and 26 healthy persons. We used
      commercially available ELISA based kits (Pathozyme TB-complex). Specificity of
      100% and sensitivity of 49% was achieved. Sensitivity increased to 59% in chronic
      cases and to 52% in culture positive cases. Sensitivity decreased to only 14% in
      group of new culture negative cases. Measurement of IgG serum level against 38
      kDa can be helpful in tuberculosis diagnosis. As the test lacks falsely positive
      results it indicates its high positive predictive value.

PMID- 10391958
TI  - [Tuberculous lymphadenitis--diagnostic difficulties].
AB  - Three cases of tuberculous lymphadenitis hospitalized in Department of
      Parasitology and Neuroinfection are presented. In all patients tuberculin test
      was positive. In 2 patients minimal lesions in lungs were present. In non patient
      BK in sputum was found. In microscopic picture of enlarged lymph nodes non
      specific inflammation granulomatosis was found but microbiological examinations
      were not done. In all patients the results of smears of lymph nodes pus were
      negative. In 2 patients culture was positive. Persistent enlarged peripheral
      lymphatic nodes, especially with fistula should be suspected of tuberculous
      etiology. Material obtained from node's biopsy should be taken to microbiological
      and histological examination.

PMID- 10391959
TI  - [The influence of salmeterol and salbutamol on bronchial constriction in patients
      with bronchial asthma].
AB  - The aim of the study was to compare bronchodilatating effect of inhaled
      salmeterol, salbutamol and both drugs administered simultaneously. 14 subjects (7
      females, 7 men), aged 30-65 years (mean 49 yrs), suffering from moderate to
      severe asthma were examined. The improvement of FEV1 greater than 15% within 15
      minutes of inhaling 200 micrograms of salbutamol was demanded. The study was
      performed in randomized, double-blinded, placebo controlled design. Throughout
      the study, all patients kept a daily score of symptoms and treatment. Each day of
      the trial, FEV1 in 30, 60, 120, 180 and 240 minute was measured. The
      statistically significant increase of FEV1 was noted only in 30 minute after
      salbutamol and in 180 minute after inhaling of salmeterol in comparison to
      salbutamol alone. No significant advantage of adding salbutamol to the patients
      previously treated with salmeterol was observed.

PMID- 10391961
TI  - [The pattern of small cell lung carcinoma in autopsy (based on material of the
      Pathology Department, National Institute of Tuberculosis and Lung Diseases in
      Warsaw].
AB  - The aim of this study was to review autopsy findings in small cell lung carcinoma
      (SCLC) patients (pts)--in order to assess the distribution of the disease at the
      time of death and to analyse the pattern of SCLC in relation with different
      therapeutic modalities. The pattern of autopsy findings was assessed in 100 pts
      SCLC: 85 pts after treatment with chemotherapy, with or without chest and cranial
      irradiation; and 15 pts without any therapy. The primary tumours were present in
      59% pts (50 of 85), the residual tumour deposits were diagnosed in 32% (27 of 85)
      pts. The significant difference in the rate of locoregional disease was found
      between pts given chemotherapy and pts after combined therapy. The tumours
      occurred significantly more frequently in pts after chemotherapy, than in pts
      after chemotherapy with irradiation on the chest (75% and 41% respectively, p =
      0.03). The chest irradiation with chemotherapy caused less frequent occurrence of
      the residual tumours than chemotherapy alone (48% and 20%, respectively, p =
      0.026). The rate of brain metastases was significantly higher in pts given
      chemotherapy than in pts treated with chemotherapy and chest irradiation or
      chemotherapy and curative brain irradiation (90%, 67% and 36% of 50 cases,
      respectively). Distant metastases were distributed in the same pattern in both
      studied groups. The distribution of metastases was not dependent on the disease
      extent at the time of diagnosis.

PMID- 10391960
TI  - [Early and late results of surgical treatment for bronchial carcinoids].
AB  - The aim of the study was to evaluate the efficacy and safety of surgical
      treatment of the bronchial carcinoids. Between 1983 and 1996 52 patients (pts)
      with typical carcinoid were operated. The group consisted of 23 males and 29
      females aged from 20 to 68 years (mean 41.3 years). In the chest X-ray and CT
      scan round shadow were found in 21 (40.4%) cases, lung tissue atelectasis in 23
      (44.1%) cases. The bronchial tree was normal in fiberoptic bronchoscopy in 8
      cases. We performed 4 pneumonectomies, 3 wedge resection and 45 lobectomies
      (including 5 "sleeve" lobectomies). We haven't recorded any early post-op deaths.
      Only two pts (3.8%) developed post-op complications--cardiac arrhythmias. In two
      cases the surgical treatment was followed by radiotherapy for metastases in
      regional lymph nodes. The period of follow-up ranged from 3 to 166 months (mean
      62.2 months). During that time we noticed the recurrence of tumor in 2 pts
      (3.8%). One patient died from cardiac reason. The 5-year survival among patients
      operated in the period 1983-1992 was 91.2%. The 10-year survival in the group of
      pts operated on between 1983 and 1987 was 90%. CONCLUSION: The surgical treatment
      of bronchial carcinoid is method of choice, very efficient and safe.

PMID- 10391962
TI  - [Three week stay at a height of 3700-4200 m. causes mild pulmonary hypertension
      in healthy men].
AB  - High altitude hypoxia leads to development of hypoxic pulmonary hypertension. We
      studied 27 healthy caucasian subjects aged 24 to 59 years, mean 41.6 +/- 9 y,
      working on 4 week shifts at the Kumtor gold mines at the altitude of 3700-4200 m.
      Pulmonary circulation was studied twice by Echo-Doppler using Toshiba SSD-160.
      The first investigation was performed at the level of 730 m at the end of 4 week
      holiday spent in the lowland, the second investigation on the 23rd day at
      altitude. Pulmonary artery acceleration time decreased from 131 +/- 14 ms to 105
      +/- 14 ms (p < 0.001). Calculated pulmonary arterial mean pressure increased from
      15.1 +/- 2 to 25.4 +/- 8 mmHg (p < 0.001). Right ventricular preejection period
      increased from 93 +/- 14 to 102 +/- 19 ms (p < 0.05). Other echo variable did not
      change. We conclude that healthy subjects submitted to 3 week exposure to high
      altitude hypoxia (oxygen pressure in the inspired air 82-88 mmHg), developed mild
      pulmonary hypertension, regressing after recovery at the lowland.

PMID- 10391963
TI  - [Familial occurrence of tuberculosis--a report of vice cases in a seven-person
      family in a period of 14 years].
AB  - Tuberculosis in five persons among the seven family members is reported. The main
      reasons for occurrence of tuberculosis in the majority of the family members were
      alcoholism and non-compliance with doctor's recommendations, then resistance of
      tubercle bacilli to antituberculous drugs, due to the above mentioned reasons.
      Even chemoprophylaxis in two of the family members did not protect then from the
      disease.

PMID- 10391964
TI  - [Respiratory failure in mitochondrial myopathy treated with noninvasive
      mechanical ventilation].
AB  - Young man suffering from mitochondrial myopathy was admitted to our Institute due
      to severe hypercapnic respiratory failure. Noninvasive mechanical ventilation
      (NWM) during sleep using nasal mask was instituted with positive results. Diurnal
      blood gases breathing air also ameliorated suggesting improvement of respiratory
      muscles function.

PMID- 10391965
TI  - [Mountain sickness].

PMID- 10391966
TI  - [Telomerase and telomeres in lung neoplasms--biological and clinical
      significance].

PMID- 10391967
TI  - [The clinical features of patients with probable dementia with Lewy bodies-
      report of 4 cases].
AB  - Recently, McKeith et al. proposed criteria for the clinical diagnosis of dementia
      with Lewy bodies (DLB). In our study the clinical features of four patients with
      progressive dementia, visual hallucinations, delusions, and parkinsonism were
      compatible with those of DLB. To evaluate the neurological and psychiatric
      features, responses to medications, magnetic resonance imaging (MRI), and single
      photon emission computed tomography (SPECT) in patients with DLB, we compared the
      above DLB patients with age- and gender-matched Parkinson's disease patients
      showing no signs of dementia. Our DLB patients presented with mild tremor,
      moderate rigidity and akinesia, severe constitutional dysfunction and recurrent
      visual hallucinations and delusions. These psychiatric symptoms became worse by
      anticholinergic agents and dopamine agonists and were difficult to control using
      neuroleptic medications. MRI revealed atrophy of the cerebrum to be more
      accentuated in the parietal region. SPECT demonstrated hypoperfusion in the
      parietal and occipital lobes. These findings suggest that parietal lobe
      dysfunction is a feature of DLB. It may, therefore, be concluded from this study
      that brain MRI and SPECT are useful in the clinical diagnosis of DLB, and that
      great caution should be taken when prescribing longacting dopamine agonists and
      neuroleptics to such patients.

PMID- 10391968
TI  - [The significance of duplex ultrasonography examination in the acute
      cardioembolic stroke patients--with special attention to evaluation of internal
      carotid arteries].
AB  - The aim of this study is to clarify whether it is possible to diagnose occlusions
      of internal carotid arteries in the acute cardioembolic stroke patients by
      observing internal carotid arteries with duplex ultrasonography. Twenty-two
      consecutive patients underwent both duplex ultrasonography examination and
      cerebral angiography within 24 hours from the onset. Two cases who had no flow
      velocity and 8 cases who had systolic flow velocity but no anterograde diastolic
      flow velocity were all diagnosed as having internal carotid occlusions by
      cerebral angiography. Eleven of 22 cases who had anterograde diastolic flow
      velocity were diagnosed as having occlusions at distal side of M 1 portion or no
      occluded lesions. Besides, among 11 cases who were diagnosed as having occlusions
      of internal carotid arteries by cerebral angiography, five had end diastolic
      ratios (ED ratio) of common carotid arteries that were less than 4.0s. It is
      useful to evaluate the existence of anterograde diastolic flow velocity by duplex
      ultrasonography for the diagnosis of internal carotid occlusions in the acute
      cardioembolic stroke patients.

PMID- 10391969
TI  - [Prandial hypoxia in progressive muscular dystrophy].
AB  - Progressive muscular dystrophy patients often show progressive body weight loss
      in early adolescence. This severe body weight loss frequently causes superior
      mesenteric artery syndrome which may result in a fatal outcome. We performed
      prandial pulse oximetry and found 12 out of 35 Duchenne muscular dystrophy
      patients, 1 out of 2 Becker muscular dystrophy patients and 1 out of 3 Limb
      Girdle muscular dystrophy patients showed prandial hypoxia with tachycardia. The
      patients became tired and eating habits were easily interrupted resulting in
      progressive body weight loss. Nasal administration of 0.2L/min oxygen to 2
      Duchenne muscular dystrophy patients, and nasal intermittent positive pressure
      ventilation to 2 Duchenne muscular dystrophy patients, 1 Becker muscular
      dystrophy patient and 1 Limb-Girdle muscular dystrophy patient for 15-30 minutes
      before eating improved the prandial hypoxia and halted the progression of body
      weight loss. This prandial hypoxia is one of the earliest signs of respiratory
      failure in progressive muscular dystrophy.

PMID- 10391970
TI  - [A case of antiphospholipid antibody syndrome showing a neurological
      deterioration and infarct development over a month].
AB  - A 67-year-old man was admitted to our hospital because of a sudden onset of gait
      disturbance and behavioral abnormalities. On the admission, he had a moderate
      consciousness disturbance and right hemiparesis with left internal carotid artery
      occlusion. Eight days after the stroke, the patient further developed left
      hemiparesis in association with right internal carotid artery occlusion. Despite
      anticoagulation therapy and plasma volume loading, neurological symptoms
      deteriorated over a month, during which CT scan demonstrated a progressive
      expansion of infarct size. Laboratory tests revealed the presence of lupus
      anticoagulant. Antiphospholipid antibody syndrome may be associated with a
      progression of ischemic stroke.

PMID- 10391971
TI  - [A case of atypical Miller Fisher syndrome associated with antiphospholipid
      antibodies].
AB  - We report a 56-year-old man with external ophthalmoplegia and ataxic gait
      following a diarrhea, being diagnosed atypical Miller Fisher syndrome (FS). On
      admission, he had severe diplopia and bilateral external ophthalmoplegia were
      observed. The deep tendon reflexes were decreased on the right upper extremity.
      He could not walk straight and his tandem gait was impaired. Serum IgG
      anticardiolipin antibody (aCL) and APTT-lupus anticoagulant (LA) were found to be
      increased. The serum of the patient had low titer of anti-GQ 1 b and anti-GM 1
      antibodies. After the first immunoadsorption therapy, his ophthalmoplegia was
      improved moderately, but peripheral facial palsy appeared. He was treated with
      immunoadsorption again, then all neurologic symptoms improved and a follow-up
      study revealed normalized aCL and LA titers. There have been no previous reports
      of FS associated with antiphospholipid antibody. The low titer of serum anti-GQ1b
      and anti-GM 1 antibodies in this patient suggests that the antiphospholipid
      antibodies, such as aCL and LA, may be linked to the pathogenesis of FS.

PMID- 10391972
TI  - [A case of Hopkins syndrome with onset at puberty].
AB  - The patient was a 15-year-old man who developed weakness of left leg 6 days after
      an acute asthmatic attack. Neurological examination revealed severe muscle
      weakness and atrophy at L5-S1 level and mild muscle weakness and atrophy at L2-4
      level in the left leg. Deep tendon reflexes were normal in the upper limbs and
      slightly brisk in the lower limbs except for absence of Achilles tendon reflex on
      the left. His sensation was normal. Needle EMG revealed neurogenic changes in
      both the left (L2-S1) and right (L2-4) leg muscles. Motor nerve conduction study
      of the left tibial and peroneal nerves revealed a marked reduction of amplitude
      and mild reduction of MCV. F-wave was not evoked in either nerves. Sensory nerve
      conduction study of the left sural nerve was normal. The titers of anti-viral
      antibodies in the paired sera showed no significant changes in any viruses
      examined including echovirus, enterovirus, coxsackievirus and poliovirus type 1,
      2 and 3. The serum IgE was elevated (1,300 IU/ml) and mite antigen-specific IgE
      was strongly positive. Spinal cord MRI revealed no abnormality in either thoracic
      or lumbar spinal cord. This patient was diagnosed as a rare case of Hopkins
      syndrome with onset at puberty.

PMID- 10391973
TI  - [Crow-Fukase syndrome associated with Castleman disease showing hypertrophic
      cranial pachymeningitis and bilateral internal carotid artery occlusion].
AB  - A 51-year-old woman was diagnosed as Crow-Fukase syndrome on July 1997,
      presenting with lymph node swelling, polyneuropathy, hepatomegaly,
      hypothyroidism, renal dysfunction, edema and skin change. Lymph node swelling and
      polyneuropathy improved in some degree after chemotherapy. She was admitted to
      our hospital on march 6, 1998 because of consciousness disturbance, right
      hemiparesis and non-fluent aphasia after fever and hypotension. The next day of
      admission, consciousness disturbance, right hemiparesis and non-fluent aphasia
      disappeared. MR images of the brain revealed low intensity on a T1-weighted image
      and high intensity on a T2-weighted image in the left parietal lobe. Furthermore,
      MR images also revealed diffuse hypertrophic dura matter with enhancement by Gd
      DTPA, which made the diagnosis of chronic cranial pachymeningitis. The cerebral
      angiographies showed bilateral internal carotid artery occlusion. The
      cerebrospinal fluid showed normal cell count, total protein level of 82 mg/dl,
      and IgG level of 18 mg/dl. Since there has been very few case reports describing
      intimate relationship between Crow-Fukase syndrome and pachymeningitis, and
      between carotid occlusion and pachymeningitis, we speculated that the
      pachymeningitis might be associated with Crow-Fukase syndrome. Furthermore,
      pachymeningitis might be a cause of her bilateral carotid occlusion. The number
      of cases of Crow-Fukase syndrome associated with cerebrovascular disease was very
      rare. This is the first case which had bilateral internal carotid artery
      occlusion probably caused by chronic cranial pachymeningitis. Therefore, it is
      necessary to pay attention to cerebrovascular disease when the patient of Crow
      Fukase syndrome is associated with pachymeningitis.

PMID- 10391974
TI  - [A case of myotonic dystrophy showing proximal dominant muscle involvement but
      not myotonia].
AB  - A 45-year-old female had progressive difficulty in climbing stairs and standing
      from a chair for 10 years. She had binocular cataracts which were operated at the
      age of 42 years. On examination, she had marked muscle wasting in the proximal
      limbs, scapular and sternomastoid muscles. She presented as marked muscle
      weakness in the proximal portion of the lower extremities and moderate in the
      upper extremities and the legs. Deep tendon reflexes were absent in all limbs.
      There was no grip myotonia, or percussion myotonia of the thenar muscle and
      tongue. Myotonia was not elucidated even after the hands were exposed to cold
      water. Moreover, none of the examined muscles revealed insertion myotonic
      discharge on electromyography. Serum CK level was normal and IgG value decreased
      to 546 mg/dl. Muscle biopsy of the left biceps muscle showed the variation in
      fiber size, increased central nuclei and many fiber with pyknotic nuclear clumps
      on HE staining. Sarcoplasmic mass and ring fibers were also found on HE staining.
      There were a few percents of ragged-red fibers on Gomori-trichrome staining, and
      type 1 fiber atrophy was found on pH 4.5 ATP-ase staining. The expansion of
      lymphocyte CTG trinucleotide repeats in the myotonin protein kinase gene was
      about 733, so that she was diagnosed as having myotonic dystrophy (MD). MRI of
      skeletal muscles exhibited marked atrophy especially in the femoral region and
      the biceps muscle. This patient had the proximal dominant muscle weakness, and
      absent myotonia even on electromyographic examination, which are unusual clinical
      features of adult onset MD.

PMID- 10391975
TI  - [Subacute necrotizing lymphadenitis associated with mononeuritis multiplex. A
      case report].
AB  - A 20-year-old man noticed lymph node swelling in his neck in May 1997. He was
      admitted to our hospital on July 30 because of numbness and weakness in the right
      hand and bilateral lower extremities. Neurological examinations revealed that the
      patient had right ulnar and bilateral deep peroneal nerve palsies. Nerve
      conduction study showed severe axonopathy in these nerves. The sural nerve biopsy
      demonstrated axonal degeneration and thickening of the small arterial wall. There
      was no significant increase of virus titer in the serum, such as EB virus, nor
      human herpesvirus 6. CSF examination was normal. During the course of this
      disorder, he acutely developed severe pain in his right testis. Pathological
      finding of the testis showed necrosis with vasculitis in the small arteries.
      Treatment with corticosteroid was effective. Usually subacute necrotizing
      lymphadenitis has been thought to be a benign disease. Only a few neurological
      complications, such as aseptic meningitis and cerebellar ataxia have been
      reported. Mononeuritis multiplex associated with subacute necrotizing
      lymphadenitis has not been reported. We speculated that the present case
      initially had some viral infection, and its reaction of the host produced
      subacute necrotizing lymphadenitis and mononeuritis multiplex.

PMID- 10391976
TI  - [Diffusion images on brain MRI in Creutzfeldt-Jakob disease].
AB  - We report a 72-year-old man with Creutzfeldt-Jakob disease. He showed a
      progressive dementia, myoclonus, and other neurological symptoms. DNA analysis
      showed a normal variation of prion gene (codon 129, Met/Met: codon 219, Glu/Glu).
      He had periodic synchronous discharge on electroencephalogram and brain atrophy
      on CT scan and MRI. Diffusion images on his brain MRI revealed a marked increase
      in signal intensity in the caudate nuclei, putamen, and cerebral cortices. These
      changes may represent spongy changes of the brain and seem to be a feature of
      brain MRI in Creutzfeldt-Jakob disease.

PMID- 10391977
TI  - [Two cases with chronic inflammatory demyelinating polyneuropathy showing high
      signal and enlargement of the brachial plexus in short TI inversion recovery of
      MRI].
AB  - We reported valuable MRI findings of the brachial plexus seen in two cases with
      chronic inflammatory demyelinating polyneuropathy (CIDP). Case 1 was a 44-year
      old man who developed slowly progressive weakness and atrophy of the extremities
      with no sensory disturbances. Studies of CSF showed a normal level of protein and
      no increase of cell counts but nerve conduction studies demonstrated a
      significant conduction block between the axilla and the elbow in the right ulnar
      nerve. Case 2 was a 34-year-old male who had been suffering from distal limb
      weakness and sensory disturbance. Protein content in CSF was markedly elevated
      without pleocytosis, and nerve conduction studies revealed a conduction block
      between the elbow and the wrist in the right ulnar nerve. He received
      corticosteroid therapy, resulting in a good recovery. Brachial plexus in both
      cases showed enlargement with marked high signal on short TI inversion recovery
      (STIR) of MRI. STIR is a fat suppressed T2 weighted image and this technique is
      known to be useful to identify the morphology of peripheral nerve tissues. CIDP
      is one form of hypertrophic neuritis and the MRI findings seen in these two cases
      strongly support the diagnosis of CIDP.

PMID- 10391978
TI  - [A case of Ramsay Hunt syndrome associated with local meningitis, multiple
      cranial neuropathy, and the second cervical nerve involvement].
AB  - A 76-year-old man with herpetic vesicle in the right auricle developed
      ipsilateral 5th, 6th, 7th, and 8th cranial nerves involvement and pain in the
      dermatome of the second cervical nerve. The CSF study revealed elevated opening
      pressure up to 220 mmH2O, and pleocytosis up to 151 cells/mm3. Ninety-nine
      percent of the CSF cells were mononuclear cells. CSF protein was 47 mg/dl, and
      CSF glucose was 62 mg/dl. On the 24th hospital day the CSF cells decreased to
      13/mm3 with 100% mononuclear cells. Titer of varicella-zoster virus (VZV)
      antibody was significantly elevated in CSF. Brain MRI and ABR demonstrated no
      abnormality. Although disorders of 5th and 6th cranial nerves and second cervical
      nerve improved, mild facial nerve palsy lasted and hearing disturbance showed no
      recovery. There are only seven cases of Ramsay Hunt syndrome associated with
      external ophthalmoplegia in the literature. However, un like the present case,
      none of these cases presented disorders of upper cervical nerves. In this case,
      we speculate that spreading of reactivated VZV caused local meningitis and
      multiple cranial nerve involvement as well as the second cervical nerve.

PMID- 10391979
TI  - [A case of adult neuronal ceroid lipofuscinosis type A].
AB  - A 20-year-old Japanese woman was diagnosed as suffering from adult type A
      neuronal ceroid lipofuscinosis (NCL) by rectal biopsy in the first year of
      manifestation. Her sister was in good health, and her parents were non
      consanguineous. She had graduated from a public high school and then went to a
      typist school, when she developed action myoclonus and dystonia. On admission,
      she was of short stature and her clinical features included high arched palate,
      cataracta, and accentuated deep tendon reflexes. Her IQ was 50. Visual failure
      was not observed. Brain MRI showed no abnormalities. Together with myoclonus and
      the abnormalities in EEG which included poly spike and wave complex, progressive
      myoclonus epilepsy was considered as differential diagnoses. Ultrastructurally,
      lipopigments of granular matrix and curvilinear profile were found in Schwann
      cells in rectal biopsy. Adult NCL, known as Kufs' disease, is classified into two
      clinical types; progressive myoclonus epilepsy (type A) and dementia with motor
      disturbance (type B). Adult NCL is very rare in Japan, and this is the first
      report of adult NCL type A in Japan.

PMID- 10391980
TI  - [A case of multiple sclerosis with abnormal single photon emission computed
      tomography (SPECT)].
AB  - A case of a 38-year-old woman with multiple sclerosis (MS) is reported. At 36
      years of the age, she was admitted to our hospital because of developing unstable
      gait and clumsiness in her hands. After intravenous and oral administration of
      steroid, her neurological symptoms improved gradually. At 38 years of the age,
      she was readmitted because of recurrence. A neurological examination revealed
      severe left sided limb ataxia and trunkal ataxia. No abnormal finding was
      demonstrated in cranial MRI at the first and second admission. Single photon
      emission computed tomography (SPECT) using 123I-IMP that was performed at the
      second admission showed an increased accumulation of 123I-IMP in the left
      cerebellar hemisphere on the 14th day from the neurological onset. After the
      therapy of steroid, her neurological signs improved and SPECT showed no
      abnormality on the 62nd day. Seven months after the second episode, she was
      readmitted because of the same neurological symptoms and T2 weighted MRI revealed
      multiple high intensity area in the pons and midbrain. She was diagnosed as
      having definite MS. These findings in SPECT may suggest the inflammatory process
      of the cerebellum in the case of MS as well as acute cerebellar ataxia.

PMID- 10391981
TI  - [Neuroimaging findings of hemiconvulsions, hemiplegia, epilepsy (HHE) syndrome].
AB  - A 32-year-old man with hemiconvulsions, hemiplegia, epilepsy (HHE) syndrome is
      described. He was well developed with a normal pregnancy and delivery, but at age
      10 months, he had status epilepticus during a febrile illness. Thereafter, he was
      noted to have left hemiparesis and mental retardation with recurrent
      hemiconvulsions. Magnetic resonance (MR) images showed atrophy and degeneration
      of the right cerebral cortex and white matter, homolateral thalamus, caudate
      nucleus, and hippocampus, with hyperintensities in both T2-weighted (TR/2200,
      TE/90) and proton (TR/2200, TE/30) images. There were also slight bilateral
      cerebellar atrophies. Quantitative single photon emission computed tomographic
      (SPECT) images using technetium-99m-ethyl cysteinate dimer (99mTc-ECD) revealed
      markedly reduced cerebral blood flow (CBF) in the right cerebral hemisphere,
      homolateral thalamus, caudate nucleus and bilateral cerebellum. Bilateral putamen
      and the medial occipital lobe showed normal findings on MR images and normal
      regional CBF in SPECT images. We suppose these selective neuronal injures in this
      case of HHE syndrome will be mainly due to histotoxic factors in epileptic brain
      damage.

PMID- 10391982
TI  - [Functional analysis of non-HLA genes within MHC region with knockout-mouse
      technology].

PMID- 10391983
TI  - [Peroxiredoxin--a novel antioxidant system in vivo].

PMID- 10391984
TI  - [How the membrane gangliosides modulate T cell activation?].

PMID- 10391985
TI  - [Reversible phosphorylation of catalytic subunit of monovalent cation
      transporting ATPases by protein kinases and phosphatases].

PMID- 10391986
TI  - [Cofilin phosphorylation and regulation of actin cytoskeletal reorganization by
      LIM-kinase].

PMID- 10391987
TI  - [Fibrinolysis and liver regeneration].

PMID- 10391988
TI  - [Neutrophil adherence-inhibiting factor, AIF, is released from lysosomes of
      activated platelets].

PMID- 10391990
TI  - The alpha 1,3-galactosyltransferase gene.

PMID- 10391989
TI  - Evolution of alpha 1,3galactosyltransferase and of the alpha-Gal epitope.

PMID- 10391991
TI  - Structure function studies of a New World monkey alpha 1,3galactosyltransferase.
      Analysis of alternative splicing and expression in baculovirus system.

PMID- 10391992
TI  - The natural anti-Gal antibody.

PMID- 10391994
TI  - The Griffonia simplicifolia I-B4 isolectin. A probe for alpha-D-galactosyl end
      groups.

PMID- 10391993
TI  - alpha-Gal epitopes in animal tissue glycoproteins and glycolipids.
AB  - alpha-Gal terminated saccharides are present on the cell surface both as
      glycolipids and glycoproteins in all mammals except Old World monkeys and humans.
      The structural diversity among identified saccharides terminated by this epitope
      in animal tissues is steadily increasing. The majority of these saccharides have
      the alpha-Gal linked to lactosamine but other core saccharides exist. The alpha
      Gal terminated saccharides are recognized by the immune system as a specific
      antigen and antibodies directed to the alpha-Gal, which do not cross-react with
      the classic blood group B trisaccharide, are found in man and Old World monkeys.
      Similar to other complex carbohydrate cell surface antigens, the alpha-Gal
      epitope is heterogeneously distributed in different organs and in different cells
      within an organ. It is present on the vascular endothelium and it is the primary
      target for human naturally occurring antibodies following pig to primate/man
      xenotransplantation leading to hyperacute rejection of the graft. Important for
      the future will be to further structurally characterize this antigen system, its
      cellular/subcellular distribution, and to identify possible of additional
      glycosyltransferases, related to the already described alpha
      1,3galactosyltransferase that may explain the structural diversity. Such
      information will be of importance in the studies of, for example, the
      pathogenesis of autoimmune diseases and for the production of genetically
      modified pigs to prevent xenograft rejection.

PMID- 10391995
TI  - alpha-Gal epitopes on viral glycoproteins.

PMID- 10391996
TI  - alpha-Galactosyl-bearing epitopes as potent immunogens in Chagas' disease and
      leishmaniasis.

PMID- 10391997
TI  - Enterotoxin A of Clostridium difficile and alpha-Gal epitopes.

PMID- 10391999
TI  - Generation of alpha 1,3galactosyltransferase deficient mice.

PMID- 10391998
TI  - Anti-Gal, alpha-Gal epitopes, and xenotransplantation.

PMID- 10392000
TI  - Anti-xenograft immune responses in alpha 1,3-galactosyltransferase knock-out
      mice.
AB  - Although originally generated to test the effect of eliminating the alpha-Gal
      epitope on HAR, it is becoming increasingly clear that GalT KO mice offer a
      convenient and inexpensive model to investigate many aspects of the anti
      xenorgraft immune response. Clearly, not all aspects of anti-xenograft rejection
      responses are identical in mice and primates, which should be kept in mind when
      interpreting results of GalT KO mouse studies. However, with this and other mouse
      models it is possible to test a large number of variables, which is impractical
      for both logistical and financial reasons with primates. Furthermore the short
      gestation time and large litter size of mice means that genetic strategies
      targeting different aspects of the anti-xenograft immune response can be combined
      and subsequently tested to identify the optimal combination of genetic and
      therapeutic approaches to achieve long term xenograft survival. In this regard
      the GalT KO mouse has been and will continue to be a valuable small animal model
      for the study of all facets of xenograft rejection involving anti-Gal antibodies.

PMID- 10392001
TI  - Modulation of alpha gal epitope expression on porcine cells.

PMID- 10392002
TI  - Graves' disease as a model for anti-Gal involvement in autoimmune diseases.

PMID- 10392003
TI  - Enhancement of autologous tumor vaccine immunogenicity by anti-Gal.

PMID- 10392004
TI  - The cover was nice.

PMID- 10392005
TI  - Team approach is best.

PMID- 10392006
TI  - An era of insurgency in medicine.

PMID- 10392007
TI  - Med Bytes.

PMID- 10392008
TI  - Forum on ethics. Group practice, medical records, and the patients.

PMID- 10392009
TI  - Standing on shaky ground.

PMID- 10392010
TI  - Cyberspace medicine.

PMID- 10392011
TI  - Under one roof.

PMID- 10392012
TI  - Escape from a PPMC.

PMID- 10392013
TI  - Focusing on the border.

PMID- 10392014
TI  - Recognizing the early stages of dementia.
AB  - Dementia is the most common psychiatric problem seen in the elderly, a steadily
      growing patient group. Cognitive impairment may be difficult to recognize,
      particularly in early phases, being mistaken for depression, hypochondriasis, or
      other conditions. Early, correct diagnosis of dementia reduces cases of
      inappropriate treatment and polypharmacy, and increases likelihood of improving
      quality of life.

PMID- 10392015
TI  - Pulmonary embolism mimicking acute myocardial infarction.
AB  - Pulmonary embolism is a major cause of death in the United States. A high index
      of suspicion is required to achieve an accurate diagnosis. We report a case of a
      patient with syncope, ischemic electrocardiographic changes, and an elevated
      troponin I level, presenting just like acute myocardial infarction. The case
      highlights the value of an early use of 2-dimensional echocardiography in
      obtaining an accurate diagnosis, thus avoiding unnecessary and inappropriate
      treatment.

PMID- 10392016
TI  - [Bone marrow allograft. Part 1: principles--modalities and indications].

PMID- 10392017
TI  - [Radioactive iodine therapy in thyrotoxicoses].

PMID- 10392018
TI  - [Treatment of febrile convulsions].

PMID- 10392019
TI  - [Upper gastrointestinal hemorrhages in children: 166 cases].

PMID- 10392020
TI  - [Coronary transluminal angioplasty factors predictive of restenosis].

PMID- 10392021
TI  - [Hospital morbidity in the elderly in the Monastir health region (Tunisia)].

PMID- 10392022
TI  - [Autopsy and microscopic study of lungs in newborns with respiratory distress: 33
      cases].

PMID- 10392023
TI  - [Dermatomyositis in children: study of seven cases].

PMID- 10392025
TI  - [Placental chorioangioma: three cases].

PMID- 10392024
TI  - [Factors related to pathologies in the early neonatal period at the University
      Hospital Center of Lome (Togo)].

PMID- 10392026
TI  - Skin metastases of urothelial carcinoma of the bladder: a case report.

PMID- 10392027
TI  - [Compressive vertebral angiomas: a case report].

PMID- 10392028
TI  - [Case report of primary lymphoma].

PMID- 10392029
TI  - [Congenital cysts and fistulas of the face and neck: often unrecognized
      dysembryoplasias].

PMID- 10392030
TI  - [Prevalence of nosocomial infections in the Charles Nicolle Hospital of Tunis].

PMID- 10392031
TI  - [Systemic candidiasis in intensive care: incidence?].

PMID- 10392032
TI  - [Epidemiology of hepatitis C virus infection and circulating genotypes in the
      Sfax region--Tunisia].

PMID- 10392033
TI  - [Nutritional intakes in a group of infants aged six to fourteen months].

PMID- 10392034
TI  - [Tuberculosis in children at the Tokoin University Medical Center of Lome, Togo.
      202 cases in the pediatric service (1980-1990)].

PMID- 10392035
TI  - [Hypophyseal thyrotropin adenomas at Yaounde (Cameroon). Analysis of two case
      reports: improvement with somatostatin analogue (SMS 201-995)].

PMID- 10392036
TI  - [Postpartal septic osteoarthritis].

PMID- 10392037
TI  - [Myelodysplasia with myelofibrosis: a unique anatomo-clinical entity].

PMID- 10392038
TI  - [A rare cause of myopathic syndrome: alcoholism].

PMID- 10392039
TI  - [A rare cause of right heart insufficiency: idiopathic dilatation of the right
      atrium (a case report)].

PMID- 10392040
TI  - [Anatomy and surgery between the Arabic-Islamic world and the Christian
      Occident].

PMID- 10392041
TI  - The internal critical level concept of nonspecific toxicity.
AB  - The internal lethal concentration (ILC) can be an effective approach in
      describing the toxicity of a chemical to aquatic organisms that can complement
      the use of the external toxic concentration characteristic of the LC50. The ILC
      is an estimate of the toxicant concentration close to the target site and can be
      estimated from bioconcentration relationships and acute toxicity data. The
      observed ILC values were found to be consistent for organic compounds exerting
      the same mode of toxic action. The nonspecific toxicants have the lowest toxicity
      and the highest ILC values, whereas the chemicals exhibiting specific modes of
      action have lower concentrations and higher toxicity. There are some reports that
      the ILC value decreases with increasing exposure periods for various organic
      chemicals with aquatic organisms. The nonspecific toxicants possibly exhibit
      their toxic action at the target site by at least two different mechanisms
      depending on the toxicant concentrations. First, the toxicants bind directly to
      membrane proteins at relatively low concentrations, resulting in reversible toxic
      effect. Second, the toxicants inhibit the membrane proteins, and alterations in
      the lipid bilayers occur at toxicant concentrations sufficient to produce
      mortality of the organisms. The nonspecific toxicity expressed as acute and
      chronic toxicity measures are found to correlate well with log Kow. However, the
      relationship between the ILC and log Kow is less satisfactory because the values
      of ILC are relatively consistent compared to those of LC50.

PMID- 10392042
TI  - Organochlorine residues and elemental contaminants in U.S. freshwater fish, 1976
      1986: National Contaminant Biomonitoring Program.
AB  - As part of the National Contaminant Biomonitoring Program (NCBP, formerly a
      component of the National Pesticide Monitoring Program), the U.S. Fish and
      Wildlife Service periodically determined concentrations of organochlorine
      chemical residues and elemental contaminants in freshwater fish collected from a
      nationwide network of stations. In late 1986 and early 1987, the last time the
      network was sampled, a total of 319 composite fish samples were collected from 97
      NCBP stations. The samples were analyzed for residues of organochlorine chemicals
      and the elements As, Cd, Cu, Hg, Pb, Se, and Zn. The mean concentration of total
      DDT and its homologs (p,p'-constituents) declined from 1984 to 1986, thus
      continuing a trend that began in 1970. The most persistent DDT homolog (p,p'-DDE)
      was detected at all stations sampled in 1986, and averaged 74% of total DDT
      residues, up from 70% in 1974-1979 but essentially unchanged from 1984.
      Collectively, these findings indicated a low rate of influx and continued
      weathering of DDT in the environment; nevertheless, DDT concentrations in fish
      from some stations in the South remained high enough to constitute a threat to
      piscivorous wildlife. Residues of polychlorinated biphenyls (PCBs) also remained
      widespread, but a significant downward trend in total PCB concentrations and
      incidence was evident, and PCB mixtures containing early eluting components were
      present at fewer stations than in the past. PCB concentrations were generally
      highest in fish from the industrialized rivers of the Northeast and Midwest and
      from the Great Lakes. Concentrations of toxaphene also declined, as did its
      incidence, from 88% of the stations sampled in 1980-1981 to 64% in 1986; however,
      analytical problems with the 1986 samples may have contributed to the latter. The
      risks represented by PCBs and toxaphene could not be evaluated on the basis of
      our data. Among cyclodiene insecticides, dieldrin and chlordane-related residues
      were the most widespread. Mean concentrations of dieldrin declined through 1986,
      but remained consistently highest in the Great Lakes. For chlordane-related
      residues, mean concentrations were lower that reported previously, and trans
      nonachlor continued to replace cis-chlordane as the most abundant component.
      Collectively, these findings suggested a lower rate of chlordane influx to the
      aquatic environment; however, a point source of cyclodiene insecticides to the
      Mississippi R. near Memphis, TN, remained evident. Residues of mirex, PCA, BHC
      isomers, endrin, heptachlor, and HCB were either found at relatively few (< 25%)
      of the stations sampled in 1986 or were characterized by relatively low
      concentrations. Concentrations of the herbicide Dacthal (DCPA) were also low, but
      incidence increased from 46% of the stations sampled in 1984 to 61% in 1986. In
      general, organochlorine chemical concentrations were lower in 1986 than at any
      time reported previously. For elemental contaminants, the geometric mean,
      maximum, and 85th percentile concentrations (respectively, all in microgram/g wet
      weight) in 1986 samples were as follows: As, 0.083, 1.53, 0.24; Cd, 0.011, 0.32,
      0.04; Cu, 0.794, 11.0, 1.7; Hg, 0.087, 0.44, 0.18; Pb, 0.058, 1.90, 0.21; Se,
      0.417, 3.41, 0.66; and Zn, 21.191, 94.5, 31.7. Mean concentrations of Cu
      increased and concentrations of As decreased relative to the 1984 collection, but
      these changes may reflect subtle differences in the species composition of the
      1986 collection relative to other collections; concentrations of both elements
      differ greatly among fishes. There were no other statistically significant
      changes from 1984 to 1986; however, mean concentrations of As, Cd, Pb, and Zn
      declined from 1976, when elemental contaminants in fish were first measured in
      the NCBP, and 1986. In contrast, mean concentrations of Hg and Se did not change
      appreciably. Moreover, and in contrast to the other elements measured in 1986,
      concentrations of Hg and Se were high enough to constitute a threat to pisc

PMID- 10392043
TI  - Management and utilization of poultry wastes.
AB  - Waste by-products such as excreta or bedding material that are generated by the
      worldwide annual production of more than 40 million metric tons (t) of poultry
      meat and 600 billion eggs are generally land applied as the final step of a
      producer's waste management strategy. Under proper land application conditions,
      the nutrients and organisms in poultry wastes pose little environmental threat.
      Environmental contamination occurs when land application of poultry wastes is in
      excess of crop utilization potential, or is done under poor management conditions
      causing nutrient loss from environmental factors such as soil erosion or surface
      runoff during rainfall. Environmental parameters of concern are N, P, and certain
      metals (Cu and Zn in particular), as well as pathogenic microorganisms that may
      be contained in poultry waste. The biochemical cycle of N is very dynamic, and N
      contained in poultry waste may either be removed by crop harvest, leave the
      animal production facility, waste treatment lagoon, or application field as a gas
      (NH3, NO, NO2, N2O, or N2), or, due to its mobility in soil, be transported in
      organic or inorganic N forms in the liquid state via surface runoff or leaching
      into groundwater. Elevated concentrations of NO3-N in groundwater used for human
      consumption is a health risk to infants that are susceptible to
      methemoglobinemia. An environmental impact resulting from elevated NO3-N is
      eutrophication of surface waters. Ammonia loss from poultry waste is an
      environmental concern because of volatilized wet and dry deposits of NH3 into
      nitrogen-sensitive ecosystems. Phosphorus in poultry wastes may contribute to
      environmental degradation by accelerating the process of eutrophication. Unlike
      N, P is very immobile in soil and must first be transported to a surface water
      environment to have an environmental impact. It is generally accepted, however,
      that this nutrient affects receiving waters via transport in eroding soil as
      sediment-bound P or in surface runoff as soluble inorganic or organic P. Numerous
      studies have reported that excess P contained in land-applied manures may
      contribute to eutrophication. Soils containing P concentrations that greatly
      exceed the agronomic potential of crops may require years or even decades to
      return to levels that are crop limiting for this nutrient. Environmental concerns
      include the capacity of such soils to adsorb new P and the amount of P loss from
      these soils from erosion, runoff, drainage, or leaching to groundwater. Although
      much information is available regarding the loss of P from agricultural fields
      from erosion and runoff, less information is available regarding P losses from
      fields receiving poultry wastes. However, studies have shown that there are many
      challenges to controlling P losses from fields receiving manures. In addition,
      subsurface transport of P resulting from repeated application of poultry manure
      onto soils that are artificially drained is an environmental concern where
      drainage waters enter or interact with water bodies sensitive to eutrophication.
      Trace elements such as As, Co, Cu, Fe, Mn, Se, and Zn are often added in excess
      to poultry feed to increase the animal's rate of weight gain, feed efficiency,
      and egg production and to prevent diseases. Because most of the excess trace
      elements are not absorbed by the bird, the concentration of elements excreted in
      the manure will reflect dietary overformulation. Because trace elements are
      generally required in very small quantities for crop growth and, like P, are
      immobile in most soil types, their concentrations will increase with repeated
      land application of poultry wastes. Of particular concern are accumulations of Cu
      and Zn in certain soil types utilized for certain crops. Copper and Zn toxicity
      for some crops have been documented in some areas receiving repeated land-applied
      poultry wastes. A potential environmental concern relative to poultry litter and
      trace elements in receiving soils involves the transpor

PMID- 10392044
TI  - What's past is prologue

PMID- 10392045
TI  - CNA turns 90. Canadian Nurses Association.

PMID- 10392046
TI  - [A common heritage].

PMID- 10392047
TI  - Multiple pregnancy, multiple needs.
AB  - Every year, more than 4,000 sets of twins and 80 sets of triplets are born in
      Canada. And those numbers are growing: Canadian women are two-and-a-half times
      more likely to have triplets, quadruplets or quintuplets today than 20 years ago,
      mainly due to increasing maternal age and the use of fertility drugs and
      reproductive technologies.

PMID- 10392048
TI  - Hospital without walls.
AB  - The rapid changes in Ontario's health care system have challenged community
      nurses to identify new possibilities for delivering care to clients and families.
      At our Markham based not-for-profit agency--Saint Elizabeth Health Care--we have
      met that challenge by redesigning our care delivery model.

PMID- 10392049
TI  - Screening for disease in pregnancy.
AB  - Screening during pregnancy is unlike screening any other population, because two
      entities are involved and potentially affected by the disease: the pregnant woman
      and the fetus. A number of serum screening tests can be performed as part of
      prenatal care. Some are routinely done on all pregnant women, some are offered to
      women thought to be at risk for a particular disease, and some are offered
      according to the woman's age, country of origin or other criterion.

PMID- 10392050
TI  - [Palliative care, a humanitarian way (Part 2)].
AB  - This portion of a study, first published last month, examines the various aspects
      of dying (including the dying person's needs); looks introspectively at the
      spiritual aspect of death; and analyzes the behavior and attitudes of care-giving
      staff, their values, motivations and needs. While dying people may have
      unpredictable attitudes and behavior, nurses need to maintain an attitude of
      caring and communication in their interventions. Important to consider when
      nursing the dying are subjects such as: establishing a helping relationship;
      appropriate communication; and self-knowledge and preconceived notions. Criticism
      most often directed at palliative care suggests that curative and palliative care
      should be integrated; should abandon their reserved territories (such as care
      units); and should develop an association that goes beyond the terminal phase.

PMID- 10392051
TI  - Justifying our practice.
AB  - Do we need an RN to do this? Or, can it be done by a less skilled worker? In the
      redesign of today's hospitals, it is inevitable that these questions are being
      asked and the role of the RN is being carefully scrutinized.

PMID- 10392052
TI  - Implementing a successful home i.v. program.
AB  - Anyone who has worked on planning a program that spans both hospital and
      community knows the differences in focus, philosophy and general organization.
      Kelowna General Hospital and the community of South Okanagan, B.C. worked beyond
      these differences, using the strengths and expertise of both spectrums of care,
      to implement a successful home infusion program. But first, the pros and cons of
      program ownership.

PMID- 10392053
TI  - Privileged to work in pediatrics. Interview by Barbara Sibbald.

PMID- 10392054
TI  - Theoretical and practical issues in recirculation; assessment of vascular access.
AB  - Haemodialysis recirculation is defined as the fraction of cleared extracorporeal
      blood flow which returns to the inlet of the extracorporeal blood line without
      systemic equilibration. There are two components of haemodialysis recirculation:
      the local component is related to access function and placement of access
      needles; the cardiopulmonary component is a characteristic of the peripheral
      arterio-venous access where access blood flow bypasses systemic tissue
      compartments. Identification of access problems requires separation of the two
      components using newly developed indicator dilution techniques such as ultrasound
      dilution. If such techniques are not available and recirculation is determined by
      techniques which measure combined effects of recirculation such as the urea
      technique, a second recirculation measurement with reversed placement of blood
      lines will permit us to distinguish between correct and reversed placement of
      blood lines. The larger of the two recirculation values can be used to identify
      accesses with insufficient access flow and access recirculation which require
      immediate intervention.

PMID- 10392055
TI  - Prolonging access function and survival, the nurse's role.
AB  - Vascular access is the lifeline of all patients undergoing HD. In a recent
      patient satisfaction survey, the area of vascular access and needling technique
      was highlighted as an area with the need for improvement, this is addressed in
      this paper by the formulation of: Individual access Vulnerability Score, an
      Access Care Plan and the implementation of a Staff cannulation training
      programme. Addressing these 3 areas of practice with a structured programme not
      only assists staff to develop and value patient access but ultimately provides a
      higher quality of service. Patient satisfaction, access complications, staff
      knowledge and clinical abilities can all be improved by the implementation of a
      more structured approach to developing and valuing vascular access.

PMID- 10392056
TI  - Living donor transplantation: impact of patient focused care on donor outcome.
AB  - Living donor transplantation offers the optimum treatment option for patients
      with end stage renal failure. In September 1995, it was agreed that the programme
      should be actively promoted in our centre and a Nurse Co-ordinator was nominated
      to facilitate it. At a year the scheme was a proven success, demonstrated by a
      net growth in the numbers of transplants performed, together with excellent graft
      and patient survival figures and improved quality and duration of donor work-up.

PMID- 10392057
TI  - The nursing management of a patient receiving Prograf as a primary
      immunosuppressive agent.
AB  - This article addresses the issues that are raised when implementing Prograf as a
      new primary immunosuppressive agent. It focuses on the nurses' role in pre- and
      post-operative management, with an emphasis on patient assessment/monitoring and
      education.

PMID- 10392058
TI  - Setting standards for donor family care.
AB  - The number of cadaveric organs made available for transplantation will never meet
      the demand. Whilst measures such as "opting in", "opting out", have been offered
      as solutions, could extra support and care to potential donor families increase
      and make a difference? It may make the donor's gift seem more valued. This in
      turn should enhance a more positive view of organ donation among their relatives,
      friends and neighbours. It may be that by paying more attention to current donor
      families, we may increase the potential donor pool in years to come.

PMID- 10392059
TI  - Nightly peritoneal dialysis (NPD): six years of experience.
AB  - From the 84 patients who initiated PD from 1990 to 1996, 15 did NPD, 3 changed
      from CAPD to NPD. In general the reason for choosing NPD were: 10/18 clinical
      motivations, 8/18 social and economical. From our experience and based on nurses'
      opinions, a patient who chooses NPD is a balanced person with good family
      support, accepts the treatment and benefits from this modality. On the other hand
      patients who withdraw from NPD for clinical reasons have no strong motivations
      and have different problems. Working to improve patient adaptation and improving
      patient treatment modality selection should be a must.

PMID- 10392060
TI  - Protocol for treatment of exit-site and tunnel infections in 177 CAPD patients.
AB  - This paper shows the most important germs that are responsible for exit-site and
      tunnel infections in CAPD patients, and the possible action to care for them.
      Prevention of PD catheter infection begins with good surgical practice in
      catheter implantation and includes appropriate preoperative patient preparation.
      Some of the operative protocols for dialytic methods used in our unit are shown.

PMID- 10392061
TI  - "A change for the better". A nursing innovation for change in the CAPD catheter
      exit site care.
AB  - The need for change was identified when an increase occurred in peritoneal
      catheter exit site infection rate of those patients who had newly inserted
      peritoneal dialysis catheters. A decision was taken to improve this situation by
      reviewing the prevailing procedure. A literature search of the recommended care
      of peritoneal dialysis catheter exit sites was carried out; a new procedure was
      written in accordance with the research recommendations, as a result of the new
      procedure of care the exit site infections rate dropped dramatically.

PMID- 10392062
TI  - Adequate peritoneal dialysis: theoretical model and patient treatment.
AB  - The objective of this study was to evaluate the relationship between adequate PD
      with sufficient weekly Kt/V (2.0) and Creatinine clearance (CCR) (60l) and
      necessary daily dialysate volume. This recommended parameter was the result of a
      recent multi-centre study (CANUSA). For this there were 40 patients in our
      hospital examined and compared in 1996, who carried out PD for at least 8 weeks
      and up to 6 years. These goals (CANUSA) are easily attainable in the early
      treatment of many individuals with a low body surface area (BSA). With higher BSA
      or missing RRF (Residual Renal Function) the daily dose of dialysis must be
      adjusted. We found it difficult to obtain the recommended parameters and tried to
      find a solution to this problem. The simplest method is to increase the volume or
      exchange rate. The most expensive method is to change from CAPD to APD with the
      possibility of higher volume or exchange rates. Selection of therapy must take
      into consideration: 1. patient preference, 2. body mass, 3. peritoneal transport
      rates, 4. ability to perform therapy, 5. cost of therapy and 6. risk of
      peritonitis. With this information in mind, an individual prescription can be
      formulated and matched to the appropriate modality of PD.

PMID- 10392063
TI  - Efficacy of intraperitoneal amino acid (IPAA) dialysate in an Asian vegetarian
      patient with chronic hypoalbuminaemia.
AB  - Protein-calorie malnutrition is commonly found in chronic CAPD patients and is a
      matter of concern since low serum albumin levels correlate with an increased risk
      of morbidity and mortality. Recognition of this link has therefore led to a
      growing interest in the efficacy of IPAA therapy as a possible treatment option.
      The present case study took place within a larger, ongoing clinical trial and
      outlines our experience of administering one exchange of 1.1% IPAA (Nutrineal,
      Baxter Healthcare Ltd) per day over 18 weeks to a patient identified as being
      protein malnourished.

PMID- 10392064
TI  - Delivering adequacy in PD therapy.
AB  - Providing appropriate peritoneal dialysis is an ongoing challenge to renal care
      providers. As the residual renal function and the peritoneal permeability are
      likely to change with time, the dose provided by the PD regimen needs to be
      adjusted. Rather than waiting for clinical signs of underdialysis, the practising
      nephrologist and the PD nurse today have access to diagnostic tools to assist in
      the prescription of adequate therapy. Peritoneal dialysis prescription involves
      setting up a personalized dialysis schedule aimed at obtaining satisfactory
      clearance and ultrafiltration rates while respecting the patient's life-style as
      far as possible. The PD nurse has the most patient contact and thus plays a
      pivotal role with the other healthcare professionals in the care of the patients.
      As providers, it is our responsibility to inform the patients about their own
      care. As PD is a method of home dialysis, patients must have self responsiveness,
      technical and psycho social skills to deal well with the method.

PMID- 10392065
TI  - Low seroconversion for hepatitis C virus (HCV) antibody achieved by universal
      precautions alone.
AB  - Since the cloning of Hepatitis C virus in 1988 positive serology for HCV antibody
      in haemodialysis populations has been reported at varying rates of 2 to 70%. To
      date there is no consensus regarding strategies which would curtail spread of HCV
      in the dialysis unit. In our satellite dialysis programme we implemented
      Universal Precautions as the sole strategy for containment and HCV monitored
      closely the outcome of this decisions.

PMID- 10392066
TI  - Universal precautions and dedicated machines as cheap and effective measures to
      control HCV spread.
AB  - Haemodialysis patients are at great risk for HCV infection, and a strict
      relationship is clear between anti-HCV positivity and dialysis age or hospital
      dialysis, irrespective of previous blood transfusions. Notwithstanding that, the
      precise root of its nosocomial nontransfusional diffusion among haemodialysis
      patients is not clear yet. As isolation is a very expensive policy, we evaluated
      whether simpler measures such as the observance of the Universal Precautions
      (UP), and the use of anti-HCV positive patient dedicated monitors can stop the
      diffusion of HCV infection in a hospital haemodialysis centre. Since January 1990
      to December 1991 (1st phase), the patients shared the monitors irrespective of
      their serological status for HCV, and training of the dialysis care staff was not
      performed with regard to the UP. Since January 1991 to June 1996 (2nd phase),
      according to the UP, strictly personal dialysis-tools were used for all patients,
      anti-HCV positive patients were assigned to dedicated monitors in defined (not
      separated) areas of the dialysis rooms and the dialysis care staff was trained to
      the strict observance of the UP. In the first phase of the follow-up 5
      seroconversions occurred; none occurred in the second one. Our study shows that
      isolation is not required for such patients. We believe that measures such as the
      application of UP, dedicated machines and continuous training of the care staff,
      instead of the isolation of positive patients, result in the same efficacy and
      are cheaper than isolation of positive patients. Therefore they are mandatory for
      all haemodialysis centres.

PMID- 10392067
TI  - Planning for success.
AB  - Being a nurse today and striving for 100% job satisfaction while ensuring a
      patient's well-being is not an easy task in the current changing and challenging
      environment. However, careful planning might be the key to success. This article
      focuses on 'How to Plan' and gives some practical tips for nurses in their daily
      work. The article then offers three case stories of renal units that have
      developed objectives and a plan to achieve a successful dialysis programme.

PMID- 10392068
TI  - Impacts on dialysis therapy.
AB  - Improvement of clinical outcome of dialysis therapy is a task for everybody
      working in a dialysis unit. Here we consider dialysis conditions such as choice
      of treatment parameters and composition of dialysis fluid which may influence
      clinical outcome of dialysis therapy. Providing 'adequate' dialysis is the aim of
      the daily work of a dialysis nurse. Haemodialysis parameters with potential
      impact on dialysis adequacy are discussed with respect to quantification and
      optimisation. Every year, each patient comes in contact with 20,000 I dialysis
      fluid during HD treatment. The composition of the fluid, its physical and
      microbiological quality and their impact on clinical outcome are considered. The
      function of PD fluid is different from that of an HD fluid thus additional
      aspects have to be considered regarding its composition. Information is given how
      the composition and biocompatibility of PD solutions impact the dialysis therapy
      and how individual patient needs are considered.

PMID- 10392069
TI  - Chronic renal failure in infancy. Two dietetic case reports.
AB  - Dietetic care of infants with end stage renal disease (ESRD) involving intensive
      nutritional support and frequent monitoring in attempts to optimise growth has
      not been previously quantified. We describe the progress of two male infants born
      with ESRD due to renal dysplasia. Child A and child B were commenced on
      continuous cyclic peritoneal dialysis at mean age of 3 months and required
      nutritional support via a gastrostomy button. Energy intakes pre-dialysis (147
      kcal/kg) and energy and protein intakes during the first year of life on CCPD
      (137 kcal/kg, 2.6 g/kg actual body weight) were greater than recommended for the
      healthy population. Over the 2 year period without growth hormone, height SDS
      increased from -1.66 to -0.17 and 0.67 to 0.78 and weight SDS increased from 
      1.26 to -0.43 and 0.31 to 1.75 for Child A and Child B respectively. Mean
      dietetic contacts (in/out patient and telephone) over the 2 years were 11.8
      contacts/mth pre-dialysis, 8.4 contacts during the first year on CCPD and 4.3
      contacts during the second year. We conclude that infants with end stage renal
      disease require frequent dietetic contact in combination with early dialysis and
      tube feeding to achieve nutritional goals and optimise growth. In addition,
      dietetic advice provides valuable family support.

PMID- 10392070
TI  - Quality of life and coping in home haemodialysis patients.
AB  - Approximately 4,034 Australians are currently receiving dialysis therapy due to
      End Stage Renal Disease (ESRD) and of these 627 are performing haemodialysis
      within the home environment. Initial emphasis on the medical model, which
      considers bodily pathology and the technological potential to prolong life, is
      now expanding to incorporate a more humanistic picture of the individuals
      response to treatment and their quality of life (QoL). This uncertain partnership
      of technology and human experience has led to an increasing awareness of the need
      for health professionals to attain an understanding of the illness experience as
      it impacts on the patient's life. The importance of considering not only absolute
      survival time but the quality of that survival has triggered rapid growth in the
      areas of coping and QoL research. This paper provides a review of the literature
      which focuses on QoL and coping in haemodialysis patients and demonstrates the
      paucity of research which investigates the special concerns of home dialysis
      patients.

PMID- 10392071
TI  - Introducing assessment criteria into patient training.
AB  - After discussion with other CAPD training centres, it became apparent that there
      was no formal evaluation of patients' ability to self care with CAPD before
      discharge. A comprehensive list of skills and knowledge was set out in a formal
      document. Daily assessment during training revealed that both patients and staff
      felt empowered with the implementation of this tool.

PMID- 10392072
TI  - Social support and renal care.
AB  - Social support has been found to have a strong influence on health but the
      precise way in which this works is not agreed. Definitions of social support also
      vary. This paper considers these definitions and theories and goes on to look at
      how social support affects coping, its possible negative aspects, and reciprocity
      in giving and receiving support. These ideas are then applied to the role of
      confidants and lay supporters as well as professional support. Finally the
      discussion is related to renal nursing.

PMID- 10392073
TI  - A memorial service for renal patients.
AB  - This article describes how nurses on a renal unit offered support to bereaved
      relatives by organising a memorial service for relatives of patients who had died
      over the previous 12 months. The structure of the service came from a variety of
      remembrance services and consisted of verses, poems, words of comfort, a minutes
      silence and a roll call of the names of all the patients who had died,
      commemorated by the lighting of a candle. Memorial services can function as a way
      of saying goodbye and also acknowledge the reality of the loss for both staff and
      relatives (1). A remembrance service was an ideal opportunity to provide support
      and comfort to bereaved relatives, reinforcing the idea that patients, relatives
      and friends are valued by those who care for them. The service proved to be very
      successful, with positive feedback from both relatives and staff. An annual
      memorial service is planned for the future.

PMID- 10392074
TI  - Recipient and non-recipient attitudes regarding xenotransplantation.
AB  - Xenotransplantation research has occurred intermittently without success this
      century and is also not an area without controversy, which includes the potential
      health risks that could occur and the use of animals. The tremendous discrepancy
      between those in need of transplantation and the number of living and cadaveric
      donors has once again renewed interest in this field. The National Kidney
      Foundation undertook an opinion survey to facilitate understanding of both
      transplant recipients' and non-recipients' knowledge of, and attitudes toward,
      xenotransplantation. The majority of respondents approved of the concept and
      greater than 70% of both groups would consider a xenotransplant. The main concern
      of both groups was the ability of the animal organ to function properly.

PMID- 10392075
TI  - Educational factors affecting modality selection: a National Kidney Foundation
      study.
AB  - Patient education has been found to have significant positive effects in a
      multitude of studies. The National Kidney Foundation undertook a study to examine
      the various factors that impact upon treatment modality selection, with this
      paper focusing specifically on the study's educational components. The majority
      of these respondents reported receiving an adequate amount of information, yet
      routinely they were not offered information on all treatments available to them.
      While most indicated being educated by one-to-one discussions, other methods were
      also employed. Those responding were most likely to receive education from
      nephrologists, however, nursing was involved with 46% of the participants.

PMID- 10392076
TI  - Erythropoietin, an update, and where to in the future?
AB  - Recombinant human erythropoietin has been produced by genetic technology since
      1985 and since then many clinical trials have repeatedly demonstrated its success
      in the correction of anaemia associated with renal failure. This paper discusses
      basic principles for its administration, potential side effects and strategies
      for non response to erythropoietin (Epo) therapy.

PMID- 10392077
TI  - The nutritional status of Asian end stage renal failure patients: a cross
      sectional study.
AB  - Nutritional status was assessed in 303 dialysis patients and the results of Asian
      and non Asian patients was compared. Mid Arm Muscle Circumference (MAMC) was
      found to be lower [22.7 +/- 2.7 v 24.2 +/- 2.9 (p = 0.008)] and TSF higher [15.9
      +/- 7.2 v 13.6 +/- 7.4 (p = 0.078)] in Asians as compared to non Asians. Body
      Mass Index (BMI), Mid Arm Circumference (MAC) and Serum Albumin were not
      significantly different in the two groups. Difficulties in assessing and
      interpreting nutritional status in the Asian dialysis population are discussed
      and areas for further work are identified.

PMID- 10392078
TI  - Is hepatitis G virus a real risk for haemodialysis patients?
AB  - Haemodialysis patients are at high risk of developing liver disease due to blood
      borne viral agents. At present hepatitis C virus (HCV) is the most common cause
      of infection in these patients. A new RNA virus of the Flaviviridae family,
      hepatitis G virus (HGV) has recently been cloned. HGV prevalence in haemodialysis
      patients ranges from 3.1% to 57.5%. The aim of this study has been to detect HGV
      RNA in our haemodialysis patients in order to evaluate the prevalence of HGV and
      to correlate the viral presence to liver disease. A total of 79 patients, on
      haemodialysis for a mean of 52 months, were tested. 3 patients (3.8%) were HBsAG
      positive and 19 patients (24%) were HCV positive. 24 of the 79 (30%) patients had
      been transfused. Only 2 of the 79 patients (2.5%) were HGV positive. These
      patients were HBsAG and anti HCV negative, both had been previously transfused
      and showed no signs of liver disease.

PMID- 10392079
TI  - The anaemia research nurse in effective multi-disciplinary management of patients
      on erythropoietin.
AB  - Following recommendations published by the Renal Association, the standard
      regarding optimal haemoglobin levels was questioned by members of the Oxford
      Renal Unit Management Team as perhaps being unrealistic in a unit responsible for
      nearly 400 patients on dialysis. Subsequent to the appointment of an anaemia
      research nurse a base-line audit revealed that only 61.3% of the dialysis
      population had a haemoglobin > 10 g/dl and also identified the reasons why the
      unit was failing to meet this pre-set target. This paper identifies how the unit
      addressed these problems which has subsequently led to a change in views about
      achieving the standard. The establishment of clear management guidelines cannot
      be over emphasised and all aspects of anaemia in this unit will now be addressed
      as part of the multi-disciplinary team function rather than being led by medical
      intervention.

PMID- 10392080
TI  - Bacterial growth prevention in liquid bicarbonate concentrate.
AB  - We describe an original Liquid Bicarbonate Concentrate (LBC) production and
      distribution unit, now functioning for five years. To prevent bacterial growth
      several measures were taken: LBC osmolarity as high as possible, fast concentrate
      turnover, UV irradiation of the tank and continuous circulation of LBC. Although,
      six and ten months elapsed before the first two positive cultures appeared after
      implementation of the new distribution circuit, subsequently, the interval
      between positive cultures became much shorter so that disinfection of the LBC
      unit is now required every 3 weeks. Changing the disinfecting agent from
      hypochlorite to peracetic acid did not succeed in increasing this interval. Our
      experience draws special the attention to the problem of bacterial growth in an
      on-line LBC production and distribution unit and defines the potential methods to
      control it. Continuous vigilance remains mandatory.

PMID- 10392081
TI  - Information technology in a dialysis department.
AB  - The use of information technology in a peritoneal dialysis service, as in any
      facility, poses the problem of the choice of the data to be stored. It is
      important to define the whole range of information which may be of use and to
      assess the costs and benefits involved. These will depend on how complete and
      reliable the stored information is, how well the management process (filing and
      processing) is integrated with its day to day use by the Department. It is
      essential to both safeguard work efficiency and guarantee processing which will
      be useful in routine operations, including checking the quality of work carried
      out, and in study and research.

PMID- 10392082
TI  - Medical English for nurses. How important is it? What to consider and how to
      structure a course?
AB  - A common language is a precondition for a forum where scientific achievements as
      well as professional nursing issues can be discussed. It enables the
      professionals to exchange results and to create a new international terminology
      for future aspects. English should be the language of choice because not only is
      it the common language of most other members in the multidisciplinary team in
      nephrology, it is acknowledged world-wide as the scientific language. The aim of
      the project was to devise a medical English course for nurses which would enable
      them to participate at an international congress in English without the aid of
      translation and to make them aware of the available medical English literature at
      their facilities. The course has 20 weekly one and a half hour lessons. There is
      a test at the beginning for self evaluation for the students and to assist the
      course teacher on the grouping of the students for workshops. Didactic elements
      were included as well as videos, slides, workshop and games. More than 50% of the
      28 nurses who attended the courses worked within in a renal setting. Evaluation
      of the course demonstrated that at the end they felt able to tackle English
      medical text and had enjoyed the course thoroughly.

PMID- 10392083
TI  - JCAHO educational strategies that work! Joint Commission on Accreditation of
      Healthcare Organizations.
AB  - Preparing a large hospital for a Joint Commission on Accreditation of Healthcare
      Organizations (JCAHO) survey is always a challenging endeavor. Because staff
      members have diverse learning needs it is important that staff be educated in the
      JCAHO standards. In this article, the author describes the educational strategies
      used to prepare a healthcare organization for an impending JCAHO survey. Learning
      styles, the domains of learning, and the accessibility to education by the
      satellite facilities were determining factors in the selection of the various
      educational strategies.

PMID- 10392084
TI  - Designing a competency-based nursing practice model in a multicultural setting.
AB  - Cultural diversity of patients and staff has challenged nurse educators to create
      new culturally sensitive learning environments and to participate in the design
      of systems that ensure standards of care for patients and standards of
      performance for nurses are met. Performance expectations require nurses to render
      age-specific, culturally congruent nursing care and function as integral members
      of interdisciplinary, multicultural healthcare teams. In this article the author
      describes the development of a Competency-based Nursing Practice Model in a
      multicultural setting and explores the role of the staff development educator
      throughout the design process.

PMID- 10392085
TI  - A video on discharge planning: an experience in amateur film making.
AB  - An instructional video entitled "A Video On Discharge Planning; An Experience in
      Amateur Film Making" was designed. The advantages and disadvantages of the video
      production process were reviewed. The film-making process is described including
      scriptwriting, actor selection, the filming process, and the editing process. An
      analysis of the filming process revealed that several measures could prove time
      saving and ensure a high quality video, such as script writing, background
      selection, actor involvement, and the filming and editing processes used. The
      conclusion lists guidelines for a health education video production.

PMID- 10392086
TI  - A culture fair: a creative, fun, and informative method of cultural awareness
      education.
AB  - Nursing has long realized that the impact of a person's culture is an important
      component of planning the care of individuals. Recently the Joint Commission on
      the Accreditation of Health Care Organizations has begun to require evidence that
      healthcare workers have knowledge of the impact of cultural background on patient
      and family response to health and illness. An education fair is a creative and
      fun method of educationg large numbers of employees with consideration for cost,
      time, and resource management. This article will address how to assess and
      utilize available resources for organizing and setting up a culture fair.

PMID- 10392087
TI  - Patient teaching for older adults and families in the long-term care setting.
AB  - Patient education can play a key role in quality long-term care, but is often an
      under-developed resource. Potential challenges related to the older adult
      population, staffing patterns, and setting are described. Topics, strategies, and
      resources are provided to promote patient education for older adults and their
      families.

PMID- 10392088
TI  - Implications for staff development of perceived self-efficacy in nurses who
      changed to home care practice.
AB  - As reform activities continue to restructure health care, traditional roles of
      nurses are being reshaped and redefined. Many nurses displaced by organizational
      downsizing are seeking employment "outside of the hospital walls," including home
      care practice. Novice home care nurses may lack confidence in their ability to
      care for clients in the home. The purpose of this study was to examine the extent
      to which perceived self-efficacy is associated with job satisfaction in nurses
      who have recently changed from hospital-based practice to home care. Self
      efficacy correlated significantly with job satisfaction. Nurses with high
      perceptions of self-efficacy tended to be more satisfied with their jobs. Using
      the theoretical framework of self-efficacy, educators can structure orientation
      programs to enhance the new nurse's perception of self-efficacy and, thereby,
      increase job satisfaction.

PMID- 10392089
TI  - Domains of health-related quality of life in elderly women with osteoporosis.
AB  - Osteoporotic spinal fractures can be painful, debilitating, and contribute to
      impaired HRQL of elderly women. The OQLQ is a validated disease-specific
      instrument developed to measure HRQL in women with spinal fracture caused by
      osteoporosis. Future intervention studies should test nursing interventions to
      decrease the burden of suffering for women with this increasingly prevalent,
      chronic disease.

PMID- 10392090
TI  - Examining pain in aggressive cognitively impaired older adults.
AB  - Few studies have explored the phenomenon of pain in people with severe cognitive
      impairment. Pain assessment, which depends primarily on people's ability to
      describe dimensions of pain, becomes problematic when clients' cognitive
      impairment is so severe they cannot respond to pain assessment tools. The purpose
      of this study was to describe the phenomenon of pain for a subgroup of aggressive
      cognitively impaired nursing home residents who were enrolled in a larger study
      of aggressive behavior. To determine if pain was a possible factor influencing
      aggression, information was sought from five sources: family members, nursing
      assistant (NA) caregivers, medical record listings of pain-related diagnoses, use
      of analgesics, and observations of aggressive behaviors. Families reported pain
      in 44% of subjects, while NAs reported pain in 66% of subjects. Seventy-six
      percent of subjects had one or more pain-causing diagnoses. Sixty-four percent of
      subjects whose family members thought they may have pain were being treated with
      analgesics, compared to 44% of subjects whose NA reported they may be
      experiencing pain. Aggression scores were significantly higher in subjects who
      had two or more pain-related diagnoses and in subjects with arthritis. Nurses who
      are aware of a history of pain, reports of pain by families and caregivers,
      presence of pain-related medical diagnoses, and who realize pain may be a trigger
      for aggressive behavior may be more likely to recognize pain in cognitively
      impaired older adults. Better pain assessment should lead to improved treatment
      of pain in this population.

PMID- 10392091
TI  - Motivating older adults to perform functional activities.

PMID- 10392093
TI  - Individualizing medication regimens for older adults.

PMID- 10392092
TI  - Entering the world of dementia: CNA interventions for nursing home residents.
AB  - People who have Alzheimer's disease (AD) often reside in nursing homes and
      frequently exhibit the behaviors of agitation, aggression, screaming, wandering,
      and repetitive actions (Beck, Heacock, Rapp, & Shue, 1993). Beck et al. (1993)
      revealed 30% to 95% of nursing home residents exhibited aggressive behaviors that
      may contribute to the overall decline of the residents. Some of the negative
      outcomes for these behaviors include: Exhaustion from wandering or repetitive
      behaviors. Social isolation. Wandering to a dangerous place. Hitting or provoking
      someone to hit back. (Beck, Heacock, Rapp, & Shue, 1994; Gerdner, Hall, &
      Buckwalter, 1996). Close observation of the clinical practice of Certified
      Nursing Assistants (CNAs) has revealed some CNAs intuitively provide care in ways
      that minimize behaviors such as agitation and aggression. However, a review of
      the literature failed to reveal information regarding how CNAs intervene in the
      behaviors of elderly residents exhibiting dementia. This gap between practice and
      research was the impetus for this study.

PMID- 10392094
TI  - HIV and the older adult.
AB  - Infection with HIV, the virus that causes AIDS, is now considered a chronic
      disease of years rather than an acute condition resulting in death. AIDS in older
      adults accounts for 11% of all AIDS cases. This article discusses current
      epidemiological trends and statistics; HIV risk factors related to aging;
      immunity and the aging process; diagnosis and treatment challenges; as well as
      gerontological nursing implications related to HIV prevention and counseling for
      adults age 50 and older. HIV infection is preventable. Nurses have a unique
      opportunity to develop theory-based intervention programs to reduce risk
      behaviors, while encouraging healthy behaviors in the older adult population.

PMID- 10392095
TI  - When considering the needs of all age groups, what is the fairest way to allocate
      health resources in the United States?

PMID- 10392096
TI  - Considerations in the use of lipid-based drug products.

PMID- 10392097
TI  - Pain management of the patient with cancer in the homecare setting.
AB  - Patients with cancer can experience pain because of disease progression or as a
      side effect of treatment. Pain management is one aspect of cancer care that
      management in the home, rather than the hospital, may be a more ideal and cost
      effective setting. Potential barriers to pain management are explored, and pain
      management skills, such as assessment and equianalgesic dosing, are reviewed. The
      hospital- or community-based nurse is provided with the basic knowledge to plan
      or participate in the care of cancer patients with pain in the homecare setting.

PMID- 10392098
TI  - Radiopharmaceuticals (Strontium 89) and radiosensitizers (idoxuridine).
AB  - Strontium 89, a radiopharmaceutical, has proved effective in treating pain
      associated with multiple osteoblastic bony metastasis from prostate or breast
      cancer. The drug is given intravenously in an outpatient setting. Pain relief may
      be noted within 1 to 2 weeks and may last for several weeks or months.
      Radiosensitizers such as idoxuridine incorporate into the DNA and increase the
      susceptibility of the cancer cell to radiation damage. Hypoxic cell sensitizers
      (such as metronidazole, misonidazole, SR 2508, and Ro-038799) increase oxygen to
      the cancer hypoxic cells and promote damage of the DNA, thus preventing cell
      repair.

PMID- 10392099
TI  - Clinical trials of parenteral antineoplastic agents.
AB  - Parenteral antineoplastic regimens are being administered in a variety of
      healthcare settings. Clinical trials play an important role in the development
      and testing of these regimens. An update on the role of clinical trials in
      identifying new agents to combat cancer is provided. Nursing considerations,
      patient selection, and disease-specific criteria are discussed.

PMID- 10392100
TI  - Women and cancer.
AB  - Current concepts in the care of women with cancer are discussed. New diagnostic
      and treatment strategies for the four major cancers affecting women are
      discussed, including high-dose therapy with stem cell support for breast cancer.
      Genetic influences and their attendant ethical considerations are discussed.
      Finally, the psychosocial considerations specific to women with cancer are
      addressed.

PMID- 10392101
TI  - Overview of bone marrow and stem cell transplantation.
AB  - Bone marrow transplants and peripheral blood mononuclear cell transplants have
      improved survival of many patients with hematologic malignancies. This aggressive
      approach uses high-dose chemotherapy and radiation therapy for acute and chronic
      leukemia, lymphoma, Hodgkin's disease, multiple myeloma, and selected solid
      tumors. High-dose therapy requires intensive medical and nursing care. The focus
      of care is the management of side effects, monitoring of toxicities, and
      prevention of complications. The outcome of bone marrow and peripheral cell
      transplants is related to patient age, underlying disease status, and type of
      transplant.

PMID- 10392102
TI  - The role of the homecare nurse throughout the continuum of blood cell
      transplantation.
AB  - Bone marrow or blood cell transplantation is becoming a frequently used treatment
      option for individuals with a variety of malignant and nonmalignant diseases. The
      technology used to treat and support patients through this process has improved
      and advanced rapidly in recent years, as has the focus to contain costs while
      maintaining quality care. The results of these trends have been improved patient
      survival, decreased length of hospital stay, and increased the use of home
      healthcare in the support of the patient before the transplant, during the
      hospital stay, and after the transplant.

PMID- 10392103
TI  - Overview of biotherapy and nursing considerations.
AB  - Much attention is being focused on biotherapy as the fourth modality of cancer
      treatment. The use of biotherapy in combination with chemotherapy presents a
      unique challenge to the nurse, particularly in the ambulatory setting. To provide
      quality care, nurses must have an understanding of the complexities of this
      therapy. An overview of biotherapy, including medications used, common side
      effects, and nursing considerations, is provided.

PMID- 10392104
TI  - The essence of pediatrics.

PMID- 10392105
TI  - Mild head injury in children: identification, clinical evaluation, neuroimaging,
      and disposition.
AB  - Pediatric head injury presents in various degrees of severity. Early intervention
      in the patient with a severe head injury is the key to preventing secondary
      central nervous system damage. Patients with a head injury are easily identified,
      often by clinical examination alone. However, patients with a mild head injury
      present a challenge to practitioners, particularly in identification, knowing
      what is important in the clinical evaluation, deciding whether to use
      neuroimaging, and knowing where to send the child for observation. Use of the
      Glasgow Coma Score, primary survey, and identification of historic and clinical
      features that are suggestive of severe head injury may guide pediatric nurse
      practitioners in providing appropriate medical care and disposition.

PMID- 10392106
TI  - Health, growth, and use of community services in NICU graduates at early school
      age.
AB  - PURPOSE: To examine outcomes related to health, growth, and use of community
      health and education services in children ages 6 to 8 years who received newborn
      intensive care because of prematurity or perinatal complications. METHOD: Parents
      of 81 children who had received neonatal intensive care at a Midwest US tertiary
      care center completed a mailed questionnaire. Three birth weight groups (very low
      birth weight [VLBW] < 1500 g, n = 35; low birth weight [LBW] 1501-2500 g, n = 24,
      and normal birth weight [NBW] > 2500 g, n = 22) were compared regarding growth,
      health, and use of community-based services using descriptive statistics and one
      way analysis of variance. FINDINGS: VLBW and NBW groups had more ongoing health
      concerns. Growth patterns were similar in all groups. VLBW and NBW groups
      demonstrated greater use of community-based services, and service use increased
      at school age. CONCLUSIONS: Comprehensive systems are needed for follow-up of
      high-risk infants to detect and refer problems early. Neonatal histories must be
      tracked throughout childhood. Seriously ill term NBW infants are at risk for
      later morbidity and require follow-up similar to that provided for VLBW children.

PMID- 10392107
TI  - Reversing growth deficiency in children: the effect of a community-based
      intervention.
AB  - INTRODUCTION: The effect of a community health nursing intervention on children
      with growth deficiency (also called nonorganic failure to thrive or growth
      failure) was examined in a pretest and post-test experimental study. This study
      evaluated the impact of the intervention on growth quotients, children's diets,
      parent-child interaction, home environment, and mothers' perceived stress.
      METHODS: The sample consisted of 39 children (ages 3 months to 3 years) with
      growth deficiency in weight or height for age, weight for height, or a decrease
      in growth across two percentiles. The children were enrolled in Special
      Supplemental Feeding Program for Women, Infants and Children (WIC) clinics in
      county health departments and were randomly assigned to experimental or control
      groups. After preliminary data were collected for the entire sample, a community
      based intervention was administered to the experimental group during home visits.
      The intervention included education about nutrition and about parenting and
      community skills. RESULTS: Data collected after the intervention by a research
      assistant blind to group assignment indicated positive changes (P < or = .05) in
      the experimental group's growth quotients, home environments, and their mothers'
      perceived stress. DISCUSSION: This study supports the community health nursing
      practice of teaching nutrition and child care during home visits to families of
      children with growth deficiency.

PMID- 10392108
TI  - Otitis media: an update.
AB  - Otitis media in children continues to be a major challenge for health care
      providers. With the emergence of resistant organisms and the increase in the
      incidence of otitis media, the management of this disease has become increasingly
      complex. The pathogenesis of otitis media is discussed, standardized terminology
      is presented, and current strategies are described. In addition, suggestions for
      managing this common illness incorporating the Agency for Health Care Policy and
      Research Guidelines on Otitis Media with Effusion in Young Children are made.

PMID- 10392109
TI  - The R.U.B.B.E.R. tool: screening children for latex allergy.
AB  - The pediatric nurse practitioner may encounter IgE-mediated allergic reactions to
      natural latex rubber not only in patients with spina bifida but also in the
      general pediatric population. The R.U.B.B.E.R. screening tool is a short research
      based questionnaire that elicits unrecognized past allergic reactions to latex
      and identifies children at risk for this condition. Management strategies include
      patient identification, referral for allergy evaluation, patient and family
      education about avoiding latex, and design of a latex-safe practice environment.

PMID- 10392110
TI  - Montelukast: a new medication for pediatric asthma management.

PMID- 10392111
TI  - Sinusitis in an infant.

PMID- 10392112
TI  - Distance education in pediatric nurse practitioner programs.

PMID- 10392113
TI  - Evaluating information on the Internet.

PMID- 10392114
TI  - Evidence-based practice: a role for nurse practitioners.

PMID- 10392115
TI  - Clinical governance: a very useful tool.

PMID- 10392116
TI  - Confidential enquiry into stillbirths and deaths in infancy.

PMID- 10392117
TI  - A home from home.

PMID- 10392118
TI  - Individualised bereavement care.
AB  - The stories of nine women who have lost a child in the neonatal period were
      obtained using semi-structured interviews. Interviews were transcribed,
      'anonymised' and sorted into categories. Although the data can be grouped in
      sections according to predominant themes such as 'discontinuation of treatment',
      'photographs and memories', 'partners' and 'conflict over treatment', the stories
      highlight the individual nature of each bereavement experience. Some of the women
      were satisfied with the individualised care they had received, but there were
      examples of staff providing care based on assumptions that would be appropriate
      for most women, but not for the person concerned.

PMID- 10392119
TI  - Supporting breastfeeding mothers.

PMID- 10392120
TI  - Advanced practice in the US. Part Two: PNP voices from the frontline.

PMID- 10392121
TI  - Cystic fibrosis: an alternative approach.
AB  - Sometimes hospital is the best place for patients with cystic fibrosis, says Lyz
      Warren. Here she describes the choices available to children and parents on a
      unit which follows the philosophy adopted by The Children's Trust.

PMID- 10392122
TI  - Using massage in the care of children.
AB  - Touch has long been an under-valued aspect of care, but more nurses are now
      bringing its benefits to patients in the form of massage. Sue Watson reviews the
      literature and discusses how massage can help in the care of infants and
      children.

PMID- 10392123
TI  - Infection control.

PMID- 10392124
TI  - Writing for publication.

PMID- 10392125
TI  - Normal birth--going ... going...

PMID- 10392126
TI  - Policy? What policy? Hospital guidelines on food and drink in labour.

PMID- 10392127
TI  - Complementary medicine and midwifery practice.

PMID- 10392128
TI  - Surrogacy: a commercial proposition?

PMID- 10392129
TI  - Too much of a good thing? The case for a reduced schedule of antenatal visits.

PMID- 10392130
TI  - Should we screen for gestational diabetes?

PMID- 10392131
TI  - Peanut allergy. Minimizing the risk during pregnancy and infancy.

PMID- 10392132
TI  - Midwives discover sex.

PMID- 10392133
TI  - Patterns of routine antenatal care for low-risk pregnancy.

PMID- 10392134
TI  - Health visitors under siege.

PMID- 10392135
TI  - Other people's lives.

PMID- 10392136
TI  - Effective techniques for massage in labour.

PMID- 10392137
TI  - Helping women access maternity rights and benefits.

PMID- 10392138
TI  - What a gas!

PMID- 10392139
TI  - Not to our taste. Midwives failure to feed women in labour.

PMID- 10392140
TI  - Moving audit into midwifery practice.

PMID- 10392141
TI  - Pleased to meet you.

PMID- 10392142
TI  - Peer support for breastfeeding.

PMID- 10392143
TI  - A woman's right not to choose.

PMID- 10392144
TI  - What the textbooks don't tell you. Interviewing pregnant women.

PMID- 10392145
TI  - Worst case scenario. Supporting women who refuse a caesarean section.

PMID- 10392146
TI  - Detection of hearing loss in infants.
AB  - Permanent Congenital Hearing Impairment (PCHI) is a major cause of delay in
      speech and language development. Average age of identification of PCHI and
      subsequent fitting of a hearing aid is currently 18 months. Technology is
      available to screen successfully infants in the neonatal period for PCHI.
      Universal screening of all infants prior to discharge has been shown to be the
      most equitable and efficient method of identifying PCHI. Targeted neonatal
      screening is a good alternative if universal screening is not currently
      available.

PMID- 10392147
TI  - Eating and drinking in labour (I).

PMID- 10392148
TI  - Childbirth in women with a history of sexual abuse (III).

PMID- 10392150
TI  - Midwives and breech births.

PMID- 10392149
TI  - Motherhood and midwifery training.

PMID- 10392151
TI  - Latching on.

PMID- 10392152
TI  - Aiming for excellence. Setting up woman-centred care at Ayrshire Central
      Maternity Hospital.

PMID- 10392153
TI  - Using focus groups in midwifery research.

PMID- 10392154
TI  - The Infant Nutrition Resource Centre.

PMID- 10392155
TI  - Reasons to be cheerful ... one, two, three. How midwives can help women and their
      families with a multiple pregnancy.

PMID- 10392156
TI  - Continuous electronic fetal heart monitoring during labour.

PMID- 10392157
TI  - Holding on tight.

PMID- 10392158
TI  - Which vitamin K preparation for the newborn?

PMID- 10392159
TI  - Waterbirth workshop.

PMID- 10392160
TI  - Microwaved mice.

PMID- 10392162
TI  - Nothing exceeds like success: managed care comes to Medicaid in New York City.
AB  - Nearly every state is encouraging or requiring Medicaid beneficiaries to enroll
      in managed care delivery systems. In New York City, Medicaid officials began with
      an incremental, but not insignificant, managed care initiative. Buoyed by its
      success, New York policy makers tried, and failed, to accelerate the transition
      to managed care. The legacy of that failure still plagues them. A comparison of
      such initiatives in other states indicates that most state officials have
      remembered what New York's leaders temporarily forgot, namely, that Medicaid
      managed care is a complex exercise that demands consultation and consensus
      building.

PMID- 10392161
TI  - Enrollment in the State Child Health Insurance Program: a conceptual framework
      for evaluation and continuous quality improvement.
AB  - Children's enrollment in the State Child Health Insurance Program (SCHIP) is a
      key indicator of program impact. Past studies demonstrate that many children
      eligible for Medicaid or for private employer-based insurance remain uninsured,
      indicating that eligibility does not guarantee either enrollment or access to
      medical care. Important features of SCHIP evaluation include not only eligibility
      thresholds and enrollment volume, but also program retention, transitions in
      coverage, and access to medical care. Focusing on SCHIP features that affect
      children's participation and continuity of coverage would allow states to
      continually improve procedures that affect enrollment. An exploration of federal
      and state policy options suggests several approaches for creating evaluation
      strategies that can stimulate ongoing improvement.

PMID- 10392163
TI  - Treating depressed older adults in primary care: narrowing the gap between
      efficacy and effectiveness.
AB  - There is a gap between the efficacy of treatments for late-life depression under
      research conditions and the effectiveness of treatments as they occur in the
      "real world" of primary care. Considerable evidence supports the efficacy of
      treatments for late-life depression, but many depressed older adults either are
      not recognized or do not receive effective treatment for depression in primary
      care. Older adults face a range of special treatment barriers: knowledge
      deficits; losses and social isolation; multiple medical problems; and lack of
      financial resources. More research is needed to understand these barriers and to
      study the effectiveness of multifaceted, population-based disease management
      interventions for late-life depression in primary care.

PMID- 10392164
TI  - Public advocacy and allocation of federal funds for biomedical research.
AB  - Members of Congress and officials of the National Institutes of Health face
      heightened pressure from public advocacy groups seeking more funding for research
      on specific health conditions. In response, Congress and the Institute of
      Medicine have urged the NIH to create more opportunities for the public to
      participate in decision making on allocation of biomedical research resources.
      The ethical and policy implications of including advocates in the deliberations
      are explored, leading to the conclusion that public participation could
      contribute to more defensible decisions under three conditions: public
      participants are fairly selected and meaningful opinions are solicited; public
      participants look beyond their narrow constituencies to consider the health needs
      of the broader public; and NIH officials develop materials to assist participants
      with their deliberations.

PMID- 10392165
TI  - [Simultaneous radiochemotherapy with cisplatin improves survival in cervical
      cancer].

PMID- 10392166
TI  - [Neoadjuvant radiochemotherapy in soft tissue sarcomas. Optimization of local
      functional tumor control].
AB  - BACKGROUND: Adequate local control rates > 90% and acceptable functional results
      are the paramount goals in the treatment of soft-tissue sarcoma. Purpose of this
      paper is to evaluate response, long-term control, functional outcome and toxicity
      following neoadjuvant radiochemotherapy (RCT) in advanced and recurrent soft
      tissue sarcoma. PATIENTS AND METHODS: Between 1992 and 1998, a total of 23
      patients in whom primary curative limb and function sparing surgery seemed
      impossible entered the study. Sixteen patients had primary and 7 patients
      recurrent sarcoma. The stages according to AJCC/UICC 1997 were as follows: rIA
      (2), rIIA (5) IIA (4), IIB (2), III (7), IV (3). RCT consisted of an accelerated
      split-course radiation (1.5 to 1.6 Gy twice daily, median total dose 60 Gy, range
      60 to 64 Gy, break of 1 week after 30 Gy) with concomitant chemotherapy using
      adriamycin (50 mg/m2/d on days 2 and 30) and ifosfamide (1.5 g/m2/d on days 1 to
      5, 29 to 33). Median follow-up was 26 months (range 2 to 92 months). RESULTS:
      Twenty-two patients underwent surgery with a curative (R0) resection being
      achieved in 20/22 (91%) patients and gross residual (R2) tumor or unclear tumor
      margins (RX) in 1 patient, respectively. Effective tumor-downstaging was
      documented in 4/22 (18%) patients (ypT0: 3 patients, ypT1: 1 patient). Long-term
      local tumor control after R0/RX resection remained 100%. Without prognostic
      impact on tumor response and local control have been the variables primary vs.
      recurrent tumor, grading, stage and gender. Delayed wound healing was only noted
      in 1/22 (5%) patients. Four patients developed distant metastases. Overall-, NED-
      and distant-metastases-free survival rates were 83%, 64% and 68%, respectively,
      at 3 years. Grade 3/4 neutropenia (WHO) was seen after 21/46 (46%) cycles of
      chemotherapy with 1 patient dying of septicemia. The functional results were good
      to excellent in 18/22 (82%) patients. CONCLUSION: Accelerated split-course
      radiation with 60 to 64 Gy and concurrent chemotherapy using
      adriamycin/ifosfamide is a safe and effective treatment for soft tissue sarcoma.
      This regimen may be considered in all cases with recurrent and advanced disease
      not amenable to primary curative or limb sparing surgery.

PMID- 10392167
TI  - [Results of irradiation of inoperable stage III non-small cell lung cancer with
      25Gy in five fractions].
AB  - BACKGROUND: Patients with advanced Stage III inoperable non-small cell lung
      cancer who were not suitable for irradiation with curative doses, were treated at
      the Department of Radiotherapy of the University Hospital of Dresden with 25 Gy
      in 5 fractions over 1 to 2 weeks. Survival of these patients was compared in this
      retrospective study to the survival of patients treated during the same period
      with 60 Gy in 30 fractions. PATIENTS AND METHOD: Between 1985 and 1994 298
      patients were treated for a histologically or cytologically proven non-small cell
      lung carcinoma with 60 Gy in 30 fractions (n = 80), with 40 Gy in 20 fractions (n
      = 26) or with 25 Gy in 5 fractions (n = 192). Overall survival was determined
      using actuarial methods. Prognostic parameters were analyzed using uni- and
      multivariate tests. RESULTS: Median overall survival for all patients was 6
      months (95% confidence interval 5; 7). In univariate analysis, survival of the
      patients treated with 60 Gy was significantly better than survival in the other
      groups. Median survival was 11 months (9; 13) after 60 Gy, 6 months (4; 8) after
      40 Gy and 5 months (4; 6) after 25 Gy. In multivariate analysis the treatment
      schedule lost its significant influence on outcome of the therapy. The most
      important prognostic parameter was the performance status of the patients.
      CONCLUSIONS: When stratified for performance status as the most important
      prognostic parameter the survival time after hypofractionated irradiation to 25
      Gy given in 5 fractions in 1 to 2 weeks was not significantly different from the
      results after conventional fractionation to 60 Gy. Hypofractionated radiation
      schedules are often more convenient for the patient, economical, and have been
      shown to be effective in symptom control. Thus, in clear palliative situations
      hypofractionated treatment with 25 Gy in 5 fractions or a comparable schedule
      appears to be a reasonable therapeutic option.

PMID- 10392168
TI  - Radiotherapy for invasive thymoma and thymic carcinoma. Clinicopathological
      review.
AB  - PURPOSE: This study reports clinicopathological features and outcome of thymic
      tumors. Twenty-seven patients with invasive thymoma and 6 patients with thymic
      carcinoma who had received radiotherapy either primary or postoperatively were
      analyzed retrospectively. PATIENTS AND METHODS: All 33 patients were irradiated
      with a mean dose of 50 Gy after complete resection (16 patients), partial
      resection (9 patients) or biopsy (8 patients). Staging was done according to the
      Masaoka classification; there were 12 Stage II, 12 Stage III and 9 Stage IV
      patients. RESULTS: In patients with invasive thymoma Stage II to IV (median
      follow-up 54.4 months) Kaplan-Meier estimates of overall survival (OS), disease
      specific (DSS) and disease-free survival (DFS) at 5 years were 63.7% (95%
      confidence interval [CI], 42 to 84%), 88.3% (CI, 75 to 100%) and 77.4% (CI, 58 to
      95%), respectively. Among the prognostic factors tested, such as age, myasthenia
      gravis, completeness of surgery and histologic subclassification, total radiation
      dose, and Masaoka Stage, the latter was the only significant predictor of
      improved survival (p = 0.04). Considering local control, radiation dose was a
      significant prognostic factor (p = 0.0006). In patients with thymic carcinoma
      (median follow-up 43.4 months) 5-year DSS, and DFS were 22.2% (CI, 0 to 60%) and
      16.7% (CI, 0 to 46%), respectively. Thymoma as compared to thymic carcinoma had a
      statistically significant better DSS (p = 0.007) and DFS (p = 0.0007).
      CONCLUSION: Postoperative radiotherapy with sufficient doses plays an important
      role as adjuvant treatment in complete or incomplete resected invasive Stage II
      to III thymoma. In unresectable thymoma Stage III to IV as well as in thymic
      carcinoma a multimodality approach should be considered to improve survival.

PMID- 10392169
TI  - [MRI simulation of bronchogenic carcinomas using an open low-field MRI].
AB  - AIM: The initial target volume for primary radiation therapy of lung cancer is
      usually determined with the aid of computed tomography. Due to the axial CT-scans
      the simulation of the RT-field is often difficult. MRI in its superior ability to
      demonstrate and characterize soft tissue and its possibilities of multiplanar
      imaging can be beneficial. As MRI is less available and more expensive the use of
      MRI in radiotherapy planning is still restricted. With the introduction of open
      low-field MRI-systems there is now a cost-saving alternative. The aim of this
      study was the clinical evaluation of the use of a new open low-field MRI in
      radiotherapy planning of bronchogenic cancer. PATIENTS AND METHODS: Fifteen
      patients undergoing primary radiotherapy for lung cancer were studied using an
      open low-field MRI-system (Picker Outlook 0.23 Tesla). Conventional CT-assisted
      treatment planning was compared to a MRI-assisted procedure. Contours from
      coronary T1-weighted MRI-sections were superimposed onto the simulator radiograph
      using a subtrascope (MR-simulation). RESULTS: Open low-field MR-imaging using T1
      weighted sequences resulted in excellent delineation of tumor masses from
      mediastinal fat, the airways and the vascular structures as well as the radial
      tumor infiltration into the vicinity of the lung (Figures 1a to 1c). This allowed
      an exact and reproducible transfer of tumor contours onto the simulator
      radiograph. The MR-simulation led to optimization in the field configuration in
      5/15 patients (Figure 2). CONCLUSIONS: Open low-field MRI-systems can be very
      useful in treatment planning. They are less expensive and need less extensive
      rebuilding compared to high-field MRI-systems. In the radiotherapy planning of
      bronchogenic carcinoma the MR-simulation is reasonable and clinically
      practicable. One of the main advantages of open MRI-systems in comparison to CT
      and standard MRI-systems in radiotherapy planning is that there is a much greater
      variety of treatment positions.

PMID- 10392170
TI  - The effect of melatonin on lipid peroxidation during radiotherapy in female rats.
AB  - BACKGROUND: Because radiotherapy is one of the causes of primary or secondary
      ovarian failure, protection of ovarian functions in the patients receiving total
      body or pelvic radiotherapy is of importance. In this study, we investigated the
      role of melatonin in the oxidative damage in both whole body and ovaries, which
      is caused by radiotherapy. MATERIALS AND METHODS: Eighteen female rats were
      divided into 3 groups, each of which consisted of 6 rats. First group was control
      group receiving no treatment, second group received total body radiotherapy (RT)
      by 2 x 360 cGy only and third group received radiotherapy plus melatonin.
      Malondialdehyde (MDA) levels in both blood and ovarian tissue were detected as
      the indicator of free radical (FR) damage. Levels of erythrocyte superoxide
      dismutase (SOD) and glutathion peroxidase (GPX) in blood were measured as the
      indicators of antioxidant level. RESULTS: Radiotherapy caused a significant
      increase in the levels of MDA in blood and ovarian tissue (p < 0.001). However,
      MDA levels decreased in the radiotherapy plus melatonin group (p < 0.05). SOD and
      GPX levels decreased insignificantly in the radiotherapy only group while they
      increased in the radiotherapy plus melatonin group significantly (p < 0.01 and p
      < 0.05, respectively). CONCLUSION: Melatonin, in rats, reduced the level of MDA,
      which is elevated by radiotherapy and increased the levels of SOD and GPX, which
      are involved in the antioxidant system.

PMID- 10392171
TI  - Radiation induced chromosome aberrations and clonogenic survival in human
      lymphoblastoid cell lines with different p53 status.
AB  - PURPOSE: To better understand the relation of radiation induced chromosome
      aberrations and clonogenic survival in cells with different p53 status. MATERIALS
      AND METHODS: The human lymphoblasts TK6 and WTK1 were derived from the same
      donor, but differ in radiosensitivity, p53 status and kinetics of apoptosis. TK6
      cells have wild type p53 (p53wt), whereas WTK1 cells have a mutated, non
      functional p53 (p53mut). Additionally, a HPV16 E6 transfected TK6 cell line
      (TK6E6), which is also negative for p53 function (p53neg), was studied. The cells
      were irradiated, incubated with colcemid, hypotonically lysed and fixed. After
      staining with Giemsa, asymmetric chromosomal exchange type aberrations were
      counted in 50 mitoses each per dose point (0 to 4 Gy). Clonogenic survival was
      determined using the microtiter plate assay. All experiments were performed in
      triplicate. RESULTS: WTK1 (p53mut) show a higher spontaneous frequency of
      chromosome aberrations than TK6 (p53wt). No significant differences were noted in
      radiation induced aberration frequency. TK6E6 (p53neg) show comparable aberration
      frequencies like TK6. However, the dose required to reduce survival to 10% (D10)
      was about 2 Gy for TK6 and TK6E6, whereas the D10 for WTK1 was approximately 3
      Gy. CONCLUSION: The p53 status influences the radiosensitivity in this
      lymphoblast cell system showing a high rate of radiation induced apoptosis. Cells
      with p53mut (WTK1), survive with a damaged genome, because they do not undergo
      apoptosis to loose their clonogenicity. There was no difference between the p53wt
      (TK6) and p53neg cells (TK6E6) suggesting a suppression of radiation induced
      apoptosis by p53mut.

PMID- 10392172
TI  - [Delayed cardiac effects of adjuvant doxorubicin and radiotherapy in breast
      cancer patients].

PMID- 10392173
TI  - [Efficacy and toxicity spectrum of continuous infusion of 5-fluorouracil compared
      with bolus administration in advanced colorectal tumors].

PMID- 10392174
TI  - [Efficacy of bilateral mastectomy in women with familial breast cancer].

PMID- 10392175
TI  - [Accelerated hyperfractionated compared with conventional radiotherapy in limited
      small-cell lung carcinoma, with concurrent chemotherapy].

PMID- 10392177
TI  - [US or CT-guided percutaneous drainage of pancreatic pseudocyst].
AB  - Authors, after illustrating the pathogenesis of Pancreatic Pseudocysts (PPC) and
      classifying them into secondary to acute pancreatitis and arising in course of
      chronic pancreatitis, underline that the use of Ultrasound (US), CT-scan,
      Magnetic Resonance, Endoscopic Retrograde CholangioPancreatography and, above
      all, percutaneous drainage of the cysts has modified the therapeutic approach to
      this pathology. They describe indications and technique of US or CT-guided
      percutaneous drainage, and report their experience about 12 cases of PPC
      secondary to acute pancreatitis and 4 of PPC arising during chronic pancreatitis.
      They analyze the limits of this technique (risk of infections, recurrences,
      fistulas), and conclude that Percutaneous Drainage of Pancreatic Pseudocysts is a
      useful therapeutic approach in the treatment of PPC secondary to acute
      pancreatitis, while its use is complementary to surgery in the treatment of PPC
      due to chronic pancreatitis.

PMID- 10392176
TI  - [Physiopathology of intestinal anastomoses and dehiscences].
AB  - A lot of mechanisms of healing of intestinal anastomoses has been explained. A
      leading role in the intestinal wall is made by the submucosal tunica, where
      collagen synthesis and degradation process take place, but local and systemic
      factors are present by a definite causal action. Technique of suture, materials
      and surgeon's experience are of fundamental importance for the success of
      operation, even if in some cases it is important to take in consideration the
      clinical situation: emergency or not, the patient's state and age, concomitant
      diseases, pharmacological or radiotherapeutic treatments. Nowadays surgical
      research tends towards biochemical and molecular field to identify the factors,
      that speed up the healing process to use them in suturing materials getting a
      quick healing as soon as possible.

PMID- 10392178
TI  - [Giant fibrovascular polyp of the esophagus].
AB  - Fibrovascular polyps of the oesophagus are rare tumor-like lesions characterized
      by development of the peduncolated intraluminal masses that can reach gigantic
      size and may have spectacular clinical presentation including regurgitation of a
      fleshy mass into the mouth and can lead to sudden death for occlusion of the
      larynx. Starting from a case observed and successfully treated by transoral
      resection we review the clinical radiographic and pathological findings of benign
      oesophageal tumor that requires surgical removal because of the progressive
      nature of the symptoms and the small, just known, risk of sudden death. The
      approach depends on the pedicule site.

PMID- 10392179
TI  - [Medullary carcinoma of thyroid gland].
AB  - The authors present the characteristic features of medullary carcinoma of thyroid
      (CMT) and underline the necessity to identify RET proto-oncogene that is the
      cause of hereditary transmission of CMT. Physiology of C cells and clinical
      syndromes are reported and the importance of a genetic screening in population at
      risk is emphasized; this test has shown to be reliable and easy to apply. They
      report their experience on techniques of amplification and restriction for RET
      proto-oncogene identification in relatives of patients with MEN or familial CMT
      syndromes. This study has allowed to recognize a population bearing the oncogene
      responsible of the disease and to achieve a correct prophylactic therapeutic
      management.

PMID- 10392180
TI  - [Nuclear risk and thyroid neoplasms in infancy].
AB  - Thyroid carcinoma is a disease with low incidence in adult and rare in child. The
      authors give oncogenic risk factors of the disease and underline environment
      factors as iodine deficiency and radiation pollution that, as shown in certain
      world areas, has a strong effect in the epidemiology of this disease. Eventually
      radiation's are the most important oncogenic risk factors but and adequate iodine
      prophylactic program can be considered a valid shield to prevent this disease.

PMID- 10392181
TI  - [Breast cancer in elderly women].
AB  - Breast cancer represents an important epidemiological and clinical problem, and
      the elderly age represents a large proportion of women with breast cancer. In
      patients older than 65-year, the frequency of breast cancer is 50% and more.
      Early diagnosis and adequate therapy may play an important role also in the
      elderly. We performed a retrospective analysis of 146 women older than 65-year to
      determine the effect of age in management of the disease.

PMID- 10392183
TI  - [Principles of rehabilitation of patients with ileostomy].
AB  - Authors, believing that ileostomy is the cause of serious clinical, functional
      and psychological consequences, dwell upon principles of rehabilitation, which
      aim is the reinstatement of ileostomized patients into daily life. The most
      important aspect is to select the position of the stoma; it is necessary to
      consider some technical and functional aspects. The Authors examine local
      problems of the stoma, the unstable electrolytical balance, and report some
      therapeutical aspects. They expose early and late complications after surgical
      therapy and conclude underlining the advantages of a rapid social reinstatement
      of patients with an ileostomy.

PMID- 10392182
TI  - [Complications of peptic ulcer disease in the elderly].
AB  - Peptic disease is even more described in the elderly patients. Is it different
      from the young people peptic disease? Is it a specific syndrome? These questions
      are debated by the authors from their experience about in the old age surgery. In
      1997, out of 569 oesophago-gastro-duodenoscopies positive for peptic disease,
      about 2/5 of the patients were older than 65-year with a high percentage of
      hypersecretive patients. Also the incidence of complications is similar in the
      aged and young patients, but their course is much more serious in the elderly.
      NSAID therapy was not always demonstrated as a determining factor of
      complications in the elderly. The ulcer perforation is the most serious
      complication; in the over-70 year aged persons a very severe course is often
      demonstrated. In conclusion in the elderly a specific diagnostic and therapeutic
      care is recommended to avoid the high incidence of deadly complications.

PMID- 10392184
TI  - [Stomach cancer in the elderly].
AB  - Gastric cancer often affect very old patients even if it is not a typical disease
      of the elderly. The Authors report their experience on 108 patients (mean age of
      77.8 years) affected by gastric cancer; early diagnosis and surgical technique
      are discussed.

PMID- 10392185
TI  - [Alpha-glucosidase and alanine-amino-peptidase in the early diagnosis of renal
      failure in obstructive jaundice].
AB  - Renal failure is a serious complication of obstructive jaundice. Early diagnosis
      and prevention of spontaneous evolution of the disease can improve prognosis,
      otherwise very poor in many cases. The Authors, on the basis of experimental
      researches from literature, expose their clinical experience about the validity
      of the determination of Alpha-Glucosidase and Alanine-Amino-Peptidase for early
      diagnosis and differentiation between organic or functional forms of renal
      failure. They conclude that determination of urinary levels of AGS and AAP is a
      valid aid for the evaluation of renal function in patients with obstructive
      jaundice.

PMID- 10392186
TI  - [Surgery of inguinal and femoral hernia in the elderly].
AB  - Old people are continuously increasing in frequency but age is not a significant
      factor to value the operative risk in hernia surgery. From June 1985 to December
      1996, 189 patients, aged > 80-year, were submitted to hernia surgery. No
      complications were noted when elective surgery was performed. Emergent procedure
      was undertaken in 7% of the patients major perioperative complications and one
      death were registered in this group of patients. Mean hospital stay has decreased
      in the period of the study: was 2.2 days in the last two years. Local anesthesia
      permitted a day surgery procedure in 60% of cases.

PMID- 10392188
TI  - [Radical surgery in stomach cancer].
AB  - One hundred ninety-six patients with gastric adenocarcinoma underwent surgical
      resection at the Istituto di 1a Clinica Chirurgica di Padova from 1983 through
      1997. Sixty-six patients (66%) underwent total gastrectomy and 53 patients
      (36.2%) subtotal distal gastrectomy macroscopically curative (H0, P0, S0-2, R0),
      in all the cases associated to incomplete D2-D3 loco-regional lymphadenectomy.
      Postoperative morbidity was zero after partial gastrectomy and 3% after total
      gastrectomy. Five-year survival, analyzed retrospectively, after total
      gastrectomy was 75% for stage I and II (56% in presence of lymph nodes metastases
      and 94% in absence) and 15% for stage III and IV; it was instead 65% for stage I
      and II (57 in presence of lymph nodes metastases and 73% in absence) and 50% for
      stage III and IV after partial gastrectomy. In a prospective study 5-year
      actuarial survival was 61% after total standard gastrectomy, 76% in the extended
      forms and 91% after partial gastrectomy, overall 5-year survival in stage I and
      II was 70%.

PMID- 10392187
TI  - [Changes in serum levels of folic acid after total gastrectomy].
AB  - The Authors, in consideration that Folic Acid is assimilated in the upper
      alimentary tract, effected a comparative study between its seric levels in normal
      patients and in patients submitted to gastrectomy for gastric cancer, at
      different times from the operation. In the patients of the first group, Folic
      Acid levels were not correlated with sex, but to age, decreasing with the
      increasing of it. In gastrectomized patients, serum levels, also if acceptable,
      were always lower than in control cases, and gradually decreasing with the
      increasing of the age. The Authors conclude that, obviously, intestinal
      assimilation and endogenous reserves are able to counterbalance for enough long
      time the insufficient alimentary absorption.

PMID- 10392189
TI  - [Port site metastasis. Prospective study of 131 cases].
AB  - Laparoscopic staging and laparoscopic treatment of gastrointestinal malignancy is
      still controversial because some studies report port sites metastases. The aim of
      the study is to determine in 131 patients, with prospective follow-up, after
      laparoscopic staging or laparoscopic treatment, the incidence of port site
      metastases. 131 patients with localized a gastrointestinal malignancy or other
      advanced malignant tumors were included. In 57 cases only laparoscopic staging
      was performed, in 25 cases the laparoscopic staging was followed by a
      laparoscopic resection and in 49 cases after laparoscopic staging a traditional
      laparotomic treatment was performed. In 57 cases (43.5%) the tumor invaded the
      serosal layer. The median follow-up was 17.7 months (3 to 62 months). 502 port
      sites were controlled. One patients (0.7%) presented one port site metastases
      after right colectomy for carcinoma with local carcinomatosis. This study confirm
      that port sites metastases are rare, and that are favorised by serosal invasion
      and support the laparoscopic staging of malignant abdominal tumors in order to
      recognize occult lesions which are not detected by conventional preoperative
      clinical, biological and radiological explorations (44.2% in this study). In
      addition, selected patients can be submitted to laparoscopic treatment of the
      disease (20%).

PMID- 10392190
TI  - [Hepatic vascular exclusion: indications and results].
AB  - The demonstration that the liver can tolerate prolonged periods of normothermic
      ischaemia represents one of the most significant developments in liver resection
      surgery. It has permitted the application of techniques involving the temporary
      interruption of blood flow to the liver, with the aim of reducing bleeding during
      resection. This has led to a widening of the range of indications for the
      excision of lesions with a high risk of bleeding, and a reduction in the number
      of blood transfusions. This study analysed the results of 125 liver resections,
      19 of which involved cirrhotic liver, carried out under conditions of
      normothermic ischaemia obtained by complete clamping of the hepatic pedicle
      either alone (112 patients) or together with caval clamping (13 patients). The
      mean duration of the ischaemia was 39 minutes (7-107). Eighty-two resections
      (65.6%) were carried out without transfusions; the mean number of units
      transfused in the other 43 cases (34.4%) was 2.1 +/- 1.3. The postoperative
      mortality rate was 0.9%; twenty-six patients (20.8%) developed postoperative
      complications and the incidence of liver failure was 5.6%. Postoperative
      disturbances of liver function tests were transitory and, in most cases, rapidly
      resolving.

PMID- 10392191
TI  - [Stromal tumors of the stomach. Our experience with 25 patients].
AB  - Stromal tumors (GIST) represent 5% of gastric neoplasms. Twenty-five patients
      with GIST underwent surgical operation: the tumor was benign, malignant, and
      borderline in 11, 12, and 2 cases, respectively. Main symptoms were abdominal
      pain (36%), and digestive haemorrhage (32%); 4 patients (16%) complained of
      abdominal mass. In 5 patients the diagnosis was incidental. Surgical operations
      (12 local resections, 9 partial gastric resections, and 4 total gastrectomies)
      were macroscopically curative in all the patients. In 3 patients the resection
      was extended to liver (1 case), spleen, pancreatic body-tail, and left kidney (1
      case), and diaphragm (1 case) because of contiguous involvement of these organs.
      Postoperative mortality and morbidity were 4% and 20%, respectively. A patient
      with benign GIST passed away 36 months after operation because of breast cancer
      disease; other 9 patients are alive from 3 months to 25 years after operation.
      Three patients with low grade malignant GIST are well at mean follow up of 53
      months. The 9 patients with high grade neoplasms are all dead (median survival
      time: 18 months). The 2 patients with borderline tumors are alive without
      evidence of disease at 3 and 8 years.

PMID- 10392192
TI  - [Emergency surgical management of lesions from ingestion of caustics. Role of
      primary endoscopic classification].
AB  - Management of caustic ingestion in adults improved in the last decade due to the
      new diagnostic developments, the better predictability of injuries from signs and
      symptoms, the intensive care improvements and the more aggressive surgical
      approach for the most severe lesions. In fact, the early surgical treatment of
      severe lesions for ingestion of caustic and corrosive substances may reduce
      mortality, morbidity and hospitalization. The role of early endoscopic
      examination is today worldwide accepted: is herein proposed a new endoscopic
      classification of caustic lesions adjusted after a retrospective analysis of a
      twenty years experience in this field, and applied in twelve patients affected by
      severe esophageal and gastric injuries then submitted to emergency surgical
      treatment and survived. It showed a great usefulness in selection of patients to
      submit immediately to surgery and may play a fundamental role in indications and
      timing of surgical management of severe injuries by caustic ingestion.

PMID- 10392193
TI  - [Surgical management of hereditary medullary carcinoma of the thyroid in patients
      with "RET" proto-oncogene mutation].
AB  - The authors report their results in 64 individuals belonging to 11 families with
      MEN 2 and familial medullary carcinoma of thyroid (CMT) syndromes. They show
      amplification and restriction techniques, type, site and incidence of genetic
      alteration in the observed cases; besides they illustrate the adopted surgical
      management related to the mutation. They stress the concept that genetic test
      allows to detect the population with altered gene before laboratory or clinical
      evidence, with the great advantage to indicate an early surgical approach. If it
      is shown a multi-organ disease, as in one patient with CMT associated with
      bilateral pheocromocytoma, the two diseases must be treated during the same
      operative time.

PMID- 10392194
TI  - [Surgical resection of lung metastases from breast cancer. Report of 12 cases].
AB  - Thirty-nine patients affected with lung metastases from different primary
      neoplastic sites have been treated between 1990 and 1998 at 2nd Surgical Division
      of "Regina Elena" National Cancer Institute of Rome. Among them, 12 were
      metastases from breast cancer-lung metastases were isolated in 9 cases and
      multifocal in 3 cases, although always in the same lung. Nine cases underwent a
      thoracotomic approach: in 6 patients we have performed a wedge resection, in 3
      cases a lobectomy. Three patients underwent a wedge resection by means of a video
      thoracoscopic approach. We have registered 2 post-operative complications and no
      deaths. Median survival rate was 40 months and 5 year actuarial survival rate was
      42%. Surgery for isolated lung metastases seen to be a safe approach and to
      improve life expectancy in most of patients.

PMID- 10392195
TI  - [Severe pelvic injuries: indications and techniques of skeletal fixation].
AB  - The aim of this work is to assess the role of immediate Hoffmann's external
      fixation frame and delayed posterior internal fixation in the management of
      severe pelvic injuries. We have also analysed the role of selective arteriography
      and embolization for controlling pelvic fractures hemorrhage and the relationship
      between embolization and external fixation in the management of severe bleeding.
      We reviewed 112 patients with severe pelvic injuries admitted to our hospital
      from 1986 to 1998 (71 males, 41 females). The average age was 39.8 years, mean
      ISS 31.2. Unstable pelvic ring fracture was present in 59 (52.6%) patients at
      admission in the emergency room: hemorrhagic shock in 43 patients (38.3%).
      Fourteen (12.5%) patients died. Eight deaths (57%) were directly caused by
      hemorrhagic shock, two secondary to major caval lesion, three brain lesions and
      two respiratory failure. The last patient died secondary to MOF. Twenty-three
      patients (20.5%) with unstable fracture underwent pelvic fracture ring fixation
      surgery: eleven (9.8%) Hoffmann's anterior external fixation frame (hemorrhage
      control in all patients) and eight (7.1%) delayed internal posterior fixation.
      Six (5.3%) patients underwent arteriography and embolization: hemorrhage was
      stopped in all cases and no patient died in this group.

PMID- 10392196
TI  - Insular carcinoma of the thyroid. A report of 8 cases.
AB  - Insular carcinoma of the thyroid (ICT) is an uncommon malignancy with
      intermediate morphology and behaviour between well-differentiated and anaplastic
      thyroid carcinoma. Eight patients with ICT underwent total thyroidectomy. A
      modified neck dissection was carried out in six of them. Cervical lymph nodes
      metastases were detected during surgery in six patients or at scintigraphy in two
      patients who did not undergo neck dissection. Postoperatively, a patient
      developed diffuse metastases not detected by 131I whole-body scintigraphy and she
      died of disease 6 months later despite radio- and chemotherapy. Another patient
      had distant metastases detected by 131I whole-body scintigraphy and successfully
      treated by radioiodine ablative therapy. Unfortunately, she developed other
      distant metastases with no 131I uptake and died of disease 23 months later
      despite chemotherapy. After a mean follow-up of 5.5 years, 6 patients (75%) were
      alive without evidence of disease. These observations confirmed the
      aggressiveness of ICTs that sometimes are not responsive to current available
      therapies. The frequent occurrence of metastases to the regional lymph node calls
      on for a modified neck dissection in all patients with ICT.

PMID- 10392197
TI  - [Non-infiltrating breast cancers].
AB  - We have taken stock about incidence, diagnostic problems, anatomic-pathological
      features, prognosis and treatment of non-infiltrating breast cancers, that are
      the lobular cancer in situ (LICS), and the duct cancer in situ (DCIS). It's been
      pointed out the shortage of specific aspect into the images diagnostics for LICS;
      besides it's been pointed out the control to keep for these kinds of tumor, that
      has to be of preservative type ("wait and see"). About DCIS, we have showed some
      still open problems, especially the difficulty in finding a prognostic criterion
      about the evolution of the disease forward invasive forms. It follows that there
      is the difficulty in defining a real treatment that should reconcile the presence
      of a non-invasive damage with the need of guaranteeing the recovery. In the age
      of preservative treatments of invasive forms, mastectomy (that is still often
      carried out), could seem to be an overtreatment, so we've showed the studies
      results, which could let us think that a preservative treatment, joined to the
      radiotherapy, could be really preferred.

PMID- 10392198
TI  - [Duodenal gangliocytic paraganglioma: intraoperative ultrasound evaluation].
AB  - Case report. A case of obstructive jaundice due to a preoperative unrecognized
      rare periampullary tumor, histologically demonstrated to be a gangliocytic
      paraganglioma of duodenum associated with Von Recklinghausen's disease, is herein
      reported. Intraoperative ultrasonography guided identification and evaluation of
      the obstructing lesion, suggesting in Whipple's procedure the most suitable
      treatment. The clinical case and ultrasonographic and Color Doppler findings are
      in detail described.

PMID- 10392199
TI  - Vagus nerve stimulation for medically refractory epilepsy; efficacy and cost
      benefit analysis.
AB  - INTRODUCTION: Vagus nerve stimulation is a novel treatment for patients with
      medically refractory epilepsy, who are not candidates for conventional epilepsy
      surgery, or who have had such surgery without optimal outcome. To date only
      studies with relatively short follow-up are available. In these studies efficacy
      increased with time and reached a maximum after a period of 6 to 12 months.
      Implantation of a vagus nerve stimulator requires an important financial
      investment but a cost-benefit analysis has not been published. PATIENTS AND
      METHODS: Our own experience with VNS in Gent comprises 15 patients with mean age
      of 29 years (range: 17-44 years) and mean duration of epilepsy of 18 years
      (range: 4-32 years). All patients underwent a comprehensive presurgical
      evaluation and were found not to be suitable candidates for resective epilepsy
      surgery. Mean post-implantation follow-up is 24 months (range: 7-43 months). In
      patients with follow-up of at least one year, efficacy of treatment in terms of
      seizure control and seizure severity was assessed one year before and after the
      implantation of a vagus nerve stimulator. Epilepsy-related direct medical costs
      (ERDMC) before and after the implantation were also compared. RESULTS: A mean
      reduction of seizure frequency from 14 seizures/month (range: 2-40/month) to 8
      seizures/month (range: 0-30/month) was achieved (Wilcoxon signed rank test n =
      14; p = 0.0016). Five patients showed a marked seizure reduction of > or = 50%; 6
      became free of complex partial seizures, 3 of whom became entirely seizure free
      for more than 12 months; 2 patients had a worthwhile reduction of seizure
      frequency between 30-50%; in 2 patients seizure frequency reduction has remained
      practically unchanged. Seizure freedom or > or = 50% seizure reduction was
      achieved within the first 4 months after implantation in 6/11 patients. Before
      the implantation, the mean yearly epilepsy-related direct medical costs per
      patient were estimated to be 8830 US$ (n = 13; range: 1879-31,129 US$; sd =
      7667); the average number of hospital admission days per year was 21 (range: 4
      100; sd = 25.7). In the 12 months after implantation, ERDMC had decreased to 4215
      US$ (range: 615-11,794 US$; sd = 3558) (Wilcoxon signed rank test n = 13; p =
      0.018) and the average number of admission days to 8 (range: 0-35) (Wilcoxon
      signed rank test n = 13; p = 0.023). CONCLUSION: VNS is an effective treatment of
      refractory epilepsy and remains effective during long-term follow-up. Cost
      benefit analysis suggests that the cost of VNS is saved within two years
      following implantation.

PMID- 10392200
TI  - Open MRI-guided neurosurgery.
AB  - OBJECTIVES: A number of different image-guided surgical techniques have been
      developed during the past decade. None of these methods can provide the surgeon
      with information about the dynamic changes that occur intra-operatively. MATERIAL
      AND METHOD: The first vertical open 0.5T MRI-scanner for intra-operative MRI
      guided neurosurgery in Germany was installed at the University of Leipzig during
      the summer 1996. Since autumn 1996 a number of surgical procedures including
      biopsies (n = 31), craniotomies (n = 32), transsphenoidal procedures (n = 8) and
      interstitial lasertherapies (n = 3) have been performed using intra-operative MR
      image guidance. RESULTS: The development of MR-compatible and MR-safe non
      magnetic instruments and components had to be solved. Specific surgical
      instruments were developed to perform biopsies, craniotomies, microsurgical
      tumour resections and transsphenoidal procedures in the 0.5-T open MRI. Several
      components required adaptation including the head holder the stereotactic
      navigation device, the high speed drill, the suction unit, the ultrasonic
      aspirator, the bipolar coagulation, the laser probe and the surgical microscope.
      All these newly developed technical features enable the neurosurgeon to perform a
      large number of surgical procedures under direct control and guidance of intra
      operative MR imaging. In contrast to frame-based for framless navigation systems,
      intra-operative MRI provides accurate and immediate information during the
      progress of surgery. These intra-operative images allow definitive localization
      and targeting of the lesions and accommodate anatomical changes that may occur
      during surgery. CONCLUSION: Intra-operative MRI is helpful for navigation as well
      as determining of tumour margins to achieve a complete and safe resection of
      intracranial lesions. Complications related to the surgical procedure are reduced
      and the risk of neurological deterioration due to tumour removal and
      postoperative complications is minimized. It can be concluded that the intra
      operative application of interventional MRI technology may represent a major step
      forward in the field of neurosurgery.

PMID- 10392201
TI  - Premeatal and retromeatal cerebellopontine angle meningioma. Two distinct
      clinical entities.
AB  - OBJECTIVE: Meningiomas represent the second most common type of neoplasm of the
      cerebellopontine angle (cpa). Their relationship to critical neural or vascular
      structures of the cpa is variable and they present with different signs and
      symptoms. MATERIALS AND METHODS: A retrosigmoid craniotomy was performed in 31
      cpa-meningiomas from January 1981 to February 1997. The mean age of the 25 women
      (81%) and the 6 men (19%) was 53 +/- 13 years. According to their location within
      the posterior fossa and with special reference to the internal auditory canal
      (IAC), they were classified in 17 cases (55%) as retromeatal (posterior to the
      iac) and in 14 cases (45%) as premeatal (anterior to the iac). RESULTS: The
      retromeatal group showed a significantly larger tumour size (21 +/- 15 vs 29 +/-
      20 mm) and the diagnosis was made later (2.7 +/- 3.2 vs 1.1 +/- 0.9 years)
      compared to premeatally located meningiomas. Before the operation, a reduction of
      the facial nerve function (64% vs 0%) and hearing function (100% vs 25%) was
      present significantly more often in premeatal meningiomas. The clinical
      appearance of the retromeatal group was dominated by cerebellar symptoms (44% vs
      0%). Both preoperative and postoperative impairment of facial nerve and auditory
      function prevailed in the premeatal group. CONCLUSION: The topological
      classification of CPA-meningiomas according to their location anterior or
      posterior to the ICA is important, because the clinical presentation, the
      surgical strategy to be applied, and the functional outcome of critical neural
      structures differ between the two subtypes. Our results provide substantial
      evidence for the paradoxical observation that premeatal meningiomas have a
      significantly worse postoperative functional outcome compared to retromeatal
      meningiomas although premeatal meningiomas become symptomatic earlier and at
      smaller sizes.

PMID- 10392202
TI  - Gamma knife radiosurgery of meningiomas in the cavernous sinus region.
AB  - For 6 years (1992-1998) we have treated 67 patients with cavernous sinus
      meningioma using the Leksell gamma knife in the Hospital Na Homolce, Prague. The
      age of the patients ranged between 19-82 years, median 57 years. Radiosurgery was
      the primary treatment in 64.2% of the patients, in the rest a microsurgical
      resection preceded. The volume of the tumour ranged from 0.9-31.4 cm3, median 7.8
      cm3. The meningioma was distant from the optic tract in 58% of the cases, in 12%
      of the cases there was a contact with the tumour and the optic tract without its
      compression and in 30% of the cases there was a compression of the optic tract
      caused by the meningioma. The dose to the tumour margin ranged from 10-14 Gy,
      median 12 Gy. The follow up was available in 53 patients, in intervals of 2-60
      months, median 19 months. There was no change in the tumour volume in 48% of the
      cases, in 52% of the cases a decrease of the tumour volume occurred. No increase
      of the tumour volume was observed. Clinical symptoms and signs improved in 35.8%
      of the patients, temporary morbidity was 3.8%. The mortality of the treatment was
      zero. Hitherto, the results of gamma knife radiosurgery of cavernous sinus
      meningioma have proved its safety and efficiency, although long term experience
      with a large group of patients is missing. Advances in neuroradiology and
      radiosurgical technique have allowed us to treat tumours with a closer contact to
      the optic tract and nerves compared with the past.

PMID- 10392204
TI  - Extradural balloon obliteration of the empty sella report of three cases
      (intrasellar balloon obliteration).
AB  - Empty sella syndrome is an anatomical and clinical entity composed of intrasellar
      reposition of the CSF and compression of the pituitary tissue, resulting in a
      clinical picture of headache, visual field defect, CSF rhinorrhea and some mild
      endocrinological disturbances. While some cases are primary with no appreciable
      aetiology, secondary cases are associated with prior operation or radiotherapy of
      the region. In our series, 3 patients with primary empty sella syndrome were
      treated by the current approach of extradural filling of the sellar cavity. This
      technique was first described by Guiot and widely accepted thereafter. We used a
      detachable silicon balloon filled with HEMA or liquid silicone for obliteration
      of the sellar cavity and obtained clinically satisfactory results without
      complications. Visual symptoms regressed and headache disappeared. But at long
      term follow-up all the balloons were found to be deflated. Despite the facility
      and efficacy of the technique we do not recommend it in the treatment of the
      empty sella because the filling of the sella is only transient and relapses may
      occur.

PMID- 10392203
TI  - Secretion of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase
      1 by meningiomas detected by cell immunoblot analysis.
AB  - To identify features of meningiomas that infiltrate dura mater, and to examine
      the role Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of
      metalloproteinase-1 (TIMP-1) secretion in meningiomas, a cell immunoblot assay
      study was performed in 20 meningiomas. MMP-9 secretion was detected in 20 (100%)
      meningiomas and was independent of histological features. TIMP-1 secretion was
      detected in 8 (40%) meningiomas. For a cell immunoblot volume which included
      approximately 1350 cells, there were 50.4 +/- 49.4 dots which showed
      immunoreactivity to MMP-9 and 2.0 +/- 4.2 which showed immunoreactivity to TIMP
      1. The number of dots that showed immunoreactivity to MMP-9 was not significantly
      different between tumours with atypical and benign histological features. TIMP-1
      secretion was found in only 8 (40%) specimens and the percentage of TIMP-1
      secreting cells was significantly lower than that of MMP-9 secretion. Thus, we
      propose that meningiomas classified histologically as both atypical and benign
      have the potential to infiltrate dura mater.

PMID- 10392205
TI  - Neurovascular compression syndrome of the eighth cranial nerve. Can the site of
      compression explain the symptoms?
AB  - Considerable skepticism still exists concerning the concept of neurovascular
      compression (NVC) syndromes of the eighth cranial nerve (8th N). If such
      syndromes exist, the sites of compression of the nerve must explain the symptoms
      encountered. We recorded compound action potentials of the cochlear nerve (CCAPs)
      during neurovascular decompression (NVD) to examine the topography of the three
      components of the 8th N. The sites of compression of the 8th N in cases of NVC
      syndrome confirmed at surgery were superimposed on the topography of the CN and
      vestibular nerve (VN) in order to determine the relationship between the sites of
      compression and the symptoms. CCAPs were clearly and consistently recorded on the
      caudal surface of the 8th N along the midline. In patients with vertigo and
      tinnitus there was vascular compression of the rostroventral (VN) and caudal
      surface (CN) of the nerve, respectively. In patients with both vertigo and
      tinnitus, there was compression of both VN and CN. Our findings clearly
      demonstrate that the symptoms of NVC of the 8th N depend on the part of the nerve
      that is compressed by blood vessels, and they support the concept of NVC syndrome
      of the 8th N.

PMID- 10392206
TI  - Endovascular stent placement for cervical internal carotid artery aneurysm
      causing cerebral embolism: usefulness of neuroradiological evaluation.
AB  - We present a case of a cervical internal carotid artery aneurysm that caused
      cerebral embolism. This lesion was supposed to be a dissecting aneurysm due to
      blunt neck injury. The large aneurysm with intramural thrombus was treated with
      endovascular placement of a balloon-expandable stent. Both CT and MRI were useful
      for evaluating the size and characteristics of the aneurysmal wall. Intravascular
      ultrasound imaging was also useful for evaluation of the satisfactory stent
      deployment and identification of the neck of the aneurysm. We discuss
      effectiveness of endovascular stenting for cervical internal carotid artery
      aneurysm with intramural thrombus and the usefulness of a combination of the
      neuroradiological imaging before, during and after the interventional procedure.

PMID- 10392207
TI  - The prognostic importance of the volume of traumatic epidural and subdural
      haematomas revisited.
AB  - The size of a traumatic intracranial haematoma at the moment of diagnosis can be
      impressive. Haematoma thickness is an inaccurate estimator of haematoma volume,
      and association with patient outcome is controversial. In this study computerized
      volumetry of offline digitized CT scans was used to relate haematoma volume with
      both patient characteristics on admission and at the six months outcome. This
      retrospective study covered the time period 1981/1990. Ninety eight patients
      operated upon for an epidural haematoma and 91 patients operated upon for an
      acute subdural haematoma were analyzed. The relative importance of clinical data,
      CT scan parameters, and calculated haematoma volumes was determined by
      multivariate analysis. Volume of the haematoma did not correlate with
      preoperative neurological condition or the six months outcome in either group,
      and consequently is not of additional prognostic value.

PMID- 10392208
TI  - Primary brainstem injury: benign course and improved survival.
AB  - Primary brainstem injury following head injury is a rare event. The victims often
      have features of supratentorial injury, and a primary isolated injury to the
      brainstem occurring due to shearing stresses or to injury from the tentorial edge
      is extremely rare. In the presence of supratentorial injury, these patients may
      have altered sensorium. Isolated brainstem injury may manifest itself as
      internuclear ophthalmoplegia, anisocoria, rigidity and cerebellar tremor. Such
      injuries are now being diagnosed more often due to improved imaging techniques.
      We treated nine such cases who had sustained primary brainstem injury in road
      traffic accidents, all but one of whom were subsequently independent. Primary
      brainstem injuries need not be associated with poor prognosis and mortality and
      may run a benign course with good quality of survival.

PMID- 10392209
TI  - Percutaneous anterior odontoid screw fixation technique. A new instrument and a
      cadaveric study.
AB  - We describe a new instrument and a percutaneous technique for closed anterior
      fixation of odontoid fracture. The instrument which we developed consists of a
      telescopic tube system. This new instrument and closed fixation technique was
      used in six cadavers with type II odontoid fractures and to two cadavers with an
      intact odontoid process. Each cadaver underwent satisfactory placement of the
      screw to the odontoid with this technique under biplanar scopy control. After
      this procedure, no serious injury was found in the parapharyngeal and
      neurovascular areas of the necks of the cadavers, in which anatomical dissection
      along the track of this instrument was performed. The instrumentation and the
      technique as a whole is seen as reliably applicable for odontoid fracture
      fixation. Also, we expect to reduce operating time and hospital costs because
      this system is simple, easily applicable and minimally invasive.

PMID- 10392210
TI  - An easy and safe method to store and disinfect explanted skull bone.
AB  - In our department extensive decompression craniectomies became the treatment of
      choice for patients with massive cerebral oedema following either trauma or acute
      cerebral infarction. The remarkable survival rates of this neurosurgical
      technique created the problem of adequate vault defect reconstruction. To
      evaluate the biological safety of using stored autologous skull flaps for this
      purpose, we compared three different disinfection methods. Skull bone fragments
      stored at -21 degrees C for different periods of time were artificially
      contaminated with clinically relevant strains of Serratia marcescens,
      Enterococcus faecium and Staphylococcus aureus. As potential methods for
      disinfection we tested immersion in 3% H2O2, boiling in normal saline for 15 and
      30 minutes and a special process of steam disinfection at a temperature of 75
      degrees C for 20 minutes. We were able to demonstrate that only steam
      disinfection completely eliminated the bacterial strains tested. Refrigeration
      plus steam disinfection of autologous skull bone prior to re-implantation seems
      to offer reliable safety for its use for defect closure. It is available at
      reasonable cost in many hospitals and does not require a bone bank.

PMID- 10392211
TI  - Effects of intracisternal methylprednisolone on lipid peroxidation in
      experimental subarachnoid haemorrhage.
AB  - The efficacy of intracisternal methylprednisolone was examined on lipid
      peroxidation in a canine subarachnoid haemorrhage (SAH) model. The concentration
      of lipid peroxides increased significantly in the cerebrospinal fluid (CSF)
      supernatant on Day 4, and also in the arterial wall on Day 7. Intracisternal
      administration of methylprednisolone reduced markedly the products of lipid
      peroxidation both in CSF and in the arterial wall. The findings suggest that
      lipid peroxidation might play a significant role in the genesis of vasospasm
      after SAH, and that direct administration of methylprednisolone into the
      subarachnoid space might reduce lipid peroxides in the arterial wall and so
      influence the prevention of vasospasm.

PMID- 10392212
TI  - Persistent patent pseudolumen of ruptured dissecting aneurysm involving the
      posterior inferior cerebellar artery after proximal clipping.
AB  - In the majority of cases of ruptured vertebral artery dissecting aneurysm after
      proximal clipping, the dissected pseudolumen persists for a very short time,
      probably because re-entry from the pseudolumen is minimal. Recent reports have
      indicated a high risk of rebleeding of dissecting aneurysms involving the
      posterior inferior cerebellar artery (PICA) after proximal clipping, probably due
      to excessive retrograde flow from the distal vertebral artery into both the PICA
      and the pseudolumen. We describe an extremely rare case of ruptured dissecting
      aneurysm involving the PICA with persistent patent pseudolumen after proximal
      clipping. The present case was assumed to have developed a moderate retrograde
      flow just sufficient to maintain the patent pseudolumen in the chronic stage.
      Neointimal formation is suggested to be a possible mechanism by which the
      pseudolumen is stabilized for a very long period.

PMID- 10392214
TI  - Surgery for anterior sacral meningoradiculocele controlled by MR imaging.

PMID- 10392213
TI  - Spontaneous disappearance of temporo-frontal arachnoid cyst in a child.
AB  - We report a child with a large temporo-frontal arachnoid cyst which resolved
      spontaneously. There was no history of a head injury. The patient was a boy aged
      1.6 years. Though a large head was pointed out (+2SD), no therapeutic
      intervention was made because the relationship of the head circumference and the
      cyst was not established. No change in cyst size was visualized on the follow-up
      CTs at the age of 2.5 years and 6 years. At the age of 7 years, the arachnoid
      cyst had completely disappeared on CT. In order not to overlook a minute change
      in cyst size, the volumetry of the cyst and the intracranial cavity was
      performed, using the Photoshop, Macintosh. Both the cyst volume and the volume
      ratio of the cyst to the intracranial cavity slightly decreased and then
      increased. It is speculated that the cyst spontaneously ruptured by factors such
      as extreme breath holding and crying on the presence of the higher intracystic
      tension which might become a factor to accelerate spontaneous rupture of the
      cyst. Since a number of paediatric cases of symptomatic arachnoid cysts in need
      of surgical intervention has been larger than that of adult cases, we can
      speculate that a large arachnoid cyst might spontaneously resolve more frequently
      than we had expected. This case demonstrates that the surgical treatment of
      asymptomatic arachnoid cyst in the middle cranial fossa is not necessarily
      indicated in children.

PMID- 10392215
TI  - Adult growing skull fracture mimicking a skull tumor.
AB  - Growing skull fractures (GSF) are rare in adults. We report the case of an adult
      who was found to have a GSF 50 years after head trauma. This case highlights the
      need to consider GSFs in the differential diagnosis of adults with intradiploic
      skull lesions.

PMID- 10392216
TI  - Intracavitary chemotherapy of polycystic craniopharyngioma with bleomycin.

PMID- 10392217
TI  - Bone metastasis of glioblastoma multiforme confirmed by fine needle biopsy.

PMID- 10392218
TI  - Empathy: a challenge for critical care.

PMID- 10392219
TI  - Women in the intensive care unit.

PMID- 10392220
TI  - The effect of earplugs on sleep measures during exposure to simulated intensive
      care unit noise.
AB  - BACKGROUND: Sleep deprivation may contribute to impaired immune function,
      ventilatory compromise, disrupted thermoregulation, and delirium. Noise levels in
      intensive care units may be related to disturbed sleep patterns, but noise
      reduction has not been tested in this setting. OBJECTIVE: To measure the effect
      of a noise reduction intervention on the sleep of healthy subjects exposed to
      simulated intensive care unit noise. METHODS: After digital audiotape recording
      of noise and development of the noise reduction intervention, 5 nocturnal 8-hour
      periods of sleep were measured in 6 paid, healthy volunteers at 7-day intervals
      in a sleep disorders center. Polysomnographic data were collected by experienced
      sleep disorders technicians and scored by certified raters. After the first 3
      quiet nights, earplugs were randomly assigned to be worn on the fourth and fifth
      nights during exposure to the recorded noise. Sound pressure levels were measured
      during all 5 nights. RESULTS: Sleep architecture and sound measurements on quiet
      nights did not differ significantly. Sound levels were significantly lower on
      quiet nights than on noise nights. Exposure to the noise increased the number of
      awakenings, percentage of stage 2 sleep, and rapid eye movement latency and
      decreased time asleep, sleep maintenance efficiency index, and percentage of
      rapid eye movement sleep. Earplugs worn during exposure to the noise produced a
      significant decrease in rapid eye movement latency and an increase in the
      percentage of rapid eye movement sleep. CONCLUSION: The results provide a
      reasonable basis for testing the effects of earplugs on the sleep of critically
      ill subjects.

PMID- 10392221
TI  - Effects of relaxing music on cardiac autonomic balance and anxiety after acute
      myocardial infarction.
AB  - BACKGROUND: Acute myocardial infarction places additional demands on an already
      compromised myocardium. Relaxing music can induce a relaxation response, thereby
      reversing the deleterious effects of the stress response. OBJECTIVES: To compare
      the effects of relaxing music; quiet, uninterrupted rest; and "treatment as
      usual" on anxiety levels and physiological indicators of cardiac autonomic
      function. METHODS: A 3-group repeated measures experimental design was used.
      Forty-five patients, 15 per group, with acute myocardial infarction were assigned
      randomly to 20 minutes of (1) music in a quiet, restful environment (experimental
      group); (2) quiet, restful environment without music (attention); or (3)
      treatment as usual (control). Anxiety levels and physiological indicators were
      measured. RESULTS: Immediately after the intervention, reductions in heart rate,
      respiratory rate, and myocardial oxygen demand were significantly greater in the
      experimental group than in the control group. The reductions in heart rate and
      respiratory rate remained significantly greater 1 hour later. Changes in heart
      rate, respiratory rate, and myocardial oxygen demand in the attention group did
      not differ significantly from changes in the other 2 groups. The 3 groups did not
      differ with respect to systolic blood pressure. Increases in high-frequency heart
      rate variability were significantly greater in the experimental and attention
      groups than in the control group immediately after the intervention. State
      anxiety was reduced in the experimental group only; the reduction was significant
      immediately and 1 hour after the intervention. CONCLUSIONS: Patients recovering
      from acute myocardial infarction may benefit from music therapy in a quiet,
      restful environment.

PMID- 10392222
TI  - Instillation of normal saline during endotracheal suctioning: effects on mixed
      venous oxygen saturation.
AB  - BACKGROUND: Instillation of normal saline before endotracheal suctioning is
      thought to facilitate removal of secretions and ultimately to improve the
      patient's oxygenation status. To date, no studies have used an in vivo measure of
      oxygenation such as mixed venous oxygen saturation to characterize the effects of
      instillation of normal saline. OBJECTIVES: To describe the effects of
      instillation of normal saline into an endotracheal tube before suctioning on
      mixed venous oxygen saturation in critically ill adult patients. METHODS: In a
      descriptive, observational study, 35 patients were assigned to either of 2 groups
      after coronary artery bypass grafting. One group had 5 mL of normal saline
      instilled at the start of endotracheal tube suctioning; the other group had the
      same endotracheal tube suctioning procedure without the use of saline. Data on
      mixed venous oxygen saturation were recorded at 1-minute intervals for a 5-minute
      baseline period and then throughout the suctioning procedure until mixed venous
      oxygen saturation returned to baseline levels. RESULTS: The time required for
      mixed venous oxygen saturation to return to baseline values after suctioning was
      an average of 3.78 minutes longer when saline was used. CONCLUSIONS: Instillation
      of normal saline before endotracheal suctioning has an adverse effect on
      oxygenation as indicated by mixed venous oxygen saturation. This finding
      contradicts the assumption that instillation of normal saline improves
      oxygenation status.

PMID- 10392223
TI  - Noninvasive assessment of hemodynamic characteristics in an episode of sustained
      narrow-complex tachycardia.

PMID- 10392224
TI  - Case report: reversal of an evolving myocardial infarction with intravenous
      thrombolysis.
AB  - This case, in many ways, represents the ideal: a timely and effective
      administration of thrombolytic agents. The rarity of this situation reinforces
      the need for earlier recognition and treatment of infarction. In an analysis of
      time delays in thrombolytic therapy, 38% were attributed to in-hospital issues,
      22% to patients' delays, 21% to problems with transportation, and 19% to
      reperfusion time. The National Heart Attack Alert Program calls for treatment
      within 1 hour of the development of signs and symptoms, including administration
      of thrombolytic agents within 30 minutes of the patient's arrival in the
      emergency department. That program seeks heightened awareness among hospital and
      prehospital providers and public education about seeking immediate treatment for
      chest pain. The prompt acquisition of additional ECGs and the subsequent rapid
      administration of a thrombolytic agent were the clinical essentials. This fact
      suggests the need to look for measures of quality other than simple "door to
      drug" times. "Data to drug" times may be another indicator of quality to address
      cases in which the initial ECG findings are not diagnostic. Furthermore,
      emergency departments may see more patients with impending infarction if public
      education campaigns are successful. This case emphasizes the need to obtain
      follow-up ECGs in light of the potential benefits from thrombolysis.

PMID- 10392225
TI  - Obtaining blood samples for coagulation studies from a normal saline lock.
AB  - OBJECTIVES: To determine the amount of blood that should be discarded from a
      peripheral normal saline lock, a capped-off intravenous port, before a blood
      sample is obtained for determination of activated partial thromboplastin time
      from patients being treated with heparin. METHODS: A prospective, quasi
      experimental design was used with 32 patients. A blood sample was obtained via
      venipuncture from each patient to serve as the control for that patient. The
      normal saline lock was flushed with 2 mL of normal saline. Four consecutive 3-mL
      blood samples were obtained directly from the normal saline lock, representing
      samples obtained after discard volumes of 0, 2, 4, and 6 times the dead space of
      the catheter and extension set (1.5 mL). Activated partial thromboplastin times
      for the venipuncture blood sample were compared with the times for the blood
      samples obtained from the normal saline lock. RESULTS: The only significant
      difference (P = .02) was that activated partial thromboplastin time was 15%
      higher in the blood sample obtained from the normal saline lock with no blood
      discarded than in the venipuncture blood sample. CONCLUSIONS: Nurses can obtain
      accurate measurements of activated partial thromboplastin time with blood samples
      obtained from normal saline locks by first discarding a volume of blood equal to
      2 times the dead space of the catheter and extension set. Obtaining blood samples
      in this manner reduces patients' discomfort due to repeated venipuncture and
      diminishes blood loss.

PMID- 10392226
TI  - Measurement of dyspnea in patients treated with mechanical ventilation.
AB  - BACKGROUND: Dyspnea, or difficult breathing, is common in patients receiving
      mechanical ventilation; however, dyspnea is not routinely or systematically
      measured. OBJECTIVE: The primary purpose of this methodological study was to
      evaluate the test-retest reliability of 5 dyspnea rating scales and the criterion
      validity of 4 dyspnea rating scales in patients receiving mechanical ventilation.
      The secondary purpose was to examine the correlations between each of these 5
      rating scales and physiological measures of respiratory function. METHODS: The
      convenience sample consisted of 28 patients on mechanical ventilation during
      their hospitalization in the intensive care units of a large, inner-city
      hospital. Patients rated their dyspnea twice at 30-minute intervals on the visual
      analogue scale, the vertical analogue dyspnea scale, the modified Borg scale, the
      numerical scale, and the faces scale. Test-retest reliability was computed by
      using the intraclass correlation coefficient. Criterion validity was evaluated by
      using the Spearman rank-order correlation coefficient. RESULTS: The 5 rating
      scales had acceptable test-retest reliabilities, with intraclass correlation
      coefficients ranging from 0.81 to 0.97. Criterion validity of the 4 scales also
      was acceptable, with Spearman rank-order correlation coefficients from 0.76 to
      0.96. The rating scales were not correlated with most of the physiological
      variables. At least half of the patients reported moderate to severe dyspnea.
      CONCLUSION: The scales showed acceptable reliability and validity, and they will
      be useful in quantifying dyspnea experienced by patients receiving mechanical
      ventilation. Further work is needed to evaluate the extent and the severity of
      dyspnea in such patients in order to evaluate the effectiveness of interventions.

PMID- 10392227
TI  - Predicting the risk of pressure ulcers in critically ill patients.
AB  - BACKGROUND: Critically ill patients are at high risk for pressure ulcers.
      OBJECTIVES: To determine the contributions of the Braden subscales in predicting
      pressure ulcers in critically ill patients and to investigate how often the
      Braden scale should be completed to assess the risk for pressure ulcers in
      critically ill patients. METHOD: The Braden scale was used to assess repeatedly
      136 adult patients without pressure ulcers in a medical intensive care unit, a
      surgical intensive care unit, and a noninvasive respiratory care unit, and the
      patients' skin was inspected routinely for pressure ulcers. RESULTS: A total of
      36 pressure ulcers, most commonly on the sacrum or coccyx and the heels (15 stage
      1, 20 stage 2, 1 stage 3), developed in 17 patients (12%). In 14 (82%) of the 17,
      the ulcers developed within 72 hours of admission to the intensive care unit. The
      risk for pressure ulcers increased as the mean sensory perception (P = .01) and
      the mean total Braden (P = .046) scores decreased. The mean sensory perception
      scores obtained at 12 and 36 hours after admission also had a significant
      relationship to the risk for pressure ulcers (P = .03). CONCLUSIONS: Patients in
      intensive care units have an increased risk for pressure ulcers. Although waiting
      until 12 hours after a patient's admission to the intensive care unit to obtain
      the initial Braden rating may be reasonable (with the second rating obtained 36
      hours after admission), additional research is needed before this practice can be
      recommended.

PMID- 10392228
TI  - Commotio cordis: sudden cardiac death in athletes.
AB  - Commotio cordis due to blunt trauma to the precordium is a rare cause of death in
      young athletes, occurring less frequently than all of the other athletics-related
      deaths. Several measures, such as the use of safety baseballs and the use of
      chest protectors, can help protect young athletes from commotio cordis. In
      general, sudden cardiac death in athletes is receiving increasing attention from
      the public as a result of recent deaths of high-profile athletes. Sudden cardiac
      death, however, is rare, with an estimated 1 out of 200,000 high school athletes
      at risk each year. However, the personal, physiological, and cardiovascular
      benefits of athletics far outweigh the risks. Therefore, the message to parents
      is to allow their children to participate in athletics because the benefits far
      outweigh the risks.

PMID- 10392229
TI  - A selective increase in plasma soluble vascular cell adhesion molecule-1 levels
      in preeclampsia.
AB  - PROBLEM: The study was conducted to determine whether altered plasma levels of
      soluble intercellular adhesion molecule (ICAM)-1 and soluble vascular cell
      adhesion molecule (VCAM)-1 are involved in the pathogenesis of preeclampsia.
      METHOD OF STUDY: Maternal plasma samples were collected from 20 patients with
      preeclampsia, 20 matched normotensive patients with uncomplicated pregnancies.
      and ten healthy nonpregnant women. Samples were assayed for soluble VCAM-1 and
      soluble ICAM-1 by specific enzyme-linked immunosorbent assay. RESULTS: Both
      soluble VCAM-1 and soluble ICAM-1 were detectable in the plasma of all
      preeclamptic, normotensive pregnant, and nonpregnant women. The mean plasma level
      of soluble VCAM-1 was significantly higher in preeclamptic women compared to
      normotensive pregnant women (1831 ng/mL +/- 534 ng/mL vs. 1254 ng/mL +/- 386
      ng/mL, respectively; P < 0.05). However, the plasma level of soluble VCAM-1 was
      unchanged during the third-trimester of normal pregnancy compared to nonpregnant
      women. The mean plasma level of soluble ICAM-1 in preeclamptic and normotensive
      pregnant women were increased when compared to nonpregnant women. However, the
      mean plasma level of soluble ICAM-1 was comparable in women with preeclampsia and
      normotensive pregnancy. CONCLUSIONS: The selective increased plasma levels of
      soluble VCAM-1 in patients with preeclampsia provide evidence for endothelial
      activation and suggest distinct pathways for neutrophil and endothelial
      activation in preeclampsia.

PMID- 10392230
TI  - Natural killer cell subpopulations and cytotoxicity for infertile patients
      undergoing in vitro fertilization.
AB  - PROBLEM: We evaluated the participation of the lymphocyte subpopulations in the
      endometrium and peripheral blood on in vitro fertilization and embryo transfer
      (IVF-ET) outcomes. METHOD OF STUDY: Peripheral blood samples were analyzed for
      the expression of CD3, CD4, CD8, CD16, and CD56, using a FACScan, and for natural
      killer (NK) cell cytotoxicity, using a 51Cr assay. Endometrial samples obtained
      at a previous phase of the IVF cycle were analyzed for the expression of CD16 and
      CD56, using a FACScan. RESULTS: The percentages of CD56+ cells and CD16+CD56+
      cells in the peripheral blood on the day of ET were significantly higher in the
      failed group than in the implanted group. In the endometrial tissue, the increase
      of the percentage of CD16+CD56dim cells and the decrease of the percentage of
      CD16-CD56bright cells in the aborted group were significant when compared with
      the those of the delivered group. CONCLUSIONS: The increase of cytotoxic NK cells
      in the peripheral blood and the endometrium may affect the therapeutic results of
      IVF-ET. It was suggested that modifications of NK cytotoxicity or of NK
      subpopulations might contribute to the improvements of IVF outcomes.

PMID- 10392231
TI  - Mouse granulated metrial gland cell cytotoxicity of Wehi 164 cells: is there a
      role for interleukin-3 and tumour necrosis factor-alpha?
AB  - PROBLEM: Mouse granulated metrial gland (GMG) cells are maternal, cytotoxic cells
      found in the uterine wall in pregnancy. In vivo, they are cytotoxic to layer 1
      labyrinthine placental cells. In an in vitro system, granulated metrial gland
      cells are highly cytotoxic to Wehi 164 fibrosarcoma cells. In this study the role
      of interleukin (IL)-3 and tumour necrosis factor (TNF)-alpha in granulated
      metrial gland cell cytotoxic activity was investigated. METHOD OF STUDY: Chromium
      release cytotoxicity assays using mouse metrial gland effector cells and Wehi 164
      target cells with the addition of IL-3 or an antibody to TNF-alpha. RESULTS: An
      antibody to TNF-alpha reduced the level of cytotoxic activity. IL-3 had no effect
      on the level of cytotoxicity. CONCLUSION: Mouse granulated metrial gland cells
      kill using a TNF-alpha mediated mechanism which is independent of IL-3
      stimulation.

PMID- 10392232
TI  - Binding of ovine uterine serpin to lymphocytes.
AB  - PROBLEM: The endometrium of the sheep produces a progesterone-induced member of
      the serpin superfamily of serine proteinase inhibitors that can inhibit
      lymphocyte proliferation and reduce natural killer cell activity. Present results
      indicate that this molecule, called ovine uterine serpin (OvUS), can bind
      specifically to lymphocytes. METHOD OF STUDY/RESULTS: Biotinylated OvUS bound to
      peripheral blood lymphocytes in a dose-dependent and saturable manner. Binding
      was inhibited by OvUS, but not by several other proteins, including serpin-enzyme
      complex (alpha 1-antitrypsin-trypsin). Heparin blocked binding when added to the
      binding reaction or when used to pretreat lymphocytes. Both lymphocytes and Madin
      Darby bovine kidney (MDBK) cells also bound fluorescein isothiocyanate-labeled
      OvUS. CONCLUSIONS: Results suggest that OvUS can interact with lymphocytes and
      other cells through binding to a cell surface molecule. Such binding may indicate
      that inhibition of lymphocyte activation by OvUS involves 1) binding of OvUS to a
      cell surface receptor or 2) competitive inhibition of binding between OvUS and a
      co-activation molecule required for lymphocyte activation.

PMID- 10392233
TI  - Severity staging in chronic sinusitis: are CT scan findings related to patient
      symptoms?
AB  - Chronic sinusitis is a prevalent problem. The symptoms of CS cause patients to
      seek medical attention, and therefore the presence of symptoms drives the use of
      health care resources. There is widespread clinical belief that computed
      tomography (CT) scan findings may be a reasonable proxy for disease severity in
      chronic sinusitis, and many authors have proposed that CT scan findings make up
      the key component in severity staging systems for chronic sinusitis. However, the
      relationship between symptom severity and CT scan findings in chronic sinusitis
      has not been well explained to date. To explore this relationship further, we
      examined data from consecutive patients with both a CT scan and a sinusitis
      symptom score, from ongoing prospective outcomes studies at two large academic
      centers in different cities (n = 254). CT scans were graded using two validated
      staging systems; symptom severity was assessed using two validated health status
      instruments and summary items. In addition, we explored multiple statistical
      modifications and permutations of CT staging to identify potential relationships
      between the two variables. In summary, no association between CT scan findings
      and symptom severity could be identified using both CT staging systems and
      patient-based symptom instruments. For instance, CT scans were examined: after
      eliminating normal scans, using different scoring algorithms, by worst side, by
      nonlinear association, when grouped into strata, and by eliminating patients with
      very severe disease; no statistical association was found between CT findings and
      patient-based symptoms using any of those techniques. Since symptom severity is a
      pivotal outcome measure in chronic sinusitis, these findings have significant
      implications for outcomes research and the development of severity staging
      systems.

PMID- 10392234
TI  - Nasal nitric oxide: a comparison of measurement techniques.
AB  - Nasal nitric oxide measurement may be a surrogate marker of upper airway
      inflammation. There is, however, no standardized measurement technique; and this
      led us to examine measurement techniques for acceptability and reproducibility.
      In five subjects we examined the flow dependence of nasal NO. In 13 healthy
      volunteers, nasal NO was measured on-line by five methods: 1) Tidal nasal and
      oral breathing: NO sampling during exclusive nasal followed by exclusive oral
      tidal breathing; 2) Fixed flow exhalation: NO sampling during exclusive nasal
      followed by exclusive oral exhalation at 100 mL/second from total lung capacity;
      3) Nasal-oral aspiration: air aspirated from the mouth via both nares at 100
      mL/second with glottis closure; 4) Aspiration from one nares: air aspirated from
      one nares at 3.3 mL/second using nitric oxide analyzer sample line with velum
      closure; 5) Nasal Insufflation: NO sampled at one nares as air insufflated into
      the other nares at a flow of 100 mL/second with velum closure. Acceptability of
      all methods was assessed by subjects and technicians. Nasal NO concentration
      showed a significant inverse correlation with transnasal flow rate. All methods
      showed excellent reproducibility as assessed by the intraclass correlation
      coefficient except tidal breathing, which showed highly variable breath-to-breath
      NO levels, although mean breath values were reproducible. Mean nasal NO
      concentrations with methods 1, 2, 3, 4, and 5 were 32.1, 50.2, 62.8, 1381, and
      60.0 ppb, respectively. Velum closure was not always achieved in methods 4 and 5,
      whereas methods 1 and 2 required separate nasal and oral procedures. Method 5 had
      reduced acceptability. NO concentrations were similar with methods that used the
      same airflow (2, 3, and 5). Nasal NO can be sampled in different ways with
      excellent reproducibility. In view of the flow dependence of nasal NO, it is
      vital to use a constant flow rate, and lower airway NO contribution must be
      excluded or subtracted. The fixed flow exhalation appears to be the preferred
      method as it is highly reproducible and acceptable.

PMID- 10392235
TI  - Nasal nitric oxide is independent of nasal cavity volume.
AB  - This study was performed to evaluate the relationship between nasal nitric oxide
      (NO) and changes in nasal cavity volume resulting from the topical application of
      xylometazoline and saline and between upright and supine posture. Nasal NO was
      measured using a fixed high flow technique that avoids contamination with lower
      airways NO. In nine healthy subjects nasal NO concentration was measured by a
      rapid response chemiluminescent analyzer. A tapered tube was inserted in one
      nostril, into which room air was insufflated to produce a constant flow of 100
      mL/second; another tube was inserted into the opposite nostril for NO sampling
      (air exit side). Subjects were instructed to keep the vellum closed while NO was
      sampled through a sideport connected to the analyzer. Nasal cavity volume was
      measured by acoustic rhinometry from a segment of the acoustic pathway, 2 to 5 cm
      from the nostril. Nasal cavity volume and NO measurements were made at baseline,
      15 minutes, and 60 minutes after intervention (administration of saline 0.9%,
      xylometazoline or posture changes on 3 consecutive days). Xylometazoline produced
      a significant increase in nasal cavity volume, together with a significant
      reduction in NO level at 15 and 60 minutes after intervention. In addition, the
      change from seated to supine position decreased the total nasal volume
      significantly, but without changes in nasal NO. No correlation was found between
      the magnitudes of changes in nasal NO and the changes in nasal volume. Topical
      application of xylomethazoline resulted in increased nasal cavity volume and
      reduced NO output. In contrast to previous published reports, a technique using
      high flow rate insufflation demonstrated an abscence of correlation between the
      magnitudes of changes in nasal NO and nasal cavity volume brought about by
      decongestant, saline, or posture.

PMID- 10392236
TI  - The effects of different levels of air pollution on atopy and symptoms of
      allergic rhinitis.
AB  - We evaluated the prevalence of symptoms of allergic rhinitis and atopy among two
      groups living in areas with different pollution levels. The study was conducted
      among high school students living in Bayrampasa (polluted by SO2 and TSP) and
      Beykoz (unpolluted, residential area) in Istanbul (n = 386). Each subject filled
      out a standardized self-administered questionnaire. Atopic status was evaluated
      by skin-prick testing using eight different allergens. Also, anterior active
      rhinomanometry was performed to evaluate the symptoms objectively. Significantly
      higher prevalence rates for symptoms of allergic rhinitis were found in
      Bayrampasa (22.8%) compared to Beykoz (6%). However, no significant difference
      was found for atopic status among the two groups. When we evaluated the atopic
      status of subjects with symptoms of allergic rhinitis between the two areas, the
      prevalence of atopic students was found to be relatively higher in the unpolluted
      area (BZ). This difference was not statistically significant. Within the atopic
      population, subjects complaining of symptoms of allergic rhinitis were
      significantly more frequent in the polluted area (BP), suggesting that air
      pollution causes an increase in symptoms of allergic rhinitis in the atopic
      population, but this is not significantly higher than the increase in symptoms of
      allergic rhinitis of the total study group. Our results suggest that pollutants
      exert irritant effects on mucous membranes of the population in general rather
      than aggrevating symptoms in predisposed individuals. Smoking was more frequent
      in the unpolluted area. Exposure to parental smoking in childhood and heating
      systems in houses were evenly distributed. Household crowding was lower in
      Beykoz. Rhinomanometric measurements among the two groups did not show
      significant difference. Multiple logistic regression models estimating the role
      of each risk factor independently showed significant odds ratio associated with
      residence in Bayrampasa for symptoms of allergic rhinitis (OR = 4.6, 95% CI = 9.0
      2.3). In conclusion, this study suggests that outdoor pollution has adverse
      effects on the symptoms of allergic rhinitis, while it has no effect on the
      prevalence of atopy in Istanbul in the 1990s.

PMID- 10392237
TI  - Allergic fungal sinusitis-induced visual loss.
AB  - In this report we review 56 adult and 26 pediatric patients who presented to our
      practice with pathologically confirmed allergic fungal sinusitis from 1989 to
      1997. Of this group, three patients presented with visual loss and were treated
      with prompt surgical decompression followed by immunomodulation.

PMID- 10392238
TI  - Possible relationship of gastroesophagopharyngeal acid reflux with pathogenesis
      of chronic sinusitis.
AB  - Gastroesophagopharyngeal reflux (GEPR) has been suggested as a cause of pediatric
      sinusitis. However, its contribution to the pathogenesis of chronic sinusitis in
      adults has not been systematically investigated. We evaluated the prevalence of
      GEPR in 11 CT confirmed chronic sinusitis patients (51 +/- 4 years) who had not
      responded to conventional therapy, and 11 normal healthy controls (44 +/- 7
      years). A 3-site ambulatory esophagopharyngeal pH monitoring technique (probe
      location: 2 cm proximal, 3-4 cm distal to UES and 5 cm proximal to LES high
      pressure zones) was used. A pharyngeal pH drop was accepted as a true reflux
      event only if it was coincident with or preceded by esophageal pH declines of a
      similar or larger magnitude. Studies were performed while subjects were on a
      uniform 2500 calorie diet (provided). RESULTS: Ambulatory pH monitoring
      documented GEPR in seven of 11 patients (1-12 episodes) and two of 11 normal
      volunteers (1,2 episodes) (p < 0.05). A total of 34 nonbelch related pharyngeal
      acid reflux events were identified in patients, but none was associated with
      coughing. In both groups, all pharyngeal acid events occurred in the upright
      position. Compared to normal controls prevalence of pharyngeal reflux of gastric
      acid is significantly higher in patients with chronic sinusitis unresponsive to
      conventional therapy and suggests a different esophagopharyngeal distribution
      pattern of gastric refluxate in this patient group; these findings suggest that
      GEPR may contribute to the pathogenesis of chronic sinusitis in some adult
      patients.

PMID- 10392240
TI  - Primary amyloidosis presenting as a nasopharyngeal mass.
AB  - Amyloid is defined as a pathologic proteinaceous substance which, when deposited
      between the cells of tissues and organs, leads to various clinical conditions.
      Immunohistochemistry has allowed for better classification and understanding of
      the pathophysiology of amyloidosis. In the upper aerodigestive tract, amyloidosis
      is a rare condition occurring most frequently in the larynx. We present the case
      of a 42-year-old woman with complete nasal obstruction due to primary
      nasopharyngeal amyloidosis. This represents the first reported case of primary
      nasopharyngeal amyloidosis containing both the lambda and kappa immunoglobulin
      light chains. The clinical and radiologic findings, as well as the management of
      primary amyloidosis of the upper aerodigestive tract, will be discussed. A review
      of the literature pertaining to nasal and nasopharyngeal amyloidosis will be
      presented.

PMID- 10392239
TI  - Prevalence of sinonasal symptoms in patients with HIV infection.
AB  - Infection with the human immunodeficiency virus (HIV) is increasing in
      prevalence, and disease patterns are changing as patient survival lengthens. The
      purpose of this cross-sectional epidemiological study was to assess the
      prevalence and severity of self-reported symptoms of otolaryngologic disease in a
      group of patients attending a general HIV outpatient clinic (n = 203), and to
      compare the prevalence of self-reported symptoms with a sample of patients
      without HIV infection (n = 100). Of the HIV-infected patients, 65% of patients
      had AIDS, 35% were HIV-positive, and the median CD4 count was 135. Although only
      11% of patients had seen an otolaryngologist in the prior 6 months, the majority
      of patients (66%) reported the presence of sinonasal disease during that time.
      Allergic rhinitis (80%) and sinusitis (54%) were the most commonly reported
      sinonasal symptoms, and 44% regularly used nasal or sinus medications. Sinonasal
      disease severity was significantly higher than the self-reported severity of
      mouth/throat disease (p = 0.01), ear disease (p = 0.03), and neck/salivary
      disease (p = 0.01). Although patients' self-reported overall health status was
      associated (p = 0.02) with CD4 count, the severity of sinonasal symptoms was not
      associated (p = 0.93) with CD4 count. Similarly, sinonasal symptom severity did
      not differ between HIV-positive and AIDS patients (p = 0.45). In other words,
      sinonasal disease severity did not improve as general health status improved.

PMID- 10392241
TI  - Endoscopic treatment of juvenile nasopharyngeal angiofibroma.
AB  - Traditional treatment of juvenile nasopharyngeal angiofibromas (JNAs) has
      included open surgical approaches for the majority of tumors. At the University
      of Washington Medical Center (UWMC), endoscopic techniques have been used for the
      removal of some small JNAs. This report describes the institutional experience in
      treating these tumors. The medical records of 15 patients at UWMC treated over a
      15-year period for JNA were reviewed. Three patients were treated only by an
      endoscopic approach, and one patient had a combined endoscopic and open
      procedure. All three of the patients treated only by the endoscopic approach were
      disease free with a minimum of 24 months follow up. The one patient treated with
      a combined endoscopic and open approach had recurrence of disease. Endoscopic
      removal after embolization effectively treated three patients with early stage
      JNAs. Indications for this procedure are discussed.

PMID- 10392243
TI  - Immunohistochemical localization of epidermal growth factors in mouse olfactory
      epithelium.
AB  - Our object was to clarify changes in epidermal growth factor (EGF) occurring in
      the olfactory epithelium with aging. We investigated the changes in EGF in the
      murine olfactory epithelium with aging by an immunohistochemical method. We
      examined six mice at each of the following stages: embryonal (embryonic days 14
      and 16), neonatal (postnatal days 1 and 7), adult (postnatal weeks 5 and 12), and
      aged (postnatal years 1.5-2). The olfactory epithelium of each mouse was stained
      with anti-EGF polyclonal IgG using an immunohistochemical method. EGF were
      observed in the whole layer of the olfactory epithelium at all stages. The
      mesenchyme under the epithelium was stained in the embryonal stage, and the
      circumference of the olfactory gland cells was also stained, although weakly, in
      the adult stage. We believe that EGF contribute to cell proliferation, growth and
      turnover of the olfactory epithelium. However, the decrease in EGF was less than
      expected in the aged mice.

PMID- 10392242
TI  - The cystic fibrosis conductance regulator gene exon sequence is normal in a
      patient with edematous eosinophilic nasal polyps.
AB  - Nasal polyps are the most common mass lesions found in the nose and their
      etiology is unknown. Nasal polyps from cystic fibrosis (CF) patients are
      histologically distinct from nasal polyps from patients without CF. It has been
      suggested that a mutation (G551D) of the cystic fibrosis transmembrane
      conductance regulator (CFTR) gene may play a role in nasal polyp formation in
      patients without CF. To investigate the possibility that this or other CFTR gene
      exon mutations are required for nasal polyp formation, the CFTR gene exons were
      sequenced from peripheral blood DNA derived from an adult patient with edematous
      eosinophilic nasal polyps and no personal or family history of CF. No mutations
      or deletions were identified in any of the CFTR exons. A single polymorphism (A
      or G) was found in exon 10, base pair 1540, amino acid 470. This polymorphism was
      detected in 11 of 16 subjects (69%) with edematous eosinophilic nasal polyps and
      10 of 21 normal subjects (48%) without nasal polyps and was not statistically
      significant (p = 0.316). These results demonstrate that mutations of the CFTR
      coding region are not a prerequisite for the formation of edematous eosinophilic
      nasal polyps.

PMID- 10392244
TI  - Distilled water nasal provocation in hyperreactive patients.
AB  - Nonisotonic aerosol may act as a provocation agent in the upper and lower airways
      of hyperreactive individuals. The purpose of the study was to compare the results
      of nasal challenge with distilled water in patients with allergic rhinitis to
      those with noninfective nonallergic rhinitis (NINAR), with respect to the
      potential clinical use of the obtained data. A group of 68 ambulatory patients
      with allergic rhinitis or NINAR (39 perennial allergic, 6 seasonal, 23 NINAR)
      were challenged with 10 mL of distilled water aerosol after the baseline active
      anterior rhinomanometry. Patients with nasal polyposis at endoscopy, significant
      unilateral septal deviation, positive bacteriologic swab, recent nasal surgery,
      and uncertain anamnestic data about the medication taken 6 weeks before the
      provocation were excluded from the study. After 10 minutes of nasal provocation,
      rhinomanometry was repeated to assess the response. In 15 patients of the
      perennial allergic group, the same measurements were performed after a 2-week
      oral antihistamine and topical steroid therapy. Nasal resistance was
      significantly increased on the more patent side of the nose after nasal
      provocation with distilled water aerosol in allergic patients in comparison to
      the nasal resistance before provocation. In the patients with NINAR, the
      provocation resulted in a significant rise on the more patent side, but the total
      nasal airway resistance (NAR) levels were also significantly increased. The
      systemic antihistamine and topical steroid 2-week therapy in patients with
      perennial allergic rhinitis significantly reduced the response to nasal distilled
      water provocation. Nasal provocation with distilled water aerosol is a cheap,
      simple, and acceptable method that provides useful clinical data on the level of
      nonspecific nasal hyperreactivity and the therapy success.

PMID- 10392245
TI  - Cardiovascular safety of second-generation antihistamines.
AB  - Reports of serious cardiac arrhythmia associated with some second-generation
      antihistamines have prompted concern for their prescription. This article reviews
      the nature of the adverse events reported and concludes that the blockade of
      potassium channels, particularly the subtype responsible for the rapid component
      of the delayed rectifier current (IKr), is largely responsible for such adverse
      cardiac events. Consequently, antihistamines with little or no interaction with
      these channels are expected to have the greatest safety margin. The main cardiac
      arrhythmia of concern is that of torsades de pointes, a potentially fatal
      phenomenon characterized by prolonged ventricular depolarization that manifests
      as a prolonged QT interval and polymorphic ventricular tachycardia, with twisting
      of the QRS complexes. Based on pre-clinical and clinical evidence, it appears
      that loratadine, cetirizine, and fexofenadine are safe from cardiac arrhythmia
      via the IKr channel, whereas astemizole and terfenadine have a propensity to
      cause ventricular tachyarrhythmias.

PMID- 10392246
TI  - Extrapancreatic organ impairment in caerulein induced pancreatitis.
AB  - BACKGROUND AND AIMS: Multiorgan function failures are the major fatal
      complications in acute pancreatitis. In this experiment, we studied 1) the
      manifestation and time course of extrapancreatic organ damage in an acute
      pancreatitis model and 2) whether the obstructive liver damage in this model is
      caused by the obstruction of common biliopancreatic duct compressed by oedematous
      pancreas. MATERIAL AND METHODS: 80 male Wistar rats were divided into two groups:
      control and caerulein groups (five subgroups in each group). In the caerulein
      group, the acute pancreatitis was induced by caerulein intraperitoneal
      injections. In the controls equal volume of saline was injected. Two subgroups,
      one in caerulein and one in control groups, had an intrapancreatic bile duct
      stent inserted transduodenally before the injections. The pancreas, liver, lung
      and kidney tissues and blood samples were obtained for the measurement or
      analysis of interstitial oedema, plasma amylase, alanine aminotransferase,
      bilirubin, urea, creatinine, alkaline phosphatase, lactate dehydrogenase, blood
      gas and electron microscopy at 1, 6, 12 and 24 hours after the last injection in
      unstented animals, and at 6 hours in stented animals. RESULTS: Lungs and kidney
      remained unchanged. Liver damage was found during the first 6-12 hours, manifest
      as increased plasma alanine aminotransferase and bilirubin and dilatation of bile
      canaliculi and hepatocyte damage in electron microscopy. The intrapancreatic bile
      duct stent did not resolve these changes. CONCLUSIONS: The liver may be the first
      evolved extrapancreatic organ in the early stage in this mild oedematous
      pancreatitis model and the hepatocyte damage is not caused by the obstruction of
      common biliopancreatic duct compressed by the oedematous pancreas.

PMID- 10392247
TI  - Eleven years' experience of postoperative morbidity and trends in handsewn ileo
      anal anastomosis with pelvic J-pouch for ulcerative colitis.
AB  - BACKGROUND AND AIMS: Restorative proctocolectomy with mucosectomy and handsewn J
      pouch-anal anastomosis is the curative operation of choice for ulcerative
      colitis. The aim of this study was to determine frequencies of various
      complications at perioperative time (within 30 days after surgery) with this
      operative method. We also evaluated the chances of failure of this restorative
      operation and the trends in operative management. MATERIAL AND METHODS:
      Evaluation was based on a register containing data on all patients operated for
      ulcerative colitis at our department since the beginning of 1985. Statistical
      analysis was made for all adult patients (over 18 years) who underwent an
      operation for ulcerative colitis during the 11 years' time period. RESULTS: A
      total of 170 adult patients underwent an elective operation for ulcerative
      colitis between March 1985 and December 1995. In 154 cases a restorative
      procedure was intended. In 142 (92%) cases this proved possible, and in 136 of
      these a handsewn J-pouch-anal anastomosis was created. The chance of failure in
      the restorative operation was higher in men (p = 0.0314). During the latter five
      years' period IAA operations were performed more often as a second-stage
      procedure. Uneventful recovery was reported in 62 (45.5%) cases. One or more
      complications were encountered in 74 (55.1%) patients. Corticosteroid treatment
      did not affect leakage frequency. In spite of the high morbidity there were no
      perioperative deaths.

PMID- 10392248
TI  - Sugiura procedure in the treatment of bleeding esophageal varices.
AB  - AIM OF THE STUDY: The aim of this study was to report our results and to make an
      attempt to define the possible role of Sugiura procedure in the treatment of
      variceal bleeding. MATERIAL AND METHODS: From January 1979 to December 1997, 39
      patients with portal hypertension and acute variceal bleeding (17 patients) or
      previous variceal bleeding (22 patients) underwent Sugiura procedure. Operations
      were performed in two stages. When performed in an emergency situation (17
      patients) thoracic operation was performed first. In elective cases abdominal
      operation was usually preferred. Complete two-stage operation was performed in 16
      patients. Twenty-three patients did not undergo the second stage because of early
      postoperative death, deterioration of condition or refusal. There were 17 men and
      22 women, aged 41.7 +/- 18.3 years (range 8-71 years). According to the Child-
      Turcotte classification of hepatic function there were 23 Child class A, 13 Child
      class B and 3 Child class C patients. SUMMARY OF RESULTS: Overall operative
      mortality was 10.3% (4 deaths per 39 patients with 54 operations), mortality in
      an emergency situation was 17.6% (3 deaths per 17 patients) and in elective cases
      4.3% (1 death per 22 patients with 37 operations). Variceal rebleeding occurred
      in 4 survivors (11.4%) at an average follow-up of 6.1 +/- 4.3 years. Survival
      rate was 84.6% at 1 year, 71.8% at 5 years and 64.1% at 10 years. CONCLUSIONS:
      Sugiura operation carries low operative risk in an elective situation and results
      in an effective prevention of recurrent variceal bleeding.

PMID- 10392249
TI  - Complications of diagnostic and therapeutic ERCP.
AB  - BACKGROUND AND AIMS: In the era of magnetic resonance cholangiopancreaticography
      (MRCP) and laparoscopic biliary surgery, indications for endoscopic retrograde
      cholangiopancreaticography (ERCP) should be profoundly considered in the light of
      ERCP related complication rate. MATERIAL AND METHODS: To evaluate the frequency
      of complications associated with diagnostic and therapeutic ERCP, all endoscopic
      procedures from 1991 to 1996 were retrospectively reviewed. RESULTS: A total of
      813 cannulations were performed on 590 patients. Endoscopic sphincterotomy (EST)
      was performed on 223 patients out of 230 attempted. Common bile duct stones were
      removed from 134 patients, an endoscopic stent was inserted in 69 patients and a
      benign stricture was dilated in 11 patients. After diagnostic ERCP, the
      complication rate was 1.8% with no mortality, after EST the complication rate was
      9.1% with a mortality rate of 0.9%. Pancreatitis was the most common complication
      with a rate of 1.5% after diagnostic ERCP and 3.9% after EST. In three patients
      the pancreatitis was severe and resulted in the deaths of two of them. Other
      complications were haemorrhage after EST (2.6%), duodenal wall or bile duct
      perforation (0.7% of the cannulations and 2.2% of EST) and cholangitis (0.6% of
      all cannulations). All of these patients survived. CONCLUSION: Complication rates
      were comparable with large series from clinics specialised in endoscopic
      procedures.

PMID- 10392251
TI  - Fibrin glue in perianal fistulas--a pilot study.
AB  - BACKGROUND AND AIMS: Anal fistula surgery is associated with considerable
      morbidity, mainly related to anal incontinence. As promising results of the use
      of fibrin glue in the treatment of complex anal fistulas were recently shown, we
      planned to do a randomized trial comparing the use of fibrin glue and surgery in
      the treatment of perianal fistulas. There were no reports of the use of fibrin
      glue in the management of previously untreated anal fistulas. MATERIAL AND
      METHODS: Prior to the planned study a pretrial pilot series of 10 patients with
      different perianal fistulas were treated. Informed consent was obtained from
      every patient. Under spinal anesthesia, the fistula track was identified and
      brushed to remove granulous tissue, then washed with hydrogen peroxide and
      thereafter filled with fibrin glue. RESULTS: We performed fibrin gluing on 10
      patients with perianal fistulas of different etiology and type. The gluing was
      done once to 7 patients, twice to 2 and three times to one patient. In all but
      one patient the fistula and symptoms recurred after only one month. One patient
      with a low trans-sphincteric fistula of which the internal opening was not found,
      was symptom-free for 6 months. At the one-month follow-up visit the external
      opening of the fistula was almost unidentifiable, suggesting that the fistula had
      healed. However, due to recurrence fistulotomy was performed after 6 months.
      CONCLUSIONS: Fistulas around the anus, with or without associated inflammatory
      bowel disease, do not seem to heal after fibrin gluing.

PMID- 10392250
TI  - The value of ultrasound-guided fine-needle aspiration biopsy (FNAB) and frozen
      section examination (FS) in the diagnosis of thyroid cancer.
AB  - BACKGROUND AND AIMS: Although only a small minority of thyroid nodules are
      malignant, a large proportion of operations are performed to exclude malignancy.
      The purpose of this study was to evaluate the role of preoperative ultrasound
      guided fine-needle aspiration biopsy (FNAB) and intraoperative frozen section
      examination (FS) in the management of thyroid cancer. MATERIAL AND METHODS: A
      retrospective study of 664 consecutive patients operated on for thyroid cancer
      from 1966 through 1994 at the Meilahti Hospital was performed. FNAB was taken
      with manual guidance in the sixties and seventies and with ultrasound guidance in
      the eighties and nineties. FS was performed in 335 cases. Malignancy was not
      known preoperatively in 210 cases. RESULTS: Ultrasound-guided FNAB was more
      accurate than manually guided FNAB (75 out of 143 or 52.4% vs. 112 out of 276 or
      40.6%) in detecting malignancy in spite of the fact that the tumors were smaller
      (23 +/- 15 mm vs. 30 +/- 22 mm, p = 0.011). A true positive FS diagnosis was
      given in 250 out of 335 (74.6%) of patients. However, in follicular carcinoma,
      the amount of true positive FS diagnoses was only 12 out of 27 (44.4%).
      CONCLUSIONS: Ultrasound guidance has improved the sensitivity of FNAB. Follicular
      neoplasia is a problem for both FNAB and FS.

PMID- 10392252
TI  - Management of clostridial gas gangrene and the role of hyperbaric oxygen.
AB  - BACKGROUND AND AIMS: Clostridial gas gangrene is one of the most dreaded
      infections in surgery. The aim of this study was to investigate the efficacy of
      surgery, antibiotic treatment, surgical intensive care and especially the role of
      hyperbaric oxygen in the management of clostridial gas gangrene. MATERIAL AND
      METHODS: 53 patients, 42 of them submitted from other hospitals in Finland. After
      the diagnosis had been made the patients underwent surgical debridement, broad
      spectrum antibiotic therapy and a series of hyperbaric oxygen (HBO) treatments at
      2.5 ATA pressure. The necrotic tissue was excised and incisions were made in the
      affected areas. Amputations were performed when necessary. RESULTS: Twelve
      patients died (22.6%). Hyperbaric oxygen therapy decreased the systemic toxicity
      and prevented further extension of the infection thereby improving the overall
      outcome of the patients. CONCLUSION: Hyperbaric oxygen therapy of gas gangrene
      seems to be life-, limb- and tissue saving. Early diagnosis remains essential.
      Patient survival can be improved if the disease is recognized early and
      appropriate therapy applied promptly. Surgical and antibiotic therapy as well as
      HBO treatment combined with surgical intensive care must be started as soon as
      possible.

PMID- 10392253
TI  - The diploma of the medical care of catastrophes (DMCC).

PMID- 10392254
TI  - Prion diseases and the immune system.
AB  - Unlike other infectious diseases, transmissible spongiform encephalopathies
      elicit no specific immune response. Indeed, because the infectious agent, the
      prion, seems to be essentially composed of a protein with a primary structure
      identical to a host encoded protein, the lymphoid system is naturally tolerant.
      However, lymphoid organs are strongly implicated in the early peripheral steps of
      the disease. Paradoxically, immunodeficient animals, which are more susceptible
      to infections by usual pathogens, appear to be partially or completely resistant
      to experimental infection by prions by peripheral route. Several studies suggest
      that in normal subjects, cells of the immune system support the replication of
      prions and might allow their spreading from the periphery to the central nervous
      system. Thus, the lymphoid system appears to behave as a Trojan horse rather than
      a protective fortification in the process of prion infection. A greater
      understanding of the pathophysiology of these aspects of prion diseases could
      lead to immunomanipulation strategies aimed at preventing prion spread into the
      central nervous system, once peripheral exposure has occurred.

PMID- 10392255
TI  - [Dengue fever with neurologic expression. Three cases in adults].
AB  - Dengue fever, unlike most other arboviral diseases, does not usually cause
      encephalitis. However, neurologic symptoms with poor prognosis have been
      regularly reported, mostly in Asian children affected by the severe dengue
      hemorrhagic fever/dengue shock syndrome, and attributed to a non specific, anoxic
      or metabolic encephalopathy. Recently, first isolations of dengue viruses from
      CSF or brain tissue, have renewed this concept. We report 3 dengue fever cases
      with neurologic manifestations and favorable outcome. Occurrence in adult age,
      during classic (benign) dengue fever (2 cases), and neurologic sequellae (1 case)
      were the three outstanding features. We point out the proteiform expression of
      these neurologic changes and their low incidence rate (< 3% in our series of
      adult dengue fever). Although their pathogenesis is poorly understood, different
      mechanisms are suggested: encephalopathy (case n. 1), acute specific encephalitis
      (questionable in case n(o) 2), or post-infective encephalitis (case n(o) 3).

PMID- 10392256
TI  - Genetic factors in IgA nephropathy.
AB  - Immunoglobulin A glomerulonephritis (IgA-GN) or Berger's disease is the most
      common glomerulonephritis when diagnosis is based on renal biopsy. The disease
      has a variable clinical course. Abnormalities in the production and/or catabolism
      of IgA are thought to play an important role in the etiology and pathogenesis of
      IgA-GN. Some evidence suggests that genetic factors determine the susceptibility
      to develop IgA-GN. Furthermore it has been proposed that genetic factors
      determine also the rate of progression. Since hypertension is an important
      predictor of progression, genes involved in blood pressure regulation have been
      analysed. A polymorphism in the gene for the angiotensin converting enzyme has
      been reported to be associated with progression. Further studies and progress in
      molecular biology will help to further elucidate the genetic factors which
      contribute to the development and progression of IgA-GN.

PMID- 10392257
TI  - Pathogenesis of IgA nephropathy.
AB  - IgA nephropathy (IgAN) is initiated by glomerular deposition of polymeric
      IgA1(pIgA1). In IgAN pIgA production is reduced in the mucosal immune system,
      perhaps mediated by a mucosal gamma delta T cell defect, and mucosal IgA
      responses to immunisation are impaired. But pIgA1 production by the marrow is
      increased. Human pIgA1 has an O-glycosylated hinge region unique to circulating
      immunoglobulins and there is reduction of galactosyl residues in the hinge of
      serum IgA1 in IgAN and Henoch-Schonlein nephritis. This reduced galactosylation
      may be due to a functional defect in plasma cell beta 1,3-galactosyltransferase.
      Altered hinge region glycosylation may alter IgA1 structure, modifying
      interactions with matrix proteins, IgA receptors and complement, and therefore
      influence mesangial deposition and subsequent injury through mechanisms other
      than classical antigen-antibody reactions. IgA clearance through the hepatic
      asialoglycoprotein receptor or Fc alpha receptors on circulating white cells may
      also be impaired. The unique features of human IgA1 have prevented development of
      satisfactory animal models for the early stages of IgAN. It is likely that events
      after pIgA1 deposition which result in glomerular inflammation and scarring are
      not specific to IgAN but generic to many forms of glomerulonephritis.

PMID- 10392258
TI  - The relevance of experimental models in the pathogenetic investigation of primary
      IgA nephropathy.
AB  - IgA nephropathy, the most common form of primary glomerulonephritis, progresses
      to terminal renal failure in about 25% of patients 10 years after the apparent
      clinical onset. Since its description in 1968 an intense research effort in order
      to clarify the pathogenetic mechanisms has involved the study of animal models of
      the disease. In this review we analyze the experimental work reported since 1979,
      when the first animal model of IgA nephropathy was published by Rifai et al. We
      also discuss the interplay between experimental data and relevant clinical
      observations. Finally, we report the new insights about the role played by
      cytokines and growth factors.

PMID- 10392259
TI  - Morphological features in IgA nephropathy.
AB  - The hallmark of Berger's disease is the mesangial and/or mesangioparietal
      deposition of IgA as the predominant or sole immunoglobulin. Despite similar
      appearance to the immunohistological pattern, morphological glomerular lesions
      differ in that they are wide ranging and variable, making precise and uniform
      classificatory approaches extremely difficult. The most characteristic and
      frequent abnormality is mesangial enlargement, which is produced by various
      combinations of excess of matrix and of hypercellularity, ranging from minimal to
      very extensive. In some cases the mesangial lesions are more severe giving a
      pattern of membrano-proliferative glomerulonephritis. The concomitant presence of
      necrotizing alterations of glomerular tuft with segmental extracapillary
      proliferation, similar to capillaritis of Henoch-Schonlein purpura and ANCA
      associated vasculitis, is now well documented and recognized by researchers. This
      similarity with vasculitic lesions is confirmed by the strong positivity of
      fibrinogen, of VCAM-1, and of the accumulation of monocytes within the same areas
      of segmental necrotic glomerular lesions. These active lesions appear to play a
      crucial role in the progression of the disease due to repeat formations of
      necrotizing/extracapillary alterations with subsequent glomerular sclerosis and
      fibrous adhesions. In the last decade, many groups of investigators have focused
      their attention on tubulo-interstitial lesions in IgA nephropathy, in particular,
      on leukocyte infiltration and intersitial fibrosis, demonstrating that the
      impairment of the glomerular filtration rate and the progression of the disease
      correlate better with tubulo-interstitial damage than with the degree of
      glomerular damage. This has also been confirmed by studies with repeat biopsies.
      Moreover, the recent availability of immunohistochemical and in situ hybridation
      methods that allow more precise evaluations of infiltrating cells and of numerous
      factors secreted by these cells (chemokines, cytokines, adhesion molecules etc
      ...) offers us incredible opportunities to expand our knowledge on mechanisms
      involved in the inflammatory process and in the progression of the disease.

PMID- 10392260
TI  - Clinical features and natural history of IgA nephropathy.
AB  - IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide.
      It is characterized by recurrent gross hematuria, microhematuria and/or
      proteinuria and diffuse mesangial IgA deposits in glomeruli. It is predominantly
      a disease of young males. Apart from primary IgAN (Berger's disease), IgA
      deposits in the glomeruli are also seen in Henoch-Schonlein purpura and in
      association with various of other diseases, particularly liver cirrhosis.
      Originally it was thought that IgAN was a benign disease, but it is now known
      that approximately 20-40% of patients develop progressive renal disease 5 to 25
      years after diagnosis and progress to end-stage renal disease. Clinical
      predictors of progressive disease are elevated serum creatinine concentration at
      presentation, increased systemic blood pressure, persistent protein excretion >
      1.0 g/day and histological predictors are glomerulosclerosis, tubular
      atrophy/interstitial fibrosis, extension of immune deposits to the perivascular
      space and crescent formation. Progression correlates more closely with the
      severity of tubulointerstitial lesions than with the degree of glomerular
      lesions. These features of IgAN reported in literature were mostly, but not
      completely, confirmed by analysis of all consecutive patients with biopsy proven
      IgAN and follow-up > 12 months in the renal units of Heidelberg and Prague using
      univariate analysis, multiple range test and multiple regression analysis.

PMID- 10392261
TI  - Treatment of immunoglobulin A nephropathy.
AB  - In this review, therapeutic trials for treatment of IgA nephropathy (Berger's
      disease) are reviewed and discussed. No disease-specific therapy exists. For
      treatment of hypertensive patients, angiotensin converting enzyme (ACE)
      inhibitors are preferred. They also decrease proteinuria and probably slow
      disease progression. However, there are still no controlled data on the
      effectiveness of ACE-inhibitors in the absence of hypertension or proteinuria.
      Renewed enthusiasm for treatment with fish oil arose after the publication of a
      randomized controlled trial in 1994 and long-term follow-up data of the trial
      cohort in 1998. Corticoid therapy in IgA nephropathy has been advocated for
      patients with nephrotic syndrome or crescentic disease. A recent non-randomised
      trial with long-term follow-up suggests that, in the presence of moderate
      proteinuria, corticosteroids may ameliorate renal function if administered before
      the creatinine clearance has decreased below 70 ml/min. Preliminary data suggest
      that mycophenolate mofetil (MMF) may reduce the risk of clinically significant
      IgA nephropathy recurring in kidney allografts. Many other promising treatment
      approaches have been tested, but in most instances results are insufficient for
      unequivocal conclusions. Several randomized controlled clinical trials are
      currently testing prednisone, fish oil, ACE-inhibitors, cyclophosphamide, MMF and
      vitamin E. In the absence of a disease-specific treatment, control of
      hypertension, proteinuria and probably dyslipidemia are pivotal. Chronic or
      recurrent infection including ton-sillitis should be treated effectively. Control
      of daily protein intake to 0.7-0.8 g/kg body weight may retard disease
      progression.

PMID- 10392262
TI  - Recurrence of IgA nephropathy after renal transplantation.
AB  - With time recurrence of IgA nephropathy in renal allografts may be found in most,
      if not all patients. However, at the present graft loss due to recurrent IgA
      nephropathy appears to be of limited importance as compared to other causes. No
      definite risk factors for recurrent disease and/or graft failure have been
      identified yet. Although recurrence rates appear to be higher in allografts from
      living related donors, graft loss rates due to IgA nephropathy are not
      significantly different. More important, sporadic cases of IgA nephropathy should
      be excluded in all living related donors.

PMID- 10392263
TI  - Clinical features of Henoch-Schonlein purpura. Italian Group of Renal
      Immunopathology.
AB  - Henoch-Schonlein purpura (HSP) is a vasculitis that often involves the kidneys
      with a IgA nephropathy indistinguishable from Berger's disease. It can affect
      patients of any age, even though an uneven distribution of prevalence and
      severity of renal disease is commonly observed as the renal involvement with
      transient hematuria without renal functional impairment is much more frequent in
      children than in adults. The Italian Group of Renal Immunopathology analyzed a
      cohort of HSP patients with the homogeneous criterium of a renal disease severe
      enough to indicate renal biopsy both in adults and in children. We report the
      clinical features of 219 HSP patients (136 adults and 83 children) enrolled from
      43 Italian Centers of Nephrology. The diagnosis was based on the detection of IgA
      nephropathy in a clinical setting of palpable purpura and/or bowel angina. The
      peak age was in second decade (28% of the patients). In 37% of the cases a
      potential eliciting factor was identified, mostly infectious (41% in children vs
      23% in adults, p < 0.05). A seasoned incidence was found in June (20% of the
      cases). Most patients had palpable purpura (96.3%), while bowel angina was
      reported in 54.1% and arthritis in 50.2% at onset. The full extrarenal syndrome
      was more frequent in children (59%) than in adults (47%, p < 0.05). The
      extrarenal signs were often not coincident with urinary manifestations. The
      clinical onset with nephrotic syndrome was more common in children than in adults
      (35% vs 24.3% respectively, p < 0.02) who more often presented with minimal or
      moderate proteinuria. The frequency of impaired renal function at onset was
      similar in both adults and children (24.2% and 31.2% respectively).

PMID- 10392264
TI  - Henoch-Schonlein nephritis in children and adults. Morphological features and
      clinicopathological correlations.
AB  - Rheumatoid purpura or Henoch-Schonlein syndrome is an IgA vasculitis affecting
      small vessels. The acute disease progresses by successive flare-ups of limited
      duration. Long-term prognosis depends mainly on the degree of initial renal
      damage. A review of the literature shows that renal involvement occurs in about
      33% of children and 63% of adults with rheumatoid purpura. The most typical
      manifestation is segmentary focal glomerulonephritis, always associated with
      granulous IgA deposits in the mesangium. When renal signs are severe enough to
      warrant renal biopsy (generally at urine protein > 1 g/d and/or organic renal
      failure) the risk of developing chronic renal failure is 18% in children and 28%
      in adults. The best prognostic features are histological. The percentage of
      crescents, the presence of interstitial fibrosis and the presence of dense sub
      epithelial deposits are correlated with risk of chronic renal failure. This risk
      is high (47%) in children with crescents in more than half the glomeruli. In
      adults, the percentage of crescents associated with unfavorable course appears to
      be lower than 50%. Predictions are only valid if no further renal flare-up
      occurs. In addition, histology cannot precisely predict the course of persistent
      renal sequelae. The severity of sequelae determines the risk and the rapidity of
      developing chronic renal failure. It is thus recommended to follow patients with
      Henoch-Schonlein nephritis for long periods.

PMID- 10392265
TI  - [Multiple myeloma manifesting as cardiac insufficiency].

PMID- 10392266
TI  - [Normolipemic plane xanthomas and non-Hodgkins malignant lymphomas].
AB  - INTRODUCTION: The association between diffuse normolipemic plane xanthomatosis
      and monoclonal dysglobulinemia is well known. The presence of cutaneous xanthomas
      with normal serum lipid levels is due to the antibetalipoproteic activity of the
      monoclonal immunoglobulin. METHODS: A 51-year-old female patient had generalized
      polyadenopathy and diffuse normolipemic plane xanthomatosis of 3 years duration.
      The clinical status of the patient was fluctuating. Lipids levels were in the
      normal range. Weight loss and new nodal enlargements revealed high-grade
      malignant non-Hodgkin's lymphoma. CONCLUSION: This case illustrates the
      development of diffuse normolipemic plane xanthomatosis in association with
      dysglobulinemia revealing non Hodgkin's lymphoma. The association has not been
      reported earlier in the literature.

PMID- 10392267
TI  - Sixth International Symposium for Rotary Blood Pumps.

PMID- 10392268
TI  - Leonardo da Vinci: precursor member of the International Society for Rotary Blood
      Pumps?

PMID- 10392269
TI  - Motor feedback physiological control for a continuous flow ventricular assist
      device.
AB  - The response of a continuous flow magnetic bearing supported ventricular assist
      device, the CFVAD3 (CF3) to human physiologic pressure and flow needs is varied
      by adjustment of the motor speed. This paper discusses a model of the automatic
      feedback controller designed to develop the required pump performance. The major
      human circulatory, mechanical, and electrical systems were evaluated using
      experimental data from the CF3 and linearized models developed. An open-loop
      model of the human circulatory system was constructed with a human heart and a
      VAD included. A feedback loop was then closed to maintain a desired reference
      differential pressure across the system. A proportional-integral (PI) controller
      was developed to adjust the motor speed and maintain the system reference
      differential pressure when changes occur in the natural heart. The effects of
      natural heart pulsatility on the control system show that the reference blood
      differential pressure is maintained without requiring CF3 motor pulsatility.

PMID- 10392271
TI  - Measurement of blood hematocrit inside the magnetically suspended centrifugal
      pump using an optical technique: application to assessment of pump flow.
AB  - To measure blood hematocrit inside the magnetically suspended centrifugal pump,
      we have performed both forward and backward light scattering measurements using a
      specially designed optical cell. In the forward scattering measurement, an
      optical fiber was used to guide the near infrared light at 780 nm into a 250
      microns gap region, and the light that forward scattered toward a detector fiber
      was measured using a phototransistor. The light intensity decreased exponentially
      with an increase in the hematocrit to around 20%. The forward scattering method
      suffered from sensitivity at the hematocrit levels around 25-45% due to the
      diffusion effect. By making the optical path length larger than several
      millimeters, the sensitivity of the forward scattering method in terms of
      hematocrit change can be improved. In the back scattering method, however, better
      sensitivity in terms of hematocrit change from 0-50% was obtained. By making the
      optical fiber separation distance less than 1 mm, the system will measure the
      first order back scattering from the shallow layer while, by making the fiber
      separation distance larger than several millimeters, the system will primarily
      measure the diffuse reflectance from the deeper layer. Both approaches will yield
      sensitive optical intensity change in terms of the physiological hematocrit
      range.

PMID- 10392270
TI  - Belt worn control system and battery for the percutaneous model of the Jarvik
      2000 heart.
AB  - A belt worn controller and lithium-ion battery pack have been developed for use
      with the initial clinical trials of the Jarvik 2000 heart. Patient interface
      considerations, safety, and simplicity were major design inputs for the system.
      The controller was developed using all analog technology to avoid difficulties
      with electromagnetic interference (EMI), to minimize susceptibility to
      electrostatic discharge, and to avoid the need for software validation. Manual
      control of pump speed is accomplished by a patient operated knob, according to
      physician instructions for rest and exercise for each individual patient. The
      system includes alarms and indicators which show the following: the amount of
      remaining battery charge, if the battery is low and needs replacement, the power
      in watts being consumed, if the power consumed is above 15 W, if the pump is
      running below the selected speed setting, and if the pump stops. The control box,
      curved to be worn on the belt, is only 2.5 inches high for comfort when sitting.
      The battery pack, also form fitted for patient comfort, weighs just over 1 1/2
      pounds and supplies 65 W-h of energy storage, sufficient to run the device for
      over 8 h at nominal load.

PMID- 10392272
TI  - Experience with emergency cardiac surgery following institution of percutaneous
      cardiopulmonary support.
AB  - Between August 1992 and February 1998, 43 patients were treated with percutaneous
      cardiopulmonary support (PCPS) in our institution, and 8 of them subsequently
      required emergency cardiac surgery. There were 3 males and 5 females with a mean
      age of 63 years (range, 37 to 81 years). The etiology of shock in these 8
      patients was acute myocardial infarction in 3, postinfarction left ventricular
      (LV) free wall rupture in 1, postinfarction ventricular septal perforation (VSP)
      in 1, LV free wall rupture and VSP in 1, and fatal arrhythmia due to severe
      aortic valvular disease in 2. The mean time interval from the onset of
      cardiogenic shock to the institution of PCPS was 77 min (range, 18 to 183 min).
      The mean time interval from the institution of PCPS until surgery was 145 min
      (range, 40 to 603 min). The surgical procedures were coronary artery bypass
      grafting (CABG) in 3 patients, closure of the LV rupture and/or closure of VSP in
      3, and aortic valve replacement in 2. Six patients were weaned from PCPS, and 2
      patients were discharged from the hospital (discharge rate, 25%). Although the
      results of emergency cardiac surgery following PCPS still are not satisfactory,
      we continue to apply PCPS and perform appropriate surgical procedures to improve
      the survival rate of the patients who would die without PCPS.

PMID- 10392273
TI  - Cardiac autonomic nervous function during long-term nonpulsatile left heart
      bypass.
AB  - We investigated the changes in cardiac autonomic nervous activities during long
      term nonpulsatile left heart bypass (NLHB) by analyzing heart rate variability. A
      pulsatile ventricular assist device was installed in 3 goats, and pulsatile left
      heart bypass (PLHB) was conducted for 2 weeks. Then, NLHB was maintained for the
      following 4 weeks. The segmental data of the R-R intervals (R-Rs) was analyzed by
      maximum entropy spectral analysis. Changes in evaluated parameters from the last
      week of PLHB to the 4th week of NLHB were as follows: the mean R-Rs increased
      from 511 ms to 692 ms; the coefficient of variation of R-R increased from 10.2 to
      14.1%; the power of the low frequency band (LF) increased from 747 ms2 to 2,855
      ms2; the power of the high frequency band (HF) increased from 512 ms2 to 1,270
      ms2; and the ratio of LF to HF increased from 2.6 to 6.5. These results indicated
      that the cardiac autonomic nervous activity, both sympathetic and
      parasympathetic, increased during long-term NLHB.

PMID- 10392274
TI  - Long-term in vivo left ventricular assist device study for 284 days with Gyro PI
      pump.
AB  - A totally implantable centrifugal artificial heart has been developed. The
      plastic prototype, the Gyro PI 601, passed 2 day hemodynamic tests as a
      functional total artificial heart (TAH), 2 week screening tests for anti
      thrombogenecity, and a 1 month system feasibility study. Based upon these
      results, a metallic prototype, the Gyro PI 700 series, was subjected to long-term
      in vivo left ventricular assist device (LVAD) studies of over 1 month. The Gyro
      PI 700 series has the same inner dimension and same characteristics of the Gyro
      PI 601 such as an eccentric inlet port, a double pivot bearing system, and a
      magnet coupling system. The PI metallic pump is also driven with the Vienna DC
      brushless motor actuator like the PI 601. The pump-actuator package was implanted
      in 3 calves in the preperitoneal space, bypassing from the left ventricular (LV)
      apex to the descending aorta. Case 1 achieved a 284 day survival. Case 2 was
      euthanized early at 72 postoperative days as a result of the functional
      obstruction of the inlet port due to the excessive growth of the calf. There was
      no blood clot inside the pumps of either case. Case 3 is on-going (22 days on
      July 24, 1998). During these periods, all cases showed no physiological
      abnormalities. In conclusion, the PI 700 series pump has excellent results as a
      long-term implantable LVAD.

PMID- 10392275
TI  - Cytokine and endothelial damage in pulsatile and nonpulsatile cardiopulmonary
      bypass.
AB  - Recently, several types of centrifugal pumps have been widely used as the main
      pumps for cardiopulmonary bypass (CPB). However, according to the results of our
      experimental studies, after cardiogenic shock, pulsatile flow was effective in
      maintaining the functions and microcirculations of end organs, especially those
      of the liver and kidney. To estimate the effectiveness of pulsatility during CPB,
      cytokine and endothelin and other metabolic parameters were measured in clinical
      pulsatile and nonpulsatile CPB cases. From March to May 1997, CPB was performed
      in 18 elective cases (14 ischemic and 4 valvular disease). In 9 cases, pulsatile
      perfusion was achieved by the Jostra HL20, which is a newly developed CPB pump
      (Group P). A nonpulsatile centrifugal pump was used in 9 patients (Group NP). In
      both groups, as chemical and metabolic mediators, interleukin-8 (IL-8),
      endothelin-1 (ET-1), and plasma free hemoglobin were measured before and during
      CPB, and 0.5, 3, 6, 9, 18 h after weaning from CPB. This pulsatile CPB pump could
      be very simply and easily controlled and could easily produce pulsatile flow.
      There were no significant differences in CPB time (CPBT), aortic cross clamp time
      (ACCT), mean aortic pressure, or pump flow during CPB between the both groups.
      The ET-1 level of Group P was significantly (p < 0.05) lower than that of Group
      NP 9 h after CPB weaning. The IL-8 level of Group P also showed a lower value
      than that of Group NP. As for plasma free hemoglobin, there were no significant
      differences between the groups. These results suggested that even in conventional
      CPB, pulsatility was effective to reduce endothelial damage and suppress cytokine
      activation. It may play a important role in maintaining the functions and
      microcirculations of end organs during CPB.

PMID- 10392276
TI  - Afferent and efferent nerve activity of arterial baroreceptor reflex under
      nonpulsatile systemic circulation.
AB  - We studied the changes in arterial baroreceptor reflex (ABR) afferent activity
      and efferent activity induced by nonpulsatile systemic circulation (NC) during
      total left heart bypass (TLHB) in rabbits. To evaluate the influence of the
      circuit priming fluid and exposure to NC, we directly measured aortic depressor
      nerve activity (ADNA) (n = 5) and renal sympathetic nerve activity (RSNA) (n = 5)
      before the start of partial left heart bypass (PLHB) (Before), after PHLB
      (After), and 5 min after the start of TLHB (During THLB) while maintaining the
      mean aortic pressure. The circuit priming fluid did not affect the ABR. ADNA
      exhibited periodic discharge at Before and After, but at During THLB, this
      periodic discharge transformed into a continuous discharge, and ADNA increased
      significantly. However, there were no significant differences in RSNA. Our
      results suggested that in the acute phase under NC, the ABR differed from that
      under natural circulation.

PMID- 10392277
TI  - Development of an ultracompact integrated heart-lung assist device.
AB  - A novel integrated heart-lung assist device has been developed as a simple to use
      portable cardiopulmonary support system. The device comprises a centrifugal pump
      and an artificial lung, which is located around the pump, in an all in one
      system. The special membrane employed precludes plasma breakthrough in protracted
      use and enables preprimed setup. Test lungs consisting of the same membrane
      preserved gas exchange function well after 3 months of preprimed storage. The
      entire blood contacting surface is treated with covalent heparin bonding to
      impart good antithrombogenicity. Heparin bonded test lungs could be continuously
      perfused without systemic anticoagulation as long as 36 days in a venoarterial
      bypass chronic animal study using goats. The prototype device (diameter, 126 mm;
      height, 59 mm; membrane area, 0.85 m2; priming volume, 180 ml) demonstrated 9
      L/min pump output at a 400 mm Hg pressure head and 180 ml/min oxygen and 110
      ml/min carbon dioxide transfer rates at 5 L/min blood flow. We conclude that this
      device has potential to be the next generation cardiopulmonary support system.

PMID- 10392278
TI  - A centrifugal pump driven tidal flow extracorporeal membrane oxygenation system
      tested with neonatal mock circulation.
AB  - In 1993, Chevalier published his experiences with tidal flow venovenous
      extracorporeal membrane oxygenation (ECMO) featuring a single lumen cannula, non
      occlusive roller pump, and alternating clamps. Using a neonatal mock circulation
      (NMC), which enables different hemodynamic states for neonatal ECMO research, the
      tested hypothesis was that it is possible to create a centrifugal pump driven
      tidal flow neonatal venovenous ECMO system. Additionally, the resulting
      hemodynamic effects in a condition of circulatory impairment were investigated.
      The ECMO circuit tested was assembled using a pediatric centrifugal pump head, a
      distensible reservoir, and a rotary clamp separating drainage from the injection
      phase. Using the NMC, end tidal volumes, mock circulation flow, and arterial and
      venous pressures were measured at different pump speeds after the drainage and
      injection phases. Effective venovenous ECMO flow (evvEF) was calculated. Mock
      circulation baseline values (ECMO clamped) were compared to values during tidal
      flow ECMO. At 3,000 rpm, a centrifugal pump speed of 75 ml/kg/min evvEF was
      reached, and it increased with higher pump speeds. At this point, the end tidal
      mock circulation flow (representing cardiac output) after drainage differed
      significantly from that during the injection phase (p < 0.01) but not from the
      baseline value. The end tidal arterial and venous pressures after the drainage
      phase were found to be significantly decreased compared to the baselines (p <
      0.01). In conclusion, a centrifugal pump driven tidal flow venovenous ECMO system
      can be created enabling sufficient tidal volumes. Tested in the described NMC
      simulating posthypoxic circulatory impairment, significant hemodynamic effects
      could be demonstrated. Animal experiments for confirmation are necessary.

PMID- 10392279
TI  - Vagal nerve activity recording in the awake condition for the control of an
      artificial heart system.
AB  - To detect useful information for an artificial heart control system, we paid
      attention to the autonomic nervous system. For stable recording, we used vagal
      nerve activity in chronic animal experiments using healthy adult goats in an
      awake condition because this nerve was sufficiently bold and large enough. Vagal
      nerve discharges were successfully recorded from awake goats. They were
      synchronized with respiration and responded to the hemodynamic changes induced by
      drug administration, suggesting that they may provide useful information for an
      artificial heart control algorithm. For automatic control, some time delay plays
      a vitally important role. Thus, predictive control for an artificial heart system
      may be desirable. It may be embodied by the use of autonomic nerve information.

PMID- 10392280
TI  - Detection of suction and regurgitation of the implantable centrifugal pump based
      on the motor current waveform analysis and its application to optimization of
      pump flow.
AB  - In this study, a detection algorithm for suction and regurgitation of the
      centrifugal pump during left heart bypass without relying on external flow or
      pressure sensors was developed and evaluated in acute studies using adult goats.
      The detection scheme relies on power spectral density (PSD) analysis of the motor
      current waveform through which the waveform deformation index (WDI) is obtained.
      This index is defined as the ratio of the fundamental component of the PSD to the
      higher PSD components, and its value increases with the deformation of the basic
      waveform. By assuming that the undistorted motor current waveform can be
      represented by a pure sine waveform, we theoretically synthesized various
      waveforms which have different second harmonic components. We were able to
      synthesize the waveform whose shape was close to the distorted motor current
      waveform under varying suction levels obtained in a mock loop study. From this
      study, we came to the conclusion that the WDI value of 0.2 can serve as a
      threshold level in deciding the suction and regurgitation speeds (rpm) during
      left heart bypass. In the study using adult goats, we were successful in
      minimizing both regurgitation and suction when the centrifugal pump speed was
      adjusted based on the WDI algorithm. The resultant bypass flow ranged from 1.5 to
      2.0 L/min which was around 60% of the total flow. Further study is underway to
      evaluate the applicability of the WDI method in optimizing bypass pump flow.

PMID- 10392281
TI  - A new control method that estimates the backflow in a centrifugal pump.
AB  - The rotary blood pump will be widely used in the near future as an implantable
      left ventricular assist device (LVAD). However, one obstacle for the centrifugal
      pump is a control method that can maintain an optimum flow rate in a
      physiological condition. Thus, the object of this study is to develop this
      optimum control system for the centrifugal pump. If the heart function and pump
      efficiency are stable, the ratio of the systole current to the the diastole
      current (S/D) will be a fixed value. However, if the heart function and pump
      efficiency are unstable, S/D will not be a fixed value. This control system was
      investigated with a calf that was subjected to an ex vivo LVAD study. The LVAD
      was a Gyro C1E3 centrifugal pump. The pump flow rate was changed to 1.5, 3.5,
      5.2, and 6.2 L/min. According to the changes of the pump flow rates, the S/D
      values were 1.01 +/- 0.01, 1.06 +/- 0.05, 1.03 +/- 0.01, and 1.03 +/- 0.01,
      respectively. There was no statistical difference among the 3 groups. In a
      separate experiment, the backflow condition S/D was 1.88 +/- 0.6, and the normal
      condition S/D was 1.35 +/- 0.5. There was a statistical difference between the 2
      groups. The results of this study suggest that S/D is not influenced by the pump
      flow rate. However, the S/D was changed when the pump was in a backflow
      condition. This method will be useful in controlling a centrifugal pump requiring
      only electrical current information.

PMID- 10392282
TI  - Experimental study on hemolysis in centrifugal blood pumps: improvement of flow
      visualization method.
AB  - To evaluate rotary blood pumps, flow visualization is commonly applied to
      determine the flow patterns in a centrifugal blood pump, which have a
      relationship to its hemolytic performance. However, it is very troublesome to
      visualize the flow near the vanes due to the high rotational speed of the
      impeller. The rotational speed of the impeller in a centrifugal blood pump is
      usually several hundred revolutions per minute. In this study, we combined a high
      speed video camera based imaging method and an optical system in which the image
      of the rotating impeller was kept stationary. In the optical system, a prism
      rotating at half the speed of the impeller reflected the image of the impeller.
      The resultant reflected image was observed by a high-speed video camera through a
      half mirror. With this optical setup, the image through the half mirror became
      stationary, and the path of a specific tracer particle could be traced for a
      longer duration. A longer duration of measurements and better quality of the
      obtained images were realized through this improvement. Movement of a specific
      tracer from the inlet portion to the outlet portion of the impeller could be
      examined using the developed method.

PMID- 10392284
TI  - Shaft/shaft-seal interface characteristics of a multiple disk centrifugal blood
      pump.
AB  - A multiple disk centrifugal pump (MDCP) is under investigation as a potential
      left ventricular assist device. As is the case with most shaft driven pumps,
      leakage problems around the shaft/shaft seal interface are of major interest. If
      leakage were to occur during or after implantation, potential events such as
      blood loss, clotting, blood damage, and/or infections might result in adverse
      effects for the patient. Because these effects could be quite disastrous,
      potential shaft and shaft seal materials have been investigated to determine the
      most appropriate course to limit these effects. Teflon and nylon shaft seals were
      analyzed as potential candidates along with a stainless steel shaft and a
      Melonite coated shaft. The materials and shafts were evaluated under various time
      durations (15, 30, 45, and 60 min), motor speeds (800, 1,000, 1,200, and 1,400
      rpm), and outer diameters (1/2 and 3/4 inches). The motor speed and geometrical
      configurations were typical for the MDCP under normal physiologic conditions. An
      air and water study was conducted to analyze the inner diameter wear, the inner
      temperature values, and the outer temperature values. Statistical comparisons
      were computed for the shaft seal materials, the shafts, and the outer diameters
      along with the inner and outer temperatures. The conclusions made from the
      results indicate that both the tested shaft seal materials and shaft materials
      are not ideal candidates to be used for the MDCP. Teflon experienced a
      significant amount of wear in air and water studies. Nylon did experience little
      wear, but heat generation was an evident problem. A water study on nylon was not
      conducted because of its molecular structure.

PMID- 10392283
TI  - Comparative study of biocompatibility between the open circuit and closed circuit
      in cardiopulmonary bypass.
AB  - The theoretical benefit of a centrifugal pump or heparin coating demonstrated
      through in vitro or in vivo studies is not recognizable in cardiopulmonary bypass
      (CPB) during chemical open heart surgery. The objective of this study was to
      investigate the influence of the interface of air and blood in current CPB with
      an open circuit system and its relative significance in relationship to the
      heparin dose and heparin coating. Using the same oxygenator and circuit, an open
      circuit and closed circuit CPB with the same priming volume were prepared for a 4
      h perfusion experiment using diluted and heparinized (3.6 U/ml) fresh human
      blood. In these experiments, both heparin-coated and noncoated circuits were
      examined. Blood was sampled before and 2, 30, 60, 120, and 240 min after the
      start of perfusion, and the platelet and white blood cell counts and beta
      thromboglobulin (beta-TG) and C3a levels were measured. The amount of adsorbed
      protein in the hollow fibers was also measured after retrieval. Although the
      results demonstrated significantly better biocompatibility of the heparin-coated
      circuit than the noncoated circuit, the difference between the open and closed
      circuits was unexpectedly small and insignificant with either the heparin-coated
      circuit or noncoated circuit. In contrast, the C3a level was higher in the closed
      circuit than the open circuit. However, the amount of adsorbed protein was
      markedly lower in the closed circuit (0.7 microgram/cm2) than in the open circuit
      (11.1 micrograms/cm2). An immunoblot of the adsorbed protein showed a higher
      density of fibrinogen bands and conversion to fibrin in the open circuit. We
      speculate that the lower blood C3a level in the open circuit suggests that C3a
      was taken in by the adsorbed protein. In conclusion, analysis of the adsorbed
      protein indicates the lower biocompatibility of the open circuit. Similar
      experiments with less heparin use and more severe conditions will be necessary to
      elucidate the essential benefit of making a CPB closed circuit.

PMID- 10392285
TI  - Analysis of optimal design configurations for a multiple disk centrifugal blood
      pump.
AB  - A multiple disk centrifugal pump was analyzed as a blood pump for use in cardiac
      assistance or as a bridge to transplant device. The original configuration
      consisted of 6 parallel disks with 0.016 inch spacing between disks. This pump
      suffered from a degradation of flow with increasing afterload. A study was
      conducted to analyze flow performance as a function of afterload, preload, and
      motor speed. Configurations were examined including 4, 5, and 6 disks each with
      spacings of 0.15, 0.20, and 0.25 inches. Flow rates were examined for variations
      in afterload from 60-130 mm Hg, in preload from 0-20 mm Hg and for motor speeds
      of 1,250, 1,500, and 1,750 rpm. Analyses of afterload effects were intended to
      determine those configurations that produced less flow degradation with
      increasing afterload. Analyses of motor speed effects were intended to determine
      any configurations that produced greater flow increases with increasing motor
      speed. A hemolysis study was also performed. Both plasma free hemoglobin and the
      index of hemolysis were compared to data reported for other centrifugal blood
      flow devices. Results indicated that a 5 disk configuration with a 0.15 inch
      spacing produced optimal flow results with minimal degradation at higher
      afterloads. No optimal configuration based upon motor speed was indicated.
      Preload effects on pump performance were minimal. Hemolysis results indicated
      minimal blood damage with levels below those of many other centrifugal blood pump
      designs.

PMID- 10392286
TI  - Development of the Valvo pump: an axial flow pump implanted at the heart valve
      position.
AB  - Pulsatile artificial hearts having a relatively large volume are difficult to
      implant in a small patient, but rotary blood pumps can be easily implanted. The
      objective of this study was to show the feasibility of using the Valvo pump, an
      axial flow pump implanted at the heart valve position, in such cases. The Valvo
      pump consists of an impeller and a motor. The motor is waterproofed with a
      ferrofluidic seal. A blood flow of 5 L/min was obtained at a pressure difference
      of 13.3 kPa (100 mm Hg) at 7,000 rpm. The normalized index of hemolysis (NIH) was
      0.030 +/- 0.003 (n = 3) for a blood flow of 5 L/min at a pressure difference of
      13.3 kPa. The pressure resistance of the ferrofluidic seal was 37.5 kPa in a
      static condition and 26.3 kPa at 10,000 rpm. The seal exhibited no leaks for 41+
      days against 20.0 kPa. The results showed that the Valvo pump can maintain
      systemic circulation with an acceptable level of hemolysis.

PMID- 10392287
TI  - Computational simulation of flows in an entire centrifugal heart pump.
AB  - A prototype computational code to numerically simulate the blood flows in an
      entire centrifugal heart pump has been developed. The unsteady incompressible
      Navier-Stokes equations are solved on a parallel computer, the Cray T3E. By
      domain decomposition, the whole flow space is decomposed to a number of
      subdomains for each of which a structured algebraic grid is assigned. The grids
      for the inlet eye and blade regions are on the rotating frame while grids for
      other regions are on the nonrotating frame, and the edge of the rotating grids
      slides over the edge of the nonrotating frame, and the edge of the rotating grids
      slides over the edge of the nonrotating grids. The code is able to simulate the
      flows in the rotor, volute, and diffuser as well as to find pump performance
      indicators. The present paper presents an overview of the code and describes a
      study on the effect of volute width.

PMID- 10392288
TI  - Red wine, green tea and vitamins: do their antioxidants play a role in
      immunologic protection against cancer or even AIDS?

PMID- 10392289
TI  - Oxidative stress induced in pathologies: the role of antioxidants.
AB  - Exposure to oxidant molecules issued from the environment (pollution, radiation),
      nutrition, or pathologies can generate reactive oxygen species (ROS for example,
      H2O2, O2-, OH). These free radicals can alter DNA, proteins and/or membrane
      phospholipids. Depletion of intracellular antioxidants in acute oxidative stress
      or in various diseases increases intracellular ROS accumulation. This in turn is
      responsible for several chronic pathologies including cancer, neurodegenerative
      or cardiovascular pathologies. Thus, to prevent against cellular damages
      associated with oxidative stress it is important to balance the ratio of
      antioxidants to oxidants by supplementation or by cell induction of antioxidants.

PMID- 10392290
TI  - Skin antioxidants: their role in aging and in oxidative stress--new approaches
      for their evaluation.
AB  - Skin is a highly metabolic tissue which possesses the largest surface area in the
      body and serves as the protective layer for internal organs [1]. Skin is also a
      major candidate and target of oxidative stress. It is designed to give both
      physical and biochemical protection, and is equipped with a large number of
      defense mechanisms. The skin tissue is exposed to a variety of damaging species
      which originate in the outer environment, in the skin itself, and in various
      endogenous sources [2, 3]. The structure of skin is quite complex being composed
      of several layers, each of which plays a specific role and carries out different
      functions [4]. Each layer is equipped with its own arsenal of defense molecules,
      and the various systems differ from each other based on the layer's
      susceptibility to oxidative stress and its function. It is generally agreed that
      one of the major and important contributions to skin aging, skin disorders and
      skin diseases results from reactive oxygen species (ROS) [1, 5]. Due to the high
      occurrence of potential biological targets for oxidative damage, skin is very
      susceptible to such reactions. For example, skin is rich in lipids, proteins, and
      DNA, all of which are extremely sensitive to the oxidation process [6-8].
      Elucidation of the mechanisms involved in skin oxidation and the examination of
      the defense systems may contribute to the understanding of skin aging and of the
      mechanisms involved in the various pathological processes of skin. This review
      addresses the antioxidant defense mechanism of the skin, the role it plays during
      the aging process, and the role skin has following exposure to oxidative
      stresses.

PMID- 10392291
TI  - Prevention of topical and ocular oxidative stress by positively charged submicron
      emulsion.
AB  - A positively charged submicron emulsion with zeta potential values ranging from
      35 to 45 mV and mean droplet size around 150-250 nm has recently been developed
      and characterized. This formulation is based on three surface-active agents, an
      egg yolk phospholipid mixture, poloxamer 188, and stearylamine, a cationic lipid
      with a pKa of 10.6. The emulsion toxicity was evaluated in three animal studies.
      The results of the ocular tolerance study in the rabbit eye indicated that hourly
      administration of one droplet of the positively charged emulsion vehicle was well
      tolerated without any toxic or inflammatory response to the ocular surface during
      the five days of the study. No marked acute toxicity was observed when 0.6 mL of
      positively charged emulsion was injected intravenously to BALB/c mice.
      Furthermore, no difference was noted between this group of animals and the group
      injected with the marketed and clinically well accepted negatively charged
      Intralipid emulsion. These observations were further confirmed in a four week
      toxicity study following intravenous administration to rats of 1 mL/kg of the
      positively charged emulsion as compared to Intralipid. No toxic effect was noted
      in any of the various organs examined, whereas the results of the hematological
      and blood chemistry tests remained in the normal range for both emulsions,
      confirming the preliminary safety study findings. In addition, it was
      demonstrated by means of a non-invasive technique that alpha-tocopherol
      positively charged emulsions prevented oxidative damage in rat skin subjected to
      UVA irradiation. The intrinsic ability of positively charged emulsified oil
      droplets to protect against reactive oxygen species cannot be excluded, and could
      act synergistically with the antioxidant alpha-tocopherol itself. The effect of
      blank and piroxicam positively charged emulsions on rabbit eye following alkali
      burn was also evaluated. The blank emulsion showed a very rapid healing rate
      during the first three days with a breakdown in day 14. Complete re
      epithelialization was observed in day 28. The same behavior (albeit less
      pronounced), was noted in piroxicam emulsion, although piroxicam is known to
      inhibit the epithelial healing process. It can therefore be deduced that the
      positively charged emulsion vehicle prevented piroxicam from interfering with the
      epithelial healing process due to the intrinsic free radical scavenger ability of
      the positively charged submicron emulsion previously demonstrated. Finally, the
      efficacy of this promising emulsion vehicle containing effective cosmetic
      ingredients in preventing skin damage and aging following oxidative stress is
      evaluated.

PMID- 10392292
TI  - Mitochondrial DNA polymorphism in the French population.
AB  - One hundred unrelated individuals of French origin were screened for mtDNA
      variation as restriction fragment length polymorphisms (RFLPs) with the
      restriction enzymes HpaI, BamHI, HaeII, MspI, AvaII and HincII. Twenty enzyme
      morphs were detected, four of which (AvaII-37Fr, -38Fr, HincII-18Fr and -19Fr)
      are new. Of the 17 mitotypes detected, five are new and they were named 1-19Fr, 6
      18Fr, 100Fr-2 (2-1-2-4-1-2), 101Fr-2 (2-1-1-1-38Fr-2) and 102Fr-2 (2-1-1-4-37Fr
      2). All new morphs and mitotypes derive from those already known due to a single
      nucleotide substitution. The French population was compared with other European,
      Mediterranean and Caucasian populations. Calculation of the genetic distances
      showed close genetic affinity with European-Mediterranean populations and
      especially with Calabrians, Majorcans and northern Italians (at negative values).

PMID- 10392293
TI  - Total magnesium concentrations of perilymph, cerebrospinal fluid and blood in
      guinea pigs fed different magnesium-containing diets.
AB  - The total magnesium (Mg) concentrations of the perilymph (PL), cerebrospinal
      fluid (CSF), plasma and red blood cells (RBCs) of anesthetized guinea pigs
      separated into three groups and fed different Mg-containing diets were determined
      by atomic absorption spectrometry. Due consideration was given to the significant
      sources of error connected with the sampling procedure, particularly
      contamination of PL with CSF. The Mg levels of the individuals fluids differed
      significantly (P < 0.05/0.01) within each group. In the normal Mg group, the mean
      values of the PL, CSF and plasma were 0.66, 0.81 and 0.97 mmol/l, respectively,
      and 7.83 mmol/kg dry weight for RBCs. The analytical data were found to depend on
      the Mg content of the animals' diet, but to a different degree in the individual
      specimens (plasma > PL > CSF). A correlation was found to exist between all
      specimens tested (P < 0.05/0.01), except for CSF and RBCs, with the closest
      relation being that between plasma and PL. These findings suggest that the
      perilymphatic Mg equilibrates with the Mg level of plasma rather than with that
      of CSF. This is the first report showing Mg data of PL, CSF, plasma and RBCs
      obtained from the same subject, and the dependency on the Mg content of the
      animals' diet.

PMID- 10392294
TI  - Factors affecting recovery of mastoid aeration after ear surgery.
AB  - Fifty-six patients after tympanomastoid surgery were examined to determine
      recovery of mastoid aeration and various pre- and intraoperative factors such as
      eustachian tube (ET) function, how the mastoid mucosa had been treated during
      surgery and whether or not a large silastic sheet had been placed in the middle
      ear or a ventilation tube used. Mastoid aeration recovery was confirmed by
      computed tomography in 27 of the 57 cases (47%) within 12 months of surgery.
      Among the factors examined, preservation of the epitympanic mucosa was found to
      be most important in mastoid aeration recovery. Use of a large silastic sheet to
      cover the area from the bony ET and tympanic cavity to epitympanum, aditus ad
      antrum or antrum was found to be of some help in recovery mastoid aeration after
      complete resection of the mucosa and mastoid air cells. Preoperative ET function,
      anterior tympanotomy and use of a ventilation tube did not influence recovery.

PMID- 10392295
TI  - Surgical treatment of the high jugular bulb in patients with Meniere's disease
      and pulsatile tinnitus.
AB  - The aim of this retrospective study was to evaluate the functional results of
      surgical lowering of the high jugular bulb in the treatment of patients with
      Meniere's disease and pulsatile tinnitus. Fifteen patients with disabling
      Meniere's disease associated with pulsatile tinnitus and a high and medial
      jugular bulb were included in this study. As treatment a complete mastoidectomy
      was performed, after which the jugular bulb was freed by an infralabyrinthine and
      subfacial approach. The bulb was then displaced downwards with surgical wax.
      Functional results of surgery were assessed by a questionnaire according to the
      1995 guidelines of the United States American Academy Committee on Hearing and
      Equilibrium, audiometric and vestibular tests, and by magnetic resonance and
      computed tomographic imaging with vascular sequences. Surgical treatment was
      contraindicated in two cases: one had hypoplasia of the contralateral sigmoid
      sinus and the other a small petrous hemangioma located around the jugular bulb
      that was discovered peroperatively. Among the 13 patients treated by definitive
      surgery, attacks of vertigo were reported as disabling in 12 cases preoperatively
      (92%) versus 1 (8%) after surgical treatment. No significant change in hearing
      was observed after surgery. Tinnitus had been reported in all patients
      preoperatively and decreased in intensity in four (31%) and disappeared in three
      (23%) after surgery.

PMID- 10392296
TI  - Posterior fossa vestibular nerve section for the management of peripheral
      vertigo.
AB  - Patients with vertigo resistant to conservative treatment require surgical
      management. Between March 1991 and August 1996, vestibular nerve sections were
      performed in 108 patients with peripheral vertigo not responding to conservative
      treatment. The diagnoses were classic Meniere's disease in 96 patients and
      recurrent vestibulopathy in 12 patients. Combined retrosigmoid retrolabyrinthine
      (n = 106) and retrolabyrinthine (n = 2) approaches were used. Patients were
      grouped according to follow-ups of less than 2 years and more than 2 years. In
      the former group (n = 49), hearing preservation and vertigo control were achieved
      in 93.9% and 100%, respectively. In the latter group (n = 59) the rates were
      89.8% and 96.6%, respectively. Overall complications were uncommon. Three
      patients had cerebrospinal fluid leakage and one had total hearing loss.
      According to our results, posterior fossa vestibular nerve section was found to
      be an effective treatment for the management of patients with intractable
      vertigo.

PMID- 10392297
TI  - Solitary fibrous tumor of the paranasal sinuses.
AB  - Although solitary fibrous tumors are well-recognized in the pleura, their
      occurrence in the paranasal sinuses is decidedly uncommon. We have encountered
      two cases of solitary fibrous tumors in the paranasal sinuses and report the
      clinicopathological findings including CD34 immunoreactivity. One tumor arose in
      a 55-year-old Japanese businessman and the other in a 53-year-old man who had
      been in the hospital for schizophrenia for 20 years. The tumors showed
      characteristic findings. Immunoperoxidase stains on paraffin sections showed
      staining of the cells for anti-vimentin, but there was no staining for anti
      keratin, anti-S-100 protein, anti-desmin, anti-glial fibrillary acidic protein
      (GFAP), or anti-actin. Anti-CD34 monoclonal antibodies also reacted with these
      tumors, as those of the pleura generally do, and were found to be useful in
      diagnosing these tumors. CD34 immunoreactivity [8]. Fukunaga et al. [6] reported
      that CD34 immunoreactivity presented in a solitary fibrous tumor of the nasal
      cavity, but separate tumors of the paranasal sinuses have not been analyzed. We
      have recently encountered two cases of solitary fibrous tumors of the paranasal
      sinuses. In this report, the clinicopathological features of these tumors of and
      their CD34 immunoreactivity were analyzed.

PMID- 10392298
TI  - Urokinase-type plasminogen activator and plasminogen activator inhibitor antigen
      in tissue extracts of paranasal sinus mucous membranes affected by chronic
      sinusitis and antrochoanal polyps.
AB  - We examined the effect of pH on the extraction of urokinase-type plasminogen
      activator (u-PA) and plasminogen activator inhibitor-1 (PAI-1) from paranasal
      sinus mucous membrane associated with chronic sinusitis and antrochoanal polyps.
      The specific activity of u-PA extracted with buffer at pH 7.4 was stronger than
      that extracted with buffer at pH 4.2. The antigen level of u-PA extracted with
      the acidic buffer was significantly higher than that extracted with the neutral
      buffer. In contrast, the difference in antigen levels of PAI-1 extracted with the
      acidic buffer and neutral buffer was not significant. Based on these results, we
      inferred that the u-PA-PAI-1 complex was extracted by the acidic buffer and the
      activity of u-PA was therefore decreased.

PMID- 10392299
TI  - Minimally invasive surgery for recurrent neuroendocrine carcinoma of the
      supraglottic larynx.
AB  - Calcitonin-secreting neuroendocrine carcinomas of the supraglottic larynx are
      infrequent tumors, making it difficult to agree on treatment plans for recurrent
      tumors. Furthermore, this rare malignancy is often confused with the more common
      medullary thyroid carcinoma, resulting in inappropriate thyroidectomies. We
      present a case report of a calcitonin-secreting recurrent neuroendocrine
      carcinoma of the supraglottic larynx, in which surgery and pentagastrin
      stimulation were performed repeatedly at various stages of the disease. The
      recurrent laryngeal tumor was ultimately identified and, after construction of a
      protective tracheostomy, resected transorally en bloc with the underlying
      arytenoid cartilage. Postoperatively, the patient did well and stimulated
      calcitonin levels never exceeded double baseline values. Laryngoscopic removal of
      smaller laryngeal carcinomas is both technically feasible and safe, even when
      tumors are recurrent. In calcitonin-secreting malignancies, pentagastrin
      stimulation may facilitate the distinction between laryngeal and medullary
      thyroid carcinoma and thus help avoid unnecessary thyroidectomies.

PMID- 10392300
TI  - An association of chronic alcohol consumption with morphological alterations of
      the laryngeal mucosa in rats.
AB  - Within the last decades a considerable amount of epidemologic evidence has been
      built up to implicate chronic alcohol consumption as a major risk factor not only
      for oral and pharyngeal cancer, but also for laryngeal cancer. The mechanisms
      that underlie alcohol-related cancers of the larynx have remained largely
      unclear. Since the epithelium of the glottic region normally has no direct
      contact with alcoholic beverages, alcohol-related alterations of glottic mucosa
      have been questioned. In the present study 20 male Wistar rats were fed
      nutritionally adequate liquid diets containing 36% of the total calories either
      as ethanol or isocaloric carbohydrates for 6 months. Morphometric analysis of the
      glottic mucosa in the ethanol-fed rats showed a significant reduction in
      epithelial thickness of the glottic epithelium of the anterior commissure as well
      as of the posterior commissure (P < 0.001). Morphometric analysis of the basal
      cell nuclei of the glottic epithelium did not show any statistically significant
      differences between ethanol-fed rats and control rats. These findings indicate
      that chronic ethanol consumption can cause a significant atrophy of the glottic
      mucosal epithelium in the rat and suggest an enhanced susceptibility toward
      locally acting chemical carcinogens.

PMID- 10392301
TI  - Ex vivo interleukin (IL)-1 beta, IL-6, IL-12 and tumor necrosis factor-alpha
      responsiveness with monocytes from patients with head and neck carcinoma.
AB  - Seventy newly diagnosed Caucasian male patients with head and neck squamous cell
      carcinomas (HNSCC) were included in the study. All patients were less than 80
      years of age, with no cachexia or auto-immune disease, and they were not taking
      immuno-active medications. Monocytes from these patients were cultured in vitro
      and supplemented with autologous serum under ex vivo conditions or cultured with
      serum-free medium. Comparison was made to monocytes from 59 patients with benign
      HN diseases. Similar physical activity levels prior to testing as well as a
      minimum stress load were ensured in both groups. Increased monocyte supernatant
      levels were determined under ex vivo conditions of interleukin-1 beta (IL-1
      beta), interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha, but not of
      interleukin-12 (IL-12) with endotoxin stimulated monocytes of HNSCC patients
      compared to control conditions. Increased monokine levels were not present with
      mononuclear cell cultures stimulated with a T-cell general stimulatory agent or
      with purified monocytes not specifically stimulated. With endotoxin-stimulated
      monocytes under in vitro conditions, an increased supernatant was shown for TNF
      alpha, but not IL-6. With serum from the different patients cultured with
      monocytes employed from a healthy control, no difference between the groups was
      shown in the IL-6 and TNF-alpha response to endotoxin stimulation. The
      differences in IL-1 beta and TNF-alpha, but not IL-6 levels were differentiated
      statistically from the smoking and alcohol histories of the patients. These
      findings suggest that the function of monocytes in general, and thus possibly all
      mononuclear phagocyte system cells in HNSCC patients, are altered.

PMID- 10392302
TI  - The use of nuclear morphometry for the prediction of survival in patients with
      advanced cancer of the larynx.
AB  - We examined retrospectively whether the quantitative morphometric analysis of
      nuclear shapes in patients with advanced cancer of the larynx could be used as a
      prognostic factor. In all, specimens were taken from 90 patients treated by
      surgery in the Department of Otolaryngology, Jagiellonian University, Cracow,
      Poland, between 1987 and 1988. The follow-up period was no shorter than 5 years.
      In the group examined there were 59 patients with T3 tumors and 31 with T4
      tumors. A neck dissection was performed on one or both sides in each case.
      Metastases in regional lymph nodes were found in 26 patients. Histologic grading
      was assessed in all cases. Fourteen parameters of nuclear shape were studied
      using a computer-assisted system of image analysis. Morphometric data were
      compared with patients' survival rates. The worse survival rates were found to be
      linked with a nuclear area (NA) > or = 64.82 micron 2 and its standard deviation
      (SDNA) > or = 20.10 micron 2, a nuclear perimeter (NP) > or = 32.45 microns and
      its variation (SDNP) > or = 4.77 microns, nuclear density (ND) > or = 22,215.63
      and its variation (SDND) > or = 6930.85 and nuclear roundness (NR) > or = 0.76.
      By using multivariate Cox regression analysis the SDND, presence of metastases in
      lymph nodes and low tumor differentiation were found to be independent prognostic
      factors. No statistically significant correlation was found between the
      parameters examined, lymph node status and tumor differentiation.

PMID- 10392303
TI  - Angiocentric lymphoma involving the temporal bone in a child.
AB  - Involvement of the temporal bone in patients with malignant lymphomas is very
      rare. Most of the reported cases have been clinically asymptomatic and were
      diagnosed only by post-mortem examinations. We present a nasal, paranasal,
      nasopharyngeal lymphoma that occurred in a 12-year-old child and also involved
      the temporal bone. Clinical presentation began with bilateral chronic otitis
      media. Histopathologically, tumor was found to be an angiocentric lymphoma of B
      cell origin. Association with Epstein-Barr virus could not be demonstrated.
      Despite combination chemotherapy (with cyclophosphamide, vincristine,
      doksorubicine, prednisolone, L-asparaginase, cytosine arabinoside, metotraxate)
      and radiotherapy (to 40 Gy), disease progressed locally as well as to cervical
      lymph nodes and the lungs.

PMID- 10392304
TI  - The role of fibroblasts from oropharyngeal mucosa in producing proinflammatory
      and mitogenic cytokines without prior stimulation.
AB  - Cytokine production by fibroblasts is not only important for immunological and
      inflammatory reactions in the epidermis and mucosa, but also for growth and
      differentiation of epithelial cells. To characterize the role of fibroblasts in
      the oropharyngeal mucosa, the expression of a panel of cytokines and cytokine
      receptors by fibroblasts isolated from normal human oropharyngeal mucosa was
      investigated by enzyme-linked immunosorbent assay (ELISA), reverse transcribed
      polymerase chain reaction (RT-PCR) and flow cytometry (FACS). Oropharyngeal
      fibroblasts produced the proinflammatory cytokines interleukin 1 alpha (IL-1
      alpha), IL-6 and IL-8 without addition of phorbol-12-myristate-13-acetate (PMA)
      or biological response modifiers, suggesting an active involvement of these cells
      in host defence mechanisms. Keratinocyte growth factor (KGF), a growth factor for
      epithelial cells, and the angiogenetic fibroblast growth factors acidic and basic
      FGF (aFGF, bFGF) were also synthesized. Expression of receptors for IL-1, IL-4,
      IL-6, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) was
      found. These results indicate that oral fibroblasts are capable of producing a
      number of cytokines without the need for additional stimuli and emphasize their
      active regulatory role in the maintenance of the oral mucosa.

PMID- 10392305
TI  - The effect of lithium administration in animal models of depression: a short
      review.
AB  - The aim of this short review was to collate the data involving the effects of
      lithium alone, or in combination, with antidepressant drugs in several animal
      models of depression. It has been shown that lithium administration reduced
      immobility in the mouse forced swimming test when given 30 min, but not 45 min,
      before testing. Further studies indicated that this activity was probably a
      result of an activity on serotonin (5-HT) 1A and 1B receptor subtypes. Lithium
      treatment has been shown to reverse helpless behaviour in the learned
      helplessness model of depression after chronic treatment (30 days), where lithium
      was administered in the drinking water. Further studies showed that acute (5
      days) administration of lithium failed to reverse behavioural deficits. In the
      olfactory bulbectomised rat model of depression, several immunological and
      enzymatic functions have been shown to be altered and these changes are
      regularised by antidepressant treatment as well as lithium administration for 15
      days. Hypokinesia (reduced locomotor activity) is a phenomenon observed following
      immobilisation stress in rats. This behavioural deficit was attenuated by lithium
      together with a wide range of antidepressant drugs used in the treatment of
      unipolar depression at non-stimulant doses. In addition, a single administration
      of lithium slightly inhibited midbrain raphe lesion-induced muricidal behaviour
      (25%); however, repeated treatment (5 days) significantly attenuated this
      behavioural deficit. Lithium treatment has also been shown to reverse behavioural
      and biochemical deficits induced by reserpine together with those induced by
      acute administration of single intracerebroventricular (i.c.v.) dose of the Na, K
      ATPase-inhibiting compound, ouabain. Long-term studies of lithium augmentation
      have not been performed, so that no clear recommendations for the duration of
      this therapy can be made. The points raised in this short review endorse the
      commencement of such studies.

PMID- 10392306
TI  - Trandolapril treatment at low dose improves mechanical and functional properties
      in perfused coronary arteries of spontaneously hypertensive rat.
AB  - The ex-vivo effects of a 1-month treatment period with trandolapril at a low dose
      (0.3 mg/kg/day) were assessed on the mechanical and functional alterations
      observed in SHR coronary arteries. The in-vitro intrinsic elastic properties of
      the wall in treated SHR coronary arteries were determined in comparison to those
      of SHR rats. In preconstricted preparations, agonist- and flow-induced
      dilatations were investigated in arteries of both groups. Arterial segments were
      cannulated at both ends using an arteriograph system. Internal diameter and wall
      thickness were continuously monitored while intraluminal pressure and flow were
      controlled. Wall thickness was reduced in arteries of treated rats compared to
      those in control SHR (mm): 52 +/- 2 vs. 41 +/- 2, P < 0.001, respectively.
      Arterial stiffness, expressed by the incremental elastic modulus-stress
      relationship, was significantly lower in arteries of treated compared to control
      SHRs. In preconstricted preparations, dilatations induced by bradykinin were
      significantly greater in treated SHR compared to control SHR arteries whereas
      dilatations induced by acetylcholine were slightly but not significantly
      increased. On the other hand, starting flow at the plateau of 5-HT-induced
      constriction led to dilatations which were not significantly different in the
      treated compared to the control group. The maximal dilatation induced by flow in
      arteries of treated rats was obtained for the same value of shear stress compared
      to that determined in preparations of control SHRs: (dyn/cm2) 63 +/- 3 vs. 61 +/-
      2, respectively, NS. These results show that together with hypertrophy, the
      abnormal mechanical properties observed in the coronary arterial wall of SHR were
      improved by a low dose of trandolapril treatment. However, differential effects
      of trandolapril treatment were observed on agonist and flow-induced dilatations.
      Although flow-induced dilatation seemed to remain unaffected, acetylcholine
      induced dilatation was slightly improved and bradykinin-induced dilatation was
      markedly increased by trandolapril treatment.

PMID- 10392307
TI  - Functional assessment of rat aorta after cold storage in different media.
AB  - Cold storage is frequently used to store isolated blood vessels for a limited
      period of time. However preservation of vascular smooth muscle and endothelial
      functions is time and medium-dependent. The present study was designed to compare
      the reactivity of rat aorta before and after cold storage for 24 and 48 h in one
      of four different solutions consisting of Hepes-buffered Krebs solution, Belzer
      solution, Krebs solution, and Eurocollins solution. Smooth muscle and endothelial
      functions of the rat aorta were assessed using in vitro isometric tension
      measurement. The results obtained for vessels preserved for 24 and 48 h were
      compared with those for vessels studied immediately after harvesting. Sensitivity
      and maximum contraction to KCl and norepinephrine were not altered in rat aorta
      preserved up to 48 h in Hepes-Krebs and Belzer solutions. In contrast, the
      amplitude of contraction elicited by KCl was significantly reduced by 50% and 77%
      in aorta stored for 24 and 48 h in Krebs solution and by 77% and 96% in those
      stored in Eurocollins solutions. Similarly, the maximal contraction elicited by
      norepinephrine was significantly reduced by 60% and 45% in arteries stored for 24
      and 48 h in Krebs solution and by 34% and 86% in those stored in Eurocollins
      solution. In contrast, cold storage in the different media did not alter the
      relaxations elicited by sodium nitroprusside and forskolin. The endothelium
      dependent relaxations in response to acetylcholine were not statistically
      modified after preservation up to 48 h in Hepes-Krebs solution. In contrast, the
      maximal relaxations to acetylcholine were significantly decreased after storage
      for 24 and 48 h in Belzer, Krebs and Eurocollins solutions. These results suggest
      that among the four media studied, Hepes-Krebs solution is the most suitable
      medium for the storage of blood vessels under hypothermic conditions.

PMID- 10392308
TI  - Effects of K(+)-channel blockers on A1-adenosine receptor-mediated negative
      inotropy and chronotropy of guinea-pig isolated left and right atria.
AB  - Adenosine has previously been shown to stimulate K(+)-efflux and to block L-type
      calcium channels in atrial myocytes. The aim of the present study was to evaluate
      the contribution of K(+)-channels in the development of the negative inotropic
      and chronotropic responses to adenosine agonists in guinea-pig left and right
      atria, respectively. Tetraethylammonium (TEA) potentiated the negative inotropic
      and chronotropic responses to R-(-)-N6-(2-phenyl-isopropyl)-adenosine (R-PIA),
      seen as leftward shifts of the concentration-response curves. Glibenclamide had
      no effect on the negative inotropic response to R-PIA but increased the rate of
      onset of the negative chronotropic response in right atria. 4-Aminopyridine (4
      AP, 10 mM), potentiated the left atrial inotropic responses to R-PIA, seen as a
      leftward shift of the concentration-response curve, but slowed the speed of onset
      of the response to a single concentration (10(-6) M) of R-PIA. This reduction in
      speed of onset of the response can explain the differences in effects of 4-AP on
      concentration-response curves reported here and previously. In the right atria, 4
      AP (10 mM) inhibited the negative chronotropic responses to R-PIA, seen as a
      rightward shift of the concentration-response curve and reduction of the maximum
      response. 4-AP also slowed the onset of the right atrial rate response to R-PIA.
      These results support the theory that K(+)-efflux plays only a minor role in the
      negative inotropic responses of guinea-pig left atria to R-PIA. This apparently
      controls the speed of onset of the response. The negative chronotropic response
      of guinea-pig right atria to R-PIA appears to be much more dependent upon K(+)
      efflux than for the negative inotropic response of the left atria.

PMID- 10392309
TI  - Influence of fluoxetine and litoxetine on 5-HT4 receptor-mediated relaxation in
      the rat isolated oesophagus.
AB  - The influence of two selective serotonin reuptake inhibitors (SSRIs), litoxetine
      and fluoxetine, has been studied on 5-HT4 receptor-mediated relaxation in the rat
      isolated oesophageal muscularis mucosae. In carbachol-precontracted oesophageal
      tissues, 5-hydroxytryptamine (5-HT) (0.1 nM-1 microM) induced concentration
      dependent relaxations. Concentration-response curves were monophasic and
      reproducible. Litoxetine at concentrations without antimuscarinic properties (10
      nM-1 microM) caused concentration-dependent relaxations, which reduced carbachol
      tone up to 37%. Higher litoxetine concentrations (3 microM-300 microM) were
      associated with marked relaxation up to the abolition of carbachol tone. The
      overall curve profile of litoxetine was biphasic in nature with a high (10 nM-1
      microM) and a low (3 microM-300 microM) potency phase. Unlike 5-HT, the second
      curve of litoxetine was not reproducible, with a reduction involving mainly the
      low potency phase. Compared to litoxetine, fluoxetine caused minimal relaxation
      (less than 10% at 1 microM). Treatment of rats with parachlorophenylalanine
      (pCPA: 375 mg kg-1 per day, for two days), to deplete endogenous 5-HT stores, did
      not modify the relaxant effect of 5-HT, while it significantly reduced the high
      potency phase of litoxetine. In tissues from untreated rats, this phase was
      reduced by the 5-HT4 receptor antagonist GR 125487 (10 nM) to an extent similar
      (P = 0.20: ANOVA for continuous-by-class effects) to that induced by pCPA
      treatment. However, in tissues from pCPA treated animals GR 125487 (10 nM)
      exerted a slight but significant antagonism of litoxetine response (P = 0.037:
      ANOVA for continuous-by-class effects) mainly involving the high potency phase.
      In tissues from untreated rats, litoxetine (1 microM) increased the relaxant
      effects of 5-HT, while in tissues from pCPA treated animals it exerted a small
      but significant depression of the maximal response to 5-HT, without changing its
      potency value. Fluoxetine (1 microM) slightly, but significantly, antagonized the
      relaxant effect of 5-HT in an unsurmountable manner. In conclusion, litoxetine up
      to 1 microM relaxed the rat isolated oesophageal muscularis mucosae through a
      mechanism involving release of endogenous 5-HT, which in turn activates 5-HT4
      receptors. However, based on results with GR 125487 in tissues from pCPA treated
      rats, a small component of litoxetine-induced relaxation may involve a direct
      activation of 5-HT4 receptors. It is unlikely that blockade of 5-HT reuptake can
      participate in the action of litoxetine, since fluoxetine, a 5-HT reuptake
      inhibitor equipotent to litoxetine, was ineffective in the same range of
      concentrations. The antimuscarinic activity of litoxetine, previously
      demonstrated in the isolated guinea-pig intestine, played a role at
      concentrations greater than 1 microM. The 5-HT-releasing action of litoxetine
      could account for the potentation by litoxetine of 5-HT-induced relaxation in
      tissues from untreated rats, which was reversed by pCPA treatment. Under these
      conditions, litoxetine depressed relaxations to high 5-HT concentrations only. In
      tissues from untreated rats, fluoxetine slightly but unsurmountably antagonized 5
      HT-induced relaxations, thus confirming previous observations in the guinea-pig
      small intestine.

PMID- 10392310
TI  - Role of CYP3A in haloperidol N-dealkylation and pharmacokinetics in rats.
AB  - Haloperidol (HP), an antipsychotic drug, is N-dealkylated by cytochrome P450
      (CYP) to 4-fluorobenzoylpropionic acid (FBPA). The purpose of this study was to
      identify whether CYP3A metabolizes HP to FBPA in hepatic microsomes of rats and
      to investigate whether an inhibitor or an inducer of CYP3A affects HP
      pharmacokinetics in rats. The rate of FBPA formation was determined in hepatic
      microsomes from 8-week-old male Sprague-Dawley rats. Among several specific CYP
      isozyme inhibitors including troleandomycin (TAO), diethyldithiocarbamate,
      furafylline and quinine, only TAO showed marked inhibition of FBPA formation.
      Anti-rat CYP3A serum inhibited FBPA formation by 76.4%, while other anti-rat CYP
      sera (1A1, 1A2, 2B1, 2C11, 2E1) only slightly did. In a pharmacokinetic study, 8
      week-old male Sprague-Dawley rats were given 0.5 mg/kg HP intravenously after
      treatment with 100 mg/kg erythromycin, a CYP3A inhibitor, or 80 mg/kg
      dexamethasone, a CYP3A inducer, intraperitoneally once a day for 7 days or 2
      days, respectively or untreated. HP half-life was prolongated to 171% of the
      average control value by erythromycin and shortened to 49% of control by
      dexamethasone. HP clearance was reduced to 63% of control by erythromycin and was
      increased to 167% of control by dexamethasone. These results suggested that CYP3A
      mainly catalyzed HP to FBPA in rats, and the modification of this enzyme activity
      would affect the pharmacokinetics of HP.

PMID- 10392311
TI  - A review of the use of health status measures in economic evaluation.

PMID- 10392312
TI  - Oral antibiotics reduce body temperature of healthy rabbits in a thermoneutral
      environment.
AB  - Nonabsorbable oral antibiotics, which reduce gut flora, decrease the daytime and
      night-time body temperatures of rats and mice. We investigated whether oral
      antibiotics would also lower the body temperature of healthy rabbits. Six rabbits
      received neomycin sulphate in their drinking water for ten days, and seven
      rabbits received a mixture of chloramphenicol and dihydroxystreptomycin for six
      days. Body temperatures, recorded using intra-abdominal radiotelemeters,
      decreased significantly, by 0.2-0.3 degree C, after three days of antibiotic
      treatment in both groups of rabbits. The drop in body temperature was transient;
      after six days body temperatures returned to pre-antibiotic levels. Antibiotic
      treatment had no effect on either the acrophase or the amplitude of the circadian
      rhythm in body temperature. Oral antibiotics therefore reduce body temperature of
      rabbits, without influencing the circadian rhythm in body temperature. Our
      results are consistent with the hypothesis that an agent arising from intestinal
      bacteria sustains an elevated body temperature in healthy animals.

PMID- 10392313
TI  - Effect of diazepam on survival of the immature pig in a confined atmosphere.
AB  - Diazepam is known to prolong survival in an atmosphere containing 5% oxygen, and
      to reduce cerebral metabolic rate and cerebral perfusion. It also depresses the
      arousal response to hypoxia and protects the optic nerve from anoxia. We
      hypothesised that diazepam might extend survival in a confined atmosphere with a
      limited amount of oxygen. Pigs consumed the oxygen in a sealed chamber until they
      reached the terminal state. The experimental pigs (n = 6) were sedated with
      diazepam 0.3 mg/kg i.v. and were compared with a control group (n = 5). We
      measured blood pressure, inspired O2 and CO2, minute ventilation, ECG, ambient
      and body temperatures, and PO2, PCO2, O2 content and pH in arterial and venous
      blood. In the diazepam-treated pigs, oxygen consumption was reduced in the
      hypoxic range (PIO2 below 60 torr) compared with the control pigs. Diazepam
      prevented the elevated hypoxic cardiac output found in the control pigs. There
      were almost no differences between the diazepam and control groups in the other
      parameters measured in the course of the exposure and in the terminal state.
      Terminal PIO2, PaO2, and PvO2 were 36.9 +/- 5.6, 27.9 +/- 8.6, 14.3 +/- 2.0 torr,
      and 36.9 +/- 5.7, 23.7 +/- 7.3, 15.7 +/- 7.6 torr in the diazepam and control
      groups, respectively. The survival time was 220 +/- 51 and 255 +/- 50 min in
      diazepam and control pigs, respectively. In spite of its anticonvulsant effect
      and the fact that it protects CNS white matter from anoxia, prolongs anoxic
      survival and eliminates the high oxygen demand in hypoxic arousal, diazepam
      failed to extend hypoxic survival in a confined atmosphere to a lower PIO2.
      However, diazepam had no deleterious effect on survival, and may therefore be
      used to ease stressful hypoxic conditions.

PMID- 10392314
TI  - Effect of cadmium-induced lipid peroxidation on EEG spectral components.
AB  - Pregnant Swiss albino rats were divided into control (C) and cadmium (Cd) groups.
      Control animals received tap water while the Cd group received Cd as CdCl2 in
      their drinking water. The rat pups were separated from their mothers 22 days
      after birth. 78 young rats were divided into two main groups: controls (C1, C2,
      C4) and cadmium groups (Cd1, Cd2, Cd4). Each sub-group included 13 rats. On
      postnatal days 30, 60, and 120, spectral analysis of EEGs recorded from the
      parietal lobes of all groups of rats was computed by fast Fourier transform (FFT)
      algorithm. The amplitude maxima were found to occupy the frequency bands of 1-2,
      2-4, 4-6, 6-8, 8-16, and 16-30 Hz. The decibel (dB) values of the maxima were
      significantly decreased in Cd1 and Cd2 groups compared with the corresponding
      control groups in all the frequency bands except 16-30 Hz. A significant
      amplitude (dB) decrease was observed in all the frequency bands of the Cd4 group
      compared with the C4 group.

PMID- 10392315
TI  - The effect of cadmium (Cd) treatment on somatosensory evoked potentials (SEPs)
      and conduction velocity in alloxane-induced diabetic rats: relation to lipid
      peroxidation.
AB  - Fifty-two healthy Swiss male albino rats, aged three months, were divided into
      four groups: Control (C), diabetic (D), cadmium (Cd), and diabetic + Cd (D+Cd).
      Diabetes was induced in D and D+Cd groups by administration of alloxane (5 mg/100
      g). Cd and D+Cd groups were injected with CdCl2 i.p. (2 mg/kg/week) for 2 months.
      Somatosensory evoked potentials (SEPs) of the four groups were recorded following
      left posterior tibial nerve (PTN) stimulation. The mean latencies of P1, N1, P2
      and N2 components were prolonged in all experimental groups compared with the
      control group. P1N1 and N1P2 amplitudes were significantly decreased in Cd and
      D+Cd groups in comparison with the control group. P2N2 amplitude was
      significantly decreased in the Cd group compared with the control group. In
      addition, conduction velocities and action potential amplitudes were determined
      from the sciatic nerves. The means of peripheral conduction velocities and action
      potential amplitudes were decreased significantly in all the experimental groups
      in comparison with the control group. Thiobarbituric acid reactive substances
      (TBARS), an indicator of lipid peroxidation, were increased in the kidneys and
      sciatic nerves of all experimental groups compared with the control group. A
      significant increase in the TBARS level of the brain was found in the Cd and D+Cd
      groups.

PMID- 10392316
TI  - Effect of cadmium and zinc salts on energy metabolism and survival of Unio
      tumidus Philipsson.
AB  - Energy metabolism of aquatic invertebrates is one of the most important targets
      of environmental pollutants, in particular, heavy metals. In this study, we
      determined changes in survival, oxygen uptake and hepato-pancreas glycogen level
      of the bivalve mollusk Unio tumidus Philipsson following chronic exposure of Cd
      and Zn salts (chlorides and sulfates). The concentrations of Cd salts were equal
      to 0.001, 0.01 and 0.1 mg/l and concentrations of Zn salts were equal to 0.01,
      0.1, 1.0 mg/l (maximal contamination level for Cd is 0.005 mg/l and for Zn is
      0.01 mg/l). Survival was registered daily whereas oxygen consumption and glycogen
      level were determined on days 3, 7 and 14. Changes in survival of U. tumidus
      along the course of Cd and Zn salt concentrations was not monotonic; the sulfates
      were more inhibitory than the chlorides. No correlation was found between changes
      in survival and changes in the oxygen uptake and the glycogen level. By analysis
      of data in the literature, it was possible to construct a general scheme of
      adaptation of aquatic invertebrates' energy metabolism to heavy metals impact:
      (1) "exhaustive" or "economical" activation of aerobic metabolism (with or
      without depletion of energy resources); (2) change to "exhaustive" anaerobic
      mechanism (with depletion of glycogen); (3) change to "economical" anaerobic
      metabolism (involving mechanisms of glycogen expenditure economy); (4) late-term
      activation of aerobic metabolism due to need for binding and excretion of
      accumulated metals. Different severity of the pollutants' impact may lead to
      prevalence of different stages of this scheme. Our results revealed most of these
      stages in U. tumidus: "economical" activation of aerobic metabolism, change to
      "exhaustive" and "economical" anaerobic metabolism, and late-term activation of
      aerobic metabolism. It can be suggested that Cd is more toxic due to late-term
      decrease in oxygen consumption whereas Zn resulted only in transient early-term
      decrease. On the other hand, mechanisms of glycogen economy during anaerobic
      metabolism were involved in the effect of Cd and not involved in the effect of
      Zn. Concerning the effect of anions, chlorides promoted transient activation of
      aerobic metabolism, while sulfates promoted the passage to anaerobic metabolism.
      Thus, the effect of sulfates seems to be more inhibitory than the effect of
      chlorides.

PMID- 10392317
TI  - The effect of direction on saccadic eye movement parameters.
AB  - The present study obtained saccadic eye movements from 25 right-handed normal
      subjects (aged 18-35 yr, mean 22.4 yr) to examine the effects of saccade
      direction on saccadic parameters (latency, duration and average velocity).
      Binocular saccadic eye movements were recorded with a direct-current
      electrooculographic system, and analysis was performed on a laboratory digital
      computer. The LED target positions were randomly selected 10, 15, 20, 25 and 30
      degrees to the left or right of the fixation points. In general, the mean values
      of the saccadic parameters over large saccade angles were in agreement with those
      previously reported. There were no significant differences between saccades
      directed to the right and to the left.

PMID- 10392318
TI  - Developments in the therapeutic applications of bisphosphonates.
AB  - The authors review the structural, pharmacologic, and clinical aspects of
      bisphosphonates, a class of drugs currently used to treat several disorders of
      bone and calcium metabolism. Pertinent literature on the bisphosphonates was
      reviewed with the help of a MEDLINE search and several bibliographies, including
      published clinical trials, monographs, and review articles. The bisphosphonates
      are analogs of pyrophosphate that, when given orally or intravenously, bind
      avidly to exposed bone mineral and disrupt bone turnover. These agents comprise
      three groups or generations, based on their potency and chemical structures. All
      three generations are effective in treating hypercalcemia, Paget's disease of
      bone, osteoporosis, and other disorders of accelerated bone turnover. The third
      generation agents have the greatest potency and offer the promise of a convenient
      way to suppress or prevent osseous metastasis in patients with certain
      malignancies. As a group, these agents are well tolerated and, when administered
      correctly, rarely cause toxicity. The bisphosphonates are safe and effective
      agents for the treatment of disorders of accelerated bone turnover.

PMID- 10392319
TI  - Absolute oral versus inhaled bioavailability: significance for inhaled drugs with
      special reference to inhaled glucocorticoids.
AB  - Orally inhaled drugs provide great benefit in the treatment of asthma as they are
      delivered directly to the site of action, i.e. the lung. The absolute oral
      inhaled bioavailability of a glucocorticoid results from the combination of the
      bioavailability of the dose delivered to the lung and the bioavailability of the
      dose delivered into the gastrointestinal (GI) tract. The majority of the dose
      delivered to the lung is absorbed and available systemically. For the portion of
      the glucocorticoid dose delivered orally, bioavailability depends upon absorption
      from the GI tract and the extent of first pass/pre-systemic metabolism in the GI
      tissue and liver. Since this oral component of the delivered dose does not
      provide any beneficial therapeutic effect but can contribute to the systemic side
      effects, it is desirable for the absolute oral bioavailability of inhaled
      glucocorticoids to be relatively low (which is the case with most of the
      glucocorticoids, < 25%). Another approach to limiting systemic exposure from
      inhaled delivery is to improve the effectiveness of the oral inhaled formulation
      and delivery device, by increasing the fraction of the total inhaled dose which
      reaches the lung. Since current inhalation technology can provide respirable
      fractions in the range of 30-50%, what is the significance of the oral component
      of systemic exposure in relation to the overall systemic exposure following the
      oral inhalation administration of glucocorticoids? Below a certain point
      (approximately 25%), lower oral bioavailability of inhaled drugs may not be
      clinically important with respect to systemic exposure if the lung targeting is
      good (30%).

PMID- 10392321
TI  - Rapid disappearance of zaleplon from breast milk after oral administration to
      lactating women.
AB  - Five lactating mothers were administered the therapeutic dose of zaleplon (10 mg)
      orally in an open-label, single-dose, pharmacokinetic study. Plasma and breast
      milk were sampled through 8 hours after dose administration for subsequent
      determinations of zaleplon and its major, though inactive, plasma metabolite 5
      oxo-zaleplon. Zaleplon concentrations peaked in plasma and milk approximately 1
      hour after dosing and then disappeared rapidly. The mean terminal half-life was
      slightly greater than 1 hour. Milk concentrations "mirrored" plasma
      concentrations closely with no discernible delay between peak times. The average
      milk-to-plasma (M/P) concentration ratio for zaleplon was approximately 0.50 over
      the time course. 5-oxo-zaleplon was undetectable in all but one milk sample. The
      maximum exposure of an infant to zaleplon during a feeding at peak milk
      concentrations was estimated to range from 1.28 micrograms to 1.66 micrograms,
      corresponding to 0.013% to 0.017% of the maternal dose or 0.320 microgram/kg to
      0.415 microgram/kg for a 4 kg infant. The results indicate that zaleplon taken by
      a nursing mother is transferred through breast milk to her infant in very small
      quantities that are unlikely to be clinically important.

PMID- 10392320
TI  - Intraindividual variability in male hepatic CYP3A4 activity assessed by
      alfentanil and midazolam clearance.
AB  - Clinical investigations using isoform-selective probes to phenotype cytochrome
      P450 activity and interaction studies using isoform-selective inhibitors to
      determine P450 involvement in drug metabolism assume minimal interday variability
      in P450 activity. CYP3A4 is the most abundant human P450 isoform and metabolizes
      approximately half of all therapeutic agents. This investigation evaluated
      interday variability in hepatic CYP3A4 activity in males, using the clearances of
      midazolam and alfentanil as metabolic probes. Midazolam (1 mg) followed 1 hour
      later by alfentanil (20 micrograms/kg) were administered by intravenous bolus to
      9 nonsmoking male volunteers (ages 30 +/- 8 years). Drug administration was
      repeated 12 and 20 days later. Venous plasma midazolam and alfentanil
      concentrations were determined by gas chromatography/mass spectrometery. Drug
      clearances were determined by noncompartmental and multiexponential analysis.
      There were no significant interday differences in plasma drug concentrations or
      clearances (3.9 +/- 1.4, 3.9 +/- 1.7, and 4.2 +/- 1.7 ml/kg/min for alfentanil,
      respectively, and 6.6 +/- 2.0, 7.9 +/- 2.4, and 7.9 +/- 2.5 ml/kg/min for
      midazolam, respectively, on days 1, 13, and 21 [mean +/- SD]). Interday
      variability in clearance was 13% +/- 6% and 19% +/- 12% for alfentanil and
      midazolam, respectively. Interday variability in the clearance of these probes,
      and presumably hepatic CYP3A4 activity, was small compared with interindividual
      variability. Consideration of interday variability in the hepatic metabolism of
      CYP3A4 substrates does not appear significant in the design of clinical trials.

PMID- 10392322
TI  - Pharmacokinetics and pharmacodynamics of sibrafiban, an orally administered
      IIb/IIIa antagonist, in patients with acute coronary syndrome.
AB  - Sibrafiban is a double prodrug that is converted to the inactive single prodrug
      and to the active IIb/IIIa antagonist following oral administration.
      Pharmacokinetics (PK) and pharmacodynamics (PD) of oral sibrafiban and its
      metabolites were evaluated in patients postacute coronary syndrome receiving once
      or twice-daily sibrafiban for up to 28 days at several dose levels. Mean peak
      concentrations of sibrafiban were < 5 ng/mL. Peak single prodrug concentrations
      occurred 1.7 +/- 1.0 (mean +/- SD) hours after sibrafiban dosing. Total apparent
      plasma clearance of the single prodrug was 40 +/- 15 L/h, and the elimination
      half-life was 2.3 +/- 0.8 hours. Mean values of the steady-state pharmacokinetics
      for total concentrations of the active drug over all doses were: time to peak
      plasma concentration, 5.0 +/- 1.7 hours; apparent clearance, 13.9 +/- 3.9 L/h;
      and half-life, 11.0 +/- 2.8 hours. Once-daily dosing resulted in high peak-trough
      excursions in active drug concentrations: trough concentrations were 21% +/- 6%
      of peak. Twice-daily dosing resulted in an AUC for the active drug on Day 28 that
      was 168% +/- 36% of that on Day 1, and steady-state trough concentrations were
      54% +/- 10% of peak with sustained inhibition of platelet aggregation. Dose
      adjusted steady-state active drug concentrations increased with increasing age
      and with decreasing renal function and body weight.

PMID- 10392323
TI  - Pharmacokinetics and pharmacodynamics of avitriptan during intravenous
      administration in healthy subjects.
AB  - Avitriptan, a selective 5-HT1-like receptor agonist, is an effective compound for
      the treatment of migraine headaches with a prolonged duration of response. A
      double-blind, placebo-controlled, parallel-group, ascending-dose study in 24
      healthy subjects was designed to assess the safety, tolerance, pharmacokinetics,
      and pharmacodynamics of avitriptan. This antimigraine drug was administered as
      two consecutive constant-rate IV infusions at three dose levels (12.7, 25.3, and
      38.0 mg), which were targeted to produce plasma concentrations in and above the
      therapeutic range. The best fitting of the plasma concentration-time data was
      obtained by using a triexponential function yielding a terminal t1/2 of 8 hours.
      The areas under the plasma concentration versus time curves were proportional to
      dose, indicating linear pharmacokinetics. Moreover, the clearance and steady
      state volume of distribution values were independent of the dose. The change in
      pulse rate and supine systolic and diastolic blood pressure was determined as
      pharmacodynamic effects of avitriptan. A "threshold log-linear" model, which
      accounts for the linear increase in pharmacodynamic effect with the log of plasma
      concentrations when the latter was higher than a certain threshold value,
      adequately described the pharmacodynamic data. The threshold plasma drug
      concentrations for the pulse rate and the diastolic and systolic blood pressure
      were 14, 74, and 161 ng/ml, respectively. Overall, avitriptan has consistent,
      linear pharmacokinetics and increases systolic and diastolic blood pressure in a
      predictable manner at a higher plasma concentration. However, this drug does not
      produce a significant change in pulse rate at the dose levels (12.7-38 mg)
      evaluated in this study.

PMID- 10392324
TI  - A pharmacokinetic study to evaluate the absolute bioavailability of triamcinolone
      acetonide following inhalation administration.
AB  - Triamcinolone acetonide is a glucocorticoid administered by oral inhalation in
      the management of asthma. With oral inhalation of glucocorticoids, systemic
      absorption can come from oropharyngeal, gastrointestinal, or airway deposition of
      the drug. The objectives of this study were to determine the absolute
      bioavailability of triamcinolone acetonide following inhalation administration
      and to delineate the airway contribution of triamcinolone acetonide absorption
      relative to the absolute bioavailability. All subjects received a 5-minute 400
      mcg intravenous infusion of triamcinolone acetonide and a single 800 mcg dose of
      inhaled triamcinolone acetonide with and without oral charcoal administration in
      a randomized three-way crossover fashion. The oral charcoal allowed for isolating
      the pulmonary component of absorption by adsorbing the oropharyngeal and
      gastrointestinal deposited drug. The mean (+/- SD) absolute bioavailability value
      for inhaled triamcinolone acetonide was 25% (8.75%). Delineation of the airway
      contribution of triamcinolone acetonide absorption showed that 10.4% of an
      inhaled dose is absorbed as triamcinolone acetonide from the lungs. Mean (+/- SD)
      total body clearance was rapid at 0.57 (0.12) L/hr/kg. The mean (+/- SD) apparent
      volume of distribution following the intravenous dose was a low 1.96 (0.31) L/kg.
      No significant differences were noted in the apparent terminal elimination half
      life of triamcinolone acetonide (approximately 2.4 hr) between treatments.

PMID- 10392325
TI  - Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an
      endothelin receptor antagonist, in healthy male volunteers.
AB  - The multiple-dose pharmacokinetics, safety, and tolerability of oral bosentan, a
      selective endothelin receptor antagonist, were investigated in healthy male
      volunteers. In study A, an ascending-dose, double-blind, placebo-controlled
      trial, doses of 100, 200, 500, and 1000 mg bosentan or placebo were given once
      daily for 8 days as tablets (100 and 500 mg dose strength). In study B, a double
      blind, placebo-controlled trial, 500 mg tablets of bosentan or placebo tablets
      were given once daily for 8 days with two additional single intravenous dose
      administrations of 250 mg bosentan 48 hours before the first and 24 hours after
      the last oral dose. The drug was very well tolerated. No effects on pulse rate,
      ECGs, or clinical laboratory tests were observed. Marginal effects on blood
      pressure were seen in subjects only when standing. The oral bioavailability of
      bosentan was 43% to 48%, with a small interindividual variability of 20%. Doses
      above 500 mg did not lead to significant further increases in plasma levels of
      bosentan. From the first to the last day of the oral treatment phase, plasma
      concentrations of bosentan decreased by 30% to 40% due to a 2-fold increase in
      plasma clearance. Absorption and plasma protein binding did not change. The 24
      hour urinary excretion of 6 beta-hydroxycortisol was increased in parallel by
      approximately 1.7-fold, indicating induction of cytochrome P450 3A isozymes. The
      two metabolites of bosentan reached plasma concentrations well below those of
      bosentan and will most likely not contribute to the pharmacological activity.

PMID- 10392326
TI  - The effect of renal insufficiency on mycophenolic acid protein binding.
AB  - Mycophenolate mofetil (MMF) is commonly used in solid organ transplant
      recipients. MMF is converted to mycophenolic acid (MPA) upon reaching the
      systemic circulation. Many acidic drugs have altered protein binding in renal
      failure, and it is possible that MPA protein binding may be decreased. The
      authors studied 23 renal transplant recipients: 8 transplant patients (7 kidney,
      1 kidney/pancreas) with chronic renal insufficiency (CRI) and 15 renal transplant
      patients with preserved renal function. Plasma was obtained for kinetic profiles
      of total MPA, free MPA, and its glucuronide metabolite (MPAG). Plasma was
      obtained from 10 hemodialysis patients and 8 healthy control volunteers to assess
      in vitro differences in MPA protein binding. Average free fraction of MPA in
      patients with chronic renal insufficiency was more than double that of patients
      with normal renal function (5.8 +/- 2.7 vs. 2.5 +/- 0.4, p < 0.01). Free MPAAUC
      was almost doubled in the patients with chronic renal insufficiency versus
      controls (2.04 +/- .08 vs. 1.03 +/- 0.6, p < 0.01). MPA protein binding is
      decreased, and free MPA concentrations are increased in patients with chronic
      renal failure.

PMID- 10392327
TI  - Clozapine and metabolite concentrations during treatment of patients with chronic
      schizophrenia.
AB  - Results presented in this article are focused on the variability in
      pharmacokinetics. The purpose of this study was (1) to investigate intra- and
      interindividual variabilities of pharmacokinetic parameters of clozapine and its
      two main metabolites in plasma after multiple oral administration in 8 chronic
      schizophrenic patients (Study 1) and (2) to gain more information regarding
      plasma concentrations of these drugs after multiple doses in a group of 25
      treatment-responsive patients (Study 2). Patients were treated with clozapine in
      fixed daily doses (given every 8-12 hours) between 200 and 900 mg. Plasma drug
      concentrations were determined by high-performance liquid chromatography. The
      mean volume of distribution and the total plasma clearance of clozapine,
      uncorrected for bioavailability, were 7 L/kg and 40.5 L/h, respectively. The
      terminal elimination half-lives averaged 10.5 hours for clozapine, 19.2 hours for
      norclozapine, and 8.6 hours for the N-oxide metabolite. Significant relationships
      were observed between clozapine and norclozapine (or clozapine N-oxide) plasma
      concentrations. Large inter- and intrapatient variations in pharmacokinetics were
      observed. Clozapine was generally well tolerated by the patients, with sedation,
      hypersialorrhea, and tiredness as the most common side effects encountered.

PMID- 10392328
TI  - Pharmacokinetic and pharmacodynamic action of etodolac in patients after oral
      surgery.
AB  - The objective of this double-blind, randomized, parallel-group study was to
      evaluate the pharmacokinetics of etodolac and the pharmacodynamic response of
      pain in patients following oral surgery who had received 200 or 400 mg of
      etodolac immediate release (IR), 400 or 1200 mg of etodolac extended release
      (ER), or a placebo. Etodolac concentrations in 441 plasma samples from 187
      patients were analyzed for population pharmacokinetics using the NONMEM program.
      A one-compartment pharmacokinetic model with first-order absorption described the
      observed data. For etodolac IR, the population mean (%CV) estimates were 3.01 L/h
      (5.3%) for clearance, 13.6 L (6.8%) for volume of distribution, and 2.31 h-1
      (33%) for ka. Respective values for etodolac ER were 3.68 L/h (11%) for
      clearance, 24.3 L (22%) for volume of distribution, and 0.172 h-1 (24%) for ka.
      These values generally agreed with previously reported values in healthy adults.
      Pharmacodynamic assessments included collection of a four-level categorical
      rating of pain intensity for up to 24 hours after treatment. Pain intensity
      difference scores were temporally related to etodolac concentrations and were
      described using an indirect response model. Mean (%CV) pharmacodynamic parameters
      were IC50 of 14.0 mg/L (9.5%), kout of 1.62 h-1 (13%), FR of 0.56 (8.2%), and
      Hill coefficients that ranged from 1.26 to 3.34 units. A single 1200 mg dose of
      etodolac ER given once daily was shown to provide substantial efficacy for 13
      hours after dose, modest effect through 24 hours, and a more sustained duration
      of action than the IR dosage form.

PMID- 10392330
TI  - The Bouchier report--a recommendation too far?

PMID- 10392329
TI  - Combination of calcium channel blockers and beta-blockers for patients with
      exercise-induced angina pectoris: beneficial effect of calcium channel blockers
      largely determined by their effect on heart rate.
AB  - The combination of calcium channel blockers and beta-blockers is more effective
      for the treatment of exercise-induced angina pectoris than beta-blocker
      monotherapy. As ischemia in exercise-induced angina is essentially preceded by an
      increase in heart rate, calcium channel blockers with a negative chronotropic
      property may perform better for this purpose than nonchronotropic compounds. A
      335-patient, 10-week, double-blind, parallel-group comparison of amlodipine 5 mg
      and 10 mg, diltiazem 200 mg and 300 mg, and mibefradil 50 mg and 100 mg treatment
      added to baseline beta-blocker treatment was performed. Exercise testing (ETT)
      was performed by bicycle ergometry. All of the calcium channels blockers
      significantly delayed the onset of 1 mm ST-segment depression on ETT (p < 0.001
      for any treatment vs. baseline). In addition, mibefradil, in both low- and high
      dose treatments, produced the largest delays (low dose: different from diltiazem
      and amlodipine by 24.1 and 29.8 seconds, respectively, p < 0.003 and < 0.001;
      high dose: different from diltiazem and amlodipine by 33.7 and 37.0 seconds,
      respectively, p < 0.001 and < 0.001). A stepwise logistic regression analysis
      revealed that this beneficial effect of calcium channel blockers was largely
      dependent on their effect on heart rate. Serious symptoms of dizziness likewise
      occurred significantly more frequently on mibefradil (p < 0.05 vs. diltiazem) and
      urged no fewer than 19 patients on mibefradil to withdraw from the trial. The
      authors conclude that calcium channel blockers with a negative chronotropic
      property provide a better delay of ischemia in patients with exercise-induced
      angina, but the concomitant risk of intolerable dizziness may reduce this
      benefit.

PMID- 10392331
TI  - Helicobacter pylori and endoscopy.
AB  - Helicobacter pylori is possibly the most common bacterial infection of humans and
      is now recognized as the most important acquired cause of peptic ulceration.
      Epidemiological evidence also recently implicated this bacterium in the
      pathogenesis of gastric cancer. The mechanism of spread of the organism, by
      either the faecal-oral or oral-oral route, raises the possibility of transmission
      of this organism from infected patients to hospital staff particularly those
      involved in endoscopy. The evidence for an increased risk to endoscopists is
      contradictory, varying from none to a five-fold increase. This review summarizes
      the evidence for mode of transmission and risk to hospital staff from this
      important bacterium.

PMID- 10392332
TI  - Subcutaneous fluid administration--better than the intravenous approach?
AB  - Hypodermoclysis is a method of subcutaneous fluid administration particularly
      useful in elderly patients and in palliative care settings where intravenous
      access may be difficult. Subcutaneous fluid delivery is an effective method of
      rehydration and of opioid administration, and can prevent the need for
      intravenous catheterization and consequently hospitalization. It is a simple
      procedure to initiate, safe, less distressing to the patient, and does not
      predispose to intravascular related infections. The reported incidence of
      infection at the delivery site is extremely low. However, local guidelines should
      be agreed so that a standardized protocol is operated and risks of localized
      infection are minimized.

PMID- 10392333
TI  - Comparative antimicrobial resistance and genomic diversity of Escherichia coli
      isolated from urinary tract infections in the community and in hospitals.
AB  - Well-defined community- and nosocomially-acquired isolates of Escherichia coli
      responsible for urinary tract infections were studied for their resistance to
      beta-lactams, quinolones, and co-trimoxazole, antibiotics widely used for
      treatment of urinary infections. For each strain, an antibiogram was obtained
      using the Vitek automat, which estimates the minimal inhibitory concentrations of
      various drugs. Nosocomial strains were significantly more amoxycillin-resistant
      than community strains (P = 0.01) and were also significantly more resistant to
      co-trimoxazole (P = 0.025) and first generation quinolones (P = 0.02) than the
      latter. To determine whether this was due to transmission of strains within the
      hospital, DNA restriction patterns, established using XbaI enzyme and separation
      by pulsed-field gel electrophoresis, were compared. Extreme genomic diversity was
      found among both the community and nosocomial strains. The increased frequency of
      resistance among nosocomial strains is thus not due to transmission of resistant
      hospital strains but probably results from the selection of resistant strains
      from the endogenous flora of patients.

PMID- 10392334
TI  - Comparison of effectiveness and required time of two surveillance methods in
      intensive care patients.
AB  - The intensive care unit (ICU) standardized protocol of the NNIS (National
      Nosocomial Infections Surveillance) system is a surveillance method of hospital
      acquired infections (HAI), which provides device-associated infection rates. The
      aim of this study was to assess the effectiveness and the required time for data
      collection and analysis of a selective surveillance method (SSM) derived from the
      NNIS ICU surveillance protocol, and to compare its data with that of a reference
      surveillance method (RSM). The sensitivity, specificity and the positive
      predictive value (PPV) of the RSM were 87.5, 100 and 100%, respectively. The
      sensitivity, specificity and the PPV of the SSM were 59.4 97.6 and 79.2%,
      respectively. Considering device-related infections only (ventilator-related
      pneumonia, catheter-related urinary tract infections, central line-related
      sepsis), the sensitivities of the RSM and the SSM were 80.9 and 90.5%,
      respectively. The SSM required only one third of the time of the RSM (1.1 h and
      3.4 h per 10 beds per week with the SSM and the RSM, respectively). We conclude
      that the SSM has a very high sensitivity for detecting device associated
      infections, but is not sensitive enough for surveying all types of HAI.

PMID- 10392335
TI  - Risk factors for acquisition of Serratia marcescens in a surgical intensive care
      unit.
AB  - Between January 1996 and May 1997, a four-fold increased rate of isolation of
      Serratia marcescens was observed amongst patients admitted to the surgical
      Intensive Care Unit (SICU) of the Leiden University Medical Center compared to
      the preceding years. Random amplification of polymorphic DNA showed the
      involvement of genotypically distinct strains, implicating multiple different
      sources. After improvement of hygienic measures the frequency of isolation of S.
      marcescens returned to baseline. A case-control study was performed to assess
      patient-related risk factors for acquisition of S. marcescens. Nineteen cases and
      38 controls were included. Hospital- and SICU-stay were significantly longer in
      case patients than in controls. By univariate analysis, statistically significant
      differences were found in body weight, the duration of mechanical ventilatory
      support, the cumulative use of antimicrobial agents, the use of aminoglycosides,
      parenteral nutrition and tube feeding. The sum of the number of days per invasive
      device (deep intravenous lines, arterial lines, wound drains and urinary
      catheters) was higher in cases than in controls (P = 0.08). Categorically, a
      cumulative number of device-days > 25 was a statistically significant risk factor
      for acquisition of S. marcescens. Multivariable logistic regression analysis
      showed that body weight, parenteral feeding and mechanical ventilation were
      independent predictors of acquisition of S. marcescens. As transmission of S.
      marcescens appears to be by the hands of personnel, the identified risk factors
      may act by necessitating an increased frequency and intensity of direct contacts.

PMID- 10392336
TI  - Detecting legionellosis by unselected culture of respiratory tract secretions and
      developing links to hospital water strains.
AB  - For a 13-month period, all respiratory tract secretions submitted for routine
      bacteriology from a large hospital complex were cultured for legionella,
      irrespective of clinical diagnosis and laboratory requests. Ten cases of
      legionellosis were detected in this manner, three of which met a strict
      epidemiological definition of hospital-acquired. Therefore, the 16 warm-water
      systems of the hospitals, spread out over two locations, were examined for the
      presence of legionella. Legionella pneumophila was found in 15 warm water
      systems, with a distinct pattern of serogroups between the two locations.
      Legionella of the same serogroups as those isolated from patients were present in
      each hospital water supply. The isolates were further typed by monoclonal
      antibodies and by genomic macrorestriction analysis. Similarity between clinical
      and environmental isolates was found in seven cases. In these cases, acquisition
      from the hospital water supply appears very likely. The strains of the remaining
      three patients did not match those in hospital water, suggesting that community
      acquired legionellosis was occurring as well. This study suggests that routinely
      culturing respiratory tract secretions of pneumonia patients for legionella can
      help diagnose unsuspected cases of legionellosis. Typing legionella strains
      beyond the serogroup level with tools such as macrorestriction analysis is useful
      to define sources of infection, which can then be targeted for control measures.

PMID- 10392337
TI  - Pseudo-outbreak of Aeromonas hydrophila isolates related to endoscopy.
AB  - Over a two-month period there was a sudden increase in Aeromonas hydrophila
      isolated from colon i.e., biopsies from patients without related symptoms.
      Strains were studied by biotyping (API 20 NE, bioMerieux), antibiotyping, plasmid
      analysis, SDS-PAGE of whole cell proteins and toxicity for cell cultures. All
      strains gave identical results. In particular SDS-PAGE of whole cell proteins
      showed an identical electrophoretic pattern for all the strains, and so all were
      considered to be of the same clone. During the study period, endoscopic materials
      were disinfected with quaternary ammonia and glutaraldehyde phenate. After these
      disinfectants were changed to glutaraldehyde 2%, there were no more isolates of
      A. hydrophila from the biopsies. We conclude that SDS-PAGE can be a useful
      technique for epidemiological characterization of A. hydrophila.

PMID- 10392338
TI  - Inactivation of duck hepatitis B virus by a hydrogen peroxide gas plasma
      sterilization system: laboratory and 'in use' testing.
AB  - Human hepatitis B virus (HBV) is an important cause of nosocomial infections and
      can be transmitted by contaminated instruments. However, tests of the efficacy of
      sterilization of materials and equipment contaminated by HBV are difficult to
      perform because the virus cannot be cultured in the laboratory. In this study, we
      aimed to evaluate the capability of a low temperature, hydrogen peroxide gas
      plasma sterilizer (Sterrad, Advanced Sterilization Products, Irvine California,)
      to inactivate duck hepatitis B virus (DHBV). In laboratory efficacy studies using
      DHBV dried on to glass filter carriers and exposed to one-half of the hydrogen
      peroxide gas plasma sterilization process, there was a 10(7) or greater decrease
      in the viral titer, with no infectivity detected on the carriers after treatment.
      In-use studies were performed using a laparoscope that was experimentally
      contaminated with DHBV to mimic the possible transmission of infection between
      successive patients. Following exposure to the hydrogen peroxide gas plasma
      sterilization process no transmission of DHBV infection from the laparoscope
      occurred despite obvious visual soiling with blood (N = 8) while the transmission
      rate for the unprocessed laparoscope (positive control) was 100% (26/26), and
      that for instruments after a water wash was 63% (7/11). In conclusion the
      hydrogen gas plasma sterilization process completely inactivates DHBV a
      representative of the hepadna group of viruses.

PMID- 10392339
TI  - Efficacy of Directigen RSV testing in patient management following admission from
      a paediatric emergency department.
AB  - We investigated the use of the Directigen Respiratory Syncytial Virus test
      performed under 'Stat Laboratory' conditions, in the management of infants after
      admission from the Paediatric Emergency Department (ED). The study group
      consisted of 242 consecutive paediatric ED patients tested by Directigen in the
      Stat laboratory during the winter 1995-1996 respiratory virus season. Specimens
      were submitted to the Virology Laboratory for confirmatory consensus testing
      utilizing in part, an in-house multiplex immunofluorescence assay (IFA) and
      conventional virus isolation methodologies. The sensitivity, specificity,
      positive and negative predictive values for Directigen, IFA, and isolation, were
      71, 91, 85, 80%; 98, 100, 100, 99%; and 51, 100, 100, 72% respectively. Re
      testing of 17 discordant original NP aspirates using Directigen, suggested that
      errors were due to technologist interpretation as well as to overt assay failure.
      The low analytical sensitivity and specificity of Directigen precludes its use in
      the clinical setting described in this study. Evening or weekend specimen
      collection, followed by IFA testing in a centralized Virology Laboratory at the
      start of the next working day, produces reliable test results. Among the small
      number of pediatric patients who might be candidates for antiviral therapy IFA
      testing should be made available on an on-call basis by Virology Laboratory.

PMID- 10392340
TI  - National prevalence survey on hospital infections in Norway.
AB  - A nationwide prevalence survey was carried out in Norwegian hospitals (excluding
      mental hospitals) on 23 October 1997. The aim was to assess the magnitude of
      major hospital-acquired infections (HAIs) prior to the introduction of quarterly
      prevalence surveys in Norway as required by the new Regulations for Communicable
      Disease Control in Hospitals. The survey included 71 of 76 possible hospitals,
      and 12,775 patients. Altogether 779 HAIs were identified--a prevalence rate of
      6.1%. Only the four major HAIs were included: urinary tract infection (36.4% of
      all HAIs); surgical wound infection (28.6%); lower respiratory tract infection
      (25.4%) and septicaemia (9.6%). Three thousand, three hundred and forty-nine
      patients had undergone surgery and the prevalence of surgical wound infection was
      6.3%. The results form a baseline for the next step in Norweigan hospital
      infection control; the quarterly prevalence surveys.

PMID- 10392341
TI  - Fungal infections in ICU.

PMID- 10392342
TI  - Treatment of superficial pseudomonal infection with citric acid.

PMID- 10392343
TI  - Pancreas transplantation.
AB  - Although intensified insulin therapy regimens enable normalization of blood
      glucose levels and related metabolic parameters, these regimens are associated
      with an increased incidence of hypoglycemic episodes. Pancreas transplantation
      has achieved the goal of providing insulin independence with stable and
      continuous normoglycemia. But because of the associated morbidity and mortality
      and the need for life-long immunosuppression after transplant, it is difficult to
      justify pancreas transplantation in diabetic patients at a pre-uremic stage.
      Pancreas transplantation is therefore performed in conjugation with renal
      transplantation. The majority of renal transplant centers, however, have been
      reluctant to perform simultaneous kidney-pancreas transplantation in insulin
      dependent uremic patients because of the additional risks associated with
      pancreas transplantation. More recently, refinements in surgical technique,
      introduction of new immunosuppressive agents, and better selection of transplant
      candidates have contributed to improved survival. Today, combined pancreas-kidney
      transplantation is an accepted treatment for carefully selected patients with
      insulin dependent diabetes and end-stage renal disease and in a small group of
      patients with uncontrolled severe metabolic problems. The effect of a euglycemic
      state after pancreas transplantation on the progression of micro- and
      macroangiopathy remains to be proved, although recently there is evidence to
      suggest that some end-organ lesions may be halted or even ameliorated. Further
      improvement in anti-rejection strategies may achieve better long-term graft
      survival and provide the incentive to perform pancreas transplantation at an
      earlier stage, before severe secondary complications of diabetes develop.

PMID- 10392344
TI  - Endocrine dysfunction in children with HIV-1 infection.

PMID- 10392345
TI  - The prevalence of mitochondrial gene mutations in childhood diabetes in Japan.
AB  - To investigate the prevalence of mitochondrial DNA mutations among Japanese
      children with IDDM as well as in those with NIDDM, a total of 155 patients with
      IDDM and 30 patients with NIDDM who were younger than 15 years of age at onset
      were studied for the following mtDNA mutations: 1) the A-->G mutation at position
      3243 of mitochondrial leucine transfer RNA (3243 mutation); 2) the G-->A mutation
      at position 3316 of mitochondrial leucine transfer RNA (3316 mutation), and 3)
      The T-->C mutation at position 3394 of the mitochondrial NADH dehydrogenase
      subunit (3394 mutation). None of the 155 IDDM patients had the 3243 mutation.
      Although two of the 155 IDDM patients had homoplasmy of 3316 and five had 3394
      mutations, these frequencies were not significant compared with healthy controls.
      None of the 30 NIDDM patients had the 3243, 3316 or 3394 mutation. The presence
      of these mutations even in control subjects suggests that the effect of the 3316
      or 3394 mutation on mitochondrial function is relatively mild. It seems that 3316
      and 3394 mutations contribute to the manifestation of diabetes together with
      other genetic and/or environmental factors.

PMID- 10392346
TI  - Quality of paediatric IDDM care in Germany: a multicentre analysis. German
      Paediatric Diabetology Group.
AB  - Quality management has been applied in recent years to improve the care of
      children and adolescents with insulin dependent diabetes mellitus (IDDM). In 1995
      the German Paediatric Diabetology Working Group published standards on quality
      control, in which relevant parameters on structure, process and outcome of care
      were defined. A computer software programme-developed at the University of Ulm
      under the auspices of the German Secretary of Health-has been used for quality
      control with central anonymous analysis in a nationwide survey. Data from 23
      paediatric centres with 2407 patients seen between January and June 1996 were
      evaluated. The results showed an admission rate to hospital of 23.8 per 100
      patient-years with an average duration of in-patient stay of 2.74 days/year. 80%
      of the patients were treated with an intensive insulin therapy regimen comprising
      three or more injections daily. The overall metabolic control was reasonably good
      with a mean HbA1c value of 7.8%. The rate of severe hypoglycaemia complicated by
      coma and/or convulsions was six per 100 patient-years and of ketoacidosis one per
      100 patient-years. Unfortunately screening for diabetic retinopathy and
      nephropathy was not carried out consistently. The incidence was 44% and 33%
      respectively.

PMID- 10392347
TI  - Human insulin induces a higher glucagon response to induced hypoglycemia in short
      normal children, compared to porcine insulin.
AB  - After transfer of diabetic patients from porcine to human insulin, many reports
      emerged supporting an increased hypoglycemia unawareness. Several studies were
      then undertaken in both diabetic and healthy adults to investigate
      counterregulatory hormone responses to both porcine and human insulin-induced
      hypoglycemia as a possible underlying cause for this different hypoglycemia
      awareness. Most studies demonstrated similar neuroendocrine responses to both
      insulin species in adults. However, no such studies have ever been performed in
      healthy children. We undertook a double-blinded study of counterregulatory
      hormone responses to both porcine and human insulin-induced hypoglycemia in 17
      short normal children randomly assigned to two groups, one receiving human and
      the other porcine insulin. We found similar responses of growth hormone,
      cortisol, epinephrine, norepinephrine and dopamine to both porcine insulin- and
      human insulin- induced hypoglycemia. Interestingly, we observed a significantly
      higher glucagon secretion when hypoglycemia was induced by human insulin. In
      conclusion, human insulin induces a higher glucagon secretion in healthy children
      than porcine insulin. Evidently, this observation cannot be extrapolated to
      diabetic patients. This study, however, further underlines the importance of
      performing investigations in children, since results found in adults differ from
      those observed in children.

PMID- 10392348
TI  - GH response to exercise: assessment of the pituitary refractory period, and
      relationship with circulating components of the GH-IGF-I axis in adolescent
      females.
AB  - The concept of pituitary refractory period for GH secretion has been previously
      described. To measure the length of this refractory period we performed an
      exercise provocation test for GH secretion immediately following multiple
      overnight GH blood sampling. In addition, we correlated the magnitude of the GH
      response to a single exercise input with mean overnight GH, IGF-I and circulating
      IGFBP levels. 23 healthy adolescent females (15-17 yr) performed 10-min constant
      cycle ergometry at a power normalized to each subject's aerobic and anaerobic
      capacity. GH was measured every 10 min starting 10 min before exercise and then
      for 60 min after the exercise bout. Mean nocturnal GH was calculated from
      overnight values obtained every 20 min over a 12-h period. Pre-exercise GHBP, IGF
      I and IGFBPs 1-5 were assessed using standard techniques. In five subjects, a
      spontaneous GH peak had preceded the exercise test by 1 hour or less, and no
      response to exercise was found. In the remaining 18 subjects, a GH peak (6.8 +/-
      1.3 ng/ml, p < 0.0001) was observed at 32 +/- 4 min after the onset of exercise.
      The GH response to exercise was not correlated with fitness, mean GH or IGF-I but
      was correlated with IGFBP-3 (r = 0.65, p < 0.05). Spontaneous GH pulses may
      acutely render the pituitary refractory to exercise stimuli. The length of this
      refractory period is approximately 1 hour. The data corroborate the idea that
      while relationships exist among the various components of the GH-IGF-I axis, no
      single factor identified to date fully reflects GH-IGF-I "tone".

PMID- 10392349
TI  - Effects of a low dose of melatonin on sleep in children with Angelman syndrome.
AB  - The effects of low dose melatonin therapy on sleep behavior and serum melatonin
      levels were studied in Angelman syndrome (AS) children suffering from insomnia.
      24-hour motor activity was monitored in 13 AS children (age 2-10 yr) in their
      home environments for 7 days prior to melatonin treatment and for 5 days during
      which a 0.3 mg dose of melatonin was administered daily 0.5-1 hour before the
      patient's habitual bedtime. Blood samples were with-drawn at hourly intervals
      over two 21-hour periods in order to measure individual endogenous serum
      melatonin levels and the levels induced by melatonin treatment. Actigraphic
      recording of motor activity, confirmed by parents' reports, showed a significant
      improvement in the patients' nocturnal sleep pattern as a result of melatonin
      treatment. Analysis of the group data revealed a significant decrease in motor
      activity during the total sleep period following melatonin treatment, and an
      increase in the duration of the total sleep period. Endogenous peak nocturnal
      melatonin values ranged from 19 to 177 pg/ml. The administration of melatonin
      elevated peak serum hormone levels to 128-2800 pg/ml in children of different
      ages and body mass. These data suggest that a moderate increase in circulating
      melatonin levels significantly reduces motor activity during the sleep period in
      Angelman syndrome children, and promotes sleep.

PMID- 10392350
TI  - Thyroid function tests in the newborn infants of preeclamptic women.
AB  - The purpose of this study was to identify possible changes in thyroid functions
      in newborn infants of preeclamptic women. Fifteen neonates (nine boys and six
      girls) of preeclamptic women and 17 healthy neonates (nine boys and eight girls)
      for the control group were included in the study. Serum thyroid-stimulating
      hormone (TSH), total triiodothyronine (TT3) and total thyroxine (TT4) levels and
      thyroid gland volumes were determined in both groups. Serum TSH and TT4 levels
      were not statistically different between the two groups. However, serum TT3 level
      was 79.22 +/- 40.19 ng/dl in the study group and 40.00 +/- 15.99 ng/dl in control
      subjects (p < 0.01). The mean right, left and total thyroid volumes were 1.3 +/-
      1.2 ml, 1.2 +/- 1.1 ml and 2.4 +/- 2.3 ml in the study group and 0.6 +/- 0.2 ml,
      0.6 +/- 0.2 ml, and 1.1 +/- 0.4 ml in the control group, respectively (p < 0.05).
      The mean thyroid volume/body weight was 0.9 +/- 0.09 ml/kg in the study group and
      0.3 +/- 0.06 ml/kg in the control group (p < 0.05). In conclusion, we would like
      to stress that preeclampsia might be a cause of fetal and neonatal thyroid
      enlargement and elevated serum TT3 level.

PMID- 10392351
TI  - Short-term changes in lower leg length in children treated for acute
      lymphoblastic leukaemia.
AB  - The lower leg length velocity (LLLV) of 14 children with a median age of 4.5 yr
      who were undergoing chemotherapy (CT) for acute lymphoblastic leukaemia (ALL) was
      studied for a median duration of 56 weeks (range 14-112). Nine children were
      studied over the first 6 months, six over the first year, four over the full 2
      year course and nine children over the 3 months before and after the end of CT.
      Over the first month of CT, during induction, median LLLV was 0 mm/wk (P5, P95: 
      1.6, 0.11); during the fourth month of CT, at the end of CNS-directed therapy,
      there was a significant rise to 0.38 mm/wk (P5, P95: -0.04, 0.81; p = 0.01, WSR).
      In the children measured following the end of CT, median LLLV rose from 0.46
      mm/wk (P5, P95: -0.02, 0.79) in month 23 to 0.84 mm/wk (P5, P95: 0.72, 1.12) (p =
      0.03). There was a positive relationship between neutrophil count and LLLV during
      continuation chemotherapy (r = 0.4, p = 0.0002); median LLLV was 0.2 mm/ wk (P5,
      P95: -0.15, 0.5) when the neutrophil count was less than 1 x 10(9)/l and 0.65
      mm/wk (P5, P95: 0.1, 1.0) (p = 0.01) when the count was above 1 x 10(9)/l. No
      significant differences in LLLV were observed between children randomised to
      different UKALLXI regimens. Intensive chemotherapy for ALL adversely affects
      lower leg growth. Growth was subnormal during the first few weeks of
      chemotherapy, but was comparable to healthy children during CNS directed and
      continuation therapy. There was a significant relationship between growth
      velocity and neutrophil count during continuation chemotherapy. On
      discontinuation of chemotherapy there was a further acceleration in lower leg
      length velocity to supranormal levels ("catch-up" growth).

PMID- 10392352
TI  - Ketoconazole treatment of gonadotropin independent precocious puberty in girls
      with McCune-Albright syndrome: a preliminary report.
AB  - McCune-Albright syndrome (MAS) in girls is characterized by gonadotropin
      independent precocious puberty (GIPP). This form of GIPP is resistant to therapy
      with GnRH analogues. As an alternative treatment, we successfully used
      ketoconazole 200 mg t.i.d. orally in two girls with MAS, GIPP and advanced bone
      age Ketoconazole led to rapid control of GIPP with cessation of menses and
      regression of pubertal signs in both patients. Ketoconazole was temporarily
      interrupted in one patient due to pruritus but later restarted without problem.
      After 1 year of therapy both patients have remained free of menses, progression
      of puberty and other side effects. Repeat sonography on ketoconazole revealed
      continued presence of ovarian cysts. Our preliminary experience indicates the
      safety and effectiveness of ketoconazole as a therapy for GIPP with potential
      advantages over previously used modes of treatment. Longer use of ketoconazole to
      suppress GIPP is required to determine whether this therapy can prolong linear
      growth with enhancement of final height.

PMID- 10392353
TI  - Severe hypoglycemia in Spanish diabetic children and adolescents. Study Group of
      Infantile Diabetes of the Spanish Paediatric Endocrinology Society.

PMID- 10392354
TI  - Fertility and its complications in a patient with salt losing congenital adrenal
      hyperplasia.
AB  - A report is made concerning fertility and its complications in a patient with
      salt losing congenital adrenal hyperplasia. Fertility with a successful outcome
      of pregnancy has rarely been reported in women with salt losing congenital
      adrenal hyperplasia. Problems which have been identified in the past include non
      compliance, poor endocrine follow up, secondary polycystic ovarian disease with
      menstrual irregularity, anovulation and problems related to sexual function.
      There has been only one report in the literature of a woman with salt losing
      congenital adrenal hyperplasia who has had two pregnancies with live births.
      There has been no previous report of subsequent problems with neonatal management
      of these children. This case highlights some of the long term hazards of
      management of salt losing congenital adrenal hyperplasia and reports for the
      first time neonatal complications possibly consequent upon prenatal maternal
      therapy.

PMID- 10392355
TI  - Localized lipoatrophy due to recombinant growth hormone therapy in a child with
      6.7 kilobase gene deletion isolated growth hormone deficiency.
AB  - Local lipoatrophy is a well known complication of insulin treatment at injection
      sites and the etiology is thought to be a cross reaction with lipid tissues and
      insulin antibody. Although mild lipoatrophy during growth hormone treatment has
      been reported in the literature, severe local lipoatrophy in injection sites in
      the extremities has not yet been published. We report a patient with isolated GH
      deficiency due to 6.7 kb gene deletion who received high dose rhGH treatment and
      developed local lipoatrophies at injection sites without any antibody detection
      after 6 years of therapy. The etiology of the lipoatrophy is suspected to be by
      the direct lipolytic effect of high doses of rhGH.

PMID- 10392356
TI  - Growth hormone isoforms in a girl with gigantism.
AB  - Several previous investigations have suggested that there may be different growth
      hormone isoforms in patients with acromegaly. We used three different site
      specific monoclonal antibodies (MAbs) to investigate growth hormone (GH) isoforms
      in serum from an 8 year-old girl with a GH and prolactin secreting adenoma. The
      pattern of GH-immunoreactivity was dependent on the circumstances of collection.
      Serum obtained after oral glucose had very little cross reactivity with MAb 352
      although concentrations of up to 15 micrograms/l were found with two other MAbs,
      033 and 665. MAb 352 does not recognize the 20,000 dalton isoform of GH (20K)
      while both MAb 033 and 665 do. The same pattern of GH immunoreactivity (low MAb
      352, equal and higher MAb 033 and 665) was seen in other baseline samples. In
      contrast, samples obtained after TRH/GnRH showed immunoreactivity patterns
      expected for a mixture of 22,000 dalton isoform of GH (22K) with only a small
      amount of 20K. GH samples obtained during sleep showed both patterns with
      episodic peaks with equal immunoreactivity superimposed on the basal pattern
      (decreased activity with MAb 352). Affinity chromatography of basal samples
      showed that a portion of the GH immunoreactivity was neither 22K nor 20K,
      although in stimulated samples, over 70% of GH was 22K or 20K GH. In conclusion,
      the nature of GH isoforms present in serum varies with GH concentration. These
      differences may contribute to the known difficulty in correlating disease
      activity and random GH measurements in patients with GH secreting adenomas.

PMID- 10392357
TI  - Blood-brain barrier for human growth hormone and insulin-like growth factor-I.
AB  - There is a blood-brain barrier (BBB) for GH. A certain, unknown amount of GH
      passes the BBB, acts on the neuronal GH receptors and directly influences the
      brain mechanisms serving the feedback and ultradian secretion of GH. The high
      density of GH receptors in the choroid plexus suggests a possible receptor
      mediated transcytosis transport. The effects of GH on brain development, neuronal
      plasticity and neuroprotection seem to be mediated by IGFs. GH and IGFs are also
      synthesized in the brain. The relative contributions to brain functions of GHs
      produced inside and outside the BBB are unknown. The cerebrospinal fluid (CSF)
      space is the compartment inside the barrier accessible to clinicians. High GH
      levels in CSF were reported in acromegaly and also a small increase was reported
      after chronic administration of hGH in GH-deficiency syndromes. For the
      practitioner it is necessary to determine the normal range of hGH levels in CSF.

PMID- 10392358
TI  - Methods for measuring body composition in newborns--a comparative analysis.
AB  - The complexity of nutritional support in infants now makes it necessary to use
      body-composition methods for accurate nutritional assessment. For this goal a
      variety of methods of determining body composition have been introduced in
      research on human nutrition. The purpose of this paper is to review the
      background and to describe the precision of established techniques, focusing on
      the results obtained in newborns and infants. The ideal method for assessing
      newborns' and infants' body composition should be non-invasive, reproducible,
      accurate, and also relatively inexpensive. In addition, we summarize in this
      paper data on body composition obtained in normal and pathological newborns by
      using dual X-ray absorptiometry, one of the reference techniques.

PMID- 10392359
TI  - Serum levels of insulin-like growth factor (IGF)-I, free IGF-I, IGF binding
      protein (IGFBP)-1, IGFBP-3 and insulin in obese children.
AB  - In simple obesity, spontaneous and stimulated growth hormone (GH) secretions are
      diminished. However, this diminished GH secretion does not result in decreased
      somatic growth in obese children. Although the increased insulin level, low
      insulin-like growth factor binding protein (IGFBP)-1 and the resulting increase
      of bioavailability of insulin-like growth factor I (IGF-I) have been suggested as
      being involved, the exact mechanism has not yet been established. We investigated
      serum IGF-I, free IGF-I, IGFBP-1, IGFBP-3 and insulin levels in 36 obese and 39
      non-obese healthy children. Insulin and IGFBP-3 were significantly higher in the
      obese group than in the control group (p < 0.05, p = 0.001, respectively). IGF-I,
      free IGF-I, free IGF-I/IGF-I and IGFBP-1 levels in the obese children were not
      significantly different from those in the control group. A positive correlation
      was found between body mass index (BMI) and IGF-I in the obese children (r =
      0.30, p = 0.05). IGFBP-3 levels correlated positively with IGF-I (r = 0.44, p <
      0.005), and free IGF-I levels (r = 0.37, p = 0.05) in the obese children. A
      negative correlation was found between IGFBP-1 and insulin levels (r = -0.30, p =
      0.05) in the obese children. We concluded that normal growth in obese children
      might be maintained through normal IGF-I and increased IGFBP-3 levels, which are
      stimulated by increased insulin levels or nutritional factors or by increased
      responsiveness to GH.

PMID- 10392360
TI  - Serum insulin-like growth factor-I (IGF-I) levels during long-term IGF-I
      treatment of children and adults with primary GH resistance (Laron syndrome).
AB  - Serum IGF-I levels were measured in 14 patients (9 children and 5 adults) with
      Laron syndrome (LS) during long-term treatment by IGF-I. Recombinant IGF-I (FK
      780, Fujisawa Pharmaceutical Co. Ltd., Japan) was administered once daily
      subcutaneously before breakfast for 3-5 years to the children and for 9 months to
      the adults. The initial daily dose was 150 micrograms/kg for children and 120
      micrograms/kg for adults. Before initiation of treatment the mean overnight
      fasting levels of serum IGF-I in the children was 3.2 +/- 0.8 nmol/l (mean +/-
      SEM), rising to 10 +/- 1.7 nmol/l during long-term treatment even on a dose of
      120 micrograms/kg/day. The serum IGF-I levels 4 hours after injection rose from
      31.2 +/- 3.5 to 48 +/- 2 nmol/l. In the adult patients, the initial basal IGF-I
      was 4.1 +/- 0.7 nmol/l, rising to 16.1 +/- 3.84 nmol/l after 8-9 months
      treatment. Serum IGF-I levels at 4 hours after injection rose in the adult
      patients from 24.1 +/- 5.8 up to 66.8 +/- 15.4 nmol/l. A progressively increasing
      half-life during long term exogenous administration of IGF-I to patients with
      Laron syndrome was demonstrated by following serum IGF-I dynamics after
      injection. Based on the fact that no antibodies to IGF-I were detected and on
      findings in previous studies, it is speculated that the increasing serum IGF-I
      levels during long-term IGF-I treatment are caused by an increase in serum IGFBP
      3 induced by chronic IGF-I administration. It is concluded that treatment with
      IGF-I necessitates regular monitoring of serum IGF-I levels; in patients in whom
      the age adjusted maximal levels are exceeded, a reduction of the daily IGF-I dose
      is indicated to avoid undesirable effects.

PMID- 10392361
TI  - One-year treatment with recombinant human growth hormone of children with
      meningomyelocele and growth hormone deficiency: a comparison of supine length and
      arm span.
AB  - Growth retardation and precocious puberty are frequently found in children with
      meningomyelocele (MMC). Lower limb contractions, spasticity and kyphoscoliosis
      may lead to disproportionate short stature. Most of these patients have
      structural brain defects or hydrocephalus which can cause growth hormone
      deficiency. In this study, 19 children aged between 3.5 and 12.8 years with MMC
      and growth hormone (GH) deficiency were treated with recombinant human GH for a
      period of 12 months. Supine length, arm span and growth velocity were compared
      before, and after 6 and 12 months of treatment with rhGH (daily dose 2.0 IU/m2
      BSA s.c.). Mean supine length standard deviation score (SDS) increased by +0.8
      SDS after 6 months and +1.2 SDS after 12 months of therapy. Mean arm span
      standard deviation score increased by +0.9 SDS and +1.3 SDS. Growth velocity
      increased in supine length from 3.3 cm/yr (-2.1 SDS) to 8.4 cm/yr (+2.4 SDS) and
      in arm span from 4.8 cm/yr (-1.3 SDS) to 8.6 cm/yr (+3.1 SDS) in the first 6
      months and was 8.1 cm/yr (+2.4 SDS) and 8.3 cm/yr (+2.6 SDS) after 12 months of
      therapy. Linear correlation between SDS growth velocity supine length and SDS
      growth velocity arm span during one year of treatment was excellent (r = 0.65, p
      < 0.0025). We surmise that body proportions do not deteriorate when growth
      velocity is stimulated in MMC patients. Both supine length and arm span
      measurements are necessary to document growth in children with spinal dysraphism.

PMID- 10392362
TI  - The effect of growth hormone treatment on stature in Aarskog syndrome.
AB  - We describe 19 males with Aarskog syndrome who were treated with growth hormone
      (GH) and enrolled in the National Cooperative Growth Study (NCGS). There was a
      significant increase in both growth rate (3.9 +/- 1.9 cm/yr vs 8.9 +/- 1.7 cm/yr,
      p < 0.001) and height SD score (change in HtSDS = 1.0 +/- 0.8). The increase in
      HtSDS was dependent on treatment duration, frequency of injections, weight-for
      height SDS, and HtSDS at enrollment. The results of our study suggest a positive
      effect of GH treatment on growth and adult height in Aarskog syndrome patients.

PMID- 10392363
TI  - Six-hour and four-hour nocturnal sampling for growth hormone.
AB  - Overnight sampling for growth hormone (GH) is a research tool for quantifying
      characteristics of spontaneous GH secretion. However, the study is costly in
      assays and blood volume, particularly that required from a small child. DESIGN
      AND PATIENTS: Existing overnight GH data from 126 normal children and from 227
      children with GH deficiency or short stature were reanalyzed, examining 6-h and 4
      h segments of this data for accuracy in representing each child's 12-h GH
      secretion. The goal was to see whether the test could be made shorter and more
      practical without losing accuracy. RESULTS: The 6-h segment 2200-0400 h
      consistently contained the majority of GH peaks. Correlation was high between GH
      values from 2200-0400 h and from the 12-h period. Normal 95% confidence limits
      (CL) for GH during 2200-0400 h were derived from data in normal children for
      gender and each pubertal stage. Data from short children were compared with the
      normal 6-h 95% CL. In short children, GH values low for 12-h were also low for 6
      h. Only a few children with normal 12-h values (1.5% of normals, 0.5% with short
      stature) had GH values outside 95% CL for 6-h. CONCLUSIONS: Six-hour GH sampling
      (2200-0400 h) is accurate and cost-efficient compared to the 12-h overnight GH
      study. These studies are primarily useful in research settings.

PMID- 10392364
TI  - Caloric restriction for 24 hours increases mean night growth hormone.
AB  - In obesity, serum growth hormone (GH) is usually low, confounding GH assessment
      of short obese children. We evaluated whether 24-h caloric restriction would
      permit better discrimination between normal GH secretion and GH deficiency (GHD)
      by elevating night GH levels. DESIGN AND PATIENTS: Serum was obtained every 20
      minutes 2000-0800 h before and 2200-0400 h after 24 hours of caloric restriction
      (8% of usual calories) in 24 normal height children [14 normal (weight for height
      10-90th percentile); 10 obese (weight for height > 95th percentile)] and in 31
      short children (height shorter than -2.0 SD below mean for age). All samples from
      both nights per child were assayed for GH simultaneously to eliminate interassay
      variability. RESULTS: Mean GH increased significantly in all groups after caloric
      restriction (P < 0.01). Obese children had lower baseline mean GH and GH
      amplitude compared to normal (P < 0.01); GH increased into normal range after
      restriction. Basal GH studies in short children were not significantly below
      normal. Surprisingly, some with low stimulated GH increased their night GH into
      the normal range after caloric restriction. CONCLUSIONS: Caloric restriction for
      24 h enhances night GH similarly in short and in normal children, and thus does
      not increase the diagnostic utility of night GH studies in non-obese short
      children. Caloric restriction reverses suppressed GH secretory state of obese
      children, perhaps by decreasing diet-dependent somatostatin inhibition of GH
      secretion.

PMID- 10392365
TI  - Diabetes complication screening in 937 children and adolescents.
AB  - Results are presented of diabetes complication screening in children and
      adolescents aged 6-20 years. Their diabetes duration was 0.02-18.4 yr and median
      HbA1c over the preceding 36 months was 8.4% [IQR 7.8-9.3]. Gradable retinal
      photographs were obtained in 937: 110 less than 11 years (< 11 yr Gp). Albumin
      excretion rate (AER) was obtained from 3 timed overnight urine collections in
      691: 100 in < 11 yr Gp. Early retinopathy was found in 27% (9% in < 11 yr Gp).
      Microalbuminuria (AER > or = 20 micrograms/min) was found in 4%. Significant
      individual risk factors for both complications were higher blood pressure,
      cholesterol, HbA1c, pubertal staging, older age and longer diabetes duration.
      Using multiple logistic regression, significant risk factors for retinopathy were
      longer duration and older age and in addition higher HbA1c. Diabetes complication
      screening detected early subclinical disease in children and adolescents who may
      benefit from lowering blood pressure and improving metabolic control. Screening
      should commence after five years of duration in young children, and after two
      years of duration in adolescents.

PMID- 10392366
TI  - Plasma and erythrocyte vitamin E levels in children with insulin dependent
      diabetes mellitus.
AB  - Vitamin E is considered to be one of the most important antioxidants. There is a
      trend today to supply diabetic children with vitamin E in order to prevent
      microvascular complications. In this study, our objective was to demonstrate
      validity of plasma and erythrocyte vitamin E levels in diabetic children. This
      study was conducted on twenty-five diabetic patients aged from 7-16 years and ten
      non-diabetic, age-matched healthy subjects as the control group. Vitamin E levels
      were measured by high-performance liquid chromatography. There was no significant
      difference between the mean plasma vitamin E levels of diabetic and control
      groups, 870.80 +/- 220.51 micrograms/dl and 891 +/- 221.21 micrograms/dl,
      respectively (p > 0.05). The mean erythrocyte vitamin E levels of diabetic and
      control groups were significantly different: 183.12 +/- 62.58 micrograms/dl and
      246.90 +/- 68.26 micrograms/dl, respectively (p < 0.05). Erythrocyte vitamin E
      levels were significantly lower than plasma vitamin E levels in both groups. We
      further investigated whether a correlation exists between plasma and erythrocyte
      vitamin E levels and duration of diabetes, insulin dose and HbA1c measurements.
      However no correlation was found. In conclusion, measurement of erythrocyte
      vitamin E levels may be considered to be more valuable than plasma vitamin E
      levels in diabetic children and supplementation may be provided according to
      erythrocyte levels rather than plasma levels.

PMID- 10392368
TI  - Effect of parenteral nutrition on oral intake.
AB  - Oral intake following a high density oral supplement (preload) is lower than that
      after a low density preload. We studied a similar effect of parenteral nutrition
      on oral intake. Twelve neurologically intact children (8-16 yr) with orthopedic
      problems and no concurrent illness were included in the study. As part of the
      inclusion criteria, all patients had documented energy intake for breakfast of +/
      10% on 3 consecutive days. On the fourth day parenteral nutrition equal to 50%
      of the mean energy intake for breakfast was provided for 4 hours before breakfast
      and energy intake measured. The composition of the parenteral energy was matched
      with that of the oral intake. The mean oral energy intake without (470 +/- 90
      kcal) and with (458 +/- 64 kcal) parenteral nutrition preload was comparable (p >
      0.05). Our conclusion is that parenteral nutrition does not affect oral intake in
      patients without underlying gastrointestinal disease.

PMID- 10392367
TI  - Helicobacter pylori infection and cytotoxic antigen associated gene "A" status in
      short children.
AB  - BACKGROUND: Helicobacter pylori is now an accepted gastroduodenal pathogen and is
      being investigated for possible implications in nongastroenterological conditions
      such as growth impairment. Subjects infected by cytotoxic Cag-A positive strains
      seem more likely to develop serious gastroduodenal diseases but the possible role
      of Cag-A positive strains in non gastroenterological diseases has not been fully
      investigated. OBJECTIVE: 1) To evaluate the prevalence of Helicobacter pylori
      infection and Cag-A positivity in short children compared to auxologically normal
      children. All the subjects were without gastro-intestinal symptoms and were not
      obese or significantly underweight. 2) To verify the reliability of the ELISA
      assay for H. pylori. SUBJECTS: H. pylori infection was assessed in 338 children,
      182 auxologically normal and 156 short children, with and without deficiency in
      growth hormone, by the determination of specific IgG antibody. In 79 subjects
      (all seropositive and a random sample of seronegative children), 13C-urea breath
      test and cytotoxic Cag-A positive strains were examined. RESULTS: The overall
      seroprevalence of H. pylori infection by IgG antibody was 18/156 (11.5%) and
      13/182 (7.1%) in short and auxologically normal children respectively. The 13C
      urea breath test was positive in 29 children: 17 (10.9%) short and 12 (6.6%)
      auxologically normal. Western blotting documented infection by cytotoxic Cag-A
      positive strains in 12/17 (70.6%) and 8/12 (66.6%) of short and auxologically
      normal children respectively. None of the differences between the two groups were
      significant. CONCLUSIONS: 1) We found a similar prevalence of H. pylori infection
      and Cag-A positivity in two large pediatric populations of short or auxologically
      normal children. Therefore: 1) Our data did not confirm a role of H. pylori
      infection in short stature in children. 2) We found a high reliability of ELISA
      assay for the detection of IgG antibodies compared to breath test.

PMID- 10392369
TI  - Early onset of diabetes mellitus associated with the mitochondrial DNA T14709C
      point mutation: patient report and literature review.
AB  - We report a family in which a mother and son were affected with diabetes mellitus
      and myopathy characterized by ragged red fibers and suggestive of mitochondrial
      disease. Mitochondrial DNA (mtDNA) analysis of DNA isolated from peripheral blood
      showed a T-->C point mutation at nucleotide position 14709, in the transfer RNA
      gene for glutamic acid. We review the association of diabetes and mtDNA
      mutations. This child's case is unusual because of the early onset of diabetes,
      which is more typical of mtDNA deletions.

PMID- 10392370
TI  - Hypertension and virilization caused by a unique desoxycorticosterone- and
      androgen-secreting adrenal adenoma.
AB  - We describe a rare androgen and desoxycorticosterone (DOC)-secreting adrenal
      tumor in a non-Cushingoid 14 year-old Haitian girl with secondary amenorrhea,
      hypertension and virilization. Her steroid pattern simulated an 11 beta
      hydroxylation defect with notable elevation of adrenal androgens, 11
      desoxycortisol (S), DOC, 17 alpha-hydroxyprogesterone and pregnenelone. Exogenous
      ACTH stimulated steroidogenesis. A CAT scan unfortunately failed to delineate an
      adrenal mass. Dexamethasone (DEX) was administered, therefore, which partially
      suppressed androgen levels, reduced DOC and S by 80% and 82% respectively, and
      normalized blood pressure. Nevertheless, the response to glucocorticoid was
      incomplete and an MRI was obtained, which revealed a right adrenal tumor. Post
      surgery, the patient promptly resumed menses and became normotensive. This case
      illustrates that ACTH and DEX cannot reliably differentiate tumor from
      hyperplasia, whereas the simultaneous increase of delta 4 and delta 5 steroids,
      present here, may favor a tumor. This case also allows speculation that the
      hypersecretion of DOC may result from inhibition of 11 beta-hydroxylase activity
      by excess androgens. The importance of appropriate imaging for diagnosis is
      underscored.

PMID- 10392371
TI  - Severe virilization in a girl with a steroid cell tumor of the ovary.
AB  - We report a 6-year-old girl with striking signs of virilization, as well as
      elevated concentrations of testosterone and 17-hydroxyprogesterone. Although the
      elevated 17-hydroxyprogesterone concentration initially suggested late-onset 21
      hydroxylase deficiency, she was found to have an ovarian mass by sonography which
      at surgery proved to be a hilus cell subtype of steroid cell tumor. This intra
      ovarian tumor appears to be the smallest tumor of its type ever reported. The
      testosterone concentration was normal three days after tumor resection and has
      remained so two years later.

PMID- 10392373
TI  - [Sentinel lymph node detection by preoperative lymphoscintigraphy and
      intraoperative gamma probe guidance in malignant melanoma].
AB  - AIM: The purpose of this work was to prove the clinical significance of nuclear
      medical procedures in pre- and intraoperative detection of the SLN. METHODS: In
      the past 4 years, we did preoperative lymphoscintigraphy in 214 patients (pts.).
      Intraoperative localisation of the SLN with a hand-held gamma probe followed in
      150 pts. RESULTS: In 214 pts. 247 lymphatic draining regions were found by
      preoperative scintigraphy. In 3 pts. with melanoma of the cheek no
      lymphatics/lymph nodes could be detected. 14 pts. showed interval lymph nodes. In
      150 pts. gamma probe guided SLNE was done. In 2 pts. with supraclavicular primary
      tumor 4 SLN had been defined by preoperative scintigraphy but only 2 could be
      found intraoperatively. In all other cases (98.7%) the sentinel node was detected
      correctly by the gamma probe and then removed. In 19 of 150 pts. (12.7%)
      metastases were detected in the pathologic specimen. The incidence of lymph node
      metastases showed a continuous increase from 0% at tumor stage pT1 to 44% at
      stage pT4. CONCLUSION: SLNE is an accurate method to determine nodal involvement
      in melanoma and minimizes operative invasiveness in melanoma surgery.

PMID- 10392372
TI  - [Reduced antithyroid agents as a result of radioiodine therapy?].

PMID- 10392374
TI  - [Preoperative assessment of asymptomatic adnexal tumors by positron emission
      tomography and F 18 fluorodeoxyglucose].
AB  - AIM: To evaluate use of F-18-FDG-PET in assessment of dignity of asymptomatic
      adnexal masses. METHODS: 85 asymptomatic patients with suspicious, asymptomatic
      adnexal masses were evaluated. Static FDG-PET (Exact HR+ or ECAT 931) imaging of
      the abdomen was performed following application of 222-555 MBq F-18-FDG.
      Iterative reconstruction was applied. PET data were analysed visually, at first
      without and second together with MRT images. Final diagnosis was made by
      histopathology. RESULTS: FDG-PET allowed correct identification of 4 of 8
      malignant adnexal tumors. False negative results were obtained in 2
      adenocarcinomas stage pT1a and 2 borderline-tumors. In 60 out of 77 benign
      adnexal masses malignancy could be excluded. False positive FDG-uptake, partly
      because of misinterpretation of gastrointestinal activity, was found in 3
      inflammatory processes, 1 teratoma, 1 benign schwannoma, 1 dermoid cyst, 1 benign
      thecoma, 1 serous cyst, 1 serous cystadenoma, 2 mucinous cystadenomas, 2 corpus
      luteum cysts, 3 endometriosic cysts and 1 sactosalpinx. The overall sensitivity
      and specificity of FDG-PET alone were 50% and 78%. Evaluation together with MRT
      images showed a sensitivity of 50% and a specificity of 86%. CONCLUSION:
      Sensitivity of FDG-PET in detection of borderline-tumors and early stage ovarian
      cancer seems to be limited. Low incidence of malignant ovarian tumors requires
      for assessment of dignity a procedure of high specificity, that is not reached by
      FDG-PET neither without nor together with MRT images for topographic orientation.
      Therefore use of FDG-PET for assessment of dignity in suspicious, asymptomatic
      ovarian tumors is limited.

PMID- 10392375
TI  - F-18-FDG positron imaging in oncological patients: gamma camera coincidence
      detection versus dedicated PET.
AB  - AIM: Of the present study was to investigate the feasibility of 2-[fluorine-18]
      fluoro-2-deoxy-D-glucose (FDG) imaging in oncological patients with a dual head
      gamma camera modified for coincidence detection (MCD). METHODS: Phantom studies
      were done to determine lesion detection at various lesion-to-background ratios,
      system sensitivity and spatial resolution. Thirty-two patients with suspected or
      known malignant disease were first studied with a dedicated full-ring PET system
      (DPET) applying measured attenuation correction and subsequently with an MCD
      system without attenuation correction. MCD images were first interpreted without
      knowledge of the DPET findings. In a second reading, MCD and DPET were evaluated
      simultaneously. RESULTS: The phantom studies revealed a comparable spatial
      resolution for DPET and MCD (5.9 x 6.3 x 4.2 mm vs. 5.9 x 6.5 x 6.0 mm). System
      sensitivity of MCD was less compared to DPET (91 cps/Bq/ml/cmFOV vs. 231
      cps/Bq/ml/cmFOV). At a lesion-to-background ratio of 4:1, DPET depicted a minimal
      phantom lesion of 1.0 cm in diameter, MCD a minimal lesion of 1.6 cm. With DPET,
      a total of 91 lesions in 27 patients were classified as malignant. MCD without
      knowledge of DPET results revealed increased FDG uptake in all patients with
      positive DPET findings. MCD detected 72 out of 91 DPET lesions (79.1%). With
      knowledge of the DPET findings, 11 additional lesions were detected (+12%). MCD
      missed lesions in six patients with relevance for staging in two patients. All
      lesions with a diameter above 18 mm were detected. CONCLUSION: MCD FDG imaging
      yielded results comparable to dedicated PET in most patients. However, a
      considerable number of small lesions clearly detectable with DPET were not
      detected by MCD alone. Therefore, MCD cannot yet replace dedicated PET in all
      oncological FDG studies. Further technical refinement of this new method is
      needed to improve image quality (e.g. attenuation correction).

PMID- 10392376
TI  - In vitro and in vivo comparison of binding of 99m-Tc-labeled anti-CEA MAb F33-104
      with 99m-Tc-labeled anti-CEA MAb BW431/26.
AB  - AIM: The purpose of this study was to assess the potential for radio
      immunodetection (RAID) of murine anti-carcinoembryonic antigen (CEA) monoclonal
      antibody (MAb) F33-104 labeled with technetium-99m (99m-Tc) by a reduction
      mediated labeling method. METHODS: The binding capacity of 99m-Tc-labeled anti
      CEA MAb F33-104 with CEA by means of in vitro procedures such as
      immunoradiometric assay and cell binding assay and the biodistribution of 99m-Tc
      labeled anti-CEA MAb F33-104 in normal nude mice and nude mice bearing human
      colon adenocarcinoma LS180 tumor were investigated and compared with 99m-Tc
      labeled anti-CEA MAb BW431/26. RESULTS: The in vitro binding rate of 99m-Tc
      labeled anti-CEA MAb F33-104 with CEA in solution and attached to the cell
      membrane was significantly higher than 99m-Tc-labeled anti-CEA MAb BW431/261
      (31.4 +/- 0.95% vs. 11.9 +/- 0.55% at 100 ng/mL of soluble CEA, 83.5 +/- 2.84%
      vs. 54.0 +/- 2.54% at 10(7) of LS 180 cells). In vivo, accumulation of 99m-Tc
      labeled anti-CEA MAb F33-104 was higher at 18 h postinjection than 99m-Tc-labeled
      anti-CEA MAb BW431/26 (20.1 +/- 3.50% ID/g vs. 14.4 +/- 3.30% ID/g). 99m-Tc
      activity in the kidneys of nude mice bearing tumor was higher at 18 h
      postinjection than at 3 h (12.8 +/- 2.10% ID/g vs. 8.01 +/- 2.40% ID/g of 99m-Tc
      labeled anti-CEA MAb F33-104, 10.7 +/- 1.70% ID/g vs. 8.10 +/- 1.75% ID/g of 99m
      Tc-labeled anti-CEA MAb BW431/26). CONCLUSION: 99m-Tc-labeled anti-CEA MAb F33
      104 is a potential novel agent for RAID of recurrent colorectal cancer.

PMID- 10392377
TI  - Extensive chemical degradation of bleomycin during attempted labelling with 51
      Cr.
AB  - AIM: Labelling of the cytostatic agent bleomycin with 51-Cr and use of the
      product for biodistribution studies have been reported in the literature. The
      labelling procedure involves incubation for 40 min at 130 degrees C. Since
      bleomycins are polar glycopeptides sensitive to hydrolytic cleavage we were
      concerned about possible degradation of the drug during these unfavourable
      conditions. We have therefore investigated the stability of bleomycin as a
      function of temperature and pH of the solution and attempted to achieve the
      maximum labelling efficiency with minimal degradation of the two principal
      bleomycin components. METHODS: The chemical stability of unlabelled bleomycin was
      investigated under labelling conditions at 130 degrees C and in buffer of pH 1-6
      at room temperature (23 degrees C) and 60 degrees C. The samples were assayed by
      high-performance liquid chromatography (HPLC). The labelling efficiency of the 51
      Cr-bleomycin complex was determined by thin layer chromatography and activity
      measurement with a high pure Germanium (HPGe)-detector at various incubation
      temperatures and times. RESULTS: Comparisons of rates of degradation of bleomycin
      with labelling efficiency as functions of temperature and time showed that under
      no condition could satisfactory labelling (> 97%) be obtained without
      considerable degradation of bleomycin. CONCLUSION: Labelling of bleomycin with 51
      Cr does not yield a product suitable for investigations in patients.

PMID- 10392378
TI  - [Imaging of an adrenal cortex carcinoma and its metastasis with FDG-PET].
AB  - We describe the case of a 42-year old female patient with a carcinoma of the
      adrenal cortex. The primary tumor was resected without residual tumor tissue;
      only two weeks later there was a new large tumor formation in the adrenal gland's
      bed. PET-investigation showed the large local recurrency, multiple lung-, and
      liver-metastasis, so that no further operative therapy was performed. FDG-PET
      seems to be suitable for diagnosis and staging of adrenal cortex carcinoma in one
      single examination.

PMID- 10392380
TI  - Evaluation of direct respiratory modulation of the QT interval variability.
AB  - To investigate the direct respiration-mediated vagal modulation of the QT
      interval variability, spectral analyses of the RTp interval (from the R wave peak
      to the T wave peak) variability (RTpV) and the RR interval variability (RRV) were
      performed in 12 subjects with normal ventricular repolarization under three
      conditions while the respiration frequency was kept at 0.2 Hz: during sinus
      rhythm, during fixed atrial pacing, and during fixed atrial pacing with autonomic
      blockade. The cross-spectrum between the RRV and RTpV was quantified by the
      squared coherence. During sinus rhythm the RRV power spectrum showed two peaks: a
      broad peak in the low frequency (LF) band and a sharp peak at 0.2 Hz which
      corresponded to the controlled respiration frequency. The RTpV power spectrum
      showed corresponding peaks to the RRV peaks in both the LF and high frequency
      (HF) bands with high coherence (mean maximum values of the squared coherence in
      the LF band 0.59 +/- 0.22, and in the HF band 0.74 +/- 0.14). During atrial
      pacing mean total power of the RTpV decreased from during sinus rhythm (from 16.3
      +/- 5.6 ms2 to 12.9 +/- 5.4 ms2, P < 0.05) and the RTpV spectral peaks were
      abolished in both the LF and HF bands concordant with disappearance of the RRV
      peaks. Autonomic blockade gave no additional change to the RTpV power spectrum
      independently of the RRV during fixed atrial pacing. The present study suggested
      that the direct respiration-mediated vagal modulation may not affect the short
      term variability of the QT interval in subjects without repolarization
      abnormality.

PMID- 10392379
TI  - Imaging of a metastatic gastrointestinal carcinoid by F-18-DOPA positron emission
      tomography.
AB  - The localization of carcinoids in the gastrointestinal tract is frequently
      difficult if not impossible with the imaging procedures used to date. It is
      reported on a patient with metastasizing carcinoid in whom various imaging
      procedures were not successful in detecting the primary tumor. Due to the
      importance of primary tumor proof for potential curative surgical therapy, a
      whole-body positron emission tomography with F-18-DOPA was performed. PET enabled
      localization of a potential primary tumor in the ileum. Moreover, in addition to
      the known abdominal lymph node and liver metastases, it detected a mediastinal
      lymph node metastasis and a pulmonary metastasis. F-18-DOPA whole-body PET may be
      a very promising imaging approach to the localization and staging of
      gastrointestinal carcinoids.

PMID- 10392381
TI  - Energy steering of biphasic waveforms using a transvenous three electrode system.
AB  - The optimal electrode configuration for endocardial defibrillation is still a
      matter of debate. Current data suggests that a two pathway configuration using
      the right ventricle (RV) as cathode and a common anode constituted by a superior
      vena cava (SVC) and a pectoral can (C) is the most effective combination. This
      may be related to the more uniform voltage gradient created by shocks delivered
      using this configuration. We hypothesized that more effective waveforms could be
      obtained by varying the distribution of the shock current between the two
      pathways of a three electrode endocardial defibrillation system. In 12 pigs, we
      compared the characteristics and the defibrillation efficacy of six biphasic
      waveforms discharged using either a two (RV-->C) or a three (RV-->SVC + C)
      electrode combination with the following configurations: Configuration 1 (W1):
      the RV apical coil was used as a cathode and the subcutaneous C as anode (RV-
      >C). Configuration 2 (W2): The RV was used as cathode and the combination of the
      atriocaval coil (SVC) and the subcutaneous C as anode (RV-->SVC + C).
      Configuration 3 (W3): The RV-->C was used for the first 25% of f+ and RV-->SVC +
      C for the remainder of the discharge including f 2 Configuration 4 (W4): The RV-
      >C was used for the first 50% of f+ and RV-->SVC + C for the remainder of the
      discharge including f 2 Configuration 5 (W5): The RV-->C was used for the first
      75% of f+ and RV-->SVC + C for the remainder of the discharge including f 2.
      Configuration 6 (W6): The RV-->C was used for f+ and RV-->SVC + C for f 2. As an
      increasing fraction of the waveform was discharged using the RV-->SVC + C
      pathways, the impedance and the pulse width decreased while the tilt, the peak,
      and the average current significantly increased. The waveforms delivered using
      the RV-->SVC + C configuration for 100% or 75% of their duration had
      significantly lower stored energy DFT than the other waveform. Current
      distribution between three endocardial electrodes can be altered during the shock
      and generates waveforms with different characteristics. Shocks with 75% or more
      of the current flowing to the RV-->SVC + C required the lowest stored energy to
      defibrillate. This method of energy steering could be used to optimize current
      delivery in a three electrodes system.

PMID- 10392382
TI  - Inverse relation of body-surface activation-recovery interval and recovery time
      to activation time in normal subjects: stronger correlation and more
      heterogeneous distribution in activation-recovery interval than in recovery time.
AB  - The activation-recovery interval (ARI), measured directly from the myocardium,
      has shown a good correlation with the action potential duration (APD) in
      experiments. APD has been reported to be inversely related to the activation time
      (AT). However, no studies have examined the correlation between the body-surface
      ARI and AT in normal subjects. Fifty normal subjects (25 men and 25 women) were
      studied to elucidate the relationship between the body-surface ARI and AT. The
      body-surface AT was defined as the duration between the QRS onset and the minimum
      dV/dt of the QRS wave, and ARI as the interval between the minimum dV/dt of the
      QRS wave and the maximum dV/dt of the T wave in each lead of an 87 unipolar lead
      system. We also measured the recovery time (RT) defined as the duration between
      the QRS onset and the maximum dV/dt of the T wave. ARI was inversely correlated
      with AT (r = -0.73). RT was also inversely correlated with AT (r = -0.61),
      however, RT had a less heterogeneous distribution than ARI (148 ms vs 159 ms).
      There were no differences between male and female subjects in the relation
      between ARI and RT or in the body-surface distribution of ARI and RT. These
      findings suggest that the body-surface ARI may reflect recovery properties over
      the cardiac surface and that APD may distribute inhomogeneously over the human
      cardiac surface with a longer RT over an area with a shorter AT. ARI calculated
      from body-surface ECG may be a useful noninvasive and repeatedly measurable
      estimate of APD.

PMID- 10392383
TI  - Effect of adenosine and verapamil in catecholamine-induced accelerated
      atrioventricular junctional rhythm: insights into the underlying mechanism.
AB  - Accelerated AV junctional rhythm is postulated to be due to enhanced automaticity
      of a high AV junctional focus. The adenosine response of this rhythm was tested
      in 17 patients (7 males, 12-83 years). The indications of electrophysiology study
      were nonspecific palpitation (n = 5), unexplained syncope (n = 6), postablation
      of accessory pathways (n = 4), and postmodification of AV nodal reentry
      tachycardia (n = 2). The sinus node and AV nodal functions were normal. Pacing
      and programmed electrical stimulation failed to induce any arrhythmia at
      baseline. The accelerated junctional rhythm (cycle length = 553 +/- 134 ms) was
      initiated spontaneously in all patients after isoproterenol infusion (1-2
      micrograms/min). It was not suppressible by overdrive pacing. Cessation of
      isoproterenol infusion terminated the rhythm in all patients. Adenosine (6 mg)
      reproducibly terminated the accelerated junctional rhythm in all patients. In six
      patients, adenosine suppressed the junctional rhythm without producing AV nodal
      block. In the other 11 patients, the junctional rhythm was terminated prior to
      the occurrence of AV nodal block. Verapamil was tested in ten patients and 5 mg
      of intravenous verapamil terminated the junctional rhythm in all patients. In
      conclusion, the mechanism of catecholamine-induced accelerated AV junctional
      rhythm is most likely enhanced automaticity, and catecholamine-induced
      accelerated AV junctional automaticity is sensitive to adenosine and verapamil.
      Adenosine appears to have differential effects on catecholamine-enhanced AV
      junctional automaticity and AV nodal conduction. This suggests that, under
      catecholamine stimulation, adenosine may have different mechanisms of action on
      AV nodal conduction and automaticity.

PMID- 10392384
TI  - Importance of the site of ventricular tachycardia origin on left ventricular
      hemodynamics in humans.
AB  - Experimental animal data have indicated that the site of ventricular tachycardia
      origin and, hence, the degree of asynchronous contraction, may influence the
      hemodynamic tolerance during sustained ventricular tachycardia. However, data in
      man are scarce. We studied patients with preserved left ventricular function and
      absence of significant coronary artery disease. Ventricular tachycardia was
      simulated with rapid pacing (at 120 and 150 beats/min), performed randomly, from
      the right ventricular apex or the right ventricular outflow tract. Following
      pacing from one site, it was repeated from the alternate site. Compared to
      outflow tract pacing, QRS duration was significantly longer during rapid pacing
      from the apex. Left ventricular pressure was recorded using a micromanometer
      tipped catheter. During sinus rhythm, peak systolic pressure was 142 +/- 14 mmHg;
      at 120 beats/min, it decreased to 109 +/- 12 mmHg during pacing from the apex and
      to 127 +/- 21 mmHg during pacing from the outflow tract (P = 0.008). This
      difference diminished at 150 beats/min (101 +/- 16 mmHg vs 112 +/- 16 mmHg,
      respectively, P = 0.21). During sinus rhythm end-diastolic pressure was 13 +/- 1
      mmHg, which did not change significantly during pacing at 120 beats/min. During
      pacing at 150 beats/min, end-diastolic pressure increased to 21 +/- 3 mmHg during
      pacing from the apex and to 16 +/- 2 mmHg during pacing from the outflow tract (P
      = 0.005). Changes in first derivative of pressure and in isovolumic relaxation
      time constant were comparable during pacing from the two sites. Thus, it seems
      that tachycardias originating from the right ventricular outflow tract result in
      more favorable left ventricular hemodynamics, compared to those from the right
      ventricular apex.

PMID- 10392385
TI  - Thoracoscopic epicardial radiofrequency ablation for vagal atrial fibrillation in
      dogs.
AB  - Epicardial radiofrequency catheter ablation of the atria in the open-chest dog
      has been shown to reduce inducibility of atrial fibrillation. Video-assisted
      endoscopic techniques decrease the operative trauma in adult thoracic surgery. We
      report our results of video-assisted thoracoscopic radiofrequency catheter
      ablation of the atria for the prevention of atrial fibrillation induction in
      canines. In 12 consecutive anesthetized dogs, induction of sustained atrial
      fibrillation was reproducibly obtained by burst pacing and cervical vagal
      stimulation. In six dogs, biatrial ablation was performed through right and left
      minithoracotomies and guided by video-assisted endoscopic techniques. The
      remaining six dogs underwent a video-guided left atrial procedure. Long
      continuous and transmural lesions were produced using epicardial temperature
      controlled radiofrequency energy delivery according to a simplified maze
      approach. Transmural lesions were demonstrated at the end of the study by
      examination of the heart. Sustained atrial fibrillation was still inducible after
      the right atrial ablation but sustained atrial fibrillation could not be induced
      following left atrial ablation. In acute canine studies: (1) epicardial
      radiofrequency catheter ablation of the atria is feasible using video-assisted
      endoscopic techniques; (2) ablation extended or confined to the left atrium
      appears to be effective in preventing the inducibility of sustained vagal atrial
      fibrillation; and (3) ablation of the right atrium alone had no antiarrhythmic
      effect.

PMID- 10392387
TI  - Diagnosis of atrial undersensing in dual chamber pacemakers: impact of
      autodiagnostic features.
AB  - Atrial undersensing occurs in a considerable number of patients, both with single
      lead VDD pacemakers and with DDD devices. The aim of this study was to
      investigate the diagnostic efficacy of electrocardiographic methods and
      autodiagnostic pacemaker features to detect atrial sensing dysfunction. Two
      hundred and thirty-one patients with AV block received single lead VDD pacemakers
      or DDD devices. Atrial sensitivity was programmed to 0.1 or 0.18 in VDD devices
      and to 0.5 mV in DDD devices; the rate limits were set to 40 and 160 beats/min.
      Twelve-lead ECG recording for 1 minute during deep respiration and change of body
      position, 24-hour Holter ECG recording, and treadmill exercise were performed 2
      weeks and 15 months after pacemaker implantation. AV synchrony and, if available,
      P wave amplitude histogram were sampled by autodiagnostic pacemaker features and
      compared to electrocardiographic findings. Atrial undersensing was assumed, if AV
      synchrony was below 100% or if minimal P wave amplitude (PWA) was equal to the
      programmed atrial sensitivity. Intermittent atrial undersensing occurred in 20.7%
      of patients. The diagnostic sensitivities of the various methods used to detect
      atrial sensing failures were: 24-hour Holter monitoring 97.5%, P wave amplitude
      histogram 90.0%, stored AV synchrony 68.0% without significant difference between
      the various devices, treadmill exercise testing 58.8%, and 12-lead ECG recording
      21.3%. In one patient, atrial undersensing was exclusively detected by exercise
      testing. In conclusion, autodiagnostic pacemaker features facilitate the
      evaluation of atrial sensing performance. However, to exclude intermittent atrial
      malesensing, routine Holter monitoring and treadmill exercise are still needed.

PMID- 10392386
TI  - Acute hemodynamic effects of alternate and combined site pacing in patients after
      cardiac surgery.
AB  - We hypothesized that pacing at sites other than the right ventricular (RV) apex
      or at two or more ventricular sites would activate the myocardium more rapidly
      and improve cardiac function in patients undergoing coronary revascularization or
      aortic valve replacement. Epicardial electrodes were placed on the right atrium
      (A), RV paraseptal area close to the RV apex (B), RV outflow tract (C), LV apex
      (D), in patients undergoing bypass surgery. At constant rate and AV delay, we
      measured CO during A pacing, DVI pacing at B, C, D, and various combinations of
      sites in random order in ten patients with EF > 50% and 27 patients with EF < or
      = 50%. When pacing at two sites, we made one electrode a cathode and one an anode
      and noted two distinct thresholds by careful observation of the 12-lead ECG.
      There were no significant differences in CO, systemic vascular resistance,
      systolic, or mean arterial pressure. Significant differences were noted in QRS
      duration, which increased progressively going from AAI to 3-site, 2-site, and
      single site pacing (P < 0.05 each comparison). Thus: (1) QRS duration correlated
      inversely with the number of ventricular sites paced; (2) despite this, CO did
      not improve irrespective of baseline EF; (3) multisite pacing produced multiple
      distinct thresholds which appeared to be related to the number of sites paced,
      and (4) unique ECG patterns confirmed multisite pacing.

PMID- 10392388
TI  - Significant differences in charge times among currently available implantable
      cardioverter defibrillators.
AB  - Capacitor charging accounts for most of the delay between arrhythmia detection
      and therapy delivery in ICDs. Long capacitor charge times may increase the risk
      of syncope in patients with poorly tolerated arrhythmias. To determine if there
      are clinically important differences in charge time among currently available
      devices, we analyzed charge times at various delivered energy levels in three
      manufacturers' devices: Medtronic, CPI, and Ventritex. Charge times were measured
      for shocks delivered for spontaneous or induced arrhythmias occurring from time
      of implant to 4 months after implant. A total of 343 shocks were assessed in 63
      patients with ICDs: 16 Medtronic (MicroJewel II, model 7223Cx), 14 CPI (Mini II,
      model 1762), and 33 Ventritex (Cadet and Contour, models V-115 and V-145). The
      curves of the relationship between charge time and delivered energy for the three
      types of devices were significantly different, with Medtronic charge times
      shorter than CPI or Ventritex (P < 0.0001), and CPI charge times shorter than
      Ventritex (P = 0.002). The difference in mean charge times between the Ventritex
      and Medtronic devices ranged from 1.7 seconds at a delivered energy of 10 +/- 2.5
      J to 8.0 seconds at a delivered energy of 30 +/- 2.5 J. Thus, clinically
      important differences in charge time exist among the three types of
      defibrillators studied. These results should be considered in selecting an ICD
      for patients with poorly tolerated arrhythmias.

PMID- 10392389
TI  - Low voltage direct current delivered through unipolar transvenous leads: an
      alternate method for the induction of ventricular fibrillation.
AB  - The induction of VF during testing of an ICD may not always be possible using
      either burst pacing or high energy T wave shocks. The purpose of this study was
      to evaluate the effectiveness of low energy DC stimulation for inducing VF in a
      porcine model. The VFT was measured using constant voltage stimuli and a step-up
      method in ten anesthetized pigs (25-30 kg). Stimuli of different durations (0.5,
      1.0, 2.0 s) were delivered (unsynchronized) between a right ventricular apical
      coil and a subcutaneous test can. Current was measured from the voltage drop
      across a series resistor (10 omega). With anodal stimulation, VF required 6.4 +/-
      0.2 V compared to 13.8 +/- 0.6 V with cathodal stimulation (P < 0.001). The
      current required to induce VF (measured 10 ms after the stimulus onset) was 58.3
      +/- 2.2 mA with anodal stimulation and 119.3 +/- 4.7 mA with cathodal stimulation
      (P < 0.001). Stimulus duration did not significantly influence the voltage or
      current required for VF induction. In 6 of the 10 pigs, synchronizing a 0.5
      second stimulus to the R wave did not significantly alter the VFT compared to
      same stimulus synchronized to mid-upslope of the T wave. The results indicate
      that VF can be consistently induced through transvenous electrodes by passing
      unsynchronized DC for 0.5-2 seconds. The induction of VF required about 50% less
      current and voltage with anodal stimulation. It should be possible to induce VF
      with the DC voltage available from the internal battery source of an ICD.

PMID- 10392390
TI  - Health-related quality-of-life assessment of patients with life-threatening
      ventricular arrhythmias.
AB  - The purpose of this study was to determine whether treatments for life
      threatening ventricular arrhythmias are associated with quality-of-life (QOL) and
      psychological distress. Multidimensional measures of QOL and psychological
      distress were used to cross-sectionally compare patients with ICDs to patients
      treated with antiarrhythmic drugs and patients without serious cardiac
      conditions. The sample consisted of 157 patients: 35 patients treated with
      antiarrhythmic medication only, 24 patients treated with ICD only, 25 patients
      treated with ICD and antiarrhythmic medication, and 73 controls. Patients
      completed the Medical Outcomes Study SF-36 health survey, the Brief Symptom
      Inventory, and background questionnaires. There were no significant differences
      in self-reported QOL and psychological distress between patients with or without
      ICD, and the occurrence of defibrillator shocks was unrelated to QOL and
      psychological distress. However, patients treated with antiarrhythmic drugs
      reported greater QOL impairment in physical functioning, vitality, emotional role
      limitations, and sleep, as well as greater psychological distress than patients
      not treated with antiarrhythmics. These limitations may be attributed to adverse
      effects arising from antiarrhythmic pharmacotherapy. Results of the present
      investigation suggest that QOL and psychological distress are maintained among
      ICD patients, whereas treatment with antiarrhythmic drugs are associated with a
      diminished QOL and greater psychological distress. These findings may assist
      cardiologists to select the optimal treatment for life-threatening ventricular
      arrhythmias that minimizes disturbances in health-related QOL and psychological
      distress and increases patient compliance.

PMID- 10392391
TI  - Change of atrial refractory period after short duration of rapid atrial pacing:
      regional differences and possible mechanisms.
AB  - It is unknown whether there are regional differences in the change of atrial
      effective refractory period (ERP) after a short duration of rapid atrial pacing.
      Furthermore, the effects of calcium channel and potassium channel on this
      phenomenon have not been extensively investigated. In opened-chest dogs, the
      endocardial monophasic action potential duration at 90% repolarization (APD90)
      from the right atrial appendage, and ERP from seven atrial sites were measured
      before and after rapid atrial pacing at 800 beats/min for 30 minutes. Both atrial
      ERP and APD90 significantly shortened after rapid atrial pacing. The postpacing
      atrial ERP and APD90 shortening persisted for 119 +/- 3 and 123 +/- 4 seconds
      after cessation of pacing, respectively. There was no significant difference in
      the magnitude or recovery course of atrial ERP shortening after pacing among the
      seven atrial sites. Pretreatment with nicorandil and d-sotalol had no effects on
      the magnitude or recovery course of atrial ERP shortening after pacing. However,
      the degree of ERP and APD90 shortening after pacing was significantly attenuated
      in the verapamil and ryanodine groups; furthermore, the recovery of ERP and APD90
      after cessation of pacing was faster in the two groups. In conclusion, shortening
      of atrial ERP induced by short-duration rapid atrial pacing was uniform in both
      atria. Both the adenosine triphosphatase (ATP) dependent potassium current and
      rapid component of the delayed rectifier did not significantly influence this
      phenomenon, but both the verapamil and ryanodine could significantly attenuate
      the degree of atrial ERP and APD90 shortening.

PMID- 10392392
TI  - Electrophysiological performance of a bipolar membrane-coated titanium nitride
      electrode: a randomized comparison of steroid and nonsteroid lead designs.
AB  - The aim of this multicenter study was to investigate the performance of a new
      cardiac pacemaker lead with a titanium nitride cathode coated with a copolymer
      membrane. In particular, the electrophysiological effect of steroid dissolved in
      this ion-exchange membrane was evaluated by randomized comparison. Ninety-five
      patients were randomized either to the 1450 T (n = 51) or the 1451 T ventricular
      lead (n = 45) and received telemeteral VVI(R) pacemakers with identical
      diagnostic features. Both leads were bipolar, were passively affixed, and had a
      porous titanium nitride tip with a surface area of 3.5 mm2. The only difference
      between the two electrodes was 13 micrograms of dexamethasone added to the 1450
      Ts membrane coating. Voltage thresholds (VTH) at pulse durations of 0.25, 0.37,
      and 0.5 ms, lead impedance, and sensing thresholds were measured at discharge, 2
      weeks, 1 month, 3 months, and 6 months after implantation. Mean amplitude and the
      slew rate from three telemetered intracardiac electrograms, chronaxie-rheobase
      product, and minimum energy consumption were calculated. After a 6-month follow
      up, mean voltage thresholds of 0.65 +/- 0.20 V and 0.63 +/- 0.34 were achieved
      for the 1450 T lead and 1451 T lead, respectively. As a result, a VTH < 1.0 V was
      obtained in all patients with 1450 T electrodes and in 97.7% of patients with
      1451 T leads after 6 months follow-up. In both electrodes, stable VTH was reached
      2 weeks after implantation, and no transient rise in threshold was observed. No
      differences were observed between the steroid and the nonsteroid group in respect
      to VTH, chronaxie-rheobase product, minimum energy consumption, and potential
      amplitude and slew rate. In conclusion, safe and efficient pacing at low pulse
      amplitudes were achieved with both leads. The tip design, independently of the
      steroid additive, prevented any energy-consuming increases in the voltage
      threshold.

PMID- 10392393
TI  - The utility of pacemaker evoked T wave amplitude for the noninvasive diagnosis of
      cardiac allograft rejection.
AB  - Previous work suggested that pacemaker evoked T wave amplitude (ETWA) may be a
      sensitive noninvasive marker of cardiac allograft rejection. A Topaz QT sensing
      rate responsive pacemaker (Vitatron Medical) was implanted at transplantation
      using epicardial ventricular leads in 45 recipients (35 males; median age 51
      years, range 20-63). The median duration of follow-up was 129 days (range 4-327).
      The ETWA at a paced rate of 100 beats/min was measured daily during
      hospitalization and at each outpatient attendance (900 readings). Endomyocardial
      biopsies were at routine intervals or when otherwise clinically indicated (257
      biopsies with concurrent ETWA data). There were 58 episodes of rejection > or =
      grade 3a in 28 patients. The biopsies were classed as either no rejection (grade
      < 3a) or rejection requiring treatment (grade > or = 3a). The median normalized
      ETWA was 100.8% (range 24.6-239.7) without rejection and 89.9% (17.0-189.7) with
      rejection (Mann-Whitney U Test: P = 0.028). The performance of ETWA monitoring as
      a diagnostic test for the individual recipient was evaluated with exponentially
      weighted moving average quality control charts. For the diagnosis of all
      rejection episodes, ETWA monitoring had a sensitivity of 55%, a specificity of
      62%, a positive predictive value of 30%, and negative predictive value of 83%. It
      is concluded that although analysis of pooled data showed a significant reduction
      in normalized ETWA with biopsy proven rejection, ETWA monitoring requires further
      refinement to improve sensitivity before it can be considered a clinically useful
      technique for the non-invasive diagnosis of cardiac allograft rejection in
      individual recipients.

PMID- 10392394
TI  - Unusual left atrial activation during atrioventricular reentrant tachycardia.

PMID- 10392395
TI  - Antiarrhythmic device advisories and recalls: managing an increasingly vulnerable
      process.

PMID- 10392396
TI  - Possible involvement of hypothyroidism as a cause of lithium-induced sinus node
      dysfunction.
AB  - Although several reports have stated that even therapeutic levels of lithium can
      induce sinus node dysfunction, the mechanism has not been fully elucidated. We
      present here two patients with sinus node dysfunction after long-term lithium
      therapy. Following lithium discontinuation, sinus node function recovered
      completely. After resuming lithium, however, irreversible sinus node dysfunction
      recurred and a permanent pacemaker was implanted in one patient. The serum
      concentration of lithium was within therapeutic levels. Nevertheless,
      hypothyroidism was associated with the sinus node dysfunction in both patients.
      Thus, thyroid function may play an important role in sinus node dysfunction
      induced by lithium.

PMID- 10392397
TI  - Symptomatic atrioventricular dual pathway double responses: a role for slow
      pathway ablation.
AB  - Two patients with symptomatic fast/slow pathway double responses were evaluated
      with electrophysiology studies. Chronic palpitations were resistant or worsened
      by medical therapy. No reentry tachycardias were induced. A nonreentrant
      paroxysmal supraventricular tachycardia was documented. Radiofrequency ablation
      of the slow pathway was safely and successfully performed. Patients remain
      asymptomatic for 16-18 months. Ablation of the slow pathway for this substrate is
      a viable option.

PMID- 10392398
TI  - Removal of infected pacemaker leads with deep hypothermic circulatory arrest and
      open surgical exploration of the superior vena cava and innominate veins.
AB  - Despite the use of transvenous methods for extraction of infected leads, failed
      attempts may result in retained lead fragments. Retained lead fragments may be a
      focus of continued infection leading to sepsis. We present two patients in which
      conversion from cardiopulmonary bypass to hypothermic circulatory arrest allowed
      direct visualization, using venotomies in the superior vena cava and innominate
      vein to achieve complete removal of retained pacemaker lead fragments. Use of
      venotomies in the extracardiac venous system is a technical addition to prior
      descriptions of lead extraction using deep hypothermia and circulatory arrest.

PMID- 10392399
TI  - Complete atrioventricular block after arsenic trioxide treatment in an acute
      promyelocytic leukemic patient.
AB  - AV block after arsenic trioxide (As2O3) treatment for refractory acute
      promyelocytic leukemia is very rare. In this patient, the block was at A-H level
      and manifested with complete AV block and Wenckebach second-degree type 3:2
      block. The junctional recovery time during complete AV block did not
      significantly prolong after administration of more arsenic trioxide. The effect
      of heart block of arsenic trioxide seemed reversible after the discontinuation of
      arsenic trioxide and was not correlated to the leukemic status as observed in
      this patient.

PMID- 10392400
TI  - Early proarrhythmia during intravenous amiodarone treatment.
AB  - We present a case of early (within the first 24 hours) development of malignant
      torsades de pointes (TdP) associated with intravenous amiodarone therapy. After
      correction of predisposing factors (heart failure, hypokalemia, digoxin)
      amiodarone again resulted in torsades. This observation suggests that in patients
      who have experienced amiodarone-induced proarrhythmia, amiodarone administration
      under different, more stable clinical conditions may still be hazardous.

PMID- 10392401
TI  - Partial rupture of the tricuspid valve after extraction of permanent pacemaker
      leads: detection by transesophageal echocardiography.
AB  - Traumatic lesions of the tricuspid valve complicating pacemaker lead extractions
      appear to be rare. We report two cases of partial rupture of the tricuspid valve,
      following apparently uneventful extraction of permanent ventricular leads,
      resulting in severe regurgitation and, in one case, chronic heart failure. TEE
      was useful to identify the traumatic mechanism of tricuspid regurgitation (TR)
      and the extent of valvular lesions in these patients. Such etiology should be
      suspected, and TEE performed, in patients developing TR or heart failure late
      after lead extraction.

PMID- 10392402
TI  - Lead failure due to the subclavian crush syndrome in a patient implanted with
      both standard and thin bipolar spiral wound leads.
AB  - Subclavian crush syndrome is a well-described cause of pacemaker lead failure
      resulting from an entrapment of a lead or leads between the clavicle and the
      first rib. A new thinner lead (ThinLine) was designed to minimize this
      complication. Our patient developed atrial and ventricular lead subclavian crush
      syndrome with both conventional and thin leads.

PMID- 10392403
TI  - Extraction and reimplantation of defibrillation leads through a thrombotic
      subclavian vein.
AB  - Venous thrombosis is one of the most frequently encountered obstacles when
      reintervening on endocardial leads. We report on two patients with a ventricular
      defibrillator requiring lead replacement in whom a subclavian vein thrombosis was
      documented prior to the intervention. We recanalized the vein and replaced the
      lead through the same path to preserve the venous access.

PMID- 10392404
TI  - Pacemaker/ICD patients and the electromagnetic environment.

PMID- 10392405
TI  - QT-syndrome.

PMID- 10392406
TI  - Physician Health Research Conference (Estes Park, Colorado--September 15-17,
      1996): progress report one year later.
AB  - The 1996 Physician Health Research Conference was the first conference to focus
      exclusively on research issues and methods for impaired physicians. The
      conference was initiated by James Shore, M.D., professor and chairman of the
      Department of Psychiatry in the School of Medicine at the University of Colorado
      Health Sciences Center and superintendent of the Colorado Psychiatric Hospital,
      and Stephen Dilts, M.D., Ph.D., medical director of the Colorado Physician Health
      Program and clinical professor of psychiatry at the University of Colorado Health
      Sciences Center. Forty participants represented a wide range of national
      organizations. The conference was supported by contributions from the American
      Medical Association, American Psychiatric Association, Colorado Physician Health
      Program, Colorado Physician Insurance Program, and the Department of Psychiatry
      and Colorado Psychiatric Hospital at the Health Sciences Center. In addition, the
      conference was cosponsored by the American Academy of Addiction Psychiatry, the
      American Society of Addiction Medicine, and the Federation of State Physician
      Health Programs. This paper summarizes the formal presentations of the
      conference.

PMID- 10392407
TI  - Issues in the recovery of physicians from addictive illnesses.
AB  - The issues discussed in this article introduce and examine topics related to
      physicians' health which are salient in their clinical usefulness or their
      heuristic value in planning future research. Physicians in general possess
      physical, emotional and intellectual strengths that are needed to face high
      stress and low social support. Physicians are also less likely to seek routine
      medical care. With many illnesses physicians are inherently resistant but have
      higher risk factors. It is postulated that the opposing tendencies cancel each
      other. Physicians have better intrinsic physical and mental health but live under
      higher stress and get less routine preventive care. Physicians also may have a
      tendency to live healthy lives without addiction but have high risk factors for
      addiction. Adults who have grown up in families with addiction have a tendency to
      choose health care professions. Genetic composition may predispose to alcoholism
      and other chemical addictions. Taking into consideration inherent health and risk
      it is thought that physicians have a similar prevalence of alcoholism and drug
      dependence as compared to the general population. Physicians have higher access
      to pharmaceutical drugs but are less inclined to use street drugs. In the New
      York State Physicians' Health Program, 88% of the participants used alcohol or
      prescription drugs and only 12 percent used marihuana or Cocaine. Additional risk
      factors for Substance Use Disorders in Physicians have been postulated to be
      pharmaco-logical optimism, intellectual strength, strong will, love of
      challenges, instrumental use of medications and a daily need for denial. These
      factors require rigorous investigation to establish their role. Clinical
      approaches and techniques discussed include the incubation period for a Substance
      Use Disorder, initial high tolerance, state dependent learning, and the signal
      properties of drugs. As recovery progresses it is postulated that it becomes
      increasingly important to deal with substitute addictions and family of origin
      issues.

PMID- 10392408
TI  - Treatment issues in the group psychotherapy of addicted physicians.
AB  - For the most part, physician-addict patients are affable, cooperative and tend to
      be bright, verbal and engaging. However, on a deeper level they experience
      significant internal obstacles to truly using treatment. The role of the healer
      adopted after years of training and work experience is not easily exchanged for
      the role of patient. Furthermore, the armour of defenses and character style that
      have been built up over a lifetime is resistant to modification. Additionally,
      most of these patients have not chosen to change. They have been ordered into
      treatment under considerable duress and are aware that retaining their hard
      earned careers is dependent on their successful performance in treatment. Given
      all these difficulties it is striking that the vast majority of these patients
      gradually come to experience a genuine and meaningful connection to the group and
      the therapeutic process. They develop close relationships with their fellow group
      members and come to use them as a support system, even at times when the group is
      not in session. They report looking forward to group and missing it when it does
      not meet. In this context they begin to take risks by sharing on a deeper level
      and slowly bring to the group issues in their life other than addiction. Their
      devotion to group is reflected by the fact that when no longer mandated, many
      continue voluntarily and maintain that the experience is central to their
      recovery. One of the major reasons recovering physicians are able to make this
      connection is that behind their fear of interpersonal relationships is a
      tremendous wish to join with others. Many report profound relief at discovering
      they are not alone and are able to use group to address their deeply felt sense
      of shame. For many this is their first experience of such strong feelings of
      attachment and affiliation to a group of peers. Their prior professional
      experience did not routinely allow for such relationships and as Smith (1978) has
      observed, their experience has been characterized by extraordinary isolation even
      as compared to the general population of addicts. There are no communities of
      drug-using doctors and no romanticized antics shared amongst fellow addicted
      physicians. A doctor's addiction is at its core an activity of secrecy and
      solitude. This investment to group can only develop in an environment that feels
      fundamentally safe. It is the creation of such an environment that is the central
      task for the therapist working with addicted physicians. The patient must come to
      learn that he can say whatever is on his mind without being criticized, ridiculed
      or punished. To a large extent this is accomplished by highlighting the
      commonality between the group members which diminishes the sense of isolation and
      shame. In addition, the therapist must maintain an accepting and non-judgmental
      stance so that the patient is free to fully experience the ambivalence inherent
      in the decision to get sober.

PMID- 10392409
TI  - Therapeutic agents of assertive community treatment.
AB  - The goal of this study was to learn how assertive community treatment (ACT)
      contributes to the improvement of those with serious mental illness in order to
      contribute to the growing clinical literature regarding the therapeutic agents of
      ACT teams. Methods included reviewing the case records of three ACT clients who
      have improved significantly, as well as interviewing the clients themselves and
      their clinicians. The results indicated that there was significant agreement
      among the case records, the clients, and their clinicians in identifying the most
      useful aspects of assertive community treatment. Primary among these factors were
      the persistence demonstrated by ACT clinicians in engaging their clients, the
      trust that clients developed in their clinicians, and as a result, the process by
      which their clinicians became "guides" to the world of psychiatric and social
      services that further facilitated their clients' community adjustment. In
      closing, we consider implications from these findings both for staff development
      for ACT team members, and for suggestions toward the development of a model of
      recovery from serious mental illness.

PMID- 10392411
TI  - [Prognostic factors during rehabilitation after shoulder prostheses for
      fracture].
AB  - PURPOSE: To evaluate the role, the difficulties of rehabilitation and to diagnose
      the eventual surgical complications after shoulder prosthesis for 4-part
      fractures. MATERIAL AND METHODS: Forty three patients (46 shoulders) who
      underwent shoulder arthroplasty after fracture of the proximal humerus underwent
      rehabilitation and follow-up at a special reeducation center for an average of 3
      months (1 to 6). There were 42 four-part fractures (with 22 fracture-dislocation)
      and 4 three-part fractures. The patients were send by five different hospitals
      and have all been operated by senior surgeons. Three types of implants were used:
      the Modular Shoulder prosthesis (27 cases), the Global prosthesis (2 cases), and
      the Aequalis prosthesis (17 cases). The rehabilitation followed the protocol
      recommended by Neer (recovery of passive joint movements, muscular strengthening
      and stretching) to which were added hydrotherapy, physiotherapy and occupational
      therapy. Forty patients (43 epaules) were reviewed and radiographed with an
      average follow-up of 29 months (18 to 72 months). RESULTS: The functional results
      were disappointing with a normalised Constant score of only 60.2 per cent and an
      average active elevation of only 96 degrees. There appeared to be two factors
      which explained these poor results. Firstly, the advanced age of the population
      (52 per cent older than 70) who was often poorly or non-motivated (22 per cent)
      and debilitated (21 per cent chronic alcoholics) and who had significant medical
      and neuro-psychiatric histories. Secondly, incompletely resolved anatomical and
      surgical problems: damage to the circumflex nerve (6.5 per cent), early migration
      of the greater tuberosity (6.5 per cent), secondary migration with malunion (15
      per cent) and/or nonunion (11 per cent) of the greater tuberosity. Migration of
      the greater tuberosity should be suspected clinically in three circumstances: 1)
      in patients who have an abnormally painful shoulder in the immediate post
      operative period (16 cases in our series); 2) when there is no progression (24
      per cent) or regression (9 per cent) of active shoulder mobility after three
      months of correct supervised rehabilitation; 3) later, if there is a dissociation
      between active anterior elevation (deficient) and passive anterior elevation
      (preserved). DISCUSSION AND CONCLUSION: The age and poor general condition of the
      patients as well as the difficulty of the surgical technique more than the
      rehabilitation, explain the disappointing results observed after shoulder
      prosthesis for four-part fractures. The discrepancy between active and passive
      elevation suggests that limited motion is not caused by a stiff shoulder because
      of glenohumeral scarring but instead by weakness of the deltoid (because of
      axillary lesion) and/or of the external rotators (because of greater tuberosity
      migration). There is some discordance between the necessity to early mobilise the
      shoulder and the high rate of tuberosity migration.

PMID- 10392410
TI  - Ethnic differences in the neuroleptic treatment of schizophrenia.
AB  - Ethnic differences in psychopharmacological treatment have received much
      attention in the last two decades. Most of the research efforts conducted so far
      in the field of ethnopsychopharmacology have focused on comparative responses to
      neuroleptics and lithium between white and Asian-American patients, and on
      comparative responses to tricyclic antidepressants among white, African-American
      and Hispanic patients. In this article we focus on the response to neuroleptic
      treatment among white, African-American and Hispanic patients suffering from
      schizophrenia. Our findings suggest that Hispanic patients need lower doses of
      neuroleptics than white or African-American patients to attain a similar response
      in the treatment of schizophrenia. Additionally, our study suggests that, if
      weight is taken to consideration, African-American patients need the same dose of
      neuroleptics as do white patients in order to attain a similar response in the
      treatment of schizophrenia. Further studies are suggested to confirm our
      findings.

PMID- 10392412
TI  - [Pott's disease paraplegia in children. Mechanics and therapeutic strategies. Six
      cases].
AB  - PURPOSE: We report a series of 6 Pott's disease paraplegias treated between 1982
      and 1996. MATERIALS AND METHOD: Out of 15 children suffering from Pott's disease,
      6 had paraplegia. Treatment consisted of anterior medullar decompression and
      anterior spine fusion with bone grafting. Two or three weeks later, posterior
      spine fusion was achieved systematically using a CD fixation device in 3 cases.
      RESULTS: Neurological signs completely disappeared in 5 children. Vertebral
      fusion was correct in all patients and kyphosis was less than 50 degrees.
      DISCUSSION: The posterior approach to the spine must be proscribed as a first
      step, except for spine dislocation. The anterior approach allowed us to drain the
      abscess, to correct the kyphosis, and to perform an anterior spine fusion. The
      posterior spine fusion was performed a few weeks later in order to avoid kyphosis
      aggravation. CONCLUSION: Prognosis of Pott's disease is good but at the present
      time, paraplegia remains too frequent. Adapted treatment must be performed
      without delay.

PMID- 10392413
TI  - [Intramedullary pinning for humeral diaphysis fractures. A minimal risk
      osteosynthesis. 82 cases].
AB  - PURPOSE: This study was designed to evaluate the complication rate of a novel
      intramedullary pinning technique described in 1988. After 10 years of clinical
      experience, it was possible to establish a significant difference in terms of
      healing delay compared with other fixation methods or conservative treatment.
      MATERIALS AND METHODS: During a 10-year period, a total of 82 fractures, mostly
      isolated, unstable fractures, were treated. Retrograde intramedullary pinning
      (RIMP) was used for proximal and midshaft fractures and antegrade pinning (AIMP)
      for distal fractures. Statistical analysis was used to investigate the role of
      all parameters that may influence healing delay. RESULTS: 92.7% of the fractures
      healed in an average time of 9 weeks. Neither location nor fracture type, nor
      even an intrefragmental gap had any significant influence on healing delay. There
      were 7 primary axial deviations of more than 10 degrees in which union was
      achieved and 6 nonunions. These nonunions were mostly proximal fractures and
      inappropriate fixation. No radial nerve injury, no infection, and no
      deterioration of the fracture site was observed. There were 27 pin migrations,
      mainly towards the shoulder, which dit not affect the final anatomic and
      functional outcome. Functional result was good in 88% of cases. Four
      algodystrophy syndromes and 6 nonunions induced stiffness, mainly in the
      shoulder. DISCUSSION: Intramedullary pinning using this technique did not induce
      any severe iatrogenic condition. Healing delay compares favorably with better
      results of conservative treatment. Improving surgical technique should further
      minimize disadvantages of this method. CONCLUSION: Humeral intramedullary pinning
      technique has a low complication rate. It is a good compromise between
      conservative treatment and conventional osteosynthesis. It causes little trauma
      to the patients, allows stabilization of any fracture site, and delay to bone
      union is similar to that with conservative treatment.

PMID- 10392414
TI  - [Cadaver study of acetabular cup mobility in the healthy hip and prosthesis by
      monopodal pressure simulation ].
AB  - PURPOSE OF THIS STUDY: The purpose of this study was to quantify relative
      displacement of anterior and posterior horn of the acetabulum lunate surface
      using Omega strain gauges while increasing loads were applied to the hip joint.
      Measurement were performed on fresh cadaver bones in unipodal stance using
      experimental method before and after socket's implantation. MATERIAL AND METHODS:
      [corrected] Nine skeletons, from fresh non-embalmed cadavers, including pelvis,
      the three last lumbar vertebrae and both femurs were maintained in unipodal
      equilibrium using metallic cables for muscle passive simulation. Loads were
      applied up to 700 N. Specific extensometric Omega strain gauges were created and
      tested, with 5 mu of sensibility. Measurement of displacement between horns were
      studied on two sides of each pelvic before and after implantation of conventional
      and prototype cemented or press fit implants. RESULTS: Among 81 loads on 18
      acetabulum healthy and implanted, displacement was significant in 58 cases with a
      spacing of horn of 7 to 140 mu with average 31.1 mu and non significant in 25
      cases. On healthy acetabulum, spacing was variable from 12 to 140 mu (average
      43.2 mu) in 18 of 26 loads. On implanted acetabulum by different sockets, spacing
      was variable from 7 to 100 mu (average 27.4 mu) in 40 of 55 loads. Displacement
      was function of rotation hip, smaller in internal rotation and larger in external
      rotation. Spacing of horns was reduced in oversize sockets. DISCUSSION: The data
      obtains by omega strain gauge suggest acetabular displacement is not univocal
      under load. There were a widening of the acetabular notch on load. This can be
      explained by the modification of primary incongruity of the two components of the
      hip joint because of acetabular deformation. Such results are in agreement with
      recently published data obtained about length of the transverse acetabular
      ligament.

PMID- 10392415
TI  - [Gait analysis of 57 healthy children by measurement of ground reaction forces on
      an Adal treadmill].
AB  - PURPOSE OF THE STUDY: The purpose of this study was to present a new treadmill
      proposed for evaluating gait in children. We analysed differences in ground
      reaction forces between boys and girls, and we calculated the symmetry index in
      healthy children. MATERIAL AND METHOD: Time and ground reaction forces of about
      30 steps were measured using a new treadmill. The apparatus consists of 2 walking
      belts which function as two independent treadmills placed side by side, separated
      by 4 mm. The 2 treadmills were mechanically separated in order to allow
      independent measurement of the ground reaction forces induced by each lower limb
      during stance phase. The children (28 boys and 29 girls), all clinically healthy,
      were divided into three groups according to their height (between 105 and 150
      cm). They walked at three different velocities (2.7 km/h, 3.6 km/h and 4.5 km/h
      according to their height). The graphs representing the subject's measurements
      were composed of fore-aft, medial-lateral, and vertical parameters. The analysis
      of these graphs considered stride, stance, double stance and nine specific
      points. We also calculated the symmetry index of each child. RESULTS: We
      determined the values of the symmetry index in healthy children. We did not find
      any significant difference in gait between girls and boys, except for Fz3 at 2.7
      kg/h, where Fz3 was higher in girls than in boys. DISCUSSION: We compared our
      results with those reported in the literature and found that ADAL has a very
      important advantage in gait analysis in children because it is simple and easily
      accepted by children.

PMID- 10392416
TI  - [Botulinum A in the treatment of equinus dynamic spasticity in children with
      cerebral palsy. Preliminary study].
AB  - PURPOSE OF THE STUDY: The purpose of this clinical prospective study is to better
      assess the efficacy of intramuscular injections of botulinum-A toxin in the
      treatment of spastic dynamic equinus deformities in children with cerebral palsy.
      MATERIAL: Ten walking children (14 feet) with cerebral palsy were treated with
      botulinum-A toxin (the American type, Botox) for spastic dynamic equinus,
      equinovalgus or equinovarus deformity of the foot. The mean age was 6 years
      (range 4 to 12 years of age). METHOD: Two units of botulinum-A toxin per kilogram
      were injected in each involved extremity: the lateral and medial gastrocnemius
      were injected in equinus or equinovalgus foot and one more injection was done in
      the tibialis posterior in equinovarus foot. A clinical assessment (based on
      opinion of caretakers, functional evaluation of gait, detailed orthopaedic
      clinical evaluation and video of the gait) and a gait analysis were performed
      prior to the first injections and then at 1, 3 and 6 months afterwards. RESULTS:
      All patients showed a clinical improvement. The functional possibilities
      increased in 6 out of the 10 children. Five children showed a better endurance in
      their walking capacities. The clinical orthopaedic exam showed improvement for 10
      out of the 14 injected feet in passive dorsiflexion from 3 to 15 degrees at one
      month. Twelve feet improved their score on the Physician Rating Scale from 1 to 4
      points. For gait analysis, 6 children (8 feet) had an improvement often minor of
      their curves in terms of improvement of the dorsal flexion of the ankle and the
      EMG of the gastrocnemius was improved in terms of decrease of spastic activity in
      7 children (10 feet). The response to the injections was seen within 10 days (3
      to 10 days) and lasted 3 to 6 months except in one child where it stopped already
      after 1 month. No side effect was noted. DISCUSSION: All ten patients of our
      study showed some type of improvement even if only minor or limited in time in
      some of them. These data corroborate previous studies performed by other authors.
      Since this study, the recommended dosage has greatly increased (from 2 U/kg up to
      10 U/kg or even more). The most interesting new element is that we noted that it
      seems to increase the endurance of the patient regarding walking distance.
      CONCLUSION: The intramuscular injection of botulinum-A toxin in spastic dynamic
      equinus deformities in children with cerebral palsy is an useful treatment
      modality, but the indications have to be respected scrupulously. The subject
      needs more study with the higher dosage and clinical evaluation to confirm the
      possible increased endurance.

PMID- 10392417
TI  - [Functioning of a bone tissue bank in 1998].
AB  - Last few years, the french legislation and reglementation concerning donated
      human tissues, safety precautions, and human tissues' uses have been deeply
      modified. Therefore, tissue banks' organisation, processing of allograft tissue,
      and the way surgeons use frozen bone graft have changed. Accordingly, authors
      describe different obligations these activities implicate and practical
      consequences for tissue banks and surgeons. First, they recall 94' laws and the
      doctrinal and ethical principles essential to understand current laws and
      official standards. Then, they specify sanitary rules all tissue banks have to
      conform to. They detail the different approaches to recovery, processing,
      preservation and distribution of transplantable bone tissue and expose modalities
      of the financing by social organisms. It follows practical consequences in bank
      functioning: supplying, importation, internal organization. In conclusion,
      authors synthesize surgeon's responsibilities in that specific activity.

PMID- 10392418
TI  - [An unusual anomaly : cervical spondylolysis in an adult].
AB  - A case of spondylolysis with exceptional involvement of the cervical spine is
      reported. The lesion turned out to be a defect in the pars interarticularis of a
      cervical vertebra. Such cases generally involve the sixth vertebra. Spondylolysis
      is asymptomatic more often than not. Positive diagnosis is supported by an
      analysis of the anatomic structures on radiographs and CT-scans. Differential
      diagnoses include congenital lesion (articular dysplasia) is always found, there
      is no argument allowing the assertion that cervical spondylolysis is a congenital
      condition rather than secondary to stress fractures.

PMID- 10392419
TI  - [Deep onchocerciasis of the left thigh. An unusual case].
AB  - INTRODUCTION: Commonly onchocercoma has been presented as superficial and
      multiple nodules. When it's unique and deeply situated, its clinical diagnosis is
      difficult. An uncommon form of onchocercoma is reported. CASE REPORT: A 37 years
      old man presented a big tumor at the inferior third of the left thigh like lipoma
      or liposarcoma because of microcalcifications. The tumor was removed. It was a
      cyst containing a liquid like an "mango juice". The histological examination was
      performed. Degenerated microfilariae of Onchocerca volvulus was found.
      DISCUSSION: A big and deep onchocerma of the thigh is uncommon and diagnosis
      before operation is very difficult. Histological examination have eliminate
      filarial infections like Dracunculus medinensis and have given the right
      diagnosis. Radiological microcalcifications and absence of microfilariae at the
      parasilogical and ophthalmological examinations recall an "aged" onchocercoma.
      For this reason, we didn't realise a chemotherapy. CONCLUSION: This tumor in
      Sahel areas is very difficult to diagnose before operation. The histological
      examination is very important in this case. We don't use chemotherapy because
      this onchocercoma looks old without alive microfilariae.

PMID- 10392420
TI  - [Retroperitoneoscopic anterior approach to the L2, L3, L4 vertebral bodies].
AB  - PURPOSE OF THE STUDY: We present a technique of retroperitoneal video assisted
      anterior approach of vertebral bodies and adjacent discs on L2-L3-L4 levels
      without CO2 insufflation. MATERIALS: A videosurgical material is required as well
      as fluoroscopic control. Ordinary anesthesia methods can be used. The patient is
      placed in right lateral decubitus. Ay. A3 cm incision is targeted moderately
      anteriorly at the level of the vertebra. Dissection of the retroperitoneal space
      is begun by blunt finger dissection and completed by a balloon. A camera is
      inserted. CO2 insufflation is not used for this open video-assisted technique.
      METHODS: We have performed 12 arthrodeses with this technique, 11 of them without
      corporectomy. In one case, a corporectomy with peroneal graft was used. RESULTS:
      Eleven arthrodesis fused. The possible complications are the same as with a full
      open procedure. DISCUSSION: Extension of this approach is limited cranially by
      the 12th rib and caudally by the iliac crest. CONCLUSION: Although this is an
      easy to perform mini open technique, a learning curve is necessary. Conservation
      to a full open procedure is possible at any point in the procedure.

PMID- 10392421
TI  - [The effect of the essential fatty acids in mare's milk on the function of the
      immune system and of nonspecific resistance in rats].
AB  - The influence of essential fatty acids of mare's milk fat on the immunocompetent
      system and nonspecific resistance of male rats weighing 135-145 g was
      investigated after 6 weeks of feeding. Rats were fed with isocaloric purified
      diets containing 15% of test fat (in control--combination of lard and sunflower
      oil) which provide the ratio of omega-6/omega-3 fatty acids equal to 0.76. An
      increase of immune responsiveness and nonspecific resistance in the group fed
      with the diet with mare's milk fat on day 6 after a single immunization of the
      animals with 5% sheep erythrocyte suspension was noted.

PMID- 10392422
TI  - [The effect of biological food supplements containing polyunsaturated fatty acids
      on the erythrocyte enzyme activity and on the hemoglobin oxygen affinity in
      volleyball players exposed to intensive physical loading].
AB  - It has been determined that in erythrocytes of professional volley-ball players
      given biopreparation "Polien" containing polyunsaturated fatty acids glycolysis
      and pentose phosphate pathway reactions are intensified and glutathione reductase
      activity decreased. At the same time the affinity of haemoglobin to oxygen
      stabilized in the sportsmen before and after intensive muscle load.

PMID- 10392423
TI  - [The effect of an antioxidant preparation based on bioflavonoids and vitamin C on
      the antioxidant activity of blood plasma].
AB  - The effect of single and long-term reception of the antioxidant preparation
      Magnum C (MC) on blood plasma antioxidant activity (AOA) of volunteers has been
      investigated. AOA was measured with chemiluminescence test using the hemoglobin
      hydrogen peroxide-luminol system. MC contains ethereal form of vitamin C and
      bioflavonoids as the basic antioxidant components. It was determined that blood
      plasma AOA was increased on the average by 36% (p < 0.01) 3 hours after single
      intake of 4 capsules of MC. In case of long-term reception of MC (1 capsule twice
      in day during 4 weeks) the greatest increase in the blood plasma AOA was about
      60% (p < 0.001) and was observed on the 14th day. On the 7th day after completion
      of MC reception the level of blood plasma AOA was, approximately, 20% above its
      initial value (p < 0.05). This is probably due to prolonged action of MC.

PMID- 10392424
TI  - [Biomedical research on a concentrate of carotenoids made from the North Atlantic
      sea cucumber Cucumaria frondosa].
AB  - Possibility of utilizing a carotenoid concentrate (CC) extracted from Cucumaria
      frondosa of the North Atlantic in foodstuffs and medicinal and prophylactic diet
      is considered. A complex of experimental studies including physiological,
      biochemical and morphological examinations has found that addition of CC in
      physiological doses to a diet of warm-blooded animals during 12 months causes no
      side effects. Utilization of CC in medicinal and prophylactic dietary nutrition
      may be beneficial.

PMID- 10392425
TI  - [The nutrition of patients who have undergone vertical gastroplasty for severe
      forms of obesity].
AB  - The energy ration value and supply of the main nutrients were studied by 24-h
      reproduction before and after operations in 33 morbid obesity patients who had
      undergone vertical gastroplastic surgery. The surgery was accompanied by reducing
      of surplus mass of the body by 25-71.7% and at the same time by reducing caloric
      content of the ration from average 4726.9 kcal before the operation to 1087 kcal
      during the first three months after the operation followed by a rise to 1490.0
      kcal in 12-24 months. The deficient quota of protein and stable reduction of
      consumption of vitamins E, PP, B2, B1, potassium, magnesium, phosphorus were
      stated in postoperative rations (to 40-50% from recommended rates). The diet
      recommended after restricting operations on the stomach for obese patients on
      principles of diets for obesity patients was designed. The need to use protein
      vitamin-mineral additives with individually adjusted compositions and dosages is
      shown.

PMID- 10392426
TI  - [The structure of the actual nutrition of diabetic patients in the city of
      Kemerovo].
AB  - Dietary intake of patients with insulin-dependent and non-insulin-dependent
      diabetes mellitus was studied. Analysis of nutrient and energetic content of
      rations is given. Unbalance of the main components and deficiency of some
      vitamins and minerals were registered.

PMID- 10392428
TI  - [Food products, food additives, packaging: ecology, manufacture and waste
      recycling (based on materials from a scientific and practical conference)].

PMID- 10392427
TI  - [The iodine allowance and the prevalence of goiter among the children in
      organized collectives in the city of Kemerovo].
AB  - Nutritional value of diets given to children attending kindergartens and schools
      in Kemerovo according to specified menu (proteins, vitamins, minerals) has been
      studied. The unbalance in diet ration leading to development of iodine deficiency
      in children of these institutions is responsible for high incidence of goiter.
      The level of iodine deficiency is 34.0% in kindergartens and 78.2% in boarding
      schools. High occurrence of goiter in children's institutions should be
      considered in planning antigoiter preventive measures.

PMID- 10392429
TI  - [The biological basis for the use of polyunsaturated fatty acids of the omega-3
      family in the prevention of atherosclerosis].

PMID- 10392430
TI  - [The role of the minor sugars in the vital activities of the human body].

PMID- 10392431
TI  - [Viral mucosal vaccines].
AB  - Reviews published reports on the development of mucosal antiviral vaccines
      administered through the mucous membranes and inducing systemic and local
      immunity. Describes methods ensuring the optimal conditions for penetration of
      mucosal vaccines in mucosal cells and discusses the possibility of local immunity
      induction in the vagina and rectum after intranasal administration of vaccine.
      Presents data on the development and trials of mucosal vaccines against some
      virus infections.

PMID- 10392432
TI  - [Human type 6, 7, and 8 herpesviruses--new pathogens in the Herpesviridae
      family].
AB  - Presents modern data on a group of novel viruses pathogenic for man: types 6, 7,
      and 8 human lymphotropic herpesviruses (HHV-6, HHV-7, and HHV-8). HHV-6 and HHV-8
      are characterized by wide cell tropism, and HHV-7 is selectively tropic to CD4+ T
      lymphocytes. HHV-6 and HHV-7 are etiological agents of exanthema subitum (roseoia
      infantum), a disease of infancy, and of many grave lymphoproliferative disorders,
      and HHV-8 is a herpesvirus associated with Kaposi's sarcoma. The morphology,
      immunobiology, pathogenesis, clinical picture, epidemiology, and therapy of HHV,
      HHV-7, and HHV-8 infection are characterized in brief.

PMID- 10392433
TI  - [A common antigenic epitope in influenza A virus (H1, H2, H5, H6) hemagglutinin].
AB  - Avian influenza A viruses belonging to hemagglutinin (HA) subtypes H5 and H6 were
      studied in the infectivity neutralization test and radioimmunoprecipitation assay
      (RIPA) with monoclonal antibody MAb C179. This MAb recognizes a conformational
      antigenic epitope in the stem region of HA formed by two regions (amino acid
      positions 318-322 in HA1 subunit and 47-58 in HA2), conserved in all H1 and H2
      influenza viruses. MAb C179 reacts with HA of H5 viruses in RIPA and neutralizes
      these strains as efficiently as H2 viruses. C179 precipitates H6 subtype HA but
      does not neutralize the infectivity of these viruses. Comparison of amino acid
      sequences of H2, H5, and H6 strains showed identical epitope recognized by MAb
      C179 in H5 and H6 HAs, which differs from epitopes of H1 and H2 by two amino
      acids in the HA2 subunit. Causes of disagreement between immunoprecipitation of
      H6 HA by MAb C179 and neutralization of this serosubtype by this MAb are
      discussed.

PMID- 10392434
TI  - [Change in the sensitivity of influenza virus, replicating in the presence of
      rimantadine, to antiviral agents].
AB  - A variant obtained by a single passage of the initial FPV in the presence of 25
      micrograms/ml rimantadine is more resistant to the drug than the parental virus.
      Sensitivity to rimantadine is higher in a variant obtained similarly by cell
      culture infection with rimantadine-resistant FPV. Potentiation of the antiviral
      effect of a combination of ribavirin (12-25 micrograms/ml) and rimantadine (0.1-6
      micrograms/ml) is decreased or null if rimantadine dose is increased to 12-25
      micrograms/ml; this phenomenon does not depend on the sensitivity of infective
      virus to rimantadine. Antiviral effect of drug combination with a high
      concentration of rimantadine is due to ribavirin alone.

PMID- 10392435
TI  - [Modeling and characteristics of liver damage in herpes infection].
AB  - An experimental model of herpetic hepatitis is developed, levels and time course
      of changes in transaminases, the main indicators of lipid metabolism, are
      characterized, and morphologic features of hepatocyte injury by herpes simplex
      virus are shown. Liver involvement in herpetic infection is described in detail.

PMID- 10392436
TI  - [Intranasal revaccination of children with live measles vaccine: development of
      local immunity].
AB  - Thirty-eight children aged 6-7 years were intranasally revaccinated against
      measles. Children without antimeasles antibodies in the serum responded to
      revaccination by their appearance in protective titers. In children with
      antibodies their titers increased (in 60%) on day 30 after intranasal
      revaccination. The efficacy of subcutaneous revaccination was the same.
      Intranasal, but not subcutaneous, revaccination resulted in appearance of
      nasopharyngeal anti-measles IgA. Intranasal method of revaccination against
      measles is convenient and safe and is recommended for clinical trials on a wide
      scale and for introduction into practice.

PMID- 10392437
TI  - [Ultrastructure of human L-68 diploid cells, infected with rubella virus].
AB  - A monolayer of human diploid cell culture L-68 (21st and 30th passages) was
      infected with a intermediate variant of rubella vaccine strain Orlov and studied
      for 8 days by light and electron microscopy. Virus reproduction was associated
      with slight cytopathic effect; virions were detected in low amounts inside
      vacuoles and cisterns of the lamellar complex, groups of virions were found in
      the cytoplasm in association with cytomembranes and outside cells. Cell cultures
      differed by the cytopathic effect of the virus on the monolayer: microfocuses
      were found in the 21st passage culture, while in the 30th passage culture the
      monolayer was diffusely damaged.

PMID- 10392438
TI  - [Effectiveness of cycloferon in treating virus-associated inflammatory
      gynecologic diseases].
AB  - Cycloferon, a low molecular weight interferon inducer synthesized in Russia, was
      used for treating chronic acute gynecological inflammations. The etiology of
      diseases was mixed in the majority of cases. Clinical efficacy of the drug was
      79%. Cycloferon, an antiviral immunomodulating drug, is recommended for combined
      therapy of chronic and acute gynecological inflammations.

PMID- 10392439
TI  - [Characteristics of reactogenic and immunogenic properties of the children's
      variant of the domestic vaccine, "Gep-A-in-Vak", against hepatitis A].
AB  - Russian cultural concentrated inactivated vaccine protecting from hepatitis A-
      Hep-A-in-vac was used for immunization of children. The vaccine is slightly
      reactogenic and completely safe in children aged 3-17 years vaccinated twice in a
      dose of 0.25 ml. Double immunization of seronegative children with a 1-month
      interval led to conversion in 89.7% children. In 64.1% children titers of
      antibodies to hepatitis A virus reached 20 mIU/ml and higher, which indicates
      rather high antigenic activity of the vaccine.

PMID- 10392440
TI  - [Cryostabilization of biological properties of plague phages].
AB  - Conditions of cryostabilization of Yersinia pestis phages preserving their
      biological properties at very low temperature are studied.

PMID- 10392441
TI  - The positive relationship between codon usage bias and translation initiation AUG
      context in Saccharomyces cerevisiae.
AB  - The relationship between the codon usage bias and the sequence context
      surrounding the AUG translation initiation codon was examined in 211
      Saccharomyces cerevisiae mRNA sequences. The codon usage bias and the number of
      matches to optimal AUG context, (A/U)A(A/C)AA(A/C)AUGUC(U/C), for translation
      initiation showed a positive relationship, indicating that these two factors are
      evolutionally under the similar natural selection constraint at the translation
      level. A new index (AUGCAI = AUG Context Adaptation Index) for the measure of
      optimal AUG context was devised, and the importance of each position of AUG
      context was also examined.

PMID- 10392442
TI  - Biotransformation of steroids by the fission yeast Schizosaccharomyces pombe.
AB  - The fungal biotransformation of steroids is of applied interest due to the
      economic importance of such stereo- and regiospecific reactions and also in the
      context of ergosterol pathway engineering to produce vitamin D and steroidal
      products. In Schizosaccharomyces pombe no steroid hydroxylation as is found in
      filamentous fungi was observed, but a cytosolic NAD(H)/NADP(H)-dependent
      hydroxysteroid dehydrogenase activity was identified. Progesterone was reduced at
      the delta 4 double bond (in vivo only) as well as at the C-3 and C-20 keto
      groups. Testosterone and 4-androstene-3,17-dione were interconverted and 5 alpha
      pregnane-3,20-dione and 5 beta-pregnane-3,20-dione were reduced to 3-hydroxy
      products. The reactions were sometimes reversible and showed regio- and stereo
      specificity. In S. pombe more than one steroid dehydrogenase homologue is likely
      to occur, as has been observed in Saccharomyces cerevisiae. Our findings indicate
      that genes encoding soluble proteins should be examined as candidates for actual
      steroid dehydrogenase activity.

PMID- 10392443
TI  - The development of bactericidal yeast strains by expressing the Pediococcus
      acidilactici pediocin gene (pedA) in Saccharomyces cerevisiae.
AB  - The excessive use of sulphur dioxide and other chemical preservatives in wine,
      beer and other fermented food and beverage products to prevent the growth of
      unwanted microbes holds various disadvantages for the quality of the end-products
      and is confronted by mounting consumer resistance. The objective of this study
      was to investigate the feasibility of controlling spoilage bacteria during yeast
      based fermentations by engineering bactericidal strains of Saccharomyces
      cerevisiae. To test this novel concept, we have successfully expressed a
      bacteriocin gene in yeast. The pediocin operon of Pediococcus acidilactici PAC1.0
      consists of four clustered genes, namely pedA (encoding a 62 amino acid precursor
      of the PA-1 pediocin), pedB (encoding an immunity factor), pedC (encoding a PA-1
      transport protein) and pedD (encoding a protein involved in the transport and
      processing of PA-1). The pedA gene was inserted into a yeast expression/secretion
      cassette and introduced as a multicopy episomal plasmid into a laboratory strain
      (Y294) of S. cerevisiae. Northern blot analysis confirmed that the pedA
      structural gene in this construct (ADH1P-MFa1S-pedA-ADH1T, designated PED1), was
      efficiently expressed under the control of the yeast alcohol dehydrogenase I gene
      promoter (ADH1P) and terminator (ADH1T). Secretion of the PED1-encoded pediocin
      PA-1 was directed by the yeast mating pheromone alpha-factor's secretion signal
      (MFa1S). The presence of biologically active antimicrobial peptides produced by
      the yeast transformants was indicated by agar diffusion assays against sensitive
      indicator bacteria (e.g. Listeria monocytogenes B73). Protein analysis indicated
      the secreted heterologous peptide to be approximately 4.6 kDa, which conforms to
      the expected size. The heterologous peptide was present at relatively low levels
      in the yeast supernatant but pediocin activity was readily detected when intact
      yeast colonies were used in sensitive strain overlays. This study could lead to
      the development of bactericidal yeast strains where S. cerevisiae starter
      cultures not only conduct the fermentations in the wine, brewing and baking
      industries but also act as biological control agents to inhibit the growth of
      spoilage bacteria.

PMID- 10392444
TI  - Copper-zinc superoxide dismutase from the marine yeast Debaryomyces hansenii.
AB  - We have isolated the cytosolic form of Cu-Zn superoxide dismutase (SOD) from the
      marine yeast Debaryomyces hansenii. This enzyme has a subunit mass of 18 kDa. The
      preparation was found to be heterogeneous by IF electrophoresis with two pI
      ranges: 5.14-4.0 and 1.6-1.8. The enzyme preparation had a remarkably strong
      stability at pH 6.0-7.0, surviving boiling for 10 min without losing more than
      60% of activity. On Western blots, this enzyme was recognized by antibodies
      raised in rabbits against D. hansenii extracts, while only a weak cross-reaction
      could be detected using antibodies generated against either Saccharomyces
      cerevisiae or bovine erythrocyte Cu-Zn SODs. In sequencing analysis, a peptide
      obtained by trypsin digestion was found to have 85% identity to the S. cerevisiae
      Cu-Zn SOD.

PMID- 10392445
TI  - Eleven novel sep genes of Schizosaccharomyces pombe required for efficient cell
      separation and sexual differentiation.
AB  - Genetic analysis of 20 sterile mutants prone to form hyphae revealed 11 novel ste
      genes (sep6 to sep16) of Schizosaccharomyces pombe. None of the mutants was
      completely mycelial. Most mutants formed branching hyphae and showed normal
      septation. Aberrant septal structures and actin distribution were seen only at 36
      degrees C. sep9-307, sep14-576 and sep15-598 showed genetic interactions with
      sep1-1, a mutation in a forkhead transcription factor homologue. Additional
      genetic interactions were detected between sep6-194, sep15-598 and cdc16-116, a
      mutant allele of an anaphase modulator of p34cdc2. sep9-307 and sep15-598 caused
      dikaryosis in wee1- background. In mating and sporulation tests, sep6-, sep7-,
      sep9-, sep10-, sep11- and sep15- proved to be defective in conjugation only,
      whereas sep8-, sep13- and sep16- were also defective in meiosis-sporulation.
      sep12- and sep14- were only partially sterile. All mutants could produce M-factor
      but sep8-, sep11-, sep15- and sep16- were defective in P-factor production. The
      mutations in sep8, sep11 and sep16 suppressed the pat1-114-driven meiosis. All
      mutants were sensitive to the presence of higher concentrations of chloride in
      the medium and to short heat shocks. The diversity of the mutant phenotypes and
      the pleiotropic effects of the mutations suggest that these sep genes might act
      in, or interact with, a multiple overlapping network of regulatory modules.

PMID- 10392446
TI  - Decapping of stabilized, polyadenylated mRNA in yeast pab1 mutants.
AB  - Interaction of the poly(A) binding protein, Pab1p, with mRNA plays an important
      role in gene expression. This work describes an analysis of pab1 mutants in
      Saccharomyces cerevisiae. Yeast pab1 mutants were found to be sensitive to
      elevated concentrations of copper (Cu) and 3-aminotriazole (3-AT) in the growth
      medium. This phenotype arises because these pab1 mutants underaccumulate mRNA,
      including the CUP1 and HIS3 mRNAs, the products of which are required for Cu and
      3-AT resistance, respectively. To determine the cause of the mRNA
      underaccumulation, mRNA turnover and production were examined in the pab1-53
      mutant. It was found that although the pattern of mRNA decay was altered, and
      substantial decapping of polyadenylated mRNA could be detected, mRNA was not
      destabilized in this strain. It was also found that the pab1 mutant was impaired
      in the production of mRNA. These data show that the decreased level of mRNA in
      the pab1-53 mutant arises from poor production, and they suggest that yeast Pab1p
      is involved in an aspect of nuclear mRNA metabolism. They also indicate that
      deadenylation can be uncoupled from decapping without significant changes in an
      mRNA's stability, and that this uncoupling can be tolerated by yeast.

PMID- 10392447
TI  - Genome-wide transcriptional analysis in S. cerevisiae by mini-array membrane
      hybridization.
AB  - Access to the powerful micro-array analytical methods used for genome-wide
      transcriptional analysis has so far been restricted by the high cost and/or lack
      of availability of the sophisticated instrumentation and materials needed to
      perform it. Mini-array membrane hybridization provides a less expensive
      alternative. The reliability of this technique, however, is not well documented
      and its reported use has, up to this point, been very limited. Our objective was
      to test whether or not mini-array membrane hybridization would reliably identify
      genes whose expression was controlled by a specific set of genetic and/or
      physiological signals. Our results demonstrate that mini-array hybridization can
      correctly identify genes whose expression is known to be controlled by the GATA
      factor regulatory network in S. cerevisiae and in addition can reliably identify
      genes not previously reported to be associated with this nitrogen control system.

PMID- 10392448
TI  - In vivo construction of cDNA libraries for use in the yeast two-hybrid system.
AB  - We describe a simple and efficient one-step method to make cDNA libraries using
      homologous recombination in yeast. cDNA from any source, together with a linear
      vector, is used to transform yeast. Through homologous recombination and gap
      repair, the cDNA is unidirectionally incorporated into the yeast expression
      vector in vivo. The cDNA-encoded proteins can then be screened for potential
      protein-protein interactions with a bait already present in the yeast. This
      method allows rapid construction and screening of cDNA libraries, even from
      extremely small amounts of mRNA, and can replace the use of conventional cDNA
      libraries.

PMID- 10392449
TI  - Imagined futures: young men's talk about fatherhood and domestic life.
AB  - As part of an extensive series of interviews about men and masculinity, small
      groups of 17 to 18-year-old male students were invited to look forward to their
      future romantic and domestic lives. Their responses were analysed using the
      approach and methods of discourse analysis in order to examine both the
      interpretative resources used within their accounts and to look at how the young
      men attempted to manage the 'ideological dilemma' (Billig, Condor, Edwards, Gane,
      Middleton & Radley, 1988) that was framed by these cultural themes. The analysis
      describes three such strategies while paying particular attention to the 'action
      orientation' (Heritage, 1984) of these constructions. Finally, the paper moves on
      to discuss, albeit briefly, the broader implications of this research.

PMID- 10392450
TI  - Interaction effects in the theory of planned behaviour: studying cannabis use.
AB  - This study employed the theory of planned behaviour (TPB) to investigate the
      factors underlying intentions and frequency of use of cannabis over a three-month
      period in a population of students (N = 249). In addition, several hypotheses in
      relation to the TPB were investigated. The TPB provided good predictions of both
      intentions (R2 = 0.653; attitude, injunctive norms and perceived behavioural
      control significant) and behaviour (R2 = 0.711; intentions significant). Other
      norm measures (descriptive and moral norms) explained additional variance in
      intentions (p < .01). In addition, habit strength and self-identity explained
      significant additional portions of the variance in intentions (p < .001), but not
      behaviour, over and above the TPB variables. Several interactions among these
      variables were also tested. Attitude moderated the impact of perceived
      behavioural control (PBC) on intentions (p < .001). Moral norms moderated the
      impact of attitudes on intentions (p < .001). Habit strength moderated the impact
      of self-identity on intentions (p < .001). PBC was found to moderate the impact
      of intentions on behaviour (p < .05). The findings are discussed in relation to
      how interaction effects further our understanding of the social processes by
      which variables are related in the TPB.

PMID- 10392451
TI  - Gamma-glutamyl transpeptidase gene organization and expression: a comparative
      analysis in rat, mouse, pig and human species.
AB  - Gamma-glutamyl transpeptidase (GGT) is an enzyme located at the external surface
      of epithelial cells. It initiates extracellular glutathione (GSH) breakdown,
      provides cells with a local cysteine supply and contributes to maintain
      intracellular GSH level. GGT expression, highly sensitive to oxidative stress, is
      a part of the cell antioxidant defense mechanisms. We describe recent advances in
      GGT gene structure and expression knowledge and put emphasis on the complex
      transcriptional organization of that gene and its conservation among different
      species. GGT gene structure has been elucidated in rat and mouse where a single
      gene is transcribed from multiple promoters into several transcripts which
      finally yield a unique polypeptidic chain. Analysis of rat, mouse, human and pig
      cDNA and gene sequences reveals a large conservation of the transcriptional
      organization of that gene. This complex structure provides flexibility in GGT
      expression controlled at the promoter level, through multiple regulatory sites,
      and at RNA level by alternate 5' untranslated sequences which may create a
      diversity in the stability and translational efficiency of the different
      transcripts. In conclusion, transcription of the GGT gene from several promoters
      offers multiple DNA and RNA targets for various oxidative stimuli and contributes
      to a broad antioxidant cell defense through GGT induction and subsequent cysteine
      supply from extracellular glutathione.

PMID- 10392453
TI  - cDNA cloning and gene expression of cecropin D, an antibacterial protein in the
      silkworm, Bombyx mori.
AB  - We have isolated a cDNA clone encoding a cecropin D precursor from the fat body
      of Bombyx mori larvae immunized with bacteria by means of differential display.
      The cDNA contains 298 bp with a coding region of 183 bp for 61 amino acids plus a
      termination codon (TAG), a 5'-untranslated region of 36 bp, and a 3'-untranslated
      region of 79 bp including the poly(A) tail. There is a polyadenylation signal
      sequence of AATAAA at position 266, 43 nucleotides downstream from the
      termination codon TAG. The homology of the deduced amino acids is greater to the
      cecropin D precursor from Hyalophora cecropia (67% identity) than to the
      precursors of cecropins A and B from B. mori (49% to both). Northern blotting
      analyses reveal that the gene expression of cecropin D is detectable by 4 h after
      the bacterial injection and reaches the maximal level at 24 h. That high level is
      maintained up to 48 h post-immunization. Additionally, the gene is expressed
      mainly in the fat body and slightly in hemocytes, but it is undetectable in other
      tissues such as the midgut, the Malpighian tubule and silk gland.

PMID- 10392455
TI  - 3-Hydroxy-3-methylglutaryl coenzyme a reductase activity in liver of athymic mice
      with or without an implanted human carcinoma.
AB  - Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase activities and cholesterol
      content in the liver of athymic mice either bearing or not an implanted human
      lung mucoepidormoid carcinoma (HLMC) and in the neoplasic tissue, were analyzed.
      The properties of the HMG-CoA reductase of HLMC grown in nude mice and those ones
      found in the liver of these animals, sacrificed either at mid-light or mid-dark,
      were similar. The hepatic reductase activity was found to be four- to five-fold
      greater at mid-dark than at mid-light (462 +/- 141 vs. 123 +/- 22 pmol min-1 mg
      protein-1). Since the Km value was not modified, the mid-dark activity could be
      due to an increase in the amount of enzyme. In contrast, HLMC reductase activity
      and cholesterol content showed similar values at mid-light and mid-dark points.
      HLMC reductase does not appear to have any diurnal variation and the cholesterol
      synthesis and content seems to be independent of food intake. HLMC-bearing nude
      mice undergo several alterations in the biosynthesis and homeostasis of
      cholesterol. Hypocholesterolemia, lower hepatic cholesterol content and higher
      HMG-CoA reductase activity are characteristic of host mice.

PMID- 10392457
TI  - Human apolipoprotein E N-terminal domain displacement of apolipophorin III from
      insect low density lipophorin creates a receptor-competent hybrid lipoprotein.
AB  - The surface of Manduca sexta low density lipophorin (LDLp) particles was employed
      as a template to examine the relative lipid binding affinity of the 22 kDa
      receptor binding domain (residues 1-183) of human apolipoprotein E3 (apo E3).
      Isolated LDLp was incubated with exogenous apolipoprotein and, following re
      isolation by density gradient ultracentrifugation, particle apolipoprotein
      content was determined. Incubation of recombinant human apo E3(1-183) with LDLp
      resulted in a saturable displacement of apolipophorin III (apo Lp-III) from the
      particle surface, creating a hybrid apo E3(1-183)-LDLp. Although subsequent
      incubation with excess exogenous apo Lp-III failed to reverse the process, human
      apolipoprotein A-I (apo A-I) effectively displaced apo E3(1-183) from the
      particle surface. We conclude that human apo E N-terminal domain possesses a
      higher intrinsic lipid binding affinity than apo Lp-III but has a lower affinity
      than human apo A-I. The apo E3(1-183)-LDLp hybrid was competent to bind to the
      low density lipoprotein receptor on cultured fibroblasts. The system described is
      useful for characterizing the relative lipid binding affinities of wild type and
      mutant exchangeable apolipoproteins and evaluation of their biological properties
      when associated with the surface of a spherical lipoprotein.

PMID- 10392458
TI  - Purification and characterization of goat pepsinogens and pepsins.
AB  - Three type-A and two type-C pepsinogens, namely, pepsinogens A-1, A-2, A-3, C-1,
      and C-2, were purified from adult goat abomasum. Their relative levels in
      abomasal mucosa were 27, 19, 14, 25, and 15%, respectively. Amino acid
      compositions were quite similar between isozymogens of respective types, but
      different between the two types especially in the Glx/Asx and Leu/Ile ratios. NH2
      terminal amino acid sequences of pepsinogens A-3 and C-2 were
      SFFKIPLVKKKSLRQNLIEN- and LVKIPLKKFKSIRETM-, respectively. Pepsins A and C showed
      maximal hemoglobin-digestive activity at around pH 2 and 3, respectively, and
      specific activities of pepsins C were higher than those of pepsins A. Two
      subtypes of pepsin A were obvious, namely pepsin A-2/3 which maintains its
      activity in the weakly acidic pH region over pH 3 and pepsin A-1, which does not.
      Hydrolysis of oxidized insulin B chain by goat pepsins A occurred primarily at
      Ala14-Leu15 and Leu15-Tyr16 bonds.

PMID- 10392459
TI  - Subcellular localization of meta-tetra (hydroxyphenyl) chlorin in human tumor
      cells subjected to photodynamic treatment.
AB  - Subcellular localization of meta-tetra (hydroxyphenyl) chlorin (mTHPC) in HT29
      human colon adenocarcinoma cells has been studied by means of fluorescence
      microscopy. The observed diffuse intracellular distribution of mTHPC fluorescence
      outside the nucleus indicates general staining of cellular organelles. No changes
      in dye fluorescence pattern are evident during and immediately after cell
      illumination. Alternatively, the changes in mTHPC fluorescence pattern are
      observed upon subsequent cell incubation, and are characterized by the appearance
      of distinct bright fluorescence zones. Reaching a maximum 1 h after illumination,
      modifications of the fluorescence pattern then gradually disappear in parallel
      with the formation of plasma membrane blebs, suggesting that cell necrotic lysis
      is taking place. Photosensitized damage to mitochondria and the Golgi apparatus
      has been studied using fluorescent probes 1 h after irradiation, the stage of
      extensive cytoplasm vacuolization, and reveal alterations of these organelles.
      Changes in the mTHPC fluorescence pattern and mTHPC photocytotoxicity, as
      measured by the MTT test 24 h after illumination, are inhibited by sodium azide,
      a singlet oxygen quencher.

PMID- 10392460
TI  - Retinal damage by light in the golden hamster: an ultrastructural study in the
      retinal pigment epithelium and Bruch's membrane.
AB  - The mechanism of the toxicity of light on the retina remains unclear despite a
      large number of investigations. The purpose of this study is to identify and
      localize the ultrastructural changes and the site of the earliest damage after
      intense light exposure. Nine adult Syrian golden hamsters (Mesocricetus auratus)
      have been maintained under constant illumination with a high-pressure mercury
      lamp (HQJ R 80 W Deluxe, Osram, Berlin, light intensity 1000 lx) for 12 h,
      followed by an additional 3 h in the dark. Light damage is assessed by light and
      electron microscopy. Morphological evaluation reveals focal damage to the retinal
      pigment epithelial (RPE) cells in close proximity to less-affected RPE cells and
      normal photoreceptors. Collagen fibers in Bruch's membrane lose their parallel
      orientation. Occasionally, fusion of cell membranes of neighboring rod outer
      segments (ROS) is also observed. Continuous, 12 h exposure of hamsters to intense
      light results in initial focal damage to some RPE cells, such that severely
      damaged RPE cells are found adjacent to intact RPE cells. Only slight damage to
      the photoreceptors is evident, suggesting that the sequence of the pathological
      changes resulting from light begins with damage to the RPE cells and associated
      Bruch's membrane.

PMID- 10392461
TI  - Measurement of intracellular Ca2+ changes using novel caged cyclic nucleotides
      and confocal laser scanning microscopy.
AB  - The intention of this study is to explore the applicability of confocal
      microscopy in conjunction with the use of caged cyclic nucleotide derivatives.
      The methodological potential of UV laser confocal microscopy has been assessed.
      It is shown that illumination of a single cell or a small area of a single cell
      is possible, whereby the intracelluar Ca2+ signal is measured at illuminated and
      non-illuminated cells. Such measurements do not have a high time resolution
      because of the specific system parameters. However, with an N2 pulse laser (not
      part of the standard microscope set-up), Ca2+ signals with a time resolution of
      around 100 ms have been measured. This facilitates investigation of the kinetics
      of Ca2+ influx. Intracellular Ca2+ measurements at HEK293 and sperm cells have
      been made here. For sperm cells the advantages of confocal microscopy are best
      evidenced in conjunction with the use of caged cyclic nucleotides; a cyclic
      nucleotide-gated Ca2+ influx at the tail of these cells has thereby been
      demonstrated for the first time.

PMID- 10392463
TI  - In vivo resistance to photofrin-mediated photodynamic therapy in radiation
      induced fibrosarcoma cells resistant to in vitro Photofrin-mediated photodynamic
      therapy.
AB  - The effects of Photofrin-mediated photodynamic therapy (PDT) on the in vitro cell
      survival and in vivo tumor growth of murine radiation-induced fibrosarcoma (RIF)
      cell tumors have been examined following in vivo PDT treatment of tumors. The
      response to in vivo PDT is examined in tumors derived from RIF-1 mouse
      fibrosarcoma cells and in tumors derived from RIF-8A cells, which show in vitro
      resistance to PDT. A significant reduction in tumor volume is observed over the
      first three days following in vivo PDT treatment of either 5 or 10 mg/ kg. The
      reduction in tumor volume is greater for a 10 compared to a 5 mg/ml dose and
      occurs to a similar extent for both RIF-1 and RIF-8A tumors. The re-growth is
      significantly delayed for RIF-1 compared to RIF-8A tumors, indicating a greater
      response for RIF-1 tumors compared to RIF-8A tumors following PDT. A reduced
      response of the RIF-8A compared to the RIF-1 tumor cells is also observed in the
      clonogenic survival of cells from tumors that were excised and explanted in vitro
      immediately following in vivo PDT treatment. These data indicate that the
      intrinsic cell sensitivity to PDT is an important component in the mechanism that
      leads to tumor response following in vivo photodynamic therapy.

PMID- 10392462
TI  - Kinetic fluorescence studies of 5-aminolaevulinic acid-induced protoporphyrin IX
      accumulation in basal cell carcinomas.
AB  - Laser-induced fluorescence (LIF) investigations have been performed in connection
      with photodynamic therapy (PDT) of basal cell carcinomas and adjacent normal skin
      following topical application of 5-aminolaevulinic acid (ALA) in order to study
      the kinetics of the protoporphyrin IX (PpIX) build-up. Five superficial and 10
      nodular lesions in 15 patients are included in the study. Fluorescence
      measurements are performed prior to the application of ALA, 2, 4 and 6 h post ALA
      application, immediately post PDT (60 J cm-2 at 635 nm), and 2 h after the
      treatment. Hence, the build-up, photobleaching and re-accumulation of PpIX can be
      followed. Superficial lesions show a maximum PpIX fluorescence 6 h post ALA
      application, whereas the intensity is already the highest 2-4 h after the
      application in nodular lesions. Immediately post PDT, the fluorescence
      contribution at 670 nm from the photoproducts is about 2% of the pre-PDT PpIX
      fluorescence at 635 nm. Two hours after the treatment, a uniform distribution of
      PpIX is found in the lesion and surrounding normal tissue. During the whole
      procedure, the autofluorescence of the lesions and the normal skin does not vary
      significantly from the values recorded before the application of ALA.

PMID- 10392464
TI  - Low doses of ultraviolet A radiation stimulate adhesion of human dermal
      fibroblasts by integrins in a protein kinase C-dependent pathway.
AB  - In this work, we have studied the modulation of fibroblast-extracellular matrix
      interactions by physiological doses of ultraviolet A (UV-A) radiation using an
      adhesion assay on collagen. We have shown that low doses of UV-A (20 kJ/m2)
      stimulate fibroblast adhesion while higher doses (100 and 200 kJ/m2) inhibit it.
      By measurement of the thiobarbituric acid reactive substances (TBARS) and use of
      the chain-breaking antioxidant vitamin E, no role of lipid peroxidation can be
      detected in these effects. By incubating fibroblasts with a specific protein
      kinase C (PKC) inhibitor, GF109203X, we have demonstrated that the stimulation of
      the adhesion by low doses of UV-A involves, at least in part, a PKC-dependent
      mechanism. In addition, using function-blocking antibodies of alpha 1, alpha 2 or
      alpha 5 integrin chains involved in extracellular matrix anchorage, we have shown
      that they decrease the stimulation of adhesion following low doses of UV-A
      radiation, demonstrating the involvement of these three integrin chains in this
      UV-A effect. In parallel, 20 kJ/M2 of UV-A are found to rapidly stimulate
      membrane expression of alpha 1, alpha 2 and alpha 5 integrin chains. This work,
      which underlines the involvement of integrins in UV-A effects, contributes to the
      evaluation of the mechanisms by which cell-matrix interactions modulate cell
      behaviour.

PMID- 10392465
TI  - Photodynamically induced effects in colon carcinoma cells (WiDr) by endogenous
      photosensitizers generated by incubation with 5-aminolaevulinic acid.
AB  - Human adenocarcinoma cells of the line WiDr have been treated with 2 mM 5
      aminolaevulinic acid (5-ALA) in the presence of 10% foetal calf serum. The
      treatment induces a linear accumulation of protoporphyrin IX (PpIX) for at least
      7.5 h. After 7.5 h of incubation about 45% of the PpIX accumulated is cell-bound,
      while the rest is found in the medium (25%) or lost from the cells during washing
      with phosphate-buffered saline (30%). Exposure to white light at an intensity of
      30 W/m2 for 18 min results in 95% reduction of clonogenicity in cells treated
      with 2 mM 5-ALA for 3.5 h. The enzymatic activities of enzymes located in cytosol
      (glyceraldehyde 3-phosphate dehydrogenase and lactate dehydrogenase) and
      lysosomes (acid phosphatase and beta-glucuronidase) are not influenced by a 5-ALA
      and light treatment inactivating about 35% of the cells. The MTT assay, which
      reflects mitochondrial dehydrogenase activity, but not succinate dehydrogenase,
      is partly inhibited by the same treatment. Treatment with 5-ALA in the absence of
      light increases O2 consumption by a factor of two, while the O2 consumption is
      inhibited when 5-ALA treatment is combined with exposure to light. In addition, 5
      ALA and light exposure enhance accumulation of rhodamine 123 by 40% and reduce
      the intracellular ATP level by 25%. Confocal laser scanning microscopical
      analysis indicates granular perinuclear localization of the PpIX formed by 5-ALA
      treatment. In conclusion, photodynamic treatment using 5-ALA as a prodrug induces
      damage to mitochondrial function without inhibiting lysosomal and cytosolic
      marker enzymes.

PMID- 10392466
TI  - Construction of spectral sensitivity function using polychromatic UV sources.
AB  - A procedure is presented for constructing the spectral sensitivity functions of
      biological dosimeters, using five polychromatic UV sources possessing different
      emission spectra. Phage T7 and uracil biological dosimeters have been used for
      measuring the dose rates of the lamps. Their spectral sensitivity functions
      consisting of two exponential terms have been constructed. The parameters of the
      spectral sensitivity functions have been determined by comparing the directly
      measured and calculated dose-rate values. The parameters of the sensitivity
      function are accepted as correct values when the deviation of the measured and
      calculated values is a minimum. Based on the deviations between the constructed
      and the experimentally determined spectral sensitivities with monochromatic
      sources, the differences between the measured and calculated results are
      interpreted. The importance of the correct spectral sensitivity data is
      demonstrated through the effectiveness spectra of a TL 01 lamp for phage T7
      killing, uracil dimerization and erythema induction.

PMID- 10392467
TI  - p53 induction in normal human skin in vitro following exposure to solar simulated
      UV and UV-B irradiation.
AB  - Exposure of normal human breast skin ex vivo to physiological levels of UV-B and
      solar simulated UV results in a UV dose- and time-dependent increase in epidermal
      p53, as determined by PAGE analysis. Peak p53 levels are detected 12 to 24 h post
      irradiation with UV-B (470-1410 mJ cm-2) and solar simulated UV (5-12 minimal
      erythema dose (MED) equivalents). Irradiation with an FS20 UV-B lamp,
      contaminated with UV-A and UV-C (74-1111 mJ cm-2), also induces peak levels after
      12 h incubation at 37 degrees C but these levels persist to 36 h post UV
      irradiation. In all cases p53 levels start to return to normal by 48 h culture. A
      significant positive correlation is demonstrated between UV-B dose (47-1645 mJ cm
      2) and p53 level (p < 0.01, R > 0.977) in explants cultured for 24 h at 37
      degrees C post irradiation. The FS20 induces a 'UV-B' dose-dependent increase in
      p53 to a maximum from 370 to 1111 mJ cm-2. Similarly, solar simulated UV induces
      a plateau of peak p53 induction between 5 and 15 MED equivalents.
      Immunohistochemical analysis using microwave retrieval on 5 microns sections
      shows the same pattern of p53 staining with UV-B and solar UV insult, but proves
      unreliable as a method of quantification. These results suggest that the skin
      explant model may be a useful tool in the evaluation of UV-induced epidermal cell
      damage, providing a valuable alternative to in vivo studies.

PMID- 10392468
TI  - Changes in blood platelets exposed to UV-B radiation.
AB  - The effects of UV-B radiation (312 nm) on the pig-blood platelet secretory
      process (platelet activation) and platelet lipid peroxidation have been studied.
      The responses of platelets to UV-B radiation are compared with the response of
      these cells to thrombin, which is a strong platelet agonist. The obtained results
      show that exposure of blood platelets to UV-B radiation (1.2 mW/cm2, 0.072-8.64
      J/cm2) causes dose-dependent platelet lipid peroxidation (measured as
      thiobarbituric acid reactive substances, TBARS) and release of adenine
      nucleotides and proteins from irradiated platelets. The dose-dependent release of
      platelet compounds from irradiated platelet does not correlate with the activity
      of platelet lactic dehydrogenase (marker of cell lysis) in the extracellular
      medium. It seems that UV-B radiation can partly activate platelets by stimulating
      the platelet secretory process and metabolism of arachidonate.

PMID- 10392469
TI  - Production of 13C-labelled anthocyanins by Vitis vinifera cell suspension
      cultures.
AB  - The use of plant cell cultures for producing isotopically (13C) labelled phenolic
      substances is reported. Vitis vinifera cells synthesize high levels of
      anthocyanins when they are cultured in a polyphenol synthesis-inducing medium.
      Three major anthocyanin monoglucosides found in red wine were identified in grape
      cells: cyanidin-3-O-beta-glucoside, peonidin-3-O-beta-glucoside, and malvidin-3-O
      beta-glucoside. Kinetic study of the intracellular level of phenylalanine and its
      metabolites showed that it is preferable to add this precursor to grape cell
      suspensions after the 5th day of culture, i.e. at the beginning of the
      exponential growth phase. After adding phenylalanine to the culture medium, its
      uptake was complete and the accumulation of anthocyanins in grape cells was
      stimulated. Incorporation of [1-13C]-phenylalanine into anthocyanins was measured
      by means of 13C satellites in the proton NMR spectrum. The maximal rate of 13C
      enrichment anthocyanins obtained with this technique reached 65%. The production
      of 13C labelled phenolic compounds was undertaken in order to investigate their
      absorption and metabolism in humans.

PMID- 10392470
TI  - Jatrophane diterpenoids from Euphorbia peplus.
AB  - From the pro-inflammatory active extract of Euphorbia peplus, a new diterpene
      polyester (1) based on the jatrophane skeleton was isolated together with the
      known compounds 2-5. The irritant activities of some jatrophane diterpenes (2, 3
      and 6-9) were also investigated: only compound 2 was found to exert a weak pro
      inflammatory activity on mouse ear.

PMID- 10392471
TI  - A spirostanol saponin from the underground parts of Ruscus aculeatus.
AB  - A new spirostanol saponin was isolated from the underground parts of Ruscus
      aculeatus and the structure was assigned as (23S,25R)-spirost-5-ene-3 beta,23
      diol 23-O-[O-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside] on the basis
      of spectroscopic analysis, including two-dimensional NMR spectroscopic techniques
      and the result of acid hydrolysis. The saponin is unique in structure having a
      diglycoside unit at C-23 of the spirostanol skeleton.

PMID- 10392472
TI  - Methodological sources of cultural insensitivity in mental health research.
AB  - The concept of procedural norms, which is taken from the analysis of science as
      an institutionally structured social process, is used to explain the persistence
      of cultural insensitivity in research. The concept refers to the canons of
      research that tell scientists what should be studied and how, and they are taught
      to successive generations of researchers. An examination of cross-cultural
      studies in mental health reveals that cultural insensitivity stems from
      procedural norms in the development of content validity based on experts'
      rational analysis of concepts, in linguistic translations that try to conform to
      the exact terms of standardized instruments, and in the uncritical transferring
      of concepts across cultures. We need a wide-ranging examination of our procedural
      norms, with the objective of keeping such norms from suppressing, biasing, or
      deflecting cultural understandings. This article proposes a dialogue on the
      intricate connections between culture and our customary methodologies.

PMID- 10392473
TI  - Global incidence of tropical and non-tropical lymphoedemas.

PMID- 10392474
TI  - Lymphatic dysplasia in paediatrics. A new classification.
AB  - A classification of dysplasias of the lymphatic system is proposed on the basis
      of the anatomical structures involved: lymph vessel-angiodysplasia,
      lymphadeno(nodal)-dysplasia and the summary of both lymphangio
      adeno(nodal)dysplasias. The suggested terminology is: LAD I
      (Lymphangiodysplasias), LAD II (Lymphadeno(nodal)dysplasia) and LAAD
      (lymphadeno(nodal)-dysplasia). With this classification we may coherently group
      the malformations we already know, relate them to the big syndromes and to all
      the other angiodysplasias and also create the reference background for another
      chapter of lymphology: primary or idiopathic lymphedema.

PMID- 10392475
TI  - Chylous reflux pathologies: diagnosis and microsurgical treatment.
AB  - BACKGROUND: This article aims to make a contribution to the present knowledge of
      the diagnosis and therapy of chylous reflux pathologies, based largely on the
      authors' clinical experience in the microsurgical treatment of these disorders.
      METHODS: In 47 patients affected by chylostatic disorders the diagnosis was based
      on the clinical history, physical examination, lymphoscintigraphy, lymphography,
      ultrasound, CT scanning and lymphangio-MR. In cases of chylous reflux towards the
      external genitalia or the lower limbs, the puncture of one of the lymphostatic
      verrucae which may be part of the symptomatology, can be sufficient for the
      clinical diagnosis. If patients suffer from hypoproteinaemia and/or an intestinal
      malabsorption syndrome, this should be dealt with to ensure them at least
      temporary metabolic compensation before surgical treatment, if any. In patients
      affected by chylous ascites, antigravitational ligatures of incompetent
      collectors, sometimes associated with lymphovenous shunts, can be a therapeutic
      solution. RESULTS: We have found that CO2 laser irradiation at very low power
      achieved full section closure of lymphatic and chylous vessels as complete as if
      they had been tied. In the case of chyloedema of the external genitalia and of/or
      the lower limbs, reductive plastic treatment completes the result after
      antigravitational ligatures and derivative microsurgery. CONCLUSIONS: A laser
      microsurgical technique used to manage chylous reflux pathologies achieved
      positive and permanent results, especially after an accurate preoperative
      diagnostic study to determine the site and nature of the lymphatic and chylous
      leakage and associated disorders.

PMID- 10392476
TI  - Lymphoedema: modern diagnostic and therapeutic aspects.
AB  - The author reports his clinical experience regarding the diagnostic assessment of
      patients with lymphedema and the selection criteria for those assigned to
      microsurgery. Patients were classified according to aetiology and stages and
      sites of the lymphedema and underwent a diagnostic protocol consisting of
      lymphoscintigraphy, lymphography (in selected cases), Doppler venous flowmetry
      and manometry, lymphangio-RM and, in the case of angiodysplasias, phlebography
      and arteriography. This protocol is essential in deciding the appropriate
      microsurgical technique in those selected for surgery, whether derivative lympho
      venous anastomosis or reconstructive lymphatic-venous-lymphatic plasty. The
      results of surgery were assessed both clinically (with the aid of photographs,
      water volumetry and measurements of limb circumference) and by
      lymphangioscintigraphy, and were classified as marked, moderate or mild
      regression of oedema. The overall results were very encouraging, particularly
      those of patients in the earlier stages of the condition. With regard to
      secondary prevention, early diagnosis plays an important role as does the
      identification of patients at high risk for the onset of lymphostatic disease
      after oncological lymphadenectomies, especially when associated with
      radiotherapy. In such cases, in order to combat right from the outset those
      lymphedemas which, based on statistical probability, are expected to show
      unrelenting progression if untreated, early microsurgery is a reasonable option.

PMID- 10392477
TI  - Diagnostic and interventional imaging of lymphatic disorders.
AB  - During the past several years, technological innovations in nuclear diagnostics
      and computer imaging have rekindled enthusiasm for visualising the lymphatic
      system in peripheral lymphoedema and related disorders of lymph flow. Isotope
      lymphography or lymphangioscintigraphy has now largely replaced conventional
      (direct) oil-contrast lymphography for evaluating lymphatic dysplasia as it is
      much simpler, safe, repeatable, and provides both structural and functional
      detail of the lymphatic system. Magnetic resonance imaging (MRI), alone or in
      combination with superparamagnetic contrast agents (lymphangiomagnetograms) or
      fat subtraction (suppression) has the potential to yield further dividends in
      understanding a variety of enigmatic oedematous states including lymphoedema.
      Other imaging techniques of promise include ultrasonography (primarily for
      filariasis), fluorescent microangiolymphography, and intradermal brominated
      fluorocarbon (primarily for lymph nodes). Not only can these readily non-invasive
      imaging techniques be used to monitor and document the efficacy of treatments
      designed to remedy defective lymph transport and function, but in certain
      conditions (e.g., chylous reflux syndrome), they can be employed to obliterate
      incompetent lymphangiectatic/lymphangiomatous truncal elements through sclerosis
      using percutaneous computer-guided catheters.

PMID- 10392478
TI  - Benzo-pyrones in the treatment of lymphoedema.
AB  - Fifty clinical trials of 4 benzo-pyrones in the treatment of lymphoedema, by over
      37 authors in 8 countries, are reviewed: 38 oral and 12 topical (11 and 6 of
      these, added to other therapies). Oral benzo-pyrones reduced oedema, symptoms (in
      almost all) and inflammation (SAI). These were significant and clinically
      important. There were no significant differences between arms and Grades 1 and 2
      legs. Combining these 20 trials gave mean annual reductions of 55% of oedema (SE:
      7.8%; 95% Confidence Interval: 40% to 71%) (p<0.001). Four trials of elephantitic
      legs gave 17% (4.8%; 7.6% to 27%), significantly less (p<0.01). Meta-analyses,
      tested by omitting non-double-blind or non-peer-reviewed trials, were robust. The
      greater the oedema, the greater the rate of reduction-lessening as time passed
      and the oedema reduced: annual reduction=37%x(79%) Period (p=0.01). Reductions
      varied with the molar dose (p=10(-8)): =0.10% (SE 0.013%) Dose (mg of coumarin or
      molar equivalent of other drugs). Topical coumarin also reduced oedema and
      symptoms. The results of some other therapies were improved by oral or topical
      benzo-pyrones 15% to 22% over a month and 0% to 78% over a year. These drugs are
      slow, but effective, cheap and convenient. Because of their slowness, compression
      garments are unnecessary. They were seldom used in trials. Side-effects are
      minimal. Only oral coumarin may cause idiosyncratic hepatitis (3 per 1,000).
      Topical coumarin does not, nor other benzo-pyrones.

PMID- 10392479
TI  - Principles of surgical treatment of chronic lymphoedema.
AB  - Lymphoedema, refractory to non-operative management, may require surgical
      treatment. Potential indications include impaired limb function, recurrent
      episodes of cellulitis and lymphangitis, intractable pain, lymphangiosarcoma and
      cosmesis (patient unwilling to undergo more conservative treatment and willing to
      proceed even with experimental operations). The principle of excisional
      operations is to remove excess tissue to decrease volume of the extremity. Good
      reduction can be achieved with staged resection of the subcutaneous tissue, with
      resection of the excess skin and using the remainder for coverage. However,
      prolonged hospitalization, poor wound healing, long surgical scars, sensory nerve
      loss, residual oedema of the foot and ankle and poor cosmetic results can be
      significant problems and prevent offering such procedures short of a large and
      truly disabling lymphoedema, not responding to medical measures. Physiologic
      operations have been aimed at restoring lymphatic transport capacity, most
      frequently with lymphovenous anastomoses or lymphatic grafting. Chylous reflux
      due to valvular incompetence has been treated effectively by ligation and
      excision of retroperitoneal lymphatics, with or without lymphovenous anastomoses.
      Lymphovenous anastomoses operations for obstructive lymphoedema have been
      performed for several decades, but their use continues to be controversial. Such
      reconstructions can be indicated in a subset of patients who have proximal
      obstruction with preserved or dilated lymphatics distally. While few groups have
      reported good late clinical results, direct confirmation of long-term patency of
      lymphovenous anastomoses in patients is unavailable. Lymphatic grafting is a
      promising operation, but it requires true microsurgical expertise and commitment
      to treat this frequently frustrating and difficult disease. Long-term patency
      rates associated with documented clinical improvement have to be reported in
      larger number of patients, operated on in more than one centre before this
      operation can be recommended for treatment as an alternative to conservative
      measures. The large number of individual surgical techniques of physiological and
      excisional operations that are practiced today worldwide to treat lymphoedema
      continues to be testimony to our frustration in dealing with this difficult
      problem.

PMID- 10392480
TI  - Role of microsurgery in the management of lymphoedema.
AB  - BACKGROUND: Microsurgical techniques in the treatment of peripheral lymphoedema
      proved to be very promising, the authors' clinical experience with derivative and
      reconstructive lymphatic microsurgical operations was analysed. METHODS: From
      1973 to 1997, 843 patients were studied and treated by microsurgical methods,
      with average follow-up of over 5 years. Microsurgical techniques mostly consisted
      of derivative lymphatic-venous or lymphatic-capsule-venous anastomoses and
      reconstructive autologous vein interpositioned grafts (lymphatic-venous-lymphatic
      plasty). Ninety percent of patients were operated on at the II-III stage, 3% at
      the I and 7% at the IV-V stage. Limb volumes were measured using the water
      displacement technique and lymphoscintigraphy was used to accurately assess the
      structural and functional status of the lymphatic drainage before and after
      variable distances of time after microsurgery. More recently, also lymphangio-MR
      was used to accurately evaluate changes in the lymphoedematous extremity before
      and after treatment. RESULTS: Postoperatively, all the patients had a reduction
      of oedema variable above all according to the stage of the pathology at the time
      of microsurgical operation. Short and long-term results were positive, as
      concerns both volumetric oedema reduction and arm function, besides the
      regression of annual incidence of acute lymphangites. The efficacy of
      microsurgical lymphatic operations has been verified, moreover, by
      lymphoscintigraphy. CONCLUSIONS: Microsurgical techniques permit, today, the
      solution of complex clinical patterns not only of secondary but also of primary,
      unilateral and bilateral, lymphoedemas, at different stages, with better results
      the more precocious the microsurgical treatment is, with stabilization of the
      result also at long distance of time from operation.

PMID- 10392481
TI  - Impaired results of a randomised double blinded clinical trial of propranolol
      versus placebo on the expansion rate of small abdominal aortic aneurysms.
AB  - BACKGROUND: To study the propranolol treatment of small abdominal aortic
      aneurysms (AAA) concerning intention to treat, side effects, and inhibition of
      expansion. METHODS:  DESIGN: Two-year lasting prospective randomised double
      blinded intervention trial. SETTING: Hospital-based mass screening for AAA with
      annual ambulatory control of small AAA. PARTICIPANTS: Of 122 screening-diagnosed
      small AAA, 51 (42%) were excluded because of contraindications or present beta
      blockage, and 17 refused participation. Thus, 54 (44.3%) were included.
      INTERVENTION: Participants were randomised to 40 mg propranolol twice a day or
      placebo. MEASURES: The same observed was used to follow-up AAA-expansion, side
      effects, quality of life (QL), branchial and ankle blood pressure (ABI), and
      pulmonary function (FEV1 and FVC). RESULTS: Sixty percent in the propranolol
      group, and 25% in the placebo group dropped out, mainly caused by dyspnoea in the
      propranolol group (RR=1.74, 95% C.I.: 1.06-2.86). Five (16.7%) died in the
      propranolol group, while 1 (4.2%) died in the placebo group (RR=1.6 (1.02-2.51)).
      Furthermore, decreased pulmonary function, ABI, and QL was noticed in the
      propranolol group. Consequently, the trial was stopped after two years. Ninety
      five percent of the measurements of the AAA were measured within 2 mm variation.
      If expansion was defined as above 2 mm annually, the relative risk of expansion
      in the placebo group was 1.17 (0.74-1.85), and 2.44 (0.88-6.77) among the non
      drop-outs. CONCLUSIONS: Only 22% of small screenings-diagnosed AAA were treatable
      with propranolol for two years. Consequently, only large scale studies are
      capable of showing potential minor inhibition of expansion by propranolol.
      However, whether such treatment ever becomes ethically acceptable is debatable.

PMID- 10392482
TI  - Factors affecting the long-term outcome of Buerger's disease (thromboangiitis
      obliterans).
AB  - BACKGROUND: Although the age at onset in patients with Buerger's disease is
      relatively young, the life expectancy has been seldom reported in detail. The aim
      of this study is to study long-term results of Buerger's disease and factors
      affecting the ultimate outcome. METHODS: From 1965 to 1980, 682 patients with
      Buerger's disease were treated in our outpatient department. We studied their
      long-term status, including concomitant diseases, and the disease progression by
      mail. RESULTS: Of the 287 mail responders, 266 were male and 21 were female, with
      a mean age of 60 years. One hundred and fifty-five of these patients are
      currently suffering from clinical symptoms. Forty-eight patients underwent minor
      amputation and 30 and major amputation. Forty-six patients underwent
      sympathectomy, and only 17 bypass reconstruction. Although there was no
      significant difference in the continuation of symptoms between current smokers
      and ex-smokers, the amputation rate was higher in current smokers and continuous
      smoking is closely related to both minor and major amputations after
      sympathectomy and to minor amputations after drug therapy. Arteriosclerotic
      diseases were recognized in 57 patients, and gastroduodenal ulcer in 44. Thirty
      three patients had died. Among 14 who died of neoplasm, three died of esophageal
      cancer and lung cancer, respectively, which were closely related to smoking.
      CONCLUSIONS: The natural history of the limbs in patients with Buerger's disease
      is not completely discouraging, and in order to obtain a favourable outcome for
      patients with Buerger's disease we recommend complete smoking cessation with drug
      therapy and surveillance for neoplasm, especially of the upper gastrointestinal
      tract and lung.

PMID- 10392483
TI  - Thrombocytosis after prophylactic administration of enoxaparin: unexpected
      findings in a Polish prospective multicenter trial on the efficacy and safety of
      enoxaparin in the prevention of postoperative thromboembolism.
AB  - BACKGROUND: Heparin-related thrombocytopenia is a common complication of heparin
      administration and therefore platelet count was monitored in our study. METHODS: 
      EXPERIMENTAL DESIGN: Prospective multicentre study. SETTING: 14 Departments of
      General, Thoracic or OrthopaedicSurgery, Poland. PATIENTS: 290 patients--150
      general or thoracic surgery patients aged above 40 years, and 140 orthopaedic
      surgery patients aged between 18 and 60 years. INTERVENTIONS: All patients
      received 20 mg (general and thoracic surgery) or 40 mg of enoxaparin (orthopaedic
      surgery) once daily subcutaneously both before surgery and during postoperative
      immobilisation. MEASURES: Platelet count was evaluated prior to surgery and on
      the 5th, 7th, 11th and 15th day following the operation. RESULTS: There was
      neither thrombocytopenia nor heparin-induced thrombosis. Paradoxically,
      postoperative platelet count in most cases increased slightly but statistically
      significantly, but in some however, even above 600 G/l, nevertheless in these
      patients no thrombotic complications occurred. Postoperative thrombocytosis was
      greater in patients with neoplasms as well as those with excessive perioperative
      blood loss and transfusions. CONCLUSIONS: As platelet count was not the main
      topic of our study, the presented data should be regarded only as preliminary.
      Further investigations to resolve the cause of the observed phenomenon of
      thrombocytosis are therefore necessary.

PMID- 10392484
TI  - Sleep apnoea syndrome and the extent of atherosclerotic lesions in middle-aged
      men with myocardial infarction.
AB  - BACKGROUND: To determine whether extended atherosclerotic lesions are correlated
      to the presence of sleep breathing disorders. METHODS:  EXPERIMENTAL DESIGN: A
      prospective clinical study. SETTING: A tertiary regional referral center.
      PATIENTS: 40 male patients < or =65 years consecutively admitted to the cardiac
      care unit for an acute myocardial infarction with serous creatinine phosphokinase
      (CPK) > or =350 IU/l and a CPK-MB fraction > or =10%. Exclusion criteria were:
      cardiac surgery on emergency, stroke, major neurological and/or psychiatric
      disturbances, alcohol consumption >50 g/day, toxicomania, clinical or biological
      hypothyroidism, clinical acromegaly and chronic obstructive pulmonary disease.
      MEASURES: Duplex ultrasonography was performed on carotid arteries, femoral
      arteries and their bifurcations. An overnight polysomnography was performed after
      hospital discharge. Patients with an apnoea index >5/hour or apnoea-hypopnea
      index >10/hour of sleep are considered to have sleep apnoea syndrome (SAS).
      Patients with additive peripheral atherosclerotic lesions are compared to
      patients with normal carotid and femoral arteries, regarding to standard
      cardiovascular risk factors and apnoeas or hypopnoeas during sleep. RESULTS:
      Duplex revealed in 18 patients carotid and/or femoral atherosclerotic lesions.
      The prevalence of SAS in patients with at least one peripheral arterial lesion
      was significantly higher (61% vs 18%, p<0.01). A nearly significant difference
      was also noted in patients with carotid lesions alone compared to those with
      normal carotid arteries (57% vs 27%, p=0.06). CONCLUSIONS: These results suggest
      a possible link between sleep breathing disorders and the pathogenesis of
      atherosclerotic lesions.

PMID- 10392485
TI  - Popliteal venous aneurysm mimicking a soft tissue tumour. A case report.
AB  - A case of a giant, thrombosed popliteal venous aneurysm without pulmonary
      embolism in a 53-year-old woman is reported. Despite thorough preoperative
      investigation including ultrasound and magnetic resonance imaging, this was
      misdiagnosed as a benign soft tissue tumour. During the operation the thrombosed
      venous aneurysm was resected and a vein graft from the contralateral saphenous
      vein was interposed. Popliteal venous aneurysm is a rare entity, presenting
      occasionally with local signs and symptoms and more often with pulmonary
      embolism. The clinician should therefore keep this in mind whenever dealing with
      a large, soft tissue popliteal fossa mass or looking for the cause of recurrent
      pulmonary embolism.

PMID- 10392486
TI  - Plasma endothelin-1 concentrations in non-insulin-dependent diabetes mellitus and
      nondiabetic patients with chronic arterial obstructive disease of the lower
      limbs.

PMID- 10392487
TI  - Is atopic dermatitis predictable?
AB  - Atopic dermatitis (AD) is a common skin disease which affects 10 to 20% of the
      population, usually with onset during infancy. The frequency of AD appears to
      have increased over the past three decades. Attempts to identify parameters
      predictive of the development of AD have been made by many investigators during
      the last decades. Although genetic factors remain unmodifiable, avoidance of
      relevant trigger factors could modify the development of AD. This paper reviews
      and discusses findings of the last several years and outlines recent advances in
      genetic studies of AD. In spite of decades of intensive research and newly
      developed technology, the parental history of AD appears to be the most valuable
      predictive parameter. However, the predictive capacity is not sufficient to
      recommend it as screening instrument. At this time, a perinatal screening with
      the objective of primary prevention of AD does not seem feasible.

PMID- 10392488
TI  - Is allergy prevention realistic and beneficial?
AB  - Allergic diseases among children have shown a marked increase during the last two
      or three decades, despite increased awareness of possible preventive measures.
      Preventive efforts have focused on new-borns and infants with a biparental
      history of allergy as they are at particularly high risk of developing allergic
      disease (40-60%). No good intervention studies have been performed in the general
      population, only in high-risk families. Unfortunately, so far known risk factors
      can only explain a small part of the recent increase in allergic diseases. The
      most important recommendation for everyone is not to smoke during pregnancy and
      when living/working with young children. Breast milk is the best for every baby,
      even from an immunologic aspect. Humidity problems should be reduced in homes,
      day-care centres and schools. It is probably wise not to keep furred pets indoors
      in homes when babies have a family history of allergy. However, the effect of
      such advice should be assessed, including the acceptability, compliance, costs
      and effectiveness. There is no doubt that we should go on with preventive
      measures both in babies at high risk of allergy and also in the general
      population. At the same time, research should try to find even more efficient
      ways to reduce the current "allergy epidemic".

PMID- 10392489
TI  - Atopic eczema: how to tackle the most common atopic symptom.
AB  - The disease management of atopic eczema includes topical and systemic treatments
      as well as the control of allergic and non-allergic trigger factors. The basis
      for topical treatment is the regular use of emollients. In addition, anti
      inflammatory treatment with -- preferably mild -- topical steroids is the
      treatment of choice. At least-one third of the children with atopic eczema during
      the first years suffer from clinically relevant food allergy requiring
      elimination diets for at least one or two years. The most common cause of
      superinfection is Staphylococcus aureus. Recent data suggests that it may induce
      purulent superinfection as well as enhance the inflammatory process by
      superantigen mediated T-cell activation. Also, a number of alternative treatment
      strategies have been investigated during the last decade: the use of gamma
      linoleic acid has been shown to be of limited benefit, while studies on
      interferon-gamma and on high-dose intravenous gamma-globulin are still anecdotal.
      The long-term effectiveness of disease management in atopic eczema depends
      largely on the understanding of the disease process as well as on the compliance
      of the parents. Thus, coping with the problem will be easier if the patient or
      the parents have been educated in understanding the pathogenesis, the role of
      trigger factors, the possibilities of prevention and the different treatment
      strategies.

PMID- 10392490
TI  - Indications for shunt insertion or III ventriculostomy in hydrocephalic children,
      guided by lumbar and intraventricular infusion tests.
AB  - The best therapeutic management for infantile hydrocephalus is not always
      obvious. Traditionally, shunt insertion has been performed when CSF dynamics have
      been considered abnormal. However, in cases of noncommunicating hydrocephalus
      endoscopic III ventriculostomy (ETV) has become a well-established treatment
      modality, but despite clinical and radiological information clinical improvement
      is not obtained in all cases. A reliable preoperative investigative procedure
      helping to select hydrocephalic children for ETV, shunt insertion or no
      operation, is urgently needed. We report three cases of infantile hydrocephalus,
      in which our operative management was guided by the results of cerebrospinal
      (CSF) infusion tests. With a lumbar infusion test we assessed the CSF resorption
      capacity, and thus whether shunting was indicated. Comparing the results with
      those of an intraventricular infusion test, we assessed the presence of any
      structural blockage of the CSF circulation between the ventricles and the
      subarachnoid compartment, which would indicate a possible effect of an ETV.
      Performance of both a lumbar infusion test and a subsequent intraventricular
      infusion test in hydrocephalic children seems to provide valuable information for
      the decision-making on surgery.

PMID- 10392491
TI  - Gliomatosis cerebri with neurofibromatosis: an autopsy-proven case.
AB  - Gliomatosis cerebri is a glial neoplastic process that is diffusely distributed
      through neural structures, whose anatomical configuration remains intact. Among
      the more than 19,000 cases hospitalized in Istanbul University Istanbul School of
      Medicine Department of Neurosurgery throughout the past 45 years, only 2 cases
      were diagnosed as gliomatosis cerebri, 1 by stereotactic ante-mortem diagnosis
      and the other after autopsy. In this paper, the autopsy-proven case of this rare
      disease with coexistent neurofibromatosis--the sixth case reported in the
      literature--is presented.

PMID- 10392492
TI  - Diffuse brain stem tumor in an adolescent with multiple enchondromatosis
      (Ollier's disease).
AB  - Among patients with enchondromatosis, those with Ollier's disease are usually
      considered to be at a lower risk for extra-osseous malignancy than those with
      Maffucci's disease. However, several reports suggest that Ollier's disease may
      also be associated with gliomas. We report here the youngest patient in the
      literature (16 years) to be detected with a brain tumor and Ollier's disease.
      This is also the first case with diffuse brain stem involvement. Thus,
      counselling of patients with Ollier's disease may become more difficult than
      initially thought.

PMID- 10392493
TI  - Fibrinolytic agents in the management of posthemorrhagic hydrocephalus in preterm
      infants: the evidence.
AB  - The objective of this study was to review current literature on the management of
      posthemorrhagic hydrocephalus in preterm infants with intraventricular
      administration of fibrinolytic agents; to this end a literature search was
      carried out electronically. The keywords used were "intraventricular hemorrhage"
      or "posthemorrhagic hydrocephalus" in combination with "fibrinolytic agent,"
      "urokinase," "streptokinase," or "recombinant tissue plasminogen activator" and
      "intraventricular administration"; the search covered the years 1966-1998 and was
      restricted to English language papers and human subjects. It was supplemented by
      a search through the reference lists of the articles identified. Articles dealing
      with intracerebral hemorrhage or hematoma, intraventricular hemorrhage in adults,
      nontherapeutic issues and laboratory research were excluded. The articles
      included are summarized in evidence and evaluation tables. Five scientific
      publications evaluating the use of a fibrinolytic agent to manage posthemorrhagic
      hydrocephalus were retrieved. In the studies described in these reports, a total
      of 62 neonates received streptokinase, urokinase or r-tPA intraventricularly. No
      two of the regimens were identical in the drug used, method of administration and
      duration of therapy. The time before therapy was started ranged from 2 to 35 days
      after the ictus. Among the case series reported, three were small series with a
      total of 38 neonates. One other case series of 18 neonates compared the treatment
      group with an historical control group. All case series showed that
      endoventricular fibrinolytic therapy was practical. The proportion of cases in
      which shunt placement was performed ranged from 11% to 100%. Only one small
      prospective, randomized, controlled study was identified. That study was too
      small to allow useful conclusions. Overall, 3 cases of secondary intraventricular
      hemorrhage were reported. However, it was not possible to determine with
      certainty whether these episodes were related to the drug therapy itself. The
      reports suffer from inadequate study design, lack of descriptive information and
      short follow-up period. There is insufficient evidence to justify the claim that
      fibrinolytic agents administered intraventricularly in posthemorrhagic
      hydrocephalus are safe and effective. More evidence is needed to prove or
      disprove the effectiveness and safety of this form of therapy.

PMID- 10392494
TI  - Diffuse brain stem glioma. A review of stereotactic biopsies.
AB  - The diagnosis and management of diffuse brain stem gliomas (DBSGs) remain a
      challenging problem for the neurosurgeon and neuro-oncologist. Opposing views on
      the necessity for biopsy have emerged over the last decade. Open biopsy, with its
      prohibitive morbidity and mortality, has been replaced by stereotactically guided
      biopsy, with markedly reduced risk. This has been paralleled by improvements in
      imaging techniques and diagnostic accuracy, which has created reluctance to
      endorse diagnostic biopsies coupled with the potential of nonrepresentative
      samples from a heterogeneous tumour mass. For typical DBSGs biopsy is now
      accepted as unnecessary. We performed a retrospective analysis of radiologically
      and histologically proven DBSGs in 18 children to assess both morbidity and
      reliability of our stereotactically guided biopsy procedure.

PMID- 10392495
TI  - Evaluation of shunt function in hydrocephalic patients with the radionuclide
      99mTc-pertechnetate.
AB  - In most cases of shunted hydrocephalus, shunt malfunction is evaluated by
      clinical examination and neuro-imaging. However if there is a discrepancy between
      neurological examination and imaging, additional shuntography can be helpful in
      the evaluation of the shunt function. In our clinic, radionuclide-imaging
      shuntography using (99m)technetium-pertechnetate was performed in 85 children
      between 1992 and 1995. The results of shuntography were evaluated visually and
      from time-activity curves. Shuntography had a sensitivity of 96%, a specificity
      of 89%, and an accuracy of 93%, proved either by surgery or by clinical follow-up
      for 2-5 years. Corresponding to these results, we recommend the use of
      shuntography in cases with an uncertain shunt function before surgical revision.

PMID- 10392496
TI  - Adjustable antisiphon shunt.
AB  - Overdrainage from siphoning, a result of negative distal pressure, has been a
      major problem with the existing differential pressure shunt devices. The
      antisiphon/siphon control devices used to reduce siphoning often malfunction
      owing to fibrous scar formation around the valve. Similarly, the functioning of
      gravity-actuated systems is adversely affected by body movements. Constant flow
      shunt systems may not be superior to existing differential pressure valves, as
      has been shown in a recent multicenter study. In view of these difficulties, we
      investigated the possibility of developing a shunt valve based on the Starling
      resistor concept of flow regulation that allows proximal pressure-dependent and
      distal pressure-independent flow. The valve designed is capable of proximal
      pressure-dependent and distal pressure-independent flow. The valve allows for
      adjustable negative pressure in the vertical position.

PMID- 10392497
TI  - A new experimental model of obstructive hydrocephalus in the rat: the micro
      balloon technique.
AB  - We used three types of specialized micro-balloons 0.7-1.35 mm in outer diameter
      instead of kaolin to develop a reproducible rat model of hydrocephalus with a low
      experimental mortality. The micro-balloon was inserted 6 mm deep into the
      cisterna magna via a burr hole immediately behind the lambda. The angle of
      introduction was 50 degrees. We also set up kaolin-induced hydrocephalic models
      in 25 rats as controls. The kaolin model revealed 52% mortality with an 80%
      induction rate of hydrocephalus, while the balloon model showed 9% mortality with
      a 60% induction rate. Balloon-induced hydrocephalus was maximal at 1 week and
      tended to decrease after 2-3 weeks. The pathological findings were not different
      between the two models. We concluded that the micro-balloon model for
      hydrocephalus is an easily reproducible model with low experimental mortality.

PMID- 10392498
TI  - Stereotactic neurosurgery in children and adolescents.
AB  - Between March 1992 and January 1998, 100 stereotactic procedures were carried out
      in our Stereotactic Department. Of these, 24 were performed on patients under 18
      years of age, 22 of them under a local anaesthetic and sedation. The ages of
      these patients ranged between 4 months and 18 years. The stereotactic procedures
      carried out were: 15 cerebral biopsies, 5 iodine-125 implants, 4 implantations of
      Rickham reservoirs with ventricular catheter, with additional holes to establish
      a connection between the cyst content and the ventricular system (internal
      drainage): 2 of these patients had arachnoidal cysts in the pineal region, 1 a
      thalamic neuroepithelial cyst and 1 a cystic craniopharyngioma, with excellent
      control of hydrocephalus. All cerebral biopsies were positive, including 3 in
      which brain stem tumours were detected. Of the 5 patients treated by
      brachytherapy, 4 had pilocytic astrocytomas and 1 an anaplastic astrocytoma. The
      sites of the tumours for which implants were used were the thalamus in 4 cases,
      and the basal ganglia (corpus striatum) in 1. In only 2 cases was there some
      transistory morbidity, and mortality was nil. The stereotactic procedures in this
      varied group were well tolerated, with low morbidity and mortality rates, which
      proves that this method is effective and safe for patients. It can also be used
      for the diagnosis of brain stem tumours. Midline cysts can also be treated by
      means of internal drainage with catheters (a minimally invasive form of surgery).

PMID- 10392499
TI  - Childhood intracranial arteriovenous malformation in Saudi Arabia.
AB  - Twenty-three patients in whom intracranial arteriovenous malformation (ICAVM)
      occurred while they were in the pediatric age group (16 years or less) were
      identified. The patients had presented to three major centers in Saudi Arabia
      (King Fahad Hospital of the University, King Faisal Specialist Hospital and
      Research Center, and Riyadh Military Hospital). The incidence of ICAVM in Saudi
      Arabia is estimated. ICAVM in the pediatric age group accounts for 7.72% of all
      ICAVM cases. Most of the pediatric patients presented with intracranial bleeding,
      and seizure was the only other mode of presentation. Spontaneous changes
      involving ICAVM occurred in 4 children, in the form of either increase or
      decrease in size or new vascularization. Most children had higher grade ICAVM and
      the morbidity rate was higher than in adults. The cure rate was 50% with
      different therapeutic modalities. This report represents the first study to
      provide the hospital-based frequency of pediatric ICAVM in Saudi Arabia.

PMID- 10392500
TI  - Surgery or conservative treatment in children with traumatic intracerebral
      haematoma.
AB  - In contrast to the case of extracerebral haematomas, the criteria for operative
      treatment of traumatic intracerebral haematoma (TIH) are not clear. The purpose
      of this study was to find factors that would be helpful in reaching a decision
      for surgical or conservative treatment of TIH. We performed a retrospective
      analysis of 31 consecutive cases of TIH treated in our department. The following
      factors were estimated: age, mechanism of injury, initial GCS or CCS score,
      neurological deficits, coexistence of arterial hypotension and respiratory
      disturbances, and localisation and size of the haematoma. The outcome was
      evaluated according to a modified GOS. Treatment was surgical for 20 patients and
      conservative for 11. Patients with GCS or CCS scores of 3-8 were treated
      surgically significantly more often than those with higher scores. The other
      factors did not correlate with type of treatment. It seems, then, that the
      clinical status of the patient, especially the level of consciousness according
      to the GCS or CCS score, is the most important predictor of the need for surgery
      in children with TIH.

PMID- 10392501
TI  - Rathke's cleft cyst as a cause of growth hormone deficiency and micropenis.
AB  - Rathke's cleft cyst has rarely been reported in pediatric patients, and such
      cysts are usually found by chance, in 2-33% of routine necropsies, as they have
      not interfered with pituitary function. In general, they are intrasellar with a
      single layer of ciliated cuboidal or columnar epithelium containing mucoid
      material. The age range in which symptomatic Rathke's cleft cysts occur is
      between 30 and 60 years. This paper reports an 8.1-year-old boy presenting with
      growth hormone deficiency and micropenis attributable to hypogonadotropic
      hypogonadism (HH), implying altered pituitary function since intrauterine life.
      At this age (before puberty) the diagnosis of HH can be made by means of the LHRH
      agonist stimulation test, since conventional LHRH is not able to discriminate HH
      from a normal prepubertal child. To our knowledge, this is the first case of
      micropenis caused by Rathke's cleft cyst interfering with gonadotropin and growth
      hormone secretion since intrauterine life.

PMID- 10392502
TI  - Unusually prolonged survival and childhood-onset epilepsy in a case of alobar
      holoprosencephaly.
AB  - Alobar holoprosencephaly is one of the most severe congenital malformations of
      the central nervous system. Most affected infants are stillborn or have a very
      short life-span. The survivors can present with neonatal seizures and/or
      infantile spasms. We report on an unusually long-lived patient with alobar
      holoprosencephaly and minor facial dysmorphism, who developed generalized
      epilepsy during childhood.

PMID- 10392504
TI  - Dynamic neutralisation of the lumbar spine confirmed on a new lumbar spine
      simulator in vitro.
AB  - A new dynamic neutralisation system for lumbar spine segments has been developed
      and tested on four cadaveric lumbar spines. Segments L4/5 (3 cases) and L3/4 (1
      case) were tested on a new lumbar spine simulator which allowed the simultaneous
      application of bending moments, compressive and shear loads. The average applied
      loads were 18.3 Nm flexion moment, 2296 N compressive and 458 N anterior shear
      load for flexion, and 12.5 Nm extension moment, 667 N compressive and 74 N
      posterior shear load for extension. The relative motion of the upper vertebra in
      respect to the lower vertebra was measured with the three-dimensional FASTRAK
      system, using an advanced computer software. The endplate centres as well as the
      centre of the screw heads were taken as reference points, identified by
      orthogonally taken radiographs. The dynamic neutralisation system described
      reduces bending angles and horizontal translations, but it expands vertical
      translations. The bulging of the posterior annulus is also reduced.

PMID- 10392503
TI  - Large-dose ascorbic acid administration suppresses the development of arthritis
      in adjuvant-infected rats.
AB  - We performed animal experiments to test the hypothesis that active oxygen species
      (AOS) play a major role in adjuvant-induced arthritis in rats and to determine
      whether large-dose ascorbic acid administration would suppress the development of
      arthritis, reducing the level of damaging AOS in the same animal model. Arthritis
      was induced in male Lewis rats by adjuvant injection into the base of the tail.
      Ascorbic acid at doses of 0.5, 1.0, and 2.0 g/kg body weight (BW) was injected
      intraperitoneally twice each week for 3 weeks (9 rats per group). The BW, hind
      paw edema, and arthritis score of the extremities were monitored during the
      period. On day 21, synovial tissues obtained from the ankle joints were examined
      histologically and for the activity of superoxide dismutase (SOD). The SOD
      activity in the red blood cells (RBC) was also measured. The arthritic control
      rats showed significant increases in paw volume and arthritis score from day 11.
      These changes were dose-dependently reduced by ascorbic acid administration. The
      infiltration of inflammatory cells into the synovial tissues was markedly
      decreased by ascorbic acid. The increases in SOD activities produced by the
      adjuvant injection were significantly reduced in both the synovium and the RBC at
      ascorbic acid doses of 1.0 and 2.0 g/kg BW. In conclusion, large-dose ascorbic
      acid administration reduced the increases in hind paw inflammatory edema,
      arthritis in the extremities, and infiltration of the inflammatory cells into the
      synovial tissue in the adjuvant-induced arthritis rats. Since these anti
      arthritic effects were associated with a decrease in SOD activities in both the
      synovium and RBC, the decrease in SOD activity could be one of the mechanisms
      underlying the suppressive effects of large-dose ascorbic acid on the development
      of arthritis in this animal model, inhibiting the damaging AOS.

PMID- 10392505
TI  - Shear strength of the cement metal interface--an experimental study.
AB  - The shear strength of the cement-metal interface using rods with different
      surface treatments and a clinical standardized cementing technique was studied.
      Under "dry" conditions, a low interface shear strength can be obtained with
      polished and smooth CoCrMo surfaces (peak-to-valley height Rt: 1 microm, average
      0.2 MPa; 5 microm, 0.38 MPa). Grit-blasted and polymethylmethacrylate (PMMA)
      precoated surfaces achieved higher values (PMMA precoat: average 5.16 MPa; CoCrMo
      peak-to-valley height Rt: 20 microm, average 8.61 MPa: 60 microm, average 7.8
      MPa). After immersion in physiological saline solution for 60 days, the PMMA
      precoated rods kept their initial stability whereas all the other test rods had
      lost their stability completely. A microscopic analysis of cross-sections
      revealed gap formations at the cement-metal interface to varying degrees (1-16
      microm). PMMA-precoated rods rarely showed any gap formation at all. The above
      mentioned gap formation was seen independently of the porosity at the cement
      metal interface and corresponds to the clinical and postmortem observed debonding
      of the interface.

PMID- 10392506
TI  - Beneficial effect of basic fibroblast growth factor on the repair of full
      thickness defects in rabbit articular cartilage.
AB  - The effects of exogenous basic fibroblast growth factor (bFGF) on the repair of
      full-thickness cartilage defects were examined. Four-millimeter diameter,
      cylindrical defects were made in rabbit articular cartilage and were filled with
      human recombinant bFGF. The addition of bFGF to the defect induced the formation
      of a thick cartilage layer composed of chondrocytes and a metachromatic-stained
      matrix after 6 weeks. The score of the bFGF-treated tissue, as evaluated by a
      semiquantitative histological scale, was significantly higher than that of the
      untreated tissue. At 24 weeks, the cartilage-like matrix that contained the
      proteoglycans and type II collagen was thicker in the bFGF-treated tissue than in
      the untreated tissue. Immunohistochemical analysis of the tissues at 6-12 weeks
      with an anti-bFGF monoclonal antibody suggested that a single application of bFGF
      increased the number of differentiating chondrocytes that synthesized bFGF at a
      high level. In contrast, immunostaining of the tissues at 6-12 weeks with a
      monoclonal antibody against proliferating cell nuclear antigen showed that the
      number of proliferating cells in the bFGF-treated tissue was fewer than in the
      untreated tissue. These findings suggest that administration of bFGF into
      cartilagenous defects promotes the differentiation of chondrocytes and their
      matrix synthesis, and that this growth factor is useful for improving cartilage
      repair.

PMID- 10392507
TI  - Relevance of the drainage along the linea aspera for the reduction of fat
      embolism during cemented total hip arthroplasty. A prospective, randomized
      clinical trial.
AB  - The aim of this study was to assess the relevance of drainage placed along the
      linea aspera for the prevention of fat embolism and cardiopulmonary impairment
      during the insertion of a cemented stem. We studied 40 patients with coxarthrosis
      randomly allocated to total hip arthroplasty with proximal drainage or without
      it. The venting hole for the drainage of the medullary cavity was placed
      posteriorly, between the greater and the smaller trochanter, in the prolongation
      of the linea aspera. The heart was monitored intraoperatively by a
      echocardiography probe positioned in the patient's oesophagus. During the
      operation we monitored the hemodynamics and blood gas values. Severe embolic
      events were observed in 85% of the control group and in 20% of the drainage group
      (P = 0.01). Embolism occurred during the insertion of the femoral component and
      continued after reduction of the hip joint. After major embolism, the pulmonary
      shunt values increased significantly in the control group (+22.7%), but there
      were no marked changes in the drainage group (+7.1%). The logical therapeutic
      measure to avoid intravasation of bone marrow, fat, and bone debris during the
      insertion of the femoral component is to prevent the rise of intraosseous
      pressure. The drainage of the venous system located along the linea aspera
      significantly reduces the risk of intraoperative embolism and cardiopulmonary
      impairment.

PMID- 10392508
TI  - Surgical excision of heterotopic bone after hip surgery followed by oral
      indomethacin application: is there a clinical benefit for the patient?
AB  - The clinical effect of surgical excision of heterotopic bone after hip surgery in
      combination with an oral indomethacin application was analysed in 21 patients in
      a retrospective study. Indomethacin (3 x 50 mg) was administered after the first
      postoperative day for a period of 6 weeks. To avoid gastrointestinal side
      effects, a mucoprotectivum (sucralfat, 3 x 1 g) was also applied. One year after
      surgery, 19 patients (90.4%) had excellent relief of pain, the average
      improvement of flexion was 40 degrees, of abduction 13 degrees, of internal
      rotation 8 degrees and of external rotation 14 degrees. Only one patient (4.8%)
      suffered a recurrence of heterotopic bone formation, and in one patient (4.8%) we
      observed gastrointestinal side-effects. Thus, we recommend surgical excision of
      heterotopic bone followed by oral indomethacin therapy as a convenient and
      reliable strategy to prevent new heterotopic bone formation after hip surgery.

PMID- 10392509
TI  - Deep vein thrombosis in elderly Hong Kong Chinese with hip fractures detected
      with compression ultrasound and Doppler imaging: incidence and effect of low
      molecular weight heparin.
AB  - Seventy-eight patients of average age 78 years suffering from an unilateral non
      pathological hip fracture underwent compression ultrasound and pulsed and colour
      Doppler examination of both legs. Twenty-three patients were randomly placed on
      low molecular weight heparin (LMWH). Twenty-nine (37%) suffered deep venous
      thrombosis (DVT). There was no statistically significant difference in the
      incidence of DVT between the control and LMWH groups, and the incidence of DVT in
      elderly Chinese patients after hip replacement for a hip fracture is similar to
      that in other studies in Caucasians. There were, however, some differences,
      namely the contiguous nature of the thrombi rather than focal segmental clots,
      and the absence of propagation or tail formation. Although the numbers are small,
      this could possibly represent a population difference. There was a significantly
      increased occurrence of DVTs on the operated side in both groups. Serial
      ultrasound examination supports evidence that DVTs occur in the 1st week
      postoperatively, but there were also a number of patients who developed DVTs in
      the 2nd week. There was no statistically significant difference in overall
      incidence of DVT between patients on prophylactic heparin and the control group.
      Patients on prophylactic heparin had no thigh DVTs in comparison to the control
      group. LMWH may thus be effective in preventing thigh DVTs and pulmonary emboli.

PMID- 10392510
TI  - Aneurysmal bone cysts of the spine.
AB  - Thirteen patients with aneurysmal bone cyst of the spine (excluding sacral
      lesions) were retrospectively reviewed. Treatment for aneurysmal bone cysts
      remains controversial, but surgical resection, irradiation, and embolization are
      common treatment modalities for those involving the spine. Of 102 patients with
      aneurysmal bone cysts, 15 had a lesion of the spine, including 2 sacral cases. Of
      the 13 patients with a lesion of the thoracic or lumbar spine, 9 underwent
      resection of the lesion, 2 curettage and cementation, and 2 only currettage.
      Eleven patients underwent segmental arthrodesis with instrumentation after
      treatment of the primary or recurrent lesion, while 2 patients underwent
      segmental arthrodesis using autogeneic bone. Nine patients did not develop a
      local recurrence after resection of the lesion. However, the 2 patients who
      underwent curettage alone developed local recurrences. None of 4 patients
      developed recurrences after curettage and cementation. After recurrence, 1
      patient underwent additional resection with irradiation, and 1 patient underwent
      resection alone. At the final follow-up, all lesions were under control. In one
      patient, lumbar kyphosis developed after segmental arthrodesis with
      instrumentation, and arthrodesis was performed again. Radical resection of
      aneurysmal bone cysts of the spine with instrumentation is the optimal method of
      acquiring a high degree of local control and preventing spinal deformity.

PMID- 10392511
TI  - Combined sciatic and femoral nerve block for knee arthroscopy: 4 years'
      experience.
AB  - Selective block of the femoral and sciatic nerves was performed on 601 patients
      undergoing knee arthroscopy. The results were good in 87%, adequate in 12%, and
      poor in 1%. The whole knee surface was covered by the nerve blockade. The
      duration of anesthesia was 152 +/- 21 min and that of analgesia, was 336 +/- 18
      min. No correlation was observed between the effectiveness of the anesthesia and
      type of surgery performed. The technique described thus proved adequate for knee
      arthroscopic surgery, reproducibility was excellent, costs and hospital stays
      were reduced with respect to general anesthesia, and surgeon and patient
      satisfaction was high.

PMID- 10392512
TI  - Postoperative ossifications of the shoulder. Incidence and clinical impact.
AB  - Periarticular ossifications of the shoulder after surgery have been described
      since the beginning of the century. Risk factors and the clinical impact of
      heterotopic bone formation have been discussed controversially. After open
      surgery on the shoulder, 131 patients (rotator cuff repair n = 106, acromioplasty
      n = 25) were included in a retrospective study if pre- and postoperative X-rays
      were available. The age of the 90 men and 41 women averaged 51 years (range 29-67
      years). The minimum follow-up was 2 years. Also, 108 patients were interviewed by
      questionnaire to estimate the subjective outcome of the procedure (5 patients
      were reported dead). A clinical examination was carried out on 86 patients using
      the Constant score for evaluation of the objective outcome. Heterotopic
      ossifications were found in 35 cases (26.7%), 28 of them after rotator cuff
      reconstruction and 7 after acromioplasty. A good to excellent result was reported
      by 89% (n = 65) of the patients without and by 80% (n = 28) of the patients with
      ossifications. The Constant score averaged 69 points and 74 points (n = 60),
      respectively. A significant difference between the two collectives could not be
      calculated. As significant risk factors for the formation of heterotopic bone,
      the existence of osteoarthritis and the duration and complexity of the procedure
      could be cited. The appearance of periarticular ossifications after surgery of
      the shoulder seems to be of minor clinical impact. Severe cases with major
      functional deficits should and can be prevented by a fast and atraumatic
      operation technique.

PMID- 10392513
TI  - Combined Kirschner wire fixation in the treatment of Colles fracture. A
      prospective, controlled trial.
AB  - For surgical treatment of the unstable Colles fracture we developed a new form of
      osteosynthesis, which consists in a modification of the dynamic Kirschner wire
      fixation described by Kapandji. It allows early motion without the typical risk
      of palmar dislocation noted with the Kapandji method. We prefer this method in
      elderly patients with reduced bone quality. The analysis of a collective of 110
      fractures including a clinical and radiological follow-up examination of 72
      patients revealed good anatomical reconstruction of the distal radius. The loss
      of motion was minimal on average and consistent with a good wrist function. Major
      restrictions resulted from stress-dependent pain as a consequence of
      posttraumatic arthritis or algodystrophy. A minor loss of reduction by dorsal
      impaction was observed in the follow-up evaluation, but it had no functional
      relevance. The most frequent complication was paraesthesia within the area of the
      superficial radial nerve. According to the NYOH score the following results were
      achieved: excellent 35%, good 50%, fair 10%, poor 5%.

PMID- 10392514
TI  - Ipsilateral fractures of the pelvis and the femur--floating hip? A retrospective
      analysis of 42 cases.
AB  - A consecutive series of 40 patients, who sustained 42 ipsilateral pelvic and
      femoral fractures, is reported. There were eight (26.6%) traumatic neurological
      deficits and three open femoral fractures. Two multiply injured patients died in
      the postraumatic period because of the severity of their injuries. No associated
      vascular injuries could be identified. All but two fractures of the femur, 8 of
      the 15 fractures of the pelvic ring and 17 of the 30 fractures of the acetabulum
      were treated by internal fixation. In 26 patients internal fixation was performed
      on both fracture components (in 17 patients this was done under the same period
      of anaesthesia). Postoperatively, a deep venous thrombosis in three patients, one
      deep wound infection and five (18.5%) iatrogenic neurological deficits had to be
      notified. In this series we could not identify any specific associated injuries
      and complications as known for the floating knee or the floating elbow. The term
      floating hip is inprecise and misleading, and its use is not recommended. The
      treatment of this fracture-combination follows the guidelines established for the
      individual lesions.

PMID- 10392516
TI  - The Salter innominate osteotomy for the treatment of developmental dysplasia of
      the hip in young adults.
AB  - The results were evaluated for 29 adult patients (33 hips) who had undergone a
      Salter innominate osteotomy because of painful developmental dysplasia of the hip
      (DDH). The mean age at the time of the index operation was 24.8 years (range 19
      35 years), and the mean duration of follow-up was 3.5 years (range 2-8 years).
      Complications included one non-union and one dislocation of the osteotomy after a
      fall; both patients had to undergo re-operation. The mean Harris hip score
      improved from 65 points preoperatively to 82 points at the latest follow-up
      examination. In hips with no coxarthrosis (n = 11), the mean Harris hip score
      improved from 78 points to 89 points; in hips with coxarthrosis grade 1 (n = 15),
      it improved from 59 points to 85 points, while in hips with coxarthrosis grade 2
      (n = 7), it improved only from 57 to 68 points. There was a diminution of
      coxarthrosis in 11 hips, no change in 17, and worsening in 5 hips. The mean
      center-edge angle of Wiberg was 11.2 deg (range 0-19 deg) preoperatively compared
      with 27.4 deg (range 21-37.5 deg) postoperatively and 27.6 deg at the latest
      follow-up examination. Our findings demonstrate that the Salter innominate
      osteotomy provides clinical improvement as well as radiographic improvement in
      adult patients with DDH, and this procedure is, compared with more complex pelvic
      osteotomies, a relatively simple and safe procedure with a low risk of
      complications.

PMID- 10392515
TI  - No effective prophylaxis of heterotopic ossification with short-term ibuprofen.
AB  - Ninety-five patients underwent primary total hip arthroplasty and routinely
      received ibuprofen for 5 days as prophylaxis for heterotopic ossification. This
      group was compared with a group of 99 patients who received indomethacin for 7
      days as prophylaxis. After a follow-up of 1 year, the incidence of heterotopic
      ossification in the ibuprofen group was significantly higher than in the
      indomethacin group. The widespread ossification, Brooker grades III and IV, was
      prevented better by indomethacin than by ibuprofen. We conclude that ibuprofen
      for 5 days is not effective as prophylaxis for heterotopic ossification after
      primary total hip arthroplasty.

PMID- 10392517
TI  - Metacarpophalangeal joint arthroplasty in rheumatoid arthritis: results of
      Swanson implants and digital joint operative arthroplasty.
AB  - We discuss 69 metacarpophalangeal (MP) implant arthroplasties performed in 30
      patients with rheumatoid arthritis. The follow-up averaged 5 years. We studied 19
      finger joint prostheses by Condamine, digital joint operative arthroplasty
      (stabilized version; DJOA) and 50 flexible silicone Swanson implants. We used a
      new comprehensive scoring system to evaluate the MP alloarthroplasties. Such a
      scoring system incorporates clinical and radiological data. The outcome following
      MP joint replacement with DJOA was never evaluated as 'good'; in 11 joints the
      result was 'fair', and in 8 joints, 'poor'. As regards MP arthroplasty with
      Swanson implants, the results were evaluated as 'good' in 40 joints, as 'fair' in
      10 joints, and in none as 'poor'. In our series, DJOA did not provide stability
      in arthritic MP joints. In all joints replaced with DJOA, dislocation of the
      articulating surfaces and signs of loosening were present. We regard three
      factors as being the main causes contributing to the poor outcome of DJOA when
      used as MP replacements. Firstly, the proximal prosthetic component is poorly
      matched to the anatomical shape of the metacarpal bone (conisation of the bone).
      Secondly, adequate coaptation cannot be achieved with this prosthetic design,
      even in the presence of extensive soft-tissue reconstruction. Thirdly, the use of
      polyethylene in MP joint replacements is questionable. In contrast, the silicone
      Swanson implants in our series provided superior results when used as MP implants
      in the rheumatoid hand.

PMID- 10392518
TI  - Immune responses to osteoarticular allografts of the knee--cytokine studies.
AB  - Immunological behaviour in correlation with bone allograft survival was studied
      in peripheral blood and synovial fluid from seven patients who had undergone
      large bone resection and allograft transplantation of the knee. Plasma and
      synovial fluid samples for cytokine measurements [interleukin (IL-1beta, IL-6)
      and tumour necrosis factor alpha (TNF-alpha)] were drawn from peripheral blood
      for diagnostic arthrocentesis. Two patients were monitored using consecutive
      sampling up to 12 months postoperatively. Graft survival was considered
      excellent, but local or diffuse resorption and also fatigue fractures were seen.
      These findings show that soluble products of T-cell, macrophage and osteoblast
      origin, produced as a response to the bone-graft antigens, might be responsible
      for the bone resorption seen in our material. The elevated IL-1beta and TNF-alpha
      levels detected support this statement.

PMID- 10392519
TI  - Functional results after partial pelvic resection in Ewing's sarcoma of the
      ilium.
AB  - Ewing's sarcoma of the pelvis has an unfavourable prognosis. The clinical and
      functional results of 7 patients who had a Ewing's sarcoma of the pelvis stage
      IIB were reviewed. All patients received multiple-agent chemotherapy pre- and
      postoperatively (modified T6 and T2 protocol according to Rosen) and underwent
      local resection of the pelvic tumour. According to Enneking, five patients had a
      type IA resection, one patient type I and another type IIA. One patient received
      a course of radiation therapy postoperatively (50 Gy). Six of seven patients
      showed a good regression of the tumour after preoperative chemotherapy. One
      patient who had a giant-cell Ewing's sarcoma died of local recurrence and lung
      metastases 29 months postoperatively. The remaining six patients were monitored
      radiographically and clinically according to Enneking's functional evaluation
      score after a follow-up period of 136 months (range 40-199 months). All were free
      of disease and had neither local recurrence nor metastases. In five patients the
      functional results were rated as "good" or "excellent". The good results depend
      mainly on the reconstruction of the pelvic girdle and its mechanical stability.

PMID- 10392520
TI  - C-reactive protein as an early indicator of the formation of heterotopic
      ossifications after total hip replacement.
AB  - The formation of heterotopic ossifications after total hip endoprosthesis
      implantation is a well-known complication. During the postoperative course
      laboratory parameters are subject to partial change due to the development of
      heterotopic ossifications. However, these changes occur relatively late at a time
      when the application of prophylactic precautions is usually already decided. Any
      meaningful prophylactic treatment, however, has to be initiated immediately after
      surgery. In a prospective study we assessed the postoperative C-reactive protein
      (CRP) levels in 95 patients twice after total hip replacement surgery. The
      initial assessment took place on the 1st day following surgery and again between
      the 5th and 7th day. All patients received three doses of 50 mg diclofenac daily
      for 7 days starting on the 1st postoperative day. Average CRP values on the 1st
      postoperative day were 6.33 +/- 2.28 mg/dl for ossification grade Brooker 0, 7.04
      +/- 1.8 mg/l for Brooker 1 and 7.65 +/- 3.7 mg/dl for Brooker grades 2-4. At the
      time of the second CRP assessment (postoperative day 5-7), CRP values in the
      groups of patients showing ossifications were higher. Whereas patients without
      ossifications (A) exhibited an average level of 4.22 +/- 3.13 mg/dl, in patients
      with ossification grade 1 (B) CRP was 5.57 +/- 2.78 mg/dl and in the group with
      ossification grades 2-4 (C) was 6.38 +/- 4.48 mg/dl. The differences between
      group A on the one hand and the combined groups B and C values on the other were
      significant (P = 0.036). We are able to assert that after total hip replacement,
      significantly higher CRP levels can be recorded immediately after surgery in
      those patients who will eventually develop heterotopic ossifications, as compared
      with those who do not. Hence, the postoperative rise of CRP levels should be
      introduced as a further risk factor for the formation of heterotopic
      ossifications since its recording at such an early stage still allows for the
      timely initiation of prophylactic treatment.

PMID- 10392521
TI  - Weight-based heparin dosing is more effective in the treatment of postoperative
      deep vein thrombosis.
AB  - Rapid clinical diagnosis and adequate treatment are the major determinants of
      successful therapy of deep vein thrombosis (DVT). In the initial treatment of
      DVT, heparin is the anticoagulant of choice. Appropriate heparin dosing is of
      major interest concerning the onset of therapeutic anticoagulation and, thus, the
      clinical outcome of the patients. This study was designed to compare a weight
      based heparin nomogram with a standard heparin nomogram for the treatment of DVT
      in orthopaedic patients. Forty patients in two groups were included in the study.
      In group one (patients treated with the weight-based heparin nomogram) the
      therapeutic range (partial thromboplastin time 1.5-2.3 times the control) was
      reached on average within 24 h (75% of the patients); 95% of the patients reached
      the therapeutic range within 48 h. In group two (patients treated with the
      standard heparin nomogram) the therapeutic range was reached on average within 48
      h (60%; 30% of the patients reached the therapeutic range within 24 h). The used
      weight-based heparin nomogram has proved to be effective, safe and superior to
      one based on standard practice concerning the time elapsed between initial
      heparin therapy and achieving the therapeutic range for intravenous
      anticoagulation.

PMID- 10392522
TI  - Collagen type I metabolism after bone surgery.
AB  - This study follows the postoperative course of serum collagen type I metabolites
      in patients after uncomplicated implantation of a cemented total hip
      endoprothesis (TEP; n = 12, mean age: 69.3 years), a cemented hemiendoprothesis
      (HEP; n = 13, mean age 79.7 years), a dynamic condylar or hip screw (DCS/DHS; n =
      12, mean age 75.1 years) and osteosynthetic treatment of a Weber B or C fracture
      (OS; n = 17, mean age 54.3 years). The course of the propeptide of human type I
      procollagen (PICP) as an anabolic marker as well as of I-carboxyterminal
      telopeptide (ICTP) as a catabolic marker of bone metabolism was characterized.
      Measurements were done preoperatively and weekly for 3 weeks after surgery. The
      concentrations of both markers increased and reached a maximum in the 2nd or 3rd
      week after surgery. However, the PICP values differed, depending on the kind of
      surgical intervention and the type of bone healing. Secondary fracture healing
      with formation of callus occurred in the DCS/DHS group, which developed the
      highest median PICP concentrations (initial 83 microg/l, second week 337
      microg/l; P < 0.001). In contrast, the primary bone healing in the OS group
      showed increasing ICTP but unchanged PICP concentrations. Patients in the
      cemented TEP and HEP groups as a kind of artificial bone healing had comparable
      concentrations. To consider the effective metabolism of collagen type I, the
      PICP/ICTP ratio was calculated. Although the median PICP and ICTP concentrations
      of the studied groups differed, the PICP/ICTP ratios were similar. In comparison
      to 54 young and healthy volunteers (median PICP/ICTP ratio: 37), the ratios of
      the studied groups were still normal but low (median ratios: < 20). This could be
      an effect of decreasing collagen type I metabolism with age. Although the results
      are in agreement with animal studies and histomorphometric investigations, the
      clinical use of PICP and ICTP determination as a tool for the detection of
      complicated bone healing is limited by the marked interindividual variability and
      the uncertain bone specificity.

PMID- 10392523
TI  - Structural properties of the fibular band in congenital total absence of the
      fibula.
AB  - Nine children with unilateral total congenital absence of the fibula were
      examined by magnetic resonance imaging (MRI), and histological study of the
      fibular band was performed in four of them. Both examinations revealed two types
      of fibular band. In type I, it was identical to fibula on MRI appearance, and
      histological studies revealed hyaline cartilage in the area of the lateral
      malleolus. In this type partial excision of the band allowed the foot to be
      corrected. In type II, the band directly attached to the calcaneus without any
      evidence of hyaline cartilage, and the feet could be corrected only by total
      excision. We suggest partial excision of the band in type I and total excision in
      type II as the initial treatment of congenital total absence of the fibula.

PMID- 10392524
TI  - Substitution of tibial bony defects with allogeneic and autogeneic cancellous
      bone: encouraging preliminary results in 18 knee replacements.
AB  - Eighteen knee replacements in 15 patients with severe gonarthritis or loosening
      of total knee arthroplasty (TKA) requiring bone grafting for bony deficiencies
      were studied before and after operation. The average follow-up was 2.4 years.
      Fifteen knees showed satisfactory clinical and radiographic results of the
      integration of the bone grafts. The Hospital for Special Surgery knee score
      improved from an average of 39 points preoperatively to 83 points at the most
      recent follow-up examination. Two of 3 knees with loosening of the tibial
      component required revision. These results are encouraging. Success depends as
      much on rigid fixation of the grafted bone and protected weight-bearing as on
      rigid, micromotion-preventing fixation of the tibial component.

PMID- 10392525
TI  - Acute arterial occlusion associated with total knee arthroplasty.
AB  - Acute arterial occlusion is a rare but limb-threatening complication in total
      knee arthroplasty. Most of the previously reported cases of this complication
      required surgical intervention. This report illustrates an unusual case of this
      complication that was managed conservatively with an acceptable outcome. The case
      is also indicative of the etiology and the optimal prevention of this
      complication. In a patient with advanced arteriosclerosis, as indicated by
      vascular calcification around the knee or in the abdomen, knee arthroplasty
      should be performed without a tourniquet, and intra-operative manipulation should
      be done cautiously because of the potential for intimal disruption.

PMID- 10392526
TI  - Giant trichoblastoma mimicking malignancy.
AB  - We report a case of giant trichoblastoma, a rare benign hair germ tumor. A 73
      year-old man presented with a soft-tissue mass on his upper arm. Magnetic
      resonance imaging analysis revealed an unique mosaic pattern on T2-weighted
      images. Needle biopsy disclosed a keratinizing tumor suggesting squamous cell
      carcinoma. The size of the tumor was 9.5 x 7 x 9.5 cm, one of the largest
      trichoblastomas ever reported. The rarity and gigantic size of the tumor,
      together with its misleading clinical features, prompted us to report our case.

PMID- 10392527
TI  - Reconstructive treatment of sclerosing osteomyelitis of the entire femur of 30
      years' duration with avoidance of segmental resection.
AB  - We describe the successful operative treatment of a patient with chronic
      sclerosing osteomyelitis of the femur in which en bloc resection was avoided.
      Therapy consisted of combined endoscopic, computed tomography and bone scan
      guided fenestration and intramedullary reaming, with removal of all sclerotic
      zones and normalization of the cortical thickness. An adequate supply of oxygen
      to the area was ensured by improved vascularisation and the application of
      hydrogen peroxide. At the medium term follow-up no recurrence was seen, and hip
      and knee function was normal.

PMID- 10392528
TI  - Loss of correction after lateral closing wedge high tibial osteotomy--a human
      cadaver study.
AB  - In 12 human cadaver tibiae, osteotomies were carried out at two levels (2 and 3
      cm from the distal joint line) with three different wedges (5 degrees, 10
      degrees, 15 degrees) to evaluate the influence of displacement of the osteotomy
      fragments on areas of cortical contact. In undisplaced osteotomies (medical
      cortical edges superposed) cortical contact areas formed 28% (level 2 cm) and
      40.5% (level 3 cm) of the cortical circumference of the proximal fragments (NS).
      Wedge angles and levels of osteotomy displayed no statistical differences. In
      displaced osteotomies cortical contact decreased significantly (P < 0.05).
      Displacing the distal fragment laterally, medial cortical contact is lost, and
      weight-bearing leads to revarisation as cancellous bone sustains only 3 MPa, and
      the measured compressive stresses at the medial edge amounted to 6 MPa on
      average. Displacing the distal fragment medially leads to a decrease of total
      cortical contact, too, but at the medial edge of the osteotomy cortical contact
      areas are still present. As a result of the study, postoperative weight-bearing
      without additional plaster cast fixation is recommended only in cases with
      undisplaced fragments.

PMID- 10392529
TI  - Primary biomechanical influence of different sterilization methods on a freeze
      dried bone-ligament transplant.
AB  - The transmission of bacteria and viruses in ligament transplants should be
      prevented by sterilization. In this study, the influence of two different methods
      on the mechanical properties of a freeze-dried medial collateral ligament was
      analyzed in sheep. Group I (n = 10) was treated with irradiation (26 kGy) and
      group II (n = 10) with ethyleneoxide. The mechanical properties changed in
      respect of the maximal load: group I (-29.9%; P < 0.05), group II (-7.7%),
      elongation: group I (-6.6%), group II (-0.3%), stress: group I (-20.1%), group II
      (-6.8%), strain: group I (-0.64%), group II (-0.3%), stiffness: group I (-10.2%),
      group II (-10.5%), energy: group I (-31.4%), group II (-6.9%) and elastic
      modulus: group I (-1.3%), group II (-5.0%). The irradiation dose significantly
      reduced the maximal load, whereas ethyleneoxide sterilization resulted only in
      minor changes. Because of the potential cancerogenity of ethyleneoxide, a close
      monitoring of aeration times and its residuals are very essential. Further
      studies with lower irradiation doses of between 15 and 26 kGy seem to be
      justified.

PMID- 10392530
TI  - Neglected rupture of the patellar tendon.
AB  - Neglected rupture of the patellar tendon is a rare but well recognised
      complication of knee trauma. We present the case of a 43-year-old man who
      sustained a complete rupture of the patellar tendon of his left knee following a
      fall. Clinical diagnosis was delayed by 2 months and was confirmed by magnetic
      resonance imaging. Treatment began with skeletal patellar traction and was
      followed by late reconstruction of the patellar tendon and transfer of the
      gracilis and semitendonosus tendons supplemented by figure-of-eight tension band
      wiring.

PMID- 10392531
TI  - The duration of the effects of a single administration of dopamine antagonists on
      ambulatory activity and motor coordination.
AB  - Pimozide, cis(Z)-flupenthixol, SCH 23390 and sulpiride were administered to male
      rats. Each subject received a single drug injection, and tests for ambulatory
      activity and motor coordination were performed 1, 24, 48 and 72 hrs later. All
      drugs reduced ambulatory activity at the test 1 hr postinjection. Pimozide and
      SCH 23390 continued to reduce ambulatory activity at the test 24 hrs after
      injection. All drugs impaired motor coordination 1 hr after injection and, with
      the exception of SCH 23390, were also effective at the 24 hrs test. Flupenthixol,
      2 mg/kg, continued to impair motor coordination also at the 48 hrs test. These
      data show that effects of dopamine antagonists on motor functions may persist for
      much longer than is generally believed. That should be important to take into
      account in experimental designs where repeated drug administration is employed.

PMID- 10392532
TI  - Acute and chronic changes in kynurenate formation following an intrastriatal
      quinolinate injection in rats.
AB  - Intrastriatal injection of the endogenous excitotoxin quinolinate in experimental
      animals causes a lesion which duplicates many features of Huntington's disease
      (HD). This lesion can be prevented by a related metabolite, kynurenate. Since
      kynurenate levels are reduced in the HD neostriatum, a deficiency in brain
      kynurenate may be the cause of neuron loss in HD. In order to investigate the
      relationship between excitotoxic neurodegeneration and kynurenate formation,
      effects of a unilateral quinolinate injection on several measures of kynurenate
      metabolism were studied in the rat striatum and substantia nigra. Within 2 hours,
      quinolinate caused an approximately 100% increase in striatal kynurenate levels
      in the absence of changes in its bioprecursor L-kynurenine or its biosynthetic
      enzymes kynurenine aminotransferases (KATs) I and II. This increase was more
      dramatic after 2 days (+735%) and was accompanied by an increase in L-kynurenine
      (+182%). No change or a slight decrease in enzyme activities were detected at
      this time-point. More chronic excitotoxic lesions produced a substantial increase
      in kynurenate levels (by approximately 2-, 4- and 4-fold, respectively, after 7
      days, 1 and 5 months). Lesion-induced changes in KAT II activity essentially
      paralleled those seen with kynurenate, whereas KAT I remained slightly decreased
      at all timepoints. Nigral KAT II activity was increased ipsilaterally 2 days, 1
      and 5 months after the striatal quinolinate injection. Kinetic analyses,
      performed in the striatum 5 months after the quinolinate injection, showed an
      almost 3-fold decrease in Km values for KAT II in the absence of v(max) changes.
      These findings indicate that 1) different mechanisms regulate kynurenate
      production at different stages after an intrastriatal quinolinate injection; 2)
      an increased substrate affinity to KAT II is responsible for the elevation of
      kynurenate in the chronically lesioned rat striatum; and 3) qualitative
      differences in kynurenate metabolism exist between the HD neostriatum and the
      excitotoxin-lesioned rat striatum, supporting the idea that (a decrease in)
      kynurenate tone may play a primary role in the pathophysiology of HD.

PMID- 10392533
TI  - Discrepancy of benzodiazepine receptor occupancy between 3H-flumazenil and 125I
      iomazenil in intact mouse brain.
AB  - The in vivo benzodiazepine (BZ) receptor occupancy in mouse brain was measured by
      employing 3H-flumazenil (FMZ) in comparison with 125I-iomazenil (IMZ), in order
      to obtain fundamental data for PET and SPECT studies, respectively. Mice were
      pretreated with various doses of flunitrazepam (FNP) 40 min prior to the tracer
      injection. At 20 min after the tracer injection, mice were killed by decapitation
      and receptor occupancy in cerebral cortex, hippocampus, cerebellum and pons
      medulla were determined by the modified method reported by Goeders and Kuhar
      (1985). In all regions studied, BZ receptor occupancy by FNP measured with 3H-FMZ
      was significantly higher than that of 125I-IMZ. For instance, 0.1 mg/kg of FNP
      inhibited almost 50% of the specific binding of 3H-FMZ, on the other hand almost
      no inhibition of 125I-IMZ with the same dose of FNP was seen. This type of
      discrepancy was also observed in other types of benzodiazepine agonists,
      nimetazepam and triazolam, or inverse agonist ethyl-beta-carboline-3-carboxylate
      (CCE). It is of interest that in in vitro binding study using brain homogenate,
      almost the same competitive inhibition curve was observed between these two
      radioligands, which strongly suggested that discrepancy of receptor occupancy is
      likely observed in intact brain. The mechanism for such discrepancy is unknown,
      although the different kinetics properties of these two radioligand seems to be
      an important factor.

PMID- 10392535
TI  - Changes in extracellular LHRH and beta-endorphin-like immunoreactivity in the
      nucleus infundibularis-median eminence of anestrous ewes under stress condition.
AB  - To clarify the effect of beta-endorphin released under stress condition on LHRH
      secretion, the concentration of LHRH and beta-endorphin-like-immunoreactivity
      (beta-END-LI) were analysed in perfusates from the nucleus infundibularis-median
      eminence of anestrous ewes subjected to footshocks stimulation. The dynamics of
      LHRH and beta-END-LI release during time-course of footshocks stimuli was
      altered. A brief facilitatory influence of stress on LHRH and beta-END-LI release
      was observed at the beginning of the stimulation on the first and third day;
      however the peaks of beta-END-LI were delayed about half an hour in relation to
      LHRH. Than on the first day of the stimulation LHRH returned to the control value
      but on the third day it declined below the control levels. Prolonged stress had
      stimulatory effect on beta-END-LI secretion during first and third day. The
      presented results indicate that: 1) short stress activates LHRH and beta-END-LI
      release, 2) prolonged stress has stimulatory effect on beta-END-LI release but
      leads to suppression of LHRH release. It is suggested that stress-induced beta
      endorphin release may be one of the factors responsible for suppression of LHRH
      activity.

PMID- 10392534
TI  - Effect of calcium on the uptake of glutamate by synaptosomes: possible
      involvement of two different mechanisms.
AB  - The effects of Ca2+ on glutamate uptake by synaptosomes were investigated.
      Glutamate uptake was decreased in the absence of Ca2+ with 2 mM EGTA added to the
      medium. After a 8-min preincubation, the uptake reduced to the greatest extent
      (about 64% of the uptake measured in Ca2+ medium). According to the kinetic
      analysis, lack of Ca2+ resulted in a reduction of the Vmax for glutamate uptake.
      These results suggested external Ca2+ was necessary for the optimal uptake of
      glutamate. TTX, an inhibitor of the voltage-dependent Na+ channel, almost
      reversed the reduction of glutamate uptake, indicating that the uptake might be
      impaired via the partial activation of the voltage-dependent tetrodotoxin
      sensitive Na+ channel. On the other hand, glutamate uptake was decreased by
      trifluoperazine, a calmodulin antagonist, and KN-62, an inhibitor of
      Ca2+/calmodulin-dependent protein kinase II, implying that intrasynaptosomal Ca2+
      might also have a role in the uptake of glutamate, and Ca2+/calmodulin-dependent
      processes, such as Ca2+/calmodulin-dependent protein kinase II, might be involved
      in the modulation of glutamate transporter activity.

PMID- 10392536
TI  - Cholecystokinin peptides in cerebrospinal fluid: a study in healthy male subjects
      lumbar-punctured without preceding strict bed-rest.
AB  - In a recent study we analysed the concentrations of two forms of cholecystokinin
      (CCK), CCK-8S (sulphated) and CCK-4 in cerebrospinal fluid (CSF) obtained from 14
      healthy male volunteers lumbar-punctured after a minimum of eight hours of strict
      bed-rest. We have now lumbar-punctured another group of 14 healthy males, using
      the same procedure except for the requirement of strict bed-rest prior to
      puncture. In contrast to our previous study, the concentration of CCK-4 (but not
      CCK-8S) was significantly higher in the second CSF fraction (7-12 ml) than in the
      first one (0-6 ml). On using the concentration ratio between the second and first
      fraction, CCK-8S (but not CCK-4) correlated positively with the atmospheric
      pressure, which is in contrast to our previous study in which a significant
      negative correlation was found. When the lumbar CSF concentrations were expressed
      as the concentration per minute of tapping-time (an estimate of the mass flow),
      atmospheric pressure, age and the neuraxis distance in the lying position made
      significant contributions to the variance in CCK-8S. A significant positive
      correlation with atmospheric pressure was found for CCK-4. In conclusion, the
      results indicate that the question of strict bed-rest or not prior to lumbar
      puncture may have to be considered when interpreting data on lumbar CSF
      concentrations of CCK. A controlled study is warranted.

PMID- 10392537
TI  - Tolerance to a suprathreshold dose of L-Dopa in MPTP mice: effects of glutamate
      antagonists.
AB  - Three experiments were performed to study the development and manipulation of
      tolerance to a suprathreshold dose of L-Dopa (20 mg/kg, s.c.) in MPTP-treated and
      control (saline-injected) C57 Bl/6 mice. The motor activity reinstatement effect
      of this dose of L-Dopa upon MPTP-treated mouse behaviour deteriorated from the
      13th injection (Test Day 8) of L-Dopa onwards and reached basal level (i.e. no
      stimulatory effects of the drug) by the 16th administration (Test Day 10).
      Administration of L-Dopa to control mice reduced locomotor and rearing activity
      throughout the tolerance development period (Test Days 1-12) during the first
      hour after injection, and then increased locomotor activity during the second
      hour. The effects of combining either a noncompetitive, MK-801, or a competitive,
      CGP 40116, glutamate antagonist with L-Dopa, following tolerance development,
      were assessed in MPTP mice on the 23rd day of L-Dopa administration (Test Day
      13). MK-801 (0.1 mg/kg, s.c.) reinstated the locomotory and rearing behaviour
      induced by L-Dopa; CGP 40116 did so also to a greater extent in the dose range
      0.01 to 0.03 mg/kg. These results indicate that MPTP-treated mice continue to
      offer a useful parkinsonian model also for the examination of different aspects
      of the "wearing-off" phenomenon of L-Dopa tolerance and in particular the
      putative glutamatergic involvement. The clinical consequences may be far-reaching
      for the utility of L-Dopa in Parkinson's disease, whether the effects
      demonstrated be of a reinstatement or synergistic nature, once therapeutically
      adequate glutamate antagonists are more readily available.

PMID- 10392538
TI  - Exogenous levodopa is not toxic to elderly subjects with non-parkinsonian
      movement disorders: further clinical evidence.
AB  - We report three women between 80 and 87 years of age who had longstanding
      essential tremor. Due to an erroneous diagnosis of Parkinsonism they had received
      levodopa preparations for 13, 16 and 25 years, respectively, with cumulative
      levodopa equivalent doses of 18.0, 9.0, and 4.1 kg. The patients showed neither
      dyskinesias nor signs of Parkinsonism. These observations do not support a
      detrimental role of chronic levodopa exposure in elderly individuals with
      essential tremor.

PMID- 10392539
TI  - Cerebrospinal fluid levels of selenium in patients with Alzheimer's disease.
AB  - We compared CSF and serum selenium levels, measured by atomic absorption
      spectrophotometry, in 27 patients with Alzheimer's disease (AD) (13 females, 14
      males, mean +/- SD age 73.6 +/- 7.4 years) without major clinical signs of
      undernutrition, and 34 matched controls (18 females, 16 males, mean +/- SD age
      70.7 +/- 7.8 years). CSF and serum selenium levels did not differ significantly
      between AD-patient (11.4 +/- 7.8 ng/ml and 28.5 +/- 13.0 ng/ml, respectively) and
      control groups (13.3 +/- 7.0 ng/ml and 22.5 +/- 17.5 ng/ml). These values were
      not correlated with age, age at onset, duration of the disease, and scores of the
      MiniMental State Examination in the AD group. Weight and body mass index were
      significantly lower in AD patients than in controls. These results suggest that
      CSF selenium concentrations are apparently unrelated with the reported oxidative
      stress processes in patients with AD.

PMID- 10392540
TI  - The activity of the pentose phosphate pathway is increased in response to
      oxidative stress in Alzheimer's disease.
AB  - In order to assess the integrity of antioxidant enzymes in Alzheimer's disease,
      the activities of glutathione peroxidase, glutathione reductase and two enzymes
      of the pentose phosphate pathway (glucose-6-phosphate dehydrogenase and 6
      phosphonogluconate dehydrogenase) were determined in three regions of postmortem
      neocortex of controls and subjects with Alzheimer's disease. The activities of
      glutathione peroxidase and glutathione reductase were unaffected in Alzheimer's
      disease. By contrast, there was a selective increase in the activities of glucose
      6-phosphate dehydrogenase and 6-phosphonogluconate dehydrogenase in the inferior
      temporal cortex of Alzheimer subjects. These changes negatively correlated with
      the Fe2+/ascorbate-induced lipid peroxidation which (in a previous study of the
      same subjects) was also found to be selectively elevated in the inferior temporal
      cortex. Increased activity of the pentose phosphate pathway probably occurs in
      response to increased prooxidant activity since both glucose-6-phosphate and 6
      phosphonogluconate inhibited H2O2-induced lipid peroxidation in a concentration
      dependant fashion (IC50 = 504 +/- 105 microM and 88 +/- 12 microM, respectively).
      Together, these data suggest that not only is oxidative stress a feature of
      Alzheimer's disease, but also that it occurs because of increased prooxidant
      activity rather than a diminished antioxidant capacity.

PMID- 10392541
TI  - Stability of RNA transcripts in post-mortem psychiatric brains.
AB  - RNA isolated from frozen human post-mortem brain tissue was used for analysis of
      five gene products with a recently developed sensitive and competitive RT-PCR
      technique. Samples varying in post-mortem intervals up to four days from
      controls, schizophrenics and alcoholics were analyzed. Evaluation of three
      housekeeping genes, as well as Trk B and Trk C demonstrated that the levels of
      mRNA transcripts were stable in brain samples at all time periods (one to four
      days) examined. This observation demonstrates that this RT-PCR protocol is a
      sensitive and reliable method to study relative amounts of mRNAs. The overall
      stability of housekeeping transcripts implicates the value of post-mortem brain
      samples for differential gene expression studies.

PMID- 10392542
TI  - Sex differences, season of birth and platelet 5-HT levels in schizophrenic
      patients.
AB  - Similar occurrence of schizophrenia was observed in men and women independent of
      their season of birth. Platelet 5-HT concentration was determined in 116 healthy
      control subjects (61 male and 55 female) and 152 patients with schizophrenia (96
      male and 56 female). Platelet 5-HT concentration was significantly higher in male
      than in female healthy persons and schizophrenic patients. Male and female
      healthy subjects born in different seasons had similar platelet 5-HT
      concentrations, whereas schizophrenic patients with different birth-seasons had
      significantly different platelet 5-HT concentrations. The highest platelet 5-HT
      levels were observed in both male and female schizophrenic patients born in
      winter when compared to matched healthy controls. Male schizophrenic patients
      born in winter had higher platelet 5-HT levels than schizophrenic men born in
      spring and summer. Female schizophrenic patients born in winter had higher
      platelet 5-HT than schizophrenic women born in all other seasons. These results
      indicated sex differences in platelet 5-HT levels in healthy persons and
      schizophrenic patients. The relationship between season of the birth and platelet
      5-HT concentration observed only in schizophrenic patients added further support
      to the presumption that schizophrenia is connected with a disturbance in the
      central serotoninergic system.

PMID- 10392543
TI  - Multiple modes of inner hair cell stimulation.
AB  - Most current theories of cochlear mechanics assume that the pattern of cochlear
      partition vibration is simple, similar to that of a bending beam. Recent evidence
      suggests, however, that the vibration of the organ of Corti can be complex and
      that multiple vibrational modes may play an important role in cochlear
      transduction. Inner hair cell (IHC) and auditory nerve responses to pure tones
      can exhibit large phase shifts and complex response waveforms with increasing
      stimulus level. In contrast, the comparable basilar membrane (BM) responses are
      much less complex, exhibiting only small phase shifts and relatively sinusoidal
      waveforms. To reconcile the differences observed between the published BM data
      and the IHC data, we have recorded receptor potentials from IHCs and compared
      these waveform data to the output of two computational models: a traditional
      linear model where IHC excitation depends only on BM displacement and a new model
      that assumes that outer hair cell (OHC) force production provides the major
      mechanical input to the IHC along with two additional mechanical components.
      Comparisons of the output of the two models with the experimental data show that
      the new model is capable of reproducing the very complex voltage responses of the
      IHC recorded in vivo whereas the traditional model performed poorly.

PMID- 10392544
TI  - Reticular lamina vibrations in the apical turn of a living guinea pig cochlea.
AB  - The reticular lamina of the apical turn of a living guinea pig cochlea was viewed
      through the intact Reissner's membrane using a slit confocal microscope.
      Vibrations were measured at selected identified locations with a confocal
      heterodyne interferometer, in response to tones applied with an acoustic
      transducer coupled to the ear canal. The position coordinates of each location
      were recorded. Mechanical tuning curves were measured along a radial track at
      Hensen's cells, outer hair cells, inner hair cells and at the osseous spiral
      lamina, over a frequency range of 3 kHz, using five sound pressure levels (100,
      90, 80, 70 and 60 dB SPL). The carrier to noise ratio obtained throughout the
      experiments was high. The response shape at any measuring location was not found
      to change appreciably with signal level. The response shape also did not change
      significantly with the radial position on the reticular lamina. However, the
      response magnitude increased progressively from the inner hair cell to the
      Hensen's cell. The observed linearity of response at the fundamental frequency is
      explained by the presence of negative feed back in the apical turn of the
      cochlea.

PMID- 10392545
TI  - PET imaging of cochlear-implant and normal-hearing subjects listening to speech
      and nonspeech.
AB  - Functional neuroimaging with positron emission tomography (PET) was used to
      compare the brain activation patterns of normal-hearing (NH) with postlingually
      deaf, cochlear-implant (CI) subjects listening to speech and nonspeech signals.
      The speech stimuli were derived from test batteries for assessing speech
      perception performance of hearing-impaired subjects with different sensory aids.
      Subjects were scanned while passively listening to monaural (right ear) stimuli
      in five conditions: Silent Baseline, Word, Sentence, Time-reversed Sentence, and
      Multitalker Babble. Both groups showed bilateral activation in superior and
      middle temporal gyri to speech and backward speech. However, group differences
      were observed in the Sentence compared to Silence condition. CI subjects showed
      more activated foci in right temporal regions, where lateralized mechanisms for
      prosodic (pitch) processing have been well established; NH subjects showed a
      focus in the left inferior frontal gyrus (Brodmann's area 47), where semantic
      processing has been implicated. Multitalker Babble activated auditory temporal
      regions in the CI group only. Whereas NH listeners probably habituated to this
      multitalker babble, the CI listeners may be using a perceptual strategy that
      emphasizes 'coarse' coding to perceive this stimulus globally as speechlike. The
      group differences provide the first neuroimaging evidence suggesting that
      postlingually deaf CI and NH subjects may engage differing perceptual processing
      strategies under certain speech conditions.

PMID- 10392546
TI  - The effect of quinine on outer hair cell shape, compliance and force.
AB  - Quinine intoxication causes a well-described syndrome that includes tinnitus,
      sensorineural hearing loss and vertigo. The pathophysiology of quinine's effects
      on hearing is unknown, but may include a peripheral component. The cochlear outer
      hair cell is known to be motile and to contribute force to amplify the vibration
      pattern of the organ of Corti. The outer hair cell is also a target of diseases
      involving tinnitus and sensorineural hearing loss, including salicylate
      intoxication. These effects may be mediated through changes either in motile
      force or in mechanical properties. Quinine's effects on outer hair cell motility
      and mechanical properties have therefore been examined in vitro. Quinine at 5.0
      mM substantially decreased active force generation in isolated guinea pig
      cochlear outer hair cells. Isolated cells also elongated and dilated in diameter
      when exposed to 5.0 mM quinine. No consistent changes in mechanical properties
      were observed. 1.0 mM quinine was ineffective in either force reduction or
      elongation. Trifluoperazine, a calmodulin inhibitor, and ML-9, a blocker of
      myosin light chain kinases, were ineffective in blocking quinine-induced force
      reduction or elongation. Deferoxamine, a hydroxyl free radical scavenger, also
      failed to block either the force decrease or the elongation.

PMID- 10392547
TI  - Cisplatin ototoxicity in developing gerbils.
AB  - This experimental study was undertaken to investigate the dose-related effect of
      cisplatin exposure in young gerbils (2 weeks of age) and explore the relationship
      between different methods used to monitor auditory function after exposure to
      cisplatin. Four groups of animals, including a control group, were used. The
      treatment groups, D1 (n = 6), D2 (n = 7) and D3 (n = 6), received one, two, and
      three doses of cisplatin (5 mg/kg/dose), respectively, at weekly intervals.
      Treated animals were first exposed to cisplatin at 2 weeks of age. Distortion
      product otoacoustic emissions (DPOAE) and auditory brainstem responses (ABR) were
      measured in treated and control animals at 6 weeks of age. The effects of dose
      and frequency on the DPOAE amplitude, as well as the relationship between the
      DPOAE and the ABR thresholds were analyzed. Animals in the D1 and D3 groups
      demonstrated significant elevation of DPOAE and ABR thresholds. Interestingly,
      animals in the D2 group demonstrated a bimodal distribution of DPOAE and ABR
      responses, with four animals severely affected and three not showing an effect. A
      tendency for a bimodal distribution of DPOAE and ABR responses was also observed
      in the D1 group, at frequencies below 8 kHz.

PMID- 10392548
TI  - Reduction in excitability of the auditory nerve following electrical stimulation
      at high stimulus rates. IV. Effects of stimulus intensity.
AB  - High rate intracochlear electrical stimulation using stimulus intensities well
      above clinical limits can induce a significant reduction in the excitability of
      the auditory nerve as measured by a reduction in the amplitude of the
      electrically evoked auditory brainstem response (EABR). The purpose of the
      present study was to assess the effect of stimulus intensity on these stimulus
      induced changes by comparing the effects of acute stimulation using stimulus
      intensities within normal clinical levels (6 dB and 12 dB above EABR threshold)
      and significantly above normal clinical levels (> 20 dB above EABR threshold;
      0.34 microC/phase). Stimulus rates of 200, 400, or 1000 pulses/s (pps) were
      delivered to bipolar scala tympani electrodes. EABRs were recorded before and
      periodically following 2 h of continuous stimulation. No reduction in EABR
      amplitude was observed following stimulation at 6 dB above EABR threshold for the
      three stimulus rates examined. However, EABRs were reduced when stimulated at 12
      dB above EABR threshold at 400 pps, and significantly reduced when stimulated at
      a rate of 1000 pps. Immediate post-stimulus response amplitudes of wave III were
      63% and 35% of the pre-stimulus amplitude at 400 and 1000 pps respectively. More
      significant reductions in EABR amplitude were observed following stimulation at
      levels more than 20 dB above EABR threshold for both 400 and 1000 pps stimuli.
      Our findings indicate that stimulus induced changes in EABR amplitude are related
      to both stimulus rate and stimulus intensity. Moreover, stimulation using
      intensities within the normal clinical range show little evidence of prolonged
      reductions in auditory nerve excitability at stimulus rates of up to 1000 pps.

PMID- 10392549
TI  - Expression pattern of adenylyl cyclase isoforms in the inner ear of the rat by RT
      PCR and immunochemical localization of calcineurin in the organ of Corti.
AB  - Most studies concerning adenylyl cyclases in the inner ear were carried out
      before the advent of molecular biology. In a PCR approach using cDNAs of six
      inner ear tissues (stria vascularis, endolymphatic sac, organ of Corti,
      vestibulum, cochlear and vestibular nerve) we found tissue specific expression of
      adenylyl cyclase isoforms. Adenylyl cyclases types 2 and 4 are predominant in the
      fluid controlling tissues, i.e. in the stria vascularis and endolymphatic sac. In
      the organ of Corti and vestibulum the Ca2+-modulated isoforms types 1, 6 and 9
      were expressed. The regulation of adenylyl cyclase 9, which is the major isoform
      expressed in the organ of Corti, proceeds via the Ca2+-activated protein
      phosphatase 2B (calcineurin, PPP3). PCR with specific primers for calcineurin
      demonstrated its abundant expression in the organ of Corti. Using a monoclonal
      antibody we localized calcineurin immunochemically to the cochlear nerve, the
      nerve fibers and the inner hair cells. In the cochlear and vestibular nerves a
      characteristic neuronal expression pattern of adenylyl cyclase isoforms was
      observed, i.e. adenylyl cyclases types 2, 3 and 8. The functional consequences of
      the adenylyl cyclase expression pattern in the inner ear are discussed in
      conjunction with its unique sensory performance.

PMID- 10392550
TI  - Expression pattern of aquaporin water channels in the inner ear of the rat. The
      molecular basis for a water regulation system in the endolymphatic sac.
AB  - Mammalian aquaporins constitute a family of so far 10 related water channel
      proteins which mediate osmotically driven water fluxes across the plasma
      membrane. Because regulation of the ionic composition and osmolality of inner ear
      fluids is of great functional significance, we investigated the expression
      patterns of aquaporins in five defined areas of the rat inner ear by RT-PCR. The
      tissues used were stria vascularis, endolymphatic sac, Reissner's membrane,
      vestibulum and organ of Corti. Aquaporin 1 transcripts were detected in all
      tissues and are probably constitutive. Aquaporin 5 was only expressed in the
      organ of Corti and in Reissner's membrane. We show that aquaporin 2, so far
      considered to be specific to the principal cells of the renal collecting duct, is
      expressed in the endolymphatic sac. Aquaporin 2 expression was not detected in
      any other inner ear region. The postnatal appearance of aquaporin 2 transcripts
      in the endolymphatic sac resembled that in the kidney, i.e. it increased
      postnatally until day 4. The full-length DNA for aquaporin 2 was cloned from cDNA
      of the endolymphatic sac. It had an irrelevant Ile54Thr mutation because it could
      be functionally expressed in Xenopus oocytes. Also exclusively in the
      endolymphatic sac of the inner ear, we detected transcripts for aquaporin
      isoforms 3 and 4 which are known to be expressed in the renal principal cells. In
      the kidney, aquaporin 2 regulation involves vasopressin-stimulated, cAMP
      dependent phosphorylation of Ser256 of aquaporin 2 which is stored in cytosolic
      vesicles. These storage vesicles also contain a serpentine calcium/polycation
      sensing receptor. Vesicle shuffling to the plasma membrane involves proteins such
      as vesicle-associated membrane protein VAMP2, syntaxin-4 and the small GTPase
      Rab3a. Using RT-PCR we were able to demonstrate the expression of all of these
      components. By analogy the data suggest that in the endolymphatic sac of the
      inner ear a system for cellular water permeability is in place which may share
      many similarities with that characterized in the principal cells of the renal
      collecting duct. These findings may have a number of interesting pharmacological
      implications which need to be addressed in future studies.

PMID- 10392551
TI  - Crystallographic and chemical composition of otoconia in the salamander
      Pleurodeles waltl.
AB  - The aim of the present study was to define the morphology and the
      crystallographic and chemical composition of otoconia in different regions of the
      inner ear in Pleurodeles waltl (urodele amphibian). The inner ear of adults was
      microdissected and otoconia were analyzed by scanning electron microscopy (SEM),
      X-ray diffraction, energy dispersive X-ray (EDX) and transmission electron
      microscopy. Two types of crystals were detected by SEM. Otoconia had different
      shapes depending on their location in the membranous labyrinth. One type had a
      cylindrical body with a triplanar smooth facet at each end, the other ones had
      either a prismatic shape with flat sides and end faces or a fusiform shape with
      rounded body and pointed end. The forms corresponded to those previously
      identified by other authors. These two types of otoconia had different X-ray
      diffraction patterns. The cylindrical otoconia were calcitic and located in the
      utricle, the other ones were aragonitic and located in the saccule, lagena and
      endolymphatic sac. An analysis by EDX indicated that both types of otoconia
      contained about 95% calcium with trace quantities of sodium, magnesium,
      phosphorus, sulfur, chlorine and potassium. Trace amounts of strontium was only
      found in the aragonitic otoconia.

PMID- 10392552
TI  - The role of envelope modulation in spectrally unresolved iterated rippled noise.
AB  - Iterated rippled noise (IRN) produces a pitch corresponding to the IRN delay. The
      pitch persists even when the sound is high-pass filtered at 12 times the
      reciprocal of the IRN delay, i.e., in the absence of resolved spectral peaks.
      Typically, when a sound produces a pitch in the absence of spectral cues, the
      pitch is explained in terms of periodic envelope modulation, for example, the
      pitch of a high-pass filtered cosine-phase harmonic complex, or the pitch of
      sinusoidally amplitude-modulated noise (SAMN). This study presents experiments
      designed to search for periodic modulation in IRN. The occurrence and
      significance of modulation is investigated in the envelope of the stimulus
      waveform as well as in the IRN envelope as represented after narrow-band
      filtering similar to that occurring in peripheral auditory filters. The results
      indicate that the envelope of band-pass filtered IRN reveals modulation but that
      the order of modulation (corresponding to the number of envelope maxima recurring
      every period) increases with increasing filter bandwidth. The occurrence of first
      order modulation, like that of SAMN, is indirectly demonstrated for spectrally
      unresolved IRN in the lower unresolved frequency range between the 10th and 20th
      spectral peaks. The significance of recurring transients sometimes visible in the
      IRN waveform with respect to their contribution to the IRN pitch was assessed by
      replacing portions of the IRN period with random noise. The results of this
      experiment indicate that this 'waveform modulation' is not essential for the IRN
      pitch perception. The presence of temporal pitch in the absence of first-order
      modulation is demonstrated in two experiments involving the detection of phase
      delays and f0 differences for spectrally separated, narrow bands of harmonic
      complexes and IRNs.

PMID- 10392554
TI  - Potassium currents in auditory hair cells of the frog basilar papilla.
AB  - The whole-cell patch-clamp technique was used to identify and characterize ionic
      currents in isolated hair cells of the leopard frog basilar papilla (BP). This
      end organ is responsible for encoding the upper limits of a frog's spectral
      sensitivity (1.25-2.0 kHz in the leopard frog). Isolated BP hair cells are the
      smallest hair cells in the frog auditory system, with spherical cell bodies
      typically less than 20 microm in diameter and exhibiting whole-cell capacitances
      of 4-7 pF. Hair cell zero-current resting potentials (Vz) varied around a mean of
      -65 mV. All hair cells possessed a non-inactivating, voltage-dependent calcium
      current (I(Ca)) that activates above a threshold of -55 mV. Similarly all hair
      cells possessed a rapidly activating, outward, calcium-dependent potassium
      current (I(K)(Ca)). Most hair cells also possessed a slowly activating, outward,
      voltage-dependent potassium current (I(K)), which is approximately 80% inactive
      at the hair cell Vz, and a fast-activating, inward-rectifying potassium current
      (I(K1)) which actively contributes to setting Vz. In a small subset of cells I(K)
      was replaced by a fast-inactivating, voltage-dependent potassium current (I(A)),
      which strongly resembled the A-current observed in hair cells of the frog
      sacculus and amphibian papilla. Most cells have very similar ionic currents,
      suggesting that the BP consists largely of one homogeneous population of hair
      cells. The kinetic properties of the ionic currents present (in particular the
      very slow I(K)) argue against electrical tuning, a specialized spectral filtering
      mechanism reported in the hair cells of birds, reptiles, and amphibians, as a
      contributor to frequency selectivity of this organ. Instead BP hair cells reflect
      a generalized strategy for the encoding of high-frequency auditory information in
      a primitive, mechanically tuned, terrestrial vertebrate auditory organ.

PMID- 10392553
TI  - Kinin and histamine stimulate Cl- secretion in gerbil middle ear epithelium:
      connection to otitis media.
AB  - The effects of bradykinin (BK) and histamine on transepithelial ion transport in
      primary cultures of gerbil middle ear epithelium were investigated. Lysyl
      bradykinin (lys-BK) elicited a transient increase in short-circuit current
      (I(sc)) when added to apical or basolateral surfaces. Lys-BK had a larger effect
      than BK or des-arg9-BK on both epithelial surfaces. Histamine induced a transient
      increase in I(sc) only when added to the basolateral surface. Mepyramine, an H1
      histamine antagonist, greatly reduced the histamine-induced I(sc). The H2 and H3
      histamine antagonists were both ineffective for inhibiting the I(sc) responses to
      histamine. Diphenylamine-2-carboxylate or 4,4'-diisothiocyanostilbene-2,2'
      disulfonic acid, Cl- channel blockers, significantly blocked the I(sc) responses
      to lys-BK or histamine. The Ca2+-mobilizing action of lys-BK and histamine was
      also investigated in single middle ear epithelial cells. BK and histamine induced
      an increase in the intracellular Ca2+ concentration. 1,2-Bis-(2
      aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, a calcium
      chelator, greatly reduced the increase in the I(sc) responses to lys-BK or
      histamine. These data indicate that BK and histamine activate intracellular Ca2+
      dependent mechanisms, leading to apical Cl- secretion in the cultured gerbil
      middle ear epithelium via B2 BK receptors and H1 histamine receptors.

PMID- 10392555
TI  - Dynamics of inner ear pressure release, measured with a double-barreled
      micropipette in the guinea pig.
AB  - The inner ear fluid pressure was measured in scala media of the guinea pig
      through one barrel of a double-barreled micropipette after a sudden volume
      increase or decrease, caused by injection or withdrawal of artificial endolymph
      through the other barrel. During injection or withdrawal, the inner ear pressure
      changed in the order of 1-10 cm water, but it returned to its initial value
      within a few seconds. The time constant for the pressure recovery depended on the
      flow direction. It was on average 1.1 s after a short overpressure and 2.8 s
      after underpressure. The obtained results could be fitted with a simple physical
      model, when it was assumed that inner ear pressure recovery is a non-linear
      process, governed by a pressure-dependent flow resistance and/or membrane
      compliance.

PMID- 10392556
TI  - Susceptibility of the noise-toughened auditory system to noise-induced trauma.
AB  - The auditory system 'toughened' by an interrupted noise exposure has been shown
      in several reports, to be less affected by (or protected from) a subsequent high
      level noise exposure. A group of chinchillas (n = 12) was exposed to an
      interrupted noise at 95 dB SPL, 0.5 kHz octave band, 6 h/day for 10 days.
      Threshold shifts measured over the 10 day exposure showed that the animals
      responded by either (1) developing a large toughening effect (i.e., thresholds
      after day 10 of the exposure were considerably better than at the end of day 1)
      (n = 5) or (2) not showing any toughening, instead thresholds continued to get
      worse over the course of the exposure (n = 7). After a 5 day interval, during
      which thresholds of all the animals returned to normal, they, along with a
      control group (n = 10) not exposed to the interrupted noise, were exposed to an
      asymptotic threshold shift producing traumatic noise (127 dB peak SPL narrow band
      impact, 1 kHz center frequency, 24 h/day for 5 days). Auditory evoked potential
      audiometry and surface preparation histology showed that there were no
      statistically significant differences in the response of any of the above groups
      to the traumatic noise. The interrupted noise exposure, whether it produced a
      toughening or not, did not provide any protection from a subsequent high-level
      noise.

PMID- 10392557
TI  - Potentiation of octave-band noise induced auditory impairment by carbon monoxide.
AB  - In previous studies from our lab, broadband noise induced hearing loss has been
      found to be potentiated by simultaneous carbon monoxide (CO) exposure. In the
      present study, octave-band noise induced auditory impairment was studied with the
      presence of CO at levels of 1500, 1200, 700, 500 and 300 ppm and zero (noise
      alone). Four octave-band noises (1.2-2.4, 2.4-4.8, 4.8-9.6 and 9.6-19.2 kHz) were
      used. Experimental subjects (rats) were grouped for the exposure (8 h) to each
      noise, CO and their combinations. The compound action potential (CAP) and
      cochlear microphonics (CM) were recorded 4 weeks after the exposure. The noise
      induced elevation of the CAP threshold and the CM iso-amplitude curve were
      potentiated by the simultaneous CO exposure when the CO level reached 500 ppm or
      higher. CO exposure alone had no effect on CAP or CM. The CO potentiation can
      occur in any frequency region depending on the noise band. The combined exposure
      can also induce threshold shifts in some cases in which both the noise and the CO
      alone did not cause threshold shifts. The size of the potentiation shown by CAP
      and CM was similar, indicating a possible origin of the CO potentiation from the
      damage to the outer hair cells. Interestingly, the hearing loss induced by noise
      alone gradually recovered (partially), but the hearing loss caused by the
      combined exposure did not. The potentiation may be due to the reduction of the
      cell's ability to repair noise induced damage by CO.

PMID- 10392558
TI  - Concepts in occupational and environmental health: contribution of the European
      Commission.

PMID- 10392559
TI  - Occupational risk to male reproduction.

PMID- 10392560
TI  - Change in semen quality and sperm chromatin structure following occupational
      styrene exposure. ASCLEPIOS.
AB  - OBJECTIVES: Organic solvents have been suspected to exert detrimental effects on
      human spermiogenesis. Styrene, which is both mutagenic and neurotoxic, was
      selected as a suitable organic solvent for further assessment of a possible
      effect on semen quality and sperm DNA damage. SUBJECTS AND METHODS: Semen samples
      were collected from 23 reinforced plastics workers at the time of employment and
      after 6 months of styrene exposure and from 21 nonexposed farmers. Intra
      individual changes in conventional semen parameters and sperm-DNA denaturation
      patterns were related to the internal dose of styrene exposure as measured by
      postshift urinary mandelic acid. RESULTS: A statistically significant decline in
      sperm density was seen during styrene exposure from 63.5 to 46.0 million
      sperm/ml, whereas no decline was seen in the nonexposed subjects. The total sperm
      count was almost halved from an initial value of 175 million sperm/ejaculate.
      However, no relationship was apparent when the sperm parameters were related to
      internal levels of exposure. However, an exposure-response relationship was shown
      for DNA-denaturation patterns, but the numbers were small. CONCLUSION: A
      declining sperm count following styrene exposure is suggested. However, the
      findings of the internal and external comparisons are inconsistent, and this may
      be due to the high intraindividual variability of semen parameters and the
      limited study size but may also be attributable to a weak internal exposure
      gradient. Spermatogenesis may be vulnerable to styrene exposure. However, due to
      the small numbers these findings are only preliminary.

PMID- 10392562
TI  - Critical evaluation of medical, statistical, and occupational data sources in the
      Kola Peninsula of Russia pertinent to reproductive health studies.
AB  - BACKGROUND: The feasibility study described herein was prompted by a report in
      1992 of possible reproductive and developmental health concerns among female
      workers in a Russian nickel refinery. OBJECTIVE: The primary goal was to
      ascertain whether medical, statistical, and occupational data bases could be
      accessed for information about the pregnancy histories, occupational histories,
      and life-style factors of the women affected. METHODS: The project was
      facilitated by construction of a registry of all births in three towns with a
      nickel refinery and verification of its contents against patients' records
      obtained from hospital delivery and gynecology departments and community
      polyclinics. Municipal Registration Board, Regional Health Statistics Board, and
      nickel company records were also reviewed. RESULTS: Reproductive/developmental
      outcome information and workplace histories were acceptable. Sample-size
      calculations indicated that a cohort or cross-sectional study would be amenable
      and suitable for the detection of an excess risk for spontaneous abortion with
      adequate statistical significance and power. Such investigations would need to be
      supplemented by workplace environmental/biological monitoring assessments for
      evaluation of exposure to occupational hazardous factors and a worker's
      questionnaire to obtain information about life-style factors. A case-control
      design is recommended for the study of congenital defects. CONCLUSIONS: A well
      designed, comprehensive epidemiology study is technically feasible because of the
      availability of a favorable pool of study subjects, reproductive/developmental
      outcome data, information to control for major confounders, and suitable
      occupational records.

PMID- 10392561
TI  - Biomonitoring of exposure to ethylene oxide and propylene oxide by determination
      of hemoglobin adducts: correlations between airborne exposure and adduct levels.
AB  - OBJECTIVES: Ethylene oxide (EO) and propylene oxide (PO) are important industrial
      chemicals. Exposure to these directly acting mutagens may be monitored by
      determination of their adducts to hemoglobin (Hb). This study establishes
      correlations between airborne concentrations of EO and PO and their Hb adducts in
      petrochemical workers. METHODS: In three different studies conducted during
      maintenance shutdown of petrochemical plants the external occupational exposure
      to EO and PO was assessed by personal air monitoring (PAM). The internal exposure
      to EO and PO was concomitantly assessed by determination of N-(2
      hydroxyethyl)valine (HOEtVal) and N-(3-hydroxypropyl)valine (HOPrVal) in blood
      samples of the operators using the N-alkyl-Edman degradation method. RESULTS: In
      the first study, PAM was applied once a month at random over a period of 4
      months. Blood samples for Hb-adduct determination were collected at the end of
      this period. No significant correlation was found between PAM and Hb-adduct data.
      In the next two studies, PAM was applied to the operators during the entire shift
      on every working day during the shutdown. Blood samples were collected before and
      immediately after the shutdown period. Highly significant correlations were found
      between the increment in the concentration of HOEtVal and HOPrVal over this
      period and the total exposure to EO and PO, respectively. CONCLUSIONS: Time
      integrated exposure to EO or PO can be readily and reliably assessed by
      measurement of the concentration of HOEtVal or HOPrVal in a small blood sample.
      In workers occupationally exposed to low concentrations of EO or PO, good
      correlations were found between these Hb adducts and the airborne concentrations
      of EO and PO. These correlations allow the calculation of tentative biological
      exposure limits (BELs) for EO and PO. At the current Dutch occupational exposure
      limit (OEL) for EO (0.84 mg m(-3), 8-h TWA) the BEL is 3.2 nmol HOEtVal/g globin.
      At the value of 10 mg m(-3) (8-h TWA), which is currently being investigated as
      the new Dutch OEL for PO, the corresponding BEL is 5.3 nmol HOPrVal/g globin.

PMID- 10392563
TI  - Detection of polycyclic aromatic hydrocarbon metabolites by high-pressure liquid
      chromatography after purification on immunoaffinity columns in urine from
      occupationally exposed workers.
AB  - OBJECTIVE: The objective in our study was to quantitate benzo[a]pyrene (B[a]P)
      metabolites by a combination of immunoaffinity chromatography and high-pressure
      liquid chromatography (HPLC) with fluorescence detection in urine from workers
      exposed to high levels of polycyclic aromatic hydrocarbons (PAH). Furthermore, by
      the simultaneous quantitation of 1-hydroxypyrene, the correlation between the
      B[a]P-tetrol and 1-hydroxypyrene would provide a means of evaluating the validity
      of 1-hydroxypyrene as a surrogate biomarker for occupational exposure to the
      potent carcinogen B[a]P in an electrode paste plant. METHODS: The study was
      carried out at an electrode paste plant that produces electrode paste for
      Soderberg electrodes. A total of 34 pre- and post-shift urine samples and 17
      personal air samples were collected from 17 workers during a normal work week.
      The concentration of 1-hydroxypyrene was measured in all urine samples. A recent
      method of quantitating B[a]P-r-7, t-8, t-9, c-10-tetrol in urine of humans
      exposed to low levels of PAH has been described. A modified version of this
      method involving purification of urine samples on immunoaffinity columns and HPLC
      analysis with fluorescence detection was used on urine samples from workers
      exposed to high levels of PAH. A monoclonal antibody (8E11) with binding affinity
      to B[a]P-tetrols was used. This antibody also binds several PAH-DNA adducts and
      metabolites, including 1-hydroxypyrene. Gas chromatography/mass spectroscopy
      (GC/MS) was also used for identification of metabolites isolated by HPLC
      fractionation. RESULTS: From personal air sampling the mean exposure to
      particulate PAHs was 38 microg/m3. The mean concentration of urinary 1
      hydroxypyrene was 3.9 micromol/mol creatinine in preshift samples and 10.2
      micromol/mol creatinine in postshift samples. We could not identify detectable
      amounts of urinary B[a]P-tetrol by HPLC or fluorescence spectroscopy after
      purification on immunoaffinity columns. However, in the HPLC analysis we
      identified several hydroxyphenantrene metabolites that were detected at
      relatively high concentrations in all of the workers' urine samples. We could not
      separate 2- and 3-hydroxyphenanthrene (2 + 3-OH-Phe) in peak 1, and peak 2
      contained both 1- and 9-hydroxyphenanthrene (1 + 9-OH-Phe). The phenanthrene
      metabolites were mainly conjugated to glucuronic acid and sulfate. There was a
      significant correlation between the 1-hydroxypyrene concentration and 2 + 3-OH
      Phe (r = 0.73) and 1 + 9-OH-Phe (r = 0.64) in the urine samples. 1-Hydroxypyrene
      was measured in all post-shift urine samples but was not significantly correlated
      with workplace pyrene exposure, indicating that skin exposure is an important
      route of pyrene exposure in this factory. As with 1-hydroxypyrene, dermal PAH
      uptake may also account for the poor correlation between 2 + 3- and 1 + 9-OH-Phe
      and ambient phenanthrene. DISCUSSION: Since dermal uptake is likely to be
      important in occupational PAH exposure in addition to inhalation, estimation of
      total PAH exposure is best achieved by quantitation of PAHs excreted into body
      fluids. However, it remains unclear whether there might be a difference in uptake
      and urinary excretion of 3-ring, 4-ring, or 5-ring PAHs and in the correlation
      between these metabolites and ambient-air PAH measurements. In summary, using
      immunaffinity chromatography, we did not find detectable amounts of B[a]P-tetrol
      in urine from workers occupationally exposed to PAH. However, by an
      HPLC/immunoaffinity method, relatively high amounts of 1-hydroxypyrene as well as
      2 + 3- and 1 + 9-OH-Phe were quantitated in the urine samples, both of which are
      relevant as biomarkers of PAH exposure.

PMID- 10392564
TI  - Tissue levels of mercury determined in a deceased worker after occupational
      exposure.
AB  - OBJECTIVES: To examine mercury (Hg) and selenium (Se) levels in autopsy samples
      from a thermometer worker who had been exposed over a long period to, and
      monitored for, mercury vapor. CASE REPORT: Hg and Se levels were determined using
      radiochemical neutron activation analysis in a worker who had commited suicide 4
      weeks after the end of 14 years of exposure and in an unexposed age-matched
      referent. Histochemical staining of cerebellum was performed according to the
      method of Danscher and Schroder. RESULTS: The Hg concentrations (wet weight) were
      25 microg/g in the kidney cortex, 1.2 microg/g in the liver, 0.72 microg/g in the
      lung, 0.025 microg/g in the testis, and 0.014-0.018 microg/g in the cerebellum
      (gray matter, dentate nucleus, and white matter). The Se level in the kidney
      cortex was high, 4.6 microg/g, whereas the concentration detected in the other
      tissue samples was normal. Light microscopy of the cerebellum was normal, and no
      histochemical staining for mercury was observed. Autopsy samples from the
      referent showed low Hg and Se levels consistent with other reports. CONCLUSIONS:
      The observed kidney-Hg, which was 50-100 times higher than that occurring in the
      general population, is in agreement with previous sparse data from ongoing
      occupational exposure. The high Se level detected in the kidney indicates
      coaccumulation with mercury. The low Hg concentration found in the cerebellum was
      unexpected, since some reports have shown much higher brain-Hg long after the
      cessation of exposure.

PMID- 10392565
TI  - Occupational exposure to sevoflurane during sedation of adult patients.
AB  - OBJECTIVES: In a field study we evaluated the workplace pollution occurring
      during conscious sedation with sevoflurane in adults. METHODS: Sevoflurane was
      given in 100% oxygen at a fresh gas flow rate of 3 l/min via a nasal mask. This
      was conducted in 25 patients scheduled for surgical procedures performed under
      regional anesthesia. Trace concentrations of sevoflurane were directly measured
      every minute in the breathing zone by means of a photoacoustic infrared
      spectrometer in an operating room with an air turnover of 20 changes/h. RESULTS:
      The mean sedation time was 49.6+/-20.4 min. The average vaporizer setting of the
      anesthesia machine was 1.63+/-0.6 vol%, resulting in a patient's mean end-tidal
      sevoflurane concentration of 0.78+/-0.2 vol%. The 8-h time-weighted average was
      calculated to be 0.58 ppm sevoflurane. CONCLUSIONS: The trace gas concentrations
      were low and comparable with values obtained under inhalation induction in adults
      and children. Although no occupational standard for sevoflurane is currently
      defined, the measured values are clearly under the standards recommended for
      enflurane (20 ppm) and isoflurane (10 ppm) by the European health authorities. We
      conclude that the new anesthesiologic method of conscious sedation with
      sevoflurane in adults using a nasal mask would not result in a violation of
      occupational standards, provided that the future value set for sevoflurane would
      be similar to those recommended for isoflurane or enflurane.

PMID- 10392566
TI  - Blood lactate changes in men during graded workloads at normal atmospheric
      pressure (100 kPa) and under simulated caisson conditions (400 kPa).
AB  - OBJECTIVES: A hyperbaric environment may influence lactate metabolism due to
      hyperoxia affecting biochemical pathways. The purpose of our study was to
      determine the blood lactate levels occurring at high workloads in a sample of
      professional divers under simulated caisson conditions. The ambient air pressure
      was equivalent to a diving depth of 30 m of seawater (400 kPa). METHODS: A total
      of 23 healthy male subjects performed graded bicycle exercise in a dry hyperbaric
      chamber up to a maximum of 3.5 W kg(-1) body weight at normal (100 kPa) and
      elevated ambient air pressure (400 kPa). The blood lactate level and the heart
      rate were measured. RESULTS: In comparison with control conditions, the heart
      rate and the peripheral blood lactate level were significantly lower at depth for
      all workloads. CONCLUSIONS: The differences between the normobaric and hyperbaric
      lactate values may be explained by an overall improvement in lactate metabolism
      at elevated ambient pressure, especially in the working muscles and the organs
      responsible for the lactate reduction, i.e., the liver. The reduced heart rate
      may be an effect of the improved tissue oxygen supply at depth.

PMID- 10392567
TI  - Report on the International Symposium on Environment, Life Style, and Fertility.
      Aarhus, Denmark, 7-10 December 1997.

PMID- 10392569
TI  - Easy assessment of ES cell clone potency for chimeric development and germ-line
      competency by an optimized aggregation method.
AB  - Production of germ-line competent chimeric mice from embryonic stem (ES) cells is
      an inevitable step in establishing gene-manipulated mouse lineages. A common
      method used for creating chimeric mice is the injection of ES cells into the
      blastocoelic cavity (blastocyst injection). The aggregation method is an
      alternative way to introduce ES cells to the host embryo which is less difficult
      than blastocyst injection. Here we re-examined the condition of embryo-ES cell
      coculture on the aggregation method and found improvement of germ-line competent
      chimeric production by a simple modification of the coculture medium. Moreover,
      R1 ES cell and its 10 gene-manipulated subclones were tested by this method.
      Although all ES cell clones showed good morphology and a normal karyotype, the
      efficiency of chimeric development and germ-line transmission varied among clones
      and were classified into three grades according to germ-line competency. In the
      first group (class A), both the incidence of chimera with high ES cell
      contribution and the rate of germ-line transmission were fairly high. Germ-line
      competent chimeras were obtained but with rather low efficiency in the second
      group (class B), while another group (class C) showed an absence of high ES cell
      contributed chimeras and no germ-line transmission. These results suggest the
      usefulness of this modified aggregation method to predict the potency of ES cell
      clones for germ-line competency.

PMID- 10392568
TI  - Discrete analysis of serum uric acid with immobilized uricase and peroxidase.
AB  - Commercially available uricase and peroxidase have been immobilized onto
      alkylamine glass and arylamine glass beads respectively. A discrete method has
      been developed to determine uric acid in serum using immobilized uricase and
      peroxidase. The method is based on generation of H2O2 from serum uric acid by
      immobilized uricase and its measurement by a colour reaction catalyzed by
      immobilized peroxidase. The minimum detection limit of the method was 8
      microg/0.1 ml sample. The mean analytical recovery of added uric acid in serum
      was 87.5%. The within and between assay coefficient of variation (C.V.) were
      <6.58% and <10.77% respectively. The serum uric acid in apparently healthy adults
      and persons suffering from different disease was found to be 25-55 microg/ml,
      32+/-2.25 (range, mean+/-S.D.) and 55-200 microg/ml; 52+/-6.4 (range, mean+/
      S.D.) respectively by our method. A good correlation (r = 0.8170) was obtained
      between the serum urate values by this method and with those obtained by
      commercial Enzo-kit method.

PMID- 10392570
TI  - Using native gel in two-dimensional PAGE for the detection of protein
      interactions in protein extract.
AB  - A two-dimensional (2-D) gel electrophoresis system in which native and sodium
      dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) are performed
      subsequently to analyze protein mixtures is described. Reasonably good resolution
      and excellent reproducibility was obtained when the proteins in the soluble
      protein extract from E. coli cells were separated using this procedure. Perhaps
      more importantly, the relevance of this native/SDS-2-D PAGE for the detection of
      protein interactions in a complicated protein mixture was examined using the
      interaction between interleukin-2 (IL-2) and its receptor alpha chain (IL
      2Ralpha) in the E. coli protein extract as a model system. Native gel was used to
      preserve the interactions between the two molecules and SDS gel was used to
      maximize the separation of the denatured proteins. Mobility changes of these two
      proteins on 2-D maps resulted from the formation of IL-2/IL-2-2Ralpha complex
      were clearly observed despite of the presence of a large number of other protein
      spots. Thus, this approach is a useful complement to the standard 2-D gel
      electrophoresis system for analyzing complicated protein mixture, especially for
      the study of protein interactions.

PMID- 10392571
TI  - Simple, high-yield purification of xanthine oxidase from bovine milk.
AB  - Xanthine oxidase, a commercially important enzyme with a wide area of
      application, was extracted from fresh milk, without added preservatives, using
      toluene and heat. The short purification procedure, with high yield, consisted of
      extraction, ammonium sulfate fractionation, and DEAE-Sepharose (fast flow) column
      chromatography. Xanthine oxidase was eluted as a single activity peak from the
      column using a buffer gradient. The purification fold, specific activity and
      yield for the purified xanthine oxidase were 328, 10.161 U/mg and 69%,
      respectively. The enzyme was concentrated by ultrafiltration, although 31% of the
      activity was lost during concentration, no change in specific activity was
      observed. Activity and protein gave coincident staining bands on native
      polyacrylamide gels. The intensity and the number of bands were dependent on the
      oxidative state(s) of the enzyme; reduction by 2-mercaptoethanol decreased the
      intensity of the slow-moving bands and increased the intensity of the fastest
      moving band. Following sodium dodecyl sulfate-polyacrylamide gel electrophoresis
      (SDS-PAGE), two major bands (molecular masses of 152 and 131 kDa) were observed,
      accounting for > or = 95% of xanthine oxidase. Native- and SDS-PAGE showed that
      the purified xanthine oxidase becomes a heterodimer due to endogenous proteases.

PMID- 10392573
TI  - Protein spot recognition on the non-denaturing and denaturing two-dimensional
      electrophoresis patterns using in situ immunosubtraction via Protein A agarose
      and antibodies.
AB  - Specific proteins in small amounts of human plasma were subtracted from patterns
      of non-denaturing two-dimensional electrophoresis (non-denaturing 2-DE) by
      layering a 7 microl aliquot of Protein A agarose-antibody complex on the top of
      an isoelectric focusing (IEF) gel before the loading of a plasma sample. The
      Protein A agarose suspension was recovered after non-denaturing IEF and was mixed
      with 8 M urea-5% 2-mercaptoethanol-1% NP-40 to extract the antibody and the
      specific plasma protein from Protein A agarose. The extract was then subjected to
      denaturing two-dimensional electrophoresis (denaturing 2-DE) and the location of
      the specific polypeptide was determined. The technique can be applied to the
      extraction and analysis of proteins in small amounts of samples.

PMID- 10392572
TI  - Examination of the protein binding behaviour of immobilised copper (II)-2,6
      diaminomethylpyridine and its application in the immobilised metal ion affinity
      chromatographic separation of several human serum proteins.
AB  - A new metal ion chelator has been developed for use in the immobilised metal ion
      affinity chromatography (IMAC) of proteins. The aromatic tridentate ligand 2,6
      diaminomethylpyridine (bisampyr), 1, was prepared as the dihydrochloride salt,
      via a two step synthesis from 2,6-pyridinedimethanol, 2, and immobilised onto
      Sepharose CL-4B through an epoxide coupling procedure. The resulting sorbent was
      chelated with Cu2+ ions to a density of 420 micromol Cu2+ ions per g gel and then
      characterised by frontal analysis using the protein, horse heart myoglobin
      (HMYO), at pH 7.0 and 9.0. From the resulting adsorption isotherms, the
      adsorption capacity, qm, for HMYO at pH 7.0 and pH 9.0 with the immobilised Cu2+
      bisampyr Sepharose sorbent was found to be 1.27 micromol protein/g gel and 1.43
      micromol protein/g gel, whilst the corresponding dissociation constants, K(D)s,
      were 18.0 x 10(-6) M and 16.0 x 10(-6) M respectively. The results confirm that
      the HMYO-Cu2+-bisampyr complex had similar stability at these pH values. This
      finding is in contrast with the situation observed with some other commonly used
      IMAC chelating ligates such as Cu2+-iminodiacetic acid (Cu2+-IDA) or Cu2+
      nitrilotriacetic acid (Cu2+-NTA). Using human serum proteins, the interactive
      properties of the immobilised Cu2+-bisampyr Sepharose sorbent were further
      characterised at pH 5.0, 7.0 and 9.0 with specific reference to the binding
      behaviour of albumin, transferrin, and alpha2-macroglobulin.

PMID- 10392574
TI  - New order from neurological disorders.
AB  - The neurological diseases described in this review supplement impact across a
      wide spectrum of the population. Here, their similarities and differences are
      highlighted, and common themes of the interactions between basic and clinical
      sciences for their understanding and treatment are explored.

PMID- 10392575
TI  - The changing landscape of ischaemic brain injury mechanisms.
AB  - Thrombolysis has become established as an acute treatment for human stroke. But
      despite multiple clinical trials, neuroprotective strategies have yet to be
      proved effective in humans. Here we discuss intrinsic tissue mechanisms of
      ischaemic brain injury, and present a perspective that broadening of therapeutic
      targeting beyond excitotoxicity and neuronal calcium overload will be desirable
      for developing the most effective neuroprotective therapies.

PMID- 10392576
TI  - Emerging insights into the genesis of epilepsy.
AB  - Epilepsies are a diverse collection of brain disorders that affect 1-2% of the
      population. Current therapies are unsatisfactory as they provide only symptomatic
      relief, are effective in only a subset of affected individuals, and are often
      accompanied by persistent toxic effects. It is hoped that insight into the
      cellular and molecular mechanisms of epileptogenesis will lead to new therapies,
      prevention, or even a cure. Emerging insights point to alterations of synaptic
      function and intrinsic properties of neurons as common mechanisms underlying the
      hyperexcitability in diverse forms of epilepsy.

PMID- 10392577
TI  - Translating cell biology into therapeutic advances in Alzheimer's disease.
AB  - Studies of the molecular basis of Alzheimer's disease exemplify the increasingly
      blurred distinction between basic and applied biomedical research. The four genes
      so far implicated in familial Alzheimer's disease have each been shown to elevate
      brain levels of the self-aggregating amyloid-beta protein, leading gradually to
      profound neuronal and glial alteration, synaptic loss and dementia. Progress in
      understanding this cascade has helped to identify specific therapeutic targets
      and provides a model for elucidating other neurodegenerative disorders.

PMID- 10392578
TI  - Prospects for new restorative and neuroprotective treatments in Parkinson's
      disease.
AB  - The degeneration of forebrain dopamine systems in Parkinson's disease has been an
      effective target for pharmaceutical research over the past four decades. However,
      although dopamine replacement may alleviate the symptoms of the disease, it does
      not halt the underlying neuronal degeneration. The past decade has seen major
      advances in identifying discrete genetic and molecular causes of parkinsonism and
      mapping the events involved in nigral cell death. This new understanding of the
      pathogenesis of the disease now offers novel prospects for therapy based on
      targeted neuroprotection of vulnerable neurons and effective strategies for their
      replacement.

PMID- 10392579
TI  - Progress in determining the causes and treatment of multiple sclerosis.
AB  - The cause of multiple sclerosis remains unknown after more than a century of
      study. Unconfirmed work has once more indicated that a viral infection may be
      important in the aetiology of the disease, and there is considerable evidence for
      an important genetic influence on disease susceptibility. The clinical course is
      as variable as that of any disease in medicine. Studies using serial magnetic
      resonance imaging have helped to define the disease course and response to
      experimental therapies. Although the predominant pathological characteristic is
      myelin loss with preservation of axons, some studies recall classic descriptions
      that irreversible axonal destruction may occur, perhaps even in the early stages
      of the illness. There are now several, partially effective therapies for
      relapsing forms of multiple sclerosis and here I review progress in determining
      the timing and course of the illness and the steps that need to be taken to
      identify more effective treatments for this disease.

PMID- 10392580
TI  - Screening options for colorectal cancer.

PMID- 10392581
TI  - Labeling the somatically preoccupied: have we gone too far?

PMID- 10392582
TI  - The role of government in controlling the HIV epidemic.

PMID- 10392583
TI  - Prophylaxis for STDs after sexual assault.

PMID- 10392584
TI  - Sister (Mary?) Joseph's node.

PMID- 10392585
TI  - Peripartum emergencies.

PMID- 10392586
TI  - Peripartum emergencies.

PMID- 10392587
TI  - Insomnia: assessment and management in primary care. National Heart, Lung, and
      Blood Institute Working Group on Insomnia.
AB  - Patients with insomnia may experience one or more of the following problems:
      difficulty falling asleep, difficulty maintaining sleep, waking up too early in
      the morning and nonrefreshing sleep. In addition, daytime consequences such as
      fatigue, lack of energy, difficulty concentrating and irritability are often
      present. Approximately 10 percent of adults experience persistent insomnia,
      although most patients do not mention it during routine office visits. Asking
      sleep-related questions during the general review of systems and asking patients
      with sleep complaints to keep a sleep diary are helpful approaches in detecting
      insomnia. Behavior and pharmacologic therapies are used in treating insomnia.
      Behavior approaches take a few weeks to improve sleep but continue to provide
      relief even after training sessions have ended. Hypnotic medications are safe and
      effective in inducing, maintaining and consolidating sleep. Effective treatment
      of insomnia may improve the quality of life for many patients.

PMID- 10392588
TI  - Case studies in international medicine.
AB  - Family physicians in the United States are increasingly called on to manage the
      complex clinical problems of newly arrived immigrants and refugees. Case studies
      and discussions are provided in this article to update physicians on the
      diagnosis and management of potentially unfamiliar ailments, including
      strongyloidiasis, hookworm infection, cysticercosis, clonorchiasis and tropical
      pancreatitis. Albendazole and ivermectin, two important drugs in the treatment of
      some worm infections, are now available in the United States.

PMID- 10392589
TI  - Cutaneous and systemic manifestations of mastocytosis.
AB  - Mastocytosis is characterized by an excessive number of apparently normal mast
      cells in the skin and, occasionally, in other organs. Characteristic skin
      lesions, called urticaria pigmentosa, are present in most patients, but clinical
      presentation can vary from a pruritic rash to unexplained collapse and sudden
      death. These lesions are typically tan to red-brown macules that appear on the
      trunk and spread symmetrically. Patients with mastocytosis often have a long
      history of chronic and acute symptoms that were unrecognized as mastocytosis.
      Skin lesions may or may not accompany systemic mastocytosis. Systemic disease may
      involve the gastrointestinal tract, the bone marrow or other organs. Even when
      the disease is considered as a possibility by the physician, the diagnosis can be
      difficult because of special technical requirements necessary for biopsy and
      because of the problems with biochemical testing. Drug therapy is initiated to
      stabilize mast cell membranes, to reduce the severity of the attacks and to block
      the action of inflammatory mediators. The mainstay of therapy is histamine H1 and
      H2 blockers and the avoidance of triggering factors.

PMID- 10392590
TI  - Endometrial cancer.
AB  - Endometrial cancer is the fourth most common cancer in women, accounting for
      approximately 6,000 deaths per year in the United States. It is more common in
      women who are older, white, affluent obese and of low parity. Hypertension and
      diabetes mellitus are also predisposing factors. Because any condition that
      increases exposure to unopposed estrogen increases the risk of endometrial
      cancer, tamoxifen therapy, estrogen replacement therapy without progestin and the
      presence of estrogen-secreting tumors are all risk factors. Smoking and the use
      of oral contraceptives appear to decrease the risk. Women with an increased risk
      and those with postmenopausal bleeding should be screened for endometrial cancer.
      Endometrial sampling is currently the most accurate and widely used screening
      technique, but ultrasonographic measurement of endometrial thickness and
      hysteroscopy have also been studied. Patients with endometrial specimens that
      show atypia have about a 25 percent likelihood of progressing to carcinoma,
      compared with less than 2 percent in patients without atypia. Endometrial cancer
      is usually treated surgically, but in patients with appropriate pathologic
      findings who decline surgical treatment, progestin therapy may be satisfactory.

PMID- 10392591
TI  - Colorectal cancer: risk factors and recommendations for early detection.
AB  - Spurred by mounting evidence that the detection and treatment of early-stage
      colorectal cancers and adenomatous polyps can reduce mortality, Medicare and some
      other payors recently authorized reimbursement for colorectal cancer screening in
      persons at average risk for this malignancy. A collaborative group of experts
      convened by the U.S. Agency for Health Care Policy and Research has recommended
      screening for average-risk persons over the age of 50 years using one of the
      following techniques: fecal occult blood testing each year, flexible
      sigmoidoscopy every five years, fecal occult blood testing every year combined
      with flexible sigmoidoscopy every five years, double-contrast barium enema every
      five to 10 years or colonoscopy every 10 years. Screening of persons with risk
      factors should begin at an earlier age, depending on the family history of
      colorectal cancer or polyps. These recommendations augment the colorectal cancer
      screening guidelines of the American Academy of Family physicians. Recent
      advances in genetic research have made it possible to identify persons at high
      risk for colorectal cancer because of an inherited predisposition to develop this
      malignancy. These patients require aggressive screening, usually by lower
      endoscopy performed at an early age. In some patients, genetic testing can guide
      screening and may be cost-effective.

PMID- 10392592
TI  - Kawasaki disease.
AB  - Kawasaki disease is a leading cause of acquired heart disease among children in
      the United States and other developed countries. Most children who contract this
      illness are less than two years old, and 80 percent of affected children are
      younger than five years of age. A generalized vasculitis of unknown etiology,
      Kawasaki disease can cause coronary artery abnormalities, including coronary
      aneurysms. From 20 to 25 percent of untreated children develop coronary artery
      abnormalities, which may resolve or persist. These abnormalities are of
      particular concern because they can lead to thrombosis, evolve into segmental
      stenosis or, rarely, rupture. The principal cause of death from Kawasaki disease
      is myocardial infarction. The cause of the disease remains unknown, but
      epidemiologic investigations and the clinical presentation suggest a microbial
      agent. Diagnostic criteria, including fever and other principal features, have
      been established. In the acute phase of the disease, treatment with
      acetylsalicylic acid and intravenously administered immunoglobulin is directed at
      reducing inflammation of the coronary arteries and myocardium. Early recognition
      and treatment of Kawasaki disease can reduce the development of potentially life
      threatening coronary artery abnormalities.

PMID- 10392593
TI  - Managing somatic preoccupation.
AB  - Somatically preoccupied patients are a heterogeneous group of persons who have no
      genuine physical disorder but manifest psychologic conflicts in a somatic
      fashion; who have a notable psychologic overlay that accompanies or complicates a
      genuine physical disorder; or who have psychophysiologic symptoms in which
      psychologic factors play a major role in physiologic symptoms. In the primary
      care setting, somatic preoccupation is far more prevalent among patients than are
      the psychiatric disorders collectively referred to as somatoform disorders (e.g.,
      somatization disorder, hypochondriasis). Diagnostic clues include normal results
      from physical examination and diagnostic tests, multiple unexplained symptoms,
      high health care utilization patterns and specific factors in the family and the
      social history. Treatment may include a physician behavior management strategy,
      antidepressants, psychiatric consultation and cognitive-behavior therapy.

PMID- 10392594
TI  - Evaluation and management of the child with speech delay.
AB  - A delay in speech development may be a symptom of many disorders, including
      mental retardation, hearing loss, an expressive language disorder, psychosocial
      deprivation, autism, elective mutism, receptive aphasia and cerebral palsy.
      Speech delay may be secondary to maturation delay or bilingualism. Being familiar
      with the factors to look for when taking the history and performing the physical
      examination allows physicians to make a prompt diagnosis. Timely detection and
      early intervention may mitigate the emotional, social and cognitive deficits of
      this disability and improve the outcome.

PMID- 10392596
TI  - Chronic non-healing ulcers.

PMID- 10392595
TI  - Angiotensin-II receptor antagonists: their place in therapy.
AB  - Angiotensin-II receptor antagonists (or blockers) are a newer class of
      antihypertensive agents. These drugs are selective for angiotensin II (type 1
      receptor); unlike angiotensin-converting enzyme inhibitors, they do not inhibit
      bradykinin metabolism or enhance prostaglandin synthesis. Angiotensin-II receptor
      antagonists are well tolerated. Cough occurs much less often with these agents
      than with angiotensin-converting enzyme inhibitors, and they do not adversely
      affect lipid profiles or cause rebound hypertension after discontinuation.
      Clinical trials indicate that angiotensin-II receptor antagonists are effective
      and safe in the treatment of hypertension. Their use in congestive heart failure
      and renal disease is under investigation.

PMID- 10392597
TI  - An HIV-positive patient who avoids treatment.

PMID- 10392598
TI  - American Thoracic Society issues consensus statement on dyspnea.

PMID- 10392600
TI  - AAP releases recommendations on use of inactivated and live oral polio vaccines.
      American Academy of Pediatrics.

PMID- 10392599
TI  - Treatment guidelines for heart failure stress multidrug approach.

PMID- 10392601
TI  - Intellectual disabilities and the next millennium: the role of the International
      Association for the Scientific Study of Intellectual Disabilities (IASSID)

PMID- 10392602
TI  - Identification of early self-injurious behaviour in young children with
      intellectual disability.
AB  - Very little is known about the early stages of self-injurious behaviour (SIB) in
      young children with developmental disabilities, even though there has been a
      great deal of research into the prevalence, assessment and treatment of well
      established SIB in older individuals. In the present initial study, teachers in
      special schools for children under II years of age with severe intellectual
      disability and/or autism were asked to identify children who were beginning to
      show early self-injury (the index group). These children were then matched to
      classroom controls (of the same ability level and mobility), and teachers were
      interviewed about the children's behaviours and skills. The index children showed
      significantly more potential SIB than the control group children, but there was
      overlap between the groups in terms of percentage duration of potential SIB,
      suggesting that teachers do not find it easy to identify children with 'early'
      SIB. The index children's skills and problem behaviours, their sensory
      impairments and degree of autism did not differ significantly from those of the
      control group. When all the children showing any potential SIB were pooled
      together, it transpired that developmental age and degree of mobility were
      significantly correlated with percentage duration of SIB, suggesting that these
      characteristics may be important risk markers. The index children were also
      observed at 3-month intervals at school over the following 18 months and self
      injury clearly escalated for some of the index children, while it did not do so
      for others. Using regression analysis, increases in SIB were shown to be
      associated only with the degree of concern expressed about the child's behaviour
      at time I by the teacher, no other variables predicting increases in SIB.

PMID- 10392603
TI  - Opportunity and the promotion of activity among adults with severe intellectual
      disability living in community residences: the impact of training staff in active
      support.
AB  - Active support, a package of procedures which includes activity planning, support
      planning and training on providing effective assistance, was introduced in five
      community residences serving 19 adults with severe intellectual disability
      following a multiple baseline design. The residents were directly observed to
      ascertain the level of assistance they received from staff and their engagement
      in activity. The introduction of active support increased the levels of
      assistance residents received, their engagement in domestic activities and their
      total engagement in activity. The intervention did not affect the level of social
      engagement. Across individuals, increases in assistance and engagement in
      activity were significantly and positively correlated. Both were significantly
      inversely related to resident adaptive behaviour. At baseline, staff gave more
      attention and assistance to people who were behaviourally more able. After the
      introduction of active support, receipt of attention was unrelated to adaptive
      behaviour and the behaviourally less able received more assistance. The disparity
      in activity between the more and less able was reduced. Gains were maintained in
      the majority of houses.

PMID- 10392604
TI  - Reliability, criterion-related validity and qualitative comments of the Fourth
      Edition of the Stanford-Binet Intelligence Scale with a young adult population
      with intellectual disability.
AB  - The test-retest reliability and concurrent, criterion-related validity of the
      Fourth Edition of the Stanford-Binet Intelligence Scale (SB-IV) were examined in
      a young adult population with intellectual disability. Forty adults with mild to
      moderate intellectual disability (mean age = 20.8 years; SD = 1.8 years) were
      administered the SB-IV and retested approximately 5 weeks later (mean = 33.4
      days, SD = 1.2). The Vineland Adaptive Behavior Scale: Interview Edition (VABS)
      was completed by a reliable informant within one week of the SB-IV testing. The
      test-retest reliability coefficients for the four SB-IV area and composite scores
      were all significant (P < 0.00). Individual subtest correlations tended to be
      lower but consistent across the two administrations. Moderate correlations were
      observed between the VABS composite and SB-IV composite scores. The present
      results provide support for the temporal reliability of the SB-IV and its
      concurrent, criterion-related validity in an exceptional sample.

PMID- 10392605
TI  - Proxy respondents and the reliability of the Quality of Life Questionnaire
      Empowerment factor.
AB  - Previous studies have questioned the reliability of Quality of Life Questionnaire
      (QOL-Q) Empowerment scores, and reported marked disagreement between consumers'
      self-reports and proxy data from staff informants. The present study examined
      agreement between consumer self-reports and proxy responses from community living
      staff for 63 adults with intellectual disability. Substantial positive
      correlations between consumers and staff were evident No significant difference
      was found between total QOL-Q Empowerment scores for self- or staff reports. It
      was concluded that the QOL-Q Empowerment factor is sufficiently reliable for use
      both by self-report and proxy respondents. Even so, proxy data are not a
      substitute for consumer self-reports and the two data sources should not be
      treated as being interchangeable.

PMID- 10392606
TI  - Communications between staff and adults with intellectual disabilities in
      naturally occurring settings.
AB  - Videotapes were made of 43 staff-client dyads in small-scale residential and day
      service settings. Frequency counts were made of carers' communicative acts, and
      two experienced speech and language therapists rated these for appropriateness.
      Recommendations for enhancing communication were also noted. The results showed
      that clients were presented with few opportunities to engage as equal partners in
      the conversational interchanges: staff overly relied on verbal acts, even when
      they were communicating with predominantly non-verbal clients; they tended to
      favour the use of directives and questions, and the majority of staff failed to
      adjust their language to the client's level of understanding. The most commonly
      recommended changes for staff were to use simpler sentences and words, to
      increase their use of non-verbal signals and open questions, to provide more
      opportunities for clients to initiate topics, and to increase their
      responsiveness to client's non-verbal signals. The explanations for staff
      behaviour are reviewed and the implications for changing practice are discussed.

PMID- 10392607
TI  - Organizational culture and staff outcomes in services for people with
      intellectual disabilities.
AB  - Organizational culture has been shown by organizational psychology to influence
      important aspects of staff behaviour. In particular, mismatches between staff
      perceptions of real and ideal organizational cultures have been shown to be
      associated with a range of negative outcomes for staff, such as stress, sickness
      and staff turnover. The present study investigates organizational culture in
      services for people with intellectual disabilities. The aim was to discover the
      prevalent organizational cultures in these services, and associations between
      organizational culture and staff outcomes. As part of a large-scale survey of
      staff in services for people with intellectual disabilities, information
      concerning organizational culture and staff outcomes was collected from 450
      staff. A self-report measure of real and ideal organizational culture produced
      nine dimensions of organizational culture: (I) tolerant/staff-oriented; (2)
      achievement-oriented; (3) innovative; (4) analytical; (5) social relationships;
      (6) rewarding staff; (7) stable work environment; (8) demanding; and (9) conflict
      management. These nine dimensions of organizational culture showed generally
      adequate psychometric properties. While there was some variation in
      organizational culture across services, there is little variation across staff
      with different job titles. Overall, the staff rated real organizational cultures
      to be relatively high in achievement orientation and fostering social
      relationships, and relatively low in managing conflict and providing rewards for
      staff. Staff rated ideal organizational cultures to be high in rewarding staff,
      being tolerant/staff-oriented and fostering social relationships, and low in
      demands on staff. Except for the dimension of making demands on staff, where
      staff rated organizations as considerably higher than ideal, staff generally
      rated organizations as being less than ideal on all dimensions of organizational
      culture. Organizational psychology theory predicts that poor 'person-organization
      fit' (i.e. a greater mismatch between real and ideal organizational culture) will
      be associated with a range of negative staff outcomes. This theory was largely
      supported by findings of the present study. The implications for practice and for
      future research are discussed.

PMID- 10392608
TI  - Family factors influencing out-of-home placement decisions.
AB  - Flying in the face of national community care policies, families of young
      children with severe disabilities continue to seek out-of-home placement The
      present paper explores the factors which influence families to care for their
      children at home or to place them out-of-home. Data for the present study were
      derived from a qualitative in-depth study of the everyday family life experiences
      of 167 families of young children with a disability and high support needs. One
      hundred and twenty-five (75%) of these families definitely did not want to place
      their child, 32 (19%) were undecided, and 10 (6%) were actively seeking or had
      already sought placement. Coded interview data were subjected to exploratory
      factor analysis to reveal eight factors influencing everyday family life. An
      analysis of variance (ANOVA) revealed significant differences between the three
      groups of families on three out of the eight factors. The families' views about
      placing their child were compared across the three groups using text analysis
      techniques. Without exception, the primary desire of all families was to care for
      their child at home. However, when placement was considered a possibility, even
      if remote, the most frequently reported reasons were family 'survival' and
      mitigating circumstances. The finding that one-quarter of the families had
      already sought or were considering placement for children in this young age range
      is provocative. The implications of the findings for policy and practice are
      discussed.

PMID- 10392609
TI  - Mortality in Down's syndrome in relation to congenital malformations.
AB  - Down's syndrome (DS) is the most common form of intellectual disability. The
      syndrome is characterized by congenital malformations, especially of the heart
      and gastrointestinal tract, which can result in high mortality rates in the
      affected population. Many improvements have been made in the medical treatment of
      this syndrome during the past few decades and the survival of individuals with DS
      has increased in the industrial world. The aim of the present study was to
      investigate mortality in relation to congenital malformations. Medical records
      from all liveborn children with DS delivered between 1973 and 1980 in northern
      Sweden were studied, and malformations and causes of death were recorded. Out of
      the 219 children included in the study, a congenital heart defect was reported in
      47.5% of subjects, 42.1% of whom had complete atrioventricular septal defect.
      Gastrointestinal tract malformations were present in 7.3% of subjects, and was
      frequently associated with a cardiac malformation and a very high mortality rate.
      Other major and minor congenital anomalies were present in 5.5% and 5.5% of
      subjects, respectively. In the 14.5-year follow-up of 213 children, the rate of
      survival was 75.6%. Mortality rates within one and 10 years after birth were
      14.6% and 23.5%, respectively. Mortality within 10 years differed significantly
      between children with (44.1%) and without (4.5%) a congenital heart defect. A
      very high mortality rate was observed among children with a congenital heart
      defect, especially when it was combined with a gastrointestinal malformation.

PMID- 10392610
TI  - Aetiology of intellectual disability--the Finnish classification: development of
      a method to incorporate WHO ICD-10 coding.
AB  - The present authors made an attempt to ease the diagnostic work of physicians who
      have patients with intellectual disability by creating an aetiological
      classification system based on the time and mechanism of injury to the central
      nervous system (CNS). The current paper presents the work-up needed for
      understanding at least the timing of the causative factor/factors. The timing
      principle opens a direct course to family counselling. This method has been very
      well accepted during its 18 years of use in Finland, and therefore, it was felt
      that it would be helpful to organize the relevant ICD-10 diagnoses according to
      the timing principle. This method has been published as a manual. An image of a
      tree became the obvious metaphor for this system. The genetic category forms the
      main root and stem, from which multiple branched roots and limbs emerge. The
      individual diagnoses appear as root nodules and leaves. The system is flexible,
      making it possible to add new branches for groups of diagnoses when improved
      diagnostic methods create these options (e.g. microdeletions). The aetiological
      diagnoses change accordingly. Over the course of further development, new
      incidents damaging the CNS may affect the functional level of an individual and
      require additional diagnoses. It is a constant challenge for physicians to keep
      the diagnoses of their patients up to date. The image of the tree helps
      professionals to think in terms of timing, and thus, makes family counselling
      easier. It is also helpful in the education of medical professionals.

PMID- 10392611
TI  - Novel adjuvants currently in clinical testing November 2-4, 1998, Fondation
      Merieux, Annecy, France: a meeting sponsored by the World Health Organization.

PMID- 10392612
TI  - EFI third annual scientific meeting, Milan, August 31st - September 1st, 1998.
      European Forum on Immunization.

PMID- 10392613
TI  - Preparation of ISCOMs with urea solubilised recombinant FMDV protein.

PMID- 10392614
TI  - A new method for risk analysis of vaccines.

PMID- 10392615
TI  - Outer membrane vesicles from group B meningococci are strongly immunogenic when
      given intranasally to mice.
AB  - Outer membrane vesicles (OMVs) from group B meningococci induced both serum and
      mucosal antibodies when given as a nasal and rectal vaccine to mice. Cholera
      toxin (CT) enhanced the antibody responses in serum both after nasal and rectal
      immunizations, and the mucosal responses after rectal immunizations only. Nasal
      immunizations, however, were most effective, with mucosal responses which were
      not dependent on the use of CT. The serum bactericidal activity was similarly not
      enhanced by CT, indicating that the positive effect of CT on the serum IgG level
      was not including bactericidal activity. A small nasal booster dose induced
      antibody responses in serum as far as eight months after intranasal and
      subcutaneous immunizations, and in saliva after intranasal immunizations. Nasal
      vaccines may thus be favorably combined with parenteral vaccines.

PMID- 10392616
TI  - Protection of kids against Cryptosporidium parvum infection after immunization of
      dams with CP15-DNA.
AB  - In this study the effectiveness of a DNA vaccine to confer protection against
      cryptosporidiosis, an enteric infection of lifestock and humans, was evaluated. A
      vaccination protocol using a recombinant plasmid encoding the 15 kDa surface
      sporozoite protein of Cryptosporidium parvum was developed in adult pregnant
      goats. The present study reports that nasal immunization of pregnant goats with
      CP15-DNA led to a transfer of immunity to offspring conferring protection against
      C. parvum infection. Kids from CP15-DNA-vaccinated dams shed significantly fewer
      oocysts and over a shorter period than did kids from unvaccinated goats. The low
      level of parasite development in protected kids did not affect their growth
      whereas unprotected kids grew much slowly. There was still a significant
      difference in the weights of protected and unprotected kids after complete
      recovery. Anti-CP15 antibodies were present in serum and colostrum from
      vaccinated goats. Nevertheless, the precise immune mechanism of protection has
      still to be determined. This vaccine should reduce the economic losses due to
      cryptosporidiosis in ruminants, specially in small ruminants (calves, lambs,
      kids). It has also the potential to reduce environmental contamination by
      reducing oocyst shedding.

PMID- 10392617
TI  - Identification of rubella virus T-cell epitopes recognized in anamnestic response
      to RA27/3 vaccine: associations with boost in neutralizing antibody titer.
AB  - Rubella virus (RV)-specific cell-mediated immunity (CMI) and antibodies were
      measured in healthy adolescents reimmunized with measles-mumps-rubella (MMR)
      vaccine. Lymphocyte proliferation to RV synthetic peptides was determined before
      and at 2, 4 and 10 weeks after, MMR. After MMR, increased CMI was observed with
      16 peptides, including six containing antibody neutralization (NT) domains.
      Positive CMI (stimulation index > or =2.0) to E1(254-285) and C(1-29) before
      vaccination was significantly associated with a boost in NT titers, while
      positive CMI at weeks 2 or 4 to E1(254-285), E1(301-314), E1(389-408), E1(462
      481), E2(134-150), E2(140-156), E2(168-179), C(1-29) and C(88-111) showed the
      same association.

PMID- 10392618
TI  - Intranasal murine model of Bordetella pertussis infection. I. Prediction of
      protection in human infants by acellular vaccines.
AB  - Bicomponent, tricomponent and pertactin DTPa vaccines were tested in sublethal
      aerosol, and lethal and sublethal intranasal murine Bordetella pertussis
      respiratory challenge models. Pertactin and bicomponent vaccines induced
      protective immunity against lethality but with little or no bacterial clearance.
      Intranasal challenge discriminated in a reproducible, statistically significant
      manner between the efficacies of bicomponent and tricomponent DTPa, in agreement
      with clinical trial data. This discrimination was not observed in the aerosol
      challenge. Pertactin had a synergistic effect with bicomponent DTPa. Intranasal
      challenge may be useful as part of the preclinical evaluation of new acellular
      pertussis formulations or DTPa-based combinations.

PMID- 10392619
TI  - Neisseria meningitidis serogroup B outer membrane vesicle vaccine in adults with
      occupational risk for meningococcal disease.
AB  - Vaccination provides a safe and effective means of reducing the risk of
      laboratory-acquired infection due to some Neisseria meningitidis serogroups.
      However, there is currently no serogroup B meningococcal vaccine licensed for use
      in the US. We used an investigational N. meningitidis serogroup B outer membrane
      vesicle (B:15:P1.7,16) vaccine produced by the National Institute of Public
      Health (NIPH) in Norway to immunize 20 researchers with occupational risk for
      disease. Three doses of vaccine were administered via intramuscular injection at
      8-week intervals. The vaccine produced moderate or severe pain with 19 (33%) of
      the 58 doses administered. Reactions were similar following first, second and
      third doses. The number and severity of reactions peaked at 24 h postvaccination
      and then gradually waned. Of 16 vaccinees with results available from all blood
      draws, 12 (75%) showed a fourfold or greater rise in serum bactericidal activity
      (SBA) against the vaccine type-strain following two doses of vaccine, and 15
      (94%) responded after three doses. Geometric mean titers increased by more than
      sixfold following two doses of vaccine when compared with prevaccination levels,
      and by more than 11-fold following a third dose. There was no significant
      difference between SBA measured using the vaccinee's own complement versus a
      donor complement source. The NIPH vaccine elicited an excellent bactericidal
      response against the vaccine type-strain in researchers with an occupational risk
      for disease. It may be useful for other laboratory personnel who routinely work
      with meningococcal strains containing similar outer membrane antigens. These
      findings reconfirm that the NIPH vaccine is immunogenic in adults and support the
      validity of using properly screened human donor complement in serum bactericidal
      assays against serogroup B meningococci.

PMID- 10392620
TI  - Poliovirus replicons encoding the B subunit of Helicobacter pylori urease elicit
      a Th1 associated immune response.
AB  - The development of a vaccine for Helicobacter pylori is a key strategy for
      reducing the worldwide prevalence of H. pylori infection. Although immunization
      with recombinant B subunit of H. pylori urease (ureB) has yielded promising
      results, for the most part, these studies relied on the use of strong adjuvant,
      cholera toxin, precluding the use in humans. Thus, the development of new vaccine
      strategies for H. pylori is essential. Previous studies from our laboratory have
      described a vaccine vector based on poliovirus in which foreign genes are
      substituted for the poliovirus capsid genes. The genomes encoding foreign
      proteins (replicons) are encapsidated into authentic poliovirions by providing
      the capsids in trans. To test the utility of replicons as a vaccine vector for H.
      pylori, a replicon was constructed which encodes ureB. Expression of ureB in
      cells from the replicon was demonstrated by metabolic labeling followed by
      immunoprecipitation with anti-urease antibodies. To investigate the
      immunogenicity of the replicons, mice containing the transgene for the receptor
      for poliovirus were immunized via the intramuscular route. Mice given three doses
      of replicons did not develop substantial antibodies to ureB as determined by
      Western blot analysis using lysates from H. pylori. In contrast, mice given two
      doses of replicon followed by a single injection of recombinant ureB developed
      serum antibodies to ureB which were predominately IgG2a. Splenic lymphocytes from
      mice immunized with replicons alone, or replicons plus recombinant ureB produced
      abundant interferon-gamma and no detectable interleukin-4 upon stimulation with
      recombinant ureB. These results establish that poliovirus replicons encoding H.
      pylori ureB are immunogenic and induce primarily a T helper 1 associated immune
      response.

PMID- 10392621
TI  - A V3 loop haptenic peptide sequence, when tandemly repeated, enhances
      immunogenicity by facilitating helper T-cell responses to a covalently linked
      carrier protein.
AB  - Subunit immunogens containing tandemly repeated copies of T- and B-cell epitopes
      have been shown to be more immunogenic than the respective immunogen containing
      only a single copy of the sequence. It has been unclear, however, whether the
      increased immunogenicity of a tandemly repeated B-cell epitope necessarily
      results from increased helper T-cell responses to intrinsic T-cell epitopes in
      the tandemly repeated sequences, or to neodeterminant T-cell epitopes created at
      the junction of adjacent repeat sequences. We examined this question by comparing
      the immunogenicity in mice of two immunogens containing one or eight tandemly
      repeated copies of an HIV-1 V3 loop haptenic sequence. Our results show that the
      tandemly repeated haptenic sequence potentiates the immunogenicity of the protein
      construct, likely through the facilitation of enhanced B-cell interaction with
      the tandem repeat construct and the consequent elicitation of increased carrier
      protein-specific helper T-cell responses.

PMID- 10392622
TI  - An economic evaluation of universal pertussis vaccination in Italy.
AB  - An economic evaluation was performed of universal acellular pertussis vaccination
      in Italy, where until recently the overall coverage of pertussis vaccination was
      estimated at 50%. Over the last two years coverage seems to have increased
      rapidly. By means of a mathematical simulation model, the consequences of
      pertussis vaccination in terms of both health effects and economic costs were
      calculated for a single birth cohort followed for 6 years. Incremental analyses
      were performed for each additional 10% increase in coverage from 50-90%. The
      results indicate that a 50% coverage rate of pertussis vaccination in Italy was
      not optimal on the basis of cost-effectiveness and cost-benefit considerations.
      Additional increases in coverage were found to yield extra health gains at modest
      net costs or even potential net savings to the health care sector. For example,
      an increase in coverage to 90% would yield direct net savings of US$42 per extra
      vaccinee in comparison to a situation of 50% coverage. The total net savings for
      this strategy would be well over US$100 per additional vaccinee. In the
      sensitivity analysis, the positive relationship between incremental coverage and
      incremental efficiency remained unchanged.

PMID- 10392623
TI  - Biodegradable lamellar particles of poly(lactide) induce sustained immune
      responses to a single dose of adsorbed protein.
AB  - The adjuvanticity of lamellar particles of poly(L-lactide) (PLA) towards adsorbed
      ovalbumin (OVA) was investigated. The aim of vaccine formulation was to maximise
      the amount of antigen retained on the particles and the time of retention during
      incubation of the formulations in PBS at 37 degrees C. Unmodified PLA lamellae
      were capable of adsorbing large quantities of OVA (up to 12.5% w/w) but major and
      rapid desorption occurred in PBS at 37 degrees C (80% released in 24 h).
      Retention of OVA on PLA lamellae was improved (25% released in 24 h) by
      precipitating the particles using aqueous sodium deoxycholate solution (DOC
      modified PLA lamellae and lyophilising the lamellae-protein preparation after
      adsorption. Sustained immune responses were elicited in mice to a single sub
      cutaneous injection of OVA adsorbed onto DOC-modified PLA lamellae. The level of
      antibodies induced and the pattern of response was similar to that induced by an
      alum-adsorbed OVA formulation. Normally boosting is required to obtain high
      levels of antibody when OVA is adsorbed on poly(DL-lactide co-glycolide) (PLG)
      microspheres. The lamellar forms of PLA may function as an efficient
      immunomodulator by effectively retaining adsorbed antigen and by activating
      immune cells due to their irregular shape. PLA lamellae have potential to
      stimulate enhanced immune responses to a variety of adsorbed antigens.

PMID- 10392625
TI  - Immunity to airborne challenge with Venezuelan equine encephalitis virus develops
      rapidly after immunization with the attenuated vaccine strain TC-83.
AB  - Mice vaccinated subcutaneously with the attenuated vaccine strain of Venezuelan
      equine encephalitis virus (VEEV) rapidly develop immunity to subcutaneous or
      airborne challenge with virulent VEEV. The specificity of this immune response
      was demonstrated by challenge with a heterologous virus (St. Louis encephalitis
      virus). Examination of the levels of VEEV-specific antibody classes in serum and
      respiratory secretions suggested that the rapid development of immunity was
      coincident with the appearance of specific IgM and IgG (but not IgA) in the
      respiratory tract. In order to confirm the role of respiratory tract antibody,
      mice were passively immunised either intraperitoneally or intranasally with
      polyclonal VEEV-specific IgG. Intranasal administration of specific IgG
      significantly enhanced protection against airborne challenge. These results
      confirm the need to emphasise local antibody production in the development of
      improved VEEV vaccines.

PMID- 10392624
TI  - Development of a tetrazolium salt assay for rapid determination of viability of
      BCG vaccines.
AB  - Standardisation and control of the live Mycobacterium bovis BCG (BCG) vaccine is
      performed as specified by the World Health Organisation (WHO) and the European
      Pharmacopoeia (EP). The conventional viable count for control of potency of BCG
      vaccine is performed by culturing on solid medium. This assay method is not only
      time consuming but may give variable results. A tetrazolium salt assay has been
      developed and evaluated as a potential additional, or replacement, test for
      determining number of viable organisms. The tetrazolium salts 3-(4,5
      dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 2,3-bis-(2
      methoxy-4-nitro-5-sulphenyl)-(2H)-tetrazolium-5-carb oxanilide (XTT) used as
      alternative substrates in the assay both gave more rapid and reproducible results
      than the conventional viable count. XTT showed greater sensitivity than MTT with
      a lower detection limit of about 7x10(4) colony forming units (c.f.u.) ml(-1).
      The XTT assay has proven effective for determining viability of suspensions
      prepared from several BCG vaccine substrains, covering a range of viable units,
      without the need for modification. This assay is easily performed and takes just
      48 h to produce an estimate of viable cell content compared with 3 weeks for the
      conventional method.

PMID- 10392626
TI  - A hemagglutinin-derived peptide-vaccine ignored by virus-neutralizing passive
      antibodies, protects against murine measles encephalitis.
AB  - The neutralizing and protective monoclonal antibody BH47 defines the sequential
      epitope H236-255 of the measles virus hemagglutinin protein (MV-H). The objective
      of this study was to design peptides combining this B cell epitope (BCE) with
      different T cell epitopes (TCE) to obtain protective immunity. Most TTB peptides
      based on the 15mer BCE H236-250 induced MV-crossreactive antibodies, but only
      certain TCE induced virus neutralizing antibodies. The shortest BCE required for
      MV-reactivity and -neutralization was the 8mer H243-250 containing residue R243
      implicated in CD46 down-regulation. Sera obtained after immunization with the TTB
      peptide containing the MV-derived TCE F421-435 protected mice against a lethal
      challenge with a neuro-adapted MV strain. Our results further demonstrate that
      this TTB peptide is fully immunogenic, even in the presence of protective levels
      of pre-existing MV-specific antibodies, suggesting that subunit vaccines based on
      such peptides could potentially be used to immunize infants in the presence of
      persisting maternal antibodies. It is therefore interesting that neutralizing
      antibodies were also obtained with a TTB peptide comprising a human promiscuous
      TCE (tt830). However, our results also emphasize the need to test sera induced
      with epitope-based vaccines against different virus strains, in particular if the
      epitope is not fully conserved.

PMID- 10392627
TI  - Effect of the bacillus of Calmette-Guerin, Propionibacter acnes and avridine as
      immunomodulators in antirabies vaccination of mice using the Fuenzalida-Palacios
      mouse brain vaccine.
AB  - Using the laboratory mice, Fuenzalida-Palacios mouse brain human rabies vaccine
      was administered in groups of animals previously inoculated with rabies virus and
      then submitted to treatments with the immunomodulators onco-BCG, avridine and
      Propionibacterium acnes. Humoral and cellular immune responses were evaluated
      through the macrophage inhibition factor (MIF), intra-pad inoculation (IPI) and
      serum neutralization (SN) tests and by the detection of gamma-interferon (IFN
      gamma). The IPI test was not effective in detecting the response of delayed-type
      hypersensitivity, contrary to MIF, which showed the immune cellular response.
      Higher levels of IFN-gamma were observed in the groups of mice vaccinated and
      treated with avridine and P. acnes. Although immunomodulating activities have
      been detected, the use of adjuvants with the Fuenzalida-Palacios type vaccine in
      mice did not reveal any encouraging results.

PMID- 10392628
TI  - Hyperimmune bovine colostrum specific for recombinant Cryptosporidium parvum
      antigen confers partial protection against cryptosporidiosis in immunosuppressed
      adult mice.
AB  - Preparturient cows were immunized three times over a six-week period with
      recombinant plasmid DNA encoding the Cryptosporidium parvum CP15/60 antigen by
      injecting the DNA in the mammary gland. Serum was collected at each immunization
      and first colostrum was collected after parturition; all were assayed for
      Cryptosporidium-specific antibodies (Ab). A serological response to C. parvum
      sporozoite and oocyst antigen was detected in cows immunized with pCP15/60
      plasmid DNA. Colostrum from these cows, unlike colostrum from normal controls,
      contained Ab specific for C. parvum sporozoites and oocysts as indicated by
      immunofluorescence Ab (IFA) staining. Colostrum was also tested for conferring
      passive immunity against C. parvum infection by oral administration to
      immunosuppressed adult inbred mice. Immune colostrum and control colostrum were
      administered to separate groups of dexamethasone (DEX)-treated adult C57BL/6NCr
      mice beginning 12 h before and at 12 h intervals for 3 days after oral C. parvum
      oocyst infection. Cryptosporidium development was assayed in ilea of immune- and
      control-colostrum-treated mice 96 h postinfection by semiquantitative PCR. Mice
      receiving immune colostrum showed partial protection (about 50% reduction)
      against intestinal C. parvum development compared to mice receiving control
      colostrum. This protection was evident at a challenge dose of 10(3) C. parvum
      oocysts per mouse; no differences were noted in parasite development between
      groups receiving immune or control colostrum and infected with 10(4) oocysts.
      This study showed that serum and colostrum Ab response to C. parvum can be
      elicited in preparturient cows by direct injection of recombinant pCP15/60
      plasmid DNA and that passive protection against cryptosporidiosis can be obtained
      by treating immunosuppressed mice with immune colostrum before and after C.
      parvum infection.

PMID- 10392629
TI  - Biochemical and immunologic comparison of virus-like particles for a rotavirus
      subunit vaccine.
AB  - A parenterally administered rotavirus vaccine composed of virus-like particles
      (VLPs) is being evaluated for human use. VLPs composed of bovine VP6 and simian
      VP7 (SA11, G3) proteins (6/7-VLPs) or of bovine VP2, bovine VP6, and simian VP7
      (SA11, G3) proteins (2/6/7-VLPs) were synthesized and purified from Sf9 insect
      cells co-infected with recombinant baculoviruses. 6/7- and 2/6/7-VLP administered
      parenterally (i.m.) in mice had comparable immunogenicity, but the 2/6/7-VLPs
      were more homogeneous and stable. The inclusion of the VP2 capsid contributed to
      particle formation and stability. The adjuvant QS-21 significantly enhanced the
      immunogenicity of 2/6/7-VLPs over A10H or saline alone. Equivalent serum
      neutralizing antibody responses were induced over the range of 1-15 microg/dose
      of 2/6/7-VLPs administered with the range of 5-20 microg/dose of QS-21. The
      immunogenicity of 2/6/7-VLPs and inactivated SA11 virus were comparable. 2/6/7
      VLPs are a promising candidate for a parenterally delivered rotavirus subunit
      vaccine.

PMID- 10392630
TI  - Collagenous fibroma (desmoplastic fibroblastoma): genetic link with fibroma of
      tendon sheath?
AB  - We observed clonal chromosome abnormalities in two fibrous soft tissue tumors
      diagnosed as collagenous fibroma (desmoplastic fibroblastoma). The involvement of
      the same band of the long arm of chromosome 11, 11q12, was observed in both
      tumors. The presence of hitherto unreported similar chromosomal abnormalities in
      this tumor supports the neoplastic nature of this lesion. In addition, a possible
      relationship with fibroma of tendon sheath, which also shows rearrangement of
      11q12, is suggested. 11q12 might be a common genetic denominator of benign
      fibroblastic lesions, such as collagenous fibroma and fibroma of tendon sheath.

PMID- 10392631
TI  - Lymphangioma and congenital pulmonary lymphangiectasis: a histologic,
      immunohistochemical, and clinicopathologic comparison.
AB  - Lymphangioma (LA) and congenital pulmonary lymphangiectasis (CPL) are part of a
      spectrum of lymphatic disorders less well characterized than other vascular
      tumors and malformations. Recent studies showed proliferative and involutional
      growth phases for hemangiomas that distinguish them from malformations. We
      investigated immunohistochemical reactivity and proliferative activity to
      determine whether a similar diagnostically/prognostically useful pattern exists
      for LA, comparing LA with CPL as a malformative lesion. Immunohistochemical tests
      for vimentin, Factor VIII-related protein, CD31, CD34, CD45RO, smooth muscle
      actin, Type IV collagen, MIB-1, bcl-2, and topoisomerase IIalpha were performed
      on 20 LAs and 10 cases of CPL. Giemsa staining was also performed to quantitate
      mast cells. Clinicopathologic correlation was performed by medical record review.
      LA and CPL shared a similar immunohistochemical profile for vimentin, Factor VIII
      related protein, CD31, CD34, smooth muscle actin, CD34, and, to a lesser extent,
      CD45RO. CD31 and CD34 displayed the most uniform pattern of endothelial
      reactivity, although CD34 had high background staining. bcl-2 was negative. Four
      LAs exhibited focal low reactivity for MIB-1 and topoisomerase IIalpha; recent
      infection and thrombosis were associated conditions. LAs displayed seven-fold
      more mast cells and more reactive T lymphocytes than did cases of CPL. LA and CPL
      had similar immunohistochemical profiles; LA resembled vascular malformations
      more than hemangiomas. CD31 and CD34 were useful for detection of small
      lymphatics at resection margins of LA, a feature associated with recurrence. MIB
      1 and topoisomerase IIalpha expression were associated with inflammatory,
      thrombotic, or reactive processes and were not diagnostically useful. Abundant
      mast cells, which also were noted in other soft tissue neoplasms, prompt
      speculation concerning their role in the growth of LAs.

PMID- 10392632
TI  - Analysis of 35 cases of localized and diffuse tenosynovial giant cell tumor: a
      report from the Chromosomes and Morphology (CHAMP) study group.
AB  - The karyotypes of 44 specimens from 35 patients with localized (n = 19) or
      diffuse (n = 16) tenosynovial giant cell tumors were studied. The majority of
      cases in both categories (11 of 19 localized; 12 of 16 diffuse) displayed clonal
      chromosomal aberrations, with a complex karyotype in three cases and a simple
      chromosomal aberration in the others. No difference in the distribution of
      karyotypic abnormalities was found between the localized and diffuse form except
      for trisomies (usually of chromosomes 5 and/or 7), which were more frequent in
      the diffuse type. The short arm of chromosome 1 (1p11-13) was most frequently
      rearranged, with 7 of 11 localized and 7 of 12 diffuse lesions affected. These
      findings indicate that the localized and diffuse forms of tenosynovial giant cell
      tumor might represent two morphologic manifestations of the same entity. The high
      frequency of clonal chromosomal abnormalities, with a clustering of structural
      rearrangements to 1p11-13, suggests that this disease is most likely neoplastic
      in nature and paves the way to search for gene(s) that might be involved in its
      development.

PMID- 10392634
TI  - Spindle-cell neuroendocrine carcinomas of the thymus (spindle-cell thymic
      carcinoid): a clinicopathologic and immunohistochemical study of seven cases.
AB  - Seven cases of spindle-cell neuroendocrine carcinomas (carcinoid tumors) of the
      thymus are presented. The patients were three women and four men between the ages
      of 26 and 74 years (median age, 50 yr). The lesions presented as large anterior
      mediastinal masses on radiographic examination and were treated by surgical
      excision. Grossly, the tumors were tan-brown and well circumscribed but
      encapsulated, and they measured from 2 to 15 cm in greatest diameter.
      Histologically, they were characterized by a dense proliferation of spindle cells
      that focally adopted a vaguely organoid pattern, with discrete nests of tumor
      cells separated by thin fibrovascular septa. Mitotic figures were present in all
      of our cases and ranged from 2 to 8 per 10 high power fields. Focal areas of
      necrosis were also present in all of the cases. Immunohistochemical studies
      performed in six cases showed positive staining for chromogranin in five cases,
      synaptophysin and keratin in four, and Leu 7 in three. Clinical follow-up showed
      that two patients died of their tumors 6 and 11 years after diagnosis; one was
      alive 8 years after diagnosis. Spindle-cell neuroendocrine carcinomas of the
      thymus (spindle-cell thymic carcinoids) should be considered in the differential
      diagnosis of spindle-cell neoplasms of the anterior mediastinum. Because of their
      aggressive clinical behavior, it is important to separate them from the other
      benign or low-grade spindle-cell tumors that are more common at this location.

PMID- 10392633
TI  - mdm-2 expression correlates with wild-type p53 status in esophageal
      adenocarcinoma.
AB  - Several immunohistochemical studies showed that p53 protein is expressed in 50 to
      80% of esophageal adenocarcinomas (EAs). Mutations of this tumor suppressor gene
      are present in 40 to 70% of EAs, so it is possible that p53 expression might
      occur as a result of mechanisms other than gene mutation. The human homologue of
      the murine double minute-2 gene (mdm-2) is a known regulator of p53 activity, and
      its expression results in stabilization of the wild-type p53 protein and loss of
      its tumor suppressor function. In this study, we evaluated the frequency of mdm-2
      amplification and expression in EA and investigated the relationship between mdm
      2 expression and p53 mutation. Thirty-three resection specimens of EAs and
      associated Barrett's esophagus were evaluated by immunohistochemical methods for
      p53 and mdm-2 expression. Sixteen of these cases were also evaluated for p53
      mutations with use of polymerase chain reaction, single-strand conformational
      polymorphism, and DNA sequencing and for mdm-2 amplification with a differential
      polymerase chain reaction-based amplification analysis. Overexpression of p53 was
      present in 23 EAs (70%), and 18 EAs (55%) overexpressed mdm-2. p53 mutation was
      observed in 7 (43%) of 16 cases, whereas mdm-2 gene amplification was not
      detected in any. To summarize, we found substantial discordance of p53
      immunohistochemical features and mutation in EA. Significant expression of mdm-2
      occurred only in cases with wild-type p53, whereas all of the cases with p53
      mutation showed little if any expression of mdm-2. Also, mdm-2 expression in
      cases with p53 overexpression but without p53 mutation exceeded mdm-2 expression
      in cases with p53 overexpression and p53 gene mutation. In cases without p53
      mutation, overexpression of mdm-2 occurred in 50% of cases and might be
      responsible for stabilization of p53 protein and possible loss of tumor
      suppressor function.

PMID- 10392635
TI  - Gastric histologic findings in patients with nonsteroidal anti-inflammatory drug
      associated gastric ulcer.
AB  - The purpose of this study was to characterize gastric histologic findings in
      patients with nonsteroidal anti-inflammatory drug (NSAID)-associated gastric
      ulcer (GU). Gastric biopsy specimens from 136 patients with NSAID-related GU were
      compared with those from a control population of 185 patients with Helicobacter
      pylori-related gastritis. Foveolar hyperplasia, edema, muscular stranding,
      vascular ectasia, and active and chronic inflammation were semiquantitatively
      graded. Lymphoid aggregates, intestinal metaplasia, atrophy, and cystic gland
      changes were noted. No single parameter reliably distinguished between the two
      populations, although moderate/severe foveolar hyperplasia, edema, and vascular
      ectasia were significantly more common in the NSAID group. With use of the Dixon
      scoring system for reflux/reactive gastropathy, with a threshold score of 11 or
      more, 39 (29%) patients in the NSAID group were correctly diagnosed as having
      reactive gastropathy (sensitivity, 29%; specificity, 100%; positive predictive
      value, 100%). When the Dixon scoring threshold score was decreased to 8 or more,
      114 (84%) patients were classified as having reactive gastropathy (sensitivity,
      84%; specificity, > 99%; positive predictive value, > 99%). We conclude that a
      decreased threshold enhances the usefulness of the reactive gastropathy score in
      the NSAID-related GU population. Additional studies, however, must be performed
      to evaluate the effect of a lowered threshold relative to a normal population and
      those with other causes of reactive gastropathy.

PMID- 10392636
TI  - Intrahepatic expression of hepatitis B virus antigens: effect of hepatitis C
      virus infection.
AB  - Coinfection with hepatitis B and C viruses (HBV, HCV) is not uncommon, but the
      expression of HBV antigens in the liver of patients with concomitant HCV
      infection has not been investigated. This study aimed to evaluate the effects of
      concomitant HCV infection on the intrahepatic expression of HBV antigens in
      chronic hepatitis. HBV surface and core antigens (HBsAg, HBcAg) were
      immunohistochemically evaluated and semiquantitatively scored in liver biopsy
      specimens from patients with chronic hepatitis, comprising 17 cases with dual
      HBV/HCV infection and 25 with HBV infection alone. The prevalence of HBV Ag
      expression proved significantly lower in the group with dual infection. In the
      presence of active HBV replication (HBV DNA-positive serum) the prevalence of
      HBsAg and HBcAg immunoreaction was similar in the two groups, though a
      significantly lower percentage of cells expressed HBcAg in the group of
      coinfected patients. HBV Ag was not detected at all among HBV DNA-negative/HCV
      RNA-positive cases. In conclusion, these observations suggest that HCV might
      influence HBV antigen expression in the liver and that either partial or complete
      suppression might occur.

PMID- 10392637
TI  - Enhanced epithelial cell turnover associated with p53 accumulation and high
      p21WAF1/CIP1 expression in ulcerative colitis.
AB  - To cast light on accelerated epithelial cell turnover as an important risk factor
      of dysplasia and carcinoma development in patients with long-standing ulcerative
      colitis (UC), we examined cell proliferation and cell death, as well as
      expression of apoptosis-related markers, including p53 and p21WAF1/CIP1, in a
      series of cases. Biopsy specimens (n = 176; 84, active phase; 92, remission) were
      endoscopically obtained from 25 Japanese patients with UC. As controls, 68 biopsy
      specimens of normal mucosa were also examined from 27 Japanese patients with
      colon polyps. We counted the numbers of mitoses, apoptotic bodies, Ki-67
      immunoreactive cells, and p21WAF1/CIP1-immunoreactive cells per 1000 crypt cells
      and the numbers of p53-positive cells per crypt. All of the indices in active UC
      were significantly higher than in either remitting UC cases or normal cases (mean
      mitotic index = 0.52, 0.28, and 0.15%, respectively; apoptotic index = 5.40,
      2.91, and 1.30%, respectively; Ki-67 labeling index = 39.5, 28.3, and 26.8%,
      respectively; p21WAF1/CIP1 labeling index = 33.6, 20.0, and 19.0%, respectively;
      p53 labeling index = 0.66, 0.13, 0.13 per crypt, respectively). In addition, the
      mitotic, apoptotic, and Ki-67 labeling indices were increased in remitting UC of
      more than 10 years' duration, in comparison with those of less than 10 years'
      duration or the normal group. Immunostaining of serial sections revealed a small
      number of crypt cells coexpressing p53 and p21WAF1/CIP1. Increases in both
      epithelial cell proliferation and cell death, partially associated with p53
      accumulation and high p21WAF1/CIP1 expression, are thus characteristic of active
      phase UC, as well as in remission of long-standing UC. Accelerated epithelial
      cell turnover caused by chronic inflammation and epithelial damage might
      predispose the mucosa to DNA damage, resulting in an elevated risk of mutation in
      line with dysplasia and carcinoma development in patients with UC.

PMID- 10392638
TI  - bcl-2 immunoreactivity, human papillomavirus DNA, and cervical intraepithelial
      neoplasia.
AB  - The aim of this study was to identify the role of bcl-2 protein expression in
      precancerous lesions of the cervix in patients from Johannesburg, South Africa
      and to correlate this expression with human papillomavirus (HPV) status. Archival
      cervical biopsy specimens (n = 107) of normal squamous epithelia (n = 18), pure
      HPV squamous epithelial lesions (n = 15), cervical intraepithelial neoplasia
      (CIN) I lesions (n = 17), CIN II lesions (n = 26), and CIN III lesions (n = 31)
      underwent bcl-2 immunohistochemical analysis with use of the streptavidin-biotin
      complex/horseradish peroxidase system and nonisotopic in situ hybridization for
      the detection of HPV DNA. Although 45 (61%) of the 74 CIN lesions demonstrated
      bcl-2 protein expression in the epithelia, most seemed to be in a patchy basal
      cell distribution, with a 1+ to 2+ intensity. Furthermore, comparison of bcl-2
      immunoreaction between the low and high grades of the CIN lesions did not reveal
      significant differences. In addition, there was no apparent link between the
      presence of HPV DNA and bcl-2 expression in the CIN lesions. In contrast to
      previous studies that showed an increase in bcl-2 immunostaining intensity with
      increasing severity of CIN, only 4 (5.4%) of our 74 CIN specimens satisfied this
      pattern. Hence, we suggest that bcl-2 protein expression might not play a
      significant role in the majority of CIN lesions in this population group and that
      it might not correlate with HPV status.

PMID- 10392640
TI  - Expression of Rab3, a Ras-related GTP-binding protein, in human nontumorous
      pituitaries and pituitary adenomas.
AB  - Rab proteins are low molecular weight GTP-binding proteins. Among these proteins,
      the Rab3 isoforms are considered to be involved in the exocytosis of synaptic
      vesicles and secretory granules in the central nervous system and anterior
      pituitary gland. In recent reports, the expression of Rab3 isoforms in anterior
      pituitary glands of mammalian species was extensively investigated. In the
      present study, we investigated the localization of Rab3 protein in 5 human
      nontumorous pituitaries and 114 human pituitary adenomas using
      immunohistochemical methods. In five human nontumorous pituitaries, Rab3 protein
      was expressed in the cytoplasm of anterior pituitary cells. Double staining for
      anterior pituitary hormones revealed the expression of Rab3 in growth hormone
      secreting cells, but rare expression was observed in the other anterior pituitary
      hormone-secreting cells. Among the pituitary adenomas, 71 (62.3%) of 114
      pituitary adenomas were positive for Rab3. Among the different pituitary adenoma
      types, the incidence of Rab3 immunopositivity was highest in growth hormone
      secreting adenomas (100%), followed by adrenocorticotropic hormone-secreting
      adenomas (71.4%), thyroid-stimulating hormone-secreting adenomas (57.1%),
      nonfunctioning adenomas (56.0%), and prolactin-secreting adenomas (33.3%). After
      an embedding immunoelectron microscopic study, Rab3 was localized along the
      limiting membrane of secretory granules in the Rab3-positive pituitary adenomas.
      Western blotting showed the molecular weight of Rab3 to be 25 kDa in the
      pituitary adenomas, which were immunohistochemically positive for Rab3 protein.
      These results suggested that Rab3 might be involved in regulating the exocytosis
      of secretory granules of the anterior pituitary cells, especially growth hormone
      secreting ones, which are particularly characterized by densely granulated
      cytologic features.

PMID- 10392639
TI  - Expression of the Ets-1 proto-oncogene correlates with malignant potential in
      human astrocytic tumors.
AB  - The protein encoded by the Ets-1 proto-oncogene is a transcription factor that
      regulates expression of matrix proteases. It has been associated with tumor
      invasion and angiogenesis. Glioma progression is characterized by increased
      invasiveness and neovascularization, so we hypothesized that expression of Ets-1
      proto-oncogene might play a role in the progression of these tumors. Therefore,
      we examined the expression of Ets-1 protein by immunohistochemical means and in
      situ hybridization in tissues obtained from 81 primary and 20 recurrent
      astrocytic tumors. Twenty-eight (65%) of 43 glioblastomas (Grade IV astrocytomas)
      stained for Ets-1. The percentage of positive cells in glioblastomas varied from
      10 to 90%. Of the 16 anaplastic astrocytomas (Grade III), 4 (25%) were moderately
      positive (<50% of cells) for Ets-1. None of 22 cases of low-grade astrocytomas
      (Grade II) expressed endogenous Ets-1. The staining score was significantly
      associated with tumor grade (P < .0001). Normal brain tissues did not express Ets
      1 protein, whereas recurrent astrocytoma cases expressed significantly more
      positivity for Ets-1 than did primary tumors (P = .03). The Ets-1 protein was
      observed mainly in the nucleus and corresponded to the cytoplasmic Ets-1 mRNA
      localization by in situ hybridization. Western and Northern blot analyses
      confirmed overexpression of Ets-1 protein and mRNA in high-grade tumors. We
      conclude that Ets-1 protein expression correlates with the malignant potential of
      tumors of astroglial origin.

PMID- 10392641
TI  - Pathologic detection of early myocardial infarction: a critical review of the
      evolution and usefulness of modern techniques.
AB  - The limitations of post mortem detection of early myocardial infarction by
      hematoxylin and eosin staining stimulated a search for the development of
      improved diagnostic methods based on biochemical and morphologic changes. Methods
      used and/or investigated included electron microscopic examination, gross and
      microscopic histochemical stains (tetrazolium salts, phosphotungstic acid
      hematoxylin, trichrome, periodic acid-Schiff, hematoxylin-basic fuchsin-picric
      acid), fluorescence, immunohistochemical techniques, and chemical analysis of
      pericardial fluid. This practical review, designed for both forensic and hospital
      based autopsy pathologists, examines the methods available for post mortem
      diagnosis of myocardial infarction for cases in which death might have occurred
      before the evolution of changes detectable by hematoxylin and eosin staining. The
      status and potential usefulness of each adjunct to classical morphologic
      examination is summarized. Recent developments are highlighted, including the
      possibility of using apoptosis as a marker for acute ischemic injury.

PMID- 10392642
TI  - Human eastern equine encephalitis: immunohistochemistry and ultrastructure.
AB  - The brain of a 7-year-old boy who died of eastern equine encephalitis (EEE) was
      examined by immunohistochemical and ultrastructural techniques to detect the
      presence and distribution of viral antigen. A mouse polyclonal antibody was most
      effective for demonstrating the presence of antigen previously unreported in this
      disease in humans. Antigen was localized to the perikaryon and dendrites of
      neurons; little was detected in glial cells. Cell death by apoptosis was
      conspicuous, but it was primarily identified in glial and inflammatory cells.
      Neuronal death was most commonly marked by cytoplasmic swelling or eosinophilia
      and nuclear pyknosis. A disassociation between the degree of inflammation and the
      presence of antigen was noted, especially in cerebral cortex and spinal cord,
      presumably where infected cells already had been cleared. Ultrastructurally, rare
      mature viral particles were seen in extracellular spaces.

PMID- 10392643
TI  - Usefulness of Ultrafast Papanicolaou-stained scrape preparations in
      intraoperative management of thyroid lesions.
AB  - The value of intraoperative pathologic consultation (including frozen-section
      [FS]analysis) in surgical management of thyroid lesions has decreased since the
      advent of preoperative fine-needle aspiration. This study presents an
      intraoperative consultation experience with tumor scrape preparations stained
      with Ultrafast Papanicolaou stain and FS analysis in 93 cases of thyroid nodules
      and 4 lymph nodes (as part of lymph node dissection due to thyroid malignancy) in
      87 patients at the University of Pisa, Pisa, Italy. FS was performed in 41 cases
      (48%). The scrape preparation diagnoses included 71 malignancies (69 papillary
      and 2 poorly differentiated carcinomas); 1 "suspicious for carcinoma"; 9
      follicular neoplasms; 13 benign (9 "no tumor seen," 1 thyroiditis, 1 hyperplastic
      nodule, and 2 nodular goiters); and 3 nondiagnostic cases. The final diagnosis
      agreed with the scrape diagnosis in 95 cases (98%). FS agreed with the final
      diagnosis in 29 cases (71%). We suggest that intraoperative scrape preparations
      of thyroid nodules stained with the Ultrafast Papanicolaou method might be a
      useful adjunct in the intraoperative management of thyroid nodules.

PMID- 10392644
TI  - Case-mix in rehabilitation: alternative ways of achieving the same goals.

PMID- 10392645
TI  - Effect of severity of arm impairment on response to additional physiotherapy
      early after stroke.
AB  - OBJECTIVE: To investigate effect of initial severity of arm impairment on
      response to additional physiotherapy for the arm after stroke. DESIGN: In this
      controlled trial, patients were randomized into one of three groups: routine
      physiotherapy (RPT) patients received no additional physiotherapy; qualified
      physiotherapy (QPT) patients received additional treatment from a qualified
      physiotherapist; assistant physiotherapy (APT) patients received additional
      treatment from a trained supervised assistant. Comparisons between the whole
      groups found no significant differences and have been reported elsewhere. In a
      post hoc analysis, the groups were subdivided according to severity of initial
      arm impairment. The subgroups were then compared. SETTING: A general hospital
      with acute and rehabilitation facilities for stroke patients. SUBJECTS: Patients
      (n = 282) between one and five weeks after stroke. INTERVENTIONS: Ten hours
      additional physiotherapy were given over a five-week period. The treatment
      approach reflected current usual British practice. 'Blind' outcome assessment was
      performed after intervention, and at three and six months after stroke. MAIN
      OUTCOME MEASURES: Rivermead Motor Assessment Arm Scale, Action Research Arm Test.
      RESULTS: In more severe patients, no benefits of additional treatment were
      detected. In less severe patients, significant benefits were found in those who
      completed treatment with the trained assistant. However, a considerable number of
      patients did not complete the additional treatment. The content of treatment
      differed between the QPT and APT groups. Treatment of less severe APT patients
      emphasized repetitive supervised practice of movements and functional tasks. No
      significant effects of additional treatment were found in terms of shoulder pain
      or spasticity. CONCLUSIONS: Regardless of whether additional physiotherapy was
      given or not, patients with severe arm impairment improved very little in arm
      function. Enabling adaptation to loss of arm function may be an appropriate
      rehabilitation strategy for some patients. Trends in the data confirm findings of
      some previous studies that intensive treatment for patients with some motor
      recovery of the upper limb is effective. Following patient assessment and
      treatment planning by a qualified physiotherapist, it may be appropriate for
      guidance of repetitive practice of motor and functional tasks to be delegated to
      trained and closely supervised assistant staff.

PMID- 10392647
TI  - Freezing episodes in hemiparetic stroke: results of a pilot survey.
AB  - OBJECTIVE: To determine whether freezing episodes commonly occur in patients who
      have had a hemiparetic stroke. DESIGN: A postal questionnaire sent to 108
      patients who had been admitted to our Stroke Unit with a hemiparesis due to an
      acute ischaemic stroke or a primary intracerebral haemorrhage. RESULTS: Ninety
      three questionnaires were returned, of which 14 were unsuitable for analysis as
      the patients were unable to walk. The remaining 79 questionnaires were analysed
      (response rate 73%). Twenty-six (33%) patients reported freezing episodes while
      walking. CONCLUSIONS: Freezing episodes have been underappreciated in patients
      who have had a hemiparetic stroke. This is potentially important as these
      patients may benefit from some of the rehabilitation techniques currently being
      developed for patients with cerebral multi-infarct states who have similar gait
      problems. Future studies should be more widely based and designed to characterize
      the nature of the freezing episodes and their relationship to the location of the
      lesion.

PMID- 10392646
TI  - Description of a new motor re-education programme for the paretic lower limb
      aimed at improving the mobility of stroke patients.
AB  - OBJECTIVE: To describe and examine the feasibility of a new treatment approach
      for the paretic lower limb and to explore its effectiveness in one chronic
      hemiparetic stroke subject. DESIGN: Case report. The treatment was conducted
      three times per week over a period of six weeks. The mobility of the patient was
      assessed prior to the treatment, at the end of the treatment and at a six-week
      follow-up. SETTINGS: The study was carried out at the research centre of the
      Institut de readaptation de Montreal. The treating therapist was an experienced
      rehabilitation professional as was the assessor, who worked at a different
      rehabilitation centre. INTERVENTIONS: The motor re-education programme was based
      on the use of a static dynamometer that measures the linear external forces
      produced at the ankle level. A computer program provided the subject with
      constant feedback on the direction and intensity of the applied force. In each
      treatment session, the subject was asked to produce several submaximal efforts in
      16 specific directions. Both the intensity and the number of repetitions were
      gradually increased. OUTCOME MEASURES: In addition to force production
      measurements, three clinical assessments of mobility were used: the Timed 'Up and
      Go', the comfortable gait speed and a 2-minute walk test. RESULTS: The maximal
      static linear forces produced by the subject increased through the treatment for
      all directions of effort, but differences were observed amongst directions.
      During the treatment programme, the subject improved his performance at the three
      clinical assessments. Even if some of the functional gain was lost at the follow
      up, the mobility was still considerably improved as compared to baseline values.
      CONCLUSION: This study demonstrated the applicability of the treatment programme
      to a stroke subject. The results seem very promising and encourage further
      investigation in order to assess more rigorously the effectiveness of this new
      approach.

PMID- 10392648
TI  - Lumbar spine range of motion as a measure of physical and functional impairment:
      an investigation of validity.
AB  - OBJECTIVE: To investigate the validity of the spinal range of motion models
      outlined in the second and fourth editions of the American Medical Association
      Guides to the evaluation of permanent impairment (AMA Guides), for assessing the
      percentage impairment in chronic low back pain patients. DESIGN: Cross-sectional
      validation study. SETTING: Outpatient department in the Rehabilitation Medicine
      Unit. SUBJECTS: A volunteer sample of 34 subjects participated in the study, 21
      females and 13 males, with a mean age of 47.7 years (1 SD = 12.1) and 40.1 years
      (1 SD = 11.1), respectively. Subjects had chronic low back with or without leg
      pain of at least six months' duration. Subjects were recruited by medical
      practitioners and physiotherapists through the Rehabilitation Unit at the
      Essendon Campus of Royal Melbourne Hospital. MAIN OUTCOME MEASURES: Lower back
      range of motion measured with a long arm goniometer and a dual inclinometer,
      Waddell Physical Impairment Scale, Waddell Disability Index, Oswestry Disability
      Index. RESULTS: Both range of motion measurement methods demonstrated poor
      validity and do not bear any consistent relationship to the level of physical or
      functional impairment in subjects with chronic low back pain. CONCLUSIONS: There
      was no evidence for a relationship between low back range of motion and
      impairment, and thus it would appear illogical to evaluate impairment in chronic
      low back pain patients using a spinal range of motion model when aiming to
      measure or compensate disability.

PMID- 10392649
TI  - Generic health status measures are unsuitable for measuring health status in
      severely disabled people.
AB  - OBJECTIVES: To assess the perceived health status of disabled people. DESIGN:
      Perceived health status was evaluated with the Short Form 36 Health Survey (SF
      36) and the Nottingham Health Profile as part of a needs assessment project
      exploring systematic differences in unmet needs for rehabilitation as perceived
      by disabled people, carers and professional staff. Disabled participants
      completed these health status questionnaires, as part of a face-to-face interview
      in participants' own homes. SUBJECTS: Ninety-two disabled people aged 16-65,
      recruited into the study from two disability registers. OUTCOME MEASURES: The
      Office of Population Censuses and Surveys (OPCS) Disability Severity Scale,
      Nottingham Health Profile, SF-36. RESULTS: Ninety-six disabled people took part
      in this study. Four were later excluded because of overwhelming communication
      difficulties. Median OPCS category was 8 (interquartile range 6-9.75). The pain
      and physical mobility domains of the Nottingham Health Profile were not completed
      by 46/92 participants (50%) because many questions referred to activities that
      these people could not perform, particularly walking. The physical functioning
      domain of the SF-36 showed severe floor effects. It was not therefore possible to
      use these measures to test the effectiveness of services provided to disabled
      people, particularly in the areas of physical functioning and pain. CONCLUSIONS:
      There is a continued need to develop and test instruments that can measure the
      outcomes of rehabilitation in severely disabled populations.

PMID- 10392650
TI  - Inter-rater reliability of postural observation after stroke.
AB  - OBJECTIVE: To explore the inter-observer reliability of bedside observations of
      stroke patients' posture using two versions of a pictorial tool. DESIGN: Three
      projects were conducted. The initial version of the tool was used in project 1.
      The modified version was used in projects 2 and 3. In each project a pair of
      observers (comprising the main observer and one of five co-observers with varying
      degrees of experience in observing posture) used the tool to make simultaneous
      observations of 19 aspects of the posture of a sample of stroke patients. Each
      patient was observed in one or more of four positions (seated, supine and lying
      on the affected and unaffected side). The degree of inter-observer agreement was
      sought by calculating kappa values and percentage agreement. SETTING: Medical
      wards, care of the elderly wards and a stroke unit. SUBJECTS: A convenience
      sample of 57 stroke patients. RESULTS: Four hundred and forty paired sets of
      observations were made (200 in project 1, 140 in project 2 and 100 in project 3).
      The main observer was in every pair. The co-observers made between 50 and 135
      sets of observations each. When the results from all three projects were amassed,
      acceptable percentage agreement (i.e. > or =70%) was obtained for 67% (n = 78)
      and 73% (n = 55) of the results collected on aspects of the posture of the
      affected upper and lower limbs respectively. In contrast, acceptable percentage
      agreement for observations relating to the head, neck and trunk was obtained for
      only 34% (n = 50) of the results collected. Uneven distributions in the data made
      kappa values difficult to interpret. Inter-observer agreement was not noticeably
      higher for pairs in which both observers had prior experience of observing
      posture after stroke than for pairs in which one observer was relatively
      inexperienced. CONCLUSIONS: The tool has potential as a quick and simple means of
      collecting information at the bedside about stroke patients' posture.
      Refinements, additional training in using the tool for observers and further
      testing are suggested before its wider use is advocated.

PMID- 10392651
TI  - Prosthesis rejection in children with a unilateral congenital arm defect.
AB  - OBJECTIVE: To determine the rate of rejection for prosthetic use in children and
      to investigate reasons for this rejection. DESIGN: Cross-sectional study of a
      cohort of children. SETTING: Rehabilitation centre, St Maartenskliniek, Nijmegen,
      The Netherlands. SUBJECTS: Thirty-two children (0-18 years) with a unilateral
      congenital arm defect who visited the clinic between September 1991 and December
      1996. METHODS: Parents of all children and 19 children (> or =6 years) completed
      a questionnaire. RESULTS: Eleven children (34%) rejected the prosthesis. A
      survival function shows that the rejection can be characterized by three periods:
      0-40 months, 40-162 months and after 162 months. In the first and last period a
      high rate of rejection is seen, while in the second period a low rate exists.
      Fitting for the first time after 2 years of age seems to be related with higher
      rejection rate. Lack of functional gain with the prosthesis, as perceived by the
      subjects and the parents, is significantly associated with increased rejection
      rate. Increased rejection rate is associated with the parents' disappointment,
      insufficient involvement of the parents in treatment, and dissatisfaction
      pertaining to emotional and social guidance. CONCLUSIONS: Rejection seems to
      occur in two main periods: within 3.5 years after being provided with a
      prosthesis and after 13.5 years of prosthetic use, when most children experience
      puberty. Fitting before the age of 2 years seems to reduce rejection rate.
      Preventing the parents' disappointment about prosthetic benefits as well as
      providing them with sufficient involvement in treatment and adequate guidance are
      essential for optimal results of prosthetic rehabilitation.

PMID- 10392652
TI  - Shoulder joint replacement for osteoarthrosis in association with thalidomide
      induced phocomelia.
AB  - The natural history of thalidomide-induced phocomelia has not yet been
      established since only 35 years have elapsed since the problems associated with
      this drug became evident. This paper presents what is considered to be the first
      case of osteoarthrosis in such an individual treated by shoulder joint
      replacement. Joint arthoplasty is almost certainly going to become an integral
      part of the life-long rehabilitation process in such affected individuals.

PMID- 10392653
TI  - The Northwick Park Care Needs Assessment (NPCNA): a directly costable outcome
      measure in rehabilitation.
AB  - BACKGROUND: The Northwick Park Dependency Score (NPDS) has been shown to be
      valid, reliable and practical to use. It was designed to be used together with a
      short set of additional questions to inform care needs in the community and
      facilitate discharge planning. AIM: To develop a conversion formula to translate
      information derived from the NPDS into a generic assessment of care needs in the
      community -- the Northwick Park Care Needs Assessment (NPCNA) -- and to evaluate
      its potential as a directly costable measure of outcome in rehabilitation.
      SETTING: An inpatient neurorehabilitation unit for young patients with brain
      injury. METHOD: Part 1, DEVELOPMENT: For each task in the NPDS, a set of
      assumptions was developed to reflect the number of people, the time taken and the
      frequency of help required. Tasks were collected into a daily timetable and
      minimum and maximum allocations made for each time slot. From this the weekly
      care hours can be calculated. A range of care package categories and their
      approximate costs were identified, and a simple set of criteria developed with
      experienced community care planners to determine the circumstances under which
      each category is applied. Part 2, EVALUATION: The assumptions and derived care
      package were evaluated in a prospective comparative study in 35 cases. Timetables
      of care needs were drawn up using (a) the NPDS-derived Care Needs Assessment
      (NPCNA) and (b) detailed structured interview with an independent assessor. The
      weekly hours of care, care package and approximate cost were then determined for
      each set of timetables, by a third independent assessor, applying the formula
      described according to strict rules. RESULTS: Assessment of the total weekly
      hours of care showed an excellent correlation between the two methods (rho 0.90,
      p <0.01) with no significant differences. There was also a high correlation in
      the category of care package allotted and thus the weekly cost of care (rho 0.73,
      p <0.01). CONCLUSION: The NPCNA provides a simple measure of care needs in total
      care hours, as well as a timetable of care from which a care package can be
      directly planned and costed. It has potential use, therefore, as an instrument
      that can demonstrate directly the effectiveness of rehabilitation in reducing the
      cost of continuing care in the community.

PMID- 10392654
TI  - Post-stroke depression and functional outcome: a cohort study investigating the
      influence of depression on functional recovery from stroke.
AB  - OBJECTIVE: To investigate the influence of depression on functional recovery
      after stroke. DESIGN: Multicentre cohort study of 85 patients admitted for
      clinical rehabilitation. A two-stage case-finding procedure was used to identify
      patients with depression. For the control group, consecutive nondepressed stroke
      patients were enrolled. Patients were interviewed at 3-6 weeks and six months
      after stroke onset. SETTING: Three rehabilitation centres in the vicinity of
      Amsterdam. MAIN OUTCOME MEASURES: Functional outcome was determined by the
      Functional Independence Measure (FIM) and the Rehabilitation Activities Profile
      (RAP). RESULTS: The prevalence of depression (35%) was comparable with the
      findings of earlier studies in other settings. Patients classified as depressed
      according to DSM III R criteria (American Psychiatric Association Diagnostic and
      statistical manual of mental disorders) had a significantly lower functional
      score, both at onset and after follow-up (FIM and RAP). There was, however, no
      significant difference in functional improvement between the depressed and the
      nondepressed group. Mean functional improvement in the six patients treated with
      antidepressants was 30% better than in the untreated (depressed) patients;
      numbers were too small for the results to attain statistical significance. Subset
      analysis showed a significantly higher outcome for nondepressed patients for the
      FIM subitems personal care and transfers. However, functional improvement was not
      significantly different for any of the subitems in depressed versus nondepressed
      patients. CONCLUSION: Stroke patients with depression have significantly lower
      functional scores both at onset and after six months. Our results suggest under
      recognition of post-stroke depression and a possible beneficial effect of
      antidepressant medication in depressed stroke patients. Further studies are
      required to determine the effect of antidepressants.

PMID- 10392655
TI  - Inflammatory pathogenesis in Alzheimer's disease: biological mechanisms and
      cognitive sequeli.
AB  - Experimental evidence from molecular biology, biochemistry, epidemiology and
      behavioral research support the conclusion that brain inflammation contributes to
      the pathogenesis of Alzheimer's disease and other types of human dementias.
      Aspects of neuroimmunology relating to the pathogenesis of Alzheimer's disease
      are briefly reviewed. The effects of brain inflammation, mediated through
      cytokines and other secretory products of activated glial cells, on
      neurotransmission (specifically, nitric oxide, glutamate, and acetylcholine),
      amyloidogenesis, proteolysis, and oxidative stress are discussed within the
      context of the pathogenesis of learning and memory dysfunction in Alzheimer's
      disease. Alzheimer's disease is proposed to be an etiologically heterogeneous
      syndrome with the common elements of amyloid deposition and inflammatory neuronal
      damage.

PMID- 10392656
TI  - Adaptations and pathologies linked to dynamic stabilization of neural circuitry.
AB  - Brain circuits for infrequently employed memories are reinforced largely during
      sleep by self-induced, electrical slow-waves, a process referred to as "dynamic
      stabilization" (DS). The essence of waking brain function in the absence of
      volitional activity is sensory input processing, an enormous amount of which is
      visual. These two functions: circuit reinforcement by DS and sensory information
      processing come into conflict when both occur at a high level, a conflict that
      may have been the selective pressure for sleep's origin. As brain waves are
      absent at the low temperatures of deep torpor, essential circuitry of hibernating
      small mammals would lose its competence if the animals did not warm up
      periodically to temperatures allowing sleep and circuit reinforcement. Blind,
      cave-dwelling vertebrates require no sleep because their sensory processing does
      not interfere with DS. Nor does such interference arise in continuously-swimming
      fishes, whose need to process visual information is reduced greatly by life in
      visually relatively featureless, pelagic habitats, and by schooling. Dreams are
      believed to have their origin in DS of memory circuits. They are thought to have
      illusory content when the circuits are partially degraded (incompetent), with
      synaptic efficacies weakened through infrequent use. Partially degraded circuits
      arise normally in the course of synaptic efficacy decay, or pathologically
      through abnormal regimens of DS. Organic delirium may result from breakdown of
      normal regimens of DS of circuitry during sleep, leaving many circuits
      incompetent. Activation of incompetent circuits during wakefulness apparently
      produces delirium and hallucinations. Some epileptic seizures may be induced by
      abnormal regimens of DS of motor circuitry. Regimens of remedial DS during
      seizures induced by electroconvulsive therapy (ECT) apparently produce temporary
      remission of delirium by restoring functional or 'dedicated' synaptic efficacies
      in incompetent circuitry. Sparing of sensory circuitry in fatal familial insomnia
      seemingly owes to supernormal circuit use in the virtual absence of sleep. ECT
      shocks and cardioverter defibrillation may have analogous remedial influences.

PMID- 10392657
TI  - The ontogeny of salt hunger in the rat.
AB  - Salt hunger is the behaviour of an animal suffering sodium deficiency. It is
      characterised by an increased motivation to seek and ingest sodium, and the
      ability to distinguish between sodium and other salts. Here I review the
      development of salt hunger in the rat. Salt hunger develops rapidly between birth
      and weaning. It can first be demonstrated 72 h postnatally when an
      intracerebroventricular injection of renin elicits greater swallowing of NaCl
      solution than water and greater mouthing of solid fragments of NaCl than of an
      artificial sweetener. However, sodium deficit per se cannot arouse the hunger at
      this age, and first elicits increased intake of NaCl only at 12 days-of-age. The
      next landmark is at 17 days-of-age when the hormonal synergy of aldosterone and
      central angiotensin II first elicits salt hunger, as it does in the adult. The
      specificity of the hunger for the sodium ion also develops postnatally: the 72 h
      old sodium-hungry neonate does not distinguish between NaCl and other mono- and
      di-valent chloride salts but, increasingly during development, the sodium hungry
      pup distinguishes salts and by weaning age NaCl is clearly preferred to other
      salts almost as it is in adults. Early development may also be a sensitive period
      for determining lifelong preferences, and indeed, acute perinatal sodium
      depletion induces a lifelong enhancement of salt intake. Taken together, these
      findings demonstrate how a behaviour develops precociously and how, when the
      behaviour becomes important at weaning, the rat pup is competent to meet its
      sodium requirements, and may be adapted to anticipate sodium deficit.

PMID- 10392658
TI  - Is learning blocked by saturation of synaptic weights in the hippocampus?
AB  - Long-term potentiation (LTP) has become a leading candidate mechanism for memory
      formation. The proposed link between LTP and memory rests primarily on a single
      type of behavioural evidence: disruption of learning by interventions that block
      critical steps in the induction of LTP. As such blockade may disrupt non-mnemonic
      functions also, the LTP-learning question should be approached with multiple
      strategies. One alternative approach is to determine whether hippocampus
      dependent learning is blocked by saturation of hippocampal LTP before training.
      Early investigations found that spatial learning was impaired after cumulative
      LTP in dentate perforant-path synapses. Several groups failed to replicate these
      findings, but it is now clear that hippocampus-dependent spatial learning is
      disrupted only if LTP is saturated throughout the terminal field of the tetanized
      pathway. Moreover, to prevent compensatory modifications in the hippocampal
      network, a massed tetanization and training protocol may be required. The
      blockade of learning by repetition of the very same stimulus that induces LTP
      suggests that LTP-like modifications are necessary for memory encoding in the
      hippocampus.

PMID- 10392659
TI  - Neurobiology of mother-infant interactions: experience and central nervous system
      plasticity across development and generations.
AB  - The optimal coordination between the new mammalian mother and her young involves
      a sequence of behaviors on the part of each that ensures that the young will be
      adequately cared for and show healthy physical, emotional, and social
      development. This coordination is accomplished by each member of the relationship
      having the appropriate sensitivities and responses to cues that characterize the
      other. Among many mammalian species, new mothers are attracted to their infants'
      odors and some recognize them based on their odors; they also respond to their
      infants' vocalizations, thermal properties, and touch qualities. Together these
      cues ensure that the mother will nurse and protect the offspring and provide them
      with the appropriate physical and stimulus environment in which to develop. The
      young, in turn, orient to the mother and show a suckling pattern that reflects a
      sensitivity to the mothers odor, touch, and temperature characteristics. This
      article explores the sensory, endocrine, and neural mechanisms that underlie this
      early mother-young relationship, from the perspective of, first, the mother and,
      then, the young, noting the parallels between them. It emphasizes the importance
      of learning and plasticity in the formation and maintenance of the mother-young
      relationship and mediation of these experience effects by the brain and its
      neurochemistry. Finally, it discusses ways in which the infants' early
      experiences with their mothers (or the absence of these experiences) may come to
      influence how they respond to their own infants when they grow up, providing a
      psychobiological mechanism for the inter-generational transmission of parenting
      styles and responsiveness.

PMID- 10392660
TI  - Social influences on endocrine activity in guinea pigs, with comparisons to
      findings in nonhuman primates.
AB  - Guinea pigs exhibit a rich and varied social organization. Studies in recent
      years have demonstrated that social stimuli have widespread neuroendocrine
      effects in guinea pigs. Here, effects on the hypothalamic-pituitary-adrenal,
      adrenal medullary/sympathetic, and hypothalamic-pituitary-gonadal systems of both
      adult and developing guinea pigs are reviewed. These systems respond to various
      social variables, or factors that affect social variables, including: separation
      from attachment objects, housing conditions, changes in housing, the familiarity
      of the environment in which social interactions occur, foraging conditions,
      surrogate-rearing, agonistic interactions, and the establishment of dominance
      rank. Similarities and differences between these findings and those in nonhuman
      primates are discussed. It is argued that the guinea pig is well suited for the
      study of socioendocrine effects throughout the life span, and can provide a
      valuable complement to nonhuman primate research in this area.

PMID- 10392661
TI  - The measurement of stress-related immune dysfunction in psychoneuroimmunology.
AB  - In recent years there has been a dramatic increase in research dedicated to the
      psycho-behavioural modulation of immune function, i.e. the field of
      Psychoneuroimmunology (PNI). This has led, necessarily, to the use of several in
      vitro and in vivo techniques in attempts to delineate the relationship between
      these two phenomena. However, since the field's inception, considerable
      uncertainty has existed over the significance of the immune outcomes detected and
      this has been compounded by the equivocal nature of some of the published data. A
      great deal of this uncertainty could, however, be overcome if a clearer
      understanding was achieved on the advantages and limitations conferred by the
      manifold immune assays described in the literature. This would, in turn,
      encourage their more appropriate use within PNI. Hence, in this review we
      describe the rationale behind, and offer an evaluation of, some of the more
      frequently used in vitro and in vivo immunological and virological techniques. We
      hope that a clear understanding of the rationale behind such assays and their
      inherent advantages and limitations will inform the discussion of the
      significance of stress-related immune impairment.

PMID- 10392662
TI  - Preclinical research on cocaine self-administration: environmental determinants
      and their interaction with pharmacological treatment.
AB  - It has been asserted that any comprehensive understanding of cocaine abuse and
      its treatment will require attention to both behavioral and pharmacological
      variables. Although the preclinical literature evaluating the effects of
      pharmacological variables on cocaine self-administration has been extensively
      reviewed, no comprehensive review of the effects of environmental variables on
      cocaine self-administration has been published. The present review summarizes and
      critiques the preclinical findings on environmental determinants of cocaine self
      administration. The influence of environmental variables on the effects of
      pharmacological interventions on cocaine self-administration are also described.
      Several environmental variables have been shown to affect cocaine self
      administration, including unit dose, schedule of cocaine delivery, schedules of
      nondrug stimuli, behavioral history, conditioned stimuli, food deprivation,
      exposure to stress, and rearing environment. Among these variables, unit dose,
      schedule of cocaine delivery, availability of alternative nondrug reinforcers,
      food deprivation, and rearing environment have also been shown to alter
      pharmacological treatment effects on cocaine self-administration. Thus, drug
      effects on cocaine self-administration are malleable and dependent upon the
      environmental context within which they occur. Suggestions for future research on
      the effects of these and other environmental variables on cocaine self
      administration and its pharmacological treatment are presented.

PMID- 10392663
TI  - The neuroanatomical and neurochemical basis of conditioned fear.
AB  - After a few pairings of a threatening stimulus with a formerly neutral cue,
      animals and humans will experience a state of conditioned fear when only the cue
      is present. Conditioned fear provides a critical survival-related function in the
      face of threat by activating a range of protective behaviors. The present review
      summarizes and compares the results of different laboratories investigating the
      neuroanatomical and neurochemical basis of conditioned fear, focusing primarily
      on the behavioral models of freezing and fear-potentiated startle in rats. On the
      basis of these studies, we describe the pathways mediating and modulating fear.
      We identify several key unanswered questions and discuss possible implications
      for the understanding of human anxiety disorders.

PMID- 10392664
TI  - Is there an increased risk of stroke associated with oral contraceptives?
AB  - In the last few years several studies were published about the relationship
      between oral contraceptive use, estrogen dose, different types of progestogens,
      cigarette smoking and the risk of stroke. There is a persistent association
      between the use of oral contraceptives containing more than 50microg of
      ethinylestradiol and the risk of stroke. Also, cigarette smoking seems to be a
      strong additive risk factor, especially in women >35 years old even with lower
      doses (< or =30microg) of estrogen. Unlike oral contraceptives containing
      >50microg of estrogen, currently there is no convincing evidence that the use of
      oral contraceptives containing <50microg in the absence of smoking is associated
      with any meaningful increase in the risk of ischaemic or haemorrhagic stroke.
      Progestogen-only pills are not associated with an increased risk of stroke. A
      specific type of progestogen in combined pills was associated with an increased
      risk of stroke in a few studies. Data regarding this issue is, however,
      inconsistent and controversial and needs further investigation. There were few if
      any studies that have addressed the effects of new types of progestogens (i.e.
      norgestimate, norgestrel or gestodene) and formulations containing 20microg of
      ethinylestradiol. At the present time we find no reason to alter the current
      practice in prescribing oral contraceptives. We do concede, however, that there
      might be a slight causal relationship between use of oral contraceptives
      containing <50microg of ethinylestradiol and stroke that did not reach
      statistical significance. This relationship is rare and should be viewed in
      context with the many benefits of oral contraceptives. Underlying risk factors
      for stroke such as factor V Leiden mutation and other thrombophilias might
      explain the role of oral contraceptive-induced stroke.

PMID- 10392665
TI  - Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link
      with methotrexate?
AB  - An increasing number of instances of lymphoma in patients with rheumatoid
      arthritis who are treated with methotrexate continue to appear. The majority of
      patients with lymphoproliferation have features of immunosuppression-associated
      lymphoma. Rheumatoid arthritis itself and the actions of methotrexate concur in
      leading to a immunosuppressed state. Possible oncogenic mechanisms and the risk
      factors for patients with rheumatoid arthritis to develop lymphoma while
      receiving methotrexate include: (i) intense immunosuppression and severe disease
      in combination with genetic predisposition and; (ii) an increased frequency of
      latent infection with prooncogenic viruses like Epstein-Barr virus. The
      aetiological role of methotrexate in the development of these lymphomas is
      supported by the spontaneous remission of these malignancies in some of patients
      with rheumatoid arthritis after methotrexate has been stopped. The physicians
      caring for patients with rheumatoid arthritis receiving methotrexate should be
      vigilant about signs and symptoms suggestive of lymphoma, mostly in those
      patients with significant comorbidity, long standing and severe disease who are
      more likely to be immunosuppressed. If a lymphoma appears in these patients,
      methotrexate should be stopped. Spontaneous remission may occur and a period of
      observation is advisable when clinically possible. If functional deterioration
      appears or there are signs of lymphoproliferative organ invasion after several
      months then specific antineoplastic treatment should be instituted.

PMID- 10392667
TI  - A preliminary risk-benefit assessment of latanoprost and unoprostone in open
      angle glaucoma and ocular hypertension.
AB  - Latanoprost and unoprostone (isopropyl unoprostone) represent the first
      commercially available prostaglandin analogues to be used for the treatment of
      glaucoma. Both compounds reduce intraocular pressure by enhancing uveoscleral
      outflow. Latanoprost, when used once daily in the evening, produces a greater
      reduction in pressure than timolol. Latanoprost produces mild conjunctival
      hyperaemia compared with timolol in some patients. Darkening of the irides has
      been reported, especially in green-brown, yellow-brown and blue/grey-brown
      irides. Hypertrichosis and hyperpigmentation of the eyelashes have also been
      demonstrated. Although latanoprost has not been proven to cause uveitis or
      cystoid macular oedema, case reports of an association exist. Latanoprost does
      not produce systemic adverse effects nor does it alter routine blood analyses.
      Unoprostone, when given twice daily, produces less of a reduction in intraocular
      pressure than timolol or latanoprost. Three times daily use may be required to
      approach the effectiveness of timolol. Unoprostone may have a similar adverse
      effect profile to latanoprost, but may to cause more corneal epithelial problems.
      Unoprostone is also not known to cause systemic adverse effects. Both agents are
      welcome additions to the treatment of glaucoma. However, additional studies and
      more experience are needed with each agents.

PMID- 10392668
TI  - Adverse skin reactions to low molecular weight heparins: frequency, management
      and prevention.
AB  - Adverse skin reactions to low molecular weight heparins (LMWH) are rare even
      though their true incidence is probably underestimated because of under
      reporting. These reactions may occur as an urticarial rash, presumably due to
      local histamine release or have the features of a classic type I immediate
      hypersensitivity reaction. They can also present as skin necrosis often due to
      vasculitis (type III Arthus reaction) or heparin-induced thrombocytopenia.
      Erythematous, well circumscribed lesions without necrosis are usually secondary
      to a delayed type IV hypersensitivity reaction. Although most LMWH-induced skin
      lesions are benign, treatment should be discontinued. In type I reactions or in
      the presence of skin necrosis with or without heparin-induced thrombocytopenia,
      the LMWH should be replaced by an alternative medication such as danaparoid
      sodium or hirudin. Platelet counts should be monitored to diagnose heparin
      induced thrombocytopenia. In a type IV delayed hypersensitivity reaction, in the
      absence of severe, extensive, life-threatening mucocutaneous manifestations, a
      first-line pragmatic approach consists, in our view, of replacing the particular
      LMWH with another one. If the skin symptoms do not improve, cutaneous tests may
      help detect the presence of a cross-reactivity between the available preparations
      of LMWHs and danaparoid sodium. In the presence of a negative subcutaneous
      provocation test, the compound can be used with little risk. If all types of LMWH
      and danaparoid sodium are positive in skin testing, mechanical prevention or oral
      anticoagulants should be used, and intravenous injections of any kind of heparin
      should be avoided because of the potential risk of anaphylactic shock.
      Alternatively, hirudin might be administered but experience with this compound is
      still very limited. Prevention is only possible in type IV hypersensitivity skin
      reactions, by avoiding long term LMWH therapy, particularly in middle-aged, obese
      women and during pregnancy. In these patients, oral anticoagulation should be
      preferred, whenever possible. In conclusion, though rare, skin reactions to LMWH
      may have important consequences which can be reduced by rapid diagnosis and
      appropriate management.

PMID- 10392666
TI  - A risk-benefit assessment of metformin in type 2 diabetes mellitus.
AB  - Metformin has been used for over 40 years as an effective glucose-lowering agent
      in type 2 (noninsulin-dependent) diabetes mellitus. Typically it reduces basal
      and postprandial hyperglycaemia by about 25% in more than 90% of patients when
      either given alone or coadministered with other therapies including insulin
      during a programme of managed care. Metformin counters insulin resistance and
      offers benefits against many features of the insulin resistance syndrome
      (Syndrome X) by preventing bodyweight gain, reducing hyperinsulinaemia and
      improving the lipid profile. In contrast to sulphonylureas, metformin does not
      increase insulin secretion or cause serious hypoglycaemia. Treatment of type 2
      diabetes mellitus with metformin from diagnosis also offers greater protection
      against the chronic vascular complications of type 2 diabetes mellitus. The most
      serious complication associated with metformin is lactic acidosis which has an
      incidence of about 0.03 cases per 1000 patients years of treatment and a
      mortality risk of about 0.015 per 1000 patient-years. Most cases occur in
      patients who are wrongly prescribed the drug, particularly patients with impaired
      renal function (e.g. serum creatinine level > 130 micromol/L or > 1.5 g/L). Other
      major contraindications include congestive heart failure, hypoxic states and
      advanced liver disease. Serious adverse events with metformin are predictable
      rather than spontaneous and are potentially preventable if the prescribing
      guidelines are respected. Gastrointestinal adverse effects, notably diarrhoea,
      occur in less than 20% of patients and remit when the dosage is reduced. The life
      threatening risks associated with metformin are rare and could mostly be avoided
      by strict adherence to the prescribing guidelines. Given the 4 decades of
      clinical experience with metformin, its antihyperglycaemic efficacy and benefits
      against Syndrome X, metformin offers a very favourable risk-benefit assessment
      when compared with the chronic morbidity and premature mortality among patients
      with type 2 diabetes mellitus.

PMID- 10392671
TI  - Early extubation after lung transplantation.

PMID- 10392670
TI  - Predictors and timing of adverse experiences during trandsdermal nicotine
      therapy.
AB  - OBJECTIVES: Difficulty sleeping is a recognised tobacco withdrawal symptom, but
      sleep problems, like application site reactions, are commonly reported as adverse
      reactions to transdermal nicotine therapy. However, no studies have examined
      potential predictive factors associated with the occurrence of expected adverse
      experiences during transdermal nicotine therapy. The subject of skin tolerability
      among patients with a history of eczema, psoriasis or other skin disorders is of
      particular interest, as are the relationships between plasma concentrations of
      nicotine, concurrent smoking, sleep problems and nausea. METHODS: The cohort
      study involving 1392 participants was designed to assess the timing, severity and
      predictive factors of adverse experiences reported during 24-hour transdermal
      nicotine therapy. Data were collected on patients aged 18 to 70 years old who
      were smokers and who had expressed a strong desire to stop smoking. The
      intervention consisted of brief behavioural counselling, a booklet containing
      smoking cessation advice and instructions for use of the patches, and a 12-week
      course of decreasing transdermal nicotine doses. RESULTS: Follow-up was available
      on 1392 out of 1481 study participants. The majority of adverse experiences were
      mild. Sleep problems occurred in 669 out of 1392 (48%) participants and most
      often commenced on the day of smoking cessation. Application site reactions
      occurred in 478 out of 1392 (34%) participants and most often occurred after 6
      days of therapy. No predictor had an adjusted hazard ratio above 2. Statistically
      significant (p < 0.05) predictors of sleep problems were successfully quitting
      smoking and female gender. Predictors of application site reactions were
      psoriasis or eczema, other skin conditions, age <40 years, female gender, place
      of birth outside Australasia, and trade or university education level.
      Substantially increased nicotine intake during therapy compared with baseline
      smoking occurred in 8% of participants who smoked concurrently, and 4% of
      participants who did not (p = 0.1). Increased nicotine intake was associated with
      a modest increase in the overall rate of adverse experiences (89% vs 63%, p =
      0.04) and dizziness/lightheadedness (17% vs 3%, p = 0.03), but not with sleep
      problems or cardiovascular events. CONCLUSIONS: Transdermal nicotine therapy
      appears to be well tolerated, even if the user smokes concurrently. Sleep
      disturbance during therapy appeared to be primarily associated with tobacco
      withdrawal rather than with nicotine excess from treatment with transdermal
      nicotine. Study participants with pre-existing skin disorders were somewhat more
      likely to report mild application site reactions than other participants.

PMID- 10392669
TI  - Prophylaxis and treatment of NSAID-induced gastroduodenal disorders.
AB  - A significant percentage of patients taking nonsteroidal anti-inflammatory drugs
      (NSAIDs) experience some type of adverse gastrointestinal symptoms, lesions of
      the gastroduodenal tract being clinically the most relevant. NSAIDs cause
      gastrointestinal damage by 2 independent mechanisms: a topical effect, which is
      pH and pKa related, and a systemic effect mediated by cyclooxygenase (COX)
      inhibition with a reduction in prostaglandin synthesis. Using endoscopy,
      gastroduodenal lesions identified include subepithelial haemorrhages, erosions
      and ulcers. The prevalence of ulceration in NSAID users has been reported as
      being between 14 and 31% with a 2-fold higher frequency of gastric ulcers
      compared with duodenal ulcers. Among the strategies used to decrease the risk of
      ulcer development are: (i) the use of analgesics other than NSAIDs; (ii) use of
      the lowest possible dosage of NSAID; (iii) the use of a COX-2 selective NSAID;
      (iv) the use of low doses of corticosteroids instead of NSAIDs; (v) avoidance of
      concomitant use of NSAIDs and corticosteroids; and (vi) use of preventive
      therapy. In an attempt to reduce the incidence of NSAID-induced gastrointestinal
      lesions, the following approaches have been proposed: (i) use of the
      prostaglandin analogue misoprostol, which is an antiulcer drug which has been
      proven to be as effective in the prevention of NSAID-induced gastric and duodenal
      ulcers as in the reduction of serious upper gastrointestinal complications; (ii)
      histamine H2 receptor antagonists (H2 antagonists), e.g. ranitidine, cimetidine
      and famotidine, which are useful in the prevention of NSAID-induced duodenal
      ulcers during long term treatment, but not in the prevention of NSAID-induced
      gastric ulcers; (iii) proton pump inhibitors, e.g omeprazole, and pantoprazole,
      whose efficacy in preventing NSAID-associated ulcers has been recently
      demonstrated; and (iv) barrier agents, e.g. sucralfate, which cannot be
      recommended as prophylactic agents to prevent NSAID-induced gastropathy. The
      first step in the treatment of NSAID-associated ulcers lies in a reduction in the
      dosage of the NSAID or discontinuation of the drug. If NSAID treatment cannot be
      withdrawn, a proton pump inhibitor appears to be the most effective treatment in
      healing ulcers, accelerating the slow healing observed with H2 antagonists.

PMID- 10392672
TI  - The use of continuous positive airway pressure by face mask and thoracic epidural
      analgesia after lung transplantation. Gothenburg Lung Transplant Group.
AB  - OBJECTIVE: To evaluate the clinical use of continuous positive airway pressure
      (CPAP) and thoracic epidural analgesia (TEA) after lung transplantation (LTx).
      DESIGN: Retrospective case series. SETTING: Cardiothoracic intensive care unit
      (ICU) at a university hospital. PARTICIPANTS: All heart-lung, bilateral, and
      single-lung transplant recipients between 1990 and 1996 at this institution (n =
      102). INTERVENTIONS: Postoperative pain was controlled by a thoracic epidural
      infusion of bupivacaine, 1 mg/mL, and sufentanil, 1 microg/mL. After extubation,
      CPAP, 5 to 10 cm H2O by face mask, was used to prevent reperfusion edema.
      MEASUREMENTS AND MAIN RESULTS: In 99 patients, the length of ventilation (LOV)
      was a median of 4.3 hours (range, 1.0 to 312.0 hours). The median LOV was 8.0
      hours (range, 1.5 to 41.0 hours) in the heart-lung recipients, 4.5 hours (range,
      2.0 to 47.0 hours) in the bilateral-lung recipients, and 3.5 hours (range, 1.0 to
      312.0 hours) in the single-lung recipients. Three transplant recipients, all with
      primary pulmonary hypertension, were prematurely extubated and reintubated
      because of pulmonary edema. Twelve hours after extubation, the median oxygenation
      index (PaO2/F(I)O2, PaO2 in kilopascal units) was greater than 35. The median ICU
      length of stay for all transplant recipients was 4 days (range, 2 to 270 days).
      CONCLUSION: The postoperative use of CPAP and TEA is associated with early and
      safe tracheal extubation after LTx and may shorten ICU stay.

PMID- 10392673
TI  - Continuous arterial blood gas monitoring during bilateral sequential lung
      transplantation.
AB  - OBJECTIVE: To determine the accuracy and clinical utility of a continuous
      arterial blood gas (ABG) monitor during lung transplantation. DESIGN:
      Prospective, observational cohort study. SETTING: University hospital.
      PARTICIPANTS: Eleven patients undergoing bilateral sequential lung
      transplantation (BSLTx). INTERVENTIONS: Repeated ABG sampling. MEASUREMENTS AND
      MAIN RESULTS: Agreement was measured by the bias (limits of agreement): pH, 0.006
      (-0.10 to 0.10); PaO2, -22 mmHg (-130 to 86 mmHg); and PaCO2, -1.6 mmHg (-13.4 to
      10.2 mmHg). Sensitivity and specificity of the Paratrend 7 (Biomedical Sensors,
      Ltd, Malvern, PA) PaO2 measurements (to detect PaO2 < 100 mmHg) were 84.6% and
      97.6%, respectively. CONCLUSION: Continuous ABG monitoring with the Paratrend 7
      shows sufficiently good agreement with laboratory blood gas analysis during BSLTx
      and thus is a convenient alternative to intermittent laboratory blood gas
      measurement. Because of the potential for significant (and sometimes rapid) acid
      base disturbances, continuous ABG monitoring may have a role during most lung
      transplantation procedures.

PMID- 10392674
TI  - Thoracic epidural anesthesia as an adjunct to general anesthesia for cardiac
      surgery: effects on ventilation-perfusion relationships.
AB  - OBJECTIVE: To determine the effects of thoracic epidural anesthesia (TEA) on
      ventilation-perfusion (VA/Q) relationships, atelectasis, and oxygenation before
      and after coronary artery bypass graft surgery (CABG). DESIGN: Prospective,
      controlled, unblinded, randomized trial. SETTING: Cardiothoracic clinic at a
      major university referral center. PARTICIPANTS: Twenty-eight patients undergoing
      elective CABG. INTERVENTIONS: Perioperative and postoperative TEA was added to
      general anesthesia (GA) in 14 patients, and 14 patients receiving GA alone served
      as controls. MEASUREMENTS AND MAIN RESULTS: VA/Q relationships were measured by
      the multiple inert gas elimination technique, and, 20 hours postoperatively,
      atelectasis was assessed by computerized tomographic scans. Arterial and mixed
      venous blood gases and hemodynamic variables were measured by standard
      techniques. TEA per se caused no change in shunt, VA/Q matching, or oxygenation.
      Induction of GA in the control group and induction of TEA caused similar
      reductions in mean arterial pressure. The TEA patients needed less morphine
      analgesia postoperatively and were extubated earlier. Extubation caused
      significant improvement in VA/Q matching. On the first postoperative day, a
      slight reduction in PaCO2 was seen in the TEA group, but no differences in shunt,
      VA/Q matching, or oxygenation compared with the GA group. Both groups showed
      extensive bilateral atelectasis. CONCLUSION: TEA can reduce respirator time and
      the need for morphine analgesics after CABG without negative effects on VA/Q
      matching, oxygenation, or atelectasis formation.

PMID- 10392675
TI  - Selective preoperative cardiac screening improves five-year survival in patients
      undergoing major vascular surgery: a cost-effectiveness analysis.
AB  - OBJECTIVE: To evaluate the long-term outcomes (5-year survival) and cost
      effectiveness of selective coronary revascularization before major vascular
      surgery. DESIGN: A decision-tree model was constructed to compare the cost
      effectiveness of four preoperative screening strategies from the perspective of
      the health care system. SETTING: Based on patient mortality, morbidity, and cost
      data from a literature review. PARTICIPANTS: Hypothetical cohort of patients
      scheduled for elective abdominal aortic aneurysm repair followed up over a 5-year
      period. INTERVENTIONS: Patients either proceeded directly to surgery or were
      screened using one of three possible preoperative screening strategies. In the
      first strategy, all patients were screened with a dipyridamole-thallium test. In
      the second strategy, all patients underwent coronary angiography. The third
      strategy, selective screening, first divided patients into high-, intermediate-,
      and low-risk groups using clinical criteria. High-risk patients underwent
      preoperative angiography. Intermediate-risk patients were screened noninvasively,
      and low-risk patients proceeded directly to surgery without further testing.
      MEASUREMENT AND MAIN RESULTS: Proceeding directly to vascular surgery resulted in
      the poorest 5-year survival rate (77.4%) compared with preoperative risk
      stratification followed by selective coronary revascularization, routine
      noninvasive testing (86.1%), selective testing (86.0%), and routine angiography
      (87.9%; p = 0.00). The incremental cost-effectiveness ratio for selective testing
      was significantly lower than for routine angiography ($44,800/years of life saved
      (YLS) v $93,300/YLS; p < 0.02). Routine noninvasive testing was not cost
      effective. Thirty-day mortality was the same for all four strategies (p = 0.84).
      CONCLUSION: Selective screening before vascular surgery may improve 5-year
      survival and be cost-effective. Neither routine noninvasive testing nor routine
      angiography appears to be cost-effective compared with currently accepted medical
      therapies.

PMID- 10392676
TI  - Cardiac troponin I cutoff values to predict postoperative cardiac complications
      after circulatory arrest and profound hypothermia.
AB  - OBJECTIVE: Cardiac failure and myocardial infarction are complications of
      thoracic aorta, thoracoabdominal aorta, or aortic arch surgery, especially when
      surgery is performed using profound hypothermia and circulatory arrest (PHCA).
      Moreover, the diagnosis of non-Q-wave postoperative myocardial infarction (PMI)
      is challenging because there is no gold standard. The aims of this study were to
      determine values for cardiac troponin I (cTnl) in patients undergoing aortic arch
      or thoracoabdominal aortic surgery with PHCA who were free of cardiac
      complications in the postoperative period, and to test the validity of cutoff
      values of cTnl to predict postoperative cardiac complications in such patients.
      DESIGN: Prospective, nonrandomized study. SETTING: Single university hospital;
      Departments of Anesthesiology, Biochemistry and Vascular Surgery. PARTICIPANTS:
      Fifty-two consecutive patients were studied over a 2-year period. None was
      excluded, even patients who underwent emergency surgery. INTERVENTIONS: Patients
      undergoing aortic arch or thoracoabdominal aortic surgery with PHCA were studied.
      Thirty patients undergoing coronary artery bypass grafting (CABG) in the same
      period constituted a control group. MEASUREMENTS AND MAIN RESULTS: The cTnl
      concentrations were determined using an immunoenzymofluorometric assay on a
      Stratus analyzer (Dade, Massy, France) on blood samples obtained at recovery and
      on day 1 (D1) and D2. Seventeen patients developed a cardiac complication, which
      was lethal in 10 patients. In patients without cardiac complication, the peak
      level for cTnl was observed on D1. Cutoff values of cTnl were identical in both
      the CABG control group (11 .6 microg/mL) and the sternotomy group (12.2
      microg/mL), but were significantly greater (20.5 microg/mL) in patients with a
      thoracotomy approach. Sensitivity and specificity of these cutoff values were
      high in both groups (control group, sensitivity = 100%, specificity = 100%;
      sternotomy group, sensitivity = 78%, specificity = 100%; thoracotomy group,
      sensitivity = 100%, specificity = 94%). CONCLUSION: In patients who underwent
      surgery using PHCA for aortic arch or descending aorta repair, myocardial damage
      related to cardiac arrest, vents or fibrillation explains the increased cutoff
      value (12.2 microg/mL). This value is similar to patients undergoing CABG surgery
      through a sternotomy approach with cardioplegia administration. In contrast, and
      probably related to the absence of cardioplegia, patients undergoing surgery
      through a left thoracotomy approach had a greater cutoff value (20.5 microg/mL).
      Values of cTnl greater than these respective cutoff values were closely related
      to cardiac complications during the postoperative period.

PMID- 10392677
TI  - Reliability of continuous jugular venous bulb hemoglobin oxygen saturation during
      cardiac surgery.
AB  - OBJECTIVE: To evaluate the accuracy and reliability of continuous measurement of
      jugular venous bulb hemoglobin oxygen saturation (SjvO2) with a fiberoptic
      catheter (SjvO(2OX)) during cardiac surgery versus simultaneous paired
      measurements of hemoglobin oxygen saturation by the Hemoximeter (SjVO(2HEM);
      Radiometer, Copenhagen, Denmark) and indirect estimations of hemoglobin oxygen
      saturation from measurements of partial pressure of oxygen in blood gases
      (SjVO(2BG)). DESIGN: A prospective study. SETTING: American Hellenic Educational
      Progressive Association General Hospital, University Hospital of Thessaloniki,
      Greece. PATIENTS: Thirty patients undergoing elective aortocoronary artery bypass
      surgery. INTERVENTIONS: In addition to routine pressure monitoring, a 4F
      fiberoptic catheter was placed in the left jugular bulb by a retrograde internal
      jugular vein approach and SIvO(2OX) was continuously measured. Before insertion,
      each catheter was calibrated in vitro. MEASUREMENTS AND MAIN RESULTS: One hundred
      twelve simultaneous paired recordings between SjvO(2OX) and SjVO2BG were
      performed to define the accuracy of SjVO(2OX) to SjVO(2BG). Sixty-one of 112
      simultaneous paired recordings between SjvO(2OX) and SjVO(2HEM) and SjVO(2HEM)
      and SjVO(2BG) were performed to define the accuracy of SjvO(2OX) to the reference
      SjVO(2HEM) and the reliability of the SjVO(2BG) measurement to SjVO(2HEM). The
      fiberoptic catheter readings varied from underestimating to overestimating
      hemoglobin saturation by a mean of -5.35% to +9.67% and of -3.22% to +7.81%
      versus Blood Gas Analyzer (Ciba-Corning) and Co-Oximeter (OSM 2b Hemoximeter,
      Radiometer) values, respectively. The mean underestimation and overestimation of
      Co-Oximeter versus Blood Gas Analyzer values were -3.18% and +4.17%,
      respectively. CONCLUSION: SjvO2 values obtained continuously from a jugular
      venous bulb fiberoptic catheter may give relatively accurate readings provided
      they are duly interpreted and errors caused by wall artifact or blood sampling
      are avoided.

PMID- 10392678
TI  - Obesity and coronary artery surgery.
AB  - OBJECTIVE: To assess whether obesity is a risk factor for morbidity and mortality
      in patients undergoing elective coronary artery revascularization. DESIGN:
      Prospective, clinical study. SETTING: University hospital. PARTICIPANTS: Three
      hundred forty-five consecutive patients who underwent elective coronary
      revascularization with cardiopulmonary bypass and without associated procedures.
      INTERVENTIONS: Patients were assigned to the obese group if their body mass index
      was greater than 30 for men and 28.6 for women, according to the World Health
      Organization indications. MEASUREMENTS AND MAIN RESULTS: Preoperative and
      intraoperative variables were collected and checked for homogeneity of the
      groups. Postoperative outcome was assessed on the basis of intubation time,
      intensive care unit (ICU) and postoperative hospital stay, mortality rate, and
      incidence of transfusions, reoperations, low-output syndrome, minor and major
      neurologic dysfunction, minor and major lung dysfunctions, renal dysfunction, and
      superficial and deep infections. The effect of obesity on postoperative outcome
      was tested with a multivariate logistic regression analysis. Obese and control
      patients had the same intubation time and ICU and postoperative hospital stay.
      Mortality and all major complications occurred with the same incidence in the two
      groups. Obese patients had a significantly (p < 0.05) greater rate of superficial
      infections and more (24.1% v 7.4%; p < 0.001) minor lung complications.
      Conversely, they had a significantly lower transfusion rate (27.5% v42.7%; p <
      0.01). CONCLUSION: Obese patients had only minor complications after coronary
      artery surgery. The large body surface area because of obesity protects them
      against the hemodilution-related transfusion risk.

PMID- 10392679
TI  - Influence of combined zero-balanced and modified ultrafiltration on the systemic
      inflammatory response during coronary artery bypass grafting.
AB  - OBJECTIVE: To evaluate whether combined zero-balanced and modified
      ultrafiltration affects the systemic inflammatory response in coronary artery
      bypass graft (CABG) patients. DESIGN: Randomized and controlled. SETTING:
      University-affiliated heart center. PARTICIPANTS: Forty-three patients scheduled
      for elective CABG. INTERVENTIONS: In the ultrafiltration group (UF group; n =
      21), zero-balanced ultrafiltration was performed during rewarming and modified
      ultrafiltration immediately after the end of cardiopulmonary bypass (CPB). A
      control group of patients (n = 22) was treated identically to the treatment group
      except no ultrafiltration process was performed. MEASUREMENTS AND MAIN RESULTS:
      Immediately after CPB (ie, after zero-balanced ultrafiltration), and again after
      the modified ultrafiltration, the concentrations of interleukin-6 and interleukin
      8 were significantly less (p < 0.05) in the UF group compared with the control
      group. Both proinflammatory cytokine levels peaked at 2 and 4 hours after CPB, at
      which time no difference between the two groups could be observed. The levels of
      measured anti-inflammatory mediators (interleukin-10 and interleukin-1 receptor
      antagonist) did not show any difference between the two groups. Intrapulmonary
      shunt fraction decreased in the course of the modified ultrafiltration from 31%
      +/- 1.2% to 25% +/- 1.3% (p < 0.01), whereas mean arterial pressure increased (69
      +/- 1.8 to 80 +/- 2.8 mmHg; p < 0.01); neither parameter changed in the control
      group. Time to extubation was shorter in the UF group (6.1 +/- 0.5 v 8.6 +/- 0.7
      hours; p < 0.05). CONCLUSION: It was concluded that the use of ultrafiltration
      diminished inflammatory response in a very limited time period immediately after
      CPB and, probably as a consequence, slightly improved clinical parameters.

PMID- 10392681
TI  - Assessment by pulse dye-densitometry indocyanine green (ICG) clearance test of
      hepatic function of patients before cardiac surgery: its value as a predictor of
      serious postoperative liver dysfunction.
AB  - OBJECTIVE: Patients with preoperative liver dysfunction occasionally have a poor
      prognosis after cardiac surgery because the liver condition is aggravated. The
      pulse dye-densitometry indocyanine green (ICG) clearance test was used as a
      preoperative evaluation technique. DESIGN: Prospective, clinical evaluation.
      SETTING: Surgical intensive care unit of a national cardiovascular center.
      SUBJECTS: Twenty-seven patients with preoperative liver dysfunction were studied.
      They were divided into four groups depending on the cause of their liver
      dysfunction. INTERVENTIONS: With the patient's informed consent, a bolus of ICG,
      20 mg, was injected, and the disappearance of ICG was measured noninvasively by
      pulse dye-densitometry. MEASUREMENTS AND MAIN RESULTS: The ICG retention rate at
      15 minutes (ICG-R15) was calculated for the regression time. The patients were
      assessed in terms of ICG-R15 and the cause of liver dysfunction. The ICG-R15
      values obtained for all 27 patients were 30% +/- 16% (mean +/- standard
      deviation). The 21 survivors had ICG-R15 values of 24% +/- 12%, whereas the 6
      patients who died after surgery had significantly greater ICG-R15 values of 50%
      +/- 13% (p < 0.05). The mean values of ICG-R15 in patients with congestive liver,
      viral hepatitis accompanied by congestive liver, viral hepatitis, and cirrhosis
      were 34%, 23%, 13%, and 42%, respectively. The 6 of 27 patients who died after
      surgery had ICG-R15 values greater than 40%. Five of the seven patients with
      cirrhosis died. CONCLUSION: These results suggest that (1) compared with Child
      Pugh classification, the value of ICG-R15 provides a more accurate surgical
      indication; and (2) liver dysfunction from cirrhosis causes postoperative
      deterioration of liver function, especially when the ICG-R15 value exceeds 40%.

PMID- 10392680
TI  - Markers of splanchnic perfusion and intestinal translocation of endotoxins during
      cardiopulmonary bypass: effects of dopamine and milrinone.
AB  - OBJECTIVES: To investigate markers of splanchnic perfusion and the extent of
      endotoxemia during cardiopulmonary bypass (CPB) and to compare the effects of
      dopamine and milrinone on both splanchnic perfusion and endotoxemia. DESIGN:
      Prospective, randomized, blinded study. SETTING: University teaching hospital.
      PARTICIPANTS: Twenty-four patients scheduled for elective coronary artery bypass
      graft surgery (CABG). INTERVENTIONS: Patients were allocated to receive placebo
      (eight patients), dopamine (eight patients), or milrinone (eight patients) during
      CPB, and at seven times intraoperatively assays were performed of arterial and
      hepatic venous endotoxin levels, as well as measurements and/or calculations of
      intramucosal gastric pH (pHi), arterial and hepatic venous lactate-pyruvate ratio
      (lac/pyr), and hepatic venous oxygen saturation (S(HV)O2). MEASUREMENTS AND MAIN
      RESULTS: Both splanchnic and systemic endotoxin levels increased significantly,
      and this was unaffected by either dopamine or milrinone. Gastric pHi did not
      change, and there were only modest increases in lac/pyr, which remained within
      the normal range of less than 10 in both splanchnic and systemic blood. In the
      placebo group, S(HV)O2 decreased at the onset of CPB and also significantly
      decreased during rewarming and at the end of CPB and surgery. In the dopamine
      treated patients, S(HV)O2 was greater compared with placebo and milrinone during
      both hypothermic and rewarming phases. CONCLUSION: Endotoxemia occurs during
      routine CPB. Neither pHi nor lac/pyr values showed adverse change, but hepatic
      venous oximetry may be a more sensitive indicator of splanchnic dysoxia in that
      S(HV)O2 was reduced during rewarming. Whether dopamine or milrinone confer
      protection against splanchnic ischemia remains uncertain.

PMID- 10392682
TI  - Efficacy of epsilon-aminocaproic acid in children undergoing cardiac surgery.
AB  - OBJECTIVE: To compare coagulation test results, blood loss, and blood product
      transfusions between patients receiving prophylactic epsilon-aminocaproic acid
      (EACA) and a control group matched for age, resternotomy, and surgery in children
      undergoing cardiac surgery. DESIGN: Nested case-control study. SETTING:
      University-affiliated, pediatric medical center. PARTICIPANTS: Same study period;
      70 patients in EACA group and 70 patients in control group. INTERVENTIONS:
      Prophylactic EACA administered intravenously (load, 150 mg/kg, infusion; 30
      mg/kg/h) to 70 patients at increased risk for bleeding (reoperation or Ross
      procedure). MEASUREMENTS AND MAIN RESULTS: Coagulation test values were measured
      before, during, and after cardiopulmonary bypass (CPB). Intraoperative blood
      loss, postoperative chest tube output, and allogenic blood product transfusions
      were recorded. Comparison of demographic and surgical data indicated close
      matching of the EACA and control groups. The EACA group ([median, 25th to 75th
      quartile] 15.6 mL/kg; 9.2 to 26.3 mL/kg) had less intraoperative blood loss than
      the control group (22.2 mL/kg; 14.3 to 36.3 mL/kg; p = 0.02). Postoperative chest
      tube output at 6 hours (p = 0.08), 12 hours (p = 0.07), and 24 hours (p = 0.08)
      was not significantly different between groups. Fewer EACA group patients
      required reexploration for bleeding (p < 0.05). There was no difference between
      groups in blood products transfused (in milliliters per kilogram or allogenic
      exposure per patient). Thromboelastography values (maximum amplitude [MA], whole
      blood clot lysis index at 30 minutes after MA) during CPB were better preserved
      in the EACA group. CONCLUSION: EACA reduced intraoperative blood loss but did not
      significantly decrease blood product transfusions. Lack of efficacy may be
      related to relative underdosing and should be further studied.

PMID- 10392683
TI  - Anesthetic management of a patient with relapsing polychondritis.

PMID- 10392684
TI  - Tension pneumothorax, pneumomediastinum, pneumoperitoneum, and subcutaneous
      emphysema in a 15-year-old Chinese girl after a double-lumen tube intubation and
      one-lung ventilation.

PMID- 10392685
TI  - Excision of a fungus ball in the right atrium using cardiopulmonary bypass in a
      patient with severe cystic fibrosis.

PMID- 10392686
TI  - Transesophageal echocardiography as a guide to central venous catheter placement
      in pediatric patients undergoing cardiac surgery.

PMID- 10392687
TI  - Airway rupture from double-lumen tubes.

PMID- 10392688
TI  - Cardiopulmonary bypass in infants and children: how is it different?

PMID- 10392689
TI  - Case 3--1999. Severe fetal bradycardia in a pregnant woman undergoing hypothermic
      cardiopulmonary bypass.

PMID- 10392690
TI  - Pro: every postthoracotomy patient deserves thoracic epidural analgesia.

PMID- 10392691
TI  - Con: every postthoracotomy patient does not deserve thoracic epidural analgesia.

PMID- 10392692
TI  - Evaluation of subclavian catheter position.

PMID- 10392693
TI  - An unexpected intraoperative echocardiographic finding in a patient with
      Eisenmenger's syndrome.

PMID- 10392694
TI  - Prediction of double-lumen tracheal tube depth.

PMID- 10392695
TI  - Method to prevent damage to the tracheal cuff of a double-lumen endotracheal tube
      during laryngoscopy.

PMID- 10392696
TI  - One-lung ventilation in patients with difficult airways.

PMID- 10392697
TI  - Thoracic surgery under epidural anesthesia.

PMID- 10392698
TI  - Air in the sinus transversus pericardi during port-access surgery causing an
      inadequate echocardiographic window.

PMID- 10392699
TI  - Magnesium and off-pump coronary artery bypass.

PMID- 10392700
TI  - Minimally invasive direct coronary artery bypass grafting techniques.

PMID- 10392701
TI  - Coronary sinus catheterization for port-access minimally invasive cardiac
      surgery.

PMID- 10392702
TI  - Port-access surgery: preparation times.

PMID- 10392703
TI  - Epidermal cell lineage.
AB  - The epidermis is a stratified squamous epithelium, which is under a constant
      state of proliferation, commitment, differentiation, and elimination so that the
      functional integrity of the tissue is maintained. The intact epidermis has the
      ability to respond to diverse environmental stimuli by continuous turnover to
      maintain its normal homeostasis throughout an organism's life. This is achieved
      by a tightly regulated balance between stem cell self-renewal and the generation
      of a population of cells that undergo a limited number of more rapid (amplifying)
      transit divisions before giving rise to nonproliferative, terminally
      differentiating cells. This process makes it an excellent model system to study
      lineage, commitment, and differentiation, although neither the identity of
      epidermal stem cells nor the precise steps and regulators that lead to mature
      epidermal cells have yet been determined. Furthermore, the identities of genes
      that initiate epidermal progenitor commitment to the epidermal lineage, from
      putative epidermal stem cells, are unknown. This is mainly due to the lack of an
      in vitro model system, as well as the lack of specific reagents, to study the
      early events in epidermal lineage. Our recent development of a differentiating
      embryonic stem cell model for epidermal lineage now offers the opportunity to
      analyze the factors that regulate epidermal lineage. These studies will provide
      new insight into epidermal lineage and lead to a better understanding of various
      hyperproliferative skin diseases such as psoriasis and cancer.

PMID- 10392704
TI  - Advances in the osteoblast lineage.
AB  - Osteoblasts are the skeletal cells responsible for synthesis, deposition and
      mineralization of the extracellular matrix of bone. By mechanisms that are only
      beginning to be understood, stem and primitive osteoprogenitors and related
      mesenchymal precursors arise in the embryo and at least some appear to persist in
      the adult organism, where they contribute to replacement of osteoblasts in bone
      turnover and in fracture healing. In this review, we describe the morphological,
      molecular, and biochemical criteria by which osteoblasts are defined and cell
      culture approaches that have helped to clarify transitional stages in osteoblast
      differentiation. Current understanding of differential expression of osteoblast
      associated genes during osteoprogenitor proliferation and differentiation to
      mature matrix synthesizing osteoblasts is summarized. Evidence is provided to
      support the hypothesis that the mature osteoblast phenotype is heterogeneous with
      subpopulations of osteoblasts expressing only subsets of the known osteoblast
      markers. Throughout this paper, outstanding uncertainties and areas for future
      investigation are also identified.

PMID- 10392705
TI  - Commitment and differentiation of stem cells to the osteoclast lineage.
AB  - Osteoclasts are hematopoietic cells which play important roles in bone remodeling
      and resorption. They have phenotypic characteristics of the monocyte/macrophage
      lineages. In this review we first describe the phylogeny of osteoclasts.
      Osteoclast generation is closely linked to the presence of bone tissues. The
      formation of bone cavities in aquatic animals is underdeveloped, even though they
      have cells which have the potential to differentiate into osteoclasts. Next we
      describe recent advances in our understanding of osteoclastogenesis that have
      resulted from the identification of critical molecules and mutated genes of
      osteopetrotic mice. Reports that transcriptional factors PU.1 and c-Fos are
      essential for commitment and (or) differentiation into the osteoclast lineage and
      novel culture systems, which have clarified some characteristics of osteoclast
      precursors, are also described. We are now able to induce mature osteoclasts from
      hematopoietic stem cells and even from totipotent embryonic stem cells. Cell
      lines that differentiate into osteoclasts are also available. Using these culture
      systems and cell lines, the interactions of osteoclasts with osteoblastic stromal
      cells, which produce critical molecules for osteoclastogenesis, have been
      studied. Very recently, one of these critical molecules, osteoclast
      differentiation factor/osteoprotegerin-ligand, was cloned. The presence of this
      factor and macrophage-colony-stimulating factor is sufficient to induce
      osteoclast development in cultures inoculated only with an osteoclast precursor
      cell line. We review the present status and the remaining questions in osteoclast
      biology.

PMID- 10392706
TI  - Odontoblast commitment and differentiation.
AB  - Histological and cytological organization confer specificity to the odontoblasts.
      These postmitotic, neural crest derived, polarized cells are aligned in a single
      layer at the periphery of the dental pulp and secrete the organic components of
      predentin-dentin. The developmental history of these cells demands a cascade of
      epigenetic signalling events comprising the acquisition of odontogenic potential
      by neural crest cells, their patterning in the developing jaws, the initiation of
      odontogenesis through interaction with the oral epithelium, commitment, and tooth
      specific spatial distribution of competent preodontoblasts able to overtly
      differentiate. Recent experimental investigations are critically summarized, many
      open questions are stressed, and current hypotheses concerning the control of
      terminal odontoblast differentiation are outlined.

PMID- 10392707
TI  - Segregation of the embryonic vascular and hemopoietic systems.
AB  - The origin of endothelial cells and their subsequent assembly into the primary
      vascular system have been mostly analyzed in the avian embryo. Following the
      discovery of specific growth factors and their cognate receptors, the molecular
      mechanisms underlying these processes have been unraveled in both birds and
      mammals. In particular, experimental studies of the angiogenic vascular
      endothelial growth factor (VEGF) and its receptors, carried out in both
      vertebrate classes, have provided significant insight into the developmental
      biology of endothelial cells. The VEGF receptor VEGFR2 is the earliest marker
      known to be expressed by endothelial precursor cells of avian and mouse embryos.
      Based on the localization of VEGFR2+ cells in the avian embryo and on clonal
      culture experiments, two types of endothelial precursor cells can be
      distinguished from gastrulation stages onward: posterior mesodermal VEGFR2+
      hemangioblasts, which have the capacity to differentiate into endothelial and
      hemopoietic cells, and anterior VEGFR2+ angioblasts, which can only give rise to
      endothelial cells.

PMID- 10392708
TI  - Hemangioblast development and regulation.
AB  - Hematopoietic and endothelial cell lineages are the first to mature from mesoderm
      in the developing embryo. However, little is known about the molecular and (or)
      cellular events leading to hematopoietic commitment. The recent applications of
      technology utilizing gene targeted mice and the employment of many available in
      vitro systems have facilitated our understanding of hematopoietic establishment
      in the developing embryo. It is becoming clear that embryonic hematopoiesis
      occurs both in the extra-embryonic yolk sac and within the embryo proper in the
      mouse. The existence of the long pursued hemangioblast, a common progenitor of
      hematopoietic and endothelial cells, is now formally demonstrated. Based on this
      new information, many studies are being conducted to understand hematopoietic
      commitment events from mesoderm. In this review, we will first discuss the
      establishment of the hematopoietic system with special emphasis on the most
      primitive hematopoietic committed cells, the hemangioblast. We will then discuss
      mesoderm-inducing factors and their possible role in hematopoietic lineage
      commitment.

PMID- 10392709
TI  - The Cdx-1 and Cdx-2 homeobox genes in the intestine.
AB  - The past years have witnessed an increasing number of reports relative to
      homeobox genes in endoderm-derived tissues. In this review, we focus on the
      caudal-related Cdx-1 and Cdx-2 homeobox genes to give an overview of the in vivo,
      in vitro, and ex vivo approaches that emphasize their primary role in intestinal
      development and in the control of intestinal cell proliferation, differentiation,
      and identity. The participation of these genes in colon tumorigenesis and their
      identification as important actors of the oncogenic process are also discussed.

PMID- 10392710
TI  - Commitment and differentiation of lung cell lineages.
AB  - To form a large diffusible interface capable of conducting respiratory gases to
      and from the circulation, the lung must undergo extensive cell proliferation,
      branching morphogenesis, and alveolar saccule formation, to generate sufficient
      surface area. In addition, the cells must differentiate into at least 40 distinct
      lung cell lineages. Specific transcriptional factors, peptide growth factor
      receptor-mediated signaling pathways, extracellular matrix components, and
      integrin-signaling pathways interact to direct lung morphogenesis and lung cell
      lineage differentiation. Branching mutants of the respiratory tracheae in
      Drosophila have identified several functionally conserved genes in the fibroblast
      growth factor signaling pathway that also regulate pulmonary organogenesis in
      mice and probably also in man. Key transcriptional factors including Nkx2.1,
      hepatocyte nuclear factor family forkhead homologues, GATA family zinc finger
      factors, pou and homeodomain proteins, as well as basic helix-loop-helix factors,
      serve as master genes to integrate the developmental genetic instruction of lung
      morphogenesis and cell lineage determination. Lung mesenchyme serves as a
      'compleat' inducer of lung morphogenesis by secreting soluble peptide growth
      factors. In general, peptide growth factors signaling through cognate receptors
      with tyrosine kinase intracellular signaling domains such as epidermal growth
      factor receptor, fibroblast growth factor receptors, hepatocyte growth
      factor/scatter factor receptor, c-met, insulin-like growth factor receptor, and
      platelet-derived growth factor receptor, stimulate lung morphogenesis, while the
      cognate receptors with serine/threonine kinase intracellular signaling domains,
      such as the transforming growth factor-beta receptor family are inhibitory. The
      extracellular matrix also plays a key role in determining branching
      morphogenesis. Pulmonary neuroendocrine (PNE) cells differentiate earliest in
      gestation among lung epithelial cells. PNE cells are principally derived from
      endoderm and not neural crest. PNE cells have been proposed to function as airway
      chemoreceptors, while PNE cell secretory granules contain many bioactive
      substances such as GRP which may direct proliferation of adjacent epithelial
      cells. Mammalian achaete-schute homolog-1 null mutant mice do not develop PNE
      cells. Candidate molecular switches in the transition from a quiescent to a
      proliferative alveolar epithelial cell (AEC) phenotype and back again following
      acute hyperoxia, include autocrine peptide growth factor signaling pathways and
      cell cycle regulatory elements. AEC type 2 also appear capable of reversible
      transdifferentiation into AEC type 1 and intermediate phenotypes in response to
      cues from extracellular matrix and cell shape, as well as soluble factors.
      Evidence for expression of telomerase by alveolar epithelial stem cells, which
      correlates with self-renewal potential, is now beginning to emerge. Lung
      regeneration following lobectomy in juvenile rodents is associated with co
      ordinated cell proliferation, re-expression of elastin and formation of alveoli.
      Retinoic acid has recently shown promise as a stimulator of alveolization in
      juvenile rats. Our future goal is to devise new rational and gene therapeutic
      strategies to stimulating lung growth and maturation, ameliorating lung injury,
      augmenting lung repair, and inducing lung regeneration. The ideal agent or agents
      would therefore mimic the instructive role of lung mesenchyme, correctly inducing
      the temporospatial pattern of lung cell lineages necessary to restore pulmonary
      gas diffusing capacity.

PMID- 10392711
TI  - Plasticity of mammary epithelia during normal development and neoplastic
      progression.
AB  - The functional unit of the mammary gland is the epithelium. It consists of
      luminal epithelial cells and myoepithelial cells that are generated from self
      renewing stem and progenitor cells. The latter two cell types are scattered
      throughout the mammary epithelium and are concentrated in specialized structures,
      the end buds. In transplantation studies the pluripotency of mammary stem cells
      has been confirmed by demonstrating that they can regenerate a complete mammary
      gland. The ability of mammary epithelial cells to produce an elaborate ductal
      system during puberty and to differentiate into milk-producing alveoli during
      pregnancy is not only influenced by their genetic make-up, but is also governed
      by local molecular signals. Recent studies suggest that the transdifferentiation
      of epithelial cells into tumor cells is under microenvironmental control, despite
      the prominence of genetic mutations in breast cancer. Consequently, disturbances
      of tissue homeostasis can alter mammary gland development or result in
      preneoplastic and neoplastic pathologies. The plasticity of mammary epithelia is
      not limited to the entry of cells into differentiation and transdifferentiation
      pathways, but extends to their ability to regain facets of their preceding stage
      of functionality. Deciphering the molecular cues that determine cell plasticity
      is prerequisite for establishing a unifying concept of mammary gland development
      and breast tumor progression.

PMID- 10392713
TI  - Genetic control of extraembryonic cell lineages studied with tetraploid<-
      >diploid chimeric concepti.
AB  - The first differentiation event during mammalian embryogenesis is the commitment
      of blastomeres to the trophectoderm cell lineage. Much remains to be learned
      about the genetic control of this first cell lineage commitment and the
      subsequent events underlying the differentiation of all extraembryonic cell
      lineages. Because of the unique features of intrauterine embryonic development,
      the study of embryogenesis in lower organisms has shed little light on mammalian
      extraembryonic lineage differentiation. Rather, two major methods in
      developmental genetics have contributed to our understanding of genetic control
      of extraembryonic cell lineages. First, abnormalities in extraembryonic tissues
      have been described in many genetically engineered mutant mouse lines. However,
      the histological description of these abnormalities does not demonstrate whether
      the observed defect is the primary cause of embryonic lethality. Second,
      tetraploid<-->diploid aggregation experiments have been used to generate chimeric
      concepti with distinct genotypes in the extraembryonic tissues and the embryo
      proper. This experimental approach has provided the definitive demonstration of
      the crucial role of several transcription factors, growth factors and
      cytoskeleton proteins in extraembryonic tissue formation. The present review
      summarizes the origin of tetraploid<-->diploid aggregation experiments and it
      usefulness for the study the genetic control of extraembryonic cell lineages.

PMID- 10392712
TI  - Cell lineages in the embryonic kidney: their inductive interactions and
      signalling molecules.
AB  - The first signalling genes acting in the inductive interactions in the kidney
      have now been identified. Differentiation of the permanent kidney or the
      metanephros is critically dependent on inductive signalling between the
      nephrogenic mesenchyme and ureteric bud epithelium. Further inductive
      interactions occur between developing nephrons, interstitial stroma, endothelial
      cells and neurones. Glial-cell-line-derived neurotrophic factor is a signal for
      the ureteric bud initiation and branching, and Wnt4 is an autocrine
      epithelializing signal at the pretubular stage of nephron formation. The signals
      for renal angiogenesis and innervation are less well defined, but seem to include
      vascular endothelial growth factor and neurotrophins, at least. The ureteric-bud
      derived signal for induction of the nephrogenic mesenchyme (to bring the cells to
      the condensate stage) is not yet known, but fibroblast growth factor 2 is a good
      candidate. None of the signalling genes identified from the embryonic kidney is
      specific to the organ, which raises some general questions. How do the organs
      develop from similar rudiments to various patterns with different cell types and
      functions? Does the information for organ-specific differentiation pathways
      retain in the epithelial or mesenchymal compartment? The present, rather
      fragmentary molecular data would favour the view that similar molecules acting in
      different combinations and developmental sequences, rather than few organ
      specific master genes, could be responsible for the divergence of patterning.

PMID- 10392715
TI  - Growth factor synergism and antagonism in early neural crest development.
AB  - This review article focuses on data that reveal the importance of synergistic and
      antagonistic effects in growth factor action during the early phases of neural
      crest development. Growth factors act in concert in different cell lineages and
      in several aspects of neural crest cell development, including survival,
      proliferation, and differentiation. Stem cell factor (SCF) is a survival factor
      for the neural crest stem cell. Its action is neutralized by neurotrophins, such
      as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and
      neurotrophin-3 (NT-3) through apoptotic cell death. In contrast, SCF alone does
      not support the survival of melanogenic cells (pigment cell precursors). They
      require the additional presence of a neurotrophin (NGF, BDNF, or NT-3).
      Fibroblast growth factor-2 (FGF-2) is an important promoter of proliferation in
      neuronal progenitor cells. In neural crest cells, fibroblast growth factor
      treatment alone does not lead to cell expansion but also requires the presence of
      a neurotrophin. The proliferative stimulus of the fibroblast growth factor -
      neurotrophin combination is antagonized by transforming growth factor beta-1
      (TGFbeta-1). Moreover, TGFbeta-1 promotes the concomitant expression of neuronal
      markers from two cell lineages, sympathetic neurons and primary sensory neurons,
      indicating that it acts on a pluripotent neuronal progenitor cell. Moreover, the
      combination of FGF-2 and NT3, but not other neurotrophins, promotes expression or
      activation of one of the earliest markers expressed by presumptive sympathetic
      neuroblasts, the norepinephrine transporter. Taken together, these data emphasize
      the importance of the concerted action of growth factors in neural crest
      development at different levels and in several cell lineages. The underlying
      mechanisms involve growth-factor-induced dependence of the cells on other factors
      and susceptibility to growth-factor-mediated apoptosis.

PMID- 10392714
TI  - Mouse gene trap approach: identification of novel genes and characterization of
      their biological functions.
AB  - The mouse gene trap strategy is an insertional mutagenesis involving an exogenous
      DNA, termed the trap vector, as a mutagen that produces a mutation in the mouse
      genome and a sequence tag to facilitate the isolation of the mutated genes. The
      trap vector consists of a reporter gene whose expression mimics that of the
      endogenous genes mutated and a selection marker that sorts cells bearing the
      inserted vector. Gene trap is a powerful method for identifying genes important
      in biological phenomena. Moreover, the method produces mutant organisms whose
      phenotypes provide invaluable information about the biological functions of the
      genes responsible for these phenotypes. Indeed, a number of genes essential for
      mouse embryogenesis have been identified by the gene trap method. Here, we
      describe the principle, results, and perspectives for applications of gene trap
      approach to the study of cell differentiation and lineage commitment.

PMID- 10392716
TI  - Cell lineage in the developing neural tube.
AB  - Acquisition of cell type specific properties in the spinal cord is a process of
      sequential restriction in developmental potential. A multipotent stem cell of the
      nervous system, the neuroepithelial cell, generates central nervous system and
      peripheral nervous system derivatives via the generation of intermediate lineage
      restricted precursors that differ from each other and from neuroepithelial cells.
      Intermediate lineage restricted neuronal and glial precursors termed neuronal
      restricted precursors and glial restricted precursors, respectively, have been
      identified. Differentiation is influenced by extrinsic environmental signals that
      are stage and cell type specific. Analysis in multiple species illustrates
      similarities between chick, rat, mouse, and human cell differentiation. The
      utility of obtaining these precursor cell types for gene discovery, drug
      screening, and therapeutic applications is discussed.

PMID- 10392717
TI  - Lineage and pluripotentiality of epithelial precursor cells in developing chicken
      skin.
AB  - How do epithelial cells in developing skin accommodate the constantly growing
      embryo? Where do cells in skin appendages come from? Are they derivatives of a
      single appendage stem cell, or are they polyclonal? Here we analyze these issues
      in developing chicken skin using a replication-defective virus carrying beta
      galactosidase and DiI microinjections. The results demonstrate that in early
      skin, epithelial cells labelled near the spine show a parallel linear stripe
      distribution pattern that is perpendicular to the midline of the trunk. This is
      similar to the human lines of Blaschko, a linear pattern on the skin, which many
      skin nevoid or acquired disorders follow. In later skin, feather buds form and
      contain a mixture of labeled and unlabeled cells, attesting to their polyclonal
      origin. When cells are traced for shorter time intervals, the labeled progeny
      appear to follow certain rules. The degree of cell dispersion and mixing
      increases with a longer incubation period between the time of labeling and
      detection. The spatial maturation sequence of skin appendages is not regulated by
      the order in which epithelial cells are generated. Epithelial cells at this
      developmental stage are pluripotent and competent to respond to new signals to
      assume appropriate fates according to their micro-environment. The results
      suggest that local interactions act upon the originally linearly deposited
      pluripotential epithelial cells to form skin appendages.

PMID- 10392718
TI  - MyoD and Myf-5 define the specification of musculature of distinct embryonic
      origin.
AB  - Mounting evidence supports the notion that Myf-5 and MyoD play unique roles in
      the development of epaxial (originating in the dorso-medial half of the somite,
      e.g. back muscles) and hypaxial (originating in the ventro-lateral half of the
      somite, e.g. limb and body wall muscles) musculature. To further understand how
      Myf-5 and MyoD genes cooperate during skeletal muscle specification, we examined
      and compared the expression pattern of MyoD-lacZ (258/2.5lacZ and MD6.0-lacZ)
      transgenes in wild-type, Myf-5, and MyoD mutant embryos. We found that the
      delayed onset of muscle differentiation in the branchial arches, tongue, limbs,
      and diaphragm of MyoD-/- embryos was a consequence of a reduced ability of
      myogenic precursor cells to progress through their normal developmental program
      and not because of a defect in migration of muscle progenitor cells into these
      regions. We also found that myogenic precursor cells for back, intercostal, and
      abdominal wall musculature in Myf-54-/- embryos failed to undergo normal
      translocation or differentiation. By contrast, the myogenic precursors of
      intercostal and abdominal wall musculature in MyoD-/- embryos underwent normal
      translocation but failed to undergo timely differentiation. In conclusion, these
      observations strongly support the hypothesis that Myf-5 plays a unique role in
      the development of muscles arising after translocation of epithelial dermamyotome
      cells along the medial edge of the somite to the subjacent myotome (e.g., back or
      epaxial muscle) and that MyoD plays a unique role in the development of muscles
      arising from migratory precursor cells (e.g., limb and branchial arch muscles,
      tongue, and diaphragm). In addition, the expression pattern of MyoD-lacZ
      transgenes in the intercostal and abdominal wall muscles of Myf-5-/- and MyoD-/-
      embryos suggests that appropriate development of these muscles is dependent on
      both genes and, therefore, these muscles have a dual embryonic origin (epaxial
      and hypaxial).

PMID- 10392720
TI  - Post translational modifications of recombinant human papillomavirus type 6b
      major capsid protein.
AB  - We have determined the post-translational modifications of the major capsid
      protein, L1 of human papillomavirus (HPV) type 6b. Since this virus cannot be
      cultured in the laboratory to obtain sufficient material for a study, a
      recombinant L1 protein produced in a vaccinia virus expression system was used in
      this investigation. Our results show that this protein is phosphorylated at
      serine residues and is also glycosylated. No myristoylation or palmitoylation was
      detected. The fraction of L1 protein incorporated into virus-like particles was
      not glycosylated. Since recombinant L1 protein is a potential human vaccine
      candidate, knowledge of the post-translation modifications of this protein may
      prove useful for the design of anti-HPV vaccines.

PMID- 10392719
TI  - Endothelin signalling in the development of neural crest-derived melanocytes.
AB  - In both mice and humans, mutations in the genes encoding the endothelin B
      receptor and its ligand endothelin 3 lead to deficiencies in neural crest-derived
      melanocytes and enteric neurons. The discrete steps at which endothelins exert
      their functions in melanocyte development were examined in mouse neural crest
      cell cultures. Such cultures, kept in the presence of fetal calf serum, gave rise
      to cells expressing the early melanoblast marker Dct even in the absence of the
      phorbol ester tetradecanoyl phorbol acetate (TPA) or endothelins. However, these
      early Dct+ cells did not proliferate and pigmented cells never formed unless TPA
      or endothelins were added. In fact, endothelin 2 was as potent as TPA in
      promoting the generation of both Dct+ melanoblasts and pigmented cells, and
      endothelin 1 or endothelin 3 stimulated the generation of melanoblasts and of
      pigmented cells to an even greater extent. The inhibition of this stimulation by
      the selective endothelin B receptor antagonist BQ-788 (N-cis-2,6
      dimethylpiperidinocarbonyl-L-alpha-methylleucyl-D -1-methoxycarbonyltryptophanyl
      D-norleucine) suggested that the three endothelins all signal through the
      endothelin B receptor. This receptor was indeed expressed in Dct+ melanoblasts,
      in addition to cells lacking Dct expression. The results demonstrate that
      endothelins are potent stimulators of melanoblast proliferation and
      differentiation.

PMID- 10392721
TI  - Structural organization of a conserved gene cluster of Tupaia herpesvirus
      encoding the DNA polymerase, glycoprotein B, a probable processing and transport
      protein, and the major DNA binding protein.
AB  - The Tupaia herpesviruses (THVs) have been isolated from malignant lymphoma tissue
      cultures and from degenerating lung and spleen cell cultures of tree shrews
      (Tupaia spp.). Recently we succeeded in the localization of the gene locus of the
      THV DNA polymerase (DPOL) gene within the viral genome. Based on these results
      the highly conserved gene cluster of herpesviruses encoding the DPOL, the
      glycoprotein B (gB), a probable processing and transport protein (PRTP), and the
      major DNA binding protein (DNBI) was characterized in the genome of THV strain 2
      (THV-2) in its entirety. The complete nucleotide sequence of the gene cluster was
      determined and it was discovered that the THV-2 gene products are most closely
      related to the corresponding proteins of mammalian cytomegaloviruses. The
      transcriptional activity of the four genes was confirmed by amplification of a
      part of the corresponding mRNAs obtained from infected cell RNA by RT-PCR. The
      homology values and the overall structure of the gene cluster, that shows
      specific colinearity with the corresponding clusters of the mammalian
      cytomegaloviruses, is further evidence that THV-2 is a member of the subfamily
      Betaherpesvirinae.

PMID- 10392722
TI  - Activity of a purified His-tagged 3C-like proteinase from the coronavirus
      infectious bronchitis virus.
AB  - Previous studies in vitro of the processing of cloned polyprotein fragments from
      the coronavirus infectious bronchitis virus (IBV) large open reading frame
      (ORF1), confirmed the activity of a predicted 3C-like proteinase (3CLP) domain
      and suggested that the proteinase is released autocatalytically from the
      polyprotein in the form of a 35 kDa protein, 3CLpro, capable of further cleavages
      in trans. In order to identify such cleavages within the ORF1 polyprotein
      mediated by 3CLpro, the proteinase was expressed in bacteria, purified and used
      in trans cleavage assays with polyprotein fragments lacking the 3CLP domain as
      targets. The proteinase was expressed as a polyprotein fragment which was able to
      process during expression in bacterial cells, releasing mature 3CLpro. A
      histidine (His6) tag was introduced close to the C-terminus of the proteinase to
      aid purification. Processing demonstrated by the tagged proteinase was
      indistinguishable from that of the wild-type enzyme indicating that the site
      chosen for the tag was permissive. From these studies we were able to demonstrate
      trans cleavages consistent with the use of most of the previously predicted or
      identified sites within the open reading frame of gene 1. This tentatively
      completes the processing map for the ORF1 region with respect to 3CLpro.

PMID- 10392723
TI  - Novel acylation of poxvirus A-type inclusion proteins.
AB  - Myristylation is one of several post-translational modifications that occur on
      vaccinia virus (VV) proteins. Previously, time course labeling of VV-infected
      cells with myristic acid had indicated that five late proteins (17, 25, 36, 38
      and 92 kDa) are myristylated. Four of these proteins were mapped to the E7R, L1R,
      AI6L and G9R open-reading frames, respectively, because of the predicted presence
      of the N-myristyltransferase recognition sequence (M-G-X-X-X-S/T/A) at their
      amino termini. In contrast, computer analyses of large (80-100 kDa) VV open
      reading frames did not reveal any predicted species with this N-terminal motif.
      By immunoprecipitation with monospecific sera and transient expression of cloned
      gene products, the myristylated 92-kDa protein has been demonstrated to be the A
      type inclusion protein encoded by the Western Reserve (WR) strain of VV. Labeling
      of cowpox virus (CPV) infected cells with myristic acid indicated that the 160
      kDa A-type inclusion protein appears to be myristylated as well. Both the VV 92
      kDa and the CPV 160-kDa A-type inclusion proteins labeled with myristic acid were
      stable to hydroxylamine treatment, suggesting an amide linkage between the fatty
      acid and the acceptor protein. HPLC analysis confirmed that the 92-kDa protein
      was in fact myristylated. This data suggests that poxvirus ATI proteins may be
      subject to a novel type of internal myristylation modification, and the roles
      such modifications may play in the replication cycles of these viruses is
      discussed.

PMID- 10392724
TI  - Cell-surface heparan sulfate facilitates human immunodeficiency virus Type 1
      entry into some cell lines but not primary lymphocytes.
AB  - Many viruses have evolved to exploit cell-surface glycosaminoglycans (GAG),
      particularly heparan sulfate, to facilitate their attachment and infection of
      host cells. Here, the case for the involvement of heparan sulfate GAG in cellular
      infection by human immunodeficiency virus Type 1 (HIV-1) compared with herpes
      simplex virus Type 1 (HSV-1) is re-examined. It is shown that HIV-1 infection is
      facilitated by heparan sulfate GAG in only one of three highly permissive cell
      lines tested, whereas HSV-1 infection is facilitated to varying extents in all
      three. To evaluate the physiological relevance of these findings, primary
      peripheral blood lymphocytes (PBL), the physiological host for HIV-1, were
      examined. It was found that treatment of PBL with heparitinase, to remove any
      traces of heparan sulfate GAG, did not alter their sensitivity to infection by
      either lymphocyte-tropic, X4-type strain HIV-1IIIB, nor the monocyte-tropic, R5
      type strain, HIV-1Ba-L. It is concluded that heparan sulfate GAG has little
      physiological role in the infection of lymphocytes by HIV-1 and that evidence
      derived from studies on immortalized cell lines suggesting a significant role
      must be interpreted with caution.

PMID- 10392725
TI  - High prevalence and phylogenetic analysis of TT-virus infection in Mongolia.
AB  - A novel DNA virus, TT-virus (TTV), was isolated from a post-transfusion hepatitis
      patient in Japan. The prevalence of TTV infection was investigated among patients
      with chronic liver disease and normal alanine aminotransferase (ALT) volunteers
      as controls in Mongolia. Polymerase chain reaction (PCR) was employed to detect
      TTV DNA using specific primers derived from open reading frame 1 (ORF1) of the
      TTV genome. Nucleotide sequences of samples positive for TTV DNA were determined.
      The sequences were analyzed by a molecular evolutionary method. Fifty (60.2%)
      hepatitis patients and 12 (42.9%) volunteers were positive for TTV DNA. The serum
      ALT levels did not differ significantly between patients with single TTV
      infection and without TTV, HBV and HCV infection. Similarly, the serum ALT levels
      did not differ significantly between controls with and without TTV infection.
      Dual infection of TTV with either HBV or HCV did not affect the ALT levels of
      hepatitis patients. The molecular evolutionary tree showed that TTV was a
      heterogeneous virus and all strains could be divided into three genotypes in
      Mongolia. A new genotype was identified that was distinct from those previously
      reported.

PMID- 10392726
TI  - Phylogenetic analysis of a highly conserved region of the polymerase gene from 11
      coronaviruses and development of a consensus polymerase chain reaction assay.
AB  - Viruses in the genus Coronavirus are currently placed in three groups based on
      antigenic cross-reactivity and sequence analysis of structural protein genes.
      Consensus polymerase chain reaction (PCR) primers were used to obtain cDNA, then
      cloned and sequenced a highly conserved 922 nucleotide region in open reading
      frame (ORF) 1b of the polymerase (pol) gene from eight coronaviruses. These
      sequences were compared with published sequences for three additional
      coronaviruses. In this comparison, it was found that nucleotide substitution
      frequencies (per 100 nucleotides) varied from 46.40 to 50.13 when viruses were
      compared among the traditional coronavirus groups and, with one exception (the
      human coronavirus (HCV) 229E), varied from 2.54 to 15.89 when compared within
      these groups. (The substitution frequency for 229E, as compared to other members
      of the same group, varied from 35.37 to 35.72.) Phylogenetic analysis of these
      pol gene sequences resulted in groupings which correspond closely with the
      previously described groupings, including recent data which places the two avian
      coronaviruses--infectious bronchitis virus (IBV) of chickens and turkey
      coronavirus (TCV)--in the same group [Guy, J.S., Barnes, H.J., Smith L.G.,
      Breslin, J., 1997. Avian Dis. 41:583-590]. A single pair of degenerate primers
      was identified which amplify a 251 bp region from coronaviruses of all three
      groups using the same reaction conditions. This consensus PCR assay for the genus
      Coronavirus may be useful in identifying as yet unknown coronaviruses.

PMID- 10392728
TI  - Never say never.

PMID- 10392727
TI  - HIV-1 subtype B in Honduras.

PMID- 10392729
TI  - Intravitreal tissue plasminogen activator for acute central retinal vein
      occlusion.
AB  - OBJECTIVES: We investigated the efficacy of intravitreal tissue plasminogen
      activator (tPA) for the treatment of acute central retinal vein occlusion.
      DESIGN: Twenty-six eyes with central retinal vein occlusion (CRVO, n=23) and hemi
      retinal vein occlusion (n=3) with recent onset of visual symptoms (< or = 21
      days) were identified and given an intravitreal injection of 65 -110 microg of
      tPA. RESULTS: Among eyes with CRVO, visual acuity improved to > or = 20/40 in 7
      of 23 patients (30.4%) at 6 weeks, and 8 of 23 patients (34.8%) at 6 months.
      Visual acuity improved or stabilized in 69.6% (16 of 23 patients) at the 6 week
      visit and persisted with longer follow-up. Four patients developed doubling of
      the visual angle. No patients developed rhegmatogenous retinal detachment,
      infection or neovascular glaucoma. One patient developed a small vitreous
      hemorrhage and 2 developed an increase in the size of pre-existing macular
      hemorrhage. CONCLUSION: Intravitreal tPA administered early in the course of
      central retinal vein occlusion did not lead to catastrophic hemorrhagic events.
      Intravitreal tPA may cause worsening of vision in some patients. While some eyes
      appear to have benefited from the therapy, no conclusions can be reached because
      there was not a concurrent control group. A randomized clinical trial is
      necessary to determine its efficacy. SUMMARY STATEMENT: Intravitreal tPA
      administered early in the course of central retinal vein occlusion did not lead
      to catastrophic hemorrhagic events. A randomized clinical trial is necessary to
      determine its efficacy.

PMID- 10392730
TI  - Intravitreal tPA and SF6 promote clearing of premacular subhyaloid hemorrhages in
      shaken and battered baby syndrome.
AB  - BACKGROUND AND OBJECTIVE: Child abuse is a serious problem in many cultures. The
      ocular signs of shaken baby include intraretinal, subretinal, and preretinal
      hemorrhages. The hemorrhages may be unilateral or bilateral and are seen in 50%
      to 80% of patients. Previous treatment was limited to observation or vitrectomy,
      but some observed eyes develop amblyopia, and pediatric vitrectomy has many
      complications. PATIENTS: We report 4 eyes in 2 children with shaken baby syndrome
      in whom we administered intravitreal tissue plasminogen activator (tPA) in an
      attempt to resolve preretinal hemorrhages earlier than observation alone without
      the complications of vitrectomy. The tPA dose ranged from 12.5-25 microg per
      injection. Eyes were injected once weekly for 3 consecutive weeks. Each time 0.25
      cc of sulfur hexafluoride gas was also injected. RESULTS: Within 1 week following
      the last tPA administration, complete resolution of the preretinal hemorrhage was
      seen. There were no associated ophthalmic complications. CONCLUSION: Intravitreal
      tPA with an expansive gas is an alternative method to observation or vitrectomy
      for resolution of preretinal hemorrhages in battered babies and may allow faster
      resolution of hemorrhages without the complications of vitrectomy.

PMID- 10392731
TI  - Excimer laser photorefractive keratectomy for high myopia and myopic astigmatism.
AB  - BACKGROUND AND OBJECTIVE: To determine the efficacy, safety, and predictability
      of excimer laser photorefractive keratectomy of high myopia and myopic
      astigmatism. PATIENTS AND METHODS: 76 eyes of 52 patients with myopia from -8.00
      to -23.50 diopters (D) with or without astigmatism up to -5.50D were treated with
      the VISX 20/20 excimer laser (VISK, Santa Clara, CA) and a multi-zone ablation
      technique. Visual acuity, manifest refraction, corneal haze, and topography were
      evaluated at 1 week and 1, 3, 6, 12, and 18 months postoperatively. RESULTS:
      Postoperative refractions were generally stable after 12 months. At the last
      follow-up all patients were within - 1.96 D of the intended correction. Eighteen
      months postoperatively, 68% of patients undergoing photorefractive keratectomy
      (PRK), and 65% of patients undergoing photo astigmatic refractive keratectomy
      (PARK), were within 1 D of planned refraction. Furthermore, 87% of patients after
      PRK and 80% of patients after PARK had a visual acuity of 20/40 or better.
      CONCLUSIONS: High myopia with or without astigmatism was successfully treated in
      most of the patients using PRK. The stability of the postoperative refraction
      during the first 18 months seems to be good. The incidence of adverse effects was
      low but improvements in the future should further reduce complications, thus
      increasing the safety of refractive procedures.

PMID- 10392732
TI  - Microbial keratitis following penetrating keratoplasty.
AB  - PURPOSE: To investigate the prevalence of microbial keratitis, predisposing risk
      factors and treatment modalities in patients who developed keratitis following
      penetrating keratoplasty (PK). PATIENTS AND METHODS: The records of 285 patients
      who had undergone PK between January 1991 and December 1995 in a tertiary care
      center were reviewed. Patients who developed postoperative microbial keratitis
      were evaluated for predisposing risk factors, microbiological etiology, response
      to broad spectrum antibiotic therapy and subsequent PK. Patients were mainly
      treated with fortified topical antibiotics with or without repeat PK. RESULTS: Of
      the 285 patient records reviewed, microbial keratitis developed in 21 eyes of 21
      patients (7.4%). Seventy-one percent of infections occurred within 6 months after
      grafting. Keratitis initially began from the donor-recipient border in 16 cases
      (76.2%) and were central or paracentral in 5 patients. Predisposing risk factors
      included loose or exposed suture (9), suture removal (1), persistent epithelial
      defect (3), graft failure (3), contact lens wear (1), Stevens-Johnson syndrome
      (1). Fifteen (71.4%) patients were culture-positive consisting of Streptococcus
      pneumoniae (7), Staphylococcus aureus (5), Pseudomonas aureginosa (2), and
      Hemophilus influenzae (1). Forty-three percent of patients were successfully
      treated with medical therapy only. Seven patients underwent second PK for visual
      rehabilitation and 4 for tectonic purposes. After medical and surgical therapy,
      graft clarity was achieved in 17 (81%) of patients. CONCLUSIONS: The microbial
      keratitis following PK is a major postoperative problem affecting the long term
      prognosis. Careful selection of patients, and preoperative and postoperative
      control of risk factors, may decrease the frequency of this complication. Several
      factors, including loose or exposed sutures, epithelial defects, ocular surface
      disorders, and graft failure, may predispose patients to develop microbial
      keratitis following PK.

PMID- 10392733
TI  - Corneal topographic changes induced by excision of perilimbal lesions.
AB  - BACKGROUND AND OBJECTIVES: To evaluate corneal topographic changes induced by
      excision of two pterygia and a perilimbal dermoid. MATERIAL AND METHODS: Using
      the EyeSys Corneal Analysis System, we retrospectively analyzed the changes in
      astigmatism, mean central corneal power, and other topographic parameters of
      three corneas before and after surgical removal of two pterygia and a perilimbal
      dermoid. RESULTS: Marked corneal steepening occurred along the preoperative flat
      meridian after the excision of the pterygia and dermoid cyst. For each patient,
      surgery increased the mean central corneal curvature and decreased total
      astigmatism. CONCLUSION: Surgical excision can ameliorate abnormal corneal
      topographic changes produced by limbal lesions.

PMID- 10392734
TI  - Penetration of ofloxacin and ciprofloxacin in aqueous humor after topical
      administration.
AB  - BACKGROUND AND OBJECTIVE: To compare the aqueous humor levels of 0.3% ofloxacin
      and 0.3% ciprofloxacin containing eyedrops in patients with healthy cornea.
      PATIENTS AND METHODS: Fifty patients with cataract were randomly assigned to have
      0.3% ofloxacin containing eyedrop (25 patients) or 0.3% ciprofloxacin containing
      eyedrop (25 patients). Both drugs were repetitively instilled to each patient for
      6 hours before the surgery. Aqueous samples were collected after penetrating the
      anterior chamber during cataract extraction and assayed by high-performance
      liquid chromatography method. RESULTS: The aqueous humor level of ofloxacin (1.43
      +/- 0.26 microg/ml, mean +/- SEM) was significantly higher than that of
      ciprofloxacin (0.35 +/- 0.07 microg/ml) following the topical application (P <
      .0002). CONCLUSION: Aqueous humor penetration of topical ofloxacin is about 4
      times higher than that of topical ciprofloxacin when the drugs are applied as
      described above.

PMID- 10392735
TI  - Management of traumatic cyclodialysis cleft associated with ocular hypotony.
AB  - BACKGROUND AND OBJECTIVE: To evaluate the efficacy of direct cyclopexy for
      treatment of traumatic cyclodialysis cleft associated with ocular hypotony.
      PATIENTS AND METHODS: Eyes with traumatic cyclodialysis cleft were treated with
      direct cyclopexy or 1.0% atropine eyedrop. RESULTS: Five eyes with a large
      cyclodialysis cleft were treated with direct cyclopexy. Postoperatively, these
      eyes obtained normal intraocular pressure. Four of the 5 eyes had good visual
      acuity, and 1 eye that had preoperative subretinal hemorrhage in the macula had
      poor visual acuity. Of the 3 eyes treated with 1.0% atropine eyedrops, 1 had good
      visual acuity, and 2 with retinal folds had fairly good and poor visual acuity.
      CONCLUSION: The present study showed that direct cyclopexy is useful for the
      treatment of traumatic cyclodialysis cleft associated with ocular hypotony, and
      that the cyclodialysis should be surgically treated before irreversible retinal
      folds develop.

PMID- 10392736
TI  - Surgical results and complications of mitomycin C-augmented trabeculectomy in
      refractory developmental glaucoma.
AB  - BACKGROUND AND OBJECTIVE: To evaluate the surgical results and complications of
      mitomycin C-augmented trabeculectomy in refractory developmental glaucoma.
      PATIENTS AND METHODS: The authors reviewed the charts of all patients of
      refractory developmental glaucoma who underwent mitomycin C-augmented
      trabeculectomy (0.4 mg/ml for 3 minutes) between September 1990 and August 1995.
      Thirty-eight eyes of 29 patients were included in the study; 34 eyes (89.5%) had
      refractory primary congenital glaucoma with documented failure of primary
      surgery, 2 eyes (5.3%) had Axenfeld-Rieger syndrome and 2 eyes (5.3%) had
      aniridia. The main outcome measures in this study were preoperative and
      postoperative intraocular pressures (IOPs),visual acuities, bleb characteristics,
      success rate, time of surgical failure, and complications. RESULTS: The IOP (mean
      +/- SD) reduced from a preoperative level of 32.6 +/- 11.8 mm Hg to 12.3 +/- 7.3
      mm Hg (P <0.0001) with the percentage reduction in IOP being 56%. Kaplan-Meier
      survival analysis showed that the success probability at 18 months was 65%, which
      was maintained till 30 months of follow-up. The bleb was characterized by its
      large, elevated, avascular, transparent appearance in all the eyes. There were no
      intraoperative complications. The postoperative complications included hyphema
      (absorbed one week) in 8 eyes (21%), uncontrolled IOP in 8 eyes (21%), shallow
      anterior chamber in 3 eyes (7.9%), hypotony without visual loss in one eye (2.6%)
      and retinal detachment in 2 eyes (5.2%) which was surgically repaired
      successfully. Visual acuity was maintained in all cases after surgery. None of
      the patients developed mitomycin-C related late bleb-leakage or endophthalmitis.
      CONCLUSION: Treatment of refractory developmental glaucoma with mitomycin C
      augmented trabeculectomy is effective and safe with an acceptable rate of
      complications.

PMID- 10392738
TI  - An unusual complication of retinal reattachment surgery.
AB  - The authors report a case with an unusual late extraocular complication of
      scleral buckling and local silicone sponge implant. Four years after the
      reattachment surgery, a ptotic upper eyelid perforated by local silicone sponge
      implant and fistula between upper eyelid and sclera were detected. Primary repair
      of upper eyelid and removal of silicone sponge were performed. One year later,
      the retina was attached and there was no problem with the upper eyelid.
      Cryotherapy, episcleral explant (scleral buckling), and local implant (sponge)
      are frequently used and effective methods for retinal reattachment surgery.
      Postoperative early and late complications have been reported. To our knowledge,
      there is no report of upper eyelid perforation, ptosis and fistula formation
      caused by silicone sponge implant rejection.

PMID- 10392737
TI  - Recurrent enterococcal endophthalmitis following cataract surgery: a case report.
AB  - Recurrent post-cataract endophthalmitis is a well-recognized postoperative
      complication that has been attributed to various organisms and different
      mechanisms. To our knowledge, there is no case of recurrent postoperative
      endophthalmitis reported where the organism was found to be sequestered in the
      posterior capsule, escaping total eradication and thus producing the recurrence.
      The following is a case report of such recurrent postoperative endophthalmitis
      caused by Enterococcus faecalis sequestered in the posterior capsule.

PMID- 10392739
TI  - Repair of scleral perforation with preserved scleral and amniotic membrane in
      Marfan's syndrome.
AB  - To describe the surgical technique used in the repair of a large scleral
      perforation in a patient with Marfan's syndrome and a past history of various
      surgical interventions in both eyes. Scleral homograft and amniotic membrane
      transplant were used to reconstruct the large scleral defect present in his left
      eye. One month after surgical intervention, the patient showed excellent
      restoration of the scleral perforation without signs of inflammation or
      infection. The combination of scleral homograft and amniotic membrane transplant
      constitute an effective alternative to autologous scleral and conjunctival grafts
      when these cannot be used.

PMID- 10392740
TI  - Combined phacoemulsification and penetrating keratoplasty.
AB  - To highlight indications, technique, and advantages of closed-chamber
      phacoemulsification and intraocular lens (IOL) implantation during penetrating
      keratoplasty for corneal opacities. Case reports of 2 patients who underwent
      combined phacoemulsification, IOL implantation and penetrating keratoplasty. The
      technique described allowed controlled capsulorrhexis, cataract removal and in
      the-bag IOL implantation. Complications due to increased posterior pressure
      during open-sky extracapsular cataract were not encountered. The surgical
      technique described in this report can only be used in selected patients
      undergoing combined corneal transplant and cataract surgery. In this group of
      patients, however, the technique offers many intra- and postoperative advantages.

PMID- 10392741
TI  - Schlemm's canal implant: a new method to lower intraocular pressure in patients
      with POAG?

PMID- 10392742
TI  - Jones tube insertion in children with canalicular agenesis.
AB  - The purpose of this report is to describe a simplified method of Jones tube
      insertion in the management of pediatric patients with symptomatic upper and
      lower punctal and canalicular agenesis. A 5-year-old female with bilateral upper
      and lower canalicular agenesis, and a 4-year-old male with agenesis of the right
      upper and lower canaliculi, underwent placement of Jones tubes without performing
      standard external conjunctivodacryocystorhinostomy. The first child requiring
      bilateral Jones tube insertion has remained asymptomatic for 24 months. The Jones
      tube dislodged in the second patient 6 weeks postoperatively. The tube was
      replaced, and the child has been asymptomatic for 16 months. The technique of
      Jones tube insertion without a previous or concomitant external
      dacryocystorhinostomy may be a useful modification in the management of pediatric
      patients with symptomatic upper and lower canalicular agenesis.

PMID- 10392743
TI  - Missense mutations in the phosphomannomutase 2 gene of two Japanese siblings with
      carbohydrate-deficient glycoprotein syndrome type I.
AB  - Carbohydrate-deficient glycoprotein syndrome type I (CDG1) is an autosomal
      recessive disorder characterized by severe nervous system involvement and a
      carbohydrate moiety deficiency in N-linked glycoproteins. Clinical symptoms are
      psychomotor retardation, stroke-like episodes or hemorrhagic episodes, hepatic
      dysfunction, polyneuropathy, and cerebellar ataxia. Marked atrophy of the
      cerebellar hemispheres and pons is recognizable on CT scan or MRI. CDGI has been
      mapped to human chromosome 16p by linkage studies. Recently, missense mutations
      in the gene for phosphomannomutase (PMM2) have been detected in Caucasian
      patients with CDG1. We studied DNA mutations in PMM2 in a Japanese family with
      CDG1. DNA sequencing of PMM2 in the siblings showed missense mutations of
      maternal origin in exon 5 and of paternal origin in exon 8. No such mutations
      were detected in 50 unrelated healthy Japanese. These findings suggest that the
      PMM2 is responsible for CDG1 in the Japanese as well as in Caucasians, and CDG1
      may be the diagnosis in OPCA of neonatal onset, more often than currently
      thought.

PMID- 10392744
TI  - Childhood cerebral lupus in an Oriental population.
AB  - In a cross-sectional study of 24 Oriental children with systemic lupus
      erythematosus (SLE) with a mean age of 11.25 years, 75% were found to have
      clinical and neurophysiological evidence of cerebral lupus. Seizures were the
      most common manifestation affecting 11 (61%) of the cases, followed by psychosis
      in five (27.7%), encephalopathy in five (27.7%), headaches in five (27.7%),
      personality changes in four (22.2%), stroke in three (16.6%), movement disorders
      in three (16.6%) and myelitis in one child (5.5%). Four children had cerebral
      lupus as the presenting manifestation of SLE. Twenty-one children had an
      electroencephalogram (EEG) of which 11 were normal. Abnormalities detected in the
      rest included focal sharps, slowing of background and electrodecremental changes.
      There was a poor correlation of EEG with the clinical presentation. Sixteen
      children with cerebral lupus had a computed tomogram (CT) of which three were
      normal. The commonest abnormality was cerebral atrophy with or without infarcts.
      Only four of the cases had lupus anticoagulant but compliment was reduced in 13.
      Sixteen of the cases also had renal involvement. Treatment was generally with
      steroids with only two patients receiving cyclophosphamide for cerebral relapse.
      Eight children (44%) made a full recovery. Learning disability was the most
      frequent sequelae affecting one-third of children seen at a 1-year follow up.
      Four (22%) had epilepsy, two (11%) had motor deficits and one child had optic
      atrophy. One child died of cerebral haemorrhage during a hypertensive crisis.

PMID- 10392745
TI  - Topography of visual EEG reactivity in school-age children.
AB  - In order to quantify the visual reactivity of EEG to opening the eyes, the
      topography of EEG power spectra for a sample of 72 healthy subjects of age
      ranging from 7 to 15 years was investigated. The EEGs were recorded from 16 scalp
      sites with eyes open (EOP) and eyes closed (ECL). Ln-transformed absolute EEG
      powers, acquired under these two states, were tested with Wilcoxon's paired test
      for differences between the powers. The absolute powers in alpha band and in
      total, were significantly higher in all derivations, under the ECL, as compared
      with the EOP, condition. Absolute powers in theta band under the ECL condition
      were also significantly higher than those under the EOP condition, except for
      frontal derivations. Changes in delta power were insignificant. Beta 1 band
      activity, when eyes were closed, was maximal in posterior and minimal in anterior
      derivations. When the eyes were open, the greatest beta 1 power was found in the
      frontal derivations. Beta 2 was the only band in which a frequent increase in
      power took place with eyes opening. Eyes opening appeared to decrease
      significantly, the beta 1 and beta 2 powers only in posterior derivations. The
      results showed that the visual blocking of EEG was mostly due to a higher degree
      of EEG desynchronization for the subjects aged 7-5 years.

PMID- 10392746
TI  - Duchenne and Becker muscular dystrophies: an Estonian experience.
AB  - The clinical and molecular features of 25 Duchenne (DMD), two intermediate
      (D/BMD) and three Becker (BMD) muscular dystrophy patients from 26 unrelated
      families were evaluated. Early psychomotor development was normal in patients
      with D/BMD and BMD. Learning to walk independently after 15 months of age was a
      risk sign of DMD in nine (36%) patients. Abnormality in crawling was seen in 13
      (54%) patients with DMD. These boys demonstrated initial symptoms earlier than
      those who learned to crawl normally. Mental retardation was established in five
      (20%) patients with DMD. Deletions in the dystrophin gene were found in 11
      families (48%). They were accumulated (9/11, 82%) in the distal region of the
      gene.

PMID- 10392748
TI  - Effects of nitric oxide synthase inhibition on the cerebral circulation and brain
      damage during kainic acid-induced seizures in newborn rabbits.
AB  - The nitric oxide (NO) synthase inhibitor, N-omega-nitro-L-arginine methyl ester
      (L-NAME), was used to investigate the effect of endogenous NO on the cerebral
      circulation and brain damage during kainic acid (KA)-induced seizures in newborn
      rabbits. The cerebral blood flow (CBF), by laser doppler flowmetry, cerebral
      oxygenation (concentrations of oxy-(HbO2), deoxy-(HbR) and total hemoglobin (tHb)
      in brain tissue), by near-infrared spectroscopy (NIRS), mean arterial blood
      pressure (MABP), electroencephalography (EEG), and hippocampal neuronal damage
      were evaluated. Pretreatment with L-NAME caused significant decreases in CBF,
      HbO2, and tHb, and a significant increase in HbR during KA-induced seizures,
      compared with pretreatment with saline (P < 0.05), without a significant
      difference in MABP. Our study also demonstrated that pretreatment with L-NAME
      reduced the seizure activity and neuronal cell death in the hippocampus elicited
      by the systemic administration of KA in the neonatal brain. These results suggest
      that NO is of major importance in the neurodestructive process in spite of its
      roles in maintaining both the CBF and cerebral oxygenation during KA-induced
      seizures in the neonatal brain.

PMID- 10392747
TI  - Early axonal and glial pathology in fetal sheep brains with leukomalacia induced
      by repeated umbilical cord occlusion.
AB  - We conducted a chronic preparation experiment involving near term fetal sheep to
      evaluate the contribution of umbilical cord occlusion to fetal brain injury. In
      experimental groups (n = 11), complete cord occlusion for 3 min followed by 5 min
      release, repeated 5 times were performed at 3 days after initial surgery.
      Instrumental cases without cord occlusion (n = 3) and uninstrumental twins (n =
      6) were also examined as controls. Multiple necrotic foci predominantly in the
      periventricular white matter were found in the fetal brains examined at 1-3 days
      after cord occlusion. To estimate the contribution of early axonal and glial
      reaction to brain injury the following immunohistochemical study was performed.
      In the lesions, coagulation necrosis, axonal swelling and microglial activation
      were demonstrated with amyloid precursor protein or ionized calcium binding
      adapter molecule 1 immunohistochemistry. The induction of tumor necrosis factor
      alpha and inducible nitric oxide synthase were also detected
      immunohistochemically in the microglia at 1 and 3 days after cord occlusion. In
      contrast, the reaction of glial fibrillary acidic protein positive astrocytes was
      faint at 1 day after occlusion, but the induction of cyclooxygenase-2 was
      observed. These findings suggest the glial reaction of cytokines and free
      radicals induced by fetal hypoxia may contribute to the occurrence of brain
      injury.

PMID- 10392749
TI  - Developmental patterns and neuropsychological assessment in patients with
      carbohydrate-deficient glycoconjugate syndrome type IA (phosphomannomutase
      deficiency).
AB  - Carbohydrate-deficient glycoconjugate (CDG) syndrome type I due to
      phosphomannomutase deficiency (CDGIA) is the most common among a group of
      metabolic disorders characterized by a defective glycosylation of
      glycoconjugates. Clinically it is a multisystem disease with an important
      involvement of the central nervous system including pontocerebellar atrophy. Here
      the developmental patterns and results of neuropsychological assessment of four
      young adults with CDGIA syndrome are reported. The patients, aged 14-26 years,
      had classical clinical findings of CDGIA syndrome and olivopontocerebellar
      atrophy of severe degree. They had a marked delay in all areas of psychomotor
      development and gained to walk with aid, perform manipulative abilities and
      develop a communicative language after the 7th year. Later on, the acquired
      abilities remained stable, while self-help skills gradually improved, allowing
      the patients to join the family life. On neuropsychological assessment, there was
      mental retardation of variable degree with a special impairment of
      visuoperceptual skills, visuospatial organization, eye-hand coordination, verbal
      memory and language. Such findings, may be partially explained by the
      supratentorial atrophy in our patients and add more evidences to the role of the
      cerebellum and brainstem in the acquisition of non-motor cognitive functions.
      This study expands our understanding on the clinical spectrum of CDGIA syndrome
      and may be helpful for planning rehabilitation and education.

PMID- 10392750
TI  - Neopterin and biopterin concentrations in cerebrospinal fluid in controls less
      than 1 year old.
AB  - Neopterin and biopterin concentrations were measured in cerebrospinal fluid (CSF)
      and urine samples from controls less than 1 year old. This is the first time for
      CSF reference data for controls less than 1 year old to be reported. The ratio of
      neopterin to biopterin in CSF 0-30 days (n = 48) of age in control samples was
      0.65 +/- 0.31 (SD), which was far lower than that in urine over the same time
      period, 4.0 +/- 1.9 (SD), (n = 51). This finding is very important when
      diagnosing 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency and peripheral
      form of PTPS deficiency in the neonatal period. Our CSF reference data for
      controls should be useful in the diagnosis of PTPS deficiency.

PMID- 10392751
TI  - MRI abnormalities in neurofibromatosis type 1 (NF1): a study of men and mice.
AB  - Hyperintense lesions on T2-weighted MR images of the brain, predominantly located
      in the basal ganglia, the brainstem and cerebellum, are a frequent finding in
      patients with neurofibromatosis type 1. Nature and significance of these lesions
      are still unknown so that the term 'unidentified bright objects' (UBOs) has been
      introduced to allow an unbiased description. We analyzed brain MRI scans of 31
      children with definite diagnosis of neurofibromatosis type 1 according to the NIH
      criteria. High-intensity lesions on T2-weighted images were present in 86% of the
      patients. They did not correlate to other MRI findings such as optic pathway
      gliomas and were not indicative of intellectual impairment. Additionally, brain
      MR imaging of Nf1 knockout mice was performed to find out if similar
      abnormalities are present in this animal model. A total of 9 Nf1 knockout mice
      was examined on a dedicated animal MRI scanner at 4.7 Tesla but no evidence of
      high-signal intensity lesions on T2-weighted images was found. Therefore, the Nf1
      mouse model seems to be unhelpful in providing further insights into the
      histological basis of hyperintense MRI abnormalities in NF1 patients.

PMID- 10392752
TI  - Merosin-positive congenital muscular dystrophy in two siblings with cataract and
      slight mental retardation.
AB  - We report on two siblings that have been followed for 14 years, with merosin
      positive congenital muscular dystrophy (CMD), cataract, retinitis pigmentosa,
      dysversion of the optic disc, but no cerebral anomalies, except for microcephaly
      and slight mental retardation (MR). The younger child had three generalized
      seizures easily controlled by anticonvulsant therapy. Both children presented
      hypotonia from birth, delayed psychomotor development, generalized muscular
      weakness, and atrophy and joint contractures of knees and ankles. The course of
      the disease, apparently static during the first 10 years of life, became
      progressive during the second decade with loss of deambulation by the age of 13.
      Creatine kinase was increased in both children. Bilateral cataract was diagnosed
      at 6-months of age. In spite of the occurrence of microcephaly, MR was slight and
      the siblings acquired reading and writing skills after the aged 10. Head magnetic
      resonance imaging showed normal results in both siblings. The classification of
      these cases within the broad spectrum of CMD is difficult since most of the known
      muscle-eye-brain syndromes generally show severe MR and brain anomalies. We
      consider these cases as corresponding to the rarer syndromes of merosin-positive
      CMD with associated features such as cataract and MR that were particularly
      emphasized during the 50th ENMC International Workshop on CMD [Dubowitz V.
      Workshop report: 50th ENMC International workshop on congenital muscular
      dystrophy. Neuromusc Disord 1997;7:539-547]. Further genetic, pathological,
      neuroradiological, and immunocytochemical studies will be necessary for better
      elucidation of the classification and pathogenesis of CMD.

PMID- 10392753
TI  - A case of relapsing acute disseminated encephalomyelitis with high dose
      corticosteroid treatment.
AB  - We report a 16-month-old boy with acute disseminated encephalomyelitis (ADEM) who
      had an early relapse despite prompt treatment with high dose methylprednisolone.
      The second episode responded to intravenous immunoglobulin (IVIg). This case
      illustrates the probability of relapses or treatment failures in ADEM after
      steroid treatment, and the use of alternative drugs.

PMID- 10392754
TI  - Arthrogryposis multiplex congenita.

PMID- 10392755
TI  - Loxosceles spider venom induces the production of alpha and beta chemokines:
      implications for the pathogenesis of dermonecrotic arachnidism.
AB  - Bites from the brown recluse spider and other Loxosceles arachnids result in
      dermonecrotic skin lesions. Neutrophils (PMN) are essential to the development of
      Loxosceles-induced skin lesions, but paradoxically, in vitro PMN activation is
      inhibited by direct exposure to Loxosceles venom. Neutrophil activation occurs in
      response to a myriad of soluble mediators that include members of both the alpha
      and beta chemokine families. Because arachnid envenomation results in the
      exposure of several different cell types to venom, we investigated venom-induced
      expression of alpha and beta chemokines in both endothelial cells (human
      umbilical vein; HUVEC) and epithelial cells (A549 pneumocytes). Chemokine
      specific capture enzyme immunoassays (EIA) were used to measure Loxosceles
      deserta venom-induced alpha chemokines: interleukin-8 (IL-8), growth-related
      oncogene-alpha (GRO-alpha), and beta chemokines: monocyte chemoattractant protein
      1(MCP-1), and regulated on activation, normal T cell expressed and secreted
      (RANTES) in cell-free conditioned media from HUVEC and A549 cell monolayers.
      Exposure of HUVECs (8 h) to Laxosceles venom resulted in the production of IL-8
      (5.2+/-1.30 ng/ml), MCP-1 (1.44+/-0.11 ng/ml) and GRO-alpha (1.97+/-0.15 ng/ml)
      in a dose and time-dependent manner. Exposure of A549 cell monolayers to venom
      resulted in IL-8 (7.74+/-0.30 ng/ml), and MCP-1 (2.61+/-0.31 ng/ml), but neither
      GRO-alpha nor RANTES accumulated during an 8-hour incubation period. Chemokines
      accumulated in a venom dose and time-dependent manner. Neither cell type secreted
      RANTES in response to Loxosceles venom. These data indicate that Loxosceles
      spider venom is a potent inducer of alpha and beta chemokines in both endothelial
      and epithelial cell types. Based on the established roles of IL-8, MCP-1, and GRO
      alpha, in inflammation, these observations have relevance to the pathophysiology
      of Loxosceles-induced dermonecrosis.

PMID- 10392756
TI  - Gram positive bacteria induce IL-6 and IL-8 production in human alveolar
      macrophages and epithelial cells.
AB  - BACKGROUND AND OBJECTIVE: Inhalation of dust from swine confinement buildings
      results in an acute inflammatory reaction in the respiratory tract. The dust has
      a high microbial content, dominated by Gram positive bacteria. The aim of the
      present study was to evaluate the significance of bacteria in the induction of IL
      6 and IL-8 release from respiratory epithelial cells and alveolar macrophages.
      The results would give an indication to what extent the bacteria contribute to
      the toxic inflammation following exposure to swine dust. METHODS: Epithelial
      cells from a human lung carcinoma cell line (A549) and human alveolar macrophages
      obtained from healthy subjects by bronchoalveolar lavage, were stimulated with
      swine dust, LPS, one Gram negative and four Gram positive bacteria strains. The
      dose-response release of IL-6 and IL-8 were studied. In addition, a bacteria-free
      supernatant was prepared from each strain and used for stimulation. RESULTS: With
      a few exceptions, a dose-dependent IL-6 and IL-8 release was demonstrated from
      both cell types after stimulation with bacteria. In epithelial cells, Escherichia
      coli was the most potent bacteria at the highest concentration of 400
      bacteria/cell regarding secretion of both IL-6 and IL-8 (P < 0.001), followed by
      Staphylococcus hominis and Staphylococcus lentus. In alveolar macrophages, S.
      lentus was the most potent strain (P < 0.001) in inducing cytokine release (P <
      0.001), followed by S. hominis and E. coli concerning IL-6 secretion or
      Micrococcus luteus and E. coli with respect to IL-8 secretion (P < 0.001).
      Differences in potency between the various bacteria could be demonstrated, both
      within the two cell types as well as between the epithelial cells and
      macrophages. Bacteria-free supernatants were also able to induce cytokine release
      in both cell types. In macrophages the supernatants were even more potent stimuli
      than whole bacteria. CONCLUSIONS: The results indicate that bacteria or bacterial
      products could be an important contributing factor to the inflammatory reaction
      following exposure to swine dust.

PMID- 10392757
TI  - In vitro and in vivo effects of genistein on murine alveolar macrophage TNF alpha
      production.
AB  - The present study was performed to determine whether genistein could inhibit in
      vivo LPS-induced alveolar macrophage TNFalpha production and thus reduce the
      alveolar neutrophil influx following LPS. In vitro incubation with genistein
      completely inhibited LPS-induced TNFalpha production by alveolar macrophages (AM)
      from BALB/c mice. Subsequently mice were pretreated with intraperitoneal
      genistein or vehicle, then received nasal LPS to induce an alveolitis. Genistein
      was then administered every eight hours for five days following LPS. At 24 hours
      after LPS, the bronchoalveolar lavage (BAL) TNFalpha and ex vivo TNFalpha
      production from AM, were lower in the genistein treated animals. As well, total
      BAL white blood cell (WBC) count was reduced in the genistein as compared to the
      vehicle-only group. The percent neutrophils and the resolution of neutrophils
      were similar between genistein and vehicle groups. Therefore, genistein was able
      to decrease AM TNFalpha production, and was associated with a decrease in BAL WBC
      count post-LPS.

PMID- 10392758
TI  - IL-10 up-regulates CCR5 gene expression in human monocytes.
AB  - The chemokine receptor CCR5 has been found to play a key role in early infection
      with macrophage-tropic isolates of HIV-1 and CCR5 deficiency is associated with a
      relative resistance to HIV-1 infection. In this context, we studied the
      regulation of CCR5 gene expression by cytokines, and in particular, interleukin
      (IL)-10 in human monocytes. CCR5 mRNA was rapidly up-regulated by exposure of
      monocytes to graded concentrations of IL-10, with near maximal stimulation with
      10 ng/ml. The effect was rapid, being detectable as early as 1 h and maximal
      between 2 and 4 h of treatment. Pretreatment of monocytes with actinomycin D
      prevented the IL-10-induced effect, suggesting a transcriptional mechanism for
      CCR5 up-regulation by IL-10. Protein expression of CCR5 was also enhanced by IL
      10, as indicated by a 3-fold increase in anti-CCR5 antibody labeling of monocytes
      treated for 20 h with IL-10. Increased surface expression of CCR5 persisted at 48
      h of treatment. Moreover, IL-10-treated monocytes responded with augmented
      intracellular Ca++ mobilization and enhanced (3-4-fold) chemotaxis in response to
      the CCR5 ligand MIP-1beta(25 ng/ml). Taken together, our data indicate that IL-10
      can modulate CCR5 expression and function. This can constitute a potentially
      important regulatory mechanism which can affect not only responses during
      inflammation, but also susceptibility to HIV-1 infection.

PMID- 10392759
TI  - FC gamma receptor mediated phagocytosis by human neutrophil cytoplasts.
AB  - Neutrophils utilize Fcgamma Receptors (FcgammaR) to bind and internalize antibody
      coated cells or immune complexes. We have compared ultrastructurally FcgammaR
      mediated phagocytosis by neutrophil cytoplasts (enucleated and granule-free
      neutrophils) prepared either by treatment with cytochalasin B (CB-cytoplasts)
      followed by ultracentrifugation or by brief heating at 45 degrees C in suspension
      followed by ultracentrifugation. The phagocytosis of antibody-coated erythrocytes
      (EIgG) or the internalization of crosslinked IgG complexes by cytoplasts prepared
      by brief heating was comparable to that of untreated neutrophils. In contrast, CB
      cytoplasts bound but failed to internalize ElgG or crosslinked IgG complexes.
      Comparison of these two methods for the preparation of neutrophil cytoplasts may
      assist in clarifying the signal transduction requirements involved following
      ligand binding to FcgammaR which initiate phagocytosis.

PMID- 10392760
TI  - Cytokine-induced neutrophil chemoattractant in a rat model of lipopolysaccharide
      induced acute lung injury.
AB  - To elucidate the role of major chemotactic factors, cytokine-induced neutrophil
      chemoattractant (CINC), leukotriene B4 (LTB4) and C5a in lipopolysaccharide (LPS)
      induced acute lung injury in rat, we employed three reagents: anti-CINC-1
      antibody, an LTB4 receptor antagonist (ONO-4057) and an anti-complementary agent
      (K-76COONa). Rats were divided into five groups: (1)control group; (2) LPS group,
      which received intratracheal instillation of LPS (100 microg/kg); (3) Anti-CINC
      group, which received intratracheal coinstillation of LPS with anti-CINC-1
      antibody (1 mg/kg); (4) LTB4-Ra group, which received intravenous ONO-4057 (10
      mg/kg) prior to intratracheal LPS; (5) Anti-C5a group, which received intravenous
      K-76COONa (100 mg/kg) prior to intratracheal LPS. The number of neutrophils in
      bronchoalveolar lavage (BAL) fluids 6 h after LPS instillation was significantly
      reduced in the Anti-CINC group, however, no reduction was found in either the
      LTB4-Ra group or Anti-C5a group. The levels of CINC-1, CINC-2alpha and CINC-3 in
      BAL fluids were significantly higher in the LPS group than in the saline
      instilled control group. In vitro, the production of CINC-1 and CINC-3 from LPS
      stimulated macrophages was significantly elevated compared to unstimulated
      macrophages 6 h later. The increase in CINC-2alpha production was markedly less
      than that of CINC-1 or CINC-3. These results indicate that CINCs, especially CINC
      1 and CINC-3 play an important role in the recruitment of neutrophils to the lung
      in LPS-induced acute lung injury.

PMID- 10392761
TI  - Inhibition of cytokine production and adhesion molecule expression by ibuprofen
      is without effect on transendothelial migration of monocytes.
AB  - The present study focusses on the effects of ibuprofen and its enantiomers on
      cytokine production by peripheral blood monocytes and endothelial cells as well
      as on the potential modulation of ADM-expression by human umbilical vein
      endothelial cells and the concomitant effects on monocyte transendothelial
      migration as measured by a cell migration assay system. This consists of an
      endothelial cell monolayer on a solid collagen substrate, i.e. an artificial
      vessel wall construct. We observed a significant inhibition by 100 microg/ml
      ibuprofen of VCAM-1 expression by endothelial cells while ELAM-1 and ICAM-1
      expression was not influenced. However, we could not see any concomitant
      inhibitory effects on the spontaneous migration of monocytes after preincubating
      the endothelial cell monolayer with ibuprofen up to concentrations of 100
      microg/ml and activating with suboptimal and optimal concentrations of TNF-alpha.
      Our monocyte transendothelial migration system reflects very sensitively
      endothelial cell-activation even by very low TNF-alpha concentrations. (S)- and
      (R)-ibuprofen were equal in their inhibitory/activating effects on cytokine
      production, with the exception of stronger IL-8 induction in endothelial cells by
      (R)-ibuprofen as compared to its chiral analogue.

PMID- 10392763
TI  - Risk factors associated with Cryptosporidium parvum infection in dairy cattle in
      southeastern New York State.
AB  - An observational analytical epidemiologic study was carried out to identify
      factors associated with the risk of infection with Cryptosporidium parvum in
      dairy herds in southeastern New York state. A random sample of 2943 cattle on 109
      farms was selected from the target population. Fecal samples were collected from
      animals in three different age groups and examined for the presence of C. parvum
      using a quantitative centrifugation concentration flotation method. Data on
      intrinsic, preweaning, postweaning, maternity, and general management factors
      were collected and evaluated for their association with the risk of infection
      with C. parvum. Indices for each of these categories of management were developed
      from factors significantly associated with the risk of infection with C. parvum.
      Significant factors were identified using the logistic regression statistical
      technique. A final analysis, including the indices, age, and season, was
      performed to identify factors significantly associated with the risk of infection
      with C. parvum while simultaneously controlling for the effect of other factors.
      The farm effect was evaluated using a mixed effect model. Preweaning factors
      found to be significantly associated with a decreased risk of infection were: use
      of ventilation in calf rearing areas, daily addition of bedding, feeding of milk
      replacer, daily disposal and cleaning of bedding, and use of antibiotics.
      Postweaning factors such as moving of the animals after weaning, cleaning of
      soiled bedding, and use of antibiotics and ionophores as preventive measures were
      significantly associated with the decreased risk of an infection with C. parvum.
      Consideration of maternity management factors showed that winter housing of cows
      individually within 2 months of calving, use of fresh colostrum to feed calves,
      and having a concrete floor in the calving area were significantly associated
      with decreased risk of C. parvum infection. The total number of dairy cattle,
      total number of other species of agricultural animals on the farm, and the
      distance of the barn water source from the septic system were found to be
      significantly associated with increased risk of C. parvum infection. In the final
      analysis, the risk of infection with C. parvum was significantly decreased with
      an increased value of the maternity management index score. The general
      management significantly affected the risk of infection with C. parvum where the
      risk increased with the increase of the value of the index. The risk of infection
      significantly decreased with increase in the age of the animal.

PMID- 10392762
TI  - Selective inflammatory response induced by intratracheal and intravenous
      administration of poly-L-arginine in guinea pig lungs.
AB  - Major basic protein (MBP) is a cationic protein found in eosinophil granules that
      was postulated to participate in the pathogenesis of bronchial asthma. Recently,
      it has been demonstrated that MBP level in serum or bronchoalveolar lavage (BAL)
      fluid was correlated with bronchial hyperresponsiveness (BHR) in asthmatics. A
      number a studies have established that MBP actions could be mimicked by synthetic
      polycations as poly-L-arginine. In this study, we investigated the effects of
      intratracheal and intravenous administration of poly-L-arginine on lung
      inflammatory response development. The intratracheal injection of poly-L-arginine
      at the doses of 1, 10, 100 nmol/animal increased the number of eosinophils (up to
      3.2 fold) and neutrophils (up to 12 fold) in BAL fluid. Eosinophil and neutrophil
      infiltration was reversed by 88% and 67% respectively following low molecular
      weight heparin treatment (500 microg/animal). The intravenous injection of
      increasing doses of poly-L-arginine (1, 10, 100, 500 nmol/animal) increased the
      number of eosinophils (up to 2.7 fold) but not neutrophil infiltration in guinea
      pig lungs. Eosinophil infiltration was reversed by 87% following low molecular
      weight heparin treatment (1.5 mg/animal). Intratracheal treatment with poly-L
      arginine (100 nmol/animal) produced an important increase of beta-glucuronidase,
      histamine, eosinophil peroxidase (EPO) and albumin levels in BAL fluid, whereas
      the intravenous treatment (500 nmol/animal) did not. These results show that the
      route of administration of poly-L-arginine greatly influences its effect on
      inflammatory cell recruitment since both administration routes elicited
      eosinophil migration but only the intratracheal route stimulated the migration of
      neutrophils. Moreover, poly-L-arginine appeared to induce other inflammatory
      responses since it increased beta-glucuronidase, histamine, EPO and albumin
      levels in BAL fluid following intratracheal treatment. These results also showed
      that low molecular weight heparin significantly blocks the inflammatory responses
      elicited by poly-L-arginine.

PMID- 10392764
TI  - The sensitivity and specificity of two methods for detecting Fasciola infections
      in cattle.
AB  - Counts of Fasciola spp. eggs in faeces and measurements of antibody concentration
      to the excretory/secretory antigens of Fasciola spp. by ELISA were related to the
      numbers of flukes in the livers of 92 cattle killed in the abattoirs of Hanoi
      City, Vietnam. In this population, about 22% of the cattle had no flukes, another
      22% had between 1 and 10 flukes, 44% between 11 and 100 flukes and 12% had more
      than 100 flukes in their livers. Of the 14 animals less than 2 years of age, only
      three were infected. At 2 years of age the mean number of flukes per liver was 10
      whereas at 3 years and older, the mean varied between 60 and 80 flukes.
      Prevalence of infection was 78.3%. No eggs of Fasciola spp. were detected in the
      faeces of one third of infected cattle and 60% of the counts were less than 100
      eggs per gram. The sensitivity of the egg counting method was 66.7% and
      specificity 100%, overall accuracy was 73.9%. Corresponding values for the ELISA
      method were 86.1, 70 and 82.6%, respectively. The positive and negative
      predictive values for the egg counting method were 100 and 45.5% and for the
      ELISA method were 91.2 and 58.3%, respectively.

PMID- 10392765
TI  - Some studies on the growth and development of Echinococcus granulosus, camel
      origin in experimentally infected dogs.
AB  - The development of Echinococcus granulosus of camel subspecies in 35
      experimentally infected dogs was studied at 3, 7, 10, 13, 18, 23, 35 and 56 days
      post-infection (d.p.i.). The morphological characteristics of each developmental
      stage is studied and discussed. Morphological characters included number, total
      length, shape, arrangement of rosteller hooks and blade length to total length
      percentage (B1/T1%). In addition, total worm length, scolex, suckers, rostellum,
      neck and segments were measured and described. Other useful characters are
      considered to be the position of common genital pore, number and distribution of
      testes, uterus, shape of ovary and vitelline glands. Generally, the results
      indicated that the segmentation first appears at 18 d.p.i. Moreover, male and
      female genitalia could be detected at the same period. However, completely
      developed genitalia appeared at 56 d.p.i. Histological examination of the small
      intestine of experimentally infected dogs revealed that the parasites were found
      in distended and thin wall crypts of Liberkuhn at the periods of 3.7 and 10
      d.p.i, while the parasite scoleces were found embeded in the mucosa at the
      periods of 13, 18 and 23 d.p.i. No significant pathological changes were
      encountered in both infected and control dogs. The data presented here are the
      first report of strobilar development of E. granulosus of camel origin in
      experimentally infected dogs.

PMID- 10392766
TI  - Dynamics of pasture contamination by gastrointestinal nematodes of cattle under
      extensive management systems: proposal for strategic control.
AB  - An epidemiological study of gastrointestinal nematode parasitism in beef cattle
      in mountainous areas of Spain was performed. The dynamics of contamination with
      gastrointestinal nematode larvae of Pyrenean pastures was studied over four years
      at five areas at different altitudes (900 m to 2100 m), grazed by animals
      according to traditional systems of beef cattle in mountainous areas. Grass
      samples were taken every two weeks and larval differentiation was performed. Worm
      egg counts of grazing animals were assessed in cows, heifers and calves. A
      consistent seasonal pattern of infective larvae on pasture through the study was
      observed. In hay meadows, located below 1000 m, infective larvae were found from
      the end of October until June of the following year. At higher altitudes (1200
      2100 m), a bimodal pattern of pasture larvae contamination was observed with
      increases in late spring (March-June) and in late autumn (September-November).
      Ostertagia spp., Cooperia spp., Trichostrongylus spp., Oesophagostomum spp., and
      Nematodirus spp. were found, with Ostertagia spp. being the most frequently
      found, followed by Cooperia spp. The highest increase of larval contamination in
      autumn coincided with the grazing of animals in hay meadows. This elevated autumn
      larval population had a very important epidemiological role because these larvae
      remained as overwintered larvae until the following grazing season, starting the
      cycle of contamination of the animals.

PMID- 10392767
TI  - Persistent efficacy of doramectin injectable against artificially induced
      infections with Cooperia punctata and Dictyocaulus viviparus in cattle.
AB  - Three studies were conducted to evaluate the persistent efficacy of doramectin
      injectable solution against experimental challenges with infective larvae of
      Cooperia punctata and Dictyocaulus viviparus. In each study, four groups of ten
      randomly-assigned calves, negative for trichostrongyle-type eggs on fecal
      examination, were treated subcutaneously in the midline of the neck with saline
      (1 ml/50 kg) on Day 0 or doramectin (200 microg/kg = 1 ml/50 kg) on Day 0, 7, or
      14. Two additional calves from the same pool of animals were randomly assigned as
      larval-viability monitors and received no treatment. On Days 14-28, approximately
      1000 and 50 infective larvae of Cooperia spp. and D. viviparus, respectively,
      were administered daily by gavage to each animal in Groups T1-T4. On Day 28, the
      two larval-viability monitor calves were inoculated in a similar manner with a
      single dose of approximately 30000 and 2000 larvae of Cooperia spp. and D.
      viviparus, respectively. Equal numbers of calves from each treatment group were
      killed on Days 42-45, as well as the two viability monitor animals to enumerate
      worm numbers. A 2% or 5% aliquot of small intestinal contents and washings were
      examined for worm quantification and identification, while 100% of the lung
      recoveries were quantified and identified. For each study and across the three
      studies, geometric mean worm recoveries for each treatment group were calculated
      from the natural log transformed data (worm count + 1) and were used to estimate
      percentage reduction. In the three studies, doramectin injectable solution was
      97.5% efficacious against lungworms for up to 28 days and was 99.8% efficacious
      in reducing infection resulting from challenge with infective larvae of C.
      punctata for at least 28 days post-treatment.

PMID- 10392768
TI  - Lymphocyte responses to mitogens and rickettsial antigens in sheep experimentally
      infected with Ehrlichia (Cytoecetes) phagocytophila.
AB  - Infection of sheep with Ehrlichia (Cytoecetes) phagocytophila, the causative
      agent of tick-borne fever (TBF), was characterised by a significant reduction in
      lymphocyte reactivity to the mitogens phytohaemagglutinin, concanavalin A,
      pokeweed mitogen and Escherichia coli lipopolysaccharide during the period of
      rickettsiaemia. The addition of the prostaglandin inhibitor, indomethacin, or the
      nitric oxide inhibitor, N(G)-monomethyl-L-arginine, had no significant effect on
      the suppressive effects of E. phagocytophila on lymphocyte reactivity to the
      mitogens. However, peripheral blood lymphocytes obtained from primed sheep
      proliferated in the presence of live or heat-inactivated E. phagocytophila.
      Antigen-specific proliferation was detected in lymphocytes samples obtained 11 to
      21 days post-inoculation with E. phagocytophila.

PMID- 10392769
TI  - Cypermethrin pour-on synergized with piperonyl butoxide: effects on Haematobia
      irritans (Diptera: Muscidae) natural populations resistant to cypermethrin.
AB  - Development of pyrethroid resistance in Haematobia irritans in Santa Fe province,
      Argentina, resulted in an increased use of pyrethroid insecticides, probably due
      to lack of suitable alternative treatments. We explored the efficacy of mixtures
      of cypermethrin and piperonyl butoxide (PBO) against pyrethroid-resistant H.
      irritans. Groups of 25 Holstein cows each, naturally infested with cypermethrin
      resistant H. irritans were assigned to treated or control groups in April,
      September, October and December 1997. Cattle in treated groups were medicated
      with pour-on oil formulations of 5% cypermethrin (dose = 4 mg per kg of body
      weight) with 5% or 10% PBO in April, and with a mixture containing 5% of both
      components thereafter. Efficacy was tested for 21 days after treatment. A
      treatment of 5% cypermethrin pour-on without PBO was evaluated in October 1997.
      Samples of horn flies were obtained before September, October and December
      treatments and exposed for 2 h to filter papers impregnated with different
      cypermethrin concentrations to determine the 50% lethal concentration (LC50). No
      difference in efficacy was found between cypermethrin pour-on formulations with
      5% or 10% of PBO (more than 94% efficacy on day 21 after treatment). Efficacy of
      5 % cypermethrin-5% PBO mixture decreased rapidly in the successive treatments
      (less than 40% efficacy was observed on day 21 after the December treatment), and
      the period after treatment with an efficacy higher than 95% was 14 days for the
      treatment carried out in April, 10 days in September; 7 days for the treatment
      performed in October and 4 days for the December treatment. The LC50 of
      cypermethrin was 36.6 microg per cm2 in September and increased to 116.6 and
      226.1 microg per cm2 in October and December, respectively. It is concluded that
      the addition of PBO to cypermethrin did not provide a treatment that would give a
      long term control of pyrethroid resistant-horn flies.

PMID- 10392770
TI  - Antibody reactivity in mice and cats to feline enteroepithelial stages of
      Toxoplasma gondii.
AB  - The reactivity of antibodies in mice and cats to feline enteroepithelial stages
      of Toxoplasma gondii was examined by means of an indirect immunofluorescent
      antibody test. Mice immunized with feline enteroepithelial stage (FES) parasites
      produced antibodies not only against FES, but also against tachyzoites,
      sporozoites/oocysts, tissue cysts and one part of the infected feline
      enterocytes. After absorption with tachyzoites, the titer of antibodies reactive
      to enterocytes was significantly reduced. In contrast, the titer of antibodies
      reactive to FES remained unchanged. The antibodies from cats immunized with FES,
      reacted specifically to FES, but not to tachyzoites, tissue cysts or enterocytes.
      These results suggest that FES parasites may have stage-specific antigen(s).

PMID- 10392771
TI  - A comparison of the bioequivalence of 0.5% fenbendazole top dress pellets or 10%
      fenbendazole oral suspension against a spectrum of equine parasites.
AB  - A controlled test was conducted to assess the efficacy bioequivalence of a single
      dose of 0.5% fenbendazole (FBZ) top dress pellets to a 10% FBZ suspension
      formulation (Panacur suspension 10%, Hoechst Roussel Vet). Thirty horses with
      naturally-acquired parasite infections, in replicates of three, were used.
      Strongyle egg per gram counts were not significantly different (P>0.1) between
      groups pretreatment, but FBZ treated groups were significantly different from the
      control group post-treatment. At necropsy, which occurred seven to nine days post
      treatment, two methods of nematode recovery were compared to assess whether a
      small aliquot can be used in a control test to determine efficacy against large
      as well as small strongyles. Both post mortem worm recovery techniques revealed
      similar efficacies of both formulations (>95%) against small and large
      strongyles, but large differences in the number of worms recovered. Six species
      of small strongyles comprised 96% of all the small strongyles recovered:
      Coronocyclus coronatus, Cylicocyclus insigne, Cylicostephanus longibursatus,
      Cylicocyclus brevicapsulatus, Cylicocyclus nassatus, and Cyathostomum catinatum.
      The results of this study demonstrated therapeutic bioequivalence between FBZ
      formulations and also the need to sample at least a 10% aliquot to accurately
      estimate number of large strongyles. No adverse reactions to treatment were
      detected.

PMID- 10392772
TI  - Identification of group I porcine enteroviruses by monoclonal antibodies in cell
      culture.
AB  - A panel of monoclonal antibodies (mAb) against porcine enteroviruses (PEV) was
      established. One of these mAbs reacts group-specifically with PEV of serotype
      group I in the indirect immunofluorescence assay (IIF). This mAb is very well
      suited for diagnosis of PEV infections. However, the mAb neither neutralizes
      virus nor does it react with virus particles in immuno electron microscopy (IEM).
      Another mAb is PEV-1 specific in IIF, neutralizes virus, and is suited for IEM.
      Both mAbs presumably recognize conformation-dependent epitopes of the virus.

PMID- 10392773
TI  - Survival of scrapie agent after exposure to sodium dodecyl sulphate and heat.
AB  - Fifty mg aliquots of macerated mouse-brain infected with the 22A strain of
      scrapie agent were treated by exposing them without mechanical mixing to (a)
      distilled water for 2 h, (b) 5% sodium dodecyl sulphate (SDS) for 2 h, (c)
      autoclaving at 121 degrees C for 15 min in distilled water, (d) autoclaving at
      121 degrees C for 15 min in 5% SDS, or (e) boiling in 5% SDS for 15 min. Prior to
      injection into mice, all samples were washed by a procedure that is described and
      was shown not to reduce infectivity titres. Although the infectivity titre of the
      sample that was autoclaved in SDS was reduced considerably, infectivity was
      present in all of the samples exposed to cold or hot SDS.

PMID- 10392774
TI  - Virus antigen expression and alterations in peripheral blood mononuclear cell
      subpopulations after classical swine fever virus infection.
AB  - Depletion in the number of lymphocytes and viral persistence are thought to be
      the most important outcomes of classical swine fever virus (CSFV) infection. To
      define the change in peripheral blood mononuclear cells (PBMC) and virus
      replication in leukocytes after CSFV infection, 8-week old pigs were infected
      with the LPC vaccine strain or virulent CSFV (HCV-YL strain). Changes in the
      relative number of PBMCs were analyzed by flow cytometry. The results showed a
      significant increase in the relative percentage of monocytes in PBMCs during
      acute CSFV infection of naive pigs (p < 0.05). Monocyte frequencies were not
      changed in LPC-vaccinated pigs and control pigs. There was also a significant
      decrease in the number of IgM+ cells (p < 0.05) and a slight decrease in the
      number of CD4+ lymphocytes after 5 days of infection. There was no change in the
      frequency of CD8+ lymphocytes in PBMCs after infection. To define which
      subpopulation of PBMCs was the target for CSFV infection, PBMC populations from
      CSFV infected pigs were separated and stained for virus antigen expression.
      Alveolar macrophages (AM) were also studied. The results showed that CSFV
      replicated in all PBMC subpopulations: CD4+, CD8+, and IgM+ lymphocytes, and
      monocytes as well as AMs. However, virus antigen expression was more intense in
      monocytes and AMs. The infection of lymphocytes may, therefore, contribute to the
      depletion in their numbers after infection and lead to defective antibody
      production during virulent CSFV infection.

PMID- 10392775
TI  - The GroES antigens of Mycobacterium avium and Mycobacterium paratuberculosis.
AB  - The GroES antigen provokes a strong immune response in human beings with
      tuberculosis or leprosy. We cloned and sequenced the Mycobacterium avium and
      Mycobacterium paratuberculosis GroES genes. M. avium and M. paratuberculosis have
      identical GroES sequences which differ from other mycobacterial species. This
      supports the current formal designation of M. paratuberculosis as M. avium subsp.
      paratuberculosis. Immunodominant epitopes from Mycobacterium tuberculosis GroES
      are conserved in M. avium, but some Mycobacterium leprae epitopes are distinct.
      GroES is unlikely to be specific as a serologic or skin test reagent, but may be
      an appropriate component of a broad mycobacterial vaccine.

PMID- 10392776
TI  - Colonization of rabbits with Staphylococcus aureus in flocks with and without
      chronic staphylococcosis.
AB  - Rabbits of 19 rabbitries were examined for the presence of Staphylococcus aureus
      in nine different body sites. Seven rabbitries experienced epidemically spreading
      signs of staphylococcosis while the other 12 rabbitries did not. S. aureus was
      isolated in all seven flocks that suffered from chronic problems of
      staphylococcosis and in 11 of the 12 clinically healthy flocks. The mean
      percentage of infected animals in these two groups was 90 and 43.3%,
      respectively. S. aureus was isolated from all body sites examined, but the ear
      and the perineum were often more intensely colonized. The number of animals
      colonized with S. aureus and the mean number of positive body sites in S. aureus
      positive rabbits were significantly higher in rabbitries with chronic
      staphylococcosis. This indicates that colonization capacity of S. aureus plays a
      role in epidemically spreading disease in rabbits. S. aureus isolates belonged to
      five different biotypes and 23 different phage types. Several different types
      simultaneously circulated in contaminated rabbitries and even simultaneously
      infected individual rabbits. Strains that belonged to the biotype-phage type
      combination mixed CV-C, 3A/3C/55/71 only occurred in rabbitries chronically
      dealing with signs of staphylococcosis. This may indicate a relationship between
      phenotypic strain properties and virulence of S. aureus.

PMID- 10392777
TI  - Differentiation of Serpulina species by NADH oxidase gene (nox) sequence
      comparisons and nox-based polymerase chain reaction tests.
AB  - The NADH oxidase genes (nox) of 18 strains of intestinal spirochaetes were
      partially sequenced over 1246 bases. Strains examined included 17 representatives
      from six species of the genus Serpulina, and the type strain 513A(T) of the human
      intestinal spirochaete Brachyspira aalborgi. Sequences were aligned and used to
      investigate phylogenetic relationships between the organisms. Nox sequence
      identities between strains within the genus Serpulina were within the range 86.3
      100%, whilst the nox gene of B. aalborgi shared between 78.8-83.0% sequence
      identity with the nox sequences of the various Serpulina strains. A phenogram
      produced based on sequence dissimilarities was in good agreement with the current
      classification of species in the genus Serpulina, although an atypical strongly
      beta-haemolytic porcine strain (P280/1), previously thought to be S. innocens,
      appeared distinct from other members of this species. Primer pairs were developed
      from the nox sequence alignments for use in polymerase chain reaction (PCR)
      identification of the pathogenic species S. hyodysenteriae (NOX1), S. intermedia
      (NOX2), and S. pilosicoli (NOX3), and for the combined non-pathogenic species S.
      innocens and S. murdochii (NOX4). The PCRs were optimised using 80 strains
      representing all currently described species in the genus Serpulina, as well as
      the type strain of B. aalborgi. Tests NOX1 and NOX4 specifically amplified DNA
      from all members of their respective target species, whilst tests NOX2 and NOX3
      were less sensitive. NOX2 amplified DNA from all 10 strains of S. intermedia from
      pigs but from only 4 of 10 strains from chickens, whilst NOX3 amplified DNA from
      only 18 of 21 S. pilosicoli strains, even at low stringency. Tests NOX1 and NOX4
      should prove useful in veterinary diagnostic laboratories, whilst NOX2 and NOX3
      require further refinement.

PMID- 10392778
TI  - Monoclonal antibodies recognising fimbriae F107 (F18) of an oedema disease
      causing strain of Escherichia coli.
AB  - Escherichia coli isolated from experimentally induced oedema disease in pigs was
      used for the isolation and purification of F107 fimbriae. The reference strain
      was probed using membrane DNA hybridisation for the presence of fed A gene. F107
      fimbriae were purified on FPLC and purity was checked on HPLC and SDS PAGE. A
      protein with major subunit of 18.9 kDa was used for Mabs preparation. Mabs
      reacted with 18.9 kDa protein previously classified as a major fimbrial subunit
      and were able to detect F107 fimbriae in immunoelectron microscopy on the surface
      of the strains 107/86 and 8872. Other strains used in this study did not express
      any fimbriae. Western blot analysis and F107 ELISA confirmed, that Mabs react
      with 18.9 kDa subunit whereas strains passaged many times in laboratory did not
      express F107 fimbriae.

PMID- 10392779
TI  - The potential use of sperm antigens as targets for immunocontraception; past,
      present and future.
AB  - Immunocontraception, and in particular the targeting of antibodies to gamete
      specific antigens implicated in sperm egg binding and fertilisation, offers an
      attractive approach to the growing global problem of overpopulation. Such an idea
      is not new; indeed several immunocontraception trials, using animal model
      systems, have been reported in recent years and a number are reviewed here.
      However, the results of these studies have been largely disappointing. We believe
      that two fundamental flaws attribute to the poor success of most of these
      preliminary immunocontraceptive trials. Firstly, loss of fertility has invariably
      been used as the assay. This presupposes that immuno-neutralisation of a single,
      gamete-specific antigen will be sufficient to cause a significant reduction in
      fertility; however, recent data suggests that such a premise may not be well
      founded for a number of reasons. Secondly, and arguably the most important flaw,
      is the almost universal, but largely inappropriate, use of systemic immunisation
      as the sole route of antigen delivery. Whilst systemic immunisation regimes may
      lead to high serum IgG levels, these levels do not correlate with specific
      antibody levels in the reproductive tract or with contraceptive efficacy. Hence,
      an alternative antigen delivery approach is required which will induce an
      effective local immune response in the reproductive tract. Here we discuss the
      ways in which this might be achieved.

PMID- 10392780
TI  - Post-obstruction rat sperm autoantigens identified by two-dimensional gel
      electrophoresis and western blotting.
AB  - Although antisperm autoantibody responses to obstruction of the male reproductive
      system have been documented, information on the nature of the cognate sperm
      autoantigens has been limited. In the present study, the patterns of sperm
      autoantigens recognized by sera from rats after obstruction of the vas deferens
      or epididymis were studied by high resolution two-dimensional (2-D) gel
      electrophoresis and western blotting. Comparisons of patterns of autoantigens
      stained on 2-D western blots of sera from prepubertal vasectomy, prepubertal
      epididymal ligation and adult vasectomy groups revealed both similarities and
      differences. Sera from sham-operated animals showed no detectable reaction or
      much lighter staining of a small number of spots. Visualization of sperm
      autoantigens on 2-D western blots supported the hypothesis that there is a
      relatively small set of sperm proteins that can be regarded as dominant post
      obstruction sperm autoantigens because they are recognized by multiple post
      obstruction sera. The 2-D analysis revealed previously undetected distinctions in
      the autoantigens recognized after adult and prepubertal vasectomy, as well as
      variations with the site of obstruction. These differences in the response may be
      due in part to changes in antigens of spermatozoa in different parts of the tract
      and at different ages, as well as variations in exposure of sperm cell proteins
      to the immune system resulting from the sites of spermatic granulomas.
      Preparative 2-D gels and western blotting with post-obstruction sera are now
      being used to identify specific sperm autoantigens by microsequencing of selected
      proteins.

PMID- 10392781
TI  - Limited uptake of foreign materials by resident macrophages in murine ovarian
      tissues.
AB  - In the present study, the distributions of exogenously administered horseradish
      peroxidase (HRP) and colloidal carbon in gonadal tissues were observed in both
      male and female mice using light microscopy. HRP was injected intravenously and
      colloidal carbon was directly injected into the gonadal parenchyma. Thereafter,
      the gonads were obtained for histological examination. The results showed that
      staining of HRP and carbon was detected in the ovaries at a low level. In
      contrast, much staining was observed in the interstitial cells of the testes for
      a long period. This suggests that ovarian tissues are less active in the uptake
      of exogenous materials than testicular tissues in vivo. However,
      immunohistochemical examination using anti-macrophage antibodies revealed that
      the ovaries contained a large number of macrophages, as did the testes, under
      normal conditions. Therefore, the results indicate that resident macrophages in
      the ovaries exhibit weak endocytic activity of foreign materials in vivo.

PMID- 10392782
TI  - Immunology of endometriosis.

PMID- 10392783
TI  - Antiphospholipid antibodies: an update from the eighth international symposium.

PMID- 10392784
TI  - A metacognitive analysis of craving: implications for treatment.
AB  - Cravings and urges are a common component of clinical interventions for substance
      use and dependence. The conceptual status of this variable remains uncertain,
      however. Cognitive, conditioning, pharmacological, and biological explanatory
      models of craving have been developed in recent years. In this article a
      metacognitive analysis of craving is outlined in which cravings are construed as
      metacognitions (i.e., statements about other cognitions). In a metacognitive
      analysis, craving for psychoactive substances is an indication that the
      individual is experiencing a cognitive event (i.e., thought, feeling, memory,
      image, sensation) that is aversive or unpleasant. Consumption of a psychoactive
      substance is a means of self-regulating such cognitive events. Identifying the
      cognitive experience implicit in the expression of cravings can inform the
      clinician of the client's deficiencies in cognitive self-regulation and other
      coping skills. An illustrative example of a metacognitive analysis is presented.

PMID- 10392785
TI  - The hope construct, will, and ways: their relations with self-efficacy, optimism,
      and general well-being.
AB  - This investigation (N = 204) examined (a) the relations between the hope
      construct (Snyder, Harris et al., 1991; Snyder, Irving, & Anderson, 1991) and its
      two essential components, "will" and "ways," and the related constructs of self
      efficacy and optimism; and (b) the ability of hope, self-efficacy, and optimism
      to predict general well-being. Maximum-likelihood factor analysis recovered will,
      ways, self-efficacy, and optimism as generally distinct and independent entities.
      Results of multiple regression analyses predicting well-being indicated that (a)
      hope taken as a whole predicts unique variance independent of self-efficacy and
      optimism, (b) will predicts unique variance independent of self-efficacy, and (c)
      ways predicts unique variance independent of optimism. Overall, findings suggest
      that will, ways, self-efficacy, and optimism are related but not identical
      constructs.

PMID- 10392786
TI  - Psychometric properties of the Portuguese version of the Beck Depression
      Inventory on Brazilian college students.
AB  - The psychometric properties of the Portuguese version of the Beck Depression
      Inventory were studied on a large Brazilian college student sample (N= 1,080; 845
      women, 235 men). The BDI scores according to sociodemographic characteristics and
      mean individual item scores for total sample and by gender were compared. BDI
      scores tend to be higher for women, for those who work, and for the younger
      participants. The reliability of the inventory estimated by alpha coefficient was
      high for the total sample (.86) and subgroups. Factor analysis showed three
      factors for the total sample (low self-esteem, cognitive-affective, and somatic)
      and two for each gender. Women combined affective and low self-esteem whereas men
      combined somatic and low self-esteem in the same dimension. Discriminant analysis
      showed that BDI highly discriminates depressive symptomatology in college
      students and measures specific aspects of depression.

PMID- 10392787
TI  - A Rorschach exploration of the DSM-IV Borderline Personality Disorder.
AB  - Rorschach data has been useful in identifying the DSM Borderline Personality
      Disorder (BPD) and has potential for improving our understanding of this
      disorder. Recently, the DSM-IV BPD has been shown to be composed of 3 primary or
      core factors: Factor I-unstable self-other images. Factor II-deficits in affect
      and thought modulation, and Factor III-impulsive self-damaging actions. In a
      sample of outpatients with personality disorders. we explored the relationships
      among 6 psychoanalytically derived Rorschach scales (primitive aggression, oral
      dependency, self-other differentiation, splitting, devaluation, and projective
      identification), and the core BPD features. Significant correlations were found
      between 5 of the Rorschach variables and BPD total scores. Correlations between
      these 5 variables and the BPD core features showed that oral dependency needs
      were negatively associated with all 3 BPD core features, whereas the defenses of
      devaluation and splitting were positively associated with these core features.
      The clinical implications of these findings are reviewed.

PMID- 10392788
TI  - Family predictors of the incidence of children's asthma symptoms: expressed
      emotion, medication, parent contact, and life events.
AB  - Self-report measures of both parents' expressed emotion, their time spent with
      their children, family life events, and children's medication compliance were
      obtained from 32 pairs of parents with a 5- to 12-year-old child with asthma and
      used to predict the number of the children's asthma-related medical contacts and
      school absences in the preceding year. Higher levels of fathers' expressed
      emotion, specifically critical comments, were associated with higher school
      absenteeism, and the amount of time fathers reported spending with their children
      on weekends was inversely related to the number of times children had an asthma
      related medical contact. These findings were interpreted as reflecting the
      father's reactions to his child's asthma. Implications for intervention are
      discussed.

PMID- 10392789
TI  - Impact of comorbid affective and alcohol use disorders on suicidal ideation and
      attempts.
AB  - The effect of concurrent affective and alcohol use disorders on suicidal ideation
      and behavior was investigated. The Diagnostic Interview Schedule Version III-R
      (DIS) was administered to 307 adult veteran men ranging in age from 23 to 78.
      Participants were classified into one of four groups based on their final DIS
      diagnosis-lifetime unipolar depression and lifetime bipolar I disorder with or
      without a lifetime alcohol use disorder. Logistic regression analyses indicated
      that veterans with a major affective disorder were at greater risk for
      suicidality than veterans without an affective disorder. However, veterans with
      unipolar depression were at no greater risk for suicidality than those with
      bipolar I disorder. Unipolar and bipolar I disorders with a concurrent alcohol
      use disorder were always associated with an increased risk for suicidality.

PMID- 10392790
TI  - Clients' assessment of the affective environment of the psychotherapy session:
      relationship to session quality and treatment effectiveness.
AB  - This study investigated clients' affective experience during therapy. Clients (N=
      268) completed Therapy Session Reports (TSR) in an early session of treatment.
      The two sections of the TSR that assess how the client felt and how the client
      perceived the therapist to be feeling were combined and factor analyzed. Six
      stable and meaningful factors were derived (Client Distressed, Client
      Remoralized, Reciprocal Intimacy, Therapist Confident Involvement, Client
      Inhibited, and Therapist Distracted). Affect scale scores were created and
      compared to session quality and treatment effectiveness. Clients' affective
      experience was highly correlated with patient-rated session quality. The
      association between clients' affective experience during the session and
      treatment effectiveness was fairly strong for relatively brief therapy but
      insignificant for relatively lengthy treatment. The implications for
      practitioners, who--in contrast to most measures of therapeutic process--have
      easy access to clients' in-session emotional experiences, are discussed.

PMID- 10392791
TI  - Authentic religious experience or insanity?
AB  - This study examined how mental health professionals make judgments about the
      religious authenticity and mental health of behaviors motivated by religious
      ideation. Participants were presented with written vignettes of religiously
      motivated behavior. The context of religious behavior varied on 6 dimensions and
      also on 3 levels of conventionality. The results indicated that the determining
      factor in the ratings was not dimensions of religious experience, but the degree
      that the experience deviated from conventional religious beliefs and practices.
      The more unconventional the behavior, the less religiously authentic and mentally
      healthy it was deemed to be.

PMID- 10392792
TI  - The relationship between trauma and personality in victims of the Boeing 737-2D6C
      crash in Coventry.
AB  - The aims of this paper were to (a) ascertain the extent of psychological distress
      and (b) identify the association between personality variables and psychological
      distress among individuals who had been exposed to an aircraft disaster in
      Coventry, U.K. Hundreds of people escaped death but were exposed to the impact of
      the disaster when a Boeing 737-2D6C 7T-VEE crashed into a woodland area on the
      edge of a large housing estate in Coventry, U.K. in 1994. Eighty-two residents
      were randomly chosen for interviews in which they were assessed using the Impact
      of Event Scale, the General Health Questionnaire, and the Eysenck Personality
      Questionnaire-R Short Scale (EPQ-R). The results showed that the Coventry
      residents' scores reached similar levels of intrusion and avoidance compared with
      standardized samples and the Lockerbie samples. Fifty-two percent reached the GHQ
      case level score, which was again similar to the Lockerbie residents. The
      Coventry residents were significantly less extroverted and neurotic than
      standardized samples. Stepwise multiple regression showed that there were
      associations between intrusion and neuroticism and intrusion and extroversion, as
      well as between avoidance and neuroticism.

PMID- 10392793
TI  - The art of assessment in psychology: ethics, expertise, and validity.
AB  - Psychological assessment is a hybrid, both art and science. The empirical
      foundations of testing are indispensable in providing reliable and valid data. At
      the level of the integrated assessment, however, science gives way to art.
      Standards of reliability and validity account for the individual instrument; they
      do not account for the integration of data into a comprehensive assessment. This
      article examines the current climate of psychological assessment, selectively
      reviewing the literature of the past decade. Ethics, expertise, and validity are
      the components under discussion. Psychologists can and do take precautions to
      ensure that the "art" of their work holds as much merit as the science.

PMID- 10392794
TI  - Drug abuse treatment entry and engagement: report of a meeting on treatment
      readiness.
AB  - Although the effectiveness of drug abuse treatment has been demonstrated
      repeatedly, many drug abusers do not enter treatment, many who do enter leave
      prematurely, and relapse following treatment is common. To further research
      treatment entry and engagement, the National Institute on Drug Abuse convened
      scientists representing diverse research traditions in December 1996. This
      article summarizes meeting presentations and recommendations. Presentations
      focused on treatment readiness/motivation for change, ethnographic reports of
      drug abusers' perceptions of and attitudes toward treatment, and reports on
      alternative treatments for high-risk drug abusers. Recommendations focused on the
      potential contribution of qualitative research, integration of qualitative and
      quantitative research approaches, development of flexible treatment approaches
      that are cognizant of patients' life circumstances, and services research to
      improve the organization and delivery of drug abuse treatment.

PMID- 10392795
TI  - MMPI-2 profiles of NGRI and civil patients.
AB  - Limited information is available comparing individuals found Not Guilty by Reason
      of Insanity (NGRI) to other psychiatric patients. This study examined the MMPI-2
      profiles of 36 NGRIs and 35 civilly committed inpatients at 3 state psychiatric
      hospitals. The NGRI and civil patient groups differed in terms of race and gender
      with more minority individuals and fewer women in the NGRI group. Therefore,
      these demographic variables were used as covariates in a MANCOVA comparing the
      MMPI-2 validity and clinical scales for these 2 groups. NGRIs and civil
      inpatients produced significantly different mean MMPI-2 profiles, with NGRIs
      reporting less pathology overall compared to civil inpatients. Specifically,
      NGRIs had lower scores on scales F, 1, 2, 7, 8, and O and higher scores on scale
      K. Contrary to expectations, NGRIs and civil patients did not differ on scale 4,
      supplementary scale Re, and content scales ANG, CYN, and ASP, or Harris-Lingoes
      subscale Pd2. Overall, these results suggest that NGRI patients are functioning
      at a higher level than civil patients. These findings are considered in terms of
      previous results and potential selection bias. Implications for treatment and
      future research are also considered.

PMID- 10392796
TI  - Genetic analysis of motor milestones attainment in early childhood.
AB  - The age of attainment for four motor developmental traits, such as turning over,
      sitting up without support, pulling up to a standing position and walking without
      support, was examined in 822 children, including 626 siblings from families with
      2 to 6 children, 68 pairs of dizygotic twins and 30 pairs of monozygotic twins.
      Correlation analysis, carried out separately for each type of sibship, showed the
      highest pairwise correlations in monozygotic twins and the lowest correlation in
      non-twin siblings for all motor milestones. Variance component analysis was used
      to decompose the different independent components forming the variation of the
      studied trait, such as genetic effect, common twin environment, common sib
      environment and residual factors. The results revealed that the major proportion
      of the total variance after adjustment for gestation age for the attainment of
      each motor skill, except pulling up to standing position, is explained by the
      common twin environment (50.5 to 66.6%), whilst a moderate proportion is
      explained by additive genetic factors (22.2 to 33.5%). Gestational age was found
      to be an important predictor of appearance of all motor milestones, affecting
      delay of 4.5 to 8.6 days for the attainment of the motor abilities for each week
      of earlier gestation. The age of attainment of the standing position was affected
      only by shared sibs environment (33.3% of the total variance) and showed no
      influence of either genetic or common twin environment. Phenotypic between trait
      correlations were high and significant for all studied traits (range between 0.40
      and 0.67, P < 0.01 in all instances). Genetic cross correlations, however, were
      not easily interpreted and did not show clear variance trends among the different
      groups of children.

PMID- 10392797
TI  - Constant multiple birth rates in the Czech Republic and the Slovak Republic until
      recently, 1972-1995.
AB  - Using vital statistics, yearly changes in the twinning and triplet rates by
      zygosity were investigated in the Czech Republic and the Slovak Republic during
      the period 1972-1995. Monozygotic (MZ) twinning rates in both countries had
      remained nearly constant (about 3 per 1000 total births) during that period. With
      a few exceptions, the dizygotic (DZ) twinning rates remained constant from 1972
      to 1994, and increased in 1995 for both countries. MZ twinning rates for both
      countries were the lowest in Europe. As for triplet rates, overall rates
      increased significantly year by year in the Czech Republic, but not in the Slovak
      Republic. The triplet rate was significantly higher in 1995 than in the period
      1972-1982 for both countries. The MZ triplet rate remained constant during that
      period in the Czech Republic. The trizygotic (TZ) triplet rates increased 3-fold
      for the Czech Republic and 4-fold for the Slovak Republic in 1972-1976 and 1992
      1995. In the later period, the TZ rate was 1.5-fold higher in the Czech Republic
      than in the Slovak Republic. The quadruplet rate increased 2.3-fold from 2.9 per
      million births in 1982-1986 to 6.7 in 1992-1995 in the Czech Republic. The
      corresponding values were 2.7, 2.20 and 5.9-fold in the Slovak Republic. Both the
      Czech and the Slovak Republics were not affected by fertility drugs and assisted
      reproductive techniques until recently.

PMID- 10392798
TI  - Individual differences in multiple dimensions of aggression: a univariate and
      multivariate genetic analysis.
AB  - Previous behaviour genetic studies of aggression have yielded inconsistent
      results: reported heritabilities for different types of aggressive behaviour
      ranging from 0 to 0.98. In the present study, 247 adult twin pairs (183 MZ pairs;
      64 same-sex DZ pairs) were administered seven self-report questionnaires which
      yielded 18 measures of aggression. Univariate genetic analyses showed moderate to
      high heritabilities for 14 of these 18 measures and for a general aggression
      factor and three correlated aggression factors extracted from the measures.
      Multivariate genetic analyses showed sizeable genetic correlations between the
      different dimensions of aggression. Thus, individual differences in many types of
      aggressive behaviour are attributable to some extent to genetic factors and there
      is considerable overlap between the genes that operate on different types of
      aggressive behaviour.

PMID- 10392799
TI  - Statistical analysis of the seasonal variation in the twinning rate.
AB  - There have been few secular analyses of the seasonal variation in human twinning
      and the results are conflicting. One reason for this is that the seasonal pattern
      of twinning varies in different populations and at different periods. Another
      reason is that the statistical methods used are different. The changing pattern
      of seasonal variation in twinning rates and total maternities in Denmark was
      traced for three periods (1855-69, 1870-94, and 1937-84). Two alternative methods
      of analysis are considered. The method of Walter and Elwood and a trigonometric
      regression model give closely similar results. The seasonal distribution of twin
      maternities for the periods in the 19th century showed highly significant
      departures. For both twin and general maternities, the main peaks can be seen
      from March to June and a local peak in September. During the spring-summer season
      the twinning rates were higher than the total birth rates, indicating a stronger
      seasonal variation for the twin maternities than for the general maternities. For
      1937-84, there was a similar, but less accentuated, pattern. Studies of other
      populations are compared with the Danish results. The more accentuated seasonal
      variation of twinning in the past indicate that some factors in the past affected
      women during summer-autumn and around Christmas time, making them more fecund and
      particularly to be more prone to polyovulation and/or more able to complete a
      gestation with multiple embryos.

PMID- 10392800
TI  - Two early case reports on conjoined twins.

PMID- 10392801
TI  - Genetics of early cancer detection behaviours in Australian female twins.
AB  - Early detection of cervical and breast cancers is an important component of
      women's health strategy. Screening programmes, health professional interventions
      and preventive behaviours such as breast self-examination provide the means to
      this end. Our twin study sought to identify the relative influence of
      environmental and genetic factors on liability to early cancer detection
      behaviours, including use of cervical smear tests, mammograms, and breast
      examination. Additive genetic and random environmental effects models gave the
      best, most parsimonious fit to the data for each early cancer detection
      behaviour. The heritability of liability to Pap smear use was 66%, mammogram use
      50%, breast examination by a doctor or nurse 38% and breast self-examination 37%.
      Genetic influences were behaviour-specific; there was no evidence for a common
      genetic influence on the four behaviours. Potential covariates investigated
      included age, amount of contact between co-twins, educational level and
      personality traits such as harm avoidance, novelty seeking, reward dependence,
      neuroticism, anxiety, depression, self-esteem, perceived control, interpersonal
      dependency and ways of coping. None were significant. The study was carried out
      before the implementation of national screening programmes with media campaigns
      to increase participation rates. Hence follow-up investigation, including data on
      regularity of behaviours, would be informative.

PMID- 10392802
TI  - Some implications of chaos theory for the genetic analysis of human development
      and variation.
AB  - Non-linear epigenetic processes are a potential underlying source of phenotypic
      differences in development. Simulation studies of twin pairs using simple non
      linear development models characterised by chaotic or near-chaotic behavior are
      presented. The effect of chaotic processes on correlations is to lower them from
      their initial values, but high initial correlations are affected much less by
      chaotic and near-chaotic processes than intermediate correlations. Therefore, we
      would predict that traits affected by chaotic processes would have high MZ and
      low DZ twin correlations and this is reminiscent of certain traits such as EEG
      spectra. However the much more frequent observation of MZ correlations close to
      twice their DZ counterparts would suggest that the role of chaos in development
      is quite limited.

PMID- 10392803
TI  - Additional aspects of third source variation for the genetic analysis of human
      development and behaviour: a commentary on Eaves et al.

PMID- 10392804
TI  - Behavioral aspects of intergenerational human cloning: twin-based perspective.

PMID- 10392805
TI  - In vivo magnetic resonance methods in pharmaceutical research: current status and
      perspectives.
AB  - In the last decade, in vivo MR methods have become established tools in the drug
      discovery and development process. In this review, several successful and
      potential applications of MRI and MRS in stroke, rheumatoid and osteo-arthritis,
      oncology and cardiovascular disorders are dealt with in detail. The versatility
      of the MR approach, allowing the study of various pathophysiological aspects in
      these disorders, is emphasized. New indication areas, for the characterization of
      which MR methods have hardly been used up to now, such as respiratory, gastro
      intestinal and skin diseases, are outlined in a subsequent section. A strength of
      MRI, being a non-invasive imaging modality, is the ability to provide functional,
      i.e. physiological, readouts. Functional MRI examples discussed are the analysis
      of heart wall motion, perfusion MRI, tracer uptake and clearance studies, and
      neuronal activation studies. Functional information may also be derived from
      experiments using target-specific contrast agents, which will become important
      tools in future MRI applications. Finally the role of MRI and MRS for
      characterization of transgenic and knock-out animals, which have become a key
      technology in modern pharmaceutical research, is discussed. The advantages of MRI
      and MRS are versatility, allowing a comprehensive characterization of a diseased
      state and of the drug intervention, and non-invasiveness, which is of relevance
      from a statistical, economical and animal welfare point of view. Successful
      applications in drug discovery exploit one or several of these aspects. In
      addition, the link between preclinical and clinical studies makes in vivo MR
      methods highly attractive methods for pharmaceutical research.

PMID- 10392806
TI  - Tumour response to hypercapnia and hyperoxia monitored by FLOOD magnetic
      resonance imaging.
AB  - Flow and oxygenation dependent (FLOOD) MR images of GH3 prolactinomas display
      large intensity increases in response to carbogen (5% CO2/95% O2) breathing. To
      assess the relative contributions of carbon dioxide and oxygen to this response
      and the tumour oxygenation state, the response of GH3 prolactinomas to 5% CO2/95%
      air, carbogen and 100% O2 was monitored by FLOOD MRI and PO2 histography. A 10
      30% image intensity increase was observed during 5% CO2/95% air breathing,
      consistent with an increase in tumour blood flow, as a result of CO2-induced
      vasodilation, reducing the concentration of deoxyhaemoglobin in the blood.
      Carbogen caused a further 40-50% signal enhancement, suggesting an additional
      improvement due to increase blood oxygenation. A small 5-10% increase was
      observed in response to 100% O2, highlighting the dominance of CO2-induced
      vasodilation in the carbogen response. Despite the large FLOOD response, non
      significant increases in tumour pO2 were observed in response to the three gases.
      Tissue pO2 is determined by the balance of oxygen supply and demand, hence
      increased blood flow/oxygenation may not necessarily produce a large increase in
      tissue PO2. The FLOOD response is determined by the level of deoxygenation of
      blood, the size of this response relating to vascular density and the potential
      of high-oxygen content gases to improve the oxygen supply to tumour tissue.

PMID- 10392807
TI  - MRI measurement of the functional blood flow changes in a large superficial vein
      draining the motor cortex.
AB  - In this study, phase-contrast MR techniques are applied in order to measure the
      blood flow changes induced by a motor task in a large superficial vein draining
      the motor cortex. The measurements were applied to six healthy volunteers, in
      motor rest conditions and during performance of a motor task. The latter
      consisted of sequential finger-to-thumb opposition. The task was actually
      executed and mentally simulated. Significant blood flow increases were found when
      changing from from mental simulation to actual execution of the motor task
      (increases ranging between 1.6 and 10.3 ml/min, i.e. 9% and 45%, respectively)
      and from resting conditions to actual execution of the motor task (increases
      ranging between 1.7 and 14.0 ml/min, i.e. 32% and 72%, respectively).

PMID- 10392808
TI  - Does RF brain heating decrease at 8 T?

PMID- 10392809
TI  - Current awareness in NMR in biomedicine.

PMID- 10392810
TI  - Altered fractionation: limited by mucosal reactions?
AB  - The effectiveness of accelerated fractionation and hyperfractionation in cancer
      of the head and neck has been confirmed by randomized studies. These new
      fractionation strategies are almost invariably accompanied by an increase of
      early normal tissue reactions, in particular mucosal reactions. This paper
      presents a survey of the available experimental and clinical mucositis data and
      aims to assess to what extent the upper aerodigestive tract mucosa is limiting to
      treatment intensification by altered fractionation. The rate of dose delivery is
      the most important determinant for early radiation reactions. With accelerated
      radiotherapy, relative to a conventional treatment of 7 weeks, the achievable
      gain in treatment time is 2 weeks at most with the mucosa being the limiting
      tissue. Any further acceleration requires a reduction of dose. Manipulations with
      the temporal distribution of dose, fraction dose, and optimization of
      interfraction intervals can improve tolerance but probably do not allow
      significant further intensification of the existing accelerated schedules. Dose
      escalation by hyperfractionation does not seem to be directly limited by early
      mucosal reactions. Late reacting tissues are more likely to limit intensification
      of these schedules. Suggestions for further improvement of treatment outcome
      include: the generation of a potent agent which can ameliorate radiation
      mucositis and so permit further intensification of radiotherapy schedules;
      combination of altered fractionation schedules with hypoxic modifiers; and
      tailoring of the treatment strategy based on patient and tumour characteristics.

PMID- 10392811
TI  - Modulation of accelerated repopulation in mouse skin during daily irradiation.
AB  - BACKGROUND AND PURPOSE: The timing of acceleration of repopulation in the
      epidermis during daily irradiation is related to the development of skin erythema
      and epidermal hypoplasia. Therefore, the relationship between impairment of the
      epidermal barrier function, the dermal inflammatory response and epidermal
      hypoplasia with the acceleration of repopulation was investigated. MATERIALS AND
      PURPOSE: Skin fields of approximately 1 cm2 on the thighs of TUC mice were given
      five daily fractions of 3 Gy in each week followed by top-up doses at the end of
      the first, the second, or the third week to determine residual epidermal
      tolerance and to calculate repopulation rates in weeks 1, 2, or 3. Systemic
      modulation of repopulation was attempted by daily indomethacine during
      fractionated irradiation whereas tape stripping or UV-B exposure before the start
      of fractionated irradiation attempted local modulation. In parallel experiments,
      the water permeability coefficient of the epidermis was determined ex vivo by
      studying transepidermal transport of tritiated water. RESULTS: Without
      modulation, no repopulation was found in the first week of daily fractionation
      but repopulation compensated 30% of the dose given in week two and 70% of the
      dose given in week three. Only tape stripping before the start of fractionated
      irradiation accelerated repopulation in week one. UV-B had no effect on
      repopulation although it stimulated proliferation as much as tape stripping.
      Indomethacin did not suppress acceleration of repopulation. A significant
      increase in transepidermal water loss was found but only after repopulation had
      already accelerated. CONCLUSIONS: Acceleration of repopulation in mouse epidermis
      during daily-fractionated irradiation is not related to the simultaneous
      development of an inflammatory response. Also, the loss of the epidermal barrier
      function is not involved in the development of the acceleration response, which
      rather seems to be triggered directly by the decreased cellularity of the
      epidermis.

PMID- 10392812
TI  - Loco-regional recurrences after mastectomy in breast cancer: prognostic factors
      and implications for postoperative irradiation.
AB  - PURPOSE: Potential risk factors including DNA flow cytometric-derived parameters
      predicting loco-regional recurrence (LRR) in early breast cancer were
      investigated. MATERIALS AND METHODS: This study included 608 patients treated by
      modified radical mastectomy between 1982 and 1987. Recommendations regarding
      local treatment as well as adjuvant systemic therapy did not change during this
      period. Patients treated by adjuvant chemotherapy were randomized to receive
      additional medroxyprogesterone acetate (MPA) treatment. Only 59 (10%) patients
      received postoperative irradiation (XRT) to the chest wall and/or axillary lymph
      nodes; another 121 (20%) patients received XRT to the internal mammary nodes
      because of centromedially located tumours. RESULTS: Patients were followed for a
      median period of 7.5 years. The event-free survival at 10 years was 50%. The
      cumulative incidence rate of LRR at 10 years was 18% (n = 93), either with (n =
      30) or without (n = 63) concurrent distant metastases. The chest wall, regional
      lymph nodes or both were involved in 41 (44%), 38 (41%) and 12 (13%) patients,
      respectively. Multivariate analysis according to the Cox model revealed two
      factors associated with LRR, i.e. pT (P < 0.05) and nodal status (P < 0.05). In
      node-positive patients extracapsular tumour extension (ECE) and pT were
      independent risk factors. DNA ploidy and S-phase fraction did not yield
      additional information. Based on pT, nodal status and extracapsular extension of
      tumour growth a high risk (> 10%) and low risk (< 10%) group for LRR could be
      identified. CONCLUSIONS: Results indicate that T-stage and nodal status, combined
      with ECE, may help to identify patients at risk for loco-regional recurrence,
      whereas DNA flow cytometry does not.

PMID- 10392813
TI  - Acute and late morbidity of using a breast positioning ring in women with
      large/pendulous breasts.
AB  - PURPOSE: To assess acute and late effects of radiation therapy in women with
      breast cancer treated with a breast positioning ring. MATERIALS AND METHODS:
      Fifty-six patients with large and/or pendulous breasts were irradiated using a
      breast positioning ring. The incidence of acute morbidity was correlated with
      patient weight and breast 'size'. Cosmesis was scored at > or = 1 year following
      radiation therapy by the patients. Dose changes in the buildup region under the
      ring were measured using a computer-controlled scanning system. RESULTS: Moist
      desquamation (MD) occurred in 60.7% (34/56) of patients treated with the breast
      ring. The incidence of MD was more common in patients with larger breasts (P =
      0.08), the severity necessitating a treatment interruption in 5 out of 56 (9%)
      patients. Cosmesis at > or = 1 year following radiation therapy was scored as >
      or = good by all patients. The surface dose under the ring was approximately 85%
      of the Dmax dose. CONCLUSIONS: The incidence or severity of acute MD in patients
      treated with a breast positioning ring appears high in patients with large
      pendulous breasts, and might be related in part, to the increased skin dose due
      to the positioning ring. To date, there appears to be no significant late normal
      tissue effects in patients treated with the positioning ring. Additional follow
      up is needed to assess the long-term consequences of the ring on cosmesis.

PMID- 10392814
TI  - Evaluation of predictive factors for local tumour control after electron-beam
      rotation irradiation of the chest wall in locally advanced breast cancer.
AB  - BACKGROUND AND PURPOSE: Different radiotherapy techniques are being used for
      chest wall irradiation after mastectomy. We review our results with the electron
      beam-rotation technique in a series of 130 high risk breast cancer patients. The
      main end point of the study was local tumour control; secondary end points were
      disease free survival, and overall survival, as well as acute and late side
      effects. MATERIAL AND METHODS: From January 1990 to June 1995, 89 patients
      underwent electron-beam-rotation irradiation of the chest wall after primary
      mastectomy and axillary lymph node dissection (group I) and 41 patients after
      excision of local recurrent breast cancer (group II) with 4 x 2.5 Gy/week to 50
      Gy total dose (4-12 MeV electrons depending on the thickness of the chest wall).
      In addition, irradiation of local-regional lymph nodes and/or a local boost of 10
      Gy were applied dependent on the resection and node status. RESULTS: After a
      median follow up of 29 months (65% stadium III/IV) the 3 year local tumour
      control, disease free survival, and overall survival were 73%, 47%, and 75%,
      respectively. Local control in group I was 78% versus 60% in group II.
      Significant predictors for local tumour control, disease free survival, and
      overall survival were resection status (R0 versus R1/2) and estrogen receptor
      status (positive versus negative). In group I, tumour grading (GI-IIa versus GIIb
      III) and estrogen receptor status were found to be additional significant
      prognostic factors for complete resected tumours. Five patients developed
      symptomatic pneumonitis (< 4%) and one patient developed a chronic fistula at the
      resection. A significant correlation between the degree of acute skin reaction
      and persistent pigmentation was observed. CONCLUSION: In high risk breast cancer
      patients postoperative irradiation with the electron-beam-rotation technique of
      the chest wall is an effective therapy resulting in 78% local tumour control at 3
      years for locally advanced breast cancer and 60% for recurrent disease. The rate
      of acute and late toxicity is low. The degree of acute skin reaction correlates
      with the degree of persistent pigmentation.

PMID- 10392815
TI  - The use of compensators to optimise the three dimensional dose distribution in
      radiotherapy of the intact breast.
AB  - BACKGROUND AND PURPOSE: Dose heterogeneity in tangential breast irradiation has
      been shown to be as high as 20% and may lead to problems in local control and
      cosmesis. In this study, dose heterogeneity in three dimensions (3D) in the
      breast irradiated with wedged tangential beams is assessed and the improvement
      which can be made by the use of individualised two dimensional (2D) compensators
      is established. The compensation required is calculated in two ways: (I) by an
      iterative technique giving a uniform dose on a plane through the isocentre normal
      to the central axis of each beam, and (II) by inverse planning using an
      optimisation technique based on simulated annealing. MATERIALS AND METHODS: A
      total of 17 patients with histologically proven T0-3, N0, N1, M0 breast cancer
      undergoing breast irradiation following wide local excision, were CT scanned
      using contiguous 1 cm slices from approximately 2 cm superior to 2 cm inferior of
      the irradiated volume. The dose distributions are determined using a 3D algorithm
      that calculates primary and scatter dose separately using a differential scatter
      air ratio method and corrects both for the presence of heterogeneities. The
      iterative technique achieves a dose variation of better than 0.5% on the plane
      through the isocentre with compensation on both beams. Compensation for the
      lateral beam only is calculated using the optimisation technique in order to
      minimise the scatter dose to the contralateral breast. The optimisation algorithm
      minimises the dose variance over the target and sets upper dose limits for the
      lung and the remainder of the irradiated volume. RESULTS: For the group of
      patients the average dose heterogeneity in 3D using wedges is 12% (range 8-17%),
      which reduces to 8% (5-16%) using compensation on a plane and to 5% (4-7%) using
      the optimisation technique. CONCLUSIONS: Inverse planning is normally used for
      complex radiotherapy techniques but when applied to tangential breast
      irradiation, can reduce the dose heterogeneity through the breast as a whole to
      as little as 4%, with potential benefits in local control and cosmesis.

PMID- 10392816
TI  - Clinical delivery of intensity modulated conformal radiotherapy for relapsed or
      second-primary head and neck cancer using a multileaf collimator with dynamic
      control.
AB  - BACKGROUND AND PURPOSE: Concave dose distributions generated by intensity
      modulated radiotherapy (IMRT) were applied to re-irradiate three patients with
      pharyngeal cancer. PATIENTS, MATERIALS AND METHODS: Conventional radiotherapy for
      oropharyngeal (patients 1 and 3) or nasopharyngeal (patient 2) cancers was
      followed by relapsing or new tumors in the nasopharynx (patients 1 and 2) and
      hypopharynx (patient 3). Six non-opposed coplanar intensity modulated beams were
      generated by combining non-modulated beamparts with intensities (weights)
      obtained by minimizing a biophysical objective function. Beamparts were delivered
      by a dynamic MLC (Elekta Oncology Systems, Crawley, UK) forced in step and shoot
      mode. RESULTS AND CONCLUSIONS: Median PTV-doses (and ranges) for the three
      patients were 73 (65-78), 67 (59-72) and 63 (48-68) Gy. Maximum point doses to
      brain stem and spinal cord were, respectively, 67 Gy (60% of volume below 30 Gy)
      and 32 Gy (97% below 10 Gy) for patient 1; 60 Gy (69% below 30 Gy) and 34 Gy (92%
      below 10 Gy) for patient 2 and 21 Gy (96% below 10 Gy) at spinal cord for patient
      3. Maximum point doses to the mandible were 69 Gy for patient 1 and 64 Gy for
      patient 2 with, respectively, 66 and 92% of the volume below 20 Gy. A treatment
      session, using the dynamic MLC, was finished within a 15-min time slot.

PMID- 10392817
TI  - A conformal technique for a ring shaped conjunctive lymphoma treatment.
AB  - Radiotherapy is commonly utilised as standard treatment in the so called mucosa
      associated lymphoid tissues (MALT), due to the low probability of distant
      relapse. The particularities of the lesion, make necessary both energy
      degradation and beam conformation. To keep homogeneity within acceptable limits,
      a lengthener attached to the electron applicator has been devised to closely fit
      the anatomy of the patient. Considering the small area of the outcoming field,
      film dosimetry is preferred, since the dimensions of an ionisation chamber and
      even of a semiconductor probe might be comparable to the field size.

PMID- 10392818
TI  - A single-variable method for the derivation of collimator scatter correction
      factors in symmetrical and asymmetrical X-ray beams.
AB  - Using a minimal set of measured data, the collimator scatter correction factor of
      an asymmetrical collimated rectangular field (X1,X2;Y1,Y2) can be calculated from
      the product of one-dimensional factors, in combination with a correction term:
      Sc(X1,X2;Y1,Y2) = S(cx1)(X1)S(cx2)(X2)S(cy1)(Y1)S(cy2)(Y2) + c delta(X;Y). Two
      forms of the function delta(X;Y) were investigated.

PMID- 10392819
TI  - Commissioning of a micro multi-leaf collimator and planning system for
      stereotactic radiosurgery.
AB  - PURPOSE: A computer controlled micro multi-leaf collimator, m3 mMLC, has been
      commissioned for conformal, fixed-field radiosurgery applications. Measurements
      were made to characterise the basic dosimetric properties of the m3, such as leaf
      transmission, leakage and beam penumbra. In addition, the geometric and
      dosimetric accuracy of the m3 was verified when used in conjunction with a
      BrainSCAN v3.5 stereotactic planning system. MATERIALS AND METHODS: The m3 was
      detachably mounted to a Varian Clinac 2100C accelerator delivering 6 MV X-rays.
      Leaf transmission, leakage, penumbra and multiple, conformal fixed field dose
      distributions were measured using calibrated film in solid water. Beam data were
      collected using a diamond detector in a scanning water tank and planned dose
      distributions were verified using LiF TLDs and film. A small, shaped phantom was
      also constructed to confirm field shaping accuracy using portal images. RESULTS:
      Mean transmission through the closed multi-leaves was 1.9 +/- 0.1% and leakage
      between leaves was 2.8 +/- 0.15%. Between opposing leaves abutting along the
      central beam-axis transmission was approximately 15 +/- 3%, but was reduced to a
      mean of 4.5 +/- 0.6% by moving the abutmen position 4.5 cm off-axis. Beam
      penumbrae were effectively constant as a function of increasing square field size
      and asymmetric fields and was seen to vary non-linearly when shaped to diagonal,
      straight edges. TMR, OAR and relative output beam data measurements of circular
      m3 fields were comparable to conventional, circular stereotactic collimators.
      Multiple, conformal field dose distributions were calculated with good spatial
      and dosimetric accuracy, with the planned 90% isodose curves agreeing with
      measurements to within 1-2 mm and to +/- 3% at isocentre. Portal films agreed
      with planned beams eye-view field shaping to within 1 mm. CONCLUSIONS: The m3
      micro multi-leaf collimator is a stable, high precision field-shaping device
      suitable for small-field, radiosurgery applications. Dose distributions can be
      accurately calculated by a planning system using only a few beam data parameters.

PMID- 10392820
TI  - Daily positioning accuracy of frameless stereotactic radiation therapy with a
      fusion of computed tomography and linear accelerator (focal) unit: evaluation of
      z-axis with a z-marker.
AB  - To evaluate quantitative positioning errors of frameless stereotactic radiation
      therapy with a fusion of computed tomography (CT) and linear accelerator unit, Z
      type CT markers were attached to patients, and CT images were obtained before and
      after daily treatment. In 40 verification tests, geometrical errors were never
      more than 1 mm.

PMID- 10392822
TI  - Seminoma of the testis: is scrotal shielding necessary when radiotherapy is
      limited to the para-aortic nodes?
AB  - PURPOSE: To evaluate the influence of different shielding conditions and field
      geometry on the scatter dose to the remaining testicle during postoperative
      radiotherapy (RT) in seminoma. MATERIALS AND METHODS: Testicular dose
      measurements were made with LiF thermoluminescent dosimeters (TLD) in 29 patients
      with stage I and IIA seminoma. The target volume consisted of para-aortic (PA)
      and para-aortic and homolateral iliac (PAI) lymph nodes in 14 and 15 patients,
      respectively. All patients had a scrotal shield as well as an additional block
      extending 7 cm inferiorly from the caudal field edge to shield the testicle from
      external scatter and collimator leakage. Doses with and without testicular blocks
      were measured for all patients. In seven patients treated exclusively to the PA
      region the gonadal dose was assessed according to four different shielding
      conditions: without any protection, with a gonadal shield alone, with the
      addition of an inferior field border block to the gonadal shield, and with the
      field border block alone. RESULTS: For patients treated with PAI fields the mean
      testicular doses per fraction were 3.89 cGy (S.D. +/- 1.44) and 1.48 cGy (S.D. +/
      0.51) without and with gonadal shielding, respectively (P-value < 0.001); the
      corresponding values for PA fields were 1.86 cGy (S.D. +/- 0.86) and 0.65 cGy
      (S.D. +/- 0.35). For the patients treated to the PA region and assessed according
      to the four different shielding conditions, the additional external block to the
      testicular shield did not reduce significantly the measured dose on the testis.
      CONCLUSIONS: These results suggest a benefit of gonadal shielding even in
      seminoma patients undergoing radiotherapy limited to the para-aortic region.

PMID- 10392821
TI  - Small-field fractionated radiotherapy with or without stereotactic boost for
      vestibular schwannoma.
AB  - PURPOSE: To assess the efficacy and toxicity of small-field fractionated
      radiotherapy with or without stereotactic boost (SB) for vestibular schwannomas.
      METHODS AND MATERIALS: Thirty-nine patients with vestibular schwannoma were
      treated with irradiation between March 1991 and February 1996. Extra-meatal tumor
      diameters were under 30 mm. Thirty-three patients received small-field
      fractionated radiotherapy followed by SB. Basic dose schedule was 44 Gy in 22
      fractions over 5 1/2 weeks plus 4 Gy in one session. Six patients received small
      field fractionated radiotherapy only (40-44 Gy in 20-22 fractions over 5-5 1/2
      weeks or 36 Gy in 20 fractions over 5 weeks).dash;p > RESULTS: Follow-up ranged
      from 6 to 69 months (median, 24 months). Tumors decreased in size in 13 cases
      (33%), were unchanged in 25 (64%), and increased in one (3%). The actuarial 2
      year tumor control rate was 97%. Fifteen patients had useful hearing (Gardner
      Robertson class 1-2) and 25 patients had testable hearing (class 1-4) before
      irradiation. The 2-year actuarial rates of useful hearing preservation (free of
      deterioration from class 1-2 to class 3-5) were 78%. The 2-year actuarial rates
      of any testable hearing preservation (free of deterioration from class 1-4 to
      class 5) were 96%. No permanent facial and trigeminal neuropathy developed after
      irradiation. The 2-year actuarial incidences of facial and trigeminal
      neuropathies were 8% and 16%, respectively. CONCLUSIONS: Small-field fractionated
      radiotherapy with or without SB provides excellent short-term local control and a
      relatively low incidence of complications for vestibular schwannoma, although
      further follow-up is necessary to evaluate the long-term results.

PMID- 10392823
TI  - Characteristics and clinical application of a treatment simulator with Ct-option.
AB  - BACKGROUND AND PURPOSE: The integration of a scanner for computed tomography (CT)
      and a treatment simulator (Sim-CT, Elekta Oncology Systems, Crawley, UK) has been
      studied in a clinical situation. Image quality, hounsfield units (HU) and
      linearity have been evaluated as well as the implications for treatment planning.
      The additional dose to the patient has also been highlighted. MATERIAL AND
      METHODS: Image data is acquired using an array of solid state X-ray detectors
      attached externally to the simulator's image intensifier. Three different fields
      of view (FOV: 25.0 cm, 35.0 cm and 50.0 cm) with 0.2 cm, 0.5 cm and 1.0 cm slice
      thickness can be selected and the system allows for an aperture diameter of 92.0
      cm at standard isocentric height. The CT performance has been characterized with
      several criteria: spatial resolution, contrast sensitivity, geometric accuracy,
      reliability of hounsfield units and the radiation output level. The spatial
      resolution gauge of the nuclear associates quality phantom (NAQP) as well as
      modulation transfer functions (MTF) have been applied to evaluate the spatial
      resolution. Contrast sensitivity and HU measurements have been performed by means
      of the NAQP and a HU conversion phantom that allows inserts with different
      electron densities. The computed tomography dose index (CTDI) of the CT-option
      has been monitored with a pencil shaped ionization chamber. Treatment planning
      and dose calculations for heterogeneity correction based on the Sim-CT images
      generated from an anthropomorphic phantom as well as from ten patients have been
      compared with similar treatment plans based on identical, yet diagnostic CT (DCT)
      images. RESULTS: The last row of holes that are resolved in the spatial
      resolution gauge of the NAQP are either 0.150 cm or 0.175 cm depending on the FOV
      and the applied reconstruction filter. These are consistent with the MTF curves
      showing cut-off frequencies ranging from 5.3 lp/cm to 7.1 lp/cm. Linear
      regression analysis of HU versus electron densities revealed a correlation
      coefficient of 0.99. Contrast, pixel size and geometric accuracy are within
      specifications. Computed tomography dose index values of 0.204 Gy/As and 0.069
      Gy/As have been observed with dose measurements in the center of a 16 cm diameter
      and 32 cm diameter phantom, respectively for large FOV. Small FOV yields CTDI
      values of 0.925 Gy/As and 0.358 Gy/As which is a factor ten higher than the
      results obtained from a DCT under similar acquisition conditions. The phantom
      studies showed excellent agreement between dose distributions generated with the
      Sim-CT and DCT HU. The deviations between the calculated settings of monitor
      units as well as the maximum dose in three dimensions were less than 1% for the
      treatment plans based on either of these HU both for pelvic as well as thoracic
      simulations. The patient studies confirmed these results. CONCLUSIONS: The CT
      option can be considered as an added value to the simulation process and the
      images acquired on the Sim-CT system are adequate for dose calculation with
      tissue heterogeneity correction. The good image quality, however, is compromised
      by the relative high dose values to the patient. The considerable load to the
      conventional X-ray tube currently limits the Sim-CT to seven image acquisitions
      per patient and therefore the system is limited in its capability to perform full
      three-dimensional reconstruction.

PMID- 10392824
TI  - Three-dimensional movement of a liver tumor detected by high-speed magnetic
      resonance imaging.
AB  - OBJECTIVE: Three-dimensional (3D) movement of a spherical liver tumor during
      respiration was investigated with magnetic resonance imaging (MRI) using a high
      speed sequence. METHODS: A marker was placed on the surface of the patient as a
      reference of distance. Repetition time (TR) was 7.7 ms, echo time (TE) was 4.2
      ms, flip angle was 20 degrees, section thickness was 8 mm, and a 256 x 128 matrix
      was used. The acquisition time was 1.0 s followed by an interval of 0.5 s. The 20
      tumor contours extracted during 30 s were superimposed on sagittal and coronal MR
      images. RESULTS: The maximum value of tumor edge location was 3.9 cm in the
      cranio-caudal direction, 2.3 cm in the ventro-dorsal direction, and 3.1 cm in the
      lateral direction. The mean length of tumor displacement observed was 2.1 cm in
      the cranio-caudal direction, 0.8 cm in the ventro-dorsal and 0.9 cm in the left
      right direction, respectively. The locus of the center of the tumor contour in
      the sagittal cross section was inclined at 23 degrees and in the coronal cross
      section was inclined at 18 degrees to the cranio-caudal axis of body. CONCLUSION:
      In conclusion, 3D movement of a spherical liver tumor was detected using rapid
      MRI sequential examinations. Magnetic resonance imaging has a potential to
      improve the accuracy of the planning target volume of a liver tumor.

PMID- 10392825
TI  - Inositol-1,4,5-trisphosphate-mediated rescue of cerebellar long-term depression
      in subtype 1 metabotropic glutamate receptor mutant mouse.
AB  - Recent reports have outlined that cerebellar long-term depression requires the
      activation of subtype 1 metabotropic glutamate receptors, since long-term
      depression is impaired in subtype 1 metabotropic glutamate receptor (mGluR1)
      knockout mice. In order to better define the role of mGluR1-activated signal
      transduction pathways, we attempted to rescue cerebellar long-term depression in
      mGluR1 knockout mice by direct activation of subsequent intracellular cascades.
      The present results demonstrate that the inositol-1,4,5-trisphosphate signal
      transduction pathway remains functional in mGluR1 knockout mice, that calcium
      release from internal stores evoked by the combined photolytic release of
      inositol- 1,4,5-trisphosphate/pairing protocol is sufficient to rescue long-term
      depression in these mutants, and that this long-term depression is sensitive to a
      protein kinase C inhibitor. Therefore, our results provide compelling evidence
      that the impairment of long-term depression observed in mGluR1 knockout mice is
      not a consequence of developmental abnormalities, but is directly due to mGluR1
      gene inactivation.

PMID- 10392826
TI  - Metabotropic glutamate receptor agonists protect from oxygen-glucose deprivation-
      and colchicine-induced apoptosis in primary cultures of cerebellar granule cells.
AB  - The effects of the metabotropic glutamate receptor agonists against apoptosis
      induced by oxygen-glucose deprivation or colchicine were studied in the primary
      cultures of mature cerebellar granule cells. Oxygen-glucose deprivation (90 min)
      or addition of colchicine (1 microM) resulted in neuronal damage as revealed by
      Trypan Blue assay 12 h later. Further analysis demonstrated that the cells
      exposed to oxygen-glucose deprivation or colchicine exhibit typical features of
      apoptosis: internucleosomal DNA fragmentation, condensation and fragmentation of
      chromatin and typical DNA ladder on agarose gel electrophoresis. Metabotropic
      glutamate receptor agonist, (1S,3R)-1-aminocycloheptane-trans-1,3-dicarboxylic
      acid, acting at group I and II receptors, and selective agonist, (2S,1'R,2R',3R')
      2(2,3-dicarboxycyclopropyl)glycine, acting at group II receptors, added to cells
      recovering from oxygen-glucose deprivation exerted neuroprotective action against
      oxygen-glucose deprivation-induced apoptosis. Similar neuroprotective effects of
      metabotropic glutamate receptor agonists were observed against colchicine-induced
      apoptosis. The results thereby provide evidence that metabotropic glutamate
      receptor agonists have therapeutic potential in the treatment of pathologies
      associated with increased neuronal apoptosis. The selective protein kinase C
      inhibitor bisindolylmaleimide (100 nM) abolished the neuroprotective action of
      (1S,3R)-1-aminocycloheptane-trans-1,3-dicarboxylic acid, whereas the activator of
      adenylyl cyclase forskolin (10 microM) abolished the neuroprotective action of
      (2S,1'R,2R',3R')-2(2,3-dicarboxycyclopropyl)glycine (30 microM) against
      colchicine-induced apoptosis. It is concluded that both phosphoinositide
      hydrolysis with consequent activation of protein kinase C and inhibition of
      adenylyl cyclase seem to contribute to the neuroprotective action of metabotropic
      glutamate receptor agonists against neuronal apoptosis in the primary culture of
      cerebellar granule cells.

PMID- 10392827
TI  - Thalamic excitation of hippocampal CA1 neurons: a comparison with the effects of
      CA3 stimulation.
AB  - CA1 is the major output area for the hippocampus, and current evidence shows that
      it is excited primarily from ipsilateral and contralateral CA3 pyramidal cells in
      the rat. Direct connections from the midline thalamic nuclei to the hippocampus
      have been described anatomically, but the physiological role of these connections
      has not been reported until the recent observation that these inputs may have a
      mild excitatory effect (subthreshold for population spikes). In this study, we
      report a more powerful excitatory effect of thalamic stimulation on the response
      of the CA1 neurons in the urethane-anesthetized rat. Electrical stimulation to
      the midline thalamus induced responses similar to responses from stimulation of
      the contralateral hippocampus (CA3), with well-developed field excitatory
      postsynaptic potentials and large population spikes. The latency of the CA1
      response suggested that the thalamic connection was monosynaptic, and there was a
      laminar CA1 response profile that depended on the site of stimulation
      (contralateral CA3 or thalamus). In an initial examination of possible
      differences in the physiological effects of these two pathways on the CA1 region,
      we tested both sites for long-term potentiation of CA1, for the effects of
      repetitive stimulation on CA1 responses (e.g., possible augmenting responses) and
      for the effect of paired-pulse stimulation. In these three measures, there were
      clear and statistically significant differences between the effects of CA3 and
      thalamic stimulation on CA1 responses. This study demonstrates that the well
      described thalamic connection to the hippocampus allows for the direct and
      powerful excitation of the CA1 region. This thalamohippocampal connection
      bypasses the trisynaptic/commissural pathway that has been thought to be the
      exclusive excitatory drive to CA1. In addition, preliminary data indicate that
      the thalamus and CA3 inputs have different physiological effects on CA1 pyramidal
      cells.

PMID- 10392828
TI  - Changes in excitatory and inhibitory circuits of the rat hippocampus 12-14 months
      after complete forebrain ischemia.
AB  - Changes in interneuron distribution and excitatory connectivity have been
      investigated in animals which had survived 12-14 months after complete forebrain
      ischemia, induced by four-vessel occlusion. Anterograde tracing with Phaseolus
      vulgaris leucoagglutinin revealed massive Schaffer collateral input even to those
      regions of the CA1 subfield where hardly any surviving pyramidal cells were
      found. Boutons of these Schaffer collaterals formed conventional synaptic
      contacts on dendritic spines and shafts, many of which likely belong to
      interneurons. Mossy fibres survived the ischemic challenge, however, large mossy
      terminals showed altered morphology, namely, the number of filopodiae on these
      terminals decreased significantly. The entorhinal input to the hippocampus did
      not show any morphological alterations. The distribution of interneurons was
      investigated by neurochemical markers known to label functionally distinct
      GABAergic cell populations. In the hilus, spiny interneurons showed a profound
      decrease in number. This phenomenon was not as obvious in CA3, but the spiny
      metabotropic glutamate receptor 1alpha-positive non-pyramidal cells, some of
      which contain calretinin or substance P receptor, disappeared from stratum
      lucidum of this area. In the CA1 region, somatostatin immunoreactivity
      disappeared from stratum oriens/lacunosum-moleculare-associated cells, while in
      metabotropic glutamate receptor 1alpha-stained sections these cells seemed
      unaffected in number. Other interneurons did not show an obvious decrease in
      number. In stratum radiatum of the CA1 subfield, some interneuron types had
      altered morphology: the substance P receptor-positive dendrites lost their
      characteristic radial orientation, and the metabotropic glutamate receptor 1alpha
      expressing cells became extremely spiny. The loss of inhibitory interneurons at
      the first two stages of the trisynaptic loop coupled with a well-preserved
      excitatory connectivity among the subfields suggests that hyperexcitability in
      the surviving dentate gyrus and CA3 may persist even a year after the ischemic
      impact. The dorsal CA1 region is lost; nevertheless hyperactivity, if it occurs,
      may have a route to leave the hippocampus via the longitudinally extensive axon
      collaterals of CA3 pyramidal cells, which may activate the subiculum and
      entorhinal cortex with a relay in the surviving ventral hippocampal CA1 region.

PMID- 10392829
TI  - Neurovascular relationships in hippocampal slices: physiological and anatomical
      studies of mechanisms underlying flow-metabolism coupling in intraparenchymal
      microvessels.
AB  - Experiments were carried out to investigate the functional and anatomical
      relationships between neuronal elements and cerebral microvessels in 300-350
      microm thick coronal hippocampal slices maintained at 33-35 degrees C, obtained
      from 150-200 g male Wistar rats. Cerebral arterioles (9-22 microm in diameter)
      were visualized in situ and pre-constricted by 22.0+/-6.6% by the addition of the
      thromboxane A2 agonist U46619 (75 nM), to the bathing medium. The glutamate
      agonist N-methyl-D-aspartate (0.01-1 mM) produced a dose-related increase in
      luminal diameter of pre-constricted vessels. In the presence of 4 microM
      haemoglobin to scavenge nitric oxide from the extravascular environment of the
      slice, the increase in diameter evoked by 0.1 mM N-methyl-D-aspartate was
      significantly reduced from 17.5+/-4.6% to 4.8+/-1.7% indicating that N-methyl-D
      aspartate-induced vasodilatation of cerebral microvessels is mediated via a
      mechanism which involves neuronally-derived nitric oxide. In a parallel
      anatomical study, beta-nicotinamide adenine dinucleotide phosphate-dependent
      diaphorase staining was used to reveal the enzyme nitric oxide synthase in
      vascular endothelium and neurons in slices. A small subpopulation (< 11 cells per
      slice) of darkly-stained multipolar neurons, 21-32 microm in diameter was
      observed to give rise to a dense network of fine diaphorase-reactive nerve fibres
      that ramified throughout the whole of the hippocampus and appeared to come into
      close apposition with arterioles. Morphometric analysis of the relationship
      between cerebral microvessels, beta-nicotinamide adenine dinucleotide phosphate,
      reduced form-dependent diaphorase-reactive neuronal elements and individual
      pyramidal layer neurons, identified by filling with biocytin, revealed that for a
      given point on a pyramidal layer neuron, the proximity of the nearest diaphorase
      reactive nerve fibre was less than 10 microm, whilst the distance to the nearest
      arteriole (the smallest functional unit for controlling blood flow) was in excess
      of 70 microm. Such a distance would probably preclude diffusion of vasoactive
      metabolites in effective concentrations from the area of increased neuronal
      activity. We therefore propose that the diaphorase-reactive nerve network
      constitutes the functional link. It is possible that during periods of increased
      neuronal activity, spillover of glutamate from synapses may activate the
      diaphorase-reactive network. Release of nitric oxide from the network in the
      vicinity of local cerebral arterioles may then produce relaxation of the vascular
      smooth muscle, enabling increased blood flow into the capillary network supplying
      the region of increased metabolic activity. This study has shown that the process
      whereby increases in neuronal activity elicit a local change in cerebral blood
      flow remains functionally intact in hippocampal slice preparations. Nitric oxide
      of neuronal origin appears to be involved in mediating the coupling between
      neurons and cerebral arterioles. Stereological analysis of the relationship
      between neuronal and vascular elements within hippocampal slices suggested that a
      small subpopulation of nitric oxide synthase-containing neurons which give rise
      to a diffuse network of fine nitric oxide synthase-containing nerve fibres that
      lie in close apposition to cerebral arterioles may provide the anatomical
      substrate for coupling of blood flow to metabolism.

PMID- 10392830
TI  - Muscarinic facilitation of the occurrence of depolarization-induced suppression
      of inhibition in rat hippocampus.
AB  - Depolarization-induced suppression of inhibition is a transient decrease in
      GABAergic input to a hippocampal pyramidal cell following a brief depolarization
      of that cell. When recorded under whole-cell voltage clamp, monosynaptic,
      bicuculline-sensitive, GABA(A)-mediated currents are suppressed for a period
      lasting up to 1 min in response to a retrograde signal released by the pyramidal
      cell. The depolarization-induced suppression of inhibition process affects
      spontaneous, action-potential-dependent inhibitory postsynaptic currents, but
      suppression of these currents is seldom observed in the absence of carbachol, a
      cholinergic agonist. Because of the central roles played by cholinergic and
      GABAergic transmission in the regulation of hippocampal rhythmic activity, it
      will be important to understand the mechanism by which carbachol facilitates the
      appearance of depolarization-induced suppression of inhibition. As preliminary
      steps in the investigation of cholinergic actions on depolarization-induced
      suppression of inhibition, it is necessary to determine which cholinergic
      receptors are involved and the degree to which activation of these receptors is
      required for depolarization-induced suppression of inhibition. Nicotine did not
      mimic the effects of carbachol, and mecamylamine, a nicotinic receptor
      antagonist, did not block them. In contrast, the actions of carbachol were
      abolished by atropine and other muscarinic receptor antagonists. The actions of
      antagonists with relative selectivities for various subtypes of muscarinic
      receptors [4-diphenylacetoxy-N-methylpiperidine methiodide, pirenzepine, 11-([2-1
      piperidinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzod iaz epine-6-one]
      suggested that cholinergic facilitation of the occurrence of depolarization
      induced suppression of inhibition is likely to be mediated through muscarinic
      receptors of the M1 or M3 rather than M2 subtype. Despite its potent facilitation
      of the occurrence of depolarization-induced suppression of inhibition, muscarinic
      stimulation was not required for expression of depolarization-induced suppression
      of inhibition. Occasionally, depolarization-induced suppression of inhibition of
      spontaneous inhibitory postsynaptic currents occurred in the absence of carbachol
      and could not be blocked by atropine, and hence was not likely to be mediated by
      endogenous acetylcholine. Also, depolarization-induced suppression of inhibition
      of monosynaptically evoked inhibitory postsynaptic currents occurred without
      carbachol perfusion, and this was also insensitive to atropine. Therefore, the
      mechanism of depolarization-induced suppression of inhibition is not dependent on
      muscarinic receptor activation. Nevertheless, in vivo, septal cholinergic input
      to the hippocampus may provide the necessary activation of interneurons to allow
      depolarization-induced suppression of inhibition to occur.

PMID- 10392831
TI  - A chronic focal epilepsy with mossy fiber sprouting follows recurrent seizures
      induced by intrahippocampal tetanus toxin injection in infant rats.
AB  - Studies were conducted to characterize a chronic epileptic condition that follows
      recurrent seizures induced by intrahippocampal tetanus toxin injection in
      infancy. Wistar rat pups received a single injection of tetanus toxin in the
      right CA3 region on postnatal day 10. Animals were monitored for epileptiform
      activity by video electroencephalographic or visual observation during the
      following three to five days. Repeat evaluation six months later demonstrated
      interictal discharges in 79% (11 of 14) and electrographic seizures in 42% (six
      of 14) of adult rats with tetanus toxin-induced seizures in infancy. Five of the
      animals had interictal activity which occurred focally in either the left (n = 2)
      or right (n = 3) hippocampus. One animal had focal interictal activity
      independently in these regions and in the left and right cortical regions. The
      remaining five animals had interictal activity in the hippocampus and
      synchronously in the ipsilateral cortex or the contralateral hippocampus.
      Electrographic seizures were focal (nine of 14) or bilateral (five of 14) in
      onset. The behaviors that accompanied these seizures were quite variable. Clonic
      face and forelimb movements were observed in some animals. However, a significant
      portion of rats had electrographic seizures with no associated behavioral change.
      Timm staining was performed on hippocampal sections from experimental and control
      animals. There was a significantly greater Timm score (aberrant Timm granules) in
      the inner molecular layer of the dentate gyrus in tetanus toxin-treated rats than
      in control rats. Our findings suggest that intrahippocampal tetanus toxin
      injection in infant rats results in a chronic focal epilepsy that persists for at
      least six months and is associated with aberrant mossy fiber sprouting in the
      dentate gyrus. The model described here contributes significantly to the evidence
      for chronic effects of recurrent seizures in early life, and provides a model for
      investigation of the molecular and cellular events that contribute to the
      development of chronic epilepsy.

PMID- 10392832
TI  - A light and electron microscopic study of NG2 chondroitin sulfate proteoglycan
      positive oligodendrocyte precursor cells in the normal and kainate-lesioned rat
      hippocampus.
AB  - The adult brain contains a large population of oligodendrocyte precursor cells
      that can be identified using antibodies against the NG2 chondroitin sulfate
      proteoglycan. The functions of this newly recognized class of glial cells in the
      normal or pathological brain are not well understood. To begin to elucidate these
      functions, we have examined the morphology and distribution of oligodendrocyte
      precursor cells in the hippocampus and neocortex of normal and kainate-lesioned
      rats by anti-NG2 immunocytochemistry using light and electron microscopy. Large
      numbers of oligodendrocyte precursor cells were present in all layers of the
      neocortex and hippocampus. These cells differed in their morphology from
      astrocytes, oligodendrocytes and microglia. The processes of these cells often
      surrounded unlabeled areas of clear cytoplasm. At the electron microscopic level,
      some of the profiles that were enclosed by oligodendrocyte precursor cell
      processes contained synaptic vesicles. Other enclosed profiles were dendrites or
      dendritic spines. NG2-immunopositive processes were also observed to interpose
      between axon terminals containing round vesicles and dendrites with thick
      postsynaptic densities. After kainate injection, the NG2-positive oligodendrocyte
      precursor cells in the hippocampus displayed reactive changes characterized by
      swollen cell bodies, an increased number of small, filopodial-like processes, and
      higher levels of immunodetectable NG2. Both viable and degenerating
      oligodendrocyte precursor cells were observed with electron microscopy. These
      observations emphasize the dynamic nature of the oligodendrocyte precursor cell
      and suggest that, in addition to participating in the glial reactions to
      excitotoxic damage, oligodendrocyte precursor cells may regulate the stability,
      structure and function of synapses in the normal central nervous system.

PMID- 10392833
TI  - Glutamatergic and dopaminergic afferents to the prefrontal cortex regulate
      spatial working memory in rats.
AB  - The integrity of the prefrontal cortex is critical for the expression of working
      memory. The prefrontal cortex is innervated by dopaminergic afferents from the
      ventral tegmental area and glutamatergic afferents from the mediodorsal thalamus.
      To determine the role of dopaminergic and glutamatergic afferents in the
      regulation of working memory, rats were trained to perform a spatial delayed
      alternation task in a T-maze. The microinjection of the ionotropic glutamate
      antagonists 6-cyano-7-nitroquinoxaline-2,3-dione or 3-(R)-2-carboxypiperazin-4
      propyl-1-phosphonic acid into the prefrontal cortex impaired working memory.
      Consistent with a role for glutamate receptor activation, microinjecting the
      GABA(B) agonist baclofen into the mediodorsal thalamus produced a dose-dependent
      disruption of working memory. In contrast, inhibition of the mesocortical
      dopamine projection was without effect on working memory. The blockade of D1
      and/or D2 dopamine receptors with SCH-23390 and sulpiride was without effect on
      working memory. Likewise, the microinjection of baclofen into the ventral
      tegmental area did not impair working memory. However, stimulating mu-opioid
      receptors in the ventral tegmental area with [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin
      produced a dose-dependent impairment of working memory that was reversed by
      blocking D1 dopamine receptors with SCH-23390 in the prefrontal cortex. These
      data demonstrate that increased dopamine tone or reduced glutamate tone in the
      prefrontal cortex disrupts working memory in a spatial delayed alternation task.

PMID- 10392834
TI  - A positron emission tomography study of self-paced finger movements at different
      frequencies.
AB  - Regional cerebral blood flow was measured in six right-handed volunteers using
      positron emission tomography during tasks involving repetitive self-paced finger
      tapping at five different frequencies. The contralateral primary sensorimotor
      cortex, the pre-supplementary motor area and the cingulate motor area showed
      significant activation during self-paced finger tapping tasks, compared with the
      resting state. A positive correlation between the regional cerebral blood flow
      and the movement frequency was found only in the primary sensorimotor cortex. In
      the pre-supplementary motor area and the cingulate motor area, however, activity
      increased when the subject employed movement frequencies faster or slower than
      his own pace. The same tendency was noted with respect to the relative
      variability of the inter-tapping interval. The results therefore indicate that
      the activity of the pre-supplementary motor area and the cingulate motor area may
      well be related to the increased difficulty in motor control rather than to the
      execution of the movement itself.

PMID- 10392835
TI  - Alpha-1-adrenergic receptors mediate sensorimotor gating deficits produced by
      intracerebral dizocilpine administration in rats.
AB  - Prepulse inhibition refers to the inhibition by a weak prepulse of the startle
      response to an intense stimulus. Prepulse inhibition is thought to provide an
      operational measure of sensorimotor gating, a putative central inhibitory process
      by which an organism filters information from its environment. Prepulse
      inhibition deficits are observed in schizophrenia patients and in rats treated
      with psychotomimetic compounds, such as the non-competitive N-methyl-D-aspartate
      antagonists phencyclidine or dizocilpine maleate. In rats, phencyclidine-induced
      prepulse inhibition deficits are blocked by clozapine, olanzapine and quetiapine,
      which are multireceptor antagonists and atypical antipsychotics, or by prazosin,
      which is a selective alpha1-adrenergic antagonist. The dorsal hippocampus and
      amygdala are two of the brain regions shown to contribute to the disruption of
      prepulse inhibition produced by non-competitive N-methyl-D-aspartate antagonists.
      The present study tested the hypotheses that quetiapine or prazosin would prevent
      deficits in prepulse inhibition produced by dizocilpine infusion into the dorsal
      hippocampus or amygdala. In separate groups of rats, either quetiapine (0 or 5.0
      mg/kg, s.c.) or prazosin (0 or 1.0 mg/kg, i.p.) was administered 15 min prior to
      bilateral infusion of dizocilpine (0 or 6.25 microg/0.5 microl/side) into either
      the dorsal hippocampus or amygdala. Rats were placed into startle chambers
      immediately after intracerebral drug infusion and prepulse inhibition was
      assessed. Confirming previous studies, prepulse inhibition was decreased after
      either intra-dorsal hippocampus or intra-amygdala infusions of dizocilpine. Both
      quetiapine and prazosin blocked the prepulse inhibition deficits produced by
      intracranial dizocilpine administration. Startle reactivity was increased by
      dizocilpine infusion into either region; these effects were not blocked by either
      quetiapine or prazosin. These results indicate that non-competitive N-methyl-D
      aspartate antagonists may disrupt sensorimotor gating via actions within the
      dorsal hippocampus or amygdala, and that alpha1-adrenergic receptors distal to
      these sites might mediate this effect.

PMID- 10392836
TI  - An L-dopaergic relay from the posterior hypothalamic nucleus to the rostral
      ventrolateral medulla and its cardiovascular function in anesthetized rats.
AB  - We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter
      in the central nervous system [Misu Y. et al. (1996) Prog. Neurobiol. 49, 415
      454]. Herein, we attempt to clarify whether lesions in the posterior hypothalamic
      nucleus decrease the tissue content of L-DOPA in the rostral ventrolateral
      medulla. We also attempt to clarify whether or not endogenous L-DOPA is evoked by
      electrical stimulation of the posterior hypothalamic nucleus. It is possible that
      evoked L-DOPA functions as a transmitter candidate to activate pressor sites of
      the rostral ventrolateral medulla in anesthetized rats. Electrolytic lesions were
      made in the bilateral posterior hypothalamic nucleus by a monopolar direct
      current of 2 mA for 10 s, 10 days before measurements. The effect of the lesions
      was to selectively decrease the tissue content of L-DOPA by one-half in the right
      rostral ventrolateral medulla. Decreases in the amounts of dopamine,
      noradrenaline or adrenaline were not observed. Decreases were also not evident in
      the right caudal ventrolateral medulla. During microdialysis of the right rostral
      ventrolateral medulla, extracellular basal levels of L-DOPA and three types of
      catecholamine were consistently detectable by high-performance liquid
      chromatography with electrochemical detection. Tetrodotoxin (1 microM) perfused
      into the right rostral ventrolateral medulla gradually decreased basal levels of
      L-DOPA by 25%; it decreased basal levels of noradrenaline and adrenaline by 25
      30% and dopamine levels by 40%. Intensive electrical stimulation of the
      ipsilateral posterior hypothalamic nucleus (50 Hz, 0.3 mA, 0.1 ms duration, twice
      for 5 min at an interval of 5 min) selectively caused the release of L-DOPA in a
      repetitive and constant manner. The stimulation was accompanied by hypertension
      and tachycardia. However, catecholamines were not released. Tetrodotoxin
      suppressed the release of L-DOPA, but partially inhibited hypertension with only
      a slight inhibition of tachycardia evoked by stimulation of the posterior
      hypothalamic nucleus. L-DOPA methyl ester, a competitive L-DOPA antagonist, was
      bilaterally microinjected into pressor sites of the rostral ventrolateral medulla
      at 1.5 microg x 2 and 3 microg x 2. The antagonist dose-dependently and
      consistently antagonized pressor and tachycardiac responses to mild transient
      stimulation of the unilateral posterior hypothalamic nucleus (33 Hz, 0.2 mA, 0.1
      ms duration, for 10 s). In addition, the antagonist alone (3 microg x 2) elicited
      hypotension and bradycardia. These results show that an L-DOPAergic relay may
      project from the posterior hypothalamic nucleus directly to pressor sites of the
      rostral ventrolateral medulla and/or indirectly to certain neurons near pressor
      sites in microcircuits of the same region. When released, L-DOPA appears to
      function tonically to activate pressor sites; it also appears to be involved in
      the maintenance and regulation of blood pressure and heart rate.

PMID- 10392837
TI  - L-dopaergic components in the caudal ventrolateral medulla in baroreflex
      neurotransmission.
AB  - L-3,4-Dihydroxyphenylalanine (L-DOPA) is probably a transmitter of the primary
      baroreceptor afferents terminating in the nucleus tractus solitarii; L-DOPA
      functions tonically to activate depressor sites of the caudal ventrolateral
      medulla, which receives input from the nucleus tractus solitarii [Misu Y. et al.
      (1996) Prog. Neurobiol. 49, 415-454]. We have attempted to clarify whether or not
      L-DOPAergic components within the caudal ventrolateral medulla are involved in
      baroreflex neurotransmission in anesthetized rats. Electrolytic lesions of the
      right nucleus tractus solitarii (1 mA d.c. for 10 s, 10 days before measurement)
      selectively decreased by 45% the tissue content of L-DOPA in the dissected
      ipsilateral caudal ventrolateral medulla. Electrolytic lesions did not decrease
      dopamine, norepinephrine and epinephrine levels. During microdialysis of the
      right caudal ventrolateral medulla, extracellular levels of L-DOPA,
      norepinephrine, epinephrine and 3,4-dihydroxyphenylacetic acid were consistently
      detectable using high-performance liquid chromatography with electrochemical
      detection. However, extracellular dopamine levels were lower than the assay
      limit. Baroreceptor activation by i.v. phenylephrine selectively evoked L-DOPA
      without increasing the levels of norepinephrine, epinephrine and 3,4
      dihydroxyphenylacetic acid. This L-DOPA release was suppressed by acute lesion in
      the ipsilateral nucleus tractus solitarii. Intermittent stimulation of the right
      aortic depressor nerve (20 Hz, 3 V, 0.3 ms duration, for 30 min) repetitively and
      constantly caused L-DOPA release, hypotension and bradycardia, without increases
      in levels of norepinephrine, epinephrine and 3,4-dihydroxyphenylacetic acid.
      Local inhibition of L-DOPA synthesis with alpha-methyl-p-tyrosine (30 microM)
      infused into the ipsilateral caudal ventrolateral medulla gradually decreased
      basal levels of L-DOPA and 3,4-dihydroxyphenylacetic acid without decreasing
      norepinephrine and epinephrine. The inhibition of L-DOPA synthesis interrupted L
      DOPA release and decreased by 65% depressor responses elicited by aortic nerve
      stimulation; however, it produced no effect on bradycardic responses. CoCl2 (119
      ng), a mainly presynaptic inhibitory transmission marker, and L-DOPA methyl ester
      (1 microg), a competitive L-DOPA antagonist, when microinjected into depressor
      sites of the right caudal ventrolateral medulla, reduced by 60% depressor
      responses to transient ipsilateral stimulation of the aortic nerve (20 Hz, 3 V,
      0.1 ms duration, for 10 s). No changes in bradycardic responses were observed.
      There may exist an L-DOPAergic relay from the nucleus tractus solitarii to the
      caudal ventrolateral medulla. L-DOPAergic components in the caudal ventrolateral
      medulla are involved in baroreflex neurotransmission via a baroreceptor-aortic
      depressor nerve-nucleus tractus solitarii-caudal ventrolateral medulla relay in
      the rat.

PMID- 10392839
TI  - Regional cholinergic denervation of cortical microvessels and nitric oxide
      synthase-containing neurons in Alzheimer's disease.
AB  - In the present study, we investigated in the human cerebral cortex whether, as in
      the rat, basal forebrain cholinergic neurons innervate cortical microvessels and
      nitric oxide synthase-containing neurons and, further, we compared the status of
      this innervation between aged controls and neuropathologically confirmed cases of
      Alzheimer's disease. Using immunocytochemistry of choline acetyltransferase
      coupled to reduced nicotinamide adenine dinucleotide phosphate-diaphorase
      histochemistry, we show in young human subjects the presence of a cholinergic
      input to the cortical microcirculation, and of numerous perisomatic and
      peridendritic contacts between cholinergic nerve terminals and reduced
      nicotinamide adenine dinucleotide phosphate-diaphorase neurons. A regional
      cholinergic denervation of both cortical microvessels and reduced nicotinamide
      adenine dinucleotide phosphate-diaphorase neurons was found in Alzheimer's
      disease patients as compared to aged controls, and it paralleled the loss of
      total cholinergic nerve terminals in the corresponding areas of the cerebral
      cortex. The vascular denervation was more severe in the temporal (77%, P < 0.05)
      than in the frontal (48%, not significant) cortex, and the reduced nicotinamide
      adenine dinucleotide phosphate-diaphorase intracortical neurons were similarly
      deprived of their cholinergic input (P < 0.01) in both regions. Interestingly, a
      significant increase in luminal diameter (48%, P < 0.01) and area (> 160%, P <
      0.01) of perfused microvessels was found in Alzheimer's tissues, possibly a
      consequence of both loss of neurogenic input and structural changes in blood
      vessel walls. The data indicate that intracortical microvessels and nitric oxide
      neurons in Alzheimer's disease are deprived of a cholinergic neurogenic control,
      a situation which is likely to result in a compromised ability to adapt cortical
      perfusion to neuronal activation during functional tasks related to cognition,
      arousal and attention. We conclude that such deficits in neurovascular regulation
      are likely to be an important pathogenic factor underlying cerebral blood flow
      dysfunctions in Alzheimer's disease.

PMID- 10392838
TI  - Structure and function of gustatory neurons in the nucleus of the solitary tract.
      IV. The morphology and synaptology of GABA-immunoreactive terminals.
AB  - In the visual, auditory and somatosensory systems, insight into the synaptic
      arrangements of specific types of neurons has proven useful in understanding how
      sensory processing within that system occurs. The neurotransmitter GABA is
      present in the nucleus of the solitary tract and based on the fact that the vast
      majority of cells respond to GABA, its agonists and antagonists, and that over
      45% of synaptic terminals in the rostral subdivision of the nucleus of the
      solitary tract are GABA-immunoreactive, GABA is thought to play an important role
      in gustatory processing. The following study was carried out to establish the
      distribution of GABA-immunoreactive terminals within the nucleus of the solitary
      tract. Specifically, the distribution on to physiologically-identified gustatory
      neurons was determined using post-embedding electron immuno-histochemistry. GABA
      immunoreactive terminals synapse with gustatory neuronal somata and all portions
      of their dendrites, but non-GABAergic terminals synapse only with distal
      dendrites of the gustatory cells and on to correspondingly small unidentified
      dendritic profiles in the neuropil. There is a differential distribution of two
      subtypes of GABA-immunoreactive terminals on to proximal and distal portions of
      the gustatory neurons as well. Finally, a model for the synaptic arrangements
      involving gustatory and GABAergic neurons is proposed.

PMID- 10392840
TI  - Beta-amyloid peptide fragment 31-35 induces apoptosis in cultured cortical
      neurons.
AB  - A synthetic fragment 31-35 of beta-amyloid peptide was used in cultured cortical
      neurons to examine whether this smaller sequence could trigger apoptotic
      degeneration in vitro by using morphological, biochemical and flow-cytometric
      examinations. The results showed that: (i) neurons treated with fragment 31-35 of
      beta-amyloid peptide exhibited membrane blebbing, compaction of nuclear
      chromatin, nuclear shrinkage and nuclear fragmentation; (ii) a typical DNA ladder
      was revealed by agarose gel electrophoresis following fragment 31-35 of beta
      amyloid peptide exposure; (iii) the internucleosome DNA fragmentation was also
      detected by flow-cytometric examination following fragment 31-35 of beta-amyloid
      peptide exposure; and (iv) the DNA fragmentation induced by fragment 31-35 of
      beta-amyloid peptide in the above two examinations could be blocked by co
      treatment with aurintricarboxylic acid or actinomycin D. It is suggested that
      fragment 31-35 of the beta-amyloid peptide may be a shorter sequence of beta
      amyloid peptide responsible for triggering an apoptotic process in cultured
      neurons.

PMID- 10392841
TI  - Long-term restoration of striatal L-aromatic amino acid decarboxylase activity
      using recombinant adeno-associated viral vector gene transfer in a rodent model
      of Parkinson's disease.
AB  - As a potential treatment for Parkinson's disease, viral vector-mediated over
      expression of striatal L-aromatic amino acid decarboxylase was tested in an
      attempt to facilitate the production of therapeutic levels of dopamine after
      peripheral L-dihydroxyphenylalanine administration. The results of microdialysis
      and enzyme activity assays indicate that striatal decarboxylation of peripherally
      administered L-dihydroxyphenylalanine was enhanced by recombinant adeno
      associated virus-mediated gene transfer of L-aromatic amino acid decarboxylase in
      unilateral 6-hydroxydopamine-lesioned rats. This gene transfer-induced increase
      in striatal decarboxylase activity was shown to remain undiminished over a six
      month period and transgene expression was demonstrated to persist for at least
      one year. Unlike previous approaches involving delivery of either tyrosine
      hydroxylase, or tyrosine hydroxylase and L-aromatic amino acid decarboxylase
      transgenes together to accomplish unregulated dopamine delivery, the current
      study proposes a pro-drug strategy (peripheral L-dihydroxyphenylalanine
      administration after L-aromatic amino acid decarboxylase transduction). This
      strategy for dosage control could potentially allow lowered L
      dihydroxyphenylalanine doses and potentially obviate complicated transcriptional
      regulation paradigms. These data suggest that the use of the non-pathogenic adeno
      associated virus to transfer the L-aromatic amino acid decarboxylase gene into
      the striatum of Parkinson's disease patients may be an attractive gene therapy
      strategy.

PMID- 10392842
TI  - Administration of recombinant human Activin-A has powerful neurotrophic effects
      on select striatal phenotypes in the quinolinic acid lesion model of Huntington's
      disease.
AB  - Huntington disease is characterized by the selective loss of striatal neurons,
      particularly of medium-sized spiny glutamate decarboxylase67 staining/GABAergic
      projection neurons which co-contain the calcium binding protein calbindin.
      Lesioning of the adult rat striatum by intrastriatal injection of the N-methyl-D
      aspartate receptor agonist quinolinic acid (100 nmol) results in a pattern of
      striatal neuropathology seven days later that resembles that seen in the
      Huntington brain. Using this animal model of human Huntington's disease we
      investigated the effect of daily intrastriatal infusion of the nerve cell
      survival molecule ActivinA (single bolus dose of 0.73 microg daily for seven
      days) on the quinolinic acid-induced degeneration of various striatal neuronal
      phenotypes. By seven days, unilateral intrastriatal infusion of quinolinic acid
      produced a partial but significant loss (P < 0.01) in the number of striatal
      neurons immunoreactive for glutamate decarboxylase (to 51.0+/-5.8% of unlesioned
      levels), calbindin (to 58.7+/-5.1%), choline acetyltransferase (to 68.6+/-6.1%),
      NADPH-diaphorase (to 47.4+/-5.4%), parvalbumin (to 58.8+/-4.1%) and calretinin
      (to 60.6+/-8.6%) in adult rats that were administered intrastriatal phosphate
      buffered saline for seven days following quinolinic acid. In contrast, in rats
      that received intrastriatal recombinant human ActivinA once daily for seven days
      following quinolinic acid, phenotypic degeneration was significantly attenuated
      in several populations of striatal neurons. Treatment with ActivinA had the most
      potent protective effect on the striatal cholinergic interneuron population
      almost completely preventing the lesion induced decline in choline
      acetyltransferase expression (to 95.1+/-5.8% of unlesioned levels, P < 0.01).
      ActivinA also conferred a significant protective effect on parvalbumin (to 87.5+/
      7.7%, P < 0.01) and NADPH-diaphorase (to 77.5+/-7.5%, P < 0.01) interneuron
      populations but failed to prevent the phenotypic degeneration of calretinin
      neurons (to 56.6+/-5.5%). Glutamate decarboxylase67 and calbindin-staining nerve
      cells represent largely overlapping populations and both identify striatal
      GABAergic projection neurons. We found that ActivinA significantly attenuated the
      loss in the numbers of neurons staining for calbindin (to 79.7+/-6.6%, P < 0.05)
      but not glutamate decarboxylase67 (to 61.1+/-5.9%) at seven days following
      quinolinic acid lesioning. Taken together these results suggest that exogenous
      administration of ActivinA can rescue both striatal interneurons (labelled with
      choline acetyltransferase, parvalbumin, NADPH-diaphorase) and striatal projection
      neurons (labelled by calbindin) from excitotoxic lesioning with quinolinic acid.
      Longer-term studies will be required to determine whether these surviving
      calbindin-expressing projection neurons recover their ability to express the
      glutamate decarboxylase67/GABAergic phenotype. These results therefore suggest
      that treatment with ActivinA may help to prevent the degeneration of vulnerable
      striatal neuronal populations in Huntington's disease.

PMID- 10392844
TI  - Changes in the axonal conduction velocity of pyramidal tract neurons in the aged
      cat.
AB  - The present study was undertaken to determine whether age-dependent changes in
      axonal conduction velocity occur in pyramidal tract neurons. A total of 260 and
      254 pyramidal tract neurons were recorded extracellularly in the motor cortex of
      adult control and aged cats, respectively. These cells were activated
      antidromically by electrical stimulation of the medullary pyramidal tract. Fast-
      and slow-conducting neurons were identified according to their axonal conduction
      velocity in both control and aged cats. While 51% of pyramidal tract neurons
      recorded in the control cats were fast conducting (conduction velocity greater
      than 20 m/s), only 26% of pyramidal tract neurons in the aged cats were fast
      conducting. There was a 43% decrease in the median conduction velocity for the
      entire population of pyramidal tract neurons in aged cats when compared with that
      of pyramidal tract neurons in the control cats (P < 0.001, Mann-Whitney U-test).
      A linear relationship between the spike duration of pyramidal tract neurons and
      their antidromic latency was present in both control and aged cats. However, the
      regression slope was significantly reduced in aged cats. This reduction was due
      to the appearance of a group of pyramidal tract neurons with relatively shorter
      spike durations but slower axonal conduction velocities in the aged cat. Sample
      intracellular data confirmed the above results. These observations form the basis
      for the following conclusions: (i) there is a decrease in median conduction
      velocity of pyramidal tract neurons in aged cats; (ii) the reduction in the
      axonal conduction velocity of pyramidal tract neurons in aged cats is due, in
      part, to fibers that previously belonged to the fast-conducting group and now
      conduct at slower velocity.

PMID- 10392843
TI  - Tyrosine hydroxylase immunoreactivity and [3H]WIN 35,428 binding to the dopamine
      transporter in a hamster model of idiopathic paroxysmal dystonia.
AB  - Recent pharmacological studies and receptor analyses have suggested that dopamine
      neurotransmission is enhanced in mutant dystonic hamsters (dt(sz)), a model of
      idiopathic paroxysmal dystonia which displays attacks of generalized dystonia in
      response to mild stress. In order to further characterize the nature of dopamine
      alterations, the present study investigated possible changes in the number of
      dopaminergic neurons, as defined by tyrosine hydroxylase immunohistochemistry, as
      well as binding to the dopamine transporter labelled with [3H]WIN 35,428 in
      dystonic hamsters. No differences in the number of tyrosine hydroxylase
      immunoreactive neurons were found within the substantia nigra and ventral
      tegmental area of mutant hamsters compared to non-dystonic control hamsters.
      Similarly, under basal conditions, i.e. in the absence of a dystonic episode, no
      significant changes in [3H]WIN 35,428 binding were detected in dystonic brains.
      However, in animals killed during the expression of severe dystonia, significant
      decreases in dopamine transporter binding became evident in the nucleus accumbens
      and ventral tegmental area in comparison to controls exposed to the same external
      stimulation. Since stimulation tended to increase [3H]WIN 35,428 binding in
      control brains, the observed decrease in the ventral tegmental area appeared to
      be due primarily to the fact that binding was increased less in dystonic brains
      than in similarly stimulated control animals. This finding could reflect a
      diminished ability of the dopamine transporter to undergo adaptive changes in
      response to external stressful stimulation in mutant hamsters. The selective
      dopamine uptake inhibitor GBR 12909 (20 mg/kg) aggravated dystonia in mutant
      hamsters, further suggesting that acute alterations in dopamine transporter
      function during stimulation may be an important component of dystonia in this
      model.

PMID- 10392845
TI  - Characterization of bone morphogenetic protein family members as neurotrophic
      factors for cultured sensory neurons.
AB  - The bone morphogenetic proteins have been implicated in several inductive
      processes throughout vertebrate development including nervous system patterning.
      Recently, these proteins have also emerged as candidates for regulating survival
      of mesencephalic dopaminergic and sympathetic neurons. Interestingly, we have
      found that several bone morphogenetic proteins can be detected in developing
      embryonic day 14 rat dorsal root ganglia by means of reverse transcription
      polymerase chain reaction and immunocytochemistry. To further elucidate their
      potential role during the period of ontogenetic neuron death, serum-free cultures
      of dorsal root sensory neurons from developing chick and rat embryos were treated
      with distinct bone morphogenetic proteins with or without simultaneous addition
      of other "established" neurotrophic factors. Our results show that bone
      morphogenetic proteins exert survival promoting effects on their own, and that
      they can positively modulate the effects of neurotrophins on sensory neurons. In
      particular, growth/differentiation factor-5, bone morphogenetic protein-2, -4, -7
      and -12 significantly increased the survival promoting effects of neurotrophin-3
      and nerve growth factor on cultured dorsal root ganglion neurons. These results
      fit well into the current concept that neurotrophic factors may act
      synergistically in ensuring neuronal survival. Moreover, these data suggest
      potential instructive interactions of bone morphogentic proteins and
      neurotrophins during sensory neuron development. Finally, the documented
      neurotrophic capacity of bone morphogenetic protein family members may have
      potential relevance for the treatment of peripheral neuropathies.

PMID- 10392846
TI  - Decreased chaos of midbrain dopaminergic neurons after serotonin denervation.
AB  - Neuropharmacological investigations aimed at understanding the
      electrophysiological correlates between drug effect and action potential trains
      have usually been carried out with the analysis of firing rate and bursting
      activity. In this study, a selective alteration of neural circuits providing
      inputs to ventral tegmental area dopaminergic neurons has been produced, and the
      corresponding electrophysiological correlates have been investigated by nonlinear
      dynamical analysis. The nonlinear prediction method combined with Gaussian-scaled
      surrogate data has been used to show the chaotic structure in the time-series
      corresponding to the electrical activity of ventral tegmental area dopaminergic
      neurons, extracellularly recorded in vivo. A decrease in chaos of ventral
      tegmental area dopaminergic neurons was found in a group of rats lesioned with
      5,7-dihydroxytryptamine, a neurotoxin which selectively destroys serotonergic
      terminals. The chaos content of ventral tegmental area dopaminergic neurons in
      the control group and the decrease of chaos in the lesioned group cannot be
      explained in terms of standard characteristics of neuronal activity (firing rate,
      bursting activity). Moreover, in the control group a positive correlation has
      been found between the density-power-spectrum of the interspike intervals and the
      chaos content measured by nonlinear prediction S score; this relation was lost in
      the lesioned group. It is concluded that the impaired serotonergic tone induced
      by 5,7-dihydroxytryptamine reduces the chaotic behaviour of the dopaminergic cell
      firing pattern, while retaining many standard interspike interval
      characteristics. The functional role of this behaviour in a neuronal coding
      problem context and the implications for the pathophysiology of some mental
      disorders are discussed.

PMID- 10392847
TI  - Stimulation of the pedunculopontine tegmental nucleus in the rat produces burst
      firing in A9 dopaminergic neurons.
AB  - Stimulation of the medial prefrontal cortex in the rat produces events in
      midbrain dopaminergic neurons which resemble natural bursts, and which are
      closely time-locked to the stimulation, albeit with a very long latency. As a
      consequence, we have previously argued that such bursts are polysynaptically
      generated via more proximal excitatory amino acidergic afferents, arising, for
      example, from the pedunculopontine tegmental nucleus. In the present study,
      single-pulse electrical stimulation applied to this nucleus (and other sites in
      the rostral pons) was found to elicit responses in the majority of substantia
      nigra (A9) dopaminergic neurons. Responses usually consisted of long-latency,
      long-duration excitations or inhibition-excitations. Thirty-seven percent of
      responses (currents combined) elicited by stimulation of the pedunculopontine
      tegmental nucleus contained time-locked bursts, the bursts being embedded in the
      long-duration excitatory phases of excitation and inhibition-excitation
      responses. Stimulation sites located within 0.5 mm of the pedunculopontine
      tegmental nucleus were also effective at eliciting time-locked bursts (although
      less so than sites located in the nucleus itself), whereas more distal sites were
      virtually ineffective. For responses containing time-locked bursts, a higher
      percentage of stimulations produced a burst when the response was elicited from
      within the pedunculopontine tegmental nucleus than when it was elicited from
      outside: the bursts themselves having a very long latency (median of 96.2 ms;
      shorter than that of medial prefrontal cortex-induced bursts). Finally, although
      there was no difference in the distribution within the substantia nigra pars
      compacta of cells which exhibited time-locked bursting and those which did not,
      stimulation-induced bursts were elicited more frequently in dopaminergic neurons
      which were classified as "bursting" on the basis of their basal activity. The
      pedunculopontine tegmental nucleus appears to be a critical locus in the rostral
      pons for the elicitation of time-locked bursts in A9 dopaminergic neurons. Since
      time-locked bursts were more often elicited from cells which exhibited bursting
      under basal conditions, this suggests that rostral pontine sites, in particular
      the pedunculopontine tegmental nucleus, may play a role in the natural burst
      activity of dopaminergic neurons. Given that bursts in dopaminergic neurons are
      generated in response to primary and secondary reinforcers, the projection from
      the pedunculopontine tegmental nucleus could be one means by which motivationally
      relevant information (arising, for example, from the medial prefrontal cortex)
      reaches these cells.

PMID- 10392848
TI  - Extent of intercellular calcium wave propagation is related to gap junction
      permeability and level of connexin-43 expression in astrocytes in primary
      cultures from four brain regions.
AB  - Astrocytes are coupled via gap junctions, predominantly formed by connexin-43
      proteins, into cellular networks. This coupling is important for the propagation
      of intercellular calcium waves and for the spatial buffering of K+. Using the
      scrape-loading/dye transfer technique, we studied gap junction permeability in
      rat astrocytes cultured from four different brain regions. The cultures were
      shown to display regional heterogeneity with the following ranking of the gap
      junction coupling strengths: hippocampus = hypothalamus > cerebral cortex = brain
      stem. Similar relative patterns were found in connexin-43 messenger RNA and
      protein levels using solution hybridization/RNase protection assay and western
      blots, respectively. The percentages of the propagation area of mechanically
      induced intercellular calcium waves for cortical, brain stem and hypothalamic
      astrocytes compared with hippocampal astrocytes were approximately 77, 42, and
      52, respectively. Thus, the extent of calcium wave propagation was due to more
      than just gap junctional permeability as highly coupled hypothalamic astrocytes
      displayed relatively small calcium wave propagation areas. Incubation with 5
      hydroxytryptamine decreased and incubation with glutamate increased the calcium
      wave propagation area in hippocampal (67% and 170% of the control, respectively)
      and in cortical astrocytes (82% and 163% of the control, respectively). Contrary
      to hippocampal and cortical astrocytes, the calcium wave propagation in brain
      stem astrocytes was increased by 5-hydroxytryptamine incubation (158% of
      control), while in hypothalamic astrocytes, no significant effects were seen.
      Similar effects from 5-hydroxytryptamine or glutamate treatments were observed on
      dye transfer, indicating an effect on the junctional coupling strength. These
      results demonstrate a strong relationship between connexin-43 messenger RNA
      levels, protein expression, and gap junction permeability among astroglial cells.
      Furthermore, our results suggest heterogeneity among astroglial cells from
      different brain regions in intercellular calcium signaling and in its
      differential modulation by neurotransmitters, probably reflecting functional
      requirements in various brain regions.

PMID- 10392850
TI  - Differential distribution of urocortin- and corticotropin-releasing factor-like
      immunoreactivities in the rat brain.
AB  - Urocortin, a novel 40 amino acid neuropeptide, is a member of the corticotropin
      releasing factor family. With 45% homology to corticotropin-releasing factor,
      urocortin binds with similar affinity to the corticotropin-releasing factor- and
      corticotropin-releasing factor-2 receptors and may play a role in modulating many
      of the same systems as corticotropin-releasing factor. To assess whether
      urocortin and corticotropin-releasing factor are localized in the same regions of
      the brain, we compared the distribution of urocortin- and corticotropin-releasing
      factor-like immunoreactivities in the rat central nervous system. Polyclonal
      antibodies to rat corticotropin-releasing factor and rat urocortin were generated
      and utilized to map the distribution of corticotropin-releasing factor- and
      urocortin-like immunoreactivities throughout the rat forebrain and brainstem.
      Characterization of the antibodies by radioimmunoassay showed no cross-reactivity
      with related peptides. Male Sprague-Dawley rats were treated with colchicine for
      18-24 h. Following colchicine treatment, the rats were perfused with
      paraformaldehyde-lysine-periodate fixative and their brains removed. Serial
      coronal sections were taken throughout the rat brain and processed for either
      corticotropin-releasing factor- or urocortin-like immunoreactivity. Urocortin
      like immunoreactivity shows a discrete localization within several regions
      including the supraoptic nucleus, the median eminence, Edinger-Westphal nucleus
      and the sphenoid nucleus. This is in contrast to the more abundant corticotropin
      releasing factor-like immunoreactivity. Regions containing high levels of
      corticotropin-releasing factor immunoreactivity include the lateral septum,
      paraventricular nucleus of the hypothalamus, median eminence and locus coeruleus.
      There are a few regions that contain both urocortin-immunoreactive and
      corticotropin-releasing factor-immunoreactive cells, such as the supraoptic
      nucleus and the hippocampus. Therefore, urocortin and corticotropin-releasing
      factor appear to have different distribution patterns which may be indicative of
      their respective physiological functions.

PMID- 10392849
TI  - Electrical stimulation of the median or dorsal raphe nuclei reduces light-induced
      FOS protein in the suprachiasmatic nucleus and causes circadian activity rhythm
      phase shifts.
AB  - Several pharmacological studies have suggested that the large median raphe
      serotonergic projection to the circadian clock in the suprachiasmatic nucleus may
      modulate circadian rhythm phase. The present experiments studied the role of
      dorsal and median raphe nuclei as regulators of circadian rhythmicity by
      evaluating the ability of electrical stimulation to shift rhythm phase or to
      alter photic induction of FOS protein synthesis. Male hamsters implanted with
      bipolar electrodes in either the median or dorsal raphe nucleus were stimulated
      during the early subjective night coincident with exposure to a saturating light
      pulse. About 90 min later, animals were anesthetized, perfused and the brains
      processed for FOS protein immunoreactivity. As previously demonstrated, light
      alone induces FOS immunoreactivity in nuclei of suprachiasmatic nucleus neurons.
      This was significantly attenuated by stimulation of either the median or dorsal
      raphe nucleus, with the extent of attenuation proportional to the intensity of
      stimulation. Electrical stimulation without light exposure had no effect on FOS
      expression. The effect of light on FOS expression in the suprachiasmatic nucleus
      was not modified by pre-treatment with the 5-HT1/2 serotonin receptor antagonist,
      metergoline, although it greatly reduced electrical stimulation-induced FOS
      expression in the hippocampus. In a second experiment, hamsters housed with
      running wheels in constant light were electrically stimulated in the median or
      dorsal raphe nucleus 6 h prior to (CT6) or 2 h after (CT14) expected activity
      onset. Regardless of which raphe nucleus was electrically stimulated,
      approximately 22 min phase advances were elicited at CT6 and 36 min phase delays
      were elicited at CT14. Despite the fact that the sole direct projection from the
      raphe complex to the suprachiasmatic nucleus is from the median nucleus, the
      present data do not distinguish between the median and dorsal raphe with respect
      to their impact on circadian rhythm regulation. Instead, two possible roles for
      each raphe nucleus are demonstrated. One main effect is that both raphe nuclei
      modulate rhythm phase. The second is an interaction between raphe efferent
      activity and light which, in the present studies, is demonstrated by the ability
      of raphe stimulation to modulate the action of light on the circadian system.
      While serotonin is a likely neurotransmitter mediating one or both effects,
      alternatives such as GABA, must be considered.

PMID- 10392851
TI  - Cellular and regional expression of glutamate dehydrogenase in the rat nervous
      system: non-radioactive in situ hybridization and comparative
      immunocytochemistry.
AB  - In the central nervous system glutamate dehydrogenase appears to be strongly
      involved in the metabolism of transmitter glutamate and plays a role in the
      pathogenesis of neurodegenerative disorders. In order to identify unequivocally
      the neural cell types expressing this enzyme, non-radioactive in situ
      hybridization, using a complementary RNA probe and oligonucleotide probes, was
      applied to sections of the rat central nervous system and, for comparison with
      peripheral neural cells, to cervical spinal ganglia. The results were
      complemented by immunocytochemical studies using a polyclonal antibody against
      purified glutamate dehydrodenase. Glutamate dehydrogenase messenger RNA was
      detectable at varying amounts in neurons and glial cells (i.e. astrocytes,
      oligodendrocytes, Bergmann glia, ependymal cells, epithelial cells of the plexus
      choroideus) throughout the central nervous system and in neurons and satellite
      cells of spinal ganglia. In some neuronal populations (e.g., pyramidal cells of
      the hippocampus, motoneurons of the spinal cord and spinal ganglia neurons)
      messenger RNA-labelling was higher than in other central nervous system neurons.
      This is remarkable because the immunostaining of neurons in the central nervous
      system regions studied was at best weak, whereas a predominantly high level of
      immunoreactivity was detected in astrocytes (and Bergmann glia). Thus, in neurons
      of the central nervous system, the detected levels of glutamate dehydrogenase
      messenger RNA and protein seem to be at variance whereas in peripheral neurons of
      spinal ganglia both in situ hybridization labelling and immunostaining are
      intense.

PMID- 10392852
TI  - Time-course of spinal sensitization following carrageenan-induced inflammation in
      the young rat: a comparative electrophysiological and behavioural study in vitro
      and in vivo.
AB  - Inflammation of peripheral tissues evokes spontaneous pain and an increased
      responsiveness to external stimuli known as hyperalgesia, produced by both
      peripheral and central changes. The central component is initiated by a sustained
      afferent barrage produced by sensitized peripheral nociceptors, but it is unclear
      to which extent ongoing nociceptive input is required to maintain these central
      changes. Here, we have used an isolated preparation of the spinal cord in vitro
      obtained from eight- to 12-day-old rats to examine spinal plasticity in the
      absence of naturally occurring afferent inputs. Spinal reflex responses in
      preparations obtained from naive rats were compared with those from animals with
      carrageenan-induced inflammation of one hindpaw of 3 h, 6 h and 20 h duration
      prior to the extraction of the cord. Measurements of thermal (heat) and
      mechanical hyperalgesia in awake animals were also made at the same time-points.
      At 6 h post-carrageenan, there was a significant increase in the wind-up evoked
      by trains of high-intensity (C-fibre) stimuli, and at 20 h increased responses to
      both trains and single high-intensity stimuli, and a novel wind-up to low
      intensity (Abeta-fibre) trains were observed. In contrast, maximal behavioural
      hyperalgesia was observed by 3 h post-carrageenan, and thermal hyperalgesia had
      resolved by 20 h, although mechanical hyperalgesia remained. These results show
      that the induction of spinal plasticity independent of peripheral input is a
      progressive process with a slow time-course, since significant hyperreflexia in
      the isolated spinal preparation appears 6 h after inflammation and develops
      further within 20 h. We conclude that during the first 3 h following
      inflammation, hyperalgesia is the result of peripheral sensitization and of
      central mechanisms that depend on an ongoing peripheral input and thus changes
      were not observed in the isolated spinal cord.

PMID- 10392853
TI  - Rat peripheral nerve components release calcitonin gene-related peptide and
      prostaglandin E2 in response to noxious stimuli: evidence that nervi nervorum are
      nociceptors.
AB  - The presence of an intrinsic afferent innervation of nerves and their connective
      tissues (nervi nervorum) suggests that these neural elements participate in
      sensation and pathological processes affecting nerves. Primary afferent
      nociceptors contain and release neuropeptides including calcitonin gene-related
      peptide, implicated in inflammatory vasodilatation. We sought to evaluate the
      ability of different peripheral nerve components, in vitro, to release calcitonin
      gene-related peptide and prostaglandin E2 in response to electrical and noxious
      chemical stimuli, using sensitive enzyme immunoassays. We observed significant
      increases in both calcitonin gene-related peptide and prostaglandin E2 in
      response to a mixture of inflammatory mediators (bradykinin, histamine, and
      serotonin; 10(-5) M) applied to the intact nerves (+37% and +700%, respectively)
      and isolated sheaths (35% and 430%, respectively), but not when this mixture was
      applied to isolated axons. Proximal (antidromic) but not distal (orthodromic)
      electrical stimulation also evoked a comparable release of calcitonin gene
      related peptide (+30%) from intact nerves. These results suggest that nervi
      nervorum nociceptors participate in neural inflammation. Capsaicin (10(-6) M)
      elicited a very large release of calcitonin gene-related peptide when applied to
      either the intact nerve (+400%), isolated sheaths (+500%), or isolated axons
      (1400%). The latter effect was substantially but not completely blocked by
      Ruthenium Red and capsazepine, and was completely blocked using a calcium-free
      bathing solution. The results support the presence of capsaicin receptors in
      peripheral nerves that can effect calcitonin gene-related peptide release from
      axons as well as from terminals.

PMID- 10392854
TI  - Behavioral, neuroendocrine and serotonergic consequences of single social defeat
      and repeated fluoxetine pretreatment in the Lewis rat strain.
AB  - We have analysed some behavioral, neuroendocrine and serotonergic consequences of
      a single (30-min) social defeat followed by 14-18 h of sensory contact with the
      aggressor, in Lewis rats, an inbred strain highly sensitive to chronic social
      stressors [Berton O. et al. (1998) Neuroscience 82, 147-159]. In addition, we
      have investigated how the aforementioned consequences are affected by
      pretreatment with the selective serotonin reuptake inhibitor, fluoxetine (7.5
      mg/kg/day for 21 days). A single social defeat triggered hypophagia and body
      weight loss, and increased anxiety in the elevated plus-maze. It did not affect
      baseline plasma adrenocorticotropic hormone levels and renin activity, but
      decreased plasma corticosterone levels. On the other hand, the responses of the
      latter variables to subsequent acute forced swim stress were blunted
      (corticosterone) or amplified (adrenocorticotropic hormone, renin activity) by
      prior defeat. The density of hippocampal serotonin transporters, but not that of
      hippocampal serotonin-1A and cortical serotonin-2A receptors, was decreased by a
      single social defeat; in addition, neither tryptophan availability and serotonin
      synthesis/metabolism, nor serotonin-1A autoreceptor-mediated functions
      (inhibition of serotonin synthesis, hyperphagia) were affected. Fluoxetine
      pretreatment diminished social defeat-induced hypophagia, body weight loss and
      anxiety without affecting these variables in control animals. This pretreatment
      increased plasma corticosterone levels in resting and acutely stressed rats, but
      abolished social defeat-elicited corticosterone hyporesponsiveness to acute
      forced swim stress. Except for a decrease in midbrain serotonin transporter
      density, fluoxetine did not affect the other serotonergic indices analysed
      herein, i.e. serotonin-1A and serotonin-2A receptor densities, serotonin
      synthesis/metabolism. A single social defeat in Lewis rats produces behavioral
      and endocrine alterations that may model some aspects of human anxiety disorders.
      In this paradigm, prior fluoxetine treatment is endowed with adaptive behavioral,
      and possibly neuroendocrine, effects without affecting the key elements of
      central serotonergic systems analysed herein.

PMID- 10392855
TI  - Stressor- or drug-induced sensitization of the corticosterone response is not
      critically involved in the long-term expression of behavioural sensitization to
      amphetamine.
AB  - Repeated exposure to drugs of abuse induces long-lasting behavioural
      sensitization, which is thought to play a role in the persistence of drug-seeking
      behaviour. Recently, we showed that repeated exposure of rats to cocaine resulted
      in a long-lasting (weeks) sensitization of the hypothalamus-pituitary-adrenal
      axis, i.e. hypersecretion of adrenocorticotropic hormone and of the
      glucocorticoid corticosterone. Moreover, we found that the administration of a
      glucocorticoid receptor antagonist abolished the expression of psychostimulant
      induced behavioural sensitization. In the present study we tested whether
      stressor- or drug-induced long-term hypersecretion of corticosterone is
      associated with the long-term expression of behavioural sensitization to
      psychostimulant drugs. To that end, groups of male Wistar rats were exposed once
      to interleukin-1beta or to footshocks, treatments that are known to induce long
      term sensitization of the hypothalamus-pituitary-adrenal axis, or were treated
      with amphetamine or morphine, according to protocols known to induce long-lasting
      behavioural (locomotor) sensitization. Three weeks later, the groups and their
      controls were challenged with amphetamine or vehicle. Previous exposure to
      interleukin-1beta or footshocks enhanced adrenocorticotropic hormone and
      corticosterone responses, but did not affect the long-term locomotor
      sensitization to amphetamine. Prior amphetamine treatment enhanced the locomotor
      response and the adrenocorticotropic hormone and corticosterone responses to
      amphetamine. Prior morphine treatment resulted in long-term locomotor
      sensitization, whereas the adrenocorticotropic hormone and corticosterone
      responses to amphetamine were decreased. From these findings and the absence of
      within-group correlation between corticosterone and locomotor responses in
      interleukin-1beta and morphine-pretreated rats, we conclude that there is no
      correlation between sensitization of the corticosterone response and behavioural
      sensitization to amphetamine. Apparently, sensitization of the corticosterone
      response is not a prerequisite for the long-term expression of behavioural
      sensitization, which suggests that drug-induced long-term behavioural
      sensitization may involve corticosteroid receptor-dependent (central) mechanisms
      that occur independent of hypothalamus-pituitary-adrenal axis responsiveness.

PMID- 10392856
TI  - Inhibition of styloglossus motoneurons during the palatally induced jaw-closing
      reflex.
AB  - The inhibition of hypoglossal motoneurons innervating the styloglossus muscle
      during transient jaw closing, the so-called jaw-closing reflex, was studied in
      cats. The application of diffuse pressure stimulation to the posterior palatal
      surface produced the jaw-closing reflex and inhibitory postsynaptic potentials in
      the styloglossus motoneurons, indicating that mechanosensory inputs from the
      posterior palatal mucosa sent inhibitory synaptic inputs to styloglossus
      motoneurons. We also demonstrated that, during the palatally induced jaw-closing
      reflex, the tongue extended at jaw closure and was still extended forward in the
      initial part of the opening phase. In all of 22 styloglossus motoneurons studied,
      the depression of firing was elicited after the onset of jaw closure. In 14 of 22
      styloglossus motoneurons, the depression of firing was elicited in the closing
      phase, and in the remaining cells it was elicited in the occlusal phase. By
      increasing the intracellular concentration of chloride ions, the inhibitory
      postsynaptic potential elicited in the styloglossus motoneuron converted to a
      depolarizing potential. It is concluded that the inhibition of styloglossus
      motoneurons may be involved in the maintenance of tongue protrusions during the
      palatally induced jaw-closing reflex, and that inhibitory postsynaptic potentials
      evoked in the styloglossus motoneurons are partly due to a chloride-dependent
      inhibitory postsynaptic potential.

PMID- 10392857
TI  - Metabolic and morphological stability of motoneurons in response to chronically
      elevated neuromuscular activity.
AB  - The purpose of this study was to determine the plasticity of spinal motoneuron
      size and succinate dehydrogenase activity in response to increased levels of
      neuromuscular activation and/or increased target size. The plantaris muscles of
      adult rats were functionally overloaded for one or 10 weeks via the removal of
      the soleus and gastrocnemius muscles bilaterally. In addition, one group of
      functionally overloaded rats at each time period was trained daily (1 h/day) on a
      treadmill. The plantaris muscle on one side in each rat was injected with the
      fluorescent tracer Nuclear Yellow two days prior to the end of the study to
      retrogradely label the associated motor pool. At one week, the plantaris weight
      was increased compared to control, whereas there was no change in motoneuron
      size. Succinate dehydrogenase activity was unaffected in either the muscle or
      motoneurons. At 10 weeks, the plantaris muscle weight was larger and the
      succinate dehydrogenase activity lower in the functionally overloaded rats
      compared to age-matched controls. Training further increased the hypertrophic
      response, whereas the succinate dehydrogenase activity returned to control
      levels. In contrast, mean motoneuron size and succinate dehydrogenase activity
      were similar among the three groups. These data indicate that overload of a
      specific motor pool, involving both an increase in activation and an increase in
      target size, had a minimal effect on the size or the oxidative potential of the
      associated motoneurons. Thus, it appears that the spinal motoneurons, unlike the
      muscle fibers, are highly stable over a wide range of levels of chronic
      neuromuscular activity.

PMID- 10392858
TI  - Distribution of monocarboxylate transporters MCT1 and MCT2 in rat retina.
AB  - Transport of lactic acid and other monocarboxylates such as pyruvate and the
      ketone bodies through cellular membranes is facilitated by specific transport
      proteins. We used chicken polyclonal antibodies to the monocarboxylate
      transporters-1 and -2 to determine their cellular and subcellular distributions
      in rat retina, and we compared these distributions to those of the glucose
      transporters-1 and -3. Monocarboxylate transporter-1 was most highly expressed by
      the apical processes of retinal pigment epithelium that surround the outer
      segments of the photoreceptor cells. In contrast to glucose transporter-1,
      monocarboxylate transporter-1 was not detected on the basal membranes of pigment
      epithelium. The luminal and abluminal endothelial plasma membranes in retina also
      exhibited heavy labeling by antibody to monocarboxylate transporter-1. In
      addition, this transporter was associated with the Muller cell microvilli, the
      plasma membranes of the rod inner segments, and all retinal layers between the
      inner and external limiting membranes. Monocarboxylate transporter-2 was found to
      be abundantly expressed on the inner (basal) plasma membrane of Muller cells and
      by glial cell processes surrounding retinal microvessels. This transporter was
      also present in the plexiform and nuclear layers but was not detected beyond the
      external limiting membrane. Recent studies have shown that lactic acid transport
      is of particular importance at endothelial and epithelial barriers where
      membranes of adjoining cells are linked by tight junctions. Our results suggest
      that monocarboxylate transporter-1 functions to transport lactate between the
      retina and the blood, both at the retinal endothelium and the pigment epithelium.
      The location of monocarboxylate transporter-2 on glial foot processes surrounding
      retinal vessels suggests that this transporter is also important in blood-retinal
      lactate exchange. In addition, the abundance of these transporters in Muller
      cells and synaptic (plexiform) layers suggests that they function in lactate
      exchange between neurons and glia, supporting the notion that lactate plays a key
      role in neural metabolism.

PMID- 10392859
TI  - Finding of the endocannabinoid signalling system in Hydra, a very primitive
      organism: possible role in the feeding response.
AB  - Hydra (Cnidaria) is the first animal organism to have developed a neural network,
      which has been proposed to control, inter alia, the "feeding response", i.e. a
      mechanism through which the coelenterate opens and then closes its mouth in the
      presence of prey and/or glutathione. Here, we report that Hydra contains: (i)
      selective cannabinoid binding sites; (ii) the endogenous cannabinoid receptor
      ligand, anandamide (arachidonoylethanolamide); (iii) a fatty acid amide hydrolase
      like activity catalysing anandamide hydrolysis; and (iv) the putative
      biosynthetic precursor of anandamide, N-arachidonoylphosphatidylethanolamine. We
      suggest that this "endogenous cannabinoid system" is involved in the modulation
      of the "feeding response". Anandamide (1 nM-1 microM) potently inhibited (up to
      45%) the glutathione-induced "feeding response" by accelerating Hydra vulgaris
      mouth closure. The effect was maximal at 100 nM anandamide and was reversed by
      the selective antagonist of the CB1 subtype of mammalian cannabinoid receptors,
      SR 141716A (50-100 nM). Specific cannabinoid binding sites were detected in
      membranes from Hydra polyps by using [3H]SR 141716A (Kd= 1.87 nM, Bmax = 26.7
      fmol/mg protein), and increasing anandamide concentrations were found to displace
      the binding of [3H]SR 141716A to these membranes (Ki = .505 nM). Hydra polyps
      were also found to contain amounts of anandamide (15.6 pmol/g) and N
      arachidonoylphosphatidylethanolamine (32.4 pmol/g), as well as the other
      "endocannabinoid" 2-arachidonoylglycerol (11.2 nmol/g), comparable to those
      described previously for mammalian brain. Finally, a fatty acid amide hydrolase
      activity (Vmax = 3.4 nmol/min/mg protein), with subcellular distribution, pH
      dependency and sensitivity to inhibitors similar to those reported for the
      mammalian enzyme, but with a lower affinity for anandamide (Km = 400 microM), was
      also detected in Hydra polyps. These data suggest that the endocannabinoid
      signalling system plays a physiological role in Hydra that is to control the
      feeding response. Hydra is the simplest living organism described so far to use
      this recently discovered regulatory system.

PMID- 10392860
TI  - C-reactive protein as a marker for cardiac ischemic events in the year after a
      first, uncomplicated myocardial infarction.
AB  - The prognostic role of C-reactive protein levels in patients with a first acute
      myocardial infarction, an uncomplicated in-hospital course, and the absence of
      residual ischemia on a predischarge ergometer test and with an echocardiographic
      ejection fraction > or = 50% has not been described. C-reactive protein was
      determined during hospitalization in 64 patients (55 men, mean age 64.6 +/- 10.4
      years). The patients were followed up for 13 +/- 4 months and the following
      cardiac events were recorded: cardiac death, new-onset angina pectoris, and
      recurrent myocardial infarction. Patients who developed cardiac events during the
      follow-up period had significantly higher C-reactive protein values than patients
      without events (3.61 +/- 2.83 vs 1.48 +/- 2.07 mg/dl, p <0.001). The probability
      of cumulative end points was: 6%, 12%, 31%, and 56% (p = 0.006; RR 3.55;
      confidence interval 1.56 to 8.04), respectively, in patients stratified by
      quartiles of C-reactive protein (< 0.45, 0.45 to 0.93, 0.93 to 2.55 and > 2.55
      mg/dl). In the Cox regression model, only increased C-reactive protein levels
      were independently related to the incidence of subsequent cardiac events (chi
      square 9.8, p = 0.001). Thus, increased C-reactive protein levels are associated
      with a worse outcome among patients with a first acute myocardial infarction, an
      uncomplicated in-hospital course without residual ischemia on the ergometer test,
      and with normal left ventricular function.

PMID- 10392861
TI  - Determinants of infarct size after thrombolytic treatment in acute myocardial
      infarction.
AB  - Both experimental and single-center clinical studies have shown that myocardium
      at risk, residual collateral flow, and duration of coronary occlusion are
      important determinants of final infarct size. The purpose of this study was to
      replicate these results on a multicenter basis to demonstrate that perfusion
      imaging using different camera and computer systems can provide reliable
      assessments of myocardium at risk and collateral flow. Sequential tomographic
      myocardial perfusion imaging with technetium-99 (Tc-99m) sestamibi was performed
      in 74 patients with first time myocardial infarction, who were enrolled in a
      multicenter, randomized, double-blind, placebo-controlled pilot study of
      poloxamer 188 as ancillary therapy to thrombolysis. All patients underwent
      thrombolysis within 6 hours of the onset of chest pain. Tc-99m sestamibi was
      injected intravenously at the initiation of thrombolytic therapy, and tomographic
      imaging was performed 1 to 6 hours later to assess myocardium at risk. Collateral
      flow was estimated noninvasively from the acute sestamibi images by 3 methods
      that assess the severity of the perfusion defect. Final infarct size was
      determined at hospital discharge by a second sestamibi study. Myocardium at risk
      (r = 0.61, p <0.0001) and radionuclide estimates of collateral flow (r = 0.58 to
      0.66, all p <0.0001) were significantly associated with final infarct size. These
      associations were independent of the treatment center. On a multivariate basis,
      myocardium at risk (p = 0.003), the radionuclide estimate of collateral flow (p =
      0.03), and treatment arm (p = 0.04) were all independent determinants of infarct
      size. Time to thrombolytic therapy showed only a trend (p = 0.10). The treatment
      center was not significant (p = 0.42). Myocardium at risk and collateral flow are
      important determinants of infarct size that are independent of treatment center.
      Tomographic imaging with Tc-99m sestamibi can provide noninvasive assessments of
      these parameters in multicenter trials of thrombolytic therapy.

PMID- 10392862
TI  - Vasomotor responses of coronary stenoses to acetylcholine and their relation to
      serum lipid levels in stable angina pectoris.
AB  - The effects of acetylcholine administration on coronary stenoses in relation to
      serum lipids level were evaluated in 18 patients (15 men, 3 women) with coronary
      artery disease and stable angina. Intracoronary acetylcholine was infused in
      concentrations 10(-7), 10(-6), 10(-5) M, followed by intracoronary bolus
      administration of isosorbide dinitrate. Computerized angiography was used to
      assess the changes in the diameter of stenoses and of proximal and distal
      segments. During acetylcholine infusion, at concentrations between 10(-7) to 10(
      5) M, there was a significant (p <0.01) dose-dependent constriction of proximal
      and distal segments and of stenoses reversed by isosorbide dinitrate. There was
      no correlation between the serum total cholesterol level and the responses of
      proximal and distal segments to acetylcholine or nitrate. A correlation (p <0.05)
      was found between the serum total cholesterol level and the response of stenoses
      to acetylcholine, but there was no correlation with the response to isosorbide
      dinitrate. In conclusion, in patients with stable angina current serum total
      cholesterol level correlates with the vasomotor response of coronary stenoses to
      intracoronary acetylcholine. These findings are consistent with a direct effect
      of cholesterol, increasing basal coronary vasomotor tone and increasing the
      stimulated vasoconstrictor response of stenoses.

PMID- 10392863
TI  - Comparative analysis of early and late angiographic outcomes using two
      quantitative algorithms in the Balloon versus Optimal Atherectomy Trial (BOAT).
AB  - Although substantial intersystem variability has been shown among several
      commercially available quantitative angiographic (QA) analysis algorithms, no
      previous study has compared the angiographic findings using 2 different QA
      systems performed at the same central angiographic laboratory. The purpose of
      this study was to compare the early and late QA results obtained with the CMS
      (MEDIS) and ARTREK (ImageComm) QA systems in the Balloon versus Optimal
      Atherectomy Trial. Directional atherectomy (n = 496) or balloon angioplasty (n =
      490) was performed in 986 patients; late QA follow-up was available in 767
      patients (77.7%). QA analysis was performed by 2 independent observers using the
      CMS and ARTREK systems. Correlation between the 2 QA systems for baseline
      measurements was good (Pearson's R = 0.78), although the CMS system resulted in
      larger baseline reference diameter (RD) (3.22 +/- 0.45 vs 3.07 +/- 0.40 mm; p
      <0.0001) and baseline minimal lumen diameters (MLD) (1.05 +/- 0.35 vs 0.92 +/-
      0.32; mm p <0.0001) than the ARTREK system. The final and follow-up RD (+0.17 and
      +0.11 mm, respectively) were also larger using the CMS system. In contrast, the
      final and follow-up measurements of MLD and percent diameter stenosis were not
      significantly different using the 2 QA systems. The QA system did not affect the
      ability to detect a difference in restenosis rates (>50% follow-up diameter
      stenosis) between the 2 treatment groups (CMS, directional atherectomy [31.8%];
      balloon angioplasty [40.5%]; p = 0.013 and ARTREK, directional atherectomy
      [33.9%], balloon angioplasty [41.3%]; p = 0.036). Only lesion irregularity
      contributed to the difference in baseline measurements of MLD and percent
      diameter stenosis. We conclude that important differences in measurements of RD,
      baseline MLD, and percent diameter stenosis were noted using the CMS and ARTREK
      systems. Both systems, however, were able to detect a treatment benefit
      associated with directional atherectomy in BOAT. The comparability of other
      angiographic systems will require similar evaluation in other studies.

PMID- 10392864
TI  - Influence of lesion length on restenosis after coronary stent placement.
AB  - The length of a coronary lesion is a significant predictor of restenosis after
      balloon angioplasty. The influence of lesion length has not comprehensively been
      assessed after coronary stent placement. This study includes 2,736 consecutive
      patients with coronary stent placement. Only patients with recent or chronic
      occlusions before the intervention were excluded. Patients were divided in 2
      groups: 573 patients with long lesions (> or = 15 mm) and 2,163 patients with
      short lesions (< 15 mm). There were no significant differences between the groups
      with respect to the procedural success rate and incidence of subacute thrombosis.
      One-year event-free survival was lower in patients with long lesions (73.3% vs
      80.0%, p = 0.001). Six-month angiography was performed in 82.5% of the eligible
      patients. The incidence of binary restenosis (> or = 50% diameter stenosis) was
      higher in patients with long lesions (36.9% vs 27.9%, p <0.001). Similarly,
      patients with long lesions presented more late lumen loss than those with short
      lesions (1.29 +/- 0.89 vs 1.07 +/- 0.77 mm, p <0.001). Multivariate models for
      both binary restenosis and late lumen loss demonstrated that lesion length was an
      independent risk factor for restenosis. The risk was further increased by
      multiple stent placement and overlapping stents that were also independent risk
      factors of restenosis. Stented segment length did not show any independent
      effect. Therefore, long lesions represent an independent risk factor for
      restenosis after coronary stent placement. The results of this study suggest that
      a possible way to reduce the risk is to cover the lesion with a minimal number of
      nonoverlapping stents.

PMID- 10392866
TI  - Comparison of sotalol versus quinidine for maintenance of normal sinus rhythm in
      patients with chronic atrial fibrillation.
AB  - Many clinicians choose sotalol for the prevention of recurrences of atrial
      fibrillation (AF) as an alternative to quinidine, which has been associated with
      an increase in long-term mortality. Using meta-analytic techniques, we compared
      the effects on maintenance of sinus rhythm and mortality of combined groups of
      patients with chronic AF treated with sotalol, quinidine, or a control drug.
      Rates of conversion at 6 months and mortality were combined for each group after
      performing sensitivity analysis to test for homogeneity. Bayesian estimates and
      corresponding 95% credibility intervals were constructed to compare the
      probabilities of achieving sinus rhythm and mortality among groups. A literature
      search revealed 4 sotalol studies, 6 quinidine studies, and 5 control studies
      that met inclusion criteria established a priori. The point estimates for
      maintaining normal sinus rhythm (at 6 months) and corresponding credibility
      intervals for the 3 groups were sotalol 50% (range 42% to 58%), quinidine 53%
      (range 48% to 59%), and control 32% (range 26% to 39%). When combining and
      comparing mortality effects, the following studies met the same inclusion
      criteria: 4 sotalol studies, 9 quinidine studies, and 7 control studies. The
      point estimates and corresponding credibility intervals for mortality in the 3
      groups were sotalol 2.2% (range 0.6% to 4.8%), quinidine 3.0% (range 1.7% to
      4.7%), and control 1.1% (range 0.3% to 2.4%). Sotalol and quinidine are
      comparable in their ability to maintain sinus rhythm at 6 months (about 50%) and
      both agents are superior to control. There is a trend for both agents to increase
      mortality with long-term therapy. These data do not support choosing sotalol over
      quinidine as a safer alternative for preventing recurrences of chronic AF.

PMID- 10392867
TI  - Hemodynamic and cardiorespiratory function following internal atrial
      defibrillation for chronic atrial fibrillation.
AB  - Internal atrial defibrillation (IAD) is able to restore sinus rhythm in patients
      with chronic atrial fibrillation (AF) and failed external electrical and/or
      pharmacologic cardioversion. To assess whether cardiorespiratory and hemodynamic
      function improve after IAD, 35 patients were prospectively investigated during
      constant workload exercise by spiroergometry and Doppler echocardiography before
      IAD, and 1 day and 1 month after IAD. Oxygen uptake kinetics, ventilation, left
      atrial mechanical function, and pulmonary artery pressure were determined
      simultaneously at rest and during steady state. During the serial follow-up, 20
      patients maintained sinus rhythm. The time interval for achieving the steady
      state (146 +/- 53 vs 132 +/- 42 seconds; p = 0.5) and the oxygen deficit (645 +/-
      190 vs 670 +/- 174 ml; p = 0.7) were not different before and 1 day after IAD,
      but decreased significantly after 1 month (98 +/- 16 seconds, p = 0.01 and 487 +/
      72 ml, p = 0.02). Exercise pulmonary artery systolic pressures were 38 +/- 13 mm
      Hg before IAD, increased significantly to 46 +/- 11 mm Hg on day 1 (p = 0.03),
      and decreased below baseline values at 1 month to 31 +/- 12 mm Hg (p = 0.07).
      Peak A-wave velocities increased from 0.51 +/- 0.1 m/s after 1 day to 0.67 +/-
      0.2 m/s after 1 month (p = 0.03). Restoration of sinus rhythm in patients with AF
      resistant to external electrical and/or pharmacologic cardioversion improves
      hemodynamic and cardiorespiratory function at daily activity exercise levels.

PMID- 10392865
TI  - Low- versus high-dose recombinant urokinase for the treatment of chronic
      saphenous vein graft occlusion.
AB  - Recanalization of a totally occluded saphenous vein graft (SVG) using
      commercially available urokinase from human kidney cells has been shown to be
      effective, but the duration of infusion and complications such as allergic
      reactions, bleeding events, and non-Q-wave myocardial infarction have limited its
      acceptance. Recently, genetic engineering has allowed the synthesis of
      recombinant urokinase (r-UK). Patients with an occluded SVG from 37 centers were
      randomized to receive a 6-hour infusion of either low-dose (125,000 IU/hour) or
      high-dose (350,000 IU/hour) r-UK followed by up to a maximum of 18 hours of r-UK
      (125,000 IU/hour) via a subselective catheter directly into the occluded vein
      graft. The primary study end point was final preintervention achievement of
      Thrombolysis In Myocardial Infarction (TIMI) flow > or = 2 using core
      angiographic analysis. One hundred seven patients were randomized and 98 received
      the study drug (low dose 52 patients, high dose 46 patients). TIMI flow > or = 2
      after completion of the study drug was higher in the high-dose group (51% vs 24%,
      p = 0.019). This difference narrowed, but a trend was still evident on the final
      angiogram after adjunctive mechanical intervention (72% vs 58%, p = 0.254).
      Bleeding complications were frequent; severe or life-threatening bleeding
      occurred in 12% of patients on the low dose and 11% of patients on the high dose
      (p = NS), including 2 intracerebral bleeds, both of which were fatal with 1 in
      each group. Thus, in patients with an occluded SVG, a randomized trial of direct
      low-dose versus high-dose r-UK infusion demonstrated increased recanalization
      rates (TIMI flow > or = 2) in the high-dose arm. Percutaneous revascularization
      of SVG with r-UK can be accomplished with acceptable success rates, but
      complications are frequent.

PMID- 10392868
TI  - Acute hemodynamic and neurohumoral effects of moxonidine in congestive heart
      failure secondary to ischemic or idiopathic dilated cardiomyopathy.
AB  - Elevated plasma norepinephrine (PNE) has been shown to be an important predictor
      of morbidity and mortality in patients with congestive heart failure (CHF).
      Moxonidine selectively stimulates imidazoline receptors located in the medulla,
      which centrally inhibit sympathetic outflow. PNE is suppressed and peripheral
      vasodilation reduces systemic blood pressure. This study evaluated the acute
      neurohumoral and hemodynamic effects of a single dose of oral moxonidine in 32
      patients (22 men, mean +/- SD age 66 +/- 10 years) with CHF. All patients were in
      New York Heart Association functional class III and stabilized on chronic therapy
      with diuretics, digitalis, and angiotensin-converting enzyme inhibitors. The mean
      PNE concentration was 509 +/- 304 pg/ml at baseline. Patients underwent invasive
      hemodynamic monitoring after double-blind randomization to either placebo (n =
      12), moxonidine 0.4 mg (n = 9), or moxonidine 0.6 mg (n = 11). Moxonidine
      produced a dose-dependent, vasodilator response compared with placebo. Analysis
      of the time-averaged change from baseline over 6 hours demonstrated that
      moxonidine 0.6 mg caused significant reductions in mean systemic arterial
      pressure (p <0.0001), mean pulmonary arterial pressure (p <0.005), systemic
      vascular resistance (p <0.05), pulmonary vascular resistance (p <0.01), and heart
      rate (p <0.05). Stroke volume was unchanged. PNE was reduced substantially (-180
      pg/ml at 4 hours, p <0.005) and the reduction was highly correlated with the
      baseline level (r = -0.968). Moxonidine was well tolerated in this single-dose
      study and resulted in a modest, dose-dependent, vasodilator response, with
      substantial reductions in systemic and pulmonary arterial blood pressure. Trials
      designed to evaluate the clinical efficacy of chronic moxonidine therapy in CHF
      added to conventional therapy would be appropriate.

PMID- 10392869
TI  - Optimizing utilization of pediatric echocardiography and implications for
      telemedicine.
AB  - Telemedicine can deliver tertiary level services to remote communities where
      subspecialty care is limited. Locally performed echocardiography has been
      initiated at several locations around Iowa. The goal of this study was to examine
      utilization and diagnostic yield of community-based echocardiographic services.
      Community physicians selected patients for remote echocardiograms (echoes), and
      studies were performed locally by sonographers trained in recording pediatric
      echoes. Echoes were sent to the pediatric echocardiography laboratory by mail or
      via telemedicine systems. Echoes were also ordered locally by pediatric
      cardiologists during outreach clinics in the same communities. Numbers of normal
      and abnormal echoes ordered by community physicions and pediatric cardiologists
      were compared by chi-square analysis. Since January 1996, community physicians
      ordered 378 echoes, whereas 154 echoes were ordered by pediatric cardiologists at
      outreach clinics. Stratifying echoes by patient age found that the percentage of
      normal studies in patients < 1 year of age was no different between groups (27%
      normal by community physicians vs 15%; chi-square 0.92; p = 0.34). The percentage
      of normal studies ordered by community physicians was significantly greater in
      patients > 1 year of age (83% normal by community physicians vs 25%; chi-square
      80.2; p <0.0001). Thus, (1) community physicians effectively identified patients
      < 1 year of age with abnormal echoes, (2) significantly fewer echoes may be
      required in patients > 1 year of age if patients are first evaluated by a
      pediatric cardiologist, and (3) patient selection will impact cost effectiveness
      of remotely obtained echoes.

PMID- 10392870
TI  - Comparison of outcome when hypoplastic left heart syndrome and transposition of
      the great arteries are diagnosed prenatally versus when diagnosis of these two
      conditions is made only postnatally.
AB  - We sought to determine the impact of prenatal diagnosis on the perioperative
      outcome of newborns with hypoplastic left heart syndrome (HLHS) and transposition
      of the great arteries (TGA). All neonates with HLHS or TGA encountered at
      Children's Hospital, Boston, Massachusetts, from January 1988 to May 1996 were
      identified and outcomes documented. Birth characteristics, preoperative,
      operative, and postoperative variables of term newborns with a prenatal diagnosis
      of HLHS or TGA who underwent a Norwood operation (n = 27) or arterial switch
      operation (n = 14), respectively, were compared with newborns with a postnatal
      diagnosis of HLHS (n = 47) or TGA (n = 28) who had undergone surgery. Of 217
      neonates with HLHS and 422 with TGA, 39 and 16, respectively, had a prenatal
      diagnosis. The preoperative mortality among neonates aggressively managed did not
      differ between the prenatal and postnatal diagnosis groups for either HLHS or TGA
      (p >0.05). Neonates with a prenatal diagnosis who underwent surgery had objective
      indicators of lower severity of illness preoperatively, including a higher lowest
      recorded pH (p = 0.03), lower maximum blood urea nitrogen (p = 0.002), and
      creatinine (p = 0.03) among newborns with HLHS, and a tendency toward higher
      minimum of partial pressure of arterial oxygen in the TGA group (p = 0.06).
      Prenatal diagnosis was not associated with an improved postoperative course or
      operative mortality (p <0.05) within a diagnostic group. Thus, a prenatal
      diagnosis improves the preoperative condition of neonates with HLHS and TGA, but
      may not significantly improve preoperative mortality or early postoperative
      outcome among neonates managed at a tertiary care center.

PMID- 10392871
TI  - Heart rate variability in healthy children and in those with congenital heart
      disease both before and after operation.
AB  - There are no reports of standard measures of heart rate variability (HRV) in
      pediatric patients with heart disease. Time domain (standard deviation of all
      normal RR intervals [SDNN], standard deviation of all 5-minute mean RR intervals,
      average standard deviation of all 5-minute RR intervals, and frequency domain
      (total, low- [LF], and high-frequency [HF] power) measures of HRV were (1)
      obtained in 45 healthy children, (2) compared between 36 children with congenital
      heart disease and age-matched controls, (3) compared before and after surgery,
      and (4) compared between age-matched postoperative patients staying <7 days
      (group I, n = 16) and those staying longer (group II, n = 16). In healthy
      children, SDNN increased rapidly during infancy and more gradually thereafter,
      while the LH/HF ratio decreased until preschool age, with a later increase into
      adolescence. Compared with controls, preoperative patients had decreased total
      (53 +/- 55 vs 84 +/- 75 beats/min2/Hz, p = 0.01) and HF (12 +/- 14 vs 29 +/- 46
      beats/min2/Hz, p = 0.03) power despite having similar heart rates. In the
      immediate postoperative period, all measures of HRV were decreased from
      preoperative values. Groups I and II did not differ in mean RR interval or HRV
      preoperatively; however, postoperatively, HRV was decreased in group II when
      compared with group I (SDNN 53 +/- 17 vs 40 +/- 14 ms, p = 0.01), although the
      mean RR interval remained comparable (499 +/- 81 vs 481 +/- 62 ms, p = 0.3). It
      is concluded that (1) there are significant age-related changes in HRV in healthy
      children, (2) preoperatively, children with congenital heart disease have reduced
      total and HF power when compared with healthy controls, (3) HRV is further
      reduced postoperatively in all patients, and (4) prolonged postoperative
      hospitalization is associated with a greater reduction in HRV.

PMID- 10392872
TI  - Management of arterial puncture site after catheterization procedures: evaluating
      a suture-mediated closure device.
AB  - To overcome the challenge associated with achievement in hemostasis after a
      catheterization procedure, a suture-based closure device was compared with manual
      compression in a 600-patient randomized trial. The major study end points
      included the incidence of vascular complications and the time to ambulation after
      the procedure. The study included diagnostic or interventional procedures. The
      suture-mediated closure was performed immediately after the procedure independent
      of the anticoagulation level, whereas manual compression was performed per
      hospital protocol with sheath removal relying on normalization of patient's
      anticoagulation status. A significant reduction in time to achieve hemostasis
      (7.8 +/- 4.8 vs 19.6 +/- 13.2 minutes, p <0001) and time to ambulation (4.5 +/-
      6.5 vs 17.8 +/- 5 hours, p <0001) was associated with use of the suture-mediated
      closure device. The incidence of vascular complications was similar in the
      overall population (5.7% for suturing device vs 11.3% for compression) or in the
      interventional patient subset (8.4% for suturing device vs 9.6% for compression).
      There was a significant reduction in the incidence of vascular complications in
      the diagnostic procedure subset (4.4% for suturing device vs 12.1% for
      compression, p <0.05). Thus, the use of a suture-mediated closure device
      represents a safe alternative to manual compression. Hemostasis and ambulation
      can be achieved faster with the suturing device than with manual compression,
      with a potential reduction in access site complications.

PMID- 10392873
TI  - Helicobacter pylori serology in patients with angiographically documented
      coronary artery disease.
AB  - We studied the relation between angiographically defined coronary artery disease
      and serologic evidence of Helicobacter pylori infection in 488 patients undergo
      ing elective coronary angiography. There was no association between Helicobacter
      pylori infection and coronary artery disease (odds ratio 1.3, 95% confidence
      interval 0.83 to 2.16).

PMID- 10392874
TI  - A new algorithm to determine complete isthmus conduction block after
      radiofrequency catheter ablation for typical atrial flutter.
AB  - The induction of a complete conduction block of the isthmus between inferior vena
      cava and tricuspid annulus is considered the best predictor for lack of
      arrhythmia recurrence if radiofrequency catheter ablation for typical atrial
      flutter is performed. We evaluated a simplified algorithm to determine complete
      isthmus block that, in our series, had a predictive accuracy of 100% when
      compared with the gold standard.

PMID- 10392875
TI  - Usefulness of low-dose dobutamine stress echocardiography in predicting recovery
      of poor left ventricular function in atrial fibrillation dilated cardiomyopathy.
AB  - Assessment of contractile reserve was performed in 16 patients with dilated
      cardiomyopathy and chronic atrial fibrillation. In this prospective study, low
      dose dobutamine echocardiography could predict recovery of left ventricular
      dysfunction and could identify tachycardiomyopathy before restoration of sinus
      rhythm.

PMID- 10392876
TI  - Prolonged QT interval and altered QT/RR relation early after radiofrequency
      ablation of the atrioventricular junction.
AB  - This study evaluated the paced QT interval in the days after radiofrequency
      ablation of the atrioventricular junction in patients with chronic rapid atrial
      fibrillation. There is an abnormality in the dynamics of the paced QT interval
      until the second day after ablation, resulting in an increased duration when the
      paced heart rate is <75 beats/min.

PMID- 10392877
TI  - Resistance exercise training increases muscle strength, endurance, and blood flow
      in patients with chronic heart failure.
AB  - Resistance exercise training was well tolerated in patients with stable, chronic
      heart failure, resulting in increased strength and endurance, and lower oxygen
      consumption at submaximum workloads but no improvement in VO2peak. There was also
      a significant increase in basal forearm blood flow following this form of
      exercise training.

PMID- 10392878
TI  - Study of myocardial contractility by pulsed wave Doppler tissue imaging does not
      reveal an inotropic effect of estrogen at physiologic dose.
AB  - We studied myocardial contractility by pulsed wave Doppler tissue imaging in 6
      postmenopausal healthy women. According to a crossover, double-blind protocol, we
      randomized patients to treatment with transdermal patches of estradiol-17beta or
      matched placebo. Estradiol-17beta did not modify local systolic and diastolic
      functions. Thus, at least when acutely administered, estrogen seems to be unable
      to determine hemodynamic changes at the myocardial level, in opposition to what
      occurs in the peripheral vascular system.

PMID- 10392879
TI  - Postcard from Riyadh: too much data, not enough wisdom.

PMID- 10392880
TI  - Guidelines for the management of colonic cancer.

PMID- 10392881
TI  - On interpreting data.

PMID- 10392882
TI  - Training, retraining and retaining rural general surgeons.

PMID- 10392883
TI  - Practice parameters for the management of colonic cancer I: surgical issues.
      Recommendations of the Colorectal Surgical Society of Australia.

PMID- 10392884
TI  - Splenic vascular lesions: unusual features and a review of the literature.
AB  - Hamartoma and peliosis are uncommon splenic lesions. Approximately 120 splenic
      hamartomas and 40 splenic peliosis have been reported in the English literature.
      In the present study, a unique case of multiple splenic hamartomas with peliosis
      was reported. The splenic lesions were incidental findings in a 36-year-old man
      with ruptured sarcomatoid renal cell carcinoma. They were diagnosed clinically as
      metastatic renal cell carcinoma. On pathological examination, peliosis was noted
      in the splenic hamartomas as well as in the splenic parenchyma. In addition, the
      clinicopathological features of five other splenic hamartomas (including one
      giant hamartoma) noted in our department were presented. A re-evaluation of the
      features of the splenic hamartomas documented in the English literature was also
      done.

PMID- 10392885
TI  - Surgical treatment of atypical mycobacterial cervicofacial adenitis in children.
AB  - BACKGROUND: Atypical mycobacteria have long been recognized as a cause of
      cervicofacial adenitis in otherwise healthy children. The disease is nearly
      always localized but if left untreated the involved lymph nodes caseate and
      discharge. The management of this condition has been considered to be surgical
      with techniques including aspiration, incision and drainage, curettage and
      excision. METHODS: Cases of atypical mycobacterial cervicofacial adenitis treated
      by curettage at the Canberra Hospital, ACT, Australia, are reviewed. RESULTS: Ten
      cases successfully treated with curettage are reported. Two patients experienced
      delayed healing of their wounds and one required a second curettage 7 months
      after primary excision for recurrent disease. CONCLUSION: Curettage is a safe and
      effective means of treating atypical mycobacterial cervicofacial adenitis in
      children. The primary cure rate of 70% is less than that for excision of the
      involved nodes (92% cure rate), which is the standard treatment for this disease.

PMID- 10392886
TI  - Adult splenic injuries: treatment patterns and predictive indicators.
AB  - BACKGROUND: With the trend towards conservation in splenic trauma, the ability to
      identify a group of patients for whom we can safely offer conservative treatment
      becomes an important factor. METHODS: Data were reviewed from the trauma register
      at the Auckland Hospital, Auckland, New Zealand, in an attempt to isolate any
      predictive factors that may allow more appropriate allocation of treatment
      modalities in the future. Methods of treatment were determined and the success or
      failure of conservative management noted. Differences in the demographics, Injury
      Severity Score (ISS) and computed tomographic (CT) findings were particularly
      sought. RESULTS: Over a period of 111 weeks 48 patients were admitted with
      splenic injuries. Fifteen (31.2%) had immediate splenectomy, 27 (56.2%) were
      initially treated non-operatively and six (10.1%) died pre-operatively. Of the
      non-operative group eight (29.6%) failed this management at an average of 4.125
      days into their hospital stay. No differences were found in age, mechanism,
      gender or ISS between the failed and successfully treated group. Using the
      Buntain classification of CT-graded splenic injury, 13 (87%) who had successful
      non-operative treatment had a grade II or III compared with six (86%) who failed
      this management being grade IV. CONCLUSION: Although these results did not reach
      statistical significance, by coupling the trends seen together with other work,
      CT grading of splenic injury is a predictive indicator and does appear to have a
      role in the early allocation of patients to appropriate treatment plans.

PMID- 10392887
TI  - Decreasing lengths of stay: the cost to the community.
AB  - BACKGROUND: Patients who are discharged earlier from hospital frequently require
      support from professional and unpaid carers at home after discharge. Hospitals
      save money per patient by discharging earlier, but it is not known whether the
      costs to community services and unpaid caters outweigh the savings to the
      hospital. METHODS: We prospectively studied the total costs, patient
      satisfaction, time off work and pain scores of 224 patients who underwent
      elective herniorrhaphy or laparoscopic cholecystectomy and who lived locally
      before and after re-engineering the elective surgical service. The components of
      the re-engineered surgical service were a peri-operative unit, pre-admission
      anaesthetic assessment based on self-reported questionnaires, day of surgery
      admissions, enhanced patient education, clinical pathways, and post-acute care.
      RESULTS: The patients treated through the re-engineered surgical service had a
      significantly shorter length of stay (LOS) (mean LOS: 2.2 vs 3.2 days; P < 0.001)
      but neither they nor their carers required more time off work. Significant
      determinants of time off work were smoking, heavy lifting at work and a higher
      pain score at day 7. Patients treated through the re-engineered surgical service
      recorded significantly higher satisfaction with their treatment. The cost saving
      to the hospital outweighed the cost of increased services provided in the
      community, so that the overall cost of providing treatment was over $200 less per
      patient through the re-engineered service. CONCLUSIONS: This study demonstrates
      that changes in care provision that result in shorter LOS and greater cost
      effectiveness may better meet patients' needs than existing systems.

PMID- 10392888
TI  - Evolution of the pelvic pouch procedure at one institution: the first 100 cases.
AB  - BACKGROUND: Total extirpation of the colon with pelvic pouch formation, and the
      avoidance of a permanent stoma, continues to pose a challenge for better results,
      both technically and functionally. The aims of this study were to investigate the
      first 100 pelvic ileal-pouch procedures, assessing changes in surgical technique,
      their relationship to morbidity and long-term outcome, and compare this to the
      few large international series. METHODS: Between 1984 and 1997, 100 patients had
      a pelvic J-shaped ileal-pouch formed, 58 two-stage and 42 three-stage procedures.
      Fifty had a hand-sewn pouch-anal anastomosis and 50 a double-stapled anastomosis.
      Seventy-three were for ulcerative colitis, five for indeterminate colitis, 20 for
      familial adenomatous polyposis (FAP), one for multiple primary colorectal
      cancers, and one for constipation. RESULTS: After a median follow-up of 68
      months, 97% of patients still have a functioning pouch. There were two
      postoperative deaths (one after-pouch formation and one after-stoma closure).
      Morbidity occurred in 52 patients, including three patients with pouch leaks and
      three pouch-anal anastomosis leaks (6% leak rate), 27% with a small bowel
      obstruction (2% early, 20% late, 5% both), a 19% anal stricture rate, and a 9%
      pouchitis rate. Three pouches have been removed (all for Crohn's disease). Median
      number of bowel movements per day was six, with 85% of patients reporting a good
      quality of life. Patients following a double-stapled procedure have less anal
      seepage and improved continence over those with a hand-sewn ileal pouch-anal
      anastomosis. CONCLUSIONS: Despite high morbidity rates, pelvic pouch formation
      provides satisfactory long-term results for patients requiring total
      proctocolectomy, with functional results and morbidity rates comparable to larger
      overseas series.

PMID- 10392889
TI  - Early gastric cancer in the young: clinicopathological study.
AB  - BACKGROUND: Thirty-four cases of early gastric carcinoma in patients under 50
      years of age treated in the period from 1985 to 1995 were reviewed. METHODS:
      These constituted 3.7% of 923 cases of gastric cancer in patients of all ages
      that were treated at Sendai National Hospital during the same 10-year period.
      Data were compared with those of 194 patients 50 years of age or older. RESULTS:
      The incidence of gastric cancer in men and women was almost the same in both
      groups. Tumours tended to be located distally in the stomach. Macroscopically,
      depressed lesions were more common in younger patients. Significant differences
      were observed in depth of invasion, histological type and histological growth
      patterns. CONCLUSIONS: The distinctive histological features of early gastric
      cancer in younger patients were a diffuse type of cancer with infiltrative
      tumours in the mucosal layer. The prognosis of younger patients was similar to
      that of older patients.

PMID- 10392890
TI  - Quality of life after emergency abdominal aortic aneurysm repair.
AB  - BACKGROUND: Quality of life issues following surgical procedures, especially
      those with high mortality, should be of prime importance. There have been few
      studies on the quality of life of patients following emergency abdominal aortic
      aneurysm repairs. The decision to continue to offer surgery to these patients,
      especially with present monetary constraints, should rely heavily on quality of
      life issues. Audits of major surgical procedures should be undertaken and quality
      of life included. METHODS: All patients in the Hawkes Bay area who had undergone
      emergency abdominal aortic aneurysm repairs since 1981 were identified and their
      quality of life assessed by means of the short form-36 (SF-36) questionnaire.
      RESULTS: One hundred and fifteen patients were identified as having had an
      abdominal aortic aneurysm repaired as an emergency. Sixty patients died peri
      operatively and 19 subsequently. There were 28 patients available to complete the
      questionnaire, of whom 75% rated their global quality of life as good to
      excellent. Using the SF-36 questionnaire, there was no statistically significant
      difference between those patients who had undergone surgery (whether proven leak
      or not) and the age-matched healthy population. CONCLUSIONS: Quality of life
      remains good to excellent in the majority of patients following emergency
      abdominal aortic aneurysm repairs. This may help justify surgery being offered to
      patients with this condition. Quality of life should be considered as an
      important outcome rather than mortality only.

PMID- 10392891
TI  - Conservative surgery and radiation therapy for invasive lobular carcinoma of the
      breast.
AB  - BACKGROUND: There is debate as to whether infiltrating lobular carcinoma (ILC)
      can be effectively treated with breast conservative surgery (CS) and radiotherapy
      (RT) because of a perceived high risk of local recurrence. This retrospective
      study examined the outcome of patients with ILC treated by CS and RT. METHODS:
      Between November 1979 and December 1994, 57 women with UICC Stage I or II ILC
      were treated by CS and RT at Westmead Hospital, New South Wales, Australia. The
      median age was 55 years (range 28-79). Twelve patients (21%) underwent a re
      excision after initial CS. The final margins were clear for 43 patients (75.4%),
      positive (invasive or in situ) for nine patients (15.8%), and indeterminate for
      five patients (8.8%). All patients received whole-breast irradiation (45-50.4 Gy)
      usually supplemented by a boost (10-30 Gy). Fifty-three of 57 patients (93%) had
      their pathology reviewed at Westmead Hospital. RESULTS: After a median follow up
      of 69 months (range 36-162) three patients (5.3%) developed a local recurrence.
      One of 43 patients (2.3%) with known clear margins developed a local recurrence
      compared with two of 14 patients (14.3%) with positive or indeterminate margins
      (P = NS). The 5- and 10-year rates of freedom from local recurrence were 96 and
      93%, respectively. The 5-year disease-free survival was 85% (node-negative, 92%;
      node-positive, 66%). Overall survival was 94% at 5 years. No patient developed a
      contralateral breast cancer. CONCLUSION: Patients with ILC can be effectively
      treated with CS and RT.

PMID- 10392892
TI  - Waiting times for appointments with orthopaedic surgeons in Victoria: 1995-97.
AB  - BACKGROUND: A number of different models have been proposed for determining
      surgical workforce requirements. METHODS: In 1995 the Workforce Subcommittee of
      the Victorian Regional Branch of the Australian Orthopaedic Association commenced
      a prospective evaluation of waiting times for both urgent and nonurgent
      appointments with orthopaedic surgeons in Victoria. RESULTS: The results for the
      3 years, 1995-97, show no significant change in the waiting time for nonurgent
      appointments and no difference between metropolitan and rural areas. The waiting
      time for an urgent appointment increased from 1995 to 1997 for the state of
      Victoria and for metropolitan Melbourne but not for rural areas. However, the
      median waiting time for an urgent appointment did not change. CONCLUSION: Overall
      the waiting times were found to be satisfactory by previously reported standards.

PMID- 10392893
TI  - Phaeochromocytoma: experience from a referral hospital in southern India.
AB  - BACKGROUND: Phaeochromocytoma has been traditionally called the 'Tumour of Tens'.
      Many investigators have reported the prevalence of extra-adrenal
      phaeochromocytoma to be more than 10%. METHODS: All consecutive adult patients
      diagnosed to have phaeochromocytoma by the departments of endocrinology and
      surgical endocrinology of the Christian Medical Hospital, India, over a period of
      10 years from 1988 to 1998, were included in the study. RESULTS: A total of 30
      patients were diagnosed to have phaeochromocytoma. Extra-adrenal
      phaeochromocytoma accounted for 26.6% of cases, Ten per cent of cases were
      bilateral, 6.6% were malignant and one patient had a familial tumour (multiple
      endocrine neoplasia IIB). The tumours were localized pre-operatively in all
      patients. Multicentric extra-adrenal tumours were not found in this series. All
      patients except one were explored by the anterior transperitoneal approach.
      Persistent hypertension was noted in 30% of patients. CONCLUSIONS: Our series
      shows a higher prevalence (26.6%) of extra-adrenal tumours than the traditionally
      described 10%. With accurate pre-operative localization, a transperitoneal
      approach may not be necessary. The laparoscopic approach needs to be evaluated in
      light of these findings.

PMID- 10392894
TI  - Superficial thrombophlebitis: underlying hypercoagulable states.

PMID- 10392895
TI  - Successful reconstruction of left main bronchus following traumatic rupture.

PMID- 10392896
TI  - Torsion of the omentum: diagnosis and resection at laparoscopy.

PMID- 10392897
TI  - Inflammatory pseudotumour secondary to actinomyces infection.

PMID- 10392899
TI  - The Wilms' tumor suppressor, WT1, inhibits 12-O-tetradecanoylphorbol-13-acetate
      activation of the multidrug resistance-1 promoter.
AB  - Overexpression of P-glycoprotein, the product of the multidrug resistance-1
      (MDR1) gene, is associated with treatment failure in some hematopoietic tumors.
      Although expression of P-glycoprotein in normal hematopoietic cells is tightly
      regulated during hematopoietic differentiation, its aberrant overexpression in
      hematopoietic malignancies occurs at the transcriptional level. We have
      demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) increases
      transcription of the MDR1 gene and activates the MDR1 promoter, and that promoter
      activation by TPA requires binding of the zinc finger transcription factor EGR1
      to specific MDR1 promoter sequences (C. McCoy and M. M. Cornwell, Mol. Cell.
      Biol., 15: 6100-6108, 1995). We demonstrate here that the Wilms' tumor (WT)
      suppressor, WT1, a member of the EGR family, inhibits the response of the MDR1
      promoter to TPA in K562 cells. Inhibition is likely a direct effect of WT1
      binding to the MDR1 promoter because: (a) WT1 expression does not inhibit the
      increase in EGR1 after TPA treatment; (b) inhibition by WT1 requires the zinc
      finger domain; (c) WT1 binds to MDR1 promoter sequences that bind EGR1 and are
      responsive to TPA; and (d) there is an inverse correlation between WT1 protein
      expression and MDR1 expression and promoter activity. These results suggest that
      the MDR1 gene is a target for regulation by WT1 and suggest mechanisms by which
      MDR1 may be regulated by WT1 and EGR1 during normal and aberrant hematopoiesis.

PMID- 10392898
TI  - Beta- and gamma-catenin mutations, but not E-cadherin inactivation, underlie T
      cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and
      pancreatic cancer.
AB  - Adenomatous polyposis coli (APC) mutations are present in >70% of colon cancers.
      The APC protein binds to beta-catenin (beta-cat), a protein first identified
      because of its role in E-cadherin (E-cad) cell adhesion. In some colon cancers
      lacking APC defects, mutations in presumptive glycogen synthase kinase 3beta
      phosphorylation sites near the beta-cat NH2 terminus appear to render beta-cat
      resistant to regulation by APC and glycogen synthase kinase 3beta. In cells with
      APC or beta-cat defects, beta-cat is stabilized and, in turn, binds to and
      activates T-cell factor (Tcf)/lymphoid enhancer factor (Lef) transcription
      factors. To further explore the role of APC, beta-cat, Tcf, and E-cad defects in
      gastrointestinal cancers, we assessed gastric and pancreatic cancers for
      constitutive Tcf transcriptional activity (CTTA). Two of four gastric and two of
      eight pancreatic cancer lines showed CTTA. One gastric and one pancreatic cancer
      had mutations in the NH2-terminal phosphorylation sites of beta-cat. The other
      gastric cancer with CTTA had a missense mutation at serine 28 of gamma-cat, a
      potential phosphorylation site in this beta-cat-related protein. Although E-cad
      is an important binding partner for beta-cat and gamma-cat, E-cad inactivation
      did not result in CTTA. The beta-cat and gamma-cat mutant proteins identified in
      our studies strongly activated Tcf transcription in vitro, whereas beta-cat
      mutant proteins with large NH2-terminal deletions had only modest effects on Tcf.
      Our results suggest a role for Tcf deregulation in gastric and pancreatic cancer,
      resulting from beta-cat and gamma-cat mutations in some cases and, in others,
      from yet to be defined defects. Furthermore, these data imply that the
      consequences of APC and beta-cat mutations are distinct from the effects of E-cad
      inactivation.

PMID- 10392900
TI  - Nuclear c-Abl is a COOH-terminal repeated domain (CTD)-tyrosine (CTD)-tyrosine
      kinase-specific for the mammalian RNA polymerase II: possible role in
      transcription elongation.
AB  - The c-Abl tyrosine kinase has been shown to interact with the COOH-terminal
      repeated domain (CTD) of mammalian RNA polymerase II and can phosphorylate the
      tyrosine residues in the CTD. Interestingly, the Drosophila or the yeast CTD were
      not efficiently phosphorylated by the mammalian c-Abl. This species-specificity
      was found to be determined by the extreme COOH-terminal CTD sequences that are
      not conserved through evolution. In vitro, COOH-terminal-truncated CTD could
      neither bind to, nor be phosphorylated by, c-Abl. In vivo, coexpression of a full
      length CTD prevents c-Abl from inducing the tyrosine phosphorylation of
      endogenous RNA polymerase II, and such inhibitory effect was not observed with
      the coexpression of COOH-terminal-truncated CTD. Serine/threonine phosphorylation
      of the CTD has been linked to the regulation of transcription elongation.
      Transcription from the human immunodeficiency virus type 1 (HIV-1) promoter
      requires CTD-phosphorylation, which is stimulated by the viral Tat protein
      through the recruitment of cellular Ser/Thr CTD kinases. In transient
      cotransfection experiments, the c-Abl kinase was found to activate the HIV
      promoter in the absence of Tat. The activation of the HIV promoter required the
      nuclear localization of c-Abl and could be correlated with increased tyrosine
      phosphorylation of RNA polymerase II. These observations suggest that tyrosine
      phosphorylation of the CTD may be functionally equivalent to its serine/threonine
      phosphorylation in stimulating transcription elongation.

PMID- 10392901
TI  - Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes.
AB  - Cyclin D1 is widely believed to regulate progression through G1 phase of the cell
      cycle, and previous studies have shown that this protein is induced during
      hepatocyte proliferation in culture and in vivo. In this study, the role of
      cyclin D1 in the cell cycle of primary rat hepatocytes was further examined.
      Following epidermal growth factor stimulation, cyclin D1 was upregulated at time
      points corresponding to the mitogen restriction point, and this was associated
      with enhanced cyclin D1-associated kinase activity. To test whether cyclin D1
      expression was sufficient to promote mitogen-independent progression through the
      G1-S transition, we constructed a replication-defective adenovirus that
      overexpressed human cyclin D1. Transfection with the cyclin D1 vector but not a
      control vector resulted in hepatocyte DNA synthesis in the absence of growth
      factor that was similar to that seen in mitogen-treated cells. Furthermore,
      cyclin D1 transfection led to activation of downstream biochemical events,
      including cyclin A and proliferating cell nuclear antigen expression and cyclin E
      and cyclin A-associated kinase activation. These results suggest that cyclin D1
      expression is sufficient to promote progression of hepatocytes through the G1
      restriction point.

PMID- 10392902
TI  - Involvement of p27Kip1 in the G1- and S/G2-phase lengthening mediated by
      glucocorticoids in normal human lymphocytes.
AB  - Glucocorticoids inhibit cell proliferation by inducing cell cycle lengthening. In
      this report, we have analyzed, in normal peripheral blood lymphocytes, the
      involvement of p27Kip1 in this slowing of proliferation. Following dexamethasone
      (DXM) treatment, p27Kip1 expression and regulation varied differently with the
      level of lymphocyte stimulation. In quiescent cells, DXM inhibited p27Kip1
      protein expression by decreasing its rate of synthesis, whereas its half-life and
      mRNA steady state remained constant. In contrast, in stimulated lymphocytes, DXM
      increased p27Kip1 expression by enhancing its mRNA steady state. This increase is
      not only a consequence of the DXM-induced interleukin 2 inhibition: we also found
      an increase in p27Kip1 mRNA stability that was not observed in quiescent
      lymphocytes. Cyclin/cyclin-dependent kinase (CDK) complexes immunoprecipitated
      with p27Kip1 are differentially modified by DXM addition: (a) G1 kinasic
      complexes (cyclin D/CDK4 or CDK6) associated with p27Kip1 are strongly decreased
      by DXM, (b) S-phase complexes (CDK2/cyclin E and A) remained stable or increased,
      and (c) the association of p27Kip1 with the phosphorylated forms of CDK1 is
      increased by DXM. In addition, CDK2 kinase activity was decreased in DXM-treated
      cells: we suggest that p27Kip1 might participate in inhibiting its catalytic
      activity. These results indicated that, in normal lymphoid cells, p27Kip1 may be
      involved in DXM antiproliferative effects. The increase of p27Kip1 expression and
      a decrease in G1 mitogenic factors, together with the redistribution of p27Kip1
      to S/G2-M regulatory complexes, may explain the lengthening of G1 and S/G2 after
      DXM treatment in lymphocytes.

PMID- 10392903
TI  - Bovine papillomavirus E2 protein activates a complex growth-inhibitory program in
      p53-negative HT-3 cervical carcinoma cells that includes repression of cyclin A
      and cdc25A phosphatase genes and accumulation of hypophosphorylated
      retinoblastoma protein.
AB  - The bovine papillomavirus E2 protein can inhibit the proliferation of HT-3 cells,
      a p53-negative cervical carcinoma cell line containing integrated human
      papillomavirus type 30 DNA. Here, we analyzed HT-3 cells to explore the mechanism
      of p53-independent E2-mediated growth inhibition. Expression of the E2 protein
      repressed expression of the endogenous human papillomavirus type 30 E6/E7 genes.
      This was accompanied by hypophosphorylation and increased accumulation of p105Rb
      and repression of E2F1 expression. The E2 protein also caused reduced cyclin
      dependent kinase (cdk) 2 activity, but this did not appear to be due to increased
      expression of cdk inhibitors. Rather, expression of cyclin A, which regulates
      cdk2 activity, and the cdc25A and cdc25B phosphatases, which are thought to
      activate cdk2, was significantly reduced at both the RNA and protein levels in
      response to E2 expression. The E2 protein reduced expression of cdc25A and cdc25B
      in both HT-3 and HeLa cells, but not in cells that were not growth-inhibited by
      the E2 protein. E2 point mutants unable to inhibit cell growth did not repress
      cdc25A and cdc25B expression, nor did the cell cycle inhibitors hydroxyurea and
      mimosine. Based on these results and the known properties of cell cycle
      components, we propose a model to account for E2-induced growth inhibition of
      cervical carcinoma cell lines.

PMID- 10392904
TI  - Oncogene expression cloning by retroviral transduction of adenovirus E1A
      immortalized rat kidney RK3E cells: transformation of a host with epithelial
      features by c-MYC and the zinc finger protein GKLF.
AB  - The function of several known oncogenes is restricted to specific host cells in
      vitro, suggesting that new genes may be identified by using alternate hosts. RK3E
      cells exhibit characteristics of epithelia and are susceptible to transformation
      by the G protein RAS and the zinc finger protein GLI. Expression cloning
      identified the major transforming activities in squamous cell carcinoma cell
      lines as c-MYC and the zinc finger protein gut-enriched Kruppel-like factor
      (GKLF)/epithelial zinc finger. In oral squamous epithelium, GKLF expression was
      detected in the upper, differentiating cell layers. In dysplastic epithelium,
      expression was prominently increased and was detected diffusely throughout the
      entire epithelium, indicating that GKLF is misexpressed in the basal compartment
      early during tumor progression. The results demonstrate transformation of
      epithelioid cells to be a sensitive and specific assay for oncogenes activated
      during tumorigenesis in vivo, and identify GKLF as an oncogene that may function
      as a regulator of proliferation or differentiation in epithelia.

PMID- 10392905
TI  - 9-(2-Phosphonylmethoxyethyl)adenine induces tumor cell differentiation or cell
      death by blocking cell cycle progression through the S phase.
AB  - In addition to its inhibitory activity against viral DNA polymerases and reverse
      transcriptase, the acyclic nucleoside phosphonate 9-(2
      phosphonylmethoxyethyl)adenine (PMEA) also markedly inhibits the replicative
      cellular DNA polymerases alpha, delta, and epsilon. We have previously shown that
      PMEA is a strong inducer of differentiation in several in vitro tumor cell models
      and has marked antitumor potential in vivo. To elucidate the molecular mechanism
      of the differentiation-inducing activity of PMEA, we have now investigated the
      effects of the drug on cell proliferation and differentiation, cell cycle
      regulation, and oncogene expression in the human erythroleukemia K562 cell line.
      Terminal, irreversible erythroid differentiation of PMEA-treated K562 cells was
      evidenced by hemoglobin production, increased expression of glycophorin A on the
      K562 cell membrane, and induction of acetylcholinesterase activity. After
      exposure to PMEA, K562 cell cultures displayed a marked retardation of S-phase
      progression, leading to a severe perturbation of the normal cell cycle
      distribution pattern. Whereas no substantial changes in c-myc mRNA levels and
      p21, PCNA, cdc2, and CDK2 protein levels were noted in PMEA-treated K562 cells,
      there was a marked accumulation of cyclin A and, most strikingly, cyclins E and
      B1. A similar picture of cell cycle deregulation was also observed in PMEA
      exposed human myeloid THP-1 cells. However, in contrast to the strong
      differentiation-inducing activity of PMEA in K562 cells, the drug completely
      failed to induce monocytic maturation of human myeloid THP-1 cells. On the
      contrary, THP-1 cells underwent apoptotic cell death in the presence of PMEA, as
      demonstrated by prelytic, intracellular DNA fragmentation and the binding of
      annexin V to the cell surface. We hypothesize that, depending on the nature of
      the tumor cell line, PMEA triggers a process of either differentiation or
      apoptosis by the uncoupling of normally integrated cell cycle processes through
      inhibition of DNA replication during the S phase.

PMID- 10392906
TI  - Retinoic acid induces selective expression of phosphoinositide 3-kinase gamma in
      myelomonocytic U937 cells.
AB  - Retinoic acid provokes growth inhibition and differentiation of the human
      leukemic cell line U937 to macrophage-like cells. We report that treatment of
      U937 cells with all-trans retinoic acid (ATRA), but not the phorbol ester 12-O
      tetradecanoylphorbol-13-acetate, results in an increased gene expression of the
      phosphoinositide 3-kinase (PI3K) species PI3Kgamma. PI3Kgamma expression was
      transcriptionally elevated, indicating that the PI3Kgamma gene may be a direct
      target for ATRA. In contrast to its effect on PI3Kgamma expression, ATRA did
      neither affect the levels of the PI3K species beta and delta nor the adapter
      proteins p85 and p101. Enhanced expression by ATRA of PI3Kgamma correlated with
      an increase of PI3K lipid kinase activity. Additionally, ATRA induced significant
      and lasting stimulation of mitogen-activated protein kinase/Erk2 activity. This
      effect was sensitive to the PI3K inhibitors wortmannin or LY294002 and,
      therefore, attributed to the upregulation of PI3Kgamma expression. Our findings
      suggest that sustained MAPK activation via PI3Kgamma precedes ATRA -dependent
      differentiation or growth inhibition.

PMID- 10392907
TI  - Molecular biology for the pediatric surgeon.
AB  - Molecular biology is leading a revolution in our understanding, diagnosis, and
      treatment of disease and will continue to do so. Medicine in the future will
      require a greater understanding of this field and its methods by medical
      practitioners. This report reviews the basic aspects of the field including
      recombinant DNA methods. Of particular importance is how molecular biology will
      impact pediatric surgeons. Accordingly, the final section of this report briefly
      reviews the molecular biology of three diseases commonly treated by pediatric
      surgeons.

PMID- 10392909
TI  - Treatment of acute neonatal vascular injuries--the utility of multiple
      interventions.
AB  - BACKGROUND/PURPOSE: Vascular injuries in neonates are a rare complication of the
      varied invasive procedures performed in these small children. Unfortunately there
      remains a reluctance to repair these injuries early, often because of the
      relative small size of the affected vessels and the nature of the patient's
      underlying medical condition. The authors report a consecutive series of patients
      treated for arterial and venous injuries early in their course using a variety of
      microsurgical techniques. METHODS: A retrospective chart review was performed of
      consecutive patients (n = 7) treated over a 2-year period. All had injury as a
      result of invasive procedures performed in the neonatal period. Both arterial and
      venous injuries that required some form of intervention were included. RESULTS:
      Five arterial and two venous injuries were identified. Surgical thrombectomy and
      microvascular repair was required in two patients. Primary healing occurred
      despite prolonged (>13 hours) warm ischemia time. Pseudoaneurysms of the brachial
      artery and radial artery were controlled with surgical ligation, and one patient
      required bilateral fasciotomies for compartment syndromes related to severe spasm
      of the common femoral arteries. Phlegmasia cerulea dolens of the lower extremity
      (n = 2) was treated with leech therapy. All patients healed without tissue loss
      or functional deficit. CONCLUSIONS: A variety of microvascular interventions have
      application to the treatment of acute vascular injuries in neonates. Early,
      aggressive use of these techniques can provide effective therapy for these
      potentially devastating injuries and allow for complete limb recovery without
      tissue loss.

PMID- 10392908
TI  - The market for pediatric surgeons: a survey of recent graduates.
AB  - PURPOSE: The aim of this study was to identify the demand for pediatric surgeons
      as perceived and experienced by recent graduates of North American training
      programs. METHODS: A survey questionnaire was mailed to every pediatric surgeon
      who had completed a certified training program in the United States or Canada
      between 1992 and 1997; 84% of the 165 responded. The data were then analyzed
      using univariate and bivariate statistics and content analysis. RESULTS: The
      number trained has risen since 1992 from 21 to 35 per year, exceeding previous
      definitions of need. However, recently trained pediatric surgeons found
      positions, and their first-year incomes had risen oven the 6-year period. In
      contrast, just 54% found first positions in the type of hospital desired, and the
      percent working in a children's hospital dropped from 65% in 1992 to 32% in 1997;
      34% cover between four and ten hospitals. The majority of those in practice for
      more than 2 years expressed the perception of a decline in market demand with
      just 30% of those 1996 to 1997 graduates perceiving a strong market. The clinical
      scope of practice was less than that for which they were trained. Three specified
      complex cases were managed by fewer than 30% of recent graduates during practice
      despite more than 60% having had fellowship experience. The scope of practice, as
      measured by variables of index procedures, was strongly associated with hospital
      type (children's or general) and by practice region. Although satisfaction with
      practice is lower for each successive class, 96% of the graduates were satisfied
      with their training programs, and 98% believed they had been well prepared,
      although 46% indicated they desired some additional training. Sixty-one percent
      believed the role of pediatric surgeons will change over the next 5 years.
      CONCLUSIONS: The market demand was strong as measured by employment and income.
      This was in contrast to the striking recent changes in the market for new
      pediatric surgeons, including a migration of practice from children's to general
      hospitals, a reduced scope of practice, a more negative perception of the
      pediatric surgery market, and concerns for narrowing of the specialty.

PMID- 10392910
TI  - Iontophoresis: a needle-free, electrical system of local anesthesia delivery for
      pediatric surgical office procedures.
AB  - BACKGROUND/PURPOSE: Delivery of local anesthesia for surgical office procedures
      for pediatric patients can be difficult. Injections are painful and often lead to
      patient anxiety, and topical anesthetics frequently provide incomplete
      anesthesia. The authors prospectively studied the efficacy of iontophoresis, a
      needle-free technique in which positively charged lidocaine and epinephrine
      molecules are drawn into the tissue by an electrical current as an anesthetic for
      pediatric surgical office procedures. METHODS: Children undergoing an office
      procedure were offered local anesthesia via iontophoresis. Prospectively
      collected data included patient characteristics, procedure, iontophoresis dose
      and time, need for additional injected anesthetic, pain during the procedure as
      determined by a 0 to 5 faces scale, and complications. A satisfaction
      questionnaire was completed at the follow-up visit or by telephone. RESULTS: Over
      an 8-month period, 34 patients with a mean age of 6.8 years (range, 3 months to
      15 years) underwent 38 office procedures with anesthesia supplied through
      iontophoresis. Skin lesion excision (n = 14) and abscess drainage (n = 12) were
      the most common procedures. Seven patients required unplanned injected
      anesthetic. A small, superficial burn was the only complication. Sixty percent of
      patients and 84% of parents rated pain as 0 to 2 (zero to mild). Overall, 88%
      were satisfied with the anesthetic. CONCLUSION: Iontophoresis appears to be an
      effective and safe alternative method of local anesthesia delivery for pediatric
      surgical office procedures.

PMID- 10392911
TI  - Chronic right-lower-quadrant abdominal pain: is there a role for elective
      appendectomy?
AB  - BACKGROUND/PURPOSE: Chronic right-lower-quadrant abdominal pain is a frequent
      problem in the pediatric population. The purpose of this report is to detail the
      outcome of management of these patients with appendectomy. METHODS: Appendiceal
      colic was judged to be present if the history showed cramping abdominal pain in
      association with McBurney's point tenderness. This is a retrospective review of
      50 consecutive pediatric patients experiencing pain for greater than 1 year. All
      patients were evaluated at a single institution by one surgeon and underwent
      elective appendectomies from April 1985 through April 1997. RESULTS: Seventy-five
      percent of the patients were girls. One hundred forty-nine imaging and endoscopic
      studies were performed with 135 negative findings. Twenty-three patients had a
      minimum of one previous emergency room visit or hospitalization for the same
      abdominal complaints. The pathological findings were distinctly different from
      those of incidental appendectomies. Three patients had undergone previous
      diagnostic explorations for abdominal pain, the appendix was not removed, and a
      subsequent appendectomy relieved the discomfort. Forty-nine of the 50 patients
      were pain free at 1 year. CONCLUSIONS: Appendiceal colic is a clinical diagnosis.
      It is anticipated that patients with cramping abdominal pain associated with
      McBurney's point tenderness could undergo less preoperative workup and expedited
      resolution of the problem in the future.

PMID- 10392912
TI  - Experience with procedural sedation in a pediatric burn center.
AB  - BACKGROUND: Burn care requires daily debridement, dressing changes, and
      assessment regarding the need for skin grafting. These procedures are painful and
      may require an operating room environment. METHODS: The authors reviewed their
      experience with 912 consecutive procedural sedations (PS) in 220 pediatric burn
      patients over a 2-year period to identify what influence PS had on patient care.
      Median patient age was 32 months, and body surface area burn was 7.2%+/-6%.
      Pharmacological techniques included oral and intravenous medications and N2O. The
      authors included all sedations given in the burn treatment area and excluded all
      treatments given in the intensive care unit or emergency unit. RESULTS: PS
      allowed for early aggressive wound debridement, virtually eliminated the need for
      operating room debridement (used in only 22 patients), and eliminated patient
      discomfort and fear often associated with subsequent debridements. Burn wound
      related complications occurred in 54 patients and included wound infection (n =
      18), graft loss (n = 9), and pneumonia (n = 4). The incidence of PS complications
      was 7% with the most common problems including decreased arterial saturation (n =
      41), emesis (n = 11), and agitation (n = 8). No patient required intubation or
      transfer to an intensive care unit bed. The average length of stay (LOS) for all
      patients was 8.7+/-6.2 days, and 6.2+/-3.8 days in the 200 patients not admitted
      to the intensive care unit. This compares favorably with the 9.5-day LOS of
      patients treated in 1990. CONCLUSIONS: PS in burn patients allows for early
      aggressive debridement, decreases the use of the operating room for debridement,
      and a decrease in length of stay when compared with our previous burn patients.
      PS has a modest risk of complications, enhances the family's cooperation and
      satisfaction with health care provided, and should be an integral part of burn
      care in children.

PMID- 10392913
TI  - Postoperative ad lib feeding for hypertrophic pyloric stenosis.
AB  - PURPOSE: The aim of this study was to compare three methods of postoperative
      feeding after pyloromyotomy for hypertrophic pyloric stenosis (HPS). METHODS: The
      authors reviewed retrospectively the charts of 308 patients who underwent
      pyloromyotomy for HPS from 1984 to 1997. Nineteen patients had prolonged
      hospitalization for other reasons and were excluded from the study, leaving 289
      patients for analysis. All procedures were performed by a single group of
      pediatric surgeons. The individual preferences of these surgeons resulted in
      three different feeding schedules: R, strictly regimented (>12 hours nothing by
      mouth, then incremental feeding over > or =24 hours), I, intermediate (>8 hours
      nothing by mouth, then incremental feeding over <24 hours), or A, ad lib (< or =4
      hours nothing by mouth, with or without a single small feeding, then ad lib
      feedings). RESULTS: Of the 289 patients, 248 (80.5%) were boys. The average age
      of the patients was 5.64 weeks (range, 1 to 21 weeks). A total of 265 of 289
      (92%) were full term. Thirty-nine of 289 (13.5%) had a family history positive
      for pyloric stenosis. A total of 104 of 289 (36%) were first-born infants, 89 of
      289 (31%) were second born. The diagnosis of pyloric stenosis was made by a
      combination of physical examination findings and diagnostic image for most
      patients. An "olive" was palpated in 60.6% of the patients. Sixty percent (60.4%)
      of patients had an upper gastrointestinal series performed, and 42.5% were
      examined by ultrasonography. Overall, 53% of the patients had postoperative
      emesis. Only 3.5% had emesis that persisted greater than 48 hours after surgery.
      Patients fed ad lib after pyloromyotomy had slightly more emesis (2.2 A v. 1.2 R,
      and 0.7 I episodes, P = .002), but tolerated full feedings sooner than patients
      fed with a regimented or intermediate schedule. No patient required additional
      therapy or readmission after tolerating two consecutive full feedings, suggesting
      that this might be a suitable discharge criterion for most patients with HPS.

PMID- 10392914
TI  - Cellular activity in the gallbladder of children with anomalous arrangement of
      the pancreaticobiliary duct.
AB  - BACKGROUND/PURPOSE: Anomalous arrangement of the pancreaticobiliary duct (AAPBD)
      is closely related to congenital biliary dilatation and frequently associated
      with biliary tract malignancy. To examine the mechanism of biliary tract
      carcinogenesis in patients with AAPBD, we investigated histologically the early
      changes in cell proliferative kinetics of the gallbladder mucosa of children with
      AAPBD. METHODS: Twenty-three specimens of gallbladder were obtained from 23
      children with AAPBD, and six control specimens were obtained from pediatric
      patients. All specimens were fixed routinely and paraffin embedded and examined
      histologically with H&E staining and immunohistochemically with monoclonal
      antibody Ki-67(MIB-1), which reacts with a human nuclear antigen associated with
      cell proliferation. Ki-67 labeling index (Ki-67 LI) was obtained by counting the
      numbers of Ki-67-positive cells per 1,000 gallbladder epithelial cells. RESULTS:
      Significant differences in Ki-67 LI were noted between children with and without
      AAPBD. Furthermore, Ki-67 LI and the incidence of epithelial hyperplasia of
      gallbladder were significantly higher in children with AAPBD in whom the major
      pancreatic duct joined the common bile duct (P-C type) than in those in whom the
      common bile duct joined the major pancreatic duct (C-P type). CONCLUSIONS:
      Cellular proliferative activity was increased in children with AAPBD, especially
      those with the P-C-type anomaly. These results suggest that the early mucosal
      changes of the gallbladder occurred in early childhood of patients with AAPBD and
      might be associated with gallbladder cancer. Early diagnosis and early surgical
      division of the biliary tract and pancreatic duct is recommended for children
      with AAPBD.

PMID- 10392915
TI  - Lymph node sampling in localized neuroblastoma: a Pediatric Oncology Group study.
AB  - BACKGROUND/PURPOSE: Lymph node (LN) sampling was required by the Pediatric
      Oncology Group (POG) staging for neuroblastoma and currently is required as a
      part of the International Neuroblastoma Staging System (INSS). This retrospective
      study of planned lymph node sampling in patients with localized neuroblastoma was
      carried out with the intent of assisting surgeons in carrying out this procedure.
      The report documents the POG experience where LN, both uninvolved and involved
      with tumor, were found based on site of primary. METHODS: From 391 patients with
      localized neuroblastoma of the abdomen, chest, and neck, 238 patients had LN
      sampling at the primary operation, and these patients constitute the major part
      of the study. In addition, 89 patients had a carefully documented search for LN,
      and 64 had neither search nor biopsy. The operative note, pathology report, and
      surgical study sheet were used in the 238 patients based on the site of the
      primary tumor to determine which nodal groups or basins underwent biopsy, and in
      which groups tumor was found. RESULTS: The pattern of drainage, based on the
      primary site of abdominal tumors, favored an arterial rather than venous pathway.
      Primary tumors and metastatic LN were more numerous on the left side. The
      abdominal drainage followed three pathways: (1) infrarenal tumors from the left
      and midline were associated with paraaortic LN; (2) right infrarenal tumors were
      associated with LN in the paracaval basin; (3) with suprarenal primaries and with
      both adrenals, the superior mesenteric-portal-celiac basins were most productive
      for nodal sampling. Tumor was found most frequently in the left adrenal-renal
      basin and in the paraaortic basin. The actual number of LN sampled in a single
      case varied from 1 to 19 LN, with a mean number of LN based on stage and primary
      from one to seven LN. The tumor spread in LN was consistent with a "watershed"
      course, but this was not statistically significant. Patients for whom LN were
      sought had a better outcome, contrasting with the patients in whom LN were not
      sought or in whom nodal sampling was not possible. CONCLUSIONS: The experience in
      this study is consistent with previous descriptions of the lymphatic drainage of
      the retroperitoneal area. Delineation of the various basins as they relate to the
      site of the primary tumor should assist the surgeon in lymph node sampling. The
      role of LN involvement still remains unclear in the light of current studies of
      biological factors and histopathology as determinants of "risk groups." It is
      hoped that this study will enable ongoing and future studies to clarify this
      problem. The adult experience with breast cancer and with melanoma has indicated
      a continued importance of anatomic factors (including LN status) along with
      biological factors.

PMID- 10392916
TI  - Prolonged intestinal exposure to amniotic fluid does not result in peel formation
      in gastroschisis.
AB  - The etiology of bowel wall changes in infants with gastroschisis remains unknown.
      Currently, debate focuses on the relative roles of amniotic fluid exposure versus
      that of intestinal ischemia. The authors report five cases of prenatally
      diagnosed gastroschisis in which the bowel was exposed to amniotic fluid for up
      to 21.3 weeks without developing any visible intestinal peel. These cases appear
      to minimize the role of prolonged amniotic fluid exposure in the development of
      bowel wall changes in gastroschisis.

PMID- 10392917
TI  - Ovary in hernia sac: prolapsed or a descended gonad?
AB  - BACKGROUND/PURPOSE: The ligament that lies in the inguinal hernia sac of girls is
      known to be the round ligament and is described as homologous to the male
      gubernaculum. An ovary in a hernia sac might be assumed to mimic descent of the
      testis. The aim of this study is to determine whether this ligament has a role in
      final ovarian position. METHODS: Samples of peritoneal tissues containing the
      ligament were obtained from 15 female infants and children who underwent inguinal
      hernia repair. Tissue specimens were evaluated through histopathologic and
      immunohistological analyses. RESULTS: The ligament consists of striated and
      smooth muscle fibers, abundant nerves, and vessels. Estrogen receptors (ER) and
      progesterone receptors (PR) were identified in submesothelial stromal and smooth
      muscle cells. No androgen receptors (AR) were found. CONCLUSIONS: Although its
      termination in the processus vaginalis is not found to be consistent with the
      classical description of the round ligament, localization of ERs and PRs prove
      that the ligament is a target organ influenced by hormones. Because the round
      ligament is supposed to be the female gubernaculum that has an altered anatomy
      and localization because of absence of androgen responsiveness, its modified
      presentation in a processus vaginalis raises the suspicion that the ovary in a
      hernia sac may not simply be prolapsed, but is a descended gonad.

PMID- 10392918
TI  - The effect of left-to-right shunting on coronary oxygenation during
      extracorporeal membrane oxygenation.
AB  - BACKGROUND/PURPOSE: Blood perfusion to the coronary artery (CA) during
      venoarterial (VA) extracorporeal membrane oxygenation (ECMO) was examined to
      determine whether it was receiving highly oxygenated ECMO blood or desaturated
      blood from the pulmonary circulation of diseased lungs. METHODS: In the first
      experiment, left ventricle output and oxygen saturation in the left ventricle
      (LV) and CA were measured in dogs placed on VA ECMO. In the second experiment,
      dogs with an artificial subclavian-pulmonary artery shunt were placed on VA ECMO
      at 100 mL/kg/min, and oxygen saturation was measured as the shunt flow increased.
      RESULTS: Without an artificial shunt, a substantial portion of coronary perfusion
      was found to be supplied by the left ventricle (54 + 30%), even at a high ECMO
      flow rate of 100 mL/kg/min and low LV output (22+/-17%) relative to ECMO flow.
      With a shunt, oxygen saturation in the CA was more than 95%, even when shunt flow
      was only 7.5% of ECMO flow and output from the left ventricle was less than 25%
      of the ECMO flow rate. CONCLUSIONS: These results suggest that an excessive "lung
      rest" strategy during VA ECMO may produce suboptimal coronary oxygenation
      possibly leading to myocardial damage. The presence of a small left-to-right
      shunt may prevent coronary hypoxia.

PMID- 10392919
TI  - Localization of calcitonin gene-related peptide within the genitofemoral nerve in
      immature rats.
AB  - BACKGROUND/PURPOSE: Calcitonin gene-related peptide (CGRP) has been proposed to
      influence migration and testicular descent by release from the genitofemoral
      nerve. The site of CGRP within the nerve has been controversial, with conflicting
      views on whether CGRP is synthesised and released from the motor nerves. METHODS:
      The genitofemoral nerve (GFN) was retrogradely labelled by fluorescent dye (DAPI)
      in 25 Sprague-Dawley rats (days 5, 16, and 31, n = 8 in each group; day 35, n =
      1). Spinal cords and dorsal root ganglia (DRG) were removed two to three days
      later and sectioned for immunofluorescence. Substance P and CGRP-containing cells
      were labelled with fluorescein-linked antibodies. Specimens were examined by
      double fluorescence to identify cells with both markers. RESULTS: The motor
      nucleus of the GFN contained 119 cells on day 7 and 284 cells by days 19 through
      34. A prominent band of CGRP-containing fibers, arising from the dorsal horn,
      synapsed with the GFN motor nucleus itself. CGRP-labelled GFN cells were found in
      the DRG by double labelling. CONCLUSIONS: CGRP from the GFN may affect
      gubernacular migration by release from the sensory nerves, rather than motor
      nerves as previously thought. The GFN motor nucleus receives CGRP-containing
      innervation from the dorsal horn, which may form part of the cremasteric reflex.

PMID- 10392920
TI  - A combined tubularized/onlay graft technique for total correction of severe
      hypospadias.
AB  - BACKGROUND/PURPOSE: A combined tubularized/onlay graft technique is described for
      the complete correction of chordee with urethroplasty in a single stage in cases
      of severe hypospadias. METHODS: Twenty-two patients with severe hypospadias
      ranging in age from 9 months to 11 years underwent single-stage correction using
      a technique developed by the author. In this method, chordee is first completely
      excised by removing all fibrotic tissue both proximal and distal to the urethral
      orifice, preserving the meatal groove. A dorsolateral preputial flap is then
      raised and tubularized to form the neourethra. The proximal end of this tube is
      anastomosed to the urethral opening using a continuous absorbable suture. Two
      parallel incisions are made in the glans on either side of the meatal groove. The
      distal part of the neourethral flap is laid over the groove and sutured on either
      side to create the glanular part of the urethra, after which the glans is
      reconstructed with the new meatal opening at the tip. The neourethral suture line
      is covered with a layer of vascularized subcutaneous tissue to protect against
      fistula formation, and the rest of the preputial skin is transferred ventrally to
      provide cover for the penile shaft. RESULTS: There were no major complications
      with minimum follow-up of 20 months. Meatal stenosis developed in two patients,
      and one had stricture at the proximal anastomosis. These were treated
      successfully with minor corrective procedures. All other patients had good
      results, and there were no cases of fistula. CONCLUSIONS: The method described
      has proved successful in the surgical correction of severe hypospadias in a
      single stage. It is easily adapted to permit urethral reconstruction after
      varying degrees of tissue excision required to obtain satisfactory correction of
      chordee. Patients do not need to undergo multiple procedures, and no major
      complications were encountered in this series.

PMID- 10392922
TI  - Testicular-sparing surgery for benign testicular tumors.
AB  - BACKGROUND/PURPOSE: Although there has been a precedent of testicular-sparing
      surgery in some centers, the authors find it is still not general practice among
      pediatric surgeons. To address this and emphasize the role of testicular-sparing
      surgery in children, four patients with testicular masses are presented who
      underwent this procedure. METHODS: Four patients who underwent testicular-sparing
      surgery between the years 1993 and 1998 were reviewed. Demographic data,
      histopathology, and follow-up data were obtained from office charts. The period
      of follow-up ranged from 1 to 5 years. RESULTS: Four patients whose ages at
      diagnosis were 1, 2, 4, and 17 years presented with unilateral testicular masses.
      The alpha-fetoprotein and beta-human chorionic gonadotropin levels were within
      normal limits. Testicular ultrasonography was carried out on all patients, and
      groin exploration with spermatic cord isolation was performed in each case. After
      enucleation, frozen sections to confirm benignity was carried out before repair
      of the testis. Follow-up of 6 months to 5 years has shown no recurrence, and on
      examination, testicular volume is normal in all cases. CONCLUSIONS: Testicular
      sparing surgery preserves testicular volume, which is important for both cosmetic
      and functional purposes. It is a viable and useful method in the management of
      benign testicular tumors in children.

PMID- 10392921
TI  - Renal effects of low to moderate doses of dopamine in newborn piglets.
AB  - PURPOSE: Administration of dopamine to adult animal and human subjects results in
      increased renal blood flow, and it may also enhance the glomerular filtration
      rate. However, renal hemodynamic effects of exogenous dopamine in the neonate are
      unclear. In this study, we examined the renal actions of low to moderate doses of
      exogenous dopamine in newborn piglets. METHODS: The animals were anesthetized,
      catheterized for vascular access and urine collection, and assigned randomly to a
      control group or treatment groups receiving dopamine infusion at 2, 5, or 10
      microg/kg/min. Data were collected at baseline, during dopamine infusion, and 1
      hour after cessation of infusion. Mean arterial blood pressure (MAP) and heart
      rate (HR) were monitored. Glomerular filtration rate (GFR), cardiac index (CI),
      and renal blood flow (RBF) were determined. Fractional excretion of sodium (FENa)
      was calculated. RESULTS: Dopamine did not alter renal blood flow nor did it
      significantly alter CI in spite of a modest increase in heart rate and mean
      arterial blood pressure. There was a statistically significant increase in GFR at
      10 microg/kg/min and in FENa at all doses. CONCLUSIONS: Low doses of dopamine
      produce significant natriuresis probably by direct action on renal tubules and at
      moderate doses via, both, increase in GFR and a direct tubular effect. Low and
      moderate doses of dopamine do not increase RBF as seen in adult animals, possibly
      because of immaturity of dopaminergic receptors in newborn piglets.

PMID- 10392923
TI  - New animal model to evaluate testicular blood flow during testicular torsion.
AB  - BACKGROUND/PURPOSE: Unilateral testicular torsion is known to cause infertility
      because of damage to the contralateral testis. Testicular damage has been
      attributed to many different mechanisms, one of which is altered contralateral
      blood flow. In our experiment, in an effort to identify the reason for
      contralateral testicular injury, the authors developed an accurate method of
      measuring blood flow in both testes before, during, and after unilateral torsion.
      METHODS: Four- to 6-week-old piglets weighing 4 to 6 kg were studied. The animals
      were anesthetized, intubated, ventilated, and catheterized for vascular access.
      Piglets were assigned randomly to a sham group or a group undergoing 360 degrees
      or 720 degrees torsion of the left testis (n = 5 per group) for 8 hours, after
      which it was untwisted. Data were collected at baseline (T = 0), 8 hours of
      torsion (T = 8), and 1 hour after detorsion (T = 9). Mean arterial blood pressure
      and heart rate were monitored continuously. Testicular blood flow was determined
      using radiolabeled microspheres. Blood flow data were evaluated by analysis of
      variance. RESULTS: In the 360 degrees torsion group, blood flow changes were
      insignificant during torsion and after detorsion. In the 720 degrees torsion
      group, blood flow to the twisted testis was reduced significantly, whereas the
      contralateral testis was unaffected. One hour after detorsion, blood flow to both
      testes was increased significantly. CONCLUSIONS: The authors describe a new
      animal model to evaluate testicular blood flow during and after testicular
      torsion. Increased blood flow after detorsion may be the cause of testicular
      damage in patients with unilateral testicular torsion.

PMID- 10392924
TI  - Experimental small bowel transplantation using newborn intestine in rats: I.
      Lipid absorption restored after transplantation of nonvascularized graft.
AB  - BACKGROUND/PURPOSE: Utilizing the characters of neovascularized activity of
      newborn organs, the authors developed a rat model of small bowel transplantation
      with a free graft of newborn intestine into the recipient's omentum. METHODS:
      Segmental intestine from newborn rats were grafted into the omentum without
      vascular anastomosis in a syngeneic combination (n = 19). The transplanted
      intestine was examined morphologically and electrophysiologically 4 weeks after
      grafting. Then, recipients' small intestine was totally substituted by the
      transplanted newborn intestine, and recipients' survival was recorded after
      orthotopical reconstruction. During the experimental periods, feces of these rats
      were collected, and total lipid excretion was measured. The short-gut rats, whose
      small bowel was totally resected, served as a control (n = 12). RESULTS: Thirteen
      of 19 grafts (68.4%) were judged as a histologically mature intestine. They
      showed typical slow waves that were identical to those of native small intestine.
      After all of the mature grafts were interposed, six recipients (46.2%) survived
      longer than 15 weeks. Control short gut animals severely lost weight and died
      except for one. CONCLUSION: Newborn intestinal transplantation could restore
      severe weight loss in the short-gut rats and save them.

PMID- 10392925
TI  - Surgical indications for patients with hyperammonemia.
AB  - BACKGROUND/PURPOSE: The authors surgically treated seven of eight patients with
      congenital portosystemic shunt and hyperammonemia. This entity is uncommon in
      children. METHODS: The patients included five boys and three girls with a mean
      age of 8 years (range, 7 months to 24 years). Preoperative symptoms included
      hyperammonemia. Hepatic encephalopathy was evident in five patients. Diagnosis
      and assessment were made by ultrasound scan, magnetic resonance imaging (MRI),
      angiography, and 123 I-iodoamphetamine per-rectal portal scintigraphy. Surgical
      banding was done for five patients and transvenous coil embolization for two. One
      patient was not a surgical candidate because there were no intrahepatic portal
      veins. RESULTS: In four of the five patients treated using surgical banding, and
      in both patients who underwent coil embolizations, hyperammonemia and clinical
      symptoms improved soon after surgery. However, in the remaining patient,
      hyperammonemia worsened after surgery, and reoperation was needed because of a
      severe portal hypertension, possibly caused by malconformation of hepatic veins.
      CONCLUSIONS: For patients with congenital portosystemic shunt, early diagnosis
      and surgery are needed to prevent damage to central nerves caused by persistent
      hyperammonemia. Maldevelopment of the intrahepatic portal veins is a surgical
      option, if the patient has a normal liver architecture, but malconformation of
      hepatic veins or severe anomalies such as cardiac defects would rule out surgical
      intervention.

PMID- 10392926
TI  - Intussusception: the accuracy of ultrasound-guided saline enema and the
      usefulness of a delayed attempt at reduction.
AB  - BACKGROUND/PURPOSE: The aim of this study was to evaluate the therapeutic value
      of ultrasound (US)-guided saline enema for intussusception and the usefulness of
      a delayed attempt after at least 30 minutes when reduction has not been complete.
      METHODS: One hundred ninety-five cases of intussusception were diagnosed with
      ultrasonography. US-guided saline hydrostatic reduction was performed in 194 with
      an additional attempt after at least 30 minutes in those cases in which only
      partial resolution had been achieved. The method was changed (the volume of the
      reservoir bag and the caliber of the catheter were increased) so we analyze two
      different periods; 85 cases are included in the first period and 110 in the
      second. RESULTS: The global rate of successful reduction was 81.9% (159 of 194
      cases), and it raised to 88.2% (97 of 110 cases) in the second period. In 15.5%
      cases (30 of 194) reduction was achieved in a delayed attempt at least 30 minutes
      after the initial partial resolution. The rate of recurrence was 9.7%. No
      perforation was seen. CONCLUSIONS: The accuracy of US-guided saline enema in
      achieving intussusception reduction is high, similar to other methods, avoiding
      radiation exposure. A delayed attempt after a period of rest increases the rate
      of reductions.

PMID- 10392927
TI  - Simple incision: a safe and definitive procedure for congenital duodenal
      diaphragm.
AB  - BACKGROUND: Duodenal diaphragms generally are treated by either a duodeno
      duodenostomy or excision. The former is a bypass procedure that involves a major
      anastomosis with its inherent postoperative problems, whereas the latter may
      result in inadvertent damage to the biliary and pancreatic ducts. To circumvent
      these problems, the authors used the technique of incision of the diaphragm on
      its lateral aspect. METHODS: Medical records of five children who underwent
      surgery for a perforate duodenal diaphragm during the period of 1992 through 1994
      were reviewed retrospectively. All patients underwent a similar procedure. A
      longitudinal duodenotomy was made and the diaphragm incised on its anterolateral
      aspect. The cut edges of the diaphragm were oversewn, and the duodenotomy closed
      in "Heineke-Mikulicz" fashion. RESULTS: At a follow-up ranging from 1 to 3 years,
      all patients are growing normally and remain free of any obstructive symptoms.
      CONCLUSIONS: This simplified approach is a safe and physiological way of
      restoring the duodenal continuity and is associated with a highly satisfactory
      outcome.

PMID- 10392928
TI  - Extraosseous osteogenic sarcoma--a rare pediatric malignancy: case report and
      review of the literature.
AB  - BACKGROUND: Osteogenic sarcoma rarely occurs in soft tissues and generally
      affects individuals beyond the second decade of life. METHODS: The authors report
      a rare case of an extra osseous osteogenic sarcoma arising in the retroperitoneum
      of an adolescent, review the literature, and outline the diagnostic and
      therapeutic dilemmas. The role of adjuvant chemotherapy, using drugs used in
      managing bony osteosarcomas, is discussed. CONCLUSIONS: Retroperitoneal sarcomas
      may simulate ovarian teratomas. Careful consideration of the differential
      diagnosis of large cystic abdominal masses in adolescent females when size
      precludes adequate assessment of tumor mobility and imaging fails to demonstrate
      the ovaries is essential if these rare tumors are to be managed effectively.

PMID- 10392929
TI  - Successful nonoperative management of neonatal acute calculous cholecystitis.
AB  - Acute cholecystitis in the neonate is rare and usually treated by
      cholecystectomy. A 1-day-old full-term girl had clinical and sonographic features
      of acute calculous cholecystitis. This was successfully managed nonoperatively
      with intravenous fluids and antibiotics, leading to complete resolution of the
      condition. The infant currently is thriving and asymptomatic with a
      sonographically normal biliary tree. Spontaneous resolution of cholelithiasis may
      occur in neonates, even in the presence of acute cholecystitis.

PMID- 10392930
TI  - Successful coil embolization in an infant with congenital intrahepatic
      portosystemic shunts.
AB  - The authors report the case of a 7-month-old Japanese infant with congenital
      intrahepatic portosystemic shunts. He had hypergalactosaemia and hyperammonemia
      at age 1 month. The diagnosis was made by ultrasonography and angiography. Coil
      embolization was performed successfully, and then hyperammonemia and
      hypergalactosaemia improved soon after surgery.

PMID- 10392931
TI  - Pulmonary lymphomatoid granulomatosis in a 4 year old.
AB  - The authors report a pulmonary lymphomatoid granulomatosis (LG) in a 4-year-old
      girl. The clinicopathologic and radiological features of this rare entity are
      discussed with special emphasis on differential diagnosis, including a brief
      literature review. LG is an aggressive multiorgan disease that primarily affects
      the adult lung. There are no specific presumptive clinical and laboratory
      findings, including tumor markers and imaging techniques, that distinguish LG
      from other pulmonary nodular lesions. The most important diagnostic aid is to
      bear this entity in mind when a child presents with pulmonary nodule associated
      with intractable long-lasting symptoms. Open lung biopsy and total excision is
      mandatory for the appropriate diagnosis and treatment.

PMID- 10392932
TI  - Congenital tracheal anomalies in the craniosynostosis syndromes.
AB  - The authors present the case of a 12-year-old girl with Pfeiffer's syndrome who
      underwent successful resection of a tracheal cartilaginous sleeve (TCS) for
      treatment of sleep apnea. There is growing recognition of the inclusion of TCS in
      the spectrum of congenital cartilage malformations seen in patients with
      craniosynostosis (CS) syndromes. This case demonstrates the difficult therapeutic
      challenge created by the combination of hypopharyngeal and intrinsic airway
      abnormalities present in CS patients. The early recognition of TCS in these
      patients may provide the opportunity for improved outcome in this severely
      affected subgroup of CS patients with otherwise high mortality.

PMID- 10392933
TI  - Multiple atresias in a low-birth-weight twin.
AB  - This report describes a case of 16 small bowel atresias in a twin who was born at
      31 weeks' gestation, weighing 1,690 g. All atresias and intestinal segments of 5
      cm or less in length were resected, resulting in nine primary anastomoses,
      preserving 75% (107 cm) of his initial small bowel length. The baby went home on
      full oral feedings after 10 weeks. Multiple anastomoses in the low-birth-weight
      neonate can be tolerated with the functional benefit of maximal bowel length. The
      time taken to tolerate feedings appears to be independent of the number of
      anastomoses. Vascular anastomoses associated with monochorionic twinning may
      place both fetuses at risk of intestinal atresia in the event of an ischemic
      insult, either concurrently or with the demise of one affecting the other.
      Prenatal ultrasound scan appears to be useful for monitoring the evolution of
      intestinal atresia. However, the risks of extreme prematurity preclude the
      delivery of the affected baby at the time of initial diagnosis, and as yet it is
      unknown whether early delivery will alter the number, type, or prognosis of
      multiple atresias.

PMID- 10392934
TI  - Surgical pathology reports from 7,314 male patients who underwent inguinal
      herniorrhaphy.

PMID- 10392935
TI  - The 1999 Charles T. Dotter Lecture. Interventional radiology 2000 and beyond:
      back from the brink.

PMID- 10392936
TI  - Stents for atherosclerotic renovascular disease.
AB  - There is extensive documentation of excellent clinical results with renal stents
      in patients who have technically failed angioplasty and who would have been
      expected to otherwise have a high incidence of clinical failure. In addition, the
      technical success of renal stents is vastly superior to that of conventional
      angioplasty in atherosclerotic renovascular disease, and stents have been a major
      factor in making the endovascular treatment of ASRVD both practical and reliable
      in experienced hands. Restenosis rates appear roughly equivalent or lower for
      stents versus PTA as far as can be determined without good comparative studies.
      Restenosis appears to be decreasing to 15%-20% in more recent series, perhaps
      because of the accumulation of knowledge regarding patient selection and
      techniques. It is, therefore, clear that the use of stents to treat technical
      failures of angioplasty will result in overall improved patency in the treated
      population; however, it remains to be determined whether stents should be
      routinely placed with the intention of inhibiting restenosis, in the presence of
      technically successful angioplasty with minimal residual stenosis or pressure
      gradient. Such a determination may require comparative study that is more
      complicated than a simple randomized comparison of angioplasty versus stents.

PMID- 10392937
TI  - Clinical outcomes of patients after a negative spiral CT pulmonary arteriogram in
      the evaluation of acute pulmonary embolism.
AB  - PURPOSE: To examine 6-month clinical outcomes of patients after acquisition of a
      spiral computed tomography (CT) pulmonary arteriogram interpreted as negative for
      acute pulmonary embolism (PE). MATERIALS AND METHODS: A retrospective review was
      performed on a consecutive series of 143 patients who underwent spiral CT
      pulmonary arteriography for possible acute PE during a 19-month period. All
      studies were performed on a HiSpeed Scanner with use of 3-mm collimation with a
      pitch between 1.3 and 2.0, depending on patient size. All imaging was performed
      during dynamic contrast material injection at rates between 3.0 and 4.0 mL/sec,
      timed to peak pulmonary arterial enhancement. For the studies interpreted as
      negative for PE through the segmental (fourth order) pulmonary arteries, follow
      up data were collected by telephone interviews with patients or surviving
      relatives, and by medical record reviews. RESULTS: Among 143 patients, 22 studies
      (15%) were positive for PE, eight (6%) were suboptimal to exclude PE to the
      segmental artery level, and 113 (79%) were interpreted as negative for acute PE.
      Among the 113 negative studies, 13 patients were lost to follow-up, leaving a
      study population of 100 patients. Eighty-one patients were alive a minimum of 6
      months after acquisition of a negative spiral CT pulmonary arteriogram (mean, 9
      months; range, 6-24 months) and were without interim diagnosis of PE. Nineteen
      patients died within the follow-up period after a negative spiral CT pulmonary
      arteriogram (mean, 3 months; range, 0-8 months); however, in none of these cases
      was acute pulmonary embolus reported as the cause of death. No documented PE was
      identified by subsequent imaging studies or autopsy within the study population.
      CONCLUSION: A series of 100 patients with a negative spiral CT pulmonary
      arteriogram did not experience significant morbidity and mortality as a result of
      pulmonary embolic disease within a 6-month follow-up period.

PMID- 10392938
TI  - Popliteal artery entrapment syndrome: arteriographic findings and thrombolytic
      therapy.
AB  - PURPOSE: To review the arteriographic appearance of popliteal artery entrapment
      syndrome (PAES) and functional popliteal artery entrapment, and determine the
      role of thrombolysis in the treatment of these disorders. MATERIALS AND METHODS:
      Retrospective review of hospital records from 1991 to 1998. RESULTS: Seven
      patients with PAES and one with functional entrapment were identified. The
      popliteal artery was occluded in two limbs and compressed in 13. Active plantar
      flexion was necessary to demonstrate impingement in nine limbs. Medial deviation
      of the popliteal artery was evident in six of 14 patent popliteal arteries, and
      lateral deviation was observed in one limb. "Classic" abrupt medial angulation of
      the popliteal artery was observed in one limb. Both limbs were involved in all
      six patients who underwent bilateral popliteal exploration. Thrombolytic therapy
      was performed in three limbs. In two instances, it permitted a less extensive
      surgical procedure than would otherwise have been required. CONCLUSIONS: There is
      considerable variability in the arteriographic appearance of PAES, which is
      arteriographically indistinguishable from functional entrapment. It is frequently
      bilateral. Thrombolytic therapy does not obviate surgery but may permit a less
      extensive procedure to be performed.

PMID- 10392939
TI  - Digital subtraction angiography of the abdominal aorta and lower extremities:
      carbon dioxide versus iodinated contrast material.
AB  - PURPOSE: To compare the diagnostic value of carbon dioxide to that of iodinated
      contrast material for digital subtraction angiography of the abdominal aorta and
      lower extremities. MATERIALS AND METHODS: Thirty-five patients underwent
      comparative CO2 and iodinated contrast material arteriography of the abdominal
      aorta and lower extremities. For each contrast study, three independent observers
      evaluated the degree of opacification and percentage of stenosis of each vessel,
      the degree of certainty of their observations, and the overall quality of the
      study. Data of CO2 and iodinated studies were compared using analysis of variance
      for repeated measures. Interobserver and intertechnique agreements were estimated
      with Cohen's kappa and intraclass correlation coefficient. RESULTS: Iodine-based
      vascular opacification was superior to that with CO2 in the central and distal
      arteries (P = .02). The degree of certainty and overall quality score were higher
      for iodine than for CO2-based contrast studies (P = .00001). The interobserver
      agreement for categorizing stenoses was higher for iodine as compared to CO2
      based angiography. No significant difference was observed between the mean
      stenosis values obtained with CO2 and iodine-based angiography in any segment.
      Intraclass correlation coefficient demonstrated a high degree of convergence of
      the two techniques for assessing the percentage of stenosis. CONCLUSION: CO2 can
      be used as an alternative to iodinated contrast material for obtaining
      arteriograms of the abdominal aorta and lower extremities for investigating
      atherosclerotic disease.

PMID- 10392940
TI  - Evaluation of a modified arrow-trerotola percutaneous thrombolytic device for
      treatment of acute pulmonary embolus in a canine model.
AB  - PURPOSE: Massive pulmonary embolus (PE) is often rapidly fatal. Surgical
      thrombectomy has a mortality rate as high as 74%. Multiple percutaneous methods
      have been tested with limited success. The purpose of this study was to evaluate
      the Arrow-Trerotola percutaneous thrombolytic device (PTD) for (i) the ability to
      clear pulmonary embolus and (ii) the effect on normal pulmonary vasculature.
      These were tested in a canine model. MATERIALS AND METHODS: Iatrogenic unilateral
      massive PEs were created in nine canines. These PEs were then treated with the
      PTD. The device was also activated in the normal pulmonary artery. Immediately
      after treatment, six animals were killed. Three animals were allowed to recover
      and underwent pulmonary arteriography 1 month later to evaluate pulmonary
      hypertension, stenosis, or occlusion; they were then killed. Autopsy specimens
      were evaluated for histologic evidence of acute or chronic vascular injury.
      RESULTS: Acutely, the PTD effectively thrombolysed the PE in all animals.
      Histologically, there was moderate intimal injury, but no evidence of pulmonary
      artery disruption. There was one device failure. One month after treatment, there
      was no radiographic evidence of pulmonary stenosis at device activation sites, no
      pulmonary hypertension, and only mild histologic evidence of scar formation.
      CONCLUSION: In preliminary animal testing, the PTD is safe and effective for
      treating large central pulmonary emboli. Human clinical trials are warranted.

PMID- 10392942
TI  - Aortoduodenal fistula: a late complication of intraluminal exclusion of an
      infrarenal aortic aneurysm.
AB  - During recent years, considerable clinical experience has been gained with
      endoluminal stent-graft procedures. Several studies have shown promising results
      up to a period of 4.5 years. However, long-term follow-up studies are still
      limited. Late endoleaks caused by stent-graft migration, disconnection of single
      components in modular stent-grafts, and limb thrombosis have been observed as
      long-term complications. We report a case in which a migrated and kinked
      bifurcated stent-graft caused an aortoduodenal fistula 20 months after stent
      graft insertion. To our knowledge, such a complication has not been reported
      before.

PMID- 10392941
TI  - Impact of different hemodynamic criteria for stent placement after suboptimal
      iliac angioplasty. Dutch Iliac Stent Trial Study Group.
AB  - PURPOSE: To investigate the consequences of different hemodynamic criteria as
      indications for stent placement after suboptimal iliac angioplasty. MATERIALS AND
      METHODS: One hundred thirty-six patients with intermittent claudication, on the
      basis of atherosclerotic disease of the iliac artery, underwent angioplasty.
      Intraarterial systolic and mean pressures were simultaneously recorded above and
      below the lesion, with and without vasodilation, and before and after
      percutaneous angioplasty. These data were used to estimate what proportion of the
      study population would be eligible for stent placement according to different
      criteria reported in the literature. Subsequently, the authors compared peak
      systolic velocity (PSV) ratios during follow-up in their patients, with and
      without indication for stent placement according to two different criteria.
      RESULTS: Applying the different thresholds reported in the literature to the
      patient group shows that stent placement would be indicated in anywhere from 4%
      to 87% of cases. No difference was observed when PSV ratios were compared in
      patients with a residual mean pressure gradient of > or = 5 and < or = 10 mm Hg
      with patients with a residual mean pressure gradient of less than 5 mm Hg.
      CONCLUSIONS: Application of the various published thresholds as indications for
      secondary stent placement leads to a wide range in proportion of cases requiring
      stent placement. Lesions with a residual mean pressure gradient of > 5 and < 10
      mm Hg fare as well as lesions with a residual mean pressure gradient of less than
      5 mm Hg. The optimal criterion is still not clear.

PMID- 10392943
TI  - Rectum and sigmoid colon necrosis due to cholesterol embolization after
      implantation of an aortic stent-graft.
AB  - Endovascular treatment of abdominal aortic aneurysms (AAAs) with stent-grafts is
      increasingly performed. Recent studies have shown that stent-graft placement for
      AAA is technically feasible and can effectively exclude aneurysms from the
      circulation. However, complications related to the procedure, such as graft
      thrombosis, migration of the prosthesis, peripheral embolization, and leaks with
      incomplete exclusion of the aneurysmal sac, have been reported. We report a case
      of rectum and sigmoid colon necrosis with fatal outcome due to cholesterol
      embolization after implantation of a stent-graft for an infrarenal AAA.

PMID- 10392944
TI  - Long-term results of treatment of benign central venous obstructions unrelated to
      dialysis with expandable Z stents.
AB  - PURPOSE: To evaluate long-term patency of self-expanding Z stents for treatment
      of benign central venous obstructions unrelated to dialysis. MATERIALS AND
      METHODS: Z stents were placed in 19 patients, (ages 26-72 years) with severe
      symptomatic obstructions of the superior or inferior venae cavae and their large
      branches and portal vein caused by surgical or catheter injury (n = 8), fibrosis
      (n = 5), cirrhosis (n = 3), Budd-Chiari syndrome (n = 2), and extrinsic
      compression (n = 1). Fourteen patients underwent stent placement primarily, five
      after local urokinase infusion for superimposed thrombosis. Follow-up was
      performed with ultrasound and venography. RESULTS: Venous congestive symptoms
      quickly resolved in all patients after stent placement. The follow-up period was
      from 1 to 94 months. Twelve patients have died during follow-up from 1 to 37
      months although all remained asymptomatic until death. Six patients remain alive,
      asymptomatic, with patent stents, and with follow-up from 24 to 94 months.
      Primary patency was 83%, and secondary patency was 100%. One patient with a
      patent stent at 12 months was lost to follow-up. No stent migrations,
      perforations, infections, or significant complications occurred. CONCLUSION:
      Benign central venous obstructions are effectively treated by the placement of
      self-expandable Z stents. Placed percutaneously into obstructive lesions with a
      minimum risk, these stents offer long-term durability and patency.

PMID- 10392945
TI  - Incidence and management of catheter occlusion in implantable arm ports: results
      in 391 patients.
AB  - PURPOSE: To evaluate the incidence and management of catheter occlusion in
      implantable arm ports. MATERIALS AND METHODS: Findings were prospectively
      examined in 391 patients in whom 393 arm ports were placed. The indications for
      port placement included chemotherapy (n = 347), antibiotic administration (n =
      35), combination chemotherapy/antibiotic use (n = 7), transfusion (n = 3), and
      phlebotomy (n = 1). Of the total catheters, 323 (82.2%) underwent tip
      modification prior to placement. Malfunctioning catheters were usually treated
      with urokinase instillation. RESULTS: Three hundred ninety-three devices were
      implanted with 247 mean days of catheter use (total, 97,256 days; range, 1-694
      days). The overall incidence of catheter occlusion was 0.14 per 100 catheter
      days. A single catheter occlusion occurred in 90 (22.9%) catheters, with a mean
      of 90.1 days before the event. A second occlusion occurred in 36 (9.2%) of the
      above catheters, with a mean of 60.1 catheter days before the second event.
      Eighty-five (24.0%) of the 347 cancer patients had at least one occlusive event,
      yielding a complication rate of 0.098 per 100 catheter days at risk (95%
      confidence interval [CI]; 0.079-0.114). Of the 35 patients receiving antibiotics,
      three (8.6%) had at least one occlusive event. This represented a complication
      rate of 0.032 per 100 catheter days at risk (95% CI; 0.010-0.061). Seventeen
      (24.3%) of the nonmodified catheters developed an occlusion versus 72 (22.3%) of
      the modified (P > .05; Fisher exact test). Of the catheters with a first
      occlusive event, 75 (98.7%) were treated successfully with urokinase
      instillation. Four (1.0%) patients developed symptomatic subclavian vein
      thrombosis. No bleeding complications occurred. CONCLUSION: Catheter occlusion is
      a common complication of long-term arm port placement, with a significantly
      higher incidence in the cancer patients in our series (P <. 05, Fisher exact
      test). Catheter tip modification, however, does not considerably affect the
      incidence of occlusion. Low-dose urokinase therapy is a safe and efficacious
      treatment of catheter occlusion, obviating the need for catheter removal.

PMID- 10392946
TI  - The apex-puncture technique for mechanical thrombolysis of loop hemodialysis
      grafts.

PMID- 10392947
TI  - Air embolism during tunneled central catheter placement performed without general
      anesthesia in children: a potentially serious complication.
AB  - Central venous catheters have had an increasingly important role in a variety of
      patient care situations, including long-term antibiotic therapy, chemotherapy,
      and nutritional support. The recent past has seen a gradual transition from
      placement of vascular access catheters by surgeons to placement by interventional
      radiologists. The interventional radiology service places a majority of the
      vascular access devices at our children's hospital, including peripherally
      inserted central catheters, tunneled central venous catheters, temporary and
      permanent hemodialysis catheters, and subcutaneous ports. Most procedures
      performed by our interventional radiology service in children can be successfully
      completed with use of intravenous (i.v.) sedation, and a few require general
      anesthesia (GA). Key advantages of GA over i.v. sedation include the ability to
      have positive pressure ventilation (PPV) or controlled apnea during the
      procedure. We report our experience of venous air embolism in three small
      children during placement of tunneled central venous catheters when GA was not
      used.

PMID- 10392948
TI  - Cystogastric transmural drainage for the treatment of symptomatic cystic
      metastases from ovarian carcinoma.
AB  - Approximately 80% of ovarian cancers are discovered when they have already
      progressed to stage III or IV lesions. The prognosis is, therefore, poor despite
      intensive treatment. Intraperitoneal dissemination is one of the most frequent
      pathways of distant spread ovarian cancer and pseudocystic metastases usually
      occur. When such cystic metastases remain symptomatic despite antitumor
      treatment, viable options are limited because palliative surgery generates high
      operative morbidity and mortality. For many years, in patients in whom the risks
      associated with surgery are high, percutaneous drainage and sclerosis under
      radiologic guidance has been performed as an effective alternative option for
      various forms of abdominal fluid collection. Such a collection in pancreatic
      pseudocyst benefits from cystogastric transmural drainage to avoid external
      drainage and achieves the same results as surgical cystogastrostomy. We report
      this transmural drainage technique under image guidance used to drain a
      symptomatic cystic metastasis, which was compressing the stomach.

PMID- 10392949
TI  - Successful treatment of a pseudoaneurysm of the cystic artery with microcoil
      embolization.
AB  - Pseudoaneurysms of visceral arteries are uncommon but well-characterized vascular
      abnormalities, usually provoked by intraabdominal inflammatory processes such as
      pancreatitis or cholecystitis, or by surgical trauma. However, pseudoaneurysms of
      the cystic artery are rare. They complicate cholecystitis or cholecystectomy, and
      manifest as hemobilia as they rupture into the biliary tree. The advent of
      transcatheter embolization techniques has begun to allow minimally invasive
      treatment of these life-threatening complications. Transcatheter embolization can
      be performed using several types of material, such as synthetic occlusive
      emulsions, gelatin sponges or other particles, or metallic microcoils. Microcoils
      are small metallic helical particles, made of stainless-steel, platinum, or
      tungsten. Super-selective catheterization of an artery and release of microcoils
      causes the vessel to thrombose and allows control of bleeding.

PMID- 10392950
TI  - Chemoembolization of hepatocellular carcinoma with cisplatin, doxorubicin,
      mitomycin-C, ethiodol, and polyvinyl alcohol: prospective evaluation of response
      and survival in a U.S. population.
AB  - PURPOSE: To evaluate response and survival after hepatic chemoembolization with
      cisplatin, doxorubicin, mitomycin-C, Ethiodol, and polyvinyl alcohol in a U.S.
      population of patients with hepatocellular carcinoma. MATERIALS AND METHODS:
      Thirty-eight consecutive patients were treated: 35% stage I, 62% stage II, 3%
      stage III. Fifty-one percent had cirrhosis. Chemoembolization was performed at
      approximately monthly intervals for one to seven sessions (mean, 2.2).
      Pretreatment and posttreatment cross-sectional imaging and alpha-fetoprotein
      (AFP) levels were obtained prospectively 1 month after treatment and then every 3
      months. Thirty-day response was calculated by means of the the World Health
      Organization/Eastern Cooperative Oncology Group criteria. RESULTS: One patient
      was lost to follow-up. In seven patients, lesions became resectable after
      chemoembolization. Among 13 evaluable patients with initially elevated AFP level,
      70% had a partial biologic response (>50% decrease in AFP), 15% had a minor
      response (25-50% decrease), and the remaining 15% remained stable. Among 25
      patients evaluable for morphologic response, 36% had a partial response, 32% had
      a minor response, and 32% remained stable. No patients had progression of disease
      while receiving therapy. The cumulative survival was 60% at 1 year, 41% at 2
      years, and 16% at 3 years. Two patients developed progressive hepatic failure.
      Thirty-day mortality was 3% (one patient). CONCLUSION: These results compare
      favorably to published response and survival data for chemoembolization of
      advanced hepatocellular carcinoma from Asia and Europe.

PMID- 10392952
TI  - Improved method for transjugular liver biopsy.

PMID- 10392951
TI  - Role of TIPS as a bridge to hepatic transplantation in Budd-Chiari syndrome.
AB  - PURPOSE: To investigate the role of transjugular intrahepatic portosystemic shunt
      (TIPS) as a bridge to transplantation for patients with Budd-Chiari syndrome
      (BCS). MATERIALS AND METHODS: Eight patients (five women, three men) with a mean
      age of 49.8 years (range, 20-61 years) were diagnosed with BCS by means of
      computed tomography, hepatic venography, and liver biopsy. One patient had acute
      liver failure, with subacute or chronic failure in seven. TIPS placement was
      attempted in all eight patients. Clinical follow-up and portograms were obtained
      in all patients until death or transplantation. RESULTS: TIPS placement was
      completed in seven of eight patients (87.5%). During the follow-up period, TIPS
      occlusion occurred in four patients. TIPS revision in this patient, although
      successful, was complicated by hemorrhage and multiorgan failure, and the patient
      died. Assisted patency rate, excluding the technical failure, was 100%. Mean
      follow-up in the six survivors with TIPS was 342 days (range, 19-660 days). All
      six survivors had complete resolution of their ascites. Albumin levels improved
      an average of 0.43 g/dL (range, 0.3-1.4 g/dL). Bilirubin levels improved in five
      of six patients (83%), decreasing by an average of 5.6 mg/dL (range, 3.0-15.2
      mg/dL). Of the six survivors, three underwent elective liver transplantation, one
      is awaiting transplantation, and one has been removed from the transplantation
      list because of clinical improvement. One patient was a candidate for
      transplantation but declined to be put on the list. CONCLUSION: Hepatic synthetic
      dysfunction improves markedly after TIPS placement in patients with BCS.
      Significant improvement in ascites can also occur. TIPS can be an effective
      bridge to transplantation for patients with BCS.

PMID- 10392953
TI  - Use of a combined CT-angiography system for demonstration of correlative anatomy
      during embolotherapy for hepatocellular carcinoma.

PMID- 10392955
TI  - Long-term effects of interstitial laser coagulation in porcine liver with portal
      inflow occlusion: central versus peripheral lesions.
AB  - PURPOSE: Interstitial laser coagulation (ILC) is an attractive modality for local
      destruction of unresectable hepatic metastases. Portal inflow occlusion
      considerably increases its destructive capacity, resulting in lesions 5 cm in
      diameter; however, effects on adjoining major intrahepatic structures are
      unknown. Therefore, the purpose of this study was to assess the effects of ILC
      with portal inflow occlusion on the central portion of the liver as compared to
      the peripheral portions. MATERIALS AND METHODS: ILC was performed in pigs with
      portal inflow occlusion. Each animal received a single laser application with
      Nd:YAG light guided simultaneously through four interstitial fibers with 5 W per
      fiber during 6 minutes. Location of treatment was randomized to either central (n
      = 8) or peripheral (n = 8). Follow-up was for 1, 2, or 3 months with evaluation
      of liver functions and weight, as well as macroscopic and microscopic assessment
      of coagulated lesions and surrounding parenchyma. RESULTS: There was no treatment
      related morbidity or mortality. No obstructive cholestasis or bile leakage was
      found. At every moment of evaluation, coagulated volumes in the central group
      were smaller than in the peripheral lesions (P = .03). Large vessels contiguous
      to the lesions in the central group were always intact and indications of portal
      hypertension or thrombosis of hepatic veins were not found. There were no
      significant differences between the two groups (liver functions [P > or = .15]
      and weight [P = .69]). CONCLUSION: ILC with portal inflow occlusion is a safe
      technique in the vicinity of vital structures in the liver of healthy pigs. These
      results justify studies to the feasibility and complication rate of portal inflow
      occlusion in patients with hepatic malignancies.

PMID- 10392954
TI  - Selective venous thrombolysis with the nipple-balloon catheter: comparative
      evaluation in vivo.
AB  - PURPOSE: To compare in an animal model of deep vein thrombosis, an intramural
      drug delivery catheter, the nipple-balloon catheter, with an occlusion balloon
      infusion guide wire system. MATERIALS AND METHODS: Ten juvenile pigs were used
      for the study. Deep vein thrombosis was induced in both hind limbs by using a
      previously described technique. Heparin was administered 30 minutes later (2,500
      IU intravenously) and bilateral thrombolysis was attempted with use of 8 mg of
      alteplase as a 0.25 mg/mL solution containing heparin 50 IU/mL (n = 10) and
      sodium/meglumine ioxaglate 40 mgI2/mL (n = 5). In one limb, the external iliac
      vein was endoluminally occluded, and 0.8 mL of alteplase was administered every 3
      minutes through a multisideport infusion wire placed coaxially through the
      balloon catheter. On the other side, a nipple-balloon catheter was used:
      alteplase was injected as two 0.4-mL aliquots every 3 minutes in overlapping
      segments of the vessel. Blood samples were taken at predetermined intervals to
      determine the partial thromboplastin time and plasma fibrinogen concentration. At
      autopsy, the thrombus mass in the iliofemoral veins was measured, and the extent
      of residual thrombosis in the venous tributaries was graded at four sites. The
      heart and the lungs were also examined for thromboemboli (n = 5). Venous
      specimens were then subjected to X-ray fluorescence spectrometry to determine
      iodine content (n = 5). RESULTS: Bilateral thrombolysis could be successfully
      completed in all animals. No procedural problem associated with the use of the
      nipple-balloon catheter was encountered. The mass of residual thrombus in the
      axial veins was significantly lower in this group (P = .005). The drug delivery
      system used did not appreciably influence thrombolysis in the tributaries. Signs
      of macroscopic damage to the veins were not observed in any animal. None of the
      venous specimens had detectable levels of iodine. Small thromboemboli were found
      in the pulmonary circulation in three of five animals. Fibrinogen levels did not
      decrease during the procedure. CONCLUSIONS: The significantly lower residual
      thrombus burden associated with use of the nipple-balloon catheter suggests that
      the device may have the potential to be an effective delivery system for
      selective thrombolysis in veins.

PMID- 10392956
TI  - Replacement of tunneled central venous dialysis catheter in the inferior vena
      cava.

PMID- 10392957
TI  - Ultrasound guidance to gain access for the "lyse and wait" technique.

PMID- 10392958
TI  - Graft-vs.-host and graft-vs.-leukemia reactions after delayed infusions of donor
      T-subsets.
AB  - Infusions of donor leukocytes have been given to allogeneic bone marrow
      recipients after transplant to treat leukemia relapse. Treatment with these
      delayed infusions of donor cells has been called delayed or donor leukocyte
      infusion (DLI). While graft-vs.-host disease (GVHD) has typically been less
      severe than expected after DLI, it still remains a significant risk factor.
      Recently, we used a full major histocompatibility complex (MHC)-mismatched model
      (C57BL/6 into AKR) to determine how increased immunogenetic disparity affects GVH
      and graft-vs.-leukemia (GVL) reactions after DLI. In contrast to an MHC-matched
      model (B10.BR into AKR), GVHD was still observed when MHC-mismatched donor T
      cells were infused 3 weeks posttransplant. Limiting dilution analysis was used to
      determine the frequency of alloreactive cytotoxic T lymphocytes (CTL) and
      interleukin (IL)-2-secreting T helper cells in the spleens of MHC-mismatched
      recipients 7 days after DLI treatment. GVHD correlated with elevated frequencies
      of alloreactive T-helper cells. One strategy for reducing the severity of GVHD
      after DLI is the selective administration of CD4 or CD8 T-subsets. Delayed
      infusion of purified T-subsets 3 weeks posttransplant resulted in significantly
      less GVHD than infusion of a mixture of the two subsets. No GVH-associated
      mortality was observed after DLI with purified donor CD4+ T cells. In GVL
      studies, MHC-mismatched CD8+ T cells were the most potent antitumor effectors
      against an acute T cell leukemia. The GVL effect of MHC-mismatched T-subsets was
      compared with that of MHC-matched subsets. When naive MHC-matched cells were
      given as DLI, depletion of either T-subset eliminated the GVL effect. CD8+ T
      cells from MHC-matched donors primed against host alloantigens, however, mediated
      a CD4 (T-helper)-independent GVL reaction. Together, these results suggest that
      administration of T-subsets can significantly reduce GVHD after DLI without loss
      of the beneficial GVL effect.

PMID- 10392959
TI  - Lymphohematopoietic graft-vs.-host reactions can be induced without graft-vs.
      host disease in murine mixed chimeras established with a cyclophosphamide-based
      nonmyeloablative conditioning regimen.
AB  - Mixed hematopoietic chimerism can be induced in mice receiving allogeneic bone
      marrow transplantation (BMT) after nonmyeloablative host conditioning with
      depletion T cells with of anti-T cell monoclonal antibodies (mAbs), low-dose (3
      Gy) total-body irradiation (TBI), and local thymic irradiation (7 Gy). These mice
      are specifically tolerant to donor and host antigens. When nontolerant donor T
      cells are given to chimeras several months after BMT, full donor-type chimerism
      develops, but graft-vs.-host disease (GVHD) does not occur. The induction of such
      lymphohematopoietic GVH reactions without GVHD could provide an approach to
      separating graft-vs.-leukemia (GVL) from GVHD in patients with hematologic
      malignancies. To make the nonmyeloablative conditioning regimen described above
      more cytoreductive for such malignancies, we have now modified it by replacing
      TBI with cyclophosphamide (CP). Treatment with anti-CD4 and anti-CD8 mAbs on day 
      5, 200 mg/kg CP on day -1, and 7 Gy thymic irradiation on day 0 was only slightly
      myelosuppressive and allowed fully major histocompatibility complex (MHC)
      mismatched (with or without multiple minor antigen disparities) allogeneic bone
      marrow to engraft and establish long-term mixed chimerism in 40 to 82% of
      recipients in three different strain combinations. The administration of
      nontolerant donor spleen cells at 5 weeks or at 5, 8, and 11 weeks posttransplant
      was capable of eliminating host hematopoietic cells, leading to full or nearly
      full donor chimerism in six of six and two of four chimeric animals in two
      different strain combinations. No clinical evidence of GVHD was observed in any
      recipients of these donor leukocyte infusions (DLI). These studies demonstrate
      that induction of mixed chimerism with nonmyeloablative conditioning followed at
      appropriate times by DLI might allow lymphohematopoietic GVH reactions, and hence
      GVL effects, to eliminate chronic hematologic malignancies without causing
      clinically significant GVHD.

PMID- 10392961
TI  - Dose rate-dependent marrow toxicity of TBI in dogs and marrow sparing effect at
      high dose rate by dose fractionation.
AB  - We evaluated the marrow toxicity of 200 and 300 cGy total-body irradiation (TBI)
      delivered at 10 and 60 cGy/min, respectively, in dogs not rescued by marrow
      transplant. Additionally, we compared toxicities after 300 cGy fractionated TBI
      (100 cGy fractions) to that after single-dose TBI at 10 and 60 cGy/min. Marrow
      toxicities were assessed on the basis of peripheral blood cell count changes and
      mortality from radiation-induced pancytopenia. TBI doses studied were just below
      the dose at which all dogs die despite optimal support. Specifically, 18 dogs
      were given single doses of 200 cGy TBI, delivered at either 10 (n=13) or 60 (n=5)
      cGy/min. Thirty-one dogs received 300 cGy TBI at 10 cGy/min, delivered as either
      single doses (n=21) or three fractions of 100 cGy each (n=10). Seventeen dogs
      were given 300 cGy TBI at 60 cGy/min, administered either as single doses (n=5)
      or three fractions of 100 cGy each (n=10). Within the limitations of the
      experimental design, three conclusions were drawn: 1) with 200 and 300 cGy single
      dose TBI, an increase of dose rate from 10 to 60 cGy/min, respectively, caused
      significant increases in marrow toxicity; 2) at 60 cGy/min, dose fractionation
      resulted in a significant decrease in marrow toxicities, whereas such a
      protective effect was not seen at 10 cGy/min; and 3) with fractionated TBI, no
      significant differences in marrow toxicity were seen between dogs irradiated at
      60 and 10 cGy/min. The reduced effectiveness of TBI when a dose of 300 cGy was
      divided into three fractions of 100 cGy or when dose rate was reduced from 60
      cGy/min to 10 cGy/min was consistent with models of radiation toxicity that allow
      for repair of sublethal injury in DNA.

PMID- 10392960
TI  - Antileukemic effect of interleukin-2-transduced murine bone marrow after
      autologous transplantation.
AB  - Myeloablative chemotherapy or radiation therapy supported by autologous stem cell
      transplantation (SCT) for the treatment of hematologic malignancies such as acute
      leukemia, lymphoma, and myeloma is associated with high rates of relapse. The
      reasons for this are 1) autologous transplantation lacks the in vivo graft-vs.
      tumor (GVT) effect associated with allogeneic SCT, which is effective in
      controlling or eliminating residual malignant cells remaining in the body after
      high-dose therapy, and 2) contaminating malignant cells in the autologous graft
      are reinfused into the body. Some researchers have attempted to administer
      immunomodulatory cytokines to simulate a GVT effect, and although this has shown
      some efficacy, it has several disadvantages. These include high toxicity
      associated with systemic administration, a short in vivo half-life, and
      insufficient levels reaching the site of residual disease. As an alternative, we
      investigated whether delivery of the cytokine interleukin (IL)-2 to the bone
      marrow can exert an antileukemic effect while avoiding the problems associated
      with systemic administration. We describe the delivery of IL-2 to the bone marrow
      by transplantation of syngeneic bone marrow, retrovirally transduced with the
      gene for IL-2, into lethally irradiated mice. We were able to efficiently
      transduce murine bone marrow with the IL-2 gene without adversely affecting
      clonogenic output from hematopoietic progenitors, and we were able to achieve
      expression of the transgene in transplanted animals. However, IL-2 transduction
      inhibited hematopoietic reconstitution in lethally irradiated mice. Marrow
      transduced with high-titer, high-expressing IL-2 retrovirus failed to engraft,
      and a low-titer, low-expressing IL-2 retrovirus also demonstrated reduced
      engraftment, although engraftment was sufficient to support survival of
      transplanted mice. Long-term, low-level expression of the IL-2 transgene was
      detectable in these mice and was effective in exerting an antileukemic effect.
      Mice transplanted with control marrow and challenged with leukemic cells suffered
      100% mortality within 70 days, whereas mice transplanted with IL-2-transduced
      marrow exhibited 50% survival over the 175-day duration of this study. The work
      shows that delivery of immunomodulatory cytokines to the bone marrow can be
      achieved by transplantation of genetically modified hematopoietic cells.
      Furthermore, low-level IL-2 expression can exert an antileukemic effect. These
      data suggest that this may be an effective immunotherapeutic strategy to reduce
      relapse after autologous transplantation, but the selection and expression of the
      cytokine must be carefully considered to minimize adverse effects on
      hematopoiesis.

PMID- 10392962
TI  - Depletion of CD34+ CD4+ cells in bone marrow from HIV-1-infected individuals.
AB  - Pancytopenia as a consequence of bone marrow abnormalities is commonly seen in
      HIV-infected individuals. To examine the effect that HIV-1 has on hematopoietic
      cells, we compared hematopoietic properties of bone marrow samples from HTV+
      patients at various stages of disease with bone marrow samples from uninfected
      donors. While the absolute number of recovered CD34+ cells and the cloning
      efficiency of these cells did not differ significantly in HIV+ donors, the
      percentage of CD34+ CD4+ cells was significantly depleted in late-stage HIV+
      patients. We observed a direct correlation between the numbers of CD34+ CD4+
      cells in the bone marrow and the peripheral CD4 count. Further characterization
      of the CD34+ CD4+ subpopulation demonstrated that these cells expressed lower
      levels of HLA-DR on their surface compared with CD34+ CD4- cells, suggesting an
      immature phenotype. We also found evidence for expression of HIV-1 coreceptors
      CXCR-4 and CKR-5 message and protein in CD34+ bone marrow cells. While this
      finding suggested that hematopoietic cells might be susceptible to HIV infection
      at an early stage of maturation, thus affecting different cell lineages as they
      matured, we did not find any evidence for infection of HIV in these cells. These
      data suggest that HIV affects early hematopoietic progenitor cells either
      directly or indirectly, and in particular CD34+ CD4+ cells. This finding has
      important implications for disease pathogenesis and for application of gene
      therapy approaches that use CD34+ hematopoietic cells.

PMID- 10392963
TI  - Role of splenic irradiation in patients with chronic myeloid leukemia undergoing
      allogeneic bone marrow transplantation.
AB  - Allogeneic bone marrow transplantation (BMT) has become the treatment of choice
      for patients of appropriate age with chronic myeloid leukemia (CML). In an
      attempt to enhance tumor cytoreduction, splenic radiation therapy (RT) has been
      done before the allogeneic transplant, but the role of splenic RT in this setting
      remains controversial. The purpose of this study is to evaluate the role of
      splenic RT before allogeneic BMT in patients with CML. Thirty-seven patients with
      chronic (n=33) or accelerated (n=4) phase CML underwent BMT from April 1990 to
      January 1998. All patients received splenic RT consisting of 500 cGy in five
      daily fractions (n=36) or 250 cGy in five daily fractions (n=1) completed within
      10 days before BMT. The conditioning regimen included total-body irradiation and
      cyclophosphamide; etoposide was added to the regimen of patients in the
      accelerated phase. Continuous-infusion cyclosporine and pulse methotrexate were
      administered to all patients for prophylaxis of graft-vs.-host disease (GVHD).
      All patients achieved hematologic and cytogenetic remission. At a median follow
      up of 37 months, the freedom from progression (FFP) and overall survival (OS)
      were 90 and 82%, respectively. None of the patients in accelerated phase have
      relapsed. Five patients have died of late transplant-related complications while
      in complete remission. Acute GVHD of grade > or = II was observed in 20% (14%
      grade II, 6% grade III). Fifty-one percent of patients developed limited chronic
      GVHD. The median posttransplant creatinine level was 1.2 mg/dL (range 0.6-4.2).
      Renal dysfunction, manifested as a persistent elevation in serum creatinine level
      (> 1.2 mg/dL), was observed in 40% of the patients. Only 8.5% had a creatinine
      level > 2.0 mg/dL, and no patient required dialysis as a result of renal
      dysfunction. Seven patients (18.9%) developed pulmonary complications, which
      included idiopathic interstitial pneumonitis (two), biopsy-proven interstitial
      fibrosis (four), and alveolar hemorrhage (one). The low relapse rate observed in
      this study may reflect the use of splenic RT as a part of the cytoreductive
      regimen before BMT. The fractionation schedule of 500 cGy in five daily fractions
      was well tolerated and did not appear to increase the toxicity of the preparative
      regimen. These favorable results indicate that splenic RT deserves further
      investigation and may be of benefit as a part of the conditioning regimen for
      patients receiving allogeneic BMT for CML.

PMID- 10392964
TI  - Tacrolimus vs. cyclosporine immunosuppression: results in advanced-stage disease
      compared with historical controls treated exclusively with cyclosporine.
AB  - A phase HI comparative trial of tacrolimus- vs. cyclosporine-based graft-vs.-host
      disease (GVHD) prophylaxis for human leukocyte antigen (HLA)-identical sibling
      bone marrow transplantation showed less GVHD but poorer survival in the
      tacrolimus arm. To test the comparability of the two treatment arms with respect
      to baseline survival prognosis, a matched control study using exclusively
      cyclosporine-treated patients from the International Bone Marrow Transplant
      Registry (IBMTR) database was performed. Controls were matched (2:1) based on age
      (within 5 years), disease, and pretransplant disease status. Two-year survival
      for tacrolimus-treated clinical trial patients was similar to that of their
      cyclosporine-treated matched controls (27 and 24%, respectively), and 2-year
      survival of the cyclosporine-treated clinical trial patients was similar to that
      of their cyclosporine-treated matched IBMTR controls (42 and 45%, respectively).
      Consistent with the clinical trial results, the cyclosporine-treated IBMTR
      controls matched to the tacrolimus group had significantly poorer 2-year survival
      than the cyclosporine-treated IBMTR controls matched to the cyclosporine group
      (24 and 45%, respectively; p < 0.01). No significant difference was seen in GVHD
      between the cyclosporine-treated clinical trial patients and their matched
      controls; however, the tacrolimus-treated clinical trial patients had
      significantly less GVHD than their cyclosporine-treated IBMTR controls (p <
      0.01). These results support the hypothesis that the survival difference in the
      phase III trial resulted from an imbalance in the underlying risk factors for
      death in the two groups rather than from the randomized immunosuppressive
      regimen.

PMID- 10392966
TI  - Molecular phylogenetic studies on Theileria parasites based on small subunit
      ribosomal RNA gene sequences.
AB  - Classification of Theileria parasites of south-east Asian countries is still
      ambiguous due to the lack of basic studies, especially their molecular genetic
      information. In this study, we included 6 known species and 14 unclassified
      Theileria parasite isolates: Theileria annulata, Theileria parva, Theileria
      taurotragi, Theileria sergenti, Theileria buffeli, Theileria types Sable,
      Theileria types A, B, B1, B2, C, D, E, F, G, G1, Theileria type Medan
      (Indonesia), Theileria type Ipoh (Malaysia) and Theileria type Thong Song
      (Thailand). Small subunit ribosomal RNA (srRNA) nucleotide sequence data were
      collected by PCR, cloning and dideoxy sequencing. The srRNA nucleotide sequences
      were aligned and analyzed by distance methods, maximum parsimony algorithms and
      maximum likelihood methods to construct phylogenetic trees. Bootstrap analysis
      was used to test the strength of the different phylogenetic reconstructions. The
      data indicated that all of the tree-building methods gave very similar results.
      This study identified two groups of Theileria, the pathogenic and benign groups,
      which are strongly supported by bootstrap analysis. The analysis also indicated
      that three subgroups (A, B and C) were generated within the benign Theileria
      group whereas the classification of Theileria type D and Thong Song is
      questionable. However, more basic information such as life cycle differences,
      vectors, modes of transmission, virulent and genetic/sexual compatability is
      essential for clearer taxonomic definition of the benign Theileria parasites.

PMID- 10392965
TI  - Epidemiology of canine leishmaniosis in Catalonia (Spain) the example of the
      Priorat focus.
AB  - An epidemiological survey of canine leishmaniosis was conducted in the Priorat, a
      rural region in the Northeast of Spain, for 10 years (1985-1994). Seroprevalence
      throughout the region, determined by dot-ELISA and IFI, was 10.2% (8-12%). Forty
      percent of the dogs studied had a low level of anti-Leishmania antibodies,
      whereas only 50% were seronegative. Only one-third of the seropositive dogs had
      evident symptoms of the disease. Annual incidence of the disease was 5.7% and the
      level of endemicity was stable during the study. Four Leishmania zymodemes (MON
      1, MON-29, MON-77, MON-105) were present in the focus, and their distribution in
      the different hosts is discussed. Apart from dogs and foxes, no other reservoir
      host has been found in the region.

PMID- 10392967
TI  - A fatty acid binding protein from Fasciola hepatica induced protection in C57/BL
      mice from challenge infection with Schistosoma bovis.
AB  - Three strains of mice (NMRI, C57/BL, BALB/c) were each immunized with a 12 kDa
      purified, native Fasciola hepatica fatty acid binding protein (Fh12) and
      challenged percutaneously with Schistosoma bovis cercariae. C57/BL mice immunized
      with Fh12 had significant reductions in S. bovis worm burden recoveries (96 and
      87% reductions over controls in two separate experiments). When using NMRI or
      BALB/c mice, Fh12 alone or in Freund's adjuvant failed to induce significant
      protection against S. bovis. In C57/BL mice vaccinated against Fh 12, antibodies
      to the IgG2a isotype, but not to the IgG1 isotype, increased by 2 weeks after the
      second immunization and remained high through 8 weeks of S. bovis infection.
      Antibodies to S. bovis increased after 4 weeks of infection. Regarding cytokine
      production by spleen mononuclear cells, C57/BL mice vaccinated with Fh12 in
      adjuvant, and having the highest protective response against challenge infection
      with S. bovis, had an increase of IFN-gamma production with Concanavalin A but no
      increase of IL-4 in similarly stimulated cells. These results suggest that the
      protection obtained in this group of mice is mediated by a Th1 immune response.

PMID- 10392968
TI  - The effects of urea supplementation on production and parasitological responses
      of sheep infected with Haemonchus contortus and Trichostrongylus colubriformis.
AB  - Merino wether lambs were individually confined and fed a basal diet of oaten
      chaff containing essential minerals which was untreated or contained 3% urea.
      Within each dietary group animals were orally infected with either 200 H.
      contortus (H), 1000 T. colubriformis (T) or both species (H + T) thrice weekly or
      remained uninfected (C). Weight gain, wool production, and parasite burden were
      measured over a 19-week period. Sheep on the diet containing urea gained more
      weight, consumed more feed and grew more wool of higher fibre diameter than their
      counterparts given no urea. On both diets uninfected sheep consumed more feed
      than infected sheep and the sheep given no urea and infected with both H and T
      worm species consumed the least feed. Parasitised sheep gained less weight than
      uninfected control sheep. Sheep with urea in their diet had lower faecal egg
      counts when infected with H alone or with H and T but there was no effect of urea
      on egg count of sheep infected with T alone. In contrast, T numbers after
      slaughter were reduced in sheep fed diets containing urea whereas H numbers were
      not affected by diet. It was concluded that supplementation with urea can
      increase resilience to parasitism thereby improving production and also enhance
      resistance mechanisms against worms in young sheep on low quality roughage diets.
      These responses can be partly attributed to stimulation of feed intake,
      presumably due to enhanced ruminal digestion, but also to elevated rumen NH3-N
      levels which would be expected to have increased rumen microbial protein
      synthesis and availability to the intestines.

PMID- 10392969
TI  - The effects of oviposition aggregation on the incidence of sheep blowfly strike.
AB  - The distribution of a parasite population within its natural host population can
      have a significant influence on the dynamics of both the host and parasite
      populations. The majority of parasite species are typically distributed in an
      aggregated manner within the host population, leaving most hosts lightly infected
      and a few hosts supporting very large parasite burdens. This paper presents a
      consideration of the effects of aggregation on the incidence of ovine cutaneous
      myiasis caused by the sheep blowfly, Lucilia sericata (Meigen). Using simulation
      analysis, the mechanisms causing larval aggregation are included in the model,
      allowing the consequences for control to be investigated. By explicitly
      incorporating host susceptibility, it becomes apparent that early in the season,
      strategies targeting the blowfly population may prove more effective in
      suppressing strike levels, whereas later in the season, treatment of the sheep
      population may be more beneficial. The analysis also shows that the greater the
      degree of aggregation, the fewer sheep that become struck and, hence, suggests
      that increasing the heterogeneity in susceptibility amongst a flock of sheep
      restricts strikes to relatively few sheep. Providing the highly-susceptible sheep
      could be identified, concentrating strikes on a low number of sheep would allow
      fewer sheep to be treated, leading to a more efficient means of controlling the
      blowfly population and suppressing strike.

PMID- 10392970
TI  - A comparative kinetic study of ivermectin and moxidectin in lactating camels
      (Camelus dromedarius).
AB  - The plasma and milk kinetics of ivermectin (IVM) and moxidectin (MXD) was
      evaluated in lactating camels treated subcutaneously (0.2 mg kg(-1)) with
      commercially available formulations for cattle. Blood and milk samples were taken
      concurrently at predetermined times from 12 h up to 60 days post-administration.
      No differences were observed between plasma and milk kinetics of IVM, while
      substantial differences were noted between plasma and milk profiles of MXD in
      that both the maximal concentration (Cmax) and the area under concentrations
      curves (AUC) were three to four-fold higher for milk than for plasma. The time
      (Tmax) to reach Cmax was significantly faster for MXD (1.0 day) than that for IVM
      (12.33 days). The Cmax and the AUC were significantly higher for MXD (Cmax = 8.33
      ng ml(-1); AUC = 70.63 ng day ml(-1)) than for IVM (Cmax = 1.79 ng ml(-1); AUC =
      30.12 ng day ml(-1)) respectively. Drug appearance in milk was also more rapid
      for MXD (Tmax = 3.66 days) compared to IVM (Tmax = 17.33 days). The extent of
      drug exchange from blood to milk, expressed by the AUCmilk/AUCplasma ratio, was
      more than three-fold greater for MXD (4.10) compared to that of IVM (1.26), which
      is consistent with the more lipophilic characteristic of MXD. However, the mean
      residence time (MRT) was similar in both plasma and milk for each drug.

PMID- 10392971
TI  - Peroral infection of pigs with Schistosoma japonicum cercariae.
AB  - Infections with the zoonotic trematode, Schistosoma japonicum in pigs serves as a
      valuable model for studying natural definitive host/parasite relationships and a
      model for human schistosomosis japonica. In the present study the efficiency of a
      peroral infection route was compared with that of an intramuscular route of
      infection. Eleven specific pathogen-free Danish Landrace/Yorkshire/Duroc
      crossbred male and female pigs were divided into two groups of five and six pigs,
      respectively. Each pig was given 1000 cercariae, either placed in droplets on the
      mucosa in the buccal cavity, or as medium-suspended cercariae injected into
      musculus biceps femoris of one of the hindlegs. Ten weeks post infection, all
      pigs were killed with pentobarbital and the venous system perfused. Worm burdens
      and liver egg counts were determined and worm fecundity was calculated. S.
      japonicum infections were established in all individuals in both groups of pigs.
      When comparing the two groups, the peroral group had significantly higher number
      of immature worms, whereas the intramuscularly infected group had significantly
      more worm nodules. However, no difference was seen in total number of worms. No
      statistical significant differences were found in neither tissue egg counts nor
      worm fecundity when comparing the two groups. The results from the present study
      showed a delay in maturation of infection following a peroral infection as
      compared with an intramuscular infection, but comparability was seen between
      overall worm establishment and egg production.

PMID- 10392972
TI  - Arthropod parasites of Nubian ibexes (Capra ibex nubiana) and gazelles (Gazella
      gazella) in Israel.
AB  - In a 20-year survey the following ectoparasites were collected from Nubian
      ibexes: larvae of an unidentified Oestrus sp. collected from the nasal cavities,
      sinuses and horns, hippoboscid flies (Lipoptena chalcomelaena) specific to the
      Nubian ibex, blood sucking lice (Linognathus africanus) and unidentified biting
      lice (Damalinia sp.). Ibexes were severely infested with the cattle tick,
      Boophilus annulatus; a few Hyalomma anatolicum excavatum ticks were also
      collected. In five ibexes kept in two zoos, showing otitis, Psoroptes cuniculi,
      was identified, and from skin scrpaings of nine animals with severe dermatitis in
      three other zoos, Sarcoptes scabiei was isolated. Infestation of Nubian ibexes
      with sucking and biting lice as well as H. anatolicum excavatum is reported for
      the first time. The ectoparasites collected from gazelles were: hippoboscid flies
      (Lipoptena capreoli), calliphorid flies (Lucilia sericata and Calliphora sp.),
      sucking lice (Linognathus africanus and Solenopotes capillatus) and unidentified
      biting lice (Damalinia sp.), fleas (Ctenocephalides felis felis), and ticks, B.
      annulatus, Rhipicepahlus bursa, Rhipicephalus turanicus, H. anatolicum excavatum
      and H. marginatum rufipes. In skin scrapings of four gazelles with local
      dermatitis in the fetlocks Chorioptes bovis was identified. Neoschoengastia sp.
      was found in craters between the claws in three gazelles.

PMID- 10392973
TI  - Slow drip of progress on safe water for all.

PMID- 10392974
TI  - Low doses of aspirin in stroke prevention.

PMID- 10392975
TI  - Time to genotype for selection of antiretroviral regimens in previously treated
      patients?

PMID- 10392976
TI  - Preoperative parathyroid scanning in secondary hyperparathyroidism.

PMID- 10392977
TI  - Choice of treatment for menorrhagia.

PMID- 10392978
TI  - Genetic counselling for hereditary breast cancer.

PMID- 10392979
TI  - Physical activity and knee osteoarthritis.

PMID- 10392980
TI  - Tackling teenage pregnancy in the UK.

PMID- 10392981
TI  - Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid
      endarterectomy: a randomised controlled trial. ASA and Carotid Endarterectomy
      (ACE) Trial Collaborators.
AB  - BACKGROUND: Endarterectomy benefits certain patients with carotid stenosis, but
      benefits are lessened by perioperative surgical risk. Acetylsalicylic acid lowers
      the risk of stroke in patients who have experienced transient ischaemic attack
      and stroke. We investigated appropriate doses and the role of acetylsalicylic
      acid in patients undergoing carotid endarterectomy. METHODS: In a randomised,
      double-blind, controlled trial, 2849 patients scheduled for endarterectomy were
      randomly assigned 81 mg (n=709), 325 mg (n=708), 650 mg (n=715), or 1300 mg
      (n=717) acetylsalicylic acid daily, started before surgery and continued for 3
      months. We recorded occurrences of stroke, myocardial infarction, and death. We
      compared patients on the two higher doses of acetylsalicylic acid with patients
      on the two lower doses. FINDINGS: Surgery was cancelled in 45 patients, none were
      lost to follow-up by 30 days, and two were lost by 3 months. The combined rate of
      stroke, myocardial infarction, and death was lower in the low-dose groups than in
      the high-dose groups at 30 days (5.4 vs 7.0%, p=0.07) and at 3 months (6.2 vs
      8.4%, p=0.03). In an efficacy analysis, which excluded patients taking 650 mg or
      more acetylsalicylic acid before randomisation, and patients randomised within 1
      day of surgery, combined rates were 3.7% and 8.2%, respectively, at 30 days
      (p=0.002) and 4.2% and 10.0% at 3 months (p=0.0002). INTERPRETATION: The risk of
      stroke, myocardial infarction, and death within 30 days and 3 months of
      endarterectomy is lower for patients taking 81 mg or 325 mg acetylsalicylic acid
      daily than for those taking 650 mg or 1300 mg.

PMID- 10392982
TI  - Intensive versus standard case management for severe psychotic illness: a
      randomised trial. UK 700 Group.
AB  - BACKGROUND: Case management has increasingly been the recommended approach to
      care for severely mentally ill patients since the number of psychiatric beds has
      decreased. Despite equivocal results, in the UK and Europe, this approach is
      becoming accepted policy. We assessed the effect of smaller case loads. METHODS:
      We randomly assigned 708 psychotic patients in four centres standard case
      management (355 patients, case load 30-35 per case manager) or intensive case
      management (353 patients, case load 10-15 per case manager). We measured clinical
      symptoms and social functioning at baseline, 1 year, and 2 years. The impact of
      treatment on hospital use was assessed at 2 years by subgroup analyses for Afro
      Caribbean and for severely socially disabled patients. Analysis was by intention
      to treat. FINDINGS: There was no significant decline in overall hospital use
      among intensive-case-management patients (mean 73.5 vs 73.1 days in those who
      received standard care [SD 0.4, 95% CI -17.4 to 18.1]), nor were there any
      significant gains in clinical or social functioning. There was no evidence of
      differential effect in Afro-Caribbean patients or the most socially disabled
      patients. INTERPRETATION: In well-coordinated mental-health services, a decline
      in case load alone does not improve outcome for these patients. Mental-health
      planners may need to pay more attention to the content of treatment rather than
      changes in service organisation.

PMID- 10392983
TI  - Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first
      weeks of antiepileptic therapy: a case-control study. Study Group of the
      International Case Control Study on Severe Cutaneous Adverse Reactions.
AB  - BACKGROUND: There is still controversy about whether all antiepileptic drugs are
      associated with the severe cutaneous reactions Stevens-Johnson syndrome (SJS) and
      toxic epidermal necrolysis (TEN). We have studied the role of antiepileptic drugs
      in SJS and TEN, taking into account potential cofactors that might confound or
      modify the risk. METHODS: The case-control study in France, Italy, Germany, and
      Portugal identified cases of SJS/TEN that developed when the patient was not in
      hospital and were validated by an expert committee. Controls were patients
      admitted to the same hospital as the case for an acute illness or an elective
      procedure. FINDINGS: 73 (21%) of the 352 SJS/TEN cases and 28 (2%) of the 1579
      controls reported intake of antiepileptic drugs. Among the 73 exposed SJS and TEN
      patients, 36 reported intake of phenobarbital, 14 of phenytoin, 21 of
      carbamazepine, 13 of valproic acid, and three of lamotrigine. Risk was highest in
      the first 8 weeks after onset of treatment. For individual antiepileptic drugs
      the univariate relative risk of SJS/TEN for 8 weeks or less of use was 57 (95% CI
      16-360; multivariate risk 59 [12-302]) for phenobarbital; 91 (26-infinity) for
      phenytoin; 120 (34-infinity) for carbamazepine; 25 (5.6-infinity) for
      lamotrigine, and 24 (5.9-infinity) for valproic acid. The result for valproic
      acid was based on four case users, all of whom reported concurrent use of other
      associate drugs. The univariate relative risk for more than 8 weeks of use was
      6.2 (2.4-17.0; multivariate risk 2.1 [0.5-9.3]) for phenobarbital, 1.2 (0-5.4)
      for phenytoin, 0.4 (0.02-2.1) for carbamazepine, and 7.0 (2.4-21.0; multivariate
      risk 2.0 [0.3-15.0]) for valproic acid. INTERPRETATION: SJS and TEN are
      associated with short-term therapy with phenytoin, phenobarbital, and
      carbamazepine. The association with valproic acid seems to be confounded by
      concomitant short-term therapy with other causal drugs. Lamotrigine also has the
      potential for severe skin reactions. The period of increased risk is largely
      confined to the first 8 weeks of treatment.

PMID- 10392984
TI  - Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled
      trial.
AB  - BACKGROUND: Growing evidence has linked HIV-1 resistance mutations and drug
      failure. The use of genotypic-resistance analysis to assist therapeutic decision
      making in patients failing therapy has not been investigated. We assessed the
      virological and immunological impact of genotypic-resistance testing. METHODS: We
      did a prospective, open, randomised, controlled study of HIV-1-infected patients
      in whom combination therapy was not successful. We randomly assigned patients
      standard care (control, n=43) or treatment according to the resistance mutations
      in protease and reverse-transcriptase genes (genotypic group, n=65). The major
      endpoint was the change in HIV-1 RNA viral load. Analysis was by intention to
      treat. FINDINGS: 108 patients were enrolled. All patients were similar for risk
      factors, age, sex, previous treatment, CD4-cell count (214/microL [SD14]) and log
      HIV-1 RNA viral load at baseline (4.7 copies/mL [0.1]). At month 3, the mean
      change in HIV-1 RNA was -1.04 log (0.14) in the study group compared with -0.46
      log (0.17) in the control group (mean difference 0.58 log [95% CI 0.14-1.02],
      p=0.01). At month 6, changes were -1.15 (0.15) log copies/mL, and -0.67 (0.19)
      log copies/mL in the genotypic group and the control group, respectively (mean
      difference 0.48 log [0.01-0.97], p=0.05). Difference in the drop in viral load
      combined at 3 months and 6 months was significant (p=0.015). At month 3, HIV-1
      RNA was lower than detection level (200 copies/mL) in 29% (19/65) of patients in
      the genotypic group versus 14% (6/43) in the control group (p=0.017). At month 6,
      the values were 32% (21/65) and 14% (6/43) (p=0.067) for the genotypic group and
      the control group, respectively. Therapy was generally well tolerated, with ten
      patients (six in the genotypic group, four in the control group) requiring toxic
      effect-related drug modification. INTERPRETATION: We found genotypic-resistance
      testing to have a significant benefit on the virological response when choosing a
      therapeutic alternative. Further study of the use of genotypic-resistance testing
      in assisting clinical decision-making is warranted.

PMID- 10392986
TI  - Augmented vasoreactivity in adult life associated with perinatal vascular insult.
AB  - BACKGROUND: Adverse environmental events occurring early in life have received
      little attention as predictors of disease in the later stages of life. At birth,
      the transition from gas exchange by the placenta to gas exchange by the lungs
      requires dramatic changes in the pulmonary circulation, which during this period
      is particularly vulnerable to noxious stimuli. We measured pulmonary-artery
      pressure responses to high-altitude exposure, a stimulus that causes pronounced
      pulmonary vasoconstriction, in young adults who had had transient perinatal
      hypoxic pulmonary hypertension and in controls of similar age and sex
      distribution. METHODS: Review of neonatal-care records at the Lausanne University
      Hospital for Children identified 15 individuals who met the eligibility criteria
      (birth at > or = 34 weeks of gestation, persistence of hypoxaemia during
      ventilation with oxygen during the first week of life, and persistence of fetal
      circulation). Ten of these individuals agreed to take part; the control group was
      ten volunteers without any history of perinatal complications. Systolic pulmonary
      artery pressure (by echocardiography) and arterial oxygen saturation were
      measured at baseline and at high altitude (4559 m). FINDINGS: The mean increase
      in pulmonary-artery pressure at high altitude was significantly greater (p=0.01)
      in the participants who had had perinatal pulmonary hypertension (from 26.2 mm Hg
      [SD 2.1] to 62.3 mm Hg [7.3]) than in the controls (from 25.8 mm Hg [2.3] to 49.7
      mm Hg [11.3]). The fall in arterial oxygen saturation was similar in the two
      groups. INTERPRETATION: These findings suggest that a transient perinatal insult
      to the pulmonary circulation leaves a persistent and potentially fatal imprint,
      which when activated in adult life predisposes to a pathological response.
      Survivors of perinatal pulmonary hypertension may be at risk of developing this
      disorder in later life.

PMID- 10392985
TI  - Preoperative imaging of parathyroid glands with technetium-99m-labelled sestamibi
      and iodine-123 subtraction scanning in secondary hyperparathyroidism.
AB  - BACKGROUND: Parathyroidectomy is unsuccessful in 10-30% of uraemic patients
      operated on for secondary hyperparathyroidism. We investigated the usefulness of
      preoperative radionuclide imaging, with simultaneous recording of the
      distribution images of iodine-123 and technetium-99m-labelled sestamibi. METHODS:
      11 patients with secondary hyperparathyroidism underwent prospective imaging and
      parathyroidectomy. Plasma concentrations of intact parathyroid hormone (PTH) were
      measured in all patients before and 6 months after subtotal parathyroidectomy.
      FINDINGS: Preoperative scanning showed 42 hot-spots suggesting enlarged
      parathyroid glands. 45 glands were discovered at surgery, and the
      parathyroidectomy was deemed successful in ten patients. Among the latter, one
      patient had a supernumerary parathyroid gland detected by scanning and resected
      from the left thymus. Another patient showed ectopic uptake corresponding to a
      large parathyroid gland in the upper mediastinum, and another had a parathyroid
      gland well above the thyroid. No false-positive scan findings were documented. In
      the patient for whom parathyroidectomy failed, preoperative scanning suggested
      five enlarged parathyroid glands, though the surgeon found only four glands, in
      their normal positions. Hyperparathyroidism persisted (intact PTH 527 ng/L, 6
      months after surgery). A second scan confirmed the preoperative scan, showing a
      fifth parathyroid gland in the middle of the right thyroid lobe. INTERPRETATION:
      Simultaneous recording of 99mTc-sestamibi and 123I improved the imaging of
      parathyroid glands in secondary hyperparathyroidism. The technique can identify
      ectopic and supernumerary parathyroid glands.

PMID- 10392987
TI  - A swollen swimmer.

PMID- 10392988
TI  - Low-frequency repetitive transcranial magnetic stimulation improves intractable
      epilepsy.

PMID- 10392989
TI  - Polycystic ovary syndrome in autoimmune disease.

PMID- 10392990
TI  - Increase in sepsis due to multi-resistant enteric gram-negative bacilli in Papua
      New Guinea.

PMID- 10392991
TI  - Prediction of death in patients with burns.

PMID- 10392992
TI  - 20 years of experience in idiopathic central diabetes insipidus.

PMID- 10392993
TI  - Non-eosinophilic corticosteroid unresponsive asthma.

PMID- 10392994
TI  - PCR-positive tests for Tropheryma whippelii in patients without Whipple's
      disease.

PMID- 10392995
TI  - No syndrome linked to breast implants, says IoM. Insitute of Medicine.

PMID- 10392996
TI  - J Craig Venter: sequencing genomes his way.

PMID- 10392997
TI  - Medical audit reaches the UK national health system.

PMID- 10392998
TI  - Sex education is key to combatting AIDS in Brazil.

PMID- 10392999
TI  - WHO warns of microbial threat.

PMID- 10393000
TI  - Croatia and Bosnia: the imprints of war--II. Restoration.

PMID- 10393001
TI  - Opioids in pain management.
AB  - Opioids are our most powerful analgesics, but politics, prejudice, and our
      continuing ignorance still impede optimum prescribing. Just over 100 years ago,
      opium poppies were still grown on the Cambridgeshire fens in the UK to provide
      oblivion for the working man and his family, but the brewing lobby argued on thin
      evidence that their potions were less dangerous. The restriction of opioid
      availability to protect society and the individual continues in many countries.
      In this review I focus on chronic and cancer pain, but many of the principles
      apply in acute pain. The justification for this focus is that patients with
      chronic pain may suffer longer and unnecessarily if we prescribe and legislate
      badly.

PMID- 10393003
TI  - Epidemiology as a basis for legislation: how far should epidemiology go?

PMID- 10393002
TI  - Suffering: the contributions of persistent pain.
AB  - Pain is a perceived threat or damage to one's biological integrity. Suffering is
      the perception of serious threat or damage to the self, and it emerges when a
      discrepancy develops between what one expected of one's self and what one does or
      is. Some patients who experience sustained unrelieved pain suffer because pain
      changes who they are. At a physiological level, chronic pain promotes an extended
      and destructive stress response characterised by neuroendocrine dysregulation,
      fatigue, dysphoria, myalgia, and impaired mental and physical performance. This
      constellation of discomforts and functional limitations can foster negative
      thinking and create a vicious cycle of stress and disability. The idea that one's
      pain is uncontrollable in itself leads to stress. Patients suffer when this cycle
      renders them incapable of sustaining productive work, a normal family life, and
      supportive social interactions. Although patients suffer for many reasons, the
      physician can contribute substantially to the prevention or relief of suffering
      by controlling pain. Suffering is a nebulous concept for most physicians, and its
      relation to pain is unclear. This review offers a medically useful concept of
      suffering that distinguishes it from pain, accounts for the contributory relation
      of pain to suffering by describing pain as a stressor, and explores the
      implications of these ideas for the care of patients.

PMID- 10393004
TI  - Prevention of vertical HIV-1 transmission.

PMID- 10393005
TI  - Prevention of vertical HIV-1 transmission.

PMID- 10393006
TI  - Prevention of vertical HIV-1 transmission.

PMID- 10393007
TI  - Making and covering of surgical footprints.

PMID- 10393008
TI  - Hereditary angio-oedema in children.

PMID- 10393009
TI  - Multiple sclerosis trials.

PMID- 10393010
TI  - Keep antihypertensive drugs away from very old people.

PMID- 10393011
TI  - Thyroid function in hyperemesis gravidarum.

PMID- 10393012
TI  - Tuberculosis in prisons.

PMID- 10393013
TI  - Preoperative fasting.

PMID- 10393014
TI  - Blood pressure measurements in genetic linkage studies.

PMID- 10393015
TI  - Two-step swallowing provocation test for elderly patients.

PMID- 10393016
TI  - Adverse effects of being a "healthy carrier".

PMID- 10393017
TI  - Vascular endothelial growth factor platelet counts and renal cancer.

PMID- 10393018
TI  - Unethical promotion of lactose-free formula.

PMID- 10393019
TI  - Emotional involvement in physician-assisted suicide.

PMID- 10393020
TI  - Research-agenda setting in developing countries.

PMID- 10393021
TI  - Effects of NATO's bombing in the Balkans.

PMID- 10393022
TI  - Evidence-based information.

PMID- 10393023
TI  - Mortality in the Democratic Republic of the Congo.

PMID- 10393024
TI  - Research funding.

PMID- 10393025
TI  - Centenarian scientists.

PMID- 10393027
TI  - The Nobel chronicles. 1960: Sir Frank Macfarlance Burnet (1899-1985), and Sir
      Peter Brian Medawar (1915-87).

PMID- 10393028
TI  - Alteration of sialyl Lewis epitope expression in pterygium.
AB  - PURPOSE: Mucin-related antigens are abundantly expressed by the cells of the
      normal human conjunctiva. The pattern of these antigens in pterygium, and
      especially the role of Galbeta1-3GlcNAc alpha2,3-sialyltransferase (ST3Gal III),
      sialyltransferase necessary to build the sialyl-Le(a) (Lewis(a)) antigen, were
      studied. METHODS: Immunoperoxidase staining was performed on 28 pterygia using
      different monoclonal antibodies: anti-M1 (against the peptidic core of gastric
      mucins encoded by MUC 5AC gene), anti-Le(a)(7LE), anti-sialyl Le(a)(NS 19-9), and
      anti-Le(b)(2-25LE). A serologic Lewis determination was done in 18 patients.
      ST3Gal III sialyltransferase expression was also studied in 10 healthy
      conjunctiva and 10 pterygia by reverse transcriptase-polymerase chain reaction
      (RT-PCR). Glyceraldehyde-3-phosphate-dehydrogenase was used as an endogenous
      internal control. RESULTS: First, Le(a), sialyl Le(a), and Le(b)
      immunoreactivities either decreased or were no longer detectable in pterygium
      goblet cells as opposed to normal conjunctiva. Second, unlike in pterygium, the
      Lewis immunoreactivity, which is mainly located in the surface epithelial cells
      in the normal conjunctiva, was occasionally restricted to the epithelial cells of
      the deep layers. However, M1 mucins did show an identical pattern expression in a
      normal conjunctiva and pterygium. ST3Gal III expression was significantly lower
      in pterygium (0.20+/-0.02 AU [arbitrary units]) than in normal conjunctiva
      (0.95+/-0.12 AU). CONCLUSIONS: ST3Gal III gene is less expressed in pterygium
      than in normal conjunctiva. This observation could explain the decrease of sialyl
      Le(a) expression observed in pterygium by immunohistology.

PMID- 10393029
TI  - cGMP phosphodiesterase-alpha mutation causes progressive retinal atrophy in the
      Cardigan Welsh corgi dog.
AB  - PURPOSE: To screen the alpha-subunit of cyclic guanosine monophosphate (cGMP)
      phosphodiesterase (PDE6A) as a potential candidate gene for progressive retinal
      atrophy (PRA) in the Cardigan Welsh corgi dog. METHODS: Single-strand
      conformation polymorphism (SSCP) analysis was used to screen short introns of the
      canine PDE6A gene for informative polymorphisms in members of an extended
      pedigree of PRA-affected Cardigan Welsh corgis. After initial demonstration of
      linkage of a polymorphism in the PDE6A gene with the disease locus, the complete
      coding region of the PDE6A gene of a PRA-affected Cardigan Welsh corgi was cloned
      in overlapping fragments and sequenced. SSCP-based and direct DNA sequencing
      tests were developed to detect the presence of a PDE6A gene mutation that
      segregated with disease status in the extended pedigree of PRA-affected Cardigan
      Welsh corgis. Genomic DNA sequencing was developed as a diagnostic test to
      establish the genotype of Cardigan Welsh corgis in the pet population. RESULTS: A
      polymorphism within intron 18 of the canine PDE6A gene was invariably present in
      the homozygous state in PRA-affected Cardigan Welsh corgis. The entire PDE6A gene
      was cloned from one PRA-affected dog and the gene structure and intron sizes
      established and compared with those of an unaffected animal. Intron sizes were
      identical in affected and normal dogs. Sequencing of exons and splice junctions
      in the affected animal revealed a 1-bp deletion in codon 616. Analysis of PRA
      affected anti obligate carrier Cardigan Welsh corgis showed that this mutation
      cosegregated with disease status. CONCLUSIONS: A single base deletion at codon
      616 in the PDE6A gene cosegregated with PRA status with zero discordance in
      Cardigan Welsh corgis with PRA. A lod score of 4.816 with a recombination
      fraction (theta) of zero strongly suggests that this mutation is responsible for
      PRA in the breed. The mutation is predicted to lead to a frame shift resulting in
      a string of 28 altered codons followed by a premature stop codon. The authors
      suggest that this type of PRA be given the name rod-cone dysplasia 3 (rcd3).

PMID- 10393030
TI  - Changes in refractive error over a 5-year interval in the Beaver Dam Eye Study.
AB  - PURPOSE: To examine changes in spherical equivalent over a 5-year period in
      persons 43 to 84 years of age. METHODS: All people 43 to 84 years of age and
      living in Beaver Dam, Wisconsin, in 1988 were invited for a baseline examination
      (1988-1990) and a 5-year follow-up examination (1993-1995). Refractions were
      determined according to the same protocol at both examinations. Aphakic and
      pseudophakic eyes were excluded as well as eyes with best corrected Snellen
      visual acuity of 20/40 and worse. After exclusions, refraction was obtained on
      3007 right eyes and 3012 left eyes of the 3684 people participating in both
      examinations. RESULTS: Right and left eyes behaved similarly. Spherical
      equivalent became more positive in the youngest subjects and more negative in
      older subjects. After adjusting for other factors, the 5-year change in spherical
      equivalent of those 45, 55, 65, and 75 years of age was +0.15, +0.18, +0.10, and 
      0.07D, respectively. Severity of nuclear sclerosis was related to the amount of
      change. Those with mild nuclear sclerosis at baseline had a change of +0.2 D,
      whereas those with severe nuclear sclerosis had a change of -0.5 D. The amount of
      change was also related to gender, diabetes, and age at onset of myopia. It was
      unrelated to education and baseline spherical equivalent. CONCLUSIONS: Changes in
      spherical equivalent over a 5-year period were small. Before the age of 70,
      people became more hyperopic. After the age of 70, people became more myopic.
      Much of the myopic change may be related to increasing nuclear sclerosis.

PMID- 10393031
TI  - Compliance with methodological standards when evaluating ophthalmic diagnostic
      tests.
AB  - PURPOSE: To draw attention to the importance of methodological standards when
      carrying out evaluations of ophthalmic diagnostic tests by reviewing the extent
      of compliance with these standards in reports of evaluations published within the
      ophthalmic literature. METHODS: Twenty published evaluations of ophthalmic
      screening/diagnostic tests or technologies were independently assessed by two
      reviewers for compliance with the following methodological standards:
      specification of the spectrum composition for populations used in the evaluation,
      analysis of pertinent subgroups, avoidance of work-up (verification) bias,
      avoidance of review bias, presentation of precision of results for test accuracy,
      presentation of indeterminate test results, and presentation of test
      reproducibility. RESULTS: Compliance ranged from just 10% (95%CI, 1%-32%) for
      presentation of test reproducibility data and avoidance of review bias to 70%
      (95%CI, 46%-88%) for avoidance of work-up bias and presentation of indeterminate
      test results. Only 5 of the 20 evaluations complied with four or more of the
      methodological standards and none with more than five of the standards.
      CONCLUSIONS: The evaluations of ophthalmic diagnostic tests discussed in this
      article show limited compliance with accepted methodological standards but are no
      worse than previously described for evaluations published in general medical
      journals. Adherence to these standards by researchers can improve the study
      design and reporting of evaluations of new diagnostic techniques. Limited
      compliance, combined with a lack of awareness of the standards among users of
      research evidence, may lead to the inappropriate adoption of new diagnostic
      technologies, with a consequent waste of health care resources.

PMID- 10393032
TI  - Proteoglycan synthesis by bovine keratocytes and corneal fibroblasts: maintenance
      of the keratocyte phenotype in culture.
AB  - PURPOSE: To determine the effect of serum on morphology, growth, and proteoglycan
      synthesis by primary cultures of collagenase-isolated bovine keratocytes.
      METHODS: Keratocytes were isolated from bovine corneas using sequential
      collagenase digestion and cultured in Dulbecco's modified Eagle's medium (DMEM),
      with and without fetal bovine serum (FBS). Proteoglycans synthesized by the cells
      in culture and by keratocytes in intact cornea culture were metabolically
      radiolabeled with 35SO4. The proteoglycans were characterized by their
      sensitivity to keratanase, chondroitinase ABC, and heparatinase and by their size
      on Superose 6 HR. Cell number was determined by measuring DNA content of the
      culture dishes. RESULTS: Keratocytes cultured in 10% FBS proliferated, appeared
      fibroblastic, and synthesized only 9% of the total glycosaminoglycan as keratan
      sulfate (KS), whereas cells in serum-free media were quiescent, appeared
      dendritic, and synthesized 47% KS, a value similar to the 45% KS for corneas
      radiolabeled overnight in organ culture. This increased proportion of KS
      synthesis in serum-free media was caused by a moderate increase in KS synthesis
      combined with a substantial decrease in chondroitin sulfate (CS) synthesis.
      Fractionation on Superose 6 High Resolution showed the size and relative amounts
      of the CS- and KS-containing proteoglycans synthesized by keratocytes in serum
      free media also more closely resembled that of keratocytes in corneas in organ
      culture than keratocytes in media containing serum. CONCLUSIONS: A comparison of
      proteoglycan synthesis and cell morphology between keratocytes in corneas in
      organ culture and in cell culture indicates that keratocytes maintain a more
      native biosynthetic phenotype and appearance when cultured in serum-free media.
      These results also suggest that culturing in the presence of serum fundamentally
      alters the keratocyte phenotype to an activated cell, mimicking certain changes
      observed during wound healing.

PMID- 10393033
TI  - Evidence of long-term survival of donor-derived cells after limbal allograft
      transplantation.
AB  - PURPOSE: Severe destruction of the corneal limbus causes conjunctival invasion
      and subsequent visual loss. Limbal allograft transplantation (LAT) was recently
      proposed for the treatment of these disorders. However, whether the method
      functions as a stem cell transplantation of the corneal epithelium remains
      unclear. This study provided evidence that donor-derived corneal epithelial cells
      survive long after LAT. METHODS: Epithelial cells on the paracentral cornea in
      patients who have undergone LAT were subjected to fluorescence in situ
      hybridization (FISH) and polymerase chain reaction restriction fragment length
      polymorphism (RFLP) analysis. X and Y chromosomes were detected using sex
      chromosome-specific probes in the FISH analysis, and HLA-DPBI antigens were
      examined in the RFLP analysis. Eyes receiving conventional penetrating
      keratoplasty (PKP) served as controls. RESULTS: Donor-derived epithelial cells
      were detected in three of five eyes (60.0%) in the FISH analysis and in seven of
      nine eyes (77.8%) in the RFLP analysis. Among these eyes, one and three eyes in
      the FISH and RFLP analysis, respectively, had both donor- and recipient-derived
      cells. In control PKP eyes, none of the eyes in the FISH analysis and one of
      eight eyes (12.5%) in the RFLP analysis had donor-derived cells. CONCLUSIONS:
      These results suggest that donor-derived cells survive much longer after LAT than
      those after PKP, and that LAT may function as stem cell transplantation of the
      corneal epithelium.

PMID- 10393034
TI  - Plasminogen activator inhibitor type 2 in human corneal epithelium.
AB  - PURPOSE: To examine normal human corneal epithelium in vivo and in vitro for
      expression and status of plasniinogcn activ:ltor inhibitor type 2 (PAI-2).
      METHODS: Normal hiuman corneas were prepared for frozen sections and for culture
      of corneal keratinocytes. PAI-2 was analyzed by immunohistochemistry and western
      blot analysis uising antibodies that recognize all forms of PAI-2. RESULTS: In
      vivo and in vitro, PAI-2 was immunohistochemically localized to the superficial
      corneal keratinocytes. Immunostaining also revealed the presence of PAI-2 in its
      relaxed (i.e., cleaved) conformation. In vivo, the staining pattern of the
      relaxed form was identical with that of total PAI-2, but in vitro the relaxed
      form was detected in a smaller subpopulation of superficial cells. In vitro, the
      staining pattern indicated a cytoplasmic localization for PAI-2. Western blot
      analysis revealed that most of the PAI-2 was cell associated and functionally
      active. CONCLUSIONS: The present results are the first to show that PAI-2 is
      found in normal human corneal epithelium in vivo and in vitro, where it can be
      considered as a differentiation product. At least in vitro, all detectable PAI-2
      is cell associated, with a cytoplasmic distribution. A subpopulation of
      keratinocytes also contains PAI-2 in its relaxed (i.e., cleaved) conformation.
      Cleavage by an as yet unidentified cytoplasmic proteinase may constitute a
      crucial aspect of the function of corneal epithelial PAI-2, which may be relevant
      to terminal differentiation and death of the corneal keratinocyte.

PMID- 10393035
TI  - Excimer laser effects on outflow facility and outflow pathway morphology.
AB  - PURPOSE: To determine the relative contributions to aqueous outflow resistance of
      the tissues distal to the inner wall of Schlemm's canal. METHODS: While
      performing constant pressure perfusion at 10 mm Hg, a 193-nm excimer laser
      (Questek) was used to precisely remove portions of sclera, unroofing Schlemm's
      canal while leaving the inner wall intact. The laser beam was masked to produce a
      beam 2 mm by 1 mm. The laser output was constant at a fluency of 75 mJ/cm2 and 20
      Hz. The excimer laser at a frequency of 1 Hz was used as the aiming beam.
      Photoablation was performed on human cadaver eyes at the limbus at an angle of 0
      degrees to 45 degrees from the optical axis. As the excimer photoablations
      progressed, Schlemm's canal was visualized by the fluorescence of the Barany's
      solution containing fluorescein dye. After perfusion fixation the eyes were
      immersion-fixed overnight. The facility of outflow before (Co) and after (Ce) the
      excimer ablation was measured in 7 eyes. RESULTS: The facility of outflow
      increased in all eyes after the excimer sinusotomy, from a mean of 0.29+/-0.02
      before the sinusotomy to 0.37+/-0.03 microl/min per mm Hg after (P < 0.05). The
      mean ratio of outflow facility after and before ablation (Ce/Co) was 1.27+/-0.08
      (range, 1.20-1.39), a reduction of outflow resistance of 21.3%. Using the formula
      of Ellingsen and Grant (1972), percentage of resistance to outflow eliminated =
      100 [1 - alphaCo/Ce - (1 - alpha)Co], where alpha = fraction of the circumference
      dissected. Assuming that because of circumferential flow approximately 50% of
      Schlemm's canal is drained by the single opening made in the outer wall ablation
      studies, this results in resistance to outflow eliminated of 35%, which is
      consistent with the calculated eliminated resistance derived from the data of
      Rosenquist et al., 1989. Light and scanning electron microscopy confirmed the
      integrity of the inner wall Schlemm's canal underlying the area of ablation.
      CONCLUSIONS: The results provide direct evidence indicating that approximately
      one third of resistance to outflow in the human eye lies distal to the inner wall
      Schlemm's canal in an enucleated perfused human eye.

PMID- 10393036
TI  - Conjugate ocular oscillations during shifts of the direction and depth of visual
      fixation.
AB  - PURPOSE: To characterize dynamic properties of combined saccade-vergence eye
      movements that occur as the point of visual fixation is shifted between objects
      lying in different directions and at different depths. METHODS: Using the scleral
      search-coil technique, eye movements were measured in 10 normal subjects as they
      made voluntary, disjunctive gaze shifts comprising a range of saccades and
      vergence movements. RESULTS: By analyzing eye acceleration records, the authors
      identified small-amplitude (0.2-0.7 degrees), high-frequency (23-33 Hz),
      conjugate horizontal oscillations of the eyes during the vergence movement that
      followed the initial saccade. When the shift of the fixation point required a
      large vergence component (17 degrees , every subject showed these oscillations;
      they were present in approximately a third of responses. Approximately 5% of
      responses showed oscillations that had horizontal and vertical components.
      Oscillations were less prominent with shifts that had smaller vergence components
      and were absent after saccades made between targets located at optical infinity.
      CONCLUSIONS: These findings suggest that a common mechanism gates both the
      saccadic and vergence components of disjunctive gaze shifts, a likely candidate
      being the pontine omnipause neurons. When a saccade is immediately followed by a
      prolonged vergence movement, the omnipause neurons remain silent, leading to
      small-amplitude saccadic oscillations. Shifts in the point of visual fixation
      that require a large vergence movement may be a useful experimental strategy to
      induce saccadic oscillations.

PMID- 10393037
TI  - CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2
      q24.3.
AB  - PURPOSE: To define the clinical characteristics and determine the gene
      localization for a previously undescribed form of congenital fibrosis of the
      extraocular muscles (CFEOM), referred to as CFEOM type 3 (CFEOM3). METHODS: A
      large family with CFEOM was identified, and participating individuals underwent
      ophthalmologic examination and donated blood for genetic analysis. The family's
      disorder was tested for linkage to the known CFEOM loci, followed by a genome
      wide search and linkage refinement using polymorphic DNA markers. RESULTS: Thirty
      eight members of this Canadian family participated in the study. Affected
      individuals are born with a nonprogressive eye movement disorder characterized by
      variable expression of ptosis and restrictive external ophthalmoplegia. Severely
      affected individuals have ptosis, primary gaze fixed in a hypo- and exotropic
      position, and marked restriction of eye movement bilaterally. Mildly affected
      individuals have normally positioned globes with a limitation of vertical gaze.
      Moderately affected individuals have asymmetrical involvement with one eye
      severely and one eye mildly affected. The disorder is autosomal dominant with
      variable expression and probable incomplete penetrance. Genetic analysis reveals
      linkage to markers on 16q24.2q24.3. A maximum lod score of 5.8 occurs at markers
      D16S3063 and D16S689, and the CFEOM3 disease gene is located within a 5.6-cM
      region flanked by D16S486 and D16S671. CONCLUSIONS: These data establish that
      CFEOM3 is a phenotypically variant and genotypically distinct form of CFEOM with
      linkage to chromosome 16qter. The authors have previously demonstrated that
      CFEOM1 results from a developmental absence of the superior division of the
      oculomotor nerve. The authors hypothesize that CFEOM3 results from a defect
      analogous to, but distinct from CFEOM1.

PMID- 10393038
TI  - Effects of Na-K-2Cl cotransport regulators on outflow facility in calf and human
      eyes in vitro.
AB  - PURPOSE: Cultured human trabecular meshwork (TM) cells possess substantial Na-K
      Cl activity, which is involved in the regulation of TM cell volume. The
      hypothesis in the present study was that drugs that affect the cotransporter
      might alter aqueous humor outflow facility (C) in the intact eye. The effects of
      agents and conditions known to modulate Na-K-CI cotransport activity and/or TM
      cell volume on C in perfused anterior segments were investigated. METHODS: Human
      and calf eyes were dissected and perfused, and C was determined according to
      standard published methods. Perfusates with modified osmolarity were used to
      cause alterations in TM cell volume. Cl-free perfusate and/or bumetanide (10(-5)
      M) was used to inhibit Na-K-Cl cotransport activity, and vasopressin (10(-7) M,
      10(-8) M) was used to stimulate cotransport activity. RESULTS: In human eyes,
      hypo-osmotic perfusate decreased C 12%, whereas hyper-osmotic perfusate increased
      C 44%. These changes lasted approximately 30 minutes, after which C began to
      normalize. Inhibition of Na-K-Cl cotransport using Cl-free medium or bumetanide
      resulted in facility increases of 27% and 22%, respectively. There was an
      additive increase in C with bumetanide plus Cl-free media. Stimulating Na-K-Cl
      cotransport with 10(-8)M and 10(-7)M vasopressin resulted in 28% and 35%
      decreases in C, respectively. The results were similar in calf eyes: Cl-free
      medium or bumetanide resulted in 41% and 52% increases in C, whereas 10(-8) M and
      10(-7) M vasopressin resulted in 14% and 19% decreases in C, respectively.
      CONCLUSIONS: Modulation of Na-K-Cl cotransport results in changes in C that may
      be mediated in part by cell volume changes.

PMID- 10393039
TI  - Microvasculature of the rat optic nerve head.
AB  - PURPOSE: To describe the arterial blood supply, capillary bed, and venous
      drainage of the rat optic nerve head. METHODS: Ocular microvascular castings from
      6 Wistar rats were prepared by injection of epoxy resin through the common
      carotid arteries. After polymerization, tissues were digested with 6 M KOH, and
      the castings washed, dried, and coated for scanning electron microscopy. RESULTS:
      Immediately posterior to the globe, the ophthalmic artery trifurcates into the
      central retinal artery and two posterior ciliary arteries. The central retinal
      artery directly provides capillaries to the nerve fiber layer and only
      contributes to capillary beds in the neck of the nerve head. The remainder is
      supplied by branches of the posterior ciliary arteries that are analogous to the
      primate circle of Zinn-Haller. Arterioles arising from these branches supply the
      capillaries of the transitional, or laminar, region of the optic nerve head.
      These capillaries are continuous with those of the neck and retrobulbar optic
      nerve head. All optic nerve head capillaries drain into the central retinal vein
      and veins of the optic nerve sheath. A flat choroidal sinus communicates with the
      central retinal vein, the choriocapillaris, and with large veins of the optic
      nerve sheath. CONCLUSIONS: The microvasculature of the rat optic nerve head bears
      several similarities to that of the primate, with a centripetal blood supply from
      posterior ciliary arteries and drainage into the central retinal and optic nerve
      sheath veins. Association of nerve sheath veins with the choroid represents an
      important difference from the primate.

PMID- 10393040
TI  - Peripheral endothelial dysfunction in normal pressure glaucoma.
AB  - PURPOSE: To assess vascular endothelial function in patients with normal pressure
      glaucoma using forearm blood flow responses to intra-arterial infusions of
      endothelial-dependent and -independent vasoactive agents. METHODS: Eight patients
      with newly diagnosed and untreated normal pressure glaucoma and eight healthy age
      and sex-matched control volunteers underwent measurement of forearm blood flow
      using venous occlusion plethysmography. Blood flow was assessed in response to
      incremental doses of sodium nitroprusside (an endothelial-independent
      vasodilator), acetylcholine (an endothelial-dependent vasodilator) and the
      vasoconstrictor N(G)-monomethyl-L-arginine (an inhibitor of nitric oxide
      synthase). RESULTS: Sodium nitroprusside caused a dose-related increase in
      forearm blood flow in patients and controls. Glaucoma patients appeared to have
      an increased vasodilatory response, but this was not significant (P = 0.23).
      Acetylcholine also induced vasodilatation in both groups, but the response was
      significantly reduced in the glaucoma group (P = 0.04). N(G)-monomethyl-L
      arginine induced a similar degree of vasoconstriction in both groups (P = 0.76).
      CONCLUSIONS: This study has shown an impairment of peripheral endothelium
      mediated vasodilatation in normal pressure glaucoma. These findings would support
      the concept of a generalized vascular endothelial dysfunction in patients with
      this condition.

PMID- 10393041
TI  - Digital image capture and automated analysis of posterior capsular opacification.
AB  - PURPOSE: To develop and validate a digital imaging and analysis technique for
      assessing the extent of posterior capsular opacification after cataract surgery.
      METHODS: Retroillumination images of the posterior capsule were obtained by using
      a digital camera mounted on a slit lamp. The images were analyzed using an
      available image analysis software program. The image acquisition and analysis
      techniques were tested for face validity, reproducibility, and the ability to
      detect progression of capsular opacity over time. RESULTS: Digital
      retroillumination images were obtained without patient discomfort. Automated
      analysis of images correlated well with clinical grading both at slit lamp
      examination and when looking at the images themselves (Spearman's correlation
      coefficient >0.7). Analysis of images taken at different times showed high
      reproducibility (intraclass correlation >0.9), and the system was able to
      identify progression of capsular opacity over a 2-year period with a mean
      increase of 15.8% in progressors versus an increase of 0.6% in nonprogressors (P
      < 0.05). CONCLUSIONS: Digital retroillumination images of the posterior capsule
      can be obtained reliably, and automated analyses correlate well with clinical
      assessment. The system presented here uses commercially available instruments and
      software, and it is practical for use in longitudinal studies of posterior
      capsule opacification. It is reliable, easy to use, and can detect small changes
      in the percentage area covered by posterior capsule opacification over time.

PMID- 10393043
TI  - Characterization of cyclosporin A transport in cultured rabbit corneal epithelial
      cells: P-glycoprotein transport activity and binding to cyclophilin.
AB  - PURPOSE: The purpose of this study was to characterize cyclosporin A (CsA) uptake
      and transport in cultured rabbit corneal epithelial cells (RCECs). METHODS: CsA
      uptake was evaluated by measuring time-dependent 3H-CsA accumulation in confluent
      RCECs. Bidirectional 3H-CsA fluxes were measured across the RCEC layers grown on
      Transwell-COL culture plate inserts. The anti-P-gp monoclonal antibody C219 was
      used in western blot analysis to probe for the presence of P-gp in these cells.
      RESULTS: The accumulation of 3H-CsA was time and temperature dependent. Steady
      state was reached by 60 minutes. The initial uptake was saturable and was
      suppressed as a function of increases in preloading with unlabeled CsA. This
      uptake process was enhanced by metabolic inhibition with either 3-O
      methylglucose, MG, or 10 mM NaN3 and 3-O-MG. The largest increase was obtained
      with 10 mM NaN3 in combination with 3-O-MG. In their presence, uptake increased
      by 40%. A multidrug-resistance (MDR)-reversing agent (i.e., 500 microM verapamil,
      100 microM vincristine, 100 microM progesterone, 100 microM testosterone, 500
      microM quinidine, or 100 microM chlorpromazine) significantly increased 3H-CsA
      accumulation. The largest increase was obtained with 500 microM quinidine (i.e.,
      36%). Conversely, verapamil and vincristine produced the largest inhibition of 3H
      CsA efflux (i.e., 19% and 28%, respectively). However, in the presence of 10
      microM unlabeled CsA, 3H-CsA efflux increased. 3H-CsA flux across RCEC layers
      showed marked directional asymmetry. The stromal (S) to tear (T) side
      transcellular 3H-CsA permeability coefficient (Ptrans) was approximately seven
      times higher than that in the T-to-S direction. The S-to-T Ptrans was reduced by
      an MDR-reversing agent by up to 40%. Western blot analysis of lysates revealed a
      170-kDa membrane protein band. CONCLUSIONS: These results suggest that in RCEC
      the tear-side-facing membrane has a P-gp-mediated drug efflux pump. In addition,
      there is suggestive evidence for the presence of the cytosolic protein,
      cyclophilin. The presence of P-gp in these cells could help protect them from
      being damaged by the uptake of toxic substances.

PMID- 10393042
TI  - A transgenic animal model of osmotic cataract. Part 1: over-expression of bovine
      Na+/myo-inositol cotransporter in lens fibers.
AB  - PURPOSE: Intracellular osmotic stress is believed to be linked to the advancement
      of diabetic cataract. Although the accumulation of organic osmolytes (myo
      inositol, sorbitol, taurine) is thought to protect the lens by maintaining
      osmotic homeostasis, the physiologic implication of osmotic imbalance (i.e.,
      hyperosmotic stress caused by intracellular over-accumulation of organic
      osmolytes) on diabetic cataract formation is not clearly understood. Studies from
      this laboratory have identified several osmotic compensatory mechanisms thought
      to afford the lens epithelium, but not the lens fibers, protection from water
      stress during intervals of osmotic crisis. This model is founded on the
      supposition that the fibers of the lens are comparatively more susceptible to
      damage by osmotic insult than is the lens epithelium. To test this premise,
      several transgenic mouse lines were developed that over-express the bovine
      sodium/myo-inositol cotransporter (bSMIT) gene in lens fiber cells. METHODS: Of
      the several transgenic mouse lines generated, two, MLR14 and MLR21, were analyzed
      in detail. Transgenic mRNA expression was analyzed in adult and embryonic
      transgenic mice by a coupled reverse transcriptase-polymerase chain reaction (RT
      PCR) and in situ hybridization on embryonic tissue sections, respectively.
      Intralenticular myo-inositol content from individual mouse lenses was quantified
      by anion exchange chromatography and pulsed electrochemical detection. Ocular
      histology of embryonic day 15.5 (E15.5) embryos from both transgenic (TG)
      families was analyzed and compared to their respective nontransgenic (NTG)
      littermates. RESULTS: Both RT-PCR and in situ hybridization determined that
      transgene expression was higher in line MLR21 than in line MLR14. Consistent with
      this, intralenticular myo-inositol from MLR21 TG mice was markedly higher
      compared with NTG littermates or MLR14 TG mice. Histologic analysis of E15.5
      MLR21 TG embryos disclosed a marked swelling in the differentiating fibers of the
      bow region and subcapsular fibers of the central zone, whereas the lens
      epithelium appeared morphologically normal. The lenticular changes, initiated
      early during lens development in TG MLR21 embryos, result in severe bilateral
      nuclear cataracts readily observable in neonates under normal rearing and dietary
      conditions. In contrast, TG MLR14 pups reared under standard conditions produced
      no lens opacity. CONCLUSIONS: Lens fiber swelling and related cataractous
      outgrowth positively correlated to the degree of lens bSMIT gene expression and
      intralenticular myo-inositol content. The affected (i.e., swollen) lens fibers
      appeared to be unable to cope with the water stress generated by the transgene
      induced over-accumulation of myo-inositol and, as a result of this inability to
      osmoregulate, suffered osmotic damage due to water influx.

PMID- 10393044
TI  - Multiple cyclic nucleotide phosphodiesterases in human trabecular meshwork cells.
AB  - PURPOSE: To characterize cyclic nucleotide phosphodiesterase isozyme activities
      in human trabecular meshwork cells and primary cultures of porcine trabecular
      meshwork cells. METHODS: Radioimmunoassay of acetylated acid extracts was used to
      determine changes in cyclic adenosine monophosphate (cAMP) and cyclic quanosine
      monophosphate (cGMP) in human trabecular meshwork cells treated with
      phosphodiesterase isoform selective inhibitors. Cyclic nucleotide
      phosphodiesterase activities were measured using the two-step radioisotope
      procedure (Thompson). Enzyme activities in the supernatant of human cells were
      fractionated using anion-exchange chromatography. Additionally, human and porcine
      trabecular meshwork cell transcripts of phosphodiesterase family-specific
      isoforms were studied by reverse transcription-polymerase chain reaction and
      nucleotide sequencing. RESULTS: In intact human cells, selective inhibitors for
      phosphodiesterase 4 (rolipram) and 5 (E4021) gene families were effective in
      augmenting cyclic nucleotide accumulation in response to isoproterenol or sodium
      nitroprusside, respectively. cAMP and cGMP hydrolytic activities, resolved using
      Trisacryl M anion-exchange chromatography, showed a cAMP phosphodiesterase peak
      that was minimally sensitivity to cGMP but modestly inhibited by rolipram and a
      cGMP phosphodiesterase peak that was sensitive to inhibition by E4021. Further
      evaluation of the cGMP phosphodiesterase demonstrated Michaelis-Menten kinetics
      and competitive inhibition by E4021. Messenger RNA transcripts for
      phosphodiesterase 4, 5, and 7 isozymes were isolated in human trabecular meshwork
      cells. However, in porcine trabecular meshwork cells only isozymes for
      phosphodiesterase 4 and 5 isozymes were detected. CONCLUSIONS: Human trabecular
      meshwork cells express phosphodiesterase 4, 5, and 7 gene family isoforms and
      enzyme activities, suggesting that selective isoform inhibitors could be used to
      augment the actions of antiglaucoma drugs that use cyclic nucleotides as second
      messengers.

PMID- 10393045
TI  - Neurogenic vasoconstriction as affected by cholinergic and nitroxidergic nerves
      in dog ciliary and ophthalmic arteries.
AB  - PURPOSE: To determine the involvement of noradrenergic and other vasoconstrictor
      nerves in the contraction of ocular arteries and the modification by cholinergic
      and nitroxidergic nerves of vasoconstrictor nerve function. METHODS: Changes in
      isometric tension were recorded in helical strips of the canine posterior ciliary
      and external ophthalmic arteries denuded of the endothelium, which were
      stimulated by transmurally applied electrical pulses (5 Hz). Vasoconstrictor
      mediators were analyzed by pharmacological antagonists, such as prazosin,
      alpha,beta-methylene ATP, a P2alpha-purinoceptor antagonist, and BIBP3226, a
      neuropeptide Y receptor antagonist. RESULTS: Transmural electrical stimulation
      produced contractions that were potentiated by N(G)-nitro-L-arginine (L-NA), a
      nitric oxide (NO) synthase inhibitor. The contraction was partially inhibited by
      prazosin and abolished by combined treatment with alpha,beta-methylene ATP but
      was not influenced by BIBP3226. Stimulation-induced contraction was attenuated by
      physostigmine and potentiated by atropine. Contractions induced by exogenous ATP
      were reversed to relaxations by alpha,beta-methylene ATP. In the strips treated
      with L-NA, prazosin, and alpha,beta-methylene ATP, the addition of L-arginine
      elicited relaxations by nerve stimulation. The ATP-induced relaxation was
      attenuated by aminophylline, whereas neurogenic relaxation was unaffected.
      CONCLUSIONS: Ciliary and ophthalmic arterial contractions by nerve stimulation
      are mediated by norepinephrine and ATP, which stimulate alpha1-adrenoceptor and
      P2X purinoceptor, respectively. ATP from the nerve is unlikely involved in
      vasodilatation. Acetylcholine derived from the nerve impairs the neurogenic
      contraction, possibly by interfering with the release of vasoconstrictor
      transmitters, and neurogenic NO also inhibits the contraction postjunctionally by
      physiological antagonism.

PMID- 10393046
TI  - Measuring geographic atrophy in advanced age-related macular degeneration.
AB  - PURPOSE: To present a method developed for measuring areas of geographic atrophy
      (GA) in advanced age-related macular degeneration, METHODS: A microfilm reader
      projected the 30 degrees fundus photograph of the macula. Retinal landmarks,
      atrophic areas, and spared areas within the atrophy were traced, without access
      to drawings of other years. The total atrophic area was calculated, as was the
      atrophy within a four-disc-area circle entered on the estimated foveal center.
      The configuration of the atrophy was documented. RESULTS: Avoidable sources of
      discrepancy included variability in peripapillary atrophy seen on the photograph,
      and variability seen in the extent of the field. Reproducibility studies found a
      median absolute difference of 0.19 Macular Photocoagulation Study disc areas (DA)
      in total atrophy between repeat drawings, with 75% of repeat drawings having a
      difference of less than 0.33 DA. For central atrophy measures, there was a median
      difference of 0.08 DA, with 75% of pairs having a difference of less than 0.18
      DA. Features making the definition of borders of GA difficult include the
      presence of drusen and pigmentary alteration, a fundus in which choroidal vessels
      are easily visible, and variation in the appearance of GA within a single area of
      atrophy. CONCLUSIONS: This method provides a reliable means of measuring the size
      of atrophic areas in GA and will be useful for measuring longitudinal change. It
      may be difficult to determine whether central spared areas are present, and
      correlation with visual acuity and macular perimetry may be helpful.

PMID- 10393047
TI  - Effects of acetazolamide on passive and active transport of fluorescein across
      the normal BRB.
AB  - PURPOSE: To investigate the effect of the carbonic anhydrase inhibitor
      acetazolamide (AZM) on passive permeability and active transport of fluorescein
      across the blood-retina barrier in healthy subjects. The study may have
      implications for the understanding of the edema-reducing effect of AZM. METHODS:
      The effect of AZM on the blood-retina barrier function was assessed by
      differential vitreous spectrofluorometry using fluorescein as a tracer. The study
      included fourteen healthy subjects in a randomized double-masked crossover trial
      with 3 days' treatment with AZM (500 mg/d) and placebo, respectively. The two
      examinations were separated by at least 1 week. Fluorescein concentration was
      determined separately from its metabolite fluorescein glucuronide. The passive
      permeability of fluorescein was determined by computerized modeling and curve
      fitting to the preretinal curve and the plasma concentration curve obtained at 30
      to 60 minutes after the injection of fluorescein. The unidirectional permeability
      due to outward active transport from vitreous to blood was estimated from the
      preretinal gradient and the plasma concentration at 7 to 10 hours after
      injection. RESULTS: Treatment with AZM was associated with significant increases
      in passive permeability and unidirectional permeability of fluorescein. For the
      passive permeability the increase was on average 0.3+/-0.4 nm/s (mean+/-SD;
      range, -0.8-1.0 nm/s), and for the unidirectional permeability the increase was
      on average 7.4 nm/s+/-7.0 (mean+/-SD; range, -3.3-19.0 nm/s). CONCLUSIONS:
      Acetazolamide caused an increase in passive permeability. Unidirectional
      permeability was increased by AZM, indicating a stimulation of the outward active
      transport of fluorescein. It has been proposed that the edema-reducing effect of
      AZM is due to stimulated ion and fluid removal from the retina to the choroid.
      The results of this study are consistent with AZM affecting the blood-retina
      barrier with stimulation of at least one ion transport mechanism.

PMID- 10393048
TI  - Regulation of gamma-glutamylcysteine synthetase subunit gene expression in
      retinal Muller cells by oxidative stress.
AB  - PURPOSE: To study regulation of gamma-glutamylcysteine synthetase (GCS) heavy and
      light subunit gene expression in Muller cells under conditions of oxidative
      stress. METHODS: Experiments were carried out with an SV40 transformed cell line
      (rMC-1) that exhibits the phenotype of rat retinal Muller cells. Endogenous
      glutathione levels were modified by treating cells with diethyl maleate (DEM),
      D,L-buthionine sulfoximine (BSO), or tert-butylhydroquinone (TBH). In other
      experiments, cells were grown in either high (28 mM) or normal (5.5 mM) glucose
      medium for 1 week to examine the effects of hyperglycemia. Cells were processed
      for reduced glutathione (GSH) measurement, RNA extraction, cell count, and, in
      some cases, lactate dehydrogenase activity. The steady state mRNA levels of GCS
      heavy and light subunits were measured by northern blot analysis using specific
      cDNA probes. Changes in mRNA levels were normalized to beta-actin or 18S rRNA.
      RESULTS: Treatment with DEM for 30 minutes depleted cell GSH to 20% to 30% of the
      normal value. GSH content recovered completely 6 hours after returning to normal
      medium. BSO treatment for 12 hours followed by a medium change for 6 hours
      resulted in a cell GSH level that was 26% that of untreated cells. If cells were
      left in BSO for 18 hours, however, GSH levels were reduced to < 1%. Treatment
      with TBH for 12 hours led to a 77% increase in cellular GSH level. Treatment with
      DEM, TBH, or BSO for 18 hours led to a significant induction of the mRNA level of
      the GCS subunits, regardless of glucose concentration in the medium. Shorter BSO
      treatment exerted no effect. Prolonged hyperglycemia resulted in 30% lower GSH
      level, 55% lower GCS heavy subunit, and 30% lower GCS light subunit mRNA levels.
      CONCLUSIONS: Oxidative stress induced the gene expression of GCS heavy and light
      subunits in Muller cells. The effect of BSO on mRNA levels correlated with the
      degree of GSH depletion. Prolonged hyperglycemia lowered GCS subunit mRNA and GSH
      levels.

PMID- 10393049
TI  - Expression of proteoglycan decorin in neural retina.
AB  - PURPOSE: To identify the expression of chondroitin/dermatan sulfate proteoglycan
      decorin in retina and to elucidate its changes during development and ischemia
      reperfusion. METHODS: Expression of decorin in rat retina was investigated by
      reverse transcription-polymerase chain reaction (RT-PCR) and
      immunohistochemistry. Distributional changes during development and transient
      ischemia in model eyes also were investigated by immunohistochemical experiments.
      RESULTS: Gene expression of decorin core protein was identified in rat retina by
      RT-PCR. Decorin immunoreactivities were shown throughout the retina, especially
      in the ganglion cell layer. In developing rat retinas, at embryonic stages
      (embryonic day 16), decorin was distributed uniformly throughout the retina. As
      retina matured, the intensity of decorin immunostaining in retinal inner layers
      and retinal pigment epithelium increased. Furthermore, in experimental transient
      retinal ischemia, after transient downregulation of the decorin core protein gene
      between 24 and 48 hours after the ischemia, recovered (or increased) expression
      was shown by semiquantitative RT-PCR experiments. Immunohistochemical studies
      revealed strong decorin immunoreactivities in the damaged inner layers 1 week
      later. CONCLUSIONS: The expression of decorin was identified in adult and
      developing rat retina. The distributional changes of decorin during the retinal
      development suggest that this proteoglycan may play a role in the differentiation
      of retinal ganglion cells. Moreover, in rat ischemia-reperfusion models, the
      alterations in gene expression and immunohistochemical localization showed the
      contribution of this proteoglycan to the damage and repair processes in diseased
      retina.

PMID- 10393050
TI  - Marked alteration of sterol metabolism and composition without compromising
      retinal development or function.
AB  - PURPOSE: To evaluate the consequences of altering retinal sterol metabolism and
      composition on the development, histologic organization, and electrophysiological
      function of the retina, under conditions that mimic the biochemical hallmarks of
      the Smith-Lemli-Opitz (SLO) syndrome. METHODS: Pregnant Sprague-Dawley rats were
      fed cholesterol-free chow containing AY9944 (treated group), an inhibitor of
      3beta-hydroxysterol delta7-reductase, from gestational day 6 through postnatal
      day (P)28. Control animals were fed the same chow, but without AY9944. In
      addition, progeny in the treated group were injected subcutaneously every other
      day from birth to P28 with an olive oil emulsion containing AY9944; control
      animals received olive oil emulsion alone. At various postnatal times, tissues
      from treated and control animals were harvested, and their sterol profiles were
      analyzed by reversed-phase high-performance liquid chromatography. Companion eyes
      from animals of both groups were examined histologically at P1. At P28, animals
      were evaluated by electroretinography; tissues were then harvested for
      biochemical analysis and companion eyes were subjected to histologic and
      ultrastructural analyses. RESULTS: Treatment of developing rats with AY9944
      caused markedly abnormal accumulation of 7-dehydrosterols and severely reduced
      cholesterol levels in all tissues examined, relative to control animals. Despite
      this, treated animals exhibited normal retinal development and had no overt
      ocular defects or decrease in electroretinographic function, up to P28.
      CONCLUSIONS: These results were unexpected, given the known biophysical effects
      of such sterol alterations on membrane properties and the profound dysmorphic and
      cognitive abnormalities associated with genetic defects in 3beta-hydroxysterol
      delta7-reductase that have been linked to the SLO syndrome. The results suggest
      that 7-dehydrosterols can substitute functionally for cholesterol in the retina
      or perhaps can act synergistically with subthreshold levels of residual
      cholesterol to allow normal cellular structure and function to be achieved.

PMID- 10393051
TI  - Caspaselike proteases activated in apoptotic photoreceptors of Royal College of
      Surgeons rats.
AB  - PURPOSE: To study the role of caspase-like proteases, especially roles of more
      extensively characterized caspase-1 and caspase-2, in apoptotic photoreceptor
      cell degeneration in Royal College of Surgeons (RCS) rats. METHODS: Both RCS and
      Sprague-Dawley rats were used. Cryosections of the retinas at various postnatal
      times were immunostained with antibodies against caspase-1 (interleukin-1beta
      converting enzyme, ICE) and caspase-2 (Nedd2/Ich-1). Double staining with TdT
      dUTP terminal nick-end labeling (TUNEL), propidium iodide, and the antibodies was
      also performed. To evaluate the time course of protein expression, western blot
      analysis was carried out. The temporal profile of caspase-like protease activity
      was studied using a fluorogenic tetrapeptide substrate, acetyl-tyrosyl-valyl
      alanyl-aspartic acid alpha (4-methyl-coumaryl-7-amide) (Ac-YVAD-MCA).
      Intravitreal injection of a caspase-1 inhibitor, acetyl-tyrosyl-valyl-alanyl
      aspartic-aldehyde (Ac-YVAD-CHO), at postnatal days 21 (P21) and P26 was performed
      to see if this caused a decrease in apoptotic cell number at P28. RESULTS: TUNEL
      positive photoreceptors of RCS rats stained strongly with antibodies against
      caspase-1 and caspase-2. Double staining studies revealed that caspase-1 and
      caspase-2 were coexpressed in apoptotic cells. Western blot analysis showed that
      active forms of caspase-1-like and caspase-2-like proteases were upregulated at
      P28, concurrent with the peak in TUNEL-positive cells. The enzymatic activity of
      caspase-1-like protease was elevated in RCS rat retinas at P28, and the inhibitor
      of caspase-1 transiently reduced the number of the apoptotic photoreceptors.
      CONCLUSIONS: Activation of caspase-like proteases plays an important role in
      photoreceptor apoptosis of RCS rats.

PMID- 10393052
TI  - VEGF increases retinal vascular ICAM-1 expression in vivo.
AB  - PURPOSE: Intraocular injections of vascular endothelial growth factor (VEGF), a
      peptide implicated in the pathogenesis of diabetic retinopathy, can induce
      retinal ischemia. Diabetic retinal ischemia may be caused, in part, by the
      adhesion of leukocytes to the retinal vasculature. In this study, the ability of
      VEGF to increase the expression of intercellular adhesion molecule-1 (ICAM-1) and
      other adhesion molecules in capillary endothelium and the retinal vasculature was
      examined. METHODS: The expression of ICAM-1, vascular cell adhesion molecule-1
      (VCAM-1), E-selectin, and P-selectin on human brain capillary endothelial cell
      monolayers exposed to VEGF was quantitated by immunoassay. The effect of VEGF on
      retinal vascular ICAM-1 expression was determined in ICAM-1 immunofluorescence
      studies of retinal flat-mounts and in RNase protection assays. RESULTS: VEGF
      increased capillary endothelial cell ICAM-1 levels in a dose- and time-dependent
      manner (6-24 hours, plateau after 6 hours; EC50, 25 ng/ml). VEGF failed to alter
      E-selectin, P-selectin, or VCAM-1 levels under the conditions tested.
      Intravitreal injections of pathophysiologically relevant concentrations of VEGF
      increased ICAM-1 protein and mRNA levels in the retinal vasculature. CONCLUSIONS:
      VEGF increases retinal vascular ICAM-1 expression. VEGF-induced increases in ICAM
      1 may promote retinal leukostasis in diabetic eyes.

PMID- 10393053
TI  - Beta-arrestin-related proteins in ocular tissues.
AB  - PURPOSE: Proteins of the arrestin family contribute to the regulation of G
      protein-mediated transduction. In this study, the presence of beta-arrestins in
      ocular tissues was investigated. METHODS: Mouse monoclonal and rabbit polyclonal
      antibodies were raised against the peptide Val-Asp-Thr-Asn-Ile-Leu-Glu-Leu-Asp
      Thr-Asn-Asp-Asp-Asp-Ile, a sequence present in beta-arrestins 1 and 2 but absent
      from visual arrestin. These antibodies were used for the immunohistologic
      detection of beta-arrestins in parafin sections of rodent eyes fixed in Bouin's
      solution. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of
      RNA from bovine retina, retinal pigmented epithelial (RPE) cells, lens epithelial
      cells, and human corneal fibroblasts was performed using beta-1 arrestin primers.
      RESULTS: In the eye, bet-arrestin staining predominated in RPE, inner segments of
      photoreceptors, synaptic spherules of rods, inner plexiform layer and ganglion
      cell fibers, epithelial cells from ciliary body, and vessels. RT-PCR amplified a
      480 bp product, corresponding to the predicted length. The sequence of PCR
      products from bovine retina and RPE cells was identical with the bovine beta
      arrestin mRNA. CONCLUSIONS: beta-arrestins were detected in several ocular
      tissues. In photoreceptor cells, their specific localization in the synaptic
      terminals and plexiform layer suggests a role of beta-arrestin in synaptic
      transmission. In other ocular tissues, the presence of beta-arrestin may be
      related either to adrenergic signal transduction or to signal transduction
      mediated by other G-protein-coupled receptors.

PMID- 10393054
TI  - Screening of the gene encoding the alpha'-subunit of cone cGMP-PDE in patients
      with retinal degenerations.
AB  - PURPOSE: To screen the exons of the gene encoding the alpha'-subunit of cone
      cyclic guanosine monophosphate (cGMP>phosphodiesterase (PDE6C) for mutations in a
      group of 456 unrelated patients with various forms of inherited retinal disease,
      including cone dystrophy, cone-rod dystrophy, macular dystrophy, and
      simplex/multiplex and autosomal recessive retinitis pigmentosa. METHODS: The 22
      exons of the PDE6C gene were screened for mutations either by denaturing gradient
      gel electrophoresis and single-strand conformation polymorphism electrophoresis
      (SSCP) or by SSCP alone; variants were sequenced directly. RESULTS: Although many
      sequence variants were found, none could be associated with disease. CONCLUSIONS:
      The results show that PDE6C was not the site of the amutations responsible for
      the types of inherited retinal degenerations analyzed in the large population of
      patients 'in the present study. The types of degeneration included those that
      predominantly affect cone-mediated function (cone and cone-rod dystrophies) or
      rod-mediated function (retinitis pigmentosa) or that have a predilection for
      disease in the macula (macular dystrophies).

PMID- 10393056
TI  - Visual function correlates with nerve fiber layer thickness in eyes affected by
      ocular hypertension.
AB  - PURPOSE: To test whether the high variability observed when measuring pattern
      electroretinogram (PERG), visual evoked potentials (VEP), and spatial contrast
      sensitivity (SCS) in eyes with ocular hypertension is associated with variation
      in nerve fiber layer thickness, as measured by optical coherence tomography
      (OCT). METHODS: The study involved 32 untreated eyes (32 patients; age range, 29
      64 years) showing a normal whiteon-white 24/2 Humphrey (San Leandro, CA)
      perimetry, IOP between 23 and 28 mm Hg, best corrected acuity of 20/20 or better,
      and none of the following papillary signs on conventional color stereo slides:
      rim notch(es), peripapillary splinter hemorrhages, or increased vertical-to
      horizontal cup-to-disc ratio. On recruitment, each eye underwent SCS testing,
      OCT, PERG, and VEP recordings. Linear regression (Pearson's test) or Spearman's
      rank regression was adopted for the analysis of the data. RESULTS: The 95%
      confidence limits of the electrophysiological data were: PERG P50 latency, 59.3
      to 63 msec; PERG P50 to N95 amplitude, 0.74 to 1.15 cmV; VEP P100 latency, 113 to
      118 msec; VEP N75 to P100 amplitude, 3.81 to 4.90 micromV. The 360 degrees nerve
      fiber layer thickness overall (NFLO) ranged between 113 and 169 microm (145+/-16
      microm; mean+/-SD) and significantly correlated with PERG P50 to N95 amplitude
      (r: 0.518; P = 0.002), PERG P50 latency (r: -0.470; P = 0.007), VEP N75 to P100
      amplitude (r: 0.460; P = 0.008), VEP P100 latency (r = -0.422; P = 0.016) and SCS
      at 3 cyc/deg (r: -0.358; P = 0.044). CONCLUSIONS: The variability of PERG, VEP,
      and SCS testing observed in eyes with ocular hypertension is associated with
      differences in NFL thickness (the thinner the layer, the worse the visual
      function).

PMID- 10393055
TI  - Inhibition of vascular endothelial cell morphogenesis in cultures by limbal
      epithelial cells.
AB  - PURPOSE: To study the in vitro angiogenic activity of human conjunctival and
      limbal epithelial cells and conjunctival, limbal, and corneal fibroblasts in a
      three-cell-type coculture model. METHODS: Human umbilical vein endothelial cells
      (EC) were cocultured with epithelial cells, fibroblasts, or epithelial cells and
      fibroblasts to test their effect on EC morphogenesis. Neutralizing antibodies to
      some known angiogenic factors were added to the culture to see whether the EC
      morphogenesis may be blocked by a particular antibody. RESULTS: Conjunctival and
      limbal epithelial cells exhibited very little or no stimulatory effect on EC tube
      formation when examined in an EC- epithelial cell coculture system. In contrast,
      conjunctival, limbal, and corneal fibroblasts all promoted EC morphogenesis when
      examined under the same culture conditions. Fibroblast-induced EC morphogenesis
      was inhibited by addition of anti-vascular endothelial growth factor (VEGF)
      and/or anti-basic fibroblast growth factor (bFGF) antibodies to the culture
      medium. In the three-cell-type coculture system consisting of ECs, fibroblasts,
      and epithelial cells, limbal epithelial cells (but not conjunctival epithelial
      cells) exhibited a strong inhibitory effect on fibroblast-induced EC tube
      formation. CONCLUSIONS: The proangiogenic activity of ocular surface fibroblasts
      is probably mediated through a paracrine mechanism by VEGF and bFGF. Limbal
      epithelial cells, but not conjunctival epithelial cells, inhibit fibroblast
      stimulated angiogenesis.

PMID- 10393057
TI  - Isoproterenol, forskolin, and cAMP-induced nitric oxide production in pig ciliary
      processes.
AB  - PURPOSE: To investigate whether isoproterenol and forskolin, two adenylylcyclase
      activators, or 8-bromo-cAMP, an adenosine 3',5'-cyclic monophosphate (cAMP)
      analog, increase nitric oxide (NO) production in isolated porcine ciliary
      processes. METHODS: Nitrite (an NO metabolite) was measured (Griess reaction)
      before and 2 hours after exposure to 0.1 to 100 microM isoproterenol (a beta
      adrenoreceptor agonist), 0.01 to 100 microM forskolin, or 0.1 to 1000 microM 8
      bromo-cAMP. Some experiments were conducted in the presence of 0.5 mM N(G)-nitro
      L-arginine methyl ester (L-NAME; a nitric oxide synthase [NOS] inhibitor), 10
      microM propranolol (a beta-adrenoreceptor antagonist), or 1 microM KT 5720 (a
      cAMP-dependent protein kinase inhibitor). cAMP production was also measured (by
      immunoassay). RESULTS: Nitrite production was increased by isoproterenol
      (maximum, 10 microM: 164%; P < 0.001), forskolin (maximum, 10 microM: 254%; P <
      0.001), and 8-bromo-cAMP (maximum, 100 microM: 184%; P < 0.001), an effect
      prevented by L-NAME (P < 0.05-0.001). Propranolol inhibited only isoproterenol
      induced (10 microM) nitrite production (P < 0.05), whereas KT 5720 (P < 0.05)
      inhibited isoproterenol- (10 microM) and 8-bromo-cAMP-induced (10 microM) nitrite
      production. Furthermore, cAMP production evoked by isoproterenol (10 microM, P <
      0.05) but not by forskolin (10 microM, P < 0.001) was inhibited by propranolol (P
      < 0.05). CONCLUSIONS: In isolated porcine ciliary processes, drugs activating
      adenylylcyclase or mimicking cAMP increase the production of NO by a mechanism
      that appears to involve both a cAMP-dependent protein kinase and NOS.

PMID- 10393058
TI  - HLA-B27 subtypes and HLA class II alleles in Japanese patients with anterior
      uveitis.
AB  - PURPOSE: Some patients with anterior uveitis (AU) have ankylosing spondylitis
      (AS) and are HLA-B27 class I-positive. The purpose of this study was to
      investigate whether there are differences in HLA at the allele level among each
      group of patients with AU. METHODS: Seventy-three patients with AU were studied.
      They were classified into three groups: 31 with AS-associated AU, 14 with HLA-B27
      associated AU, and 28 with idiopathic AU. Three control groups without AU were
      used: 138 random subjects, 33 HLA-B27-positive healthy subjects, and 19 HLA-B27
      positive patients with AS. DRB1 and DQB1 genotyping was performed using
      polymerase chain reaction (PCR)-single-strand conformation polymorphism (PCR
      SSCP) and PCR-restriction fragment length polymorphism. HLA-B27 subtype was
      determined by PCR-SSCP. RESULTS: There was no difference in the frequency of any
      class I antigen except HLA-B27 among the patients studied. The frequencies of HLA
      DR12 in AS-associated AU and HLA-DR1 in HLA-B27-associated AU showed an increase.
      In HLA-B27-associated AU, DRB1*0101 and DQB1*0501 were increased compared with
      HLA-B27-positive control subjects. When HLA-B27 subtype distribution was compared
      among the groups, the proportion of B*2704 was significantly lower in HLA-B27
      associated AU (P = 0.037), however, such a difference was not present in AS
      associated groups. CONCLUSIONS: These results indicated that B*2704 seemed to be
      less susceptible to AU compared with B*2705 in Japanese subjects. The increase of
      HLA-DR12 and HLA-DR1 in AU may be caused by linkage disequilibrium with B*2704
      and B*2705, respectively.

PMID- 10393059
TI  - Characterization of a mouse Cx50 mutation associated with the No2 mouse cataract.
AB  - PURPOSE: Recently, a missense mutation in the mouse connexin 50 (Cx50) gene has
      been associated with the nuclear opacity 2 (No2) mouse cataract. This missense
      mutation (D47A) resulted in an aspartate-to-alanine substitution at amino acid
      position 47 in the first extracellular domain of Cx50. To better understand the
      role of Cx50 in the pathogenesis of congenital cataract, the functional
      consequences of the D47A mutation in the Xenopus oocyte expression system were
      studied. METHODS: D47A was constructed using polymerase chain reaction (PCR)
      mutagenesis. Xenopus oocytes were injected with in vitro transcribed cRNA
      encoding wild-type mouse Cx50 (Cx50wt), wild-type rat Cx46 (Cx46wt), D47A, or
      combinations of wild-type and mutant connexins. The oocytes were then
      devitellinized and paired. Gap junctional conductance (Gj) was measured using a
      dual two-microelectrode voltage-clamp technique. RESULTS: Homotypic oocyte pairs
      expressing wild-type Cx50 or Cx46 were well coupled. In contrast, oocytes
      injected with D47A cRNA did not form gap junctional channels when paired
      homotypically. To test whether the D47A mutation could interact with wild-type
      connexins in a dominant negative manner, oocytes were injected with equal amounts
      of mutant and wild-type connexin cRNA, mimicking the heterozygous condition.
      Expression of D47A did not inhibit the development of junctional conductance in
      paired oocytes induced by wild-type Cx50 or Cx46. CONCLUSIONS: These results
      indicate that the D47A mutation acts as a loss-of-function mutation without
      strong dominant inhibition. In No2 mice, the mutation would be predicted to
      result in a reduction in intercellular communication, leading to
      cataractogenesis. It may also cause other qualitative changes such as a change in
      permeability for small molecules.

PMID- 10393060
TI  - Human ocular vasodynamic changes in light and darkness.
AB  - PURPOSE: To determine whether changes in the retinal blood flow in light and
      darkness occur in humans. METHODS; The systolic and diastolic flow velocities
      were measured by color Doppler in the ophthalmic and the central retinal arteries
      in 12 healthy individuals in light and darkness. RESULTS: In the ophthalmic
      artery there was a trend toward lower systolic velocity in darkness compared with
      that in the light, but there was no change in diastolic velocity. In the central
      retinal artery the systolic and the diastolic flow velocities were markedly
      increased in darkness. After re-exposure to light the systolic flow velocity
      decreased. CONCLUSIONS: Darkness is associated with increased blood flow velocity
      in the central retinal artery, probably reflecting increased retinal metabolic
      demands by the photoreceptors.

PMID- 10393061
TI  - N(epsilon)(carboxymethyl)lysin and the AGE receptor RAGE colocalize in age
      related macular degeneration.
AB  - PURPOSE: To investigate whether glycoxidation products and the receptor for
      advanced glycation end products (RAGE) are present and colocalize in subfoveal
      membranes of patients with age-related macular degeneration (ARMD). METHODS:
      Surgically removed subfoveal fibrovascular membranes from 12 patients, 11 related
      to ARMD and 1 to an idiopathic membrane, were analyzed for the presence of the
      glycoxidation product N(epsilon)-(carboxymethyl)lysin (CML), one of the receptors
      for advanced glycation end products, RAGE, and the activation of NFkB, using
      immunohistochemistry. RESULTS: CML-like immunoreactivity was found in all ARMD
      specimens examined adjacent or colocalized with RAGE, but not in the idiopathic
      membrane. RAGE immunoreactive material was found in CD68-positive cells and in
      the fibrous matrix. CD68-positive cells and surrounding areas stained for p50,
      the activated form of NFkB. CONCLUSIONS: These results indicate that
      glycoxidation products are present in subretinal membranes of patients with ARMD.
      The concomitant expression of RAGE in these membranes and the finding of
      activated NFkB is suggestive of an implication of glycoxidation product formation
      in the pathogenesis of the disease.

PMID- 10393062
TI  - Frequency of mutations in the gene encoding the alpha subunit of rod cGMP
      phosphodiesterase in autosomal recessive retinitis pigmentosa.
AB  - PURPOSE: To determine the mutation spectrum of the PDE6A gene encoding the alpha
      subunit of rod cyclic guanosine monophosphate (cGMP)phosphodiesterase and the
      proportion of patients with recessive retinitis pigmentosa (RP) due to mutations
      in this gene. METHODS: The single-strand conformation polymorphism (SSCP)
      technique and a direct genomic sequencing technique were used to screen all 22
      exons of this gene for mutations in 164 unrelated patients with recessive or
      isolate RP. Variant DNA fragments revealed by SSCP analysis were subsequently
      sequenced. Selected alleles that altered the coding region or intron splice sites
      were evaluated further through segregation analysis in the families of the index
      cases. RESULTS: Four new families were identified with five novel mutations in
      this gene that cosegregated with disease. Combining the data presented here with
      those published earlier by the authors, eight different mutations in six families
      have been discovered to be pathogenic. Two of the mutations are nonsense, five
      are missense, and one affects a canonical splice-donor site. CONCLUSIONS: The
      PDE6A gene appears to account for roughly 3% to 4% of families with recessive RP
      in North America. A compilation of the pathogenic mutations in PDE6A and those
      reported in the homologous gene PDE6B encoding the beta subunit of rod cGMP
      phosphodiesterase shows that the cGMP-binding and catalytic domains are
      frequently affected.

PMID- 10393063
TI  - Topography of cone electrophysiology in the enhanced S cone syndrome.
AB  - PURPOSE: To investigate the topography of cone electroretinographic (ERG)
      responses in the enhanced S cone syndrome (ESCS). METHODS: A 19-year-old female
      with ESCS who was one of the original cases defining the syndrome was studied.
      Full-field, focal (Maculoscope) and multifocal (VERIS) ERGs were performed using
      white light. Multifocal ERG responses were also generated with red and blue
      stimuli and with a slow m-sequence to elicit off-responses. Results were analyzed
      by averaging data in rings at increasing eccentricity from the fovea and compared
      to data recorded identically from a normal subject. RESULTS: The full-field ERG
      from this patient showed typ ical large slow photopic waveforms and was unchanged
      from recordings made 9 years earlier. The focal ERG showed signals of borderline
      low amplitude from the fovea with the multifocal ERG, the ESCS responses from the
      central macula had a relatively normal waveform, and those 9 degrees to 20
      degrees from fixation showed the prolonged wave-form that characterizes the full
      field ERG. Responses were larger to blue light than red light in ESCS in both
      center and periphery. The central ESCS responses were relatively normal in timing
      to both red and blue light, whereas the peripheral ESCS responses were markedly
      delayed to both. Off-responses were seen in ESCS only near the foveal center.
      CONCLUSIONS: The marked differences between central and peripheral ERG responses
      in ESCS suggest that there are different distributions of S, L, and M cones in
      these regions and that S cones may feed into different neural pathways in the
      center and periphery. It was postulated that in ESCS, S cones may partially
      replace L and M cones centrally and feed into the usual S cone pathways. In the
      periphery, however, there is little L and M cone b-wave activity in ESCS, and S
      cones may usurp both the space and neural pathways of the rods.

PMID- 10393064
TI  - Severe ocular abnormalities in C57BL/6 but not in 129/Sv p53-deficient mice.
AB  - PURPOSE: To demonstrate the importance of genetic background interaction on the
      development of ocular phenotypes in p53-deficient mice. METHODS: Eyes of adult
      mice, homozygous and heterozygous for the p53 gene disruption in the 129/SvJ and
      C57BL/6J (B6) genetic backgrounds, and their F1 progeny were examined by indirect
      ophthalmoscopy and by light microscopy. RESULTS: Indirect ophthalmoscopy revealed
      unilateral or bilateral vitreal opacities, fibrous retrolental tissue, and
      retinal folds in adult B6 mice but not in 129/Sv mice homozygous for a p53 null
      mutation. In B6 p53-/- mice, blood vessels extended from the peripapillary inner
      retina through the posterior vitreous and into the retrolental membrane. Optic
      nerves were hypoplastic. CONCLUSIONS: These findings indicate that alleles from
      the B6 background contribute to the aberrant ocular phenotypes observed in p53
      deficiency. They also suggest that p53 or the pathway in which it functions may
      be important for normal eye development.

PMID- 10393065
TI  - The rhodopsin content of human eyes.
AB  - PURPOSE: To measure the total amount of rhodopsin in human eyes across the life
      span and to test the hypothesis that the rhodopsin content of infants' and the
      elderly's eyes is lower than at other ages. METHODS: Rhodopsin was extracted from
      retinal and pigment epithelial fractions of 196 eyes of 102 donors, ages 27
      weeks' gestation through 94 years, using quantitative procedures. To recover
      photopigment bleached by unavoidable light exposure, the fractions from 78 eyes
      were incubated with 9-cis retinal. The total photopigment (retinal plus pigment
      epithelial fractions) per eye was examined for significant changes with age,
      using the higher value from pairs of eyes. RESULTS: The median rhodopsin content
      of the higher eye of adults is 6.45 nmoles (range, 3.33-10.84 nmoles) with 8
      nmoles or more recovered from 28% of all adult eyes. The rhodopsin content of
      infants' eyes (< 12 months post-term) is significantly lower than that of older
      individuals and increases with age. After infancy, no change with age is found.
      For both infants and adults, 9-cis retinal significantly increases the amount of
      photopigment recovered without reducing the variance in the amount of
      photopigment recovered. The rhodopsin content is estimated to be 50% of the
      median adult amount early in infancy, approximately 5 weeks postterm (95%
      confidence interval, 0-10 weeks postterm). CONCLUSIONS: A developmental increase
      in rhodopsin content occurs during infancy. Thereafter rhodopsin content remains
      constant. The amount of rhodopsin recovered from human eyes is quite variable.
      Bleaching alone cannot explain the variability.

PMID- 10393066
TI  - The course of maturation of rod-mediated visual thresholds in infants.
AB  - PURPOSE: To measure the developmental course of infants' rod-mediated thresholds.
      METHODS: Thresholds for detecting stimuli (2 degrees diameter, 50 msec duration)
      presented at 10 degrees (parafoveal site) or 30 degrees (peripheral site) from a
      central fixation target were estimated using a preferential-looking method. Nine
      infants were tested at both stimulus positions at ages 10, 18, and 26 weeks.
      RESULTS: At 10 weeks, infants' thresholds at both sites were significantly higher
      than those of adults. The infants' average threshold at 10 degrees was 0.5 log
      unit higher than the infants' average threshold at 30 degrees. Adults' thresholds
      at the two sites were equal. Thresholds of all infants decreased with age until
      by age 26 weeks the parafoveal and peripheral thresholds were equal and were the
      same as those of adults. The rate of change of parafoveal thresholds was
      significantly faster than the rate of change of peripheral thresholds.
      CONCLUSIONS: Although postreceptoral factors cannot be ruled out, the results
      suggest that developmental increases in rod outer segment length and rhodopsin
      density account for most of the threshold changes during infancy.

PMID- 10393067
TI  - Lipofuscin turnover.

PMID- 10393068
TI  - TIGR and stretch in the trabecular meshwork.

PMID- 10393069
TI  - Modes of cardiovascular regulation during middle childhood.
AB  - Obtaining meaningful baseline measures of children's cardiovascular activity
      (CVA) has been difficult because of constraints inherent to laboratory procedures
      that are used to assess individual differences in response to stress. To
      circumvent these problems, we performed repeated baseline measures of pulse rate
      (PR) and blood pressure for 174 children (aged 7-10 yr) in their natural school
      setting throughout 2 1-week periods. In addition, experimental assessments of
      cardiovascular reactivity (CVR) were conducted after each baseline period while
      children participated in a challenging cognitive task. Multivariate analyses of
      physiological indices revealed three primary styles of cardiovascular
      functioning. Two of them, characterizing children either with high PR and low
      blood pressure or conversely with low PR and high blood pressure, have already
      been described in the research literature. However, analyses also revealed a
      third group of children (48% of the subjects) who had both low PR and low blood
      pressure. Findings indicate developmental differences in cardiovascular
      regulation and highlight the need to consider both variations in baseline CVA as
      well as in CVR when examining children's physiological adaptation in everyday
      settings.

PMID- 10393070
TI  - Differences in toileting habits between children with chronic encopresis,
      asymptomatic siblings, and asymptomatic nonsiblings.
AB  - No studies have compared toileting-specific behaviors of encopretic children with
      those of asymptomatic children and have controlled for environmental factors such
      as parental attitudes, parenting styles, and bathroom facilities. This study
      prospectively examined the toileting habits of 86 chronically encopretic children
      compared with those of 27 asymptomatic siblings and 35 asymptomatic nonsiblings.
      Although encopretic children experienced significantly more soiling than did
      controls, the total number of daily bowel movements passed in the toilet (+/-SD)
      was comparable in the three groups (.92 +/- .76 in encopretic children compared
      with 1.14 +/- .43 and 1.08 +/- .47 in siblings and nonsiblings, respectively).
      Encopretic children experienced pain with defecation more often than did
      controls. During the 14-day study period, encopretic children complained of pain
      on 2.75 +/- 4.03 days compared with .58 +/- 1.84 days among sibling controls and
      2.31 +/- 3.21 days among nonsibling controls. The mean pain score in encopretic
      children was .76 +/- 1.00 compared with .05 +/- .15 and .26 +/- .38 among
      siblings and nonsiblings, respectively. All three groups of children sat on the
      toilet without parental prompting the same number of times each day. In summary,
      children with chronic encopresis do not seem to avoid toileting, and they exhibit
      toileting behaviors that are very similar to those of asymptomatic siblings as
      well as to those of nonsibling controls.

PMID- 10393071
TI  - Approaches to the measurement of depressive symptomatology in children with
      cancer: attempting to circumvent the effects of defensiveness.
AB  - This study explored an alternative self-report approach to the measurement of
      depressive symptoms in children that was hypothesized to be less prone to the
      distorting influences of defensiveness. Children with cancer (n = 107) and
      healthy controls (n = 442) completed measures of adaptive style (defensiveness,
      anxiety), a standard depression inventory, and an anhedonia measure used as a
      proxy estimate of depressive symptoms. As predicted, children with cancer
      reported significantly fewer depressive symptoms than did healthy controls on the
      depression inventory, whereas no differences were found on the measure of
      anhedonia. However, self-report of anhedonia was found also to be subject to the
      influence of defensiveness, and neither the depression inventory nor the
      anhedonia measure was significantly related to parent and physician ratings of
      depression. An approach that combined self-report measures of depression and
      anhedonia did not significantly improve the identification of children rated as
      depressed by parents or physicians. Measurement of anhedonia may provide an
      interesting avenue for further research, but there is still no adequately
      validated self-report instrument for the measurement of depressive symptoms in
      children with cancer.

PMID- 10393072
TI  - Psychosocial adjustment of children with chronic illness: an evaluation of three
      models.
AB  - This study was designed to assess social, emotional, and behavioral functioning
      of children with chronic illness and to evaluate three models addressing the
      impact of chronic illness on psychosocial functioning: discrete disease,
      noncategorical, and mixed. Families of children with cancer, sickle cell disease,
      hemophilia, and juvenile rheumatoid arthritis participated, along with families
      of classroom comparison peers without a chronic illness who had the closest date
      of birth and were of the same race and gender (COMPs). Mothers, fathers, and
      children provided information regarding current functioning of the child with
      chronic illness or the COMP child. Child Behavior Checklist and Children's
      Depression Inventory scores were examined. Results provided support for the
      noncategorical model. Thus, the mixed model evaluated in this study requires
      modifications before its effectiveness as a classification system can be
      demonstrated.

PMID- 10393073
TI  - Sleep and behavior problems among preschoolers.
AB  - This study described the relationship between amount of sleep and behavior
      problems among preschoolers. Participants were 510 children aged 2 to 5 years who
      were enrolled through 68 private pediatric practices. Parents reported on the
      amount of sleep their child obtained at night and in 24-hour periods. With
      demographic variables controlled, regression models were used to determine
      whether sleep was associated with behavior problems. The relationship between
      less sleep at night and the presence of a DSM-III-R psychiatric diagnosis was
      significant (odds ratio = 1.23, p = .026). Less night sleep (p < .0001) and less
      sleep in a 24-hour period (p < .004) were associated with increased total
      behavior problems on the Child Behavior Checklist; less night sleep (p < .0002)
      and less 24-hour sleep (p < .004) were also associated with more externalizing
      problems on that measure. Further research is needed to ascertain whether sleep
      is playing a causal role in the increase of behavior problems.

PMID- 10393074
TI  - Comparison of internalizing and externalizing symptoms in children with attention
      deficit hyperactivity disorder with and without comorbid tic disorder.
AB  - This study examined the relation between internalizing and externalizing symptoms
      in two groups of prepubertal boys (with and without multiple chronic tic
      disorder) with diagnosed attention-deficit hyperactivity disorder (ADHD). Parents
      and teachers completed the Child Behavior Checklist (CBCL) and Teacher's Report
      Form (TRF), respectively. Children were carefully evaluated for the absence of a
      chronic tic disorder. Boys with ADHD and chronic multiple tic disorder
      (ADHD/+tics) received significantly higher (p = .0032, Bonferroni correction)
      scores for the Anxious/Depressed, Thought Problems, and Attention Problem scales
      of the CBCL and the Delinquent Behavior, Thought Problems, and Somatic Complaints
      scales of the TRF than did boys without chronic tic disorder (ADHD/-tics).
      Although many of the individual items that differentiated (p < .05) the two
      groups of boys pertained to behaviors that characterize motor tics, obsessions,
      or compulsions, the ADHD/+tics group exhibited higher rates of anxious behavior
      (CBCL) and obscene language (TRF) than did the ADHD/-tics group.
      Anxiety/depressive symptoms were associated with aggressive/oppositional behavior
      in both samples. Children with mild tic disorder were more similar (CBCL) to
      ADHD/-tics boys than they were to children with more severe tic disorder. The
      relatively higher rate of comorbidity in the ADHD/+tics group suggests that tics
      may be a marker for more severe symptomatology in clinic-referred samples of
      children with ADHD. Furthermore, these data suggest that it is not the presence,
      per se, but rather the severity of tic disorder that is associated with higher
      rates of emotional and behavioral disturbances.

PMID- 10393075
TI  - Parental request to withhold a hearing test in a newborn of deaf parents.

PMID- 10393076
TI  - A fork in the road: decision time for behavioral pediatrics.
AB  - The rapid growth of managed care, and especially that of managed behavioral
      healthcare organizations (MBHOs), is likely to diminish the role of developmental
      behavioral pediatrics and separate care for medical and behavioral problems.
      Thus, a rethinking of the practice of developmental-behavioral pediatrics is
      required. This study reviews the structure of MBHOs, identifies barriers to the
      provision of services by developmental-behavioral pediatricians, describes
      alternative practice models for consideration, and makes recommendations. The
      aims of the recommendations are to stimulate an active discussion about these
      issues, spark an advocacy effort, and ensure the continued participation of
      developmental-behavioral pediatricians in the care of children with special
      needs. The study concludes that managed care will push developmental-behavioral
      pediatricians into integration with primary care group practices or into
      specialty mental health networks. Immediate discussion, action, and advocacy will
      be required to ensure a presence in these decisions for developmental-behavioral
      pediatricians.

PMID- 10393077
TI  - Predictors of early school age outcomes in very low birth weight children.

PMID- 10393079
TI  - The mechanism of activation of NADPH oxidase in the cell-free system: the
      activation process is primarily catalytic and not through the formation of a
      stoichiometric complex.
AB  - It is commonly assumed that activation of the superoxide-generating NADPH oxidase
      requires the formation of a stable complex between flavocytochrome b-245 (the
      gp91phox/p22phox heterodimer) and the cytosolic cofactors p47phox, p67phox and
      Rac2. This association is thought to convert flavocytochrome b-245, which
      contains the NADPH-binding site, flavin and haem centres, from an inactive into
      an active state. Here we provide evidence that, in the cell-free system, this
      activation process does not necessarily require the formation of a stable
      stoichiometric complex between the phox proteins. To explain this data we propose
      the hypothesis that p67phox (and possibly Rac2), are capable of activating
      flavocytochrome b-245 in a catalytic fashion, where a single molecule of p67phox
      (or Rac2) is capable of activating multiple flavocytochrome b-245 molecules.

PMID- 10393081
TI  - Osteocalcin binds tightly to the gamma-glutamylcarboxylase at a site distinct
      from that of the other known vitamin K-dependent proteins.
AB  - Vitamin K-dependent proteins contain a propeptide that is required for
      recognition by the enzyme gamma-glutamylcarboxylase. Substrates used in vitro for
      carboxylation studies lacking a prosequence are characterized by Km values in the
      millimolar range, whereas the Km for peptides containing a prosequence is three
      or four orders of magnitude smaller. Here we report that descarboxy-osteocalcin
      is an exception in this respect. With descarboxy-osteocalcin in purified
      propeptide-free recombinant carboxylase, the Km was 1.8 microM. Furthermore,
      osteocalcin was an inhibitor of descarboxy-osteocalcin carboxylation with a Ki of
      76 microM. In contrast with the other vitamin K-dependent proteins, free
      propeptides do not inhibit descarboxy-osteocalcin carboxylation. Moreover,
      propeptide-containing substrates were inhibited neither by osteocalcin nor by its
      propeptide. From our studies we conclude that descarboxy-osteocalcin must have an
      internal recognition sequence that binds to gamma-glutamylcarboxylase at a site
      different from the propeptide-recognition site.

PMID- 10393080
TI  - Talin contains three similar vinculin-binding sites predicted to form an
      amphipathic helix.
AB  - Using recombinant talin polypeptides and an SDS/PAGE-blot overlay assay, we have
      previously identified three regions of talin that are involved in binding to
      vinculin [Gilmore, Wood, Ohanian, Jackson, Patel, Rees, Hynes and Critchley
      (1993) J. Cell Biol. 122, 337-347]. We have confirmed these observations by using
      a yeast two-hybrid assay and shown that talin residues 498-656, 852-950 and 1929
      2029 are each capable of binding to vinculin residues 1-258. We have further
      defined the three vinculin-binding sites in talin to residues 607-636, 852-876
      and 1944-1969; alignment of these sequences shows 59% similarity, although there
      are only two identical residues. Predictions of secondary structure indicate that
      this vinculin-binding motif forms an amphipathic alpha-helix. The hydrophobic
      face of helix 607-636 contains three aligned leucines (residues 608, 615 and
      622), which show conservative substitutions in the other two sites. To test the
      possibility that this might constitute a leucine zipper involved in vinculin
      binding, we mutated each leucine residue to an alanine. The results showed that
      this leucine repeat is not essential to the interaction between talin and
      vinculin. We also used the yeast two-hybrid system to define further the talin
      binding site within vinculin residues 1-258. C-terminal deletions made in
      accordance with exon boundaries showed that vinculin residues 1-167 are capable
      of interacting with each of the three vinculin-binding sites in talin. However,
      all N-terminal deletions abolished binding. The results suggest that the talin
      binding site in vinculin has a relatively complex fold, whereas the vinculin
      binding motif in talin is contained within a short linear peptide sequence that
      is repeated three times in the talin rod domain.

PMID- 10393078
TI  - The mitochondrial permeability transition pore and its role in cell death.
AB  - This article reviews the involvement of the mitochondrial permeability transition
      pore in necrotic and apoptotic cell death. The pore is formed from a complex of
      the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase
      and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and
      inner membranes. In vitro, under pseudopathological conditions of oxidative
      stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore
      state allowing free diffusion of low-Mr solutes across the inner membrane. These
      conditions correspond to those that unfold during tissue ischaemia and
      reperfusion, suggesting that pore opening may be an important factor in the
      pathogenesis of necrotic cell death following ischaemia/reperfusion. Evidence
      that the pore does open during ischaemia/reperfusion is discussed. There are also
      strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can
      recruit a number of other proteins, including Bax, and that the complex is
      utilized in some capacity during apoptosis. The apoptotic pathway is amplified by
      the release of apoptogenic proteins from the mitochondrial intermembrane space,
      including cytochrome c, apoptosis-inducing factor and some procaspases. Current
      evidence that the pore complex is involved in outer-membrane rupture and release
      of these proteins during programmed cell death is reviewed, along with
      indications that transient pore opening may provoke 'accidental' apoptosis.

PMID- 10393082
TI  - Identification of pituitary adenylate cyclase-activating polypeptide1-38-binding
      factor in human plasma, as ceruloplasmin.
AB  - 125I-Pituitary adenylate cyclase-activating polypeptide (PACAP) 1-38 is able to
      bind a factor in human plasma, which can be displaced by unlabelled PACAP 1-38
      and PACAP 28-38 but not by the other biologically active form, PACAP 1-27.
      Likewise, 125I-PACAP 28-38 binds this plasma factor, whereas 125I-PACAP 1-27 does
      not. Apparent Kd values were measured to be 12.0+/-1.3 and 3.4+/-1.5 nM for PACAP
      1-38 and PACAP 28-38, respectively, using a competition assay with 125I-PACAP 28
      38. Purification of the PACAP 1-38-binding factor from human blood was made by
      ethanol precipitation of serum followed by Ni2+-chelating and anion-exchange
      chromatography. A 120-kDa band on SDS/PAGE, as well as some proteolytic products,
      was blotted on to PVDF membrane and their N-terminal amino acid sequences
      determined. In combination with a mass-spectrometric fingerprinting of a tryptic
      digest of the 120-kDa band, this PACAP 1-38-binding factor was identified as
      ceruloplasmin. Purified commercial ceruloplasmin shows identical mobility on
      SDS/PAGE to the PACAP 1-38-binding factor and the same binding characteristics to
      PACAP 1-38, 1-27 and 28-38, using the same amount of ceruloplasmin as was
      expected to be found in the human plasma. Furthermore, the ability of plasma to
      bind 125I-PACAP 1-38 or 28-38 disappeared when ceruloplasmin was
      immunoprecipitated from plasma with rabbit anti-human ceruloplasmin Ig.

PMID- 10393083
TI  - Cloning and characterization of gp36, a human mucin-type glycoprotein
      preferentially expressed in vascular endothelium.
AB  - A mucin-type glycoprotein has been described in murine, rat and canine tissues as
      a differentiation antigen and influenza-virus receptor. We have cloned a cDNA
      from human placenta RNA encoding the corresponding human protein, a type-I
      integral membrane protein of 162 amino acids. Madin-Darby canine kidney cells
      transfected with the cDNA clone directed the cell-surface expression of a 36-kDa
      O-glycosylated sialoglycoprotein, gp36, and two minor isoforms of 28 and 70 kDa.
      gp36 has a broad tissue distribution with strong expression in lung, placenta and
      skeletal muscle, as shown by PCR screening of different cDNA libraries.
      Immunohistochemical detection of gp36 in cryo-sections of human placenta, kidney,
      lung and nasal polyps showed that the glycoprotein is expressed at the apical
      plasma membrane of vascular endothelial cells. Expression of gp36 was not
      restricted to endothelial cells, as alveolar epithelial cells were found to
      express gp36 as well.

PMID- 10393084
TI  - Purification and enzymic properties of the fructosyltransferase of Streptococcus
      salivarius ATCC 25975.
AB  - The recombinant fructosyltransferase (Ftf) of Streptococcus salivarius was
      expressed in Escherichia coli and purified to electrophoretic homogeneity after a
      combination of adsorption, ion-exchange and gel-filtration chromatography. The N
      terminal signal sequence of the Ftf was removed by E. coli at the same site as in
      its natural host. The purified Ftf exhibited maximum activity at pH 6.0 and 37
      degrees C, was activated by Ca2+, but inhibited by the metal ions Cu2+, Zn2+,
      Hg2+ and Fe3+. The enzyme catalysed the transfer of the fructosyl moiety of
      sucrose to a number of acceptors, including water, glucose and sucrose via a Ping
      Pong mechanism involving a fructosyl-enzyme intermediate. While this mechanism of
      catalysis is utilized by the levansucrases of Bacillus subtilis and Acetobacter
      diazotrophicus and the values of the kinetic constants for the three enzymes are
      similar, sucrose was a far more efficient fructosyl-acceptor for the Ftf of S.
      salivarius than for the two other enzymes.

PMID- 10393085
TI  - Expression of I2PP2A, an inhibitor of protein phosphatase 2A, induces c-Jun and
      AP-1 activity.
AB  - Transient expression of I2PP2A, a potent inhibitor of protein phosphatase 2A
      (PP2A), in HEK-293 cells increased the concentration and DNA binding of the proto
      oncogene c-Jun. In contrast, expression of the catalytic subunit of PP2A (PP2AC)
      markedly decreased the concentration and DNA binding of c-Jun. Expression of
      I2PP2A also increased the transcriptional activity of activator protein-1, and
      this effect was diminished in a dose-dependent manner by expression of PP2AC.
      Densitometric analysis following Western blotting of extracts with antibodies
      specific for phospho-Ser63 and Ser73 suggests that the effects of I2PP2A and
      PP2AC expression might be mediated, in part, by changes in the phosphorylation of
      c-Jun at Ser63. The results indicate that I2PP2A elicits effects that are
      consistent with it acting as an inhibitor of PP2A in intact cells, and suggest
      that PP2A might exhibit site selectivity with respect to c-Jun phosphorylation.

PMID- 10393086
TI  - Expression, purification and biochemical characterization of recombinant murine
      secretory component: a novel tool in mucosal immunology.
AB  - Reconstitution of secretory IgA (S-IgA) by the association in vitro of secretory
      component (SC) and polymeric IgA (pIgA) obtained from hybridomas is a valuable
      tool in the study of the structure-function relationship in this particular class
      of antibody. Although dimeric IgA (dIgA) can be obtained and purified from
      hybridoma clones, SC remains tedious to isolate in sufficient amounts from
      colostral milk. Several murine models for the study of mucosal immunity are
      available, which could potentially benefit from the use of cognate IgA antibodies
      in various molecular forms, including dIgA and S-IgA. We report here on the
      establishment of two expression systems allowing the production of milligram
      amounts of pure recombinant murine SC (rmSC) with preserved murine pIgA-binding
      capability. The first system relies on the use of recombinant vaccinia virus to
      prompt infected HeLa cells to express the murine SC protein, whereas the second
      system is based on a stably transfected cell clone exhibiting murine
      glycosylation. The second source of rmSC will permit the study of the role of its
      sugar moieties in pathogen-host interactions, and the evaluation of its function
      in passive protection without risking adverse immune responses. The extensive
      biochemical characterization conducted in this study demonstrates that rmSC is a
      dependable and convenient alternative to the natural product, and indicates that
      the J chain is dispensable in the recognition of pIgA and SC in vitro, whereas it
      is required for proper pIgA-polymeric Ig receptor interaction in vivo.

PMID- 10393087
TI  - Reductive half-reaction of the H172Q mutant of trimethylamine dehydrogenase:
      evidence against a carbanion mechanism and assignment of kinetically influential
      ionizations in the enzyme-substrate complex.
AB  - The reactions of wild-type trimethylamine dehydrogenase (TMADH) and of a His-172-
      >Gln (H172Q) mutant were studied by rapid-mixing stopped-flow spectroscopy over
      the pH range 6.0-10.5, to address the potential role of His-172 in abstracting a
      proton from the substrate in a 'carbanion' mechanism for C-H bond cleavage. The
      pH-dependence of the limiting rate for flavin reduction (klim) was studied as a
      function of pH for the wild-type enzyme with perdeuterated trimethylamine as
      substrate. The use of perdeuterated trimethylamine facilitated the unequivocal
      identification of two kinetically influential ionizations in the enzyme-substrate
      complex, with macroscopic pKa values of 6.5+/-0.2 and 8.4+/-0.1. A plot of
      klim/Kd revealed a bell-shaped curve and two kinetically influential ionizations
      with macroscopic pKa values of 9.4+/-0.1 and 10.5+/-0.1. Mutagenesis of His-172,
      a potential active-site base and a component of a novel Tyr-His-Asp triad in the
      active site of TMADH, revealed that the pKa of 8.4+/-0.1 for the wild-type enzyme
      substrate complex represents ionization of the imidazolium side-chain of His-172.
      H172Q TMADH retains catalytic competence throughout the pH range investigated. At
      pH 10.5, and in contrast with the wild-type enzyme, flavin reduction in H172Q
      TMADH is biphasic. The fast phase is dependent on the trimethylamine
      concentration and exhibits a kinetic isotope effect of about 3; C-H bond cleavage
      is thus partially rate-limiting. In contrast, the slow phase does not show
      hyperbolic dependence on substrate concentration, and the observed rate shows no
      dependence on isotope, revealing that C-H bond cleavage is not rate-limiting. The
      analysis of H172Q TMADH, together with data recently acquired for the Y169F
      mutant of TMADH, reveals that C-H bond breakage is not initiated via abstraction
      of a proton from the substrate by an active-site base. The transfer of reducing
      equivalents to flavin via a carbanion mechanism is therefore unlikely.

PMID- 10393089
TI  - Cell polarization is required for ricin sensitivity in a Caco-2 cell line
      selected for ricin resistance.
AB  - It has been proposed that killing of mammalian cells by ricin requires efficient
      endocytic delivery to the trans-Golgi network (TGN) prior to retrograde transport
      to the endoplasmic reticulum and entry to the cytosol. In polarized epithelial
      cells, an efficient membrane-traffic pathway to the TGN is present from the
      basolateral but not the apical plasma-membrane domain. Thus one can hypothesize
      that a ricin-resistant phenotype might be demonstrated by polarized cells that
      fail to differentiate and thus fail to develop an efficient membrane-traffic
      pathway from the basolateral plasma membrane to the TGN. We have isolated and
      studied a ricin-resistant Caco-2 cell clone (Caco-2-RCAr clone 2) which, when
      grown on plastic, was deficient in differentiation, measured by the development
      of polarized-cell-surface marker enzymes. The deficiency in differentiation was
      partially reversed, and ricin sensitivity was restored, when the cells were grown
      on filter supports. Our data provide the first evidence of a ricin-resistant cell
      line where resistance is due to the lack of development of polarized cell
      surfaces. The observed ricin resistance is consistent with the requirement that
      ricin is delivered to the TGN before its A chain enters the cytosol to mediate
      cell killing.

PMID- 10393088
TI  - Upstream stimulatory factor regulates Pdx-1 gene expression in differentiated
      pancreatic beta-cells.
AB  - The homeobox gene Pdx-1 plays a key role in the development of the pancreas. In
      the adult, however, expression of the Pdx-1 gene is restricted to pancreatic beta
      cells and endocrine cells of duodenal epithelium. Recently, the transcription
      factor, upstream stimulatory factor (USF), has been shown to bind in vitro to a
      mutationally sensitive E-box motif within the 5'-flanking region of the Pdx-1
      gene [Sharma, Leonard, Lee, Chapman, Leiter and Montminy (1996) J. Biol. Chem.
      271, 2294-2299]. In the present study, we show that USF not only binds to the Pdx
      1 gene promoter but also functionally regulates the expression of the Pdx-1 gene
      in differentiated pancreatic beta-cells. Adenovirus-mediated overexpression of a
      dominant negative form of USF2 decreased binding of endogenous USF to the E-box
      element by approximately 90%. This reduction in endogenous USF binding led to a
      greater than 50% decrease in Pdx-1 gene promoter activity, which, in turn,
      resulted in marked reductions in Pdx-1 mRNA and protein levels. Importantly, the
      lower Pdx-1 protein levels led to a greater than 50% reduction in Pdx-1 binding
      activity to the A3 element on the insulin gene promoter, and a significant
      reduction in insulin mRNA levels. Overall, our results show that USF functionally
      regulates Pdx-1 gene expression in differentiated pancreatic beta-cells and
      provide the first functional data for a role of USF in the regulation of a normal
      cellular gene.

PMID- 10393090
TI  - A shift in the equilibrium constant at the catalytic site of proton-translocating
      transhydrogenase: significance for a 'binding-change' mechanism.
AB  - In mitochondria and bacteria, transhydrogenase uses the transmembrane proton
      gradient (Deltap) to drive reduction of NADP+ by NADH. We have investigated the
      pre-steady-state kinetics of NADP+ reduction by acetylpyridine adenine
      dinucleotide (AcPdADH, an analogue of NADH) in complexes formed from the two,
      separately prepared, recombinant, peripheral subunits of the enzyme: the dI
      component, which binds NAD+ and NADH, and the dIII component, which binds NADP+
      and NADPH. In the stopped-flow spectrophotometer the reaction proceeds as a
      single-turnover burst of hydride transfer to NADP+ on dIII before product NADPH
      release becomes limiting in steady state. The burst is biphasic. The results
      indicate that the fast phase represents direct hydride transfer from AcPdADH to
      NADP+ in dI:dIII complexes, and that the slow phase, which predominates when
      [dI]<[dIII], corresponds to dissociation of the protein complexes during multiple
      turnovers of dI. Measurements on the amplitude of the burst, and on the apparent
      first-order rate constant of the fast phase, indicate that the equilibrium
      constant of the hydride-transfer step on the enzyme is shifted relative to that
      in solution. This has consequences for a model proposed earlier, in which Deltap
      is used, not at the hydride-transfer step, but to change the binding affinities
      of NADP+ and NADPH.

PMID- 10393091
TI  - Lipoprotein cholesterol uptake mediates up-regulation of bile-acid synthesis by
      increasing cholesterol 7alpha-hydroxylase but not sterol 27-hydroxylase gene
      expression in cultured rat hepatocytes.
AB  - Lipoproteins may supply substrate for the formation of bile acids, and the amount
      of hepatic cholesterol can regulate bile-acid synthesis and increase cholesterol
      7alpha-hydroxylase expression. However, the effect of lipoprotein cholesterol on
      sterol 27-hydroxylase expression and the role of different lipoproteins in
      regulating both enzymes are not well established. We studied the effect of
      different rabbit lipoproteins on cholesterol 7alpha-hydroxylase and sterol 27
      hydroxylase in cultured rat hepatocytes. beta-Migrating very-low-density
      lipoprotein (betaVLDL) and intermediate-density lipoprotein (IDL) caused a
      significant increase in the intracellular cholesteryl ester content of cells (2.
      3- and 2-fold, respectively) at a concentration of 200 microgram of
      cholesterol/ml, whereas high-density lipoprotein (HDL, 50% v/v), containing no
      apolipoprotein E (apo E), showed no effect after a 24-h incubation. betaVLDL and
      IDL increased bile-acid synthesis (1. 9- and 1.6-fold, respectively) by up
      regulation of cholesterol 7alpha-hydroxylase activity (1.7- and 1.5-fold,
      respectively). Dose- and time-dependent changes in cholesterol 7alpha-hydroxylase
      mRNA levels and gene expression underlie the increase in enzyme activity.
      Incubation of cells with HDL showed no effect. Sterol 27-hydroxylase gene
      expression was not affected by any of the lipoproteins added. Transient
      expression experiments in hepatocytes, transfected with a promoter-reporter
      construct containing the proximal 348 nucleotides of the rat cholesterol 7alpha
      hydroxylase promoter, showed an enhanced gene transcription (2-fold) with
      betaVLDL, indicating that a sequence important for a cholesterol-induced
      transcriptional response is located in this part of the cholesterol 7alpha
      hydroxylase gene. The extent of stimulation of cholesterol 7alpha-hydroxylase is
      associated with the apo E content of the lipoprotein particle, which is important
      in the uptake of lipoprotein cholesterol. We conclude that physiological
      concentrations of cholesterol in apo E-containing lipoproteins increase bile-acid
      synthesis by stimulating cholesterol 7alpha-hydroxylase gene transcription,
      whereas HDL has no effect and sterol 27-hydroxylase is not affected.

PMID- 10393092
TI  - Multiple-site phosphorylation of the 280 kDa isoform of acetyl-CoA carboxylase in
      rat cardiac myocytes: evidence that cAMP-dependent protein kinase mediates
      effects of beta-adrenergic stimulation.
AB  - Two major forms of mammalian acetyl-CoA carboxylase (EC 6.4.1.2), ACC-alpha and
      ACC-beta, have been described and the sequences of the isoforms deduced. ACC-beta
      is the predominant isoform expressed in heart and skeletal muscles, in which a
      major role of malonyl-CoA is probably to regulate fatty acid beta-oxidation. The
      regulatory properties of ACC-beta are incompletely defined but it is known that
      some cellular stresses lead to inhibition in parallel with the activation of AMP
      activated protein kinase (AMP-PK). Here we examine the phosphorylation state of
      ACC-beta within intact rat cardiac ventricular myocytes. Treatment of myocytes
      with the beta-adrenergic agonist isoprenaline (isoproterenol) led to increased
      ACC-beta phosphorylation that was maximal within 2 min and with 50 nM agonist.
      Effects of isoprenaline were revealed by the incorporation of 32P into ACC in
      cells incubated with [32P]Pi and also by a marked decrease (approx. 80%) in
      subsequent phosphorylation in vitro with cAMP-dependent protein kinase (PKA).
      Analysis of tryptic phosphopeptides revealed that ACC-beta was phosphorylated at
      multiple sites by incubation in vitro with PKA or AMP-PK. Treatment of myocytes
      with isoprenaline affected all the major phosphorylation sites of ACC-beta that
      were recognized in vitro by purified PKA, so that subsequent phosphorylation in
      vitro was greatly diminished after cell stimulation. beta-Adrenergic stimulation
      led to decreases in cellular malonyl-CoA concentrations but no changes in kinetic
      properties of ACC were detected after cell homogenization and partial
      purification of proteins. The results suggest that: (1) ACC-beta is rapidly
      phosphorylated at multiple sites within intact cardiac ventricular myocytes after
      beta-adrenergic stimulation, (2) ACC-beta is phosphorylated in vitro by PKA and
      AMP-PK at multiple sites, including at least one site accessible to each kinase,
      as well as kinase-selective sites, and (3) PKA is a physiologically significant
      ACC-beta kinase.

PMID- 10393093
TI  - Molecular analysis of sialoside binding to sialoadhesin by NMR and site-directed
      mutagenesis.
AB  - The molecular interactions between sialoadhesin and sialylated ligands have been
      investigated by using proton NMR. Addition of ligands to the 12 kDa N-terminal
      immunoglobulin-like domain of sialoadhesin result in resonance shifts in the
      protein spectrum that have been used to determine the affinities of sialoadhesin
      for several sialosides. The results indicate that alpha2, 3-sialyl-lactose and
      alpha2,6-sialyl-lactose bind respectively 2- and 1.5-fold more strongly than does
      alpha-methyl-N-acetylneuraminic acid (alpha-Me-NeuAc). The resonances
      corresponding to the methyl protons within the N-acetyl moiety of sialic acid
      undergo upfield shifting and broadening during titrations, reflecting an
      interaction of this group with Trp2 in sialoadhesin as observed in co-crystals of
      the terminal domain with bound ligand. This resonance shift was used to measure
      the affinities of mutant and wild-type forms of sialoadhesin in which the first
      three domains are fused to the Fc region of human IgG1. Substitution of Arg97 by
      alanine completely abrogated measurable interaction with alpha-Me-NeuAc, whereas
      a conservative substitution with lysine resulted in a 10-fold decrease in
      affinity. These results provide the first direct measurement of the affinity of
      sialoadhesin for sialosides and confirm the critical importance of the conserved
      arginine in interactions between sialosides and members of the siglec family of
      sialic acid-binding, immunoglobulin-like lectins.

PMID- 10393094
TI  - p44/42 mitogen-activated protein kinase is involved in the expression of
      ornithine decarboxylase in leukaemia L1210 cells.
AB  - The involvement of p44/42 mitogen-activated protein kinase (MAPK) in the
      induction of ornithine decarboxylase (ODC) was investigated by using PD98059, a
      specific MAPK-kinase (MEK1/2) inhibitor, and other signal-transduction
      inhibitors. In d,l-alpha-difluoromethylornithine (DFMO)-resistant L1210 cells
      stimulated to grow from quiescence, treatment with PD98059 inhibited p44/42 MAPK
      phosphorylation and the induction of ODC activity and protein. A marked reduction
      of the accumulation of mature ODC mRNA and its intron-containing precursor was
      observed, whereas ODC turnover was hardly affected. PD98059 also reduced the
      content of antizyme, but not that of antizyme mRNA. U0126, a novel and more
      potent inhibitor of MEK1/2, provoked a dose-dependent inhibition of ODC induction
      at lower concentrations with respect to PD98059. Other effective inhibitors of
      ODC induction proved to be genistein, manumycin A, herbimycin A, LY294002,
      wortmannin and KT5823, suggesting the involvement of other key proteins of signal
      transduction pathways, i.e. Ras, Src, phosphatidylinositol 3-kinase and cGMP
      dependent protein kinase, which may have a positive impact on MAPK. Cells kept in
      a DFMO-free medium, and thus containing high levels of putrescine and spermidine,
      showed enhanced MAPK phosphorylation and lower sensitivity to PD98059, compared
      with cells maintained in the presence of DFMO. In conclusion, these results
      indicate that the activation of p44/42 MAPK may favour the expression of ODC, and
      that polyamines, in turn, may affect the phosphorylation state of MAPK.

PMID- 10393095
TI  - Polyunsaturated fatty acids inhibit fatty acid synthase and spot-14-protein gene
      expression in cultured rat hepatocytes by a peroxidative mechanism.
AB  - In vivo, polyunsaturated fatty acids (PUFA) inhibit the expression of hepatic
      genes related to the lipogenic process such as fatty acid synthase and spot-14
      protein (S14) genes. In vitro studies have suggested that this was a direct
      transcriptional effect of PUFA. In hepatocytes, the inhibition of the lipogenic
      rate by PUFA is not specific, but is linked to a cytotoxic effect due to
      peroxidative mechanisms. We have investigated whether peroxidation could also
      explain the inhibitory effect of PUFA on gene expression. Rat hepatocytes were
      cultured for 24 h with mono-unsaturated or PUFA. PUFA inhibited the expression of
      fatty acid synthase and S14 genes, and this inhibition was directly related to
      the number of unsaturations. However, the beta-actin and albumin mRNA
      concentrations were also affected by the most unsaturated fatty acids, suggesting
      a non-specific effect of PUFA on gene expression. Measurement of lactate
      dehydrogenase released into the medium indicated a cytotoxicity of PUFA. This was
      associated with their peroxidation as evaluated by the presence of thiobarbituric
      acid-reactive substances in the culture medium. The addition of high
      concentrations of antioxidants abolished lipid peroxidation and lactate
      dehydrogenase leakage and completely reversed the inhibitory effect of PUFA on
      gene expression. This suggests (i) that the results obtained previously in
      cultured hepatocytes in the presence of low concentrations of antioxidants must
      be interpretated cautiously and (ii) that in vivo, the inhibitory effect of PUFA
      on lipogenesis-related genes could be indirect through hormonal or metabolic
      changes or that their effect on gene expression is somehow linked to peroxidative
      mechanisms.

PMID- 10393096
TI  - 39-kDa receptor-associated protein (RAP) facilitates secretion and ligand binding
      of extracellular region of very-low-density-lipoprotein receptor: implications
      for a distinct pathway from low-density-lipoprotein receptor.
AB  - We have expressed the extracellular regions of the low-density-lipoprotein (LDL)
      receptor and the very-low-density-lipoprotein (VLDL) receptor, along with the
      full-length forms of the receptors, in insect cells in a baculovirus system. The
      extracellular region of the LDL receptor has been secreted successfully into the
      culture medium, and it retained the capacities of binding 125I-labelled LDL and
      beta-VLDL. In contrast, the extracellular region of the VLDL receptor remained
      intracellular and it did not bind 125I-beta-VLDL. This difference in expression
      behaviour between the homologous regions of the two receptors suggests that the
      two receptor systems are different in receptor-protein maturation or protein
      targeting. Next we developed the co-expression system with 39-kDa receptor
      associated protein (RAP). This co-expression facilitated the secretion of the
      extracellular region of the VLDL receptor into the culture medium and the
      secreted receptor bound 125I-beta-VLDL. The VLDL receptor remaining intracellular
      that was co-expressed with RAP also showed binding capacity to 125I-beta-VLDL,
      implying that the existence of RAP prevented receptor-protein aggregation or
      improved protein-folding status of the truncated VLDL receptor. On the other
      hand, expression of the extracellular region of the LDL receptor was not
      facilitated by RAP co-expression. Thus RAP plays an essential role in maintenance
      of the active conformation and secretion of the extracellular region of the VLDL
      receptor.

PMID- 10393097
TI  - Characterization of trehalose phosphorylase from Schizophyllum commune.
AB  - During growth on d-glucose, the basidiomycete Schizophyllum commune produces an
      intracellular alpha,alpha-trehalose phosphorylase. Specific phosphorylase
      activity increases steadily during the exponential growth phase, up to a maximum
      of approx. 0.08 unit/mg of protein, and decreases after the available d-glucose
      in the medium has been fully depleted. The variation with time of the
      concentrations of intracellular alpha,alpha-trehalose and Pi is reciprocal to
      that of trehalose phosphorylase activity, indicating that the enzyme makes
      temporary use of the pool of alpha, alpha-trehalose (approx. 0.42 mmol/g dry
      cell) via phosphorolysis. The enzyme has been purified, 150-fold, to homogeneity
      in 55% yield and characterized. It is a monomeric 61 kDa protein, which seems to
      lack regulation at the level of enzyme activity. The enzyme catalyses the
      reversible phosphorolysis of alpha,alpha-trehalose into alpha-d-glucose 1
      phosphate and alpha-d-glucose in the absence of cofactors, with a catalytic
      centre activity at 30 degrees C of 14 s(-1). Double-reciprocal analysis of the
      initial velocities for trehalose phosphorolysis and synthesis yields intersecting
      patterns, and no exchange reaction occurs between alpha-d-glucose 1-phosphate and
      the phosphate analogue arsenate. Therefore trehalose phosphorylase operates by a
      ternary-complex, rather than a Ping-Pong, kinetic mechanism. The specificity
      constants (kcat/Km) of phosphate (6000 M(-1).s(-1)) and alpha-d-glucose 1
      phosphate (3500 M(-1).s(-1)) compared with those of alpha,alpha-trehalose (161 M(
      1).s(-1)) and d-glucose (260 M(-1).s(-1)), together with the inhibition by NaCl,
      which is competitive with respect to phosphate with a Ki of 67 mM, suggest an
      important role for ionic enzyme-phosphate interactions in the catalytic mechanism
      of trehalose phosphorylase. The isolated enzyme requires alpha,alpha-trehalose
      (0.1-0.3 M) for its conformational stability.

PMID- 10393098
TI  - Histidine-193 of rat glucosylceramide synthase resides in a UDP-glucose- and
      inhibitor (D-threo-1-phenyl-2-decanoylamino-3-morpholinopropan-1-ol)-binding
      region: a biochemical and mutational study.
AB  - Glucosylceramide synthase (GCS) catalyses the transfer of glucose from UDP
      glucose (UDP-Glc) to ceramide to form glucosylceramide, the common precursor of
      most higher-order glycosphingolipids. Inhibition of GCS activity has been
      proposed as a possible target of chemotherapeutic agents for a number of
      diseases, including cancer. Design of new GCS inhibitors with desirable
      pharmaceutical properties is hampered by lack of knowledge of the secondary
      structure or catalytic mechanism of the GCS protein. Thus we cloned the rat
      homologue of GCS to begin studies to identify its catalytic regions. The
      histidine-modifying agent diethyl pyrocarbonate (DEPC) inhibited recombinant rat
      GCS expressed in bacteria; this inhibition was rapidly reversible by
      hydroxylamine and could be diminished by preincubation of GCS with UDP-Glc. These
      data suggest that DEPC acts on histidine residues within or near the UDP-Glc
      binding site of GCS. Mutant proteins were expressed in which the eight histidine
      residues in GCS were individually replaced by other amino acids. H193A (His193-
      >Ala) and H193N (His193-->Asn) mutants were unaffected by 0.1 mM DEPC, a
      concentration that inhibited other histidine mutants and the wild-type enzyme by
      at least 60%. These results indicate that His193 is the primary target of DEPC
      and is at, or near, the UDP-Glc-binding site of GCS. His193 mutants were also
      insensitive to the GCS inhibitor d-threo-1-phenyl-2- decanoylamino-3
      morpholinopropan-1-ol, at concentrations which inhibited the wild-type enzyme by
      >80%. These results have significance for both an understanding of the GCS active
      site and also for the possible design of new and specific inhibitors of GCS.

PMID- 10393100
TI  - Peptidase activity of beta-lactamases.
AB  - Although beta-lactamases have generally been considered as being devoid of
      peptidase activity, a low but significant hydrolysis of various N-acylated
      dipeptides was observed with representatives of each class of beta-lactamases.
      The kcat/Km values were below 0.1 M(-1). s(-1), but the enzyme rate enhancement
      factors were in the range 5000-20000 for the best substrates. Not unexpectedly,
      the best 'peptidase' was the class C beta-lactamase of Enterobacter cloacae P99,
      but, more surprisingly, the activity was always higher with the phenylacetyl- and
      benzoyl-d-Ala-d-Ala dipeptides than with the diacetyl- and alpha-acetyl-l-Lys-d
      Ala-d-Ala tripeptides, which are the preferred substrates of the low-molecular
      mass, soluble dd-peptidases. A comparison between the beta-lactamases and dd
      peptidases showed that it might be as difficult for a dd-peptidase to open the
      beta-lactam ring as it is for the beta-lactamases to hydrolyse the peptides, an
      observation which can be explained by geometric and stereoelectronic
      considerations.

PMID- 10393099
TI  - Evidence for the involvement of a small subregion of the endoplasmic reticulum in
      the inositol trisphosphate receptor-induced activation of Ca2+ inflow in rat
      hepatocytes.
AB  - The roles of a subregion of the endoplasmic reticulum (ER) and the cortical actin
      cytoskeleton in the mechanisms by which Ins(1,4,5)P3 induces the activation of
      store-operated Ca2+ channels (SOCs) in isolated rat hepatocytes were
      investigated. Adenophostin A, a potent agonist at Ins(1,4,5)P3 receptors, induced
      ER Ca2+ release and the activation of Ca2+ inflow. The concentration of
      adenophostin A that gave half-maximal stimulation of Ca2+ inflow (10 nM) was
      substantially lower than that (20 nM) which gave half-maximal ER Ca2+ release. A
      low concentration of adenophostin A (approx. 13 nM) caused near-maximal
      stimulation of Ca2+ inflow but only 20% of maximal ER Ca2+ release. Similar
      results were obtained using another Ins(1,4,5)P3-receptor agonist, 2-hydroxyethyl
      alpha-d-glucopyranoside 2,3',4'-trisphosphate. Anti-type-1 Ins(1,4,5)P3-receptor
      monoclonal antibody 18A10 inhibited vasopressin-stimulated Ca2+ inflow but had no
      observable effect on vasopressin-induced ER Ca2+ release. Treatment with
      cytochalasin B at a concentration that partially disrupted the cortical actin
      cytoskeleton inhibited Ca2+ inflow and ER Ca2+ release induced by vasopressin by
      73 and 45%, respectively. However, it did not substantially affect Ca2+ inflow
      and ER Ca2+ release induced by thapsigargin or 13 nM adenophostin A,
      intracellular Ca2+ release induced by ionomycin or Ins(1,4, 5)P3P4(5)-1-(2
      nitrophenyl)ethyl ester ['caged' Ins(1,4,5)P3] or basal Ca2+ inflow. 1-(5
      Chloronaphthalene-1-sulphonyl)homopiperazine, HCl (ML-9), an inhibitor of myosin
      light-chain kinase, also inhibited vasopressin-induced Ca2+ inflow and ER Ca2+
      release by 53 and 44%, respectively, but had little effect on thapsigargin
      induced Ca2+ inflow and ER Ca2+ release. Neither cytochalasin B nor ML-9
      inhibited vasopressin-induced Ins(1,4,5)P3 formation. It is concluded that the
      activation of SOCs in rat hepatocytes induced by Ins(1,4,5)P3 requires the
      participation of a small region of the ER, which is distinguished from other
      regions of the ER by a different apparent affinity for Ins(1,4,5)P3 analogues and
      is associated with the plasma membrane through the actin skeleton. This
      conclusion is discussed briefly in relation to current hypotheses for the
      activation of SOCs.

PMID- 10393101
TI  - Rapid internalization and surface expression of a functional, fluorescently
      tagged G-protein-coupled glutamate receptor.
AB  - l-Glutamate is the principal excitatory neurotransmitter in the vertebrate
      central nervous system, where it mediates many of its actions via G-protein
      coupled metabotropic glutamate (mGlu) receptors. Since little is known about the
      dynamics of mGlu receptors at the plasma membrane, we have constructed a fusion
      protein comprising the mGlu receptor subtype 1alpha (mGlu1alpha) and green
      fluorescent protein (GFP). Using imaging of Ca2+ release from intracellular
      stores as a functional assay, the agonist pharmacology of this fluorescently
      tagged receptor was found to be similar to that of the wild-type receptor when
      expressed in HEK-293 cells. Receptor movement and function were measured
      simultaneously by combined imaging of Ca2+, using fura-red, and GFP fluorescence
      in single cells. Exposure to agonist induced a rapid loss of up to 30% of
      membrane-associated fluorescence, with a corresponding decrease in the functional
      response. Following removal of the agonist there was recovery of both the
      membrane fluorescence and the functional response. These data suggest that the
      surface expression of G-protein-coupled glutamate receptors might be rapidly
      regulated in response to agonist activation.

PMID- 10393102
TI  - Calexcitin interaction with neuronal ryanodine receptors.
AB  - Calexcitin (CE), a Ca2+- and GTP-binding protein, which is phosphorylated during
      memory consolidation, is shown here to co-purify with ryanodine receptors (RyRs)
      and bind to RyRs in a calcium-dependent manner. Nanomolar concentrations of CE
      released up to 46% of the 45Ca label from microsomes preloaded with 45CaCl2. This
      release was Ca2+-dependent and was blocked by antibodies against the RyR or CE,
      by the RyR inhibitor dantrolene, and by a seven-amino-acid peptide fragment
      corresponding to positions 4689-4697 of the RyR, but not by heparin, an
      Ins(1,4,5)P3-receptor antagonist. Anti-CE antibodies, in the absence of added CE,
      also blocked Ca2+ release elicited by ryanodine, suggesting that the CE and
      ryanodine binding sites were in relative proximity. Calcium imaging with bis-fura
      2 after loading CE into hippocampal CA1 pyramidal cells in hippocampal slices
      revealed slow, local calcium transients independent of membrane depolarization.
      Calexcitin also released Ca2+ from liposomes into which purified RyR had been
      incorporated, indicating that CE binding can be a proximate cause of Ca2+
      release. These results indicated that CE bound to RyRs and suggest that CE may be
      an endogenous modulator of the neuronal RyR.

PMID- 10393103
TI  - Resynthesis of phosphatidylinositol in permeabilized neutrophils following
      phospholipase Cbeta activation: transport of the intermediate, phosphatidic acid,
      from the plasma membrane to the endoplasmic reticulum for phosphatidylinositol
      resynthesis is not dependent on soluble lipid carriers or vesicular transport.
AB  - Receptor-mediated phospholipase C (PLC) hydrolysis of phosphoinositides is
      accompanied by the resynthesis of phosphatidylinositol (PI). Hydrolysis of
      phosphoinositides occurs at the plasma membrane, and the resulting diacylglycerol
      (DG) is converted into phosphatidate (PA). Two enzymes located at the endoplasmic
      reticulum (ER) function sequentially to convert PA back into PI. We have
      established an assay whereby the resynthesis of PI could be followed in
      permeabilized cells. In the presence of [gamma-32P]ATP, DG generated by PLC
      activation accumulates label when converted into PA. The 32P-labelled PA is
      subsequently converted into labelled PI. The formation of labelled PI reports the
      arrival of labelled PA from the plasma membrane to the ER. Cytosol-depleted,
      permeabilized human neutrophils are capable of PI resynthesis following
      stimulation of PLCbeta (in the presence of phosphatidylinositol-transfer
      protein), provided that CTP and inositol are also present. We also found that
      wortmannin, an inhibitor of endocytosis, or cooling the cells to 15 degrees C did
      not stop PI resynthesis. We conclude that PI resynthesis is dependent neither on
      vesicular transport mechanisms nor on freely diffusible, soluble transport
      proteins. Phosphatidylcholine-derived PA generated by the ADP-ribosylation-factor
      stimulated phospholipase D pathway was found to accumulate label, reflecting the
      rapid cycling of PA to DG, and back. This labelled PA was not converted into PI.
      We conclude that PA derived from the PLC pathway is selected for PI resynthesis,
      and its transfer to the ER could be membrane-protein-mediated at sites of close
      membrane contact.

PMID- 10393104
TI  - Endocytic delivery of intramolecularly quenched substrates and inhibitors to the
      intracellular yeast Kex2 protease1.
AB  - Kex2 in the yeast Saccharomyces cerevisiae is a transmembrane, Ca2+-dependent
      serine protease of the subtilisin-like pro-protein convertase (SPC) family with
      specificity for cleavage after paired basic amino acids. At steady state, Kex2 is
      predominantly localized in late Golgi compartments and initiates the proteolytic
      maturation of pro-protein precursors that transit the distal secretory pathway.
      However, Kex2 localization is not static, and its itinerary apparently involves
      transiting out of the late Golgi and cycling back from post-Golgi endosomal
      compartments during its lifetime. We tested whether the endocytic pathway could
      deliver small molecules to Kex2 from the extracellular medium. Here we report
      that intramolecularly quenched fluorogenic substrates taken up into intact yeast
      revealed fluorescence due to specific cleavage by Kex2 protease in endosomal
      compartments. Furthermore, the endocytic delivery of protease inhibitors
      interfered with Kex2 activity for precursor protein processing. These
      observations reveal that the endocytic pathway does intersect with the cycling
      itinerary of active Kex2 protease. This strategy of endocytic drug delivery has
      implications for modulating SPC protease activity needed for hormone, toxin and
      viral glycoprotein precursor processing in human cells.

PMID- 10393105
TI  - Metabolic characteristics of a human hepatoma cell line stably transfected with
      hormone-sensitive lipase.
AB  - Clones of HepG2 cells were selected that stably express the cDNA for hormone
      sensitive lipase (HSL). When cells were cultured in the presence of labelled
      extracellular oleate, accumulation of labelled fatty acid as cellular
      triacylglycerol (TAG) was significantly lower in the transfectants compared with
      the wild-type cells. There was no change in the net rate of phospholipid (PL)
      synthesis. Culture of cells containing isotopically prelabelled TAG resulted in a
      greater net loss of TAG from the transfected cells than from the wild-type cells.
      The excess loss of labelled TAG was primarily due to an increased TAG fatty acid
      oxidation. Free fatty acid release into the medium was not increased in the
      transfectants, nor was the very low rate of lipoprotein lipid secretion. Also,
      there was no increased net trafficking of fatty acids from TAG into PLs. Changes
      in the 3H:14C ratio of TAG prelabelled with [3H]glycerol and [14C]oleate
      suggested that none of excess TAG fatty acid released in the transfected cells
      underwent intracellular re-esterification to TAG prior to oxidation. The results
      suggest that fatty acids mobilized by HSL are directed immediately into the
      oxidative pathway and are not available for biosynthetic processes. It appears
      likely, therefore, that intracellular TAG-derived fatty acids which enter the
      oxidative pathway exist in a different compartment from those that are directed
      towards synthesis.

PMID- 10393107
TI  - Launching the germline in Caenorhabditis elegans: regulation of gene expression
      in early germ cells.
AB  - One hundred years after Weismann's seminal observations, the mechanisms that
      distinguish the germline from the soma still remain poorly understood. This
      review describes recent studies in Caenorhabditis elegans, which suggest that
      germ cells utilize unique mechanisms to regulate gene expression. In particular,
      mechanisms that repress the production of mRNAs appear to be essential to
      maintain germ cell fate and viability.

PMID- 10393106
TI  - Goblet-cell-specific transcription of mouse intestinal trefoil factor gene
      results from collaboration of complex series of positive and negative regulatory
      elements.
AB  - Intestinal trefoil factor (ITF) is expressed selectively in intestinal goblet
      cells. Previous studies of the rat ITF gene identified one cis-regulatory
      element, designated the goblet-cell-response element (GCRE), present in the
      proximal region of the promoter. To identify additional cis-regulatory elements
      responsible for goblet-cell-specific expression, a DNA fragment containing 6353
      bp of the 5'-flanking region of the mouse ITF gene was cloned and its promoter
      activity was examined extensively. In human and murine intestinal-derived cell
      lines (LS174T and CMT-93), the luciferase activities of a 6.3-kb construct were 5
      and 2-fold greater than the smaller 1.8-kb construct, respectively. In contrast,
      the activity in non-intestinal cell lines (HepG2 and HeLa) was 2-4-fold lower
      than the smaller construct. In the region downstream from the 1.8-kb position,
      strong luciferase activities in LS174T and HepG2 cells were observed using a 201
      bp construct. Interestingly, increased activity was almost completely suppressed
      in cells transfected with a 391-bp construct. Detailed analyses of this region
      revealed the existence of a 11-bp positive regulatory element (-181 to -170;
      ACCTCTTCCTG) and a 9-bp negative regulatory element (-208 to -200; ATTGACAGA) in
      addition to the GCRE. All three elements were well conserved among human, rat and
      mouse ITF gene promoters. In addition, a mutant 1.8-kb construct in which the
      negative regulatory region was deleted yielded the same approximate luciferase
      activity as a 6.3-kb construct, suggesting binding of a goblet-cell-specific
      silencer inhibitor (SI) between -6.3 and -1.8 kb. The SI present in goblet cells
      may block the silencers' binding to the pre-initiation complex and allow
      increased transcriptional activity driven by specific and non-specific enhancers.
      High-level expression of the mouse ITF gene specifically in intestinal goblet
      cells may be achieved through the combined effects of these regulatory elements.

PMID- 10393108
TI  - Migration and function of glia in the developing Drosophila eye.
AB  - Although glial cells have been implicated widely in the formation of axon tracts
      in both insects and vertebrates, their specific function appears to be context
      dependent, ranging from providing essential guidance cues to playing a merely
      facilitory role. Here we examine the role of the retinal basal glia (RBG) in
      photoreceptor axon guidance in Drosophila. The RBG originate in the optic stalk
      and have been thought to migrate into the eye disc along photoreceptor axons,
      thus precluding any role in axon guidance. Here we show the following. (1) The
      RBG can, in fact, migrate into the eye disc even in the absence of photoreceptor
      axons in the optic stalk; they also migrate to ectopic patches of differentiating
      photoreceptors without axons providing a continuous physical substratum. This
      suggests that glial cells are attracted into the eye disc not through haptotaxis
      along established axons, but through another mechanism, possibly chemotaxis. (2)
      If no glial cells are present in the eye disc, photoreceptor axons are able to
      grow and direct their growth posteriorly as in wild type, but are unable to enter
      the optic stalk. This indicates that the RBG have a crucial role in axon
      guidance, but not in axonal outgrowth per se. (3) A few glia close to the entry
      of the optic stalk suffice to guide the axons into the stalk, suggesting that
      glia instruct axons by local interaction.

PMID- 10393109
TI  - Mutations affecting tail and notochord development in the ascidian Ciona
      savignyi.
AB  - Ascidians are among the most distant chordate relatives of the vertebrates.
      However, ascidians share many features with vertebrates including a notochord and
      hollow dorsal nerve cord. A screen for N-ethyl-N-nitrosourea (ENU)-induced
      mutations affecting early development in the ascidian Ciona savignyi resulted in
      the isolation of a number of mutants including the complementing notochord
      mutants chongmague and chobi. In chongmague embryos the notochord fails to
      develop, and the notochord cells instead adopt a mesenchyme-like fate. The
      failure of notochord development in chongmague embryos results in a severe
      truncation of tail, although development of the tail muscles and caudal nerve
      tracts appears largely normal. Chobi embryos also have a truncation of the tail
      stemming from a disruption of the notochord. However, in chobi embryos the early
      development of the notochord appears normal and defects occur later as the
      notochord attempts to extend and direct elongation of the tail. We find in chobi
      tailbud embryos that the notochord is often bent, with cells clumped together,
      rather than extended as a column. These results provide new information on the
      function and development of the ascidian notochord. In addition, the results
      demonstrate how the unique features of ascidians can be used in genetic analysis
      of morphogenesis.

PMID- 10393110
TI  - egl-27 generates anteroposterior patterns of cell fusion in C. elegans by
      regulating Hox gene expression and Hox protein function.
AB  - Hox genes pattern the fates of the ventral ectodermal Pn.p cells that lie along
      the anteroposterior (A/P) body axis of C. elegans. In these cells, the Hox genes
      are expressed in sequential overlapping domains where they control the ability of
      each Pn.p cell to fuse with the surrounding syncytial epidermis. The activities
      of Hox proteins are sex-specific in this tissue, resulting in sex-specific
      patterns of cell fusion: in hermaphrodites, the mid-body cells remain unfused,
      whereas in males, alternating domains of syncytial and unfused cells develop. We
      have found that the gene egl-27, which encodes a C. elegans homologue of a
      chromatin regulatory factor, specifies these patterns by regulating both Hox gene
      expression and Hox protein function. In egl-27 mutants, the expression domains of
      Hox genes in these cells are shifted posteriorly, suggesting that egl-27
      influences A/P positional information. In addition, egl-27 controls Hox protein
      function in the Pn.p cells in two ways: in hermaphrodites it inhibits MAB-5
      activity, whereas in males it permits a combinatorial interaction between LIN-39
      and MAB-5. Thus, by selectively modifying the activities of Hox proteins, egl-27
      elaborates a simple Hox expression pattern into complex patterns of cell fates.
      Taken together, these results implicate egl-27 in the diversification of cell
      fates along the A/P axis and suggest that chromatin reorganization is necessary
      for controlling Hox gene expression and Hox protein function.

PMID- 10393111
TI  - Differential interactions between Brother proteins and Runt domain proteins in
      the Drosophila embryo and eye.
AB  - Brother and Big brother were isolated as Runt-interacting proteins and are
      homologous to CBF(beta), which interacts with the mammalian CBF(alpha) Runt
      domain proteins. In vitro experiments indicate that Brother family proteins
      regulate the DNA binding activity of Runt-domain proteins without contacting DNA.
      In both mouse and human there is genetic evidence that the CBF(alpha) and
      CBF(beta) proteins function together in hematopoiesis and leukemogenesis. Here we
      demonstrate functional interactions between Brother proteins and Runt domain
      proteins in Drosophila. First, we show that a specific point mutation in Runt
      that disrupts interaction with Brother proteins but does not affect DNA binding
      activity is dysfunctional in several in vivo assays. Interestingly, this mutant
      protein acts dominantly to interfere with the Runt-dependent activation of Sxl
      lethal transcription. To investigate further the requirements for Brother
      proteins in Drosophila development, we examine the effects of expression of a
      Brother fusion protein homologous to the dominant negative CBF(beta)::SMMHC
      fusion protein that is associated with leukemia in humans. This Bro::SMMHC fusion
      protein interferes with the activity of Runt and a second Runt domain protein,
      Lozenge. Moreover, we find that the effects of lozenge mutations on eye
      development are suppressed by expression of wild-type Brother proteins,
      suggesting that Brother/Big brother dosage is limiting in this developmental
      context. Results obtained when Runt is expressed in developing eye discs further
      support this hypothesis. Our results firmly establish the importance of the
      Brother and Big brother proteins for the biological activities of Runt and
      Lozenge, and further suggest that Brother protein function is not restricted to
      enhancing DNA-binding.

PMID- 10393112
TI  - The role of brinker in mediating the graded response to Dpp in early Drosophila
      embryos.
AB  - Brinker (Brk), a novel protein with features of a transcriptional repressor,
      regulates the graded response to Decapentaplegic (Dpp) in appendage primordia of
      Drosophila. Here, we show that in the embryo brk also has differential effects on
      Dpp target genes, depending on the level of Dpp activity required for their
      activation. Low-level target genes, like dpp itself, tolloid and early zerknullt,
      show strong ectopic expression in ventrolateral regions of brk mutant embryos;
      intermediate-level target genes like pannier show weak ectopic expression, while
      high-level target genes like u-shaped and rhomboid are not affected. Ectopic
      target gene activation in the absence of brk is independent of Dpp, Tkv and
      Medea, indicating that Dpp signaling normally antagonizes brk's repression of
      these target genes. brk is expressed like short gastrulation (sog) in
      ventrolateral regions of the embryo abutting the dpp domain. Here, both brk and
      sog antagonize the antineurogenic activity of Dpp so that only in brk sog double
      mutants is the neuroectoderm completely deleted.

PMID- 10393113
TI  - Opposing roles for neurotrophin-3 in targeting and collateral formation of
      distinct sets of developing cortical neurons.
AB  - Neurotrophin-3 and its receptor TrkC are expressed during the development of the
      mammalian cerebral cortex. To examine whether neurotrophin-3 might play a role in
      the elaboration of layer-specific cortical circuits, slices of layer 6 and layers
      2/3 neurons were cultured in the presence of exogenously applied neurotrophin-3.
      Results indicate that neurotrophin-3 promotes axonal branching of layer 6 axons,
      which target neurotrophin-3-expressing layers in vivo, and that it inhibits
      branching of layers 2/3 axons, which avoid neurotrophin-3-expressing layers. Such
      opposing effects of neurotrophin-3 on axonal branching were also observed with
      embryonic cortical neurons, indicating that the response to neurotrophin-3 is
      specified at early developmental stages, prior to cell migration. In addition to
      its effects on fiber branching, axonal guidance assays also indicate that
      neurotrophin-3 is an attractive signal for layer 6 axons and a repellent guidance
      cue for layers 2/3 axons. Experiments with specific antibodies to neutralize
      neurotrophin-3 in cortical membranes revealed that endogenous levels of
      neurotrophin-3 are sufficient to regulate branching and targeting of cortical
      axons. These opposing effects of neurotrophin-3 on specific populations of axons
      demonstrate that it could serve as one of the signals for the elaboration of
      local cortical circuits.

PMID- 10393114
TI  - Xenopus GDF6, a new antagonist of noggin and a partner of BMPs.
AB  - In Xenopus, ectodermal cell fates are determined by antagonistic interaction
      between the BMP subfamily of TGF-(beta) ligands and the organizer-specific
      secreted factors (e.g. noggin, chordin and follistatin). Inhibition of BMP
      function by these factors can convert cells from an epidermal to a neural cell
      fate. In this study, we report that GDF6, a new member of the Xenopus TGF-(beta)
      family, can function in antagonistic interaction with neural inducers. GDF6
      induces epidermis and inhibits neural tissue in dissociated cells, and this
      activity is blocked by the presence of noggin. We demonstrate that GDF6 binds
      directly to the neural inducer noggin. Furthermore, we find that GDF6 and BMP2
      can form heterodimers and the process seems to require cotranslation of the
      proteins in the same cells. In normal embryos, GDF6 and BMP2 are coexpressed in
      several places, including the edge of the neural plate at early neurula stages,
      suggesting that GDF6 may synergize with BMPs to regulate patterning of the
      ectoderm. Our data show for the first time that noggin can bind directly to and
      inhibit another TGF-(beta) family member: GDF6. In addition, BMP and GDF6
      heterodimers may play an important role in vivo to regulate cell fate
      determination and patterning.

PMID- 10393116
TI  - Post-transcriptional regulation of Xwnt-8 expression is required for normal
      myogenesis during vertebrate embryonic development.
AB  - The Xenopus Wnt-8 gene is transiently expressed in ventral and lateral mesoderm
      during gastrulation and plays a critical role in patterning these tissues. In the
      current study, we show that the spatial and temporal pattern of expression of
      endogenous Xwnt-8 is regulated, in part, at a post-transcriptional level. We have
      identified a novel sequence element in the 3' untranslated region of the Xwnt-8
      RNA that controls the polyadenylation status of reporter and endogenous Xwnt-8
      RNAs, directs rapid RNA degradation beginning precisely at the early gastrula
      stage, and represses translation of transcripts throughout development.
      Expression of endogenous Xwnt-8 is normally downregulated within lateral
      (presomitic) mesoderm following gastrulation. We demonstrate that rapid
      degradation of Xwnt-8 transcripts, mediated by these regulatory elements in the
      3' untranslated region, is essential to this process and that downregulation is
      required to prevent overcommitment of somitic cells to a myogenic fate. These
      studies demonstrate a role for post-transcriptional regulation of zygotic gene
      expression in vertebrate embryonic patterning.

PMID- 10393115
TI  - Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular
      respecification within the basal telencephalon: evidence for a transformation of
      the pallidum into the striatum.
AB  - The telencephalon is organized into distinct longitudinal domains: the cerebral
      cortex and the basal ganglia. The basal ganglia primarily consists of a dorsal
      region (striatum) and a ventral region (pallidum). Within the telencephalon, the
      anlage of the pallidum expresses the Nkx2.1 homeobox gene. A mouse deficient in
      Nkx2.1 function does not form pallidal structures, lacks basal forebrain TrkA
      positive neurons (probable cholinergic neurons) and has reduced numbers of
      cortical cells expressing GABA, DLX2 and calbindin that migrate from the pallidum
      through the striatum and into the cortex. We present evidence that these
      phenotypes result from a ventral-to-dorsal transformation of the pallidal
      primordium into a striatal-like anlage.

PMID- 10393117
TI  - Inductive regulation of cell fusion in leech.
AB  - Cell-cell fusion is a component of many different developmental processes, but
      little is known about how cell-cell fusion is regulated. Here we investigate the
      regulation of a stereotyped cell-cell fusion event that occurs among the
      endodermal precursor cells of the glossiphoniid leech Helobdella robusta. We find
      that this fusion event is regulated inductively by a cell that does not itself
      fuse. We also show that biochemical arrest (by microinjection with ricin A chain
      or ribonuclease A) of the inducer or either of the fusion partners prevents
      fusion, but only if the arrest is initiated during a critical period long before
      the time at which fusion normally occurs. If the arrest occurs after this
      critical period, fusion occurs on schedule. These results suggest that both
      fusion partners play active roles in the process and that neither the induction
      nor the fusion itself requires concomitant protein synthesis.

PMID- 10393118
TI  - Evidence that the Dictyostelium Dd-STATa protein is a repressor that regulates
      commitment to stalk cell differentiation and is also required for efficient
      chemotaxis.
AB  - Dd-STATa is a structural and functional homologue of the metazoan STAT (Signal
      Transducer and Activator of Transcription) proteins. We show that Dd-STATa null
      cells exhibit several distinct developmental phenotypes. The aggregation of Dd
      STATa null cells is delayed and they chemotax slowly to a cyclic AMP source,
      suggesting a role for Dd-STATa in these early processes. In Dd-STATa null
      strains, slug-like structures are formed but they have an aberrant pattern of
      gene expression. In such slugs, ecmB/lacZ, a marker that is normally specific for
      cells on the stalk cell differentiation pathway, is expressed throughout the
      prestalk region. Stalk cell differentiation in Dictyostelium has been proposed to
      be under negative control, mediated by repressor elements present in the
      promoters of stalk cell-specific genes. Dd-STATa binds these repressor elements
      in vitro and the ectopic expression of ecmB/lacZ in the null strain provides in
      vivo evidence that Dd-STATa is the repressor protein that regulates commitment to
      stalk cell differentiation. Dd-STATa null cells display aberrant behavior in a
      monolayer assay wherein stalk cell differentiation is induced using the stalk
      cell morphogen DIF. The ecmB gene, a general marker for stalk cell
      differentiation, is greatly overinduced by DIF in Dd-STATa null cells. Also, Dd
      STATa null cells are hypersensitive to DIF for expression of ST/lacZ, a marker
      for the earliest stages in the differentiation of one of the stalk cell sub
      types. We suggest that both these manifestations of DIF hypersensitivity in the
      null strain result from the balance between activation and repression of the
      promoter elements being tipped in favor of activation when the repressor is
      absent. Paradoxically, although Dd-STATa null cells are hypersensitive to the
      inducing effects of DIF and readily form stalk cells in monolayer assay, the Dd
      STATa null cells show little or no terminal stalk cell differentiation within the
      slug. Dd-STATa null slugs remain developmentally arrested for several days before
      forming very small spore masses supported by a column of apparently
      undifferentiated cells. Thus, complete stalk cell differentiation appears to
      require at least two events: a commitment step, whereby the repression exerted by
      Dd-STATa is lifted, and a second step that is blocked in a Dd-STATa null
      organism. This latter step may involve extracellular cAMP, a known repressor of
      stalk cell differentiation, because Dd-STATa null cells are abnormally sensitive
      to the inhibitory effects of extracellular cyclic AMP.

PMID- 10393119
TI  - Proximal to distal cell communication in the Drosophila leg provides a basis for
      an intercalary mechanism of limb patterning.
AB  - Proximodistal patterning in the Drosophila leg is elaborated from the circular
      arrangement of the proximal domain expressing escargot and homothorax, and the
      distal domain expressing Distal-less that are allocated during embryogenesis. The
      distal domain differentiates multiply segmented distal appendages by activating
      additional genes such as dachshund. Secreted signaling molecules Wingless and
      Decapentaplegic, expressed along the anterior-posterior compartment boundary, are
      required for activation of Distal-less and dachshund and repression of homothorax
      in the distal domain. However, whether Wingless and Decapentaplegic are
      sufficient for the circular pattern of gene expression is not known. Here we show
      that a proximal gene escargot and its activator homothorax regulate proximodistal
      patterning in the distal domain. Clones of cells expressing escargot or
      homothorax placed in the distal domain induce intercalary expression of dachshund
      in surrounding cells and reorient planar cell polarity of those cells. Escargot
      and homothorax-expressing cells also sort out from other cells in the distal
      domain. We suggest that inductive cell communication between the proximodistal
      domains, which is maintained in part by a cell-sorting mechanism, is the cellular
      basis for an intercalary mechanism of the proximodistal axis patterning of the
      limb.

PMID- 10393120
TI  - Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic
      lethality.
AB  - Notch family genes encode transmembrane proteins involved in cell-fate
      determination. Using gene targeting procedures, we disrupted the mouse Notch2
      gene by replacing all but one of the ankyrin repeat sequences in the cytoplasmic
      domain with the E. coli (beta)-galactosidase gene. The mutant Notch2 gene encodes
      a 380 kDa Notch2-(beta)-gal fusion protein with (beta)-galactosidase activity.
      Notch2 homozygous mutant mice die prior to embryonic day 11.5, whereas
      heterozygotes show no apparent abnormalities and are fully viable. Analysis of
      Notch2 expression patterns, revealed by X-gal staining, demonstrated that the
      Notch2 gene is expressed in a wide variety of tissues including neuroepithelia,
      somites, optic vesicles, otic vesicles, and branchial arches, but not heart.
      Histological studies, including in situ nick end labeling procedures, showed
      earlier onset and higher incidence of apoptosis in homozygous mutant mice than in
      heterozygotes or wild type mice. Dying cells were particularly evident in neural
      tissues, where they were seen as early as embryonic day 9.5 in Notch2-deficient
      mice. Cells from Notch2 mutant mice attach and grow normally in culture,
      demonstrating that Notch2 deficiency does not interfere with cell proliferation
      and that expression of the Notch2-(beta)-gal fusion protein is not toxic per se.
      In contrast to Notch1-deficient mice, Notch2 mutant mice did not show
      disorganized somitogenesis, nor did they fail to properly regulate the expression
      of neurogenic genes such as Hes-5 or Mash1. In situ hybridization studies show no
      indication of altered Notch1 expression patterns in Notch2 mutant mice. The
      results indicate that Notch2 plays an essential role in postimplantation
      development in mice, probably in some aspect of cell specification and/or
      differentiation, and that the ankyrin repeats are indispensable for its function.

PMID- 10393121
TI  - Zebrafish sparse corresponds to an orthologue of c-kit and is required for the
      morphogenesis of a subpopulation of melanocytes, but is not essential for
      hematopoiesis or primordial germ cell development.
AB  - The relative roles of the Kit receptor in promoting the migration and survival of
      amniote melanocytes are unresolved. We show that, in the zebrafish, Danio rerio,
      the pigment pattern mutation sparse corresponds to an orthologue of c-kit. This
      finding allows us to further elucidate morphogenetic roles for this c-kit-related
      gene in melanocyte morphogenesis. Our analyses of zebrafish melanocyte
      development demonstrate that the c-kit orthologue identified in this study is
      required both for normal migration and for survival of embryonic melanocytes. We
      also find that, in contrast to mouse, the zebrafish c-kit gene that we have
      identified is not essential for hematopoiesis or primordial germ cell
      development. These unexpected differences may reflect evolutionary divergence in
      c-kit functions following gene duplication events in teleosts.

PMID- 10393122
TI  - MesP1 is expressed in the heart precursor cells and required for the formation of
      a single heart tube.
AB  - The Mesp1 gene encodes the basic HLH protein MesP1 which is expressed in the
      mesodermal cell lineage during early gastrulation. Disruption of the Mesp1 gene
      leads to aberrant heart morphogenesis, resulting in cardia bifida. In order to
      study the defects in Mesp1-expressing cells during gastrulation and in the
      specification of mesodermal cell lineages, we introduced a (beta)-galactosidase
      gene (lacZ) under the control of the Mesp1 promoter by homologous recombination.
      The early expression pattern revealed by (beta)-gal staining in heterozygous
      embryos was almost identical to that observed by whole mount in situ
      hybridization. However, the (beta)-gal activity was retained longer than the mRNA
      signal, which enabled us to follow cell migration during gastrulation. In
      heterozygous embryos, the Mesp1-expressing cells migrated out from the primitive
      streak and were incorporated into the head mesenchyme and heart field. In
      contrast, Mesp1-expressing cells in the homozygous deficient embryos stayed in
      the primitive streak for a longer period of time before departure. The expression
      of FLK-1, an early marker of endothelial cell precursors including heart
      precursors, also accumulated abnormally in the posterior region in Mesp1
      deficient embryos. In addition, using the Cre-loxP site-specific recombination
      system, we could determine the lineage of the Mesp1-expressing cells. The first
      mesodermal cells that ingressed through the primitive streak were incorporated as
      the mesodermal component of the amnion, and the next mesodermal population mainly
      contributed to the myocardium of the heart tube but not to the endocardium. These
      results strongly suggest that MesP1 is expressed in the heart tube precursor
      cells and is required for mesodermal cells to depart from the primitive streak
      and to generate a single heart tube.

PMID- 10393123
TI  - The C. elegans gene lin-36 acts cell autonomously in the lin-35 Rb pathway.
AB  - The Caenorhabditis elegans gene lin-36 acts to antagonize Ras-mediated vulval
      induction in a pathway that includes genes with products similar to the mammalian
      retinoblastoma (Rb) protein and the Rb-binding protein p48. We report that lin-36
      encodes a novel protein of 962 amino acids. We demonstrate that lin-36 functions
      in and is expressed in the vulval precursor cells, establishing that the lin-36
      pathway is involved in intercellular signaling. We also report that the lin-36
      pathway and/or another pathway that is functionally redundant with the lin-36
      pathway antagonize a ligand-independent activity of the receptor tyrosine
      kinase/Ras vulval induction pathway.

PMID- 10393124
TI  - The zebrafish diwanka gene controls an early step of motor growth cone migration.
AB  - During vertebrate embryogenesis different classes of motor axons exit the spinal
      cord and migrate on common axonal paths into the periphery. Surprisingly little
      is known about how this initial migration of spinal motor axons is controlled by
      external cues. Here, we show that the diwanka gene is required for growth cone
      migration of three identified subtypes of zebrafish primary motoneurons. In
      diwanka mutant embryos, motor growth cone migration within the spinal cord is
      unaffected but it is strongly impaired as motor axons enter their common path to
      the somites. Chimera analysis shows that diwanka gene activity is required in a
      small set of myotomal cells, called adaxial cells. We identified a subset of the
      adaxial cells to be sufficient to rescue the diwanka motor axon defect. Moreover,
      we show that this subset of adaxial cells delineates the common axonal path prior
      to axonogenesis, and we show that interactions between these adaxial cells and
      motor growth cones are likely to be transient. The studies demonstrate that a
      distinct population of myotomal cells plays a pivotal role in the early migration
      of zebrafish motor axons and identify the diwanka gene as a somite-derived cue
      required to establish an axonal path from the spinal cord to the somites.

PMID- 10393125
TI  - Chronic ethanol, oxygen tension and hepatocyte energy metabolism.
AB  - Hepatocytes from ethanol-fed animals, isolated from either whole liver or the
      periportal or perivenous regions of the lobule, exhibited an ethanol-related
      decrease in energy state only when they were oxygen deficient. This was
      accompanied by an ethanol-related decrease in hepatocyte viability. Both
      periportal and perivenous hepatocytes from ethanol-fed rats demonstrated
      increased respiration. The observations reported here are consistent with an
      ethanol-induced increase in oxygen utilization which could render the perivenous
      region of the lobule relatively oxygen deficient in the intact liver. This oxygen
      deficit may cause the decreases in energy state and cell viability associated
      with chronic ethanol consumption. Ethanol-associated loss in hepatocyte viability
      appeared to correlate better with a decrease in energy state than with an
      increase in the products of oxidative stress. An investigation of the association
      between viability and cellular malondialdehyde levels revealed no effects of
      chronic ethanol consumption on MDA levels in hepatocytes that demonstrated
      ethanol-related decreases in cell viability.

PMID- 10393126
TI  - The expression of monocyte chemoattractant protein-1 and other chemokines by
      osteoblasts.
AB  - Chemokines are low molecular weight secretory proteins that function principally
      as stimulators of leukocyte recruitment. There are four defined chemokine
      subfamilies based on their primary structure, CXC, CC, C and CX3C. Members of the
      CC chemokine subfamily, a such as monocyte chemoattractant protein 1 (MCP-1) are
      chemotactic for monocytes and other leukocyte subsets. Because monocytes produce
      factors that regulate bone formation or resorption, such as PDGF, IL-1 or TNF,
      chemokines that initiate their recruitment are likely to be important in
      regulating osseous metabolism. In the studies below, data is presented
      demonstrating mechanisms of MCP-1 expression in osteoblastic cells. These studies
      establish that MCP-1 is induced during osseous inflammation and in
      developmentally regulated bone remodelling, and is associated with enhanced
      monocyte recruitment when applied to osseous lesions.

PMID- 10393127
TI  - An experimental model for the endometriosis in athymic mice.
AB  - Endometriosis is an adhesion disorder characterized by the presence of
      endometrial tissue in ectopic sites outside the uterus. The disease is associated
      with dysmenorrhea, pelvic pain and infertility. Although endometriosis is the
      most common gynecologic disorder, relatively little is known regarding its
      etiology, pathogenesis and the course of the disease. This situation is primarily
      due to the absence of experimental systems to examine the mechanism of
      endometrial cell adhesion, role of inflammatory cells and the interactions of
      epithelial, and stromal cells with the peritoneum and ovarian tissue leading to
      the development of this disorder. Dissociated human endometrial cells were
      suspended in peritoneal fluids of individuals with and without endometriosis and
      were injected into the peritoneal cavity of athymic mice. This led to development
      of ectopic adhesions of endometrial cells at the peritoneal and ovarian surfaces.
      Endometrial cells which were marked with fluorescent lipophylic dyes, prior to
      intraperitoneal injection, could be visualized without surgery at such sites. The
      studies demonstrate a model for endometriosis in athymic mice.

PMID- 10393128
TI  - Activating oligomerization as intermediate level of signal transduction: analysis
      of protein-protein contacts and active sites in several glycolytic enzymes.
AB  - A number of enzymes have inactive monomeric and active oligomeric forms. This
      suggests presence of definite interglobular contact -active site interaction in
      the enzymes. Although the phenomenon is widely studied in vitro as part of
      folding process the biological roles of the phenomenon, termed here as
      "activating oligomerization" are not clearly understood. In this work a procedure
      for analysis of protein-protein interactions was elaborated. Using spatial
      structures of several glycolytic enzymes potential role of kinase phosphorylation
      in regulation of oligomerization of the proteins as well as association of
      domains in a two-domain protein was assessed. In the enzymes 15-75% of kinase
      sites (mainly protein kinase C and casein kinase 2 sites) are placed in
      interglobular contact region(s). Upon being phosphorylated these sites may
      prevent oligomer formation. In structures of all the enzymes definite evidences
      of connection between active site and interglobular contact were found. Two
      structural mechanisms of interglobular contact influence on the active site were
      proposed. In addition to known mechanism of oligomerization initiated by
      allosteric metabolites the influence may be also exerted through functional
      sequence overlap and/or interdomain contact stabilization mechanisms.
      Implications for regulation of enzyme cellular function(s), signal transduction
      and metabolic analysis are considered. It is concluded that activating
      oligomerization may represent an intermediate level of enzyme cellular
      regulation.

PMID- 10393129
TI  - Multiprobe RNase protection assay with internally labeled radioactive probes,
      generated by RT-PCR and nested PCR.
AB  - RNase Protection Assay (RPAs) is a highly sensitive and reproducible method of
      quantitating the levels of specific mRNA transcripts. The introduction of the
      commercially available Multiprobe RPAs allow comparing and quantifying the
      expression of up to different mRNA species in a single sample of 1-20 micrograms
      of total RNA. To generate probes which are not commercially available, we
      prepared highly specific probes by RT-PCR and nested PCR. Then, after ligation of
      a T7 promoter, another PCR was performed with a primer set consisting of a
      specific sense primer and antisense T7 primer. Only the antisense strand of the
      double stranded PCR-product contained the T7-promoter sequence on its 5' end,
      allowing in vitro transcription and internal labeling with [alpha-32]UTP. Probe
      concentration was determined in a scintillation counter and equal counts were
      introduced in the assay. In vitro transcription of the PCR generated probes
      resulted in radioactive probes with a very high specific activity, allowing
      simultaneous analysis of 70 different RNA samples. RPA could be performed under
      the same conditions as recommended for the commercially available probe sets,
      avoiding time consuming optimization of reaction conditions. Negative controls
      consisted of yeast RNA and sense RNA probes. Positive controls were single
      stranded templates, generated by asymmetric PCR. Dilution series revealed a high
      reproducibility and the potential of this technique to semi-quantitate mRNA in
      different RNA samples. In conclusion, probes may be generated by RT-PCR and
      nested PCR that will work with the commercially available Multiprobe RPAs. The
      high probe yield allows analysis of a great number of samples using the same set
      of probes with a high reproducibility.

PMID- 10393130
TI  - Understanding ethnic differences in energy balance: can we get there from here?

PMID- 10393131
TI  - Time to reassess the optimal dietary prescription for women with gestational
      diabetes.

PMID- 10393132
TI  - Body-composition changes with diet and exercise in obese women: a comparison of
      estimates from clinical methods and a 4-component model.
AB  - BACKGROUND: Most methods available to clinicians for estimating body-composition
      changes have been validated against estimates from densitometry, based on a 2
      component (fat mass and fat-free mass) model. OBJECTIVE: Estimates of changes in
      percentage body fat (%BF) from dual-energy X-ray absorptiometry (DXA), skinfold
      thicknesses (SFTs), bioelectrical impedance analysis (BIA), and body mass index
      (BMI; in kg/m2) were compared with estimates from a 4-component (fat, water,
      mineral, and protein) model (%BFd,w,m), a more accurate method. DESIGN:
      Determinations of body density from hydrostatic weighing, body water from
      deuterium dilution, bone mineral and %BF from whole-body DXA, resistance from
      BIA, and anthropometric measures were made in 27 obese women (BMI: 31.1 +/- 4.9)
      assigned to 1 of 3 groups: control (C; n = 9), diet only (DO; n = 9), or diet
      plus aerobic exercise (DE; n = 9). RESULTS: After the 16-wk intervention, changes
      in body mass (BM) averaged 0.5 +/- 2.0, -7.2 +/- 7.4, and -4.0 +/- 3.3 kg and
      changes in %BFd,w,m averaged 2.1 +/- 1.0%, -1.2 +/- 1.4%, and -2.4 +/- 1.6% in
      the C, DO, and DE groups, respectively. Compared with changes in %BFd,w,m, the
      errors (SD of bias) for estimates of changes in %BF by DXA, BIA, SFTs, and BMI
      were similar (range: +/-2.0-2.4% of BM). BIA, SFTs, and BMI provided unbiased
      estimates of decreases in %BFd,w,m, but DXA overestimated decreases in %BF in the
      DO and DE groups. CONCLUSIONS: DXA, BIA, SFTs, and BMI are comparably accurate
      for evaluating body-composition changes induced by diet and exercise
      interventions; however, small changes in %BF may not be accurately detected by
      these clinical methods.

PMID- 10393133
TI  - Energy metabolism in African Americans: potential risk factors for obesity.
AB  - BACKGROUND: Recent reports have identified a lower resting metabolic rate in
      African Americans than in whites, but most studies included only females and used
      short-term measurements with ventilated-hood systems. OBJECTIVE: Our objective
      was to compare 24-h measurements of energy metabolism between African American
      and white women and men using a respiratory chamber. DESIGN: Thirty-eight African
      American (x +/- SD: 32 +/- 7 y of age, 24 +/- 10% body fat) and 288 white (31 +/-
      7 y of age, 26 +/- 12% body fat) subjects spent 24 h in a respiratory chamber for
      measurement of 24-h energy expenditure (24EE), sleeping metabolic rate (SMR), 24
      h respiratory quotient (24RQ), and substrate oxidation rates. RESULTS: After
      adjustment for sex, age, and body composition (by hydrodensitometry), African
      Americans had lower SMR (-301 +/- 105 kJ/d; P < 0.01) and higher 24RQ (0.014 +/-
      0.004; P < 0.001) than whites, whereas 24EE was similar. A sex-specific analysis,
      using a subset of 38 whites with an equal sex distribution and similar age and
      body weight, revealed that African American women had lower SMR (-442 +/- 182
      kJ/d; P < 0.05) and lower 24EE (-580 +/- 232 kJ/d; P < 0.05), but similar 24RQ
      values compared with white women. African American men tended to have lower SMRs
      than white men (-355 +/- 188 kJ/d; P = 0. 07), but had higher 24RQ values,
      accounting for a 992 +/- 327-kJ/d lower 24-h fat oxidation rate (P < 0.005).
      CONCLUSIONS: These data not only confirm the findings of a lower metabolic rate
      in African American than in white women, but also suggest that fat oxidation is
      lower in African American men than in white men.

PMID- 10393134
TI  - Relation between the intake of milk fat and the occurrence of conjugated linoleic
      acid in human adipose tissue.
AB  - BACKGROUND: Conjugated linoleic acid (CLA) is a group of naturally occurring
      fatty acids mainly present in fats from ruminants. CLA has been shown to be a
      potential anticarcinogen. OBJECTIVE: In this study, the relation between bovine
      milk fat intake and the occurrence of CLA in human adipose tissue was
      investigated. DESIGN: One hundred twenty-three men weighed and recorded the foods
      they consumed for 1 wk. Afterward, recall interviews were conducted by telephone
      monthly for 7 consecutive months to inquire about food consumption during the
      previous 24 h. The entire dietary recording procedure was repeated once. The
      fatty acid composition of adipose tissue and serum was analyzed. RESULTS: The
      average amount of one isomer of CLA--9-cis,11-trans-octadecadienoic acid (9c,11t
      18:2)--as a percentage of total fatty acids was found to be 0.50% in adipose
      tissue and 0.25% in serum. The amount of 9c,11t-18:2 in adipose tissue was
      significantly correlated with milk fat intake (r = 0.42). The percentage of
      9c,11t-18:2 in both adipose tissue and in serum was strongly correlated with
      myristoleic acid (14:1). CONCLUSION: The amount of 9c,11t-18:2 in human adipose
      tissue was significantly related to milk fat intake.

PMID- 10393135
TI  - Food preferences and reported frequencies of food consumption as predictors of
      current diet in young women.
AB  - BACKGROUND: Self-reported food preferences and frequencies of food consumption
      have served as proxy measures of the current diet in consumer research and in
      nutritional epidemiology studies, respectively. OBJECTIVE: The objective was to
      determine whether food preferences and food-frequency scores are associated
      variables that are predictive of nutrient intakes. DESIGN: College-age women (n =
      87) completed a 98-item food-frequency questionnaire and rated preferences for
      many of the same foods on a 9-point category scale. Estimated intakes of fat,
      fiber, and vitamin C were obtained by using 3-d food records. RESULTS: For
      virtually all item pairs tested, food preferences and reported frequencies of
      consumption of the same foods were significantly correlated with each other. The
      median Pearson correlation coefficient was 0.40 (range: -0.04 to 0.62).
      Correlations improved when foods were aggregated into factor-based food groups.
      The slope of the relation between food preferences and frequency of consumption
      varied with food category. Both food preferences and food frequencies predicted
      dietary outcomes. Fat consumption was predicted equally well by either approach
      in a multiple regression model. Intakes of fiber and vitamin C were better
      predicted by food-frequency scores than by stated preferences for vegetables and
      fruit. CONCLUSIONS: Reported frequencies of food consumption, the core of the
      food-frequency approach, were associated with food likes and dislikes. Food
      preferences were a predictor of dietary intakes and may provide an alternative to
      the food-frequency approach for dietary intake assessment.

PMID- 10393136
TI  - Manganese absorption and retention by young women is associated with serum
      ferritin concentration.
AB  - BACKGROUND: The interaction between iron and manganese in the gut is well
      characterized but iron status has not been shown to affect manganese absorption.
      OBJECTIVE: The objective of this study was to determine whether iron status as
      determined by serum ferritin concentrations affects manganese absorption,
      retention, balance, and status. DESIGN: The subjects were healthy young women; 11
      had serum ferritin concentrations >50 microg/L and 15 had serum ferritin
      concentrations <15 microg/L. In a crossover design, subjects consumed diets that
      supplied either 0.7 or 9.5 mg Mn/d for 60 d. Manganese absorption and retention
      were assessed during the last 30 d of each dietary period by using an oral dose
      of 54Mn; balance was assessed simultaneously. RESULTS: Dietary manganese did not
      affect manganese status, but high serum ferritin depressed arginase activity. The
      interaction of ferritin status and dietary manganese affected 54Mn absorption and
      biological half-life. Absorption was greatest in subjects with low ferritin
      concentrations when they were consuming the low-manganese diet, and was least in
      subjects with high ferritin concentrations. Biological half-life was longest when
      subjects with high ferritin concentrations consumed the low-manganese diet, and
      was shortest in all subjects consuming the high-manganese diet. Manganese balance
      was only affected by the amount of manganese in the diet. CONCLUSIONS: These
      results show that iron status, as measured by serum ferritin concentration, is
      strongly associated with the amount of manganese absorbed from a meal by young
      women. When greater amounts of manganese are absorbed, the body may compensate by
      excreting manganese more quickly.

PMID- 10393137
TI  - Effects of high compared with low calcium intake on calcium absorption and
      incorporation of iron by red blood cells in small children.
AB  - BACKGROUND: The potential benefits of increasing calcium intake in small children
      must be balanced with the potential risk to iron utilization from high calcium
      intakes. OBJECTIVE: This study was designed to evaluate the relation between
      calcium intake and calcium absorption and iron incorporation into red blood
      cells. DESIGN: We performed a multitracer, crossover study of the absorption of
      calcium and red blood cell incorporation of iron in 11 preschool children aged 3
      5 y who had been adapted for 5 wk to low- (502 +/- 99 mg) and high- (1180 +/- 117
      mg) calcium diets. Stable-isotope studies were performed by using 44Ca and 58Fe
      given orally with meals and 46Ca given intravenously. RESULTS: Iron incorporation
      into red blood cells 14 d postdosing was similar (6.9 +/- 4.2% compared with 7.9
      +/- 5.5%; NS) with the low- and high-calcium diets, respectively. Total calcium
      absorption (181 +/- 50 compared with 277 +/- 91 mg/d; P = 0.002) was greater in
      children with the higher calcium intake. CONCLUSIONS: Our findings indicate that
      small children may benefit from calcium intakes similar to those recommended for
      older children without adverse effects on dietary iron utilization.

PMID- 10393138
TI  - Serum vitamin C concentrations and diabetes: findings from the Third National
      Health and Nutrition Examination Survey, 1988-1994.
AB  - BACKGROUND: Previous studies suggested that diabetes mellitus may lower serum
      vitamin C concentrations, but most of these studies used clinic-based populations
      with established diabetes of varying duration and did not adjust for important
      covariates. OBJECTIVE: Using a population-based sample and adjusting for
      important covariates, we asked whether serum vitamin C concentrations in persons
      with newly diagnosed diabetes differed from those in persons without diabetes.
      DESIGN: Data were obtained from the third National Health and Nutrition
      Examination Survey (1988-1994). Serum vitamin C was assayed by using reversed
      phase HPLC with multiwavelength detection. Diabetes status (n = 237 persons with
      diabetes; n = 1803 persons without diabetes) was determined by oral-glucose
      tolerance testing of the sample aged 40-74 y. RESULTS: After adjustment for age
      and sex, mean serum vitamin C concentrations were significantly lower in persons
      with newly diagnosed diabetes than in those without diabetes. After adjustment
      for dietary intake of vitamin C and other important covariates, however, mean
      concentrations did not differ according to diabetes status. CONCLUSION: When
      assessing serum vitamin C concentrations by diabetes status in the future,
      researchers should measure and account for all factors that influence serum
      vitamin C concentrations.

PMID- 10393139
TI  - Maternal plasma phospholipid polyunsaturated fatty acids in pregnancy with and
      without gestational diabetes mellitus: relations with maternal factors.
AB  - BACKGROUND: The fatty acids arachidonic acid (AA; 20:4n-6) and docosahexaenoic
      acid (DHA; 22:6n-3) are essential for fetal growth and development, but their
      metabolism may be altered in insulin resistance. OBJECTIVES: The objectives were
      to determine maternal plasma phospholipid polyunsaturated fatty acid
      concentrations in pregnant women receiving dietary therapy for gestational
      diabetes mellitus (GDM) and to identify maternal factors associated with plasma
      phospholipid AA and DHA concentrations in the third trimester. DESIGN: Fasting
      plasma phospholipid fatty acids were determined in women with GDM (n = 15)
      receiving dietary therapy only and in healthy, pregnant women without GDM
      (control group, n = 15) at 27-30, 33-35, and 36-39 wk gestation. RESULTS:
      Maternal plasma phospholipid (as % by wt of total fatty acids and mg/L) linoleic
      acid (18:2n-6), AA, and 22:5n-6 concentrations did not differ significantly
      between women with GDM and control subjects. The other n-6 long-chain
      polyunsaturated fatty acids (% by wt) were lower in GDM subjects than in control
      subjects. Plasma phospholipid (expressed as % by wt and mg/L) linolenic acid
      (18:3n-3) and summed precursors of DHA were lower and DHA (% by wt and mg/L),
      adjusted for dietary DHA intake, was 13% higher in GDM subjects than in control
      subjects. Maternal blood hemoglobin A1C was inversely related to plasma
      phospholipid AA (% by wt) (r = -0.56, P = 0.03) in control subjects and
      positively associated with plasma phospholipid AA (% by wt) in women with GDM (r
      = 0.76, P = 0.001). Pregravid body mass index was negatively associated with
      plasma phospholipid DHA (% by wt) in control subjects (r = -0.55, P = 0.04) and
      in women with GDM with a body mass index (in kg/m2) <30 (r = -0.76, P = 0.007).
      CONCLUSIONS: This is the first report documenting alterations in maternal plasma
      phospholipid PUFAs in pregnant women receiving dietary therapy for GDM. In
      pregnant woman, both with and without GDM, maternal glycemic control and
      pregravid BMI appear to be significant predictors of plasma phospholipid AA and
      DHA, respectively, during the third trimester. Additionally, dietary DHA
      significantly affects phospholipid DHA concentrations.

PMID- 10393140
TI  - Plasma lipoprotein fatty acids are altered by the positional distribution of
      fatty acids in infant formula triacylglycerols and human milk.
AB  - BACKGROUND: Triacylglycerol digestion involves hydrolysis of fatty acids
      esterified at the glycerol 1,3 positions by gastric and pancreatic lipase to
      produce 2-monoacylglycerols and unesterified fatty acids, which are then
      absorbed, reesterified to triacylglycerol, and secreted in chylomicrons. Palmitic
      acid (16:0) is predominantly esterified to the 2 position of human milk
      triacylglycerol but to the 1,3 positions in the oils used in infant formulas.
      OBJECTIVE: We aimed to determine whether the position of 16:0 in human milk and
      infant formula triacylglycerol influences the position of fatty acids in
      postprandial plasma chylomicron triacylglycerol. DESIGN: Full-term infants were
      fed formula with 25-27% 16:0 with either 39% of the 16:0(synthesized
      triacylglycerol) or 6% of the 16:0 (standard formula) esterified at the
      triacylglycerol 2 position, or were breast-fed (23% 16:0, 81% at the
      triacylglycerol 2 position) from birth to 120 d of age. Chylomicron fatty acids
      and plasma lipids were assessed at 30 and 120 d of age. RESULTS: Infants fed the
      synthesized triacylglycerol formula, standard formula, or breast milk had
      15.8%,8.3%, and 28.0% 16:0 in the chylomicron triacylglycerol 2 position (P <
      0.05). These results suggest that >/=50% of the dietary triacylglycerol 2
      position 16:0 is conserved through digestion, absorption, and chylomicron
      triacylglycerol synthesis in breast-fed and formula-fed infants. Infants fed the
      synthesized triacylglycerol formula had significantly lower HDL-cholesterol and
      apolipoprotein A-I and higher apolipoprotein B concentrations than infants fed
      the standard formula. CONCLUSION: Dietary triacylglycerol fatty acid distribution
      may alter lipoprotein metabolism in young infants.

PMID- 10393141
TI  - Lack of enteral nutrition during critical illness is associated with profound
      decrements in biliary lipid concentrations.
AB  - BACKGROUND: Food in the intestine drives the enterohepatic circulation of bile
      components. OBJECTIVE: We investigated whether parenteral or enteral delivery of
      nutrients alters serum and biliary lipids in critically ill patients. DESIGN:
      Eight intensive care unit (ICU) patients who had received >/= 5 d of total
      parenteral nutrition (TPN) were compared with 8 ICU patients who had fasted for
      >/=5 d. Both groups were studied before and after 5 d of enteral nutrition (EN).
      Each patient served as his or her own control. Duodenal bile was analyzed for
      biliary lipid content and serum lipids were determined simultaneously. Duodenal
      bile samples from 18 healthy persons served as controls. RESULTS: Bile salt
      concentrations in all ICU patients were 17% of control values before EN (P <
      0.005) and 34% of control values after 5 d of EN (P < 0.005). Phospholipid
      concentrations were 12% of control before EN (P < 0. 0005) but increased almost 4
      fold after EN (P < 0.0005). Biliary cholesterol concentrations were 20% of
      control values before EN (P < 0.001) and did not improve afterward. No difference
      in bile composition was observed between fasted ICU patients and those who
      received TPN. The inverse correlation between the severity of illness and biliary
      lipid concentrations observed before EN disappeared with enteric stimulation. The
      low serum concentrations of HDL cholesterol and apolipoprotein A-I increased
      significantly with EN in all ICU patients. CONCLUSION: Lack of EN during critical
      illness was associated with profound decrements in biliary lipid concentrations
      that normalized partially after 5 d of EN. We hypothesize that loss of enteric
      stimulation in ICU patients impairs hepatic lipid metabolism.

PMID- 10393142
TI  - Differences in essential fatty acid requirements by enteral and parenteral routes
      of administration in patients with fat malabsorption.
AB  - BACKGROUND: Essential fatty acid (EFA) requirements of patients receiving home
      parenteral nutrition (HPN) are uncertain. OBJECTIVE: The objective was to
      evaluate the influence of the route of administration (enteral compared with
      parenteral) on plasma phospholipid EFA concentrations. DESIGN: Intestinal
      absorption, parenteral supplement of EFAs, and plasma phospholipid EFA
      concentrations were investigated in balance studies in 4 groups (A, B, C, and D)
      of 10 patients with short-bowel syndrome and a fecal loss of >2000 kJ/d. Groups A
      (fat malabsorption <50%) and B (fat malabsorption >50%) did not receive HPN,
      whereas group C received HPN containing lipids (7.5 and 1.2 g/d linoleic and
      linolenic acids, respectively) and group D received fat-free HPN. RESULTS:
      Intestinal absorption of linoleic and linolenic acids was 8.9 and 1.3 g/d and 2.
      6 and 0.4 g/d in groups A and B, respectively, whereas EFA absorption was
      negligible in groups C and D. Thus, intestinal absorption of EFAs in group A
      corresponded to parenteral EFA supplements in group C, whereas group D was almost
      totally deprived of EFAs. The median plasma phospholipid concentration of
      linoleic acid decreased by 21.9%, >16.3%, >13.8%, 11.0%, and >7.7% and linolenic
      acid by 0.3%, 0.2%, 0.2%, >0.2%, and 0.1%, respectively, in 10 healthy control
      subjects and groups A, B, C, and D (P < 0.001). CONCLUSIONS: Intestinally
      absorbed EFAs maintained plasma EFA status better than did an equal quantity of
      parenterally supplied EFAs. Intravenous requirements of EFAs in patients with
      negligible absorption of EFAs are probably higher than the amounts recommended to
      patients with preserved intestinal absorption of EFAs.

PMID- 10393143
TI  - Fish consumption and cancer risk.
AB  - BACKGROUND: Although several studies have investigated the relation between fish
      consumption and the risk of cardiovascular diseases, less attention has been paid
      to the relation between fish consumption and cancer risk. OBJECTIVE: The relation
      between frequency of consumption of fish and risk of selected neoplasms was
      analyzed by using data from an integrated series of case-control studies
      conducted in northern Italy between 1983 and 1996. DESIGN: The overall data set
      included the following incident, histologically confirmed neoplasms: oral cavity
      and pharynx (n = 181), esophagus (n = 316), stomach (n = 745), colon (n = 828),
      rectum (n = 498), liver (n = 428), gallbladder (n = 60), pancreas (n = 362),
      larynx (n = 242), breast (n = 3412), endometrium (n = 750), ovary (n = 971),
      prostate (n = 127), bladder (n = 431), kidney (n = 190), thyroid (n = 208),
      Hodgkin disease (n = 80), non-Hodgkin lymphomas (n = 200), and multiple myelomas
      (n = 120). Control subjects were 7990 patients admitted for acute, nonneoplastic
      conditions unrelated to long-term modifications of diet. Odds ratios (ORs) were
      computed for subsequent levels of fish consumption compared with no or occasional
      consumption (<1 serving/wk) by using multiple logistic regression, including
      terms for several covariates. RESULTS: There was a consistent pattern of
      protection against the risk of digestive tract cancers with fish consumption:
      oral cavity and pharynx, OR = 0.5 for the highest compared with the lowest level
      of consumption; esophagus, OR = 0.6; stomach, OR = 0.7; colon, OR = 0.6; rectum,
      OR = 0.5; and pancreas, OR = 0.7. There were inverse trends in risk of larynx (OR
      = 0.7), endometrial (OR = 0.8), and ovarian (OR = 0.7) cancers and multiple
      myeloma (OR = 0.5). No pattern of cancer risk in relation to fish consumption was
      observed for cancers of the liver, gallbladder, breast, bladder, kidney, or
      thyroid or for lymphomas. CONCLUSION: This study suggests that the consumption of
      even relatively small amounts of fish is a favorable indicator of the risk of
      several cancers, especially of the digestive tract.

PMID- 10393144
TI  - Physical activity, protein intake, and appendicular skeletal muscle mass in older
      men.
AB  - BACKGROUND: Aging is associated with physical inactivity, low energy intake, and
      loss of skeletal muscle mass. It is not clear whether regular physical activity
      and adequate dietary protein intake can attenuate the loss of skeletal muscle
      mass. OBJECTIVE: We hypothesized that the maintenance of physical activity and
      dietary protein intake would attenuate the age-related decline in total
      appendicular skeletal muscle mass. DESIGN: Total appendicular skeletal muscle
      mass was determined by dual-energy X-ray absorptiometry in 44 healthy, older
      white men aged 49-85 y. Physical activity level was determined by using a
      uniaxial accelerometer over a 9-d period. Dietary protein intake was estimated
      from a 3-d food record. RESULTS: Aging was inversely associated with total
      appendicular skeletal muscle mass in older men (r = -0.43; slope: -0. 119 +/-
      0.039 kg/y; P < 0.01). An effect of age on appendicular skeletal muscle mass
      persisted after standing height and physical activity were controlled for (r = 
      0.34; slope: -0.120 +/- 0.052 kg/y; P = 0.03). Furthermore, an effect of age on
      appendicular skeletal muscle mass persisted after standing height and dietary
      protein intake per kilogram body mass was controlled for (r = -0.41; slope: 
      0.127 +/- 0.045 kg/y; P < 0.01). CONCLUSIONS: Maintaining regular physical
      activity and adequate protein intake may not offset the age-related loss of
      appendicular skeletal muscle mass in older men. Prospective studies are needed to
      confirm these results and to determine whether anabolic physical activity (eg,
      strength training) can attenuate the age-related loss of muscle mass in the
      elderly.

PMID- 10393146
TI  - Oxidized LDL, diet, and natural antibodies.

PMID- 10393145
TI  - Effect of a lifestyle intervention on bone mineral density in premenopausal
      women: a randomized trial.
AB  - BACKGROUND: The positive association between body weight and bone mineral density
      (BMD) is well documented; in contrast, the effect of changes in body weight on
      BMD is not well understood, particularly, in normal-weight populations.
      OBJECTIVE: We examined the effect of a lifestyle intervention aimed at lowering
      dietary fat intake and increasing physical activity to produce modest weight loss
      or prevent weight gain on BMD in a population of 236 healthy, premenopausal women
      aged 44-50 y. DESIGN: All women were participating in a clinical trial known as
      The Women's Healthy Lifestyle Project and were randomly assigned to intervention
      or control groups. Dual-energy X-ray absorptiometry of BMD at the lumbar spine
      and proximal femur were made before and after 18 mo of participation in the
      trial. RESULTS: The intervention group (n = 115) experienced a mean (+/-SD)
      weight loss of 3.2 +/- 4.7 kg over the 18 mo compared with a weight gain of 0.42
      +/- 3.6 kg in the control group (n = 121) (P < 0.001). The annualized rate of hip
      BMD loss was 2-fold higher (P < 0.015) in the intervention group (0.81 +/- 1.3%)
      than in the control group (0.42 +/- 1.1%); a similar, although nonsignificant
      pattern was observed for the loss in spine BMD: 0.70 +/- 1.4% and 0.37 +/- 1.5%
      (P = 0.093) in the intervention and control groups, respectively. Large increases
      in physical activity attenuated spine BMD loss, but had no significant effect on
      BMD loss at the hip. CONCLUSIONS: The intervention group, who modified their
      lifestyle to lose weight, had a higher rate of BMD loss at the hip and lumbar
      spine than did the weight-stable control group. Recommendations for weight loss
      must be made with consideration that such an endorsement may result in BMD loss.

PMID- 10393148
TI  - Prebiotics or probiotics for lactose intolerance: a question of adaptation.

PMID- 10393149
TI  - Dietary supplement or drug? The case for cholestin.

PMID- 10393151
TI  - Dietary fat and obesity.

PMID- 10393154
TI  - Improving study design.

PMID- 10393156
TI  - Single-nutrient interventions with zinc.

PMID- 10393159
TI  - Defining obesity in childhood: current practice2.
AB  - A survey of information from 26 countries was performed to examine the methods,
      cutoff points, and reference materials used to define obesity in childhood and
      adolescence. The body mass index (in kg/m2) was used frequently, as well as
      several other methods. Reference materials used were often based on national
      surveys, although reference data from other countries were sometimes used. The
      data presented was often insufficient to judge the representativeness of the
      reference material. Cutoff points varied considerably. Available data allow
      neither a meaningful international estimation of the prevalence of obesity nor
      international comparisons. Although associated with considerable problems, this
      situation can be improved with an international consensus which, by necessity,
      will be riddled with uncertainties and compromises.

PMID- 10393160
TI  - Validity of the body mass index as an indicator of the risk and presence of
      overweight in adolescents.
AB  - The validity of the body mass index (BMI) as an indicator of the risk of becoming
      overweight and of the presence of overweight was evaluated in 6 groups of
      adolescents comprising several ethnic groups (n = 1570, aged 9-19 y). With use of
      triceps skinfold thickness and estimated percentage body fat as the criteria for
      adiposity, BMI had high specificities (86.1-98.8% for risk of overweight and 96.3
      100% for presence of overweight) and lower but variable sensitivities (4.3-75.0%
      for risk of overweight and 14.3-60% for presence of overweight). Thus, almost all
      adolescents who were not at risk for overweight or who were not overweight were
      classified correctly. In contrast, many adolescents who were at risk of
      overweight or who were overweight were not correctly identified as measured by
      BMI. Partial correlations, controlling for age, between BMI and the triceps
      skinfold thickness and estimated percentage body fat were generally moderate to
      moderately high, whereas BMI and triceps skinfold thickness appeared to be
      equally related to estimated total body fatness and percentage body fat in
      Mexican American and Austrian white males. BMI was better correlated with trunk
      skinfold thicknesses, but when relative subcutaneous fat distribu-tion was
      statistically controlled, the trunk-extremity contrast in the correlations was no
      longer apparent.

PMID- 10393161
TI  - Fatness and body mass index from birth to young adulthood in a rural Guatemalan
      population.
AB  - Body mass index (BMI; wt in kg/ht2 in m) has been proposed as a simple and valid
      measure for monitoring fatness. Using data from a 25-y longitudinal study of
      rural Guatemalans, we found that, as children, this population was stunted (mean
      height-for-age z = -2.6) and had low triceps skinfold thicknesses ( approximately
      10% of reference medians), yet had mean BMIs above US reference medians. As young
      adults, mean BMIs were at the 50th and 20th percentiles for women and men,
      respectively. BMIs between ages 1 and 5 y were moderately correlated (r = 0.2
      0.3) with those in young adulthood. BMI was correlated with subscapular (r = 0.5
      0.8) and triceps (r = 0.2-0.7) skinfold thicknesses at all ages and with
      predicted percentage body fat in adolescence (r = 0.65) and adulthood (r = 0.8).
      Fatness was highly centralized, with ratios of subscapular to triceps skinfold
      thicknesses at the 50th-90th percentiles of reference medians at all ages. BMI
      was a poor indicator of central fat; the correlation between BMI and waist-to-hip
      ratio in 14-17-y-old males was -0.21). In stunted populations in developing
      countries, BMI alone should be interpreted with caution. In stunted children,
      BMIs may be high despite small extremity skinfold thicknesses; BMI alone may
      overestimate the prevalence of fatness in these children. In adults, measures in
      addition to BMI may be required to identify centralized adiposity in these
      populations.

PMID- 10393162
TI  - Tracking of body mass index in children in relation to overweight in adulthood.
AB  - Body mass index (BMI; in kg/m2) values at or above the 75th percentile are
      associated with increased morbidity and mortality in adulthood, and there are
      significant correlations between BMI values in childhood and in adulthood. The
      present study addresses the predictive value of childhood BMI for overweight at
      35 +/- 5 y, defined as BMI >28 for men and BMI >26 for women. Analyses of data
      from 555 white children showed that overweight at age 35 y could be predicted
      from BMI at younger ages. The prediction is excellent at age 18 y, good at age 13
      y, but only moderate at ages <13 y. For 18-y-olds with BMIs above the 60th
      percentile, the probability of overweight at age 35 y is 34% for men and 37% for
      women. A clinically applicable method is provided to assign an overweight child
      to a group with a known probability of high BMI values in adulthood.

PMID- 10393163
TI  - Relation between visceral fat and disease risk in children and adolescents.
AB  - This review examines whether the relations and metabolic parameters necessary for
      the development of syndrome X are present in children and whether the metabolic
      complications of obesity in children are explained by excess intraabdominal
      adipose tissue (IAAT), or visceral fat. Despite the limited use of imaging
      techniques in research studies, an increasing number of studies reported on IAAT
      and its relation to disease risk in children and adolescents. For this article we
      reviewed studies that documented the early accumulation of IAAT in children and
      adolescents and the factors that contribute to variation in the degree of IAAT
      accumulation. We also reviewed studies that showed the clinical relevance of IAAT
      in children and adolescents through significant relations with adverse health
      effects including dyslipidemia and glucose intolerance in obese and nonobese
      children and adolescents of different ethnic groups.

PMID- 10393164
TI  - Comparison of weight and height relations in boys from 4 countries.
AB  - Height and weight data from children in the United States, United Kingdom, Japan,
      and Singapore were analyzed to investigate differences in growth between the
      groups of children. An investigation into the adjusted weight indexes of the form
      index = weight/heightp for differing powers of p (Benn index) showed that the
      power of p required to produce a correlation of zero between the index and height
      varied with age. For the United States, Japan, and Singapore the p value was just
      below 3.0 for children aged 6 y, increased to approximately 3.5 for children aged
      approximately 10 y, and decreased to approximately 2.0 at age approximately 18 y.
      A consequence of the p value being mostly >2.0 is that BMI (wt/ht2) tends to be
      greater for tall children than for short children. The US data (from the second
      National Health and Nutrition Examination Survey) also contained information on
      skinfold thickness. Relating skinfold thickness to indexes of the same form for
      height and weight suggested that the best relation was achieved with p values of
      approximately 2.0 except for children aged 12-16 y, for whom the optimal values
      for p were higher. The highest value, 2.9, was achieved at ages 12-13 y. Overall,
      the use of BMI as an indicator of adiposity appears acceptable for children aged
      6-7 and 17-18 y. However, BMI should be used with caution when assessing children
      aged 8-16 y.

PMID- 10393165
TI  - Curve smoothing and transformations in the development of growth curves.
AB  - Growth charts such as those published by the National Center for Health
      Statistics (NCHS) consist of a set of smoothed percentile curves showing the
      distribution of different aspects of body size for infants, children, and
      adolescents. The original NCHS growth charts are currently being revised to
      incorporate additional national data, to include growth curves for body mass
      index (BMI, in kg/m2), to reduce or eliminate dis-continuities, and to use new
      and improved methods of smoothing. Methods of curve smoothing in the development
      of growth curves are briefly discussed in the context of this revision by using
      examples based on the provisional data set for revision of the growth curves.
      Among the factors that may affect the construction of the revised growth curves
      are sample sizes, sampling weights, and secular trends. The use of BMI or other
      weight-height indexes in growth curves presents some new issues because these
      transformations of weight and height data do not increase monotonically with age.
      Some of the advantages and disadvantages of several different approaches to
      creating smoothed percentiles and standardized scores are discussed briefly.
      These effects need to be considered in the broader context of constructing growth
      curves. No single method of developing smoothed curves is clearly the best for
      all purposes, and estimates of overweight and underweight may be sensitive to the
      method chosen. Alternative approaches to constructing smoothed curves by using
      weight-height functions other than BMI might warrant further exploration.

PMID- 10393166
TI  - The European Childhood Obesity Group (ECOG) project: the European collaborative
      study on the prevalence of obesity in children.
AB  - During the European Congress on Obesity held in Barcelona in 1996, the European
      Childhood Obesity Group (ECOG) proposed a study designed to estimate the
      prevalence of obesity by country. An overview of existing systems revealed that
      most countries have no suitable structure in place for the determination of
      obesity in children and that the most practical sources of samples would be the
      school systems. A protocol was drawn up for these countries, whereas for those
      countries already collecting data, guidelines were defined to clarify the
      criteria allowing inclusion in the common analysis. The target population is 7-9
      y-old children. The study design consists of separate cross-sectional population
      studies by country with a cluster probability sample of 2000 children attending
      primary school. The minimum common data will be age, weight, height, and hip,
      thigh, and waist circumferences. The participating countries will be encouraged
      to collect harmonized data on social indicators, lifestyle, diet, physical
      activity, and anthropometric measures of the parents. Children will be measured
      either by centrally based traveling examiners or, in countries with limited
      resources, by local staff. Each country will computerize its own data and send a
      copy to a center responsible for the common analysis. The main analysis will be
      of body mass index distribution in children from the different populations and
      determination of the proportion of children with a BMI above the 90th percentile
      of a common reference population. Members of the ECOG in 14 European countries
      have confirmed their interest in the project.

PMID- 10393167
TI  - A new international growth reference for young children.
AB  - Growth references for children are among the most widely used instruments in
      public health and clinical medicine. A comprehensive review by the World Health
      Organization (WHO) of the use and interpretation of anthropometric data concluded
      that the present international growth reference for infants does not describe
      physiologic growth adequately; thus, a new anthropometric reference was
      recommended for young children from birth to 5 y. The approach taken by the WHO
      for development of a new reference is guided by the principle that anthropometric
      reference data must always reflect the functional context of their intended uses
      and an awareness of the consequences of their application. The new reference will
      be constructed from data to be collected in a longitudinal study of infants who
      will be exclusively or predominantly breast-fed for >/=4 mo with continued breast
      feeding throughout the first year, and a cross-sectional study of infants and
      young children aged 18-71 mo. The sample will be drawn from >/=7 diverse
      geographic sites around the world. The adopted protocol is expected to provide a
      single international reference that represents the best standard possible of
      optimal growth for all children <5 y of age. Furthermore, documentation will be
      sufficient to allow for possible future revision of the reference as substantial
      new biological information on the growth of infants and young children becomes
      available.

PMID- 10393168
TI  - Workshop on childhood obesity: summary of the discussion.
AB  - Childhood obesity is rapidly emerging as a global epidemic that will have
      profound public health consequences as overweight children become overweight
      adults. To address this problem, action is needed at national and international
      levels. However, well-documented evidence of the trends in and global prevalence
      of obesity in children and adolescents is required to develop sound public health
      policies. There is no internationally acceptable index to assess childhood
      obesity nor is there an established cutoff point to define overweight in
      children. The purpose of the workshop was to establish a reasonable index with
      which to assess adiposity (overweight) in children and adolescents worldwide. We
      present here a summary of the discussion on the establishment of an index. The
      participants concluded that although body mass index (BMI; in kg/m2) is not a
      perfect measure in children because it covaries with height, it has been
      validated against measurements of body density. Because a consistent and
      pragmatic definition for overweight in children and adolescents is required, BMI
      may therefore be appropriate. However, other alternatives may be considered in
      the future. The group suggested a scheme for cutoff points for children and
      adolescents based on internationally accepted BMI cutoff points for adult
      morbidity of 25 and 30 to identify grade 1 and grade 2 overweight, respectively.
      Use of these cutoff points would provide a new approach to identifying childhood
      obesity and make the definition for children and adolescents consistent with that
      for adults.

PMID- 10393169
TI  - Crystal structure of the histone acetyltransferase domain of the human PCAF
      transcriptional regulator bound to coenzyme A.
AB  - The human p300/CBP-associating factor, PCAF, mediates transcriptional activation
      through its ability to acetylate nucleosomal histone substrates as well as
      transcriptional activators such as p53. We have determined the 2.3 A crystal
      structure of the histone acetyltransferase (HAT) domain of PCAF bound to coenzyme
      A. The structure reveals a central protein core associated with coenzyme A
      binding and a pronounced cleft that sits over the protein core and is flanked on
      opposite sides by the N- and C-terminal protein segments. A correlation of the
      structure with the extensive mutagenesis data for PCAF and the homologous yeast
      GCN5 protein implicates the cleft and the N- and C-terminal protein segments as
      playing an important role in histone substrate binding, and a glutamate residue
      in the protein core as playing an essential catalytic role. A structural
      comparison with the coenzyme-bound forms of the related N-acetyltransferases,
      HAT1 (yeast histone acetyltransferase 1) and SmAAT (Serratia marcescens
      aminoglycoside 3-N-acetyltransferase), suggests the mode of substrate binding and
      catalysis by these enzymes and establishes a paradigm for understanding the
      structure-function relationships of other enzymes that acetylate histones and
      transcriptional regulators to promote activated transcription.

PMID- 10393170
TI  - Crystal structures of adenine phosphoribosyltransferase from Leishmania donovani.
AB  - The enzyme adenine phosphoribosyltransferase (APRT) functions to salvage adenine
      by converting it to adenosine-5-monophosphate (AMP). APRT deficiency in humans is
      a well characterized inborn error of metabolism, and APRT may contribute to the
      indispensable nutritional role of purine salvage in protozoan parasites, all of
      which lack de novo purine biosynthesis. We determined crystal structures for APRT
      from Leishmania donovani in complex with the substrate adenine, the product AMP,
      and sulfate and citrate ions that appear to mimic the binding of phosphate
      moieties. Overall, these structures are very similar to each other, although the
      adenine and AMP complexes show different patterns of hydrogen-bonding to the
      base, and the active site pocket opens slightly to accommodate the larger AMP
      ligand. Whereas AMP adopts a single conformation, adenine binds in two mutually
      exclusive orientations: one orientation providing adenine-specific hydrogen bonds
      and the other apparently positioning adenine for the enzymatic reaction. The core
      of APRT is similar to that of other phosphoribosyltransferases, although the
      adenine-binding domain is quite different. A C-terminal extension, unique to
      Leishmania APRTs, extends an extensive dimer interface by wrapping around the
      partner molecule. The active site involves residues from both subunits of the
      dimer, indicating that dimerization is essential for catalysis.

PMID- 10393171
TI  - Crystal structures of the bovine beta4galactosyltransferase catalytic domain and
      its complex with uridine diphosphogalactose.
AB  - beta1,4-galactosyltransferase T1 (beta4Gal-T1, EC 2.4.1.90/38), a Golgi resident
      membrane-bound enzyme, transfers galactose from uridine diphosphogalactose to the
      terminal beta-N-acetylglucosamine residues forming the poly-N-acetyllactosamine
      core structures present in glycoproteins and glycosphingolipids. In mammals,
      beta4Gal-T1 binds to alpha-lactalbumin, a protein that is structurally homologous
      to lyzozyme, to produce lactose. beta4Gal-T1 is a member of a large family of
      homologous beta4galactosyltransferases that use different types of glycoproteins
      and glycolipids as substrates. Here we solved and refined the crystal structures
      of recombinant bovine beta4Gal-T1 to 2.4 A resolution in the presence and absence
      of the substrate uridine diphosphogalactose. The crystal structure of the bovine
      substrate-free beta4Gal-T1 catalytic domain showed a new fold consisting of a
      single conical domain with a large open pocket at its base. In the substrate
      bound complex, the pocket encompassed residues interacting with uridine
      diphosphogalactose. The structure of the complex contained clear regions of
      electron density for the uridine diphosphate portion of the substrate, where its
      beta-phosphate group was stabilized by hydrogen-bonding contacts with conserved
      residues including the Asp252ValAsp254 motif. These results help the
      interpretation of engineered beta4Gal-T1 point mutations. They suggest a
      mechanism possibly involved in galactose transfer and enable identification of
      the critical amino acids involved in alpha-lactalbumin interactions.

PMID- 10393172
TI  - Projection structure of NhaA, a secondary transporter from Escherichia coli, at
      4.0 A resolution.
AB  - Electron cryomicroscopy of frozen-hydrated two-dimensional crystals of NhaA, a
      Na+/H+ antiporter from Escherichia coli predicted to have 12 transmembrane alpha
      helices, has facilitated the calculation of a projection map of NhaA at 4.0 A
      resolution. NhaA was homologously expressed in E.coli with a His6 tag,
      solubilized in dodecyl maltoside and purified in a single step using Ni2+
      affinity chromatography. Two-dimensional crystals were obtained after
      reconstitution of purified protein with E.coli lipids. The projection map reveals
      that this secondary transporter has a highly asymmetric structure in projection.
      NhaA exhibits overall dimensions of approximately 38x48 A with a ring-shaped
      density feature probably corresponding to a bundle of tilted helices, adjacent to
      an elongated region of density containing several peaks indicative of
      transmembrane helices. Two crystal forms with p22121 symmetry show tightly packed
      dimers of NhaA which differ in the interactions between adjacent dimers. This
      work provides the first direct glimpse into the structure of a secondary
      transporter.

PMID- 10393173
TI  - The mll-AF9 gene fusion in mice controls myeloproliferation and specifies acute
      myeloid leukaemogenesis.
AB  - The MLL gene from human chromosome 11q23 is involved in >30 different chromosomal
      translocations resulting in a plethora of different MLL fusion proteins. Each of
      these tends to associate with a specific leukaemia type, for example, MLL-AF9 is
      found mainly in acute myeloid leukaemia. We have studied the role of the Mll-AF9
      gene fusion made in mouse embryonic stem cells by an homologous recombination
      knock-in. Acute leukaemias developed in heterozygous mice carrying this fusion as
      well as in chimeric mice. As with human chromosomal translocation t(9;11), the
      majority of cases were acute myeloid leukaemias (AMLs) involving immature
      myeloblasts, but a minority were acute lymphoblastic leukaemia. The AMLs were
      preceded by effects on haematopoietic differentiation involving a
      myeloproliferation resulting in accumulation of Mac-1/Gr-1 double-positive mature
      myeloid cells in bone marrow as early as 6 days after birth. Therefore, non
      malignant expansion of myeloid precursors is the first stage of Mll-AF9-mediated
      leukaemia followed by accumulation of malignant cells in bone marrow and other
      tissues. Thus, the late onset of overt tumours suggests that secondary
      tumorigenic mutations are necessary for malignancy associated with MLL-AF9 gene
      fusion and that myeloproliferation provides the pool of cells in which such
      events can occur.

PMID- 10393174
TI  - Eukaryotic 20S proteasome catalytic subunit propeptides prevent active site
      inactivation by N-terminal acetylation and promote particle assembly.
AB  - Proteins targeted for degradation by the ubiquitin-proteasome system are degraded
      by the 26S proteasome. The core of this large protease is the 20S proteasome, a
      barrel-shaped structure made of a stack of four heptameric rings. Of the 14
      different subunits that make up the yeast 20S proteasome, three have proteolytic
      active sites: Doa3/beta5, Pup1/beta2 and Pre3/beta1. Each of these subunits is
      synthesized with an N-terminal propeptide that is autocatalytically cleaved
      during particle assembly. We show here that the propeptides have both common and
      distinct functions in proteasome biogenesis. Unlike the Doa3 propeptide, which is
      crucial for proteasome assembly, the Pre3 and Pup1 propeptides are dispensable
      for cell viability and proteasome formation. However, mutants lacking these
      propeptide-encoding elements are defective for specific peptidase activities, are
      more sensitive to environmental stresses and have subtle defects in proteasome
      assembly. Unexpectedly, a critical function of the propeptide is the protection
      of the N-terminal catalytic threonine residue against Nalpha-acetylation. For all
      three propeptide-deleted subunits, activity of the affected catalytic center is
      fully restored when the Nat1-Ard1 Nalpha-acetyltransferase is mutated. In
      addition to delineating a novel function for proteasome propeptides, these data
      provide the first biochemical evidence for the postulated participation of the
      alpha-amino group in the proteasome catalytic mechanism.

PMID- 10393175
TI  - Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9
      activation and apoptosis.
AB  - Apaf-1 plays a critical role in apoptosis by binding to and activating procaspase
      9. We have identified a novel Apaf-1 cDNA encoding a protein of 1248 amino acids
      containing an insertion of 11 residues between the CARD and ATPase domains, and
      another 43 amino acid insertion creating an additional WD-40 repeat. The product
      of this Apaf-1 cDNA activated procaspase-9 in a cytochrome c and dATP/ATP
      dependent manner. We used this Apaf-1 to show that Apaf-1 requires dATP/ATP
      hydrolysis to interact with cytochrome c, self-associate and bind to procaspase
      9. A P-loop mutant (Apaf-1K160R) was unable to associate with Apaf-1 or bind to
      procaspase-9. Mutation of Met368 to Leu enabled Apaf-1 to self-associate and bind
      procaspase-9 independent of cytochrome c, though still requiring dATP/ATP for
      these activities. The Apaf-1M368L mutant exhibited greater ability to induce
      apoptosis compared with the wild-type Apaf-1. We also show that procaspase-9 can
      recruit procaspase-3 to the Apaf-1-procaspase-9 complex. Apaf-1(1-570), a mutant
      lacking the WD-40 repeats, associated with and activated procaspase-9, but failed
      to recruit procaspase-3 and induce apoptosis. These results suggest that the WD
      40 repeats may be involved in procaspase-9-mediated procaspase-3 recruitment.
      These studies elucidate biochemical steps required for Apaf-1 to activate
      procaspase-9 and induce apoptosis.

PMID- 10393176
TI  - Manipulation of outer root sheath cell survival perturbs the hair-growth cycle.
AB  - Transgenic mice that overexpress the anti-apoptotic gene bcl-xL under the control
      of the keratin 14 promoter have significantly shorter hair than non-transgenic
      littermates. The deficit in hair length correlated with a decrease in the
      duration of anagen, the growth phase of the hair cycle. A prolongation in
      telogen, the resting phase of the hair cycle, was also observed in adult animals.
      In the developing hair bulb, bcl-xL transgene expression was observed exclusively
      in the outer root sheath (ORS) cells. Bcl-xL expression enhanced the survival of
      ORS cells treated with apoptotic stimuli. The results suggest that preventing the
      apoptotic death of ORS cells during anagen leads to a more rapid termination of
      progenitor cell commitment/proliferation, while the increased survival of ORS
      cells during telogen delays the initiation of a new hair cycle. ORS cells produce
      fibroblast growth factor-5 (FGF-5), which acts in a paracrine fashion to
      terminate precursor cell division during anagen. The short hair phenotype of bcl
      xL transgenic mice was substantially reversed in FGF-5-deficient mice. Thus, the
      production of growth inhibitory factors by ORS cells may provide a mechanism
      through which the hair-growth cycle is regulated by cell survival.

PMID- 10393177
TI  - A Caenorhabditis elegans JNK signal transduction pathway regulates coordinated
      movement via type-D GABAergic motor neurons.
AB  - The c-Jun N-terminal kinase (JNK) of the MAP kinase superfamily is activated in
      response to a variety of cellular stresses and is involved in apoptosis in
      neurons. However, the roles of the JNK signaling pathway in the nervous system
      are unknown. The genes for the Caenorhabditis elegans homolog of JNK, JNK-1, and
      its direct activator, JKK-1, were isolated based on their abilities to function
      in the Hog1 MAP kinase pathway in yeast. JKK-1 is a member of the MAP kinase
      kinase superfamily and functions as a specific activator of JNK. Both jnk-1 and
      jkk-1 are expressed in most neurons. jkk-1 null mutant animals exhibit defects in
      locomotion that can be rescued by the conditional expression of JKK-1 in mutant
      adults, suggesting that the defect is not due to a developmental error.
      Furthermore, ectopic expression of JKK-1 in type-D motor neurons is sufficient to
      rescue the movement defect. Thus, the C.elegans JNK pathway functions in type-D
      GABAergic motor neurons and thereby modulates coordinated locomotion.

PMID- 10393178
TI  - The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and
      endocytosis, and attenuates macrophage proliferation.
AB  - Colony-stimulating factor-1 (CSF-1) activation of the CSF-1 receptor (CSF-1R)
      causes Cbl protooncoprotein tyrosine phosphorylation, Cbl-CSF-1R association and
      their simultaneous multiubiquitination at the plasma membrane. The CSF-1R is then
      rapidly internalized and degraded, whereas Cbl is deubiquitinated in the
      cytoplasm without being degraded. We have used primary macrophages from gene
      targeted mice to study the role of Cbl. Cbl-/- macrophages form denser colonies
      and, at limiting CSF-1 concentrations, proliferate faster than Cbl+/+
      macrophages. Their CSF-1Rs fail to exhibit multiubiquitination and a second wave
      of tyrosine phosphorylation previously suggested to be involved in preparation of
      the CSF-1-CSF-1R complex for endocytosis. Consistent with this result, Cbl-/-
      macrophage cell surface CSF-1-CSF-1R complexes are internalized more slowly, yet
      are still lysosomally degraded, and the CSF-1 utilization by Cbl-/- macrophages
      is reduced approximately 2-fold. Thus, attenuation of proliferation by Cbl is
      associated with its positive regulation of the coordinated multiubiquitination
      and endocytosis of the activated CSF-1R, and a reduction in the time that the CSF
      1R signals from the cell surface. The results provide a paradigm for studies of
      the mechanisms underlying Cbl attenuation of proliferative responses induced by
      ligation of receptor tyrosine kinases.

PMID- 10393179
TI  - Small G protein Ral and its downstream molecules regulate endocytosis of EGF and
      insulin receptors.
AB  - The involvement of Ral and its downstream molecules in receptor-mediated
      endocytosis was examined. Expression of either RalG23V or RalS28N, which are
      known to be constitutively active and dominantnegative forms, respectively, in
      A431 cells blocked internalization of epidermal growth factor (EGF). Stable
      expression of RalG23V or RalS28N in CHO-IR cells also inhibited internalization
      of insulin. Internalization of EGF and insulin was not affected by full-length
      RalBP1 which is an effector protein of Ral, but was inhibited by its C-terminal
      region which binds directly to Ral and POB1. POB1 is a binding protein of RalBP1
      and has the Eps15 homology (EH) domain. Deletion mutants of POB1 inhibited
      internalization of EGF and insulin. However, internalization of transferrin was
      unaffected by Ral, RalBP1, POB1 and their mutants. Epsin and Eps15 have been
      reported to be involved in the regulation of endocytosis of the receptors for EGF
      and transferrin. The EH domain of POB1 bound directly to Epsin and Eps15. Taken
      together with the observation that EGF and insulin activate Ral, these results
      suggest that Ral, RalBP1 and POB1 transmit the signal from the receptors to Epsin
      and Eps15, thereby regulating ligand-dependent receptor-mediated endocytosis.

PMID- 10393180
TI  - Glycosylphosphatidylinositol biosynthetic enzymes are localized to a stable
      tubular subcompartment of the endoplasmic reticulum in Leishmania mexicana.
AB  - Glycosylphosphatidylinositols (GPI) are essential components in the plasma
      membrane of the protozoan parasite Leishmania mexicana, both as membrane anchors
      for the major surface macromolecules and as the sole class of free glycolipids.
      We provide evidence that L.mexicana dolichol-phosphate-mannose synthase (DPMS), a
      key enzyme in GPI biosynthesis, is localized to a distinct tubular subdomain of
      the endoplasmic reticulum (ER), based on the localization of a green fluorescent
      protein (GFP)-DPMS chimera and subcellular fractionation experiments. This
      tubular membrane (termed the DPMS tubule) is also enriched in other enzymes
      involved in GPI biosynthesis, can be specifically stained with the fluorescent
      lipid, BODIPY-C5-ceramide, and appears to be connected to specific subpellicular
      microtubules that underlie the plasma membrane. Perturbation of microtubules and
      DPMS tubule structure in vivo results in the selective accumulation of GPI anchor
      precursors, but not free GPIs. The DPMS tubule is closely associated
      morphologically with the single Golgi apparatus in non-dividing and dividing
      cells, appears to exclude luminal ER resident proteins and is labeled, together
      with the Golgi apparatus, with another GFP chimera containing the heterologous
      human Golgi marker beta1,2-N-acetylglucosaminyltransferase-I. The possibility
      that the DPMS-tubule is a stable transitional ER is discussed.

PMID- 10393181
TI  - Phosphorylation by CK2 and MAPK enhances calnexin association with ribosomes.
AB  - Calnexin was initially identified as an endoplasmic reticulum (ER) type I
      integral membrane protein, phosphorylated on its cytosolic domain by ER
      associated protein kinases. Although the role of the ER luminal domain of
      calnexin has been established as a constituent of the molecular chaperone
      machinery of the ER, less is known about the role of the cytosolic
      phosphorylation of calnexin. Analysis by two-dimensional phosphopeptide maps
      revealed that calnexin was in vitro phosphorylated in isolated microsomes by
      casein kinase 2 (CK2) and extracellular-signal regulated kinase-1 (ERK-1) at
      sites corresponding to those for in vivo phosphorylation. In canine pancreatic
      microsomes, synergistic phosphorylation by CK2 and ERK-1 led to increased
      association of calnexin with membrane-bound ribosomes. In vivo, calnexin
      associated ERK-1 activity was identified by co-immunoprecipitation. This activity
      was abolished in cells expressing a dominant-negative MEK-1. Activation of ERK-1
      in cells by addition of serum led to a 4-fold increase in ribosome-associated
      calnexin over unstimulated cells. Taken together with studies revealing calnexin
      association with CK2 and ERK-1, a model is proposed whereby phosphorylation of
      calnexin leads to a potential increase in glycoprotein folding close to the
      translocon.

PMID- 10393182
TI  - The TIM17.23 preprotein translocase of mitochondria: composition and function in
      protein transport into the matrix.
AB  - We have analysed the structural organization of the TIM17.23 complex, the
      preprotein translocase of the mitochondrial inner membrane specific for protein
      targeting to the matrix. The components Tim17, Tim23 and Tim44 are present in
      this complex in equimolar amounts. A sub-complex containing Tim23 and Tim44 but
      no Tim17, or a sub-complex containing Tim23 and Tim17 but no Tim44 was not
      detected. Tim44 is peripherally associated at the matrix side. Tim44 forms dimers
      which recruit two molecules of mt-Hsp70 to the sites of protein import. A
      sequential, hand-over-hand mode of interaction of these two mt-Hsp70.Tim44
      complexes with a translocating polypeptide chain is proposed.

PMID- 10393183
TI  - An adipogenic cofactor bound by the differentiation domain of PPARgamma.
AB  - Ligand activation of the nuclear receptor PPARgamma induces adipogenesis and
      increases insulin sensitivity, while activation of other PPAR isoforms (-alpha
      and -delta) induces little or no fat cell differentiation. Expression and
      activation of chimeras formed between PPARgamma and PPARdelta in fibroblasts has
      allowed us to localize a major domain of PPARgamma responsible for adipogenesis
      to the N-terminal 138 amino acids, a region with AF-1 transcriptional activity.
      Using this region of PPARgamma as bait, we have used a yeast two-hybrid screen to
      clone a novel protein, termed PGC-2, containing a partial SCAN domain. PGC-2
      binds to and increases the transcriptional activity of PPARgamma but does not
      interact with other PPARs or most other nuclear receptors. Ectopic expression of
      PGC-2 in preadipocytes containing endogenous PPARgamma causes a dramatic increase
      in fat cell differentiation at both the morphological and molecular levels. These
      results suggest that interactions between PGC-2, a receptor isoform-selective
      cofactor and PPARgamma contribute to the adipogenic action of this receptor.

PMID- 10393184
TI  - A novel RNA polymerase II-containing complex potentiates Tat-enhanced HIV-1
      transcription.
AB  - The HIV-1-encoded Tat protein controls transcription elongation by increasing
      processivity of RNA polymerase II (Pol II). Here, we have identified a Tat
      stimulatory activity (Tat-SF) as a novel RNA Pol II-containing complex.
      Remarkably, Tat-SF contains the previously identified Tat cofactors Tat-SF1, P
      TEFb and hSPT5/Tat-CT1, in addition to RNA Pol II and other unidentified
      polypeptides, but none of the SRB/MED proteins or other factors found associated
      with the previously described RNA Pol II holoenzyme complex. Tat-SF supports
      basal, Sp1-activated and Tat-activated transcription in a reconstituted system,
      and a Tat-SF-derived fraction lacking RNA Pol II can complement non-responsive
      RNA Pol II complexes for Tat-enhanced HIV-1 transcription, indicating that Tat-SF
      contains factors that are critical for Tat function. Both Tat-SF and RNA Pol II
      holoenzyme are present in HeLa nuclear extracts and each can be recruited to the
      HIV-1 promoter. Our results indicate that Tat-SF is a Tat cofactor-containing RNA
      Pol II complex whose recruitment to the promoter provides elongation factors
      important for Tat-enhanced HIV-1 transcription following TAR RNA synthesis.

PMID- 10393185
TI  - The Pax3-FKHR oncoprotein is unresponsive to the Pax3-associated repressor hDaxx.
AB  - The Pax3-FKHR fusion protein is present in alveolar rhabdomyosarcoma and results
      from the t(2;13) (q35;q14) chromosomal translocation. Its oncogenic activity is
      dependent on a combination of protein-DNA and protein-protein interactions
      mediated by the Pax3 homeodomain recognition helix. In this report we demonstrate
      that human Daxx (hDaxx) interacts with Pax3 in vivo and with DNA-bound Pax3 in
      vitro. This interaction is mediated primarily through the homeodomain recognition
      helix with the additional involvement of the octapeptide domain and its N
      terminal flanking amino acids. Through this interaction hDaxx represses the
      transcriptional activity of Pax3 by approximately 80%. The Pax3-FKHR fusion is
      unresponsive to this repressive effect despite an observed endogenous interaction
      with hDaxx in a rhabdomyosarcoma tumor cell line. Therefore, these data support
      the model that fusion of FKHR to Pax3 not only adds a strong transactivation
      domain, but also deregulates transcriptional control of Pax3 by overriding the
      natural repressive effect of hDaxx.

PMID- 10393186
TI  - Nucleosome structure completely inhibits in vitro cleavage by the V(D)J
      recombinase.
AB  - Lineage specificity and temporal ordering of immunoglobulin (Ig) and T-cell
      receptor (TCR) gene rearrangement are reflected in the accessibility of
      recombination signal sequences (RSSs) within chromatin to in vitro cleavage by
      the V(D)J recombinase. In this report, we investigated the basis of this
      regulation by testing the ability of purified RAG1 and RAG2 proteins to initiate
      cleavage on positioned nucleosomes containing RSS substrates. We found that
      nicking and double-strand DNA cleavage of RSSs positioned on the face of an
      unmodified nucleosome are entirely inhibited. This inhibition was independent of
      translational position or rotational phase and could not be overcome either by
      addition of the DNA-bending protein HMG-1 or by the use of hyperacetylated
      histones. We suggest that the nucleosome could act as the stable unit of
      chromatin which limits recombinase accessibility to potential RSS targets, and
      that actively rearranging gene segments might be packaged in a modified or
      disrupted nucleosome structure.

PMID- 10393187
TI  - Silencing at Drosophila telomeres: nuclear organization and chromatin structure
      play critical roles.
AB  - Transgenes inserted into the telomeric regions of Drosophila melanogaster
      chromosomes exhibit position effect variegation (PEV), a mosaic silencing
      characteristic of euchromatic genes brought into juxtaposition with
      heterochromatin. Telomeric transgenes on the second and third chromosomes are
      flanked by telomeric associated sequences (TAS), while fourth chromosome
      telomeric transgenes are most often associated with repetitious transposable
      elements. Telomeric PEV on the second and third chromosomes is suppressed by
      mutations in Su(z)2, but not by mutations in Su(var)2-5 (encoding HP1), while the
      converse is true for telomeric PEV on the fourth chromosome. This genetic
      distinction allowed for a spatial and molecular analysis of telomeric PEV.
      Reciprocal translocations between the fourth chromosome telomeric region
      containing a transgene and a second chromosome telomeric region result in a
      change in nuclear location of the transgene. While the variegating phenotype of
      the white transgene is suppressed, sensitivity to a mutation in HP1 is retained.
      Corresponding changes in the chromatin structure and inducible activity of an
      associated hsp26 transgene are observed. The data indicate that both nuclear
      organization and local chromatin structure play a role in this telomeric PEV.

PMID- 10393188
TI  - A fork junction DNA-protein switch that controls promoter melting by the
      bacterial enhancer-dependent sigma factor.
AB  - Results of binding assays using DNA fork junction probes indicate that sigma 54
      contains multiple determinants that regulate melting to allow RNA polymerase to
      remain in closed promoter complexes in order to respond to enhancers. Gel
      mobility shift studies indicate that the -12 promoter element and parts of sigma
      54 act together to form a molecular switch that controls melting. The DNA
      sequences and the sigma 54 N-terminus help direct polymerase to the location
      within the -12 promoter element where melting will initiate. However, the fork
      junction that would lead to melting does not form, due to the action of an
      inhibitory DNA element. Such unregulated melting is inhibited further by the lack
      of availability of the single-strand binding elements, which are needed to spread
      opening from the junction to the transcription start site. Thus, in the absence
      of looping enhancer protein, proper regulation is maintained as the sigma 54
      polymerase remains bound in an inactive state. These complex protein-DNA
      interactions allow the controls over protein recruitment and DNA melting to be
      separated, enhancing the diversity of accessible mechanisms of transcription
      regulation.

PMID- 10393189
TI  - The NES-Crm1p export pathway is not a major mRNA export route in Saccharomyces
      cerevisiae.
AB  - Nuclear export signal (NES)-containing proteins are recognized by the NES
      receptor CRM1/Crm1p (also called exportin 1/Xpo1p). In vertebrates and
      Schizosaccharomyces pombe, the toxin leptomycin B (LMB) inhibits CRM1-mediated
      export by interacting directly with CRM1 and disrupting the trimeric Ran-GTP-CRM1
      NES export complex. In Saccharomyces cerevisiae, LMB is not toxic and is
      apparently unable to interact with Crm1p. A second difference between the systems
      is that LMB has no effect on mRNA export in vertebrate systems, whereas there is
      evidence that S.cerevisiae Crm1p plays a role in mRNA export. Here we show that a
      single amino acid change converts S. cerevisiae Crm1p from being LMB insensitive
      to fully LMB sensitive, indicating that Crm1p is the only relevant LMB target.
      This new strain has no phenotype, but LMB has a rapid and potent inhibitory
      effect on NES-mediated export. In situ hybridization assays show that LMB also
      causes nuclear accumulation of poly(A)+ RNA but with a significant delay compared
      with the effect on NES-mediated export. Biochemical assays indicate little or no
      LMB effect on cytoplasmic protein synthesis, indicating that the NES-Crm1p
      pathway is not a major mRNA export route in S.cerevisiae. We conclude that Crm1p
      structure and function is conserved from S.cerevisiae to man.

PMID- 10393190
TI  - Polyadenylation accelerates the degradation of the mitochondrial mRNA associated
      with cytoplasmic male sterility in sunflower.
AB  - In sunflower, PET1-cytoplasmic male sterility is correlated with the presence of
      a novel mitochondrial gene (orf522) located 3' to the atpA gene. The dicistronic
      atpA-orf522 transcripts are preferentially destabilized in male florets of
      'restored to fertility' plants as compared with sterile plants. In this report,
      we show that atpA-orf522 transcripts may be polyadenylated in vivo at their 3'
      termini and that a tissue-specific increase in the level of polyadenylated atpA
      orf522 transcripts correlates with the tissue-specific instability of atpA-orf522
      mRNAs in male florets of the restored hybrid plants. In addition, we have
      identified two distinct ribonuclease activities in sunflower mitochondria, one of
      which preferentially degrades polyadenylated as compared with non-polyadenylated
      RNA substrates corresponding to the 3' UTR of atpA-orf522 transcripts. These in
      vivo and in vitro results show that polyadenylation is involved in the
      degradation pathway of the mitochondrial atpA-orf522 transcripts and that
      polyadenylation can be developmentally regulated by a nuclear gene(s) upon
      restoration of fertility.

PMID- 10393191
TI  - Distinct regions of influenza virus PB1 polymerase subunit recognize vRNA and
      cRNA templates.
AB  - The influenza virus RNA polymerase is a heterotrimer comprising the PB1, PB2 and
      PA subunits. PB1 is the core of the complex and accounts for the polymerase
      activity. We have studied the interaction of PB1 with model cRNA template by in
      vitro binding and Northwestern analyses. The binding to model cRNA was specific
      and showed an apparent Kd of approximately 7x10(-8) M. In contrast to the
      interaction with vRNA, PB1 was able to bind equally the 5' and 3' arm of the cRNA
      panhandle. The N-terminal 139 amino acids of PB1 and sequences between positions
      267 and 493 proved positive for binding to cRNA, whereas the interaction with
      vRNA template previously was mapped to the N- and C-terminal regions. Competition
      experiments using the 5' and 3' arms of either the vRNA or cRNA panhandle
      indicated that the N-terminal binding site is shared by both templates. The data
      indicate that the PB1 RNA-binding sites are constituted by: (i) residues located
      at the N-terminus (probably common for vRNA and cRNA binding) and, either (ii)
      residues from the central part of PB1 (for cRNA) or (iii) residues from the C
      terminal region of PB1 (for vRNA), and suggest that PB1 undergoes a
      conformational change upon binding to cRNA versus vRNA templates.

PMID- 10393192
TI  - Assaying RNA chaperone activity in vivo using a novel RNA folding trap.
AB  - In the absence of proteins, RNAs often misfold in vitro due to alternative base
      pairings which result from the molecule being trapped in inactive conformations.
      We identify an in vivo folding trap in the T4 phage td gene, caused by nine base
      pairs between a sequence element in the upstream exon of the td gene and another
      at the 3' end of the intron. During translation, the ribosome resolves this
      interaction; consequently the intron folds correctly and splicing occurs. The
      introduction of a stop codon upstream of this base pairing prevents resolution of
      the inactive structure so that splicing cannot proceed. We have used this folding
      trap to probe for RNA binding proteins which, when overexpressed, either resolve
      the misfolded structure or impede its formation in vivo. We distinguish between
      proteins which recognize the intron structure and those which bind non
      specifically and apparently ignore the intron. The first class, e.g. Neurospora
      crassa CYT-18, can rescue the exonic trap and intron mutants which cause a
      structural defect. However, known RNA chaperones such as Escherichia coli StpA
      and S12 and the HIV protein NCp7, only resolve the exonic trap without
      suppressing intron mutations. Thus, this structural trap enables detection of RNA
      chaperone activity in vivo.

PMID- 10393193
TI  - Concerted evolution of the tandem array encoding primate U2 snRNA (the RNU2
      locus) is accompanied by dramatic remodeling of the junctions with flanking
      chromosomal sequences.
AB  - The genes encoding primate U2 snRNA are organized as a nearly perfect tandem
      array (the RNU2 locus) that has been evolving concertedly for >35 Myr since the
      divergence of baboons and humans. Thus the repeat units of the tandem array are
      essentially identical within each species, but differ between species.
      Homogeneity is maintained because any change in one repeat unit is purged from
      the array or fixed in all other repeats. Intriguingly, the cytological location
      of RNU2 has remained unchanged despite concerted evolution of the tandem array.
      We had found previously that junction sequences between the U2 tandem array and
      flanking DNA were subject to remodeling over a region of 200-300 bp during the
      past 5 Myr in the hominid lineage. Here we show that the junctions between the U2
      tandem array and flanking DNA have undergone dramatic rearrangements over a
      region of 1 to >10 kbp in the 35 Myr since divergence of the Old World Monkey and
      hominid lineages. We argue that these rearrangements reflect the high level of
      genetic activity required to sustain concerted evolution, and propose a model to
      explain why maintenance of homogeneity within a tandemly repeated multigene
      family would lead to junctional diversity.

PMID- 10393194
TI  - SmpB, a unique RNA-binding protein essential for the peptide-tagging activity of
      SsrA (tmRNA).
AB  - In bacteria, SsrA RNA recognizes ribosomes stalled on defective messages and acts
      as a tRNA and mRNA to mediate the addition of a short peptide tag to the C
      terminus of the partially synthesized nascent polypeptide chain. The SsrA-tagged
      protein is then degraded by C-terminal-specific proteases. SmpB, a unique RNA
      binding protein that is conserved throughout the bacterial kingdom, is shown here
      to be an essential component of the SsrA quality-control system. Deletion of the
      smpB gene in Escherichia coli results in the same phenotypes observed in ssrA
      defective cells, including a variety of phage development defects and the failure
      to tag proteins translated from defective mRNAs. Purified SmpB binds specifically
      and with high affinity to SsrA RNA and is required for stable association of SsrA
      with ribosomes in vivo. Formation of an SmpB-SsrA complex appears to be critical
      in mediating SsrA activity after aminoacylation with alanine but prior to the
      transpeptidation reaction that couples this alanine to the nascent chain. SsrA
      RNA is present at wild-type levels in the smpB mutant arguing against a model of
      SsrA action that involves direct competition for transcription factors.

PMID- 10393195
TI  - Induced fit in initial selection and proofreading of aminoacyl-tRNA on the
      ribosome.
AB  - The fidelity of aminoacyl-tRNA (aa-tRNA) selection by the bacterial ribosome is
      determined by initial selection before and proofreading after GTP hydrolysis by
      elongation factor Tu. Here we report the rate constants of A-site binding of a
      near-cognate aa-tRNA. The comparison with the data for cognate aa-tRNA reveals an
      additional, important contribution to aa-tRNA discrimination of conformational
      coupling by induced fit. It is found that two rearrangement steps that limit the
      chemical reactions of A-site binding, i.e. GTPase activation (preceding GTP
      hydrolysis) and A-site accommodation (preceding peptide bond formation), are
      substantially faster for cognate than for near-cognate aa-tRNA. This suggests an
      induced-fit mechanism of aa-tRNA discrimination on the ribosome that operates in
      both initial selection and proofreading. It is proposed that the cognate codon
      anticodon interaction, more efficiently than the near-cognate one, induces a
      particular conformation of the decoding center of 16S rRNA, which in turn
      promotes GTPase activation and A-site accommodation of aa-tRNA, thereby
      accelerating the chemical steps. As kinetically favored incorporation of the
      correct substrate has also been suggested for DNA and RNA polymerases, the
      present findings indicate that induced fit may contribute to the fidelity of
      template-programed systems in general.

PMID- 10393196
TI  - A role for a replicator dominance mechanism in silencing.
AB  - The role of the natural HMR-E silencer in modulating replication initiation and
      silencing by the origin recognition complex (ORC) was examined. When natural HMR
      E was the only silencer controlling HMR, the silencer's ORC-binding site (ACS)
      was dispensable for replication initiation but essential for silencing,
      indicating that a non-silencer chromosomal replicator(s) existed in close
      proximity to the silencer. Further analysis revealed that regions flanking both
      sides of HMR-E contained replicators. In contrast to replication initiation by
      the intact silencer, initiation by the non-silencer replicator(s) was abolished
      in an orc2-1 mutant, indicating that these replicators were extremely sensitive
      to defects in ORC. Remarkably, the activity of one of the non-silencer
      replicators correlated with reduced silencing; inactivation of these replicators
      caused by either the orc2-1 mutation or the deletion of flanking sequences
      enhanced silencing. These data were consistent with a role for the ORC bound to
      the HMR-E silencer ACS in suppressing the function of neighboring ORC molecules
      capable of inhibiting silencing, and indicated that differences in ORC-binding
      sites within HMR itself had profound effects on ORC function. Moreover,
      replication initiation by natural HMR-E was inefficient, suggesting that closely
      spaced replicators within HMR contributed to an inhibition of replication
      initiation.

PMID- 10393198
TI  - Post-replicative base excision repair in replication foci.
AB  - Base excision repair (BER) is initiated by a DNA glycosylase and is completed by
      alternative routes, one of which requires proliferating cell nuclear antigen
      (PCNA) and other proteins also involved in DNA replication. We report that the
      major nuclear uracil-DNA glycosylase (UNG2) increases in S phase, during which it
      co-localizes with incorporated BrdUrd in replication foci. Uracil is rapidly
      removed from replicatively incorporated dUMP residues in isolated nuclei.
      Neutralizing antibodies to UNG2 inhibit this removal, indicating that UNG2 is the
      major uracil-DNA glycosylase responsible. PCNA and replication protein A (RPA) co
      localize with UNG2 in replication foci, and a direct molecular interaction of
      UNG2 with PCNA (one binding site) and RPA (two binding sites) was demonstrated
      using two-hybrid assays, a peptide SPOT assay and enzyme-linked immunosorbent
      assays. These results demonstrate rapid post-replicative removal of incorporated
      uracil by UNG2 and indicate the formation of a BER complex that contains UNG2,
      RPA and PCNA close to the replication fork.

PMID- 10393197
TI  - DDP1, a single-stranded nucleic acid-binding protein of Drosophila, associates
      with pericentric heterochromatin and is functionally homologous to the yeast
      Scp160p, which is involved in the control of cell ploidy.
AB  - The centromeric dodeca-satellite of Drosophila forms altered DNA structures in
      vitro in which its purine-rich strand (G-strand) forms stable fold-back
      structures, while the complementary C-strand remains unstructured. In this paper,
      the purification and characterization of DDP1, a single-stranded DNA-binding
      protein of high molecular mass (160 kDa) that specifically binds the unstructured
      dodeca-satellite C-strand, is presented. In polytene chromosomes, DDP1 is found
      located at the chromocentre associated with the pericentric heterochromatin but
      its distribution is not constrained to the dodeca-satellite sequences. DDP1 also
      localizes to heterochromatin in interphase nuclei of larval neuroblasts. During
      embryo development, DDP1 becomes nuclear after cellularization, when
      heterochromatin is fully organized, being also associated with the condensed
      mitotic chromosomes. In addition to its localization at the chromocentre, in
      polytene chromosomes, DDP1 is also detected at several sites in the euchromatic
      arms co-localizing with the heterochromatin protein HP1. DDP1 is a multi-KH
      domain protein homologous to the yeast Scp160 protein that is involved in the
      control of cell ploidy. Expression of DDP1 complements a Deltascp160 deletion in
      yeast. These results are discussed in view of the possible contribution of DNA
      structure to the structural organization of pericentric heterochromatin.

PMID- 10393199
TI  - Criss-crossed interactions between the enhancer and the att sites of phage Mu
      during DNA transposition.
AB  - A bipartite enhancer sequence (composed of the O1 and O2 operator sites) is
      essential for assembly of the functional tetramer of phage Mu transposase (MuA)
      on supercoiled DNA substrates. A three-site interaction (LER) between the left
      (L) and right (R) ends of Mu (att sites) and the enhancer (E) precedes tetramer
      assembly. We have dissected the role of the enhancer in tetramer assembly by
      using two transposase proteins that have a common att site specificity, but are
      distinct in their enhancer specificity. The activity of these proteins on
      substrates containing hybrid enhancers reveals a 'criss-crossed' pattern of
      interaction between att and enhancer sites. The left operator, O1, of the
      enhancer interacts specifically with the transposase subunit at the R1 site
      (within the right att sequence) that is responsible for cleaving the left end of
      Mu. The right operator, O2, shows a preferential interaction with the transposase
      subunit at the L1 site (within the left att sequence) that is responsible for
      cleaving the right end of Mu.

PMID- 10393200
TI  - Regulation of DNA replication by iterons: an interaction between the ori2 and
      incC regions mediated by RepE-bound iterons inhibits DNA replication of mini-F
      plasmid in Escherichia coli.
AB  - In bacteria, plasmids and some DNA viruses, DNA replication is initiated and
      regulated by binding of initiator proteins to repetitive sequences. To understand
      the control mechanism we used the plasmid mini-F, whose copy number is
      stringently maintained in Escherichia coli, mainly by its initiator protein RepE
      and the incC region. The monomers of RepE protein bound to incC iterons, which
      exert incompatibility in trans and control the copy number of mini-F plasmid in
      cis. Many incompatibility defective mutants carrying mutations in their incC
      iterons had lost the affinity to bind to RepE, while one mutant retained high
      level binding affinity. The mutated incC mini-F plasmids lost the function to
      control the copy number. The copy number of the wild-type mini-F plasmid did not
      increase in the presence of excess RepE. These results suggested that the control
      of replication by incC iterons does not rely on their capacity to titrate RepE
      protein. Using a ligation assay, we found that RepE proteins mediated a cross
      link structure between ori2 and incC, for which the dimerization domain of RepE
      and the structure of incC seem to be important. The structure probably causes
      inhibition of extra rounds of DNA replication initiation on mini-F plasmids,
      thereby keeping mini-F plasmid at a low copy number.

PMID- 10393201
TI  - A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein.
AB  - Mammalian DNA polymerases alpha and beta lack 3' exonuclease activity and are
      unable to edit errors after DNA synthesis. However, editing exonucleases can be
      functions of separate polypeptides. We isolated a widely distributed DNA-specific
      3' exonuclease from rabbit liver nuclei, sequenced tryptic peptides by mass
      spectrometry, and identified the corresponding human open reading frame. The
      protein expressed from the cloned human sequence exhibits 3' exonuclease
      activity. The human clone shares sequence homology with the editing function of
      the Escherichia coli DNA polymerase III holoenzyme, i.e., the DnaQ/MutD protein,
      and weakly with the editing 3' exonuclease domain of eukaryotic DNA polymerase
      epsilon. The gene maps to human chromosome 3p21.2-21.3. In a reconstituted human
      DNA repair system containing DNA polymerase beta and DNA ligase III-XRCC1,
      accurate rejoining of a 3' mismatched base residue at a single-strand break is
      dependent on addition of the exonuclease.

PMID- 10393202
TI  - Rosiglitazone (BRL49653), a PPARgamma-selective agonist, causes peroxisome
      proliferator-like liver effects in obese mice.
AB  - The PPAR (peroxisome proliferator activated receptor) transcription factors are
      ligand-activated nuclear receptors that regulate genes involved in lipid
      metabolism and homeostasis. PPARalpha is preferentially expressed in liver and
      PPARgamma preferentially in adipose tissue. Activation of PPARalpha leads to
      peroxisome proliferation and increased beta-oxidation of fatty acids in rodents.
      PPARgamma-activation leads to adipocyte differentiation and improved insulin
      signaling of mature adipocytes. Both PPAR receptors are believed to be functional
      targets for treatment of hyperlipidemia in man. We have treated obese diabetic
      mice (ob/ob), which have highly elevated levels of plasma triglycerides, glucose
      and insulin, for 1 week with WY14,643 (180 micromol/kg/day), a selective
      PPARalpha agonist, or rosiglitazone (BRL49653; 2.5 micromol/kg/day), a selective
      PPARgamma agonist. The doses used produce a similar therapeutic effect in both
      treatment groups (lowering of triglycerides and glucose). High resolution two
      dimensional gel electrophoresis of livers showed that WY14,643 and rosiglitazone
      both produced changes in expression pattern of many proteins involved in
      peroxisomal fatty acid beta-oxidation. However, similar experiments performed in
      lean mice showed significant up-regulation of these proteins only with WY14,643
      treatment. Furthermore, the proteins up-regulated by the drugs in obese mice had
      a higher basal expression in obese controls compared to the lean littermates.
      Liver PPARgamma mRNA levels were determined and we observed that PPARgamma2 mRNA
      levels were elevated in obese mice compared to lean littermates. As PPARalpha and
      PPARgamma recognize similar DNA response elements, it is likely that the effects
      of rosiglitazone on PPARalpha responsive genes in livers of the ob/ob mice are
      mediated by PPARgamma2.

PMID- 10393204
TI  - 27-hydroxycholesterol: production rates in normal human subjects.
AB  - We attempted to quantitate production of bile acid via the 27-hydroxylation
      pathway in six human subjects. After bolus intravenous injection of known amounts
      of [24-14C]cholic acid and [24-14C]chenodeoxycholic acid, each subject underwent
      a constant intravenous infusion of a mixture of [22, 23-3H]-27-hydroxycholesterol
      and [2H]-27-hydroxycholesterol for 6;-10 h. Production rate of 27
      hydroxycholesterol was calculated from the infusion rate of [2H]-27
      hydroxycholesterol and the serum ratio of deuterated/protium 27
      hydroxycholesterol, which reached a plateau level by 4 h of infusion. Conversion
      of 27-hydroxycholesterol to cholic and chenodeoxycholic acids was determined from
      the 3H/14C ratio of these two bile acids in bile samples obtained the day after
      infusion. In five of the six subjects, independent measurement of bile acid
      synthesis by fecal acidic sterol output was available from previous studies.
      Endogenous production of 27-hydroxycholesterol averaged 17.6 mg/day and ranged
      from 5.0 to 28.2 mg/day, which amounted to 8.7% (range 3.0;-17.9%) of total bile
      acid synthesis. On average 66% of infused 27-hydroxycholesterol was converted to
      bile acid, of which 72.6% was chenodeoxycholic acid. These data suggest that
      relatively little bile acid synthesis takes place via the 27-hydroxylation
      pathway in healthy humans. Nevertheless, even this amount, occurring
      predominantly in vascular endothelium and macrophages, could represent an
      important means for removal of cholesterol deposited in endothelium.

PMID- 10393203
TI  - Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results
      in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I.
AB  - The transport of HDL cholesteryl esters (CE) from plasma to the liver involves a
      direct uptake pathway, mediated by hepatic scavenger receptor B-I (SR-BI), and an
      indirect pathway, involving the exchange of HDL CE for triglycerides (TG) of TG
      rich lipoproteins by cholesteryl ester transfer protein (CETP). We carried out
      HDL CE turnover studies in mice expressing human CETP and/or human
      lecithin:cholesterol acyltransferase (LCAT) transgenes on a background of human
      apoA-I expression. The fractional clearance of HDL CE by the liver was delayed by
      LCAT transgene, while the CETP transgene increased it. However, there was no
      incremental transfer of HDL CE radioactivity to the TG-rich lipoprotein fraction
      in mice expressing CETP, suggesting increased direct removal of HDL CE in the
      liver. To evaluate the possibility that this might be mediated by SR-BI, HDL
      isolated from plasma of the different groups of transgenic mice was incubated
      with SR-BI transfected or control CHO cells. HDL isolated from mice expressing
      CETP showed a 2- to 4-fold increase in SR-BI-mediated HDL CE uptake, compared to
      HDL from mice lacking CETP. The addition of pure CETP to HDL in cell culture did
      not lead to increased selective uptake of HDL CE by cells. However, when human
      HDL was enriched with TG by incubation with TG-rich lipoproteins in the presence
      of CETP, then treated with hepatic lipase, there was a significant enhancement of
      HDL CE uptake. Thus, the remodeling of human HDL by CETP, involving CE;-TG
      interchange, followed by the action of hepatic lipase (HL), leads to the enhanced
      uptake of HDL CE by cellular SR-BI. These observations suggest that in animals
      such as humans in which both the selective uptake and CETP pathways are active,
      the two pathways could operate in a synergistic fashion to enhance reverse
      cholesterol transport.

PMID- 10393205
TI  - Oxidized low density lipoproteins induce apoptosis in PHA-activated peripheral
      blood mononuclear cells and in the Jurkat T-cell line.
AB  - Oxidized low density lipoproteins (oxLDLs) and activated T lymphocytes are
      present in early atherosclerotic plaques. It has been shown that oxLDLs are
      cytotoxic to cultured vascular cells but their possible toxic action on T
      lymphocytes has not been described. Peripheral blood lymphocytes from healthy
      individuals were stimulated in vitro with the polyclonal activator
      phytohemagglutinin and treated with various doses of native and mildly oxidized
      LDLs. Low doses of oxLDLs inhibited cell growth and DNA synthesis after 48 h
      culture and at 200 microg apoB/ml we observed a loss of cell viability. Dead
      cells did not exhibit significant increase of alteration of membrane integrity
      (i.e., necrosis) but showed chromatin fragmentation evaluated by DNA staining
      with 4', 6-diamidino-2-phenylindole and propidium iodide. This fragmentation
      increased with TBARS and hydroperoxide levels. The expression of early apoptosis
      marker Apo2.7 rose among the CD3(+) T-cell population. In addition, morphological
      analysis showed apoptotic features (cell shrinking, nucleus condensation, and
      fragmentation). Study of phosphatidylserine expression using Annexin V confirmed
      that oxLDLs induced apoptosis in activated lymphocytes. In the Jurkat T-cell line
      cultured with oxLDLs, apoptotic morphological changes (condensation and nucleus
      fragmentation) were observed and they were accompanied by DNA fragmentation
      visualized by propidium iodide staining and electrophoresis showing apoptotic
      ladder. These results demonstrate that mildly oxidized LDLs induce apoptosis in a
      part of activated and proliferating T cells. T-lymphocyte apoptosis induction in
      atherosclerotic lesions might contribute to the development of an inappropriate
      local T cell response.

PMID- 10393207
TI  - Heme-binding by Drosophila retinoid- and fatty acid-binding glycoprotein (RFABG),
      a member of the proapolipophorin gene family.
AB  - We previously have cloned and characterized a retinoid- and fatty acid-binding
      glycoprotein (RFABG) isolated from the heads of Drosophila melanogaster. The
      protein is composed of two glycosylated subunits (Mr = >200,000 and 70,000) and
      is a member of the proapolipophorin gene family. Spectral analysis of purified
      RFABG revealed an absolute absorbance peak at 405 nm, which is typical for a heme
      containing protein. The aim of the present study was to characterize the heme
      binding properties of RFABG. Upon saturation of the protein solution with carbon
      monoxide followed by dithionite reduction, a red shift of the Soret peak to 424
      nm and the characteristic alpha- and beta- bands at 567 and 539 nm were observed.
      Native RFABG contains approximately 0.175 moles of heme (mol/mol) indicating that
      purified RFABG is primarily the apoprotein. Hemin-agarose affinity chromatography
      of the native RFABG followed by Western blot analysis showed a single
      immunoreactive band at 70 kDa, indicating that the heme-binding domain resides in
      the 70 kDa subunit. Although retinoid and fatty acid also bind to the 70 kDa
      subunit, no competition was observed when an excess of heme was added to a
      solution of retinoid or fatty acid bound to RFABG. Heme added to a solution of
      purified RFABG bound in a saturable manner with an affinity of 3.8 x 10(-7)
      m.Thus, the current study clearly demonstrates that retinoid- and fatty acid
      binding glycoprotein is a novel heme-binding protein, which may be involved in
      the transport and/or metabolism of heme in Drosophila.

PMID- 10393206
TI  - Metabolic and genetic determinants of HDL metabolism and hepatic lipase activity
      in normolipidemic females.
AB  - The metabolic and genetic determinants of HDL cholesterol (HDL-C) levels and HDL
      turnover were studied in 36 normolipidemic female subjects on a whole-food low
      fat metabolic diet. Lipid, lipoprotein, and apolipoprotein levels, lipoprotein
      size, and apolipoprotein turnover parameters were determined, as were genetic
      variation at one site in the hepatic lipase promoter and six sites in the
      apolipoprotein AI/CIII/AIV gene cluster. Menopause had no significant effect on
      HDL-C or turnover. Stepwise multiple regression analysis revealed that HDL-C was
      most strongly correlated with HDL size, apolipoprotein A-II (apoA-II), and
      apolipoprotein A-I (apoA-I) levels, which together could account for 90% of the
      variation in HDL-C. HDL size was inversely correlated with triglycerides, body
      mass index, and hepatic lipase activity, which together accounted for 82% of the
      variation in HDL size. The hepatic lipase promoter genotype had a strong effect
      on hepatic lipase activity and could account for 38% of the variation in hepatic
      lipase activity. The apoA-I transport rate (AI-TR) was the major determinant of
      apoA-I levels, but AI-TR was not associated with six common genetic polymorphism
      in the apoAI/CIII/AIV gene cluster.A simplified model of HDL metabolism is
      proposed, in which A-I and apoA-II levels combined with triglycerides, and
      hepatic lipase activity could account for 80% of the variation in HDL-C.

PMID- 10393208
TI  - Transcriptional elongation of the rat apolipoprotein A-I gene: identification and
      mapping of two arrest sites and their signals.
AB  - Previous studies have shown that the elongation phase of apoA-I gene
      transcription is regulated and contributes to hormone-induced changes in the
      expression of this gene in rat liver. We have now identified, by in vitro
      transcription studies with HeLa nuclear extracts, two transcriptional arrest
      sites within exon 3 and intron 3, respectively. Two truncated transcripts of 510
      and approximately 1100 nucleotides in length, termed attenuator 1 RNA and
      attenuator 2 RNA, respectively, were observed when a rat apoA-I genomic fragment
      extending from -309 to +1842 relative to the transcription start site was
      transcribed in vitro in the presence of KCl or Sarkosyl. The attenuation events
      were promoter-independent as transcription of the apoA-I gene driven by the
      cytomegalovirus promoter resulted in transcriptional arrest at both sites.
      Transcription studies using deletion constructs as templates identified
      nucleotides +976 to +1158 as a region that contained the signal for
      transcriptional arrest at attenuator site 2. Computational analysis predicted a
      stem;-loop structure in the nascent RNA immediately upstream of the arrest site.
      Deletion of attenuator 2 signal or deletion of sequences +147 to +216 located far
      upstream of the actual elongation block site 1 abrogated arrest at site 1. Thus,
      complex long-range interactions may be involved in the transcriptional arrest at
      site 1. These elongation blocks identified in vitro are consistent with earlier
      in vivo data based on nuclear run-on assays and represent, to our knowledge, the
      first example describing transcriptional attenuation as a mechanism controlling
      the expression of a member of the apolipoprotein gene family.

PMID- 10393209
TI  - Macrophage-enhanced formation of cholesteryl ester-core aldehydes during
      oxidation of low density lipoprotein.
AB  - Oxidation of low density lipoproteins (LDL) results in changes to the lipoprotein
      particle that are potentially pro-atherogenic. To investigate mechanisms
      contributing to the formation of cholesteryl ester (CE)-core aldehydes (9
      oxononanoyl- and 5-oxovaleroyl-cholesterol; 9-ONC and 5-OVC, respectively) LDL
      was incubated in the presence of mouse macrophages (J774 cells) under different
      culture conditions. Here we demonstrate that the formation of core aldehydes
      occurs only in transition metal-containing HAM's F10 medium but not in Dulbecco's
      modified Eagle's medium (DMEM), independent of supplementation with iron and
      copper at concentrations up to ten times higher than present in HAM's F10. The
      antioxidative properties of DMEM could be ascribed to the higher amino acid and
      vitamin content as compared to HAM's F10 medium. Supplementation with these
      components efficiently inhibited LDL oxidation in HAM's F10. Stimulation of J774
      cells with phorbol ester (PMA) resulted in significantly enhanced 9-ONC and 5-OVC
      formation rates that were accompanied by increased consumption of LDL cholesteryl
      linoleate (Ch18:2) and cholesteryl arachidonate (Ch20:4) in the cellular
      supernatant. In PMA (10 ng/ml) activated cells, approximately 5% of Ch18:2
      contained in LDL was converted to 9-ONC and 4% of Ch20:4 was converted to 5-OVC.
      With respect to core aldehyde formation, lipopolysaccharide (LPS, 10 microg/ml)
      was a less effective stimulant as compared to PMA. Part of the core aldehydes
      accumulated within the cells. Our study demonstrates that i) J774 macrophages are
      able to promote/accelerate core aldehyde formation in HAM's F10 medium, and ii)
      that core aldehyde formation rates can be increased by stimulation of the cells
      with PMA, and, although to a lesser extent, with LPS. Finally we could show that
      iii) a small amount of the core aldehydes is internalized by J774 macrophages.

PMID- 10393210
TI  - Ca2+-induced fusion of sulfatide-containing phosphatidylethanolamine small
      unilamellar vesicles.
AB  - The fusogenic properties of sulfatide-containing 1,2-dioleoyl-3-sn 
      phosphatidylethanolamine (DOPE) small unilamellar vesicles (SUVs) in the presence
      of CaCl2 were studied by mixing membrane lipids based on an assay of fluorescence
      resonance energy transfer (FRET). Fusion of the vesicles was also confirmed by
      mixing aqueous contents with the Tb/dipicolinate (DPA) assay. The half-times of
      lipid mixing revealed that the fusion rate decreased with increasing molar
      concentration of sulfatide. This inhibitory effect was more obvious at sulfatide
      concentrations higher than 30 mol%, where hydration at the membrane surface
      reached its maximum and the fusion was no longer pH-sensitive in the range of pH
      6.0 - 9.0. Similar inhibitory effect was also observed in Ca2+-induced fusion of
      DOPE/ganglioside GM1 vesicles but at a lower concentration of the
      glycosphingolipid (20 mol%). In contrast, increasing the concentration of
      phosphatidylserine (PS) in DOPE/PS SUVs resulted in an increase in the rate of
      Ca2+-induced lipid mixing and the pH sensitivity of this system was not affected.
      These results are consistent with an increasing steric hindrance to membrane
      fusion at higher molar concentration and larger headgroup size of the
      glycosphingolipids. Interestingly, the pH sensitivity of the sulfatide-containing
      liposomes was retained when they were allowed to fuse with synaptosomes in the
      absence of Ca2+ by a mechanism involving protein mediation.

PMID- 10393211
TI  - Hepatic triglyceride lipase promotes low density lipoprotein receptor-mediated
      catabolism of very low density lipoproteins in vitro.
AB  - We demonstrate here that hepatic triglyceride lipase (HTGL) enhances VLDL
      degradation in cultured cells by a LDL receptor-mediated mechanism. VLDL binding
      at 4 degrees C and degradation at 37 degrees C by normal fibroblasts was
      stimulated by HTGL in a dose-dependent manner. A maximum increase of up to 7-fold
      was seen at 10 microg/ml HTGL. Both VLDL binding and degradation were
      significantly increased (4-fold) when LDL receptors were up-regulated by
      treatment with lovastatin. HTGL also stimulated VLDL degradation by LDL receptor
      deficient FH fibroblasts but the level of maximal degradation was 40-fold lower
      than in lovastatin-treated normal fibroblasts. A prominent role for LDL receptors
      was confirmed by demonstration of similar HTGL-promoted VLDL degradation by
      normal and LRP-deficient murine embryonic fibroblasts. HTGL enhanced binding and
      internalization of apoprotein-free triglyceride emulsions, however, this was LDL
      receptor-independent. HTGL-stimulated binding and internalization of apoprotein
      free emulsions was totally abolished by heparinase indicating that it was
      mediated by HSPG. In a cell-free assay HTGL competitively inhibited the binding
      of VLDL to immobilized LDL receptors at 4 degrees C suggesting that it may
      directly bind to LDL receptors but may not bind VLDL particles at the same time.
      We conclude that the ability of HTGL to enhance VLDL degradation is due to its
      ability to concentrate lipoprotein particles on HSPG sites on the cell surface
      leading to LDL receptor-mediated endocytosis and degradation.

PMID- 10393212
TI  - Targeted disruption of the murine lecithin:cholesterol acyltransferase gene is
      associated with reductions in plasma paraoxonase and platelet-activating factor
      acetylhydrolase activities but not in apolipoprotein J concentration.
AB  - Lecithin:cholesteryl acyltransferase (LCAT) deficiency resulting from targeted
      disruption of the Lcat gene in the mouse is associated with dramatic decreases in
      HDL concentration and the accumulation of nascent HDL in the plasma. We examined
      whether LCAT deficiency in mice is associated with a concomitant decrease in two
      antioxidative enzymes, paraoxonase (PON) and platelet-activating factor
      acetylhydrolase (PAF-AH). In control Lcat (+/+) mice both these enzymes are
      transported on HDL. Compared to Lcat (+/+) mice, HDL-cholesterol is reduced 94%
      and apoA-I, 90%, in Lcat (-/-) mice; this reduction in HDL is paralleled by a 71%
      decrease in PAF-AH activity and in a 58% decrease in PON activity. Apolipoprotein
      J (apoJ) levels, rather than being decreased, were significantly (P = 0.01)
      higher (36%) in Lcat (-/-) than in Lcat (+/+) mice, and the apo J/PON ratio was 3
      fold greater in Lcat (-/-) than in Lcat (+/+) animals. Even though apolipoprotein
      A-I (apoA-I) concentration and PON activity were drastically reduced, there was
      no reduction in apoA-I and PON liver mRNA levels suggesting that post
      transcriptional events are responsible for the reduction of plasma PON and apoA-I
      levels. Fast protein liquid chromatography (FPLC) revealed that in Lcat (+/+)
      mice both PON and PAF-AH activity is associated with large, apoA-I-containing HDL
      particles (9.7 nm by non-denaturing gradient gel electrophoresis) while in Lcat (
      /-) mice both enzymes are associated with small 8.2 nm particles. We conclude
      that the concomitant reduction in HDL and apoA-I concentrations and PON and PAF
      AH activities is best explained by rapid clearance of the small HDL particles
      found in LCAT deficiency.

PMID- 10393214
TI  - Hepatic lipase promotes the selective uptake of high density lipoprotein
      cholesteryl esters via the scavenger receptor B1.
AB  - Hepatic lipase (HL) plays a major role in high-density lipoprotein (HDL)
      metabolism both as a lipolytic enzyme and as a ligand. To investigate whether HL
      enhances the uptake of HDL-cholesteryl ester (CE) via the newly described
      scavenger receptor BI (SR-BI), we measured the effects of expressing HL and SR-BI
      on HDL-cell association as well as uptake of 125I-labeled apoA-I and [3H]CE-HDL,
      by embryonal kidney 293 cells. As expected, HDL cell association and CE selective
      uptake were increased in SR-BI transfected cells by 2- and 4-fold, respectively,
      compared to controls (P < 0.001). Cells transfected with HL alone or in
      combination with SR-BI expressed similar amounts of HL, 20% of which was bound to
      cell surface proteoglycans. HL alone increased HDL cell association by 2-fold but
      had no effect on HDL-CE uptake in 293 cells. However, in cells expressing SR-BI,
      HL further enhanced the selective uptake of CE from HDL by 3-fold (P < 0.001). To
      determine whether the lipolytic and/or ligand function of HL are required in this
      process, we generated a catalytically inactive form of HL (HL-145G). Cells co
      transfected with HL-145G and SR-BI increased their HDL cell association and HDL
      CE selective uptake by 1.4-fold compared to cells expressing SR-BI only (P <
      0.03). Heparin abolished the effect of HL-145G on SR-BI-mediated HDL-CE selective
      uptake.Thus, the enhanced uptake of HDL-CE by HL is mediated by both its ligand
      role, which requires interaction with proteoglycans, and by lipolysis with
      subsequent HDL particle remodeling. These results establish HL as a major
      modulator of SR-BI mediated selective uptake of HDL-CE.

PMID- 10393213
TI  - Characterization of a cholesterol response element (CRE) in the promoter of the
      cholesteryl ester transfer protein gene: functional role of the transcription
      factors SREBP-1a, -2, and YY1.
AB  - Cholesteryl ester transfer protein (CETP) is expressed in human adipocytes, where
      it acts to promote selective uptake of HDL-CE (Benoist, F., M. McDonnell, P. Lau,
      R. Milne, and R. McPherson. 1997. J. Biol. Chem. 272: 23572;-23577). In contrast
      to other major sterol-responsive genes such as 3-hydroxy-3-methylglutaryl
      coenzyme A reductase CETP expression is up-regulated rather than down-regulated
      in response to cholesterol. To define elements involved in cholesterol-mediated
      up-regulation of CETP gene expression, deletion derivatives of the CETP promoter
      were cloned into a luciferase reporter construct and transfected into the human
      liposarcoma cell line SW872, cultured in the presence or absence of lipoproteins.
      A fragment associated with a positive cholesterol response was identified between
      nucleotides -361 and -138 (relative to the initiation site of transcription) of
      the promoter. This region contains a tandem repeat of a sequence known to mediate
      sterol dependent regulation of the hamster HMG-CoA reductase gene. We have
      putatively denoted this region, the cholesterol response element (CRE). Using gel
      mobility shift assays we demonstrate that both YY1 and SREBP-1 interact with the
      CRE of CETP. Furthermore, in transient co-transfection experiments, both YY1 and
      SREBP-1a were found to trans-activate, in a dose-dependent manner, the luciferase
      activity of constructs harboring the CRE. We also demonstrate that SREBP-2, is
      able to trans-activate a luciferase construct harboring the CRE although much
      less effectively as compared to SREBP-1. Finally, functional analysis of the CRE
      confirms its regulatory role in modulating CETP gene expression through its
      interaction with YY1 and SREBP-1a.

PMID- 10393215
TI  - Linoleic acid kinetics and conversion to arachidonic acid in the pregnant and
      fetal baboon.
AB  - Linoleic acid plasma kinetics in pregnant baboons and its conversion to long
      chain polyunsaturates (LCP) in fetal organs is characterized over a 29-day period
      using stable isotope tracers. Pregnant baboons consumed an LCP-free diet and
      received [U-13C]linoleic acid (18:2*) in their third trimester of gestation. In
      maternal plasma, 18:2* dropped to near baseline by 14 days post-dose, while
      labeled arachidonic acid (20:4*) plateaued at 10 days at about 70% of total
      labeled fatty acids. After 2;-5 days, total tracer fatty acids decreased in
      visceral organs, but increased in the fetal brain. Maximal fetal incorporation of
      18:2* was 1;-2 days post-dose; thereafter it dropped while 20:4* increased
      reciprocally. Labeled 20:4 replaced 18:2* in neural tissues by 5 days post-dose.
      In liver, kidney, and lung, 20:4* became dominant by 12 days, but in heart the
      crossover was >29 days. Fetal brain 20:4* plateaued by 21 days at 0. 025% of
      dose, while fetal liver 20:4* was constant from 1 to 29 days at 0.006% of dose.
      Under these dietary conditions we estimate that the fetus derives about 50% its
      20:4 requirement from conversion of dietary 18:2, with the balance from maternal
      stores, and conclude that 1) fetal organs accumulate 18:2 within a day of a
      maternal dose and convert much of it to 20:4 within weeks, 2) modest dietary 18:2
      levels may support fetal brain requirements for 20:4, and 3) the brain retains n;
      6 fatty acids uniquely compared with major visceral organs.

PMID- 10393216
TI  - Possible involvement of proteolytic degradation of tyrosinase in the regulatory
      effect of fatty acids on melanogenesis.
AB  - The purpose of this study was to investigate the mechanism of fatty acid-induced
      regulation of melanogenesis. An apparent regulatory effect on melanogenesis was
      observed when cultured B16F10 melanoma cells were incubated with fatty acids,
      i.e., linoleic acid (unsaturated, C18:2) decreased melanin synthesis while
      palmitic acid (saturated, C16:0) increased it. However, mRNA levels of the
      melanogenic enzymes, tyrosinase, tyrosinase-related protein 1 (TRP1), and
      tyrosinase-related protein 2 (TRP2), were not altered. Regarding protein levels
      of these enzymes, the amount of tyrosinase was decreased by linoleic acid and
      increased by palmitic acid, whereas the amounts of TRP1 and TRP2 did not change
      after incubation with fatty acids. Pulse-chase assay by [35S]methionine metabolic
      labeling revealed that neither linoleic acid nor palmitic acid altered the
      synthesis of tyrosinase. Further, it was shown that linoleic acid accelerated,
      while palmitic acid decelerated, the proteolytic degradation of tyrosinase. These
      results suggest that modification of proteolytic degradation of tyrosinase is
      involved in regulatory effects of fatty acids on melanogenesis in cultured
      melanoma cells.

PMID- 10393217
TI  - Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B
      production in miniature pigs.
AB  - An orally bioavailable acyl coenzyme A:cholesterol acyltransferase (ACAT)
      inhibitor, avasimibe (CI-1011), was used to test the hypothesis that inhibition
      of cholesterol esterification, in vivo, would reduce hepatic very low density
      (VLDL) apolipoprotein (apo) B secretion into plasma. ApoB kinetic studies were
      carried out in 10 control miniature pigs, and in 10 animals treated with
      avasimibe (10 mg/kg/d, n = 6; 25 mg/kg/d, n = 4). Pigs were fed a diet containing
      fat (34% of calories) and cholesterol (400 mg/d; 0.1%). Avasimibe decreased the
      plasma concentrations of total triglyceride, VLDL triglyceride, and VLDL
      cholesterol by 31;-40% 39-48%, and 31;-35%, respectively. Significant reductions
      in plasma total cholesterol (35%) and low density lipoprotein (LDL) cholesterol
      (51%) concentrations were observed only with high dose avasimibe. Autologous 131I
      labeled VLDL, 125I-labeled LDL, and [3H]leucine were injected simultaneously into
      each pig and apoB kinetic data were analyzed using multicompartmental analysis
      (SAAM II). Avasimibe decreased the VLDL apoB pool size by 40;-43% and the hepatic
      secretion rate of VLDL apoB by 38;-41%, but did not alter its fractional
      catabolism. Avasimibe decreased the LDL apoB pool size by 13;-57%, largely due to
      a dose-dependent 25;-63% in the LDL apoB production rate. Hepatic LDL receptor
      mRNA abundances were unchanged, consistent with a marginal decrease in LDL apoB
      FCRs. Hepatic ACAT activity was decreased by 51% (P = 0.050) and 68% (P = 0.087)
      by low and high dose avasimibe, respectively. The decrease in total apoB
      secretion correlated with the decrease in hepatic ACAT activity (r = 0.495; P =
      0.026). We conclude that inhibition of hepatic ACAT by avasimibe reduces both
      plasma VLDL and LDL apoB concentrations, primarily by decreasing apoB secretion.

PMID- 10393218
TI  - Quantitative trait loci analysis for the differences in susceptibility to
      atherosclerosis and diabetes between inbred mouse strains C57BL/6J and C57BLKS/J.
AB  - Mice from the inbred strain C57BLKS/J (BKS) exhibit increased susceptibility to
      both diabetes and atherosclerosis compared to C57BL/6J (B6) mice. To determine
      whether the differences in diabetes and atherosclerosis are related, we carried
      out a cross between B6-db/db and BKS. We selected 99 female F2-db/db progeny,
      tested the progeny for plasma lipids, plasma glucose, and fatty-streak lesions,
      and used quantitative trait loci (QTL) analysis to identify the chromosomal
      regions associated with these phenotypes. No major QTL were found for total
      cholesterol, VLDL-cholesterol, or triglycerides. Two suggestive QTL were found
      for HDL-cholesterol (LOD scores of 2. 7 and 2.8), and two suggestive loci were
      found for plasma glucose (LOD scores of 2.3 and 2.0). Lesion size was not
      correlated with plasma lipid levels or glucose. Lesion size was determined by a
      locus at D12Mit49 with a LOD score of 2.5 and a significant likelihood ratio
      statistic. The gene for apolipoprotein apoB lies within the region, but apoB
      levels were similar in strains B6 and BKS. The QTL on Chr 12 was confirmed by
      constructing a congenic strain with BKS alleles in the QTL region on a B6 genetic
      background. We conclude that susceptibilities to diabetes and atherosclerosis are
      not conferred by the same genes in these strains and that a major gene on Chr 12,
      which we name Ath6, determines the difference in atherosclerosis susceptibility.

PMID- 10393220
TI  - Lipolysis-induced iron release from diferric transferrin: Possible role of
      lipoprotein lipase in LDL oxidation.
AB  - Conditions leading to oxidation of LDL in vivo are still unknown. While the
      occurrence of oxidized lipoproteins and catalytic free iron in advanced
      atherosclerotic lesions has been demonstrated, the origin of both is unclear. In
      vivo, iron metabolism is tightly regulated by iron-binding proteins that ensure
      that virtually no free iron exists. We examined whether physiological events such
      as lipolysis might reduce pH, facilitate iron release from transferrin (Tf), and
      promote low density lipoprotein (LDL) oxidation. Lipolysis is brought about by
      lipoprotein lipase (LpL), a triglyceride hydrolase present on endothelial cell
      surfaces and in atherosclerotic lesions. LpL hydrolysis of Intralipid lowered pH
      from 7.40 to 7.00 in 10% human serum and from 7.40 to 6.88 in phosphate-buffered
      saline. Similar decreases in pH were also observed when very low density
      lipoproteins were hydrolyzed by LpL. Lipolysis was accompanied by a 2-fold
      increase in the release of 59Fe from Tf. Tf binding to subendothelial matrix
      (SEM), a site of key events in atherosclerosis, increased 2-fold as the pH
      decreased from 7.40 to 6.00. More free iron also bound to SEM as the pH decreased
      below 7.40. We next tested whether a reduction in pH promotes LDL oxidation. More
      oxidation products were found in LDL incubated at low pH for 24 h in 10% human
      serum. Malonaldehyde contents (nmol/mg protein), measured as TBARS, were 7.11 +/-
      0.34 at pH 7.40, 7.65 +/- 0.49 at pH 7.00, 9.00 +/- 1.18 at pH 6.50, and 11. 54
      +/- 0.63 at pH 6.00. Based on these results, we hypothesize that lipolysis
      induced acidic conditions enhance iron release from Tf and increase formation of
      oxidized LDL.

PMID- 10393219
TI  - Chylomicron metabolism in an animal model for hyperlipoproteinemia type I.
AB  - Mink homozygous for the mutation Pro214Leu in lipoprotein lipase (LPL) had only
      traces of LPL activity but amounts of LPL protein in their tissues similar to
      those of normal mink. In normal mink, lymph chylomicrons from rats given
      [3H]retinol (incorporated into retinyl esters, providing a core label) and
      [14C]oleic acid (incorporated mainly in triglycerides (TG)) were rapidly cleared
      from the circulation. In the homozygous mink, clearance was much retarded. The
      ratio of TG to core label in plasma did not decrease and much less [14C]oleic
      acid appeared in plasma. Still, half of the labeled material disappeared from the
      circulating blood within 30;-40 min and the calculated total turnover of TG in
      the hypertriglyceridemic mink was almost as large as in normal mink. The core
      label was distributed to the same tissues in hypertriglyceridemic mink as in
      normal mink. Half to two-thirds of the cleared core label was in the liver. The
      large difference was that in the hypertriglyceridemic mink, TG label (about 40%
      of the total amount removed) followed the core label to the liver and there was
      no preferential uptake of TG over core label in adipose or muscle tissue. In
      normal mink, only small amounts of TG label (<10%) appeared in the liver, while
      most was in adipose and muscle tissues. Apolipoprotein B-48 dominated in the
      accumulated TG-rich lipoproteins in blood of hypertriglyceridemic mink, even in
      fasted animals.

PMID- 10393221
TI  - Isolated rabbit enterocytes as a model cell system for investigations of
      chylomicron assembly and secretion.
AB  - A method is described for the isolation of viable enterocytes from rabbit small
      intestine. The procedure can also be used to isolate populations of epithelial
      cells from the crypt/villus gradient. The isolated enterocytes synthesized and
      secreted apoB-48 and triacylglycerol in particles of the density of chylomicrons.
      Secretion was stimulated by addition of bile salt/lipid micelles. Pulse-chase
      experiments demonstrated that newly synthesized apoB-48 is degraded
      intracellularly and that degradation is inhibited by provision of lipid micelles,
      suggesting that regulation of chylomicron assembly and secretion is broadly
      similar to that of very low density lipoprotein assembly in hepatocytes. This
      procedure for preparation of isolated enterocytes will provide a useful model
      system for investigation of the molecular details of chylomicron assembly.

PMID- 10393222
TI  - Staphylococcal infections in children: part 2.

PMID- 10393223
TI  - Epidemiology of travel-related morbidity and mortality in children.

PMID- 10393225
TI  - Toilet training.

PMID- 10393224
TI  - Consultation with the specialist: increased intracranial pressure.

PMID- 10393226
TI  - Index of suspicion. Case 1. Cyanotic congenital heart disease.

PMID- 10393228
TI  - Earning CME credit-completing the PIR quiz 

PMID- 10393227
TI  - Trichotillomania.

PMID- 10393233
TI  - Reprogramming the male gamete genome: a window to successful gene therapy.
AB  - Hematopoiesis and spermatogenesis both initiate from a stem cell capable of
      renewal and differentiation. Each pathway reflects the expression of unique
      combinations of facultative, i.e. tissue-specific and constitutive, i.e.
      housekeeping, genes in each cell type. In spermatogenesis, as in hematopoiesis,
      commitment is mediated by the mechanism of potentiation whereby specific
      chromatin domains are selectively opened along each chromosome. Within each open
      chromatin domain, a unique battery of gene(s) is availed to tissue-specific and
      ubiquitous transacting factors that are necessary to initiate transcription. In
      the absence of an open domain, trans-factor access is denied, and the initiation
      of transcription cannot proceed. Cell-fate is thus ultimately defined by the
      unique series of open-potentiated cell-specific chromatin domains. Defining the
      mechanism that opens chromatin domains is fundamental in understanding how
      differentiation from stem cells is controlled and whether cell-fate can be
      modified. A recent examination of the mammalian spermatogenic pathway [Kramer,
      J.A., McCarrey, J.M, Djakiew, D., Krawetz, S.A., 1998. Differentiation: the
      selective potentiation of chromatin domains. Development 125, 4749-4755] supports
      the view that cell fate is mediated by global changes in chromatin conformation.
      This stride underscores the possibility of moderating differentiation through
      chromatin conformation. It is likely that gene therapeutics capable of
      selectively potentiating individual genic domains in populations of
      differentiating and/or replicating cells that modify cellular phenotype will be
      developed in the next millennium.

PMID- 10393234
TI  - The origin and evolution of human T-cell lymphotropic virus type II (HTLV-II) and
      the relationship with its replication strategy.
AB  - In this review, the origin and evolution of the human T-cell lymphotropic virus
      type II (HTLV-II) are discussed, with particular emphasis on its high genomic
      stability. In particular, it appears that the virus originated in the African
      continent and has been infecting human populations for several thousands of
      years. The very low divergence accumulated on average between different viral
      strains during such a long period could be explained by considering that in
      infected individuals the viral amplification could be due mainly to the clonal
      expansion of the infected cells, via cellular mitosis, rather than to reverse
      transcription. HTLV-II was introduced into the American continent during one or
      more migrations of HTLV-II-infected Asian populations over the Bering land
      bridge, some 15,000-35,000 years ago. Finally, during the last few decades, HTLV
      II has been transmitted from native Amerindians to injecting drug users (IDUs).
      It might be speculated that at least two separate introductions of HTLV-II in
      European IDUs from US IDUs have occurred, due to the practice of needle-sharing
      among IDUs.

PMID- 10393235
TI  - Cloning and analysis of Pycnoporus cinnabarinus cellobiose dehydrogenase.
AB  - We have cloned and sequenced a gene encoding cellobiose dehydrogenase (CDH) from
      Pycnoporus cinnabarinus (Pci). PCR primers that may recognize a homologous cdh
      were designed using regions of complete conservation of amino acid sequence
      within the known sequences of Trametes versicolor (Tv) and Phanerochaete
      chrysosporium (Pc) CDH. Upstream primers hybridized to regions encoding the heme
      domain, whereas downstream primers recognized highly conserved regions within the
      flavin domain. Eight different primer pairs yielded three PCR products close in
      size to the control amplification, which used cloned Tv cdh as template. The PCR
      products that were close to the control size were cloned, and one of these, a 1.8
      kb product, was completely sequenced. The PCR product was highly homologous to
      both Tv and Pch cdh, and contained eight putative introns. The cloned product was
      used to isolate a full-length clone encoding CDH from a Pci genomic library. Pci
      cdh encoded a protein with 83% identity with Tv CDH and 74% identity with Pch
      CDH. Northern blot analysis revealed that Pci cdh was transcribed as a single
      mRNA species and was expressed in the presence of cellulose as the carbon source.

PMID- 10393236
TI  - Functional expression of human and Arabidopsis protein phosphatase 2A in
      Saccharomyces cerevisiae and isolation of dominant-defective mutants.
AB  - Protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine-specific protein
      phosphatase, comprises a catalytic subunit and two distinct regulatory subunits,
      A and B. The primary sequence of the catalytic (C) subunit is highly conserved in
      evolution, and its function has been shown to be essential in yeast, Drosophila
      and mice. In many eukaryotes, the C subunit is encoded by at least two nearly
      identical genes, impeding conventional loss-of-function genetic analysis. We
      report here the development of a functional complementation assay in S.
      cerevisiae that has allowed us to isolate dominant-defective alleles of human and
      Arabidopsis C subunit genes. Wild-type human and Arabidopsis C subunit genes can
      complement the lethal phenotype of S. cerevisiae PP2A-C mutations. Site-directed
      mutagenesis was used to create two distinct, catalytically impaired C subunit
      mutants of the human and Arabidopsis genes. In both cases, expression of the
      mutant subunit in yeast prevented growth, even in the presence of functional C
      subunit proteins. This dominant growth defect is consistent with a dominant
      interfering mode of action. Thus, we have shown that S. cerevisiae provides a
      rapid system for the functional analysis of heterologous PP2A genes, and that two
      mutations that abrogate phosphatase activity exhibit dominant-defective
      phenotypes in S. cerevisiae.

PMID- 10393237
TI  - Structure of genes encoding chromosomal HMG1 proteins from maize.
AB  - The high mobility group (HMG) proteins of the HMG1 family are architectural
      proteins in chromatin that are considered to facilitate the formation of complex
      nucleoprotein structures in various biological processes such as transcription
      and recombination. Plants express a variety of these non-sequence-specific DNA
      bending proteins. The sequences encoding the maize HMGa and HMGc1 proteins were
      isolated from a genomic DNA library. Determination of the nucleotide sequences of
      these genes revealed that the coding region of both genes has a similar genomic
      structure, comprising seven exons and six introns. The positioning of the introns
      is conserved between the two genes, whereas the number of introns and their
      positions are entirely different in the related animal genes. In the 5' flanking
      region of the hmgc1 gene, a copia-like retrotransposon was identified. In
      addition to the genes encoding HMGa and HMGc1, several genomic fragments
      (retropseudo gene, fragments of the genes) were isolated and characterised.

PMID- 10393238
TI  - Cadmium metallothionein gene of Tetrahymena pyriformis.
AB  - A genomic sequence from Tetrahymena pyriformis, encoding a cadmium-induced
      metallothionein has been cloned. The gene encodes a transcript of 487 bases, with
      an intronless coding region of 324 nt, using TGA as the stop codon, TAA coding
      for glutamine, and the translational initiation sequence AAAATGG. Two regions of
      internal similarity in the coding sequence support the hypothesis that the
      Tetrahymena protein arose by gene duplication. The sequences of untranslated
      regions show some similarities with nematode MT-1 and MT-2 transcripts. Sequence
      of 525 bases upstream of the transcription start contains a TATA box, a CAAT box
      reverse complement, and many short stretches partially matching the AP-1 and ACE
      1 binding sites, but no characteristic sequences found in other metallothionein
      promoters.

PMID- 10393239
TI  - Interaction between the two ubiquitously expressed transcription factors NF-Y and
      Sp1.
AB  - The regulation of the rat fatty acid synthase gene by mediators such as diet,
      hormones, cAMP, sterols or retinoic acid is controlled by three NF-Y binding
      sites. All three sites have a neighbouring Sp1-binding GC-box. This NF-Y/Sp1
      motif is conserved in the FAS promoters of rat, human, goose and chicken. We have
      previously shown cooperative binding of NF-Y and Sp1 to the promoter region at 
      500 coincident with a diet-induced DNAse I-hypersensitive site. Here, we show an
      in-vivo interaction of NF-YA with Sp1 using the yeast two-hybrid system. The
      interacting domains are located between amino acids 55 and 139 of the NF-Y
      subunit NF-YA and between amino acids 139 and 344 of Sp1. In addition, we show by
      co-immunoprecipitation direct interaction of NF-Y subunit NF-YA with Sp1 in
      extracts of rat hepatoma cells H4IIE. Furthermore, we demonstrate by the GST pull
      down assay that NF-YA interacts physically with Sp1 in-vitro in the absence of
      DNA. Therefore, NF-Y can be added to the list of transcription factors
      interacting with Sp1.

PMID- 10393240
TI  - Isolation and characterization of the three Waxy genes encoding the granule-bound
      starch synthase in hexaploid wheat.
AB  - Complete genomic DNA sequences of three homoeologous Waxy structural genes,
      located on the chromosomes 7A, 4A, and 7D in hexaploid wheat (Triticum aestivum
      L. cv. Chinese Spring), were separately determined and analyzed. Those structural
      genes in lengths from start to stop codon were 2781bp in Wx-7A, 2794bp in Wx-4A,
      and 2862bp in Wx-7D, each of which consisted of 11 exons and ten introns. They
      were closely similar to one another in the nucleotide sequences, with 95.6-96.3%
      homology in mature protein regions, 88. 7-93.0% in transit-peptide regions, and
      70.5-75.2% in the introns. These wheat Waxy genes were GC-rich when compared with
      standard values for plant genomes reported so far. This was reflected in the
      extremely high G/C occupation frequency at the third position of the codons in
      the coding regions. The sequence divergence in the exon regions was mostly due to
      the substitution of nucleotides, whereas that found in the introns was attributed
      to substitution, insertion and/or deletion of nucleotides. Only the Wx-4A gene
      contained a trinucleotide insertion (CAA) in the region encoding the transit
      peptide. Most of the substitutions observed in the exon regions were categorized
      as synonymous, and higher sequence similarities (96.5-97. 4%) were conserved at
      the protein level. The phylogenetic tree obtained in terms of the amino acid
      sequence variations showed a well-resolved phylogenetic relationship among wheat
      Waxy genes and those from other plants.

PMID- 10393241
TI  - RNA editing in an untranslated region of the Ginkgo chloroplast genome.
AB  - mRNAs in plant cell organelles can be subject to RNA editing, an RNA processing
      step altering the identity of single nucleotide residues. In higher plant
      chloroplasts, editing proceeds by C-to-U conversions at highly specific sites.
      All known plastid RNA editing sites are located in protein-coding regions and,
      typically, change the coding properties of the mRNA. To gain more insight into
      the evolution of editing, we have determined the molecular structure and RNA
      editing pattern of the psbE operon of the primitive seed plant Ginkgo biloba. We
      report here the identification of altogether four sites of C-to-U editing, two of
      which are unique to Ginkgo and have not been found in other species.
      Surprisingly, one of the sites is located in an intercistronic spacer, thus being
      the first chloroplast editing site detected outside a protein-coding region. This
      indicates that the plastid editing machinery can operate also in untranslated
      regions and without having apparent functional consequences.

PMID- 10393242
TI  - Induction of the rat Cu/Zn superoxide dismutase gene through the peroxisome
      proliferator-responsive element by arachidonic acid.
AB  - The Cu/Zn superoxide dismutase (SOD1) catalyzes the dismutation of superoxide
      radicals produced from biological oxidation and environmental stresses. From the
      sequence analysis of transcription factor binding sites, the peroxisome
      proliferator-responsive element (PPRE) was located between nt -797 and -786 of
      the 5'-flanking sequence of the SOD1 gene. A promoter region was fused to a
      chloramphenicol acetyl-transferase gene, and the resultant construct was
      transiently transfected into HepG2 cells. The expression of the SOD1 gene was
      induced by arachidonic acid (AA). Functional analyses of the PPRE site by
      deletion, mutations, and the heterologous promoter system confirmed the induction
      of the SOD1 gene by AA through the PPRE site. Gel mobility shift assays showed AA
      inducible binding of the peroxisome proliferator-activated receptor (PPAR) to the
      PPRE. The intensity of PPAR binding was also increased by the treatment of
      retinoic acid (RA) and 9-cis retinoic acid (9-cis RA). These results suggest that
      the PPRE participates in the induction of the rat SOD1 gene by the peroxisome
      proliferator.

PMID- 10393243
TI  - Organization and structure of the mouse gamma-glutamyl hydrolase gene and the
      functional identification of its promoter.
AB  - The organization and structure of the murine GH gene encoding gamma-glutamyl
      hydrolase were determined. The murine GH gene spans 24kb and was found to be
      distributed in nine exons. The intron/exon coding junctions delineated conformed
      to the GT-AG rule. The 5' UTR and 3' UTR along with some coding sequences were
      incorporated in exons 1 and 9, respectively, whereas exons 2-8 incorporated only
      coding sequence. A relatively GC-rich region of the genome 5' of exon 1 was
      distinctly promoter-like and encoded a number of putative cis-acting elements,
      including six Sp1 sites known to be involved in the regulation of transcription
      but no TATA sequence motif. Primer extension analysis of this region with mouse
      liver and S180 cell mRNA revealed several tsps within the region encompassing the
      Sp1 sites. Functional analysis of this 5' upstream region of sequence was carried
      out by inserting it into the pGL3 reporter gene vector for transfection into
      NIH3T3 cells. The transcription of the luciferase gene that resulted in these
      cells established the identity of this region as an active promoter for the mouse
      GH gene.

PMID- 10393244
TI  - Upstream elements bestow T-cell and haemopoietic progenitor-specific activity on
      the granzyme B promoter.
AB  - Cytotoxic T cells and early haemopoietic progenitors share the expression of a
      number of specific genes. Of these, granzyme B has attracted particular interest
      because of its role in inducing apoptosis during cytotoxic T cell-mediated target
      cell killing, and its potential role in the mobilisation and homeostasis of
      haemopoietic stem cells. Studies of granzyme B regulation should therefore yield
      valuable information concerning the molecular control of these processes, and
      also identify elements capable of directing gene expression to two cell types of
      relevance to gene therapy. Here we show that proximal regulatory elements already
      known to direct promoter activity in T cells are similarly active in haemopoietic
      progenitors. However, this activity is not strictly specific, since the promoter
      regions also direct low levels of reporter gene expression in fibroblasts. More
      importantly, we also report the presence of two previously unidentified clusters
      of DNaseI hypersensitive sites upstream from the murine granzyme B gene, and show
      that these regions impart both increased transcriptional activity and the
      appropriate cell type specificity on the granzyme B promoter. These upstream
      regulatory regions are therefore likely to play a key role in the coordination of
      granzyme B expression in vivo.

PMID- 10393245
TI  - Isolation and characterization of PDE10A, a novel human 3', 5'-cyclic nucleotide
      phosphodiesterase.
AB  - A gene encoding a novel human 3', 5'-cyclic nucleotide phosphodiesterase (PDE)
      was identified and characterized. PDE10A1 encodes a protein that is 779 amino
      acids in length. An incomplete cDNA for a second 5'-splice variant, PDE10A2, was
      isolated. The proteins encoded by the two variants share 766 amino acids in
      common. This common region includes an amino-terminal domain with partial
      homology to the cGMP-binding domains of PDE2, PDE5 and PDE6 as well as a carboxy
      terminal region with homology to the catalytic regions of mammalian PDEs.
      Northern analysis revealed that PDE10A is widely expressed. The PDE10A gene was
      mapped to three yeast artificial chromosomes (YACs) that contain human DNA from
      chromosome 6q26-27. A recombinant protein corresponding to the 766 amino acid
      region common to PDE10A1 and PDE10A2 was expressed in yeast. It hydrolyzed both
      cAMP and cGMP. Inhibitors that are selective for other PDE families are poor
      inhibitors of PDE10A; however, PDE10A is inhibited by the non-specific PDE
      inhibitor, IBMX.

PMID- 10393246
TI  - Characterization and localization to chromosome 7 of psihGABPalpha, a human
      processed pseudogene related to the ets transcription factor, hGABPalpha.
AB  - GABP is a heteromeric transcription factor complex which consists of the ets
      related protein, GABPalpha, and the Notch-related protein, GABPbeta. We isolated
      a human genomic DNA fragment which is highly homologous and colinear with human
      GABPalpha cDNA, but which lacks introns. This processed pseudogene,
      psihGABPalpha, is expressed as RNA in U937 human myeloid cells, but a mutation at
      the site that corresponds to the ATG start methionine codon prevents its
      translation into protein. The pseudogene was localized to chromosome 7 using a
      somatic cell hybrid mapping panel and it is not syntenic with authentic
      GABPalpha, which was localized to chromosome 21. We have identified
      psihGABPalpha, a novel, GABPalpha-related processed pseudogene which is expressed
      as a RNA transcript in human myeloid cells.

PMID- 10393247
TI  - NIMA-related kinases: isolation and characterization of murine nek3 and nek4
      cDNAs, and chromosomal localization of nek1, nek2 and nek3.
AB  - The Aspergillus NIMA kinase plays a key role in controlling entrance into
      mitosis, and recent evidence suggests that mammalian NIMA-related kinases perform
      similar functions. We report here the cloning of the mouse nek3 and nek4 genes.
      Mouse nek3 is probably the ortholog of the partially sequenced, human nek3,
      whereas murine nek4 cDNA is probably the ortholog of human STK2. Nek4 is highly
      conserved between mouse and human, whereas Nek3 is somewhat less conserved (96.5
      and 88% identity in the kinase domains, respectively). Northern analysis shows
      preferential expression of nek3 in mitotically active tissue, whereas nek4 is
      highly abundant in the testis. Within the developing testicular germ cells, in
      situ analysis demonstrated that nek1, 2 and 4 exhibit differential patterns of
      expression, suggesting overlapping, but non-identical functions. Linkage
      analysis, using the mouse recombinant inbred strain panel (BXD), was used to
      localize nek1, 2 and 3. nek1 was mapped between Cpe and D8Mit8 on chromosome 8 at
      around 32cM, nek2 was mapped to the distal region of chromosome 1, and nek3 was
      mapped to the most centromeric region of chromosome 8.

PMID- 10393248
TI  - A serine residue in the N-terminal acidic region of rat RPB6, one of the common
      subunits of RNA polymerases, is exclusively phosphorylated by casein kinase II in
      vitro.
AB  - RPB6 is one of the common subunits of all eukaryotic RNA polymerases and is
      indispensable for the enzyme function. Here, we isolated a rat cDNA encoding
      RPB6. It contained 127 amino acid (a.a.) residues. From alignment of RPB6
      homologues of various eukaryotes, we defined two conserved regions, i.e. an N
      terminal acidic region and a C-terminal core. In this study, we investigated in
      vitro phosphorylation of rat RPB6 by casein kinase II (CKII), a pleiotropic
      regulator of numerous cellular proteins. Three putative CKII-phosphorylated a.a.
      within rat RPB6 were assigned. We found that serines were phosphorylated by CKII
      in vitro. Mutagenesis studies provided evidence that a serine at a.a. position 2
      was exclusively phosphorylated. Finally, an RPB6-engaged in-gel kinase assay
      clarified that CKII was a prominent protein kinase in rat liver nuclear extract
      that phosphorylates RPB6. Therefore, RPB6 was implied to be phosphorylated by
      CKII in the nucleus. We postulate that the N-terminal acidic region of the RPB6
      subunit has some phosphorylation-coupled regulatory functions.

PMID- 10393249
TI  - Cloning, characterisation, and functional expression of the Mus musculus SKD1
      gene in yeast demonstrates that the mouse SKD1 and the yeast VPS4 genes are
      orthologues and involved in intracellular protein trafficking.
AB  - The mouse SKD1 protein displays a high degree of sequence identity (62%) to the
      yeast Vps4 protein, which is involved in the transport of proteins out of a
      prevacuolar/endosomal compartment. We isolated the mouse SKD1 locus and found
      that the SKD1 gene is split into 11 exons covering a region of 29kb of the
      genome. Interestingly, the exon/intron structure reflects to a certain degree the
      proposed domain structure of the protein, since the 5' located coiled-coil region
      and the AAA domain are flanked by introns. Analysis of the promoter region, which
      revealed features common for 'housekeeping genes', is consistent with previous
      results of a mouse multi-tissue Northern blot, confirming that SKD1 is a
      ubiquitously expressed gene. Expression of the full-length SKD1 cDNA in a vps4
      disrupted yeast strain suppressed the temperature-sensitive growth defect of the
      vps4 mutant strain. Overexpression of wild type and expression of mutant Vps4 and
      SKD1 proteins, harbouring single amino acid exchanges in their AAA domains,
      induced a dominant-negative vacuolar protein sorting defect in wild type yeast
      cells, indicating that mouse SKD1 protein and yeast Vps4p fulfil similar
      functions.

PMID- 10393250
TI  - Characterization of a human gene with sequence homology to Saccharomyces
      cerevisiae SIR2.
AB  - The proteins encoded by the SIR1, SIR2, SIR3 and SIR4 genes in yeast repress
      transcription at the mating type loci and telomeres. Among the SIR genes, SIR2 is
      the most evolutionarily conserved, and a number of genes with homology to SIR2
      have been identified. In addition to transcriptional silencing, the product of
      SIR2 gene (Sir2p) has been shown to be involved in DNA repair and suppression of
      rDNA recombination. In the present study, the complete sequence of a human gene,
      SIR2L, with homology to the yeast SIR2 gene is presented. Comparison of the
      predicted sequence of the protein encoded by the SIR2L gene (SIR2Lp) with Sir2p
      or other proteins with homology to Sir2p reveals 20-33% overall identity and four
      highly conserved regions, the significance of which is unknown. SIR2L codes for a
      2.1kb transcript which is expressed in various human tissues. The expression
      level of the transcript is found to be relatively high in the heart, brain and
      skeletal muscle tissues and low in lung and placenta. The intracellular location
      of SIR2Lp was visualized by fusion to the Green Fluorescent Protein or with a
      FLAG-tag. The results indicate that unlike Sir2p in yeast, SIR2Lp in human cells
      is found primarily in the cytoplasm. Using a mammalian inducible expression
      system, we also observed that unlike SIR2 in yeast, overexpression of SIR2L in
      human cancer cells has no effect on cell growth. Thus, although the human SIR2L
      gene appears to be related to the yeast SIR2 gene, it does not appear to have
      similar functions.

PMID- 10393251
TI  - Sequence of 10q24 locus surrounding the HOX11 oncogene reveals a new gene HUG1
      expressed in a T-ALL cell line.
AB  - HOX11 is a gene encoding a homeobox protein which is found to be deregulated in T
      cell acute lymphoblastic leukaemia (T-ALL). As a basis for studying the mechanism
      of deregulation of HOX11 expression in leukaemia, the locus containing the HOX11
      proto-oncogene at 10q24 was cloned from a genomic P1 Artificial Chromosome (PAC)
      library. The PAC clone with an insert size of 120kb was isolated and mapped by
      restriction analysis. A series of contiguous subclones were then obtained which
      span 20kb surrounding the HOX11 gene. These subclones were used to sequence
      across the entire 20kb region to the 3' boundary of the PAC insert. This work
      provides for the first time the full intron and 5' non-coding sequences of the
      HOX11 gene which will aid the identification of novel transcriptional control
      elements which may be involved in silencing HOX11 expression in normal cells. The
      sequence information was also used to search for novel large open reading frames
      (ORFs). One such ORF (1.1kb) would encode a protein of at least 39kDa. This basic
      protein (pI, 12.5) would be very proline rich and could potentially encode a
      novel transcription factor. In order to establish if this ORF corresponds to a
      bona fide transcribed gene, RT-PCR analysis was performed. The mRNA for this
      protein is expressed in the T-ALL cell line Jurkat and has been designated HUG1,
      for HOX11 Upstream Gene.

PMID- 10393252
TI  - One of the non-exchangeable nucleotides of the mitochondrial F1-ATPase is bound
      at a beta-subunit: evidence for a non-rotatory two-site catalytic mechanism 
AB  - In active MF1, one of the two non-exchangeable tightly bound adenine nucleotides
      is an ATP, while the other is an ADP. The respective sites are called the T-site
      and the D-site. The activity of the enzyme correlates linearly with the amount of
      bound ATP, ADP at the T-site being inhibitory. When MF1 is stored at room
      temperature in 50% glycerol and 100 mM Tris-HCl (pH 7.3) after slow passage
      through a Sephadex column, the tightly bound ATP is slowly dephosphorylated to
      ADP which is subsequently released, without effect on activity. When enzyme with
      about one residual ADP left (at the D-site) was incubated at pH 7.3, after
      dilution of the glycerol, with 400 &mgr;M [14C]ATP under varying conditions, the
      amount of tightly bound nucleotide triphosphate again correlated well with
      activity, the residual ADP being bound at the D-site. Optimal results were
      obtained when the incubation was performed in the presence of a regenerating
      system. Binding of 2-azido-ATP instead of ATP to the T-site as a triphosphate, as
      indicated by the specific activity of the enzyme, appeared to be optimal when the
      binding was performed at pH 6.4 in the absence of Mg2+ and with high
      concentrations of the nucleotide. Under such conditions, 3 mol 2-azido-AXP per
      mol F1 remained tightly bound after ammonium sulfate precipitation and column
      centrifugation, in addition to about one residual ADP at the D-site. After a 2
      min period of turnover with ATP/Mg2+ as substrate two mol 2-azido-AXP were left
      on the enzyme, of which one was bound at a beta-site. These results show that one
      of the non-catalytic nucleotide binding sites that contain tightly bound
      nucleotides, is a beta-site, in conflict with the requirements for a rotatory tri
      site mechanism for ATP hydrolysis. This beta-site can further be identified with
      the T-site. The validity of these conclusions for F1 from other sources and for
      catalysis by membrane-bound enzyme is discussed.

PMID- 10393253
TI  - Spectroscopic and molecular characterization of a long wavelength absorbing
      antenna of Ostreobium sp.
AB  - One of the strains of the marine green alga Ostreobium sp. possesses an
      exceptionally large number of long wavelength absorbing chlorophylls (P. Haldall,
      Biol. Bull. 134, 1968, 411-424) as evident from a distinct shoulder in the
      absorption spectrum at around 710 nm while in the other strain this shoulder is
      absent. Therefore, Ostreobium offers a unique possibility to explore the origin
      of these red-shifted chlorophylls, because strains with and without these
      spectral forms can be compared. Here, we characterize these red forms
      spectroscopically by absorption, fluorescence and CD spectroscopy. In the CD
      spectra at least three spectroscopic red forms are identified which lead to an
      unusual room temperature fluorescence spectrum that peaks at 715 nm. The gel
      electrophoretic pattern from thylakoids of Ostreobium sp. shows an intense band
      at 22 kDa which correlates with the presence or absence of long wavelength
      absorbing pigments. By protein sequencing of the N-terminus of the 22-kDa
      polypeptide and sequence alignments, this was identified as an Lhca1-type light
      harvesting complex. The abundance of this polypeptide - and a possibly co
      migrating one - in Ostreobium sp. indicates an antenna size of approximately 340
      chlorophyll molecules (Chl a and Chl b) per PS IIalpha reaction center, which is
      significantly larger than in higher plants ( approximately 240). The red forms
      are more abundant in the interior of the thalli where a 'shade-light' light field
      is expected than in the white-light exposed surface. This demonstrates that algae
      exist which may be able to up-regulate the synthesis of large amounts of LHCI and
      associated red forms under appropriate illumination conditions.

PMID- 10393254
TI  - Oxygen uncouples light absorption by the chlorosome antenna and photosynthetic
      electron transfer in the green sulfur bacterium chlorobium tepidum 
AB  - In photosynthetic green sulfur bacteria excitation energy is transferred from
      large bacteriochlorophyll (BChl) c chlorosome antennas via small BChl a antennas
      to the reaction centers which then transfer electrons from cytochrome c to low
      potential iron-sulfur proteins. Under oxidizing conditions a reversible mechanism
      is activated in the chlorosomes which quenches excited BChl c. We used flash
      induced cytochrome c oxidation to investigate the effect of this quenching on
      photosynthetic electron transfer in whole cells of Chlorobium tepidum. The extent
      of cytochrome c photooxidation under aerobic conditions decreased to approx. 3%
      of that under anaerobic conditions when BChl c was excited under light-limiting
      conditions. Photooxidation obtained by excitation of BChl a was similar under
      aerobic and anaerobic conditions. We interpret this drastic decrease in energy
      transfer from BChl c to the reaction center as a consequence of the quenching
      mechanism which is activated by O2. This reversible uncoupling of the chlorosome
      antenna might prevent formation of toxic reactive oxygen species from
      photosynthetically produced reductants under aerobic conditions. The green
      filamentous bacterium Chloroflexus aurantiacus also contains chlorosomes but
      energy transfer from the BChl c and BChl a antennas to the reaction center in
      this species was not affected by O2.

PMID- 10393255
TI  - Kinetic modeling of rotary CF0F1-ATP synthase: storage of elastic energy during
      energy transduction 
AB  - F0F1-ATP synthase uses proton-motive force to produce ATP from ADP and Pi. With
      regard to its rotary mechanics, this energy transducing molecular machine assumes
      a unique position among all enzymes. In the work presented here we put forward a
      detailed functional model which is based on experimental results obtained with
      ATP synthase from spinach chloroplasts. We focus on the role of the elastic
      element, realized by the stalk-like subunit gamma, whose function is energy
      transduction between F0 and F1 taking into account the H+/ATP coupling ratio of
      four. Fitting parameters are the rate constants and the torsional rigidity of
      gamma, which have been adjusted according to the experimental results where the
      influence of transmembrane DeltapH on the rates of ATP synthesis/hydrolysis is
      put to the test. We show that the input and output of torsional energy are
      regulated by purely statistical principles, giving rise to the amount of
      transiently stored energy to be sliding, depending on DeltapH. During conditions
      of maximal turnover gamma turns out to be wound up towards 102 degrees which
      corresponds to a torque of 5.3. 10-20 N.m.

PMID- 10393256
TI  - Effects of the mitogen concanavalin A on pathways of thymocyte energy metabolism.
AB  - The lectin concanavalin A (Con A) acts as a mitogen that preferentially activates
      T-cells. It stimulates the energy metabolism of thymocytes within seconds of
      exposure. We studied short-term effects (<30 min) of Con A on a conceptually
      simplified model system of rat thymocyte energy metabolism in the concentration
      range of 0-2 microg Con A per 107 cells, using metabolic control analysis. The
      model system consisted of three blocks of reactions, linked by the common
      intermediate mitochondrial membrane potential (Delta[psi]m): the substrate
      oxidation reactions, which produce the linking intermediate, and the proton
      conductance (or leak) and ATP turnover pathways which consume Delta[psi]m.
      Firstly, we used top-down elasticity analysis to establish which subsystems are
      targeted by Con A. Secondly, we quantitatively analysed the steady-state
      regulation of the system variables by Con A: how do the subsystem fluxes respond
      to Con A individually and as a whole? Our results indicate that: (1) steady-state
      respiration and Delta[psi]m increase as Con A concentration is raised, but at
      higher concentrations the increase in respiration is less and Delta[psi]m falls;
      (2) Con A independently changes the kinetics of the reactions that produce and
      consume Delta[psi]m: the Delta[psi]m-producing reactions are inhibited, and the
      reactions involved in ATP turnover are stimulated; and (3) the overall effects of
      Con A are mostly mediated by effects on ATP turnover.

PMID- 10393257
TI  - The mobile loop region of the NAD(H) binding component (dI) of proton
      translocating nicotinamide nucleotide transhydrogenase from Rhodospirillum
      rubrum: complete NMR assignment and effects of bound nucleotides.
AB  - The dI component of transhydrogenase binds NAD+ and NADH. A mobile loop region of
      dI plays an important role in the nucleotide binding process, and mutations in
      this region result in impaired hydride transfer in the complete enzyme. We have
      previously employed one-dimensional 1H-NMR spectroscopy to study wild-type and
      mutant dI proteins of Rhodospirillum rubrum and the effects of nucleotide
      binding. Here, we utilise two- and three-dimensional NMR experiments to assign
      the signals from virtually all of the backbone and side-chain protons of the loop
      residues. The mobile loop region encompasses 17 residues: Asp223-Met239. The
      assignments also provide a much strengthened basis for interpreting the
      structural changes occurring upon nucleotide binding, when the loop closes down
      onto the surface of the protein and loses mobility. The role of the mobile loop
      region in catalysis is discussed with particular reference to a newly-developed
      model of the dI protein, based on its homology with alanine dehydrogenase.

PMID- 10393258
TI  - Uphill energy transfer in LH2-containing purple bacteria at room temperature 
AB  - Uphill energy transfer in the LH2-containing purple bacteria Rhodopseudomonas
      acidophila, Rhodopseudomonas palustris, Rhodobacter sphaeroides, Chromatium
      vinosum and Chromatium purpuratum was studied by stationary fluorescence
      spectroscopy at room temperature upon selective excitation of the B800 pigments
      of LH2 and the B880 pigments of LH1 at 803 nm and 900 nm, respectively. The
      resulting fluorescence spectra differed significantly at wavelengths shorter than
      the fluorescence maximum but agreed at longer wavelengths. The absorption spectra
      of the species studied were decomposed into five bands at approx. 800, 820, 830,
      850 and 880 nm using the shapes of the absorption spectra of the LH1-RC only
      species Rhodospirillum rubrum and the isolated B800-850 complex from Rps.
      acidophila strain 10050 as guide spectra. This allowed a quantification of the
      number of pigments in each pigment group and, consequently, the antenna size of
      the photosynthetic unit assuming 36 bacteriochlorophyll a molecules in an LH1-RC
      complex. In most of the LH2-containing purple bacterial strains the number of LH2
      rings per LH1-RC was less than the idealized number of eight (Papiz et al.,
      Trends Plant Sci. 1 (1996) 198-206), which was achieved only by C. purpuratum.
      Uphill energy transfer was assayed by comparing the theoretical fluorescence
      spectrum obtained from a Boltzmann equilibrium with the measured fluorescence
      spectrum obtained by 900 nm excitation. The good match of both spectra in all the
      purple bacteria studied indicates that uphill energy transfer occurs practically
      up to its thermodynamically maximal possible extent. All strains studied
      contained a small fraction of either poorly connected or unconnected LH2
      complexes as indicated by higher fluorescence yields from the peripheral
      complexes than predicted by thermal equilibration or kinetic modeling. This
      impedes generally the quantitative analysis of blue-excited fluorescence spectra.

PMID- 10393259
TI  - Xanthophyll pigments in light-harvesting complex II in monomolecular layers:
      localisation, energy transfer and orientation 
AB  - Monomolecular layers of the largest light-harvesting pigment-protein complex of
      Photosystem II (LHCII) were formed at the argon-water interface. The molecular
      area of the LHCII monomer in monomolecular layers determined from the isotherms
      of compression is found to be close to 14 nm2, which corresponds well to the
      molecular dimensions of the protein evaluated on the basis of crystallographic
      studies. Monolayers of LHCII were deposited on a glass support by means of the
      Langmuir-Blodgett technique and subjected to spectroscopic studies: electronic
      absorption spectrophotometry and spectrofluorometry. The fluorescence excitation
      spectra of chlorophyll a in monolayers of LHCII were analysed using gaussian
      deconvolution. Comparison of the absorption and fluorescence excitation spectra
      enabled calculation of the rate of excitation energy transfer in the system.
      Excitation energy was found to be transferred to chlorophyll a from chlorophyll b
      with 97% efficiency, from neoxanthin with 85%, from lutein with 62% and from
      violaxanthin with at least 54% efficiency. The analysis of the position of the 0
      0 absorption band of the xanthophylls revealed that neoxanthin is located in the
      same protein environment as lutein but in a different environment than
      violaxanthin. The analysis of fluorescence excitation spectra of chlorophyll a in
      LHCII, recorded with the excitation light beam polarised in two orthogonal
      directions, enabled the determination of the mean orientation angle of the
      accessory xanthophyll pigments with respect to the plane of the sample. The mean
      orientation of lutein found in this study (approx. 51 degrees ) corresponds well
      to the crystallographic data. Neoxanthin was found to adopt a similar orientation
      to lutein. The transition dipole moment of violaxanthin was found to form a mean
      angle of 71 degrees with the axis spanning two polar regions of the protein,
      perpendicular to the plane of the monolayer, suggesting planar orientation of
      this pigment with respect to the plane of the thylakoid membrane. These
      experimentally determined xanthophyll orientations are discussed in terms of
      importance of peripheral xanthophyll pigments in supramolecular organisation of
      LHCII and the operation of the xanthophyll cycle within the thylakoid membrane.

PMID- 10393260
TI  - Proton linkage of cytochrome a oxidoreduction in carbon monoxide-treated
      cytochrome c oxidase 
AB  - Oxidoreduction of the low spin haem a of cytochrome c oxidase was recently
      reported to be coupled to release/uptake of nearly one proton from/to the enzyme
      at pH 7.5 in the presence of CO to block oxidoreduction of the binuclear haem
      a3/CuB centre (N. Capitanio et al., Biochim. Biophys. Acta, 1318 (1997) 255-265).
      This is difficult to reconcile with earlier findings from several laboratories
      that the pH-dependence of the Em of haem a is ca. 10 mV/pH unit over a wide pH
      range in such conditions, which implies redox coupling of only ca. 0.17 H+/e-. In
      order to resolve this discrepancy, we have performed careful measurements of
      proton release coupled to oxidation of haem a and CuA in CO-inhibited cytochrome
      aa3 from bovine heart mitochondria. We find that oxidation of these centres by
      ferricyanide leads to release of a total of 0.20 protons per enzyme molecule at
      pH 7.7, increasing to 0.43 protons at pH 6.6, far short of a full 1 H+/e-. Using
      vesicles reconstituted with cytochrome c oxidase, we also found that all this
      proton release occurs towards the outside of the vesicles. The observed
      dependence can be explained by a model in which oxidoreduction of haem a is
      coupled to uptake and release of ca. 0.17 H+/e-, while oxidoreduction of CuA is
      linked to a protonatable group which has a pKa of 6.2 when CuA is in the reduced
      state. In agreement with existing data, this model predicts that the Em of CuA
      will only be slightly pH dependent in the pH range of these measurements.

PMID- 10393261
TI  - Specificity of mutations induced by methyl methanesulfonate in mismatch repair
      deficient human cancer cell lines.
AB  - Recently, we showed that the cytotoxic and mutagenic response in human cells to
      the model SN2 alkylating agent methyl methanesulfonate (MMS) can be modulated by
      the mismatch repair (MMR) pathway. That is, human cancer cell lines defective in
      MMR are more resistant to the cytotoxic effects of MMS exposure and suffer more
      induced mutations at the HPRT locus than MMR-proficient cell lines. Since MMS
      produces little O6-methylguanine (O6-meG), the observed hypermutability and
      resistance to cytotoxicity in MMR-defective cells likely results from lesions
      other than O6-meG. MMS produces a high yield of N7-methylguanine (N7-meG) and N3
      methyladenine (N3-meA), which can lead to the formation of promutagenic abasic
      sites, and these lesions may be responsible for the observed cytotoxic and/or
      mutagenic effects of MMS. To further investigate the mechanism of MMS
      mutagenesis, two MMR-defective human cancer cell lines were treated with MMS and
      the frequency and the types of mutations produced at the HPRT locus were
      determined. MMS treatment (1.5 mM) produced a 1.6- and a 2.2-fold increase in
      mutations above spontaneous levels in HCT116 and DLD-1 cell lines, respectively.
      An average 3.7-fold increase in transversion mutations was observed, which
      accounted for greater than one-third of all induced mutations in both cell lines.
      In contrast, an average 1.6-fold increase was seen among transition mutations
      (the class expected from O-alkylation products). Since transversion mutations are
      not produced by O6-meG, these findings suggest that abasic sites may be the
      lesion responsible for a large proportion of MMS mutagenicity in MMR-defective
      cells. Furthermore, these data suggest the MMS-induced damage, either abasic site
      inducing base alterations (i.e., N7-meG and N3-meA) or the resulting abasic sites
      themselves, may be substrates for recognition and/or repair by MMR proteins.

PMID- 10393262
TI  - The effect of folate deficiency on the hprt mutational spectrum in Chinese
      hamster ovary cells treated with monofunctional alkylating agents.
AB  - Folic acid deficiency acts synergistically with alkylating agents to increase DNA
      strand breaks and mutant frequency at the hprt locus in Chinese hamster ovary
      (CHO) cells. To elucidate the mechanism of this synergy, molecular analyses of
      hprt mutants were performed. Recently, our laboratory showed that folate
      deficiency increased the percentage of clones with intragenic deletions after
      exposure to ethyl methanesulfonate (EMS) but not N-nitroso-N-ethylurea (ENU)
      compared to clones recovered from folate replete medium. This report describes
      molecular analyses of the 37 hprt mutant clones obtained that did not contain
      deletions. Folate deficient cells treated with EMS had a high frequency of G>A
      transitions at non-CpG sites on the non-transcribed strand, particularly when
      these bases were flanked on both sides by G:C base pairs. Thirty-three percent of
      these mutations were in the run of six G's in exon 3. EMS-treated folate replete
      cells had a slightly (but not significantly) lower percentage of G>A transitions,
      and the same sequence specificity. Treatment of folate deficient CHO cells with
      ENU resulted in predominantly T>A transversions and C>T transitions relative to
      the non-transcribed strand. These findings suggest a model to explain the synergy
      between folate deficiency and alkylating agents: (1) folate deficiency causes
      extensive uracil incorporation into DNA; (2) greatly increased utilization of
      base excision repair to remove uracil and to correct alkylator damage leads to
      error-prone DNA repair. In the case of EMS, this results in more intragenic
      deletions and G:C to A:T mutations due to impaired ligation of single-strand
      breaks generated during base excision repair and a decreased capacity to remove
      O6-ethylguanine. In the case of ENU additional T>A transversions and C>T
      transitions are seen, perhaps due to mis-pairing of O2-ethylpyrimidines.
      Correction of folate deficiency may reduce the frequency of these types of
      genetic damage during alkylator therapy.

PMID- 10393263
TI  - Comparison of selectable and plaque assay systems to detect menadione- and UV
      induced lacI mutations in mammalian cells.
AB  - We have compared the spontaneous mutation frequency and spectrum of lacI genes
      recovered from a rat embryonic fibroblast line transfected with a lambda-phage
      shuttle vector (Rat2lambdalacI) using both the traditional plaque assay as well
      as a positive selection assay. In addition, mutation frequencies and spectrum
      were determined after treatment of the cells with either the intracellular
      superoxide-generating compound, menadione, or UVC light. The differences in
      mutation frequency between the two systems suggested that the selectable assay
      was better at discerning relatively small mutation frequency increases, more
      rapidly and at lower cost, than the plaque assay method. Some novel lacI
      mutations were observed in mutants derived from the selectable assay. This
      indicates that the selectable assay system may be a useful tool for assessing the
      mutagenic potential of different agents.

PMID- 10393265
TI  - Congenital abnormalities and indicators of germinal mutations in the vicinity of
      an acrylonitrile producing factory.
AB  - The results of an environmental mutation and teratologic epidemiological study
      are presented which was performed in inhabitants living in the surrounding region
      of an acrylonitrile factory in Nyergesujfalu. The endpoint of the study was
      congenital abnormalities in 46,326 infants born to mothers living in the 30
      settlements of the study region within a 25 km radius of the acrylonitrile
      factory between 1980 and 1996. The ascertainment of cases with congenital
      abnormalities was based on the dataset of the Hungarian Congenital Abnormality
      Registry complemented with the review of pediatric, pathology and cytogenetic
      records. A particular attention was paid to the indicators of germinal mutations
      as sentinel anomalies, Down syndrome and unidentified multiple congenital
      abnormalities and the indicators of teratogens as the specific pattern of
      multiple congenital abnormalities. Three congenital abnormalities: pectus
      excavatum in Tata, 1990-1992 (OR with 95%CI: 78.5, 8.4-729.6), undescended testis
      in Nyergesujfalu between 1980 and 1983 (8.6, 1.4-54.3) and in Esztergom, 1981
      1982 (4. 2, 1.3-13.5) and clubfoot in Tata, 1980-1981 (5.5, 1.5-20.3) showed
      significant time-space clusters in the study region. There was a decrease in risk
      of undescended testis with increasing distance from the acrylonitrile factory. An
      unusual increase was found in the combination of oral cleft and cardiac septal
      defects in multimalformed babies in Tatabanya, 1990. The detailed analysis of
      congenital abnormalities in all settlements of a given territory may help to
      detect clusters of congenital abnormalities and their possible relation to the
      environmental hazards.

PMID- 10393264
TI  - Involvement of G2-dependent DNA double-strand break repair in the formation of
      ultraviolet light B-induced chromosomal aberrations.
AB  - Wortmannin, an inhibitor of DNA double-strand break (DSB) repair added 19 h
      before harvest enhanced the incidence of ultraviolet light B (UVB)-induced
      chromatid aberrations in Chinese hamster V79 cells. Posttreatment with wortmannin
      for last 3 h of culture also enhanced the yield of breakage-type chromatid
      aberrations and suppressed the yield of exchange-type chromatid aberrations
      almost completely. Thus, the inhibition of DSB repair in the G2 phase stimulated
      the breakage-type aberration formation, while suppressing the exchange-type
      aberration formation. We propose the model of UVB-induced chromatid-type
      aberration formation which might be fully related to G2-dependent DSB repair
      pathway.

PMID- 10393266
TI  - Relatively low-dose cyclophosphamide is likely to induce apoptotic cell death in
      rat thymus through Fas/Fas ligand pathway.
AB  - Cyclophosphamide (CPA) is widely used as an efficiently antineoplastic drug, but
      also causes immunosuppression as its adverse-side effect. To understand the
      effect of low- or relative low-dose CPA on the immune system, apoptotic cell
      death in rat thymus, either exposed to different doses of CPA (0, 2, 7, 20 and 70
      mg/kg) for 12 h or exposed to 70 mg/kg for different times (4-48 h), was
      investigated by DNA fragmentation (DNA ladder) detection and in situ
      morphological examination using hematoxylin and eosin (H and E) staining.
      Immunohistochemical staining for Fas protein expression in the thymus of rats
      exposed to CPA was performed. Results showed that exposure of rats to CPA 0-70
      mg/kg for 12 h did not cause significant decrease in the ratio of thymus weight
      to body weight. However, the ratio of thymus weight to body weight was decreased
      significantly at 48 h after exposure to 70 mg/kg CPA. Exposure to 20 and 70 mg/kg
      CPA for 12 h caused a visible DNA ladder in gel electrophoresis. DNA ladder
      formation was increased progressively in the groups from 8 h to optimal magnitude
      at 12-24 h and then disappeared at 48 h after 70 mg/kg CPA. This pattern was
      confirmed by a quantitative evaluation of the apoptotic cells using H and E
      staining. Expression of Fas protein was enhanced in the thymus of rats exposed to
      70 mg/kg CPA for 4-8 h as compared to control rats. These results are different
      from previous studies on high dose CPA and the induction of the apoptotic cell
      death in thymus by low or relative low doses of CPA might be a result of Fas/Fas
      ligand interactions.

PMID- 10393268
TI  - Mutagenicity and co-mutagenicity of static magnetic fields detected by bacterial
      mutation assay.
AB  - Possible mutagenic and co-mutagenic effects of strong static magnetic fields were
      estimated using bacterial mutagenicity test. Mutagenic potential of static
      magnetic fields up to 5T (T:1T=10,000 G) was not detected by the bacterial
      mutagenicity test using four strains of Salmonella typhimurium (TA98, TA100,
      TA1535 and TA1537) and Escherichia coli WP2 uvrA either in the pre-incubation
      method or in the plate incorporation method. In the co-mutagenicity test, E. coli
      WP2 uvrA cells were treated with various chemical mutagens and were
      simultaneously exposed to a 2T or a 5T static magnetic field. Mutation rate in
      the exposed group was significantly higher than that in the non-exposed group
      when cells were treated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), N-methyl
      N'-nitro-N-nitrosoguanidine (MNNG), ethylmethanesulfonate (EMS), 4-nitroquinoline
      N-oxide (4-NQO), 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ) or 2-(2-furyl)
      3-(5-nitro-2-furyl) acrylamide (AF-2). The mutagenicity of 2-aminoanthracene (2
      AA), 9-aminoacridine (9-AA), N4-aminocytidine and 2-acetoamidofluorene (2-AAF)
      was not affected by the magnetic field exposure. Possible mechanisms of the co
      mutagenicity of magnetic fields are discussed.

PMID- 10393267
TI  - DNA adduct formation and persistence in liver and extrahepatic tissues of
      northern pike (Esox lucius) following oral exposure to benzo[a]pyrene,
      benzo[k]fluoranthene and 7H-dibenzo[c,g]carbazole.
AB  - The formation and persistence of DNA adducts in liver, intestinal mucosa, gills
      and brain of juvenile northern pike (Esox lucius) following oral exposure to
      benzo[a]pyrene (BaP), benzo[k]fluoranthene (BkF) and 7H-dibenzo[c,g]carbazol
      (DBC) were analysed by 32P-postlabelling. The dosage was 25 micromol/kg body
      weight of each substance, administered on 5 occasions with an interval of 12-14
      days. Sampling was carried out 9 days after the second treatment, and 9, 16, 33
      and 78 days after the fifth treatment. Pikes were also fed with the substances
      singly for comparison of adduct patterns. A complex pattern of adducts was
      detected in all examined tissues from fish treated with the mixture. Total adduct
      levels were highest in intestine (347+/-17.4 nmol adducts/mol nucleotides, mean+/
      SE), followed by liver (110+/-9.3), gills (69+/-6) and brain (14+/-4.2). In pike
      treated with BaP alone, one major adduct was detected in all examined tissues.
      This BaP-adduct made up approximately 50% of the total amount of adducts in the
      brain. Corresponding values in liver, intestine and gills were 23, 31 and 34%,
      respectively. One relatively weak BkF-adduct and at least 10 different DBC
      adducts were detected in all analysed tissues. Total adduct level in the
      intestine declined to 29.4% of the maximum value 78 days after the last exposure,
      while there was no significant decline in adduct levels in liver, gills or brain.
      The results suggest that intestine is more susceptible to adduct formation than
      liver after oral exposure, and that adduct levels in the intestine represent
      ongoing or relatively recent exposure. DNA adducts in the other investigated
      tissues were much more persistent and may therefore accumulate during long-term
      exposure.

PMID- 10393269
TI  - Sister chromatid exchange data fit with a mixture of Poisson distributions.
AB  - Bowman et al. [K.O. Bowman, Wesley Eddings, Marvin A. Kastenbaum, L. R. Shenton.
      Sister chromatid exchange data and Gram-Charlier series, Mutat. Res., 403 (1998)
      159-169.] have shown that a Gram-Charlier modification of a negative binomial
      distribution gives a reasonable fit to counts of sister chromatid exchange (SCE)
      data originally presented by Bender et al. [M.A. Bender, R.J. Preston, R. C.
      Leonard, B.E. Pyatt, P.C. Gooch, On the distribution of spontaneous SCE in human
      peripheral blood lymphocytes, Mutat. Res., 281 (1992) 227-232. ]. Here we show
      that a mixture of a generalized Poisson distributions also fits the data.
      Advantages of the generalized Poisson mixture include a simplified model
      involving only four parameters which fits the data more closely according to the
      chi-squared goodness-of-fit criterion.

PMID- 10393270
TI  - Structure/function studies on the bacterial carbohydrate transporters, enzymes
      II, of the phosphoenolpyruvate-dependent phosphotransferase system.

PMID- 10393271
TI  - Attenuated total reflection infrared spectroscopy of proteins and lipids in
      biological membranes.

PMID- 10393273
TI  - Corrigendum to: 'Microtubule-based membrane movement'.

PMID- 10393272
TI  - Membrane-targeting of signalling molecules by SH2/SH3 domain-containing adaptor
      proteins.
AB  - SH2/SH3 domain-containing adaptor proteins play a critical role in regulating
      tyrosine kinase signalling pathways. The major function of these adaptors, such
      as Grb2, Nck, and Crk, is to recruit proline-rich effector molecules to tyrosine
      phosphorylated kinases or their substrates. In recent years dozens of novel
      proteins have emerged that are capable of associating with the SH2 and the SH3
      domains of adaptors. In this review, the author attempts to summarise these novel
      binding partners of Grb2, Nck, and Crk, and to discuss current controversies
      regarding function and regulation of protein multicomplexes held together by
      SH2/SH3 adaptor molecules at the plasma membrane.

PMID- 10393274
TI  - Distinct responses of a recA::luxCDABE Escherichia coli strain to direct and
      indirect DNA damaging agents.
AB  - The recombinant Escherichia coli strain DPD2794 containing a recA::luxCDABE
      fusion is used to detect genotoxicity of various chemicals. Genotoxic agents were
      previously categorized into two groups, Direct DNA Damaging (DDD) agents and
      Indirect DNA Damaging (IDD) agents; these two groups have been distinguished with
      this strain. Minimum detectable concentrations of the DDD agents were about one
      to five orders of magnitude lower than those of the IDD agents. The response
      patterns of this strain to DDD agents differed from those to IDD agents in terms
      of kinetics and the forms of the dose-dependent response.

PMID- 10393275
TI  - Genotoxicity of microcystic cyanobacteria extract of a water source in China.
AB  - The water pollution of toxic cyanobacteria (blue-green algae) is a worldwide
      problem and worsens with industrialization. Microcystins are potent cyclic
      heptapeptidic hepatotoxins produced mainly by Microcystis aeruginosa, and their
      hepatotoxicity has been well-documented. In contrast, information on the
      genotoxic effects of microcystins is relatively scarce. In our present study, the
      genotoxicity of microcystic cyanobacteria extract (MCE) of a water source in
      China was studied using Salmonella typhimurium assay (Ames test), comet assay
      (Single cell gel electrophoresis) and mouse micronucleus test. Results from Ames
      test indicated that MCE had strong mutagenicity regardless of the presence of S9.
      Moreover, MCE was able to induce DNA damage in primary cultured rat hepatocytes
      examined by comet assay. In addition, MCE also enhanced bone marrow
      micronucleated polychromatic erythrocytes in mice. The analysis of HPLC showed
      that the main component of MCE was microcystin-LR. The understanding of the
      potent genotoxicity of MCE will help to establish the possible link between water
      cyanobacteria contamination and high risk of primary liver cancer found in some
      endemic areas.

PMID- 10393276
TI  - Evaluation of Escherichia coli DJ4309 expressing human P450 1A2 in mutagenicity
      testing of complex food mixtures.
AB  - Heterocyclic aromatic amines (HAAs) are potent bacterial mutagens and potential
      human carcinogens formed in heat processed proteins. The Ames test (strain TA98)
      is a useful mutagenicity test system to screen food products for these compounds.
      HAAs require activation to their genotoxic forms, and in the Ames test, a rat
      liver S-9 preparation is normally used. In order to better understand the
      mechanisms of mutagen activation with respect to human metabolism, new bacterial
      strains containing human cytochrome P450s and other metabolic enzymes have
      recently been developed. We have investigated the capacity of one of these
      strains, DJ4309 [Josephy et al., Chem. Res. Toxicol. 11 (1998) 70-74] as a
      screening tool for mutagens in food products. DJ4309 expresses the human P450
      1A2, human NADPH cytochrome reductase and the bacterial acetyl CoA:arylamine N
      acetyltransferase. This strain is as sensitive as the Ames system to the
      mutagenic effects of the heterocyclic aromatic amines 2-amino-3-methylimidazo[4,5
      f]quinoline, 2-amino-3, 4-dimethylimidazo[4,5-f]quinoline and 2-amino-3,8
      dimethylimidazo[4, 5-f]quinoxaline, but less sensitive to 2-amino-1-methyl-6
      phenylimidazo[4,5-b]pyridine. However, the mutagenicity of the arylamine 2
      aminofluorene is considerably higher in DJ4309 than in the Ames test system. Meat
      extracts with a total HAA content ranging from less than 2 ng/g to 20 ng/g are
      efficiently detected by the Ames TA98 strain with rat liver S-9 activation.
      DJ4309 is less sensitive, with fewer revertants induced over the same dose range.
      Unknown compounds present in the meat extracts appear to inhibit the activity of
      the P450 1A2 enzyme in the DJ4309 strain. We have therefore demonstrated that
      although DJ4309 is a useful tool for mechanistic studies in chemical
      carcinogenesis, the screening of complex food matrices for HAAs by this bacterial
      strain must be conducted with caution.

PMID- 10393277
TI  - The influence of age, sex and smoking habits on the background level of fish
      detected translocations.
AB  - Chromosomal aberrations have been used for biological dosimetry for many years
      but dicentric yield decreases with time after irradiation. Since translocation
      yields should persist in peripheral lymphocytes with time they should prove to be
      a better indicator in the detection of old and chronic exposures to ionising
      radiations. The precondition, however, is knowledge of the control level in
      healthy subjects exposed only to normal background and also knowledge of
      confounding factors. From 42 healthy subjects, aged between 21 and 73 years,
      about 120,000 FISH-painted cells were scored using DNA probes for chromosomes 2,
      4 and 8, and an all-human centromere probe. The statistical analyses revealed no
      influence of gender on the translocation frequency. Smoking habits-even a daily
      consumption of >30 cigarettes-seem to have only a marginal impact on the
      translocation yield, whereas an age-dependence has been established. Because of
      the high background level of translocations and the variation in the frequency
      between subjects, the lowest detectable limit for radiation exposures should be
      between 0.3 and 0.5 Gy, assuming that blood stem cells have a similar radiation
      sensitivity to that of peripheral lymphocytes for the induction of
      translocations.

PMID- 10393278
TI  - Mutagenic substances in pyrolysate obtained by burning polyvinylchloride-product
      at 1000 degrees C.
AB  - In order to detect possible mutagenic substances in pyrolysate obtained by
      burning polyvinyl chloride product (PVC-P) at approximately 1000 degrees C,
      mutagenicity of rough extracts obtained by extraction with various solvents for
      the products was investigated by means of reversion mutation assay using
      Salmonella typhimurium TA98 and TA100 with or without microsomal metabolic
      activation (S9 mix). Strong mutagenicity in TA98 without S9 mix was observed in
      acetone-extract of PVC-P. The extract was fractionated into acidic, neutral and
      basic by liquid-liquid distribution and the mutagenicity in TA98 without S9 mix
      was found in the neutral fraction. Identification of mutagenic substances in the
      neutral fraction from acetone extract, which showed the strongest mutagenicity,
      was attempted by means of thin layer chromatography and capillary gas
      chromatography. The results suggest that mutagenic substances from pyrolysate of
      PVC-P are benzanthrone and an isomer of benzo(c)cinnoline. The results also
      suggest that burning wastes containing plastic products is not always safe even
      if at 1000 degrees C and further research on the problem is necessary.

PMID- 10393279
TI  - Mutagenic activity of 2-phenylbenzotriazole derivatives related to a mutagen,
      PBTA-1, in river water.
AB  - A mutagen, 2-[2-(acetylamino)-4-[bis(2-methoxyethyl)amino]-5-methoxyphenyl]5-ami
      no-7-bromo-4-chloro-2H-benzotriiazole (PBTA-1), isolated from water of the
      Nishitakase River in Kyoto exhibits potent mutagenic activity in Salmonella
      typhimurium TA98 with S9 mix and has characteristic moieties, including bromo,
      chloro, acetylamino, bis(2-methoxyethyl)amino and primary amino groups on a 2
      phenylbenzotriazole skeleton. The mutagenicities of PBTA-1, its congeners and
      five related 2-phenylbenzotriazoles were examined in S. typhimurium TA98 with S9
      mix in order to elucidate the structure-activity relationships. The data obtained
      suggest that a primary amino group plays an essential role in the mutagenic
      activity as do aromatic amines including heterocyclic amines in cooked foods. The
      effect of planarity of the 2-phenylbenzotriazole ring was significant, and in
      addition, halogen groups of PBTA-1 influenced the enhancement of the mutagenic
      activity.

PMID- 10393281
TI  - Alkaline single cell gel electrophoresis and human biomonitoring for
      genotoxicity: a study on subjects with residential exposure to radon.
AB  - Based on theoretical estimates and various correlation studies, it has been
      suggested that ingestion of radon in drinking water represents an increased risk
      for cancer. Such a risk has never been conclusively shown in epidemiological or
      experimental animal studies, however, and it has been questioned whether the
      radon level in the drinking water is of any significance in terms of overall
      radon exposure. Using primary DNA damage as a biological marker for an ongoing
      exposure to ionising radiation, the present study was undertaken to investigate
      whether people with different types of residential radon exposures differed with
      regard to their levels of DNA damage in circulating lymphocytes. DNA damage was
      measured in coded blood samples from 125 residents living in 45 households with
      different levels of radon-222 in the drinking water (10-2410 Bq/l) and indoor air
      (35-1025 Bq/m3) using alkaline single cell gel electrophoresis (the 'Comet'
      assay). Increased levels of radon in indoor air (>200 Bq/m3) were found to be
      associated with an increased level of DNA damage in peripheral lymphocytes
      (P</=0.05). No such correlation was seen for the radon concentrations in the
      drinking water, and there was no obvious relationship between the radon levels in
      drinking water and in indoor air. The results of the present study suggest that
      measures taken to reduce residential radon exposures should be focused on
      reducing radon levels in indoor air rather than minimising radon levels in
      drinking water.

PMID- 10393280
TI  - Development of a new genotoxicity test system with Salmonella typhimurium
      OY1001/1A2 expressing human CYP1A2 and NADPH-P450 reductase.
AB  - In order to develop a new tester strain detecting environmental promutagens and
      procarcinogens, we introduced two plasmids into Salmonella typhimurium TA1535;
      one contains the cDNAs of human cytochrome P450 (P450 or CYP) 1A2 and NADPH-P450
      reductase and the other (pOA101) a umuC"lacZ fusion gene. The newly developed
      tester strain, S. typhimurium OY1001/1A2, was found to express P450 at a level of
      0.15 nmol/ml in whole cell culture. Membrane fractions, when isolated from this
      tester strain, contained 0.04 P450 nmol/mg protein and a reductase activity of
      170 nmol cytochrome c reduced/min/mg protein and were active in catalyzing CYP1A2
      dependent 7-ethoxyresorufin O-deethylation and metabolic activation of
      heterocyclic aromatic amines to DNA-damaging products in a conventional tester S.
      typhimurium NM2009 strain, only when NADPH was added as a reducing equivalent. In
      the OA1002/1A2 strain, heterocyclic aromatic amines (e.g., IQ, MeIQ, and MeIQx)
      were found to be activated to reactive metabolites that cause induction of umuC
      gene expression in a dose-dependent manner, without addition of external NADPH.
      These results indicate that the newly established strain can be of use to detect
      mutagenic and carcinogenic potencies of environmental chemicals without addition
      of metabolic activation system.

PMID- 10393283
TI  - The "shoulders of giants", again.

PMID- 10393282
TI  - The lack of binding of methyl-n-amyl ketone (MAK) to rat liver DNA as
      demonstrated by direct binding measurements, and 32P-postlabeling techniques.
AB  - It has been reported that 14C-labeled methyl-n-amyl ketone (MAK, 2-heptanone) is
      able to bind spontaneously, in vitro, to isolated rat liver DNA to the extent of
      400 pmol/mg DNA; and that 14C-MAK, when given by gavage to female Fischer 344
      rats, resulted in HPLC chromatograms of isolated, hydrolyzed liver DNA in which
      some radiolabel was not associated with the four normal DNA bases dA, dT, dC, and
      dG. The present studies were undertaken to re-examine the hypothesis that MAK is
      able to bind to rat liver DNA. In the in vitro study, liver nuclear DNA was
      incubated with [2-14C]-labeled MAK (25 mCi/mmol) in the absence, or in the
      presence of rat liver microsomes, precipitated, washed free of unbound MAK, and
      counted by scintillation spectrometry. No binding to DNA by MAK was detectable.
      In the in vivo study, groups of five female F344 rats were exposed by inhalation
      to 0, 80, 400, or 1000 ppm MAK for 6 h/day for 10 days. DNA was purified from the
      liver nuclei of the 0 and 1000 ppm dosed animals, and 32P-postlabeling techniques
      were used to assay for adducts. No DNA adducts were detected using these
      techniques. It was concluded that MAK lacks the ability to bind to rat liver DNA
      in vitro and in vivo.

PMID- 10393284
TI  - 1998 revision of the Canadian Asthma Consensus Guidelines. Asthma Consensus
      Conference Editorial Committee.

PMID- 10393285
TI  - Inhaler education for hospital-based pharmacists: how much is required?
AB  - OBJECTIVE: To compare the effectiveness of a more intensive educational
      intervention with a less intensive intervention on the ability of hospital
      pharmacists to be prepared to educate patients regarding inhaled device
      technique. DESIGN: Randomized controlled trial. Inhaler technique and knowledge
      were assessed pre-education, immediately after and three months after education
      by a research assistant blinded to the educational allocation. SETTING: Tertiary
      hospital pharmacy department. POPULATION STUDIED: Hospital-based pharmacists.
      INTERVENTION: A 1 h 'hands-on' session with feedback (more intense education,
      MIE) or written materials describing inhaler use (less intense education, LIE).
      MAIN RESULTS: The change in overall score from pre-education to early
      posteducation for MIE was greater than for LIE (mean [95% CI]) (2.64 [1.27 to
      4.01] versus 1.26 [0.05 to 2.47], P<0.001). Assessment scores improved for all
      device demonstrations and general knowledge. The change in score from the pre
      education to the late posteducation period was only slightly higher in the MIE
      group than the LIE group, a difference that was not statistically significant
      (1.78 [0.82 to 2.74] versus 1. 22 [0.06 to 2.39], P=0.09). Scores in both groups
      were lower in the late posteducation period compared with the early posteducation
      period. Greater increases in total score in the immediate posteducation period
      were associated with a low baseline score and the MIE intervention. CONCLUSION:
      Individual coaching in inhaler technique produces greater improvement in inhaler
      knowledge among hospital pharmacists than provision of written materials.
      However, the advantage of the more intensive intervention was short-lived, with
      little advantage evident in three months.

PMID- 10393286
TI  - Bronchial mucus properties in lung cancer: relationship with site of lesion.
AB  - OBJECTIVE: To compare the biophysical properties of mucus from the left and right
      mainstem bronchi in patients undergoing diagnostic bronchoscopy because of a
      unilateral radiological abnormality. It was hypothesized that abnormalities in
      the properties of mucus would be greater on the side with the lesion and that
      this would be most obvious in patients with unilateral lung cancer. PATIENTS AND
      METHODS: Bilateral paired samples of bronchial mucus were taken from 38 nonatopic
      patients (aged 59.8+/-12.6 years) including 16 nonsmokers, 14 current smokers and
      eight exsmokers (more than one year). Twenty of the 38 patients had a
      radiologically defined unilateral abnormality. Eight of these 20, including one
      nonsmoker, had lung cancer. The viscoelastic properties of the collected mucus
      were determined by magnetic microrheometry, and the analysis was carried out
      without knowledge of the histological diagnosis or source. RESULTS: The
      rheological properties of mucus strongly suggested which was the abnormal side.
      Within the group of 20 patients with a unilateral radiological abnormality, mucus
      from the side of the lesion had a lower value of the loss tangent, tan d100
      (P=0.004), indicating greater mucus recoil. This is consistent with poor mucus
      cough clearability on the lesion side. All eight cancer patients fit this mucus
      rheological pattern with a lower value of tan d100 on the affected side
      (P=0.007). Four of the five other patients with a similar mucus abnormality were
      categorized as high cancer risk by other criteria, while six of seven patients
      with mucus that did not have this abnormality were considered to be lower risk.
      Based on the mucus analysis done at the time of the bronchoscopy, two of the
      'noncancer' patients initially designated as high risk had cancer detected after
      several months of follow- up. Only two of the 18 patients without a defined
      unilateral lesion fit the mucus 'cancer pattern'. CONCLUSIONS: These findings are
      consistent with the hypothesis that either abnormalities in mucus properties may
      represent a risk factor for the development of lung cancer or that bronchial
      mucus abnormalities may be associated with products secreted by the tumours that,
      in turn, may suppress mucus clearance.

PMID- 10393287
TI  - Effect of dead volume on the efficiency and the cost to deliver medications in
      cystic fibrosis with four disposable nebulizers.
AB  - OBJECTIVES: To evaluate the factors that affect nebulizer efficiency and to
      compare the relative cost effectiveness of nebulized medications used in the
      treatment of cystic fibrosis (CF), delivered by four types of disposable jet
      nebulizers that are widely used in hospitals. DESIGN: The Hudson 1730 Updraft II,
      Baxter Misty-Neb, Marquest Whisper Jet (WJ), and Marquest Acorn II were evaluated
      in terms of respirable aerosol output (particles 5 microm or less), nebulizer
      dead (residual) volume (VD), and time for complete nebulization using saline,
      salbutamol and tobramycin at flows of 6 and 8 L/min. The respirable fraction (RF)
      was determined by laser diffraction, and drug output was calculated from the
      initial volume and concentration of the drug in the nebulizer minus the product
      of final drug concentration and the VD following nebulization. COST ANALYSIS: The
      expected pulmonary deposition (DE) was estimated, and incorporated with the
      material and labour costs to determine the cost effectiveness of each type of
      nebulizer. RESULTS: With a DE greater than two times that of the WJ at a cost of
      2.4 times less, the Updraft II proved most efficient and cost effective of all
      the nebulizers evaluated in this study. CONCLUSIONS: The cost effectiveness of
      each nebulizer was determined by its efficiency, which in turn was predominantly
      related to its VD and RF at each flow. The efficiencies of these four devices
      were different and could not have been predicted from specifications provided by
      the respective manufacturers.

PMID- 10393288
TI  - The 1996 and 1997 National survey of physician asthma management practices:
      background and study methodology.
AB  - OBJECTIVES: To collect national baseline information on asthma management
      practices by physicians, and to compare these practices with the recommendations
      of the Canadian Asthma Consensus Conference ('the guidelines'). DESIGN: Cross
      sectional survey of representative samples of physicians in Canada in late 1996
      and early 1997. POPULATION STUDIED: Five specialty types of physicians who manage
      asthma patients: respirology, pediatrics, internal medicine, allergy and clinical
      immunology, and general practice and family medicine. Stratified sampling by
      province and specialty was used to select physicians for the study. Weighting was
      used in the analysis to generalize the results to the national level for the five
      specialty groups of physicians. METHOD: Mailed questionnaire, self-administered
      by the respondent; three mailings of the questionnaires were used to increase the
      response rate. MAIN RESULTS: The frequency with which each of the five specialty
      types chose specific asthma management choices was determined, using weighted
      percentages representative of the specialty groups on a national basis. ANOVA
      determined the statistically significant differences among the five specialties
      in choosing particular asthma management actions. Then, logistic regression was
      used to calculate the odds ratios showing an association between the
      characteristics of the physician respondents and specific asthma management
      choices that they made in the survey. CONCLUSIONS: The data analysis demonstrated
      significant variations among physicians in asthma management practices, according
      to specialty type and other characteristics. The initial report was released in
      April 1998, and manuscripts for journal submissions are being prepared.

PMID- 10393289
TI  - Asthma education, action plans, psychosocial issues and adherence.
AB  - This article deals with four separate but not disparate topics. The first section
      discusses asthma education, reviews the current literature and attempts to
      challenge some of the dogma that is associated with this area. Knowledge alone
      does not guarantee appropriate behaviour, due to a variety of adverse
      socioeconomic and psychological factors that need to be considered for each
      patient. Action plans and peak flow monitoring have both been disappointing in
      terms of reducing asthma morbidity; the former needs to be individualized, and
      the latter may be useful in specific situations. Space precludes an in-depth
      discussion of psychological issues and adherence, but an attempt has been made to
      address salient issues, particularly related to the first two topics.
      Psychological factors, especially anxiety, play an important role in asthma
      outcome. Adherence to medication prescriptions and other management strategies
      need to be taken into account when an individual's treatment program is planned.

PMID- 10393291
TI  - Specific lipid-protein interactions in a novel honeycomb lattice structure of
      bacteriorhodopsin.
AB  - In the purple membrane of Halobacterium salinarium, bacteriorhodopsin trimers are
      arranged in a hexagonal lattice. When purple membrane sheets are incubated at
      high temperature with neutral detergent, membrane vesicularization takes place,
      yielding inside-out vesicles with a diameter of 50 nm. The vesicular structure
      becomes unstable at low temperature, where successive fusion of the vesicles
      yields a crystal which is composed of stacked planar membranes. X-ray
      crystallographic analysis reveals that the bacteriorhodopsin trimers are arranged
      in a honeycomb lattice in each membrane layer and that neighbouring membranes
      orient in opposite directions. The native structure of the trimeric unit is
      preserved in the honeycomb lattice, irrespective of alterations in the in-plane
      orientation of the trimer. One phospholipid tightly bound to a crevice between
      monomers in the trimeric unit is suggested to act as a glue in the formation of
      the trimer.

PMID- 10393290
TI  - New delivery systems and propellants.
AB  - The removal of chlorofluorocarbon (CFC) propellants from industrial and household
      products has been agreed to by over 165 countries of which more than 135 are
      developing countries. The timetable for this process is outlined in the Montreal
      Protocol on Substances that Deplete the Ozone Layer document and in several
      subsequent amendments. Pressured metered dose inhalers (pMDIs) for medical use
      have been granted temporary exemptions until replacement formulations, providing
      the same medication via the same route, and with the same efficacy and safety
      profiles, are approved for human use. Hydrofluoroalkanes (HFAs) are the
      alternative propellants for CFCs-12 and -114. Their potential for damage to the
      ozone layer is nonexistent, and while they are greenhouse gases, their global
      warming potential is a fraction (one-tenth) of that of CFCs. Replacement
      formulations for almost all inhalant respiratory medications have been or are
      being produced and tested; in Canada, it is anticipated that the transition to
      these HFA or CFC-free pMDIs will be complete by the year 2005. Initially, an HFA
      pMDI was to be equivalent to the CFC pMDI being replaced, in terms of aerosol
      properties and effective clinical dose. However, this will not necessarily be the
      situation, particularly for some corticosteroid products. Currently, only one CFC
      free formulation is available in Canada - Airomir, a HFA salbutamol pMDI. This
      paper discusses the in vitro aerosol characteristics, in vivo deposition and
      clinical data for several HFA pMDIs for which there are data available in the
      literature. Alternative delivery systems to the pMDI, namely, dry powder inhalers
      and nebulizers, are briefly reviewed.

PMID- 10393292
TI  - Structure of the histidine-containing phosphotransfer (HPt) domain of the
      anaerobic sensor protein ArcB complexed with the chemotaxis response regulator
      CheY.
AB  - The three-dimensional structure of the HPt domain of ArcB complexed with CheY has
      been determined using the molecular-replacement method. The structure was refined
      to a crystallographic R factor of 18.3% at 2.68 A resolution. The final model
      included 1899 protein atoms (117 residues from the HPt domain and 128 residues
      from CheY), one sulfate ion and 44 solvent molecules. In the crystal, CheY
      molecules stacked along the a axis of the cell with no interactions between
      neighbouring rows and the HPt domain bridged the CheY molecules. The phosphodonor
      residue His715 was fully exposed to the solvent region, even though the HPt
      domain was in contact with four molecules of CheY. CheY showed significant
      conformational change. This indicates that the HPt domain has a rigid structure
      when complexed with CheY.

PMID- 10393293
TI  - Structure of the native (unligated) mannose-specific bulb lectin from Scilla
      campanulata (bluebell) at 1.7 A resolution.
AB  - The X-ray crystal structure of native Scilla campanulata agglutinin, a mannose
      specific lectin from bluebell bulbs and a member of the Liliaceae family, has
      been determined by molecular replacement and refined to an R value of 0.186 at
      1.7 A resolution. The lectin crystallizes in space group P21212 with unit-cell
      parameters a = 70. 42, b = 92.95, c = 46.64 A. The unit cell contains eight
      protein molecules of Mr = 13143 Da (119 amino-acid residues). The asymmetric unit
      comprises two chemically identical molecules, A and B, related by a non
      crystallographic twofold axis perpendicular to c. This dimer further associates
      by crystallographic twofold symmetry to form a tetramer. The fold of the
      polypeptide backbone closely resembles that found in the lectins from Galanthus
      nivalis (snowdrop) and Hippeastrum (amaryllis) and contains a threefold symmetric
      beta-prism made up of three antiparallel four-stranded beta-sheets. Each of the
      four-stranded beta-sheets (I, II and III) possesses a potential saccharide
      binding site containing conserved residues; however, site II has two mutations
      relative to sites I and III which may prevent ligation at this site. Our study
      provides the first accurate and detailed description of a native (unligated)
      structure from this superfamily of mannose-specific bulb lectins and will allow
      comparisons with a number of lectin-saccharide complexes which have already been
      determined or are currently under investigation.

PMID- 10393294
TI  - Haloalkane dehalogenase from Xanthobacter autotrophicus GJ10 refined at 1.15 A
      resolution.
AB  - Crystals of the 35 kDa protein haloalkane dehalogenase from Xanthobacter
      autotrophicus GJ10 diffract to 1.15 A resolution at cryogenic temperature using
      synchrotron radiation. Blocked anisotropic least-squares refinement with SHELXL
      gave a final conventional R factor of 10.51% for all reflections in the 15-1.15 A
      resolution range. The estimated r.m.s. errors of the model are 0.026 and 0.038 A
      for protein atoms and all atoms, respectively. The structure comprises all 310
      amino acids, with 28 side chains and two peptide bonds in multiple conformations,
      two covalently linked Pb atoms, 601 water molecules, seven glycerol molecules,
      one sulfate ion and two chloride ions. Water molecules accounting for alternative
      solvent structure are modelled with a fixed occupancy of 0.5. The structure is
      described in detail and compared with previously reported dehalogenase structures
      refined at 1.9-2.3 A resolution. An analysis of the protein's geometry and
      stereochemistry reveals eight mean values of bond lengths and angles which
      deviate significantly from the Engh & Huber parameters, a wide spread in the main
      chain omega torsion angle around its ideal value of 180 (6) degrees and a role
      for C-HcO interactions in satisfying the hydrogen-bond acceptor capacity of main
      chain carbonyl O atoms in the central beta-sheet.

PMID- 10393295
TI  - Structures of the deoxy and CO forms of haemoglobin from Dasyatis akajei, a
      cartilaginous fish.
AB  - The three-dimensional structures of the deoxy- and carbonmonoxyhaemoglobin (Hb)
      from Dasyatis akajei, a stingray, have been determined at 1.6 and 1.9 A
      resolution, respectively. This is one of the most distantly related vertebrate
      Hbs to human HbA. Both structures resemble the respective forms of HbA,
      indicating that the alpha2beta2-type tetramer and the mode of the quaternary
      structure change are common to Hbs of jawed vertebrates. Larger deviations
      between D. akajei Hb and human HbA are observed in various parts of the molecule,
      even in the E and F helices. Significant mutations and/or conformational changes
      are also observed around the haems, in the C-terminal region of the beta subunit,
      in the alpha1beta2 interface and in the organic phosphate-binding site of HbA.
      Despite these structural differences, the oxygen affinity, haem-haem interaction,
      Bohr effect and organic phosphate effect of D. akajei Hb are all only moderately
      reduced. Compared with human HbA, the overall r.m.s. deviation of main-chain
      atoms in the helical regions of bony fish Hbs is smaller than that of D. akajei
      Hb.

PMID- 10393296
TI  - Meaningful refinement of polyalanine models using rigid-body simulated annealing:
      application to the structure determination of the A31P Rop mutant.
AB  - Conventional refinement methods, when applied to even correctly positioned
      polyalanine models of a target structure, result in a systematic distortion of
      the molecular geometry and to a concomitant increase in the mean phase difference
      from the correct phase set. Here, it is shown that iterative rigid-body simulated
      annealing refinement of polyalanine models employing successively fewer residues
      per rigid body (down to one alanine residue per body) at a very high initial
      temperature (of the order of T0 = 10000 K) and with the geometric energy terms
      switched on, not only preserves the geometry of the model but can also converge
      to an essentially correct polyalanine trace of the target structure, even when
      the starting model deviates systematically and significantly from the sought
      structure. As an example of the application of the method, details are presented
      of the structure determination of the Ala31Pro mutant of the Rop protein, where
      an initial roughly positioned polyalanine model (giving an average phase
      difference of 78.2 degrees from the final phase set) was successfully refined
      against a 1.8 A resolution native data set, leading to an essentially correct
      model of the main chain with an average displacement of its atomic positions from
      the final model of 0.275 A. The phases calculated from this refined polyalanine
      model had an average difference of 43.8 degrees from the final phase set
      (corresponding to a mean figure of merit of 0.72) and gave a readily
      interpretable electron-density map.

PMID- 10393297
TI  - Errors and reproducibility in electron-density map interpretation.
AB  - Three investigators, with varying levels of experience, independently built and
      refined the structure of Escherichia coli ribokinase at 2.6 A resolution. At the
      end of the refinement/rebuilding processes the models had essentially converged,
      although each had its own particular pattern of remaining errors. The subsequent
      refinement of the same structure at 1.8 A resolution allowed an overall quality
      check of each of the lower resolution models, and an analysis of which graphics
      based tools were generally most efficient in locating these errors. Criteria
      which are useful in the application of Ramachandran, main-chain and side-chain
      database and real-space fit analyses are presented.

PMID- 10393298
TI  - Feasibility study for the measurement of a large set of triplet phases from a
      small protein.
AB  - The feasibility of measuring a set of triplet phases large enough to solve the
      structure of a small protein has been evaluated. A total of about 850 triplet
      phases have been measured from the tetragonal form of hen egg-white lysozyme.
      From these triplet phases, about 750 single phases can be derived. The
      experimental details of these measurements as well as the results, the values of
      the measured triplet phases, are reported. Additional experimental data from
      other small proteins are also presented.

PMID- 10393299
TI  - Macromolecular crystal annealing: evaluation of techniques and variables.
AB  - Additional examples of successful application of macromolecular crystal annealing
      are presented. A qualitative evaluation of variables related to the annealing
      process was conducted using a variety of macromolecular crystals to determine in
      which cases parameters may be varied and in which cases the original
      macromolecular crystal annealing protocol is preferred. A hypothesis is presented
      relating the solvent content of the crystal to the specific protocol necessary
      for the successful application of annealing.

PMID- 10393300
TI  - Automated production of small-molecule dictionaries for use in crystallographic
      refinements.
AB  - Many macromolecules are now being studied crystallographically in complexes with
      a range of ligands and other associated molecules. It is necessary to have
      templates describing the expected geometry of such molecules before refinement
      and model building can be carried out. This paper describes a method for
      generating templates beginning from the SMILES description of the molecule, the
      final format of the molecular template being based on the mmCIF definitions for
      chemical composition. Additionally, the program SMILE2DICT, which converts the
      SMILES string to a more extended format, is described. The description details
      the input required, the output produced and how the program relates to attempts
      to automate the procedure of model building for crystallographic refinement.
      Examples of input to and output from the program are given.

PMID- 10393301
TI  - Crystallization and preliminary diffraction studies of a recombinant major
      urinary protein.
AB  - A monoclinic crystal form of a recombinant major urinary protein, (MUP) from
      mouse, has been obtained. MUP is a member of the lipocalin family whose
      biological function relates to olfaction and sexual communication. Crystals were
      grown by the vapour-diffusion technique against a mother liquor containing CdCl2.
      Crystals belong to the monoclinic space group P21 with the cell parameters a =
      37.14, b = 55.79, c = 37.67 A, and beta = 93.24 degrees. The crystals diffract to
      beyond 1.4 A resolution at a synchrotron beamline.

PMID- 10393302
TI  - Crystallization and preliminary crystallographic analysis of the snake muscle
      fructose 1,6-bisphosphatase.
AB  - The snake muscle fructose 1,6-bisphosphatase, a typical allosteric enzyme which
      plays important roles in gluconeogenesis, was crystallized in the presence of
      polyethylene glycol 3350 and magnesium chloride at pH 8.5. The crystals diffract
      to 2.3 A on a rotating-anode X-ray source. The space group was determined to be
      either P3121 or its enantiomorph P3221, with unit-cell parameters a = b = 83.7, c
      = 202.41 A, alpha = beta = 90 and gamma = 120 degrees. There are two subunits in
      the asymmetric unit. Preliminary molecular-replacement studies indicate that the
      first enantiomorph is the correct one.

PMID- 10393304
TI  - Crystallization and preliminary X-ray diffraction studies of the carboxylesterase
      EST2 from Alicyclobacillus acidocaldarius.
AB  - EST2, a thermophilic carboxylesterase from Alicyclobacillus acidocaldarius,
      belonging to the HSL group of the esterase/lipase superfamily, has been
      crystallized for the first time. Ammonium sulfate was used as a precipitant and
      the crystallization proceeded at pH 7.8. The crystals belong to space group
      P41212 or its enantiomorph P43212, with unit-cell parameters a = b = 78.8, c =
      106. 4 A. A complete data set has been collected at the synchrotron source
      Elettra in Trieste to 2.4 A resolution, using a single frozen crystal.

PMID- 10393303
TI  - Crystallization and preliminary X-ray analysis of wild-type and V103L mutant Myb
      R2 DNA-binding domain.
AB  - The R2 subdomain of the mouse c-Myb DNA-binding domain and its V103L mutant have
      been crystallized by the vapour-diffusion method using highly concentrated sodium
      citrate at pH 6.8 as a precipitant. Using ammonium sulfate as precipitant in MES
      buffer only produced crystals for the mutant R2. All crystals are isomorphous and
      belong to space group P212121. The unit-cell dimensions for wild-type R2 crystals
      grown from sodium citrate precipitant are a = 28.83, b = 40.18, c = 49.23 A.
      Crystals contain one R2 molecule per asymmetric unit. They are stable during 3 d
      exposure to X-rays and diffract to 1.37-1.45 A resolution.

PMID- 10393305
TI  - N-Acetyl-L-glutamate kinase from Escherichia coli: cloning of the gene,
      purification and crystallization of the recombinant enzyme and preliminary X-ray
      analysis of the free and ligand-bound forms.
AB  - The gene for Escherichia coli N-acetyl-L-glutamate kinase (NAGK) was cloned in a
      plasmid and expressed in E. coli, allowing enzyme purification in three steps.
      NAGK exhibits high specific activity (1.1 micromol s-1 mg-1), lacks Met1 and
      forms dimers (shown by cross-linking). Crystals of unliganded NAGK diffract to 2
      A and belong to space group P6122 or its enantiomorph P6522 (unit-cell parameters
      a = b = 78.6, c = 278.0 A) with two monomers in the asymmetric unit. Crystals of
      NAGK with acetylglutamate and the ATP analogue AMPPNP diffract to 1.8 A and
      belong to space group C2221 (unit-cell parameters a = 60.0, b = 71.9, c = 107.4
      A), with one monomer in the asymmetric unit. NAGK crystallization will allow the
      determination of proposed structural similarities to carbamate kinase.

PMID- 10393306
TI  - Crystallization and preliminary X-ray diffraction studies of D-glyceraldehyde-3
      phosphate dehydrogenase from the hyperthermophilic archaeon Methanothermus
      fervidus.
AB  - The homotetrameric holo-D-glyceraldehyde-3-phosphate dehydrogenase from the
      hyperthermophilic archaeon Methanothermus fervidus has been crystallized in the
      presence of NADP+ using the hanging-drop vapour-diffusion method. Crystals grew
      from a solution containing 2-methyl-2,4-pentanediol and magnesium acetate. A
      native data set has been collected to 2.1 A using synchrotron radiation and
      cryocooling. Diffraction data have been processed in the orthorhombic system
      (space group P21212) with unit-cell dimensions a = 136.7, b = 153.3, c = 74.9 A
      and one tetramer per asymmetric unit.

PMID- 10393307
TI  - Crystallization and preliminary X-ray diffraction study of the endo
      polygalacturonase from Fusarium moniliforme.
AB  - Endo-polygalacturonases catalyze the fragmentation and solubilization of the
      homogalacturonan of the plant cell wall. These enzymes are extracellularly
      targeted glycoproteins produced by a number of organisms such as fungi, bacteria
      and plants, and are involved in both pathological and physiological processes.
      Single crystals of the endo-polygalacturonase from the phytopathogenic fungus
      Fusarium moniliforme were obtained by the vapour-diffusion method at 294 K. The
      starting material as well as the crystal consist of three forms with different
      degrees of glycosylation. The crystals belong to the orthorhombic space group
      P212121 and diffract to 1.9 A resolution on a synchrotron-radiation source under
      cryocooling conditions.

PMID- 10393308
TI  - Crystallization and preliminary studies of the DNA-binding domain Za from ADAR1
      complexed to left-handed DNA.
AB  - The proteolytically defined Z-DNA binding domain Za of human adenosine deaminase
      type 1 (hADAR1) has been crystallized in complex with the DNA oligomer
      d(TCGCGCG). The crystals were obtained from a solution containing ammonium
      sulfate as precipitating agent and belong to the tetragonal space group P4212. A
      complete diffraction data set has been collected to a resolution of 2.4 A. The
      unit-cell dimensions are a = b = 85.9, c = 71.3 A. A Raman spectrum of the
      complex indicates that the DNA in the complex adopts the left-handed Z
      conformation.

PMID- 10393309
TI  - Rhombohedral crystals of 2-dehydro-3-deoxygalactarate aldolase from Escherichia
      coli.
AB  - 2-Dehydro-3-deoxygalactarate (DDG) aldolase (E.C. 4.1.2.20) catalyzes the
      reversible aldol cleavage of DDG and 2-dehydro-3-deoxyglucarate to pyruvate and
      tartronic semialdehyde. Rhombohedral crystals of recombinant DDG aldolase from
      Escherichia coli K-12 were obtained. The crystals belong to space group R32 with
      unit-cell parameters a = 93 A, alpha = 85 degrees. The crystals diffract to
      beyond 1.8 A resolution on a Cu Kalpha rotating-anode generator. The asymmetric
      unit is likely to contain two molecules, corresponding to a packing density of
      1.34 A3 Da-1.

PMID- 10393310
TI  - Crystallization, characterization and measurement of MAD data on crystals of
      dengue virus NS3 serine protease complexed with mung-bean Bowman-Birk inhibitor.
AB  - Crystallization and preliminary characterization of the essential dengue virus
      NS3 serine protease complexed with a Bowman-Birk-type inhibitor from mung beans
      are reported. As the structure proved resistant to solution by molecular
      replacement and multiple isomorphous replacement methods, multi-wavelength
      anomalous diffraction data at the LIII edge of a holmium derivative have been
      measured. Promising Bijvoet and dispersive signals which are largely consistent
      with expected values have been extracted from the data. The structure, when
      determined, will provide a structural basis for the design, synthesis and
      evaluation of inhibitors of the protease for chemotherapy of dengue infections.

PMID- 10393311
TI  - Crystallization and preliminary diffraction studies of the RNA polymerase subunit
      RPB5 from Saccharomyces cerevisiae.
AB  - Crystals of the RNA polymerase subunit RPB5 from Saccharomyces cerevisiae have
      been obtained by vapour-diffusion techniques. The protein has been overexpressed
      in bacterial cells as a fusion with glutathione S-transferase. Two monoclinic
      crystal forms can be grown under different sets of conditions. In both cases, the
      diffraction is consistent with space group P21, with unit-cell parameters a = 45.
      3, b = 135.3, c = 47.3 A, beta = 118.6 degrees for crystal form I and a = 48.4, b
      = 137.1, c = 47.1 A, beta = 118.6 degrees for crystal form II.

PMID- 10393312
TI  - Crystallization and preliminary X-ray studies on the molbindin ModG from
      Azotobacter vinelandii.
AB  - Crystals of the molbindin ModG (subunit Mr = 14359 Da), a cytoplasmic molybdate
      binding protein from Azotobacter vinelandii, were grown by vapour diffusion. Both
      apo and tungstate-bound forms were crystallized and X-ray data were collected at
      100 K. Apo-ModG crystallizes in space group P6322, with unit-cell dimensions a =
      b = 90.62, c = 79.46 A. Native data to a resolution of 2.5 A were collected from
      a single crystal, which showed a marked improvement in diffraction quality after
      annealing. Data from a single-site gold derivative were also collected at 2.7 A
      resolution. Crystals of the ligand-bound form of ModG belong to space group P321,
      with unit-cell parameters a = b = 50.57, c = 79.29 A. X-ray data to a resolution
      of 2.0 A were collected.

PMID- 10393314
TI  - Crystallization and preliminary X-ray diffraction studies of a 40 kDa calcium
      binding protein specifically expressed in plasmodia of Physarum polycephalum.
AB  - A calcium binding protein with a molecular mass of 40 kDa (CBP40), the gene
      product of plasmodial-specific LAV1-2 of Physarum polycephalum, was crystallized
      in the presence of EDTA. The crystals diffracted X-rays up to a resolution of 3.0
      A. They belonged to the trigonal space group, P3221 (or P3121), with unit cell
      dimensions of a = b = 64.4 A and c = 207.2 A. Ca2+-bound crystals were obtained
      by soaking in a CaCl2 solution, which gave diffraction data of similar quality.
      The Ca2+-soaked crystals belonged to the same space group as those crystallized
      in the presence of EDTA with unit cell dimensions of a = b = 64.4 A and c = 209.4
      A.

PMID- 10393313
TI  - Carboxypeptidase Y: structural basis for protein sorting and catalytic triad.
AB  - A yeast vacuolar protease, carboxypeptidase Y (CPY), is known to be involved in
      the C-terminal processing of peptides and proteins; however, its real function
      remains unclear. The CPY biosynthetic pathway has been used as a model system for
      protein sorting in eukaryotes. CPY is synthesized as a prepro-form that travels
      through the ER and Golgi to its final destination in vacuoles. In the course of
      studies on the transport mechanism of CPY, various post-translational events have
      been identified, e.g. carbohydrate modification and cleavage of the pre-segments.
      In addition, sorting signals and various sorting vehicles, similar to those found
      in higher eukaryotic cells, have been found. The catalytic triad in the active
      site of CPY makes this enzyme a serine protease. A unique feature distinguishing
      CPY from other serine proteases is its wide pH optimum, in particular its high
      activity at acidic pH. Several structural properties which might contribute to
      this unique feature exist such as a conserved free cysteine residue in the S1
      substrate binding pocket, a recognition site for a C-terminal carboxyl group, and
      a disulfide zipper motif. The structural bases in CPY functions are discussed in
      this article.

PMID- 10393315
TI  - Hyperproduction of recombinant ferredoxins in escherichia coli by coexpression of
      the ORF1-ORF2-iscS-iscU-iscA-hscB-hs cA-fdx-ORF3 gene cluster.
AB  - Fe-S proteins acquire Fe-S clusters by an unknown post-translational mechanism.
      To study the in vivo synthesis of the Fe-S clusters, we constructed an
      experimental system to monitor the expressed ferredoxin (Fd) as a reporter of
      protein-bound Fe-S clusters assembled in Escherichia coli. Overexpression of five
      Fds in a T7 polymerase-based system led to the formation of soluble apoFds and
      mature holoFds, indicating that assembly of the Fe-S cluster into apoFd
      polypeptides is a rate-limiting step. We examined the coexpression of the E. coli
      ORF1-ORF2-iscS-iscU-iscA-hscB-hsc A-fdx-ORF3 gene cluster, which has recently
      been suggested to be involved in the formation or repair of Fe-S protein [Zheng,
      L., Cash, V.L., Flint, D.H., and Dean, D.R. (1998) J. Biol. Chem. 273, 13264
      13272], with reporter Fds using compatible plasmids. The production of all five
      reporter holoFds examined was dramatically increased by the coexpression of the
      gene cluster, and apparent specificity to the polypeptides or to the type of Fe-S
      clusters was not observed. The increase in holoFd production was observed under
      the coexpression conditions in all culture media examined, with either 2 x YT
      medium or Terrific broth, and with or without supplemental cysteine or iron.
      These results indicate that the proteins encoded by the gene cluster are involved
      in the assembly of the Fe-S clusters in a wide variety of Fe-S proteins.

PMID- 10393316
TI  - Structure, evolution, and liver-specific expression of sterol 12alpha-hydroxylase
      P450 (CYP8B).
AB  - The rat CYP8B cDNA encoding sterol 12alpha-hydroxylase was cloned and sequenced.
      The amino acid sequence of the heme-binding region of CYP8B was close to those of
      CYP7A (cholesterol 7alpha-hydroxylase) and CYP7B (oxysterol 7alpha-hydroxylase).
      Molecular phylogenetic analysis suggests that CYP8B and the CYP7 family derive
      from a common ancestor. The P450s of the CYP7 and CYP8 families, except for CYP8A
      (prostacyclin synthase), catalyze the oxygenation of sterols from an alpha
      surface in the middle of the steroid skeleton. These facts suggest that CYP8B is
      a P450 closely linked to those of the CYP7 family. CYP8B was expressed
      specifically in liver. Hepatic CYP8B mRNA level and the 12alpha-hydroxylase
      activity were altered by cholestyramine feeding, starvation, streptozotocin
      induced diabetes mellitus, and administration of clofibrate, dexamethasone or
      thyroxin, indicating the pretranslational regulation of CYP8B expression. The
      enhanced CYP8B mRNA expression in streptozotocin-induced diabetic rats was
      significantly decreased by insulin within 3 h of its administration. These facts
      demonstrate a regulatory role of insulin in CYP8B expression as a suppressor.

PMID- 10393317
TI  - Amino acid sequence and some properties of phytolacain R, a cysteine protease
      from full-growth fruits of pokeweed, Phytolacca americana.
AB  - A cysteine protease, phytolacain R from full-growth greenish fruits of pokeweed,
      Phytolacca americana L, was purified to electrophoretic homogeneity by a simple
      purification procedure employing CM-Sepharose ion-exchange chromatography. The
      enzyme was present in low content in the young fruits about 50 d after flowering
      but gradually accumulated in growing fruits. Its molecular mass was estimated to
      be ca. 23 kDa by SDS-PAGE, and its sugar content was zero. Its amino acid
      sequence was established by automated sequence analysis of the peptides obtained
      by cleavage with Achromobacter protease I, chymotrypsin, trypsin, and cyanogen
      bromide. The enzyme is composed of 218 amino acid residues, of which it shares
      110 residues (50%) with papain, 104 (47%) with actinidain, and 87 (40%) with stem
      bromelain. The amino acid residues forming the substrate-binding the S2 pocket of
      papain, Tyr61, Tyr67, Pro68, Trp69, Val133, and Phe207, were predicted to be
      replaced by Gly, Trp, Met, His, Ala, and Met in phytolacain R, respectively. As a
      consequence of these substitutions, the S2 pocket is expected to be less
      hydrophobic in phytolacain R than in papain.

PMID- 10393318
TI  - Conformations of vertebrate striated muscle myosin monomers in equilibrium with
      filaments.
AB  - Porcine cardiac myosin monomers in equilibrium with filaments under physiological
      conditions were observed to have two conformations, extended and folded forms,
      upon electron microscopy and gel filtration HPLC. The conformational state was
      independent of ATP and the phosphorylation of regulatory light chain. The folded
      monomers of cardiac myosin were mainly in an open conformation with only one bend
      in the tail, and may not trap the hydrolysis products of ATP, as assessed by
      single turnover experiments. These properties are similar to those of the folded
      monomers of rabbit skeletal myosin [Katoh, T., Konishi, K., and Yazawa, M. (1998)
      J. Biol. Chem. 273, 11436-11439]. The conformational states of skeletal and
      cardiac myosin monomers were not affected by pH between 7.0 and 8.5. Although
      significant disassembly of filaments and thus an increase in the monomer
      concentration were observed with an increase in pH. The results indicate that the
      pH-dependent change in filament assembly is due to a shift of equilibrium between
      the filaments and extended monomers toward filament disassembly. The Mg2+-ATPase
      activity of these myosin monomers decreased with a decrease in the salt
      concentration below approximately 0.1 M, suggestive of the formation of a closed
      conformation similar to the conformation of 10S smooth myosin. The results
      suggest that the conformational change from the extended to the folded form is a
      common property of various myosin IIs.

PMID- 10393319
TI  - Overexpression of the aldose reductase gene induces apoptosis in pancreatic beta
      cells by causing a redox imbalance.
AB  - To determine the role of the polyol metabolizing pathway under hyperglycemic
      conditions, the effects of aldose reductase (AR) on the cellular functions of
      pancreatic beta-cells were examined. Stable transfectants of rat AR cDNA were
      obtained with a pancreatic beta-cell line, HIT, in which a negligible amount of
      AR was originally expressed. Overproduction of AR triggered DNA fragmentation, as
      judged with the TUNEL method and agarose gel electrophoresis. Morphological
      analysis by electron microscopy also clearly showed apoptosis of the AR
      overexpressing HIT cells. Induction by interleukin-1beta of gene expression such
      as those of an inducible form of nitric oxide synthase (NOS-II) and Mn-superoxide
      dismutase (Mn-SOD), was much lower in the transfectants than in the control
      cells, while the expression of constitutively expressed genes such as those for
      Cu,Zn-superoxide dismutase and insulin was not changed. The susceptibility to
      interleukin-1beta stimulation of the expression of the NOS II and Mn-SOD genes
      was due to suppressed NF-kappaB activity, which is essential for the expression
      of these genes. In addition, the intracellular NADPH/NADP+ ratio was considerably
      lower in the AR-transfected cells than in control cells. Thus, the overexpression
      of AR in pancreatic beta-cells induced apoptosis that may be caused by a redox
      imbalance.

PMID- 10393321
TI  - Interaction of collagen molecules from the aspect of fibril formation: acid
      soluble, alkali-treated, and MMP1-digested fragments of type I collagen.
AB  - Collagen type I extracted with acid or digested with pepsin forms fibrils under
      physiological conditions, but this ability is lost when the collagen is treated
      with alkaline solution or digested with matrix metalloproteinase 1 (MMP1). When
      acid-soluble collagen was incubated with alkali-treated collagen, the fibril
      formation of acid-soluble collagen was inhibited. At 37 degrees C, at which
      alkali-treated collagen is denatured, the lag time was prolonged but the growth
      rate of fibrils was not affected. At 30 degrees C, at which the triple helical
      conformation of alkali-treated collagen is retained, the lag time was prolonged
      and the growth rate reduced. Heat-denatured alkali-treated collagen and MMP1
      digested fragments have no inhibitory effect on the fibril formation of acid
      soluble collagen. This means that the triple helical conformation and the
      molecular length are important factors in the interaction of collagen molecules
      and that alkali-treated collagen acts as a competitive inhibitor for fibril
      formation of collagen. We found that alkali-treated collagen and MMP1-digested
      fragments form fibrils that lack the D periodic banding pattern and twisted
      morphology under acidic conditions at the appropriate ionic strength. We also
      calculated the relative strengths of hydrophobic and electrostatic interactions
      between collagen molecules. When the hydrophobic interaction between linear
      collagen molecules was considered, we found a pattern of periodic maximization of
      the interactive force including the D period. On the other hand, the
      electrostatic interaction did not show the periodic pattern, but the overall
      interaction score affected fibril formation.

PMID- 10393320
TI  - Multi-ubiquitination of a nascent membrane protein produced in a rabbit
      reticulocyte lysate.
AB  - During a large-scale in vitro translation analysis of a human full-length cDNA
      bank, we found many clones producing in vitro translation products showing ladder
      bands on a fluorogram with the equidistance of about 9 kDa at the position larger
      than the molecular mass expected from the open reading frame. We have analyzed a
      clone showing a typical pattern of the ladder bands. This clone encoded a 188
      amino acid polypeptide containing a putative transmembrane domain. A green
      fluorescent protein-tagged polypeptide expressed in COS7 cells was localized in
      the endoplasmic reticulum and the Golgi apparatus. The ladder bands were observed
      in a rabbit reticulocyte lysate system, but not in a wheat germ extract system.
      Addition of the glutathione S-transferase-fused ubiquitin into the lysate caused
      upward shifts of the ladder bands. Addition of microsomal membranes prevented the
      formation of the ladder bands. Time course experiments demonstrated that the in
      vitro translation products increased in the presence of microsomal membranes, but
      were gradually degraded in their absence. These results suggest that the ladder
      formation resulted from the ubiquitination of misfolded polypeptide that failed
      to translocate to its proper position, and that an exclusion mechanism of
      misfolded membrane protein works in the rabbit reticulocyte lysate system.

PMID- 10393322
TI  - Molecular cloning and functional expression of the human Golgi UDP-N
      acetylglucosamine transporter.
AB  - We have cloned the human UDP-N-acetylglucosamine (UDP-GlcNAc) transporter cDNA,
      which was recognized through a homology search in the expressed sequence tags
      database (dbEST) based on its similarity to the human UDP-galactose transporter.
      The chromosomal location of the UDP-GlcNAc transporter gene was assigned to
      chromosome 1p21 by fluorescence in situ hybridization (FISH). The transporter was
      expressed ubiquitously in every tissue so far examined. Expression of the
      transporter cDNA in CHO-K1 cells in its native and in a C-terminally HA-tagged
      form indicated that the human UDP-GlcNAc transporter was localized in the Golgi
      apparatus. The membrane vesicles prepared from yeast cells expressing the cDNA
      product exhibited UDP-GlcNAc-specific transporting activity. Comparison among UDP
      galactose, CMP-sialic acid, and UDP-GlcNAc transporters from several organisms
      enabled us to identify residues highly conserved among the transporters and
      residues specific for each group of transporters.

PMID- 10393323
TI  - Function of the propeptide region in recombinant expression of active
      procathepsin L in Escherichia coli.
AB  - In order to determine the functional role of the procathepsin L propeptide region
      for the preparation of active recombinant rat cathepsin L (CL), cDNAs encoding
      two short-length propeptides (C-terminal 2 and 27 residues) and the full-length
      (96 residues) one plus the entire CL were expressed as two soluble fusion
      proteins with a fragment of maltose-binding protein and an insoluble fusion
      protein with glutathione-S-transferase in Escherichia coli, respectively. After
      refolding of the insoluble fusion protein, each gene product was purified to
      homogeneity by amylose or glutathione-Sepharose-4B affinity column, and digestion
      with factor Xa and alpha-thrombin under alkaline conditions (pH approximately
      8.0) led to the elution of two pure short-length procathepsin Ls (PCLs) and a
      full-length one, respectively. The enzymatic activity, estimated by hydrolytic
      assaying of benzoxycarbonyl-Phe-Arg-7-(4-methyl)coumarylamide under acidic
      conditions (pH 5.5), indicated that the two short-length PCLs exhibited in a
      great loss of the activity, as compared with the full-length PCL. The CD spectra
      of the short-length PCLs were different from that of the full-length one. The
      present results clearly show that the full-length propeptide is essential for
      construction of the active tertiary structure of CL at the stage of recombinant
      protein expression, although the expression of CL itself in E. coli does not
      require the propeptide. Based on the tertiary structure of PCL, the propeptide
      region necessary for the construction of the CL active structure has been
      discussed.

PMID- 10393324
TI  - Sphingosine 1-phosphate formation and intracellular Ca2+ mobilization in human
      platelets: evaluation with sphingosine kinase inhibitors.
AB  - Sphingosine 1-phosphate (Sph-1-P) is considered to play a dual role in cellular
      signaling, acting intercellularly as well as intracellularly. In this study, we
      examined the role of Sph-1-P as a signaling molecule in human platelets, using DL
      threo-dihydrosphingosine (DHS) and N,N-dimethylsphingosine (DMS), inhibitors of
      Sph kinase and protein kinase C. Both DMS and DL-threo-DHS were confirmed to be
      competitive inhibitors of Sph kinase obtained from platelet cytoplasmic
      fractions. In intact platelets labeled with [3H]Sph, stimulation with 12-O
      tetradecanoylphorbol 13-acetate or thrombin did not affect [3H]-Sph-1-P
      formation. While both DMS and DL-threo-DHS inhibited not only [3H]Sph-1-P
      formation but also protein kinase C-dependent platelet aggregation,
      staurosporine, a potent protein kinase inhibitor, only inhibited the protein
      kinase C-dependent reaction. Hence, it is unlikely that Sph kinase activation and
      the resultant Sph-1-P formation are mediated by protein kinase C in platelets.
      Furthermore, Ca2+ mobilization induced by platelet agonists that act on G protein
      coupled receptor was not affected by DMS or DL-threo-DHS. Our results suggest
      that Sph-1-P does not mediate intracellular signaling, including Ca2+
      mobilization, in platelets.

PMID- 10393325
TI  - Roles of asp126 and asp156 in the enzyme function of sphingomyelinase from
      Bacillus cereus.
AB  - To elucidate the roles of conserved Asp residues of Bacillus cereus
      sphingomyelinase (SMase) in the kinetic and binding properties of the enzyme
      toward various substrates and Mg2+, the kinetic data on mutant SMases (D126G and
      D156G) were compared with those of wild type (WT) enzyme. The stereoselectivity
      of the enzyme in the hydrolysis of monodispersed short-chain sphingomyelin (SM)
      analogs and the binding of Mg2+ to the enzyme were not affected by the
      replacement of Asp126 or Asp156. The pH-dependence curves of kinetic parameters
      (1/Km and kcat) for D156G-catalyzed hydrolysis of micellar SM mixed with Triton X
      100 (1:10) and of micellar 2-hexadecanoylamino-4-nitrophenylphosphocholine (HNP)
      were similar in shape to those for WT enzyme-catalyzed hydrolysis. On the other
      hand, the curves for D126G lacked the transition observed for D156G and WT
      enzymes. Comparison of the values and the shape of pH-dependence curves of
      kinetic parameters indicated that Asp126 of WT SMase enhances the enzyme's
      catalytic activity toward both substrates and its binding of HNP but not SM. The
      deprotonation of Asp126 enhances the substrate binding and slightly suppresses
      the catalytic activity toward both substrates. Asp156 of WT SMase acts to
      decrease the binding of both substrates and the catalytic activity to HNP but not
      SM. From the present study and the predicted three-dimensional structure of B.
      cereus SMase, Asp126 was thought to be located close to the active site, and its
      ionization was shown to affect the catalytic activity and substrate binding.

PMID- 10393326
TI  - Fluoride-binding to the Escherichia coli bd-type ubiquinol oxidase studied by
      visible absorption and EPR spectroscopies.
AB  - Cytochrome bd-type ubiquinol oxidase in the aerobic respiratory chain of
      Escherichia coli contains two hemes b (b558 and b595) and one heme d as redox
      metal centers. To clarify the structure of the reaction center, we analyzed the
      fully oxidized enzyme by visible and EPR spectroscopies using fluoride ion as a
      monitoring probe. The visible spectral changes upon fluoride-binding were typical
      of ferric iron-chlorine species, indicating heme d as a primary binding site. The
      negative peak at 645 nm in the difference spectrum indicates that heme b595 also
      provides the low-affinity fluoride-binding site. Fluoride-binding caused a
      complete disappearance from the EPR spectra of the low-spin signals ascribable to
      heme d and spectral changes in both rhombic and axial high-spin signals. After
      fluoride-binding, each component of the rhombic high-spin signal showed
      superhyperfine splitting arising from the interaction of the unpaired spin of the
      heme d iron with the nuclear magnetic moment of 19F. The axial high-spin species
      was converted to a new rhombic high-spin species assignable to heme b595
      fluoride. The g = 2 component of this new species also gave 19F-superhyperfine
      splitting. These results indicate that both heme d and heme b595 can coordinate
      with a fluoride ion with different affinities in the fully oxidized state.

PMID- 10393327
TI  - Genomic structure and expression of the medaka fish homolog of the mammalian
      guanylyl cyclase B.
AB  - We have isolated a 3.9-kbp-long cDNA and approximately 93 kbp long genomic DNA
      encoding a membrane guanylyl cyclase (designated OlGC1) from the medaka fish
      Oryzias latipes, and determined their nucleotide sequences. The open reading
      frame for the OlGC1 cDNA predicts a protein of 1,055 amino acids. Phylogenetic
      analysis indicates OlGC1 to be a medaka fish homolog of mammalian guanylyl
      cyclase B (GC-B), a member of the natriuretic peptide receptor family. Northern
      blot analysis demonstrated 3.9 kb OlGC1 transcripts in the eye and brain, while
      reverse transcription-polymerase chain reaction (RT-PCR) analysis showed OlGC1
      transcripts in a number of adult peripheral organs as well as embryos during
      early stages of development. The OlGC1 gene consists of 22 exons with an
      exon/intron organization similar to that of the human and rat GC-A genes, except
      that OlGC1 has several very large introns. The OlGC1 gene has no apparent TATA
      box or CAAT box in the region 1.2 kbp upstream of the putative transcription
      initiation point, but several consensus sequences for cis-regulatory elements,
      including an NF-IL6-binding element, a shear stress responsive element, and
      multiple GM-CSF-binding elements, are present in that region.

PMID- 10393329
TI  - Roles of troponin isoforms in pH dependence of contraction in rabbit fast and
      slow skeletal and cardiac muscles.
AB  - Skinned fibers prepared from rabbit fast and slow skeletal and cardiac muscles
      showed acidotic depression of the Ca2+ sensitivity of force generation, in which
      the magnitude depends on muscle type in the order of cardiac>fast skeletal>slow
      skeletal. Using a method that displaces whole troponin-complex in myofibrils with
      excess troponin T, the roles of Tn subunits in the differential pH dependence of
      the Ca2+ sensitivity of striated muscle were investigated by exchanging
      endogenous troponin I and troponin C in rabbit skinned cardiac muscle fibres with
      all possible combinations of the corresponding isoforms expressed in rabbit fast
      and slow skeletal and cardiac muscles. In fibers exchanged with fast skeletal or
      cardiac troponin I, cardiac troponin C confers a higher sensitivity to acidic pH
      on the Ca2+ sensitive force generation than fast skeletal troponin C
      independently of the isoform of troponin I present. On the other hand, fibres
      exchanged with slow skeletal troponin I exhibit the highest resistance to acidic
      pH in combination with either isoform of troponin C. These results indicate that
      troponin C is a determinant of the differential pH sensitivity of fast skeletal
      and cardiac muscles, while troponin I is a determinant of the pH sensitivity of
      slow skeletal muscle.

PMID- 10393328
TI  - Formation of the aldehydic choline glycerophospholipids in human red blood cell
      membrane peroxidized with an azo initiator.
AB  - The production of phospholipid hydroperoxide and aldehydic phospholipid was
      examined in human red blood cell (RBC) membranes after peroxidation with 2,2
      azobis(2-amidinopropane)dihydrochloride (AAPH) or xanthine/xanthine oxidase
      (XO/XOD/Fe3+). Both radical-generation systems caused a profound decrease in the
      amount of polyunsaturated fatty acid (PUFA) in choline glycerophospholipid (CGP)
      and induced formation of peroxidized CGP in RBC membranes to different extents.
      No consistent generation of peroxidized lipids from CGP was evident after
      peroxidation with XO/XOD/Fe3+, which caused the apparent decomposition of
      phospholipids and the formation of large amounts of thiobarbituric acid-reactive
      substance (TBARS). On the other hand, CGP hydroperoxide was formed as a primary
      product of peroxidation with AAPH. Aldehydic CGP was also detected as a secondary
      product of hydroperoxide decomposition in AAPH-peroxidized RBC membranes.
      Aldehydic CGP was preferentially generated from arachidonoyl CGP rather than from
      linoleoyl CGP in AAPH-peroxidized membranes. AAPH mainly oxidized CGP to
      hydroperoxide and aldehydic phospholipids. The sum of hydroperoxide and aldehyde
      of CGP corresponded to the loss of CGP due to peroxidation by AAPH. This result
      indicates that CGP was mainly converted into these two oxidized phospholipids in
      AAPH-peroxidized RBC membranes.

PMID- 10393330
TI  - AP-2 enhances Sp1-dependent activation of the growth-regulated human ATP/ADP
      translocator.
AB  - The mammalian ATP/ADP translocator isoform-2 (ANT2) gene is growth-activated.
      Regulation of the gene appears to involve Sp1, as an essential activator, and a
      suppressor through an Sp1 core element next to the transcription start. We show
      here that the proximal promoter also binds AP-2 strongly and specifically to two
      sites, one of which overlaps the Sp1 proximal suppressor site. AP-2 binds with an
      affinity of 10 to15 fold higher than that of Sp1. AP-2 alone does not alter the
      ANT2 promoter activity in transfected SL2 cells, but enhances the Sp1-dependent
      activation of the promoter several fold. Enhancement by AP-2 is observed only
      when Sp1 is limiting for transcription activation. These data suggest that the
      cellular AP-2/Sp1 ratio might influence ANT2 expression in developing or
      differentiating cells.

PMID- 10393331
TI  - Connective tissue growth factor induces the proliferation, migration, and tube
      formation of vascular endothelial cells in vitro, and angiogenesis in vivo.
AB  - Connective tissue growth factor (CTGF) is a novel cysteine-rich, secreted
      protein. Recently, we found that inhibition of the endogenous expression of CTGF
      by its antisense oligonucleotide and antisense RNA suppresses the proliferation
      and migration of vascular endothelial cells. In the present study, the following
      observations demonstrated the angiogenic function of CTGF in vitro and in vivo:
      (i) purified recombinant CTGF (rCTGF) promoted the adhesion, proliferation and
      migration of vascular endothelial cells in a dose-dependent manner under serum
      free conditions, and these effects were inhibited by anti-CTGF antibodies; (ii)
      rCTGF markedly induced the tube formation of vascular endothelial cells, and this
      effect was stronger than that of basic fibroblast growth factor or vascular
      endothelial growth factor; (iii) application of rCTGF to the chicken
      chorioallantoic membrane resulted in a gross angiogenic response, and this effect
      was also inhibited by anti-CTGF antibodies. (iv) rCTGF injected with collagen gel
      into the backs of mice induced strong angiogenesis in vivo. These findings
      indicate that CTGF is a novel, potent angiogenesis factor which functions in
      multi-stages in this process.

PMID- 10393332
TI  - Effect of vanadate on force and myosin light chain phosphorylation in skinned
      aortic smooth muscle.
AB  - The effects of vanadate were examined on Ca2+-activated force and phosphorylation
      of 20-kDa myosin light chain in membrane-permeabilized rabbit aortic smooth
      muscle strips. Addition of vanadate during maximum contraction reduced the force
      in a dose-dependent manner, and inhibited it almost completely at 1 mM. Two
      dimensional polyacrylamide gel electrophoretic analyses revealed that vanadate
      also reduced the phosphorylation of 20- kDa myosin light chain in a dose
      dependent manner from approximately 50% in the absence of vanadate to
      approximately 20% in the presence of 1 mM vanadate. The effects of 1 mM vanadate
      on purified myosin light chain kinase and phosphatase were then examined using
      purified myosin as substrate, and it was found that vanadate neither inhibited
      myosin light chain kinase nor activated myosin light chain phosphatase. These
      results indicate that the reduction in the 20-kDa myosin light chain
      phosphorylation level by vanadate may be effected through its inhibition of the
      force generation in skinned smooth muscle strip, as evidenced by the finding that
      vanadate eliminated the enhancement of myosin light chain kinase activity brought
      about by the interaction between purified myosin and actin.

PMID- 10393333
TI  - Metabolism of oxidized phosphatidylcholines formed in oxidized low density
      lipoprotein by lecithin-cholesterol acyltransferase.
AB  - The possible involvement of lecithin-cholesterol acyltransferase (LCAT) in the
      metabolism of oxidized phosphatidylcholine (PC) in plasma was investigated. A
      variety of oxidized products are formed from PC following oxidation of low
      density lipoproteins (LDL). A significant increase in LDL oxidation levels in
      patients with familial LCAT deficiency (FLD) has been previously demonstrated by
      a sensitive sandwich ELISA for oxidized LDL using the monoclonal antibody DLH3
      which recognizes oxidized products of PC. In the present study, we found that
      LCAT produces various metabolites from oxidized PC and that oxidized PC molecules
      in LDL particles serve as substrates. When the neutral lipid fraction was
      separated by TLC after the incubation of oxidized 1-palmitoyl-2-[1-14C]linoleoyl
      PC with human plasma, a number of radioactive bands were formed in addition to
      cholesteryl ester. These products were not formed from native 1-palmitoyl-2-[1
      14C]linoleoyl PC. Plasma from FLD patients also failed to form the additional
      products from oxidized PC. The addition of dithio-bis(nitrobenzoate) (DTNB), an
      LCAT inhibitor, or the inactivation of LCAT activity by treating the plasma at 56
      degrees C for 30 min abolished the generation of these products from oxidized PC.
      The activity was recovered in the high density lipoprotein (HDL) fraction but not
      in the LDL fraction separated from normal plasma. When 1-palmitoyl-2-[1-14C](9
      oxononanoyl) PC and 1-stearoyl-2-[1-14C](5-oxovaleroyl)PC, PC oxidation products
      that contain short chain aldehydes, were incubated with human plasma, radioactive
      products in the neutral lipid fraction were observed on TLC. LDL containing
      oxidized PC was measured by sandwich ELISA using an anti-apolipoprotein B
      antibody and DLH3. The reconstituted oxidized PC-LDL particles were found to have
      lost their ability to bind DLH3 upon incubation with HDL, while the reactivity of
      the reconstituted oxidized PC-LDL remained unchanged in the presence of DTNB.
      These results suggest that LCAT is capable of metabolizing a variety of oxidized
      products of PC and preventing the accumulation of oxidized PC in circulating LDL
      particles.

PMID- 10393334
TI  - Conformation of the primary binding loop folded through an intramolecular
      interaction contributes to the strong chymotrypsin inhibitory activity of the
      chymotrypsin inhibitor from Erythrina variegata seeds.
AB  - We previously demonstrated that amino acid residues Gln62 (P3), Phe63 (P2), Leu64
      (P1), and Phe67 (P3') in the primary binding loop of Erythrina variegata
      chymotrypsin inhibitor (ECI), a member of the Kunitz inhibitor family, are
      involved in its strong inhibitory activity toward chymotrypsin [Iwanaga et al.
      (1998) J. Biochem. 124, 663-669]. To determine whether or not these four amino
      acid residues predominantly contribute to the strong inhibitory activity of ECI,
      they were simultaneously replaced by Ala. The results showed that a quadruple
      mutant, Q62A/F63A/L64A/F67A, retained considerable inhibitory activity (Ki, 5.6 x
      10(-7) M), indicating that in addition to the side chains of these four amino
      acid residues, the backbone structure of the primary binding loop in ECI is
      essential for the inhibitory activity toward chymotrypsin. Two chimeric proteins,
      in which the primary binding loops of ECI and ETIa were exchanged: an
      isoinhibitor from E. variegata with lower chymotrypsin inhibitory activity, were
      constructed to determine whether the backbone structure of the primary binding
      loop of ECI was formed by the amino acid residues therein, or through an
      interaction between the primary binding loop and the residual structure
      designated as the "scaffold." A chimeric protein, ECI/ETIa, composed of the
      primary binding loop of ECI and the scaffold of ETIa showed weaker inhibitory
      activity (Ki, 1.3 x 10(-6) M) than ECI (Ki, 9.8 x 10(-8) M). In contrast, a
      chimera, ETIa/ECI, comprising the primary binding loop of ETIa and the scaffold
      of ECI inhibited chymotrypsin more strongly (Ki, 5.7 x 10(-7) M) than ETIa (Ki,
      1.3 x 10(-6) M). These results indicate that the intramolecular interaction
      between the primary binding loop and the scaffold of ECI plays an important role
      in the strong inhibitory activity toward chymotrypsin. Furthermore, surface
      plasmon resonance analysis revealed that the side chains on the primary binding
      loop of ECI contribute to both an increase in the association rate constant (kon)
      and a decrease in the dissociation rate constant (koff) for the ECI-chymotrypsin
      interaction, whereas the backbone structure of the primary binding loop mainly
      contributes to a decrease in the dissociation rate constant.

PMID- 10393336
TI  - Design and synthesis of para-fluorophenylalanine amide derivatives as thrombin
      receptor antagonists.
AB  - An antagonist specific for the thrombin receptor is expected to be a remedy for
      thrombosis. Structure-activity studies of thrombin receptor-tethered ligand
      SFLLRNP have revealed the importance of the Phe-2-phenyl group in receptor
      recognition and the replacement of the Phe-2 by para-fluorophenylalanine [(p
      F)Phe] was found to enhance its activity [Nose, T. et al. (1993) Biochem.
      Biophys. Res. Commun. 193, 694-699]. In order to obtain a small sized antagonist,
      a series of (p-F)Phe derivatives was designed and synthesized novel structural
      elements essential for receptor interactions being introduced at both the N and C
      termini. beta-Mercaptopropionyl (betaMp) or its derivative activated by S-3-nitro
      2-pyridinesulphenyl (Npys) was introduced at the N-terminus, and phenylmethyl
      amines were coupled to the C-terminus. All compounds were inactive when assayed
      for human platelet aggregation, indicating that they are not agonists. beta
      Mercaptopropionyl derivatives were also inactive as antagonists. However, Npys
      containing analogs were found to inhibit the agonist activity of SFLLRNP. In
      particular, SNpys-betaMp-(p-F)Phe-NH-R [R = -CH(C6H5)2 and -CH2-CH-(C6H5)2]
      potently suppressed platelet aggregation. The results suggested that (p-F)Phe can
      be used as a structural core to construct an effective antagonist conformation.

PMID- 10393335
TI  - Ipriflavone down-regulates endothelin receptor levels during differentiation of
      rat calvarial osteoblast-like cells.
AB  - Ipriflavone (7-isopropoxy-3-phenyl-4H-1-benzopyran-4-one) is a synthetic
      flavonoid that has been shown to stimulate the activity of osteoblasts. We show
      here that ipriflavone also promotes the deposition of calcium and the formation
      of mineralized nodules by newborn rat calvarial osteoblast-like (ROB) cells as
      well as the activity of alkaline phosphatase. We reported previously that
      endothelin-1 inhibits the differentiation of ROB cells [Y. Hiruma et al. (1998)
      J. Cardiovasc. Pharmacol. 31, S521-S523]. Therefore, we examined the effects of
      ipriflavone on the expression of endothelin receptors in ROB cells by polymerase
      chain reaction-Southern blot analysis and in binding assays with 125I-labeled
      endothelin-1. Ipriflavone reduced levels of endothelin ETA receptors (to 48% of
      the control level) in ROB cells around day 7 in our standard cultures, while it
      had no apparent effect on the expression of the mRNA for the endothelin ETA
      receptor. By contrast, treatment with 10(-7) M endothelin-1 on days 6 through 9
      alone suppressed mineralization by ROB cells. Ipriflavone also reduced the
      ability of endothelin-1 to inhibit mineralization by ROB cells. These results
      suggest that the acceleration of osteoblastic differentiation by ipriflavone
      might be due, at least in part, to a time-specific down-regulation of endothelin
      receptors.

PMID- 10393337
TI  - A brain region-specific gene product Lhx6.1 interacts with Ldb1 through tandem
      LIM-domains.
AB  - LIM-homeodomain (LHX) transcription factors play critical roles in cell fate
      determination during development, in particular, in CNS. The transcriptional
      activity of several LHX proteins is postulated to be regulated by interaction
      with an LIM-domain binding protein, Ldb1. We have now identified a novel LHX
      molecule, termed Lhx6.1, that is closely related to a recently reported Lhx6
      molecule. The Lhx6.1 transcript is found in several restricted regions in the
      developing CNS, mostly within the embryonic forebrain. We further show that
      Lhx6.1 interacts with Ldb1 through tandem LIM-domains, implying transcriptional
      regulation of Lhx6.1 by Ldb1.

PMID- 10393338
TI  - Apolipoprotein B production and very low density lipoprotein secretion by calf
      liver slices.
AB  - Secretion of triglycerides by the liver in ruminants as components of very low
      density lipoproteins particles is low as compared with that in primates or
      rodents. The rate-limiting steps for the hepatic export of very low density
      lipoproteins have been studied in liver slices to determine the origin of the low
      lipotropic capacity of calf liver compared to that of rat liver. The rates of
      production of apolipoprotein B (apo B) and albumin as well as the rate of
      secretion of VLDL-apolipoproteins were measured during 12-h incubation of liver
      slices in organo-culture using [35S]methionine-cysteine labeling. Hepatic apo B
      production was similar in the two animal species but the VLDL-apolipoprotein
      secretion rate for calf liver slices amounted to only 20% of that observed for
      rat liver slices. Although calf and rat liver slices synthesized similar amounts
      of total protein, the hepatic production of albumin, measured in cells and media,
      was much higher in calf than rat liver slices (around 2.7-fold), whereas the rate
      secretion of albumin was similar in the two species. Our results showed that the
      slow rate of secretion of VLDL by calf liver cells was not consecutive to a low
      rate of synthesis of apo B but rather to a defect in VLDL assembly and/or
      secretion.

PMID- 10393339
TI  - Effects of subunit I mutations on redox-linked conformational changes of the
      Escherichia coli bo-type ubiquinol oxidase revealed by Fourier-transform infrared
      spectroscopy.
AB  - Cytochrome bo is the heme-copper terminal ubiquinol oxidase in the aerobic
      respiratory chain of Escherichia coli, and functions as a redox-coupled proton
      pump. As an extension to our mutagenesis and Fourier-transform infrared studies
      on ion pumps, we examined the effects of subunit I mutations on redox-linked
      protein structural changes in cytochrome bo. Upon photo-reduction in the presence
      of riboflavin, Y288F and H333A showed profound effects in their peptide backbone
      vibrations (amide-I and amide-II), probably due to the loss of CuB or replacement
      of high-spin heme o with heme B. In the frequency region of protonated carboxylic
      C=O stretching vibrations, negative 1,743 cm-1 and positive 1,720 cm-1 bands were
      observed in the wild-type; the former shifted to 1,741 cm-1 in E286D but not in
      other mutants including D135N. This suggests that Glu286 in the D-channel is
      protonated in the air-oxidized state and undergoes hydrogen bonding changes upon
      reduction of the redox metal centers. Two pairs of band shifts at 2,566 (+)/2,574
      (-) and 2,546 (+)/2,556 (-) cm-1 in all mutants indicate that two cysteine
      residues not in the vicinity of the metal centers undergo redox-linked hydrogen
      bonding changes. Cyanide had no effect on the protein structural changes because
      of the rigid local protein structure around the binuclear center or the presence
      of a ligand(s) at the binuclear center, and was released from the binuclear
      center upon reduction. This study establishes that cytochrome bo undergoes unique
      redox-linked protein structural changes. Localization and time-resolved analysis
      of the structural changes during dioxygen reduction will facilitate understanding
      of the molecular mechanism of redox-coupled proton pumping at the atomic level.

PMID- 10393340
TI  - Calcium-induced changes in the location and conformation of troponin in skeletal
      muscle thin filaments.
AB  - Troponin is the regulatory protein of striated muscle. Without Ca2+, the
      contraction of striated muscle is inhibited. Binding of Ca2+ to troponin
      activates contraction. The location of troponin on the thin filaments and its
      relation to the regulatory mechanism has been unknown, though the Ca2+-induced
      dislocation of tropomyosin has been studied. By binding troponin(C+I) to actin in
      an almost stoichiometric ratio and reconstituting actin-tropomyosin-troponin(C+I)
      filaments, we reconstructed the three-dimensional structure of actin-tropomyosin
      troponin(C+I) with or without Ca2+ from electron cryomicrographs to about 2.5 or
      3 nm resolution, respectively. Without Ca2+, the three-dimensional map reveals
      the extra-density region due to troponin(C+I), which extends perpendicularly to
      the helix axis and covers the N-terminal and C-terminal regions of actin. In the
      presence of Ca2+, the C-terminal region of actin became more exposed, and
      troponin(C+I) became V-shaped with one arm extending towards the pointed end of
      the actin filament. This structure can be considered to show the location of
      troponin(C+I) in at least one of the states of skeletal muscle thin filaments.
      These Ca2+-induced changes of troponin(C+I) provide a clue to the regulatory
      mechanism of contraction.

PMID- 10393342
TI  - A cambialistic SOD in a strictly aerobic hyperthermophilic archaeon, Aeropyrum
      pernix.
AB  - The superoxide dismutase (SOD) gene of Aeropyrum pernix, a strictly aerobic
      hyperthermophilic archaeon, was cloned and expressed in Escherichia coli, and its
      gene product was characterized. The molecular mass of the protein, based on the
      deduced amino acid sequence, was 24.6 kDa. The sequence showed overall similarity
      to the sequences of known Mn- and Fe-SODs. The metal binding residues conserved
      in Mn- and Fe-SODs were also found in A. pernix SOD. When the SOD gene was
      expressed in E. coli cells, the product formed a homodimer, and contained both Mn
      and Fe. Metal reconstitution experiments showed that A. pernix SOD is
      cambialistic, i.e. active with either Fe or Mn. The specific activities were 906
      U/mg with Mn and 175 U/mg with Fe. No loss of activity of Mn-reconstituted SOD
      was observed at 105 degrees C even after 5 h incubation. Sodium azide, an
      inhibitor of SODs, did not inhibit the Mn-reconstituted SOD from A. pernix even
      at concentrations up to 400 mM. This SOD from an aerobic hyperthermophilic
      archaeon, Aeropyrum pernix, was extremely thermostable and active with either Mn
      or Fe. With Mn as a metal cofactor, it was more thermostable, and less sensitive
      to sodium azide and sodium fluoride than with Fe.

PMID- 10393341
TI  - Topological and functional characterization of the N-glycans of soybean (Glycine
      max) agglutinin.
AB  - Soybean agglutinin (SBA), is a noncovalently bound tetramer comprised of four
      identical subunits having a single N-glycan chain, Man9GlcNAc2, that is known to
      be essential for regeneration of the functional tetrameric structure from
      unfolded subunits. In this study, SBA was found to have strong affinity for
      concanavalin A, indicating that the N-glycans are extensively solvent-exposed.
      The susceptibilities of the N-glycans to alpha-mannosidase and endo-beta-N
      acetylglucosaminidase revealed that their distal areas have nonreducing ends
      embedded among the subunits, whereas their proximal regions are solvent-exposed.
      Endo-beta-N-acetylglucosaminidase-digested SBA was unable to retain its
      conformation and gradually unfolded. Periodate-oxidized SBA, whose N-glycans
      closely correspond to the invariant pentasaccharide core, tended to dissociate
      into the subunits, but permitted to stay as folded monomers. This SBA species was
      capable of refolding from unfolded subunits but unable to form the functional
      tetramer. It seems probable that the proximal regions of the N-glycans function
      in the formation and stabilization of the subunit conformation, whereas the
      branches outside the invariant cores stabilize the tetrameric structure.

PMID- 10393343
TI  - Binding of cholera toxin B-subunits to derivatives of the natural ganglioside
      receptor, GM1.
AB  - In a previous paper we showed that the B-pentamer of cholera toxin (CT-B) binds
      with reduced binding strength to different C(1) derivatives of N-acetylneuraminic
      acid (NeuAc) of the natural receptor ganglioside, GM1. We have now extended these
      results to encompass two large amide derivatives, butylamide and
      cyclohexylmethylamide, using an assay in which the glycosphingolipids are
      adsorbed on hydrophobic PVDF membranes. The latter derivative showed an affinity
      approximately equal to that earlier found for benzylamide ( approximately 0.01
      relative to native GM1) whereas the former revealed a approximately tenfold
      further reduction in affinity. Another derivative with a charged C(1)-amide
      group, aminopropylamide, was not bound by the toxin. Toxin binding to C(7)
      derivatives was reduced by about 50% compared with the native ganglioside.
      Molecular modeling of C(1) and C(7) derivatives in complex with CT-B gave a
      structural rationale for the observed differences in the relative affinities of
      the various derivatives. Loss of or altered hydrogen bond interactions involving
      the water molecules bridging the sialic acid to the protein was found to be the
      major cause for the observed drop in CT-B affinity in the smaller derivatives,
      while in the bulkier derivatives, hydrophobic interactions with the protein were
      found to partly compensate for these losses.

PMID- 10393344
TI  - Thimet oligopeptidase cleaves the full-length Alzheimer amyloid precursor protein
      at a beta-secretase cleavage site in COS cells.
AB  - We developed an assay method using a novel quenched fluorescent substrate (QFS)
      flanking the beta-cleavage site of amyloid precursor protein (APP), and purified
      a candidate beta-secretase from bovine brain. N-terminal amino acid analysis
      showed the candidate to be thimet oligopeptidase (TOP). The cDNA for human TOP
      was cloned from a human brain cDNA library and expressed in COS cells. The enzyme
      was further purified on a Ni2+-agarose column. TOP cleaved the Swedish
      Alzheimer's substrate (SEVNLDAEFR) as well as the normal substrate (SEVKMDAEFR).
      We then coexpressed TOP with APP695 in COS cells, collected transfected cells and
      conditioned media, and analyzed them by immunoblotting. The antibody against the
      specific secreted APP cleaved by beta-secretase (sAPPbeta) detected the secretion
      of sAPPbeta only from APP/hTOP-overexpressing cells, and not from cells
      overexpressing of antisense hTOP cDNA. Finally, we analyzed the
      immunolocalization of overexpressed hTOP in COS cells. Most hTOP was localized in
      the nuclei, but a small amount was localized in the Golgi or other organelles
      around the nuclei. These results suggest that TOP has a beta-secretase-like
      activity responsible for the processing of APP.

PMID- 10393345
TI  - Short-chain acyl-CoA-dependent production of oxalate from oxaloacetate by
      Burkholderia glumae, a plant pathogen which causes grain rot and seedling rot of
      rice via the oxalate production.
AB  - In Burkholderia glumae (formerly named Pseudomonas glumae), isolated as the
      causal agent of grain rot and seedling rot of rice, oxalate was produced from
      oxaloacetate in the presence of short-chain acyl-CoA such as acetyl-CoA and
      propionyl-CoA. Upon purification, the enzyme responsible was separated into two
      fractions (tentatively named fractions II and III), both of which were required
      for the acyl-CoA-dependent production of oxalate. In conjugation with the oxalate
      production from oxaloacetate catalyzed by fractions II and III, acetyl-CoA used
      as the acyl-CoA substrate was consumed and equivalent amounts of CoASH and
      acetoacetate were formed. The isotope incorporation pattern indicated that the
      two carbon atoms of oxalate are both derived from oxaloacetate, and among the
      four carbon atoms of acetoacetate two are from oxaloacetate and two from acetyl
      CoA. When the reaction was carried out with fraction II alone, a decrease in
      acetyl-CoA and an equivalent level of net utilization of oxaloacetate were
      observed without appreciable formation of CoASH, acetoacetate or oxalate. It
      appears that in the oxalate production from oxaloacetate and acetyl-CoA, fraction
      II catalyzes condensation of the two substrates to form an intermediate which is
      split into oxalate and acetoacetate by fraction III being accompanied by the
      release of CoASH.

PMID- 10393347
TI  - Rapid structural changes in nerve fibers and cells associated with their
      excitation processes.
AB  - In a variety of nerve fibers, cells and other excitable tissues, the electric
      responses to electric stimuli were found to be accompanied by a transient
      swelling of the tissues. The rising phase of this swelling coincides with that of
      the electric response. By use of a heat-sensor made of polyvinylidene fluoride
      film, it was also shown that the electric responses of many types of excitable
      tissues are accompanied by simultaneous heat production. To elucidate the origin
      of this swelling and heat production, the process of Ca2+-Na+ exchange in
      synthetic anionic gel beads and rods was investigated. It is asserted that the
      observed signs of nerve excitation are manifestations of a rapid structural
      change of the cortical gel layer of the protoplasm, plasmalemma-ectoplasm
      complex. The importance of the rapid movement and rearrangement of water
      molecules in the cortical gel layer in association with excitation processes is
      emphasized.

PMID- 10393346
TI  - Exploration of universal cysteines in the binding sites of three opioid receptor
      subtypes by disulfide-bonding affinity labeling with chemically activated thiol
      containing dynorphin A analogs.
AB  - A ligand containing an SNpys group, i.e. 3-nitro-2-pyridinesulfenyl linked to a
      mercapto (or thiol) group, can bind covalently to a free mercapto group to form a
      disulfide bond via the thiol-disulfide exchange reaction. This SNpys chemistry
      has been successfully applied to the discriminative affinity labeling of mu and
      delta opioid receptors with SNpys-containing enkephalins [Yasunaga, T. et al.
      (1996) J. Biochem. 120, 459-465]. In order to explore the mercapto groups
      conserved at or near the ligand binding sites of three opioid receptor subtypes,
      we synthesized two Cys(Npys)-containing analogs of dynorphin A, namely, [D-Ala2,
      Cys(Npys)8]dynorphin A-(1-9) amide (1) and [D-Ala2, Cys(Npys)12]dynorphin A-(1
      13) amide (2). When rat (mu and delta) or guinea pig (kappa) brain membranes were
      incubated with these Cys(Npys)-containing dynorphin A analogs and then assayed
      for inhibition of the binding of DAGO (mu), deltorphin II (delta), and U-69593
      (kappa), the number of receptors decreased sharply, depending upon the
      concentrations of these Cys(Npys)-containing dynorphin A analogs. It was found
      that dynorphin A analogs 1 and 2 effectively label mu receptors (EC50 = 27-33
      nM), but also label delta receptors fairly well (160-180 nM). However, for kappa
      receptors they showed drastically different potencies as to affinity labeling;
      i.e., EC50 = 210 nM for analog 1, but 10,000 nM for analog 2. Analog 2 labeled
      kappa receptors about 50 times more weakly than analog 1. These results suggested
      that dynorphin A analog 1 labels the Cys residues conserved in mu, delta, and
      kappa receptors, whereas analog 2 only labels the Cys residues conserved in mu
      and delta receptors.

PMID- 10393348
TI  - Kinetics of excess CO2 output during and after intensive exercise.
AB  - In order to clarify the kinetics of excess CO2 output during and after intensive
      exercise, six male subjects were each instructed to perform 40-, 60- and 80-s
      cycle ergometer exercises (282 +/- 9 W, 90 rpm). Ventilation and gas exchange
      parameters were recorded breath-by-breath, and lactate concentration (La) was
      repeatedly measured with blood samples from a finger tip. The increase in La from
      the resting value to peak value and the duration of exercise showed a significant
      linear relationship (r = 0.91, p<0.01) passing through zero, indicating that
      lactic acid was produced at a constant rate in working muscles from the beginning
      of exercise. However, in contrast to this increase in La, excess V.CO2, defined
      as the difference between V.CO2 and V.O2, showed a temporary negative value after
      the start of exercise. Subsequently, excess V.CO2 became positive, reaching a
      peak at 60 s post-exercise, and then decreased down to zero at about 9 min after
      the end of the 80-s exercise. End-tidal CO2 rose above the pre-exercise level
      during exercise and at about 3 min post-exercise, and thereafter remained below
      the pre-exercise level. Excess CO2, calculated by the sum of excess V. CO2 from
      the start of exercise to the 10th min after the end of exercise, was
      significantly COrrelated with the increase in La from resting to 10 min post
      exercise (r = 0.88, p<0.01). These results suggest that although excessive CO2
      output (excess CO2) in response to intensive exercise is related to the increase
      in lactic acid, the time course of excessive CO2 output (excess V.CO2) is
      delayed, relative to the production of lactic acid, and is affected by
      hyperventilation.

PMID- 10393349
TI  - Hybrid logistic characterization of isometric twitch force curve of isolated
      ferret right ventricular papillary muscle.
AB  - We previously found that the isovolumic pressure curve of the left ventricle and
      the isometric twitch force curve of the right ventricular in situ papillary
      muscle, both of the blood-perfused canine heart, were precisely fitted by our
      newly proposed hybrid logistic function. This function describes the difference
      between the two S-shaped logistic functions for the rising and falling
      components: A/[1+exp{-(4B/A)(t-C)}]-D/[1+exp{-(4E/D)(t-F)}]+G. This function
      characterizes comprehensively both ventricular and in situ papillary muscle
      contraction and relaxation. In the present study, we hypothesized that this
      function could also characterize the force curve of the most popular, standard
      type, isolated and Tyrode-superfused papillary muscle preparation. To test this
      hypothesis, we investigated how precisely the hybrid logistic function could fit
      112 isometric twitch force curves observed in eight isolated and Tyrode
      superfused ferret right ventricular papillary muscles at different muscle lengths
      and extracellular Ca2+ concentrations. We always obtained a precise curve fitting
      with a correlation coefficient above 0.9987. This fitting was much more precise
      than sinusoidal and polynomial exponential function curve fittings. These results
      supported the present hypothesis. We conclude that our hybrid logistic function
      reasonably characterizes the force curve of the isolated myocardial preparation.
      This result broadens the generality of the hybrid logistic characterization of
      ventricular isovolumic pressure and myocardial isometric twitch force generation.
      The hybrid logistic characterization seems to be an integrative expression of
      contractile processes in myocardial twitch contraction.

PMID- 10393350
TI  - Effect of vitamin C and E in modulating peripheral vascular response to local
      cold stimulus in man at high altitude.
AB  - At high altitude (HA), cold stress is aggravated by hypoxia, perhaps due to the
      increased formation of free radicals which trigger oxidative stress. This may be
      one of the contributing factors for adverse effects including disturbances in
      microcirculation and capillary permeability resulting in decreased peripheral
      blood flow. This leads to altered cold-induced-vasodilatation (CIVD) response on
      exposure to HA. The present study was conducted on 40 male volunteers (4 groups
      of 10 each) to evaluate the utility of supplementation of vitamin C (500 mg/d)and
      vitamin E (400 mg/d) singly, as well as in combination, in modulating peripheral
      vascular response by assessing CIVD response under local cold stimulus both at
      Delhi (200 m) and at HA (3,700 m). On exposure to 3,700 m, decreased CIVD
      response was observed in all the groups. The responses were better in vitamin
      supplemented groups, in general, as compared to the placebo group. The best CIVD
      response was seen in the vitamin C (singly)-treated group. Administration of
      vitamin C and E together did not result in any additional benefit. Facilitation
      of CIVD response due to supplementation of vitamin C may be attributed to its (a)
      antioxidant effect, and (b) major physiological functions of increased metabolism
      and thermogenic properties, facilitation of collagen synthesis, restoration of
      intercellular substances and better maintenance of the rheological status of the
      blood. Hence, vitamin C is effective for improving peripheral blood flow and
      thereby reduces the incidence of cold injuries during acclimatization or outdoor
      duties at HA.

PMID- 10393351
TI  - The effect of oral creatine supplementation on the curvature constant parameter
      of the power-duration curve for cycle ergometry in humans.
AB  - For high-intensity cycle ergometer exercise, the tolerable duration (t) is well
      characterized as a hyperbolic function of power output, P : t = W'/(P-thetaF),
      where thetaF may be termed the "fatigue threshold." The purpose of this study was
      to determine the effect of oral creatine (Cr) supplementation on the curvature
      constant parameter (W') of the power-duration curve. A double-blind research
      method and a cross-over design were employed for creatine/placebo
      supplementation. Eight healthy male subjects (aged 18 to 22 years) each performed
      four or five high-intensity square-wave exercise bouts on an electrically braked
      cycle ergometer after 5 d of Cr monohydrate (CR: 20 g of Cr with artificial
      sweetener/d) or placebo (PL: 6 g of glucose/d) supplementation. Each subject
      performed a single high-intensity exercise trial per day for four or five
      successive days to determination the P-t hyperbolic relation. After 6 weeks (the
      washout time of Cr from the muscles), each subject performed the other condition
      (i.e., PL or CR) and repeated the same experimental procedure. There was no
      significant difference for thetaF between PL and CR conditions (PL: 214.4 +/-
      23.6, CR: 207.0 +/- 19.8 W, mean +/- SD). In contrast, W' was significantly
      increased by the Cr supplementation (PL: 10.9 +/- 2.7, CR: 13.7 +/- 3.0 kJ;
      p<0.05). The results indicated that Cr and/or PCr content in muscles seems to be
      one of the important determinants of the curvature constant parameter (W') of the
      power-duration hyperbolic curve for cycle ergometry.

PMID- 10393352
TI  - Contractile potentiation by endothelin-1 involves protein kinase C-delta activity
      in the porcine coronary artery.
AB  - The relationship between potentiation of serotonin (5-hydroxytryptamine, 5-HT)
      induced contraction by endothelin-1 (ET-1) and the activity of protein kinase C
      (PKC) was examined in the porcine coronary artery. Low concentrations (30-100 pM)
      of ET-1 selectively potentiated the 5-HT-induced contraction 1.5 to 2 times over
      the control without any additional increase in myosin light-chain
      phosphorylation. The potentiation was attenuated by PKC down-regulation caused by
      phorbol 12-myristate 13-acetate. By Western blot analysis with isoform-specific
      antibodies to PKC, at least four isoforms (PKCalpha, PKCbeta1, PKCdelta and
      PKCzeta) were identified in the porcine coronary artery. PKCalpha and PKCdelta
      were mostly in the cytosol fraction, whereas PKCbeta1 and PKCzeta were almost
      equally distributed in the cytosol and membrane fractions in the resting and
      contractile states. Of the four isoforms, only PKCdelta was translocated from the
      cytosol to the membrane fraction during the contractile potentiation by ET-1.
      These results suggest that the activity of PKCdelta, a Ca2+-independent PKC
      isoform, is involved in the potentiation of 5-HT-induced contraction by ET-1 in
      the porcine coronary artery.

PMID- 10393353
TI  - Regional hemodynamic responses to exogenous catecholamines and vasoactive
      peptides in conscious rats.
AB  - The vasoactive hormones vasopressin, angiotensin II, adrenaline, and
      noradrenaline may all be released after central neural stimulation, but our
      knowledge of their relative actions on regional vascular resistances is
      incomplete. A comprehensive account of these patterns will help our understanding
      of their contributions to centrally generated patterns of blood flow. In the
      present study, regional blood flows and resistances of five major arteries were
      measured during sequential intravenous infusions of a range of doses of each
      substance in conscious rats. Vasopressin strongly increased superior mesenteric,
      hindquarters, carotid, and renal resistance but did not affect celiac artery
      resistance until the highest infusion rate. Both angiotensin II and noradrenaline
      increased resistance, although to different extents, in all vascular beds except
      the hindquarters, which was unaffected. Adrenaline infused at pressor rates
      markedly increased superior mesenteric resistance while moderately increasing
      renal, carotid and celiac arterial resistances. At subpressor rates, however,
      adrenaline increased celiac resistance but decreased hindquarters vascular
      resistance without significantly affecting the other beds. It is concluded that
      each vasoactive substance released into the systemic circulation causes its own
      characteristic pattern of vascular responses. This information should be useful
      for understanding the humoral basis of hemodynamic responses to central stimuli.

PMID- 10393354
TI  - Attenuation of urinary sodium excretion during cold-air exposure in trained
      athletes.
AB  - To clarify whether an increase in urinary sodium (Na) excretion during cold-air
      exposure is attenuated in trained athletes, we analyzed the urinary and hormonal
      responses to cold-air exposure at 15 degrees C in trained (TR, n = 9) and
      untrained men (UT, n = 9). During 15 degrees C exposure in the UT group, the
      urinary Na excretion (UNaV), fractional excretion of Na and urinary Na to K ratio
      (UNa/K) increased significantly (p<0.01-0.05), but there were no variations in
      creatinine clearance or the filtered Na load. In the TR group, however, no
      significant changes were demonstrated in these parameters. The amount of increase
      in plasma noradrenaline and of decrease in plasma volume were greater, and the
      ADH and adrenaline responses were smaller in the TR group than those found in the
      UT group during 15 degrees C air exposure. A significant positive correlation was
      demonstrated between the increase of UNaV and both the relative changes of UNa/K
      and mean blood pressure. These results indicated that natriuresis during cold-air
      exposure was induced by the decrease in tubular reabsorption of Na, and that
      natriuresis was attenuated in trained athletes.

PMID- 10393355
TI  - Roles of vasopressin and hypertonicity in basolateral Na/K/2Cl cotransporter
      expression in rat kidney inner medullary collecting duct cells.
AB  - The basolateral Na/K/2Cl cotransporter mRNA (rNKCC1) increased when the cultured
      kidney inner medullary collecting duct (IMCD) cells of rats were exposed to
      vasopressin (10(-8) M) and/or hypertonicity (500 mOsm/kgH2O). However, only
      hypertonicity was effective in increasing the expression of rNKCC1 protein.

PMID- 10393356
TI  - A fully-automated environmental chamber for examination of long-term effects of
      intermittent hypoxia on medium-size animals.
AB  - We describe the design and construction of a fully-automated environmental
      chamber for the simultaneous exposure of up to four medium-size laboratory
      animals to long-term intermittent hypoxia. The air-sealed automated environmental
      chamber consists of a box equipped with a ventilation fan and three electrically
      activated solenoid valves. Our system was used to expose four rabbits to 12 h of
      repetitive episodes of hypoxia (environmental O2 concentration 12-13%) lasting 45
      min followed by breathing room air for 15 min. During environmental hypoxia, the
      mean arterial PaO2 and PaCO2 were 41 +/- 3.0 and 24 +/- 0.7 mmHg (mean +/- SEM),
      respectively. In this system, opening and closing of the solenoid valves is fully
      computerized to allow different settings of the duration and severity of hypoxia.
      The chamber is safe and fully automated and cost-effective for studying the
      effects of long-term intermittent hypoxemia in medium-size animals.

PMID- 10393357
TI  - Primary effusional lymphoma: A new non-Hodgkin s lymphoma entity.
AB  - A distinct non-Hodgkin s lymphoma (NHL) entity that grow in the body cavities as
      lymphomatous effusions in the absence of clinically identifiable tumor masses has
      been defined as primary effusional lymphoma (PEL). This lymphoma characterized by
      distinetive morphology, immunophenotype, genotype and association with Kaposi s
      sarcoma-associated herpesvirus (KHSV)/human herpesvirus-8 (HHV-8) infection. In
      this minireview, the clinico-pathological and biological characteristics of PELs
      are summarized.

PMID- 10393358
TI  - Analysis of p53 mutation and cyclin D1 expression in breast tumors.
AB  - P53 and cyclin D1 are interacting regulatory genes and both are frequently
      altered in breast cancer. We analysed p53 mutation by SSCP and sequencing methods
      as well as p53 protein accumulation immunohistochemically in 34 consecutively
      operated breast tumors. None of 4 fibroadenomas revealed p53 mutation or p53
      protein accumulation. Mutation of p53 was present in 7 carcinomas.
      Immunohistochemistry revealed accumulation of p53 protein in 6 carcinomas and
      there was a significant correlation between p53 mutation and protein
      accumulation. Overexpression of cyclin D1 protein was observed in 11 carcinomas
      by immunohistochemistry and no correlation was observed between cyclin D1
      overexpression and p53 mutation or accumulation. Our data support the concept
      that the p53-cyclin D1 signal pathway and the cyclin D1 cascade are disregulated
      in breast cancer.

PMID- 10393359
TI  - Decreased programmed cell death in the uterine cervix associated with high risk
      human papillomavirus infection.
AB  - The relationship between apoptosis, apoptosis regulatory proteins, cell
      proliferation and human papillomavirus infection during various phases of tumor
      progression in the uterine cervix was studied. Apoptosis was defined by
      morphological criteria and the TUNEL assay. Expression of p53, bcl-2, bax, cyclin
      D1, Ki 67 and E6 protein was evaluated by immunocytochemistry. Presence of mutant
      p53 was detected using a mutant specific ELISA. Type of HPV infection was
      determined by PCR using type specific primers. Apoptosis showed significant
      negative correlation with increasing histological abnormality (p=0.0005). Higher
      tumor cell proliferation was associated with increasing histological abnormality
      (p=0.001 for Ki 67 and cyclin D1). There was significant correlation between
      histological grade and immunoreactivity of p53 (p=0.0001 ) and bcl-2 (p=0.0002).
      However, mutant p53 was expressed by only 12 of the 230 samples. Expression of
      bax and the bax/bcl-2 ratio showed an inverse correlation to histological grade
      (p=0.0003 and 0.0001, respectively). There was also an inverse correlation
      between extent of apoptosis and immunoreactivity of p53 (p=0.0001) and bcl-2
      (p=0. 0001). A significant positive correlation between expression of the bax
      protein and apoptosis was evident (p=0.0001). HPV infection significantly
      correlated to the extent of histological abnormality (p=0.0001). High risk HPV-E6
      protein also showed this significant correlation (p=0.0002). There was an inverse
      correlation between apoptosis and HPV infection (p=0.0002). High risk HPV
      infection was associated with decreased apoptosis and also increased human cell
      proliferation. Lowest levels of bax/bcl-2 ratio was also associated with HPV 16
      and 18 infection (p=0.0001). Modulation of apoptosis and apoptotic regulatory
      proteins by high risk HPV infection may be an important factor in the development
      of cervical cancer.

PMID- 10393360
TI  - Expression of c-erbB-2 oncoprotein in gastric carcinoma: correlation with
      histopathologic characteristics and analysis of Ki-67.
AB  - Amplification and overexpression of the c-erbB-2 gene has been demonstrated in
      several tumors and thought to be important determinants of biologic behaviors of
      carcinomas. In this study, correlation between c-erbB-2 expression und
      histopathologic parameters, including proliferative activity of gastric
      carcinomas was evaluated. Paraffin-embedded tissue sections from 62 patients who
      underwent curative resection of gastric carcinoma were analyzed
      immunohistochemically for the expression of c-erbB-2 and Ki-67. Strong membrane
      staining for c-erbB-2 was detected in 11 of 62 gastric carcinomas (17,7%) and no
      positive reaction was evident in noncancerous tissue. The incidence of c-erbB-2
      positivity in intestinal type carcinomas (24,3%) was higher than that of diffuse
      type carcinomas (4,76%). Positive staining for c-erbB-2 was present in one of the
      9 (11,1%) early gastric carcinomas and 10 of 53 (18, 8%) advanced gastric
      carcinomas. However, no statistically significant relationships were found
      between c-erbB-2 expression and histopathologic type, depth on invasion, the
      tumor size or lymph node metastases. Among the metastatic lymph nodes, 3 were
      positively stained with c-erbB-2 whereas the primary tumors of two cases had been
      found to be negative. Additionally, no correlation was found between c-erbB-2
      reactivity and proliferative activity of carcinoma cells. The results suggest
      that expression of c-erbB-2 protein may occur selectively in intestinal type of
      gastric carcinomas. However, c-erbB-2 expression is not a reliable marker of
      malignant potential in gastric carcinomas.

PMID- 10393361
TI  - Elevated hepatic glucocorticoid receptor expression during liver regeneration in
      rats.
AB  - In rats within the first week of partial hepatectomy reconstruction of the normal
      histological structure of the liver already starts. To approach the possible role
      of endogenous glucocorticoids in the process of regeneration we measured the
      changes in the expression of steroid glucocorticoid receptor gene after various
      regeneration intervals. After partial hepatectomy, between 0.5 168 hours from the
      surgery, the gene expression (mRNA) of glucocorticoid receptor was determined by
      reverse transcription followed by PCR and normalized to that of glycerolphoshate
      dehydrogenase. Two peaks of glucocorticoid receptor mRNA were detected first,
      between 3 and 6 hours (first peak) and a second between 24 and 36 hours.
      Immunoreactive glucocorticoid receptor was detected by immunohistochemistry using
      monoclonal anti-glucocorticoid receptor. Three days after the surgery
      immunohistochemical studies showed substantially more immunoreactive GcR protein
      in the regenerated liver than in the controls. These semiquantitative data
      provide evidence suggesting elevation of glucocorticoid receptor expression
      during regeneration of liver at mRNA and protein levels.

PMID- 10393362
TI  - Paracrine effects of IL-4 transfection on TS/A adenocarcinoma cells mediate
      reduced in vivo growth.
AB  - The in vitro/in vivo growth capacity and phenotype of TS/A and the IL4
      transfected TS/A-IL4 cell lines were studied by cell cycle analysis, expression
      of ICAM-1/CD54, transferrin receptor/CD71 and E-cadherin and by histology of the
      primary tumors. TS/A-IL4, unlike the TS/A line, shows in vitro a marked increase
      in the fibroblastoid cell type and a decreased E-cadherin expression.
      Administration of conditioned medium containing IL4 obtained from the TS/A-IL4
      cell line, stimulates CD54 expression in the TS/A cell line. TS/A-IL4 tumors grow
      more slowly in vivo and are ultimately rejected. These processes are accompanied
      by a marked increase in collagen and extracellular matrix proteins and increased
      recruitment and degranulation of mast cells. The paracrine effect of IL4,
      released by the transfected tumor cells, might be responsible for the reduced in
      vivo growth of the TS/A cell line in the presence of TS/A-IL4 cells.

PMID- 10393363
TI  - Is breast cancer cluster influenced by environmental and occupational factors
      among hospital nurses in Hungary?
AB  - An unusual cluster of 8 breast cancer and 8 other malignant tumor cases (ovarian,
      uterus, lung, colon and brain tumors and malignant melanoma) developed in a
      period of 12 years among 98 nurses exposed to ethylene oxide (EtOx) for 5 15
      years in a unit using gas sterilizer in a hospital of the archiepiscopal city of
      Eger, Hungary. EtOx concentration in air samples of the working area varied from
      5 to 150 mg/m3. The question was, if there was any causal relationship between
      the elevated incidence of breast cancer and the EtOx exposure, the other
      possibility was, that this cluster appeared accidentally. EtOx is a human
      carcinogen, however, no increased breast cancer incidence in EtOx-exposed
      subjects was reported in the literature. We followed up for two consecutive years
      the 27 non cancer patients, EtOx-exposed nurses and 11 unexposed hospital
      controls with the aid of a multiple genotoxicology monitor including chromosomal
      aberration, sister-chromatide exchange, HPRT point mutation and DNA repair
      studies. The results were compared with data from 30 local historical controls,
      48 historical controls from Budapest, 14 hospital controls and 9 EtOx exposed
      nurses from Budapest. Significantly high chromosome aberration yields (especially
      chromosome type exchanges) were alike detected in EtOx-exposed and the two other
      control groups in Eger. These results could not be interpreted as a consequence
      of EtOx exposure only, since in the EtOx-exposed group from Budapest, beside an
      increased total aberration frequency, the obtained exchange type aberration
      yields were as low as the historical controls. A plausible explanation can be the
      natural low dose radioactivity (222Rn) of the local tap-water due to a specific
      geological situation in Eger. The spontaneous breast cancer incidence in Hungary
      doubled in the last 10 years compared with the previous 20 years (1960 1980),
      especially in Eger. The appearance of the high breast cancer incidence in the
      hospital of Eger indicates the combined effect of EtOx and a more common local
      etiologic factor, such as the naturally radioactive tap-water. However, since the
      reported studies did not involve the investigation either of the genetic
      predisposition, or the effects of other possible environmental, occupational,
      and/or life style confounding factors, further studies (partly in progress) are
      necessary to clarify the importance of these factors.

PMID- 10393365
TI  - Estimating the overlap between sentinel lymph nodes and axillary node samples in
      breast cancer.
AB  - Management of the axilla in breast cancer patients is a controversial issue.
      Axillary sampling and sentinel lymphadenectomy are both conservative surgical
      approaches which aim to stage the disease. These procedures target selective
      treatment of node-positive patients and seem to allow the omission of axillary
      clearance in node-negative ones. In this way, they reduce the rate of
      complications in an otherwise overtreated subset of patients. Forty consecutive
      patients with palpable T1 and T2 breast carcinoma underwent sentinel
      lymphadenectomy following mapping with Patent blue dye, with subsequent axillary
      clearance and excision of the tumor or mastectomy. Then the largest/firmest 3,4,5
      and 6 nodes were selected from all the lymph nodes in order to model an axillary
      sample. It was suggested that these are the nodes that are the most likely to be
      included in the specimen during sampling, because of their size and consistency.
      The probability of the sentinel lymph nodes falling into the sample of the 3-6
      largest/firmest nodes was calculated. The sentinel nodes predicted the axillary
      nodal status in 95%, while the samples of the largest 3, 4, 5 and 6 nodes were
      predictive in 95, 96, 98 and 98%, respectively. The two methods of evaluation
      displayed a considerable overlap, as the sentinel node would have been included
      in the 3 6 largest/firmest nodes in 79 92% of the cases, depending on the number
      of largest nodes evaluated. The overlap was greater after fine needle aspiration
      of the primary tumor. Although the two alternative staging procedures of 3, 4, 5
      or 6 node sampling and sentinel lymphadenectomy with the vital blue dye technique
      cannot be simultaneously done without one influencing the other, and the first
      method was only modeled, the results suggest that there is a considerable overlap
      between the two; axillary sampling may often remove the sentinel lymph nodes.

PMID- 10393364
TI  - Magnetic resonance imaging of bone marrow versus bone marrow biopsy in malignant
      lymphoma.
AB  - Bone marrow involvement is a frequent finding in malignant lymphoma. Bone marrow
      biopsy of the posterior iliac crest is routinely performed for staging. Abnormal
      magnetic resonance imaging (MRI) signals of bone marrow was also reported to be
      indicative of bone marrow involvement. This study included 60 patients with
      malignant lymphoma. Unilateral bone marrow biopsy of the posterior iliac crest
      was performed. MRI of lumbar spine was studied within 24 hours of bone marrow
      biopsy. 22 healthy controls were used for the detection of MRI objectivity during
      visual evaluation. In 83% of patients (50/60), biopsy and MRI results agreed
      completely. In two patients, histologic sections failed to show any evidence of
      bone marrow involvement despite abnormal MRI signals suggestive of involvement.
      In three patients, MRI was completely normal despite biopsy proven bone marrow
      infiltration. False negativity (3/60) and false positivity (2/60) rates were very
      low. Negative biopsy findings with positive or equivocal MRI results should not
      exclude bone marrow involvement and needs further evaluation with bilateral or
      guided biopsy. Thus, we conclude that MRI of bone marrow is a fairly sensitive,
      noninvasive modality and might be of potential value in detecting bone marrow
      infiltration in malignant lymphoid neoplasms which can be utilized as a useful
      adjunct to standard staging procedures.

PMID- 10393366
TI  - A correlative study of gliomas using in vivo bromodeoxyuridine labeling index and
      computer-aided malignancy grading.
AB  - An in vivo bromodeoxyuridine (BrdU) labeling index (LI) was estimated in 43 cases
      of astrocytic tumors and mixed gliomas by one hour intra-operative intravenous
      infusion at a dose of 200 mg/m2 and correlated with (a) histological grading
      using a computer aided malignancy classifier TESTAST-268; and (b) histological
      typing using WHO classification. The lowest BrdU LI was seen in pilocytic and
      gemistocytic astrocytomas followed by astrocytomas, anaplastic astrocytomas and
      glioblastoma multiforme in that order. Mixed oligoastrocytomas followed the
      pattern of their astrocytic counterparts. Tumors of similar histological type
      showed different BrdU LI values especially amongst astrocytomas and
      glioblastomas. A statistically significant difference in the BrdU LI was also
      noted between the higher TESTAST grades of astrocytomas (T III and IV) versus the
      lower TESTAST grades (T II). Unlike earlier reports in literature, in the present
      study the category of BrdU LI of <1 contained no case of anaplastic astrocytoma
      or glioblastoma multiforme (TESTAST grades III and IV). Likewise, the category of
      BrdU LI >5 contained only anaplastic astrocytoma and glioblastoma multiforme
      (TESTAST grades III and IV). Maximum spread of cases was seen in the BrdU LI
      category of 1-5, not only in terms of histological types but also TESTAST grades.
      Thus there appeared to be a positive trend of increasing BrdU LI values both with
      histological types and increasing TESTAST grades. Further, an interesting
      observation was that by using a combination of TESTAST grades and BrdU LI, the
      histologically homogenous glioblastoma group could be further subdivided into 4
      categories which showed a trend towards prognostic correlation. Thus, this study
      though preliminary with number of cases being small in some groups, highlights
      the possible usefulness of combined histological typing, TESTAST grading and in
      vivo BrdU LI for prognostication of gliomas especially glioblastoma multiforme.

PMID- 10393367
TI  - HLA antigens in Iranian patients with B-cell chronic lymphocytic leukemia.
AB  - The frequency of HLA class-I and class-II antigens was investigated in 32 Iranian
      patients with B-cell chronic lymphocytic leukemia (B-CLL), using the
      microlymphocytotoxicity method. A significant increase in the HLA-B13 (P<0.01)
      and DR53 (P < 0.05) and a significant negative association with the A11 (P <
      0.05), B35 (P < 0. 05), Cw3 (P < 0.05), and DR1 (P < 0.02) antigens were observed
      in these patients, compared to the control normal population. These results
      suggest involvement of some HLA antigens in the multifactorial process of
      predisposition to B-CLL.

PMID- 10393368
TI  - Epidermal growth factor receptor, somatostatin and bcl-2 in human pancreatic
      tumor xenografts. An immunohistochemical study.
AB  - Xenografted human pancreatic tumors (5 ductal adenocarcinomas, 1 leiomyosarcoma,
      altogether 26 samples) were investigated about their immunohistochemical
      expression of epidermal growth factor receptor (EGFR), somatostatin (SS) and bcl
      2 protein. The expression of the EGFR varied from tumor to tumor. One originally
      negative carcinoma became immunoreactive during passagings, one tumor has lost
      its early positive expression, and in 3 cancer lines a phenotypically constant
      pattern was seen. SS immunoreactivity was practically absent in all tumor
      samples. Concerning bcl-2 expression, different staining patterns were observed
      among the carcinomas, but the leiomyosarcoma has retained its strong positivity
      during xenograftings. In the PZX-5 carcinoma line that was originally negative,
      the one month Sandostatin treatment induced the strong expression of bcl-2
      protein suggesting a development of an acquired resistance against programmed
      cell death in this tumor.

PMID- 10393369
TI  - A case of bilateral testicular lymphoma.
AB  - Authors report on a 75-year-old man with bilateral testicular lymphoma. He
      complained of painless right testicular enlargement. Orchidectomy was indicated
      by ultrasound examination and the diagnosis (large cell, non-Hodgkin lymphoma B
      cell origin) was established by histology and immunohistochemistry. Two months
      later, the left testis enlarged, orchidectomy was performed, and a lymphoma with
      identical histology was found. PET revealed retroperitoneal spread of the tumor.
      Irradiation (18 Gy) was applied. Three months later, because of gastric
      metastases of the lymphoma the patient underwent CVP and CAVP (Cyclophosphamide,
      Adriablastin, Vincristin, Prednisolone) chemotherapy. Despite of the repeated
      courses, eleven months after the primary diagnosis the patient died due to of
      multiple metastases.

PMID- 10393370
TI  - Central neurocytoma with malignant course. Neuronal and glial differentiation and
      craniospinal dissemination.
AB  - Central neurocytoma is a benign neuronal tumor of young adults in the lateral
      cerebral ventricles with characteristic X ray and light microscopic findings. In
      many respects typical central neurocytoma is reported below, with recurrence in
      the third month requiring reoperation. Death ensued in the fifth postoperative
      month. Subsequent histology proved progressive vascular proliferation and
      increasing, unusual glial differentiation of the neuronal tumor. At autopsy
      tumorous seeding blocked the liquor circulation. A thin tumorous layer covered
      the surface of all ventricles, the cerebellum and medulla oblongata. The GFAP
      positive cells out-numbered the synaptophysin positive ones. Increase of GFAP
      positivity and vascular proliferation of the central neurocytoma may be alarming
      signs suggesting a malignant course in addition to the other atypical features.

PMID- 10393371
TI  - Pericardial involvement by thymomas. Entirely intrapericardial thymoma and a
      pericardial metastasis of thymoma with glomeruloid vascular proliferations.
AB  - Thymomas are usually found in the anterior mediastinum, the normal location of
      the thymus. Involvement of the pericardium by thymic tumors is seen in invasive
      or metastasized thymoma. Very rarely, thymomas arise primarily in the
      pericardium. These tumors are believed to derive from thymic tissue which was
      misplaced in the pericardium during embryologic development. In contrast to
      patients with orthotopic thymoma who commonly suffer from paraneoplastic
      diseases, especially myasthenia gravis, patients with intrapericardial thymoma
      manifestations mainly have symptoms of congestive heart failure which are caused
      by local complications of tumor growth. In this study, we present two cases of
      thymoma involving the pericardium. Both tumors were polygonal-oval cell thymomas.
      In one of the cases diagnosis of an entirely intrapericardial thymoma was
      established by autopsy. In the other case, explorative thoracotomy revealed
      massive pericardial and pleural tumor manifestations. The latter tumor showed a
      peculiar histological pattern with multiple glomeruloid bodies, a finding
      reported only once for thymomas.

PMID- 10393372
TI  - Minimal-change nephrotic syndrome and acute renal failure in a patient with aged
      onset insulin-dependent diabetes mellitus and autoimmune thyroiditis.
AB  - A 61-year-old woman with a 2-year history of insulin-dependent diabetes mellitus
      (IDDM) developed nephrotic syndrome. Renal biopsy showed minimal-change nephrotic
      syndrome (MCNS), and no evidence of diabetic glomerulosclerosis. Although steroid
      therapy was initiated, plasma urea and creatinine rose and hemodialysis was
      required. After 4 weeks, she responded to steroids and her renal function
      returned to normal. MCNS, which is not associated with diabetic
      glomerulosclerosis, has rarely been seen in IDDM patients with nephrotic
      syndrome. Her human leukocyte antigen typing was A24, BW52, BW61, DR2 and DR9.
      This typing has been reported to be associated with both IDDM and renal disease.

PMID- 10393373
TI  - Chronic interstitial nephritis due to 5-aminosalicylic acid.
AB  - Nephrotoxicity has recently been reported with the use of 5-aminosalicylic acid
      (5-ASA) which has structural similarities to phenacetin and aspirin. The present
      paper describes 2 cases of interstitial nephritis and 1 case of end-stage failure
      associated with 5-ASA treatment. The first patient presented with severe renal
      failure which was partially reversed with 5-ASA discontinuation and steroid
      therapy. The second had severe renal failure (serum creatinine 469 mmol/l) but
      renal function stabilized with 5-ASA withdrawal. The third patient had end-stage
      renal failure and underwent hemodialysis and a successful kidney transplant.

PMID- 10393374
TI  - Current status of renal replacement therapy for acute renal failure. A survey of
      US nephrologists. The National Kidney Foundation Council on Dialysis.
AB  - Although the management of acute renal failure (ARF) constitutes a major
      component of the activities of practicing nephrologists, minimal information is
      available on the dialysis techniques utilized to treat ARF in the USA. It is
      evident from several recent publications that there are wide variations in the
      dialytic and nondialytic management of ARF. In order to obtain a better
      understanding of the current practice for dialytic management of ARF, the
      National Kidney Foundation (NKF) Council on Dialysis commissioned a survey of NKF
      members. This article describes the results of this survey and provides a
      snapshot of the current management practices for ARF. It is our hope that this
      information will provide a baseline for further research in this area.

PMID- 10393375
TI  - Detection of de novo hepatitis C virus infection by polymerase chain reaction in
      hemodialysis patients.
AB  - Patients on chronic hemodialysis (HD) treatment have been identified by
      serological testing, including second- and third-generation enzyme-linked
      immunosorbent assay (ELISA), as a high-risk group for hepatitis C virus (HCV)
      infection. Previous studies have shown that de novo cases of HCV may occur in HD
      units in the absence of other parenteral exposures, which suggests the spread of
      HCV between patients. In addition, the reverse-transcription polymerase chain
      reaction (RT-PCR), which directly detects HCV virus, has identified HCV infection
      in chronic HD patients who are seronegative. The aim of this study was to
      determine the incidence of HCV infection detected by RT-PCR technology in a large
      cohort of chronic HD patients. One hundred and twenty chronic HD patients, HCV
      negative by serological assays (second-generation ELISA) and molecular techniques
      (branched DNA and RT-PCR), were observed for a mean period of 9.5 months. They
      were tested monthly for serum alanine aminotransferase levels (ALT) and by second
      generation ELISA. At the end of the follow-up period, they were again evaluated
      by branched DNA and RT-PCR testing. HCV RNA was detected in patients' sera by RT
      followed by PCR using two separate primer sets from the 5'-untranslated region of
      the HCV genome. Southern blot was performed using a digoxigenin-labeled probe.
      Two patients who had HCV RNA detectable by RT-PCR at the end of the follow-up
      period remained branched-DNA-negative. Thus, the incidence of de novo acquisition
      of HCV infection in the current investigation was 2.1% per year. In 1 patient RT
      PCR positivity and anti-HCV ELISA seroconversion occurred. The 2nd patient
      remained anti-HCV ELISA-negative, although viremic. In both patients, the onset
      of positivity by RT-PCR was associated with a rise of ALT levels into the
      'abnormal range' in our laboratory. In these 2 patients, de novo acquisition of
      HCV infection was observed in the absence of obvious parenteral risk factors
      other than their presence in the HD environment. In conclusion, de novo
      acquisition of HCV infection may be undetected by ELISA and branched-DNA assays.
      The need to monitor chronic HD patients by serial ALT testing is emphasized. RT
      PCR should be incorporated into diagnostic testing for HCV infection in chronic
      HD patients. RT-PCR technology can identify HCV in HD individuals with raised ALT
      activity.

PMID- 10393376
TI  - Trimethoprim-sulfamethoxazole therapy in outpatients: is hyperkalemia a
      significant problem?
AB  - A prospective, randomized clinical study was undertaken to determine the effect
      of standard-dose trimethoprim-sulfamethoxazole combination treatment on serum
      potassium concentrations in outpatients treated in an ambulatory clinic. Ninety
      seven patients were treated with oral antibiotics for a variety of infections.
      Fifty-one patients treated with trimethoprim-sulfamethoxazole (trimethoprim, 320
      mg/day; sulfamethoxazole, 1,600 mg/day) constituted the treatment group, while 46
      patients treated with other antibiotics served as controls. Serum potassium,
      sodium, and chloride concentrations, serum carbon dioxide content, blood urea
      nitrogen level, serum creatinine level, and serum glucose concentration were
      measured. The baseline serum potassium concentration in the treatment group was
      4.30 +/- (SD) 0.36 mmol/l, and it increased significantly (p < 0.001) to 4.66 +/-
      0.45 mmol/l on day 5 of therapy. Subgroup analysis of mean serum potassium
      concentration on day 5 of therapy failed to detect clinically relevant
      hyperkalemia. In patients with a serum creatinine level equal to or greater than
      1.1 mg/dl (K+, 4.83 +/- 0.48 mmol/l), a nonsignificant difference (p = 0.3) in
      the potassium concentration was noted on day 5 as compared with patients with a
      serum creatinine level <1.1 mg/dl (K+, 4.63 +/- 0.44 mmol/l). Although diabetics
      had a higher serum potassium concentration (K+, 4.91 +/- 0.44 mmol/l) than
      nondiabetics (K+, 4.61 +/- 0.44 mmol/l), the difference was not statistically
      significant (p = 0.055). Patients aged >/=50 years (K+, 4.82 +/- 0.59 mmol/l) had
      a significantly different (p = 0.046) serum potassium concentration on day 5 than
      patients aged <50 years (K+, 4.55 +/- 0.28 mmol/l). In contrast, the baseline
      serum potassium concentration in the control group was 4.37 +/- 0.45 mmol/l, and
      it decreased (p = 0.1) to 4.22 +/- 0.4 mmol/l on 5 days of drug therapy.
      Trimethoprim-sulfamethoxazole therapy, when used to treat a variety of
      infections, leads to an increase in serum potassium concentration in most
      patients. After 5 days of therapy with this drug, the treatment group developed a
      statistically significant rise in the serum potassium concentration as compared
      with the control group. However, severe hyperkalemia (K+ >/=5.5 mmol/l) occurred
      in only 3 patients (6%) treated with trimethoprim-sulfamethoxazole. In addition,
      none of the subgroups of treated patients developed clinically important
      hyperkalemia. This suggests that outpatients, in contrast to acquired
      immunodeficiency syndrome patients and hospitalized patients with mild renal
      insufficiency, develop severe or life-threatening hyperkalemia less commonly when
      treated with this antimicrobial regimen. However, outpatients having risk factors
      which may predispose to the development of hyperkalemia should be carefully
      monitored when treated with trimethoprim-sulfamethoxazole.

PMID- 10393377
TI  - A new treatment forInterdialytic hyperkalemia - the use of fosinopril sodium.
AB  - Fosinopril sodium is the first of the phosphinic acid class of angiotensin
      converting enzyme inhibitors (ACEI). It is used as an antihypertensive agent, but
      differs from other ACEI in its dual routes of excretion (liver and kidney), and
      less incidence of hyperkalemia and cough. We conducted a study in known chronic
      hemodialysis patients who developed interdialytic hyperkalemia in spite of other
      treatments to control hyperkalemia. We used fosinopril in this group of patients
      to assess the effect of fosinopril on serum potassium (K) levels. Twenty-four
      patients were given fosinopril 10 mg at 18:00 h daily for 8 weeks. K levels were
      measured before and after each dialysis treatment. Interdialytic weight gains
      were recorded. The average pretrial potassium level was 6.57 mmol/l (+/- 0.47),
      and the posttrial level was 5.34 (+/- 0.76); p </= 0.0001. No statistically
      significant interdialytic weight gain or reduction occurred. No first dose
      hypertensive effect or cough were reported. We have found the use of fosinopril
      to be successful in lowering predialysis serum K levels in hyperkalemic dialysis
      patients.

PMID- 10393378
TI  - Urinary epidermal growth factor excretion in children with chronic renal failure.
AB  - To investigate the excretion of urinary epidermal growth factor (EGF) in children
      with chronic renal failure (CRF), we have measured the urinary EGF/creatinine
      ratio (EGF/Cr) and the 24-hour urine EGF concentration in 19 children with CRF,
      11 children with kidney disease and normal creatinine clearance, and 12 healthy
      children. Children with CRF had a significantly lower daily urine EGF
      concentration as well as urinary EGF/Cr. In contrast, children with kidney
      disease and normal renal function had normal daily urine EGF levels and urinary
      EGF/Cr. Accompanied by no difference in serum EGF between these two groups of
      patients, these data provide indirect evidence of the kidney as a source of human
      urinary EGF. There was a positive correlation of urinary EGF/Cr with creatinine
      clearance in all renal patients (r = 0.608, n = 30, p < 0.001). A much better
      correlation was found between daily urine EGF and creatinine clearance (r =
      0.855, n = 30, p < 0.001). Our results implicate that there is a functional
      relationship between glomerular filtration and urinary EGF excretion, and that
      the urinary EGF/Cr may be a reliable indicator of urinary EGF excretion in
      children with CRF.

PMID- 10393379
TI  - Effect of usual doses of folate supplementation on elevated plasma homocyst(e)ine
      in hemodialysis patients: no difference between 1 and 5 mg daily.
AB  - Hyperhomocyst(e)inemia is a probable contributor to the excess atherosclerosis of
      patients with chronic renal failure on dialysis. Although treatment with folate 2
      mg daily is usually effective in normalizing plasma homocyst(e)ine (H(e)) in
      patients with normal renal function, higher doses of folate or other approaches
      to treatment may be necessary in renal failure. There is no agreement among
      dialysis units regarding the 'correct' dose of folate supplementation; routine
      doses range from 1 to 5 mg daily. To determine whether one of these doses is more
      effective, we compared H(e) in 55 hemodialysis taking 1 mg folate versus 73
      patients taking 5 mg folate daily at two dialysis units. In the group as a whole,
      mean H(e) was 28.23 +/- 17.49, significantly higher than in a group of 290
      volunteers with normal renal function 12.31 +/- 6.17 (p = 0. 0001). H(e) levels
      were 28.93 +/- 16.79 micromol/l on 5 mg folate and 27.31 +/- 18.49 on 1 mg; p =
      0.61. There was no significant relationship between adequacy of dialysis (Kt/V)
      and H(e). In a small group of peritoneal dialysis patients, H(e) was
      significantly lower at 18.8 +/- 7.89 (p = 0.026), but further study is required
      in a larger sample to confirm that observation. It appears that routine doses of
      folate in use in dialysis units are not sufficient to reduce H(e) to levels
      associated with average cardiovascular risk; new approaches to treatment of
      hyperhomocyst(e)inemia in dialysis patients are required.

PMID- 10393381
TI  - Growth factors in continuous ambulatory peritoneal dialysis effluent. Their
      relation with peritoneal transport of small solutes.
AB  - Recent studies reveal conflicting results on the change of solute transfer with
      time on continuous ambulatory peritoneal dialysis (CAPD) and recurrent
      peritonitis. Herein, we performed a cross-sectional study of 76 patients on CAPD
      to examine their peritoneal permeability by measuring the dialysate to serum
      ratio of creatinine (D/P) and the mass transfer area coefficients of creatinine
      (MTACCr) or glucose (MTACGlu). Transforming growth factor-beta1 (TGF-beta1),
      platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) were
      measured in the dialysate by ELISA. TGF-beta1 mRNA in peritoneal macrophages were
      determined by a quantitative polymerase chain reaction. We failed to observe any
      correlation between the duration on dialysis and the peritoneal permeability in
      those patients with no previous peritonitis. Frequency of peritonitis episode did
      not affect the MTACCr, MTACGlu, or D/P. The MTACCr correlated well with MTACGlu
      (r = 0.78, p = 0. 001) and with D/P (r = 0.98, p < 0.0001). No inverse
      correlation was demonstrated between dialysate PDGF or EGF and the peritoneal
      permeability. A positive correlation was demonstrated between the dialysate TGF
      beta1 and MTACCr, MTACGlu or D/P (r = 0.64, 0.54, and 0.64 respectively, p <
      0.001). The dialysate TGF-beta1 levels in patients with low D/P (</=0.5) were
      only half of that in patients with normal or high D/P (p = 0.0002). The dialysate
      levels of TGF-beta1 did not correlate with PDGF or EGF. These findings raise the
      possibility that, other than diffusion across the peritoneal membrane from
      circulation, there could also be an intrinsic production of TGF-beta1 by
      peritoneal cells in these CAPD patients. Our findings raise the speculation that
      TGF-beta1 in dialysate from stable CAPD patients may exert an inhibitory action
      to fibroblast. Such action of TGF-beta1 could reduce the risk of peritoneal
      sclerosis and hence, maintains a satisfactory peritoneal permeability to small
      solutes.

PMID- 10393380
TI  - Effects of simvastatin and pravastatin on hyperlipidemia and cyclosporin blood
      levels in renal transplant recipients.
AB  - Thirty-one renal transplant recipients, submitted to treatment with cyclosporin
      in association with other immunosuppressive agents, were also treated for 9
      months with two hydroxymethylglutaryl coenzyme A reductase inhibitors,
      simvastatin (10 mg/day) or pravastatin (20 mg/day), for concomitant
      hypercholesterolemia and hypertriglyceridemia. Both drugs significantly decreased
      total cholesterol and triglyceride serum levels, but they did not modify whole
      blood trough concentrations of polyclonal and monoclonal cyclosporin or
      polyclonal/monoclonal cyclosporin ratio. No alterations of the clinical and
      laboratory parameters investigated were found. The results of this study show the
      efficacy and safety of hydroxymethylglutaryl coenzyme A reductase inhibitors in
      the treatment of hyperlipidemia in kidney transplant patients.

PMID- 10393382
TI  - QRS amplitude and volume changes during hemodialysis.
AB  - BACKGROUND: According to several studies the QRS amplitude of the ECG increases
      during hemodialysis. The detailed background to this phenomenon has not been
      defined. Two main mechanisms have been suggested: myocardial ischemia and volume
      changes. New noninvasive technologies make possible a comparison of QRS complex
      changes synchronously with myocardial ischemia and extracellular water
      (ECW)/blood volume (BV) changes during hemodialysis. METHODS: In this study
      hemodialysis-related changes in body weight, biochemical blood variables, BV,
      ECW, ST segment and QRS complex were analyzed in 15 patients (age 36-76, time on
      dialysis 0-6 years) undergoing chronic hemodialysis treatment. QRS complex and ST
      segment changes were measured using a dynamic vectorcardiographic monitoring
      system. The ECG parameters measured were QRS vector difference (QRS-VD) and ST
      vector magnitude (ST-VM6). Bioimpedance analysis was used to detect changes in
      the ECW. Continuous measurement of BV changes was implemented using an on-line
      optical reflection method based on the reflection of infrared light by
      erythrocyte membranes. Blood hemoglobin (B-Hb), hematocrit (B-Hcr), plasma sodium
      (P-Na), chloride (P-Cl), magnesium (P-Mg), potassium (P-K), ionized calcium (P
      iCa), phosphate (P-Pi), creatinine (P-Crea) and urea (S-Urea) were monitored.
      RESULTS: The mean QRS-VD increase during the dialysis session was almost fourfold
      (372 +/- 300%) from 4.16 +/- 2. 40 to 15.60 +/- 7.0 microVs (p < 0.001). This
      change was due to a change in amplitude, since the duration of the QRS complex
      did not alter significantly. The correlation between the changes in QRS-VD and
      body weight from the start to the end of the dialysis session was moderate and
      statistically significant (r = -0.55, p < 0.05). The correlation between the
      changes in QRS-VD and ECW varied from r = -0.67 to -0.97, being statistically
      significant in all patients (p < 0.001). The correlation between BV and QRS-VD
      was assessed at one minute intervals during the dialysis and varied from r = 
      0.22 to -0. 98, being significant in 14 of the 15 patients (p < 0.001).
      Significant ST segments alterations (ST-VM6 elevation > 100 microV) did not occur
      during dialysis. Laboratory parameters reflecting volume and osmotic changes
      during hemodialysis correlated with QRS-VD change: B-Hcr (r = 0.56, p < 0.05), B
      Hb (r = 0.63, p < 0.05), P-Na (r = 0.62, p < 0.05) and S-Urea (r = -0.62, p <
      0.05). CONCLUSIONS: The increase in QRS complex amplitude during hemodialysis is
      correlated to reduced ECW. The mechanism involved is most probably augmentation
      of electrical resistance of the tissues around the heart caused by loss of
      interstitial fluid.

PMID- 10393384
TI  - A low-calorie unrestricted protein diet attenuates kidney damage in
      uninephrectomized spontaneously hypertensive rats.
AB  - BACKGROUND/AIMS: Uninephrectomized, spontaneously hypertensive rats (UNX-SHR)
      develop glomerular hyperfiltration, hyperfusion, and interstitial infiltrate of
      the remnant kidney. Consequently, UNX-SHR is a useful animal model to investigate
      mechanisms involved in the progression of hypertensive renal disease. METHODS:
      Body weight; tail systolic blood pressure (SBP); urine excretion of protein,
      urea, and electrolytes; and serum biochemistry were determined in UNX-SHR at 2
      months of age prior to uninephrectomy (week 0), prior to treatment (week 8) with
      a low-calorie (LC) or control diet, and one month after diet treatment (week 12).
      The LC diet was modified to allow equal intake of protein, sodium phosphorus, and
      other nutrients in both groups. RESULTS: UNX-SHR treated with the LC diet had
      significantly lower body weights and SBP at the end of the experiment than did
      the controls (p < 0.0001). Changes in serum biochemistry and 24-hour urinary
      excretion of protein, sodium, potassium, and urea nitrogen in both groups were
      not statistically significant. The final glomerular filtration rate and renal
      plasma flow were similar in both groups, but the LC diet significantly reduced
      the glomerular damage index (0.0007), mesangial expansion index (p < 0.002),
      volume of interstitium per cortex (p < 0.0003), tubular interstitium volume
      fraction (p < 0.0008), glomerular volume (p < 0.02), and remnant kidney weight (p
      < 0.01). CONCLUSION: We demonstrated that in UNX-SHR, the prevention of renal
      damage by LC diet may involve diminished glomerular growth and interstitial
      infiltrate without changes in renal hemodynamics. Consequently, LC diet,
      regardless of protein ingestion, may be an important tool in the prevention of
      renal damage in hypertension. Additional studies of obese-hypertensive rats may
      confirm the beneficial effect of a LC diet and weight reduction on the renal
      damage of obesity-hypertension.

PMID- 10393383
TI  - Treatment of secondary hyperparathyroidism in hemodialyzed patients with high
      dose calcium carbonate without vitamin D3 supplements.
AB  - BACKGROUND: Vitamin D compounds are usually indicated for the treatment of
      secondary hyperparathyroidism in dialysis patients. The possibility to induce a
      reversal of hyperparathyroidism with calcium supplementation alone is
      controversial. The present study was conducted to assess if oral calcium
      carbonate may constitute a therapeutic option for the control of
      hyperparathyroidism in patients with high PTH concentrations at the beginning of
      the treatment with chronic hemodialysis. METHODS: Thirty-one patients with end
      stage renal failure with an intact PTH concentration above 250 pg/ml at the
      beginning of chronic hemodialysis therapy were treated with high doses of calcium
      carbonate; no patient received either aluminium-containing binders or vitamin D
      compounds. To minimize hypercalcemia, a calcium dialysate concentration of 2.5
      mEq/l was used in all patients. The goal of the study was to reduce the intact
      PTH concentration to 250 pg/ml with oral calcium carbonate supplements alone.
      RESULTS: Throughout the first year on hemodialysis treatment, the intact PTH
      concentration decreased from 538 +/- 256 to 251 +/- 218 pg/ml (p < 0.001). By the
      end of the study, the therapeutic objective was achieved in 22 patients (71%)
      ('responder' group). The remaining 9 patients were classified as the 'treatment
      failure' group. The basal intact PTH concentration was not different between both
      groups (508 +/- 235 vs. 612 +/- 303 pg/ml, respectively, p = n.s.), but 5
      'treatment failure' patients admitted to take a dose of calcium carbonate lower
      than that prescribed. There were 40 episodes of hyperphosphatemia (11% of all
      measurements) in 7 of 31 patients, 5 of them belonged to the noncompliance
      'treatment failure' patients. Only 15 episodes (4% of all measurements) of
      transient hypercalcemia (range 11.1 - 11.9 mg/dl) were detected in 8 patients.
      CONCLUSIONS: Secondary hyperparathyroidism in hemodialysis patients can often be
      reverted by oral calcium carbonate alone. But a good adherence to treatment is
      absolutely necessary.

PMID- 10393385
TI  - Decreased glomerular proteinase activity in the streptozotocin diabetic rat.
AB  - Decreased glomerular proteinase activity may contribute to matrix accumulation in
      diabetes. Male Sprague-Dawley rats were rendered diabetic by injection of
      streptozotocin (STZ) 65 mg/kg i.v.; age-matched, sham-injected rats served as
      controls. Glomeruli from diabetic rats 1 month after STZ injection demonstrated
      significant decreases in collagenase and cathepsin B activities compared to
      control glomeruli. Treatment with insulin resulted in a slight (but not
      significant) increase in collagenase activity and normalized cathepsin B
      activity. We conclude that decreased glomerular collagenase and cathepsin B
      activities are present in STZ diabetes. These alterations may contribute to
      mesangial matrix accumulation.

PMID- 10393386
TI  - Cytokines, pulmonary surfactant and consequences of intrauterine infection.
AB  - Excess of inflammatory cytokines is implicated in the sequence of inflammatory
      diseases during the perinatal period. Specific cytokines induce spontaneous
      premature labor and accelerate fetal lung maturity in case of chorioamnionitis.
      In addition, they are involved in the pathogenesis of chronic lung disease,
      periventricular white matter damage, shock and multiorgan damage. Deficient
      cytokine response of the immature lung is associated with severe respiratory
      distress syndrome and persistent fetal circulation syndrome. Surfactant
      supplementation remains the cornerstone among therapies in the premature infant.
      Brief courses of glucocorticoids, antioxidants or inhaled nitric oxides remain to
      be fully evaluated as possible adjunct therapies shortly after birth in small
      premature infants with severe cardiorespiratory failure.

PMID- 10393387
TI  - Surfactant lavage for the management of severe meconium aspiration syndrome.
AB  - Meconium aspiration syndrome (MAS) continues to be a major cause of morbidity and
      mortality in newborn infants. Recent studies on the pathophysiology of MAS showed
      that the meconium is more potent and toxic than we had previously appreciated. On
      the basis of animal experiences and a clinical pilot study, we propose that early
      tracheobronchial lavage with diluted surfactant is an effective and safe method
      for treatment of severe MAS.

PMID- 10393388
TI  - Use of knockout mice to study surfactant protein structure and function.
AB  - Pulmonary surfactant protein B (SP-B) is a 79 amino acid peptide that is
      intimately associated with surfactant phospholipids in the alveolar airspace.
      Mutations of the SP-B gene that result in complete absence of SP-B are invariably
      fatal in the neonatal period. The pathology associated with SP-B deficiency
      suggests that SP-B plays a critical role in integrating the synthesis, assembly
      and metabolism of the surfactant complex. A strategy is described to elucidate
      the role of SP-B in surfactant homeostasis by characterizing the pathophysiology
      associated with cell specific expression of SP-B constructs in vivo. Human SP-B
      constructs, under control of lung cell-specific promoters, were expressed in SP-B
      knockout mice in order to achieve expression of the human transgene in a null
      background. The effect of transgene expression on lung structure and function was
      assessed by biochemical, morphological and physiological analyses of the
      surfactant system in fetal and postnatal offspring.

PMID- 10393389
TI  - Functional roles and structural analysis of lung collectins SP-A and SP-D.
AB  - Pulmonary surfactant proteins A and D (SP-A and SP-D) belong to the collectin
      subgroup of the C-type lectin superfamily along with mannose-binding protein
      (MBP) and conglutinin. Phospholipids are also ligands for collectins, in addition
      to carbohydrates and glycosphingolipids. SP-A binds
      dipalmitoylphosphatidylcholine, and SP-D and MBP bind phosphatidylinositol. SP-A
      also interacts with alveolar type II cells, implicating SP-A in surfactant
      phospholipid homeostasis. We analyzed an epitope for anti-SP-A monoclonal
      antibodies that block SP-A-specific functions using a phage display peptide
      library and SP-A/MBP chimeric proteins. We also investigated the regions of SP-A
      and SP-D that are required for ligand interactions using SP-A/SP-D chimeras. Lung
      collectins play key roles in the innate immune system of the lung which is
      critical for immediate antibody-independent host defense. We have found that SP-A
      exhibits different interactions with distinct serotypes of lipopolysaccharides
      and affects differently their elicited cellular responses by a direct interaction
      with the lipopolysaccharide receptor CD14. In addition to the basic aspects, lung
      collectins as clinical markers will be discussed.

PMID- 10393390
TI  - Early nasal continuous positive airway pressure and minimal handling in the
      treatment of very-low-birth-weight infants.
AB  - Continuous positive airway pressure (CPAP) was introduced in 1971 and at that
      time welcomed as 'the missing link' between oxygen and ventilator treatment of
      premature infants. Originally CPAP was administered by tracheal tube (or head
      box) which because of the inherent risk of complications necessitated a cautious
      approach. New, more simple and less risky methods of application, such as nasal
      CPAP (N-CPAP), permitted earlier treatment which in randomized trials showed a
      reduction in inspired oxygen concentration, reduced need for mechanical
      ventilation and a reduction in the rate of death. Early N-CPAP/minimal handling
      today is an established first-line treatment in a number of centers in Denmark
      and Sweden, while N-CPAP outside Scandinavia apparently is used less often.
      However, recently the method has gained new interest as more publications have
      demonstrated that N-CPAP/minimal handling is both feasible and effective in most
      very-low-birth-weight infants. Early rescue treatment with fast-acting
      surfactant, given during a brief intubation, has increased the effectiveness of N
      CPAP further. Descriptive studies on N-CPAP suggest that the risk of
      bronchopulmonary dysplasia may be lower than in conventional intensive treatment
      because of the relatively low need for mechanical ventilation. This question is
      at the present time being addressed in a randomized controlled trial in England.

PMID- 10393391
TI  - Clinical trials of postnatal corticosteroids: inhaled and systemic.
AB  - Chronic lung disease (CLD) remains a common problem in neonatal intensive care
      units. Corticosteroids are being used increasingly to prevent or treat CLD.
      Uncertainties remain including the timing, duration and route of administration,
      and ratio of benefits to costs. This paper reviews the outcome of 39 randomized
      clinical trials of postnatal corticosteroid treatment. Twenty-five trials studied
      systemic steroids at three different postnatal ages; early (<96 h), moderately
      early (7-14 days), and delayed (>3 weeks). Fourteen-trials studied inhaled
      steroids (early: <7 days; late: >14 days) and inhaled versus systemic steroids.
      Systemic steroids have short-term beneficial effects improving gas exchange and
      lung mechanics to facilitate earlier extubation when used at any postnatal age in
      infants who are ventilator dependent. Early and moderately early steroids also
      reduce the risk of CLD at both 28 days and 36 weeks. For moderately early steroid
      use, there is also a reduction in neonatal mortality with 1 extra survivor for
      approximately every 16 babies treated (95% confidence interval 9-55). Proven
      adverse effects are either gastro-intestinal (bleeding) or metabolic
      (hyperglycaemia and hypertension). Unproven but potential adverse effects include
      decreased brain and lung growth. Inhaled steroids have been studied less
      thoroughly. Some studies report improvement in gas exchange and lung mechanics,
      but long-term benefits are not apparent to date in the published material. Trials
      comparing inhaled and systemic steroids suggest a more rapid response with the
      latter, but no significant differences in the rate of CLD at either 28 days or 36
      weeks were found. Further research is necessary to define the roles of systemic
      and inhaled steroids in the prevention and treatment of CLD and to allow
      comparison of benefits to costs.

PMID- 10393392
TI  - Effect of isosorbide-5-mononitrate on exercise performance and clinical status in
      patients with congestive heart failure. Results of the Nitrates in Congestive
      Heart Failure (NICE) Study.
AB  - BACKGROUND AND AIMS: Nitrate therapy improves hemodynamics in patients with heart
      failure, but the chronic effects of oral nitrates on exercise performance and
      clinical status have not been well studied. METHODS: Oral isosorbide-5
      mononitrate (ISMN) (50 mg once daily) or placebo was administered to 136 patients
      (NYHA Class 2-3) treated for heart failure, all receiving captopril and most also
      furosemide. Endpoints were treadmill exercise time at 12 weeks by modified
      Naughton protocol (primary), with an additional 12-week follow-up period.
      Secondary endpoints included left ventricular dimensions, ejection fraction,
      cardiothoracic ratio, functional class, quality of life, hospitalizations and
      plasma norepinephrine and atrial natriuretic peptide in a four-center substudy.
      RESULTS: Intention-to-treat analysis showed that mean change in treadmill
      exercise duration tended to be greater in patients receiving ISMN than placebo
      (treatment difference +42 s, 95% CI -5, +90 s at 12 weeks and +21 s, 95% CI -25,
      +74 s after 24 weeks) (NS). Treatment difference was greater in the prespecified
      subgroup with ejection fraction 31-40% (+55 s, 95% CI -11, +136 s at 12 weeks and
      +65 s, 95% CI +3, +147 s) (p = 0.035) at 24 weeks. No deleterious effects (i.e.
      hypotension) were observed with ISMN, although headache was reported in 19% of
      the active treatment group (p = 0.0001). CONCLUSIONS: ISMN added to captopril
      increased treadmill exercise time in patients with heart failure and a lesser
      reduction in baseline ejection fraction, although for the group as a whole, the
      increase in treadmill time was not significant.

PMID- 10393393
TI  - Aspirin sensitivity: the role for aspirin challenge and desensitization in
      postmyocardial infarction patients.
AB  - Aspirin is one of the world's most commonly used medications and its use benefits
      many diverse conditions. Adverse reactions, however, are relatively common as
      well. Hypersensitivity to aspirin can be manifested as acute asthma, urticaria
      and/or angioedema, or a systemic anaphylactoid reaction. We report 3 cases in
      whom aspirin was indicated for secondary prophylaxis of myocardial infarction but
      in whom a remote history of an untoward reaction to it prevented its initial use.
      These patients all underwent further evaluation of their pulmonary and allergic
      history and all 3 were challenged with aspirin. Two patients were found not to be
      sensitive and started on aspirin, the other had a classic asthmatic reaction to
      the drug and was successfully desensitized to aspirin allowing for its use.

PMID- 10393394
TI  - Nonischemic end-systolic performance. Effect of alterations in regional and
      global left ventricular contractility.
AB  - Nonischemic end-systolic performance decreases during ischemia. These changes in
      performance are likely to be dependent on the size and site of the ischemic zone,
      as well as the prevailing loading conditions. This study was designed to examine
      the effect of regional and generalized changes in inotropy on nonischemic end
      systolic performance, independent of the ischemic zone size. Twenty dogs were
      instrumented with sonomicrometers and micromanometer pressure gauges. End
      systolic pressure-thickness relationship data were obained during vena-caval
      balloon inflation. Measurements were obtained before and 90 s after left
      circumflex (LC) artery occlusion. Then, simultaneous with the occlusion of the LC
      artery, isoproterenol (0.04 microg/ml) was infused into the left anterior
      descending artery. After recovery, the same protocol was repeated before and
      after propranolol (0.5 mg/kg). In a separate set of animals, the same
      measurements were made following 2.5 and 5 microg/kg/min dobutamine. The effect
      of ischemia on the nonischemic end-systolic pressure-thickness relationship was
      expressed as the extent to which the relationship is shifted to the left.
      Infusion of intracoronary isoproterenol into the perfusion bed of the nonischemic
      zone produced a significant increase in the slope of the end-systolic pressure
      thickness relationship. During ischemia, however, the extent of leftward shift of
      this relationship was less than that following beta-blockade. Intravenous
      dobutamine resulted in a dose-dependent increase in the slope of the nonischemic
      end-systolic pressure thickness relationship, but the extent of leftward
      displacement of the relationship in response to regional ischemia was less than
      that following the control occlusion. The nonischemic segment is coupled with the
      nonfunctioning ischemic zone in such a way that it is required of the nonischemic
      segment to operate at decreased end-systolic thickness for any end-systolic
      pressure, the extent of which is to be determined, in part, by the size of the
      ischemic zone and the contractile state of the nonischemic myocardium. The lower
      the contractile state prior to coronary occlusion the greater extent of leftward
      shift of the pressure-thickness relationship.

PMID- 10393395
TI  - Recurrence risk of supraventricular tachycardia in pediatric patients.
AB  - We analyzed risk of recurrence of supraventricular tachycardia (SVT) in 70
      pediatric patients using both Kaplan-Meier survival analysis and logistic
      regression of likelihood of recurrence, each with covariates: (1) age at onset of
      SVT; (2) presence of Wolff-Parkinson-White syndrome (WPW), and (3) gender. Among
      38 patients who had onset of SVT <1 year, only 11 had a recurrence, while among
      32 older patients, 30 had a recurrence of SVT (p < 0.00001, Fisher's exact test).
      The survival analyses, stratified by age at onset <1 versus >1 year, were
      significantly different (p < 0.0001) as was stratification by presence of WPW (p
      < 0.01). Logistic regression analysis showed that the only significant predictor
      of recurrence was age at onset; the additional information provided by presence
      of WPW and gender did not significantly add to the prediction of recurrence. The
      odds ratio of recurrence for age at onset >1 versus <1 year was 34.6, with a 95%
      confidence interval of 6.98-172.

PMID- 10393396
TI  - Extracellular amino acids as markers of myocardial ischemia during cardioplegic
      heart arrest.
AB  - Extracellular levels of amino acids in the myocardial interstitium are sensitive
      indicators of myocyte function. Lowered ATP leads to a rapid extracellular
      appearance of amino acids with a high intra- to extracellular concentration
      ratio, such as taurine and glutamate. Nitrogen fluxes are reflected by glutamine,
      while alanine, glycine, serine and leucine are markers of proteolysis. In
      addition, degradation of membrane phospholipids is reflected by other primary
      amines, such as phosphoethanolamine. The time course of these changes was
      determined before, during and after cardioplegic heart arrest. Two regions of the
      heart were monitored in 20 patients by means of microdialysis sampling. After
      only 20 min of heart arrest, extracellular taurine, glutamate and
      phosphoethanolamine increased transiently up to 25 times the basal level. Ten-20
      min later, glutamine increased by 6 times. A doubling of alanine, glycine, serine
      and leucine levels took place 30 min after release of the aortic cross-clamp.
      After 2 h, all were at levels similar to those recorded 15-30 h later. Levels of
      taurine and glutamate in the anterior wall of the heart correlated significantly
      with those of its lateral wall. The response to surgery and heart arrest was
      studied in a group of patients with ischemic heart disease as well as in another
      group of patients, who underwent heart surgery for nonischemic reasons. The
      response of taurine and glutamine was significantly higher for the patients with
      ischemic heart disease, in spite of a shorter mean time of heart arrest. No sex
      differences were recorded. High levels of amino acids coincided frequently with
      clinical events, which were suggestive of ischemia, but were also recorded in a
      few patients without diagnosed events. We conclude that monitoring of
      extracellular amino acids is valuable for evaluation and development of
      cardioprotective strategies.

PMID- 10393397
TI  - Bolus versus continuous low dose of enalaprilat in congestive heart failure with
      acute refractory decompensation.
AB  - The first dose of angiotensin-converting enzyme (ACE) inhibitors may trigger a
      considerable fall of blood pressure in chronic heart failure. The response may be
      dose-related. To determine hemodynamic and systemic oxygenation effects of low
      dose enalaprilat, we administered intravenous enalaprilat (0.004 mg/kg) as bolus
      (group B) or continuous 1-hour infusion (group C) in 20 patients with congestive
      heart failure due to ischemic heart disease with acute decompensation refractory
      to inotropic, vasodilator and diuretic therapy. Hemodynamic and systemic
      oxygenation variables were recorded at baseline (+0 min), +30, +60, +120, +180,
      and +360 min after the start of intervention. Mean arterial pressure (MAP) (p <
      0. 001), mean pulmonary artery pressure (MPAP) (p < 0.001), pulmonary artery
      occlusion pressure (PAOP) (p < 0.001), oxygen extraction ratio (ER) (p < 0.026)
      decreased regardless of enalaprilat application. Compared to group B, there was
      in group C prolonged decrease of MAP, MPAP, PAOP, ER and increase of pulmonary
      artery oxyhemoglobin saturation in regard to baseline values. Cardiac index,
      heart rate, central venous pressure and oxygen consumption index did not change.
      A low dose of intravenous enalaprilat (0.004 mg/kg) can be used to safely improve
      hemodynamics and systemic oxygenation in congestive heart failure due to ischemic
      heart disease with acute refractory decompensation.

PMID- 10393398
TI  - Soluble PECAM-1, but not P-selectin, nor osteonectin identify acute myocardial
      infarction in patients presenting with chest pain.
AB  - We sought to determine plasma levels of platelet/endothelial cell adhesion
      molecule-1 (PECAM-1), P-selectin, and platelet-derived osteonectin, and
      prospectively compare these data with the discharge diagnosis in patients
      presenting with chest pain in a community hospital Emergency Department. Soluble
      antigens were measured by ELISA in 44 subjects including patients with acute
      myocardial infarction (AMI) (n = 13), chest pain of noncardiac origin (n = 17),
      and compared to those of age- and sex-matched healthy controls (n = 14). Elevated
      soluble PECAM-1 (64.5 +/- 18.3 ng/ml, p = 0.019), but not P-selectin (149.5 +/-
      49.8 ng/ml, p = NS), nor osteonectin (549. 5 +/- 159.1 ng/ml, p = NS), occurred
      in the AMI group as compared to patients with noncardiac chest pain (46.2 +/- 7.5
      ng/ml, 118.2 +/- 40.1 ng/ml, and 619.4 +/- 74.4 ng/ml, respectively). Increased
      plasma PECAM-1 may serve as a useful marker in the early detection of patients
      with AMI. Larger studies will be necessary to confirm the utility of soluble
      PECAM-1 in identifying AMI among patients presenting with chest pain.

PMID- 10393399
TI  - Platelet reactivity and streptokinase resistance following antecedent
      streptokinase therapy for myocardial infarction.
AB  - AIMS: To assess the efficacy of second-time administration of streptokinase (SK).
      First-time thrombolysis with SK in myocardial infarction (MI) is established but
      the efficacy of subsequent SK is unknown. METHODS AND RESULTS: Platelet
      reactivity to shear stress, spontaneous and SK-induced thrombolysis were measured
      in vitro in 28 patients who had received SK for MI and compared to 15 controls.
      SK antibody (Ab) titres were inversely related to time from MI. Platelet
      reactivity was greatly enhanced in patients (p < 0.0001). Spontaneous
      thrombolysis in patients was poor and in 17 failed to occur. In contrast,
      thrombolysis occurred in all but 1 control. In patients platelet reactivity was
      strongly related to thrombolytic activity (r = -0.516; p = 0.0029). SK in vitro
      was at least 4 times more effective in controls than in patients. CONCLUSION: The
      chances of achieving patency with second administration of SK are poor. Ab titre
      is not a reliable predictor of resistance.

PMID- 10393400
TI  - Fibrinolytic therapy and n-acetylocysteine in the treatment of patients with
      acute myocardial infarction: its influence on authentic plasma hydroperoxide
      levels and polymorphonuclear neutrophil oxygen metabolism.
AB  - Recently it has been demonstrated that the administration of n-acetylocysteine
      (NAC), in combination with streptokinase, significantly diminished oxidative
      stress in patients with myocardial infarction. The aim of our study was to assess
      the influence of NAC treatment, as adjunct therapy in an evolving myocardial
      infarction, on the polymorphonuclear count, superoxide anion and hydrogen
      peroxide levels and nitric oxide production by PMNs and authentic plasma
      hydroperoxide (ROOH). Treatment of patients with NAC in addition to reperfusion
      therapy was accompanied by a significant decrease in the number of circulating
      polymorphonuclear neutrophils. However, the oxygen metabolism of PMNs was not
      affected by NAC administration. The concentration of authentic plasma
      hydroperoxide was significantly reduced by the administration of NAC which
      suggests diminished oxidative stress during acute myocardial infarction.

PMID- 10393401
TI  - Fuzzy cluster analysis of positive stress tests: comparison with stress
      echocardiography and nuclear perfusion imaging in patients with triple vessel and
      left main coronary disease.
AB  - Fuzzy cluster analysis (FCA) was used to classify 166 outpatient positive
      treadmill stress tests as mildly, moderately, or severely abnormal. The method
      combines ST-segment change with five other stress test variables, and then
      computes a similarity measure to determine how closely each patient's stress test
      resembles a prototypical mildly, moderately, or severely abnormal stress test.
      All patients had coronary angiography within 1 month of their stress tests. For
      the 45 patients with triple vessel disease (TVD), FCA classified 34 of these
      stress tests as severely abnormal (sensitivity = 75%). For the 22 patients with
      left main disease (LM), FCA classified 19 stress tests as severely abnormal
      (sensitivity = 86%). For the combined group with high-grade disease (TVD + LM),
      the sensitivity was 79%. A literature review shows that for stress
      echocardiography, multiple exercise-induced wall motion abnormalities have a
      sensitivity in the 70-80% range for patients with high-grade disease. For nuclear
      stress testing, the high-risk pattern of multiple reversible defects, with or
      without increased lung uptake, has a sensitivity in the range of 70-80% for
      patients with high-grade disease. Thus classification of a positive stress test
      as severely abnormal by FCA has a sensitivity comparable to high-risk patterns on
      stress echocardiography and nuclear stress testing in patients with TVD or LM.

PMID- 10393402
TI  - Familial isolated noncompaction of the left ventricular myocardium.
AB  - Noncompaction of the ventricular myocardium (sometimes referred to as 'spongy
      myocardium') is believed to represent an arrest in endomyocardial morphogenesis.
      The gross anatomical appearance is characterized by numerous excessively
      prominent trabeculations and deep intertrabecular recesses. Distinct
      morphological features can be diagnosed on two-dimensional echocardiography. We
      present here a family of isolated noncompaction of the left ventricular
      myocardium, in which 5 affected individuals suggested the presence of some
      genetic abnormalities in this disorder.

PMID- 10393403
TI  - Atherosclerosis is not an infectious process.

PMID- 10393404
TI  - Anomalous coronary arteries.

PMID- 10393405
TI  - Mapping the ischaemic penumbra with PET: implications for acute stroke treatment.
AB  - The ischaemic penumbra has been documented in the laboratory animal as a severely
      hypoperfused, non-functional, but still viable cortex surrounding the
      irreversibly damaged ischaemic core; with elapsing time, more penumbra gets
      recruited into the core, while tissue reperfusion is able to stop this
      deleterious process until a certain point in time. As saving the penumbra should
      improve clinical outcome, it should constitute the main target of acute stroke
      therapy. In a series of PET studies performed 5-18 h after stroke onset, we were
      able to (i) document, for the first time in man, the existence of tissue
      fulfilling operational criteria for penumbra in about one third of the cases;
      (ii) show that long-term neurological recovery is proportional to the volume of
      penumbra that eventually escapes infarction, and (iii) detect penumbral tissue as
      late as 16 h after symptom onset in occasional patients, suggesting the
      therapeutic window may be protracted in such cases. Mapping the penumbra in the
      individual patient with neuroimaging procedures should allow to formulate a
      pathophysiological diagnosis, and thus to design a rational management of the
      stroke patient and to improve the selection of candidates for therapeutic trials.

PMID- 10393406
TI  - Carotid and vertebral artery injury following severe head or cervical spine
      trauma.
AB  - In order to determine the frequency of neck vessel injuries, Doppler
      investigations were performed in 60 patients following either severe head injury
      (n = 29), cervical spine injury (n = 26), or combined head and cervical spine
      injury (n = 5). The majority of patients were referred to our hospital for early
      rehabilitation; before admission Doppler investigations had been performed in
      only 2 patients. Clinically, 3 patients sustained severe cerebral ischemia due to
      neck vessel trauma: 1 patient with left-sided ICA dissection after head trauma
      revealed Doppler abnormalities only in the early phase of the disease; the second
      patient demonstrated persistent Doppler abnormalities due to traumatic right
      sided ICA and VA occlusion. The third patient sustained a fatal vertebral and
      basilar artery thrombosis following cervical spine injury. In 57 patients without
      clinical signs suspicious of neck vessel trauma, sonography revealed
      abnormalities in 3 patients (11%) with severe head injury and in 6 patients (20%)
      with cervical spine or combined head and spine injury, in both groups mainly
      related to the vertebrobasilar system. Neck vessel injury is probably an
      underdiagnosed complication of severe head or cervical spine trauma. Although
      interpretation of Doppler findings may be difficult, particularly in the
      vertebrobasilar system, Doppler investigations can be recommended as a screening
      method to exclude neck vessel injuries.

PMID- 10393407
TI  - What is the cost of admitting patients with transient ischaemic attacks to
      hospital?
AB  - Financial constraints at our institution prompted us to evaluate the management
      of patients referred to the Acute Stroke Service because of transient ischaemic
      attack (TIA). We analysed age, gender, length of stay, hospital costs, discharge
      disposition and stroke recurrence for all cases of TIA admitted to the Acute
      Stroke Service between January 1, 1994, and December 31, 1996. During this time,
      110 cases of TIA were admitted. All had a CT head scan, 60% had carotid Doppler
      ultrasound, and 30% had transthoracic echocardiography. No patients admitted with
      TIA died, and 92% were discharged home. The average annual cost of in-patient
      management of TIA was 328,000 Canadian dollars, of which 95% were accounted for
      by the cost of the hospital bed alone. If hospitalisation of patients with TIA
      could be reduced, significant cost-savings could be realised.

PMID- 10393408
TI  - Increased risk of intracranial hemorrhage when aspirin is combined with warfarin:
      A meta-analysis and hypothesis.
AB  - BACKGROUND: Oral anticoagulation with vitamin K antagonists increases the risk of
      intracranial hemorrhage; whether addition of aspirin to oral anticoagulation
      augments this risk is unclear. METHODS: Meta-analysis of randomized clinical
      trials in which aspirin was added to oral anticoagulants. RESULTS: Six randomized
      clinical trials were identified, including a total of 3,874 participants. Use of
      aspirin with oral anticoagulants was associated with more than double the
      frequency of intracranial hemorrhage (relative risk = 2.4, 95% CI = 1.2-4.8, p =
      0.02). CONCLUSION: We hypothesize that aspirin when added to oral vitamin K
      antagonists may increase the risk of intracranial hemorrhage, but this
      observation requires confirmation. The magnitude of this effect is uncertain, and
      the clinical importance is likely different for different patient populations.

PMID- 10393409
TI  - Impaired vasoreactivity of the basilar artery system in patients with brainstem
      lacunar infarcts.
AB  - BACKGROUND AND PURPOSE: Diminished vasoreactivity (VR) has been evidenced in
      patients with hemispheric small vessel disease, however, there is no data
      regarding vertebrobasilar (VB) territory VR changes in patients with subcortical
      vascular encephalopathy located in the brainstem. Therefore, we compared the
      cerebral blood flow velocity (CBFV) responses of the VB system during different
      vasoregulatory challenges in healthy volunteers to those in patients with
      brainstem lacunar infarcts. METHODS: In 20 patients with brainstem lacunar
      infarcts and in 10 healthy volunteers the VR of the VB system was measured by
      analyzing the CBFV changes during different stimulation paradigms (ventilation,
      tilting and acetazolamide tests). During transcranial Doppler registration the
      systemic blood pressure and the expiratory partial CO2 pressure were monitored.
      RESULTS: During hypercapnia the VR was significantly higher in the control group
      than in the patient group (10.1 +/- 4.9 vs. 3.4 +/- 5.0 cm/s/kPa, p = 0.0025). In
      a subgroup of patients with mean baseline CBFV <25 cm/s the VR was 1.5 +/- 2.4
      cm/ s/kPa, while patients with mean baseline CBFV >25 cm/s showed a significantly
      higher value (7.8 +/- 6.9 cm/s/kPa). Furthermore, in patients with mean baseline
      CBFV <25 cm/s the pulsatility index was significantly higher than in patients
      with mean baseline CBFV >25 cm/s (1.11 +/- 0.26 vs. 0.86 +/- 0.19, p = 0.0325),
      reflecting significantly higher vascular resistance in the former group. Although
      CBFV measurements during tilting and acetazolamide tests tended to support these
      findings, they showed no significant differences between patients and controls.
      CONCLUSION: Patients with cerebral microangiopathy involving the brainstem showed
      impaired VR in the VB flow territory in association with baseline CBFV.

PMID- 10393410
TI  - Validity of stroke diagnosis on hospital discharge records in Saskatchewan,
      Canada: implications for stroke surveillance.
AB  - This study examines the validity of the diagnosis of stroke on hospital discharge
      records in Saskatchewan, Canada. In total, 1,494 records with a discharge
      diagnosis of 'stroke' or a 'stroke-related condition' were reviewed. The clinical
      algorithm of the 1980 USA National Survey of Stroke was considered the 'gold
      standard'. The positive predictive value of a primary diagnosis of stroke in the
      tertiary-care hospitals was about 90%. In community hospitals the majority of
      stroke cases were coded as ICD9 436 in which the positive predictive value was
      78%. The variation between regions would limit the use of hospital discharge data
      for stroke surveillance.

PMID- 10393411
TI  - Influence of different screening procedures on the stroke prevalence estimates:
      the Italian Longitudinal Study on Aging.
AB  - Stroke prevalence surveys are more and more needed for health care and facility
      planning. Prevalence estimates and costs of the definition procedure may vary
      depending on different screening strategies. We evaluated the impact of these
      different strategies on the overall diagnostic procedure and on stroke prevalence
      estimates in the Italian Longitudinal Study on Aging. A population sample of 5,
      632 individuals aged 65-84 years was screened for stroke by a simple question on
      previous stroke diagnosis, questions on possible stroke symptoms and a simple
      neurological examination. Those screened positive by any of these procedures were
      fully examined by a neurologist for conclusive diagnosis. We determined the
      positive predictive value of each procedure on the final stroke diagnosis and
      calculated prevalence as if each procedure had been used separately. Using the
      three procedures combined, the prevalence rate was 6.0% (95% confidence interval,
      5.4-6.7%). If each procedure had been used as the unique screening tool, the
      rates would have been 5.1% (4.5-5. 7%), 4.1% (3.6-4.7%) and 2.3% (1.9-2.7%), and
      positive predictive values 66.4, 55.2 and 45.1%, respectively. Different
      screening procedures can affect stroke prevalence estimates. Compared to more
      complex screening strategies, the use of a simple question about previous
      diagnosis as the unique screening tool leads to only a slight underestimation of
      stroke prevalence and avoids a 66% increase in the number of subjects to be
      examined in a second-level specialist evaluation, potentially reducing the costs
      of the overall diagnostic procedure.

PMID- 10393413
TI  - Endovascular treatment of carotid dissecting aneurysms.
AB  - BACKGROUND AND PURPOSE: Cervical arterial dissection is a well-recognised cause
      for acute ischaemic stroke. Dissecting aneurysms commonly occur in the affected
      vessels contributing to the clinical presentation. Persistence of these aneurysms
      may provide a source of future embolic events as well as causing local symptoms
      or even be at risk of spontaneous rupture. METHODS: We describe 4 patients with
      traumatic internal carotid artery (ICA) dissections with aneurysm formation at
      the skull base. Three of the 4 patients still had carotid aneurysms on follow-up
      investigations and so underwent endovascular procedures using stenting and coil
      techniques. The carotid aneurysm resolved spontaneously in the fourth patient.
      RESULTS: The endovascular procedures resulted in significant reduction or
      obliteration of the flow within the carotid aneurysms with restoration of the
      true lumen diameter in the adjacent ICA in all 3 patients. No perioperative
      complications were experienced except for transient headache in 2 patients.
      CONCLUSIONS: In patients with persistent aneurysms the exact risk of subsequent
      ischaemic events remains unknown and prospective long-term studies are needed to
      ascertain this risk. If recurrent stroke rates are found to be high, then carotid
      stenting (with or without coil insertion) is a feasible invasive approach which
      could be considered in these patients.

PMID- 10393412
TI  - Venous microemboli in patients with artificial heart valves.
AB  - BACKGROUND: Detection of microemboli signals (MES) in patients with artificial
      heart valves has been extensively described, but the underlying material remains
      unclear. We assumed that the detection of MES in the jugular vein of patients
      with prosthetic valves would clearly argue for gaseous embolic material, since
      formed emboli are unable to cross through the capillaries. METHODS AND RESULTS:
      Twenty-five patients with artificial heart valves, 15 patients with asymptomatic
      carotid artery disease, and 25 normal controls were examined. Monitoring was
      performed simultaneously over the dominant jugular vein and the ipsilateral
      middle cerebral artery for 30 min per subject, using 2-MHz transducers of a color
      duplex scanner for the jugular vein and a pulsed-wave Doppler for the middle
      cerebral artery. Data were harvested in an eight-channel digital recorder and MES
      counts evaluated by two separate observers. MES prevalence in the middle cerebral
      artery was 100, 13 and 0% in patients with artificial heart valves, asymptomatic
      carotid artery disease, and normal controls, respectively. No MES were detected
      in the jugular veins of patients with carotid artery disease or in normal
      controls, while their prevalence was 68% in patients with artificial heart
      valves. The interobserver agreement was satisfactory. CONCLUSION: Our results
      suggest that the embolic material of at least a part of MES in patients with
      artificial heart valves is gaseous.

PMID- 10393414
TI  - Indomethacin for brain edema following stroke.
AB  - Conventional therapies for raised intracranial pressure (ICP) frequently are not
      effective. We report a patient with raised ICP following a large hemispheric
      stroke. After conventional therapies had failed, indomethacin was repeatedly
      administered. After bolus infusion (50 mg), the ICP fell by a mean of 8.1 mm Hg,
      and the mean arterial blood pressure increased by a mean of 7.1 mm Hg, leading to
      a mean increase in the cerebral perfusion pressure by 15.3 mm Hg. After 1 h, the
      ICP had returned to baseline values after most infusions. Continuous infusion of
      indomethacin was not effective. We conclude that indomethacin may reduce elevated
      ICP over a short time in patients with ischemic brain edema even after
      conventional therapy has failed.

PMID- 10393415
TI  - Chromosome assignments of rat phenol sulfotransferase ST1A1 and ST1C1 genes
      (Sult1a1 and Sult1c1) by fluorescence in situ hybridization.

PMID- 10393416
TI  - Assignment of the gene encoding mannan-binding lectin-associated serine protease
      2 (MASP2) to human chromosome 1p36.3-->p36.2 by in situ hybridization and somatic
      cell hybrid analysis.

PMID- 10393417
TI  - Reciprocal chromosome painting shows that genomic rearrangement between rat and
      mouse proceeds ten times faster than between humans and cats.
AB  - Reciprocal chromosome painting between mouse and rat using complete chromosome
      probe sets of both species permitted us to assign the chromosomal homology
      between these rodents. The comparative gene mapping data and chromosome painting
      have a better than 90% correspondence. The reciprocal painting results
      graphically show that mouse and rat have strikingly different karyotypes. At
      least 14 translocations have occurred in the 10-20 million years of evolution
      that separates these two species. The evolutionary rate of chromosome
      translocations between these two rodents appears to be up to 10 times greater
      than that found between humans and cats, or between humans and chimpanzees, where
      over the last 5-6 million years just one translocation has occurred. Outgroup
      comparison shows that the mouse genome has incorporated at least three times the
      amount of interchromosomal rearrangements compared to the rat genome. The utility
      of chromosome painting was also illustrated by the assignment of two new
      chromosome homologies between rat and mouse unsuspected by gene mapping: between
      mouse 11 and rat 20 and between mouse 17 and rat 6. We conclude that reciprocal
      chromosome painting is a powerful method, which can be used with confidence to
      chart the genome and predict the chromosome location of genes. Reciprocal
      painting combined with gene mapping data will allow the construction of large
      scale comparative chromosome maps between placental mammals and perhaps other
      animals.

PMID- 10393418
TI  - High resolution multicolor-banding: a new technique for refined FISH analysis of
      human chromosomes.
AB  - A new multicolor-banding technique has been developed which allows the
      differentiation of chromosome region specific areas at the band level. This
      technique is based on the use of differently labeled overlapping microdissection
      libraries. The changing fluorescence intensity ratios along the chromosomes are
      used to assign different pseudo-colors to specific chromosome regions. The
      multicolor banding of human chromosome 5 is presented as an example.

PMID- 10393419
TI  - Comparative FISH-mapping of six expressed gene loci to river buffalo and sheep
      chromosomes.
AB  - Six expressed gene loci (NF1, CRYB1, CHRNB1, TP53, P4HB and GH1), recently
      assigned to cattle chromosome 19 by both radiation hybrid analysis and FISH
      mapping, were comparatively FISH-mapped to river buffalo chromosome (BBU) 3p and
      sheep chromosome (OAR) 11, extending the physical map in these two important
      bovids. The six loci mapped to the same homoeologous chromosome bands of BBU 3p
      and OAR 11, and their gene order was centromere-NF1-CRYB1-CHNRB1-TP53-(GH1,
      P4HB).

PMID- 10393420
TI  - Molecular cloning and fine mapping of API5L1, a novel human gene strongly related
      to an antiapoptotic gene.

PMID- 10393421
TI  - Cloning and characterization of ASH2L and Ash2l, human and mouse homologs of the
      Drosophila ash2 gene.
AB  - Drosophila ash2 belongs to the trithorax (trx) gene family. The ash2 product
      positively regulates expression of homeotic selector genes, and is implicated in
      early development and formation of various disc patterns in the fruit fly.
      Through large-scale sequencing of human genomic DNA coupled with in silico gene
      trapping, we identified a gene (ASH2L) on chromosome 8p11.2 whose predicted
      product was highly homologous to ash2, characterized it, and identified its mouse
      counterpart. The human ash2 cDNA is 2368 bp long, encoding 628 amino acids. The
      16-exon gene spans more than 34 kb of genomic DNA between STS markers WI-9207
      (centromere) and AFMA295ZD5 (telomere) on chromosome 8, with transcription
      oriented telomere to centromere. The ash2 genes are highly conserved among
      different species, including C. elegans and yeast. The presence of a conserved
      bipartite nuclear localization signal and a PHD finger motif in the human ash2
      gene suggests that the gene product would function as a transcriptional regulator
      in humans, as its homologue does in Drosophila.

PMID- 10393422
TI  - Characterization of the human laminin beta2 chain locus (LAMB2): linkage to a
      gene containing a nonprocessed, transcribed LAMB2-like pseudogene (LAMB2L) and to
      the gene encoding glutaminyl tRNA synthetase (QARS).
AB  - The laminin beta2 chain is an important constituent of certain kidney and muscle
      basement membranes. We have generated a detailed physical map of a 110-kb genomic
      DNA segment surrounding the human laminin beta2 chain gene (LAMB2) on chromosome
      3p21.3-->p21.2, a region paralogous with the chromosome 7q22-->q31 region that
      contains the laminin beta1 chain gene locus (LAMB1). Several CpG islands and a
      novel polymorphic microsatellite marker (D3S4594) were identified. The 3' end of
      LAMB2 lies 16 kb from the 5' end of the glutaminyl tRNA synthetase gene (QARS).
      About 20 kb upstream of LAMB2 we found a gene encoding a transcribed, non
      processed LAMB2-like pseudogene (LAMB2L). The sequence of 1.75 kb of genomic DNA
      at the 3' end of LAMB2L was similar to exons 8-12 of the laminin beta2 chain
      gene. The LAMB2L-LAMB2-QARS cluster lies telomeric to the gene encoding the
      laminin-binding protein dystroglycan (DAG1).

PMID- 10393424
TI  - Assignment of human proliferation associated p100 gene (C20orf1) to human
      chromosome band 20q11.2 by in situ hybridization.

PMID- 10393423
TI  - Physical mapping of the bovine, caprine and ovine homologues of the paired box
      gene PAX8.
AB  - The PAX8 gene, a member of the human paired box gene family, was mapped by FISH
      to chromosome 11 in cattle and goat and to the short arm of chromosome 3 in
      sheep. The cytogenetic position of PAX8 on BTA 11 and on its homologue OAR 3p
      lies in the region where the interleukin beta (IL1B) gene has been previously
      located, (BTA 11q22. 1-->q22.3 and OAR 3p25-->q26 respectively; Lopez-Corrales et
      al., 1998). The results indicated that PAX8 as well as interleukin beta and
      interleukin alpha (IL1B and IL1A) genes detected on the human chromosome segment
      HSA 2q13-->q21 maintain a similar order and location in these three related
      species. In addition, the breakpoint in conserved synteny can now be narrowed to
      a position between the protein C (PROC) and PAX8 genes, which lie in close
      proximity on HSA 2.

PMID- 10393425
TI  - Assignment of STAC to human chromosome band 3p22.3 between D3S3718 and D3S1611.

PMID- 10393426
TI  - FISH mapping of the mouse Ret oncogene to the junction of G-bands E3/F1 on
      chromosome 6 indicates a need for reassessment of the physical and consensus
      maps.

PMID- 10393427
TI  - Assignment of the human dynein heavy chain gene DNAH17L to human chromosome 17p12
      by in situ hybridization and radiation hybrid mapping.

PMID- 10393428
TI  - Assignment of KCNK6 encoding the human weak inward rectifier potassium channel
      TWIK-2 to chromosome band 19q13.1 by radiation hybrid mapping.

PMID- 10393429
TI  - Assignment of the histone deacetylase gene (Hdac3) to mouse chromosome 18B3 by in
      situ hybridization.

PMID- 10393430
TI  - Comparative genomic in situ hybridization discloses recurrent gain of chromosome
      4 in experimental gliomas of the rat.
AB  - The genetic characterization of experimental tumors is essential in order to
      evaluate their relevance as appropriate animal models for human neoplasms. We
      have used flow cytometry and a recently established Comparative Genomic in situ
      Hybridization (CGH) protocol for the rat (Kappler et al., 1998) to investigate
      chromosome copy number changes in five ethylnitrosourea induced gliomas of the
      rat. Flow cytometry showed aneuploid DNA indices in three of the tumors
      investigated. CGH analysis of primary tumors revealed whole chromosome and
      subchromosomal gains of rat chromosomes (RNO) 1, 2, 4, 6, 7, 10, 11, 12, and 13.
      Loss of RNO 5q23-->q35 was apparent in one tumor. High level copy number gains
      were not observed using CGH as well as semiquantitative PCR with Tgfa, Met and
      Hbb primers. Low copy number gain of RNO 4 represents the most common aberration,
      since it was detected in four of five tumors investigated. Three tumors showed
      gain of RNO 7, while two tumors showed gains of RNO 10q31-->qter and RNO 12q.
      Deletion of RNO 5q23-->q35 and gain of RNO 4 occurred mutually exclusively.
      Therefore, we conclude that these two alterations may represent different
      pathways in the pathogenesis of experimental gliomas in the rat. Findings are
      discussed in analogy to human gliomas.

PMID- 10393432
TI  - Assignment of DLK1 to human chromosome band 14q32 by in situ hybridization.

PMID- 10393431
TI  - Human and mouse GPAA1 (Glycosylphosphatidylinositol anchor attachment 1) genes:
      genomic structures, chromosome loci and the presence of a minor class intron.
AB  - Many eukaryotic cell surface proteins are anchored to the membrane with
      glycosylphosphatidylinositol (GPI) that is covalently linked to the carboxyl
      terminus. A Saccharomyces cerevisiae gaa1 mutant is defective in
      posttranslational attachment of GPI to proteins. A recent report demonstrated
      that the GPAA1 gene encodes a component of a transamidase that mediates GPI
      anchor attachment. Here, we report structures and chromosome loci of human and
      mouse GPAA1 genes. Both genes consist of twelve exons that span about 4 kb. Human
      and mouse GPAA1s are located at 8q24.3 and 15E, respectively. There is a human
      pseudo GPAA1 gene (GPAA1P1) that is located at 2q12-->q14. Introns 8 of human and
      mouse GPAA1s were minor class introns bearing AT at the 5' splice sites and AC
      and AT at the 3' splice sites, respectively. The 3' splice sites of corresponding
      introns of African green monkey, Chinese hamster, dog and rat were AC, AT, AT and
      AA, respectively. The mouse GPAA1 gene (Gpaa1) bearing AG at the 3' splice site
      prepared by site-directed mutagenesis was functional, indicating that any
      nucleotide is allowed at the 3' end of a minor class intron.

PMID- 10393433
TI  - Assignment of the aquaporin-8 water channel gene (AQP8) to human chromosome
      16p12.

PMID- 10393434
TI  - Molecular cloning and characterization of the tumor transforming gene (TUTR1): a
      novel gene in human tumorigenesis.
AB  - We cloned and sequenced the cDNA of a potent tumor transforming gene (TUTR1) from
      human testis and determined its primary structure. The TUTR1 cDNA is composed of
      656 nucleotides and encodes a novel protein of 202 amino acids. The predicted
      TUTR1 protein is extremely hydrophilic and contains two proline-rich motifs at
      its C-terminus. Northern blot analysis of the mRNA from various human tissues and
      tumors revealed that TUTR1 mRNA is highly expressed in tumors of the pituitary
      gland, adrenal gland, ovary, endometrium, liver, uterus, and kidney as well as in
      cell lines derived from tumors of the pituitary, breast, endometrium, and ovary.
      With the exception of the testis, the levels of TUTR1 mRNA were either very low
      or undetectable in normal human tissues. Overexpression of TUTR1 in mouse
      fibroblasts (NIH 3T3) cells resulted in an increase in cell proliferation,
      induced cellular transformation in vitro, and promoted tumor formation in nude
      mice. These results suggest that TUTR1 is a novel and potent transforming gene,
      which may be involved in tumorigenesis in numerous different human tumors.

PMID- 10393435
TI  - Comparative cytogenetic mapping of COL14A1, the gene for human and mouse collagen
      XIV.
AB  - Utilizing the FISH technique, the gene for collagen XIV was mapped in the human
      and the mouse genome. The human gene (COL14A1) was assigned to chromosome bands
      8q23-->q24.1. This assignment is in agreement with the localization of the
      undulin gene (UND), whose product has been suggested to be a variant of collagen
      XIV. The mouse gene (Col14a1) was assigned to chromosome 15 band D. Thus,
      collagen XIV represents another example of a gene that belongs to human/mouse
      homology group 90.

PMID- 10393436
TI  - Assignment of human teratocarcinoma derived growth factor (TDGF) sequences to
      chromosomes 2q37, 3q22, 6p25 and 19q13.1.
AB  - The human teratocarcinoma derived growth factor 1 (TDGF1) gene maps on chromosome
      (Chr) 3p21.3. One pseudogene (TDGF3) maps on Chr Xq21-->q22. We now report the
      nucleotide sequence and chromosome location of three additional TDGF pseudogenes.
      The three new sequences (TDGF2, TDGF4 and TDGF5) are truncated at the 5' end and
      have accumulated several point mutations, deletions and insertions. TDGF2, TDGF4
      and TDGF6 map on Chrs 2q37, 6p25 and 3q22, respectively. Finally, Southern blot
      analysis of DNA from normal individuals shows a highly variable restriction
      pattern of the TDGF sequences.

PMID- 10393437
TI  - The application of AFLP fingerprinting to construct a YAC contig containing ADH2
      and MTP on sheep chromosome 6.
AB  - The low density of genetic markers on livestock maps limits progress in
      positional cloning projects. We demonstrate a strategy of combining comparative
      mapping with AFLP fingerprinting to develop physical maps in a defined region of
      the sheep genome. Sequence tagged sites for alcohol dehydrogenase 2 (ADH2) and
      microsomal triglyceride transfer protein (MTP) were developed and used to screen
      a sheep yeast artificial chromosome (YAC) library. Nine YACs were identified
      containing the microsatellite marker BM1329 and either ADH2 or MTP. Additional
      markers in the region were not available, and AFLP analysis was developed to
      identify sheep-specific bands within the YACs to determine their degree of
      overlap. Fourteen bands common to more than one YAC were analysed and provided
      the markers necessary to develop a YAC contig containing the three STS markers.
      One YAC (yac260B5) containing all three markers (ADH2, MTP, and BM1329) was
      mapped to sheep chromosome 6q1.6-->q1.8 by FISH analysis.

PMID- 10393439
TI  - A complete set of repeat-depleted, PCR-amplifiable, human chromosome-specific
      painting probes.
AB  - We describe the generation of a complete set of human chromosome-specific
      painting probes depleted in repetitive sequences. These probes yield highly
      specific signals when hybridized without the addition of a blocking agent, such
      as Cot-1 DNA, and without probe preannealing prior to hybridization. Fluorescent
      intensities and signal-to-background ratios for these probes are comparable to
      those of untreated probes hybridized with Cot-1 DNA. We demonstrate the
      suitability of these probes for applications with very complex probe sets, such
      as multiplex-FISH.

PMID- 10393438
TI  - The structural organization of the human aldehyde reductase gene, AKR1A1, and
      mapping to chromosome 1p33-->p32.
AB  - Genomic DNA encoding for human aldehyde reductase (AKR1A1), a member of the aldo
      keto reductase superfamily, was isolated and characterized. The genomic DNA is
      approximately 16 kb in length and contains eight exons which encode the entire
      coding region and the 3'-untranslated sequences. AKR1A1 was localized on
      chromosome 1p33-->p32 by fluorescence in situ hybridization.

PMID- 10393440
TI  - Assignment of HSD17B5 encoding type 5 17 beta-hydroxysteroid dehydrogenase to
      human chromosome bands 10p15-->p14 and mouse chromosome 13 region A2 by in situ
      hybridization: identification of a new syntenic relationship.

PMID- 10393441
TI  - Assignment1 of the PTP-SL/PTPBR7 gene (Ptprr/PTPRR) to mouse chromosome region
      8A2 by in situ hybridization.

PMID- 10393442
TI  - Abnormal methylation does not prevent X inactivation in ICF patients.
AB  - DNA undermethylation is a characteristic feature of ICF syndrome and has been
      implicated in the formation of the juxtacentromeric chromosomal abnormalities of
      this rare syndrome. We have previously shown that in female ICF patients the
      inactive X chromosome (Xi) is also undermethylated. This result was unexpected
      since female ICF patients are not more severely affected than male patients. Here
      we show that CpG island methylation is abnormal in some ICF patients but in other
      ICF patients, the difference in methylation pattern between Xi and Xa (active X)
      is maintained. The consequences of Xi undermethylation on gene expression were
      investigated by enzyme assays. They showed that significant gene expression did
      not correlate with CpG island methylation status. The widespread Xi
      undermethylation does not affect overall Xi replication timing and does not
      prevent Barr body formation suggesting that a normal methylation pattern is not
      required for normal chromatin organization of Xi. Molecular investigation of some
      X-chromosome intron regions showed that the methylation changes in ICF female
      patients extend to non CpG islands sequences. Our results suggest that the
      genetic alteration of DNA methylation in ICF syndrome has little consequence on X
      chromosome gene expression and chromatin organization.

PMID- 10393443
TI  - Absence of male-pattern baldness in men with X-linked recessive ichthyosis? A
      hypothesis to be challenged.
AB  - X-linked recessive ichthyosis (XRI) is caused by a deficiency of steroid
      sulfatase. Because this enzyme plays an important role in androgen metabolism, we
      advance the hypothesis that men with XRI do not show androgenetic alopecia or
      develop only mild forms of this common type of hair loss. Clinical studies should
      show whether this hypothesis can be supported.

PMID- 10393444
TI  - Longitudinal study of a patient with herpes-simplex-virus-associated erythema
      multiforme: viral gene expression and T cell repertoire usage.
AB  - BACKGROUND: Erythema multiforme is a polymorphous self-limited, often recurrent
      eruption that can follow herpes simplex virus (HSV) infection, hereby designated
      HAEM. Studies of relatively large groups of patients during one recurrent episode
      indicated that HAEM pathogenesis is associated with HSV gene expression, Vbeta2 T
      cell infiltration of lesional skin and altered T cell receptor (TCR) repertoire
      usage by HSV-stimulated peripheral blood mononuclear cells (PBMC). However, HAEM
      recurrences are not always preceded by overt HSV eruptions and virus cannot be
      isolated from HAEM lesional skin. Therefore, it is unknown whether all HAEM
      recurrences experienced by a given patient are HSV related. OBJECTIVE: The
      studies described in this report were designed to examine whether all HAEM
      recurrences experienced by a given patient are HSV related. METHODS: We describe
      one patient who was studied longitudinally during 6 HAEM recurrences and in the
      intervening lesion-free periods. Lesional skin from all HAEM episodes was studied
      for HSV gene expression and infiltration by Vbeta2 and Vbeta3 T cells. PBMC
      obtained at these times were assayed for TCR repertoire usage upon HSV
      stimulation. RESULTS: Lesional skin from all HAEM episodes was positive for HSV
      gene expression (RNA and protein) as well as Vbeta2 T cell infiltration. HSV
      stimulated PBMC obtained at these times had an altered TCR repertoire
      characterized by a predominance of Vbeta2 cells. The duration of viral gene
      expression, Vbeta2 cell infiltration and altered TCR repertoire usage correlated
      with the duration of clinical symptoms. CONCLUSION: The data suggest that HSV and
      a virus-specific immunopathology component are involved in the causation of all
      HAEM episodes experienced by the patient.

PMID- 10393445
TI  - Autoantibodies against oxidatively modified low-density lipoprotein in patients
      with Behcet's disease.
AB  - BACKGROUND: Change of lipids and lipoprotein metabolism and an imbalance of the
      oxidant-antioxidant system related to the disease activity have been reported in
      Behcet's disease. Therefore, there is a tendency of oxidative modification of
      lipids and lipoproteins in patients with the disease. OBJECTIVE: To investigate
      serum autoantibodies against oxidatively modified low-density lipoprotein (oxLDL)
      as a marker for the degree of in vivo oxidation of lipoproteins in Behcet's
      disease. METHODS: Serum autoantibodies against oxLDL, total cholesterol,
      triacylglycerol, HDL cholesterol, LDL cholesterol, apolipoprotein (Apo) AI, Apo
      B, alpha1-antitrypsin, alpha2-macroglobulin and erythrocyte sedimentation rate
      were determined in 37 patients and 30 sex- and age-matched healthy volunteers.
      Autoantibodies against oxLDL were measured by a commercial enzyme-linked
      immunosorbent assay. RESULTS: Serum autoantibody levels against oxLDL were
      significantly higher in patients than in controls (425 +/- 365 and 187 +/- 132
      mU/ml, respectively; p < 0.05). The levels of autoantibodies against oxLDL in the
      patients were found to correlate with total cholesterol, LDL cholesterol, HDL
      cholesterol and alpha1-antitrypsin levels (r = 0.38, p < 0.05; r = 0.42, p <
      0.05; r = -0.38, p < 0.05; r = 0.42, p < 0. 05, respectively). CONCLUSION: It has
      been shown in previous studies that high autoantibody titers against oxLDL may be
      important in diseases with atherosclerosis as seen in systemic lupus
      erythematosus and rheumatoid arthritis. High autoantibody titers against oxLDL
      are not specific for Behcet's disease but probably important for pathologic
      processes in the disease. We suggest that increased levels of autoantibodies
      against oxLDL may be a factor responsible for endothelial dysfunction and
      development of vascular pathology in Behcet's disease.

PMID- 10393446
TI  - Comparative analysis of severe aphthosis and Behcet's disease: 104 cases.
AB  - BACKGROUND: The nosologic field of aphthosis is not well defined. While criteria
      for Behcet's disease (BD) are lacking in severe unipolar or bipolar aphthosis,
      these disorders however lead to an important impairment of quality of life. The
      aim of this study was to assess the relationship between severe aphthosis and BD.
      METHODS: Records of all patients hospitalized for aphthosis or BD during a 20
      year period were reviewed. RESULTS: According to clinical data, cases (n = 104)
      were classified as unipolar aphthosis (group I, n = 53), bipolar aphthosis (group
      II, n = 30) or BD (group III, n = 21). The characteristics of aphthae (number,
      localization, recurrences, presence of scars) were similar in all groups.
      Specific cutaneous manifestations (erythema nodosum, pseudofolliculitis,
      papulonodules) were present in 15, 17 and 95% of patients of groups I, II and
      III. Cutaneous puncture hypersensitivity was present in 14 out of 18 patients of
      group III and no patient of the two other groups. At least one extramucous
      specific manifestation (cutaneous, ophthalmologic, neurologic, articular,
      vascular) was present in 43% of patients of group I and II, and 100% in group
      III. CONCLUSION: These data support the hypothesis of a continuous spectrum
      linking severe aphthosis to BD.

PMID- 10393447
TI  - Solar urticaria: A consideration of the mechanism of inhibition spectra.
AB  - BACKGROUND: Solar urticaria is a rare disorder characterized by pruritus,
      erythema and wheal upon sunlight exposure. Inhibition spectra (IS), which prevent
      wheal formation, have been found mainly in Japanese patients and lie mostly in
      longer wavelengths than the action spectrum (AS). The exact mechanism of AS and
      IS has not been clarified. PATIENTS AND METHODS: To elucidate the mechanism of AS
      and IS, we conducted photobiological studies including in vitro irradiated serum
      injection tests and measurements of plasma histamine levels in 3 patients with
      IS. RESULTS: All patients had AS ranging between 400 and 490 nm and IS ranging
      between 520 and 610 nm. A wheal reaction appeared soon after the termination of
      IS irradiation. The patients developed no wheal or erythema upon intradermal
      injection of preirradiated serum. Plasma histamine levels were not elevated
      during irradiation with slide projector light, but marked elevation of histamine
      was observed when wheals developed after the termination of inhibitory
      irradiation. CONCLUSION: These results suggest that the IS in our cases might
      inactivate photoallergens produced by AS and, additionally, stabilize mast cell
      degranulation.

PMID- 10393448
TI  - Cutaneous reaction to ultraviolet irradiation in human-immunodeficiency-virus
      infected patients. A case-control study.
AB  - BACKGROUND: HIV-infected patients, like renal transplant recipients, are at
      increased risk of developing skin cancer in photoexposed areas. Previous studies
      demonstrated that prolonged ultraviolet (UV)-induced erythema and a decreased and
      delayed tanning could be correlated with an increased risk of skin cancers.
      OBJECTIVE: As HIV-infected patients are at an increased risk of developing skin
      cancers, we aimed to assess the cutaneous response to UV irradiation in these
      patients. METHODS: Twelve HIV-infected patients and 12 healthy volunteers were
      included in a prospective case-control study. No patient or volunteer had a
      history of skin cancer or photodermatosis. The minimal erythemal dose (MED) was
      determined using a solar simulator UV source, and, then, each subject underwent
      an exposure of 6 MED. The erythemal and pigmentation responses were studied using
      a visual scale and a tristimulus colorimeter over a 4-week period. RESULTS: We
      failed to demonstrate any significant differences between HIV-infected patients
      and controls for erythema and delayed pigmentation. No difference was found for
      MED between the two groups although most HIV-infected patients received
      potentially photosensitive drugs. CONCLUSIONS: Our results suggest that, as a
      group, the HIV-infected patients without a history of photosensitivity or skin
      cancer did not demonstrate a greater susceptibility to intense UV irradiation in
      terms of erythema and pigmentation induced by intense UV exposition.

PMID- 10393449
TI  - Cigarette smoking as a triggering factor of hidradenitis suppurativa.
AB  - BACKGROUND: Hidradenitis suppurativa is a chronic inflammatory skin disease
      involving the axillary, inguinal and anogenital regions and sometimes, in
      addition, the submammary or sacral areas. The etiology of this condition is
      unknown. OBJECTIVE: A matched-pair case-control study was performed to evaluate
      the influence of smoking habits on the manifestation of this disease. METHODS:
      Patients who had received surgical treatment for hidradenitis suppurativa in two
      dermatological centers completed a questionnaire dealing with family history,
      course of the disease and smoking habits. To form a randomized matched-pair
      control group, an equal number of patients admitted for various other skin
      diseases such as atopic dermatitis, varicose veins, skin tattoos, alopecia areata
      or melanoma was matched for sex and age and evaluated for smoking habits.
      Statistical analysis was performed by use of several chi2 tests in a cross-table
      setting. Moreover, a comparison to the expected smoking prevalence in Germany
      based on national statistics was performed. RESULTS: Out of 84 patients treated
      for hidradenitis suppurativa, 63 subjects (27 men, 36 women) completed the
      questionnaire. The rate of active cigarette smokers was 88.9% (56 patients),
      whereas 4 subjects (6.4%) had never smoked. 3 patients (4.8%) stated to be ex
      smokers, but 2 of these had quit smoking only recently and after onset of the
      disease. The rate of smokers in the matched-pair control group was 46%. The
      significantly higher proportion of active smokers among patients with
      hidradenitis suppurativa can be expressed by an odds ratio of 9.4, the calculated
      95% confidence interval was 3.7-23.7 (p < 0.001). The expected smoking prevalence
      in Germany was 26.7% according to national statistics. 73% of our patients had no
      family history of hidradenitis suppurativa whereas 27% reported at least one
      affected first-degree relative. CONCLUSION: From the exceedingly high rate of
      smokers among patients with this condition we conclude that cigarette smoking is
      a major triggering factor of hidradenitis suppurativa. Remarkably, the disease
      can be categorized as a smoking sequel that is neither of vascular nor neoplastic
      nature. Because familial occurrence was rather rarely reported, and because an
      environmental factor in the form of cigarette smoking appears to be of crucial
      importance to trigger the disease, we assume that the genetic basis of
      hidradenitis suppurativa is polygenic rather than mendelian. Smoking cessation
      should be encouraged particularly in patients with hidradenitis suppurativa
      although it is unknown whether this improves the course of the disease.

PMID- 10393450
TI  - The Dyshidrotic Eczema Area and Severity Index - A score developed for the
      assessment of dyshidrotic eczema.
AB  - BACKGROUND: Dyshidrotic eczema of the palms and soles is a common condition,
      which can be rather resistant to treatment. Therapy studies and their
      comparability are of clinical importance. OBJECTIVE: As standardized assessment
      methods for the severity of this particular form of eczema are lacking, we
      developed a severity index for dyshidrotic eczema. METHODS: The Dyshidrotic
      Eczema Area and Severity Index (DASI) is based on the severity grade of single
      items - number of vesicles per square centimetre (V), erythema (E), desquamation
      (S) and itch (I) - and the extension of the affected area (A) and is calculated
      with defined score points (p) as: DASI = (pv + pE = pS + pI) x pA. RESULTS: In
      two treatment studies on dyshidrotic hand eczema, the DASI was found to be a
      simple and useful tool to assess the severity of dyshidrotic eczema and the
      effect of therapy. CONCLUSION: The DASI needs to be further validated in larger
      cohorts.

PMID- 10393451
TI  - Type 2 segmental manifestation of multiple glomus tumors: A review and
      reclassification of 5 case reports.
AB  - BACKGROUND: In various autosomal dominant skin disorders, segmental forms
      reflecting mosaicism have been reported. Recently, two different types of mosaic
      manifestation have been delineated. Type 1 reflects heterozygosity for the
      underlying mutation and shows a degree of severity as observed in the
      corresponding nonmosaic phenotype. Type 2 originates from loss of heterozygosity,
      shows an excessively severe involvement and is usually superimposed on the
      disseminated lesions of the ordinary trait. OBJECTIVE: We wanted to exemplify
      further the proposed rule of dichotomy. METHODS: We have screened the literature
      on multiple glomus tumors, a trait that follows an autosomal dominant mode of
      transmission. RESULTS: We found 5 cases of multiple glomus tumors suggesting a
      type 2 segmental involvement. In all of these cases, a unilateral band-like or
      patchy arrangement of excessively pronounced glomus tumors was associated with
      disseminated lesions corresponding to the ordinary phenotype, and in 3 cases
      other family members were affected with disseminated glomus tumors. The
      unilateral agminated lesions were reported to be present in early childhood,
      whereas the disseminated lesions appeared later. CONCLUSION: Multiple glomus
      tumors can be added to the list of autosomal dominant skin disorders that may
      show a type 2 segmental involvement.

PMID- 10393452
TI  - Antibacterial efficacy of benzoyl peroxide in phospholipid liposomes. A vehicle
      controlled, comparative study in patients with papulopustular acne.
AB  - BACKGROUND: Literature reports indicate that phospholipid liposomes facilitate
      the accumulation of active agents in the infundibulum. OBJECTIVE: The study
      hypothesis of an improved antibacterial efficacy of benzoyl peroxide (BPO) in
      phospholipid liposomes was tested in comparison with a commercial and a
      pharmacopoeial BPO preparation. METHODS: The infundibular bacterial samples were
      obtained with the Permabond technique from 20 acne patients who had been treated
      with the test substances (vehicle-controlled) for 2 weeks twice per day in a
      single-blinded, comparative study on the upper back. RESULTS: A significant
      antibacterial effect in the infundibula (Propionibacteria and Micrococcaceae,
      both: p < 0.001) for a BPO phospholipid liposome formulation could be
      demonstrated. In comparison to the other significantly efficacious BPO
      formulations which were also tested (commercial product and pharmacopoeial
      formulation), the BPO phospholipid liposome formulation showed a significantly
      greater antibacterial efficacy for Propionibacteria and Micrococcaceae (both: p <
      0.01). CONCLUSION: A BPO formulation in phospholipid liposomes may represent an
      improvement of the conventional external BPO treatment of acne.

PMID- 10393453
TI  - Predictive factors for failure of isotretinoin treatment in acne patients:
      results from a cohort of 237 patients.
AB  - BACKGROUND: The efficacy of oral isotretinoin in acne has been established,
      though the role of the mean daily dose (MDD) is still unclear. OBJECTIVE: To
      determine the predictive factors of resistance to oral isotretinoin and the role
      of the MDD of isotretinoin on relapse of acne while taking into account patient
      characteristics and the total cumulative dose (TCD). METHODS: Two hundred and
      thirty-seven patients treated with oral isotretinoin for the first time were
      enrolled by a single dermatologist. Patients with closed comedonal acne and with
      hyperandrogenism received adequate therapy prior to isotretinoin. RESULTS: Closed
      comedonal acne was the only predictive factor of resistance to isotretinoin with
      an adjusted OR = 2.7 (95% CI: 1.0-7.3). The estimated rates of relapse at 1, 3
      and 5 years were 14, 40 and 48%, respectively. Age and grade of facial acne were
      the only predictive factors for relapse with adjusted relative risks of 0.6 (95%
      CI: 0.4-0.8) for age >/= 20 and 1.5 (95% CI: 1.0-2.2) for grade > 3. CONCLUSION:
      MDD, TCD, closed comedonal acne and hyperandrogenism that have been adequately
      treated prior to isotretinoin treatment had no prognostic value for relapse.

PMID- 10393454
TI  - Mycosis fungoides with mucinosis follicularis in childhood.
AB  - Mycosis fungoides is a cutaneous T-cell lymphoma (CTCL) usually observed in mid
      to late adulthood. It occurs only rarely during childhood. Follicular mucinosis
      is a chronic dermatosis involving the sebaceous glands and outer root sheaths. It
      is normally differentiated into a juvenile benign form and an adult form possibly
      associated with mycosis fungoides. We report a 12-year-old boy who presented with
      an 8-month history of erythematous mucinous plaques on the scalp. Three months
      later, he developed erythematous patches and plaques on his whole body,
      accompanied by cervical lymphadenopathy. A biopsy showed follicular mucinosis and
      epidermotropism of the lymphocytic infiltrate. Immunophenotyping and a PCR
      clonality test were consistent with CTCL. The patient received PUVA treatment and
      local steroids, resulting in partial remission. Mycosis fungoides should be
      considered in the differential diagnosis of chronic, scaling dermatoses in
      childhood. Moreover, follicular mucinosis in childhood can be associated with
      mycosis fungoides.

PMID- 10393455
TI  - Nail changes secondary to docetaxel (Taxotere).
AB  - Docetaxel is a new taxoid antineoplastic drug widely used for advanced breast
      cancer. Skin and nail toxicity are one of the more frequent nonhematologic
      adverse reactions. Besides dark pigmentations and Beau's lines, subungual
      hemorrhage, orange discoloration, acute painful paronychia, onycholysis,
      subungual hyperkeratosis and transverse loss of the nail plate are described. The
      type of nail alteration is related with the number of cycles administered and
      there are no efficacious preventive measures to avoid its development. Clinicians
      should recognize the clinical picture of these adverse nail reactions because
      docetaxel is used for several neoplastic disorders.

PMID- 10393456
TI  - Multiple fixed drug eruption caused by iomeprol (Iomeron), a nonionic contrast
      medium.
AB  - Most cases of drug eruption caused by nonionic contrast media (NICM) reported to
      date have been of the erythema multiforme type. Herein we report the first case
      of multiple fixed drug eruption (FDE) caused by iomeprol (Iomeron(R)). A 67-year
      old woman developed multiple pea-sized erythematous papules on the trunk and
      extremities 4 days after receiving 100 ml of iomeprol for a computed tomography
      examination. Some of the papules coalesced, forming 7 large plaques on the limbs.
      Six months later, the patient was mistakenly administered iomeprol again. On the
      following morning, erythematous plaques admixed with vesicles recurred at the
      same sites as during the previous episode. In both episodes, the lesions cleared
      leaving pigmentation that faded with 6 weeks. Both patch testing and an
      intradermal test with iomeprol on lesional pigmented skin were positive. The
      present case indicates that NICM may cause multiple FDE and that repeated
      administration of the causative agent may increase the severity of the eruption.

PMID- 10393457
TI  - Vegetating iododerma with fatal outcome.
AB  - A 65-year-old woman on whom a cardiac catherization using iodine contrast had
      been performed developed 5 days later acute renal failure, respiratory
      insufficiency and cutaneous lesions consisting of two great vegetating masses
      located on both cheeks and pustular vesicular lesions on the extremities. A
      fortnight later, the patient died. We would like to stress this case because of
      the exceptional nature of vegetating iododerma at present, and the importance of
      recognizing a possibly fatal disease.

PMID- 10393458
TI  - Metastasizing porocarcinoma of the head with lethal outcome.
AB  - Porocarcinoma is a very rare malignant tumor arising from the duct of eccrine
      sweat glands. Its prognosis is variable. We report on a patient who developed
      lymph node and multiple distant metastases, and who died of this malignancy only
      6 months after the initial diagnosis.

PMID- 10393459
TI  - Lichenoid cutaneous drug reaction at injection sites of granulocyte colony
      stimulating factor (Filgrastim).
AB  - Colony-stimulating factors are widely used for bone marrow recovery after
      chemotherapy. Various cutaneous side-effects have been described in most cases
      involving neutrophils. We report the first case of lichenoid reaction at
      injection sites of granulocyte colony-stimulating factor (G-CSF) in a 40-year-old
      patient treated for breast cancer. The eruption cleared after drug withdrawal, no
      recurrence was observed after drug replacement by granulocyte-macrophage colony
      stimulating factor. Mainly lymphocyte-mediated lichenoid eruption to G-CSF was
      shown. Cutaneous side-effects to G-CSF do not share unequivocal pathogeny based
      on stimulation of neutrophils.

PMID- 10393460
TI  - Corticosteroid-induced pancreatitis in patients with autoimmune bullous disease:
      case report and prospective study.
AB  - Corticosteroid pulse therapy using very high doses may produce corticosteroid
      induced pancreatitis (CIP) that is unexpected during conventional oral
      corticosteroid therapy and may sometimes be fatal. Our goal was to evaluate the
      relation between pulse corticosteroid administration and pancreatitis. A case of
      CIP is reported, and a prospective study was performed. Corticosteroid pulse
      therapy followed by 30 mg prednisolone orally was utilized in 7 hospitalized
      patients with autoimmune bullous disease, and serum pancreatic enzymes were
      measured during therapy. The case report revealed reproducible pancreatitis in a
      dose-dependent manner after 2 corticosteroid regimens. In the prospective study,
      serum pancreatic enzyme levels increased significantly within several days after
      pulse therapy, then decreased with tapering of the dose of oral prednisolone.
      Laboratory pancreatic alterations appear to be induced within days after pulse
      corticosteroid administration in a dose-dependent manner: less than 25 mg of oral
      prednisolone may be below threshold to alter the pancreatic enzyme level.

PMID- 10393461
TI  - Elastic nevus with normal expression of elastin and elastin-related proteins
      mRNAs.
AB  - A 3-year-old Japanese girl presented with disseminated white papules on the
      trunk. A biopsied specimen of the lesional skin revealed a focal accumulation of
      elastic fibers in the mid to deep dermis. No skeletal involvement was detected.
      This case was considered to be elastic nevus without systemic involvement. Since
      an elevated elastin expression in the fibroblasts of typical Buschke-Ollendorff
      syndrome (BOS) has been reported, elastin and elastin-related protein mRNA levels
      in the cultured patient fibroblasts were determined. There were no significant
      differences of steady-state levels of elastin, fibrillin 1 and microfibril
      associated glycoprotein 1 mRNAs between patient and matched control fibroblasts.
      Elastic nevus without skeletal involvement may be etiologically different from
      typical BOS.

PMID- 10393462
TI  - Epidermolysis bullosa acquisita with combined features of bullous pemphigoid and
      cicatricial pemphigoid.
AB  - Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal blistering
      disease associated with autoantibodies against type VII collagen. The classical
      or mechanobullous form of EBA is characterized by skin fragility, trauma-induced
      blisters and erosions with mild mucous membrane involvement and healing with
      scars. Furthermore, bullous-pemphigoid-like and cicatricial pemphigoid-like
      features have been described. We report a patient who developed a bullous skin
      disease with upper airway obstruction requiring tracheotomy. The diagnosis of EBA
      was established by immunoblot, showing a band at 290 kD (collagen VII), and NaCl
      split skin immunofluorescence (IgG deposition at the floor of the split). This
      case presented with clinical features of both bullous pemphigoid and cicatricial
      pemphigoid which to our knowledge is the first report of such a combination in
      EBA. The patient also presented tracheal involvement that has never been
      described either.

PMID- 10393463
TI  - Diabetic neuropathic foot ulcer: successful treatment by low-intensity laser
      therapy.
AB  - OBJECTIVE: To evaluate the efficacy of low-intensity laser irradiation for the
      induction of wound healing of a diabetic neuropathic foot ulcer. CASE: We report
      a case of a man with insulin-dependent diabetes mellitus, sensory neuropathy,
      macroangiopathy and microangiopathy who had been suffering from an ulcer of his
      first left toe accompanied by osteomyelitis for 6 weeks. RESULTS: After a total
      of 16 sessions of low-intensity laser therapy using a 670-nm diode laser
      administered within a 4-week period the ulcer healed completely. During a follow
      up period of 9 months, there was no recurrence of the ulcer even though the
      patient's metabolic condition remained unstable. CONCLUSIONS: Although laser
      therapy was not applied as a monotherapy, the present observation suggests that
      it might constitute a useful side-effect-free alternative treatment modality for
      the induction of wound healing of neuropathic ulcers in diabetic patients.
      Therefore large properly controlled randomized studies seem justified.

PMID- 10393464
TI  - Dermatophytic granuloma caused by Microsporum canis in a heart-lung recipient.
AB  - We present a case of dermatophytic granuloma caused by Microsporum canis in a
      heart-lung recipient. This 66-year-old man was seen for erythematous pustules and
      papules on the forearm. The diagnosis was suspected after histological
      examination showing an inflammatory infiltrate in the upper dermis with giant
      cells containing intracytoplasmic fungal elements. Cultures of the skin biopsy
      confirmed the diagnosis identifying M. canis. Our case emphasizes the possibility
      of deep dermatophytic infections in immunocompromised patients. There are only 4
      additional reports of M. canis infection responsible for invasion of the dermis
      in such patients. The follicle involvement probably explains these dermal lesions
      due to the progression of the dermatophyte from the hair follicle to the dermis.
      In our observation topical antifungal therapy alone was unsuccessful and
      fluconazole seems to be the treatment of choice for these M. canis invasive
      dermal cutaneous infections.

PMID- 10393465
TI  - History and nomenclature of alpha1-adrenoceptors 
AB  - Until 1974 it was widely accepted that alpha-adrenoceptors represented a
      homogeneous population of receptors. Following the discovery of presynaptic,
      release-modulating receptors and based on differences in potency for the alpha
      adrenoceptor antagonist phenoxybenzamine, it was proposed in 1974 that alpha
      adrenoceptors should be subdivided in alpha1- and alpha2-subtypes. The concept of
      subtypes of the alpha1-adrenoceptor was first suggested in the mid 1980s on the
      basis of the different affinities for the agonist, oxymetazoline, and the
      antagonists, WB4101 and phentolamine on certain alpha1-adrenoceptor mediated
      pharmacological preparations. Subsequent characterization of the alpha1
      adrenoceptor using radioligand binding and functional studies has led to the
      identification of three native prazosin-high-affinity alpha1-adrenoceptor
      subtypes designated alpha1A, alpha1B, and alpha1D, corresponding to the three
      alpha1-adrenoceptor subtypes (alpha1a, alpha1b, and alpha1d) characterized by
      molecular cloning techniques. Studies concerning the distribution of alpha1
      adrenoceptors in the human prostate tissue have shown that the predominant cloned
      alpha1a-adrenoceptor subtype characterized by RNAase protection assays
      corresponds to the alpha1A-subtype. Both obstruction and lower urinary tract
      symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are enhanced
      by noradrenergic activation of stromal alpha1-adrenoceptors in the enlarged
      prostate. Therefore, the prostatic alpha1-adrenoceptors have become an important
      target for the pharmacotherapeutic treatment of BPH. In this context, Alfuzosin
      was the first uroselective alpha1-adrenoceptor antagonist to be evaluated in the
      treatment of BPH and was subsequently marketed, initially in France, in 1987.
      This drug has since become the standard alpha1-adrenoceptor blocker in the
      treatment of BPH and is widely marketed in Europe. Many of the alpha1
      adrenoceptor antagonists currently prescribed in the treatment of BPH do not
      exhibit in vitro selectivity between alpha1A, alpha1B, and alpha1D-subtypes and
      yet they have good clinical tolerance in terms of low incidence of cardiovascular
      effects. One possibility to explain these findings is that another alpha1
      adrenoceptor subtype could be implicated in human prostatic smooth muscle
      contraction. There is some evidence that an alpha1-adrenoceptor subtype with
      lower affinity for prazosin designed alpha1L, which has not been cloned yet, may
      be the predominant alpha1-subtype involved in the contractile response of the
      human prostatic smooth muscle to noradrenaline.

PMID- 10393467
TI  - Structure-function relationships of the alpha1b-adrenergic receptor.
AB  - The alpha1b-adrenergic receptor (AR) is a member of the large superfamily of
      seven transmembrane domain (TMD) G protein-coupled receptors (GPCR). Combining
      site-directed mutagenesis of the alpha1b-AR with computational simulations of
      receptor dynamics, we have explored the conformational changes underlying the
      process of receptor activation, i.e. the transition between the inactive and
      active states. Our findings suggest that the structural constraint stabilizing
      the alpha1b-AR in the inactive form is a network of H-bonding interactions
      amongst conserved residues forming a polar pocket and R143 of the DRY sequence at
      the end of TMDIII. We have recently reported that point mutations of D142, of the
      DRY sequence and of A293 in the distal portion of the third intracellular loop
      resulted in ligand-independent (constitutive) activation of the alpha1b-AR. These
      constitutively activating mutations could induce perturbations resulting in the
      shift of R143 out of the polar pocket. The main role of R143 may be to mediate
      receptor activation by triggering the exposure of several basic amino acids of
      the intracellular loops towards the G protein. Our investigation has been
      extended also to the biochemical events involved in the desensitization process
      of alpha1b-AR. Our results indicate that immediately following agonist-induced
      activation, the alpha1b-AR can undergo rapid agonist-induced phosphorylation and
      desensitization. Different members of the G protein coupled receptor kinase
      family can play a role in agonist-induced regulation of the alpha1b-AR. In
      addition, constitutively active alpha1b-AR mutants display different
      phosphorylation and internalization features. The future goal is to further
      elucidate the molecular mechanism underlying the complex equilibrium between
      activation and inactivation of the alpha1b-AR and its regulation by
      pharmacological substances. These findings can help to elucidate the mechanism of
      action of various agents displaying properties of agonists or inverse agonists at
      the adrenergic system.

PMID- 10393466
TI  - Molecular pharmacology of human alpha1-adrenergic receptors: unique features of
      the alpha 1a-subtype.
AB  - alpha1-Adrenergic receptors (alpha1ARs) are G protein-coupled receptors important
      in the dynamic component of benign prostatic hyperplasia. alpha1ARs stimulate
      predominantly phospholipase C-beta, resulting in mobilization of calcium from
      intracellular stores and, ultimately, smooth muscle contraction. cDNAs encoding
      three human alpha1ARs (alpha1a, alpha1b, alpha1d) have been cloned, expressed
      stably in cells, and characterized pharmacologically. Extensive species
      heterogeneity in tissue distribution emphasizes the importance of studying
      alpha1ARs in human tissues. Because of the important role of alpha1aARs in
      mediating prostate smooth muscle contraction, this current review describes
      alpha1a carboxyl terminal splice variants, examines alpha1AR subtype distribution
      in various tissues and the role of the putative alpha1LAR in human prostate,
      provides a brief discussion regarding regulation of this receptor by agonist, and
      finally discusses implications of distinct alpha1AR subtype distribution in human
      bladder compared with prostate.

PMID- 10393468
TI  - Adrenoceptor pharmacology: urogenital applications.
AB  - Although the selective alpha1-adrenoceptor antagonists were initially developed
      as antihypertensive drugs, and they are still utilized for this indication, the
      alpha1-adrenoceptor blockers are now used extensively for the symptomatic
      treatment of benign prostatic hyperplasia (BPH). As a result, a number of new
      drugs in this class have been specifically developed for use in BPH. The utility
      of alpha1-adrenoceptor antagonists in BPH derives from the observation, made
      several decades ago, that the irreversible, alpha1- adrenoceptor selective
      antagonist phenoxybenzamine, blocked the contractile activity of norepinephrine
      in isolated strips of rat or human prostate. Following the further
      subclassification of alpha1-adrenoceptors into the alpha1A-, alpha1B- and alpha1D
      adrenoceptor subtypes, the relationship between subtype selectivity and efficacy
      in BPH has been investigated in the hope of developing more selective drugs for
      the treatment of this disorder. Molecular characterization of the adrenoceptor
      population in human prostate clearly shows the alpha1A-adrenoceptor subtype to
      predominate, and highly selective alpha1A-adrenoceptor antagonists have been
      identified and investigated in BPH. However, controversy remains as to whether
      prostatic smooth muscle contraction is mediated by the alpha1A-adrenoceptor, or
      by another novel alpha1-adrenoceptor subtype (not corresponding to any of the
      three known recombinant alpha1-adrenoceptors), or both. alpha1-Adrenoceptor
      agonists have been used clinically for the treatment of stress incontinence,
      acting to increase urethral tone by contracting urethral smooth muscle. Research
      efforts are ongoing to identify agents of this class having a selective action on
      urethral versus vascular smooth muscle, in order to produce a greater effect on
      the urethra without producing dose-limiting increases in blood pressure. Local
      administration of vascular smooth muscle relaxants, either alone or in
      combination, has been used for the treatment of erectile dysfunction. An alpha1
      adrenoceptor antagonist is often used as one comportent in such mixtures, which
      act to relax trabecular smooth muscle. The recent demonstration that a
      systemically administered drug can produce a sufficiently selective action on
      cavernosal smooth muscle to allow efficacy without producing limiting systemic
      side effects has renewed interest in the possibility of systemic administration
      of alpha1-adrenoceptor antagonists for this indication.

PMID- 10393469
TI  - The distribution of noradrenergic nerves in the human lower urinary tract. A
      review.
AB  - The purpose of this presentation is to describe the distribution of noradrenergic
      nerves in the human genitourinary system. The techniques which have been employed
      include formaldehyde-induced fluorescence and immunocytochemical methods to
      demonstrate dopamine beta-hydroxylase and tyrosine hydroxylase. These methods
      have been applied to human fetal, neonatal, infant, child and adult tissues
      removed either at post mortem examination or by surgical excision. The
      innervation of the fetal urinary bladder is well established by 13 weeks and, as
      in older specimens, the detrusor receives a sparse noradrenergic nerve supply. In
      contrast the smooth muscle of the terminal ureter is well supplied by this type
      of autonomic nerve. An additional incomplete muscle layer has been identified as
      a nomal component of the terminal ureter which is richly innervated by
      noradrenergic nerves. In some cases this muscle forms a complete collar which may
      be responsible for ureteric obstruction. By comparison with the detrusor, bladder
      neck smooth muscle receives a dense noradrenergic nerve supply particularly in
      the male. Unlike the detrusor, the structure and innervation of the vas deferens,
      seminal vesicle and prostate are poorly differentiated in the fetus. In the
      infant and child, the structure of the intramural smooth muscle of these organs
      remains immature although a rich noradrenergic nerve supply resembing the adult
      has been established in the fetus by 30 weeks. In the fetus, autonomic ganglia
      occur in association with noradrenaline rich paraganglia and surprisingly, with
      sensory nerve endings resembling pacinian corpuscles. Shortly after birth
      paraganglia are no longer associated with the autonomic ganglia of the
      genitourinary system. On the basis of size at least two types of autonomic neuron
      populate these autonomic ganglia. One type is relatively large and devoid of
      catecholamines but is closely associated with pericellular noradrenergic nerve
      fibres. The second type of neuron is small, contains noradrenaline and is
      arranged in clusters closely related to the capsule of the prostate gland. The
      significance of these observations will be considered with respect to the
      neurological control of the genitourinary system.

PMID- 10393470
TI  - alpha1- and alpha2-adrenoceptors in BPH.
AB  - The dynamic obstruction of the bladder outlet secondary to benign prostatic
      hyperplasia (BPH), and the contractile properties of the human prostate are
      mediated primarily by alpha1-adrenoceptors. There are now at least three subtypes
      (A, B, and D) of alpha1-adrenoceptors, and recent work revealed that alpha1A
      adrenoceptor and alpha1B-adrenoceptor may have a prime role for prostatic
      obstruction, and contraction of artery, respectively. Very recently, the presence
      of a low affinity alpha1-adrenoceptor for prazosin, named alpha1L, in the human
      BPH tissue has been determined. Because the DNA sequence of alpha1L-adrenoceptor
      has not yet been cloned, the alpha1L-adrenoceptor may be another form of the
      alpha1A-adrenoceptor, or another pharmacologically distinct alpha1-adrenoceptor
      which mediates the norepinephrine-induced contraction of the prostatic smooth
      muscle. Furthermore, the contribution of alpha1-adrenoceptors in the prostate to
      symptoms (not only obstructive, but irritative symptoms) which are elicited by
      prostatic obstruction remains to be determined.

PMID- 10393471
TI  - Preclinical pharmacology of alpha1-adrenoceptor antagonists.
AB  - The implication of a single adrenoceptor subtype in the contractility of
      prostatic and urethral smooth muscle cells led to the concept that drugs with
      selectivity for this subtype may exhibit functional uroselectivity. Comparison of
      the affinities of the alpha1-adrenoceptor antagonists revealed that few compounds
      show selectivity for one of the three cloned alpha1-adrenoceptor subtypes
      (alpha1a/A, alpha1b/B, alpha1d/D) whereas most of them had a similar affinity for
      the three subtypes. Moreover, data supporting a relationship between selectivity
      for the alpha1a/A-adrenoceptor subtype and functional uroselectivity are still
      lacking and recent data challenged the relevance of the selectivity for a given
      cloned alpha1-adrenoceptor subtype in predicting functional uroselectivity. In
      vivo data showed that alpha1-adrenoceptor antagonists without adrenoceptor
      subtype selectivity, like alfuzosin or to a minor extent doxazosin, showed
      functional uroselectivity whereas prazosin and terazosin were not shown to be
      uroselective. Compounds considered to be selective for the alpha1a/A
      adrenoceptor, like tamsulosin or 5-Me-urapidil, did not show functional
      uroselectivity since they modified urethral and blood pressures in a manner which
      was not correlated to their selectivity for the cloned alpha1-adrenoceptor
      subtypes. Meanwhile, the identification in prostatic tissue, of a new sub-family
      of alpha1-adrenoceptors with low affinity for prazosin and denominated alpha1L
      gave rise to numerous studies. However, its functional role as well as the
      affinity of the known antagonists for this receptor subtype remains to be
      clarified. In conclusion, the existing alpha1-adrenoceptor antagonists have
      different pharmacological profiles in vivo which are yet not predictable from
      their receptor pharmacology based on the actual state of knowledge of the alpha1
      adrenoceptor classification.

PMID- 10393472
TI  - Signal transduction pathways associated with alpha1-adrenoceptor subtypes in
      cells and tissues including human prostate.
AB  - The complexity of the signal transduction pathways linked to alpha1A
      adrenoceptors are becoming clearer. At one time it was thought that the alpha1A
      subtype was linked to the influx of extracellular Ca2+ while the alpha1B-subtype
      was linked via inositol phosphate formation to the release of intracellular Ca2.
      However the coupling of the alpha1-adrenoceptors to G-proteins leads to the
      activation of a number of different effector enzymes which produce intracellular
      second messengers and alterations in biological activity. One area of diversity
      is in the many forms of the Galpha, beta, gamma heterotrimeric G-proteins which
      confer specificity towards certain effectors. All alpha1-adrenoceptor subtypes
      have been shown to couple to phospholipase C in many cells and tissues leading to
      the breakdown of PiP2 to give IP3, which releases intracellular Ca2+, and
      diacylglycerol, which stimulates protein kinase C. Additional effectors which can
      couple to alpha1-adrenoceptors include phospholipase D, adenylate cyclase and the
      mitogen-activated protein kinase pathway. The latter involves a longer term
      response and causes increased cell growth and may be important in, for example,
      the prostate as well as in vascular smooth muscle and the heart. In human
      prostate alpha1-adrenoceptor activation leads to the release of intracellular
      Ca2+ from ryanodine-sensitive store followed by an influx of extracellular Ca2+,
      a mechanism different from that linked to the same receptor subtype in several
      other smooth muscles. Therefore a given alpha1-subtype may be coupled to a
      variety of different signal transduction mechanisms in different systems.
      Further, there may be different effector mechanisms linked to alpha1-subtypes in
      a given cell or tissue e.g. phospholipase C and mitogen-activated protein kinase.
      An increased understanding of the complexity of signal transduction mechanisms
      and the elucidation of the details in a particular tissue will open up new
      possibilities for therapeutic interventions.

PMID- 10393473
TI  - Clinical pharmacology of alpha1-adrenoceptor antagonists.
AB  - Benign prostatic hyperplasia (BPH) is the most prevalent condition to affect men
      beyong middle age. alpha1-adrenoceptor blockers have been used in the treatment
      of BPH for more than 20 years and their effect on the lower urinary tract is now
      well established. These agents as a class have produced consistent improvements
      in both symptom scores and urinary flow rates in around 60-70% of patients
      treated. This efficacy is balanced against a small, but significant, incidence of
      side-effects, that consist of headaches, dizziness, nasal stuffiness, tiredness
      and very occasionally postural hypotension. There are important other effects of
      alpha1-adrenoceptor blockers; for example in men with hypertension, these agents
      generally produce a clinically significant reduction in both systolic and
      diastolic blood pressures. There is also well documented evidence of a reduction
      in LDL cholesterol levels as well as serum triglycerides. A new and interesting
      observation is that patients receiving certain alpha1-adrenoceptor blockers
      notice improvement in their sexual function and in particular in the quality of
      their erectile response. This effect has been attributed to decreased sympathetic
      vasoconstrictor tone to the helicine arteries supplying the lacunar spaces of the
      corpora cavernosa in the penis. In summary alpha1-adrenoceptor blockers produce
      significant improvements in symptoms and flow rates in patients with bladder
      outflow obstruction due to benign prostatic hyperplasia. This is balanced against
      a small but significant incidence of side-effects, but some of these side
      effects, such as a reduction in blood pressure in hypertensive patients,
      improvement in lipid profile and improvement in erectile function could be
      construed as beneficial.

PMID- 10393474
TI  - Clinical experience in Europe with uroselective alpha1-antagonists.
AB  - alpha1-Adrenoreceptors are thought to be involved in prostate smooth muscle
      contractions and could hence play a role in the dynamic component of intravesical
      obstruction associated with symptomatic BPH. Consequently, since the mid-eighties
      alpha receptor blocking agents have been used for the treatment of BPH. Non
      selective alpha blockers are usually associated with systemic side-effects which
      resulted in an exclusion or withdrawal of many patients from this form of
      treatment. With the availability of so-called uroselective alpha blockers the
      management picture has changed since it was anticipated that these compounds
      cause lesser side-effects with at least the same, or even better, efficacy.
      Comparative clinical studies are essential for determining the eventual
      advantages of the uroselective alpha1-antagonists and a large number of such
      studies have been performed worldwide studying the various available compounds.
      European studies with terazosin showed clear superiority of the drug over the
      placebo while causing only limited side-effects. Various other studies using
      alpha-blocking agents such as doxazosin, tamsulosin and alfuzosin yielded
      identical results. Especially with tamsulosin and alfuzosin, the side-effects
      were comparable with those encountered in the placebo group. About 7% of the
      patients using tamsulosin experienced retrograde ejaculation in one study which
      did not occur in the alfuzosin studies. Important studies in Europe have also
      investigated the value of a combination of an alpha blocker with a 5alpha
      reductase inhibitor. Comparable studies in which both alfuzosin and doxazosin
      were combined with the 5alpha-reductase inhibitor Proscar have shown that a
      combination is not superior to a blocker monotherapy and especially in the ALFIN
      study the results show that alfuzosin monotherapy is superior to Proscar in the
      management of symptomatic BPH. European studies have evaluated Quality of Life,
      sexuality as well as socio-economical outcome of the treatment with alpha1
      receptor antagonists. These studies completed the spectrum of clinical research
      in Europe in the important field of management of symptomatic BPH with
      uroselective alpha1 antagonists.

PMID- 10393476
TI  - Future prospects for uroselective alpha-1-antagonists.

PMID- 10393475
TI  - alpha1-adrenoceptor selectivity: the North American experience.
AB  - OBJECTIVE: The recent publication of multicentre US studies raises the
      possibility that the response to tamsulosin is dose-related and less than maximum
      at 0.4 mg. The objective of the present study was to calculate pharmacologically
      equivalent, alpha-blocking doses of doxazosin and tamsulosin in a clinical
      setting and thereby to examine further the concept of 'uroselectivity' and
      'prostate selectivity'. METHODS: Healthy male volunteers were monitored in
      controlled, crossover studies. The effects of placebo or alpha blocker on
      phenylephrine (PE)-induced urethral and vascular responses, were determined.
      These were related to plasma drug concentrations and used with in vitro
      radioligand binding data to derive receptor occupancy. RESULTS: Doxazosin
      effectively blocked PE-induced vascular and urethral changes over the dose range
      1-16 mg. There was no evidence for target organ selectivity. The degree of
      blockade of the PE-induced responses by tamsulosin was highly dependent on the
      time of measurement, post drug administration. The degree of observed blockade
      with tamsulosin at 0.4 mg was substantially less than that observed at 0.8 mg
      tamsulosin and/or 1 mg doxazosin. CONCLUSIONS: These studies provide no evidence
      of prostate selectivity for tamsulosin. 0.4 mg tamsulosin is a sub-optimal
      blocking dose and is equivalent to 1 mg of doxazosin and terazosin (1-2 mg). It
      is recommended that future comparative studies on benefit/risk in patients should
      include a range of doses encompassing the ED50.

PMID- 10393478
TI  - alpha1-adrenoceptors in urethral function.
AB  - The external urethral sphincteric mechanism generates forces which seal the
      urethra and can be measured as urethral pressure. Resting pressure can be
      augmented transiently through a reflex pathway during increases in intra
      abdominal pressure. The exact role of the various components of the urethral wall
      that generate this pressure is so far unknown. Urethral contributions to
      continence come from the mucosal hermetic seal, the submucosa and its vascular
      filling and the smooth and striated muscle. In humans alpha1-adrenoceptor
      antagonists can reduce urethral pressure, whereas agonists have little effect. A
      significant part of urethral resting tone is thought to be mediated through the
      smooth muscles. In vitro, longitudinal and circular smooth muscle components
      possess spontaneous tone and are innervated by excitatory and inhibitory nerves.
      Both types possess alpha1-adrenoceptors and contract on stimulation of intrinsic
      sympathetic nerves or application of alpha1-adrenoceptor agonists. In human
      urethra, longitudinal smooth muscle predominates but its functional role is
      unclear. alpha1 stimulation may also affect the vasculature of the submucosa, the
      striated muscle of the urethra or transmitter release from neurones in the
      control pathways. Insufficient knowledge of alpha1-adrenoceptor distribution and
      function within the urethra and the surrounding tissues currently prevents
      accurate prediction of the therapeutic potential of alpha1-adrenoceptor ligands.

PMID- 10393477
TI  - Modulation of voiding and storage reflexes by activation of alpha1-adrenoceptors.
AB  - OBJECTIVE: This paper reviews recent studies in animals that examined the effect
      on lower urinary tract function of alpha1-adrenoceptor agonists and antagonists.
      METHODS: Bladder reflexes were studied in vivo on anesthetized rats and cats
      using cystometrographic and electrophysiologic techniques. Neurally-evoked
      bladder contractions and release of acetylcholine (ACh) were also studied in rat
      bladder strips in vitro. RESULTS: Administration of the alpha1-adrenoceptor
      agonist, phenylephrine (PE) to isolated strips of rat bladder enhanced neurally
      evoked bladder contractions and increased basal tone. The former effects of PE
      were blocked by a selective alpha1A antagonist and the latter by an alpha1B
      antagonist. Activation of alpha1A receptors by PE enhanced ACh release evoked by
      electrical field stimulation in bladder strips. PE also enhanced transmission in
      cat bladder ganglia. PE or noradrenaline act on alpha- and beta-adrenoceptors on
      urothelial cells to release nitric oxide. It is concluded that facilitatory
      alpha1A-adrenoceptors are located prejunctionally in the bladder, whereas alpha1B
      adrenoceptors are located postjunctionally. In the central nervous system of the
      rat and cat facilitatory alpha1-adrenergic mechanisms can modulate the
      sympathetic, parasympathetic and somatic outflow to the urinary tract. In
      addition inhibitory alpha1 adrenoceptor mechanisms have been detected in the rat
      spinal cord. Activation of these receptors with PE raises the intravesical
      pressure threshold for inducing micturition and decreases voiding frequency.
      CONCLUSIONS: alpha1-adrenoceptors are located at various sites in the bladder and
      in the neural pathways controlling lower urinary tract function. At most sites
      these receptors mediate facilitatory responses that enhance smooth muscle
      activity or facilitate storage or voiding reflexes. However, alpha1-adrenoceptor
      inhibitory mechanisms in the rat spinal cord, can also reduce the frequency of
      voiding reflexes. This effect is possibly mediated by an inhibition in the
      afferent limb of the micturition reflex pathway.

PMID- 10393479
TI  - Importance of agonists in alpha-adrenoceptor classification and localisation of
      alpha1-adrenoceptors in human prostate.
AB  - alpha-Adrenoceptor blocker drugs are commonly used in the clinical (non-surgical)
      treatment of BPH. alpha1-adrenoceptors were originally sub-divided using agonists
      but, subsequently, were sub-divided using only antagonists in ligand-ligand
      interactions, which did not require agonists at all. Ultimately, proof that
      adrenoceptors are functional receptors for the natural ligands, noradrenaline and
      adrenaline, requires that agonists be used. The earlier excitement engendered by
      finding varying agonist potency series in different tissues has not been
      revisited to place it in the context of current concepts of alpha1-adrenoceptor
      subtypes. This review will consider the advantages and limitations of different
      agonists for the study of alpha1-adrenoceptor subtypes including 'extreme'
      examples where the archetypal alpha1-adrenoceptor agonist phenylephrine activates
      alpha2-adrenoceptors and others where UK14304, often the alpha2-adrenoceptor
      agonist of choice, activates alpha1-adrenoceptors. New work will also be
      presented showing the interaction between agonists and the fluorescent alpha1
      adrenoceptor antagonist QAPB. This introduces the novel point of view of studying
      the displacement of antagonists by agonists. Possible errors in antagonist
      classification arising from complexity in the actions of agonists and the
      recently developed method of fluorescent ligand binding on isolated living human
      prostatic smooth muscle cells will be discussed.

PMID- 10393480
TI  - Pharmacological management of incontinence.
AB  - Many patients with incontinence do not need surgery - for these patients symptoms
      can often be considerably improved by conservative measures, including drugs.
      Several different pharmacological actions are potentially useful depending on the
      underlying cause of the incontinence: a) Detrusor instability (DI) responds to
      drugs reducing bladder contractility: Anticholinergic agents, e.g. oxybutynin and
      tolterodine, act at postganglionic parasympathetic cholinergic receptor sites on
      the detrusor muscle, reducing the strength of the detrusor contraction. Tricyclic
      antidepressants, e.g. imipramine, have anticholinergic effects, block presynaptic
      uptake of amine neurotransmitters and directly inhibit detrusor muscle. Alpha
      adrenergic antagonists may have a role to play by dual actions on bladder
      overactivity (due to altered receptor function) and by reducing outlet
      resistance. b) Genuine stress incontinence (GSI) may be treated using alpha
      adrenergic agonists, e.g. phenylpropanolamine, to increase outlet resistance by
      stimulating smooth muscle of the urethra and bladder neck. c) In nocturnal
      enuresis reduction of nocturnal urine output with the anti-diuretic hormone (ADH)
      analogue DDAVP (1-deamino, 8-arginine vasopressin) is beneficial. d) Bladder
      emptying may be facilitated in patients with retention and 'overflow'
      incontinence by alpha-adrenergic antagonists, which reduce outlet resistance, and
      perhaps by parasympathomimetics, e.g. bethanecol. e) In postmenopausal women,
      systemic oestrogen replacement reduces filling symptoms including urge
      incontinence. Evidence for oestrogen replacement alone in GSI is lacking, but
      combination with alpha-agonists is beneficial in milder GSI. For the future,
      tolterodine and other new anticholinergics offer the hope of treatment for DI
      with fewer of the side effects that limit the use of established drugs. Better
      understanding of the pathophysiology of DI may provide new targets for drug
      therapy, such as hyperpolarisation of detrusor muscle membrane. Alpha-agonists
      may find a greater role in the future, as may ADH analogues for noctural
      symptoms.

PMID- 10393481
TI  - alpha1-adrenoceptors and bladder function.
AB  - OBJECTIVE: To discuss the role of alpha-adrenoceptors (alpha-ARs) in the control
      of lower urinary tract function with special emphasis on their importance in the
      pathologically changed bladder. METHODS: Evaluation of published information.
      RESULTS: The functional role of the alpha-ARs in the normal detrusor muscle has
      not been established. Changes in the function of these alpha-ARs may occur in
      e.g., bladder outflow obstruction, bladder overactivity, and 'neurogenic'
      bladders. The filling (irritative) symptoms in patients with benign prostatic
      hyperplasia and outflow obstruction, which are relieved by alpha-AR antagonist
      treatment, have been associated with bladder dysfunction produced by the
      obstruction. There is evidence for involvement of alpha-ARs in the spinal control
      of both the sympathetic, somatic (filling) and parasympathetic (voiding) efferent
      activity to the lower urinary tract. The beneficial effects of alpha-AR
      antagonists on filling symptoms, which can be obtained even in the absence of
      outflow obstruction, give support for the involvement of extravesical, possibly
      spinal, alpha-ARs in their pathogenesis. CONCLUSIONS: A more complete
      understanding of the role of alpha-ARs in the control of the normal or
      functionally changed bladder should be helpful in the development of drugs for
      treatment of lower urinary tract disorders.

PMID- 10393482
TI  - Pharmacology of alpha-adrenoceptors in male sexual function.
AB  - Data issued from morphological and physiological experiments suggests that the
      noradrenergic system, through ascending pathways to the brain and descending
      pathways to the spinal cord, may regulate male sexual functions. Adrenoceptors
      have been shown to be present in the brain and spinal cord of animals and humans.
      The activity of spinal preganglionic neurons is modulated by noradrenaline.
      Pharmacological approaches aiming at selectively targeting alpha1- or alpha2
      adrenoceptors have been conducted in patients with erectile dysfunction or in
      monkeys and rats in a variety of tests. Briefly, conclusions arising from these
      studies are: activation of alpha1-adrenoceptors facilitates copulation, where
      activation of alpha2-adrenoceptors inhibits copulation. alpha2-adrenoceptors
      antagonists like yohimbine facilitate sexual behavior, reducing ejaculation
      latency in male rats and increasing their sexual motivation. Furthermore,
      yohimbine induces copulation in rats either castrated or sexually naive. In
      contrast, activation of alpha1-adrenoceptors depresses sexual responses in
      another context, i.e. reflexive erections. Activation of alpha2-adrenoceptors
      activates reflexive erections in rats, and alpha2-adrenoceptors antagonists
      (yohimbine) inhibit them. Today's challenge is to separate the effects of any
      drug acting at the level of the alpha-adrenoceptors on the central vs. peripheral
      control of sexual functions, on the brain vs. spinal cord control of the same
      functions, and the search for any specialization of alpha-adrenoceptors subtypes
      in a given sexual function. Treatment of sexual dysfunctions in man (e.g.
      ejaculation) focusing on the spinal cord as a pharmacological target should also
      be expanded. Finally, considering the similarities between neural networks
      controlling male and female sexual functions, the treatment of female sexual
      dysfunction with comparable pharmacological approaches should be evaluated.

PMID- 10393483
TI  - BPH and sexuality.
AB  - Quality of life has become a very important parameter in benign prostatic
      hyperplasia (BPH) and one of the major concepts identified by the patients to be
      important is related to sexuality after BPH therapy. The impact on sexuality
      resulting from the various treatment modalities of BPH, either medical, surgical
      or instrumental has been too often neglected in the past and poorly investigated.
      The present article reviews the influence on sexual function of current therapies
      for symptomatic BPH.

PMID- 10393484
TI  - Growth hormone heterogeneity in human pituitary and plasma.
AB  - Several isoforms of growth hormone (GH) have been identified in humans. There are
      many reasons for this heterogeneity. At the genetic level, two genes encode GH:
      GH-N, expressed in the pituitary, and GH-V, expressed in the placenta. At the
      mRNA level, GH-N undergoes alternative splicing into 20K and 22K isoforms. Post
      translationally, 22K GH undergoes modifications, such as acetylation at its amino
      terminus, deamidation, and oligomerization. The picture is complicated further in
      the circulation, where GH binds to two GH-binding proteins, each with different
      affinities for the GH isoforms. In addition, a highly heterogeneous mixture of GH
      fragments has been demonstrated. The implications of this heterogeneity relate to
      differences between GH immunoassays, such that assay results cannot be compared
      between laboratories. The reasons for GH heterogeneity and its practical and
      clinical implications are considered here.

PMID- 10393485
TI  - International standards for growth hormone.
AB  - Since 1955, with the establishment by the World Health Organization of the first
      International Standard (IS) for bovine growth hormone (GH) for bioassay, there
      have been a number of developments in the standardization of GH. Two GH ISs are
      in current use: the IS for human GH established in 1982 and the IS for somatropin
      (recombinant DNA-derived GH) established in 1994. The availability of two such
      standards does not encourage reproducibility of GH estimates between different
      laboratories. The author proposes that the international validation and adoption
      of the IS for somatropin, which has the advantage of an internationally agreed
      specific activity of 3 IU/mg, as the primary reference standard for all GH
      immunoassays would finally eliminate this source of variation in GH estimates.

PMID- 10393486
TI  - Serum growth hormone measurements in clinical practice: An audit of performance
      from the UK National External Quality Assessment scheme.
AB  - The replacement of growth hormone (GH) radioimmunoassays with a variety of more
      specific immunometric methods in diagnostic service laboratories has led to a
      worsening of between-laboratory agreement, reflecting differences in method bias.
      Incorrect calibration and differences in specificity are important causes of
      method bias, but the impact of this on interpretation is not clear. In order to
      maximize the diagnostic reliability of GH testing for small stature,
      manufacturers should carefully calibrate their methods against the appropriate GH
      International Standard, and should use antibodies of broadly agreed specificity.
      Laboratories performing GH tests should participate in a reliable External
      Quality Assessment (EQA) scheme and guidelines for investigation that incorporate
      normal GH responses should be agreed.

PMID- 10393487
TI  - Variety in growth hormone determinations due to use of different immunoassays and
      to the interference of growth hormone-binding protein.
AB  - More than 30 years after their introduction, growth hormone (GH) immunoassays
      showed the poorest inter-laboratory agreement of the various hormone assays
      evaluated in 1998 by the UK National External Quality Assessment Scheme, in which
      different laboratories using different assays reported that analyses of identical
      samples differed two- to threefold in value. There is therefore an urgent
      requirement and desire within the scientific community, particularly within
      centres diagnosing and treating GH deficiency and acromegaly, to resolve this
      problem and to develop a GH assay(s) that measures solely all of the relevant
      components of circulating GH immunoreactivity. The main confounders in the
      estimation of GH levels (now that the use of GH standards other than that
      recommended by the World Health Organization has largely been eliminated) are GH
      heterogeneity, anti-GH antiserum binding site specificity and interference from
      circulating high-affinity GH-binding protein (GHBP). The effects of these factors
      are closely related. The present study investigates these factors, focussing on
      the influence of GHBP and antibody binding site specificity on various assays for
      GH. The findings lead the authors to suggest that a solution to the problem may
      be to develop a GH assay that measures specifically and solely all serum 22 kDa
      GH, as this is the major circulating fraction and carries the dominant GH
      bioactivity.

PMID- 10393488
TI  - Consensus on how to measure growth hormone in serum.

PMID- 10393489
TI  - Towards better decision making in growth hormone therapy.
AB  - Controlled clinical trials are not always possible or warranted. Other sources of
      data include observational studies, meta-analyses, expert opinions, subjective
      judgements, and mathematical/statistical models developed from large databases.
      Decision analysis is presented as a preferred methodology for analysis in
      situations of uncertainty, in combination with cost-benefit and cost
      effectiveness analyses. Special emphasis is given to quality-of-life
      considerations in growth hormone (GH) therapy and ways to measure it and express
      patient preferences.

PMID- 10393490
TI  - What randomized trials and systematic reviews can offer decision makers.
AB  - It is important to recognize the studies that yield the most reliable evidence
      upon which to base treatment decisions. Randomized trials have a particular place
      in providing high-quality unbiased comparisons of different treatments, when
      carried out to a high methodological standard. Empirical evidence shows that such
      trials are not always done well, and also that poor methodology is associated
      with biased findings. Consumers of the published literature need to be able to
      recognize which trials can be trusted. Systematic reviews and meta-analyses offer
      an organized approach to assessing all the relevant literature on a topic,
      particularly when several randomized trials address the same treatment
      comparison. Like trials, systematic reviews and meta-analyses need to be carried
      out to a high standard. They offer particular potential for providing the most
      useful information for clinical decision making. Critical aspects of these types
      of study are considered in this paper.

PMID- 10393491
TI  - What observational studies can offer decision makers.
AB  - Observational studies, for example cohort and case-control studies in which
      patients are allocated treatment on a non-random basis, are thought by some
      investigators to be flawed. This view results from the fact that, unlike
      experimental methods (randomized controlled trials; RCTs), the results of such
      observational studies are vulnerable to confounding. However, this view assumes
      that satisfactory adjustment of differences in risk or prognosis between
      treatment groups is impossible and it ignores some of the limitations of RCTs.
      While many of the problems involved in conducting RCTs could be overcome, the
      practical implications for researchers and funding bodies mean this is often not
      possible. In such circumstances, observational studies offer an alternative to an
      absence of any scientific evidence. While making use of observational methods,
      researchers must acknowledge the associated limitations: the inevitable inability
      to take unknown confounders into account, non-blinding of practitioners and
      patients, and the inclusion of practitioners' and patients' treatment
      preferences.

PMID- 10393492
TI  - Clinical research databases and clinical decision making in chronic diseases.
AB  - Chronic diseases are the major source of morbidity, mortality, and resource
      utilization. Large-scale longitudinal databases are rapidly proliferating in both
      single- and multi-institutional settings, providing clinical data on a broad
      range of patients who receive 'real world' management. Although bias and changing
      medical management may limit the types of questions that can be addressed using
      the data contained in longitudinal clinical databases, many initial hypotheses
      can be generated from the data. Because chronic diseases persist over long
      periods of time, understanding the impact of temporal relationships, and of
      concurrent clinical events and contexts is critical to meaningful interpretation
      of clinical data. Adapting techniques initially developed for the physical
      sciences and for statistical process control can produce visual displays of
      clinical data that capture complex temporal and contextual information. With
      these tools, investigators can quickly explore vast quantities of clinical data,
      and discover new temporal relationships and emerging trends.

PMID- 10393493
TI  - What clinicians can offer: assessing and communicating probabilities for
      individual patient decision making.
AB  - Accurate diagnostic and prognostic probabilities are important for physicians and
      their patients because of their impact on decisions. For individual patient
      decision making, physicians have to rely on their own judgement. Research has
      shown that physicians' probability assessments are often not of high quality and
      that a variety of factors have a detrimental influence on their judgements. Using
      a formula or a model may produce superior assessments. Most treatment decisions
      involve uncertainty and value conflict in the sense that there is a trade off
      between the possible harms of alternative treatments and their benefits. The
      communication of diagnostic and prognostic probabilities to patients occurs
      largely in verbal terms, which can lead to ambiguity in communication. The
      precise words and context chosen for communication are very important and can
      have a major effect on patients' decisions.

PMID- 10393494
TI  - Patient attitudes and preferences regarding treatment: GH therapy for childhood
      short stature.
AB  - This paper examines the role of parents' attitudes and preferences regarding
      growth hormone therapy for childhood short stature. Four main questions are
      addressed. First, what are the demographic characteristics of families seeking
      medical advice for their child's short stature? Second, what are parents'
      attitudes towards short stature? Third, what are parents' treatment preferences
      (i.e. what characteristics of growth treatments are important to parents)?
      Finally, how do the attitudes of parents affect physician decision making?
      Several studies are reviewed and data are presented to answer these questions.

PMID- 10393495
TI  - What decision analysis can offer the clinical decision maker. Why outcome
      databases such as KIGS and KIMS are vital sources for decision analysis.
AB  - Cognitive Continuum Theory can be used to explain why the relationship between
      research and practice is more problematic than is customarily assumed. The
      various possible sources of evidence for clinical decision making and the
      alternative approaches to such decision making can be located within the main
      modes of this continuum, each of which embodies a different balance of intuition
      and analysis. Decision analysis is the only technique that provides the
      analytical depth necessary to arrive at a decision that systematically
      identifies, structures and integrates all the relevant evidence on clinical
      parameters and patient preferences, within whatever mode that evidence is
      generated. The inappropriateness of using research criteria in action evaluations
      is pointed out. In order to illustrate the application of the Cognitive Continuum
      Theory and decision analysis to growth hormone (GH) therapy, and to stimulate
      discussion of this area, a primitive clinical decision analysis and prototype
      'clinical guidance tree' for GH is presented here.

PMID- 10393496
TI  - KIGS and KIMS as tools for evidence-based medicine.

PMID- 10393497
TI  - Typing of hepatitis C virus by a new method based on restriction fragment length
      polymorphism.
AB  - A new restriction fragment length polymorphism (RFLP) analysis has been developed
      for hepatitis C virus (HCV) typing in the viral 5' non-coding region and
      contiguous core region. These genomic sequences were chosen for the relative
      nucleotide homology among different genotypes and for the presence of polymorphic
      sites. By employing two endonucleases (AccI and MboI) and, in some instances, a
      third one (EcoRII), we can unambiguously and reproducibly distinguish between
      genotypes and subtypes 1a, 1b, 1c, 2a, 2c, 2b, 3a, 3b, 4a, 5a and 6a. The method
      was applied for diagnosing two Italian groups of HCV-infected individuals
      reflecting a randomly collected population and a group of intravenous drug users.
      The accuracy of this method has been validated by comparison with INNOLiPA and by
      sequencing. Our approach represents an improvement over previous RFLP methods,
      since typing is accurate and simpler.

PMID- 10393498
TI  - A putative host cell receptor for tick-borne encephalitis virus identified by
      anti-idiotypic antibodies and virus affinoblotting.
AB  - Anti-idotypic monoclonal antibodies (anti-ID MAbs) were made against two mouse
      MAbs that neutralize the infectivity of the tick-borne encephalitis (TBE) virus.
      Three of the anti-ID MAbs (1) inhibited the binding of respective idiotypic MAb
      to the TBE virus antigen, (2) inhibited the infectivity of TBE virus when
      preincubated with virus-susceptible cells, and (3) bound to the surface of virus
      susceptible but not virus-nonsusceptible cells. They recognized a 35-kD protein
      in immunoblotting analysis. Identification of this protein as a component of a
      putative TBE virus receptor was supported by the viroblot technique. In this
      assay, two polypeptide signals of 35 and 18 kD were obtained after incubation of
      blotted cell membrane proteins with the TBE virion antigen.

PMID- 10393499
TI  - A novel protein tag from herpes simplex virus type 1 DNA polymerase.
AB  - An epitope (HPOL) derived from the so-called thumb region of the herpes simplex
      virus type 1 DNA polymerase in combination with a monoclonal antibody (MAb 1051c)
      was tested for protein tagging. Using a conventional expression vector, a DNA
      cassette encoding the HPOL epitope was fused to the C-terminus of the
      dihydrofolate reductase (DHFR) gene such that the recombinant DHFR contained both
      a N-terminal HIS-tag and a C-terminal HPOL tag. Expression of recombinant DHFR in
      Escherichia coli cells was compared by Western blot analysis using either mouse
      RGS.HIS antibody or MAb 1051c. Immunostaining revealed that both antibodies
      reacted specifically with DHFR, but the detection sensitivity achieved with MAb
      1051c was about 15-fold greater using a standard staining protocol. An HPOL
      antibody column was successfully applied for affinity purification of DHFR,
      demonstrating the usefulness of the HPOL epitope/MAb 1051c system for protein
      tagging, expression monitoring and purification of HPOL-tagged recombinant
      proteins.

PMID- 10393500
TI  - Sequence analysis of the matrix/nucleocapsid gene region of turkey coronavirus.
AB  - A reverse transcriptase, polymerase chain reaction (RT-PCR) procedure was used to
      amplify a segment of the genome of turkey coronavirus (TCV) spanning portions of
      the matrix and nucleocapsid (MN) protein genes (approximately 1.1 kb). The MN
      gene region of three epidemiologically distinct TCV strains (Minnesota, NC95,
      Indiana) was amplified, cloned into pUC19, and sequenced. TCV MN gene sequences
      were compared with published sequences of other avian and mammalian
      coronaviruses. A high degree of similarity (>90%) was observed between the
      nucleotide, matrix protein, and nucleocapsid protein sequences of TCV strains and
      published sequences of infectious bronchitis virus (IBV). The matrix and
      nucleocapsid protein sequences of TCV had limited homology (<30%) with MN
      sequences of mammalian coronaviruses. These results demonstrate a close genetic
      relationship between the avian coronaviruses, IBV and TCV.

PMID- 10393501
TI  - Human cytomegalovirus stimulates cellular dihydrofolate reductase activity in
      quiescent cells.
AB  - Human cytomegalovirus (HCMV) productively infects quiescent fibroblasts in which
      the levels of deoxynucleotide triphosphates (dNTPs) and cell functions involved
      in DNA metabolism are very low. Since sufficient dNTPs levels are essential for
      human HCMV replication, host cell enzymes involved in the biosynthesis of dNTPs
      might be expected to be stimulated by viral infection in quiescent cells. We
      report that HCMV infection of quiescent fibroblasts stimulates the activity of
      cellular dihydrofolate reductase (DHFR), a key enzyme in DNA precursor synthesis.
      We also demonstrate that suppression of DHFR activity by the specific inhibitor
      methotrexate prevents HCMV replication and DNA synthesis. These observations
      indicate that induction of DHFR activity by HCMV is required for efficient viral
      replication in quiescent fibroblasts.

PMID- 10393502
TI  - Human immunodeficiency virus type 2 infection in Spain. The HIV-2 Spanish Study
      Group.
AB  - The first cases of human immunodeficiency virus type 2 (HIV-2) infection in Spain
      were identified in 1988, in 3 African immigrants living in Barcelona. Since then,
      up to December 1998, 92 individuals with HIV-2 infection have been reported in
      Spain. Most are adult men, infected through heterosexual contacts, originating
      from West African countries, and currently living in the largest urban Spanish
      cities. Fifteen individuals have developed AIDS, meanwhile the rest remain
      asymptomatic. For 22 subjects, HIV-2 subtyping was performed on proviral DNA, 16
      being infected with subtype A (8 Spanish born and 8 African immigrants) and the
      remaining with subtype B (two Spanish born and 4 originating from Equatorial
      Guinea). Coinfection with HIV-1 was demonstrated in 9 individuals. In conclusion,
      HIV-2 is currently circulating in Spain with a low prevalence and without
      evidence for increase over time.

PMID- 10393504
TI  - Characterization of potential insertion sites in the core antigen of hepatitis B
      virus by the use of a short-sized model epitope.
AB  - Core particles of hepatitis B virus (HBV) are able to improve the immunogenicity
      of foreign sequences exposed on the particle surface. The insertion site in the
      core antigen of HBV (HBcAg) determines the surface presentation and thus the
      immunogenicity of the foreign sequence. For direct comparison of the value of
      potential insertion sites in the core antigen, we constructed vectors allowing
      insertions of a model marker epitope DPAFR. This epitope was inserted at the N
      terminus, the c/e1 loop, behind amino acid (aa) 144 and behind aa 183 (DPAF
      only). In addition, we generated a mosaic construct allowing the co-expression of
      HBcAg and a HBcAg/DPAFR fusion protein due to a suppressor tRNA-mediated
      readthrough mechanism. All 6 constructs allowed the formation of chimaeric or
      mosaic core-like particles. Western blot analyses and a direct ELISA demonstrated
      the presence of the DPAFR sequence in the chimaeric and mosaic particles.
      Competitive ELISA and immune electron-microscopic data suggested the c/e1 loop as
      the insertion site of choice for presenting foreign sequences on the surface of
      chimaeric HBV core particles. However, the N-terminal fusion also allowed partial
      surface exposure of the DPAFR motif. In contrast, in particles of constructs
      carrying the DPAFR insert at aa position 144 or 183, respectively, the epitope
      seemed not to be surface accessible.

PMID- 10393503
TI  - T cell-mediated and non-specific inflammatory mechanisms contribute to the skin
      pathology of HPV 16 E6E7 transgenic mice.
AB  - One of three lines of mice transgenic for the E6 and E7 genes of human
      papillomavirus type 16 (HPV16) expressed from an alphaA-crystallin promoter also
      expresses the transgene ectopically in the skin. This line, designated
      alphaACE6E7#19, develops skin disease from 3 months of age, characterised by
      epidermal hyperplasia and eventual skin loss. Administration of complete Freund's
      adjuvant (CFA) to alphaACE6E7#19 mice, but not to non-transgenic littermate
      controls, induced local epidermal hyperplasia which was histologically similar to
      the spontaneously arising skin pathology. Local application of 2,4
      dinitrochlorobenzene (DNCB) to DNCB-sensitised alphaACE6E7#19 mice, but not DNCB
      sensitised controls, also induced hyperplasia. Treatment with cyclosporin A (CsA)
      or systemic depletion of CD4+ cells significantly reduced the incidence of skin
      disease. These data suggest that local inflammation, and cytokines produced by T
      helper cells, contribute to the induction of hyperplastic skin disease in
      alphaACE6E7#19 mice. Spontaneous skin disease with similar histological
      appearance, frequency, age of onset and severity in alphaACE6E7#19 mice was
      observed in scid-/- alphaACE6E7#19 mice, despite immune paresis. Antigen-specific
      immune responses and T-cell cytokines are therefore not necessary for the
      induction of skin disease. We propose that epidermal hyperplasia associated with
      HPV16 E6 and E7 expression in skin is accelerated by local secretion of pro
      inflammatory cytokines, whose production can be enhanced by activated CD4+ T
      cells.

PMID- 10393505
TI  - Network vascular communication initiated by increases in tissue adenosine.
AB  - Vascular communication of vasomotor signals appears to coordinate the
      distribution of tissue blood flow. This study was performed to determine whether
      elevated tissue concentrations of adenosine or nitric oxide could induce vascular
      communicating signals. To test this, remote arteriolar responses were tested when
      drugs were applied either directly to an arteriole ( approximately 20 microm
      diameter), or into the tissue in a region (with no vessels over 10 microm in
      diameter) that was 500 microm away from the arteriole and that bore no defined
      relationship to the flow path of the remote arteriole. In anesthetized hamster
      cheek pouch (n = 25), or cremaster muscle (n = 10), remote arteriolar responses
      were measured in response to nitric oxide (NO) donors (10(-5) to 10(-3) M),
      adenosine (10(-5) to 10(-3) M), or papaverine (10(-5) to 10(-2) M) applied for 40
      120 s. Papaverine caused no remote response when applied directly while adenosine
      and NO donors caused similar, late-onset (10-20 s), dose-dependent, remote
      responses in both preparations. Remarkably however, only adenosine initiated a
      consistent remote arteriolar dilation when applied to the tissue site. Thus,
      increases in tissue adenosine may be critical for vascular communication of
      metabolic demands without regard to the specific blood flow path.

PMID- 10393506
TI  - Evidence that an endothelial cytosolic protein binds to the 3'-untranslated
      region of endothelial nitric oxide synthase mRNA.
AB  - Changes in the endothelial nitric oxide synthase (eNOS) expression could be
      involved in the endothelium-dependent vasorelaxing dysfunction associated with
      cardiovascular diseases. We have recently demonstrated the existence of
      endothelial cytosolic proteins that bind to the 3'-untranslated region (3'-UTR)
      of eNOS mRNA and could be involved in eNOS mRNA stabilization. In the present
      work, we have characterized the cytosolic proteins that bind to 3'-UTR eNOS mRNA.
      An endothelial cytosolic protein (MW 60-kD) specifically bound to 3'-UTR eNOS
      mRNA as determined by a cross-linking assay followed by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis. The endothelial cytosolic protein recognized
      a cytidine (C)-rich region within 3'-UTR eNOS mRNA. Furthermore, tumor necrosis
      factor-alpha (TNF-alpha) increased the level of the 60-kD endothelial cytosolic
      protein. In addition, TNF-alpha reduced eNOS mRNA levels and this was prevented
      by coincubation with cycloheximide. Cycloheximide also prevented the binding
      activity of the endothelial cytosolic protein to 3'-UTR eNOS mRNA. In summary,
      these data suggest that a 60-kD endothelial cytosolic protein binds to 3'-UTR
      eNOS mRNA. TNF-alpha increased the 60-kD protein levels. Cycloheximide prevented
      the binding activity of the cytosolic protein to 3'-UTR eNOS mRNA related to TNF
      alpha; this effect was associated with greater eNOS mRNA levels. Further specific
      studies are needed to determine the involvement of this 60-kD endothelial
      cytosolic protein in the regulation of eNOS mRNA stabilization and in the
      endothelial dysfunction associated with cardiovascular diseases.

PMID- 10393507
TI  - Effects of diabetes and insulin treatment of diabetic rats on hyaluronan and
      hyaluronectin production in injured aorta.
AB  - The present study was conducted to determine the effect of diabetes with and
      without insulin treatment on the production of hyaluronen (HA) and distribution
      of hyaluronectin (HN) in the rat aorta 14 days after injury with a catheter
      balloon. Injury increased intima-media wet weight (+11%) and DNA content
      (+37.5%). This increase was slightly enhanced in untreated diabetic rats (+14.7%
      for wet weight and +48.9% for DNA content) and was significantly greater in
      diabetic rats treated with insulin (+28.9% for wet weight and +54% for DNA
      content). HA content increase in the injured aorta of nondiabetic rats (+43.6%)
      was similar in untreated diabetic (+44.7%) and more pronounced in diabetic rats
      treated with insulin (+91.3%). HA was markedly expressed in the neointima of
      nondiabetic rats, particularly near the lumen of the aorta. In untreated diabetic
      rats, HA was present throughout the neointima and not mainly close to the lumen.
      HA staining in the neointima of diabetic rats treated with insulin was similar to
      that in nondiabetic rats. HN was strongly expressed throughout the neointima of
      all groups. Injury enhanced the production of a high molecular mass HN (>400
      kDa); this was not observed either in untreated or in insulin-treated diabetic
      rats. In conclusion, insulin treatment promoted the proliferative response of
      aorta to injury and this was associated mainly with increased HA production. This
      finding suggests that HA, which has been shown to play a crucial role in smooth
      muscle cell proliferation and migration, may be involved in the promoting effect
      of insulin treatment on arterial wall reaction to injury.

PMID- 10393508
TI  - Assessment of local differences in intima-media thickness in the human common
      carotid artery.
AB  - Intimal thickening may be focal in nature and is especially found in areas with
      low shear rate. To be able to study the relation between intima-media thickness
      (IMT) and wall shear rate appropriately, a method to assess IMT locally is
      required. It was the aim of the present study to investigate the ability of a
      recently developed automated method to assess local differences in IMT, if any,
      in relatively short arterial segments. Therefore, intrasession interlocation
      differences in IMT were assessed at the posterior wall of the common carotid
      artery close to the bulb (0 mm) and 10 and 20 mm more upstream in terms of mean
      difference +/- 2 standard deviations. Prior to this study we investigated the
      ability of the system to reproducibly assess IMT locally (intersession
      intralocation) in terms of repeatability coefficient (= 2 standard deviations).
      The measurements were performed in the common carotid artery 20 mm proximal to
      the bulb. The study was performed on young and older subjects presumed to be
      healthy. The intersession intralocation repeatability coefficient was 0.07 mm in
      the young group and 0.11 mm in the older group. The IMT close to the bulb (0 mm)
      was significantly larger (+/-0.050-0.065 mm) than that at the other locations in
      both age groups. We conclude that local IMT can be assessed reproducibly and
      local differences in wall morphology in short arterial segments can be studied
      reliably.

PMID- 10393509
TI  - Evidence for structural alterations in resistance arteries of patients with
      severe congestive heart failure.
AB  - Congestive heart failure (CHF) is characterized by an increase in total
      peripheral resistance. It was the specific aim of this study to investigate
      whether structural factors participate in the increased peripheral resistance
      that can be observed in severe heart failure. We determined forearm vascular
      resistance (FVR) at rest and after 10 min ischemia (Rmin; mm Hg/ml/min/100 ml)
      using venous occlusion plethysmography. Rmin was studied since it is largely
      dependent on the structural characteristics of resistance arteries. 24 patients
      with CHF [71.5 +/- 2.3 years; New York Heart Association (NYHA) functional class
      I-IV] with no history of arterial hypertension and casual arterial blood pressure
      < 140/90 mm Hg and 24 normotensive healthy control subjects (52.5 +/- 4.1 years)
      were included in our study. The patients were subdivided into those with 'mild'
      (NYHA class I and II; n = 10) and 'severe' (NYHA class III and IV; n = 14) heart
      failure. There were no significant differences between the two groups for
      echocardiographically determined ejection fraction and mean arterial blood
      pressure. Resting FVR averaged 40.5 +/- 4.4 mm Hg/ml/min/100 ml in control
      subjects and was 43.6 +/- 7.9 (nonsignificant vs. control) and 51.0 +/- 5 mm
      Hg/ml/min/100 ml (p < 0.05 vs. control) in patients with mild and severe CHF,
      respectively. No significant correlation between age and Rmin could be
      demonstrated in either the patient or the control group. Furthermore, Rmin did
      not differ between patients with mild CHF and control subjects. However, Rmin was
      significantly elevated in patients with severe CHF (5.7 +/- 0.39 mm Hg/ml/min/100
      ml) as compared to patients with mild CHF (4.0 +/- 0.39 mm Hg/ml/min/100 ml; p <
      0.05) and controls (4.5 +/- 0.26 mm Hg/ml/min/100 ml; p < 0.05). In conclusion,
      our study supports the concept that structural alterations contribute to the
      increased peripheral resistance in patients with heart failure. These changes are
      correlated with the severity of clinical symptoms.

PMID- 10393510
TI  - Regulation of arachidonic acid release by calcium influx in human endothelial
      cells.
AB  - In response to stimuli, endothelial cells release arachidonic acid, a lipid
      precursor of various vasoactive substances. We have investigated the
      relationships between cytosolic Ca2+ movements and arachidonic acid release in
      human umbilical vein endothelial cells. Histamine, a receptor-dependent agonist,
      and thapsigargin, a specific inhibitor of sarco-/endoplasmic Ca2+ pumps, time-
      and dose-dependently increased the release of [1-14C]-arachidonic acid. This
      release was inhibited by AACOCF3, a selective inhibitor of cytosolic
      phospholipase A2 (PLA2). In the absence of Ca2+ influx, arachidonic acid release
      was suppressed in both histamine- and thapsigargin-stimulated cells, despite
      marked elevations of cytosolic Ca2+ concentration ([Ca2+]i). In the presence of
      Ca2+ influx, arachidonic acid release was reduced in cells treated with BAPTA, an
      intracellular Ca2+ buffer, or with SK&F 96365, a receptor-operated Ca2+ channel
      blocker. Arachidonic acid release was analyzed as a function of the two
      successive phases of Ca2+ response to stimulation: Ca2+ peak and plateau phase,
      reflecting Ca2+ mobilization from internal stores and Ca2+ influx, respectively.
      The amount of arachidonic acid released was directly related to [Ca2+]i values
      measured at the influx phase with a 80 nM [Ca2+]i threshold, similar to that
      reported for PLA2 translocation. This suggests that Ca2+ entry from the
      extracellular space is essential for activating cytosolic PLA2 in human
      endothelial cells.

PMID- 10393511
TI  - Role of prostacyclin and nitric oxide in regulation of basal microvascular
      hydraulic permeability in cat skeletal muscle.
AB  - The effects of prostacyclin, nitric oxide (NO) and beta2-receptor stimulation on
      capillary filtration coefficient (CFC) and vascular tone were analyzed in an
      autoperfused cat skeletal muscle in vivo preparation, to evaluate if these
      substances are involved in regulation of basal microvascular hydraulic
      permeability. CFC was increased from control (100%) to 124% with the prostacyclin
      synthase inhibitor tranylcypromine and restored by simultaneous infusion of
      prostacyclin at 0.1 ng.kg-1. min-1, with further reduction to 76% at 1 ng. kg
      1.min-1. Prostacyclin at these doses did not influence vascular tone. NO
      inhibition by L-NAME increased CFC to 116% of control, with a vascular resistance
      increase of 45%. CFC was restored by simultaneous infusion of the NO precursor L
      arginine. L-arginine given alone reduced CFC to 86% of control. Tranylcypromine
      and L-NAME given together increased CFC to 141% of control and CFC was reduced to
      86% by prostacyclin at 1 ng.kg-1. min-1 with no significant further reduction by
      adding L-arginine. Adrenaline alone, in a vasodilating dose verifying beta2
      stimulation, or when followed by simultaneous beta-blockade with propranolol, did
      not influence CFC. We conclude that NO and especially prostacyclin are involved
      in bi-directional regulation of basal microvascular hydraulic permeability and
      can account for up to 30-40% increase or decrease from a basal value.
      Physiological beta2 stimulation has no effect on basal hydraulic permeability.
      The permeability-reducing effects of prostacyclin and NO are additive. NO, but
      not prostacyclin, is involved in regulation of basal vascular tone.

PMID- 10393512
TI  - Microcirculation Physiome Project.

PMID- 10393513
TI  - Effects of muramyl peptides on macrophages, monokines, and sleep.
AB  - Muramyl peptides are fragments of peptidoglycan from the cell walls of bacteria.
      Because of their unique chemistry, the immune system recognizes that muramyl
      peptides are products of bacteria, and it responds by becoming activated to
      resist infection. This resistance to infection is nonspecific, and extends to
      unrelated species of bacteria, fungi, and viruses. A key mechanism of the
      resistance to infection is activation of macrophages. Macrophage activation
      results in increased production of microbicidal oxygen radicals like superoxide
      and peroxide, and in increased secretion of inflammatory cytokines like
      interleukin-1beta and tumor necrosis factor-alpha. These cytokines, besides
      activating neutrophils, B lymphocytes, and T lymphocytes, act on the central
      nervous system to induce physiological responses like fever and sleep. These
      physiological responses also aid in combating infection. Muramyl peptides also
      activate macrophages and other cells of the immune system to kill cancer cells.
      Muramyl peptides and similar agents will become more important as therapeutic
      agents in the future, due to increasing resistance of microbes to antibiotics,
      and increasing numbers of patients with immunodeficiencies.

PMID- 10393514
TI  - Differential effects of one and repeated endotoxin treatment on pituitary-
      adrenocortical hormones in the mouse: role of interleukin-1 and tumor necrosis
      factor-alpha.
AB  - The role of endogenous interleukin-1beta (IL-1beta) and tumor necrosis factor
      alpha (TNF-alpha) in modulating the hypothalamic-pituitary-adrenal (HPA) axis
      response was examined in male C57BL/6 mice injected with endotoxin
      (lipopolysaccharide, LPS) or saline at 24-hour intervals for 4 or 8 consecutive
      days. The mice were divided into four groups: (1) LPS injections for 4 or 8 days
      and LPS injection on day 5 or 9, respectively (LPS-LPS); (2) LPS injections for 4
      or 8 days and saline injection on day 5 or 9, respectively (LPS-saline); (3)
      saline injections for 4 or 8 days and LPS injection on day 5 or 9, respectively
      (saline-LPS), and (4) saline injections for 4 or 8 days and saline injection on
      day 5 or 9 (saline-saline). The mice were sacrificed by decapitation 2 h after
      the last injection and plasma levels of hormones and cytokines and tissue levels
      of IL-1beta were measured. Plasma adrenocorticotropin (ACTH) levels were
      significantly attenuated in the LPS-LPS group compared with the dramatic
      increases in the saline-LPS group following 4 or 8 days of endotoxin treatment.
      Plasma corticosterone concentrations were comparable in the LPS-LPS group after 4
      days' treatment, but significantly lower following 8 days of treatment when
      compared with saline-LPS group. Repeated endotoxin treatment followed by a single
      saline injection (LPS-saline) did not alter the levels of IL-1beta in plasma or
      any of the tissues examined. IL-1beta levels in the hippocampus, hypothalamus,
      adrenal gland and plasma were elevated to comparable levels in the saline-LPS and
      LPS-LPS groups after 4 days of treatment. In contrast to the plasma IL-1beta
      response, TNFalpha levels were dramatically increased in the saline-LPS group but
      not in the LPS-LPS group following the 4-day treatment regimen. Increases in IL
      1beta concentrations were seen in all tissues following one endotoxin challenge
      in the saline-LPS group following the 8-day treatment regimen, while increases
      were significantly attenuated in the hypothalamus, adrenal gland and plasma in
      LPS-LPS for 8 days. The sustained increases in tissue levels of IL-1beta
      following 4-day endotoxin treatment appears to have functional consequences since
      [125I]IL-1alpha binding was significantly decreased in the LPS-saline group
      compared with the saline-saline group. Furthermore, [125I]IL-1alpha binding was
      markedly reduced in the LPS-LPS group compared with the saline-LPS group. There
      was a significant positive correlation between plasma ACTH and IL-1beta after a
      single and repeated LPS treatment for 4 days, while a significant correlation was
      seen between plasma ACTH and TNFalpha following one but not repeated LPS
      treatment. These data demonstrate a differential regulation of IL-1beta and
      TNFalpha by repeated endotoxin treatment and suggest that while TNFalpha may be
      important modulating the attenuated pituitary adrenocortical response following
      the 4-day endotoxin treatment, IL-1beta appears to be the primary regulator of
      the response following the 8-day endotoxin treatment in the regulation of the HPA
      axis.

PMID- 10393515
TI  - Effect of secretion of splenocytes after superior ovarian nerve section on the
      ovarian steroidogenesis.
AB  - It is known that ovary and spleen are innervated extensively by afferent and
      efferent noradrenergic sympathetic nerve fibers from the celiac ganglion.
      Furthermore, immune cells located in the ovary influence the ovarian physiology.
      However, the peripheral interaction between the immune and neuroendocrine system
      is poorly understood. This work was undertaken to study the effect of superior
      ovarian nerve (SON) transection, in adult rats, on the number of splenocyte beta
      adrenergic receptors and their possible relation to ovarian steroidogenesis,
      measuring the effect of secretions of those splenocytes on progesterone and
      estradiol release from the ovary. Seven days after SON transection, the
      splenocytes were isolated and then cultured for 48 h. Their number of beta
      adrenergic receptors, measured using [125I]-cyanopindolol as ligand, increased,
      and their culture media, used to stimulate ovaries from 60-day-old intact
      (neither SON-transected nor sham-operated) rats in vitro on diestrous day 2
      showed a decrease in progesterone release and an increase in estradiol release in
      relation to splenocyte culture media of control rats (sham-operated; p < 0.001,
      respectively). The effects of in vivo SON transection were simulated by an in
      vitro system modulating the splenocyte beta-adrenergic receptor number. The
      splenocytes from SON-transectioned rats were preincubated with and without
      norepinephrine (NE) 10(-6) M for 48 h, a low and high number of beta-adrenergic
      receptors respectively, and then were stimulated with NE 10(-6) M for 24 h. After
      that, the culture medium from splenocytes with a low number of beta-adrenergic
      receptors induced progesterone release from the ovaries of intact rats (p < 0.
      001), but produced no change in estradiol release. The data suggest that
      splenocyte secretions, which participate in the ovarian steroidogenic response,
      particularly in progesterone release, might be controlled by adrenergic
      influences since the number of splenocyte beta-adrenergic receptors changes
      through SON-celiac ganglion-noradrenergic postganglionic innervation of the
      spleen. In estradiol release, probably other neurotransmitters than
      norepinephrine (NE) are involved when the SON is sectioned. In this paper we also
      show functional evidence for modulation of immune function by the sympathetic
      nervous system and its principal neurotransmitter, NE.

PMID- 10393516
TI  - Peripheral effects of centrally administered interleukin-1beta in mice in
      relation to its clearance from the brain into the blood and tissue distribution.
AB  - Administration of interleukin IL-1 induces acute-phase response and inhibition of
      gastric secretion more efficiently when administered intracerebroventricularly
      (i.c.v.) than when the same dose of IL-1 is administered systemically. In this
      study we describe the pharmacokinetics of IL-1beta, administered centrally or
      systemically, in the serum or in peripheral tissues. IL-1beta administered i.c.v.
      resulted in higher peak IL-1beta concentrations, and lasted longer, than
      intravenous (i.v.) or intraperitoneal (i.p.) administration. Higher IL-1beta
      levels in the liver and heart were observed after i. c.v. administration
      (compared to the i.p. or i.v. route). Our data suggest that centrally injected IL
      1 induces higher circulating and hepatic IL-1 levels and contributes to the fact
      that the i.c.v. route of administration is particularly effective in inducing a
      liver acute-phase response.

PMID- 10393517
TI  - Beta-adrenergic receptor subtype effects on stress fever and thermoregulation.
AB  - Exposure to psychological stress increases body temperature (Tb). This stress
      fever may be immunologically beneficial in some patient populations but
      detrimental in others (e.g., HIV-infected individuals). For this reason, it is
      desirable to determine pharmacological methods of preventing stress fever. In
      rats, stress fever is modeled by exposure to a novel environment or 'open field.'
      The beta-adrenergic antagonists, nadolol and propranolol, block this stress
      fever. Neither of these beta-antagonists discriminates between subtypes of beta
      receptors. The purpose of this study was to determine the relative contribution
      of the different beta-receptor types to stress fever using beta1-, beta2-, and
      beta3-receptor subtype selective antagonists (atenolol [beta1], ICI-118551
      [beta2], and SR 59230A [beta3]) and agonists (dobutamine [beta1], salbutamol
      [beta2], and BRL 37344 [beta3]) on the Tb of rats. Tb was measured with a
      biotelemetry system. Our data suggest that central nervous system beta-receptor
      blockade with subtype-selective antagonists prevents the stress-induced rise in
      Tb; however, the beta3-antagonist was effective only at doses that produced
      hypothermia in a non-stressed control group. The stress-induced fever was
      mimicked by central nervous system administration of the selective beta2-agonist,
      salbutamol, and the beta3-agonist, BRL 37344. We hypothesize that the blockade of
      stress-induced fever by beta-blockers may be due to the sedative actions of these
      drugs.

PMID- 10393518
TI  - Retinoid therapy: compatible skin care.
AB  - Topically applied tretinoin (a retinoid) has been used for over 25 years to treat
      acne and disorders of keratinization. Now, tretinoin emollient cream, 0.05%
      (Renova(R)), may be prescribed for the treatment of photodamaged and
      chronologically aged skin, in conjunction with appropriate skin care and sun
      protection routines. Mild to moderate cutaneous side effects to topical
      tretinoin, such as xerosis, peeling, erythema and subjective irritation, are
      experienced by a majority of patients undergoing retinoid therapy. Results of
      clinical compatibility testing show that concomitant use of effective
      moisturizers, mild cleansers and daily sunscreens greatly enhance skin tolerance
      and patient comfort. A frequently prescribed regimen for topical treatment of
      photodamaged skin includes a combination of tretinoin and glycolic acid. While
      many clinicians report the use of both these agents for the management of their
      patients, little information exists in the literature about their compatibility
      in concomitant use. The results of a double-blind clinical study demonstrate that
      daytime usage of one of two 8% glycolic acid lotions in addition to nightly
      applications of Renova was well tolerated as part of a comprehensive skin care
      and sun protection program.

PMID- 10393519
TI  - Cosmetics for the eye area after cosmetic surgical procedures.
AB  - Cosmetic enhancement of the eye area after esthetic surgery allows the patient to
      get back into the mainstream of life faster. It also improves their psychic state
      by blocking out discoloration, helping to disguise incision scars and
      artistically coloring the face to enhance the results of the surgery. The
      patients automatically feel better, when they look better. After a surgical
      procedure, there are temporary and permanent structural changes that appear with
      blepharoplasty and laser surgery. Although these surgeries will take away loose
      skin, puffy fat deposits and wrinkles, they do not change the bone structure or
      eye placement. Before starting a makeup application, analyzation of the eyes for
      their structural features help the artist know the value of colors to be used.
      The measuring points of the brow along with the importance of framing the eye
      will also be discussed. Once the brows and the eyes have been analyzed, the
      artist needs to take into consideration the personality of the patient. This
      helps the artist decide on the colors, value, intensity and design which will be
      applied to the patient. Before eye makeup can be applied, the use of primers,
      concealers and/or camouflage creams will be used to block out any discoloration
      in the eye area. We will look at concerns in formulation of products that will go
      around the eyes after surgery. The application of cosmetic products should be
      used as an accessory. Women have a variety of dress styles: casual, business or
      evening. The style of makeup application should work in conjunction with what
      they are wearing and how they are feeling at the time. Just as there are many
      facets to a woman, there are various styles of application to fit her
      personality.

PMID- 10393520
TI  - Assessing the bioactivity of cosmetic products and ingredients.
AB  - Cosmetic ingredients can produce physical effects on the skin as well as positive
      and negative bioactive effects. Such effects have now been identified,
      categorized and interpreted. Because of this ongoing research and increased
      understanding, cosmetics, especially skin care products, are being improved.
      Targeting specific bioactive effects from newly developed cosmetic products is
      now possible. This development is aided by refining and expanding existing
      instrumental analysis which is now capable of elucidating more detailed and
      statistically significant differences from the use of certain ingredients in
      cosmetics. However, the ultimate proof of these changes will remain the consumer
      response to such products. Physical effects and the positive and negative
      bioactive effects from specific cosmetic ingredients will be discussed in
      relationship to the anatomy, physiology and condition of human skin. Examples of
      selected cosmetic ingredients in relationship to the anatomy, physiology and
      condition of human skin will be given. Demonstrations of selected cosmetic
      ingredient effects will be by way of clinical observation, instrumental analysis
      and consumer evaluation.

PMID- 10393521
TI  - Successful treatment of oxidative stress in vitiligo.
AB  - Patients with vitiligo have low catalase levels in their involved and uninvolved
      epidermis in association with high levels of hydrogen peroxide (H2O2). H2O2 has
      been confirmed for the first time in vivo using Fourier Transform Raman
      spectroscopy. A topical substitution with a UVB-activated pseudocatalase can
      successfully remove epidermal H2O2 in vitiligo. This approach leads to recovery
      of the oxidative damage in the epidermis and remarkable repigmentation in this
      disorder.

PMID- 10393522
TI  - Cosmetic problems in skin of color.
AB  - Practitioners are confronted with a myriad of cutaneous diseases affecting skin
      of color. Skin of color, which encompasses the pigmented skin of those of African
      American, Asian and Hispanic descent is susceptible to several unique and
      cosmetically disfiguring problems. Acne vulgaris, pseudofolliculitis barbae,
      postinflammatory hyperpigmentation and photoaging are diseases which commonly
      necessitate visits to the dermatologist and are of major cosmetic concern for
      those with skin of color. Effective treatments are needed to quickly resolve the
      inflammatory lesions of acne and pseudofolliculitis. The number of agents
      available for the treatment of postinflammatory hyperpigmentation is limited, and
      some agents are minimally effective. In addition to more effective therapeutic
      agents, development of enhanced camouflaging techniques are also necessary.
      Finally, sunscreens which provide more complete protection for skin of color are
      needed to address the issue of both photoaging and hyperpigmentation. We look to
      the cosmetic industry to develop new products and to improve currently existing
      products to address the cosmetic concerns of skin of color.

PMID- 10393523
TI  - Nail cosmetics and esthetics.
AB  - Healthy-looking nails are important to a well-groomed appearance. Four features
      are important to the appearance of an esthetic nail: nail length/shape, nail
      surface texture, nail color, and perionychial integrity.

PMID- 10393524
TI  - Current and future nail research - areas ripe for study.
AB  - This discussion examines five common topics that affect nails adversely,
      onychomycosis, brittle nails, developmental nail disorders, chronic paronychia
      and onycholysis. What is known about these processes, what areas of research, old
      and new, might lead to improved understanding of the underlying basis of the
      problems and what prospects the future might hold are considered.

PMID- 10393525
TI  - Laboratory assessment of hair follicle growth.
AB  - This article reviews the methods currently used to assess hair growth properties
      of a compound. The methods exploit in vivo, in vitro and ex vivo methodology. The
      challenge for the field remains to develop a purely in vitro system which
      reflects in detail the in vivo state.

PMID- 10393526
TI  - Efficacy testing for hair care products.
AB  - For the efficacy testing of hair care products, a number of methods are
      available. Scanning electron microscopy and atomic force microscopy are most
      suitable for surface evaluation; the swelling properties in the course of a
      treatment are determined using a fiber-swelling analyzer, and the luster may be
      reliably determined by means of a multiangle goniophotometer. Further, surface
      tension is a suitable method to evaluate the hydrophilic/hydrophobic properties
      of a hair section, and is sensitive enough to indicate the individual hormone
      cycle.

PMID- 10393527
TI  - Immunohistochemical detection of H-ras protooncoprotein p21 indicates favorable
      prognosis in node-negative breast cancer patients.
AB  - We tested primary breast carcinoma tissues from 297 patients using a monoclonal
      antibody (clone 235-1.7.1.) for the expression of p21(ras). 58% of tumors were
      p21(ras)-positive. When calculated in a univariate fashion, p21 expression
      correlated with proliferation activity (proliferating cell nuclear antigen) only.
      Using the log-rank test (median observation time 94 months) a significantly worse
      prognosis (disease-free survival, overall survival) relation was found with
      larger tumors, nodal involvement, anaplasia, rising proliferation activity, and
      lack of steroid receptors. Detection of p21(ras) correlated with a more favorable
      prognosis but only in node-negative patients. Stepwise correlation according to
      the Cox hazard model ranked p21 expression as a most significant predictor of
      prognosis second only to nodal status. These data suggest that detection of
      p21(ras) indicates the presence of a parameter which may act as tumor suppressor
      and benefit patients' survival.

PMID- 10393529
TI  - A novel stimulus, oncogene, induces expression of CD80 (B7-1) gene.
AB  - CD80, a cell surface molecule found on antigen-presenting cells which particpates
      in costimulatory signaling, is frequently detected on transformed and tumor
      cells. We examined the effect of transformation by v-myc, k-ras, and SV40 T
      antigen oncogenes on the expression of a CD80 promoter/luciferase gene as well as
      the endogenous CD80 promoter gene in murine fibroblast cell lines. All three
      transformed cell lines were tumorigenic in nude mice, however expression of the
      CD80/luciferase transgene or endogenous CD80 was detected only in the v-myc and k
      ras transformed cell lines. In both cell lines, CD80 expression was first
      detected more than 30 passages after transformation. Therefore, induction of CD80
      expression was a late event following transformation and was not essential for
      the establishment of the transformed phenotype.

PMID- 10393528
TI  - Cloning and sequencing of human oncodevelopmental soluble placental tissue
      protein 17 (PP17): homology with adipophilin and the mouse adipose
      differentiation-related protein.
AB  - Using a monospecific anti-PP17 antiserum, we detected 4 different molecular
      weight PP17 immunoreactive proteins (31,500 kD PP17a, 48, 000 kD PP17b, 60,900 kD
      PP17c and 74,000 kD PP17d) in different normal adult and fetal human tissues, and
      in term placenta, by chemiluminescence Western blot analysis. These proteins are
      overexpressed in cervix carcinoma tissue. Furthermore, increased amounts of PP17b
      are secreted into the circulation in cervix carcinoma patients; after radical
      surgery, PP17b serum levels are decreased, and the protein probably has an
      oncodevelopmental significance. cDNAs were isolated from a human placental cDNA
      library with the monospecific anti-PP17 antiserum. Sequence analysis of the
      clones showed that they encode for the 251 residue long PP17a variant, which is
      identical to the previously isolated and characterized PP17 antigen described in
      1983. An alignment search of the protein databank showed that PP17a is homologous
      to human adipophilin and mouse adipose differentiation-related protein. PP17c
      turned out to be a dimer of PP17a, while PP17b and PP17d immunoreactive proteins
      recently detected on Western blots require further investigations.

PMID- 10393531
TI  - A study on the lectin reactivity of alpha-fetoprotein produced by hepatoid
      adenocarcinomas and yolk sac tumors.
AB  - The carbohydrate structure of glycoproteins is considered to be tissue-specific
      or cell type-specific, but there have been no reports on the differences of the
      carbohydrate structure of alpha-fetoproteins (AFPs) produced by histologically
      identical tumors in different tissues. The lectin affinity electrophoresis of
      hepatoid adenocarcinomas and yolk sac tumors from different organs suggested that
      either the tumor heterogeneity or the tissue specificity is possibly involved,
      the lectin reactivity of the AFP sugar chain structure produced by the tumors in
      different tissues.

PMID- 10393530
TI  - The association between c-fos and c-jun expression and estrogen and progesterone
      receptors is lost in human endometrial cancer.
AB  - In normal human endometrium, expressions of the proto-oncogenes c-fos and c-jun
      parallel. We have previously shown that the expression of c-jun is related to
      proliferation and estrogen receptor (ER) status in endometrial epithelial cells.
      In this study, we analyzed endometrial cancer tissues for c-fos and c-jun
      messenger RNA (mRNA) expression by Northern blotting. Proto-oncogene expression
      was compared with ER and progesterone receptor (PR) status and with the
      proliferation marker Ki-67, as well as with histological grade and the use of
      hormone-replacement therapy (HRT). Messenger RNA for c-fos was detected in 35 of
      37 cancer tissues and mRNA for c-jun in 37 of 40 tissue samples studied. No
      correlation was observed between the relative mRNA levels of c-fos and c-jun,
      suggesting distinct control mechanisms, if any, in endometrial cancer. In
      contrast to normal endometrium, there was no correlation between the proto
      oncogene expression and Ki-67, ER or PR immunoreactivity. Neither were there any
      correlations between c-fos or c-jun expression and the histological grade of the
      tumor or preceding HRT. Our results reveal the loss of association between proto
      oncogene expression and ovarian steroid receptors or cell proliferation in
      malignant endometrium. This gives further support to the hypothesis that
      alterations in estrogen and progesterone signalling pathways are involved in the
      pathogenesis of endometrial cancer.

PMID- 10393532
TI  - Targeting phthalocyanines to tumor cells using epidermal growth factor
      conjugates.
AB  - Epidermal growth factor (EGF) was used as a vector for targeted delivery of
      phthalocyanines to tumor cells. The conjugates of EGF with disulfochloride
      aluminum phthalocyanine [Pc(Al)] and disulfochloride cobalt phthalocyanine
      [Pc(Co)] were synthesized. The cytotoxic activity of the conjugates against the
      human breast carcinoma cell line MCF-7 was determined. The cytotoxic activity of
      the EGF-Pc(Co) conjugate was 4.5 times higher than that of the EGF-Pc(Al)
      conjugate. The antitumor activity of the EGF-Pc(Co) conjugate was also studied in
      vivo in murine melanoma B16. Compared to free Pc(Co), intravenous injections of
      Pc(Co) conjugated with EGF inhibited tumor development and increased mean life
      span and mean survival time of experimental animals.

PMID- 10393533
TI  - Telomerase activity in Indian patients with carcinomas of the aerodigestive
      tract.
AB  - The activation of telomerase, a ribonucleoprotein maintaining telomeric length,
      might represent an additional required event in the multigenetic process of
      tumorigenesis in human cancer. To investigate whether telomerase activity is a
      prerequisite or a useful indicator of malignant potential, we assayed the enzyme
      in squamous cell carcinomas and tried to observe any correlation with clinical
      staging and histopathological grading. We have studied telomerase activity in 23
      samples of squamous cell carcinomas of the aerodigestive tract and in 22
      corresponding samples of adjoining tissues using the telomerase repeat
      amplification assay. Telomerase activity was detected in 100% of the tumor
      samples studied. The telomerase activity increased with tumor grading, but was
      not statistically significant. Low levels of enzyme activity were also detected
      in 60.86% of the adjoining normal tissue samples. Reactivation of telomerase may
      play an important role in the carcinogenesis of aerodigestive tract tumors.
      Detection of enzyme activity in the adjoining normal tissue is suggestive of
      microinvasion of tumor cells and/or early activation of telomerase in the
      progression towards cancer, before possible pathological identification.

PMID- 10393534
TI  - Potassium and sodium binding to the outer mouth of the K+ channel.
AB  - Molecular dynamics simulations of the K+ channel from Streptomyces lividans (KcsA
      channel) were performed in a membrane-mimetic environment with Na+ and K+ in
      different initial locations. The structure of the channel remained stable and
      well preserved for simulations lasting up to 1.5 ns. Salt bridges between Asp80
      and Arg89 of neighboring subunits, not detected in the X-ray structure, enhanced
      the stability of the tetrameric structure. Na+ or K+ ions located in the channel
      vestibule lost part of their hydration shell and diffused into the channel inner
      pore in less than a few hundred picoseconds. This powerful catalytic action was
      caused by strong electrostatic interactions with Asp80 and Glu71. The hydration
      state of the metal ions turned out to depend significantly on the conformational
      flexibility of the channel. Furthermore, Na+ entered the channel inner pore bound
      to more water molecules than K+. The different hydration state of the two ions
      may be a determinant factor in the ion selectivity of the channel.

PMID- 10393535
TI  - The camptothecin-resistant topoisomerase I mutant F361S is cross-resistant to
      antitumor rebeccamycin derivatives. A model for topoisomerase I inhibition by
      indolocarbazoles.
AB  - DNA topoisomerase I is a major cellular target for antitumor indolocarbazole
      derivatives (IND) such as the antibiotic rebeccamycin and the synthetic analogue
      NB-506 which is undergoing phase I clinical trials. We have investigated the
      mechanism of topoisomerase I inhibition by a rebeccamycin analogue, R-3, using
      the wild-type human topoisomerase I and a well-characterized recombinant enzyme,
      F361S. The catalytic activity of this mutant remains fully intact, but the enzyme
      is resistant to inhibition by camptothecin (CPT). Here we show that the mutated
      enzyme is cross-resistant to the rebeccamycin analogue. Despite their profound
      structural differences, CPT and R-3 interfere similarly with the activity of the
      wild-type and mutant topoisomerase I enzymes, and the drug-induced cleavable
      complexes are equally sensitive to the NaCl concentration. CPT and IND likely
      recognize identical structural elements of the topoisomerase I-DNA covalent
      complex; however, differences do exist in terms of sequence-specificity of
      topoisomerase I-mediated DNA cleavage. For the first time, a molecular model
      showing that CPT and IND share common steric and electronic features is proposed.
      The model helps to identify a specific pharmacophore for topoisomerase I
      inhibitors.

PMID- 10393536
TI  - The cleavage step of ribonuclease P catalysis is determined by ribozyme-substrate
      interactions both distal and proximal to the cleavage site.
AB  - The cleavage step of bacterial RNase P catalysis involves concentration
      independent processes after the formation of the ribozyme-substrate complex that
      result in the breaking of a phosphodiester bond. The 2'OH group at the cleavage
      site of a pre-tRNA substrate is an important determinant in the cleavage step. We
      determined here that in contrast to a tRNA substrate, the 2'OH at the cleavage
      site of two in vitro selected substrates has no effect, whereas a 2'OH located
      adjacent to the cleavage site has a similarly large effect on the cleavage step.
      This result indicates that a unique 2'OH in the vicinity of the cleavage site
      interacts with the ribozyme to achieve the maximal efficiency of the cleavage
      step. Individual modifications in a pre-tRNA substrate that disrupt ES
      interactions proximal to the cleavage site generally have little effect on the
      usage of this unique 2'OH. Ribozyme modifications that delete the interactions
      involving the T stem-loop of the tRNA have a large effect on the usage of this
      unique 2'OH and also alter the location of this 2'OH. We propose a new ES complex
      prior to the bond-breaking step in the reaction scheme to explain these results.
      This second ES complex is in fast equilibrium with the initial ES complex formed
      by bimolecular collision. The ribozyme interaction with this unique 2'OH shifts
      the equilibrium in favor of the second ES complex. The formation of the second ES
      complex may require optimal geometry of the two independently folding domains of
      this ribozyme to precisely position crucial functional groups and Mg2+ ions in
      the active site. Such a domain geometry is significantly favored by the RNase P
      protein. In the absence of the protein, spatial rearrangement of these domains in
      the ES complex may be necessary.

PMID- 10393537
TI  - Role of N-glycosylation in the expression and functional properties of human AT1
      receptor.
AB  - The role of N-glycosylation in the pharmacological properties and cell surface
      expression of AT1 receptor was evaluated. Using site-directed mutagenesis, we
      substituted both separately and simultaneously the asparagine residues in all
      three putative N-linked glycosylation consensus sequences (N-X-S/T) of AT1
      receptor (positions 4, 176, and 188) with aspartic acid. Expression of these
      mutant receptors in COS-7 cells followed by photolabeling with [125I]-[p-benzoyl
      Phe8]AngII and SDS-PAGE revealed ligand-receptor complexes of four different
      molecular sizes, indicating that the three N-glycosylation sites are actually
      occupied by oligosaccharides. Binding studies showed that the affinity of each
      mutant receptor for [Sar1,Ile8]Ang II was not significantly different from that
      of wild-type AT1 receptor. Moreover, the functional properties of all mutant
      receptors were unaffected as evaluated by inositol phosphate production. However,
      the expression levels of the aglycosylated mutant were 5-fold lower than that of
      the wild-type AT1 receptor. Use of green fluorescent protein-AT1 receptor fusion
      proteins in studying the cellular location of the aglycosylated mutant
      demonstrated that it was distributed at a much higher density to the ER-Golgi
      complex than to the plasma membrane in HEK 293 cells. Together, these results
      suggest an important role of N-glycosylation in the proper trafficking of AT1
      receptor to the plasma membrane.

PMID- 10393538
TI  - Crystal structure of GABA-aminotransferase, a target for antiepileptic drug
      therapy.
AB  - gamma-Aminobutyrate aminotransferase (GABA-AT), a pyridoxal phosphate-dependent
      enzyme, is responsible for the degradation of the inhibitory neurotransmitter
      GABA and is a target for antiepileptic drugs because its selective inhibition
      raises GABA concentrations in brain. The X-ray structure of pig GABA-AT has been
      determined to 3.0 A resolution by molecular replacement with the distantly
      related enzyme ornithine aminotransferase. Both omega-aminotransferases have the
      same fold, but exhibit side chain replacements in the closely packed binding site
      that explain their respective specificities. The aldimines of GABA and the
      antiepileptic drug vinyl-GABA have been modeled into the active site.

PMID- 10393539
TI  - Influence of the R(61,2)- and S(61,2)-alpha-(N6-adenyl)styrene oxide adducts on
      the A.C mismatched base pair in an oligodeoxynucleotide containing the human N
      ras codon 61.
AB  - Conformational studies of R- and S-alpha-(N6-adenyl)styrene oxide adducts
      mismatched with deoxycytosine at position X6 in d(CGGACXAGAAG).d(CTTCTCGTCCG),
      incorporating codons 60, 61 (underlined), and 62 of the human N-ras
      protooncogene, are described. These were the R- and S(61,2)C adducts. The
      S(61,2)C adduct afforded a stable solution structure, while the R(61,2)C adduct
      resulted in a disordered structure. Distance restraints for the S(61, 2)C adduct
      were calculated from NOE data using relaxation matrix analysis. These were
      incorporated as effective potentials into the total energy equation. The
      structures were refined using restrained molecular dynamics calculations which
      incorporated a simulated annealing protocol. The accuracy of the emergent
      structures was evaluated by complete relaxation matrix methods. The structures
      refined to an average rms difference of 1.07 A, determined by pairwise analysis.
      The experimentally determined structure was compared to NOE intensity data using
      complete relaxation matrix back-calculations, yielding an R1x value of 11.2 x 10(
      )2. The phenyl ring of the styrene in the S(61,2)C adduct was in the major groove
      and remained oriented in the 3'-direction as observed for the corresponding
      S(61,2) adduct paired with thymine [Feng, B., Zhou, L., Pasarelli, M., Harris, C.
      M., Harris, T. M., and Stone, M. P. (1995) Biochemistry 34, 14021-14036]. A shift
      of the modified adenine toward the minor groove resulted in the styrenyl ring
      stacking with nucleotide C5 on the 5'-side of the lesion, which shifted toward
      the major groove. Unlike the unmodified A.C mismatch, neither the S(61,2)C nor
      the R(61,2)C adduct formed protonated wobble A.C hydrogen bonds. This suggests
      that protonated wobble A.C pairing need not be prerequisite to low levels of
      alpha-SO-induced A --> G mutations. The shift of the modified adenine toward the
      minor groove in the S(61,2)C structure may play a more important role in the
      genesis of A --> G mutations. The disordered structure of the R(61,2)C adduct
      provides a potential explanation as to why that adduct does not induce A --> G
      mutations.

PMID- 10393540
TI  - A distinctive RNA fold: the solution structure of an analogue of the yeast
      tRNAPhe T Psi C domain.
AB  - The structure of an analogue of the yeast tRNAPhe T Psi C stem-loop has been
      determined by NMR spectroscopy and restrained molecular dynamics. The molecule
      contained the highly conserved modification ribothymidine at its naturally
      occurring position. The ribothymidine-modified T Psi C stem-loop is the product
      of the m5U54-tRNA methyltransferase, but is not a substrate for the m1A58-tRNA
      methyltransferase. Site-specific substitutions and 15N labels were used to
      confirm the assignment of NOESY cross-peaks critical in defining the global fold
      of the molecule. The structure is unusual in that the loop folds far over into
      the major groove of the curved stem. This conformation is stabilized by both
      stacking interactions and hydrogen bond formation. Furthermore, this conformation
      appears to be unique among RNA hairpins of similar size. There is, however, a
      considerable resemblance to the analogous domain in the crystal structure of the
      full-length yeast tRNAPhe. We believe, therefore, that the structure we have
      determined may represent an intermediate in the folding pathway during the
      maturation of tRNA.

PMID- 10393541
TI  - The solution structure of oxidized Escherichia coli cytochrome b562.
AB  - The solution structure of the oxidized, paramagnetic form of cytochrome b562 from
      Escherichia coli (106 amino acids) is here reported as obtained from 1653
      meaningful NOEs (from a total of 2051 unique NOEs), 33 (3)JHNHalpha values, and
      339 pseudocontact shifts. The structure displays the typical four-helix bundle
      motif, and a disordered loop between helices alpha2 and alpha3, as found in the
      solid state. The solution structure has a conformation intermediate between the
      two independent solid-state molecules, although different orientations are
      observed for a few residues. The magnetic susceptibility tensor is similar to
      that of cytochrome c, which has the same ligands, although the anisotropy is
      somewhat smaller. This difference in the electronic structure is consistent with
      the thermal accessibility in cytochrome b562 of states with S > 1/2. The
      structure is also compared with the solution structure of the apoprotein, and
      some information on the role of the cofactor on the protein folding and mobility
      is obtained. Helix alpha4 seems to be the most sensitive to the chemical
      environment in terms of structure and mobility. The pKa values affecting the
      hyperfine-shifted signals are also discussed. Quite intriguing is the comparison
      of the structure of cytochrome b562 with the available structures of cytochromes
      c' which display a similar folding motif and similar pKa values but very little
      sequence similarity.

PMID- 10393542
TI  - Study of ligand-receptor interactions by fluorescence correlation spectroscopy
      with different fluorophores: evidence that the homopentameric 5-hydroxytryptamine
      type 3As receptor binds only one ligand.
AB  - The 5-hydroxytryptamine receptor of type 3 was investigated by fluorescence
      correlation spectroscopy (FCS). Binding constants of fluorescently labeled
      ligands, the stoichiometry, and the mass of the receptor are readily accessible
      by this technique, while the duration of measurement is on the order of seconds
      to minutes. The receptor antagonist 1,2,3, 9-tetrahydro-3-[(5-methyl-1H-imidazol
      4-yl)methyl]-9-(3-aminopropyl)- 4H-carbazol-4-one (GR-H) was labeled with the
      fluorophores rhodamine 6G, fluorescein, N-[7-nitrobenz-2-oxa-1,3-diazol-4-yl],
      and the cyanine dye Cy5. These labels cover a large part of the visible
      electromagnetic spectrum. It is shown that the photophysical and chemical
      properties have a direct influence on the measurement quality (duration of
      measurement, signal-to-noise ratio) and the ligand-receptor interactions
      (dissociation constants), respectively. This makes it necessary to choose a
      suitable label or a combination of labels for receptor studies. The affinities of
      the fluorescently labeled ligands determined by FCS were virtually identical to
      the values obtained by radioligand binding experiments. Moreover, the
      dissociation constant of a nonfluorescent receptor ligand was determined
      successfully by an FCS competition assay. The experimental results showed that
      only one antagonist binds to the receptor, in agreement with measurements
      previously published [Tairi et al. (1998) Biochemistry 37, 15850-15864].

PMID- 10393544
TI  - Energetics and cooperativity of tertiary hydrogen bonds in RNA structure.
AB  - Tertiary interactions that allow RNA to fold into intricate three-dimensional
      structures are being identified, but little is known about the thermodynamics of
      individual interactions. Here we quantify the tertiary structure contributions of
      individual hydrogen bonds in a "ribose zipper" motif of the recently crystallized
      Tetrahymena group I intron P4-P6 domain. The 2'-hydroxyls of P4-P6 nucleotides
      C109/A184 and A183/G110 participate in forming the "teeth" of the zipper. These
      four nucleotides were substituted in all combinations with their 2'-deoxy and
      (separately) 2'-methoxy analogues, and thermodynamic effects on the tertiary
      folding DeltaG degrees ' were assayed by the Mg2+ dependence of electrophoretic
      mobility in nondenaturing gels. The 2'-deoxy series showed a consistent trend
      with an average contribution to the tertiary folding DeltaG degrees' of -0.4 to 
      0.5 kcal/mol per hydrogen bond. Contributions were approximately additive,
      reflecting no cooperativity among the hydrogen bonds. Each "tooth" of the ribose
      zipper (comprising two hydrogen bonds) thus contributes about -1.0 kcal/mol to
      the tertiary folding DeltaG degrees'. Single 2'-methoxy substitutions
      destabilized folding by approximately 1 kcal/mol, but the trend reversed with
      multiple 2'-methoxy substitutions; the folding DeltaG degrees' for the quadruple
      2'-methoxy derivative was approximately unchanged relative to wild-type. On the
      basis of these data and on temperature-gradient gel results, we conclude that
      entropically favorable hydrophobic interactions balance enthalpically unfavorable
      hydrogen bond deletions and steric clashes for multiple 2'-methoxy substitutions.
      Because many of the 2'-deoxy derivatives no longer have the characteristic
      hydrogen-bond patterns of the ribose zipper motif but simply have individual long
      range ribose-base or ribose-ribose hydrogen bonds, we speculate that the
      energetic value of -0.4 to -0.5 kcal/mol per tertiary hydrogen bond may be more
      generally applicable to RNA folding.

PMID- 10393543
TI  - Quantification of formaldehyde-mediated covalent adducts of adriamycin with DNA.
AB  - Duplex DNA incubated with adriamycin, dithiothreitol (DTT), and Fe3+ under
      aerobic, aqueous conditions yields double-stranded (DS) DNA bands by denaturing
      polyacrylamide gel electrophoresis (DPAGE) analysis, characteristic of DNAs which
      are interstrand cross-linked. Another laboratory has provided evidence that
      formaldehyde produced under these conditions promotes the covalent linkage of
      adriamycin to one strand of DNA and suggested that this complex results in the
      anomalous DPAGE behavior. We provide herein strong support for this
      interpretation. We show: (a) that mixtures of DNA and adriamycin incubated with
      DTT/Fe3+, H2O2, or formaldehyde all show DS DNA bands on DPAGE, (b) that the DS
      DNA bands and the formaldehyde-mediated lesion (detected by an indirect, GC-MS
      analysis) form with similar time courses, and in similar amounts, and (c) that
      the DNA in the DS DNA bands contains approximately one such lesion per DNA,
      whereas the single-stranded DNA is devoid of it. These results further support
      the interpretation that adriamycin does not create interstrand cross-links in
      DNA, and that the DS DNA observed in DPAGE experiments derives from the
      formaldehyde-mediated monoadduct.

PMID- 10393545
TI  - Evidence that constitutively active luteinizing hormone/human chorionic
      gonadotropin receptors are rapidly internalized.
AB  - The luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor, which
      belongs to the family of G-protein coupled receptors, plays an important role in
      gonadal steroidogenesis. Substitution of aspartic acid 556 of the LH/hCG receptor
      with glycine (D556G) creates a constitutively active receptor that activates
      adenylyl cyclase in the absence of hormone. To examine receptor internalization,
      human embryonic kidney cells (293 T) expressing wild type (WT) or D556G mutant
      receptors were incubated with [125I]hCG and subsequently analyzed for cell
      surface bound and internalized radioactivity. Comparison of the rate constants of
      internalization of the D556G mutant and WT receptors revealed that the rate of
      internalization of the D556G mutant was five times greater than that of the WT
      receptor. Although the D556G receptor internalizes [125I]hCG rapidly, a
      corresponding increase in [125I]hCG degradation was not seen. The internalization
      of another constitutively active LH/hCG receptor (aspartic acid 556 to tyrosine)
      was also greater than that of the WT receptor. Internalization of receptor bound
      [125I]hCG was inhibited by a hypertonic sucrose solution, confirming that the
      ligand enters the cell by receptor-mediated endocytosis. Furthermore, the
      constitutively active D556G and D556Y LH/hCG receptors utilize the arrestin
      dependent internalization pathway. These results suggest that the active state
      conformation of the constitutively active receptor is conducive to rapid
      internalization.

PMID- 10393546
TI  - Mechanism of Cdk2/Cyclin E inhibition by p27 and p27 phosphorylation.
AB  - The biochemical interactions between the Cdk2/Cyclin E kinase and its inhibitor
      p27, were investigated using purified, recombinant p27 and CAK-phosphorylated
      Cdk2/Cyclin E. From kcat/Km determinations using either histone H1 or pRb as
      substrates, we found that Cdk2/Cyclin E has 60-fold higher specificity for pRb
      than for histone H1. The IC50 value of p27 increased with increasing Cdk2/Cyclin
      E concentrations while it remained constant at various ATP and histone H1
      concentrations, suggesting that p27 acts as a tight binding inhibitor of
      Cdk2/Cyclin E. We also found that p27 could be phosphorylated by Cdk2/Cyclin E
      only at high enzyme concentrations, and that p27 forms a stable interaction with
      Cdk2/Cyclin E regardless of its phosphorylation state. Our results further
      indicate that the Cdk2/Cyclin E/p27 ternary complex is kinetically inactive as an
      enzyme; instead it serves as a substrate for Cdk2/Cyclin E. These results suggest
      that if phosphorylation of p27 by Cdk2/Cyclin E is involved in its ubiquitin
      dependent degradation, as previously suggested, then the target for such event is
      the phosphorylated p27 bound to Cdk2/Cyclin E and not free p27.

PMID- 10393547
TI  - Characterization of G protein-coupled receptor regulation in antisense mRNA
      expressing cells with reduced arrestin levels.
AB  - Previous studies with overexpressing wild-type or dominant negative nonvisual
      arrestins have established a role for these proteins in beta2-adrenergic receptor
      (beta2AR) internalization, desensitization, and resensitization. To validate and
      extend such findings, we employed an antisense strategy to target the nonvisual
      arrestins, arrestin-2 and arrestin-3, and determined the associated effects on
      the regulation of G protein-coupled receptor (GPCR) signaling. HEK293 cells
      stably expressing antisense constructs targeting arrestin-2 exhibited a selective
      reduction (approximately 50%) in arrestin-2 levels, while arrestin-3 antisense
      constructs resulted in reductions (>/=50%) in both arrestin-2 and arrestin-3
      levels. Initial analysis of these cells demonstrated that a reduced level of
      arrestin expression resulted in a significant decrease in the extent of agonist
      induced internalization of exogenously expressed beta2ARs, but had no effect on
      internalization of either m2 or m3 muscarinic acetylcholine receptors. Additional
      characterization involved assessing the role of arrestins in the regulation of
      endogenous GPCRs in these cells. Reduced arrestin levels significantly decreased
      the rate of endogenous beta2AR internalization, desensitization, and
      resensitization. Further analysis demonstrated that the desensitization of
      endogenous A2b adenosine and prostaglandin E2-stimulated receptors was also
      attenuated in cells with reduced arrestin levels. The effects on the beta2
      adrenergic, A2b adenosine, and PGE2-stimulated receptors were similar among cell
      lines that exhibited either a selective reduction in arrestin-2 levels or a
      reduction in both arrestin-2 and -3 levels. These findings establish the utility
      of antisense approaches in the examination of arrestin-mediated GPCR regulation.

PMID- 10393549
TI  - Different equilibrium stability behavior of ScFv fragments: identification,
      classification, and improvement by protein engineering.
AB  - A classification of scFv fragments concerning their unfolding/refolding
      equilibria is proposed. It is based on the analysis of different mutants of the
      levan-binding A48 scFv fragment and the HER-2 binding 4D5 scFv fragment as well
      as a "hybrid" scFv carrying the VL domain of 4D5 and the VH domain of an A48
      mutant. The denaturant-induced unfolding curves of the corresponding scFv
      fragments were measured and, if necessary for the classification, compared with
      the denaturation of the isolated domains. Depending on the relative intrinsic
      stabilities of the domains and the stability of the interface, the different scFv
      fragments were grouped into different classes. We also demonstrate with several
      examples how such a classification can be used to improve the stability of a
      given scFv fragment, by concentrating engineering efforts on the "weak part" of
      the particular molecule, which may either be the intrinsic stability of VL, of
      VH, or the stability of the interface. One of the scFv fragments obtained by this
      kind of approach is extremely stable, starting denaturation only at about 7 M
      urea. We believe that such extremely stable frameworks may be very suitable
      recipients in CDR grafting experiments. In addition, the thermodynamic
      equilibrium stabilities of seven related A48 scFv mutants covering a broad range
      of stabilities in urea unfolding were shown to be well correlated with thermal
      aggregation properties measured by light scattering and analytical gel
      filtration.

PMID- 10393548
TI  - Generation of a complete, soluble, and catalytically active sterol 14 alpha
      demethylase-reductase complex.
AB  - Sterol 14 alpha-demethylation is one of the key steps of sterol biosynthesis in
      eukaryotes and is catalyzed by cytochrome P450 sterol 14 alpha-demethylase (other
      names being CYP51 and P45014DM) encoded by ERG11. This enzyme activity is
      supported by an associated NAPDH-dependent reductase encoded by NCPR1 (NCP1),
      which is also associated with the endoplasmic reticulum. A diglycine linker
      recognition site (Gly-Gly-Ile-Glu-Gly-Arg-Gly-Gly) for the protease factor Xa,
      also containing a thrombin recognition site, was inserted just beyond the N
      terminal hydrophobic segment of Candida albicans Erg11p. This modified enzyme was
      heterologously expressed at a level of 2.5 nmol of Erg11p/mg of protein as an
      integral endoplasmic reticulum protein. Following purification, treatment of the
      modified protein with factor Xa or thrombin resulted in sequence-specific
      cleavage and production of a soluble N-terminal truncated Erg11p which exhibited
      spectral characteristics identical to those of the purified full-length, wild
      type form. Furthermore, reconstitution of the soluble enzyme with soluble yeast
      Ncpr1p, expressed and purified as an N-terminal deletion of 33 amino acids
      encompassing its membrane anchor, resulted in a fully functional and soluble
      eukaryotic Erg11p system. The complex was disrupted by high-salt concentration,
      reflecting the importance of electrostatic forces in the protein-protein
      interaction. The results demonstrate the membrane anchor serves to localize
      Erg11p to the ER where the substrate is located, but is not essential in either
      Ncpr1p or Erg11p activity. The possibility of cocrystallization of an active
      soluble eukaryotic 14 alpha-demethylase can be envisaged.

PMID- 10393551
TI  - Alteration of ganglioside composition by stable transfection with antisense
      vectors against GD3-synthase gene expression.
AB  - Gangliosides are ubiquitous components of mammalian cells. Their expression is
      frequently altered in many tumor types. We previously showed that alteration of
      the ganglioside composition often resulted in changes in cellular morphology and
      differentiation of cultured cells. In this study, we targeted sialyltransferase
      gene expression by the antisense knockdown experiment, and the results showed
      that inhibition of the expression of gangliosides GD3 and O-acetylated GD3 (OAc
      GD3) in the neuroblastoma F-11 cells greatly reduced the tumor growth in nude
      mice. The sense and antisense vectors containing either a 5' end fragment or the
      entire sequence of the cDNA coding for GD3-synthase were prepared and used in
      separate experiments to transfect the F-11 cells which express high levels of
      gangliosides GD3 and OAc-GD3. Single clones were isolated and expanded. Both the
      activity of the GD3-synthase and the concentrations of GD3 and OAc-GD3 in the
      antisense-transfected cells were dramatically decreased as a result of
      transfection with the antisense expression vectors. Further characterization of
      the antisense-transfected cells showed reduced rates of cell growth and neurite
      formation and changes in cellular morphology. When the cells were inoculated in
      athymic nude mice, the tumor growth rate was remarkably suppressed although the
      tumor incidence was not affected by the altered ganglioside composition. These
      results indicate that the tumor-associated ganglioside(s) is(are) involved in
      regulation of tumor growth, probably through the stimulation of angiogenesis of
      the tumor.

PMID- 10393550
TI  - Effects of substitutions of lysine and aspartic acid for asparagine at beta 108
      and of tryptophan for valine at alpha 96 on the structural and functional
      properties of human normal adult hemoglobin: roles of alpha 1 beta 1 and alpha 1
      beta 2 subunit interfaces in the cooperative oxygenation process.
AB  - Using our Escherichia coli expression system, we have produced five mutant
      recombinant (r) hemoglobins (Hbs): r Hb (alpha V96 W), r Hb Presbyterian (beta
      N108K), r Hb Yoshizuka (beta N108D), r Hb (alpha V96W, beta N108K), and r Hb
      (alpha V96W, beta N108D). These r Hbs allow us to investigate the effect on the
      structure-function relationship of Hb of replacing beta 108Asn by either a
      positively charged Lys or a negatively charged Asp as well as the effect of
      replacing alpha 96Val by a bulky, nonpolar Trp. We have conducted oxygen-binding
      studies to investigate the effect of several allosteric effectors on the
      oxygenation properties and the Bohr effects of these r Hbs. The oxygen affinity
      of these mutants is lower than that of human normal adult hemoglobin (Hb A) under
      various experimental conditions. The oxygen affinity of r Hb Yoshizuka is
      insensitive to changes in chloride concentration, whereas the oxygen affinity of
      r Hb Presbyterian exhibits a pronounced chloride effect. r Hb Presbyterian has
      the largest Bohr effect, followed by Hb A, r Hb (alpha V96W), and r Hb Yoshizuka.
      Thus, the amino acid substitution in the central cavity that increases the net
      positive charge enhances the Bohr effect. Proton nuclear magnetic resonance
      studies demonstrate that these r Hbs can switch from the R quaternary structure
      to the T quaternary structure without changing their ligation states upon the
      addition of an allosteric effector, inositol hexaphosphate, and/or by reducing
      the temperature. r Hb (alpha V96W, beta N108K), which has the lowest oxygen
      affinity among the hemoglobins studied, has the greatest tendency to switch to
      the T quaternary structure. The following conclusions can be derived from our
      results: First, if we can stabilize the deoxy (T) quaternary structure of a
      hemoglobin molecule without perturbing its oxy (R) quaternary structure, we will
      have a hemoglobin with low oxygen affinity and high cooperativity. Second, an
      alteration of the charge distribution by amino acid substitutions in the alpha 1
      beta 1 subunit interface and in the central cavity of the hemoglobin molecule can
      influence the Bohr effect. Third, an amino acid substitution in the alpha 1 beta
      1 subunit interface can affect both the oxygen affinity and cooperativity of the
      oxygenation process. There is communication between the alpha 1 beta 1 and alpha
      1 beta 2 subunit interfaces during the oxygenation process. Fourth, there is
      considerable cooperativity in the oxygenation process in the T-state of the
      hemoglobin molecule.

PMID- 10393552
TI  - Prion proteins carrying pathogenic mutations are resistant to phospholipase
      cleavage of their glycolipid anchors.
AB  - Familial prion diseases are linked to mutations in the gene encoding PrP, a
      protein of unknown function that is attached to the plasma membrane of neurons
      and several other cell types by a phosphatidylinositol-containing, glycolipid
      anchor. We have previously found that PrP molecules carrying disease-associated
      mutations display several biochemical attributes of PrPSc, the pathogenic isoform
      of PrP, when expressed in cultured Chinese hamster ovary cells. One of the
      distinctive properties of these mutant PrPs is their abnormal association with
      cell membranes, as revealed by their retention on the cell surface after
      treatment with a bacterial phospholipase that normally cleaves the glycolipid
      anchor. We demonstrate here that mutant PrP molecules, either expressed on intact
      cells or solubilized in nondenaturing detergents, are partially resistant to
      phospholipase cleavage. The anchor becomes fully susceptible to the enzyme when
      the proteins are denatured in SDS. These results suggest that the mutant PrP
      conformation, state of aggregation, or association with other molecules renders
      the glycolipid anchor physically inaccessible to cleavage. This conclusion stands
      in contrast to our previous suggestion that mutant PrP molecules are poorly
      released from the cell surface because they possess a secondary mechanism of
      membrane attachment in addition to the glycolipid anchor. Since PrPSc from
      scrapie-infected brain and cultured cells is also inefficiently released from
      membranes by phospholipase, resistance to this enzyme may be a molecular marker
      of the scrapie state.

PMID- 10393553
TI  - Unique binding site for Mn2+ ion responsible for reducing an oxidized YZ tyrosine
      in manganese-depleted photosystem II membranes.
AB  - Binding of Mn2+ to manganese-depleted photosystem II and electron donation from
      the bound Mn2+ to an oxidized YZ tyrosine were studied under the same equilibrium
      conditions. Mn2+ associated with the depleted membranes in a nonsaturating manner
      when added alone, but only one Mn2+ ion per photosystem II (PS II) was bound to
      the membranes in the presence of other divalent cations including Ca2+ and Mg2+.
      Mn2+-dependent electron donation to photosystem II studied by monitoring the
      decay kinetics of chlorophyll fluorescence and the electron paramagnetic
      resonance (EPR) signal of an oxidized YZ tyrosine (YZ+) after a single-turnover
      flash indicated that the binding of only one Mn2+ ion to the manganese-depleted
      PS II is sufficient for the complete reduction of YZ+ induced by flash
      excitation. The results indicate that the manganese-depleted membranes have only
      one unique binding site, which has higher affinity and higher specificity for
      Mn2+ compared with Mg2+ and Ca2+, and that Mn2+ bound to this unique site can
      deliver an electron to YZ+ with high efficiency. The dissociation constant for
      Mn2+ of this site largely depended on pH, suggesting that a single amino acid
      residue with a pKa value around neutral pH is implicated in the binding of Mn2+.
      The results are discussed in relation to the photoactivation mechanism that forms
      the active manganese cluster.

PMID- 10393554
TI  - Regulation of the bacteriorhodopsin photocycle and proton pumping in whole cells
      of Halobacterium salinarium.
AB  - Single-turnover kinetics of the bacteriorhodopsin photocycle and proton-pumping
      capabilities of whole cells were studied. It was found that the Delta mu
      (tilde)H+ of the cell had a profound influence on the kinetics and components of
      the cycle. For example, comparing the photocycle in whole cells to that seen in
      PM preparations, we found that (1) the single-turnover time of the cycle was
      increased approximately 10-fold, (2) the mole fraction of M-fast (at high actinic
      light) decreased from 50 to 20%, and (3) the time constant for M-slow increased
      significantly. The level of Delta mu(tilde)H+ was dependent on respiration, ATP
      formation and breakdown, and the magnitude of a pre-existing K+ diffusion
      gradient. The size of the Delta mu(tilde)H+ could be manipulated by additions of
      HCN, nigericin, and DCCD (N,N'-dicyclohexylcarbodamide). At higher levels of
      Delta mu(tilde)H+, further changes in the photocycle were seen. (4) Two slower
      components of M-decay appeared as major components. (5) The apparent conversion
      of the M-fast to the O intermediate disappeared. (6) A partial reversal of an
      early photocycle step occurred. The photocycle of intact cells could be changed
      to that seen in purple membrane suspensions by the energy-uncoupler CCCP or by
      lysis of the cells. In fresh whole cells, light-induced proton pumping was not
      seen until the K+ diffusion potential was dissipated and proton accumulation
      facilitated by use of a K+-H+ exchanger (nigericin), respiration was inhibited by
      HCN, and ATP synthesis and breakdown were inhibited by DCCD. In stored cells, the
      pre-existing K+ diffusion gradient was diminished through slow diffusion, and
      only DCCD and HCN were required to elicit proton extrusion.

PMID- 10393555
TI  - P+HA- charge recombination reaction rate constant in Rhodobacter sphaeroides
      reaction centers is independent of the P/P+ midpoint potential.
AB  - The kinetics of the P+HA- (oxidized donor, reduced bacteriopheophytin acceptor)
      recombination reaction was measured in a series of reaction center mutants of
      Rhodobacter sphaeroides with altered P/P+ midpoint potentials between 410 and 765
      mV. The time constant for P+HA- recombination was found to range between 14 and
      26 ns and was essentially independent of P/P+ midpoint potential. Previous work
      has shown that the time constant for initial electron transfer in these mutants
      at room temperature is also only weakly dependent on the P/P+ midpoint potential,
      ranging from about 2.5 ps to about 50 ps. These results, taken together, imply
      that heterogeneity in the P/P+ midpoint potential within the reaction center
      population is not likely the dominant cause of the substantial kinetic complexity
      observed in the decay of the excited singlet state of P on the picosecond to
      nanosecond time scale. In addition, the pathway of P+HA- decay appears to be
      direct or via P+BA- rather than proceeding back through P, even in the highest
      potential mutant, as is evident from the fact that the rate of P+HA-
      recombination is unaltered by pushing P+HA- much closer to P in energy. Finally,
      the midpoint potential independence of the P+HA- recombination rate constant
      suggests that the slow rate of P+HA- recombination arises from an inherent
      limitation in the maximum rate of this process rather than because it occurs in
      the inverted region of a classical Marcus rate vs free energy curve.

PMID- 10393556
TI  - Chromophore-protein-water interactions in the L intermediate of
      bacteriorhodopsin: FTIR study of the photoreaction of L at 80 K.
AB  - Using FTIR spectroscopy, perturbations of several residues and internal water
      molecules have been detected when light transforms all-trans bacteriorhodopsin
      (BR) to its L intermediate having a 13-cis chromophore. Illumination of L at 80 K
      results in an intermediate L' absorbing around 550 nm. L' thermally converts to
      the original BR only at >130 K. In this study, we used the light-induced
      transformation of L to L' at 80 K to identify some amino acid residues and water
      molecules that closely interact with the chromophore and distinguish them from
      those residues not affected by the photoreaction. The L minus L' FTIR difference
      spectrum shows that the chromophore in L' is in the all-trans configuration. The
      perturbed states of Asp96 and Val49 and of the environment along the aliphatic
      part of the retinal and Lys216 seen in L are not affected by the L --> L'
      photoreaction. On the other hand, the environments of the Schiff base of the
      chromophore, of Asp115, and of water molecules close to Asp85 returned in L' to
      their state in which they originally had existed in BR. The water molecules that
      are affected by the mutations of Thr46 and Asp96 also change to a different state
      in the L --> L' transition, as indicated by transformation of a water O-H
      vibrational band at 3497 cm-1 in L into an intense peak at 3549 cm-1 in L'.
      Notably, this change of water bands in the L --> L' transition at 80 K is
      entirely different from the changes observed in the BR --> K photoreaction at the
      same temperature, which does not show such intense bands. These results suggest
      that these water molecules move closer to the Schiff base as a hydrogen bonding
      cluster in L and L', presumably to stabilize its protonated state during the BR
      to L transition. They may contribute to the structural constraints that prevent L
      from returning to the initial BR upon illumination at 80 K.

PMID- 10393557
TI  - Effects of release factor 1 on in vitro protein translation and the elaboration
      of proteins containing unnatural amino acids.
AB  - An in vitro protein synthesizing system was modified to facilitate the improved,
      site-specific incorporation of unnatural amino acids into proteins via
      readthrough of mRNA nonsense (UAG) codons by chemically misacylated suppressor
      tRNAs. The modified system included an S-30 extract derived from Escherichia coli
      that expresses a temperature-sensitive variant of E. coli release factor 1 (RF1).
      Mild heat treatment of the S-30 extract partially deactivated RF1 and improved
      UAG codon readthrough by as much as 11-fold, as demonstrated by the incorporation
      of unnatural amino acids into positions 25 and 125 of HIV-1 protease and
      positions 10 and 22 of E. coli dihydrofolate reductase. The increases in yields
      were the greatest for those amino acids normally incorporated poorly in the in
      vitro protein synthesizing system, thus significantly enhancing the repertoire of
      modified amino acids that can be incorporated into the proteins of interest. The
      substantial increase in mutant protein yields over those obtained with an S-30
      extract derived from an RF1 proficient E. coli strain is proposed to result from
      a relaxed stringency of termination by RF1 at the stop codon (UAG). When RF1
      levels were depleted further, the intrinsic rate of DHFR synthesis increased,
      consistent with the possibility that RF1 competes not only at stop codons but
      also at other mRNA codons during peptide elongation. It thus seems possible that
      in addition to its currently accepted role as a protein factor involved in
      peptide termination, RF1 is also involved in functions that control the rate at
      which protein synthesis proceeds.

PMID- 10393558
TI  - Characterization of an inverted repeat with a zero spacer (IR0)-type retinoic
      acid response element from the mouse nuclear orphan receptor TR2-11 gene.
AB  - An inverted repeat with zero nucleotides in the spacer (IR0, 5'-GGGTCA CGAACT-3')
      element was localized in the proximal promoter region of the mouse TR2-11 gene,
      and characterized as a functional retinoic acid response element (RARE). In gel
      mobility shift assays, heterodimers of retinoic acid receptor alpha (RARalpha)
      and retinoid X receptor beta (RXRbeta) bound specifically to this element.
      Neither receptor alone was able to bind to this element efficiently. The
      dissociation constant (Kd) with respect to RAR-RXR binding was estimated to be 8
      nM. The biological activity of this IR0 element was assessed in a heterologous
      reporter system. The IR0-containing reporter was induced by RA in COS-1 cells in
      the presence of exogenously provided RARalpha and RXRbeta. In addition, the IR0
      oligomers could be bound by nuclear extracts isolated from COS-1 cells harboring
      the expression vectors for RARalpha and RXRbeta, but not by extracts isolated
      from control COS-1 cells. RA responsiveness of this IR0 was further confirmed in
      P19 cells that expressed endogenous RARs and RXRs. Collectively, these data
      demonstrated, for the first time, the presence of a natural RARE of the IR0 type,
      and suggested a potential cross-talk between nuclear orphan receptor TR2-11 and
      RAR-RXR families.

PMID- 10393559
TI  - Control of the histone-acetyltransferase activity of Tip60 by the HIV-1
      transactivator protein, Tat.
AB  - Tip60, a cellular histone-acetyltransferase, is known to interact with the HIV-1
      encoded transactivator protein, Tat. In this work, we show that the interaction
      of Tat with Tip60 efficiently inhibits the Tip60 histone-acetyltransferase
      activity. Besides its histone-acetyltransferase activity, Tip60 can undergo an
      autoacetylation which is not affected by Tat interaction. Our data show that
      Tip60 does not significantly influence Tat-dependent transcriptional activation
      of the 5'-LTR of HIV, suggesting that its interaction with Tat affects some
      intrinsic cellular process. We were then able to identify a cellular gene, Mn
      dependent superoxide dismutase (Mn-SOD), that has a Tip60-dependent
      transcriptional activity. Interestingly, the simultaneous expression of Tat and
      Tip60 abolishes the effect of Tip60 on the activity of the Mn-SOD promoter. We
      postulate that the HIV-1 transactivator, Tat, in targeting Tip60 hinders the
      expression of cellular genes (such as Mn-SOD) which normally interfere with the
      efficient replication and propagation of the virus.

PMID- 10393560
TI  - HlyC, the internal protein acyltransferase that activates hemolysin toxin: the
      role of conserved tyrosine and arginine residues in enzymatic activity as probed
      by chemical modification and site-directed mutagenesis.
AB  - Internal fatty acylation of proteins is a recognized means of modifying
      biological behavior. Escherichia coli hemolysin A (HlyA), a toxic protein, is
      transcribed as a nontoxic protein and made toxic by internal acylation of two
      lysine residue epsilon-amino groups; HlyC catalyzes the acyl transfer from acyl
      acyl carrier protein (ACP), the obligate acyl donor. Conserved residues among the
      respective homologous C proteins that activate 13 different RTX (repeats in
      toxin) toxins of which HlyA is the prototype likely include some residues that
      are important in catalysis. Possible roles of two conserved tyrosines and two
      conserved arginines were investigated by noting the effects of chemical modifiers
      and site-directed mutagenesis. TNM modification of HlyC at pH 8.0 led to
      extensive inhibition that was prevented by the presence of the substrate
      myristoyl-ACP but not by the product, ACPSH. NAI had no effect. Y70G and Y150G
      greatly diminished enzyme activity, whereas mutations Y70F and Y150F exhibited
      wild-type activity. Modification of arginine residues with PG markedly lowered
      acyltransferase activity with moderate protection by both myristoyl-ACP and
      ACPSH. Under optimum conditions, four separate mutations of the two conserved
      arginine residues (R24A, R24K, R87A, and R87K) had little effect on
      acyltransferase activity.

PMID- 10393561
TI  - Identification of Ser424 as the protein kinase A phosphorylation site in CTP
      synthetase from Saccharomyces cerevisiae.
AB  - The URA7-encoded CTP synthetase [EC 6.3.4.2, UTP:ammonia ligase (ADP-forming)] in
      the yeast Saccharomyces cerevisiae is phosphorylated on a serine residue and
      stimulated by cAMP-dependent protein kinase (protein kinase A) in vitro. In vivo,
      the phosphorylation of CTP synthetase is mediated by the RAS/cAMP pathway. In
      this work, we examined the hypothesis that amino acid residue Ser424 contained in
      a protein kinase A sequence motif in the URA7-encoded CTP synthetase is the
      target site for protein kinase A. A CTP synthetase synthetic peptide (SLGRKDSHSA)
      containing the protein kinase A motif was a substrate (Km = 30 microM) for
      protein kinase A. This peptide also inhibited (IC50 = 45 microM) the
      phosphorylation of purified wild-type CTP synthetase by protein kinase A. CTP
      synthetase with a Ser424 --> Ala (S424A) mutation was constructed by site
      directed mutagenesis. The mutated enzyme was not phosphorylated in response to
      the activation of protein kinase A activity in vivo. Purified S424A mutant CTP
      synthetase was not phosphorylated and stimulated by protein kinase A. The S424A
      mutant CTP synthetase had reduced Vmax and elevated Km values for ATP and UTP
      when compared with the protein kinase A-phosphorylated wild-type enzyme. The
      specificity constants for ATP and UTP for the S424A mutant CTP synthetase were
      4.2- and 2.9-fold lower, respectively, when compared with that of the
      phosphorylated enzyme. In addition, the S424A mutant enzyme was 2.7-fold more
      sensitive to CTP product inhibition when compared with the phosphorylated wild
      type enzyme. These data indicated that the protein kinase A target site in CTP
      synthetase was Ser424 and that the phosphorylation of this site played a role in
      the regulation of CTP synthetase activity.

PMID- 10393562
TI  - Significance of controlling crystallization mechanisms and kinetics in
      pharmaceutical systems.

PMID- 10393563
TI  - An investigation into the supramolecular structure of ternary gel systems using
      oscillatory rheometry, microscopy, and low frequency dielectric spectroscopy.
AB  - A series of ternary gel systems based on cetostearyl alcohol (CSA) and
      cetomacrogol 1000 or sodium lauryl sulfate have been studied using oscillatory
      rheology, differential interference contrast (DIC) microscopy, cryoscanning
      electron microscopy (cryo-SEM), and low-frequency dielectric analysis in order to
      elucidate the nature of the lamellar structures formed in relation to
      composition. The effects of altering the concentration of CSA (0.25% to 8% w/w)
      for 1% and 2% w/v cetomacrogol 1000 and 0.5% and 1% w/v sodium lauryl sulfate
      systems have been investigated, with marked increases in the storage and loss
      moduli seen on increasing the concentration of CSA for both surfactants. DIC
      microscopy indicated that at low CSA concentrations, needlelike structures were
      seen which, on increasing the concentration, were observed to congregate into
      nuclei. At concentrations of 4% CSA and above, neospherical structures were also
      observed. Cryo-SEM revealed that the needlelike objects were sheet structures
      ascribed to lamellar gel phases, while the nuclei were folded "rosettes" formed
      by those sheets, with the spherical structures being ascribed to cetostearyl
      alcohol. It was also noted that the lamellae were more tightly folded at 8% w/w
      CSA, which may be associated with the higher rheological moduli for these
      systems. Low-frequency dielectric analysis was performed over a frequency range
      of 10(4) Hz to 10(-2) Hz. A decrease in both the dielectric loss and capacitance
      was observed as the concentration of cetostearyl alcohol was increased. The
      dielectric data were described in terms of an equivalent circuit model based on a
      modified Maxwell-Wagner response. A good correlation was found between the fitted
      and experimental data and the effect of altering the gel composition on specific
      features of the equivalent circuit are discussed.

PMID- 10393564
TI  - Correlation and estimation of gas-chloroform and water-chloroform partition
      coefficients by a linear free energy relationship method.
AB  - A linear free energy relationship, LFER, has been used to correlate 150 values of
      gas-chloroform partition coefficients, as log Lchl with a standard deviation, sd,
      of 0.23 log units, a correlation coefficient r2 of 0.985, and an F-statistic of
      1919. The equation reveals that bulk chloroform is dipolar/polarizable, of little
      hydrogen-bond basicity, but as strong a hydrogen-bond acid as bulk methanol or
      bulk ethanol. However, the main influence on gaseous solubility in chloroform is
      due to solute-solvent London dispersion interactions. A slightly modified LFER
      has been used to correlate 302 values of water-chloroform partition coefficients,
      as log Pchl. The correlation equation predicts log Pchl for a further 34
      compounds not used in the equation with sd = 0.17 log units. When the LFER is
      applied to all 335 log Pchl values, the resulting equation has sd = 0.25, r2 =
      0.971, and F = 2218.

PMID- 10393565
TI  - Saturable transport of H2-antagonists ranitidine and famotidine across Caco-2
      cell monolayers.
AB  - The purpose of this study was to investigate the mechanism by which the H2
      antagonists ranitidine and famotidine interacted with the paracellular space
      during their transport across Caco-2 cell monolayers. Transport experiments with
      ranitidine and famotidine across Caco-2 cell monolayers were performed to
      determine the apical-to-basolateral flux at various concentrations. Kinetic
      analysis of the transport data showed that ranitidine and famotidine were
      transported by both saturable and nonsaturable processes. Na+, K+-ATPase
      inhibitor ouabain and metabolic inhibitors sodium azide + 2-deoxy-D-glucose did
      not affect ranitidine transport, suggesting that the active transport was not
      involved. Famotidine and some other guanidine-containing compounds, e.g.,
      guanethidine, Arg-Gly, L-arginine methyl ester, and L-argininamide, inhibited the
      transport of ranitidine, whereas other guanidine-containing compounds with an
      additional negative charge, e.g., L-arginine, did not. 2,4, 6-Triaminopyrimidine
      (TAP), an inhibitor of paracelluar cationic conductance, also inhibited the
      transport of both ranitidine and famotidine. On the basis of these results, it is
      proposed that the saturable transport of ranitidine and famotidine across Caco-2
      cell monolayers appears to be via a facilitated diffusion process mediated by the
      paracellular anionic sites. This mechanism is consistent with the observation
      that ranitidine and famotidine caused a concentration-dependent increase in
      transepithelial electrical resistance (TEER) across Caco-2 cell monolayers,
      presumably by blocking the paracellular anionic sites and thus inhibiting the
      flux of cations (e.g., Na+).

PMID- 10393566
TI  - Lyophilization of protein formulations in vials: investigation of the
      relationship between resistance to vapor flow during primary drying and small
      scale product collapse.
AB  - During the lyophilization process, formulations containing protein, bulking
      agent, or lyoprotectant form a dry product layer that can affect the transport of
      sublimed water vapor. We carried out an investigation of the primary drying
      segment of lyophilization to evaluate the relationship between the resistance to
      water vapor flow through the dried layer and the microstructure of the dried
      cake. Recombinant humanized antibody HER2 (rhuMAb HER2) formulated in trehalose
      was studied, as were protein-free formulations containing trehalose and sucrose.
      Sublimation rate and product temperature data were used to compute the resistance
      to mass transfer. Dried cake structure was examined by scanning electron
      microscopy and a novel fluorescence microscopy method. Collapse temperatures were
      determined by freeze-drying microscopy. Mass transfer resistance was found to
      decrease with increases in temperature for each material. Resistance also
      depended on composition, decreasing in the formulation series, rhuMAb HER2,
      trehalose, sucrose. The lyophilized material consisted of porous cakes, with a
      distinct denser region at the top. Formulation and temperature affected the
      microstructure of the dried cakes. The formulated trehalose and sucrose were
      seen, by both microscopy techniques, to possess small (2-20 microm) holes in
      their platelike structures after lyophilization. The quantity of holes was higher
      for material dried at higher temperature. The collapse temperature (Tc) of a
      material appeared to play a role in the process, as lower Tc was correlated with
      lower resistance and a greater extent of holes. Our results are consistent with
      the theory that lower resistance to water vapor flow in the primary drying stage
      of lyophilization may be due to small-scale product collapse.

PMID- 10393567
TI  - Selection of solid dosage form composition through drug-excipient compatibility
      testing.
AB  - A drug-excipient compatibility screening model was developed by which potential
      stability problems due to interactions of drug substances with excipients in
      solid dosage forms can be predicted. The model involved storing drug-excipient
      blends with 20% added water in closed glass vials at 50 degrees C and analyzing
      them after 1 and 3 weeks for chemical and physical stability. The total weight of
      drug-excipient blend in a vial was usually kept at about 200 mg. The amount of
      drug substance in a blend was determined on the basis of the expected drug-to
      excipient ratio in the final formulation. Potential roles of several key factors,
      such as the chemical nature of the excipient, drug-to-excipient ratio, moisture,
      microenvironmental pH of the drug-excipient mixture, temperature, and light, on
      dosage form stability could be identified by using the model. Certain physical
      changes, such as polymorphic conversion or change from crystalline to amorphous
      form, that could occur in drug-excipient mixtures were also studied. Selection of
      dosage form composition by using this model at the outset of a drug development
      program would lead to reduction of "surprise" problems during long-term stability
      testing of drug products.

PMID- 10393568
TI  - Isolation and identification of a major metabolite of PNU-107859, an MMP
      inhibitor from the biliary fluid of rats.
AB  - PNU-107859, an important representative structure in a novel class of matrix
      metalloproteinases (MMP) inhibitors known as thiadiazoles, was found to be
      quickly eliminated from rats. A major metabolite (approximately 10% of total
      dose) was found to be present in the bile of rats. The metabolite in question was
      isolated and purified from the bile fluids collected from six cannulated rats.
      From a total of approximately 75 mg of PNU-107859 administered to rats, 3.3 mg of
      the metabolite was recovered. The NMR and mass spectrometry results indicated
      that the metabolite is a glucuronide conjugate (1-deoxy-1beta-substituted D
      glucopyranosiduronic acid) of the intact drug. Furthermore, the UV, MS, and NMR
      data established that the conjugate is located at the nitrogen alpha to the
      thiocarbonyl of the thiadiazole ring.

PMID- 10393569
TI  - Preparation of a complex of dexamethasone palmitate-low density lipoprotein and
      its effect on foam cell formation of murine peritoneal macrophages.
AB  - In the early progression of atherosclerosis, LDL migrates in the subendothelial
      space of the artery and plays an important role in foam cell formations of
      macrophages. LDL may serve as a carrier of site-specific delivery of drugs to
      atherosclerotic lesions. In this exploratory study, dexamethasone palmitate (DP)
      was incorporated in LDL, and an inhibitory effect of this complex on foam cell
      formations was examined. LDL was isolated from human plasma, and the DP-LDL
      complex was prepared by incubation in the presence of Celite 545. No degradation
      nor modification of LDL was observed. The DP/LDL molar ratio of the complex was
      35-50:1. Foam cell formations of murine macrophages were induced by incubation
      with oxidized LDL. When macrophages were pretreated with the DP-LDL complex,
      accumulation of cholesterol ester in the macrophages induced by oxidized LDL,
      i.e., an index of foam cell formation, was decreased. These findings indicated
      that the DP-LDL complex showed similar characteristics to LDL, and the DP-LDL
      complex inhibited foam cell formations of macrophages in vitro. This study
      provides the basis for further study of the DP-LDL complex as a drug-carrier
      complex for treatment of atherosclerosis.

PMID- 10393570
TI  - Tripeptide discriminations using circular dichroism detection.
AB  - A general spectroscopic method is described that might be applied to validating
      amino acid sequences in peptides and protein fragments with a view to it becoming
      a routine procedure with which to characterize biotechnology drug products. The
      tripeptides are the L-enantiomers of GGA, GGH, GGI, GGL, GGF, GHG, LGG, and YGG.
      The simple procedure calls for their complexation with Cu(II) ion in strong
      aqueous base. Binding the first three residues in the sequence, beginning at the
      amine terminus, completes the coordination sphere of the Cu(II) ion, so
      duplication of the initial sequence from peptide to peptide could be an important
      limiting factor in determining the extent of differentiation that is possible.
      The analytical focus is the selectivity associated with the chirality properties
      of the peptides. Detection is by circular dichroism operating in the visible
      range. The eight analytes were chosen as representative of a series where the
      sequences are most similar and therefore potentially the most difficult to
      discriminate spectroscopically. All have just one chiral center. Using
      ellipticity data at all (n = 1500) wavelengths in the measured spectra, and two
      novel data reduction procedures, total discrimination among all eight analytes is
      achieved. The method has considerable potential for use in quality control of
      peptide and protein biotechnological drug forms, especially their enantiomeric
      purities.

PMID- 10393571
TI  - Predicting the total entropy of melting: application to pharmaceuticals and
      environmentally relevant compounds.
AB  - Experimental entropy of melting values for physical property estimation schemes,
      such as solubility and vapor pressure, are not readily available. In this study a
      semiempirical equation, which contains two molecular parameters, is used to
      estimate the total entropy of melting for a variety of pharmaceutically and
      environmentally relevant compounds. A database of experimental entropy values
      consisting of over 370 different compounds was compiled from literature. A
      molecular rotational symmetry number and a molecular flexibility number for each
      compound were defined. The simple equation does very well in predicting the total
      entropy of melting for the complex set of molecules with an average error of 21%.

PMID- 10393572
TI  - Effects of true density, compacted mass, compression speed, and punch deformation
      on the mean yield pressure.
AB  - Compressibility properties of pharmaceutical materials are widely characterized
      by measuring the volume reduction of a powder column under pressure. Experimental
      data are commonly analyzed using the Heckel model from which powder deformation
      mechanisms are determined using mean yield pressure (Py). Several studies from
      the literature have shown the effects of operating conditions on the
      determination of Py and have pointed out the limitations of this model. The
      Heckel model requires true density and compacted mass values to determine Py from
      force-displacement data. It is likely that experimental errors will be introduced
      when measuring the true density and compacted mass. This study investigates the
      effects of true density and compacted mass on Py. Materials having different
      particle deformation mechanisms are studied. Punch displacement and applied
      pressure are measured for each material at two compression speeds. For each
      material, three different true density and compacted mass values are utilized to
      evaluate their effect on Py. The calculated variation of Py reaches 20%. This
      study demonstrates that the errors in measuring true density and compacted mass
      have a greater effect on Py than the errors incurred from not correcting the
      displacement measurements due to punch elasticity.

PMID- 10393573
TI  - General solution for diffusion-controlled dissolution of spherical particles. 1.
      Theory.
AB  - Three classical particle dissolution rate expressions are commonly used to
      interpret particle dissolution rate phenomena. Our analysis shows that an
      assumption used in the derivation of the traditional cube-root law may not be
      accurate under all conditions for diffusion-controlled particle dissolution.
      Mathematical analysis shows that the three classical particle dissolution rate
      expressions are approximate solutions to a general diffusion layer model. The
      cube-root law is most appropriate when particle size is much larger than the
      diffusion layer thickness, the two-thirds-root expression applies when the
      particle size is much smaller than the diffusion layer thickness. The square-root
      expression is intermediate between these two models. A general solution to the
      diffusion layer model for monodispersed spherical particles dissolution was
      derived for sink and nonsink conditions. Constant diffusion layer thickness was
      assumed in the derivation. Simulated dissolution data showed that the ratio
      between particle size and diffusion layer thickness (a0/h) is an important factor
      in controlling the shape of particle dissolution profiles. A new semiempirical
      general particle dissolution equation is also discussed which encompasses the
      three classical particle dissolution expressions. The success of the general
      equation in explaining limitations of traditional particle dissolution
      expressions demonstrates the usefulness of the general diffusion layer model.

PMID- 10393574
TI  - An evaluation of the shape of some popular nickel titanium alloy preformed arch
      wires.
AB  - The mathematical Beta function is shown to be an accurate planar representation
      of the natural human arch form defined by the spatial coordinates of the labial
      and buccal dental/bracket interfacing surfaces in the maxillary and mandibular
      arches. Graphic planar representations of the corresponding bracket base spatial
      coordinates of 33 popular preformed nickel titanium arch wires and bracket
      assemblies were superimposed on each of the relevant maxillary and mandibular
      natural forms. The arch forms of the preformed nickel titanium arch wires and
      bracket assemblies did not emulate the natural human arch form. The average
      mandibular natural human arch form first molar/canine width ratio is 2.38/1; the
      same preformed arch wire/bracket ratio is 1.87/1. These ratios for the maxillary
      arch are 1.92/1 and 1.54/1, respectively. The average canine width exceeded the
      natural canine width by 5.95 mm in the mandibular arch and 8.23 mm in the
      maxillary arch. The corresponding mandibular first molar and maxillary first
      molar widths exceeded the natural human first molar arch width by 0.84 mm and
      2.68 mm, respectively. These findings have implications with respect to
      posttreatment stability and facial esthetics. "Round tripping" teeth resulting
      from subsequent change to stainless steel arch wires to restore a more natural
      human arch form and size may result in deleterious tissue effects.

PMID- 10393575
TI  - Cephalometric changes after the correction of class III malocclusion with
      maxillary expansion/facemask therapy.
AB  - The purpose of this study was to analyze the cephalometric changes that occurred
      during and after the correction of Class III malocclusion. The records of 24
      Class III patients treated with a banded expansion appliance and custom facemask
      were compared with 24 Class I and 27 Class III untreated controls. Cephalometric
      means were calculated for the annualized data and compared univariately with
      unpaired t tests to determine significant differences. Treatment results showed
      more convexity of the facial profile from anterior displacement and downward and
      backward rotation of the maxilla and clockwise rotation of the mandible. The
      maxillary teeth moved forward while the lower incisors retruded. Postprotraction
      results showed the maxilla did not relapse after treatment but grew anteriorly
      similar to the Class III controls but less than the Class I controls. Mandibular
      growth was similar for the treatment and control groups. Dental changes
      compensated for decreasing overjet whereas the soft tissue profile showed no
      significant posttreatment changes. Results in the intercontrol comparison showed
      the Class III controls had significantly less forward movement of A-point and
      greater forward movement of the mandible than Class I controls. Because of these
      differences using a Class I control group to compare to a Class III treatment
      group will tend to underestimate the treatment effects and overestimate
      posttreatment changes. Overcorrection of the Class III malocclusion is
      recommended to compensate for postprotraction growth deficiency of the maxilla.

PMID- 10393576
TI  - More on the Herbst and TMD controversy.

PMID- 10393577
TI  - Distraction osteogenesis in Silver Russell syndrome to expand the mandible.
AB  - Distraction osteogenesis is a method commonly used to activate bone regeneration
      in nonunions and osseous defects and for lengthening procedures of tubular bones.
      This technique involves the sectioning of a bone and the subsequent deliberate,
      controlled movement of the opposing sectioned edges to lengthen, widen, or
      reposition a bone, or all three. In this report, a patient with Silver Russell
      syndrome and severe mandibular hypoplasia was treated by means of distraction
      osteogenesis of the midsymphysis to widen the mandible in concert with sagittal
      ramus osteotomies to lengthen the mandible. This treatment created significantly
      increased arch length in the mandible, which was necessary to facilitate the
      patient's orthodontic treatment. We believe this is the first reported case of
      distraction osteogenesis to widen the mandible with the use of a tooth-borne
      appliance.

PMID- 10393578
TI  - Comparison of treatment outcomes with banded and bonded RPE appliances.
AB  - The purpose of this retrospective study was to compare the treatment outcomes
      with a banded (n = 38) versus a bonded (n = 55) rapid palatal expansion appliance
      followed by edgewise orthodontics. Both lateral cephalometric radiographs and
      orthodontic study casts were evaluated at pretreatment and posttreatment time
      periods. Overall, the banded rapid palatal expansion group had more vertical
      change than the bonded group. However, most of these changes were less than 1
      degrees or 1 mm and may be considered clinically insignificant. This study could
      not establish superiority of one type of rapid palatal expansion technique over
      another.

PMID- 10393579
TI  - The effect of first premolar extraction on vertical dimension.
AB  - The purpose of this study was to evaluate the vertical changes occurring in Class
      I patients treated orthodontically with first premolar extraction and to compare
      these changes with those occurring in Class I patients treated orthodontically
      without extractions. Records of 40 Class I nonextraction cases (24 girls, 16
      boys) and 40 Class I maxillary and mandibular first premolar extraction cases (23
      girls, 17 boys) were obtained. The pretreatment and posttreatment cephalograms
      were digitized, and 6 linear and 8 angular cephalometric measurements were
      selected to evaluate vertical changes. Evaluation of the treatment results of the
      extraction and nonextraction cases showed that the vertical changes occurring
      after the extraction of maxillary and mandibular first premolars were not
      different than those occurring in the nonextraction cases.

PMID- 10393580
TI  - Surgically assisted rapid palatal expansion: orthodontic preparation for clinical
      success.
AB  - Close root proximity between the maxillary central incisors presents a problem in
      the surgical management of a maxillary palatal expansion. During the surgical
      fracture of this interdental area, the possibility exists for a separation to
      occur between the root surface and the bone. If this does occur, it is paramount
      that the gingival attachment remain intact. Asymmetric separation places more
      stress on the mesial gingival attachment because of the anatomy of the gingival
      fiber apparatus. Gingival detachment results in epithelial downgrowth in an
      apical direction, which in turn prevents bone apposition in a coronal direction.
      The resulting osseous defect is difficult to treat with an osseous graft
      procedure, as there are few if any intrabony walls. Treatment planning should
      include analysis of a recent periapical radiograph of the incisor roots to
      determine the need for orthodontic root separation before surgery. A postsurgical
      periapical radiograph should be taken to determine where the interdental
      separation has occurred. The expansion schedule should be adjusted depending on
      the symmetry of the separation and the health of the gingival attachment.

PMID- 10393581
TI  - Orthodontic correction of a Class II Division 1 subdivision right open bite
      malocclusion in an adolescent patient with a cervical pull face-bow headgear.

PMID- 10393582
TI  - Nonsurgical correction of a class II malocclusion with a vertical growth
      tendency.
AB  - Malocclusion, with a superimposed vertical growth tendency, is often difficult to
      treat without a combined surgical orthodontic approach. Certain situations,
      however, may preclude surgery as a treatment option. The following case report
      demonstrates the use of orthodontic mechanotherapy alone in successfully treating
      a patient that exhibited a Class II Division I malocclusion with a high
      mandibular plane angle and vertical growth tendency.

PMID- 10393583
TI  - Orthodontic correction of an adult Angle Class II Division 2 deep bite.

PMID- 10393584
TI  - Fifteen-year reproducibility of natural head posture: A longitudinal study.
AB  - Natural head posture continues to be widely used as the logical reference
      position for the evaluation of craniofacial morphology. The basic underlying
      premise is that the long-term clinical reproducibility (variability) of natural
      head posture is significantly less than the variability of conventional reference
      planes with respect to the vertical. This study reports the 15-year longitudinal
      reproducibility of natural head posture. Twenty Chinese adults in Hong Kong, who
      had initial natural head posture radiographs at age 12 years, were followed up
      and had repeated cephalograms after 15 years. The method error (reproducibility)
      after 15 years was 2.2 degrees, which compared favorably with the 5-year
      reproducibility (method error = 3.0 degrees ) and the 5 to 10 minutes
      reproducibility (method error = 1.9 degrees ). The individual variability of
      natural head posture reproducibility increased slightly over time. After 15 years
      the variance of natural head posture (4.8 degrees [= 2.2(2)]) remains
      significantly less than the variance of intracranial reference planes to the
      vertical (25 degrees to 36 degrees ). Cephalometric analyses based on natural
      head posture therefore remain valid over time.

PMID- 10393585
TI  - Comparison of the debonding characteristics of two innovative ceramic bracket
      designs.
AB  - Two new ceramic brackets-one designed with a metal-lined arch wire slot and the
      other with an epoxy resin base-have been recently introduced. The new brackets
      are thought to combine the esthetic advantages of ceramics and the functional
      advantages of debonding metal brackets. The purpose of this study was to compare
      the following: 1) the shear bond strength of the 2 brackets, and 2) the bond
      failure location when the brackets are debonded with pliers. Sixty-one Clarity
      (3M Unitek) collapsible ceramic brackets and 66 MXi (TP Orthodontics, Inc)
      brackets were bonded to the teeth with the same bonding system. The Zwick
      Universal Test Machine (Zwick Gm bH & Co) was used to determine the shear bond
      strength force levels needed to debond the brackets. The appropriate pliers also
      were used to debond both types of brackets to determine the mode of bond failure
      that will be encountered clinically. After debonding, all the teeth and brackets
      were examined with 10x magnification. Any adhesive that remained after the
      bracket removal was assessed according to the Adhesive Remnant Index. The
      findings indicated that the shear bond strength of the Clarity ceramic brackets
      was significantly greater than that of the MXi ceramic brackets. However, both
      brackets exhibited forces that were adequate for clinical use. The Adhesive
      Remnant Index scores for both the shear test and the plier debonding indicated a
      similar bond failure pattern when the 2 ceramic brackets were compared with each
      other. This suggests that, when these brackets are debonded with the Weingart
      (Ormco) and ETM (Ormco) pliers, there was a greater tendency for most of the
      adhesive to remain on the enamel surface. In conclusion, the most efficient
      method to debond the MXi ceramic bracket is by placing the blades of the ETM 346
      pliers between the bracket base and the enamel surface. On the other hand, the
      most efficient method of debonding the Clarity bracket is by using the Weingart
      pliers and applying pressure to the tiewings. When the 2 ceramic brackets were
      debonded as recommended here, most of the residual adhesive remained on the
      enamel surface, a pattern similar to the one observed previously with metal
      brackets. The failure at the bracket-adhesive interface decreases the probability
      of enamel damage but necessitates the removal of more residual adhesive after
      debonding.

PMID- 10393586
TI  - Condylar positional changes after mandibular advancement surgery with rigid
      internal fixation.
AB  - The purpose of this retrospective investigation was to describe condylar
      positional changes in patients after mandibular advancement surgery. By
      superimposing on clearly identifiable cephalometric landmarks (ie, mandibular
      symphysis and rigid fixation screws), condylar positional changes from
      immediately after surgery to orthodontic appliance removal were extrapolated.
      Although the mandibular symphysis generally moved in either an anterior or
      posterior direction after surgery, condylar movements were exclusively in an
      upward vertical direction. Correlations were found between several measured
      variables, including a tendency for increased superior postsurgical movement of
      the condyles with increasing magnitudes of surgical advancement of the mandible.
      This long-term instability of skeletal relationships may be caused by a wide
      variety of interacting factors and events.

PMID- 10393588
TI  - The benefits of certification by the american board of orthodontics 

PMID- 10393589
TI  - Kyrle W. preis 

PMID- 10393587
TI  - A retrospective study of Angle Class I malocclusions treated orthodontically
      without extractions using two palatal expansion methods.
AB  - The correction and relapse of mandibular anterior crowding was evaluated in a
      population of 58 patients with Angle Class I malocclusion who were treated
      orthodontically without extraction of permanent teeth. The subjects were
      retrospectively evaluated from records taken before treatment, posttreatment, and
      postretention. The postretention period averaged 8 years (minimum of 4 and
      maximum of 20 years). All cases in Groups A and B were given orthopedic treatment
      to develop the maxillary apical base in the transverse and anteroposterior
      planes. Group A was treated with expansion of the inner bow of the face bow
      appliance (Kloehn), and Group B was treated with the Haas palatal expansion
      appliance. Both groups were then treated orthodontically with tandem mechanics.
      The response variables measured were: overbite, overjet, intercanine distance,
      intermolar distance, and irregularity index. Study groups A and B were not
      significantly different for subject age, retention, or postretention time.
      Moreover, the groups did not show significant difference for any of the response
      variables before treatment. However, there was a statistically significant
      difference in the treatment times (P =.0133). A statistically significant
      treatment effect was observed for most response variables in the groups.
      Overbite, overjet, and irregularity index were significantly reduced, intermolar
      distance was significantly increased, and intercanine distance showed no
      significant change in Groups A and B. In the postretention period, there was a
      tendency for variables to change slightly toward their before treatment values
      but no compromise of orthodontic correction was noted. The irregularity index in
      Group A was corrected from 4.8 to 1.1 mm and remained at 1.1 mm in the
      postretention period. The irregularity index in Group B was corrected from 5.1 to
      1.2 mm (P =.0001) and changed slightly from 1. 2 to 1.7 mm (P =.0540) in the
      postretention period. We concluded that mandibular incisors tended to become more
      crowded postretention. However, in contrast to previous reports, we calculate
      this relapse to be small. Neither before treatment nor posttreatment variables
      were predictive of relapse.

PMID- 10393590
TI  - Dr. Robert M. Nelson 1918 to 1998 

PMID- 10393591
TI  - Walter arnett doyle-Aug 9, 1933 to feb 13, 1999 

PMID- 10393592
TI  - Presentations with Dentofacial Planner images.

PMID- 10393594
TI  - Asthma therapy with aerosols: are nebulizers obsolete? A continuing controversy.

PMID- 10393593
TI  - Syndrome of Periodic Fever, Aphthous stomatitis, Pharyngitis, and Adenitis
      (PFAPA)--what it isn't. What is it?

PMID- 10393595
TI  - Prenatal cigarette smoke exposure: are we sleeping through the alarm?

PMID- 10393596
TI  - High-frequency ventilation versus conventional ventilation: No winner-but no
      loser.

PMID- 10393597
TI  - Another step toward rational treatment of cancer pain in children...but
      pharmacokinetic analysis doesn't tell the whole story.

PMID- 10393598
TI  - Periodic fever syndrome in children.
AB  - OBJECTIVES: To describe the presentation, clinical course, therapeutic response,
      and long-term follow-up of patients with a syndrome of periodic fever, aphthous
      stomatitis, pharyngitis, and cervical adenitis (PFAPA). STUDY DESIGN: Patients
      with PFAPA (n = 94) referred over a 10-year period completed a registry form and
      provided medical records. Follow-up telephone calls were made in late 1997 to
      determine the persistence of episodes and sequelae. RESULTS: PFAPA episodes
      lasted 4.8 days (95% confidence interval 4.5 to 5.1) and recurred every 28 days
      (confidence interval 26 to 30), with a maximal temperature of 40.5 degrees C
      (confidence interval 40. 4 degrees to 40.6 degrees ). Of the 83 children
      available for follow-up, 34 no longer had episodes. In the remainder the episodes
      did not differ in character but recurred less frequently over time. The affected
      children had no long-term sequelae. Glucocorticoids were highly effective in
      controlling symptoms. Tonsillectomy and cimetidine treatment were associated with
      remission in a small number of patients. CONCLUSIONS: PFAPA is a not uncommon
      cause of periodic fever in children. In some children the syndrome resolves,
      whereas symptoms in others persist. Long-term sequelae do not develop. The
      syndrome is easily diagnosed when regularly recurring episodes of fever are
      associated with aphthous stomatitis, pharyngitis, or cervical adenitis.

PMID- 10393599
TI  - Comparison of albuterol delivered by a metered dose inhaler with spacer versus a
      nebulizer in children with mild acute asthma.
AB  - OBJECTIVE: In children with mild acute asthma, to compare treatment with a single
      dose of albuterol delivered by a metered dose inhaler (MDI) with a spacer in
      either a weight-adjusted high dose or a standard low-dose regimen with delivery
      by a nebulizer. STUDY DESIGN: In this randomized double-blind trial set in an
      emergency department, 90 children between 5 and 17 years of age with a baseline
      forced expiratory volume in 1 second (FEV1 ) between 50% and 79% of predicted
      value were treated with a single dose of albuterol, either 6 to 10 puffs (n = 30)
      or 2 puffs (n = 30) with an MDI with spacer or 0.15 mg/kg with a nebulizer (n =
      30). RESULTS: No significant differences were seen between treatment groups in
      the degree of improvement in percent predicted FEV1 (P =.12), clinical score,
      respiratory rate, or O2 saturation. However, the nebulizer group had a
      significantly greater change in heart rate (P =.0001). Our study had 93% power to
      detect a mean difference in percent predicted FEV1 of 8 between the treatment
      groups. CONCLUSION: In children with mild acute asthma, treatment with 2 puffs of
      albuterol by an MDI with spacer is just as clinically beneficial as treatment
      with higher doses delivered by an MDI or by a nebulizer.

PMID- 10393600
TI  - Inhalation therapy in asthma: nebulizer or pressurized metered-dose inhaler with
      holding chamber? In vivo comparison of lung deposition in children.
AB  - OBJECTIVE: To compare lung deposition from a nebulizer and a pressurized metered
      dose inhaler (pMDI)/holding chamber to determine their efficiency in aerosol
      delivery to children. STUDY DESIGN: Children with stable asthma (n = 17) aged 2
      to 9 years inhaled in random order radiolabeled salbutamol from a nebulizer and a
      pMDI through a nonstatic holding chamber. Body and lung deposition of
      radiolabeled salbutamol was assessed with a gamma camera. RESULTS: Mean (absolute
      dose) total lung deposition expressed as a percentage of the nebulized dose was
      5.4% (108 microg) in younger children (<4 years) and 11.1% (222 microg) in older
      children (>4 years). Mean (absolute dose) total lung deposition expressed as a
      percentage of the metered dose was 5.4% (21.6 microg) in younger and 9.6% (38.4
      microg) in older children. CONCLUSIONS: For the same age groups we have shown
      equivalent percentages of total lung deposition of radiolabeled salbutamol
      aerosolized by either a nebulizer or a pMDI/holding chamber. However, the
      delivery rate per minute and the total dose of salbutamol deposited were
      significantly higher for the nebulizer.

PMID- 10393601
TI  - Prenatal exposure to cigarette smoking is associated with a decrease in arousal
      in infants.
AB  - OBJECTIVE: Sudden infant death syndrome has been related to both exposure to
      prenatal cigarette smoke and impaired arousability from sleep. We evaluated
      whether healthy infants born to mothers who smoked during pregnancy had higher
      auditory arousal thresholds than those born to mothers who did not smoke and
      whether the effects of smoking occurred before birth. STUDY DESIGN: Twenty-six
      newborns were studied with polygraphic recordings for 1 night: 13 were born to
      mothers who did not smoke, and 13 were born to mothers who smoked (>9 cigarettes
      per day). Other infants with a median postnatal age of 12 weeks were also
      studied, 21 born to nonsmoking mothers and 21 born to smoking mothers. White
      noise of increasing intensity was administered during rapid eye movement sleep to
      evaluate arousal and awakening thresholds. RESULTS: More intense auditory stimuli
      were needed to induce arousals in newborns (P =.002) and infants (P =. 044) of
      smokers than in infants of nonsmokers. Behavioral awakening occurred
      significantly less frequently in the newborns of smokers (P =.002) than of
      nonsmokers. CONCLUSIONS: Newborns and infants born to smoking mothers had higher
      arousal thresholds to auditory challenges than those born to nonsmoking mothers.
      The impact of exposure to cigarette smoke occurred before birth.

PMID- 10393602
TI  - Randomized comparison of high-frequency ventilation with high-rate intermittent
      positive pressure ventilation in preterm infants with respiratory failure.
AB  - OBJECTIVE: In a randomized, controlled, multicenter trial, we tested the
      hypothesis that high-frequency ventilation (HFV) with a high lung volume strategy
      results in fewer treatment failures than intermittent positive pressure
      ventilation (IPPV) with high rates and low peak inspiratory pressures. STUDY
      DESIGN: Infants with a gestational age between >/=24 weeks and <30 weeks,
      requiring mechanical ventilation within 6 hours of birth, were randomly assigned
      to receive either IPPV or HFV until 240 hours after randomization, extubation, or
      meeting treatment failure criteria. Treatment failure, the primary end point, was
      determined when air leaks, an oxygenation index >35 to 45 (depending on
      gestational age), death, or chronic lung disease occurred. Chronic lung disease
      was defined as persistent requirement of mechanical ventilation, continuous
      positive airway pressure, or supplemental oxygen at a postmenstrual age of 36
      weeks. Secondary end points included the incidence of intracranial hemorrhage.
      RESULTS: The third scheduled interim analysis led to termination of the trial
      after recruitment of 284 infants. Treatment failure criteria were met by 46% of
      infants receiving IPPV and 54% of infants receiving HFV (1-tailed primary
      hypothesis, P =.92; 2-tailed chi2 test, P =.15). Air leaks occurred in 31% and
      42% (P =.042), CLD in 23% and 25%, and grade 3-4 intracranial hemorrhage in 13%
      and 14% of IPPV-treated and HFV-treated patients, respectively. The mortality
      rate before discharge was 10% in both groups. CONCLUSION: HFV with a high lung
      volume strategy did not cause less lung injury in preterm infants than IPPV with
      a high rate and low peak inspiratory pressures.

PMID- 10393603
TI  - Population pharmacokinetics of oral morphine and its glucuronides in children
      receiving morphine as immediate-release liquid or sustained-release tablets for
      cancer pain.
AB  - OBJECTIVES: (1) To determine the pharmacokinetics of morphine, morphine-6
      glucuronide (M6G), and morphine-3-glucuronide (M3G) in children with cancer
      receiving morphine as immediate-release morphine liquid or sustained-release
      tablets. (2) To determine differences with age within the group and from adults.
      (3) To explore relationships between plasma concentration and pain measurements.
      STUDY DESIGN: Blood samples were collected and plasma analyzed by high
      performance liquid chromatography with electrochemical and fluorescence
      detection. Population pharmacokinetic parameters were derived with the program P
      PHARM. RESULTS: Forty children with a median age of 11.4 years (range 1.7 to 18.7
      years) received a median dose of 1.4 mg/kg/d (range 0.4 to 24.6 mg/kg/d). A
      median of 4 blood samples per child was collected. Plasma clearance of morphine
      was 23.1 mL/min per kg body weight. The volume of distribution was 5.2 L/kg.
      Molar ratios of M3G/morphine, M6G/morphine, and M3G/M6G were 21.1, 4.7, and 4.2,
      respectively. Children <11 years had significantly higher clearance and larger
      volume of distribution for morphine and its glucuronides than older children and
      adults. Regression analysis indicated average plasma morphine concentration equal
      to dose (mg/kg/d) x 8.6 (95% confidence interval 7.4 to 9.9). Significant pain
      was present in 30% of the children. Higher pain scores were recorded in children
      with average morphine concentrations <12 ng/mL (P <.01 MW). CONCLUSION: Age
      differences in morphine pharmacokinetics exist within children and compared with
      adults. The study supports a starting dose of 1.5 to 2. 0 mg/kg/d to provide
      plasma morphine concentrations >12 ng/mL in children with cancer pain unrelieved
      by mild to moderate strength analgesia.

PMID- 10393604
TI  - Granulocyte colony-stimulating factor in the cord blood of premature neonates
      born to mothers with pregnancy-induced hypertension.
AB  - OBJECTIVES: To estimate the cord blood levels of granulocyte colony-stimulating
      factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in
      preterm infants and to study the relationship of these levels to pregnancy
      induced hypertension (PIH) and absolute neutrophil counts. STUDY DESIGN: G-CSF
      and GM-CSF levels in the cord blood of preterm neonates (n = 74) either with or
      without maternal PIH were estimated by enzyme-linked immunosorbent assay.
      RESULTS: Infants in the PIH group had lower white blood cell, absolute
      neutrophil, absolute lymphocyte, and monocyte counts. The levels of G-CSF in cord
      blood were significantly lower in infants whose mothers had PIH (P =.04) and in
      infants with neutropenia (P =. 01). G-CSF levels were positively correlated with
      both absolute neutrophil count (P =.02) and total white blood cell count (P
      =.01). GM-CSF was undetectable in all subjects. According to logistic regression
      with neutropenia as the dependent variable, only maternal PIH (P <.001),
      gestational age (P <.001), and G-CSF (P =.01) were independently related.
      CONCLUSION: In this study maternal PIH and low gestational age were significantly
      associated with neutropenia in premature infants. Low G-CSF levels may contribute
      to the neutropenia that is commonly seen in infants born to mothers with PIH.

PMID- 10393605
TI  - Newborn hearing screening: will children with hearing loss caused by congenital
      cytomegalovirus infection be missed?
AB  - OBJECTIVE: To predict whether universal newborn auditory screening will identify
      most infants with sensorineural hearing loss (SNHL) caused by congenital
      cytomegalovirus (CMV) infection. STUDY DESIGN: A cohort of 388 children born
      between 1980 and 1996 at one hospital and identified during the newborn period as
      having congenital CMV infection received repeated hearing evaluations to assess
      whether hearing loss had occurred. RESULTS: SNHL was detected in 5.2% of all
      infants at birth. Late-onset SNHL occurred among the children throughout the
      first 6 years of life. By the age of 72 months, the cumulative incidence of SNHL
      was 15.4% in the cohort. Children with clinically apparent disease at birth had
      significantly more SNHL than children without any apparent disease (22.8% vs 4.0%
      at 3 months and 36.4% vs 11.3% at 72 months of age). CONCLUSIONS: Universal
      screening of hearing in neonates will detect less than half of all SNHL caused by
      congenital CMV infection. Because most infants with congenital CMV infection are
      without symptoms at birth, these children are unlikely to be recognized as being
      at risk for SNHL and will not receive further hearing evaluations to detect late
      onset hearing loss. A combined approach of universal screening of neonates for
      hearing, as well as for detection of congenital CMV infection, needs to be
      considered.

PMID- 10393606
TI  - Adrenal function in premature infants during inhaled beclomethasone therapy.
AB  - OBJECTIVE: We tested the hypothesis that inhaled beclomethasone therapy for
      prevention of bronchopulmonary dysplasia does not cause adrenal suppression.
      STUDY DESIGN: Infants receiving ventilatory support with birth weights </=1250 g
      and born at <33 weeks' gestation, age 3 to 14 days, were enrolled in a
      multicenter randomized trial to study the efficacy and safety of beclomethasone
      therapy versus placebo for prevention of bronchopulmonary dysplasia. Adrenal
      function was assessed on study day 21 (+/- 2 days) by determination of basal and
      stimulated plasma cortisol levels. Initially, cortisol response was assessed with
      insulin-induced hypoglycemia test (IIHT) (n = 63) until an interim analysis
      revealed insignificant cortisol response in both study groups. Thereafter,
      cosyntropin stimulation was used (n = 85). RESULTS: Beclomethasone therapy was
      associated with lower median basal cortisol levels (5 microg/dL beclomethasone, 6
      microg/dL placebo, P =.04). IIHT revealed insignificant change in cortisol
      response within each group. Cortisol response to cosyntropin stimulation was
      similar for each group (17 microg/dL beclomethasone, 18 microg/dL placebo, P
      =.86). CONCLUSION: Beclomethasone therapy was associated with a small decrease in
      basal cortisol levels. There was no evidence of adrenal suppression in response
      to cosyntropin stimulation during beclomethasone therapy. Lack of cortisol
      response to hypoglycemia may reflect missed timing and/or decreased response of
      the premature infants' hypothalamic-pituitary-adrenal axis to hypoglycemia.

PMID- 10393607
TI  - Clinical utility of adrenal ultrasonography in the diagnosis of congenital
      adrenal hyperplasia.
AB  - Rapid, accurate diagnosis of congenital adrenal hyperplasia (CAH) is essential in
      the neonate with ambiguous genitalia, life-threatening salt loss, or both. We
      aimed to determine the accuracy of adrenal ultrasonography in the diagnosis of
      CAH in a retrospective analysis of 52 children with ambiguous genitalia or salt
      losing crises. Adrenal ultrasounds were interpreted as follows: "normal" if the
      adrenals were normal in size (adrenal limb width <4 mm), had a smooth surface,
      and a central echogenic stripe with a hypoechoic rim, and "abnormal" if they were
      increased in size (limb width >4 mm), had a lobulated or cerebriform surface, or
      showed abnormal echogenicity. Group 1 consisted of 25 neonates and infants with
      CAH; group 2, 19 children with conditions other than CAH; and group 3, 8 with
      treated CAH: 7 receiving replacement therapy and 1 whose mother received
      glucocorticoids during pregnancy. In all children in groups 2 and 3, adrenal
      ultrasounds were read as normal. In group 1 adrenal ultrasonography was normal in
      2 (8%) and abnormal in 23 (92%). Thus adrenal ultrasonography has a sensitivity
      of 92% and a specificity of 100% for diagnosing CAH. Adrenal ultrasonography is a
      highly sensitive and specific adjunct in the diagnosis of CAH. The presence of
      enlarged, lobulated adrenals with stippled echogenicity is invariably associated
      with CAH.

PMID- 10393608
TI  - The effect of adenotonsillectomy on serum insulin-like growth factor-I and growth
      in children with obstructive sleep apnea syndrome.
AB  - OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) in children is frequently
      associated with growth interruption. The objective of this study was to evaluate
      the effect of OSAS and adenotonsillectomy on the insulin-like growth factor-I
      (IGF-I) axis in children. STUDY DESIGN: Thirteen prepubertal children (mean age,
      6.0 +/- 2.8 years) were studied before and after adenotonsillectomy (T&A).
      Weight, height, overnight polysomnography, and IGF-I and IGF-binding protein-3
      levels were evaluated before and 3 to 12 months after T&A. The children's weights
      and heights were monitored for 18 months. RESULTS: The respiratory disturbance
      index improved from 7.8 +/- 9.1 events/h to 1.0 +/- 2.1 events/h after T&A (P
      <.02). Slow-wave sleep increased from 29.1% +/- 7.2% to 34.6% +/- 9.8% after T&A
      (P <.02). The weight standard deviation score increased from 0.86 +/- 1 to 1. 24
      +/- 0.9, 18 months after T&A (P <.01). Serum IGF-I levels increased from 146.3 +/
      76.2 ng/mL before T&A to 210.3 +/- 112.5 ng/mL after surgery (P <.01), but IGF
      binding protein-3 levels did not change significantly. CONCLUSION: The
      respiratory improvement after T&A in children with OSAS is associated with a
      significant increase in serum IGF-I levels and weight. We conclude that the IGF-I
      axis is affected in children with OSAS.

PMID- 10393609
TI  - Shwachman syndrome: phenotypic manifestations of sibling sets and isolated cases
      in a large patient cohort are similar.
AB  - OBJECTIVES: With the use of clinical data from a large international cohort, we
      evaluated and compared affected siblings and isolated cases. STUDY DESIGN: Data
      from 116 families were collected, and patients conforming to our predetermined
      diagnostic criteria were analyzed. Phenotypic manifestations of affected siblings
      and singletons were compared with the use of t tests, Wilcoxon scores, and chi2
      analysis. RESULTS: Eighty-eight patients (33 female, 55 male; median age 5.20
      years) fulfilled our predetermined diagnostic criteria for Shwachman syndrome; 63
      patients were isolated cases, and 25 affected siblings were from 12 multiplex
      families. Steatorrhea was present in 86% (57 of 66), and 91% (78 of 86) displayed
      a low serum trypsinogen concentration. Patients older than 4 years more often had
      pancreatic sufficiency. Neutropenia occurred in 98%, anemia in 42%, and
      thrombocytopenia in 34%. Myelodysplasia or cytogenetic abnormalities were
      reported in 7 patients. Short stature with normal nutritional status was a
      prominent feature. CONCLUSIONS: Clinical features among patients with Shwachman
      syndrome varied between patients and with age. Similarities in phenotype between
      isolated cases and affected sibling sets support the hypothesis that Shwachman
      syndrome is a single disease entity.

PMID- 10393610
TI  - Familial aggregation in Behcet's disease: high frequency in siblings and parents
      of pediatric probands.
AB  - OBJECTIVE: To examine familial aggregation of Behcet's disease (BD) in pediatric
      compared with non-pediatric patients. METHODS: A retrospective study was
      conducted to analyze data collected from 572 patients with BD in whom the
      diagnosis was made with criteria defined by the International Study Group for BD.
      The age of attaining criteria (the age at which the patient met the study group
      criteria) was evaluated for each patient. Recurrence risks were calculated for
      the pediatric group from information provided by 45 families. RESULTS: Of the 505
      patients from whom the age of attaining criteria could be ascertained, 106 showed
      definitive BD before the age of 16 years and were considered as pediatric
      patients with BD; the other 399 were classified as non-pediatric patients.
      Thirteen of the 106 pediatric patients (12.3%) and only 9 of the 399 non
      pediatric patients (2.2%) had relatives affected by BD. This excess of familial
      cases in the pediatric group compared with the non-pediatric group was
      significant (P <.0001, chi2 analysis). Moreover, the mean age of attaining
      criteria in familial cases (17. 95 years [SD = 8.62]) was significantly lower
      than in sporadic cases (27.28 years [SD = 11]; P <.0001, Student t test). The
      recurrence risk among siblings and parents who met the International Study Group
      criteria was 0.1. CONCLUSION: Our data support the hypothesis of a genetic
      component in the pathogenesis of BD, and we propose the inclusion of familial
      history in the definition of pediatric BD.

PMID- 10393611
TI  - In vivo brain myo-inositol levels in children with Down syndrome.
AB  - The Na+/myo-inositol cotransporter (SLC5A3) gene, located on the long arm of
      human chromosome 21, may play a key role in osmoregulation including the
      regulation of levels of the "idiogenic osmole," myo-inositol, in brain cells. To
      determine whether the levels of myo-inositol are increased in the basal ganglia
      of children with Down syndrome, we performed in vivo brain hydrogen 1-nuclear
      magnetic resonance or 1H-magnetic resonance spectroscopy and measured plasma
      osmolality in a cohort of children with trisomy 21. Myo-inositol is elevated in
      the corpus striatum of infants and children with Down syndrome, even in the
      absence of hypertonic stress.

PMID- 10393612
TI  - Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome:
      clinical characteristics and outcome.
AB  - We report 28 patients (20 male) with a syndrome characterized by abrupt onset of
      fever, malaise, aphthous stomatitis, tonsillitis, pharyngitis, and cervical
      adenopathy (PFAPA syndrome). Episodes of fever occurred at intervals of 5.1 +/-
      1.3 weeks beginning at the age of 4.2 +/- 2.7 years. Fever, malaise, tonsillitis
      with negative throat cultures, and cervical adenopathy were reported in all 28
      patients, aphthae in 19, headache in 5, abdominal pain in 5, and arthralgia in 3.
      Mild hepatosplenomegaly was observed in 6 patients. Mild leukocytosis, elevation
      of the erythrocyte sedimentation rate, and fibrinogen were found during attacks.
      These episodes of illness resolved spontaneously in 4.3 +/- 1.7 days. Serum IgD
      was found elevated (>100 U/mL) in 12 of the 18 patients tested (140.2 +/- 62.4
      U/mL). Affected children grow normally, have no associated diseases, and have no
      long-term sequelae. Attacks were aborted by a single dose of oral prednisone (2
      mg/kg) at the beginning of the attack in all 15 patients in whom this medication
      was prescribed. In 9 patients the syndrome has completely resolved (beginning at
      the age of 2.9 +/- 1.3 and lasting 8 +/- 2.5 years). In 3 other patients complete
      resolution of the attacks occurred after tonsillectomy was performed. PFAPA is
      sporadic, and no ethnic predilection was found. Increased awareness of the
      clinical syndrome has resulted in more frequent diagnosis and adequate treatment.

PMID- 10393613
TI  - Bilirubin levels and severe retinopathy of prematurity in infants with estimated
      gestational ages of 23 to 26 weeks.
AB  - Oxidative injury may contribute to the development of retinopathy of prematurity
      (ROP), and bilirubin may be a physiologically important antioxidant. Therefore we
      evaluated the relationship of ROP to bilirubin levels in 157 infants born at 23
      to 26 weeks estimated gestational age. We found no definite association between
      bilirubin levels and severe ROP.

PMID- 10393614
TI  - Incidence and outcome of a 10-fold indomethacin overdose in premature infants.
AB  - We reviewed the incidence and morbidity of a 10-fold medication error among all
      premature infants treated with indomethacin. We detected 4 incidents among 1059
      indomethacin doses given to infants weighing less than 1000 g. None of the
      infants had intracranial hemorrhage, necrotizing enterocolitis, or significant
      deterioration of renal function.

PMID- 10393615
TI  - No difference in iron status between children with low and moderate lead
      exposure.
AB  - We compared the iron status between children 11 to 33 months old with confirmed
      blood lead levels of 20 to 44 microg/dL and demographically similar children with
      blood lead levels of <10 microg/dL. There were no differences. Laboratory
      investigation or empirical treatment for iron deficiency is not justified on the
      basis of moderately elevated blood lead levels alone.

PMID- 10393616
TI  - Efficacy of cyclosporin A in children with type 2 autoimmune hepatitis.
AB  - The conventional treatment of autoimmune hepatitis (AIH) with prednisone and
      azathioprine induces remission in most cases but is often associated with poorly
      tolerated side effects. We carried out a retrospective study to evaluate the
      efficacy of and the tolerance to cyclosporin treatment in 15 children and
      adolescents with type 2 AIH. Eight children received cyclosporin as primary
      immunosuppression because of risk factors for poor tolerance of steroids. Five
      other patients with relapsing AIH refused to resume treatment with steroids and
      were treated with cyclosporin. In both groups alanine aminotransferase activity
      returned to normal within 6 months. Side effects were minimal and well tolerated.
      No relapse occurred in 10 patients after 1 to 6 years. Cyclosporin was withdrawn
      in 3 patients after 1, 2, and 3 years and replaced by low doses of prednisone in
      combination with azathioprine. In 2 other children with acute liver failure,
      which progressed despite treatment with steroids and azathioprine, the addition
      of cyclosporin was followed by normalization of prothrombin time.

PMID- 10393617
TI  - The effect of a weight-bearing physical activity program on bone mineral content
      and estimated volumetric density in children with spastic cerebral palsy.
AB  - After an 8-month physical activity intervention in children with cerebral palsy,
      increases in femoral neck bone mineral content (BMC) (9.6%), volumetric bone
      mineral density (v BMD) (5.6%), and total proximal femur BMC (11.5%) were
      observed in the intervention group (n = 9) compared with control subjects (n = 9;
      femoral neck BMC, -5. 8%; v BMD, -6.3%; total proximal femur BMC, 3.5%).

PMID- 10393618
TI  - The natural history of intolerance to soy and extensively hydrolyzed formula in
      infants with multiple food protein intolerance.
AB  - Infants (n = 18) with intolerance to extensively hydrolyzed formulas and soy who
      responded to an L-amino acid-based elemental formula (AAF) were studied until 3
      years of age. By 2 years of age most tolerated non-formula foods, and by 3 years
      only 3 required AAF. Growth normalized during AAF feeding in 4 infants with
      failure to thrive.

PMID- 10393619
TI  - Crusted (Norwegian) scabies induced by use of topical corticosteroids and treated
      successfully with ivermectin.
AB  - Crusted scabies is mainly observed in children with immunosuppression or mental
      illness. Treatment is very difficult, and relapse is frequent after topical
      scabicidal therapy. We describe a case of crusted scabies, induced by long-term
      application of a topical corticosteroid, relapsing after topical treatment and
      dramatically improved by ivermectin. We suggest that ivermectin is a safe and
      effective alternative therapy for the treatment of severe Sarcoptes scabiei
      infestation in children unresponsive to conventional treatment.

PMID- 10393620
TI  - Retinal hemorrhages caused by accidental household trauma.
AB  - Traumatic retinal hemorrhages in young children are considered pathognomonic of
      child abuse. We identified 3 children with unilateral retinal hemorrhages caused
      by accidental household trauma. The hemorrhages were ipsilateral to intracranial
      hemorrhage and isolated to the posterior retinal pole.

PMID- 10393621
TI  - Metamorphosis from miction pause to Mickey Mouse.

PMID- 10393623
TI  - Reply 

PMID- 10393624
TI  - Reply 

PMID- 10393625
TI  - Reply 

PMID- 10393622
TI  - Potential risks of chest physiotherapy in preterm infants.

PMID- 10393626
TI  - Compensated shock and dopamine.

PMID- 10393627
TI  - Medicine and Human Rights: Reflections on the Fiftieth Anniversary of the
      Doctors' Trial.
AB  - 1996 marks the fiftieth anniversary of the commencement of the trial of Nazi
      physicians at Nuremberg, a trial that has been variously designated as the
      "Doctors' Trial" and the "Medical Case." In addition to documenting atrocities
      committed by physicians and scientists during WWII, the most significant
      contribution of the trial has come to be known as the "Nuremberg Code," a
      judicial codification of 10 prerequisites for the moral and legal use of human
      beings in experiments. Anniversaries provide us with an opportunity to reflect
      upon the past, but they also enable us to renew our efforts to plan for the
      future. This article describes briefly the historical evolution of the Nuremberg
      Code, discusses its current relevance and applicability by using a case study
      example, and proposes future steps to be taken by the international community.

PMID- 10393628
TI  - The "French Doctors' Movement" And Beyond (An Introductory Editorial).

PMID- 10393629
TI  - A Historical Survey of Humanitarian Action.
AB  - Humanitarian medical associations emerged in France in the 1970s, working first
      in the developing world and then within their own country. Medecins Sans
      Frontieres (Doctors Without Borders) and Medecins du Monde (Doctors of the World)
      have been active in the debate concerning the boundaries of international
      humanitarian law. Some of the many associations which now exist around the world
      have put the "right of interference" redefined by the United Nations as "the
      right of access to victims" (Resolution 43-141) into practice, while others
      strongly oppose it. This article, contributed by a witness to some of the most
      severe crises in recent history, from Biafra to Rwanda, provides a history of
      humanitarian action and examines the roles of states, churches, and
      nongovernmental organizations both with respect to their humanitarian missions,
      and in the interpretation of international humanitarian law. How can
      "interference" in the face of the unacceptable be reconciled with the concept of
      state sovereignty? How can genocide be prevented and ruthless dictators barred
      from disposing of their populations with impunity? This article suggests the
      current limits, and perhaps even a retreat in humanitarian thinking given the
      context of a new world order.

PMID- 10393630
TI  - From Solferino to Sarajevo.
AB  - Behind an apparent consensus on humanitarianism among politicians, soldiers,
      diplomats, intellectuals, and artists, and while public aid has become an
      important element of the Western response to contemporary tragedies, numerous
      voices are questioning the role of humanitarian aid in conflict situations. This
      article provides a historical perspective of humanitarianism, from the emergence
      of basic concepts in the eighteenth century to modern times. The post-World War
      II era witnessed intellectual critiques of humanitarian action, and, in the 1980s
      humanitarian aid became, consciously or not, an important instrument of the
      antitotalitarian struggle. The end of Soviet communism and the evolution of
      international relations have profoundly changed the work of humanitarian
      organizations. Today, the gap is immense between proclaimed humanitarian
      principles and values, and the actions undertaken to defend them. This article
      examines how humanitarian action has attempted to keep humanitarian aid from
      contributing to aggravation of the victim's fate rather than to their relief.

PMID- 10393631
TI  - Ethnic Cleansing and Other Lies: Combining Health and Human Rights in the Search
      for Truth and Justice in the Former Yugoslavia.
AB  - The establishment of the International Criminal Tribunal for the former
      Yugoslavia reflects the human rights idea that there can be no justice without
      truth and that notions of justice must inform the process of extracting some
      truth from the many stories, myths and lies that have been told about "ethnic
      cleansing." This article uses a three-pronged approach to combine the normative
      framework of human rights with the practical, quantitative methods of public
      health. This approach provides powerful mechanisms for extablishing truth and
      accountability for ethnic cleansing. First, clinical and forensic evidence is
      critical in documenting when and whether ethnic cleansing actually occurred.
      Second, public health methodology can be brought to bear to define both the
      nature of the legally cognizable crimes committed and the nature of the harms
      ensuing from those crimes. Third, public health tools can help reinforce
      conceptions of individual responsibility and identity formation that refute the
      premises of ethnic cleansing and which are essential to the future of the
      Tribunal and to international human rights law in general.

PMID- 10393632
TI  - Evolution of the Physicians' Peace Movement: A Historical Perspective.
AB  - Historically, physicians have chosen to consider medical ethics rather than
      patient rights, as well as preferring responsibility for the individuals seeking
      their help rather than for the health of populations. Protests against planning
      for war, and discussions about sustainment of global well-being, were received
      within the medical profession with both encouragement and hostility. Against the
      mounting threat of nuclear war, International Physicians for Prevention of
      Nuclear War (IPPNW) was created, bringing up to 70 national affiliates together
      into a global federation which spoke with a single voice to oppose the grim
      reality of nuclear war. IPPNW sought to concentrate its concerns on collective
      issues rather than individual rights, and on changing ways of thinking rather
      than on saving individual lives. To this end it has enlarged its agenda to the
      establishment of more equitable distribution of resources, protection of the
      global environment, and non-military ways of building regional and global
      security. IPPNW seeks to promote rights through discussion, education, and non
      partisan collective advocacy and consensus-building. This paper traces the
      evolution of medical groups that formed to promote peace and prevent war.

PMID- 10393634
TI  - Human Rights Education in Public Health Graduate Schools: 1996 Survey.

PMID- 10393633
TI  - The Health Professional as Human Rights Promoter: Ten Years of Physicians for
      Human Rights (USA).
AB  - The founding of Physicians for Human Rights (PHR) arose out of concern within the
      scientific and medical community about the human rights violations affecting
      their colleagues and the severe health effects of human rights violations on the
      general population. PHR, as a membership organization, has pioneered the field of
      the activist health professional in human rights, through its many missions
      documenting violations both of human rights and of humanitarian law; its advocacy
      efforts; and its educational programs. It identifies new challenges and effective
      strategies to protest abuses, engage governments and professional colleagues in
      dialogue, and support likeminded health professionals who work in situations in
      which their obligations to their patients are often overridden by their
      obligations to States that want to hide human rights violations.

PMID- 10393635
TI  - African Commission of Health and Human Rights Promoters.

PMID- 10393660
TI  - More on the herbst and TMD controversy 

PMID- 10393636
TI  - A Selected Bibliography on Current Issues in Humanitarian Action.

PMID- 10393661
TI  - Potential risks of chest physiotherapy in preterm infants.

PMID- 10393663
TI  - Psychosocial aspects of short stature and growth hormone therapy.

PMID- 10393662
TI  - Sudden unexpected death syndrome and nicotine.

PMID- 10393664
TI  - Reply 

PMID- 10393667
TI  - Identity claims and projections: descriptions of self and crowds in secondary
      school.

PMID- 10393669
TI  - Adolescent crowd orientations: a social and temporal analysis.

PMID- 10393668
TI  - From "headbangers" to "hippies": delineating adolescents' active attempts to form
      an alternative peer culture.

PMID- 10393670
TI  - Identity development and peer group participation.

PMID- 10393671
TI  - The contextual influences of sibling and dating relations on adolescents'
      personal relations with their close friends, dating partners, and parents: the
      Sullivan-Piaget-Hartup hypothesis considered.

PMID- 10393672
TI  - Physical inactivity: an easily modified risk factor?

PMID- 10393673
TI  - Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA
      and ETB receptor blockade.
AB  - BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor. However, its
      mitogenic effects on vascular smooth muscle cells (SMCs) remain controversial. We
      investigated the role of ET-1 in human SMC growth and its synergistic effect with
      platelet-derived growth factor (PDGF). METHODS AND RESULTS: Human aortic SMCs
      were cultured and cell proliferation was assayed by [3H]thymidine incorporation.
      PDGF receptor expression, activation of mitogen-activated protein kinase (MAPK),
      cell cycle regulators such as cyclin-dependent kinase 2 (Cdk2), Cdk inhibitor
      (p27(Kip1)), and retinoblastoma protein (pRb) were analyzed by immunoblotting. ET
      1 on its own was unable to stimulate [3H]thymidine incorporation but dramatically
      potentiated the effect of PDGF-BB up to 6-fold (P<0.001). Most of the
      potentiating effects (88%) were blocked by the ETA receptor antagonist LU135252
      and slightly further blocked by the ETA/B receptor antagonist bosentan (P<0.05).
      ET-1 stimulated MAPK, but it neither potentiated PDGF-induced MAPK activation nor
      overexpressed PDGF receptors. In contrast to PDGF-BB, ET-1 had no regulatory
      effects on Cdk2, p27(Kip1), and pRb. CONCLUSIONS: In human SMCs, ET-1 activates
      MAPK but has no mitogenic effects on its own. However, ET-1 markedly potentiates
      proliferation to PDGF, mainly via ETA receptors. This may represent an important
      function of ET-1 for vascular structural changes in patients and provide new
      therapeutic opportunities for ET-1 receptor antagonists.

PMID- 10393674
TI  - Effects of walking on coronary heart disease in elderly men: the Honolulu Heart
      Program.
AB  - BACKGROUND: Effects of walking on the risk of coronary heart disease morbidity
      and mortality have not been identified in the elderly. The purpose of this study
      was to determine whether walking is associated with a reduced risk of coronary
      heart disease in a sample of elderly men. METHODS AND RESULTS: For this study,
      distance walked (mile/d) was examined at a baseline examination that occurred
      from 1991 to 1993 in the Honolulu Heart Program. Incident coronary heart disease
      from all causes was observed over a 2- to 4-year follow-up period. Subjects
      followed up were 2678 physically capable elderly men aged 71 to 93 years. During
      the course of follow-up, 109 men developed coronary heart disease. Men who walked
      <0.25 mile/d had a 2-fold increased risk of coronary heart disease versus those
      who walked >1. 5 mile/d (5.1% versus 2.5%; P<0.01). Men who walked 0.25 to 1.5
      mile/d were also at a significantly higher risk of coronary heart disease than
      men who walked longer distances (4.5% versus 2.5%; P<0. 05). Adjustment for age
      and other risk factors failed to alter these findings. CONCLUSIONS: Findings from
      the Honolulu Heart Program, which targeted physically capable elderly men,
      suggest that the risk of coronary heart disease is reduced with increases in
      distance walked. Combined with evidence that suggests that an active lifestyle
      reduces the risk of cardiovascular disease in younger and more diverse groups,
      this suggests that important health benefits could be derived by encouraging the
      elderly to walk.

PMID- 10393675
TI  - Relationship between delay in performing direct coronary angioplasty and early
      clinical outcome in patients with acute myocardial infarction: results from the
      global use of strategies to open occluded arteries in Acute Coronary Syndromes
      (GUSTO-IIb) trial.
AB  - BACKGROUND: Time to treatment with thrombolytic therapy is a critical determinant
      of mortality in acute myocardial infarction. Little is known about the
      relationship between the time to treatment with direct coronary angioplasty and
      clinical outcome. The objectives of this study were to determine both the time
      required to perform direct coronary angioplasty in the Global Use of Strategies
      to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) trial and its
      relationship to clinical outcome. METHODS AND RESULTS: Patients randomized to
      direct coronary angioplasty (n=565) were divided into groups based on the time
      between study enrollment and first balloon inflation. Patients randomized to
      angioplasty who did not undergo the procedure were also analyzed. The median time
      from study enrollment to first balloon inflation was 76 minutes; 19% of patients
      assigned to angioplasty did not undergo an angioplasty procedure. The 30-day
      mortality rate of patients who underwent balloon inflation </=60 minutes after
      study enrollment was 1.0%; 61 to 75 minutes after enrollment, 3.7%; 76 to 90
      minutes after enrollment, 4.0%; and >/=91 minutes after enrollment, 6.4%. The
      mortality rate of patients assigned to angioplasty who never underwent the
      procedure was 14.1% (P=0.001). Logistic regression analysis revealed that the
      time from enrollment to first balloon inflation was a significant predictor of
      mortality within 30 days; after adjustment for differences in baseline
      characteristics, the odds of death increased 1.6 times (P=0.008) for a movement
      from each time interval to the next. CONCLUSIONS: The time to treatment with
      direct PTCA, as with thrombolytic therapy, is a critical determinant of
      mortality.

PMID- 10393676
TI  - Impact of cilostazol on restenosis after percutaneous coronary balloon
      angioplasty.
AB  - BACKGROUND: Restenosis after percutaneous transluminal coronary (balloon)
      angioplasty (PTCA) remains a major drawback of the procedure. We previously
      reported that cilostazol, a platelet aggregation inhibitor, inhibited intimal
      proliferation after directional coronary atherectomy and reduced the restenosis
      rate in humans. The present study aimed to determine the effect of cilostazol on
      restenosis after PTCA. METHODS AND RESULTS: Two hundred eleven patients with 273
      lesions who underwent successful PTCA were randomly assigned to the cilostazol
      (200 mg/d) group or the aspirin (250 mg/d) control group. Administration of
      cilostazol was initiated immediately after PTCA and continued for 3 months of
      follow-up. Quantitative coronary angiography was performed before PTCA and after
      PTCA and at follow-up. Reference diameter, minimal lumen diameter, and percent
      diameter stenosis (DS) were measured by quantitative coronary angiography.
      Angiographic restenosis was defined as DS at follow-up >50%. Eligible follow-up
      angiography was performed in 94 patients with 123 lesions in the cilostazol group
      and in 99 patients with 129 lesions in the control group. The baseline
      characteristics and results of PTCA showed no significant difference between the
      2 groups. However, minimal lumen diameter at follow-up was significantly larger
      (1.65+/-0.55 vs 1.37+/-0.58 mm; P<0.0001) and DS was significantly lower (34.1+/
      17.8% vs 45.6+/-19. 3%; P<0.0001) in the cilostazol group. Restenosis and target
      lesion revascularization rates were also significantly lower in the cilostazol
      group (17.9% vs 39.5%; P<0.001 and 11.4% vs 28.7%; P<0. 001). CONCLUSIONS:
      Cilostazol significantly reduces restenosis and target lesion revascularization
      rates after successful PTCA.

PMID- 10393677
TI  - Muscle metaboreflex contribution to sinus node regulation during static exercise:
      insights from spectral analysis of heart rate variability.
AB  - BACKGROUND: It is currently assumed that during static exercise, central command
      increases heart rate (HR) through a decrease in parasympathetic activity, whereas
      the muscle metaboreflex raises blood pressure (BP) only through an increase in
      sympathetic outflow to blood vessels, because when the metaboreflex activation is
      maintained during postexercise muscle ischemia, BP remains elevated while HR
      recovers. We tested the hypotheses that the muscle metaboreflex contributes to HR
      regulation during static exercise via sympathetic activation and that the
      arterial baroreflex is involved in the HR recovery of postexercise muscle
      ischemia. METHODS AND RESULTS: Eleven healthy male volunteers performed 4-minute
      static leg extension (SLE) at 30% of maximal voluntary contraction, followed by 4
      minute arrested leg circulation (ALC). Autonomic regulation of HR was
      investigated by spectral analysis of HR variability (HRV), and baroreflex control
      of heart period was assessed by the spontaneous baroreflex method. SLE resulted
      in a significant increase in the low-frequency component of HRV that remained
      elevated during ALC. The normalized high-frequency component of HRV was reduced
      during SLE and returned to control levels during ALC. Baroreflex sensitivity was
      significantly reduced during SLE and returned to control levels during ALC when
      BP was kept elevated above the resting level while HR recovered. CONCLUSIONS: The
      muscle metaboreflex contributes to HR regulation during static exercise via a
      sympathetic activation. The bradycardia that occurs during postexercise muscle
      ischemia despite the maintained sympathetic stimulus may be explained by a
      baroreflex-mediated increase in parasympathetic outflow to the sinoatrial node
      that overpowers the metaboreflex-induced cardiac sympathetic activation.

PMID- 10393678
TI  - Effect of hypertension on mortality in Pima Indians.
AB  - BACKGROUND: The effect of hypertension on mortality was examined in 5284 Pima
      Indians, 1698 of whom had type 2 diabetes at baseline or developed it during
      follow-up. METHODS AND RESULTS: During a median follow-up of 12.2 years (range,
      0.01 to 24.8 years), 470 nondiabetic subjects and 488 diabetic subjects died. In
      the nondiabetic subjects, 45 of the deaths were due to cardiovascular disease,
      208 to other natural causes, and 217 to external causes; in the diabetic
      subjects, 106 of the deaths were due to cardiovascular disease, 85 to diabetic
      nephropathy, 226 to other natural causes, and 71 to external causes. In the
      nondiabetic subjects, after adjusting for age, sex, body mass index, and serum
      cholesterol concentration in a proportional hazards model, hypertension predicted
      death from cardiovascular disease (death rate ratio [DRR]=2.8; 95% CI, 1.4 to 5.
      6; P=0.003). In the diabetic subjects, after additional adjustment for duration
      of diabetes, plasma glucose concentration, and proteinuria, hypertension strongly
      predicted deaths from diabetic nephropathy (DRR=3.5; 95% CI, 1.7 to 7.2;
      P<0.001), but it had little effect on deaths from cardiovascular disease
      (DRR=1.4; 95% CI, 0.88 to 2.3; P=0.15). CONCLUSIONS: We propose that the weak
      relationship between hypertension and cardiovascular disease in diabetic Pima
      Indians is not because of a diminished effect of hypertension on cardiovascular
      disease in diabetes, but because of a relatively greater effect of hypertension
      on the progression of diabetic nephropathy. Factors that may account for this
      finding in Pima Indians include a younger age at onset of type 2 diabetes, a low
      frequency of heavy smoking, favorable lipoprotein profiles and, possibly,
      enhanced susceptibility to renal disease.

PMID- 10393679
TI  - In vivo human brachial artery elastic mechanics: effects of smooth muscle
      relaxation.
AB  - BACKGROUND: The effects of smooth muscle relaxation on arterial wall mechanics
      are controversial. We used a new, in vivo, noninvasive technique to measure
      brachial artery wall mechanics under baseline conditions and following smooth
      muscle relaxation with nitroglycerin (NTG). METHODS AND RESULTS: Eight healthy,
      normal subjects (6 male, 2 female; age 30+/-3.1 years) participated in the study.
      The nondominant brachial artery was imaged through a water-filled blood pressure
      cuff using an external ultrasound wall-tracking system at baseline and following
      0.4 mg sublingual NTG. Simultaneous radial artery pressure waveforms were
      recorded by tonometry. Transmural pressure (TP) was reduced by increasing water
      pressure in the cuff. Brachial artery area, unstressed area, compliance, stress,
      strain, incremental elastic modulus (Einc), and pulse wave velocity (PWV) were
      measured over a TP range from 0 to 100 mm Hg. Baseline area versus TP curves
      generated 30 minutes apart were not significantly different. NTG significantly
      shifted area versus TP (P<0.0001) and compliance versus TP (P<0.001) curves
      upward, whereas the Einc versus TP (P<0.05) and PWV versus TP (P<0. 01) curves
      were shifted downward. NTG also significantly shifted stress versus strain
      (P<0.01) and Einc versus strain (P<0.01) curves to the right. CONCLUSIONS: We
      conclude that brachial artery elastic mechanics can be reproducibly measured over
      a wide range of TP and smooth muscle tone using a new noninvasive ultrasound
      technique. Smooth muscle relaxation with NTG increases isobaric compliance and
      decreases isobaric Einc and PWV in the human brachial artery.

PMID- 10393680
TI  - Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms:
      implications for smooth muscle cell viability, inflammatory processes, and the
      expansion of abdominal aortic aneurysms.
AB  - BACKGROUND: There is no treatment proven to limit the growth of abdominal aortic
      aneurysms, in which the histological hallmarks include inflammation and medial
      atrophy, with apoptosis of smooth muscle cells and destruction of elastin.
      METHODS AND RESULTS: Aneurysm biopsies were used for explant cultures, the
      preparation of smooth muscle cell cultures, and isolation of macrophages. Tissue
      macrophages stained strongly for cyclooxygenase 2. Prostaglandin E2 (PGE2)
      concentrations in aneurysm tissue homogenates, conditioned medium from explants,
      and isolated macrophages were 49+/-22 ng/g, 319+/-38 ng/mL, and 22+/-21 ng/mL,
      respectively. PGE2 inhibited DNA synthesis and proliferation in normal aortic
      smooth muscle cells (IC50, 23.2+/-3.8 and 23.6+/-4.5 ng/mL, respectively). In
      smooth muscle cells derived from aneurysmal aorta, PGE2 also caused cell death,
      with generation of oligonucleosomes. Conditioned medium from the mixed smooth
      muscle and monocyte cultures derived from explants also had potent growth
      inhibitory effects, and fractionation of this medium showed that the growth
      inhibitory molecule(s) coeluted with PGE2. In explants, indomethacin 10
      micromol/L or mefenamic acid 10 micromol/L abolished PGE2 secretion and
      significantly reduced IL-1beta and IL-6 secretion. In a separate case-control
      study, the expansion of abdominal aortic aneurysms was compared in 15 patients
      taking nonsteroidal anti-inflammatory drugs and 63 control subjects; median
      growth rates were 1.5 and 3.2 mm/y, respectively, P=0.001. CONCLUSIONS: The
      adverse effects of PGE2 on aortic smooth muscle cell viability and cytokine
      secretion in vitro and the apparent effect of anti-inflammatory drugs to lower
      aneurysm growth rates suggest that selective inhibition of PGE2 synthesis could
      be an effective treatment to curtail aneurysm expansion.

PMID- 10393681
TI  - Interleukin-6 and RANTES in Takayasu arteritis: a guide for therapeutic
      decisions?
AB  - BACKGROUND: In patients with Takayasu arteritis, circulating lymphocytes are
      activated, and histological findings indicate that cell-mediated immunity plays
      an important role in the pathogenetic sequence leading to vascular lesions.
      METHODS AND RESULTS: To delineate the profile of inflammatory and chemoattractant
      cytokines involved in T-cell activation in Takayasu arteritis, we measured by
      ELISA serum levels of interleukin (IL)-6, IL-1beta, and RANTES in 18 patients.
      Subsequently, we wanted to establish whether any of these molecules could be used
      as a marker to monitor the clinical course of the disease and to predict disease
      exacerbations. We found that all patients with Takayasu arteritis studied during
      an active phase of the disease have increased serum concentration of IL-6
      compared with healthy control subjects (P<0.01). Enhanced IL-6 serum levels
      paralleled disease activity to the extent that its serum concentrations were
      comparable to those of control subjects when patients were studied in remission.
      RANTES concentrations were also higher than normal in the serum of all patients
      with Takayasu arteritis (P<0.01) studied during an active phase of the disease.
      RANTES serum levels tended to normalize in remission, but values remained higher
      than those of control subjects (P<0.05). In contrast, serum concentrations of IL
      1beta were below the detection limit of ELISA in both healthy subjects and all
      patients with Takayasu arteritis. A positive correlation was found between either
      IL-6 (rho=0.705, P<0.01) or RANTES (rho=0.607, P<0.05) serum level and disease
      activity. CONCLUSIONS: The close correlation of serum IL-6 and RANTES levels with
      disease activity suggests that these cytokines contribute to vasculitic lesions
      in Takayasu arteritis and raises the possibility that their monitoring in serum
      helps clinicians find adequate treatment adjustments in individual patients.

PMID- 10393682
TI  - Impact of prophylactic immediate posttransplant ganciclovir on development of
      transplant atherosclerosis: a post hoc analysis of a randomized, placebo
      controlled study.
AB  - BACKGROUND: Coronary artery disease occurs in an accelerated fashion in the donor
      heart after heart transplantation (TxCAD), but the cause is poorly understood.
      The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and
      decreased by use of calcium blockers. Our group observed that prophylactic
      administration of ganciclovir early after heart transplantation inhibited CMV
      illness, and we now propose to determine whether this therapy also prevents
      TxCAD. METHODS AND RESULTS: One hundred forty-nine consecutive patients (131 men
      and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or
      placebo during the initial 28 days after heart transplantation. Immunosuppression
      consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine,
      prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post
      hoc analysis of this trial designed to assess efficacy of ganciclovir for
      prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined
      by annual angiography as the presence of any stenosis. Because calcium blockers
      have been shown to prevent TxCAD, we analyzed the results by stratifying patients
      according to use of calcium blockers. TxCAD could not be evaluated in 28 patients
      because of early death or limited follow-up. Among the evaluable patients,
      actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir
      treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10%
      (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor
      age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir
      (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of
      calcium blocker use revealed differences in TxCAD incidence when ganciclovir and
      placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for
      ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68),
      50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS).
      CONCLUSIONS: TxCAD incidence appears to be lower in patients treated with
      ganciclovir who are not treated with calcium blockers. Given the limitations
      imposed by post hoc analysis, a randomized clinical trial is required to address
      this issue.

PMID- 10393683
TI  - Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft
      model.
AB  - BACKGROUND: Chronic graft vascular disease (CGVD) in cardiac allografts has been
      defined as a slowly evolving vasculopathy unresponsive to conventional
      immunosuppression. We compared 4 rodent models of CGVD to evaluate the
      reproducibility of CGVD in heart allografts. Rapamycin (Rapa) and cyclosporine
      (CSA) were then used to treat CGVD. METHODS AND RESULTS: Hearts were harvested
      and placed heterotopically into allogenic recipients. CGVD scores of PVG
      allografts from ACI recipients treated with CSA on days 1 through 10 were
      significantly elevated on day 90 (n=16) compared with other models
      (immunosuppression used): (1) Lewis to F344 recipients (CSA), (2) Brown Norway to
      Lewis (FK506), and (3) DA to Wistar-Firth (methylprednisolone, azathioprine,
      CSA). Although delayed (day 60 to 90) CSA treatment had no effect (n=6), delayed
      Rapa (3 mg. kg-1. d-1 IP) reversed CGVD in PVG grafts (0.22+/-0.19 on day 90,
      n=6). ACI isografts showed no evidence of CGVD (n=6) at day 90.
      Immunohistochemistry of PVG grafts revealed perivascular infiltrates consisting
      of CD4(+) T cells and limited numbers of macrophages persisting up to day 90.
      Flow cytometry demonstrated increased levels of anti-donor antibody at day 90,
      which was significantly inhibited by Rapa treatment. CONCLUSIONS: PVG grafts
      developed a significant increase in CGVD without evidence of ongoing myocardial
      rejection. This CGVD appeared to be mediated by both cellular and humoral
      mechanisms, given CD4(+) perivascular infiltrates and increased levels of anti
      donor antibody. The anti-CGVD effectiveness of Rapa during a period in which
      there was little myocardial cellular infiltrate supports a novel mechanism of
      effect such as smooth muscle or B-cell inhibition.

PMID- 10393684
TI  - Prolonged diastolic time fraction protects myocardial perfusion when coronary
      blood flow is reduced.
AB  - BACKGROUND: Because coronary blood flow is impeded during systole, the duration
      of diastole is an important determinant of myocardial perfusion. The aim of this
      study was to show that coronary flow modulates the duration of diastole at
      constant heart rate. METHODS AND RESULTS: In anesthetized, open-chest dogs,
      diastolic time fraction (DTF) increased significantly when coronary flow was
      reduced by lowering perfusion pressure from 100 to 70, 55, and 40 mm Hg. On
      average, DTF increased from 0.47+/-0.04 to 0.55+/-0.03 after a pressure step from
      100 to 40 mm Hg in control, from 0.42+/-0.04 to 0.47+/-0.04 after administration
      of adenosine, and from 0.46+/-0.07 to 0.55+/-0.06 after L-NMMA (mean+/-SD, 6 dogs
      for control and adenosine, 4 dogs for L-NMMA, all P<0.05). Flow normalized to its
      value at full dilation and pressure of 90 mm Hg (375+/-25 mL/min) increased
      during the period of reduced pressure at 40 mm Hg; control, from 0.005+/-63 (2
      seconds after pressure step) to 0.09+/-0.06 (15 seconds after pressure step);
      with adenosine, from 0.19+/-0.06 to 0. 22+/-0.06; and with L-NMMA, from 0.013+/
      0.007 to 0.12+/-0.02 (all P<0.05). The increase in DTF at low pressure may be
      explained by a decrease in interstitial volume at low pressure, which either
      decreases the preload of the myocytes or reduces the buffer capacity for ions
      determining repolarization, thereby causing an earlier onset of relaxation.
      CONCLUSIONS: Because the largest increase in DTF occurs at pressures below the
      autoregulatory range when blood flow to the subendocardium is closely related to
      DTF, modulation of DTF by coronary blood flow can provide an important regulatory
      mechanism to match supply and demand of the myocardium when vasodilatory reserve
      is exhausted.

PMID- 10393685
TI  - Effect of metoprolol administration on renal sodium handling in experimental
      congestive heart failure.
AB  - BACKGROUND: Long-term metoprolol therapy improves cardiac performance and
      decreases mortality in patients with chronic congestive heart failure (CHF). This
      study examined the effect of long-term metoprolol therapy on renal sodium
      handling in an experimental rat model of CHF. METHODS AND RESULTS: Rats with left
      coronary ligation and myocardial infarction-induced CHF were treated with
      metoprolol (1.5 mg. kg-1. h-1) or vehicle for 3 weeks by osmotic minipump. They
      were then evaluated for their ability to excrete a short-term sodium load (5%
      body weight isotonic saline infusion over 30 minutes) and a long-term sodium load
      (change from low- to high-sodium diet over 8 days). All CHF rats had left
      ventricular end-diastolic pressure >10 mm Hg, and heart weight/body weight ratios
      averaged 0.68+/-0.02% (versus control of approximately 0.40%). Compared with
      vehicle CHF rats (n=19), metoprolol CHF rats (n=18) had lower basal values of
      mean arterial pressure (122+/-3 versus 112+/-3 mm Hg) and heart rate (373+/-14
      versus 315+/-9 bpm) and decreased heart rate responses to intravenous doses of
      isoproterenol. During short-term isotonic saline volume loading, metoprolol CHF
      rats excreted 54+/-4% more of the sodium load than vehicle CHF rats. During long
      term dietary sodium loading, metoprolol CHF rats retained 28+/-3% less sodium
      than vehicle CHF rats. CONCLUSIONS: Metoprolol treatment of rats with CHF results
      in an improved ability to excrete both short- and long-term sodium loads.

PMID- 10393686
TI  - Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a
      different sort.
AB  - BACKGROUND: Studies of atrial fibrillation (AF) due to atrial tachycardia have
      provided insights into the remodeling mechanisms by which "AF begets AF" but have
      not elucidated the substrate that initially supports AF before remodeling occurs.
      We studied the effects of congestive heart failure (CHF), an entity strongly
      associated with clinical AF, on atrial electrophysiology in the dog and compared
      the results with those in dogs subjected to rapid atrial pacing (RAP; 400 bpm)
      with a controlled ventricular rate (AV block plus ventricular pacemaker at 80
      bpm). METHODS AND RESULTS: CHF induced by 5 weeks of rapid ventricular pacing
      (220 to 240 bpm) increased the duration of AF induced by burst pacing (from 8+/-4
      seconds in control dogs to 535+/-82 seconds; P<0.01), similar to the effect of 1
      week of RAP (713+/-300 seconds). In contrast to RAP, CHF did not alter atrial
      refractory period, refractoriness heterogeneity, or conduction velocity at a
      cycle length of 360 ms; however, CHF dogs had a substantial increase in the
      heterogeneity of conduction during atrial pacing (heterogeneity index in CHF
      dogs, 2. 76+/-0.16 versus 1.46+/-0.10 for control and 1.51+/-0.06 for RAP dogs;
      P<0.01) owing to discrete regions of slow conduction. Histological examination
      revealed extensive interstitial fibrosis (connective tissue occupying 12.8+/-1.9%
      of the cross-sectional area) in CHF dogs compared with control (0.8+/-0.3%) and
      RAP (0. 9+/-0.2%) dogs. CONCLUSIONS: Experimental CHF strongly promotes the
      induction of sustained AF by causing interstitial fibrosis that interferes with
      local conduction. The substrates of AF in CHF are very different from those of
      atrial tachycardia-related AF, with important potential implications for
      understanding, treating, and preventing AF related to CHF.

PMID- 10393687
TI  - C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon?
AB  - BACKGROUND: Circulating levels of C-reactive protein (CRP) may constitute an
      independent risk factor for cardiovascular disease. How CRP as a risk factor is
      involved in cardiovascular disease is still unclear. METHODS AND RESULTS: By
      reviewing available studies, we discuss explanations for the associations between
      CRP and cardiovascular disease. CRP levels within the upper quartile/quintile of
      the normal range constitute an increased risk for cardiovascular events, both in
      apparently healthy persons and in persons with preexisting angina pectoris. High
      CRP responses after acute myocardial infarction indicate an unfavorable outcome,
      even after correction for other risk factors. This link between CRP and
      cardiovascular disease has been considered to reflect the response of the body to
      the inflammatory reactions in the atherosclerotic (coronary) vessels and adjacent
      myocardium. However, because CRP localizes in infarcted myocardium (with
      colocalization of activated complement), we hypothesize that CRP may directly
      interact with atherosclerotic vessels or ischemic myocardium by activation of the
      complement system, thereby promoting inflammation and thrombosis. CONCLUSIONS:
      CRP constitutes an independent cardiovascular risk factor. Unraveling the
      molecular background of this association may provide new directions for
      prevention of cardiovascular events.

PMID- 10393688
TI  - Cardiovascular evaluation in thoracopagus twins.

PMID- 10393689
TI  - Unhealthy effects of atmospheric temperature and pressure on the occurrence of
      myocardial infarction and coronary deaths. A 10-year survey: the Lille-World
      Health Organization MONICA project (Monitoring trends and determinants in
      cardiovascular disease).
AB  - BACKGROUND: Associations between an increase in coronary heart disease occurrence
      and low atmospheric temperatures have been reported from mortality data and
      hospital admission registries. However, concomitant increases in
      noncardiovascular case fatality rates and selection bias of hospital cases may
      weaken this observation. In this study, we addressed the question of the
      relationships between fatal and nonfatal coronary diseases and meteorological
      variables in 10-year data (1985 to 1994) collected in a morbidity registry (Lille
      WHO MONICA Project) monitoring 257 000 men from 25 to 64 years of age. METHODS
      AND RESULTS: The impacts of atmospheric temperature (in Celsius) and pressure (in
      millibars) on daily rates of myocardial infarction (MI) and coronary deaths were
      studied. Percentages of variation of event rates according to meteorological
      variations were derived from the relative risks estimated with a Poisson
      regression model. During the 10-year longitudinal survey, 3616 events occurred.
      Rates of events decreased linearly with increasing atmospheric temperature. For
      atmospheric pressure, we detected a V-shaped relationship, with a minimum of
      daily event rates at 1016 mbar. A 10 degrees C decrease was associated with a 13%
      increase in event rates (P<0.0001); a 10-mbar decrease <1016 mbar and a 10-mbar
      increase >1016 mbar were associated with a 12% increase (P=0.001) and an 11%
      increase (P=0. 01) in event rates, respectively. These effects were independent
      and influenced both coronary morbidity and mortality rates, with stronger effects
      in older age groups and for recurrent events. CONCLUSIONS: This longitudinal
      study is the first to estimate the attributable effect of meteorological
      variables on MI morbidity in population and strongly argues for a systematic
      fight against cold in cardiovascular disease prevention, particularly in older
      ages and after a first MI.

PMID- 10393690
TI  - Percutaneous transcatheter management of giant coronary aneurysms.

PMID- 10393691
TI  - A Fas pathway to pulmonary fibrosis.

PMID- 10393692
TI  - Understanding tight junction clinical physiology at the molecular level.

PMID- 10393694
TI  - Essential roles of the Fas-Fas ligand pathway in the development of pulmonary
      fibrosis.
AB  - The Fas ligand is predominantly expressed in activated T lymphocytes and is one
      of the major effector molecules of cytotoxic T lymphocytes and natural killer
      cells. Previously, we found excessive apoptosis of epithelial cells and
      infiltrating lymphocytes expressing Fas ligand mRNA in the lung tissue of
      bleomycin-induced pulmonary fibrosis in mice. Here we demonstrated that the
      administration of a soluble form of Fas antigen or anti-Fas ligand antibody
      prevented the development of this model and that lpr and gld mice were resistant
      against the induction of pneumopathy. These results suggest that the Fas-Fas
      ligand pathway plays an essential role in the development of pulmonary fibrosis
      and that preventing this pathway could have therapeutic value in lung injury and
      fibrosis.

PMID- 10393693
TI  - Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung
      fibrosis in mice.
AB  - TGF-beta plays an important role in lung fibrosis, which is a major cause of
      suffering and death seen in pulmonary disease. Smad7 has been recently identified
      as an antagonist of TGF-beta signaling. To investigate whether this novel
      molecule can be exploited for therapy of lung fibrosis, we determined the effect
      of exogenous Smad7, introduced by a recombinant human type 5 adenovirus vector,
      on bleomycin-induced lung fibrosis in mice. C57BL/6 mice with bleomycin-induced
      lungs received an intratracheal injection of a recombinant adenovirus carrying
      mice Smad7 cDNA. These mice demonstrated suppression of type I precollagen mRNA,
      reduced hydroxyproline content, and no morphological fibrotic responses in the
      lungs when compared with mice administered adenovirus carrying Smad6 cDNA. In
      addition, we found that expression of Smad7 transgene blocked Smad2
      phosphorylation induced by bleomycin in mouse lungs. These data indicated that
      gene transfer of Smad7 (but not Smad6) prevented bleomycin-induced lung fibrosis,
      suggesting that Smad7 may have applicability in the treatment of pulmonary
      fibrosis.

PMID- 10393695
TI  - Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary
      beta2-adrenergic receptor gene delivery.
AB  - Exogenous gene delivery to alter the function of the heart is a potential novel
      therapeutic strategy for treatment of cardiovascular diseases such as heart
      failure (HF). Before gene therapy approaches to alter cardiac function can be
      realized, efficient and reproducible in vivo gene techniques must be established
      to efficiently transfer transgenes globally to the myocardium. We have been
      testing the hypothesis that genetic manipulation of the myocardial beta
      adrenergic receptor (beta-AR) system, which is impaired in HF, can enhance
      cardiac function. We have delivered adenoviral transgenes, including the human
      beta2-AR (Adeno-beta2AR), to the myocardium of rabbits using an intracoronary
      approach. Catheter-mediated Adeno-beta2AR delivery produced diffuse multichamber
      myocardial expression, peaking 1 week after gene transfer. A total of 5 x 10(11)
      viral particles of Adeno-beta2AR reproducibly produced 5- to 10-fold beta-AR
      overexpression in the heart, which, at 7 and 21 days after delivery, resulted in
      increased in vivo hemodynamic function compared with control rabbits that
      received an empty adenovirus. Several physiological parameters, including
      dP/dtmax as a measure of contractility, were significantly enhanced basally and
      showed increased responsiveness to the beta-agonist isoproterenol. Our results
      demonstrate that global myocardial in vivo gene delivery is possible and that
      genetic manipulation of beta-AR density can result in enhanced cardiac
      performance. Thus, replacement of lost receptors seen in HF may represent novel
      inotropic therapy.

PMID- 10393696
TI  - Apo A-I inhibits foam cell formation in Apo E-deficient mice after monocyte
      adherence to endothelium.
AB  - We have previously shown that expression of the human apo A-I transgene on the
      apo E-deficient background increases HDL cholesterol and greatly diminishes fatty
      streak lesion formation. To examine the mechanism, prelesional events in
      atherosclerotic plaque development were examined in 6- to 8-week-old apo E
      deficient and apo E-deficient/human apo A-I transgenic mice. A quantitative
      assessment of subendothelial lipid deposition by freeze-fracture and deep-etch
      electron microscopy indicated that elevated apo A-I did not affect the
      distribution or amount of aortic arch subendothelial lipid deposits.
      Immunohistochemical staining for VCAM-1 demonstrated similar expression on
      endothelial cells at prelesional aortic branch sites from both apo E-deficient
      and apo E-deficient/human apo A-I transgenic mice. Transmission electron
      microscopy revealed monocytes bound to the aortic arch in mice of both genotypes,
      and immunohistochemical staining demonstrated that the area occupied by bound
      mononuclear cells was unchanged. Serum paraoxonase and aryl esterase activity did
      not differ between apo E-deficient and apo E-deficient/human apo A-I transgenic
      mice. These data suggest that increases in apo A-I and HDL cholesterol inhibit
      foam cell formation in apo E-deficient/human apo A-I transgenic mice at a stage
      following lipid deposition, endothelial activation, and monocyte adherence,
      without increases in HDL-associated paraoxonase.

PMID- 10393697
TI  - Microchimerism of maternal origin persists into adult life.
AB  - Recent studies indicate that fetal cells persist in maternal blood for decades
      after pregnancy. Maternal cells are known to engraft and persist in infants with
      immunodeficiency, but whether maternal cells persist long-term in immunocompetent
      offspring has not specifically been investigated. We developed sensitive human
      leukocyte antigen-specific (HLA-specific) PCR assays and targeted nonshared
      maternal HLA genes to test for persistent maternal microchimerism in subjects
      with scleroderma and in healthy normal subjects. Nonshared maternal-specific DNA
      was found in 6 of 9 scleroderma patients. In situ hybridization with double
      labeling for X and Y chromosome-specific sequences revealed female cells in
      peripheral blood samples from 2 male scleroderma patients. HLA-specific PCR also
      frequently revealed persistent maternal microchimerism in healthy control
      subjects. The mean age of all subjects with maternal microchimerism was 28 years
      (range: 9-49 years). With few exceptions, mothers of subjects with persistent
      maternal microchimerism were HLA incompatible with subjects for class I and class
      II alleles. These results clearly indicate that HLA-disparate maternal cells can
      persist in immunocompetent offspring well into adult life. The biological
      significance of maternal microchimerism and whether it might contribute to
      autoimmune disease requires further investigation.

PMID- 10393698
TI  - Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver
      injury in graft-versus-host disease.
AB  - We examined the molecular pathogenesis of graft-versus-host disease-associated
      (GVHD-associated) liver injury in mice, focusing on the role of chemokines. At
      the second week after cell transfer in the parent-into-F1 model of GVHD, CD8(+) T
      cells -- especially donor-derived CD8(+) T cells -- infiltrated the liver,
      causing both portal hepatitis and nonsuppurative destructive cholangitis (NSDC).
      These migrating cells expressed CCR5. Moreover, macrophage inflammatory protein
      1alpha (MIP-1alpha), one of the ligands for CCR5, was selectively expressed on
      intralobular bile duct epithelial cells, endothelial cells, and infiltrating
      macrophages and lymphocytes. Administration of anti-CCR5 antibody dramatically
      reduced the infiltration of CCR5(+)CD8(+) T lymphocytes into the liver, and
      consequently protected against liver damage in GVHD. The levels of Fas ligand
      (FasL) mRNA expression in the liver were also decreased by anti-CCR5 antibody
      treatment. Anti-MIP-1alpha antibody treatment also reduced liver injury. These
      results suggest that MIP-1alpha-induced migration of CCR5-expressing CD8(+) T
      cells into the portal areas of the liver plays a significant role in causing
      liver injury in GVHD; thus, CCR5 and its ligand may be the novel target molecules
      of therapeutic intervention of hepatic GVHD.

PMID- 10393699
TI  - Heme oxygenase-1 gene induction as an intrinsic regulation against delayed
      cerebral vasospasm in rats.
AB  - Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) causes
      cerebral ischemia and infarction. To date, the pathogenesis and gene expression
      associated with vasospasm remain poorly understood. The present study used
      fluorescent differential display to identify differentially expressed genes in a
      rat model of SAH. By using quantitative RT-PCR, we found that heme oxygenase-1
      (HO-1) mRNA was prominently induced in the basilar artery and modestly in brain
      tissue in a rat vasospasm model. A significant correlation was observed between
      the degree of vasospasm and HO-1 mRNA levels in the basilar arteries exhibiting
      vasospasm. Intracisternal injection of antisense HO-1 oligodeoxynucleotide (ODN)
      significantly delayed the clearance of oxyhemoglobin and deoxyhemoglobin from the
      subarachnoid space and aggravated angiographic vasospasm. Antisense HO-1 ODN
      inhibited HO-1 induction in the basilar arteries but not in the whole brain
      tissue. This phenomenon was not observed in the nontreated, sense HO-1 ODN
      treated, or scrambled ODN-treated arteries. We report the protective effects of
      HO-1 gene induction in cerebral vasospasm after SAH, a finding that should
      provide a novel therapeutic approach for cerebral vasospasm.

PMID- 10393700
TI  - Exposure of human islets to cytokines can result in disproportionately elevated
      proinsulin release.
AB  - Infiltration of immunocytes into pancreatic islets precedes loss of beta cells in
      type 1 diabetes. It is conceivable that local release of cytokines affects the
      function of beta cells before their apoptosis. This study examines whether the
      elevated proinsulin levels that have been described in prediabetes can result
      from exposure of beta cells to cytokines. Human beta-cell preparations were
      cultured for 48 or 72 hours with or without IL-1beta, TNF-alpha, or IFN-gamma,
      alone or in combination. None of these conditions were cytotoxic, nor did they
      reduce insulin biosynthetic activity. Single cytokines did not alter medium or
      cellular content in insulin or proinsulin. Cytokine combinations, in particular
      IL-1beta plus IFN-gamma, disproportionately elevated medium proinsulin levels.
      This effect expresses an altered functional state of the beta cells characterized
      by preserved proinsulin synthesis, a slower hormone conversion, and an increased
      ratio of cellular proinsulin over insulin content. The delay in proinsulin
      conversion can be attributed to lower expression of PC1 and PC2 convertases. It
      is concluded that disproportionately elevated proinsulin levels in pre-type 1
      diabetic patients might result from exposure of their beta cells to cytokines
      released from infiltrating immunocytes. This hormonal alteration expresses an
      altered functional state of the beta cells that can occur independently of beta
      cell death.

PMID- 10393701
TI  - Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose
      deficient hinge region and antiglycan antibodies.
AB  - Circulating immune complexes (CICs) isolated from sera of patients with IgA
      nephropathy (IgAN) consist of undergalactosylated, mostly polymeric, and J chain
      containing IgA1 and IgG antibodies specific for N-acetylgalactosamine (GalNAc)
      residues in O-linked glycans of the hinge region of IgA1 heavy chains. Antibodies
      with such specificity occur in sera of IgAN patients, and in smaller quantities
      in patients with non-IgA proliferative glomerulonephritis and in healthy
      controls; they are present mainly in the IgG (predominantly IgG2 subclass), and
      less frequently in the IgA1 isotype. Their specificity for GalNAc was determined
      by reactivity with IgA1 myeloma proteins with enzymatically removed N
      acetylneuraminic acid (NeuNAc) and galactose (Gal); removal of the O-linked
      glycans of IgA1 resulted in significantly decreased reactivity. Furthermore, IgA2
      proteins that lack the hinge region with O-linked glycans but are otherwise
      structurally similar to IgA1 did not react with IgG or IgA1 antibodies. The re
      formation of isolated and acid-dissociated CICs was inhibited more effectively by
      IgA1 lacking NeuNAc and Gal than by intact IgA1. Immobilized GalNAc and asialo
      ovine submaxillary mucin (rich in O-linked glycans) were also effective
      inhibitors. Our results suggest that the deficiency of Gal in the hinge region of
      IgA1 molecules results in the generation of antigenic determinants containing
      GalNAc residues that are recognized by naturally occurring IgG and IgA1
      antibodies.

PMID- 10393702
TI  - Nuclear DNA origin of mitochondrial complex I deficiency in fatal infantile
      lactic acidosis evidenced by transnuclear complementation of cultured
      fibroblasts.
AB  - We have studied complex I (NADH-ubiquinone reductase) defects of the
      mitochondrial respiratory chain in 2 infants who died in the neonatal period from
      2 different neurological forms of severe neonatal lactic acidosis. Specific and
      marked decrease in complex I activity was documented in muscle, liver, and
      cultured skin fibroblasts. Biochemical characterization and study of the genetic
      origin of this defect were performed using cultured fibroblasts. Immunodetection
      of 6 nuclear DNA-encoded (20, 23, 24, 30, 49, and 51 kDa) and 1 mitochondrial DNA
      encoded (ND1) complex I subunits in fibroblast mitochondria revealed 2 distinct
      patterns. In 1 patient, complex I contained reduced amounts of the 24- and 51-kDa
      subunits and normal amounts of all the other investigated subunits. In the second
      patient, amounts of all the investigated subunits were severely decreased. The
      data suggest partial or extensive impairment of complex I assembly in both
      patients. Cell fusion experiments between 143B206 rho degrees cells, fully
      depleted of mitochondrial DNA, and fibroblasts from both patients led to
      phenotypic complementation of the complex I defects in mitochondria of the
      resulting cybrid cells. These results indicate that the complex I defects in the
      2 reported cases are due to nuclear gene mutations.

PMID- 10393703
TI  - In vitro generation of endothelial microparticles and possible prothrombotic
      activity in patients with lupus anticoagulant.
AB  - Microparticles (MPs) resulting from vesiculation of platelets and other blood
      cells have been extensively documented in vitro and have been found in increased
      numbers in several vascular diseases, but little is known about MPs of
      endothelial origin. The aim of this study was to analyze morphological,
      immunological, and functional characteristics of MPs derived from human umbilical
      vein endothelial cells (HUVECs) stimulated by TNF, and to investigate whether
      these MPs are detectable in healthy individuals and in patients with a
      prothrombotic coagulation abnormality. Electron microscopy evidenced bleb
      formation on the membrane of TNF-stimulated HUVECs, leading to increased numbers
      of MPs released in the supernatant. These endothelial microparticles (EMPs)
      expressed the same antigenic determinants as the corresponding cell surface, both
      in resting and activated conditions. MPs derived from TNF-stimulated cells
      induced coagulation in vitro, via a tissue factor/factor VII-dependent pathway.
      The expression of E-selectin, ICAM-1, alphavbeta3, and PECAM-1 suggests that MPs
      have an adhesion potential in addition to their procoagulant activity. In
      patients, labeling with alphavbeta3 was selected to discriminate EMPs from those
      of other origins. We provide evidence that endothelial-derived MPs are detectable
      in normal human blood and are increased in patients with a coagulation
      abnormality characterized by the presence of lupus anticoagulant. Thus, MPs can
      be induced by TNF in vitro, and may participate in vivo in the dissemination of
      proadhesive and procoagulant activities in thrombotic disorders.

PMID- 10393704
TI  - The myeloperoxidase system of human phagocytes generates Nepsilon
      (carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation
      end products at sites of inflammation.
AB  - Reactive aldehydes derived from reducing sugars and peroxidation of lipids
      covalently modify proteins and may contribute to oxidative tissue damage. We
      recently described another mechanism for generating reactive aldehydes from free
      alpha-amino acids. The pathway begins with myeloperoxidase, a heme enzyme
      secreted by activated neutrophils. Conversion of alpha-amino acids to aldehydes
      requires hypochlorous acid (HOCl), formed from H2O2 and chloride by
      myeloperoxidase. When L-serine is the substrate, HOCl generates high yields of
      glycolaldehyde. We now demonstrate that a model protein, ribonuclease A (RNase
      A), exposed to free L-serine and HOCl exhibits the biochemical hallmarks of
      advanced glycation end (AGE) products -- browning, increased fluorescence, and
      cross-linking. Furthermore, Nepsilon-(carboxymethyl)lysine (CML), a chemically
      well-characterized AGE product, was generated on RNase A when it was exposed to
      reagent HOCl-serine, the myeloperoxidase-H2O2-chloride system plus L-serine, or
      activated human neutrophils plus L-serine. CML production by neutrophils was
      inhibited by the H2O2 scavenger catalase and the heme poison azide, implicating
      myeloperoxidase in the cell-mediated reaction. CML was also generated on RNase A
      by a myeloperoxidase-dependent pathway when neutrophils were activated in a
      mixture of amino acids. Under these conditions, we observed both L-serine
      dependent and L-serine-independent pathways of CML formation. The in vivo
      production of glycolaldehyde and other reactive aldehydes by myeloperoxidase may
      thus play an important pathogenic role by generating AGE products and damaging
      tissues at sites of inflammation.

PMID- 10393705
TI  - The chemokine receptor CXCR3 is expressed on malignant B cells and mediates
      chemotaxis.
AB  - B- and T-cell recirculation is crucial for the function of the immune system,
      with the control of cell migration being mainly mediated by several chemokines
      and their receptors. In this study, we investigated the expression and function
      of CXCR3 on normal and malignant B cells from 65 patients with chronic
      lymphoproliferative disorders (CLDs). Although CXCR3 is lacking on CD5(+) and
      CD5(-) B cells from healthy subjects, it is expressed on leukemic B lymphocytes
      from all (31/31) patients with chronic lymphocytic leukemia (CLL). The presence
      of CXCR3 was heterogeneous in other B-cell disorders, being expressed in 2 of 7
      patients with mantle cell lymphoma (MCL), 4 of 12 patients with hairy cell
      leukemia (HCL), and 11 of 15 patients with other subtypes of non-Hodgkin's
      lymphomas (NHLs). Chemotaxis assay shows that normal B cells from healthy
      subjects do not migrate in response to IFN-inducible protein 10 (IP-10) and IFN
      gamma-induced monokine (Mig). In contrast, a definite migration in response to IP
      10 and Mig has been observed in all malignant B cells from patients with CLL, but
      not in patients with HCL or MCL (1/7 cases tested). Neoplastic B cells from other
      NHLs showed a heterogenous pattern. The migration elicited by IP-10 and Mig was
      inhibited by blocking CXCR3. No effect of IP-10 and Mig chemokines was observed
      on the cytosolic calcium concentration in malignant B cells. The data reported
      here demonstrate that CXCR3 is expressed on malignant B cells from CLDs,
      particularly in patients with CLL, and represents a fully functional receptor
      involved in chemotaxis of malignant B lymphocytes.

PMID- 10393707
TI  - MEMORANDUM FOR: science writers and editors on the journal press list 

PMID- 10393708
TI  - Genetics of smoking-related cancer and mutagen sensitivity.

PMID- 10393706
TI  - Der p 1 facilitates transepithelial allergen delivery by disruption of tight
      junctions.
AB  - House dust mite (HDM) allergens are important factors in the increasing
      prevalence of asthma. The lung epithelium forms a barrier that allergens must
      cross before they can cause sensitization. However, the mechanisms involved are
      unknown. Here we show that the cysteine proteinase allergen Der p 1 from fecal
      pellets of the HDM Dermatophagoides pteronyssinus causes disruption of
      intercellular tight junctions (TJs), which are the principal components of the
      epithelial paracellular permeability barrier. In confluent airway epithelial
      cells, Der p 1 led to cleavage of the TJ adhesion protein occludin. Cleavage was
      attenuated by antipain, but not by inhibitors of serine, aspartic, or matrix
      metalloproteinases. Putative Der p 1 cleavage sites were found in peptides from
      an extracellular domain of occludin and in the TJ adhesion protein claudin-1. TJ
      breakdown nonspecifically increased epithelial permeability, allowing Der p 1 to
      cross the epithelial barrier. Thus, transepithelial movement of Der p 1 to
      dendritic antigen-presenting cells via the paracellular pathway may be promoted
      by the allergen's own proteolytic activity. These results suggest that opening of
      TJs by environmental proteinases may be the initial step in the development of
      asthma to a variety of allergens.

PMID- 10393709
TI  - Fenretinide: the death of a tumor cell.

PMID- 10393710
TI  - Prevention study turns spotlight on bladder cancer.

PMID- 10393711
TI  - Alternative medicines gain in popularity, merit closer scrutiny.

PMID- 10393713
TI  - Defining the euro: what exactly does it mean? 

PMID- 10393712
TI  - The Euro: single currency brings little change to cancer research.

PMID- 10393714
TI  - General motors cancer research foundation awards honor top cancer innovators 

PMID- 10393715
TI  - PSA as a treatment marker for prostate cancer?

PMID- 10393716
TI  - Stat bite: U.S. non-Hodgkin's lymphoma incidence, 1973-1996.

PMID- 10393718
TI  - OECI names officers 

PMID- 10393717
TI  - Snipping "SNPs": a new tool for mining gene variations.

PMID- 10393719
TI  - Detection and clinical importance of micrometastatic disease.
AB  - Metastatic relapse in patients with solid tumors is caused by systemic
      preoperative or perioperative dissemination of tumor cells. The presence of
      individual tumor cells in bone marrow and in peripheral blood can be detected by
      immunologic or molecular methods and is being regarded increasingly as a
      clinically relevant prognostic factor. Because the goal of adjuvant therapy is
      the eradication of occult micrometastatic tumor cells before metastatic disease
      becomes clinically evident, the early detection of micrometastases could identify
      the patients who are most (and least) likely to benefit from adjuvant therapy. In
      addition, more sensitive methods for detecting such cells should increase
      knowledge about the biologic mechanisms of metastasis and improve the diagnosis
      and treatment of micrometastatic disease. In contrast to solid metastatic tumors,
      micrometastatic tumor cells are appropriate targets for intravenously applied
      agents because macromolecules and immunocompetent effector cells should have
      access to the tumor cells. Because the majority of micrometastatic tumor cells
      may be nonproliferative (G0 phase), standard cytotoxic chemotherapies aimed at
      proliferating cells may be less effective, which might explain, in part, the
      failure of chemotherapy. Thus, adjuvant therapies that are aimed at dividing and
      quiescent cells, such as antibody-based therapies, are of considerable interest.
      From a literature search that used the databases MEDLINE(R), CANCERLIT(R),
      Biosis(R), Embase(R), and SciSearch(R), we discuss the current state of research
      on minimal residual cancer in patients with epithelial tumors and the diagnostic
      and clinical implications of these findings.

PMID- 10393720
TI  - Inherited susceptibility to bleomycin-induced chromatid breaks in cultured
      peripheral blood lymphocytes.
AB  - BACKGROUND: Susceptibility to bleomycin-induced chromatid breaks in cultured
      peripheral blood lymphocytes may reflect the way a person deals with carcinogenic
      challenges. This susceptibility (also referred to as mutagen sensitivity) has
      been found to be increased in patients with environmentally related cancers,
      including cancers of the head and neck, lung, and colon, and, in combination with
      carcinogenic exposure, this susceptibility can greatly influence cancer risk. The
      purpose of this study was to assess the heritability of mutagen sensitivity.
      METHODS: Heritability was determined by use of a maximum likelihood method that
      employed the FISHER package of pedigree analysis. Bleomycin-induced breaks per
      cell values for 135 healthy volunteers without cancer were determined. These
      individuals were from 53 different pedigrees and included 25 monozygotic twin
      pairs (n = 50), 14 pairs of dizygotes (twin pairs and siblings, n = 28), and 14
      families selected on the basis of a first-degree relative who was successfully
      treated for head and neck cancer and who had no sign of recurrence for at least 1
      year. All data were analyzed simultaneously, and different models of familial
      resemblance were fitted to the data. All P values are two-sided. RESULTS: Our
      results showed no evidence for the influence of a shared family environment on
      bleomycin-induced chromatid breaks. Genetic influences, however, were
      statistically significant (P =. 036) and accounted for 75% of the total variance.
      CONCLUSIONS: The high heritability estimate of the susceptibility to bleomycin
      induced chromatid breaks indicates a clear genetic basis. The findings of this
      study support the notion that a common genetic susceptibility to DNA damage--and
      thereby a susceptibility to cancer--may exist in the general population.

PMID- 10393721
TI  - Risk of endometrial cancer following estrogen replacement with and without
      progestins.
AB  - BACKGROUND: Unopposed estrogen replacement therapy (i.e., estrogen without
      progestins) increases the risk of endometrial cancer. In this study, we examined
      the endometrial cancer risk associated with combined estrogen-progestin regimens
      currently in use, since the safety profiles of these regimens have not been
      clearly defined. METHODS: We conducted a nationwide population-based, case
      control study in Sweden of postmenopausal women aged 50-74 years. We collected
      information on use of hormone replacement from 709 case patients with incident
      endometrial cancer and from 3368 control subjects. We used unconditional logistic
      regression to calculate odds ratios (ORs) as estimates of relative risks. All
      individual comparisons were made with women who never used the respective hormone
      replacement regimens. RESULTS: Treatment with estrogens alone was associated with
      a marked duration- and dose-dependent increase in the relative risk of
      endometrial cancer. Five or more years of treatment had an OR of 6.2 for
      estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated
      estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the
      association was considerably weaker than that for estrogen alone; the OR was 1.6
      (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was
      confined to women with cyclic use of progestins, i.e., fewer than 16 days per
      cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more
      years of use]), whereas continuous progestin use along with estrogens was
      associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of
      use). CONCLUSION: The risk of developing endometrial cancer is increased after
      long-term use of estrogens without progestins and with cyclically added
      progestins. Continuously added progestins may be needed to minimize the
      endometrial cancer risk associated with estrogen replacement therapy.

PMID- 10393722
TI  - Increase of ceramide and induction of mixed apoptosis/necrosis by N-(4
      hydroxyphenyl)- retinamide in neuroblastoma cell lines.
AB  - BACKGROUND: The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR or
      fenretinide) is toxic to myeloid leukemia and cervical carcinoma cell lines,
      probably in part due to its ability to increase levels of reactive oxygen species
      (ROS). We have studied the effects of 4-HPR on neuroblastoma cell lines. Since
      neuroblastomas commonly relapse in bone marrow, a hypoxic tissue compartment, and
      many chemotherapeutic agents are antagonized by hypoxia, our purpose was to study
      in these cell lines several factors influencing 4-HPR-induced cytotoxicity,
      including induced levels of ROS, effects of physiologic hypoxia and antioxidants,
      levels of ceramide, and the mechanism of cell death. METHODS: ROS generation was
      measured by carboxydichlorofluorescein diacetate fluoresence. Ceramide was
      quantified by radiolabeling and thin-layer chromatography. Immunoblotting was
      used to assess p53 protein levels. Apoptosis (programmed cell death) and necrosis
      were analyzed by nuclear morphology and internucleosomal DNA fragmentation
      patterns. Cytotoxicity was measured by a fluorescence-based assay employing
      digital imaging microscopy in the presence or absence of the pancaspase enzyme
      inhibitor BOC-d-fmk. Statistical tests were two-sided. RESULTS/CONCLUSIONS: In
      addition to increasing ROS, 4-HPR (2.5-10 microM) statistically significantly
      increased the level of intracellular ceramide (up to approximately 10-fold;
      P<.001) in a dose-dependent manner in two neuroblastoma cell lines, one of which
      is highly resistant to alkylating agents and to etoposide. Cell death induced by
      4-HPR was reduced but not abrogated by hypoxia in the presence or absence of an
      antioxidant, N-acetyl-L-cysteine. Expression of p53 protein was not affected by 4
      HPR. Furthermore, the pan-caspase enzyme inhibitor BOC-d-fmk prevented apoptosis,
      but not necrosis, and only partially decreased cytotoxicity induced by 4-HPR,
      indicating that 4-HPR induced both apoptosis and necrosis in neuroblastoma cells.
      IMPLICATIONS: 4-HPR may form the basis for a novel, p53-independent chemotherapy
      that operates through increased intracellular levels of ceramide and that retains
      cytotoxicity under reduced oxygen conditions.

PMID- 10393724
TI  - Expression of p73 and its relation to histopathology and prognosis in
      hepatocellular carcinoma.
AB  - BACKGROUND: The protein p73, the first identified homologue of the tumor
      suppressor gene p53 (also known as TP53), has been shown to induce apoptosis
      (programmed cell death), but its function in tumor development has not been
      established. This study was undertaken to investigate the expression of p73 in
      liver tissue of patients with hepatocellular carcinoma (HCC) and to determine
      whether this expression has any impact on prognosis. METHODS: In situ
      hybridization and immunohistochemistry for the detection of p73 RNA transcripts
      and protein, respectively, were performed in tissues from 193 patients with
      curatively (R0-) resected HCC. Patients receiving liver transplantation were
      excluded. The results obtained were analyzed with respect to their association
      with pathohistologic stage, Edmondson grade, p53 expression status and several
      histopathologic factors of possible prognostic value, and, finally, with patient
      survival. RESULTS: RNA transcripts encoding p73 were detected by in situ
      hybridization in tumor cells but not in stromal, endothelial, or inflammatory
      cells or in cholangiocytes. Transcripts were also found occasionally in non
      neoplastic hepatocytes. By immunohistochemistry, we detected p73 protein in 61
      (32%) of the 193 carcinomas examined. Positive immunohistochemical staining was
      confined to the cell nucleus. Univariate survival analysis showed that p73
      expression status was statistically significantly related to prognosis (two-sided
      P<.0001). Patients with p73-positive tumors had a poorer prognosis than those
      with p73-negative carcinomas. Multivariate Cox survival analysis identified the
      age of the patient, p73 expression status, co-existing cirrhosis, and Edmondson
      grade as independent prognostic factors. CONCLUSION: The protein p73 is
      overexpressed by a subset of HCCs and could serve as a useful indicator of
      prognosis in patients with this disease.

PMID- 10393723
TI  - Increased blood glucose and insulin, body size, and incident colorectal cancer.
AB  - BACKGROUND: Abdominal obesity--an elevated level of visceral adipose tissue--has
      been linked to colorectal cancer. Furthermore, elevated levels of visceral
      adipose tissue have been associated with hyperinsulinemia, and insulin is a
      growth factor in the colon. We assessed whether waist circumference, a surrogate
      measure of visceral adipose tissue, and metabolic parameters associated with
      visceral adipose tissue were related to colorectal cancer. METHODS: In the
      Cardiovascular Health Study cohort, we examined the relationship of baseline
      measurements of body size, glucose, insulin, and lipoproteins to incident
      colorectal cancer. All P values are two-sided. RESULTS: Among 5849 participants,
      102 incident cases of colorectal cancer were identified. Individuals in the
      highest quartile of fasting glucose had a nearly twofold increased risk of
      colorectal cancer (relative risk [RR] = 1.8; 95% confidence interval [CI] = 1.0
      3.1), and the linear trend RR (LT RR = 1.2; 95% CI = 1.0-1.5) for fasting glucose
      level was statistically significant (P =. 02). Glucose and insulin levels 2 hours
      after oral glucose challenge also exhibited statistically significant
      associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95% CI =
      1.2-4. 7]/LT RR = 1.3 [95% CI = 1.0-1.6; P =.02]; 2-hour insulin levels: RR = 2.0
      [95% CI = 1.0-3.8]/LT RR = 1.2 [95% CI = 1.0-1.5; P =.04]). Analysis of fasting
      insulin levels suggested a threshold effect, with values above the median
      associated with colorectal cancer (RR = 1.6; 95% CI = 1.1-2.4; P =.02). Higher
      levels of waist circumference were also statistically significantly associated
      with colorectal cancer (RR = 1.9; 95% CI = 1.1-3.3; P =.02). CONCLUSIONS: These
      data provide, to our knowledge, the first direct evidence of an association
      between elevated visceral adipose tissue level, its associated metabolic effects,
      and colorectal cancer.

PMID- 10393725
TI  - Renal cell cancer: chromosome 3 translocations as risk factors.

PMID- 10393726
TI  - Mitotic kinase expression and colorectal cancer progression.

PMID- 10393727
TI  - Fruits, vegetables, and cancer prevention trials.

PMID- 10393728
TI  - More about: sunscreen use, wearing clothes, and number of nevi in 6- to 7-year
      old European children.

PMID- 10393729
TI  - RESPONSE: more about: sunscreen use, wearing clothes, and number of nevi in 6- to
      7-year-Old european children 

PMID- 10393730
TI  - Re: Cell and molecular biology of simian virus 40: implications for human
      infections and disease.

PMID- 10393731
TI  - RESPONSE: re: cell and molecular biology of simian virus 40: implications for
      human infections and disease 

PMID- 10393732
TI  - Delayed adjuvant tamoxifen in postmenopausal women with axillary node-negative
      breast cancer: mortality over 10 years.

PMID- 10393733
TI  - Aging and gastrointestinal physiology.
AB  - This article reviews the effects of aging on the immune system, specifically the
      role of apoptosis. Nutrition and malnutrition in the elderly and their
      implications are examined. The structural and functional changes that occur with
      aging in the gastrointestinal tract are also described. Medical care for the
      elderly population can significantly be improved by the understanding of the
      physiology of aging in the gastrointestinal tract. This improved understanding
      can assist in distinguishing disease states from normal changes that occur with
      age.

PMID- 10393734
TI  - The aging esophagus.
AB  - Various esophageal diseases affect large sections of the elderly population. This
      article reviews many of the diseases that involve the esophagus. Dysphagia,
      esophageal motility disorders, gastroesophageal reflux disease, and Barrett
      esophagus are discussed with particular emphasis on management issues. The
      availability of recent technologic advances and the current therapeutic options
      should positively impact the consequences of these diseases.

PMID- 10393735
TI  - Peptic-ulcer disease in the elderly.
AB  - Peptic-ulcer disease causes significant morbidity and mortality in the elderly.
      It frequently presents in an atypical manner and is associated with a high
      incidence of complications. The prevalence of Helicobacter pylori increases with
      age and can have an important role in the development of ulcers. Nonsteroidal
      anti-inflammatory drugs also contribute to the increased incidence of ulcers and
      the development of complications in the elderly. Although management of ulcer
      disease in the elderly is similar to that in the younger population,
      consideration must be given to the potential for increased incidence of side
      effects and medication interactions. When endoscopy and surgery are performed
      there should be an appreciation for the risks associated with concurrent
      illnesses that can accompany advanced age.

PMID- 10393736
TI  - Small bowel diseases in the elderly.
AB  - Small bowel diseases in the elderly are discussed including small bowel
      gastrointestinal bleeding and malabsorption syndromes such as celiac disease.
      Crohn's disease and nonsteroidal enteropathy also cause considerable morbidity in
      the elderly population and are reviewed. Finally, a brief discussion of
      malignancies of the small bowel (adenocarcinoma, carcinoid, and so forth)
      occurring in the elderly is presented.

PMID- 10393737
TI  - Inflammatory bowel disease in the elderly.
AB  - Inflammatory bowel disease exhibits a bimodality in age-specific incidence rates,
      with the second peak occurring from 60 to 70 years of age. In the elderly, both
      ulcerative colitis and Crohn's disease tend to involve the left side of the
      colon. The course of disease and the basic principles of management in geriatric
      populations do not differ from those in younger patients; however, elderly
      patients do pose distinct problems in differential diagnosis and in therapy
      choice.

PMID- 10393738
TI  - Constipation in the elderly.
AB  - Constipation is a common concern in the elderly and accounts for significant
      expenditures on over-the-counter drugs. Although normal aging is not associated
      with abnormal bowel motility, pathologic and psychosocial conditions lead to
      increased symptoms in elderly patients. Careful clinical evaluation to eliminate
      serious conditions including colon neoplasia is important. Medical management
      with emphasis on fiber, bulk agents, fluid intake, and exercise, as well as
      appropriate use of laxatives is reviewed.

PMID- 10393739
TI  - Gastrointestinal bleeding in the elderly.
AB  - Gastrointestinal bleeding is a problem encountered frequently in the elderly.
      This article reviews its diagnosis and management, focusing on issues
      particularly relevant in geriatric care. The article begins with an overview of
      acute gastrointestinal (GI) bleeding and follows with more focused descriptions
      of upper GI bleeding, lower GI bleeding, and the growing problem of bleeding of
      obscure origin. The article concludes with recommendations for the evaluation of
      positive fecal occult blood tests.

PMID- 10393740
TI  - Mesenteric ischemia in the elderly.
AB  - Mesenteric ischemia is a well-recognized clinical entity among the elderly.
      Although first described more than 500 years ago, advances in both diagnostic and
      treatment regimens only minimally have improved on the bleak morbidity and
      mortality rates associated with this disease. Significant progress, however, has
      been made in understanding the pathophysiology behind a visceral vascular
      compromise. Using this knowledge, physicians have been able to rechannel their
      efforts. Rather than focusing on the development of new treatment options for
      bowel infarction, physicians place more emphasis on the prevention and early
      detection of bowel ischemia. The goal is to identify accurately individuals at
      risk and intervene medically before irreversible infarction occurs. After briefly
      discussing the history, epidemiology, and pathophysiology of mesenteric ischemia,
      this article reviews the past, current, and future approaches to the diagnosis
      and treatment of this challenging condition.

PMID- 10393741
TI  - Liver diseases.
AB  - Liver diseases in the elderly often reflect an age-associated decrease in the
      capacity to respond to metabolic and infectious insults. Because the geriatric
      population is growing rapidly, physicians can expect to encounter an increasing
      number of older patients with liver disease. In this article, the authors discuss
      the clinical manifestations of the most common liver diseases seen in the
      geriatric population.

PMID- 10393742
TI  - Biliary disease in the elderly patient.
AB  - Biliary disease in the elderly patient presents unique diagnostic and therapeutic
      challenges to the generalist as well as the specialist. Diseases of this organ
      system are the leading indication for acute abdominal surgery in this age group.
      Since the number of persons over the age of 80 years has been predicted to
      increase at a rate five to six times that of the general population, an
      understanding of the unique characteristics of biliary disease in the elderly
      population is of increasing importance to clinicians.

PMID- 10393743
TI  - Pancreatic disease in the elderly.
AB  - This article reviews age-related alterations in pancreatic structure and function
      and provides an update of advances in clinical understanding of the epidemiology,
      pathogenesis, and pathophysiology of acute pancreatitis, chronic pancreatitis,
      and pancreatic adenocarcinoma. This article also provides guidelines for the
      integration of recent radiologic, endoscopic, surgical, and oncologic advances in
      these areas into the current clinical practice of the gerontologist and
      gastroenterologist.

PMID- 10393744
TI  - Nutrition in the elderly.
AB  - The elderly represent the fastest growing segment of the American population.
      Nutrition has a significant influence on the development and progression of
      certain diseases. This article reviews the pathophysiology of aging and its
      effect on nutritional status and the incidence, pathogenesis, and impact of
      malnutrition in the elderly. The authors provide nutritional recommendations in
      health and disease.

PMID- 10393745
TI  - Gastrointestinal cancer in the elderly.
AB  - Gastrointestinal cancer is a commonly encountered problem in the elderly.
      Screening for colorectal cancer is cost effective and is increasingly important
      in this population because incidence rises rapidly in the seventh and eighth
      decades of life. Surgery remains by far the most important curative option and
      may be appropriate even at an advanced age. For patients who are not curable,
      quality of life is the yardstick by which palliative options should be evaluated.

PMID- 10393747
TI  - Proximal median neuropathies.
AB  - Proximal median neuropathies are uncommon. They are usually caused by overuse of
      the forearm, anatomic variations, or both. Forearm pain, weakness of muscles
      supplied by the affected nerves, and sensory loss, including the thenar eminence,
      are common clinical findings. Nerve conduction studies and needle
      electromyography are helpful in the diagnosis of these syndromes. Treatment is
      avoidance of overuse and release of mechanical compression. Prognosis is
      generally good.

PMID- 10393746
TI  - Distal median neuropathies.
AB  - Distal median neuropathy is the most common entrapment neuropathy affecting the
      upper extremity. Although most often idiopathic, there are a large number of
      associated medical disorders. Electrophysiologic testing plays a central role in
      the diagnosis of distal median neuropathy in establishing localization; assessing
      severity; and excluding disorders of the proximal median nerve, plexus, and nerve
      roots which can mimic the clinical symptoms of distal median neuropathy.
      Treatment is usually successful, especially when diagnosis is established early
      in the course before any significant axonal loss has occurred.

PMID- 10393748
TI  - Ulnar neuropathy at the elbow.
AB  - Among the entrapment neuropathies, ulnar neuropathy at the elbow is second only
      to carpal tunnel syndrome in frequency; however, diagnosis and management are
      considerably more difficult in ulnar lesions than in carpal tunnel syndrome.
      Electrodiagnosis is the most important means of identifying and localizing ulnar
      neuropathies at the elbow, but even sophisticated techniques may sometimes fail
      to confirm diagnosis and localization preoperatively. Mild lesions are best
      managed conservatively. More severe lesions require surgical intervention. Simple
      decompression is now preferred over transposition in the majority of cases, but
      careful correlation of electrodiagnostic abnormalities and findings at surgery
      are necessary to ensure optimal outcome.

PMID- 10393749
TI  - Ulnar neuropathy at the wrist.
AB  - Compression of the ulnar nerve at the level of the wrist is rare and often
      difficult to diagnose. This article describes the various types of lesions that
      may occur and discusses the different electrophysiologic techniques that may aid
      the electromyographer in localizing lesions to the wrist.

PMID- 10393750
TI  - Thoracic outlet syndromes.
AB  - The term thoracic outlet syndromes, is a group designation for several distinct
      disorders (one of questionable validity) involving various components of the
      brachial plexus, the blood vessels, or both, at various points between the base
      of the neck and the axilla. Four of the five subgroups (true neurologic TOS,
      arterial vascular TOS, venous vascular TOS, and traumatic neurovascular TOS) are
      universally recognized to be rare lesions, with characteristic clinical and
      laboratory presentations; and none is particularly controversial. In contrast,
      disputed neurologic TOS is highly controversial. This article limits discussion
      to the three subgroups of TOS in which neurologic symptoms are caused, or
      reputedly are caused, by compromise of the brachial plexus fibers.

PMID- 10393751
TI  - Radial neuropathy.
AB  - The radial nerve is the largest branch of the brachial plexus, and is commonly
      involved in upper extremity mononeuropathies. The radial nerve is primarily
      responsible for motor innervation of the upper extremity extensors, as well as
      receiving cutaneous innervation from most of the posterior arm, forearm, and
      hand. There are a variety of sites at which the radial nerve is susceptible to
      trauma and entrapment. Localizing radial nerve lesions is dependent on clinical
      knowledge of radial nerve anatomy, and sensory and motor examination.

PMID- 10393752
TI  - Proximal neuropathies of the upper extremity.
AB  - This article provides a comprehensive review of the diagnosis and management of
      mononeuropathies of the long thoracic, suprascapular, axillary, and
      musculocutaneous nerves. Although these nerves are frequently injured in
      conjunction with other portions of the brachial plexus, this discussion focuses
      on isolated injury to each of these nerves. The anatomy, clinical presentation,
      differential diagnosis, findings on electrodiagnostic evaluation, origin,
      management, and prognosis of each mononeuropathy is discussed.

PMID- 10393753
TI  - Nerve entrapments of the upper extremity: A surgical perspective.
AB  - The surgeon's perspective of nerve entrapment lesions in the upper extremity is
      discussed in this article. The focus is on the most common lesions of the median,
      ulnar, and radial nerves. An understanding of the anatomy and the potential
      pathologies provide the basis for surgical treatment. Current treatment protocols
      are discussed with the authors' recommendations that are based upon experience
      and literature review.

PMID- 10393754
TI  - Peroneal neuropathy.
AB  - The clinical and electrodiagnostic presentation of peroneal neuropathies are
      detailed in this article. There is a special emphasis on nerve conduction study
      findings and their relationship to prognosis and management. The differential
      diagnosis of foot drop, including when caused by the anterior compartmental
      syndrome of the leg, is also discussed.

PMID- 10393755
TI  - Entrapment neuropathies of the tibial (posterior tibial) nerve.
AB  - Entrapment neuropathies of the tibial nerve are relatively rare. They are often
      misdiagnosed largely because of the clinician's low index of suspicion. The
      clinical features, diagnostic studies, and treatment of these disorders are
      reviewed in detail in this article. Almost all of these disorders can now be
      confirmed through nerve conduction and other image studies.

PMID- 10393756
TI  - Sciatic neuropathy.
AB  - Injuries to the sciatic nerve cause neurologic deficits in the peroneal and
      tibial nerve distributions. Interestingly, most injuries result in more severe
      deficits to the peroneal division compared to the tibial division. Thus, it can
      sometimes be difficult to distinguish sciatic neuropathy from peroneal
      neuropathy. The long course of the sciatic nerve leaves it vulnerable to nerve
      injury from a variety of causes. Most sciatic neuropathies are acute in onset,
      such as from hip arthroplasty and hip fracture or dislocation, but some occur
      from prolonged compression, such as during coma. Entrapment of the sciatic nerve
      by mass lesions or by the piriformis muscle is relatively rare.

PMID- 10393757
TI  - Femoral and obturator neuropathies.
AB  - Femoral, saphenous, and obturator neuropathies have diverse causes, many of which
      are iatrogenic. They have overlapping, but distinct, clinical features.
      Electrodiagnostic testing can distinguish between these disorders and others in
      the differential diagnosis. Imaging studies may demonstrate the origin of the
      neuropathy in some cases. Conservative treatment is usually sufficient, but
      occasionally surgical exploration of the affected nerve is indicated.

PMID- 10393758
TI  - Proximal sensory neuropathies of the Leg.
AB  - This article addresses the proximal sensory neuropathies of the leg,
      concentrating on those nerves that are purely sensory or have a predominately
      sensory onset. These include the lateral femoral cutaneous nerve, the
      ilioinguinal nerve, the genitofemoral nerve, and the posterior femoral cutaneous
      nerve. The obturator and femoral nerves are also summarily mentioned with respect
      to their sensory symptoms.

PMID- 10393759
TI  - Infantile and juvenile scoliosis.
AB  - The diagnosis and treatment of scoliosis in the infantile and juvenile age groups
      is a challenging and demanding endeavor. The diagnosis must be firmly
      established. Once a deformity has proven to be progressive, surgical intervention
      will likely be necessary because orthotic treatment is less effective in these
      cases. The surgeon is then faced with the dilemma of deciding on the most
      appropriate surgical treatment.

PMID- 10393760
TI  - Cause and natural history of adolescent idiopathic scoliosis.
AB  - Adolescent idiopathic scoliosis is a highly prevalent disorder of the spine,
      occurring in phenotypically normal individuals for unknown reasons. The role of
      genetic factors in this condition has been widely documented through clinical
      observations and population studies. Multiple areas of research, including
      connective tissue, neuromotor mechanisms, hormonal system, and biomechanics, have
      been explored for a potential relationship to the cause of idiopathic scoliosis;
      however, no clear evidence supports any one area as a etiologic factor of this
      disorder. The main difficulty of most investigations is to determine whether the
      observed abnormalities are primary or secondary features in the scoliotic
      deformity. It is hoped that continued research efforts will aid in the
      understanding of this disorder in an effort to improve the ability to assign a
      more specific prognosis.

PMID- 10393761
TI  - Adolescent idiopathic scoliosis.
AB  - Because of the relatively recent understanding of the untreated natural history
      of idiopathic scoliosis, many patients do not require treatment and are simply
      observed. Immature patients whose curves are between 25 degrees and 40 degrees
      are at high risk for further progression and should be treated with a brace.
      Seventy percent to 80% of the time, the patient can expect that the brace will
      prevent further progression. Curves in growing children greater than 40 degrees
      require a spinal fusion. Modern scoliosis surgery provides excellent correction
      of deformity and allows immediate ambulation without a cast or brace. This
      article reviews the diagnosis, cause, and treatment recommendations for
      adolescent idiopathic scoliosis.

PMID- 10393762
TI  - Video-assisted thoracoscopy.
AB  - New therapeutic modalities for disorders of the pediatric spine must include
      video-assisted thoracoscopy. The endoscopic approach to the spine has involved an
      evolutionary approach. What began as an isolated drainage of a vertebral abscess
      was continued as a method of single discectomy; release of the annulus fibrosis
      with or without ligation of segmental vessels; rib resection for costoplasty; rib
      harvesting for intervertebral fusion; and most recently, insertion of
      correctional implants and fusion.

PMID- 10393763
TI  - Congenital spine deformities: scoliosis, kyphosis, and lordosis.
AB  - By definition, congenital spine deformities-scoliosis, kyphosis, and lordosis-are
      due to abnormal vertebral development. Thus, affected children tend to have a
      curvature noted much earlier in life than typical patients with idiopathic
      scoliosis. This early development of the deformity has resulted in a tendency for
      the young child with congenital deformities to receive less than optimal care.
      These curves must not be allowed to progress. In many cases, early fusion is
      necessary, which is preferable to allowing severe curves to develop.

PMID- 10393764
TI  - Spinal cord monitoring: current state of the art.
AB  - The intraoperative application of evoked potential and electromyographic (EMG)
      monitoring has increased significantly over the last 2 decades. Cranial nerve
      monitoring is widely accepted and used by otologists, neurologic surgeons, and
      ophthalmologists. Direct and indirect techniques for assessing the peripheral
      nervous system are used by plastic and orthopedic surgeons when performing
      intraoperative nerve grafting. Myriad techniques and applications for monitoring
      the spinal cord and peripheral nervous system have been developed, evaluated, and
      used by orthopedic and neurologic surgeons involved in spinal surgery.

PMID- 10393765
TI  - Management of neuromuscular scoliosis.
AB  - Neuromuscular scoliosis is classified as a neuropathic or myopathic type.
      Cerebral palsy is the most common form of neuropathic type, and Duchenne's
      muscular dystrophy best characterizes the principles and recommended treatment
      for the myopathic type. Nonoperative measures rarely fully control a progressive
      scoliosis. Careful preoperative planning and surgery can achieve a well-balanced
      spine over a level pelvis with a good functional result.

PMID- 10393766
TI  - Kyphosis deformity in myelomeningocele.
AB  - Management of the child with myelomeningocele and kyphosis is an extreme
      challenge to the orthopedic surgeon and spine surgeon on many fronts. Delayed or
      observation treatment may result in loss of functional independence and self
      esteem. Early surgical correction may result in loss of truncal height, intra
      abdominal upward volume effect on the diaphragm, and loss of pulmonary capacity.
      Late surgical reconstruction may be associated with significant morbidity and
      mortality. Early surgical intervention with preservation of growth may prove
      safer and result in improved function and independence.

PMID- 10393767
TI  - Cervical spine disorders in children.
AB  - Care of children with disorders of the cervical spine requires an understanding
      of the anatomic and biologic features particular to the developing pediatric
      spine. Congenital and developmental alterations further complicate evaluation and
      treatment of children. Basic knowledge of pediatric cervical spine disorders in
      Down syndrome, Klippel-Feil syndrome, osteochondrodysplasias,
      mucopolysaccharidoses, and post-traumatic instability is essential for all
      orthopedic surgeons. Thorough patient evaluation and appropriate early management
      may prevent potentially serious neurologic injury and other complications related
      to cervical spine pathology.

PMID- 10393768
TI  - Back pain in children.
AB  - Children and adolescents occasionally have back symptoms, but rarely come to a
      physician's office for more severe back pain. When a child or adolescent appears
      in the clinic with complaints of back pain, a careful detailed evaluation is
      appropriate. The incidence of findings in children with significant back pain is
      high; therefore, a detailed history, physical examination, and evaluation are
      needed. It is also legitimate to continue monitoring children even if no obvious
      cause is initially identified because often a diagnosis subsequently will be
      made.

PMID- 10393769
TI  - Scheuermann's disease.
AB  - Scheuermann's disease is the most common cause of structural kyphosis in
      adolescence. The mode of inheritance is likely autosomal dominant and the
      etiology remains largely unknown. Indications for treatment remain controversial
      because the true natural history of the disease has not been clearly defined.
      Brace treatment appears to be very effective if the diagnosis is made early.
      Surgical treatment is rarely indicated for severe kyphosis (> 75 degrees ) with
      curve progression, refractory pain, or neurologic deficit.

PMID- 10393770
TI  - Management of spondylolysis and spondylolisthesis in the pediatric and adolescent
      population.
AB  - Spondylolysis and low-grade spondylolisthesis are diagnoses that, for most
      patients, have a benign prognosis and can be managed nonoperatively. For most
      symptomatic patients for whom this management fails, fusion in situ yields
      satisfactory and lasting results and remains the gold standard against which
      other surgical treatment must be compared. Patients with high-grade slips and
      slip angles may benefit from instrumented fusion in situ or combined
      anterior/posterior procedures, or may be considered for reduction and fusion.
      Reduction maneuvers are technically demanding and carry significant risk of
      neurologic injury. Surgical experience and in-depth understanding of the
      indications, the complications, and, especially, the limitations of each
      technique are required.

PMID- 10393771
TI  - Spinal manifestations of skeletal dysplasias.
AB  - Skeletal dysplasias, disorders of abnormal bone and cartilage development, are a
      heterogeneous group, each disorder with its own genetics, prevalence, prognosis,
      and treatment. More than 150 distinct conditions have been identified. Despite
      their obvious differences, the osteochondrodysplasias share many clinical and
      radiographic features. These patients present to the orthopedic surgeon for
      evaluation of disproportionate short stature, which may be apparent at birth or
      manifest itself only with further growth. This article discusses bone dysplasias
      commonly associated with spinal abnormalities. Spinal pathology can lead to
      deformity, neurologic sequelae, pain, and cardiopulmonary compromise and further
      contribute to short stature.

PMID- 10393772
TI  - Pediatric spine fractures.
AB  - Children have more elastic soft tissue and more potential for remodeling than
      adults. Certain injuries are unique to children, including posterior limbus
      injuries, most cases of spinal cord injury without radiographic abnormalities,
      and spinal trauma in child abuse. This article discusses the pathomechanics,
      clinical presentation, treatment, and some of the complications of injuries of
      the thoracolumbar spine in children.

PMID- 10393773
TI  - Classification of otitis media and surgical principles.
AB  - Otitis media is an important disease of children and adults and is caused by
      multiple interrelated factors, including infection, eustachian tube dysfunction,
      allergy, and barotrauma. This article includes a pertinent review of the
      literature regarding otitis media. The pathogenesis, classification, and
      treatment of otitis media in children and adults are also reviewed in this
      article. Additionally, therapy is discussed with emphasis on the surgical options
      appropriate at each stage.

PMID- 10393774
TI  - Tympanostomy tubes: types, indications, techniques, and complications.
AB  - This article reviews current concepts and applications involving tympanostomy
      tubes. The various types of tympanostomy tubes, indications, complications, and
      techniques are discussed. Applications ranging from otitis media to dysfunction
      of the eustachian tube associated with nasopharyngeal carcinoma are included.
      Experience drawn from patient care and currently published studies support the
      conclusions made in this article.

PMID- 10393775
TI  - Otitis media with effusion and early sequelae: flexible approach.
AB  - Patients suffering from chronic otitis media often have a variety of associated
      disease processes and pathologic conditions. The identification and recognition
      of these factors are critical to the effective treatment of the condition. This
      article provides an overview of the conditions associated with chronic otitis
      media, a detailed review of the disease process, and guidelines for surgical
      therapy.

PMID- 10393776
TI  - A review of type 3 tympanoplasty.
AB  - With the introduction of newer technologies, the advent of antibiotics, and
      improved surgical methods; the past 25 years have seen a great revolution,
      refinement, and improvement of tympanoplastic procedures. Furthermore, the
      methods of classification have been modified. The introduction of ossicular
      reconstruction with biocompatible implants greatly enhanced the success of type 3
      tympanoplasty. This article reviews the classification, indications, surgical
      techniques, biomechanical properties, and expected hearing results of type 3
      tympanoplasty.

PMID- 10393777
TI  - The flexible endaural tympanoplasty: pathology-guided, pathogenesis-oriented
      surgery for the middle ear.
AB  - The flexible approach to tympanoplasty has been found to be adaptable to various
      forms of pathologic conditions found in the temporal bone, including inflammation
      and infection, congenital stenosis, benign and malignant tumors, and traumatic
      injuries. This approach finds its best indication among all pathologic conditions
      in the temporal bone, in the surgical treatment of otitis media, and its
      sequelae. A procedure conceived to treat this dynamic process must be adaptable
      to new circumstances and new findings and be ready to manage unexpected
      situations. The flexible tympanoplasty is a step-wise approach designed to
      explore the contents of the middle ear methodically and in the process disclose,
      confirm, and often treat disease.

PMID- 10393778
TI  - Grafting techniques.
AB  - Grafting of the tympanic membrane is different and more difficult than skin
      grafting elsewhere on the body because it covers an air-containing cavity. The
      two main techniques of grafting are the overlay and underlay methods. The
      advantages, disadvantages, types of grafting materials, and surgical approaches
      of both the overlay and underlay methods are discussed and evaluated. This
      article also reviews the evolution of tympanic membrane grafting techniques and
      evaluates the causes behind success or failure.

PMID- 10393779
TI  - Canalplasty.
AB  - An essential requisite for successful ear surgery is a patent external ear. A
      number of anatomic variants or abnormalities may obstruct its lumen, resulting in
      conductive hearing loss, hampering access for routine ear cleansing, or obscuring
      underlying pathology. This article reviews a surgical technique for canalplasty
      that can be modified to successfully treat either bone or soft tissue blockages
      of the external auditory canal.

PMID- 10393781
TI  - Middle ear reconstructive techniques.
AB  - Middle ear reconstructive techniques have increased to such an extent that the
      otolaryngologist is faced with a bewildering number of surgical options. The
      literature, however, has yet to demonstrate any technique to be optimal in every
      surgical scenario. This is because of the lack of direct comparisons between
      techniques and dissimilar criteria for measuring success. This article uses
      hearing results and the ability to resist extrusion as the principle measures of
      success, and provides middle ear reconstructive techniques proven to be
      successful for commonly faced surgical dilemmas.

PMID- 10393780
TI  - Ossiculoplasty.
AB  - Homograft human bone is not only the most logical choice for grafting material,
      but also the closest transplantation material to the host histologically. This
      article discusses surgical repair of the ossicular chain with homograft bone
      transplants, including rationale for present surgical techniques, a thorough
      description of simple methods of microlathing homograft bone grafts, and
      instructions for maintaining an ossicular replacement bone bank. Furthermore,
      results in all types of ossiculoplasty and a method of classification of
      tympanoplasty are presented in this article.

PMID- 10393782
TI  - Tympanoplasty: prudent considerations of silent otitis media and interactions of
      middle ear and inner ear.
AB  - Otitis media is a common problem, often with simple, minimally invasive
      solutions; however, a small subset of patients progress to chronic disease
      despite provision of standard therapies. The flexible approach to tympanoplasty
      is a prudent consideration for patients with chronic otitis media, especially
      children. This article discusses the findings and implications of silent otitis
      media, interactions of the middle ear and inner ear, and obstructive sites in the
      middle ear cleft. Tympanoplasty by the flexible approach is described in the
      context of these findings.

PMID- 10393783
TI  - Mastoid and tympanomastoid procedures in otitis media: classic mastoidectomy
      (simple, modified, and radical) and current adaptations; open-cavity, closed
      cavity, and intact-bridge tympanomastoidectomy.
AB  - Otitis media is a multifactorial, multifaceted disease that manifests itself in
      the middle ear, mastoid, and eustachian tube. To select a rational therapy,
      physicians must have an understanding of the anatomy, function, and pathology of
      the organs involved and of the mechanisms of disease. The purpose of this article
      is to provide surgical principles in tympanomastoidectomy and an overall concept
      of the procedures available. Simple mastoidectomy is described in detail as a
      general approach.

PMID- 10393784
TI  - Open-cavity tympanomastoidectomy.
AB  - A large number of considerations determine whether an open-cavity or closed
      cavity technique is most appropriate for an individual patient. These
      considerations in the selection of technique, as well as the advantages and
      disadvantages of both open-cavity and closed-cavity tympanomastoidectomy are
      reviewed in this article. Emphasis is placed on the technical details required to
      produce a problem free and functional open-cavity tympanomastoidectomy.

PMID- 10393785
TI  - Closed tympanomastoidectomy.
AB  - The role of closed tympanomastoidectomy in the treatment of chronic ear disease
      continues to be a subject of debate. This article reviews the position of closed
      tympanomastoidectomy in the armamentarium of the otolaryngologist. In this
      article the technique is described and indications are reviewed. A brief history
      of closed tympanomastoidectomy and the issue of outcome from surgery are also
      addressed.

PMID- 10393786
TI  - A one-stage, versatile procedure: intact-bridge mastoidectomy.
AB  - Patients who have never had otologic surgery or whose previous surgery has
      preserved the bridge or canal wall can undergo an intact-bridge mastoidectomy.
      The intact-bridge mastoidectomy can achieve the advantages of improved hearing
      (as in intact-wall techniques) and eradicated cholesteatoma (as in open-cavity
      techniques). This article reviews the surgical techniques of intact-bridge
      mastoidectomy.

PMID- 10393787
TI  - Complications and their management in tympanomastoid surgery.
AB  - Chronic diseases of the ear and their surgical treatment can endanger the
      delicate structures of the temporal bone in close relationship with the middle
      ear. The experience and expertise of the otologic surgeon, based on perfect
      knowledge of the complex anatomy of the whole temporal bone, are unfortunately
      built up partly through the management of complications encountered in
      tympanomastoid surgery and may require knowledge of basic neuro-otologic
      procedures. Paralysis and paresis of the facial nerve and labyrinthine, and dural
      and vascular injuries may have consequences not only in the final result of
      surgery but also in endangering the patient's life. All major complications are
      discussed and some possible treatments are proposed. Minor complications
      affecting the temporomandibular joint, the dura, the external auditory canal, and
      the bony canal wall are also covered, along with some suggestions on how to keep
      these consequences within reasonable percentages.

PMID- 10393788
TI  - Flexible approach to tympanomastoidectomy.
AB  - This article identifies pathologic obstructive sites within the temporal bone
      germane to the pathogenesis of chronic otitis media. Surgical approaches to the
      middle ear and mastoid are thoroughly discussed in the context of middle ear and
      mastoid pathology. Specifically, canal treatment techniques including canalplasty
      and meatoplasty are detailed in conjunction with middle ear reconstruction in the
      effort to obtain and maintain a disease free state. Mastoidectomy approaches and
      techniques, and their relationship to external and middle ear treatment are
      demonstrated in this article.

PMID- 10393789
TI  - Thiersch skin grafting and postoperative care of otologic patients.
AB  - Postoperative care is as important as the actual surgical procedure, if not more
      important. Thiersch skin grafting remains an excellent technique to ensure proper
      healing in the mastoid cavity and ear canal. Successful surgical outcomes depend
      on a well-coordinated effort by the surgical team and the patient. Preoperative
      planning, intraoperative surgical technique, and postoperative care and follow-up
      are discussed in this article.

PMID- 10393791
TI  - 14th meeting of the benelux society for microcirculation. amsterdam, the
      netherlands, february 5, 1999 

PMID- 10393792
TI  - Reflections on emerging frameworks of health and human rights.

PMID- 10393790
TI  - Production, crystallization and preliminary X-ray analysis of the human integrin
      alpha1 I domain.
AB  - Integrin alpha1beta1 is one of the main collagen receptors in many cell types. A
      fast large-scale production, purification and crystallization method for the
      integrin alpha1 I domain is reported here. The alpha1 I domain was crystallized
      using the vapour-diffusion method with a reservoir solution containing a mixture
      of PEG 4000, sodium acetate, glycerol and Tris-HCl buffer. The crystals belong to
      the C2 space group, with unit-cell parameters a = 74.5, b = 81.9, c = 37.3 A,
      alpha = gamma = 90.0, beta = 90.8 degrees. The crystals diffract to 2.0 A and a
      94.2% complete data set to 2.2 A has been collected from a single crystal with an
      Rmerge of 5.8%.

PMID- 10393793
TI  - Gender, health, and human rights.

PMID- 10393794
TI  - The nature and scope of human rights obligations concerning women's right to
      health.

PMID- 10393795
TI  - An international human right to reproductive health care: toward definition and
      accountability.

PMID- 10393798
TI  - From Mexico to Beijing: A New Paradigm.

PMID- 10393796
TI  - Health, Human Rights and Lesbian Existence.
AB  - This essay briefly examines the intersection of "health and human rights"
      strategies with two critical international human rights movements: women's rights
      and gay rights. It concludes that within international frameworks defining a
      woman's right to health, reproductive health has played a predominant role, and
      when discussions of health and human rights have addressed issues of
      homosexuality, they have tended to focus on the explosive conjunction of AIDS and
      discrimination in the lives of gay men. Nevertheless, despite the fact that
      strategies for achieving a human right to health have tended to focus on issues
      less than central to many lesbians' lives, the emerging health and human rights
      paradigm by allowing a "whole person" analysis that takes into account the
      dynamics of individual and social relations as well as basic human needsmay
      paradoxically offer lesbians the potential to counteract the harms that have
      evolved within the arenas of health and human rights independently, while
      avoiding the pitfalls of identity-based claims.

PMID- 10393800
TI  - Child Beauty, Child Rights and the Devaluation of Women.

PMID- 10393801
TI  - A Selected Bibliography of Women's Health and Human Rights.

PMID- 10393802
TI  - Chmadrin: a novel Ki-67 antigen-related perichromosomal protein possibly
      implicated in higher order chromatin structure.
AB  - A novel perichromosomal protein, which we have named chmadrin, was identified
      from rat kangaroo PtK2 cells. The deduced amino acid sequence revealed structural
      homologies in several limited regions to the Ki-67 antigen (pKi-67). The
      subcellular localization of chmadrin was found to be similar to that of pKi-67
      throughout the cell cycle, that is, predominantly nucleolar during interphase and
      perichromosomal in the mitotic phase. In addition, a certain population of the
      protein was found to be localized in heterochromatic foci in interphase nuclei.
      Transient expression analysis of the truncated proteins corresponding to the
      conserved regions clearly demonstrated the structural basis for the
      characteristic cellular localization. Residues 494-778, which show extensive
      similarity to the corresponding region of pKi-67, were efficiently targeted to
      nucleoli, whereas a repetitive structure found at the C-terminal portion, whose
      similarity to pKi-67 is weak, was localized precisely to mitotic chromosomes. The
      C-terminal portion was designated the 'LR domain' since several LR (leucine and
      arginine) pairs commonly appear in chmadrin and pKi-67. When overproduced in the
      interphase nuclei, the LR domain induced the formation of aberrant
      heterochromatin as a structural constituent. These are the first empirical data
      suggesting the involvement of perichromosomal proteins in the organization of
      chromatin structure.

PMID- 10393803
TI  - A human intracellular apyrase-like protein, LALP70, localizes to
      lysosomal/autophagic vacuoles.
AB  - Using antibodies against autophagic vacuole membrane proteins we identified a
      human cDNA with an open reading frame of 1848 bp, encoding a protein of 70 kDa,
      which we named lysosomal apyrase-like protein of 70 kDa (LALP70). Sequence
      analysis revealed that LALP70 belongs to the apyrase or GDA1/CD39 family and is
      almost identical to a human uridine diphosphatase, with the exception of nine
      extra amino acids in LALP70. Members of this family were originally described as
      ectoenzymes, with some intracellular exceptions. Transfected LALP70 fused to the
      green fluorescent protein localized in the cytoplasm with a punctate pattern in
      the perinuclear space. These structures colocalized with the autophagic marker
      monodansylcadaverine and the lysosomal protein lamp1. Hydrophobicity analysis of
      the encoded protein revealed a transmembrane region at the N and C termini. Most
      of the sequence is arranged between these transmembrane domains, and contains
      four apyrase conserved regions. In vitro transcription/translation in the
      presence of microsomes showed that no signal sequence is cleaved off and that the
      translation product is protected from trypsin treatment. Our data indicate that
      LALP70 is a type III lysosomal/autophagic vacuole membrane protein with the
      apyrase conserved regions facing the luminal space of the vacuoles.

PMID- 10393805
TI  - A hyperphosphorylated form of RNA polymerase II is the major interphase antigen
      of the phosphoprotein antibody MPM-2 and interacts with the peptidyl-prolyl
      isomerase Pin1.
AB  - The monoclonal antibody MPM-2 recognizes a subset of M phase phosphoproteins in a
      phosphorylation-dependent manner. It is believed that phosphorylation at MPM-2
      antigenic sites could regulate mitotic events since most of the MPM-2 antigens
      identified to date have M phase functions. In addition, many of these proteins
      are substrates of the mitotic regulator Pin1, a peptidyl-prolyl isomerase which
      is present throughout the cell cycle and which is thought to alter its mitotic
      targets by changing their conformation. In interphase cells, most MPM-2
      reactivity is confined to nuclear speckles. We report here that a
      hyperphosphorylated form of the RNA polymerase II largest subunit is the major
      MPM-2 interphase antigen. These findings were made possible by the availability
      of another monoclonal antibody, CC-3, that was previously used to identify a 255
      kDa nuclear matrix protein associated with spliceosomal components as a
      hyperphosphorylated form of the RNA polymerase II largest subunit. MPM-2
      recognizes a phosphoepitope of the large subunit that becomes hyperphosphorylated
      upon heat shock in contrast to the phosphoepitope defined by CC-3, whose
      reactivity is diminished by the heat treatment. Therefore, these two antibodies
      may discriminate between distinct functional forms of RNA polymerase II. We also
      show that RNA polymerase II large subunit interacts with Pin1 in HeLa cells. Pin1
      may thus regulate transcriptional and post-transcriptional events by catalyzing
      phosphorylation-dependent conformational changes of the large RNA polymerase II
      subunit.

PMID- 10393804
TI  - LAP2 binding protein 1 (L2BP1/BAF) is a candidate mediator of LAP2-chromatin
      interaction.
AB  - Lamina-associated polypeptide (LAP) 2, which directly interacts with B-type
      lamins and chromosomes, is an integral membrane protein specifically distributed
      along the inner nuclear membrane of the nuclear envelope. The chromatin- and
      lamin-binding activity of LAP2 suggests that LAP2 plays an important role in
      targeting mitotic vesicles to chromosomes and reorganizing the nuclear structure
      at the end of mitosis. Here I identified a LAP2 interacting protein, termed L2BP1
      (LAP2 binding protein 1). The rat L2BP1 cDNA sequence is predicted to encode a
      protein of 89 amino acids which turns out to be a rat homolog of mouse and human
      BAF (Barrier-to-Autointegration Factor). L2BP1 is distributed diffusely
      throughout the nucleus in interphase cells. It is, however, highly concentrated
      at the chromosomes during the M-phase. Further, the L2BP1 binding domain of LAP2
      overlaps its chromosome-binding region. These findings suggest that L2BP1 is a
      candidate mediator of LAP2-chromosome interaction at the end of mitosis.

PMID- 10393806
TI  - The major olive pollen allergen (Ole e I) shows both gametophytic and sporophytic
      expression during anther development, and its synthesis and storage takes place
      in the RER.
AB  - The distribution of Ole e I (the major olive pollen allergen) and its transcripts
      was investigated in the anther from premeiotic stages until the dehiscent pollen
      stage. Crude protein extracts were analyzed by immunoblotting and probed with a
      monoclonal antibody to Ole e I. The protein, with three variants, was found to
      accumulate from the early microspore stage onwards. In addition to the previously
      reported localization of the protein, Ole e I has been immunolocalized for the
      first time within the pollen wall and in the tapetum. Reverse transcription
      polymerase chain reaction analysis using specific oligonucleotides and RNA
      extracted from whole anthers revealed that the Ole e I gene is expressed from the
      late tetrad stage onwards. No expression was found in control tissues such as
      petals, roots or leaves. Light microscopy in situ hybridization on developing
      flower buds and dehiscent pollen confirmed the transcripts to be present in both
      the microspores and the sporophytic tissue (tapetum). Labeling was found
      primarily in the tapetum, reaching the highest concentration in the cytoplasm of
      the developing and mature pollen, once tapetum started to degenerate. In situ
      hybridization at the transmission electron microscope level showed the
      transcripts to accumulate on ribosomes of the rough endoplasmic reticulum. These
      studies, together with others carried out previously by us, indicated that both
      synthesis and storage of Ole e I take place in the endoplasmic reticulum,
      coincidentally with the conspicuous changes suffered by this membrane system
      during pollen development. This process is most likely controlled at the
      transcriptional level. The localization of the protein in the pollen ectexine
      bring new insights into the function of the allergen, which are discussed.

PMID- 10393807
TI  - The SFL activity secreted by metastatic carcinoma cells is related to laminin 5
      and mediates cell scattering in an integrin-independent manner.
AB  - We have previously reported that an in vivo-selected metastatic variant of NBT-II
      rat carcinoma cells, M-NBT-II, produces and secretes a factor with cell
      scattering activity, SFL, that is potentially involved in tumor progression. This
      biological activity was purified and characterized as a laminin 5 (LN5) -related
      protein. This SFL/LN5 protein consists of the (alpha)3, (beta)3 and (gamma)2
      chains of expected sizes. Laminin 5 is a multifunctional secreted glycoprotein
      thought to be involved in cell adhesion and migration, mainly via its interaction
      with (alpha)3(beta)1 and (alpha)6(beta)4 integrins. SFL/LN5, and purified human
      laminin 5, induced the scattering and motility of MDCK cells and the formation of
      actin stress fibers and focal contacts in A549 cells. These events were dependent
      on activation of the small GTP-binding protein Rho. (Alpha)v colocalized with
      vinculin in the focal contacts of activated cells whereas (alpha)3 and (alpha)6
      integrins did not. Blocking antibodies directed against (alpha)3 and (alpha)6
      integrins or the laminin 5 integrin-binding site did not abolish SFL/LN5
      biological activity, which, in contrast, was completely inhibited by heparin.
      Thus, SFL/LN5 activity in epithelial cell scattering and cytoskeletal
      reorganization is probably independent of integrin receptors.

PMID- 10393809
TI  - Rvs167p, the budding yeast homolog of amphiphysin, colocalizes with actin
      patches.
AB  - In this report, we have shown that the yeast amphiphysin-like protein Rvs167p was
      localized mainly in small cortical patches throughout the cell in unbudding
      cells. During budding, the patches were polarized at bud emergence site. During
      mating, Rvs167p was concentrated at the tip of the shmoo. Rvs167p colocalized
      with actin patches during yeast vegetative growth and mating. Complete disruption
      of the actin cytoskeleton using Latrunculin-A did not affect Rvs167p localization
      in patches throughout the cell. In rvs167 mutant cells, actin patches are
      mislocalized and in rvs161 or abp1 mutant cells, Rvs167p localization is not
      affected. These observations suggest that Rvs167p may localize the actin cortical
      complex properly. Finally, the amphiphysin-conserved N-terminal domain of
      Rvs167p, called the BAR domain, was required but not sufficient for the correct
      localization of the protein.

PMID- 10393808
TI  - F-actin as a functional target for retro-retinoids: a potential role in
      anhydroretinol-triggered cell death.
AB  - The retro-retinoids, metabolites of vitamin A (retinol), belong to a family of
      lipophilic signalling molecules implicated in regulation of cell growth and
      survival. Growth-promoting properties have been ascribed to 14-hydroxy-retro
      retinol (14HRR), while anhydroretinol (AR) was discovered to act as a natural
      antagonist triggering growth arrest and death by apoptosis. Based on
      morphological studies and inhibition of apoptosis by the kinase blocker,
      herbimycin A, it has been suggested that retro-retinoids exhibit their function
      in the cytosolic compartment. F-actin emerged as a functional target for retro
      retinoid action. By FACS analysis and fluorescence microscopy of phalloidin-FITC
      labeled cells we demonstrated that F-actin reorganization was an early event in
      AR-triggered apoptosis. Fluorescence images of AR-treated fibroblasts displayed
      short, thick, stick-like and punctate structures, and membrane ruffles at the
      cell periphery along with an increased diffuse staining pattern. Reversal of the
      AR effect by 14HRR or retinol indicates that F-actin is a common site for
      regulation by retro-retinoids. Inhibition of both cell death and actin
      depolymerisation by bcl-2 implies that cytoskeleton reorganization is downstream
      of bcl-2-related processes. Furthermore, stabilization of microfilaments by
      jasplakinolide increased the survival potential of AR treated cells, while
      weakening the cytoskeleton by cytochalasin B abetted apoptosis. Thus the
      cytoskeleton is an important way station in a communication network that decides
      whether a cell should live or die.

PMID- 10393810
TI  - A novel zymogen granule protein (ZG29p) and the nuclear protein MTA1p are
      differentially expressed by alternative transcription initiation in pancreatic
      acinar cells of the rat.
AB  - Using a polyclonal antibody against purified zymogen granule membrane components
      from rat pancreas a cDNA coding for the 29 kDa protein (ZG29p) was identified by
      immunoscreening of a hormonally stimulated pancreas cDNA library. Western blot
      analysis suggests that ZG29p is a pancreas-specific protein and
      immunofluorescence shows that ZG29p is mainly associated with zymogen granules.
      Analysis of subcellular fraction applying immunoblotting revealed that ZG29p was
      localized mainly in the soluble fraction of zymogen granules and in a Golgi- and
      RER-enriched fraction, but was absent from the cytosol. In isolated zymogen
      granule content ZG29p was associated with protein complexes containing amylase as
      main constituent. The cDNA coding for ZG29p is homologous to the C-terminal
      region of the candidate metastasis-associated gene mta1. Northern blot analysis
      and RT-PCR showed that no MTA1 mRNA is present in pancreas from fasted rats and
      in the rat pancreas carcinoma cell line AR4-2J in its protodifferentiated state.
      Although no ZG29p specific mRNA was seen in the northern blot analysis, RT-PCR
      showed that ZG29p was expressed under both non-stimulated and stimulated
      conditions. The expression of MTA1 was up-regulated in the pancreas by endogenous
      cholecystokinin release and in AR4-2J after induction of cellular differentiation
      by dexamethasone. Western blotting and immunofluorescense studies indicated that
      MTA1p is localized in the nucleus in all tissues studied. Using genomic DNA in
      PCR analysis it was shown that two short introns are present flanking the
      sequences of the 5'end of ZG29p cDNA. One intron contains consensus elements
      required for pancreas specific transcription initiation, suggesting that MTA1 and
      ZG29 are differentially expressed by alternative transcription initiation in the
      pancreas. The localisation of MTA1p in the nucleus of most cell types could
      signify a general role in gene regulation, while the cell type specific and
      exclusive expression of ZG29p in pancreatic acinar cells could indicate a role in
      granule formation.

PMID- 10393812
TI  - H-2M molecules, like MHC class II molecules, are targeted to parasitophorous
      vacuoles of Leishmania-infected macrophages and internalized by amastigotes of L.
      amazonensis and L. mexicana.
AB  - In their amastigote stage, Leishmania are obligatory intracellular parasites of
      mammalian macrophages, residing and multiplying within phagolysosomal
      compartments called parasitophorous vacuoles (PV). These organelles have
      properties similar to those described for the MHC class II compartments of
      antigen-presenting cells, sites where peptide-class II molecule complexes are
      formed before their expression at the cell surface. After infection with
      Leishmania amazonensis or L. mexicana, endocytosis and degradation of class II
      molecules by intracellular amastigotes have also been described, suggesting that
      these parasites have evolved mechanisms to escape the potentially hazardous
      antigen-presentation process. To determine whether these events extend to other
      molecules of the antigen-presentation machinery, we have now studied the fate of
      the MHC molecule H-2M in mouse macrophages infected with Leishmania amastigotes.
      At least for certain class II alleles, H-2M is an essential cofactor, which
      catalyses the release of the invariant chain-derived CLIP peptide from the
      peptide-binding groove of class II molecules and facilitates the binding of
      antigenic peptides. H-2M was detected in PV of mouse macrophages infected with
      various Leishmania species including L. amazonensis, L. mexicana, L. major and L.
      donovani. PV thus contain all the molecules required for the formation of peptide
      class II molecule complexes and especially of complexes with parasite peptides.
      The present data indicate, however, that if this process occurs, it does not lead
      to a clear increase of SDS-stable compact (alpha)(beta) dimers of class II. In PV
      that contained L. amazonensis or L. mexicana, both class II and H-2M molecules
      often colocalized at the level where amastigotes bind to the PV membrane,
      suggesting that these molecules are physically associated, directly or
      indirectly, and possibly interact with parasite components. Furthermore, as class
      II molecules, H-2M molecules were internalized by amastigotes of these Leishmania
      species and reached parasite compartments that also contained class II molecules.
      Immunostaining of H-2M within parasites was increased by treatment of infected
      macrophages with the cysteine protease inhibitors Z-Phe-AlaCHN2 or Z-Phe-PheCHN2
      or by incubation of the parasites with the same inhibitors before infection.
      These data thus support the idea that amastigotes of certain Leishmania species
      capture and degrade some of the molecules required for antigen presentation. To
      examine whether endocytosis of class II molecules by the parasites occurs through
      interactions with parasite components involving their peptide-binding groove, we
      made use of the fact that a large fraction of the class II molecules of H
      2M(alpha) knock-out H-2(b) mice are occupied by the peptide CLIP and are unable
      to bind other peptides. We found that, in Leishmania-infected macrophages of
      these mutant mice, class II-CLIP complexes reached PV and were internalized by
      amastigotes. These results thus prove that endocytosis of class II molecules by
      amastigotes (1) is H-2M-independent and (2) does not necessarily involve the
      peptide-binding pocket of these molecules. Altogether, these data are compatible
      with an endocytic mechanism based on general properties shared by classical and
      non-classical class II molecules.

PMID- 10393811
TI  - Phorbol ester promotes endocytosis by activating a factor involved in endosome
      fusion.
AB  - Previous studies indicate that a zinc- and phorbol ester-binding factor is
      necessary for in vitro endosome fusion and for the effect of Rab5 on endosome
      fusion. Rab5 is a small GTPase that regulates membrane fusion between early
      endosomes derived from either receptor-mediated endocytosis or fluid-phase
      endocytosis. In its GTP-bound form, Rab5 promotes endocytosis and enhances fusion
      among early endosomes. To determine if PMA stimulates endocytosis by activating a
      factor required for endosome fusion, we overexpressed wild-type Rab5, a dominant
      negative mutant (Rab5:S34N), and a GTPase deficient mutant (Rab5:Q79L) in BHK-21
      cells. The phorbol ester PMA stimulates endocytosis and increases the number and
      the size of endocytic vesicles, even in the presence of Rab5:S34N. Zinc depletion
      with N,N,N',N'-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) and addition of
      calphostin C (CPC), an inhibitor of PKC that interacts with zinc and phorbol
      ester binding motifs, inhibited both basal and Rab5-stimulated fluid phase
      endocytosis. These two reagents also inhibited the size and number of endocytic
      vesicles promoted by Rab5. These results suggest that PMA stimulates endocytosis
      by regulating the dynamics of the early endosome compartment.

PMID- 10393813
TI  - The Emery-Dreifuss muscular dystrophy phenotype arises from aberrant targeting
      and binding of emerin at the inner nuclear membrane.
AB  - The product of the X-linked Emery-Dreifuss muscular dystrophy gene is a single
      membrane-spanning protein called emerin, which is localized to the inner nuclear
      membrane of all tissues studied. To examine whether a number of the mutant forms
      of emerin expressed in patients are mislocalized, we transfected GFP-emerin cDNA
      constructs reflecting these mutations into undifferentiated C2C12 myoblasts and
      showed that both wild type and all the mutant emerins are targeted to the nuclear
      membrane, but the mutants to a lesser extent. Mutant Del236-241 (deletion in
      transmembrane region) was mainly expressed as cytoplasmic aggregates, with only
      trace amounts at the nuclear envelope. Complete removal of the transmembrane
      region and C-terminal tail relocated emerin to the nucleoplasm. Mutations in
      emerin's N-terminal domain had a less severe effect on disrupting nuclear
      envelope targeting. This data suggests that emerin contains multiple non
      overlapping nuclear-membrane-targeting determinants. Analysis of material
      immunoisolated using emerin antibodies, from either undifferentiated C2C12
      myoblasts or purified hepatocyte nuclei, demonstrated that both A- and B-type
      lamins and nuclear actin interact with emerin. This is the first report of
      proteins interacting with emerin. The EDMD phenotype can thus arise by either the
      absence or a reduction in emerin at the nuclear envelope, and both of these
      disrupt its interactions with that of structural components of the nucleus. We
      propose that an emerin-nuclear protein complex exists at the nuclear envelope and
      that one of its primary roles is to stabilize the nuclear membrane against the
      mechanical stresses that are generated in muscle cells during contraction.

PMID- 10393814
TI  - Subcellular distribution of the Xenopus p58/lamin B receptor in oocytes and eggs.
AB  - The p58/lamin B receptor of vertebrates is localized in the inner nuclear
      membrane. Antibodies raised against the bacterially expressed amino-terminal half
      of Xenopus p58 (Xp58) revealed that in Xenopus oocytes the vast majority of this
      membrane protein is localized in cytoplasmic membranes. Only very small amounts
      of p58 not detectable by immunofluorescence microscopy were contained in the
      oocyte nuclear envelope. In contrast, nuclear membranes of 2-cell stage embryos
      were successfully stained with p58 antibodies, nuclei reconstituted in vitro in
      Xenopus egg extracts contained p58, and the nucleoplasmic domain of Xp58 could be
      specifically bound to sperm chromatin in vitro. One major difference between
      oocytes and early embryonic cells is that no chromatin is associated with the
      oocyte inner nuclear membrane whereas the complement of lamins is identical in
      both cell types. To gain insight into the properties of oocyte p58 we
      microinjected isolated nuclei of cultured rat cells into the cytoplasm of Xenopus
      oocytes. The oocyte p58 was detectable by immunofluorescence microscopy within 16
      20 hours in the nuclear membrane of rat nuclei. Our data indicate that the
      peripheral chromatin but not lamins are required for the retention of p58 in the
      inner nuclear membrane. Sucrose step gradient centrifugation of total oocyte
      membranes revealed that the oocyte p58 was predominantly recovered in membrane
      fractions that did not contain lamins whereas membrane associated lamins and p58
      of unfertilized eggs were found in the same fractions. By electron microscopical
      immunolocalizations one major population of meiotic p58 vesicles was identified
      that contained exclusively p58 and a second minor population (ca. 11% of p58
      vesicles) contained in addition to p58 membrane bound B-type lamins. Egg vesicles
      containing pore membrane proteins were predominantly recovered in gradient
      fractions that did not contain p58 and B-type lamins. Our data indicate that the
      targeting of p58 to chromatin at the end of mitosis in the early Xenopus embryo
      is a process independent from that of lamin targeting. Comparable to the
      situation in oocytes and eggs, a significant proportion of p58 of interphase
      cells could be recovered in fractions that did not contain lamins. This
      population of p58 molecules could be extracted from A6-cells with buffers
      containing 1% Triton X-100/0.15 M NaCl and could be pelleted by a 50,000 g
      centrifugation. A- and B-type lamins were not detectable in the p58 containing
      pellet.

PMID- 10393815
TI  - Role of endothelial cell extracellular signal-regulated kinase1/2 in urokinase
      type plasminogen activator upregulation and in vitro angiogenesis by fibroblast
      growth factor-2.
AB  - Downstream signaling triggered by the binding of fibroblast growth factor-2
      (FGF2) to its tyrosine-kinase receptors involves the activation of mitogen
      activated protein kinase kinase (MEK) with consequent phosphorylation of
      extracellular signal-regulated kinases (ERKs). Here we demonstrate that FGF2
      induces ERK1/2 activation in bovine aortic endothelial (BAE) cells and that the
      continuous presence of the growth factor is required for sustained ERK1/2
      phosphorylation. This is prevented by the MEK inhibitors PD 098059 and U0126,
      which also inhibit FGF2-mediated upregulation of urokinase-type plasminogen
      activator (uPA) and in vitro formation of capillary-like structures in three
      dimensional type I collagen gel. Various FGF2 mutants originated by deletion or
      substitution of basic amino acid residues in the amino terminus or in the
      carboxyl terminus of FGF2 retained the capacity to induce a long-lasting
      activation of ERK1/2 in BAE cells. Among them, K128Q/R129Q-FGF2 was also able to
      stimulate uPA production and morphogenesis whereas R129Q/K134Q-FGF2 caused uPA
      upregulation only. In contrast, K27, 30Q/R31Q-FGF2, K128Q/K138Q-FGF2 and
      R118,129Q/K119,128Q-FGF2 exerted a significant uPA-inducing and morphogenic
      activity in an ERK1/2-dependent manner only in the presence of heparin.
      Furthermore, no uPA upregulation and morphogenesis was observed in BAE cells
      treated with the deletion mutant (delta)27-32-FGF2 even in the presence of
      soluble heparin. Thus, mutational analysis of FGF2 dissociates the capacity of
      the growth factor to induce a persistent activation of ERK1/2 from its ability to
      stimulate uPA upregulation and/or in vitro angiogenesis. In conclusion, the data
      indicate that ERK1/2 phosphorylation is a key step in the signal transduction
      pathway switched on by FGF2 in endothelial cells. Nevertheless, a sustained
      ERK1/2 activation is not sufficient to trigger uPA upregulation and
      morphogenesis. FGF2 mutants may represent useful tools to dissect the signal
      transduction pathway(s) mediating the complex response elicited by an angiogenic
      stimulus in endothelial cells.

PMID- 10393816
TI  - Muscle growth and development in normal-sex-ratio and all-female diploid and
      triploid Atlantic salmon.
AB  - Muscle development and growth were investigated in diploid populations of normal
      sex-ratio and all-female Atlantic salmon (Salmo salar L.) and their triploid
      counterparts produced by high-pressure treatment. Somites were formed at the rate
      of 6 h-1 in both diploids and triploids at 6 degrees C. The rostral-to-caudal
      development of myotubes, myofibrils and acetylcholinesterase staining at the
      myosepta was slightly more advanced in triploid than in diploid fish, although
      the differences were smaller than among individual families. The c-met receptor
      tyrosine kinase was used as a molecular marker for the satellite cells involved
      in postembryonic muscle growth. Satellite cell nuclei comprised 17.5 % of total
      myonuclei in smolts and they were 24 % more abundant in diploid than in triploid
      fish. Cells expressing the myogenic regulatory factor myf-6, a marker of
      satellite cells committed to differentiation, represented 14.8 % of total
      myonuclei in diploids and 12.5 % in triploids. At ambient temperatures, the
      number of white muscle fibres in normal-sex-ratio fish increased more than 30
      fold between the alevin and smolt stages, and approximately 3.5-fold further
      during the first year of seawater growth. The rate of muscle fibre recruitment in
      seawater stages was significantly greater in diploid than in triploid fish,
      reaching 1162 fibres day-1 and 608 fibres day-1, respectively, in all-female
      groups 800 days post-hatching. For 42 cm fork-length fish, there were
      approximately one-third more muscle fibres per myotome in diploid than in
      triploid groups, 649 878 and 413 619, respectively, for all-female fish. The
      probability density function of muscle fibre diameters in each fish was estimated
      using non-parametric smoothing techniques, and the mean densities for diploids
      (fD) and triploids (fT) were calculated. The peak fibre diameter was
      approximately 20 (micro)m in all age classes, irrespective of ploidy. Distinct
      bimodal distributions of muscle fibre diameter were evident in all groups 775
      days and 839 days post-hatching, reflecting seasonal cycles of fibre recruitment.
      fD and fT were compared using a non-parametric bootstrap technique and the
      reference band representing the null-hypothesis indicated that there was no
      difference with ploidy. Reference bands for normal-sex-ratio fish at 315 days and
      470 days indicated that diploids had a higher percentage of smaller-diameter
      fibres and that triploid distributions had a thicker right-hand tail. Similar
      differences in fD and fT of muscle fibre diameters were found for all-female
      fish, although the statistical evidence was less strong. Reference bands
      indicated differences in the middle range of the distributions of muscle fibre
      diameter in fish 620-775 days post-hatch, with triploids having a thicker right
      hand tail. Thus, a lower density of satellite cells was associated with reduced
      rates of fibre recruitment but a compensatory increase in muscle fibre
      hypertrophy in triploid compared with diploid fish.

PMID- 10393817
TI  - The distribution of a CRF-like diuretic peptide in the blood-feeding bug Rhodnius
      prolixus.
AB  - The blood-feeding bug Rhodnius prolixus ingests a large blood meal, and this is
      followed by a rapid diuresis to eliminate excess water and salt. Previous studies
      have demonstrated that serotonin and an unidentified peptide act as diuretic
      factors. In other insects, members of the corticotropin-releasing factor (CRF)
      related peptide family have been shown to play a role in post-feeding diuresis.
      Using fluorescence immunohistochemistry and immunogold labelling with antibodies
      to the Locusta CRF-like diuretic hormone (Locusta-DH) and serotonin, we have
      mapped the distribution of neurones displaying these phenotypes in R. prolixus.
      Strong Locusta-DH-like immunoreactivity was found in numerous neurones of the
      central nervous system (CNS) and, in particular, in medial neurosecretory cells
      of the brain and in posterior lateral neurosecretory cells of the mesothoracic
      ganglionic mass (MTGM). Positively stained neurohaemal areas were found
      associated with the corpus cardiacum (CC) and on abdominal nerves 1 and 2. In
      addition, Locusta-DH-like immunoreactive nerve processes were found over the
      posterior midgut and hindgut. Double-labelling studies for Locusta-DH-like and
      serotonin-like immunoreactivity demonstrated some co-localisation in the CNS;
      however, no co-localisation was found in the medial neurosecretory cells of the
      brain, the posterior lateral neurosecretory cells of the MTGM or neurohaemal
      areas. To confirm the presence of a diuretic factor in the CC and abdominal
      nerves, extracts were tested in Malpighian tubule secretion assays and cyclic AMP
      assays. Extracts of the CC and abdominal nerves caused an increase in the rate of
      secretion and an increase in the level of cyclic AMP in the Malpighian tubules of
      fifth-instar R. prolixus. The presence of the peptide in neurohaemal terminals of
      the CC and abdominal nerves that are distinct from serotonin-containing terminals
      indicates that the peptide is capable of being released into the haemolymph and
      that this release can be independent of the release of serotonin.

PMID- 10393818
TI  - Flight performance during hunting excursions in Eleonora's falcon Falco
      eleonorae.
AB  - Among birds, falcons are high-performance flyers, in many cases adapted for
      aerial hunting and hence suitable targets for investigating limits to flight
      performance. Using an optical range finder, we measured flight tracks of
      Eleonora's falcon (Falco eleonorae), a species breeding in the Mediterranean
      region and specialised for hunting autumn passage bird migrants, when commuting
      between their nesting colony and offshore hunting areas (straight transportation
      flight) and when searching for prey (transecting and searching flight). Airspeed
      during searching flight was significantly slower than during straight
      transportation and transecting flight, but there was no significant difference in
      airspeed between the latter two flight modes. Straight transportation flight was
      significantly faster than predicted minimum power speed. Also, during straight
      transportation flight, the falcons responded to head- and tailwinds by increasing
      their airspeed when flying into the wind. However, they did not show any
      significant airspeed adjustments with respect to the angle between the track and
      the heading, as would be expected in birds trying to maintain a constant track
      direction. Mean sustainable climb rate (during (greater than or equal to) 240 s)
      was 1.4+/-0.31 m s-1 (mean +/- s.d., N=13), which is rather a high rate for a
      bird the size of an Eleonora's falcon. The climb rate was used to calculate
      maximum load-carrying capacity and maximum sustained horizontal flapping flight
      speed. The mean wingbeat frequency during powered climbing flight was 4.68 Hz,
      which was used to estimate the mass-specific muscle work. When falcons were
      leaving the colony for offshore hunting, they gained altitude by slope-soaring
      when there was an onshore wind. We formulated a simple criterion for the required
      gliding-flight rate of climb during an initial slope-soaring episode when
      minimizing the energy cost of reaching a certain altitude far out over the sea
      (which is where the prey is to be found). This climb rate was 0.36 m s-1, and our
      observations indicated that the falcons experienced climb rates above this value
      when soaring in slope-lift.

PMID- 10393819
TI  - Energy metabolism during embryonic development and larval growth of an Antarctic
      sea urchin.
AB  - Developmental energetics of an Antarctic sea urchin, Sterechinus neumayeri, were
      quantified to describe the physiological bases underlying ontogenetic changes in
      metabolic rate at extreme cold temperatures (-1.5 degrees C). Rates of
      development from a four-arm to a six-arm larval stage were not affected by food
      availability. The respiratory cost of development to the six-arm larval stage
      (day 60) was 14.0 mJ for fed larvae and 8.2 mJ for unfed larvae. We observed
      three phases of metabolic regulation during development. During embryogenesis
      (day 0-22), increasing metabolic rates were proportional to increases in cell
      numbers. During early larval development (day 22-47), the differences in
      respiratory rate between fed and unfed larvae were not accounted for by cell
      number, but by cell-specific metabolic rate (respiratory rate normalized to DNA
      content). Once an advanced larval stage had been reached (day 47-60), cell
      specific respiratory rate and mitochondrial densities (citrate synthase activity
      normalized to DNA content) were more equivalent between fed and unfed larvae,
      suggesting that size-specific metabolic rates were determined at a level of
      physiological regulation that was independent of cell numbers or feeding history.

PMID- 10393820
TI  - Na+/K+-ATPase activity during early development and growth of an Antarctic sea
      urchin.
AB  - In Antarctic environments, the physiological bases for long larval life spans
      under natural conditions of limited food availability are not understood. The Na+
      pump is likely to be involved with hypometabolic regulation in such cold
      environments. Changes in the activity and metabolic importance of Na+/K+-ATPase
      were measured in embryos of the Antarctic sea urchin Sterechinus neumayeri and in
      larvae reared under different feeding conditions. The rate of increase of total
      Na+/K+-ATPase activity was 3.9 times faster in fed than in unfed larvae. During
      development and growth, there was an increase in the percentage of total,
      potential Na+/K+-ATPase activity that was physiologically utilized. In early (10
      day-old) gastrulae, 17 % was utilized in vivo, increasing to 77 % in six-arm
      pluteus (48-day-old) larvae. The metabolic importance of in vivo Na+/K+-ATPase
      activity also increased during development, accounting for 12 % of metabolic rate
      at day 10 and 84 % at day 48. When compared at the same enzyme assay temperature
      (15 degrees C), the protein-specific total Na+/K+-ATPase activities for late
      embryonic (prism) and early larval (pluteus) stages of S. neumayeri were 2.6
      times lower than those for comparable developmental stages of two temperate sea
      urchin species (Strongylocentrotus purpuratus and Lytechinus pictus).

PMID- 10393821
TI  - Neuronal control of catecholamine secretion from chromaffin cells in the rainbow
      trout (Oncorhynchus mykiss).
AB  - The goal of the present investigation was to assess the relative involvement of
      nicotinic and muscarinic cholinergic receptors in the neuronal control of
      catecholamine secretion from the chromaffin tissue of rainbow trout (Oncorhynchus
      mykiss). This was accomplished by first developing and validating a nerve
      stimulating technique able specifically to activate the nerve fibres innervating
      the chromaffin cells in order to elicit secretion of catecholamines. Using an in
      situ saline-perfused posterior cardinal vein preparation, it was demonstrated
      that whole-body field stimulation caused specific voltage-dependent neuronal
      stimulation of adrenaline and noradrenaline secretion. The contribution of non
      specific depolarization was negligible. Several experimental results confirmed
      the specificity of the field stimulation technique. First, pre-treatment with
      neostigmine (an anticholinesterase) prolonged and more than doubled the amount of
      adrenaline secreted in response to electrical stimulation. Second, pre-treatment
      with the nicotinic receptor antagonist hexamethonium inhibited the electrically
      evoked secretion of adrenaline and noradrenaline. Third, perfusion with Na+-free
      saline or removal of the spinal cord abolished secretion of both catecholamines
      in response to the electrical stimulus. By using the field stimulation technique,
      this study is the first to demonstrate conclusively a role for muscarinic
      receptors in catecholamine secretion from trout chromaffin cells. Specifically,
      muscarinic cholinergic stimulation enhances nicotinic-evoked secretion of
      catecholamines and, under intense stimulation, may directly cause secretion. The
      results of the present study suggest the presence of muscarinic receptors on
      rainbow trout chromaffin cells with a functional role in the cholinergic control
      of catecholamine secretion.

PMID- 10393822
TI  - An interneurone of unusual morphology is tuned to the female song frequency in
      the bushcricket Ancistrura nigrovittata (Orthoptera, Phaneropteridae).
AB  - The interneurone AN5-AG7 of the duetting bushcricket Ancistrura nigrovittata has
      its soma in the seventh (penultimate) abdominal ganglion. Its major postsynaptic
      arborizations with dense thin branches of smooth appearance are found in the
      prothoracic ganglion. The branches terminate in the auditory neuropile,
      predominantly at the same location as those auditory receptors that respond best
      to the female song frequency. Correspondingly, AN5-AG7 responds preferentially to
      frequencies between 24 and 28 kHz, thereby matching the carrier frequency of the
      female response song quite well. At frequencies below 24 kHz, AN5-AG7 receives
      inhibition, which is sometimes seen as clear inhibitory postsynaptic potentials.
      At these frequencies, thresholds of excitatory postsynaptic potentials are
      considerably lower than spike thresholds. In contrast, above 20 kHz, the two
      thresholds match and they correspond to the behavioural threshold. The AN5-AG7
      interneurone is more sensitive to soma-contralateral stimuli and it receives
      predominantly inhibition, but also some excitation, from the soma-ipsilateral
      ear. Response strength is not greatly affected by stimulus duration but shows
      prominent habituation. This habituation depends only weakly on intensity and
      frequency. Some AN5-AG7 interneurones show very small graded potentials and no
      spiking responses to any acoustic stimuli.

PMID- 10393823
TI  - Effects of size, motility and paralysation time of prey on the quantity of venom
      injected by the hunting spider Cupiennius salei.
AB  - Previous experimental studies have shown that neotropical wandering spiders
      (Cupiennius salei) inject more venom when attacking larger crickets. It has been
      postulated that this is a consequence of predator-prey interactions during
      envenomation, which increase in intensity with the size of a given prey species.
      The present study was designed to test this hypothesis using anaesthetized
      crickets of different sizes that were moved artificially. Cupiennius salei was
      found (1) to inject more venom the greater the intensity of the struggling
      movement of the crickets (prey size kept constant); (2) to inject more venom the
      longer the duration of the struggling movement of the crickets (prey size and
      intensity of movement kept constant); and (3) to inject equal amounts into
      crickets of different size (duration and intensity of movement kept constant).
      These results indicate that C. salei alters the amount of venom it releases
      according to the size and motility of its prey. Venom expenditure depends mainly
      on the extent of the interactions with the prey during the envenomation process,
      whereas prey size is of minor significance. The regulation of venom injection in
      concert with behavioural adaptations in response to various types of prey
      minimizes the energetic cost of venom production, thus increasing the
      profitability of a given prey item.

PMID- 10393824
TI  - Diet-induced plasticity in the taste system of an insect: localization to a
      single transduction pathway in an identified taste cell.
AB  - We studied exposure-induced sensitivity changes in an identified taste cell from
      Manduca sexta, a herbivorous caterpillar. This taste cell occurs within the
      lateral styloconic sensillum and responds selectively to compounds that humans
      characterize as bitter (e.g. caffeine, salicin and aristolochic acid). We made
      extracellular recordings from several classes of identified taste cell within the
      lateral sensillum, both before and after dietary exposure (for 48 h) to a
      suprathreshold concentration of caffeine, salicin or aristolochic acid. Our
      results revealed (1) that dietary exposure to caffeine desensitized the bitter
      sensitive taste cell to caffeine, whereas dietary exposure to salicin or
      aristolochic acid did not desensitize the same taste cell to salicin or to
      aristolochic acid; (2) that dietary exposure to caffeine failed to alter the
      responsiveness of the sugar-, salt- or inositol-sensitive taste cells within the
      same sensillum; (3) that the caffeine-induced desensitization phenomenon
      generalized to salicin, a compound that stimulates the same transduction pathway
      as caffeine, but not to aristolochic acid, a compound that stimulates a different
      pathway; and (4) that chronically stimulating the lateral sensillum with
      caffeine, in the absence of ingestion, was sufficient to induce desensitization.
      We conclude that caffeine causes desensitization through a direct effect on a
      single transduction pathway within the bitter-sensitive taste cell.

PMID- 10393825
TI  - NO2- uptake and HCO3- excretion in the intestine of the European flounder
      (Platichthys flesus).
AB  - Ion transport across isolated intestinal segments from the European flounder
      (Platichthys flesus) was studied with the primary aim of evaluating the
      mechanisms of nitrite (NO2-) uptake and HCO3- excretion. A double-radiolabelling
      technique was applied to monitor unidirectional Cl- and Na+ influx. Furthermore,
      net fluxes of NO2-, HCO3-, Cl-, Na+ and water were recorded. NO2- uptake was
      inhibited by mucosal application of bumetanide (10(-)4 mol l-1) but not DIDS (10(
      )3 mol l-1), suggesting that NO2- is transported across the intestine via the
      Na+/K+/2Cl- cotransporter rather than via a Cl-/HCO3- exchanger. In addition to
      transport via the Na+/K+/2Cl- cotransporter, NO2- uptake may also occur through
      the Na+/Cl- cotransporter and by conductive transport. NO2- and Cl- influx rates
      seemed to reflect their mucosal concentrations, and NO2- did not influence
      unidirectional influx or net flux of Cl-. HCO3- efflux was significantly reduced
      in the presence of 10(-)3 mol l-1 DIDS in the mucosal solution. This may indicate
      the presence of an apical Cl-/HCO3- exchanger in the intestinal epithelium, which
      would not comply with the current model of HCO3- excretion in the intestine of
      marine teleost fish. An alternative model of HCO3- excretion across the
      intestinal epithelium is proposed.

PMID- 10393826
TI  - Muscle growth and development in Atlantic cod larvae (Gadus morhua L.), related
      to different somatic growth rates.
AB  - The present study describes the development of the axial musculature in first
      feeding larvae of Atlantic cod (Gadus morhua L.) with different somatic growth
      rates achieved by using different nutritional conditions. Muscle growth was
      assessed by determining the number of muscle fibres (hyperplasia) and the growth
      of existing fibres (hypertrophy). Larvae were fed rotifers containing a high (1.
      4; treatment 1) or low (0.2; treatment 2) ratio of docosahexaenoic acid to
      eicosapentaenoic acid from day 5 after hatching. From day 17, the larvae were fed
      Artemia nauplii with the same enrichment in both treatments. Treatment 1 gave the
      highest somatic growth rate and hence the highest dry mass at the end of the
      experiment, but no difference in larval standard length was found between
      treatments. In slow-growing larvae, higher priority was thus put into reaching a
      certain length than into increasing muscle mass. The largest fibres, which were
      present from hatching, increased in cross-sectional area during larval
      development, but no differences were found between treatments in the cross
      sectional area of individual fibres or the total cross-sectional area of these
      fibres at the end of the experiment. The first white recruitment fibres were
      observed at the dorsal and ventral apices of the myotome at approximately the
      onset of first feeding (larval length 4.5 mm). In larvae 8.5 mm long, the total
      cross-sectional area of white muscle fibres in the treatment 2 group was 75 % of
      that in the treatment 1 group. The highest somatic growth rate was associated
      with an increased contribution of hyperplasia to axial white muscle growth. In
      the faster-growing larval group, the relative contribution of hyperplasia to the
      total white muscle cross-sectional area was 50 %, whereas it was 41 % in the
      slower-growing larval group. The subsequent growth potential may thus be
      negatively affected by inadequate larval feeding.

PMID- 10393827
TI  - Effect of low ambient mineral concentrations on the accumulation of calcium,
      magnesium and phosphorus by early life stages of the air-breathing armoured
      catfish Megalechis personata (Siluriformes: Callichthyidae).
AB  - The accumulation of calcium, magnesium and phosphorus was measured during an 8
      week period in the early life stages of the air-breathing armoured catfish
      Megalechis personata acclimated to low-mineral fresh water (0.073 mmol l-1
      calcium, 0.015 mmol l-1 magnesium, <0.001 mmol l-1 phosphate) and high-mineral
      fresh water (0.59 mmol l-1 calcium, 1.94 mmol l-1 magnesium, <0.001 mmol l-1
      phosphate). The fish accumulated calcium twice as fast and phosphorus 1.5 times
      as fast in low-mineral fresh water (LMF) as in high-mineral fresh water (HMF),
      while the rate of accumulation of magnesium did not differ in LMF and HMF. The
      difference in the rates of accumulation of calcium and phosphorus between LMF and
      HMF was independent of the growth performance (food intake) in LMF and HMF. The
      mineral content of young M. personata from natural swamps and rainforest creeks
      in Suriname followed the LMF accumulation curves. The transition from aquatic
      respiration to bimodal respiration in the third week after hatching did not
      affect rates of mineral accumulation. The high rates of accumulation of calcium
      and magnesium of M. personata in LMF of 654 and 58 micromol h-1 kg-1,
      respectively, exceed the rates of uptake of calcium and magnesium of teleosts
      reported in the literature. The high rates of mineral accumulation in the early
      life stages of M. personata reflect the exponential growth during the first 8
      weeks after hatching and the requirements of the juveniles while building their
      dermal armour. M. personata is well-adapted to neotropical fresh waters with an
      extremely low mineral content. The accumulation of calcium and phosphorus is
      discussed in relation to the function of the bony armour of M. personata.

PMID- 10393828
TI  - Vascular endothelium, hemodynamic forces, and atherogenesis.

PMID- 10393829
TI  - Genetics and clinicopathological findings in thyroid carcinomas associated with
      familial adenomatous polyposis.

PMID- 10393830
TI  - Diagnosis and classification of the small round-cell tumors of childhood.

PMID- 10393831
TI  - Use of tumor-specific gene expression for the differential diagnosis of
      neuroblastoma from other pediatric small round-cell malignancies.
AB  - The differential diagnosis of neuroblastoma from other small round-cell tumors of
      childhood, although clinically of great importance, is sometimes difficult due to
      the almost indistinguishable appearance of such tumors by conventional
      microscopy. Because neuroblastomas are characterized by the synthesis of
      catecholamines, we investigated the possibility that expression of genes involved
      in this pathway could serve as a molecular marker for this disease. A reverse
      transcriptase polymerase chain reaction assay was used to analyze expression of
      tyrosine hydroxylase and dopa decarboxylase in 84 pediatric malignancies
      including 55 neuroblastomas, 6 Ewing's sarcomas/primitive neuroectodermal tumors,
      7 lymphomas, 6 leukemias, 2 rhabdomyosarcomas, 6 osteosarcomas, and 2
      phaeochromocytomas. Of the 55 neuroblastoma samples analyzed, 54 expressed
      clearly detectable levels of both genes. The one sample that did not express
      either of the genes was rediagnosed both clinically and by molecular genetic
      analysis as a Ewing's sarcoma. Of the 29 non-neuroblastoma tumor samples
      examined, the only tumor samples that expressed clearly detectable levels of both
      tyrosine hydroxylase and dopa decarboxylase were phaeochromocytomas. Like
      neuroblastomas, these tumors are characterized by high levels of catecholamines.
      These findings suggest that expression of genes involved in catecholamine
      biosynthesis may be useful for differentiating neuroblastoma from other small
      round-cell tumors of childhood.

PMID- 10393832
TI  - Presence of sodium dodecyl sulfate-stable amyloid beta-protein dimers in the
      hippocampus CA1 not exhibiting neurofibrillary tangle formation.
AB  - The amyloid cascade hypothesis of Alzheimer's disease postulates that
      accumulation of amyloid beta-protein (Abeta) precedes neurofibrillary tangle
      formation or neuronal loss in the cortex. Although this temporal profile has been
      proved in the neocortex by silver staining and immunocytochemical methods, CA1 of
      the hippocampus exhibits a distinct temporal profile during normal aging: the
      formation of neurofibrillary tangles precedes senile plaque formation. This
      temporal profile has been further confirmed by two-site enzyme immunoassay (EIA)
      quantitation of sodium dodecyl sulfate (SDS)-dissociable Abeta42; neurofibrillary
      tangles are already present despite undetectable levels of SDS-dissociable
      Abeta42. However, when the same specimens were subjected to Western blotting,
      many cases with or without neurofibrillary tangles showed some accumulation of
      SDS-stable Abeta dimers that cannot be detected by EIA. Thus, the temporal
      profile prerequisite for the hypothesis is still valid in CA1, and this finding
      also suggests that SDS-stable Abeta dimers have some significant effects on CA1
      pyramidal neurons, which are most vulnerable to neurofibrillary tangle formation.

PMID- 10393833
TI  - The AMY antigen co-occurs with abeta and follows its deposition in the amyloid
      plaques of Alzheimer's disease and down syndrome.
AB  - Novel plaque-like "AMY" lesions were recently described in the brains of patients
      with Alzheimer's disease (AD). Using three Abeta antibodies, we now document the
      co-occurrence of AMY immunoreactivity (IR) with amyloid beta-peptide (Abeta) in
      the large majority of plaques in AD brain. AMY IR was detected in many compacted
      plaques, whereas its co-localization with early, diffuse Abeta deposits was rare.
      AMY IR overlapped considerably or fully with Abeta and, in more severely affected
      AD brains, decorated the periphery of some plaques. In a temporal series of 29
      Down syndrome (DS) brains from patients aged 12 to 73 years, the earliest AMY IR
      was detected in some plaques at age 15, following the earliest appearance of
      Abeta plaques (age 12 years), and then accrued within a subset of Abeta deposits,
      namely, the more spherical, compacted plaques. Brains from DS patients 29 years
      and older showed AMY staining in many Abeta plaques, as seen in AD. Brains from
      eight monkeys aged 17 to 34 years and thirty APP transgenic mice aged 8 to 20
      months showed Abeta IR but no AMY IR. We conclude that AMY IR represents an
      amyloid-associated antigen that co-deposits in most but not all Abeta plaques in
      AD and DS and that accumulation of the AMY antigen follows Abeta deposition in
      plaques.

PMID- 10393834
TI  - Evidence that Par-4 participates in the pathogenesis of HIV encephalitis.
AB  - Progressive neuronal degeneration in brain regions involved in learning and
      memory processes is a common occurrence in patients infected with human
      immunodeficiency virus type 1 (HIV-1). We now report that levels of Par-4, a
      protein recently linked to neuronal apoptosis in Alzheimer's disease, are
      increased in neurons in hippocampus of human patients with HIV encephalitis and
      in monkeys infected with a chimeric strain of HIV-1 and simian immunodeficiency
      virus. Par-4 levels increased rapidly in cultured hippocampal neurons following
      exposure to the neurotoxic HIV-1 protein Tat, and treatment of the cultures with
      a Par-4 antisense oligonucleotide protected the neurons against Tat-induced
      apoptosis. Additional findings show that Par-4 participates at an early stage of
      Tat-induced neuronal apoptosis before caspase activation, oxidative stress, and
      mitochondrial dysfunction. Our data suggest that Par-4 may be a mediator of
      neuronal apoptosis in HIV encephalitis and that therapeutic approaches targeting
      the Par-4 apoptotic cascade may prove beneficial in preventing neuronal
      degeneration and associated dementia in patients infected with HIV-1.

PMID- 10393835
TI  - High expression of HHV-8-encoded ORF73 protein in spindle-shaped cells of
      Kaposi's sarcoma.
AB  - Human herpesvirus 8 (HHV-8) has been demonstrated previously in Kaposi's sarcoma
      (KS) tissues by immunohistochemistry, in situ polymerase chain reaction, and in
      situ hybridization. The HHV-8-encoded protein ORF73 is a 222- or 234-kd protein
      named latent nuclear antigen (LNA) or latency-associated nuclear antigen (LANA)
      that is identified in HHV-8-infected cell lines by immunofluorescence assay. In
      the present study, a rabbit antibody against a recombinant ORF73 protein was
      developed. Immunofluorescent staining of a HHV-8-infected cell line, TY-1, showed
      that the staining pattern of the anti-ORF73 antibody overlapped completely the
      LANA staining pattern obtained using KS patients' sera. Immunoblotting analysis
      showed that the anti-ORF73 antibody reacted specifically with 222- and 234-kd
      proteins that were present in TY-1 and BCBL-1 cell lysates. Immunohistochemistry
      using a catalyzed signal amplification system demonstrated that the anti-ORF73
      antibody reacted exclusively with the majority of KS spindle-shaped cells,
      showing a nuclear dot-like staining pattern. Some of the ORF73 protein-positive
      cells also expressed CD34 and vimentin but not CD68 or factor-VIII-related
      antigen. These data indicate that the anti-ORF73 antibody recognizes LANA and
      that most KS cells are infected with HHV-8 in the latent phase. Our findings also
      suggest that ORF73 protein plays an important role in the pathogenesis of KS.

PMID- 10393837
TI  - Hibernomas are characterized by homozygous deletions in the multiple endocrine
      neoplasia type I region. Metaphase fluorescence in situ hybridization reveals
      complex rearrangements not detected by conventional cytogenetics.
AB  - Hibernomas are benign tumors of brown fat, frequently characterized by
      aberrations of chromosome band 11q13. In this study, the chromosome 11 changes in
      five hibernomas were analyzed in detail by metaphase fluorescence in situ
      hybridization. In all cases, complex rearrangements leading to loss of chromosome
      11 material were found. Deletions were present not only in those chromosomes that
      were shown to be rearranged by G-banding, but in four cases also in the
      ostensibly normal homologues, resulting in homozygous loss of several loci. Among
      these, the gene for multiple endocrine neoplasia type I (MEN1) was most
      frequently deleted. In addition to the MEN1 deletions, heterozygous loss of a
      second region, approximately 3 Mb distal to MEN1, was found in all five cases,
      adding to previous evidence for a second tumor suppressor locus in 11q13.

PMID- 10393836
TI  - cDNA cloning, expression pattern, and chromosomal localization of Mlf1, murine
      homologue of a gene involved in myelodysplasia and acute myeloid leukemia.
AB  - The NPM-MLF1 fusion protein is expressed in blasts from patients with
      myelodysplasia/acute myeloid leukemia (MDS/AML) containing the t(3;5) chromosomal
      rearrangement. Nucleophosmin (NPM), a previously characterized nucleolar
      phosphoprotein, contributes to two other fusion proteins found in lympho
      hematopoietic malignancies, anaplastic large cell lymphoma (NPM-ALK) and acute
      promyelocytic leukemia (NPM-RARalpha). By contrast, the function of the carboxy
      terminal fusion partner, myelodysplasia/myeloid leukemia factor 1 (MLF1), is
      unknown. To aid in understanding normal MLF1 function, we isolated the murine
      cDNA, determined the chromosomal localization of Mlf1, and defined its tissue
      expression by in situ hybridization. Mlf1 was highly similar to its human
      homologue (86% and 84% identical nucleotide and amino acid sequence,
      respectively) and mapped to the central region of chromosome 3, within a segment
      lacking known mouse mutations. Mlf1 tissue distribution was restricted during
      both development and postnatal life, with high levels present only in skeletal,
      cardiac, and selected smooth muscle, gonadal tissues, and rare epithelial tissues
      including the nasal mucosa and the ependyma/choroid plexus in the brain. Mlf1
      transcripts were undetectable in the lympho-hematopoietic organs of both the
      embryonic and adult mouse, suggesting that NPM-MLF1 contributes to the genesis of
      MDS/AML in part by enforcing the ectopic overexpression of MLF1 within
      hematopoietic tissues.

PMID- 10393838
TI  - Mitochondrial DNA depletion syndrome is expressed in amniotic fluid cell
      cultures.
AB  - Mitochondrial DNA depletion syndrome is an autosomal inherited disease associated
      with grossly reduced cellular levels of mitochondrial DNA in infancy. Most
      patients are born after a full and uncomplicated pregnancy, are normal at birth,
      but develop symptoms in the early neonatal period. These observations have led to
      the suggestion that the patients have a defect affecting the control of
      mitochondrial DNA copy number after birth. Using immunocytochemical techniques,
      we demonstrated that the disease is already expressed in amniotic fluid cells.
      Detection of mitochondrial DNA depletion in these fetal cells indicates that the
      defect may already be expressed early in embryological development.

PMID- 10393840
TI  - Genomic imbalances associated with acquired resistance to platinum analogues.
AB  - During the past several years, a panel of human tumor cell lines (predominantly
      ovarian) with acquired resistance to cisplatin, the orally bioavailable analogue
      JM216, and the structurally hindered analogue AMD473, has been established and
      characterized for underlying mechanisms of resistance. We have examined these
      resistant cell lines for gains and losses of DNA associated with the acquisition
      of resistance using the molecular cytogenetic technique of comparative genomic
      hybridization. Our comparison of three analogues has shown the most frequently
      observed changes to include amplification of 4q (5/7) and 6q (5/7), followed by
      amplification of 5q (3/7). We have defined four minimal common overrepresented
      regions, two each on 4q and 6q, which are potential loci of genes associated with
      platinum analogue resistance. Additional consistent abnormalities appear to be
      associated with cell lines sharing specific resistance mechanisms. For example,
      amplification of 12q was observed in the CH1 lines made respectively resistant to
      JM216 and AMD473 in which increased DNA repair appears to be a major mechanism of
      resistance for both agents. Hence, these comparative genomic hybridization
      studies have identified distinct chromosomal aberrations which may correlate with
      defined mechanisms of resistance and contain hitherto unrecognized genes that may
      provide targets for future therapeutic intervention.

PMID- 10393839
TI  - Endostatin binds to blood vessels in situ independent of heparan sulfate and does
      not compete for fibroblast growth factor-2 binding.
AB  - Endostatin is a carboxyl-terminal proteolytic fragment of collagen XVIII and a
      potent inhibitor of angiogenesis. The mechanism of action is unknown, but the
      crystal structure of endostatin predicts a prominent heparan sulfate binding
      site, suggesting that endostatin competitively inhibits heparin-binding
      angiogenic factors, such as basic fibroblast growth factor (FGF-2). The goal of
      the study was to map endostatin binding sites in intact human tissues and to
      determine whether this binding is heparan sulfate dependent. In situ binding was
      performed with recombinant epitope-tagged murine endostatin. Endostatin
      predominantly binds to blood vessels of different calibers in a saturable
      fashion. In addition, binding to some epithelial basement membranes is seen. The
      localization pattern is similar to that reported for collagen XVIII, endostatin's
      parent molecule. In breast carcinomas, endostatin co-localizes largely with FGF
      2. In a surprising contrast to FGF-2, endostatin binding is resistant to
      treatment with heparitinase, demonstrating that binding is not mediated by
      heparan sulfate proteoglycans. Furthermore, FGF-2 and heparin do not compete for
      endostatin binding, providing additional evidence for the discreteness of
      endostatin and FGF-binding sites.

PMID- 10393841
TI  - Lipid deposition in rat aortas with intraluminal hemispherical plug stenosis. A
      morphological and biophysical study.
AB  - A new method was devised to create a stenosis in the rat abdominal aorta. To
      restrict blood flow, a hemispherical plug was inserted into the aorta through a
      renal artery. This type of intrinsic (intraluminal) stenosis minimizes possible
      intramural effects associated with external compression or ligation which
      severely deform the arterial wall. In the aorta of hypercholesterolemic rats,
      lipid deposits were distributed in crescent-shaped patches proximal and distal to
      the plug, whereas lipid deposition in the opposite aortic wall was inhibited.
      Based on enlarged physical scale models used to study the flow field, the regions
      of lipid deposition were found to coincide with regions of low shear stress,
      stagnation, and recirculation. Shear stress was elevated at the wall opposite the
      plug. These results show that when confounding mural effects are minimized, lipid
      deposition is promoted in regions of low shear stress with recirculation and
      inhibited in regions of elevated shear stress.

PMID- 10393843
TI  - Deletions of the INK4A gene in superficial bladder tumors. Association with
      recurrence.
AB  - The INK4A and the INK4B genes map to chromosome 9p21, an area frequently deleted
      in bladder neoplasms. In addition to the p16 protein, the INK4A encodes for a
      second product, termed p19(ARF). We analyzed tissues from 121 patients with
      initial Ta and T1 tumors. Deletions of the INK4A gene were observed in 17 of 121
      (14.1%) cases. Point mutations were identified in 2 of 64 (3.1%) tumors. The
      INK4A-exon 1beta and the INK4B gene were codeleted with INK4A in all of the
      homozygously deleted cases analyzed. The p16 promoter underwent de novo
      methylation in 7 of 47 (14.9%) evaluable cases. The p16-positive phenotype was
      observed in 18 of 56 (32%) evaluable cases. p16 negative phenotype correlated
      with deletion and methylation status. A statistically significant association
      between INK4A homozygous deletions and tumor size was observed (P = 0.003).
      Patients bearing tumors with INK4A homozygous deletions had a lower recurrence
      free survival (P = 0.040) than those with wild type INK4A. In conclusion,
      deletions and methylation of the INK4A gene occur frequently in superficial
      bladder tumors. However, only those deletions that affect both the p16 and the
      p19(ARF), deregulating both the pRb and p53 pathways, correlated with
      clinicopathological parameters of worse prognosis.

PMID- 10393842
TI  - Endothelial cell heterogeneity in venules of mouse airways induced by polarized
      inflammatory stimulus.
AB  - We sought to determine whether the changes in microvascular endothelial cells
      (EC) caused by a polarized chronic inflammatory stimulus depend on proximity to
      the stimulus. C3H mice were infected with Mycoplasma pulmonis, which attaches to
      the airway epithelium and creates a polarized inflammatory stimulus across the
      airway wall. At 1, 2, or 4 weeks, the tracheal vasculature was stained by
      perfusion of silver nitrate to mark EC borders or biotinylated Lycopersicon
      esculentum lectin to label the EC surface and adherent leukocytes. E-selectin
      immunoreactivity and EC proliferation were also localized. We found that the
      size, shape, and immunoreactivity for adhesion molecules on EC nearest the airway
      lumen (subepithelial EC) were different from those on the opposite surface of the
      same vessels. Subepithelial EC were smaller, more irregular in shape, had greater
      E-selectin immunoreactivity, and had twice as many adherent leukocytes. In
      contrast, proliferating EC were uniformly distributed around the vessel
      circumference. We conclude that the polarized stimulus created by M. pulmonis
      infection differentially changes the size, shape, and function of EC nearest the
      airway epithelium. This heterogeneity may result from a gradient of inflammatory
      mediators that triggers the influx of leukocytes into the airway lumen.

PMID- 10393844
TI  - Suppression of prostate carcinoma cell invasion by expression of antisense L
      plastin gene.
AB  - Based on the finding that gene expression for the actin-bundling protein L
      plastin is inducible by androgen and that L-plastin is overexpressed in malignant
      epithelium of the prostate, we examined the functional consequences of L-plastin
      down-regulation in prostate carcinoma cell lines by both transfection and
      retroviral infection. We constructed retroviral vectors to express two different
      regions of the L-plastin gene, a 1713-bp 3'-coding portion and a 163-bp 5'
      untranslated region, both in antisense orientation. Introduction of either
      constructs into prostate carcinoma cell lines, PC-3 and its isogenic but
      metastatic variant PC-3M cells, reduced the growth rates of both cell lines. In
      vitro invasion and motility of PC-3 and PC-3M cells were drastically suppressed
      (approximately 10-fold) by the expression of the antisense constructs. Evidence
      was obtained to indicate that L-plastin protein levels were indeed decreased by
      the antisense expression. The antisense construct for the 5'-untranslated region
      with the most unique sequence for the L-plastin gene was more effective in down
      regulation efficiency compared with the larger antisense construct in the coding
      region, which maintains homology to other members of the plastin gene family.
      Cells infected with the 163-bp antisense virus, which were also tested in a nude
      mouse diaphragm invasion model, showed suppression of in vivo invasion of both PC
      3 and PC-3M cells. These results suggested that overexpression of L-plastin might
      be functionally involved in prostate cancer invasion and metastasis, and raised
      the possibility that L-plastin gene-specific antisense delivery could potentially
      be a useful approach to interfere with prostate cancer progression in vivo.

PMID- 10393845
TI  - A cell culture system for the study of amyloid pathogenesis. Amyloid formation by
      peritoneal macrophages cultured with recombinant serum amyloid A.
AB  - A murine macrophage culture system that is both easy to employ and amenable to
      manipulation has been developed to study the cellular processes involved in AA
      amyloid formation. Amyloid deposition, as identified by Congo red-positive, green
      birefringent material, is achieved by providing cultures with recombinant serum
      amyloid A2 (rSAA2), a defined, readily produced, and highly amyloidogenic
      protein. In contrast to fibril formation, which can occur in vitro with very high
      concentrations of SAA and low pH, amyloid deposition in culture is dependent on
      metabolically active macrophages maintained in neutral pH medium containing rSAA2
      at a concentration typical of that seen in acute phase serum. Although amyloid
      enhancing factor is not required, its addition to culture medium results in
      larger and more numerous amyloid deposits. Amyloid formation in culture is
      accompanied by C-terminal processing of SAA and the generation of an 8.5-kd
      fragment analogous to amyloid A protein produced in vivo. Consistent with the
      possibility that impaired catabolism of SAA plays a role in AA amyloid
      pathogenesis, treatment of macrophages with pepstatin, an aspartic protease
      inhibitor, results in increased amyloid deposition. Finally, the amyloidogenicity
      exhibited by SAA proteins in macrophage cultures parallels that seen in vivo, eg,
      SAA2 is highly amyloidogenic, whereas CE/J SAA is nonamyloidogenic. The
      macrophage culture model presented here offers a new approach to the study of AA
      amyloid pathogenesis.

PMID- 10393846
TI  - Presenilin overexpression arrests cells in the G1 phase of the cell cycle. Arrest
      potentiated by the Alzheimer's disease PS2(N141I)mutant.
AB  - To investigate the mechanism by which presenilin (PS) overexpression induces
      apoptosis, we studied the effects of these proteins on cell cycle progression.
      Transiently transfected HeLa cells were bromodeoxyuridine (BrdU) labeled to
      visualize DNA synthesis by immunofluorescence and stained with propidium iodide
      to measure DNA content by fluorescence-activated cell sorting (FACS). BrdU
      labeling was decreased in cells expressing presenilin-1 (PS1), presenilin-2
      (PS2), an Alzheimer's disease-associated missense mutation PS2(N141I), and the
      carboxyl-terminally deleted PS2 construct PS2(166aa), compared with mock and
      neurofilament-light (NF-L) transfected cells. Analysis of BrdU incorporation in
      mitotically synchronized HeLa cells suggested that cells were arresting in the G1
      phase of the cell cycle, and this was confirmed by FACS analysis. Interestingly,
      cell cycle progression was more inhibited by the expression of PS2(N141I)
      compared with wild-type PS2. In addition, ATM, the gene product mutated in ataxia
      telangiectasia, does not appear to be a downstream effector of PS-induced cell
      cycle arrest as transfection of PS constructs into an ataxia-telangiectasia cell
      line also resulted in cell cycle inhibition. Quantitative immunoblotting of whole
      cell lysates from PS-transfected cells did not reveal increases or decreases in
      the steady-state levels of p21, p27, p53, pRb, or c-myc, suggesting that the
      presenilins mediate cell cycle arrest by mechanisms other than simple changes in
      the steady-state levels of these cell-cycle-related proteins.

PMID- 10393847
TI  - Injection of pre-psoriatic skin with CD4+ T cells induces psoriasis.
AB  - Psoriasis is an immunologically mediated skin disease linked to several different
      class I major histocompatibility complex alleles. However, the phenotype of the
      pathogenic lymphocyte and nature of the T cell activating event which triggers
      conversion of symptomless (PN) skin into psoriatic plaques (PP skin) is unknown.
      This study extends our previous observations in which autologous blood-derived
      immunocytes were injected into PN skin engrafted onto SCID mice to produce full
      fledged PP lesions. The first question addressed is whether injected CD4+ T cells
      or CD8+ T cells were responsible for phenotypic conversion of PN to PP skin. In
      five different patients only CD4+ but not CD8+ T cell lines produced psoriatic
      lesions. Next, immunological events occurring within PN skin following injection
      of CD4+ T cells in grafts that had sufficient tissue available for detailed
      analysis was examined. In two patients, intraepidermal resident CD8+ T cells were
      induced to proliferate during lesion development, expressing acute activation
      markers CD25 and CD69. In another patient, injection of CD4+ T cells revealed
      CD69 expression by intraepidermal CD4+ as well as CD8+ T cells. To explore the
      molecular basis for local T cell activation and proliferation, we discovered that
      intraepidermal immunocytes, including both CD4 and CD8+ T cells, expressed
      surface receptors (ie, CD94, CD158a, CD158b) typically confined to natural killer
      cells (ie, natural killer receptors; NKRs) accumulated immediately before onset
      of acute lesions. The presence of NKR bearing immunocytes was also observed in 10
      of 15 different biopsies of chronic plaques taken directly from patients, whereas
      PN skin (n = 8) or normal skin from healthy donors (n = 8), did not contain such
      NKR positive immunocytes. Of particular relevance to psoriasis is that these NKRs
      recognize various class I alleles including those typically inherited by
      psoriatic family members such as HLA-C and HLA-B allotypes. We conclude that
      injection of CD4+ T cells into PN skin triggers a series of local immunologically
      mediated stimulatory events that produce further T cell activation and appearance
      of both CD4 and CD8+ T cells that express NKRs.

PMID- 10393848
TI  - The role of the hairless (hr) gene in the regulation of hair follicle catagen
      transformation.
AB  - Mice that carry a mutation at the hairless (hr) locus develop seemingly normal
      hair follicles (HF) but shed their hairs completely soon after birth.
      Histologically, their HFs degenerate into characteristic utriculi and dermal
      cysts shortly after the entry of the HF into the first regression phase
      (catagen), during the initiation of HF cycling. Here, we show that at least nine
      distinct stages of HF disintegration can be distinguished in hr/hr mice. Toward
      the end of HF morphogenesis (day 15 postpartum) the proximal hair bulb in hr/hr
      skin undergoes premature and massive apoptosis. This is associated with a
      dyscoordination of cell proliferation in defined HF compartments, malpositioning
      of the proximal inner root sheath, striking atrophy of outer root sheath, and
      failure of trichilemmal keratinization in the developing club hair. Rather than
      undergoing their normal catagen-associated involution, the hair bulb and central
      outer root sheath disintegrate into separate cell clusters, thus disrupting all
      epithelial contact with the dermal papilla. Dermal papilla fibroblasts fail to
      migrate upward, and break up into clusters of shrunken cells stranded in the
      reticular dermis as dermal cyst precursors, while the upper HF epithelium
      transforms into utriculi. Some dermal papilla cells, which normally never undergo
      apoptosis, also become TUNEL+ in hr/hr skin, and their normally high expression
      of a key adhesion molecule, neural cell adhesion molecule, declines. Thus, loss
      of a functional hr gene product (a putative zinc finger transcription factor)
      initiates a premature, highly dysregulated catagen, which results in the
      destruction of the normal HF architecture and abrogates the HF's ability to
      cycle. This provides new insights into the pathobiology of the hr mutation, and
      suggests that the normal hr gene product is a crucial element of catagen control.

PMID- 10393849
TI  - Estrogen deficiency accelerates autoimmune exocrinopathy in murine Sjogren's
      syndrome through fas-mediated apoptosis.
AB  - Estrogenic action has been suggested to be responsible for the strong female
      preponderance of autoimmune diseases, but the role of estrogens in the female has
      not been well characterized. We evaluated the effects of estrogen deficiency in a
      murine model for autoimmune exocrinopathy of Sjogren's syndrome (SS). Severe
      destructive autoimmune lesions developed in the salivary and lacrimal glands in
      estrogen-deficient mice, and these lesions were recovered by estrogen
      administration. We detected an intense estrogen receptor in splenic CD8(+) T
      cells compared with that in CD4(+) T cells, and concanavalin-A-stimulated
      blastogenesis of splenic CD8(+) T cells with estrogens was much higher than that
      of CD4(+) T cells. We found a significant increase in serum autoantibody
      production against the organ-specific autoantigen alpha-fodrin. Moreover, an
      increased proportion of TUNEL+ apoptotic epithelial duct cells was observed in
      estrogen-deficient mice. It was demonstrated that Fas-mediated apoptosis in
      cultured salivary gland cells was clearly inhibited by estrogens in vitro. These
      results indicate that dysfunction of regulatory T cells by estrogen deficiency
      may play a crucial role on acceleration of organ-specific autoimmune lesions, and
      estrogenic action further influences target epithelial cells through Fas-mediated
      apoptosis in a murine model for SS.

PMID- 10393850
TI  - Transgene expression and repression in transgenic rats bearing the
      phosphoenolpyruvate carboxykinase-simian virus 40 T antigen or the
      phosphoenolpyruvate carboxykinase-transforming growth factor-alpha constructs.
AB  - Transgenic Sprague-Dawley rats expressing either human transforming growth factor
      alpha (TGFalpha) or simian virus 40 large and small T antigen (TAg), each under
      the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter, were
      developed as an approach to the study of the promotion of hepatocarcinogenesis in
      the presence of a transgene regulatable by diet and/or hormones. Five lines of
      PEPCK-TGFalpha transgenic rats were established, each genetic line containing
      from one to several copies of the transgene per haploid genome. Two PEPCK-TAg
      transgenic founder rats were obtained, each with multiple copies of the
      transgene. Expression of the transgene was undetectable in the TGFalpha
      transgenic rats and could not be induced when the animals were placed on a high
      protein, low-carbohydrate diet. The transgene was found to be highly methylated
      in all of these lines. No pathological alterations in the liver and intestine
      were observed at any time (up to 2 years) during the lives of these rats. One
      line of transgenic rats expressing the PEPCK-TAg transgene developed pancreatic
      islet cell hyperplasias and carcinomas, with few normal islets evident in the
      pancreas. This transgene is integrated as a hypomethylated tandem array of 10 to
      12 copies on chromosome 8q11. Expression of large T antigen is highest in
      pancreatic neoplasms, but is also detectable in the normal brain, kidney, and
      liver. Mortality is most rapid in males, starting at 5 months of age and reaching
      100% by 8 months. Morphologically, islet cell differentiation in the tumors
      ranges from poor to well differentiated, with regions of necrosis and fibrosis.
      Spontaneous metastasis of TAg-positive tumor cells to regional lymph nodes was
      observed. These studies indicate the importance of DNA methylation in the
      repression of specific transgenes in the rat. However, the expression of the
      PEPCK-TAg induces neoplastic transformation in islet cells, probably late in
      neuroendocrine cell differentiation. T antigen expression during neoplastic
      development may result in a pervasive change in the islet cell growth properties
      with selection of a transformed phenotype as a possible requirement for cell
      viability.

PMID- 10393852
TI  - Origin of microsatellite instability in gastric cancer.
AB  - Microsatellite instability (MSI) is observed in 13-44% of gastric carcinoma. The
      etiology of MSI in gastric carcinoma has not been clearly defined. To assess the
      role of mismatch repair in the development of MSI in gastric cancer, expression
      of hMSH2 and hMLH1 was explored. We examined 117 gastric carcinomas for MSI and
      observed instability at one or more loci in 19 (16%) of these tumors. Of the 19
      tumors with MSI, nine exhibited low-rate MSI (MSI-L) with instability at <17% of
      loci, whereas the remaining 10 exhibited high-rate MSI (MSI-H) with instability
      at >33% of loci examined. Immunohistochemical staining for hMLH1 and hMSH2 was
      performed on eight of the tumors with MSI-H, five with MSI-L, and 15 tumors
      without MSI. All eight tumors with MSI-H showed loss of staining for either hMLH1
      (n = 5) or hMSH2 (n = 3). In contrast, tumors with MSI-L or without MSI all
      showed normal hMSH2 and hMLH1 protein expression patterns. Moreover, all eight of
      the tumors with MSI-H also showed instability at BAT-26, whereas none of the MSI
      L tumors or tumors without instability showed instability at BAT-26. These
      findings suggest that the majority of high-level MSI in gastric cancer is
      associated with defects of the mismatch repair pathway. Although larger studies
      are needed, BAT-26 appears to be a sensitive and specific marker for the MSI-H
      phenotype in gastric carcinoma.

PMID- 10393853
TI  - Specific inhibitors of platelet-derived growth factor or epidermal growth factor
      receptor tyrosine kinase reduce pulmonary fibrosis in rats.
AB  - The proliferation of myofibroblasts is a central feature of pulmonary fibrosis.
      In this study we have used tyrosine kinase inhibitors of the tyrphostin class to
      specifically block autophosphorylation of the platelet-derived growth factor
      receptor (PDGF-R) or epidermal growth factor receptor (EGF-R). AG1296
      specifically inhibited autophosphorylation of PDGF-R and blocked PDGF-stimulated
      [3H]thymidine uptake by rat lung myofibroblasts in vitro. AG1478 was demonstrated
      as a selective blocker of EGF-R autophosphorylation and inhibited EGF-stimulated
      DNA synthesis in vitro. In a rat model of pulmonary fibrosis caused by
      intratracheal instillation of vanadium pentoxide (V2O5), intraperitoneal delivery
      of 50 mg/kg AG1296 or AG1478 in dimethylsulfoxide 1 hour before V2O5 instillation
      and again 2 days after instillation reduced the number of epithelial and
      mesenchymal cells incorporating bromodeoxyuridine (Brdu) by approximately 50% at
      3 and 6 days after instillation. V2O5 instillation increased lung hydroxyproline
      fivefold 15 days after instillation, and AG1296 was more than 90% effective in
      preventing the increase in hydroxyproline, whereas AG1478 caused a 50% to 60%
      decrease in V2O5-stimulated hydroxyproline accumulation. These data provide
      evidence that PDGF and EGF receptor ligands are potent mitogens for collagen
      producing mesenchymal cells during pulmonary fibrogenesis, and targeting tyrosine
      kinase receptors could offer a strategy for the treatment of fibrotic lung
      diseases.

PMID- 10393851
TI  - Apoptosis and tumorigenesis in human cholangiocarcinoma cells. Involvement of
      Fas/APO-1 (CD95) and calmodulin.
AB  - We have previously demonstrated that tamoxifen inhibits the growth of human
      cholangiocarcinoma cells in culture and inhibits tumor growth when cells are
      injected into nude mice. However, the mechanism of action of tamoxifen remains
      unknown. Here we demonstrate that tamoxifen and trifluoperazine, both potent
      calmodulin antagonists, induce apoptosis in vitro, probably acting via the Fas
      system, in human cholangiocarcinoma cells. Human cholangiocarcinoma cell lines
      heterogeneously express Fas antigen on their surface. Fas-negative and Fas
      positive surface-expressing cells were isolated, cloned, and cultured. Fas
      antibody, tamoxifen, and trifluoperazine induced dose-dependent apoptosis only in
      Fas-positive cells; Fas-negative cells were unaffected. Furthermore, apoptosis
      induced by tamoxifen in Fas-positive cells was blocked by an inhibitory Fas
      antibody. Tamoxifen was not acting through an anti-estrogenic mechanism, because
      neither Fas-negative nor Fas-positive cells expressed estrogen receptors and the
      pure anti-estrogen compound, ICI 182780, did not induce apoptosis in either cell
      line. Fas-negative cells, but not Fas-positive cells, were able to produce tumors
      when subcutaneously injected into nude mice. These findings suggest Fas may be a
      candidate oncogene involved in the pathogenesis of cholangiocarcinoma.
      Furthermore, the similarity between the pro-apoptotic effects of tamoxifen and
      trifluoperazine support an underlying molecular mechanism for Fas-mediated
      apoptosis that involves calmodulin.

PMID- 10393855
TI  - 15-lipoxygenase-2 (15-LOX-2) is expressed in benign prostatic epithelium and
      reduced in prostate adenocarcinoma.
AB  - Human 15S-lipoxygenase-2 (15-LOX-2) is a recently identified lipoxygenase that
      has approximately 40% sequence identity to the known human 5S-, 12S-, and 15S
      lipoxygenases. 15-LOX-2 has a limited tissue distribution, with mRNA detected in
      prostate, lung, skin, and cornea, but not in numerous other tissues, including
      peripheral blood leukocytes. In the current study, we have characterized the
      distribution of 15-LOX-2 in the human prostate by immunohistochemistry,
      demonstrated the ability of benign prostate tissue to form 15S
      hydroxyeicosatetraenoic acid (15S-HETE) from exogenous arachidonic acid (AA), and
      begun characterizing possible alterations in 15-LOX-2 in prostate adenocarcinoma.
      Incubation of benign prostate tissue with [14C]AA resulted in formation of
      [14C]15-HETE, as determined by reverse- and straight-phase high-performance
      liquid chromatography. 15-HETE was the major AA metabolite formed. By
      immunohistochemistry, 15-LOX-2 is located in secretory cells of peripheral zone
      glands and large prostatic ducts and somewhat less uniformly in apical cells of
      transition and central zone glands. 15-LOX-2 was not detected in the basal cell
      layer, stroma, ejaculatory ducts, seminal vesicles, or transitional epithelium.
      Immunostaining of 18 radical prostatectomy specimens showed a loss of 15-LOX-2 in
      the majority of prostate adenocarcinomas; 14 of 18 cases showed loss of 15-LOX-2
      in >25% of the tumor (mean, 74.9% negative for 15-LOX-2; range, 38.9% to 100%).
      Incubation of paired pure benign and pure malignant prostate tissue from the same
      radical prostatectomies showed that 15-HETE formation was markedly reduced (>90%)
      or undetectable in incubations of prostate adenocarcinoma. 15-LOX-2 is a novel
      human lipoxygenase with a limited tissue distribution that is strongly expressed
      in benign prostate glandular epithelium and lost to a variable degree in the
      majority of prostate adenocarcinomas.

PMID- 10393856
TI  - Expression of the eukaryotic translation initiation factors 4E and 2alpha in non
      Hodgkin's lymphomas.
AB  - Transition of cells from quiescence to proliferation requires an increase in the
      rate of protein synthesis, which is regulated in part by two key translation
      initiation factors, 4E and 2alpha. The expression and activity of both factors
      are increased transiently when normal resting cells are stimulated to
      proliferate. They are constitutively elevated in oncogene transformed cultured
      cells, and overexpression of either initiation factor in rodent cells makes them
      tumorigenic. In this study we investigate an association between the expression
      of translation initiation factors and lymphomagenesis. We have analyzed the
      expression of the protein synthesis initiation factors 4E and 2alpha by
      immunohistochemistry in reactive lymph nodes and several types of non-Hodgkin's
      lymphoma representing a wide range of clinical behaviors based on the Revised
      European-American Lymphoma behavioral classification. The study included 7 benign
      lymph nodes with follicular hyperplasia, 26 indolent lymphomas (6 marginal zone
      lymphomas, 7 small lymphocytic lymphomas, and 13 follicular lymphomas, grades 1
      and 2), 16 moderately aggressive lymphomas (8 mantle cell lymphomas and 8
      follicular lymphomas, grade 3), 24 aggressive lymphomas (14 large-B-cell
      lymphomas and 10 anaplastic large-cell lymphomas), and 15 highly aggressive
      lymphomas (7 lymphoblastic lymphomas and 8 Burkitt's lymphomas). Strong
      expression of initiation factors 4E and 2alpha was demonstrated in the germinal
      centers of reactive follicles. Minimal or no expression was seen in the mantle
      zones and surrounding paracortices, indicating that high expression of initiation
      factors 4E and 2alpha is associated with the active proliferation of lymphocytes.
      Most cases of aggressive and highly aggressive lymphomas showed strong expression
      of initiation factors 4E and 2alpha, in contrast to the cases of indolent and
      moderately aggressive lymphoma, in which their expression was intermediate
      between the germinal centers and the mantles of reactive follicles. A positive
      correlation was found between the expression of both initiation factors 4E and
      2alpha and the Revised European-American Lymphoma behavior classification (P <
      0.05). Thus, constitutively increased expression of initiation factors 4E and
      2alpha may play an important role in the development of lymphomas and is
      correlated with their biological aggressiveness.

PMID- 10393854
TI  - Deficiency of SHP-1 protein-tyrosine phosphatase activity results in heightened
      osteoclast function and decreased bone density.
AB  - Mice homozygous for the motheaten (Hcphme) or viable motheaten (Hcphme-v)
      mutations are deficient in functional SHP-1 protein-tyrosine phosphatase and show
      severe defects in hematopoiesis. Comparison of femurs from mev/mev mice revealed
      significant decreases in bone mineral density (0.33 +/- 0.03 mg/mm3 for
      mev/mevversus 0.41 +/- 0.01 mg/mm3 for controls) and mineral content (1.97 +/-
      0.36 mg for mev/mevversus 10.64 +/- 0.67 for controls) compared with littermate
      controls. Viable motheaten mice also showed reduced amounts of trabecular bone
      and decreased cortical thickness. These bone abnormalities were associated with a
      14% increase in numbers of multinucleated osteoclasts and an increase in
      osteoclast resorption activity. In co-cultures of normal osteoblasts with mutant
      or control bone marrow cells, numbers of osteoclasts developing from mutant mice
      were increased compared with littermate control mice. Although mev/mev
      osteoclasts develop in the absence of colony-stimulating factor (CSF)-1,
      nevertheless cultured osteoclasts show increased size in the presence of CSF-1.
      CSF-1-deficient osteopetrosis (op/op) mutant mice develop severe osteosclerosis.
      However, doubly homozygous mev/mevop/op mice show an expansion of bone marrow
      cavities and reduced trabecular bone mass compared with op/op mice. Western blot
      analysis showed that several proteins that were markedly hyperphosphorylated on
      tyrosine residues were detected in the motheaten osteoclasts, including a novel
      126-kd phosphotyrosine protein. The marked hyperphosphorylation of a 126-kd
      protein in motheaten osteoclasts suggests that this protein depends on SHP-1 for
      dephosphorylation. These findings demonstrate that the decreased SHP-1 catalytic
      activity in me/me and mev/mev mice results in an increased population of
      activated osteoclasts and consequent reduction in bone density.

PMID- 10393857
TI  - Interleukin-18, interferon-gamma, IP-10, and Mig expression in Epstein-Barr virus
      induced infectious mononucleosis and posttransplant lymphoproliferative disease.
AB  - T cell immunodeficiency plays an important role in the pathogenesis of
      posttransplant lymphoproliferative disease (PTLD) by permitting the unbridled
      expansion of Epstein-Barr virus (EBV)-infected B lymphocytes. However, factors
      other than T cell function may contribute to PTLD pathogenesis because PTLD
      infrequently develops even in the context of severe T cell immunodeficiency, and
      athymic mice that are T-cell-immunodeficient can reject EBV-immortalized cells.
      Here we report that PTLD tissues express significantly lower levels of IL-18,
      interferon-gamma (IFN-gamma), Mig, and RANTES compared to lymphoid tissues
      diagnosed with acute EBV-induced infectious mononucleosis, as assessed by
      semiquantitative RT-PCR analysis. Other cytokines and chemokines are expressed at
      similar levels. Immunohistochemistry confirmed that PTLD tissues contain less IL
      18 and Mig protein than tissues with infectious mononucleosis. IL-18, primarily a
      monocyte product, promotes the secretion of IFN-gamma, which stimulates Mig and
      RANTES expression. Both IL-18 and Mig display antitumor activity in mice
      involving inhibition of angiogenesis. These results document greater expression
      of IL-18, IFN-gamma, Mig, and RANTES in lymphoid tissues with acute EBV-induced
      infectious mononucleosis compared to tissues with PTLD and raise the possibility
      that these mediators participate in critical host responses to EBV infection.

PMID- 10393858
TI  - Evaluation of the clonal relationship between primary and metastatic renal cell
      carcinoma by comparative genomic hybridization.
AB  - The outcome of patients with renal cell carcinoma is limited by the development
      of metastasis after nephrectomy. To evaluate the genetic basis underlying
      metastatic progression of human renal cell carcinoma in vivo, we performed a
      comparative genomic hybridization analysis in 32 clear-cell renal-cell carcinoma
      metastases. The most common losses involved chromosomes 3p (25%), 4q (28%), 6q
      (28%), 8p (31%), and 9p (47%). The most common gains were detected at 17q (31%)
      and Xq (28%). There was one high-level gene amplification at chromosome 11q22-23.
      The mean number of aberrations in lymph node (4.8 +/- 2.8) and lung metastases
      (6.2 +/- 4.0) was lower than in other hematogenous metastases (11.5 +/- 8.7, P <
      0.05), suggesting that hematogenous dissemination is linked to an acquisition of
      complex genomic alterations. As genetic differences between primary tumors and
      metastases give information on genetic changes that have contributed to the
      metastatic process, relative DNA sequence copy number changes in 19 matched tumor
      pairs were compared. Genomic changes, which frequently occurred in metastases but
      not in the corresponding primary tumor were losses of 8p and 9p and gains of 17q
      and Xq. An abnormal function of genes in these regions may contribute to the
      metastatic process. According to a statistical analysis of shared genetic changes
      in matched tumor pairs, a high probability of a common clonal progenitor was
      found in 11 of 19 patients (58%). Six metastases (32%) were genetically almost
      completely different from the primary, suggesting that detection of genomic
      alterations in primary tumors gives only a restricted view of the biological
      properties of metastatic renal cell carcinoma.

PMID- 10393859
TI  - Nitric oxide inhibits HIV tat-induced NF-kappaB activation.
AB  - To evaluate the roles of nitric oxide (NO) on human immunodeficiency virus (HIV)
      Tat-induced transactivation of HIV long terminal repeat (HIV-LTR), we examined
      the effect of NO in the regulation of nuclear factor (NF)-kappaB, a key
      transcription factor involved in HIV gene expression and viral replication. In
      the present study, we demonstrate that HIV Tat activates NF-kappaB and that this
      activation can be attenuated by endogenous or exogenous NO. Inhibition of
      endogenous NO production with the NO synthase (NOS) inhibitor L-NMMA causes a
      significant increase in Tat-induced NF-kappaB activity. In addition, NO
      attenuates signal-initiated degradation of IkappaBalpha, an intracellular
      inhibitor of NF-kappaB, and blocks the DNA binding activity of the NF-kappaB
      p50/p50 homodimer and p50/p65 heterodimer. To determine how NO is induced by HIV
      Tat, reverse transcription polymerase chain reaction was used to demonstrate the
      induction of NOS-2 and NOS-3 mRNA by Tat. Although a putative NF-kappaB binding
      site was identified in the -74 GGAGAGCCCCC -64 region of the NOS-3 gene promoter,
      gel mobility shift assays and site-directed mutation analyses suggest that the
      putative NF-kappaB site is not of primary importance. Rather, several Sp-1 sites
      adjoining the putative NF-kappaB binding site in the promoter region of NOS-3
      gene are required for the induction of NOS-3 gene expression by Tat.

PMID- 10393861
TI  - Preeclampsia is associated with widespread apoptosis of placental
      cytotrophoblasts within the uterine wall.
AB  - Preeclampsia is a serious pregnancy complication diagnosed by signs of widespread
      maternal endothelial dysfunction. In normal pregnancy, a subpopulation of
      placental cytotrophoblast stem cells executes an unusual differentiation program
      that leads to invasion of the uterus and its vasculature. This process attaches
      the conceptus to the uterine wall and starts the flow of maternal blood to the
      placenta. Preeclampsia is associated with abnormal cytotrophoblast
      differentiation, shallow invasion, and decreased blood flow to the placenta. To
      determine whether abnormal differentiation and/or hypoxia leads to
      cytotrophoblast apoptosis, we used the TUNEL (terminal deoxynucleotidyl
      transferase-mediated dUTP nick end labeling) method to label DNA strand breaks in
      tissue sections of the placenta and the uterine wall to which it attaches.
      Control samples (n = 9) showed almost no apoptosis, but in samples from patients
      with preeclampsia, 15-50% of the cytotrophoblasts that invaded the uterine wall
      were labeled (8/9 samples). These same cells failed to stain for Bcl-2, a
      survival factor normally expressed by trophoblasts in both the placenta and the
      uterine wall. Our results show that preeclampsia is associated with widespread
      apoptosis of cytotrophoblasts that invade the uterus. The magnitude of programmed
      cell death in this population may account for the sudden onset of symptoms in
      some patients, as well as the associated coagulopathies.

PMID- 10393860
TI  - Human cytomegalovirus infection decreases expression of thrombospondin-1
      independent of the tumor suppressor protein p53.
AB  - Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis. It has been shown
      that promoter sequences of the TSP-1 gene can be transactivated by the wild-type
      tumor suppressor protein p53. As human cytomegalovirus (HCMV) infection
      inactivates wild-type p53 of various cell types, we investigated whether HCMV
      infection is associated with reduced TSP-1 production. We found, in conjunction
      with accumulated p53, that TSP-1 mRNA and protein expression was significantly
      reduced in HCMV-infected cultured human fibroblasts. To determine whether the
      observed TSP-1 suppression depends on p53 inactivation, the p53-defective
      astrocytoma cell line U373MG was infected with HCMV. In these cells TSP-1
      expression was also significantly reduced by HCMV infection whereas expression of
      the p53 mutant variant remained unaltered. In both cell lines the decreased
      expression of TSP-1 mRNA occurred early after infection (4 hours), indicating
      that HCMV inhibits TSP-1 transcription during the immediate-early phase of
      infection before HCMV DNA replication. Inhibition of HCMV DNA synthesis by
      ganciclovir did not influence TSP-1 reduction whereas the antisense
      oligonucleotide ISIS 2922, complementary to HCMV immediate-early mRNA, completely
      prevented the HCMV-mediated TSP-1 suppression. These findings strongly suggest a
      novel role for HCMV in the modulation of angiogenesis due to p53-independent down
      regulation of TSP-1 expression.

PMID- 10393862
TI  - Development of hyperplasias, preneoplasias, and mammary tumors in MMTV-c-erbB-2
      and MMTV-TGFalpha transgenic rats.
AB  - Human cDNAs corresponding to two epidermal growth factor-related products that
      are overexpressed in human breast cancers, that for c-erbB-2 (HER-2) and for
      transforming growth factor alpha (TGFalpha), have been cloned downstream of the
      mouse mammary tumor virus (MMTV) long terminal repeat promoter and injected into
      the pronucleus of fertilized oocytes of Sprague-Dawley rats to produce transgenic
      offspring. Expression of the transgenic mRNAs is not detectable in mammary tissue
      from virgin transgenic rats but is detected in mammary tissue from certain lines
      of mid-pregnant transgenic rats. When two such lines of either type of transgenic
      rat are subjected to repeated cycles of pregnancy and lactation, they produce,
      primarily in the mammary glands, extensive pathologies, whereas virgin transgenic
      rats produce no such abnormalities. Multiparous transgenic female offspring from
      c-erbB-2-expressing lines develop a variety of focal hyperplastic and benign
      lesions that resemble lesions commonly found in human breasts. These lesions
      include lobular and ductal hyperplasia, fibroadenoma, cystic expansions, and
      papillary adenomas. More malignant lesions, including ductal carcinoma in situ
      and carcinoma, also develop stochastically at low frequency. The mammary glands
      of transgenic females invariably fail to involute fully after lactation. Similar
      phenotypes are observed in female MMTV-TGFalpha transgenic rats. In addition,
      multiparous TGFalpha-expressing female transgenics frequently develop severe
      pregnancy-dependent lactating hyperplasias as well as residual lobules of
      hyperplastic secretory epithelium and genuine lactating adenomas after weaning.
      These transgenic rat models confirm the conclusions reached in transgenic mice
      that overexpression of the c-erbB-2 and TGFalpha genes predisposes the mammary
      gland to stochastic tumor development.

PMID- 10393863
TI  - Development of keratoacanthomas and squamous cell carcinomas in transgenic
      rabbits with targeted expression of EJras oncogene in epidermis.
AB  - Activated ras genes have been frequently identified in both benign and malignant
      human tumors, including keratoacanthoma and squamous cell carcinoma. In this
      study, we developed two lines of transgenic rabbits in which the expression of
      EJras has been specifically targeted to the rabbit epidermal keratinocytes, using
      the upstream regulatory region of cottontail rabbit papillomavirus. All of the F1
      transgenic progenies developed multiple keratoacanthomas at about 3 days after
      birth. The rabbits developed an average of 20 tumors, which usually reached the
      size of approximately 1 cm in diameter and then spontaneously regressed in about
      2 months, similar to keratoacanthoma regression in humans. In addition, up to 18%
      of the rabbits then developed squamous cell carcinoma at about 5 months of age.
      The expression of EJras was detectable in all of the keratoacanthomas and
      squamous cell carcinomas. These results strongly support the involvement of the
      ras oncogene in both the initiation and regression of keratoacanthoma, and in the
      development of squamous cell carcinomas. These novel transgenic rabbits, with
      their consistent tumorigenic phenotype at an early age, high similarity to the
      human lesions, and easy accessibility for examination, manipulation, biopsy, and
      treatment, should provide a unique model system for studying ras activation
      related tumor initiation, regression, and progression, and for evaluating
      antitumor therapies.

PMID- 10393864
TI  - More than one way to see it move?

PMID- 10393866
TI  - Sorting out mutation rates.

PMID- 10393865
TI  - Postmitochondrial regulation of apoptosis during heart failure.

PMID- 10393867
TI  - Convicting a human tumor virus: guilt by association?

PMID- 10393868
TI  - Is most of neural plasticity in the thalamus cortical?

PMID- 10393870
TI  - The neurobiology of pain.

PMID- 10393871
TI  - John C. Liebeskind (1935-1997): a tribute.

PMID- 10393869
TI  - Benzene, NQO1, and genetic susceptibility to cancer.

PMID- 10393872
TI  - Sodium channels and pain.
AB  - Although it is well established that hyperexcitability and/or increased baseline
      sensitivity of primary sensory neurons can lead to abnormal burst activity
      associated with pain, the underlying molecular mechanisms are not fully
      understood. Early studies demonstrated that, after injury to their axons, neurons
      can display changes in excitability, suggesting increased sodium channel
      expression, and, in fact, abnormal sodium channel accumulation has been observed
      at the tips of injured axons. We have used an ensemble of molecular,
      electrophysiological, and pharmacological techniques to ask: what types of sodium
      channels underlie hyperexcitability of primary sensory neurons after injury? Our
      studies demonstrate that multiple sodium channels, with distinct
      electrophysiological properties, are encoded by distinct mRNAs within small
      dorsal root ganglion (DRG) neurons, which include nociceptive cells. Moreover,
      several DRG neuron-specific sodium channels now have been cloned and sequenced.
      After injury to the axons of DRG neurons, there is a dramatic change in sodium
      channel expression in these cells, with down-regulation of some sodium channel
      genes and up-regulation of another, previously silent sodium channel gene. This
      plasticity in sodium channel gene expression is accompanied by
      electrophysiological changes that poise these cells to fire spontaneously or at
      inappropriate high frequencies. Changes in sodium channel gene expression also
      are observed in experimental models of inflammatory pain. Thus, sodium channel
      expression in DRG neurons is dynamic, changing significantly after injury. Sodium
      channels within primary sensory neurons may play an important role in the
      pathophysiology of pain.

PMID- 10393873
TI  - A comparison of the potential role of the tetrodotoxin-insensitive sodium
      channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain.
AB  - Alterations in sodium channel expression and function have been suggested as a
      key molecular event underlying the abnormal processing of pain after peripheral
      nerve or tissue injury. Although the relative contribution of individual sodium
      channel subtypes to this process is unclear, the biophysical properties of the
      tetrodotoxin-resistant current, mediated, at least in part, by the sodium channel
      PN3 (SNS), suggests that it may play a specialized, pathophysiological role in
      the sustained, repetitive firing of the peripheral neuron after injury. Moreover,
      this hypothesis is supported by evidence demonstrating that selective "knock
      down" of PN3 protein in the dorsal root ganglion with specific antisense
      oligodeoxynucleotides prevents hyperalgesia and allodynia caused by either
      chronic nerve or tissue injury. In contrast, knock-down of NaN/SNS2 protein, a
      sodium channel that may be a second possible candidate for the tetrodotoxin
      resistant current, appears to have no effect on nerve injury-induced behavioral
      responses. These data suggest that relief from chronic inflammatory or
      neuropathic pain might be achieved by selective blockade or inhibition of PN3
      expression. In light of the restricted distribution of PN3 to sensory neurons,
      such an approach might offer effective pain relief without a significant side
      effect liability.

PMID- 10393874
TI  - Tetrodotoxin-resistant Na+ currents and inflammatory hyperalgesia.
AB  - Several mechanisms have been identified that may underlie inflammation-induced
      sensitization of high-threshold primary afferent neurons, including the
      modulation of voltage- and Ca2+-dependent ion channels and ion channels
      responsible for the production of generator potentials. One such mechanism that
      has recently received a lot of attention is the modulation of a tetrodotoxin
      (TTX)-resistant voltage-gated Na+ current. Evidence supporting a role for TTX
      resistant Na+ currents in the sensitization of primary afferent neurons and
      inflammatory hyperalgesia is reviewed. Such evidence is derived from studies on
      the distribution of TTX-resistant Na+ currents among primary afferent neurons and
      other tissues of the body that suggest that these currents are expressed only in
      a subpopulation of primary afferent neurons that are likely to be involved in
      nociception. Data from studies on the biophysical properties of these currents
      suggest that they are ideally suited to mediate the repetitive discharge
      associated with prolonged membrane depolarizations. Data from studies on the
      effects of inflammatory mediators and antinociceptive agents on TTX-resistant Na+
      currents suggest that modulation of these currents is an underlying mechanism of
      primary afferent neuron sensitization. In addition, the second-messenger pathways
      underlying inflammatory mediator-induced modulation of these currents appear to
      underlie inflammatory mediator-induced hyperalgesia. Finally, recent antisense
      studies have also yielded data supporting a role for TTX-resistant Na+ currents
      in inflammatory hyperalgesia. Although data from these studies are compelling,
      data presented at the Neurobiology of Pain colloquium raised a number of
      interesting questions regarding the role of TTX-resistant Na+ currents in
      inflammatory hyperalgesia; implications of three of these questions are
      discussed.

PMID- 10393876
TI  - Ion channels gated by heat.
AB  - All animals need to sense temperature to avoid hostile environments and to
      regulate their internal homeostasis. A particularly obvious example is that
      animals need to avoid damagingly hot stimuli. The mechanisms by which temperature
      is sensed have until recently been mysterious, but in the last couple of years,
      we have begun to understand how noxious thermal stimuli are detected by sensory
      neurons. Heat has been found to open a nonselective cation channel in primary
      sensory neurons, probably by a direct action. In a separate study, an ion channel
      gated by capsaicin, the active ingredient of chili peppers, was cloned from
      sensory neurons. This channel (vanilloid receptor subtype 1, VR1) is gated by
      heat in a manner similar to the native heat-activated channel, and our current
      best guess is that this channel is the molecular substrate for the detection of
      painful heat. Both the heat channel and VR1 are modulated in interesting ways.
      The response of the heat channel is potentiated by phosphorylation by protein
      kinase C, whereas VR1 is potentiated by externally applied protons. Protein
      kinase C is known to be activated by a variety of inflammatory mediators,
      including bradykinin, whereas extracellular acidification is characteristically
      produced by anoxia and inflammation. Both modulatory pathways are likely,
      therefore, to have important physiological correlates in terms of the enhanced
      pain (hyperalgesia) produced by tissue damage and inflammation. Future work
      should focus on establishing, in molecular terms, how a single ion channel can
      detect heat and how the detection threshold can be modulated by hyperalgesic
      stimuli.

PMID- 10393875
TI  - Calcium regulation of a slow post-spike hyperpolarization in vagal afferent
      neurons.
AB  - Activation of distinct classes of potassium channels can dramatically affect the
      frequency and the pattern of neuronal firing. In a subpopulation of vagal
      afferent neurons (nodose ganglion neurons), the pattern of impulse activity is
      effectively modulated by a Ca2+-dependent K+ current. This current produces a
      post-spike hyperpolarization (AHPslow) that plays a critical role in the
      regulation of membrane excitability and is responsible for spike-frequency
      accommodation in these neurons. Inhibition of the AHPslow by a number of
      endogenous autacoids (e.g., histamine, serotonin, prostanoids, and bradykinin)
      results in an increase in the firing frequency of vagal afferent neurons from
      <0.1 to >10 Hz. After a single action potential, the AHPslow in nodose neurons
      displays a slow rise time to peak (0.3-0.5 s) and a long duration (3-15 s). The
      slow kinetics of the AHPslow are due, in part, to Ca2+ discharge from an
      intracellular Ca2+-induced Ca2+ release (CICR) pool. Action potential-evoked Ca2+
      influx via either L or N type Ca2+ channels triggers CICR. Surprisingly, although
      L type channels generate 60% of action potential-induced CICR, only Ca2+ influx
      through N type Ca2+ channels can trigger the CICR-dependent AHPslow. These
      observations suggest that a close physical proximity exists between endoplasmic
      reticulum ryanodine receptors and plasma membrane N type Ca2+ channels and
      AHPslow potassium channels. Such an anatomical relation might be particularly
      beneficial for modulation of spike-frequency adaptation in vagal afferent
      neurons.

PMID- 10393877
TI  - Causalgia, pathological pain, and adrenergic receptors.
AB  - Control of expression of molecular receptors for chemical messengers and
      modulation of these receptors' activity are now established as ways to alter
      cellular reaction. This paper extends these mechanisms to the arena of
      pathological pain by presenting the hypothesis that increased expression of alpha
      adrenergic receptors in primary afferent neurons is part of the etiology of pain
      in classical causalgia. It is argued that partial denervation by lesion of
      peripheral nerve or by tissue destruction induces a change in peripheral
      nociceptors, making them excitable by sympathetic activity and adrenergic
      substances. This excitation is mediated by alpha-adrenergic receptors and has a
      time course reminiscent of experimental denervation supersensitivity. The change
      in neuronal phenotype is demonstrable after lesions of mixed nerves or of the
      sympathetic postganglionic supply. Similar partial denervations also produce a
      substantial increase in the number of dorsal root ganglion neurons evidencing the
      presence of alpha-adrenergic receptors. The hypothesis proposes the increased
      presence of alpha-adrenergic receptors in primary afferent neurons to result from
      an altered gene expression triggered by cytokines/growth factors produced by
      disconnection of peripheral nerve fibers from their cell bodies. These additional
      adrenergic receptors are suggested to make nociceptors and other primary afferent
      neurons excitable by local or circulating norepinephrine and epinephrine. For
      central pathways, the adrenergic excitation would be equivalent to that produced
      by noxious events and would consequently evoke pain. In support, evidence is
      cited for a form of denervation supersensitivity in causalgia and for increased
      expression of human alpha-adrenergic receptors after loss of sympathetic
      activity.

PMID- 10393878
TI  - Forebrain mechanisms of nociception and pain: analysis through imaging.
AB  - Pain is a unified experience composed of interacting discriminative, affective
      motivational, and cognitive components, each of which is mediated and modulated
      through forebrain mechanisms acting at spinal, brainstem, and cerebral levels.
      The size of the human forebrain in relation to the spinal cord gives anatomical
      emphasis to forebrain control over nociceptive processing. Human forebrain
      pathology can cause pain without the activation of nociceptors. Functional
      imaging of the normal human brain with positron emission tomography (PET) shows
      synaptically induced increases in regional cerebral blood flow (rCBF) in several
      regions specifically during pain. We have examined the variables of gender, type
      of noxious stimulus, and the origin of nociceptive input as potential
      determinants of the pattern and intensity of rCBF responses. The structures most
      consistently activated across genders and during contact heat pain, cold pain,
      cutaneous laser pain or intramuscular pain were the contralateral insula and
      anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the
      cerebellar vermis. These regions are commonly activated in PET studies of pain
      conducted by other investigators, and the intensity of the brain rCBF response
      correlates parametrically with perceived pain intensity. To complement the human
      studies, we developed an animal model for investigating stimulus-induced rCBF
      responses in the rat. In accord with behavioral measures and the results of human
      PET, there is a progressive and selective activation of somatosensory and limbic
      system structures in the brain and brainstem following the subcutaneous injection
      of formalin. The animal model and human PET studies should be mutually
      reinforcing and thus facilitate progress in understanding forebrain mechanisms of
      normal and pathological pain.

PMID- 10393879
TI  - A visceral pain pathway in the dorsal column of the spinal cord.
AB  - A limited midline myelotomy at T10 can relieve pelvic cancer pain in patients.
      This observation is explainable in light of strong evidence in support of the
      existence of a visceral pain pathway that ascends in the dorsal column (DC) of
      the spinal cord. In rats and monkeys, responses of neurons in the ventral
      posterolateral thalamic nucleus to noxious colorectal distention are dramatically
      reduced after a lesion of the DC at T10, but not by interruption of the
      spinothalamic tract. Blockade of transmission of visceral nociceptive signals
      through the rat sacral cord by microdialysis administration of morphine or 6
      cyano-7-nitroquinoxaline-2,3-dione shows that postsynaptic DC neurons in the
      sacral cord transmit visceral nociceptive signals to the gracile nucleus.
      Retrograde tracing studies in rats demonstrate a concentration of postsynaptic DC
      neurons in the central gray matter of the L6-S1 spinal segments, and anterograde
      tracing studies show that labeled axons ascend from this region to the gracile
      nucleus. A similar projection from the midthoracic spinal cord ends in the
      gracile and cuneate nuclei. Behavioral experiments demonstrate that DC lesions
      reduce the nocifensive responses produced by noxious stimulation of the pancreas
      and duodenum, as well as the electrophysiological responses of ventral
      posterolateral neurons to these stimuli. Repeated regional blood volume
      measurements were made in the thalamus and other brain structures in anesthetized
      monkeys in response to colorectal distention by functional MRI. Sham surgery did
      not reduce the regional blood volume changes, whereas the changes were eliminated
      by a DC lesion at T10.

PMID- 10393880
TI  - The spinal biology in humans and animals of pain states generated by persistent
      small afferent input.
AB  - Behavioral models indicate that persistent small afferent input, as generated by
      tissue injury, results in a hyperalgesia at the site of injury and a tactile
      allodynia in areas adjacent to the injury site. Hyperalgesia reflects a
      sensitization of the peripheral terminal and a central facilitation evoked by the
      persistent small afferent input. The allodynia reflects a central sensitization.
      The spinal pharmacology of these pain states has been defined in the
      unanesthetized rat prepared with spinal catheters for injection and dialysis.
      After tissue injury, excitatory transmitters (e.g., glutamate and substance P)
      acting though N-methyl-D-aspartate (NMDA) and neurokinin 1 receptors initiate a
      cascade that evokes release of (i) NO, (ii) cyclooxygenase products, and (iii)
      activation of several kinases. Spinal dialysis show amino acid and prostanoid
      release after cutaneous injury. Spinal neurokinin 1, NMDA, and non-NMDA receptors
      enhance spinal prostaglandin E2 release. Spinal prostaglandins facilitate release
      of spinal amino acids and peptides. Activation by intrathecal injection of
      receptors on spinal C fiber terminals (mu,/delta opiate, alpha2 adrenergic,
      neuropeptide Y) prevents release of primary afferent peptides and spinal amino
      acids and blocks acute and facilitated pain states. Conversely, consistent with
      their role in facilitated processing, NMDA, cyclooxygenase 2, and NO synthase
      inhibitors act to diminish only hyperalgesia. Importantly, spinal delivery of
      several of these agents diminishes human injury pain states. This efficacy
      emphasizes (i) the role of facilitated states in humans, (ii) shows the
      importance of spinal systems in human pain processing, and (iii) indicates that
      these preclinical mechanisms reflect processes that regulate the human pain
      experience.

PMID- 10393881
TI  - Supraspinal contributions to hyperalgesia.
AB  - Tissue injury is associated with sensitization of nociceptors and subsequent
      changes in the excitability of central (spinal) neurons, termed central
      sensitization. Nociceptor sensitization and central sensitization are considered
      to underlie, respectively, development of primary hyperalgesia and secondary
      hyperalgesia. Because central sensitization is considered to reflect plasticity
      at spinal synapses, the spinal cord has been the principal focus of studies of
      mechanisms of hyperalgesia. Not surprisingly, glutamate, acting at a spinal N
      methyl-D-aspartate (NMDA) receptor, has been implicated in development of
      secondary hyperalgesia associated with somatic, neural, and visceral structures.
      Downstream of NMDA receptor activation, spinal nitric oxide (NO.), protein kinase
      C, and other mediators have been implicated in maintaining such hyperalgesia.
      Accumulating evidence, however, reveals a significant contribution of supraspinal
      influences to development and maintenance of hyperalgesia. Spinal cord
      transection prevents development of secondary, but not primary, mechanical and/or
      thermal hyperalgesia after topical mustard oil application, carrageenan
      inflammation, or nerve-root ligation. Similarly, inactivation of the rostral
      ventromedial medulla (RVM) attenuates hyperalgesia and central sensitization in
      several models of persistent pain. Inhibition of medullary NMDA receptors or NO.
      generation attenuates somatic and visceral hyperalgesia. In support, topical
      mustard oil application or colonic inflammation increases expression of NO.
      synthase in the RVM. These data suggest a prominent role for the RVM in mediating
      the sensitization of spinal neurons and development of secondary hyperalgesia.
      Results to date suggest that peripheral injury and persistent input engage
      spinobulbospinal mechanisms that may be the prepotent contributors to central
      sensitization and development of secondary hyperalgesia.

PMID- 10393882
TI  - Neurotrophins and hyperalgesia.
AB  - Nerve growth factor (NGF), a member of the neurotrophin family, is crucial for
      survival of nociceptive neurons during development. Recently, it has been shown
      to play an important role in nociceptive function in adults. NGF is up-regulated
      after inflammatory injury of the skin. Administration of exogenous NGF either
      systemically or in the skin causes thermal hyperalgesia within minutes. Mast
      cells are considered important components in the action of NGF, because prior
      degranulation abolishes the early NGF-induced component of hyperalgesia.
      Substances degranulated by mast cells include serotonin, histamine, and NGF.
      Blockade of histamine receptors does not prevent NGF-induced hyperalgesia. The
      effects of blocking serotonin receptors are complex and cannot be interpretable
      uniquely as NGF losing its ability to induce hyperalgesia. To determine whether
      NGF has a direct effect on dorsal root ganglion neurons, we have begun to
      investigate the acute effects of NGF on capsaicin responses of small-diameter
      dorsal root ganglion cells in culture. NGF acutely conditions the response to
      capsaicin, suggesting that NGF may be important in sensitizing the response of
      sensory neurons to heat (a process that is thought to operate via the capsaicin
      receptor VR1). We also have found that ligands for the trkB receptor (brain
      derived neurotrophic factor and neurotrophin-4/5) acutely sensitize nociceptive
      afferents and elicit hyperalgesia. Because brain-derived neurotrophic factor is
      up-regulated in trkA positive cells after inflammatory injury and is transported
      anterogradely, we consider it to be a potentially important peripheral component
      involved in neurotrophin-induced hyperalgesia.

PMID- 10393884
TI  - Pain perception: is there a role for primary somatosensory cortex?
AB  - Anatomical, physiological, and lesion data implicate multiple cortical regions in
      the complex experience of pain. These regions include primary and secondary
      somatosensory cortices, anterior cingulate cortex, insular cortex, and regions of
      the frontal cortex. Nevertheless, the role of different cortical areas in pain
      processing is controversial, particularly that of primary somatosensory cortex
      (S1). Human brain-imaging studies do not consistently reveal pain-related
      activation of S1, and older studies of cortical lesions and cortical stimulation
      in humans did not uncover a clear role of S1 in the pain experience. Whereas
      studies from a number of laboratories show that S1 is activated during the
      presentation of noxious stimuli as well as in association with some pathological
      pain states, others do not report such activation. Several factors may contribute
      to the different results among studies. First, we have evidence demonstrating
      that S1 activation is highly modulated by cognitive factors that alter pain
      perception, including attention and previous experience. Second, the precise
      somatotopic organization of S1 may lead to small focal activations, which are
      degraded by sulcal anatomical variability when averaging data across subjects.
      Third, the probable mixed excitatory and inhibitory effects of nociceptive input
      to S1 could be disparately represented in different experimental paradigms.
      Finally, statistical considerations are important in interpreting negative
      findings in S1. We conclude that, when these factors are taken into account, the
      bulk of the evidence now strongly supports a prominent and highly modulated role
      for S1 cortex in the sensory aspects of pain, including localization and
      discrimination of pain intensity.

PMID- 10393883
TI  - Src, a molecular switch governing gain control of synaptic transmission mediated
      by N-methyl-D-aspartate receptors.
AB  - The N-methyl-D-aspartate (NMDA) receptor is a principal subtype of glutamate
      receptor mediating fast excitatory transmission at synapses in the dorsal horn of
      the spinal cord and other regions of the central nervous system. NMDA receptors
      are crucial for the lasting enhancement of synaptic transmission that occurs both
      physiologically and in pathological conditions such as chronic pain. Over the
      past several years, evidence has accumulated indicating that the activity of NMDA
      receptors is regulated by the protein tyrosine kinase, Src. Recently it has been
      discovered that, by means of up-regulating NMDA receptor function, activation of
      Src mediates the induction of the lasting enhancement of excitatory transmission
      known as long-term potentiation in the CA1 region of the hippocampus. Also, Src
      has been found to amplify the up-regulation of NMDA receptor function that is
      produced by raising the intracellular concentration of sodium. Sodium
      concentration increases in neuronal dendrites during high levels of firing
      activity, which is precisely when Src becomes activated. Therefore, we propose
      that the boost in NMDA receptor function produced by the coincidence of
      activating Src and raising intracellular sodium may be important in physiological
      and pathophysiological enhancement of excitatory transmission in the dorsal horn
      of the spinal cord and elsewhere in the central nervous system.

PMID- 10393885
TI  - Implications of immune-to-brain communication for sickness and pain.
AB  - This review presents a view of hyperalgesia and allodynia not typical of the
      field as a whole. That is, exaggerated pain is presented as one of many natural
      consequences of peripheral infection and injury. The constellation of changes
      that results from such immune challenges is called the sickness response. This
      sickness response results from immune-to-brain communication initiated by
      proinflammatory cytokines released by activated immune cells. In response to
      signals it receives from the immune system, the brain orchestrates the broad
      array of physiological, behavioral, and hormonal changes that comprise the
      sickness response. The neurocircuitry and neurochemistry of sickness-induced
      hyperalgesia are described. One focus of this discussion is on the evidence that
      spinal cord microglia and astrocytes are key mediators of sickness-induced
      hyperalgesia. Last, evidence is presented that hyperalgesia and allodynia also
      result from direct immune activation, rather than neural activation, of these
      same spinal cord glia. Such glial activation is induced by viruses such as HIV-1
      that are known to invade the central nervous system. Implications of exaggerated
      pain states created by peripheral and central immune activation are discussed.

PMID- 10393886
TI  - Brain-derived neurotrophic factor is an endogenous modulator of nociceptive
      responses in the spinal cord.
AB  - The primary sensory neurons that respond to noxious stimulation and project to
      the spinal cord are known to fall into two distinct groups: one sensitive to
      nerve growth factor and the other sensitive to glial cell-line-derived
      neurotrophic factor. There is currently considerable interest in the ways in
      which these factors may regulate nociceptor properties. Recently, however, it has
      emerged that another trophic factor-brain-derived neurotrophic factor (BDNF)-may
      play an important neuromodulatory role in the dorsal horn of the spinal cord.
      BDNF meets many of the criteria necessary to establish it as a
      neurotransmitter/neuromodulator in small-diameter nociceptive neurons. It is
      synthesized by these neurons and packaged in dense core vesicles in nociceptor
      terminals in the superficial dorsal horn. It is markedly up-regulated in
      inflammatory conditions in a nerve growth factor-dependent fashion. Postsynaptic
      cells in this region express receptors for BDNF. Spinal neurons show increased
      excitability to nociceptive inputs after treatment with exogenous BDNF. There are
      both electrophysiological and behavioral data showing that antagonism of BDNF at
      least partially prevents some aspects of central sensitization. Together, these
      findings suggest that BDNF may be released from primary sensory nociceptors with
      activity, particularly in some persistent pain states, and may then increase the
      excitability of rostrally projecting second-order systems. BDNF released from
      nociceptive terminals may thus contribute to the sensory abnormalities associated
      with some pathophysiological states, notably inflammatory conditions.

PMID- 10393887
TI  - The postnatal development of spinal sensory processing.
AB  - The mechanisms by which infants and children process pain should be viewed within
      the context of a developing sensory nervous system. The study of the
      neurophysiological properties and connectivity of sensory neurons in the
      developing spinal cord dorsal horn of the intact postnatal rat has shed light on
      the way in which the newborn central nervous system analyzes cutaneous innocuous
      and noxious stimuli. The receptive field properties and evoked activity of
      newborn dorsal horn cells to single repetitive and persistent innocuous and
      noxious inputs are developmentally regulated and reflect the maturation of
      excitatory transmission within the spinal cord. These changes will have an
      important influence on pain processing in the postnatal period.

PMID- 10393890
TI  - Does a neuroimmune interaction contribute to the genesis of painful peripheral
      neuropathies?
AB  - Painful peripheral neuropathies are precipitated by nerve injury from disease or
      trauma. All such injuries will be accompanied by an inflammatory reaction, a
      neuritis, that will mobilize the immune system. The role of the inflammation
      itself is difficult to determine in the presence of structural damage to the
      nerve. A method has been devised to produce a focal neuritis in the rat sciatic
      nerve that involves no more than trivial structural damage to the nerve. This
      experimental focal neuritis produces neuropathic pain sensations (heat- and
      mechano-hyperalgesia, and cold- and mechano-allodynia) in the ipsilateral hind
      paw. The abnormal pain sensations begin in 1-2 days and last for 4-6 days, with a
      subsequent return to normal. These results suggest that there is a neuroimmune
      interaction that occurs at the outset of nerve injury (and perhaps episodically
      over time in slow developing conditions like diabetic neuropathy) that produces
      neuropathic pain. The short duration of the phenomena suggest that they may prime
      the system for more slowly developing mechanisms of abnormal pain (e.g., ectopic
      discharge in axotomized primary afferent neurons) that underlie the chronic phase
      of painful neuropathy.

PMID- 10393888
TI  - Transcriptional and posttranslational plasticity and the generation of
      inflammatory pain.
AB  - Inflammatory pain manifests as spontaneous pain and pain hypersensitivity.
      Spontaneous pain reflects direct activation of specific receptors on nociceptor
      terminals by inflammatory mediators. Pain hypersensitivity is the consequence of
      early posttranslational changes, both in the peripheral terminals of the
      nociceptor and in dorsal horn neurons, as well as later transcription-dependent
      changes in effector genes, again in primary sensory and dorsal horn neurons. This
      inflammatory neuroplasticity is the consequence of a combination of activity
      dependent changes in the neurons and specific signal molecules initiating
      particular signal-transduction pathways. These pathways phosphorylate membrane
      proteins, changing their function, and activate transcription factors, altering
      gene expression. Two distinct aspects of sensory neuron function are changed as a
      result of these processes, basal sensitivity, or the capacity of peripheral
      stimuli to evoke pain, and stimulus-evoked hypersensitivity, the capacity of
      certain inputs to generate prolonged alterations in the sensitivity of the
      system. Posttranslational changes largely alter basal sensitivity.
      Transcriptional changes both potentiate the system and alter neuronal phenotype.
      Potentiation occurs as a result of the up-regulation in the dorsal root ganglion
      of centrally acting neuromodulators and simultaneously in the dorsal horn of
      their receptors. This means that the response to subsequent inputs is augmented,
      particularly those that induce stimulus-induced hypersensitivity. Alterations in
      phenotype includes the acquisition by A fibers of neurochemical features typical
      of C fibers, enabling these fibers to induce stimulus-evoked hypersensitivity,
      something only C fiber inputs normally can do. Elucidation of the molecular
      mechanisms responsible provides new opportunities for therapeutic approaches to
      managing inflammatory pain.

PMID- 10393889
TI  - Cellular mechanisms of neuropathic pain, morphine tolerance, and their
      interactions.
AB  - Compelling evidence has accumulated over the last several years from our
      laboratory, as well as others, indicating that central hyperactive states
      resulting from neuronal plastic changes within the spinal cord play a critical
      role in hyperalgesia associated with nerve injury and inflammation. In our
      laboratory, chronic constriction injury of the common sciatic nerve, a rat model
      of neuropathic pain, has been shown to result in activation of central nervous
      system excitatory amino acid receptors and subsequent intracellular cascades
      including protein kinase C translocation and activation, nitric oxide production,
      and nitric oxide-activated poly(ADP ribose) synthetase activation. Similar
      cellular mechanisms also have been implicated in the development of tolerance to
      the analgesic effects of morphine. A recently observed phenomenon, the
      development of "dark neurons," is associated with both chronic constriction
      injury and morphine tolerance. A site of action involved in both hyperalgesia and
      morphine tolerance is in the superficial laminae of the spinal cord dorsal horn.
      These observations suggest that hyperalgesia and morphine tolerance may be
      interrelated at the level of the superficial laminae of the dorsal horn by common
      neural substrates that interact at the level of excitatory amino acid receptor
      activation and subsequent intracellular events. The demonstration of
      interrelationships between neural mechanisms underlying hyperalgesia and morphine
      tolerance may lead to a better understanding of the neurobiology of these two
      phenomena in particular and pain in general. This knowledge may also provide a
      scientific basis for improved pain management with opiate analgesics.

PMID- 10393891
TI  - Distinct neurochemical features of acute and persistent pain.
AB  - To address the neurochemistry of the mechanisms that underlie the development of
      acute and persistent pain, our laboratory has been studying mice with deletions
      of gene products that have been implicated in nociceptive processing. We have
      recently raised mice with a deletion of the preprotachykinin-A gene, which
      encodes the peptides substance P (SP) and neurokinin A (NKA). These studies have
      identified a specific behavioral phenotype in which the animals do not detect a
      window of "pain" intensities; this window cuts across thermal, mechanical, and
      chemical modalities. The lowered thermal and mechanical withdrawal thresholds
      that are produced by tissue or nerve injury, however, were still present in the
      mutant mice. Thus, the behavioral manifestations of threshold changes in
      nociceptive processing in the setting of injury do not appear to require SP or
      NKA. To identify relevant neurochemical factors downstream of the primary
      afferent, we are also studying the dorsal horn second messenger systems that
      underlie the development of tissue and nerve injury-induced persistent pain
      states. We have recently implicated the gamma isoform of protein kinase C
      (PKCgamma) in the development of nerve injury-induced neuropathic pain. Acute
      pain processing, by contrast, is intact in the PKCgamma-null mice. Taken
      together, these studies emphasize that there is a distinct neurochemistry of
      acute and persistent pain. Persistent pain should be considered a disease state
      of the nervous system, not merely a prolonged acute pain symptom of some other
      disease conditions.

PMID- 10393893
TI  - The mu opiate receptor as a candidate gene for pain: polymorphisms, variations in
      expression, nociception, and opiate responses.
AB  - There are differences between human individuals and between mouse strains in
      levels of mu opiate receptor (muOR) expression, responses to painful stimuli, and
      responses to opiate drugs. One of the best candidates for contributing to these
      differences is variation at the muOR gene locus. Support for this idea comes from
      analyses of the human and murine muOR genes. Assessments of individual
      differences in human muOR expression add further support. Studies with mice,
      including knockout-transgenic, quantitative trait locus, and strain-comparison
      studies, also strongly support the possibility that muOR gene alleles would be
      strong candidates for contributing to individual differences in human nociception
      and opiate drug responses. This paper reviews current analyses of the murine and
      human muOR genes, their important variants, and correlations between these
      variants and opiate influences on pain.

PMID- 10393894
TI  - A continuous topological change during phase transitions in amphiphile/water
      systems.
AB  - Amphiphiles are molecules such as surfactants or lipids that have a polar head
      group (hydrophilic) attached to nonpolar hydrophobic alkyl chains. Because of
      this characteristic they self-assemble in water and give rise to a wide range of
      phases with different structures and properties. Aqueous dispersions of
      amphiphiles are present in every aspect of day-to-day life-e.g., forming
      biological cell membranes, stabilizing emulsified food, or being used as soap.
      Time-resolved x-ray diffraction has been used to study the
      hexadecylhexa(oxyethylene glycol) ether (C16EO6)/water system, which shows an
      intermediate phase whose structure depends on the thermal path between lamellar
      and hexagonal structures. Heating the hexagonal phase from room temperature leads
      to a lamellar phase via an Ia3d cubic structure. Cooling from the lamellar phase
      initially leads epitaxially to an intermediate Rm before the hexagonal phase is
      reached. Both cubic and Rm phases are formed by very similar rod units, but the
      overall structures differ because of their spatial distribution and they both
      bridge morphologically the hexagonal and lamellar phases. The Ia3d does so on
      heating, whereas the Rm does on cooling. The structural path during the phase
      transitions is determined by topological similarities between the forming phase
      and the one from which it originates. Although the estimated curvature energies
      for these two phases are similar, on cooling, kinetics and topology are initial
      factors determining the path for the phase transitions, whereas on heating energy
      is the dominant factor.

PMID- 10393895
TI  - Vortices in rotating superfluid 3He.
AB  - In this review we first present an introduction to 3He and to the ROTA
      collaboration under which most of the knowledge on vortices in superfluid 3He has
      been obtained. In the physics part, we start from the exceptional properties of
      helium at millikelvin temperatures. The dilemma of rotating superfluids is
      presented. In 4He and in 3He-B the problem is solved by nucleating an array of
      singular vortex lines. Their experimental detection in 3He by NMR is described
      next. The vortex cores in 3He-B have two different structures, both of which have
      spontaneously broken symmetry. A spin-mass vortex has been identified as well.
      This object is characterized by a flow of spins around the vortex line, in
      addition to the usual mass current. A great variety of vortices exist in the A
      phase of 3He; they are either singular or continuous, and their structure can be
      a line or a sheet or fill the whole liquid. Altogether seven different types of
      vortices have been detected in 3He by NMR. We also describe briefly other
      experimental methods that have been used by ROTA scientists in studying vortices
      in 3He and some important results thus obtained. Finally, we discuss the possible
      applications of experiments and theory of 3He to particle physics and cosmology.
      In particular, we report on experiments where superfluid 3He-B was heated locally
      by absorption of single neutrons. The resulting events can be used to test
      theoretical models of the Big Bang at the beginning of our universe.

PMID- 10393892
TI  - The genetic mediation of individual differences in sensitivity to pain and its
      inhibition.
AB  - The underlying bases of the considerable interindividual variability in pain
      related traits are starting to be revealed. Although the relative importance of
      genes versus experience in human pain perception remains unclear, rodent
      populations display large and heritable differences in both nociceptive and
      analgesic sensitivity. The identification and characterization of particularly
      divergent populations provides a powerful initial step in the genetic analysis of
      pain, because these models can be exploited to identify genes contributing to the
      behavior-level variability. Ultimately, DNA sequence differences representing the
      differential alleles at pain-relevant genes can be identified. Thus, by using a
      combination of "top-down" and "bottom-up" strategies, we are now able to
      genetically dissect even complex biological traits like pain. The present review
      summarizes the current progress toward these ends in both humans and rodents.

PMID- 10393896
TI  - A dimeric mutant of human pancreatic ribonuclease with selective cytotoxicity
      toward malignant cells.
AB  - Monomeric human pancreatic RNase, devoid of any biological activity other than
      its RNA degrading ability, was engineered into a dimeric protein with a cytotoxic
      action on mouse and human tumor cells, but lacking any appreciable toxicity on
      mouse and human normal cells. This dimeric variant of human pancreas RNase
      selectively sensitizes to apoptotic death cells derived from a human thyroid
      tumor. Because of its selectivity for tumor cells, and because of its human
      origin, this protein represents a potentially very attractive, novel tool for
      anticancer therapy.

PMID- 10393897
TI  - Protective immunity against murine hepatitis virus (MHV) induced by intranasal or
      subcutaneous administration of hybrids of tobacco mosaic virus that carries an
      MHV epitope.
AB  - Hybrids of tobacco mosaic virus (TMV) were constructed with the use of fusion to
      the coat protein peptides of 10 or 15 amino acids, containing the 5B19 epitope
      from the spike protein of murine hepatitis virus (MHV) and giving rise to TMV
      5B19 and TMV-5B19L, respectively. The TMV hybrids were propagated in tobacco
      plants, and the virus particles were purified. Immunogold labeling, with the use
      of the monoclonal MAb5B19 antibody, showed specific decoration of hybrid TMV
      particles, confirming the expression and display of the MHV epitope on the
      surface of the TMV. Mice were immunized with purified hybrid viruses after
      several regimens of immunization. Mice that received TMV-5B19L intranasally
      developed serum IgG and IgA specific for the 5B19 epitope and for the TMV coat
      protein. Hybrid TMV-5B19, administered by subcutaneous injections, elicited high
      titers of serum IgG that was specific for the 5B19 epitope and for coat protein,
      but IgA that was specific against 5B19 was not observed. Mice that were immunized
      with hybrid virus by subcutaneous or intranasal routes of administration survived
      challenge with a lethal dose (10 x LD50) of MHV strain JHM, whereas mice
      administered wild-type TMV died 10 d post challenge. Furthermore, there was a
      positive correlation between the dose of administered immunogen and protection
      against MHV infection. These studies show that TMV can be an effective vaccine
      delivery vehicle for parenteral and mucosal immunization and for protection from
      challenge with viral infection.

PMID- 10393898
TI  - The gamma-subunit rotation and torque generation in F1-ATPase from wild-type or
      uncoupled mutant Escherichia coli.
AB  - The rotation of the gamma-subunit has been included in the binding-change
      mechanism of ATP synthesis/hydrolysis by the proton ATP synthase (FOF1). The
      Escherichia coli ATP synthase was engineered for rotation studies such that its
      ATP hydrolysis and synthesis activity is similar to that of wild type. A
      fluorescently labeled actin filament connected to the gamma-subunit of the F1
      sector rotated on addition of ATP. This progress enabled us to analyze the
      gammaM23K (the gamma-subunit Met-23 replaced by Lys) mutant, which is defective
      in energy coupling between catalysis and proton translocation. We found that the
      F1 sector produced essentially the same frictional torque, regardless of the
      mutation. These results suggest that the gammaM23K mutant is defective in the
      transformation of the mechanical work into proton translocation or vice versa.

PMID- 10393899
TI  - Structure of the subunit c oligomer in the F1Fo ATP synthase: model derived from
      solution structure of the monomer and cross-linking in the native enzyme.
AB  - The structure of the subunit c oligomer of the H+-transporting ATP synthase of
      Escherichia coli has been modeled by molecular dynamics and energy minimization
      calculations from the solution structure of monomeric subunit c and 21
      intersubunit distance constraints derived from cross-linking of subunits. Subunit
      c folds in a hairpin-like structure with two transmembrane helices. In the c12
      oligomer model, the subunits pack to form a compact hollow cylinder with an outer
      diameter of 55-60 A and an inner space with a minimal diameter of 11-12 A.
      Phospholipids are presumed to pack in the inner space in the native membrane. The
      transmembrane helices pack in two concentric rings with helix 1 inside and helix
      2 outside. The calculations strongly favor this structure versus a model with
      helix 2 inside and helix 1 outside. Asp-61, the H+-transporting residue, packs
      toward the center of the four transmembrane helices of two interacting subunits.
      From this position at the front face of one subunit, the Asp-61 carboxylate lies
      proximal to side chains of Ala-24, Ile-28, and Ala-62, projecting from the back
      face of a second subunit. These interactions were predicted from previous
      mutational analyses. The packing supports the suggestion that a c-c dimer is the
      functional unit. The positioning of the Asp-61 carboxyl in the center of the
      interacting transmembrane helices, rather than at the periphery of the cylinder,
      has important implications regarding possible mechanisms of H+-transport-driven
      rotation of the c oligomer during ATP synthesis.

PMID- 10393900
TI  - Recruitment of cyclin T1/P-TEFb to an HIV type 1 long terminal repeat promoter
      proximal RNA target is both necessary and sufficient for full activation of
      transcription.
AB  - Transcriptional activation of the HIV type 1 (HIV-1) long terminal repeat (LTR)
      promoter element by the viral Tat protein is an essential step in the HIV-1 life
      cycle. Tat function is mediated by the TAR RNA target element encoded within the
      LTR and is known to require the recruitment of a complex consisting of Tat and
      the cyclin T1 (CycT1) component of positive transcription elongation factor b (P
      TEFb) to TAR. Here, we demonstrate that both TAR and Tat become entirely
      dispensable for activation of the HIV-1 LTR promoter when CycT1/P-TEFb is
      artificially recruited to a heterologous promoter proximal RNA target. The level
      of activation observed was indistinguishable from the level induced by Tat and
      was neither inhibited nor increased when Tat was expressed in trans. Activation
      by artificially recruited CycT1 depended on the ability to bind the CDK9
      component of P-TEFb. In contrast, although binding to both Tat and TAR was
      essential for the ability of CycT1 to act as a Tat cofactor, these interactions
      became dispensable when CycT1 was directly recruited to the LTR. Importantly,
      activation of the LTR both by Tat and by directly recruited CycT1 was found to be
      at the level of transcription elongation. Together, these data demonstrate that
      recruitment of CycT1/P-TEFb to the HIV-1 LTR is fully sufficient to activate this
      promoter element and imply that the sole role of the Tat/TAR axis in viral
      transcription is to permit the recruitment of CycT1/P-TEFb.

PMID- 10393901
TI  - Lovastatin-mediated G1 arrest is through inhibition of the proteasome,
      independent of hydroxymethyl glutaryl-CoA reductase.
AB  - In this paper we present the finding that lovastatin arrests cells by inhibiting
      the proteasome, which results in the accumulation of p21 and p27, leading to G1
      arrest. Lovastatin is an inhibitor of hydroxymethyl glutaryl (HMG)-CoA reductase,
      the rate-limiting enzyme in cholesterol synthesis. Previously, we reported that
      lovastatin can be used to arrest cultured cells in the G1 phase of the cell
      cycle, resulting in the stabilization of the cyclin-dependent kinase inhibitors
      (CKIs) p21 and p27. In this report we show that this stabilization of p21 and p27
      may be the result of a previously unknown function of the pro-drug, beta-lactone
      ring form of lovastatin to inhibit the proteasome degradation of these CKIs. The
      lovastatin mixture used in this study is 80% open-ring form and 20% pro-drug,
      beta-lactone form. We show that while the lovastatin open-ring form and
      pravastatin (a lovastatin analogue, 100% open ring) inhibit the HMG-CoA reductase
      enzyme, lovastatin pro-drug inhibits the proteasome but does not inhibit HMG-CoA
      reductase. In addition, many of the properties of proteasome inhibition by the
      pro-drug are the same as the specific proteasome inhibitor lactacystin. Lastly,
      mevalonate (used to rescue cells from lovastatin arrest) unexpectedly abrogates
      the lactacystin and lovastatin pro-drug inhibition of the proteasome. Mevalonate
      increases the activity of the proteasome, which results in degradation of the
      CKIs, allowing lovastatin- and lactacystin-arrested cells to resume cell
      division. The lovastatin-mediated inhibition of the proteasome suggests a unique
      mechanism for the chemopreventative effects of this agent seen in human cancer.

PMID- 10393902
TI  - RNase P RNAs from some Archaea are catalytically active.
AB  - The RNA subunits of RNase Ps of Archaea and eukaryotes have been thought to
      depend fundamentally on protein for activity, unlike those of Bacteria that are
      capable of efficient catalysis in the absence of protein. Although the eukaryotic
      RNase P RNAs are quite different than those of Bacteria in both sequence and
      structure, the archaeal RNAs generally contain the sequences and structures of
      the bacterial, phylogenetically conserved catalytic core. A spectrum of archaeal
      RNase P RNAs were therefore tested for activity in a wide range of conditions.
      Many remain inactive in ionically extreme conditions, but catalytic activity
      could be detected from those of the methanobacteria, thermococci, and
      halobacteria. Chimeric holoenzymes, reconstituted from the Methanobacterium RNase
      P RNA and the Bacillus subtilis RNase P protein subunits, were functional at low
      ionic strength. The properties of the archaeal RNase P RNAs (high ionic-strength
      requirement, low affinity for substrate, and catalytic reconstitution by
      bacterial RNase P protein) are similar to synthetic RNase P RNAs that contain all
      of the catalytic core of the bacterial RNA but lack phylogenetically variable,
      stabilizing elements.

PMID- 10393903
TI  - Peroxynitrite-mediated modification of proteins at physiological carbon dioxide
      concentration: pH dependence of carbonyl formation, tyrosine nitration, and
      methionine oxidation.
AB  - The ability of peroxynitrite to modify amino acid residues in glutamine
      synthetase (GS) and BSA is greatly influenced by pH and CO2. At physiological
      concentrations of CO2 (1.3 mM), the generation of carbonyl groups (0.2-0.4
      equivalents/subunit) is little affected by pH over the range of 7.2-9.0, but, in
      the absence of CO2, carbonyl formation increases (from 0.1- 1.2
      equivalents/subunit) as the pH is raised from 7.2 to 10.5. This increase is
      attributable, in part but not entirely, to the increase in peroxynitrite (PN)
      stability with increasing pH. Of several amino acid polymers tested, only those
      containing lysine residues yielded carbonyl derivatives. In contrast, the
      nitration of tyrosine residues of both GS and BSA at pH 7.5 almost completely
      depends on the presence of CO2. However, the pH profiles of tyrosine nitration in
      GS and BSA are not the same. With both proteins, nitration decreases
      approximately 65% with increasing pH over the range of 7.2-8.4, but, then in the
      case of GS only, there is a 3.4-fold increase in the level of nitration over the
      range pH 8.4-8.8. The oxidation of methionine residues in both proteins and in
      the tripeptide Ala-Met-Ala was inhibited by CO2 at both high and low pH values.
      These results emphasize the importance of controlling the pH and CO2
      concentrations in studies involving PN and indicate that PN is not likely to
      contribute appreciably to carbonyl formation or oxidation of methionine residues
      of proteins at physiological pH and CO2 concentrations.

PMID- 10393904
TI  - A protein-protein interaction map of yeast RNA polymerase III.
AB  - The structure of the yeast RNA polymerase (pol) III was investigated by
      exhaustive two-hybrid screening using a library of random genomic fragments fused
      to the Gal4 activation domain. This procedure allowed us to identify contacts
      between individual polypeptides, localize the contact domains, and deduce a
      protein-protein interaction map of the multisubunit enzyme. In all but one case,
      pol III subunits were able to interact in vivo with one or sometimes two partner
      subunits of the enzyme or with subunits of TFIIIC. Four subunits that are common
      to pol I, II, and III (ABC27, ABC14.5, ABC10alpha, and ABC10beta), two that are
      common to pol I and III (AC40 and AC19), and one pol III-specific subunit (C11)
      can associate with defined regions of the two large subunits. These regions
      overlapped with highly conserved domains. C53, a pol III-specific subunit,
      interacted with a 37-kDa polypeptide that copurifies with the enzyme and
      therefore appears to be a unique pol III subunit (C37). Together with parallel
      interaction studies based on dosage-dependent suppression of conditional mutants,
      our data suggest a model of the pol III preinitiation complex.

PMID- 10393905
TI  - Kinase interaction domain of kinase-associated protein phosphatase, a
      phosphoprotein-binding domain.
AB  - Kinase-associated protein phosphatase interacts specifically with plant receptor
      like protein kinases. This interaction is thought to be a key step in signal
      perception and transduction. The minimal kinase interaction (KI) domain of kinase
      associated protein phosphatase was mapped to a 119-aa segment spanning residues
      180 to 298. A forkhead-associated (FHA) homology region resides in this minimal
      KI domain. Site-directed mutagenesis of four highly conserved sites in this FHA
      homology region abolishes the KI domain's interaction with receptor-like protein
      kinases, indicating that the FHA region is essential for binding. Serial deletion
      analysis indicates that 30 aa on each side of the FHA region are also needed for
      binding; this minimal functional unit is designated as the KI domain. Kinetic
      studies using surface plasmon resonance indicate that the binding between the KI
      domain and receptor-like protein kinases has a dissociation constant (KD) of
      about 25-100 nM, which is similar to the binding affinity of two other well
      characterized phosphorylation-dependent protein-binding domains (14-3-3 and Src
      homology 2) and their high-affinity phosphopeptide ligands.

PMID- 10393906
TI  - The in situ spatial arrangement of the influenza A virus matrix protein M1
      assessed by tritium bombardment.
AB  - Intact influenza A virions were bombarded with thermally activated tritium atoms,
      and the intramolecular distribution of the label in the matrix protein M1 was
      analyzed to determine the in situ accessibility of its tryptic fragments. These
      data were combined with the previously reported x-ray crystal structure of the M1
      fragment 2-158 [Sha, B. & Luo, M. (1997) Nat. Struct. Biol. 4, 239-244] and the
      predicted topology of the C domain (159-252) to propose a model of M1 arrangement
      in the virus particle.

PMID- 10393907
TI  - NIH shift in flavin-dependent monooxygenation: mechanistic studies with 2
      aminobenzoyl-CoA monooxygenase/reductase.
AB  - The flavoprotein 2-aminobenzoyl-CoA monooxygenase/reductase from the eubacterium
      Azoarcus evansii catalyzes the dearomatization of 2-aminobenzoyl-CoA. The
      reaction consists in an O2-dependent monooxygenation at the benzene position 5,
      which is followed immediately by an NADH-dependent hydrogenation of the
      intermediate at the same catalytic locus. The reaction was studied by 1H, 2H, and
      13C NMR spectroscopy of the products. The main product was characterized as 5-oxo
      2-aminocyclohex-1-ene-1-carboxyl-CoA by two-dimensional NMR spectroscopy. Thus,
      [5-2H]2-aminobenzoyl-CoA was converted into [6-2H]5-oxo-2-aminocyclohex-1-ene-1
      carboxyl-CoA, indicating a 5 --> 6 shift of the [5-2H] label. Label from NAD2H
      was transferred to the 3 position of the cyclic eneamine, whereas label from
      solvent D2O was incorporated into the 4 and the 6 positions of 5-oxo-2
      aminocyclohex-1-ene-1-carboxyl-CoA. The labeling pattern is compatible with the
      monooxygenation proceeding via what is formally an NIH shift, yielding 5-oxo-2
      aminocyclohex-1, 3-diene-1-carboxyl-CoA as a protein-bound intermediate. It is
      suggested that this shift in flavin-dependent monooxygenation may have general
      validity.

PMID- 10393908
TI  - Adhesive properties of the isolated amino-terminal domain of platelet
      glycoprotein Ibalpha in a flow field.
AB  - We have examined the interaction between the amino-terminal domain of platelet
      glycoprotein (GP) Ibalpha and immobilized von Willebrand Factor (vWF) under flow
      conditions in the absence of other components of the GP Ib-IX-V complex. Latex
      beads were coated with a recombinant fragment containing GP Ibalpha residues 1
      302, either with normal sequence or with the single G233V substitution that
      causes enhanced affinity for plasma vWF in platelet-type pseudo-von-Willebrand
      disease. Beads coated with native fragment adhered to vWF in a manner comparable
      to platelets, showing surface translocation that reflected the transient nature
      of the bonds formed. Thus, the GP Ibalpha extracellular domain is necessary and
      sufficient for interacting with vWF under high shear stress. Beads coated with
      the mutated fragment became tethered to vWF in greater number and had lower
      velocity of translocation than beads coated with the normal counterpart,
      suggesting that the G233V mutation lowers the rate of bond dissociation. Our
      findings define an approach for studying the biomechanical properties of the GP
      Ibalpha-vWF bond and suggest that this interaction is tightly regulated to allow
      rapid binding at sites of vascular injury, while permitting the concurrent
      presence of receptor and ligand in the circulation.

PMID- 10393909
TI  - Selective interaction of the C2 domains of phospholipase C-beta1 and -beta2 with
      activated Galphaq subunits: an alternative function for C2-signaling modules.
AB  - Phospholipase C (PLC)-beta1 and PLC-beta2 are regulated by the Gq family of
      heterotrimeric G proteins and contain C2 domains. These domains are Ca2+-binding
      modules that serve as membrane-attachment motifs in a number of signal
      transduction proteins. To determine the role that C2 domains play in PLC-beta1
      and PLC-beta2 function, we measured the binding of the isolated C2 domains to
      membrane bilayers. We found, unexpectedly, that these modules do not bind to
      membranes but they associate strongly and specifically to activated [guanosine 5'
      [gamma-thio]triphosphate (GTP[gammaS])-bound] Galphaq subunits. The C2 domain of
      PLC-beta1 effectively suppressed the activation of the intact isozyme by
      Galphaq(GTP[gammaS]), indicating that the C2-Galphaq interaction may be
      physiologically relevant. C2 affinity for Galphaq(GTP[gammaS]) was reduced when
      Galphaq was deactivated to the GDP-bound state. Binding to activated Galphai1
      subunits or to Gbetagamma subunits was not detected. Also, Galphaq(GTP[gammaS])
      failed to associate with the C2 domain of PLC-delta, an isozyme that is not
      activated by Galphaq. These results indicate that the C2 domains of PLC-beta1 and
      PLC-beta2 provide a surface to which Galphaq subunits can dock, leading to
      activation of the native protein.

PMID- 10393910
TI  - Identification of the endonuclease domain encoded by R2 and other site-specific,
      non-long terminal repeat retrotransposable elements.
AB  - The non-long terminal repeat (LTR) retrotransposon, R2, encodes a sequence
      specific endonuclease responsible for its insertion at a unique site in the 28S
      rRNA genes of arthropods. Although most non-LTR retrotransposons encode an
      apurinic-like endonuclease upstream of a common reverse transcriptase domain, R2
      and many other site-specific non-LTR elements do not (CRE1 and 2, SLACS, CZAR,
      Dong, R4). Sequence comparison of these site-specific elements has revealed that
      the region downstream of their reverse transcriptase domain is conserved and
      shares sequence features with various prokaryotic restriction endonucleases. In
      particular, these non-LTR elements have a Lys/Arg-Pro-Asp-X12-14aa-Asp/Glu motif
      known to lie near the scissile phosphodiester bonds in the protein-DNA complexes
      of restriction enzymes. Site-directed mutagenesis of the R2 protein was used to
      provide evidence that this motif is also part of the active site of the
      endonuclease encoded by this element. Mutations of this motif eliminate both DNA
      cleavage activities of the R2 protein: first-strand cleavage in which the exposed
      3' end is used to prime reverse transcription of the RNA template and second
      strand cleavage, which occurs after reverse transcription. The general
      organization of the R2 protein appears similar to the type IIS restriction
      enzyme, FokI, in which specific DNA binding is controlled by a separate domain
      located amino terminal to the cleavage domain. Previous phylogenetic analysis of
      their reverse transcriptase domains has indicated that the non-LTR elements
      identified here as containing restriction-like endonucleases are the oldest
      lineages of non-LTR elements, suggesting a scenario for the evolution of non-LTR
      elements.

PMID- 10393911
TI  - A more unified picture for the thermodynamics of nucleic acid duplex melting: a
      characterization by calorimetric and volumetric techniques.
AB  - We use a combination of calorimetric and volumetric techniques to detect and to
      characterize the thermodynamic changes that accompany helix-to-coil transitions
      for five polymeric nucleic acid duplexes. Our calorimetric measurements reveal
      that melting of the duplexes is accompanied by positive changes in heat capacity
      (DeltaCP) of similar magnitude, with an average DeltaCP value of 64.6 +/- 21.4
      cal deg-1 mol-1. When this heat capacity value is used to compare significantly
      different transition enthalpies (DeltaHo) at a common reference temperature,
      Tref, we find DeltaHTref for duplex melting to be far less dependent on duplex
      type, base composition, or base sequence than previously believed on the basis of
      the conventional assumption of a near-zero value for DeltaCP. Similarly, our
      densimetric and acoustic measurements reveal that, at a given temperature, all
      the AT- and AU-containing duplexes studied here melt with nearly the same volume
      and compressibility changes. In the aggregate, our results, in conjunction with
      literature data, suggest a more unified picture for the thermodynamics of nucleic
      acid duplex melting. Specifically, when compared at a common temperature, the
      apparent large differences present in the literature for the transition
      enthalpies of different duplexes become much more compressed, and the melting of
      all-AT- and all-AU-containing duplexes exhibits similar volume and
      compressibility changes despite differences in sequence and conformation. Thus,
      insofar as thermodynamic properties are concerned, when comparing duplexes, the
      temperature under consideration is as important as, if not more important than,
      the duplex type, the base composition, or the base sequence. This general
      behavior has significant implications for our basic understanding of the forces
      that stabilize nucleic acid duplexes. This behavior also is of practical
      significance in connection with the use of thermodynamic databases for designing
      probes and for assessing the affinity and specificity associated with
      hybridization-based protocols used in a wide range of sequencing, diagnostic, and
      therapeutic applications.

PMID- 10393912
TI  - Functional interaction between human topoisomerase IIalpha and retinoblastoma
      protein.
AB  - DNA topoisomerase II-an essential nuclear enzyme in DNA replication and
      transcription, chromatin segregation, and cell cycle progression-is also a target
      of clinically useful anticancer drugs. Preliminary observations of a positive
      correlation between the expression of topoisomerase (topo) IIalpha and the
      retinoblastoma protein (Rb) in a series of rhabdomyosarcoma cells prompted us to
      ask whether these two proteins interact in vivo. Using human rhabdomyosarcoma and
      leukemic cell lines, we found a physical association between topo IIalpha and Rb
      protein by reciprocal immunoprecipitation and immunoblotting, in which topo
      IIalpha appeared to interact primarily with the underphosphorylated form of Rb.
      Experiments with truncated glutathione S-transferase-Rb fusion proteins and
      nuclear extracts of Rh1 rhabdomyosarcoma cells indicated that topo IIalpha binds
      avidly to the A/B pocket domain of Rb, which contains the intact spacer amino
      acid sequence. To determine whether this interaction has functional consequences
      in vivo, we expressed wild-type and mutant Rb in human cervical carcinoma cells
      lacking functional Rb. Wild-type, but not mutant, Rb inhibited topo II activity
      in nuclear extracts of these transfected cells. Moreover, purified wild-type Rb
      inhibited the activity of purified human topo IIalpha, indicating a direct
      interaction between these two proteins. We conclude that topo IIalpha associates
      physically with Rb in interactions that appear to have functional significance.

PMID- 10393913
TI  - Design, total chemical synthesis, and binding properties of a [Leu-91-N1-methyl-7
      azaTrp]Ras-binding domain of c-Raf-1.
AB  - The Ras-binding domain (RBD) of c-Raf-1 has been synthesized chemically, taking
      advantage of the chemical ligation of two peptide fragments of the protein. This
      procedure allowed incorporation of an unnatural amino acid (N1-methyl-7
      azatryptophan) at position 91 of RBD, producing a protein with fluorescent
      properties distinct from and distinguishable from those of proteins containing
      the natural fluorophore tryptophan. The resulting protein was shown to interact
      with Ras in a manner that was almost indistinguishable from that of unmodified
      RBD based on transient kinetic monitoring of the binding event. Modified RBD
      containing the L-isomer of the unnatural amino acid or its racemic D,L mixture
      appeared to interact identically with Ras. The approach demonstrates a general
      procedure for the introduction of unnatural amino acids that can be used for
      monitoring protein-protein interactions and for the introduction of an unnatural
      backbone structure at strategic positions.

PMID- 10393914
TI  - Single-nucleotide polymorphisms can cause different structural folds of mRNA.
AB  - Single-nucleotide polymorphisms (SNPs) are the most common type of genetic
      variation in man. Genes containing one or more SNPs can give rise to two or more
      allelic forms of mRNAs. These mRNA variants may possess different biological
      functions as a result of differences in primary or higher order structures that
      interact with other cellular components. Here we report the observation of marked
      differences in mRNA secondary structure associated with SNPs in the coding
      regions of two human mRNAs: alanyl tRNA synthetase and replication protein A, 70
      kDa subunit (RPA70). Enzymatic probing of SNP-containing allelic fragments of the
      mRNAs revealed pronounced allelic differences in cleavage pattern at sites 14 or
      18 nt away from the SNP, suggesting that a single-nucleotide variation can give
      rise to different mRNA folds. By using phosphorothioate oligodeoxyribonucleotides
      complementary to the region of different allelic structures in the RPA70 mRNA,
      but not extending to the SNP itself, we find that the SNP exerts an allele
      specific effect on the accessibility of its flanking site in the endogenous human
      RPA70 mRNA. This further supports the allele-specific structural features
      identified by enzymatic probing. These results demonstrate the contribution of
      common genetic variation to structural diversity of mRNA and suggest a broader
      role than previously thought for the effects of SNPs on mRNA structure and,
      ultimately, biological function.

PMID- 10393915
TI  - Structure of the soluble methane monooxygenase regulatory protein B.
AB  - The soluble methane monooxygenase (sMMO; EC 1.14.13.25) from the
      pseudothermophile Methylococcus capsulatus (Bath) is a three-component enzyme
      system that catalyzes the selective oxidation of methane to methanol. We have
      used NMR spectroscopy to produce a highly refined structure of MMOB, the 16-kDa
      regulatory protein of this system. This structure has a unique and intricate fold
      containing seven beta-strands forming two beta-sheets oriented perpendicular to
      each other and bridged by three alpha-helices. The rate and efficiency of the
      methane hydroxylation by sMMO depend on dynamic binding interactions of the
      hydroxylase with the reductase and regulatory protein components during
      catalysis. We have monitored by NMR the binding of MMOB to the hydroxylase in the
      presence and absence of the reductase. The results of these studies provide
      structural insight into how the regulatory protein interacts with the
      hydroxylase.

PMID- 10393916
TI  - Self-assembly of helical ribbons.
AB  - The self-assembly of helical ribbons is examined in a variety of multicomponent
      enantiomerically pure systems that contain a bile salt or a nonionic detergent, a
      phosphatidylcholine or a fatty acid, and a steroid analog of cholesterol. In
      almost all systems, two different pitch types of helical ribbons are observed:
      high pitch, with a pitch angle of 54 +/- 2 degrees, and low pitch, with a pitch
      angle of 11 +/- 2 degrees. Although the majority of these helices are right
      handed, a small proportion of left-handed helices is observed. Additionally, a
      third type of helical ribbon, with a pitch angle in the range 30-47 degrees, is
      occasionally found. These experimental findings suggest that the helical ribbons
      are crystalline rather than liquid crystal in nature and also suggest that
      molecular chirality may not be the determining factor in helix formation. The
      large yields of helices produced will permit a systematic investigation of their
      individual kinetic evolution and their elastic moduli.

PMID- 10393917
TI  - Folding of a pressure-denatured model protein.
AB  - The noncovalent complex formed by the association of two fragments of
      chymotrypsin inhibitor-2 is reversibly denatured by pressure in the absence of
      chemical denaturants. On pressure release, the complex returned to its original
      conformation through a biphasic reaction, with first-order rate constants of
      0.012 and 0.002 s-1, respectively. The slowest phase arises from an
      interconversion of the pressure-denatured state, as revealed by double pressure
      jump experiments. Below 5 microM, the process was concentration dependent with a
      second-order rate constant of 1,700 s-1 M-1. Fragment association at atmospheric
      pressure showed a similar break in the order of the reaction above 5 microM, but
      both first- and second-order folding/association rates are 2.5 times faster than
      those for the refolding of the pressure-denatured state. Although the folding
      rates of the intact protein and the association of the fragments displayed
      nonlinear Eyring behavior for the temperature dependence, refolding of the
      pressure-denatured complex showed a linear response. The negligible heat capacity
      of activation reflects a balance of minimal change in the burial of residues from
      the pressure-denatured state to the transition state. If we add the higher energy
      barrier in the refolding of the pressure-denatured state, the rate differences
      must lie in the structure of this state, which has to undergo a structural
      rearrangement. This clearly differs from the conformational flexibility of the
      isolated fragments or the largely unfolded denatured state of the intact protein
      in acid and provides insight into denatured states of proteins under folding
      conditions.

PMID- 10393918
TI  - Atomic levers control pyranose ring conformations.
AB  - Atomic force microscope manipulations of single polysaccharide molecules have
      recently expanded conformational chemistry to include force-driven transitions
      between the chair and boat conformers of the pyranose ring structure. We now
      expand these observations to include chair inversion, a common phenomenon in the
      conformational chemistry of six-membered ring molecules. We demonstrate that by
      stretching single pectin molecules (1 --> 4-linked alpha-D-galactouronic acid
      polymer), we could change the pyranose ring conformation from a chair to a boat
      and then to an inverted chair in a clearly resolved two-step conversion: 4C1
      right arrow over left arrow boat right arrow over left arrow 1C4. The two-step
      extension of the distance between the glycosidic oxygen atoms O1 and O4
      determined by atomic force microscope manipulations is corroborated by ab initio
      calculations of the increase in length of the residue vector O1O4 on chair
      inversion. We postulate that this conformational change results from the torque
      generated by the glycosidic bonds when a force is applied to the pectin molecule.
      Hence, the glycosidic bonds act as mechanical levers, driving the conformational
      transitions of the pyranose ring. When the glycosidic bonds are equatorial (e),
      the torque is zero, causing no conformational change. However, when the
      glycosidic bond is axial (a), torque is generated, causing a rotation around C--
      C bonds and a conformational change. This hypothesis readily predicts the number
      of transitions observed in pyranose monomers with 1a-4a linkages (two), 1a-4e
      (one), and 1e-4e (none). Our results demonstrate single-molecule mechanochemistry
      with the capability of resolving complex conformational transitions.

PMID- 10393919
TI  - Native-state hydrogen-exchange studies of a fragment complex can provide
      structural information about the isolated fragments.
AB  - Ordered protein complexes are often formed from partially ordered fragments that
      are difficult to structurally characterize by conventional NMR and
      crystallographic techniques. We show that concentration-dependent hydrogen
      exchange studies of a fragment complex can provide structural information about
      the solution structures of the isolated fragments. This general methodology can
      be applied to any bimolecular or multimeric system. The experimental system used
      here consists of Ribonuclease S, a complex of two fragments of Ribonuclease A.
      Ribonuclease S and Ribonuclease A have identical three-dimensional structures but
      exhibit significant differences in their dynamics and stability. We show that the
      apparent large dynamic differences between Ribonuclease A and Ribonuclease S are
      caused by small amounts of free fragments in equilibrium with the folded complex,
      and that amide exchange rates in Ribonuclease S can be used to determine
      corresponding rates in the isolated fragments. The studies suggest that folded
      RNase A and the RNase S complex exhibit very similar dynamic behavior. Thus
      cleavage of a protein chain at a single site need not be accompanied by a large
      increase in flexibility of the complex relative to that of the uncleaved protein.

PMID- 10393920
TI  - Role of the nonheme Fe(II) center in the biosynthesis of the plant hormone
      ethylene.
AB  - The final step of ethylene biosynthesis in plants is catalyzed by the enzyme 1
      aminocyclopropane-1-carboxylic acid (ACC) oxidase (ACCO). In addition to ACC,
      Fe(II), O2, CO2, and ascorbate are required for in vitro enzyme activity. Direct
      evidence for the role of the Fe(II) center in the recombinant avocado ACCO has
      now been obtained through formation of enzyme.(substrate or cofactor).NO
      complexes. These NO adducts convert the normally EPR-silent ACCO complexes into
      EPR-active species with structural properties similar to those of the
      corresponding O2 complexes. It is shown here that the ternary Fe(II)ACCO.ACC.NO
      complex is readily formed, but no Fe(II)ACCO.ascorbate.NO complex could be
      observed, suggesting that ascorbate and NO are mutually exclusive in the active
      site. The binding modes of ACC and the structural analog alanine specifically
      labeled with 15N or 17O were examined by using Q-band electron nuclear double
      resonance (ENDOR). The data indicate that these molecules bind directly to the
      iron through both the alpha-amino and alpha-carboxylate groups. These
      observations are inconsistent with the currently favored mechanism for ACCO, in
      which it is proposed that both ascorbate and O2 bind to the iron as a step in O2
      activation. We propose a different mechanism in which the iron serves instead to
      simultaneously bind ACC and O2, thereby fixing their relative orientations and
      promoting electron transfer between them to initiate catalysis.

PMID- 10393921
TI  - Validation of the single-stranded channel conformation of gramicidin A by solid
      state NMR.
AB  - The monovalent cation selective channel formed by a dimer of the polypeptide
      gramicidin A has a single-stranded, right-handed helical motif with 6.5 residues
      per turn forming a 4-A diameter pore. The structure has been refined to high
      resolution against 120 orientational constraints obtained from samples in a
      liquid-crystalline phase lipid bilayer. These structural constraints from solid
      state NMR reflect the orientation of spin interaction tensors with respect to a
      unique molecular axis. Because these tensors are fixed in the molecular frame and
      because the samples are uniformly aligned with respect to the magnetic field of
      the NMR spectrometer, each constraint restricts the orientation of internuclear
      vectors with respect to the laboratory frame of reference. The structural motif
      of this channel has been validated, and the high-resolution structure has led to
      precise models for cation binding, cation selectivity, and cation conductance
      efficiency. The structure is consistent with the electrophysiological data and
      numerous biophysical studies. Contrary to a recent claim [Burkhart, B. M., Li,
      N., Langs, D. A., Pangborn, W. A. & Duax, W. L. (1998) Proc. Natl. Acad. Sci. USA
      95, 12950-12955], the solid-state NMR constraints for gramicidin A in a lipid
      bilayer are not consistent with an x-ray crystallographic structure for
      gramicidin having a double-stranded, right-handed helix with 7.2 residues per
      turn.

PMID- 10393922
TI  - RecA polymerization on double-stranded DNA by using single-molecule manipulation:
      the role of ATP hydrolysis.
AB  - The polymerization of RecA on individual double-stranded DNA molecules is
      studied. A linear DNA (lambda DNA, 48.5 Kb), anchored at one end to a cover glass
      and at the other end to an optically trapped 3-micrometers diameter polystyrene
      bead, serves as a template. The elongation caused by RecA assembly is measured in
      the presence of ATP and ATP[gammaS]. By using force extension and hydrodynamic
      recoil, a value of the persistence length of the RecA-DNA complex is obtained. In
      the presence of ATP, the polymer length is unstable, first growing to saturation
      and then decreasing. This suggests a transient dynamics of association and
      dissociation for RecA on a double-stranded DNA, the process being controlled by
      ATP hydrolysis. Part of this dynamics is suppressed in the presence of
      ATP[gammaS], leading to a stabilized RecA-DNA complex. A one-dimensional
      nucleation and growth model is presented that may account for the protein
      assembly.

PMID- 10393924
TI  - Arrangement of radial actin bundles in the growth cone of Aplysia bag cell
      neurons shows the immediate past history of filopodial behavior.
AB  - Filopodia that protrude forward from the lamellipodium, located at the leading
      edge of a neuronal growth cone, are needed to guide the extension of a nerve
      cell. At the core of each filopodium an actin bundle forms and grows into the
      lamellipodium. By using kymographs of time-lapse polarized light images we
      examined the relationship between the behavior of the filopodia, the actin
      bundles immediately proximal to the filopodia, and the shapes and composition of
      actin bundles in the whole lamellipodium. We find that the shapes of actin
      bundles, such as tilt, fork, and fused zones, originate at the leading edge and
      are surprisingly well preserved during retrograde transport of the actin
      cytoskeleton in the whole lamellipodium. The number of filaments that make up the
      radial actin bundles, as displayed by their birefringence retardation, also is
      preserved during retrograde flow over a distance of 4-8 microm from the leading
      edge into the lamellipodium. Thus, the disposition of the actin bundles in the
      lamellipodium frozen at any time point preserves and portrays a history of the
      past behavior of actin bundles proximal to the filopodia and the behavior of the
      filopodia themselves. These findings suggest that the arrangement of actin
      bundles in static image records, such as electron or fluorescence micrographs of
      fixed and stained specimens, can in fact reveal the sequence of the past history
      of filopodial behavior and the generation, density, fusion, etc. of the filaments
      in the actin bundles.

PMID- 10393923
TI  - Five-transmembrane domains appear sufficient for a G protein-coupled receptor:
      functional five-transmembrane domain chemokine receptors.
AB  - The putative seven-transmembrane (TM) domains have been the structural hallmark
      for the superfamily of heterotrimeric G protein-coupled receptors (GPCRs) that
      regulate a variety of cellular functions by mediating a large number of
      extracellular signals. Five-TM GPCR mutants of chemokine receptor CCR5 and CXCR4,
      the N-terminal segment of which connected directly to TM3 as a result of a
      deletion of TM1-2 and the first intracellular and extracellular loops, have been
      obtained in this study. Laser confocal microscopy and flow cytometry analysis
      revealed that these five-TM mutant GPCRs were expressed stably on the cell
      surface after transfection into human embryonic kidney 293 cells. The five-TM
      CCR5 and CXCR4 functioned as normal chemokine receptors in mediating chemokine
      stimulated chemotaxis, Ca2+ influx, and activation of pertussis toxin-sensitive G
      proteins. Like the wild-type GPCRs, the five-TM mutant receptors also underwent
      agonist-dependent internalization and desensitization and were subjected to
      regulation by GPCR kinases and arrestins. Our study indicates that five-TM
      domains, at least in the case of CCR5 and CXCR4, appear to meet the minimum
      structural requirements for a functional GPCR and suggests possible existence of
      functional five-TM GPCRs in nature during evolution.

PMID- 10393925
TI  - Endogenous presenilin 1 redistributes to the surface of lamellipodia upon
      adhesion of Jurkat cells to a collagen matrix.
AB  - Most familial early-onset Alzheimer's disease cases are caused by mutations in
      the presenilin 1 (PS1) gene. Subcellular localization of the endogenous PS1 is
      essential for understanding its function, interactions with proteins, and role in
      Alzheimer's disease. Although numerous studies revealed predominant localization
      of PS1 to endoplasmic reticulum and Golgi, there are conflicting reports on the
      localization of PS1 to the cell surface. We found that endogenous PS1 is highly
      expressed in T lymphocytes (Jurkat cells). Using a variety of methods, we present
      evidence that endogenous PS1 is localized to the cell surface in addition to
      intracellular membrane compartments. Moreover, PS1 appeared in high levels on the
      surface of lamellipodia upon adhesion of the cells to a collagen matrix. The
      redistribution of PS1 in adhered cells was strikingly similar to that of the well
      characterized adhesion protein CD44. Cell surface PS1 formed complexes in vivo
      with actin-binding protein filamin (ABP-280), which is known to form bridges
      between cell surface receptors and cytoskeleton and mediate cell adhesion and
      cell motility. Taken together, our results suggest a role of PS1 in cell adhesion
      and/or cell-matrix interaction.

PMID- 10393926
TI  - Ran-independent nuclear import of cyclin B1-Cdc2 by importin beta.
AB  - Mitosis is triggered in vertebrate cells by the cyclin B1-Cdc2 complex. The
      activation of this complex at the end of G2 phase is accompanied by its
      translocation from the cytoplasm to the nucleus. We used digitonin-permeabilized
      human cells to analyze the mechanism by which cyclin B1-Cdc2 is imported into the
      nucleus. Cyclin B1-Cdc2 import was not blocked by inhibitors of the importin
      alpha-dependent import pathway or by dominant negative versions of the GTPase Ran
      or importin beta. However, the rate of cyclin B1 import was decreased by
      immunodepletion of importin beta from cytosol. Purified importin beta promoted
      cyclin B1 import in the absence of cytosol or Ran and in the presence of the
      dominant negative Ran mutant. We conclude that cyclin B1 import is mediated by an
      unusual importin beta-dependent mechanism that does not require Ran.

PMID- 10393927
TI  - O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase.
AB  - The rapid response to hypoxia in the pulmonary artery (PA), carotid body, and
      ductus arteriosus is partially mediated by O2-responsive K+ channels. K+ channels
      in PA smooth muscle cells (SMCs) are inhibited by hypoxia, causing membrane
      depolarization, increased cytosolic calcium, and hypoxic pulmonary
      vasoconstriction. We hypothesize that the K+ channels are not themselves "O2
      sensors" but rather respond to the reduced redox state created by hypoxic
      inhibition of candidate O2 sensors (NADPH oxidase or the mitochondrial electron
      transport chain). Both pathways shuttle electrons from donors, down a redox
      gradient, to O2. Hypoxia inhibits these pathways, decreasing radical production
      and causing cytosolic accumulation of unused, reduced, freely diffusible electron
      donors. PASMC K+ channels are redox responsive, opening when oxidized and closing
      when reduced. Inhibitors of NADPH oxidase (diphenyleneiodonium) and mitochondrial
      complex 1 (rotenone) both inhibit PASMC whole-cell K+ current but lack the
      specificity to identify the O2-sensor pathway. We used mice lacking the gp91
      subunit of NADPH oxidase [chronic granulomatous disease (CGD) mice] to assess the
      hypothesis that NADPH oxidase is a PA O2-sensor. In wild-type lungs, gp91 phox
      and p22 phox subunits are present (relative expression: macrophages > airways and
      veins > PASMCs). Deletion of gp91 phox did not alter p22 phox expression but
      severely inhibited activated O2 species production. Nonetheless, hypoxia caused
      identical inhibition of whole-cell K+ current (in PASMCs) and hypoxic pulmonary
      vasoconstriction (in isolated lungs) from CGD vs. wild-type mice. Rotenone
      vasoconstriction was preserved in CGD mice, consistent with a role for the
      mitochondrial electron transport chain in O2 sensing. NADPH oxidase, though a
      major source of lung radical production, is not the pulmonary vascular O2 sensor
      in mice.

PMID- 10393928
TI  - Time-resolved analysis and visualization of dynamic processes in living cells.
AB  - Recent development of in vivo microscopy techniques, including green fluorescent
      proteins, has allowed the visualization of a wide range of dynamic processes in
      living cells. For quantitative and visual interpretation of such processes, new
      concepts for time-resolved image analysis and continuous time-space visualization
      are required. Here, we describe a versatile and fully automated approach
      consisting of four techniques, namely highly sensitive object detection, fuzzy
      logic-based dynamic object tracking, computer graphical visualization, and
      measurement in time-space. Systematic model simulations were performed to
      evaluate the reliability of the automated object detection and tracking method.
      To demonstrate potential applications, the method was applied to the analysis of
      secretory membrane traffic and the functional dynamics of nuclear compartments
      enriched in pre-mRNA splicing factors.

PMID- 10393929
TI  - Bax-induced cell death in tobacco is similar to the hypersensitive response.
AB  - Bax, a death-promoting member of the Bcl-2 family of proteins, triggered cell
      death when expressed in plants from a tobacco mosaic virus vector. Analysis of
      Bax deletion mutants demonstrated a requirement for the BH1 and BH3 domains in
      promoting rapid cell death, whereas deletion of the carboxyl-terminal
      transmembrane domain completely abolished the lethality of Bax in plants. The
      phenotype of cell death induced by Bax closely resembled the hypersensitive
      response induced by wild-type tobacco mosaic virus in tobacco plants carrying the
      N gene. The cell death-promoting function of Bax in plants correlated with
      accumulation of the defense-related protein PR1, suggesting Bax activated an
      endogenous cell-death program in plants. In support of this view, both N gene-
      and Bax-mediated cell death was blocked by okadaic acid, an inhibitor of protein
      phosphatase activity. The ability of Bax to induce cell death and a defense
      reaction in plants suggests that some features of animal and plant cell death
      processes may be shared.

PMID- 10393930
TI  - Nephrin is specifically located at the slit diaphragm of glomerular podocytes.
AB  - We describe here the size and location of nephrin, the first protein to be
      identified at the glomerular podocyte slit diaphragm. In Western blots, nephrin
      antibodies generated against the two terminal extracellular Ig domains of
      recombinant human nephrin recognized a 180-kDa protein in lysates of human
      glomeruli and a 150-kDa protein in transfected COS-7 cell lysates. In
      immunofluorescence, antibodies to this transmembrane protein revealed reactivity
      in the glomerular basement membrane region, whereas the podocyte cell bodies
      remained negative. In immunogold-stained thin sections, nephrin label was found
      at the slit between podocyte foot processes. The congenital nephrotic syndrome of
      the Finnish type (NPHS1), a disease in which the nephrin gene is mutated, is
      characterized by massive proteinuria already in utero and lack of slit diaphragm
      and foot processes. These features, together with the now demonstrated
      localization of nephrin to the slit diaphragm area, suggests an essential role
      for this protein in the normal glomerular filtration barrier. A zipper-like model
      for nephrin assembly in the slit diaphragm is discussed, based on the present and
      previous data.

PMID- 10393931
TI  - p200 ARF-GEP1: a Golgi-localized guanine nucleotide exchange protein whose Sec7
      domain is targeted by the drug brefeldin A.
AB  - The drug brefeldin A (BFA) disrupts protein traffic and Golgi morphology by
      blocking activation of ADP ribosylation factors (ARFs) through an unknown
      mechanism. Here, we investigated the cellular localization and BFA sensitivity of
      human p200 ARF-GEP1 (p200), a ubiquitously expressed guanine nucleotide exchange
      factor of the Sec7 domain family. Multiple tagged forms of the full-length
      polypeptide localized to tight ribbon-like perinuclear structures that overlapped
      with the Golgi marker mannosidase II and were distinct from the pattern observed
      with ERGIC53/58. Analysis of several truncated forms mapped the Golgi
      localization signal to the N-terminal third of p200. BFA treatment of transiently
      or stably transfected cells resulted in the redistribution of Golgi markers and
      in loss of cell viability, thereby indicating that overproduction of p200 may not
      be sufficient to overcome the toxic effect. A 39-kDa fragment spanning the Sec7
      domain catalyzed loading of guanosine 5'-[gamma-thio]triphosphate onto class I
      ARFs and displayed clear sensitivity to BFA. Kinetic analysis established that
      BFA did not compete with ARF for interaction with p200 but, rather, acted as an
      uncompetitive inhibitor that only targeted the p200-ARF complex with an
      inhibition constant of 7 microM. On the basis of these results, we propose that
      accumulation of an abortive p200-ARF complex in the presence of BFA likely leads
      to disruption of Golgi morphology. p200 mapped to chromosome 8q13, 3.56 centirays
      from WI-6151, and database searches revealed the presence of putative isoforms
      whose inhibition may account for the effects of BFA on various organelles.

PMID- 10393932
TI  - Nuclear and cell membrane effects contribute independently to the induction of
      apoptosis in human cells exposed to UVB radiation.
AB  - UVB-induced DNA damage is a crucial event in UVB-mediated apoptosis. On the other
      hand, UVB directly activates death receptors on the cell surface including CD95,
      implying that UVB-induced apoptosis can be initiated at the cell membrane through
      death receptor clustering. This study was performed to measure the relative
      contribution of nuclear and membrane effects in UVB-induced apoptosis of the
      human epithelial cell line HeLa. UVB-mediated DNA damage can be reduced by
      treating cells with liposomes containing the repair enzyme photolyase followed by
      exposure to photoreactivating light. Addition of photolyase followed by
      photoreactivation after UVB reduced the apoptosis rate significantly, whereas
      empty liposomes had no effect. Likewise, photoreactivating treatment did not
      affect apoptosis induced by the ligand of CD95, CD95L. UVB exposure at 4 degrees
      C, which prevents CD95 clustering, also reduced the apoptosis rate, but to a
      lesser extent. When cells were exposed to UVB at 4 degrees C and treated with
      photolyase plus photoreactivating light, UVB-induced apoptosis was almost
      completely prevented. Inhibition of caspase-3, a downstream protease in the CD95
      signaling pathway, blocked both CD95L and UVB-induced apoptosis, whereas blockage
      of caspase-8, the most proximal caspase, inhibited CD95L-mediated apoptosis
      completely, but UVB-induced apoptosis only partially. Although according to these
      data nuclear effects seem to be slightly more effective in mediating UVB-induced
      apoptosis than membrane events, both are necessary for the complete apoptotic
      response. Thus, this study shows that nuclear and membrane effects are not
      mutually exclusive and that both components contribute independently to a
      complete response to UVB.

PMID- 10393933
TI  - Nuclear localization of the p120(ctn) Armadillo-like catenin is counteracted by a
      nuclear export signal and by E-cadherin expression.
AB  - The Armadillo protein p120(ctn) associates with the cytoplasmic domain of
      cadherins and accumulates at cell-cell junctions. Particular Armadillo proteins
      such as beta-catenin and plakophilins show a partly nuclear location, suggesting
      gene-regulatory activities. For different human E-cadherin-negative carcinoma
      cancer cell lines we found expression of endogenous p120(ctn) in the nucleus.
      Expression of E-cadherin directed p120(ctn) out of the nucleus. Previously, we
      reported that the human p120(ctn) gene might encode up to 32 protein isoforms as
      products of alternative splicing. Overexpression of p120(ctn) isoforms B in
      various cell lines resulted in cytoplasmic immunopositivity but never in nuclear
      staining. In contrast, upon expression of p120(ctn) cDNAs lacking exon B, the
      isoforms were detectable within both nuclei and cytoplasm. A putative nuclear
      export signal (NES) with a characteristic leucine-rich motif is encoded by exon
      B. This sequence element was shown to be required for nuclear export and to
      function autonomously when fused to a carrier protein and microinjected into cell
      nuclei. Moreover, the NES function of endogenously or exogenously expressed
      p120(ctn) isoforms B was sensitive to the nuclear export inhibitor leptomycin B.
      Expression of exogenous E-cadherin down-regulated nuclear p120(ctn) whereas
      activation of protein kinase C increased the level of nuclear p120(ctn). These
      results reveal molecular mechanisms controlling the subcellular distribution of
      p120(ctn).

PMID- 10393934
TI  - Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19)
      gene.
AB  - It is well established that spermatogenesis is controlled by gonadotrophins and
      testosterone. However, a role for estrogens in male reproduction recently was
      suggested in adult mice deficient in estrogen receptor alpha. These mice became
      infertile primarily because of an interruption of fluid reabsorption by the
      efferent ductules of the epididymis, thus leading to a disruption of the
      seminiferous epithelium [Hess, R. A., Bunick, D., Lee, K. H., Bahr, J., Taylor,
      J. A., Korach, K. S., and Lubahn, D. B. (1997) Nature (London) 390, 509-512].
      Despite the demonstration of the aromatase enzyme, which converts androgens to
      estrogens, and estrogen receptors within the rodent seminiferous epithelium, the
      role of aromatase and estrogen in germ cell development is unknown. We have
      investigated spermatogenesis in mice that lack aromatase because of the targeted
      disruption of the cyp19 gene (ArKO). Male mice deficient in aromatase were
      initially fertile but developed progressive infertility, until their ability to
      sire pups was severely impaired. The mice deficient in aromatase developed
      disruptions to spermatogenesis between 4.5 months and 1 year, despite no
      decreases in gonadotrophins or androgens. Spermatogenesis primarily was arrested
      at early spermiogenic stages, as characterized by an increase in apoptosis and
      the appearance of multinucleated cells, and there was a significant reduction in
      round and elongated spermatids, but no changes in Sertoli cells and earlier germ
      cells. In addition, Leydig cell hyperplasia/hypertrophy was evident, presumably
      as a consequence of increased circulating luteinizing hormone. Our findings
      indicate that local expression of aromatase is essential for spermatogenesis and
      provide evidence for a direct action of estrogen on male germ cell development
      and thus fertility.

PMID- 10393936
TI  - The agricultural pathology of ant fungus gardens.
AB  - Gardens of fungus-growing ants (Formicidae: Attini) traditionally have been
      thought to be free of microbial parasites, with the fungal mutualist maintained
      in nearly pure "monocultures." We conducted extensive isolations of "alien"
      (nonmutualistic) fungi from ant gardens of a phylogenetically representative
      collection of attine ants. Contrary to the long-standing assumption that gardens
      are maintained free of microbial pathogens and parasites, they are in fact host
      to specialized parasites that are only known from attine gardens and that are
      found in most attine nests. These specialized garden parasites, belonging to the
      microfungus genus Escovopsis (Ascomycota: anamorphic Hypocreales), are
      horizontally transmitted between colonies. Consistent with theory of virulence
      evolution under this mode of pathogen transmission, Escovopsis is highly virulent
      and has the potential for rapid devastation of ant gardens, leading to colony
      mortality. The specialized parasite Escovopsis is more prevalent in gardens of
      the more derived ant lineages than in gardens of the more "primitive" (basal) ant
      lineages. Because fungal cultivars of derived attine lineages are asexual clones
      of apparently ancient origin whereas cultivars of primitive ant lineages were
      domesticated relatively recently from free-living sexual stocks, the increased
      virulence of pathogens associated with ancient asexual cultivars suggests an
      evolutionary cost to cultivar clonality, perhaps resulting from slower
      evolutionary rates of cultivars in the coevolutionary race with their pathogens.

PMID- 10393935
TI  - DIO-1 is a gene involved in onset of apoptosis in vitro, whose misexpression
      disrupts limb development.
AB  - The DIO-1 (death inducer-obliterator-1) gene, identified by differential display
      PCR in pre-B WOL-1 cells undergoing apoptosis, encodes a putative transcription
      factor whose protein has two Zn finger motifs, nuclear localization signals, and
      transcriptional activation domains, expressed in the limb interdigitating webs
      during development. When overexpressed, DIO-1 translocates to the nucleus and
      activates apoptosis in vitro. Nuclear translocation as well as induction of
      apoptosis are lost after deletion of the nuclear localization sequences. DIO-1
      apoptotic induction is prevented by caspase inhibitors and Bcl-2 overexpression.
      The in vivo role of DIO-1 was studied by misexpressing DIO-1 during chicken limb
      development. The most frequently observed phenotype was an arrest in limb
      outgrowth, an effect that correlates with the inhibition of mesodermal and
      ectodermal genes involved in this process. Our data demonstrate the ability of
      DIO-1 to trigger apoptotic processes in vitro and suggest a role for this gene in
      cell death during development.

PMID- 10393937
TI  - Influence of drinking water and diet on the stable-hydrogen isotope ratios of
      animal tissues.
AB  - Despite considerable interest in using stable-hydrogen isotope ratio (deltaD)
      measurements in ecological research, it was previously unknown whether hydrogen
      derived from drinking water, in addition to that derived from diet, contributed
      to the nonexchangeable hydrogen in animal tissues. We raised four experimental
      groups of quail (Coturnix coturnix japonica) from hatch on two isotopically
      distinct diets (mean nonexchangeable deltaD: -146 and -60 per thousand, Vienna
      Standard Mean Ocean Water Standard) and drinking waters (mean deltaD: -130 and
      +196 per thousand, Vienna Standard Mean Ocean Water Standard). Here we show that
      both dietary and drinking water hydrogen are incorporated into nonexchangeable
      hydrogen in both metabolically active (i.e., muscle, liver, blood, fat) and
      inactive (i.e., feather, nail) tissues. Approximately 20% of hydrogen in
      metabolically active quail tissues and 26-32% of feathers and nail was derived
      from drinking water. Our findings suggest environmental interpretations of deltaD
      values from modern and fossil animal tissues may need to account for potentially
      large isotopic differences between drinking water and food and require a good
      understanding of the physiological ecology of study organisms.

PMID- 10393938
TI  - Damage to photosystem II in symbiotic dinoflagellates: a determinant of coral
      bleaching.
AB  - Coral bleaching has been defined as a general phenomenon, whereby reef corals
      turn visibly pale because of the loss of their symbiotic dinoflagellates and/or
      algal pigments during periods of exposure to elevated seawater temperatures.
      During the summer of 1997, seawater temperatures in the Florida Keys remained at
      or above 30 degrees C for more than 6 weeks, and extensive coral bleaching was
      observed. Bleached colonies of the dominant Caribbean reef-building species,
      Montastrea faveolata and Montastrea franksi, were sampled over a depth gradient
      from 1 to 17 m during this period of elevated temperature and contained lower
      densities of symbiotic dinoflagellates in deeper corals than seen in previous
      "nonbleaching" years. Fluorescence analysis by pulse-amplitude modulation
      fluorometry revealed severe damage to photosystem II (PSII) in remaining
      symbionts within the corals, with greater damage indicated at deeper depths.
      Dinoflagellates with the greatest loss in PSII activity also showed a significant
      decline in the D1 reaction center protein of PSII, as measured by immunoblot
      analysis. Laboratory experiments on the temperature-sensitive species Montastrea
      annularis, as well as temperature-sensitive and temperature-tolerant cultured
      symbiotic dinoflagellates, confirmed the temperature-dependent loss of PSII
      activity and concomitant decrease in D1 reaction center protein seen in symbionts
      collected from corals naturally bleached on the reef. In addition, variation in
      PSII repair was detected, indicating that perturbation of PSII protein turnover
      rates during photoinhibition at elevated temperatures underlies the physiological
      collapse of symbionts in corals susceptible to heat-induced bleaching.

PMID- 10393939
TI  - Species richness and resource availability: a phylogenetic analysis of insects
      associated with trees.
AB  - The data on the number of species of insects associated with various trees in
      Britain have been reanalyzed to factor out possible bias from phylogenetic
      effects. It was found that tree availability (range and abundance) continues to
      provide a good predictor (r = 0. 852) of insect-species richness, slightly better
      than straightforward cross-species analyses. Of the two components of tree
      availability, tree abundance gives a much better prediction than tree range. The
      species richness on trees of major taxa with similar trophic habits (Lepidoptera
      and Hymenoptera/Symphyta and the two suborders of the Homoptera-Auchenorrhyncha
      and Sternorrhyncha) shows positive correlations; there is thus no evidence of
      competitive exclusion at this taxonomic level.

PMID- 10393940
TI  - Diversity of Holocene life forms in fossil glacier ice.
AB  - Studies of biotic remains of polar ice caps have been limited to morphological
      identification of plant pollen and spores. By using sensitive molecular
      techniques, we now demonstrate a much greater range of detectable organisms; from
      2000- and 4000-year-old ice-core samples, we obtained and characterized 120
      clones that represent at least 57 distinct taxa and reveal a diversity of fungi,
      plants, algae, and protists. The organisms derive from distant sources as well as
      from the local arctic environment. Our results suggest that additional taxa may
      soon be readily identified, providing a plank for future studies of deep ice
      cores and yielding valuable information about ancient communities and their
      change over time.

PMID- 10393941
TI  - Evidence that a plant virus switched hosts to infect a vertebrate and then
      recombined with a vertebrate-infecting virus.
AB  - There are several similarities between the small, circular, single-stranded-DNA
      genomes of circoviruses that infect vertebrates and the nanoviruses that infect
      plants. We analyzed circovirus and nanovirus replication initiator protein (Rep)
      sequences and confirmed that an N-terminal region in circovirus Reps is similar
      to an equivalent region in nanovirus Reps. However, we found that the remaining C
      terminal region is related to an RNA-binding protein (protein 2C), encoded by
      picorna-like viruses, and we concluded that the sequence encoding this region of
      Rep was acquired from one of these single-stranded RNA viruses, probably a
      calicivirus, by recombination. This is clear evidence that a DNA virus has
      incorporated a gene from an RNA virus, and the fact that none of these viruses
      code for a reverse transcriptase suggests that another agent with this capacity
      was involved. Circoviruses were thought to be a sister-group of nanoviruses, but
      our phylogenetic analyses, which take account of the recombination, indicate that
      circoviruses evolved from a nanovirus. A nanovirus DNA was transferred from a
      plant to a vertebrate. This transferred DNA included the viral origin of
      replication; the sequence conservation clearly indicates that it maintained the
      ability to replicate. In view of these properties, we conclude that the
      transferred DNA was a kind of virus and the transfer was a host-switch. We
      speculate that this host-switch occurred when a vertebrate was exposed to sap
      from an infected plant. All characterized caliciviruses infect vertebrates,
      suggesting that the host-switch happened first and that the recombination took
      place in a vertebrate.

PMID- 10393942
TI  - The evolution of language.
AB  - The emergence of language was a defining moment in the evolution of modern
      humans. It was an innovation that changed radically the character of human
      society. Here, we provide an approach to language evolution based on evolutionary
      game theory. We explore the ways in which protolanguages can evolve in a
      nonlinguistic society and how specific signals can become associated with
      specific objects. We assume that early in the evolution of language, errors in
      signaling and perception would be common. We model the probability of
      misunderstanding a signal and show that this limits the number of objects that
      can be described by a protolanguage. This "error limit" is not overcome by
      employing more sounds but by combining a small set of more easily distinguishable
      sounds into words. The process of "word formation" enables a language to encode
      an essentially unlimited number of objects. Next, we analyze how words can be
      combined into sentences and specify the conditions for the evolution of very
      simple grammatical rules. We argue that grammar originated as a simplified rule
      system that evolved by natural selection to reduce mistakes in communication. Our
      theory provides a systematic approach for thinking about the origin and evolution
      of human language.

PMID- 10393944
TI  - A human DAZ transgene confers partial rescue of the mouse Dazl null phenotype.
AB  - In a subset of infertile men, a spectrum of spermatogenic defects ranging from a
      complete absence of germ cells (sertoli cell only) to oligozoospermia is
      associated with microdeletions of the DAZ (deleted in azoospermia) gene cluster
      on human distal Yq. DAZ encodes a testis-specific protein with RNA-binding
      potential recently derived from a single-copy gene DAZL1 (DAZ-like) on chromosome
      3. Y chromosomal DAZ homologues are confined to humans and higher primates. It
      remains unclear which function unique to higher primate spermatogenesis DAZ may
      serve, and the functional status of the gene recently has been questioned. To
      assess the extent of functional conservation we have tested the capacity of a
      human DAZ gene contained in a 225-kb yeast artificial chromosome to complement
      the sterile phenotype of the Dazl null mouse (Dazl-/-), which is characterized by
      severe germ-cell depletion and meiotic failure. Although Dazl-/- mice remained
      infertile when the DAZ transgene was introduced, histological examination
      revealed a partial and variable rescue of the mutant phenotype, manifest as a
      pronounced increase in the germ cell population of the seminiferous tubules and
      survival to the pachytene stage of meiosis. As well as constituting definitive
      proof of the spermatogenic role of the DAZ gene product, these findings confirm
      the high degree of functional conservation between the DAZ and DAZL1 genes,
      suggesting they may constitute a single target for contraceptive intervention and
      raising the possibility of therapeutic up-regulation of the DAZL1 gene in
      infertile men.

PMID- 10393943
TI  - The nop-1 gene of Neurospora crassa encodes a seven transmembrane helix retinal
      binding protein homologous to archaeal rhodopsins.
AB  - Opsins are a class of retinal-binding, seven transmembrane helix proteins that
      function as light-responsive ion pumps or sensory receptors. Previously, genes
      encoding opsins had been identified in animals and the Archaea but not in fungi
      or other eukaryotic microorganisms. Here, we report the identification and
      mutational analysis of an opsin gene, nop-1, from the eukaryotic filamentous
      fungus Neurospora crassa. The nop-1 amino acid sequence predicts a protein that
      shares up to 81.8% amino acid identity with archaeal opsins in the 22 retinal
      binding pocket residues, including the conserved lysine residue that forms a
      Schiff base linkage with retinal. Evolutionary analysis revealed relatedness not
      only between NOP-1 and archaeal opsins but also between NOP-1 and several fungal
      opsin-related proteins that lack the Schiff base lysine residue. The results
      provide evidence for a eukaryotic opsin family homologous to the archaeal opsins,
      providing a plausible link between archaeal and visual opsins. Extensive analysis
      of Deltanop-1 strains did not reveal obvious defects in light-regulated processes
      under normal laboratory conditions. However, results from Northern analysis
      support light and conidiation-based regulation of nop-1 gene expression, and NOP
      1 protein heterologously expressed in Pichia pastoris is labeled by using all
      trans [3H]retinal, suggesting that NOP-1 functions as a rhodopsin in N. crassa
      photobiology.

PMID- 10393945
TI  - Stability of the mitochondrial genome requires an amino-terminal domain of yeast
      mitochondrial RNA polymerase.
AB  - Mitochondrial RNA (mtRNA) polymerases are related to bacteriophage RNA
      polymerases, but contain a unique amino-terminal extension of unknown origin and
      function. In addition to harboring mitochondrial targeting information, we show
      here that the amino-terminal extension of yeast mtRNA polymerase is required for
      a mtDNA maintenance function that is separable from the known RNA polymerization
      activity of the enzyme. Deletion of 185 N-terminal amino acids from the enzyme
      results in a temperature-sensitive mitochondrial petite phenotype, characterized
      by increased instability and eventual loss of the mitochondrial genome.
      Mitochondrial transcription initiation in vivo is largely unaffected by this
      mutation and expression of just the amino-terminal portion of the protein in
      trans partially suppresses the mitochondrial defect, indicating that the amino
      terminal extension of the enzyme harbors an independent functional domain that is
      required for mtDNA replication and/or stability. These results suggest that amino
      terminal extensions present in mtRNA polymerases comprise functional domains that
      couple additional activities to the transcription process in mitochondria.

PMID- 10393946
TI  - Myxococcus cells respond to elastic forces in their substrate.
AB  - Elasticotaxis describes the ability of Myxococcus xanthus cells to sense and to
      respond to elastic forces within an agar gel on which they rest. Within 5 min of
      the application of stress, each cell begins to reorient its long axis
      perpendicular to the stress force. The cells then glide in that direction, and
      the swarm becomes asymmetric. A quantifiable assay for the strength of
      elasticotaxis is based on the change in swarm shape from circular to elliptic. By
      using a collection of isogenic motility mutants, it has been found that the
      ability to respond to stress in agar depends totally on adventurous (A) motility,
      but not at all on social (S) motility or on the frz genes. In fact, S- mutants
      (which are moving only by means of A motility) respond to the applied stress more
      strongly than does the wild type, despite the fact that their spreading rates are
      slower than that of the wt strain. Based on the swarming and elasticotactic
      phenotypes of isogenic frizzy strains that were also defective either in A or S
      motility, frz behaves as if part of the S motility system.

PMID- 10393947
TI  - Analysis of human peripheral blood T cells and single-cell-derived T cell clones
      uncovers extensive clonal CpG island methylation heterogeneity throughout the
      genome.
AB  - Methylation of cytosine residues in CpG dinucleotides is generally associated
      with silencing of gene expression. DNA methylation, as a somatic event, has the
      potential of diversifying gene expression in individual cells of the same
      lineage. There is little quantitative data available concerning the extent of
      methylation heterogeneity in individual cells across the genome. T cells from the
      peripheral blood can be grown as single-cell-derived clones and can be analyzed
      with respect to their DNA methylation patterns by restriction landmark genomic
      scanning. The use of the methylation-sensitive enzyme NotI to cut and end-label
      DNA fragments before their separation in two dimensions provides a quantitative
      assessment of methylation at NotI sites that characteristically occur in CpG
      islands. We have undertaken quantitative analysis of two-dimensional DNA patterns
      to determine the extent of methylation heterogeneity at NotI sites between
      peripheral blood single-cell-derived T cell clones from the same individual. A
      total of 1,068 NotI-tagged fragments were analyzed. A subset of 156 fragments
      exhibited marked methylation heterogeneity at NotI sites between clones. Their
      average intensity among clones correlated with their intensity in uncultured,
      whole-blood-derived T cells, indicating that the methylation heterogeneity
      observed in clones was largely attributable to methylation heterogeneity between
      the individual cells from which the clones were derived. We have cloned one
      fragment that exhibited variable NotI-site methylation between clones. This
      fragment contained a novel CpG island for a gene that we mapped to chromosome 4.
      The methylation status of the NotI site of this fragment correlated with
      expression of the corresponding gene. Our data suggest extensive diversity in
      vivo in the methylation and expression profiles of individual T cells at multiple
      unrelated loci across the genome.

PMID- 10393948
TI  - A maternally methylated CpG island in KvLQT1 is associated with an antisense
      paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome.
AB  - Loss of imprinting at IGF2, generally through an H19-independent mechanism, is
      associated with a large percentage of patients with the overgrowth and cancer
      predisposition condition Beckwith-Wiedemann syndrome (BWS). Imprinting control
      elements are proposed to exist within the KvLQT1 locus, because multiple BWS
      associated chromosome rearrangements disrupt this gene. We have identified an
      evolutionarily conserved, maternally methylated CpG island (KvDMR1) in an intron
      of the KvLQT1 gene. Among 12 cases of BWS with normal H19 methylation, 5 showed
      demethylation of KvDMR1 in fibroblast or lymphocyte DNA; whereas, in 4 cases of
      BWS with H19 hypermethylation, methylation at KvDMRl was normal. Thus,
      inactivation of H19 and hypomethylation at KvDMR1 (or an associated phenomenon)
      represent distinct epigenetic anomalies associated with biallelic expression of
      IGF2. Reverse transcription-PCR analysis of the human and syntenic mouse loci
      identified the presence of a KvDMR1-associated RNA transcribed exclusively from
      the paternal allele and in the opposite orientation with respect to the
      maternally expressed KvLQT1 gene. We propose that KvDMR1 and/or its associated
      antisense RNA (KvLQT1-AS) represents an additional imprinting control element or
      center in the human 11p15.5 and mouse distal 7 imprinted domains.

PMID- 10393950
TI  - Exon shuffling mimicked in cell culture.
AB  - Undesired side products of DNA transfections are usually discarded. However,
      here, we show that such products may provide insight into mutational events that
      are also a major driving force in protein evolution. While studying the small
      heat-shock protein alphaA-crystallin, we transfected the hamster alphaA
      crystallin gene into a mouse muscle cell line. One of the stable transfected cell
      lines expressed, in addition to the expected normal alphaA- and alternatively
      spliced alphaAins-crystallins, two slightly larger, immunologically cross
      reacting proteins. These proteins were found to be encoded by a mutant alphaA
      crystallin gene with a large intragenic duplication, arisen by illegitimate
      recombination at two CCCAT homologies, approximately 1.8 kilobases apart in the
      normal hamster alphaA-crystallin gene. As a consequence, a tandem-duplicated exon
      3 sequence is present in the mature mRNA of this gene, resulting in a 41-residue
      repeat in the translated proteins. Cells expressing the elongated alphaA
      crystallins have normal growth characteristics and the usual diffuse cytoplasmic
      distribution of immunoreactive alphaA-crystallin. Size-exclusion chromatography
      of cell extracts indicated that the mutant proteins are readily incorporated into
      the normal large water-soluble alphaA-crystallin complexes, showing that the
      insert does not disturb the integrity of these complexes. This viable alphaA
      crystallin mutant thus mimics the origins and effects of exon duplication, which
      is a common consequence of exon shuffling in mammalian genome evolution.

PMID- 10393949
TI  - SIAH-1 promotes apoptosis and tumor suppression through a network involving the
      regulation of protein folding, unfolding, and trafficking: identification of
      common effectors with p53 and p21(Waf1).
AB  - We have previously described biological model systems for studying tumor
      suppression in which, by using H-1 parvovirus as a selective agent, cells with a
      strongly suppressed malignant phenotype (KS or US) were derived from malignant
      cell lines (K562 or U937). By using cDNA display on the K562/KS cells, 15 cDNAs
      were now isolated, corresponding to genes differentially regulated in tumor
      suppression. Of these, TSAP9 corresponds to a TCP-1 chaperonin, TSAP13 to a
      regulatory proteasome subunit, and TSAP21 to syntaxin 11, a vesicular trafficking
      molecule. The 15 cDNAs were used as a molecular fingerprint in different tumor
      suppression models. We found that a similar pattern of differential regulation is
      shared by activation of p53, p21(Waf1), and the human homologue of Drosophila
      seven in absentia, SIAH-1. Because SIAH-1 is differentially expressed in the
      various models, we characterized it at the protein and functional levels. The 32
      kDa, mainly nuclear protein encoded by SIAH-1, can induce apoptosis and promote
      tumor suppression. These results suggest the existence of a common mechanism of
      tumor suppression and apoptosis shared by p53, p21(Waf1), and SIAH-1 and
      involving regulation of the cellular machinery responsible for protein folding,
      unfolding, and trafficking.

PMID- 10393951
TI  - IL-4 enhances proliferation and mediator release in mature human mast cells.
AB  - Tissue mast cells (MC) are recognized as key effector cells of immediate-type
      allergic reactions releasing inflammatory mediators and cytokines on stimulation
      with antigen, but they also might be involved in IgE-independent inflammatory and
      tissue repair processes. The mechanism of human MC regulation in tissue is not
      fully understood. Here, we show that IL-4, in synergy with stem cell factor
      (SCF), regulates the function of purified human MC isolated from intestinal
      tissue. Whereas SCF induced only marginal proliferation of MC cultured in vitro
      up to 4 weeks, addition of IL-4 and SCF strongly increased the proliferation
      rate. Moreover, IL-4, which by itself had no visible effect on human MC, enhanced
      the release of histamine, leukotriene C4, and IL-5 in MC triggered by IgE
      receptor crosslinking. The IL-4 effects occurred in a dose-dependent fashion
      (ED50 = 100 pg/ml) and could be totally blocked by a competitive IL-4 receptor
      antagonist. Our data indicate that IL-4 is an important regulator of human MC
      function and suggest that mature MC retain the capacity to proliferate in a
      particular tissue environment.

PMID- 10393953
TI  - On the role of thymic epithelium vs. bone marrow-derived cells in repertoire
      selection of T cells.
AB  - T lymphocytes mature in the thymus to become functional T cells. Studies with
      chimeric mice and T cell receptor (TCR) transgenic (tg) mice have indicated that
      the major histocompatibility gene complex (MHC) of thymic radio-resistant
      (presumed to be epithelial) cells positively select the MHC-restricted T cell
      repertoire. Surprisingly, mice without a thymus reconstituted with an MHC
      incompatible thymus generate effector T cells which are, in general, specific for
      the host and not for the thymic MHC. The present study reanalyzed this
      longstanding paradox in nude mice that were reconstituted with an MHC
      incompatible thymus plus or minus immunologically defective bone marrow-derived
      cells or in nude mice expressing a transgenic T cell receptor. A pathway of
      thymus-dependent but thymic MHC-independent T cell maturation is revealed where
      expansion of the antiviral T cell repertoire depends on the MHC of bone marrow
      derived cells. These results indicate an alternative, if not a general, pathway
      of T cell maturation and selection: the thymus may function essentially as an
      organ promoting T cell receptor expression; T cell specificity, however, reflects
      repertoire expansion plus cell survival and effector T cell induction driven by
      the MHC of bone marrow-derived cells. Therefore pure thymus defects can be
      efficiently reconstituted by allo- and xenogeneic thymic grafts.

PMID- 10393952
TI  - Antigen-specific modulation of experimental myasthenia gravis: nasal tolerization
      with recombinant fragments of the human acetylcholine receptor alpha-subunit.
AB  - Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are
      antibody-mediated autoimmune diseases in which the nicotinic acetylcholine
      receptor (AcChoR) is the major autoantigen. The immune response in these diseases
      is heterogeneous and is directed to a wide variety of T and B cell epitopes of
      AcChoR. Candidate molecules for specific immunotherapy of MG should, therefore,
      have a broad specificity. We used recombinant fragments of the human AcChoR,
      encompassing the extracellular domain of the alpha-subunit, or shorter fragments
      derived from it, in experiments to modulate EAMG. We have demonstrated that
      intranasal administration of these recombinant fragments, which represent a major
      portion of epitopes involved in MG, prevents the induction of EAMG in rats and
      immunosuppresses an ongoing disease, as assessed by clinical symptoms, weight
      loss, and muscle AcChoR content. These effects on EAMG were accompanied by a
      marked reduction in the proliferative T-cell response and IL-2 production in
      response to AcChoR, in reduced anti-self AcChoR antibody titers and in an isotype
      switch of AcChoR-specific antibodies, from IgG2 to IgG1. We conclude that nasal
      tolerance induced by appropriate recombinant fragments of human AcChoR is
      effective in suppressing EAMG and might possibly be considered as a therapeutic
      modality for MG.

PMID- 10393954
TI  - Control of separate pathogenic autoantibody responses marks MHC gene
      contributions to murine lupus.
AB  - Previous studies have suggested that MHC and non-MHC genes contribute to the
      development of autoimmune disease in F1 hybrids of New Zealand black (NZB) and
      white (NZW) mice. We conducted a genome-wide screen of 148 female (NZB x NZW)F1 x
      NZB backcross mice to map dominant NZW genetic loci linked with lupus disease
      traits. In this backcross analysis, inheritance of the NZW MHC (H2(d/z) vs.
      H2(d/d)) was strongly linked with the development of lupus nephritis (P
      approximately 1 x 10(-16)), increasing the risk of disease by over 30-fold.
      H2(d/z) was also linked with elevated serum levels of IgG autoantibodies to
      single-stranded DNA, double-stranded DNA, histones, and chromatin but not with
      anti-gp70 autoantibodies, measured as circulating gp70-anti-gp70 immune
      complexes. Non-MHC contributions from NZW seemed weak in comparison to MHC,
      although NZW loci on chromosomes 7 and 16 were noted to be suggestively linked
      with autoantibody production. Strikingly, H2(d/z) (compared with H2(d/d))
      enhanced antinuclear antibodies in a coordinate fashion but did not affect anti
      gp70 production in the current backcross. However, the opposite influence was
      noted for H2(d/z) (compared with H2(z/z)) when (NZB x NZW)F1 x NZW backcross mice
      were analyzed. These results suggest that H2(z) and H2(d) haplotypes
      differentially regulate two different sets of nephritogenic autoantibody
      responses. This study confirms a critical role for H2(z) compared with other
      dominant NZW loci in (NZB x NZW)F1 mice and provides an explanation as to why
      H2(d/z) heterozygosity is required for full expression of disease in this model.

PMID- 10393955
TI  - Dichotomy between naive and memory CD4(+) T cell responses to Fas engagement.
AB  - Engagement of Fas (APO-1, CD95), a member of the tumor necrosis factor receptor
      superfamily, can induce apoptotic cell death. However, Fas engagement also can
      costimulate lymphocyte proliferation. The physiologic regulation of these two
      outcomes is poorly understood. Here, we have used two systems, the first in vitro
      and the second in vivo, to demonstrate that naive and memory CD4(+) T cells
      display dichotomous responses to Fas ligation. Naive CD4(+) T cells (CD44(lo),
      CD45RB+, CD62L+) die as a consequence of Fas ligation in the presence of anti-CD3
      antibody, whereas memory T cells (CD44(hi), CD45RB-, CD62L-), freshly isolated
      from the same starting population and subjected to the same stimulation
      conditions, are costimulated to proliferate by Fas ligation. In vitro, we
      demonstrate that CD28-mediated signals or T helper 1 and T helper 2
      differentiation cytokines alter the response of naive T cells, but not of memory
      T cells, to Fas ligation. In vivo experiments in hen egg lysozyme (HEL) T cell
      receptor transgenic mice show that CD4(+) T cells from HEL-naive mice are killed
      by Fas ligation, but CD4(+) T cells from long-term HEL-exposed mice are
      costimulated by Fas ligation. Thus, the physiological outcome of Fas ligation in
      CD4(+) T cells is determined primarily by the antigenic history of the T cell.

PMID- 10393956
TI  - The mast cell tumor necrosis factor alpha response to FimH-expressing Escherichia
      coli is mediated by the glycosylphosphatidylinositol-anchored molecule CD48.
AB  - Mast cells are well known for their harmful role in IgE-mediated hypersensitivity
      reactions, but their physiological role remains a mystery. Several recent studies
      have reported that mast cells play a critical role in innate immunity in mice by
      releasing tumor necrosis factor alpha (TNF-alpha) to recruit neutrophils to sites
      of enterobacterial infection. In some cases, the mast cell TNF-alpha response was
      triggered when these cells directly bound FimH on the surface of Escherichia
      coli. We have identified CD48, a glycosylphosphatidylinositol-anchored molecule,
      to be the complementary FimH-binding moiety in rodent mast cell membrane
      fractions. We showed that (i) pretreatment of mast cell membranes with antibodies
      to CD48 or phospholipase C inhibited binding of FimH+ E. coli, (ii) FimH+ E. coli
      but not a FimH- derivative bound isolated CD48 in a mannose-inhibitable manner,
      (iii) binding of FimH+ bacteria to Chinese hamster ovary (CHO) cells was markedly
      increased when these cells were transfected with CD48 cDNA, and (iv) antibodies
      to CD48 specifically blocked the mast cell TNF-alpha response to FimH+ E. coli.
      Thus, CD48 is a functionally relevant microbial receptor on mast cells that plays
      a role in triggering inflammation.

PMID- 10393957
TI  - Heterophile antibodies segregate in families and are associated with protection
      from type 1 diabetes.
AB  - Markedly elevated levels of serum IL-4 were reported previously in 50% of a small
      group of type 1 diabetes nonprogessors. To determine the patterns of expression
      for this phenotype, a larger cohort of 58 families containing type 1 diabetic
      patients was examined. Analysis of the two-site ELISA assay used to measure serum
      IL-4 revealed evidence for heterophile antibodies, i.e., nonanalyte substances in
      serum capable of binding antibodies mutivalently and providing erroneous analyte
      (e.g., IL-4) quantification. Interestingly, relatives without type 1 diabetes
      were significantly more likely to have this phenotype than were patients with the
      disease (P = 0.003). In addition, the trait appears to have clustered within
      certain families and was associated with the protective MHC allele DQB1*0602 (P =
      0.008). These results suggest that heterophile antibodies represent an in vivo
      trait associated with self-tolerance and nonprogression to diabetes.

PMID- 10393958
TI  - Megakaryocyte hyperplasia and enhanced agonist-induced platelet activation in
      vasodilator-stimulated phosphoprotein knockout mice.
AB  - Vasodilator-stimulated phosphoprotein (VASP), a substrate of cAMP- and cGMP
      dependent protein kinases, is associated with focal adhesions, cell-cell
      contacts, microfilaments, and highly dynamic membrane regions. VASP, which is
      expressed in most cell types and in particularly high levels in human platelets,
      binds to profilin, zyxin, vinculin, F-actin, and the Listeria monocytogenes
      surface protein ActA. VASP is a member of the enabled (Ena)/VASP protein family
      and is thought to be involved in actin filament formation and integrin
      alphaIIbbeta3 inhibition in human platelets. To gain further insight into the in
      vivo function of this protein, VASP-deficient mice were generated by homologous
      recombination. VASP-/- mice demonstrated hyperplasia of megakaryocytes in bone
      marrow and spleen but exhibited no other macroscopic or microscopic
      abnormalities. Activation of platelets with thrombin induced a more than 2-fold
      higher surface expression of P-selectin and fibrinogen binding in VASP-deficient
      platelets in comparison to wild type. These data support the concept that VASP is
      a negative modulator of platelet and integrin alphaIIbbeta3 activation. Although
      the limited phenotypic differences between wild-type and VASP-/- mice suggested
      functional compensation of VASP by members of the Ena/VASP family, alterations in
      the expression levels of mammalian enabled (Mena) and Ena-VASP-like (Evl) protein
      were not detected. VASP-deficient mice may provide an interesting model system
      for diseases in which enhanced platelet activation plays a major role.

PMID- 10393959
TI  - Sustained ex vivo expansion of hematopoietic stem cells mediated by
      thrombopoietin.
AB  - The hematopoietic stem cell (HSC) is defined as a cell that can either self
      replicate or generate daughter cells that are destined to commit to mature cells
      of different specific lineages. Self-replication of the most primitive HSC
      produces daughter cells that possess a long (possibly unlimited) clonal lifespan,
      whereas differentiation of HSC produces daughter cells that demonstrate a
      progressive reduction of their clonal lifespan, a loss of multilineage potential,
      and lineage commitment. Previous studies indicated that the proliferation of HSC
      ex vivo favors differentiation at the expense of self-replication, eventually
      resulting in a complete loss of HSC. In contrast, transplantation studies have
      shown that a single HSC can repopulate the marrow of a lethally irradiated mouse,
      demonstrating that self-renewal of HSC occurs in vivo. Thrombopoietin (TPO) has
      been shown to function both as a proliferative and differentiative factor for
      megakaryocytes and as a survival and weakly proliferative factor for HSC. Our
      studies focused on the effects of exogenous TPO on HSC in mouse long-term bone
      marrow cultures (LTBMC). Previous results indicate that HSC decline in LTBMC in
      the absence of TPO. In contrast, the continuous presence of TPO resulted in the
      generation of both long- and short-term repopulating HSC as detected by an in
      vivo competitive repopulation assay. HSC were generated over a 4-month period at
      concentrations similar to normal bone marrow. Our results demonstrate that TPO
      can mediate the self-replication of HSC in LTBMC, and provide proof that HSC can
      self-replicate ex vivo.

PMID- 10393960
TI  - Long-term survival and function of intrahepatic islet allografts in rhesus
      monkeys treated with humanized anti-CD154.
AB  - Reported effects of anti-CD154 treatment on autoimmunity, alloreactivity, and
      inflammatory events mediated by macrophages and endothelial cells indicated that
      it might be an ideal agent for the prevention of intrahepatic islet allograft
      failure. This hypothesis was tested in MHC-mismatched rhesus monkeys.
      Transplantation of an adequate number of viable islets resulted in engraftment
      and insulin independence in six of six recipients treated with anti-CD154 (hu5c8)
      induction plus monthly maintenance therapy (post-operative day >125, >246, >266,
      >405, >419, >476). Anti-CD154 (hu5c8) displayed no inhibitory effect on islet
      cell function. For monkeys followed for >100 days, continued improvement in graft
      function, as determined by first phase insulin release in response to intravenous
      glucose, was observed after the first 100 days post-transplant. No evidence of
      toxicity or infectious complications has been observed. All recipients treated
      with anti-CD154 became specifically nonresponsive to donor cells in mixed
      lymphocyte reactions. Furthermore, three monkeys are now off therapy (>113, >67,
      and >54 days off anti-CD154), with continued insulin independence and donor
      specific mixed lymphocyte reaction hyporeactivity. In striking contrast to all
      previously tested strategies, transplantation of an adequate number of functional
      islets under the cover of anti-CD154 (hu5c8) monotherapy consistently allows for
      allogeneic islet engraftment and long-term insulin independence in this highly
      relevant preclinical model.

PMID- 10393961
TI  - Tissue factor is required for uterine hemostasis and maintenance of the placental
      labyrinth during gestation.
AB  - We employed a novel mouse line that expresses low levels of human tissue factor
      (TF) in the absence of murine TF to analyze the role of TF in gestation. Low-TF
      female mice had a 14-18% incidence of fatal postpartum uterine hemorrhage,
      suggesting that TF plays an important role in uterine hemostasis. Low-TF female
      mice mated with low-TF male mice had a 42% incidence of fatal midgestational
      hemorrhage (n = 41), whereas no fatal midgestational hemorrhages were observed in
      low-TF female mice mated with wild-type male mice (n = 43). Placentas of low-TF
      embryos from both low-TF and normal (+/-) TF females were abnormal and contained
      numerous maternal blood pools in the labyrinth. Placentas of TF null embryos
      surviving beyond embryonic day 10.5 exhibited similar defects. The mouse maternal
      embryonic placental barrier consists of four cellular layers (layers I, II, and
      III and endothelial cells), where layer I lines the maternal lacunae. Comparison
      of TF-deficient placentas with control placentas by immunohistochemical and
      ultrastructural analyses revealed thinning of layer I and a reduction in the
      number of cellular contacts of layer I trophoblasts spanning the maternal blood
      space between adjacent trabeculae. These structural changes in low-TF and TF null
      placentas result in enlarged maternal lacunae, as determined by morphometric
      analysis, and placental hemorrhage, which leads to midgestational death of low-TF
      female mice. This study demonstrated that TF is required for uterine hemostasis
      and revealed an unexpected role of TF in the maintenance of the placental
      labyrinth.

PMID- 10393962
TI  - Apoptosis in heart failure: release of cytochrome c from mitochondria and
      activation of caspase-3 in human cardiomyopathy.
AB  - Apoptosis has been shown to contribute to loss of cardiomyocytes in
      cardiomyopathy, progressive decline in left ventricular function, and congestive
      heart failure. Because the molecular mechanisms involved in apoptosis of
      cardiocytes are not completely understood, we studied the biochemical and
      ultrastructural characteristics of upstream regulators of apoptosis in hearts
      explanted from patients undergoing transplantation. Sixteen explanted hearts from
      patients undergoing heart transplantation were studied by electron microscopy or
      immunoblotting to detect release of mitochondrial cytochrome c and activation of
      caspase-3. The hearts explanted from five victims of motor vehicle accidents or
      myocardial ventricular tissues from three donor hearts were used as controls.
      Evidence of apoptosis was observed only in endstage cardiomyopathy. There was
      significant accumulation of cytochrome c in the cytosol, over myofibrils, and
      near intercalated discs of cardiomyocytes in failing hearts. The release of
      mitochondrial cytochrome c was associated with activation of caspase-3 and
      cleavage of its substrate protein kinase C delta but not poly(ADP-ribose)
      polymerase. By contrast, there was no apparent accumulation of cytosolic
      cytochrome c or caspase-3 activation in the hearts used as controls. The present
      study provides in vivo evidence of cytochrome c-dependent activation of cysteine
      proteases in human cardiomyopathy. Activation of proteases supports the
      phenomenon of apoptosis in myopathic process. Because loss of myocytes
      contributes to myocardial dysfunction and is a predictor of adverse outcomes in
      the patients with congestive heart failure, the present demonstration of an
      activated apoptotic cascade in cardiomyopathy could provide the basis for novel
      interventional strategies.

PMID- 10393963
TI  - A potential mechanism underlying the increased susceptibility of individuals with
      a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity.
AB  - NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron reductase that
      detoxifies quinones derived from the oxidation of phenolic metabolites of
      benzene. A polymorphism in NQO1, a C609T substitution, has been identified, and
      individuals homozygous for this change (T/T) have no detectable NQO1. Exposed
      workers with a T/T genotype have an increased risk of benzene hematotoxicity.
      This finding suggests NQO1 is protective against benzene toxicity, which is
      difficult to reconcile with the lack of detectable NQO1 in human bone marrow. The
      human promyeloblastic cell line, KG-1a, was used to investigate the ability of
      the benzene metabolite hydroquinone (HQ) to induce NQO1. A concentration
      dependent induction of NQO1 protein and activity was observed in KG-1a cells
      cultured with HQ. Multiple detoxification systems, including NQO1 and glutathione
      protect against benzene metabolite-induced toxicity. Indeed, exposure to a
      noncytotoxic concentration of HQ induced both NQO1 and soluble thiols and
      protected against HQ-induced apoptosis. NQO1 protein and activity increased in
      wild-type human bone marrow cells (C/C) exposed to HQ, whereas no NQO1 was
      induced by HQ in bone marrow cells with the T/T genotype. Intermediate induction
      of NQO1 by HQ was observed in heterozygous bone marrow cells (C/T). NQO1 also was
      induced by HQ in wild-type (C/C) human bone marrow CD34(+) progenitor cells. Our
      data suggest that failure to induce functional NQO1 may contribute to the
      increased risk of benzene poisoning in individuals homozygous for the NQO1 C609T
      substitution (T/T).

PMID- 10393964
TI  - Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption.
AB  - Osteopontin is one of the major noncollagenous bone matrix proteins produced by
      osteoblasts and osteoclasts, bone cells that are uniquely responsible for the
      remodeling of mineralized tissues. Osteoclasts express the alphavbeta3 integrin,
      which is one of the receptors for osteopontin. Recent knockout studies revealed
      that noncollagenous bone matrix proteins are functionally important in regulation
      of bone metabolism. However, the significance of the presence of osteopontin in
      in vivo has not been known. We report here that osteopontin knockout mice are
      resistant to ovariectomy-induced bone resorption compared with wild-type mice.
      Microcomputed tomography analysis indicated about 60% reduction in bone volume by
      ovariectomy in wild-type mice, whereas the osteopontin-deficient mice exhibited
      only about 10% reduction in trabecular bone volume after ovariectomy. Reduction
      in uterine weight was observed similarly in both wild-type and osteopontin
      deficient mice, indicating the specificity of the effect of osteopontin
      deficiency on bone metabolism. We propose that osteopontin is essential for
      postmenopausal osteoporosis in women. Strategies to counteract osteopontin's
      action may prove effective in suppressing osteoporosis.

PMID- 10393965
TI  - Targeting tumor vasculature endothelial cells and tumor cells for immunotherapy
      of human melanoma in a mouse xenograft model.
AB  - An immunotherapy treatment for cancer that targets both the tumor vasculature and
      tumor cells has shown promising results in a severe combined immunodeficient
      mouse xenograft model of human melanoma. The treatment involves systemic delivery
      of an immunoconjugate molecule composed of a tumor-targeting domain conjugated to
      the Fc effector domain of human IgG1. The effector domain induces a cytolytic
      immune response against the targeted cells by natural killer cells and
      complement. Two types of targeting domains were used. One targeting domain is a
      human single-chain Fv molecule that binds to a chondroitin sulfate proteoglycan
      expressed on the surface of most human melanoma cells. Another targeting domain
      is factor VII (fVII), a zymogen that binds with high specificity and affinity to
      the transmembrane receptor tissue factor (TF) to initiate the blood coagulation
      cascade. TF is expressed by endothelial cells lining the tumor vasculature but
      not the normal vasculature, and also by many types of tumor cells including
      melanoma. Because the binding of a fVII immunoconjugate to TF might cause
      disseminated intravascular coagulation, the active site of fVII was mutated to
      inhibit coagulation without affecting the affinity for TF. The immunoconjugates
      were encoded as secreted molecules in a replication-defective adenovirus vector,
      which was injected into the tail vein of severe combined immunodeficient mice.
      The results demonstrate that a mutated fVII immunoconjugate, administered
      separately or together with a single-chain Fv immunoconjugate that binds to the
      tumor cells, can inhibit the growth or cause regression of an established human
      tumor xenograft. This procedure could be effective in treating a broad spectrum
      of human solid tumors that express TF on vascular endothelial cells and tumor
      cells.

PMID- 10393967
TI  - Secretin PulD: association with pilot PulS, structure, and ion-conducting channel
      formation.
AB  - The outer membrane protein PulD (secretin) of Klebsiella oxytoca is required for
      transport of pullulanase across this membrane. We have purified a multimeric PulD
      complex from an Escherichia coli strain expressing all the proteins involved in
      pullulanase secretion. The outer membrane-anchored lipoprotein PulS was found to
      copurify with PulD. The molar ratio of the two proteins is close to 1:1, and the
      size of the complex is approximately 1 MDa. Scanning transmission electron and
      cryo-electron microscopy analyses showed that the purified complex is a
      cylindrical structure having a central cavity of approximately 7.6 nm and
      peripheral radial spokes. Fusion of proteoliposomes containing the purified
      complex with a planar lipid bilayer resulted in the appearance of small, voltage
      activated, ion-conducting channels. We conclude that the central cavity seen in
      the electron microscope is part of a large gated channel and propose that the
      observed current fluctuations correspond to voltage-induced, relatively minor
      displacements of domains in the purified complex rather than to a complete
      opening of the secretin channel.

PMID- 10393966
TI  - HIV-1 Nef increases T cell activation in a stimulus-dependent manner.
AB  - Lentiviral Nef increases viral replication in vivo, plays a direct role in
      pathogenesis, and increases viral particle infectivity. We now find that HIV Nef
      also increases the activation of T cells, a cellular state required for optimal
      viral replication. This enhancement is stimulant-dependent. As defined by IL-2
      generation, activation of T cells stimulated with classical mitogens [phorbol 12
      myristate 13-acetate (PMA) + anti-CD3, PMA + phytohemagglutinin, and PMA +
      ionomycin] is unaffected by the expression of Nef. However, Nef increases IL-2
      secretion when cells are stimulated through the T cell receptor and the
      costimulus receptor (CD28). This increase in activation, which depends on Nef
      myristylation, is caused by an increase in the number of cells reaching full
      activation and not by an increase in the amount of IL-2 secreted per cell. These
      findings demonstrate that Nef lowers the threshold of the dual-receptor T cell
      activation pathway. The capacity of Nef to increase T cell activity may be very
      important in vivo when Nef is the predominant or the only viral gene product
      expressed.

PMID- 10393968
TI  - Structural basis of chaperone self-capping in P pilus biogenesis.
AB  - PapD is an immunoglobulin-like chaperone that mediates the assembly of P pili in
      uropathogenic strains of Escherichia coli. It binds and caps interactive surfaces
      on pilus subunits to prevent their premature associations in the periplasm. We
      elucidated the structural basis of a mechanism whereby PapD also interacts with
      itself, capping its own subunit binding surface. Crystal structures of dimeric
      forms of PapD revealed that this self-capping mechanism involves a rearrangement
      and ordering of the C2-D2 and F1-G1 loops upon dimerization which might ensure
      that a stable dimer is not formed in solution in spite of a relatively large
      dimer interface. An analysis of site directed mutations revealed that chaperone
      dimerization requires the same surface that is otherwise used to bind subunits.

PMID- 10393969
TI  - A single amino acid substitution in the cyclin D binding domain of the infected
      cell protein no. 0 abrogates the neuroinvasiveness of herpes simplex virus
      without affecting its ability to replicate.
AB  - The infected cell protein no. 0 (ICP0) of herpes simplex virus 1 is a promiscuous
      transactivator shown to enhance the expression of genes introduced into cells by
      infection or transfection. The protein interacts with several viral and cellular
      proteins. Earlier studies have shown that ICP0 binds and stabilizes cyclin D3 but
      does interfere with the phosphorylation of retinoblastoma protein, its major
      function. Cyclin D3 plays a key role in the transition from G1 to S phase. To
      define the role of cyclin D3 in productive infection, the ICP0 binding site for
      cyclin D3 was mapped and mutagenized by substitution of aspartic acid codon 199
      with the alanine codon. We report that the substitution precluded the interaction
      of this protein with cyclin D3 in the yeast two-hybrid system and the
      stabilization of cyclin D3 in infected cells. A recombinant virus carrying this
      mutation could not be differentiated from wild-type parent with respect to
      replication in dividing cells but yielded 10-fold less progeny from infected
      resting cells and serum-deprived or contact-inhibited human fibroblasts. In mice,
      the mutant was only slightly less pathogenic than the wild-type parent by
      intracerebral route but was significantly less neuroinvasive after peripheral
      inoculation. Replacement of the mutated amino acid with aspartic acid restored
      wild-type phenotype. Stabilization of cyclin D3 therefore is linked to higher
      virus yields in nondividing cells and potentially higher virulence in
      experimental and natural hosts. One function of ICP0 is to scavenge the cell for
      proteins that could bolster viral replication.

PMID- 10393970
TI  - Discovery of virulence genes of Legionella pneumophila by using signature tagged
      mutagenesis in a guinea pig pneumonia model.
AB  - Legionella pneumophila is the cause of Legionnaires' disease, which is a form of
      potentially fatal pneumonia. To identify genes required for virulence of the
      bacterium, a library of 1,386 L. pneumophila signature tagged transposon mutants
      was studied for guinea pig virulence. The mutants were screened in pools of 96
      each in a guinea pig model of L. pneumophila pneumonia. Sixteen unique mutant
      clones were determined to have attenuated virulence after being screened twice in
      the animal model. All 16 mutants failed to multiply in both lungs and spleens.
      Four of the sixteen had no apparent defect for intracellular multiplication in
      macrophages. Partial DNA sequences of the interrupted genes adjacent to the
      transposon insertions showed that six of them had mutations in five known L.
      pneumophila virulence genes: dotB, dotF/icmG, dotO/icmB, icmX, and proA. Three of
      the sequenced clones contained mutations in genes without known homology to other
      published bacterial genes, and seven clones appeared to be homologous to five
      different known bacterial genes but are still being characterized. With this
      methodology, we demonstrate the existence of L. pneumophila genes responsible for
      non-macrophage-related virulence. The discovery of L. pneumophila virulence genes
      indicates the utility of the signature tagged mutagenesis technique for pulmonary
      pathogens.

PMID- 10393972
TI  - Immediate thalamic sensory plasticity depends on corticothalamic feedback.
AB  - Multiple neuron ensemble recordings were obtained simultaneously from both the
      primary somatosensory (SI) cortex and the ventroposterior medial thalamus (VPM)
      before and during the combined administration of reversible inactivation of the
      SI cortex and a reversible subcutaneous block of peripheral trigeminal nerve
      fibers. This procedure was performed to quantify the contribution of descending
      corticofugal projections on (i) the normal organization of thalamic somatosensory
      receptive fields and (ii) the thalamic somatosensory plastic reorganization that
      immediately follows a peripheral deafferentation. Reversible inactivation of SI
      cortex resulted in immediate changes in receptive field properties throughout the
      VPM. Cortical inactivation also significantly reduced but did not completely
      eliminate the occurrence of VPM receptive field reorganization resulting from the
      reversible peripheral deafferentation. This result suggests that the thalamic
      plasticity that is seen immediately after a peripheral deafferentation is
      dependent upon both descending corticofugal projections and ascending
      trigeminothalamic projections.

PMID- 10393971
TI  - Intracellular sigma1 receptor modulates phospholipase C and protein kinase C
      activities in the brainstem.
AB  - Most physiological effects of sigma1 receptor ligands are sensitive to pertussis
      toxin, suggesting a coupling with cell membrane-bound G proteins. However, the
      cloning of the sigma1 receptor has allowed the identification of an intracellular
      protein anchored on the endoplasmic reticulum. Here, we show, using the isolated
      adult guinea pig brainstem preparation, that activation of the sigma1 receptor
      results in its translocation from the cytosol to the vicinity of the cell
      membrane and induces a robust and rapid decrease in hypoglossal activity, which
      is mediated by phospholipase C. The subsequent activation of protein kinase C
      beta1 and beta2 isoforms and the phosphorylation of a protein of the same
      molecular weight as the cloned sigma1 receptor lead to a desensitization of the
      sigma1 motor response. Our results indicate that the intracellular sigma1
      receptor regulates several components implicated in plasma membrane-bound signal
      transduction. This might be an example of a mechanism by which an intracellular
      receptor modulates metabotropic responses.

PMID- 10393973
TI  - Synaptic depression creates a switch that controls the frequency of an
      oscillatory circuit.
AB  - Synaptic depression is a form of short-term plasticity exhibited by many
      synapses. Nonetheless, the functional significance of synaptic depression in
      oscillatory networks is not well understood. We show that, in a recurrent
      inhibitory network that includes an intrinsic oscillator, synaptic depression can
      give rise to two distinct modes of network operation. When the maximal
      conductance of the depressing synapse is small, the oscillation period is
      determined by the oscillator component. Increasing the maximal conductance beyond
      a threshold value activates a positive-feedback mechanism that greatly enhances
      the synaptic strength. In this mode, the oscillation period is determined by the
      strength and dynamics of the depressing synapse. Because of the regenerative
      nature of the feedback mechanism, the circuit can be switched from one mode of
      operation to another by a very small change in the maximal conductance of the
      depressing synapse. Our model was inspired by experimental work on the pyloric
      network of the lobster. The pyloric network produces a simple motor rhythm
      generated by a pacemaker neuron that receives feedback inhibition from a
      depressing synapse. In some preparations, elimination of the synapse had no
      effect on the period of the rhythm, whereas in other preparations, there was a
      significant decrease in the period. We propose that the pyloric network can
      operate in either of the two modes suggested by the model, depending on the
      maximal conductance of the depressing synapse.

PMID- 10393974
TI  - Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis.
AB  - HIV-1 glycoprotein gp120 induces injury and apoptosis in rodent and human neurons
      in vitro and in vivo and is therefore thought to contribute to HIV-associated
      dementia. In addition to CD4, different gp120 isolates bind to the alpha- or beta
      chemokine receptors CXCR4 and CCR5, respectively. These and other chemokine
      receptors are on brain macrophages/microglia, astrocytes, and neurons. Thus,
      apoptosis could occur via direct interaction of gp120 with neurons, indirectly
      via stimulation of glia to release neurotoxic factors, or via both pathways. Here
      we show in rat cerebrocortical cultures that recapitulate the type and proportion
      of cells normally found in brain, i.e., neurons, astrocytes, and
      macrophages/microglia, that the beta-chemokines RANTES (regulated on activation,
      normal T cell expressed and secreted) and macrophage inflammatory protein (MIP
      1beta) protect neurons from gp120SF2-induced apoptosis. The gp120SF2 isolate
      prefers binding to CXCR4 receptors, similar to the physiological alpha-chemokine
      ligands, stromal cell-derived factor (SDF)-1alpha/beta. SDF-1alpha/beta failed to
      prevent gp120SF2 neurotoxicity, and in fact also induced neuronal apoptosis. We
      could completely abrogate gp120SF2-induced neuronal apoptosis with the tripeptide
      TKP, which inhibits activation of macrophages/microglia. In contrast, TKP or
      depletion of macrophages/microglia did not prevent SDF-1 neurotoxicity.
      Inhibition of p38 mitogen-activated protein kinase ameliorated both gp120SF2- and
      SDF-1-induced neuronal apoptosis. Taken together, these results suggest that
      gp120SF2 and SDF-1 differ in the cell type on which they stimulate CXCR4 to
      induce neuronal apoptosis, but both ligands use the p38 mitogen-activated protein
      kinase pathway for death signaling. Moreover, gp120SF2-induced neuronal apoptosis
      depends predominantly on an indirect pathway via activation of chemokine
      receptors on macrophages/microglia, whereas SDF-1 may act directly on neurons or
      astrocytes.

PMID- 10393975
TI  - Macaque inferior temporal neurons are selective for disparity-defined three
      dimensional shapes.
AB  - Real-world objects are three-dimensional (3D). Yet, it is unknown whether the
      neurons of the inferior temporal cortex, which is critical for object
      recognition, are selective for the 3D shape of objects. We tested for such
      selectivity by comparing responses to stereo-defined curved 3D shapes derived
      from identical pairs of monocular images. More than one-third of macaque inferior
      temporal neurons were selective for 3D shape. In the vast majority of those
      neurons, this selectivity depended on the global binocular disparity gradient and
      not on the local disparity. Thus, inferior temporal cortex processes not only two
      dimensional but also 3D shape information.

PMID- 10393976
TI  - Somatic stiffness of cochlear outer hair cells is voltage-dependent.
AB  - The mammalian cochlea depends on an amplification process for its sensitivity and
      frequency-resolving capability. Outer hair cells are responsible for providing
      this amplification. It is usually assumed that the membrane-potential-driven
      somatic shape changes of these cells are the basis of the amplifying process. It
      is of interest to see whether mechanical reactance changes of the cells might
      accompany their changes in cell shape. We now show that the cylindrical outer
      hair cells change their axial stiffness as their membrane potential is altered.
      Cell stiffness was determined by optoelectronically measuring the amplitude of
      motion of a flexible vibrating fiber as it was loaded by the isolated cell.
      Voltage commands to the cell were delivered in a tight-seal whole-cell
      configuration. Cell stiffness was decreased by depolarization and increased by
      hyperpolarization.

PMID- 10393977
TI  - Structure of tau exon 10 splicing regulatory element RNA and destabilization by
      mutations of frontotemporal dementia and parkinsonism linked to chromosome 17.
AB  - Coding region and intronic mutations in the tau gene cause frontotemporal
      dementia and parkinsonism linked to chromosome 17. Intronic mutations and some
      missense mutations increase splicing in of exon 10, leading to an increased ratio
      of four-repeat to three-repeat tau isoforms. Secondary structure predictions have
      led to the proposal that intronic mutations and one missense mutation destabilize
      a putative RNA stem-loop structure located close to the splice-donor site of the
      intron after exon 10. We have determined the three-dimensional structure of this
      tau exon 10 splicing regulatory element RNA by NMR spectroscopy. We show that it
      forms a stable, folded stem-loop structure whose thermodynamic stability is
      reduced by frontotemporal dementia and parkinsonism linked to chromosome 17
      mutations and increased by compensatory mutations. By exon trapping, the
      reduction in thermodynamic stability is correlated with increased splicing in of
      exon 10.

PMID- 10393978
TI  - Determination of the rate of the glutamate/glutamine cycle in the human brain by
      in vivo 13C NMR.
AB  - Recent 13C NMR studies in rat models have shown that the glutamate/glutamine
      cycle is highly active in the cerebral cortex and is coupled to incremental
      glucose oxidation in an approximately 1:1 stoichiometry. To determine whether a
      high level of glutamatergic activity is present in human cortex, the rates of the
      tricarboxylic acid cycle, glutamine synthesis, and the glutamate/glutamine cycle
      were determined in the human occipital/parietal lobe at rest. During an infusion
      of [1-13C]-glucose, in vivo 13C NMR spectra were obtained of the time courses of
      label incorporation into [4-13C]-glutamate and [4-13C]-glutamine. Using a
      metabolic model we have validated in the rat, we calculated a total tricarboxylic
      acid cycle rate of 0.77 +/- 0.07 micromol/min/g (mean +/- SD, n = 6), a glucose
      oxidation rate of 0.39 +/- 0.04 micromol/min/g, and a glutamate/glutamine cycle
      rate of 0.32 +/- 0.05 micromol/min/g (mean +/- SD, n = 6). In agreement with
      studies in rat cerebral cortex, the glutamate/glutamine cycle is a major
      metabolic flux in the resting human brain with a rate approximately 80% of
      glucose oxidation.

PMID- 10393979
TI  - Estrogen-inducible, sex-specific expression of brain-derived neurotrophic factor
      mRNA in a forebrain song control nucleus of the juvenile zebra finch.
AB  - The expression of brain-derived neurotrophic factor (BDNF) mRNA is increased
      significantly within the high vocal center (HVc) of male but not female zebra
      finches from posthatching day 30-35 on. The population of HVc cells expressing
      BDNF mRNA included 35% of the neurons projecting to the nucleus robustus of the
      archistriatum (RA). In the RA and in RA-projecting neurons of the lateral portion
      of the magnocellular nucleus of the anterior neostriatum, BDNF mRNA was expressed
      at very low levels in both sexes. The BDNF-receptor trkB mRNA was expressed in
      the RA, in RA-projecting neurons of lateral portion of the magnocellular nucleus
      of the anterior neostriatum, and in the HVc, except in most of its RA-projecting
      neurons. Premature stimulation and an inhibitory effect on the normal increase of
      the BDNF mRNA expression in juvenile males occurred after treatments with 17beta
      estradiol and the aromatase inhibitor fadrozole, respectively. The up-regulation
      of the BDNF expression in the HVc could be a mechanism by which estrogen triggers
      the differentiation of cells within and connected to the HVc of male zebra
      finches.

PMID- 10393980
TI  - Local and systemic delivery of a stable aspirin-triggered lipoxin prevents
      neutrophil recruitment in vivo.
AB  - Aspirin (ASA) triggers a switch in the biosynthesis of lipid mediators,
      inhibiting prostanoid production and initiating 15-epi-lipoxin generation through
      the acetylation of cyclooxygenase II. These aspirin-triggered lipoxins (ATL) may
      mediate some of ASA's beneficial actions and therefore are of interest in the
      search for novel antiinflammatories that could manifest fewer unwanted side
      effects. Here, we report that design modifications to native ATL structure
      prolong its biostability in vivo. In mouse whole blood, ATL analogs protected at
      carbon 15 [15(R/S)-methyl-lipoxin A4 (ATLa1)] and the omega end [15-epi-16-(para
      fluoro)-phenoxy-LXA4 (ATLa2)] were recoverable to approximately 90 and 100% at 3
      hr, respectively, compared with a approximately 40% loss of native lipoxin A4.
      ATLa2 retains bioactivity and, at levels as low as approximately 24 nmol/mouse,
      potently inhibited tumor necrosis factor-alpha-induced leukocyte recruitment into
      the dorsal air pouch. Inhibition was evident by either local intra-air pouch
      delivery (approximately 77% inhibition) or systemic delivery by intravenous
      injection (approximately 85% inhibition) and proved more potent than local
      delivery of ASA. Rank order for inhibiting polymorphonuclear leukocyte
      infiltration was: ATLa2 (10 micrograms, i.v.) approximately ATLa2 (10 micrograms,
      local) approximately dexamethasone (10 micrograms, local) >ASA (1.0 mg, local).
      Applied topically to mouse ear skin, ATLa2 also inhibited polymorphonuclear
      leukocyte infiltration induced by leukotriene B4 (approximately 78% inhibition)
      or phorbol ester (approximately 49% inhibition), which initiates endogenous
      chemokine production. These results indicate that this fluorinated analog of
      natural aspirin-triggered lipoxin A4 is bioavailable by either local or systemic
      delivery routes and is a more potent and precise inhibitor of neutrophil
      accumulation than is ASA.

PMID- 10393981
TI  - Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D3
      1alpha-hydroxylase gene in normocalcemic rats.
AB  - Regulation of vitamin D metabolism has long been examined by using vitamin D
      deficient hypocalcemic animals. We previously reported that, in a rat model of
      chronic hyperparathyroidism, expression of 25-hydroxyvitamin D3-1alpha
      hydroxylase (CYP27B1) mRNA was markedly increased in renal proximal convoluted
      tubules. It is believed that the major regulator for the expression of renal
      CYP27B1 is parathyroid hormone (PTH). However, in the normocalcemic state, the
      mechanism to regulate the renal CYP27B1 gene could be different, since plasma
      levels of PTH are very low. In the present study, the effect of PTH and
      calcitonin (CT) on the expression of renal CYP27B1 mRNA was investigated in
      normocalcemic sham-operated rats and normocalcemic thyroparathyroidectomized
      (TPTX) rats generated by either PTH or CaCl2 infusion. A single injection of CT
      dose-dependently decreased the expression of vitamin D receptor mRNA in the
      kidney of normocalcemic sham-TPTX rats. Concomitantly, CT greatly increased the
      expression of CYP27B1 mRNA in the kidney of normocalcemic sham-TPTX rats. CT also
      increased the expression of CYP27B1 mRNA in the kidney of normocalcemic TPTX
      rats. Conversion of serum [3H]1alpha,25(OH)2D3 from 25-hydroxy[3H]vitamin D3 in
      vivo was also greatly increased by the injection of CT into sham-TPTX rats and
      normocalcemic TPTX rats, but not into hypocalcemic TPTX rats. In contrast,
      administration of PTH did not induce the expression of CYP27B1 mRNA in the kidney
      of vitamin D-replete sham-TPTX rats and hypocalcemic TPTX rats. PTH increased the
      expression of renal CYP27B1 mRNA only in vitamin D-deficient hypocalcemic TPTX
      rats. These results suggest that CT plays an important role in the maintenance of
      serum 1alpha,25(OH)2D3 under normocalcemic physiological conditions, at least in
      rats.

PMID- 10393982
TI  - Intracellular Ca2+ oscillations drive spontaneous contractions in cardiomyocytes
      during early development.
AB  - Activity of cardiac pacemaker cells is caused by a balanced interplay of ion
      channels. However, it is not known how the rhythmic beating is initiated during
      early stages of cardiomyogenesis, when the expression of ion channels is still
      incomplete. Based on the observation that early-stage embryonic stem cell-derived
      cardiomyocytes continuously contracted in high extracellular K+ solution, here we
      provide experimental evidence that the spontaneous activity of these cells is not
      generated by transmembrane ion currents, but by intracellular [Ca2+]i
      oscillations. This early activity was clearly independent of voltage dependent L
      type Ca2+ channels and the interplay between these and ryanodine sensitive Ca2+
      stores. We also show that intracellular Ca2+ oscillations evoke small membrane
      depolarizations and that these can trigger L-type Ca2+ channel driven action
      potentials.

PMID- 10393983
TI  - High gene density is conserved at syntenic loci of small and large grass genomes.
AB  - Comparative genomic analysis at the genetic-map level has shown extensive
      conservation of the gene order between the different grass genomes in many
      chromosomal regions. However, little is known about the gene organization in
      grass genomes at the microlevel. Comparison of gene-coding regions between maize,
      rice, and sorghum showed that the distance between the genes is correlated with
      the genome size. We have investigated the microcolinearity at Lrk gene loci in
      the genomes of four grass species: wheat, barley, maize, and rice. The Lrk genes,
      which encode receptor-like kinases, were found to be consistently associated with
      another type of receptor-like kinase (Tak) on chromosome groups 1 and 3 in
      Triticeae and on chromosomes homoeologous to Triticeae group 3 in the other grass
      genomes. On Triticeae chromosome group 1, Tak and Lrk together with genes
      putatively encoding NBS/LRR proteins form a cluster of genes possibly involved in
      signal transduction. Comparison of the gene composition at orthologous Lrk loci
      in wheat, barley, and rice revealed a maximal gene density of one gene per 4-5
      kb, very similar to the gene density in Arabidopsis thaliana. We conclude that
      small and large grass genomes contain regions that are highly enriched in genes
      with very little or no repetitive DNA. The comparison of the gene organization
      suggested various genome rearrangements during the evolution of the different
      grass species.

PMID- 10393984
TI  - The alternative oxidase lowers mitochondrial reactive oxygen production in plant
      cells.
AB  - Besides the cytochrome c pathway, plant mitochondria have an alternative
      respiratory pathway that is comprised of a single homodimeric protein,
      alternative oxidase (AOX). Transgenic cultured tobacco cells with altered levels
      of AOX were used to test the hypothesis that the alternative pathway in plant
      mitochondria functions as a mechanism to decrease the formation of reactive
      oxygen species (ROS) produced during respiratory electron transport. Using the
      ROS-sensitive probe 2',7'-dichlorofluorescein diacetate, we found that antisense
      suppression of AOX resulted in cells with a significantly higher level of ROS
      compared with wild-type cells, whereas the overexpression of AOX resulted in
      cells with lower ROS abundance. Laser-scanning confocal microscopy showed that
      the difference in ROS abundance among wild-type and AOX transgenic cells was
      caused by changes in mitochondrial-specific ROS formation. Mitochondrial ROS
      production was exacerbated by the use of antimycin A, which inhibited normal
      cytochrome electron transport. In addition, cells overexpressing AOX were found
      to have consistently lower expression of genes encoding ROS-scavenging enzymes,
      including the superoxide dismutase genes SodA and SodB, as well as glutathione
      peroxidase. Also, the abundance of mRNAs encoding salicylic acid-binding catalase
      and a pathogenesis-related protein were significantly higher in cells deficient
      in AOX. These results are evidence that AOX plays a role in lowering
      mitochondrial ROS formation in plant cells.

PMID- 10393985
TI  - Regulation of thylakoid protein phosphorylation at the substrate level:
      reversible light-induced conformational changes expose the phosphorylation site
      of the light-harvesting complex II.
AB  - Light-dependent activation of thylakoid protein phosphorylation regulates the
      energy distribution between photosystems I and II of oxygen-evolving
      photosynthetic eukaryotes as well as the turnover of photosystem II proteins. So
      far the only known effect of light on the phosphorylation process is the redox
      dependent regulation of the membrane-bound protein kinase(s) activity via
      plastoquinol bound to the cytochrome bf complex and the redox state of thylakoid
      dithiols. By using a partially purified thylakoid protein kinase and isolated
      native chlorophyll (chl) a/b light-harvesting complex II (LHCII), as well as
      recombinant LHCII, we find that illumination of the chl-protein substrate exposes
      the phosphorylation site to the kinase. Light does not activate the
      phosphorylation of the LHCII apoprotein nor the recombinant pigment-reconstituted
      complex lacking the N-terminal domain that contains the phosphothreonine site.
      The suggested light-induced conformational change exposing the N-terminal domain
      of LHCII to the kinase is evidenced also by an increase in its accessibility to
      tryptic cleavage after light exposure. Light activates preferentially the
      trimeric form of LHCII, and the process is paralleled by chl fluorescence
      quenching. Both phenomena are slowly reversible in darkness. Light-induced
      exposure of the LHCII N-terminal domain to the endogenous protein kinase(s) and
      tryptic cleavage occurs also in thylakoid membranes. These results demonstrate
      that light may regulate thylakoid protein phosphorylation not only via the signal
      transduction chain connecting redox reactions to the protein kinase activation,
      but also by affecting the conformation of the chl-protein substrate.

PMID- 10393988
TI  - Committee proposals and restrictive rules.
AB  - I analyze a game-theoretic model of committee-legislature interaction in which a
      majority decision to adopt either an open or closed amendment rule occurs
      following the committee's proposal of a bill. I find that, in equilibrium, the
      closed rule is almost always chosen when the dimension of the policy space is >1.
      Furthermore, the difference between the equilibrium outcome and that which would
      have occurred under the open rule can be arbitrarily small.

PMID- 10393986
TI  - Stress-induced behaviors require the corticotropin-releasing hormone (CRH)
      receptor, but not CRH.
AB  - Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal
      stress response, causing stimulation of corticotropin and glucocorticoid
      secretion. CRH is also widely believed to mediate stress-induced behaviors,
      implying a broader, integrative role for the hormone in the psychological stress
      response. Mice lacking the CRH gene exhibit normal stress-induced behavior that
      is specifically blocked by a CRH type 1 receptor antagonist. The other known
      mammalian ligand for CRH receptors is urocortin. Normal and CRH-deficient mice
      have an identical distribution of urocortin mRNA, which is confined to the region
      of the Edinger-Westphal nucleus, and is absent from regions known to mediate
      stress-related behaviors. Since the Edinger-Westphal nucleus is not known to
      project to any brain regions believed to play a role in anxiety-like behavior, an
      entirely different pathway must be postulated for urocortin in the Edinger
      Westphal nucleus to mediate these behaviors in CRH-deficient mice. Alternatively,
      an unidentified CRH-like molecule other than CRH or urocortin, acting through the
      CRH receptors in brain regions believed to mediate stress-induced behaviors, may
      mediate the behavioral response to stress, either alone or in concert with CRH.

PMID- 10393987
TI  - The mechanism of isoluminant chromatic motion perception.
AB  - An isoluminant chromatic display is a color display in which the component colors
      have been so carefully equated in luminance that they stimulate only color
      sensitive perceptual mechanisms and not luminance-sensitive mechanisms. The
      nature of the mechanism by which isoluminant chromatic motion is perceived is an
      important issue because color and motion processing historically have been
      associated with different neural pathways. Here we show that isoluminant
      chromatic motion (i) fails a pedestal test, (ii) has a temporal tuning function
      that declines to half-amplitude at 3-6 Hz, and (iii) is perceived equally well
      when the entire motion sequence is presented monocularly (entire motion sequence
      to one eye) versus interocularly (the frames of motion sequence alternate between
      eyes so that neither eye individually could perceive motion). These three
      characteristics indicate that chromatic motion is detected by the third-order
      motion system. Based on this theory, it was possible to take a moving isoluminant
      red-green grating and, by simply increasing the chromatic contrast of the green
      component, to generate the full gamut of motion percepts, from compelling smooth
      motion to motion standstill. The perception of motion standstill when the third
      order mechanism is nullified indicates that there is no other motion computation
      available for purely chromatic motion. It follows that isoluminant chromatic
      motion is not computed by specialized chromatic motion mechanisms within a color
      pathway but by the third-order motion system at a brain level where binocular
      inputs of form, color, depth, and texture are simultaneously available and where
      selective attention can exert a major influence.

PMID- 10393989
TI  - Right hemispheric dominance of inhibitory control: an event-related functional
      MRI study.
AB  - Normal human behavior and cognition are reliant on a person's ability to inhibit
      inappropriate thoughts, impulses, and actions. The temporal and spatial
      advantages of event-related functional MRI (fMRI) were exploited to identify
      cortical regions that showed a transient change in fMRI signal after the
      withholding of a prepotent motor response. The temporal specificity of the event
      related fMRI design also minimized possible contamination from response
      inhibition errors (i. e., commission errors) and other extraneous processes.
      Regions identified were strongly lateralized to the right hemisphere and included
      the middle and inferior frontal gyri, frontal limbic area, anterior insula, and
      inferior parietal lobe. Contrary to the prominence traditionally given to ventral
      frontal regions for response inhibition, the results suggest that response
      inhibition is accomplished by a distributed cortical network.

PMID- 10393990
TI  - Plasma homocysteine concentrations of preterm infants.
AB  - Mild hyperhomocysteinemia in adults is associated with an increased risk of
      vascular disease. Although information is available about plasma homocysteine
      concentrations in childhood, data are entirely lacking for preterm infants
      despite their known abnormalities of sulfur amino acid metabolism. We measured
      plasma total homocysteine concentrations of 9 preterm infants (gestational age 23
      31 weeks) within 48 h of birth and over the subsequent 14 days of life, and 4
      term infants (gestational age 36-39 weeks) on a single occasion within 72 h of
      birth. As measured within 48 h of birth, average plasma homocysteine and cysteine
      concentrations of the preterm infants were 3.8 +/- 0.3 and 122 +/- 8 microM, both
      significantly less than those of the term infants (6.1 +/- 1.3 and 187 +/- 39)
      and of normal adults (8.2 +/- 0.5 and 232 +/- 6). Plasma homocysteine (but not
      cysteine) appeared to gradually increase during the first 2 weeks of life (p =
      0.053). Our results indicate that hyperhomocysteinemia does not normally occur in
      preterm infants.

PMID- 10393991
TI  - Postnatal exposure to androgens alters renal ornithine decarboxylase ontogeny and
      abolishes renal sexual dimorphism in mice.
AB  - The mouse kidney presents marked sexual dimorphism, manifested not only in renal
      size but also in the subcellular structure and enzyme activity. Ornithine
      decarboxylase (ODC), a key enzyme in the biosynthetic pathway of polyamines, is
      induced in the kidney by androgens, and its activity is higher in the kidney of
      male mice. The renal differences between male and female mice are not manifested
      during the first weeks of life and start to be expressed after weaning,
      simultaneously with the increase in plasma testosterone concentration. Treatment
      of newborn mice before postnatal day 21 with a single dose of testosterone
      propionate (TP, 200 microg/animal) did not increase renal ODC activity or renal
      size. From day 21 the same treatment elicited significant increases in renal ODC,
      especially in females where the basal activity of control animals was much lower
      than in males. The repeated injection of TP during the first 10 days of life (200
      microg/animal, days 1, 4, 7 and 10) promoted an early increase in renal ODC
      activity but abolished the physiological rise observed in male mice at puberty
      and adulthood. This treatment dramatically reduced the secretion of the sexual
      hormones, testosterone, estradiol and progesterone, by the gonads, and diminished
      renal size as well as ODC and beta-glucuronidase activities in male mice.
      Stanozolol produced effects similar to those of TP, while the nonsteroidal
      antiandrogen, flutamide, did not apparently affect the normal development of the
      male or female kidney. The results indicate that: (a) kidney sexual dimorphism is
      not congenital; (b) neonatal androgens are not required to induce the sexual
      dimorphism of the mouse kidney; (c) the neonatal kidney is unresponsive to
      testosterone; (d) the premature and repeated exposure to supraphysiological
      levels of testosterone may accelerate the ontogeny of renal ODC but can abolish
      later testosterone secretion and hence alter the sexual characteristics of the
      male kidney, and (e) the postnatal treatment with androgens does not affect the
      response of the adult kidney to exogenous androgens. One can conclude that the
      postnatal manipulation of androgens may accelerate the development of the
      mechanisms of androgen responsiveness in some tissues but it may alter neural
      structures, probably the GnRH pulse generator, that control testosterone
      secretion.

PMID- 10393993
TI  - Expression of intestinal trefoil factor in developing rat intestine.
AB  - Intestinal trefoil factor (ITF or TFF3), a small peptide secreted at the mucosal
      surface by goblet cells throughout the mature intestine, appears to play
      important roles in the maintenance and repair of the intestinal mucosal barrier.
      To study the expression of TFF3 during development, intestinal tissues were
      collected from rats at different development stages and examined by Northern blot
      analysis, Western blot analysis and immunohistochemical staining for TFF3 mRNA
      and protein expression. The results demonstrate that rat TFF3 mRNA is not
      detected until the 17th gestational day (term = 22 days), the expression is
      greater on gestational day 20 and increased further postnatally. TFF3 protein is
      first detected by Western blotting and immunohistochemical staining on
      gestational day 20. Further increases in TFF3 protein expression are demonstrated
      at around the weaning period. In conclusion, significant expression of rat TFF3
      commences late in gestation and its expression is relatively deficient in
      immature rats. Expression of TFF3 may be deficient in premature infants and,
      therefore, may have a role in the development of necrotizing enterocolitis.

PMID- 10393992
TI  - Oxidative damage in fetal rat brain induced by ischemia and subsequent
      reperfusion. Relation to arachidonic acid peroxidation.
AB  - To determine whether ischemia followed by subsequent reperfusion can induce fetal
      cerebral oxidative damage, we created a model of fetal ischemia/reperfusion using
      rats at day 19 of pregnancy. Fetal ischemia was induced by unilateral occlusion
      of the utero-ovarian artery for 20 min. Reperfusion was achieved by releasing the
      occlusion and restoring the circulation for 30 min. The opposite uterine horn was
      used as control. We measured brain mitochondrial respiratory control index (RCI)
      and the concentration of thiobarbituric acid-reactive substances (TBARS) in each
      group. Arachidonic acid (AA) peroxidation induced by the incubation of brain
      microvessel fraction and AA was measured. AA peroxidation was also evaluated with
      and without aspirin, an inhibitor of cyclooxygenase and phenidone, which inhibits
      both of cyclooxygenase and lipoxygenase. The RCI significantly decreased by the
      occlusion with (p < 0.01) or without reperfusion (p < 0.05). The TBARS level
      significantly increased with occlusion plus reperfusion (p < 0.01). AA
      peroxidation was significantly greater in the occlusion and occlusion plus
      reperfusion groups than in the control groups (p < 0. 01). Aspirin did not affect
      peroxidation, while phenidone significantly inhibited it in a concentration
      dependent manner (p < 0.001). Accordingly, ischemia followed by reperfusion is
      likely to induce fetal cerebral lipid peroxidation, which may inhibit
      mitochondrial respiratory activity. The phenidone-inhibited enzyme lipoxygenase
      may participate importantly in this peroxidation.

PMID- 10393994
TI  - Cross-desensitization to furosemide and salbutamol in isolated neonatal guinea
      pig airways.
AB  - Airway hyperresponsiveness in neonatal chronic lung disease is treated with both
      furosemide, a diurectic that inhibits the Na-K-2Cl cotrasporter, and salbutamol,
      a beta2-adrenoceptor agonist. Tachyphylaxis to both drugs in vitro has been
      described. This study was conducted to determine if the relaxation response in
      newborn guinea pig airways to furosemide and salbutamol can be cross-desensitized
      in vitro. Tracheal ring segments from 4- to 7-day-old guinea pigs were suspended
      in HEPES buffer for measurement of isometric tension. Segments were pre-treated
      with either furosemide (300 microM, 1 h) or salbutamol (10 microM, 30 min). After
      constriction with 3 microM acetylcholine, relaxation response to salbutamol or
      furosemide, respectively, was measured. Pretreatment with furosemide diminished
      relaxation response to salbutamol [87 +/- 3% (n = 11) vs. 117 +/- 8% (n = 10), p
      < 0.05], as compared to saline-treated controls. In addition, pretreatment with
      salbutamol diminished relaxation response to furosemide [53 +/- 2% (n = 11) vs.
      saline-treated (83 +/- 7%, n = 7, p < 0.05) and DMSO-treated controls (69 +/- 5%,
      n = 5, p < 0.05)]. Measurements of 86Rb uptake, cyclic AMP levels and responses
      in the presence of charybdotoxin make it unlikely that Na-K-2Cl cotransporter
      activity, stimulation of cAMP, or opening of maxi-K+ channels are mechanisms
      involved in the cross-desensitization to furosemide and salbutamol in vitro.

PMID- 10393995
TI  - Neonatal and adult rabbit renal brush border membrane vesicle solute reflection
      coefficients.
AB  - The interaction between solute and water in epithelial transport is represented
      by the solute reflection coefficient. Because the osmotic water transport process
      changes in the rabbit proximal tubule during maturation, there is a potential for
      the solute reflection coefficients to also undergo maturational changes. In the
      present study, we directly examined solute reflection coefficients in neonatal
      and adult brush border membrane vesicles (BBMV) using the stop-flow light
      scattering technique. Reflection coefficients for NaCl, KCl, NaHCO3 and urea were
      found to be identical in the neonatal and adult BBMV and were not different from
      1. Thus, although the water transport pathway undergoes changes in the proximal
      tubule during maturation, there is no evidence for changes in solute and water
      interaction. Because the reflection coefficients are not different from 1, there
      is no evidence for solvent drag in the proximal tubule apical membrane in either
      the neonatal or adult tubule.

PMID- 10393996
TI  - Effects of caffeine on heart mitochondria in newborn rats.
AB  - Caffeine consumption has been implicated in the development of cardiovascular
      disease. Therefore, in the present study, litters of rats were combined upon
      birth, and 8 pups were randomly assigned to each dam. Dams with pups were divided
      into 2 groups: group 1 received a 20% protein diet as a control, and group 2
      received the 20% protein diet supplemented with caffeine (4 mg/100 g body
      weight). Pups from both groups were killed on days 11 and 15. Transmission
      electron microscopy revealed swollen, disrupted, degenerating mitochondria and
      intracellular edema in the hearts of rats in the caffeine groups when compared
      with those of the controls. Plasma Cu concentration was significantly decreased.
      These results indicate that early exposure to caffeine through maternal milk
      adversely affects cardiac mitochondria of rat pups and may be associated with
      decreased plasma Cu levels. It is unclear whether these results apply to the
      human infant. Interspecies extrapolation from rat to human must be made with
      caution.

PMID- 10393997
TI  - Do cry features reflect pain intensity in preterm neonates? A preliminary study.
AB  - The purpose of this study was to investigate if cries from preterm neonates would
      reflect changes in pain intensity following interventions. The cries from 25
      preterm neonates from an original sample of 122 were audiorecorded while the
      infant was undergoing heelstick during a randomized crossover design testing the
      efficacy of: pacifier with sucrose or water, or prone position as compared to
      standard care. Both pacifier conditions reduced procedural pain according to a
      validated composite pain measure (the Premature Infant Pain Profile). There were
      proportionately fewer cries in the two pacifier groups compared to the prone
      positioning and standard care groups, and cry duration was positively correlated
      with PIPP scores. However, neither cry duration nor fundamental frequency
      reflected group differences. Further research is needed to determine if cry is a
      sensitive and valid indicator of pain in preterm infants.

PMID- 10393998
TI  - Failure of gamma-interferon to decrease mortality from group B streptococcal
      sepsis in neonatal rats.
AB  - Newborns possess an altered immune response to infection with impaired leukocyte
      chemotaxis and deficient production of gamma-interferon (IFN-gamma). IFN-gamma
      enhances neonatal leukocyte activation and movement. We proposed that IFN-gamma
      in conjunction with penicillin compared to penicillin therapy without IFN-gamma
      would increase survival from group B streptococcal sepsis in a neonatal rat
      model. Newborn rats were infected with 10(5) cfu of group B streptococci at 48-72
      h of age and randomized to receive either serum albumin (controls), rat
      recombinant IFN-gamma, albumin and penicillin, or IFN-gamma and penicillin.
      Survival 120 h postinfection revealed: controls 5% (1/21); IFN-gamma 4% (1/24);
      penicillin 23% (5/22); and IFN-gamma plus penicillin 10% (2/21). Survival
      analysis with a lognormal parametric regression model revealed only the
      penicillin group to have improved survival compared to controls. Contrasting the
      penicillin group with the IFN-gamma plus penicillin group did not reveal a
      statistically significant difference by the Wald chi2 statistic (p = 0.25).

PMID- 10393999
TI  - Characterization of the Na+/Ca2+ exchanger on rat mast cells. Evidence for a
      functional role on the regulation of the cellular response.
AB  - The Na+/Ca2+ exchanger has not been characterized in rat mast cells, although its
      existence has been previously suggested. In this work, we determine that this
      exchanger exists on rat mast cells and that it has an important regulatory role
      on the cellular function. We have studied uptake and release of 45Ca in the
      presence of different external sodium concentrations and, under the same
      conditions, the simultaneous uptake of 22Na and 45Ca. The results show that
      uptake and release of 45Ca in these cells are related to the concentration of
      sodium in the extracellular medium and that there is also a perfect coupling
      between 22Na and 45Ca fluxes. In these conditions, we evaluated the intracellular
      calcium levels in fura-2 loaded cells. When the extracellular sodium
      concentration was lower than 60 mM, we observed an increase in intracellular
      calcium, reaching its maximum when the extracellular medium has no sodium. Then
      we investigated the effect on histamine release. The ionophore A23187 elicits
      histamine release in rat mast cells, depending on the extracellular calcium
      concentration. This drug releases more histamine (up to twofold) with sodium
      concentrations <60 mM. In the presence of 2,4-dichlorobenzamil hydrochloride, a
      Na+/Ca2+ exchanger inhibitor, the release of histamine induced by the ionophore
      was lower than in controls in media with low external sodium, and, on the
      contrary, at extracellular sodium concentrations >60 mM, the histamine release
      was higher than in controls. In the same conditions, but when the Na+-K+ ATPase
      was inhibited by ouabain, and as a consequence more sodium was inside the cells,
      a high increase in histamine release induced by A23187 in a sodium-free medium
      was observed. Under the same conditions, a high increase in intracellular calcium
      takes place. The overall data are preliminary evidence suggesting the existence
      of a Na+/Ca2+ exchanger in rat mast cells with a threshold to get reversed at 60
      mM external sodium, lower concentrations of this ion increasing internal calcium
      and producing higher histamine release.

PMID- 10394001
TI  - Effect of verapamil enantiomers and metabolites on cardiac K+ channels expressed
      in Xenopus oocytes.
AB  - The effect of verapamil and its enantiomers and metabolites on cardiac action
      potential repolarizing potassium channels was tested. For this purpose, the
      potassium channels Kv1.1, Kv1.5, Kir2.1, and HERG, and the IsK subunit of the IKs
      channel complex were expressed in Xenopus oocytes and two-electrode voltage-clamp
      experiments were performed. Verapamil induced a concentration-dependent block of
      Kv1. 1-, Kv1.5-, IKs-, and HERG-induced currents with IC50 values of 14.0 +/- 2.7
      microM (n = 4), 5.1 +/- 0.5 microM (n = 6), 161.0 +/- 26.3 microM (n = 4), and
      3.8 +/- 0.2 microM (n = 5), respectively. The same potency of HERG channel
      inhibition was observed for the optical enantiomers (+)-verapamil (IC50 = 3.5 +/-
      0.4 microM, n = 5) and (-)-verapamil (IC50 = 4.0 +/- 0.7 microM, n = 4), as well
      as the derivatives norverapamil (D591; IC50 = 3.8 +/- 0.3 microM, n = 4) and D703
      (IC50 = 2.2 +/- 0.4 microM, n = 4). The verapamil metabolites D620 and D617 did
      not block HERG-induced currents at concentrations of up to 30 microM (n = 3).
      These results demonstrate that cardiac delayed rectifier potassium currents are
      sensitive targets to calcium channel blockers.

PMID- 10394000
TI  - Demonstration of a probenecid-inhibitable anion exchanger involved in the release
      of cortisol and cAMP and in the uptake of p-aminohippurate in bovine
      adrenocortical cells.
AB  - Recently we provided evidence for the involvement of a probenecid-inhibitable
      anion exchanger in cortisol release from primary cultures of bovine
      adrenocortical cells. In the present study, we further characterized this
      exchange transporter. Adrenocorticotropic hormone stimulated 3H-p-aminohippurate
      (3H-PAH) uptake into as well as cortisol release from the cells about two- and
      tenfold, respectively. Probenecid inhibited both 3H-PAH uptake and cortisol
      release by about 55 and 63%. Preincubation of the cells with 1 mM PAH trans
      stimulated 3H-PAH uptake by 30%, whereas cortisol release was inhibited by 30%.
      3H-PAH uptake was cis-inhibited by 1 mM glutarate or by 1 mM cortisol in the
      medium, while cortisol release was trans-stimulated by glutarate. PAH in the
      incubation medium showed saturable cis-inhibition of 3H-PAH uptake. The release
      of cyclic adenosine monophosphate, a substrate of the renal PAH exchanger, was
      also inhibited by probenecid and trans-stimulated by glutarate. In summary, the
      trans-stimulation and cis-inhibition experiments support the concept of an anion
      exchanger involved in cortisol and cyclic adenosine monophosphate release from
      and PAH uptake into adrenocortical cells.

PMID- 10394002
TI  - Transduction for sweet taste of saccharin may involve both inositol 1,4,5
      trisphosphate and cAMP pathways in the fungiform taste buds in C57BL mice.
AB  - The transduction pathways for sweet and bitter tastes were investigated with
      assays of inositol 1,4,5-trisphosphate (IP3) and cyclic adenosine monophosphate
      (cAMP) levels in mouse fungiform taste buds. Recordings of taste responses were
      also made in the chorda tympani nerve. Stimulation of the tongue with saccharin
      elicited a significant increase in IP3 levels in the fungiform papilla only at 20
      mM but in cAMP levels at 3 and 20 mM, without affecting those of the nonsensory
      epithelial tissue. Formation of both IP3 and cAMP induced by 20 mM saccharin was
      suppressed by pretreatment of the tongue with pronase, a proteolytic enzyme which
      specifically inhibits sweet responses. Quinine and denatonium elicited both
      significant increases in IP3 levels at a concentration of 20 mM and slight
      decreases in cAMP levels at concentrations of 1-20 mM in the fungiform papilla.
      Recording of the chorda tympani nerve showed good responses by saccharin,
      quinine, and denatonium at concentrations of 1 mM and higher. These results
      suggest that the fungiform taste cells in C57BL mice have pronase-sensitive
      receptors for saccharin, coupled to both the IP3 and the cAMP pathways; the
      former participates only at high concentration, while the latter acts from low to
      high concentrations. The results also do not rule out the possibility that a
      phosphodiesterase-mediated cAMP decrease may be involved in bitter transduction
      for quinine and denatonium.

PMID- 10394003
TI  - Lack of osmosensitive CD9 expression in rat liver cells.
AB  - CD9 mRNA was found to be strongly expressed in H4IIE rat hepatoma cells and rat
      liver macrophages (Kupffer cells), whereas the expression was weak in primary rat
      liver parenchymal cells. An osmosensitive regulation of CD9 mRNA levels was not
      detectable in all three cell types, whereas this has recently been described for
      Madin Darby canine kidney cells and rabbit renal papillary cells (see text). The
      findings suggest that osmoregulation of specific genes may exhibit cell type
      specificity.

PMID- 10394005
TI  - European Surveillance of Infections in Cancer Patients--ESIC.
AB  - Major advances in cancer therapy result from development of multidrug
      chemotherapy regimens. Besides death from tumor progression, infections are
      currently one of the major causes of mortality and morbidity. Because of the risk
      of complications and mortality, the treatment for febrile neutropenia is
      admission to hospital and administration of broad-spectrum antibiotics. Response
      rates of initial antimicrobial treatment vary considerably (40-92%). Due to the
      heterogeneity of populations in randomized studies, comparison of efficacy and
      identification of risk factors is limited. This is the main reason why the
      European Society of Biomodulation and Chemotherapy (ESBiC) is conducting a
      surveillance study that concentrates more on the evaluation of risk factors than
      on the therapeutic outcome of prospective randomized antimicrobial regimens:
      European Surveillance of Infections in Cancer Patients (ESIC). The present
      contribution is to determine which cancer patients are at low risk for fever, and
      can benefit from first-line treatment with treatment options such as monotherapy
      as well as on an outpatient basis.

PMID- 10394007
TI  - In vitro bactericidal activities of a new oral cephalosporin, E1100, and
      morphologic changes on Escherichia coli.
AB  - Escherichia coli is one of the most common aerobic bacteria in pelvic
      inflammatory diseases. Oral cephalosporins have been widely used against those
      infections. We investigated in vitro morphologic changes induced on E. coli by a
      new oral cephalosporin, E1100, and its bactericidal activity on this organism.
      Morphologic changes were observed by electron microscopy. E1100 induced
      morphologic changes (filamentation) and exerted a bactericidal activity on E.
      coli. The filamentation induced by E1100 was time and concentration dependent.

PMID- 10394004
TI  - Antioxidant defense in the follicular fluid of water buffalo.
AB  - Oxidative damages to the oocyte or follicular cells were suggested to trigger
      atresia. In water buffalo, loss of the blood-follicle barrier sieving effect on
      the diffusion of plasma haptoglobin was previously found to be associated with
      atretic oocytes. The redox status of water buffalo follicles was evaluated by
      measuring in follicular fluid both the total antioxidant capacity (TAC),
      expressed as Trolox equivalents, and the concentration of specific free radical
      scavengers, determined by high-performance liquid chromatography. Among follicles
      at random stages of the reproductive cycle (n = 74), a number (n = 32) were
      analyzed also for the cumulus-oocyte morphology or plasma haptoglobin
      penetration. The haptoglobin follicular concentration compatible with the barrier
      selectivity function was calculated to be less than 53% of the concentration in
      plasma. The data on TAC, retinol, alpha-tocopherol, gamma-tocopherol, ascorbic
      acid, and uric acid fluctuated in a wide range. The relative (follicular vs.
      plasmatic) levels of alpha-tocopherol were found to be negatively correlated with
      those of retinol (p < 0.01). In the follicles, the alpha-tocopherol levels were
      1.25 +/- 0.35 or 1.99 +/- 0.72 microM when the haptoglobin concentration was <53
      or >53% of the concentration in plasma, respectively. The concentration of
      ascorbic acid or uric acid was higher (up to 10- or 30-fold, respectively) in
      follicular fluid than in plasma. Fluids containing haptoglobin >53% or associated
      with cumulus-oocyte complexes of bad quality displayed levels of uric acid about
      20-fold higher than in plasma. The results suggest that a high penetration of
      haptoglobin in the follicle and cumulus-oocyte degradation is associated with
      alterations of the level of the major antioxidants, particularly with enhancement
      of the uric acid concentration.

PMID- 10394008
TI  - In vitro activities of meropenem and other antimicrobial agents against British
      meningococcal isolates.
AB  - The in vitro activity of meropenem was compared with those of penicillin,
      ampicillin, cefuroxime, cetriaxone, cefotaxime, rifampicin, chloramphenicol,
      sulphadiazine and ciprofloxacin against 121 British meningococcal isolates by a
      microdilution method in Mueller-Hinton broth and by the E test. All meningococcal
      strains were susceptible to the agents except for ampicillin (88.4%), penicillin
      (88.4%), sulphadiazine (57.9%) and rifampicin (95%). The emergence of resistance
      problems among meningococcal isolates stresses the need for their constant
      monitoring and of the development of new agents. In this study we have shown that
      meropenem is highly active in vitro against Neisseria meningitidis. Recent
      studies have indicated that meropenem is highly active clinically and
      bacteriologically in the treatment of bacterial meningitis. Thus, the potentials
      of meropenem as meningococcal prophylactic and therapeutic agent needs to be
      fully evaluated.

PMID- 10394006
TI  - Minimum inhibitory and minimal lethal concentration against Chlamydia trachomatis
      dependent on the time of addition and the duration of the presence of
      antibiotics.
AB  - The purpose of this study was to investigate the properties of several
      antimicrobial agents found to be effective against Chlamydia trachomatis and to
      verify the eradication therapy schedule. The in vitro activities of two
      quinolones (sparfloxacin, ofloxacin), of three macrolides (azithromycin,
      erythromycin, clarithromycin) and of a tetracycline (doxycycline) against C.
      trachomatis were evaluated by several methods for the determination of the
      minimum inhibitory concentration (MIC) and minimal lethal concentration (MLC).
      MLC of azithromycin was only 2 times higher than that of MIC. On the other hand,
      MLCs of other antibiotics were 4-16 times higher than their respective MICs. When
      all antimicrobial agents were added to the infected culture at different times,
      we found that the quinolones even at a concentration of 64 microg/ml could not
      inhibit the formation of inclusion if they were added after 20 h from the start
      of infection. The corresponding period for macrolides and doxycycline was 24 h.
      When the antibiotics were removed at 8 h after the start of the infection, all
      antibiotics except azithromycin and clarithromycin were needed at a concentration
      much higher than their MLCs to inhibit the formation of inclusion. We consider
      macrolides, especially azithromycin, to be an excellent anti-C. trachomatis drug
      because of its lower MICs and MLCs values which were also closer together.

PMID- 10394009
TI  - Apoptosis of cultured neuroblastoma cells is induced by ceramide and not by
      ligation of the Fas/Apo-1/CD95 receptor.
AB  - The expression of the Fas/APO-1/CD95 receptor on the neuroblastoma cell lines IMR
      32, Kelly, SK-N-SH, LS and SiMa was investigated. The induction of apoptosis was
      attempted by incubation with Fas antibody IgM and IgG, Fas ligand and with
      ceramide. All neuroblastoma cell lines proved to be positive for Fas/APO-1/CD95
      receptor expression by FACS. However, propidium iodide staining in FACS showed
      that neither incubation with the Fas antibody nor with the Fas ligand resulted in
      convincing apoptosis of the neuroblastoma cells. On the other hand, incubation
      with ceramide rapidly led to all signs of apoptosis morphologically and in the
      FACS. Therefore, other pathways than Fas/Apo-1/CD95 ligation must be of
      significance for the apoptosis of these neuroblastoma cell lines.

PMID- 10394010
TI  - Killing of gram-negative bacteria by ciprofloxacin within both healthy human
      neutrophils and neutrophils with inactivated O2-dependent bactericidal
      mechanisms.
AB  - The intraphagocytic killing of Escherichia coli, Serratia marcescens, Pseudomonas
      aeruginosa, and Salmonella typhi by ciprofloxacin (0.1, 1 and 5 microg/ml) within
      human neutrophils with intact and impaired (by phenylbutazone treatment) O2
      dependent killing mechanisms was studied and compared with the extracellular
      killing in the same medium of the intraphagocytic killing, but omitting
      neutrophils. The MIC/MBC of ciprofloxacin in vitro (assays performed according to
      NCCLS specifications) were: 0.015/0.06 for E. coli, 0.12/32 for S. marcescens,
      1/16 for P. aeruginosa, and 0.007/0.06 for S. typhi. Ciprofloxacin showed
      bactericidal activity both extracellular and within phenylbutazone-treated and
      untreated neutrophils. The minimum concentration of ciprofloxacin to kill 90% of
      phagocytosed bacteria within neutrophils with normal O2-dependent killing power
      after 30 min was: 0.1 microg/ml for E. coli, and S. typhi, 1 microg/ml for P.
      aeruginosa, and 5 microg/ml for S. marcescens. In contrast, exposure for 60 min
      was required to reach this percentage within phenylbutazone treated neutrophils.
      The minimum concentration to kill 90% of extracellular bacteria after 30 min was:
      0.1 microg/ml for E. coli, P. aeruginosa and S. typhi, and 5 microg/ml, for S.
      marcescens. A positive interaction between ciprofloxacin and the O2-dependent
      mechanisms of phagocytes was found. The reactive oxygen metabolites produced in
      the respiratory burst did not affect the intraphagocytic activity of
      ciprofloxacin. Phenylbutazone treatment of phagocytes would be a good
      experimental model to study the intraphagocytic killing of drugs in situations
      such as AIDS and chronic granulomatous disease where inefficient oxidative
      mechanisms of neutrophils exist.

PMID- 10394011
TI  - Effect of fluconazole on human polymorphonuclear leucocyte functions ex vivo
      against Candida albicans.
AB  - Polymorphonuclear leucocytes (PMNs) are important components of host defence
      against fungi. We investigated the ex vivo effect of fluconazole on chemotaxis,
      adherence, superoxide anion (O-2) generation and intracellular killing of Candida
      albicans blastoconidia after the administration of fluconazole (300 mg per os) to
      healthy volunteers. With regard to chemotaxis in response to zymosan-activated
      serum (ZAS), as measured using an agarose gel technique, fluconazole neither
      increased, nor decreased the chemotaxis of PMNs. The adherence was significantly
      enhanced after exposure of PMNs to fluconazole under ex vivo conditions, whereas,
      O-2 production after stimulation of PMNs with ZAS was not affected by
      fluconazole. The effect of fluconazole on intracellular killing of C. albicans
      blastoconidia by PMNs was determined by viable colony count, after release of
      yeast cells from disturbed neutrophils. Fluconazole under in vitro conditions, at
      a therapeutic concentration, significantly increased the intracellular killing of
      C. albicans by PMNs at 30 min when compared with the results obtained in ex vivo
      experiments (p < 0.001). During 90 min of exposure, no significant difference was
      found between in vitro and ex vivo conditions (p > 0.05).

PMID- 10394012
TI  - Pharmacodynamics of intermittent- and continuous-infusion cefepime alone and in
      combination with once-daily tobramycin against Pseudomonas aeruginosa in an in
      vitro infection model.
AB  - Cefepime, a fourth-generation cephalosporin, is currently one of the primary
      agents used in combination with an aminoglycoside when treating Pseudomonas
      aeruginosa infections. The bactericidal activity of cefepime administered as
      intermittent doses (IT) or continuous infusion (CI) both alone and in combination
      with once-daily tobramycin (ODT) against two clinical strains of P. aeruginosa
      was compared using an in vitro infection model. Cefepime concentrations simulated
      human pharmacokinetics after a 1-gram Q12 regimen, or a 1-gram loading dose
      followed by a 2-gram Q24 CI regimen; the ODT regimen mimicked peak concentrations
      of >/=10 x MIC. All regimen simulations were run in duplicate over 48 h and a
      growth control (no antimicrobials added) was run concurrently. Strains tested,
      PSA5 and PSA10, had MICs of 2 and 8 microg/ml to cefepime, respectively; both
      MICs to tobramycin were 1.0 microg/ml. CI regimens resulted in concentrations
      approximately 6x and 2x the MIC for PSA5 and PSA10, respectively. The change in
      log10 colony-forming units (CFU) per milliliter over time for both P. aeruginosa
      isolates was compared to initial inocula for all treatment regimens. Initial
      bolus doses of both IT and CI regimens resulted in a similar decrease in the
      log10 CFU/ml of both organisms over the first 12 h of the study. After subsequent
      doses, however, both IT regimens showed greatly diminished bactericidal activity,
      while both CI regimens were persistently bactericidal without the observation of
      significant regrowth. As a result, a statistical difference in log10 CFU/ml
      between both IT and CI regimens with and without ODT was realized at 24, 36 and
      48 h for each isolate. Unlike IT dosing, CI cefepime alone or in combination with
      ODT optimizes bactericidal activity by maximizing the percent of the dosing
      interval that concentrations remained above the MIC resulting in undiminished
      bacterial inhibition when compared to IT regimens. These data further suggest
      that CI is the most efficient method of administration of beta-lactam
      antibiotics.

PMID- 10394013
TI  - Ionic binding of 3H-gentamicin and short-time bactericidal activity of gentamicin
      against Pseudomonas aeruginosa isolates with different lipopolysaccharide
      structures.
AB  - The clinical isolates of Pseudomonas aeruginosa can be roughly classified into
      long- and short-LPS strains and LPS-deficient strains. Ionic binding of 3H
      gentamicin was the highest in the long-LPS strains followed in descending order
      by short-LPS and LPS-deficient strains. However, PAC605 strain, completely
      lacking in the repeated units of O-polysaccharide and also lacking in some of the
      neutral sugar residues of the core oligosaccharide region, highly bound to 3H
      gentamicin and it is suggested that the negatively charged sites on the deep-core
      oligosaccharide region and/or on lipid A participated in the binding to 3H
      gentamicin. This manner of binding may be also applied to P. aeruginosa No. 45
      (LPS-deficient), a clinical isolate.

PMID- 10394014
TI  - Nitazoxanide, a nitrothiazolide antiparasitic drug, is an anti-Helicobacter
      pylori agent with anti-vacuolating toxin activity.
AB  - Nitazoxanide (NTZ), a synthesized drug of the nitrothiazolide class, was
      initially developed as an antiparasitic compound. This compound has recently been
      shown to have antibacterial activities against some bacterial pathogens. In the
      present study, NTZ and its main metabolite tizoxanide (TIZ) were found to have
      strong minimum inhibitory concentrations (MICs) against both metronidazole (MTZ)
      resistant strains and sensitive clinical isolates of Helicobacter pylori. The
      MIC90 of both NTZ and TIZ against 37 clinical isolates was 8 microg/ml.
      Vacuolating toxin activity of H. pylori assayed by HeLa cell vacuole formation
      was inhibited by NTZ at a sub-MIC. In contrast, urease production by H. pylori
      was not specifically affected by the sub-MIC of NTZ. An acidic pH (pH 5.0) medium
      reduced the antimicrobial activity of the drug in terms of growth inhibition due
      to the low growth rate of the bacteria, but killing activity of NTZ against the
      bacteria was still observed. Thus, it was apparent that both NTZ and TIZ are
      highly effective against H. pylori, even when the bacteria are resistant to MTZ.

PMID- 10394015
TI  - Nosocomial staphylococcal meningitis in neonates successfully treated with
      intraventricular teicoplanin.

PMID- 10394017
TI  - Amphotericin B colloidal dispersion. Pre-clinical review.
AB  - Amphotericin B Colloidal Dispersion (ABCD, AmphocilTM), a noncovalent complex of
      amphotericin B and cholesteryl sulfate, is active in vitro and in vivo against a
      wide variety of fungal species; its activity is broadly comparable to the range
      of activity of conventionally formulated amphotericin B (CAB). The
      pharmacokinetics of ABCD and CAB differ. ABCD is more rapidly removed from
      circulation than CAB, with more than 99% clearance one hour after administration,
      but has a much more prolonged terminal elimination phase. Preclinical safety
      studies have shown that ABCD is significantly better tolerated and less
      nephrotoxic than CAB. ABCD does cause renal tubular damage after high doses, but
      only at doses five- to eight-fold higher than those of CAB. Preclinical studies
      suggest that the efficacy, but not the toxicity of ABCD and CAB will be
      identical. ABCD may thus provide a safer therapeutic alternative to CAB.

PMID- 10394019
TI  - Clinical efficacy of amphotericin B colloidal dispersion against infections
      caused by Aspergillus spp.
AB  - Three published clinical trials of the efficacy of amphotericin B colloidal
      dispersion (ABCD) against infections caused by Aspergillus spp were reviewed. A
      total of 376 patients was treated. Systemic aspergillosis was identified in 67
      evaluable patients. Overall, a complete or partial response was achieved in 47.8%
      of the evaluable patients, although there were substantial differences in the
      response rates between studies. Reasons for recruitment caused a marked
      difference in response rates. The overall response rate for ABCD in patients in
      which conventional amphotericin B (CAB) was contra-indicated or had previously
      failed was 34.3%, whereas the response rate in bone marrow transplant (BMT) or
      patients with renal impairment was 57.9 and 62.5% respectively. The efficacy of
      ABCD at doses of 4 mg/kg/day appears to be at least as good as in studies using
      CAB. The levels of renal toxicity were low at a dose of 4 mg/kg/day. Dose
      limiting studies indicate that dosages can be safely increased to 7.5 mg/kg/day
      creating opportunity for improved efficacy.

PMID- 10394016
TI  - The challenge of invasive fungal infection.
AB  - Systemic fungal infections cause almost 25% of the infection-related deaths in
      leukaemic patients. Particularly those with prolonged neutropenia are at risk but
      mycoses also feature in critically ill intensive care patients and in individuals
      who are treated for solid tumours and AIDS, or who received an organ transplant.
      The spread of AIDS and the more aggressive cytotoxic chemotherapy in combination
      with an improved management of haemorrhages and bacterial infections in leukaemic
      and other cancer patients facilitated the occurrence of these invasive fungal
      infections. These life-threatening complications remain both difficult to
      diagnose and to treat and therefore carry a poor prognosis. For many years, the
      only realistic option to treat systemic infections was amphotericin B, whose
      administration was known to be associated with numerous adverse effects. Now less
      toxic formulations of amphotericin have become available for clinical use, as
      well as several new triazoles that appear to provide an effective and less toxic
      alternative for the treatment of certain fungal infections.

PMID- 10394018
TI  - Clinical efficacy of amphotericin B colloidal dispersion against infections
      caused by Candida spp.
AB  - Five clinical trials of the efficacy of amphotericin B colloidal dispersion
      (ABCD) primarily in patients unable to tolerate or failing treatment with
      conventional amphotericin B (CAB) were reviewed. A total of 572 patients were
      treated. Systemic candidal infections were identified in 107 evaluable patients
      and 239 in the intent-to-treat population. Seventy percent of the evaluable
      patients and 50% of the intent-to-treat patients achieved a complete or partial
      response. There were no significant differences either in response rates for
      different underlying causes or in response rates according to enrollment reason.
      The efficacy of ABCD at doses of 3-4 mg/kg/ day in disseminated candidiasis
      appears to be similar to that in studies using CAB. Renal and hepatic toxicity of
      ABCD is low.

PMID- 10394022
TI  - Treatment of visceral leishmaniasis with amphotericin B colloidal dispersion.
AB  - Amphotericin B is an effective antileishmanial agent whose use is limited by drug
      toxicity. The development of less toxic, lipid encapsulated formulations of
      amphotericin B as antimycotic agents has made these formulations available for
      testing against visceral leishmaniasis, a disease ideally suited for 'liposomal'
      therapy since the parasites are only found within reticuloendothelial
      macrophages. In phase II experiments of Amphotericin B Colloidal Dispersion
      (ABCD) for Brazilian kala-azar, 10 of 10 patients were cured with 2 mg/kg/day for
      10 days; 9 of 9 patients were cured with 2 mg/kg/day for 7 days; 9 of 10 patients
      were cured with 2 mg/kg/day for 5 days. The ability to cure 90% of kala-azar
      patients with a regimen of merely 5 days is remarkable considering that 20-40
      days of treatment with pentavalent antimonials and a 28-40 day course of (every
      other-day) amphotericin B desoxycholate therapy are otherwise needed. Although
      ABCD did frequently cause a syndrome of fever and respiratory distress during
      infusion for children less than 6 years of age, the virtual absence of kidney
      toxicity was striking.

PMID- 10394020
TI  - Renal sparing by amphotericin B colloidal dispersion: clinical experience in 572
      patients.
AB  - Data from five clinical trials of amphotericin B colloidal dispersion (ABCD) in
      the treatment of invasive mycoses were pooled to analyze the renal sparing
      effects of ABCD. Serum creatinine levels at baseline and either during or at end
      of treatment were available for 499 of 572 patients (87.2%). The median
      cumulative dose of ABCD administered to the 499 evaluable patients was 4,050
      (range: 30-74,250) mg, and the median duration of treatment was 18 (range: 1-407)
      days. For the entire group of evaluable patients, the median change in serum
      creatinine during treatment with ABCD was -0. 1 mg/dl; for the subgroups of
      patients enrolled in the trials because of amphotericin B toxicity or preexisting
      renal impairment, the median changes in serum creatinine were -0.3 and -0.2
      mg/dl, respectively. There was no trend of increasing serum creatinine with
      increasing cumulative dose of ABCD (correlation coefficient = -0. 016). ABCD was
      prematurely discontinued in 19 of 572 patients (3.3%) because of elevated serum
      creatinine levels. Unlike conventional amphotericin B, ABCD is not associated
      with dose-dependent nephrotoxicity.

PMID- 10394021
TI  - The population pharmacokinetics of amphotericin B colloidal dispersion in
      patients receiving bone marrow transplants.
AB  - The purpose of this study was to identify the pharmacokinetics of Amphotericin B
      Colloidal Dispersion in patients undergoing bone marrow transplantations with
      systemic fungal infections and to assess the influence of ABCD on renal function.
      Seventy-five patients (42 females, 33 males) with a median age of 34.5 years and
      median weight of 70.0 kg were enrolled in the study. The plasma concentration
      data was available in 51/75 patients and was best described by a two-compartment
      model; both plasma clearance and volume of distribution increased with escalating
      doses; the overall average terminal elimination half-life was 29 h. Serum
      creatinine values over the duration of therapy were available in 59/75 patients.
      Overall, there was no net change in renal function over the duration of therapy.

PMID- 10394023
TI  - Safety and efficacy of amphotericin B colloidal dispersion. An overview.
AB  - The efficacy and safety of Amphotericin B Colloidal Dispersion (ABCD) have been
      investigated on 572 patients in five Phase I/II clinical trials. The patients
      were all selected to present a challenging test; having a fungal infection
      superimposed on severe illness. In 442 cases ABCD was used after amphotericin B,
      which had been withdrawn. One hundred and forty patients had pre-existing
      nephrotoxicity. Most patients received doses of 3-6 mg/kg/day of ABCD. Complete
      or partial recovery was reported in 149/260 (57.3%) patients evaluable for
      therapeutic response. Patients with Candida infection responded better than those
      with systemic aspergillosis showing 70.1% recovery vs. 48.8%. ABCD therapy made
      no difference to serum creatinine levels, even in patients with pre-existing
      renal failure, nor to liver function as measured by SGOT, alkaline phosphatase
      and total bilirubin levels in serum. Infusion-related adverse events were the
      most frequently reported side effects of ABCD. However these studies show clearly
      that ABCD can be administered safely to patients without the risks of renal
      toxicity, even when renal toxicity had already developed following therapy with
      conventional amphotericin B deoxycholate.

PMID- 10394025
TI  - Epidermal growth factor protects against pancreatic damage in cerulein-induced
      pancreatitis.
AB  - Epidermal growth factor (EGF) exhibits gastroprotective and ulcer-healing action.
      These observations prompted us to determine the influence of EGF on cerulein
      induced pancreatitis (CIP) in the rat. Acute pancreatitis was induced by
      subcutaneous infusion of cerulein (10 microg/kg/h) for 5 h. Initially EGF was
      administrated twice at doses of 1, 5, 10 or 100 microg/kg s.c. (first injection
      30 min prior to cerulein infusion, and the second injection 2.5 h after the start
      of cerulein infusion) and from this part of study 10 microg/kg was chosen for the
      next experiments. CIP led to a significant decrease in DNA synthesis and a
      reduction in pancreatic blood flow (PBF) by 42 and 30%, respectively, as well as
      a significant increase in pancreatic weight, plasma amylase concentration, plasma
      interleukin-1beta (IL-1beta) level and the development of the histological signs
      of pancreatic damage with marked edema, leukocyte infiltration and vacuolization
      of acinar cells. Treatment with EGF attenuated the pancreatic tissue damage in
      CIP as manifested by partial reversal of the drop in DNA synthesis and
      improvement of pancreatic histology. Moreover, EGF administration attenuated the
      fall in PBF and significantly reduced the cerulein-evoked increase in pancreatic
      weight. Also plasma amylase and IL-1beta were decreased in rats treated with EGF.
      We conclude that: (1) EGF exerts a protective effect against CIP, and (2) the
      beneficial activity of EGF in CIP seems to depend on the increase in pancreatic
      cell proliferation, the reduction in cytokine generation and the attenuation of
      the fall in PBF.

PMID- 10394024
TI  - Complex formation among rat pancreatic secretory proteins under mild alkaline pH
      conditions.
AB  - Previous in vitro studies have demonstrated that enzyme proteins liberated from
      isolated zymogen granules of the rat pancreas aggregate already at neutral or
      slightly basic pH and form small particles which in the acidic pH range
      progressively condense into dense cores of about the size of zymogen granules. To
      characterize the protein composition of the original particles in more detail non
      denaturing agarose gel electrophoresis was employed. Five major protein complexes
      were identified which upon separation of individual complexes in 1-D or 2-D gel
      electrophoresis were shown to be composed of a distinct set of known enzymes and
      several unknown proteins. Complexes 1-4 quickly dissociated when enzyme
      activation was induced by enterokinase, but complex 5 was resistant even to this
      treatment. All 5 complexes revealed a distinct fine structure when eluted from
      the gels and studied in negative staining electron microscopy. These findings
      suggest that pancreatic zymogens form complexes already in the lumen of the rough
      endoplasmic reticulum and are transported as such to the Golgi complex where they
      aggregate into granule cores due to the internal acidic pH. Complex formation may
      thus facilitate zymogen sorting within the rough endoplasmic reticulum and may
      prevent premature enzyme activation within cellular compartments.

PMID- 10394026
TI  - Stimulatory effect of nitric oxide on bicarbonate secretion in bullfrog duodenums
      in vitro.
AB  - The effect of nitric oxide (NO) on HCO-3 secretion was examined in vitro using an
      isolated preparation of bullfrog duodenum. The tissue was bathed in unbuffered
      Ringer's solution gassed with 100% O2 on the mucosal side and HCO-3 Ringer's
      solution gassed with 95% O2-5% CO2 on the serosal side. The HCO-3 secretion was
      measured by the pH-stat method using 2 mmol/l HCl as the titrant to keep the
      mucosal pH at 7.4. (+/-)-(E)-Ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamine
      (NOR3) was used as a NO donor and added to the serosal solution. To analyze the
      NOR3 action on HCO-3 secretion, the effects of dibutyryl adenosine-3',5'-cyclic
      monophosphate (dbcAMP), dibutyryl guanosine-3',5'-cyclic monophosphate (dbcGMP),
      methylene blue, and indomethacin on the HCO-3 response were also examined. NOR3
      (1x10(-4) and 3x10(-4) mol/l) caused an increase in HCO-3 secretion in a dose
      dependent manner, and this effect appeared with an about 30-min time lag,
      reaching the level of 1.5-2.5 times greater than basal values at 1-2 h later.
      Both dbcAMP (1x10(-3) mol/l) and dbcGMP (1x10(-3) mol/l) also caused a
      significant increase in HCO-3 secretion in bullfrog duodenums in vitro, although
      the onset of the HCO-3 response to dbcGMP was delayed as compared to the former.
      The stimulatory action of NOR3 on duodenal HCO-3 secretion was significantly
      attenuated by methylene blue (5x10(-5) mol/l) and indomethacin (1x10(-5) mol/l),
      the latter also inhibiting the HCO-3 response to dbcGMP. The release of
      prostaglandin E2 in the serosal solution was significantly increased after
      addition of NOR3 (3x10(-4) mol/l) and dbcGMP (1x10(-3) mol/l) in an indomethacin
      sensitive manner. These results suggest that the NO donor increases duodenal HCO
      3 secretion in vitro, and this action of NO donor is cGMP-dependent and mediated
      by endogenous prostaglandins. Duodenal HCO-3 secretion may be regulated locally
      by NO/cGMP in addition to prostaglandin/cAMP.

PMID- 10394028
TI  - Immunohistochemical localization of calcitonin gene-related peptide in the human
      gastric mucosa.
AB  - BACKGROUND/AIM: There have been only a few studies on the distribution of
      calcitonin gene-related peptide (CGRP) in the human stomach, in which it was
      stated that CGRP fibers are rare in that organ. The aim of the present study was
      to investigate the immunohistochemical localization of CGRP in the human gastric
      mucosa obtained by endoscopic biopsy from patients with gastric ulcers. METHODS:
      Immunohistochemistry was carried out according to the indirect immunoperoxidase
      method using an anti-human CGRP antibody. Biopsies were taken from the ulcer
      margin in 18 patients (age 37-78, average 57.4 years) and from two endoscopically
      normal portions (antrum and body) in 7 other patients (age 36-65, average 51.0
      years). One biopsy specimen was obtained from each portion. RESULTS: Twelve of
      the eighteen biopsy specimens from the ulcer margin, 6 of the 7 biopsy specimens
      from normal portions of the antrum and 3 of the 7 biopsy specimens from normal
      portions of the body showed CGRP-immunoreactive staining. Intense staining was
      more marked in the specimens from the ulcer margin compared to those of the
      normal portions. CONCLUSIONS: CGRP immunoreactivity was observed in the human
      gastric mucosa in considerable abundance, and it is presumed that CGRP might
      participate in a restoration mechanism of the ulcer.

PMID- 10394027
TI  - Effect of chain length on absorption of biologically active peptides from the
      gastrointestinal tract.
AB  - OBJECTIVES: Protein digestion generates many peptides in the gut lumen. Some of
      these peptides possess biological effects when tested using in vitro systems. It
      is clear that dipeptides and tripeptides can be absorbed intact from the
      gastrointestinal tract. However, the fate of larger peptides and small proteins
      remains unclear. Equally unclear are the biologic potencies of absorbed peptides
      and the quantity of peptide that must be administered into the gut to produce a
      biologic effect. Thus, the purpose of this study was to determine the effect of
      amino acid chain length on the ability of enterally administered peptides to
      produce biologic effects. METHODS: Small bowel feeding tubes, jugular catheters,
      and arterial lines were placed into adult male Sprague-Dawley rats. Rats were
      administered intravenous (50 microg) and enteral (125 and 500 microg) thyrotropin
      releasing hormone (TRH, a tripeptide), intravenous (100 microg) and enteral (100
      and 500 microg) luteinizing hormone-releasing hormone (LHRH, a decapeptide), and
      intravenous (0.5 mg) and enteral (0.5 and 25 mg) insulin (a 51-amino acid
      polypeptide). The quantity of peptide administered represented less than 0.5% of
      a rat's normal daily protein intake. The biologic effect of TRH, LHRH, and
      insulin were assessed using thyroid-stimulating hormone (TSH) response, follicle
      stimulating hormone (FSH) response, and glucose. We also measured serum levels of
      insulin in the rats following enteral insulin administration. RESULTS: The
      results indicate that enteral TRH (125 and 500 microg) produced the same TSH
      response as intravenous TRH. The response to 500 microg enteral LHRH was 50% of
      the response to intravenous LHRH and the response to 25 mg enteral insulin was
      30% of the response to 0.5 mg intravenous insulin. Serum insulin levels increased
      significantly following both 0.5 and 25 mg enteral insulin. CONCLUSIONS: These
      results support the concept that small (di- and tripeptides) and large (10-51
      amino acids) peptides generated in the diet can be absorbed intact through the
      intestines and produce biologic effects at the tissue level. The potency of the
      enterally administered peptides decreases as the chain length increases. We
      postulate that absorbed dietary peptides play a role in the modulation of organ
      function and disease progression.

PMID- 10394029
TI  - Gallbladder volume in adults and its relationship to age, sex, body mass index,
      body surface area and gallstones. An epidemiologic study in a nonselected
      population in France.
AB  - BACKGROUND/AIMS: The role of a large gallbladder volume with regard to a
      predisposition for gallstones is unknown. It is possible that an increase in
      gallbladder volume could result in impaired gallbladder motility and bile stasis.
      We looked for factors affecting gallbladder volume in a random population in the
      southeast of France. METHODS: To assess the relationship between gallbladder
      volume and gallstones, 528 subjects over the age of 30 were studied (72 with
      lithiasis). Age, sex, body mass index, body surface area and gallbladder volume
      were collected for each subject. A linear regression analysis was performed to
      look for significant variables. RESULTS: The overall adjusted prevalence of
      cholelithiasis was 13.9% in our population. On linear regression analysis, two
      variables (age and surface area) were found to be independently correlated with
      gallbladder volume. Gallbladder volume was significantly increased in subjects
      over 50 years (p < 0.001). There was a positive correlation between gallbladder
      volume and body surface area (r = 0. 33, p < 0.001). In this study, the presence
      or absence of gallstones did not significantly affect the gallbladder volume.
      CONCLUSIONS: We report that there is dilatation of the gallbladder with age and
      with an increase in body surface area. Whether this could represent risk factors
      for the occurrence of gallstone remains uncertain.

PMID- 10394031
TI  - Successful symptomatic management of a patient with Menetrier's disease with long
      term antibiotic treatment.
AB  - We present the case of a 79-year-old female patient with criteria typical for
      Menetrier's disease, i.e. enlargement of the gastric folds due to foveolar
      hyperplasia associated with severe protein-loss along with epigastric pain,
      nausea, vomiting and weight loss. Gastrin levels were within the normal range,
      but elevated Helicobacter pylori antibody titers (83 microg/ml) were indicative
      of a recent infection. Histologic examination of a gastric polyp, which was
      removed in toto, revealed the presence of early gastric cancer of the mucosal
      type. After initiation of antibiotic treatment with clarithromycin (3 x 250
      mg/day) and metronidazole (2 x 500 mg/day) in combination with lansoprazole (30
      mg/day), the patient's condition improved rapidly along with abrogation of
      protein loss. Under maintenance treatment as indicated above, the patient has
      been free of symptoms now for a period of more than 2 years. On repetitive
      endoscopic follow-up, there was no change in gastric mucosa morphology either
      endoscopically or histologically, and also no evidence of recurrence of a
      malignant lesion. We conclude that this therapeutic regimen represented an
      effective alternative to surgical intervention in this patient and should be
      considered in similar cases.

PMID- 10394030
TI  - Portal hyperglutamatemia after dietary supplementation with monosodium glutamate
      in pigs.
AB  - The aim of the present work was to examine in pigs the effect of a dietary
      supplementation with the flavor enhancer monosodium glutamate (MSG) on intestinal
      amino acid metabolism. For this purpose, pigs weighing 60 +/- 2 kg received a
      standard meal twice a day for 1 week, supplemented with either 10 g MSG per meal
      or, as control experiments, an isonitrogenous amount of glycine together with an
      equal amount of sodium in the form of NaCl, the animals being their own control
      in all experiments. At the end of this period, pigs received a MSG or glycine
      NaCl-supplemented meal and samples of portal and arterial blood were collected
      for amino acid analysis in plasma. The results demonstrate after MSG
      supplementation rapid significant increases in glutamate concentration in the
      portal and arterial blood plasma after a test meal which resulted in a positive
      portoarterial difference. In comparison, after glycine-NaCl supplementation,
      glutamate concentrations were almost identical in portal and arterial plasma.
      Furthermore, significant increased aspartate concentration in the portal blood
      plasma was observed after MSG supplementation when compared with control
      experiments. When enterocytes were isolated at the end of the supplementation
      period from the jejunum and examined for their metabolic capacities towards L
      glutamate and L-glutamine, it was found that metabolism did not differ according
      to the supplement used, with glutamate and glutamine being oxidized and
      transaminated at a similar level. It is concluded that the portal
      hyperglutamatemia observed shortly after the ingestion of a MSG- supplemented
      meal is likely due to the saturation of the intestinal capacity to metabolize
      glutamate with no measurable adaptation of the metabolic pathways controlling
      glutamate metabolism in enterocytes.

PMID- 10394033
TI  - Abstracts 

PMID- 10394032
TI  - Coincidence of Crohn's disease and a high-risk gastrointestinal stromal tumor of
      the terminal ileum.
AB  - A 51-year-old male patient presented with characteristic radiologic features of
      Crohn's disease in the terminal ileum plus a large tumorous lesion in the right
      lower abdomen. Because of rapid crescent symptoms of bowel obstruction, the
      patient underwent surgery revealing a high-risk gastrointestinal stromal tumor
      (GIST) of the terminal ileum within an area of Crohn's ileitis. Whereas the
      association of chronic inflammatory bowel disease (IBD) and gastrointestinal
      adenocarcinoma is well known, other primary intestinal tumors are rare in these
      patients, particularly at the time of onset of clinical symptoms. This is the 3rd
      patient reported in the literature with a sarcoma complicating IBD, and in fact,
      the first description of the coincidence of Crohn's disease and GIST. Though the
      present case is likely to be a mere coincidence of two pathologically distinct
      entities (without any potential causal relationship), it should remind one of the
      possibility of small bowel 'Crohn's carcinoma' in patients with a sudden change
      in symptomatology as well as in those in whom intestinal obstruction fails to
      resolve with adequate therapy.

PMID- 10394034
TI  - Psychiatric comorbidity in opiate addicts.
AB  - The present study investigates whether a correlation exists between mental
      symptoms and opiate dependency. During a 5-year follow-up study in Hamburg, of
      350 opiate addicts who were in contact with the help system at the time of the
      initial investigation, 219 (63%) could be interviewed three times at 1-year
      intervals. The investigation instruments were standardized questionnaires such as
      EuropASI, CIDI, SCL-90-R and BDI. The general life situation of the investigated
      persons had, on the whole, improved in the course of the last 2-3 years. Drug
      consumption had markedly decreased. One third of the opiate addicts were in a
      comparatively good mental condition on all three survey interviews, for 17% there
      was a worsening of the condition, and for another 17% the negative mental
      condition was reinforced. A correlation can be established between mental
      disorders/symptoms and drug addiction or drug-related problems. The more
      unfavorable the course of the mental symptoms, the greater the problems of the
      client's current life situation. There is also an overall relationship between
      increased drug consumption and mental symptoms like depressivity and anxiety, and
      the psychosocial functioning level. However, the expected correlations between
      mental disorders and the extent of drug consumption are not very marked. This
      indicates that specific constellations of drug consumption and mental disorders
      are not isolated but are related, as elements of a complex behavioral pattern, to
      the development of other life areas of the client.

PMID- 10394035
TI  - Overdoses and suicide attempts: different relations to psychopathology and
      substance abuse? A 5-year prospective study of drug abusers.
AB  - Two hundred Norwegian drug abusers who consecutively applied for treatment in a
      therapeutic community were interviewed at intake and personally followed up on
      average 5 years after. Millon Clinical Multiaxial Inventory and Symptom Checklist
      90 were used to assess the clients. Frequent use of opiates and number of months
      in inpatient treatment were associated with overdoses, while being a case on the
      Borderline scale or depression was related to suicide attempts. The study shows
      that overdoses and suicide attempts can be distinguished on the basis of their
      different psychopathological risk variables and their different relationship to
      substances. To understand the background of these phenomena is of importance in
      planning preventive action to hinder fatal overdose and suicide.

PMID- 10394037
TI  - Can light or moderate drinking benefit mental health?
AB  - Observational studies in several cultures show light and moderate drinking to be
      associated with better emotional and social adjustment than abstinence. However,
      adjustments for pre-existing personality characteristics and socialisation need
      to be made, and abstainers who are ex-drinkers must be excluded. There is still
      insufficient evidence to suggest that emotional health can be improved by light
      or moderate drinking. For cognition, consumption of up to 65 g/day is not
      associated with chronic inefficiencies. With regard to cognitive decline in older
      people, emerging evidence suggests the possibility that such decline may be
      reduced by light drinking. The elderly in institutions probably benefit from a
      'social hour' when alcoholic beverage is available. Doctors considering giving
      advice to drink to improve health should be very cautious and note a number of
      caveats.

PMID- 10394038
TI  - Screening for concomitant alcohol abuse in schizophrenia: clinical significance
      of the Munich Alcoholism Test and laboratory tests.
AB  - For the early and correct diagnosis of the comorbidity of schizophrenia and
      alcoholism, a valid laboratory marker would be most helpful in clinical practice.
      Seventy schizophrenics admitted to a general psychiatric unit of an urban
      hospital located in a large industrial area in Germany prospectively underwent a
      detailed addiction history, the Munich Alcoholism Test (MALT) and determinations
      of serum gamma-glutamyltransferase (gammaGT) and carbohydrate-deficient
      transferrin (CDT). Cutoff levels for laboratory tests represented the 95th
      percentile of data obtained from 100 matched healthy controls. Using the MALT, we
      found evidence of concomitant alcohol consumption in 42.8% of the study patients.
      The sensitivities of gammaGT and CDT for detecting alcohol abuse (confirmed using
      DSM III-R criteria) were 70.6 and 58.8%, respectively. Our data suggest that the
      MALT can be used as a reliable screening test for alcohol use in schizophrenia.
      In neuroleptic-treated schizophrenics with pathological gammaGT, but low MALT
      scores, the corresponding CDT may serve as a highly specific marker to verify a
      concomitant alcohol abuse.

PMID- 10394036
TI  - Cannabis psychosis and acute schizophrenia. a case-control study from India.
AB  - Twenty cases of cannabis psychosis were compared with a control group of 20
      patients with 'acute schizophrenic episode' on a number of demographic, clinical,
      illness-related and outcome variables in a case-control study design using a
      retrospective chart review. The two groups were comparable on demographic, past
      and family histories of mental illness, premorbid personality, psychomotor
      activity, Schneiderian first-rank symptoms and mild cognitive deficits. The
      cases, in contrast to the control group, had a psychosis of shorter duration
      characterized by reactive and congruent affect, relative absence of schizophrenic
      formal thought disorder and a predominantly polymorphic clinical picture. Relapse
      was always preceded by cannabis use. This study suggests that, in spite of
      certain overlaps, 'cannabis psychosis' may still be considered nosologically
      distinct from schizophrenia in India. The implication of the study is that the
      role of cannabis in any acute psychosis should be investigated carefully so as to
      prevent an overdiagnosis of schizophrenia.

PMID- 10394040
TI  - Treatment outcome in alcoholism - a comparison of self-report and the biological
      markers carbohydrate-deficient transferrin and gamma-glutamyl transferase.
AB  - The primary source for evaluating treatment outcome in alcoholism is usually
      verbal self-report. Because the validity of self-report is often doubted, more
      objective markers for treatment outcome are needed. In this study, we compared
      self-report data from 238 male alcohol-dependent patients participating in a
      combined 6-week inpatient followed by a 1-year outpatient treatment program with
      the biological markers carbohydrate-deficient transferrin (CDT) and gamma
      glutamyl transferase (GGT). According to self-report, over 70% of the patients
      had a positive treatment outcome (57% abstinence, 16% intermediate relapse).
      These results are supported by the general reduction of CDT and GGT during the
      treatment period (p < 0. 001). When we performed a cross-sectional analysis at 6
      months during the outpatient program, there was a high consistency of self-report
      data with the biological markers (CDT 93%, GGT 91%, CDT/GGT 85%). Our results
      support the hypothesis that in abstinence- oriented treatment programs, self
      reports are valid and can be used as the basis of measurement for treatment
      outcome.

PMID- 10394039
TI  - Epidemiological study on the follow-up of patients on methadone prescriptions in
      France. Working Group of the National Commission for Substitute Treatments.

PMID- 10394041
TI  - Ambros Uchtenhagen.

PMID- 10394043
TI  - Sensory dysfunction in HTLV-I-associated myelopathy/tropical spastic paraparesis.
      A comprehensive neurophysiological study.
AB  - We performed a comprehensive clinical and neurophysiological evaluation of
      function of the large- and small-caliber afferent pathways in 29 patients with
      HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Sensory
      symptoms, particularly cutaneous paresthesias, were present in 11 (37.9%)
      patients. On examination, a mild distal impairment of vibration and sense of
      position were found in 14 (48.2%) and 5 (17.2%) patients, respectively. Ten
      (34.4%) patients had distal tactile hypoesthesia and 7 (24.1%) presented pinprick
      hypoesthesia. Quantitative somatosensory thermotest showed cold hypoesthesia in
      58.6% of patients. Nerve conduction studies and electromyography were normal.
      Tibial somatosensory evoked potentials were abnormal in 88.5% of patients. All of
      the sensory abnormalities found were restricted to sensations carried by
      myelinated (A-beta and A-delta) fibers. Unmyelinated C fibers mediating warm
      sensation and thermal pain appeared unimpaired. Our findings indicate that the
      sensory dysfunction in HAM/TSP patients is probably due to a lesion restricted to
      the central nervous system.

PMID- 10394045
TI  - Effect of long-term oxygen therapy on cognitive and neurological dysfunction in
      chronic obstructive pulmonary disease.
AB  - The aim of this study was to assess effect of long-term oxygen therapy (LTOT) on
      the function of central and autonomic nervous system in patients with hypoxaemic
      chronic obstructive pulmonary disease (COPD). A battery of neuropsychological
      tests was used together with the Short Test of Mental Status in addition to
      transcranial Doppler ultrasonography, and five cardiovascular tests as well as a
      questionnaire on autonomic function. Ten COPD patients, 4 males and 6 females,
      with a mean age of 65.9 +/- 7.3 (SD) years, were studied at the beginning and
      after 3 months of LTOT. At start PaO2 was 6.7 +/- 1.1 kPa without oxygen and 9.9
      +/- 1.5 kPa after 3 months with oxygen. Our results demonstrate that
      neuropsychological function, cerebral blood flow velocity and autonomic function
      were positively influenced after 3 months of LTOT although the changes did not
      reach statistical significance. The COPD patients were cognitively impaired as
      compared to age-matched healthy controls. Our findings were consistent with the
      previous notion of improvement of hypoxic cognitive dysfunction by LTOT.

PMID- 10394044
TI  - Cimetidine-associated optic neuropathy.
AB  - Two cases of optic neuropathy associated with cimetidine therapy are reported.
      Recovery occurred in both after drug withdrawal. Rechallenge with the same agent
      totally reproduced the condition in the first case. Cimetidine exerts an
      unequivocal toxicity on the central and peripheral nervous systems. Since its
      introduction in 1976, it has been used in over 100 million patients, but only 3
      cases of optic neuropathy have been reported as far as we know. Although the
      mechanism of toxicity is still unclear, cimetidine is a well-recognized zinc
      chelator, and zinc deficiency has been implicated in causing optic neuropathy.
      Hence, it can be concluded that cimetidine produced this toxicity through its
      mechanism of zinc chelation. However, close ophthalmic follow-up of such patients
      is unnecessary, but an unexplained visual deterioration should prompt immediate
      drug withdrawal.

PMID- 10394042
TI  - Late-onset epilepsy associated with regional brain cortical dysplasia.
AB  - RATIONALE: Cortical dysplasia (CD) designates a diverse group of malformations
      resulting from one or more abnormalities in the development of the cerebral
      cortex. The clinical manifestations of CD are varied, probably depending on the
      type, location and extent of CD. Epilepsy is a potential late manifestation of
      any cortical malformation. To our knowledge, however, no study has focused
      specifically on late onset of epilepsy in patients with localized CD. MATERIAL
      AND METHODS: We studied patients with localized CD confirmed by MRI. Patients
      were divided into 2 groups according to age at onset of epilepsy. Group 1
      included patients in whom the first seizure occurred up to the age of 12 (early
      onset group) and group 2 included patients in whom the first seizure occurred
      after the age of 12 (late-onset group). The two groups were compared with regard
      to the type of CD, clinical findings and EEG findings. RESULTS: Thirty-three
      patients with various forms of CD were studied. Onset of epilepsy occurred in
      adolescence or adulthood in 9 cases (37%). In 6 of these (17% overall), the first
      seizure occurred in adulthood. CD were posterior bilateral pachygyria (1),
      unilateral polymicrogyria (3), focal dysplasia with subcortical gray matter
      heterotopia (1), perisylvian bilateral polymicrogyria (1), bioccipital
      polymicrogyria (1) and bilateral nodular periventricular gray matter heterotopia
      (2). The incidence of neurological signs was lower in the late-onset group.
      Mental retardation was moderate or absent, thus allowing a fairly normal
      lifestyle. All patients presented partial seizures with a lower incidence of drug
      resistance (p < 0.01). EEG demonstrated preservation of background activity and
      absence of diffuse or multifocal abnormalities. CONCLUSION: Onset of epilepsy
      with various forms of CD may be delayed until adolescence or adulthood. Prognosis
      of epilepsy is usually more favorable in these cases.

PMID- 10394046
TI  - Human parvovirus B19 infection in multiple sclerosis.
AB  - The association of human parvovirus B19 (PVB19) infection with the development of
      several systemic autoimmune diseases has been confirmed in other studies. To
      determine if there is any association of PVB19 infection with multiple sclerosis
      (MS), we studied the prevalence of serum anti-PVB19 IgG and IgM by an enzyme
      linked immunosorbent assay and PVB19-specific DNA in the cerebrospinal fluid
      (CSF) by the polymerase chain reaction method in a total of 46 patients during
      exacerbation or remission of MS. Anti-PVB19 IgG was detected in 65.8% of the
      patients' sera. The percentage was significantly higher than that in age-matched
      healthy control subjects (40%; p = 0.019), but was not higher in patients with
      other neurological diseases (50%; p = 0.16). There was no correlation between
      serum anti-PVB19 IgG status and antinuclear antibodies or oligoclonal IgG bands
      in CSF. Serum anti-PVB19 IgM and PVB19 DNA in CSF were consistently negative in
      the patients during exacerbation of MS. Although MS patients may be commonly
      infected with PVB19, our results suggest that there is no active PVB19 infection
      during exacerbation of MS.

PMID- 10394047
TI  - Decreased regional cerebral metabolic rate for glucose in systemic lupus
      erythematosus patients with psychiatric symptoms.
AB  - To determine brain functional abnormality in systemic lupus erythematosus (SLE)
      patients with psychiatric symptoms, we evaluated 12 active SLE patients with or
      without psychiatric symptoms by means of [18F]2-fluoro-2-deoxy-D-glucose positron
      emission tomography (PET), magnetic resonance imaging and neuropsychological
      testing. Patients with psychiatric symptoms showed significantly poorer
      performance in tests which subserved attentional function. The PET study revealed
      that the psychiatric patients had significantly decreased regional cerebral
      metabolic rates for glucose in the prefrontal, inferior parietal and anterior
      cingulate regions. Prefrontal, inferior parietal and anterior cingulate
      dysfunction may be related to attentional deficits that are involved in various
      psychiatric symptoms in SLE. PET is an invaluable tool to reveal such brain
      functional abnormality seen in SLE patients with psychiatric symptoms.

PMID- 10394048
TI  - Gabapentin as treatment for hemifacial spasm.
AB  - Hemifacial spasm, a life-long condition characterized by involuntary unilateral
      contractions of the facial muscles, is a disabling disorder often resulting in
      patient irritation and social embarassment. Its probable etiology is
      neurovascular compression of the facial nerve at its root exit zone. The current
      medical treatment consists of either baclofen or anticonvulsant drugs, with
      limitation due to side effects or low efficacy. In recent years botulinum toxin
      injection and microvascular decompression of the facial nerve have been shown to
      be highly successful. However, both procedures share some complications and
      require special techniques. We present 5 patients affected by hemifacial spasm
      who responded well to the novel anticonvulsant drug gabapentin. Gabapentin was
      administered at a dose ranging from 900 to 1,600 mg daily, with rapid and clear
      improvement of spasms and absence of any remarkable adverse effects. Our findings
      suggest that gabapentin may be an effective treatment for patients with
      hemifacial spasm with a very good ratio of therapeutic effects to side effects
      when compared with other drugs currently used.

PMID- 10394049
TI  - Hypointense and hyperintense lesions on magnetic resonance imaging in secondary
      progressive MS patients.
AB  - Cranial magnetic resonance imaging (MRI) is widely used to monitor disease
      activity in clinical trials in multiple sclerosis (MS). The purpose of this study
      is to examine lesion burden as determined from hypointense regions on
      postcontrast T1-weighted scans (or black holes), and lesion burden on
      conventional T2-weighted scans, from a cohort of secondary progressive MS
      patients who participated in a placebo-controlled, randomized, double-blind cross
      over trial assessing the therapeutic efficacy of cladribine. T2 lesion volumes
      and black hole volumes are approximately normal distributed when log-transformed,
      and are highly correlated (adjusted R2 = 0.63). Changes in clinical scores could
      be predicted with a reasonable degree of precision from baseline scores and
      changes in T2 lesion volumes (adjusted R2 values 0.52-0.7). Stratification
      schemes for clinical trials should include the acute proportion of the disease
      (enhancing T1 lesions), degree of permanent damage (black holes), and T2 lesion
      volume.

PMID- 10394053
TI  - Five new polymorphisms in the complement C7 gene and their association with C7
      deficiency.
AB  - Five new polymorphisms in the C7 gene are described: 2 in intron 1, and 1 each in
      introns 7, 8 and 15. Four of these are single nucleotide exchanges, while the
      fifth is a T insertion at 10 sequential Ts. Allele frequency data are presented
      for intervening sequence (IVS)1+ 55 in 6 normal population groups. We present new
      and updated data in these populations on a previously described C7 polymorphism
      in exon 13 (cDNA 1792 A/T). We also report the extended haplotypes associated
      with C7 deficiency for which marker investigation is a useful, and in some cases
      vital, adjunct to the identification of the gene defects. Almost without
      exception, a particular haplotype is associated with a particular mutation
      causing the deficiency state. Haplotyping is especially useful where polymerase
      chain reaction failure on one chromosome could be a cause for difficulties in
      detecting a molecular defect due to heterozygosity for large deletions or
      unidentified variations at the locations of the primers.

PMID- 10394052
TI  - Molecular, serological and population studies of the alleles and products of HLA
      B*41.
AB  - The HLA-B41 specificity was first identified over 25 years ago and, although both
      serological and biochemical studies have suggested its subdivision, it is only
      recently that two HLA-B*41 alleles (B*4101 and B*4102) have been identified and
      sequenced. We designed three oligonucleotide primers, combined in two mixtures to
      define these alleles by PCR using sequence-specific primers (PCR-SSP) in a random
      normal population of 9,464 HLA-A, B, DR, DQ typed Northern European Caucasoid
      donors from the Welsh Bone Marrow Donor Registry. The HLA-B41 phenotype frequency
      was 0.835%, and of the 79 HLA-B41 subjects 22 (27.85%) were B*4101 and 57
      (72.15%) were B*4102. The phenotype frequencies of B*4101 and B*4102 were 0.232
      and 0.602%, respectively, and the gene frequencies were 0.00116 and 0.00301,
      respectively. Formal two-locus linkage disequilibrium (LD) analysis demonstrated
      significant associations between B*4101 and A30 and DR11, and between B*4102 and
      A66 and DR13. LD analysis of three loci showed significant associations between
      B*4101, DR7, DQ2 and B*4101, DR11, DQ7 (DQB1*0301/0304) and between HLA-A3,
      B*4102, DR13; A66, B*4102, DR7; A66, B*4102, DR13; B*4102, DR13, DQ6 and B*4102,
      DR13, DQ7. Examination of the HLA phenotypes (including HLA-C) of the B*41
      subjects, together with the LD analysis findings, suggested four different HLA
      haplotypes bearing B*4101 and five B*4102 haplotypes. The most frequent B*4101
      haplotype was: HLA- A30 or other A allele, Cw*1701, B*4101, DRB1*1102, DQB1*0301
      and the most freqent B*4102 haplotype was: A*6601 or A3 or other A allele,
      Cw*1701, B*4102, DRB1*1303, DQB1*0301. In addition, the well-known association of
      A66 with B41 was between A*6601 and B*4102, and although both B*41 alleles were
      commonly in association with Cw*1701, B*4101 was found with Cw*07. One
      dimensional isoelectric focusing (1D-IEF) analysis of HLA-B proteins from 2
      B*4101 and 2 B*4102 subjects clearly showed that the B41.1 and B41.2 1D-IEF
      variants, identified in the 10th International Histocompatibility Workshop,
      corresponded to B*4101 and B*4102 products, respectively. Serological titration
      studies, with 59 lymphocytotoxic pregnancy antisera, containing an HLA-B41
      component and stimulated by up to five different HLA-B specificities, were unable
      to differentiate the two groups of B*41 subjects. This suggests that partition of
      the HLA-B41 specificity will not normally be achieved by classical serological
      methods. It is suggested that the previous alleged serological subdivision of HLA
      B41 was founded on the unwitting use of antisera detecting the HLA-Cw*17
      products.

PMID- 10394050
TI  - Plasma alpha1,3-fucosyltransferase deficiency in schizophrenia.
AB  - Levels of plasma alpha1,3-fucosyltransferase (alpha1,3FT) were assayed in 44
      patients with schizophrenia and in 50 healthy controls. Significantly reduced
      enzyme activities were observed in patients (p < 0.05) and 4 unrelated patients
      were found, for the first time in Japan, to be deficient in the enzyme activity.
      Two point mutations in the coding region of the FUT6 gene encoding plasma
      alpha1,3FT that were responsible for the inactivation of the enzyme activity were
      detected in those patients. Genotyping of the Le gene (FUT3) in these patients
      demonstrated that 2 of them were also FUT3 deficient and were grouped as Lewis-
      individuals whereas the rest were Lewis+.

PMID- 10394051
TI  - Multiple sclerosis: association to HLA DQalpha in a tropical population.
AB  - Studies performed in subtropical populations have found significant association
      between the phenotype multiple sclerosis (MS) and the major histocompatibility
      complex (MHC). We present the results of a case-control study conducted on a
      tropical population (Antioquia, Colombia) in order to detect a possible
      association between MS and HLA DQalpha (HLA DQA1*) alleles. Forty chromosomes
      belonging to MS patients were compared to two sets of controls (40 and 910
      chromosomes, respectively). The HLA DQA1*0101 and DQA1*0102 alleles were found in
      a significantly higher proportion among the cases than among the controls,
      whereas the HLA DQA1*0103 allele was found in a significantly lower proportion of
      the cases. These results suggest that the association of HLA DQA1*0101, DQA1*0102
      and DQA1*0103 to the MS phenotype found in Caucasian subtropical populations
      remains in individuals with MS inhabiting the tropics. This finding could mean
      that the major genetic component associated to the MHC in subtropical populations
      is the same in the tropics.

PMID- 10394054
TI  - Interleukin-15 enhances HIV-1-driven polyclonal B-cell response in vitro.
AB  - Interleukin-15 (IL-15) is a recently described cytokine, produced by
      monocytes/macrophages, with biological activities similar to IL-2. Since IL-15
      was shown to stimulate human B-cell proliferation and immunoglobulin secretion,
      we investigated its effect on human B-cells stimulated with heat-inactivated
      human immunodeficiency virus type 1 (iHIV-1) in vitro. We observed a dose
      dependent elevation of [3H]-thymidine incorporation and immunoglobulin production
      by B-cells incubated in the presence of iHIV-1. Moreover, IL-15 stimulated HIV-1
      driven B-cell proliferation similarly to IL-2. As to immunoglobulin secretion, IL
      15 was able to potentiate the stimulatory effect of IL-10. The highest amounts of
      iHIV caused a decrease in B-cell proliferation and immunoglobulin secretion to
      baseline levels, even in the presence of cytokines. These findings indicate that
      during the late stages of AIDS, when monocytes/macrophages become the major site
      of viral production, IL-15, in concert with other monocyte-derived cytokines, may
      promote polyclonal B-cell activation and hypergammaglobulinaemia, which are
      frequently associated with HIV infection.

PMID- 10394055
TI  - The human immunoglobulin heavy diversity (IGHD) and joining (IGHJ) segments.
AB  - The 'Human Immunoglobulin Heavy Diversity (IGHD) and Joining (IGHJ) segments',
      fifth report of the 'IMGT Locus on Focus' section, comprises six tables entitled:
      (1) 'Human germline IGHD segments at 14q32.33'; (2) 'Human IGHD alleles'; (3)
      'Human germline IGHJ segments at 14q32.33'; (4) 'Human IGHJ alleles'; (5) 'Human
      germline IGHD orphons on chromosome 15 (15q11.2)'; (6) 'Correspondence between
      the different human IGHD nomenclatures', and two figures: (1) 'Protein display of
      human IGH D-REGIONs'; (2) 'Protein display of human IGH J-REGIONs'. These tables
      and figures 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- 10394059
TI  - Effect of a logopedic instruction program after adenoidectomy on open mouth
      posture: a single-blind study.
AB  - The effect of adenoidectomy (controls) on habitual open mouth posture was
      compared with adenoidectomy in combination with a logopedic instruction program
      (cases). One hundred and fifty-nine children were included (aged 2-10 years, mean
      age 4.6 years). The instruction program consisted of three individual logopedic
      sessions at 1 week, 2 weeks and 4 weeks postoperatively. One week preoperatively,
      2 months and 1 year postoperatively an estimation of open mouth posture was
      carried out. Two months postoperatively there was a significant difference
      between the two groups (p = 0.001), but 1 year postoperatively this difference
      had disappeared (p = 0.526). The logopedic instruction program was not effective
      for the youngest age-group (<3.6 years).

PMID- 10394056
TI  - Interobserver agreement on normal swallowing physiology as viewed by
      videoendoscopy.
AB  - This study examines the agreement of 2 observers in identifying selected normal
      oropharyngeal swallow events in the 1- and 5-ml swallows of 3 normal young adult
      males as identified by videoendoscopy at each of two endoscopic positions: (1)
      with the tip of the endoscope just at or below the tip of the uvula (high
      position), and (2) with the tip of the endoscope just below the tip of the
      epiglottis (low position), and thereby defines the needed focus for observer
      training in endoscopic assessment of swallowing. Overall, the more and less
      experienced examiners agreed on seeing or not seeing the onsets and terminations
      of the 12 events 83% of the time. Scope position affected observer agreement on
      several events while bolus volume did not.

PMID- 10394057
TI  - Specific language impairments and behavioural problems.
AB  - The behavioural functioning of 56 children with a specific language impairment
      (SLI), aged 8, 10, and 12 years, was examined by using the Child Behaviour
      Checklist. Parents as well as teachers filled in the questionnaire. The data
      shows that 48% of the children with SLI were considered to have behavioural
      problems either at home or in school. The problems differ significantly from the
      norm group on internalizing behaviour and total behaviour. The children do not
      demonstrate more externalizing behaviour than children in the norm group. It is
      hypothesized that the absence of aggressive behaviour might be a characteristic
      of children with SLI.

PMID- 10394058
TI  - Comparison of different voice samples for perceptual analysis.
AB  - Choice of voice sample material can influence perceptual judgments by a jury. The
      twofold purpose of this study was first to validate the pertinence of a sustained
      vowel for perceptual voice analysis in French speakers and second to test the
      hypothesis that use of only the stabilized portion of the vowel would lead to
      underestimation of dysphonia. Voice samples were recorded in 60 dysphonic
      patients and 20 normal controls. Three different sample materials were obtained
      for each subject, i.e. connected speech, a sustained vowel including both the
      initial and stable portion (complete sustained vowel), and a sustained vowel
      including only the stable portion (stabilized sustained vowel). The jury was
      composed of 7 experienced listeners. Jury consistency was measured as a
      percentage of agreeing judgments for the same subject. No difference in
      consistency was observed using the three sample materials. Judgments on
      stabilized sustained vowels were confirmed as less severe than judgments on
      connected speech. Judgments on complete sustained vowels were comparable to
      judgments on connected speech.

PMID- 10394060
TI  - Public awareness of stuttering.
AB  - The results are reported of a questionnaire study into the awareness of
      stuttering of lay persons in part of Belgium. 1,362 subjects were interviewed.
      Questions pertained to various aspects of stuttering including prevalence, onset,
      gender distribution and occurrence in different cultures, cause, treatment,
      intelligence and hereditariness. Although most respondents were to some extent
      familiar with stuttering, their overall knowledge of the disorder appeared
      generally limited.

PMID- 10394061
TI  - Mosaic evolution in the origin of the Hominoidea.
AB  - The initial appearance of hominoids, or apes, and the selective pressures that
      led to their emergence are currently disputed. Central to the argument are the
      proconsulids, variously described as the earliest apes or as stem catarrhines,
      based on facial and postcranial data, respectively. The present paper reports on
      incongruence and parsimony analyses applied to a combined data set. The results
      demonstrate that proconsulids are cladistic hominoids, and that the apparent
      incongruence between the data sets is due to mosaic evolution; the earliest
      changes in Hominoidea occurred in the face. These results suggest that the
      initial divergence of hominoids involved selection for an ape-like face, and was
      not driven by an adaptive shift to below-branch locomotion.

PMID- 10394062
TI  - Sexual behavior and extragroup copulations in a wild population of common
      marmosets (Callithrix jacchus).
AB  - Sexual behavior and mating patterns are described for 3 free-ranging groups of
      common marmosets living in a coastal forest in northeastern Brazil. Each group
      contained 2 breeding females. Within groups, sexual behavior was generally
      restricted to breeding females and a single behaviorally dominant male. Of 101
      mounts and copulations, 24 involved pairings of individuals from 2 different
      groups. Extragroup sexual behavior was performed by both breeding and nonbreeding
      group members, and 65% of all adults mounted or copulated with an extragroup
      individual at least once. Sexual behavior occurred throughout the female
      reproductive cycle but was significantly more frequent during an 11-day
      'conception period'. Thus, while female marmosets show no physical signs of
      estrus, both males and females likely do have some information about the timing
      of ovulation. Mating patterns in this population included both polygyny and
      monogamy and varied between groups and over time.

PMID- 10394063
TI  - The mother's participation in infant carrying in captive groups of Leontopithecus
      chrysomelas and Callithrix jacchus.
AB  - Callithrix and Leontopithecus exhibit ecological differences that have
      implications for the patterns of infant care. In C. jacchus, which uses a small
      home range because it depends mainly on plant exudates, infants can forage
      independently early in their life. L. chrysomelas, which feeds mainly on fruits
      and insects, needs larger home ranges and, therefore, its infants have a more
      extensive period of dependence. Three families of C. jacchus and four families of
      L. chrysomelas were studied in captivity. The animals were observed starting from
      the birth of the infants up to their 8th week of age. Our results suggest that
      the pattern of infant transfer in L. chrysomelas did not follow the one reported
      for L. rosalia in that transfers from the mother occurred much earlier. L.
      chrysomelas infants were carried for about 15% of total time during the 8th week
      of life against less than 1% in C. jacchus in the same week. Infant care seems to
      be more extensive in L. chrysomelas than in C. jacchus, and the period of
      exclusive mother carrying in L. chrysomelas is shorter than that observed in L.
      rosalia.

PMID- 10394064
TI  - Nutritional aspects of fruit choice by chimpanzees.

PMID- 10394065
TI  - Impact of deforestation on a population of alouatta caraya in northern argentina 

PMID- 10394068
TI  - Spontaneous use of tools by wedge-capped capuchin monkeys (Cebus olivaceus) 

PMID- 10394067
TI  - Use of millipedes by black lemurs to anoint their bodies 

PMID- 10394066
TI  - Infant killers of budongo 

PMID- 10394069
TI  - A juvenile sichuan golden monkey (Rhinopithecus roxellana) predated by a goshawk
      (Accipiter gentilis) in the qinling mountains 

PMID- 10394070
TI  - Ribosomal protein S4 gene of the African green monkey (Cercopithecus aethiops).

PMID- 10394071
TI  - Patterns of social visual attention in the red-capped mangabey (Cercocebus
      torquatus torquatus) in the context of food competition 

PMID- 10394072
TI  - Quality of life in chronic illness.
AB  - The concept of health-related quality of life (QOL) is differentiated from
      generalized QOL. If we are to understand attitudes and behavior of older people
      regarding the end of life, we need to take account not only of the distress and
      impairments resulting from poor health, but also of the positive features in the
      non-health-related areas of their lives that may make them wish to endure the
      negative aspects of poor health and its treatment side effects. The concept of
      Valuation of Life is suggested as the mental process that intervenes between
      negative and positive aspects of daily life on the one hand and older people's
      wishes for prolonged life and life-extending treatment on the other hand.
      Research is described which yielded a Valuation of Life Scale. Although many
      facets of good and poor physical and mental health were related to Valuation of
      Life, it was primarily positive aspects such as relationships with friends,
      meaningful time use and positive emotion that were independently associated with
      Valuation of Life. Valuation of Life was, in turn, the major independent
      predictor of the number of years people wished to live under a number of
      conditions of good health, disability, cognitive impairment and pain. It is
      concluded that both individual treatment decisions and social policy based on QOL
      associated with health and illness be informed by knowledge that positive aspects
      of life other than in the health sector are important considerations.

PMID- 10394074
TI  - Nutritional and cognitive status in elderly subjects living in service flats, and
      the effect of nutrition education on personnel.
AB  - BACKGROUND: There is limited knowledge about the nutritional and cognitive status
      in elderly and chronically ill subjects living in sheltered housing. OBJECTIVE:
      To perform a 6-month follow-up study in order to investigate (1) nutritional
      status and its relationship to cognitive function in elderly people living in
      service flats, and (2) the effect of a 9-hour educational program given to
      personnel working in the service flats. METHODS: Of 93 eligible subjects, 28
      agreed to participate (age 81 +/- 7 years, 75% women). Body mass index (BMI),
      triceps skin fold (TSF), arm muscle circumference (AMC), appetite, Subjective
      Global Assessment (SGA), serum albumin, serum insulin-like growth factor-1 (IGF
      1) and Mini Mental Test (MMT) were assessed on two occasions with a 6-month
      interval. The staff of the service flats answered a questionnaire before and 6
      months after an educational program. RESULTS: At the start, BMI, TSF and AMC were
      within the normal ranges, e.g. BMI 26.6 +/- 3.1 for men and 25.6 +/- 3.2 for
      women. Three subjects were suspected to be malnourished and 2 were malnourished
      according to SGA. Among 20 randomly selected subjects who chose not to
      participate in the investigation, age, sex, BMI, weight loss and appetite were
      not significantly different from those values in participants. However, none of
      the latter had a BMI <20 compared to 10% in non-participants. The MMT results
      suggested cognitive dysfunction in 41% of the subjects. On the first test
      occasion, MMT correlated with BMI (r = 0.43, p < 0.03), weight loss (r = 0.4, p <
      0.05) and age (r = -0.38, p < 0.05). The ability of the personnel to suggest
      suitable nutrition for fictitious patient cases appeared to have improved after
      the educational program. At the 6-month follow-up, the BMI in men rose to 27.0 +/
      3.4 (p < 0. 05), while other anthropometric measurements remained unchanged.
      Serum IGF-1 lay within the normal range, as did serum albumin which, however,
      rose from 39.1 +/- 2.9 to 41.2 +/- 3.5 g/l (p < 0.01). CONCLUSION: Fifteen to
      twenty percent of the individuals studied in the service flats displayed definite
      or possible signs of malnutrition. Cognitive function correlated with BMI, weight
      loss and age. The educational program appeared to increase the nutritional
      knowledge in personnel working in the service flats. At the 6-month follow-up,
      the nutritional status of the residents had not deteriorated.

PMID- 10394073
TI  - Na,K-ATPase and Ca-ATPase activities of the myocardial sarcolemma in aging rats
      after aorta coarctation: role of invertors.
AB  - In this work we used aorta coarctation as a model of myocardial hypertrophy. We
      studied the role of intracellular regulators of plasma membrane status-invertors
      in the mechanisms of changes of membrane enzyme activities in the emergency stage
      of myocardial hypertrophy. We used Wistar rats of various ages: adult (6-8
      months) and old (26-28 months) rats. It was shown that 4-6 days after aorta
      coarctation, in adult rats the activities of both Na,K-ATPase and Ca-ATPase of
      the sarcolemma of cardiomyocytes increased, but in old rats only the Ca-ATPase
      activity. Experiments with cell hybrids (cytosol of experimental rats and
      isolated sarcolemma of cardiomyocytes of intact rats) revealed that cytosol of
      cardiomyocytes of adult animals after aorta coarctation activated Na, K-ATPase
      and Ca-ATPase. Cytosol of old intact animals after aorta coarctation did not
      activate Na,K-ATPase, but activated Ca-ATPase. It was supposed that 4-6 days
      after aorta coarctation, intracellular regulators (invertors) activating Na,K
      ATPase and Ca-ATPase of rat sarcolemma were synthesized in cytosol of adult
      animals. Invertors activating Na,K-ATPase did not appear after the aorta
      coarctation in old animals, but factors activating Ca2+-ATPase appeared. Cytosol
      of adult experimental rats activated Na,K-ATPase of sarcolemmas of cardiomyocytes
      of intact old animals. The data proved the ability of Na,K-ATPase of sarcolemma
      of old animals to respond to regulating factors. Based on the divergence between
      the results of experiments with the Na,K-ATPase and Ca-ATPase activities in old
      rats, it can be supposed that we were dealing with two different invertors.

PMID- 10394076
TI  - Effect of upper gastrointestinal endoscopy on circulation in the elderly.
AB  - BACKGROUND: Upper gastrointestinal endoscopy in the elderly is increasingly
      becoming more common, despite the possibility that a minimal load on the
      circulation can cause serious complications such as shock and cardiac arrest.
      OBJECTIVE: The effects of endoscopy on the heart and the possibility of
      predicting circulatory accidents were studied using natriuretic peptide levels.
      METHODS: The patients were randomly chosen according to their age and divided
      into an elderly group (over 60 years of age, 64 patients) and a young group
      (under 30 years of age, 20 patients). The patients in the elderly group were
      further subdivided into two groups based on the presence or absence of
      circulatory complications (46 patients with circulatory complications and 18
      without complications). The load on the heart was evaluated by measuring human
      atrial natriuretic peptide (hANP) and human brain natriuretic peptide (hBNP)
      which are secreted by the myocardial cells in response to cardiac load. Specimens
      were obtained before and after endoscopy. RESULTS: The hANP level was
      significantly higher after endoscopy in the elderly group, regardless of the
      presence or absence of circulatory complications. No significant difference was
      observed in the hBNP level. No significant increase in hANP or hBNP levels was
      observed after endoscopy in the young group. CONCLUSIONS: These observations
      suggest an increased atrial load during endoscopy in the elderly. The increase in
      pulse rate during endoscopy is one possible cause of atrial load. Therefore, the
      risk of circulatory system damage must be recognized when endoscopy is performed
      in the elderly. The measurement of plasma hANP and hBNP levels may provide
      effective indices for evaluating cardiac load during endoscopy.

PMID- 10394075
TI  - Lack of effect of 1 year intake of a high-dose vitamin and mineral supplement on
      cognitive function of elderly women.
AB  - OBJECTIVE: To determine if long-term, high-vitamin supplementation could reverse
      cognitive malfunction in old people. METHODS: We performed a longitudinal study
      relating the 12-month outcome to baseline values. Twenty non-vitamin-deficient
      elderly females with a Folstein mini mental state examination score indicating
      cognitive malfunctions were recruited to ascertain if feeding a high-dose vitamin
      mineral supplement for 1 year could, by mass vitamin action, reverse some
      existing cognitive malfunctions. Ten females were fed a high-dose vitamin-mineral
      supplement pill with each of three daily meals for 1 year; the other 10 did not
      receive this supplementation. Twelve blood vitamin analyses and a Folstein mini
      mental state examination were performed for each of the 20 subjects before and
      after 1 year; each subject served as its own control. RESULTS: No improvement in
      cognitive malfunction was noted despite elevation of blood vitamins. CONCLUSION:
      Feeding of a high-dose vitamin and mineral supplement for 1 year did not improve
      cognitive malfunction in non-vitamin-deficient elderly in this study.

PMID- 10394077
TI  - Gastric mucosal defences in the elderly.
AB  - BACKGROUND: Elderly subjects are more prone to develop gastric injury, but human
      data on the state of mucosal protective mechanisms are scarce. The aim of the
      study was to assess gastric mucus and bicarbonate secretion as well as local
      microcirculation in elderly patients. METHODS: Fasting gastric juice was
      collected in 45 elderly patients and in 45 control subjects devoid of endoscopic
      gastric abnormalities. Total mucoproteins, 'mucoprotective index' (as qualitative
      expression of mucus secretion) and gastric bicarbonate (Feldman's method) were
      measured. In addition in 24 elderly patients, and in a matching group of younger
      subjects, gastric mucosal blood flow was measured by laser Doppler flowmetry.
      RESULTS: Mucus and bicarbonate production was significantly reduced (p < 0.01) in
      elderly patients, the quality of mucus secretion being unaltered. Gastric mucosal
      perfusion was also significantly decreased (p < 0. 01) in aged subjects.
      CONCLUSION: In the elderly gastric mucosal defences are impaired. This is in
      keeping with a reduced gastric prostaglandin biosynthesis and may account for the
      higher susceptibility of the mucosa to damaging agents. The possible role of
      atrophic gastritis and Helicobacter pylori infection as independent confounding
      factors remains to be determined.

PMID- 10394078
TI  - Trimethoprim-induced hyperkalemia: An analysis of reported cases.
AB  - BACKGROUND: Trimethoprim has been recently implicated in the development of
      hyperkalemia when administered at standard doses to immunocompetent patients.
      However, many clinicians are unaware of this potentially dangerous adverse
      effect. OBJECTIVE: To review reported cases of trimethoprim-induced hyperkalemia
      in immunocompetent patients and identify predisposing factors, treatment, and
      outcome. METHODS: A MEDLINE literature search was performed using the key words
      'trimethoprim' and 'hyperkalemia'. All English-language case reports and
      bibliographies of immunocompetent patients with trimethoprim-induced hyperkalemia
      were reviewed. RESULTS: Nine cases were identified. The mean patient age was 77.6
      years, and the mean duration of therapy was 10.2 days. Seven patients received
      standard oral dosages of trimethoprim-sulfamethoxazole for common infections, and
      2 patients were concurrently receiving angiotensin-converting enzyme inhibitors.
      The mean pretreatment levels of creatinine and potassium were 1.01 mg/dl and 4.55
      mmol/l, respectively. The mean peak serum potassium level was 7.0 mmol/l. No
      deaths attributable to hyperkalemia occurred. CONCLUSIONS: Hyperkalemia due to
      trimethoprim typically affects elderly patients administered standard oral
      dosages, even in the presence of a normal serum creatinine level. Concurrent
      angiotensin-converting enzyme inhibitor therapy may increase the risk of
      hyperkalemia. The prognosis is favorable with standard therapy for hyperkalemia
      and withdrawal of trimethoprim.

PMID- 10394081
TI  - Aging, antiaging, ontogenesis and periods of age development.
AB  - An internally contradictory character of individual development may suggest a new
      periodization of the latter. Etagenesis is an age-associated development of an
      organism from the zygote to death. Ontogenesis is the period of realization of
      the genetic program of the organism's development under effects of exogenic
      factors, the period of growth and shaping of its main structure and functions,
      and the period of formation of its reproductive function. Mesogenesis is the
      period of the relatively stable state which is characterized by changing the
      balance between the processes of aging and antiaging, i.e. the vitauct.
      Gerontogenesis is the period during which destructive processes of aging prevail
      over antiaging processes. No strict borderlines between the above periods exist.

PMID- 10394079
TI  - Regular non-vigorous physical activity and cholesterol levels in the elderly.
AB  - BACKGROUND: High-density lipoprotein cholesterol (HDL-C) is a powerful
      independent risk factor for coronary heart disease (CHD) among the elderly.
      Regular vigorous physical activity has been found to raise the concentration of
      HDL-C and thus reduce the risk of CHD. There is little data on the effect of non
      vigorous activity on HDL-C in the elderly. OBJECTIVE: The aim of this study was
      to compare CHD risk factors, especially HDL-C, in a group of elderly persons who
      engage in regular non-vigorous physical activity with a group of frail elderly
      examined in a previous study. METHODS: Each subject (51 women and 19 men) had
      anthropometric measures taken and completed a questionnaire on lifestyle and
      medical history. Total cholesterol (TC), HDL-C and lipoprotein (a) were analysed.
      Results were compared with those of a frail group examined previously using
      similar methodology. RESULTS: HDL-C, adjusted for age, body mass index (BMI) and
      waist-to-hip ratio (WHR), was greater among women (p < 0.01) and men (p < 0.05)
      who were engaged in a regular physical activity at least once a week. TC was
      higher among active women (p < 0.001), but there was also a trend towards a lower
      TC/HDL ratio. Therefore, although TC is higher in active women, this could be due
      to a higher proportion of the cholesterol fraction consisting of HDL-C. WHR was
      negatively associated with HDL-C in frail men (p < 0. 05), active men (p < 0.01)
      and active women (p < 0.05). BMI was negatively associated with HDL-C in frail
      women (p < 0.05). CONCLUSIONS: This sample of elderly people who participate in
      regular weekly non-vigorous physical activity have a higher HDL-C than frail
      individuals who do little or no exercise. Since HDL-C is consistently reported to
      be inversely associated with CHD in the elderly, an elevation in HDL-C
      concentration may provide some protection to elderly persons who participate in
      regular nonvigorous physical activity compared to frail elderly individuals who
      are largely sedentary. Caution should be exercised in the interpretation of a TC
      only reading in active elderly women without an accompanying measure of HDL.

PMID- 10394082
TI  - Risk factors associated with increased falls in a hip fracture population.

PMID- 10394080
TI  - Risk factors for early emergency hospital readmission in elderly medical
      patients.
AB  - BACKGROUND: Early emergency readmissions is a common and important problem in the
      elderly patient. Identification of the risk factors for early emergency
      readmissions is needed to prevent this occurring. OBJECTIVE: The aim of this
      study was to study the risk factors for early emergency readmission in the
      elderly medical patient. METHODS: A case-control study (sex- and age-matched) was
      conducted from March to December 1996. 380 elderly (age 65 years or over) medical
      patients with emergency hospital readmission (within 28 days) and 380 matched
      controls were recruited from an acute university general hospital in Hong Kong.
      Potential risk factors which included demographic, socio-economic, principal
      medical diseases, comorbid diseases, dysphagia, physical functional status and
      mental status were studied. RESULTS: In bivariate analyses for the risk factors
      of early emergency readmission, institutional caregiver, previous visiting nurse
      service, adverse drug reaction, chronic obstructive pulmonary disease, end-stage
      renal failure, mobility being chair- or bed-bound, dysphagia, use of a
      nasogastric tube feeding, urinary incontinence and bowel incontinence were
      significant. Readmission cases had higher mean number of comorbid diseases, lower
      mean Barthel Index, higher mean number of impairments in Activities of Daily
      Living (ADL) tasks and lower mean Abbreviated Mental Test score than controls. In
      multivariate logistic regression model, the number of ADL impairments (OR = 1.13,
      95% CI = 1.08-1.19), no income (OR = 2. 28, 95% CI = 1.19-4.37), adverse drug
      reaction (OR = 4.19, 95% CI = 1.56-11.2), advanced malignancy (OR = 2.45, 95% CI
      = 1.37-4.37), congestive heart failure (OR = 1.63, 95% CI = 1.05-2.53), chronic
      obstructive airways disease (OR = 2.1, 95% CI = 1.47-3.02), end-stage renal
      failure (OR = 5.48, 95% CI = 1.69-17.75), dysphagia (OR = 3.9, 95% CI = 1.5
      10.11) and the number of comorbid diseases (OR = 1.3, 95% CI = 1.13-1.49) were
      significant risk factors for early emergency readmissions. Living in a private
      old aged home was associated with a lower risk of readmissions (OR = 0.53, 95% CI
      = 0. 36-0.93). CONCLUSIONS: Definite medical, functional and socio-economic
      factors were found to be risk factors for early emergency readmissions in the
      elderly medical patient. A multiple risk factors intervention approach should be
      considered in designing future prevention strategies.

PMID- 10394083
TI  - Pharmacokinetics of Fem7, a once-weekly, transdermal oestrogen replacement system
      in healthy, postmenopausal women.
AB  - This open-label, randomized study in 36 healthy postmenopausal women,
      investigated the pharmacokinetics of Fem7, (an oestradiol matrix-type patch), at
      doses of 25, 50, 75 and 100 microg/24 h, applied once weekly. Maximum plasma
      concentrations of oestradiol and oestrone were observed 14-20 h after patch
      application, remaining within the therapeutic range until removal, and returning
      to baseline within 12 h thereafter. Plasma oestradiol concentrations increased in
      a dose-dependent manner for all four doses, and plasma oestrone increased for the
      three highest doses. Fem7 treatment was well tolerated at all four doses and no
      severe adverse reactions were reported. Fem7 is a convenient and well-tolerated
      form of hormone-replacement therapy that delivers oestradiol in a consistent and
      predictable manner.

PMID- 10394084
TI  - A controlled study for gender selection using swim-up separation.
AB  - OBJECTIVE: To evaluate the success for gender selection using a sample of semen
      separated by a modified swim-up technique. DESIGN: We retrospectively compared
      the gender outcome of two treatments (A and B) for either a male or female
      offspring with those who conceived spontaneously. SETTING: Private practice of
      one author (M. A.K.). PATIENTS, PARTICIPANTS: The treatment groups consisted of
      52 total pregnancies for couples who conceived by the separation technique. Of
      these 52 participants, 15 desired a female offspring and were placed into
      treatment A and 37 desired a male offspring and were placed into treatment B. The
      control groups consisted of 162 women who were presented with initial
      consultation for gender selection and conceived spontaneously. Control group A
      consisted of 80 women who initially chose a female offspring, and control group B
      consisted of 82 participants who initially chose a male. INTERVENTIONS: In
      treatment group A, one timed intrauterine insemination (IUI) was carried out with
      the bottom 0.5 ml of the separated semen on cycle days 12-14, when the follicle
      was 18-22 mm. Patients in this group were also administered clomiphene citrate
      and human chorionic gonadotropin. In treatment group B, one timed IUI was done
      with the top 0.5 ml of the separated semen, when the follicle was 18-22 mm. MAIN
      OUTCOME MEASURE: The gender outcome of the pregnancies of two treatment and
      control groups was evaluated based on the known desired gender. RESULTS: The
      success rate for conceiving a female child after intervention (treatment group A)
      was 86.7% effective (p = 0.002) as compared to the control group A. Couples
      seeking a male child (treatment group B) were 89.2% effective (p = 0.0002) as
      compared to the control group B. CONCLUSIONS: This study reveals that the
      modified swim-up method with additional monitoring results in statistically
      significant gender preselection.

PMID- 10394085
TI  - Evaluation of intrauterine growth pattern of twins by linear discriminant
      analysis of the values of biparietal diameter, femur length and abdominal
      circumference1.
AB  - In a cross-sectional study, the intrauterine growth pattern of 32 twins was
      compared to that of 205 singletons by analysis of the coefficients of the
      equations of biparietal diameter (BPD), femur length (FL) and abdominal
      circumference (AC). Lower values were observed in twins from the 20th week. BPD
      and AC curves showed a progressively diverging pattern, and yielded different
      coefficients of equations. AC showed the highest discriminant capacity followed
      by BPD and FL. Combined values of the two series solved by discriminant function
      output produced an overlapping of 58%. Based on our data, nomograms of growth of
      singletons should not be used for twins.

PMID- 10394086
TI  - Pyelocaliectasis and intrarenal artery doppler indices in uncomplicated
      pregnancies.
AB  - The effect of pyelocaliectasis on intrarenal arterial Doppler indices was
      evaluated in healthy pregnant women with respect to nonpregnant controls. There
      was no significant difference between the pregnant and nonpregnant subjects
      regarding the systolodiastolic ratio, resistivity index and pulsatility index
      throughout the second and third trimesters (p for all > 0.05). There were 134
      kidneys with grade 0, 38 kidneys with grade I and 24 cases with grade II
      pyelocaliectasis in the pregnant population. Grade II caliectasis was found only
      in the right kidneys. The nonpregnant women all had grade 0 caliectasis. Doppler
      indices were not significantly different in various grades of caliectasis, and
      right and left kidneys had similar Doppler indices. The results of this study
      suggest that pyelocaliectasis increases with advancing gestational age and is
      more frequent and prominent on the right side but has no effect on intrarenal
      Doppler indices in healthy pregnant women. In cases of prominent alterations in
      Doppler indices, renal pathological conditions should be sought.

PMID- 10394087
TI  - Regulation of prostaglandin F2alpha by the specific inhibition of secretory type
      II phospholipase A2: implications for the management of premature labour.
AB  - Arachidonic acid mobilisation by phospholipase A2 (PLA2) and subsequent
      prostaglandin synthesis is thought to be a pivotal event in the onset and/or
      maintenance of human labour. The purpose of this study was to examine the
      efficacy of a monoclonal human type II PLA2 antibody (10 B2) in reducing
      prostaglandin F2alpha (PGF2alpha) production in Chinese hamster ovary (CHO) cells
      (that overexpress human recombinant type II PLA2) and in human placental
      explants. 10 B2 caused a concentration-dependent inhibition of PLA2 activity (p <
      0.00001) and PGF2alpha release (p < 0.01) by CHO cells. 1 microM of 10 B2
      inhibited PLA2 activity (p < 0.00001) and PGF2alpha production (p < 0.0001) in
      human placental explants. The latter effect was significantly reversed by the
      addition of arachidonic acid (30 microM; p < 0.01). On the basis of these
      findings, it is proposed that 10 B2 inhibits PGF2alpha production by interfering
      with the extracellular activity of type II PLA2.

PMID- 10394088
TI  - The severity of polyhydramnios, estimated fetal weight and preterm delivery are
      independent risk factors for the presence of congenital malformations.
AB  - OBJECTIVE: To evaluate maternal and fetal factors associated with congenital
      malformations in patients with polyhydramnios. STUDY DESIGN: The study group
      consisted of 275 singleton pregnancies with an amniotic fluid index (AFI) >25.0
      cm. An equal number of controls were matched for maternal age, gravidity, parity
      and gestational age. The proportion of cases and controls with malformations was
      compared. Polyhydramnios cases were categorized into three groups by severity:
      mild (AFI 25-30 cm), moderate (AFI: 30.1-35.0 cm) and severe (AFI >35.1 cm).
      Among cases, logistic regression analysis was utilized to estimate the risk for
      fetal congenital malformations in relation to severity of polyhydramnios,
      estimated fetal weight, maternal diabetic status and gestational age at delivery.
      RESULTS: Congenital malformations were detected in 40 of 275 cases (14.5%) with
      polyhydramnios and in 9 cases (3.3%) of the control group (p < 0.01). The
      relative risks of congenital malformations increased with the severity of
      polyhydramnios: 3.2 (95% CI 1.5-6.8), 5.7 (95% CI 2. 4-13.3) and 13.1 (95% CI 5.8
      29.5) for mild, moderate and severe polyhydramnios, respectively. Congenital
      malformations among polyhydramnios cases were present in 54.5% of small-for
      gestational age fetuses, in contrast to 12.7% for average-for-gestational age
      fetuses and 10.8% for large-for-gestational age fetuses (p < 0.001). Maternal
      diabetic status did not significantly affect the fetal anomaly rate once
      polyhydramnios was detected. Premature newborns in the polyhydramnios group had a
      higher malformation rate (24%) than did term newborns (11.3%) (p < 0.02). In the
      study group, multiple logistic analysis confirmed the significance of severe
      polyhydramnios, small-for-gestational age status and preterm delivery as
      independent contributors to the malformation risk. CONCLUSIONS: Polyhydramnios
      (AFI >35 cm), small-for-gestational age fetus and preterm delivery are
      independent risk factors for congenital malformations.

PMID- 10394089
TI  - Morphine suppresses the oxytocin response in breast-feeding women.
AB  - The activity of opiate-mediated regulatory mechanisms of oxytocin secretion
      during breast-feeding was studied by the administration of either morphine,
      naloxone or placebo to women prior to the commencement of breast-feeding.
      Seventeen healthy women in the first week after delivery who had established
      lactation were randomized to receive either intravenous morphine 5 mg (n = 6),
      naloxone 2.4 mg (n = 6) or a placebo, sterile water (n = 5), which was given
      prior to commencement of breast-feeding. Oxytocin levels were measured by
      radioimmunoassay prior to initiation of breast-feeding and then at 2-min
      intervals until the feed was complete. Breast-feeding produced a significant rise
      in oxytocin levels in the control and naloxone groups but no significant rise in
      the patients given morphine. There was a significant reduction in oxytocin
      response following morphine administration when compared to placebo but not
      between naloxone and placebo. In conclusion, oxytocin secretion to breast-feeding
      is inhibited by exogenous morphine when compared to a control group but the
      administration of naloxone did not produce a significant difference from control.

PMID- 10394090
TI  - Birth-weight-specific perinatal mortality in Japan, 1989-1993: singleton versus
      multifetal pregnancies.
AB  - OBJECTIVE: To investigate the relation between birth weight and perinatal
      mortality in multifetal pregnancies, which is more than 5 times higher than for
      singleton infants. METHODS: We assessed the incidence of perinatal deaths based
      on birth weight in 89,566 infants of multifetal pregnancies and 6,025,199 infants
      of singleton pregnancies in Japan. Perinatal death was defined as stillbirth and
      early neonatal death (death <1 week of age). RESULTS: The incidence of perinatal
      death was consistently lower for infants of multifetal pregnancies than for
      infants of singleton pregnancies at birth weights of 500-2,499 g. However, the
      incidence of infants of multifetal pregnancies with birth weights >/=2,500 g
      consistently exceeded that in singleton infants weighing >/=2,500 g. The relative
      risk (95% CI) of perinatal death among infants of multifetal pregnancies compared
      with singleton infants in the same category of birth weight was 0.88 (0.84-0.93)
      at 500 g. The relative risk decreased to 0.31 (0.25-0.39) at 1,900 g, increased
      to >1.0 at 2,500 g, to 3.7 (2.2-6.1) at 3,000 g, and to 14.9 (7.8-28.4) at
      >/=3,500 g. CONCLUSIONS: Japanese infants of multifetal pregnancies reaching
      >/=2,500 g in body weight have a significantly higher risk of perinatal death
      than singleton infants in the same category of body weight. Increased monitoring
      of fetuses of multifetal pregnancies who weigh >/=2,500 g may be helpful in
      reducing the incidence of perinatal mortality.

PMID- 10394091
TI  - Screening sonohysterography in infertility.
AB  - This prospective comparative study was carried out to assess the value of
      sonohysterography (SHG) in evaluating both the endometrial cavity and tubal
      patency in infertile patients and to compare its results with
      hysterosalpingography (HSG), diagnostic hysteroscopy and laparoscopic
      chromopertubation. It comprised 84 infertile women who were examined using SHG
      the day before combined diagnostic laparoscopy and hysteroscopy. Eighty-three
      patients had had HSG within 6 months. As regards the appearance of the
      endometrial cavity, the results of SHG agreed with hysteroscopy in 72.2% (k =
      0.31) while HSG agreed with hysteroscopy in 75.6% (k = 0.39) of cases. The
      appearance of the right and left tubes using SHG agreed with laparoscopy in 72.4%
      (k = 0.16) and 60.5% (k = 0.13), respectively, while HSG agreed with laparoscopy
      in 94% (k = 0.52) and 90.4% (k = 0. 51), respectively. However, when the
      appearance of fluid in DP was considered as an indirect indicator of patency of
      at least one tube at SHG, the agreement with laparoscopy rised to 88.1% (k =
      0.24) and 85.7% (k = 0.18) for both tubes respectively. In conclusion, SHG is
      similar to HSG as regards the appearance of the endometrial cavity but it is
      inferior to it for evaluating tubal factor. The implication of SHG in the
      infertility work-up as a simple and fast procedure can minimize costs and abuses
      of sophisticated techniques particularly in the developing countries with limited
      resources.

PMID- 10394094
TI  - Observations of high iron diamine-alcian blue stain in uterine cervical glandular
      lesions.
AB  - We studied epithelial glycoproteins in uterine cervical lesions, including
      glandular lesions, and investigated whether a more accurate diagnosis could be
      obtained using high iron diamine-alcian blue (HID-AB) stain and immunostaining
      with carcinoembryonic antigen (CEA). In addition, we examined the usefulness of
      preoperative diagnosis using biopsy specimens stained with HID-AB and CEA. Normal
      endocervical glands showed a predominance of sulfomucin, while adenocarcinoma
      predominantly showed sialomucin. CEA was highly detected in adenocarcinoma, but
      not in normal endocervix or in glandular dysplasia, suggesting that this stain
      has high specificity. The staining patterns of biopsy specimens and hysterectomy
      specimens were similar. Therefore HID-AB stain and CEA stain may be useful as a
      supplementary means of diagnosing uterine cervical lesions.

PMID- 10394093
TI  - Evaluation of the body composition and fat distribution in long-term users of
      hormone replacement therapy.
AB  - The aim of the study was to evaluate the body composition and fat distribution in
      long-term users of hormonal replacement therapy (HRT). 18 healthy menopausal
      women, long-term users of HRT (transdermal estradiol 50 microg continuously
      administered and 10 mg/day of medroxyprogesterone acetate for 12 days/month) and
      18 healthy menopausal women, who had never used HRT were included in the study.
      Age, menopausal age, parity, weight and height (body mass index, weight/height2),
      and lifestyle habits were similar. Waist and hip circumference, body composition
      and waist/hip ratio were measured and the results were analyzed. No significant
      difference was demonstrated in fat and water percentage, and waist/hip ratio.
      Nevertheless, the waist circumference of long-term HRT users was significantly
      lower than that of non-users. In conclusion, abdominal fat in long-term HRT users
      is lower than that of non-users of similar age, menopausal age and body mass
      index.

PMID- 10394095
TI  - Krukenberg tumors: can management be improved?
AB  - OBJECTIVE: The Montefiore Medical Center experience with women with
      gastrointestinal (GI) cancer was reviewed to: (1) evaluate clinical parameters in
      patients with Krukenberg tumor (GI cancer metastatic to the ovaries) and (2)
      evaluate oophorectomy in GI cancer patients. METHODS: (1) Charts of all female
      patients admitted between 1985 and 1996 with gastric or colon cancer were
      reviewed. RESULTS: The frequency of Krukenberg tumor was 7/1,021 (0.7%). The
      median age at presentation was 39.5 years (range 35-80); 5 were premenopausal, 2
      of whom were postpartum. Krukenberg tumor was significantly more common in the
      premenopausal patients with gastric cancer (p = 0.002), colon cancer (p = 0.001),
      and in both sites combined (p < 0.001). Our rate of pregnancy-associated
      Krukenberg tumors (28.6%) was significantly higher (p < 0.05) than that found in
      4 of 5 large studies. The average survival of our 7 patients was 12.3 months
      (range 4 days to 26 months), with secondary debulking and chemotherapy offering 1
      patient the longest longevity. Only 19/788 (2.4%) women had oophorectomy during
      their colon cancer surgery revealing 2 (10.5%) Krukenberg tumors, 6 (31.6%)
      benign solid or cystic ovarian tumors, and 11 (57.9%) normal or atrophic ovaries.
      CONCLUSIONS: Krukenberg tumors are rare. There is no uniformity of data reported
      in the literature. Krukenberg tumors were more common in premenopausal women with
      gastric or colon cancer compared to postmenopausal women. Our rate of pregnancy
      associated Krukenberg tumors appeared to be higher compared to other studies.
      Prophylactic oophorectomy in pre- and postmenopausal women should be considered
      at the time of GI cancer surgery, and requires further study. A national registry
      combined with prospective, multisite studies are needed to gather data and
      evaluate treatment.

PMID- 10394092
TI  - Evaluation of serum prolactin levels in patients with endometriosis and
      infertility.
AB  - The aim of this study was to clarify the significance of serum prolactin
      concentrations in patients with infertility and endometriosis. Forty patients
      with infertility and laparoscopically proven endometriosis were recruited into
      the study. Basal serum prolactin levels and prolactin levels after TRH
      administration were measured. The mean basal serum prolactin concentrations were
      12.5, 16.5, 19.5, and 26.5 ng/ml and those after thyrotropin-releasing hormone
      (TRH) administration were 88.3, 114.2, 125.3 and 138.8 ng/ml in patients with
      stages I, II, III and IV endometriosis, respectively. A statistically significant
      relationship was found between the basal serum prolactin levels as well as those
      after TRH injection and the stage of the endometriosis. The patients were divided
      in two groups. Group I consisted of 20 patients who did not receive any
      treatment, while group II consisted of 20 patients who were initially treated
      with GnRH analogues for 24 week and subsequently with several therapeutic schemes
      in order to improve their fecundity. The pregnancy rate was not different between
      the two groups. The patients, however, who did not become pregnant had higher
      serum prolactin concentrations after TRH administration as compared to those who
      conceived. We conclude that occult hyperprolactinemia may be a cause of
      infertility in patients with endometriosis.

PMID- 10394096
TI  - Increased natural killer cell activities in patients treated with gonadotropin
      releasing hormone agonist.
AB  - Natural killer (NK) cell activity in patients treated with gonadotropin-releasing
      hormone agonists (GnRH-a) was studied. The subjects were 8 patients with
      endometriosis (6 with ovarian endometrial cyst, 2 with adenomyosis) and 3
      patients with uterine leiomyoma. Changes in serum estradiol (E2) concentration
      and NK cell activity in peripheral blood were analyzed before and after GnRH-a
      treatment (buserelin 900 microg/day for 4-5 months). NK cell activity was
      determined by 51Cr release assay and E2 by radioimmunoassay. NK cell activity
      before GnRH-a treatment was 37.7 +/- 19.0%, and after therapy activity increased
      significantly to 50. 8 +/- 18.2%. However, no significant correlation between the
      increase in NK cell activity and the decrease in E2 concentration was found.
      Results indicate that the standard GnRH-a treatment for endometriosis and uterine
      leiomyoma might increase NK cell activity. The etiology of the increase of NK
      activity with GnRH-a treatment is likely related to factors other than E2
      concentration.

PMID- 10394098
TI  - Genetically engineered plant allergens with reduced anaphylactic activity.
AB  - Allergy immunotherapy is based on the administration of increasing amounts of the
      disease-eliciting allergens in order to yield allergen-specific non
      responsiveness. Success of this therapy is associated with modulation of the
      immune response to allergenic molecules at the level of T-helper cells and the
      induction of blocking antibodies. The extracts used for immunotherapy are highly
      heterogenous preparations from natural sources and contain additional components,
      mostly proteins which are not well defined. Recombinant DNA technology offers
      novel tools for production of pure and well-characterised allergens for specific
      immunotherapy. However, high IgE reactivity of pure recombinant allergens is
      associated with an increased risk of potentially life-threatening anaphylactic
      reactions. A major improvement in allergen-specific immunotherapy may be achieved
      by using genetically engineered recombinant allergens with reduced anaphylactic
      activity. Recently the site- directed mutagenesis technique has been applied
      successfully to produce variants of major grass, birch and oilseed rape allergens
      with reduced IgE reactivity but retained T-cell reactivity. These modified
      allergens with reduced anaphylactic potential are novel candidates for safer and
      more effective allergen-specific immunotherapy.

PMID- 10394097
TI  - Prenatal diagnosis of nonmosaic trisomy 9 in a fetus with severe renal disease.
AB  - We report a case of nonmosaic trisomy 9 presenting at 21 weeks of gestation with
      polycystic, echogenic horseshoe kidney, collapsed bladder, absent amniotic fluid,
      and intrauterine growth restriction. Color Doppler imaging demonstrated no blood
      flow signals from renal vessels. Fetal blood sampling confirmed a 47,XX,+9
      karyotype, with no evidence of mosaicism, and increased serum beta2-microglobulin
      levels of 10.7 mg/l, consistent with severe renal failure. A repeat scan at 23
      weeks also revealed a dysmorphic face, bilateral microphthalmia, and a cerebellar
      vermian defect. Follow-up examinations showed progressive growth restriction
      leading to fetal death at 33 weeks of gestation. This report demonstrates that
      fetuses with nonmosaic trisomy 9 may present with severe renal abnormalities and
      confirms that cases seen in the second and third trimesters usually have a dismal
      outcome.

PMID- 10394099
TI  - Early interleukin-4: its role in the switch towards a Th2 response and IgE
      mediated allergy.
AB  - The etiology of IgE-mediated allergies is complex and, thus far, not completely
      understood. A common feature, however, is the overproduction of IgE-inducing
      cytokines, e.g. interleukin-4(IL-4), compared to IgE-antagonistic cytokines, such
      as interferon-gamma or IL-12. IgE-inducing cytokines are produced by T helper
      type 2 (Th2) cells. The differentiation of naive T cells towards the Th2
      phenotype seems to be crucially dependent upon the particular cytokines present
      in the early stages of an immune response. Concerning the factors driving Th2
      differentiation, the so-called 'early IL-4' seems to play an important role,
      although there is some controversy over the degree of its requirement and its
      cellular source. We have recently demonstrated that basophils might be such a
      source, since they rapidly release IL-4 upon antigen-specific or nonantigen
      specific stimuli, such as certain lectins. This makes lectins interesting
      candidates for inducing a Th2 response and IgE-mediated allergy in unsensitized
      individuals.

PMID- 10394100
TI  - Activation of Fc epsilon RI inhibits the pyruvate kinase through direct
      interaction with the gamma-chain.
AB  - The downstream signaling components of high-affinity IgE receptor (FcepsilonRI)
      were studied using yeast two-hybrid screening of the cDNA library constructed
      from RBL-2H3 cells. The cytoplasmic part of the gamma-chain but not that of the
      beta-chain was found to interact with pyruvate kinase in the yeast. The in-vitro
      translated pyruvate kinase also specifically interacted with the bacterially
      expressed glutathione-S transferase fusion protein of the cytoplasmic part of the
      gamma-chain. When RBL-2H3 cells were challenged with antigen, the activity of
      pyruvate kinase gradually decreased, reaching the minimum activity around 5 min
      after the activation, and then slowly returned to the normal level. The dose
      response curve (antigen vs. pyruvate kinase activity) plotted at 5 min after
      stimulation showed that the pyruvate kinase was dose-dependently inhibited and
      the maximum inhibition was reached at the concentration of 0.1 microgram/ml of
      antigen. Direct interaction between FcepsilonRI and pyruvate kinase was also
      demonstrated by co-immunoprecipitation in RBL-2H3 cells. These data suggest that
      pyruvate kinase is functionally linked with FcepsilonRI and might exert an
      important role in controlling cellular functions following the activation of
      FcepsilonRI.

PMID- 10394103
TI  - Phenotype of IL-16-producing cells in bronchial mucosa: evidence for the human
      eosinophil and mast cell as cellular sources of IL-16 in asthma.
AB  - BACKGROUND: We have previously shown increased expression of the CD4+ cell
      chemoattractant interleukin (IL)-16 in bronchial biopsies of atopic asthmatic
      subjects compared to normal controls. IL-16 immunoreactive cells were identified
      as both epithelial cells and non-epithelial inflammatory cells. The aim of this
      study was to characterize and compare the phenotype of non-epithelial
      inflammatory cells that express IL-16 immunoreactivity in bronchial biopsies from
      non-atopic normal controls and atopic asthmatic subjects. METHODS: Sections from
      endobronchial biopsies obtained from non-atopic normal controls and atopic
      asthmatics were processed for double immunocytochemistry. IL-16 immunoreactivity
      was assessed using a polyclonal anti-IL-16 antibody and the avidin-biotin complex
      diaminobenzidine method. The phenotype of IL-16 immunoreactive cells was assessed
      using anti-CD3, anti-MBP, anti-tryptase and anti-CD68 mAbs and the alkaline
      phosphatase complex-Fast Red method. RESULTS: In normal subjects, the majority of
      IL-16 immunoreactive cells were CD3+ T cells (71.1+/-10.3%) and CD68+ macrophages
      (22.4+/-8.1%). IL-16 immunoreactivity coexpressed with tryptase+ mast cells in 4
      of 7 normal subjects whereas IL-16 immunoreactivity coexpressed with MBP+
      eosinophils in only 1 normal subject. In atopic asthmatic subjects, IL-16
      immunoreactive cells were mainly CD3+ T cells (60.8+/-8.7%) and MPB+ eosinophils
      (16.8+/-8.2%). IL-16 immunoreactivity also coexpressed with tryptase+ mast cells
      (10.6+/-4.0%) in all asthmatic subjects. The number of IL-16 immunoreactive cells
      that coexpressed MBP was higher in asthmatic subjects compared to normal controls
      (p = 0.003). CONCLUSION: Our data show that T cells are the major non-epithelial
      cellular source of IL-16 in normal and asthmatic airways. Eosinophils and mast
      cells comprised other potential cellular sources of IL-16 in asthmatic airways.

PMID- 10394101
TI  - Molecular cloning of the guinea pig GRO gene and its rapid expression in the
      tissues of lipopolysaccharide-injected guinea pigs.
AB  - BACKGROUND: CXC chemokines, IL-8 and GRO, play a role in the recruitment of
      neutrophils in the human. The functional orthologues in the rat and mouse are
      CINC/KC and MIP-2. The lack of IL-8 made these animals less useful to study the
      role of IL-8 and GRO. METHODS: Guinea pig (gp) cDNA libraries were screened for
      GRO and IL-1beta. A gp genomic library was screened with a gpGRO cDNA probe.
      Expression of gpIL-8, gpGRO, gpTNFalpha, and gpIL-1beta was investigated by
      Northern analysis and/or by in situ hybridization. RESULTS: Two gpGRO cDNAs, a
      3.0-kb gpGRO genomic DNA, and a gpIL-1beta cDNA were cloned. gpGRO and gpIL-8
      mRNA were detected in different tissues including lungs 1 h after intraperitoneal
      injection of lipopolysaccharide (LPS) into guinea pigs. gpGRO, gpIL-8,
      gpTNFalpha, and gpIL-1beta expression peaked at 3 h in the lungs. Both gpGRO and
      gpIL-8 mRNA were detected in the cells in alveolar spaces and bronchial
      epithelial cells. However, gpGRO mRNA, but not gpIL-8, was also expressed in
      endothelial cells and vascular smooth muscle cells. CONCLUSIONS: gpGRO and gpIL-8
      mRNA rapidly accumulated in the lungs of guinea pigs after LPS injection.
      Expression of gpIL-8 and gpGRO mRNA appeared to be independent from TNFalpha- or
      IL-1beta-stimulation in this model. A high level expression of gpGRO in vascular
      cells suggest an important role of GRO in the sequestration of neutrophils and
      multi-organ injuries induced by LPS. The guinea pig will provide an excellent
      model to study the roles of IL-8 and GRO, important inflammatory mediators in the
      human.

PMID- 10394102
TI  - Expression of B7-1, B7-2, and interleukin-12 in anti-Fas antibody-induced
      pulmonary fibrosis in mice.
AB  - BACKGROUND: We have previously reported that the inhalation of anti-Fas antibody
      induced pulmonary fibrosis in mice. To induce an effective immune response,
      antigen-presenting cells have to not only present antigenic peptide with MHC
      molecules to T lymphocytes, but also express B7 costimulating molecules. The
      purpose of this study is to investigate whether B7 family costimulating molecules
      and interleukin-12 (IL-12), which primarily promote cellular immunity, are
      associated with anti-Fas antibody-induced pulmonary fibrosis. METHODS: We
      examined the expression of B7-1, B7-2, and IL-12 using the revese transcription
      polymerase chain reaction (RT-PCR), RT-in situ PCR, and immunohistochemistry.
      RESULTS: We observed the upregulation of B7-1, B7-2, and IL-12 p40 mRNA after
      anti-Fas antibody inhalation. B7-2 and IL-12 p40 mRNA appeared to be expressed in
      mononuclear cells, while B7-1 mRNA and protein were expressed in bronchiolar
      epithelial cells as well as macrophages. CONCLUSION: These findings indicate that
      the T-cell-mediated immune response in this model involved the upregulation of B7
      1, B7-2, and IL-12, and that the aberrant expression of B7-1 in bronchiolar
      epithelial cells may induce autoreactive T cell proliferation against themselves.

PMID- 10394104
TI  - Soluble intercellular adhesion molecule-1 in sera of children with bronchial
      asthma exacerbation.
AB  - Previous studies have suggested that intercellular adhesion molecule-1 (ICAM-1;
      CD54) may be involved in the pathogenesis of asthma. In addition, a soluble form
      of intercellular adhesion molecule-1 (sICAM-1) has been detected in increased
      concentrations in the sera from adult patients with certain inflammatory, immune,
      or malignant diseases. To determine whether bronchial asthma exacerbation in
      children is associated with increased levels of serum sICAM-1 and to investigate
      the effect of the severity of exacerbation on these levels, the concentrations of
      sICAM-1 were measured in sera of 20 healthy control children and 45 asthmatic
      children (15 with mild, 15 with moderate, and 15 with severe asthma exacerbation)
      using an immunoenzymatic assay. Assessment of the severity of asthma exacerbation
      was based on clinical and physiological parameters. The mean (+/- SD) level of
      serum sICAM-1 for asthmatic children (390.0+/-108.3 ng/ml) was significantly
      higher than that for healthy (193.2+/-33.95 ng/ml; p = 0.000). We have also found
      a differential rise of serum sICAM-1 level which correlates well with the
      severity of asthma exacerbation. The elevated concentrations of serum sICAM-1 in
      acute bronchial asthma may reflect the extensive inflammatory response occurring
      in the airways during acute exacerbation of the disease with airway obstruction.
      The results of this study suggest that serum sICAM-1 is a promising serological
      marker of the severity of inflammation in bronchial asthma in children and it
      would not only facilitate staging of inflammation but also allow the monitoring
      of therapy and intervention.

PMID- 10394105
TI  - High levels of Olea europaea pollen and relation with clinical findings.
AB  - BACKGROUND: Olea europaea pollen is an important cause of seasonal allergic
      rhinitis and bronchial asthma in southern Spain. For patients allergic to grass
      pol- len the critical concentration of airborn pollen is 50 grains/m3, but in the
      case of Olea pollinosis no data is available. METHODS: Fifty-six seasonal
      allergic rhinitis patients (29 in 1994 and 27 in 1995) were included in this
      study, all of whom lived in Jaen. Daily symptom card were filled in and pollen
      counts during May and June were performed in both years. A linear regression
      model was used for analysis of the airborne pollen concentration and the symptom
      score. RESULTS: Significant correlations among daily counts of Olea pollen and
      rhinitis symptoms were obtained. Most of our monosensitized patients needed a
      high Olea pollen concentration in the atmosphere (around 400 grains/m3) to suffer
      at least from mild allergic rhinitis symptoms. CONCLUSION: Local conditions with
      a wide area dedicated to olive tree cultivars result in a high concentration of
      this pollen in the atmosphere. Monosensitized Olea patients in our area seem to
      need exceptionally high levels to suffer from allergic symptoms.

PMID- 10394106
TI  - Cord-blood-derived human cultured mast cells produce interleukin 13 in the
      presence of stem cell factor.
AB  - BACKGROUND: Mast cells have been regarded as a potential source of cytokines.
      Although the human mast cell line HMC-1 and human lung mast cells have been shown
      to produce interleukin (IL) 13, it still remains uncertain whether cord-blood
      derived human cultured mast cells produce IL-13. METHODS: Human cultured mast
      cells were raised from cord blood cells in the presence of stem cell factor (SCF)
      and IL-6. Levels of IL-13 mRNA were examined by a semiquantitative reverse
      transcriptase-polymerase chain reaction. IL-13 levels in the supernatants were
      measured with an enzyme-linked immunosorbent assay. RESULTS: When the IgE
      sensitized cultured mast cells were activated with anti-IgE, mRNA for IL-13 was
      amplified with a peak at 3 h after the stimulation. IL-13 was not detected in the
      supernatants of the activated mast cells in the absence of SCF, whereas the mast
      cells secreted significant amounts of IL-13 after the stimulation in the presence
      of SCF. Calcium ionophore A23187 also stimulated the mast cells to release IL-13
      into the supernatant in the presence of SCF. CONCLUSIONS: These observations
      suggest that human mast cells can produce IL-13 under the condition with SCF. The
      cord-blood-derived human cultured mast cells will help in studying the functional
      properties of human mast cells in allergic diseases.

PMID- 10394107
TI  - 1,25-dihydroxyvitamin D3 stimulates transforming growth factor-beta1 synthesis by
      mouse renal proximal tubular cells.
AB  - 1,25-dihydroxyvitamin D3 [1,25-(OH)2 D3] is a secosteroid hormone with effects on
      cell growth, differentiation and immunoregulatory functions in a number of
      tissues not primarily involved in mineral metabolism. We recently demonstrated
      growth-regulating effects of 1, 25-(OH)2 D3 on human mesangial cells and proximal
      tubular cells. To investigate whether 1,25-(OH)2 D3 might also affect the
      synthesis of cytokines and growth factors in proximal tubular cells, we assessed
      in the present study the expression and secretion of transforming growth factor
      beta1 (TGF-beta1) in a mouse proximal tubular cell line (MCT) in vitro. TGF-beta1
      synthesis was measured by a monospecific ELISA in culture supernatant. The
      secreted TGF-beta1 was proven to be biologically active by means of a bioassay
      system (CCL-64 mink lung epithelial cell proliferation assay). TGF-beta1 gene
      expression was assessed by RT-PCR. To analyze whether TGF-beta1 expression
      mediates the 1,25-(OH)2 D3-induced antiproliferative actions in MCT,
      proliferation studies in the absence or presence of a blocking monoclonal anti
      TGF-beta1-3 antibody were performed. 1, 25-(OH)2 D3 (10(-11) to 10(-7) M)
      specifically increased the TGF-beta1 protein secretion in MCT with a maximum at
      10(-8) M. No detectable effect was found with 25 D3 at 10 times higher
      concentrations. A synthetic 20-epi analogue, MC 1288, increased TGF-beta1
      secretion up to similar amounts at equimolar concentrations as the natural
      hormone 1,25-(OH)2 D3. Steady-state TGF-beta1 mRNA concentration in MCT was
      transiently increased by 1, 25-(OH)2 D3 between 12 and 24 h, returning to control
      values at 48 h. Blocking TGF-beta1 did not reduce or abrogate the
      antiproliferative effect of 1,25-(OH)2 D3. In conclusion, 1,25-(OH)2 D3
      stimulates TGF-beta1 expression in renal proximal tubular cells, a growth factor
      with anti-inflammatory and profibrotic actions which plays an important role in
      the development and progression of nephrosclerosis.

PMID- 10394109
TI  - Protopanaxatriol ginsenosides inhibit glucose uptake in primary cultured rabbit
      renal proximal tubular cells by arachidonic acid release.
AB  - Ginsenosides are involved in protective action against renal dysfunction and the
      regulation of renal functions. However, the effects of ginsenosides on glucose
      reabsorption are not yet known in renal proximal tubular cells. The aim of this
      study was to examine the effects of ginsenosides, protopanaxadiol (PD) saponin
      and protopanaxatriol (PT) saponin, on alpha-methyl-D-glucopyranoside (alpha-MG)
      uptake and its mechanism of action in primary cultured rabbit renal proximal
      tubular cells (PTCs). The alpha-MG uptake was inhibited by 90% by 0.5mM
      phloridizin and by removal of Na+ in the PTCs. These are typical characteristics
      described for the proximal tubule. To determine the time- and dose-dependent
      effects of PD and PT saponins on alpha-MG uptake, PTCs were incubated with
      different concentrations of PD and PT saponins (10-100 microg/ml) and for
      different time periods (from 10 min to 24 h). PT saponin (>/=50 microg/ml) from
      30 min inhibited alpha-MG uptake; however, PD saponin did not alter the alpha-MG
      uptake at any doses and time periods. In the kinetic analysis of alpha-MG uptake,
      PT saponin produced a significant decrease in Vmax. The PT saponin induced
      inhibition of alpha-MG uptake was blocked by mepacrine, a phospholipase A2
      inhibitor. In addition, PT saponin increased [3H] arachidonic acid release by
      218% of that of control, and this effect was also completely blocked by
      mepacrine. In conclusion, PT saponin inhibited, in part, alpha-MG uptake through
      the phospholipase A2 signal pathway in primary cultured rabbit renal PTCs.

PMID- 10394108
TI  - Leukotriene D4 inhibits Na+ uptake through cAMP and PLC pathways in primary
      cultured renal proximal tubular cells.
AB  - Leukotriene D4 (LTD4) is one of the slow-reacting substances of anaphylaxis and
      is reported to have a diverse response including the mediation of glomerular
      nephritis. However, little is known about the functions of LTD4 and its
      mechanisms of action in primary cultured rabbit renal proximal tubular cells
      (PTCs). The purpose of this study is to investigate the effect of LTD4 on Na+
      uptake and its related signal transduction pathways in PTCs. LTD4 (>10(-9) M)
      significantly inhibited the Na+ uptake after 15 min (in nmol/mg protein: controls
      431.7+/-11.4 vs. LTD4 (10(-9) M) 355.0+/-23.6; p<0. 05); and its effect was
      blocked by MK-571 (10(-6) M), a leukotriene receptor antagonist, in PTCs.
      Preincubation with cilastatin, a renal dipeptidase inhibitor, and polyclonal
      antibody against renal dipeptidase potentiated the inhibitory effect of LTD4 on
      Na+ uptake. SQ 22536 (10(-6) M), an adenylate cyclase inhibitor, and the
      myristoylated protein kinase A inhibitor amide 14-22 (PKI; 10(-5) M) blocked the
      effect of LTD4 on Na+ uptake (in nmol/mg protein: LTD4 349.9+/-18.5 vs. SQ
      22536+LTD4 476.5+/-22.0 and PKI+LTD4 440.3+/-19. 3; p<0.05), and LTD4 induced an
      increase in cyclic adenosine monophosphate (cAMP), suggesting the involvement of
      cAMP in the inhibition of Na+ uptake. In addition, U 73122 (10(-6) M) and
      neomycin (10(-4) M), phospholipase C (PLC) inhibitors, W-7 (10(-4) M), a
      calmodulin antagonist, and bisindolylmaleimide I, a protein kinase C (PKC)
      inhibitor, blocked the LTD4-induced inhibition of Na+ uptake, strongly suggesting
      involvement of the PLC-PKC signal pathways in the effect of LTD4. LTD4
      significantly increased [Ca2]i by 49+/-7% as compared with baseline. TMB-8 (10(
      5) M) and BAPTA/AM (10(-5) M), intracellular calcium mobilization blockers,
      completely blocked the LTD4-induced inhibition of Na+ uptake (in nmol/mg protein:
      LTD4 347.6+/-19.0 vs. TMB-8+LTD4 436.4+/-22.3 and BAPTA/AM+LTD4 419.9+/-14.3;
      p<0.05); however, EGTA (1 mM), a calcium chelator, partially blocked the LTD4
      induced inhibition of Na+ uptake. In conclusion, LTD4-induced inhibition of Na+
      uptake may be involved in both cAMP and PLC-PKC signal pathways in PTCs. In
      addition, Ca2+, which comes from the intracellular Ca2+ mobilization, is
      primarily responsible for the LTD4-induced inhibition of Na+ uptake.

PMID- 10394110
TI  - Suppressed activities of cathepsins and metalloproteinases in the chronic model
      of puromycin aminonucleoside nephrosis.
AB  - Glomerulosclerosis and tubulointerstitial fibrosis are the hallmarks of chronic
      renal diseases. In the present study, we have investigated the potential
      involvement of various proteinases in these alterations in the model of puromycin
      aminonucleoside (PAN) nephrosis. Two groups of male Wistar rats were given either
      three or seven injections of PAN (2.0 mg/100 g body weight) over a 4- and 12-week
      period, respectively. The two control groups received saline injections.
      Activities of cathepsins (B, H and L) were determined in isolated glomeruli and
      proximal tubules. Moreover, collagenase-like and gelatinase-like activities were
      analyzed in isolated glomeruli. Three weeks after weekly PAN injection, the rats
      developed heavy proteinuria (140.8+/-22.0 vs. 13.5+/-3.29 mg/day; p<0.001), and
      at week 11 protein excretion reached 606.6+/-23.00 vs. 22.8+/-1.5 mg/day. Renal
      morphology revealed minimal glomerular mesangial changes at the 4th week after
      PAN administration. At the 12th week a marked mesangial matrix accumulation as
      well as severe tubulointerstitial infiltration and fibrosis associated with
      tubular dilation and atrophy were observed. Glomerular cathepsins B, H, and L and
      gelatinase-like activities decreased at the 4th week after the first PAN
      injection and remained at this low level throughout the entire study period.
      Glomerular collagenase-like activity decreased at the 4th week (p<0.05) and was
      still mildly lower than that of the control group at the 12th week, but without
      significance. In the isolated proximal tubules, the activities of cathepsins B,
      H, and L showed the same pattern of decreases as those found in the glomeruli
      over the whole experimental period. Taken together, our data in the model of
      chronic PAN nephrosis suggest that the suppressed activities of cathepsins as
      well as the decreased gelatinase- and collagenase-like activities participate in
      the accumulation of extracellular matrix and thereby may contribute to the
      development of glomerulosclerosis and tubulointerstitial fibrosis.

PMID- 10394111
TI  - Short- and long-term effects of fish oil on proteinuria, morphology and renal
      hemodynamics in the Milan normotensive rat model of spontaneous
      glomerulosclerosis.
AB  - BACKGROUND/AIMS: A diet rich in polyunsaturated Omega3 fatty acids has been shown
      to modulate the course of several experimental models of renal disease. The short
      and long-term effects of an 8% fish oil (FO) chow on proteinuria, renal blood
      flow and glomerular morphology were evaluated in Milan normotensive rats that
      spontaneously develop progressive glomerulosclerosis. METHODS: Eight rats each
      were pairfed FO- versus cholesterol-enriched or control diets for either 2 or 32
      weeks. 4/48 animals died (2-week trial: 1 rat on the FO and 1 rat on the control
      diet; 32-week trial: 1 rat on the cholesterol and 1 rat on the control diet) and
      were excluded from all statistic analyses. RESULTS: After 2 weeks the renal blood
      flows were higher in the FO animals versus controls (8.75+/-2.19 vs. 6.87+/-1.91
      ml/min/g, p<0.05), and the prostaglandin E2/thromboxane B2 ratio shifted towards
      the vasodilatative prostaglandin E2 (1. 76+/-0.18 vs. 0.91+/-0.19, p<0.05).
      During the long-term trial proteinuria in the FO animals progressed faster and to
      a higher level (176.5+/-32.2 vs. 82.7+/-36.7 mg/24 h at week 32, p<0.01). After
      32 weeks the renal blood flow was significantly lower in th FO group 2.8+/-1.1
      vs. 4.6+/-1.9 ml/min/g, (p<0.05), and the rats had an accelerated development of
      nephrosclerosis, with sclerotic lesions in 60.3+/-6.6% of the glomeruli as
      compared with 46.5+/-9.8% in the cholesterol and 39.8+/-5.9 in the control group
      (p<0.05). CONCLUSION: The short-time effects of FO on renal hemodynamics did not
      alleviate the progress of renal damage in Milan normotensive rats, but the
      morphologic and functional signs of injury were rather pronounced with FO
      feeding.

PMID- 10394112
TI  - A Th1 response is essential for induction of crescentic glomerulonephritis in
      mice.
AB  - Crescentic glomerulonephritis can be induced in rodents by injection of
      heterologous antibodies against the glomerular basement membrane. There is
      evidence that glomerular inflammation in that model represents a delayed-type
      hypersensitivity response to the heterologous immunoglobulin, whereas the
      antibody response is not important. The aim of the present study was to test this
      hypothesis. Delayed-type hypersensitivity is mediated by T cells with the Th1
      phenotype. We compared mice immunized with rabbit immunoglobulin G in complete
      Freund's adjuvant or in incomplete Freund's adjuvant, producing, respectively,
      Th1- or Th2-biased responses to the antigen. Intravenous injection of rabbit
      antimouse glomerular basement membrane serum provoked proteinuria, infiltration
      with T cells and macrophages, as well as profound histological damage in the
      group treated with complete Freund's adjuvant. There was no evidence of
      glomerulonephritis in the group which received incomplete Freund's adjuvant.
      Deposits of mouse IgG along the glomerular basement membrane were similar in both
      groups. Thus, a Th1 response appears to be essential for the induction of
      glomerulonephritis in this model.

PMID- 10394114
TI  - Magnesium supplements' effect on magnesium balance in athletes during prolonged
      restriction of muscular activity.
AB  - Electrolyte supplements may be used to prevent negative electrolyte balance
      during hypokinesia (HK) (decreased number of kilometres per day). The aim of this
      study was to evaluate the effect of daily intakes of magnesium (Mg) supplements
      on Mg balance during prolonged HK. Studies were done during a 30-day period of
      pre-HK and during a 364-day period of HK. Forty male athletes aged 22-26 years
      were chosen as subjects. They were equally divided into four groups:
      unsupplemented ambulatory control (UACS), unsupplemented hypokinetic subjects
      (UHKS), supplemented hypokinetic subjects (SHKS) and supplemented ambulatory
      control subjects (SACS). The SHKS and UHKS groups were maintained under an
      average running distance of 1.7 km/day, while the SACS and UACS groups
      experienced no changes in their professional training and routine daily
      activities. The SHKS and SACS groups took daily 23 mg Mg as Mg lactate per
      kilogram body weight. Mg balance, urinary and faecal Mg excretion and serum Mg
      concentration, anthropometric characteristics and peak oxygen uptake were
      measured. Negative Mg balance, faecal and urinary Mg excretion and serum Mg
      concentration increased significantly (p</=0.01) in the SHKS and UHKS groups when
      compared with the SACS and UACS groups. Serum, urinary and faecal Mg changes and
      negative Mg balance were much greater and appeared much faster in the SHKS group
      than in the UHKS group. Body weight and peak oxygen uptake decreased
      significantly (p</=0.01) in the SHKS and UHKS when compared with the SACS and
      UACS groups. By contrast, the corresponding parameters did not change
      significantly in the SACS and UACS groups when compared with the baseline control
      values. It was concluded that prolonged HK induces a significant negative Mg
      balance accompanied by significant Mg changes in urine, faeces and serum. Thus,
      using Mg supplements was not effective to prevent negative Mg balance in athletes
      during prolonged HK.

PMID- 10394113
TI  - Nitric oxide-dependent renal vasodilatation is not altered in rat with rHuEpo
      induced hypertension.
AB  - BACKGROUND: Recombinant human erythropoietin (rHuEpo) is the treatment of choice
      in anemia associated with end-stage renal disease. Its major side effect is
      hypertension, which occurs in 8-30% of uremic patients. The exact mechanism of
      rHuEpo-induced hypertension has not been fully elucidated, and several
      possibilities have been proposed, such as a direct vascular effect of the drug
      with a shift in the balance of constrictor and relaxing endothelial factors
      (endothelins and nitric oxide (NO)). Recent papers suggested an enhanced rather
      than reduced activity of endogenous NO system in rats with normal renal function
      and rHuEpo-induced hypertension. Our study was designed to verify whether, in
      spite of enhanced activity of the renal NO system, rHuEpo may affect endothelium
      dependent (acetylcholine-induced) and/or endothelium-independent (sodium
      nitroprusside-induced) vasorelaxation and to evaluate basal NO release by the
      infusion of NG-nitro-L-arginine methyl ester (L-NAME) in an isolated and perfused
      rat kidney model. METHODS: To investigate this hypothesis, we have determined
      systemic and renal NO activity in Wistar rats treated with a hypertensive dose of
      rHuEpo (150 IU/kg b.w. every other day for 2 weeks) by measuring stable NO
      metabolites (NO2+NO3) in the urine and have also evaluated variations in renal
      vascular resistance after the injection of Ach, SNP and the infusion of L-NAME.
      RESULTS: Hematocrit, hemoglobin concentration and arterial blood pressure were
      significantly increased in the treated group as compared with the controls.
      Urinary excretion of NO2+NO3 was significantly higher in treated than in the
      controls (438+/-66 vs. 294+/-36 nM/ml/min, p<0.01, respectively). There were no
      significant differences in the dose-response curves to Ach and SNP between the
      two groups. The renal vasoconstriction following the infusion of L-NAME was also
      similar in the two groups. CONCLUSIONS: The analysis of our results seems to
      indicate that the endogenous NO system activity was enhanced in rHuEpo-induced
      hypertension in rats with normal renal function and a resistance to NO was not
      developed in renal circulation. Further studies seem to be necessary to better
      clarify the exact mechanisms underlying the development of rHuEpo-induced
      hypertension.

PMID- 10394116
TI  - Wrist measurement of blood pressure: some critical remarks to oscillometry.
AB  - Oscillometric blood pressure measuring devices worn at the wrist are preferred by
      a growing part of hypertensive patients for self-measurement because of their
      compactness and ease of use. However, little is known about the accuracy of such
      instruments. The accuracy of such devices was evaluated by measuring the blood
      pressure at the end of a coronary angiography procedure in 27 subjects nearly
      simultaneously in the aortic arch, using a Statham P23 transducer, and at the
      wrist, using the blood pressure watch (BPW) by NAIS-Matsushita. Four replicate
      comparative measurements were performed in each subject. On average, the blood
      pressure measured by the BPW was found to be higher: systolic +1.2+/-(SD)10.2 mm
      Hg, diastolic +4.1+/-7.2 mm Hg. The correlation coefficient between the two
      methods was 0.85 for the systolic and 0.84 for the diastolic pressure, but 39% of
      the systolic and 22% of the diastolic differences were outside the range of +/-1
      SD. There was no correlation between systolic differences and blood pressure or
      patients' variables, but multiple regression analysis revealed that the diastolic
      blood pressure differences were negatively correlated with the aortic diastolic
      pressure (r = 0.89, p<0.001), indicating that the BPW is less accurate to detect
      lower values. CONCLUSIONS: (1) Though the average systolic and diastolic
      deviations between both methods and the relative correlation coefficients suggest
      that the BPW is to be used carefully for monitoring blood pressure, the great
      variability of differences and the inability of the BPW to detect lower diastolic
      blood pressure calls for a mandatory validation test by an approved protocol
      before this new device can be recommended for general use. (2) On the basis of
      our results for wrist oscillometry with the BPW and data reported in the
      literature for upper-arm oscillometric devices, we recommend to use oscillometric
      devices only when they were validated properly. In particular, the oscillometric
      measurement should be employed with caution for epidemiological studies or for
      investigation of population groups (e.g., children or pregnant women) that are
      expected to display lower diastolic pressures.

PMID- 10394115
TI  - Does leptin play a role in the pathogenesis of essential hypertension?
AB  - BACKGROUND: Leptin is produced and released by adipocytes in proportion to fat
      stores. Leptin as an anorectic hormone plays an important role in the regulation
      of food intake, energy expenditure, and insulin secretion. In contrast,
      neuropeptide Y, insulin, cortisol, and growth hormone are presumed to be appetite
      modulators. Leptin and neuropeptide Y are both involved in the activation of
      sympathetic tone. Increased body fat stores in obese patients are involved in the
      pathogenesis of some metabolic disorders (e.g., hyperinsulinaemia, glucose
      intolerance) and arterial hypertension. METHODS AND RESULTS: Based on this
      pathophysiological background, we tried to assess the relationship between plasma
      leptin and blood pressure in 41 patients with essential hypertension (EHP; 20
      females, 21 males, mean age 38.7+/-1.9 years, mean body mass index - BMI - 25.8+/
      0.5 kg/m2) and in an appropriately sex- and BMI-matched control group of 27
      normotensive healthy subjects (NHS; 11 females, 16 males, mean age 39.7+/-2.5
      years, mean BMI 24.8+/-0.6 kg/m2). The plasma leptin concentration did not differ
      significantly between EHP and NHS (13.0+/-1.9 vs. 8.1+/-1.0 ng/ml, respectively).
      In both groups a significant positive correlation was found between BMI and
      plasma leptin concentration (p<0.0001). A significant positive correlation
      (p<0.02) was found between leptinaemia and mean (MAP), systolic and diastolic
      blood pressures, if data were analyzed for all examined subjects or separately
      only for women. Such a correlation could not be confirmed for male NHS and EHP
      subjects. The plasma neuropeptide Y concentration was higher in EHP than in NHS
      (77.1+/-23.0 vs. 63.6+/-9.8pg/ml, p = 0.05). In contrast to neuropeptide Y plasma
      insulin, cortisol, and growth hormone concentrations were similar in EHP and in
      NHS. CONCLUSION: Both EHP and NHS are characterized by a positive correlation
      between BMI and leptinaemia. Leptin may be indirectly involved in blood pressure
      regulation, especially in women of both NHS and EHP.

PMID- 10394117
TI  - Indirect and direct simultaneous, comparative blood pressure measurements with
      the Bosotron 2 device.
AB  - Testing the accuracy of the automatic blood pressure measuring device Bosotron 2,
      we performed simultaneous, same-arm, comparative blood pressure measurements with
      three instruments (A, B, and C) of the device and by auscultation in the
      antecubital fossa by a trained observer in 24 volunteers each. The volunteers
      were evenly matched for age, sex, and blood pressure level. The mean systolic
      differences and their standard deviations (24 subjects each, n = 288 single
      measurements) were -1.32+/-3.8 mm Hg for instrument A, -0.99+/-3.9 mm Hg for
      instrument B, and -1.12+/-5.0 mm Hg for instrument C. The corresponding values
      for the diastolic differences were -2.71+/-4.4, -3.46+/-4.3, and -2.72+/-3.9 mm
      Hg, respectively. Combining the results for the three instruments, the comparison
      yielded a good accuracy (mean difference) and sufficient repeatability of the
      differences (standard deviation) for the systolic and diastolic blood pressures
      (systolic -1.14+/-4.3 mm Hg; diastolic -2.96+/-4.2 mm Hg). In addition to the
      British Hypertension Society protocol, in 33 patients with coronary artery
      disease the measurements using the three Bosotron 2 devices were compared with
      measurements within the aortic arch. The mean systolic/diastolic differences (+/
      SD) were +1.45+/-4.3 and +7. 27+/-4.7 mm Hg for instrument A, +4.70+/-12.8 and
      +1.73+/-7.4 mm Hg for instrument B, and -3.74+/-8.0 and +5.61+/-2.6 mm Hg for
      instrument C. Combining the results of the three instruments, the blood pressure
      was determined to be only slightly higher (systolic +1.74+/-9.6 mm Hg; diastolic
      +4.87+/-5.6 mm Hg) by the Bosotron 2 R device as compared with the aortic arch
      pressure. The Bosotron 2 R device seems to be suitable for clinical use and for
      monitoring blood pressure during clinical-pharmacological studies.

PMID- 10394119
TI  - Phase I study of high-dose epirubicin in platinum-pretreated patients with
      ovarian carcinoma.
AB  - BACKGROUND: In vitro data demonstrated a dose-response relationship for
      doxorubicin in ovarian cancer (OC) cell lines. However, this dose-response
      question for doxorubicin was never carefully addressed in OC patients. These data
      and the more favorable toxicity profile of the anthracycline analogue epirubicin
      prompted us to study high-dose epirubicin (HDE) in relapsed OC patients. PATIENTS
      AND METHODS: This phase I study included 19 OC patients with measurable or
      evaluable disease and no more than one prior (cisplatin-containing) chemotherapy
      regimen. Dose escalation was not allowed in individual patients. Epirubicin was
      administered by rapid intravenous infusion (<5 min) once every 3 weeks and
      studied at the following dose levels: 120, 135, 150, 180 and 200 mg/m2 (at least
      3 patients per dose level). None of the patients received hematopoietic growth
      factors. We defined the maximum tolerated dose (MTD) as the dose at which we
      observed WHO grade 4 hematologic toxicity in >/=50% and/or WHO grade 3
      nonhematologic toxicity in >/=30% of the patients. RESULTS: The MTD was 200
      mg/m2, with DLT being both hematologic (leukopenia and/or thrombocytopenia) and
      nonhematologic (mucositis). Objective responses were observed in 6 patients
      (response rate 32%), 3 of them occurring in 10 patients with primary platinum
      resistance. CONCLUSIONS: HDE is tolerable and has activity in second-line after
      cisplatin-based chemotherapy in OC patients. The recommended dose for phase II
      trials in such patients is 150 mg/m2, with escalation to 180 mg/m2 if toxicity
      permits.

PMID- 10394118
TI  - Platinum-based chemotherapy of primary extragonadal germ cell tumours: the
      Hellenic Cooperative Oncology Group experience.
AB  - Extragonadal germ cell tumours (EGCT) are uncommon, most frequently arise in the
      mediastinum and retroperitoneum and have variable responses to platinum-based
      chemotherapy. A retrospective analysis was performed on 38 patients with EGCT
      treated with cisplatin-based (CDDP) or carboplatin-based (CBDCA) chemotherapy
      between 1984 and 1998. Twenty-four patients had nonseminomatous germ cell tumours
      (NSGCT) and 14 seminoma. Twenty-two tumours arose in the mediastinum (13
      nonseminomas, 9 seminomas) and 16 in the retroperitoneum (11 NSGCT, 5 seminomas).
      Initial surgery included complete resection in 1 patient, biopsy in 27 patients
      and debulking surgery in 10 patients. Complete response rates with chemotherapy
      +/- surgery were as follows: mediastinum 14 of 21 (66.66%) patients (8 of 12-75%
      NSGCT, 6 of 9-66.66% seminomas) and retroperitoneum 14 of 16 (87.5%) patients (9
      of 11-81.81% NSGCT, 5 of 5-100% seminomas). One patient who underwent complete
      resection of a mediastinal malignant teratoma combined, received PVB chemotherapy
      on an adjuvant basis and remains alive and disease-free. Three additional
      seminoma patients who achieved partial response after chemotherapy remain alive
      and disease-free following mediastinal radiotherapy. All 14 patients with
      extragonadal seminomas remain alive with no evidence of disease at a median
      follow-up of 49 months (range 7-164), giving an overall survival of 100%. Nine of
      13 (69.23%) patients with mediastinal NSGCT are long-term disease-free at a
      median follow-up of 43.5 months (range 7-152). Nine of 11 (81.81%) patients with
      retroperitoneal NSGCT remain alive and disease-free at a median follow-up of 56
      months (range 14-110). Complete surgical resection of residual mass was
      undertaken in 10 patients (3 seminomas, 7 nonseminomas). The histology revealed
      necrosis/fibrosis in 6 patients (3 seminomas, 3 NSGCT) and viable cancer in 4
      patients. Patients who had viable malignant cells in the resected specimens
      received two more courses of VelP chemotherapy. None of our patients had relapsed
      at the time of this analysis. None of our 6 patients who underwent testicular
      biopsy (1 patient) or orchiectomy (5 patients) due to suspicious ultrasound of
      the testis were found to have testicular tumour or fibrotic scar. In conclusion,
      this retrospective analysis showed significant responses in patients with either
      mediastinal or retroperitoneal NSGCT treated with CDDP- or CBDCA-based
      chemotherapy +/- surgery. All patients with extragonadal seminomas remain alive
      with no evidence of disease, regardless of the site at presentation.

PMID- 10394120
TI  - Proliferative activity of Hurthle cell thyroid tumours.
AB  - To improve our understanding of the basic biological mechanisms of Hurthle cell
      tumours (HCT), proliferative activity in 20 HCT was determined by Ag-NOR
      (nucleolar organiser regions) counting and by immunohistochemical markers
      proliferating cell nuclear antigen (PCNA) and MIB-1. Ten surgically removed
      Hurthle cell adenomas (HCA) and 10 Hurthle cell carcinomas (HCC) were used for
      the study. For comparison, a group of 10 thyroid adenomas without Hurthle cells
      (SA) was also evaluated. There were significant differences in the percentages of
      PCNA- and MIB-1-positive nuclear areas between HCA and HCC as well as between SA
      and HCA. The mean number of Ag-NORs per nucleus showed no significant differences
      between our groups. However, determination of percentages with 5 or more Ag-NORs
      per nucleus within one focal plane of sections was more useful for the
      differentiation between thyroid tumours included in our study. The combination of
      three types of cell kinetic markers may provide insight into the still poorly
      understood relationships among karyological abnormalities, enhanced proliferation
      speed, clonal expansion and invasiveness of HCT.

PMID- 10394122
TI  - So-called carcinosarcoma of the esophagus: A clinicopathologic,
      immunohistochemical and DNA flow-cytometric analysis of 6 cases.
AB  - Six cases of carcinosarcoma of the esophagus were studied clinicopathologically,
      immunohistochemically and with DNA flow cytometry. Transitional areas with
      morphology intermediate between carcinoma and sarcoma were found microscopically
      in all cases. Immunohistochemically, the carcinomatous areas contained keratin
      positive cell components in all cases while vimentin-positive cells were found in
      sarcomatous areas in 5 cases. By DNA flow analysis of microdissection, the
      sarcomatous components of the tumors showed an aneuploid pattern with one
      exception, in contrast the carcinomatous components were diploid in all cases. In
      these few cases, PCNA, S-phase fraction and the mitotic rate were extremely high,
      apparently indicating a correlation with malignant behavior. Accordingly,
      examination by immunohistochemistry and DNA ploidy is useful for the analysis of
      biological properties in the so-called carcinosarcoma of the esophagus.

PMID- 10394121
TI  - Prognosis for pedunculated hepatocellular carcinoma.
AB  - We retrospectively compared the outcome of 13 patients at our institution and
      that of 163 reported cases of pedunculated hepatocellular carcinoma (HCC) with
      that of conventional HCC subdivided by tumor diameter (group A: less than 2 cm;
      group B: 2-5 cm, group C: more than 5 cm). The survival of patients with
      pedunculated HCC in the 163 reported cases was no different from that of group B,
      but less favorable than in group A (p < 0.01) and more favorable than in group C
      (p < 0.01). Among the 163 patients with pedunculated HCC, the 113 cases of
      surgically treated patients had higher survival than the 21 patients treated with
      transcatheter arterial embolization (n = 16) or transcatheter arterial infusion
      chemotherapy (n = 5) (p < 0.01) and than 29 conservatively treated patients (p <
      0.001). A total of 70 patients out of 163 (42%) died within 1 year after
      diagnosis. Additionally, almost all cases of pedunculated HCC showed
      histologically moderately or poorly differentiated characteristics according to
      Edmondson and Stainer's classification or the WHO classification. These results
      suggest that pedunculated HCC has not a favorable prognosis if appropriate
      surgical resection has not been performed very early within a few months because
      of its rapid progressive nature.

PMID- 10394124
TI  - Genetic aberrations detected by comparative genomic hybridization in biliary
      tract cancers.
AB  - In order to elucidate cytogenetic changes characteristic of biliary tract cancer,
      we examined the genetic imbalances in 18 biliary tract cancers using comparative
      genomic hybridization (CGH). The most common sites of increases in copy number,
      in order of frequency, were 17q (33% of the cases), 5p (28%), 3q (22%), 7p (22%),
      8q (22%), and 12p (22%), whereas copy number decreases of 6q (28%), 18q (28%), 4q
      (22%), 5q (22%), and 9p (22%) were frequent. The average number of chromosomal
      aberrations was significantly greater in stage IV than in stage III tumors (7.9
      vs. 2.2/tumor, p < 0.05). The frequent aberrations detected in this study may be
      related to the development and/or progression of biliary tract cancers. This is
      the first report on CGH of biliary tract cancers.

PMID- 10394123
TI  - Anti-tumor effect of angiogenesis inhibitor TNP-470 on the human nasopharyngeal
      carcinoma cell line NPC/HK1.
AB  - The efficacy and targeting cells of angiogenesis inhibitor TNP-470 on human
      squamous cell nasopharyngeal carcinoma (NPC) were investigated. The colorimetric
      MTT assay was used to evaluate the IC50 values of NPC/HK1 cells and human dermal
      microvascular endothelial cells (HDMEC) for TNP-470. An NPC human tumor model was
      built by tumor-bearing nude mice using the NPC cell line of NPC/HK1. TNP-470 (30
      mg/kg s.c.) was injected every other day. The results showed that the IC50 of
      NPC/HK1 cells for TNP-470 was 3.8 times higher than that of HDMEC. A significant
      difference in tumor volume between control and treatment groups was found after 7
      days of treatment and increased thereafter. At the end of the treatment, tumor
      volume was 773.7 +/- 287.1 mm3 (n = 8) in the control group versus 454.5 +/-
      132.8 mm3 (n = 8) in the treatment group (p = 0. 013); the ratio of the mean
      tumor volume in treated animals to that of control animals was 0.587, resulting a
      41.3% decrease in tumor growth. The necrotic area was larger in the treatment
      group. Physical toxicity did not result from the treatment. These studies suggest
      that angiogenesis inhibitor TNP-470 is effective in the treatment of squamous
      cell NPC without obvious toxicity.

PMID- 10394125
TI  - Enhanced expression of thymidylate synthase may be of prognostic importance in
      advanced cervical cancer.
AB  - The enhanced expression of thymidylate synthase (TS) has been associated with a
      poor prognosis in patients with several types of epithelial tumors. To determine
      the association between TS expression and the prognosis of patients with advanced
      cervical cancer after radiation therapy, we immunohistochemically assayed TS
      levels in paraffin-embedded tissue sections from 66 patients with stage IIIb
      cervical cancer using a polyclonal antibody to recombinant human TS. In the 30
      patients with high TS expression, the cumulative 5- and 8-year survival rates
      were 36.8% (95% CI: 17. 4-56.2) and 31.6% (95% CI: 12.4-50.7), respectively. In
      contrast, the 36 patients with low TS expression showed a significantly (p < 0.
      001) better prognosis, with cumulative 5- and 8-year survival rates of 87.2% (95%
      CI: 75.5-99.0) and 69.2% (95% CI: 50.7-87.7), respectively. These results suggest
      that TS expression may be useful in determining the prognosis of patients with
      advanced cervical cancer.

PMID- 10394126
TI  - Prognostic significance of CEA, CA 19-9 and CA 72-4 preoperative serum levels in
      gastric carcinoma.
AB  - The prognostic value of preoperative serum levels of CEA, CA 19-9 and CA 72-4
      tumor markers was investigated in 153 patients resected for gastric cancer. The
      positivity rates for CEA, CA 19-9 and CA 72-4 were 20.9, 34.6 and 28.1%,
      respectively. Multiple logistic regression analysis for positive levels of tumor
      markers indicates that CEA positivity is significantly related to the depth of
      invasion (p < 0.005) and the presence of distant metastasis (p < 0. 05), CA 19-9
      positivity is related to nodal involvement (p < 0.05) and the depth of invasion
      (p < 0.05), whereas CA 72-4 positivity is influenced by tumor size (p < 0.005)
      and noncurative surgery (p < 0. 05). Positive levels of each tumor marker were
      associated with a worse prognosis if compared with negative cases using
      univariate analysis. Multivariate analysis of curatively resected cases
      identified depth in gastric wall (p < 0.0001), nodal status (p < 0. 0005), and
      tumor location in the upper third (p < 0.05) as significant prognostic variables;
      CEA, CA 19-9 and CA 72-4 serum positivity did not reach statistical significance.
      However, when the positivity of the three markers was associated, a p value <
      0.05 was observed. The analysis of survival curves stratified by tumor stage
      revealed that marker positivity significantly affects survival in stages I, II
      and IV (p < 0.05). The combined assay of CEA, CA 19-9 and CA 72-4 preoperative
      serum levels provides additional prognostic information in patients resected for
      gastric cancer; patients with preoperative positivity for one of these tumor
      markers should be considered at high risk of recurrence even in early stages of
      gastric carcinoma.

PMID- 10394129
TI  - Administration in a hypotonic solution is preferable to dose escalation in
      intraperitoneal cisplatin chemotherapy for peritoneal carcinomatosis in rats.
AB  - An animal model of intraperitoneal (i.p.) cisplatin chemotherapy using hypotonic
      solutions of sodium chloride has been developed as a treatment for peritoneal
      carcinomatosis. The concentrations of platinum in the plasma and in the i.p.
      fluid of Donryu rats were measured after i.p. injection of hypotonic (103 or 154
      mosm/l) and isotonic (308 mosm/l) solutions that contained an equal amount of
      cisplatin. The maximum concentration (Cmax) and the area under the curve of
      concentration versus time (AUC) of platinum in the plasma increased
      proportionately with increases in the dose of cisplatin and they were
      significantly higher in rats given cisplatin in hypotonic solutions than in those
      given the drug in isotonic solution. The Cmax and AUC of total platinum were
      similar for the solution of 103 mosm/l with 2.5 mg/kg cisplatin and the isotonic
      solution with 5.0 mg/kg cisplatin. The Cmax and AUC of free platinum in the
      plasma did not increase with increases in the dose of cisplatin in isotonic
      solution but did increase after hypotonic injection. However, the solutions of
      lower osmolarity gave a decreased AUC of platinum in the i.p. fluid. Hypotonic
      conditions continued for 30 min at most after i.p. injection of hypotonic
      solutions. When the same dose of cisplatin was given to rats with tumors derived
      from AH100B carcinoma cells, the amount of platinum taken by i.p. solid tumors
      from the solution of 103 mosm/l was about twice that from the isotonic solution
      and was much the same as that taken up from the isotonic solution with twice the
      amount of cisplatin. These results indicate that hypotonic i.p. cisplatin
      chemotherapy might be preferable to escalation of the dose of i.p. cisplatin in
      the treatment of peritoneal carcinomatosis.

PMID- 10394127
TI  - Cytogenetic aberrations detected by flow cytometry and fluorescence in situ
      hybridization in colorectal cancers: two cytogenetic pathways in colorectal
      carcinogenesis.
AB  - We measured DNA content by flow cytometry and determined the number of
      chromosomes 7, 17 and 18 by fluorescence in situ hybridization using DNA probes
      in 38 sporadic colorectal adenocarcinomas including 14 early cancers. Based on
      DNA ploidy and the copy number of chromosome 18, colorectal cancers were divided
      into two groups. In early cancers (mucosal and submucosal adenocarcinomas),
      monosomy 18 with DNA hypotriploidy was detected exclusively in 6 sessile tumors
      without adenoma portions. Seven of the remaining 8 tumors in which adenoma
      portions coexisted manifested disomy 18 and DNA diploidy or near diploidy. These
      tumors were considered to occur along the adenoma-carcinoma sequence. In
      contrast, monosomy 18 was accompanied by DNA diploidy or near diploidy in
      advanced cancers penetrating the muscularis propria. In advanced cancers, DNA
      hypertriploidy was linked with disomy 18 and chromosomes 7 and 17 were trisomic
      or tetrasomic. Observations indicate at least two different cytogenetic pathways
      in colorectal carcinogenesis. According to these findings, two thirds of advanced
      cancers were estimated to originate from adenoma, and the others were not.

PMID- 10394128
TI  - Sialyl Tn is a frequently expressed antigen in colorectal cancer: No correlation
      with patient prognosis.
AB  - Immunohistochemical expression of sialyl Tn antigen (STn), previously claimed to
      be a prognostic factor in colorectal cancer, was evaluated in 239 patients with
      colorectal adenocarcinoma. Formalin-fixed, paraffin-embedded specimens were
      stained with the monoclonal antibody C1282. STn immunoreactivity was seen in 189
      of 239 tumors (79%). There was no significant correlation between STn
      immunoreactivity and Dukes stage, tumor location, histological type or gender.
      However, STn was significantly more often expressed in younger patients. There
      was so significant difference in survival between STn-negative patients (median
      survival 68 months) and STn-positive patients (median survival 79 months). In a
      Cox multivariate analysis, Dukes stage was the strongest predictor of outcome,
      followed by the age of the patient, whereas STn did not provide any prognostic
      information.

PMID- 10394130
TI  - Extrahepatic Hodgkin's disease with intrahepatic cholestasis: report of two
      cases.
AB  - Liver is involved in about 5-8% of newly diagnosed Hodgkin's disease (HD) cases.
      The incidence reaches up to 50-60% in postmortem studies. In the literature only
      a few cases of idiopathic cholestatic jaundice have been described without an
      apparent cause and a paraneoplastic etiology has been suggested. We report 2
      cases with HD presenting with obstructive jaundice without obvious liver
      involvement. The first case died soon after diagnosis; the second case received
      chemotherapy and radiotherapy, and she is well at 26 months' follow-up.
      Extrahepatic HD with intrahepatic cholestasis is an extremely rare situation
      without an established approach. Such cases like the present ones may help to
      understand the pathogenesis of the liver involvement of HD and determine the best
      management of these cases.

PMID- 10394131
TI  - Baculovirus expression, purification and evaluation of recombinant pneumococcal
      surface adhesin A of Streptococcus pneumoniae.
AB  - Pneumococcal surface adhesin A (PsaA), with a molecular mass of approximately 37
      kD by SDS-PAGE, is a common surface protein expressed by all 90 serotypes of
      Streptococcus pneumoniae. S. pneumoniae serotype 6B genomic DNA was amplified to
      generate a DNA fragment carrying the full-length psaA sequence and was cloned
      into a baculovirus expression system. We expressed either cell-associated or cell
      free nonfusion PsaA polypeptides using two insect cell lines, Spodoptera
      frugiperda (Sf9) and Trichoplusia ni 5B1-4 (High-Five). Recombinant PsaA (rPsaA)
      polypeptides were partially purified by partitioning in PBS/Triton X-114 buffers
      and by weakly basic ion exchange filter chromatography. Membrane-bound
      'hydrophobic rPsaA' (hrPsaA) expressed by either Sf9 or High-Five cells had a
      molecular mass of approximately 38 kD by SDS-PAGE and partitioned in a Triton X
      114 phase, it reacted with both rabbit polyclonal and five monoclonal anti-PsaA
      antibodies by dot blot or Western blot analysis. High-Five-cell-expressed
      'soluble rPsaA' (srPsaA) with a molecular mass of approximately 37 kD by SDS
      PAGE, was isolated from the serum-free culture medium and did not partition in
      the Triton X-114 phase; it reacted with anti-PsaA rabbit polyclonal and mouse
      monoclonal antibodies by ELISA and Western blot analysis. Both rPsaA polypeptide
      forms were immunogenic in Swiss-Webster adult female mice. In an infant mouse
      model of bacteremia, survival rates for mice given mouse anti-rPsaA immune serum
      (from mice immunized with High-Five-expressed srPsaA; 20 microl, 1:50,000 titer)
      24 h before bacteremic challenge were greater than for the control group (48 h
      postchallenge, 20 vs. 90% survival rates) when challenged with S. pneumoniae
      serotype 6B. These results indicate that rPsaA is immunogenic and elicits
      protective antibody in mice similar to native protein.

PMID- 10394134
TI  - Screening for invasion of the individual human brain tumour in an autologous
      confrontation system in vitro.
AB  - Invasiveness is the major cause of death in patients bearing a brain tumour. The
      invasiveness or infiltrative capacity of a primary brain tumour has a prognostic
      value for the evaluation of the process in vivo. So a model to imitate invasion
      might give information on the in vivo behaviour and outcome of the disease for
      the individual patient. The developed in vitro model represents an assay in which
      the patients' brain tumour-derived cells are confronted with connective tissue
      from the patient himself, i.e. an autologous system to evaluate the individual
      behaviour of the tumour, in contrast to other invasion models. The test can be
      applied with tumour-derived material collected by a stereotactic biopsy.

PMID- 10394133
TI  - Effect of cytotoxic chemotherapy on serum lipid levels in breast cancer patients.
AB  - Seventy patients with breast cancer at various clinical stages and 15 patients
      with fibroadenoma were investigated. After chemotherapy, a significant increase
      in total triglycerides in malignant breast cancer patients before and after
      menopause has been observed. The increase in total cholesterol was not
      significant after chemotherapy. The levels of LDL and HDL cholesterol were
      significantly decreased in pre- and postmenopausal women treated with
      chemotherapy.

PMID- 10394132
TI  - Alteration of signal-transducing molecules and phenotypical characteristics in
      peripheral blood lymphocytes from gastric carcinoma patients.
AB  - The mechanisms underlying the impaired immune response frequently observed in
      cancer patients are not fully understood. Alteration of T-cell-associated signal
      transduction molecules has recently been implicated in immune suppression in
      tumor-bearing hosts. Furthermore, T cells from tumor-bearing host, irrespective
      of the presence of the zeta-chain, showed a lack of proliferative activity and
      cytotoxic function. In the present study, we investigated the expression of the
      zeta-chain molecule and the p56(lck) and p59(fyn) protein tyrosine kinase (PTK)
      levels in peripheral blood T lymphocytes (T-PBL) from patients with advanced
      gastric carcinomas; for this, flow cytometric analysis and immunoblotting,
      respectively, were used. We also compared the results of flow cytometric analysis
      of PBL between stomach cancer patients and normal healthy volunteers. In T-PBL
      from 22 tumor-bearing hosts, significantly reduced zeta-chain expression (16/22,
      73%) was observed. Moreover, the expression level of p56(lck) in T-PBL from
      patients was significantly lower than that of p59(fyn). Flow cytometric analysis
      of T-PBL indicated a markedly increased CD8+28- cell population in T-PBL from 19
      tumor-bearing hosts.

PMID- 10394136
TI  - Three-dimensional spheroid model in tumor biology.
AB  - It is becoming more and more apparent that monolayer cultures of tumor cells
      cannot completely represent the characteristics of three-dimensional solid
      tumors. Consequently, the multicellular tumor spheroid model, which is of
      intermediate complexity between in vivo tumors and monolayer cultures, was
      developed. In this review, the major similarities between spheroids and solid
      tumors are discussed. After a brief survey of the different spheroid culturing
      techniques, the general morphological and growth characteristics of these systems
      are examined and compared to solid tumors. Finally, selected studies regarding
      the use of tumor spheroids to examine cell response to antineoplastic agents and
      radiation, cell death including both necrosis and apoptosis and cell adhesion in
      spheroids are reviewed.

PMID- 10394137
TI  - In situ detection of human monocyte/macrophage serine esterase-1 mRNA expression
      in human tissues.
AB  - Human monocyte/macrophage serine esterase (HMSE) can be distinguished from
      esterases of other blood cells by a specific isoelectric focusing pattern of five
      enzyme variants. Using a HMSE-1 cDNA, expression of mRNA was investigated by
      nonradioactive in situ hybridization of human biopsy specimens and cytospin
      preparations. HMSE-1 transcripts could be detected in the myelomonocytic cell
      line U-937, blood monocytes and in tissue macrophages. Immune accessory cells of
      the monocyte/macrophage lineage did not express detectable amounts of HMSE-1
      mRNA. These results indicate that HMSE-1 represents a cell-lineage-specific
      enzyme which can be used to characterize physiological and neoplastic variants of
      the human monocyte/macrophage cell system. The method described will enable
      further insight into the physiological function of HMSE-1.

PMID- 10394135
TI  - Reconstructed human cornea produced in vitro by tissue engineering.
AB  - The aim of the present study was to produce a reconstructed human cornea in vitro
      by tissue engineering and to characterize the expression of integrins and
      basement membrane proteins in this reconstructed cornea. Epithelial cells and
      fibroblasts were isolated from human corneas (limbus or centre) and cultured on
      plastic substrates in vitro. Reconstructed human corneas were obtained by
      culturing epithelial cells on collagen gels containing fibroblasts. Histological
      (Masson's trichrome staining) and immunohistological (laminin, type VII collagen,
      fibronectin as well as beta1, alpha3, alpha4, alpha5, and alpha6 integrin
      subunits) studies were performed. Human corneal epithelial cells from the limbus
      yielded colonies of small fast-growing cells when cultured on plastic substrates.
      They could be subcultured for several passages in contrast to central corneal
      cells. In reconstructed cornea, the epithelium had 4-5 cell layers by the third
      day of culture; basal cells were cuboidal. The basement membrane components were
      already detected after 3 days of culture. Integrin stainings, except for the
      alpha4 integrin, were also positive after 3 days. They were mostly detected at
      the epithelium-stroma junction. Such in vitro tissue-engineered human cornea,
      which shows appropriate histology and expression of basement membrane components
      and integrins, provides tools for further physiological, toxicological and
      pharmacological studies as well as being an attractive model for gene expression
      studies.

PMID- 10394138
TI  - The relationship between new variant Creutzfeldt-Jakob disease and bovine
      spongiform encephalopathy.
AB  - Creutzfeldt-Jakob disease (CJD) has been transmitted in the laboratory and also
      by iatrogenic accident. However, research has failed to find evidence that its
      most common form (sporadic CJD) is a natural infection and, in particular, that
      there is a causal link with scrapie. Bovine spongiform encephalopathy (BSE)
      probably resulted from scrapie infection in cattle food. In the wake of the BSE
      epidemic, a novel clinico-pathological form of CJD has been recognized: new
      variant CJD (nvCJD). This paper reviews the relationship between nvCJD and BSE
      and presents the accumulated evidence supporting the view that nvCJD resulted
      from BSE contamination of human food.

PMID- 10394139
TI  - Quantitating donor behaviour to model the effect of changes in donor management
      on sufficiency in the blood service.
AB  - BACKGROUND AND OBJECTIVE: To describe donor behaviour quantitatively and apply
      the information on actual donations derived during observed changes in blood
      collection in Melbourne between July 1990 and June 1996 to construct a logical
      model to examine the effects of changes in donor management on the sufficiency of
      the blood supply. METHOD: Computerised donation data files were searched to
      determine time to next or previous donation for donors giving blood between 1990
      and 1996 stratified by age, donation history and venue. Actual numbers of whole
      blood donation given by new and repeat donors, July 1990 to June 1996, and
      numbers of donors refused were used to construct and test a logical predictive
      model. RESULTS: 558,682 donation intervals were analysed. Donor return rates at 2
      years were shown to increase with donor donation history and donor age. The
      prediction model showed that a 25% decline in whole blood collections over 2
      years could be explained by the cumulative effect of a decrease in donor return
      rates of 2-4%. Between 1990 and 1996 many donors moved from static city
      collection sites to suburban mobiles. New donor attendance correlated with repeat
      donor attendance. Donor complaints correlated with donor deferral numbers.
      CONCLUSIONS: The model showed that large shifts in nett blood collections can be
      explained by relatively small shifts in donor return rates at 2 years.

PMID- 10394140
TI  - Effect of heat on stored red cells during non-flow conditions in a blood-warming
      device.
AB  - BACKGROUND AND OBJECTIVES: While blood is flowing within a transfusion-warming
      device, the blood temperature is usually less than that applied externally. If
      the flow is temporarily stopped, the temperature can rise above 37 degrees C in
      some warming devices. We sought to determine whether temperatures near 45 degrees
      C achieved during prolonged non-flow conditions in a blood warmer are harmful to
      red cell integrity. MATERIALS AND METHODS: After 42 days of storage at 4 degrees
      C, red cells were exposed to 44.7 degrees C for 30 min while stationary in a
      blood warming device (Augustine Medical, Inc., 241 Fluid Warming Set) and
      examined for cell counts, hemolysis and osmotic fragility. RESULTS: Red cell,
      white cell and platelet counts, hemoglobin, PCV and potassium were unchanged
      following heat treatment. Plasma hemoglobin was 508+/-132 mg/dl following heat
      treatment compared to 396+/-188 for the control (p>0. 05). In the osmotic
      fragility test, hemolysis remained within normal limits when tested at 0.60 and
      0.65% sodium chloride (NaCl) and was unchanged at the 0.5% NaCl level. At the
      0.75% NaCl level, there was 16+/-5.1% hemolysis of heated 42-day-old red cells
      compared to 11+/-3.4% for the control (both of which being above the 9% upper
      limit for fresh control red cells). CONCLUSIONS: We conclude that elevated
      temperatures achieved during temporary cessation of flow in the Augustine
      Medical, Inc., 241 Fluid Warming Set for as long as 30 min do not cause notable
      hemolysis or other damage to red cells.

PMID- 10394141
TI  - Decreased hemolysis and lipid peroxidation in blood during storage in the
      presence of nicotinic acid.
AB  - BACKGROUND AND OBJECTIVES: There is increase in lipid peroxidation with
      consequent increase in hemolysis when blood is stored in di-(2-ethyl
      hexyl)phthalate (DEHP) plasticized bags. Studies carried out by us and others
      have indicated the ability of red cells to synthesize NAD+ from added nicotinic
      acid. Apart from the role of NAD+ in glycolysis, NADPH is required for reduction
      of oxidized glutathione to its reduced form by glutathione reductase. Reduced
      glutathione is an important antioxidant, which protects cell membrane from
      oxidative damage. Reduced glutathione is also involved in the regeneration of
      vitamin E, another important membrane antioxidant. In view of these, a study was
      undertaken to find out the effect of addition of nicotinic acid to the citrate
      phosphate-dextrose-adenine (CPDA) solution on lipid peroxidation and integrity of
      red cells when whole blood is stored in DEHP plasticized bags. MATERIALS AND
      METHODS: Blood was collected in Penpol blood storage bags (which is a DEHP
      plasticized bag) in CPDA solution in the presence and absence of nicotinic acid.
      Various parameters of lipid peroxidation and membrane stability - level of
      malondialdehyde (MDA), conjugated dienes, vitamin E, reduced glutathione, plasma
      Hb and K+, levels of adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3
      DPG) were studied in the blood samples after various periods. RESULTS: Plasma Hb
      and K+ concentrations were significantly lower in the presence of added nicotinic
      acid both after 28 and 42 days. Concentration of MDA and conjugated dienes was
      lower and the levels of reduced glutathione and vitamin E higher in the presence
      of nicotinic acid. ATP levels were not significantly different, but 2,3-DPG
      levels were higher. pH of the blood was nearer to 7.0 in the presence of
      nicotinic acid, while leaching out of DEHP into the blood was significantly
      lower. CONCLUSION: Inclusion of nicotinic acid in the CPDA solution has a
      beneficial effect in that (1) it reduces plasma Hb and K+; (2) reduces lipid
      peroxidation and increases antioxidant protection; (3) maintains pH nearer to
      7.0, and (4) decreases the leaching out of DEHP into the blood.

PMID- 10394142
TI  - Evaluation of the use of a platelet-counting tool in plateletpheresis.
AB  - OBJECTIVE: For years, blood transfusion centers in Taiwan have used the
      Quantitative Buffy Coat (QBC(R)) Hematology System for platelet counts on
      capillary blood samples in the laboratory screening of apheresis donors. The
      system has not been evaluated for the prediction of yields in plateletpheresis.
      Methods : The QBC instrument was evaluated for reproducibility of platelet counts
      and compared with five electronic cell counters. We also collected both capillary
      and venous blood from voluntary donors before donation and counted platelets,
      comparing the QBC system and an electronic blood cell counter (Sysmex K1000). The
      correlation between donors' predonation platelet counts and plateletpheresis
      yields was analyzed. RESULTS: The R values for platelet counts between the QBC
      Hematology System and other electronic counters are lower (0.759-0. 890) than
      among the electronic counters (0.929-0.973). The mean capillary platelet count
      and the mean venous platelet count were 241. 9+/-50.3x10(3)/microl and 233.2 +/
      47.9x10(3)/microl by the QBC system, and 244.9+/-54.1x10(3)/microl and 218.9+/
      46.5x10(3)/microl by the Sysmex K1000, respectively. Linear regression analysis
      showed that platelet yields correlated well with donors' predonation platelet
      counts using the Sysmex K1000 counter (R = 0.777- 0.890, p<0.001), but not with
      the QBC system (R = 0.326 approximately 0.755, p<0.05). CONCLUSION: The QBC
      Hematology System is not accurate enough to determine predonation platelet counts
      that are to be used for calculating the number of processing cycles for
      plateletpheresis.

PMID- 10394143
TI  - Preparation of leukodepleted platelet concentrates from pooled buffy coats:
      prestorage filtration with Autostop BC.
AB  - BACKGROUND AND OBJECTIVES: Our requirements for leukocyte-depleted platelet
      concentrates (LD-PC) for an adult patient are: platelets >240x10(9), leukocytes
      <5x10(6), volume of 150-400 ml; and at the end of storage a pH between 6.8 and
      7.4 and presence of the swirling effect. Our aim was to develop a standardized,
      semiautomated method for the production of LD-PC, by pooling of buffy coats (BC),
      and prestorage leukoreduction by filtration. MATERIALS AND METHODS: Whole blood
      was collected in Top and Bottom systems, and separated automatically with the
      Compomattrade mark G3 equipment into a red cell concentrate, a plasma and a BC.
      Subsequently, a pool of 5 BC was made, and 200 g plasma from one of the donors
      was added. Then, after soft spin centrifugation, the platelet rich plasma was
      leukocyte depleted by filtration using the Autostoptrade markBC filter, and
      stored in a 1,000 ml polyolefin platelet storage bag. RESULTS: BC (n = 60) had a
      volume of 51+/-2 ml (mean +/- SD) with a hematocrit of 0.44+/-0.03 l/l and
      contained 80+/-5% of the platelets and 74+/-12% of the leukocytes of the whole
      blood. Routinely prepared LD-PC (n = 15,037) contained a median of 341x10(9)
      platelets (range 49-599x10(9)), with only 104/15,037 (0.7%) containing fewer than
      240x10(9) platelets; the median volume was 263 ml (range 134-373 ml). In 118/917
      (13%) LD-PC leukocytes were observed in the Nageotte hemocytometer, but only
      twice exceeding 1x10(6) leukocytes per unit, and none exceeding 5x10(6) (median
      <0. 6x10(6); range <0.6-1.41x10(6)). Storage experiments of the LD-PC (n = 12)
      revealed adequate oxygenation and maintenance of pH and swirling effect up to 9
      days. CONCLUSIONS: This method warrants with 99% confidence that LD-PC contain
      more than 240x10(9) platelets; with 97.5% confidence that 100% of the LD-PC
      contain <5x10(6) leukocytes, and with 95% confidence that more than 99% of the LD
      PC contain fewer than 1x10(6) leukocytes; these LD-PC can be stored
      satisfactorily for up to 9 days.

PMID- 10394144
TI  - Processing of human cord blood by three different procedures for red blood cell
      depletion and mononuclear cell recovery.
AB  - BACKGROUND AND OBJECTIVES: Human cord blood (CB) is an important source of stem
      cells which may be used for hematopoietic reconstitution as an alternative to
      bone marrow transplantation. Banking of CB would be accomplished by removing red
      blood cells (RBC) and plasma from CB collections. Our aim was to compare three
      different procedures for CB processing. MATERIALS AND METHODS: Poligeline,
      hydroxyethyl starch gel (HES) and gelatin were used as separation media in
      processing 79 CB units for RBC depletion and mononuclear cell (MNC) recovery.
      RESULTS: The best MNC recoveries were obtained performing the HES- and the
      gelatin-based procedures (80.9 and 84.7%, respectively), but the gelatin
      procedure allowed us to obtain the highest RBC depletion (96.4%); CD34+ cell
      recovery was higher using HES or gelatin as separation media (85.6 and 85.9%,
      respectively). CONCLUSION: The best results, as far as RBC removal and MNC
      recovery are concerned, were obtained by using gelatin as RBC sedimentation
      medium. Gelatin is a low-cost, animal-derived reagent, which has been
      successfully used for CB transplantation; the procedure is simple to perform and
      appears to be suitable for large-scale banking in view of CB transplantation.

PMID- 10394145
TI  - Treatment of post-transfusion graft-versus-host disease with nafmostat mesilate,
      a serine protease inhibitor.
AB  - BACKGROUND: Cytotoxic T lymphocytes from donors are thought to injure the target
      organs in post-transfusion graft-versus-host disease (PT-GVHD) through perforin
      granzyme- and Fas-dependent cell killings. The protease involved is a serine
      protease, and nafmostat mesilate (NM), a serine protease inhibitor, has been
      found to inhibit the in vitro allocytotoxicity of the T cell clone established
      from a patient with PT-GVHD, thus suggesting the usefulness of NM for treatment
      of PT-GVHD. CASE REPORT: A 47-year-old male with esophageal cancer, who received
      3 units of packed red cells and 20 units of platelet concentrates from 5
      unrelated donors, was diagnosed as having PT-GVHD on the basis of typical
      clinical features, HLA typing of the patient and the responsible donor, and a
      mixed chimera of CD8+ lymphocytes on microsatellite DNA polymorphism analysis. NM
      was administered to inhibit the activity of the serine proteases, thought to be
      granzymes; a liver dysfunction and thrombocytopenia with leukocytopenia
      simultaneously improved. Subsequently, a high-dose methylprednisolone pulse
      therapy and monoclonal anti-CD3 were administered to reduce the donor's
      proliferating lymphocytes, which resulted in lymphopenia accompanied by
      elimination of the donor's lymphocytes and normalization of the CD4/CD8 ratio.
      However, recurrence of the proliferation of the responsible donor's lymphocytes
      developed after cessation of NM administration, probably because of excessive
      immunosuppression caused by steroids and the monoclonal anti-CD3. CONCLUSION:
      This case indicates that administration of a serine protease inhibitor may
      improve PT-GVHD symptoms by inhibiting cytotoxic T-cell-mediated killing of
      target cells in fatal PT-GVHD. Steroids and monoclonal anti-CD3 were probably
      responsible for the transient clinical improvements. More studies are required,
      however, on mechanisms to eliminate the donor's lymphocytes.

PMID- 10394146
TI  - A single point mutation at a splice site generates a silent RH50 gene in a
      composite heterozygous RHnull blood donor.

PMID- 10394147
TI  - Do patients know they have been transfused?

PMID- 10394148
TI  - Raynaud's syndrome in workers who use vibrating pneumatic air knives.
AB  - PURPOSE: The use of vibrating tools has been shown to cause Raynaud's syndrome
      (RS) in a variety of workers, including those who use chain saws, chippers, and
      grinders. The diagnosis of RS in workers who use vibrating tools is difficult to
      document objectively. We studied a patient cohort with RS caused by the use of a
      vibrating pneumatic air knife (PAK) for removal of automobile windshields and
      determined our ability to document RS in these workers by means of digital
      hypothermic challenge testing (DHCT), a vascular laboratory study that evaluates
      digital blood pressure response to cooling. METHODS: Sixteen male autoglass
      workers (mean age, 36 years) with RS were examined by means of history, physical
      examination, arm blood pressures, digital photoplethysmography, screening
      serologic studies for underlying connective tissue disorder, and DHCT. RESULTS:
      No patient had RS before they used a PAK. The mean onset of RS (color changes,
      100%; pain, 93%; parathesias, 75%) with cold exposure was 3 years (range, 1.5 to
      5 years) after initial PAK use (mean estimated PAK use, 2450 hours). Fifty-six
      percent of workers smoked cigarettes. The findings of the physical examination,
      arm blood pressures, digital photoplethysmography, and serologic testing were
      normal in all patients. At 10 degrees C cooling with digital cuff and patient
      cooling blanket, a significant decrease in digital blood pressure was shown by
      means of DHCT in 100% of test fingers versus normothermic control fingers (mean
      decrease, 75%; range, 25% to 100%; normal response, less than 17%; P <.001). The
      mean follow-up period was 18 months (range, 1 to 47 months). No patient continued
      to use the PAK, but symptoms of RS were unchanged in 69% and worse in 31%.
      CONCLUSION: PAK use is a possible cause of vibration-induced RS. The presence of
      RS in workers who use the PAK was objectively confirmed by means of DHCT.
      Cessation of PAK use in the short term did not result in symptomatic improvement.

PMID- 10394149
TI  - The correlation of early flow disturbances with the development of infrainguinal
      graft stenosis: a 10-year study of 341 autogenous vein grafts.
AB  - PURPOSE: Although duplex surveillance of infrainguinal bypass grafts is widely
      accepted, the optimal frequency and intensity of graft surveillance remains
      controversial. Earlier reports have suggested that grafts can be stratified into
      high-risk and low-risk groups based on the presence or absence of early graft
      flow disturbances. The purpose of this study was to provide long-term data in
      determining whether early graft flow disturbances detected by means of duplex
      scanning can predict the development of intrinsic vein graft stenosis. METHODS:
      We reviewed a series of patients undergoing prospective duplex graft surveillance
      after autogenous infrainguinal bypass grafting procedures from 1987 to 1997.
      Patients included in the study underwent at least one duplex scan within 3 months
      of graft implantation and were observed for a minimum of 6 months. Grafts were
      categorized as abnormal when a focal flow disturbance with a peak systolic
      velocity greater than 150 cm/s was identified within 3 months of graft
      implantation. RESULTS: Of 341 vein grafts in 296 patients who met inclusion
      criteria, 89 grafts (26%) required revision for intrinsic stenosis; the mean
      follow-up period was 35 months (range, 6 months to 10 years). Early flow
      disturbances were detected in 84 (25%) grafts. Grafts with early flow
      disturbances were more likely to ultimately require revision (43% vs 21%; P =.
      0001) and required initial revision earlier (8 months vs 16 months; P =.019).
      Eighty-two percent of initial graft revisions occurred in the first 2
      postoperative years; 69% occurred in the first year. However, an annual 2% to 4%
      incidence of late-appearing graft stenosis persisted during long-term follow-up.
      An additional 24 patients (7% of grafts) required an inflow or outflow
      reconstruction. CONCLUSION: Grafts with early postoperative flow disturbances
      detected by means of duplex scanning have nearly three times the incidence of
      graft-threatening stenosis and an earlier requirement for revision, when compared
      with normal grafts. This suggests that the biology and etiology of these lesions
      may differ. These data support not only aggressive efforts to detect early graft
      lesions to stratify grafts at highest risk, but also continued lifelong graft
      surveillance to detect late-appearing lesions, inflow and outflow disease
      progression, and maximize graft patency.

PMID- 10394150
TI  - Effect of outflow level and maximum graft diameter on the velocity parameters of
      reversed vein bypass grafts.
AB  - OBJECTIVE: The objective of this study was to define a normal range of distal
      graft velocity (DGV) and peak systolic velocity (PSV) on the basis of outflow
      level and maximum graft diameter for infrainguinal reversed vein bypass grafting
      (RVG). METHODS: This study was designed as a prospective study of consecutive
      patients who underwent infrainguinal RVG from 1994 to 1997 in a university
      hospital and university-affiliated teaching hospital. All patients who underwent
      infrainguinal bypass grafting from 1994 to 1997 were placed in a prospective
      protocol with duplex scanning to better define the hemodynamics of normally
      functioning RVG. Graft revisions were performed for patients with velocity ratios
      of more than 2.5. One hundred twenty-one patients were entered into this
      protocol, and 114 were followed more than 3 months after RVG. Seven patients were
      excluded: five for death within 3 months, one for graft infection, and one for
      graft occlusion before the baseline duplex scanning. DGV and PSV were determined
      for each type of outflow (popliteal, crural, and pedal) and for ranges of maximum
      graft diameter. These then were correlated with subsequent graft occlusion or
      graft revision (graft failure). RESULTS: Grafts with larger diameters were
      associated with lower DGVs (P <.001), and more proximal outflow arteries were
      associated with higher DGVs (popliteal, 75 cm/s; crural, 50 cm/s; and pedal, 40
      cm/s; P <.01). The mean PSVs were 150, 140, and 122 cm/s for popliteal, crural,
      and pedal grafts, respectively, but the difference was not statistically
      significant. The assisted primary patency rates for the grafts in this series
      were 99%, 92%, and 92% at 1, 2, and 3 years. CONCLUSION: Graft diameter and
      location of the distal anastomosis significantly affect the flow velocity in RVG.
      Other variables did not influence these parameters. Currently established
      criteria for arteriography or graft repair on the basis of graft velocity
      parameters may be improved if they can be modified depending on diameter and
      outflow.

PMID- 10394151
TI  - Reoperation for carotid stenosis is as safe as primary carotid endarterectomy.
AB  - PURPOSE: Patients with recurrent carotid artery stenosis are sometimes referred
      for carotid angioplasty and stenting because of reports that carotid reoperation
      has a higher complication rate than primary carotid endarterectomy. The purpose
      of this study was to determine whether a difference exists between outcomes of
      primary carotid endarterectomy and reoperative carotid surgery. METHODS: Medical
      records were reviewed for all carotid operations performed from September 1993
      through March 1998 by vascular surgery faculty at a single academic center. The
      results of primary carotid endarterectomy and operation for recurrent carotid
      stenosis were compared. RESULTS: A total of 390 operations were performed on 352
      patients. Indications for primary carotid endarterectomy (n = 350) were
      asymptomatic high-grade stenosis in 42% of the cases, amaurosis fugax and
      transient ischemic symptoms in 35%, global symptoms in 14%, and previous stroke
      in 9%. Indications for reoperative carotid surgery (n = 40) were symptomatic
      recurrent lesions in 50% of the cases and progressive high-grade asymptomatic
      stenoses in 50%. The results of primary carotid endarterectomy were no
      postoperative deaths, an overall stroke rate of 1.1% (three postoperative
      strokes, one preoperative stroke after angiography), and no permanent cranial
      nerve deficits. The results of operations for recurrent carotid stenosis were no
      postoperative deaths, no postoperative strokes, and no permanent cranial nerve
      deficits. In the primary carotid endarterectomy group, the mean hospital length
      of stay was 2.6 +/- 1. 1 days and the mean hospital cost was $9700. In the
      reoperative group, the mean length of stay was 2.6 +/- 1.5 days and the mean cost
      was $13,700. The higher cost of redo surgery is accounted for by a higher
      preoperative cerebral angiography rate (90%) in redo cases as compared with
      primary endarterectomy (40%). CONCLUSION: In this series of 390 carotid
      operations, the procedure-related stroke/death rate was 0.8%. There were no
      differences between the stroke-death rates after primary carotid endarterectomy
      and operation for recurrent carotid stenosis. Operation for recurrent carotid
      stenosis is as safe and effective as primary carotid endarterectomy and should
      continue to be standard treatment.

PMID- 10394152
TI  - The contribution of inducible nitric oxide and cytomegalovirus to the stability
      of complex carotid plaque.
AB  - BACKGROUND: Although the association between inflammation and atherosclerosis is
      well established, the biologic events that trigger the local inflammatory
      response within plaque are not fully understood. Cytotoxic free radicals and
      infectious agents, both of which are associated with an inflammatory response,
      have previously been implicated in the initiation and progression of
      atherosclerosis. In this study, we analyzed carotid plaque for evidence of
      oxidative vascular injury by determining the presence and distribution of
      inducible nitric oxide synthase (iNOS) expression and nitrotyrosine formation and
      for evidence of infection with cytomegalovirus. METHODS: Carotid plaque from 51
      patients who underwent endarterectomy for either primary (n = 37) or recurrent (n
      = 14) stenosis were examined histologically (hematoxylin-eosin staining and
      Masson's trichrome staining) and with immunohistochemistry with specific
      antibodies to alpha-smooth muscle actin, macrophages (CD68), T-lymphocytes (CD3),
      and T-cell activation (human leukocyte antigen-DR). Twenty-eight specimens from
      patients with primary (n = 15) and recurrent (n = 13) stenosis were examined for
      the presence of iNOS and nitrotyrosine with immunohistochemistry and in situ
      hybridization (iNOS). Twenty-three additional specimens (22 primary, and 1
      recurrent) were analyzed with antibodies to p53, cytomegalovirus, and the
      polymerase chain reaction (cytomegalovirus, n = 8). RESULTS: Primary
      atherosclerotic lesions were either complex heterogenous cellular plaques (n =
      29) or relatively acellular fibrous plaques (n = 8). Ten of 14 recurrent plaques
      were either complex or fibrous lesions, and the remaining four were typical of
      myointimal thickening. CD68-positive staining cells were detected in all
      specimens regardless of their structural morphology. CD3-positive cells were
      interspersed between macrophages in all heterogeneous cellular plaques and only
      infrequently noted in fibrous plaques. iNOS and nitrotyrosine immunoreactivity
      were detected in macrophages and smooth muscle cells in all complex and fibrous
      plaques and in two of four myointimal plaques. The presence of iNOS and
      nitrotyrosine in plaque correlated with the existence of symptoms in 80% of
      primary and 62% of recurrent lesions. Cytomegalovirus was detected in only two of
      23 carotid specimens (9%). CONCLUSION: The association between ischemic
      cerebrovascular symptoms and iNOS and nitrotyrosine immunoreactivity in complex
      primary and recurrent carotid plaque and the infrequent occurrence of
      cytomegalovirus in primary carotid lesions suggests that ongoing free radical
      oxidative damage rather than viral infection may contribute to plaque instability
      in patients with complex and fibrous carotid plaques.

PMID- 10394153
TI  - Isolated inferior mesenteric artery revascularization for chronic visceral
      ischemia.
AB  - PURPOSE: Complete visceral artery revascularization is recommended for the
      treatment of chronic visceral ischemia. However, in rare cases, it may not be
      possible to revascularize either the celiac or superior mesenteric (SMA)
      arteries. We have managed a series of patients with isolated revascularization of
      the inferior mesenteric artery (IMA) and now report our experience gained over a
      period of three decades. METHODS: Records were reviewed from 11 patients with
      chronic visceral ischemia who underwent isolated IMA revascularization (n = 8) or
      who, because of failure of concomitant celiac or SMA repairs, were functionally
      left with an isolated IMA revascularization (n = 3). All the patients had
      symptomatic chronic visceral ischemia documented with arteriography. Five
      patients had recurrent visceral ischemia after failed visceral revascularization,
      and two patients had undergone resection of ischemic bowel. The celiac or the SMA
      was unsuitable for revascularization in five cases, and extensive adhesions
      precluded safe exposure of the celiac or the SMA in five cases. IMA
      revascularization techniques included: bypass grafting (n = 4), transaortic
      endarterectomy (n = 4), reimplantation (n = 2), and patch angioplasty (n = 1).
      RESULTS: There was one perioperative death, and the remaining 10 patients had
      cured or improved conditions at discharge. One IMA repair thrombosed acutely but
      was successfully revascularized at reoperation. The median follow-up period was 6
      years (range, 1 month to 13 years). Two patients had recurrent symptoms develop
      despite patent IMA repairs and required subsequent visceral revascularization;
      interruption of collateral circulation by prior bowel resection may have
      contributed to recurrence in both patients. Objective follow-up examination with
      arteriography or duplex scanning was available for eight patients at least 1 year
      after IMA revascularization, and all underwent patent IMA repairs. There were no
      late deaths as a result of bowel infarction. CONCLUSION: Isolated IMA
      revascularization may be useful when revascularization of other major visceral
      arteries cannot be performed and a well-developed, intact IMA collateral
      circulation is present. In this select subset of patients with chronic visceral
      ischemia, isolated IMA revascularization can achieve relief of symptoms and may
      be a lifesaving procedure.

PMID- 10394154
TI  - Endovascular, transperitoneal, and retroperitoneal abdominal aortic aneurysm
      repair: results and costs.
AB  - PURPOSE: Contemporary treatment of abdominal aortic aneurysms (AAA) includes
      transabdominal (TA), retroperitoneal (RP), and endovascular (EV) repair. This
      study compares the cost and early (30-day) results of a consecutive series of AAA
      repair by means of these three methods in a single institution. METHODS: A total
      of 125 consecutive AAA repairs between February 1993 and August 1997 were
      reviewed. Risk factors, 30-day morbidity and mortality rates, and hospital stay
      and cost were analyzed according to method of repair (TA, RP, EV). Cost was
      normalized by means of a conversion factor to maintain confidentiality. Cost
      analysis includes conversion to TA repair (intent to treat) in the EV group.
      RESULTS: One hundred twenty-five AAA repairs were performed with the TA (n = 40),
      RP (n = 24), or EV (n = 61) approach. Risk factors among the groups (age,
      coronary artery disease, hypertension, diabetes, chronic obstructive pulmonary
      disease, and cigarette smoking) were not statistically different, and thus the
      groups were comparable. The average estimated blood loss was significantly lower
      for EV (300 mL) than for RP (700 mL) and TA (786 mL; P>.05). Statistically
      significant higher cost for TA and RP for pharmacy and clinical laboratories
      (likely related to increased length of stay [LOS]) and significantly higher cost
      for EV in supplies and radiology (significantly reducing cost savings in LOS)
      were revealed by means of an itemized cost analysis. Operating room cost was
      similar for EV, TA, and RP. There were six perigraft leaks (9.6%) and six
      conversions to TA (9.6%) in the EV group. CONCLUSION: There were no statistically
      significant differences in mortality rates among TA, RP, and EV. Respiratory
      failure was significantly more common after TA repair, compared with RP or EV,
      whereas wound complications were more common after RP. Overall cost was
      significantly higher for TA repair, with no significant difference in cost
      between EV and RP. EV repair significantly shortened hospital stay and intensive
      care unit (ICU) use and had a lower morbidity rate. Cost savings in LOS were
      significantly reduced in the EV group by the increased cost of supplies and
      radiology, accounting for a similar cost between EV and RP. Considering the
      increased resource use preoperatively and during follow-up for EV patients, the
      difference in cost between TA and EV may be insignificant. EV repair is unlikely
      to save money for the health care system; its use is likely to be driven by
      patient and physician preference, in view of a significant decrease in the
      morbidity rate and length of hospital stay.

PMID- 10394155
TI  - An assessment of the current applicability of the EVT endovascular graft for
      treatment of patients with an infrarenal abdominal aortic aneurysm.
AB  - OBJECTIVE: To determine the percentage of elective abdominal aortic aneurysms
      (AAAs)/aortoiliac aneurysms that currently can be repaired with endovascular
      grafts (EVGs), the reasons for rejection of EVGs, and the future role of EVG in
      the treatment of AAA. METHODS: From January 1997 to May 1998, patients at three
      hospitals (a university hospital, a university-affiliated teaching hospital, and
      a Veterans Administration hospital with university faculty and residents) were
      evaluated for EVGs as part of a national clinical trial with grafts manufactured
      by Endovascular Technologies (EVT, Menlo Park, Calif). All patients at two
      hospitals and patients treated by the participating surgeons at the third
      hospital were screened for EVG. Patients with AAAs that were ruptured,
      symptomatic, or involved renal or mesenteric arteries and patients who declined
      treatment were excluded from the study. Evaluation included clinical examination,
      computed tomography scan, and selective arteriography. The decision to proceed
      with EVG was made by the vascular surgeon, with input and concurrence of medical
      personnel from a company with extensive experience in endograft repair. The main
      outcome measures were the determination of the percentage of elective AAAs
      currently being treated with an EVG and the reasons for exclusion of patients
      from EVG placement. RESULTS: A total of 162 patients underwent elective treatment
      of an AAA, 22 (14%) with an EVG (14 bifurcated, eight tube) and 140 (86%) with
      traditional resection. Indications for not proceeding with an EVG included
      insufficient proximal cuff in 29 patients (21%), distal common iliac aneurysm or
      insufficient distal iliac neck in 29 patients (21%), proximal neck too large for
      an EVG in 24 patients (17%), symptomatic iliac stenosis in 23 patients (16%),
      iliac stenosis precluding introducer passage in 17 patients (12%), patient
      preference in 11 patients (8%), and calcification, kink, or extensive thrombus
      involving the proximal neck precluding safe graft attachment in seven patients
      (5%). Of the 22 patients treated with an EVG, three were converted to open
      resection, because of iliac stenosis in two patients and premature stent
      deployment in one patient (initial technical success rate, 86%). CONCLUSION:
      Based on currently available technology, 80% of patients were not candidates for
      an EVG because of proximal calcification, short aortic or distal cuff, coexisting
      distal iliac aneurysm, and stenotic iliac disease. Even with the use of
      adjunctive procedures, most patients still require open repair. Significant
      changes in design will be necessary to apply these devices to most patients with
      an AAA.

PMID- 10394156
TI  - Improved results with conventional management of infrarenal aortic infection.
AB  - PURPOSE: Interest in alternative methods, such as autogenous vein grafts and
      aortic allografts, for the management of infrarenal aortic infection (IRAI) has
      been stimulated by the historically disappointing results with conventional
      surgical management. Recently, there have been dramatic improvements in the
      results of axillofemoral bypass grafting (AXFB) followed by excision of the IRAI
      that have gone relatively unrecognized. The purpose of this report is the
      presentation of modern-day results in the treatment of IRAI with conventional
      surgical methods. METHODS: From January 1, 1983, through June 30, 1998, patients
      with IRAI underwent treatment with AXFB and complete excision of the IRAI. The
      patients were followed for survival, limb salvage, and AXFB graft patency. The
      results were tabulated with life-table methods. RESULTS: During the 15-year study
      period, 60 patients (51 men, nine women; mean age, 68 years) underwent treatment
      for IRAI (50 graft infections, including 16 graft-enteric fistulae, and 10
      primary aortic infections). The mean follow-up period was 41 months. The
      perioperative mortality rate was 13% (12% for graft infection, and 20% for
      primary infection). The overall 2-year and 5-year survival rates were 67% and
      47%, respectively. The limb salvage rates at 2 and 5 years were 93% and 82%,
      respectively. The 5-year primary AXFB graft patency rate was 73%. CONCLUSION:
      These results show an improvement with the conventional management of IRAI equal
      or superior to those results reported with alternative methods, including femoral
      vein grafts or aortic allografts. These results should be regarded as the modern
      standard with which alternative therapies can be compared.

PMID- 10394157
TI  - Vascular surgery and the Internet: a poor source of patient-oriented information.
AB  - OBJECTIVE: Increasing numbers of patients use the Internet to obtain medical
      information. The Internet is easily accessible, but available information is
      under no guidelines or regulations. We sought to evaluate the type, quality, and
      focus of vascular disease information presented on the Internet and the role in
      patient education with simple search techniques. METHODS: The arbitrarily chosen
      search phrases "abdominal aortic aneurysm (AAA)," "carotid surgery (CEA),"
      "claudication surgery," and "leg gangrene surgery" were entered into five common
      Internet search engines. No attempt was made to refine searches. As indicated by
      the search engines, the 50 most commonly encountered web sites for both AAA and
      CEA were reviewed. The first 25 claudication sites and the first 25 gangrene
      sites were combined for a total of 50 leg ischemia (LIS) sites. An information
      score (IS) was developed as a weighted score ranging from 0 (poor) to 100
      (outstanding) and was designed to assess how well the web page educated the
      patient about the disease, the treatment options, and the medical and surgical
      complications. Each vascular surgery web site was classified according to the
      author, the referenced information source, and the therapeutic recommendations.
      This was followed by an evaluation of each web site with the IS independently
      scored by two observers. RESULTS: Of the 150 web sites, 146 were accessible.
      Ninety-six sites (65.8%) had no useful patient-oriented information (IS < 10).
      The mean IS and the ranges were: AAA, 14.9 (0 to 72.0); CEA, 17.5 (0 to 77.0);
      and LIS, 12.2 (0 to 44.5; P =.9). The mean IS of the 59 sites with scores of more
      than 10 were: AAA, 39.8 (n = 17); CEA, 44.8 (n = 19); and LIS, 24.8 (n = 23; P
      <.01, as compared with LIS scores). Differences in IS between observers were not
      significant (P =.9). Misleading or unconventional care recommendations were
      recognized in one AAA site (1 of 47, 2.1%), two CEA sites (2 of 49, 4.1%), and 13
      LIS sites (13 of 50, 26.0%). The Joint Vascular Societies web page was identified
      only as a tertiary link. CONCLUSION: Patient-oriented vascular surgery
      information, for common vascular diseases, is difficult to find on the Internet.
      The overall quality is poor, and information is difficult to obtain in part
      because of the large number of irrelevant sites. Of the sites that were relevant
      to patient education (33%), one third presented information that was classified
      by the authors as misleading or unconventional. This was most apparent in the leg
      ischemia sites. The Internet is a poor overall source of patient-oriented
      vascular surgery information and education. Focused and refined searches and
      improvements in search engines and educational web sites may yield improved
      information. Public and medical community awareness needs to be improved
      regarding the severe limitations of the Internet as an information resource.

PMID- 10394158
TI  - In situ replacement of infected aortic grafts with rifampicin-bonded prostheses:
      the Leicester experience (1992 to 1998)
AB  - PURPOSE: Prosthetic graft infection after aortic aneurysm surgery is a life
      threatening complication. Treatment options include total graft excision and
      extra-anatomic bypass grafting or in situ replacement of the graft. The latter
      option is gaining increasing popularity, but the long-term outcome remains
      uncertain, particularly in light of the increasing prevalence of methicillin
      resistant Staphylococcus aureus (MRSA). We performed a prospective nonrandomized
      study to assess the outcome after graft excision and in situ replacement with a
      rifampicin-bonded prosthesis for the treatment of major aortic graft infection.
      METHODS: In a 6-year period from January 1992 to December 1997, 11 patients
      (eight men, three women) with major aortic graft infection underwent total graft
      excision and in situ replacement with a rifampicin-bonded prosthesis. The median
      age of the patients was 66 years (range, 49 to 78 years). Four patients had a
      hemorrhage from an aortoenteric fistula, three had a retroperitoneal abscess, two
      had graft occlusion, one had a perigraft collection shown by means of computed
      tomography, and one had a ruptured suprarenal false aneurysm. Organisms were
      cultured from 10 patients. RESULTS: MRSA was isolated in two patients, both of
      whom had originally undergone repair of a ruptured abdominal aortic aneurysm. Two
      patients died (18.2%) within 30 days, and three patients (27.6%) had nonfatal
      complications (peritoneal candidiasis, transient renal impairment, and profound
      anorexia). Two patients died late in the follow-up period. Seven patients remain
      alive and clinically free of infection. CONCLUSION: The long-term results after
      total graft excision and in situ replacement with a rifampicin-bonded prosthesis
      appear to be favorable. However, MRSA aortic graft infection appears to be
      associated with a poor prognosis.

PMID- 10394159
TI  - Do residual arteriovenous fistulae after in situ saphenous vein bypass grafting
      influence patency?
AB  - PURPOSE: The purpose of this study was to evaluate the influence on patency of
      residual arteriovenous fistulae (AVF) after in situ saphenous vein bypass
      grafting. METHODS: Between January 1, 1994, and December 31, 1996, 98 in situ
      saphenous vein bypass grafting procedures were performed in 94 patients. Patency
      was evaluated with duplex scanning after operation and at 1, 3, 6, 9, and 12
      months. RESULTS: The indications for operation were intermittent claudication in
      two patients and critical leg ischemia in 92 patients. Two above-knee and 48
      below-knee femoropopliteal and 48 femorocrural in situ saphenous vein bypass
      grafting procedures were performed. The median follow-up period was 9 months
      (range, 1.5 to 12.5 months). There were no residual AVF in 45 veins (44%; group
      1), but 110 residual AVF were found in 53 veins (56%; group 2). In group 2, 36
      AVF in 18 veins were surgically or radiologically occluded mainly as a result of
      a flow velocity decrease distal to the AVF, but the remaining 74 AVF were treated
      conservatively. The 1-year cumulative primary patency rates were 68% in group 1
      and 74% in group 2 (log-rank test, 0.47; degree of freedom = 1; P =.52). The 1
      year cumulative assisted primary patency rates were 68% in group 1 and 81% in
      group 2 (log-rank test, 2.19; degree of freedom = 1; P =. 14). CONCLUSION:
      Residual AVF after in situ bypass grafting without influence on bypass graft
      hemodynamics do not compromise patency and thrombose spontaneously.

PMID- 10394160
TI  - Incidence, time-of-onset, and anatomical distribution of recurrent stenoses after
      remote endarterectomy in superficial femoral artery occlusive disease.
AB  - PURPOSE: The incidence, time-of-onset, and anatomical distribution of recurrent
      stenoses after remote endarterectomy in superficial femoral artery (SFA)
      occlusive disease were studied. METHODS: Patients undergoing SFA remote
      endarterectomy procedures were examined with duplex surveillance. Patients were
      examined at 6 weeks, 3, 6, 9, and 12 months, and then annually. Recurrent
      stenosis was defined as a peak systolic velocity ratio of 2.5 or higher. Duplex
      results were also compared with clinical and hemodynamic changes. RESULTS:
      Restenoses were identified in 46 of 101 (46%) limbs treated after a mean interval
      of 5.8 months (range, 1 to 18 months). These 46 limbs formed the base of this
      study. The median follow-up period was 25 months. Thirty-eight (83%) of all
      restenoses were detected within 1 year. The lesions were located within the
      entire SFA and were not specifically related to the adductor canal or distal
      stented region only. Multiple stenoses were found in 21 limbs. Only 10 (22%)
      restenoses were correlated with worsening of clinical symptoms, change of ankle
      brachial index, or both. Ten of 23 cases (43%) of nonrevised restenoses
      progressed to occlusion. These 10 occlusions occurred in all patients with
      restenosis that developed within the first year. Nonrevised late restenoses (more
      than 1 year) were not associated with any reocclusion. CONCLUSION: Recurrent
      stenoses after SFA remote endarterectomy were noticed in 46 of 101 (46%) limbs.
      Most restenoses (83%) developed within the first year. In the nonrevised group,
      time-of-onset restenosis (less than 1 year) was correlated with a higher risk for
      occlusion ( P =.02). The location of restenoses were found without any anatomical
      site of preference along the entire endarterectomized SFA segment.

PMID- 10394161
TI  - Prediction of imminent amputation in patients with non-reconstructible leg
      ischemia by means of microcirculatory investigations.
AB  - PURPOSE: We investigated the usefulness of skin microcirculatory investigations
      to predict imminent major amputation in patients with non-reconstructible
      critical limb ischemia. METHODS: One hundred eleven patients with non
      reconstructible chronic rest pain or small ulcers and an ankle blood pressure of
      50 mm Hg or less or an ankle-to-brachial pressure index of 0.35 or less were
      included. Nailfold capillary microscopy (CM; big toe, sitting), transcutaneous
      oxygen pressure (TcpO2; forefoot, supine; 44 degrees C), and laser Doppler
      perfusion measurements (LD; pulp of big toe, supine) were performed at rest and
      during reactive hyperemia. Patients were classified according to their skin
      microcirculatory status just before the start of the treatment in three groups:
      those with a "good," "intermediate," or "poor" microcirculation, according to a
      combination of predefined cutoff values (Poor: capillary density less than
      20/mm2, absent reactive hyperemia in CM and LD, TcpO2 less than 10 mm Hg; good:
      capillary density of 20/mm2 or more, present reactive hyperemia in CM and LD,
      TcpO 2 of 30 mm Hg or more). Subsequently, patients received maximum conservative
      therapy from the surgeon, who was unaware of the microcirculatory results. After
      a follow-up period of as long as 36 months, limb survival and disposing factors
      were analyzed and compared with the initial microcirculatory status. RESULTS: Cox
      regression analysis showed a significant prognostic value of the microcirculatory
      classification (hazard ratio = 0.28, P <.0001), but not of the Fontaine stage,
      ankle blood pressure, or the presence of diabetes mellitus for the occurrence of
      an amputation. Positive and negative predictive values were 73% and 67%,
      respectively. The cumulative limb survival at 6 and 12 months was 42% and 17% in
      the poor microcirculatory group, 80% and 63% in the intermediate microcirculatory
      group, and 88% and 88% in the good microcirculatory group ( P <.0001, log-rank).
      CONCLUSION: Microcirculatory screening and classification is useful in detecting
      non-reconstructible critical ischemia that requires amputation, which is not
      detectable by means of the clinical stage or blood pressure parameters. Most of
      the poor patient group will require amputation. In the intermediate and good
      groups, nonsurgical treatment appears sufficient for limb salvage.

PMID- 10394162
TI  - Selection of patients for carotid endarterectomy.
AB  - OBJECTIVE: The aim of this study was the definition of the duplex scan parameters
      that best select patients for carotid endarterectomy. METHODS: This study was set
      in a regional vascular unit. Duplex scanning and angiography were performed
      prospectively on 50 patients who were symptomatic (100 carotid bifurcation) to
      identify the most accurate and sensitive duplex scan criteria to identify an 80%
      to 99% stenosis according to the European Carotid Symptomatic Trial. With data
      from the European Carotid Symptomatic Trial, we estimated the effect of three
      different approaches used to select patients for carotid endarterectomy. The
      first approach was the selection of patients for carotid surgery on the basis of
      duplex scanning alone with the most accurate duplex scan criteria (approach I).
      The second approach was the selection of patients for carotid surgery on the
      basis of duplex scanning alone with a 100% sensitive duplex scan criteria
      (approach II). The third approach was the selection of patients for angiography
      with duplex scanning (100% sensitive criteria) and then the use of angiography to
      define which patients should undergo surgery (approach III). RESULTS: All three
      approaches appeared to have a similar potential in stroke reduction. However,
      approach I, which minimized the number of patients who underwent surgery (19%
      less than approach II) or invasive imaging (65% less than approach III), appeared
      to be the most appropriate. CONCLUSION: These data support the selection of
      patients for carotid endarterectomy on the basis of duplex scanning alone. The
      duplex scan criteria should be validated against angiography.

PMID- 10394163
TI  - Locoregional versus general anesthesia in carotid surgery: is there an impact on
      perioperative myocardial ischemia? Results of a prospective monocentric
      randomized trial.
AB  - PURPOSE: The incidence of cardiac morbidity and mortality in patients who undergo
      carotid surgery ranges from 0.7% to 7.1%, but it still represents almost 50% of
      all perioperative complications. Because no data are available in literature
      about the impact of the anesthetic technique on such complications, a prospective
      randomized monocentric study was undertaken to evaluate the role of local
      anesthesia (LA) and general anesthesia (GA) on cardiac outcome. METHODS: From
      November 1995 to February 1998, 107 patients were classified by the cardiologist
      as cardiac patients (IHD; history of myocardial infarction, previous myocardial
      revascularization procedures, or myocardial ischemia documented by means of
      positive electrocardiogram [ECG] stress test results) or noncardiac patients
      (NIHD; no history of chest pain or negative results for an ECG stress test). The
      patients were operated on after the randomization for the type of anesthesia
      (general or local). Continuous computerized 12-lead ECG was performed during the
      operative procedure and 24 hours postoperatively. The end points of the study
      were ECG modifications (upsloping or downsloping more than 2 mm) of the sinus
      tachycardia (ST) segment. RESULTS: Fifty-five patients were classified as IHD,
      and 52 were classified as NIHD. Twenty-seven of the 55 IHD patients (49%) and 24
      of 52 NIHD patients (46%) were operated on under GA. Thirty-six episodes of
      myocardial ischemia occurred in 22 patients (20.5%). Episodes were slightly more
      frequent (58%) and longer in the postoperative period (intraoperative, 10 +/- 5
      min; postoperative, 60 +/- 45 min; P <. 001). As expected, the prevalence of
      myocardial ischemia was higher in the group of cardiac patients than in
      noncardiac group (15 of 55 patients [27%] vs 7 of 52 patients [13%]; P <.02). By
      comparing the two anesthetic techniques in the overall population, we found a
      similar prevalence of patients who had myocardial ischemia (GA, 12 of 52 [23%];
      LA, 10 of 55 [18%]; P = not significant) and a similar number of ischemic
      episodes per patient (GA, 1.5 +/- 0.4; LA, 1.8 +/- 0.6; P = not significant).
      Episodes of myocardial ischemia were similarly distributed in intraoperative and
      postoperative periods in both groups. It is relevant that under GA, IHD patients
      represent most of the population who suffered myocardial ischemia (83%). On the
      contrary, in the group of patients operated on under LA, the prevalence was
      equally distributed in the two subpopulations. CONCLUSION: The results confirm
      the different hemodynamic impact of the two anesthetic techniques. Patients who
      received LA had a rate of myocardial ischemia that was half that of patients who
      had GA. The small number of cardiac complications do not permit us to make any
      definitive conclusion on the impact of the two anesthetic techniques on early
      cardiac morbidity, but the relationship between perioperative ischemic burden and
      major cardiac events suggests that LA can be used safely, even in high-risk
      patients undergoing carotid endarterectomy.

PMID- 10394164
TI  - A model of in vivo human venous thrombosis that confirms changes in the release
      of specific soluble cell adhesion molecules in experimental venous
      thrombogenesis.
AB  - PURPOSE: The mechanisms of venous thrombogenesis have been studied by using
      animal models and cells in culture. The results from these systems may not,
      however, be relevant to the human condition. The aim of this study was to develop
      a method by which thrombus could be safely produced in a human vein in vivo. The
      model that was developed was used as a means of studying the changes in soluble
      adhesion molecule expression in human venous thrombogenesis. METHODS: An
      autologous thrombin extract was used to generate experimental thrombi in the
      disconnected portion of the long saphenous veins of 30 patients who were
      undergoing routine bilateral varicose vein surgery. The contralateral vein was
      perfused with thrombin extract diluent buffer to act as the control. The
      concentration of soluble P-, E- and L-selectin, intercellular adhesion molecule 1
      (ICAM-1), and vascular cell adhesion molecule-1 were measured by means of
      specific enzyme-linked immunosorbent assays in samples of blood taken from veins
      in which thrombus had formed and in contralateral control veins. RESULTS:
      Thrombosis invariably formed when at least 100 IU of thrombin activity was
      administered. Thrombus formation was independent of the time that the thrombin
      extract was allowed to remain within the emptied vessel. Thrombosis never
      developed in control vessels that were similarly treated with the buffer used to
      dilute the thrombin extract. Experimental thrombi were composed mainly of red
      cells, with layers of fibrin next to platelet and leukocyte packages. These
      findings are similar to those observed in samples of established human venous
      thrombi. There were small but significantly higher levels of the adhesion
      molecules, soluble P-selectin, and vascular cell adhesion molecule-1 in blood
      taken from veins in which experimental thrombi had formed, compared with controls
      (P =.015 and.007, respectively; Wilcoxon signed rank test). Serum levels of
      soluble L-selectin, E-selectin, and ICAM-1 were not affected by thrombosis.
      CONCLUSION: This model is safe and reproducible. It produces thrombi with a
      morphology similar to that described for established human deep venous thrombi.
      The model may be appropriate for the study of the early changes that occur during
      human venous thrombogenesis and may also be of value in testing the efficacy of
      novel antithrombotic agents.

PMID- 10394165
TI  - Leukocyte activation in patients with venous insufficiency.
AB  - PURPOSE: Cell activation may play an important role in the production of venous
      insufficiency, just as leukocytes participate in the cause of venous ulcer. If
      activated, monocytes observed on venous endothelium can migrate into the venous
      wall and produce toxic metabolites and free oxygen radicals that may participate
      in valve destruction and venous wall weakening. At present, it remains uncertain
      to what degree leukocytes are actually activated in patients. This study was
      designed to explore the level of activation and to examine whether patient plasma
      contains an activator that leads to leukocyte activation of unstimulated naive
      leukocytes from volunteers without venous insufficiency disease. METHODS: Twenty
      one patients (4 men, 17 women), who ranged in age from 34 to 69 years (mean age,
      53.2 years), with chronic venous disease were compared with 16 healthy control
      volunteers (4 men, 12 women), who ranged in age from 18 to 65 years (mean age,
      48.4 years). All the patients underwent evaluation with Doppler ultrasound
      scanning and were classified with the CEAP score.1 Nearly all the patients who
      smoked or were hypertensive were excluded. The blood types (ABO and Rh) of the
      controls were matched to the study group. Isolates of patient whole blood,
      plasma, or leukocytes were incubated with isolates of control whole blood,
      plasma, or leukocytes to separate actual activation from spontaneously observed
      activation. The granulocyte activation was measured with nitroblue tetrazolium
      (NBT) reduction and quantitation of granulocyte pseudopod formation. Hydrogen
      peroxide production in patient plasma was measured with a recently developed
      electrode method. RESULTS: Leukocytes from healthy blood and patient plasma had
      significantly higher NBT-positive granulocyte counts than either patient blood,
      healthy blood, or patient blood incubated in healthy plasma. In a comparison of
      patient groups across the CEAP classes, the NBT-positive granulocyte counts were
      significantly greater in classes 4, 5, and 6 than in classes 2 and 3 (P <.001).
      Pseudopod formation was significantly greater in mixtures of granulocytes in
      healthy blood and patient plasma than in all other groups. There was no
      difference in the level of pseudopod formation in control leukocytes incubated
      with patient plasma in patients across the CEAP spectrum. The patient plasma
      produced significantly higher hydrogen peroxide values than did the controls.
      CONCLUSION: These results suggest that patient plasma may contain an activating
      factor for granulocytes. The finding that activated neutrophils were fewer in
      number in patient whole blood than in healthy blood incubated in patient plasma
      could suggest that activated neutrophils in patients with chronic venous
      insufficiency might be trapped in the peripheral circulation. It is unknown what
      factors in the plasma might induce activation of naive neutrophils, but such
      activators could possibly be important in the pathogenesis of primary venous
      dysfunction and the development of chronic venous insufficiency.

PMID- 10394166
TI  - Power Doppler ultrasound scan imaging of the level of red blood cell aggregation:
      an in vitro study.
AB  - PURPOSE: The purpose of this study was to evaluate the effect of the shear rate
      on red blood cell (RBC) aggregation with power Doppler ultrasound scanning (PDU),
      pulsed-wave Doppler scanning, and color Doppler flow imaging. METHODS: Equine and
      porcine blood were circulated with a steady flow in a phantom with a diameter of
      9.52 mm. The color Doppler flow imaging mode was used to estimate the velocity
      profile and the shear rate across the tube. A transfer function that related the
      Doppler scan power, measured in gray level with the PDU method, to the power,
      measured in decibels with the pulsed-wave Doppler scan technique, was used to
      estimate the echogenicity of blood and the level of aggregation. RESULTS: For the
      four experiments reported, the power peaked at low shear rates probably because
      of increased RBC collisions and aggregation and then decreased thereafter because
      of disaggregation. The largest power variations were measured at shear rates of
      less than 40 seconds -1. At flow rates that varied between 75 and 500 mL/min, the
      echogenicity was low near the wall of the tube, increased toward the middle, and
      decreased at the tube center. The Doppler scan power was uniform across the tube
      at flow rates of 750 and 1000 mL/min. CONCLUSION: PDU is reliable to quantify the
      echogenicity of blood and the level of RBC aggregation. In comparison with other
      methods proposed to measure RBC aggregation, ultrasound scanning is applicable in
      vivo and may help to improve our basic understanding of the relationship between
      the hemodynamic of the circulation and RBC aggregation in human vessels.

PMID- 10394167
TI  - Association of smooth muscle cell phenotypic modulation with extracellular matrix
      alterations during neointima formation in rabbit vein grafts.
AB  - PURPOSE: To clarify the mechanisms of structural changes underlying vein graft
      stenosis that limits efficacy of bypass grafting operation, we examined the
      accumulation and distribution of various extracellular matrix (ECM) components
      during neointima formation in rabbit vein grafts and analyzed their correlation
      with proliferation and phenotypic modulation of smooth muscle cells (SMCs).
      METHODS AND RESULTS: An autologous external jugular vein graft was transplanted
      into the carotid artery in 25 rabbits. After the restoration of blood flow, the
      graft was markedly dilated. Medial SMCs in the graft appeared to be injured, and
      they began to proliferate at day 4 and subsequently migrated and formed the
      neointima at day 7. The neointima observed at days 7 and 14 contained ECM
      components, including type I collagen, heparan sulfate, and chondroitin sulfate,
      and the intimal SMCs were phenotypically modulated from the differentiated-type
      (SM2-positive and SM embryonic-negative) to the dedifferentiated-type (SM2
      negative and SM embryonic-positive) as determined with immunostainings for myosin
      heavy chain isoforms. The intimal SMC proliferation was maximal at 2 weeks and
      then decreased rapidly. However, the neointima continued to thicken thereafter
      throughout the 6-month period of the experiment, and ECM accumulation, such as
      type I collagen and decorin, a small dermatan sulfate proteoglycan, was a
      prominent feature observed in the hypocellular region of the deep intima from 2
      months after the transplantation. The phenotype of the intimal SMCs gradually
      returned to the differentiated-type from the deep intima after 2 months, but a
      small number of the intimal SMCs remained in the dedifferentiated phenotype even
      at 6 months after the operation. CONCLUSION: The neointima in the vein graft was
      formed initially by means of migration and proliferation of the phenotypically
      modulated, dedifferentiated-type SMCs and continued to thicken by means of
      sustained ECM accumulation, including type I collagen and decorin, in association
      with the prolonged presence of the dedifferentiated-type SMCs. These chronologic
      features in cell kinetics and ECM accumulation may contribute to the frequent
      occurrence of graft wall thickening that occurs in the vein grafts.

PMID- 10394168
TI  - Splenic artery aneurysms: methods of laparoscopic repair.
AB  - PURPOSE: Surgical therapy for splenic artery aneurysms (SAAs) has traditionally
      consisted of a laparotomy with resection of the aneurysm and possibly a
      splenectomy. Our early experience with the laparoscopic approach to treat SAAs is
      reported. METHODS: A retrospective review of medical records was conducted on all
      patients who underwent laparoscopic resection of SAAs at the Cleveland Clinic
      Foundation from May 1996 to August 1997. RESULTS: Four patients with SAAs, three
      women and one man, with an average age of 55 years (range, 37 to 63 years),
      underwent successful laparoscopic SAA repair. The average size of the aneurysm
      was 3.2 cm (range, 2.5 to 5.0 cm). Three patients underwent an aneurysm
      resection, whereas one patient underwent simple ligation. Intraoperative
      ultrasound scanning with Doppler was used in three cases as a means of localizing
      the aneurysm and identifying all feeding vessels; the complete cessation of flow
      within the aneurysm in the case in which the feeding vessels were simply ligated
      was also documented. The average intraoperative time was 150 minutes (range, 100
      to 190 minutes). The mean estimated blood loss was 105 mL (range, 20 to 300 mL).
      There were no intraoperative complications. The average hospital stay was 2.2
      days (range, 1 to 4 days). CONCLUSION: The laparoscopic approach to splenic
      artery aneurysm by aneurysmectomy or splenic artery ligation can be safe and
      effective. The laparoscopic approach affords a short hospital stay and an
      effective result.

PMID- 10394169
TI  - Cryptococcal aortitis presenting as a ruptured mycotic abdominal aortic aneurysm.
AB  - Mycotic processes occasionally complicate atherosclerotic aortic disease and
      usually require aggressive surgical therapy to control sepsis and prevent
      arterial rupture. Rarely, fungal organisms are responsible for primary infection
      of the abdominal aorta. We report the first case of Cryptococcal aortitis
      presenting as a ruptured abdominal aortic aneurysm. The surgical, pathologic, and
      microbiologic aspects of fungal aortitis are discussed.

PMID- 10394170
TI  - Management of dialysis access-associated steal syndrome: use of intraoperative
      duplex ultrasound scanning for optimal flow reduction.
AB  - Dialysis access-associated steal syndrome (DASS) is an uncommon complication
      after the creation of an arteriovenous fistula and can cause irreversible
      ischemic damage in severe cases. Dialysis access-associated steal syndrome has
      been managed with the surgical reduction of the volume flow in the fistula, but
      this is associated with a certain incidence of access loss. Several methods are
      described to achieve the delicate balance between essential flow in the fistula
      and an adequate limb perfusion pressure. We have developed a new method with
      duplex ultrasound scanning to quantitate the reduction in volume flow, which will
      allow effective dialysis and provide adequate limb perfusion. The preoperative
      assessment was reproduced on the operating table with intraoperative duplex
      scanning. A 65-year-old woman who underwent this treatment has had resolution of
      her ischemic symptoms and maintains long-term patency of her dialysis access.

PMID- 10394171
TI  - Disclosure of competition of interest.

PMID- 10394172
TI  - Gastrocnemius muscle transfer in limb-sparing surgery for bone tumors around the
      knee.
AB  - Limb-sparing surgery for bony tumors around the knee, resulting in large
      segmental defects, involves its replacement with an endoprosthesis. The viability
      of the overlying skin flaps is of utmost importance. Their healing without
      breakdown is essential or else leads to prosthesis exposure, infection and
      perhaps prosthesis removal. In this situation, gastrocnemius muscle transfer is a
      robust vascular option, not only providing soft padding to cover the
      endoprosthesis, but also supporting the vascularity of the skin flaps. Out of 16
      such muscle transfers done, 15 survived completely with good wound healing. One
      patient developed a severe infection of the wound associated with skin flap
      breakdown and necrosis of part of the muscle flap. There was 1 case of wound
      haematoma which was treated successfully.

PMID- 10394173
TI  - The lateral tongue flap: a salvage option for reconstruction of buccal
      recurrences.
AB  - BACKGROUND: Surgery in an irradiated, previously operated field is fraught with
      danger. Though microvascular tissue transfers are being gone, they may not be
      feasible in all circumstances. METHODS: A lateral tongue flap was executed in 11
      cases of intraoral buccal recurrence. The aims of this study were to evaluate the
      procedure, the function of the remaining tongue and the speed of rehabilitation
      with respect to preoperative functional status. RESULTS: Out of 11 such
      reconstructions in a period of 12 months, only 1 flap had tip necrosis while a
      haematoma developed in 2 cases. Swallowing, speech, and tongue protrusion were
      not significantly hampered by the procedure. Patients were rehabilitated very
      quickly (within 2 weeks), to preoperative functional status. CONCLUSIONS: The
      Lateral Tongue Flap is a simple, robust vascular transfer and an effective
      salvage reconstructive option in a post-excisional defect caused by a recurrent
      intraoral cancer.

PMID- 10394174
TI  - Revascularization of a free nerve graft wrapped in omentum.
AB  - The revascularization of free nerve grafts wrapped in omentum was assessed in an
      experimental model using rats. Revascularization of the grafts, using the
      original vessels, proceeded in the same way as reported in earlier studies, being
      in progress on the 4th day after the operation and essentially complete on the
      8th day. The observations made in the experiment suggest that using omentum does
      not offer much of an advantage with nerve grafts transplanted to tissues with a
      good blood supply. Using omentum would seem indicated for grafts transplanted
      into cicatrized or irradiated tissues.

PMID- 10394175
TI  - Phalloplasty using a lateral groin flap in female-to-male transsexuals.
AB  - The paper presents a one-stage procedure for neophallus construction using a
      lateral groin flap. In the years 1991-1997, 127 female-to-male transsexuals
      underwent surgery in the Department of Plastic Surgery of the Medical University
      of Lodz using this method. Good results were obtained in 96 patients (75.6%).
      Necrosis of the distal part of the flap or other complications that adversely
      affected the final results of the treatment occurred in 20 cases (20.5%). In 5
      cases the flap was completely lost. Phalloplasty along with urethra was done in 5
      female-to-male transsexuals. In 47 patients the constructed penis was stiffened
      with the use of three types of prostheses.

PMID- 10394176
TI  - Surgical treatment of pigmented melanocytic nevi depending upon their size and
      location.
AB  - Cutaneous melanocytic nevi may cause cosmetic defects and represent a risk of
      malignant transformation. Most problems are posed by nevi of the face or those
      covering large areas of the body, the so-called giant congenital nevus. From 1986
      until 1995, 295 patients with pigmented nevi underwent surgical treatment. The
      method employed depended upon the size and location of the melanocytic nevus.
      Results were evaluated according to a three-stage scale with consideration of the
      cosmetic outcome and satisfaction of the patients. Good results were obtained in
      280 patients, satisfactory ones in 11 patients, and unsatisfactory ones
      (requiring corrective treatment) in 4 patients. Small and medium size nevi (up to
      5 cm in diameter) can be removed in a one-stage procedure with suturing of the
      wound, local plasty or free-tissue skin graft. Blepharal and central facial
      lesions are best reconstructed with full-tissue skin grafting. Large nevi (over 5
      cm in diameter) mandate a staged excision or removal at one-stage with prior use
      of a tissue expander or presuturing. Giant nevi require staged treatment with the
      use of an intermediate thickness skin graft or removal of superficial layers of
      the nevus, always preceded however by a histopathological examination.

PMID- 10394177
TI  - Therapeutical aspects of using citalopram in burns.
AB  - CONCLUSION OF THE ICU: Preliminary results from this stage of our study
      demonstrate a significant decrease of the duration of oedema, probably due to the
      effects of the inhibition of vascular hyperpermeability. This means that patients
      under Citalopram therapy can undergo surgical procedures such as necrectomies and
      autografts sooner because they are stabilized as early as the beginning of their
      treatment. Particularly the patients with burned faces and deep dermal burns have
      a better prognoses in respect to cosmetics. CONCLUSION OF THE PSYCHOLOGIST: From
      the beginning of the study to the present time, no patient experienced PTSD. The
      compared group of out-patients had been treated on average of 3 months when the
      first signs of a reduction in the clinical symptoms of PTSD was registered. The
      clinical onset of the therapeutical effect--on average in the third week--is
      comparable with references from anxiety or inhibitory depression treatment by
      using Citalopram. We suggest, at present, that the above-mentioned, preliminary
      results of our study have shown that Citalopram treatment has a beneficial effect
      on emotional disturbances in severely burned patients. CONCLUSION OF THE SCAR
      SPECIALIST: Seropram is a very useful preparation in burn praxis. When we apply
      it as a bolus 40 mg i.v. immediately after admission to the ICU, the scarring
      process is very good and hypertrophic scars are not seen. When we apply Seropram
      in the form of a continual infusion, using the injectomat during a 24-hour
      period, scarring is better than in the control group, but hypertrophic scarring
      is not out of the question.

PMID- 10394178
TI  - [Diagnosis of cystic fibrosis].

PMID- 10394179
TI  - [Risk factors for the acute leukemias in children].

PMID- 10394180
TI  - [Perineal bag versus urethral catheterization of suprapubic aspiration for the
      diagnosis of urinary tract infections in infants in emergency units].
AB  - OBJECTIVE: Our objective was to determine the utility of urine cultures collected
      by sterile perineal bags as a method of diagnosis of urinary tract infection in
      infants. PATIENTS AND METHODS: Forty-two patients, aged 0 to 27 months, were
      diagnosed with urinary tract infections based on the growth of more than 100,000
      colonies/ml in two urine cultures collected by sterile bags. Confirmation of the
      infection was done by urine cultures obtained by suprapubic aspiration or
      urethral catheterization. A urinalysis was simultaneously performed. RESULTS:
      Urinary tract infection was confirmed in only 6 out of 42 patients. The positive
      predictive value of the sterile bag was 14%, increasing to 42% combined with an
      abnormal urinalysis. CONCLUSIONS: The sterile perineal bag is not an accurate
      method to collect urine for diagnosis of urinary tract infections in febrile
      infants or those who need prompt diagnosis and treatment.

PMID- 10394182
TI  - [Renal function and functional renal reserve in adolescents who acquired minimal
      change nephrotic syndrome in childhood].
AB  - OBJECTIVE: The aim of this study was to evaluate glomerular filtration rate (GFR)
      and renal functional reserve (RR) in young patients after diagnosis of minimal
      change nephrotic syndrome (MCNS) during childhood. PATIENTS AND METHODS: GFR and
      RR were evaluated in 15 young patients (10 female) diagnosis of childhood MCNS
      18.5 +/- 4 years before. Creatinine clearance (CC) was measured before and after
      an acute protein load to determine GFR and RR. Based on the tendency towards
      relapses, the study subjects were divided into two groups: Group A had less than
      five relapses and group B five or more relapses. Study subjects (groups A and B)
      and control subjects (group C) were matched for sex and age. RESULTS: Group B
      showed a higher GFR than groups A and C (group B = 133.9 +/- 16.26 ml/min/1.73
      m2, group A = 107.91 +/- 18.19 ml/min/1.73m2; p = 0.014, group C = 113.89 +/-
      13.17 ml/min/1.73m2, p = 0.015). RR was significantly lower (absolute and
      relative) in group B than in group C (group B = 10.9 +/- 15.46 ml/min/1.73m2,
      group C = 38.58 +/- 21.47 ml/min/1.73m2, p = 0.016 and group B = 8.56 +/- 11.75%,
      group C = 34.35 +/- 21.43%, p = 0.016, respectively). CONCLUSIONS: After
      childhood MCNS, young patients who presented more than five relapses showed an
      increase in GFR and a decrease in RR.

PMID- 10394181
TI  - [Tobacco consumption among school children and its relation to the environment].
AB  - OBJECTIVE: The aim of our study was to know the prevalence of tobacco consumption
      and the influence of the immediate environment in schoolchildren. PATIENTS AND
      METHODS: Participants were a random sample of 1,195 sixth and eighth grade
      schoolchildren from our rural area (N = 14,537) with a mean age of 12.7 +/- 1.27
      years. Data were collected from a confidential and anonymous survey about tobacco
      consumption. RESULTS: We found that 18.6% of children are currently smokers and
      22% of them smoke daily. Forty-four percent of schoolchildren had tried tobacco
      occasionally. The mean age to start tobacco consumption was 11 years old.
      Regarding family environment, 56% of the fathers consumed tobacco daily in
      contrast to 22% of mothers. Logistic-regression analyses showed an independent
      association between smoking habits, alcohol and coffee consumption and smoking
      (habit in the best friend). CONCLUSIONS: A great number of schoolchildren had
      consumed tobacco occasionally. Group of friends had an important influence in the
      smoking habit, unlike the family environment. Moreover, tobacco consumption
      showed an independent association with bad habits like drinking alcohol and
      coffee.

PMID- 10394183
TI  - [Seroprevalence of antibodies against measles, rubella, mumps and varicella among
      school children in Madrid].
AB  - OBJECTIVE: The aim of this study was to assess the seroprevalence of antibodies
      against MMR and varicella in a population of children between 6 and 7 years of
      age vaccinated against measles, mumps and rubella at 15 months of age. PATIENTS
      AND METHODS: This cross-sectional study was carried out in a group of healthy
      children (6-7 years of age) of the Autonomous Community of Madrid, Spain.
      Vaccination against MMR at 15 months of age was documented for all children
      included in the study. Blood samples were drawn from all participants and sera
      were stored at -20C until they were tested at the end of the study. Measles,
      mumps, rubella and varicella antibody levels were measured by means of the enzyme
      linked immunosorbent assay (ELISA) method (IgG Genzyme Virotech GmbH). Positive
      values were defined as optical density values of > or = 0.20 for measles, > or =
      0.30 for mumps, > or = 0.40 for rubella and > or = 0.36 for varicella. Prevalence
      (and the corresponding 95% confidence limits) assessed by the presence of anti
      measles, anti-mumps, anti-rubella and anti-VZV antibodies on the study population
      were calculated. The Chi-squared test was used to evaluate differences in
      prevalence between sexes. The Chi-squared test was used to evaluate differences
      in prevalence between the sexes. RESULTS: A total of 174 children were recruited
      between October and November 1997. The mean age (SD) and male/female ratio were
      6.4 (0.5) years and 0.8 (45.6%/54.5%), respectively. Prevalence of antibodies
      against measles, rubella, mumps and varicella were 92% (88-96%), 95% (92-98%),
      81% (76-86%) and 85% (90-90%), respectively. There were no significant
      differences between the sexes in relationship to the prevalence of measles,
      mumps, rubella or varicella antibodies. CONCLUSIONS: Approximately 20% of these 6
      to 7 year old children vaccinated at 15 months of age were unprotected against
      the mumps. Eight percent and 5% were sero-negative for measles and rubella,
      respectively. Administration of the second dose of MMR vaccine at 4 to 6 years of
      age instead of at 11 years would contribute to avoid the accumulation of non
      immune children. Eighty-five percent of the study population was sero-positive
      for VZV. These data suggest that, in Spain, VZV infections commonly affect
      children younger than 5 years of age.

PMID- 10394184
TI  - [Demand of microbiological diagnosis by pediatricians from the Salamanca area].
AB  - OBJECTIVE: The purpose of this study was to assess the referrals made by
      pediatricians for microbiological diagnoses and to evaluate the process by
      determining the index of contaminated urine samples. PATIENTS AND METHODS: A
      transverse retrospective study was carried out on the referrals made to the
      microbiology laboratory of the University Hospital in Salamanca during 1997. The
      study was limited to the health area of Salamanca, which covers a population of
      358,408 inhabitants. The data are distributed according to care levels and
      referral indicators (proportions and indices) are elaborated. RESULTS: The
      referrals and results of the 65,462 samples that were processed during this
      period were analyzed. Of the total, 10,120 (28%) were positive. The overall rate
      of pediatric referrals was 533 per 1,000 inhabitants. The highest demand was for
      serology, urinary and fecal studies. The rate of positive results in the
      different pediatric samples was 156/1000. The rate of results in urine was
      154/1000. The rate of contaminated urine samples was 92/1000. CONCLUSIONS: The
      types of microbiological analyses in greatest demand are serology and urine
      cultures. The relationship between referrals and positive results is 4:1. The
      quality of the process can be improved through patient instruction and by means
      of suitable sample collection and transport.

PMID- 10394185
TI  - [Uremic hemolytic syndrome. Analysis of 43 cases].
AB  - OBJECTIVE: The purpose of this study was to describe the epidemiological,
      clinical and evolution features of hemolytic uremic syndrome (HUS). PATIENTS AND
      METHODS: A retrospective study of 43 cases of HUS during the last 14 years (1984
      1998) was performed. RESULTS: The mean age of the patients was 3.2 years, the
      incidence during the summer season was the highest and 39 cases (90%) previously
      had acute gastroenteritis. All children had acute renal failure, 32 of them (74%)
      required peritoneal dialysis. Anuria was found in 22 case (51%) and the mean
      duration was 10.3 days. The most frequent complications were: Hypertension in 21
      cases (48%), peritonitis in 9 cases (20%), seizures in 8 patients (16%) and 3
      deaths (6%). The mean hospital stay was 14.5 days. After one year of ambulatory
      control, 76% of the children were completely recovered and only two cases (6%)
      had chronic renal failure. Seizures associated significantly with a bad prognosis
      (p < 0.05). CONCLUSIONS: HUS has a very important morbimortality. Seizures in the
      acute phase were associated with a bad prognosis. Anuria for more than 7 days and
      oliguria for more than 15 days were also predictors of a worse prognosis, but
      this was not significant.

PMID- 10394186
TI  - [Dietary pattern of adolescents in Guipuzcoa].
AB  - OBJECTIVE: Multiple international studies demonstrate an imbalance in the dietary
      pattern of adolescents resulting in a nutritional intake that is inadequate to
      guarantee the biochemical basis of genetic expression, health and development of
      the person. PATIENTS AND METHODS: A 24 hour survey (five days, weekly, holidays
      and seasonal rotation) in reference to RDA was given to a population of 2,407
      adolescents between 14 and 16 years of age. The population included 1,232 girls
      (51.2%) and 1,175 boys (48.8%). The sample was determined by simple aleatory
      sampling (margin of error lower than 2%, level of trust 95%) which was followed
      by descriptive and analytic statistical processing of the data. RESULTS: There is
      an excessive intake of lipids, saturated fats and cholesterol in both sexes. The
      caloric contribution in the form of complex carbohydrates and fiber is
      insufficient. The average intake of nutrients is sufficient, except for vitamins
      A and B6, folate, calcium, magnesium and zinc in both sexes and phosphorous and
      iron in girls. The dietary models of boys and girls present significant
      differences in nutrients. CONCLUSIONS: The dietary pattern moves away from the
      balance of the Mediterranean diet and it is characterized by an excessive intake
      of meat, fats, sugars and candies, refined products and alcohol, as well as an
      insufficient intake of fruits, fresh vegetables, whole cereals, fish and low-fat
      dairy products. This results in an excessive intake of saturated fats and
      cholesterol, as well as an insufficient average intake of vitamins A and B6,
      folate, calcium, magnesium, zinc and iron.

PMID- 10394187
TI  - [High rate of early hospitalization in healthy newborns].
AB  - OBJECTIVE: The length of hospital stay of healthy term newborns and their mothers
      varies in different developed countries. The American Academy of Pediatrics
      defines early postpartum discharge (EPD) as a discharge occurring within 48 hours
      of postpartum. EPD has been advocated by patients as part of the humanization of
      care after delivery and by health services as a more efficient management of
      resources. Controversies in relation to EPD focus on its impact on initiation and
      maintenance of breastfeeding, the possible increase of readmissions of newborns
      with jaundice and the influence on newborn screening for endocrine and metabolic
      disorders. PATIENTS AND METHODS: Five years ago we started an EPD program for
      healthy term newborns. We present a descriptive observational study including a
      series of 2798 consecutive live newborns over a period of 19 months (April 1996
      to October 1997). Data about breastfeeding at the time of discharge, coverage of
      hypothyroidism and phenylketonuria screening and readmissions for newborn
      jaundice were collected during this period. RESULTS: During the defined period of
      time, 2798 live newborns were registered. Of these, 2109 (75.38%) were included
      in the EPD group, the majority of them (75.86%) between 24 and 40 hours
      postpartum. Breastfeeding was implemented in 95.82% of the newborns, 3.56% of the
      mothers decided to use artificial formulas and 0.52% were prescribed artificial
      formulas due to health problems in the mother. In relation to newborn screening
      of endocrine and metabolic diseases, we found similar coverage of hypothyroid
      screening compared to the other 7 maternities in our province (public and
      private) and of phenylketonuria screening compared to the other 5 primary care
      districts. Regarding newborn jaundice, we detected 47 readmissions, which is
      2.23% of the total EPD. These newborns were treated with phototherapy and none
      required exchange transfusion. The mean value of total serum bilirubin at the
      time of readmission was 18.7 mg/dl, with a range between 15.1 and 22.6 mg/dl.
      CONCLUSIONS: In our experience, 75.38% of live newborns were included in a EPD
      program that has been shown to be safe in relation to controversial subjects,
      although the limitations of an observational study must be taken into
      consideration. The safety of this program is inferred by the high proportion of
      breastfeeding on EPD (95.82%), coverage of endocrine and metabolic screening
      comparable to other surrounding hospitals and adequate control of
      hyperbilirubinemia in the newborn period.

PMID- 10394188
TI  - [Brachial plexus palsy associated with birth. A review of 30 cases].
AB  - OBJECTIVE: Our objective was to perform an updated analysis of the incidence and
      risk factors during pregnancy and labor related to obstetrical brachial palsy.
      PATIENTS AND METHODS: A retrospective study of all cases of brachial palsy
      associated with birth detected in our hospital between January 1994 and March
      1998 was performed. Data recorded included age of mother, parity, gestational age
      at the moment of birth, type of birth, presentation, duration of delivery, sex of
      child, weight, Apgar test at 5 minutes, arterial pH of umbilical cord, type of
      brachial palsy, side affected and association with other injuries. RESULTS:
      Thirty cases of brachial palsy associated with birth were diagnosed. The
      incidence was 1.04%. In addition to a high birth weight, other factors related to
      the increase in the incidence of obstetric brachial palsy were the presence of
      dystocia of shoulders at birth, the use of forceps and Apgar and pH under the
      usual limits. No case of distal paralysis was found. CONCLUSIONS: This study
      demonstrates the influence of the risk factors known in the development of
      brachial palsy associated with birth. However, it also establishes doubts about
      the etiology of traction as the only cause. In addition, it stresses the
      necessity of adequate birth planning of babies suspected of being macrosomic.

PMID- 10394189
TI  - [Osteoarticular infection by Kingella kingae: two case reports].

PMID- 10394190
TI  - [Severe intrauterine and postnatal lead poisoning].

PMID- 10394191
TI  - [Congenital cutaneous candidiasis: a disease to remember].

PMID- 10394192
TI  - [Persistent csf abnormalities in neonatal meningitis due to Streptococcus
      agalactiae].

PMID- 10394193
TI  - [Biotinidase deficiency: importance of its neonatal diagnosis and early
      treatment].

PMID- 10394194
TI  - [Stylohyoid syndrome in childhood].

PMID- 10394196
TI  - [Non-neurological characteristics of Gm1 gangliosidosis type 1. A report of three
      cases within the same family].

PMID- 10394195
TI  - [X-linked adrenoleukodystrophy. A case report].

PMID- 10394198
TI  - [Epidemiology and methodology applied to pediatrics (V): biases].

PMID- 10394197
TI  - [Acute osteomyelitis after plantar puncture].

PMID- 10394199
TI  - [Advances in the study of pediatric infectious diseases].

PMID- 10394200
TI  - [Asymptomatic persistent hyperphosphatasemia of non-genetic origin (APHN). A
      report of a new case].

PMID- 10394201
TI  - [Vaccinal failures after the immunization with vaccine against H. influenzae type
      B].

PMID- 10394202
TI  - [High risk in patients with Creutzfeldt-Jakob disease. Specific protective
      measures for the medical personnel].

PMID- 10394203
TI  - [Conservative treatment of the BPH syndrome. Diagnosis and drug therapy].

PMID- 10394204
TI  - [Interventional therapy of BPH syndrome].
AB  - The invasive treatment modalities available for BPH can be divided into
      interstitial therapy without removal of tissue (e.g. stents), and those involving
      delayed tissue ablation (thermal/coagulation procedures, e.g. laser ablation,
      microwave thermo-ablation, high-intensity ultrasound). The latter procedures
      (coagulation) more often permit a non-bloody intervention, the sphincter usually
      remains uninjured, and retrograde ejaculation is less frequent. A third group of
      options is interventional treatment with immediate ablation of tissue
      (vaporization, resection), which is more invasive and associated with a higher
      risk of complications than the two first-mentioned groups. An advantage of these
      options is the avoidance of a longer-term catheterization with its associated
      risks. Help is provided for deciding which procedure should be used in which
      patient.

PMID- 10394205
TI  - [The future of pancreas diagnosis. An exclusive training service of the Gastro
      Ligue for dermatologists].

PMID- 10394206
TI  - [Smoking withdrawal in practice and clinic].

PMID- 10394207
TI  - [Is non-toxic cancer therapy through biotechnology a possibility?].

PMID- 10394208
TI  - [Gene diagnosis in the hand of the physician].

PMID- 10394209
TI  - [Galenic alternatives to unstable tocopherol acetate. "Smeared" or cheated?-
      Vitamin E in facial ointments].

PMID- 10394210
TI  - Orthodontics at the turn of the century. A discussion of some relevant aspects.
AB  - Some changing paradigms, that might influence orthodontics in the future, are
      being discussed: economic problems related to our welfare systems; development of
      the media societies; concepts of normality; future changes as regards the type of
      treatment records; evaluation of treatment outcome; "exaggerated orthodontics?";
      orthodontics and facial aesthetics; Newtonian paradigms and scientific
      revolution; the growth of knowledge; phenomenology; tacit knowledge; decision
      making.

PMID- 10394211
TI  - X-ray diagnosis of impacted upper canines in panoramic radiographs and computed
      tomographs.
AB  - Ten orthodontists were asked to diagnose the number of impacted upper canines and
      the number of resorbed lateral and/or central incisor roots in 30 panoramic
      radiographs (P1) from 30 patients. In order to objectify these diagnoses,
      transversal CT images of all 30 patients were examined in addition. Addition of
      the recordings in the 30 patients revealed that the 10 orthodontists had
      diagnosed 350 impacted/displaced canines. On comparison of the P1 and CT results,
      the latter revealed that, in fact, 390 canines were impacted or displaced, not
      just 350. Addition of the recordings further showed that, based on P1, the
      investigators had diagnosed 73 resorptions in the 1,200 incisors examined.
      However, the CT showed 160 resorptions; this corresponds to a sensitivity value
      of 45.6%. The CT showed 1,040 incisors with no resorptions, whereas the
      investigators diagnosed only 925 teeth as not resorbed in the P1. The specificity
      was thus 88.9%. These results show that, due to their low reliability, panoramic
      radiographs are not an appropriate means of diagnosing resorptions in front teeth
      in connection with impacted canines.

PMID- 10394212
TI  - Validity of the computer-assisted cephalometric growth prognosis VTO (Visual
      Treatment Objective) according to Ricketts.
AB  - The computer-assisted growth prognosis "Visual Treatment Objective" (VTO)
      according to Ricketts gives an individual prediction based on empirically
      obtained mean growth rates and includes the expected influence of orthodontic
      treatment. The objective of the present study was to investigate the validity of
      the VTO over a period of 2 and 5 years. For this purpose, lateral
      teleradiographic images of 180 patients were analyzed before the start and after
      the completion of active treatment, and the actual outcome was compared with the
      prognosis. For both prognostic periods, the VTO yielded a satisfactory prognosis
      of maxillary inclination, of the anteroposterior position of the maxilla, of
      growth in mandibular length, of the anteroposterior position and rotation of the
      mandible, of the positional relation of the mandible and maxilla, of basicranial
      configuration, and of vertical craniofacial development. For neither of the 2
      prognostic periods did the VTO give a satisfactory prognosis of dental relations,
      of dentoskeletal relations or of soft-tissue configuration. The VTO is capable of
      giving a largely valid prognosis of skeletal growth tendencies. However, in view
      of the large number of parameters affected by therapeutic measures, the VTO
      prognosis must be expected to differ from the actual treatment outcome.

PMID- 10394213
TI  - Cephalometric differentiation between vertical and horizontal malocclusions in
      122 Europeans using the Denture Frame Analysis and standard measurements.
      Differentiation between vertical and horizontal malocclusion.
AB  - This study evaluated the ability of some cephalometric measurements to
      differentiate between horizontal and vertical malocclusions and normal occlusion.
      Based upon the Angle classification and the vertical incisor overbite, 122
      randomly selected subjects were assigned to 3 horizontal and 3 vertical groups:
      neutrocclusion, distocclusion, mesiocclusion as well as open bite, normal
      overbite, and deep bite. Evaluation of the lateral cephalograms was based on
      Denture Frame Analysis and cephalometric standard measurements (SNA, SNB, ANB,
      Wits appraisal, Bjork polygon, overbite depth indicator, incisor inclination,
      incisor protrusion, facial height ratio). The statistical evaluation assessed the
      ability of the measurements to show significant differences between the
      individual horizontal and vertical groups. Using Denture Frame Analysis, all
      vertical groups could be differentiated by the occlusomandibular angle (OP-MP)
      and all horizontal groups by the angle between the A-B plane and the mandibular
      plane as well as by the inclination of the upper incisors to the A-B plane with
      statistical significance (p < 0.05). Among the standard measurements, the Wits
      appraisal was the only one to show differences between all horizontal groups with
      statistical significance. None of the standard measurements could fully
      differentiate the vertical groups. The above measurements from the Denture Frame
      Analysis distinguished the types of malocclusion in anteroposterior and vertical
      direction including significant distinction between the neutrocclusion group and
      the malocclusion groups. Therefore a cephalometric classification was feasible in
      terms of hyper- and hypodivergence as well as of a mesial or distal dentofacial
      relationship.

PMID- 10394214
TI  - Systematic decalcification prophylaxis during treatment with fixed appliances.
AB  - In a practical setting, 4 different prophylactic methods were compared with
      regard to their effects on the incidence of decalcification during orthodontic
      fixed appliance therapy and on the frequency of premature debonding resulting
      from imminent or already manifest decalcification. This study showed that the use
      of a system in which selection and care were oriented solely along the clinical
      impression was associated with the highest rate of decalcification and premature
      debonding. The findings were significantly better (p < 0.05), when a prophylactic
      regimen of oral hygiene was implemented which was based on patient selection (API
      < 30%) and regular oral hygiene check-ups during the treatment. When the DMFT
      index was considered in addition to the API value, and the number of the initial
      lesions at the beginning of treatment were included for selecting patients, the
      incidence of decalcification was significantly reduced even further (p < 0.05). A
      more comprehensive or "optimized prophylaxis" utilizing saliva test parameters
      and active prophylactic interventions implemented by a dental hygienist during
      the treatment phase also had a favorable impact on the main outcome parameters.
      The present findings indicate that decalcification can be markedly reduced by
      using a treatment regimen that targets the decalcification risk and a systematic,
      individualized prophylaxis during active treatment with fixed appliances.

PMID- 10394215
TI  - The influence of caries of the deciduous teeth upon development of the dentition
      in patients with cleft lip, jaw and palate.
AB  - In 417 children aged 3 to 8 years with cleft lip, jaw and palate, the prevalence
      of caries and the degree of treatment of deciduous teeth were compared with those
      of 258 cleft patients who had received preventive treatment. The prevalence of
      caries was reduced by more than 50% by preventive treatment. A statistically
      significant effect of the cleft on the prevalence of caries could not be
      demonstrated. Longitudinal investigations on casts showed reduction of leeway
      spaces in consequence of caries and early extractions. Recommendations are made
      for curative pediatric dental treatment.

PMID- 10394216
TI  - Approaching the new millennium.

PMID- 10394217
TI  - Professional links: an international program for nursing knowledge exchange.
AB  - A review of current literature reveals that health problems are remarkably
      similar worldwide. Achieving optimal health outcomes more efficiently and cost
      effectively has become a focus of health care providers throughout the world.
      Although issues are complex, collective strategies can improve health outcomes.
      Nursing must share in this responsibility by establishing collaborative working
      relationships with local, national, and international colleagues to seek joint
      solutions to common problems. The international exchange program, Professional
      Links, was established to foster such collaboration among professional nurses.
      The program generates the exchange of ideas and innovations between centers of
      health care excellence and perpetuates sharing and learning among nurses for the
      purpose of accomplishing optimal pediatric health at a global level.

PMID- 10394218
TI  - Developing guidelines for smoking cessation interventions for pregnant
      adolescents.
AB  - More than 400,000 deaths a year in the United States are attributed to active and
      passive tobacco smoke exposure. Healthy People 2000 objectives target a reduction
      in the tobacco use of high-risk populations such as youth and pregnant women.
      This article describes guidelines for health professionals to address smoking
      cessation when working with pregnant adolescents and teen mothers who smoke.

PMID- 10394219
TI  - Mothers' experiences of living worried when parenting children with spina bifida.
AB  - This study describes the lived experience of mothers of children with spina
      bifida. Thirteen mothers of children between the ages of 12 and 18 years
      participated in at-home, audiotaped interviews. Each participant was asked to
      describe, through narrative, what it is like to be the mother of a child with
      spina bifida. The researcher used Heideggerian hermeneutical methodology to
      transcribe and analyze interview texts. Examination of the data revealed the
      constitutive pattern living worried and its two relational themes: treating them
      like other children and staying in the struggle. Nurses can use narratives to
      create supportive relationships with mothers of children with disabilities and to
      pursue research that extends the understanding of these women and their
      struggles.

PMID- 10394220
TI  - Well-being of families with healthy and technology-assisted infants in the home:
      a comparative study.
AB  - This descriptive, correlation study was guided by the Double ABCX Model of Family
      Adjustment and Adaptation. The purpose was to explore the relationships between
      stressors/strains, coping, and well-being of families with healthy and technology
      assisted infants. A total of 172 families participated in the study (Healthy: n =
      87; Technology-assisted: n = 85). The families completed a demographic
      instrument, Family Inventory of Life Events; Family Crisis Oriented Personal
      Evaluation Scale; and Family Well-Being Assessment Scale. Increased
      stressors/strains were related to decreased family well-being. There were
      significant differences between families with healthy and technology-assisted
      infants. Families with technology-assisted infants experienced more
      stressors/strains and lower well-being than families with healthy infants.
      However, level of coping for both groups was high; there was no significant
      difference between the two groups with regard to family coping.

PMID- 10394222
TI  - Head start: program and legislative update.

PMID- 10394221
TI  - Adolescent sexuality and sexually transmitted diseases: attitudes, beliefs,
      knowledge, and values.
AB  - This study described rural adolescents' attitudes, beliefs, knowledge, and values
      with regard to sexuality and sexually transmitted diseases (STDs). Rotter's
      Social Learning Theory (1954) provided the theoretical framework for this
      descriptive, correlational design. The convenience sample consisted of 170
      students from one rural high school. Consistent with past studies, results
      included the following: participants had more correct than incorrect knowledge
      related to sexual intercourse and STDs; the majority had positive attitudes
      toward condom use and believed it was OK for peers to have sex with a "steady;"
      the value of an exciting life correlated positively with attitudes toward sex;
      knowledge of sexual intercourse correlated positively with attitudes toward
      condom use; and the value health correlated positively with knowledge of sex and
      attitudes toward condom use, and negatively with attitudes toward sex. The
      findings in this study suggest the need for ongoing research with adolescents in
      the area of sexuality and STDs. Additionally, the findings support past studies,
      which revealed that knowledge of sexual intercourse and STDs has little impact on
      attitudes toward sexual intercourse. With the serious nature of some of the
      undesired consequences of adolescent sexual behavior, current and accurate
      information on this population is needed to assist health educators in developing
      interventions in this area.

PMID- 10394223
TI  - A survey of pediatric nurses' knowledge about breastfeeding.
AB  - The purpose of this study was to obtain baseline data on pediatric nurses'
      knowledge about breastfeeding, to inform an education program being developed in
      a large Melbourne pediatric teaching hospital. A pediatric breastfeeding
      questionnaire was developed. A random sample of 278 nurses in a variety of
      clinical units was selected. The questionnaire return rate was 54%. Overall, the
      difference in the mean percentage knowledge scores between the most experienced
      and the least experienced nurses was small. The result indicate that an ongoing
      lactation education program and a Breastfeeding Day-Stay Unit would benefit
      nursing staff, mothers, and babies.

PMID- 10394224
TI  - Parenting of at-risk infants in the face of uncertainty: home apnea monitoring of
      subsibs.
AB  - This article describes the experiences of a group of parents in New Zealand who
      lost infants to sudden infant death syndrome (SIDS) and who monitored their
      subsequent infants or subsibs (infants born after the death of an infant due to
      SIDS) at home for signs of apnea. Their caregiving experiences are explored
      within the framework of the substantive theory developed by Cohen (1993) that
      describes how another group of parents, those caring for children with chronic
      life-threatening illnesses, copes with living under conditions of sustained
      uncertainty. Attention is drawn to the similarities in both the grieving
      processes and coping strategies used by both groups of parents in these parallel
      situations.

PMID- 10394225
TI  - Sentinel lymph node mapping for staging breast cancer: preliminary results of a
      prospective study.
AB  - Axillary lymph node dissection is the gold standard for staging breast cancer,
      but it is associated with significant morbidity and complications. Sentinel lymph
      node mapping technique has demonstrated a successful detection of the node or
      nodes more likely to have metastasis. Two techniques are being used to detect
      sentinel lymph node-intraoperative use of gamma detecting probe after injection
      of radio tracer preoperatively and the injection of blue dye and lymphatic
      mapping intraoperatively. We used both techniques. Twenty-four patients underwent
      sentinel lymph node mapping. Blue dye and gamma detecting probe identified
      sentinel lymph nodes in 78% and 77% of patients, respectively. Overall, 23 of 24
      patients had a sentinel lymph node identified (96%). Ten patients had metastatic
      disease in the axilla. Out of these ten patients the only positive node/nodes
      were the sentinel lymph node in six patients. The other four patients had
      positive non-sentinel lymph node along with positive sentinel lymph node. All of
      the patients who had metastatic disease in the axilla were detected by the
      sentinel lymph node mapping technique. Therefore, no patient had positive non
      sentinel lymph node if the sentinel lymph node was negative. This technique was
      100% predictive of the axillary status. Sentinel lymph node mapping technique
      will change the management of breast cancer and will allow two-thirds of the
      patients with breast cancer to be managed without axillary lymph node dissection
      with a resulting reduction in morbidity and cost.

PMID- 10394226
TI  - Maryland's high cancer mortality rate: a review of contributing demographic
      factors.
AB  - For many years, Maryland has ranked among the top states in cancer mortality.
      This study analyzed mortality data from the National Center for Health Statistics
      (CDC-Wonder) to help explain Maryland's cancer rate and rank. Age-adjusted rates
      are based on deaths per 100,000 population from 1991 through 1995. Rates and
      ranks overall, and stratified by age, are calculated for total cancer mortality,
      as well as for four major sites: lung, breast, prostate, and colorectal. Because
      states differ in their racial/gender mix, race/gender rates among states are also
      compared. Although Maryland ranks seventh in overall cancer mortality, its rates
      and rank by race and gender subpopulation are less high. For those under 75,
      white men ranked 26th, black men ranked 20th, and black and white women ranked
      12th and 10th, respectively. Maryland's overall rank, as with any state, is a
      function of the rates of its racial and gender subpopulations and the relative
      size of these groups in the state. Many of the disparities between Maryland's
      overall high cancer rank and its lower rank by subpopulation also characterize
      the major cancer sites. Although a stratified presentation of cancer rates and
      ranks may be more favorable to Maryland, it should not be used to downplay the
      attention cancer mortality in Maryland deserves.

PMID- 10394227
TI  - Fat embolism syndrome in a case of abdominal lipectomy with liposuction.
AB  - Fat embolism syndrome is reported in a patient who underwent abdominoplasty and
      suction lipectomy for body contouring. Within 48 hours after surgery, she
      experienced adult respiratory distress syndrome, secondary to fat embolism
      syndrome. This was proven on bronchoscopy by evidence of fat laden macrophages.
      Aggressive respiratory support over 12 days resulted in patient survival.

PMID- 10394228
TI  - Effect of a disease management tool on residents' compliance with American
      Diabetes Association standard of care for type 2 diabetes mellitus. American
      Diabetes Association.
AB  - Diabetes mellitus is the fourth leading cause of death in the United States and a
      major cause of blindness and heart disease. Often, physicians do not comply with
      American Diabetes Association standards of practice. We report improved resident
      physicians' compliance with American Diabetes Association (ADA) standards of care
      for patients with Type 2 diabetes mellitus after the implementation of a disease
      management tool for diabetes mellitus.

PMID- 10394229
TI  - Imaging case of the month. Gallstone ileus.

PMID- 10394231
TI  - Epidemiology and Disease Control Program. May/June, 1999. Selected communicable
      diseases in Maryland in 1998.

PMID- 10394230
TI  - The health of merchant seamen in Baltimore and its history.
AB  - This article provides the history of health care provisions for seamen in
      Baltimore and presents an analysis of the distribution of diseases of merchant
      seamen in baltimore in 1995.

PMID- 10394233
TI  - [Algorithms for the initial management of precocious or delayed female puberty].
AB  - An algorithmic approach is proposed for the initial management of disorders of
      female puberty: premature pubarche and precocious or delayed breast development.

PMID- 10394232
TI  - [Image of the month. Recombinant FSH crystal observed in polarized light].

PMID- 10394235
TI  - [Genetic counseling and prenatal diagnosis].
AB  - Fetal medicine is in full expansion thanks to the tremendous progress made in
      both fetal access techniques and genetic analysis. In this article, we discuss
      the role of the genetician within a group of prenatal diagnosis and his
      contribution to the assessment of fetal diagnosis and prognosis. We describe the
      different approaches (invasive and non invasive) to fetal investigation i.e.
      ultrasonography, maternal serum screening, preimplantation diagnosis and FISH.

PMID- 10394234
TI  - [Contraception].
AB  - Prescribing a contraceptive method is a routine act in medical and gynecological
      practice. A large variety of available methods allows to adapt the prescription
      to most patients, taking care of contra-indications. In this review article, we
      will describe the various contraceptive methods available, their mechanisms of
      action and properties, highlighting their advantages and disadvantages.

PMID- 10394236
TI  - [Successful PMA. Review of the activities of the Center for Medically Assisted
      Procreation of University of Liege, 1985-1997].
AB  - Assisted reproductive treatments (ART) hold an increasing place in the field of
      female infertility but also of male infertility with the development of new
      micromanipulative technologies. From January 1985 to December 1997, more than
      3,000 ovarian punctures were achieved at the CPMA of the University of Liege and
      more than 40,000 oocytes were recovered. Global results show a take home baby
      rate of 23% per ovum pick-up and 27% per embryo transfer. Embryo cryopreservation
      offers an efficient solution to the problem of supernumerary embryos and opens
      the way for IVF-derived procedures such as oocyte or embryo donation, surrogate
      mother. The transfer of frozen-thawed embryos increases the total ongoing
      pregnancy rate per cycle of 31%. One of the aims of our Centre in the near future
      is the development of new technologies such as control of chromosomal
      abnormalities or genetic defect in preimplantation embryos and clinical
      applications of oocyte or ovarian tissue freezing.

PMID- 10394237
TI  - [Skin during pregnancy].
AB  - Hormonal modifications associated with pregnancy induce some physiopathological
      changes in the skin. The main alterations occur in the pigmentary and vascular
      systems. Other changes affect the dermis, hair growth and the sebaceous gland
      activity. Some infectious and auto-immune dermatoses are influenced by pregnancy
      and vice versa. Various dermatological treatments have a negative impact on the
      foetus. In addition, there exists a small number of specific dermatoses of
      pregnancy.

PMID- 10394238
TI  - [Ultrasound in obstetrics and gynecology: 3D ultrasonography].
AB  - The first paper concerning the use of ultrasound in soft tissue exploration was
      published in 1942. From that, following a logarithmic curve, ultrasound has
      become the main exploration technique in obstetrics and gynecology, essentially
      due to the absence of side-effect. In obstetrics, a new knowledge of the embryo
      and the fetus has been obtained. The morphology of the conceptus along the
      intrauterine life is more precisely defined. The fetal well-being and its
      metabolic function can be approached by the real time imaging and Doppler
      application. In gynecology, ultrasound has become the first imaging technique
      orientations, when mediet, the use of the others.

PMID- 10394239
TI  - [Drugs in pregnancy].
AB  - Since the dramatic observations of fetal abnormalities associated to thalidomide
      use during pregnancy, the risk of malformations when prescribing drugs in
      pregnant women is a well-known problem, among the public as well as among medical
      doctors. However, the complexity of the problem, the lack of robust scientific
      data and the emotional context characterizing this period make the prescription
      of medications to a pregnant woman a difficult task for every people involved in
      health care, the pharmacist, the general practitioner and even the gynaecologist.

PMID- 10394240
TI  - [Hypertension at pregnancy].
AB  - High blood pressure during pregnancy (BP > or = 140/90 mmHg) is sometimes already
      noted before conception, with usually a good prognosis (although it could
      predispose to preeclampsia). alpha-methyldopa is the best treatment when needed
      (agents blocking the renin angiotensin system are not recommended). Preeclampsia,
      a form of hypertension noted after 20 weeks of gestation with proteinuria is a
      more serious condition (BP > or = 140/90 mmHg or increase in BP from the 1st
      trimester > or = 25/15 mmHg). It is generated by placental ischemia and creates
      maternal endothelial lesions which in turn decrease the blood flow to placenta
      leading to maternal and fetal syndromes. Hospitalisation is mandatory. No measure
      other than delivery is known to attenuate or reverse its progression. Treating
      hypertension during pregnancy (when blood pressure > or = 170/110 mmHg) aims at
      preventing maternal risk (stroke or eclampsia) but has few effect on foetal
      lesions. Prevention of this syndrome, which represents the first secondary cause
      of hypertension, is until now disappointing.

PMID- 10394241
TI  - [Venous diseases and pregnancy].
AB  - The pregnancy and the puerperium are critical conditions for the venous system of
      the lower limbs. The risk of venous thromboembolism is important in the presence
      of contributing factors. The management of the disease (diagnosis, treatment,
      prophylaxis) has to be tailored to each individual patient. This period is also
      characterized by the appearance of specific varices or the aggravation of
      preexistent lesions. The treatment is mostly conservative including the use of
      elastic stockings. The post-partum condition is no contraindication for
      pregnancy, but requires a specific management.

PMID- 10394242
TI  - [Gestational diabetes: definition, screening and management].
AB  - Defined as glucose intolerance with onset or first recognition during pregnancy,
      gestational diabetes mellitus represents in fact an heterogeneous clinical entity
      which may concern 1 to 4% of all pregnant women in our country. Its adverse
      effects on the mother and her child, the need for a universal screening and the
      mode of screening are still controversial. Screening may be made either by a
      first test with a 50 g oral glucose load (the so-called O'Sullivan test),
      confirmed if positive by a 100 g oral glucose tolerance test (OGTT), or at first
      glance by a 75 g OGTT performed between the 24th and 28th weeks of gestation. The
      treatment of gestational diabetes is based on diet. In case of diet failure to
      obtain good glucose control, insulin therapy should be proposed.

PMID- 10394243
TI  - [Gestational diabetes: physiopathology and prognostic significance for the
      mother].
AB  - Pregnancy is associated with important changes in mother metabolism, especially
      in late gestation, among which a decreased glucose tolerance caused by insulin
      resistance. In some of these women, glucose intolerance is increased by a defect
      in B-cell function and diabetes mellitus occurs. These women who develop a
      gestational diabetes need a close follow-up because they are at high risk for
      further development of diabetes, especially type 2 diabetes.

PMID- 10394244
TI  - [Prevention of prematurity in the French community at the approach of the year
      2000].
AB  - The actual results confirm the dominating influence of psychosocial factors on
      prematurity and low birth weight. The study performed in Liege indicates that
      these factors must be taken into account for better care of the future mother.
      The systematic use of a prenatal questionnaire on psychosocial factors draws
      attention towards the personal situation of the future mother. Detection of some
      organic or psychosocial risk factors must prompt prophylactic measures even in
      the absence of any sign of pathologies. Prevention of prematurity has, over the
      last 30 years, been the primary objective of prenatal follow-up. Its importance
      must be further emphasized.

PMID- 10394246
TI  - [Anesthesia, analgesia and obstetrics: a high-risk association!].
AB  - The authors review the changes in obstetric anesthesia and analgesia that have
      contributed to a decreased maternal mortality as well as those accounting for the
      clinically significant improvements of maternal and neonatal morbidity.

PMID- 10394245
TI  - [HELLP syndrome].
AB  - The HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelet count) is a
      clinical expression of a multilayered disease whose central pathophysiology is
      abnormal placentation. Clinical research aims logically to search for new
      predictive and specific markers for the early identification of pregnant women at
      risk of developing a HELLP syndrome, the most common cause of feto-maternal
      mortality and morbidity.

PMID- 10394247
TI  - [Group B streptococcus, primary cause of life-threatening infections in infants.
      Epidemiology and prevention strategy].
AB  - As soon as the early 70's, group B streptococci (GBS) became clearly predominant
      in neonatal infections. There was a dramatic increase in the incidence of GBS
      neonatal sepsis and meningitis throughout developed countries and GBS emerged as
      the leading cause of severe neonatal infections. Most of these infections,
      associated with high mortality and morbidity, could be prevented by intrapartum
      chemoprophylaxis given to risk mothers. AAP, ACOG and the CDC issued guidelines
      for their prevention. Today, in Belgium, there are still no recommendations for
      the prevention of GBS early-onset infections.

PMID- 10394249
TI  - [Concerning some important sexual problems].
AB  - Sexology is the study of normal and abnormal sexual phenomena, as well as the
      treatment of sexual dysfunctions. Sexual science is at the dawn of its history,
      with many of its aspects--be they physiological or sociological--still awaiting
      investigations. It appears that about three-quarters of all cases of sexual
      dysfunctions can be handled by the general practitioner or by the gynecologist.
      As for the remaining patients, they should be referred to a psychologist
      sexologist or a psychiatrist specialized in sexual therapy. The practitioner has
      to be careful not to allow himself to be drawn in a situation of uncontrolled
      psychotherapy. First of all, he must begin with a full and systematic
      gynecological examination of the patient.

PMID- 10394248
TI  - [When the child does not appear ... supporting parents and medical staff during
      perinatal death].
AB  - The period of perinatal mourning, too often unrecognized, has nevertheless wide
      repercussions for the future of the parents and the family. Supporting the
      bereaved in a timely and sympathetic manner starts with the announcement of the
      death and continues with such positive actions as taking photographs, physical
      contact with the baby,... After the immediate period of bereavement, support
      groups bring the parents and the professionals together with considerably
      beneficial effects.

PMID- 10394250
TI  - [Hormone replacement therapy: practical recommendations].
AB  - In addition to vasomotor symptoms, trophic and functional urogenital problems,
      postmenopause is characterized by an increased risk of osteoporosis,
      cardiovascular disease and cognitive problems. The goal of estrogen replacement
      therapy is to reduce these risks. Numerous therapeutic schemes are available and
      allow to reach a better acceptance of the treatment and, in some cases, to avoid
      uterine bleeding. The goal of this individual adaptation of the treatment is to
      obtain the best benefit/risk balance for each patient, with the best clinical
      tolerance, allowing to continue the treatment as long as possible. Moreover, new
      molecules proposed as monotherapies have been recently marketed. In this article,
      we will review the various modalities of hormone replacement therapy, their
      advantages and disadvantages, and contraindications.

PMID- 10394251
TI  - [Inhibition of sexual desire associated with menopause].
AB  - Physicians or gynaecologists, specifically in their general practice or in the
      setting of a menopause clinic, are more and more frequently confronted to sexual
      complaints of menopausal women. Among these, decline in sexual desire is probably
      the most usually reported. The first study to evaluate a potential relationship
      between sexual functioning and menopause was conducted by Hallstrom in 1977.
      Thereafter, a review of the literature was able to show that there is nearly a
      consensus regarding the role of oestrogens in that condition. They effectively
      relieve vaginal atrophy and resulting dyspareunia. There is less agreement,
      however, regarding a direct effect of oestrogens on more complex sexual behaviour
      and motivation. When analyzing potential influence of sex hormones, oestrogens
      may exert a positive effect on the quality of the sexual relationship whereas
      androgens can definitely increase sexual "motivation" including sexual desire. In
      spite of the potentially important part played by androgens as promoters of
      libido and in the maintenance of sexual functioning in men and women, the exact
      role of the hormonal treatment in relieving sexual complaints still keeps
      controversial. In some women whose decline of sexual desire can be reasonably
      attributed to menopause, androgens in non-masculinizing adequate dosages, can be
      effectively included in the postmenopausal hormone replacement regimen. However,
      aetiology of diminished sexual motivation and desire is far from univocal
      particularly in the human being where psychological, social and cultural
      influences are endowed with a prominent importance. It is accordingly conspicuous
      that our sexual life is not reduced to hormonal fluctuations only. A short
      critical review of the literature devoted to the main aspects of changes of
      sexual desire associated with menopause is presented.

PMID- 10394252
TI  - [Cutaneous melanomas, a spectrum of emerging cancers in women of Wallonia.
      Outlook by the Mosan Study Group of Pigmented Neoplasms].
AB  - The Mosan Study Group of Pigmented Neoplasms was founded about 15 years ago. It
      has collected more than 20,000 cutaneous malignancies including melanomas and
      basal and squamous cell carcinomas. The incidence of these cancers is on the rise
      in Wallonia. In particular, malignant melanomas represent a spectrum of emerging
      cancers characterized by a proteiform biological outcome. They mostly affect
      young women. The major risk factor appears to be iterative and unwise ultraviolet
      exposures. The prevention of melanomas is basically founded on such a dogma and
      accordingly relies on sunscreens. However, controversies about their beneficial
      effects are rife and fueled by axiomas and contradictory sophisms. At the
      exception of surgery, the therapeutic options for the diverse types of melanomas
      do not yet fulfill the scope of evidence-based medicine.

PMID- 10394253
TI  - [Dermatologic diseases of the nipple and areola].
AB  - Several diseases of the nipple and areola have a specific dermatological
      presentation. They may be classified into five main categories including
      dysembryoplasias, mastalgia, inflammatory dermatoses, hyperkeratoses and
      neoplasms.

PMID- 10394254
TI  - [Evaluation of nonpharmacologic invasive treatment in cardiology: the example of
      implantable automatic defibrillators].
AB  - Substantial therapeutic advances have been achieved in cardiology in the last
      fifteen years. They are due to the progress of cardiovascular pharmacology and
      interventional cardiology. Many devices are now competing with drugs. In France,
      the evaluation procedures of these two types of treatment are highly different.
      The benefit/risk ratio is not evaluated sufficiently before the marketing
      authorization of the devices. The procedures leading to reimbursement by Social
      Security are completely different for the drugs and the devices, and
      harmonization of these procedures is essential. It could allow the avoidance of
      paradoxical situations such as that of the automatic implantable defibrillator
      whose efficacy is now validated by controlled studies; but payment for which is
      not reimbursed by Social Security. The consequence is a serious dearth of this
      item, the implantation ratio per million residents in France being lower than
      that of all neighbouring countries.

PMID- 10394255
TI  - [The problem of therapeutic efficacy indices. 1. Elements of the problem].
AB  - Efficacy indices measure the efficacy of therapies. They derive, by definition,
      from two quantities, the basal or control risk of event, Rc, observed in the
      control group, and the on-treatment risk, Rt, observed in the treated group. In
      clinical trials and meta-analyses, each is an unbiased measure of efficacy.
      Although they are a combination of frequencies, these indices are used in
      clinical practice to predict the benefit in treated patients. Their relevance to
      express efficacy depends on the type of clinical condition, and is better for
      acute diseases than for chronic diseases. In order to be useful for prescribers,
      they should meet certain specifications. In addition, they should be considered
      in the more general framework of effect models.

PMID- 10394256
TI  - [Patient-centered consultation of "good practice guidelines": OncoDoc, a decision
      support system for the management of breast cancer patients].
AB  - Beyond considerations of cost-effectiveness, clinical practice guidelines (CPG)
      can reduce practice variations and thus improve the quality of care. However,
      despite the proliferation of implemented CPG and their wide diffusion thanks to
      Internet-based technologies, physicians' compliance with formal standards is
      weak. Developed according to a document-based paradigm, OncoDoc proposes an
      original framework for implementing CPG. Domain knowledge has been encoded as a
      decision tree whose branches are both exclusive and exhaustive. This generic
      knowledge is operationalized at the point of care by the interactive building,
      through hypertextual navigation, of a patient-based clinical context leading to
      specific therapeutic recommendations. OncoDoc has first been applied to the
      management of breast cancer patients and demonstrated within a full-scale
      experimentation in a clinical setting a compliance of 80 per cent.

PMID- 10394257
TI  - Comparison of bisoprolol and verapamil in hypertension: influence on left
      ventricular mass and function--a pilot study.
AB  - The objective of this study was to test the influence of bisoprolol and verapamil
      on left ventricular filling in hypertensive patients in a 6 month randomized,
      double-blind trial in 54 hypertensive patients not previously treated with beta
      blockers or calcium inhibitors. After administration of placebo for 14 days, an M
      echocardiogram of the left ventricle was recorded to determine left ventricular
      mass. Blood flow was evaluated by pulsed Doppler sonography. After randomization
      into two groups, one group received 10 mg of bisoprolol and the other 240 mg of
      verapamil LP in a single dose in the morning. After 2 months' treatment, the
      patients whose blood pressure was not well controlled were given a diuretic. Echo
      Doppler was performed again by the same operator after 4-10 days on active
      treatment, after 6 months and after a subsequent 2 weeks of placebo for the
      patients treated with a single drug. The reduction in blood pressure was
      comparable in the two treated groups, but there was no significant decrease in
      left ventricular mass. Left ventricular filling was improved only in the patients
      receiving bisoprolol. The effect was observed immediately after the first
      administration and throughout the 6 months' treatment period declining slowly
      during the placebo wash-out. This effect appeared to be independent of any
      alteration in heart rate and was thought to be a specific action of this drug.

PMID- 10394258
TI  - [Renal differential aging processes and ofloxacin pharmacokinetics in the
      elderly].
AB  - Ageing generates an important inter- and intra-individual variability in drug
      pharmacokinetics. The increasing frequency of ofloxacin adverse effects in
      elderly patients results from increased ofloxacin plasma levels about two or
      threefold over normal concentrations. A retrospective study of ofloxacin
      population pharmacokinetics in 17 elderly patients (83.6 +/- 6.8 years) shows the
      existence of three subgroups according to ofloxacin total clearance [group 1:
      1.44 l/h, group 2: 4.37 l/h and group 3: 15.08 l/h] reflecting the important
      inter-individual variability. No correlation between this clearance and
      creatinine clearance, nor between this clearance and age, could be established,
      showing the limits of traditional drug monitoring in the elderly. Ofloxacin
      pharmacokinetic parameters estimated by the non-parametric software NPEM2 in the
      17 elderly patients (absorption rate constant, Ka: 2.668 +/- 1.256 h-1; apparent
      volume of distribution related to weight, Vs: 1.272 +/- 0.778 l/kg; elimination
      rate constant, Ks: 0.265 +/- 0.247 10(-3) min/ml/h) are clearly different from
      those estimated in young adults. These results show the limits of classic drug
      monitoring in the elderly, and also the interest of adaptive control of a drug
      regimen.

PMID- 10394259
TI  - [Adverse effects of glycolic irrigation solutions].
AB  - The aim of this study was to evaluate the frequency and the gravity of Trans
      Urethral Resection of the Prostate Syndrome or 'TURP Syndrome,' which occurs when
      irrigating fluids containing 1.5 per cent glycocolle are used. All the adverse
      effects that occurred with 5 products containing 1.5 per cent glycocolle which
      were notified to the pharmacovigilance structures in France were reviewed. The
      adverse effects notified comprised 24 cases of TURP Syndrome and 5 of renal
      failure. TURP Syndrome consisted of neurological signs (92 per cent);
      cardiovascular signs (54 per cent); visual disturbance (42 per cent) and
      digestive signs (25 per cent). Hyponatraemia occurred in all patients (mean 113
      +/- 6 mmol.l-1) and 25 per cent of patients died. In 27 per cent of cases TURP
      Syndrome occurred when glycocolle was in contravention of AMM guidelines. The
      Drugs Agency has requested that modification be included in the Vidal
      pharmacopoeia (warnings and adverse reactions) and on glycocolle bags and that
      surgeons and anaesthetists be informed.

PMID- 10394260
TI  - [Adverse effects and drugs for Alzheimer's disease].
AB  - Molecules currently available or in late phases of development for the treatment
      of Alzheimer's disease have modest and apparently equivalent efficacies. Thus,
      the choice will depend on the safety profile of these drugs and on the patient
      characteristics. The aim of this review is to undertake an inventory of adverse
      effects and interactions reported in the literature for anticholinesterasics (the
      only ones approved by authorities). As most of the molecules described in this
      article are still in early phases of development, data reported here mainly
      issued from clinical trials carried out on specific populations. Most of these
      reported adverse effects have not been attributed according to the rules of
      pharmacovigilance. Nevertheless, we believe that the data presented in this
      review will be of great interest to clinicians and pharmacovigilance specialists
      as the compounds concerned become available on the market.

PMID- 10394262
TI  - [Substitution treatment for opiate dependence: survey of community pharmacies in
      Aquitaine].
AB  - The prescription of maintenance treatment for opioid dependence has increased
      dramatically in France since the approval of high-dose buprenorphine in general
      practice. Community pharmacists are particularly involved since daily dispensing
      is recommended. A postal survey was conducted within a representative network of
      community pharmacies in Aquitaine, south-western France. The objective was to
      assess quantitative and qualitative data on these treatments in the region
      through pharmacists' opinions and experiences. Out of 61 responders, 62 per cent
      had already dispensed maintenance treatment. During the survey, 88 patients were
      under treatment at these pharmacies. Nearly 80 per cent of the pharmacists agreed
      with the dispensing of these treatments and more than 60 per cent had a positive
      opinion of them. Community pharmacists feel concerned by the treatment for opioid
      dependence.

PMID- 10394261
TI  - [Dependence on psychotropic drugs and substitution treatment: recent trends. The
      OPPIDUM study of the Centers for Evaluation and Information on Drug Dependence
      (CEIP), October 1997].
AB  - The aim of this study was to identify the latest trends in psychotropic drug use
      and the effect of the increase of maintenance treatments for serious opioid
      addiction. The results are based on data from OPPIDUM, an annual survey primarily
      concerned with the consumption of licit and illicit drugs. The study involved
      1066 drug addicts recruited during the month of October 1997 from 38 French
      health centres connected with the Centres for Evaluation and Information on Drug
      Addiction (CEIP). The most frequently reported drugs were benzodiazepines (n =
      323), some of which, especially flunitrazepam (Rohypnol, n = 123), are extremely
      addictive. The data showed a slight decrease in heroin consumption as well as a
      marked increase in the use of maintenance treatments. The association between
      benzodiazepines and buprenorphine (Subutex) should consequently be studied,
      whether buprenorphine is being used illicitly or prescribed as a maintenance
      treatment.

PMID- 10394263
TI  - [Morphine and neuropathic pain].

PMID- 10394264
TI  - [Acute anterior uveitis during treatment with fludarabine].

PMID- 10394265
TI  - [Case report of a patient treated with nicorandil who developed buccal
      aphthosis].

PMID- 10394266
TI  - [Dextropropoxyphene-paracetamol and general convulsive crisis: case report].

PMID- 10394267
TI  - [Recurrent subcutaneous edema induced by isotretinoin].

PMID- 10394268
TI  - [Zolpidem intoxication].

PMID- 10394269
TI  - Lack of adverse reaction when switching SSRIs to NASSRIs in polymedicated
      depressed inpatients.

PMID- 10394271
TI  - [Home-brew and hillbilly culture: attitudes, hypocrisy and health].

PMID- 10394270
TI  - Serotonin syndrome after sertraline, buspirone and loxapine?

PMID- 10394272
TI  - [Glaucoma].

PMID- 10394273
TI  - [Sentinel lymph node].

PMID- 10394275
TI  - [Intraocular contact lens to correct severe refractive error].
AB  - Collamer (collagen-acryl copolymer) intraocular contact lenses were implanted in
      the posterior chamber (sulcus) in phakic eyes to correct severe myopic patients.
      In addition to being myopic, they had visual problems (diminishing, contact lens
      coating) or direct organic eye problems (keratitis, conjunctivitis, vessel
      ingrowth in cornea) wearing glasses or standard contact lenses in everyday life.
      Seven lenses were implanted in four patients with preoperative myopia (spherical
      equivalents) ranging from -8.75 to -20.5 diopters (D), average myopia was -15.4,
      average follow up was 13.2 months. Mean postop myopia (spherical equivalent) was 
      1.96. Best spectacle-corrected visual acuity improved in all eyes with
      approximately two lines in Snellen's chart. No iritis or cataract was observed;
      one anterior angel closure required an additional iridotomia in one eye. The lens
      was well accepted, and a good functional outcome occurred within a short delay.
      The method holds promise as an important supplementary treatment for patients
      with severe refraction anomalies. It is, in fact, the only treatment for the most
      severe myopic and hypermetropic patients if they are to preserve their
      accommodative abilities.

PMID- 10394274
TI  - [Home-brew and alcohol drinking of adolescents].
AB  - Studies have shown that adolescents in Nordland county consume more alcohol than
      the national average, and that home-made liquor is an important element in the
      local alcohol traditions. We conducted a school based survey of 435 high school
      students in the municipality of Alstahaug, Nordland county, with a response rate
      of 85%. We found that home-made liquor was frequently consumed by students of all
      ages. Boys started drinking at an earlier age than girls, and continued drinking
      higher amounts. Access to alcohol was easy for students of all ages. The students
      bought alcohol themselves, had others buy it for them, or they made their own
      liquor. Nearly all interviewees who drank much beer, wine or brandy, also had a
      high consumption of home-made liquor. The consumption of liquor among adolescents
      in the Alstahaug community seems to be unusually high and warrants preventive
      action.

PMID- 10394276
TI  - [Normal tissue radiation toxicity in radiotherapy of localized prostatic cancer].
AB  - Radical radiotherapy of prostate cancer has to balance tumour control against the
      risk of radiation injury of normal tissue. The normal tissue toxicity is the main
      dose-limiting factor, and consequently a limiting factor of the curative
      potential of prostate cancer by irradiation. The SOMA scale is a new toxicity
      scoring system that registers late side effects from the most important
      anatomical sites. The SOMA scale is internationally approved and facilitates a
      standardised evaluation of radiation toxicity. The scoring system is based on
      four main components: subjective, objective, management and analysis. The SOMA
      scoring system was applied to a group of 21 patients from Ullevaal Hospital who
      were given intentionally curative radiation therapy for localised prostate
      cancer. The SOMA scale scoring system appears to be a valuable tool in the
      evaluation of normal tissue toxicity. It may contribute to a new standard in
      quality assurance of radiation therapy of prostate cancer.

PMID- 10394277
TI  - [Leptin--a fatty tissue hormone with many functions].
AB  - The importance of genetic factors in obesity is under investigation. During the
      last few years, our understanding of the regulation of body weight in mammals has
      broadened to include several new proteins based on the cloning of genes from
      rodent mutants and characterization of their effects on energy stores and
      metabolism. Since its discovery in 1994, leptin has been acknowledged as an
      adipocyte-derived signal molecule, able to limit food intake and increase energy
      expenditure by interacting with specific leptin receptors located in the central
      nervous system and in peripheral tissues. Leptin is also important for growth,
      reproduction and neuroendocrine signalling. Although leptin is mainly synthesized
      in adipocytes, it is also expressed in the placenta, epithelium of the stomach
      and breast glands and, under certain conditions, in skeletal muscles. The
      importance of leptin is demonstrated by the discovery of mutations in the genes
      encoding leptin and its receptor among some subjects with morbid obesity and
      infertility. Plasma concentration of leptin should be measured in obese infertile
      adolescents since replacement could be curative among individuals with leptin
      deficiency.

PMID- 10394279
TI  - [Familial Mediterranean fever].
AB  - Familial Mediterranean fever is a hereditary disease prevalent among populations
      in the Mediterranean area, characterized by sporadic episodes of acute
      inflammation primarily of the pleural, peritoneal and joint spaces. There is no
      diagnostic test for routine use. The disease is still uncommon in Norway, but we
      expect an increased incidence because of immigration. Due to the lack of
      pathognomonic features many patients undergo unnecessary explorative laparotomy
      before the diagnosis is established. In this report we present a patient with a
      typical history of familial Mediterranean fever. To our knowledge this is the
      first case ever published in Norway. It is important to keep the disease in mind
      as a differential diagnosis in patients with recurrent fever and pain, as
      colchicine represent an efficient treatment in order to prevent both further
      attacks and secondary amyloidosis.

PMID- 10394278
TI  - [Endometrial hyperplasia--diagnosis and treatment].
AB  - The International Society of Gynecological Pathologists recently agreed on a
      classification of endometrial hyperplasia into two main groups; hyperplasias with
      and without atypia. The lesions were further subdivided into simple and complex
      hyperplasia. These guidelines were subsequently adopted by the World Health
      Organization. The disease is a result of oestrogen/gestagen imbalance with
      oestrogen overexpression. The most important prognostic factor is cellular
      atypia. Progress to invasive cancer is seen in about 20% of the patients with
      atypical hyperplasia, and most frequently occurs in postmenopausal women. The
      treatment of endometrial hyperplasia depends on histologic type, patients' age
      and whether the hyperplasia is a result of endogenous or exogenous oestrogen
      overexpression. The risk for progression to invasive cancer is minimal in
      oestrogen treated patients with simple or complex hyperplasia without atypia.
      Women under 40 years of age in this group can safely be treated with gestagens.
      In postmenopausal women with simple or complex hyperplasia with atypia, the
      recommended treatment is surgery including removal of the uterus and the ovaries.

PMID- 10394280
TI  - [A 59-year old man with back pain and nocturnal sweating].

PMID- 10394281
TI  - [Is exercise therapy and manipulation effective in low back pain?].
AB  - We evaluated the effectiveness of exercises and manipulation on pain, disability
      and sick leave in a systematic review of randomized controlled trials including
      patients with low back pain. Low back pain is commonly a self-limiting illness
      and most patients are free of symptoms within 14 days. On the basis of 11
      studies, no additional benefits from exercises and manipulation were found in
      patients with acute complaints (0-4 weeks); thus, our results do not support
      guidelines that prescribe manipulation in the acute stage. One study found
      reduced disability and sick leave in the subacute stage (4-12 weeks) when
      patients were told that it was safe to move and this strategy was reinforced by a
      graded exercise program and visits to the workplace. Seven studies evaluated
      manipulation; the effectiveness was no better than other treatments or placebo.
      Based on seven studies in patients with chronic low back pain (> 12 weeks), there
      is strong evidence that exercises reduce disability and pain, but their
      effectiveness on sick leave is not documented. Four studies compared different
      exercise regimens, but found no evidence in favour of one particular method. The
      effectiveness of manipulation in patients with chronic pain is poorly documented.

PMID- 10394282
TI  - [Mobilizing or stabilizing exercise in degenerative disk disease in the lumbar
      region?].
AB  - Degenerative disc disease may affect younger and middle-aged people with a kind
      of premature disc degeneration. The majority of these low back pain patients are
      not candidates for a spinal fusion and are in need of a structured conservative
      treatment. In a controlled clinical trial, 27 low back pain patients (mean age 40
      years, range 25-48) with a mean duration of symptoms of 7.4 years, were
      randomized to mobilizing (n = 12) or stabilizing (n = 15) daily half hour
      exercise for an eight weeks period. A clinical overall score (COS) based on pain
      intensity (VAS), physical signs, functional status (Oswestry) and analgetics was
      used as outcome criterion. The treatment results were best for the group
      undergoing stabilizing treatment. They achieved a 17% reduction in COS, compared
      to a 10% increase in the group undergoing mobilizing treatment (p = 0.02). These
      types of exercises are discussed in relation to the instability theory in disc
      degeneration.

PMID- 10394283
TI  - [Chiropractic in general and in low back pain].
AB  - The practice of chiropractic was for many years regulated by "The Quack Act" in
      Norway, and the numbers of chiropractors decreased year by year. They are now
      authorized health care practitioners with academic training; most Norwegian
      students attending courses in chiropractic or clinical biomechanics go to
      European universities. An international council ensures reciprocity and a quality
      assured academic programme in all recognized colleges of chiropractic. Recent
      research have broadened our understanding of the biomechanical interrelationship
      between the nervous system, the musculature and the skeletal articulations. In
      the early 1990s, several studies documented favourable effect of chiropractic
      treatment of low back disorders. These studies are now substantiated by new
      studies, especially concerning cost-effectiveness. Several reports also give
      evidence that chiropractic manipulation is beneficial especially in combination
      with light exercise. There are conflicting results concerning the efficacy of
      varying types of exercise programmes. Patients may benefit from increased
      cooperation between medical doctors and chiropractors. Most acute low back
      syndromes should be assessed by the chiropractor in order to prevent chronic
      illness.

PMID- 10394284
TI  - [Physiotherapy as manual therapy].
AB  - Manual therapy includes methods where the therapist's hands are used to stretch,
      mobilize or manipulate the spinal column, paravertebral structures or extremity
      joints. The aims of these methods are to relieve pain and improve function. In
      Norway only specially qualified physiotherapists and chiropractors are authorized
      to perform manipulation of joints (high velocity thrust techniques). To become a
      qualified manual therapist in Norway one must have a minimum of two years of
      clinical practice as physiotherapist followed by two year full time postgraduate
      training in manual therapy (a total of six years). Historically the Norwegian
      manual therapy system was developed in the 1950s by physiotherapists and medical
      doctors in England (James Cyriax and James Mennell) and Norway. As a result
      doctors allowed physiotherapists to use manipulation as a treatment method of
      both spinal and peripheral joints. In 1957 the Norwegian health authorities
      introduced reimbursement for manual therapy performed by physiotherapists.

PMID- 10394285
TI  - [Pharmacological principles for the treatment of heroin abuse].

PMID- 10394286
TI  - [Is there a rational need for sleeping pills of group B?].

PMID- 10394287
TI  - [Increasing drug abuse problems "down under"].

PMID- 10394289
TI  - [Prevention of influenza in nursing homes].

PMID- 10394290
TI  - [Electronic databases and studies on hospital mortality].

PMID- 10394291
TI  - [The structural and functional levels of the vascular system and brain pathology
      in atherosclerosis and arterial hypertension (experience with systems analysis)].

PMID- 10394292
TI  - [The safety problems of new vaccines].
AB  - The paper characterizes the etiological factors that produce side effects and
      postvaccinal complications. It presents a classification of the types of sides
      effects. The study of the immunological safety of vaccines is a new trend in
      assessing the quality of vaccines and their standardization. Due to the design of
      new-generation vaccines (gene-engineering, synthetic, DNA vaccines, etc.), their
      safety gain in their particular significance. It is necessary to make a strict
      government surveillance over the design, testing of these agents. Possible ways
      of reducing the adverse effects of vaccines.

PMID- 10394293
TI  - [The evaluation of the human immune system: the complexities and achievements].

PMID- 10394294
TI  - [From transplantation of the thymus to molecular reconstruction of the immune
      system].
AB  - The results of the first global grafting of the thymus and a thymus-sternum block
      are given. The grafting of immunocompetent organs in children with the Louis-Bar
      syndrome is shown to cause to a partial and in some cases significant recovery of
      immunological parameters. Thus, blast-cell transformation showed 10-40%
      increases, the titers of antibodies to Staphylococcus and Escherichia coli rose,
      and immunoglobulin A that was generally absent in these children before surgery
      appeared. The clinical effect of grafting was noticeably observed 20-30 days
      after surgery. The most significant parameters were as follows: cessation of
      sinusitis, rhinitis, bronchitis, and purulent skin lesions. Neurological
      syndromes improved: tremor and staggering gait diminished, ocular convergence
      normalized. Thereafter such operations were made in 27 patients with Bruton's
      disease and in 3 patients with lymphogranulomatosis. The grafting of
      immunocompetent organs led to the design of agents derived from the thyroid gland
      (Tactivin) and bone marrow (myelopid). The immunobiological and clinical effects
      of Tactivin in the past 15-20 years are given in detail. The basic principles in
      immunomodulating therapy with thymic agents are presented.

PMID- 10394295
TI  - [The immunodiagnosis and immunotherapy of tumors].
AB  - Recent studies into the immunology of tumors have allowed the oncological use of
      immunological methods to be substantially extended. This increases the
      potentialities of immunodiagnosis, primarily to identify a number of tumor
      associated antigens, which has promoted early differential diagnosis and
      monitoring of the course of disease. On the other hand, diagnosis of
      immunodeficiencies in cancer patients has become better: a panel of monoclonal
      antibodies to differentiated immunocompetent cell antigens has been developed,
      their subpopulations revealed, the time course of whose quantitative composition
      correlates with the clinical course and prognosis of disease. Evidence for
      immunological disorders serves as a basis for using different immunotherapies in
      the complex treatment of cancer patients. Present-day oncological care uses a
      great variety of immunomodulators; however, preferable treatment includes
      cytokines (interferons, interleukins) whose application substantially enhances
      the efficiency of treatment in patients having certain tumors. Progress in
      biotechnology and gene engineering has contributed to the development of new
      trends in the therapy of tumors, namely the design of anticancer vaccines
      obtained by inserting the genes of cytokines and their receptors, tumor
      associated antigens and other agents into the genome of a tumor cell. So far
      single clinical observations are yielding promising results.

PMID- 10394296
TI  - [The targetted delivery of antitumor preparations by using protein vectors].
AB  - The prospects of the endocytosis-mediated targeted delivery of antitumor drugs to
      the target cells by means of vector proteins, such as nerve growth factor (NGF),
      epidermal growth factor (EGF), and the oncofetal protein alpha-fetoprotein (AFP),
      are discussed. The high selectivity and efficiency of antitumor effects of
      synthetic covalent EGF- and AFP-conjugates with chemical agents (antitumor
      antibiotics) and antisense oligonucleotides are compared with individual
      biologically active compounds in in vitro and in vivo animal studies. The
      molecular mechanisms of action of the above conjugates have been studied.
      Evidence is given for the fact that it is expedient to use them to overcome
      multidrug resistance in the clinical setting. The findings are the first
      important step in designing novel target antitumor drugs based on biologically
      active vector proteins showing their effects by receptor-mediated endocytosis.

PMID- 10394297
TI  - [The regulatory functions of pro-inflammatory cytokines and acute-phase
      proteins].
AB  - The paper provides a brief review of recent basic studies made by the Department
      of Immunology, Institute of Experimental Medicine, Saint Petersburg. They show
      that with a panel of macrophage-like cell lines of varying maturation (P388D, THP
      1, U937, HL-60), the ability to produce TNF alpha spontaneously and to synthesize
      TNF alpha in response to atherogenic low-density lipoprotein stimulation
      correlates with the degree of cell differentiation that can be in turn induced by
      agents such as phorbol myristic acetate. The TNF alpha molecular site responsible
      for the macrophage-activating action of TNF alpha was identified as peptide 123
      131. The latter was demonstrated to be uninvolved in the cytotoxic activity of
      TNF alpha. In addition to its activating and modulating effects against
      neutrophils, monocytes, and lymphocytes, the acute-phase reactant C-reactive
      protein was found to be able to bind the antiinflammatory cytokines IL-4 and TGF
      beta.

PMID- 10394298
TI  - [The immunological aspects of maternal-fetal interrelationships].
AB  - The paper deals with different aspects of the relationships occurring between the
      pregnant woman and the fetus having paternal antigens. Analysis of a great deal
      of recent information clearly indicates that local uterine immunity plays a great
      role during pregnancy. The specific features of the gene expression of major
      histocompatibility by an invasive trophoblast and the immunosuppressive function
      of placental fibrinoid are discussed. A detailed account of the immunocompetent
      cells, including T lymphocytes, giant granular lymphocytes, and macrophages, that
      are involved in immunological responsiveness within the decidua is given.

PMID- 10394299
TI  - [Immunological imbalance in the newborn infant and its correction in a system to
      prevent neonatal morbidity and infant mortality].
AB  - Immunological changes were examined in neonates having a different clinical
      status and varying effects of immunomodulation. The paper shows it expedient to
      use intravenous immunoglobulin as part of a package of measures to nurse
      premature neonates. A method for evaluating the responsiveness of immunocytes in
      the newborn has been developed, which is based on the determination of the
      equilibrium between activation-induced T-cell proliferation and apoptosis.

PMID- 10394300
TI  - [Human resistance to generalized bacterial infections (exemplified by
      meningococcal infection)].
AB  - The hierarchical organization of human host defense systems against systemic
      bacterial infections is considered by using meningococcal disease as a model. The
      bactericidal action of the complement system is the most potent defense mechanism
      against meningococci. The antibody-independent alternative pathway of complement
      activation is more important in infancy. When the specific antibody level
      increases by natural immunization or vaccination, the antibody-dependent
      classical pathway of complement activation provides an additional protection. The
      bactericidal effect of human phagocytes, primarily neutrophils, is mediated
      partly by the receptors of complement components and immunoglobulins and serves
      as an additional mechanism of resistance. The relative risk of meningococcal
      disease may be approximately estimated as 1,000 for the individuals without blood
      complement bacteriolytic activity, as 80 for those without specific bactericidal
      antibodies, and as 3 for individuals with ineffective phagocytosis as compared to
      those with the normal complement system, high levels of bactericidal antibodies,
      and effective phagocytosis by neutrophils.

PMID- 10394302
TI  - [Adaptogens as agents for prophylactic oncology].
AB  - The paper considers whether it is advisable to use the new acting preparations
      adaptogens, including phytoadaptogens, in oncological care for prevention of
      cancer. The adaptogens are shown to have a regulating action, to be able to
      activate the protective properties of the body, to protect it from extreme
      exposures and to stimulate regenerative processes. The author associates the
      antitumor effect of adaptogens with the immunomodulating (they can activate
      macrophages, natural killer cells, antigen-dependent T lymphocytes) and
      interferonogenic actions and with the their ability to suppress experimental
      tumor growth, to enhance tissue differentiation, to improve intercellular
      adhesion, to reduce the likelihood of metastasis spreading. Furthermore, the use
      of adaptogens, and phytoadaptogens in particular, decreases the toxic effects of
      chemotherapy and improves drug tolerance.

PMID- 10394301
TI  - [Immobilized antigenic preparations with magnetic properties in the diagnosis and
      treatment of rheumatic diseases].
AB  - A procedure was first developed to prepare the immobilized granulated antigen
      agents (IGAA) based on collagens of types I, II, III, IgG, native DNA, RNA,
      cardiolipin, superoxide dismutase, and glutathione reductase. The agents were
      applied to both immunofluorescence and enzyme immunoassay to identify specific
      antibodies. IGAA were effective in early diagnosis, prognosis, and control of
      therapy for systemic lupus erythematosus, systemic sclerosis, rheumatoid
      arthritis due to their high capacity. These antigen agents were used in vitro and
      in vivo in hyperimmune laboratory animals as magnetic sorbents and exhibited high
      capacities and low traumatic properties for blood cells. IGAA may be regenerated,
      sterilized, and reused.

PMID- 10394303
TI  - Protecting public health in the face of uncertain risks: the example of diesel
      exhaust.

PMID- 10394304
TI  - The ebb and flow of radon.

PMID- 10394305
TI  - Elimination and reintroduction of a sexually transmitted disease: lessons to be
      learned?

PMID- 10394306
TI  - Diesel exhaust exposure among adolescents in Harlem: a community-driven study.
AB  - OBJECTIVES: This study sought individual-level data on diesel exhaust exposure
      and lung function among adolescents in Harlem as part of a community-driven
      research agenda. METHODS: High school students administered in-person surveys to
      seventh grade students to ascertain information on demographics, asthma history,
      and self-reported and maternal smoking. Urine samples were assayed for 1
      hydroxypyrene (1-HP), a marker of diesel exhaust exposure, and cotinine, a marker
      of tobacco smoke exposure. Computer-assisted spirometry was used to measure lung
      function. RESULTS: Three quarters (76%) of the participating students had
      detectable levels of 1-HP. Three students (13%) had an FEF25-75 of less than or
      equal to 80% of their predicted measurements, and 4 students (17%) had results
      between 80% and 90% of the predicted value, all of which are suggestive of
      possible lung impairment. CONCLUSIONS: These data suggest that most adolescents
      in Harlem are exposed to detectable levels of diesel exhaust, a known exacerbator
      and possible cause of chronic lung disorders such as asthma. Community-driven
      research initiatives are important for empowering communities to make needed
      changes to improve their environments and health.

PMID- 10394307
TI  - Managed care plan performance since 1980: another look at 2 literature reviews.
AB  - OBJECTIVES: This article compares the quality of care provided by managed care
      plans (MCPs) and indemnity (or fee-for-service [FFS]) plans since 1980. METHODS:
      The 44 studies examined are the studies that Miller and Luft cited in their 1994
      and 1997 reviews of the literature comparing MCPs with FFS plans. These studies
      are examined to determine how well they met Miller and Luft's selection criteria
      and, in addition, whether they controlled for differences in the breadth of
      insurance coverage. RESULTS: The 44 studies generated 57 observations. MCPs
      scored better than FFS plans on 10 of these, equally well on 25, and worse on 22.
      However, only 44 of these observations met the Miller-Luft criteria plus the
      coverage criterion. Four of these indicated that MCP care was better, 19 that MCP
      and FFS care were equivalent, and 21 that MCP care was worse. CONCLUSIONS: The
      small body of reliable studies comparing the quality of MCP care with that of FFS
      care indicates that the quality of care provided by MCPs tends to be equal or
      inferior to that provided by FFS plans.

PMID- 10394308
TI  - Occupational exposure to diesel exhaust and lung cancer: a meta-analysis.
AB  - OBJECTIVES: We undertook a meta-analysis of epidemiological studies investigating
      the relationship between occupational diesel exhaust exposure and lung cancer.
      METHODS: Thirty of 47 studies initially identified as potentially relevant met
      specified inclusion criteria. We extracted or calculated 39 independent estimates
      of relative risk and derived pooled estimates of risk for all studies and for
      numerous study subsets by using a random-effects model. We also examined
      interstudy heterogeneity by using linear metaregressions. RESULTS: There was
      substantial heterogeneity in the pooled risk estimates for all studies combined
      and for most subsets. Several factors consistent with higher study quality,
      however, contributed to increased pooled estimates of risk and lower
      heterogeneity, including (1) adjustment for confounding by cigarette smoking and
      other covariates, (2) having a lower likelihood of selection bias, and (3) having
      increased study power. CONCLUSION: This analysis provides quantitative support
      for prior qualitative reviews that have ascribed an etiologic role to
      occupational diesel exhaust exposure in lung cancer induction. Among study
      populations most likely to have had substantial exposure to diesel exhaust, the
      pooled smoking-adjusted relative risk was 1.47 (95% confidence interval = 1.29,
      1.67).

PMID- 10394309
TI  - The impact of smoke-free workplaces on declining cigarette consumption in
      Australia and the United States.
AB  - OBJECTIVES: This study estimates the contribution of smoke-free workplaces to the
      recent national declines in cigarette consumption in Australia and the United
      States. METHODS: Nineteen studies of the impact of smoke-free workplaces on
      workday cigarette consumption were reviewed. The number and cost of cigarettes
      forgone were calculated and extrapolated to a scenario in which all indoor work
      areas were smoke-free. RESULTS: Of the 19 studies, 18 reported declines in daily
      smoking rates, and 17 reported declines in smoking prevalence. Smoke-free
      workplaces are currently responsible for an annual reduction of some 602 million
      cigarettes, or 1.8% of all cigarettes that might otherwise be consumed, in
      Australia, and an annual reduction of 9.7 billion cigarettes (2%) in the United
      States. Approximately 22.3% of the 2.7 billion decrease in cigarette consumption
      in Australia between 1988 and 1995 can be attributed to smoke-free workplaces, as
      can 12.7% of the 76.5 billion decrease in the United States between 1988 and
      1994. CONCLUSIONS: If workplaces were universally smoke-free, the number of
      cigarettes forgone annually would increase to 1.14 billion (3.4%) in Australia
      and 20.9 billion (4.1%) in the United States.

PMID- 10394310
TI  - Health care worker disability due to latex allergy and asthma: a cost analysis.
AB  - OBJECTIVES: The reported prevalence of occupational allergy to natural rubber
      latex is 8% to 17%, and that of latex-induced occupational asthma is 2.5% to 6%.
      Conversion of medical facilities to "latex-safe" can reduce employee
      sensitization, impairment, and disability. The purpose of this study was to
      determine the cost of a latex-safe approach, compared with that of continued
      latex glove use, and to identify the level of worker disability required to make
      the latex-safe approach financially preferable to a health care institution.
      METHODS: The costs of 2 strategies--latex-safe vs the status quo--were calculated
      from the perspective of 3 health care institutions. A break-even point was
      calculated for each facility. RESULTS: In all facilities, the cost of using
      nonlatex gloves exceeded the cost of using latex gloves. In all 3 facilities,
      however, 1% or fewer of those at risk would have to become fully disabled or
      fewer than 2% would have to become partially disabled for the continued use of
      latex gloves to exceed the cost of the latex-safe approach. CONCLUSION: Health
      care facilities, regardless of size, are likely to benefit financially from
      becoming latex-safe even if latex-related disability levels are extremely low.

PMID- 10394311
TI  - Back pain prevalence in US industry and estimates of lost workdays.
AB  - OBJECTIVES: Back pain is the most common reason for filing workers' compensation
      claims and often causes lost workdays. Data from the 1988 National Health
      Interview Survey were analyzed to identify high-risk industries and to estimate
      the prevalence of work-related back pain and number of workdays lost. METHODS:
      Analyses included 30074 respondents who worked during the 12 months before the
      interview. A case patient was defined as a respondent who had back pain every day
      for a week or more during that period. RESULTS: The prevalence of lost-workday
      back pain was 4.6%, and individuals with work-related cases lost 101.8 million
      workdays owing to back pain. Male and female case patients lost about the same
      number of workdays. Industries in high-risk categories were also identified for
      future research and intervention, including those seldom studied. CONCLUSIONS:
      This study provides statistically reliable national estimates of the prevalence
      of back pain among workers and the enormous effect of this condition on American
      industry in terms of lost workdays.

PMID- 10394312
TI  - Back injury in municipal workers: a case-control study.
AB  - OBJECTIVES: The purpose of this study was to identify factors associated with
      acute low back injury among municipal employees of a large city. METHODS: For
      each of 200 injured case patients, 2 coworker controls were randomly selected,
      the first matched on gender, job, and department and the second matched on gender
      and job classification. In-person interviews were conducted to collect data on
      demographics, work history, work characteristics, work injuries, back pain,
      psychosocial and work organization, health behaviors, and anthropometric and
      ergonomic factors related to the job. Psychosocial work organization variables
      were examined with factor analysis techniques; an aggregate value for job strain
      was entered into the final model. Risk factors were examined via multivariate
      logistic regression techniques. RESULTS: High job strain was the most important
      factor affecting back injury (odds ratio [OR] = 2.12, 95% confidence interval
      [CI] = 1.28, 3.52), and it showed a significant dose-response effect. Body mass
      index (OR = 1.54, 95% CI = 1.08, 2.18) and a work movement index (twisting,
      extended reaching, and stooping) (OR = 1.42, 95% CI = 0.97, 2.08) were also
      significant factors. CONCLUSIONS: Results suggest that increasing workers'
      control over their jobs reduces levels of job strain. Ergonomic strategies and
      worksite health promotion may help reduce other risk factors.

PMID- 10394313
TI  - Residential radon exposure and risk of lung cancer in Missouri.
AB  - OBJECTIVES: This study investigated residential radon exposure and lung cancer
      risk, using both standard radon dosimetry and a new radon monitoring technology
      that, evidence suggests, is a better measure of cumulative radon exposure.
      METHODS: Missouri women (aged 30 to 84 years) newly diagnosed with primary lung
      cancer during the period January 1, 1993, to January 31, 1994, were invited to
      participate in this population-based case-control study. Both indoor air radon
      detectors and CR-39 alpha-particle detectors (surface monitors) were used.
      RESULTS: When surface monitors were used, a significant trend in lung cancer odds
      ratios was observed for 20-year time-weighted-average radon concentrations.
      CONCLUSIONS: When surface monitors were used, but not when standard radon
      dosimetry was used, a significant lung cancer risk was found for radon
      concentrations at and above the action level for mitigation of houses currently
      used in the United States (148 Bqm-3). The risk was below the action level used
      in Canada (750 Bqm-3) and many European countries (200-400 Bqm-3).

PMID- 10394314
TI  - Association between iron deficiency and low-level lead poisoning in an urban
      primary care clinic.
AB  - OBJECTIVES: The purpose of this study was to examine the association between iron
      deficiency and low-level lead poisoning. METHODS: Data were collected in an urban
      primary care clinic from 3650 children aged 9 to 48 months. Iron deficiency was
      defined as a red cell mean corpuscular volume (MCV) of less than 70 fL and a red
      cell distribution width (RDW) of more than 14.5 in children younger than 2 years,
      and an MCV of less than 73 fL and RDW of more than 14.5 in those 2 years or
      older. RESULTS: After adjustment for age, hemoglobin concentration, and insurance
      status, the odds ratios for iron deficiency predicting blood lead levels greater
      than or equal to 5 micrograms/dL and greater than or equal to 10 micrograms/dL
      were 1.63 (95% confidence interval [CI] = 1.29, 2.04) and 1.44 (95% CI = 1.004,
      2.05). CONCLUSIONS: Iron deficiency is significantly associated with low-level
      lead poisoning in children aged 9 to 48 months.

PMID- 10394315
TI  - Trends in medical employment: persistent imbalances in urban Mexico.
AB  - OBJECTIVES: This study examined the extreme medical unemployment and
      underemployment in the urban areas of Mexico. The conceptual and methodological
      approach may be relevant to many countries that have experienced substantial
      increases in the supply of physicians during the last decades. METHODS: On the
      basis of 2 surveys carried out in 1986 and 1993, the study analyzed the
      performance of physicians in the labor market as a function of ascription
      variables (social origin and gender), achievement variables (quality of medical
      education and specialty studies), and contextual variables (educational
      generation). RESULTS: The study reveals, despite some improvement, persistently
      high levels of open unemployment, qualitative underemployment (i.e., work in
      activities completely outside of medicine), and quantitative underemployment
      (i.e., work in medical activities but with very low levels of productivity and
      remuneration). The growing proportion of female doctors presents new challenges,
      because they are more likely than men to be unemployed and underemployed.
      CONCLUSIONS: While corrective policies can have a positive impact, it is clear
      that decisions regarding physician supply must be carefully considered, because
      they have long-lasting effects. An area deserving special attention is the
      improvement of professional opportunities for female doctors.

PMID- 10394316
TI  - The duration and timing of exposure: effects of socioeconomic environment on
      adult health.
AB  - OBJECTIVES: This study investigated timing and duration effects of socioeconomic
      status (SES) on self-rated health at 33 years of age and established whether
      health risks are modified by changing SES and whether cumulative SES operates
      through education. METHODS: Data were from the 1958 British birth cohort.
      Occupational class at birth and at 16, 23, and 33 years of age was used to
      generate a lifetime SES score. RESULTS: At 33 years of age, 12% of men and women
      reported poor health. SES at birth and at 16, 23, and 33 years of age was
      significantly associated with poor health: all ages except 16 years in men made
      an additional contribution to the prediction of poor health. No large differences
      in effect sizes emerged, suggesting that timing was not a major factor. Odds of
      poor health increased by 15% (men) and 18% (women) with a 1-unit increase in the
      lifetime SES score. Strong effects of lifetime SES persisted after adjustment for
      education level. CONCLUSIONS: SES from birth to 33 years of age had a cumulative
      effect on poor health in early adulthood. This highlights the importance of
      duration of exposure to socioeconomic conditions for adult health.

PMID- 10394317
TI  - The impact of ethnicity, family income, and parental education on children's
      health and use of health services.
AB  - OBJECTIVES: This study characterized ethnic disparities for children in
      demographics, health status, and use of services; explored whether ethnic
      subgroups (Puerto Rican, Cuban, and Mexican) have additional distinctive
      differences; and determined whether disparities are explained by differences in
      family income and parental education. METHODS: Bivariate and multivariate
      analyses of data on 99,268 children from the 1989-91 National Health Interview
      Surveys were conducted. RESULTS: Native American, Black, and Hispanic children
      are poorest (35%, 41% below poverty level vs 10% of Whites), least healthy (66%
      74% in excellent or very good health vs 85% of Whites), and have the least well
      educated parents. Compared with Whites, non-White children average fewer doctor
      visits and are more likely to have excessive intervals between visits. Hispanic
      subgroup differences in demographics, health, and use of services equal or
      surpass differences among major ethnic groups. In multivariate analyses, almost
      all ethnic group disparities persisted after adjustment for family income,
      parental education, and other relevant covariates. CONCLUSIONS: Major ethnic
      groups and subgroups of children differ strikingly in demographics, health, and
      use of services; subgroup differences are easily overlooked; and most disparities
      persist even after adjustment for family income and parental education.

PMID- 10394318
TI  - Child outcomes when child care center classes meet recommended standards for
      quality. NICHD Early Child Care Research Network.
AB  - OBJECTIVES: This study assessed outcomes for children when child care centers
      meet recommended care standards. METHODS: Data from the NICHD Study of Early
      Child Care were used to examine the association between meeting standards for
      child-staff ratios, group sizes, caregiver training, and caregiver education and
      children's development at 24 and 36 months of age. RESULTS: There were 5 major
      findings: (1) most classes observed did not meet all 4 recommended standards
      (compliance ranged from 10% at 6 months of age to 34% at 36 months of age); (2)
      linear associations were found between number of standards met and child
      outcomes, and this was more the case at 36 months than at 24 months of age: (3)
      there was no evidence of threshold effects; (4) children in classes that met more
      standards had better school readiness and language comprehension scores as well
      as fewer behavior problems at 36 months of age; and (5) child outcomes were
      predicted by child-staff ratio at 24 months and caregiver training and education
      at 36 months of age. CONCLUSIONS: Outcomes were better when children attended
      classes that met recommended child-staff ratios and recommended levels of
      caregiver training and education.

PMID- 10394319
TI  - Tuberculosis and the HIV epidemic: increasing annual risk of tuberculous
      infection in Kenya, 1986-1996.
AB  - OBJECTIVES: The purpose of this study was to assess the impact of the increased
      incidence of tuberculosis (TB) due to HIV infection on the risk of TB infection
      in schoolchildren. METHODS: Tuberculin surveys were carried out in randomly
      selected primary schools in 12 districts in Kenya during 1986 through 1990 and
      1994 through 1996. Districts were grouped according to the year in which TB
      notification rates started to increase. HIV prevalence in TB patients and changes
      in TB infection prevalence were compared between districts. RESULTS: Tuberculous
      infection prevalence rates increased strongly in districts where TB notification
      rates had increased before 1994 (odds ratio = 3.1, 95% confidence interval = 2.3,
      4.1) but did not increase in districts where notification rates had increased
      more recently or not at all. HIV prevalence rates in TB patients were 50% in
      districts with an early increase in notification rates and 28% in the other study
      districts. CONCLUSIONS: Countries with an increasing prevalence of HIV infection
      will need additional resources for TB control, not only for current patients but
      also for the patients in additional cases arising from the increased risk of TB
      infection.

PMID- 10394321
TI  - Clinician follow-up of children screened for lead poisoning.
AB  - OBJECTIVES: This study assessed clinicians' compliance with Centers for Disease
      Control and Prevention recommendations for follow-up of children with blood lead
      (BPb) levels of 0.48 mumol/L (10 micrograms/dL) or higher. METHODS: Clinicians'
      success at follow-up was determined for 3 BPb ranges: > or = 0.97 mumol/L, 0.73
      through 0.92 mumol/L, and 0.48 through 0.68 mumol/L (> or = 20 micrograms/dL, 15
      19 micrograms/dL, and 10-14 micrograms/dL, respectively). RESULTS: A total of 410
      children with elevated BPb levels were followed over a 12-month period; within 4
      months, 71% of those with initial levels of 0.97 mumol/L or greater were retested
      and 57% and 34% of children with initial BPb levels of 0.73 through 0.92 mumol/L
      and 0.48 through 0.68 mumol/L, respectively, were retested. CONCLUSIONS: Follow
      up of children with elevated BPb levels is inadequate within an urban ambulatory
      care network.

PMID- 10394320
TI  - The association between occupational lead exposure and serum cholesterol and
      lipoprotein levels.
AB  - OBJECTIVES: This study sought to clarify the possible associations between blood
      lead level and serum cholesterol and lipoprotein levels in subjects
      occupationally exposed to lead. METHODS: Levels of blood lead, serum total
      cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein
      cholesterol, and triglycerides in 56 male industrial employees who were exposed
      to lead were compared with those in 87 unexposed employees. RESULTS: Mean blood
      lead levels were 42.3 (+/- 14.9) micrograms/dL in the exposed group and 2.7 (+/-
      3.6) micrograms/dL in the nonexposed group. The exposed subjects had higher mean
      levels of total cholesterol and HDL cholesterol. CONCLUSIONS: Blood lead levels
      are positively associated with total and HDL cholesterol.

PMID- 10394322
TI  - The relation of gestation length to short-term heat stress.
AB  - OBJECTIVES: This study examined the association between gestation length and heat
      exposure during the summer months of the Chicago heat wave of 1995. METHODS:
      Birth data from Illinois vital records containing 11,792 singleton vaginal births
      were analyzed to calculate mean gestational ages. RESULTS: No evidence was found
      to suggest an association between shortened gestation and increased maximum
      apparent temperature. CONCLUSIONS: The data propose no special precautions for
      pregnant women exposed to short-term heat stress of the intensity evaluated in
      this study. However, the possible effects of chronic heat exposure on gestation
      cannot be ruled out.

PMID- 10394323
TI  - Elimination and reintroduction of primary and secondary syphilis.
AB  - OBJECTIVES: This study was conducted to define factors associated with the
      epidemic spread, elimination, and reintroduction of primary and secondary
      syphilis in King County, Washington, from 1987 through 1998. METHODS: Reports of
      primary and secondary syphilis in King County from 1987 through 1998 were
      reviewed retrospectively. RESULTS: During the epidemic spread of syphilis, only
      15.8% of cases were imported. A total of 24.0% of patients reported cocaine use,
      and 18.3% of female patients reported having commercial sex. During the
      elimination of syphilis, significantly higher percentages of cases were imported
      and lower percentages of patients reported cocaine use or female commercial sex.
      During the reintroduction of syphilis in 1997-1998, 68% of patients were men who
      reported sex with men; of this 68%, 66% were sero-positive for HIV. Most men
      reporting sex with men were 30 years or older and recruited many anonymous
      partners. CONCLUSIONS: As syphilis wanes, local control must focus on outbreaks
      following its reintroduction. Resurgence of syphilis among men reporting sex with
      men recapitulates the epidemiology of syphilis before the historical advent of
      AIDS, warranting immediate attention to this problem.

PMID- 10394325
TI  - Schizophrenia and major affective disorder among Medicaid recipients with
      HIV/AIDS in New Jersey.
AB  - OBJECTIVES: This study sought to identify and characterize seriously mentally ill
      patients with HIV infection. METHODS: Medicaid beneficiaries with HIV/AIDS were
      identified through the merging of New Jersey HIV/AIDS Registry and Medicaid
      eligibility files. Claims histories were used to classify individuals as having
      schizophrenia, major affective disorder, or no serious mental illness. RESULTS:
      Of 8294 individuals, 476 (5.7%) were classified as having schizophrenia, and 564
      (6.8%) were classified as having major affective disorder. Those with serious
      mental illness were more likely than other groups to be injection drug users and
      to have claims indicative of substance abuse. CONCLUSIONS: Individuals with
      serious mental illness are a significant but little-recognized subgroup of those
      with HIV infection.

PMID- 10394324
TI  - Name-based reporting of HIV-positive test results as a deterrent to testing.
AB  - OBJECTIVES: This study evaluated attitudes toward name-based reporting of HIV.
      METHODS: One hundred thirty high-risk, male repeat testers received information
      on the public health benefits of name-based reporting and reported their
      intentions to test. RESULTS: Of the 67 men who were randomly selected and asked
      their intentions before hearing the benefits, 63% said they would not test if
      reporting were required. After hearing the benefits, 19% changed their minds (P <
      .014). Of the 63 men who were asked only after hearing the benefits, 44% would
      not test. CONCLUSIONS: Implementing name-based reporting without working before
      hand to change attitudes could undermine the benefits of both testing and HIV
      surveillance.

PMID- 10394326
TI  - Trends in AIDS among Hispanics in the United States, 1991-1996.
AB  - OBJECTIVES: This article describes recent trends in AIDS among US Hispanics.
      METHODS: Incidence rates were calculated from AIDS surveillance data for persons
      diagnosed from 1991 through 1996. Increases in the number of cases among
      Hispanics were calculated by linear regression. RESULTS: Of the 415,864 persons
      diagnosed with AIDS from 1991 through 1996, 19% were Hispanic. Among Hispanics
      with AIDS, 67% were born in the United States or Puerto Rico. The relative risk
      (RR) of AIDS for Hispanics compared with Whites was highest for women (RR = 7.0),
      followed by children (RR = 6.2) and men (RR = 2.8). Increases in the number of
      cases were higher among foreign-born Hispanics. CONCLUSIONS: An understanding of
      which Hispanic subgroups are at greatest risk for HIV infection is important for
      prevention efforts.

PMID- 10394327
TI  - State and federal revenues from tobacco consumed by minors.
AB  - OBJECTIVES: The purpose of this study was to estimate the value of cigarettes
      consumed in 1997 by youths younger than 18 years. METHODS: Price, population, and
      consumption data were used to compute conservative and comprehensive estimates,
      which were then averaged. RESULTS: An estimated 3.76 million daily smokers aged
      12 through 17 years consume an estimated 924 million packs of cigarettes per
      year, generating $222 million in federal tax revenues, $293 million in state tax
      revenues, and $480 million in tobacco company profits, and producing a retail
      value of $1.86 billion. CONCLUSIONS: The revenues from cigarettes smoked by
      youths could be used to enforce laws prohibiting the sale of tobacco to minors.

PMID- 10394328
TI  - Driver distance from the steering wheel: perception and objective measurement.
AB  - OBJECTIVES: This study assessed the accuracy of driver perceptions of the
      distance between the driver's nose and the steering wheel of the vehicle as a
      factor in considering driver disconnection of an airbag contained in the steering
      wheel for preventing injury to the driver in an accident. METHODS: A cross
      sectional survey of 1000 drivers was done to obtain perceived and objective
      measurements of the distance between the driver's nose and the steering wheel of
      the vehicle. RESULTS: Of 234 drivers who believed that they sat within 12 inches
      of the steering wheel, only 8 (3%) actually did so, whereas of 658 drivers who
      did not believe that they sat within 12 inches of the wheel, 14 (2%) did so.
      Shorter drivers were more likely than taller ones to both underestimate and
      overestimate their seating distance. CONCLUSIONS: Considerable misperception of
      drivers' distance from the wheel indicates that drivers should objectively
      measure this distance.

PMID- 10394330
TI  - Radiation accident preparedness: report of a training program involving the
      United States, Eastern Europe, and the newly independent states.

PMID- 10394329
TI  - Estimating the proportion of homes with functioning smoke alarms: a comparison of
      telephone survey and household survey results.
AB  - OBJECTIVES: This study determined the proportion of homes with functioning smoke
      alarms in a low-income area experiencing a high rate of residential fire-related
      injuries. METHODS: An on-site survey of households was conducted to confirm the
      results of a telephone survey. RESULTS: In the telephone survey, 71% of
      households reported having functioning smoke alarms. In the household survey, 66%
      of households reported having functioning alarms; however, when the alarms were
      tested, the percentage dropped to 49%. CONCLUSIONS: Telephone surveys may
      overestimate the presence of functioning smoke alarms in some populations. Thus,
      the use of telephone surveys to establish baseline measures could significantly
      affect the evaluation of smoke-alarm giveaway programs.

PMID- 10394331
TI  - Linking health promotion with entertainment television.

PMID- 10394332
TI  - Herbicide and insecticide exposures among dairy farm pesticide applicators.

PMID- 10394333
TI  - Geographic information systems.

PMID- 10394334
TI  - APHA's involvement in international health.

PMID- 10394335
TI  - Childhood lead poisoning prevention.

PMID- 10394336
TI  - [A plea for a better nutritional management of cancer patients].

PMID- 10394337
TI  - [Postoperative irradiation of bronchial cancers: has the page been turned?].

PMID- 10394338
TI  - [Carcinogenic effects of low radiation doses].
AB  - The carcinogenic effect of low doses of ionizing radiation has been a matter of
      much debate over the last few years. The French Academy of Science published a
      report on the subject in 1995. The central point of discussion concerns the
      validity of the linear no threshold relationship for estimating, by
      extrapolation, the carcinogenic effect of low doses. The aim of this article is
      to analyze the epidemiological data on the effect of low doses and the biological
      data on the mechanisms of carcinogenesis that have been obtained since 1995.
      These data strengthen doubts concerning the validity of current risk evaluations
      at low doses.

PMID- 10394339
TI  - Comparison of the conventional 'box technique' with two different 'conformal'
      beam arrangements for prostate cancer treatment.
AB  - PURPOSE: To quantify the possible advantages arising from the use of 'conformal'
      radiotherapy of localized prostate cancer, and to compare the dose distributions
      obtained with two different 'conformal' techniques. PATIENTS AND METHODS: Twelve
      patients with localized prostate cancer were enrolled in the study. For each
      patient, three techniques were planned: the standard 'box technique' (A), a four
      fields 'conformal' technique (B), and a 6-fields conformal technique (C). For
      each of the 36 3D plans, dose-volume histograms (DVH) were obtained, along with
      the mean, maximum and minimum doses for the clinical and planning target volumes
      (CTV, PTV) for the rectum, the bladder, and the femoral heads. The resulting data
      were compared. RESULTS: On average, the standard technique resulted in the
      exposure of a significantly larger bladder volume to the higher doses; a similar,
      but less remarkable difference has been observed for the rectal volume. The
      coverage of the PTV appears to be significantly more homogeneous with the two
      conformal techniques. CONCLUSIONS: The results presented here add to the evidence
      available in the literature and suggest a possible advantage of both the
      conformal techniques over the standard 'box technique' for the treatment of
      localized prostate cancer. The 6-field conformal technique does not seem superior
      to the four field one.

PMID- 10394340
TI  - [Treatment of soft tissue sarcomas of the extremities and the trunk by
      conservative surgery and postoperative irradiation. Apropos of a series of 96
      patients].
AB  - AIM OF STUDY: Retrospective study of a series of 96 patients presenting with soft
      tissues sarcoma. Homogeneous treatment between 1980-1992 with conservative
      surgery and post operative irradiation. PATIENTS AND METHODS: Median age of the
      96 patients was 58 years. Tumor site was: upper limb 20, lower limb 46, trunk 30.
      In 35 cases largest diameter of the tumor was 5 cm or less (T1). All patients
      were M0. The most frequent pathological sub type was: malignant histiocytofibroma
      28, liposarcoma 28. A gross complete surgery was performed in 89 cases.
      Radiotherapy was performed with cobalt or x 18 MV photons. The dose delivered was
      50 Gy with a boost of 10 Gy. No adjuvant chemotherapy was given. RESULTS: Mean
      follow up was 68 months. Local relapse was seen in 19 patients, six were salvaged
      by surgery, a limb amputation rates were necessary in 4 cases. The 5 and 10 year
      overall survival was 70% and 64%. There was no severe radiation toxicity
      requiring surgery. A good function of the limb was preserved in all cases.
      CONCLUSION: These results are in agreement with those of the literature and
      justify a conservative approach for these soft tissues sarcomas.

PMID- 10394341
TI  - [Evaluation of a series of 137 carcinomas of the endometrium of stage I
      TNM/UICC].
AB  - PURPOSE: To assess retrospectively the long-term results of the combination of
      surgery and radiotherapy in carcinoma classified cT1. PATIENTS AND METHODS: From
      1974 to 1993, 137 women suffering from endometrial carcinoma cT1Nx-0 M0 were
      entered into the study. The median age was 62 years (range: 39-85 years) and the
      median follow up was 67 months (range: 0-224 months). RESULTS: Surgery was
      performal in 132 women (96.35%). For cT1, the 5-year overall and specific
      survivals were 81.1% and 84.5%, respectively. The 10-year overall and specific
      survivals were 68.8% and 82.2%, respectively. Concerning cT1pT1, the 5-year
      overall and specific survivals, were 83.9% and 87.4%. The 10-year overall and
      specific survivals were 71.1% and 85%, respectively. Histological grade, pelvic
      lymph node involvement and myometrial infiltration influence significantly the
      overall and specific survivals of cT1pT1 tumors. According to multivariate
      analysis, pelvic lymph node involvement was a powerful prognostic factor for both
      the overall and specific survivals. If we rule out pelvic lymph node involvement,
      WHO histological grade was a significant prognostic factor. CONCLUSION:
      Combination of surgery and radiotherapy is still a common procedure for cT1
      tumors. When surgery is done before radiotherapy, tailored irradiation may
      further take place, according to WHO histological grade and pelvic lymph node
      status.

PMID- 10394342
TI  - The single-isocentre treatment of head and neck cancer: time gain using MLC and
      automatic set-up.
AB  - PURPOSE: In this manuscript, we studied the difference in the treatment time
      required to execute a single-isocentre three-field irradiation of the head and
      neck, using either tray-mounted cerrobend blocks or a multileaf collimator (MLC)
      for field shaping and automatic set-up. MATERIALS AND METHODS: A total of twenty
      consecutive, unselected patients (16 males, four females), were eligible for this
      study because the dose they were to received was 44 Gy (2 Gy/fraction) to the
      head, neck and supraclavicular regions. Patients were randomly allocated to one
      of two treatment groups. The first group (n = 11) was treated on a Philips SL-75
      linear accelerator (SL-75), using 5 MV photons and tray-mounted cerrobend blocks.
      The second group (n = 9) was treated on a Philips SL-25 linear accelerator (SL-25
      MLC), using 6 MV photons and a MLC. Patients of the second group were treated
      using the automatic set-up facility of the SL-25-MLC, without entering the
      treatment room between consecutive fields. RESULTS: Overall treatment time was
      significantly shorter on the SL-25-MLC than on the SL-75 (P < 0.0001). The
      difference in total treatment-execution time was in the range of 157 s per
      treatment session. The largest difference was observed in the set-up time. There
      was an average of a 125 s time gain per treatment day (P < 0.0001) in favour of
      the SL-25-MLC. CONCLUSIONS: Compared to tray-mounted cerrobend blocks, a MLC and
      automatic set-up results in a significant time advantage when a single isocentre
      technique is used to treat head and neck cancer.

PMID- 10394343
TI  - [Postoperative radiotherapy of a benign tumor of the ankle].
AB  - Pigmented villonodular synovitis is a rare benign tumor. The high rate or
      recurrence after surgery exposes the risk of non-conservative or non-functional
      treatment. External irradiation of post-surgical residual disease seems to be
      useful for the prevention of relapse and conservation with a good functional
      result. We report a clinical observation of a case with a diffuse type of
      pigmented villonodular synovitis of the ankle, operated on three times, and then
      treated by external irradiation. The published results in terms of response and
      functional prognosis of 14 cases of multi-recurrent villonodular synovitis
      treated by irradiation seem to confirm this therapeutic option.

PMID- 10394344
TI  - [Liposarcoma of the larynx. Review of the literature apropos of a case].
AB  - Liposarcoma of the larynx is an uncommon tumor. Only 27 cases have been described
      in literature. We report a new case occurring in a 50-year-old patient. The
      treatment consisted of a total laryngectomy with lymph node dissection followed
      by adjuvant irradiation. Prognosis for laryngeal liposarcoma is better than that
      of non laryngeal liposarcoma. This tumor is at high risk of local recurrence and
      seldom has metastatic potential.

PMID- 10394345
TI  - Multimedia educational services in stereotactic radiotherapy.
AB  - The computer-based learning methods in medicine have been well established as
      stand-alone learning systems. Recently, these systems were enriched with the use
      of telematics technology to provide distance learning capabilities. Stereotactic
      radiotherapy is one of the most representative advanced radiotherapy techniques.
      Due to the multidisciplinary character of the technique and the rapid evolution
      of technology implemented, the demands in training have increased. The potential
      of interactive multimedia and Internet technologies for the achievement of
      distance learning capabilities in this domain are investigated. The realization
      of a computer-based educational program in stereotactic radiotherapy in a
      multimedia format is a new application in the computer-aided distance learning
      field. The system is built according to a client and server architecture, based
      on the Internet infrastructure, and composed of server nodes. The impact of the
      system may be described in terms of: time and transportation costs saving,
      flexibility in training (scheduling, rate and subject selection), online
      communication and interaction with experts, cost effective access to material
      (delivery or access by a large number of users and revision of the material by
      avoiding high costs of computer-based training systems and database development).

PMID- 10394346
TI  - Blunt cerebrovascular injuries.
AB  - On the basis of our experience and the available literature, we submit that
      aggressive screening for BCI based on injury patterns is warranted. However,
      several important clinical issues remain unresolved. The precise injury patterns
      and relative cerebrovascular risks remain to be defined. Furthermore, the optimal
      diagnostic screening test remains to be identified, with consideration of the
      relative risk-benefit profile. Finally, we must determine the best methods for
      the treatment of BCI. Although the definitive study has yet to be completed, the
      use of heparin was associated with a trend toward improved outcomes in
      symptomatic patients. In addition, no asymptomatic patient experienced the
      development of new neurologic deficits during heparin therapy. Therefore we
      believe that the early institution of heparin therapy is indicated. The role of
      endovascular stenting, however, remains unclear.

PMID- 10394347
TI  - [Drug prescriptions and costs in diabetic polyneuropathy].
AB  - BACKGROUND AND OBJECTIVE: Numerous medications are used in the treatment of
      diabetic polyneuropathy (PNP) without evidence of their efficacy. This study was
      undertaken to obtain the costs of drugs prescribed to patients with PNP
      throughout the Federal Republic of Germany in primary-care practices. PATIENTS
      AND METHODS: Data (stored in the Medi-Plus data bank of the Institute for Medical
      Statistics, Frankfurt) from 400 primary-care practices were analysed for the year
      1996 with regard to diagnoses and prescriptions for 40,112 diabetics over the age
      of > or = 20 years. A polyneuropathy (PNP) had been diagnosed in 3548 patients
      (8.8%) (age: 68 +/- 12 years, 56% women). The cost of medications listed for the
      treatment of PNP was identified and extrapolated to the total prescription cost
      for treated diabetic PNP in the whole of Germany. In addition the proportion of
      costs for drugs with unproven efficacy was calculated. RESULTS: Antidepressives
      were prescribed for 13%, carbamazepine for 4%, and lipoic (thioctic) acid for 41%
      of diabetics with PNP. Annual costs per patient (mean value) were DM 203 for
      lipoic acid, DM 53 for vasoactive drugs and DM 42 for analgesics. Projection for
      the estimated total number of diabetic patients with PNP treated in primary care
      practices (n = 361,400) gave a total cost of DM 116 million (95% confidence
      limit: DM 109-123), of which DM 41 million (35%) was for medications of unproven
      efficacy. CONCLUSION: In Germany one third of drug costs for diabetic patients
      with PNP in primary care is for medications of unproven efficacy. Cost-effective
      guidelines for the treatment of diabetic PNP are urgently required.

PMID- 10394349
TI  - [Fatty liver in adult celiac disease].
AB  - HISTORY AND ADMISSION FINDINGS: A 31-year-old woman was admitted because of
      heptomegaly and abnormal liver functions. For years she had suffered from
      diarrhoea but its cause had never been elucidated. She was underweight and had
      mild ankle edema. The liver margin was palpable at 20 cm below the midcostal
      margin, but the abdominal examination was otherwise unremarkable. INVESTIGATIONS:
      Sonography revealed a very large fatty liver. Biopsy showed fatty infiltration of
      nearly all the hepatocytes, without significant inflammation and fibrosis. Small
      intestinal biopsy showed the typical histology of coeliac disease. Laboratory
      tests indicated abnormal liver function with increased transaminases, alkaline
      phosphatase, GPT and LDH, but no sign of inflammatory aetiology. These findings
      suggested that the liver changes were due to the coeliac disease. TREATMENT AND
      COURSE: After the patient had been put on a gluten-free diet the diarrhoea
      stopped and she started to gain weight. The liver function tests briefly became
      worse, but over the following 6 weeks normalized completely. The patient gained 5
      kg in the subsequent 18 months and the liver became sonographically normal. The
      small-intestinal biopsy now showed merely discrete villar atrophy. CONCLUSION:
      Coeliac disease should be considered in any case of fatty liver of unknown cause.
      Strict gluten-free dietary treatment of the underlying cause can quickly lead to
      complete regression of the hepatic changes.

PMID- 10394348
TI  - [Fatal liver failure after corticosteroid treatment of a hepatitis B virus
      carrier].
AB  - HISTORY AND ADMISSION FINDINGS: A 69-year-old man, a known carrier of hepatitis B
      virus (HBV) after blood transfusion, developed increasingly severe jaundice with
      high transaminase levels after receiving steroids in high doses. Significant
      preceding conditions included chronic obstructive pulmonary disease, coronary
      heart disease, ulcerative colitis in remission and diabetes mellitus. On
      admission he was jaundiced and experienced pain on pressure below the right
      costal margin. INVESTIGATIONS: Serology demonstrated reactivated hepatitis B with
      an increase of the HBV-DNA concentration in serum, as well as seroconversion with
      HBe antigen, anti-HBc-IgM antibodies and absence of anti-HBe antibodies.
      DIAGNOSIS, TREATMENT AND COURSE: The history and serological findings indicated
      reactivation of the hepatitis B by the steroid treatment. Progressive liver
      failure developed. A marked reduction of virus particles in the blood occurred
      after a therapeutic trial with the nucleoside analog lamivudine, but the patient
      died of liver failure 30 days after admission. CONCLUSION: Steroids should be
      given to known hepatitis B carriers only if strictly indicated, because of the
      danger of acute deterioration of liver functions by reactivation of the disease
      with possibly fatal consequences. If steroids are administered, liver functions
      and serological hepatitis markers should be closely monitored so that any
      necessary treatment can be quickly initiated.

PMID- 10394350
TI  - [Performing interventional bronchoscopic procedures].

PMID- 10394351
TI  - [Current issues in somatic gene therapy].

PMID- 10394352
TI  - [Surfing the Internet with side effects: problems surrounding smart drugs].

PMID- 10394353
TI  - [Can hemorrhoids facilitate the transit of allergens from feces into the blood
      circulation?].

PMID- 10394354
TI  - [Coexistence of two different neuroendocrine tumors of the upper gastrointestinal
      tract and of the pancreas].

PMID- 10394355
TI  - [Coexistence of two different neuroendocrine tumors of the upper gastrointestinal
      tract and of the pancreas].

PMID- 10394356
TI  - [The duodenojejunal flexure--a gap in the routine diagnosis of gastrointestinal
      hemorrhage].

PMID- 10394357
TI  - The 19S regulatory complex of the proteasome functions independently of
      proteolysis in nucleotide excision repair.
AB  - The 26S proteasome degrades proteins targeted by the ubiquitin pathway, a
      function thought to explain its role in cellular processes. The proteasome
      interacts with the ubiquitin-like N terminus of Rad23, a nucleotide excision
      repair (NER) protein, in Saccharomyces cerevisiae. Deletion of the ubiquitin-like
      domain causes UV radiation sensitivity. Here, we show that the ubiquitin-like
      domain of Rad23 is required for optimal activity of an in vitro NER system.
      Inhibition of proteasomal ATPases diminishes NER activity in vitro and increases
      UV sensitivity in vivo. Surprisingly, blockage of protein degradation by the
      proteasome has no effect on the efficiency of NER. This establishes that the
      regulatory complex of the proteasome has a function independent of protein
      degradation.

PMID- 10394358
TI  - RNA polymerase II targets pre-mRNA splicing factors to transcription sites in
      vivo.
AB  - Biochemical evidence indicates that pre-mRNA splicing factors physically interact
      with the C-terminal domain of the largest subunit of RNA polymerase II. We have
      investigated the in vivo function of this interaction. In mammalian cells,
      truncation of the CTD of RNA pol II LS prevents the targeting of the splicing
      machinery to a transcription site. In the absence of the CTD, pre-mRNA splicing
      is severely reduced. The presence of unspliced RNA alone is not sufficient for
      the accumulation of splicing factors at the transcription site, nor for its
      efficient splicing. Our results demonstrate a critical role for the CTD of RNA
      pol II LS in the intranuclear targeting of splicing factors to transcription
      sites in vivo.

PMID- 10394359
TI  - Cap-dependent translation initiation in eukaryotes is regulated by a molecular
      mimic of eIF4G.
AB  - eIF4G uses a conserved Tyr-X-X-X-X-Leu-phi segment (where X is variable and phi
      is hydrophobic) to recognize eIF4E during cap-dependent translation initiation in
      eukaryotes. High-resolution X-ray crystallography and complementary biophysical
      methods have revealed that this eIF4E recognition motif undergoes a disorder-to
      order transition, adopting an L-shaped, extended chain/alpha-helical conformation
      when it interacts with a phylogenetically invariant portion of the convex surface
      of eIF4E. Inhibitors of translation initiation known as eIF4E-binding proteins
      (4E-BPs) contain similar eIF4E recognition motifs. These molecules are molecular
      mimics of eIF4G, which act by occupying the same binding site on the convex
      dorsum of eIF4E and blocking assembly of the translation machinery. The
      implications of our results for translation initiation are discussed in detail,
      and a molecular mechanism for relief of translation inhibition following
      phosphorylation of the 4E-BPs is proposed.

PMID- 10394360
TI  - A role for TBP dimerization in preventing unregulated gene expression.
AB  - The recruitment of the TATA box-binding protein (TBP) to promoters in vivo is
      often rate limiting in gene expression. We present evidence that TBP negatively
      autoregulates its accessibility to promoter DNA in yeast through dimerization.
      The crystal structure of TBP dimers was used to design point mutations in the
      dimer interface. These mutants are impaired for dimerization in vitro, and in
      vivo they generate large increases in activator-independent gene expression.
      Overexpression of wild-type TBP suppresses these mutants, possibly by
      heterodimerizing with them. In addition to loss of autorepression, dimerization
      defective TBPs are rapidly degraded in vivo. Direct detection of TBP dimers in
      vivo was achieved through chemical cross-linking. Taken together, the data
      suggest that TBP dimerization prevents unregulated gene expression and its own
      degradation.

PMID- 10394361
TI  - Activation of Vav by Nef induces cytoskeletal rearrangements and downstream
      effector functions.
AB  - Nef of primate lentiviruses is critical for high levels of viremia and the
      progression to AIDS. Nef associates with and activates a serine/threonine kinase
      (Nef-associated kinase [NAK]) via the small GTPases Rac1 and Cdc42. We identified
      the protooncogene and guanine nucleotide exchange factor Vav as the specific
      binding partner of Nef proteins from HIV-1 and SIV. The interaction between Nef
      and Vav led to increased activity of Vav and its downstream effectors. Both
      cytoskeletal changes and the activation of c-Jun N-terminal kinase (JNK) were
      observed. Furthermore, a dominant-negative Vav protein inhibited NAK activation
      and viral replication. Thus, the interaction between Nef and Vav initiates a
      signaling cascade that changes structural and physiological parameters in the
      infected cell.

PMID- 10394362
TI  - PTP-ER, a novel tyrosine phosphatase, functions downstream of Ras1 to
      downregulate MAP kinase during Drosophila eye development.
AB  - Activation of ERK/MAPK is a key event downstream of RAS. The duration, extent,
      and timing of MAPK activity is integral to signal specificity. Consequently,
      inactivation of MAPK by phosphatases has emerged as a critical element in the
      precise control of signal output. We have cloned and characterized a novel
      cytoplasmic protein tyrosine phosphatase, PTP-ER, which is related to mammalian
      PCPTP1, LC-PTP/HePTP, and STEP tyrosine phosphatases. PTP-ER mutants produce
      extra R7 cells and enhance activated Ras1 signaling. Ectopic expression of PTP-ER
      dramatically inhibits RAS1/MAPK signaling. PTP-ER binds to and inactivates
      Drosophila ERK/MAPK; however, it is unable to dephosphorylate and downregulate
      Drosophila MAPKSevenmaker. Resistance to PTP-ER activity partially accounts for
      the Sevenmaker mutant phenotype.

PMID- 10394363
TI  - Synip: a novel insulin-regulated syntaxin 4-binding protein mediating GLUT4
      translocation in adipocytes.
AB  - Insulin-stimulated glucose transport and GLUT4 translocation require regulated
      interactions between the v-SNARE, VAMP2, and the t-SNARE, syntaxin 4. We have
      isolated a novel syntaxin 4-binding protein, Synip, which specifically interacts
      with syntaxin 4. Insulin induces a dissociation of the Synip:syntaxin 4 complex
      due to an apparent decrease in the binding affinity of Synip for syntaxin 4. In
      contrast, the carboxyterminal domain of Synip does not dissociate from syntaxin 4
      in response to insulin stimulation but inhibits glucose transport and GLUT4
      translocation. These data implicate Synip as an insulin-regulated syntaxin 4
      binding protein directly involved in the control of glucose transport and GLUT4
      vesicle translocation.

PMID- 10394364
TI  - Functional organization of clathrin in coats: combining electron cryomicroscopy
      and X-ray crystallography.
AB  - The sorting of specific proteins into clathrin-coated pits and the mechanics of
      membrane invagination are determined by assembly of the clathrin lattice. Recent
      structures of a six-fold barrel clathrin coat at 21 A resolution by electron
      cryomicroscopy and of the clathrin terminal domain and linker at 2.6 A by X-ray
      crystallography together show how domains of clathrin interact and orient within
      the coat and reveal the strongly puckered shape and conformational variability of
      individual triskelions. The beta propeller of the terminal domain faces the
      membrane so that recognition segments from adaptor proteins can extend along its
      lateral grooves. Clathrin legs adapt to different coat environments in the barrel
      by flexing along a segment at the knee that is free of contacts with other
      molecules.

PMID- 10394365
TI  - The crystal structure of the human hepatitis B virus capsid.
AB  - Hepatitis B is a small enveloped DNA virus that poses a major hazard to human
      health. The crystal structure of the T = 4 capsid has been solved at 3.3 A
      resolution, revealing a largely helical protein fold that is unusual for
      icosahedral viruses. The monomer fold is stabilized by a hydrophobic core that is
      highly conserved among human viral variants. Association of two amphipathic alpha
      helical hairpins results in formation of a dimer with a four-helix bundle as the
      major central feature. The capsid is assembled from dimers via interactions
      involving a highly conserved region near the C terminus of the truncated protein
      used for crystallization. The major immunodominant region lies at the tips of the
      alpha-helical hairpins that form spikes on the capsid surface.

PMID- 10394366
TI  - The crystal structure of rna1p: a new fold for a GTPase-activating protein.
AB  - rna1p is the Schizosaccharomyces pombe ortholog of the mammalian GTPase
      activating protein (GAP) of Ran. Both proteins are essential for nuclear
      transport. Here, we report the crystal structure of rna1p at 2.66 A resolution.
      It contains 11 leucine-rich repeats that adopt the nonglobular shape of a
      crescent, bearing no resemblance to RhoGAP or RasGAP. The invariant residues of
      RanGAP form a contiguous surface, strongly indicating the Ran-binding interface.
      Alanine mutations identify Arg-74 as a critical residue for GTP hydrolysis. In
      contrast to RasGAP and RhoGAP, Arg-74 could be substituted by lysine and
      contributed significantly to the binding of Ran. Therefore, we suggest a GAP
      mechanism for rna1p, which constitutes a variation of the arginine finger
      mechanism found for Ras GAP and RhoGAP.

PMID- 10394367
TI  - Disruption of the Pfg27 locus by homologous recombination leads to loss of the
      sexual phenotype in P. falciparum.
AB  - Transmission of malaria depends upon the differentiation and development of the
      sexual stages of the parasite. In Plasmodium falciparum, it is a complex,
      multistage process, involving the expression of a large number of sexual stage
      specific proteins. Pfg27 is one such protein, abundantly expressed at the onset
      of gametocytogenesis. We report successful disruption of the Pfg27 locus using
      homologous recombination and show that it is essential for the maintenance of the
      sexual phenotype. Transfectants lacking Pfg27 abort early in sexual development,
      resulting in vacuolated, highly disarranged, and disintegrating parasites. This
      suggests a critical role for Pfg27 in the sexual development of the parasite.

PMID- 10394368
TI  - Loss-of-function mutations in PPAR gamma associated with human colon cancer.
AB  - The gamma isoform of the peroxisome proliferator-activated receptor, PPAR gamma,
      regulates adipocyte differentiation and has recently been shown to be expressed
      in neoplasia of the colon and other tissues. We have found four somatic PPAR
      gamma mutations among 55 sporadic colon cancers: one nonsense, one frameshift,
      and two missense mutations. Each greatly impaired the function of the protein.
      c.472delA results in deletion of the entire ligand binding domain. Q286P and
      K319X retain a total or partial ligand binding domain but lose the ability to
      activate transcription through a failure to bind to ligands. R288H showed a
      normal response to synthetic ligands but greatly decreased transcription and
      binding when exposed to natural ligands. These data indicate that colon cancer in
      humans is associated with loss-of-function mutations in PPAR gamma.

PMID- 10394369
TI  - Phosphatidylinositol 3-phosphate recognition by the FYVE domain.
AB  - Recognition of phosphatidylinositol 3-phosphate (Ptdlns(3)P) is crucial for a
      broad range of cellular signaling and membrane trafficking events regulated by
      phosphoinositide (PI) 3-kinases. PtdIns(3)P binding by the FYVE domain of human
      early endosome autoantigen 1 (EEA1), a protein implicated in endosome fusion,
      involves two beta hairpins and an alpha helix. Specific amino acids, including
      those of the FYVE domain's conserved RRHHCRQCGNIF motif, contact soluble and
      micelle-embedded lipid and provide specificity for Ptdlns(3)P over Ptdlns(5)P and
      Ptdlns, as shown by heteronuclear magnetic resonance spectroscopy. Although the
      FYVE domain relies on a zinc-binding motif reminiscent of RING fingers, it is
      distinguished by ovel structural features and its ptdlns(3)P-binding site.

PMID- 10394370
TI  - [The role of hyperbaric oxygen therapy in radiation-induced digestive disorders.
      36 cases].
AB  - OBJECTIVES: Study the effect of hyperbaric oxygen on chronic irradiation induced
      digestive disorders. PATIENTS AND METHODS: A retrospective study was conducted in
      36 patients (mean age 66 +/- 11 years) with chronic digestive tract necrosis
      which had developed a mean 42 months after irradiation therapy. Hyperbaric oxygen
      therapy was given a mean 17 months after symptom onset: failing healing (n = 9),
      rectal bleeding (n = 19), profuse diarrhea (n = 9), recurrent anal abscess (n =
      1). The severity of the digestive tract radionecrosis was quantified using the
      Soma-Lent scale. Hyperbaric oxygen therapy was grade 1 (n = 1), grade 2 (n = 11),
      grade 3 (n = 16), grade 4 (n = 8). RESULTS: Thirty-six patients underwent a mean
      67 hyperbaric sessions (100% O2, 2.5 atm, 90 min). Three patients died within one
      month of the first session due to radiation enteritis, a neoplastic process or
      another concomitant cause. Immediate outcome after hyperbaric oxygen therapy was
      cure (n = 3) or improvement (n = 16) in 19 patients (53%) and failure in 17
      (47%). Long-term results evaluated in 32 subjects with a mean 52 months follow-up
      were: cure (n = 9) or improvement (n = 12) in 21 patients (66%) and failure in 11
      (34%). Nine patients died within a mean 25 months after the end of the hyperbaric
      sessions. Death was related to digestive tract radionecrosis in 1 case and
      neoplasia in 5. CONCLUSION: Hyperbaric oxygen therapy provides clinical relief in
      2 out of 3 patients and can be a useful alternative to conventional treatment in
      patients with chronic radiation-induced necrosis of the digestive tract.

PMID- 10394371
TI  - [Underestimation of medical activity measured by daily activity scores].
AB  - OBJECTIVES: To assess the effectiveness of a scoring system (omega) for medical
      activity. METHODS: In 100 consecutive patients (phase A), the omega scores were
      calculated by the physician in charge and controlled by an independent physician.
      In 100 additional patients, the omega scores were controlled again while using
      corrective measures (phase B). RESULTS: Phase A: at least one item was forgotten
      in 54% of the stays. The amount of medical activity lost (MAL) was 14 +/- 13%.
      Phase B: there was no significant reduction in the number of stays with forgotten
      items (45%, p = 0.41 vs phase A) and the MAL was 17 +/- 16% (p = 0.19 vs 6 +/- 10
      days, p = 0.002) and high omega II score (items recorded every time they are
      performed) (0.8 +/- 1.3 vs 0.4 +/- 0.7, p = 0.01) were associated with forgetting
      items. The MAL was negatively correlated with the length of stay (r = -0.69, p <
      0.001) and omega score (r = -0.40, p = 0.001). CONCLUSION: In routine practice,
      scoring systems may underestimate medical activity.

PMID- 10394372
TI  - [Hemorrhagic mandibular metastasis of renal origin: usefulness of therapeutic
      embolization].
AB  - BACKGROUND: Vascular metastatic tumors of the mandible are unusual and management
      of bleeding may be difficult. CASE REPORT: An 83-year-old woman with a mandibular
      metastasis from a renal-cell carcinoma developed oral pain and episodes of
      bleeding of 2-weeks duration. Embolization was successful in stopping blood loss
      which occurred during surgical biopsy. Eight months after embolization, the
      patient is pain free and no bleeding has recurred. DISCUSSION: Embolization
      during arteriography procedures for tumor exploration can be useful in acute
      situations to improve survival and patient comfort. The aim may be palliative
      care or preparation for curative excision.

PMID- 10394373
TI  - [Muscarine syndrome. Experience at the Marseille Antipoison Center].

PMID- 10394374
TI  - [An unusual cause of unilateral mydriasis].

PMID- 10394375
TI  - [Hypocalcemia in a patient treated with estramustine].

PMID- 10394376
TI  - [Heart failure: an indication for beta blockaders].

PMID- 10394377
TI  - [Robots and news reports. Fears of the year 2000].

PMID- 10394378
TI  - [Access to health services: difficulties encountered by refugees residing on Ile
      de-France. Charity and full-coverage health care: two divergent concepts?].
AB  - Theoretically, since 1992, 100% of socially underprivileged persons residing in
      France have unlimited access to health care. However, before they become fully
      integrated into the society, many refugees in various legal situations do not
      have access to health care. The mechanisms behind this exclusion unmask the
      difficulties the health care system has in managing the underprivileged
      population. This work was conducted at the Comede health care facility specially
      designed to care for refugees. According to the current French legislation,
      health care protection and medical insurance coverage is a right of all persons
      living in France. Although the establishment of a large number of centers
      specifically designated for the underprivileged population has improved access to
      health care, repeat visits and uninterrupted care cannot be assured unless the
      patient has been awarded 100% free health care status. There are several
      obstacles to acquiring this status: complexity of the legal procedures,
      recipients unaware of their rights and the procedures of the health care system,
      information limited to specialized journals, restrictive or illegal action by the
      health protection services. All of these obstacles can be overcome if the
      patients are given precise information, notably by their physician. Instead of
      effectively applying the procedures concerning patients rights to health care,
      the system has developed free health care facilities which do not necessarily
      provide uninterrupted care. To provide the universal health care coverage
      promised by the legislators, the only criteria for access to care must be
      residence in France. Acquiring this status should be considerably simplified and
      requires the active participation of the entire health care community.

PMID- 10394379
TI  - [Behcet disease. Genetic factors, immunologic aspects and new therapeutic
      methods].
AB  - PATHOGENESIS: The pathogenesis of Behcetp3disease is still unknown, although a
      genetic predisposition appears to play an important role with a strong
      association with the MICA gene located between the HLA-B and TNF genes rather
      than HLA B51. Abnormal immune responses affect especially cellular immunity and
      significant T-cell proliferative responses by the gamma o subset of T cells are
      shown after stimulation with heat shock protein peptides. Systemic levels of the
      soluble TNF R-75 and IL 12 could be the best biological markers of disease
      activity. NEW THERAPEUTIC APPROACHES: Systemic colchicine being implicated in
      polynuclear neutrophil over-production of toxic super-oxides, its prescription
      for controlling eye involvement should be reevaluated. Steroids and
      immunosuppressive drugs are still the treatment of choice for severe
      manifestations of the disease. Beneficial effects of cyclosporine are established
      in uveitis. Tacrolimus (FK 506) and pentoxifylline may be valuable.

PMID- 10394380
TI  - [Relationship between corticotropin and arginine vasopressin in endocrine
      diseases].
AB  - VASOPRESSIN: The action of vasopressin (AVP) is not limited to regulating water
      excretion but also plays an essential role in regulating the corticotropic axis
      during stress. PHYSIOLOGY: Vasopressin is synthesized in the hypothalamus and
      stored in the posterior pituitary. It acts on 3 types of receptors (RV). RV1a are
      vascular receptors mediating the vasoconstrictor and glycogenolytic effects of
      the hormone. Anterior pituitary RV1b or V3 mediate stimulating effects on the
      corticotropic axis. Renal RV2 regulate water and urea excretion. Hypothetical
      extrarenal RV2 would be responsible for the vasodilator and procoagulant effects
      of the hormone. MODIFICATIONS IN ENDOCRINE DISEASES: Pituitary or adrenal
      hypocorticism syndromes include hyponatremia with secondary plasma hypoosmolality
      and reduced glomerular filtration due to the direct effect of glucocorticoids and
      also the effect of vasopressinism. Certain endogenous hypercorticisms appear to
      be related to an overexpression of RV: in ACTH-independent Cushingis syndrome,
      adrenal overexpression of eutopic RV1a, and in ACTH-dependent Cushingis syndrome,
      pituitary overexpression of eutopic RV1b or ectopic RV2. In addition,
      inappropriate secretion of antidiuretic hormone is frequent after transphenoidal
      surgery, particularly for corticotropic adenomas. DYNAMIC TESTS: The
      physiological response of ACTH and also AVP to corticotropin releasing hormone
      (CRH) in the petrous sinus, the unusual responses of certain corticotropic tumors
      to dDAVP, or certain forms of ACTH-independent hypercortisolism to lysine
      vasopressin (LVP) suggest excessive or ectopic expression of RV in corticotropic
      or adrenal cells: tumorgenesis of these cells could also depend, at least
      partially, on AVP.

PMID- 10394381
TI  - [Risk of transmission of hepatitis C through endoscopy of the digestive tract].
AB  - NOSOCOMIAL TRANSMISSION: Increasingly implicated in HCV infection in patients
      with no patent risk factors, nosocomial transmission has been demonstrated
      between patients hospitalized in the same ward and from health carers to
      patients. The risk of HCV transmission by medical instruments could only be
      quantified with a prospective study of examined patients. There is a theoretical
      risk for all endoscopic examinations whatever organ explored. Instrumental
      manipulations have been found as the only risk factor in blood donors. VALUE OF
      FORMER DISINFECTION GUIDELINES: Disinfection protocols for endoscopes have been
      found to eliminate 3 viruses (HCV, HBV, HIV). The endoscope-related risk could be
      due to minimal bleeding provoked by biopsies (risk factors independent of HCV
      infection) via the operator channel. THREE REPORTED CASES OF HVC INFECTION: One
      case of HVC infection following retrograde cholangiography and two after
      coloscopy have been reported. In all three cases disinfection was found to be
      insufficient. Recently, an official statement by the French health authorities
      indicates that a 20-min gluteraldehyde bath is necessary for optimal efficacy.
      Instruments susceptible to cause bleeding must be sterilized. The sterilization
      process must be tracable. The anesthesia-related risk appears to be due to use of
      multidose bottles or reuse of syringes. SAFE ENDOSCOPY: Disinfection procedures
      must be rigorously applied. One new perspective is the culture of titratable
      virus models. Several arguments show that well-conducted disinfection of
      endoscopes and medical instruments can eliminate all risk of viral transmission,
      including HCV.

PMID- 10394382
TI  - Progress of the Proton-Ion Medical Machine Study (PIMMS).
AB  - The Proton-Ion Medical Machine Study (PIMMS) was set up following an agreement
      between Professor M. Regler of the Med-AUSTRON (Austria) and Professor U. Amaldi
      of the TERA Foundation (Italy) to join their efforts in the design of a medical
      synchrotron that could later be adapted to individual national needs. CERN agreed
      to host this study inside its PS Division and to contribute one full-time member
      to the study team. The study group has worked in collaboration with GSI (Germany)
      and was more recently joined by Onkologie 2000 (Czech Republic). Work started in
      January 1996 and is expected to finish during 1998. The agreed aim of the study
      was to investigate and design a generic facility that would allow the direct
      clinical comparison of protons and carbon ions for cancer treatment. The
      accelerator was to be designed primarily for high-precision active beam scanning
      with both protons and ions, but was also to be capable of delivering proton beams
      with passive spreading.

PMID- 10394383
TI  - Aspects of medical physics of Med-Austron.
AB  - Before starting proton/light ion therapy with the Med-Austron treatment units a
      transcription of the concepts of photon therapy is necessary: the needed beam
      directions, the influence of beam geometry on the treatment planning volume,
      correction factors and properties of solid state detectors. Especially the
      effects of the active beam scanning must be taken under consideration. From a
      medical physicist's point of view this paper describes the status quo and gives
      an overview of open questions, which must be answered before starting patient
      treatment. Arguments for a gantry were presented as well as a comparison of PTVs
      in photon and proton/light ion therapy. In the field of dosimetry diamond-,
      electron-spin- and lyoluminescence detector materials were tested with photons
      and some of them irradiated with heavy particles like neutrons and protons. The
      results show that these materials are suitable in general, but detailed
      measurements must follow.

PMID- 10394384
TI  - Treatment planning for conformal stereotactic radiotherapy.
AB  - Due to three dimensional planning techniques it is possible to conform the high
      dose region precisely to a target volume inside the brain. Special patient
      fixation and positioning systems allow a high precision in repositioning of the
      patient thus allowing fractionated stereotactic radiotherapy. Conformation can be
      achieved with many different irradiation techniques for example with a linear
      accelerator using noncoplanar arcs or conformal static beams. Noncoplanar arc
      therapy with multiple isocenters and conformal static beam therapy with one
      isocenter are compared. In both cases the DVHs of the planning target volume and
      normal tissue are calculated and discussed.

PMID- 10394385
TI  - The NAC proton treatment planning system.
AB  - A three-dimensional proton treatment planning system called PROXELPLAN has been
      used at the National Accelerator Centre (NAC) since October 1994. This system is
      entirely based on the VOXELPLAN planning system, developed at the Deutches
      Krebsforschungszentrum (DKFZ), Heidelberg, Germany. The VOXELPLAN system provides
      the treatment planning infrastructure while the proton dose distributions are
      calculated using a software module that was initially developed at the Royal
      Marsden Hospital, UK. The proton module has been extensively modified and
      refined. It uses a rayline-tracing algorithm which is suitable for planning
      current treatments but is not sufficiently dynamic to accommodate the use of
      compensators. A sophisticated pencil beam algorithm is currently under
      development.

PMID- 10394386
TI  - Treatment planning for light ions: how to take into account relative biological
      effectiveness (RBE).
AB  - A new treatment planning program was developed for the heavy ion therapy facility
      at GSI, which is tailored to the special needs for an active beam delivery using
      a magnetic raster scanner. It also includes a biological model for the estimation
      of biological effective dose for carbon ions and realizes a fully biological
      treatment planning. Biological effective dose distributions and RBE maps can be
      displayed and assessed from the graphical user interface.

PMID- 10394387
TI  - Treatment planning for the heavy-ion facility at GSI.
AB  - A new treatment planning program was developed for the heavy-ion therapy facility
      at GSI. In addition, a concise quality standard for treatment planning has been
      set up. It covers acceptance and constancy checks of all critical aspects in
      treatment planning. Dose verification measurements done during the commissioning
      phase show an overall good agreement with the treatment planning calculations.

PMID- 10394388
TI  - Initial experience of using an active beam delivery technique at PSI.
AB  - At PSI a new proton therapy facility has been assembled and commissioned. The
      major features of the facility are the spot scanning technique and the very
      compact gantry. The operation of the facility was started in 1997 and the
      feasibility of the spot scanning technique has been demonstrated in practice with
      patient treatments. In this report we discuss the usual initial difficulties
      encountered in the commissioning of a new technology, the very positive
      preliminary experience with the system and the optimistic expectations for the
      future. The long range goal of this project is to parallel the recent
      developments regarding inverse planning for photons with a similar advanced
      technology optimized for a proton beam.

PMID- 10394390
TI  - Oblique gantry--an alternative for heavy-ion cancer therapy.
AB  - PROBLEM: To design a gantry-type beam delivery system for heavy-ion therapy
      beams. In order to allow for installation of the gantry in hospital environment,
      small overall gantry size and low weight are required. The isocentric
      configuration is to be preferred. SOLUTION: A new gantry concept with oblique
      output beam is introduced. Transformations between the treatment angle, angles of
      gantry and patient table rotations are derived. RESULTS AND CONCLUSIONS: The
      isocentric gantry with the overall radius of 2.8 m is feasible using the 60
      degrees output beam. The oblique output beam imposes some restrictions on gantry
      capabilities, which has to be carefully evaluated by radiation oncology
      community.

PMID- 10394389
TI  - The GSI Cancer Therapy Project.
AB  - At the Heavy Ion Research Institute GSI in Darmstadt an experimental cancer
      treatment program with a five years duration has been developed. A new method for
      cancer treatment with ions is applied, using rasterscan method in addition to an
      active pulse to pulse variation of ion beam properties, including the energy,
      intensity and focusing. An overview of this Cancer Therapy Project is presented,
      that covers both accelerator aspects to provide the required beam variations
      within a short time and the installations at the treatment place for rasterscan
      control. In addition to a description of the technical design (control-hard- and
      software) experimental results will be shown, containing the achieved beam
      properties and measurements of rasterscan performance.

PMID- 10394392
TI  - Status report of the NAC particle therapy programme.
AB  - The 200 MeV cyclotron facility at the National Accelerator Centre has been
      operational since 1987. Between September 1988 and December 1997 a total of 973
      patients (26,916 fields) had been treated on the 66 MeV p+Be isocentric neutron
      therapy system. Patients are currently being treated according to several
      protocols, including tumors of the head and neck, salivary gland and breast and
      soft tissue sarcomas, uterine sarcomas and paranasal sinuses. A multiblade post
      collimator trimmer has recently being installed. This device provides improved
      neutron beam shaping capability. Between September 1993 and December 1997 a total
      of 243 patients (4008 fields) had been treated (mainly intracranial stereotactic
      irradiations) on the fixed horizontal 200 MeV proton therapy facility. The
      facility incorporates an innovative automatic patient positioning system. Two new
      fixed beam lines for proton therapy are presently being designed (horizontal and
      30 degrees to the vertical) for an existing unused treatment vault. Spot scanning
      systems will be developed for both beam lines.

PMID- 10394393
TI  - The application of PET to quality assurance of heavy-ion tumor therapy.
AB  - At the new heavy ion tumor therapy facility of the Gesellschaft fur
      Schwerionenforschung at Darmstadt positron emission tomography (PET) has been
      implemented for in-beam and in-situ therapy control, i.e. during the tumor
      irradiation. The components necessary for this dedicated PET-imaging and their
      integration into the framework of therapy planning and quality assurance of heavy
      ion cancer treatments are presented. Results of the first application of this PET
      method to patient treatments are reported.

PMID- 10394391
TI  - Nuclear data for radiotherapy: presentation of a new ICRU report and IAEA
      initiatives.
AB  - An ICRU report entitled "Nuclear Data for Neutron and Proton Radiotherapy and for
      Radiation Protection" is in preparation. The present paper presents an overview
      of this report, along with examples of some of the results obtained for evaluated
      nuclear cross sections and kerma coefficients. These cross sections are evaluated
      using a combination of measured data and the GNASH nuclear model code for
      elements of importance for biological, dosimetric, beam modification and
      shielding purposes. In the case of hydrogen both R-matrix and phase-shift
      scattering theories are used. In the report neutron cross sections and kerma
      coefficients will be presented up to 150 MeV and proton cross sections up to 250
      MeV. An IAEA Consultants' Meeting was also convened to examine the "Status of
      Nuclear Data needed for Radiation Therapy and Existing Data Development
      Activities in Member States". Recommendations were made regarding future
      endeavours.

PMID- 10394394
TI  - Quality assurance at the heavy-ion therapy facility at GSI.
AB  - In the present stage between the technological realization and the clinical
      phase, quality management gains a predominant role at the heavy ion therapy
      facility at GSI. Specific quality inspection procedures had to be developed for
      the subsequent parts of the beam delivery system, the treatment planning, the
      raster scanning device, the patient positioning, the dose verification and the
      safety interlock system. In the meantime the acceptance test of the whole
      facility has been carried out and an overview about our first experience with
      quality assurance procedures at the heavy ion irradiation facility is given, with
      a special emphasis on the medical physics part.

PMID- 10394395
TI  - RBE, reference RBE and clinical RBE: applications of these concepts in hadron
      therapy.
AB  - Introduction of heavy particles (hadrons) into radiation therapy aims at
      improving the physical selectivity of the irradiation (e.g. proton beams), or the
      radiobiological differential effect (e.g. fast neutrons), or both (e.g. heavy-ion
      beams). Each of these new therapy modalities requires several types of
      information before prescribing safely the doses to patients, as well as for
      recording and reporting the treatments: (i) absorbed dose measured in a
      homogeneous phantom in reference conditions; (ii) dose distribution computed at
      the level of the target volume(s) and the normal tissues at risk; (iii) radiation
      quality from which a RBE evaluation could be predicted and (iv) RBE measured on
      biological systems or derived from clinical observation. In hadron therapy, the
      RBE of the different beams raises specific problems. For fast neutrons, the RBE
      varies within wide limits (about 2 to 5) depending on the neutron energy
      spectrum, dose, and biological system. For protons, the RBE values range between
      smaller limits (about 1.0 to 1.2). A clinical benefit can thus not be expected
      from RBE differences. However, the proton RBE problem cannot be ignored since
      dose differences of about 5% can be detected clinically in some cases. The
      situation is most complex with heavy ions since RBE variations are at least as
      large as for fast neutrons, as a function of particle type and energy, dose and
      biological system. In addition, RBE varies with depth. Radiation quality thus has
      to be taken into account when prescribing and reporting a treatment. This can be
      done in different ways: (a) description of the method of beam production; (b)
      computed LET spectra and/or measured microdosimetric spectra at the points
      clinically relevant; (c) RBE determination. The most relevant RBE data are those
      obtained for late tolerance of normal tissues at 2 Gy per fraction ("reference
      RBE"). The "clinical RBE" selected by the radiation oncologist when prescribing
      the treatment will be close to the reference RBE, but other factors (such as
      heterogeneity in dose distribution) may influence the selection of the clinical
      RBE. Combination of microdosimetric data and experimental RBE values improves the
      confidence in both sets of data.

PMID- 10394396
TI  - RBE and its interpretation.
AB  - Beams of heavy ions like carbon offer both, an improved dose distribution
      superior to any other type of radiation and an increased relative biological
      efficiency, RBE, which is restricted to the target volume only. The various
      dependencies of RBE on dose, atomic number and tissue sensitivity are described
      in this paper and are discussed in the framework of the local effect model.

PMID- 10394397
TI  - Risk assessment for cancer induction after low- and high-LET therapeutic
      irradiation.
AB  - The risk of induction of a second primary cancer after a therapeutic irradiation
      with conventional photon beams is well recognized and documented. However, in
      general, it is totally overwhelmed by the benefit of the treatment. The same is
      true to a large extent for the combinations of radiation and drug therapy. After
      fast neutron therapy, the risk of induction of a second cancer is greater than
      after photon therapy. Neutron RBE increases with decreasing dose and there is a
      wide evidence that neutron RBE is greater for cancer induction (and for other
      late effects relevant in radiation protection) than for cell killing. Animal data
      on RBE for tumor induction are reviewed, as well as other biological effects such
      as life shortening, malignant cell transformation in vitro, chromosome
      aberrations, genetic effects. These effects can be related, directly or
      indirectly, to cancer induction to the extent that they express a "genomic"
      lesion. Almost no reliable human epidemiological data are available so far. For
      fission neutrons a RBE for cancer induction of about 20 relative to photons seems
      to be a reasonable assumption. For fast neutrons, due to the difference in energy
      spectrum, a RBE of 10 can be assumed. After proton beam therapy (low-LET
      radiation), the risk of secondary cancer induction, relative to photons, can be
      divided by a factor of 3, due to the reduction of integral dose (as an average).
      The RBE of heavy-ions for cancer induction can be assumed to be similar to
      fission neutrons, i.e. about 20 relative to photons. However, after heavy-ion
      beam therapy, the risk should be divided by 3, as after proton therapy due to the
      excellent physical selectivity of the irradiation. Therefore a risk 5 to 10 times
      higher than photons could be assumed. This range is probably a pessimistic
      estimate for carbon ions since most of the normal tissues, at the level of the
      initial plateau, are irradiated with low-LET radiation.

PMID- 10394398
TI  - Oxygen tension in transplanted mouse osteosarcomas during fractionated high-LET-
      and low-LET radiotherapy--predictive aspects for choosing beam quality?
AB  - PURPOSE: The lower OER of high-LET radiations, compared to conventional (low-LET)
      radiations, has often been put forward as an argument for using high-LET
      radiotherapy in the management of hypoxic tumours. Among the different neutron
      beams used in therapy, the reactor fission neutrons have the lowest OER. The aim
      of the present study is to follow the variations of tumour oxygenation status
      during fractionated irradiation with different radiation qualities. Little
      information is available so far after fractionated high-LET irradiation. In
      addition, the RBE of reactor fission neutrons for effects on tumours and on
      normal tissues are compared. MATERIAL AND METHODS: Murine OTS 64-osteosarcomas
      were transplanted in 102 balb-C mice and irradiated by 36 Gy of photons in
      fractions of 3 Gy five times a week (group P-36/3) or by 12 Gy of reactor fission
      neutrons in fractions of 2 Gy two times a week (group N-12/2). Irradiations
      started at a tumor volume of 500 to 600 mm3. A third group received no
      radiotherapy, but all investigations (group CG). Tumor volume and tumor
      oxygenation were measured once a week under therapy and during three weeks after
      therapy. For in vivo-evaluation of oxygen status a computerized polarographic
      needle electrode system (KIMOC pO2 histograph, Eppendorf) was used. The median
      pO2 and the hypoxic fraction (pO2 values < 5 mm Hg) of single tumors and of total
      groups were calculated from pooled histograms and from row data as well. RESULTS:
      In correlation with the increase of tumor volume, from day 1 to day 42 of follow
      up the median pO2 decreased from 20 mm to 8 mm Hg and the hypoxic fraction
      increased from 7% to 31%. After fractionated photon therapy a growth delay of
      three weeks was observed. Six weeks after beginning of the irradiation the median
      tumor volume had been doubled again. After fission neutron therapy growth delay
      continued until the end of the follow-up period. In both of the irradiated groups
      a significant decrease of median pO2 values and an increase of the hypoxic
      fraction were observed under radiotherapy. Hypoxia was more intensive after
      neutrons with a decrease of the median pO2 from 20 mm Hg to 1 mm Hg vs. 10 mm Hg
      after photon therapy and with an increase of the hypoxic fraction from 7% to 78%
      vs. 36% respectively. Two weeks after the end of therapy the median pO2 and the
      hypoxic fraction of both treated groups reached the levels prior to irradiation
      indicating a complete reoxygenation. CONCLUSION: During fractionated irradiation
      of murine osteosarcomas with photons and reactor fission neutrons, a marked
      hypoxia was observed for both radiation qualities, but hypoxia was more intense
      during fractionated neutron irradiation. After irradiation, a complete
      reoxygenation occurred in both groups independently of the degree of hypoxia
      observed during the treatment. The RBE of reactor fission neutrons, after
      fractionated irradiation, was much higher for effects on murine osteosarcomas
      compared to their RBE observed for normal tissues in previous experiments.
      Present data are in agreement with our clinical observations on more than 300
      patients treated with reactor fission neutrons for advanced and hypoxic tumours
      with various histologies.

PMID- 10394400
TI  - The role of high-LET radiotherapy compared to conformal photon radiotherapy in
      adenoid cystic carcinoma.
AB  - Tumors of the base of skull represent a challenging radiooncological target due
      to their close proximity to dose limiting critical normal tissue structures. A
      critical review of the literature provides evidence that high-LET radiotherapy
      offers a therapeutic gain factor compared to low-LET radiation and should be the
      treatment of choice in advanced salivary gland malignancies, which are inoperable
      or not completely resected, and in recurrent disease. Modern techniques of
      conformal high LET radiotherapy, e.g. heavy ion beam radiotherapy, will help to
      reduce the long and the short term toxicity of radiotherapy.

PMID- 10394399
TI  - Proton therapy for tumors of the skull base.
AB  - Charged particle beams are ideal for treating skull base and cervical spine
      tumors: dose can be focused in the target, while achieving significant sparing of
      the brain, brain stem, cervical cord, and optic nerves and chiasm. For skull base
      tumors, 10-year local control rates with combined proton-photon therapy are
      highest for chondrosarcomas, intermediate for male chordomas, and lowest for
      female chordomas (94%, 65%, and 42%, respectively). For cervical spine tumors, 10
      year local control rates are not significantly different for chordomas and
      chondrosarcomas (54% and 48%, respectively), nor is there any difference in local
      control between males and females. Observed treatment-related morbidity has been
      judged acceptable, in view of the major morbidity and mortality which accompany
      uncontrolled tumor growth.

PMID- 10394401
TI  - Results of fast neutron therapy of adenoid cystic carcinoma of the salivary
      glands.
AB  - INTRODUCTION: Patients with adenoid cystic carcinoma (ACC) of the salivary glands
      in the head and neck region have been reported to benefit from neutron
      radiotherapy according to significant clinical experience. A prospective clinical
      trial on the efficacy and treatment related morbidity of fast neutron
      radiotherapy was performed between 1986 and 1995 at the (d + T) 14 MeV neutron
      generator in Munster. MATERIAL AND METHODS: 72 consecutive patients with ACC were
      treated with fast neutrons, 66 after surgery, 6 for primarily unresectable
      disease, 43/66 for macroscopic residual disease, 23/66 for unresectable recurrent
      disease. 45/72 tumors were localized in the minor, 27 in the major salivary
      glands. T-stage was in 13 pts T2, in 33 T3, in 26 T4; positive nodes were in 10
      pts, M+ in 15 pts. Mean tumor volume was 89 cm3. Neutron therapy was 15.03 Gy in
      3 weeks with 1.67 Gy per fraction three times per week. Individual computer
      assisted treatment planning was performed based on CT and/or MRI, using bolus
      material if necessary. Target volume was the macroscopic tumor volume with a
      generous safety margin. RESULTS: Complete response was achieved in 28 pts,
      partial response in 35 pts. Local control was observed in 73.4% after a mean
      observation period of 36 months. Overall and recurrence free survival was 85%/81%
      at two years, and 58%/53% at 5 years (Kaplan-Meier). In univariate analysis tumor
      volume (> 100 cm3), distant metastases, histologic subtype (solid) and neutron
      dose (< 15 Gy) turned out to be significant parameters for predicting outcome, in
      multivariate analysis tumor volume and histologic subtype remained the only
      significant parameters. Acute morbidity was grade III/IV (EORTC/RTOG) in 6% for
      skin (desquamation), in 4% for mucosa (ulceration), late morbidity (grade III/IV)
      in one patient with local temporal brain necrosis. CONCLUSION: According to this
      experience and taking into account the so far collected experience, fast neutron
      radio-therapy remains the treatment of choice for large and unresectable primary
      and recurrent ACC, and residual disease after surgery.

PMID- 10394403
TI  - Fractionated stereotactic radiotherapy with linear accelerator for uveal melanoma
      -preliminary Vienna results.
AB  - PURPOSE: To study local tumor control and radiogenic side-effects after
      fractionated stereotactic radiotherapy for uveal melanoma. PATIENTS AND METHODS:
      Between June 1997 and February 1998, 21 patients suffering from uveal melanomas
      have been treated with stereotactic 6 MeV LINAC (Saturne 43, General Electric,
      France) in conjunction with a stereotactic frame system (BrainLAB, Germany).
      Immobilization of the eye was ensured with an optical fixation system which was
      proven reliable. During radiotherapy, movements of the irradiated eye were
      controlled on a monitor and documented by video recording. All patients co
      operated very well with the optical fixation system. In 1164 measurements, the
      median value of horizontal deviation of the diseased eye during treatment was 0.3
      mm (range: 0 to 1.3 mm). Median vertical deviation was 0.2 mm (range: 0 to 1.2
      mm). For all patients, mean tumor prominence before treatment was 6.0 +/- 2.2 mm.
      In 20 patients, the total dose of 70 Gy (at 80%) was delivered in 5 fractions
      within 10 days. In one patient with a ciliary body tumor, the total dose of 70 Gy
      was divided into 7 fractions for better sparing of the anterior eye segment.
      RESULTS: After a follow-up of at least 6 months, local tumor control was seen in
      all eyes. Mean tumor thickness reduction after 3, 6 and 9 months was 7%, 13% and
      31%, respectively. Up to now, only mild subacute side-effects located in the
      anterior eye segment have been noticed. CONCLUSION: Optical fixation of the eye
      allows high precision stereotactic radiotherapy with small safety margins.
      Fractionated stereotactic radiotherapy and 70 Gy total dose delivered in 5
      fractions seems to be appropriate for local tumor control in uveal melanoma.
      Further long-term studies with extended number of patients will be necessary to
      conclude on the use of linac-based fractionated stereotactic radiotherapy for
      uveal melanoma.

PMID- 10394402
TI  - Proton therapy for uveal melanomas and other eye lesions.
AB  - Charged particle beams are ideal for treating intra-ocular lesions, since they
      can be made to deposit their dose in the target, while significantly limiting
      dose received by non-involved ocular and orbital structures. Proton beam
      treatment of large numbers of uveal melanoma patients consistently achieves local
      control rates in excess of 95%, and eye retention rates of approximately 90%.
      Visual preservation is related to initial visual acuity, tumor size and location,
      and dose received by the macula, disc, and lens. The probability of distant
      metastasis is increased by larger tumor diameter, more anterior tumor location,
      and older patient age. Proton therapy is also effective treatment for patients
      with ocular angiomas, hemangiomas, metastatic tumors, and retinoblastomas, and
      may be beneficial for patients with exudative ("wet") age-related macular
      degeneration.

PMID- 10394404
TI  - Treatment results of fast neutron irradiation in soft tissue sarcomas.
AB  - PURPOSE: Surgery is the standard treatment of soft-tissue sarcomas. Adjuvant
      radiotherapy with photons after less radical resection can improve local control.
      The rate of tumor control achieved in patients with G1 and G2 soft tissue
      sarcomas incompletely resected and treated postoperatively with neutron
      irradiation is similar to that seen in patients undergoing complete tumor
      resection and adjuvant photon irradiation. PATIENTS AND METHODS: At the
      Department of Radiotherapy and Radiation Oncology of the University of Munster,
      61 patients with soft tissue sarcomas were irradiated postoperatively with fast
      neutrons. Mainly tumors of low or intermediate malignancy (R0; 27%; R1, 21%; R2,
      52%) were treated. Malignant fibrous histiocytoma, liposarcoma, and neurogenic
      sarcomas dominated. 46 patients were irradiated with fast neutrons alone, and 15
      patients were treated with mixed beam therapy (photons and neutrons). RESULTS:
      The median follow-up period was 44 months. Overall five-year survival probability
      analysed by Kaplan-Meyer method was 42.5%. The local control rate was 57.7%. 15
      patients showed complete remission, 18 patients had a partial remission. Only 11%
      of the patients showed grade III and IV side effects during neutron irradiation.
      CONCLUSION: Neutron irradiation is efficocious in treating highly and
      intermediately differentiated soft tissue sarcomas. The result of surgical
      resection seems to be a very important prognostic factor for patients with soft
      tissue sarcomas.

PMID- 10394405
TI  - Three dimensional conformal neutron radiotherapy for prostate cancer.
AB  - The conditions for safe and effective conformal neutron radiotherapy have been
      established at Wayne State University.

PMID- 10394406
TI  - Conformal proton beam therapy of prostate cancer--update on the Loma Linda
      University medical center experience.
AB  - BACKGROUND: The ability to eradicate localized prostate cancer is dependent upon
      the radiation dose which can be delivered to the prostate. This dose is often
      limited by the tolerance of normal organs (rectum, bladder). Conformal beam
      therapy takes advantage of the unique depth dose characteristics of heavy charged
      particles (the Bragg Peak) to escalate the radiation dose delivered to the
      prostate while minimizing treatment-related toxicity. METHOD: 643 patients with
      localized prostate cancer were treated with protons alone or a combination of
      protons and photons. All treatment was planned on a 3-D planning system and all
      received doses between 74-75 CGE (Cobalt Gray Equivalent) at 1.8-2.0 CGE/day.
      Patients were evaluated for toxicity and response to treatment. RESULTS: Five
      year actuarial clinical and biochemical disease-free survival rates for the
      entire group are 89 and 79% respectively. A statistically significant difference
      in biochemical disease-free survival was seen between patients in the "early"
      (T1b-2b, PSA < 15) and "advanced" (T1b-2b, PSA > 15 or T2c-T4, PSA < 50)
      subgroups (89% vs. 68% at 4.5 years, p < 0.001). A PSA nadir of less than 0.51
      ng/ml predicted for the highest chance of freedom from biochemical recurrence.
      Minimal radiation proctitis was seen in 21% of patients; toxicity of greater
      severity was seen in less than 1%. CONCLUSIONS: Conformal proton beams therapy
      produced high rates of response and minimal toxicity. A phase III dose escalation
      trial is in progress to help define the optimum radiation dose for the treatment
      of early stage prostate cancer.

PMID- 10394407
TI  - Three dimensional conformal photon radiotherapy at a moderate dose level of 66 Gy
      for prostate carcinoma: early results.
AB  - BACKGROUND: The therapeutic outcome and toxicity of 3-D conformal photon external
      beam therapy of prostate cancer is well documented in the literature. Progress is
      still in work for optimization of treatment strategies by risk-adapted dose
      escalation studies to improve local tumor control without increase of radiation
      side effects. PATIENTS AND METHODS: We present our experience of 291 patients
      treated between January 1994 and August 1997 with a 3-D planned four-field box
      technique and a central dose of 66 Gy. Biochemical response of patients with
      radiotherapy alone (group 1, n = 72 pts.) has been analyzed in detail. Acute
      radiation side effects are given for all patients (n = 291), late radiation side
      effects are given for patients treated between Jan 1994 and Jan 1996 with a
      median follow-up of 22 months (n = 115 pts.). RESULTS: We have observed a
      biochemical response (nadir PSA < 1 after 12 months, < 2 after 6 months) for
      patients treated with radiotherapy alone without hormone manipulation in 67%.
      Incidence of late rectal and bladder morbidity (grade 2 and 3) was 9.4% and 4%,
      respectively. CONCLUSION: Compared to other reports our results indicate a high
      rate of local tumor control (early biochemical response) and a low rate of late
      morbidity. Nevertheless, we will start a risk-adapted dose escalation study up to
      74 Gy for unfavorable subgroups (G2-3, Gleason Score > 7, PSA > 10) to improve
      treatment outcome.

PMID- 10394408
TI  - Prostate preservation by combined external beam and HDR brachytherapy in nodal
      negative prostate cancer.
AB  - PURPOSE: The combined external beam- and high-dose rate brachytherapy (HDR-BT) of
      localized prostate cancer was introduced at Kiel University in 1986. The aim of
      this intermediate analysis was to judge the Kiel method of localized prostate
      cancer radiation treatment after ten years experience. PATIENTS AND METHODS: In
      the past ten years 174 patients with histological proven localized prostate
      cancer were subjected to combined tele-/HDR-brachytherapy. Local staging in all
      of the cases by transrectal ultrasound, nodal staging in the majority of the
      cases by CT or MRI. Average age of the patients was 68.2 years (44-84). According
      to AJCC/UICC staging T1B, T2, T3 was found in 2, 113 and 59 cases, respectively.
      Highly differentiated tumors (G1) were found in 27, moderately differentiated
      (G2) in 87, poorly differentiated (G3) in 60 cases. The mean follow-up was 47.1
      months with the median of 51.7 months. Total prescribed dose 50 Gy on the small
      pelvis and 70 Gy on the prostate capsule due to the integration of two, 15 Gy
      each, HDR-brachytherapy fractions in 6 weeks. RESULTS: Ten patients died of
      prostate cancer and 18 of intercurrent diseases resulting in a 5 years overall
      survival rate of 83% and tumor specific survival rate of 94%. Twenty-one patients
      showed a clinical progression, of these 14 systemic, 5 local and 2 both systemic
      and local. Additional 16 patients had PSA elevation only. The 5-years biochemical
      and/or clinical progression-free survival in the cohort was 79% and 73% for the
      T3 tumors. Side effects were 27 cases of proctitis/colitis and 20 cases of
      dysuria/cystitis. CONCLUSION: The integrated HDR-BT combined with external beam
      radiation treatment is a method with excellent tumor control rates at five years
      superior to those of external beam treatment alone or external beam combined with
      iodine-125 implants. This form of radiotherapy would appear to be particularly
      well-suited to treatment of advanced localized (T3) tumors.

PMID- 10394409
TI  - Proton radiation therapy for pediatric malignancies: status report.
AB  - Proton radiation therapy allows high degrees of conformity of radiation dose
      around irregular target volumes of variable sizes. Long-term follow-up in adults,
      and preliminary data for pediatric patients suggest that local control and
      survival can be improved in histologies requiring high radiation dose, without
      increased incidence of late toxicities. In the pediatric patient, avoidance of
      even moderate amounts of irradiation to normal tissues is of paramount
      importance. Conformal 3-D planned proton irradiation can contribute to this goal.
      For late effects, one can expect that reduced dose and volume irradiated will
      reduce radiation effects. However, full expression of late effects may occur in
      children five to ten years after treatment, or even later. Proton irradiation is
      therefore also indicated and used at Loma Linda University Medical Center for
      pediatric solid neoplasms in which conventional dose levels yield satisfactory
      local control and survival.

PMID- 10394410
TI  - Proton beam therapy (PT) in the management of CNS tumors in childhood.
AB  - At the Centre de Protontherapie d'Orsay, nine children with intra-cranial
      malignancies were treated between July 1994 and January 1998. Immediate and late
      tolerances were excellent in all cases (follow-up 2 to 50 months). Two patients
      recurred locally (marginal failures), seven are alive and doing well. At Loma
      Linda, 28 children were treated between 1991 and 1994, 16 for a benign tumor of
      the brain and twelve for a malignant one. With a follow-up of seven to 49 months,
      three patients died (grade 2 to 4 gliomas), one is living with a persistent
      disease. Four children had treatment-related toxicity (one cataract, two hormonal
      failures and two seizures). The other children are doing well. At MGH Boston, 18
      children with skull base-cervical spine chordomas have been reported. At five
      years, actuarial survival and disease-free survival have been 68 and 63%,
      respectively. Children with cervical sites had a worse prognosis (p = 0.008).
      Four children had radiation-related morbidity: two pituitary failures, one
      temporal lobe necrosis, one temporal muscle fibrosis. In this experience, such
      rare tumors seemed to behave in children like in adults.

PMID- 10394411
TI  - Cancer epidemiology and patient recruitment for hadron therapy.
AB  - Patient recruitment is an important issue in the feasibility study of a hadron
      therapy programme such as Med-AUSTRON. Data on cancer incidence in Europe,
      Austria, and neighbouring countries are reviewed for the most frequent tumors
      suitable for charged particle therapy. From these data, the numbers of potential
      patients suitable for MED-AUSTRON are derived for each tumor site by applying the
      coefficients proposed in the EULIMA-1992 feasibility study. Whatever the
      assumptions made, a sufficient and adequate recruitment for MED-AUSTRON can be
      expected. However, an appropriate referring system has to be established within
      Austria and also in the neighbouring countries.

PMID- 10394413
TI  - Some factors influencing the cost of a hospital based proton therapy centre.
AB  - The nowadays availability of state-of-the-art proton therapy equipment from
      commercial companies, on a contract basis, makes it easier to precisely account
      for equipment prices as well as to better evaluate the consequences of the
      equipment characteristics on operating costs and possible patient throughput.
      This paper presents some data which can be used for the evaluation of these
      items.

PMID- 10394412
TI  - Costs of standard and conformal photon radiotherapy in Austria.
AB  - BACKGROUND: The increasing shortage of health care resources necessitates a more
      rational use of the funds available. New treatment strategies in radiotherapy
      generate additional expenses. In this study, the expenses incurred for standard
      radiotherapy in patients with prostate and lung cancer were compared with those
      for conformal photon therapy. MATERIAL AND METHODS: To itemize the direct costs,
      a distinction was made between pretreatment measures (independent of the tumor
      entity) and treatment measures proper. The cost analysis was based on a break
      down by personnel, material and equipment depreciation costs. Overheads were not
      considered. RESULTS: Conformal photon therapy was found to be over 60% more
      expensive than standard radiotherapy for prostate cancer and over 100% for lung
      cancer. The additional expenses were attributable to the more expensive linear
      accelerator equipment and the additional time needed for CT localization and
      planning as well as for patient positioning and verification during daily
      therapy. CONCLUSION: Conformal photon therapy should be examined for its clinical
      usefulness in dedicated studies and allocated an adequate place in the
      reimbursement schemes for radiotherapy. If it should be found to produce higher
      cure rates, other costing procedures, e.g. cost--benefit analyses, should be used
      for establishing the costs of treatment strategies.

PMID- 10394414
TI  - The cost-effectiveness of mixed beam neutron-photon radiation therapy in the
      treatment of adenocarcinoma of the prostate.
AB  - The results of clinical trials in the treatment of adenocarcinoma of the prostate
      using, mixed beam neutron/photon therapy, neutrons alone and photon therapy in
      combination with hormone treatment are compared. These trials indicate that
      neutron therapy is superior to photon/hormone therapy in achieving local control.
      The costs of delivering these two different therapies in a large US academic
      radiation oncology center at Wayne State University (WSU) are compared. The cost
      of a full course of mixed beam therapy is $20,142 compared to $18,871 for the
      photon/hormone treatment. Although the WSU neutron facility is a state-of-the-art
      installation, it is also a prototype device; it is estimated that a modern
      neutron facility based on this design would operate more cost effectively
      reducing the cost of a course of mixed beam therapy to $18,532.

PMID- 10394415
TI  - Organisation and management of the first clinical trial of BNCT in Europe (EORTC
      protocol 11961).EORTC BNCT study group.
AB  - Boron Neutron Capture Therapy is based on the ability of the isotope 10B to
      capture thermal neutrons and to disintegrate instantaneously producing high LET
      particles. The only neutron beam available in Europe for such a treatment is
      based at the European High Flux Reactor HFR at Petten (The Netherlands). The
      European Commission, owners of the reactor, decided that the potential benefit of
      the facility should be opened to all European citizens and therefore insisted on
      a multinational approach to perform the first clinical trial in Europe on BNCT.
      This precondition had to be respected as well as the national laws and
      regulations. Together with the Dutch authorities actions were undertaken to
      overcome the obvious legal problems. Furthermore, the clinical trial at Petten
      takes place in a nuclear research reactor, which apart from being conducted in a
      non-hospital environment, is per se known to be dangerous. It was therefore of
      the utmost importance that special attention is given to safety, beyond normal
      rules, and to the training of staff. In itself, the trial is an unusual Phase I
      study, introducing a new drug with a new irradiation modality, with really an
      unknown dose-effect relationship. This trial must follow optimal procedures,
      which underscore the quality and qualified manner of performance.

PMID- 10394416
TI  - Postoperative treatment of glioblastoma with BNCT at the petten irradiation
      facility (EORTC protocol 11,961).
AB  - The boron neutron capture therapy is based on the reaction occurring between the
      isotope 10B and thermal neutrons. A low energy neutron is captured by the nucleus
      and it disintegrates into two densely ionising particles, Li nucleus and He
      nucleus (alpha particle), with high biological effectiveness. On the basis of
      comprehensive preclinical investigations in the frame of the European
      Collaboration with Na2B12H11SH (BSH), as boron delivery agent, the first European
      phase I, clinical trial was designed at the only available epithermal beam in
      Europe, at the High Flux Reactor, Petten, in the Netherlands. The goal of this
      study is to establish the safe BNCT dose for cranial tumors under defined
      conditions. BNCT is applied as postoperative radiotherapy in 4 fractions, after
      removal of the tumor for a group of patients suffering from glioblastoma, who
      would have no benefit from conventional treatment, but have sufficient life
      expectancy to detect late radiation morbidity due to BNCT. The starting dose is
      set at 80% of the dose where neurological effects occurred in preclinical large
      animal experiments following a single fraction. The radiation dose will be
      escalated, by constant boron concentration in blood, in 4 steps for cohorts of
      ten patients, after an observation period of at least 6 months after the end of
      BNCT of the last patient of a cohort. The adverse events on healthy tissues due
      to BSH and due to the radiotherapy will be analysed in order to establish the
      maximal tolerated dose and dose limiting toxicity. Besides of the primary aim of
      this study the survival will be recorded. The first patient was treated in
      October 1997, and further four patients have been irradiated to-date. The
      protocol design proved to be well applicable, establishing the basis for
      scientific evaluation, for performance of safe patient treatment in a very
      complex situation and for opening the possibility to perform further clinical
      research work on BNCT.

PMID- 10394417
TI  - Dosimetry of the boron neutron capture reaction for BNCT and BNCEFNT.
AB  - The use of paired proportional counters, constructed from A-150 tissue equivalent
      plastic (TEP) and A-150 TEP loaded with an appropriate amount of 10B (50 to 200
      ppm), for the dosimetry of the boron neutron capture reaction has been
      investigated for several years at the Gershenson Radiation Oncology Center. This
      method has been used for determining the dose components (fast neutron, gamma ray
      and boron capture product dose) in both Boron Neutron Capture Therapy (BNCT)
      beams and in beams proposed for boron neutron capture enhancement of fast neutron
      therapy (BNCEFNT). A disadvantage of this method, when standard 1/2" diameter
      Rossi type proportional counters are used, is that the beam intensity must be
      relatively low in order to avoid saturation effects (pulse pile-up) in the
      counter. This is a major problem if measurements are to be made in a reactor
      beam, since reducing the beam intensity generally results in a change in the
      neutron spectrum. In order to overcome this problem, miniature cylindrical
      proportional counters have been developed which may be used in high intensity
      beams. The operational characteristics of these counters are compared with the
      standard 1/2" spherical counters. A further disadvantage of proportional counters
      is the relatively long time it takes to collect data, particularly if detailed
      information (depth-dose curves and beam profiles) is required. This problem could
      be overcome by using a set of ionization chambers (an A-150 TEP chamber, a Mg
      chamber and a Mg chamber with a 25 microns boron loaded inner wall) which can be
      scanned in a water phantom. After calibration against the paired proportional
      counters it should be possible to extract the fast neutron, gamma ray and boron
      neutron capture product doses from measurements made with these three ionization
      chambers. A set of such chambers has been used to make preliminary measurements
      in a fast neutron beam and the results of these measurements are presented.

PMID- 10394418
TI  - New drugs for BNCT: an experimental approach.
AB  - New kinds of boron-containing drugs were developed and tested in several murine
      tumor models. The boron-containing ether lipid B-Et-11-OMe was injected in
      mammary carcinoma (AT17) and osteosarcoma (OTS-64) bearing mice. Furthermore
      boron-substituted ferrocenium derivatives were tested. Two were excessively
      toxic; the third could be investigated. Boron accumulation and time-dependent
      biodistribution were determined using alpha-particle sensitive films and
      inductively coupled plasma-atomic emission pectrometry (ICP-AES) and -mass
      spectrometry (ICP-MS) of tumors, organs and tissues. Additionally, a new method
      of boron detection by NMR is in preparation.

PMID- 10394419
TI  - A challenge for high-precision radiation therapy: the case for photons.
AB  - The sophistication of Hadron facilities led to major technical and conceptual
      advances in the treatment immobilization, reproducibility, planning and
      execution. Some of these developments have had a pivotal impact on conventional
      treatments, which can now approach the dose localization advantage of protons in
      the majority of clinical situations. While the biological advantages of neutrons
      may finally be combined with excellent dose localization in Heavy Ion Facilities,
      modern surgical or systemic treatment methods may reduce high LET advantages.
      Clinical trials still need to define the relative merits of these approaches in
      their most modern implementation. The advantage gap has certainly been narrowed
      by recent developments in conventional therapy.

PMID- 10394421
TI  - [Do the facts justify it? CRP without artificial respiration?].

PMID- 10394420
TI  - A challenge for high-precision radiation therapy: the case for hadrons.
AB  - Developments in Hadron therapy, i.e., fast neutrons, protons, pions, heavy ions
      and boron neutron capture therapy are reviewed. For each type of particle,
      operational and closed facilities are listed as well as planned new facilities.
      Improvements in clinical results have always been linked to technological
      developments and better physical selectivity of the irradiation. Exploring the
      benefit of further improvement in dose localization expected from protons and
      conformal therapy is the challenge for the coming years. The radiobiological
      rationale for high-LET radiation in cancer treatment, proposed in the fifties, is
      still valid and has not been contradicted by recent radiobiological findings.
      This justifies the planning of a therapy facility where protons and heavy ions
      (carbon ions) could be applied, under optimal physical and technical conditions.
      Appropriate selection between low- and high-LET radiation for a particular tumor
      is indeed a radiobiological problem, independent of technical development.

PMID- 10394422
TI  - ["Topless" cardiopulmonary resuscitation? Should heart-lung resuscitation be
      preformed without artificial resuscitation?].
AB  - A paper published in various US journals on Emergency Medicine in 1997, has
      raised considerable concerns. The authors question if it is justified to continue
      to recommend initial ventilation as part of basic CPR when performed by lay
      bystanders. A few aspects need to be discussed and some questions have to be
      answered before any changes in the current recommendations may even be
      considered: e.g. 1. How convincing does the available evidence support the
      following hypotheses: 1.1. Lay CPR without mouth-to-mouth-ventilation provides
      better outcome after cardiac arrest than lay CPR with mouth-to-mouth-ventilation.
      1.2. Endotracheal intubation may be detrimental in patients suffering from
      hemodynamic compromises, particularly from VF. 2. Is it scientifically and
      ethically acceptable to design and perform prospective randomized controlled
      trials (RCTs) to evaluate the efficacy of those components of BCLS and ACLS which
      have in accordance with AHA-, ERC Guidelines and ILCOR Statements in the past
      been applied in millions of cardiac arrest victims and have obviously enabled the
      patients to lead a meaningful life after survival; under conditions of the
      proposed study design patients of the study group would be left without the
      treatment option ventilation, thus diminishing their chances of survival. Ad 1:
      The arguments presented by the authors are hardly convincing. The authors
      themselves state elsewhere that reluctance to perform mouth-to-mouth-ventilation
      should not represent a major problem because most cardiac arrests of cardiac
      etiology occur at home and in the presence of a relative or friend. Moreover,
      unreliable recommendations for mouth-to-mouth-ventilation (AHA), lack of
      training, retention of skills and knowledge, and a deficit in motivation include
      the main causes of the disappointingly low figures of bystander CPR worldwide.
      This situation cannot be improved simply by eliminating a lifesaving component of
      CPR-ventilation. Instead, the proposal to abandon the administration of
      unreasonably high ventilation volumes (800-1200 ml/breath) from the present
      guidelines and to recommend volumes ranging from 400-500 ml/breath recently made
      by the ERC should be given serious consideration. Furthermore, equipment and
      training manikins need to be adapted to these more reasonable volumes.
      Independently of the mechanisms of slow decreases in SaO2 after cardiac arrest
      (provided no compressions are performed) independently of gasping, ventilatory
      effects of standard compression or ACD-HCPR in the absence of mouth-to-mouth
      ventilation, it is essential to realise that the patient's airways need to be
      maintained open at all times (this is unlike animal experiments where the airways
      are primarily kept open by the respective tissue structures): The minimum
      requirement of First Responder CPR is the guarantee that open airways are
      maintained. It may possibly be discussed if the present sequence of ABC might be
      changed to CAB, a practice adopted in the Netherlands many years ago, however,
      outcome trials an CAB have not been published to date. In addition, greater
      demands should be made of training requirements in BLS, attendance of refresher
      courses should be required, and other groups of the population should be included
      into these programmes than only relatives or friends of patients at risk of a
      cardiac arrest. The programmes need to be made mandatory for greater variety of
      groups and individuals to increase the efficacy and efficiency of bystander
      resuscitation. The hypotheses made by the above-mentioned authors are neither
      scientifically nor ethically acceptable. Ad 2: Pepe's argument regarding the
      efficacy of endotracheal intubation (ETI) in VF-patients has not been
      scientifically proven and lacks conclusive evidence. ETI serves to protect the
      airways and lungs against aspiration of regurgitated material and to facilitate
      artificial ventilation including PEEP, both under anaesthesia and resuscitation.
      The efficacy of ETI in the OR has long b

PMID- 10394423
TI  - [Remifentanil and alfentanil: Sympathetic-adrenergic effect in the first
      postoperative phase in patients at cardiovascular risk].
AB  - Extubation and the immediate postoperative period are critical periods with
      strong sympatho-adrenergic stimulation. The aim of the present study was to
      investigate this period after balanced anaesthesia with remifentanil and
      alfentanil in cardiac risk patients. METHODS: 52 patients with coronary artery
      disease or with risk factors for coronary heart disease scheduled for elective
      extraperitoneal and extrathoracic operation were included in this study.
      Anaesthesia was induced by intravenous administration of etomidate, vecuronium
      and remifentanil (n = 27, 1 microgram/kg) or alfentanil (n = 25, 25
      micrograms/kg). Anaesthesia was maintained with an Isoflurane/N2O/O2 mixture and
      by continuous intravenous infusion of remifentanil (0.25 microgram/kg/min) or
      alfentanil (45 micrograms/kg/h). During the first 60 minutes after extubation
      haemodynamic parameters were monitored and catecholamines were determined at
      defined time intervals. Parameters of recovery, the requirement of analgesics and
      cardiac medications were compared in both groups. Myocardial ischaemia was
      assessed by two-channel Holter electrocardiography. RESULTS: The beginning of
      spontaneous respiration and time of extubation were similar in both groups. The
      time interval until opening eyes and the time between the beginning of
      spontaneous respiration and extubation was shorter in the patients treated with
      remifentanil. In this group patients suffered earlier from pain and had a higher
      pain score. Although the plasma catecholamines were comparable in both groups, in
      the patients treated with remifentanil changes in haemodynamic parameters were
      more pronounced. The incidence of shivering and the requirements of analgesics
      and cardiac medications were higher in these patients. The incidence of ST
      segment changes indicating myocardial ischaemia was similar. CONCLUSIONS: After
      balanced anaesthesia with remifentanil a more pronounced sympatho-adrenergic
      stimulation occurs because of the more rapid clearance of the analgesic effect in
      the recovery period compared to alfentanil requiring more analgesics and
      medications for the control of the haemodynamic parameters. Because of these
      specific pharmacological effects the use of remifentanil in cardiac risk patients
      has to be critically discussed.

PMID- 10394424
TI  - [Percutaneous tracheotomy in intensive care. Practicability and early
      complications of the translaryngeal Fantoni technique].
AB  - Tracheostomy is considered the airway management of choice in long-term
      ventilated ICU patients. In the last few years, percutaneous dilatational
      tracheostomy (PDT) has been established as an attractive and safe alternative to
      conventional open tracheostomy. Recently, there is another percutaneous technique
      according to Fantoni with translaryngeal airway access (TLT) available. Our study
      seeks to evaluate TLT in terms of complications and practicability. In 47
      patients of our surgical ICU, elective TLT was performed. Mean operative time was
      9.8 +/- 10.9 (range 6-27) minutes. Severe complications, such as bleeding,
      aspiration or infection of the tracheostoma have never been noted. A slight
      deterioration of arterial oxygen tension occurred in 25 patients
      intraoperatively, demanding to rise the concentration of inspired oxygen
      temporarily. However, no patient became hypoxic during the procedure. Since
      during the procedure gas exchange may worsen, TLT should not be employed in
      patients whose inspired oxygen concentration exceeds 80%. Despite the fact that
      severe complications associated with TLT have recently not yet been reported,
      physicians who perform TLT should be well-trained in the technique of
      conventional open tracheostomy, too. According to our present data, TLT seems to
      be an attractive and safe alternative to PDT. Nevertheless, for a definitive
      evaluation of TLT, further investigations in larger groups of patients and in the
      long term seem to be necessary.

PMID- 10394426
TI  - [History of the development of intensive care medicine in Germany. Contemporary
      considerations. 5. Structural development of pediatric intensive care medicine].

PMID- 10394425
TI  - [Propofol for intubation of infants after halothane induction].
AB  - The unwanted side effects of muscle relaxants used for anaesthesia in the newborn
      and infants resulted in a search for alternatives to atraumatic intubation (IN).
      The study was aimed to investigate conditions of intubation, time of intubation
      as well as changes in systolic, mean and diastolic blood pressure (RRs/RRm/RRd)
      and heart rate (HR) under the use of propofol (P) after narcosis induction by
      mask. PATIENTS AND METHODS: The study was approved by the local ethics committee.
      The data was analysed from 100 infants aged between 4 days and 56 weeks (weight
      2110-9230 g) in the ASA I and II groups (Group [Gr] A and B both with 50
      patients). In both groups induction was performed inhalationally with halothane
      (1.5-2.0 vol%) and pure oxygen. After that propofol for intubation was applied in
      a dose of 2 mg/kg i.v. In Gr A blood pressure and heart rate were registered at
      three measuring points (MP): MP 1 = before P administration, MP 2 = after P, MP 3
      = following intubation; in Gr B at MP 1 and MP 3. Additionally in Gr B the
      intubation time was recorded in seconds (t1 = time after P administration to
      beginning of IN, t2 = time after P administration to the end of the IN, t3 = t2
      t1). In both groups the conditions of intubation were assessed (score 1-
      excellent, 2--good, 3--bad, 4--impossible intubation). RESULTS: The means of
      RRs/RRm/RRd/HR varied in Gr A at MP 2 by -11.20*/-9.18*/-8.58*/-3.52 mmHg/bpm and
      at MP 3 by -2.74/-2.26/-2.04/+5.46 mmHg/bpm in comparison to MP 1 (p < 0.05 =
      significant*). Compared to MP 1 in Gr B the mean values of RRs/RRm/RRd/HR varied
      at MP 3 by -0.89/+0.50/-0.80/+4.20* mmHg/bpm. T1 (mean, SD) was 10.88 +/- 3.52
      seconds (s), t2 26.22 +/- 6.12 s, and t3 was therefore 15.78 +/- 6.28 s.
      Conditions of intubation were found to be excellent or good in both groups (Gr A
      and B [100 patients]: score 1 = 95x = 95%, score 2 = 5x = 5%). CONCLUSION: In the
      observation period, changes in heart rate stayed in the range of reference. In
      our opinion the excellent and good conditions for intubation, as well as the
      ultrashort drug-onset and intubation time demonstrate the good characteristics
      afforded by propofol to perform intubation in infancy.

PMID- 10394427
TI  - [Nursing following cesarean section].

PMID- 10394428
TI  - [Axillary plexus anesthesia].

PMID- 10394429
TI  - [Prehospital infarct management. Report on the seminar-congress
      "Interdisciplinary Intensive Care Medicine", Garmisch-Partenkirchen March, 7-12,
      1999].

PMID- 10394430
TI  - [Anesthesia in the brachial plexus].

PMID- 10394431
TI  - [What is the function of "practice guidelines"?].

PMID- 10394432
TI  - [High-dose interferon-alpha and adjuvant treatment of melanoma with poor
      prognosis: requiem for a drug marketing license?].

PMID- 10394433
TI  - [Humoral immune deficits and the skin].

PMID- 10394434
TI  - [Systemic treatment of acne: proposal. The French Agency of Sanitary Safety of
      Health Products].

PMID- 10394435
TI  - [Systemic treatment of acne: recommendations. The French Agency of Sanitary
      Safety of Health Products].

PMID- 10394437
TI  - [Pilotropic T-cell lymphoma without mucinosis: 5 new cases].
AB  - BACKGROUND: Pilotropic cutaneous T-cell lymphomas without mucinosis are rare,
      with 27 cases previously reported. Diagnosis and classification may be difficult.
      The clinical course and histopathological and immunohistochemical findings in 5
      patients are described. PATIENTS AND METHODS: Patients were selected from the
      register of the French Study Group for cutaneous lymphomas. The criteria for
      inclusion were clinical pilofollicular manifestations and histological features
      of pilotropic T-cell lymphoma without mucinosis. RESULTS: Five patients were
      selected. The most frequent clinical manifestations were follicular keratosis,
      alopecia and follicular papules. Typical lesions of mycosis fongoides were
      present for several years in 3 patients, and lymphomatoid papulosis preexisted in
      one patient. Histopathological analysis showed an infiltrate composed of CD3+ and
      CD4+ atypical lymphocytes involving the follicular epithelium with alteration of
      the hair follicle walls. Epidermotropism was associated with pilotropism and
      situated near the follicular lesions or farther apart. Alcian blue stains results
      were negative in all specimens. PCR studies showed the presence of a T-cell clone
      in the skin lesions in all cases. COMMENTS: Diagnosis of pilotropic cutaneous T
      cell lymphomas without mucinosis may be difficult in case of discrete
      epidermotropism, minimal infiltrate or involvement of the follicular epithelium.
      Pilotropism could define a particular variant of T-cell lymphomas.

PMID- 10394436
TI  - [Primary cutaneous leiomyosarcoma: 32 cases].
AB  - BACKGROUND: Superficial leiomyosarcomas are rare tumors, which may be confined to
      the dermis or extend to subcutaneous tissues. PATIENTS AND METHODS: We report the
      results of a retrospective study of 32 patients treated for leiomyosarcomas
      through a twenty-two year period (from 1975 to 1997). RESULTS: Mean age was 45
      years, with 50 p. 100 of patients less than 35 years of age. Forty seven percent
      of the tumors were located on the lower limbs and mean diameter was 2.8 cm. Three
      clinical types have been isolated: nodule beneath normal epidermis (50 p. 100),
      purple nodule ulcerated or not (28 p. 100), swelling tumor (22 p. 100). Sixteen
      percent were intradermal, whereas sixty nine percent involved subcutaneous
      tissues. With regard to tumor grade, 37 p. 100 of tumors were grade I, 44 p. 100
      of tumors were grade II, and 19 p. 100 were grade III. Immunohistochemical
      staining showed positive reactions for all tumors with anti-vimentin and anti
      alpha smooth muscle actin. Main treatment was complete surgical excision. Follow
      up informations were available for all patients and 75 p. 100 of them had a
      follow up period longer than a year. Five patients with leiomyosarcomas involving
      the subcutis developed local recurrences, and two of them died of the disease.
      DISCUSSION: Leiomyosarcomas can occur at any age without predominant sex-ratio.
      Main prognostic factors are tumor size, distal location, depth of tumor invasion
      and pathological grade. Immunohistological staining with anti-alpha smooth muscle
      actin is more sensitive and specific than with anti-desmin or anti-HHF 35. Main
      treatment is surgical excision with wide margins.

PMID- 10394438
TI  - [Symptomatology and markers of the severity of erythematous drug eruptions].
AB  - OBJECTIVES: Skin reactions to drugs affect about 2.2 percent of inpatients. More
      often, they are described as morbilliform or maculopapular. The objectives of
      this study were to characterize these skin reactions and to look for severity
      markers. METHODS: We retrospectively analyzed 133 cases of drug reactions
      collected in a Dermatology unit from 1973 to 1995 for whom, photographs and blood
      cell count were available. Well recognized disorders were excluded (Stevens
      Johnson syndrome, Lyell syndrome, TEN, AGEP, vasculitis, phototoxicity, fixed
      drug eruption). Severity was defined on 3 criteria: hospitalization, skin
      reaction prolonged more than 21 days and visceral involvement. For each criteria,
      we studied the association with clinical and laboratory findings, first with
      univariate analysis, then with multivariate analysis for significant
      associations. RESULTS: Characteristics of the 133 included cases were: women: 58
      p. 100, mean age: 52 years, inpatients: 80 p. 100, mean interval from beginning
      of drug therapy to reaction: 12 days, mean duration: 26 days, responsible drugs:
      antibiotics: 41 p. 100, nonsteroidal antiinflammatory drugs: 11 p. 100,
      anticonvulsants: 10 p. 100. A few reactions showed a monomorphous pattern fitting
      a single denomination in a classic dermatological nomenclature: maculopapular: 10
      p. 100, morbilliform: 6 p. 100, scarlatiniform: 5 p. 100, small papules: 5 p.
      100. Polymorphous reactions were observed in 73 p. 100 of cases with 3 different
      patterns on the average. Nearly half of the cases exhibited maculopapular and
      scarlatiniform lesions simultaneously. We observed fever (61 p. 100), mucosal
      lesions (26 p. 100), lymphadenopathy (30 p. 100), eosinophilia (count > 500/mm3:
      44 p. 100, > 1500/mm3: 17 p. 100), and visceral involvement (22 p. 100),
      including hepatitis (18 p. 100). Four severity markers were identified: fever,
      lymphadenopathy, erythema involving more than 60 p. 100 of the body surface area,
      eosinophilia. CONCLUSION: This study underlines the polymorphous clinical
      presentation of skin reactions to drugs and the minority of maculopapular or
      morbilliform patterns leading us to propose the term of "erythematous drug
      reactions". Despite several biases (hospital recruitment of more severe
      reactions, retrospective analysis) this study is the first to show some severity
      markers. Close to the criteria used to define the "hypersensitivity syndrome"
      these simple clinical markers may have important practical implications.

PMID- 10394439
TI  - [Hand-foot-mouth syndrome recurring during common variable deficiency].
AB  - BACKGROUND: Common variable immunodeficiency is characterized by
      hypogammaglobulinemia and recurrent bacterial infections. More uncommonly, these
      patients develop chronic enterovirus infectious meningoencephalitis. Recurrent
      enterovirus skin infection has not been reported to date in subjects with common
      variable immunodeficiency. CASE REPORT: A 26-year-old man had suffered repeated
      episodes of otorhinolaryngological and pulmonary infections since childhood. He
      experienced three episodes of vesicular cutaneous eruption involving the palms of
      both hands, the plantar aspect of the feet and the buccal mucosa. The patient was
      hospitalized in March 1995 at the third episode. Temperature was 38 degrees C. He
      had maculopapulous and vesicular eruptions on the palm of the hands and plantar
      aspect of the feet with irritation in some areas. Petichial lesions were seen on
      the palate. PCR demonstrated viral DNA and cell cultures of a lesion biopsy were
      positive for enterovirus. Gammaglobulinemia was 4 g/l with low B cell count.
      DISCUSSION: Viral infections are uncommon in patients with common variable
      immunodeficiency as cellular immunity remains normal. Severe viral infections
      caused by enteroviruses have however been reported, generally associating
      chronic, and generally fatal, meningoencephalitis. Our case would be the first
      case of a recurrent hand, foot and mouth disease in such patients.

PMID- 10394441
TI  - [Diagnostic case. Pseudohypoparathyroidism type Ia].

PMID- 10394440
TI  - ["Buffalo neck": an unintended secondary effect of treatment with anti-HIV
      protease inhibitors].
AB  - BACKGROUND: Lipodystrophy and other fat distribution disorders have been reported
      in patients receiving protease inhibitor therapy for HIV infection. CASE REPORT:
      A 50-year-old HIV-positive patient was given protease inhibitor therapy
      (indinavir) for 6 months when he developed a lipomatous formation in the
      retrocervical area. Abdominal fat also increased in volume and the subcutaneous
      fat on the lower limbs decreased. DISCUSSION: We describe the main clinical
      features of these fat distribution disorders and discuss the pathogenic
      hypothesis of an interaction between antiprotease activity and hepatic
      lipoprotein receptor binding.

PMID- 10394442
TI  - [Diagnostic case. Osteonevus of Nanta].

PMID- 10394443
TI  - [Nodules of the external ear].

PMID- 10394444
TI  - [Bowenoid papulosis].

PMID- 10394445
TI  - [Diseases associated with adnexal tumors. I--Follicular tumors].

PMID- 10394446
TI  - [A study of contact photoallergy].

PMID- 10394447
TI  - [The use of EMLA cream in pediatrics].

PMID- 10394448
TI  - [Is scleroderma an allo-immune disease?].

PMID- 10394449
TI  - [Should premature infants be vaccinated?].

PMID- 10394450
TI  - [Analgesia with saccharose during heel capillary prick. A randomized study in 37
      newborns of over 33 weeks of amenorrhea].
AB  - BACKGROUND: To evaluate the efficiency of intraoral saccharose administration for
      analgesia among neonates born after at least 33 weeks of gestation. POPULATION
      AND METHOD: Thirty-seven neonates from two neonatal units were tested using an
      objective scale of infants' pain. A double blind study of the heel prick response
      after saccharose vs. water administration was performed. RESULTS: Prior
      administration of saccharose significantly reduced the pain reaction (1.24 vs.
      2.24, P < 10(-5)). CONCLUSION: The analgesia obtained after an intraoral
      saccharose administration can be useful for repeated punctures for which common
      procedures of analgesia are ineffective. Beyond its use for heel prick, this
      procedure could be proposed for venous punctures when ELMA analgesia is not
      possible.

PMID- 10394451
TI  - [Impact of vaccination against Haemophilus influenzae on the incidence of
      invasive infections from Haemophilus influenzae type B in the Nord-Pas-de-Calais
      region].
AB  - BACKGROUND: In industrialized countries where immunization against Haemophilus
      influenzae b (Hib) is largely used, the incidence of invasive Hib infections has
      dramatically decreased. The aim of this study was to analyse the impact of
      immunization against Hib on the incidence of invasive Hib infections in the Nord
      Pas-de-Calais area in France. PATIENTS AND METHODS: This retrospective
      multicenter study enrolled 11 of the 18 hospitals in the Nord-Pas-de-Calais area,
      comparing two periods: 1991-1993 (before immunization), and 1994-1996 (during
      immunization). All children less than 60 months of age and having an invasive Hib
      infection were included. The Pasteur-Merieux Company was asked to provide the
      number of vaccines sold in the Nord-Pas-de-Calais area during the study period.
      RESULTS: The number of vaccines sold in 1992 was 56,208; this reached 189,173 in
      1996, corresponding to an immunization ratio higher than 90%. One hundred and two
      children representing 155 invasive Hib infections were studied. The annual
      incidence was 42 during the first period (meningitis: 18.6; septicemia: 14.6;
      epiglottitis: 5.6), and nine (meningitis: 5; septicemia: 2.6; epiglottitis: 0.3)
      during the second period, that is a 78% decrease. CONCLUSION: These results
      confirm previous data in the literature by demonstrating that immunization in the
      Nord-Pas-de-Calais area has dramatically decreased the incidence of invasive Hib
      infections.

PMID- 10394452
TI  - [Use of hypnotics in children: description and analysis].
AB  - BACKGROUND: Sleep disorders are frequent in pre-school children and in the French
      population, often leading to the prescription of hypnotics or sedatives.
      Therefore, this represents an important health problem in this population.
      PATIENTS AND METHODS: We studied the hypnotic consumption in children, aged
      between 1 month to 4 years (23 +/- 11.3 months), who complained of insomnia.
      Parents completed 203 sleep questionnaires including information on the hypnotics
      consumption of their offspring (112 boys and 91 girls). The questionnaire was
      also related to the parent's sleep patterns and hypnotics consumption. Seventy
      percent of the sample had received medication, at least once before the
      evaluation, and at any age. A positive correlation between hypnotics consumption
      in mothers and children, particularly boys (odds-ratio = 4.8; 1.1-8.7) was found.
      CONCLUSION: These data confirm the early exposition to hypnotics of children in
      the French population, and the existence of a familial pattern of consumption,
      mostly influenced by the mother. These data should permit the identification of
      subgroups at risk for early exposition and to encourage non-pharmacologic
      approaches in the treatment of insomnia in young children.

PMID- 10394453
TI  - [Antiseptic treatment of the umbilical cord in newborns: survey and
      recommendations].
AB  - AIM: To determine whether umbilical cord care of the neonate is in accordance
      with the guidelines of antiseptic treatment at this age of life. MATERIAL AND
      METHODS: A survey was conducted during the 3rd trimester of 1996 in 57 maternity
      units and departments of neonatalogy in the region of Provence-Alpes-Cote d'Azur
      (south of France). A questionnaire was sent to the head of each unit asking the
      modalities of disinfection of the umbilical cord. RESULTS: Fifty units answered
      the questionnaire. Six different groups of antiseptic products were used,
      corresponding to 17 distinct commercial preparations. The simultaneous
      association of several products (two or three) was done in 70% of cases. Eosin
      was the most frequently used (60%), in association with 25 units. Alcohol was
      used in 28 centers (56%). It was associated 22 times. Chlorhexidine was used in
      16 units (32%), twice alone, and with another topic 14 times. The commercial
      association chlorhexidine-benzalkonium chloride (Biseptine) was reported seven
      times (six times in association with another topical treatment). Ektogan (a
      powder of Zn and Mg peroxide and Zn oxide) was used in ten centers, always in
      association. Hexamidine was used in four units, once in association. Silver
      nitrate, Milian solution, iodinated alcohol, and povidone iodine were
      respectively used once. CONCLUSION: This survey shows that a great variety of
      umbilical cord care modalities is used in this region, and that the
      recommendations for antiseptic treatment in young babies, are not always
      respected. According to these, eosin, ethanol, Ektogan and iodine should not be
      used for this purpose. Although chlorhexidine has been proven to be the most
      suitable disinfectant, it comes only in third place, used in association in 95%
      of the cases. Several studies in neonates have shown that it is well tolerated
      and efficient even if it delays cord separation. This study should lead to
      interdisciplinary consensual guidelines for umbilical cord care.

PMID- 10394454
TI  - [Congenital tuberculosis: difficulties in early diagnosis].
AB  - BACKGROUND: Neonatal and/or congenital tuberculosis is insufficiently understood.
      CASE REPORTS: Case 1. A premature hypotrophic neonate presented at the age of 45
      days, without any maternal contact, a bilateral bronchopneumopathy. Whilst the
      pregnancy and birth had not been affected by any noteworthy problem, the mother
      died from miliary tuberculosis despite rifampin, isoniazid and pyrazinamide
      treatment. Her baby also died on day 52 from multivisceral failure. Culture of
      tracheal secretions confirmed a few weeks later the diagnosis of tuberculosis.
      Case 2. A premature, hypotrophic neonate presented on day 22 signs of respiratory
      distress (miliary), icterus and hepatosplenomegaly. Whilst the pregnancy and
      birth had not been affected by any particular problem, the mother, 18 days after
      giving birth, presented miliary and pleural tuberculosis. Despite treatment with
      rifampin, isoniazid and pyrazinamid started on day 22, the baby died on day 27
      from multivisceral failure. The post-mortem liver biopsy confirmed the diagnosis
      of tuberculosis. Case 3. A baby born at term was hospitalized on day 4 for
      jaundice. Whilst the pregnancy and birth had not presented any problem, the
      mother developed a pleural tuberculosis on day 10. Breast-feeding was stopped.
      Due to the presence of opacities at the top of the right lung, the child was
      given rifampin, isioniazid, and pyrazinamide. The course was marked by the
      appearance of hepatomegaly and poor weight gain up to day 25, followed by an
      improvement. CONCLUSION: The frequency of congenital tuberculosis is probably
      under-estimated. Its early diagnosis is essential but often difficult as the
      initial manifestations are delayed. Improved screening of women at risk and
      sensitization of the medical community are necessary.

PMID- 10394455
TI  - [Hypertensive manifestation of an acute intestinal intussusception].
AB  - BACKGROUND: Hypertension may be associated with intussusception. CASE REPORT: An
      8-month-old infant showed the following symptoms: lethargy, vomiting and
      hypertension. Abdominal ultrasound suggested the diagnosis of intussusception,
      which was confirmed by barium enema. The hypertension resolved after the
      intussusception was reduced. CONCLUSION: Intussusception should be considered a
      diagnostic possibility in infants who show a history of vomiting and in whom
      lethargy and systematic hypertension are noted. This case re-affirms the
      diagnostic usefulness of abdominal ultrasonography.

PMID- 10394456
TI  - [Fulminant hepatitis in two children treated with sulfasalazine for Crohn
      disease].
AB  - The main adverse effects of salazopyrin are usually dose-dependent and mild.
      Exceptionally, idiosyncratic reactions occur which may be life-threatening. CASE
      REPORTS: Two 10-year old children were treated for Crohn's disease with
      salazopyrin. At day 21 and day 10 respectively, pharyngitis, rash, and fever were
      noted. During the following days, high-grade fever persisted, while jaundice,
      severe cytolysis and acute liver failure also occurred. Drug hepatotoxicity was
      suspected and salazopyrin was withdrawn on day 29 and day 24 respectively.
      Development of hepatic encephalopathy led to urgent liver transplantation in both
      cases. CONCLUSION: Salazopyrin is a possible cause of fulminant immunoallergic
      hepatitis. Prompt therapeutic interruption is urgent, but it may not alter the
      outcome and or preclude the need for liver transplantation. We suggest that
      salazopyrin therapy be avoided in pediatric inflammatory bowel disease whenever
      possible, and that the use of pure amino-salicylates be preferred.

PMID- 10394457
TI  - [Pneumopericardium with favorable outcome in a ventilated premature infant].
AB  - Pneumopericardium is a rare and severe complication of artificial ventilation in
      neonates. CASE REPORT: A preterm neonate born after 29 weeks of gestation was
      placed under ventilatory support for bronchopulmonary dysplasia. At 63 days of
      life, just after a severe bronchospasm which required bag ventilation with high
      pressures, she collapsed and required immediate cardiopulmonary resuscitation
      with epinephrine infusion. The diagnosis of pneumopericardium was deduced from
      the chest X-ray obtained in emergency, on which there was also a right
      pneumothorax. Cardiac recovery with return of spontaneous circulation was only
      obtained after evacuation of the pneumopericardium with a 23-gauge needle via the
      sub-xiphoid route. The pneumothorax was drained and the long-term evolution was
      favorable. CONCLUSION: In the case of cardiopulmonary compromise, the early
      diagnosis of pneumopericardium should lead to the immediate evacuation of the
      pneumopericardium in order to improve the prognosis.

PMID- 10394458
TI  - [Proton pump inhibitors in pediatrics].
AB  - For the past ten years or so, proton pump inhibitors (PPI) such as omeprazole,
      lansoprazole, or pantoprazole, have become the reference treatment for peptic
      disorders in adults. PPIs have recently begun to be used in pediatrics, and this
      use is likely to expand. They act on the final step of gastric acid secretion by
      completely inhibiting the ATPase (proton pump) at the surface of the gastric
      parietal cells, thus yielding long term inhibition which is not correlated with
      the plasma concentration of the drug, in contrast to the effects of H2-blocker
      drugs. Our knowledge of this new class of treatment in pediatrics is still
      fragmentary, but the reported pharmacokinetic and clinical data indicate that
      they are suitable for use in children. While the short-term risk of complications
      appears to be minimal, the tolerance of these drugs in chronic use requires
      careful monitoring because of the potential consequences of prolonged inhibition
      of acid secretion.

PMID- 10394459
TI  - [Iron supplementation in preterm infants treated with erythropoietin].
AB  - Anemia in premature infants can be prevented by prophylactic treatment with
      recombinant human erythroprotein (r-huEPO). r-HuEPO as been used for a long time
      in patients with end-stage renal failure. The main factor which can limit r-HuEPO
      efficiency is limited iron bioavailability. Adapted iron supplementation is
      needed when preterm infants receive r-HuEPO in order to avoid the depletion of
      iron stores. Oral iron supplementation is simple but indigestibility is frequent.
      Furthermore, the intestinal absorption and utilization of oral iron is limited.
      Parenteral iron supplementation is possible in infants who are very pre-term as
      they are parenterally fed during the first weeks of life. There are various
      preparations of intravenous iron with different physicochemical properties.
      Toxicity and side-effects of parenteral iron preparations depend on these
      properties. Two parenteral iron preparations are available in France: iron
      saccharate (Venofer) and iron-dextrin (Maltofer). Iron delivery and possible side
      effects of these preparations are different and need to be considered before use
      in preterm infants.

PMID- 10394460
TI  - [Radiologic case of the month].

PMID- 10394461
TI  - [Psoriasis in childhood].
AB  - Psoriasis is a common chronic disease in childhood of yet unclear etiology.
      Thirty per cent of psoriatic patients experience onset of their disease before 15
      years of age. Psoriasis is exceptionally congenital but may present in infancy as
      a napkin dermatitis. There are specific pediatric clinical forms, but at the
      beginning the eruption is usually discrete, and the diagnosis can be difficult.
      Pustular, erythrodermic and arthropathic forms are rare. Treatment must weigh the
      advantages and disadvantages of the possible therapies and be kept to the minimum
      compatible with asymptomatic control.

PMID- 10394462
TI  - [Hip dislocation. Organization of screening and follow-up].
AB  - Early detection and low-risk treatment are the two main objectives of the
      management of developmental dislocation of the hip. The best way to evaluate
      neonatal hips is to perform clinical and ultrasound examinations at the same
      time, and to confront their results. Early diagnosis allows to restrict treatment
      to infants with neonatal dislocation who do not improve by 4 weeks of age. On the
      other hand, neonates with reductible dislocated hips must be treated at birth and
      followed at the joint consultation. Early diagnosis and management must not
      decrease later efforts to detect dislocated hip until walking age.

PMID- 10394463
TI  - [Prematurity and sudden infant death syndrome. Polysomnography in question].
AB  - Systematic recording of cardiorespirographic events has been recommended by some
      authors in premature and/or very low birth weight infants before or shortly after
      hospital's discharge. Their objective is the recognition of babies at risk of
      sudden infant death syndrome (SIDS) and prevention by home monitoring. After an
      extensive review of the recent literature, prematurity itself does not appear as
      a risk factor of SIDS. Late apneas are common, but their prognostic significance
      remains uncertain. Although it is clear that bronchopulmonary dysplasia carries a
      greater risk of acute life threatening events and infantile death, their
      prevention mainly relies upon an adequate oxygen supplementation. As a
      consequence no more than the general infant population, premature infants require
      neither polysomnographic recording nor home monitoring.

PMID- 10394464
TI  - [Temperature measurement in the neonate: the post-mercury era].

PMID- 10394465
TI  - [Visceral leishmaniasis: a new oral treatment?].

PMID- 10394466
TI  - [Smoke alarms and domestic fire death rates in children].

PMID- 10394467
TI  - Increasing public trust and confidence in psychiatric research.

PMID- 10394468
TI  - Schizophrenia research series: from molecule to public policy.

PMID- 10394469
TI  - Schizophrenia: new phenes and new genes.

PMID- 10394470
TI  - Elementary phenotypes in the neurobiological and genetic study of schizophrenia.
AB  - This review describes the strategy of using elementary phenotypes for
      neurobiological and genetic linkage studies of schizophrenia. The review
      concentrates on practical aspects of selecting the phenotype and then
      understanding the confounds in its measurement and interpretation. Examples from
      the authors' studies of deficits in P50 inhibition and smooth pursuit eye
      movement dysfunction are presented. These two phenotypes share considerable
      similarity in their neurobiology, including a similar response to nicotine. They
      also appear to co-segregate with the genetic risk for schizophrenia as autosomal
      co-dominant phenotypes. Although most schizophrenic patients inherit these
      abnormalities unilinealy, i.e., from one parent, apparent bilineal inheritance
      produces a more severe illness, observed clinically as childhood-onset
      schizophrenia. The initial study showing linkage of the P50 deficit to the
      chromosome 15q14 locus of the alpha 7-nicotinic acetylcholine receptor is an
      example of the potential usefulness of these phenotypes for combined genetic and
      neurobiological study of schizophrenia.

PMID- 10394471
TI  - Forebrain induction, retinoic acid, and vulnerability to schizophrenia: insights
      from molecular and genetic analysis in developing mice.
AB  - Schizophrenia is thought to be a disease of early development that ultimately
      affects forebrain neurons and circuits. There may be a relationship between
      disrupted forebrain development; malformations of the limb, face, and heart; and
      signaling via the steroid-like hormone retinoic acid (RA) in some schizophrenic
      patients. The limbs, face, heart, and forebrain all develop from sites where
      neural crest-derived, RA-producing mesenchyme contributes to induction and
      differentiation of adjacent epithelia. Induction between neural crest-derived, RA
      producing mesenchyme, the anterior neural tube, and the anterior surface
      epithelium of the embryo guides regional differentiation and pathway formation
      during forebrain development. Furthermore, there are at least two mouse mutations
      -in the Pax-6 and Gli-3 genes--that cause peripheral malformations and
      specifically disrupt neural crest mediated, RA-dependent induction and
      differentiation in the forebrain. These observations suggest that induction might
      provide a common target for genes that alter morphogenesis of peripheral
      structures, disrupt RA-signaling, and compromise forebrain development. In the
      forebrain, some of these disruptions might influence the numbers or cellular
      properties of neurons and circuits. Such changes might be reflected in the
      aberrant forebrain function that characterizes schizophrenia.

PMID- 10394472
TI  - The neurodevelopmental basis of schizophrenia: clinical clues from cerebro
      craniofacial dysmorphogenesis, and the roots of a lifetime trajectory of disease.
AB  - A "read-back" analysis of schizophrenia, from chronic illness, through the first
      psychotic episode, to psychosocial and neurointegrative abnormalities of
      childhood and infancy, leads to the intrauterine period as a primary focus for
      etiological events. Evidence for a characteristic topography of cerebro
      craniofacial dysmorphology in schizophrenia is reviewed, and interpreted to
      estimate: (i) the timing of dysmorphic event(s); (ii) the nature of early
      cellular and molecular mechanisms which might determine that topography of
      dysmorphogenesis; and (iii) the population homogeneity of these processes. It is
      argued that early cerebro-craniofacial dysmorphogenesis in schizophrenia should
      be conceptualized as a first stage not in a static but rather in a dynamic,
      lifetime trajectory of disease.

PMID- 10394473
TI  - The regulation of forebrain dopamine transmission: relevance to the
      pathophysiology and psychopathology of schizophrenia.
AB  - Since the discovery that the therapeutic efficacy of antipsychotic drugs was
      significantly correlated to their ability to block dopamine D2 receptors,
      abnormal dopamine transmission in the forebrain has been postulated to underlie
      psychosis in schizophrenia. In the past 15 years, an impressive amount of
      clinical and basic research aimed at the study of schizophrenia has indicated
      that prefrontal and temporal cortical abnormalities may be more important in the
      etiology of many of the symptoms of schizophrenia, including psychosis. However,
      the cortical systems that appear to have structural and/or metabolic
      abnormalities in schizophrenia patients potently regulate forebrain dopamine
      transmission through a number of mechanisms. In turn, dopamine modulates
      excitatory transmission mediated by frontal and temporal cortical projections to
      the basal ganglia and other regions. The present review summarizes the multiple
      interactions between forebrain DA systems and frontal and temporal
      corticostriatal transmission. It then examines the role of these interactions in
      normal behaviors and the psychopathology of schizophrenia.

PMID- 10394474
TI  - Increased dopamine transmission in schizophrenia: relationship to illness phases.
AB  - BACKGROUND: Abnormalities of dopamine function in schizophrenia are suggested by
      the common antidopaminergic properties of antipsychotic medications. However,
      direct evidence of a hyperdopaminergic state in schizophrenia has been difficult
      to demonstrate, given the difficulty to measure dopamine transmission in the
      living human brain. Such evidence has recently emerged. Three studies reported an
      increase in dopamine transmission following acute amphetamine challenge in
      patients with schizophrenia compared to matched healthy control subjects, thus
      demonstrating a dysregulation of dopamine in schizophrenia. In all studies, a
      large variance was observed within the schizophrenic group in the magnitude of
      this finding, and clinical predictors of this effect could not be identified.
      METHODS: In this paper, we combined previously published and newly acquired data
      to obtain sufficient power to address this question. RESULTS: The most important
      findings derived from this extended data set are: 1) dysregulation of dopamine
      function revealed by the amphetamine challenge is present at onset of illness and
      in patients never previously exposed to neuroleptic medications; 2) this
      dysregulation was observed in patients experiencing an episode of illness
      exacerbation, but not in patients studied during a remission phase. CONCLUSIONS:
      A hyperdopaminergic state is present in schizophrenia during the initial episode
      and subsequent relapses, but not in periods of remission. This finding has
      important consequences for the development of new treatment strategies for the
      remission phase.

PMID- 10394475
TI  - Treatment-resistant schizophrenic patients respond to clozapine after olanzapine
      non-response.
AB  - BACKGROUND: Treatment-resistance in schizophrenia remains a public health
      problem. Clozapine has been shown to be effective in about one third of this
      population, but carries with it medical risks and weekly blood draws. As
      olanzapine is a drug with a very similar biochemical profile to clozapine, it is
      important to evaluate whether non-response to olanzapine predicts clozapine non
      response. METHODS: Forty-four treatment-resistant patients received eight weeks
      of olanzapine, either in a double-blind trial or subsequent open treatment at a
      mean daily dose of 25 mg/day. Two of 44 patients (5%) responded to olanzapine
      treatment. Patients who did not respond could then receive clozapine. Twenty
      seven subsequently received an 8-week open trial of clozapine. RESULTS: Patients
      who did and did not receive clozapine did not differ demographically or in
      psychopathology. Eleven of 27 (41%) met a priori response criteria during
      clozapine treatment (mean dose 693 mg/day) after failing to respond to
      olanzapine. CONCLUSIONS: This study demonstrates that failure to respond to
      olanzapine treatment does not predict failure to clozapine. Treatment-resistant
      patients who fail on olanzapine may benefit from a subsequent trial of clozapine.

PMID- 10394476
TI  - An MRI study of adolescent patients with either schizophrenia or bipolar disorder
      as compared to healthy control subjects.
AB  - BACKGROUND: There are few imaging studies in adolescent patients with either
      schizophrenia or bipolar disorder. Such studies are of interest because
      adolescents may have a more severe illness and neurodevelopmental events may have
      a greater role in their pathophysiology. METHODS: We compared 20 patients with
      schizophrenia and 15 patients with bipolar disorder (10 to 18 years) to 16 normal
      adolescents on magnetic resonance imaging (MRI) measures of intracranial volume
      and ventricular and sulcal enlargement. Two planned comparison contrasts were
      employed, one comparing the two patient groups to each other (contrast 1), and
      one comparing both patient groups combined to control subjects (contrast 2).
      RESULTS: None of the contrast 1 comparisons (schizophrenia vs bipolar) were
      statistically significant. Contrast 2 comparisons (control subjects vs patients)
      were statistically significant for intracranial volume (reduced in patients) as
      well as frontal and temporal sulcal size (increased in patients). CONCLUSIONS:
      The patient groups were not statistically significantly different from each other
      on any measure. The combined patient groups were different from control subjects
      on intracranial volume and frontal and temporal sulcal size. Also, there was
      evidence for ventricular enlargement, after removal of a control subject with an
      extreme value. These findings indicate that the same abnormalities noted in adult
      populations are present in adolescents.

PMID- 10394477
TI  - SPECT study of visual fixation in schizophrenia and comparison subjects.
AB  - BACKGROUND: The consistent association of impaired eye movements and
      schizophrenia suggests a relationship between the neurobiology of the illness and
      visual pursuit systems. Visual fixation (VF), an eye "movement" task at zero
      velocity, is the simplest such abnormality in schizophrenia patients and their
      relatives. METHODS: We used a VF task for a functional imaging study. Six
      neuroleptic-free schizophrenia patients and eight gender and mean age matched
      comparison subjects had SPECT scans with 20 mCi of Tc99-HMPAO, during VF on a
      simple blue line intersection. MEDX data saved in ANALYZE format for SPM 95 was
      used to generate paired t-test statistical data for display in Talairach space,
      with rCBF changes given as Z-scores. RESULTS: Patients, compared to controls, had
      increased rCBF in both the parahippocampal gyrus (bilaterally) and in the right
      fusiform gyrus. They had decreased rCBF in the left frontal cortex, including
      medial and superior frontal gyri and anterior cingulate. Overall, compared to
      controls, patients had medial temporal lobe hyperperfusion along with left
      prefrontal hypoperfusion. CONCLUSIONS: These findings are consistent with the
      hypothesized imbalance between the medial temporal and frontal lobes that is
      postulated for schizophrenia. It was of interest that the relative rCBF
      differences between schizophrenia patients and controls in this small sample were
      observable with this cognitively non-demanding visual fixation task.

PMID- 10394478
TI  - P300 amplitude is related to clinical state in severely and moderately ill
      patients with schizophrenia.
AB  - BACKGROUND: Relationships between illness severity and neurobiologic
      abnormalities in schizophrenia were studied in subpopulations varying in clinical
      severity. METHODS: Auditory ERPs were collected from 28 severely ill, chronically
      hospitalized schizophrenic men from a state hospital; 29 moderately ill inpatient
      and outpatient schizophrenic men from a veterans hospital; and 30 healthy male
      subjects from the community as controls. Clinical symptoms were evaluated in
      patients using the Brief Psychiatric Rating Scale (BPRS). RESULTS: Both
      schizophrenic patient groups had smaller P300 amplitude than the control
      subjects. Severely ill patients had smaller P300s than moderately ill patients
      and scored higher on three BPRS factor scores as well as BPRS Total. Among
      severely ill patients, P300 amplitude was unrelated to clinical symptoms. Among
      moderately ill patients, P300 was related to Withdrawal/Retardation,
      Anxiety/Depression, and BPRS Total. After combining patients, Thinking
      Disturbance emerged as an additional correlate of P300. Group differences in P300
      could not be accounted for by group differences in symptom severity using
      analysis of covariance. CONCLUSIONS: Reduced P300 amplitude marks the diagnosis
      of schizophrenia, but also reflects individual differences in severity, including
      positive symptoms. Previous failures to find relationships between positive
      symptoms and P300 may have been due to a restricted range of clinical severity.

PMID- 10394479
TI  - Relationship between nailfold plexus visibility and clinical, neuropsychological,
      and brain structural measures in schizophrenia.
AB  - BACKGROUND: Although all published studies investigating the association between
      nailfold plexus visibility and schizophrenia have found the subpapillary plexus
      (the vascular network into which capillaries drain) to be unusually visible in
      many schizophrenia patients, little else is known about this putative marker for
      schizophrenia liability. METHODS: Plexus visibility was rated in 63 chronic
      schizophrenia, 67 first-episode schizophrenia, 9 schizophreniform, and 66
      unipolar and bipolar depressed patients, all with psychosis, and 119
      nonpsychiatric controls. Smooth-pursuit eye tracking, clinical features,
      neuropsychological performance, and lateral ventricle size were assessed.
      RESULTS: Approximately 21% of chronic schizophrenia, 22% of first-episode
      schizophrenia, and 22% of schizophreniform patients had highly visible plexus
      compared to only 8% of unipolar, bipolar, and nonpsychiatric controls.
      Schizophrenia patients with visible plexus had worse oculomotor performance.
      Additionally, chronic schizophrenia patients with visible plexus had more
      negative symptoms, worse course, more severe illness, worse occupational
      functioning, and worse neuropsychological performance on tasks thought to be
      sensitive to frontal dysfunction. An inverse relationship between plexus
      visibility and lateral ventricle size was found. CONCLUSIONS: This study provides
      evidence that schizophrenia patients with plexus visibility are characterized by
      oculomotor dysfunction, negative symptoms, severe symptomatology, chronic course,
      neuropsychological dysfunction, and an absence of enlarged ventricles.

PMID- 10394480
TI  - Elevation of CD5+ B lymphocytes in schizophrenia.
AB  - BACKGROUND: A variety of immunologic alterations have been observed in patients
      with schizophrenia. These findings have lent support to theories that autoimmune
      mechanisms may be important in some patients with the illness. The CD5+ B
      lymphocyte, a B-cell subset associated with autoimmune disease, has been the
      subject of two previously published studies yielding disparate results. METHODS:
      In this study, we used immunofluorescent flow cytometry to measure CD5+ B cells,
      total B and T cells, and CD4 and CD8 subsets in patients with schizophrenia and
      in normal control subjects. RESULTS: A significantly higher percentage of
      patients with schizophrenia, relative to normal control subjects, exhibited an
      elevated level of CD5+ B cells (27.6% vs 6.7%). Antipsychotic withdrawal had no
      effect on CD5+ B-cell levels, suggesting that medication effects were not the
      cause of this difference. No other studied lymphocyte subsets differed between
      the two groups. CONCLUSIONS: A subset of patients with schizophrenia have
      elevated levels of CD5+ B cells. This finding replicates an earlier study by
      another group and provides further evidence suggestive of autoimmune
      manifestations in schizophrenia.

PMID- 10394481
TI  - Schizophrenia and the influenza epidemics of 1957 in Japan.
AB  - BACKGROUND: We tested the hypothesis that the exposure to an influenza epidemic
      during the second trimester of gestation is associated with an increased risk of
      later development of schizophrenia. METHODS: There were three influenza epidemics
      (A/B mixed type, the first A2 type and the second A2 type) in 1957 in Kochi,
      Japan. We compared the risk of developing schizophrenia in birth cohorts exposed
      to these three influenza epidemics during gestation with that in birth cohorts
      not exposed. To identify subjects who had developed schizophrenia, we surveyed
      patients with schizophrenia who received medical care at all psychiatric
      institutions in Kochi prefecture. RESULTS: There is a pattern that schizophrenic
      births increase twice or more among female subjects who were exposed to each of
      three influenza epidemics in the fifth month of gestation. The increase in the
      female births exposed to the second A2 epidemic was significant (relative risk
      2.86, 95% confidence interval 1.37-5.26). This pattern across the three epidemics
      was not observed in male subjects. CONCLUSIONS: Prenatal exposure to an influenza
      epidemic during the second trimester increased the risk of later development of
      schizophrenia in female births.

PMID- 10394482
TI  - Smoking and therapeutic response to clozapine in patients with schizophrenia.
AB  - BACKGROUND: Of patients with schizophrenia, 70 to 80% smoke. Nicotine corrects
      certain information processing and cognitive psychomotor deficits seen in many
      patients with schizophrenia. Clozapine, but not conventional antipsychotics, has
      been shown to correct some of these deficits. METHODS: We assessed
      psychopathology and smoking in 70 patients with treatment refractory
      schizophrenia (55 smokers and 15 nonsmokers) at baseline when they were receiving
      conventional antipsychotics and again after they were switched to clozapine.
      RESULTS: Smokers showed significantly greater therapeutic response to clozapine
      than nonsmokers. Smokers smoked less when treated with clozapine than when
      treated with conventional antipsychotics. CONCLUSIONS: Certain patients with
      schizophrenia have contributing pathophysiologic mechanisms that respond
      favorably to either nicotine or clozapine.

PMID- 10394483
TI  - Transcranial magnetic stimulation of left temporoparietal cortex in three
      patients reporting hallucinated "voices".
AB  - BACKGROUND: Prior studies suggest that auditory hallucinations of "voices" arise
      from activation of speech perception areas of the cerebral cortex. Low frequency
      transcranial magnetic stimulation (TMS) can reduce cortical activation. METHODS:
      We have studied three schizophrenic patients reporting persistent auditory
      hallucinations to determine if low frequency TMS could curtail these experiences.
      One hertz stimulation of left temporoparietal cortex was compared with sham
      stimulation using a double-blind, cross-over design. RESULTS: All three patients
      demonstrated greater improvement in hallucination severity following active
      stimulation compared to sham stimulation. Two of the three patients reported near
      total cessation of hallucinations for > or = 2 weeks. CONCLUSIONS: TMS may
      advance our understanding of the mechanism and treatment of auditory
      hallucinations.

PMID- 10394484
TI  - Schizoaffective disorder: evidence for reversed cerebral asymmetry.
AB  - BACKGROUND: Schizoaffective disorder is one of the most severe of the affective
      psychoses, but its pathophysiology is poorly understood. Because cerebral
      lateralization may be disturbed in psychotic disorders generally, studies
      examining cerebral asymmetry may improve understanding of the neurobiology
      specific to schizoaffective disorder. This study examines cerebral lateralization
      in this patient population using magnetic source localization. METHODS: We
      studied 16 subjects with schizoaffective disorder and 16 controls. Magnetic
      source localization was used to identify the location of the 20 msec latency
      somatosensory evoked field component (M20). RESULTS: In control subjects, the
      source location was further anterior in the right hemisphere. The subjects with
      schizoaffective disorder were reverse lateralized. CONCLUSIONS: The findings of a
      reversed asymmetry of the M20 in patients with schizoaffective disorder suggest
      an anatomical shift in the placement of the post central gyrus in this disorder,
      compatible with a disorder of cerebral lateralization. Whether this finding
      converges or diverges with measurement of the M20 in other psychotic disorders
      will require further investigation.

PMID- 10394485
TI  - Lack of repetition priming effect on visual event-related potentials in
      schizophrenia.
AB  - BACKGROUND: The present study was designed to assess, using event-related
      potentials, whether aberrant semantic processing reported in schizophrenia
      results from primary semantic overactivation or contextual dysregulation.
      METHODS: The visual event-related brain potentials were compared between 9
      schizophrenic subjects and 16 normal control subjects performing two kinds of
      semantic categorization tasks with different nontarget stimuli: 1) nontargets
      comprising words, pseudowords, and unpronounceable foreign letters and 2)
      nontargets comprising initial presenting words, immediate repetition words, and
      delayed repetition words. RESULTS: Schizophrenic subjects showed no evidence
      suggestive of a greater negative potential associated with words and pseudowords,
      but they did show a lack of amplitude change associated with immediately repeated
      words relative to that in control subjects. CONCLUSIONS: These results suggest
      that aberrant semantic activation in schizophrenia results mainly from a failure
      to utilize information from preceding words or context, and could explain the
      increased N400 to the congruent or related words recently reported in this
      disease.

PMID- 10394486
TI  - Olanzapine acute administration in schizophrenic patients increases delta sleep
      and sleep efficiency.
AB  - BACKGROUND: A delta sleep deficit has been observed in schizophrenic patients.
      Olanzapine is a novel atypical antipsychotic agent with affinity at dopaminergic,
      serotonergic, muscarinic, adrenergic and histaminergic binding sites. The present
      study was designed to analyze a sleep promoting effect reported for olanzapine.
      METHODS: Twenty schizophrenic patients (DSM-IV) were studied, who were drug free
      and inpatients. Patients slept for 5 consecutive nights in the sleep unit as
      follows: one acclimatization night; two baseline nights (the first for sleep
      disorder screenings); and two olanzapine nights (10 mg olanzapine, one hour
      before sleep onset). RESULTS: Sleep continuity variables and total sleep time
      showed an overall improvement with olanzapine. Waking time was reduced since the
      first night of olanzapine administration. The main sleep architecture changes
      were: reduction in sleep stage 1, while sleep stage 2 and delta were
      significantly enhanced. Rapid eye movement density was also increased by the
      second olanzapine night. CONCLUSIONS: Total sleep improvement was due to the
      increase in sleep stages 2 and delta sleep. This may be related to serotonergic
      antagonistic properties of olanzapine. Olanzapine seems to have a sleep promoting
      effect in schizophrenic patients.

PMID- 10394488
TI  - Physiology of lactation.
AB  - The physiology of human lactation is described with secretions on mammary gland
      anatomy and development, the mechanisms of milk secretion and ejection, and the
      temporal sequence of events during the transition from pregnancy to lactation
      (lactogenesis). Finally, interactions between lactation and maternal metabolism
      are briefly described and the interaction of lactation with fertility discussed.

PMID- 10394487
TI  - Dopamine2 receptor occupancy and the action of clozapine: does it make a
      difference to add a neuroleptic?

PMID- 10394489
TI  - Clinical aspects of lactation. Promoting breastfeeding success.
AB  - Human milk is universally recognized as the preferred nutrition for infants.
      Exclusive breastfeeding is ideal for approximately 6 months of life, and
      continued breastfeeding complemented by solid foods is recommended throughout the
      baby's first year, and longer if desired. This article offers counseling
      strategies to help physicians promote successful breastfeeding, beginning with
      effective prenatal education and a screening breast exam to detect lactation risk
      factors. Optimal initiation of breastfeeding is reviewed, including supportive
      hospital practices, correct breastfeeding technique, and the regulation of milk
      production. The early follow-up of the breastfeeding infant and criteria for
      assessing the successful initiation of breastfeeding are discussed. Practical
      strategies are offered for preventing and managing common lactation difficulties,
      such as postpartum breast engorgement, sore nipples, mastitis, maternal
      employment, and impaired let-down.

PMID- 10394490
TI  - Nutritional and biochemical properties of human milk, Part I: General aspects,
      proteins, and carbohydrates.
AB  - Human milk provided by healthy and well-nourished mothers is believed to cover
      the infant's nutrient requirements during the first half year of life. It is
      composed of a mixture of nutritive components as well as other bioactive factors
      with relevant physiologic effects in the neonate infant. Human milk composition
      has a dynamic nature and varies with time postpartum, during a nursing, and with
      the mother's diet and certain diseases. The changes of human milk composition
      with time of lactation seem to match the changing needs of the growing infant
      over time. Human milk proteins are a source of peptides, amino acids, and
      nitrogen for the infant, but also in the protein fraction reside other properties
      of human milk that may benefit the breastfeeding infant. Specific whey proteins
      are involved in the development of the immune response (immunoglobulins), whereas
      others participate in the nonimmunologic defense (lactoferrin). In addition,
      human milk contains a complex mixture of oligosaccharides that are present only
      in minute amounts in other mammal's milk. They may act as inhibitors of bacterial
      adhesion to epithelial surfaces, and thus play an important role in preventing
      infectious diseases in the newborn infant. Oligosaccharides may also promote the
      development of a so-called bifidus flora. In the next years, future research will
      lead to improved characterization of human milk components and elucidation of
      their individual mechanisms of action, which will increase our knowledge about
      the properties of human milk and the benefits of breastfeeding for the infant.

PMID- 10394491
TI  - Nutritional and biochemical properties of human milk: II. Lipids, micronutrients,
      and bioactive factors.
AB  - Human milk lipids contain preformed LCPUFA in considerable amounts, which serve
      as precursors for the formation of prostaglandins, prostacyclins, and other lipid
      mediators, as well as essential components in membrane-rich tissues (such as the
      brain and the retina), thus affecting functional outcomes. Besides a balanced
      nutrient composition and a number of conditionally essential nutrients, human
      milk provides different types and classes of bioactive factors, such as enzymes,
      hormones, and growth factors, many of which appear to have a role in supporting
      infantile growth and development. The bioactive agents include antimicrobial
      factors (e.g., secretory IgA, oligosaccharides, FA); anti-inflammatory agents;
      transporters (e.g., lactoferrin); and digestive enzymes (e.g., BSSL). Several
      nonpeptide hormones (thyroid hormones, cortisol, progesterone, pregnanediol,
      estrogens, and artificial contraceptive) and peptide hormones and growth factors
      (erythropoietin, hHG, gonadotropin-releasing hormone, epidermal growth factor
      insulin, insulin-like growth factor-I, nerve growth factor, transforming growth
      factor-alpha, gastrointestinal regulatory peptides and thyroid-parathyroid
      hormones) have been isolated and quantitated in human milk. Some of these
      components are also involved in the maturation of the gastrointestinal tract of
      the infant. In addition to the passive benefits provided by human milk, several
      data support the hypothesis that breastfeeding promotes the development of the
      infant's own immune system, which might confer long-term benefits for the newborn
      infant. The risk of IDDM, Crohn's disease, and atopic disease is lower in
      individuals who had been breastfed during infancy. Areas of major interest in
      human milk research include the study of human milk synthesis and the
      contributions of dietary composition and maternal metabolism to human milk
      composition, infantile utilization of human milk components, and the study of
      bioactive components, such as oligosaccharides, proteins and peptides, and lipids
      and their in vivo fate and biologic effects in the recipient infant.

PMID- 10394492
TI  - Expression of functional immunomodulatory and anti-inflammatory factors in human
      milk.
AB  - In addition to well-recognized antimicrobial substances, a growing body of
      evidence has accrued during the last decade regarding the presence and function
      of immunomodulatory and anti-inflammatory factors present in human milk and their
      role in protecting the mature newborn as well as the premature infant against
      infections. In addition, it is now appreciated that a number of these factors
      present in human milk may actively modulate the synthesis and maturation of the
      recipient immune system. This complex and interactive system of bioactive
      substances in human milk appears ideally to be designed to function by
      noninflammatory mechanisms, to operate often in a complementary or synergistic
      manner, to resist the digestive process in the recipient gastrointestinal tract,
      and to supplement developmentally delayed immune factors of the infant. The in
      vivo fate and effects of these immune factors in human milk, however, are still
      poorly understood. Clinical studies in conjunction with a broader use of
      experimental animal models and basic research are needed in the future to address
      these questions.

PMID- 10394493
TI  - The use of human milk and breastfeeding in premature infants.
AB  - Human milk is beneficial in the management of premature infants. The beneficial
      effects generally relate to improvements in host defenses, digestion, and
      absorption of nutrients, gastrointestinal function, neurodevelopment, and
      maternal psychological well-being. The use of fortified human milk generally
      provides the premature infant adequate growth, nutrient retention, and
      biochemical indices of nutritional status when fed at approximately 180 mL/kg/day
      compared with unfortified human milk. Human milk can only support the needs of
      the premature infant if adequate milk volumes are produced. Intensive efforts at
      lactation support are desirable. Therefore, neonatal centers should encourage the
      feeding of fortified human milk for premature infants along with skin-to-skin
      contact as a reasonable method to enhance milk production and promote success
      with early breastfeeding, while potentially facilitating the development of an
      enteromammary response.

PMID- 10394494
TI  - Slow weight gain and low milk supply in the breastfeeding dyad.
AB  - There are a large number of women who perceive a reduction in milk supply. With
      appropriate, knowledgeable advice, most are able to continue breastfeeding
      successfully. If an infant is not gaining weight normally, the mother's milk
      production must be assumed to be low (usually a secondary phenomenon); meanwhile,
      consider the possibility of an organic problem in mother or infant. The complex
      interactional nature of the problem requires attention to history, physical
      examination, differential diagnosis, and thoughtful problem solving. There are
      situations that require infant supplementation for optimal growth; when this is
      the case, supplementation should be provided in a way that best supports
      continued breastfeeding to the fullest extent possible. Anticipatory guidance,
      early detection of problems, and prompt intervention are the keys to ensuring
      copious milk production and normal infant growth.

PMID- 10394495
TI  - Jaundice in the breastfed infant.
AB  - Maternal perception of insufficient milk is a widespread phenomenon in modern
      breastfeeding. This article addresses underlying physiology, feeding patterns,
      growth patterns, and medical complications as they impact milk supply and infant
      growth. The complexity of mother-infant factors leads to a broad differential
      diagnosis. Problem-oriented management is discussed with the goal of preventing
      low milk supply, intervening promptly for feeding problems, promoting infant
      growth, and preserving the breastfeeding relationship.

PMID- 10394496
TI  - Drugs and breastfeeding.
AB  - Breastfeeding provides important benefits to mother and infant and should be
      strongly encouraged as the optimal infant feeding choice for most infants. In
      assessing the impact of maternal medication on breastfeeding, the clinician must
      always weigh the many benefits of breastfeeding for the mother and infant against
      the risk of exposing the infant to the drug as it appears in breast milk. With
      regard to the vast majority of medications, continued breastfeeding is
      advantageous to both mother and infant.

PMID- 10394497
TI  - Given the benefits of breastfeeding, are there any contraindications?
AB  - There are many benefits to the infant to be breastfed and to the mother to
      breastfeed. There are, however, a few conditions where the tremendous benefit may
      be outweighed by maternal infection, disease, drugs, or contaminants as these are
      rare. HIV is the only infection that is an absolute contraindication in developed
      countries. Galactosemia is the only infant disease and there are a few
      medications that are contraindicated.

PMID- 10394498
TI  - Health sequelae of breastfeeding for the mother.
AB  - Breastfeeding is known to demand use of maternal nutrient stores, but few comment
      on the positive health benefits of breastfeeding for the mother. Breastfeeding
      reduces the risk of postpartum blood loss by increasing the rate of uterine
      contraction, lowers the risk of postpartum blood loss by increasing the rate of
      uttering contraction, lowers the risk of postpartum blood loss by increasing the
      rate of uterine contraction, lowers the risk of premenopausal breast cancer and
      also reduces the risk of ovarian cancer, reduces lifetime menstrual blood loss,
      may reduce rate or severity of infections, may reduce the risk of spinal and hip
      fracture after menopause, and may support bonding with the infant as well as an
      improved sense of self-esteem and success with mothering. This article reviews
      the literature on short- and long-term sequelae of breastfeeding for women.

PMID- 10394499
TI  - The breast or the bottle? Determinants of infant feeding behaviors.
AB  - Although various trends have placed breastfeeding in and out of vogue, in the
      twentieth century the greater availability of human milk substitutes mandates
      that a woman choose her infant's feeding method. It appears that intrapsychic
      factors or life experiences, as well as certain social conditions, influence that
      choice. For example, the economic state of society historically has had
      significant impact on the role of women and the value placed on woman's unique
      biologic contributions. Likewise, personality and attitudinal factors also may
      act as potential mediators of observed differences between lactating and
      nonlactating mothers in their mother-infant interactions. Finally, once the
      decision to breastfeed or bottle-feed has been made and carried through,
      additional physiologic mechanisms may mediate conscious behavioral intentions.
      The phenomenon of human lactation, then, is sensitive to a variety of
      interrelated factors that can be grouped as follows: (1) individual personality,
      (2) social forces, and (3) psychophysiologic mechanisms. An in-depth
      understanding of the specific factors that affect a woman's decision to
      breastfeed will have far-reaching implications for future educational and
      interventional programs.

PMID- 10394500
TI  - Reaching the goals of "Healthy People 2000" regarding breastfeeding.
AB  - The Healthy People 2000 objectives for breastfeeding were to move the
      breastfeeding initiation rate to 75% from 54% and the breastfeeding continuation
      rate to 50% at age 6 months from the 1988 baseline of 21%. The 1996 data
      indicated that the goal will not be met either for initiation or duration in
      spite of governmental strategic planning and coalition building, the
      acknowledgement of the benefits of breastfeeding by professional associations,
      the implementation of the Baby-Friendly Hospital Initiative, or the efforts of
      individual health professionals. Clearly, there is still work to be done. The
      Baby-Friendly Hospital Initiative was organized within Baby-Friendly USA too late
      in the decade to have had any impact on the 1996 data. It may take an additional
      decade before sufficient hospitals and birthing centers are engaged in the
      process to make a measurable difference in duration. Work protection legislation
      was not introduced until 1998. A national breastfeeding committee was not formed
      until 1998. National breastfeeding promotion programs were still either in the
      planning stage or in early stages of implementation in 1996. There is no paid
      maternity leave guaranteed by legislation for women in the United States. The
      International Code on Marketing has not been addressed, except to propose ways of
      examining the issue. The blueprints developed by the Surgeon General's Workshop
      on Breastfeeding and the Call for Action workshop enumerated strategies that will
      be carried over to the 2010 objectives. New blueprints will be developed to meet
      the 2010 goals, but it is not enough to strategize and plan. The substantive
      advantages of breastfeeding make accomplishment of the goals imperative if we are
      to achieve "health for all."

PMID- 10394501
TI  - Test-retest reliability of the ulnar F-wave minimum latency in normal adults.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to measure the test-retest
      reliability of the ulnar F-wave minimum latency (Fmin) in normal adults. A
      reliable Fmin measure allows clinicians to ascribe changes in latency to true
      changes in a subject and not merely random daily variation. SUBJECTS AND METHODS:
      Fmin in the Abductor Digiti Minimi muscle was measured bilaterally in 49 healthy
      adults (n = 98) with a three day separation between tests. RESULTS: The Fmin
      reliability estimate as measured by intraclass correlation coefficient (3,1) was
      0.59 with a standard error of measurement (SEM) of 1.3 msec. A paired t-test
      showed no significant difference (t = 1.7, df = 97, p > 0.05) between the mean
      scores from the two testing sessions. DISCUSSION AND CONCLUSIONS: We found
      moderate reliability and relatively low precision (high SEM) in Fmin scores taken
      from healthy individuals on two separate days. Strict adherence to our protocol
      and an acceptable overall precision of measurements (as measured by mean scores)
      suggest the contributions of rater and instrument error were low in our study. We
      conclude that 1) valid clinical interpretation of minimum F-wave latency findings
      is questionable because the Fmin measurement appears to have only moderate
      reliability, and 2) the lability of the phenomenon itself is the most likely
      contributor to variability in the Fmin latencies. Further research is warranted
      before electrophysiologists may be justified in attributing small changes in the
      Fmin to actual changes in the subject.

PMID- 10394502
TI  - Reciprocal facilitation of motor evoked potentials immediately before voluntary
      movements in Parkinson's disease.
AB  - Changes of motor evoked potentials (MEPs) from the agonist and antagonist forearm
      muscles were investigated in 13 patients with Parkinson's disease and age-matched
      controls, in whom transcranial magnetic stimulation (TCMS) was delivered to the
      cortical hand motor area immediately before voluntary wrist flexion. MEPs
      recorded from the agonist muscles, namely the wrist flexors, were gradually
      facilitated in accordance with a shortening of the interval between TCMS and
      wrist flexion in both groups. In contrast, MEPs recorded from the antagonist
      muscles, namely the wrist extensors, were gradually facilitated as the intervals
      were shortened only in parkinsonian patients. The reciprocal facilitation of the
      antagonist MEPs was statistically significant when TCMS was delivered within 80
      msec before the voluntary movements, suggesting the presence of the same
      underlying mechanism of symptomatic cocontraction observed in patients with
      Parkinson's disease.

PMID- 10394503
TI  - Motor unit discharge pattern in soleus muscles associated with rapid body sway.
AB  - Motor unit discharge (MUD) patterns of the soleus muscles associated with rapid
      forward body sway were studied in relation to displacement of the center of foot
      pressure (CFP) and to angular changes in the position of the ankle joint.
      Subjects were instructed to shift the CFP from a relaxed bending posture (N) to a
      leaning posture half of maximally forward (1/2F) by swaying their bodies,
      pivoting at the ankles as rapidly and accurately as possible following an
      auditory signal. Ten motor units recorded from 5 subjects were studied. During
      body sway accompanied by elongation of the soleus muscle, a stereotyped serial
      motor unit discharge pattern was observed: cessation of unit discharge
      (acceleration phase), and then resumption of unit discharge (deceleration and
      stop phase). The rate of MUD during the deceleration and stop phase was higher
      than that when subjects held their bodies during holding his body at N or 1/2F. A
      strong positive correlation was observed between the timing of the resumption of
      MUD and both the CFP changes and the angular changes in the position of the ankle
      joint. These results strongly suggest that peripheral inputs are important for
      control of both the timing of the resumption and the frequency of MUD in the
      performance of a rapid body sway.

PMID- 10394504
TI  - Unusual late responses in a patient with an Arnold-Chiari malformation.
AB  - We studied a young man with spastic right hemiparesis, in whom supramaximal
      stimulation of the left posterior tibial nerve produced toe movements of the both
      feet and associated late responses in the flexor hallucis brevis muscle
      bilaterally. These findings indicate that, in this patient, there are central
      connections between peripheral afferents and contralateral alpha-motor neurons.
      It may be that such connections are normally present but that they are too weak
      in normal subjects to produce firing of the alpha-motor neurons by themselves. If
      so, the loss of cortical inhibition in our patient may have allowed these
      connections to produce movement.

PMID- 10394505
TI  - Temporary muscle weakness in the early phase of distraction during femoral
      lengthening. Clinical and electromyographical observations.
AB  - Limb lengthening by distraction osteogenesis has a high complication rate. Much
      of the response of muscle and nerve to distraction is still unknown. Thirteen
      children, mean age 12.6 yr (8.4-17.3) were surgically treated by the Ilizarov
      procedure for acquired and congenital femoral limb-length discrepancy. All
      children showed a decrease in muscle strength in the quadriceps, shortly after
      the operation, followed by an improvement before distraction started. After an
      elongation in the early phase of distraction (1 to 2 cm), muscle weakness was
      again observed and the muscle strength gradually increased after ending of
      distraction. To provide an explanation for this clinical observation, in one
      patient (limb lengthening of 4.1 cm) muscle strength measurements were extended
      with investigations of Hoffman (H) reflex of m. vastus medialis and determination
      of muscle-fiber conduction velocity of m. vastus lateralis by using the invasive
      method (IMFCV). The examinations were performed every two weeks during 20 weeks
      and 12 weeks after removing the cast. A severe decrease in muscle strength of the
      corrected limb was found after 1.2 cm of distraction with a recovery in muscle
      strength before lengthening was ended. EMG study showed the same tendency.
      Denervation was observed as evidence by positive sharp waves and reduced IMFCV
      findings. Evidence for reinnervation before lengthening was ended, was found by
      an increased range of velocities consisting of a combination of slow potentials
      and gradual increase of the velocity of reinnervated fibers (increased Fast/Slow
      ratio). The latencies of M waves and H-M interval from both legs separated as
      well after 2.25 cm of distraction. At the end of the follow-up period, the H-M
      interval reached the preoperative value. It is suggested that these neurogenic
      changes are an effect of axonal dysfunction and the local effect due to
      intraoperative trauma and stretching might affect nerve blood flow adversely.

PMID- 10394506
TI  - Twitch-obtaining intramuscular stimulation (TOIMS) in acute partial radial nerve
      palsy.
AB  - Twitch Obtaining Intramuscular Stimulation (TOIMS) is useful in the management of
      chronic nerve-related pain. The best understanding of the mechanism of action of
      TOIMS can occur on treating acute nerve-related symptoms. An opportunity to use
      TOIMS treatments in an acute, partial left radial palsy within 24 hours of onset
      did occur. Following treatment to the affected triceps and brachioradialis
      muscles, there was an immediate improvement in the amplitude, area and conduction
      velocity of the left radial motor and sensory nerves at the lower arm level.
      There was also improvement in numbness and all symptoms abolished after four
      treatments. Serial multiple motor unit action potential (multi-MUAP) analysis
      performed in the triceps and extensor communis (EDC) showed signs of motor unit
      enlargement. The triceps MUAPs showed an increase in duration and size index
      (area/amplitude) by the 3rd month. Both parameters stabilized at 18 months.
      Phases increased at the 6th month only. In EDC, the size index increased
      progressively by the 3rd month. The duration increased at the 6th month with
      stabilization by the 18th month. Phases and turns increased on day 3 examination
      only. EDC showed reduction in the firing rate with time. By relaxing the muscles
      through the effects of intramuscular exercise and also by improving local
      ischemia, TOIMS averted prolonged conduction abnormalities and probably a more
      serious axonal injury.

PMID- 10394507
TI  - Hyperlipidemia and neuropathy.
AB  - Detailed histories/physical examinations (n = 47) and nerve conduction studies (n
      = 34) were performed in a large kindred with congenital partial lipodystrophy
      (CPL) in an effort to evaluate the association of hyperlipidemia and neuropathy.
      CPL, in the absence of diabetes, did not predispose to either focal
      mononeuropathy or generalized polyneuropathy, and the likelihood of either did
      not correlate with the degree of cholesterol or triglyceride elevation. This
      study does not provide support for an association between neuropathy and
      hyperlipidemia.

PMID- 10394508
TI  - Innervation anomalies in upper and lower extremities (an electrophysiological
      study).
AB  - A hundred and eight subjects were studied for the frequent occurrence innervation
      anomalies in upper and lower extremities. Martin-Gruber Anomalies (MGA) were
      found in 19 (17.5%) subjects. The anomaly was bilateral in 14 subjects (73.6%).
      No case of motor ulnar to median nerve anastomosis in the forearm could be found.
      The 73.1, 20.8 and 14.3% incidences of the neural communication between the ulnar
      and median nerves in the hand were detected, in the Abductor Pollicis Brevis
      (APB), in the First Dorsal Interosseus (FDI) and in the Abductor Digiti Minimi
      (ADM) muscles, respectively. The existence of an accessory deep peroneal nerve
      was found in 23 (21.3%) subjects and 40 (18.5%) of legs. The anomaly was
      bilateral in 17 subjects (74%). We observed both MGA and accessory deep peroneal
      nerve in 9 cases.

PMID- 10394509
TI  - Contribution of motor unit activity enhanced by acute fatigue to physiological
      tremor of finger.
AB  - The contribution of motor unit activity to a physiological tremor (hereafter
      called as tremor) in a middle finger is studied by both a power spectrum and a
      correlation analysis in which the correlation coefficient and the coherence
      spectrum are obtained when five kinds of loads, 0, 50, 100, 150, and 200 g, are
      added to the middle finger for two minutes in a loading experiment on twelve male
      subjects. A weight of 200 g is applied to the subjects for ten minutes in a
      fatigue experiment. Throughout both experiments, the middle finger remains
      stretched from the load of the weight. The tremor is measured by an accelerometer
      (MT-3T, Nihon Kohden, Japan) attached to the middle finger, and the surface
      electromyogram (EMG) is measured by bipolar electrodes placed on m. extensor
      digitorum communis. A power spectrum analysis is carried out on the tremor and
      EMG, and a correlation analysis is performed on the relationship between the
      tremor and the demodulated EMG. It is found in the loading experiment that when
      the weight on the finger increases, the amplitude of the tremor oscillation
      increases since the activity of the motor units of the muscle is enhanced by the
      phenomenon of recruitment. Two frequency components of the tremor spectra at 10
      Hz and 25 Hz under a no load condition reflect the components of the activity of
      the motor units of the muscle because the tremor shows a significant correlation
      in the frequency zone of 10 Hz and 25 Hz with the demodulated EMG. The lower
      frequency component of the tremor spectrum at 10 Hz results in synchronized
      activity of the motor units, while the higher frequency at 25 Hz occurs from the
      stretch reflex loop via the motoneurons of the spinal cord. The shift of the
      higher frequency component to the lower frequency domain due to the load of the
      weight originates from the prolongation of the response time of the finger
      mechanical system because the lag time at the peak of the correlation coefficient
      increases with the load of the weight. It is found in the fatigue experiment that
      the amplitude of the tremor oscillation increases with the progress of fatigue.
      The increase is caused by the recruitment of the motor unit activity of the
      muscle holding the finger as well as by the synchronization of the firings of the
      motoneurons. The progress of the synchronization is verified by the fact that the
      mean power frequency (MPF) of the EMG spectrum decreases and the correlation
      between the tremor and the demodulated EMG increases with the progress of
      fatigue. The mechanisms of the increase of the amplitude of the tremor
      oscillation under the load of the weight to the finger and under the state of
      fatigue of the finger are elucidated by the analysis of the tremor and EMG.

PMID- 10394510
TI  - Inhibitory deficits in probable Alzheimer's disease. A study of movement related
      potentials and EMG response.
AB  - We have recently reported contralateral associated EMG responses to voluntary
      hand movement in Alzheimer's disease. Several aspects of this process were not
      fully explained in our last paper. In the present one we present data on the
      register of movement-related potentials (Negative Shift, NS) and Lateralized
      Readiness Potential (LRP), which have shown a very fine capacity to reveal
      processes that occur in the motor cortex while movement execution is being
      prepared. The associated EMG responses (so called by us) have almost all the
      characteristics of the partial errors revealed by cognitive psychology. First, it
      is a covert response, so it can only be detected by EMG recording; second, the
      appearance of this partial error changes the reaction time in the same way as
      described by Coles: mainly, by increasing reaction time as compared with clear
      responses. Nevertheless, contrary to partial errors, the associated EMG response
      does not constantly appear before the correct response. Associated EMG responses
      always appear after correct responses, with a constant delay of 54 +/- 28 ms. Our
      results show also an incorrect response preparation related to associated EMG
      response. We interpreted this specific feature in relation to inhibitory deficits
      in motor cortex and associated callosal pathways that avoid a correct response
      performance in Alzheimer patients.

PMID- 10394511
TI  - [Microinvasive ductal carcinoma of the breast. Role of axillary lymph node
      dissection].
AB  - The role of axillary lymph node dissection for microinvasive ductal carcinoma in
      situ of the breast was analyzed in a series of 60 consecutive cases. Forty-four
      cases were subclinical mammographically-detected carcinomas revealed by the
      clusters of microcalcifications. Although pathologists differ in their criteria
      for microinvasion, the maximal size considered in this retrospective study was 2
      mm. Axillary lymph node involvement was found in 3 cases (i.e. 5%) which harbored
      poor histologic features: comedocarcinoma subtype, high nuclear grade, and size
      of the ductal carcinoma in situ greater than 3 cm, requiring total mastectomy.
      While there is no need for axillary dissection in women with pure ductal
      carcinoma in situ, the management is quite different in proven microinvasion.
      Owing to the weakness of prognostic information given by cellular, biochemical
      and molecular features, instead of lymph node status, axillary dissection is
      still recommended in microinvasive ductal carcinoma in situ.

PMID- 10394512
TI  - [Importance of defecography in the evaluation of genital prolapses].
AB  - OBJECTIVE: To determine the interest of defecography for the initial evaluation
      of genital prolapses. PATIENTS AND METHODS: A retrospective study of 125 patients
      who had undergone systematically a defecography for the initial evaluation of a
      genital prolapse. RESULTS: 10% of defecogaphies were normal. On clinical
      examination a rectocele was found in 94% of patients and an enterocele in 33%. At
      defecography, these abnormalities were seen only in 39% and 15% respectively. 39%
      of patients with radiological rectocele had an intussusception at defecography.
      CONCLUSION: Defecography is appropriate to diagnose and to assess constitutional
      abnormalities associated with genital prolapse (rectocele, enterocele) and other
      anomalies which interact with it (intussusception, sphincter and pubo-rectal
      dyskinesia). Most of women with genital prolapse showed abnormal defecograms. We
      observed a marked discordance between clinical and radiological evaluation,
      specially for rectocele. Defecography is of great interest in the evaluation of
      posterior genital prolapses, specially in women complaining of dyschesia.
      Defecography may be proposed in case of: posterior vaginal wall prolapse
      (rectocele, enterocele), dyschesia, post-operative prolapse and before a
      cervicopexy.

PMID- 10394513
TI  - [Complications of cordocentesis associated with fetal therapy].
AB  - OBJECTIVES: To evaluate the technical and obstetrical risk factors of
      percutaneous umbilical blood sampling (PUBS) when associated with simultaneous
      fetal therapy. STUDY DESIGN: Retrospective study. One thousand PUBS have been
      performed in our department between 1984 and 1992. One hundred and forty one of
      them were done with another invasive fetal procedure. Technical and obstetrical
      circumstances were related to pregnancy follow-up and complications. RESULTS:
      Pregnancy complication rate increased when PUBS was associated with another
      invasive procedure (fetal losses: 12.9%, premature rupture of membranes (PROM):
      11.6%). No chorioamnionitis nor perinatal infection was observed. As expected,
      previous fetal status was a main risk factor. Significant relationships have been
      found between fetal loss risk and therapy procedures such as amnioinfusion and
      severe IUGR and as well as abnormal post operative fetal tracing. The duration of
      cord bleeding after needle retrieval was the single risk factor pointed out for
      PROM. CONCLUSION: The study of the predictors of fetal complications is necessary
      to separate the genuine risk of previous fetal status and the risk of the
      invasive procedure itself.

PMID- 10394515
TI  - [Maternal and fetal prognosis of occipito-posterior presentation].
AB  - Occipito-posterior persistent presentation is a relatively rare obstetrical
      condition, occurring in 2 to 4.5% of deliveries. Failure of the occiput to
      spontaneously rotate has been associated with increased maternal and neonatal
      morbidity. We performed a retrospective study of 210 vaginal occiput posterior
      deliveries to investigate the influence of this position on maternal and fetal
      morbidity. Our results demonstrate that overall prognosis of occipito-posterior
      persistent presentation is good but less auspicious than occipito-anterior
      presentation on account of importance of perineal injuries and maternal and fetal
      infections. Forceps extraction in posterior presentation is criticized today. In
      our opinion, the vacuum extractor is the better instrument because it is less
      aggressive to maternal tissues and also because, in most cases, the fetal head
      rotates anteriorly after provoked flexion.

PMID- 10394514
TI  - [Clinical importance of fetal pulse oximetry. I. Methodological evaluation.
      Multicenter study. French Study Group on Oximetry of Fetal Pulse].
AB  - OBJECTIVE: To evaluate the feasibility of intrapartum fetal pulse oximetry, the
      distribution of fetal oxygen saturation values, and the relation with the
      neonatal outcome in a population with an abnormal fetal heart rate (FHR). STUDY
      DESIGN: A prospective multicenter observational study, from June 1994 to November
      1995. Fetal oxygen saturation was continuously recorded using a Nellcor N-400
      fetal pulse oximeter in case of abnormal FHR during labor. Simultaneous readings
      of fetal oxygen saturation and of fetal blood analysis (FBA) were obtained at
      inclusion and before birth. Feasibility, adverse effects, distribution of fetal
      oxygen saturation values and relation with neonatal outcome were assessed.
      RESULTS: 74 patients were included. From 172 attempted sensor placements, the
      procedure was impossible in three cases and fetal oxygen saturation values were
      obtained in 164 cases (95.3%). Physicians considered sensor placement an easier
      task than FBA attempt (easy in 87.5% vs 78.9% for FBA, p = 0.03). The mean
      reliable signal time (+/- SD) was 64.7 +/- 32% during the first stage. There were
      no serious adverse effects in the study population. The mean fetal oxygen
      saturation during the first stage of labor was 42.2 +/- 8.0% (10th-90th centile
      range: 30-53%). Fetal oxygen saturation was significantly correlated with scalp
      pH (r = 0.29; p = 0.01) but not with neonatal umbilical artery pH or gas values.
      There was a significant association between a low fetal oxygen saturation (< 30%)
      and a poor neonatal condition. CONCLUSION: The feasibility of fetal pulse
      oximetry is satisfactory in clinical practice. It is easy to use and provides a
      fair rate of recorded values, even in a population with suspicion of fetal
      distress. A low fetal oxygen saturation is significantly associated with an
      abnormal neonatal outcome.

PMID- 10394516
TI  - [Comparison of blood loss during cesarean section and during vaginal delivery
      with episiotomy].
AB  - OBJECTIVE: The aim of our study was to compare blood loss during vaginal delivery
      with episiotomy and during cesarean section, to determine risk factors, and to
      determine whether clinical assessment of blood loss at delivery is well
      evaluated. PATIENTS AND METHODS: We retrospectively matched 97 vaginal deliveries
      with episiotomy with 97 cesarean deliveries which has occurred between 1 November
      1991 and 30 April 1993. Matching criteria were age, parity, term and birth
      weight. Blood loss at delivery was defined by a drop in hematocrit greater than
      10% between the pre-delivery anesthesia work-up and the laboratory results 3 days
      post-partum. RESULTS: We found that hemoglobin and hematocrit fell more after
      vaginal deliveries than after cesarean section (p < 0.05 and p < 0.01). The fall
      in hemoglobin level and hematocrit were significantly greater after forceps
      delivery with episiotomy than after spontaneous vaginal delivery (p < 0.01 and p
      < 0.01). Among the vaginal deliveries, 11 showed laboratory criteria
      corresponding to blood loss at delivery despite clinical diagnosis in only 2 of
      them. Unwarranted clinical diagnosis of blood loss at delivery was however made
      11 times after vaginal delivery and 19 times after cesarean (20%). CONCLUSION:
      Our findings demonstrate that blood loss during vaginal delivery with episiotomy
      is greater than during cesarean section and affirms the determining role of
      forceps use in association with episiotomy in this blood loss. Clinical
      assessment of blood loss at delivery lacks precision.

PMID- 10394517
TI  - [Management of severe post-partum hemorrhage using selective arterial
      embolization].
AB  - OBJECTIVES: To evaluate the efficacy and safety of uterine embolization in the
      management of intractable post-partum hemorrhage. MATERIALS AND METHODS: From
      July 1994 to December 1997, 51 patients with severe primary (n = 37) or secondary
      (n = 14) post-partum hemorrhage were treated by arterial uterine embolization. In
      all cases, hemostatic uterine embolization was performed because of persistent
      hemorrhage despite adapted obstetrical measures and early introduction of
      uterotonic drugs. RESULTS: In case of immediate post-partum hemorrhage, primary
      and secondary success rates were 89% et 97% respectively. In one patient with
      placenta accreta, delayed hysterectomy was necessary. One patient died of
      associated cerebral hemorrhage while vaginal bleeding had stopped. The success
      rate reached 100% in case of secondary post-partum hemorrhage. CONCLUSION:
      Emergency arterial embolization is a safe and effective means of controlling
      severe post-partum hemorrhage after failure with medical treatment.

PMID- 10394518
TI  - [Do obstetric causes of death explain the differences in maternal mortality
      between France and Europe?].
AB  - In view of understanding why the level of maternal mortality is higher in France
      than in other European countries, a specific study of frequency and causes has
      been carried out in these 13 countries. Two different sources of data were used:
      the annual civil death data from national offices which are published by the WHO,
      and the MOMS data. It was hypothesized that the pattern of causes plays a role in
      the level of maternal mortality. This hypothesis was checked with results issuing
      from a European concerted action where deaths were classified by a European group
      of medical experts using identical criteria. There were apparently more cases of
      hemorrhage, direct obstetric causes, and indirect obstetric causes in France than
      in the other European countries. The higher level of indirect obstetric causes
      may be explained by stronger registration regulations for maternal deaths
      recently implemented in France. Due to the higher level of hemorrhage as cause of
      maternal death in France, we suggest in-depth research is needed in the near
      future to study prevalence and management of obstetrical hemorrhage in France.

PMID- 10394519
TI  - [Parametrial pregnancy. Report of a case of "paracervical" pregnancy treated by
      medico-surgical management].
AB  - We report an exceptional case of para-cervical pregnancy. Ultrasonography enabled
      accurate diagnosis after explorative laparoscopy. Treatment was conservative
      involving methotrexate and surgical ablation of the pregnancy by vaginal approach
      with a successful outcome.

PMID- 10394520
TI  - [Exanthematic pustulosis of pregnancy: favorable evolution using calcium and
      vitamin D2].
AB  - A 26-year-old pregnant woman was hospitalized in an emergency setting for a skin
      eruption. She had developed pustules distributed on round patch-like areas of
      rash localized at the umbilicus and the larger skin folds. She was given
      calcitriol and calcium with good results. Systemic steroids are usually given for
      exanthematic pustulosis of pregnancy but with variable efficacy. Few cases of
      successful treatment with calcium and vitamin D have been reported. We suggest
      this alternative treatment could be useful in other cases.

PMID- 10394521
TI  - [Response of J.-M- Thoulon to the letter of Cl. Sureau].

PMID- 10394522
TI  - [How to avoid transfusion in the post-partum period: importance of an intravenous
      iron supplement].

PMID- 10394523
TI  - The effect of smoking on oocyte quality and hormonal parameters of patients
      undergoing in vitro fertilization-embryo transfer.
AB  - PURPOSE: The aim of the present study was to investigate the influence of smoking
      on different parameters such as oocyte count, embryo score, and basal hormone
      values within the scope of in vitro fertilization-embryo transfer (IVF-ET).
      METHODS: Eight hundred thirty-four women undergoing IVF-ET treatment were
      classified as smokers or nonsmokers on the basis of questionnaires. Additionally,
      we divided them into three groups according to their stimulation protocol-
      "combined stimulation" [I; clomiphene citrate plus human menopausal gonadotropin
      (hMG)], "ultrashort" [II; gonadotropin releasing hormone agonist (GnRHa) plus hMG
      or follicle-stimulating hormone (FSH)], and "long downregulation protocol" (III)-
      and further classified again as smokers or nonsmokers within the groups. RESULTS:
      In general, smoking patients were significantly (P = 0.0195) younger than
      nonsmokers and showed a significantly (P = 0.0379) lower embryo score and a
      tendency (P = 0.0931) to produce fewer oocytes. There was no significant
      difference concerning the number of normally or pathologically fertilized and
      transferred oocytes and embryos suitable for cryopreservation. Women who smoked
      had significantly (P = 0.0112) higher basal 17-beta-estradiol (E2), luteinizing
      hormone (LH) (P = 0.0001), and dehydroepian-drosteronesulfate (DHEAS) (P =
      0.0039) levels, but their basal human prolactin (HPRL) levels were significantly
      (P = 0.0033) lower than those of nonsmokers. According to the stimulation
      protocol used, we found the following results. Smoking patients in group I showed
      a significantly (P = 0.023) lower embryo score and produced fewer oocytes (P =
      0.0113), with fewer of them being fertilized (P = 0.0072) and transferred (P =
      0.0067). Women who smoked had significantly (P = 0.0002) higher basal LH levels,
      but their HPRL levels were significantly (P = 0.031) lower than those of
      nonsmokers. Furthermore, they had a thinner endometrium on the day of embryo
      transfer (P = 0.0366). In group II we measured significantly elevated basal E2
      levels (P = 0.0089) and higher LH values (P = 0.0092) in smokers. Group III
      showed a trend (P = 0.0565) toward lower HPRL values in smokers. CONCLUSIONS:
      Although the fertilization rate of oocytes and the pregnancy rate were not
      significantly different between smokers and nonsmokers, we found significantly
      alterated hormonal parameters and negatively influenced oocyte parameters,
      particularly after clomiphene stimulation. So we might consider using only GnRHa
      protocols for smoking patients. Additionally, we advise our patients to stop
      smoking before an IVF-ET treatment because of the complex effects of smoking on
      the reproductive and hormonal system.

PMID- 10394524
TI  - A study failing to determine significant benefits from assisted hatching:
      patients selected for advanced age, zonal thickness of embryos, and previous
      failed attempts.
AB  - PURPOSE: Pregnancy and implantation rates after mechanical assisted hatching (AH)
      in patients aged > or = 38 years, with embryos > or = 15 microns in zonal
      thickness and two or more failed attempts, were assessed at two infertility
      centers using fresh and frozen embryo transfer (FET) cycles. METHODS: AH was
      performed on 3-day-old embryos. Spare embryos cryopreserved at the two-pronucleus
      stage were subjected to AH after 2 days of culture and transferred to
      artificially prepared uteri. RESULTS: In fresh cycles, no significant differences
      in pregnancy rates (clinical and ongoing) and implantation rates were observed
      between the AH and the controls for all three selected patient groups (Centers 1
      and 2). In FET cycles, AH tended to give poor results for > or = 38 year olds
      (clinical pregnancy rates of 0 and 5.0% with AH vs 13.3 and 16.7% for controls at
      Centers 1 and 2, respectively). With AH, embryos with thick zonae implanted to
      the same extent as those in the control group and achieved pregnancies for
      patients with multiple failures (four to six attempts for some) in both fresh and
      FET cycles. CONCLUSIONS: AH failed to show significant benefits in all three
      patient groups. A larger study group may confirm the effects of AH on
      frozen/thawed embryos and outcomes for multiple failure cases.

PMID- 10394525
TI  - Psychotherapeutic counseling and pregnancy rates in in vitro fertilization.
AB  - PURPOSE: Since the Austrian propagation bill of July 1, 1992, was passed into
      law, Austrian physicians are committed to offer psychological counseling to women
      before performing assisted reproductive techniques, unless refused by the
      patient. The acceptance of psychotherapeutic counseling (PSITCO) and its
      influence on pregnancy rate were carefully reviewed. METHODS: The study comprised
      1156 consecutive patients (mean age, 33.3 years) and 1736 in vitro fertilization
      (IVF) cycles. In a consent form for follicle puncture, the patients were
      interviewed about PSITCO as follows. Several methods of psychological support
      during IVF-embryo transfer treatment were offered to patients especially
      psychotherapy, hypnotherapy, and relaxation and physical perception exercises.
      RESULTS: Forty-two and three-tenths percent of patients rejected PSITCO, 17.8%
      had already received PSITCO, and 10.4% were willing to undergo PSITCO. The
      acceptance of PSITCO had no relevance on pregnancy rate. The cumulative
      calculation of pregnancy rates showed that up to 56.4% of women who had undergone
      PSITCO conceived. In patients who were planning to undergo PSITCO, the pregnancy
      rate was 41.9%. Concerning the cumulative pregnancy rate, this study showed that
      patients who accepted or underwent PSITCO had a higher pregnancy rate than those
      who did not avail themselves of this possibility. CONCLUSIONS: These results
      should encourage sterility specialists to consider psychological therapy as an
      essential aspect of IVF. Solely a written declaration of the patient stating
      his/her awareness of the possibility to undergo PSITCO is, in our opinion,
      insufficient.

PMID- 10394526
TI  - Randomized autocontrolled comparison of the embryo culture performance of Nunc
      and Falcon petri dishes.
AB  - PURPOSE: Our purpose was to compare the embryo culture performance of two types
      of petri dishes (Nunc and Falcon). METHODS: Mouse zygotes were cultured up to the
      expanded blastocyst stage in both types of dishes. The oocytes from 50 in vitro
      fertilization cycles were randomly divided between the two types of dishes.
      Fertilization, cleavage, and embryo quality were compared. Oocytes from another
      50 cycles were all cultured at random in either type of dish. Pregnancy and
      implantation rates were compared between the two types. RESULTS: Of 91 mouse
      zygotes, 81 cleaved to two-cell-stage embryos, and 64 became expanded blastocysts
      in Falcon dishes; of 99 zygotes, 81 cleaved to two-cell-stage embryos and 66
      became expanded blastocysts in Nunc dishes. Of 248 oocyte-cumulus complexes
      (OCC), 145 fertilized in Falcon dishes, and of 269 OCC, 175 fertilized in Nunc
      dishes. The high quality embryo ratio was 51 out of 118 in Falcon dishes, not
      different from that in Nunc dishes, 58 out of 139. In Falcon dishes 72 out of 118
      embryos were at least at the four-cell stage after 45 hr, versus 70 out of 139 in
      Nunc dishes. Twenty-three clinical pregnancies were obtained in the first 50
      cycles with sibling oocytes. In the second group, with randomization of the
      cycles between Nunc and Falcon, 8 pregnancies were obtained in the Nunc and 10 in
      the Falcon dishes. The implantation rate in this second group of 50 cycles was 9
      out of 61 in Falcon and 11 out of 57 in Nunc dishes.

PMID- 10394527
TI  - Stimulation of early embryonic development in cattle by coculture with
      surfactant.
AB  - PURPOSE: Our purpose was to determine the efficacy of Surfacten, a bovine
      pulmonary surfactant, on the maturation of in vitro bovine ova. METHODS: We used
      Surfacten as a supplement to the coculture media both at the onset of coculture
      and after cleavage in bovine ova had been determined. The controls received no
      Surfacten. RESULTS: The maturation rate in bovine embryos to the blastocyst stage
      statistically improved (P < 0.05) in the series in which Surfacten was added to
      the media at the onset of coculture, compared with the controls and the series in
      which Surfacten was added after cleavage had been determined. CONCLUSIONS:
      Surfacten, a commercially available surfactant which is a naturally occurring
      phospholipid that dramatically increases in the cervical mucus and the ampullaris
      of the oviduct at or near the time of ovulation, improves the maturation of
      bovine embryos in vitro by making the coculture medium approach the conditions
      found in the oviducts.

PMID- 10394528
TI  - Bypassing spermiogenesis for several generations does not have detrimental
      consequences on the fertility and neurobehavior of offspring: a study using the
      mouse.
AB  - PURPOSE: This study was conducted to determine whether the omission of
      spermiogenesis and all prefertilization events for five generations in mice
      affects the fertility or behavior of offspring. METHODS: Fifth-generation hybrid
      (C57BL/6 x DBA/2) mice were produced using round spermatid injection (ROSI).
      Control groups consisted of mice born after natural mating with and without sham
      operation. The growth, fertility, and behavior of offspring were compared.
      Behavior tests conducted assessed elementary reasoning (Krushinsky test),
      emotionality (Mouse Defense Test Battery), and spatial learning and memory
      (Morris water maze). RESULTS: There were no significant differences in the growth
      and fertility of fifth-generation ROSI mice compared to natural fertilization
      mice. We also found no evidence of significant learning or behavioral deficits of
      the fifth-generation ROSI mice. CONCLUSIONS: In this study, we found no evidence
      that bypassing the natural biological processes involved in spermiogenesis
      produces adverse effects on the growth, fertility, or behavior of mouse
      offspring.

PMID- 10394529
TI  - Tenacity of exogenous human papillomavirus DNA in sperm washing.
AB  - PURPOSE: Sperm cells have been shown to take up exogenous DNA readily. The
      hypothesis was that sperm washing would remove exogenous viral DNA infecting
      sperm cells. The objective was to compare three types of sperm washing procedures
      for their capacity to remove exogenous human papillomavirus (HPV) DNA from
      infected sperm. METHODS: Prewashed sperm were equally divided and sperm in one
      portion were exposed to L1 HPV DNA fragments for 30 min at 37 degrees C.
      Untreated washed sperm served as the control. After transfection, the sperm were
      washed by either centrifuge, two-layer Isolate colloid wash, or test-yolk buffer
      procedures. Sperm parameters were measured on a Hamilton Thorn HTM-C analyzer.
      Sperm DNA were extracted and polymerase chain reaction (PCR) was carried out
      targeting the L1 consensus gene of HPV and the designated sentinel gene, 17q21
      spanning the D17S855 gene. Amplified products were analyzed in 2% agarose gel
      electrophoresis. RESULTS: PCR analyses detected the consensus L1 HPV gene in
      sperm after they were processed through either of the three procedures. Controls
      were negative for the L1 gene. Extracted DNA were verified by PCR amplification
      of 17q21 spanning the D17S855 gene. Transfected sperm had higher percentages of
      total motility and progression compared with the control. Centrifuged, washed,
      transfected sperm exhibited a greater curvilinear velocity and hyperactivation.
      CONCLUSIONS: The data showed that washing would not remove exogenous HPV DNA from
      sperm cells. The viral DNA was tenaciously bound to the sperm, suggesting an
      internalization into the sperm. The viral DNA also increased the motility of the
      sperm by affecting the velocity and progression of the sperm, which suggested
      either an increase in metabolism, an enhancement of the calcium-regulated
      motility mechanism, or an artifact of PCR reagents. More studies are needed to
      elucidate the mechanism of DNA stimulated sperm motility.

PMID- 10394530
TI  - Are cumulus cells necessary for the spontaneous maturation of germinal vesicle
      stage oocytes to metaphase II.
AB  - PURPOSE: In this study we investigated the need of the support from cumulus cells
      for germinal-vesicle (GV) oocytes collected from stimulated ovaries to complete
      their maturation to metaphase II (MII). METHODS: We compared the maturation rate
      of GV oocytes after coculture with cumulus cells (study group) with their
      spontaneous maturation in culture medium alone (control group). RESULTS: Sixty
      four and nine-tenths percent of the GV oocytes matured to metaphase II in the
      coculture group, and of these, 43.5% gave normal 2pn zygotes following
      intracytoplasmic sperm injection (ICSI), while 73.8% of the GV oocytes
      spontaneously matured to the MII stage and 30% of these reached the zygote stage
      after ICSI. CONCLUSIONS: It is probable that a follicular factor is responsible
      for this arrested maturation in the human and that maturation occurs
      spontaneously when the oocytes are separated from their follicular fluid
      environment after collection.

PMID- 10394531
TI  - G-protein regulation of the solubilized human zona pellucida-mediated acrosome
      reaction and zona pellucida binding.
AB  - PURPOSE: The study aimed to evaluate the (i) regulatory role of Gi-like protein
      during the acrosome reaction (AR) of normal sperm donors and (ii) the role of
      intact acrosomes during sperm-zona binding. METHODS: The acrosomal exocytosis of
      spermatozoa incubated with solubilized zona pellucida (ZP) at a final
      concentration of 1 ZP/microliter was compared with 10 microM calcium ionophore
      A23187 and 30% (v/v) pooled human follicular fluid (HFF). Spermatozoa were
      incubated with 1, 10, and 100 ng/ml pertussis toxin (PT) during capacitation to
      functionally inactivate the Gi-like protein. The sperm-zona binding potential of
      100 ng/ml PT-treated spermatozoa followed, by exposure to 1 ZP/microliter,
      revealed significantly higher zona-bound spermatozoa compared to controls treated
      with 1 ZP/microliter only. RESULTS: PT treatment of spermatozoa did not affect
      sperm motility, however, inhibited the percentage AR induced by solubilized ZP.
      In contrast, the A23187- and HFF-induced ARs were not sensitive to PT treatment.
      PT inhibition of the ZP-induced AR occurred in a concentration-dependent manner,
      with maximal effects observed at 100 ng/ml PT. CONCLUSIONS: In conclusion, it
      seems that PT-sensitive Gi-like protein in human spermatozoa plays an important
      regulatory role in the AR induced by the human ZP, and this underlines the
      importance of intact acrosomes during sperm-zona binding.

PMID- 10394533
TI  - Clinical ethics consultations: some reflections on the report of the SHHV-SBC.

PMID- 10394532
TI  - Viral screening and assisted conception treatment--the Bourn Hall experience.

PMID- 10394534
TI  - Ethics consultants: could they do better?

PMID- 10394535
TI  - The Task Force report: comprehensible forest or unknown beetles?

PMID- 10394536
TI  - Beyond case consultation: an expanded model for organizational ethics.

PMID- 10394537
TI  - The application of the Task Force report in rural and frontier settings.

PMID- 10394538
TI  - Moving the conversation forward.

PMID- 10394539
TI  - Brain death, pregnancy, and posthumous motherhood.

PMID- 10394540
TI  - Legal trends in bioethics.

PMID- 10394541
TI  - Maintenance of increased Bcl-2 expression in uterine leiomyomas after GnRH
      agonist therapy.
AB  - OBJECTIVE: To compare the immunohistochemical expression of Bcl-2 in uterine
      leiomyomas in patients undergoing myomectomy or hysterectomy with and without
      preoperative treatment with the gonadotropin-releasing hormone receptor agonist
      (GnRH-a) leuprolide acetate (LA). STUDY DESIGN: Retrospective case-control study.
      Seventeen patients with symptomatic uterine leiomyomata were included. Of the 17
      patients, 7 were treated with LA (3.75 mg) in three monthly doses prior to
      myomectomy or hysterectomy. Ten patients who did not receive LA and underwent
      hysterectomy for leiomyomas served as controls. Formalin-fixed, paraffin-embedded
      archival tissue from 17 leiomyomas were immunostained with a monoclonal antibody
      against Bcl-2 protein. Positivity was scored semiquantitatively on a three-tier
      scale. RESULTS: Immunostaining for Bcl-2 protein was intense (2-3+) in 7 LA
      treated and 10 untreated leiomyomas but was scarce (0-1+) in normal myometrial
      smooth muscle. CONCLUSION: Abundant expression of Bcl-2 protein may be
      responsible for the growth of leiomyomas by preventing apoptotic cell death. Its
      increased expression is maintained in GnRH-a-treated leiomyomas.

PMID- 10394542
TI  - Oncogene expression and microvessel count in recurrent and nonrecurrent stage Ib
      squamous cell carcinoma of the cervix.
AB  - OBJECTIVE: To evaluate p53, epidermal growth factor receptor (EGFR) and c-erbB-2
      oncogene expression and compare it with microvessel count (MVC) in determining
      the clinical outcome of stage Ib squamous cell carcinoma (SCC) of the cervix.
      STUDY DESIGN: Immunostaining with p53, EGFR, C-erbB-2 and factor VIII antibodies
      was performed on tumor sections from 22 patients (11 with cancer recurrence, 11
      free of cancer after four years). The levels of oncogene expression were
      semiquantitatively graded (0-4). Microvessels were counted (per 200 x field) in
      areas of highest neovascularization. RESULTS: Eight of 11 patients (72.7%) with
      recurrence expressed EGFR as compared with 5 of 11 patients (45.5%) free of
      disease. This difference is not significant (P = .39). An equal number of
      patients with and without recurrence expressed c-erbB-2. Five of 11 patients
      (45.5%) with recurrence expressed p53, as compared with 6 of 11 (54.5%) free of
      disease (P = 1.00). Eight of 11 patients (72.7%) with recurrence had an MVC above
      24 as compared with 2 of 11 patients (18.2%) free of disease; this difference was
      statistically significant (P = .03). CONCLUSION: The expression of EGFR, p53 and
      c-erbB-2 appears to have little prognostic value in stage Ib SCC of the uterine
      cervix. The prognostic value of MVC is in keeping with previous findings.

PMID- 10394543
TI  - Advanced FISH with directly labeled X, Y and 18 DNA probes as a tool for rapid
      prenatal diagnosis.
AB  - OBJECTIVE: To examine a rapid technique for identification and determination of
      fetal sex chromosomes and one autosome (chromosome 18) in uncultured amniotic
      fluids using fluorescence in situ hybridization (FISH) with directly labeled DNA
      probes and ignoring the use of proteinase K and Rnase. STUDY DESIGN: Twenty-five
      amniotic samples taken from pregnant women who were in their 18th gestational
      week and had advanced maternal age were studied for analysis of sex chromosomes
      and chromosome 18 with the FISH technique as well as standard cytogenetic
      analysis. RESULTS: Four hours after amniocentesis was performed, we identified
      the sex of the fetuses and disomy of chromosome 18 in a minimal sample of
      uncultured amniotic fluid by using directly labeled DNA probes for chromosomes X,
      Y and 18 (VYSIS) and ignoring the use of proteinase K and Rnase. CONCLUSION: The
      possibility of shortening the time required for identification of aneuploidies in
      a second-trimester fetus is useful in cases where fetal anomalies are
      ultrasonically diagnosed at a relatively advanced gestational age.

PMID- 10394544
TI  - A new laparoscopic retroperitoneal posterior culdoplasty technique.
AB  - OBJECTIVE: To test the hypothesis that laparoscopic retroperitoneal culdoplasty
      executed with a CO2 laser is comparable to the same operation performed with
      mechanical laparoscopic instruments and to extend a previously reported series of
      laparoscopic posterior culdoplasties. STUDY DESIGN: A prospective, cohort,
      comparison, clinical study was conducted to determine relative risk on 30
      subjects who met inclusion criteria for this trial. Group I patients (n = 15)
      were subjected to laparoscopic culdoplasty with a CO2 laser, group II subjects (n
      = 15) were exposed to the same intervention with 5-mm laparoscopic mechanical
      instruments. Both groups were observed for intraoperative, immediate
      postoperative and delayed complications. During the postoperative follow-up
      period, the following parameters were recorded: dyschesia, dyspareunia, sexual
      dysfunction, pelvic pain (preoperative and postoperative rating scale for pain
      used). RESULTS: There was no significant difference in clinical and demographic
      data between the two groups. All planned laparoscopic culdoplasties for
      symptomatic enterocele were successfully carried out, with no conversions to
      laparotomy or vaginal surgery. In group I, average operating time was 1 hour, 11
      minures, and in group II it averaged 47 minutes (P = .03). There were no
      intraoperative complications or blood transfusions. During the early recovery
      period, 26% in group I vs. 6% in group II (P = .04) reported transitional urine
      retention. Two of those patients from group I developed symptoms of lower urinary
      tract infections. In group I, one patient (3%) (P = .10) developed a recurrence
      of enterocele, grade 2. In group II, one patient (3%) (P = .10) experienced
      difficulty during sexual intercourse following laparoscopic culdoplasty. In all
      patients but two, symptoms of dyschesia, dyspareunia and sexual dysfunction
      related to anatomy distortion and pelvic pain were cured. CONCLUSION:
      Laparoscopic retroperitoneal posterior culdoplasty executed with mechanical
      instruments yielded a clinical outcome similar to that of surgery performed with
      a CO2 laser. The operative time was statistically significantly longer when the
      operation was performed with a laser. Using a laser increases the potential for
      complications associated with the laser itself and increases the cost of the
      operation. Ninety-three percent of patients remained symptom free after surgery.

PMID- 10394545
TI  - Kielland vs. nonrotational forceps for the second stage of labor.
AB  - OBJECTIVE: To examine and compare maternal and neonatal morbidity after use of
      two types of obstetric forceps used in the management of the second stage of
      labor. STUDY DESIGN: This retrospective investigation was conducted from January
      1993 to December 1995 and included 55 infants delivered with Kielland forceps as
      compared to 213 infants delivered with nonrotational forceps. The maternal and
      neonatal charts were reviewed for data collection. Maternal complications
      compared included blood loss, vaginal lacerations, postpartum hemorrhage, and
      third- and fourth-degree perineal lacerations. Infant data collected compared
      fetal lacerations, nerve palsies, shoulder dystocias, blood gas values and
      admissions to the neonatal intensive care unit. Statistical analysis was
      performed by Fisher's exact, chi 2 and Student's t test. RESULTS: Women in both
      groups were similar with respect to age, gravidity, parity and estimated
      gestational age at delivery. Infants were similar in both groups with respect to
      fetal weight, admissions to the neonatal intensive care unit, nerve compromise,
      scalp lacerations and facial bruising. The Kielland group had statistically
      significantly longer labor, 671 +/- 285.8 vs. 614 +/- 226.5 minutes (P < .05) and
      longer second stage of labor 184 +/- 74.71 vs. 161 +/- 65.79 minutes (P < .05).
      The Kielland group also had a statistically higher percentage of one-minute Apgar
      scores < 6, 18.2% vs. 4.7% (P < .05), and meconium present at delivery, 14.5% vs.
      5.6% (P < .05). CONCLUSION: Management of the second stage of labor can be
      accomplished safely with Kielland forceps and rotation of the fetal head.
      Supervision by an experienced operator will allow residents to be trained with
      respect to appropriate patient selection and application of these forceps.

PMID- 10394546
TI  - Economic impact of automated primary screening for cervical cancer.
AB  - OBJECTIVE: To construct a markovian model to project the marginal cost of the
      AutoPap System as compared to manual cervical cytologic screening. STUDY DESIGN:
      Data from a clinical trial and published literature were entered into a seven
      state markovian decision-analytic model to estimate the marginal cost per year of
      life saved that could be attributed to changes in primary screening technology.
      RESULTS: Annual screening with AutoPap produced a meaningful increase in life
      expectancy of 32.1 days relative to manual screening at a marginal savings of
      $628 per person (or a marginal savings of $7,144 per life-year saved). Less
      frequent screening yielded lower positive savings. CONCLUSION: Automated
      screening for cervical cancer has the potential to significantly improve health
      care outcomes and reduce cost.

PMID- 10394547
TI  - Vaginal hysterectomy for correcting genital prolapse. Long-term evaluation.
AB  - OBJECTIVE: To determine whether a transvaginal hysterectomy with anterior and
      posterior repair is effective in the long term in treating uterovaginal prolapse
      and stress urinary incontinence (SUI). STUDY DESIGN: Seventy-four patients
      subjected to vaginal hysterectomy for the treatment of severe genital prolapse,
      on average five years before the study, were contacted by letter for evaluation.
      Four of these patients had died, and 47 (67.1%) responded to the letter. The mean
      age of the patients at the time of reevaluation was 66.1 +/- 10.6 years, and mean
      parity was 6.6 deliveries. RESULTS: All patients but two presented some degree of
      genital prolapse at the time of reevaluation, with three cases of total vaginal
      vault prolapse. White patients (87.2%) predominated over African (black) patients
      (12.8%). SUI associated with prolapse persisted in 14 of the 20 patients, and 6
      others had this complaint after surgical correction (22.2% of previously
      continent patients). CONCLUSION: The rate of unsuccessful surgical correction of
      severe genital prolapse was very high (95.7%), and cure of SUI was low (30%),
      with SUI actually arising after surgical correction in 25% of continent patients.
      In addition to parity, there seems to be a racial factor linked to the onset and
      maintenance of this pathology, with a higher prevalence among white patients.

PMID- 10394548
TI  - Sildenafil in the treatment of female sexual dysfunction induced by selective
      serotonin reuptake inhibitors.
AB  - OBJECTIVE: To review the literature describing female orgasmic disorder and
      impaired sexual desire disorder by selective serotonin reuptake inhibitors
      (SSRIs) and their treatment, including the use of sildenafil. STUDY DESIGN:
      Literature reviews of all available published articles on this topic from 1989 to
      1996 were done. This paper also includes a sample case of a 38-year old woman who
      suffers from fluoxetine-induced arousal and orgasmic disturbance. RESULTS:
      Treatment approaches include the use of "antidotes," such as cyproheptadine,
      yohimbine, amantadine, granisetron and ginkgo biloba. This article also reports a
      case of successful female use of sildenafil, which was released by the Food and
      Drug Administration in March 1998 for erectile dysfunction in men. CONCLUSION:
      Sildenafil is beneficial in reversing female sexual dysfunction induced by SSRIs.
      This paper also discusses sildenafil's action in the background of nitric oxide
      and cyclic guaninosine monophosphate in penile/clitoral erection.

PMID- 10394549
TI  - One-day therapy for vaginal candidiasis. A review.
AB  - Shorter courses of therapy have been developed for most antifungal agents used
      for the treatment of vaginal candidiasis, including clotrimazole, econazole,
      isoconazole, miconazole, terconazole and fluconazole. A search of the medical
      literature identified 14 studies that compared single-dose therapy for vaginal
      candidiasis in nonpregnant women. These studies, conducted according to similar
      study designs, provided sufficient information to evaluate clinical and mycologic
      cure rates. There were few significant differences in either the clinical or
      mycologic cure rates of single-dose therapy, and no one therapy was consistently
      better than any other. Until further information is available, the choice of
      therapy will continue to be based on individual clinician preference.

PMID- 10394550
TI  - Prolapse of the neovagina in Mayer-Rokitansky-Kuster-Hauser syndrome. A case
      report.
AB  - BACKGROUND: Mayer-Rokitansky-Kuster-Hauser syndrome is a rare entity. The
      creation of a sigmoid vagina was performed in some patients with this syndrome in
      the past, though it is not widely used now. We report on a patient who developed
      prolapse of a sigmoid vagina 33 years after the operation. CASE: A 57-year-old
      woman presented with a "falling-out" sensation in the vagina, pain, leukorrhea
      and dyspareunia. She had undergone an operation for creation of a sigmoid vagina
      33 years earlier in our hospital. She and her husband desired conservation of the
      ability for sexual intercourse. The transabdominal method of retroperitoneal
      sacropexy of the sigmoid vagina was performed. The patient has maintained a
      satisfactory sexual life with her husband since the operation. CONCLUSION: There
      are a few cases of prolapse of a sigmoid vagina in the literature, while the
      repair methods are not described in detail. To our knowledge, this is the first
      report of reconstruction of a sigmoid vaginal prolapse. Although the reasons for
      the neovaginal prolapse were not understood, the retroperitoneal sacropexy was
      successful in this case.

PMID- 10394551
TI  - Ruptured tuboovarian abscess in late pregnancy. A case report.
AB  - BACKGROUND: Tuboovarian abscess is an unusual obstetric complication that causes
      maternal and fetal morbidity and mortality. CASE: A woman, G1, P0, with a 32-week
      pregnancy presented with abdominal pain. Physical examination on admission
      revealed fever and unremarkable abdominal signs. Eleven hours after admission,
      signs of peritonitis became prominent, necessitating emergency laparotomy.
      Surgical findings included an 8-cm, right, ruptured tuboovarian abscess with
      massive purulent contamination of the abdominal cavity. Cesarean hysterectomy
      with bilateral salpingo-oophorectomy was performed. Neither the newborn nor the
      mother had postoperative complications. CONCLUSION: Since there are discrepancies
      in the incidences of tuboovarian abscess in pregnant and nonpregnant groups, the
      pathogenesis of tuboovarian abscess may be different in the two populations. In
      pregnancy, diagnosis and management are also more difficult than in the
      nonpregnant state. Clinical data may not reveal the diagnosis until surgery is
      mandatory. Because most pregnant women with tuboovarian abscesses are young,
      conservative surgery should be attempted if the pathology is limited to only one
      side of the adnexa and further reproduction is desired.

PMID- 10394552
TI  - Heterotopic pregnancy with term delivery after rupture of a first-trimester tubal
      pregnancy. A case report.
AB  - BACKGROUND: Because heterotopic pregnancy is rare, the presence of an
      intrauterine pregnancy tends to impede early diagnosis and definitive
      intervention for the ectopic component. Delay in diagnosing the condition and
      failure to proceed quickly with the requisite anesthesia and surgery can
      jeopardize both maternal well-being and survival of the intrauterine fetus. CASE:
      A patient with heterotopic pregnancy carried the intrauterine pregnancy to term
      following first-trimester rupture of the tubal pregnancy, with hypovolemic shock.
      CONCLUSION: Prompt diagnosis, rapid fluid and blood resuscitation, heart-sparing
      anesthesia and gentle, expeditious surgery collectively contributed to the
      favorable outcome for the mother and surviving infant.

PMID- 10394553
TI  - Transhepatic artery chemoembolization for liver metastases of primary
      retroperitoneal endodermal sinus tumor. A case report.
AB  - BACKGROUND: Primary retroperitoneal endodermal sinus tumors (EST) are extremely
      rare and highly malignant. Hepatic metastases from EST are often very difficult
      to manage and carry a dismal prognosis. Transhepatic artery chemoembolization has
      been widely applied in primary unresectable hepatoma and had been reported to
      have antitumor activity for some metastatic tumors. We report a case in which
      transhepatic artery chemo-embolization was employed to control hepatic metastases
      from EST. CASE: A 35-year-old woman presented to our service with primary
      retroperitoneal EST associated with multiple hepatic metastases. The patient
      underwent aggressive debulking surgery followed by a combination chemotherapy
      regimen of cisplatin, vinblastine and bleomycin. Transhepatic artery
      chemoembolization with adriamycin, lipoidol and gelfoam was subsequently employed
      to treat hepatic metastases. CONCLUSION: The combination of transhepatic artery
      chemoembolization and systemic chemotherapy after surgical resection of primary
      retroperitoneal EST was effective in controlling the hepatic disease in this
      case.

PMID- 10394554
TI  - Bilateral ovarian stromal hyperplasia concealing a nonhilar, pure stromal-Leydig
      cell tumor. A case report.
AB  - BACKGROUND: Of ovarian stromal tumors containing Leydig cells, nonhilar, pure
      stromal-Leydig cell tumor is rare. CASE: An obese, diabetic, borderline
      hypertensive 41-year-old woman with a five-year history of oligomenorrhea and
      amenorrhea presented with complaints of masculinization. Physical examination
      revealed hirsutism and an enlarged clitoris. The only abnormal serum marker was
      elevated testosterone. At laparotomy both ovaries were enlarged and suspected to
      have bilateral stromal hyperthecosis. Histology revealed stromal hyperplasia
      along with a 1.5-cm, testosterone-producing pure stromal-Leydig cell tumor of the
      right ovary. CONCLUSION: Bilateral ovarian enlargement secondary to stromal
      hyperplasia in patients with masculinizing signs can conceal a small, unilateral
      pure stromal-Leydig cell tumor.

PMID- 10394555
TI  - Symptomatic cervical macrocyst as a late complication of subtotal hysterectomy. A
      case report.
AB  - BACKGROUND: Ablation of the endocervical canal is sometimes performed as an
      adjunct to subtotal hysterectomy in an attempt to reduce mucous discharge and the
      risk of future neoplasia. Cystic accumulations within the canal of a partially
      obliterated cervical stump have not previously been reported to follow this
      practice. CASE REPORT: A 41-year-old woman presented with subacute cramping and
      cystic enlargement of the cervical stump on clinical, sonographic and magnetic
      resonance evaluation four years subsequent to a subtotal hysterectomy performed
      for menorrhagia. Cervical biopsies and cytology were benign, and vaginal
      trachelectomy was performed. Pathology demonstrated the fluid pocket to be a very
      large retention cyst (nabothian) that had occupied and distended the partially
      obliterated endocervical canal. CONCLUSION: Ablation of the cervical canal at
      subtotal hysterectomy may result in symptomatic entrapment of nabothian cysts.
      Internalization of the transformation zone and partial obliteration of the canal
      are postulated as predisposing factors.

PMID- 10394556
TI  - Uterine rupture after use of a prostaglandin E2 vaginal insert during vaginal
      birth after cesarean. A report of two cases.
AB  - BACKGROUND: Prostaglandin E2, when used for cervical ripening, often initiates
      labor. Single dosing and ease of removal contribute to the common use of a
      commercially available prostaglandin E2 vaginal insert. We describe two cases of
      uterine rupture among 57 pregnancies undergoing attempted vaginal birth after
      cesarean section. CASES: Two cases of women attempting vaginal birth after a
      single low transverse cesarean section were treated with the insert either at 41
      weeks, 4 days, or 39 weeks, 3 days, for postdatism or preeclampsia. Signs of
      uterine rupture included persistent suprapubic pain and repetitive fetal heart
      rate variable decelerations followed by bradycardia. Infant outcomes were
      favorable, and tears along the prior low transverse uterine scar were repaired
      without additional morbidity. CONCLUSION: This prostaglandin compound is not
      exempt from being associated directly or indirectly with uterine rupture and
      requires informed consent and continuous monitoring.

PMID- 10394557
TI  - Stories of violence and shame.

PMID- 10394558
TI  - Two cultures, one epidemic.
AB  - HIV infection is a global epidemic, and health care providers involved in
      HIV/AIDS care must be aware of how communities with different cultures, values,
      beliefs, and resources are coping. This article describes a 3-month volunteer
      experience with the Shona people of Zimbabwe, Africa. Similarities and uniqueness
      between an urban setting in an industrial country and a rural environment in a
      developing country are explored.

PMID- 10394559
TI  - HIV, pregnancy, and zidovudine: what do women know?
AB  - AIDS is a major cause of death among women and children, representing the fourth
      leading cause of death among women ages 25 to 44 and the seventh leading cause of
      death among children ages 1 to 4 in the United States. In 1994, National
      Institutes of Health announced the findings of the AIDS Clinical Trials Group
      study (076) that found that the use of the antiretroviral drug zidovudine (AZT)
      reduced perinatal transmission of HIV by two thirds. These findings have direct
      implications for the growing number of women with HIV disease, their children and
      families, and the multiple systems that deliver ongoing services and care. In
      response to these findings, complex clinical, legal, and ethical issues have
      emerged that must be addressed to decrease the incidence of perinatal HIV
      transmission and to provide quality health care services. The purpose of this
      research was to assess what HIV-infected women presently know regarding AZT use
      in pregnancy to reduce prenatal transmission and to identify their views of the
      impact of this information on reproductive decision making. A one-page survey
      developed for this study was used to address these questions. A convenience
      sample of 204 HIV-infected women completed the survey. Data from 192 were usable.
      Of the sample, 121 (63.7%) women reported knowledge regarding the use of AZT in
      pregnancy. Only 73.5% of those who reported knowledge regarding AZT prophylaxis
      demonstrated accurate knowledge about the effects of its use. A relationship was
      found between knowledge about AZT use during pregnancy and women's decision to
      consider pregnancy, chi 2(2, N = 146) = 32.7, p = .0001, with women who reported
      that they were knowledgeable about AZT prophylaxis as more likely to consider
      pregnancy than those who reported that they were not knowledgeable.

PMID- 10394560
TI  - Intervention for hyperlipidemia associated with protease inhibitors.
AB  - In the past 3 years, treatment for HIV infection has significantly improved the
      prognosis for HIV-infected persons. The administration of protease inhibitors for
      the treatment of HIV infection has had a significant role in the reduction of
      AIDS-related complications. Recent findings have indicated that protease
      inhibitors may significantly increase lipids to levels that pose a health risk
      that may be greater than the illness itself. This article reviews the initial
      findings of a study that investigated the impact of interventions for the
      treatment of protease inhibitor-related hyperlipidemia. The purpose of the study
      was to determine if initiation of interventions based on the National Cholesterol
      Education Program Guidelines would be effective in lowering protease inhibitor
      related hyperlipidemia without disrupting the effectiveness of the HIV therapy. A
      total of 45 HIV-infected individuals who were taking a protease inhibitor and had
      abnormally elevated lipids were enrolled into this study. Mean serum cholesterol
      level prior to initiation of a protease inhibitor regimen was 170 mg/dl as
      compared to a mean cholesterol at time of enrollment of 289 mg/dl and
      triglycerides of 879 mg/dl. Interventions included diet and exercise and the
      prescription of gemfibrozil alone or in combination with atorvatstatin. During
      the course of the study, overall intervention significantly reduced serum
      cholesterol level to 201 mg/dl (p. 01) over a study period of ten months. Case
      studies of five medical events related to hyperlipidemia are included. Currently,
      26 participants continue in the study. Sixteen participants discontinued protease
      inhibitor therapy during the course of the study and thus ended their
      participation.

PMID- 10394561
TI  - A case study: the use of cidofovir for the management of progressive multifocal
      leukoencephalopathy.
AB  - Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection of
      the brain in advanced stages of AIDS. PML is caused by the JC virus, which leads
      to a decline in mental acuity and motor functions over a period of weeks or
      months. Currently, there is no treatment or cure for PML. Cidofovir, an antiviral
      agent, at the standard dosages for the treatment of cytomegalovirus (CMV) was
      implemented in the treatment and management of a 35-year-old, newly diagnosed
      AIDS, White male with PML. The patient presented with impaired motor functions of
      the left upper and lower extremities, which resulted in hemiparalysis and
      hemiparesis. The use of cidofovir infusions at standard recommendations for
      treatment and management of CMV has resulted in improvement and some resolution
      of the patient's paralysis and paresthesia. The patient has remained on the
      cidofovir for more than a year, with no signs of advancement of his PML or AIDS.
      Further investigation and extensive clinical trials are needed in the treatment
      and management of PML with the use of cidofovir.

PMID- 10394562
TI  - Adherence to combination therapy in persons living with HIV: balancing the
      hardships and the blessings.
AB  - Evidence from clinical trials demonstrates the benefits of combination therapy in
      persons living with HIV (PLWHIV); however, there is little information about the
      patient's experience when taking a complex regimen. Thus, the primary purpose of
      this preliminary study was to describe the everyday experience of PLWHIV who were
      prescribed combination therapy in order to identify a potential intervention to
      enhance adherence to this regimen. The secondary purpose was to examine the
      association between adherence to combination therapy and quality of life. The
      researchers purposively sampled six PLWHIV (two women and four men) to reflect
      the diverse demographic characteristics of the population of PLWHIV. The themes
      that evolved were decision making, difficulties, problem solving, and quality of
      life. Clinical indicators provide only one measure of the effectiveness of
      combination therapy. When the informants described the outcome of this therapy as
      "having their life back," they spoke of having quality in their lives that they
      viewed as more than their physical health.

PMID- 10394563
TI  - Chicago ANAC nurses find mock drug trial informative--and fun!

PMID- 10394564
TI  - Hemophilia: a story of success--disaster and the perseverance of the human
      spirit, Part 2.

PMID- 10394565
TI  - Depressive symptoms and HIV disease.

PMID- 10394566
TI  - HCFA mandates Medicaid reimbursement for AIDS wasting drug.

PMID- 10394567
TI  - Patient's adherence to antiretroviral medications to control HIV disease.

PMID- 10394568
TI  - [Mortality in a cohort of intravenous drug users before the introduction of
      potent HIV therapy].
AB  - BACKGROUND: The HIV/AIDS epidemics has contributed to an excess of morbidity and
      mortality in injecting drug users. The main goal of this study is to estimate
      incidence and factors associated with mortality from different causes among
      intravenous drug users. SUBJECTS AND METHODS: Prospective study of patients
      admitted to a detoxification unit between 1987 and 1990. At baseline they
      underwent interviews (drug injecting patterns) and venipuncture for HIV and other
      parameters including T-cell subsets. Viral status was determined for those who
      returned at least once. Cumulative incidence, overall and cause-specific
      mortality rates were calculated according to gender, HIV at admission and length
      of injecting drugs. RESULTS: 420 patients (334 men, 86 women), 69.6% HIV+, were
      admitted to treatment; the mean age of participants was 26 years and the mean
      duration of injecting drugs was 73 months. Three hundred and eighty seven
      patients were followed-up (92% of the initial cohort) for 2,029 persons-years and
      101 deaths occurred. The overall mortality rate was 50/1000 persons-year (52/1000
      for men and 40/1000 for women). The relative risk (RR) for death among women
      compared with men was 1.3 (95% CI = 0.8-2.2). The mortality rates for HIV+ was
      60/1000 persons-year and 29/1000 persons-year for the seronegatives (RR: 2.1; 95%
      CI = 1.2-3.4). The HIV+ patients with CD4/microliter < or = 500 showed a
      threefold increase in mortality rates compared to HIV+ patients without
      immunosuppression (CI = 1.7-5.3). The cause-specific mortality rates were 27/1000
      persons-year for HIV/AIDS, 15/1000 persons-year for drug overdose, 3/1000 persons
      year for violence/trauma and 1/1000 persons-year for non-AIDS conditions.
      CONCLUSIONS: In this hospital cohort, HIV/AIDS and overdose have had a marked
      effect on mortality among intravenous drug users. Detoxification units may
      provide clinical services and extensive use of antiretroviral treatment for HIV
      infected drug users as a strategy to reduce the risk of death from AIDS.

PMID- 10394569
TI  - [Insertion/deletion polymorphism of the gene encoding for angiotensin-converting
      enzyme and microalbuminuria in essential arterial hypertension].
AB  - BACKGROUND: To assess the influence of insertion/deletion polymorphism in the ACE
      gene on the microalbuminuria in essential hypertension. PATIENTS AND METHODS:
      Seventy-nine patients with essential hypertension (37 males and 42 females) (mean
      age 39 [7] years, body mass index 28 [4] kg/m2), never treated with
      antihypertensive drugs were included in the study. Urinary albumin excretion
      (UAE) was assessed in two different days. Ambulatory blood pressure (BP) was
      assessed during 24 h period. Genotype ACE gene and gene frequencies were
      determined by an assay based on the polymerase chain reaction (PCR). RESULTS: The
      distribution of phenotypes was: II = 14 (17%), ID = 32 (40%) and DD = 33 (43%).
      The mean for UAE tended to be higher in the DD group (53.82 [88.4] mg/24 h) than
      ID (27.8 [39.6] mg/24 h) and II (23.8 [16.7] mg/24 h). Likewise, the average for
      UAE were higher in the DD group than in the II + ID group (26.6 [34.0] mg/24 h)
      (p = 0.06), although the differences did not achieved statistical significance.
      The relationship between log UAE and 24-hour mean BP was significantly higher in
      the DD group (r2 = 0.232; p = 0.005) than that observed in the other groups (r2 =
      0.060; p = 0.101). CONCLUSIONS: In the present study with young patients with
      essential hypertension, in DD genotype, UAE seems to be higher and more dependent
      of BP levels than in the other hypertensives.

PMID- 10394570
TI  - [Non-compliance of the treatment with antibiotics in non-severe acute
      infections].
AB  - BACKGROUND: To determine the nonfulfillment of antiinfectious therapy in clinical
      practice. MATERIAL AND METHODS: Fulfillment was quantified by tablet counting
      (TC) in the homes of 366 patients undergoing antibiotic treatment and the motives
      and predictive factors were identified. RESULTS: Nonfulfillment was of 61% (95%
      confidence interval [CI] 55.4-66.6%). Patient improvement was the main reason for
      discontinuation (54.5%). The predictive factors were greater length of treatment
      (p = 0.000004), dose (p = 0.0019) and number of tablets (p = 0.0000).
      CONCLUSIONS: Nonfulfillment of antiinfectious treatment in clinical practice is
      high, mainly due to clinical improvement and to the greater complexity and length
      of treatment.

PMID- 10394571
TI  - [Predictive factors of the presence of bacteremia in males with urinary
      infection].
AB  - BACKGROUND AND PATIENTS AND METHODS: Possible predictive factors of the presence
      of bacteremia in 135 males with parenchymatous urinary tract infection (PUI) are
      studied by means of univariate and multivariate analysis. RESULTS: Thirty percent
      of the patients had bacteremia. In the multivariate analysis the following
      factors were significative: duration of symptoms > 5 days, a serum creatinine
      level > 1.2 mg/dl and duration of symptoms > 5 days. CONCLUSIONS: One third of
      the males with community acquired PUI have bacteremia. The best predictors of the
      presence of bacteremia are a serum creatinine level > 1.2 mg/dl and duration of
      symptoms > 5 days.

PMID- 10394572
TI  - [On the heroin epidemic, its impact, its context, and health policy].

PMID- 10394573
TI  - [Psychiatric investigation in Spain: shine and shade].

PMID- 10394574
TI  - [Evaluation of the quality of life in patients with HIV and AIDS infection].

PMID- 10394575
TI  - [Steroid hormones, signal transduction, genetic expression, and gynecologic
      cancer].

PMID- 10394577
TI  - [Dyslipemia in the elderly].

PMID- 10394576
TI  - [Prevention of gastroduodenal ulcer induced by non-steroidal anti-inflammatory
      agents].

PMID- 10394578
TI  - [Apropos of family terrorism].

PMID- 10394579
TI  - [Gynecomastia in a male and ginseng].

PMID- 10394580
TI  - [Narcolepsy associated with autoimmune polyglandular syndrome].

PMID- 10394581
TI  - [Febrile syndrome without focus. Prevalence, etiology, and predictive factors of
      bacteremia].

PMID- 10394582
TI  - Stump the professor.

PMID- 10394583
TI  - Practical considerations in the performance of physical examinations on women
      with disabilities.
AB  - There are over 28 million women with disabilities in the United States (1). This
      includes women with mobility and self-care limitations of varying degrees. Many
      of these women have difficulty obtaining comprehensive, accessible, and dignified
      physical examinations. Additionally, patients and clinicians are often
      misinformed about issues pertaining to healthcare needs of women with
      disabilities (2). This article outlines strategies to overcome physical barriers
      and gaps in knowledge, and proposes creative solutions for common problems
      encountered during the performance of the basic physical examination of a woman
      who has disabilities. It discusses the reality of sexually transmitted disease,
      promotes awareness of abuse in the population of women with disabilities, and
      offers guidelines physicians can follow in assisting their patients in resolving
      this abuse.

PMID- 10394584
TI  - Herpes simplex hepatitis in pregnancy: a case report and review of the
      literature.
AB  - Fulminant hepatic dysfunction in the third trimester of pregnancy accompanied by
      fever may result from disseminated herpes simplex virus. Since 1969, 24 cases of
      herpes simplex hepatitis, including the current case, have been reported.
      Mucocutaneous lesions are present in only half of cases; therefore, suspicion for
      diagnosis of this disease is low. Twenty-five percent of cases were not diagnosed
      until autopsy. Maternal and perinatal mortality are high, approaching 39 percent
      for both mother and fetus. Early recognition with initiation of antiviral therapy
      appears to be most important in maximizing survival.

PMID- 10394585
TI  - Automated cervical cytology: meta-analyses of the performance of the AutoPap 300
      QC System.
AB  - The objective of this study was to review current knowledge regarding the
      performance of the AutoPap 300 QC System (NeoPath Inc., Redmond, WA) for
      automated cervical cytology screening. To this goal, we identified all studies
      published in the English language that included the AutoPap 300 QC automated
      cervical cytology system. The studies were obtained from a MEDLINE search through
      October 1998; additional sources were identified through cross-referencing.
      Studies concerning the AutoPap 300 QC System containing complete data are
      presented descriptively. Meta-analyses about the performance of the AutoPap 300
      QC System were performed. The central goal of the meta-analyses was to estimate
      the overall false-negative rate of the AutoPap 300 QC System when applied in
      either of the two following modalities: primary screening and quality control. Of
      the 14 studies concerning the performance of the AutoPap 300 QC System as a
      primary screening modality, four studies provided complete data about the number
      of abnormal slides, review rate, and number of slides selected. Meta-analysis of
      these four studies indicate sensitivities ranging between 85 and 100 percent.
      Regarding the performance of the AutoPap 300 QC System in the quality control
      modality, of the 14 studies reviewed, 5 studies provided complete data including
      the number of false-negatives, review rate, and number of slides selected. Meta
      analysis of these five studies indicate an average sensitivity of the AutoPap 300
      QC System applied as a rescreening modality of 37 percent (95% CI; 34-40
      percent), with observed salvage ratios of between 3.5 and 5.6 when review rate of
      the AutoPap 300 QC System was set at 10 percent.

PMID- 10394586
TI  - Silk purse in Atlanta: a commentary on SWOG 9509, an advanced non-small cell lung
      cancer trial.

PMID- 10394587
TI  - Defining the emetogenicity of cancer chemotherapy regimens: relevance to clinical
      practice.
AB  - Significant progress has been made in recent years in developing more effective
      and better tolerated means to prevent nausea and vomiting induced by cancer
      chemotherapy. The most significant development has been the introduction of a new
      class of antiemetic agents, the selective antagonists of the type 3 serotonin
      receptor. With the new antiemetic therapeutic options and their attendant higher
      costs has come a need to define evidence-based guidelines to assist in their
      judicious and cost-effective use. A number of predictive factors for antiemetic
      risk have been defined. Some of these factors relate to the patient population
      (age, gender, history of ethanol consumption, and prior experience with
      chemotherapy), and some relate to the treatments administered. Clearly, the most
      important of all these factors in predicting risk of emesis is the intrinsic
      emetogenicity of the chemotherapy. Although an "ideal" emetogenic classification
      schema for chemotherapy has yet to be realized, recent developments in this area
      have allowed a more precise estimation of emetogenic risks and have provided
      antiemetic guideline groups with a useful foundation on which to base their
      treatment recommendations.

PMID- 10394588
TI  - Surgical treatment and other regional treatments for colorectal cancer liver
      metastases.
AB  - The liver is the most common site of distant metastasis from colorectal cancer.
      About one-fourth of patients with liver metastases from colorectal cancer have no
      other sites of metastasis and can be treated with regional therapies directed
      toward their liver tumors. Surgical resection of colorectal cancer liver
      metastases can result in a 24%-38% five-year survival, but only a minority of
      patients are candidates for resection. Other regional therapies such as
      cryosurgery, radiofrequency ablation, and hepatic intra-arterial chemotherapy may
      be offered to patients with unresectable but isolated liver metastases. The
      efficacy of these treatments is still being determined. For most patients with
      spread of metastatic colorectal cancer beyond the liver, systemic chemotherapy
      rather than regional therapy is a more appropriate option.

PMID- 10394589
TI  - New treatment strategies for malignant gliomas.
AB  - Although survival in patients with malignant gliomas remains limited, there is
      renewed optimism with the emergence of novel treatment strategies. Cytotoxic
      agents such as temozolomide and CPT-11 have shown promising clinical activity.
      Biological treatments for brain tumors, including antisense oligonucleotides,
      gene therapy, and angiogenesis inhibitors, are also being evaluated in clinical
      trials. Delivery strategies have been developed to overcome challenges presented
      by the blood-brain barrier. These noteworthy treatments, alone or in combination,
      may ultimately prolong survival and enhance quality of life in this group of
      patients.

PMID- 10394590
TI  - Leukemia in infants.
AB  - Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in infants
      have in common a high incidence of translocations of the MLL gene at chromosome
      band 11q23. Similar translocations occur in leukemias associated with
      chemotherapies that target DNA topoisomerase II. MLL has numerous different
      partner genes. The role of the many MLL fusion proteins in leukemogenesis is not
      yet understood. The t(4;11) translocation, the most common translocation in
      infant ALL, adversely affects the outcome. Additional genetic changes, especially
      Ikaros alterations, are found in infant ALL. Other forms of myeloid leukemia in
      infants present as myelodysplastic and myeloproliferative syndromes, which may be
      associated with constitutional disorders. This review will consider all leukemia
      in infants, but will focus on leukemias with MLL gene translocations.

PMID- 10394591
TI  - Gemcitabine: single-agent and combination therapy in non-small cell lung cancer.
AB  - With the advent of several newer agents with single-agent response rates greater
      than 20% and approximately 30%-40% in combination therapy, non-small cell lung
      cancer (NSCLC) may now be considered a malignancy that is moderately sensitive to
      chemotherapy. Examples of these agents include the taxanes, paclitaxel and
      docetaxel; vinorelbine, a new vinca alkaloid, and the camptothecins, of which CPT
      11 is the most actively studied agent. Another new and exciting agent is
      gemcitabine, a nucleoside analogue structurally related to cytosine arabinoside.
      Gemcitabine's mechanism of action is activated by deoxycytidine kinase to dFdCMP,
      dFdCDP and dFdCTP. The latter two compounds, when incorporated into DNA, result
      in chain termination. Phase I studies using a short infusion schedule given
      weekly for three weeks followed by one week off established 1,000-1,250
      mg/m2/week as the maximum tolerated dose. Single-agent gemcitabine has been
      extensively studied in patients with chemotherapy-naive advanced NSCLC with
      response rates of approximately 20%. Response rates for the combination of
      gemcitabine plus cisplatin are approximately 28%-54% in phase II trials.
      Recently, this combination has been studied in randomized phase II and III trials
      revealing improvements in response rates, time to progression and, in the phase
      III trial, survival. Current and future studies are evaluating gemcitabine in non
      cisplatin combinations (i.e., taxanes).

PMID- 10394592
TI  - Commentary on "Gemcitabine: single-agent and combination therapy in non-small
      cell lung cancer". The Oncologist 1999;4:241-251.

PMID- 10394593
TI  - A staff dialogue on do not resuscitate orders: psychosocial issues faced by
      patients, their families, and caregivers.
AB  - Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at
      Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at
      MGH. The Schwartz Center is a non-profit organization dedicated to supporting and
      advancing compassionate health care delivery which provides hope to the patient,
      support to caregivers, and encourages the healing process. The Center sponsors
      the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers
      reflect on important psychosocial issues faced by patients, their families, and
      their caregivers, and gain insight and support from fellow staff members. The
      following case of a woman who developed lymphoma was discussed at the July and
      August, 1997 Schwartz Center Rounds. There were considerable delays and
      uncertainties in the diagnosis, which was followed by an unpredictably chaotic
      clinical course. Although she had made it clear to her doctor that she did not
      want "heroic measures," she had unexpectedly rallied so many times that her son
      and her husband wanted her doctors to do everything possible to keep her alive,
      including the performance of cardiopulmonary resuscitation (CPR). The clinical
      benefit of CPR in the event of cardiac arrest in those with cancer is discussed,
      as are do not resuscitate (DNR) orders, living wills, and healthcare proxies. In
      addition, the issues that surround DNR status, including who should discuss DNR
      status with a patient, and how and when it should be discussed, are reviewed.
      Staff raised concerns about the effect of discussing DNR status on the doctor
      patient relationship, and wondered whether writing DNR orders adversely affect
      the care of patients.

PMID- 10394594
TI  - The molecular perspective: the ras oncogene.

PMID- 10394595
TI  - Clinical utility in maximizing CD34+ cell count in stem cell grafts.

PMID- 10394596
TI  - [Spinal injuries--many questions still open!].

PMID- 10394597
TI  - [Atlas fractures].
AB  - Fractures of the atlas account for 1-2% of all vertebral fractures. We divide
      atlas fractures into 5 groups: isolated fractures of the anterior arch of the
      atlas, isolated fractures of the posterior arch, combined fractures of the
      anterior and posterior arch (so-called Jefferson fractures), isolated fractures
      of the lateral mass and fractures of the transverse process. Isolated fractures
      of the anterior or posterior arch are benign and are treated conservatively with
      a soft collar until the neck pain has disappeared. Jefferson fractures are
      divided into stable and unstable fracture depending on the integrity of the
      transverse ligament. Stable Jefferson fractures are treated conservatively with
      good outcome while unstable Jefferson fractures are probably best treated
      operatively with a posterior atlanto-axial or occipito-axial stabilization and
      fusion. The authors preferred treatment modality is the immediate open reduction
      of the dislocated lateral masses combined with a stabilization in the reduced
      position using a transarticular screw fixation C1/C2 according to Magerl. This
      has the advantage of saving the atlanto-occipital joints and offering an
      immediate stability which makes immobilization in an halo or Minerva cast
      superfluous. In late instabilities C1/2 with incongruency of the lateral masses
      occurring after primary conservative treatment, an occipito-cervical fusion is
      indicated. Isolated fractures of the lateral masses are very rare and may, if the
      lateral mass is totally destroyed, be a reason for an occipito-cervical fusion.
      Fractures of the transverse processes may be the cause for a thrombosis of the
      vertebral artery. No treatment is necessary for the fracture itself.

PMID- 10394598
TI  - [Traumatic spondylolisthesis of the axis].
AB  - In common the traumatic spondylolisthesis is not a life threatening injury. An
      exact diagnosis is mandatory as well as a differentiated therapy. Especially the
      correct decision about the therapy (operative vs conservative) including the
      technical demanding operative procedures is based on an experienced surgeon.
      These patients should be transferred to a specialised centre.

PMID- 10394599
TI  - [Therapeutic concept for injuries of the lower cervical spine].
AB  - Over a period of two and half years, the Spinal Surgery Working Group of the
      Deutsche Gesellschaft fur Unfallchirurgie (German Association for Trauma Surgery)
      DGU has carried out a prospective study of relevant injuries of the cervical
      vertebral column in 544 patients. The lower section C3 to Th1 of the cervical
      vertebral column was affected in 308 cases (56 per cent). The injuries of the
      cervical vertebral column were caused primarily by accidents in road traffic and
      in the pursuit of recreational activities. More than half of the patients had
      multiple injuries. The share of degenerative concomitant changes as a cause for
      relevant injuries increased with age considerably. In case of a qualified trauma
      with the suspicion of an injury, the immobilisation of the cervical vertebral
      column has to be retained until the X-ray diagnosis inclusive of a computer
      tomography has been completed as this is obligatory for the clarification of
      suspected findings or for pre-operative planning, respectively. The diagnostic
      range is complemented by guided function imaging to reveal instabilities, and
      magnetic resonance imaging, which has to be carried out in case any X-ray
      pathology is absent and neurological functional deficit exists. Patients with
      neurological deficits, which were found in 43 per cent of the cases suffering
      from injuries of the lower cervical vertebral column, should be treated as
      quickly as possible with a high dose of methyl prednisolone. A recovery of the
      neurological abolition by at least one ASIA level was observed in 10 per cent of
      the patients concerned. A conservative therapy with a cervical collar was pursued
      in 24 per cent of the cases with stable injuries. An operative treatment
      indication, which was diagnosed in 76 per cent of the cases, aims at the early
      recovery of the anatomy with decompression of the spinal cord, reposition, and
      stabilisation of segments concerned. The point of the operation was determined by
      the neurological status, the existing dislocation, and the increasing instability
      as well as the concomitant injuries. Positioning necessary for intensive medical
      interventions required an early stabilisation of the spinal column. The front
      access with plate spondylodesis as a standard procedure with various special
      implants has proved to be safe and reliable in the healing result. Dorsal
      accesses shall remain reserved for definable individual indications and should be
      prevented in case of injuries of the cervical medulla, if possible, to spare the
      cervical muscles.

PMID- 10394600
TI  - [Acceleration injuries of the cervical spine in seat-belted automobile drivers.
      Determination of the trauma mechanism and severity of injury].
AB  - The analysis of 1,176 whiplash-type neck distortions was sought from a total of
      3,838 restrained car driver incident reports. The percentage of these injuries
      increased from less than 10% in 1985 to over 30% in 1997. These occurred mostly
      with head-on or with multiple collisions, and only in 15% with pure rear-end
      collisions. In 23.2%, delta v amounted 10 km/h or less, which corresponds to a
      very minor crash. The average delta v was the highest in the cases of head-on
      collisions. Letters were sent to the injured to find out about the duration and
      type of complaints caused by a cervical spine injury. Of the 138 patients who
      returned the questionnaires, 121 (88%) indicated that they had or were still
      suffering from their symptoms. Percentage of various complaints were as follows:
      pain (74%), tension (6%) and stiffness (5%) in the head (27%), neck (55%) and
      shoulder (8%). The duration of the complaints was longest after multiple
      collisions and when the onset of complaints was later than 24 hours after trauma.
      Women and elderly persons predominated slightly in the group with longer duration
      of complaints. A correlation between the severity of the accompanying injuries
      and duration of complaints occurred. Also, with this retrospective study there
      was considerable difficulties in the lack of adequate follow-up for these
      patients with less severe injuries. In order to better evaluate this problem,
      prospective studies are necessary which include documentation of diagnosis,
      treatment protocols, duration and type of complaints.

PMID- 10394601
TI  - [Anatomical and functional aspects of the thoracic and lumbar spine].
AB  - The vertebral bodies and vertebral arches show a characteristic distribution of
      cortical and cancellous bone. The pedicles are loaded by uniplanar bending that
      is reflected by the arrangement of the Corticalis. The ligaments of the vertebral
      column consist of longitudinal and (with exception of the lig. longitudinal
      anterius) horizontal/oblique segmental ligament bundles. In combination with the
      anulus fibrosus, the ligaments work as a kind of gear system. They regulate the
      process of movements of adjacent vertebral bodies in a very precise manner and
      control the final phase of motion. Besides maintaining the necessary amount of
      pretension the intervertebral disc distributes the loads uniformly onto the
      adjacent vertebral bodies. The intervertebral joints are important for guided
      motion, by restricting the extent in specific planes and directions. Because of
      their position, they are able to take up the shear forces and to simultaneously
      restrict them in different planes. The integrity of the fascia thoracolumbalis
      warrants the protective function of the autochthonuos muscles.

PMID- 10394602
TI  - [Combined surgery for fractures of the thoraco-lumbar junction using the inlay
      span method].
AB  - The combined intervention of thoracolumbar fractures using the graft inlay
      technique. Instable fractures of the thoracolumbar junction must be reduced in an
      open or closed fashion and fixed internally. Clearance of the spinal channel in
      case of obstruction is mandatory followed by reconstruction of the anterior part
      of the spine. Using the combined interventions of transpedicular screw techniques
      and antero-lateral approaches (transthoracal or retroperitoneal) instable
      fractures of the thoracolumbar junction can be fixed in comparison to the dorsal
      intervention the anterior approach is very demanding. The proximity of the big
      vessels as well as thoracal and abdominal organs and the available space to place
      the implants need exact preoperative planning. The indications for reconstruction
      of the anterior part of the spine are influenced by the fracture types and
      localisations as well as biomechanical considerations. One of the many
      possibilities to reconstruct the anterior part of the spine is the graft inlay
      technique, which can be used for mono- or bisegmental spondylodesis. Despite the
      biological advantages in terms of fusion rates substantial complications can
      occur using this method for anterior reconstruction of the spine.

PMID- 10394603
TI  - [Management of injuries of the thoracic and lumbar vertebrae in children].
AB  - Traumatic injuries of the thoracic and lumbar spine are rare in children and
      differ in pathomorphology, healing process and prognosis from those in adults.
      Before growth arrest the vertebral epiphysis has an important role in
      pathomorphology and prognosis; therefore, treatment should recognize the age
      dependent potential for growth and remodelling. This study demonstrates the
      different anatomic and pathomorphologic characteristics of traumatic spinal
      injuries in 40 children. Additionally, prognosis and the various forms of
      treatment are discussed in the context of the recent literature. In total we
      observed 85% compression-type injuries and 15% distraction- and rotation-type
      injuries. Vertebral body fractures were treated conservatively and segmental
      disruptions by fusion. Long-term follow-up was performed on average 8 years after
      the accident in 26 patients clinically and in 21 patients radiologically. Most
      patients had no physical complaints or clinical symptoms. Additionally, the
      radiographs did not demonstrate any post-traumatic defects. In summary, spinal
      injuries up to the age of 12 without initial neurologic symptoms have a favorable
      prognosis.

PMID- 10394604
TI  - [Loading on internal spinal fixation devices].
AB  - The loads acting on internal spinal fixation devices were measured for different
      activities in ten patients using telemeterized bisegmental implants. The highest
      loads were found for walking and lateral bending of the upper body while
      standing. When bending forwards the upper body, the fixator loads were only
      slightly altered. The forces and moments were not higher during sitting than
      during standing. Therefore, sitting should be allowed for patients with
      instrumented spines as soon as getting up is allowed. The forces and moments in
      the fixators were often altered due to anterior interbody fusion. Especially in
      patients with degenerative instability, the implant loads were higher after
      anterior interbody fusion than before. Braces were not able to markedly reduce
      the fixator loads. Therefore, it does not seem helpful to brace patients after
      mono- or bisegmental stabilization of the thoracic or lumbar spine.

PMID- 10394605
TI  - Insomnia research and future opportunities.

PMID- 10394606
TI  - Characteristics of insomnia in the United States: results of the 1991 National
      Sleep Foundation Survey. I.
AB  - The National Sleep Foundation in conjunction with the Gallup Organization
      conducted telephone interviews with a sample of Americans (N = 1000) to examine
      the prevalence and nature of difficulty with sleep. Consistent with other
      national studies, about one-third of Americans reported some type of sleep
      problem. Approximately one in four reported occasional insomnia while 9% reported
      that their sleep difficulty occurred on a regular nightly basis. The problem most
      frequently reported by insomniacs was waking up in the morning feeling drowsy or
      tired, followed by waking up in the middle of the night, difficulty going back to
      sleep after waking up and difficulty falling asleep initially. Importantly,
      insomniacs rarely visited a physician to discuss their sleep problem and four out
      of ten insomniacs self-medicated with either over-the-counter medications or with
      alcohol. Two-thirds of the insomniacs reported that they did not have an
      understanding of available treatments for insomnia.

PMID- 10394607
TI  - Daytime consequences and correlates of insomnia in the United States: results of
      the 1991 National Sleep Foundation Survey. II.
AB  - The daytime consequences and correlates of insomnia were examined in the National
      Sleep Foundation and the Gallup Organization survey of 1,000 randomly selected
      Americans. Respondents were grouped as having occasional insomnia, chronic
      insomnia or no insomnia. There were dramatic differences in reported waking
      behaviors and psychosocial measures by insomniacs compared to those who do not
      report sleep difficulty. These problems include impaired concentration, impaired
      memory, decreased ability to accomplish daily tasks and decreased enjoyment of
      interpersonal relationships. Importantly, most of these variables showed an
      increasing degree of impairment with greater frequency of sleep disturbance.
      These findings suggest that insomnia negatively impacts aspects of waking
      function related to quality of life.

PMID- 10394608
TI  - Insomnia in primary care patients.
AB  - STUDY OBJECTIVES: To determine the prevalence and characteristics of insomnia in
      primary care patients, to examine patients' help-seeking behavior, and to compare
      the frequency of insomnia in primary care patients to the general population.
      METHODS: 286 patients from primary care clinics in San Diego, California (n =
      96), and in Haleiwa and Honolulu, Hawaii (n = 190) participated. Sleep study
      questionnaires were distributed by front desk receptionists to all patients over
      18 years of age upon arrival at the clinic for an appointment with the physician.
      Completed questionnaires were collected at the clinic or returned by mail.
      Comparisons were made by using nonparametric statistics. A logistic regression
      analysis using backward elimination was done to develop a model showing
      predictors of who would consult with the physician about a sleep problem.
      RESULTS: The prevalence of insomnia in primary care patients was 69%, with 50%
      reporting occasional insomnia and 19% reporting chronic insomnia. As expected,
      patients with chronic insomnia had the most severe sleep complaints as well as
      the poorest daytime functioning, and exhibited the most help-seeking behaviors.
      The four predictors of discussing insomnia with a physician were how patients
      felt physically, number of years of insomnia, age, and income. CONCLUSIONS: The
      primary care population has a higher prevalence of insomnia than the general
      population, probably because of concomitant psychiatric and medical illnesses.
      Although many of the characteristics of the sleep complaints are easily detected,
      most patients with insomnia are not treated effectively.

PMID- 10394609
TI  - Incidence and remission of insomnia among elderly adults: an epidemiologic study
      of 6,800 persons over three years.
AB  - To determine incidence and remission rates of insomnia in older adults and
      associated risk factors. Three-year longitudinal study, 1982-198--East Boston,
      MA; New Haven, CT; Iowa and Washington counties, IA. Participants were 6,899 men
      and women aged 65 years and older. Self-reported difficulty falling asleep or
      early morning arousal (insomnia), along with physician diagnosis of heart
      disease, stroke, cancer, diabetes, or hip-fracture, self-report of physical
      disability, depressive symptomatology, perceived health status, and use of
      medications ascertained at both baseline and three-year follow-up. Nearly 15% of
      the 4,956 participants without symptoms of insomnia at baseline reported chronic
      difficulty falling asleep or early morning arousal at follow-up, suggesting an
      annual incidence rate of approximately 5%. Incident insomnia was associated with
      depressed mood, respiratory symptoms, fair to poor perceived health, and physical
      disability. In multivariate analyses, these risk factors explained the higher
      incidence of insomnia among those with medical conditions such as heart disease,
      stroke, and diabetes. Other factors associated with an increased risk of insomnia
      included use of prescribed sedatives, and widowhood. Only 7% of the incident
      cases of insomnia occurred in the absence of associated risk factors. Of the
      nearly 2,000 survivors with chronic insomnia at baseline, almost half no longer
      reported symptoms upon follow-up and were more likely to report improved self
      perceived health compared to those who continued to report symptoms. Chronic
      disease, depressed mood, physical disability, poor perceived health, widowhood,
      and use of sedatives are associated with development and remission of insomnia
      symptoms. Because the vast majority of incident cases of insomnia were among
      persons with one or more of these risk factors, these data do not support a model
      of incident insomnia caused by the aging process per se.

PMID- 10394610
TI  - Incidence and remission of insomnia among elderly adults in a biracial cohort.
AB  - OBJECTIVES: To determine the incidence and remission rates of insomnia in older
      adults according to race and associated risk factors in a three-year longitudinal
      study. METHODS: 2,971 men and women, aged 65 years and older, completed
      questionnaires administered by trained interviewers at baseline and three years
      later. Data concerning difficulty falling asleep or early morning arousal
      (insomnia), along with self-reports of physical disability, respiratory symptoms,
      depressive symptomatology, perceived health status, and use of prescribed
      sedative medication, were collected and analyzed. RESULTS: Overall, 15% of the
      participants without symptoms of insomnia at baseline reported chronic difficulty
      falling asleep or early morning arousal three years later in follow-up
      interviews. African-American women had a significantly (p < 0.01) higher
      incidence of insomnia (19%) compared with African-American men (12%) or with
      white men and women (both 14%). Men were more likely than women to no longer
      report symptoms at follow-up (64% vs 42%; p < 0.01). For both races, the presence
      of depressed mood was a risk factor for the incidence of insomnia, and the
      absence of depressed mood was a predictor of remission. CONCLUSIONS: Insomnia
      occurs more frequently in African-American women than in African-American men or
      than in white men or women. Regardless of race, women are less likely than men to
      resolve their insomnia. The high prevalence and incidence of morbidity in elderly
      African-American women may contribute to their high rate of insomnia.

PMID- 10394611
TI  - Quality of life in people with insomnia.
AB  - OBJECTIVE: To determine whether subjects with insomnia report greater reductions
      in quality of life (QoL) than subjects without insomnia when assessed with self
      report instruments. METHODS: Questionnaires were completed by individuals
      recruited through media advertisements and screened with a structured telephone
      interview. Data obtained from 261 individuals with insomnia (INS group) were
      compared with those of 101 individuals with no sleep complaint, or controls (CTL
      group). RESULTS: Subjects in the INS group obtained lower mean sum scores on the
      Medical Outcomes Study Cognitive Scale than did subjects in the CTL group (25.34
      +/- 0.34 vs 31.91 +/- 0.58, t = 9.53, p < 0.0001). The INS group also obtained
      lower mean scores on all subscales of the SF-36 Questionnaire compared with those
      in the CTL group (each, p < 0.0001 or lower), indicating impairments across
      multiple QoL domains. Psychiatric assessment revealed that subjects in the INS
      group obtained significantly higher mean item scores than subjects in the control
      group on the Zung Depression Scale (2.22 +/- 0.03 vs. 1.52 +/- 0.03, p < 0.0001)
      and the Zung Anxiety Scale (1.96 +/- 0.02 vs. 1.40 +/- 0.04, p < 0.0001). In
      addition, subjects in the INS group reported significantly greater impairments in
      specific QoL domains on the QoL inventory, and the Work and Daily Activities
      Inventory. No differences were observed between subjects in the INS group who
      were receiving treatment for insomnia versus those who were untreated.
      CONCLUSIONS: The results of this study indicate that significant QoL impairments
      are associated with insomnia.

PMID- 10394612
TI  - The direct economic costs of insomnia in the United States for 1995.
AB  - STUDY OBJECTIVES: To assess the direct economic costs of insomnia in the United
      States in 1995. METHODS: The costs of prescription medications were based on 1995
      data compiled by IMS America, Ltd. (Plymouth Meeting, PA). Non-prescription
      medication expenditures were provided by Information Resources, Inc. (Chicago,
      IL). The costs of physician visits related to insomnia were estimated from
      unpublished data of the 1994 National Ambulatory Medical Care Survey conducted by
      the National Center for Health Statistics and from the America Medical
      Association Center for Health Policy Research. Several other sources were used
      for other cost estimates. RESULTS: Total cost for substances used to treat
      insomnia was $1.97 billion, less than half of which was for prescription
      medication. Health care services for insomnia totaled $11.96 billion, 91% of
      which is attributable to nursing home care. The total direct costs in the United
      States for insomnia in 1995 were estimated to be $13.9 billion. CONCLUSIONS:
      Increased efforts are needed in several domains to offset the cost of insomnia
      including clinical research on the consequences of untreated and treated
      insomnia, development and implementation of curricula to provide knowledge about
      sleep and sleep disorders for medical students, physicians, and other health
      professionals, education to increase public awareness of insomnia and sleep
      disorders, and more support for basic research on neural mechanisms involved in
      healthy and disordered sleep.

PMID- 10394613
TI  - The direct costs of insomnia in France.
AB  - Several reports indicate that use of hypnotics is significantly higher in France
      relative to other European countries, but few reports exist concerning the cost
      of this high consumption of psychotropic medications. The purpose of the present
      study was to estimate the direct costs that may be attributed to insomnia in
      France. Data were derived from previously published surveys in this field. It
      includes the cost of sleep medications and of substances used to promote sleep,
      outpatient visits to physicians or to other health professionals and sleep
      recordings and treatment by sleep specialists. The final estimate of the total
      direct cost of insomnia in France in 1995 was FF 10,232,992,500 ($2,067,271,100).
      Public authorities have to understand that an increase in the direct costs of
      insomnia may be balanced by the reduction of the daytime consequences of insomnia
      and then by the reduction of the indirect costs of insomnia.

PMID- 10394614
TI  - Insomnia: assessment and management in primary care.

PMID- 10394615
TI  - Prevalence, costs, and consequences of insomnia. Reference bibliography: 1993
      1998.

PMID- 10394616
TI  - Complete mineralization of methylparathion by Pseudomonas sp. A3.
AB  - Organophosphorus insecticides are widely used in agriculture. Despite their
      biodegradable nature, some are highly toxic and their residues are found in the
      environment. Reports on the mineralization of a spectrum of these insecticides by
      a single potential strain are scarce. We have isolated a soil isolate,
      Pseudomonas sp. A3, through enrichment technique, able to degrade methylparathion
      (MP), malathion, monocrotophos, and Diazinon. The potential of this strain to
      mineralize MP as a carbon and/or phosphorus source has been evaluated. On
      hydrolysis of MP, the aromatic portion (p-nitrophenol) was used as a carbon and
      energy source whereas the alkyl moiety (dithiomethylphosphorothioate) was broken
      down for the phosphorus source. The results from the experiments involving [U
      14C]p-nitrophenol provided the evidence for incorporation of carbon into the
      cellular constituents and release of CO2 from this insecticide. During the
      breakdown of MP, nitrite was released as a catabolic by-product.

PMID- 10394617
TI  - Production and characterization of an antibody specific for a novel protein
      serine/threonine kinase, MPK38, highly expressed in hematopoietic cells.
AB  - We report an antibody that selectively recognizes MPK38, a new protein
      serine/threonine kinase closely related to the SNF1 serine/threonine kinase
      family. This antibody recognized a region of the N-terminal kinase catalytic
      domain and part of the remaining C-terminal portion and was sensitive enough to
      detect a 72-kDa recombinant MPK38 in insect cells by Western blotting. Immunoblot
      analysis showed that the recombinant MPK38 was expressed in a time-dependent
      manner and reached a maximum after 48 h postinfection. In addition, the immune
      complex kinase assay revealed that the recombinant and endogenous MPK38 protein
      autophosphorylated in vitro. Phosphoamino acid analysis of autophosphorylated
      MPK38 protein showed that the phosphorylation was exclusively on serine and
      threonine residues, suggesting that MPK38 is a protein serine/threonine kinase.
      Thus, this antibody could be helpful for elucidating the biological functions of
      MPK38 in the MPK38-expressing cells.

PMID- 10394618
TI  - Heat-shock and stringent responses have overlapping protease activity in
      Escherichia coli. Implications for heterologous protein yield.
AB  - The cellular response of a heat-shocked controlled chemostat of Escherichia coli
      JM105 [pSH101] was characterized and compared to that of a similar culture
      induced by isopropyl-beta-D-thiogalactopyranoside (IPTG). The proteases elicited
      by the IPTG pulse were previously shown to be upregulated by the stringent stress
      response and were shown here to be upregulated by heat shock, although to a
      lesser extent. Owing to the apparent overlap between these responses, a relaxed
      mutant (rel-, devoid of the stringent response; JM109) was examined for its
      response to both a chemically imposed stringent response and to IPTG induction in
      controlled chemostats. There was no significant upregulation of protease activity
      under either imposed stress. More important, a nine-fold increase of
      chloramphenicol acetyl-transferase (CAT) activity was found for the IPTG-induced
      relaxed mutant culture. Additionally, the responses from heat shock and IPTG
      induction were examined in batch cultures. The culture that was simultaneously
      IPTG-induced and heat-shocked was observed to have the highest CAT activity as
      well as the most rapid loss in activity after a maximum. Control experiments
      indicated that the heat shock did not affect loss of CAT activity; instead, the
      loss of activity correlated with the amount of CAT synthesized. Furthermore, an
      increase in CAT expression was found during heat shock. Results indicated that
      heat shock and, alternatively, the use of stringent response-mutant hosts could
      both be used to facilitate increased recombinant protein yields in the E. coli
      expression system.

PMID- 10394619
TI  - A simple structured model for continuous production of a hybrid antibiotic by
      Streptomyces lividans pellets in a fluidized-bed bioreactor.
AB  - A simple structured model is developed for the description of the experiments of
      continuous production of a hybrid antibiotic by Streptomyces lividans TK21
      pellets in a fluidized-bed reactor. The model is based on the effect of internal
      and external phosphate concentrations on antibiotic production during cyclic
      feeding. These concentrations can be calculated on the basis of the equations
      postulated by the model. The model also considers the cell growth, reflected in
      changes of the pellet size along the culture. The model parameters are evaluated
      sequentially by performing experiments at different operational conditions. The
      validity of the model and its corresponding parameters is corroborated further by
      the satisfactory modeling of the bioreactor operation during an extended period
      of time at various operation conditions.

PMID- 10394620
TI  - Development and application of a system for analysis of mixed cultures of
      microorganisms.
AB  - Development and application of a system for real-time quantitative assessment of
      individual cell activities in a mixed culture system was investigated. This was
      based on a concept that the activities of individual cells in a mixed culture can
      be assessed if the cells are physically separated (in separate compartments) in a
      vessel while the culture conditions, including the broth components, are
      maintained the same in all the compartments during the cultivation. On this
      basis, three different apparatus (M-1, M-2, and M-3) were constructed using
      various types of membranes. In terms of mass transfer characteristics and
      membrane fouling, the M-3 apparatus was the most effective system for analysis of
      mixed cultures at high cell densities. With the M-3 apparatus, the
      interrelationships between two alcohol-producing strains (Saccharomyces
      cerevisiae and Zymomonas mobilis) under anaerobic and aerobic conditions were
      studied. Under anaerobic condition, except for possible competition for
      nutrients, there were no significant effects of the activities of one
      microorganism on the other. However, under aerobic condition, amensalism was
      observed because acetaldehyde that was produced by Z. mobilis inhibited the
      growth of S. cerevisiae.

PMID- 10394621
TI  - Transient electric birefringence of human erythroid spectrin dimers and tetramers
      at ionic strengths of 4 mM and 53 mM.
AB  - In conventional electrooptic studies the sample ionic strength must for technical
      reasons be kept below about 3 mM, which is only 2% of the ionic strength at
      physiological conditions. In particular for flexible polyelectrolytic
      macromolecules it can in general not be ruled out that both the conformational
      average and dynamics at ionic strength 3 mM and below may differ significantly
      from what it is at physiological conditions. Here we report on the first
      electrooptic study of human erythroid spectrin dimers and tetramers at ionic
      strengths higher than 3 mM. All measurements in this study were carried out at
      both ionic strength 4 mM (2.5 mM HEPES + 1 mM NaCl) and 53 mM (2.5 mM HEPES + 50
      mM NaCl). Spectrin tetramers were studied only at 4 degrees C whereas the dimers
      were studied at both 4 degrees C and 37 degrees C. At 4 degrees C there is a
      striking quantitative similarity between the transient electric bire-fringence
      (TEB) of spectrin dimers and tetramers. Also, the TEB of spectrin dimers at 37
      degrees C was very similar to the results at 4 degrees C. The contour length and
      the molecular weight of spectrin dimers and tetramers are known. The dominating
      TEB relaxation time is in all cases only a fraction of what is predicted
      theoretically if the spectrin dimers and tetramers are assumed to be stiff and
      extended molecules. In sum, the new TEB data constitute strong electrooptic
      evidence confirming that spectrin dimers and tetramers have a highly flexible
      structure, and demonstrate for the first time that a major part of the intrachain
      dynamics of the spectrin is quite insensitive to an increase of the ionic
      strength from 4 mM to 53 mM. Use of the reversing electric field pulse technique
      for all conditions studied yields TEB data suggesting that the orientation of
      both spectrin dimers and tetramers in an electric field is dominated by a
      permanent rather than an induced electric dipole moment.

PMID- 10394622
TI  - Lipid domains in the exoplasmic and cytoplasmic leaflet of the human erythrocyte
      membrane: a spin label approach.
AB  - The existence of different lipid domains in the monolayers of the human
      erythrocyte membrane was investigated at 4 degrees C by employing spin-labelled
      phospholipid analogues. Spectra of analogues located exclusively either in the
      exoplasmic or in the cytoplasmic leaflet of erythrocyte membranes were recorded.
      Spectra were simulated by variation of order parameter describing the average
      amplitude of motion of the long molecular axis of the nitrogen 2 p pi orbital of
      the spin label and of the respective correlation times. For both leaflets at
      least three components were required to fit the experimental spectra, differing
      mainly in the order parameter. While the parameters of each component are not
      very different between both membrane halves, the relative contribution of each
      component to the spectrum is different between the exoplasmic and cytoplasmic
      leaflet. The order parameter of the most fluid component, presumably resembling
      the lipid bulk phase, is smaller in the cytoplasmic leaflet in comparison to the
      exoplasmic one. The lateral coexistence of different lipid domains in the human
      red blood cell membrane is concluded. The molecular nature of those domains is
      discussed.

PMID- 10394623
TI  - Elasticity of normal and cancerous human bladder cells studied by scanning force
      microscopy.
AB  - Scanning force microscopy was used for the determination of the elastic
      properties of living cells in their culture conditions. The studies were carried
      out on human epithelial cells. Two similar lines of normal cells (Hu609 and
      HCV29) and three cancerous ones (Hu456, T24, BC3726) were measured using the
      scanning force microscope in order to collect the force versus indentation
      curves. The BC3726 line originates from the HCV29 cell line which was transformed
      by the v-ras oncogene. To evaluate their elastic properties, Young's modulus
      values were determined. The present study has shown that normal cells have a
      Young's modulus of about one order of magnitude higher than cancerous ones. Such
      a change might be attributed to a difference in the organisation of cell
      cytoskeletons and requires further studies.

PMID- 10394624
TI  - Modelling action potentials and membrane currents of mammalian skeletal muscle
      fibres in coherence with potassium concentration changes in the T-tubular system.
AB  - During prolonged activity the action potentials of skeletal muscle fibres change
      their shape. A model study was made as to whether potassium accumulation and
      removal in the tubular space is important with respect to those variations.
      Classical Hodgkin-Huxley type sodium and (potassium) delayed rectifier currents
      were used to determine the sarcolemmal and tubular action potentials. The resting
      membrane potential was described with a chloride conductance, a potassium
      conductance (inward rather than outward rectifier) and a sodium conductance
      (minor influence) in both sarcolemmal and tubular membranes. The two potassium
      conductances, the Na-K pump and the potassium diffusion between tubular
      compartments and to the external medium contributed to the settlement of the
      potassium concentration in the tubular space. This space was divided into 20
      coupled concentric compartments. In the longitudinal direction the fibre was a
      cable series of 56 short segments. All the results are concerned with one of the
      middle segments. During action potentials, potassium accumulates in the tubular
      space by outward current through both the delayed and inward rectifier potassium
      conductances. In between the action potentials the potassium concentration
      decreases in all compartments owing to potassium removal processes. In the outer
      tubular compartment the diffusion-driven potassium export to the bathing solution
      is the main process. In the inner tubular compartment, potassium removal is
      mainly effected by re-uptake into the sarcoplasm by means of the inward rectifier
      and the Na-K pump. This inward transport of potassium strongly reduces the
      positive shift of the tubular resting membrane potential and the consequent
      decrease of the action potential amplitude caused by inactivation of the sodium
      channels. Therefore, both potassium removal processes maintain excitability of
      the tubular membrane in the centre of the fibre, promote excitation-contraction
      coupling and contribute to the prevention of fatigue.

PMID- 10394625
TI  - Temperature-dependent conformational changes in a voltage-gated potassium
      channel.
AB  - Temperature was used as a biophysical tool to investigate the energy changes
      associated with conformational change during the gating of a non-inactivating
      voltage-gated K+ channel present in the membrane of alpha T3-1 cells, a
      gonadotroph cell line. The time course of the current activation was described by
      a single exponential function at three temperatures: 15, 25 and 35 degrees C. The
      Q10 values were between 1.5 to 1.9 and in agreement with the activation energy
      determined from Arrhenius plots of the forward and backward rate constants
      associated with channel opening. The Gibb's free energy change associated with
      channel opening and closing at various membrane potentials estimated by two
      approaches yield similar values. The changes in Gibb's free energy (delta G
      degree) with depolarization potential is a quadratic and more prominent at 15
      than at 25 or 35 degrees C. The results suggest that increase in temperature
      favours movement of voltage sensing segments, and reduces the restraint on them
      brought about by other parts of the channel molecule.

PMID- 10394626
TI  - Conformation of bovine myelin basic protein purified with bound lipids.
AB  - The basic protein of myelin (called MBP) is an extrinsic protein of the myelin
      membrane. Its structure and function are still unknown. MBP has been extensively
      studied in its water-soluble form, but it is also known in a detergent-soluble
      form, which is purified with endogenous myelin lipids and should correspond to
      the native form of the protein in the membrane. In order to acquire insight into
      the structure of MBP, we have carried out circular dichroism (CD) experiments on
      the protein both in the lipid-free and in the lipid-bound form. Our data clearly
      show that lipid-free MBP is mainly disordered with only a small amount having
      alpha-helix and beta-sheet motifs. On the other hand, the lipid-bound form of MBP
      appears to have a consistent amount of ordered secondary structure. Theoretical
      predictions, made using different computational methods, substantially confirm
      the tendency of the protein to assume an ordered secondary structure in
      accordance with our CD results.

PMID- 10394627
TI  - Fast atom bombardment tandem mass spectrometric analysis of phospholipids in
      Drosophila melanogaster.
AB  - Direct determination of the phospholipid components in adult Drosophila
      melanogaster was carried out by using fast atom bombardment tandem mass
      spectrometry (FAB-MS/MS) of both the positive and negative ions. Approximately 50
      molecular species were detected, including phosphatidylethanolamine (PE),
      phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylinositol (PI).
      Eight PE, one PC and three PS molecular species were identified. Some variations
      with age and a few differences among the D. melanogaster strains in the PE and PC
      molecular species were found. There was a difference in the fatty acid structure
      of a 741 Da PE molecular species between the wild-types and a mutant strain
      (EthAR201) which requires a higher concentration of diethylether for anesthesia
      than the wild-types; in the mutant sn-1-oleoyl-2-linoleoyl (18:1/18:2) but in the
      wild-types sn-1-linoleoyl-2-oleoyl (18:2/18:1) were speculated. This suggests
      that this technique will be useful for the screening of phospholipid molecular
      species mutation.

PMID- 10394628
TI  - Mass spectrometric analysis of Klebsiella pneumoniae ssp. pneumoniae rough strain
      R20 (O1-: K20-) lipopolysaccharide preparations: identification of novel core
      oligosaccharide components and three 3-deoxy-D-manno-oct-2-ulopyranosonic
      artifacts.
AB  - In an attempt to find the best approach for the mass spectrometric analysis of
      the whole range of lipopolysaccharide (LPS) structures from Klebsiella pneumoniae
      ssp. pneumoniae rough strain R20 (O1-:K20-), various methods of LPS preparation
      were applied and the products were analyzed using a range of mass spectrometric
      techniques. The most productive approach proved to be the removal of lipid A by
      mild acid hydrolysis and the study of the core oligosaccharide structures using
      nanoelectrospray time-of-flight mass spectrometry (TOF-MS) in combination with
      collision-induced dissociation tandem mass spectrometry. This procedure is very
      sensitive, but results in the generation of a reducing 3-deoxy-D-manno-oct-2
      ulopyranosonic acid residue (Kdo) that is susceptible to the formation of
      artifacts, which give rise to pseudomolecular ions 18, 46, and 88 Da below the
      pseudomolecular ion for the unmodified species. Alternatively, matrix-assisted
      laser desorption/ionization TOF-MS combined with post-source decay can be used to
      study the de-O-acylated LPS preparation and especially to identify those residues
      bearing phosphate groups and the residues involved in the linkage between the
      core and lipid A. In addition to the five LPS core structures defined using NMR
      spectroscopy by Susskind et al., several extra related LPS structure were
      identified. Larger LPS species were observed, which surprisingly do not represent
      species containing longer versions of the novel Klebsiella heptoglycan, but
      instead are species having the defined core and heptoglycan extended with up to
      three extra hexuronic acid and one or two extra hexose residues.

PMID- 10394629
TI  - Using a matrix-assisted laser desorption/ionization time-of-flight mass
      spectrometer for combined in-source decay/post-source decay experiments.
AB  - Mass spectrometric experiments with fragment ions have not yet been possible with
      a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass
      spectrometer because intense signals of fragment ions were rarely observed during
      continuous extraction and the mass resolution of in-source formed fragment ions
      has been low. This paper describes a combination of MALDI in-source decay and
      post-source decay experiments on a MALDI-TOF mass spectrometer equipped with
      delayed extraction. Fragment ions initially formed in the ion source were
      selected by the precursor ion gate and investigated by post-source decay. The in
      source formed fragment ions were sufficiently excited to undergo further
      metastable decay. The new method was applied to linear peptides, the cyclic
      peptide gramicidin S and a pentasaccharide, leading to unambiguous structural
      information.

PMID- 10394630
TI  - Electron ionization mass fragmentometric detection of urinary ecgonidine, a
      hydrolytic product of methylecgonidine, as an indicator of smoking cocaine.
AB  - When cocaine is smoked, methylecgonidine (anhydroecgonine methyl ester) is also
      consumed as a pyrolytic product. Methylecgonidine, on incubation with human liver
      homogenate, was metabolized to a stable compound, ecgonidine. The compound was
      also formed when methylecgonidine was exposed to a urine pH > or = 8.0.
      Ecgonidine is a zwitterion and highly water soluble. A method was developed to
      identify ecgonidine quantitatively in urine. After removal of cocaine,
      benzoylecgonine and methylecgonidine from urine at pH 5.5 +/- 0.5 using a solid
      phase extraction (SPE) technique, the pH of the solution was readjusted to 2.0
      3.0. The acidic solution reduced the dissociation of the carboxylic acid and
      improved the lipophilic and cationic character of ecgonidine. The compound was
      extracted from the solution with the SPE technique with an 89-99% yield.
      Ecgonidine was then detected as a tert-butyldimethylsilyl derivative by a gas
      chromatographic/electron ionization mass spectrometric method. Quantitation was
      linear over the concentration range 7-2000 ng ml-1. Concentrations as low as 7 ng
      ml-1 can be detected by this procedure. Ecgonidine was detected in > 95% of
      benzoylecgonine-positive urine specimens from a random drug testing program,
      indicating smoking as the major route of cocaine administration.

PMID- 10394631
TI  - Comparative mass spectrometric analyses of Photofrin oligomers by fast atom
      bombardment mass spectrometry, UV and IR matrix-assisted laser
      desorption/ionization mass spectrometry, electrospray ionization mass
      spectrometry and laser desorption/jet-cooling photoionization mass spectrometry.
AB  - Photofrin (porfimer sodium) is a porphyrin derivative used in the treatment of a
      variety of cancers by photodynamic therapy. This oligomer complex and a variety
      of porphyrin monomers, dimers and trimers were analyzed with five different mass
      spectral ionization techniques: fast atom bombardment, UV and IR matrix-assisted
      laser desorption/ionization, electrospray ionization, and laser desorption/jet
      cooling photoionization. All five approaches resulted in very similar oligomer
      distributions with an average oligomer length of 2.7 +/- 0.1 porphyrin units. In
      addition to the Photofrin analysis, this study provides a side-by-side comparison
      of the spectra for the five different mass spectrometric techniques.

PMID- 10394632
TI  - Expressed sequence tags (ESTs) from desiccated Tortula ruralis identify a large
      number of novel plant genes.
AB  - The desiccation-tolerant moss Tortula ruralis [Hedw.] Gaerten., Meyer & Scherb.
      has both a constitutive protection system and an active rehydration induced
      recovery mechanism apparently unique to bryophytes. Immediately following
      rehydration, desiccated T.ruralis gametophytes produce a set of polypeptides
      whose synthesis is unique to the rehydrated state. We report the construction of
      a cDNA expression library from the polysomal mRNA of desiccated gametophytes and
      the single-pass sequencing of randomly selected clones. 152 expressed sequence
      tags (ESTs) were generated representing more than 60,000 bp of non-redundant DNA
      sequence. 44 ESTs (29%) demonstrated significant homology to previously
      identified nucleotide and/or polypeptide sequences, such as ribosomal proteins,
      desiccation-related peptides, early light-inducible proteins and a V-type ATPase.
      Analysis of a subset of these homologous ESTs reveals that codon preference in
      T.ruralis is similar to that of vascular plants, particularly the Magnoliopsida.
      108 ESTs (71%) demonstrated no significant homology to deposited sequences and
      represent a large number of novel plant genes. Analysis of these ESTs will define
      the range of genes involved in cellular repair and recovery and may provide
      greater insight to the complex phenotype of vegetative desiccation-tolerance.

PMID- 10394633
TI  - Sequence analysis of expressed sequence tags from an ABA-treated cDNA library
      identifies stress response genes in the moss Physcomitrella patens.
AB  - Partial cDNA sequencing was used to obtain 169 expressed sequence tags (ESTs) in
      the moss, Physcomitrella patens. The source of ESTs was a random cDNA library
      constructed from 7 day-old protonemata following treatment with 10(-4) M abscisic
      acid (ABA). Analysis of the ESTs identified 69% with homology to known sequences,
      61% of which had significant homology to sequences of plant origin. More
      importantly, at least 11 ESTs had significant similarities to genes which are
      implicated in plant stress-responses, including responses which may involve ABA.
      These included a cDNA associated with desiccation tolerance, two heat shock
      protein genes, one cold acclimation protein cDNA and five others that may be
      involved in either oxidative or chemical stress or both, i.e., Zn/Cu-superoxide
      dismutase, NADPH protochlorophyllide oxidoreductase (PorB), selenium binding
      protein, glutathione peroxidase and glutathione S transferase. Analysis of codon
      usage between P. patens and seed plants indicated that although mosses and higher
      plants are to a large extent similar, minor variations also exists that may
      represent the distinctiveness of each group.

PMID- 10394634
TI  - Comparison of local and systemic induction of acquired disease resistance in
      cucumber plants treated with benzothiadiazoles or salicylic acid.
AB  - The accumulation of chitinase and its involvement in systemic acquired disease
      resistance was analyzed using acibenzolar-S-methyl and salicylic acid (SA).
      Resistance against scab (pathogen: Cladosporium cucumerinum) and the accumulation
      of chitinase were rapidly induced in cucumber plants after treatment with
      acibenzolar-S-methyl. In contrast, SA protected the plants from C. cucumerinum
      and the accumulation of chitinase was induced only on the treated leaves. The
      accumulation of chitinase in response to inoculation with the pathogen was
      induced more rapidly in cucumber plants previously treated with acibenzolar-S
      methyl than in plants pretreated with SA or water. Thus, it appears that a
      prospective signal(s), that induces systemic resistance, can be transferred from
      leaves treated with acibenzolar-S-methyl to the untreated upper and lower leaves
      where systemic resistance is elicited. In contrast, exogenously applied SA is not
      likely to function as a mobile, systemic resistance-inducing signal, because SA
      only induces localized acquired resistance.

PMID- 10394635
TI  - A novel glycine-rich protein is associated with starch grain accumulation during
      anther development.
AB  - LIM14, originally identified as a lily gene associated with microsporogenesis,
      encodes a protein which has two distinct domains, one with glycine-serine repeats
      and the other with a hydrophobic signal peptide at the N-terminus. The putative
      LIM14 protein, however, is distinct from the glycine-rich cell wall proteins
      which have been described before. RNA analyses indicated that the LIM14
      transcript is specifically detected in the anther from zygotene to young pollen
      stage. By using antibodies raised against recombinant LIM14 protein, we detected
      anther-specific 15 kDa protein. Immunofluorescence microscopy demonstrated that
      the LIM14 protein is associated with starch grains in the anther wall cells just
      prior to microspore mitosis and then accumulates at a higher level with the
      starch grains of immature pollen. We tagged LIM14 with the GUS and GFP reporter
      genes and introduced them into tobacco BY-2 cells. Analysis of the transformed
      cells revealed that the chimeric proteins are functional and specifically
      targeted to plastids. These results indicate that LIM14 is an anther-specific
      protein that may play a role in starch accumulation and amyloplast
      differentiation during anther development and pollen formation.

PMID- 10394636
TI  - Characterization of an auxin-inducible 1-aminocyclopropane-1-carboxylate synthase
      gene, VR-ACS6, of mungbean (Vigna radiata (L.) Wilczek) and hormonal interactions
      on the promoter activity in transgenic tobacco.
AB  - A genomic clone for VR-ACS6, an isozyme of auxin-inducible ACC synthase of
      mungbean, was isolated, and its promoter activity was examined in transgenic
      tobacco. The clone contained 1,612 bp long 5' untranscribed region and its coding
      sequence consisted of three exons and two introns. Genomic Southern hybridization
      indicated that VR-ACS6 is a single copy gene. The transcription initiation site
      was a cytosine present at 231-base upstream the translation start codon. The VR
      ACS6 promoter contained DNA sequences homologous to various functionally
      identified auxin-responsive elements. To demonstrate hormonal response of the
      promoter region, transgenic tobacco plants carrying the 1,719 bp VR-ACS6
      promoter/-glucuronidase (GUS) fusion gene were generated. Strong GUS expression
      occurred by auxin treatment of leaves of T0 transformants and hypocotyls of T1
      etiolated seedlings. Magnitude of the response to auxin was dose-dependent, and
      the increased GUS activity was detected at 0.1 microM and higher concentrations
      of IAA. Other plant hormones did not induce GUS activity, but greatly modified
      the response to auxin. Cytokinin enhanced the IAA-induced expression of GUS
      reporter gene, whereas ABA and ethylene suppressed the expression. These
      characteristics of VR-ACS6 promoter activity in transgenic tobacco are in good
      accordance with the expression patterns of the gene in mungbean hypocotyls.
      Histochemical staining showed that GUS activity was evident in both etiolated and
      light grown seedings treated with IAA. Cytokinin enhanced the intensity of auxin
      induced GUS stain and also expanded the stained area, whereas ABA and ethylene
      reduced both intensity and area of the stain.

PMID- 10394638
TI  - High-fluence blue light stimulates transcription from a higher plant chloroplast
      psbA promoter expressed in a cyanobacterium, Synechococcus (sp. strain PCC7942).
AB  - High-fluence white and blue light, but not red light, enhanced transcription of
      the barley chloroplast psbA promoter when heterologously expressed as a lacZ
      transcriptional fusion in the cyanobacterium, Synechococcus sp. strain PCC7942.
      Analysis of Arabidopsis thaliana phytochrome mutants, phyAphyB and hy2, indicated
      that a distinct blue phototransduction pathway stimulates psbA expression. The
      evolutionary implications of these findings are discussed.

PMID- 10394639
TI  - Molecular cloning and characterization of a cDNA encoding caltractin from
      Dunaliella salina.
AB  - We cloned a cDNA encoding caltractin, a 20 kDa calcium-binding protein, from
      Dunaliella salina (DSCALT). The Ca(2+)-bound mobility shift detected in
      Chlamydomonas caltractin was hardly detectable in DSCALT. Also, some differences
      were found in the electrophoretic mobility between the native DSCALT and the
      bacterial-expressed DSCALT. This difference may have resulted from the
      posttranslational modification. Immunoblot analysis revealed that this protein
      might be localized mainly in the basal body complex, the major microtubule
      organizing center (MTOC) in D.salina and the functional homologue of the
      centrosome of the animal cell.

PMID- 10394640
TI  - The structure and organization of two cysteine endopeptidase genes from rice.
AB  - REP-1 is a major cysteine endopeptidase that digests seed storage glutelin of
      rice. A cDNA clone (pRP60) for REP-1 and a cDNA clone (pRP80) for a related
      enzyme were previously isolated. The expression of both mRNAs is regulated by
      gibberellin. In this study, we revealed the structure and organization of Rep1
      and RepA, genes corresponding to pRP60 and pRP80 mRNAs, respectively. Rep1 has no
      introns whereas RepA consists of five exons and four introns, and both genes
      exist as one copy gene in the rice genome. The gibberellin-responsive elements
      conserved in cereal alpha-amylase genes are not included in the 5'-upstream
      region of Rep1 or RepA. A molecular phylogenetic tree of plant cysteine
      endopeptidases was constructed, and their relationship was discussed.

PMID- 10394641
TI  - Safe and effective use of combination antiretroviral treatment.

PMID- 10394642
TI  - The newborn infant.

PMID- 10394643
TI  - Diagnosis of cutaneous T-cell lymphoma detecting T-cell receptor gamma chain gene
      monoclonality by denaturing gradient gel electrophoresis.
AB  - Cutaneous T-cell lymphomas represent a group of malignant lymphoproliferative
      disorders characterised by the occurrence of a monoclonal population of T
      lymphocytes. Diagnosis of early stages of this disease is a difficult challenge
      for both the dermatologist and the dermatopathologist. With the aid of the
      polymerase chain reaction it is possible to amplify specific regions of the T
      cell receptor gamma gene. The amplification products can then be separated by
      denaturing gradient gel electrophoresis in order to detect a monoclonal
      population of T-lymphocytes in the infiltrate. We studied 4 patients with the
      clinicopathologic diagnosis of mycosis fungoides and 2 patients diagnosed as
      large plaque parapsoriasis. A monoclonal population was detected in 3 of the 4
      mycosis fungoides cases and in 1 of the patients with large plaque parapsoriasis.
      This indicates that our analysis can help us establishing a diagnosis, and it can
      also help us to identify patients with a possible early stage of the disease,
      which clinically or histologically is not yet recognised as such.

PMID- 10394644
TI  - The bifocal strategy. A new model for flexible liaison between departments of
      somatic medicine and psychiatrists or psychologists.
AB  - A discrepancy exists between what is known about those conditions which are
      termed today in the DSM-IV somatizations or somatoform disorders and the fact
      that only 1-10% of the patients classified in these categories are seen by a
      psychiatrist or psychologist. Much is however at stake, considering the
      discomfort of these conditions, their complications (e.g. acute attacks of
      bronchial asthma, myocardial infarction) and their high cost to society. The
      bifocal strategy, used experimentally for more than 16 years on a group of 180
      patients, belongs to the ambit of liaison psychiatry. It is marked by a practical
      concern to defuse the process of somatization. This strategy has proved useful
      from several points of view, as it has enabled: the design of a simple but
      efficient model for close collaboration between the somatic practitioner and the
      liaison psychiatrist; the defusing, in an appreciable proportion of cases, of the
      somatization process; a significant contribution to be made to health-care policy
      in Belgium, with official recognition and renewed status being accorded to
      liaison psychiatry.

PMID- 10394645
TI  - How epileptogenic are the recent antibiotics?
AB  - OBJECTIVE: To review the clinical and experimental data concerning the serious
      neurologic adverse events, and more particularly seizures, which could be related
      to the administration of recent antibiotics, with special reference to
      cephalosporins, monobactams, carbapenems, and fluoroquinolones. DATA SOURCES: We
      have searched in the MEDLINE database over the years 1966-1998 the pertinent
      publications dealing with antibiotics related neurotoxicity. We used the
      thesaurus function and the following key words: antibiotics, neurotoxicity,
      seizures. Additional references were found in the articles sorted by the MEDLINE
      search. DATA SYNTHESIS: Neurotoxic manifestations following antibiotics
      administration are infrequently encountered under usual conditions. Experimental
      studies are helpful to demonstrate that these compounds might interact with a
      major component of the neurotransmission, the gamma aminobutyric acid (GABA)
      receptor complex. Structure-toxicity relationships can be described. For the
      clinician, the recognition of some predisposing factors related either to the
      patient (age, previous central nervous system disorder ...) or to the drug
      metabolism (reduced renal clearance, drug interactions ...) may help to minimise
      the risk of adverse neurologic manifestations. Several factors have to be taken
      into account before assessing causality: delay from administration, evolution,
      origin of the adverse event (risk factors, other drugs, non pharmacological
      origin), possibility of rechallenge, confirmation by biological testing or in
      vitro experiments....

PMID- 10394646
TI  - Belgian consensus recommendations for flow cytometric immunophenotyping. The
      Belgian Association for Cytometry/Belgische Vereniging voor
      Cytometrie/Association Belge de Cytometrie.
AB  - This paper summarises the guidelines and recommendations that were generated
      during a number of discussion forums attended by the majority of Belgian
      cytometry laboratory professionals. These forums focused on the rational and
      optimal use of flow cytometric evaluations in the clinical laboratory setting.
      The aim was to improve the coherence of the testing panels and the quality of the
      results and--as such--the clinical diagnostic information. It was also the aim to
      provide the Belgian prescribing physician and interested laymen with an updated
      overview of the flow cytometric possibilities. Emphasis is placed on
      immunophenotyping of haematological malignancies, hematopoietic progenitor cell
      counting and follow-up of the viral infection caused by the human
      immunodeficiency virus.

PMID- 10394647
TI  - Mucormycosis, a threatening opportunistic mycotic infection.
AB  - Mucormycosis is a rare and invasive mycotic opportunistic infection, occurring
      mostly in predisposed patients, mainly diabetics and immunocompromised
      individuals. The evolution of this fungal infection is frequently fatal unless
      aggressive treatment is started, or predisposing factors are handled. Our first
      patient was a known diabetic who had ketoacidotic coma at admission, complicated
      with pulmonary mucormycosis, and needed surgical resection followed by
      antimycotic therapy. The second patient did not survive his severe aplastic
      anemia (with neutropenia) and hemochromatosis (treated with desferrioxamine),
      complicated with a systemic Rhizopus infection, despite treatment with
      amphotericin B and granulocyte-colony-stimulating factors.

PMID- 10394648
TI  - [Results of a screening program for prostatic cancer].
AB  - OBJECTIVE: To set up the epidemiology of prostate cancer in the geographical area
      of Getafe, Madrid (Spain) and to detect curable prostate cancer. The results of
      screening 2.576 men are reported. PATIENTS & METHODS: Patients underwent digital
      rectal examination (DRE) and PSA determination. Patients with suspicious DRE or
      PSA greater than 4 ng/ml were further evaluated with transrectal ultrasonography
      (TRUS) and biopsy. The diagnostic performances of the tests or combinations of
      tests were determined. RESULTS: Mean age was 59.9 years (median 58 years). Ninety
      four patients (3.6 per cent) had abnormal DRE while PSA was higher than 4 ng/ml
      in 169 patients (6.5% of the total). 6.8 biopsies were needed to prove one
      cancer. The higher sensitivity corresponded to the PSA (93%). The test of
      greatest specificity was the rectal examination (97%). Positive predictive value
      raised to 78.9% when both DRE and PSA were abnormal. Advanced tumor stages were
      more common (39.4%) than in previous experiences. CONCLUSIONS: PSA should be the
      first diagnostic test when screening for prostate cancer. Neither the DRE nor the
      TRUS have any place in patients with PSA below 4 ng/ml. In summary we can't
      encourage screening programs for prostate cancer so far.

PMID- 10394649
TI  - [Aqueous diuresis and prophylaxis of recurrent nephrolithiasis].
AB  - Crystal precipitation in urine results from factors such as ionic strength, pH,
      soluble complexes formation, formation site and retention of initial solid
      particle. Among the most frequent causes are poor diuresis and changes in urine
      pH, their influence being quantified in different ways. Effects of water diuresis
      such as prophylaxis for urinary calculi are due to the intrinsic properties of
      the water contained in the urine, solid particles dragging, action on urine
      infection and changes in urine pH. Urinary flow has an influence on pH, so that
      its decrease coincides with concentrate urine and low pH, whereas its increase
      involves the presence of dilute urine and high pH. The purpose of this study is
      to understand the relationship between increased urine volume due to greater
      water intake and changes in urine pH, as well as the physiological intervening
      mechanisms.

PMID- 10394650
TI  - [Effects of experimental vasectomy on testicular structure: ultrastructural
      study].
AB  - We have performed experimental vasectomies in dogs in order to study effects of
      vas deferens ligature with close technique, on the testicular ultrastructure. We
      point out the existence of alterations: structural changes of the seminiferous
      epithelium, great extracellular spaces which are generated for the premature
      exfoliation of germinal cells, degeneration of the germinal shock cells, the
      appearance of immature germinal cells and multinucleate spermatids in every
      stages of the spermatogenesis, the fall of mature spermatozoid number, thickening
      of basal membrane, relative increase in the Sertoli's cells size as well as their
      phagocytic function, and existence of spermaphagos unfasted into tubular lumen.
      The Leydig's interstitial islets show an absolutely normal cellular and vascular
      configuration.

PMID- 10394651
TI  - [Incidence of prostatic cancer in symptomatic patients with non-suspicious rectal
      palpation and PSA levels greater than 10 ng/ml].
AB  - OBJECTIVE: To evaluate the overall incidence of prostate cancer in patients with
      symptoms of prostatism, no suspicious DRE and PSA > 10 ng/ml. MATERIAL AND
      METHOD: 397 eligible patients based on the above criteria, mean age 69.3 +/- 7.7
      years and mean PSA level of 21.3 +/- 29.3 ng/ml, underwent ultrasound-guided
      transrectal biopsy of the peripheral and central areas. Patients with no cancer
      in the biopsy and surgery indication underwent prostate surgery. Incidence of
      cancer in the transitional area was evaluated in these patients. RESULTS: Biopsy
      was found to be positive for cancer in 15.4% patients. Patients with prostate
      cancer had PSA concentrations (p = 0.06) and PSAD (p < 0.0001) lower than cancer
      free patients. Thirteen (21%) of these patients underwent radical prostatectomy;
      an extracapsular tumour was found in 46% of the surgical specimens. Of the 336
      patients with benign histology in the biopsy, 94 (28%) underwent prostate
      surgery. Cancer in the transitional zone was found in 15% cases (5 T1a and 8
      T1b), with significant differences between PSA (0.03) and PSAD (0.04)
      concentrations between patients with BPH or T1b tumour in the surgical specimen
      but not among patients with BPH and T1a cancer. CONCLUSIONS: Approximately 30% of
      these patients had prostate cancer, half of them found in the transitional area.
      PSA and PSAD did not show enough diagnostic strength to identify these patients.
      Most patients with cancer had clinically significant tumours. Therefore, we
      believe that prior to deciding the course of therapy these patients should
      undergo another series of biopsies including the transitional area, mainly in
      those with long-term life expectancy.

PMID- 10394652
TI  - [Chromophobe carcinoma of the kidney].
AB  - INTRODUCTION: Chromophobe renal cell carcinoma, described in 1985 is a type of
      renal carcinoma which is relatively uncommon (5%). Although the majority of
      studies published suggest a more favourable prognosis, conclusive evidence does
      not exist. In this study we present the clinical and ultrastructural
      characteristics and particularly the prognoses of 15 patients taken from a group
      of 230, all of whom had been diagnosed as suffering from renal carcinoma and for
      which they had received surgical treatment. MATERIAL AND METHODS: 230 kidneys
      were analysed between June 1990 and December 1997. The tissue was fixed and dyed
      with H-E, Hale's acid iron colloid and PAS. Two models were defined, typical and
      eosinophil. In 8 cases the tissue was processed in order to quantify the DNA
      using flow cytometry. RESULTS: Of the 230 kidneys analyzed, 15 were identified as
      being compatible with a diagnosis of chromophobe carcinoma, representing 6.5% of
      the group studied whilst 73% corresponded to the typical model. The average
      follow-up period for the 15 patients studied was of three and a half years. Upon
      completion of the study, 14 out of the 15 patients were still alive and the
      remaining one had died from causes unrelated to his illness. The average period
      of survival was 43 months. The tumors had an average diameter of 7.9 cm. The
      nuclear grade was GII on 10 occasions (seven T2, one T3a and two T3b) and GIII on
      5 (four T2, one T3a and two T3b). The study of flow cytometry showed four cases
      of multiploids two of aneuploids one tetraploid and one diploid. CONCLUSIONS:
      Chromophobe renal cell carcinoma is a relatively uncommon (6.5%) type of renal
      carcinoma. The typical ultrastructural type is the most common (73%). The highly
      favourable pathologic stage (p2 73%) and the significantly low nuclear grade (66%
      GII) suggest that this is a tumour with a rather better prognosis, as is shown by
      an increased period of survival.

PMID- 10394653
TI  - [Iatrogenic ureteral lesions in open surgery: review of 10 years].
AB  - OBJECTIVE: To carry out a revision of iatrogenic ureteral damage during open
      surgery occurred in our hospital over a 10-year period, to review the literature
      and to contrast the results. MATERIAL AND METHOD: Between January 1987 and
      December 1996, 19 cases of iatrogenic ureteral damage were reported in 18
      patients. Ureteral damage was the result of gynaecological surgery in 8 cases
      (42%), general surgery in 5 cases (26.5%), vascular surgery in 4 cases (21.1%)
      and urological surgery in 2 cases (10.5%). Four patients had been given
      radiotherapy. In 15 of the ureteral units involved, reconstructive open surgery
      was performed while the remaining 4 units received conservative therapy. RESULTS:
      In 11 cases of open surgery the results were good, 2 cases are nephrostomy
      carriers and 2 underwent nephrectomy. Conservative treatment was resolutive in
      all instances. CONCLUSIONS: Gynaecological and general surgery are the major
      causes of ureteral iatrogeny in our media. In more than half the cases, diagnosis
      is late. Radiotherapy was associated to late diagnosis in all cases. When
      diagnosed early, both surgical and conservative therapy achieve good results.

PMID- 10394654
TI  - [Radical prostatectomy in clinically localized prostatic adenocarcinoma. Factors
      influencing biochemical progression free survival].
AB  - MATERIAL AND METHOD: Study of biochemical progression (PSA > 0.5 ng/ml) and
      biochemical progression-free survival in 160 patients diagnosed with clinically
      localized prostate adenocarcinoma who underwent radical prostatectomy at the
      University Clinic in Navarra between 1988-1997. RESULTS: At the end of the study,
      120 patients (75%) are alive and free of progression, 33 (20%) are alive and in
      progression, 3 (1.9%) died of cancer, and 4 (2.5%) died for other causes.
      Biochemical progression occurred in 43/160 (27%) patients. Progression is related
      to previous PSA, both in absolute terms and divided into greater or smaller than
      15 ng/ml; to Gleason grade greater or smaller than 7 or divided into 2-4, 5-7, 8
      10; to pathological stage and to urethro-vesical junction stenosis. Biochemical
      progression-free survival (BPFS) in the univariate study is related to PSA (the
      ideal prognostic cut-off value being 15 ng/ml); to Gleason, specially when
      divided into 2-4, 5-7, 8-10; to the pathological stage and to margins. The
      multivariate study evidences that the single most influential factors are PSA
      (divided as greater or smaller than 15 ng/ml), Gleason grade (divided into: 2-4,
      5-7, 8-10) and margins involvement. There are 3 highly reliable risk groups based
      on PSA, Gleason and clinical stage. When these are introduced as variables in the
      multivariate study, they appear as the strongest predictive variables.
      CONCLUSIONS: The influential factors on progression-free survival are PSA (15
      ng/ml being the best prognostic cut-off value), Gleason grade (divided into 2-4,
      5-7, 8-10) and margins' positivity, which are the single most significant
      pathological factor ahead of clinical stage. Serum PSA, clinical stage and
      Gleason grade allow to define three reliable risk groups.

PMID- 10394655
TI  - [Influence of prostatic intraepithelial neoplasia on blood levels of PSA and free
      PSA percentage].
AB  - OBJECTIVE: To analyze the influence of prostatic intra-epithelial neoplasia (PIN)
      on serum total PSA levels and free PSA percentage. MATERIAL AND METHODS: Total
      and free PSA concentrations (IRMA Tandem and Tandem free PSA, Hybritech Inc) were
      determined in 349 patients with normal DRE and PSA greater than 4 ng/ml,
      undergoing prostatic biopsy by sextant and in 81 patients with prostate cancer in
      clinical stage T1c N0 M0 undergoing radical prostatectomy. In the group of
      patients undergoing prostatic biopsy, benign hyperplasia was diagnosed in 284
      (81.6%) patients, 234 (82.4%) were PIN free, 41 (14.4%) with low grade PIN and 9
      (3.2%) with high grade PIN. Cancer was diagnosed in 65 patients (18.6%), 30 of
      whom (46.2%) had associated high grade PIN. High grade PIN was detected in 62
      (76.5%) patients in the group undergoing radical prostatectomy. RESULTS: No
      statistically significant differences were detected among total PSA and free PSA
      percentage serum concentrations relative to the detection of associated PIN,
      regardless of its degree, in patients undergoing prostatic biopsy. Cancer
      detection was the single most significant contributing variable. In patients
      undergoing radical prostatectomy, high degree PIN did not influence
      significantly. The greatest contribution in this group was the pathological
      stage. CONCLUSIONS: PSA serum concentration and PSA percentage are not influenced
      by the existence of PIN. High degree PIN is strongly associated to cancer.
      Accordingly, repeat biopsies are warranted in any patient presenting such
      lesions.

PMID- 10394656
TI  - [Extensive ureteral lesions: management with substitution with small intestine].
AB  - Wide ureteral injuries are unusual but not exceptional and have few conservative
      therapeutic options, specially those that involve the upper ureter.
      Autotransplantation, ureteral substitution by intestine and combined Boari
      bladder flap-psoas bladder hitch are basically the only chances to avoid
      nephrectomy. In this paper we report five cases in which ileum was used to
      substitute the ureter and review the most outstanding literature about this
      subject.

PMID- 10394657
TI  - [Metanephric adenoma of the kidney and chronic myeloproliferative syndrome. An
      unusual association].
AB  - The metanephric adenoma is an uncommon tumour included in the class of benign
      renal epithelial tumours. This paper presents the case of a 64-year old female
      with incidentally diagnosed renal tumoration affecting the patient concomitantly
      to a chronic myeloproliferative syndrome with myelofibrosis. Left kidney
      ultrasound and CAT findings suggested a diagnosis of renal cell carcinoma. Left
      radical nephrectomy was performed. The pathoanatomical study confirmed the
      diagnosis of a renal metanephric adenoma 9 x 7.5 cm in size. Although some cases
      of metanephric adenoma have been described in patients with haematological
      conditions, polycythemia being specially frequent, no case associated to chronic
      myeloproliferative syndrome has been found in the literature.

PMID- 10394658
TI  - [Leiomyosarcoma of the bladder. Report of a new case and review of the
      literature].
AB  - Contribution of a new case of bladder leiomyosarcoma due to the rarity of its
      presentation. There are barely one hundred cases reported in the medical
      literature. Clinico-pathological, therapeutic and prognostic assessment of this
      type of bladder sarcoma and discussion on the convenience of complementary
      therapy after surgery.

PMID- 10394659
TI  - [Subcutaneous supramammary metastasis of prostatic carcinoma].
AB  - The subcutaneous dissemination at the prostate carcinoma is rare. Generally, but
      not frequently, it is seen in patients in advanced stages of the disease and in
      the terminal phase. We wish to communicate the case of a subcutaneous metastasis
      as the primary appearance of this neoplasm, whose existence was confirmed by
      immunohistological examination by means of PAAF, and with satisfactory response
      to testosterone deprivation.

PMID- 10394660
TI  - [Dissolution of ammonium-magnesium phosphate lithiasis with medical systemic
      treatment. Report of a case].
AB  - Presentation of one case of ammonium-magnesium phosphate calculi breakdown using
      systemic medical treatment with oral Acetohydroxamine acid dosed at 125 mg/8 h
      and antibiotic therapy based on the antibiogram results. This type of treatment
      is generally used in an attempt to eradicate the infection, and as prophylaxis of
      relapse following surgical treatment or SWEL in these difficult to eradicate
      calculi due to their high tendency to recur.

PMID- 10394662
TI  - [Etiopathogenesis and management of paraneoplastic fever and Stauffer syndrome in
      renal carcinoma].
AB  - Some paraneoplastic syndromes as fever, cachexia, loss of weight or hepatic
      dysfunction, are relatively frequent in patients affected by a renal cell
      carcinoma (RCC). However their pathogeny has been unknown until a short time ago.
      The advances in immunology have permitted to identify the interleukin-6 as the
      responsible for these changes. In spite of our better knowledge, the treatment of
      these paraneoplastic syndromes, when persist after the removal of the tumor,
      continues being a challenge. We present the case of a patient with a renal cell
      carcinoma that began as a feverish syndrome, developing thereinafter a hepatic
      dysfunction or Stauffer's syndrome. The paraneoplastic symptoms persisted after
      removal of the tumor. No response to the administered treatment has been
      observed. The patient died two months after the surgery.

PMID- 10394661
TI  - [Primary abscess of the psoas. Report of a case].
AB  - Psoas abscess is an uncommon condition at the present time. The initial anodyne
      signs and symptoms make diagnosis difficult. It can be diagnosed and rated as
      primary when the origin is not found, or secondary when a focus for infection
      spreading is detected. Drainage either percutaneously or by open surgery, and
      antibiotic therapy are the choice treatment, achieving an important survival
      rate. This paper presents a new case of psoas abscess, including a revision of
      the diagnosis and treatment of this condition.

PMID- 10394663
TI  - [Images in urology].

PMID- 10394665
TI  - Yes, religion and spirituality do matter in health.

PMID- 10394664
TI  - Healing and modern physics: exploring consciousness and the small-is-beautiful
      assumption.

PMID- 10394666
TI  - Readers react to Dr Murray's remarks about homeopathy.

PMID- 10394667
TI  - Readers react to Dr. Murray's remarks about homeopathy.

PMID- 10394668
TI  - Ruminating on the psychological dynamics of intolerance.

PMID- 10394669
TI  - Alternative therapies symposium offers attendee 'deep personal resonance'.

PMID- 10394670
TI  - More impressions of New York symposium.

PMID- 10394671
TI  - National Cancer Institute's OCCAM partners with NCCAM to expand research on
      unconventional cancer treatments.

PMID- 10394672
TI  - The Marino Center for Progressive Health: a team approach to coordinated care.

PMID- 10394673
TI  - Assessing the risks and benefits of herbal medicine: an overview of scientific
      evidence.
AB  - The use of herbal medicine is widespread and growing, with as many as 3 in 10
      Americans using botanical remedies in a given year. Because many herbal medicines
      have significant pharmacological activity, and thus potential adverse effects and
      drug interactions, healthcare professionals must be familiar with this
      therapeutic modality. This article summarizes the history and current use of
      plant-based medicine and highlights the evidence of the risks and benefits
      associated with 6 plants: echinacea, garlic, ginger, ginkgo, St John's wort, and
      valerian. Therapies outside the medical mainstream tend to suffer from a dearth
      of research and critical evaluation. Critics and supporters alike note the
      conceptual and practical difficulties in studying many complementary and
      alternative therapies such as acupuncture, homeopathy, and meditation. Herbal
      medicine, however, lends itself well to standard evaluation methods. This article
      summarizes and evaluates evidence from randomized controlled trials and meta
      analyses. We present the results of meta-analyses and subsequent randomized
      controlled trials for garlic and St John's wort; a comprehensive critical review
      and subsequent randomized controlled trials for ginkgo; and summaries of all
      identified randomized controlled trials for echinacea, ginger, and valerian.

PMID- 10394674
TI  - Gamma radiation fluctuations during alternative healing therapy.
AB  - CONTEXT: The actual identification (let alone measurement) of "healing energy"
      has been elusive and controversial. Although healing energy has been defined as
      "subtle" and "undetectable," preliminary research indicates that these
      descriptions may be inaccurate. OBJECTIVE: To assess the fluctuation of extremely
      high-frequency electromagnetic fields, or gamma rays, during Polarity therapy
      treatment. DESIGN: A series of gamma detection rate experiments were performed to
      establish a background and baseline count rate among 10 treatment and 20 control
      (10 sham and 10 standing-observer) subjects. SETTING: The Columbus Polarity
      Therapy Institute in Columbus, Ohio, and Public Health Information Services, Inc,
      in Dublin, Ohio. PARTICIPANTS: 30 volunteers recruited from Polarity and
      nonparticipant groups. INTERVENTION: Polarity therapy, a holistic bioenergy
      modality. MAIN OUTCOME MEASURES: The detection rate at 4 anatomical locations in
      space relative to each subject's body was measured using an Nal(Tl) gamma
      radiation detector operated in integral count mode. RESULTS: Marked decreases in
      gamma counts were found at every anatomical site location for all subjects during
      Polarity therapy, with less change noted during the standing-observer and sham
      sessions. Gamma radiation decreased in 100% of subjects during therapy sessions
      at every body site tested, regardless of which therapist performed the treatment.
      CONCLUSIONS: This preliminary study suggests a consistent and dramatic decrease
      in the number of gamma rays measured in a subject's electromagnetic field during
      one type of alternative healing energy treatment (Polarity therapy). The authors
      strongly recommend the collection of additional data, especially on subjects with
      cancer, whose long-term survival might be enhanced as a result of the radiation
      hormesis effects of alternative energy therapies.

PMID- 10394675
TI  - Side effects of pharmaceuticals not elicited by comparable herbal medicines: the
      case of tetrahydrocannabinol and marijuana.
AB  - OBJECTIVE: Herbalists claim that the polypharmacy of botanical remedies provides
      2 advantages over single-ingredient drugs: (1) primary active ingredients in
      herbs are synergized by secondary compounds, and (2) secondary compounds mitigate
      the side effects caused by primary active ingredients. To examine this second
      claim, medical marijuana was compared with its primary active ingredient,
      tetrahydrocannabinol. DATA SOURCES: A search on MEDLINE (1966-1999), AGRICOLA
      (1990-1999), and Biological and Agricultural Index (1964-1999) using keywords
      "cannabinoids," "marijuana," "tetrahydrocannabinol," "Cannabis," and "hemp."
      Phytochemical and ethnobotanical data were searched with the Agricultural
      Research Service database. Unindexed botanical journals were scanned by hand.
      STUDY SELECTION: Studies documenting the efficacy of secondary compounds
      mitigating side effects of tetrahydrocannabinol consisting of double-blind
      trials, unblinded studies, animal models, and in vitro experiments. DATA
      EXTRACTION AND DATA SYNTHESIS: Data validity was assessed by consensus, weighted
      by source (peer-reviewed article vs popular press), identification methodology
      (analytical chemistry vs clinical history), and frequency of independent
      observations. CONCLUSIONS: Good evidence suggests that some side effects of
      tetrahydrocannabinol are mitigated by other volatile compounds present in the
      essential oil of marijuana. Inhaling tetrahydrocannabinol, which avoids first
      pass hepatic metabolism, has advantages over ingesting it. Other cannabinoids,
      terpenoids, and flavonoids can reduce tetrahydrocannabinol-induced anxiety,
      cholinergic deficits, and immunosuppression. Other compounds increase cerebral
      blood flow, enhance cortical activity, kill respiratory pathogens, and provide
      anti-inflammatory activity. The hazards of marijuana smoke can be reduced with
      appropriate technology. Proprietary Cannabis extracts containing a mixture of
      cannabinoids, terpenoids, and flavonoids are currently being developed and
      tested.

PMID- 10394676
TI  - Benefits of massage therapy for hospitalized patients: a descriptive and
      qualitative evaluation.
AB  - CONTEXT: Some acute and long-term care facilities are instituting massage therapy
      programs to support their patients' health, healing, and quality of life.
      Evaluation of the impact of these programs from the perspective of patients,
      providers, and therapists is important for administrative decision making and the
      design of future outcomes research. OBJECTIVE: To uncover and elucidate a range
      of patient outcomes of a therapeutic massage program within an acute care
      setting. DESIGN: Descriptive and qualitative evaluation. Surveys and narrative
      reports were completed by 70 patients, 14 healthcare providers, and 4 massage
      therapists. SETTING: A large university hospital. PATIENTS: 113 hospitalized
      patients received 1 to 4 massages during the course of their hospital stay.
      INTERVENTION: Massage therapy. MAIN OUTCOME MEASURES: Narrative data were coded
      into 8 categories (pain, sleep, tension/anxiety, body awareness, physical
      functioning, psychological support, enhancing healing, and value). Selected
      patient responses were included to elaborate the meanings of these categories.
      RESULTS: The most frequently identified outcomes were increased relaxation (98%),
      a sense of well-being (93%), and positive mood change (88%). More than two thirds
      of patients attributed enhanced mobility, greater energy, increased participation
      in treatment, and faster recovery to massage therapy. Thirty-five percent stated
      that benefits lasted more than 1 day. CONCLUSIONS: The study supported the value
      of this hospital-based massage therapy program and uncovered a range of benefits
      of massage therapy for hospitalized patients that should be studied further.

PMID- 10394677
TI  - Are psychosocial factors related to response to acupuncture among patients with
      knee osteoarthritis?
AB  - CONTEXT: Acupuncture has been found to be beneficial in the treatment of patients
      with knee osteoarthritis. However, response among such patients is highly
      variable. Identification of subjects with greater response would facilitate a
      more rational use of acupuncture. OBJECTIVE: To examine the relationship between
      demographic and psychosocial variables and response to acupuncture as defined by
      reduction in pain and disability at the end of an 8-week course of treatment.
      DESIGN: Retrospective study. SETTING: Outpatients attending rheumatologists or
      primary care physicians. PATIENTS: 37 patients with symptomatic knee
      osteoarthritis who had previously participated in a controlled trial using
      acupuncture were recalled for an interview approximately 1 year later.
      INTERVENTION: Structured interview, questionnaire completion, and an examination.
      MAIN OUTCOME MEASURES: Depression, anxiety, helplessness, self-efficacy, and
      fatigue were measured by standard instruments. Knee examination and assessment of
      pain threshold were measured by dolorimetry. RESULTS: Response at 8 weeks was
      significantly related to duration of symptoms. A statistically nonsignificant
      trend was found for older and more educated subjects to have a better response;
      anxiety and fatigue were found to be inversely related to response (also
      statistically nonsignificant). Subjects with localized medial pain had
      significantly better response in terms of pain and disability than did subjects
      with generalized knee pain. CONCLUSION: Other than a weak relationship with
      anxiety (at 8 weeks only), no evidence of a link between psychosocial variables
      and response to acupuncture was found. Prospective studies are needed to confirm
      these results.

PMID- 10394678
TI  - Jeff Levin, MPH, PhD. The power of love. Interview by Bonnie Horrigan.
AB  - Jeff Levin is an epidemiologist and writer living in Kansas. He was trained in
      religion, sociology, public health, preventive medicine, and gerontology at Duke
      University, the University of North Carolina, the University of Texas Medical
      Branch, and the University of Michigan. From 1989 to 1997 he served on the
      faculty of the Department of Family and Community Medicine at Eastern Virginia
      Medical School in Norfolk, Va. Dr Levin pioneered basic research on the
      epidemiology of religion. He has been funded by several National Institute of
      Health (NIH) grants, totaling more than $1 million in support. He has also
      received funding from private sources including the American Medical Association
      and the Institute of Noetic Sciences. Dr Levin is a senior research fellow of the
      National Institute for Healthcare Research; an advisory board member of the
      Center on Aging, Religion, and Spirituality; and past president of the
      International Society for the Study of Subtle Energies and Energy Medicine. He
      has been chair of the NIH Working Group on Quantitative Methods in Alternative
      Medicine, is a former member of the NIH Workgroup on Measures of Religiousness
      and Spirituality, and is a member of the editorial boards of several peer
      reviewed scientific journals including Alternative Therapies. Dr Levin is the
      author of more than 110 scholarly publications, including 5 books. These include
      his edited book Religion in Aging and Health (Sage Publications); the newly
      published Essentials of Complementary and Alternative Medicine (Lippincott,
      Williams & Wilkins), which he edited with Dr Wayne Jonas; and the forthcoming
      God, Faith, and Health (John Wiley & Sons). Alternative Therapies interviewed Dr
      Levin at his home in Topeka, Kan, where he lives with his wife, Dr Lea Steele
      Levin.

PMID- 10394679
TI  - Current licensure for acupuncture in the United States.
AB  - This article reviews current licensure and certification standards for the
      practice of acupuncture in the United States. It serves as a current reference
      for the regulation of the practice of acupuncture, the licensing of
      acupuncturists, and the certification and training of physicians, chiropractors,
      dentists, podiatrists, and naturopathic physicians to practice acupuncture. Two
      national accreditation bodies are responsible for certifying acupuncture training
      and practice. The Accreditation Commission of Acupuncture and Oriental Medicine
      establishes accreditation criteria and curriculum evaluation of acupuncture
      training programs. The National Certification of Acupuncture and Oriental
      Medicine certifies individuals to practice acupuncture in the United States.
      Although national standards have been established, regulations regarding training
      and the practice of acupuncture are determined individually by each state, and
      tend to vary widely. Typical acupuncture training curricula for physicians and
      chiropractors are discussed, and variations in training requirements by state for
      acupuncturists and each of the other 5 disciplines is provided.

PMID- 10394680
TI  - Qigong therapy in the treatment of metastatic colon cancer.

PMID- 10394681
TI  - [Progression of profound perceptive deafness in children].
AB  - We have studied 340 cases of deep neurisensorial deafness in children and their
      evolution along a 7.2 years term. Conventional audiometry has been used as
      commonest method for assessing the auditive function. In a considerable number of
      cases (15.9%) hearing loss was progressive and some relation referring to sex,
      the bearing of hearing aids and the etiology is statistically contemplated.

PMID- 10394682
TI  - [Our experience in chondrosarcoma. Three case reports].
AB  - Sarcoma of the larynx are extremely rare neoplasms that account for approximately
      1% of all tumors of this organ. Less than 0.1% correspond to chondrosarcomas.
      Three cases of laryngeal chondromas are described. The patient's age ranged
      between 65 and 75 years, and all they were men. Two of the tumors arose in the
      cricoid cartilage, and the other one, in the left wing of the thyroid cartilage.
      Two of the cases corresponded to high-grade, indifferentiated chondrosarcoma. Two
      of the patients were alive and free of recurrence of metastases 5 years after
      surgery.

PMID- 10394683
TI  - [Histochemical study with lectins submucous glands of the hamster's tongue].
AB  - A histochemical study, with lectins, in oropharyngeal cavity of 5 Syrian golden
      Hamsters (Mesocricetus auratus) was performed in order to know the tongue
      submucous glands characteristics. Results showed a strong reactivity to HPA
      lectin for secretions of submucous glands of the Hamster's tongue and a slight
      reactivity to N-WGA and to WGA lectins.

PMID- 10394684
TI  - [Adenoid cystic carcinoma of the larynx. Case report and literature review].
AB  - Adenoid cystic carcinoma is a rare neoplasm that comprise approximately 0.25% of
      all laryngeal malignancies. The rarity of these lesions has prohibited
      clarification of definitive therapy. Traditionally, radical surgery is performed
      because of the usually high stage at presentation. A case of larynx ACC is
      reported. The literature on this topic has been reviewed, in order to describe
      the natural course and the different treatments of this tumor.

PMID- 10394685
TI  - [Front chest pain and paresis of recurrent nerve: sapho syndrome].
AB  - The AA. present a rarely encountered case combining a left recurrent palsy due to
      an sclerosis and hyperostosis of the first costoesternal joint, which improved
      after an antiinflammatory treatment.

PMID- 10394686
TI  - [The effect of pharmacological treatment in the compensation of vertigo].
AB  - From the age of sixty, vertigo is mainly due to vertebro-basilar insufficiency.
      It has been described that the association of Dihydroergocristine-Piracetam (D-P)
      is a useful treatment for vertebro-basilar insufficiency. That is why we have
      designed a comparative study between D-P an a Placebo, so that to prove if this
      association can be usefull in the treatment of vertigo occasioned by
      cerebrovascular insufficiency. Fifty patients complaining of vertigo were
      included in the study after an untreated term. 19 received a daily capsule of
      Placebo, and the other 31, treated with D-P, were divided in two groups: 16
      patients received a dose of 3 mg Dihydroergocristine + 1.6 g Piracetam every 12
      hours per os; and 15 other were treated with 1.5 mg Dihydroergocristine + 0.8 g
      Piracetam every 8 hours during 90 days. The patients were evaluated at the
      beginning of the study and 90 days later, with anamnesis and vestibular tests. In
      the last consultation the patients autoevaluated themselves the effect and the
      tolerance to the drugs received. In the Placebo group it was observed an
      improvement or disappearance of vertiginous symptoms in the 68.5% of the cases,
      while with D-P was 93.7% at the dose of 3 mg Dihydroergocristine + 1.6 g
      Piracetam each 12 hours and 100% with the dose 1.5 mg Dihydroergocristine + 0.8 g
      Piracetam each 8 hours. None of the treated patients with D-P worsened their
      symptoms. We observe a considerable decrease in the number of patients with
      vegetative symptoms in the group treated with D-P related to the Placebo group,
      though the symptoms persisted more time in the group treated with D-P that in the
      Placebo group. The group treated with D-P get a higher percentage of improvements
      and disappearance of auditive and cervical symptoms that the groups treated with
      Placebo. In the vestibulo-spinal and cerebellous tests it was observed a better
      improvement with D-P at the dose of 1.5 mg of Dihydroergocristine + 0.8 g
      Piracetam each hours compared with the other two groups. It can be concluded that
      the association D-P is an effective treatment for vertigo, getting also a higher
      normalization of the vestibular tests than Placebo.

PMID- 10394687
TI  - [Retro-inframandibular approach to tumors of the deep parotid lobe].
AB  - Two cases of pleomorphic adenoma of the parotid deep lobe are presented. Both of
      them were removed through back-submandibular approach. We favor this procedure as
      the best for tumors of the parapharyngeal space, whereas the mandibulotomies are
      indicated when dealing with strong adhesions, reoperations or malignancies.

PMID- 10394688
TI  - [Fibrous craniofacial dysplasia].
AB  - A case report of fibrous dysplasia affecting only the craniofacial right side, in
      a 56-year-old woman, seen in our outpatients Department suffering from fronto
      orbital headache and subjective hypoacusis of the right side, besides a syndrome
      of dizziness of 6 years development.

PMID- 10394689
TI  - [Methods and qualitative technics in primary care research].

PMID- 10394690
TI  - [The consumption of drugs and natural remedies in the older population of a rural
      area].
AB  - OBJECTIVES: To evaluate the knowledge about medical treatment on people with more
      than 70 years old, specifically, the understanding, reason for prescription and
      dosage. To describe the use of natural remedies in the rural environment. To
      correlate the medication and the natural remedies consumption with health's self
      perception. DESIGN: Cross-sectional study. SETTING: Health Center of Santa
      Eugenia de Berga. Barcelona. PATIENTS: Covered people aged 70 or more, not in an
      institution, selected by systematic sampling obtained from an updated age and sex
      register. MEASUREMENTS: A standard questionnaire was used, gathering aspects
      about medicine and natural remedies consumption and health's self-perception.
      RESULTS: The average of medicines was 3.08 (SD 2.5) for person. Therapeutics
      groups most prevalent were cardiovascular and nervous system drugs. The patients
      remembered correctly the reason of the prescription of the 77% of the medicines
      and the dosage of the 85%. The 25% of patients needed assistance of some family
      for to take the medication. We have found statistical significance between
      health's self-perception and the number of consumed drugs. The 47% of aged
      population used natural remedies. CONCLUSIONS: The knowledge of medical treatment
      of our elderly people is satisfactory. We detect in our study a high rate of
      polymedication. It is necessary, if possible, to rationalize and to reduce the
      number of drugs. It is useful to revise and to update periodically the elderly
      people medication. The natural remedies is included on the people's pharmacology
      and its use is important.

PMID- 10394691
TI  - [The evaluation of the self-financing capacity within the territorial compass of
      a primary care management].
AB  - OBJECTIVE: The main objective of this study is to calculate the point of
      financial balance in the geographical setting of the Tortosa PC Area, to evaluate
      the business results, and to reflect on the side-effects and potential problems
      of self-management. DESIGN: Retrospective and descriptive study. SETTING: The
      units studied were the seven base health districts operating during 1997.
      MEASUREMENTS AND MAIN RESULTS: The products or services considered for the
      calculation of income are included in the Order of 29/9/97. The overall result
      meant a deficit of 0.019 milliards. Pharmaceutical prescription accounted for
      58.45% of the total cost. 96.26% of the total activity was products or services
      undertaken in the PCC, where 95.95% of the income was obtained. All the points of
      balance, except for in-home activity of nursing personnel, were above the
      activity recorded. The products with greatest volume were the most profitable
      overall for the business. CONCLUSIONS: 1. The overall result meant a subsidy to
      running costs of 0.019 milliards. 2. If it did not occur otherwise, our systems
      for recording activity would have to be adapted to the products financed and
      accountancy information at the operational unit level. 3. Given that what is
      measured can be improved, we can identify problems and synergically involve the
      clinics in improving service efficiency and at the same time achieving a higher
      level of responsibility for services in a new context of self-management both for
      each operational unit and overall. 4. Defining the point of financial balance has
      to enable a framework of target incentives to be established by means of
      simultaneous information on cost and profit elements in the activity undertaken.

PMID- 10394692
TI  - [The effectiveness of an informational seminar on occupational health].
AB  - OBJECTIVE: The aim of this research was to evaluate the effectiveness of an
      information seminar concerning health at work, as an in-work training procedure.
      DESIGN: A quasi-experimental before-and-after study was conducted through a 20
      question survey on health at work. This questionnaire was administered before and
      after the seminar. Quantitative changes were evaluated through frequency
      indicators and the statistical significance of the changes was established
      through the chi-squared and Student's t tests and one-way two-tailed ANOVA.
      SETTING: Primary care in Castilla y Leon. PARTICIPANTS: A three-and-a-half hour
      long information seminar, with 102 primary care professionals--doctors,
      pharmacists, vets and nurses--was held. RESULTS: Results showed an improvement in
      the complex of training-information areas used as criteria to evaluate the
      acquisition of knowledge on health at work. The greatest positive change (36%)
      was found for matters relating to general principles of health at work for risk
      factors, and for work-connected pathologies. CONCLUSIONS: The information seminar
      is proposed as a procedure to use in on-going training of primary care health
      professionals.

PMID- 10394693
TI  - [The reform of primary health care: the economic, care and satisfaction results].
AB  - OBJECTIVE: To compare the overall effect on the general public before and after
      the primary care reform, its economic outcome and professional satisfaction,
      following the model of the European Foundation for Quality Management. DESIGN: A
      descriptive analysis of results at reformed primary care centres compared with
      results at non-reformed centres in the same city. SETTING: The study was
      conducted at Sant Boi de Llobregat, a town of 77,591 inhabitants in Baix
      Llobregat county (Barcelona). 32.7% of the population was covered by two reformed
      centres. The rest was covered by one single non-reformed primary care centre.
      MEASUREMENTS AND RESULTS: Clinical audits and data on pharmaceutical prescription
      quality were used to find attendance. For economic results, the formula of
      attribution of cost/inhabitant and cost/inhabitant seen, including the costs of
      labour, structure, referral, further tests and pharmacy, were used. The
      satisfaction of the outside customer (user) was measured by a population survey.
      Internal customer satisfaction was measured by a survey of the professionals.
      Results were compared with those for 1997. The study showed that the reformed
      primary care sector's results, measured in terms of professional satisfaction,
      user-outside customer, attendance, economic results and social impact, were
      better than the non-reformed sector's. Inside and outside customers' satisfaction
      was higher in the reformed network. The cost per inhabitant in the reformed
      network was 31,874 pesetas, against 25,177 in the non-reformed network. The cost
      per inhabitant seen was 34,482 and 44,603, respectively. CONCLUSIONS: The reform
      creates efficient resource management and greater satisfaction of the general
      public and professionals, when an indicator sensitive to the real use of services
      is used.

PMID- 10394694
TI  - [A reliability analysis of FACES III (the version in Spanish). Family
      Adaptability and Cohesion Evaluation Scales].
AB  - OBJECTIVE: To determine through five methods (Cronbach's alpha, split, Guttman
      method, parallel and strict parallel) the confidence coefficient of FACES III,
      instrument validated on spanish version, and to evaluate it's consistency with
      these five statistical methods. DESIGN: Descriptive, cross-sectional. SETTING:
      Tlalpan Area, south of Federal District, Mexico, divided into geo-statistical
      zones. PATIENTS AND OTHER PARTICIPANTS: A randomised sample of 270 dwellings with
      proportional coverage, based on 17,895 ordinary dwellings of the area.
      INTERVENTION: Domicile survey using FACES III (Family Adaptability and Cohesion
      Evaluation Scales); April-May 1995. MEASUREMENTS AND MAIN RESULTS: The confidence
      coefficient of FACES III spanish version was calculated using no standardised
      Cronbach's Alpha = 0.69; split I = 0.73 and split II = 0.66; Guttman method =
      0.75; parallel = 0.69 and strict parallel = 0.53. CONCLUSIONS: Cronbach's
      coefficient demonstrated more advantages than the other statistical methods in
      relation with the ordinal measurement scale of FACES III. We suggest to take into
      consideration three important aspects for the correct confidence analysis of this
      kind of instruments: Variance analysis depending on the scale of items (F test,
      Friedman or Cochran) Inter-items interactions analysis (nonadditivity) and the
      use of the balance value as purge element of error' source. Analysis of Tukey
      estimate, coefficient of concordance (W) and Hotelling's T squared. It's
      necessary the evaluation and analysis of this aspects before the report of
      confidence's coefficient values whose can have hidden skew.

PMID- 10394695
TI  - [The education of type-2 diabetics: why not in groups?].
AB  - OBJECTIVE: To evaluate the efficacy of a programme of group education for
      diabetics, which succeeded in reducing base glucaemia, body mass index and
      glycosylated haemoglobin, stimulating insulin-treated patients' self-monitoring
      of glucaemia, improving their understanding of the disease, and bringing into
      group education 75% of the target population. DESIGN: A controlled clinical trial
      with paired samples, lasting two years. SETTING: "Las Fuentes Norte" Health
      Centre, Zaragoza. PATIENTS: 243 type-2 diabetics, distributed at random, with 120
      in the intervention group and 123 in the control group. All patients with no
      history of group education in the previous two years and with no restrictions on
      their attending talks and monitoring were included. No-one gave up in the first
      year; 9 did in the second year. INTERVENTION: Group health education workshop for
      two days in the first and second years. MEASUREMENTS AND MAIN RESULTS: In the
      intervention group, at the end of the study, success in the survey increased by
      4.2; base glucaemia dropped by 17.1 mg/dl, glycate haemoglobin went down by 0.5,
      and self-analysis went up by 14.2%, all with significant differences (p < 0.005
      and CI 95%). The body mass index went down by 0.3 without significant
      differences. Knowledge was lost between the first and second year, with worse
      metabolic control. In the control group there were no significant differences in
      any variable. CONCLUSIONS: A stable programme of group education may be
      effective, especially because of the increase in knowledge of the disease,
      fostering excellent conditions for a change to a healthier life-style.

PMID- 10394696
TI  - [Attention to the carers of the patient with dementia].

PMID- 10394697
TI  - [Research and qualitative evaluation: the theoretical and conceptual bases].

PMID- 10394698
TI  - [Why is an early referral to a consult with a nephrologist necessary for patients
      with diabetic nephropathy?].

PMID- 10394699
TI  - [The financing of topical antihemorrhoidal agents by drawing on Social Security].

PMID- 10394700
TI  - [Hypertransaminemia secondary to hyperthyroidism].

PMID- 10394701
TI  - [Has the control of arterial hypertension improved in recent years?].

PMID- 10394702
TI  - [Decision on the advice of the European Union relative to the adoption of
      community programs in the area of public health (1996-2000)].

PMID- 10394703
TI  - Formylpeptide receptor antagonists: structure and activity.

PMID- 10394704
TI  - [Planning a statistical inquiry for evaluation of patient information].
AB  - This article deals with the patient package insert and the information to the
      patient-consumer. The law in force states that the patient package insert is an
      informative instrument for the consumer so it should be exhaustive,
      comprehensible and immediate. A statistical investigation has been performed in
      order to evaluate the clearness of patient package insert and the quality of the
      drug information. The protocol consists of the methodology of the investigation,
      the study pilot, the sampling and, finally, the questionnaire.

PMID- 10394705
TI  - In vitro and in vivo evaluation of oral systems for time and site specific
      delivery of drugs (Chronotopic technology).
AB  - This paper reports the in vivo and in vitro evaluation of an oral system for time
      and/or site specific drug delivery prepared according to Chronotopic technology.
      The proposed device consists of a drug containing core coated by a hydrophilic
      polymeric layer, which determines the delay in release onset. By applying an
      outer gastroresistant film, and by properly modulating the delay duration, a
      colon-specific release can be achieved. The obtained results show that the
      proposed delivery system is capable of releasing drug after a programmed time
      (time-specific release) and of targeting the colon (site-specific release) when
      an external gastroresistant film is applied on units coated with an appropriate
      amount of a hydrophilic retarding polymer.

PMID- 10394706
TI  - [The effectiveness of gamma-irradiated products on microspheres of polylactide-co
      glycolide containing bupivacaine].

PMID- 10394707
TI  - [Permeation of acyclovir through the intestinal mucosa of the rat: experiments
      with an in vitro mathematical model].

PMID- 10394708
TI  - Similarity and categorisation: neuropsychological evidence for a dissociation in
      explicit categorisation tasks.
AB  - A series of experiments are reported on a patient (LEW) with difficulties in
      naming. Initial findings indicated severe impairments in his ability to freesort
      colours and facial expressions. However, LEW's performance on other tasks
      revealed that he was able to show implicit understanding of some of the classic
      hallmarks of categorical perception; for example, in experiments requiring the
      choice of an odd-one-out, the patient chose alternatives dictated by category
      rather than by perceptual distance. Thus, underlying categories appeared normal
      and boundaries appeared intact. Furthermore, in a two-alternative forced-choice
      recognition memory task, performance was worse for within-category decisions than
      for cross-category decisions. In a replication of the study of Kay and Kempton
      [Kay, P., Kempton, W., 1984. What is the Sapir-Whorf hypothesis? American
      Anthropologist 86, 65-78], LEW showed that his similarity judgements for colours
      could be based on perceptual or categorical similarity according to task demands.
      The consequences for issues concerned with perceptual categories and the
      relationship between perceptual similarity and explicit categorisation are
      considered; we argue for a dissociation between these kinds of judgements in the
      freesort tasks. LEW's inability to make explicit use of his intact (implicit)
      knowledge is seen as related to his language impairment.

PMID- 10394709
TI  - Mentalising, schizotypy, and schizophrenia.
AB  - Despite accumulating evidence that patients with schizophrenia perform poorly in
      mentalising tasks, doubts remain about the primacy of the role played by
      defective mentalising in schizophrenia. This study investigated the relationship
      between mentalising ability and self-reported schizotypal traits in non-clinical
      adults who reported no history of psychiatric illness in order to test two
      counter-proposals: (1) defective mentalising is a primary cause of psychotic
      symptoms in schizophrenia; and (2) defective mentalising in schizophrenia is a
      secondary consequence of the chronic asociality that is typical of general
      psychiatric illness. Mentalising ability was tested using a false-belief picture
      sequencing task that has been used elsewhere to demonstrate poor mentalising in
      patients with schizophrenia. Evidence of selective mentalising deficits in high
      schizotypal non-clinical subjects discounted the view that defective mentalising
      is restricted to psychiatric illness and strengthened the case for continuity
      models of psychosis-proneness. Furthermore, evidence that poor mentalisers in the
      normal population are more likely to self-report psychotic-like traits, as well
      as asocial or idiosyncratic behaviours, refuted suggestions that defective
      mentalising is linked solely to asocial symptomatology and supported the view
      that defective mentalising may have a fundamental role to play in the explanation
      of psychotic symptoms. In order to specify what that role might be, alternative
      theoretical accounts of defective mentalising were tested. Neither executive
      planning deficits nor failure to inhibit cognitively salient inappropriate
      information could adequately explain the pattern of selective mentalising
      deficits found in high schizotypal non-clinical subjects. Our findings suggest
      that there exists a domain-specific cognitive module that is dedicated to
      inferring and representing mental states which, when dysfunctional, causes
      defective mentalising that manifests phenomenologically in psychotic-like traits
      and impoverished social awareness of variable expression and ranging severity.

PMID- 10394710
TI  - The perceived intentionality of groups.
AB  - Heider and Simmel [Heider, F., Simmel, M., 1944. An experimental study of
      apparent behavior. American Journal of Psychology 57, 243-259] found that people
      spontaneously describe depictions of simple moving objects in terms of purposeful
      and intentional action. Not all intentional beings are objects, however, and
      people often attribute purposeful activity to non-object individuals such as
      countries, basketball teams, and families. This raises the question of whether
      the same effect found by Heider and Simmel would hold for non-object individuals
      such as groups. We replicate and extend the original study, using both objects
      and groups as stimuli, and introducing two control conditions with groups that
      are not engaged in structured movement. We found that under the condition that
      best promoted the attribution of intentionality, moving groups are viewed as
      purposeful and goal-directed entities to the same extent that moving objects are.
      These results suggest that the psychological distinction between the notion of
      'intentional entity' and the notion of 'object' can be found even in the
      perception of moving geometrical figures.

PMID- 10394711
TI  - The role of motion in children's categorization of objects.
AB  - Perceptual cues play a fundamental role in early categorization of objects. What
      is meant by perceptual cues in the literature, however, is not always clear. It
      is fair to say that they are typically understood to be static shape cues. A
      number of recent studies have suggested that dynamic perceptual cues, such as
      motion, may also be important in early categorization. The study presented here
      explored the role that motion plays in children's categorization of animal and
      non-animal kinds, such as geometric figures. Motion was directly pitted against
      shape as a cue for categorization. Results showed that 4-year-old children,
      confronted with a choice between shape and motion, significantly used motion cues
      over shape cues to categorize objects, regardless of whether they were animals or
      geometric figures. Seven-year-olds also tended to use motion more often to
      categorize animals but not when dealing with geometric figures. Older children,
      who have been found to have a clearer natural kind/artifact distinction, seem to
      appreciate the uniqueness of movement to animals and see motion as more relevant
      to their categorization but relatively less so to categorize geometric figures.
      This developmental shift in the categorization of animals and geometric figures
      based on motion was further confirmed by testing adults on the same tasks. Adults
      were found to base their judgements significantly more often on motion for
      animals but not for geometric figures. These findings support the view that
      children are initially guided by motion in object categorization, suggesting that
      motion plays an overriding role that is central in the process of concept
      acquisition and in the mechanisms by which concepts are later structured.

PMID- 10394712
TI  - Age of acquisition in face categorisation: is there an instance-based account?
AB  - An instance-based model of the effects of age of acquisition (AoA) is offered and
      derived predictions are considered. A face-categorisation experiment is reported
      which tested these predictions. Nine participants made speeded-categorisation
      judgements of 185 faces from two TV shows. Ratings were given for the faces'
      frequency of occurrence in the shows and, for each face, the length of time the
      character was in the show and the time since they had left was found. Regression
      analyses were used to find how the factors affected the speed of categorisation.
      Speed of categorisation was found to follow a negative power function of the
      frequency and time on the show and a positive power function of the time since
      they had left. This was supportive of the instance-based account and suggests
      that effects of AoA with words and objects can be explained in terms of
      cumulative frequency.

PMID- 10394713
TI  - Overview: the many uses and applications of transgenic plants.

PMID- 10394714
TI  - Lessons in gene transfer to plants by a gifted microbe.

PMID- 10394715
TI  - Particle bombardment mediated transformation.

PMID- 10394716
TI  - Plant viral vectors based on tobamoviruses.
AB  - The potential of plant virus-based transient expression vectors is substantial.
      One objective is the production of large quantities of foreign peptides or
      proteins. At least one commercial group (Biosource Technologies) is producing
      large quantities of product in the field, has built factories to process truck
      loads of material and soon expects to market virus-generated products. In the
      laboratory, large amounts of protein have been produced for structural or
      biochemical analyses. An important aspect of producing large amounts of a protein
      or peptide is to make the product easily purifiable. This has been done by
      attaching peptides or proteins to easily purified units such as virion particles
      or by exporting proteins to the apoplast so that purification begins with a
      highly enriched product. For plant molecular biology, virus-based vectors have
      been useful in identifying previously unknown genes by overexpression or
      silencing or by expression in different genotypes. Also, foreign peptides fused
      to virions are being used as immunogens for development of antisera for
      experimental use or as injected or edible vaccines for medical use. As with
      liposomes and microcapsules, plant cells and plant viruses are also expected to
      provide natural protection for the passage of antigen through the
      gastrointestinal tract. Perhaps the greatest advantage of plant virus-based
      transient expression vectors is their host, plants. For the production of large
      amounts of commercial products, plants are one of the most economical and
      productive sources of biomass. They also present the advantages of lack of
      contamination with animal pathogens, relative ease of genetic manipulation and
      the presence eukaryotic protein modification machinery.

PMID- 10394717
TI  - Transgenic plants for therapeutic proteins: linking upstream and downstream
      strategies.
AB  - We have described two very different and innovative plant-based production
      systems--postharvest production and recovery of recombinant product from tobacco
      leaves using an inducible promoter and oleosin-mediated recovery of recombinant
      product from oilseeds using a seed-specific promoter. Both base technologies are
      broadly applicable to numerous classes of pharmaceutical and industrial proteins.
      As with any emerging technology, the key to success may lie in identifying those
      products and applications that would most benefit from the unique advantages
      offered by each system. The postharvest tobacco leaf system appears effective for
      proteins requiring complex posttranslational processing and endomembrane
      targeting. Because of the remarkable fecundity and biomass production capacity of
      tobacco, biomass scale-up is very rapid and production costs are low. Clearly the
      development of equally cost-effective extraction and purification technologies
      will be critical for full realization of the commercial opportunities afforded by
      transgenic plant-based bioproduction. The recovery of protein from tobacco leaves
      or oleosin-partitioned proteins by oil-body separations represent significant
      break-throughs for cost-effective commercialization strategies. Additional low
      cost, high-affinity separation technologies need to be developed for effective
      scale-up purification of plant-synthesized recombinant proteins. Clearly
      successful commercialization of plant-synthesized biopharmaceuticals must
      effectively link upstream strategies involving gene and protein design with
      downstream strategies for reproducible GMP-level recovery of bioactive
      recombinant protein. Both the tobacco and oilseed systems are uniquely designed
      to address issues of biomass storage, product recovery, quality assurance, and
      regulatory scrutiny in addition to issues of transgene expression and protein
      processing.

PMID- 10394718
TI  - Feasibility of antibody production in plants for human therapeutic use.
AB  - From the description above, the diversity of antibodies as a class of potential
      therapeutic agents is weighed against the constraints of developing any
      therapeutic molecule. Although much of this limit is specific to the antibody
      design, plant-based production systems have a potential to impact
      commercialization by making larger volume products manageable, with lower up
      front capital requirements. Due to their novel glycosylation pattern (Faye et al.
      1989), plants at present may not create antibodies with all the functions of
      mammalian-glycosylated antibodies (Wright and Morrison 1994). This is not a limit
      for all current products. Success is dependent on fusing the efficient
      agriculture infrastructure with the narrow tolerances required for a drug
      production system. Further validation of plants as a production system will come
      as more therapeutics from plants follow the corn-produced material through human
      clinical trials.

PMID- 10394719
TI  - Pokeweed antiviral protein and its applications.

PMID- 10394720
TI  - Transgenic plants as edible vaccines.

PMID- 10394721
TI  - Cowpea mosaic virus-based vaccines.

PMID- 10394722
TI  - [The effect on the health of the population of the lead exhaust from vehicular
      traffic].
AB  - The study of the effects of motor transport exhausts in the city of Perm on human
      lead levels has indicated that the employees of the State Motor-Vehicle
      Inspectorate whose working place is a highway have increased lead concentrations
      which in the blood are 3 times greater than normal values and which in the urine
      are 1.3 times higher. The content of lead in the hairs of children residing in
      vicinity of highways was 2.4 times as high as that in the controls and that in
      the urine was 1.5 times greater. Lead accumulation in the body caused higher
      blood levels of reticulocytes and red blood cells by 1.4-2 and 1.5 times,
      respectively, as compared to the controls. The findings suggest that petrol
      tetraethylene exerts adverse effects on human health.

PMID- 10394723
TI  - [The relationship of population morbidity to specific industrial wastes].
AB  - The present-day ecological crisis progressively deteriorates the population's
      health and demographic indices. Since 1990 primary morbidity has shown a 50.2%
      increase in the town of Samara. There has been a rise in the incidence of
      diseases, primarily those of the blood, digestive, respiratory, and other
      systems. A correlation analysis revealed that there was an association of
      morbidity with the environmental content of specific industrial chemical
      pollutants. The incidence of respiratory diseases is related to the
      concentrations of CO, NO2 and SO2 in the ambient air.

PMID- 10394724
TI  - [The effect of atmospheric pollution on the health status of the population].
AB  - The data on the general distribution of adult populations from different
      districts of the town of Balakovo are presented by the level of atmospheric air
      pollution from chemical industry and that of radioactivity. The data obtained in
      Balakovo may be useful in examining the modifying impact of low-level technogenic
      radiation and other environmental factors on human health.

PMID- 10394725
TI  - [The hygienic evaluation of the quality of the water from the Beresh River by its
      physicochemical indices].
AB  - The physicochemical properties of the water sampled from the Beresh [correction
      of Beresha] River before and after the development of the Sharypovsk industrial
      center were studied. The rates of increases in the levels of river water
      pollutants, sulfates, biogenic mineral substances, phenols, and petroleum
      products were found. Measures against river water pollution are recommended.

PMID- 10394727
TI  - [The sanitary microbiological and biochemical characteristics of the soils under
      the conditions of urbanization].
AB  - The study of soils under technogenesis and urbanization has shown that their
      biogenic properties are preserved. Sanitary assessment of urban soils has
      demonstrated their moderate and severe pollution, bean plants being found to have
      self-purifying capacities in the soils.

PMID- 10394726
TI  - [Mercury in the environment and in the bodies of animals in the central chernozem
      region].
AB  - The data on the mercury levels in the organs of wild ungulates and agricultural
      animals and in the environmental objects of the central black earth region are
      presented. The biogeochemical parameters of organisms were calculated. Species-
      and organ-specific indicators of toxic elements were proposed.

PMID- 10394728
TI  - [An estimation of the effect of low doses of irradiation on the population in the
      area of the eastern Urals radioactive trace on the health status of offspring].
AB  - High morbidity among the children whose parents and/or grandparents who resided
      in the areas with relatively low pollution levels (0.2-2.0 Ci/km2) after the 1957
      radiation accident at the production association "Mayak" is mainly formed under
      the influence of combined social, hygienic, and biomedical factors. The very
      residence of any child's ancestor in the low polluted areas produce no
      substantial impact on the nonspecific resistance of children.

PMID- 10394730
TI  - [The medical prophylactic problems of driving locomotives by an engineer without
      an assistant].
AB  - The medically preventive aspects of driving safety for engine drivers without an
      assistant are considered in the paper. It shows it necessary to solve the problem
      of preventing the fatigue of the visual and acoustic analyzers in the drivers in
      the research setting and to optimize the control desk and the driver's whole cab.

PMID- 10394729
TI  - [A radiation hygiene assessment of the use of the deicing preparation Kama-M in
      Moscow].
AB  - The content of radionuclides and metals in the agent to control the ice-crusted
      ground Kama-M was determined. An investigation has shown that the radioactive
      background of the agent is caused only by the presence of 40K as part of KCl.
      Small quantities of 226Ra and 232Th are present in the insoluble sediment. The
      concentrations of metals are very low and produce no environmental effects. The
      levels of superficial pollutions vary from 1.3 to 4.8 beta-particles per cm2/min
      and the power of an exposure dose is at the level of background values (9-20
      microR/hour), which is no greater than the permissible ones.

PMID- 10394731
TI  - [Improved medical criteria in occupational selection for the work of an engineer
      without an assistant].

PMID- 10394732
TI  - [The physiological hygiene bases for the requirements for illumination and color
      decor of the quarters for the station masters].
AB  - The values 100 to 200 lux are the most favourable levels of illumination for
      differentiation of red and green luminous objects. The 500-1000-lux illumination
      causes a considerable reduction in the visual range of red and green objects.
      Comparative assessment of the colour of materials used for a control desk has
      indicated that the colours in the mid-wave range are the best in differentiating
      red and green objects.

PMID- 10394733
TI  - [Industrial health and the health status of trolley bus drivers].

PMID- 10394734
TI  - [Problems of hygienic assessment in the certification of work sites by the
      working conditions].
AB  - The rating of working places by labour conditions is an important first practical
      step of introducing state management by an occupational risk. To achieve the
      goals of rating stipulated in the guidelines requires the correction and
      specification of some rating provisions.

PMID- 10394735
TI  - [Assessing the health status of workers by using chemiluminescent study methods].
AB  - A hygienic assessment of the working conditions and health of the workers engaged
      in the manufacture of pyromellitic dianhydride is given. A survey of 135 workers
      has shown changes in blood and urinary chemiluminescence in some of them.

PMID- 10394736
TI  - [Hygienic assessment and regulation of the academic load in the middle grades of
      high schools].
AB  - The difficulties of educational subjects were comprehensively assessed by
      determining the easiness of reading of educational texts, their component
      complexity and abstraction, the subjective difficulty of subjects, by analyzing
      the pupils' progress in studies. A table covering the difficulties of subjects
      taught in the 5-8th forms of gymnasia has been made up in terms of these
      parameters. Evidence is given for an approach to the biological rhythmological
      organization of educational burden.

PMID- 10394737
TI  - [The health status of pupils in the middle grades of a high school of the arts].

PMID- 10394738
TI  - [A hygienic assessment of the work of students on Macintosh computers].
AB  - Various kinds of works of 6-11th-form schoolchildren on Macintosh computers were
      physiologically and hygienically assessed at the lesson of information science
      and computer engineering (ISCE), as well as typing. The fatigue of a visual
      analyzer was due to the time of looking through the data available on the
      display; the adverse changes of the higher nervous activity depends on the
      complexity of educational materials and the intensity of work on a computer.
      Three-hour studies in ISCE should be excluded from the time able of lessons as
      they do not meet hygienic requirements.

PMID- 10394739
TI  - [The current problems of electromagnetic safety in computer classes].
AB  - He paper presents the data on the present-day situation in the computer classes
      in general educational schools to show electromagnetic safety. It shows that most
      of 37 classes do not satisfy the requirement of electromagnetic safety and
      proposes modes of elimination of this danger.

PMID- 10394740
TI  - [The assessment of functional reserves in adolescents during loading].

PMID- 10394741
TI  - [The hygienic conditions in children's and teenagers' institutions].
AB  - The leading risk factors in children and teenagers at the educational
      establishments of Samara Province can be considered to be unfavourable changes
      that determine the teaching conditions: impairments in an educational process,
      school routine, dietary deficiencies, nonobservance of sanitary and hygienic
      requirements for water supply and sewer system, aerothermal and light conditions,
      for the equipment of workshops and school furniture. With the participation of
      sanitary surveillance bodies, Samara Province has been introducing (in 1998-1999)
      a comprehensive assessment of a risk.

PMID- 10394743
TI  - [The effect of the molecular radicals of organophosphorus compounds on their
      biological activity].

PMID- 10394742
TI  - [An approach to predicting the acute toxicity of chemical substances].

PMID- 10394744
TI  - [The hygienic standards for tiolon in the atmosphere of populated places].

PMID- 10394745
TI  - [A toxicological hygiene evaluation of modifications to the SOZh-20-M coolant
      lubricant fluid].

PMID- 10394746
TI  - [The use of chromatographic methods in controlling wastes in the pharmaceutical
      industry].

PMID- 10394747
TI  - [A comparative evaluation of the psychodiagnostic methods used in studying the
      psychological status of the population].

PMID- 10394748
TI  - [An accelerated method for detecting coliphages in the drinking water].

PMID- 10394749
TI  - [An improved system of hygiene education and instruction for specified population
      contingents].

PMID- 10394750
TI  - [Experience in conducting research in the social hygiene monitoring system].

PMID- 10394751
TI  - [The comparative efficacy of different methods of cleaning the teeth].

PMID- 10394752
TI  - The case for change in early infant hearing screening in Ireland.

PMID- 10394753
TI  - The Irish Bosnian War experience. Assessment of the Irish experience with Bosnian
      Medevac patients from August '93 to December '95.

PMID- 10394754
TI  - Benign paroxysmal positional vertigo--an old disease with a new cure?

PMID- 10394755
TI  - Folic acid knowledge and use among expectant mothers in 1997: a comparison with
      1996.
AB  - This study examined changes in folic acid knowledge and use among antenatal women
      in Dublin maternity hospitals between 1996 and 1997, following a campaign to
      improve the very low uptake of peri-conceptional folic acid. The results showed
      significant improvements between the two years. Almost 76% of respondents had
      heard of folic acid in 1997 compared with 54% in 1996 (p < 0.01), with a shift in
      the proportion of people hearing of folic acid from hospital doctors to general
      practitioners (GP). Almost 43% of respondents in 1997 knew that folic acid can
      prevent spina bifida compared with 21% in 1996 (p < 0.01). A higher proportion
      was taking folic acid prior to conception in 1997 (16% vs 6%, p < 0.01). We
      conclude that the improvements may have been in part due to the promotional
      campaign among health professionals, women's groups and the media. However, less
      than a fifth of women were taking folic acid peri-conceptionally in 1997 and
      there is still scope for much improvement.

PMID- 10394756
TI  - The spectrum of mycobacterial disease in a Dublin teaching hospital.
AB  - We describe our experience at our combined tuberculosis and public health clinic,
      which has been in existence since 1991, and compare it to a previous review of
      tuberculosis at St. Vincent's Hospital from 1974 to 1979. A total of 107 patients
      were treated, 58 male and 49 female, with a mean age of 53 years. Seventy-seven
      patients had pulmonary tuberculosis, 23 extrapulmonary and three had both. Four
      patients had miliary tuberculosis. Our figures reflect the fall in incidence of
      tuberculosis in Ireland since the 1970's and a rise in smear negative and
      presumptive cases. The epidemiology of tuberculosis in Ireland is little changed
      except for an increasing impact of immigration. Problems such as late diagnosis,
      especially in older patients, and non-compliance remain significant. In addition,
      there were four deaths from tuberculosis. However, our combined clinic has led to
      the appropriate management of patients by Respiratory Medicine specialists and a
      great move to ambulatory diagnosis and management. We believe it is the best
      model for the effective management of tuberculosis in Ireland.

PMID- 10394757
TI  - Unfractionated heparin, time for a change?
AB  - BACKGROUND: In Ireland physician transfer to utilisation of Low Molecular Weight
      Heparin for Venous Thromboembolism has been slow, despite evidence of efficacy
      and concern about the level of anticoagulation achieved with Unfractionated
      Heparin. OBJECTIVE: To examine the effectiveness of Unfractionated Heparin
      administration in a teaching hospital in Ireland. Primary outcomes measured were
      time to therapeutic APTT and length of hospital stay. METHODS: We identified 50
      consecutive eligible patients treated with continuous intravenous unfractionated
      heparin for Venous Thromboembolism from the period August 1994 to December 1996
      at Beaumont Hospital, Dublin, Ireland. Data analysed included length of hospital
      stay, costing data and anticoagulation parameters (time to therapeutic APTT,
      percentage of time within therapeutic range, number of diagnostic tests, heparin
      dosages). RESULTS: A significant number of patients (22%) never achieved
      therapeutic APTT levels. Of those who did achieve therapeutic APTT levels at some
      time during their therapy, therapeutic range APTT was maintained only 28% of the
      time on heparin. 57% of the time results were below therapeutic while 15% of the
      time results were above therapeutic. Also 26% of the patients were discharged
      with INR results outside the therapeutic range despite an average length of stay
      of 13.3 days (over twice the ideal of 6 days). Ineffective anticoagulation
      influenced hospital length of stay in 60% of cases in our evaluation. Average
      cost of treatment with Unfractionated Heparin was 5897.86 Pounds versus the
      projected cost of Low Molecular Weight Heparin at 2562.78 Pounds for 6 days of in
      patient therapy or 60.78 Pounds for outpatient therapy (excluding physician visit
      costs). CONCLUSIONS: Unfractionated Heparin therapy as reviewed in our study is
      sub-optimal with inadequate anti coagulation and prolonged hospitalisation. Low
      Molecular Weight heparin, with comparable therapeutic effect documented
      elsewhere, overall may cost less.

PMID- 10394758
TI  - Norwegian crusted scabies treated with ivermectin.

PMID- 10394759
TI  - Seasonal variation of community acquired pneumococcal pneumonia admissions.

PMID- 10394760
TI  - European and Irish paediatric services.

PMID- 10394763
TI  - Nutrition and hydration: moral and pastoral reflections. National Conference of
      Catholic Bishops Committee for Pro-life Activities.

PMID- 10394761
TI  - The posthumous gift of life: the world according to Kane.

PMID- 10394762
TI  - Michael Martin and Robert Wendland: beyond the vegetative state.

PMID- 10394764
TI  - Regulating research on the terminally ill: a proposal for heightened safeguards.

PMID- 10394765
TI  - Preventive law by corporate professional team players: liability and
      responsibility in the work of company doctors.

PMID- 10394766
TI  - Cough up the money: a prescription for regulating Russian organized crime out of
      U.S. health care.

PMID- 10394767
TI  - Lake v. Arnold: the disabled and the confused jurisprudence of 42 U.S.C. section
      1985(3).

PMID- 10394768
TI  - California penal code section 645: legislators practice medicine on child
      molesters.

PMID- 10394769
TI  - Asleep at the wheel of auto safety? Recent air bag regulations by the National
      Highway Traffic Safety Administration.

PMID- 10394770
TI  - NHTSA: putting the brakes on the air bag crisis or just a lot of hot air?

PMID- 10394771
TI  - Reliability and validity testing of the Self-Efficacy for Functional Activities
      Scale.
AB  - Self-efficacy expectations for functional activities were defined operationally
      by having individuals rate their perceived judgment or confidence in their
      ability to perform each specific activity of daily living (ADL) (bathing,
      dressing, transferring, ambulating, and stair climbing) at a given point in time.
      The Self-Efficacy for Functional Activities (SEFA) scale initially included 27
      items focusing on efficacy expectations related to performance of each ADL
      independently, with adaptive equipment, and with the help of another person.
      After initial pilaf testing the scale was revised to include 9 items which
      focused on efficacy expectations related to performance of each ADL
      independently, or with the help of another person. Two additional studies were
      done and provided some evidence for the reliability and validity of the SEFA when
      used with older adults.

PMID- 10394772
TI  - Measures of body size based on height, weight, and reported ideal weight:
      conceptual distinctions and empirical demonstrations.
AB  - Using height, weight, and self-reported weight, eight additional measures of body
      size were computed. The purpose of this paper was to specify conceptual
      distinctions and test hypothesized relationships among those newly constructed
      measures. Using a sample of healthy African American and European American women,
      correlations among the measures and race differences were assessed. High
      correlations suggested only two independent constructs, but theoretical
      considerations would suggest retaining, in addition to the traditional measure of
      body mass index, three new constructs: ideal body mass, a discrepancy measure,
      and a desirability measure. The only significant race difference was on ideal
      body mass. African American women reported a larger ideal body mass index than
      European American women. The use of actual versus self-report measures of height
      and weight, different conceptualizations of ideal weight, and clinical
      implications also were discussed.

PMID- 10394773
TI  - Additional construct validity of the Schwartz Cancer Fatigue Scale.
AB  - The purpose of this article is to report the results of additional construct
      validity testing of the Schwartz Cancer Fatigue Scale. Latent variable modeling
      was used to determine the best fit of the data to the model. Testing with a
      heterogeneous sample (n = 303) did not support the proposed model. Using
      exploratory techniques a six-item, two-factor scale was formed which demonstrated
      that all measures of fit were consistently strong, and that the standardized
      solution factors loaded strongly. Reliabilities for the total scale and subscales
      were all greater than 0.80. These results provide preliminary support for the
      reliability and validity of the two-factor model of the six-item Schwartz Cancer
      Fatigue Scale.

PMID- 10394774
TI  - Measuring patient satisfaction outcomes across provider disciplines.
AB  - The purpose of this methodological research was to modify and test an instrument
      measuring patient satisfaction outcomes with primary care providers who represent
      different disciplines. The Patient Satisfaction with Health Care Provider Scale
      (PSHCPS) was adapted from a questionnaire indexing four satisfaction dimensions:
      Access, Humaneness, Quality, and General Satisfaction (Cherkin, Hart, &
      Rosenblatt, 1988). Following modification, the PSHCPS was administered to 167
      adults with NP or MD providers at a university-based, managed-care setting for
      the medically indigent. The total scale Cronbach's alpha was .93. Factor analysis
      supported an unidimensional scale with 18 items loading above .40 and 43%
      explained variance.

PMID- 10394775
TI  - Development of an instrument to measure community acceptance of nurse
      practitioners and physician assistants.
AB  - The purpose of this study was to identify the significant dimensions of the
      concept of community acceptance of nurse practitioners/physician's assistants and
      to construct a reliable and valid instrument which would reflect these
      dimensions. The methodological approach included: conceptualization of
      categories, development of items for each category, development of the tool,
      administration of the tool, and psychometric analysis of results. Community input
      through focus-group interviews and post-administration questions provided
      qualitative data. The survey tool, consisting of items in four conceptualized
      categories (knowledge, access, competence, and trust), was administered in five
      rural communities. The responses of 967 residents were analyzed through factor
      analysis. The criterion, eigenvalue > or = 1.0, resulted in seven factors.
      Oblique rotation was applied to the seven factors and marker variables (loadings
      > .70) facilitated the identification of the underlying dimensions of each
      factor. Overall, 98% of the items assigned to the original categories were
      maintained after factor analysis. The identification of these dimensions helped
      to simplify the description and understanding of community acceptance of nurse
      practitioners and physicians' assistants. Community acceptance of these advanced
      health care providers is a necessary precursor to use of services.

PMID- 10394776
TI  - Measurement of staff empowerment within health service organizations.
AB  - A measure of empowerment was developed and its psychometric properties evaluated.
      Employees (n = 52) of two hospitals participated in semistructured interviews and
      a pilot test of the research instrument. A second study was undertaken with
      professional, support, and administrative staff (n = 405) of four community
      hospitals. Psychometric evaluation included factor analysis, reliability
      estimation, and validity assessment. Subjects responded to questionnaires
      measuring empowerment, leadership behavior, organizational citizenship behavior
      and job behaviors related to quality improvement. Factor analysis indicated three
      dimensions of empowerment: behavioral, verbal, and outcome empowerment.
      Coefficient alphas ranged from .83 to .87. The three dimensions were positively
      related to leadership behavior that encouraged self-leadership and negatively
      related to directive leadership. The three dimensions discriminated between the
      empowerment level of managers compared to that of nonmanagement staff.
      Empowerment predicted organizational citizenship behavior and job behaviors
      related to quality improvement.

PMID- 10394777
TI  - Pine Bluff's health is mission of Shuffield Award winner.

PMID- 10394778
TI  - [Current views on pathogenesis of cholelithiasis].

PMID- 10394779
TI  - [New approaches to pharmacotherapy of rheumatoid arthritis: clinical perspectives
      of the drug subreum (OM-89)].

PMID- 10394780
TI  - [Specific aspects of the course of bronchial asthma therapy in perimenopausal
      period].
AB  - Bronchial asthma (BA) course and menopausal features were studied in 58
      perimenopausal women. Effects of menopause on BA clinical manifestations were
      considered. 19 patients on climonorm therapy were examined immunologically. It
      was found that premenopause and perimenopause deteriorate BA clinical picture
      whereas hormone replacement therapy with climonorm produce a positive effect on
      menopause and BA. In long-term hormone treatment it is necessary to follow up
      immune status.

PMID- 10394781
TI  - [Transesophageal echocardiography in diagnosis of infectious endocarditis].
AB  - Transthoracic and transesophagal echocardiography (TT EChG and TE EChG) were
      performed in 43 patients with infectious endocarditis (IE). Sensitivity and
      specificity of TE EChG in detection of vegetations were higher (92 and 75%, 81
      and 50% for TE EChG and TT EChG, respectively). Vegetations and thromboembolism
      were unrelated. With TE EChG, morphologically verified perforations of valvular
      cusps were revealed 3 times more frequently than with TT EChG. Along with
      detection of vegetations and dysfunction of the prosthetic valve, an essential
      diagnostic marker of IE of the artificial valve is visualization of
      paraprosthetic fistulas in 2 of 5 patients. Indications for TT and TE EChG and
      techniques of their performance are described. TT EChG is used in screening for
      IE. TE EChG is conducted in complications of IE.

PMID- 10394782
TI  - [Combined polychemotherapy of patients with chronic hepatitis C].

PMID- 10394783
TI  - [Population study of antibodies to some potential pathogens of
      spondyloarthopathies: the study of the Chukotka population].
AB  - The paper presents the results of the study of specific immune response
      stimulated by some enterobacteria in populations with high incidence of HLA-B27.
      A, M and G antibodies to Yersinia, Clebsiella, Salmonella and Campilobacter were
      studied on 292 plasma samples. The levels of the antibodies varied with
      anthropological parameters of the examinees (gender, age, nationality). The
      presence of the gene HLA-B27 in the genotype levels gender dimorphism of the
      specific humoral immune response. This may be of importance in pathogenesis of
      spondyloarthropathies which occur more frequently in men.

PMID- 10394785
TI  - [Changes in hepatic cells ultrastructure in predicting acute hepatic failure in
      cholelithiasis in presenile and senile patients].

PMID- 10394784
TI  - [Antibodies to various phospholipids in SLE patients with primary
      antiphospholipid syndrome].
AB  - Antiphospholipid antibodies (aPL) represent a heterogeneous population reacting
      with negatively charged, less frequently neutral phospholipids and/or
      phospholipid-binding serum proteins. The study was made of antibodies to a wide
      spectrum of phospholipids: to negatively charged phospholipids such as
      phosphatide acid (aPA), cardiolipin (aCL), phosphatidylcholine (aPS),
      phosphatidylinositol (aPI), phosphatidylglycerol (aPG) and to neutrally charged
      phospholipid--phosphatidylcholine (aPC)--in 54 patients with systemic lupus
      erythematosus (SLE) and 29 patients with primary antiphospholipid syndrome
      (PAPS). The test for lupus anticoagulant (LAC) was also made. aPL in SLE patients
      free of antiphospholipid syndrome were detected in 61, 36 and 9% (aPC, aPS and
      aPA, aCL, respectively). aPI and aPG did not exceed normal values. 81% of SLE
      patients with antiphospholipid syndrome were LAC positive and 88% aPL positive.
      60, 53, 44, 40, 13 and 17 were positive to aPC, aPA, aPS, aCL, aPG and aPI,
      respectively. Among patients with PAPS, the highest positivity was by LAC,
      occurrence of the other aPL was the same as in SLE patients with antiphospholipid
      syndrome. aCL, aPA, aPC, aPS, aPG and aPI were found in 55, 52, 41, 38, 31 and
      21% of cases, respectively. In clinical manifestations of antiphospholipid
      syndrome and negative tests for LAC and aCL it is advisable to make tests for aPS
      and aPC. aPC occur in SLE patients more frequently than the other aPL: in 63% of
      SLE patients free of antiphospholipid syndrome and in 60% of SLE patients with
      this syndrome. Antibodies to other phospholipids, but not to cardiolipin, were
      present in SLE + APS in half of the cases but in SLE + PAPS in one third of the
      patients. Occurrence of aCL in the serum of SLE + PAPS patients is associated
      with the presence of antibodies to any other phospholipid irrespective of the
      charge. The severity of vascular changes did not correlate with the number of aPL
      variant found in the serum.

PMID- 10394786
TI  - [Clinical observations of the psychotropic action of tramal].

PMID- 10394787
TI  - [Symptomatic antidiarrheal agents].

PMID- 10394788
TI  - [Diagnostic errors in the treatment of patients with pleural diseases].
AB  - As illustrated by analysis of 342 case histories, none of 280 patients admitted
      for two years to the Center for Diagnosis and Treatment of Pleural Diseases had
      the verified admission diagnosis. Missed diagnosis was possible because the
      physicians in charge had not prescribed pleural puncture, tomography of the lungs
      and mediastinum after maximal removal of the exudate. Other causes were
      inadequate investigation of the pleural fluid, administration of antibacterial
      therapy and glucocorticoids in obscure diagnosis. Poor diagnosis of pleural
      disease reflects the absence of clear-cut policy of management of such patients
      as a result of which in general practice pleural diseases are detected 2 weeks
      after visit to a doctor, on the average. To the specialized center the patients
      are sent only 47 days after the disease onset. Specialists of the center make
      differential diagnosis with early use of needle biopsy of the pleura which
      enables to reduce the time of making diagnosis to 10-12 days.

PMID- 10394789
TI  - [A case of spontaneous gas gangrene in a female patients wtih diabetes mellitus
      and chronic lymphoid leukemia].

PMID- 10394790
TI  - [A case of right atrial wall infectious endocarditis complicated by by mycotic
      aortic aneurysm].

PMID- 10394791
TI  - [On scientific heritage of N.S. Mochanov in the field of pulmonology (on the
      100th anniversary of his birth)].

PMID- 10394792
TI  - [Memorable dates and anniversaries in the history of medicine in 1999].

PMID- 10394793
TI  - [The tumor suppressor p53: "guardian of our genomes"].

PMID- 10394794
TI  - [Leukemias in children and adolescents].

PMID- 10394795
TI  - [Comparison of cholesterol synthesizing enzymes (CSE) inhibitors].

PMID- 10394796
TI  - Mechanism of impaired oxygen extraction in sepsis. Shunt and the pO2 gap.

PMID- 10394797
TI  - Severe sepsis trials: why have they failed?

PMID- 10394798
TI  - A hospital-wide system for managing the seriously ill.

PMID- 10394799
TI  - Epidemiological study on high grade trauma. Friuli VG Major Trauma Study Group.
AB  - A better understanding of trauma epidemiology may allow to enhance the
      organisation of trauma systems with a potentially relevant impact on the level of
      trauma care. A one year epidemiology study (1st March 1998-28th February 1999)
      was planned in Friuli Venezia Giulia with the aim to collect all prehospital,
      hospital and outcome data of patients who sustained a major trauma (ISS > 15)
      within the regional border. In 12 months 15,429 traumatized patients (14,108
      residents) were admitted to any one of the Regional hospitals. Over 1% of the
      whole population sustained injuries severe enough to cause hospital admission.
      630 people (77.3% male, 27.7% female average age 42 ys) had a major trauma. The
      incidence of major trauma is 525 per million people per year. RTA was by far the
      most important cause of major injuries (78.6%) followed by work accidents (6.8%),
      domestic (5.9%) and sport accidents (1.9%). Only 1.2% of all the major injuries
      was the consequence of interpersonal violence. One hundred-sixty-six trauma
      victims died on the spot (149) or before hospital arrival (17). 464 patients with
      major injuries reached the hospital alive. More than two third of the patients
      with ISS > 15, suffered from a multiple trauma. 70% had a severe injury to the
      head (AIS > or = 3). Head trauma occurred as an isolated injury in only 35.3%.
      Hospital mortality within 30 days from admission (trauma death) was 25.1%. The
      results of the follow-up at 6 months are still incomplete. However the
      preliminary data clearly show that a high percentage of the patients who were
      discharged alive from the ICU had a good neurologic recovery.

PMID- 10394800
TI  - [Cranial trauma and multiple trauma: from the street to the operating room].
AB  - Brain injury occurs with a range of severity: even less severe cases should be
      carefully observed since they may deteriorate. By definition severe head injury
      has a Glasgow Coma Scale score of 8 or less; comatose patients are defined as
      cases who do not obey commands, do not open their eyes and do not speak. Very
      often (50% of case in our series) brain injury is associated with relevant
      extracranial injuries that may add to the severity of cases and may worsen
      outcome. The conceptual framework for treating head injury is based on the
      evidence that after the impact, the initial damage may be exacerbated by insults
      capable of further disturbing cerebral metabolism, leading to a final damage
      defined as secondary damage. Secondary damage represents the final end of many
      pathways that can be studied at the biochemical level and are centered in a
      calcium influx into the neuronal cell. Most probably there is a genetic
      susceptibility to secondary damage leading to a range of cellular dysfunctions
      for any given level of insult. The management of traumatic brain injury is aimed
      at interrupting the chain of events leading to secondary brain damage and from
      this perspective the fact that damage may develop over time can be seen as a
      window of opportunity for timely treatment. The milestone of treatment is the
      removal of surgical masses. This surgical treatment can be performed only in a
      brain that is properly perfused and once coagulation is preserved. Therefore the
      organization of treatment from rescue to neuro-traumatological centers should
      provide appropriate restoration of the volume and a normal oxygen delivery to the
      brain and to the overall organism.

PMID- 10394801
TI  - [Volumetric hemodynamic monitoring].

PMID- 10394802
TI  - [Anesthesia accidents: accidental esophageal intubation].
AB  - Accidental oesophageal intubation is a common mistake in inexperienced
      anaesthetists, but unrecognized oesophageal intubation is fortunately a rare
      event because, in anaesthetic malpractice claims, it frequently resulted in death
      or brain damage. The connection of these complications with the lack of
      experience of the anaesthetist and/or the difficult intubation is not so evident
      in the literature. The precocious detection of tube dislocation depends on the
      systematic verification of endotracheal tube position after insertion. The paper
      describes the clinical and instrumental tests used for detecting tracheal or
      oesophageal intubation. Clinical signs are often unreliable and, between
      technical tests, capnography is the most reliable of correct tracheal positioning
      if waves are regular and repeated; when unavailable, the negative pressure
      aspiration test is a simple and reliable alternative.

PMID- 10394803
TI  - [Therapeutic applications of hypothermia in intensive care].
AB  - A brief review about the effects of hypothermia is presented, with regards to the
      difference between accidental hypothermia and controlled mild hypothermia (Core
      temperature = 33-35 degrees C). Mild hypothermia does not seem to affect the
      cardiac performance, while recent experimental reports show potential protective
      effects on the cardiac muscle during acute infarction. Mild hypothermia improve
      the outcome of brain function after cardiac arrest and head injury, while
      experimental reports show a potential protective effect of local spinal cord
      cooling during ischemic injury. Induced hypothermia of single organ is widely
      applied in liver resection and in other surgical procedures, further the cardiac
      ones. In the acute respiratory failure, mild hypothermia may induce a decrease in
      PaCO2, in sedated and muscle relaxed patients, due to the decrease of metabolic
      demand. In this setting a mild induced hypothermia potentially may decrease the
      side effects of therapeutic hypoventilation (permissive hypercapnia) both on
      haemodynamics and brain circulation. Preliminary data are presented about five
      ALI/ARDS patients, enclosed in a randomized trial, who were mechanically
      ventilated and cooled with an air-sheet: three patients died because of
      underlying disease and two patients survived with complete recovery. Mild
      controlled hypothermia seems to provide new interesting clinic uses.

PMID- 10394804
TI  - [Superficial cervical plexus block in association with laryngeal mask in
      parathyroid surgery].
AB  - Superficial cervical plexus block in association with laryngeal mask for the
      airways control has improved the postoperative outcome, in comparison with a
      previous group in general anaesthesia, performed by the same equipment. The local
      anaesthetic infiltration as a preemptive analgesia give us good evidences in pain
      control. The laryngeal mask contributes to a good surgical field and avoid the
      neck hypertension.

PMID- 10394805
TI  - Gas exchange: large surface and thin barrier determine pulmonary diffusing
      capacity.
AB  - The lung is characterized by its diffusing capacity for oxygen, DLO2, which is
      estimated from morphometric information as a theoretical capacity. It is
      determined by the large gas exchange surface, the thin tissue barrier, and the
      amount of capillary blood. The question is asked whether DLO2 could be a limiting
      factor for O2 uptake in heavy exercise, particularly in athletes with their 50%
      higher O2 demand. This is answered by studying the relation between DLO2 and
      maximal O2 consumption in different sedentary and athletic mammals, comparing
      horse and cow, dog and goat, and, finally, the most athletic mammal, the
      pronghorn antelope of the Rocky Mountains. It is concluded that in athletic
      species the lung is just sufficient to satisfy the O2 needs and can therefore be
      a limiting factor for aerobic work.

PMID- 10394806
TI  - Gas exchange in acute respiratory failure.
AB  - Acute respiratory failure is accompanied by a severe gas exchange impairment that
      is signified by a large shunt and no or only little of additional ventilation
      perfusion mismatch. The shunt is caused by perfusion of collapsed and
      consolidated lung tissue that is mainly located in the lower, dependent lung
      region. The ventilation, on the other hand, is redistributed towards upper, non
      dependent regions. By applying external PEEP, or producing an intrinsic PEEP by
      shortening the expiratory period, not only recruitment of collapsed or
      consolidated lung tissue may be achieved, but also a redistribution of inspired
      gas towards more dependent regions. Spontaneous breathing seems to improve gas
      exchange, and in proportion to its share of total ventilation, when added to
      mechanical ventilation. A shift from total mechanical ventilation to partial or
      fully spontaneous breathing may be the road of the future and should be tested
      further.

PMID- 10394807
TI  - Oxygen toxicity and tolerance.
AB  - Normobaric oxygen toxicity is well described in all animal species. However
      susceptibility to oxygen exposure is highly variable according to age, species
      and strains. Similarly in humans, prolonged high oxygen exposure is reported to
      induce cough, shortness of breath, decrease vital capacity and increase alveolo
      capillary permeability. The toxic FIO2 threshold (length of exposure and level)
      is still debated. In patients with previous lung injury, this threshold is even
      more difficult to delineate as pathologic pulmonary lesions might result from
      hyperoxia or primary lung insult. Oxygen free-radicals play a key role in the
      pathophysiology of oxygen toxicity. Oxygen resistance or tolerance is obtained
      with intraperitoneal, intravenous and intratracheal endotoxin or cytokines
      administration. Previous exposure to high oxygen concentration is also reported
      to increase survival rate and decrease pulmonary lesions in animal models.
      Protection may rely on antioxidant enzymes synthesis, nitric oxide production,
      neutrophils recruitment and modulation of alveolar macrophages activity. In
      humans, oxygen tolerance might be suspected through several clinical studies
      reporting favorable outcome after long term-oxygen exposure. Better knowledge of
      the risks of prolonged high oxygen exposure is important to re-evaluate the goals
      of mechanical ventilation (FIO2, SaO2, PEEP) and/or to develop treatments to
      prevent oxygen toxicity (surfactant, antioxidant enzymes).

PMID- 10394808
TI  - Toxicity of high PaO2.
AB  - There is no mammalian life without oxygen. At the same time, oxygen can be toxic.
      This paper focuses on extrapulmonary manifestations of oxygen toxicity.
      Hyperbaric and normobaric applications of oxygen are relevant to the
      anesthesiologist and carry different risks of oxygen toxicity. Normobaric O2 is
      tolerated for relatively long periods and has no acute sequelae. Chronic exposure
      to normobaric O2 will increase the concentration of oxygen radicals in the
      tissues and produce organ damage. This has to be weighed against the risk of
      withholding possibly life-saving oxygen therapy. High FiO2 can be used to
      increase plasma dissolved oxygen to offset low hemoglobin based oxygen transport
      capacity of blood during acute pre- or intraoperative normovolemic hemodilution
      with the aim of reducing allogeneic transfusion requirements. Administration of
      hyperbaric oxygen can be followed by a spectrum of neurologic disturbances
      leading to frank convulsions. The mechanism leading to cerebral seizure activity
      is not fully understood but is possibly linked to oxygen radical production and
      the L-Arginine-NO system.

PMID- 10394809
TI  - [Discharge criteria and postoperative complications].

PMID- 10394810
TI  - Regional anaesthesia for outpatients.
AB  - Regional anaesthesia is useful in day surgery when properly applied. Most
      commonly used techniques are IVRA, axillary block, local/infiltration plus
      monitored anaesthesia care. Spinal anaesthesia is also frequently used in DS.
      Depending on the technique used RA may fasten or prolong discharge when compared
      to general anaesthesia. The use of monitored anaesthesia care as an adjunct to RA
      increases patient acceptability and satisfaction with different blocks. In most
      cases there is less pain after operation if RA was used when compared to GA but
      control of pain is important at the time when the block wears off. Patient
      information and cooperation as well as timely discharge of patients home is
      important for successful RA in DS.

PMID- 10394811
TI  - New anaesthetics & techniques for day case surgery.
AB  - A variety of drugs and techniques have been introduced into day surgery over
      recent years and, although the tide of development appears to have slowed, may of
      these will still be relatively new to many. Experience with the laryngeal mask
      continues to grow and it is now a firmly-established airway management tool in a
      wide variety of procedures. The cuffed oropharyngeal airway is an interesting
      recent arrival, but produces inferior airway control and is not a true
      alternative to the laryngeal mask. Desflurane and sevoflurane offer faster
      recovery through low solubility although the differences are small. Sevoflurane
      offers the interesting prospect of inhalation induction opening up the
      possibility of a radical change in technique and philosophy. In the intravenous
      arena remifentanil offers short-lived opioid side effects, but also short-lived
      analgesia, while propofol has a new, computer-assisted delivery system. In
      combination, these developments offer another opportunity for a dramatically
      altered technique. The long-awaited "depth of anaesthesia" monitor may have
      arrived, offering the possibility of more finely titrated anaesthesia with
      earlier (but not intraoperative!) awakening. Reliability is as yet uncertain and
      a simple technique with spontaneous ventilation may achieve similar results at
      substantially lower cost. The relative place of all these developments will take
      several years to become apparent and the future remains interesting.

PMID- 10394812
TI  - Immunomodulation in sepsis: the role of hemofiltration.
AB  - Inflammation is a normal and biologically important process essential for host
      defense and repair of tissue injury. However, given the cyto-destructive capacity
      of inflammation, it is tightly controlled even in severe sepsis. There are both
      pro- and anti-inflammatory components of the inflammatory response, which are
      initiated simultaneously and co-exist in a single organism. Significant morbidity
      and mortality results when the inflammatory response becomes unstable and its
      components uncoupled. Restoring immune stability likely requires reestablishing a
      balance between pro- and anti-inflammatory processes as well as restoring the
      normal feedback mechanisms necessary for systemic control. Selective manipulation
      of inflammation by augmenting or blocking specific components continues to fail
      as a therapeutic approach to human sepsis, perhaps because such targeted
      manipulation of the immune response is unable to restore balance and immune
      stability. It has been recently shown that continuous veno-venous hemofiltration
      (CVVH) can nonselectively affect the plasma concentrations of immune mediators in
      patients with sepsis and multiple organ dysfunction syndrome (MODS).
      Hemofiltration offers tremendous potential advantages over other forms of
      immunomodulation because it is both non-specific and self-regulating. CVVH can
      remove both soluble pro- and anti-inflammatory substances and does so in direct
      relationship to the circulating mediator concentrations. The ultimate value of
      this technique will depend on whether immunomodulation is an appropriate goal for
      patients with sepsis. The avoidance of unintended immunomodulation is also an
      important issue, and evidence already suggests that this should be a priority.

PMID- 10394813
TI  - Present and future options in continuous renal replacement therapies of sepsis
      and MOF.
AB  - Conventional continuous extracorporeal treatments such as hemofiltration and
      hemodiafiltration have not achieved significant reduction in cytokine plasma
      levels, in spite of their increasing popularity mainly related to the unnecessary
      fluid restriction thereby rendering adequate caloric intake possible (Actualites
      Nephrologiques, 1994). This is mainly due to reduced filtration, to saturability
      of the adsorption-related phenomena and to the absence of a convective mass
      transfer. New approaches have been more recently introduced. The concept of blood
      purification has been applied in some new innovative techniques that use non
      selective or selective sorbents. We will focus on the criteria used by others and
      us to assess the efficiency in vitro and in animal models of sepsis of more
      recently introduced non-selective and selective devices. Among the innovative
      techniques, modalities aimed at the plasma treatment will receive emphasis. These
      modalities that are based on plasma filtration with the use of different
      sorbents. The preliminary results obtained from ongoing clinical trials will be
      presented. We will also expand on the technical, biological and clinical aspects
      that should be addressed in order to establish a new modality as innovative in
      the treatment of sepsis.

PMID- 10394814
TI  - Hemofiltration during cardiopulmonary bypass.
AB  - Several factors combine to facilitate the evolution towards heart and multi-organ
      failure following cardiac surgery. Some of these factors are related to pure
      cardiac aspects like the existence of a preoperative heart disease, the use of
      aortic cross clamping or performance of cardiotomy. Cardiopulmonary bypass (CPB)
      also plays an important role in the occurrence of postoperative organ
      dysfunctions by two principal means: firstly by inducing a profound hemodilution,
      which impairs oxygen transport through tissues. This phenomenon is pointed out in
      the postoperative period by the existence of increased transpulmonary O2
      gradients, extravascular lung water volume and subsequent impairments of O2
      transport. Secondly CPB is deleterious by triggering an important inflammatory
      reaction. This reaction is largely related to the ratio of the circuit area to
      the patient's body surface area and is therefore maximal in children. It has been
      widely demonstrated that the very early paths of this reaction imply several
      humoral factors including kinins, coagulation factor-XII and complement
      fragments. The activation of these factors is self-amplified and triggers both
      expression and release of numerous mediators by endothelial cells and leukocytes.
      Finally, these mediators are responsible for the well described "post-bypass
      syndrome" which is, from a clinical viewpoint, very close to hyperkinetic septic
      shocks. Several methods have been proposed to reduce the deleterious effects of
      both cardiac surgery and CPB. The older one is hypothermia that considerably
      reduces the triggering of the inflammatory mediators network. Heparin-coated
      circuits may also reduce this reaction to some extent. Hemofiltration has been
      introduced in the 90's in CPB management. Because of its very high tolerance in
      patients with compromised circulatory status this technique was already used in
      the postoperative period to treat patients with acute renal failure. Initially
      hemofiltration was intended to correct the accumulation of extravascular water
      during or immediately following the surgical procedure. Nevertheless several of
      its "side-effects" appeared to be useful like reduction of postoperative blood
      loss and immediate hemodynamics improvement. Several studies attempted to point
      out the mechanism of action of hemofiltration and although removal of
      inflammatory mediator occurs, there is currently no proofs that this removal is
      the actual mechanism by which this technique acts. At the early beginning of the
      use of its utilization hemofiltration during cardiac surgery aimed either to
      concentrate blood at the end of the procedure or to rapidly restore a normal
      fluid and electrolytes balance. Today some new implementations of this technique
      are proposed either to reduce the triggering of the inflammatory reaction to CPB
      or to reduce the immediate postoperative drug support.

PMID- 10394815
TI  - Continuous renal replacement therapy in patients with HELLP syndrome.

PMID- 10394816
TI  - Results from ethical international surveys on the management of the continuous
      renal replacement therapy.
AB  - OBJECTIVE: To examine the ethical approach of clinicians to the continuous renal
      replacement therapy (CRRT). DESIGN: Review of international surveys. RESULTS:
      Many surveys have been carried out in order to evaluate the clinical approach and
      management of the continuous renal replacement therapy (CRRT). Nothing has been
      proposed in order to evaluate it from a bioethical point of view, even if many
      surveys dealt with the problem of the ethically correct administration of vital
      supports. These data demonstrate that an ethically correct approach to the
      management of life-saving support can be sometimes difficult. Results of a recent
      study on the ethical approach of intensivists and nephrologists to CRRT will be
      shown and discussed. CONCLUSIONS: Several ethical questions in the management of
      CRRT and other vital support are still unsolved. Practical and psychological
      aspects of the curing process are sometimes stronger than bioethical principles.

PMID- 10394817
TI  - Prognostic meaning of temporary clipping in patients with intracranial aneurysm.
AB  - The prognostic meaning of the routine use of the methods of temporary clipping of
      the afferent vessel in patients with intracranial aneurysm (Grading 0-III) was
      the aim of the analysis in this study. In the period 1 January, 1991-31 December
      1997, 304 patients underwent surgery for non-giant intracranial aneurysm and a
      follow-up angiography. 157 patients were operated by routinely using the
      temporary clipping of the afferent vessel, whereas in 147 patients the surgical
      procedure was performed by traditional methods. The statistical analysis showed a
      significant reduction (p < 0.001) in terms of risk of surgical complications in
      the patients who underwent surgery with the temporary clip method compared to
      those operated with the traditional method, with a relative risk of such
      complications about three times greater in the latter. The routine use of
      temporary clipping offers, therefore, the possibility of a significant
      improvement of the surgical results, not influenced by a further involvement for
      the structure, due to the short application time.

PMID- 10394819
TI  - Which metabolic strategies in the early phase of injury?

PMID- 10394818
TI  - Interventional neuroradiology. Recent developments and anaesthesiologic aspects.
AB  - AIM: To summarise recent developments in interventional neuroradiology (INR) and
      to discuss related anaesthesiologic considerations. SUMMARY: Important
      Procedures: embolisation of cerebral aneurysms with Guglielmi detachable coils
      (GDC) as well as intra-arterial thrombolysis and angioplasty for acute ischaemic
      stroke and chronic atherosclerotic stenosis of cerebral arteries have been
      recently introduced into clinical practice. Their role in the management of
      aneurysms and cerebral ischaemia still remains to be defined. Embolisation of
      strongly vascularised neoplasms, arteriovenous malformations or fistulas and
      percutaneous transluminal angioplasty of refractory vasospasms after subarachnoid
      haemorrhage are standard procedures with established indications. The balloon
      occlusion test of the carotid artery and the WADA test are also frequently
      performed interventions in INR. ANAESTHETIC CONSIDERATIONS: The role of the
      anaesthetist in INR consists in providing patient comfort by analgesia and
      sedation, adequate monitoring, maintenance of vital functions and (if required)
      the management of systemic heparinisation. The patient's underlying condition,
      the duration and the kind of intervention have to be considered to decide on the
      anaesthetic management. Most of the procedures can safely be performed under
      light sedation, which allows continuous neurological evaluation of the patient.
      Knowledge of the risks and hazards of the different procedures and close
      collaboration with the neuroradiologist form the basis for appropriate management
      in case of a potentially fatal ischaemic or haemorrhagic complication that may
      occur in 1 to 8% of interventions. For prompt control of airway, respiration and
      blood pressure in these emergencies experienced anaesthesia staff is required.

PMID- 10394820
TI  - [Artificial nutrition in the critical patient: a useful thing?].

PMID- 10394821
TI  - Enteral nutrition: just a fuel or an immunity enhancer?
AB  - Based on a review of randomized, controlled clinical trials, enteral feeding
      improves septic morbidity in critically ill and/or malnourished patients. Enteral
      feeding may be better than parenteral feeding, but a definitive study is not
      available. Immune-enhancing diets further improve septic morbidity in critically
      ill and/or malnourished patients. Active components identified include arginine,
      glutamine, and omega-3 fats, but the relative efficacy of any single immune
      enhancing component versus their combination is impossible to state based on the
      presently available evidence.

PMID- 10394822
TI  - Noninvasive positive pressure ventilation in trauma patients with acute
      respiratory failure.
AB  - The effectiveness of noninvasive pressure support ventilation (NIPSV) in treating
      trauma patients with acute respiratory failure (ARF) was evaluated in a
      retrospective clinical study. Forty-six conscious patients with ARF admitted to
      the general intensive care units (ICUs) of three hospitals between July 1988 and
      July 1991 were surveyed. Patients received NIPSV after a period of spontaneous
      breathing with supplemental oxygen. Blood gas levels and respiratory parameters
      were measured before the application of the mask and after 1, 6 and 12 h of
      NIPSV. Thirty-three (72%) patients were successfully weaned to spontaneous
      breathing (success group). Nine patients with hypercapnia and four with
      hypoxaemic respiratory failure failed to respond to prolonged mask ventilation
      and were intubated (failure group). Of the 13 patients who failed NIPSV, nine
      died after switching to invasive ventilation after a mean time of 10 +/- 3 days.
      No deaths occurred during NIPSV. A mean pressure support ventilation (PSV) of
      11.7 +/- 4.2 cmH2O and positive end-expiratory pressure (PEEP) of 4.5 +/- 2.7
      cmH2O were required to significantly increase arterial oxygen tension
      (Pa,O2)/inspiratory oxygen fraction (Fi,O2) from 152.4 +/- 41.7 (spontaneous
      breathing) to 277.9 +/- 108.7 (NIPSV) (p < 0.01) within the first hour. The
      expiratory tidal volume (VT) increased from 356.1 +/- 103.7 (spontaneous
      breathing) to 648.1 +/- 77.1 mL (NIPSV) (p < 0.01) with a concomitant reduction
      in the respiratory frequency (fR) from 31.4 +/- 5.2 (spontaneous breathing) to
      20.4 +/- 4.3 (NIPSV) without significant differences between the success and
      failure group. In the 22 patients who were hypercapnic at the point of entering
      the study, the arterial carbon dioxide tension (Pa,CO2) decreased from 73.0 +/-
      1.0 kPa (52.5 +/- 7.8 mmHg) (spontaneous breathing) to 5.5 +/- 1.0 kPa (41.5 +/-
      7.5 mmHg) (NIPSV) (p < 0.01) and pH increased from 7.29 +/- 0.05 to 7.33 +/- 0.04
      (p < 0.05). The median length of time of use of NIPSV was 55.5 h (range 6-144).
      In conclusion, noninvasive pressure support ventilation might effectively be used
      in a selected group of trauma patients as a means of treating respiratory
      failure.

PMID- 10394823
TI  - Bronchoalveolar lavage and transbronchial lung biopsy in alveolar and/or ground
      glass opacification.
AB  - In order to assess the diagnostic yield of bronchoalveolar lavage (BAL) and
      transbronchial lung biopsy (TBB) in pulmonary diseases with a ground-glass and/or
      alveolar pattern on high-resolution computed tomography (HRCT) scan, a
      prospective study was undertaken. Thirty-six patients (17 males, 19 females),
      mean age 53 yrs, selected on the basis of the presence of an alveolar and/or
      ground-glass pattern on chest HRCT scan, were submitted to fibreoptic
      bronchoscopy. All patients underwent BAL. TBBs were performed in 33 cases. A
      specific diagnosis was achieved, taking into account data obtained by means of
      serology, microbiology, cytology and histopathology in appropriate clinical
      settings. Twelve (33%) patients only had the appearance of a ground-glass
      opacity, whereas 24 (67%) had associated areas of airspace consolidation. BAL was
      performed in all cases and gave a definitive diagnosis in 21 (58%). The
      diagnostic yield of BAL in patients with only ground-glass opacities was no
      different from that in those patients also showing areas of alveolar
      consolidation (58 versus 58%). In eight patients (six with ground-glass opacity
      and two with alveolar consolidation), BAL provided useful but not definitive
      information. In these patients, a definitive diagnosis was achieved by means of
      TBB in seven cases and by open lung biopsy in one case. TBB was performed in 33
      out of 36 patients and gave positive results in 25 (76%). The diagnostic yield of
      TBB in patients showing areas of alveolar consolidation was significantly higher
      than in those with pure ground-glass opacity, i.e. 95% (21 of 22) and 36% (4 of
      11) respectively (p < 0.001). BAL and TBB were performed during the same
      bronchoscopy in 33 patients, and an accurate diagnosis was achieved in 30 (91%).
      Overall, the diagnostic yield of TBB (76%) and BAL (56%) did not differ
      significantly in the whole patient group (p = 0.12), or in patients with a ground
      glass opacification (58 versus 36%, p = 0.3). However, in patients with areas of
      alveolar consolidation, the diagnostic sensitivity of TBB (95%) was significantly
      greater than the diagnostic sensitivity of BAL (54%) (p = 0.03). In conclusion
      this study shows that high-resolution computed tomography can be helpful in
      predicting the diagnostic accuracy of bronchological procedures, in particular of
      bronchoalveolar lavage and transbronchial biopsy, and that alveolar and/or ground
      glass are favourable patterns for these diagnostic tools.

PMID- 10394824
TI  - The effect of hyperoxaemia on erythropoietin secretion in anaemic patients.
AB  - Erythropoietin (EPO) controls red cell production. Hypoxaemia, reduced blood
      oxygen-carrying capacity and increased affinity of haemoglobin (Hb) for oxygen
      are the primary stimuli for EPO secretion. The effect of hyperoxaemia (arterial
      oxygen tension (Pa,O2) > 13.3 kPa) on EPO secretion has not been thoroughly
      studied and is not fully understood. The primary purpose of this study was to
      evaluate EPO production in patients with acute respiratory failure as well as to
      determine the effect of hyperoxaemia on EPO secretion in patients with and
      without anaemia. A prospective clinical study was carried out in a 14-bed general
      (medical and surgical) intensive care unit in a university hospital. Twenty-one
      patients with acute or acute on chronic respiratory failure, requiring mechanical
      ventilation, were included in this study. The patients were divided into two
      groups; group I comprised patients who developed anaemia, and group II patients
      who did not. EPO levels and haematological parameters were measured in venous
      blood under three oxygenation conditions: hypoxaemia, hyperoxaemia and
      normoxaemia. All patients exhibited high EPO levels during hypoxaemia (mean value
      108.7 +/- 27 mU.mL-1 (+/- SD)). During hyperoxaemia, EPO levels decreased in both
      groups (mean value 21.6 +/- 15.2 mU.mL-1 in group I, 36.8 +/- 19 mU.mL-1 in group
      II). During normoxaemia, EPO levels increased again in group I patients, but in
      group II patients EPO production remained stable. In conclusion, hyperoxaemia
      inhibits erythropoietin secretion in spite of anaemia and low arterial oxygen
      tension. Hyperoxaemia may be a contributing factor to anaemia in intensive care
      unit patients under oxygen therapy.

PMID- 10394827
TI  - Disseminated tuberculosis with gradual evolution and unusual localization.
AB  - We present a case of disseminated tuberculosis (pulmonary, skeletal and lymph
      nodes) accompanied by subcutaneous abscesses and with unusual localization,
      osteolytic lesions of the skull caused by Mycobacterium tuberculosis var.
      hominis. Although the patient was immunocompetent, the disease had a gradual and
      unexpected progression. In the malign forms of tuberculosis, treatment must be
      extended for a year or more.

PMID- 10394826
TI  - Successful treatment of spleen tuberculosis in a patient with human
      immunodeficiency virus infection.
AB  - Tuberculosis in human immunodeficiency virus (HIV)-infected patients may act as a
      cofactor that accelerates the clinical course of HIV infection, and, indeed, HIV
      infected patients with tuberculosis have a reduced survival rate compared to
      those without tuberculosis. Diagnosis of tuberculosis in HIV-positive patients
      can be difficult because of nonspecific symptoms and the time required for the
      identification of mycobacteria by means of culture techniques. Recently,
      antiretroviral combination therapies have improved the outcome of several
      acquired immune deficiency syndrome (AIDS)-associated conditions. Unfortunately,
      the use of antiretroviral therapy for patients coinfected with HIV and
      Mycobacterium tuberculosis is still to be fully evaluated. The complexity of side
      effects due to antituberculosis medication and drug interaction represent
      important issues and combining an effective anti-HIV treatment with
      antituberculosis therapy is still a clinical challenge. We discuss here a case of
      spleen tuberculosis in a human immunodeficiency virus-positive patient who had a
      successful response after a diagnostic splenectomy and medical treatment that
      included classical antituberculosis treatment associated with antiretroviral
      therapy without protease inhibitors.

PMID- 10394825
TI  - Report of eight cases of pulmonary actinomycosis and their treatment with
      imipenem-cilastatin.
AB  - Studies on the efficacy of antimicrobial agents against actinomycosis in vivo
      have been limited apart from those involving penicillin. A prospective ministudy
      on the efficacy of imipenem-cilastatin in the treatment of pulmonary
      actinomycosis was performed based on preliminary encouraging in vitro and in vivo
      data. Eight patients were diagnosed as having pulmonary actinomycosis using
      fibreoptic bronchoscopy (7) and percutaneous transthoracic needle biopsy (1) in
      the authors' unit between 1994 and 1996. Each patient received a 4-week course of
      imipenem-cilastatin that comprised 2 weeks of intravenously administered drug
      (500 mg at 8-hourly intervals) and 2 weeks of intramuscularly administered drug
      (500 mg at 12-hourly intervals). Seven patients showed a very good clinical and
      radiographic response as well as bronchoscopically-documented treatment success.
      Treatment failed in one patient. Amongst the former group, one patient was lost
      to follow-up, another relapsed 3 months after treatment cessation and the rest
      remained relapse-free when followed-up for 18-44 months (mean 30.2 months).
      Furthermore, all patients showed good clinical tolerance and no abnormal
      treatment-related laboratory findings. The favourable outcome for most patients
      in this mini-study suggest that a 4-week parenteral course of imipenem-cilastatin
      is an efficacious treatment for pulmonary actinomycosis. This antimicrobial
      regimen might be a promising alternative to the time-honoured long-course
      treatment with intravenous and oral penicillin.

PMID- 10394828
TI  - Asthma controller therapy: role of antileukotrienes, a new therapeutic class.
AB  - Asthma is a chronic disease and should be treated with both controller and
      reliever drugs. Asthma controller therapy is not used sufficiently widely,
      probably due to low compliance with inhaled drugs, lack of response in some
      patients to low-medium doses of inhaled steroids and possible adverse events.
      This review analyses a new class of antiasthmatic drugs, leukotriene receptor
      antagonists (antileukotrienes). At present, two antileukotrienes are available in
      Italy: zafirlukast and montelukast. Antileukotrienes improve symptoms and also
      inhibit the effects of some of the inflammatory mediators involved in the
      pathogenesis of asthma; therefore, antileukotrienes may be used in monotherapy.
      In addition, the oral administration route is an advantage for compliance.
      Antileukotrienes significantly improve pulmonary function, asthma symptoms and
      inhaled and oral steroid and short-acting beta 2-agonist use. Moreover,
      antileukotrienes produce a 50% mean reduction in the incidence of asthma
      exacerbations compared with placebo. From the economic point of view, asthma
      controller therapy using antileukotrienes is associated with a > 50% (compared
      with placebo) reduction in healthcare costs (hospitalization due to asthma
      exacerbation, healthcare contact and absenteeism from work or school), which
      globally account for 93% of asthma-related costs. Antileukotrienes are indicated
      in the treatment of persistent mild-to-severe asthma, seasonal allergic asthma,
      exercise-induced asthma and aspirin-induced asthma. Antileukotrienes are well
      tolerated independently of the duration of treatment and the incidence of the
      observed adverse events is substantially similar to that observed using placebo.
      Owing to good tolerability and compliance and the economic advantages, these
      agents may be considered a valid therapeutic option for the control and
      management of asthma as a chronic disease.

PMID- 10394829
TI  - Pulmonary hypertension in acute respiratory distress syndrome.
AB  - A mild degree of pulmonary hypertension is commonly observed in patients with
      acute respiratory distress syndrome (ARDS). Vasoconstriction plays a dominant
      role in increasing the mean closing pressure of the pulmonary vascular bed.
      Pulmonary hypertension increases right ventricular afterload, but right
      ventricular failure rarely occurs in patients with ARDS. Although the initial
      magnitude of pulmonary hypertension is not an indicator of mortality, pulmonary
      artery pressure increases in nonsurvivors but not in survivors when followed for
      7 days. Pulmonary vascular tone is closely related to gas exchange, and the
      increase in pulmonary artery pressure is a protective mechanism to minimize
      ventilation-perfusion mismatching in ARDS. Consequently, generalized pulmonary
      vasodilation by intravenous vasodilators aggravates arterial hypoxaemia.
      Conversely, selective administration of vasodilators, such as inhaled nitric
      oxide, in well-ventilated lung units improves gas exchange by diverting pulmonary
      blood flow to better oxygenated regions. However, preliminary results from large
      prospective randomized controlled trials indicate that inhaled nitric oxide does
      not reduce mortality nor the duration of mechanical ventilation in patients with
      ARDS.

PMID- 10394830
TI  - Respiratory muscles in heart failure.
AB  - This paper reviews respiratory muscle performance in patients suffering from
      congestive heart failure. Respiratory muscle dysfunction is well documented in
      these patients, and is thoroughly discussed. The mechanisms underlying its
      development and the potential consequences are also presented.

PMID- 10394831
TI  - Respiratory muscle function in endocrine diseases.
AB  - This review reports evidence showing that the function of the respiratory muscles
      (RMs) is affected in endocrinopathies and emphasizes that clinicians should look
      for RM weakness in hormone inbalances. Although there is a potential
      pathophysiological mechanism for affecting RM in diabetes insipidus,
      hypoparathyroidism, Cushing's disease, pheochromocytoma, adrenalin deficiency or
      androgen disorder, no study was found in the available literature. Therefore,
      investigations are urgently needed in these diseases. Controversial results have
      been reported in acromegaly, hypopituitarism, diabetes mellitus and steroid
      induced (iatrogenic) RM myopathy. Obviously, these are areas for further
      research. Respiratory muscle dysfunction has been well documented in thyroid
      disease and there is general agreement that both hypo- and hyperthyroidism are
      associated with reversible respiratory muscle weakness.

PMID- 10394832
TI  - Mortality in and prevalence of chronic obstructive pulmonary disease in different
      parts of Europe.
AB  - A prerequisite for acquiring data on death and illness in chronic obstructive
      pulmonary disease is the application of agreed operational definitions. The
      International Union against Tuberculosis and Lung Diseases recommended that
      International Classification of Diseases 490-496 be grouped together for
      mortality statistics. A task force of the European Respiratory Society have given
      operative criteria for chronic obstructive pulmonary disease which depend very
      much on spirometric reference values collected 25 years ago. The mortality rates
      in chronic obstructive disease vary more than 5-fold among the European
      countries. Deaths due to chronic obstructive pulmonary disease as a proportion of
      all deaths increase greatly with age and are considerably lower in females than
      in males. Community surveys in countries of both northern and southern Europe
      indicate that 4-6% of the adult population suffer from clinically relevant
      chronic obstructive pulmonary disease. The prevalence increases greatly with age;
      however two-thirds have only a mild reduction in lung function.

PMID- 10394833
TI  - Overviews of respiratory rehabilitation in chronic obstructive pulmonary disease.
AB  - The purpose of this study was to critically appraise overviews of respiratory
      rehabilitation in chronic obstructive pulmonary disease (COPD) in order to verify
      to what extent they convey evidence-based information helpful in implementing new
      rehabilitation programmes. A Medline search (1985-September 1995) for overviews
      related to rehabilitation, exercise therapy, education and/or psychological
      support in COPD was conducted. Chapters of major textbooks of respiratory
      medicine were also included. The search was limited to the English literature.
      Two independent reviewers assessed the overviews according to a validated index
      of scientific quality of research overviews using the following criteria: 1) the
      literature search method; 2) the inclusion criteria for original articles in the
      overview; 3) the validity assessment of the original articles; 4) the synthesis
      of findings; and (5) the conclusion of the overview. Thirty-eight overviews were
      included. Overall, the methodological quality of the overviews was low (quality
      score: median 2/7; range 1-5). In only one overview did the author state that the
      work was based on the results of a literature search. The methodological quality
      of the primary studies included in the overviews was not included in any of the
      reviews. The conclusions were only partially supported by the results extracted
      from the cited primary studies. The widespread application of respiratory
      rehabilitation in chronic obstructive pulmonary disease should be preceded by
      demonstrable improvements in function attributable to the intervention. Evidence
      based overviews of the literature could assist in implementing new rehabilitation
      programmes.

PMID- 10394834
TI  - The effects of poverty and ageing on the increase in tuberculosis.
AB  - Among the causes of the current increase in tuberculosis worldwide are poverty
      and ageing. It has been widely accepted that tuberculosis and poverty have been
      closely linked since the scientific study of the disease began. The decline of
      tuberculosis in developed countries before the arrival of specific chemotherapy
      was largely attributed to improvement in social conditions. With the rapidly
      increasing world population and the wider disparity of income, more and more
      people are falling into poverty, whichever way it is defined. Studies in the
      developed world show that the close association between tuberculosis and poverty
      remains. Some workers in the field even suggest that tuberculosis cannot be
      controlled until the issue of global poverty has been addressed. This may be too
      pessimistic. It may be possible to define accurately which aspects of poverty are
      most closely associated with tuberculosis and to deal with those specifically.
      Within developed countries longevity is increasing. The population now in their
      seventies, or older, even in developed countries, will have been alive when the
      disease was highly prevalent in the communities in which they lived. The majority
      will, therefore, have acquired infection, and in a substantial minority of these
      infection may reactivate to cause disease as the ageing process weakens host
      immunity. In the indigenous Caucasian population of Western Europe, rates of
      disease are highest in elderly males. Previous research showed that beyond the
      age of forty, the incidence of disease declined with increasing age. The higher
      rates in the elderly were a result of the residue of higher rates from birth
      cohorts born earlier. Data presented in this article suggest that this pattern
      may be altering such that the incidence of disease actually increases after a
      certain age is reached. This could have important repercussions for disease
      incidence in the emerging economies of the Pacific Rim, where longevity is
      increasing most rapidly.

PMID- 10394835
TI  - Protein kinase C--a potential modifier of carotid body function.
AB  - This article deals with the potential role of protein kinase C (PKC) in signal
      transduction in the carotid body. The carotid body is a chemosensory organ which,
      by sensing reductions in arterial blood oxygen tension, is primarily responsible
      for the hyperventilation of hypoxia. The mechanisms of transduction of the
      hypoxic stimulus into a neural signal regulating respiration are not clear.
      Hypoxia increases the phosphoinositide-specific phospholipase C (PLC) activity in
      the carotid body. The PLC-derived signalling molecules are known to activate PKC.
      The enzyme might, thus, have the potential to interact with the process of
      chemoreception. This article demonstrates that PKC is present in the
      chemoreceptor cells of the cat carotid body and discusses the biology of the
      enzyme relevant to chemosensory function. This gives rise to the hypothesis that
      PKC-mediated mechanisms alter chemoreceptor cell function to a sufficient extent
      to metamorphose the hypoxic signal into an increased discharge frequency in the
      apposed sinus nerve endings.

PMID- 10394836
TI  - Indications for long-term oxygen therapy: a reappraisal.
AB  - Domiciliary long-term oxygen therapy (LTOT) is a routine modality of treatment in
      advanced chronic obstructive pulmonary disease (COPD). More than 1 million
      patients worldwide receive LTOT. The patients who are eligible for LTOT are those
      who, in the steady state, present with severe hypoxaemia (arterial oxygen tension
      (Pa,O2 < or = 7.3 kPa (55 mmHg). Patients with a Pa,O2 of 7.4-7.8 kPa (56-59
      mmHg) are also eligible if such hypoxaemia is accompanied by an elevated
      haematocrit and clinical signs of cor pulmonale. LTOT was found to prolong life
      expectancy, improve sleep, cognitive functions and emotional status and prevent
      the progression of hypoxic pulmonary hypertension. It seems that such effects
      apply to patients with severe hypoxaemia. Recent studies have demonstrated that,
      in patients with moderate hypoxaemia, Pa,O2 > 7.3 kPa (55 mmHg), LTOT does not
      prolong life. The effects of LTOT on quality of life in that group of patients
      remain to be elucidated. Some chronic obstructive pulmonary disease patients with
      a satisfactory arterial oxygen tension at rest and awake desaturate during sleep
      and receive nocturnal oxygen supplementation. The patients who qualify for oxygen
      treatment during sleep are those in whom arterial oxygen saturation during sleep
      falls below 90% for > or = 2 h. The long-term physiological effects of oxygen
      administered only during sleep are controversial. Some data suggest that oxygen
      supplementation in patients desaturating during sleep prevents the progression of
      hypoxic pulmonary hypertension and prolongs life. Other studies do not confirm
      those findings.

PMID- 10394837
TI  - Measures of functional status and quality of life in chronic obstructive
      pulmonary disease.
AB  - A variety of studies exist as to methods of assessing quality of life in chronic
      obstructive pulmonary disease. Neither the American Thoracic Society nor the
      European Consensus Statement for COPD recommend any specific quality-of-life or
      functional assessment measure as a gold standard. The present study identifies
      measures of COPD quality of life and functional status reported in selected
      literature in 1994-1997. A total of 37 measures were identified; of these eight
      were measures of general health, 10 were COPD/disease-specific questionnaires,
      and 19 were functional status indices. These measures provide valuable data, and
      further study is necessary to determine which measures should be integrated into
      standards of care.

PMID- 10394838
TI  - General practice spirometry in North Staffordshire.
AB  - Spirometry is suggested, in North American and European guidelines, to be the
      most important measurement of lung function for the management of patients with
      chronic obstructive pulmonary disease (COPD). The aim of this study was to
      determine attitudes to and utilization of spirometry in general practices within
      North Staffordshire. All 95 practices in North Staffordshire were surveyed by
      telephone, using a standard proforma. Eighty-four practices (48 fundholding)
      containing 224 general practitioners (GPs) and serving 472,420 patients, agreed
      to take part. The survey was completed by practice nurses on 63 occasions, GPs on
      14 and practice managers on seven. Eighteen practices possessed a spirometer,
      although eight did not use it. The measurements were performed by doctors in five
      of the practices, nurses in two and by both in three. Only two users had received
      formal training in the performance and interpretation of spirometry. Of the three
      practices using pneumotachograph spirometers, none knew how often the machine
      should be calibrated. Spirometry was used by five practices for diagnosis
      (although only four used it to determine forced expiratory volume in one second
      (FEV1)), three for monitoring and only one for bronchodilator reversibility
      testing. Although 44 (52%) practices thought that, ideally, spirometry should be
      available in the practice, only 10 of the 18 who had spirometers were currently
      providing this facility. Furthermore, the poor training puts into question the
      validity of some of the results obtained. Open access to hospital spirometry is
      one method of addressing these problems, and 73 (87%) practices, including 16 who
      already owned a spirometer, said that they would use such a service.

PMID- 10394839
TI  - Long-term benefits of short-stay inpatient pulmonary rehabilitation in severe
      chronic obstructive pulmonary disease.
AB  - The beneficial effects of pulmonary rehabilitation programmes on the overall
      quality of life in patients with chronic obstructive pulmonary disease (COPD) has
      been well documented. However, there has been a paucity of studies demonstrating
      the long-term benefits of short-stay inpatient pulmonary rehabilitation (SSIPR)
      programmes in patients with severe COPD (forced expiratory volume in one second
      (FEV1) < 40% of predicted). The authors have previously reported that their
      multidisciplinary SSIPR programme improved outcome measurements immediately post
      rehabilitation in 38 patients with severe COPD. The purpose of this study was to
      evaluate the long-term (1-yr follow-up) benefits of SSIPR in these patients. The
      outcome measurements used were: timed 12-min walking distance, Borg dyspnoea
      scale, annual days of acute care hospitalization, and Pulmonary Functional Status
      Scale. All outcome measurements were significantly improved at 1 yr post-SSIPR as
      compared to pre-SSIPR values. The 12-min walking distance was significantly
      improved in patients 1 yr post-SSIPR (251 m) as compared to either pre-SSIPR (133
      m, p < 0.0001) or immediately post-SSIPR (224 m, p < 0.01). The number of annual
      days of acute care hospitalization was reduced from 15.4 pre-SSIPR to 3.8 (p <
      0.0001) 1 yr post-SSIPR. The Borg dyspnoea scale measurement showed improvement,
      both at rest and after 12 min walking at 1 yr post-SSIPR. Also, the Pulmonary
      Functional Status Scale analysis showed significant (p < 0.001) sustained
      improvement at 1 yr post-SSIPR as compared to pre-SSIPR. In conclusion, it has
      been demonstrated that long-term sustained outcome benefits can be achieved from
      a comprehensive short-stay inpatient pulmonary rehabilitation programme for
      patients with severe chronic obstructive pulmonary disease.

PMID- 10394840
TI  - Effects of long-term oxygen therapy on quality of life and survival in chronic
      airflow limitation.
AB  - Chronic airflow limitation (CAL) is a major contributor to the burden of ill
      health in Australia and, where hypoxia is present, can be treated with home
      oxygen therapy (HOT). At Flinders Medical Centre, a prospective longitudinal
      study was undertaken to examine the impact of HOT on the health-related quality
      of life (HRQoL) of subjects with CAL. All eligible adult patients, aged < 80 yrs,
      with a primary diagnosis of CAL who met the prescription guidelines of the
      Thoracic Society of Australia and New Zealand were offered HOT and invited to
      participate. After baseline assessment, subjects were followed-up 3, 6 and 12
      months after commencement of HOT. Physiological assessment and three validated
      HRQoL measures were applied, the Nottingham Health Profile (NHP), the Chronic
      Respiratory Questionnaire (CRQ) and, for a subset of the patients, the Medical
      Outcomes Study short-form 36-item questionnaire (SF-36). This study reports the
      results from January 1, 1991 to July 31, 1997. One hundred and fourteen CAL
      patients were included in the study. Female subjects experienced significant
      improvements from baseline in the energy, emotional reactions, sleep and physical
      mobility areas of the NHP, in the fatigue, emotional function and mastery
      dimensions of the CRQ and in the role-physical, vitality, role-emotional, and
      mental health dimensions of the SF-36. Males experienced significant improvements
      in the emotional reactions, sleep and social isolation areas of the NHP, in the
      fatigue dimension of the CRQ and in the vitality dimension of the SF-36. Some of
      the improvements in the various domains persisted for > 6 months. Female patients
      prescribed home oxygen therapy appear to have a greater overall improvement in
      health-related quality of life and survival than males. Follow-up is continuing.

PMID- 10394841
TI  - Administration of fluconazole in children below 1 year of age.
AB  - For this review, 78 studies regarding the use of fluconazole in a total of 726
      children below 1 year of age were evaluated. The range of fluconazole dosage was
      2-50 mg kg-1 day-1, with 162 days being the maximum duration of treatment.
      According to current experience, fluconazole seems to be well tolerated and
      efficacious against systemic candidosis and candidaemia in children below 1 year
      of age, including neonates and very low-birthweight infants (VLBWIs). The
      recommended daily dosage is 6 mg kg-1. (In Germany, fluconazole is approved for
      children between 1 and 16 years in cases in which there is no therapeutic
      alternative for treatment of systemic infections caused by Candida spp. and
      Cryptococcus neoformans in a dosage of 3-6 mg kg-1 day-1 and for superficial
      Candida infections in a dosage of 1-2 mg kg-1 day-1.) In patients with impaired
      renal function, the daily dose should be reduced in accordance with the
      guidelines given for adults. In neonates during the first 2 weeks of life, this
      dosage should be administered only every 72 h. In weeks 2-4 of life, the same
      dose should be given every 48 h, following which daily dosing is appropriate.
      This posology is derived from the age-related pharmacokinetics of fluconazole,
      with a higher volume of distribution and a prolonged plasma elimination half
      life, especially during the first month of life. Drug monitoring during treatment
      should be performed to ensure therapeutic plasma concentrations of fluconazole
      within a range between 4 and 20 micrograms ml-1. The benefit of fluconazole
      should be investigated in prospective studies for treatment of systemic
      candidosis with administration of higher dosages as well as for early empiric
      therapy in VLBWIs.

PMID- 10394842
TI  - Dosage adjustment of fluconazole during continuous renal replacement therapy
      (CAVH, CVVH, CAVHD, CVVHD).
AB  - Continuous arterio-venous haemofiltration (CAVH), continuous veno-venous
      haemofiltration (CVVH), continuous arterio-venous haemodialysis (CAVHD) and
      continuous veno-venous haemodialysis (CVVHD) are increasingly used in patients
      with acute renal failure (ARF). The elimination rate of fluconazole varies
      considerably depending on the procedure used. (In Germany, fluconazole is
      approved for the treatment of life-threatening fungal infections caused by
      Candida spp. and Cryptococcus neoformans at a dosage of up to 800 mg day-1.) The
      elimination rate of fluconazole by CVVHD depends on the combined
      dialysate/ultrafiltrate flow rate, but is much higher than achieved with CVVH and
      intermittent dialysis, with a fluconazole clearance in patients with CVVHD 2 l h
      1 exceeding the values of healthy persons. To achieve therapeutic plasma levels
      during continuous renal replacement therapy, the same loading dose as in patients
      without renal failure should be administered, followed by a maintenance dose that
      is adjusted for anuric patients by multiplying by a factor that takes into
      account the extracorporeal elimination of the absorbed dose (CAVH, CVVH x 2.2,
      ultrafiltrate flow 0.5 l h-1; CAVHD, CVVHD x 3.8, combined
      dialysate/ultrafiltrate flow 1.5 l h-1). Despite the broad therapeutic margin of
      fluconazole, drug monitoring is recommended to achieve therapeutic drug levels in
      life-threatening indications because there have been only a few investigations of
      this, all involving relatively low dosages (up to 200 mg day-1).

PMID- 10394843
TI  - Pathogenesis and treatment of hyperkeratotic tinea pedis in Japan.
AB  - In this paper, we describe the major characteristics of hyperkeratotic tinea
      pedis and review therapeutic results obtained in the Department of Dermatology of
      Kitasato University Hospital and those reported in the literature in Japan and
      abroad.

PMID- 10394845
TI  - Lack of sialidase activity in Candida albicans and Candida glabrata.
AB  - Because several micro-organisms having close contact to animal hosts and man
      produce sialidase (EC 3.2.1.18) as a tool for adhesion and invasion, we
      investigated two Candida species for the presence of this enzyme. Two sensitive
      assays, a fluorometric test with 4-methylumbelliferyl-alpha-D-N-acetylneuraminic
      acid and a radiometric test with 3H-labelled sialyllactitol as sialidase
      substrates, were applied to detect sialidase activity. None of 40 Candida
      albicans and 10 C. glabrata strains grown in three different media exhibited
      sialidase activity, but the positive control Ophiostoma stenoceras produced
      sialidase under comparable conditions. Our surprising negative findings are
      divergent from an earlier positive report, which may be due to strain selection
      or bacterial contamination. These results indicate that sialidase is probably of
      no relevance in cutaneous or mucosal candidoses.

PMID- 10394844
TI  - Identification of CARE-2-negative Candida albicans isolates as Candida
      dubliniensis.
AB  - Among 302 clinical yeast isolates originally identified as Candida albicans, we
      found 16 isolates that did not hybridize with the C. albicans-specific repetitive
      DNA element CARE-2. These 16 isolates produced abundant chlamydospores, did not
      grow at 43 degrees C, and exhibited a distinct randomly amplified polymorphic DNA
      profile. Sequence analysis of part of the 28S rDNA demonstrated that the CARE-2
      negative isolates are not an atypical subgroup of C. albicans but belong to the
      recently described new species C. dubliniensis.

PMID- 10394846
TI  - Effects of modified pellicles on Candida biofilm formation on acrylic surfaces.
AB  - The role of saliva or serum proteins, such as mucin, fibronectin (FN) and mannan
      binding protein, on Candida biofilm formation was investigated. Supplementation
      of saliva with FN had no significant effect on biofilm formation. In contrast,
      biofilm formation on either mucin-coated or FN-coated acrylic surfaces was
      significantly less than that of the control. These results suggest that salivary
      mucin or FN alone does not facilitate biofilm formation of Candida.
      Supplementation of serum with FN increased biofilm formation of C. glabrata
      compared with the control. Pretreatment of serum with anti-FN monoclonal antibody
      significantly reduced biofilm formation, as did pretreatment of serum with anti
      mannan-binding protein monoclonal antibody or Con-A. Therefore, Candida biofilm
      formation on acrylic surfaces appears to be a complex phenomenon involving a
      multiplicity of proteins operating intraorally.

PMID- 10394847
TI  - Oropharyngeal candidosis in AIDS patients: an epidemiological study using
      restriction analysis of Candida albicans total genomic DNA.
AB  - This study investigates the epidemiology of Candida albicans strains isolated
      from oral and rectal swabs obtained before and after treatment with antifungal
      drugs in hospitalized AIDS patients. Twenty-one health care workers from the
      hospital unit were also studied. Samples were obtained from the oral cavity and
      hands. The molecular fingerprinting restriction endonuclease-digested genomic DNA
      technique was used. A total of 94 C. albicans strains were isolated: 76 from
      patients and 18 from the health care workers. Each sample was digested
      independently with EcoRI and HinfI restriction enzymes, electrophoresed on 0.8%
      agarose gels and stained with ethidium bromide. The strains were sorted into
      groups according to patterns. Analysis of the different restriction patterns
      suggests that most of the infective strains had an endogenous source, whereas the
      recurrences of candidosis, after antifungal therapy, could be considered as
      persistence or reinfection by a different strain. Our data show that horizontal
      transmission by strains carried by health care workers does not play an important
      role in the overall epidemiology of candidosis.

PMID- 10394848
TI  - Systemic mycoses during prophylactical use of liposomal amphotericin B (Ambisome)
      after liver transplantation.
AB  - We investigated the prophylactical administration of liposomal amphotericin B
      (Ambisome) in the early phase after liver transplantation (LTx). Fifty-eight
      patients received Ambisome prophylactically after LTx. Ambisome (1 mg kg-1 day-1)
      was given intravenously for 7 days after LTx. Immunosuppressive prophylaxis was
      cyclosporin A (CsA) based in 11 patients. Forty-seven patients had a tacrolimus
      based immunosuppressive regimen. CsA and tacrolimus dosages were adjusted to
      trough levels of 150-250 ng ml-1 (EMIT) and 5-15 ng ml-1 (MEIA II) respectively.
      Three patients died from sepsis due to Aspergillus fumigatus infection. Reasons
      for a fatal outcome were foudroyant Aspergillus pneumonia in a patient
      transplanted for fulminant hepatic failure on post-operative day (pod) 8;
      Aspergillus sepsis with severe endocardidtis in a patient with two
      retransplantations for graft non/dysfunction on pod 24; and disseminated
      aspergillosis due to Aspergillus fumigatus in a patient retransplanted for
      primary non-function (pod 19). All three patients underwent haemofiltration for
      renal failure. One patient with Candida albicans sepsis (pod 4) recovered under
      increased dosage of Ambisome (3 mg kg-1 per day). Ambisome (1 mg kg-1 per day)
      seems to be beneficial against systemic Candida infections. However, the onset of
      systemic Aspergillus infections could not be prevented. Obviously, higher
      Ambisome doses appear to be necessary against Aspergillus. We recommend the use
      of Ambisome (3 mg kg-1 per day) for patients with risk factors such as graft dys
      /non-function, retransplantation, haemofiltration and complicated acute liver
      failure to prevent invasive aspergillosis.

PMID- 10394849
TI  - In vitro activity of rilopirox against fluconazole-susceptible and fluconazole
      resistant Candida isolates from patients with HIV infection.
AB  - The in vitro antifungal activity of the new hydroxypyridone antimycotic rilopirox
      has been evaluated against 38 fluconazole-susceptible and -resistant clinical
      isolates of Candida albicans together with other Candida species isolated from
      patients with human immunodeficiency virus (HIV) infection and oropharyngeal
      candidosis. Minimum inhibitory concentrations (MICs) of both rilopirox and
      fluconazole were measured by a microdilution method using high-resolution medium
      supplemented with asparagine and glucose at pH 7.0. In comparison, an agar
      dilution technique was carried out for susceptibility testing of the antifungal
      agents. Rilopirox was found to be able to inhibit growth of all clinical yeast
      isolates. The rilopirox MICs at which 50% and 90% of strains were inhibited
      (MIC50 and MIC90 respectively), as determined by the microdilution method, were 4
      and 8 micrograms ml-1 respectively. The highest MIC values for rilopirox using
      microdilution and the agar dilution method were 32 or 25 micrograms ml-1
      respectively. On the other hand, for fluconazole, the MIC50 and MIC90 achieved
      were 0.5 and 128 micrograms ml-1, respectively, which means that the MIC90 value
      of fluconazole was 16-fold higher than that of rilopirox. Using the agar dilution
      technique, the MIC values of rilopirox were in the range 0.006-25 micrograms ml-1
      with a median of 3.12 micrograms ml-1. For fluconazole, the MIC90 value was four
      fold higher than that for rilopirox, indicating a considerable proportion of
      yeast strains with high MICs of 100 micrograms ml-1, suggesting in vitro
      resistance to this azole antifungal. All strains with diminished fluconazole
      susceptibility were susceptible to rilopirox. Even Candida krusei and Candida
      glabrata exhibited good in vitro susceptibility to rilopirox. Therefore, this new
      antifungal agent may be used as an alternative not only in the treatment of
      vaginal candidosis, but also in oropharyngeal Candida infections, e.g. in AIDS
      patients.

PMID- 10394850
TI  - Evaluation of CHROMagar Candida for rapid screening of clinical specimens for
      Candida species.
AB  - CHROMagar Candida is a new differential culture medium that allows selective
      isolation of yeasts and simultaneously identifies colonies of Candida albicans,
      Candida glabrata, Candida tropicalis and Candida krusei. We evaluated this medium
      and compared it with a reference medium, Sabouraud glucose agar, for the
      presumptive identification of yeast species isolated directly on the medium from
      1150 clinical specimens. A total of 731 specimens showed no growth, 299 isolates
      (70.2%) showed growth to the same extent on both media. Forty mixed cultures were
      detected on both media. More than one isolate was detected in 30 of the tested
      specimens on either CHROMagar (26 specimens) or Sabouraud glucose agar (four
      specimens). We found a sensitivity of 98.8% and a specificity of 100% for C.
      albicans, 66.7% and 99.8% for C. tropicalis, 100% and 100% for C. krusei, and 98%
      and 95.7% for C. glabrata. Regarding these results, CHROMagar Candida is
      recommended as a useful isolation medium capable of the presumptive
      identification of yeasts and better detection of mixed cultures in clinical
      specimens.

PMID- 10394851
TI  - Molecular differentiation of dermatophyte fungi.
AB  - Our previous studies of the ribosomal DNA variation in dermatophytes have shown
      that these fungi are monophyletic in origin. However, this approach did not allow
      us to differentiate all the species defined by classical means. Therefore, we
      studied the internal transcribed spacer 1 (ITS 1) region of 17 species of the
      fungal order Onygenales, comprising the pathogenic keratinophilic fungi.
      Interspecific nucleotide composition and sequence length variation of the ITS 1
      region was high, mean identities were as low as 40% and sequence lengths varied
      from 169 to 293 basepairs. Each established dermatophyte species could be
      identified. In contrast, the flanking sequences at the 3' end of 18S and the 5.8S
      rDNA were conserved. Although the value of the ITS 1 region as a phylogenetic
      tool may be limited because of its high variability, it provides the information
      necessary to design species-specific probes, or polymerase chain reaction
      restriction fragment polymorphism systems useful for taxonomic or rapid
      diagnostic tests.

PMID- 10394852
TI  - Species-specific primers of chitin synthase 1 gene for the differentiation of the
      Trichophyton mentagrophytes complex.
AB  - Species-specific primers were designed from nucleotide sequences of the chitin
      synthase 1 gene (CHS1) of Arthroderma benhamiae, A. simii and A. vanbreuseghemii.
      The A. benhamiae-specific primer amplified a 560-bp fragment from A. benhamiae
      but not from A. simii and A. vanbreuseghemii. The A. simii-specific primers
      amplified a 470-bp fragment from A. simii but not from A. benhamiae and A.
      vanbreuseghemii. The A. vanbreuseghemii-specific primers amplified a 360-bp
      fragment from A. vanbreuseghemii but not from A. benhamiae and A. simii. With
      these species-specific primers of CHS1 genes, 10 clinical isolates from humans
      and animals were examined by polymerase chain reaction analyses. These isolates
      proved to be identical to A. vanbreuseghemii.

PMID- 10394853
TI  - Clinical and mycological features of dermatophytosis in renal transplant
      recipients.
AB  - Dermatophytosis was detected in 42% of 100 renal transplant recipients screened,
      of whom 17% had the infection for more than 1 year. Tinea cruris and tinea
      corporis were the common clinical types observed. Tinea unguium presented as
      proximal subungual white onychomycosis (PSWO) in 3% of patients. The lesions in
      the majority were non-inflammatory, scaly and without central clearance. The
      commonest isolate was Trichophyton rubrum.

PMID- 10394854
TI  - Clinical and pharmacokinetic investigations of oral intraconazole in the
      treatment of onychomycosis.
AB  - A clinical study was carried out in 19 patients with onychomycosis in whom
      itraconazole was orally administered in a single daily dose of 100 mg. A follow
      up period was instituted subsequent to the administration period to that the
      course of the nail lesions could be monitored. The concentrations of the drug in
      the plasma and in the nails were also determined. In patients in whom
      itraconazole was administered for 12-16 weeks, the decrease in the turbidity and
      thickening of the nails was maintained even after the administration period was
      completed. The efficacy rating in the overall evaluation at 12 weeks was 84.2%
      (16/19). In the evaluation performed at 24 weeks, the rating was 94.7% (18/19).
      These data indicate that the effect of itraconazole was maintained even after
      completion of the administration period. The retention of the drug in the nail
      after completion of the administration period was investigated in terms of the
      mean concentration of the drug in the nail with the passage of time in patients
      administered itraconazole for 10-16 weeks. It was found that a certain level of
      itraconazole was retained in the nail until at least the 24th week. Adverse
      reactions seen in this study consisted of diarrhoea and drug eruption, one case
      cach, and elevations of glutamic oxaloacetic transaminase and glutamic pyruvic
      transminase in one case.

PMID- 10394855
TI  - A comparison among four regimens of itraconazole treatment in onychomycosis.
AB  - The purpose of this study was to compare the efficacy of different dosage
      regimens in the management of onychomycosis with itraconazole and to determine
      the results of a further 1-week intermittent pulse treatment in non-cured
      patients. In this study, 153 patients were randomly allocated to four groups.
      Patients in group A were treated with daily doses of 100 mg for 3 months in the
      case of fingernail onychomycosis and for 4 months in the case of toenail
      onychomycosis. Patients in the other groups received a intermittent pulse
      therapy, in which the drug was taken for 1 week, then discontinued for 3 weeks,
      three cycles for fingernail and four cycles for toenail infection. The daily
      doses were 400 mg (group B), 300 mg (group C) and 200 mg (group D). After
      therapy, non-cured patients were treated further with one cycle in which the
      daily dose was 400 mg. Patients were subsequently observed for 9 months and
      efficacy was assessed by mycological examination and the growth of unaffected
      nails. At the end of the therapy, the cure rates in the four groups were 19.1%
      (A), 15.2% (B), 18.9% (C) and 17.9% (D), and no significant differences were
      found between each of B, C, D and A. At the end of the study, the cure rates were
      76.2%, 91.3%, 78.4%, 28.6% respectively. The group that received further
      treatment had a cure rate of 55.6% at the end of the first month and of 83.3% in
      the second month. Drug tolerability was equally good in the four groups.
      Intermittent pulse therapy with a daily dose of 400 mg had the highest cure rate.
      Treatment of improved but non-cured patients with a dose of 400 mg intermittent
      pulse therapy markedly increased the cure rate. All treatment regimens were well
      tolerated.

PMID- 10394856
TI  - In vitro susceptibility of opportunistic Fusarium spp. to essential oils.
AB  - The inhibitory effects of essential oils extracted from 10 Indian plants were
      evaluated against five fungi. The plants used for extraction of essential oils
      were six species of the genus Eucalyptus and Ocimum basilicum, Prosopis cineraria
      and Derris indica. The fungi used in the experiments were Fusarium solani, F.
      oxysporum, F. pallidoroseum, F. acuminatum and F. chlamydosporum. The
      susceptibility of the Fusarium species was tested by the paper disc method and
      the serial dilution technique. The results were compared with the inhibitory
      effects of miconazole on the fungi. The essential oils extracted from the
      Eucalyptus species markedly inhibited fungal growth. Prosopis cineraria did not
      show inhibiting properties. Among the fungi, F. oxysporum proved to be the most
      resistant species.

PMID- 10394857
TI  - The green colour effect (GCE) of the killer strain Cryptococcus laurentii CBS 139
      on Staib agar.
AB  - Attention is drawn to the observation that the type strain Cryptococcus laurentii
      CBS 139, producing killer toxins (mycocins) directed at Cr. neoformans var.
      gattii, causes a green colour effect (GCE) on Staib agar (Guizotia abyssinica
      creatinine agar) in combination with an intense assimilation of creatinine. Five
      (9.6%) out of 52 strains of Cr. laurentii of various origin, showed a GCE and
      intense creatinine assimilation. Further research must show if all Cr. laurentii
      strains, characterized by a GCE similar to that of the strain CBS 139, are also
      capable of producing killer toxins. For further ecological and epidemiological
      research on strains producing killer toxins directed against species of the genus
      Cryptococcus, it is proposed to use Staib agar as differential culture medium
      indicating both colour effects, i.e. the GCE and the brown colour effect (BCE).

PMID- 10394858
TI  - Case report. A disseminated infection due to Chrysosporium queenslandicum in a
      garter snake (Thamnophis)
AB  - A male garter snake (Thamnophis) from a private terrarium was spontaneously and
      simultaneously infected with Chrysosporium queenslandicum and Geotrichum
      candidum. The autopsy revealed disseminated mycotic alterations in skin, lungs
      and liver. Chrysosporium queenslandicum grew well at 28 degrees C, the optimal
      temperature of the animal. This is the first description of a Chrysosporium
      queenslandicum infection in a garter snake.

PMID- 10394859
TI  - Case report. Cutaneous phaeohyphomycosis caused by Cladosporium oxysporum.
AB  - The case of a 66-year-old woman with Cushing syndrome and a 1-year history of
      papulo-nodular lesions on the right leg is reported. Biopsy revealed septate
      hyphae and yeast-like cells in granulomatous dermo-hypodermal lesions. Culture of
      biopsy fragments on Sabouraud glucose agar without cycloheximide produced
      colonies that were olive green on top and greenish black underneath. On the basis
      of microscope findings and scanning electron microscopy observation of fragments
      of colonies, a diagnosis of cutaneous phaeohyphomycosis due to Cladosporium
      oxysporum was made. The patient was initially treated with itraconazole, which
      led to clinical improvement, but mycological recovery was obtained after a course
      of ketoconazole, made necessary by the presence of pituitary adenoma. To our
      knowledge, this is the first reported case of subcutaneous phaeohyphomycosis due
      to Cl. oxysporum.

PMID- 10394860
TI  - Case report. Successful therapy of disseminated histoplasmosis in AIDS with
      liposomal amphotericin B.
AB  - A 36-year-old HIV-infected male patient presented with relapsing fever episodes
      to 39 degrees C, night sweats and weight loss. Computerized tomography of the
      abdomen showed enlarged multiple lymph nodes. After surgical resection of
      multiple lymph nodes, disseminated infection with Histoplasma capsulatum was
      diagnosed. Amphotericin B desoxycholate was initiated for 24 days. Fourteen days
      after therapy was discontinued, the patient suffered similar symptoms again.
      Subsequent treatment with liposomal amphotericin B led to rapid improvement
      within 3 days. Upon discharge, maintenance therapy with 600-mg itraconazole
      capsules was initiated and decreased to 400-mg 14-days later. Itraconazole
      therapy was continued until the patient died more than 2 years later because of
      complications of the underlying disease. At autopsy there were no signs of
      histoplasmosis.

PMID- 10394861
TI  - Interventional neuroradiology.
AB  - The purpose of this article is to provide an overview of all aspects concerning
      interventional neuroradiology of vascular central nervous diseases. Today,
      interventional neuroradiology can help many patients that, even until a few years
      ago, did not have any possibility for a safe cure. Complex cerebral arteriovenous
      malformations and fistulas, inoperable aneurysms and intravascular thromboses are
      often treated with interventional neuroradiology alone, while in other cases a
      combination of neurosurgery and radiation may help in reaching a good outcome for
      the patients. In the past few decades the efforts by neuroradiologists and
      collaborating clinicians to develop treatment strategies and methods for these
      and other high-risk diseases represent a vast, fascinating field of modern
      medicine. The article therefore focusses on the state-of-the-art and describes
      presently used methods for diseases that can be treated with interventional
      neuroradiology. Literature dealing with the historical development of
      interventional neuroradiology and important publications of recent scientific
      work are reviewed, providing the reader with an overview of the most pertinent
      material on each disease discussed. Aspects of training and ethics are discussed
      and emphasis is focussed on the importance of recognizing these aspects as
      essential in any case of interventional radiological treatment.

PMID- 10394862
TI  - MR imaging of experimentally induced intracranial hemorrhage in rabbits during
      the first 6 hours.
AB  - PURPOSE: To evaluate the MR appearance of intracranial, especially
      intraparenchymal, hemorrhage during the first 6 hours after bleeding with various
      pulse sequences in an animal model. MATERIAL AND METHODS: Intracerebral hematomas
      and subarachnoid hemorrhage were created by injecting autologous blood in 9
      rabbits. MR studies were performed using a 1.5 T scanner with pixel size and
      slice thickness comparable to those used in clinical practice before blood
      injection, immediately after injection, and at regular intervals during 6 hours.
      The images were compared with the hematoma sizes on formalin-fixed brain slices.
      RESULTS: In every animal, susceptibility-weighted gradient-echo (GRE) pulse
      sequences depicted the intraparenchymal hematomas and blood escape in the
      ventricles or subarachnoid space best as areas of sharply defined, strong
      hypointensity. The findings remained essentially unchanged during follow-up. The
      sizes corresponded well to the post-mortem findings. Gradient- and spin-echo
      (GRASE) imaging revealed some hypointensities, but these were smaller and less
      well defined. Spin-echo (SE) sequences (proton density-, T1- and T2-weighted) as
      well as a fluid-attenuated inversion recovery turbo spin-echo sequence (fast
      FLAIR) depicted the hemorrhage sites as mostly isointense to brain. CONCLUSION:
      Susceptibility-weighted GRE imaging at 1.5 T is highly sensitive to both
      hyperacute hemorrhage in the brain parenchyma and to subarachnoid and
      intraventricular hemorrhage.

PMID- 10394864
TI  - Ultrasonography of malignant breast neoplasms. Analysis of carcinomas missed as
      tumor.
AB  - PURPOSE: To analyze the malignant breast neoplasms missed as tumor on
      ultrasonography (US). MATERIAL AND METHODS: A total of 355 malignant tumors were
      confirmed at histology among 2,985 consecutive patients who underwent breast US.
      There were no prospectively recorded mammographic findings in 28 of the 355
      tumors. The remaining 327 tumors included 16 ductal carcinomas in situ (DCIS) and
      66 invasive carcinomas with suspicious microcalcifications on mammography.
      Excluding these 82 tumors because US would not have been indicated using strict
      criteria, a subpopulation of 245 noncalcified invasive malignant tumors remained
      for analysis. The neoplasms missed as tumor on US were analyzed for the whole
      tumor group (n=355) and the subpopulation (n=245). RESULTS: 42 (11.8%) of the 355
      malignant neoplasms were missed as tumor on US, including 6 (2.5%) of the 243
      palpable and 36 (32.1%) of the 1 12 nonpalpable malignancies. Most of the missed
      tumors were DCIS and microinvasive ductal carcinomas dominated by DCIS. In the
      subpopulation, 14 (5.7%) of the 245 malignancies were missed as tumor on US,
      including 4 (2.2%) of the 180 palpable and 10 (15.4%) of the 65 nonpalpable
      lesions. Of the 245 malignancies, 6 (2.4%) had a normal US finding, including 2
      palpable retropapillary tumors and 4 incidental findings at histology.
      CONCLUSION: Using strict criteria for performing US as an adjunct to mammography,
      by far the most malignant breast neoplasms are diagnosed as a tumor on US.

PMID- 10394863
TI  - Ultrasonographic evaluation of invasive lobular carcinoma.
AB  - PURPOSE: To compare ultrasonographic (US) and mammographic findings and tumor
      size measurements of invasive lobular carcinoma (ILC). MATERIAL AND METHODS: US
      diagnoses and mammographic findings were compared in 95 patients with pure ILC,
      including 46 palpable and 49 nonpalpable tumors. The diameters of tumors measured
      by mammography, US, and pathology were compared in 70 of the 95 patients using
      scatter plots and correlation analysis. RESULTS: Eighty-two (86.3%) of the ILCs
      were correctly diagnosed as malignant tumor, 5 (5.3%) were diagnosed as focal
      abnormality, and only 2 patients had normal findings on US. The most common
      mammographic findings were a spiculated mass (57%) and a focal asymmetric density
      (15%). US correctly diagnosed 8 of 12 patients with normal or equivocal
      mammographic findings. The correlation of tumor size assessment on imaging and
      pathology revealed that US measurements including the "halo" (r=0.69) was
      superior to that of mammography (r=0.59). ILCs larger than 30 mm were heavily
      underestimated by both methods. CONCLUSION: Malignant tumor was diagnosed on US
      in most of the patients with ILC. US tumor measurement including the "halo"
      predicted tumor size most accurately. The correlation between imaging
      measurements and tumor diameter on histology was lower for ILCs than reported for
      populations of mixed carcinomas.

PMID- 10394866
TI  - Automated stereotactic core needle biopsy of microcalcifications with correlation
      to surgical biopsy.
AB  - PURPOSE: To compare pathologic findings from stereotactic core and excisional
      biopsies in patients with microcalcifications in the breast. MATERIAL AND
      METHODS: Stereotactic core needle biopsies of 101 lesions with mammographic
      evidence of microcalcifications were performed with long-throw (2.2 cm) automated
      core biopsy devices fitted with 2.1-mm needles. The core specimens were placed on
      microscope slides and radiographed. The pathologic features of core and
      excisional specimens were compared. RESULTS: In 100 of the 101 breast lesions, a
      correct choice for an additional diagnostic procedure or definitive treatment
      could have been made upon histopathologic findings of the core needle biopsy.
      CONCLUSION: Stereotactic core needle biopsy is a reliable alternative to surgical
      biopsy of breast lesions with microcalcifications provided that specimen
      radiography has been performed to ensure that appropriate tissue has been
      obtained. Excisional biopsy may be avoided if microcalcifications are visible in
      radiographs of core biopsy specimen with benign histology.

PMID- 10394865
TI  - Contribution of ultrasonography and fine-needle aspiration cytology to the
      differential diagnosis of palpable solid breast lesions.
AB  - PURPOSE: To define the role of ultrasonography (US) and fine-needle aspiration
      biopsy (FNAB) relative to mammography in differentiating between benign and
      malignant palpable solid breast lesions, and to assess the contribution of FNAB
      cytology to the delay between referral and the definitive diagnosis of breast
      cancer. MATERIAL AND METHODS: We retrospectively reviewed the mammograms and US
      images of 84 palpable breast lesions, 63 of them also blindly. The lesions were
      classified as benign, indeterminate or malignant by both modalities. The results
      were compared with histologic diagnoses. The cytologic reports of 57 lesions were
      reviewed and compared to the final diagnoses. The delay from referral until
      diagnosis was calculated for each case. RESULTS: Eighty-one of the 84 lesions
      (96%) were visible as a local abnormality at US. Fifty-two of the 53 cancers were
      seen as a tumor (n=51) or an architectural distortion (n=1). In the blinded
      analysis, the sensitivity of FNAB cytology was 92%, specificity 83%, and overall
      accuracy 88%. There were no false-negative malignancies in the three modalities
      combined. The delay until the date of the final diagnosis was shorter in the
      group with a cytologic diagnosis positive for malignancy. CONCLUSION: Malignancy
      is unlikely if the US, mammographic and cytologic findings of a palpable breast
      lesion are all benign. Active and critical use of these three modalities could
      cut down the number of surgical biopsies of benign breast lesions and provide
      prompt surgical treatment for malignant lesions.

PMID- 10394867
TI  - Sensitivity and specificity of planar scintimammography with 99mTc-sestamibi.
AB  - PURPOSE: The aim of our prospective study was to determine the diagnostic
      accuracy of planar breast imaging with 99mTc-MIBI in detecting malignant disease.
      MATERIAL AND METHODS: Ninety-six consecutive patients with 121 clinically- and/or
      mammographically-detected breast lesions underwent preoperative planar
      scintimammography. Ten minutes after injection of 700 MBq 99mTc-MIBI, two lateral
      prone and one anterior supine projections with an acquisition time of 8 minutes
      each were obtained. Interpretation of scintimammographic results was made blindly
      and any focal accumulation of MIBI in the breasts was the criterion for an
      abnormal scintigram. All lesions were operated on and histologically verified.
      RESULTS: Histologically, 86 malignant and 35 benign lesions were found in 121
      breast lesions. A sensitivity of 83.7% and a specificity of 74.2% for malignancy
      was achieved at planar scintimammography. CONCLUSION: Scintimammography with
      99mTc-MIBI is an imaging modality of modest usefulness in the investigation of
      breast lesions. The method has a low sensitivity in lesions smaller than 10 mm in
      diameter, which decreases the clinical use of the method.

PMID- 10394868
TI  - Wrist and finger joint MR imaging in rheumatoid arthritis.
AB  - PURPOSE: To elaborate the best MR imaging protocol for studies in rheumatoid
      arthritis (RA) and to evaluate the sensitivity and interobserver agreement with
      respect to detection of bone erosions (MR and radiography) and grading of
      synovial membrane hypertrophy (MR imaging only). MATERIAL AND METHODS: MR imaging
      and conventional radiography of wrist and metacarpophalangeal (MCP) joints were
      performed in 41 RA patients and 3 healthy controls. The following pulse sequences
      were applied: T1-weighted spin-echo (T1-SE) with and without contrast
      enhancement, T2-SE, T2-turbo-SE, T1-2D-FLASH, T1-3D-FLASH, fat-saturated-T1-SE,
      STIR and 3D-DESS. RESULTS: Bone erosions were found by MR compared to radiography
      in 261 versus 85 bones of the wrist (ratio 3.1) and 59 versus 21 MCP joint
      quadrants (ratio 2.81). MR and radiography interobserver agreements were both
      approximately 90%. Likewise, MR scored synovial membrane hypertrophy in wrist and
      MCP joints with a high interobserver agreement. The most informative MR sequence
      appeared to be contrast-enhanced T1-SE MR, preferably with fat saturation. A STIR
      sequence or T2-weighted fat saturation sequence was useful in screening for joint
      disease. CONCLUSION: The sensitivity of MR is superior to conventional
      radiography with respect to detection of bone erosions in wrist and MCP joints.
      The interobserver agreement for MR and radiography was similar. Thus, MR of wrist
      and finger joints may become a useful supplement to conventional radiography in
      the evaluation of RA patients in clinical trials and clinical practice.

PMID- 10394869
TI  - MR imaging in tibial shaft fractures. A potential method for early visualization
      of delayed union.
AB  - PURPOSE: To evaluate the relationship between MR findings at the fracture site
      during the healing process and the outcome of patients with tibial shaft
      fracture. MATERIAL AND METHODS: Twelve consecutive patients with an uncomplicated
      tibial fracture treated conservatively were imaged by MR 1 to 3 days, 1 week, 3
      weeks, 6 weeks and 12 weeks after the trauma. MR imaging consisted of
      sagittal/coronal T1-weighted, T2-weighted, proton density, short-tau inversion
      recovery, and contrast-enhanced T1-weighted spin-echo images. The images were
      analysed for the extent of signal pathology in the bone marrow adjacent to the
      fracture, the extent of soft tissue oedema, and the intensity and homogeneity of
      the contrast enhancement of the callus. RESULTS: The differences between normal
      (n=7) and delayed union (n=5) were observed within 3 to 6 weeks after the trauma,
      mainly in the homogeneity of the callus in T2-weighted and contrast-enhanced
      images. CONCLUSION: MR imaging is a potentially valuable method for early
      visualization of delayed union in tibial shaft fractures.

PMID- 10394870
TI  - MR imaging in biofix-osteosynthesis.
AB  - PURPOSE: Osteosynthesis by means of bioresorbable implants, mostly of self
      reinforced poly-L-lactide (SR-PLLA), has been used in humans for about 10 years.
      The aim of this study was to examine the controversy between histological studies
      confirming fragmentation of the biomaterial and radiological studies showing no
      breaking of the material. MATERIAL AND METHODS: Six patients with displaced
      malleolar fractures operatively treated with biodegradable SR-PLLA screws
      underwent MR examinations at 1.5 T, immediately postoperatively and after one to
      two years. RESULTS: The biodegradable osteosynthetic screws were clearly seen on
      all MR images. Of 12 screws, 6 were broken at the final examination (5
      syndesmotic transfixation screws and 1 screw through the growth cartilage).
      CONCLUSION: The breaking of a biodegradable osteosynthesis is possible to
      document on MR images.

PMID- 10394871
TI  - Radiographic absorptiometry of the phalanges as a screening instrument to detect
      osteoporosis of the hip.
AB  - OBJECTIVE: To determine the validity of radiographic absorptiometry (RA) of the
      phalanges in detecting osteoporosis of the femoral neck, measured by dual energy
      X-ray absorptiometry (DXA). MATERIAL AND METHODS: In a group practice, 494
      Caucasian women aged 55 to 84 years were recruited. Hand radiographs and DXA
      measurements of the hip were performed in 449 women. 409 (91.1%) hand radiographs
      had sufficient quality for analysis by RA. Change of bone mass by age was
      obtained by using linear regression. Correlations between RA and DXA were
      calculated. Sensitivity and specificity of RA were calculated for several RA cut
      off levels. RESULTS: The mean bone mineral density at the femoral neck was 0.866
      g/cm2 and 92.57 arbitrary units at the phalanges. A moderate correlation of 0.53
      (p<0.01) was found between RA and DXA. Depending on the cut-off level used, the
      sensitivity and specificity of RA in detecting osteoporosis at the femoral neck
      was 0.84-0.55 and 0.61-0.88, respectively. CONCLUSION: RA may be used as a
      screening technique to detect osteoporosis, but confirmation is necessary in the
      subgroup with a positive outcome on RA.

PMID- 10394872
TI  - Comparative evaluation of plain films, ultrasound and CT in the diagnosis of
      intestinal obstruction.
AB  - BACKGROUND: There are limited studies in the literature comparing plain
      radiography, US and CT in the evaluation of intestinal obstruction. We carried
      out this prospective study to compare the relative efficacies of these three
      imaging techniques in patients with intestinal obstruction. MATERIAL AND METHODS:
      Thirty-two patients presenting with clinical suspicion of intestinal obstruction
      were subjected to plain radiography, US and CT and the findings were compared
      with reference to the presence or absence of obstruction, the level of
      obstruction and the cause of obstruction. The final diagnosis was obtained by
      surgery (n=25), or by contrast studies and/or clinical follow-up in those who
      were treated conservatively (n=7). RESULTS: Out of 32 patients, 30 had mechanical
      intestinal obstruction (22 had small bowel obstruction and 8 had large bowel
      obstruction). Of the remaining 2 patients, 1 had adynamic ileus and the other had
      a mesenteric cyst. CT had high sensitivity (93%), specificity (100%) and accuracy
      (94%) in diagnosing the presence of obstruction. The comparable sensitivity,
      specificity and accuracy were, respectively. 83%, 100% and 84% for US and 77%,
      50% and 75% for plain radiography. The level of obstruction was correctly
      predicted in 93% on CT, in 70% on US and in 60% on plain films. CT was superior
      (87%) to both US (23%) and plain radiography (7%) in determining the aetiology of
      obstruction. CONCLUSION: CT is a highly accurate method in the evaluation of
      intestinal obstruction especially for determining the level and cause of
      obstruction and should be the technique of choice when clinical or plain
      radiographic findings are equivocal.

PMID- 10394874
TI  - Ultrasound-guided fine needle aspiration biopsy of gall bladder malignancies.
AB  - PURPOSE: To establish the safety and efficacy of US-guided fine needle aspiration
      biopsy (FNAB) in gall bladder malignancies. MATERIAL AND METHODS: 142 patients
      suspected to have gall bladder malignancies underwent FNAB under real-time US
      guidance. The most common sonographic appearances were a mass filling or
      replacing the gall bladder (n=98), focal or diffuse wall thickening (n=25) and
      intraluminal polypoidal mass (n=19). FNAB was performed with a 0.7-mm spinal
      needle using a free-hand technique. RESULTS: On initial FNAB, 115 patients were
      diagnosed to have malignancy. In the remaining 27 patients, aspirates on first
      FNAB showed either inflammatory pathology (n=14) or the sample was suspicious of
      malignancy (n=7), or the aspirates were non-representative (n=6). Of these 27
      patients, 13 underwent repeat FNAB because of the high suspicion of malignancy
      and 12 of them showed malignancy. The FNAB diagnosis of inflammatory disease of 7
      patients was confirmed on subsequent surgery and 8 patients were lost to follow
      up. Thus, a total of 127/142 were diagnosed to have gall bladder malignancy.
      Adenocarcinoma was the most common malignancy (89.76%). No procedure-related
      complications were encountered. CONCLUSION: US-guided FNAB is a safe and accurate
      technique to diagnose gall bladder malignancy. Either a repeat FNAB or surgical
      biopsy is recommended when the suspicion of malignancy is high and the initial
      FNAB is negative.

PMID- 10394873
TI  - Ferric ammonium citrate as a positive bowel contrast agent for MR imaging of the
      upper abdomen. Safety and diagnostic efficacy.
AB  - PURPOSE: To evaluate the safety and diagnostic efficacy of two different doses of
      ferric ammonium citrate as a paramagnetic oral contrast agent for MR imaging of
      the upper abdomen. MATERIAL AND METHODS: Ninety-nine adult patients referred for
      MR imaging for a known or suspected upper abdominal pathology were included in
      this randomized multicenter double-blind clinical trial. Imaging was performed
      with spin-echo (T1- and T2-weighted) and gradient-echo (T1-weighted) techniques
      before and after administration of either 1200 mg or 2400 mg of ferric ammonium
      citrate dissolved in 600 ml of water. Safety analysis included monitoring of
      vital signs, assessment of adverse events, and laboratory testing. Efficacy with
      regard to organ distension, contrast distribution, bowel enhancement and
      delineation of adjacent structures was graded qualitatively. RESULTS: No serious
      adverse events were reported for either of the two concentrations. A total of 31
      minor side effects were noted, of which significantly more occurred in the higher
      dose group (p<0.01). The diagnostic confidence in defining or excluding disease
      was graded as better after contrast administration for 48% of all images. Marked
      or moderate enhancement of the upper gastrointestinal tract was achieved at both
      doses in 69.5% of cases with no evident difference between the two doses. The
      higher dose tended to show better results in terms of the contrast assessment
      parameters. CONCLUSION: Ferric ammonium citrate is a safe and effective oral
      contrast agent for MR imaging of the upper abdomen at two different dose levels.
      The higher dose showed a tendency toward better imaging results while the lower
      dose caused significantly fewer side effects. Therefore the 1200 mg dose can be
      recommended in view of the risk-to-benefit ratio.

PMID- 10394876
TI  - CT of liver cysts in patients with autosomal dominant polycystic kidney disease.
AB  - PURPOSE: The purpose of this study was to illustrate the CT appearances of liver
      cysts in patients with autosomal dominant polycystic kidney disease (ADPKD).
      MATERIAL AND METHODS: Contrast-enhanced CT images of 24 patients with ADPKD were
      retrospectively evaluated for the presence, number, size and distribution of
      liver cysts. An attempt was made to categorize these cysts into peribiliary cysts
      (located adjacent to larger portal triads or in the hepatic hilum) and
      intrahepatic cysts (within the liver parenchyma but not in contact with larger
      portal triads). When it was not possible to definitely categorize the cysts into
      either type, the cysts were labeled as indeterminate. RESULTS: Liver cysts were
      seen in 13 (54%) patients. Intrahepatic cysts were seen in 12 patients, and were
      mainly peripheral in location with sizes ranging from less than 10 mm to 8 cm.
      Peribiliary cysts were seen in all 13 patients and were usually less than 10 mm
      in size. These cysts were seen as discrete cysts (8 patients), a string of cysts
      (10 patients), or as a tubular structure paralleling the portal vessels,
      mimicking biliary dilatation (11 patients). Twelve patients also showed
      indeterminate cysts which defied definite categorization into either type; two
      common causes of confusion included large (more than 10 mm) discrete cysts in the
      hilar region and the presence of a vessel adjacent to peripheral cysts.
      CONCLUSION: Liver cysts in patients with ADPKD show a wide variety of appearances
      on CT. Familiarity with these findings is essential to avoid confusion with other
      abnormalities.

PMID- 10394875
TI  - The incidence of gallbladder stones and gallbladder function in beta-thalassemic
      children.
AB  - PURPOSE: To determine gallbladder motor function and gallstone prevalence in beta
      thalassemic children. Abnormalities in gallbladder function or bile acid
      metabolism may contribute to gallstone formation in these patients. MATERIAL AND
      METHODS: In 17 beta-thalassemic patients and 12 normal healthy children with
      similar age, sex and weight, gallbladder size was measured using real-time US,
      and volume was calculated using the ellipsoid method. RESULTS: In the beta
      thalassemic patients, cholelithiasis was present in 2 patients (11.8%). Sludge,
      which can be a predisposing factor for cholelithiasis and cholecystitis when it
      persists, was detected in 5 patients (29.4%). One of the patients had both
      cholelithiasis and sludge. Compared with the control group, beta-thalassemic
      children had larger fasting volume, residual volume, and smaller contraction
      index. CONCLUSION: Beta-thalassemic patients have enlarged gallbladders that
      retain an increased residual volume of bile. Gallbladder enlargement, bile
      stasis, and impaired emptying of sludge may be important events in the
      pathogenesis of pigment gallstones in beta-thalassemic patients.

PMID- 10394877
TI  - Small hepatocellular carcinoma supplied by the right renal capsular artery. A
      case report.
AB  - We present a case of hepatocellular carcinoma (HCC), which was fed only by the
      right renal capsular artery. Ten years earlier, this patient underwent surgery
      for a solitary HCC in segment IV. However, the hepatic artery was patent and did
      not participate in feeding the HCC. We consider the renal capsular artery as an
      essential extrahepatic parasitic feeding artery to HCC.

PMID- 10394878
TI  - HRCT in miliary lung disease.
AB  - PURPOSE: To analyze high resolution CT (HRCT) features of a miliary pattern in
      different diseases. MATERIAL AND METHODS: Eight HRCT studies with a miliary lung
      pattern were retrospectively reviewed with the diagnoses tuberculosis (n=3),
      Candida albicans (n=1), sarcoidosis (n=3), and metastatic adenocarcinoma (n=1).
      RESULTS: In all cases, HRCT showed diffusely disseminated nodules up to 3 mm. In
      2 cases of tuberculosis and 1 of sarcoidosis, the lesions predominated in the
      upper/middle lung zones. In the case of metastatic adenocarcinoma the nodules
      were more sparse in the lung periphery while in 1 case of sarcoidosis, HRCT
      revealed a predominance of the lesions in the outer third of the lungs. Cyst-like
      lesions of 12 mm were observed in 2/3 cases of tuberculosis and in metastatic
      adenocarcinoma. Notably thickened interlobular septa and interlobar fissures were
      each seen in 2/3 cases of sarcoidosis. In general, a random relationship of
      miliary nodules to secondary lobular structures and bronchovascular bundles was
      observed, despite the co-existence of centrilobular, subpleural and paraseptal
      nodules. CONCLUSION: HRCT features that potentially contribute in making a
      differential diagnosis are: a) A peripheral distribution of nodules, an increased
      number of thickened interlobular septae, and a notable thickening of interlobar
      fissures, all of which are indicative of sarcoidosis; and b) Multiple cyst-like
      lesions which should direct attention to tuberculous or metastatic origin. The
      predominance of miliary nodules in relation to cephalocaudal axis, their margin
      and size are not helpful features to the differential diagnosis of diseases
      presenting a miliary pattern.

PMID- 10394879
TI  - Renal masses--evaluation by amplitude coded colour Doppler sonography and
      multiphasic contrast-enhanced CT.
AB  - OBJECTIVE: To assess the efficacy of amplitude coded colour Doppler US (aCDS) in
      the evaluation of renal masses as shown by multiphasic contrast-enhanced CT.
      MATERIAL AND METHODS: Eighty patients (155 kidneys) with suspicion of renal
      masses underwent aCDS and spiral CT. The findings were classified into normal
      kidneys, kidneys with tumours, kidneys with cysts, and those with "other
      findings" (i.e. bleeding, calcifications, inflammation, parenchymal hypertrophy).
      The aCDS findings were compared to CT results and to histological findings or
      clinical, laboratory and follow-up data. RESULTS: Eighteen renal cell carcinomas
      and 8 other tumours were found; 78 kidneys had cysts, 12 polycystic kidneys and
      10 fibrotic kidneys were detected, 20 kidneys showed other findings. Diagnostic
      aCDS data were obtained in 129 kidneys (83.2%) showing pathology with an accuracy
      of 94%. CT adequately showed pathology in all patients with some diagnostic
      uncertainty in the evaluation of complicated cysts. CONCLUSION: Though contrast
      enhanced multiphasic spiral CT is the method of choice for evaluating renal
      masses, US including aCDS can provide valuable information, particularly in
      differentiating vascularized from non-vascularized lesions and in the evaluation
      of complicated renal cysts.

PMID- 10394880
TI  - Timing adjustment in gadolinium MR angiography by raw data recombination.
      Technical note.
AB  - To solve the problem of injection timing in gadolinium MR angiography, a simple
      procedure is proposed which allows the acquisition interval to be chosen after
      injection. Starting simultaneously with the injection, several consecutive
      acquisitions are made, after which raw data acquired in a contiguous interval
      with a variable starting time are recombined to one data set, which is then used
      for delayed image reconstruction.

PMID- 10394881
TI  - Overexpression of human telomerase RNA is an early event in oesophageal
      carcinogenesis.
AB  - Telomerase, the ribonucleoprotein enzyme that elongates telomeres, is repressed
      in normal human somatic cells but is reactivated during tumour progression. The
      purpose of this study was to investigate the localization of human telomerase RNA
      (hTR) expression in human oesophageal dysplasia and cancer by using in situ mRNA
      hybridization (ISH) with avidin-biotin staining. Ki-67 immunoreactivity was also
      examined. We analysed 51 squamous cell carcinomas, 9 dysplasias and 60 normal
      mucosae. The integrity of the mRNA in each sample was verified by using a poly
      d(T)20 probe. Seventy-six samples (63%) showed no mRNA degradation; these
      included 30 carcinomas, 7 dysplasias and 39 normal mucosae. At the single-cell
      level, high levels of hTR expression were found in the cytoplasm and especially
      in the nucleus. Most (>90%) cancer cells demonstrated high levels of hTR
      expression in 29 (97%) of the 30 tumours. Most dysplastic cells also showed high
      levels of hTR in all 7 dysplastic cases. In all 39 normal mucosae, most basal
      cells indicated high levels of hTR expression, which were also seen in
      infiltrating lymphocytes. The distribution of hTR-expressing cells was similar to
      that of Ki-67-positive cells. These data suggest that overexpression of hTR may
      be correlated with the proliferative activity that defined by Ki-67
      immunoreactivity and is an early event in carcinogenesis of the oesophagus.

PMID- 10394882
TI  - Loss of immunohistochemical E-cadherin expression in colon cancer is not due to
      structural gene alterations.
AB  - E-cadherin, a transmembrane cell adhesion molecule, has been observed to have an
      altered pattern of immunoreactivity in several types of carcinomas. In lobular
      breast cancer, loss of immunoreactivity has been shown to be due either to out-of
      frame deletions or to nonsense mutations of the E-cadherin gene. We analysed 29
      cases of completely resected colon carcinoma with immunohistochemistry using the
      HEC-D1 antibody. Normal protein expression similar to that in the adjacent
      nonmalignant mucosa was seen in 6 cases, whereas 23 tumours had reduced or absent
      E-cadherin expression. In the 8 cases with no expression of E-cadherin revealed
      by immunohistochemistry, the entire E-cadherin cDNA sequence was analysed. In
      these cases, sequence analysis failed to reveal any cDNA mutations despite the
      negative immunohistochemistry. Possible explanations for this discrepancy include
      regulatory defects in the E-cadherin promoter, abnormalities at the translation
      or protein processing levels and mutations in other parts of the gene that were
      not investigated by the cDNA analysis (e.g. intronic sequences), which could play
      a role in causing abnormal processing of the E-cadherin protein.

PMID- 10394883
TI  - Absence of p53 gene mutations in hepatocarcinomas from a Mediterranean area of
      Spain. A study of 129 archival tumour samples.
AB  - The incidence of p53 gene abnormalities in human hepatocellular carcinoma (HCC)
      varies in different geographical areas, being higher in regions where hepatitis
      virus infection and dietary exposure to aflatoxin B1 are the most common
      aetiological agents. These mutations are less frequently encountered in Europe,
      although some studies have reported p53 protein overexpression in up to 45% of
      cases analysed. We have analysed 129 tumour samples of primary malignant hepatic
      neoplasms recovered from paraffin blocks processed in two pathology laboratories
      in a Mediterranean area of Spain (Valencia and Gerona). Among 14 cases in which
      p53 immunohistochemistry expression proved positive, 5 stained in more than 50%
      of the cell nuclei. By PCR-SSCP analysis we could detect the complete sequence
      from exon 5 through 8 in 70 cases and part of this region in the remaining cases,
      but no mutations were found. We found no relationship with the clinical stage,
      tumour stage or clinical outcome. We conclude that p53 gene alterations are not a
      major event in the malignant transformation of hepatic cells in this region of
      the Mediterranean. The variable incidence of p53 gene alterations in other
      geographical areas may reflect a different genetic background for the aetiology
      of HCC.

PMID- 10394884
TI  - Expression of MUC1, Thomsen-Friedenreich antigen, Tn, sialosyl-Tn, and alpha2,6
      linked sialic acid in hepatocellular carcinomas and preneoplastic hepatocellular
      lesions.
AB  - The expression of epithelial mucins and Thomsen-Friedenreich-related antigens in
      preneoplastic and neoplastic hepatocellular lesions was systematically
      investigated using an in situ immunohistochemical staining approach. MUC1, MUC2,
      TF, sialosyl-TF, Tn, sialosyl-Tn, alpha2,3-linked sialic acid, and alpha2,6
      linked sialic acid were examined in normal and cirrhotic human liver and in human
      hepatocellular carcinomas (HCCs) and cholangiocarcinomas. Normal hepatocytes and
      preneoplastic foci of altered hepatocytes did not express MUC1, MUC2, TF, Tn, s
      Tn, or alpha2,6-linked sialic acid. In contrast, HCCs showed positive reactions
      for MUC1, TF, Tn, s-Tn, and alpha2,6-linked sialic acid. MUC2 was absent in
      normal biliary epithelial cells, but present in cholangiocarcinomas. The staining
      of MUC1, or s-Tn and alpha2,6-linked sialic acid in human normal liver tissues
      and various liver diseases did not change after specific treatments such as
      periodate oxidation or saponification, indicating that their expression in HCC
      does not result from incomplete glycosylation or low O-acetylation, respectively.
      MUC1, TF, Tn, s-Tn, and alpha2,6-linked sialic acid may be useful as indicators
      of progression of HCC in tissue sections, and perhaps also as targets for
      diagnostic and therapeutic approaches in vivo.

PMID- 10394885
TI  - Sarcomatoid hepatocellular-carcinoma showing rhabdomyoblastic differentiation in
      the adult cirrhotic liver.
AB  - An unusual case of a massive liver tumour composed of rhabdomyosarcoma with a
      small focus of hepatocellular carcinoma in a 52-year-old man is presented. He had
      hepatitis B virus (HBV) surface antigen in his serum. Macroscopically, a large
      tumour with satellite nodules occupied the right lobe of the cirrhotic liver.
      Microscopically, the tumours were composed of small and short spindle-shaped
      undifferentiated cells, mixed with desmin-positive round rhabdomyoblasts and
      elongated striated muscle cells, strongly suggestive of rhabdomyosarcoma of the
      liver. Elevated levels of alpha-fetoprotein in the serum led us to examine the
      liver tumour closely in multiple sections, which disclosed a hepatocellular
      carcinoma component measuring 2 cm in diameter within the massive tumour.
      Immunohistochemically, the hepatocellular carcinoma cells were alpha-fetoprotein
      positive. There was neither a tumour capsule, nor distinct demarcation, and
      cytokeratin-positive clusters of undifferentiated cells were intermingled with
      the hepatocellular carcinoma and rhabdomyosarcoma at the border. The invading
      tumour outside the liver and metastatic tumours were pure rhabdomyosarcomas. It
      is suggested that the present case should be diagnosed as rhabdomyosarcoma
      transformed from hepatocellular carcinoma.

PMID- 10394886
TI  - Comparison of alterations of chromosome 17 in carcinoma of the ovary and of the
      breast.
AB  - Breast and ovarian carcinomas share a region of allelic loss on chromosome 17q25,
      suggesting that these tumours may arise by similar molecular pathways. We
      analysed paraffin-embedded tissues from 84 sporadic ovarian carcinomas and 42
      sporadic infiltrating ductal carcinomas of the breast for abnormalities on
      chromosome 17. Loss of heterozygosity (LOH) of at least one informative marker on
      17q was identified in 49 of 82 (60%) ovarian carcinomas, as against only 6 of 40
      (15%) informative breast carcinomas (P<0.0001). In ovarian carcinoma, LOH was
      most commonly observed for GH on 17q23 (56%), and was also frequently observed at
      17q21 (46%). In contrast, LOH of D17S 1330/CTT16 on 17q25 was observed in only
      19% of ovarian tumours. LOH in breast carcinomas was most frequently observed at
      17q21 (16%), less frequently at 17q23 (7%) and not identified at all at 17q25 in
      any breast cancers. Immunohistochemical analysis demonstrated overexpression of
      the p53 gene product in 38 of 84 (45%) ovarian carcinomas, as against 10 of 42
      (24%) breast carcinomas (P = 0.0195). p53 immunoreactivity was significantly
      associated with LOH in ovarian and breast cancers. Immunohistochemical expression
      of HER2/neu was observed in 6 of 84 (7%) ovarian and 3 of 42 (7%) breast
      carcinomas. There was no relationship between HER2/neu immunoreactivity and LOH.
      Although sporadic carcinomas of breast and ovary share some regions of allelic
      loss on chromosome 17q, differences in other alterations on this chromosome
      suggest divergent pathways of tumour development.

PMID- 10394887
TI  - Renal arterioles in patients with type I diabetes and microalbuminuria before and
      after treatment with antihypertensive drugs.
AB  - Antihypertensive drugs can slow or even reverse the progression of diabetic
      nephropathy at the microalbuminuric stage. This study was performed to obtain
      quantitative data on changes in the renal arterioles in a follow-up study. Twelve
      patients with type I diabetes and with microalbuminuria were allocated to
      treatment for 3 years with either an ACE inhibitor (group I, 6 patients) or a
      beta blocker (group II, 6 patients). Baseline and follow-up renal needle biopsy
      specimens were taken and serially sectioned at 1 microm for light microscopy,
      enabling identification of arterioles as afferent or efferent. Thin sections for
      electron microscopy were made at 50-microm intervals, and micrographs were taken
      of arteriolar profiles. Matrix volume fraction of the media and a calculated
      matrix thickness were obtained. At baseline, structural parameters were higher
      than normal values. At follow-up all patients were normoalbuminuric. Both groups
      showed only minor changes in arteriolar structures over 3 years. In the afferent
      arterioles in group II there was a significant increase in the matrix volume
      fraction of the media, and there was a tendency to an increase in matrix
      thickness in both groups. In the efferent arterioles there were no significant
      changes in parameters. There were no differences between the two groups in
      arteriolar structural changes from baseline to follow-up. Thus, this study shows
      a slight but significant matrix accumulation in the afferent arterioles during
      treatment with antihypertensive drugs. This may have implications for the
      progression to overt nephropathy, which indicates a need for more long-term
      studies of treatment with antihypertensive drugs in incipient nephropathy in type
      I diabetes.

PMID- 10394888
TI  - Death from pulmonary thromboembolism in severe obesity: lack of association with
      established genetic and clinical risk factors.
AB  - Several clinical and environmental conditions are causally related to sudden
      death from acute pulmonary thromboembolism (APT). Morbid obesity, despite its
      frequency and association with adverse health effects, is usually considered at
      most only an additive risk factor for APT. We reviewed protocols and histories
      from 7227 consecutive autopsies performed between 1985 and 1996 at the Mayo
      Clinic, including all deaths from APT where no clinical or environmental risk
      factor could be identified in the study. Body mass indices (BMI) were calculated
      and compared with those of age- and sex-matched controls who had died suddenly
      and naturally without evidence of APT. Resistance to activated protein C is the
      most common molecular clotting defect predisposing to APT, and it is caused by a
      point mutation in the factor V gene (R506Q). Genomic DNA was extracted from
      archival tissues of all cases and controls, and the R506Q status was determined
      by polymerase chain reaction amplification, restriction endonuclease digestion,
      and direct sequencing. APT was found as the immediate cause of death in 433
      patients, with 36 (8%) having no previously established risk factors. Twenty-four
      of these persons (67%) were morbidly obese (BMI >30 kg/m2). compared with only
      five controls (14%, P<0.0001). Four patients in both groups, each with a BMI <30
      kg/m2. had at least one allele positive for R506Q. Morbid obesity is an
      independent risk factor in cases of sudden death from APT after the exclusion of
      previously established clinical, environmental, and molecular risk factors.

PMID- 10394889
TI  - Hepatitis C virus infection of peripheral nerves in type II cryoglobulinaemia.
AB  - Peripheral neuropathy is a frequent complication in patients suffering from type
      II mixed cryoglobulinaemia (mCGII), a sort of vasculitis that is strongly
      associated with hepatitis C virus (HCV) infection and characterised by high
      concentrations of anti-HCV antibodies and HCV RNA in the cryoprecipitates. We
      report the finding of HCV RNA in homogenates of nerve biopsies from five such
      patients, by reverse transcription-polymerase chain reaction (RT-PCR)
      amplification of different regions of the viral genome. HCV RNA was localized in
      epineurial cells by in situ RT-PCR. Our data suggest that HCV infection of nerves
      plays a major role in mCGII-associated neuropathy.

PMID- 10394890
TI  - Oncocytic myoepithelioma and pleomorphic adenoma of the salivary glands.
AB  - Twenty oncocytic myoepitheliomas (MEs) and pleomorphic adenomas (PAs) were
      composed of interlacing fascicles of swollen spindle-shaped or/and epithelioid
      oncocytic myoepithelial cells showing intense finely granular immunoreactivity
      with anti-mitochondrial antibody. Focal vacuolation of the cytoplasm of oncocytic
      myoepithelial cells and their gradual transition into sebaceous metaplasia were
      observed in 3 cases. Another unusual feature found in 5 cases was the presence of
      slit-like adenomatoid spaces lined with double-layered oncocytic myoepithelium
      closely resembling Warthin's tumour. The nuclei of oncocytic cells were
      characterized by enlargement, hyperchromasia and polymorphism, which should not
      be confused with malignancy. Oncocytic change in myoepithelial cells in MEs and
      PAs can cause pitfalls in the differential diagnosis of salivary gland tumours.
      We describe some unusual histological features associated with onococytic
      metaplasia in benign myoepithelial cell-derived salivary gland tumours, hoping to
      help to avoid the overdiagnosis of malignancy.

PMID- 10394891
TI  - Myofibroblastoma of the breast with diverse histological features.
AB  - We report two cases of myofibroblastoma with unusual pathological features, in a
      66-year-old woman and a 49-year-old man. Both tumours were unilateral, grossly
      nodular and well circumscribed, but not encapsulated. The lesions were made up of
      bipolar spindle cells arranged in fascicular clusters separated by bands of
      hialinized collagen; one included several islands of mature cartilage next to fat
      cells. The other contained atypical mononucleated and multinucleated giant cells.
      No mitotic figures were observed. Immunohistochemically, both tumours showed
      strong and diffuse cytoplasmic staining for vimentin and CD 34 and focal
      positivity for alpha-smooth muscle actin, and both were negative for
      cytokeratins, CD 68, Ham 5, 6, Mac 387, and S-100 protein. Desmin was positive in
      one case. Ultrastructural study revealed populations composed of fibroblastic
      cells without signs of myofibroblastic differentiation in one case; the second
      featured abundant undifferentiated mesenchymal cells with myofibroblastic
      differentiation. Both patients remain disease-free 38 and 36 months after
      lumpectomy.

PMID- 10394892
TI  - Cerebrovascular involvement in systemic AA and AL amyloidosis: a clear
      haematogenic pattern.
AB  - Amyloid deposits in cerebral vessels are common in beta-amyloid diseases
      (Alzheimer's disease, congophilic amyloid angiopathy, Down's syndrome and
      hereditary cerebral amyloidosis with haemorrhage of the Dutch type). We report of
      20 autopsies on patients who had died with systemic amyloidosis of the AA,
      Alambda and Akappa types: the brains were examined for the occurrence of amyloid.
      Vascular amyloid was detected in choroid plexus (in 17 of 20 cases), infundibulum
      (5 of 8), area postrema (6 of 11), pineal body (3 of 7) and subfornical organ (2
      of 3), but not in cortical and leptomeningeal vessels. Immunohistochemical
      classification of the cerebral amyloid and the systemic amyloid syndrome showed
      identity proving the same origin of both. The distribution is indicative of a
      haematogenic pattern of amyloid deposition in systemic amyloidosis and is
      different from that in Alzheimer's, prion, ATTR and cystatin C diseases. It
      corresponds to areas of the brain with a "leaky" blood-brain barrier.
      Additionally, all the cases with AA amyloidosis exhibited an Abeta coreactivity
      in choroid plexus vessels. In one exceptional case, Abeta reactivity of AA
      amyloid also occurred outside of the brain.

PMID- 10394893
TI  - Expression of inducible nitric oxide synthase in macrophages and smooth muscle
      cells in various types of human atherosclerotic lesions.
AB  - Nitric oxide (NO) is an important regulatory agent in blood vessels. We studied
      the expression of inducible nitric oxide synthase (iNOS) in different types of
      human atherosclerotic lesions using simultaneous in situ hybridization and
      immunocytochemistry. Since nitric oxide and its derivates or reaction products
      can have both oxidative and antioxidative effects, we also studied the presence
      of oxidized low-density lipoproteins (ox-LDL) and peroxynitrite-modified proteins
      in the same lesions as indicators of oxidative damage. Twenty-seven aortic
      samples were studied from seven autopsies. Samples were classified
      microscopically as normal areas, initial lesions (type I), fatty streaks (type
      II), intermediate lesions (type III), atheroma (type IV), fibroatheroma lesions
      (type Va) and fibrotic lesions (type Vc). In normal arterial wall iNOS mRNA was
      expressed at a low level in smooth muscle cells (SMCs). Absence of, or a low
      level of, epitopes characteristic of ox-LDL was found in the normal arterial
      wall. The expression of iNOS mRNA and protein was induced in macrophages and SMCs
      in the majority of early lesions and in all advanced atherosclerotic lesions.
      Epitopes characteristic of ox-LDL and peroxynitrite-modified proteins tended to
      be colocalized in iNOS-positive lesions. We consider that iNOS and oxidative
      injuries may play an important part in atherogenesis.

PMID- 10394894
TI  - Squamous cell carcinoma and lipomatous pseudohypertrophy of the pancreas.
AB  - A 68-year-old woman who had been treated for non-insulin-dependent diabetes
      mellitus for the past 20 years was admitted to hospital because of abdominal pain
      and weight loss. Radiological investigation revealed a tumour in the body of the
      pancreas and numerous intraductal calcifications in both the tail and the head of
      the pancreas. Left-sided pancreatectomy was performed to remove the tumour. The
      resection specimen showed fatty enlargement of the parenchyma and numerous
      intraductal calcifications in the tissue adjacent to the tumour, which was 7 cm
      in diameter and was found to be a primary squamous cell carcinoma with a spindle
      cell component. There was also lipomatous pseudohypertrophy.

PMID- 10394895
TI  - Characterization of the ORF YBR264c in Saccharomyces cerevisiae, which encodes a
      new yeast Ypt that is degraded by a proteasome-dependent mechanism.
AB  - We identified the ORF YBR264c during the systematic sequencing of the
      Saccharomyces cerevisiae genome. It encodes a putative protein of 218 amino
      acids. We demonstrate here that the gene is indeed expressed and encodes a new
      Ypt in yeast. This protein specifically binds guanine nucleotides and interacts
      via its C-terminal end with the unique Rab GDP Dissociation Inhibitor (RabGDI).
      In accordance with a recent proposal, the gene is now designated YPT10. No mutant
      phenotype could be associated with inactivation of the gene. However,
      overexpression of YPT10 resulted in defects in growth; microscopic examination of
      such cells revealed an overabundance of vesicular and tubular structures,
      suggesting some alteration in the function of the Golgi apparatus. In addition,
      degradation of the Ypt10 protein, which possesses a PEST sequence, is shown to be
      dependent on proteasome activity.

PMID- 10394896
TI  - A mutation in the secretion pathway of the yeast Yarrowia lipolytica that
      displays synthetic lethality in combination with a mutation affecting the signal
      recognition particle.
AB  - In an attempt to identify proteins involved in the translocation step of protein
      secretion, a genetic screen was carried out in the yeast Yarrowia lipolytica. A
      conditional lethal mutant which has a defect in the 7S RNA of the signal
      recognition particle was mutagenized and screened for second-site mutations that
      specifically exacerbate its temperature sensitivity. This approach had previously
      allowed the characterization of an endoplasmic reticulum component, Sls1p,
      involved in protein translocation. A second mutation, sls2-1, was isolated that
      causes synthetic lethality when combined with the 7S RNA mutation. On its own,
      the sls2-1 mutation confers a temperature-sensitive growth phenotype. The
      secretory phenotype of the sls2 mutant consists in abnormal secretion of several
      polypeptides, and thus differs from the defect in secretory protein synthesis
      associated with the 7S RNA and sls1-1 mutations. Two new Y. lipolytica genes were
      identified which can relieve the growth defect of sls2-1 cells: SLS2 itself and
      SSL2, a multicopy suppressor of the temperature sensitivity of the sls2 mutant.
      The SLS2 gene encodes a polypeptide that can potentially be farnesylated and
      phosphorylated, and shares some homology with an S. cerevisiae protein of unknown
      function. Ssl2p resembles calmodulin-dependent serine/threonine protein kinases.
      These two proteins may interact to regulate protein sorting.

PMID- 10394897
TI  - Nuclear factors GT-1 and 3AF1 interact with multiple sequences within the
      promoter of the Tdc gene from Madagascar periwinkle: GT-1 is involved in UV light
      induced expression.
AB  - Plant secondary metabolites of the terpenoid indole alkaloid (TIA) class comprise
      several compounds with pharmaceutical applications. A key step in the TIA
      biosynthetic pathway is catalysed by the enzyme tryptophan decarboxylase (TDC),
      which channels the primary metabolite tryptophan into TIA metabolism. In
      Catharanthus roseus (Madagascar periwinkle), the Tdc gene is expressed throughout
      plant development. Moreover, Tdc gene expression is induced by external stress
      signals, such as fungal elicitor and UV light. In a previous study of Tdc
      promoter architecture in transgenic tobacco it was shown that the -538 to -112
      region is a quantitative determinant for the expression level in different plant
      organs. Within this sequence one particular region (-160 to -99) was identified
      as the major contributor to basal expression and another region (-99 to -37) was
      shown to be required for induction by fungal elicitor. Here, the in vitro binding
      of nuclear factors to the -572 to -37 region is described. In extracts from
      tobacco and C. roseus, two binding activities were detected that could be
      identified as the previously described nuclear factors GT-1 and 3AF1, based on
      their mobility and binding characteristics. Both factors appeared to interact
      with multiple regions in the Tdc promoter. Mutagenesis of GT-1 binding sites in
      the Tdc promoter did not affect the basal or elicitor-induced expression levels.
      However, induction of the Tdc promoter constructs by UV light was significantly
      lower, thereby demonstrating a functional role for GT-1 in the induction of Tdc
      expression by UV light.

PMID- 10394898
TI  - Radiation-sensitive Arabidopsis mutants are proficient for T-DNA transformation.
AB  - Stable transformation of plants by Agrobacterium T-DNAs requires that the
      transgene insert into the host chromosome. Although most of the Agrobacterium Ti
      plasmid genes required for this process have been studied in depth, few plant
      encoded factors have been identified, although such factors, presumably DNA
      repair proteins, are widely presumed to exist. It has previously been suggested
      that the UVH1 gene product is required for stable T-DNA integration in
      Arabidopsis. Here we present evidence suggesting that uvh1 mutants are
      essentially wild type for T-DNA integration following inoculation via the vacuum
      infiltration procedure.

PMID- 10394899
TI  - AFLP analysis of genetic diversity within and between Arabidopsis thaliana
      ecotypes.
AB  - The degree of genetic diversity within and between 21 Arabidopsis thaliana (L.)
      Heynh ecotypes was estimated by AFLP analysis. Within seven of the 21 ecotypes, a
      low but significant level of polymorphism was detected, and for five of these
      ecotypes two or three distinct subgroups could be distinguished. As these
      ecotypes represent natural populations, this intraecotypic diversity reflects
      natural genetic variation and diversification within the ecotypes. The source of
      this diversity remains unclear but is intriguing in view of the predominantly
      self-fertilizing nature of Arabidopsis. Interrelationships between the different
      ecotypes were estimated after AFLP fingerprinting using two enzyme combinations
      (EcoRI/MseI and SacI/MseI) and a number of selective primer pairs. SacI
      recognition sites are less evenly distributed in the genome than EcoRI sites, and
      occur more frequently in coding sequences. In most cases, AFLP data from only one
      enzyme combination are used for genetic diversity analysis. Our results show that
      the use of two enzyme combinations can result in significantly different
      classifications of the ecotypes both in cluster and ordination analysis. This
      difference most probably reflects differences in the genomic distribution of the
      AFLP fragments generated, depending on the enzymes and selective primers used.
      For closely related varieties, as in the case of Arabidopsis ecotypes, this can
      preclude reliable classification.

PMID- 10394900
TI  - A G-box element from the Catharanthus roseus strictosidine synthase (Str) gene
      promoter confers seed-specific expression in transgenic tobacco plants.
AB  - The enzyme encoded by the strictosidine synthase (Str) gene from Catharanthus
      roseus catalyses a key step in the biosynthesis of the pharmaceutically important
      terpenoid indole alkaloids. Str cDNA and genomic clones have already been
      isolated, allowing us to study the regulation of Str gene expression. Here we
      focus on the role of a putative cis-acting element, CACGTG, in the Str promoter.
      This sequence is known as a G-box, and functions as a transcription-regulating
      sequence in a number of other promoters. By means of electrophoretic mobility
      shift assays it was demonstrated that the Str G-box is capable of interacting
      with nuclear factors in tobacco and with the cloned tobacco G-box-binding factor
      TAF-1. Disruption of the Str G-box sequence by two single-nucleotide mutations
      prevented binding of factors, thereby demonstrating the specificity of the
      observed interactions. Functional analysis in transgenic tobacco plants
      demonstrated that these mutations also reduced the transcriptional activity of
      constructs containing tetramers of the Str G-box sequence. Expression directed by
      a tetramer of the Str G-box fused to a truncated promoter containing only a TATA
      box was confined to seeds and was found to increase during seed maturation. Thus,
      the Str G-box tetramer is able to direct seed-specific expression independently
      of other regulatory sequences. G-box-directed expression in leaves required the
      presence of an enhancer region from the cauliflower mosaic virus (CaMV) 35S
      promoter. The results indicate that the G-box needs to interact with other
      elements to drive expression in leaf, and that it can by itself confer seed
      specific expression as a multimer. The fact that only some of the G-boxes found
      in different promoters serve as seed-specific elements indicates that sequences
      flanking the G-box determine the transcriptional activity in different tissues.
      Based on sequence comparisons we propose that the nucleotides at positions -4, 
      3, -2 and/or +4 are important in determining seed-specific expression.

PMID- 10394901
TI  - Isolation and characterisation of five different hydrophobin-encoding cDNAs from
      the fungal tomato pathogen Cladosporium fulvum.
AB  - Five different hydrophobin-encoding cDNA clones from Cladosporium fulvum were
      isolated from cDNA libraries, made from nutrient-depleted mycelium. One cDNA
      clone was identical to the previously isolated hydrophobin HCf-1. The other
      clones were named HCf-2, -3, -4 and -5. HCf-1, -2, -3 and -4 show a high degree
      of identity, and are predicted to encode class I hydrophobins. HCf-5 encodes a
      class II hydrophobin. The expression patterns of these hydrophobins at various
      stages of development, and in liquid media lacking either carbon or nitrogen, or
      both, showed clear differences. All hydrophobins were more strongly expressed
      during sporulation than before, with HCf-4 and -5 showing the highest increase.
      Expression of HCf genes in infected plants was also higher at 16 days than at 10
      days after infection. The expression of HCf-5 in sporulating mycelium was much
      lower in planta than in vitro. All HCf genes were upregulated under conditions of
      nutrient deprivation. HCf-1, -2, -3 and -4 showed highest levels of transcription
      in medium lacking both carbon and nitrogen. Expression of HCf-5 was highest in
      medium lacking nitrogen but containing carbon. HCf-1 was generally the most
      abundant hydrophobin. The introduction of multiple copies of HCf-1, which caused
      co-suppression of the endogenous HCf-1 gene, was shown to affect the expression
      of HCf-2, -3 and -4 also. Expression of HCf-4 was suppressed, but expression of
      HCf-2 and -3 was upregulated. Expression of HCf-5 was not changed.

PMID- 10394902
TI  - Transcription of the avirulence gene Avr9 of the fungal tomato pathogen
      Cladosporium fulvum is regulated by a GATA-type transcription factor in
      Aspergillus nidulans.
AB  - The avirulence gene Avr9 of the fungal tomato pathogen Cladosporium fulvum is
      highly induced during infection of tomato plants. Expression of the Avr9 gene can
      also be induced in vitro when cells are grown on synthetic liquid medium
      containing little or no nitrogen. The Avr9 promoter contains six copies of the
      sequence TAGATA and six additional copies of the core sequence GATA within 0.4 kb
      upstream of the translation start site. In the filamentous fungi Aspergillus
      nidulans and Neurospora crassa, these promoter sequences have been identified as
      the binding sites for a wide-domain GATA-type regulator (AREA in A. nidulans and
      NIT2 in N. crassa) involved in nitrogen utilization. Quantification of GUS
      activity of A. nidulans transformants containing a single copy of the fully
      active Avr9 promoter-uidA (GUS) reporter gene fusion in different areA
      backgrounds, following starvation for nitrogen, showed that induction of the Avr9
      promoter is regulated similarly in A. nidulans and C. fulvum. This suggests that
      AREA can regulate the Avr9 promoter and that C. fulvum contains an AREA-like
      regulator that can bind to these specific sequence motifs. Comparison of the
      induction profiles of Avr9 and niaD showed that Avr9 expression is independent of
      NIRA, as is niaD expression upon nitrogen starvation. Studies with Avr9 promoter
      uidA fusions in which all or most of these sequences had been deleted, showed
      that Avr9 promoter activity is dependent on the presence of these specific cis
      regulatory elements, suggesting that they do indeed function in transcriptional
      regulation of the Avr9 gene.

PMID- 10394903
TI  - Differential regulation of six novel MYB-domain genes defines two distinct
      expression patterns in allotetraploid cotton (Gossypium hirsutum L.).
AB  - A PCR-based strategy was employed to identify myb-related genes potentially
      involved in the differentiation and development of cotton seed trichomes. cDNA
      clones representing six newly identified cotton myb-domain genes (GhMYB) of the
      R2R3-MYB family were characterized in the allotetraploid species Gossypium
      hirsutum L. (2n = 4x = 52; AADD). Several interesting motifs and domains in the
      transregulatory region (TRR) were identified as potential candidates for
      modulating GhMYB activity. One such structural feature is a basic 40-amino acid
      stretch (TRR1) located immediately downstream of the DNA-binding domain (DBD) in
      five of the GhMYBs. Furthermore, the conserved motif GIDxxH identified in a
      subset of plant MYBs is also present in the same position in the TRR1 domains of
      GhMYB1 and GhMYB6, exactly 12 amino acid residues downstream of the last
      tryptophan in the R3 repeat of the DBD. At least two of the GhMYBs (GhMYB4 and
      GhMYB5) contain unidentified ORFS in the 5' leader sequence (5'-uORFs) that may
      serve to regulate the synthesis of these particular GhMYB proteins at the
      translational level. Multiple alignment of DBD sequences indicated that GhMYBs
      show structural similarity to plant R2R3-MYB factors implicated in
      phenylpropanoid biosynthesis. GhMYB5 is the most distantly related cotton R2R3
      MYB and is found in an isolated cluster that includes the drought-inducible
      AtMYB2. Sequence comparisons of DBD and TRR domains from GhMYBs, MIXTA (AmMYBMx)
      and G11 (AtMYBG11) did not reveal any striking similarity beyond conserved
      motifs. However, based on earlier phylogenetic analysis, GhMYB2, GhMYB3, and
      GHMYB4 are members of a cluster that contains GLABROUS1, while GhMYB1 and GhMYB6
      belong to a closely related cluster. Semi-quantitative RT-PCR analysis revealed
      two discrete patterns of GhMYB gene expression. Type I cotton MYB (GhMYB-1, -2,
      and -3) transcripts were found in all tissue-types examined and were relatively
      more abundant than those derived from type II GhMYB genes (GhMYB-4, -5, and -6),
      which showed distinct, tissue-specific expression patterns. The developmental
      regulation of GhMYBs is consistent with a role for these DNA-binding factors in
      the differentiation and expansion of cotton seed trichomes.

PMID- 10394904
TI  - The Drosophila cinnamon gene is functionally homologous to Arabidopsis cnx1 and
      has a similar expression pattern to the mammalian gephyrin gene.
AB  - Molybdoenzymes are involved in a variety of essential pathways including nitrate
      assimilation, sulfur and/or purine metabolism and abscisic acid biosynthesis.
      Most organisms produce several such enzymes requiring a molybdopterin cofactor
      for catalytic function. Mutations that result in a lack of the molybdopterin
      cofactor display a pleiotropic loss of molybdoenzyme activities, and this
      phenotype has been used to identify genes involved in cofactor biosynthesis or
      utilization. Although several cofactor genes have been analyzed in prokaryotes,
      much less is known concerning eukaryotic molybdenum cofactor (MoCF) genes. This
      work is focused on the Drosophila MoCF gene cinnamon (cin) which encodes a
      multidomain protein, CIN, that shows significant similarity to three proteins
      encoded by separate prokaryotic MoCF genes. These domains are also present in the
      product of cnx1, an Arabidopsis MoCF gene, and in GEPHYRIN, a rat protein thought
      to organize the glycine receptor, GlyR, within the postsynaptic membrane. Since
      this apparent consolidation of separate prokaryotic genes into a single
      eukaryotic gene is a feature of other conserved metabolic pathways, we wished to
      determine whether the protein's function is also conserved. This report shows
      that the plant gene cnx1 can rescue both enzymatic and physiological defects of
      Drosophila carrying cin mutations, indicating that the two genes serve similar or
      identical functions. In addition, we have investigated the relationship between
      CINNAMON and GEPHYRIN, using immunohistochemical methods to localize the CIN
      protein in Drosophila embryos. Most of the CIN protein, like GEPHYRIN in the rat
      CNS, is localized to the cell borders and shows a tissue-specific pattern of
      expression. In a parallel study, antibody to GEPHYRIN revealed the same tissue
      specific expression pattern in fly embryos. Both antibodies show altered staining
      patterns in cin mutants. Taken together, these results suggest that GEPHYRIN may
      also carry out a MoCF-related function.

PMID- 10394905
TI  - A novel role for the mating type (MAT) locus in the maintenance of cell wall
      integrity in Saccharomyces cerevisiae.
AB  - The cell wall and stress response component (Wsc) protein family in the yeast
      Saccharomyces cerevisiae is encoded by at least three genes, WSC1, WSC2, and
      WSC3. The Wsc proteins are putative upstream activators of the RHO1-regulated
      PKC1-MAP kinase cascade, and are required for maintenance of cell wall integrity
      and the stress response. Deletion of WSC1 causes a cell lysis defect that is
      exacerbated by deleting WSC2 or WSC3. This cell lysis defect can be rescued by
      adding osmotic stabilizers, such as 1 M sorbitol, to the medium, and by
      overexpressing PKC1 or RHO1. To advance our understanding of the function of the
      WSC genes, we performed a genetic screen to identify other components of the
      pathways they regulate. Here we report our findings. MATa1 and MATalpha2 were
      identified as dosage-dependent suppressors of the lysis defect of a wsc delta
      mutant. Overexpression of MATa1 or MATalpha2 was found to suppress the heat shock
      sensitivity, in addition to the lysis defect, of the wsc delta mutant. Phenotypic
      suppression by these two genes, MATa1 and MATalpha2, is significantly stronger
      when they are overexpressed in cells of the opposite mating type. Deletion of
      MATa1 exacerbates the lysis defect of haploid and diploid wsc delta strains. Our
      results suggest that the MAT locus plays a role in responses similar to those
      regulated by WSC and provide evidence for a regulatory effect of the MAT locus
      outside the realm of cell type determination.

PMID- 10394906
TI  - The Drosophila melanogaster gene for the NADH:ubiquinone oxidoreductase acyl
      carrier protein: developmental expression analysis and evidence for alternatively
      spliced forms.
AB  - We have isolated the Drosophila melanogaster gene encoding the mitochondrial acyl
      carrier protein (mtACP), a subunit of NADH:ubiquinone oxidoreductase involved in
      de novo fatty acid synthesis in the mitochondrion. This gene expresses two
      distinct mature transcripts by alternative splicing, which encode mature
      polypeptides of 86 (mtACP1A) and 88 (mtACP1B) amino acids, respectively.
      Drosophila mtACP1 is 72% identical to mammalian mtACP, 47% identical to
      Arabidopsis thaliana mtACP, and 46% identical to Neurospora crassa mtACP. The
      most highly conserved region encompasses the site that binds pantetheine-4'
      phosphate in all known ACPs. Southern analysis of genomic DNA and in situ
      hybridization to salivary gland chromosomes indicate that a single gene (mtacp1),
      located at 61F6-8, encodes the two isoforms of D. melanogaster mtACP1. Sequence
      analysis revealed that the gene contains four exons and that exons IIIA and IIIB
      are alternatively spliced. A P-element-induced loss-of-function mutation in the
      mtacp1 gene causes lethality, indicating that the gene is essential for
      viability. Developmental Northern analysis shows that mtacp1 is expressed at
      higher levels during late embryogenesis, in the pupa and in the adult. RNA in
      situ hybridization on embryos indicates that the mtacp1 gene is highly expressed
      in the tracheal system. Zygotic mtacp1 function is required for both male and
      female gametogenesis.

PMID- 10394907
TI  - Construction and characterization of bacterial artificial chromosome libraries
      from the silkworm, Bombyx mori.
AB  - Two bacterial artificial chromosome (BAC) libraries were constructed using
      nuclear DNA from posterior silkglands of the silkworm (Bombyx mori) strains p50
      and C108. The libraries contain a total of 36,864 clones, or approximately 9
      genome equivalents. The average insert sizes in the libraries were 134.5 kb and
      120.8 kb, respectively. PCR-based screening was performed on the p50 library
      using probes for 34 sequence-tagged sites (STSs). Between 3 and 11 (6.1 hits on
      average) clones were isolated with each STS, in good agreement with the library
      size, 5.8 genome equivalents. The previously reported close linkage between the
      Bombyx homologs of the invected (Bm in) and engrailed (Bm en) genes was confirmed
      by construction of a BAC contig that contained both. Moreover, screening revealed
      novel information about the chromosomal organization of the sericin-1 and DH-PBAN
      genes, which were localized within a 22-kb interval and are divergently oriented.
      These results show that it is possible to construct contigs and analyze
      chromosome organization using these libraries.

PMID- 10394908
TI  - Mobilisation of the streptococcal plasmid pMV158: interactions of MobM protein
      with its cognate oriT DNA region.
AB  - The streptococcal plasmid pMV158 encodes the relaxase protein, MobM, involved in
      its mobilisation. Purified MobM protein specifically cleaved supercoiled or
      single-stranded DNA containing the plasmid origin of transfer, oriT. Gel
      retardation and DNase I footprinting assays performed with DNA fragments
      containing the plasmid oriT provided evidence for specific binding of MobM by
      oriT DNA. Dissection of the MobM-binding sequence revealed that the oriT region
      protected by MobM spanned 28 nucleotides, and includes an inversely repeated
      sequence, termed IR2. MobM exhibits a high degree of similarity with the mob gene
      product of the Streptococcus ferus plasmid pVA380-1. Although the origins of
      transfer of pMV158 and pVA380-1 show 20% sequence divergence in a 24-bp sequence
      included in their oriT regions, the pMV158 MobM was able to cleave a supercoiled
      derivative of pVA380-1 in vitro.

PMID- 10394909
TI  - The function of the chicken p34CDC2 protein kinase in fission yeast is cold
      sensitive for cell cycle progression through the G1 phase and temperature
      sensitive for traversal of mitosis.
AB  - The protein kinase p34cdc2 is required at the onset of DNA replication and for
      entry into mitosis. The catalytic subunit and its regulatory proteins, notably
      the cyclins, are conserved from yeast to man. This suggests that the control
      mechanisms necessary for progression through the cell cycle in fission yeast are
      conserved throughout evolution. This work describes the characterization of a
      fission yeast strain that is dependent for cell cycle progression on the activity
      of the p34CDC2 protein kinase from chicken. The response of the chicken p34CDC2
      protein kinase to cell cycle components of fission yeast was examined. Cells
      expressing the chicken p34CDC2 protein divide at reduced size at 31 degrees C.
      Cells are temperature sensitive at 35.5 degrees C and die as a result of mitotic
      catastrophe. This phenotype can be rescued by delaying cell cycle progression at
      the G1-S transition by adding low concentrations of hydroxyurea.
      Schizosaccharomyces pombe cells that are dependent on chicken p34CDC2 are cold
      sensitive. At 19 degrees C to 25 degrees C cells arrest in the G1 phase, while
      traversal of the G2-M transition is not blocked at low temperature. Expression of
      chicken p34CDC2 in the cold-sensitive G2-M mutant cdc2A21 suppresses the G1
      arrest.

PMID- 10394910
TI  - Genetic analysis of leaf form mutants from the Arabidopsis Information Service
      collection.
AB  - Although a vast inventory of morphological mutants of Arabidopsis thaliana is
      available, only some have been used for genetic studies of leaf development. Such
      is the case with the Arabidopsis Information Service (AIS) Form Mutants
      collection, assembled by A. R. Kranz and currently stored at the Nottingham
      Arabidopsis Stock Centre, which includes a large number of mutant lines, most of
      which have been little studied. With the aim of contributing to the genetic
      dissection of leaf ontogeny, we have subjected 57 mutant lines isolated by others
      to genetic analysis; 47 of which were from the AIS collection. These are
      characterized by vegetative leaves of abnormal shape or size, and were chosen as
      candidates for mutations in genes required for leaf morphogenesis. The mutant
      phenotypes studied were shown to be inherited as single recessive Mendelian
      traits and were classified into 10 phenotypic classes. These mutant strains were
      found to fall into 37 complementation groups, 7 of which corresponded to known
      genes. Results of the phenotypic analysis and data on the genetic interactions of
      these mutants are presented, and their possible developmental defects discussed.

PMID- 10394911
TI  - The oxidative stress response mediated via Pos9/Skn7 is negatively regulated by
      the Ras/PKA pathway in Saccharomyces cerevisiae.
AB  - Exposure of Saccharomyces cerevisiae to elevated concentrations of hydrogen
      peroxide induces transcription of several genes involved in the oxidative stress
      response. Two major transcription factors are involved in this induction,
      Pos9/Skn7 and Yap1. Fusions of either Yap1 or Pos9/Skn7 with the Gal4 DNA binding
      domain are active as transcription factors. Gal4-Yap1-dependent reporter gene
      activity is only weakly regulated by oxidative stress. In contrast, fusion of the
      Gal4 DNA binding domain to the Pos9/Skn7 protein results in a transcription
      factor that is independent of the YAP1 gene and is strictly regulated by
      oxidative stress, indicating that a signaling cascade impinges on the Pos9/Skn7
      protein. We have observed that the Ras/PKA (cAMP-dependent protein kinase A)
      pathway affects this signaling. When PKA activity was low (in the presence of
      multicopy PDE2 or a cyr1(D822-->A) mutation) maximum reporter gene activity was
      observed even in the absence of oxidative stress. In contrast, high PKA activity
      (in strains mutant for either pde2 or bcy1, or expressing the dominant active
      Ras2Val19) resulted in a complete loss of activation following oxidative stress.
      The transcription of Pos9/Skn7 target genes was also affected in Ras/PKA pathway
      mutants. Furthermore, we demonstrated that activated Pos9/Skn7 is necessary for
      Yap1-dependent reporter gene induction.

PMID- 10394912
TI  - The Additional sex combs gene of Drosophila is required for activation and
      repression of homeotic loci, and interacts specifically with Polycomb and super
      sex combs.
AB  - The protein products of Polycomb group (PcG) and trithorax group (trxG) genes are
      required for the maintenance of the transcriptionally repressed and active
      states, respectively, of the homeotic genes. Mutations in PcG genes produce gain
      of-function (posterior) homeotic transformations, while mutations in trxG genes
      produce loss-of-function (anterior) homeotic transformations. Double mutant
      combinations between a PcG gene and a trxG gene suppress the homeotic
      transformations seen with either mutation alone, suggesting that PcG and trxG
      genes act antagonistically. The PcG gene Additional sex combs (Asx) is
      interesting because one mutant allele, AsxP1, causes both anterior and posterior
      homeotic transformations. AsxP1 and other Asx mutations were crossed to mutations
      in the PcG gene Polycomb (Pc) and the trxG gene trithorax (trx). Asx alleles
      enhance both PcG and trxG homeotic transformations, showing that Asx is required
      for both the activation and the repression of homeotic loci. Asx also shows
      strong allele-specific interactions with the PcG genes Pc and super sex combs
      (sxc). Together, these data indicate that there are functional interactions
      between Asx, Pc and sxc in vivo. ASX may interact with a PcG complex containing
      PC and SXC and mediate activation versus repression at target loci, perhaps by
      interacting directly with the TRX protein.

PMID- 10394913
TI  - Altered biological properties of cell membranes in Escherichia coli dnaA and seqA
      mutants.
AB  - We present evidence that biological properties of cell membranes are altered in
      dnaA and seqA mutants of Escherichia coli relative to wild-type bacteria. We
      found that bacteriophage lambda forms extremely large plaques on the dnaA seqA
      double mutants. On the single mutants, dnaA and seqA, the plaques are also bigger
      than those formed on the wild-type host. However, no significant differences in
      intracellular phage lambda development were observed between wild-type and mutant
      hosts, indicating that differences in burst size do not account for the observed
      differences in plaque size. On the other hand, more efficient release of the
      phage lytic proteins and/or higher sensitivity of the cell membranes to these
      proteins may result in more efficient cell lysis. We found that the efficiency of
      adsorption of bacteriophage lambda to the dnaA seqA mutant cells is decreased at
      0 degrees C , but not at 30 degrees C, relative to the wild-type strain. A
      considerable increase in the permeability of membranes of the mutant cells for
      beta-galactosidase is demonstrated. The dnaA and seqA mutants are more sensitive
      to ethanol (an organic solvent) than wild-type bacteria, and the seqA strain and
      the double mutant dnaA seqA are very sensitive to deoxycholate (a detergent). We
      conclude that lesions in the genes dnaA and seqA result in alterations in cell
      membranes, such that the permeability and possibly also other properties of the
      membranes are significantly altered relative to wild-type bacteria.

PMID- 10394914
TI  - Specificity of the lipase-specific foldases of gram-negative bacteria and the
      role of the membrane anchor.
AB  - Folding of lipases that are secreted by Pseudomonads and other gram-negative
      bacteria via the type II secretion pathway is facilitated by dedicated
      chaperones, called lipase-specific foldases (Lifs). Lifs are membrane-anchored
      proteins with a large periplasmic domain. The functional interaction between the
      Lif and its cognate lipase is specific, since the Pseudomonas aeruginosa Lif was
      found not to substitute for Lifs from Burkholderia glumae or Acinetobacter
      calcoaceticus. However, the P. aeruginosa Lif was able to activate the lipase
      from the closely related species P. alcaligenes. Hybrid proteins constructed from
      parts of the P. aeruginosa and B. glumae Lifs revealed that the C-terminal 138
      amino acids of the B. glumae Lif determine the specificity of the interaction
      with the cognate lipase. Furthermore, the periplasmic domain of the B. glumae Lif
      was functional when cloned in frame with a cleavable signal sequence, which
      demonstrates that the membrane anchor is not essential for Lif function in vivo.
      However, the recombinant Lif was released into the medium, indicating that the
      function of the membrane anchor is to prevent secretion of the Lif together with
      the lipase.

PMID- 10394915
TI  - Analysis of yeast pms1, msh2, and mlh1 mutators points to differences in mismatch
      correction efficiencies between prokaryotic and eukaryotic cells.
AB  - Genetic stability relies in part on the efficiency with which post-replicative
      mismatch repair (MMR) detects and corrects DNA replication errors. In Escherichia
      coli, endogenous transition mispairs and insertion/deletion (ID) heterologies are
      corrected with similar efficiencies--but much more efficiently than transversion
      mispairs--as revealed by mutation rate increases in MMR mutants. To assess the
      relative efficiencies with which these mismatches are corrected in the yeast
      Saccharomyces cerevisiae, we examined repair of defined mismatches on
      heteroduplex plasmids and compared the spectra for >1000 spontaneous SUP4-o
      mutations arising in isogenic wild-type or MMR-deficient (pms1, mlh1, msh2)
      strains. Heteroduplexes containing G/T mispairs or ID heterologies were corrected
      more efficiently than those containing transversion mismatches. However, the
      rates of single base-pair insertion/deletion were increased much more (82-fold or
      34-fold, respectively) on average than the rate of base pair substitutions (4.4
      fold), with the rates for total transitions and transversions increasing to
      similar extents. Thus, the relative efficiencies with which mismatches formed
      during DNA replication are repaired appear to differ in prokaryotic and
      eukaryotic cells. In addition, our results indicate that in yeast, and probably
      other eukaryotes, these efficiencies may not mirror those obtained from an
      analysis of heteroduplex correction.

PMID- 10394916
TI  - Genetic evidence for interactions between yeast importin alpha (Srp1p) and its
      nuclear export receptor, Cse1p.
AB  - The yeast Srp1p protein functions as an import receptor for proteins bearing
      basic nuclear localization signals. Cse1p, the yeast homolog of mammalian CAS,
      recycles Srp1p back to the cytoplasm after import substrates have been released
      into the nucleoplasm. In this report we describe genetic interactions between
      SRP1 and CSE1. Results from genetic suppression and synthetic lethality studies
      demonstrate that these gene products interact to ensure accurate chromosome
      segregation. We also describe new mutant alleles of CSE1 and analyze a new
      temperature-sensitive allele of CSE1, cse1-2. This allele causes high levels of
      chromosome missegregation and cell cycle arrest during mitosis at the
      nonpermissive temperature.

PMID- 10394917
TI  - A simple and accurate method for generating co-dominant markers: an application
      of conformation-sensitive gel electrophoresis to linkage analysis in the
      silkworm.
AB  - A simple and sensitive method for linkage analysis is described, which is based
      on conformation-sensitive gel electrophoresis (CSGE). Using urea-containing
      agarose gels or a commercially available polyacrylamide-derived matrix, 13
      polymorphic markers were newly identified for known genes of the silkworm, Bombyx
      mori, which had been scored as monomorphic by PCR-RFLP analysis. This method for
      detecting polymorphisms is quite sensitive, and can be performed with inexpensive
      reagents and apparatus that is available in most molecular biology laboratories.

PMID- 10394918
TI  - Transposition of the piggyBac element in embryos of Drosophila melanogaster,
      Aedes aegypti and Trichoplusia ni.
AB  - The Lepidopteran transposable element piggyBac is being recognized as a useful
      vector for genetic engineering in a variety of insect species. This transposon
      can mediate transformation in the Dipteran species Ceratitis capitata, and can
      potentially serve as a versatile vector for transformation of a wide variety of
      insect species. Using a plasmid-based interplasmid transposition assay, we have
      demonstrated that this transposon, of the short inverted terminal repeat type, is
      capable of transposition in embryos of three different insect species, Drosophila
      melanogaster, the yellow fever mosquito Aedes aegypti, and its host of origin,
      Trichoplusia ni. This assay can confirm the potential utility of piggyBac as a
      gene transfer tool in a given insect species, and provides an experimental model
      for assessing molecular mechanisms of transposon movement.

PMID- 10394919
TI  - Circadian clock-regulated expression of an RNA-binding protein in Arabidopsis:
      characterisation of a minimal promoter element.
AB  - The Atgrp7 transcript encodes a clock-regulated, glycine-rich, RNA-binding
      protein in Arabidopsis thaliana and shows a circadian variation in steady-state
      abundance. Constitutive overexpression of its product, AtGRP7, in transgenic
      Arabidopsis plants depresses the oscillations of the endogenous Atgrp7
      transcript, indicating that both the transcript and the protein are part of a
      clock-regulated negative feedback circuit. Here we characterise the upstream
      region of the Atgrp7 gene in order to begin to dissect the molecular basis of
      this oscillating autoregulatory feedback loop. Fusion of a 1.5-kb promoter
      fragment to the beta-glucuronidase (gus) reporter gene leads to circadian
      oscillations in the level of the gus transcript in transgenic Arabidopsis plants,
      with highest levels in the evening, indicating that transcription of the Atgrp7
      gene is rhythmically activated by the endogenous circadian clock. A 265-bp
      fragment upstream of the transcription start site is necessary for high-amplitude
      Atgrp7 cycling. Within this region, a 56-bp clock-responsive element that confers
      a low-amplitude circadian oscillation (approximately threefold) with peak
      abundance in the early evening maps between positions -112 and -57. Another
      element necessary for augmenting the amplitude of the oscillation lies between 
      178 and -264. Genetic crosses between a line bearing a promoter-gus fusion and
      plants that overexpress AtGRP7 show that the promoter by itself does not mediate
      the negative feedback of AtGRP7 on the oscillations of its own transcript.

PMID- 10394920
TI  - Molecular cloning and characterisation of a maize cDNA for a homologue of the
      large subunit of the eukaryotic initiation factor 3 (eIF3).
AB  - In order to identify genes that are specifically expressed in distinct cell
      populations of the maize root apex, we have constructed PCR-directed cDNA
      libraries from microdissected populations of cells, and screened them by
      differential hybridisation. A meristem-specific cDNA was isolated and
      characterised. This cDNA, termed ZmeIF3A, encodes a protein homologous to the
      large subunit of the eukaryotic translation Initiation Factor 3 (eIF3), which is
      an essential multi-protein complex for the initiation of protein synthesis. The
      ZmeIF3A protein is most similar to the yeast homologue RPG1, lacking the repeated
      C-terminal domain characteristic of its mammalian counterparts. However, despite
      this similarity, it fails to replace the RPG1 protein in complementation
      experiments on yeast mutants. Analysis of gene expression in situ showed that the
      ZmeIF3A transcript is expressed in the region of the root meristem surrounding
      the central stele. ZmeIF3A mRNA is also expressed in the young root, the male
      inflorescence, and the developing cob and seed. In maize, ZmeIF3A is encoded by
      one or two genomic sequences. This is the first report on the isolation and
      characterisation of a cDNA from higher plants that encodes a product homologous
      to a component of the eIF3 complex.

PMID- 10394922
TI  - Multiple Ty-mediated chromosomal translocations lead to karyotype changes in a
      wine strain of Saccharomyces cerevisiae.
AB  - Enological strains of Saccharomyces cerevisiae display a high level of chromosome
      length polymorphism, but the molecular basis of this phenomenon has not yet been
      clearly defined. In order to gain further insight into the molecular mechanisms
      responsible for the karyotypic variability, we examined the chromosomal
      constitution of a strain known to possess aberrant chromosomes. Our data revealed
      that the strain carries four rearranged chromosomes resulting from two reciprocal
      translocations between chromosomes III and I, and chromosomes III and VII. The
      sizes of the chromosomal fragments exchanged through translocation range from 40
      to 150 kb. Characterization of the breakpoints indicated that the translocations
      involved the RAHS of chromosome III, a transposition hot-spot on the right arm of
      chromosome I and a region on the left arm of chromosome VII. An analysis of the
      junctions showed that in all cases Ty elements were present and suggested that
      the translocations result from recombination between transposable Ty elements.
      The evidence for multiple translocations mediated by Ty elements in a single
      strain suggests that spontaneous Ty-driven rearrangement could be quite common
      and may play a major role in the alteration of karyotypes in natural and
      industrial yeasts.

PMID- 10394921
TI  - The topoisomerase II-associated protein, Pat1p, is required for maintenance of
      rDNA locus stability in Saccharomyces cerevisiae.
AB  - The Pat1 protein of Saccharomyces cerevisiae was identified during a screen for
      proteins that interact with topoisomerase II. Previously, we have shown that pat1
      delta mutants exhibit a slow-growth phenotype and an elevated frequency of both
      mitotic and meiotic chromosome mis-segregation. Here, we have studied the effects
      of deleting the PAT1 gene on chromosomal stability, with particular reference to
      rates of homologous recombination within the rDNA locus. This locus was analyzed
      because rDNA-specific hyperrecombination is known to occur in conditional top2
      mutants. We show that pat1 delta strains mimic top2 mutants in displaying an
      elevated rate of intrachromosomal excision recombination at the rDNA locus, but
      not elsewhere in the genome. The elevated rate of recombination is dependent upon
      Rad52p, but not upon Rad51p or Rad54p. However, pat1 delta strains display
      additional manifestations of more general genomic instability, in that they show
      mild sensitivity to UV light and an increased incidence of interchromosomal
      recombination between heteroalleles.

PMID- 10394924
TI  - Glucose repression of the Kluyveromyces lactis invertase gene KlINV1 does not
      require Mig1p.
AB  - Kluyveromyces lactis, a budding yeast related to Saccharomyces cerevisiae, can
      grow on a wider variety of substrates and shows less sensitivity to glucose
      repression than does Saccharomyces cerevisiae. Many genes that are subject to
      glucose repression in S. cerevisiae are repressed only weakly or not at all in K.
      lactis. The molecular basis for this difference is largely unknown. To compare
      the mechanisms that regulate glucose repression in K. lactis and S. cerevisiae,
      we decided to clone and analyse an invertase gene from K. lactis. The SUC2 gene,
      which encodes invertase in S. cerevisiae, is strongly regulated by glucose and
      serves as a model system for studies on glucose repression. The invertase gene of
      K. lactis, KlINV1, was isolated by colony hybridization using a conserved region
      within the inulinase gene of K. marxianus as a probe. Two independent clones
      obtained were shown to contain the same ORF of 1827 bp. The deduced amino acid
      sequence is 59% similar to that of the K. marxianus inulinase and shows 49%
      similarity to ScSuc2p. Gene disruption experiments and low-stringency Southern
      analysis indicate that KlINV1 is a unique gene in K. lactis. Northern analysis
      revealed that the transcription of KlINV1 is strongly repressed in the presence
      of glucose, but, in contrast to the case in S. cerevisiae, repression is
      independent of KlMig1p.

PMID- 10394923
TI  - Analysis of the replication region of the cryptic plasmid pHE1 from the moderate
      halophile Halomonas elongata.
AB  - The basic replicon of the narrow-host-range plasmid pHE1 from the moderately
      halophilic bacterium Halomonas elongata ATCC 33174 has been identified and
      characterized. The replicon consists of a 1.7-kb DNA fragment, which contains the
      genetic information required for autonomous replication and stable maintenance.
      Analysis of its sequence revealed the presence of two ORFs which seem to form one
      transcription unit. ORF1 encodes a replication initiator protein (RepA), which
      has a high degree of homology to the theta-replicase (RepA) protein of ColE2
      plasmid and to the RepA proteins of a family of replicons from gram-positive and
      gram-negative bacteria, also related to ColE2. The product encoded by ORF2 showed
      a certain similarity to the RepB proteins of the same family of replicons and
      perhaps represents the pHE1 RepB function. Deletion analysis suggests that the
      pHE1 origin of replication (ori) is located in an 800-bp region upstream of repA.
      A third putative gene, incA, was found on the complementary strand to the leader
      region of the repA mRNA. This, together with the presence in the 5' untranslated
      region of the repA mRNA of inverted repeats that could form stable stem-loop
      structures, suggests that the incA gene encodes a small antisense RNA. A possible
      control mechanism for pHE1 replication is proposed, involving an RNA molecule
      which sequesters the translational initiation region of the replication protein
      RepA. The basic replicon characterized here shows very interesting properties
      that should allow it to be used in the construction of cloning and expression
      vectors for moderate halophiles.

PMID- 10394925
TI  - Double-strand break repair can lead to high frequencies of deletions within short
      CAG/CTG trinucleotide repeats.
AB  - Trinucleotide repeats undergo contractions and expansions in humans, leading in
      some cases to fatal neurological disorders. The mechanism responsible for these
      large size variations is unknown, but replication-slippage events are often
      suggested as a possible source of instability. We constructed a genetic screen
      that allowed us to detect spontaneous expansions/contractions of a short
      trinucleotide repeat in yeast. We show that deletion of RAD27, a gene involved in
      the processing of Okazaki fragments, increases the frequency of contractions
      tenfold. Repair of a chromosomal double-strand break (DSB) using a trinucleotide
      repeat-containing template induces rearrangements of the repeat with a frequency
      60 times higher than the natural rate of instability of the same repeat. Our data
      suggest that both gene conversion and single-strand annealing are major sources
      of trinucleotide repeat rearrangements.

PMID- 10394926
TI  - Allelic polymorphisms and RFLP in the human immunoglobulin lambda light chain
      locus.
AB  - The organization of the human immunoglobulin lambda light chain locus (IGL) was
      recently described. This locus has been entirely sequenced. To evaluate the
      extent of the genomic variability existing inside that locus, we compiled all the
      available sequences of germline IGLV genes to find variants of Vlambda sequences.
      We also looked for RFLP polymorphisms in a reputedly highly polymorphic human
      population from eastern Senegal, and compiled all RFLP data previously published.
      Analysis of these data indicates that IGLV alleles are frequent and increase the
      diversity of the lambda light chain repertoire in the human population. In
      contrast, RFLP and polymorphism by insertion and/or deletion are limited in that
      locus. This observation reinforces our hypothesis that the human IGL locus has
      undergone less evolutionary shuffling than the human kappa or heavy-chain loci.

PMID- 10394927
TI  - Combined RxFISH/G-banding allows refined karyotyping of solid tumors.
AB  - Chromosome banding analysis of solid tumors often yields incomplete karyotypes
      because of the complex rearrangements encountered. The addition of fluorescence
      in situ hybridization (FISH) methods has helped improve the accuracy of solid
      tumor cytogenetics, but the absence of screening qualities from standard FISH
      approaches has proved a severe limitation. We describe the cytogenetic analysis
      of ten solid tumors using G-banding followed by cross-species color banding
      (RxFISH), a FISH-based screening technique giving a chromosome-specific banding
      pattern based on the genomic homologies between humans and gibbons. The addition
      of RxFISH analysis in all cases led to the identification of previously
      unidentified intra- as well as interchromosomal rearrangements, thus giving a
      much more certain and detailed karyotype. In two gastric stromal sarcomas, a
      tumor type for which no cytogenetic data were hitherto available, numerical
      chromosomal aberrations dominated, but one of the tumors also carried an
      unbalanced 7;17-translocation with the same breakpoint in chromosome 17 as that
      seen in endometrial stromal sarcomas.

PMID- 10394928
TI  - A high degree of aneuploidy in frozen-thawed human preimplantation embryos.
AB  - We have studied the chromosomal content in 68 normally fertilised freeze-thawed
      human embryos of good morphology from 34 patients with an average maternal age of
      32,6 years. Forty embryos showed post-thaw cellular division and twenty-eight
      post-thaw cleavage arrest. After spreading of the embryos on microscope slides,
      analysis of chromosomes X, Y, 15, 16, 17 and 18 was performed using two rounds of
      fluorescent in situ hybridisation (FISH). According to the results, the embryos
      were divided into four groups: (I) normal, all nuclei uniformly diploid, (II)
      diploid mosaics, normal diploid blastomeres in combination with abnormal
      blastomeres, (III) abnormal, all nuclei abnormal, (IV) chaotic, the chromosome
      constitution varies randomly from cell to cell. Approximately 25% of the embryos
      had normal number of the chromosomes tested, while the majority of the embryos
      were abnormal. Most of the abnormal embryos were diploid mosaics (57%). This was
      true for the embryos showing cleavage division as well as the embryos showing
      cleavage arrest. Our data show a slightly higher incidence of abnormal embryos
      compared to those obtained with FISH in non-cryopreserved embryos and confirm
      that the majority of preimplantation embryos fertilised in vitro contain abnormal
      blastomeres. The results, mechanisms, significance and implications are
      discussed.

PMID- 10394930
TI  - Phenylketonuria mutations in Germany.
AB  - We report the spectrum of mutations and associated modified haplotypes in
      patients with phenylketonuria living in Germany. A total of 546 independent
      alleles was investigated, including 411 of German and 65 of Turkish descent.
      Mutations were identified for 535 PKU alleles (98%) and there were 91 different
      mutations. The most common mutation was R408W on 22% of alleles. Two mutations,
      IVS12+1G-->A and IVS10-11G-->A accounted for just under 10% of alleles, whereas
      the remaining mutations were found at relative frequencies of 6% or less; 43
      mutations were observed once only. IVS10-11G-->A was the most common mutation
      (38% of alleles) in the subgroup of patients of Turkish descent. Modified
      haplotypes were determined from the analysis of four silent mutations, three
      diallelic restriction fragment length polymorphisms, a variable number of tandem
      repeats minisatellite and a short tandem repeat microsatellite in the
      phenylalanine hydroxylase gene, showing that a considerable proportion of
      mutations must have recurred in independent founders; other mutations may have
      changed chromosomal haplotype backgrounds by gene conversion. The spectrum of PKU
      mutations in Germany reflects the history of a heterogenous Central European
      population living at the crossroads of migration throughout the centuries.

PMID- 10394929
TI  - The mutation spectrum of the bestrophin protein--functional implications.
AB  - Best's macular dystrophy (BMD), also known as vitelliform macular degeneration
      type 2 (VMD2; OMIM 153700), is an autosomal dominant form of macular degeneration
      with mainly juvenile onset. BMD is characterized by the accumulation of
      lipofuscin within and beneath the retinal pigment epithelium. The gene causing
      the disease has been localized to 11q13 by recombination breakpoint mapping.
      Recently, we have identified the causative gene encoding a protein named
      bestrophin, and mutations have been found mainly to affect residues that are
      conserved from a family of genes in Caenorhabditis elegans. The function of
      bestrophin is so far unknown, and no reliable predictions can be made from
      sequence comparisons. We have investigated the bestrophin gene in 14 unrelated
      Swedish, Dutch, Danish, and Moroccan families affected with BMD and found eight
      new mutations. Including the previously published mutations, 15 different
      missense mutations have now been detected in 19 of the 22 families with BMD
      investigated by our laboratory. Interestingly, the mutations cluster in certain
      regions, and no nonsense mutations or mutations causing frame-shifts have been
      identified. Computer simulations of the structural elements in the bestrophin
      protein show that this protein is probably membrane bound, with four putative
      transmembrane regions.

PMID- 10394931
TI  - Enrichment of fetal trophoblasts and nucleated erythrocytes from maternal blood
      by an immunomagnetic colloid system.
AB  - The aim of this study was to isolate fetal trophoblasts and nucleated
      erythrocytes from maternal blood using the immunomagnetic colloid system. About
      25 ml of maternal blood was collected from pregnant women between of 14 and 20
      weeks gestation. Nucleated erythrocytes (NRBCs) were isolated from 5 ml of
      maternal blood and a nested polymerase chain reaction for the Y chromosome was
      used to determine fetal origin. The sensitivity of the fetal gender diagnosis was
      80% and the specificity was 86%. Both fetal trophoblasts and NRBCs were isolated
      from the remaining 20 ml of maternal blood. The fetal gender of the trophoblast
      enriched fraction was determined using fluorescence in situ hybridisation (FISH)
      with dual-colour XY-specific DNA probes. XY-specific signals were observed in
      0.38% of cells sorted from all pregnant women carrying male fetuses (n = 10).
      Simultaneous immunophenotyping for the fetal haemoglobin and FISH using XY probes
      were used to evaluate the fetal origin of cells enriched with anti-CD71. The mean
      percentage of male fetal erythroblasts was 0.24% and the number of fetal
      erythroblasts was estimated to be about 672 in 20 ml of maternal blood. The
      number of fetal erythroblasts detected in our study was greater than that
      detected by most other separation techniques. Our study shows that it would be
      feasible to use the immunomagnetic colloid system for the isolation of both
      trophoblasts and NRBCs from the same maternal blood sample with relatively good
      efficiency.

PMID- 10394932
TI  - Estimates of sperm sex chromosome disomy and diploidy rates in a 47,XXY/46,XY
      mosaic Klinefelter patient.
AB  - A 47,XXY/46,XY male was investigated for the incidence of aneuploidy in sperm sex
      chromosomes using a three-colour X/Y/18 fluorescence in situ hybridisation (FISH)
      protocol. A total of 1701 sperm nuclei were analysed. The ratio of X-bearing to Y
      bearing sperm did not differ from the expected 1:1 ratio although there were more
      23,Y sperm than 23,X sperm (844 vs 795). There was a significantly increased
      proportion of disomy XY and XX sperm compared with normal controls (0.41% vs
      0.10%, P < 0.001 and 0.29% vs 0.04%, P < 0.01). However, the incidence of YY
      sperm was similar to the controls (0.06% vs 0.02%). The diploidy rate was also
      significantly increased (1.7% vs 0.13%, P < 0.0001), as was disomy 18 (0.71% vs
      0.09%) and 25,XXY (0.47% vs 0%). The results support the hypothesis that some
      47,XXY cells are able to undergo meiosis and produce mature spermatozoa. Patients
      with mosaic Klinefelter syndrome with severe oligozoospermia have significantly
      elevated incidences of disomy XY and XX sperm and may be at a slightly increased
      risk of producing 47,XXX and 47,XXY offspring. Additionally, they may be at risk
      of producing offspring with autosomal trisomies. Hence, patients with Klinefelter
      mosaicism scheduled for intracytoplasmic sperm injection intervention should
      first undergo FISH analysis of their sperm to determine their risk.

PMID- 10394933
TI  - Exclusion of RAI2 as the causative gene for Nance-Horan syndrome.
AB  - Nance-Horan syndrome (NHS) is an X-linked condition characterised by congenital
      cataracts, microphthalmia and/or microcornea, unusual dental morphology,
      dysmorphic facial features, and developmental delay in some cases. Recent linkage
      studies have mapped the NHS disease gene to a 3.5-cM interval on Xp22.2 between
      DXS1053 and DXS443. We previously identified a human homologue of a mouse
      retinoic-acid-induced gene (RAI2) within the NHS critical flanking interval and
      have tested the gene as a candidate for Nance-Horan syndrome in nine NHS-affected
      families. Direct sequencing of the RAI2 gene and predicted promoter region has
      revealed no mutations in the families screened; RAI2 is therefore unlikely to be
      associated with NHS.

PMID- 10394934
TI  - Multicolor fluorescence in situ hybridization analysis of the spermatozoa of a
      male heterozygous for a reciprocal translocation t(11;22)(q23;q11).
AB  - A reciprocal translocation between chromosomes 11 and 22 is a site-specific
      translocation that has been seen in many families with no common ancestry. This
      translocation is of particular interest because balanced carriers have a 0.7-3.7%
      risk of having children with the supernumerary der(22), resulting from a 3:1
      segregation. We have used a three color fluorescence in situ hybridization (FISH)
      with specific DNA probes to determine the chromosome segregation pattern of a
      male carrier of a translocation t(11;22)(q23;q11). The probes selected included a
      centromeric marker for chromosome 11, a marker closely linked to the centromere
      of chromosome 22, and a third probe distal to the translocation breakpoint of
      chromosome 22. The results showed that 3:1 segregation is preferential in this
      patient, with 40.1% of spermatozoa belonging to this segregation type. Alternate
      segregation followed with 27.4% of analyzed spermatozoa; 17.6% resulted from
      adjacent 1 and 12.5% resulted from adjacent 2 segregation. We detected 0.5% of
      presumably diploid spermatozoa. Complementary adjacent 1 products were observed
      at statistically different frequencies (P = 0.02). Complementary adjacent 2
      products without recombination in the interstitial segments were also seen at
      different frequencies (P = 0.002). In 3:1 segregation, the products containing
      one chromosome were observed more frequently than those with three chromosomes (P
      = 0.0001). The 24,+der(22) gamete was seen more frequently than all of the other
      gametes combined which had 24 chromosomes resulting from 3:1 segregation. The
      results of this study demonstrate that in this t(11;22) carrier, 3:1 segregation
      is preferential but not exclusive.

PMID- 10394935
TI  - A group of schwannomas with interstitial deletions on 22q located outside the NF2
      locus shows no detectable mutations in the NF2 gene.
AB  - Schwannomas are tumors arising mainly at cranial and spinal nerves. Bilateral
      vestibular schwannoma is the hallmark of neurofibromatosis type2 (NF2). The NF2
      gene has been cloned and comprehensive analysis of its mutations in schwannomas
      shows that up to 60% of tumors carry inactivating mutations. Thus, the genetic
      mechanism behind the development of more than 40% of schwannomas without NF2
      mutations is unknown. We have therefore studied tumor tissue from 50 human
      schwannomas by allelotyping and have found chromosome 22 deletions in over 80% of
      the cases. We detected 14 cases (27%) that revealed partial deletions of one copy
      of chromosome 22, i.e., terminal and/or interstitial deletions. We sequenced the
      NF2 gene in seven of these tumors and detected only one case with mutations. The
      deletion mapping of chromosome 22 in tumors with partial deletions indicates that
      several regions, in addition to the NF2 locus, harbor genes involved in
      schwannoma tumorigenesis. Our findings suggest that heterogeneity in the
      mechanisms leading to the development of schwannomas probably exists. These
      findings are in agreement with the recent analysis of schwannomas from familial
      and sporadic cases of schwannomatosis and point to a possible role of an
      additional gene, which, in cooperation with the NF2 tumor suppressor, causes
      schwannomas.

PMID- 10394936
TI  - Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome.
AB  - Pfeiffer syndrome (PS) is one of the classical craniosynostosis syndromes
      correlated with specific mutations in the human fibroblast growth factor receptor
      (FGFR) genes, FGFR1 and FGFR2. In this study, we set out to examine the exons in
      FGFR2 most commonly associated with mutations in PS, exons IIIa and IIIc, in a
      panel of 78 unrelated individuals with PS by the most sensitive method (direct
      DNA sequencing). We have identified a total of 18 different mutations among 40
      patients; eight of these mutations have not been previously described. The
      mutational spectrum displays a non-random character with the frequent involvement
      of cysteine codons.

PMID- 10394937
TI  - Association between coding variability in the LRP gene and the risk of late-onset
      Alzheimer's disease.
AB  - We have sequenced the entire (89 exons) open reading frame of the LRP gene in 12
      cases of Alzheimer's disease (AD) from Northern France. We have found no novel
      changes but confirm the occurrence of a polymorphism in exon 6 of the gene
      (A216V). This polymorphism is rare (2.8% of controls) and is in linkage
      equilibrium with previously reported polymorphisms. The V216 allele is negatively
      associated with the disease in a large case-controlled series. These data suggest
      that the LRP receptor may be involved in the pathobiology of AD, but the
      association that we report here cannot explain the previously reported genetic
      data implicating the LRP gene in AD. If the LRP gene is a major site of genetic
      variability leading to AD, there must be other biologically relevant variability
      in promoter or other regulatory elements of this large gene.

PMID- 10394938
TI  - A deletion/insertion leading to the generation of a direct repeat as a result of
      slipped mispairing and intragenic recombination in the factor VIII gene.
AB  - A deletion/insertion in the human factor VIII gene was found in a patient with
      severe hemophilia A; 316 bp were removed, viz., those enclosing part of intron 15
      and the first 7 bp of exon 16. In addition to the deletion, 6 bp were added to
      the deletion breakpoints; this resulted in the duplication of an existing 13-bp
      unit. Thus, an overlapping 13-bp direct repeat was generated at the deletion
      junction. Moreover, the deleted fragment itself was flanked by two homologous 6
      bp sequences, one unit being lost by the deletion. A combination of slipped
      mispairing during replication and an intragenic recombination is discussed to
      describe this deletion/insertion process.

PMID- 10394939
TI  - Gene symbol: AGXT. Disease: primary hyperoxaluria type I.

PMID- 10394940
TI  - Identification of cis-regulatory elements required for endosperm expression of
      the rice storage protein glutelin gene GluB-1.
AB  - Rice storage protein glutelin genes are coordinately regulated during seed
      development. A previous 5' deletion analysis using transgenic tobacco revealed
      that the minimum 5' region necessary for endosperm specificity was within -245 bp
      of the transcription start site, and included the AACA and GCN4 motifs that are
      highly conserved in the 5'-flanking regions of all glutelin genes. In this paper,
      the sequence elements essential for endosperm-specific expression are
      characterized in stable transgenic tobacco plants by both loss-of-function and
      gain-of-function experiments using this minimum promoter. Base substitution
      analysis shows that the proximal AACA motif between -73 and -61, and the GCN4
      motif between -165 and -158 act as critical elements. An ACGT motif between -81
      and -75, and Skn-I-like elements between -173 and -169 also play important roles
      in controlling the seed-specific expression. When the distal region between -245
      and -145 containing the AACA and the GCN4 motifs or the proximal region between 
      113 and -46 containing the ACGT and AACA motifs is fused to a truncated promoter
      (-90 to +9) of the CaMV 35S gene fused to the beta-glucuronidase (GUS) reporter
      gene, high levels of seed-specific expression are observed in these fusions,
      thereby indicating that either pair of motifs is sufficient to confer seed
      expression in these fusions. However, when substituted for by the CaMV 35S core
      promoter (-46 to +1), seed expression is abolished, suggesting that the sequence
      between -90 and -46 of the CaMV 35S promoter containing G-box-like motif (as-1
      element) is required for such specific expression in addition to AACA and GCN4
      motifs. Therefore, we conclude that at least three cis-regulatory elements, the
      AACA motif, GCN4 motif and ACGT motif, are necessary to mediate endosperm
      expression of the GluB-1 glutelin gene.

PMID- 10394941
TI  - Distribution of two isoforms of NADP-dependent isocitrate dehydrogenase in
      soybean (Glycine max).
AB  - Two different cDNAs that encode NADP-specific isocitrate dehydrogenase (NADP-IDH)
      isozymes of soybean (Glycine max) were characterized. The nucleotide sequences of
      the coding regions of these cDNAs have 74% identity to each other and give
      predicted amino acid sequences that have 83% identity to each other. Using PCR
      techniques, their coding regions were subcloned into a protein overexpression
      vector, pQE32, to yield pIDH4 and pIDH1, respectively. Both IDH4 and IDH1 enzymes
      were expressed in Escherichia coli as catalytically active His6 tagged proteins,
      purified to homogeneity by affinity chromatography on nickel chelate resin and
      rabbit polyclonal antibodies to each were generated. Surprisingly, antiserum to
      IDH4 did not react with IDH1 protein and IDH1 antiserum reacted only very weakly
      with IDH4 protein. IDH4 antibody reacts with a protein of expected molecular
      weight in cotyledon, young leaf, young root, mature root and nodules but the
      reaction with mature leaf tissue was low compared to other tissues. Western blot
      results show that IDH1 was not expressed in young roots but a protein that reacts
      with the IDH1 antibody was highly expressed in leaves, showing that there was
      tissue-specific accumulation of NADP-IDH isozymes in soybean.

PMID- 10394942
TI  - Characterization and heterologous expression of laccase cDNAs from xylem tissues
      of yellow-poplar (Liriodendron tulipifera).
AB  - Four closely related cDNA clones encoding laccase isoenzymes from xylem tissues
      of yellow-poplar (Ltlacc2.1-4) were identified and sequenced. The inferred yellow
      poplar laccase gene products were highly related to one another (79-91% at the
      amino acid level) and showed significant similarity to other blue copper
      oxidases, especially with respect to the copper-binding domains. The encoded
      proteins had N-terminal signal sequences and 17-19 potential N-linked
      glycosylation sites. The mature proteins were predicted to have molecular masses
      of ca. 61 kDa (unglycosylated) and high isoelectric points (pI 9.3-9.5). The
      canonical copper ligands were conserved, with the exception of a Leu residue
      associated with the axial position of the Type-1 cupric ion. The residue at this
      position has been proposed to influence the redox potential of Type-1 cupric
      ions. Northern blot analysis revealed that the yellow-poplar laccase genes are
      differentially expressed in xylem tissues. The genes were verified as encoding
      active laccases by heterologous expression in tobacco cells and demonstration of
      laccase activity in extracts from transformed tobacco cell lines.

PMID- 10394943
TI  - The IRT1 protein from Arabidopsis thaliana is a metal transporter with a broad
      substrate range.
AB  - The molecular basis for the transport of manganese across membranes in plant
      cells is poorly understood. We have found that IRT1, an Arabidopsis thaliana
      metal ion transporter, can complement a mutant Saccharomyces cerevisiae strain
      defective in high-affinity manganese uptake (smf1 delta). The IRT1 protein has
      previously been identified as an iron transporter. The current studies
      demonstrated that IRT1, when expressed in yeast, can transport manganese as well.
      This manganese uptake activity was inhibited by cadmium, iron(II) and zinc,
      suggesting that IRT1 can transport these metals. The IRT1 cDNA also complements a
      zinc uptake-deficient yeast mutant strain (zrt1zrt2), and IRT1-dependent zinc
      transport in yeast cells is inhibited by cadmium, copper, cobalt and iron(III).
      However, IRT1 did not complement a copper uptake-deficient yeast mutant (ctr1),
      implying that this transporter is not involved in the uptake of copper in plant
      cells. The expression of IRT1 is enhanced in A. thaliana plants grown under iron
      deficiency. Under these conditions, there were increased levels of root
      associated manganese, zinc and cobalt, suggesting that, in addition to iron, IRT1
      mediates uptake of these metals into plant cells. Taken together, these data
      indicate that the IRT1 protein is a broad-range metal ion transporter in plants.

PMID- 10394944
TI  - Disruption of specific flavonoid genes enhances the accumulation of flavonoid
      enzymes and end-products in Arabidopsis seedlings.
AB  - Polyclonal antibodies were developed against the flavonoid biosynthetic enzymes,
      CHS, CHI, F3H, FLS, and LDOX from Arabidopsis thaliana. These antibodies were
      used to perform the first detailed analysis of coordinate expression of flavonoid
      metabolism at the protein level. The pattern of flavonoid enzyme expression over
      the course of seedling development was consistent with previous studies
      indicating that chalcone synthase (CHS), chalcone isomerase (CHI), flavanone 3
      hydroxylase (F3H), and flavonol synthase (FLS) are encoded by 'early' genes while
      leucoanthocyanidin dioxygenase (LDOX) is encoded by a 'late' gene. This
      sequential expression may underlie the variations in flavonoid end-products
      produced during this developmental stage, as determined by HPLC analysis, which
      includes a shift in the ratio of the flavonols, quercetin and kaempferol.
      Moreover, immunoblot and HPLC analyses revealed that several transparent testa
      lines blocked at intermediate steps of the flavonoid pathway actually accumulated
      higher levels of specific flavonoid enzymes and end-products. These results
      suggest that specific intermediates may act as inducers of flavonoid metabolism.

PMID- 10394945
TI  - Arabidopsis thaliana 'extra-large GTP-binding protein' (AtXLG1): a new class of G
      protein.
AB  - Heterotrimeric GTP-binding proteins, composed of alpha, beta, and gamma subunits,
      are involved in signal transduction pathways in animal and plant systems. In
      plants, physiological analyses implicate heterotrimeric G-proteins in ion channel
      regulation, light signaling, and hormone and pathogen responses. However, only
      one class of plant G alpha genes has been identified to date. We have cloned a
      novel gene, 'Arabidopsis thaliana extra-large GTP-binding protein' (AtXLG1).
      AtXLG1 appears to be a member of a small gene family and is transcribed in all
      tissues assayed: roots, leaves, stems, flowers, and fruits. The conceptually
      translated protein from AtXLG1 is 99 kDa, twice as large as typical G alpha
      proteins. The carboxy-terminal half of the AtXLG1 protein has significant
      homology to animal and plant G alpha proteins. This region includes a GTP-binding
      domain, a predicted helical domain, and an aspartate/glutamate-rich loop, which
      are characteristics of G alpha's. Despite the absence of some of the amino acids
      implicated in GTP binding and hydrolysis by crystallographic and mutational
      analyses of mammalian G alpha's, recombinant AtXLG1 binds GTP with specificity.
      The amino-terminal region of AtXLG1 contains domains homologous to the bacterial
      TonB-box, which is involved in energy transduction between the inner and outer
      bacterial membranes, and to zinc-finger proteins. Given the unique structure of
      AtXLG1, it will be of interest to uncover its physiological functions.

PMID- 10394946
TI  - A new class of plant homeobox genes is expressed in specific regions of
      determinate symbiotic root nodules.
AB  - A cDNA containing a homeobox sequence was isolated from a soybean nodule-specific
      expression library. This homeobox cDNA, Ndx (nodulin homeobox), represents a
      small gene family with at least two members in soybean (Glycine max) and three in
      Lotus japonicus. One complete 3304 bp Ndx cDNA from L. japonicus encodes a
      protein, NDX, of 958 amino acids. An unusual type of homeodomain that differs in
      two of the most conserved amino acid positions in the consensus sequence is
      located close to the C-terminal and appears to be the only DNA-binding domain.
      Weak Ndx gene expression in the root increases very shortly after infection with
      Rhizobium and remains throughout nodule development. In situ hybridizations show
      cell-specific expression patterns that suggest developmentally separate regions
      in maturing determinate nodules. Thus in the maturing nodule Ndx and
      leghemoglobin genes are expressed in a mutually exclusive fashion. The Ndx
      transcript is also detectable in the young nodule primordium. Ndx expression is
      not confined to the root nodule since Ndx is also expressed in shoot and root
      meristems, indicating that the Ndx gene products might also be involved in
      developmental processes in other plant tissues.

PMID- 10394947
TI  - Temporal and spatial gene expression of cytochrome B5 during flower and fruit
      development in olives.
AB  - We report the characterisation of two cytochrome b5 genes and their spatial and
      temporal patterns of expression during development in olive, Olea europaea. A PCR
      generated probe, based on a tobacco cytochrome b5 sequence, was used to isolate
      two full-length cDNA clones (cytochrome b5-15 and cytochrome b5-38) from a
      library derived from 13 WAF olive fruits. The cDNAs encoded proteins of 17.0 and
      17.7 kDa, which contained all the characteristic motifs of cytochromes b5 from
      other organisms and exhibited 63% identity and 85% similarity with each other.
      The olive cytochrome b5-15 cDNA was then used as a probe for more detailed
      analysis. Southern blotting revealed a gene family of at least 4-6 members while
      northern blotting and in situ hybridisation showed a highly specific pattern of
      gene expression. Very low levels of cytochrome b5 mRNA were detected in tissues
      characterised by high rates of lipid accumulation, such as young expanding
      leaves, maturing seeds and ripening mesocarp. The cytochrome b5 genes were not
      induced at 6 degrees C and their response to ABA was relatively slow compared
      with fatty acid desaturase genes. In contrast, high levels of cytochrome b5 gene
      expression were found in young fruits at the pattern formation (globular/heart)
      stage of embryogenesis and in vascular and transmitting tissues of male and
      female reproductive organs. The data are consistent with a major role for
      cytochrome b5 in developmental processes related to plant reproduction in
      addition to being an electron donor to microsomal desaturases.

PMID- 10394948
TI  - The S7 ribosomal protein gene is truncated and overlaps a cytochrome c biogenesis
      gene in pea mitochondria.
AB  - The pea mitochondrial genome contains a truncated rps7 gene lacking ca. 40 codons
      at its 5' terminus. This single-copy sequence is immediately downstream of and
      slightly overlapping an actively transcribed and edited reading frame of 744 bp
      (designated ccb248) homologous to the bacterial helC gene which encodes a subunit
      of the ABC-type heme transporter involved in cytochrome c biogenesis. This region
      of mitochondrial DNA appears recombinogenic, and the carboxy-termini of helC-type
      proteins are predicted to vary in sequence and length among plants. Sequences
      corresponding to the 5' coding region of rps7 were not detected elsewhere in the
      pea mitochondrial genome using wheat rps7 probes, and only a very short internal
      rps7 segment was observed in soybean mitochondrial DNA. The presence of rps7
      homologous sequences in the nuclear genomes of pea and soybean is consistent with
      the recent transfer of a functional mitochondrial rps7 gene to the nucleus in
      certain plant lineages.

PMID- 10394949
TI  - Characterization of the pea rDNA replication fork barrier: putative cis-acting
      and trans-acting factors.
AB  - It was previously shown that in pea (Pisum sativum), rDNA repeats contain a polar
      replication fork barrier that blocks progression of the replication machinery
      moving in the direction opposite to transcription. This barrier maps in the
      untranscribed spacer close to the 3' end of the 25S gene. Very similar barriers
      are also found in the rDNA of yeast, Xenopus and mammalian cultured cells. This
      high conservation indicates that the rDNA barrier plays a relevant biological
      role. Progression of replication forks through the DNA sequence where the barrier
      maps in pea was investigated in plasmids replicating in Escherichia coli and
      Saccharomyces cerevisiae. No barrier was detected in these heterologous systems,
      indicating that the DNA sequence by itself was insufficient to block the
      replication machinery. Therefore, trans-acting factors were likely to be
      required. Taking advantage of the natural sequence heterogeneity in pea rDNA, we
      obtained evidence that a 27 bp imperfect tandem repeat is involved in the arrest
      of replication. Moreover, nuclear protein(s) specifically bound to this repeat
      suggesting that this DNA/protein complex is responsible for the polar arrest of
      replication forks.

PMID- 10394950
TI  - Characterization of three distinct cDNA clones encoding cysteine proteinases from
      maize (Zea mays L.) callus.
AB  - In previous work, a 33 kDa cysteine proteinase was found in callus initiated from
      maize (Zea mays L.) resistant to fall armyworm feeding. A callus cDNA library
      from the maize inbred Mp708 was screened with oligonucleotides derived from the N
      terminal amino acid sequence of the 33 kDa proteinase and several cDNA clones
      were isolated and sequenced. A cDNA clone encoding the 33 kDa cysteine
      proteinase, mir1, was identified. Two additional clones, mir2 and mir3, encoding
      putative cysteine proteinases were also identified. mir2 and mir3 are distinct
      from mir1 and each other, but show a high degree of homology. All of the mir cDNA
      clones map to distinct sites on the maize genome. Amino acid sequences encoded by
      the mir clones are similar to other known cysteine proteinases and are most
      closely related to the oryzain-alpha and -beta precursors. The ERFNIN motif and a
      12 amino acid conserved sequence are present in the propeptide region of the
      putative proteinases encoded by mir clones. mir2 and mir3 appear to have C
      terminal extensions. The phylogenetic tree of nucleotide sequences of mir1, mir2,
      mir3 and other representative cysteine proteinases from protozoa, plants and
      animals was constructed.

PMID- 10394951
TI  - Analysis of promoters from tyrosine/dihydroxyphenylalanine decarboxylase and
      berberine bridge enzyme genes involved in benzylisoquinoline alkaloid
      biosynthesis in opium poppy.
AB  - Tyrosine/dihydroxyphenylalanine decarboxylase (TYDC) and the berberine bridge
      enzyme (BBE) represent the entry point and a key branch point, respectively, in
      the biosynthesis of benzylisoquinoline alkaloids in select species of the
      Papaveraceae and Fumariaceae. Genomic clones for tydc7 and bbe1 from opium poppy
      (Papaver somniferum L.) were isolated. Deletion analysis of tydc7 and bbe1 5'
      flanking regions revealed the location of putative regulatory domains necessary
      for expression of the beta-glucuronidase (gus) reporter gene in a transient assay
      system based on the microprojectile bombardment of cultured opium poppy cells. A
      105-nucleotide region between -393 and -287 of the tydc7 5'-flanking region, and
      a 155-nucleotide region between -355 and -200 of the bbe1 5'-flanking region,
      were found to be essential for promoter activity. RNA gel blot analysis showed
      that tydc7 and bbe1 expression is induced in cultured opium poppy cells in
      response to wounding or treatment with a pathogen-derived elicitor. Time-courses
      for the induction of tydc7 and bbe1 mRNAs in wounded cells were nearly identical
      to those for GUS activity in cells bombarded with select promoter-gus constructs
      when the -393 to -287 region of tydc7, or the -355 to -200 region of bbe1, was
      present. Our data suggest that the wound signal caused by the entry of DNA-coated
      microcarriers into opium poppy cells was sufficient to induce tydc7 and bbe1
      promoter activity, and that wound-responsive regulatory elements are located
      within domains identified by deletion analysis.

PMID- 10394952
TI  - Alternative transcription initiation sites generate two LCA1 Ca2+-ATPase mRNA
      transcripts in tomato roots.
AB  - The tomato LCA1 gene encodes a Ca2+-ATPase and gives rise to two major mRNA
      transcripts and two distinct protein products of different size in tomato roots.
      The basis of the transcript size difference was investigated to assess whether
      the mRNA transcripts encoded distinct protein products. Primer extension and S1
      nuclease analysis identified two transcription initiation sites at -72 and -1392
      from the start of translation. RNA gel blot analysis of poly(A)+ RNA isolated
      from phosphate-starved tomato roots using probes designed to domains of the 5'
      untranslated region (UTR) or the full-length LCA1 cDNA identified mRNAs of 4.7
      and 3.6 kb, corresponding to mRNA originating from transcription initiation sites
      -1392 and -72, respectively. Screening of a cDNA library derived from phosphate
      starved tomato roots yielded three cDNA clones, LCA1A, LCA1B and LCA1C (3.6, 4.5
      and 5.1 kb respectively). These cDNAs contain full-length LCA1 mRNA sequence
      derived from each transcription initiation site, with LCA1C additionally
      containing an intron of 0.6 kb. Sequence analysis indicated 100% identity between
      the three size classes of cDNA clones except for the differential 5'-UTR and the
      unspliced intron. Overall, the results indicate that the two major LCA1 mRNA
      transcripts are derived by differential transcription initiation and that two of
      the mRNAs may encode identical protein products, while a third mRNA may
      correspond to a non-functional truncated protein.

PMID- 10394953
TI  - An Atropa belladonna hyoscyamine 6beta-hydroxylase gene is differentially
      expressed in the root pericycle and anthers.
AB  - The AbH6H gene for hyoscyamine 6beta-hydroxylase (H6H), which converts
      hyoscyamine to scopolamine, was isolated from Atropa belladonna. This plant also
      possesses a related sequence, Ab psiH6H, which appears to be a non-functional
      pseudo-gene. AbH6H RNA was detected in cultured root, native root and anther, but
      not in stem, leaf, pistil, petal, and sepal tissues. In situ hybridization,
      immunohistochemistry and promoter::GUS transgene analysis showed that AbH6H is
      expressed specifically in root pericycle cells, and in tapetum and pollen mother
      cells. A 671 bp 5'-upstream region from AbH6H was sufficient for pericycle
      specific expression in hairy roots of A. belladonna and Hyoscyamus niger, which
      both produce scopolamine, but cell-specific regulation was severely compromised
      in tobacco hairy roots, which do not produce scopolamine.

PMID- 10394954
TI  - Structure, organization and expression of two closely related novel Lea (late
      embryogenesis-abundant) genes in Arabidopsis thaliana.
AB  - We have isolated and sequenced a 9.5 kb genomic region from A. thaliana, located
      on chromosome 2, which contains two tandemly arranged closely related genes
      (AtM10 and AtM17) coding for a new family of LEA proteins. The deduced proteins
      have a molecular mass of 11 and 29 kDa, respectively, are extremely hydrophilic
      except at their N-termini and share 70% amino acid (aa) identity. A 47 aa motif
      containing a 6-cysteine domain is present once in AtM10 and four times in AtM17.
      The short intergenic region, the identical position of the intron and the overall
      sequence homology suggest that these two genes evolved through a duplication
      event. This conclusion is supported by the presence of two homologous
      strictosidine synthase-like (pseudo)genes downstream from AtM17 and AtM10.
      Expression studies, using AtM10 and AtM17 cDNAs, revealed that both transcripts
      accumulate exclusively in seeds from late embryogenesis until two days after
      imbibition. Expression of both genes in young seedlings is repressed during ABA,
      salt or drought treatment, whereas a cold stress induces the expression of AtM17
      only. In situ hybridization revealed that AtM10 transcripts are detected
      throughout the embryo while those of AtM17 are more localized to cotyledon cells.

PMID- 10394957
TI  - Inhibition of epidermal-growth-factor-receptor-dependent signalling by
      tyrphostins A25 and AG1478 blocks growth and induces apoptosis in colorectal
      tumor cells in vitro.
AB  - Growth effects of tyrphostins A25 and AG1478 on colorectal tumor cells were
      studied to explore therapeutic potential. Cell number, DNA synthesis and
      apoptotic index were measured as growth parameters and cell-death-associated
      proteins Bcl-2 and Bak and protein phosphorylation were analyzed. Both
      tyrphostins inhibited DNA synthesis and induced apoptosis in tumor cell cultures
      with different patterns of activity. A25 displayed strong selectivity for the
      cell lines expressing high levels of epidermal growth factor (EGF), HT29/HI1 and
      SW480. Inhibition of DNA synthesis was efficient in all cells except T84, and the
      apoptotic index increased two- to fivefold. By contrast, AG1478 was highly
      effective in all cell lines. In addition, it caused cell loss in VACO235 adenoma
      cells at concentrations lower than those necessary to inhibit BrdU incorporation,
      reflecting preferential retention of cells actively synthesizing DNA. Induction
      of apoptosis was more efficient with AG1478 than with A25 (tenfold in VACO235).
      Insulin-like growth factor (IGF1) did not rescue cells exposed to A25 or to high
      concentrations of AG1478, but was effective with suboptimal amounts of AG1478.
      Both compounds inhibited phosphorylation of the EGF receptor as well as
      additional proteins. AG1478 induced expression of Bak and down-regulated Bcl-2.
      In summary, tyrphostins may provide alternatives for colorectal tumor treatment.
      Their broader range of activities and the lower susceptibility to interactions
      with IGF1 can be an advantage over receptor antibodies.

PMID- 10394955
TI  - Identification of a rice APETALA3 homologue by yeast two-hybrid screening.
AB  - A cDNA clone OsMADS16 was isolated from the rice young inflorescence cDNA
      expression library by the yeast two-hybrid screening method with OsMADS4 as bait.
      We have previously shown that the OsMADS4 gene is a member of the PI family and
      that the MADS-box gene is involved in controlling development of the second and
      third whorls of rice flowers. The sequence comparison indicated that OsMADS16
      belongs to the AP3 family. The OsMADS16 protein contains a PI-derived motif,
      FAFRVVPSQPNLH, that is a conserved sequence in AP3 family genes at the C-terminal
      region. In addition, OsMADS16 contains a paleoAP3 motif, YGGNHDLRLG, downstream
      of the PI-derived motif. The paleoAP3 motif is a consensus sequence in the C
      terminal region of the AP3 family genes of lower eudicot and magnolid dicot
      species. RNA blot analysis showed that the OsMADS16 gene was expressed in the
      second and third whorls, whereas the OsMADS4 transcripts were present in the
      second, third, and fourth whorls. These expression patterns of the OsMADS16 and
      OsMADS4 genes are very similar to those of AP3 and PI, respectively. In the yeast
      two-hybrid system, OsMADS4 interacted only with OsMADS16 among several rice MADS
      genes investigated, suggesting that OsMADS4 and OsMADS16 function as a
      heterodimer in specifying sepal and petal identities. The OsMADS16 protein
      displayed transcription activation ability in yeast, whereas AP3 did not. It was
      also shown in yeast that OsMADS16 interacted with PI whereas OsMADS4 did not
      interact with AP3. These differences between OsMADS16 and AP3 indicate that the
      functions of the AP3 family genes of monocots and dicots diverged during
      molecular evolution processes of the B function genes. Deletion analysis showed
      that the 155-200 amino acid region of the OsMADS16 protein plays an important
      role in the transcription activation ability.

PMID- 10394956
TI  - Characterization of closely related delta-TIP genes encoding aquaporins which are
      differentially expressed in sunflower roots upon water deprivation through
      exposure to air.
AB  - We isolated five sunflower (Helianthus annuus) cDNAs belonging to the TIP
      (tonoplast intrinsic protein) family. SunRb7 and Sun gammaTIP (partial sequence)
      are homologous to tobacco TobRb7 and Arabidopsis gamma-TIP, respectively.
      SunTIP7, 18 and 20 (SunTIPs) are closely related and homologous to Arabidopsis
      delta-TIP (SunTIP7 and 20 have already been presented in Sarda et al., Plant J.
      12 (1997) 1103-1111). As was previously shown for SunTIP7 and 20, expression of
      SunTIP18 and SunRb7 in Xenopus oocytes caused an increase in osmotic water
      permeability demonstrating that they are aquaporins. In roots, in situ
      hybridization revealed that SunTIP7 and 18 mRNAs accumulate in phloem tissues.
      The expression of TIP-like genes was studied in roots during 24 h water
      deprivation through exposure to air. During the course of the treatment, each
      SunTIP gene displayed an individual response: SunTIP7 transcript abundance
      increased, SunTIP18 decreased whereas that of SunTIP20 was transitorily enhanced.
      By contrast, SunRb7 and Sun gammaTIP mRNA levels did not fluctuate. Due to the
      changes in their transcript levels, it is proposed that SUNTIP aquaporins encoded
      by delta-TIP-like genes play a role in the sunflower response to drought.

PMID- 10394959
TI  - Enrichment polymerase chain reaction for the detection of Ki-ras mutations:
      relevance of Taq polymerase error rate, initial DNA copy number, and reaction
      conditions on the emergence of false-positive mutant bands.
AB  - Screening for oncogene mutations as a marker for malignancy can be a powerful
      tool for the early diagnosis of cancer. The enrichment polymerase chain reaction
      (PCR) is a sensitive method for the detection of low-frequency mutations in small
      samples. However, false-positive results, caused by methodological errors, may
      have severe clinical implications. When applied to the detection of Ki-ras
      mutations in pancreatic secretions, the assay sensitivity is limited to
      approximately 1:1400. Our investigation of Ki-ras mutations in blood samples from
      patients with pancreatic carcinoma revealed PCR bands presumably derived from
      mutant Ki-ras in samples from healthy volunteers, while all blood samples of the
      patients with pancreatic carcinomas showed a wild-type band pattern. Mathematical
      modeling of the PCR reaction reveals that the rate of false positive PCR results
      depends on the initial amount of DNA, the Taq polymerase error rate, the number
      of PCR reaction cycles, reaction efficiency and the restriction endonuclease
      chosen. The overall error rate of false positive results of the enrichment PCR
      can be reduced to the square of the rate of a single-step analysis if repeated
      amplifications of the same DNA specimen show an identical result.

PMID- 10394958
TI  - Up-regulation of ICH-1L protein by thromboxane A2 antagonists enhances cisplatin
      induced apoptosis in non-small-cell lung-cancer cell lines.
AB  - We evaluated the effect of thromboxane A2 (TXA2) blockade on cisplatin-induced
      apoptosis in non-small-cell lung cancer (NSCLC) cell lines. Cisplatin induced
      apoptosis in PC/9 and PC-9/CDDP in a dose-dependent manner. Treatment with
      specific TXA2 antagonist, calcium 5(Z)-1R,2S,3S,4S-7-[3
      phenylsulfonylaminobicyclo[2,2,1]hept-2-yl]- 5-heptonoate hydrate (S-1452) and
      5(Z-6-[(1R,2R,3R,4S)-3-(N-4-bromobenzenesulfonyl aminomethyl)
      bicyclo[2,2,1]heptane-2-yl]-hex-5-enoic acid (ONO-NT-126), enhanced the cisplatin
      induced apoptosis in each cell line. Acetyl-L-aspartyl-glutamyl-valyl-aspart-1
      aldehyde (Ac-DEVD-CHO) inhibited cisplatin-induced apoptosis and enhancement of
      the apoptosis by TXA2 blockade, but acetyl-L-tyrosyl-valyl-alanyl-aspart-1
      aldehyde (Ac-YVAD-CHO) had no effect on the apoptosis. There was no difference in
      the interleukin-1beta-converting enzyme (ICE) protease protein expression in
      either cell line. Cysteine protease p32(CPP32) protein expression was lower in PC
      9/CDDP but was not changed by S-1452, cisplatin, or cotreatment with cisplatin
      and S-1452. Ice and Ced-3 homolog (ICH-1L) expression was significantly lower in
      PC-9/CDDP and was up-regulated by S-1452 or ONO-NT-126. These data suggest that
      ICH-1L might play a critical role in cisplatin-induced apoptosis and that TXA2
      blockade up-regulates ICH-1L protein expression. Overexpression of ICH-1L and
      treatment with cisplatin might result in an increase in apoptosis in NSCLC cell
      lines.

PMID- 10394960
TI  - Antioxidant enzyme activities and lipid peroxides in the plasma of patients with
      benign prostatic hyperplasia or prostate cancer are not predictive.
AB  - In this study, lipid peroxide and total sulfhydryl contents and activities of
      superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were
      investigated in the plasma of patients with benign prostatic hyperplasia (BPH)
      and prostate cancer. No significant change was found in lipid peroxidation or
      antioxidant systems in the plasma of patients with BPH and prostate cancer. The
      results indicate that evaluation of the prooxidant-antioxidant balance in the
      plasma of BPH and prostate cancer patients cannot be used as a marker to
      discriminate between these diseases.

PMID- 10394961
TI  - Clinical usefulness of telomerase activity and telomere length in the
      preoperative diagnosis of gastric and colorectal cancer.
AB  - It has been reported that telomerase activity and telomeric reduction can be
      detected in many human cancers. Although it is well known that telomerase
      activity and telomere length have important implications for cancer biology,
      their clinical usefulness in the preoperative diagnosis of gastric and colorectal
      cancer has not been elucidated. Therefore, we examined telomerase activity and
      telomere length in gastric and colorectal cancer using tissue samples obtained by
      fiberscopy. Telomerase activity was measured by a telomeric repeat amplification
      protocol (TRAP). Although telomerase activity was detected in 1/12 (8%) cases of
      gastric polyp and in 2/9 (22%) cases of colorectal polyp, its positivity in
      gastric cancer and colorectal cancer was 7/10 (70%) and 21/26 (81%; P<0.0003 and
      P<0.0001, respectively). Telomere length was analyzed by Southern blotting, and
      telomeric reduction in gastric cancer was significantly greater than that in
      gastric polyp (P<0.0003). However, there was no telomeric reduction between
      colorectal cancer and colorectal polyp. The results of the present study indicate
      that determination of telomerase activity and telomere length may serve as a
      useful method for preoperative diagnosis of gastric and colorectal cancer.

PMID- 10394962
TI  - Chemotherapy in the treatment of recurrent glioblastoma multiforme: ifosfamide
      versus temozolomide.
AB  - PURPOSE: Despite the progress made in neurosurgery and radiotherapy, the
      prognosis of glioblastoma multiforme (GB) is poor, due to the lack of an
      effective salvage therapy. In vitro analysis revealed activity for ifosfamide and
      temozolomide. The usefulness of these agents in recurrent disease was
      investigated. METHODS: Six adult patients with recurrent GB received one to four
      courses of 1,500 mg/m2 ifosfamide given over 5 days intravenously. Furthermore,
      temozolomide (100-200 mg/m2) was given orally over 5 days to 14 patients.
      RESULTS: After ifosfamide treatment, one partial response and two cases of stable
      disease were observed. The median survival time was 24 weeks (range of 9-52
      weeks). Toxicity analysis revealed one paranoid reaction, three grade III
      leukocytopenia, and one grade I-II nausea, anemia, and hematuria. Temozolomide
      therapy resulted in three partial responses and four cases of stable disease. The
      median survival time (Kaplan-Meier) was 21 weeks (range 4-64 weeks). The major
      toxicities were grade I-II nausea and hematological side effects (one case of
      grade IV leuko- and thrombocytopenia). CONCLUSIONS: Ifosfamide treatment might be
      a feasible approach, but it necessitates hospitalization. Temozolomide showed
      promising results. Due to its oral application, the patient's quality of life
      (time out of hospital) is favorable. Subgroups with improved survival were
      observed.

PMID- 10394963
TI  - Microvessel density of hepatocellular carcinoma: its relationship with prognosis.
AB  - PURPOSE: To elucidate the relationship between angiogenesis and prognosis after
      curative resection of hepatocellular carcinoma (HCC). METHODS: An
      immunohistochemical study using anti-CD34 monoclonal antibody was carried out on
      surgical specimens from 78 HCC patients who had undergone curative resection;
      microvessel density (MVD) was counted and the overall survival and disease-free
      survival were analyzed retrospectively. RESULTS: Blood vessels in the tumor were
      strongly stained by anti-CD34 antibody, but not those in the surrounding liver
      parenchyma. There were three types of tumor vessels: capillary-like (n = 59),
      sinusoid-like (n = 16) and mixed-type (n = 3). The median MVD count was 100 per
      field. The HCC were designated as hypovascular (n = 36) with an MVD count below
      100, and hypervascular (n = 42) with an MVD count of 100 or more per field. The 5
      year survival and disease-free survival rates were 49.7% and 42.8% respectively,
      and statistical analysis showed that the MVD level was not correlated with tumor
      size, capsule status, Edmondson's grade, alpha-fetoprotein level, associated
      cirrhosis, gamma-glutamyltransferase, and serum HBsAg status. The sinusoid-like
      tumor vessels appeared more frequently in the more differentiated tumors
      (P<0.05). No statistical difference in overall and disease-free survival between
      different MVD levels and microvessel types was found. Tumor size was the only
      predicting factor in the entire series. In patients with small HCC (< or =5 cm, n
      = 40), 5-year survival and disease-free survival rates were 58.9% and 52.7%
      respectively, higher than the values in large HCC (39.8% and 32.0% respectively,
      P<0.05). The MVD level was an independent predicting factor of disease-free
      survival, 5-year disease-free survival in the hypovascular group (74.6%) being
      better than that in the hypervascular group (34.7%, P<0.05). CONCLUSIONS: The MVD
      level was not related to tumor size, capsule statuo, Edmondson's grade, alpha
      fetoprotein level, associated cirrhosis, gamma-glutamyltransferase and serum
      HBsAg status. In the entire series, tumor size was the only factor influencing
      survival after curative resection. However, in patients with small HCC, the MVD
      level was an independent factor of disease-free survival. The pathological and
      clinical implications of different types of tumor vessels in HCC remain to be
      studied.

PMID- 10394964
TI  - An effective and more convenient drug regimen for prophylaxis against paclitaxel
      associated hypersensitivity reactions.
AB  - "Standard" prophylaxis for paclitaxel-associated hypersensitivity reactions has
      included the systemic administration of H1 and H2 histamine antagonists, along
      with oral dexamethasone taken both the night prior to, and the morning of, each
      paclitaxel treatment. To improve patient convenience and compliance with steroid
      delivery, the Gynecologic Cancer Program of the Cleveland Clinic Foundation has
      treated patients with an all-intravenous prophylaxis regimen (diphenhydramine 50
      mg, famotidine 20 mg, dexamethasone 20 mg) given 30 min prior to paclitaxel
      (without any earlier oral steroid dosing). To date, we have treated more than 200
      patients who received all courses of paclitaxel with this simplified prophylactic
      regimen, of whom approximately 9% developed hypersensitivity reactions (major or
      minor). This incidence is comparable to our previously reported experience with
      hypersensitivity reactions in a similar number of patients receiving the standard
      prophylaxis (including oral dexamethasone) with their initial course of
      paclitaxel, and subsequent cycles employing this all-intravenous program. We
      conclude that this "modified" regimen for paclitaxel-associated hypersensitivity
      reactions (with all drugs administered approximately 30 min prior to the delivery
      of paclitaxel) is as effective as, and more convenient than, the standard
      regimen, and avoids delaying chemotherapy as a result of a patient failing to
      remember to take one or both oral steroid doses.

PMID- 10394966
TI  - Summary of the proceedings of the United States and Japan Head and Neck Cancer
      Clinical Trials Summit, 19-20 September 1997, Kyoto, Japan.

PMID- 10394965
TI  - Re: "Renal cell cancer correlated with occupational exposure to
      trichloroethylene".

PMID- 10394967
TI  - How adequate are the new guidelines on clinical evaluation of bacteriological
      outcome in uncomplicated UTI?
AB  - While the Infectious Diseases Society of Americas guidelines for clinical trials
      of antibiotics have proven valuable for defining inclusion criteria in studies of
      urinary tract infections, they are far from perfect when it comes to defining
      outcome of treatment. This was obvious in a trial comparing a beta-lactam
      antibiotic and a fluoroquinolone for treatment of acute uncomplicated cystitis in
      women. Depending on how failure was defined in terms of bacterial count and
      pyuria, failure rates with one and the same regimen varied between 6 and 67% of
      patients treated with the beta-lactam. Another finding was that pyuria measured
      with microscopy of urine sediment was a highly unreliable technique. Systematic
      studies are needed to define the optimal criteria for measuring outcome in these
      infections.

PMID- 10394968
TI  - Adequacy of the new guidelines on clinical evaluation of drug efficacy in acute
      uncomplicated cystitis.
AB  - The adequacy of the newly revised criteria for the evaluation of clinical
      efficacy of antimicrobial agents in acute uncomplicated cystitis harmonized to
      the IDSA/FDA guidelines was studied. Low bacterial counts were significantly more
      frequently found in midstream urine than in catheter urine. Non-uropathogens were
      isolated with significantly higher frequency from patients with bacteriuria of
      10(3) colony forming units (cfu)/ml than from patients with higher bacterial
      counts. It is important to exclude non-uropathogens when patients with
      bacteriuria of 10(3) cfu/ml are included in the study. Although the clinical
      failure rate was very low in patients with eradication of the pathogen, the
      clinical cure rate was only 67% in patients with microbiological failure.
      Microbiological and clinical outcomes coincided in 93% of the patients. However,
      the coincidence rate was lower when the eradication rate was low.

PMID- 10394969
TI  - Experience with the new guidelines on evaluation of new anti-infective drugs for
      the treatment of urinary tract infections.
AB  - The new guidelines of Infectious Diseases Society of America (IDSA) and European
      guidelines of the European Society of Clinical Microbiology and Infectious
      Diseases (ESCMID) on evaluation of new anti-infective drugs for the treatment of
      urinary tract infection (UTI) were published in 1992 and 1993, respectively. The
      experience with these guidelines, including the recommendations for improvement
      published by an international expert group, are being updated and discussed. The
      IDSA and ESCMID guidelines define five categories of UTI. Some aspects specific
      for each group are discussed concerning definition, stratification and outcome.
      For patients with chronic bacterial prostatitis, a category of its own is
      proposed rather than using the general category of complicated UTI. The greatest
      advantage of the new guidelines in comparison with the former FDA guidelines is
      enrolment of patients according to intention to treat, as has always been
      recommended by the guidelines of the Japanese UTI Committee. Two problems arising
      in studies of all categories are addressed: (i) false positive bacteriuria and
      (ii) handling of dropouts and missing data. Compared with the former FDA
      guidelines, the new IDSA and ESCMID guidelines reflect much better the clinical
      situation of the physician taking care of individual patients. Therefore, the
      results of studies performed according to these guidelines are clinically more
      significant. A worldwide harmonization of guidelines may finally lead to valid
      and acceptable results in any country.

PMID- 10394970
TI  - Guidelines and evaluation of new anti-infective drugs for treatment of urinary
      tract infections.

PMID- 10394971
TI  - Prostatitis--the Japanese viewpoint.
AB  - Japanese inclusion criteria in acute and chronic bacterial prostatitis are
      explained. Objective criteria of acute prostatitis are a bacterial count of 10(4)
      cfu/ml or more and 10 or more WBCs/hpf in VB1 or VB2. Criteria for chronic
      prostatitis are a bacterial count of 10(3) cfu/ml or more (if only Gram-positive
      cocci are isolated from EPS, a bacterial count of 10(4) cfu/ml or more is
      required) and 10 or more WBCs/hpf (including macrophages) in EPS or VB3.
      Secondly, we describe recent topics such as bacterial biofilm formation in
      prostatic tissues by electron microscopy in three out of 12 patients with
      intractable chronic prostatitis.

PMID- 10394972
TI  - Prostatitis: US perspective.
AB  - The diagnosis and management of prostatitis syndromes is a challenge to the
      clinician. Careful history and examination of the prostate fluid and quantitative
      segmented bacteriologic cultures will lead to proper categorization into the
      recognized forms of the prostatitis syndrome. Antimicrobial therapy is effective
      in the majority of men with acute and chronic bacterial prostatitis (CBP).
      Fluoroquinolone agents appear to have an increasingly important role in this
      regard, although a randomized, prospective, double-blind study is still lacking.
      Alpha-1-selective blocking agents may relieve symptomatology of chronic pelvis
      pain syndrome (CPPS). Other non-prostatic sources of voiding symptoms should be
      sought and ruled out, especially malignancy or inflammatory disorders.

PMID- 10394973
TI  - Introduction to biofilm.

PMID- 10394974
TI  - Biofilms in infectious disease and on medical devices.
AB  - Microbial biofilms constitute a major reason for infections to occur and persist
      at various sites in the human body, especially in association with medical
      devices. The organisms invariably form these biofilms on surfaces which have host
      proteins and other substances coating them. Once adherent, the bacteria multiply
      and anchor themselves in quite intricate structures which appear to allow for
      communication and information transfer between organisms. For the treating
      physician, many antibiotics are unable to eradicate dense biofilms, and therefore
      much work is required to devise ways to prevent their occurrence and clear them
      from the host.

PMID- 10394975
TI  - Bacterial biofilms and catheters in experimental urinary tract infection.
AB  - Employing in vitro and in vivo models of catheter-associated infection, biofilm
      formation of Pseudomonas aeruginosa in artificial urine and bactericidal activity
      of several classes alone or in combination with a macrolide antibiotic were
      investigated. In the course of continuous urine flow, bacteria adherent to a
      Teflon catheter formed microcolonies at 6 h and a biofilm at 24 h. Following 24 h
      of urine flow, the thickness and the density of the biofilm increased to about 20
      microm and 10(8) cfu/mm3, respectively. Of the antibiotics examined, the
      fluoroquinolones showed the most potent bactericidal activity against the P.
      aeruginosa biofilms. However, those antibiotics were not always potentiated by
      the combination with a macrolide antibiotic.

PMID- 10394976
TI  - Biofilm in complicated urinary tract infection.
AB  - We studied the clinical efficacy of oral treatment with ciprofloxacin (CPFX)
      alone and combined with clarithromycin (CAM) in patients with complicated urinary
      tract infection with or without an indwelling catheter. Patients were randomly
      allocated to 600 mg CPFX (CPFX group) or to 600 mg CPFX plus 600 mg CAM
      (combination group) for 14 days. Evaluation was done on day 14 according to the
      criteria advocated by the Japanese Urinary Tract Infection Committee. In patients
      with a urinary catheter, the combination achieved a higher complete bacterial
      elimination rate (50.0%) and clinical efficacy rate (83.9%) than CPFX alone (30.0
      and 61.5%, respectively). While no significant difference was found in the
      bacterial elimination rate between the two groups, the clinical efficacy of the
      combination (40.0%) was superior to that of CPFX alone (23.3%) in patients with
      an indwelling catheter. The better clinical efficacy of the combination may
      partly be attributed to the antibiofilm effect of CAM in the clinical setting.
      The results also indicate that difficulties still remain in the treatment of
      complicated urinary tract infections in patients with an indwelling catheter.

PMID- 10394977
TI  - Practice guidelines for urinary tract infection in the era of managed care.
AB  - Acute uncomplicated cystitis among young women is very common, relatively easy to
      diagnose, and easy to treat with short-course antimicrobial regimens. However,
      there is great variability among physicians in the approaches to diagnosis and
      management. Cystitis, therefore, lends itself well to management by clinical
      practice guidelines which de-emphasize costly office visits, pre-therapy urine
      cultures and long courses of therapy. As cystitis guidelines continue to be
      developed by medical care organizations, however, it is important that they be
      evidence based, include the participation of practicing physicians and provide a
      mechanism for evaluation to ensure that quality of care and patient satisfaction
      are not compromised.

PMID- 10394978
TI  - Pharmacoeconomics of treating uncomplicated urinary tract infections.
AB  - The frequency of urinary tract infections (UTIs) and mounting pressure for cost
      containment in medical care emphasize the need to consider costs of evaluating
      and treating UTIs. Many clinicians base antibiotic choice on drug cost, probably
      because this information is objective and readily available. However, the cost of
      treating UTI patients involves other factors, such as pathogenic susceptibility
      and consequences of inadequately treated infection. These factors and their
      associated costs can be difficult to assess and weigh against issues such as drug
      cost. The direct cost of treating a UTI patient includes not only initial medical
      evaluation and treatment, but what occurs subsequently. If initial treatment is
      provided with a drug for which a pathogen is not sensitive, patients will be
      likely to continue to experience symptoms and return for re-evaluation, resulting
      in a more thorough evaluation and a second antibiotic, generally a more expensive
      fluoroquinolone. The most important predictor of high cost-effectiveness is high
      efficacy against the most common urinary pathogen, Escherichia coli. The lower
      the effectiveness of antibiotics against this pathogen, the greater the number of
      revisits and cases of progression to pyelonephritis. Increased follow-up care
      results in diminished cost-effectiveness. Antibiotic cost is a poor predictor of
      cost-effectiveness, illustrated by the finding that the most and least expensive
      drugs, ofloxacin and trimethoprim-sulfamethasoxazole, are approximately equally
      cost-effective. Both of these are more cost-effective than other drugs,
      nitrofurantoin and amoxicillin, considered in this analysis.

PMID- 10394979
TI  - When to do culture in urinary tract infections.
AB  - A brief review of the value of quantitative bacteriology of the urine in patients
      with symptoms of urinary tract infections is presented. Changes in our approach
      to the diagnosis of urinary tract infections are briefly discussed. The economic
      value of empiric treatment without urine cultures in young women with dysuria and
      frequency is presented along with our approach to patients with asymptomatic
      bacteriuria in the presence of an indwelling bladder catheter. In addition,
      specific groups of patients with symptomatic urinary tract infections who require
      urine cultures in order to receive optimal antimicrobial therapy is reviewed.
      Although these suggestions may not be appropriate for all patients in each
      category, their use in some patients is likely to result in economic benefits
      without reducing the quality of their health care.

PMID- 10394980
TI  - Rational diagnostic steps in acute pyelonephritis with special reference to
      ultrasonography and computed tomography scan.
AB  - Depending on the severity of the clinical syndrome, acute pyelonephritis may
      require more extensive imaging diagnostics. In the uncomplicated form of the
      disease, ultrasonography does not appear to be absolutely necessary. In
      clinically severe cases, however, which fail to respond to antibiotic therapy,
      ultrasound is the optimal procedure for ruling out urinary tract obstruction.
      Where there is clinical suspicion of complications proven risk factors,
      persistent fever and/or continuing pathological inflammation parameters (elevated
      C-reactive protein levels in serum)-ultrasonography is the primary imaging
      technique for the exclusion of pyonephrosis, as well as for other complicating
      factors such as calculi, etc. In cases of insufficient response to antibiotic
      therapy, we recommend performing a renal computed tomography scan with contrast
      medium, in order to rule out hypoenhancing zones as hints for severe tissue
      alterations. This procedure is in accordance with the suggestions of the Society
      for Uroradiology. In the future, DMSA scintigraphy might constitute an equivalent
      diagnostic method for the exclusion of these focal inflammatory changes. Above
      all, DMSA scintigraphy makes it possible to anticipate the development of scars
      following acute pyelonephritis.

PMID- 10394981
TI  - Urinary infections in the elderly: symptomatic of asymptomatic?
AB  - Asymptomatic bacteriuria is common in the elderly, occurring in as many as 25-50%
      of elderly nursing home residents. Asymptomatic bacteriuria itself should not be
      treated with antimicrobial therapy. Difficulties in communication, chronic
      genitourinary symptoms, and the high frequency of positive urine cultures, make
      ascertainment of symptomatic infection problematic for the functionally impaired
      elderly. Chronic genitourinary symptoms are not a manifestation of acute urinary
      infection, although acute deterioration in symptoms may be consistent with
      infection. Fever in an institutionalized elderly subject with a positive urine
      culture and without an indwelling catheter is due to urinary infection in less
      than 10% of episodes. However, there are no criteria to differentiate urinary
      infection from other sites in this clinical scenario. Thus, neither urine culture
      nor clinical presentation allows a diagnosis of symptomatic urinary infection to
      be made with a high level of certainty. Decisions with respect to antimicrobial
      therapy must be made on an individual basis and with an understanding of these
      diagnostic limitations. It is not realistic to expect to optimize antimicrobial
      usage in this population until issues of diagnostic uncertainty are addressed.

PMID- 10394982
TI  - Urinary tract infection in geriatric patients.
AB  - Elderly patients with urinary tract infection (UTI) are believed less likely to
      be cured by antimicrobial therapy than younger patients. The reasons for this
      poorer outcome have not yet been clarified. We have investigated the effect of
      antimicrobial therapy in elderly patients with complicated UTI. Four-hundred and
      eighty patients, 244 men and 236 women, who had complicated UTI (266 symptomatic
      and 236 asymptomatic) and were 20-79 years of age, were treated with one of three
      different drugs; one was a newer quinolone and two were oral cephems.
      Multivariate logistic regression analysis of treatment outcome revealed that the
      clinical response was significantly related to general underlying diseases and
      diseases of the urinary tract, but not to age, symptomatic or asymptomatic UTI,
      or infection site such as the kidney or bladder. We concluded that the clinical
      effectiveness of an antimicrobial agent was not directly related to age, and that
      urological examination for underlying diseases and control of them is quite
      important for effective treatment and control of complicated UTIs, especially in
      elderly patients.

PMID- 10394983
TI  - Management of Urinary tract infections in the nursing home elderly: a proposed
      algorithmic approach.
AB  - The objective of this paper is to review the microbiology, clinical presentation,
      diagnosis, and treatment of urinary tract infections (UTIs) in the nursing home
      elderly, and recommend an algorithmic approach to the management of UTIs in this
      population.

PMID- 10394984
TI  - Management of asymptomatic candiduria.
AB  - Candiduria is a common nosocomial infection, occurring predominantly in elderly
      debilitated subjects with frequent co-morbid pathology, especially diabetes
      mellitus. The majority of candiduric patients are catheterized or have been
      recently catheterized or instrumented. Physician surveys indicate considerable
      variation in attitude towards treatment of asymptomatic candiduria. Management of
      candiduria is seriously limited by lack of understanding of the natural history
      of this infection as well as reliable data of treatment efficacy based upon
      controlled studies. The recent availability of oral antifungal agents has
      strongly influenced physicians in adopting a more interventional role. Most
      therapeutic studies quoted in the literature compare active intervention with a
      variety of systemic or local measures. Reference is made to a recent placebo
      controlled prospective study, in which fluconazole was significantly more
      effective than placebo in short-term eradication of asymptomatic candiduria.
      Nevertheless, follow-up of these asymptomatic patients revealed identical
      candiduria rates within 1 month of cessation of therapy. In most studies,
      evidence of clinical benefit in asymptomatic patients by the eradication of
      candiduria has not been evident. In conclusion, the majority of hospitalized
      patients, particularly those with continued catheterization, do not require local
      or systemic antifungal therapy for asymptomatic candiduria.

PMID- 10394985
TI  - Fungal urinary tract infections in patients at risk.
AB  - Fungal urinary tract infection (UTI) represents a high-risk event in severely ill
      patients. Its increasing incidence in recent years is associated with extensive
      and prolonged use of broad-spectrum antimicrobial agents, corticosteroids,
      immunosuppressive and cytotoxic drugs. Other important risk factors comprise
      higher age, diabetes mellitus, chronic renal failure, hemodialysis, renal
      transplantation, structural or functional abnormalities of urinary tract with
      indwelling urinary catheter or nephrostomy. Fifty hospitalized symptomatic
      patients with funguria of > 10(5) CFU/ml and leucocyturia were analysed for
      etiology, risk factors and outcome. Candida albicans was isolated in 36 patients,
      non-albicans Candida species (Candida tropicalis, Candida krusei) and non-Candida
      yeasts (Blastoschizomyces capitatus) in 14 patients, respectively. All patients
      were treated with systemic antifungals. In total, 42 patients of 50 (84%) were
      cured (32/36 with C. albicans and 10/14 with non-C. albicans associated
      funguria). Systemic antifungal therapy should be considered in high-risk patients
      with fungal UTI.

PMID- 10394986
TI  - Inhibitors of bacterial growth in urine: what is the role of betaines?
AB  - It has long been recognised that some individuals produce urine that is
      inhibitory to uropathogens. This may be partly explained by inhibitors. Several
      inhibitors have been identified in urine including urea and organic acids.
      Bacteria adapt to high osmolarity by activating osmoregulated betaine porters and
      accumulating organic osmolytes intracellularly. The preferred substrate is
      glycine betaine, which is present in urine, and promotes rapid growth by
      balancing osmotic forces and stabilising macromolecular structures against the
      toxicity of urea and low pH. Other dietary betaines such as trigonelline may also
      be taken but enhance urea toxicity. The importance of such compounds in vivo is
      unknown.

PMID- 10394987
TI  - The influence of ofloxacin (Tarivid) on the parasite-host inter-relationship in
      patients with chronic urinary tract infection.
AB  - In urinary tract infection (UTI), the aim of antimicrobial chemotherapy is either
      to attenuate the virulence of infective micro-organisms, to influence the
      interaction between germs and host or to kill bacteria. In 25 females (aged
      49.8+/-14.7 years) with chronic UTI, parameters of inflammation (CRP, alpha 2
      globulin, leukocytes, ESR) as well as renal function were analyzed under the
      treatment with ofloxacin 2 x 200 mg. Subsequently, bacterial attachment,
      bacterial count, leukocytes, antibody-coated bacteria (ACB), immunoglobulin (Ig)
      G, albumin, a2-microglobulin, Tamm Horsfall protein, secretory IgA (sIgA) and
      lysozyme were determined in urine. The micro-organisms were examined with regard
      to the expression of hemolysin, aerobactin, P-fimbriae and according to their
      plasmid profile. Ofloxacin serum levels were analyzed once prior to, on day 6
      during and on day 3 after drug administration. In all cases, the acute clinical
      symptoms had disappeared after 10 days of treatment, all bacteria were
      eliminated, and the parameters of inflammation in serum and urine had returned to
      normal. On the sixth day of therapy, no expression of P-fimbriae was detectable
      in the Escherichia coli strains isolated, and the attachment rate decreased from
      42+/-30.9% to 11.1+/-18.1%. The sIgA level rose from 42.6+68.5 prior to therapy
      to 88.8+/-136.8 mmol/l on day 3 after therapy; acute symptoms of UTI did not
      recur in any case during the period of 1 year.

PMID- 10394988
TI  - The prevalence of antimicrobial resistance among uropathogens causing acute
      uncomplicated cystitis in young women.
AB  - Four hundred and fifty-two urine isolates from women with acute uncomplicated
      cystitis and a positive urine culture presenting to a sexually transmitted
      disease clinic were collected during 1989-1991, and 213 specimens were collected
      over 1995-1997. The predominant species was Escherichia coli, representing 68% of
      the isolates; others included Staphylococcus saprophyticus (8%), Group B
      streptococci (7%), Proteus spp. (6%), Klebsiella spp. (4%) and Enterococcus
      spp.(3%). More than 10% of the E. coli isolates were resistant to ampicillin,
      cephalothin, tetracycline and trimethoprim sulfamethoxazole (TMP SMX ) during
      both study periods, with the greatest increase in resistance to ampicillin and
      TMP/SMX between the two periods. Six hundred and four urinary tract infection
      isolates, including 83% E. coli, 7% S. saprophyticus, 3%, Klebsiella spp. 2%
      Proteus spp., 2% enterococci, 1% Enterobacter spp. and 2% other organisms, were
      collected from women with acute cystitis attending a university student health
      service during 1995. Among E. coli isolates, 25% were resistant to ampicillin,
      24% to tetracycline and 11%, to TMP SMX. Resistance to fluoroquinolones was
      essentially absent among gram-negative pathogens. Continued evaluation of
      susceptibility patterns of pathogens causing acute uncomplicated cystitis to
      traditional as well as new antimicrobials in well defined populations is
      necessary to ascertain the optimal empiric therapy.

PMID- 10394989
TI  - Urinary tract infections in HIV disease.
AB  - HIV-positive patients are liable to acquire opportunistic infections. Their
      liability to acquire other common infectious conditions is less frequently
      reported. In order to determine the frequency of urinary tract infections (UTI)
      in HIV-positive patients, we performed a retrospective analysis. The control
      group was formed from patients with community acquired pneumonia. We reviewed
      charts of 96 HIV-positive patients and of 314 patients in the control study
      group. The analysis has shown that patients with HIV had a UTI more frequently
      than the controls. Besides the difference in the frequency, we observed the
      difference in the etiology. Enterococci were the most frequent isolates in
      patients with HIV disease, whereas Escherichia coli was most frequently isolated
      in the controls. These facts should be taken into consideration when treatment of
      a UTI with suspected bacteremia in AIDS patients is initiated.

PMID- 10394990
TI  - Psychopharmacology of conditioned reward: evidence for a rewarding signal at D1
      like dopamine receptors.
AB  - A neutral stimulus can acquire conditioned rewarding properties through
      association with an intrinsically rewarding stimulus. The acquisition of
      responding for conditioned rewards requires that environmental stimuli and reward
      processes interact in a highly specific manner; analyses of this phenomenon may
      provide valuable insight into the processes that underlie reward-related
      learning. The effects of dopaminergic agents with different mechanisms of action
      in this paradigm have revealed several interesting dissociations suggesting that
      a rewarding signal at dopamine D1-like receptors may mediate both the acquisition
      of rewarding properties by neutral stimuli and their ability to control behavior.
      Dopamine-induced changes in responding for conditioned reward are susceptible to
      modulation by other neurotransmitter systems. In many cases, the molecular and
      cellular bases of these interactions support the notion that signaling through D1
      like receptors is critical for a conditioned reward to direct responding. The
      model outlined in this paper reflects a comprehensive integration of the existing
      literature in the field, and has several implications that are readily testable
      by future research. Moreover, given the known biochemical coupling of D1-like
      receptors, this model may help in characterizing the sequence of intracellular
      events, from signal transduction to possible transcriptional and/or translational
      regulation, that give rise to the acquisition of rewarding properties by neutral
      stimuli.

PMID- 10394991
TI  - Heroin self-administration in dependent Wistar rats: increased sensitivity to
      naloxone.
AB  - RATIONALE: Non-dependent and dependent opiate users appear to be driven by two
      distinct motivational factors: the primary reinforcing properties of the drug,
      and the negative reinforcing effects associated with relieving the negative
      affective component of opiate withdrawal in the dependent state. OBJECTIVE: To
      investigate the motivational significance of opioid dependence on heroin self
      administration (HSA) in rodents. METHODS: Rats were trained to self-administer
      heroin intravenously (0.06 mg/kg per infusion; FRI), and opiate dependence was
      induced by subcutaneous implantation of two morphine (75 mg base) pellets. Rats
      in a non-dependent control group received placebo pellets. Three days after
      pellet implantation, HSA was resumed in daily 3-h sessions until baseline
      criteria were met and testing was conducted with subcutaneous injections of
      vehicle or naloxone (0, 0.003, 0.01, 0.03 mg/kg) 115 min into the session.
      RESULTS: Morphine-dependent rats significantly increased HSA upon 0.01 mg/kg
      naloxone treatment, but decreased response rates at 0.03 mg/kg. Placebo pellet
      implanted rats increased heroin intake at the 0.01 and 0.03 mg/kg doses. In a
      second experiment, the HSA session was shortened to 1 h and the training dose
      reduced to 0.03 mg/kg per infusion in new groups of animals. HSA in placebo
      pellet-implanted rats was increased only following the highest dose of the
      antagonist, while dependent rats were still affected by naloxone doses of 0.003
      0.03 mg/kg. When subjected to a progressive-ratio schedule (experiment 3),
      breaking point values in dependent animals were 198% above baseline. CONCLUSIONS:
      The present study supports the hypothesis that dependence-induction by morphine
      pellet implant in rats resulted in increased sensitivity to very small naloxone
      doses, as measured by changes in HSA. Taken together, these data suggest that
      opiate dependence, as measured by changes in sensitivity to naloxone, is a
      continuum which can contribute to the motivational state of drug-seeking.

PMID- 10394992
TI  - Behavioural profiles in the mouse defence test battery suggest anxiolytic
      potential of 5-HT(1A) receptor antagonists.
AB  - RATIONALE: Compounds varying in selectivity as 5-HT1A receptor antagonists have
      recently been reported to produce anxiolytic-like effects comparable to those of
      benzodiazepines in the mouse elevated plus-maze procedure. OBJECTIVE: In view of
      the potential clinical significance of these findings, the present experiments
      compared the behavioural effects of diazepam (0.5-3.0 mg/kg) with those of
      several non-selective 5-HT1A receptor antagonists [NAN-190, 0.1-3.0 mg/kg, MM-77,
      0.03-1.0 mg/kg, (S)-UH-301, 0.3-3.0 mg/kg and pindobind-5-HT1A, 0.03-1.0 mg/kg],
      and three selective 5-HT1A receptor antagonists (WAY100635, 0.01-3.0 mg/kg, p
      MPPI, 0.1-3.0 mg/kg and SL88.0338, 0.3-3.0 mg/kg) in the mouse defence test
      battery (MDTB). METHODS: In this well-validated anxiolytic screening test, Swiss
      mice are directly confronted with a natural threat (a rat) as well as situations
      associated with this threat. Primary measures taken during and after rat
      confrontation were flight, risk assessment (RA), defensive threat/attack and
      escape attempts. RESULTS: Diazepam significantly decreased flight reactions after
      the rat was introduced into the runway, reduced RA activities of mice chased by
      the rat, increased RA responses displayed when subjects were constrained in a
      straight alley and reduced defensive upright postures and biting upon forced
      contact. All the selective 5-HT1A receptor antagonists and NAN-190 also reduced
      flight, RA in the chase test, and defensive threat and attack behaviours. (S)-UH
      301 and pindobind-5-HT1A reduced RA in the chase test, but only partially
      modified defensive threat and attack. Unlike the other drugs tested, MM-77
      produced significant effects only at doses which also markedly reduced
      spontaneous locomotor activity, suggesting a behaviourally non-specific action.
      In contrast to diazepam, the 5-HT1A receptor ligands failed to affect RA in the
      straight alley test. Following removal of the rat from the test area, only
      diazepam and (S)-UH-301 reduced escape behaviour (contextual defence) at doses
      which did not decrease locomotion. Overall, the present findings indicate that
      except for one RA behaviour and escape responses, the 5-HT1A receptor ligands
      studied modified the same defensive behaviours as diazepam, suggesting potential
      therapeutic efficacy in the management of anxiety disorders. However, the
      magnitude of the effects of the 5-HT1A compounds on defence was generally smaller
      than that of the benzodiazepine. CONCLUSION: As all of the 5-HT1A compounds
      tested in this series share antagonistic activity in models of postsynaptic 5
      HT1A receptor function, it is proposed that this action accounts for their
      effects on defence.

PMID- 10394993
TI  - The discriminative stimulus effects of naloxone and naltrexone in morphine
      treated rhesus monkeys: comparison of oral and subcutaneous administration.
AB  - RATIONALE: Opioid antagonists are used to reverse the toxic effects of opioids,
      to diagnose opioid dependence and to treat opioid and other (alcohol) drug abuse.
      OBJECTIVES: This study compared the discriminative stimulus effects of two opioid
      antagonists (naloxone and naltrexone), after parenteral and oral administration.
      METHODS: The discriminative stimulus effects of naloxone and naltrexone were
      evaluated every 15 min over a 2-h period in four morphine-treated (3.2 mg/kg per
      day) rhesus monkeys discriminating between subcutaneous (SC) injections of
      naltrexone (0.01 or 0.032 mg/kg) and saline, while responding under a fixed-ratio
      5 schedule of stimulus shock termination. RESULTS: Within 15 min of SC
      administration, naloxone and naltrexone produced greater than 90% drug
      appropriate responding at doses of 0.032 and 0.01 mg/kg, respectively. The
      largest dose of naloxone (3.2 mg/kg) administered orally produced 82% drug
      appropriate responding within 90 min; the same dose of naltrexone administered
      orally produced greater than 90% drug-appropriate responding within 30 min.
      Although both drugs were at least 100-fold more potent when administered SC, as
      compared to orally, there was little difference (3-fold) between the potency of
      naloxone and naltrexone by either route. CONCLUSIONS: These results fail to
      support the view that naloxone has reduced bioavailability after oral
      administration, as compared to naltrexone, or that its pharmacokinetic profile is
      particularly advantageous for some therapeutic settings (e.g. Talwin Nx).

PMID- 10394994
TI  - The effect of m-CPP on tics and obsessive-compulsive phenomena in Gilles de la
      Tourette syndrome.
AB  - RATIONALE: Family genetic and phenomenological studies support an
      interrelationship between Gilles de la Tourette syndrome (GTS) and obsessive
      compulsive disorder (OCD). Some authors consider GTS as part of a
      serotonergically mediated cluster of OCD spectrum disorders. OBJECTIVE: To study
      serotonergic mechanisms in GTS, the effect of the relatively selective 5-HT2c
      agonist meta-chlorophenylpiperazine (m-CPP) was assessed. METHODS: We studied the
      behavioural effects of m-CPP on tics, obsessions, compulsions and impulsions of
      GTS. Twelve medication-free GTS patients (ten men, two women) were included in a
      single dose 0.5 mg/kg oral m-CPP challenge study with a double-blinded placebo
      controlled cross-over design. Global symptom scores, target symptom scores as
      well as biochemical measures were followed up to 24 h after baseline. RESULTS:
      While m-CPP caused a significant rise in plasma cortisol and prolactin levels, no
      significant effects were found on the tics, obsessions and compulsions.
      Impulsions showed a trend to ameliorate. CONCLUSIONS: This study does not support
      a predominant role for 5-HT on the tics in GTS. The trend of impulsions to
      ameliorate after m-CPP can be interpreted as circumstantial support for
      impulsivity-related 5-HT hypofunctionality in GTS. However, the large variability
      of m-CPP plasma concentrations found in this study casts doubts upon the
      reliability of m-CPP as a probe for challenge studies.

PMID- 10394995
TI  - Blockade of cannabinoid (CB1) receptors by 141716 selectively antagonizes drug
      induced reinstatement of exploratory behaviour in gerbils.
AB  - RATIONALE: A cannabinoid hypothesis of schizophrenia has been proposed according
      to which cognitive dysfunction could be associated with dysregulation of an
      endogenous cannabinoid system. OBJECTIVE: The present study investigated whether
      SR 141716, a selective CB1 receptor antagonist, was able to reduce the
      hyperactivity induced in gerbils by various stimulant drugs known to produce or
      exacerbate schizophrenic symptoms. METHODS: Cocaine, d-amphetamine, morphine, and
      Win 55212-2 were administered intraperitoneally (IP) either immediately before
      placing the animals in the test apparatus (non-habituated gerbils) or after a 2-
      to 3-h habituation period in the actimeter (habituated gerbils). SR 141716 was
      given IP 30 min before the injection of stimulant drugs. Horizontal activity was
      recorded every 10 min for 1 h in Digiscan activity monitor. RESULTS: SR 141716
      (0.3-3 mg/kg) dose-dependently suppressed the enhanced locomotor activity induced
      by each stimulant drug in habituated gerbils, but not in non-habituated animals.
      Clozapine, an atypical antipsychotic compound, but not haloperidol, shared with
      SR 141716, the ability to differentially affect drug-induced hyperactivity in
      habituated versus non-habituated gerbils. CONCLUSION: The activation of
      cannabinoid systems is a required, permissive element in the ability of cocaine,
      d-amphetamine, morphine, and Win 55212-2 to reinstate behaviour, i.e., to
      override stimulus satiation.

PMID- 10394996
TI  - Antidepressant-like effect of ethanol revealed in the forced swimming test in
      Sardinian alcohol-preferring rats.
AB  - RATIONALE: A large body of evidence indicates high comorbidity between depression
      and alcohol abuse. The self-medication hypothesis proposes that depressed
      subjects may abuse ethanol because it reduces the symptoms of depression. The
      present study evaluated whether ethanol may exert an antidepressant-like action
      in genetically selected alcohol-preferring rats, either Sardinian alcohol
      preferring (sP) or Marchigian Sardinian alcohol-preferring (msP) rats, and for
      comparison in Sardinian alcohol-non-preferring (sNP) rats. METHODS: The forced
      swimming test (FST) was used to evaluate the antidepressant-like action of
      ethanol; in this test the effect of ethanol ingestion on the immobility time was
      determined. RESULTS: Ethanol-naive sP rats exhibited a longer period of
      immobility in comparison to sNP rats. Both in ethanol-naive sP and msP rats,
      voluntary ethanol drinking reduced the immobility time. A similar effect was
      obtained when repeated (five or nine) intragastric administrations of 0.7 g/kg
      ethanol were given during the 24 h prior to the test in msP and in sP, but not in
      sNP rats. Desipramine, like ethanol, sharply reduced immobility at doses of 5 or
      20 mg/kg, given 3 times in the 24 h before the test in msP rats. The reduced
      immobility induced by ethanol in msP rats was apparently not the consequence of a
      general motor activation, because 9 IG administrations of ethanol, 0.7 g/kg,
      failed to alter locomotor activity in the open field test. Moreover, blood
      alcohol levels and rectal temperature of msP, sP and sNP after IG ethanol
      administration were not statistically different. CONCLUSIONS: The present results
      provide evidence for an antidepressant-like action of ethanol in sP and msP rats
      and suggest that this action may contribute to sustain their high ethanol
      drinking.

PMID- 10394997
TI  - Inositol reduces depressive-like behaviors in two different animal models of
      depression.
AB  - RATIONALE: Myo-inositol is an isomer of glucose that is a precursor in the
      phosphatidylinositol (PIP) cycle, a source of two second messengers:
      diacylglycerol (DAG) and inositol triphosphate (IP3). Clinical studies have
      reported that inositol is effective in relieving symptoms of depression.
      OBJECTIVE: The present study examined the effects of inositol on two animal
      models of depression: the Porsolt forced swim test, a behaviorally based model;
      and the reserpine-induced immobility model, a pharmacologically based model.
      METHODS AND RESULTS: Chronic inositol injections (daily for 14 days) of 1.2 g/kg
      (but not at lower doses) reduced immobility time and increased struggle time in
      the Porsolt test compared with control animals. The same dose and treatment
      schedule also reduced complete immobility time but did not affect ambulatory
      activity in the reserpine test compared with controls. Chronic oral treatment
      with inositol (10% in food for 14 days) had effects similar to IP inositol in the
      Porsolt test. CONCLUSIONS: The effect of inositol in animal models of depression
      supports its possible importance as a new treatment for the disorder, and permits
      research on its mechanisms of action.

PMID- 10394998
TI  - Concurrent progressive-ratio schedules to compare reinforcing effectiveness of
      different phencyclidine (PCP) concentrations in rhesus monkeys.
AB  - RATIONALE: Progressive ratio (PR) schedules have become well accepted for testing
      the reinforcing effectiveness of drugs. This study extends the methods to
      concurrent PR schedules with different concentrations of orally delivered
      phencyclidine (PCP). OBJECTIVE: The sensitivity of the procedure is tested by
      presenting different PCP concentrations with independently-operating PR
      schedules. METHOD: PCP self-administration was investigated in seven rhesus
      monkeys. Six different PCP concentrations (0.03-1.0 mg/ml) and water were
      randomly paired (21 pairings). Liquid delivery (24 ml) was contingent upon lip
      contact responses on solenoid-operated drinking spouts; whereby, the response
      requirement or fixed-ratio (FR) increased (from 8 to 16, 32, 64, 128... to 4096)
      after each successful completion of a previous FR and subsequent liquid delivery.
      Monkeys self administered PCP during daily 3-h sessions, and each pair of
      concentrations was held constant until behavior had stabilized for at least 4
      days. RESULTS: The higher of the two PCP concentrations always maintained greater
      responding, PR break point (BP), or the last ratio completed, and liquid
      deliveries than did the lower concentration. However, the monkeys did not
      exclusively respond on the drinking spout that yielded the higher drug
      concentration. When examined across all drug pairings, the percentage of total
      available deliveries of the higher concentration was significantly greater than
      those of the lower concentration. The monkeys maximized the amount (mg) consumed
      for the response output. Responding, BPs and liquid deliveries maintained by 0.12
      and 0.25 mg/ml PCP were significantly greater than other PCP concentrations;
      however, drug intake (mg) increased directly with PCP concentration. CONCLUSION:
      These results indicate that concurrent PR schedules using oral drug self
      administration and a concurrent choice paradigm reliably provide an estimation of
      relative reinforcing strength, and behavior maintained by these schedules is
      sensitive to small changes in PCP concentration.

PMID- 10394999
TI  - Enhancement of sustained attention performance by the nicotinic acetylcholine
      receptor agonist ABT-418 in intact but not basal forebrain-lesioned rats.
AB  - RATIONALE: Loss of telencephalic cholinergic projections has been postulated to
      contribute significantly to the cognitive decline associated with aging and
      dementia. OBJECTIVE: The effects of the nicotinic acetylcholine receptor agonist
      ABT-418, a potential therapeutic drug for the treatment of the age- and dementia
      associated cognitive disorders, were tested in an animal model of the cortical
      cholinergic deafferentation-induced impairments in sustained attention. METHODS:
      Animals were trained in an operant task designed to test sustained attention
      performance. A partial loss of cortical cholinergic inputs was produced by
      infusions of 192 IgG-saporin into the basal forebrain. The effects of the
      systemic administration of ABT-418 (0.04, 0.13, 0.39 mg/kg) and the
      psychostimulant methylphenidate (0.2, 0.4, 0.8 mg/kg) were assessed. RESULTS:
      Compared with sham-lesioned animals, this lesion resulted in a decrease in the
      relative number of hits while the relative number of correct rejections remained
      unaffected. Administration of ABT-418 significantly improved the relative number
      of hits. Furthermore, this effect of ABT-418 interacted with the effects of the
      lesion. Unexpectedly, this interaction was based on a significant enhancement of
      the performance of sham-lesioned animals while no effects were found in 192 IgG
      saporin-lesioned animals. Administration of methylphenidate did not affect
      performance. CONCLUSIONS: While these data do not support the hypothesis that
      administration of ABT-418 attenuates the impairments in attentional performance
      that result from loss of cortical cholinergic inputs, they support previous
      notions about this drug's ability to enhance cognitive processes in intact
      subjects.

PMID- 10395000
TI  - Stress reinstates nicotine seeking but not sucrose solution seeking in rats.
AB  - RATIONALE: Intermittent footshock stress effectively reinstates extinguished
      heroin-, cocaine- and alcohol-taking behaviors, but not behaviors previously
      maintained by food reinforcers. Here we tested further the generality of the
      phenomenon of stress-induced reinstatement by determining the effect of footshock
      on reinstatement of operant responding previously maintained by nicotine or
      palatable sucrose solutions. METHODS: Groups of rats were trained to self
      administer either nicotine (0.03 mg/kg per infusion, 14 days) or sucrose (10 or
      30% w/v, 14-20 days). After extinction of the nicotine- or the sucrose-reinforced
      behaviors for 5-15 days, the rats were exposed to intermittent footshock stress
      (5 and 15 min, 0.8 mA) during tests for reinstatement. RESULTS: Footshock
      reliably reinstated nicotine seeking after extinction of the drug-reinforced
      behavior. In contrast, the same parameters of footshock stress did not
      consistently reinstate operant responding previously maintained by sucrose
      solutions. CONCLUSIONS: These and previous data suggest that stressors may be
      more effective stimuli for reinstatement of behaviors previously maintained by
      drug reinforcers as compared with non-drug reinforcers.

PMID- 10395001
TI  - The apoptosis cascade--morphological and immunohistochemical methods for its
      visualization.
AB  - Apoptosis is involved in morphogenesis of embryonic tissues as well as in
      homeostasis of adult organs and tissues. It is the main process by which organs
      maintain cell mass and at the same time eliminate excess and aged cells that have
      lost their functional importance. The typical morphological signs of apoptosis
      (cellular shrinkage, membrane blebbing, nuclear condensation and fragmentation)
      are the final results of a complex biochemical cascade of events, some of which
      are inextricably linked to the process of differentiation. Studies that analyze
      all stages of this cascade, rather than the final morphological stages of
      apoptotic death, are essential in order that specific link(s) between
      differentiation and apoptosis are appreciated. This review outlines the main
      stages of the apoptosis cascade together with current methods for their
      morphological visualization. Starting with (a) receptors and ligands known to
      induce apoptosis, we continue with (b) early initiator stages of apoptosis, and
      (c) proteins regulating and potentially inhibiting further progression of the
      cascade, into (d) irreversible execution stages of the cascade, and finally (d)
      the morphological events of apoptotic death. For each stage we present those
      aspects of the biochemical background that are morphologically relevant, together
      with proven methods for their visualization. We offer technical advice at each
      stage based upon our experience of studying differentiation and apoptosis in
      human placental trophoblast.

PMID- 10395002
TI  - Apoptosis during inner ear development in human and mouse embryos: an analysis by
      computer-assisted three-dimensional reconstruction.
AB  - Apoptosis in the developing inner ear tissue of human (Carnegie stage 14 to 21,
      approximately 5 to 8 weeks of gestation) and mouse (10.5 to 14 days of gestation)
      embryos was systematically analyzed by a computer-assisted three-dimensional
      reconstruction of the serial histological sections and by the TUNEL method.
      Morphogenetic events such as folding between the utricular portion and
      endolymphatic duct, constriction of the junction of the saccule with the cochlea
      and folding of the vestibular portion to form the semicircular ducts were
      accompanied by a localized distribution of apoptosis. The apoptosis was also
      related to the innervation of the cochlear and vestibular epithelia from the
      sensory ganglion of the eighth cranial nerve and the differentiation of the otic
      epithelia into the sensory epithelia. These results suggest that apoptosis plays
      an important role in the development of the inner ear.

PMID- 10395003
TI  - Differential maturational patterns of nitric oxide synthase-I and NADPH
      diaphorase in functionally distinct cortical areas of the mouse cerebral cortex.
AB  - Nitric oxide (NO) regulates several functions both in the developing and the
      adult central nervous systems (CNS). During development, NO is assumed to
      contribute to the histogenetic differentiation of the CNS especially through the
      modulation of programmed neuronal death. The embryonal and postnatal changes in
      the distribution of the cortical NO producing system were studied in Balb/c mice
      using immunocytochemistry for nitric oxide synthase-I (NOS-I) and NADPH
      diaphorase (NADPH-d) enzyme histochemistry. NOS-I reactive neurons (RN) appeared
      first at embryonic day 14 (E14) in the spinal cord in the vicinity of the central
      canal, and later, at E16-18, in the thalamus and striatum. The first cortical
      region to present NOS-I reactivity was the parietal cortex, which happened at E18
      20. After E20 the number of NOS-I RN increased in every cortical area, plateauing
      at postnatal day 4 (P4). In parietal regions, however, the highest density of NOS
      I RN was observed already at P1. The neuronal packing density (PD) of NOS-I RN
      declined until adulthood, interrupted by a transient increase in some cortical
      areas at the onset of puberty. The heterochronous appearance of NOS-I during pre-
      and postnatal development of different brain regions and the sequence of up- and
      downregulation of expression until adult stages points to an important role of NO
      in brain development and functional differentiation.

PMID- 10395004
TI  - Evidence for polar cytoplasm/nuage in rat oocytes.
AB  - In many organisms oocytes contain dark-staining material, termed nuage, that is
      concentrated at one pole of the oocyte cytoplasm and that influences the further
      development of the oocyte after fertilization. In mammalian oocytes,
      ultrastructural studies have detected small patches of nuage-like material, but
      thus far no nuage-rich zone of polar cytoplasm has been reported. Here, we report
      that when large sections of rat ovary embedded in methacrylate resin are stained
      with toluidine blue and surveyed, many oocytes contain a narrow, sharply defined,
      basophilic zone of polar cytoplasm that appears analogous to the polar cytoplasm
      of Xenopus and other non-mammalian species. This basophilic polar cytoplasm was
      common in multilaminar follicles and was not visible in smaller, primordial
      follicles. In one out of five oocytes stimulated with hCG to complete the first
      meiotic division, a relatively faint region of cortical basophilia was
      detectable. Further studies will be needed to ascertain if this nuage-like
      material has an influence upon the development of oocytes similar to that seen in
      non-mammalian species.

PMID- 10395005
TI  - Apoptosis in the early involuting stellate reticulum of rat molar tooth germs.
AB  - When the enamel organ of the rat tooth germ is fully developed at the tip of the
      prospective cusp, amelogenesis begins, and at this site the overlaying stellate
      reticulum begins its involution. During the involution process, there is a
      gradual decrease in intercellular spaces, invasion by blood vessels, appearance
      of macrophage-like cells and reduction in the number of stellate reticulum cells.
      Since reduction or disappearance of cells during embryonic development in organs
      and tissues has been shown to occur by apoptosis, we decided to examine early
      involuting regions of the stellate reticulum in the hope of detecting apoptosis.
      For this purpose, upper first molars of Wistar newborn rats aged 1 and 3 days
      were fixed in formaldehyde for the TUNEL method and in glutaraldehyde
      formaldehyde for light and electron microscopy. Paraffin sections revealed TUNEL
      positive structures, i.e. brown-yellow-stained bodies, in the central portion of
      the stellate reticulum, and next to the outer enamel epithelium and stratum
      intermedium. Examination of ultrathin sections confirmed the TUNEL findings: some
      stellate reticulum cells showed nuclei containing crescent-like electron-opaque
      condensed masses of peripheral chromatin, typical of apoptosis. Also, apoptotic
      bodies of various sizes and appearances were frequently observed within stellate
      reticulum cells. We should like to suggest that apoptosis is associated with the
      reduction in the number of cells during regression of the reticulum.

PMID- 10395006
TI  - The development of the pressure-bearing tendon of the bullfrog, Rana catesbeiana.
AB  - The plantaris longus tendon of the bullfrog is a pressure-bearing tendon and
      develops a fibrocartilage-like arrangement in the area subjected to compressive
      forces. The fibrocartilage-like tissue shows some distinct aspects of cellular
      and fibrillar structure and distribution as compared to the mammalian
      counterparts. In this work, the development of the plantaris longus tendon was
      assessed by investigating some of its structural, cytochemical and
      immunocytochemical aspects in developing tadpoles. The pressure-bearing region is
      structurally distinct from the tension region as early as at stage 35 of larval
      development. There is little extracellular matrix in both regions, but the former
      shows round mesenchymal-like cells with many processes and cell junctions, while
      the latter is populated by fibroblasts. As development proceeds, the cells in the
      compression region retract the processes, loose the connections to each other,
      become rounded and produce abundant proteoglycans and some collagen fibers.
      Progressively, their organelles become localized in a restricted perinuclear area
      and are surrounded by a constantly increasing amount of vimentin. The fibroblasts
      of the tension region produce mostly collagen fibrils, which are packed and
      aligned to each other. These cells become more elongated and show a diminished
      cytoplasmic area. The results allow for the conclusion that the compression
      region does not arise by simple hyperplasia of the peripheral layers of a normal
      tendon, but from a programmed sequence of developmental steps. This assumption is
      based on the fact that muscle fibers are still developing when the tendon is
      already showing a differentiated compression region. We further suggest that
      mechanical stimulation is a secondary factor most likely associated with the
      maintenance of the differentiated phenotype of this tendon.

PMID- 10395007
TI  - Activity-dependent neurotrophic factor: a potent regulator of embryonic growth
      and development.
AB  - Activity-dependent neurotrophic factor is a potent, neuroprotective molecule
      released from astroglia following stimulation by vasoactive intestinal peptide
      and, at least in part, accounts for the neuroprotective actions of vasoactive
      intestinal peptide. As well as enhancing neuronal survival, vasoactive intestinal
      peptide is known to regulate embryonic growth during the early postimplantation
      period of development. The current study was designed to assess activity
      dependent neurotrophic factor's role in the growth-regulatory properties of
      vasoactive intestinal peptide. Treatment of whole cultured day-9 mouse embryos
      with activity-dependent neurotrophic factor (10(-13) M) resulted in a growth of
      3.1 somites, compared with 1.6 somites in control embryos after a 4 h incubation
      period. Significant increases were also seen in cross-sectional area, protein and
      DNA content and bromodeoxyuridine incorporation. Activity-dependent neurotrophic
      factor-treated embryos were morphologically indistinguishable from control
      embryos of the same size. Anti-activity-dependent neurotrophic factor ascites
      significantly inhibited growth. In addition, co-treatment of embryos with anti
      activity-dependent neurotrophic factor ascites inhibited vasoactive intestinal
      peptide-stimulated growth. Although anti-vasoactive intestinal peptide treatment
      inhibited growth, it did not inhibit activity-dependent neurotrophic factor
      induced growth. These data indicate that an activity-dependent neurotrophic
      factor-like substance is an endogenous and potent growth-promoting factor in the
      early postimplantation embryo and that vasoactive intestinal peptide-regulated
      growth of embryos occurs, at least in part, through the action of activity
      dependent neurotrophic factor.

PMID- 10395008
TI  - Early postnatal development of the rat corticostriatal pathway: an anterograde
      axonal tracing study using biocytin pellets.
AB  - The ontogenetic development of the neocortical projections to the striatum was
      studied in postnatal rats by sensitive anterograde tracing with biocytin. The
      developmental status of this mainly glutamatergic pathway is important as it
      plays a major role in regulation of striatal maturation and induction of
      excitotoxic striatal neurodegeneration resembling the type found in Huntington's
      disease. Biocytin pelletts were injected into the motorcortex caudal forelimb
      area of newborn rats and of rats aged 3, 6, 13, 27 and 61 days followed by
      sacrifice and visualisation of the tracer 24 h later, at P1, P7, P14, P28 and
      P62, respectively. Biocytin pellets were also injected into the motorcortex jaw
      lip-tongue area and into the cingulate cortex of newborn and 6-day-old rats. The
      biocytin pellets produced intense anterograde labelling of corticofugal
      projection fibres from the injection sites, as well as a local Golgi-like
      labelling of neurons. From postnatal day 1 into adult age efferent fibres from
      the motorcortex caudal forelimb area displayed a progressively denser innervation
      of the ipsilateral and contralateral, dorsolateral striatum. The terminating
      fibres were most dense in the ipsilateral striatum. In the dorsolateral striatum
      the corticostriatal fibres displayed a patch/matrix-like arrangement from
      postnatal day 14 onwards. Injections into the motorcortex jaw-lip-tongue area at
      postnatal days 0 and 6 displayed a progressive, denser innervation of the
      ipsilateral and contralateral ventrolateral striatum. The cingulate
      corticostriatal fibre projection, was more developed at birth than the projection
      from the motorcortex and increased its fibre density in the ipsilateral
      dorsomedial striatum up to at least day 7. IN CONCLUSION: the ipsilateral
      corticostriatal projections from the rat motorcortex and cingulate areas are
      present in newborn rats. During postnatal life the pathway develops further and
      specialisation of the terminating fibres into a patch/matrix like arrangement can
      be identified by postnatal day 14.

PMID- 10395009
TI  - The anchoring zone in the human placental amnion: bunches of oxytalan and
      collagen connect mesoderm and epithelium.
AB  - This study deals with the examination of the elastic fibre system as well as
      collagen fibrils and collagen type IV in the amnion of the human chorionic plate
      of uncomplicated pregnancies at term. In organs other than placenta, the elastic
      fibre system comprises elastic fibres, elaunin and oxytalan microfibrils. The
      investigation was performed by light and electron microscopy and
      immunocytochemistry. Abundant oxytalan fibres were present in all amnionic
      layers, while no elastic fibres were found. Oxytalan microfibrils formed a broad
      sub-epithelial layer and were intermingled with collagen fibrils in the subjacent
      compact layer and in the amnionic mesoderm. Light microscopically, bunches
      containing orcein-stained oxytalan and collagen-type-IV-immuno-stained
      microfibrils were seen rising from the amnionic mesoderm perpendicularly towards
      the epithelial layer, where they obviously inserted. It can be assumed that the
      subepithelial microfibrillar layer and the following compact layer form an
      anchoring zone between the amnionic mesoderm and the epithelium that may
      contribute to the maintenance of strength. The ultrastructure of the bunches
      clearly showed collagen fibrils mixed with oxytalan microfibrils. No collagen
      type I-immunostaining was found in the bunches. After pretreatment of cryostat
      sections with elastase, oxytalan-orcein-staining was absent, but collagen type IV
      immunoreactivity was not altered. Furthermore, after oxytalan-orcein-staining
      resp. anti-collagen type IV incubation, all positive fibres revealed an identical
      morphological pattern. We propose that oxytalan and collagen type IV may
      represent further members of the microfibril complex.

PMID- 10395010
TI  - E-cadherin in the developing mouse gonad.
AB  - Expression of the cell adhesion molecule E-cadherin in the developing mouse has
      been investigated by immunocytochemistry and disaggregated organ culture. The
      principal aims were firstly, to determine whether E-cadherin is expressed in the
      indifferent gonad and if so with which cell population(s) it is associated.
      Secondly, to investigate the pattern of expression in the mesonephros, especially
      in relation to ventral mesonephric tubule cells, which contribute to the somatic
      cell population of the gonad. Thirdly, to discover whether there are any sex
      differences in expression of E-cadherin in differentiating gonads. Germ cells in
      the indifferent gonad showed strong immunoreactivity whereas somatic cells were
      unstained unless their membranes were in contact with those of germ cells.
      Positive staining for E-cadherin was found in epithelial cells of the mesonephric
      duct and tubules. Staining was weak at the ventral margins of the ventral
      mesonephric tubules. At later stages, germ cell immunoreactivity could be
      correlated with stages of ovarian differentiation, being reduced or absent
      between germ cells at 16 days post coitum, when ovigerous cords become
      dissociated as a prelude to follicle formation. Stronger staining reappeared
      briefly at 17 days post coitum, the time of follicular cell attachment to
      oocytes, before waning again 2 days later. Similarly, immunoreactivity in the
      differentiating testis was initially restricted to the germ cell population but
      pre-Sertoli cells were strongly positive between 16 and 19 days post coitum. The
      most striking sex difference was seen in the somatic cell population, where
      Leydig cells of the testis became strongly positive for E-cadherin from 17 days
      post coitum onwards. At this time, unlike controls, dissociated cells from gonads
      of either sex were unable to reform their initial contacts when cultured in the
      presence of the antibody to E-cadherin, confirming its functional importance.

PMID- 10395011
TI  - Neuronal and glial structures of the superficial layers of the human superior
      colliculus.
AB  - We studied neuronal and glial elements in the superficial layers of the human
      superior colliculus by means of Nissl stains, Golgi impregnations, histochemical
      demonstration of NADPH-d activity and immunohistochemistry for glial fibrillary
      acidic protein (GFAP) in astrocytes. The glia-neuron interface was visualized
      with Wisteria floribunda agglutinin (WFA), which is a marker for perineuronal
      nets. The laminar pattern and the morphology of the major cell types closely
      resembled that found in other species although the thickness of the stratum
      zonale varied and the diversity of interneurons was greater than in other
      mammals. Furthermore, the stratum griseum superficiale showed a characteristic
      clustering of cells, the surfaces of which were intensely labeled by WFA. The
      clusters disappeared when GFAP expression increased.

PMID- 10395013
TI  - Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 1.
      Acute treatments are active in the forced swim test.
AB  - Previous studies have demonstrated that antagonists at the NMDA receptor are as
      efficacious as tricyclic antidepressants in pre-clinical antidepressant screening
      procedures and in blocking or reversing the behavioral deficits associated with
      animal analogs of major depressive symptomatology. The NMDA receptor complex
      gates Ca2+, which interacts with calmodulin to subsequently activate nitric oxide
      (NO) synthase. We hypothesized that NO synthase antagonists might display
      antidepressant-like properties, similar to NMDA receptor antagonists. We examined
      the effects of N(G)-nitro-L-arginine (L-NNA), its dextrorotatory enantiomer, D
      NNA, N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine
      (L-NMMA) at doses from 1 to 30 mg/kg in the forced swim test in mice. We now
      report that NO synthase antagonists are as efficacious as imipramine (15 mg/kg)
      in reducing the duration of immobility in the mouse forced swim test. The effects
      of NO synthase antagonists, as well as those of imipramine were blocked by pre
      treatment with L-arginine (L-Arg) (500 mg/kg). In contrast to imipramine, the NO
      synthase antagonists were without effect on locomotor activity over the dose
      range active in the forced swim test (3-10 mg/kg). Likewise, L-Arg was without
      effect on locomotor activity. These data support the hypothesis that NO synthase
      antagonists possess antidepressant properties and may represent a novel class of
      therapeutics for major depressive disorders.

PMID- 10395012
TI  - Imaging of renal medullary interstitial cells in situ by confocal fluorescence
      microscopy.
AB  - Renal medullary interstitial cells are a prevalent and characteristic feature of
      the inner medulla of the kidney, but the physiological significance of this is
      unclear. We have developed a method for imaging renal medullary interstitial
      cells in situ by loading the cells with fluorescent dyes and monitoring their
      distribution using confocal microscopy. The pH-sensitive probe 2'7'-bis
      (carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester was used as a
      marker of cytoplasmic volume and therefore of cell morphology. Nile Red was used
      to demonstrate the presence of renal medullary interstitial cell lipid droplets.
      Papillae were excised from 100 g Sprague-Dawley rats and loaded with the
      appropriate dye. The papillae were then examined using a Leica TCS 4D confocal
      microscope and oil immersion lenses. Fluorescence was excited (488 nm) using an
      argon laser and emission wavelengths above 515 nm collected using a long pass
      filter. Images of papillae loaded with 2'7'-bis-(carboxyethyl)-5-(and-6)
      carboxyfluorescein acetoxymethyl ester clearly demonstrate a ladder-like
      arrangement of renal medullary interstitial cells. More detailed examination
      revealed the presence of cytoplasmic extensions that appear to make close contact
      with adjacent loops of Henle. Three-dimensional reconstructions of serial
      sections revealed spiral arrangements in some ladders of renal medullary
      interstitial cells. Nile Red-labelled lipid droplets of 0.5-1.0 microm diameter
      were located throughout the cytoplasm of renal medullary interstitial cells and
      especially within the cytoplasmic extensions. These experiments highlight the
      ability of confocal microscopy to allow investigation of renal medullary
      interstitial cells in situ.

PMID- 10395014
TI  - Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 2.
      Chronic treatment results in downregulation of cortical beta-adrenoceptors.
AB  - Down-regulation of cortical beta-adrenoceptors is observed in rodents following
      chronic treatment with many clinically effective antidepressant therapies.
      [3H]dihydroalprenolol binding to cortical beta-adrenoceptors was examined in mice
      treated with the nitric oxide (NO) synthase antagonist N(G)-nitro-L-arginine (L
      NNA). Administration of L-NNA (0.1, 0.3 mg/kg) for 21 days produced a significant
      reduction (28%, 31%, respectively, P<0.05) in [3H]dihydroalprenolol binding to
      cortical membranes without affecting Kd. Dose 1 mg/kg of L-NNA given chronically
      also produced a 20% decrease in beta-adrenoceptor density, but this effect was
      not statistically significant. While chronic treatment with imipramine (15 and 30
      mg/kg) produced respectively a 30% and 25% (P<0.05) reduction in the density of
      [3H]dihydroalpenolol, single injection of either imipramine (15 and 30 mg/kg) or
      L-NNA (0.1, 0.3, and 1 mg/kg) had no effect on [3H]dihydroalprenolol binding.
      These findings are consistent with the hypothesis that drugs which can affect the
      Ca2+ -calmodulin/nitric oxide synthase/guanylyl cyclase signaling pathway may
      represent a novel approach to the treatment of depression and are congruent with
      our previous observation, which has demonstrated the antidepressant-like
      properties of NO synthase inhibitors in the forced swim test.

PMID- 10395015
TI  - Possible involvement of spinal protein kinase C in thermal allodynia and
      hyperalgesia in diabetic mice.
AB  - We examined the tail-flick response to various heat intensities in diabetic and
      non-diabetic mice. Heat intensities were set to one of five values by adjusting
      the source voltage of a 50-W projection bulb to 25, 35, 50, 65 and 80 V. These
      heat intensities produced surface skin heating rates of 0.1, 0.4, 0.9, 3.0 and
      7.3 degrees C/s, respectively. Tail-flick latencies at source voltages of 35 and
      50 V in diabetic mice were significantly shorter than those in non-diabetic mice.
      However, there were no significant differences in tail-flick latencies at 25, 65
      and 80 V. In non-diabetic mice, tail-flick latencies were not affected by
      intrathecal (i.t.) pretreatment with capsaicin 24 h before testing. Tail-flick
      latencies at 35 and 50 V in diabetic mice were increased by pretreatment with
      capsaicin. Moreover, although tail-flick latencies in non-diabetic mice were not
      affected by i.t. pretreatment with calphostin C, a selective protein kinase C
      inhibitor, those at 35 and 50 V in diabetic mice were increased. However, i.t.
      pretreatment with (8R, 9S, 11S)-(-)-9-hydroxy-9-n-hexyloxy-carbonyl-8-methyl-2,
      3, 9, 10-tetrahydro-8, 11-epoxy-1H, 8H, 11H-2, 7b, 11a-triazadibenzo [a,
      g]cycloocta[cde]-trinden-1-one (KT5720), a selective protein kinase A inhibitor,
      did not affect tail-flick latencies in either diabetic or non-diabetic mice. In
      non-diabetic mice, i.t. pretreatment with phorbol 12,13-dibutyrate (PDB), a
      protein kinase C activator, decreased tail-flick latencies at 35 and 50 V. Tail
      flick latencies in diabetic mice were not affected by i.t. pretreatment with PDB
      60 min before testing. Furthermore, the attenuation of tail-flick latencies
      induced by i.t. pretreatment with PDB in non-diabetic mice was reversed by i.t.
      pretreatment with capsaicin 24 h before testing. These results indicate that
      diabetic mice exhibit thermal allodynia and hyperalgesia. Furthermore, this
      thermal allodynia and hyperalgesia in diabetic mice may be due to the enhanced
      release of substance P followed by activation of protein kinase C in the spinal
      cord.

PMID- 10395016
TI  - Structure-activity relationships of naturally occurring and synthetic opioid
      tetrapeptides acting on locus coeruleus neurons.
AB  - Intracellular recording was used to study the effects of eight opioid
      tetrapeptides with similar amino acid sequences, namely endomorphin-1 (Tyr-Pro
      Trp-Phe-NH2), endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), morphiceptin (Tyr-Pro-Phe-Pro
      NH2), hemorphin-4 (Tyr-Pro-Trp-Thr), Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2), Tyr-W-MIF-1
      (Tyr-Pro-Trp-Gly-NH2), TAPS (Tyr-D-Arg-Phe-Sar) and DALDA (Tyr-D-Arg-Phe-Lys
      NH2), on neurons of the rat locus coeruleus, using a submerged brain slice
      preparation. All the tetrapeptides inhibited the spontaneous firing of all
      neurons of the locus coeruleus tested. Higher concentrations also caused
      hyperpolarization of the neurons and a reduction in input resistance. These
      inhibitory effects were rapidly and completely reversed by CTAP (D-Phe-Cys-Tyr-D
      Trp-Arg-Thr-Pen-Thr-NH2, a selective micro-opioid receptor antagonist). The IC50
      of the opioid tetrapeptides, in terms of inhibition of spontaneous firing of
      locus coeruleus neurons, as compared to the concentrations which produced a 5-mV
      hyperpolarization (HC5 mV) were calculated, giving the same rank order of
      potency: TAPS (IC50 = 1.9 nM, HC5 mV = 3.4 nM) > endomorphin-1 (IC50 = 8.8 nM,
      HC5 mV = 22.1 nM) and endomorphin-2 (IC50 = 5.3 nM, HC5 mV = 16.1 nM)> DALDA
      (IC50 = 20 nM, HC5 mV = 143 nM) > morphiceptin (IC50 = 65 nM, HC5 mV = 335 nM) >
      Tyr-W-MIF-I (IC50 = 3.8 microM, HC5 mV = 6.7 microM) > hemorphin-4 (IC50 = 6.7
      microM, HC5 mV = 36.9 microM) > Tyr-MIF-1 (IC50 = 37.5 microM, HC5 mV = 76.2
      microM). Comparison of the ability of endomorphin-1 and endomorphin-2 to inhibit
      spontaneous firing based on single-cell recordings (n = 5) showed these two
      peptides to be equipotent. Based on these results, the structure-activity
      relationships of these opioid tetrapeptides are discussed herein.

PMID- 10395017
TI  - Leptin inhibits norepinephrine and dopamine release from rat hypothalamic
      neuronal endings.
AB  - Noradrenergic and dopaminergic afferents arising from the brain stem to the
      hypothalamus still play a poorly characterised role in food intake control. We
      have studied the effect of leptin, an adipocyte-derived hormone which has been
      implicated in the regulation of feeding behaviour, on [3H]norepinephrine and
      [3H]dopamine release from perfused hypothalamic neuronal endings (synaptosomes)
      in vitro. We have found that leptin (0.01-10 nM) does not modify basal, while it
      inhibits depolarization-induced norepinephrine and dopamine release. We can
      hypothesize that at least part of the anorectic activity of leptin in the
      hypothalamus is effected through an inhibition of noradrenergic and dopaminergic
      firing.

PMID- 10395018
TI  - Effect of tedisamil on cell communication, impulse propagation, and excitability
      of the failing heart.
AB  - In the present work, the effect of tedisamil on gap junctional conductance (gj)
      and conduction velocity was investigated in the failing heart of cardiomyopathic
      hamsters (TO-2 strain). It was found that tedisamil (10(-7) M) increased gj by
      53.8+/-1% (n = 23) in cell pairs isolated from 2 months old cardiomyopathic
      hamsters. The effect of tedisamil was suppressed by intracellular dialysis of an
      inhibitor of protein kinase A and also by adenosine indicating that the drug
      increases gj through the activation of adenylcyclase. Tedisamil also increased
      the conduction velocity and cardiac refractoriness of ventricular muscle from
      young cardiomyopathic hamsters. At an advanced stage of the disease, however,
      when the beta-adrenoceptor, adenylcyclase signaling system is impaired, tedisamil
      was unable to increase gj. The present results indicate that the antiarrhythmic
      action of tedisamil is in part related to an increase in junctional conductance
      and conduction velocity.

PMID- 10395019
TI  - Postjunctional alpha2-adrenoceptors in the rat tail artery: effect of sex and
      castration.
AB  - To investigate sex-related differences in vasoconstrictor responses to
      postjunctional alpha2-adrenoceptor activation, isolated ring segments of tail
      arteries from Fischer-344 rats were studied. Addition of the alpha2-adrenoceptor
      agonist, UK-14304 [5-bromo-6-(2-imidazoline-2yl)-aminol-quinoxaline], enhanced
      vasoconstriction to the selective alpha1-adrenoceptor agonist, methoxamine, in
      arteries from both males and females. The response to UK-14304 was significantly
      greater in arteries from males as compared to female arteries. Addition of alpha2
      adrenoceptor antagonist, idazoxan or rauwolscine, shifted norepinephrine
      concentration response curves to the right. Antagonist effects also tended to be
      greater in arteries from males as compared to females. After gonadectomy, male
      female differences persisted; thus, removal of sex hormones in either males or
      females did not alter responses to either agonists or antagonists of alpha2
      adrenoceptors. These findings suggest that sex differences in alpha2-adrenoceptor
      function are not maintained by either male or female gonadal steroid hormones but
      may be developmentally regulated.

PMID- 10395020
TI  - Effects of NKH477 on renal functions and cyclic AMP production in anesthetized
      dogs.
AB  - The present study was undertaken to evaluate the effects of an adenylate cyclase
      activator N,N-dimethyl-beta-alanine[3R-(3alpha, 4alphabeta, 5beta, 6beta,
      6aalpha, 10alpha, 10abeta, 10balpha)]-5(acetyloxy)-3-ethenyldodecahydro-10, 10b
      dihydroxy-3, 4a, 7, 7, 10a-pentamethyl-1-oxo-1H-naphtho [2,1-b] pyran-6-yl ester
      hydrochloride (NKH477) on renal functions and cyclic AMP production in the dog
      kidney. The intrarenal arterial infusion of NKH477 (30, 100 and 300 ng kg(-1)
      min(-1)) increased renal blood flow, glomerular filtration rate, urine flow rate,
      urinary Na+ and cyclic AMP excretion, fractional Na+ excretion and arterial and
      renal venous plasma cyclic AMP concentrations in a dose-dependent manner. The
      intrarenal arterial infusion of rolipram (0.3 microg kg(-1) min(-1)), a cyclic
      AMP-specific phosphodiesterase inhibitor, also caused the same renal responses as
      NKH477. The increasing effects of NKH477 on renal blood flow, fractional Na+
      excretion and renal venous plasma cyclic AMP concentration were facilitated in
      the presence of rolipram. NKH477 reduced glomerular filtration rate and
      filtration fraction in the presence of rolipram. The increasing effects of NKH477
      on urine flow rate and urinary Na+ excretion were not affected by rolipram. The
      present results suggest that NKH477 increases glomerular filtration and
      suppresses tubular sodium reabsorption through activation of cyclic AMP
      production, and thereby induces natriuresis. The results also demonstrate that
      renal cyclic AMP level during the activation of adenylate cyclase is regulated by
      phosphodiesterase IV in both the vascular and tubular sites.

PMID- 10395021
TI  - Methotrexate produces delayed emesis in dogs: a potential model of delayed emesis
      induced by chemotherapy.
AB  - We investigated the emetic effects of cisplatin and methotrexate in dogs, the
      effects of ondansetron on cisplatin-induced vomiting, and the effects of
      ondansetron, dexamethasone and a combination of the two on the vomiting induced
      by methotrexate. Ondansetron was administered 30 min before cisplatin
      administration. Ondansetron, dexamethasone or a combination of the two was
      administered 8, 24 and 48 h after methotrexate administration. Cisplatin (3
      mg/kg, i.v.) induced acute vomiting but failed to induce delayed vomiting. The
      acute vomiting was markedly inhibited by ondansetron (3 mg/kg, p.o.; 1 mg/kg,
      i.v.). Methotrexate (2.5 mg/kg, i.v.) caused delayed vomiting, which was partly
      inhibited by ondansetron (1 mg/kg, i.v.) or dexamethasone (2.5 mg/kg, i.v.). The
      combination of the two agents was more effective. These results suggest that
      methotrexate-induced emesis in dogs would be useful for studying delayed emesis.

PMID- 10395022
TI  - Muscarinic cholinoceptor subtypes mediating tracheal smooth muscle contraction
      and inositol phosphate generation in guinea pig and rat.
AB  - The effects of the muscarinic cholinoceptor antagonists atropine (non-selective),
      pirenzepine (M1-selective), methoctramine (M2-selective) and 4-diphenylacetoxy-N
      methylpiperidine methiodide (4-DAMP; M3-selective) were examined on the
      responsiveness of guinea pig and rat tracheal tissue to acetylcholine and
      carbachol. Results indicate that smooth muscle contraction in isolated tracheal
      tissue from both species was mediated primarily by muscarinic M3 cholinoceptors.
      The effects of atropine, pirenzepine and 4-DAMP were similar against the
      contractile actions of acetylcholine and carbachol in both species and in
      epithelium-intact and epithelium-denuded tissue. In contrast, differences in the
      effects of methoctramine in antagonising contractile responses to acetylcholine
      and carbachol were observed between the two species and following epithelium
      removal in the guinea pig. Thus, whilst this study has found that tracheal smooth
      muscle contraction in the guinea pig and rat is mediated primarily by muscarinic
      M3 cholinoceptors, anomalies in the functional inositol phosphate generation
      results obtained with the muscarinic cholinoceptor antagonists highlight species
      differences in the actions of acetylcholine and carbachol in eliciting smooth
      muscle contraction suggesting the possible existence of functional non-M3
      muscarinic cholinoceptors.

PMID- 10395023
TI  - Vascular mitogen-activated protein kinase activity is enhanced via angiotensin
      system in spontaneously hypertensive rats.
AB  - The vascular structural remodeling function may be altered in genetically
      hypertensive animals, spontaneously hypertensive rats (SHR). To examine this
      possibility, we measured the activity of mitogen-activated protein (MAP) kinases,
      enzymes believed to be involved in the pathway for cell proliferation, in rat
      aorta strips, and examined whether the endothelium removal-induced MAP kinase
      activation function is altered in SHR and whether vascular angiotensin and
      endothelin systems are responsible for the alteration of MAP kinase activation in
      SHR. Male 4-week-old SHR and age-matched Wistar Kyoto rats (WKY) supplied by
      Charles River Japan were used. Endothelium-denuded aorta strips were incubated at
      37 degrees C in medium. MAP kinase activity after incubation was time-dependently
      increased in strips from SHR and WKY. MAP kinase activation was greater in SHR
      than in WKY aorta strips. Similarly, MAP kinase activation was enhanced in aorta
      strips from 4-week-old SHR and stroke prone SHR supplied by the Diseases Model
      Cooperative Research Association (Kyoto, Japan). In aorta strips from SHR and
      WKY, the angiotensin receptor antagonist, losartan, and the endothelin receptor
      antagonist, cyclo (D-alpha-aspartyl-L-prolyl-D-valyl-L-leucyl-D
      tryptophyl)(BQ123), caused concentration-dependent inhibition of MAP kinase
      activation. The losartan-induced but not BQ123-induced inhibition of MAP kinase
      activation was greater in SHR than in WKY aorta strips. Angiotensin II caused a
      concentration-dependent increase in MAP kinase activity and the angiotensin II
      induced MAP kinase activation was greater in SHR than in WKY aorta strips. These
      results indicate that endothelium removal-induced MAP kinase activation is
      enhanced in aorta strips from young SHR, suggesting that vascular structural
      remodeling function may be enhanced in SHR. It appears that the enhancement of
      MAP kinase activation results, at least in part, from enhanced function of
      vascular angiotensin system in SHR.

PMID- 10395024
TI  - Effect of cyclosporin A or tacrolimus on the function of blood-brain barrier
      cells.
AB  - Recently, it has been reported that continuous treatment with cyclosporin A or
      tacrolimus induces encephalopathy in transplant patients. The mechanism of
      immunosuppressant-induced encephalopathy is unclear. We investigated the
      cytotoxicity to brain capillary endothelial cells and the effect of these two
      drugs on P-glycoprotein function using mouse brain capillary endothelial (MBEC4)
      cells. The transcellular transport of [3H]sucrose was significantly increased and
      the cellular viability, based on 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl
      tetrazolium bromide (MTT) assay and trypan blue exclusion test, was decreased by
      cyclosporin A (approximately 50% at 5 microM; P<0.005), while tacrolimus showed a
      much smaller effect. These findings indicate that the toxicity of cyclosporin A
      was greater than that of tacrolimus. The uptake of [3H]vincristine, a substrate
      of P-glycoprotein, was increased by these two drugs. The expression of P
      glycoprotein in MBEC4 cells was reduced, but there was no effect on mdr1b mRNA
      levels. The decrease in the expression of P-glycoprotein may be due to the
      inhibition of the turnover of P-glycoprotein, which involves translation. In
      conclusion, the direct cytotoxic effect on the brain capillary endothelial cells
      and the inhibition of P-glycoprotein may be partly involved in the occurrence of
      immunosuppressant-induced encephalopathy.

PMID- 10395025
TI  - Role of sodium ion influx in depolarization-induced neuronal cell death by high
      KCI or veratridine.
AB  - Intracellular Na+ concentration plays an important role in the regulation of
      cellular energy metabolism; i.e., increased intracellular Na+ concentration
      stimulates glucose utilization both in cultured neurons and astrocytes. Both high
      KCI and veratridine, which have been known to cause neuronal damage, elicit
      increased glucose utilization, presumably via increased intracellular Na+
      concentration. In the present study, we examined the role of intracellular Na+
      influx in the mechanisms of neuronal cell damage induced by high KCl or
      veratridine assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
      bromide (MTT) colorimetric method. Rat primary cultures of striatal neurons were
      incubated with high KCl (final concentrations: 25, 50 mM) or veratridine (0.1-100
      microM) with or without various inhibitors. High KCl depolarizes cell membrane,
      thus, leading to Na+ influx through an activation of voltage-sensitive Na+
      channels, while veratridine elicits Na+ influx by directly opening these
      channels. After 24-h incubation with elevated [K+]o or veratridine, glucose
      contents in the medium decreased significantly (approximately by 7 mM), but
      remained higher than 18 mM. High [K+]o reduced percent cell viability
      significantly (approximately 50% at 25 mM, approximately 40% at 50 mM [K+]o,
      P<0.01), but tetrodotoxin (100 nM) had no protective effect, indicating that Na+
      influx was not essential to high K+ -induced cell death. DL-2-Amino-5
      phosponovaleric acid (APV) (1 mM) completely blocked cell death induced by
      elevated [K+]o, while 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 microM) did
      not. In contrast, veratridine (>10 microM) caused cell damage in a dose-dependent
      and tetrodotoxin-sensitive manner, but none of APV, CNQX, or bepridil (Na+ -Ca2+
      exchanger blocker) had any protective effect. Nifedipine (50 approximately 100
      microM), however, reduced percent cell damage induced by veratridine.

PMID- 10395026
TI  - No requirement of P2X1 purinoceptors for platelet aggregation.
AB  - ADP produces a series of responses in rabbit platelets such as shape changes,
      aggregation and intracellular Ca2+ mobilization. In human platelets, the P2X1
      receptor mediates a rapid increase in intracellular Ca2+ concentration ([Ca2+]i)
      upon stimulation with ADP. We investigated whether this phenomenon is also
      present in rabbit platelets. We found that the P2X1 receptor-mediated response
      was absent because there was (1) no elevation of [Ca2+]i in response to
      alpha,beta-methylene-ATP, a selective P2X1 receptor agonist, in fura-2-loaded
      platelets; (2) no change in the ADP-induced [Ca2+]i increase and platelet
      aggregation after P2X1 receptor desensitization with alpha,beta-methylene-ATP;
      (3) complete inhibition of the ADP-induced [Ca2+]i elevation by the P2Y1 receptor
      specific antagonist, A3'P5'PS, with a similar ID50 value both in the presence and
      absence of external Ca2+. These results indicate that ADP-induced [Ca2+]i
      elevation is mainly mediated by P2Y1 receptors in rabbit platelets. We conclude
      that the P2X1 receptor does not play a significant role in the ADP-induced
      platelet shape changes and aggregation.

PMID- 10395027
TI  - Enhancement of low density lipoprotein catabolism by non-steroidal anti
      inflammatory drugs in cultured HepG2 cells.
AB  - Several clinical studies have shown that different types of non-steroidal anti
      inflammatory drugs (NSAIDs) can reduce the cholesterol content of atherosclerotic
      blood vessels. The mechanism of this reduction is not established. One
      possibility is that NSAIDs affect low density lipoprotein (LDL) catabolism. In
      this study, we investigated the effect of the NSAIDs, indomethacin, flufenamic
      acid, ibuprofen, acetaminophen, and also acetylsalicylic acid on LDL binding,
      cell-association and degradation in cultured hepatoma HepG2 cells. LDL was
      labelled with 125I to study LDL catabolism. Furthermore, dextran sulphate, a
      substance that is known to release bound LDL from its receptors, was used to
      study LDL receptor activity. Reverse transcription-polymerase chain reaction was
      used to study the messenger RNA (mRNA) of LDL receptor. Our results show that
      flufenamic acid, indomethacin, and to a lesser extent ibuprofen, and
      acetaminophen increase LDL binding, cell-association, and degradation. Flufenamic
      acid was most potent and increased LDL catabolism by 50-70%, whereas
      acetylsalicylic acid had only a modest effect. Also, flufenamic acid and
      indomethacin were both found to increase the synthesis of mRNA of the LDL
      receptor with a subsequent increase of LDL receptor protein. We also investigated
      the effect of indomethacin on LDL binding in the presence of the 3-hydroxy-3
      methylglutaryl CoA (HMG CoA) reductase inhibitor, fluvastatin. We found that both
      indomethacin and fluvastatin had an additive up-regulatory effect on LDL receptor
      activity. In addition the effect of flufenamic acid on cell-associated LDL was
      examined in the presence of cyclosporine, which is known to decrease LDL
      catabolism. The results show that flufenamic acid can restore the inhibitory
      effect of cyclosporine. The study thus shows that NSAIDs enhance LDL catabolism
      due to increased synthesis of the mRNA for LDL receptor protein. This action
      might contribute to the lipid-lowering effect of NSAIDs.

PMID- 10395028
TI  - Morphine prevents peroxynitrite-induced death of human neuroblastoma SH-SY5Y
      cells through a direct scavenging action.
AB  - N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine (NOC12), a nitric
      oxide donor, 3-morpholinosydnonimine (SIN-1), a generator of peroxynitrite (ONOO
      ), and peroxynitrite induced cell death accompanied by DNA fragmentation in human
      neuroblastoma SH-SY5Y cell cultures. Morphine prevented the cell death induced by
      SIN-1 or peroxynitrite, but not that induced by NOC12. The protective effect of
      morphine was concentration-dependent (10-100 microM), but was not antagonized by
      naloxone. The selective ligands for opioid receptor subtypes, [D-Ala2, N-Me-Phe4,
      Gly-ol5]enkephalin (DAMGO, micro-opioid receptor agonist), [D-Pen2,5]enkephalin
      (DPDPE, delta-opioid receptor agonist) and trans-(+/-)-3,4-dichloro-N-methyl-N-(2
      [1-pyrrolidinyl]-cyclohexyl)benze neacetamide (U-50488, kappa-opioid receptor
      agonist) even at the concentration of 100 microM did not prevent the cell death
      induced by SIN-1. From measurement of the absorbance spectrum of peroxynitrite,
      the decomposition of peroxynitrite in 0.25 M potassium phosphate buffer (pH 7.4)
      was very rapid and complete within seconds. However, the absorbance was very
      stable in the presence of morphine. In addition, morphine inhibited peroxynitrite
      induced nitration of tyrosine in a concentration-dependent manner. These results
      indicate that morphine rapidly reacts with peroxynitrite. The present study
      showed that morphine prevented peroxynitrite-induced cell death through its
      direct scavenging action, suggesting that morphine can protect cells against
      damage caused by peroxynitrite.

PMID- 10395029
TI  - Kainic acid into the parapyramidal region protects against gastric injury by
      ethanol.
AB  - Neurons in the parapyramidal region of the ventral medulla project to the dorsal
      vagal complex and intermediolateral column. Kainic acid (0.5-5.0 ng)
      microinjected unilaterally into the parapyramidal region reduced 45% ethanol
      induced gastric lesions by 50-60% in urethane anesthetized rats. Microinjections
      at sites nearby, but outside of the parapyramidal region, had no effect. These
      results provide the first evidence that the activation of parapyramidal region
      neurons influences gastric function and suggests a possible role of this ventral
      medulla region in gastric regulation.

PMID- 10395030
TI  - Reversal by [D-Ala2,D-Leu5]enkephalin of the dopamine transporter loss caused by
      methamphetamine.
AB  - A single administration of 40 mg/kg (i.p.) of methamphetamine caused a loss of
      dopamine transporter in the striatum of albino Swiss (CD-1) mouse for at least 3
      weeks. The administration of a single dose of [D-Ala2,D-Leu5]enkephalin (DADLE)
      (18 mg/kg, i.p.), given at day 14 after the administration of methamphetamine,
      caused a significant, transient restoration of dopamine transporter level in the
      striatum. These results suggest that delta-opioid peptide DADLE is able to
      reverse the neuronal damage caused by methamphetamine.

PMID- 10395031
TI  - NGD 94-1 as an agonist at human recombinant dopamine D4.4 receptors expressed in
      HEK293 cells.
AB  - The atypical antipsychotic, clozapine has some selectivity for dopamine D4
      receptors and is a silent antagonist at these receptors. NGD 94-1 (2-phenyl-4(5)
      [4-(2-pyrimidinyl)-piperazin-1-yl-methyl]-imidazole ) is a highly selective
      dopamine D4 receptor ligand recently introduced as a putative antipsychotic
      mimicking the dopamine D4 receptor antagonist effects of clozapine. We show that
      NGD 94-1 is not silent. It behaved as an agonist in human embryonic kidney 293
      cells expressing human recombinant dopamine D4.4 receptors. This questions the
      clinical use of NGD 94-1.

PMID- 10395032
TI  - Distinct mechanisms for the endocytosis of muscarinic receptors and Gq/11.
AB  - To determine whether the agonist-mediated endocytosis of muscarinic receptors and
      Gq/11 are mechanistically related events, the internalization of Gq/11 was
      monitored under conditions established to prevent muscarinic receptor
      endocytosis. Incubation of SH-SY5Y neuroblastoma cells with oxotremorine-M
      resulted in the translocation of both muscarinic receptors and Gq/11 into a
      'light vesicle' membrane fraction. Although muscarinic receptor translocation was
      prevented by either the depletion of phosphoinositides or by disruption of
      clathrin assembly, the endocytosis of Gq/11 was unaffected. These results
      demonstrate that the agonist-induced internalization of muscarinic receptors and
      Gq/11 proceed via distinct mechanisms.

PMID- 10395033
TI  - Reproducibility of liver biopsy grading and staging.

PMID- 10395034
TI  - Hepatitis E virus -- an update.
AB  - Hepatitis E virus (HEV) is the principal cause of enterically-transmitted, non-A,
      non-B hepatitis and has been associated with excess mortality in pregnant women
      infected during epidemics. Molecular cloning of the viral genome led to the
      development of diagnostic tests, including enzyme immunoassays for antibody and
      RT-PCR for viral RNA. Candidate vaccines have not yet reached clinical trials.
      The virus resembles caliciviruses, with a positive sense RNA genome encoding
      three open reading frames. The geographical distribution of the virus, which may
      infect domestic animals as well as humans, may be wider than thought originally.

PMID- 10395035
TI  - Genetic alterations in the S gene of hepatitis B virus in patients with acute
      hepatitis B, chronic hepatitis B and hepatitis B liver cirrhosis before and after
      liver transplantation.
AB  - BACKGROUND: Several studies have shown that hepatitis B immunoglobulin (HBIG)
      imposes a selection pressure on the hepatitis B virus (HBV) S gene, and that the
      emergence of mutations in this region would make reinfection after orthotopic
      liver transplantation (OLT) possible. AIMS: This study was undertaken to analyze
      the presence of HBV S-gene mutations in the different stages of HBV infection and
      the relationship between HBIG therapy and the emergence of mutations in liver
      transplant recipients. METHODS: The frequency and location of mutations in the
      coding region of the HBV S gene were studied by PCR and direct sequencing in 30
      patients (7 with acute self-limited hepatitis B, 16 with chronic hepatitis B and
      7 recipients of (OLT) for HBV-related end stage liver disease who became
      reinfected). RESULTS: The average number of amino acid changes was higher in
      patients with a more advanced stage of disease, 0.57 mutations/100 positions in
      acute hepatitis B and 1.57 in chronic hepatitis B (1.28 in HBeAg-positive and 1.8
      in anti-HBe-positive patients). The average number of substitutions in the
      transplanted patients was 2.7 before OLT and 3 after OLT. No amino acid
      substitutions were detected in the "a" determinant of HBsAg in acute hepatitis B,
      however, 8 substitutions were observed in 6 chronic patients. In 3 OLT patients,
      4 substitutions were observed in samples before and after OLT. One of these
      patients, who had protective levels of anti-HBs, showed 3 additional new amino
      acid substitutions after OLT, suggesting escape mutant selection by the effect of
      HBIG therapy. No changes were observed between the consensus sequences obtained
      several years before and after transplantation, indicating consensus sequence
      stability. CONCLUSION: These results show that there is an accumulation of HBV S
      gene mutations in HBV-related end-stage liver disease. Prophylaxis with HBIG
      mainly obtained from acute self-limited hepatitis patients who have a highly
      homogeneous viral population, may be one factor underlying the reinfection after
      liver transplantation.

PMID- 10395036
TI  - Interobserver study of liver histopathology using the Ishak score in patients
      with chronic hepatitis C virus infection.
AB  - AIMS/BACKGROUND: Assessing the histopathological degree of liver damage is
      essential to the routine care of patients with chronic hepatitis C virus (HCV)
      infection. Several scoring systems have been proposed in attempts to standardize
      the histological assessment. One scoring system has been proposed by Ishak et al.
      Although widely endorsed, its interobserver reliability has not been evaluated.
      METHODS: 95 liver biopsies from patients with chronic HCV infection were scored
      by three independent observers. Interface hepatitis, confluent necrosis, focal
      necrosis, portal inflammation, and fibrosis were assessed. RESULTS: Confluent
      necrosis, which is more common in acute hepatitis, was not seen in any biopsy.
      For each of the remaining variables of inflammation (periportal hepatitis, focal
      necrosis, and portal inflammation) we found agreement in 95-96% for all three
      observers. Kappa scores ranged from 0.11 to 0.41 and weighted kappa scores from
      0.18 to 0.53. For staging we noted 84% agreement, kappa scores of 0.26-0.47, and
      weighted kappa scores of 0.57-0.69. CONCLUSION: The Ishak system is associated
      with good interobserver reliability if a deviance of one categorical level in
      each variable of the system is accepted as agreement. Compared to the Knodell
      system it provides more detailed information but is less reliable regarding
      fibrosis.

PMID- 10395037
TI  - Estrogen-progestogen therapy for low bone mineral density in primary biliary
      cirrhosis.
AB  - AIMS/BACKGROUND: Patients with primary biliary cirrhosis (PBC) often have
      osteoporosis of the high-turnover type, suggesting that estrogen could have a
      beneficial effect. However, the cholestatic potential of estrogen could imply a
      risk of increased cholestasis in a disease characterized by cholestasis. The aim
      of the present study was to test whether hormone replacement therapy (HRT) could
      be used to increase bone mineral density (BMD) in PBC patients with osteoporosis,
      without causing deterioration of the liver function. METHODS: Nine female PBC
      patients with osteoporosis and one with osteopenia were offered HRT for two
      years. The change in BMD was compared to the change in ten age-matched female PBC
      patients who had less severe or no osteopenia and who did not receive HRT. Liver
      function tests were checked at six-month intervals. RESULTS: HRT patients showed
      a statistically significant increase in lumbar spine BMD and total body BMD
      whereas control patients showed a significant decrease in lumbar and total body
      BMD. In contrast to the controls, HRT patients also showed a decrease in truncal
      fat (-3.8%). Neither of the groups showed any statistically significant changes
      in the liver function tests. CONCLUSIONS: HRT is safe and effective in female PBC
      patients with osteoporosis.

PMID- 10395038
TI  - Down-regulation of vascular alpha1-adrenoceptors does not account for the loss of
      vascular responsiveness to catecholamines in experimental cholestasis.
AB  - AIMS/BACKGROUND: Vascular hyporesponsiveness to sympathomimetic stimulation
      occurs in jaundice. Recently, we reported that this vascular adrenergic
      hyporesponsiveness was associated with the loss of reactivity of vascular alpha1
      adrenoceptors. This study examines the possibility that the vascular adrenergic
      hyporesponsiveness is due to down-regulation of vascular alpha1-adrenoceptors.
      METHODS: This question was addressed by measuring the changes in the plasma
      norepinephrine (NE) and epinephrine (E) concentrations, determined by high
      performance liquid chromatography, and the affinity and number of alpha1
      adrenoceptors determined by a competitive antagonist radioligand binding assay in
      vascular smooth muscle membranes prepared from 3-day bile duct ligated (BDL)
      rats. The results were compared to data obtained from 3-day bile duct manipulated
      (sham-operated; SO) and control (C) rats. RESULTS: Compared to C and SO rats, the
      plasma concentrations of NE and E in the BDL rats were significantly elevated
      reflecting increased sympathetic nervous system activity. BDL did not change
      either the affinity or the number of vascular alpha1-adrenoceptors. CONCLUSIONS:
      Since the affinity and number of vascular alpha1-adrenoceptors were unchanged in
      the face of elevated plasma concentrations of catecholamines in the BDL rats, we
      have concluded that down-regulation of vascular alpha1-adrenoceptors does not
      account for the vascular adrenergic hyporesponsiveness in experimental
      cholestasis.

PMID- 10395040
TI  - Inhibition of concanavalin A-induced acute T cell dependent hepatic damage in
      mice by hypothyroidism.
AB  - AIMS/BACKGROUND: Concanavalin A (Con A) activates T lymphocytes and causes acute
      T-cell-mediated hepatic injury in mice. Decreased thyroid hormonal production is
      associated with a variety of immunological manifestations, including inactivation
      of macrophages with reduced TNF production and reduced soluble IL-2 receptors in
      the serum. We have recently shown that hypothyroidism prevents the development of
      cirrhosis and also minimizes hepatic damage in rats with fulminant hepatic
      failure. In the present study we examined the effects of hypothyroidism on a
      mouse model of Con A induced T cell-mediated acute hepatitis. METHODS:
      Hypothyroidism was induced both medically (MMI, PTU) and surgically. Eight groups
      of 10 mice each were studied: euthyroid controls (2 groups: water, Con A) and
      hypothyroid (6 groups: MMI, PTU, Surgical, MMI-Con A, PTU-Con A, Surgical-Con A).
      RESULTS: Hepatic inflammation was significantly decreased in each of the Con A
      treated hypothyroid groups of mice. The serum transaminases, TNF-alpha and IL-6
      levels were significantly elevated in the Con A treated group while near normal
      levels were found in the hypothyroid Con A treated groups (mean+/-SE AST: 1499+/
      18 vs 78+/-10 IU/l, p<0.001; TNF: 2500+/-250 vs 135+/-15 pg/ml, p<0.001, IL-6:
      12,200+/-300 vs 1260+/-140 pg/ml, p<0.001, respectively). CONCLUSIONS:
      Hypothyroidism, independent of the mode of induction, can effectively inhibit the
      development of acute T cell-mediated liver damage in mice. These results suggest
      that some decrease in thyroid function might have a role in the prevention of
      immune mediated liver diseases.

PMID- 10395039
TI  - Cytoplasmic expression of hepatitis B core antigen in chronic hepatitis B virus
      infection: role of precore stop mutants.
AB  - AIMS/BACKGROUND: The cytoplasmic expression of HBcAg is a possible target of
      immune hepatocytolysis and it is important for the pathogenesis of hepatic injury
      in chronic hepatitis B virus (HBV) infection. Cytoplasmic HBcAg expression has
      been suggested to be related to the precore sequence of HBV, HBV DNA level or
      cell cycle of hepatocytes and the aim of this study was to understand its
      mechanism. MATERIAL/METHODS: We studied the expression pattern of HBcAg and its
      relationship to serum HBV DNA levels, cell proliferation activity of hepatocytes
      and precore mutation using 66 patients' sera and biopsied liver specimens of
      chronic hepatitis B. RESULTS: The expression patterns of HBcAg were cytoplasmic
      predominant (CP) in 17 cases, nuclear and cytoplasmic (NC) in 10 cases and
      nuclear predominant (NP) in 9 cases and negative in 30 cases. CP expression cases
      showed a higher grade of hepatitis activity than NP expression cases. Serum HBV
      DNA levels showed a wide range and there was no significant difference according
      to the expression pattern of HBcAg. Cell proliferation activity of hepatocytes,
      measured by Ki-67 (MIB-1) labelling index was higher in CP expression cases than
      in NP expression cases and it was also significantly higher in cases of high
      grade than in low grade hepatitis activity. The precore region was evaluated by
      primer extension assay in 51 cases and there were 16 cases of 1896 precore
      mutant, 23 cases of wild type, 12 cases of mixed infection of 1896 precore mutant
      type and wild type. CP expression of HBcAg was significantly more frequent in
      1896 precore mutant cases (86%) than in wild type cases (26%). CONCLUSION: CP
      expression of HBcAg is the major pattern of 1896 precore mutant cases and it
      might be involved in the severe liver injury of precore mutants. One of the
      mechanisms regulating CP HBcAg expression is suggested to be precore mutation of
      HBV as well as cell cycle of hepatocyte.

PMID- 10395041
TI  - Hepatic stellate cell activation and liver fibrosis are associated with
      necroinflammatory injury and Th1-like response in chronic hepatitis C.
AB  - BACKGROUND/AIMS: The involvement of a direct viral cytopathic effect or an immune
      mediated mechanism in the progression of hepatic damage in chronic hepatitis C is
      controversial. The type of immune response is itself a matter of controversy, and
      histological data are lacking. The aim of this study was to identify the factors
      associated with the progression of liver injury in 30 HCV/RNA-positive untreated
      patients with chronic hepatitis. METHODS: Necroinflammatory and architectural
      damage were evaluated using Ishak's score. Activated hepatic stellate cells (HSC)
      were visualized by immunohistochemistry for alpha-smooth muscle actin (alphaSMA)
      and quantitated by morphometry. Plasma HCV/RNA was evaluated using a competitive
      RT-PCR method. To study the type of immune response involved in the progression
      of liver injury, interferon gamma (IFNgamma)-positive cells (as expression of a
      Th1-like response) were evaluated by immunohistochemistry and quantitated by
      morphometry. RESULTS: HSC were mostly detected close to areas of lobular
      necroinflammation or lining fibrotic septa. The alphaSMA- and Sirius Red-positive
      parenchyma correlated significantly with necroinflammatory and architectural
      scores. IFNgamma-positive cells were detected in periportal areas associated with
      the inflammatory infiltrates and significantly correlated with architectural
      damage. No relationship was found between the histological features of liver
      injury and viral load. CONCLUSIONS: HSC activation and progression of liver
      injury are unrelated to viral load but associated with a Th1-like response, a
      plausible target for the treatment of chronic hepatitis C.

PMID- 10395042
TI  - Is major liver surgery associated with an increased systemic inflammatory
      response? A prospective comparison of hemihepatectomy and other major abdominal
      surgery.
AB  - AIMS/BACKGROUND: Extensive liver resection is associated with a higher morbidity
      and mortality than other major abdominal surgery. Because the liver is
      responsible for the clearance of pathogenic particles as well as the clearance
      and degradation of several inflammatory mediators, the high rate of complications
      after liver surgery may be due to an enhanced or prolonged inflammatory response.
      The objective of this prospective study was to investigate whether major liver
      resection is associated with an enhanced systemic inflammatory response. METHODS:
      The course of various inflammatory parameters was studied in 12 patients
      undergoing a hemihepatectomy and the results were compared with those of 12
      patients undergoing other major abdominal surgery. RESULTS: After
      hemihepatectomy, the plasma levels of IL-6, IL-8, sPLA2 and elastase were similar
      to the levels after other major abdominal surgery, though the hepatectomized
      patients showed higher levels of lactoferrin, possibly due to impaired hepatic
      clearance. In addition, the hemihepatectomized patients showed signs of impaired
      liver function, as was indicated by increased plasma bilirubin and ASAT levels,
      whereas the other patients did not. CONCLUSIONS: The inflammatory response
      associated with major liver resection is not significantly different from that
      after other major abdominal surgery, and therefore does not explain the increased
      complication rate that is seen after major liver resection. We infer that the
      most important factor in the development of complications after liver resection
      may be the hepatic failure itself.

PMID- 10395043
TI  - Primary sclerosing cholangitis (PSC): clinical, laboratory and survival analysis
      in children and adults.
AB  - BACKGROUND: Primary sclerosing cholangitis (PSC) is an uncommon disorder, rarely
      diagnosed in children, moreover, data on its natural history and survival are
      still lacking. AIM: The study was undertaken to compare clinical, laboratory and
      survival rates in two series of PSC: one in a pediatric group (group A) and the
      other in an adult population (group B). METHODS: Group A included 9 patients (5
      males, 4 females, mean age 10 yrs, range 7-15); group B included 28 patients (19
      males, 9 females, mean age 32 years, range 19-60). The mean follow-up was 5.2
      years in group A and 6.9 years in group B (range 1-14 years). ERCP and
      colonoscopy were performed in each case. Survival was analyzed using the Kaplan
      Meier method. RESULTS: At presentation children showed significantly higher
      levels of IgG and AST compared to adults (p<0.05); moreover, interface hepatitis
      occurred in 50% of children and in 14.2% in adults (p=ns). During follow-up the
      following major events occurred: oesophageal bleeding (n=2) in group A;
      progressive liver failure (n=6), cholangiocarcinoma (n=3), colonic cancer (n=1)
      in group B. Liver transplantation (OLTx) was performed in 4 adults (one died
      after a retransplantation). No deaths were observed in children. The Kaplan-Meier
      curve in adults shows a 65% rate of survival at 10 years. CONCLUSIONS: The
      present findings on PSC suggest a more severe activity of the disease in children
      than in adults at presentation; nonetheless, the prognosis seems to be better in
      children than in adults. The Mayo score prognostic index does not predict the
      development of liver/colonic cancer. A poor outcome (defined as death or being
      listed for OLTx) only occurred in adults.

PMID- 10395044
TI  - 3,4-Methylenedioxymethamphetamine (ecstasy)-induced hepatotoxicity: effect on
      cytosolic calcium signals in isolated hepatocytes.
AB  - AIMS/BACKGROUND: Hepatocellular damage has been reported as a consequence of 3,4
      methylenedioxymethamphetamine (MDMA) intake. However, little is known about the
      cellular mechanisms involved. The present study was undertaken to evaluate the
      effects of MDMA on cell viability as well as free calcium levels ([Ca2+]i) in
      short-term cultured hepatocytes. Reduced glutathione (GSH), adenosine-5'
      triphosphate (ATP) and lipid peroxidation were investigated to evaluate the toxic
      effect of MDMA, in vitro, using freshly isolated rat hepatocytes. METHODS: In
      order to measure cytosolic free Ca2+ concentrations ([Ca2+]i), rat hepatocytes
      were loaded with the Ca2+ indicator fura-2-acetoxymethylester (fura-2-AM).
      RESULTS: A sustained rise of ([Ca2+]i) after incubation with MDMA was the most
      noteworthy finding. In Ca2+-free medium, MDMA caused a reduced increase of
      ([Ca2+]i). On the other hand, MDMA (0.1-5 mM) induced a concentration-dependent
      and time exposure-dependent GSH and ATP depletion. Although it did not reach
      statistical significance, GSH deficits were accompanied by a tendency to increase
      lipid peroxidation 3 h after MDMA incubation. CONCLUSIONS: The above data suggest
      that the marked rise of ([Ca2+]i) and subsequent ATP and GSH depletion can lead
      to a rapid decrease in cell viability.

PMID- 10395045
TI  - High, persistent hepatocellular proliferation and apoptosis precede
      hepatocarcinogenesis in growth hormone transgenic mice.
AB  - AIMS/BACKGROUND: Growth hormone (GH) transgenic mice are known to develop
      hepatocellular adenomas and carcinomas. In order to understand more about
      hepatocarcinogenesis in the GH-transgenic mouse model we quantitated the rates of
      hepatocellular proliferation and apoptosis in these mice. METHODS: Two lines of
      GH-transgenic mice and non-transgenic control mice were generated and sacrificed
      at regular intervals between one and nine months. Hepatocellular replication was
      measured by in vivo incorporation of bromodeoxyuridine (BrdU) and counting BrdU
      positive nuclei in histological liver sections. Serial sections taken from these
      mouse livers were also assessed for rates of hepatocellular apoptosis using the
      in situ end-labelling of fragmented DNA (TUNEL) method. RESULTS: High levels of
      hepatocellular replication were sustained life-long in this model. Increased
      rates of hepatocellular proliferation preceded the onset of hepatic inflammation,
      a prominent feature in the liver pathology of GH-transgenic mice. In tumour
      tissue, cellular proliferation was up to 17-fold greater than in surrounding non
      tumour tissue. Apoptosis rates were also elevated in non-tumour regions of GH
      transgenic mouse livers compared to controls. Interestingly, large dysplastic
      hepatocytes were common in the fraction of cells undergoing apoptosis, especially
      in older mice with inflamed livers. The increase in the rate of hepatocellular
      apoptosis in GH-transgenic animals largely balanced the augmented levels of
      proliferation seen in these mice. In tumour tissue, however, the profound
      increase in the number of proliferating tumour cells outstripped the increase in
      apoptosis. CONCLUSION: Relatively high and enduring levels of hepatocellular
      replication and apoptosis precede hepatocarcinogenesis in GH-transgenic mice.
      Increased cellular proliferation and resistance to apoptosis were evident in
      tumour growth in older animals.

PMID- 10395046
TI  - Macrophages are essential for lymphocyte infiltration in formyl peptide-induced
      cholangitis in rat liver.
AB  - BACKGROUND/AIMS: Cholangitis in rats induced by N-formyl L-methionine L-leucine L
      tyrosine (fMLT) is characterized by infiltration of mononuclear cells around bile
      ducts in portal tracts. METHODS: We investigated the initial process in fMLT
      induced cholangitis histochemically. RESULTS: Administration of fMLT into the
      colons of adult male Wistar rats with acetate-induced colitis resulted in an
      infiltration of mostly macrophages and granulocytes into the portal tracts on day
      1. Abnormal peroxidation as demonstrated by the nitro blue tetrazolium (NBT)
      reaction occurred in bile duct cells as well, although no apparent necrosis of
      the bile duct cells was observed. On day 4, the majority of the inflammatory
      cells in the portal tracts were CD4+ or CD8+ T lymphocytes. The oxidative
      products of the NBT reaction also disappeared from the bile duct cells.
      Administration of carrageenan, a potent inhibitor of macrophage function,
      resulted in a significant decrease in lymphocyte infiltration into the portal
      tracts. On day 8, portal inflammation subsided. CONCLUSIONS: In formyl peptide
      induced cholangitis, macrophages and granulocytes may injure bile ducts
      transiently. Further, macrophages are necessary for the subsequent migration of T
      lymphocytes around the bile ducts.

PMID- 10395047
TI  - Macrovesicular steatosis induced by interferon alfa therapy for chronic
      myelogenous leukaemia.

PMID- 10395048
TI  - Why is the death rate from lung cancer falling in the Russian Federation?
AB  - Age standardised death rates (European standard population) from lung cancer in
      the Russian Federation, have been rising since at least 1965, levelled out in the
      late 1980s and have subsequently decreased. The reasons for this decline are not
      apparent. This study seeks to identify the reasons for the decline in mortality
      from lung cancer in the Russian Federation in the 1990s. Changes in age-specific
      mortality from lung cancer in the Russian Federation between 1990 are described
      and age-cohort analysis, based on age-specific death rates for lung cancer is
      undertaken for the period 1965 to 1995. As other work has shown that any recent
      deterioration in coding of cause of death has been confined largely to the
      elderly, this suggests that the trend is not a coding artefact. Age-period-cohort
      analysis demonstrates the existence of a marked birth cohort effect, with two
      major peaks corresponding to those born around 1926 and 1938. These groups would
      have reached their early teens during the second world war and the period
      immediately after the death of Stalin, respectively. The present downward trend
      in death rates from lung cancer in the Russian Federation is partly due to a
      cohort effect and it is expected that this will soon reverse, with a second peak
      occurring in about 2003.

PMID- 10395049
TI  - Knowledge of HIV serostatus and preventive behaviour among European injecting
      drug users: second study. European Community Study Group on HIV in Injecting Drug
      Users.
AB  - The objective of the study was to analyse the effect of knowledge of HIV
      serostatus on behaviours preventing the acquisition or transmission of HIV among
      European IDU, and to compare results with a previous similar study conducted 3
      years before. Data were gathered in 1992-1993 during a retrospective multicentre
      cross-sectional study of IDU recruited in 11 European countries, in specialized
      centers and on the street. We compared, between groups with different HIV
      serological status (IDU who knew well before their HIV-positive serological
      status, IDU who knew their HIV-negative serostatus and IDU who did not know
      before their serological status), the respective proportions of IDU who reported
      that, during the six months prior to interview, (1) always used condoms, (2)
      never gave their used injecting equipment to other IDU, (3) always injected drugs
      safely. We only included IDU who had known their serological status for at least
      six months prior to interview. Results were compared to the similar survey
      conducted in 1990. From 2171 IDU recruited, data of 1334 IDU were included in the
      analysis. Compared with IDU who did not know their HIV serostatus, only IDU
      knowing their HIV-positive serostatus used condoms significantly more often (37%
      compared to 15%, rate ratio (RR): 2.4; 95% confidence interval (CI): 1.8-2.3) and
      never gave their used injecting equipment to other IDU (69% compared to 53%, RR:
      1.3; 95% CI: 1.2-1.4). In comparison with the 1990 study, only condom use
      significantly improved and only for IDU who knew their HIV-negative serostatus
      (13% compared to 9%, RR: 1.6; 95% CI: 1.1-2.3). This study confirms among
      European IDU the relation between knowing own HIV serological status to
      preventive behaviours. However, there were only minor improvements between 1990
      and 1992-1993, indicating that prevention of HIV transmission among IDU must be
      reinforced.

PMID- 10395051
TI  - Low seroprevalence of HTLV-I and HTLV-II in patients with a sexually transmitted
      disease. Study Group for HTLV and STDs.
AB  - To determine the prevalence of HTLV I-II among highly sexually active adults, a
      seroprevalence study was conducted in Italy between March 1992 and March 1993
      among 1506 patients with a newly diagnosed STD. Individuals were tested with an
      enzyme immunoassay that employs a double viral lysate from HTLV-I and HTLV-II
      infected cell lines; confirmation and discrimination between HTLV-I and II were
      performed by a dot-blot immunoassay. One patient (0.07%) was confirmed HTLV-I
      positive and one (0.07%) HTLV-II positive. The HTLV-I positive was a Romanian
      woman, and the other was an intravenous drug user. The 0.13% HTLV prevalence
      observed in this study is intermediate between the 0.034% found among Italian
      blood donors and the 3.5-6% found among Italian intravenous drug users. These
      data suggest that there is not a high prevalence of these viruses among Italians
      with STDs.

PMID- 10395050
TI  - Hepatitis C virus infection in four haemodialysis units of southern Italy:
      epidemiological report.
AB  - The haemodialysis patients are an high risk population for hepatitis viral
      infections. While the incidence of HBV has decreased worldwide, HCV is now the
      major cause of viral infection in these patients. The aim of our study was to
      define a complete map of patients undergoing routine replacement therapy by
      haemodialysis in the province of Foggia, Southern Italy, who were HCV Ab
      positive, the presence of viraemia and their genotypes; moreover, we investigated
      the probable factors involved in determining the infection as well as the means
      of prevention. MATERIALS AND METHODS: We enrolled 330 patients treated in four
      haemodialysis centres (DC) and six secondary units; mean age was 57 years and
      mean duration of dialysis 76 months. Samples were drawn to determine cytolysis
      indexes and the HCV Ab status; in HCV positive patients, we also looked for
      viraemia and HCV genotypes. Data were analysed by a transversal cross-section
      study. RESULTS AND CONCLUSIONS: Prevalence of HCV infection was 0.43 (males 0.45,
      females 0.42). The risk of contracting the infection was shown to be
      significantly different in the various DCs and did not seem to be related to the
      severity of the preventive measures. There was no significant difference between
      the various DCs in the comparison between the odds of HCV-RNA+ and HCV-RNA-
      patients. No significant prevalence of a given genotype emerged from a cross
      sectional study related to the comparison between different genotypes. Moreover,
      transfusions of blood products seemed to have no significant relation to HCV
      infection. Finally, patients treated with haemodialysis for more than 36 months
      run a seven time greater risk of contracting HCV infection.

PMID- 10395052
TI  - Use of health services by the climacteric women in primary health care: the need
      for an integral approach.
AB  - During the climacteric, women experience multiple health problems. As their needs
      are not catered for in an integral fashion due to the lack of any specific
      programme or mechanism to provide for this, they show an increased use of the
      health services, and an increased rate of referrals to different specialists.
      This study, carried out in a Basic Health Zone in San Fernando (Cadiz, Andalusia,
      Spain) on a sample of climacteric women who attended the Health Centre during
      1995, examines these points and shows a significantly higher use of the health
      services in relation to the rest of the female population (those who are not in
      the climacteric age group) as well as a high percentage of referrals (74.6%) to
      specialists. It was found that both the level of knowledge about the climacteric
      and the use of the health services were influenced by the educational level (p <
      0.001) and age (p < 0.05). Women who felt that their families provided an
      understanding and supportive attitude were found to have less psychological
      problems and, consequently, less consultations and referrals for this reason (p <
      0.00001). The authors hope that their findings will provide a basis for the
      setting up of a programme of integral health care for climacteric women at the
      level of primary health care. With careful planning and the drawing up of a
      strategic plan, it would be possible to provide for the needs of this population
      group in a more satisfactory way, and it would also permit a rationalization of
      the resources available.

PMID- 10395053
TI  - Seasonal changes in calcitropic hormones in Israeli men.
AB  - Seasonal changes in calcitropic hormones might be expected, being that dietary
      calcium intake may differ with fluctuations in climate and temperature, and
      vitamin D is diet- and sunlight-dependent. While there are studies on elderly
      subjects, prospective data on younger men is limited. The objective of this study
      was to clarify possible seasonal changes in homeostatic regulators of calcium in
      Israeli men aged 25-64 years. The study was a prospective follow-up analysis of
      data collected during June-August 1995 and 1996 (summer) and January March 1995
      and 1996 (winter). Subjects were ninety-five industrial male employees with and
      without occupational lead exposure. The main outcome measures were summer and
      winter serum concentrations of parathyroid hormone (PTH), 25-hydroxyvitamin D (25
      OH-D), and 1,25-dihydroxyvitamin D (calcitriol). Summer and winter values of PTH
      were similar (38.2 and 39.8 ng/l, respectively). 25-OH-D levels were
      significantly higher in summer (32.8 ng/ml) than in winter (25.4 ng/ml) after
      controlling for possible confounders (p < 0.0001). Calcitriol levels were
      significantly higher in summer (79.1 pmol/l) than in winter (73.5 pmol/l) in
      univariate analyses, but not after controlling for possible confounders. We
      conclude that healthy men show considerable seasonal changes in 25-OH-D levels
      even in Israel, a relatively sunny country all the year round. Summer values of
      25-OH-D, were 35% higher than in winter. These fluctuations should be taken into
      account during evaluation of pathological conditions and in research. Given an
      adequate diet and vitamin D status there are no seasonal variations in PTH or in
      calcitriol levels.

PMID- 10395054
TI  - Impaired glucose tolerance, diabetes mellitus, and gallstone disease: an extended
      study of male self-defense officials in Japan.
AB  - Few studies have investigated the relation between glucose tolerance status and
      ultrasonographically determined gallstone disease. Using a 75-g oral glucose
      tolerance test, we examined the association of impaired glucose tolerance (IGT)
      and non-insulin-dependent diabetes mellitus (NIDDM) with gallstone disease in
      Japanese men. Subjects were men aged 48 to 59 of the Japan Self-Defense Forces
      who received a preretirement health examination between October 1986 to December
      1994. After exclusion of 12 men under insulin treatment in the consecutive series
      of 7637 men, 174 were found to have gallstones; 103 were at the state of
      postcholecystectomy, and 6899 had normal gallbladder. IGT and NIDDM were
      associated with a modestly increased risk of gallstone disease; adjusted odds
      ratios were 1.3 (95% confidence interval [CI]: 0.9-1.8) for IGT and 1.3 (95% CI:
      0.8-2.0) for NIDDM after adjustment for hospital, rank, smoking, alcohol use, and
      body mass index. Adjusted odds ratio for IGT and NIDDM combined was 1.3 (95% CI:
      1.0-1.7, p=0.08). When prevalent gallstones and postcholecystectomy were
      considered separately, NIDDM showed a significant, positive association with
      postcholecystectomy, but not with prevalent gallstones. The findings add to
      evidence that glucose intolerance is associated with a modest increase in the
      risk of gallstone disease.

PMID- 10395055
TI  - Tuberculosis in Lebanese jails: prevalence and risk factors.
AB  - A survey was conducted in 1995 to assess the prevalence of TB infection using the
      PPD skin test infection among 3931 inmates in all 21 jails in Lebanon. Forty-five
      percent of participants had a positive PPD skin test. The likelihood of testing
      positive was higher among men versus women, and among those who had been
      incarcerated for more than 3 years versus less than that. Compared to prisoners
      whose usual residence was Central Lebanon, those from North Lebanon and those
      from outside Lebanon (mostly Syria and Egypt) had a higher risk for PPD
      positivity, those from Bekaa a lower risk, and those from South Lebanon about the
      same risk. Among those with positive PPD tests, 7% had abnormal chest X-rays
      suggestive of active infection. Results suggest that TB infection is an important
      health problem in correctional facilities in Lebanon and that special control
      programs should target North Lebanon. The importance of screening the
      incarcerated population with chest X-rays rather than PPD skin tests is
      discussed.

PMID- 10395056
TI  - Intestinal parasite carriage in workers exposed to sewage.
AB  - The presence of protozoan cysts and helminth eggs in sewage and the very low
      minimal infective doses of parasites suggest an occupational risk for workers
      exposed to sewage. The objective of this study was to assess this risk in a group
      of raw sewage-exposed workers. The relationship between sewage exposure and
      intestinal parasite carriage was estimated by a multiple cross-sectional survey
      comparing yearly prevalence rates in 126 employees working in sewers in Paris,
      France, with the prevalence rate in 363 food-handlers employed between 1988 and
      1993. The incidence of intestinal parasitic infestation was estimated among
      sewage-exposed workers. Four parasite species were identified among sewage
      exposed workers: whipworm, Giardia lamblia, Entamoeba coli and Endolimax nanus.
      The prevalence mean of intestinal parasite carriage was 11.8% (57/480), related
      to the presence of protozoa in 91% of samples. G. lamblia was present in 3.5%
      (17/480) of samples. The incidence of positive parasitological stool examination
      was 5.9/100 person-years. The incidence of G. lamblia in stool examinations was
      1.7/100 person-years. Age-adjusted odds ratios were significantly higher in
      exposed workers in 1988 (OR: 6.5; 95% CI: 2.0-14.5), 1990 (OR: 4.4; 95% CI: 1.2
      10.1) and 1991 (OR: 3.4; 95% CI: 1.0-8.2), but not during the other three years.
      The results of this study emphasize an occupational risk of intestinal protozoan
      infestation in workers exposed to sewage. The decrease of adjusted OR with time
      reflects the efficacy of compliance with rules of hygiene.

PMID- 10395057
TI  - Serum antibodies to polioviruses in Alexandria, Egypt.
AB  - Random sera, in a total of 192, were collected in the Fever Hospital of
      Alexandria, Egypt, and analysed for the presence of antibodies against
      polioviruses. The results show good antibody levels, only three sera (1.5%) were
      negative for poliovirus type 1, 5 (2.6%) for poliovirus type 2 and 10 (5.2%) for
      poliovirus type 3; one subject was completely negative.

PMID- 10395058
TI  - Asymptomatic canine leishmaniasis in Greater Athens area, Greece.
AB  - Leishmania (L.) infantum is the etiological agent of human and canine visceral
      leishmaniasis in the Mediterranean subregion. Domestic dogs are the main
      reservoir of the parasite in most urban areas. A survey of 1638 asymptomatic dogs
      registered in Greater Athens area was carried out in the Hellenic Pasteur
      Institute during the period 1986-1994 to investigate the prevalence of canine
      visceral leishmaniasis in apparently healthy dogs. Dog sera was tested using the
      indirect fluorescent antibody technique (IFAT). Of the 1638 dogs, 366 (22.4%) had
      anti-Leishmania infantum antibodies at titre greater than or equal to 1/200 which
      were considered positive; 53 (3.2%) had antibody titres of 1/100 and were
      considered uncertain; and 1219 (74.4%) dogs were seronegative. From the 366
      seropositive dogs, 212 were positive at 1/1600 serum dilution, 57 at 1/800, 38 at
      1/400 and 59 at 1/200. The results were plotted according the site of residence,
      breed and age. The rate of asymptomatic infections with L. infantum dogs in
      Greater Athens area appears to be significantly high. Although there is an
      apparent lack of clinical symptoms in these dogs, asymptomatic animals harbor a
      chronic L. infantum infection and as such consist a 'dangerous' reservoir with
      regard to the spread of the disease.

PMID- 10395059
TI  - Surveillance of brucellosis in a rural area of Greece: application of the
      computerized mapping programme.
AB  - Long term active surveillance of brucellosis was implemented in a rural area
      (Fokida) of Greece from 1989 to 1993 while the rural area of Grevena was selected
      as a control area. The computerised mapping programme was used to identify and
      protect the suspected animal brucellosis free zones. Health education of the
      inhabitants was further used to teach them how to avoid the risk factors. Three
      suspected brucellosis free zones were identified and two of them were
      successfully protected. The incidence for the 10 year period (1979-1988) was
      estimated at 1.4/1000/year for the study area and 1.6/1000/year for the control
      area. During the surveillance period the incidence in the study area dropped to
      0.2/1000/year while in the control area it decreased to 1.0/1000/year. The
      methodology of identification and protection of suspected brucellosis free zones
      combined with health education proved to be efficient in reducing the incidence
      of the disease. The same methodology could be used in the country level, in
      countries where it is difficult to implement and maintain an animal control
      programme in the whole country.

PMID- 10395060
TI  - Epidemiology of blood collection in France.
AB  - The objectives of the cross-sectional study (EpiCoS) were to describe, at
      different stages, volunteers offering their blood, and to characterize various
      ways of collecting blood. From 15 September 1996 to 31 December 1996, individuals
      presenting at fixed or mobile sessions in one of 11 randomly selected blood banks
      were included after they had a medical examination. Variables studied were
      relative to type of collection, individuals, medical examination, patterns of
      blood letting, use of collected donations and if unused, reasons for discarding.
      Sixty four thousand and ninety two volunteers, aged 17-66 years old were
      included. The proportion of exclusion during medical examination was 10.8% (95%
      confidence interval (CI): 10.6-11.0%). Exclusions were more frequent among new
      volunteers and were mostly related to the safety of recipients. Most of the
      57,003 donations were whole blood (94.0%) and collected in mobile sessions
      (89.9%). Five percent of collected donations were discarded; 3.5% (95% CI: 3.4
      3.7%) of donations discarded for biological abnormalities, including 1.5% only
      for initial screen reactions to infectious disease markers (HBs antigen, anti-HBc
      antibodies, anti-HCV antibodies, anti-HIV antibodies, anti-HTLV antibodies,
      malaria antibodies and anti-syphilitic antibodies). The most frequent biological
      abnormality was a high alanine aminotransferase level. A follow-up of these
      indicators, within the French haemovigilance system, should allow further
      identification of risk factors and high-risk contexts, and planning means of
      optimizing blood collection in France.

PMID- 10395061
TI  - Non-responders to a postal questionnaire on respiratory symptoms and diseases.
AB  - Only few data have been published about non-responders in epidemiological studies
      on respiratory diseases. The aim of this study was to examine the characteristics
      of the non-responders and the reasons for non-response in a survey of respiratory
      health. All 9132 subjects, born 1925-1926, 1940-1941, 1955-1956 and 1970-1971 and
      living in eight representative areas in Norrbotten, Sweden, were invited to a
      prevalence study on asthma, chronic bronchitis and respiratory symptoms. The
      response rate was 85%. A sample of the non-responders from the cross-sectional
      postal questionnaire study was contacted by telephone and interviewed using the
      same questionnaire as had been used in the postal survey. Of the 1397 non
      responders a stratified sample of 182 subjects were selected for this study and
      144 agreed to participate. The response rate was increasing by increasing age.
      The main reason for non-response was that the subjects had forgotten to mail the
      questionnaire, lack of interest or lack of time. There were significantly higher
      proportions of current smokers and manual workers among the non-responders. The
      prevalence rates of wheezing, long-standing cough, sputum production, attacks of
      breathlessness, asthma and use of asthma medicines were significantly higher
      among the non-responders compared with the responders according both univariate
      and multivariate logistic regression analyses, in which the influences of age,
      sex, smoking habits, socioeconomic group and area of domicile were taken into
      account. The prevalence of respiratory symptoms and diseases was slightly
      underestimated in the postal survey.

PMID- 10395062
TI  - Italian influenza surveillance network: results of the first year of activity.
      The Collaborative Group for influenza surveillance.

PMID- 10395063
TI  - Myofibrillar protein structure and assembly during idiopathic dilated
      cardiomyopathy.
AB  - A neutral protease, mekratin, active in human hearts at end stage idiopathic
      dilated cardiomyopathy (IDC), mediates the breakdown of cardiac myosin LC2.
      Myosin purified from IDC heart tissue forms unusually short synthetic thick
      filaments. Therefore, determination of filament length and mekratin distribution
      in IDC heart muscle were initiated. Native thick filaments were prepared directly
      from control and IDC tissues and analyzed. Also, paraffin-embedded tissue
      sections were stained with a fluorescently-labeled anti-protease antibody to
      establish its distribution in myocardial tissues. Control sections had only very
      weak, background levels of fluorescence whereas IDC sections stained intensely
      throughout, indicating a wide ranging distribution of the protease within the
      myocyte cytoplasm. SDS-PAGE revealed LC2 to be present in stoichiometric amounts
      in control but greatly reduced in IDC heart muscle. Native thick filaments from
      control myocardium were structurally stable. They had a median length of 1.65
      microm with well-defined bare zones and displayed the 43 nm helical periodicity
      typical of the relaxed arrangement of myosin heads close to the filaments'
      shafts. In contrast, native IDC filaments were less stable, and had a median
      length of 0.9 microm. These filaments were highly disordered: they had no surface
      periodicity and myosin heads were positioned away from the filaments' shafts. The
      shorter, less stable, aperiodic thick filaments from IDC hearts appear to result
      from depletion of LC2 caused by increased activity of mekratin in the IDC
      myocardium.

PMID- 10395064
TI  - Induction of Egr-1 mRNA and protein by endothelin 1, angiotensin II and
      norepinephrine in neonatal cardiac myocytes.
AB  - The early growth response gene Egr-1 is a nuclear transcription factor known to
      serve as an intermediary in a broad range of signal transduction processes.
      Recent studies have assigned Egr-1 a new role as an amplifier of gene expression.
      Egr-1 mRNA is expressed in the myocardium and is rapidly induced in response to
      hypertrophic stimuli. However, induction of the Egr-1 protein has not yet been
      demonstrated in the myocardium; on the other hand, in skeletal muscle cells we
      have shown translational regulation of Egr-1. To further investigate the role of
      Egr-1 in the regulatory mechanisms of a variety of signal transduction processes
      we have therefore asked whether bona fide hypertrophic stimuli induce Egr-1
      protein subsequently to its mRNA in neonatal rat cardiomyocytes or whether
      translational block occurs. In confocal laser studies the Egr-1 protein was
      nuclearly localized. Norepinephrine (NE, 2 microM), angiotensin II (AII, 0.1
      microM), and endothelin 1 (E1, 0.1 microM) each induced the Egr-1 mRNA 6-8 fold
      and the Egr-1 protein 3-5 fold (n = 3, p < 0.01). Therefore, in contrast to
      skeletal muscle cells, these stimuli increased Egr-1 mRNA and protein levels.
      These results point further to the role of Egr-1 as a possible amplifier of
      signal transduction in the myocardium.

PMID- 10395065
TI  - Androgen effects on the solubility and conformational change of the androgen
      receptor in baculovirus expression system.
AB  - To purify the androgen receptor (AR) efficiently from baculovirus expression
      system, we fused 6 histidine residues with the N-terminal domain of AR as a tag
      to specifically bind to Ni+2-affinity column. Our data indicated that adding
      androgen can increase the binding capacity of his-tag AR to the Ni+2-affinity
      column, and this increased binding capacity of AR could be due to the exposure of
      histidine residues of N-terminal domain induced by androgen. The androgen
      enhanced binding to Ni+2-column also correlated with the increasing solubility of
      AR. Electrophoretic mobility shift assay further indicated that only purified AR
      could interact with androgen response element. Together, our data suggest that
      the binding of androgen to the hormone binding domain of AR may result in the
      conformational change of the N-terminal domain of AR and increase the hydrophilic
      property of AR.

PMID- 10395066
TI  - Growth arrest and induction of apoptosis in breast cancer cells by antisense
      depletion of protein kinase A-RI alpha subunit: p53-independent mechanism of
      action.
AB  - The enhanced expression of the RI alpha subunit of cyclic AMP-dependent protein
      kinase type 1 (PKA-1) has been correlated with cancer cell growth. We have
      investigated the effects of sequence-specific inhibition of RI alpha gene
      expression on the growth of MCF-7 human breast cancer cells. We report that RI
      alpha antisense treatment results in a reduction in RI alpha expression at both
      mRNA and protein levels and inhibition of cell growth. The growth inhibition was
      accompanied by changes in cell morphology, cleavage of poly(ADP-ribose)
      polymerase (PARP) and appearance of apoptotic nuclei. In addition, bcl-2 protein
      level was reduced and p53 expression increased in growth arrested cells.
      Interestingly, RI alpha antisense inhibited cell viability and induced apoptosis
      in the absence of p53, suggesting that these actions of RI alpha antisense are
      exerted independent of p53. In contrast, two- and four-base mismatched control
      oligonucleotides had no effect on either cell growth or morphology. These results
      demonstrate that the RI alpha antisense, which efficiently depletes the growth
      stimulatory molecule RI alpha, induces cell differentiation and apoptosis,
      providing a new approach to combat breast cancer cell growth.

PMID- 10395068
TI  - TCR kappa, a new splicing of the murine TCR zeta gene locus, is modulated by
      glucocorticoid treatment.
AB  - T-cell receptor (TCR) is a multichain receptor in which the TCRzeta subunit is
      important for membrane assembly and signal transduction. Four alternative
      splicings of the murine TCRzeta gene locus have been previously described. We
      here describe a new alternative splicing of murine TCRzeta gene, TCRkappa, cloned
      by RT-PCR, that is encoded by exons 1-7, a portion of exon 9 and the whole exon
      10 of TCRzeta gene. The protein encoded by TCRkappa mRNA is identical to that
      encoded by TCReta mRNA, because the stop codon is present in the exon 9 before
      splicing with exon 10. RNAse protection assays carried out on total RNA from
      thymocytes indicate that TCRkappa mRNA is 1 half with respect to TCReta mRNA,
      suggesting that TCRkappa mRNA contributes to determine the TCReta protein levels.
      The 3' untranslated region of TCRkappa mRNA is different from that of TCReta and
      this might lead to different t(1/2) for each species in vivo. We also show that
      dexamethasone (DEX), a synthetic glucocorticoid hormone, increases the amount of
      TCRkappa in the hybridoma T-cell line 3DO (about 5-fold increase), as indicated
      by reverse transcriptase-polymerase chain reaction (RT-PCR) and RNAse protection
      assays. This newly described effect of DEX may constitute a further molecular
      mechanism that contributes to its immunomodulating activity.

PMID- 10395067
TI  - Post mortem changes in Ca2+ transporting proteins of sarcoplasmic reticulum in
      dependence on malignant hyperthermia status in pigs.
AB  - Meat quality of pigs is dependent on biochemical and biophysical processes in the
      time course post mortem (p.m.) and is associated with the intracellular Ca2+
      homeostasis. However, there is little known about changes in the Ca2+
      transporting proteins controlling the Ca2+ uptake of sarcoplasmic reticulum (SR)
      in the time course p.m. In this study changes in the Ca2+ transporting proteins
      were investigated in homogenates of longissimus muscles of 4 malignant
      hyperthermia susceptible (MHS) and 6 malignant hyperthermia resistant (MHR)
      Pietrain pigs. Muscle samples were obtained at different time intervals: biopsy 2
      h prior slaughtering and from the carcass immediately after exsanguination (0 h),
      45 min, 4 h, and 22 h p.m. The SR Ca2+ uptake rate was measured immediately after
      homogenization with closed calcium release channel (CRC), with opened CRC and
      without manipulation of CRC. Additionally the SR Ca2+ ATPase activity was
      determined. The results show: (i) The ability of SR to sequester Ca2+ declined to
      about 60% in the first 45 min p.m. in MHS samples irrespective of CRC state,
      whereas in MHR samples this decline was about 5%; (ii) Ca2+ uptake and Ca2+
      ATPase activity were not different between the biopsy and 0 h samples, i.e. the
      stress of slaughter was of no immediate influence; (iii) The Ca2+ ATPase activity
      of the SR declined at about the same rate as the Ca2+ uptake in both MHS and MHR
      pig samples in the course of time p.m.; (iv) In samples, taken immediately after
      exsanguination, the Ca2+ ATPase activity of MHS pigs was higher than that of MHR
      pigs. However, in samples taken 4 h p.m. Ca2+ ATPase activity of MHS pigs has
      declined to about 30% of the value at 0 h; (v) The CRC can be closed and opened
      in all samples up to 22 h p.m. and seems to be fully functional at all sampling
      times; (vi) The CRC of MHS pigs is almost fully open, whereas the CRC of MHR pigs
      is only partially open at all sampling times; (vii) The permeability of the SR
      membrane to Ca2+ (determined as the ratio of SR Ca2+ ATPase with and without
      ionophore A23187) is the same in both MHS and MHR and did not change with ongoing
      time; (viii) No uncoupling of uptake from ATP hydrolysis occurred up to 4 h p.m.,
      but the coupling differed between MHS and MHR for all time intervals with lower
      values for MHS pigs. The results suggest that the decreasing Ca2+ uptake rate of
      homogenates, sampled at different times p.m., is essentially caused by changes in
      the Ca2+ pump and not by changes in the CRC or an increased phospholipid membrane
      permeability to Ca2+.

PMID- 10395069
TI  - Characterization of ornithine decarboxylase and regulation by its antizyme in
      Thermus thermophilus.
AB  - Ornithine decarboxylase (ODC), the key enzyme of polyamine biosynthesis was
      highly purified from the thermophilic bacterium Thermus thermophilus. The enzyme
      preparation showed a single band on SDS-polyacrylamide gel electrophoresis, a pH
      optimum of 7.5 and a temperature optimum at 60 degrees C. The native enzyme which
      is phosphorylated could, upon treatment with alkaline phosphatase, lose all
      activity. The inactive form could be reversibly activated by nucleotides in the
      order of NTP>NDP>NMP. When physiological polyamines were added to the purified
      enzyme in vitro, spermine or spermidine activated ODC by 140 or 40%,
      respectively, while putrescine caused a small inhibition. The basic amino acids
      lysine and arginine were competitive inhibitors of ODC, while histidine did not
      affect the enzyme activity. Among the phosphoamino acids tested, phosphoserine
      was the most effective activator of purified ODC. Polyamines added at high
      concentration to the medium resulted in a delay or in a complete inhibition of
      the growth of T. thermophilus, and in a decrease of the specific activity of
      ornithine decarboxylase. The decrease of ODC activity resulted from the
      appearance of a non-competitive inhibitor of ODC, the antizyme (Az). The T.
      thermophilus antizyme was purified by an ODC-Sepharose affinity column
      chromatography, as well as by immunoprecipitation using antibodies raised against
      the E. coli antizyme. The antizyme of E. coli inhibited the ODC of T.
      thermophilus, and vice versa. The fragment of amino acids 56-292 of the E. coli
      antizyme, produced as a fusion protein of glutathione S-transferase, did not
      inhibit the ODC of E. coli or T. thermophilus.

PMID- 10395070
TI  - A mannose-binding glycoprotein found in the 4 day post coital rat uterus is
      involved in pregnancy.
AB  - Experiments were conducted to study the functional implication of a mannose
      binding glycoprotein found in the day 4 post coital (p.c.) rat uterus, using a
      mono-specific polyclonal antibody raised against the glycoprotein. Western Blot
      and immunohistochemical techniques were employed to study the distribution of the
      glycoprotein, and the results suggest that this glycoprotein is present only in
      the day 4 p.c. uterus and is specifically localized in the stromal cells.
      Administration of anti-UA (Uterine Agglutinin) antiserum against the glycoprotein
      into the day 4 p.c. uterine lumen inhibits carrying of embryo to term. The
      antiserum is not embryo toxic. After in vivo in utero intra-luminal
      administration of anti-UA antiserum in day 4 p.c. rat the antiserum has been
      specifically localized in the uterine stroma by immunohistochemistry. After
      intravenous injection, the glycoprotein is cleared mainly through the kidney and
      liver. The possible role of this glycoprotein in the implantation process in rats
      has been discussed. From the data it is evident that UA may not be directly
      involved in sugar-sugar interactions with embryo since it is not present in any
      significant amount in pregnant uterus from day 5 onwards. Since other experiments
      show that UA does have some role to play in early pregnancy, UA probably acts
      through some other factor, and preliminary studies suggest that this factor maybe
      TGF-beta3.

PMID- 10395072
TI  - Stimulatory effect of regucalcin on proteolytic activity in rat renal cortex
      cytosol: involvement of thiol proteases.
AB  - The effect of regucalcin, a calcium-binding protein, on neutral proteolytic
      activity in the cytosol of rat kidney cortex was investigated. Proteolytic
      activity was significantly increased in the presence of regucalcin (0.01-0.25
      microM) in the enzyme reaction mixture. This increase was not significantly
      altered by the addition of CaCl, (0.01 and 1.0 mM) or EGTA (1.0 mM), indicating
      that the effect of regucalcin was independent on Ca2+. The effect of regucalcin
      to increase proteolytic activity was completely prevented in the presence of N
      ethylmaleimide (5 mM), a modifying reagent of thiol groups. Proteolytic activity
      was clearly elevated by dithiothreitol (5 mM). This elevation was further
      enhanced by regucalcin (0.1 microM). Meanwhile, the stimulatory effect of
      regucalcin on proteolytic activity was not significantly altered in the presence
      of diisopropylfluorophosphate (2.5 mM), an inhibitor of serine proteases. Also,
      the regucalcin effect was not appreciably changed by the addition of EDTA (2.5
      mM), a chelator of metal ions, indicating that it is not involved in metal
      related proteases. These results demonstrate that regucalcin can increase
      proteolytic activity in the cytosol of rat kidney cortex. Regucalcin may activate
      thiol proteases independent on Ca2+.

PMID- 10395071
TI  - Ala99ser mutation in RI alpha regulatory subunit of protein kinase A causes
      reduced kinase activation by cAMP and arrest of hormone-dependent breast cancer
      cell growth.
AB  - Expression of the RIalpha regulatory subunit of protein kinase A type I is
      increased in human cancer cell lines, in primary tumors, in cells after
      transformation, and in cells upon stimulation of growth. Ala99 (the
      pseudophosphorylation site) of human RIalpha was replaced with Ser (RIalpha-p)
      for the structure-function analysis of RIalpha. MCF-7 hormone-dependent breast
      cancer cells were transfected with an expression vector for the wild-type RIalpha
      or mutant RIalpha-p. Overexpression of RIalpha-P resulted in suppression of
      protein kinase A type II, the isozyme of type I kinase, production of kinase
      exhibiting reduced cAMP activation, and inhibition of cell growth showing an
      increase in G0/G1 phase of the cell cycle and apoptosis. The wild-type RIalpha
      overexpression had no effect on protein kinase A isozyme distribution or cell
      growth. Overexpression of protein kinase A type II regulatory subunit, RIIbeta,
      suppressed RIalpha and protein kinase A type I and inhibited cell growth. These
      results show that the growth of hormone-dependent breast cancer cells is
      dependent on the functional protein kinase A type I.

PMID- 10395073
TI  - Arginine vasopressin increases the rate of protein synthesis in isolated perfused
      adult rat heart via the V1 receptor.
AB  - Arginine vasopressin (AVP) is known to contribute significantly to the
      pathogenesis of congestive heart failure and hypertension. However, little is
      known about its effect on the myocardium. The present study was conducted to
      determine whether AVP directly increases the rate of protein synthesis in
      isolated, perfused rat heart, and, if so, the mechanism involved. Elevation of
      the aortic pressure from 60 to 120 mmHg in perfused rat heart accelerated the
      rate of protein synthesis which was associated with increases in cAMP levels and
      Ca2+ uptake. AVP (100 microM) increased Ca2+ uptake and accelerated the rate of
      protein synthesis without a change in cAMP concentration. The latter events were
      inhibited by OPC-21268 (100 microM), a selective V1 receptor antagonist, or
      amiloride (100 microM), an inhibitor of the Na+/H+ exchange system. However,
      increases in cAMP concentrations, Ca2+ uptake, and rates of protein synthesis
      associated with the elevated aortic pressure were not inhibited by amiloride.
      Thus, AVP directly increased the rate of protein synthesis via the V1 receptor
      that is sensitive to amiloride, a mechanism that differs from the cAMP-dependent
      mechanism that is responsible for the cardiac hypertrophy induced by pressure
      overload.

PMID- 10395074
TI  - Negative regulation of glucocorticoid-dependent induction of c-fos by ras in
      intestinal epithelial cells.
AB  - In order to investigate the regulatory mechanisms involved in the expression of
      fos and jun family members by glucocorticoids, and the effect of ras
      transformation in intestinal epithelial cells, we used the rat cell line IEC-6.
      Dexamethasone treatment induced transiently c-jun mRNAs, in contrast to the
      sustained expression of c-fos, whereas its effect on junB expression resulted in
      a later increase. Dexamethasone-dependent stimulation of c-fos and c-jun was
      modulated predominantly at the level of transcription. Sustained levels of
      induced c-fos and c-jun proteins were observed after dexamethasone treatment. AP
      1 DNA-binding capacity of c-fos, and to a smaller extent c-jun, was increased by
      glucocorticoids later than after serum treatment. To analyse the effect of ras on
      the glucocorticoid response of AP-1 components, we studied several IEC-6 cell
      clones transformed by the Ha-ras oncogene. In comparison to normal cells, these
      transformants displayed increased AP-1 DNA-binding activity with higher levels of
      junB and variable levels of c-jun in the AP-1 complex. Ras transformation
      repressed the growth-inhibitory properties of glucocorticoids. Furthermore, ras
      inhibited the glucocorticoid-dependent induction of c-fos protein and mRNA,
      leading to changes in AP-1 composition as compared to normal cells. As assessed
      by transient transfection luciferase assays, glucocorticoids induced
      significantly a minimal promoter containing 3 copies of an AP-1 DNA-binding site
      as well as the murine c-fos -276 to +112 promoter in non-transformed cells. In
      contrast, glucocorticoid addition did not induce these constructs in two ras
      transformed cell lines. These results suggest that ras negatively modulates
      specific responses of intestinal epithelial cells to glucocorticoids.

PMID- 10395075
TI  - Transport and metabolism of exogenous fumarate and 3-phosphoglycerate in vascular
      smooth muscle.
AB  - The keto (linear) form of exogenous fructose 1,6-bisphosphate, a highly charged
      glycolytic intermediate, may utilize a dicarboxylate transporter to cross the
      cell membrane, support glycolysis, and produce ATP anaerobically. We tested the
      hypothesis that fumarate, a dicarboxylate, and 3-phosphoglycerate (3-PG), an
      intermediate structurally similar to a dicarboxylate, can support contraction in
      vascular smooth muscle during hypoxia. To assess ATP production during hypoxia we
      measured isometric force maintenance in hog carotid arteries during hypoxia in
      the presence or absence of 20 mM fumarate or 3-PG. 3-PG improved maintenance of
      force (p < 0.05) during the 30-80 min period of hypoxia. Fumarate decreased peak
      isometric force development by 9.5% (p = 0.008) but modestly improved maintenance
      of force (p < 0.05) throughout the first 80 min of hypoxia. 13C-NMR on tissue
      extracts and superfusates revealed 1,2,3,4-(13)C-fumarate (5 mM) metabolism to
      1,2,3,4-(13)C-malate under oxygenated and hypoxic conditions suggesting uptake
      and metabolism of fumarate. In conclusion, exogenous fumarate and 3-PG readily
      enter vascular smooth muscle cells, presumably by a dicarboxylate transporter,
      and support energetically important pathways.

PMID- 10395076
TI  - Role of protein kinase C and 72 kDa heat shock protein in ischemic tolerance
      following heat stress in the rat heart.
AB  - Heat stress (HS) and the subsequent expression of 72 kDa heat shock protein (HSP
      72) has been shown to enhance post-ischemic functional recovery and reduce
      infarct size. Because the synthesis of heat shock proteins involves activation of
      heat shock transcription factors through phosphorylation, we hypothesized that
      inhibition of protein kinase C (PKC) would block HS mediated protection and
      expression of HSP 72 in the heart. Five groups of rats were studied (1) Sham
      anesthetized, (2) HS group--animals were heat shocked by raising the whole body
      core temperature to 42 degrees C for 15 min, (3) Vehicle group--HS rats treated
      with 50% DMSO in saline, (4) PKC inhibitor-treated group--specific PKC
      antagonist, chelerythrine chloride (5 mg/kg, i.p) given 30 min prior to HS and
      (5) Vehicle treated control--non-HS rats treated with vehicle prior to
      ischemia/reperfusion. Hearts were subjected to 30 min of regional ischemia and 90
      min of reperfusion 24 h after HS. Risk area was delineated by injection of 10%
      Evan's blue and infarct size determined using computer morphometry of tetrazolium
      stained sections. Infarct size (% area at risk) reduced significantly from 49.4
      +/- 2.3% (n = 7) in sham to 10.0 +/- 2.5% (p < 0.01) and 9.1 +/- 3.0% in HS and
      vehicle treated HS groups respectively (p < 0.05) Treatment with chelerythrine
      prior to HS increased infarct size to 49.4 +/- 2.3% (p < 0.05). Infarct size in
      chelerythrine-treated non-HS ischemic/reperfused heart was 40.7 +/- 5.4%, which
      did not differ significantly from vehicle-treated sham group. Western blot
      analysis demonstrated marked increase in HSP 72 in HS groups (with or without
      vehicle treatment) and pretreatment with chelerythrine chloride failed to inhibit
      the expression of HSP 72. The results suggest that HS-induced ischemic tolerance
      is mediated via PKC pathway and this protection does not appear to be directly
      related to the expression of HSP 72 in rat heart.

PMID- 10395077
TI  - Molecular study of the rat liver NADH: cytochrome c oxidoreductase complex during
      development and ageing.
AB  - The mechanisms involved in ageing are yet to be fully understood but it is
      thought that changes produced in energy transfer pathways occurring in the
      mitochondria may be responsible for the lack of energy typical of the later
      stages of life. The aim of the present investigation was to determine the
      enzymatic activity of the liver NADH cytochrome c oxidoreductase complex (Complex
      I-III) in mitochondria isolated from the liver of rats of 3 different age groups:
      lactating, animals (15-17 days), adult females (3-5 months) and old animals (26
      30 months). The activities of the unbound Complexes I and III were also
      determined. An increase in Complex I-III activity was detected during development
      (142 +/- 10 vs. 447 +/- 23 micromol cyt. c/mg/min, p < 0.001) ang ageing (447 +/-
      23 vs. 713 +/- 45 micromol cyt. c/mg/min, p < 0.001). However, unbound Complex I
      showed a reduction in activity during the ageing period whilst Complex III
      activity moderately increased. Immunological studies indicated only a moderate
      increase in the amount of Complex I-III and studies on the purified complex
      suggested that the increase in activity was due to effects other than an increase
      in enzyme quantity. The analysis of protein bands and the quantification of
      prosthetic groups showed particular reductions in the relative concentrations of
      Complex I subunits including the 51 kDa unit, which binds FMN, confirmed by a
      similar reduction in levels of the nucleotide. In contrast, 4 of the 5 subunits
      which increased during the lifetime of the animals corresponded to those of
      Complex III. These subunits are responsible for the binding of catalytic groups.
      The results suggest that, in addition to the increase in the amount of enzyme,
      binding factors between Complexes I and III may also play an important role in
      the observed increase in Complex I-III activity.

PMID- 10395078
TI  - Long term feeding effects of heated and fried oils on lipids and lipoproteins in
      rats.
AB  - Long term feeding effects (20 weeks) of heated and fried oils at 5 and 20% level
      in the diet on growth, plasma and tissue lipids were studied in rats. Three
      vegetable oils of widespread usage viz., peanut oil, sesame oil and coconut oil
      with varying saturation and unsaturation were chosen for the study. No
      significant difference in growth rate, feed efficiency ratio, and liver weights
      were observed. Higher plasma cholesterol levels were observed in heated oil fed
      group of rats compared to corresponding fried oil groups. Low levels of HDL-c and
      increased LDL-c and VLDL-c were noted in heated/fried oil groups. Significantly
      low levels (p < 0.001) of triglyceride were observed in heated/fried sesame oil
      group of rats. No significant change in phospholipid was observed in any of the
      groups. Significantly low levels of liver cholesterol and high triglyceride
      levels (at 20%) were observed in coconut oil group. The fatty acid composition of
      plasma and liver reflected the type of diet consumed. Although linoleic acid
      levels were quite low in some of the heated/fried oil groups the arachidonic acid
      levels were quite high indicating repair mechanism. The results of the study
      however do not present any deleterious effect on growth, plasma and tissue lipid
      profile of rats as the conditions employed for heating/frying were not too
      drastic and the oils were not heat abused.

PMID- 10395080
TI  - Effects of chloroperoxidase and hydrogen peroxide on the viabilities of
      Aspergillus flavus conidiospores.
AB  - The effects of chloroperoxidase [EC 1.1.1.10] and hydrogen peroxide on the
      viabilities of quiescent and germinating conidiospores of an aflatoxigenic
      fungus, Aspergillus flavus, were determined. Hydrogen peroxide was found
      moderately lethal and chloroperoxidase produced a 30-fold increase in the
      lethality of hydrogen peroxide to germinating conidia, which were 75-fold more
      susceptible to chloroperoxidase than were quiescent conidia. According to
      infrared examinations of fungal corpses, mortality occurred by oxidation rather
      than peroxidative chlorination.

PMID- 10395081
TI  - Reversible phosphorylation control of skeletal muscle pyruvate kinase and
      phosphofructokinase during estivation in the spadefoot toad, Scaphiopus couchii.
AB  - Both pyruvate kinase (PK) and phosphofructokinase (PFK) occur in two different
      forms, separable by isoelectric focusing (IEF), in skeletal muscle of the
      spadefoot toad Scaphiopus couchii. During estivation (aerobic dormancy) the
      proportions of the two forms changed compared with controls; in both cases the
      amount of enzyme in Peak I (pI = 5.3-5.4) decreased whereas activity in Peak II
      (isoelectric point = 6.2-6.4) increased. In vitro incubation of crude muscle
      extracts with 32P-ATP under conditions that promoted the activity of cAMP
      dependent protein kinase led to strong radiolabeling associated with Peak I, but
      not Peak II, and reverse phase HPLC confirmed that 32P was associated with the
      subunits of both PK and PFK found in Peak I. Specific radiolabeling of Peak I PK
      and PFK by protein kinase A was further confirmed using immunoprecipitation. In
      total, this information allowed identification of the Peaks I and II enzymes as
      the phosphorylated and dephosphorylated forms, respectively, and the effect of
      estivation was to increase the proportion of dephosphorylated PK and PFK in
      muscle. Analysis of the kinetic properties of partially purified PK and PFK
      revealed significant kinetic differences between the two forms of each enzyme.
      For PK, the Peak II (low phosphate) enzyme showed a 1.6-fold higher Km for
      phosphoenolpyruvate and a 2.4-fold higher Ka for fructose-1,6-bisphosphate than
      did the Peak I (high phosphate) form. These kinetic properties suggest that Peak
      II PK is the less active form, and coupled with the shift to predominantly the
      Peak II form during estivation (87% Peak II vs. 13% Peak I), are consistent with
      a suppression of PK activity in estivating muscle, as part of the overall
      metabolic rate depression of the estivating state. A similar shift to
      predominantly the Peak II, low phosphate, form of PFK (75% Peak II, 25% Peak I)
      in muscle of estivating animals is also consistent with metabolic suppression
      since phosphorylation of vertebrate skeletal muscle PFK is typically stimulated
      during exercise to enhance enzyme binding to myofibrils in active muscle. Peak II
      PFK also showed reduced sensitivity to inhibition by Mg:ATP (I50 50% higher)
      compared with the Peak I form suggesting that the enzyme in estivating muscle is
      less tightly regulated by cellular adenylate status than in awake toads. The data
      indicate that reversible phosphorylation control over the activity states of
      enzymes of intermediary metabolism is an important mechanism for regulating
      transitions between dormant and active states in estivating species.

PMID- 10395079
TI  - Mechanisms of resistance to pathogenesis in muscular dystrophies.
AB  - A mechanistic definition of the dystrophic process is proposed, and the effects
      of growth factors vs. down-regulation of growth are critically analyzed. A
      conceptual scheme is presented to illustrate the steps leading to pathology, and
      various compensatory systems which ameliorate the pathology are examined,
      particularly in regards to the mdv mouse which is resistant to the deficiency of
      dystrophin, the main protein product of the Duchenne and Becker muscular
      dystrophy (DMD/BMD) gene. These compensatory systems are analyzed in terms of the
      differential resistance of fiber types to pathogenesis. The generation of a
      stable population of maturationally arrested centronucleated fibers which express
      the mature adult myosin isoforms is proposed to be the main strategy of mdx
      muscle to minimize apoptosis. Physiological properties of these fibers, such as
      utrophin expression, and high mitochondrial and endoplasmic reticulum content,
      together with probable increased glycerophosphorylcholine concentrations and
      facile access to the vascular system, are hypothesized to be instrumental in
      their resistance to pathogenesis. It is proposed that the major element that
      determines the susceptibility of most human muscles to the dystrophic process is
      their inability to arrest the maturation of regenerated fibers at the
      centronucleated stage with a concomitant expression of the adult myosins.

PMID- 10395082
TI  - Vasopressin accelerates protein synthesis in neonatal rat cardiomyocytes.
AB  - Arginine vasopressin (AVP) has been shown to promote vascular smooth muscle cell
      hypertrophy and hyperplasia of fibroblasts. The present study examines the effect
      of AVP and endothelin-1 (ET-1) on protein, DNA, and RNA synthesis in primary
      cultures of serum deprived neonatal rat cardiomyocytes (RC) as assessed by
      changes in [3H] phenylalanine, [3H] thymidine, and [14C] uridine incorporation
      respectively. Both AVP and ET-1 evoked significant increases in protein synthesis
      in RC of 36 +/- 12% (p < 0.05) and 53 +/- 22% (p < 0.01) respectively. The
      stimulating action of AVP on [3H] phenylalanine incorporation was abolished by
      pretreatment with 2-nitro-4carboxyphenyl-N, N-diphenylcarbamate (NCDC), a
      phospholipase C (PLC) inhibitor. [14C] uridine incorporation was significantly
      higher in cells incubated with ET-1 (95 +/- 12%) but not AVP (9 +/- 11%). Neither
      AVP nor ET-1 significantly affected cell number or [3H]thymidine incorporation,
      suggesting a lack of a hyperplastic effect. AVP evoked an increase in [Ca2+]i
      levels (162 +/- 12 nmol/L from a basal value of 77 +/- 6 nmol/L) which was
      completely abolished by pretreatment with either NCDC or cyclopiazonic acid
      (sarcoplasmic reticulum (SR) Ca2+ pump inhibitor) but unaffected by ryanodine
      (ryanodine sensitive SR Ca2+ store depletor). Taken together, these data suggest
      that AVP, in a PLC dependent manner, both stimulates protein synthesis and
      augments [Ca2+]i release in RC from ryanodine insensitive (IP3 sensitive) Ca2+
      stores. Thus, AVP may promote cardiac hypertrophy via direct effects on
      cardiomyocyte protein synthesis secondary to IP3 mediated [Ca2+]i release.

PMID- 10395083
TI  - Induction of permeability transition in pancreatic mitochondria by cerulein in
      rats.
AB  - Hyperstimulation with cholecystokinin analogue cerulein induces a mild edematous
      pancreatitis in rats. There is evidence for a diminished energy metabolism of
      acinar cells in this experimental model. The aim of this study was to demonstrate
      permeability transition of the mitochondrial inner membrane as an early change in
      mitochondrial function and morphology. As functional parameters, the respiration
      and membrane potential of mitochondria isolated from control and cerulein-treated
      animals were measured, and changes in volume and morphology were investigated by
      swelling experiments and electron microscopy. Five hours after the first
      injection of cerulein, the leak respiration was nearly doubled and the resting
      membrane potential was decreased by about 17 mV. These alterations were reversed
      by extramitochondrial ADP or did not occur when cyclosporin A was added to the
      mitochondrial incubation. A considerable portion of the mitochondria isolated
      from cerulein-treated animals was swollen and showed dramatic changes in
      morphology such as a wrinkled outer membrane and the loss of a distinct cristae
      structure. These data provide evidence for the opening of the mitochondrial
      permeability transition pore at an early stage of cerulein induced pancreatitis.
      This suggests that the permeability transition is an initiating event for lysis
      of individual mitochondria and the initiation of apoptosis and/or necrosis, as
      had been shown to occur in this experimental model.

PMID- 10395084
TI  - Urokinase plasminogen activator induces human smooth muscle cell migration and
      proliferation via distinct receptor-dependent and proteolysis-dependent
      mechanisms.
AB  - In order to define the relative contribution of the proteolytic domain and the
      receptor-binding domain of urokinase plasminogen activator (uPA) toward its
      mitogenic properties we studied the effects of different uPA isoforms on
      migration and proliferation of human aortic smooth muscle cells (hSMC). The
      isoforms tested included native human glycosylated uPA, and two recombinant uPA
      forms, namely a recombinant uPA with wild type structure (r-uPA), and a uPA
      mutant in which the first 24 N-terminal amino acid residues of the receptor
      binding domain were replaced by 13 foreign amino acid residues (r-uPAmut). Cell
      migration was evaluated using a micro-Boyden chamber assay, and cell
      proliferation assessed by measurement of [3H]-thymidine incorporation into DNA.
      Competition binding studies on hSMC using 125I-r-uPA as ligand demonstrated that
      r-uPA and r-uPAmut exhibited equivalent displacement profiles. However, migration
      of hSMC was promoted by r-uPA and not by r-uPAmut. r-uPA-induced migration
      occurred at concentrations (half-maximally effective concentration of 2 nM)
      approximating the Kd for uPA-uPAR binding (1 nM). r-uPA-induced migration was not
      affected by the plasmin inhibitor aprotinin. In contrast to their differential
      chemotactic properties, uPA, r-uPA and r-uPAmut, which possess similar
      proteolytic activities, all stimulated [3H]-thymidine incorporation in hSMC.
      Since the [3H]-thymidine incorporation response to each isoform occurred at
      concentrations (> 50 nM) much higher than necessary for uPAR saturation by ligand
      (1 nM), this mitogenic response may be independent of binding to uPAR. [3H]
      thymidine incorporation responses to r-uPA and -uPAmut were sensitive to the
      plasmin inhibitor aprotinin, and uPA stimulated DNA synthesis was inhibited by
      plasminogen activator inhibitor. We conclude that hSMC migration in response to
      uPA depends upon on its binding to uPAR, whereas uPA-stimulated DNA synthesis in
      these cells requires proteolysis and plasmin generation.

PMID- 10395085
TI  - Regional heterogeneities in the production of uric acid from adenosine in the
      bivascularly perfused rat liver.
AB  - The heterogeneity of the liver parenchyma in relation to uric acid production
      from adenosine was investigated using the bivascularly perfused rat liver in the
      anterograde and retrograde modes. Adenosine was infused in livers from fed rats
      during 20 min at four different concentrations (20, 50, 100 and 200 microM)
      according to four experimental protocols as follows: (A) anterograde perfusion,
      with adenosine infusion into the portal vein; (B) anterograde perfusion, with
      adenosine in the hepatic artery, (C) retrograde perfusion, with adenosine in the
      hepatic vein; (D) retrograde perfusion, with adenosine in the hepatic artery.
      With protocols A, B, and D uric acid production from adenosine was always
      characterized by initial bursts followed by progressive decreases toward smaller
      steady-states. With protocol C the initial burst was present only when 200 microM
      adenosine was infused. The initial bursts in uric acid production were
      accompanied by simultaneous increases in the ratio of uric acid
      production/adenosine uptake rate. These initial bursts are thus representing
      increments in the production of uric acid that are not corresponded by similar
      increments in the metabolic uptake rates of adenosine. Global analysis of uric
      acid production revealed that the final steady-state rates were approximately
      equal for all infusion rates with protocols A, B and C, but smaller with protocol
      D. This difference, however, can be explained in terms of the differences in
      accessible cellular spaces, which are much smaller when protocol D is employed.
      When the analysis was performed in terms of the extra amounts of uric acid
      produced during the infusion of adenosine, where the initial bursts are also
      taken into account, different dose-response curves were found for each
      experimental protocol. These differences cannot be explained in terms of the
      accessible cell spaces and they are likely to reflect regional heterogeneities.
      From the various dose-response curves and from the known characteristics of the
      microcirculation of the rat liver it can be concluded that the initial bursts in
      uric acid production are generated in periportal hepatocytes. The reason for this
      heterogeneity could be related to the metabolic effects of adenosine, especially
      to oxygen uptake inhibition, which is likely to produce changes in the ATP/AMP
      ratios.

PMID- 10395086
TI  - The DHHC domain: a new highly conserved cysteine-rich motif.
AB  - A unique clone from a human pancreatic cDNA library was isolated and sequenced.
      Examination of the deduced polypeptide sequence of the clone showed a new form of
      cysteine-rich domain that included a region with the form of a Cys4 zinc-finger
      like metal binding site followed by a complex Cys-His region. Searches of the
      Swiss-Protein data bank found a similar 48-residue domain in fifteen open reading
      frames deduced from A. thaliana, C. elegans, S. cerevisiae and S. pombe genomic
      sequences. The high degree of conservation of this domain (13 absolutely
      conserved and 17 highly conserved positions) suggests that it has an important
      function in the cell, possibly related to protein-protein or protein-DNA
      interactions. The gene recognized by the clone is is localized to human
      chromosome 16, and is conserved in vertebrates. The 2 Kb message is expressed in
      various human fetal and adult tissues. An antibody made to a peptide sequence of
      the deduced protein showed reactivity in immunoblots of monkey lung and retinal
      subcellular fractions and immunohistochemically in late fetal mouse tissues and a
      limited number of adult mouse tissues, including pancreatic islets, Leydig cells
      of the testis, and the plexiform layers of the retina.

PMID- 10395087
TI  - Modulation of the low affinity Ca2+-binding sites of skeletal muscle and blood
      platelets Ca2+-ATPase by nordihydroguaiaretic acid.
AB  - The antioxidant nordihydroguaiaretic acid (NDGA) inhibited the different
      sarco/endoplasmic reticulum Ca2+-ATPase isoforms found in skeletal muscle and
      blood platelets. For the sarcoplasmic reticulum, but not for the blood platelets
      Ca2+-ATPase, the concentration of NDGA needed for half-maximal inhibition was
      found to vary depending on the substrate used and its concentration in the assay
      medium. The phosphorylation of the sarcoplasmic reticulum Ca2+-ATPase by ATP and
      by Pi were both inhibited by NDGA. In leaky vesicles, measurements of the ATP<-
      >Pi exchange showed that NDGA increases the affinity for Ca2+ of the E2
      conformation of the enzyme, which has low affinity for Ca2+. The effects of NDGA
      on the Ca2+-ATPase were not reverted by the reducing agent dithiothreitol nor by
      the lipid-soluble antioxidant butylated hydroxytoluene.

PMID- 10395088
TI  - A monoclonal antibody recognizing an epitope shared by receptors for growth
      hormone, prolactin, interleukin 2 and interleukin 6.
AB  - Monoclonal antibody (MAb) termed R7B4 was generated throughout the idiotypic-anti
      idiotypic network from mice immunized with human and bovine growth hormones (GH).
      The Ab was selected on the basis that it did not recognize human GH (hGH) neither
      insolubilized nor in solution but inhibited 125I-hGH binding to receptors from
      rat and rabbit liver and from Nb2-cell membranes. Since it inhibited Nb2-cell
      mitogenesis stimulated by hGH, prolactins or placental lactogens, MAb R7B4
      behaved as an antagonist of lactogenic hormones. Furthermore, the Ab impaired
      proliferative activity of interleukin 2 (IL-2) on Nb2 cells as well as growth of
      7TD1 cells, an interleukin 6 (IL-6) dependent hybridoma not expressing GH
      receptors. Biotin-labeled MAb R7B4 specifically bound to rat liver microsomes,
      and the Ab was able to recognize Nb2 and 7TD1-cell membranes as shown by flow
      cytometry experiments. However, MAb binding was not hampered by hGH, indicating
      that the Ab did not mimic GH binding site to receptors. Immunoblot assays
      indicated that rat and rabbit liver as well as Nb2-cells membrane antigens
      recognized by MAb R7B4 were similar to those revealed by a MAb directed to
      prolactin receptors. In addition, MAb R7B4 was able to detect two bands probably
      corresponding to the somatogenic receptor in rabbit liver microsomes as well as
      three different proteins in 7TD1-cells showing molecular weights similar to those
      of the IL-6 receptor complex. Results suggest that MAb R7B4 is directed to an
      epitope shared by receptors for lactogenic and somatogenic hormones, IL-2 and IL
      6. To our knowledge, these data are the first experimental evidence of the
      existence of structural similarity between some of the receptors grouped in the
      cytokine receptor superfamily.

PMID- 10395089
TI  - Identification of amino acids involved in the binding of hMIP-1 alpha to CC-CKR1,
      a MIP-1 alpha receptor found on neutrophils.
AB  - Human macrophage inflammatory protein-1alpha (hMIP-1alpha) and human macrophage
      inflammatory protein-1beta (hMIP-1beta) are chemokines involved in a diverse
      range of immunological effects. Both hMIP-1alpha and hMIP-1beta are involved in
      the activation of monocytes and THP-1 cells probably through a common
      receptor(s). However, only hMIP-1alpha can bind to neutrophils with high
      affinity, presumably through CC-CKR1 (CKR1). Since the structure of these two
      proteins is highly conserved, non-conserved amino acids must define the disparate
      binding patterns that these two proteins exhibit. Measurements of binding,
      chemotaxis and calcium influx conducted with hMIP-1alpha and hMIP-1beta chimeric
      proteins and mutants show that two amino acids (37K and 43L) are important in the
      binding and signaling of hMIP-1alpha through CKR1. Furthermore, we also show that
      mutations of the three charged amino acids at the C-terminus of hMIP-1alpha and
      hMIP-1beta (amino acids 61, 65 and 67), do not adversely affect the binding to
      THP-1 cells.

PMID- 10395090
TI  - Detection of hepatitis C virus RNA in the hearts of patients with hepatogenic
      cardiomyopathy.
AB  - We examined the Hepatitis C virus (HCV) genome in the myocardium and liver
      obtained at autopsy from seven patients with HCV-positive liver cirrhosis and
      hepatocellular carcinoma (HCC) by in situ hybridization and histopathological
      studies. The HCV virus genome was detected in the myocardium of one patient as
      well as in the liver in three out of seven patients. However, Epstein-Barr (EB)
      virus genome could not be detected in liver or myocardium. In the patient who
      showed positive reaction to HCV in myocardium, both serum HCV and Hepatitis B
      virus (HBV) antibodies were positive. It is unknown whether this was related to
      an immunological abnormality of the host or to an interaction between RNA and DNA
      viruses. In conclusion, we could identify the HCV genome in the myocardium of a
      patient with hepatogenic myocardosis.

PMID- 10395091
TI  - Characterization of learning and memory behaviors and the effects of metrifonate
      in the C57BL strain of mice.
AB  - In the near future, a number of transgenic mouse models with neuropathological
      characteristics of Alzheimer's disease are expected to become widely available.
      It will be important to characterize their behavior in models for learning and
      memory. As a first step, we have characterized normal, medial septal-lesioned and
      hippocampal-lesioned C57BL mice, in different behavioral tests, i.e., water maze
      spatial navigation, Y-maze and passive avoidance behavior. These experiments were
      complemented by an investigation of the effects of acute treatment with an
      acetylcholinesterase inhibitor, metrifonate, in these behavioral tests. Normal
      C75BL mice perform very well in the water maze and the Y-maze, but suboptimally
      in the passive avoidance task. Lesioning of the medial septum or the dorsal
      hippocampus clearly impaired the performance of the mice. In medial septal
      lesioned mice, metrifonate stimulated spatial navigation and alleviated the loss
      of activity in the Y-maze and passive avoidance. In hippocampal-lesioned mice,
      metrifonate had no effect on spatial navigation. It is concluded that C75BL mice
      are useful for testing in classical models for learning and memory, and that
      septohippocampal pathology is very likely to induce cognitive deficits in some of
      these models.

PMID- 10395092
TI  - 5-HT1A receptor antagonists neither potentiate nor inhibit the effects of
      fluoxetine and befloxatone in the forced swim test in rats.
AB  - Recent clinical data suggest that coadministration of pindolol with an
      antidepressant, particularly the 5-hydroxytryptamine (5-HT) reuptake inhibitor
      fluoxetine, can shorten the time to onset of clinical activity and increase the
      proportion of responders. We have examined the interaction of antidepressants
      with 5-HT1A receptors using the forced swim test in rats using both (+/-)
      pindolol and the selective 5-HT1A receptor antagonist WAY 100,635 (N-[2-[4-(2
      methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl) cyclohexanecarboxamide
      trihydrochloride) in combination with either fluoxetine or the selective
      monoamine oxidase-A inhibitor befloxatone. 8-Hydroxy-dipropylaminotetralin (8-OH
      DPAT; 0.125-1 mg/kg s.c.), used as a reference for 5-HT1A agonist activity,
      reduced immobility in the forced swim test and this effect was significantly
      antagonised by WAY 100,635. WAY 100,635 alone (0.01-0.1 mg/kg s.c.) was without
      effect, although a higher dose, 0.3 mg/kg s.c., had a nonsignificant tendency to
      increase immobility. In contrast, (+/-)-pindolol (1-16 mg/kg s.c.) significantly
      reduced immobility, but to a lesser extent than 8-OH-DPAT. As expected, the
      antidepressants fluoxetine (10-80 mg/kg p.o.) and befloxatone (0.03-1 mg/kg p.o.)
      dose-dependently reduced immobility time. When the antidepressants were combined
      with WAY 100,635 (0.1 mg/kg), WAY 100,635 either had no effect or, at relatively
      high doses, significantly reduced their activity in this test. Combination of the
      antidepressants with (+/-)-pindolol (2 or 4 mg/kg s.c.) failed to reveal a
      significant interaction. These results demonstrate that the anti-immobility
      effects of fluoxetine and befloxatone are neither facilitated nor antagonised by
      doses of WAY 100,635 that completely reverse the effects of 8-OH-DPAT.
      Furthermore, there was no evidence that coadministration of the antidepressants
      with (+/-)-pindolol was able to facilitate their antidepressant-like effects.
      Thus, whereas direct agonist activity at 5-HT1A receptors can modulate immobility
      in the forced swim test, this receptor subtype does not appear to play a major
      role in the antidepressant-like effects of fluoxetine or befloxatone under the
      conditions used in this study.

PMID- 10395094
TI  - Effects of cocaine on dopamine in subregions of the rat prefrontal cortex and
      their efferents to subterritories of the nucleus accumbens.
AB  - The present study sought to investigate the contributions of the ventral
      prelimbic/infralimbic cortices and shell subterritory of the nucleus accumbens as
      well as the dorsal prelimbic/anterior cingulate cortices and core subregion of
      the nucleus accumbens to the acute systemic effects of cocaine (20 mg/kg i.p.) on
      both locomotor activity and simultaneous dialysate dopamine levels using a dual
      probe microdialysis design. Basal dopamine levels were significantly higher in
      the ventral medial prefrontal cortex compared with the dorsal medial prefrontal
      cortex and higher concentrations of dopamine were also observed in the core of
      the nucleus accumbens compared with its shell counterpart. Cocaine produced a
      significant decrease in dopamine levels in both the ventral and dorsal medial
      prefrontal cortices. In contrast, cocaine significantly increased dialysate
      dopamine in the shell of the nucleus accumbens, whereas only a slight increase in
      dopamine was observed in the core subregion of the nucleus accumbens. A
      significant negative relationship between dopamine levels in the ventral and
      dorsal medial prefrontal cortices and dialysate dopamine concentrations in the
      shell and core of the nucleus accumbens was observed. Finally, in both the
      ventral and dorsal medial prefrontal cortices, the magnitude of the locomotor
      response to cocaine was inversely related to dialysate dopamine levels. In
      contrast, the magnitude of the locomotor response to cocaine became progressively
      larger as dopamine levels increased in the shell of the nucleus accumbens. These
      results show a dissociation in the pattern of dopamine release in subterritories
      of both the medial prefrontal cortex and nucleus accumbens in response to the
      acute systemic administration of cocaine.

PMID- 10395093
TI  - Effects of prolyl endopeptidase inhibitors and neuropeptides on delayed neuronal
      death in rats.
AB  - We investigated the effects of the prolyl endopeptidase inhibitors 1-[1
      (Benzyloxycarbonyl)-L-prolyl]prolinal (Z-Pro-Prolinal) and N-benzyloxycarbonyl
      thioprolyl-thioprolinal-dimethylaceta l (ZTTA) on delayed neuronal death induced
      by four-vessel-occlusion transient ischemia in rats. We also examined the effects
      of [pGlu4, Cyt6, ArgS]vasopressin (vasopressin-(4-9)) and thyrotropin-releasing
      hormone (TRH) on the delayed neuronal death. Furthermore, we investigated the
      role of vasopressin receptors in the effects of vasopressin and prolyl
      endopeptidase inhibitors. Z-Pro-Prolinal, vasopressin-(4-9) and TRH protected
      pyramidal cells in the CA1 subfield of the rat hippocampus from delayed neuronal
      death after 10-min ischemia. The effect of vasopressin-(4-9) was abolished by
      vasopressin receptor antagonists. The effect of Z-Pro-Prolinal was also abrogated
      by the antagonists. These results suggest that the neuroprotective effect of
      prolyl endopeptidase inhibitors is mediated by neuropeptides such as
      [Arg8]vasopressin and TRH, and indicate the involvement of vasopressin receptors
      in the neuroprotective effect of vasopressin-(4-9) and prolyl endopeptidase
      inhibitors.

PMID- 10395095
TI  - Aminoguanidine induces constrictive vascular remodeling and inhibits smooth
      muscle cell death after balloon injury.
AB  - We examined the effects of aminoguanidine, an inhibitor of inducible nitric oxide
      synthase, in the rat model of balloon injury. Arteries were assessed by
      histomorphometry, and vascular smooth muscle cell death and proliferation were
      examined 24 h and 14 days after balloon injury by in situ terminal
      deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) of
      fragmented DNA and expression of proliferating cell nuclear antigen,
      respectively. Aminoguanidine decreased the luminal area 14 days after balloon
      injury (0.19+/-0.04 mm2 vs. 0.35+/-0.02 mmr2; P < 0.005), and this effect was
      attributable to reduction of the total vessel area, i.e., constrictive vascular
      remodeling (0.42+/-0.03 mm2 vs. 0.55+/-0.03 mm2; P < 0.005). At 24 h after
      injury, the percentage of TUNEL-positive cells in the medial layer was reduced by
      aminoguanidine (2.0+/-1.0% vs. 17.3+/-5.4%; P < 0.05), and the percentage of
      proliferating cells was increased (18.4+/-5.5% vs. 4.9+/-2.2%; P < 0.05).
      Aminoguanidine did not influence the density of VSMC nuclei in the injured artery
      wall, systemic blood pressure or endothelium-dependent vasorelaxation. We
      conclude, that in the rat model of balloon injury, aminoguanidine induces luminal
      loss by constrictive vascular remodeling in association with reduced early VSMC
      death and increased proliferation.

PMID- 10395096
TI  - Delayed administration of ethyl eicosapentate improves local cerebral blood flow
      and metabolism without affecting infarct volumes in the rat focal ischemic model.
AB  - The objective of this study was to assess whether delayed administration of ethyl
      eicosapentate has a favorable effect on cerebral blood flow and metabolism in
      rats suffering from cerebral infarction. Adult male Sprague-Dawley rats weighing
      250-300 g were used. Left middle cerebral artery occlusion was induced for 2 h.
      After 24-h reperfusion, rats were treated with ethyl eicosapentate (100 mg kg(
      1); ethyl eicosapentate treated) or saline (saline treated) by gavage, once a day
      for 4 weeks. After 4 weeks, local cerebral blood flow and local cerebral glucose
      utilization were measured autoradiographically, and infarction size was measured.
      In the ischemic side, the local cerebral blood flow and local cerebral glucose
      utilization values in the parietal cortex and the lateral caudoputamen, which
      constituted the ischemic core, were equivalent to zero in both groups. The peri
      infarcted areas, i.e., the frontal cortex and medial caudoputamen, were
      significantly higher in the ethyl eicosapentate treated group than the saline
      treated group. In the non-ischemic side, ethyl eicosapentate treated group had a
      tendency to improve local cerebral blood flow and local cerebral glucose
      utilization values in a medial caudoputamen. These results suggest that ethyl
      eicosapentate treatment may be beneficial for maintaining cerebral circulation
      and metabolism except for infarction area after cerebral infarction.

PMID- 10395097
TI  - MCI-154, a Ca2+ sensitizer, increases survival in cardiomyopathic hamsters.
AB  - To assess the long-term efficacy of a Ca2+ sensitizer MCI-154, 6-[4-(4'
      pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate, on
      chronic heart failure, we studied the effects of the agent on the life span of
      cardiomyopathic hamsters of the BIO-14.6 strain. At approximately 150 days of
      age, 210 male hamsters were randomly divided into three groups: MCI-154 0.1 mg
      kg(-1), day(-1)(MCI-154-low), MCI-154 1 mg kg(-1) day(-1) (MCI-154-high), and
      control group. The median survival time in control, MCI-154-low and MCI-154-high
      groups was 227, 243 and 260 days after the start of treatment, respectively.
      Final survival rate at 284 days in control, MCI-154-low and MCI-154-high groups
      was 0, 17.1 and 38.6%, respectively. The cumulative survival times in the two MCI
      154 treated groups were significantly prolonged in comparison with that in the
      control group (P < 0.0001). Thus, the present study clearly showed that MCI-154
      prolonged the life span of cardiomyopathic hamsters, suggesting that long-term
      therapy with MCI-154 would be promising in the treatment of congestive heart
      failure.

PMID- 10395098
TI  - Superoxide anion and K+ channels mediate electrical stimulation-induced
      relaxation in the rat basilar artery.
AB  - Electrical field stimulation (a single pulse, 0.2 ms) caused a rapid relaxation
      of rat basilar artery segments precontracted with different agents, but not with
      30 mM KCl. This relaxation was not modified by endothelium removal, 10 microM
      tetrodotoxin, 1 microM propranolol, 1 microM atropine, 30 microM indomethacin, 10
      microM methylene blue, 100 microM N(G)-nitro-L-arginine methyl ester or 1 microM
      cimetidine but it was significantly reduced by 50 and 100 U/ml superoxide
      dismutase. Charybdotoxin (0.1 and 0.2 microM), a blocker of large-conductance
      Ca2+-activated K+ channels (BK(Ca)), decreased the relaxation elicited by
      electrical stimulation, whereas it was unaltered by 10 microM glibenclamide or 1
      microM apamin, blockers of ATP-sensitive (K(ATP)) or small-conductance K(Ca)
      channels, respectively. Thapsigargin (0.01 and 0.1 microM), an inhibitor of
      sarcoplasmic reticulum Ca2+-ATPase, increased the electrical stimulation-induced
      relaxation, which was nearly abolished by charybdotoxin. These results show that
      electrical stimulation induces endothelium-independent and non-neurogenic
      relaxations in the rat basilar artery. This response appears to involve
      generation of superoxide anion, increase of cytosolic free Ca2+ concentration and
      subsequent activation of BK(Ca) channels.

PMID- 10395099
TI  - The protective role of endogenous glutathione in carrageenan-induced pleurisy in
      the rat.
AB  - In the present study we investigated the protective role of endogenous
      glutathione, a known free radical scavenger, in rats subjected to carrageenan
      induced pleurisy. In vivo depletion of endogenous glutathione pools with L
      buthionine-(S,R)-sulfoximine (BSO, 1 g/kg for 24 h, intraperitoneally) enhances
      the carrageenan-induced degree of pleural exudation and polymorphonuclear
      leukocyte migration in rats subjected to carrageenan-induced pleurisy. Lung
      myeloperoxidase activity and lipid peroxidation were significantly increased in
      BSO pretreated rats. However, the inducible nitric oxide (NO) synthase in lung
      samples was unaffected by BSO pretreatment. Immunohistochemical analysis for
      nitrotyrosine revealed a positive staining in lungs from carrageenan-treated
      rats, which was massively enhanced by BSO pretreatment. Furthermore, in vivo BSO
      pretreatment significantly increased peroxynitrite formation as measured by the
      oxidation of the fluorescent dye dihydrorhodamine 123, enhanced the appearance of
      DNA damage, the decrease in mitochondrial respiration and partially decreased the
      cellular level of NAD+ in ex vivo macrophages harvested from the pleural cavity
      of rats subjected to carrageenan-induced pleurisy. In vivo treatment with
      exogenous glutathione (50 mg/kg i.p.) significantly reverts the effects of BSO
      and exerts anti-inflammatory effects. Thus, endogenous glutathione plays an
      important protective role against carrageenan-induced local inflammation.

PMID- 10395100
TI  - Insurmountable angiotensin AT1 receptor antagonists: the role of tight antagonist
      binding.
AB  - Angiotensin II increased the inositol phosphates production (EC50 = 3.4+/-0.7 nM)
      in Chinese hamster ovary (CHO) cells expressing the cloned human angiotensin AT1
      receptor (CHO-AT1 cells). Coincubation with angiotensin AT1 receptor antagonists
      produced parallel rightward shifts of the concentration-response curve without
      affecting the maximal response. The potency order is 2-ethoxy-1-[(2'-(1H-tetrazol
      5-yl)biphenyl-4-yl)methyl]-1H-benz imidazoline-7-carboxylic acid (candesartan) >
      2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]i midazole-5
      carboxylic acid (EXP3174) > 2-n-butyl-4-spirocyclopentane-1-[(2'-(1H-tetrazol-5
      yl)biphe nyl-4-yl)methyl]2-imidazolin-5-one (irbesartan)> of 2-n-butyl-4-chloro-5
      hydroxymethyl-1-(2'-(1H-tetrazol-5-yl)bipheny l-4-yl)methyl]imidazole (losartan).
      Additionally, preincubation with these antagonists depressed the maximal
      response, i.e., 95%, 70%, 30% of the control response for candesartan, EXP3174
      and irbesartan and not detectable for losartan. Increasing the antagonist
      concentration or prolonging the preincubation time did not affect this
      depression. Furthermore, these values remained constant for candesartan and
      EXP3174, when the angiotensin II incubation time varied between 1 and 5 min. Our
      data indicate that antagonist-receptor complexes are divided into a fast
      reversible/surmountable population and a tight binding/insurmountable population
      at the very onset of the incubation with angiotensin II.

PMID- 10395101
TI  - Molecular characterization of HLA class I in Colombians carrying HLA-A2: high
      allelic diversity and frequency of heterozygotes at the HLA-B locus.
AB  - Polymerase chain reaction using sequence-specific oligonucleotide probes (PCR
      SSOP) typing was used to analyze HLA class I A, B and C alleles in three
      different Colombian populations. Fifty-nine samples were from Hispano-American
      Mestizos living in the urban areas of Cali (referred to here as Aso population).
      Forty-four and thirty samples were from the African Black populations of Zacarias
      (Zac) and Punta Soldado (PS), respectively. Samples were selected for expression
      of HLA-A2 by monoclonal antibody staining and allele-specific hybridization, and
      their HLA-A2 subtype distribution has been reported previously. Although only a
      limited number of samples was analyzed, the data suggest the existence of a
      remarkable degree of HLA class I polymorphism in the populations studied, with
      representatives of most serological classes. Despite their common African origin,
      the populations Zac and PS, both resident in malaria endemic regions, showed some
      striking differences in allelic distribution for all three class I loci.
      Furthermore, the samples from Aso and PS, but not Zac, showed a low percentage of
      blank alleles at the HLA-B locus (0 and 0.4%, respectively), suggesting the
      possibility of a heterozygote advantage for HLA-B alleles in Colombian
      populations.

PMID- 10395102
TI  - Association of tumor necrosis factor receptor 2 (TNFR2) polymorphism with
      susceptibility to systemic lupus erythematosus.
AB  - Multiple genetic as well as environmental factors are considered to be involved
      in the development of systemic lupus erythematosus (SLE). A number of previous
      studies have suggested a possible role for tumor necrosis factor (TNF) in the
      pathogenesis of SLE. In addition, one of the candidate loci suggested by the
      genome-wide linkage analysis corresponds to the chromosomal position encompassing
      the TNF receptor 2 gene (TNFR2). The purpose of this study was to analyze the
      polymorphism of TNFR2 and its possible association with the susceptibility to
      SLE, using the case-control association analysis. Polymorphism screening of the
      exons containing previously reported nonsynonymous base substitutions was carried
      out by the polymerase chain reaction (PCR)-single strand conformation
      polymorphism (SSCP) method, using genomic DNA from 81 Japanese patients with SLE
      and 207 healthy individuals. Two alleles were present in exon 6, coding for
      methionine (196M) and arginine (196R) at position 196. 30 of 81 patients (37.0%)
      with SLE were positive for the 196R allele, which was significantly more frequent
      compared with 39 of 207 healthy individuals (18.8%) (chi2=10.6, df=l, P=0.001,
      odds ratio=2.53, 95% CI: 1.45-4.43). Genotype analysis revealed that the presence
      of one 196R allele was sufficient for rendering susceptibility. The association
      of 196R allele with SLE was independent from that of HLA-DRB1*1501. In
      conclusion, the TNFR2 196R allele was found to be significantly associated with
      the susceptibility to SLE in the Japanese population. Further population and
      functional studies will be of particular importance to establish TNFR2 as one of
      the susceptibility genes to SLE.

PMID- 10395103
TI  - Diversity of HLA-B17 alleles and haplotypes in East Asians and a novel Cw6 allele
      (Cw*0604) associated with B*5701.
AB  - The distribution of HLA-B17 alleles and their association with HLA-A, -C and 
      DRB1 alleles were investigated in seven East Asian populations Japanese, South
      Korean, Chinese-Korean, Man, Northern Han, Mongolian and Buryat populations). The
      B17 alleles were identified from genomic DNA using group-specific polymerase
      chain reaction (PCR) followed by hybridization with sequence-specific
      oligonucleotide probes (SSOP). In all of these East Asian populations, except
      Japanese and Chinese-Koreans, B*5701 was detected and strongly associated with
      A*0101, Cw*0602 and DRB1*0701. In contrast, B*5801 was detected in all the seven
      populations and strongly associated with A*3303, Cw*0302, DRB1*0301 and
      DRB1*1302. The A*3303-Cw*0302-B*5801-DRB1*1302 haplotype was observed in South
      Korean, Chinese-Korean, Buryat and Japanese populations, while A*3303-Cw*0302
      B*5801-DRB1*0301 was predominantly observed in the Mongolian population. A
      similar haplotype, A*0101-Cw*0302-B*5801-DRB1*1302, was observed in the Buryat
      population. A novel Cw6 allele, Cw*0604, was identified in the Man population.
      This Cw allele was observed on the haplotype A*0101-B*5701-DRB1*0701. Thus, we
      confirmed, at the sequence level, that the common haplotypes carrying B*5701 and
      B*5801 have been conserved and shared in East Asian populations.

PMID- 10395104
TI  - Single strand conformational polymorphism analysis of human CD1 genes in
      different ethnic groups.
AB  - CD1 molecules are able to present unusual antigens, lipids or glycolipids from
      mycobacterium cell walls to T lymphocytes. Previous studies have suggested that
      polymorphism of these genes is very limited, in contrast with classical major
      histocompatibility complex (MHC) antigen-presenting molecules. Our aim was to
      study possible allelic variations of exons 2 and 3, encoding for the alpha1 and
      alpha2 domains, respectively, of human CD1A, -B, -C and -D genes. We analyzed
      genomic samples of unrelated, healthy individuals from different ethnic
      background: 70 Caucasians from Europe, 33 Black Africans (13 from Tanzania and 20
      Zulus), 19 Caucasians from the Sahara and 44 Asian individuals. We have found
      CD1A to be a biallelic locus with a common allele which was present in the
      majority of the individuals studied. The second allele differed from the common
      one by a single-point mutation, resulting in a change of Cys to Trp at position
      52 in the alpha1 domain. This second allele was found in heterozygosis in 7 out
      of 70 Caucasians from Europe (allelic frequencies P=0.95 and q=0.05). In the
      Chinese population, we found the second allele present in heterozygosis in 19
      from the 44 individuals studied, and we also found 6 homozygous individuals for
      the second allele (allelic frequencies P=0.64 and q=0.35). In addition, we
      detected a synonymous mutation (C to T transition) in codon 34 of CD1C exon 2 in
      4 out of 20 Zulus and in 2 of the 13 Blacks from Tanzania.

PMID- 10395105
TI  - Intronic sequence motifs of HLA-DQB1 are shared between humans, apes and Old
      World monkeys, but a retroviral LTR element (DQLTR3) is human specific.
AB  - Long terminal repeats (LTRs) of the human endogenous retrovirus K (HERV-K) family
      have been found at several sites within the human genome, of which one is located
      in the vicinity of HLA-DQB1. Since this DQLTR3 is only present on some
      haplotypes, we performed a linkage analysis in 130 Caucasian families. In order
      to date the integration event we also investigated the presence of this DQLTR3 in
      apes and Old World monkeys. Additionally, we sequenced the adjacent region of
      DQLTR3-positive and -negative haplotypes in humans, apes and old world monkeys to
      elucidate their evolution. Linkage analysis revealed a differential integration
      of DQLTR3 on specific HLA-DQ haploypes: there was a high frequency of this LTR on
      haplotypes containing HLA-DQB1*0302 (0.96) and a moderate frequency on HLA
      DQB1*0402 (0.78), HLA-DQB1*0303 (0.44), HLA-DQB1*0502 (0.38) and HLA-DQB1*0301
      (0.35). HLA-DQB1*0201 (0.18), HLA-DQB1*0503 (0.15), HLA-DQB1*0603 (0.15), HLA
      DQB1*0602 (0.04), HLA-DQB1*0501 (0.03) and HLA-DQB1*0604 were rarely positive or
      devoid of DQLTR3. In apes and Old World primates there was no DQLTR3 rendering it
      a human specific insertion. Sequence analysis of the adjacent region showed two
      different motifs in humans corresponding to either presence or absence of DQLTR3.
      Two different motifs were observed within three sequences of Macaca mulatta: One
      motif is closely related to the sequence from Macaca nemestrina and Macaca
      fascicularis whereas the other sequence is more closely related with that of
      Papio papio and Cercopithecus aethiops. Therefore the analysis of retroviral
      elements as well as intronic sequences of MHC-DQB1 could help to clarify the
      evolution of this gene region as well the phylogenic relationship between humans,
      apes and Old World monkeys.

PMID- 10395106
TI  - Immunophenotypic characterization of human bone marrow endosteal cells.
AB  - In order to determine the relationship between bone marrow (bm) endosteal cells
      (EDC) and hemopoietic progenitors, we have analyzed the immunophenotype of EDC
      using various antibodies (Ab) against mesenchymal antigens. The Ab were applied
      on paraffin sections of normal bm (iliac crest, n=17; talus, n=1; phalanx, n=1),
      myeloregenerative bm (after chemotherapy), and hematologic disorders (acute
      myeloid leukemia (AML), n=8; chronic myeloid leukemia (CML), n=6; myelodysplastic
      syndromes (MDS), n=14; severe aplastic anemia (SAA), n=4; essential
      thrombocythemia (ET), n=2; idiopathic (primary) osteomyelo-fibrosis (IMF), n=1;
      polycythemia vera (PV), n=1). In normal bm, EDC were found to react with Ab
      against vimentin, tenascin, alpha-smooth muscle actin, osteocalcin, CD51, and
      CD56, but did not react with Ab against CD3, CD15, CD20, CD34, CD45, CD68, or
      CD117. An identical phenotype of EDC was found in AML, MDS, SAA, ET, IMF, PV,
      myeloregenerative bm, and peripheral bones lacking active hemopoiesis (talus,
      phalanx). In patients with CML, EDC reacted with Ab to CD51, but did not react
      with Ab to CD56. Based on their unique antigen profile, EDC were enriched from
      normal bm by enzyme digestion and cell sorting. However, these enriched cells
      (CD56+, CD45-, CD34-) did not give rise to hemopoietic cells under the culture
      conditions used, i.e. in the presence of the growth factors IGF-1, bFGF, SCF, IL
      3, and GM-CSF Together, our data do not support the hypothesis that EDC are
      totipotent mesenchymal progenitors giving rise to hemopoietic cells.

PMID- 10395107
TI  - A new beta 2 microglobulin mutation found in a melanoma tumor cell line.
AB  - Beta2 microglobulin mutations are an important mechanism for HLA class I total
      loss, (phenotype No. I) and have been described in colon carcinomas, melanomas
      and lymphomas. We describe a new beta2 microglobulin mutation detected in the
      melanoma cell line GR-34. The new mutation reported here was identified as a
      deletion of 4 bases (TTCT) in the highly repetitive sequence CTCTCTCTTTCT located
      in the leader sequence of the beta2 microglobulin gene at codon 15-16 of exon 1.
      The mutation produces a frameshift in the open reading frame sequence with the
      appearance of a stop codon at position 42. We also demonstrate that the second
      beta2 microglobulin gene is deleted. Comparisons with beta2 microglobulin
      mutations in other tumor cell lines suggest a mutation hot spot in exon 1.

PMID- 10395108
TI  - A null HLA-A*68 allele in a bone marrow donor.
AB  - The authors describe an A*68 allele present at the molecular level but not
      expressed at the cell surface. This non expression results from the deletion of
      one nucleotide in exon 1, which causes a shift of the reading frame leading to an
      early non-sense codon in the same exon.

PMID- 10395109
TI  - Biotinylation of class I MHC molecules abrogates recognition by W6/32 antibody.
AB  - W6/32 is one of the most common monoclonal antibodies (mAb) used to characterize
      human class I major histocompatibility complex (MHC) molecules. It recognizes a
      conformational epitope on the intact MHC molecule containing both beta2
      microglobulin (beta2-m) and the heavy chain. Labelling proteins by biotinylation
      is a very useful technique of for their detection, purification and analysis. A
      common method for biotinylating proteins is through the use of N
      hydroxysuccinimide (NHS) biotin or Sulfo-NHS-biotin where the free amino groups
      on the protein are used for coupling the biotin moiety. However, W6/32 was unable
      to effectively immunoprecipitate biotinylated human class I MHC molecules
      including the human non-classical HLA-G molecule. FACScan analysis confirmed that
      biotinylating human class I MHC and HLA-G molecules prevents the recognition of
      these molecule by W6/32. In contrast, the recognition by another conformation
      dependent monoclonal antibody, ME1, specific to HLA-B27 molecules, remained
      totally unaffected.

PMID- 10395110
TI  - HLA class II polymorphism in a Gabonese Banzabi population.
AB  - The HLA class II typing of 167 unrelated Gabonese individuals from the Banzabi
      ethnic group was assessed by polymerase chain reaction-restriction fragment
      length polymorphism (PCR-RFLP). The most frequent alleles at each locus were
      DRB1*1501-3 (0.31), DQA1*0102 (0.50), DQB1*0602 (0.42) and DPB1*0402 (0.29). The
      estimation of the haplotype frequencies as well as the observation of the
      segregation of several haplotypes using additional HLA typing of relatives,
      revealed that the three-locus haplotype DRB1*1501-3-DQA1*0102-DQB1*0602 was found
      at the highest frequency (0.31) among these individuals. This haplotype is not
      typically African and has already been described in Caucasians, but its presence
      at high frequency is exclusive to populations originating from Central Africa,
      and can thus be designated as a particular genetic marker of these populations.

PMID- 10395111
TI  - HLA-B*4703: sequence confirmation, serology and distribution.
AB  - This study has confirmed the nucleotide sequence of exons 2 and 3 of the B*4703
      allele, discovered by an unusual HLA-B47 and Bw6 serological pattern, in two
      subjects of Black/Japanese and Caribbean Black descent. Titration studies on 25
      HLA-B47 cross-reactive sera, stimulated by B13, B27, B44 and B60, and nine Bw6
      antisera/monoclonal antibodies, showed that the B*4703 product can be
      distinguished from the established HLA-B47 specificity. The phenotypes of these
      donors and an International Cell Exchange donor suggests an association between
      B*4703 and Cw*0701/ 06 in Black subjects. No examples of B*4703 (or B*4702) were
      found in 10,194 PCR-SSP HLA-A,B typed Welsh Bone Marrow Donor Registry panel
      members indicating a phenotype frequency of <0.0098% in this primarily Northern
      European Caucasoid population.

PMID- 10395112
TI  - Identification of an HLA-A11 serological variant and its characterization by
      sequencing based typing.
AB  - We have identified an HLA-A11 variant allele, A*1105, segregating in a Caucasoid
      family. The variant antigen expressed by this allele failed to cross-react with
      most Caucasoid anti-HLA-A11 antisera tested. Sequencing based typing has been
      used to characterize this new allele and this showed that it has a novel mutation
      at a polymorphic position (502) in exon 3. In comparison with A*1101, the
      mutation (A-->G) results in an amino acid change from positively-charged lysine
      to negative glutamate and this may explain the altered HLA-A11 serological
      profile exhibited by this antigen. The new allele was found in a patient with
      acute lymphoid leukaemia (ALL), her father and two siblings.

PMID- 10395113
TI  - Identification of a novel HLA-DQA1 allele (DQA1*0106) by sequence-based DQA1
      typing.
AB  - We report here a novel DQA1 allele (DQA1*0106) identified during sequence-based
      HLA-DQA1 typing. Polymerase chain reaction with proofreading pfu DNA polymerase
      and subsequent sequencing yielded identical results as that with Taq DNA
      polymerase. Molecular cloning and sequencing confirmed that the new DQA1 allele
      is identical to DQA1*01021/2 at exon 2 except for a single nucleotide
      substitution (ACT-->GCT), changing codon 44 from Thr to Ala. This is the first
      report of polymorphism at codon 44 of HLA-DQA1 alleles.

PMID- 10395114
TI  - Sequence of HLA-A*6808.
AB  - A novel HLA-A*68 allele was identified by reference strand conformation analysis
      of a DNA sample studied for the International Cell Exchange program. Direct
      sequencing of HLA-A locus PCR products confirmed the presence of A*6602 and an
      A*68 allele which differed from A*68011 by two nucleotides at positions 538 and
      539. The presence of this sequence motif in this allele which has been named
      A*6808 was verified by DNA sequencing of full-length A*6808 clones. No other
      coding differences between A*68011 and A*6808 were identified. The two nucleotide
      substitutions found in A*6808 effect an amino acid difference in the encoded
      protein at residue 156 within the peptide binding site which may evoke
      alloreactive immune response after HLA-A68 mismatched transplants.

PMID- 10395115
TI  - Characterization of a novel HLA-Cw*04 variant in a Laotian family: HLA-Cw*0406.
AB  - The sequence of a new HLA-Cw*04 allele has been identified in a Laotian family.
      This allele, designated Cw*0406, differs from Cw*0403 by a single nucleotide
      substitution at codon 156 (CGG-->CTG) in the alpha2 domain, leading to an amino
      acid change from Arginine to Leucine. Further screening by specific amplification
      of two ethnically different populations, i.e. French (n=150) and Lebanese
      (n=100), provided no case of Cw*406, suggesting that the distribution of this
      allele may be restricted.

PMID- 10395116
TI  - Regional drug information service.
AB  - BACKGROUND: Drug information centers (DICs) were established in Europe more than
      two decades ago. The majority of German DICs were created in the 90s. The
      regional University hospital-based DIC, which offers services to physicans, is
      now in operation for three and a half years . OBJECTIVE: To evaluate the types of
      enquiries received and the profile of the users of a drug information service.
      METHODS: The working procedure at a regional center in Dresden, Germany, is
      described. The topics for consultation (adverse reactions, pharmacokinetics,
      etc.) are presented, and the types of drugs involved are classified according to
      the Anatomical Therapeutic Chemical (ATC) classification. Users are grouped by
      medical specialty. Future plans for the DIC are discussed. RESULTS: A total of
      516 enquiries were received. Questions concerning therapeutic use (34%), adverse
      drug reactions (28%), pregnancy/lactation (16%), and pharmacokinetics/dosage
      (15%) were asked most frequently. Cardiovascular drugs (20%), systemic
      antiinfectives (19%) as well as drugs targeting the central nervous system (15%)
      and alimentation/metabolism (9%) were the predominant foci of enquiries. The
      major users of the DIC were internists (19%), general practitioners (19%),
      pediatricians (18%), and gynecologists (11%). CONCLUSIONS: The types of questions
      and users of this service were generally similar to those recorded at many other
      European DICs. The service has begun producing educational bulletins on drug
      related topics of clinical relevance.

PMID- 10395117
TI  - Limiting cefotaxime pediatric dosing to adult standards: a pharmacokinetic
      simulation study.
AB  - OBJECTIVE: The recommended cefotaxime dose of 50 mg/kg every six to eight hours
      for pediatric patients with a body weight greater than 20 kg exceeds the standard
      1-gram dose recommended for adult patients. This study estimated whether limiting
      the cefotaxime dose recommended for children with mild to moderate infections to
      a standard 1-gram dose would achieve serum concentrations and time above the
      MIC90 comparable to those in adults. METHODS: Serum concentration profiles were
      simulated from mean cefotaxime pharmacokinetic parameters that have been
      published for children and for adults using widely available spreadsheet
      software. The simulations employed an open, one-compartment, multiple-dose model
      and were calculated using a common commercial spreadsheet. The model was used to
      predict serum concentrations using dosage regimens of 1 g or 50 mg/kg
      administered every six or eight hours in pediatric patients of various weights
      with pediatric pharmacokinetic parameters and 1 g every six or eight hours for
      adult patients with adult pharmacokinetic parameters. The time that cefotaxime
      concentrations exceeded the MIC90 for pediatric pathogens was also calculated.
      RESULTS: The 50 mg/kg pediatric dosing regimens administered every 8 hours (q8h)
      or every 6 hours (q6h) consistently produced peak serum concentrations and area
      under the concentration versus time curve (AUC) values higher than those in
      adults. Serum concentrations and AUCs generated for the 1-gram regimens for
      various pediatric weight categories were also above those predicted in adults.
      The time above the MIC90 for pediatric patients was equivalent to or exceeded
      those of the adult simulations for all pathogens. CONCLUSIONS: The results
      support the concept of limiting cefotaxime dosage regimens to 1 g administered
      every 6 or 8 hours for mild to moderate infections in children weighing more than
      20 kg. This dosage regimen could lead to dose standardization procedures, which
      could produce reductions in drug costs associated with individualized dosage
      preparation.

PMID- 10395118
TI  - A limited sampling approach in bioequivalence studies: application to long half
      life drugs and replicate design studies.
AB  - OBJECTIVES: The objectives of this study was to develop a limited sampling model
      (LSM) to predict the area under the curve (AUC) and the maximum plasma
      concentration (Cmax) for the assessment of bioequivalence studies. METHODS: Two
      drugs (A and B) were selected for this purpose. Drug A was chosen to test
      bioequivalence of two formulations with a long half-life (> 35 hours), whereas
      drug B was chosen to test the bioequivalence of two formulations (half-life = 12
      hrs) with a replicate design study. The LSM for both drugs was developed using 5
      blood samples each from 15 healthy subjects. The relationship between plasma
      concentration (independent variable) at selected time points with the AUC or Cmax
      (dependent variable) was evaluated by multiple linear regression analysis. The
      multiple linear regression which gave the best correlation coefficient (r) for 5
      sampling time vs AUC or Cmax was chosen as the LSM. The predicted AUC and Cmax
      from the LSM were then used to assess bioequivalence of two different
      formulations of each drug following a single oral dose. RESULTS: The model
      provided good estimates of both AUC and Cmax for both drugs. The 90% confidence
      intervals on log-transformed observed and predicted AUC and Cmax were comparable
      for both drugs. CONCLUSIONS: The method described here may be used to estimate
      AUC and Cmax for bioequivalence studies for drugs with long half-lives or for
      highly variable drugs which may require replicate design studies without detailed
      blood sampling.

PMID- 10395119
TI  - Average bioequivalence of two oral formulations of fluconazole in healthy
      subjects after multiple dosing.
AB  - OBJECTIVES: To assess the average bioequivalence of two oral dosage forms of
      fluconazole--test (Fungolon, Antibiotic Co.) and reference (Diflucan, Pfizer)--in
      18 healthy volunteers in a multiple dose-balanced, two-period, crossover study
      design. MATERIALS AND METHODS: The dosage regimen consisted of seven days
      treatment (first day 100 mg and 50 mg thereafter for six days given orally) and a
      washout period of two weeks between different treatments. Plasma samples were
      taken at regular time intervals according to the study protocol for measuring of
      plasma fluconazole concentrations. The primary and secondary parameters AUC(168
      192), Cav, %PTF, Cmax, %Swing, %AUCF, 100 Cmax/AUC, T above Cav, and Tmax were
      estimated. RESULTS: The point estimates--geometric means of the ratios test
      (T)/reference (R) and the 90% confidence intervals (CI) for the ratios of
      expected medians (T)/(R), assuming a multiplicative model, estimated by
      parametric and nonparametric analysis--were in the defined ranges for accepting
      of bioequivalence for two of the primary metrics. The point estimates and the 90%
      CIs after parametric analysis of AUC(168-192) were 1.00 (0.98-1.02) and for the
      metric %PTF exceeded the accepted range for bioequivalence after parametric
      analysis the point estimate and 90% CI were 0.93 and (0.799-1.08). CONCLUSION:
      The two preparations were considered to be bioequivalent in the rate and extent
      of absorption with significant variability across subjects.

PMID- 10395120
TI  - A new concept regarding the mechanism of action of omeprazole.
AB  - OBJECTIVES: In this paper we investigated in humans and in animals the in vitro
      and in vivo effect of omeprazole upon purified and erythrocyte carbonic anhydrase
      (CA) I and II isozymes, as well as on gastric mucosa CA IV. METHOD: In vitro, we
      observed the effect of omeprazole at concentrations between 10(-8)-10(-4) M on
      purified CA I and CA II, and also on isolated gastric mucosa CA IV, renal and
      pulmonary CA IV activity, using the dose-response relationship. In vivo, we
      studied the effect of omeprazole (Losec) on gastric CA I, II and IV, as well as
      on erythrocyte CA I and CA II, in humans and in animals. RESULTS: In vitro
      omeprazole inhibits pH-dependent purified CA I and CA II and gastric mucosa CA IV
      according to dose-response relationship. In vivo, the i.v. administration of
      omeprazole in rabbits and in humans shows a decrease of erythrocyte CA I and CA
      II activity as well as of gastric mucosa CA I, II and IV. CONCLUSIONS: Omeprazole
      in its active form (sulfenamide) selectively inhibits gastric mucosa CA IV and
      does not modify the activity of the same isozyme from the kidney and lung proving
      that the enzyme has an organ specificity. Our results lead to the conclusion that
      omeprazole possesses a dual mechanism of action: both H+K+ATPase and CA
      inhibition--enzymes that could be in a functional coupling. This dual mechanism
      of action might explain the higher effectiveness of treatment using substituted
      benzimidazole inhibitors compared to other therapies.

PMID- 10395121
TI  - Comparison of pharmacokinetics of clodronate after single and repeated doses.
AB  - OBJECTIVE: Pharmacokinetics of orally given clodronate disodium, a drug for the
      treatment of hypercalcemia and bone resorption, were studied after a single dose
      of 400, 800 and 1600 mg given randomly to 11 healthy volunteers in a crossover
      manner, in 7-14 hospitalized cancer patients given 400, 800 and 1600 mg twice
      daily, each dosage for one week, and during the customary therapy in 15
      additional cancer patients treated in hospital with 400 mg thrice daily for > or
      = 2 weeks. METHODS: Clodronate concentrations in serum and urine were measured by
      capillary gaschromatography with mass-selective detection. Pharmacokinetic
      parameters were calculated with a three-compartmental model. RESULTS: After a
      single oral dose to healthy volunteers the absolute clodronate concentrations
      increased almost dose-dependently. The mean cumulative excretion in urine was
      1.72-2.77% of the dose, an interindividual range being from 0.92% to 5.52%. With
      800 and 1600 mg twice daily for one week to cancer patients the serum drug
      concentrations increased almost progressively with increasing the dose. In cancer
      patients serum drug concentrations were clearly higher and renal drug clearances
      (mean 25-62 ml/min) lower than in healthy volunteers (mean 123-149 ml/min). The
      mean urinary excretions were 2.24-3.14% of the dose and interindividual ranges
      from 0.18% to 19.0%. During the routine cancer therapy with 400 mg thrice daily,
      the clodronate excretions in urine on two successive days were on an average
      3.26% (range 0.0-10.5%). CONCLUSIONS: Absolute concentrations in serum and
      excretions in urine of orally given clodronate increase dose-dependently, but
      during the maintenance therapy in hospitalized cancer patients the renal drug
      clearances seem to be lower than in healthy volunteers. This and the large
      interindividual variation in kinetics propose therapeutic monitoring of
      clodronate for optimizing the oral dose of the drug.

PMID- 10395122
TI  - Distribution of amiodarone in heart tissues following intrapericardial
      administration.
AB  - The distribution of amiodarone (A) in heart tissues of open chest anesthetized
      animals was studied at 20 and 60 min following the insertion of an isotonic
      solution of the drug into the pericardial sac (PS) in doses from 0.25 to 3 mg per
      kg body weight (BW) for pigs and after 60 min in doses of 3 to 6 mg for dogs.
      Most of the A absorbed by the myocardium was found in the subepicardium part of
      the left ventricular (LV) wall. For both species the percentage of drug absorbed
      by the myocardium was largely and inversely related to the dose given, while
      uptake by the atria was positively related to the dose and was higher than that
      in the subepicardial LV wall. Sixty minutes after i.v. administration of A (3.0
      mg per kg BW) the drug was evenly distributed across the LV wall (16 microg per g
      wet tissue), which was significantly lower (p < 0.02) than that of subepicardal
      LV wall (30 microg) after intrapericardial (IP) administration. This study shows
      that satisfactory drug concentrations in predicted and specific distribution in
      the heart tissue were derived shortly after intrapericardial administration
      without measurable circulation in the blood.

PMID- 10395123
TI  - Fixed drug eruption in hands caused by omeprazole.
AB  - OBJECTIVE: Omeprazole is one of the most widely prescribed gastric antisecretory
      drugs. It is generally well tolerated and significant adverse reactions occur
      rarely. The objective of this report is to describe a case of fixed drug eruption
      that occurred during omeprazole treatment. CASE REPORT: A 37-year-old white
      female patient admitted with epigastric pain and heartburn symptoms. An upper
      gastrointestinal endoscopy revealed reflux esophagitis and the patient was given
      20 mg b.i.d. omeprazole. She developed dark-red coloration on her hands, at the
      fourth day of treatment, which has been defined as fixed drug eruption. These
      lesions were attributed to treatment and recurred soon after a rechallenge with
      omeprazole. CONCLUSION: Fixed drug eruption is associated with many drugs but
      this is the first such report with omeprazole. We suggest being aware of such
      reactions during omeprazole usage.

PMID- 10395124
TI  - Pharmacokinetic aspects of second-generation H1 antihistamines: a reply to
      Philpot.

PMID- 10395125
TI  - Reversible fulminant hepatitis following intravenous amiodarone loading.
      Amiodarone hepatotoxicity.

PMID- 10395126
TI  - Applications of musculoskeletal sonography.
AB  - To successfully examine the musculoskeletal system sonographically, one must
      understand the normal musculoskeletal anatomy and function and be aware of the
      abnormal processes that affect the musculoskeletal structures. The goal of this
      review article is to provide a systematic approach to sonographic examination of
      the musculoskeletal system. The general sonographic appearances of normal and
      abnormal muscles, tendons, ligaments, bursae, and nerves are reviewed. The
      article then applies this general information to specific clinical applications
      by reviewing the normal anatomy of and specific pathologic conditions that affect
      the shoulder, elbow, hand, wrist, hip, knee, ankle, and foot.

PMID- 10395127
TI  - Quantitative assessment of power Doppler mapping in the detection of renal
      allograft complications.
AB  - PURPOSE: We evaluated the usefulness of power Doppler (PD) imaging with a
      quantitative parameter in the identification of renal transplant complications.
      METHODS: One hundred eight transplanted kidneys were subjected to PD
      examinations. The blood flow area ratio (BFAR), defined as the percentage of the
      area of color pixels within a given cross-sectional area placed over a region of
      a transplanted kidney, was measured using built-in color histogram software and
      used as a quantitative parameter for evaluating the status of allograft blood
      perfusion. The mean BFARs in the normal, acute rejection (AR), acute tubular
      necrosis (ATN), chronic rejection (CR), and cytomegalovirus infection (CMV)
      groups were compared. RESULTS: The BFAR in the normal group tended to decrease
      gradually with the time interval since transplantation, but the mean value,
      0.68+/-0.08, was significantly higher than that in the complication groups: AR,
      0.43+/-0.18; ATN, 0.43+/-0.14; CR, 0.15+/-0.14; and CMV, 0.36+/-0.10 (p < 0.01
      for all). When a BFAR of 0.60 or greater was used as the diagnostic criterion for
      normal allografts, a sensitivity, specificity, and accuracy of more than 90%
      could be achieved in the diagnosis of complications. However, owing to
      overlapping BFARs among the complication groups, the BFAR alone had a limited
      ability to differentiate the types of complications. CONCLUSIONS: Although PD
      imaging has some limitations in identifying the nature of renal allograft
      complications, the use of the quantitative parameter BFAR in the PD assessment of
      renal allografts may be useful in detecting complications. Further studies are
      needed to explore the BFAR's clinical value.

PMID- 10395128
TI  - Sonography: a useful tool to detect the mechanical causes of renal transplant
      dysfunction.
AB  - PURPOSE: The purpose of this study was to evaluate the utility of sonography in
      distinguishing between mechanical and nonmechanical causes for renal transplant
      dysfunction. METHODS: We reviewed all ultrasound examination reports (n = 286)
      for 63 consecutive patients who received 64 renal transplants. We assessed the
      sensitivity and specificity of different degrees of hydronephrosis (mild,
      moderate, or severe) in detecting urinary tract obstruction; different volumes of
      new or increasing peritransplant fluid in detecting urine leaks; different total
      volumes of peritransplant fluid in predicting significant compression of the
      transplant; and Doppler vascular criteria for predicting arterial and venous
      occlusion. RESULTS: All mechanical complications were detected (100% sensitivity)
      with specificities of 91.9% for ureteral obstruction (criterion, moderate
      hydronephrosis), 83.4% for urine leaks (criterion, any new fluid or any
      increase), 91.4% for fluid collections that compressed the transplant (criterion,
      > 100 ml), and 100% for vascular occlusion (criteria, no flow for arterial
      occlusion; no venous flow and reversal of arterial flow during diastole for
      venous occlusion). CONCLUSIONS: Sonography is very useful in distinguishing
      between mechanical and nonmechanical causes for renal transplant dysfunction. It
      has high sensitivity and acceptable specificity in this setting.

PMID- 10395129
TI  - Sonographically detected subacromial/subdeltoid bursal effusion and biceps tendon
      sheath fluid: reliable signs of rotator cuff tear?
AB  - PURPOSE: Our purpose was to determine the association between sonographically
      detected subacromial/subdeltoid (SA/SD) bursal and biceps tendon sheath effusions
      and arthrographically proven rotator cuff tears. METHODS: Shoulder sonography
      reports and sonograms of 105 shoulders in 102 patients who also underwent
      arthrography were retrospectively reviewed for the presence of fluid within the
      biceps tendon sheath and SA/SD bursa. Reports and sonograms for 151 asymptomatic
      shoulders were also reviewed. RESULTS: Biceps tendon sheath effusion and/or
      bursal fluid were detected in 50 (48%) of 105 shoulders. Fifty-one patients had
      rotator cuff tears; 28 of them had effusions at 1 or both sites. The sensitivity,
      specificity, and positive predictive value (PPV) of biceps tendon sheath
      effusions for diagnosing rotator cuff tear were 35%, 74%, and 56%, respectively.
      For SA/SD bursal effusions, the sensitivity, specificity, and PPV were 8%, 94%,
      and 57%, respectively. For combined biceps tendon sheath and bursal effusions,
      the sensitivity, specificity, and PPV were 12%, 91%, and 54%, respectively. There
      was no statistically significant association between rotator cuff tears and
      effusions in the biceps tendon sheath, SA/SD bursa, or both. Among the 151
      asymptomatic shoulders, 12 (7.9%) had biceps tendon sheath fluid, 5 (3.3%) had
      SA/SD bursal effusion, and 2 (1.3%) had both biceps tendon sheath and bursal
      effusions. CONCLUSIONS: The sonographic detection of intraarticular fluid, SA/SD
      bursal fluid, or both has a low sensitivity and PPV in the diagnosis of rotator
      cuff tears. Isolated intra-articular and/or SA/SD bursal effusions are not
      reliable signs of rotator cuff tear.

PMID- 10395130
TI  - Sonographic evaluation of umbilical cord insertion with umbilical coiling index.
AB  - PURPOSE: The aim of this study was to investigate the association between
      umbilical cord hypocoiling and abnormal placental insertion of the umbilical
      cord. METHODS: Umbilical coiling was measured by sonography in 253 pregnant women
      in their second or third trimester. An umbilical coiling index, defined here as
      the reciprocal of the length of 1 umbilical vascular coil, of less than 0.1 was
      considered hypocoiled. The distance from the placental edge to the insertion of
      the umbilical cord was measured after delivery, and the results were used to
      classify cord insertion as normal, marginal, or velamentous. RESULTS: Cord
      insertion was abnormal in 66.7% of the fetuses with umbilical hypocoiling but in
      only 1.3% of those whose coiling index was > or = 0.1 (p < 0.05). CONCLUSIONS:
      Hypocoiling of the umbilical cord was highly associated with abnormal cord
      insertion. The presence of a hypocoiled umbilical cord may indicate the presence
      of abnormal cord insertion and thus may be useful for obstetric management.

PMID- 10395131
TI  - Testicular plasmacytoma: appearance on gray-scale and power Doppler sonography.
AB  - A case of testicular plasmacytoma, a very rare neoplasm, is presented. The gray
      scale and power Doppler sonographic findings are illustrated. The lesion appeared
      as a hypoechoic, intratesticular mass that was markedly hypervascular. When
      marked hypervascularity is present in a testicular mass in a patient unlikely to
      have orchitis on clinical grounds, plasmacytoma should be considered in the
      differential diagnosis.

PMID- 10395132
TI  - Endoscopic sonography in the diagnosis of xanthogranulomatous cholecystitis.
AB  - Xanthogranulomatous cholecystitis (XGC) is an unusual inflammatory disease of the
      gallbladder that may simulate gallbladder cancer. We report the findings with
      conventional sonography, endoscopic sonography (EUS), and CT in 3 cases of XGC.
      EUS could visualize hyperechoic nodules in the gallbladder wall, probably
      representing xanthogranulomas, but loss of the multilayered structure of the
      gallbladder wall and infiltration into adjacent organs make differentiating XGC
      from gallbladder cancer difficult with EUS alone.

PMID- 10395133
TI  - Cystic lymphangioma of the breast.
AB  - Cystic lymphangioma of the breast is a rare benign lymphatic tumor. We report
      sonographic and mammographic findings in an unusual case in a 36-year-old woman.

PMID- 10395134
TI  - Asymptomatic ureteral varices: detection by Doppler sonography.
AB  - Retroperitoneal ectatic or varicose veins may cause ureteral extrinsic pressure
      defects. Doppler sonography may be helpful in the characterization of these
      vascular lesions. We report the sonographic findings in a case of asymptomatic
      idiopathic left ureteral varices.

PMID- 10395135
TI  - Prenatal collapse of cysts in a dysplastic kidney.
AB  - Postnatal regression of prenatally or neonatally detected multicystic dysplastic
      kidney disease has been widely documented. However, renal cysts can regress
      during gestation, although they usually become larger in utero. We present a case
      of prenatally detected multicystic dysplastic kidney with an atypical course.
      During the third trimester, unilateral multicystic renal lesions in the fetus
      first enlarged and later involuted; by the second postpartum year, the kidney had
      become hypoplastic and nonfunctional. Our case also shows that before birth,
      blood flow in the affected kidney, measured with Doppler imaging, was normal
      until the cysts involuted.

PMID- 10395136
TI  - Temporally overlapping nosocomial outbreaks of Serratia marcescens infections: an
      unexpected result revealed by pulsed-field gel electrophoresis.

PMID- 10395137
TI  - Another disinfectant for enterococci.

PMID- 10395138
TI  - Infection control practices of general dental practitioners.

PMID- 10395139
TI  - Impact of nosocomial infections on outcome: myths and evidence.

PMID- 10395140
TI  - Attributable morbidity and mortality of catheter-related septicemia in critically
      ill patients: a matched, risk-adjusted, cohort study.
AB  - OBJECTIVE: To determine the attributable risk of death due to catheter-related
      septicemia (CRS) in critically ill patients when taking into account severity of
      illness during the intensive-care unit (ICU) stay but before CRS. DESIGN:
      Pairwise-matched (1:2) exposed-unexposed study. SETTING: 10-bed medical-surgical
      ICU and an 18-bed medical ICU. PATIENTS: Patients admitted to either ICU between
      January 1, 1990, and December 31, 1995, were eligible. Exposed patients were
      defined as patients with CRS; unexposed controls were selected according to
      matching variables. METHODS: Matching variables were diagnosis at ICU admission,
      length of central catheterization before the infection, McCabe Score, Simplified
      Acute Physiologic Score (SAPS) II at admission, age, and gender. Severity scores
      (SAPS II, Organ System Failure Score, Organ Dysfunction and Infection Score, and
      Logistic Organ Dysfunction System) were calculated four times for each patient:
      the day of ICU admission, the day of CRS onset, and 3 and 7 days before CRS.
      Matching was successful for 38 exposed patients. Statistical analysis was based
      on nonparametric tests for epidemiological data and on Cox's models for the
      exposed-unexposed study, with adjustment on matching variables and prognostic
      factors of mortality. RESULTS: CRS complicated 1.17 per 100 ICU admissions during
      the study period. Twenty (53%) of the CRS cases were associated with septic
      shock. CRS was associated with a 28% increase in SAPS II. Crude ICU mortality
      rates from exposed and unexposed patients were 50% and 21%, respectively. CRS
      remained associated with mortality even when adjusted on other prognostic factors
      at ICU admission (relative risk [RR], 2.01; 95% confidence interval [CI95], 1.08
      3.73; P=.03). However, after adjustment on severity scores calculated between ICU
      admission and 1 week before CRS, the increased mortality was no longer
      significant (RR, 1.41; CI95, 0.76-2.61; P=.27). CONCLUSION: CRS is associated
      with subsequent morbidity and mortality in the ICU, even when adjusted on
      severity factors at ICU admission. However, after adjustment on severity factors
      during the ICU stay and before the event, there was only a trend toward CRS
      attributable mortality. The evolution of patient severity should be taken into
      account when evaluating excess mortality induced by nosocomial events in ICU
      patients.

PMID- 10395142
TI  - Nosocomial methicillin-resistant and methicillin-susceptible Staphylococcus
      aureus primary bacteremia: at what costs?
AB  - OBJECTIVE: To determine the attributable hospital stay and costs for nosocomial
      methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S.
      aureus (MRSA) primary bloodstream infections (BSIs). DESIGN: Pairwise-matched
      (1:1) nested case-control study. SETTING: University-based tertiary-care medical
      center. PATIENTS: Patients admitted between December 1993 and March 1995 were
      eligible. Cases were defined as patients with a primary nosocomial S. aureus BSI;
      controls were selected according to a priori matching criteria. MEASUREMENTS:
      Length of hospital stay and total and variable direct costs of hospitalization.
      RESULTS: The median hospital stay attributable to primary nosocomial MSSA BSI was
      4 days, compared with 12 days for MRSA (P=.023). Attributable median total cost
      for MSSA primary nosocomial BSIs was $9,661 versus $27,083 for MRSA nosocomial
      infections (P=.043). CONCLUSION: Nosocomial primary BSI due to S. aureus
      significantly prolongs the hospital stay. Primary nosocomial BSIs due to MRSA
      result in an approximate threefold increase in direct cost, compared with those
      due to MSSA.

PMID- 10395141
TI  - Risk assessment for surgical-site infections in orthopedic patients.
AB  - OBJECTIVE: To assess the relative importance of risk factors for surgical-site
      infections (SSIs) in orthopedic patients and thereby determine which risk factors
      to monitor in the national surveillance of SSI in The Netherlands. DESIGN:
      Reanalysis of data on SSI and associated risk factors from two surveillance
      projects on nosocomial infections, carried out in 1992 and 1993 in The
      Netherlands: Project Surveillance Nosocomial Infections in the region of Utrecht
      (PSZU) and the first Project Surveillance Surgical Wound Infections (SWIFT-1).
      Odds ratios (ORs) were calculated for age, gender, preoperative stay, and the
      number of operations. In addition, in PSZU, other nosocomial infections, and, in
      SWIFT-1, prophylactic antibiotics, acute surgery, and wound contamination were
      studied. PARTICIPANTS: The study was confined to hospitalized orthopedic patients
      (PSZU, 4,872; SWIFT-1, 6,437). RESULTS: In PSZU, the following ORs were
      significant in a multivariate model: age 0-44 years, 1.0; 45-64 years, 1.6; 65-74
      years, 4.7; and 75-99 years, 6.0. For a preoperative stay over 4 days, the OR was
      3.3 (95% confidence interval [CI95], 2.5-4.0), and for multiple surgery, 2.5
      (CI95, 1.9-3.0). For females, the OR was 0.8 (not significant). The same model
      applied to SWIFT-1 gave similar ORs. Adjustment for additional nosocomial
      infections (PSZU) decreased the ORs for ages over 65 years remarkably. The OR for
      additional nosocomial infections in patients under 65 years of age was 15.6
      (CI95, 4.3-57.4). Adjustment for prophylactic antibiotics, acute surgery, and
      wound-contamination class (SWIFT-1) did not influence the ORs of the original
      model, but showed that wound-contamination class was an important risk factor.
      CONCLUSIONS: Age, additional nosocomial infections, wound-contamination class,
      preoperative stay, and the number of operations were identified as important risk
      factors for SSI in Dutch orthopedic patients.

PMID- 10395143
TI  - A survey of methods used to detect nosocomial legionellosis among participants in
      the National Nosocomial Infections Surveillance System.
AB  - OBJECTIVE: To help define the scope of nosocomial legionnaire's disease (LD) and
      to assess use of recommended diagnostic methods and transmission control
      practices. METHODS: We surveyed 253 hospitals participating in the National
      Nosocomial Infections Surveillance (NNIS) System. The anonymous survey included
      questions about episodes of nosocomial LD, environmental sampling practices,
      maintenance of hospital water systems, and diagnostic techniques. RESULTS: Of 192
      hospitals that responded, 29% reported at least one episode of nosocomial LD from
      1990 through 1996, and 61% of these reported at least two episodes. Of 79
      hospitals with transplant programs, 42% reported nosocomial LD, compared with 20%
      of hospitals without transplant programs. Environmental sampling had been
      conducted by 55% of hospitals, including 79% of those reporting nosocomial LD.
      Legionella were isolated in 34% that sampled potable water and 19% that sampled
      cooling system reservoirs. Supplemental potable-water decontamination systems
      were installed in 20% of hospitals. Only 19% routinely performed testing for
      legionellosis among patients at high risk for nosocomial LD. CONCLUSIONS:
      Nosocomial LD is relatively common among NNIS hospitals, especially those
      performing organ transplants. Environmental sampling for Legionella is a common
      practice among NNIS hospitals, and Legionella often are isolated from sampled
      hospital cooling towers and hospital potable-water systems. Hospitals have
      responded to suspected nosocomial LD infection with a variety of water sampling
      and control strategies; some have not attempted to sample or decontaminate water
      systems despite identified transmission.

PMID- 10395144
TI  - Vancomycin use in a university medical center: effect of a vancomycin
      continuation form.
AB  - OBJECTIVE: To examine the impact of a new policy to ensure appropriate use of
      vancomycin in a 461-bed tertiary-care hospital. DESIGN: We instituted a policy
      that allowed physicians to prescribe vancomycin but that required them to
      complete a vancomycin continuation form and document that use conformed to
      Hospital Infection Control Practices Advisory Committee (HICPAC) guidelines if
      they wished to continue the drug beyond 72 hours. Vancomycin was stopped
      automatically at 72 hours if use was not consistent with guidelines, if an
      infectious diseases consultant did not approve the drug, or if the form was not
      completed. A pharmacist and infectious diseases specialist monitored use of
      vancomycin prospectively and interacted with prescribers when indicated.
      Educational efforts were limited to printing the HICPAC guidelines on the form
      and providing information about the policy in a newsletter. Patterns of
      prescribing and the economic impact of the form were evaluated over a 6-month
      period. RESULTS: Only 29% to 48% of vancomycin orders initially met HICPAC
      guidelines, but 77% to 96% of use was appropriate after 72 hours when the form
      was used. Inappropriate surgical prophylaxis, empirical therapy of intensive-care
      unit and transplant patients, and therapy for inadequately documented coagulase
      negative staphylococcal infections remained problems. Vancomycin use fell from a
      mean of 136 (+/-52) g/1,000 patient days in the 12 months before the form to 78
      (+/-22) g/1,000 patient days in the 9 months after institution of the form
      (P<.05). Net vancomycin acquisition costs and costs of ordering vancomycin serum
      levels fell by $357 and $19 per 1,000 patient days, respectively (P<.05). This
      represented annualized saving of approximately $47,000 in drug and monitoring
      costs. No adverse patient outcomes were seen as a result of the program.
      CONCLUSIONS: A vancomycin continuation form can decrease inappropriate vancomycin
      use and may save money. Additional educational efforts may be required to
      increase compliance with HICPAC guidelines during initial prescribing.

PMID- 10395145
TI  - Nosocomial tuberculosis exposure in an outpatient setting: evaluation of patients
      exposed to healthcare providers with tuberculosis.
AB  - OBJECTIVE: To evaluate the risk of tuberculosis (TB) transmission to patients
      potentially exposed to two healthcare providers who worked in outpatient settings
      for several weeks prior to being diagnosed with acid-fast bacilli smear-positive
      pulmonary TB. DESIGN: Potentially exposed patients were notified by letter and
      television reports of the recommended evaluation for TB infection or disease and
      availability of free screening at the hospital. Prevalence of infection in the
      screened patients and the incidence rate of TB over the subsequent 2 years were
      compared to those of a control group of unexposed outpatients. SETTING: An urban
      inner-city hospital. PATIENTS: 1,905 patients with potential exposure to the ill
      healthcare workers; 487 (25%) presented for evaluation. Controls consisted of 951
      unexposed patients. RESULTS: 361 potentially exposed patients had their
      tuberculin test read; 97 (27%) had a purified protein derivative > or = 10 mm. In
      the comparison group, 148 (25%) of 600 with test readings had a > or = 10-mm
      reaction (risk ratio, 1.18; 95% confidence interval, 0.86-1.60). In multivariate
      analysis, male gender, non-white race, and older age were significantly
      associated with a positive tuberculin test; exposure was not. No TB cases were
      identified during screening. Two years after the exposure, 7 TB cases had been
      reported to the state registry among 1,905 potentially exposed patients (184
      cases/100,000 person-years) versus 4 cases in the comparison group of 951 (210
      cases/100,000 person-years). CONCLUSIONS: Evaluation of patients exposed to
      healthcare workers with TB disease in ambulatory settings of an inner-city
      hospital revealed no evidence of transmission of Mycobacterium tuberculosis due
      to the exposure.

PMID- 10395146
TI  - Treatment of a Legionella pneumophila-colonized water distribution system using
      copper-silver ionization and continuous chlorination.
AB  - The detection in April 1997 of a case of nosocomial legionellosis in our hospital
      led to the discovery that both our hot- and cold-water circuits were heavily
      colonized with Legionella pneumophila. Conventional methods for eradication of
      the organisms were unsuccessful, so a copper-silver (Cu-Ag) ionization system and
      a continuous chlorination system were installed. Five months later, the number of
      colonized sites decreased from an initial 58.3% to 16.7%.

PMID- 10395147
TI  - Effect of zidovudine postexposure prophylaxis on the development of HIV-specific
      cytotoxic T-lymphocyte responses in HIV-exposed healthcare workers.
AB  - We evaluated the effects of zidovudine postexposure prophylaxis (PEP) on the
      development of human immunodeficiency virus (HIV) envelope-specific cytotoxic T
      lymphocyte responses in 20 healthcare workers with occupational exposures to HIV.
      Seven healthcare workers were treated with zidovudine PEP. Only 1 of 7 treated,
      versus 6 of 13 not treated, developed an HIV envelope-specific cytotoxic T
      lymphocyte response. These data suggest that zidovudine abrogated HIV-specific
      cytotoxic T-lymphocyte responses. HIV-specific cytotoxic T-lymphocyte responses
      may be useful as a surrogate marker of HIV replication in the evaluation of new
      regimens for PEP of occupational HIV exposures.

PMID- 10395148
TI  - Occupational exposure and voluntary human immunodeficiency virus testing: a
      survey of Maryland hospitals.
AB  - A survey was conducted to estimate how often healthcare providers were exposed to
      patients' blood and the percentage of incidents in which patients agreed to human
      immunodeficiency virus (HIV) testing. Data from 38 hospitals with 53,508
      employees revealed 2,244 exposures. Of 1,732 requests for information regarding
      the HIV status of the source patient, only 77 (6%) resulted in the patient's
      refusal to consent to an HIV test.

PMID- 10395149
TI  - Monitoring rotavirus environmental contamination in a pediatric unit using
      polymerase chain reaction.
AB  - Rotavirus environmental contamination in a pediatric unit was investigated.
      Surfaces were swabbed, then viruses eluted, ultracentrifuged, and detected by
      polymerase chain reaction (PCR) amplification. Of 55 samples, 25 (46%) tested
      positive. Rotavirus RNA was more prevalent on surfaces in direct contact with
      children (thermometers and play mats) than on other environmental surfaces
      (washbasins, door handles, etc). PCR has proved useful for monitoring rotavirus
      environmental contamination.

PMID- 10395150
TI  - Evaluation of a disinfection procedure for hysteroscopes contaminated by
      hepatitis C virus.
AB  - We assessed the ability of a standard disinfection procedure to eliminate
      hepatitis C virus (HCV) from the air-water channel of hysteroscopes. The residual
      HCV RNA remaining after the disinfection procedure was measured by polymerase
      chain reaction. When correctly applied to hysteroscopes, the standard
      disinfection procedure was sufficient to eliminate the risk of HCV transmission.

PMID- 10395151
TI  - Perioperative antibiotic prophylaxis in Spanish hospitals: results of a
      questionnaire survey. Hospital Pharmacy Antimicrobial Prophylaxis Study Group.
AB  - A questionnaire survey was sent to a random sample of the Spanish network of
      National Health System public acute-care hospitals. Of responding institutions
      (representing 25% of Spanish hospital beds), nearly 75% had active surveillance
      programs for the prevention and control of surgical-site infections (SSIs), but
      only 20% performed postdischarge surveillance. Overall, perioperative antibiotic
      prophylaxis (PAP) was used in 84% of all surgical procedures. For 77% of
      procedures, there were written guidelines for the choice and use of PAP.
      Cefazolin was the most commonly used antibiotic (38%). Duration of PAP was
      shorter than 24 hours in 75% of procedures, and only a single dose was given in
      52% of procedures. PAP was commonly used in breast (52%) and inguinal hernia
      repair (69%) procedures, as well as in laparoscopic abdominal surgery (86%). In
      summary, the use of PAP in Spanish hospitals is adequate, but improvements can be
      made in the frequency of prolonged PAP and in the use of broad-spectrum
      antibiotics. Surveillance systems for SSI, including postdischarge follow-up,
      also should be improved.

PMID- 10395152
TI  - Implementation of a practical antibiotic policy in the Czech Republic.
AB  - We describe the antibiotic control policy at the Faculty Hospital in Olomouc,
      Czech Republic. Practical examples of successful implementation of the policy are
      provided.

PMID- 10395153
TI  - Implementation of an interactive computer-assisted infection monitoring program
      at the bedside.
AB  - A new computer-assisted infection monitoring (CAI) software program has been
      developed for use in an intensive-care unit (ICU). By means of an interactive
      dialogue with physicians at the bedside, infection diagnoses and therapeutic
      decisions were recorded prospectively during a 3-month test period. By linking
      epidemiological data with information about therapeutic decisions, CAI could
      assess the quality of the therapeutic decisions. Antibiotics chosen empirically
      before the availability of any culture results, matched the antibiotic
      susceptibility patterns of the subsequently identified pathogens in 74% of the
      cases. Therapy chosen in collaboration with the computer after the pathogen was
      known, but before sensitivity results were available, corresponded with the
      eventual antibiograms of the microorganisms in 90% of the cases. Data analysis by
      CAI allowed us to assess critically the diagnostic and therapeutic habits in our
      ICU. Using the query-by-example method, CAI automatically calculated device
      associated infection rates.

PMID- 10395154
TI  - A retrospective investigation of an intensive outpatient substance abuse
      treatment program.
AB  - Outpatient treatment for chemical dependency has been found to be both clinically
      effective and cost efficient. The purpose of this retrospective investigation was
      to evaluate program completion data and variables related to attrition for an
      intensive outpatient substance abuse treatment program. Subjects were 488 clients
      enrolled in the Smithers Evening Rehabilitation Program between 1991 and 1995.
      Client drug preference was found to be an important factor related to treatment
      retention, with cocaine abusers having the highest attrition rates. In addition,
      increasing age was an advantage in predicting who would complete the initial
      phase of treatment. Implications for programmatic changes, clinical practice, and
      future research are considered.

PMID- 10395155
TI  - An efficient tool for screening for maladaptive family functioning in adolescent
      drug abusers: the Problem Oriented Screening Instrument for Teenagers.
AB  - The assessment of maladaptive family functioning among adolescent drug abusers is
      particularly important because maladaptive family functioning has been linked to
      adolescent drug abuse/delinquent behaviors, and there are now highly effective
      family interventions available for treating these family dysfunctions. The
      purpose of the study reported in this article was to investigate the degree to
      which the Problem Oriented Screening Instrument for Teenagers screen for the
      family domain provides useful information regarding family functioning when used
      with clinic-referred youths with behavior problems. Participants in this study
      were 135 Hispanic and African-American youth referred for the treatment of severe
      behavior problems, including drug use. Our findings provide support for the
      usefulness of the 11-item POSIT family functioning screen. Data supporting the
      criterion validity of the POSIT Family screen, its ability to classify families
      correctly in terms of their family functioning, and its significant loading on
      the latent variable resulting from a confirmatory factor analysis all lend
      support to the usefulness of this screen of family functioning. In addition,
      analyses designed to explore the relationships between gender and race/ethnicity
      and the POSIT Family subscale showed that differences in scores by gender and
      race/ethnicity are not unique to the POSIT, but rather reflect similar
      differences in family functioning reported by the adolescent on more extensive
      family measures.

PMID- 10395156
TI  - A cost-effectiveness and cost-benefit analysis of contingency contracting
      enhanced methadone detoxification treatment.
AB  - We examined treatment costs in an ongoing study in which 102 opioid-addicted
      patients had been randomly assigned to either 180-day methadone detoxification or
      the same treatment enhanced with contingency contracting. In the latter
      condition, study participants received regular reinforcers contingent on negative
      urine toxicology screens and breath analyses for a range of drugs and alcohol.
      Both conditions involved psychosocial treatment, and all participants were
      stabilized to a daily methadone dose of approximately 80 mg during the first 4
      months, followed by a 2-month taper. Individuals participating in the enhanced
      condition were more likely to provide continuously drug-free urine samples and
      alcohol-free breath samples during the final month of treatment than were
      participants in the control condition. Cost of treatment was calculated
      individually for each participant based on actual services received. First, unit
      cost for each service was determined, including adjusted staff salaries for
      direct treatment and opportunity cost of facilities utilized during service
      delivery. Next, we valued each patient's use of services during the first 120
      days of the study and then added the cost of methadone, laboratory work, and
      contingent reinforcers. A subsample (n = 45) also provided data on health care
      utilization during treatment, which we valued using standard Medicare unit costs.
      The marginal cost of enhancing the standard treatment with contingency
      contracting was approximately 8%. An incremental cost of $17.27 produced an
      additional 1% increase in the number of participants providing continuously
      substance-free urine and breath samples during month 4 of the study. For every
      additional dollar spent on treatment, a $4.87 health care cost offset was
      realized; however, this difference was statistically insignificant due to extreme
      variances and small subsample size.

PMID- 10395157
TI  - Family and peer correlates of behavioral self-regulation in boys at risk for
      substance abuse.
AB  - Behavioral self-regulation (BSR), defined herein as the degree to which one can
      control one's own activity and reactivity to environmental stimuli, has been
      posited to be salient to the onset of adolescent substance abuse. The goal of
      this study was to clarify particular family and peer correlates of BSR in at-risk
      sons. Subjects were 10-through 12-year-old sons of substance-abusing fathers
      (high-average risk [HAR]; n = 176) and normal controls (low-average risk [LAR]; n
      = 199). A BSR latent trait was developed using multiple measures and multiple
      informants. Analyses included separate hierarchical linear regressions for HAR
      and LAR groups. In the hierarchical linear model for HAR sons, family dysfunction
      and deviant peer affiliation were significantly associated with BSR, whereas for
      LAR sons, only peer affiliation was significantly associated with BSR. The above
      family and peer correlates differed in proportions of variance explained for BSR
      in HAR and LAR sons. These findings extend previous studies by showing that, in a
      hierarchical linear model, BSR in HAR sons is associated with specific
      interpersonal, family, and peer factors. These findings suggest that empirical,
      theory-guided interventions to prevent worsening of BSR in HAR boys should
      address specific interpersonal, family, and peer factors.

PMID- 10395158
TI  - Stress and substance use among military women and men.
AB  - This paper examines the relationship between perceived stress (at work, in family
      or personal life, and from being a woman in the military) and substance use
      (heavy drinking, illicit drug use, cigarette smoking) among active-duty military
      women and men. Data were drawn from over 16,000 respondents to the 1995
      Department of Defense Survey of Health Related Behaviors Among Military
      Personnel. Findings indicated substantial substance use and perceived high stress
      in the armed forces. Further, the relation between substance use and stress
      varied by gender. Military women reported substantially lower rates of heavy
      drinking than men, but had similar rates of illicit drug use and cigarette
      smoking. Both military women and men were more likely to describe their military
      duties as more stressful than their family or personal lives; for women, the
      stress associated with being a woman in the military was second to stress at
      work. Stress at work or in the family was an important predictor of substance use
      among military men, but not among military women. For military women, stress
      associated with being a woman in the military was predictive of illicit drug use
      and cigarette use. These findings suggest that more effective stress management
      strategies may need to be implemented for military men to reduce the link between
      stress and heavy alcohol use, illicit drug use, and smoking.

PMID- 10395159
TI  - Intimate violence and post-traumatic stress disorder among individuals with
      cocaine dependence.
AB  - Intimate physical assault and post-traumatic stress disorder (PTSD) were assessed
      in a sample of 91 adults seeking treatment for cocaine dependence. Physical
      assault included self-report of aggravated assault with a weapon, aggravated
      assault without a weapon, and simple assault. PTSD was assessed with a structured
      interview. Overall, 85.7% of the participants reported having been physically
      assaulted at least once during their lifetime. Slightly less than half of these
      individuals (46.2%) reported physical assault by an intimate partner. Close to
      half also met criteria for PTSD at some point in their lives. Women were more
      likely than men to be physically assaulted by an intimate partner and to report
      PTSD. Men who experienced physical assault by an intimate were more likely to
      report PTSD than men assaulted by others. Male victims of intimate violence had
      higher scores on certain subscales measuring addiction severity than male victims
      assaulted by others. Findings suggest careful assessment of intimate violence is
      essential given its high prevalence among cocaine-dependent women and men and its
      association with PTSD.

PMID- 10395160
TI  - HIV testing in substance abusers.
AB  - HIV testing among substance abusers in the United States is a significant public
      and individual health issue in need of further examination. We analyzed interview
      data gathered over 15 months in 1992 and 1993 from 2315 patients on presentation
      for addiction treatment to determine the frequency of and factors associated with
      previous HIV testing. Among this group of alcohol, heroin, and cocaine abusers,
      53% (1231) reported previous HIV testing. Although in bivariate and multivariable
      analyses those with identifiable risk factors for HIV were more likely to have
      been tested, 27% of injection drug users, 38% with multiple sexual partners, and
      39% of those with a history of a sexually transmitted disease (STD) had not been
      HIV tested. Other factors associated with previous HIV testing included having a
      primary care physician, the primary care physician's awareness of the patient's
      substance abuse problem, and having received prior addiction care. However, 38%
      of substance abusers who had previously received addiction treatment beyond
      detoxification had not been tested. Of those tested, 10% (n = 122) reported a
      positive test, and 7% (n = 81) had not received the test results. Of those with
      positive test results, 37% were not injection drug users. Promotion of HIV
      testing among alcohol and other drug abusers in both medical and substance abuse
      treatment settings should be a priority.

PMID- 10395161
TI  - Longitudinal changes in sexual risk behavior among HIV+ and HIV- male injecting
      drug users.
AB  - Injecting drug users (IDUs) play a prominent role in the transmission of human
      immunodeficiency virus (HIV), particularly in urban areas such as New York City,
      where they comprise nearly half of all adult acquired immunodeficiency syndrome
      (AIDS) cases. Intervention studies have demonstrated that IDUs are responsive to
      safer sex messages, but sexual behavior appears to be more resistant to change
      than drug use behavior. This multidisciplinary study (without an intervention
      component) assesses changes in sexual risk behavior as a function of time, HIV
      status, and disease progression in a cohort of HIV+ and HIV- male IDUs (N = 144)
      for 4 years. RESULTS: For HIV+ and HIV- men, there were increases in abstinence
      and monogamy, with decreases in the frequency of unprotected vaginal/anal sex and
      sexual risk index scores. With the exception of monogamy, HIV+ men reported lower
      levels of risk. Although there was also a decline in substance use, this
      accounted for only some of the decline in sexual risk behavior. Among the HIV+
      men, a CD4 level below 200 was associated with more abstinence and monogamy. HIV
      related medical symptoms were associated with increased abstinence, less
      unprotected sex, and lower sexual risk index scores. Lower neuropsychological
      memory test scores were associated with increased abstinence and lower sexual
      risk index scores. Neurological impairment and depression were not associated
      with sexual risk behavior. CONCLUSION: IDU men in New York City have modified
      their sexual behavior toward safer practices. Lower levels of risk are found
      among HIV+ men, particularly those with more progressed HIV illness.
      Nevertheless, a substantial amount of sexual risk behavior remained in this
      cohort, indicating the continued need for education and intervention.

PMID- 10395162
TI  - An exploratory analysis of women and men within a self-help, communal-living
      recovery setting: a new beginning in a new house.
AB  - In the present exploratory study, women without children (n = 13) and women with
      children (n = 23) were compared to men (n = 35) on demographic and self-reported
      variables on entering a communal-living, self-help recovery program called Oxford
      House. Men were more often hospitalized for their addiction than either group of
      women, and men and women with children were older and had been previously
      hospitalized longer for their addiction than women without children. There were
      no significant differences among groups in terms of their codependency on others,
      and men felt a stronger sense of camaraderie with other residents than women with
      or without children. Men and women with children also tended to feel they shared
      more in the decisions within their house than did women without children.
      Further, with partial correlates (controlling for the number of children), women
      with children indicated that the greater their self-reported codependency, the
      less accepting they were of their children and the more depressed they were about
      their parenting abilities. Dysfunctional characteristics of the children also
      were related to negative characteristics in the children reported by their
      mothers. In short, men and women with and without children entering an Oxford
      House have similar profiles, yet women with children have additional stressors
      associated with parental responsibilities.

PMID- 10395163
TI  - Subject-collateral reports of drinking in inpatient alcoholics with comorbid
      cocaine dependence.
AB  - Greater substance abuse severity has been associated with less reliable self
      reports of drinking in individuals with only an alcohol use disorder. In
      addition, individuals with multiple substance use disorders often report greater
      substance abuse severity. Therefore, it is important to be confident in the self
      reports of substance use in individuals with multiple substance use disorders.
      Although there is considerable confidence in the use of collateral reports as a
      measure of drinking in individuals with only a diagnosis of alcohol abuse or
      dependence, information about subject-collateral agreement for individuals who
      meet the criteria for more than one substance use disorder is lacking. In this
      study, we examined subject-collateral reports of substance abuse in individuals
      presenting for alcohol treatment who met DSM-III-R criteria for alcohol and
      cocaine use disorder (n = 85). We then compared subject-collateral reports of
      those individuals to subject-collateral reports for individuals with only a
      diagnosis of alcohol abuse or dependence (n = 99). Overall, the results
      demonstrate that self-reports of individuals with alcohol and cocaine use
      disorders are generally valid. The results revealed no significant differences
      between groups on measures of subject-collateral consistency for several alcohol
      use variables. However, a significant difference was found for the number of days
      of drug use, with subject-collateral agreement being greater for individuals with
      an alcohol and cocaine use disorder. Additional analyses revealed that subject
      collateral discrepancy scores were positively related to the participants'
      severity of alcohol and drug dependence. Recommendations for enhancing the
      accuracy of self-reports of drinking and drug use in alcoholics with comorbid
      cocaine use disorders are discussed.

PMID- 10395164
TI  - Drinking, binge drinking, and other drug use among southwestern undergraduates:
      three-year trends.
AB  - This study examined substance use patterns and consequences in college students
      over a three year period. Students were surveyed at a large, southwestern
      university, allowing for a diverse sample that included a large percentage of
      minority respondents. Students (total N = 2710) in 1994, 1995, and 1996 responded
      anonymously to the Core Survey of Alcohol and Drugs. Over 80% of students at each
      time point were current drinkers, and over one-third at each time period reported
      binge drinking. Binge drinking was associated with greater weekly drinking and
      with a range of negative consequences. Underage drinking was prevalent at all
      time points, and underage drinkers reported drinking in a range of on- and off
      campus situations. Hispanic students reported higher rates of binge drinking than
      other ethnic groups. Nonwhite, non-Hispanic students reported greater rates of
      abstinence than other students. Although other drug use was much less prevalent,
      drug use in combination with drinking was associated with more problematic
      patterns of drinking and more negative consequences. Results are discussed in
      terms of implications for interventions with college students.

PMID- 10395165
TI  - Occupational risk factors associated with alcohol and drug problems.
AB  - Ames and Janes provide a theoretical framework that explains alcohol and/or drug
      problems among workers. Existing studies of occupational risk factors for alcohol
      and drug problems across multiple occupations and industries provide mixed
      findings with respect to Ames and Janes' framework. In a preliminary study, the
      relationships between occupational characteristics and measures of alcohol and
      drug problems were investigated among a sample of workers from a variety of
      occupations and industry settings. Some support was found for all of the major
      elements of Ames and Janes' framework: normative regulation of drinking, quality
      and organization of work, workplace factors, and drinking subcultures.

PMID- 10395166
TI  - Inhalant abuse and the abuse of other drugs.
AB  - AIMS: To examine the relationship between inhalant abuse and other substances of
      abuse. DESIGN: Survey using a structured interview administered by a single
      trained interviewer. SETTING: A juvenile detention facility. PARTICIPANTS: 209
      children incarcerated at the facility over a 3-month period. SELECTION PROCEDURE:
      Consecutive sample. INTERVENTIONS: None. MEASUREMENTS/FINDINGS: The structured
      interview was adapted from the American Drug and Alcohol Survey, which has been
      extensively used to obtain substance abuse epidemiologic data. We collected
      information on inhalants, alcohol, marijuana, downers, pep pills, lysergic acid
      diethylamide (LSD), cocaine, designer drugs, phencyclidine (PCP), Talwin and
      Ritalin, speed, and narcotics. The chi-square or Fisher exact test were used when
      appropriate. Mean ages of initial experimentation were as follows: inhalants, 9.7
      years; marijuana, 11.9 years; alcohol (inebriated), 12.0 years; cigarettes, 11.2
      years; for the remaining substances of abuse, the mean age was 13.2-14.7 years.
      Thirty subjects had used inhalants. Significant relationships were found between
      inhalants and cocaine (p = .004), Talwin and Ritalin (p = .001), downers (p =
      .01), and narcotics (p = .003). CONCLUSIONS: For children incarcerated in a
      juvenile detention facility in our community, inhalant abuse is associated with
      the later use of other substances of abuse. If this finding is replicated in
      other populations, it underscores the need for effective preventive strategies.

PMID- 10395167
TI  - Neuropsychological deficits in withdrawn cocaine-dependent males.
AB  - Previous research suggests that cocaine abuse may result in neuropsychological
      deficits. To examine this further, we compared cocaine-withdrawn patients (N =
      35) to normal controls (N = 17) on tasks of attention, concentration, perceptual
      motor speed, and cognitive flexibility. The withdrawn cocaine patients performed
      significantly worse on Arithmetic, Grooved Peg Board Dominant and Non-Dominant,
      and Trails B tests. These findings suggest that withdrawn cocaine-dependent
      patients have more neuropsychological impairment than normal controls.

PMID- 10395168
TI  - Changes in the secretion of insulin-like growth factor binding proteins -2 and -4
      associated with the development of tamoxifen resistance and estrogen independence
      in human breast cancer cell lines.
AB  - We investigated the secretion of insulin-like growth factor binding proteins
      (IGFBPs) by estrogen-dependent ZR-75-1 and MCF-7 human breast cancer cells, and
      tamoxifen-resistant (ZR-75-9a1 and LY2) and estrogen-independent (ZR-PR-LT)
      variants which express altered levels of IGF-I receptor. IGFBP species (35 kDa
      and 44 kDa) were detectable in conditioned serum-free medium (SFM) by
      immunoblotting and positively identified as IGFBP-2 and -3, respectively.
      Secretion of IGFBP-2 into SFM by the tamoxifen-resistant and estrogen-independent
      cell lines was markedly reduced and secretion into SFM of the 24-kDa species,
      assigned the identity of IGFBP-4, was also reduced in the tamoxifen-resistant
      lines. There was no clear correlation between patterns of IGFBP secretion and IGF
      I receptor expression.

PMID- 10395169
TI  - Dimethylarsinic acid effects on DNA damage and oxidative stress related
      biochemical parameters in B6C3F1 mice.
AB  - Adult female B6C3F1 mice were given 720 mg/kg of DMA by oral gavage at one of
      three times (2 h, 15 h, or at both 21 and 4 h) before sacrifice. Significant (P <
      0.05) decreases in liver GSH and GSSG contents (15-37%) were observed. Some
      evidence of DMA-induced hepatic DNA damage (at the P < 0.10 level only) was
      observed. Pulmonary and hepatic ODC activities were reduced (19-59%) by DMA
      treatment. Overall, these biochemical studies show that mice are much less
      responsive to DMA than rats.

PMID- 10395170
TI  - Differential responses of staurosporine on protein kinase C activity and
      proliferation in two murine neuroblastoma cell lines.
AB  - We studied the effect of staurosporine (SSP), a broad-spectrum protein kinase
      inhibitor, on the levels of protein kinase C (PKC) activity and proliferation in
      two murine neuroblastoma cell lines, Neuro2a and its clone NB41A3. The PKC
      activity was examined in whole cell lysate, cytosolic and particulate fractions.
      A differential response to SSP treatment in the enzyme activity in whole cell
      lysate and particulate fractions was demonstrated in the two cell lines. The data
      on proliferation indicated that Neuro2a cells were more sensitive to the SSP
      treatment with significant inhibition in DNA synthesis in a time course study.
      Our findings suggest that the data on basal levels of PKC activity in tumors will
      be of significance in studies using PKC inhibitors as an approach for therapeutic
      intervention.

PMID- 10395171
TI  - A combination of dietary protein depletion and PHA-induced gut growth reduce the
      mass of a murine non-Hodgkin lymphoma.
AB  - The results presented in this study show that a switch from a non-protein diet
      (NPD) to one of a normal protein content (LA) on the day of subcutaneous
      injection of non-Hodgkin lymphoma tumour cells greatly favoured the development
      and growth of the tumour. Interestingly, however, inclusion of the plant lectin
      phytohaemagglutinin (PHA) in the LA diet appeared to compete with the effect of
      switch to the protein-rich diet, resulting in decreased tumour size and an
      increased incidence of necrosis. PHA was shown to induce hyperplasia of the gut
      even in the presence of the growing tumour. This observation together with the
      fact that gut hyperplasia also occurred in animals which were fed NPD
      supplemented with PHA, indicated the strength of PHA as a growth signal. It would
      seem likely that this 'normal' growth is able to compete with the tumour for
      important growth factors and nutrients, including polyamines, effectively
      starving the tumour for these molecules and resulting in its decreased rate of
      proliferation.

PMID- 10395172
TI  - Synergism between mild hyperthermia and interferon-beta gene expression.
AB  - In the present study, the synergistic effect of mild hyperthermia in combination
      with gene expression of interferon-beta (IFN-beta) was examined in vitro in the
      human glioma cell line U87MG. The cells transiently expressed the IFN-beta gene
      under the control of the mouse mammary tumor virus promoter and were then
      subjected to temperature elevation (41 degrees C for 1 h). In terms of the cell
      killing effect, the optimum scheme was obtained by transfection for 4 days before
      hyperthermia, i.e. rate in the time course of IFN-beta gene expression. The
      relative specific growth rate decreased to 32% compared with the control while it
      was only 40% under the hyperthermic conditions. These observations suggest that
      IFNbeta expression was able to enhance the sensitivity of transfected glioma
      cells to mild hyperthermia.

PMID- 10395173
TI  - Clinical relevance of pRb and p53 co-overexpression in soft tissue sarcomas.
AB  - The goal of this study was to examine the relationship between
      immunohistochemical pRb detectability and p53 overexpression in 198 soft tissue
      sarcomas (STS) with regard to its clinical relevance. Distinct pRb detectability
      multivariately shows a correlation to survival rate (relative risk (RR)=1.59,
      P=0.037). p53 positivity was also multivariately correlated to poor prognosis
      (RR=2.17, P=0.0014). Stratification of pRb staining to p53 results shows a
      prognostical graduation. Patients with negativity for both proteins have the most
      favorable prognosis (projected 5-year survival rate (psr)=54.5%). In contrast to
      this, positivity for both antibodies has the highest risk (RR=2.48, P=0.02) and
      the poorest prognosis (psr=17.4%). To conclude, these results explain that the
      clinical relevance of immunohistochemical pRb positivity in STS is connected with
      p53 in the form of having an increasing effect on the known prognostic relevance
      of p53 overexpression.

PMID- 10395174
TI  - Effects of low dose catechol on glandular stomach carcinogenesis in BALB/c mice
      initiated with N-methyl-N-nitrosourea.
AB  - The effects of low dose catechol administration in the diet on stomach
      carcinogenesis in mice after initiation with N-methyl-N-nitrosourea (MNU) in the
      drinking water were investigated. Male, 6-week-old, BALB/c mice were given MNU in
      the drinking water intermittently for 1-week periods at 1-week intervals for a
      total of 3 weeks at a concentration of 120 ppm (groups 1 and 3). Groups 2 and 4
      served as non-initiated controls. From week 7, groups 1 and 3 were divided into
      four subgroups and the mice were fed on a diet containing 4 ppm (groups la and
      3a), 20 ppm (groups 1b and 3b), 100 ppm (groups 1c and 3c), 500 ppm (groups 1d
      and 3d) or 0 ppm (groups 2 and 4) catechol for 44 weeks. At week 50, appreciably
      enhanced development of pepsinogen 1 altered pyloric glands (PAPG) was noted in
      groups 1c and 1d. The incidences of adenomatous hyperplasia and carcinomas were
      not affected in any of the catechol-treated groups as compared with corresponding
      controls on a basal diet. Thus, the administration of catechol in the diet at low
      doses enhanced only preneoplastic lesion development and not neoplastic lesion
      development. From these results, we conclude that the biological significance of
      the catechol promoting effect at probable human exposure levels on gastric cancer
      is probably limited, while the PAPG may be a sensitive endpoint lesion for mouse
      glandular stomach carcinogenesis.

PMID- 10395175
TI  - On the mechanism of cogenotoxic action between ingested amphibole asbestos fibres
      and benzo[a]pyrene: II. Tissue specificity studies using comet assay.
AB  - Epidemiological data seem to be equivocal on the probable increase in cancer
      incidence in populations exposed to asbestos-fibre contaminated drinking water.
      Although animal experiments failed to demonstrate carcinogenicity of oral
      asbestos exposure, the large surface area of the fibres, however, creates the
      possibility of cogenotoxic action with adsorbed water-borne organics. In our
      animal model, rats were gavaged with untreated UICC crocidolite and anthophyllite
      fibres and fibres that had been allowed to adsorb benzo[a]pyrene molecules from
      aqueous solutions. Peritoneal macrophages and intestine, parietal peritoneum and
      omentum samples were obtained from the animals after 24 h. The alkaline single
      cell microgel electrophoresis assay (comet assay) was performed on cells isolated
      from the solid tissues. Tail moment was applied as a basis of evaluation
      following image analysis. Our results indicate high levels of DNA strand breaks
      in the cells prepared from the omentum and intestine. We could also demonstrate a
      significant potentiating effect of the adsorbed carcinogen on the induction of
      DNA damage in the omentum. The parietal peritoneum and macrophages were not
      involved in the early genotoxic alterations under study. Our results support the
      molecular model of asbestos cocarcinogenesis, including both asbestos-induced
      deletions and mutations caused by a mutagen carried by the same fibres.

PMID- 10395176
TI  - Heterozygous p53-deficient mice are not susceptible to 2-amino-3,8
      dimethylimidazo[4,5-f]quinoxaline (MeIQx) carcinogenicity.
AB  - 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a very potent mutagen
      which induces tumors in the liver, lung and hematopoietic system of CDF1 mice and
      the liver, Zymbal gland and skin in F344 rats. The recent development of
      transgenic knockout mice allows their introduction for sensitive screening of
      environmental carcinogens due to the rapid development of tumors. P53 gene
      deficient mice (p53-/-) were found to spontaneously develop malignant lymphoma
      and hemangiosarcoma, whereas heterozygotes (p53+/-) mice display a high incidence
      of tumors of the urinary bladder when treated with N-butyl-N-(4
      hydroxybutyl)nitrosamine. In the present study, to determine whether p53 gene
      knockout mice can be utilized in a short-term assay model for the screening of
      heterocyclic amines (HCAs), the effects of MeIQx, as a representative compound,
      at low doses were examined. Male and female p53+/- mice and wild type littermates
      (p53+/+) were continuously given diets containing 0, 0.1, 1, 10 and 100 ppm MeIQx
      for 1 year. No significant difference in tumor induction was observed other than
      an increase in liver adenomas in males receiving 10 ppm MeIQx treatment. The
      results indicate that p53+/- mice have no practical advantages for use in short
      term carcinogenicity tests of HCAs.

PMID- 10395177
TI  - Mutation analysis of hBUB1 in aneuploid HNSCC and lung cancer cell lines.
AB  - Aneuploidy is frequently observed in many types of human cancer cells, suggesting
      that mutations of genes required for chromosomal stability may occur in human
      tumors. The BUB gene is a component of the mitotic checkpoint in budding yeast
      that delays anaphase in the presence of spindle damage thus increasing the
      probability of successful delivery of a euploid genome to each daughter cell.
      Recently, human homologues of the BUB gene were identified and mutant alleles of
      hBUB1 were detected in two colorectal tumor cell lines. Transfection of one
      mutant allele led to dominant disruption of the mitotic checkpoint control in a
      euploid cell, suggesting that aneuploidy in some tumors could be due to defects
      in the mitotic checkpoint. We analyzed the entire coding sequence of hBUB1 for
      mutation in 31 head and neck squamous cell carcinoma (HNSCC) and lung cancer cell
      lines, most with severe aneuploidy. We found expression of the hBUB1 gene in all
      cell lines and only a single nucleotide substitution in one cell line without a
      resultant change in amino acid sequence. Our study demonstrates that hBUB1 is
      rarely a target for genetic alterations in tumors of the respiratory tract.

PMID- 10395178
TI  - The roles of diesel exhaust particle extracts and the promotive effects of NO2
      and/or SO2 exposure on rat lung tumorigenesis.
AB  - This experiment was carried out to clarify the roles of diesel exhaust particle
      (DEP) extracts and the promotive effects of nitrogen dioxide (NO2) and/or sulfur
      dioxide (SO2) exposure on rat lung tumorigenesis. F344 male rats were
      intratracheally administered DEP extract-coated carbon black particles (DEcCBP)
      and exposed to 6 ppm NO2 and/or 4 ppm SO2 for 10 months. At 18 months after
      starting the experiment, lung lesions were histopathologically investigated and
      DNA in rat lungs was analyzed for the presence of adducts using the 32P
      postlabeling assay. Infiltration of alveolar macrophages, which was significant
      in the lungs of rats administered carbon black particles, was not prominent in
      those administered DEcCBP. DEcCBP occasionally formed small hyaline masses in the
      alveolar ducts and alveolar bronchiolization developed in the epithelium of
      alveolar ducts near the masses. Lung tumorigenesis and DNA aduct formation were
      observed in the animals administered DEcCBP with exposure to NO2 and/or SO2, but
      not in those administered DEcCBP alone. The results of the present study
      suggested that DEP extracts eluting from the small masses cause DNA damage in
      alveolar epithelial cells and alveolar epithelial cell proliferation, and that
      NO2 and/or SO2 exposure promote lung tumor induction by DEP extracts.

PMID- 10395179
TI  - Differential expression of CYP1A1, CYP1A2, CYP1B1 in human kidney tumours.
AB  - The presence of mRNA of individual members of the CYP1 gene family in normal and
      neoplastic kidney has been investigated by RTPCR. CYP1B1 mRNA was consistently
      expressed in both normal and neoplastic kidney while CYP1A1 was present in the
      majority of normal and neoplastic whereas CYP1A2 was infrequently expressed.
      Expression of the Ah receptor and Arnt which are involved in the transcriptional
      activation of the CYP1 genes was also studied. The Ah receptor mRNA and Arnt mRNA
      were consistently expressed both in kidney tumours and normal kidney. These
      results indicate differential expression of individual members of the CYP1 gene
      family in normal and neoplastic kidney and suggest that several mechanisms
      including the Ah receptor complex could be involved in their regulation.

PMID- 10395180
TI  - Cytotoxic effects of the components in heat-treated mistletoe (Viscum album).
AB  - Major cytotoxic components were fractionated from Korean mistletoe and the
      changes of their cytotoxic effects caused by heat treatment were investigated.
      The high cytotoxicity of isolated lectin I completely disappeared by heating for
      30 min. The fractions of viscotoxins and alkaloids maintained their activities
      even after heating for 60 and 180 min, respectively. The alkaloid fraction was
      more cytotoxic to tumor MSV cells than to non-tumor A31 cells and the activity
      pattern was not changed by heat treatment. The possible contributions of
      alkaloids and viscotoxins to the activities of heat-treated mistletoe extracts
      such as tea or decoctions are discussed.

PMID- 10395181
TI  - Membrane fluidity characteristics of human lung cancer.
AB  - Membrane fluidity of non-cultured lung cancer tissue was studied by electron
      paramagnetic resonance (EPR). EPR spectra of a lipophilic spin probe in a tissue
      of resected tumor samples from 51 patients were compared with computer simulated
      spectra, which were superimpositions of spectra characterizing membrane domains
      with different fluidity. The membranes of tumor tissues were more fluid, than
      those of normal lungs; the most fluid domains were enlarged and their order
      parameter decreased in comparison to normal tissue. An empirical fluidity
      parameter (H13) was defined as the criterion to correlate EPR and clinical data.
      The histology of tumor, the quantitative presence of different tumor and non
      tumor cells and the pathohisthological stage of the disease had no significant
      influence on fluidity.

PMID- 10395182
TI  - Relationship between chromosomal aberrations by fluorescence in situ
      hybridization and DNA ploidy by cytofluorometry in osteosarcoma.
AB  - An analysis of the chromosomal aberrations and DNA ploidy in the interphase
      nuclei of seven human osteosacomas was preformed by double-target fluorescence in
      situ hybridization (FISH) and DNA cytofluorometry. The FISH study of the
      numerical aberrations in chromosomes 1 and 17 or the structural aberrations in
      chromosome arm 1p or 17p was carried out by using four locus specific DNA
      markers, with one pair consisting of 1q12 and 1p36 and the other pair consisting
      of the 17 cemtromere and 17p13.3. There was no significant differences in the
      percentage of deletions in chromosome 1 and 17 between osteosarcomas and normal
      tissues. However, all seven tumors studied had extra copies. Cells with more than
      three probe signals were regarded as having chromosome polysomy. The percentage
      of polysomy of chromosome 1 was 20.0-64.0%, and chromosome 17 was 28.0-60.0%. The
      DNA ploidy patterns of hyperdiploid cells showing a greater DNA content than
      diploid cells were obtained by DNA cytoflurometry. Five of the seven tumors were
      non-diploid, and the remaining two were diploid. The percentage of polysomy was
      correlated with the percentage of hyperdiploid cells in each tumor. Thus, these
      findings indicated that the DNA ploidy changes were closely correlated with
      aberrations in the chromosome copy number in osteosarcomas.

PMID- 10395183
TI  - Inhibitory effect of Epstein-Barr virus activation by Citrus fruits, a cancer
      chemopreventor.
AB  - To search useful compounds in Citrus fruit for cancer chemoprevention, we carried
      out a primary screening of extracts of fruit peels and seeds from 78 species of
      the genus Citrus and those from two Fortunella and one Poncirus species, which
      were closely related to the genus Citrus. These Citrus extracts inhibited the
      Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O
      tetradecanoylphorbol 13-acetate (TPA) as a useful screening method for anti-tumor
      promoters. Our results indicated that Citrus containing substances may be inhibit
      susceptibility factors involved in the events leading to the development of
      cancer.

PMID- 10395184
TI  - Short stature and prognosis of coronary heart disease in women.
AB  - OBJECTIVES: To investigate the effect of short stature on prognosis following an
      acute event of coronary heart disease (CHD) in women. SETTING: All women who were
      hospitalized for an acute event of CHD in any of the 10 cardiology clinics in
      greater Stockholm were investigated for the first time in the Stockholm Female
      Coronary Risk Study between 1991 and 1994, and were followed until August 1997
      for recurrent coronary events. DESIGN: A follow-up study of women with either
      acute myocardial infarction (AMI) or unstable angina pectoris. Median follow-up
      period was 4.8 years. SUBJECTS: A total of 292 Swedish women. aged 65 years or
      younger. MAIN OUTCOME MEASURES: Recurrent AMI, death from CHD or
      revascularization procedure (percutaneous transluminal coronary angioplasty and
      coronary artery bypass grafting). RESULTS: Independent of the confounding effects
      of other risk factors of clinical importance for CHD (age, socioeconomic status,
      menopausal status, index event, congestive heart failure, angina severity,
      diabetes, hypertension, smoking, triglycerides and HDL cholesterol), the shortest
      25% of women (< 160 cm) had a 2.1-fold (95% CI = 1.0-4.4) increased rate of
      developing adverse cardiac events (cardiovascular death, recurrent AMI or
      revascularization procedure) compared with the tallest 25% (> 165 cm). In
      addition, an increased rate was observed for each 10 cm difference in height
      (hazard ratio = 1.7, 95% CI = 1.4-2.7). Similar results were observed when
      analysing each outcome separately. CONCLUSIONS: These data indicate that short
      stature is a strong predictor of poor prognosis after an acute coronary event in
      women, independent of socioeconomic status and other risk factors for CHD.

PMID- 10395185
TI  - Comparison of secondary prevention measures after myocardial infarction in
      subjects with and without diabetes mellitus.
AB  - OBJECTIVES: To survey and compare secondary prevention measures in diabetic and
      non-diabetic patients following myocardial infarction (MI). DESIGN: Follow-up of
      a cohort of patients who suffered their first MI 1 year previously. SETTING:
      Three district general hospitals. MAIN OUTCOME MEASURES: Review 1 year post-MI
      for signs of left ventricular failure (LVF), serum cholesterol, smoking status,
      weight, blood pressure and glycaemic control. Assessment of appropriate treatment
      with aspirin, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors and
      lipid-lowering therapy before discharge and at least 1 year post-MI. RESULTS: A
      total of 189 non-diabetic and 86 diabetic patients were studied. Most patients
      received beta-blockers and aspirin appropriately, and most gave up smoking. In
      non-diabetic subjects, cholesterol fell significantly (P < 0.05), as did the
      proportion of patients with cholesterol > 5.5 mmol L(-1) (P < 0.05), whereas
      cholesterol did not fall significantly in diabetic subjects, due to a lower
      proportion of patients being on lipid-lowering therapy (27.5 vs. 37.9%). A higher
      proportion of non-diabetic patients with LVF were treated with ACE inhibitors
      compared with diabetic subjects (73.6 vs. 61.%). Glycaemic control did not
      improve in the diabetic subjects. CONCLUSIONS: Patients with diabetes do not
      receive optimal secondary prevention measures compared with their non-diabetic
      counterparts. This issue needs to be addressed by all units dealing with patients
      with diabetes in order to reduce the mortality and morbidity of MI in such
      patients.

PMID- 10395186
TI  - Ethical aspects of clinical trials: the attitudes of the public and out-patients.
AB  - OBJECTIVES: To investigate attitudes to clinical research amongst potential
      research participants. DESIGN: Questionnaire-survey. SETTING: Two medical out
      patient clinics and the background population. SUBJECTS: A total of 508 randomly
      selected citizens in Copenhagen County (64% responded) and 200 consecutive
      patients attending the out-patient clinics (64% responded). OUTCOME MEASURES:
      Attitudes toward different aspects of clinical research. RESULTS: Positive
      attitudes toward medical research were disclosed. The majority found scientific
      testing necessary, although only a minority considered participation a moral
      obligation. Both personal benefits and altruistic motives for participation were
      highly rated, whereas former positive experiences from trial participation had
      only minor impact on decisions. Several respondents stated former trial
      participation had changed their attitudes negatively. Lack of feedback of results
      was of major importance for this change. Attitudes are significantly influenced
      by the presence of independent research ethics committees, whereas trial
      technicalities such as drawing lots and blinding was found problematic by only a
      few respondents. Altruistic motives of physicians to conduct trials were highly
      rated by a majority of respondents, but the motive of promoting doctors' careers
      was also judged important. Respondents rated nondiscomforting procedures as
      acceptable or having only a small impact or strain on their lives. CONCLUSION:
      Attitudes toward medical research are positive amongst out-patients and the
      general public. Altruistic and nonaltruistic motives both concerning trial
      participation and concerning the motives of physicians to conduct medical
      research were rated highly. Lack of feedback concerning results of trials to
      participants was important for a negative change in attitude toward
      participation.

PMID- 10395187
TI  - Habitual dietary intake versus glucose tolerance, insulin sensitivity and insulin
      secretion in postmenopausal women.
AB  - OBJECTIVE: The major aim was to study the relation between habitual dietary
      intake and glucose tolerance, insulin sensitivity and insulin secretion in
      postmenopausal women. Dietary intake was also compared between women with normal
      (NGT) or impaired glucose tolerance (IGT). DESIGN: Habitual dietary intake was
      studied using a modified diet history method, from which the energy,
      carbohydrate, fat and protein intake was calculated. Glucose tolerance was
      determined as the 2 h glucose value after a 75 g oral glucose tolerance test.
      Insulin sensitivity was studied with a euglycemic, hyperinsulinaemic clamp,
      whilst insulin secretion was measured as the acute (2-5 min) response to iv
      arginine (5 g) at fasting, 14 and >25 mmol L(-1) glucose. SETTING: Clinical
      research unit at the University Hospital in Malmo, Sweden. Subjects. A total of
      74 women (mean+/-SD age 58.7+/-0.4 years). RESULTS: In the entire group, the 2 h
      glucose level correlated with polyunsaturated fat intake (PUFA, r = 0.41, P <
      0.001), and negatively with carbohydrate intake (r = -0.23, P = 0.05). The
      relation between 2 h glucose and PUFA was independent of body fat content and
      insulin sensitivity in a multivariate model. Insulin sensitivity correlated with
      energy intake (r = 0.31, P = 0.007) and PUFA (r = -0.27. P = 0.022). However,
      these correlations were not significant after adjustment for body fat content in
      a multivariate model. There were no correlations between insulin secretory
      variables and habitual dietary intake. Of the 74 women, 60 had NGT and 14 had
      IGT. The NGT and IGT groups did not differ in intakes of total energy,
      carbohydrate or protein. The IGT women had higher intake of PUFA (P = 0.003),
      whilst the total, saturated and monounsaturated fat intake did not differ between
      the groups. CONCLUSION: Dietary parameters are not independently associated with
      insulin sensitivity or insulin secretion in postmenopausal women. Furthermore,
      dietary habits are largely similar in women with NGT and IGT, although subtle
      differences cannot be excluded due to the small study size. Therefore, habitual
      intake of total carbohydrate or total fat seems not to be the major determinant
      of glucose tolerance in nondiabetic Caucasian postmenopausal women.

PMID- 10395188
TI  - Prevalence of APC resistance and its relationship to arterial and venous
      thromboembolism in a general population sample of elderly Swedish men: The Study
      of Men Born in 1913.
AB  - BACKGROUND: Most studies of hereditary resistance to activated protein C (APC
      resistance) as a risk factor for venous thromboembolism are derived from case
      control studies of hospitalized patients, whilst the importance of this condition
      in the general population has been only sparsely investigated. OBJECTIVE: To
      study the prevalence of APC resistance and its relationship to morbidity and
      mortality in a general population sample of elderly men. DESIGN: Cross-sectional
      and prospective follow-up study. SETTING: General community: The Study of Men
      Born in 1913. SUBJECTS: A random population sample of 404 men, all 75 years of
      age. MAIN OUTCOME MEASURES: Four hundred and four men participated in a screening
      examination in 1988. The APC ratio was analysed in 382 of them. All the men were
      followed up for 5 years. Medical records were reviewed for all the men with a
      history of deep vein thrombosis, pulmonary embolism, myocardial infarction or
      stroke. RESULTS: Twenty-five men (6.5%) were found to have APC resistance. The
      incidence of venous thromboembolism, myocardial infarction or stroke did not
      differ between men with or without APC resistance, either retrospectively or
      during follow-up. Only two men experienced a deep vein thrombosis before the age
      of 80 and there was no case of pulmonary embolism. Mortality during 5 years of
      follow-up did not differ between men with and without APC resistance. CONCLUSION:
      The prevalence of APC resistance was 6.5% in this study of Swedish men. Although
      the size of the population sample is somewhat small, the study shows that,
      amongst elderly men, the association between APC resistance and venous
      thromboembolic disease was weak and men with this hereditary condition did not
      have any increase in morbidity or mortality compared with men without APC
      resistance.

PMID- 10395189
TI  - Pulmonary embolism: a follow-up study of the relation between the degree of right
      ventricle overload and the extent of perfusion defects.
AB  - OBJECTIVES: To describe the course of changes in perfusion lung scintigraphy (LS)
      after acute pulmonary embolism (PE) and test the hypothesis that patients with
      persistent pulmonary hypertension (PH)/right ventricle (RV) dysfunction after
      acute PE can be differentiated from those without through larger perfusion
      defects (PDf) on LS. Design. Prospective, one-year follow-up study with repeated
      LS and echocardiography-Doppler investigations. SETTING: Single centre,
      University Hospital. SUBJECTS: Patients with clinical suspicion of acute PE with
      a diagnosis confirmed by LS and/or pulmonary angiography and able to undergo
      repeated investigations. Of the 78 patients included, a six-week follow-up was
      completed in 67 and a one-year follow-up in 64. MAIN OUTCOME MEASURES: Time
      course of PDf in relation to time course of pulmonary artery systolic pressure
      (PAsP) and RV function. RESULTS: Initially, PDf decreased exponentially, until
      the beginning of a stable phase, which was achieved within 54 days for 90% of the
      patients and within 148 days for all. The temporal relation for the regress of
      PDf and decrease in PAsP was loose. Patients with persistent PDf suffered PH/RV
      dysfunction more often than those without. However, the variability in the degree
      of haemodynamic changes for a given extent of PDf was large. CONCLUSIONS: After
      acute PE, LS is of use for the identification of the group of patients that may
      have persistent PH/RV dysfunction. However. since the identification of
      individual patients is uncertain, LS cannot replace echocardiography-Doppler in
      the identification of persistent PH/RV dysfunction after acute PE.

PMID- 10395190
TI  - Genes involved in animal models of obesity and anorexia.
AB  - Pathological deviations in bodyweight is a major increasing health problem in
      industrialized societies. It is currently unclear what genetic mechanisms are
      involved in the long-term control of human body-weight and to what extent these
      genes are involved in pathological deviations of bodyweight control such as
      anorexia and obesity. Major support for the concept of genetic control of
      bodyweight has recently emerged from different animal models. A number of new
      genes have been found during recent years that, when mutated, have a negative
      effect on bodyweight in animals and sometimes also in man. Although available
      evidence points toward a multifactorial nature of weight disorders in most human
      subjects, the single genes isolated in animal models may become powerful tools to
      elucidate the genetics also in man. In addition, these genes may serve to promote
      the development of targeted small-drug pharmaceuticals aimed at novel biochemical
      pathways. Finally, the uncovering of several quantitative trait loci (QTL)
      influencing body mass, body fat or fat topography in the mouse and rat has now
      also made it possible to perform studies of polygenically caused obesity in
      rodents. The role of the Genome Project in developing a complete gene map will
      greatly facilitate transforming these OTLs to actual molecules involved in the
      biology of bodyweight.

PMID- 10395191
TI  - The role of TNFalpha and TNF receptors in obesity and insulin resistance.
AB  - Insulin resistance, a smaller than expected response to a given dose of insulin,
      is associated with many common diseases including, ageing, polycystic ovarian
      disease, syndrome X, cancer, infections, trauma and, most significantly, obesity
      and type 2 diabetes mellitus. The biochemical basis of insulin resistance in type
      2 diabetes has been the subject of many studies. Earlier studies have indicated
      that quantitative regulation of the insulin sensitive glucose transporters (Glut
      4) and insulin receptors themselves may contribute to this disorder, however,
      these two factors are probably inadequate to explain the extent of insulin
      resistance. This point also became apparent by the development of only mild
      hyperinsulinaemia in mice with a targeted mutation in the Glut-4 gene. Studies on
      postreceptor defects in type 2 diabetes has recently focused on the intrinsic
      catalytic activity of the insulin receptor and downstream signalling events. A
      reduction in tyrosine phosphorylation of both the insulin receptor (IR) and the
      insulin receptor substrate-1 (IRS-1) has been noted in both animal and human type
      2 diabetes. Importantly, this appears to occur in all of the major insulin
      sensitive tissues, namely the muscle, fat and liver. It is now clear that
      decreased signalling capacity of the insulin receptor is an important component
      of this disease. I will review some of the potential mechanisms underlying this
      deficiency.

PMID- 10395192
TI  - Genetically engineered mice in drug development.
AB  - Complex metabolic diseases like type 2 diabetes (noninsulin-dependent diabetes)
      and obesity present a difficult challenge to pharmaceutical companies in their
      attempts to develop new therapies. The polygenic nature of these diseases and the
      influence of nongenetic factors make it difficult to identify the most critical
      molecular processes to target for drug development. Transgenic animal models
      provide an approach to evaluate specific sites in metabolic and hormone
      signalling pathways under physiologic (as opposed to in vitro) conditions. The
      advantages and limitations of using transgenic animals in drug development will
      be covered and an overview of recent information from transgenic studies relevant
      to type 2 diabetes and obesity will be given.

PMID- 10395193
TI  - Contributions of studies on uncoupling proteins to research on metabolic
      diseases.
AB  - The coupling of O2 consumption to ADP phosphorylation in mitochondria is partial.
      This is particularly obvious in brown adipocyte mitochondria which use a
      regulated uncoupling mechanism generating heat production from substrate
      oxidation, and catalysing thermogenesis in rodents or infants in response to
      cold, and arousing hibernators. In the case of brown adipose tissue, the
      uncoupling mechanism is related to a specific protein in the inner mitochondrial
      membrane referred to as UCP1. Although the biological importance of UCP1 in human
      adults is not demonstrated, genetic analysis of various human cohorts suggested a
      participation of UCP1 to control of fat content and body weight. Very recently,
      the cloning of UCP2 and UCP3, two homologues of UCP1, has renewed the field of
      research on the importance of respiration control in metabolic processes and
      metabolic diseases. UCP2 is widely expressed in organs, whereas UCP3 is mainly
      present in muscles. These proteins may explain why the coupling of respiration to
      ADP phosphorylation is less than perfect. Their biological importance should be
      studied. They also represent new putative targets for drugs against metabolic
      diseases such as obesity.

PMID- 10395195
TI  - Genetics of human obesity: lessons from mouse models and candidate genes.
AB  - Obesity is a common disorder with potentially serious negative implications on
      health and quality of life and a rising prevalence worldwide, warranting
      effective treatments. The disorder runs in families, and important knowledge is
      expected to follow the identification of human obesity genes. Although
      statistical analysis of inheritance of obesity in humans suggests a large genetic
      component in obesity, up to 80%, few actual obesity genes have been identified so
      far. However, a number of obesity causing genes have successfully been cloned
      from rodents with monogenic forms of obesity, and it is probable that new
      knowledge in the field of human obesity will result from these findings.

PMID- 10395194
TI  - Leptin and its potential role in human obesity.
AB  - Genetic studies in inbred obese mice have revealed the ob gene, its product
      leptin and the leptin receptor as important factors in the regulation of both
      appetite and energy expenditure. Treatment with recombinant leptin has resulted
      in a marked weight reduction in obese animals with ob gene mutations as well as
      in normal mice. Also mutations in the Ob receptor gene result in marked obesity
      in rodents. These data have given hope of new treatment options in obesity.
      Further support of leptin being involved in regulation of obesity in man comes
      from the observation that inactivating mutations in the human ob gene lead to
      profound early onset obesity. However, the role of leptin and its feedback system
      in man is still only partly revealed. This review focuses on our present
      knowledge and hypotheses about the leptin pathway in humans and its potential
      importance in the clinic of obesity.

PMID- 10395196
TI  - Adrenoceptor genes in human obesity.
AB  - The genes causing obesity in rodent models have been characterized, but do not
      seem to be important for human obesity. Recently the putative association between
      obesity and polymorphism in human beta-adrenergic receptor genes have been
      studied intensely in the light of the important role of these receptors in the
      regulation of energy mobilization and utilization. A polymorphism (Trp64Arg) in
      the beta3-adrenergic receptor gene is associated with obesity (relative risk
      approximately 2) in some but not all investigations on Caucasian and Japanese
      populations. When expressed in artificial cell systems, the polymorphism is
      associated with alterations of the beta -adrenoceptor. The genetic allele
      variance influences also the native receptor function when measured in isolated
      human fat cells. The human beta2-adrenoceptor gene shows a high degree of
      polymorphism. The role of beta2-receptor gene polymorphism for obesity has so far
      only been investigaed in women. A Gln27Glu variant is markedly associated with
      obesity with a relative risk for obesity of approximately 7 and odds ratio of
      approximately 10. Women who are homozygous for 27Glu have approximately 20 kg
      higher fat mass than controls. Thus, polymorphism in genes coding for different
      beta-adrenoceptor subtypes may be important for the development of human obesity.

PMID- 10395198
TI  - Expressed immunoglobulin repertoire of LPS-stimulated splenocytes of unimmunized
      mice as studied by two-dimensional gel electrophoresis.
AB  - The repertoire of isolated immunoglobulin polypeptide chains synthesized by LPS
      stimulated splenic B cells from unimmunized 6 weeks old mice was studied by two
      dimensional gel electrophoresis. These B cells formed mainly mu heavy chains,
      while only a small amount of gamma chains was detected on two-dimensional
      electrophoregrams. The number and character of spots corresponding to each class
      and type of H and L chains were analyzed. Most of the detected 52 spots, which
      corresponded to L chains, were well resolved with clearly defined round
      boundaries. Six of them belonged to two isotypes of lambda chains and the rest to
      the kappa chain. About 25 clusters corresponded to mu chains. They had different
      appearance from those of L chains and their characteristic elliptic form with
      prolonged vertical axes indicated the presence of several H chain variants of
      slightly different length (due probably to the length variations of CDR3 and
      carbohydrate heterogeneity) in each cluster. The limited number of spots both of
      H and L chains is explained as being due to restrictions in the expressed
      repertoire of preimmune splenic B cells, which have no somatic mutations in the
      immunoglobulin genes. The concept of macrorepertoire (referring to the relatively
      small number of detected molecular species) and microrepertoire (describing the
      mutationally altered molecules) is introduced.

PMID- 10395197
TI  - Drug-induced inhibition of insulin recognition by T-cells: the antirheumatic drug
      aurothiomalate inhibits MHC binding of insulin peptide.
AB  - Previous work has shown that the Au(I) moiety of the antirheumatic drug disodium
      aurothiomalate (Au(I)TM) can selectively inhibit the response of murine CD4+ T
      cell hybridomas to antigenic peptides containing two or more cysteine (Cys)
      residues. Here, we investigated the mechanism that underlies the inhibitory
      effect of Au(I)TM on T-cell recognition of bovine insulin (BI). We found that low
      concentrations of Au(I)TM (10 microM) inhibited the BI-induced proliferation of
      bulk T-cells from BI-immunized BALB/c mice as well as the IL-2 release of Ab- and
      Ad-restricted T-cell hybridoma clones. Au(I)TM was found to inhibit binding of
      the immunodominant BI peptide A1-14 to isolated MHC class II molecules. We
      suggest that Au(I) forms stable chelate complexes with thiol groups of two Cys
      residues in the BI A1-14 peptide. Conceivably, formation of these metal-peptide
      complexes keeps the peptide in a sterical conformation that cannot undergo
      binding to MHC class II molecules, resulting in an inhibition of T-cell
      activation due to insufficient peptide presentation.

PMID- 10395200
TI  - A novel immunoglobulin superfamily junctional molecule expressed by antigen
      presenting cells, endothelial cells and platelets.
AB  - The architecture of lymphoid microenvironments depends upon complex interactions
      between several stromal cell types. We describe in this report the cloning of a
      cDNA which encodes a novel membrane molecule containing two external Ig-like
      domains. It is expressed at the junction between endothelial cells including HEV.
      It is also expressed by platelets and MHC class II+ antigen presenting cells in
      thymic medulla and T-cell areas in peripheral lymphoid organs. These cells which
      lack in RelB-deficient mice include tissue-derived dendritic, epithelial cells
      and macrophages. Thus, this molecule might contribute to the organization of cell
      junctions in different microenvironments.

PMID- 10395199
TI  - Intracellular expression and functional properties of an anti-p21Ras scFv derived
      from a rat hybridoma containing specific lambda and irrelevant kappa light
      chains.
AB  - A rat single-chain Fv (Y238 scFv) was derived from the Y13-238 monoclonal
      antibody, a non-neutralizing anti-Ras antibody. The Y13-238 hybridoma expresses
      two functional light chains. N-terminus microsequencing of these chains showed
      the presence of the Y3 Ag1.2.3 Vkappa chain derived from the rat fusion partner
      and of a rat Vlambda chain. Primers designed for rat Vlambda amplification
      allowed the cloning of a functional scFv that could bind p21Ras. The kinetics of
      interaction of purified Y238 scFv with the p21Ras protein was evaluated by
      BIAcore with a NTA sensor chip and gave an apparent affinity constant in the
      nanomolar range (K(D)=4.58+/-0.63 nM). Immunoprecipitation experiments of Y238
      scFv expressed in Xenopus laevis oocytes confirmed the specificity of the scFv
      for the Ras protein. Y238 scFv could be intracellularly expressed in oocytes and
      in mammaliam cells without adverse effect on the Ras signalling cascade. This
      scFv was therefore used as control in experiments where another anti-Ras scFv
      (Y259 scFv, derived from the neutralizing anti-Ras mAb Y13-259) blocked the Ras
      pathway in vitro and led to tumor regression in a nude mouse model [Cochet, O.,
      Kenigsberg, M., Delumeau, I., Virone-Oddos, A., Multon, M.C., Fridman, W.H.,
      Schweighoffer, F., Teillaud, J.L., Tocque, B., 1998. Intracellular expression of
      an antibody fragment-neutralizing p21 ras promotes tumor regression. Cancer Res.
      58, 1170-1176.]. Finally, BIAcore analyses indicated that the epitopes recognized
      by Y238 and Y259 scFvs are not overlapping and allowed a more precise definition
      of the Y13-238 epitope.

PMID- 10395201
TI  - Ovarian and breast cytotoxic T lymphocytes can recognize peptides from the amino
      enhancer of split protein of the Notch complex.
AB  - In this study we investigated recognition by ovarian tumor associated lymphocyte
      (OVTAL), and breast tumor associated lymphocytes (BRTAL), of peptides
      corresponding to the sequence 125-135 of the Aminoenhancer of split (AES)
      protein. Three of these peptides designated as G75:AES1/2 (128-135), G60: AES1/2
      (127-137) and G61: AES1/2 (125-133) correspond to the wildtype AES sequence,
      while the fourth G76:GPLTPLPV, AES1/2 (128-135) corresponds to a variant sequence
      of the peptide G75 with the N-terminal Leu substituted to glycine. These
      sequences were chosen for study because mass-spectrometric analysis (MS) of a CTL
      active HPLC peptide fraction eluted from immunoaffinity precipitated HLA-A2
      molecule, revealed: (a) the presence of an ion with a mass-to-charge ratio (m/z)
      of 793 which was more abundant than other ions of similar masses; (b) the
      tentatively reconstituted sequence of the ion 793 matched the sequence of peptide
      G76. We found that AES peptides G75 (128-135) and G76 (128-135) (L128G)
      reconstituted CTL recognition at concentrations ranging between 200-500 nM. These
      concentrations are lower than concentrations reported to activate effector
      function of CTL recognizing other epithelial tumor Ag. Furthermore, analysis with
      cloned CD8+ T cells indicated that G75 and G76 were not cross-reactive
      specificities, suggesting a key role for the N-terminal residues of the variant
      peptide in dictating specificities. Since the AES proteins are part of a set of
      transcriptional repressors encoded by the Enhancer of split [E(spl)] genes, and
      since these repressors are activated to suppress cell differentiation in response
      to Notch receptors signalling, the AES peptides may represent a novel class of
      self-antigens that deserve further consideration as tumor Ag in epithelial
      cancers.

PMID- 10395202
TI  - Role of SHIP in FcgammaRIIb-mediated inhibition of Ras activation in B cells.
AB  - Previous studies by our lab and others established that co-crosslinking sIg and
      IgG receptor FcgammaRIIb in B cells in a feedback suppression model (negative
      signaling) promoted tyrosine phosphorylation of the inositol 5-phosphatase SHIP
      and its interaction with Shc and that these events were associated with
      inhibition of the Ras pathway. We therefore hypothesized a competition model in
      which the SH2 domain of SHIP competes with that of Grb2 for binding to phospho
      Shc to inhibit the Ras pathway. Here, we provide evidence consistent with this
      hypothesis. First, FcgammaRIIb-deficient B cells, which do not undergo SHIP
      tyrosine phosphorylation nor interaction with Shc, displayed an active Ras
      pathway under negative signaling conditions; reconstitution of FcgammaRIIb
      expression restored the block in Ras. Second, under conditions of negative
      signaling leading to SHIP-Shc interaction in wild-type B cells, we observed a
      profound reduction in the activation-induced association of Grb2 to Sos.
      Experiments reported here and elsewhere revealed the Grb2-Sos interaction
      required the engagement of the Grb2 SH2 domain by phospho-Shc. Third, we
      demonstrated that phospho-Shc cannot concomitantly bind Grb2 and SHIP, indicating
      that the two proteins competed for the same phospho-tyrosine residue on Shc.
      These data are consistent with the proposed competition model, and further
      indicate that the activation induced Grb2-Sos association is rate limiting for
      Ras activation.

PMID- 10395204
TI  - Searching for a neurobiological signature of attention deficit hyperactivity
      disorder.

PMID- 10395203
TI  - HIV-1 and chemokines in the brain: location, location--location?

PMID- 10395205
TI  - A pinch of salt for NMDA receptors.

PMID- 10395206
TI  - The regulation of D2 dopamine receptor gene expression: epigenetic factors should
      not be forgotten.

PMID- 10395207
TI  - Molecular heterosis as the explanation for the controversy about the effect of
      the DRD2 gene on dopamine D2 receptor density.

PMID- 10395208
TI  - Evidence for an association between heroin dependence and a VNTR polymorphism at
      the serotonin transporter locus.

PMID- 10395209
TI  - Family-based association analysis of the hSKCa3 potassium channel gene in bipolar
      disorder.

PMID- 10395210
TI  - Polyglutamine tracts: no evidence of a major role in bipolar disorder.

PMID- 10395211
TI  - The molecular basis for electrogenic computation in the brain: you can't step in
      the same river twice.
AB  - Neural computation has classically been considered to be a process that depends,
      in large part, on the integration of excitatory and inhibitory synaptic signals
      by postsynaptic neurons; these cells generate sequences of action potentials that
      convey their messages, in turn, to still other neurons. We now appreciate that
      synaptic activity is a dynamic process that can be altered by mechanisms that
      include sprouting, pruning, facilitation, potentiation, and depression. But what
      about the electrogenic properties of neurons, ie the capability of these cells to
      generate all-or-non action potentials? Recent work indicates that the
      electrogenic machinery within neurons is also dynamic as a result of plasticity
      in the expression of sodium channels within the neuronal membrane. Molecular and
      functional remodeling of electrogenic membrane has been most extensively studied
      in developing and diseased neurons, but also occurs in the normal brain. The
      molecular plasticity of electrogenic membrane has important functional
      implications, since it can retune the neuron, changing its input-output
      relations.

PMID- 10395212
TI  - Analysis of genome-wide CAG/CTG repeats, and at SEF2-1B and ERDA1 in
      schizophrenia and bipolar affective disorder.
AB  - A shift towards larger CAG/CTG triplet repeats and schizophrenia (SCZ) and
      bipolar affective disorder (BPAD) has been detected by several recent studies,
      using the Repeat Expansion Detection (RED) technique, however no specific loci
      have been shown to be responsible for this shift. Further analyses by our group
      of RED (CTG)10 ligation products amongst an extended sample of patients and
      comparison with controls matched for age, sex and ethnicity show no significant
      differences in distribution (P= 0.23, n=95; P=0.93, n=91, for SCZ and BPAD
      respectively). Alleles at two recently discovered unstable trinucleotide repeat
      loci at 18q21.1 (SEF2-1B) and 17q21.3 (ERDA1) have also been analysed in
      affecteds and matched controls. We observed no increase in frequency of larger
      alleles (>37 repeats) in affected individuals at SEF2-1B (BPAD: P=0.95, n= 100;
      SCZ: P=0.61, n=97) or at ERDA1 (BPAD: P= 0.4, n = 101; SCZ: P= 0.05, n = 151,
      with larger alleles more frequent in controls). Our findings suggest that larger
      CAG/CTG repeats at these loci are neither major contributory factors to the
      etiology of psychosis, nor in linkage disequilibrium with a gene that is.
      Furthermore, when the RED results were compared to allele sizes at SEF2-1B and
      ERDA1, it was observed that a majority of SCZ, BPAD and control individuals with
      large RED products had a large allele at either or both sites (78% for RED
      products > or =270 bp; 62% for RED products > or =180 bp).

PMID- 10395213
TI  - D4 dopamine receptor-mediated phospholipid methylation and its implications for
      mental illnesses such as schizophrenia.
AB  - Previous studies have shown D2-like dopamine receptor involvement in the
      regulation of phospholipid methylation (PLM), while others have documented
      impaired methionine and folate metabolism in schizophrenia. Utilizing
      [14C]formate labeling in cultured neuroblastoma cell lines, we now show that D4
      dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM.
      The effect of DA was potently blocked by highly D4R-selective antagonists and
      stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was
      dependent upon the activity of methionine cycle enzymes, but DA failed to
      increase PLM in [3H]methionine labeling studies, indicating that a methionine
      residue in the D4R might be involved in mediating PLM. A direct role for MET313,
      located on transmembrane helix No. 6 immediately adjacent to phospholipid
      headgroups, was further suggested from adenosylation, site-directed mutagenesis
      and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia
      patients vs control samples showed a four-fold lower activity in the
      schizophrenia group. These findings reveal a novel mechanism by which the D4R can
      regulate membrane composition. Abnormalities in D4R-mediated PLM may be important
      in psychiatric illnesses such as schizophrenia.

PMID- 10395214
TI  - Genotypic association between the dopamine D3 receptor and tardive dyskinesia in
      chronic schizophrenia.
AB  - Dopamine receptor antagonism is a common mechanism underlying the therapeutic
      efficacy of all classical antipsychotic drugs. It is also thought to underlie the
      propensity of these agents to induce the movement disorder, tardive dyskinesia
      (TD), in one fifth of chronically exposed schizophrenia patients. We examined the
      polymorphic serine to glycine substitution in the first exon of the gene encoding
      the dopamine D3 receptor (DRD3) inn 53 schizophrenia patients with TD, 63 matched
      patients with similar antipsychotic exposure but no TD and 117 normal controls.
      There was a difference in allele frequency that was of borderline significance (P
      = 0.055), due to an excess of the DRD3gly allele (allele 2) in the schizophrenia
      patients with TD. The difference in genotype distribution among the groups was
      highly significant (chi2 = 19.1, d.f. 4, P = 0.0008) due to an excess of the
      DRD3ser-gly genotype in the schizophrenia patients with TD. The difference
      between the schizophrenia patients with TD and the controls was highly
      significant (chi2 = 19.0, d.f. 2, P = 0.00007), even after correction for
      multiple testing, as was the difference between the combined group of
      schizophrenia patients and the controls (chi2 = 12.2, d.f. 2, P = 0.002).
      Comparing the schizophrenia patients with and without TD, genotypes containing
      the gly allele (DRD3ser-gly and DRD3gly-gly genotypes combined) were
      significantly associated with dyskinesia (OR = 2.62, 95% CI 1.18-5.59, P = 0.02).
      DRD3 genotype and age at first antipsychotic treatment contributed significantly
      to total score on the Abnormal Involuntary Movements Scale (AIMS). The
      contribution of DRD3 to the variance in AIMS total was 5.2% and the total
      proportion of the variance accounted for by these two variables together was
      11.9%. These results support and extend the report by Steen et al (1997) of an
      association between DRD3 and TD in schizophrenia patients.

PMID- 10395216
TI  - Mapping of hKCa3 to chromosome 1q21 and investigation of linkage of CAG repeat
      polymorphism to schizophrenia.
AB  - CAG trinucleotide polymorphisms in the neuronal small conductance calcium
      activated potassium channel gene hKCa3 have been reported to be associated with
      schizophrenia. Attempts to confirm this finding have met with mixed results. We
      investigated hKCa3 CAG allele lengths in families from the National Institute of
      Mental Health (NIMH) Schizophrenia Genetics Initiative, by comparing transmission
      to discordant siblings and parental transmission to affected offspring. Overall,
      there was no convincing evidence that hKCa3 CAG lengths differ between
      schizophrenics and controls. We did, however, observe a trend (P = 0.063) toward
      over-representation of long (> or = 19) CAG repeats in the shorter of the two
      hKCa3 alleles in schizophrenics. There was no evidence of excessive parental
      transmission of long CAG repeat alleles to affected offspring. In addition, we re
      mapped hKCa3 and found that it resides on chromosome 1q21, in a region which has
      been linked to familial hemiplegic migraine, but not to schizophrenia. These data
      provide no significant support for the association of hKCa3 with schizophrenia.

PMID- 10395215
TI  - hKCa3/KCNN3 potassium channel gene: association of longer CAG repeats with
      schizophrenia in Israeli Ashkenazi Jews, expression in human tissues and
      localization to chromosome 1q21.
AB  - We demonstrate a significant association between longer CAG repeats in the
      hKCa3/KCNN3 calcium-activated potassium channel gene and schizophrenia in Israeli
      Ashkenazi Jews. We genotyped alleles from 84 Israeli Jewish patients with
      schizophrenia and from 102 matched controls. The overall allele frequency
      distribution is significantly different in patients vs controls (P = 0.00017,
      Wilcoxon Rank Sum test), with patients showing greater lengths of the CAG repeat.
      Northern blots reveal substantial levels of approximately 9 kb and approximately
      13 kb hKCa3/KCNN3transcripts in brain, striated muscle, spleen and lymph nodes.
      Within the brain, hKCa3/KCNN3transcripts are most abundantly expressed in the
      substantia nigra, lesser amounts are detected in the basal ganglia, amygdala,
      hippocampus and subthalamic nuclei, while little is seen in the cerebral cortex,
      cerebellum and thalamus. In situ hybridization reveals abundant hKCa3/KCNN3
      message localized within the substantia nigra and ventral tegmental area, and
      along the distributions of dopaminergic neurons from these regions into the
      nigrostriatal and mesolimbic pathways. FISH analysis shows that hKCa3/KCNN3 is
      located on chromosome 1q21.

PMID- 10395218
TI  - Genetic association study of a polymorphic CAG repeats array of calcium-activated
      potassium channel (KCNN3) gene and schizophrenia among the Chinese population
      from Taiwan.
AB  - Chandy et al suggested that a novel human neuronal small conductance, calcium
      activated potassium channel gene, KCNN3, might be a candidate for schizophrenia.
      The KCNN3 cDNA sequences contain two stretches of CAG trinucleotide repeats
      encoding two separate polyglutamine segments near the N-terminus of this channel
      protein. The second CAG repeat was found to be highly polymorphic in the
      Caucasian population from both Europe and USA. Upon comparing the allelic
      frequency distribution between schizophrenic patients and ethnically matched
      controls, a significant excess of longer CAG repeats in schizophrenic patients
      was observed. A similar result was obtained in a recent replication study by
      Bowen et al, performed in Caucasians from UK or Eire. These results suggest an
      association between the longer CAG repeat allele of the KCNN3 gene and
      schizophrenia susceptibility. To verify if similar results can be observed in the
      Chinese population, we carried out a case-control study to compare the allelic
      frequency distribution of the CAG repeat of the KCNN3 gene between 92 Chinese
      schizophrenic patients and 100 normal controls from Taiwan. No significant
      difference of the allelic frequency distribution of the second CAG repeats was
      detected between the two groups (Wilcoxon Rank Sum test, P = 0.664). In addition,
      no over-representation of CAG repeats longer than the mode (19 repeats) was found
      in the patients' group (Fisher's exact test, P = 0.739). Thus, our data do not
      support that the second polymorphic CAG repeat of the KCNN3 gene may have an
      association with schizophrenia in our population.

PMID- 10395217
TI  - Association between hSKCa3 and schizophrenia not confirmed by transmission
      disequilibrium test in 193 offspring/parents trios.
AB  - A possible association between the small conductance calcium-regulated potassium
      channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et
      al using a case-control design with patients with schizophrenia (n=141) and
      matched controls (n = 158). The gene may be considered as an excellent candidate
      gene for psychiatric disorders, since it plays a role in modulating neuronal
      firing patterns by regulating the slow component of after hyperpolarisation. In
      addition, the gene contains a highly polymorphic trinucleotide sequence (CAG)
      within exon 1, which encodes a polyglutamine stretch. The possible contribution
      of unstable trinucleotide repeats to the development of psychiatric disorders has
      previously been discussed. Chandy et al reported an over-representation of
      alleles with higher repeat number in schizophrenics as compared to controls (P =
      0.0035). In an attempt to replicate these findings, we have performed a family
      based study with 193 offspring/parent combinations using a sample of 49 multiplex
      families (two or more affected siblings with parents) and a second sample of 83
      simplex families (one affected offspring with parents). No evidence for the
      association of longer repeats with schizophrenia was obtained when each sample
      was tested separately or when both samples were combined and tested for
      transmission disequilibrium.

PMID- 10395220
TI  - Serotonin transporter gene (5-HTTLPR) is not associated with depressive
      symptomatology in mood disorders.
AB  - Disturbances of the serotoninergic neutrotransmitter system have been implicated
      in the pathogenesis of mood disorders. A functional polymorphism in the upstream
      regulatory region of the serotonin transporter gene (5-HTTLPR) has been recently
      reported to be associated with both unipolar and bipolar disorder. In this study,
      we investigated the possibility that the 5-HTTLPR might be associated with
      depressive symptomatology in a sample of mood disorder subjects. One hundred and
      thirty-two psychiatric inpatients affected by major depressive (n = 67) and
      bipolar (n = 65) disorder (DSM-IV) were assessed at admission by the Hamilton
      Depression Rating Scale (HAMD-21, divided into Core, Sleep, Activity, Psychic
      anxiety, Somatic anxiety and Delusion clusters) and were typed using PCR
      techniques. The only prior treatment permitted was low dose benzodiazepines (<5
      mg diazepam or equivalent); no prior (<2 weeks) antidepressant or neuroleptic
      treatment was allowed. 5-HTTLPR variants were not associated with total
      depressive symptomatology as measured by HAMD. The short 5-HTTLPR variant was
      marginally associated with higher psychic anxiety scores (F = 7.11, d.f. = 1,262,
      P = 0.008). The association was stronger among bipolars and early onset subjects.
      5-HTTLPR variants were not associated with the remaining symptom clusters. The
      upstream regulatory region of the serotonin transporter gene has not, therefore,
      a major influence on the depressive symptomatology in mood disorder subjects.

PMID- 10395219
TI  - Mutational analysis of phospholipase A2A: a positional candidate susceptibility
      gene for bipolar disorder.
AB  - Evidence for the involvement of genetic factors in the pathogenesis of bipolar
      affective disorder is now well established. However, the mode of inheritance is
      non-mendelian and this makes the identification of susceptibility loci difficult.
      A short-cut to localisation of a disease gene for an oligogenic/multifactorial
      disorder such as bipolar disorder may come from observation of cosegregation with
      a monogenic trait. We have described a family (pedigree 324) in which there was
      cosegregation of major affective disorder and Darier's disease, a dominantly
      inherited skin disorder, and hypothesised that this reflects genetic linkage
      between genes involved in these disorders. Genetic mapping studies have placed
      the locus for Darier's disease on chromosome 12q23-q24. We conducted subsequent
      linkage studies (1995) upon 45 bipolar families (without Darier's disease). These
      results showed some evidence in favour of linkage with chromosome 12q markers
      with maximum evidence at a trinucleotide repeat marker within intron 1 of the
      phospholipase A2A (PLA2A) gene. Evidence for linkage was more significant when
      analysing the 22 families comprising the Cardiff centre sample, which were
      expected to be most genetically similar to pedigree 324.

PMID- 10395221
TI  - Investigation of cholecystokinin system genes in panic disorder.
AB  - There is evidence for the role of the cholecystokinin (CCK) neurotransmitter
      system in the neurobiology of panic disorder (PD). The CCK receptor agonist, CCK
      tetrapeptide (CCK-4) fulfills criteria for a panicogenic agent and there is
      evidence that PD might be associated with an abnormal function of the CCK system.
      For example, PD patients show an enhanced sensitivity to CCK-4, and exhibit lower
      CSF and lymphocyte CCK concentration as compared to healthy controls (reviewed by
      Bradwejn et al.). Also, untreated PD patients display an increased CCK-4-induced
      intracellular Ca2+ mobilization in T cells relative to treated PD, depression and
      schizophrenia. The CCK receptors have been classified into two subtypes: CCK-A
      and CCK-B. We report here a study of polymorphisms in the CCK pre-pro hormone
      gene (CCK), CCK-AR, and CCK-BR in DSM-IV panic patients (n = 99) vs controls
      matched for gender and ethnicity. The CCK polymorphism revealed no association
      with PD. We identified a new polymorphism for the CCK-A receptor gene, and tested
      it in our sample, with negative results. A single nucleotide polymorphism has
      been found in the coding region of the CCK-B receptor gene (CCK-BR) and D Collier
      (personal communication) identified a highly polymorphic dinucleotide (CT)n
      microsatellite in the 5' regulatory region. For the CCK-B receptor gene
      polymorphism, PD patients showed a significant association. Our genetic
      dissection of the CCK system thus far suggests that the CCK-B receptor gene
      variation may contribute to the neurobiology of panic disorder.

PMID- 10395222
TI  - Association between the functional variant of the catechol-O-methyltransferase
      (COMT) gene and type 1 alcoholism.
AB  - Catechol-O-methyltransferase (COMT) is an enzyme which has a crucial role in the
      metabolism of dopamine. It has been suggested that a common functional genetic
      polymorphism in the COMT gene, which results in 3 to 4-fold difference in COMT
      enzyme activity, may contribute to the etiology of mental disorders such as
      bipolar disorder and alcoholism. Since ethanol-induced euphoria is associated
      with the rapid release of dopamine in limbic areas, it is conceivable that
      subjects who inherit the allele encoding the low activity COMT variant would have
      a relatively low dopamine inactivation rate, and therefore would be more
      vulnerable to the development of ethanol dependence. The aim of this study was to
      test this hypothesis among type 1 (late-onset) alcoholics. The COMT polymorphism
      was determined in two independent male late onset (type 1) alcoholic populations
      in Turku (n = 67) and Kuopio (n = 56). The high (H) and low (L) activity COMT
      genotype and allele frequencies were compared with previously published data from
      3140 Finnish blood donors (general population) and 267 race- and gender-matched
      controls. The frequency of low activity allele (L) was markedly higher among the
      patients both in Turku (P = 0.023) and in Kuopio (P = 0.005) when compared with
      the general population. When all patients were compared with the general
      population (blood donors), the difference was even more significant (P = 0.0004).
      When genotypes of all alcoholics (n = 123) were compared with genotypes of
      matched controls, the odds ratio (OR) for alcoholism for those subjects having
      the LL genotype vs those with HH genotype was 2.51, 95% CI 1.22-5.19, P = 0.006.
      Also, L allele frequency was significantly higher among alcoholics when compared
      with controls (P = 0.009). The estimate for population etiological (attributable)
      fraction for the LL genotype in alcoholism was 13.3% (95% CI 2.3-25.7%). The
      results indicate that the COMT polymorphism contributes significantly to the
      development of late-onset alcoholism.

PMID- 10395223
TI  - Polymorphisms in the dopamine D2 receptor gene and their relationships to
      striatal dopamine receptor density of healthy volunteers.
AB  - The density of striatal dopamine D2 receptors has been shown to vary considerably
      among healthy subjects. This variability might be due to genetic or environmental
      factors. In the present analysis we searched for relationships between dopamine
      D2 receptor gene (DRD2) polymorphisms and striatal dopamine D2 receptor density
      in vivo, as measured by positron emission tomography and [11C]raclopride in 56
      healthy subjects. There was a significant association between presence of a
      putative functional DRD2 promoter allele (-141C Del) and high striatal dopamine
      receptor density (t= 2.32, P= 0.02). In agreement with some previous studies the
      presence of the DRD2 TaqIA1 allele was associated with measures of low dopamine
      receptor density (t=2.58, P=0.01). Also the DRD2 TaqIB1 allele was associated
      with low dopamine receptor density (t= 2.58, P= 0.01) wheras there was no
      significant relationship between another common silent intronic DRD2 short tandem
      repeat polymorphism (STRP) and striatal dopamine D2 receptor density. The results
      suggest that DRD2 genotypes may participate differentially in the regulation of
      striatal dopamine D2 receptor density in healthy human subjects. The results
      should be interpreted with caution because of the limited sample size.

PMID- 10395224
TI  - Thyroid stimulating immunoglobulin (TSI) in Graves' disease.

PMID- 10395225
TI  - Molecular basis of resistance to thyroid hormone (RTH).

PMID- 10395226
TI  - Germline mutation of the multiple endocrine neoplasia type 1 (MEN1) gene in a
      family with primary hyperparathyroidism.
AB  - Familial primary hyperparathyroidism (FHP) is a rare hereditary disorder
      characterized by isolated parathyroid tumors without any other lesions related to
      multiple endocrine neoplasia (MEN). Primary hyperparathyroidism is usually
      expressed at an early age and is highly penetrated in MEN type 1 (MEN1),
      suggesting that some FHP may be a variant type or early stage of MEN1. The MEN1
      gene has recently been cloned and its germline mutations have been considered to
      play an important role in the tumorigenesis of MEN1. We studied a Japanese family
      with primary hyperparathyroidism which included 4 patients. To investigate the
      possible relationship between primary hyperparathyroidism in this family and the
      MEN1 gene, we analyzed a proband for a germline mutation of the MEN1 gene in this
      study. We identified a novel heterozygous mutation (1350del3) at codon 414 in
      exon 9. Restriction digestion analysis revealed the same mutation pattern in his
      brother with hyperparathyroidism. These findings suggest that our patients may
      belong to a variant type of MEN1.

PMID- 10395227
TI  - Prolactin-producing cells differentiate from G0/G1-arrested somatotrophs in
      vitro: an analysis of cell cycle phases and mammotroph differentiation.
AB  - In order to analyze the relationship between cell proliferation and mammotroph
      differentiation, we studied a somatotrophic cell line, MtT/S. MtT/S cell is known
      to differentiate into PRL-producing cells in response to stimulation with insulin
      or insulin-like growth factor-1 (IGF-1). Double immunostaining for
      bromodeoxyuridine (BrdU), which labels proliferating cells, and for GH or PRL
      showed that most BrdU-labeled cells were GH-immunopositive, whereas considerably
      few PRL-positive cells were labeled with BrdU. This was confirmed by
      immunostaining of proliferating cells with antibody to proliferating cell nuclear
      antigen (PCNA). Furthermore, flow-cytometry analysis indicated that most of the
      PRL-producing cells were in the G0/G1 phase of the cell cycle. In order to
      determine whether cell cycle changes are required for transdifferentiation of PRL
      producing cells, MtT/S cells were cultivated in serum restricted medium for 7
      days to reduce their mitotic activity and then treated with insulin and epidermal
      growth factor (EGF). Under these conditions, the cell cycle of MtT/S cells was
      significantly delayed, but the percentage of PRL-producing cells induced was
      almost identical to that under control conditions, showing that mitosis is not
      required for PRL- producing cell differentiation. We also labeled MtT/S cells
      with BrdU for 24 h during PRL-producing cell induction by insulin and EGF, and as
      a result BrdU-labeled proliferative cells were specifically absent from PRL
      producing cell populations. These data, taken as whole, suggest that PRL cells
      differentiated from G0/G1 arrested somatotrophs and the PRL cells which appeared
      had their cell proliferation activity significantly declined. In conclusion, this
      is the first report showing the relationship cell between proliferation and
      differentiation of PRL cells.

PMID- 10395228
TI  - Establishment of two substrains, diabetes-prone and non-diabetic, from Long-Evans
      Tokushima Lean (LETL) rats.
AB  - Diabetes mellitus in Long-Evans Tokushima Lean (LETL) rats closely resembles type
      1 diabetes in human beings, e.g., no gender differences in the incidence of
      diabetes and no T lymphopenia. Although the LETL rats have been established as an
      inbred strain, the incidence of diabetes is only approximately 20%. In the
      present study, we established two substrains, one a diabetes-prone (KDP) and the
      other a non-diabetic (KND) from the original inbred LETL rats. The features of
      KDP rats are a high incidence of diabetes (over all approximately 70%) without
      lymphopenia and 100% development of mild to severe insulitis at 120-220 days of
      age. In contrast, the KND substrain is characterized by the complete absence of
      diabetes incidence. Among 165 SSLP marker loci throughout all rat chromosomes, no
      loci showed variation among KDP and KND substrains and their parental LETL rats.
      In this regard, the genetic background of these two substrains, KDP and KND,
      appears to be uniform except for the major gene(s) that is responsible for the
      diabetes. In this context, these two substrains of LETL rats should serve as
      useful tools for research on the pathogenesis and for the genetic analysis of
      type 1 diabetes. In this report, we have not only established, but also
      characterized these two substrains, and provided their fundamental data.

PMID- 10395229
TI  - Evidence for an inverse relationship between apoptosis and inducible nitric oxide
      synthase expression in rat granulosa cells: a possible role of nitric oxide in
      ovarian follicle atresia.
AB  - Ovarian follicle atresia is thought to be induced through apoptosis of granulosa
      cells. This study was designed to investigate the possible involvement of nitric
      oxide (NO) in granulosa cell apoptosis. In immature rat ovaries obtained 48 h
      after pregnant mare serum gonadotropin administration, immunohistochemistry and
      terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling
      (TUNEL), a method to detect apoptotic cells, revealed that inducible NO synthase
      (iNOS) was predominantly localized in granulosa cells in most healthy immature
      follicles with TUNEL-negative granulosa cells. In contrast, all atretic follicles
      with TUNEL-positive granulosa cells were iNOS-negative whatever the developmental
      stage of the follicle. In cultured granulosa cells, the addition of S-nitroso-N
      acetyl-DL-penicillamine (SNAP), an NO generator, directly inhibited spontaneously
      occurring apoptosis. These results suggest that NO produced by iNOS in granulosa
      cells of immature follicles may prevent ovarian follicle atresia by inhibiting
      granulosa cell apoptosis in an autocrine/paracrine manner.

PMID- 10395230
TI  - A family of MEN1 with a novel germline missense mutation and benign
      polymorphisms.
AB  - The gene responsible for multiple endocrine neoplasia type 1 (MEN1) has recently
      been cloned, and its germline mutations were identified in patients with this
      syndrome. The majority of the mutations, frameshift or nonsense mutations, are
      expected to result in a loss of function of the gene product menin. Since the
      consequence of less common missense or in-frame deletion mutations is not clear,
      careful judgment is necessary regarding the role(s) of such mutations in MEN1
      disease. Here we describe a large multigenerational MEN1 family with a novel
      germline missense mutation and three benign polymorphisms. The proband was a man
      with hyperparathyroidism and thymic carcinoid. We performed biochemical studies
      and DNA analyses of the MEN1 gene simultaneously and independently as family
      screening studies. Seven patients including the proband were identified, and all
      of them carried a heterozygous germline missense mutation E45G, but 5 members
      with normal biochemical results did not. This mutation was not observed in 50
      normal volunteers. This novel missense mutation is therefore almost conclusively
      responsible for the disease. Although all of the mutant gene carriers in the
      present study already had clinical diseases, an MEN1 gene analysis in younger
      individuals at risk would be very useful in identifying carriers before the onset
      of the symptoms.

PMID- 10395231
TI  - Evaluation of highly sensitive thyrotropin assay for detecting thyroid diseases
      in neonatal screening: preliminary studies.
AB  - TSH concentrations in dried blood samples on filter paper were determined by a
      conventional enzyme-linked immunosorbent assay (ELISA), used for routine neonatal
      screening for primary hypothyroidism, and a highly sensitive bioluminescence
      ELISA (BL-ELISA) using firefly luciferase to examine whether central
      hypothyroidism and hyperthyroidism can be efficiently detected as cases of
      primary hypothyroidism. Samples were obtained from 3 patients with congenital
      central hypothyroidism, 5 patients with congenital primary hypothyroidism, 6
      patients with hyperthyroidism, 31 neonatal babies with low birth weight
      (premature babies) and 242 newborn babies with normal birth weight from the
      general population (normal babies). The TSH values were low in central
      hypothyroidism and hyperthyroidism. Their deviations from the mean TSH value for
      normal babies by the BL-ELISA method (-3.12 SD and -4.79 SD in central
      hypothyroidism and hyperthyroidism respectively) were greater than those by the
      ELISA method (-2.00 SD and -2.97 SD respectively). The TSH values were high in
      primary hypothyroidism and normal in premature babies while deviations were the
      same when BL-ELISA and ELISA were used. These findings indicate that the highly
      sensitive TSH assay (BL-ELISA) can be used for detecting both primary and central
      hypothyroidism as well as hyperthyroidism in neonatal screening.

PMID- 10395232
TI  - Measurement of red blood cell zinc concentration with Zn-test kit: discrimination
      between hyperthyroid Graves' disease and transient thyrotoxicosis.
AB  - We have previously reported in patients with hyperthyroidism that the red blood
      cell (RBC) zinc (Zn) concentration reflects the mean thyroid hormone
      concentration over the preceding months. In the present study, the concentration
      of RBC Zn was measured by a simple and easy method with a Zn-test Wako kit.
      Within-run and between-run precision were 1.4% and 1.3%, respectively. The
      relationship between RBC concentration and dilution was linear. The average
      recovery was 103%. A good correlation (r=0.97) was obtained between this method
      and atomic absorption spectrophotometry. The mean concentration of RBC Zn in 39
      euthyroid controls was 12.6 +/- 1.3 mg/l, ranging from 10.4 to 15.1 mg/l. The RBC
      Zn concentrations in 38 patients with Graves' disease, in 10 patients with silent
      thyroiditis and in 3 patients with gestational thyrotoxicosis were 7.3 +/- 1.6
      (3.2-9.8), 12.0 +/- 1.6 (9.5-14.2) and 11.8 +/- 1.7 (10.5-13.7) mg/l,
      respectively. The concentration of RBC Zn was able to differentiate hyperthyroid
      Graves' disease from transient thyrotoxicosis except in 1 case and was a better
      index than TSH-binding inhibitory immunoglobulin. These results indicate that
      measuring RBC Zn with the Zinc-test Wako kit is very useful in differentiating
      hyperthyroid Graves' disease from transient thyrotoxicosis.

PMID- 10395233
TI  - Hypercalcemia in an euthyroid patient with secondary hypoadrenalism and diabetes
      insipidus due to hypothalamic tumor.
AB  - A 20-year-old Japanese man with a hypothalamic tumor (most likely germ-cell
      tumor) which caused secondary hypoadrenalism, hypogonadism and diabetes insipidus
      developed hypercalcemia and acute renal failure. The serum levels of intact PTH
      (iPTH), PTH-related protein (PTH-rP), 1,25-dihydroxy vitamin D (1,25- (OH)2 D),
      ACTH, cortisol, gonadotropins and testosterone were decreased, but his serum
      levels of triiodothyronine (T3) and thyroxine (T4) were within the normal range
      at admission, with depressed TSH and slightly increased thyroglobulin. The
      hypercalcemia was refractory to extensive hydration and calcitonin, but was
      ameliorated by pamidronate. After irradiation of the hypothalamic tumor,
      panhypopituitarism gradually developed. The patient has been normocalcemic for
      the last 2 years and is doing well under replacement therapy with glucocorticoid,
      L-thyroxine, methyltestosterone and 1-desamino D arginine vasopressin (dDAVP). As
      to the mechanism of euthyroidism at admission, transient destructive thyroiditis
      associated with hypopituitarism or delayed development of hypothyroidism
      following the hypoadrenalism was suggested. This is the first reported case of
      hypercalcemia in secondary hypoadrenalism due to hypothalamic tumor.
      Hypercalcemia was most likely induced by increased bone resorption, which was
      probably elicited by the combined effects of deficient glucocorticoid and
      sufficient thyroid hormones in addition to hypovolemia and reduced renal calcium
      excretion. Furthermore, severe dehydration due to diabetes insipidus and
      disturbance of thirst sensation caused by the hypothalamic tumor aggravated the
      hypercalcemia, leading to acute renal failure.

PMID- 10395235
TI  - A progesterone antagonist cannot prevent fetal survival if the uterine horn is
      incised.
AB  - The fetuses released into the abdominal cavity by uterine incision escape from
      most physical influences of the uterus. This study examined whether these fetuses
      require progesterone actions for survival during late pregnancy in rats. A
      longitudinal incision in one uterine horn (with the other horn intact) together
      with bilateral ovariectomy (OVX), removal of the main progesterone-production
      sites, or sham OVX, were performed on day 18 of pregnancy. Thereafter the rats
      were given daily subcutaneous injections of anti-progesterone RU 486 (10 mg/kg),
      or vehicle alone, and the fetal survival rate in each uterine horn was examined
      on day 21. In those controls which received sham OVX plus injections of vehicle,
      fetal survival rates were more than 80% in both uterine horns. In the other
      groups, which received sham OVX plus injections of RU 486, or OVX plus injections
      of vehicle, or OVX plus injections of RU 486, the fetal survival rates in the
      intact uterine horns were 4%, 0% and 0%, respectively. In the incised uterine
      horns of these groups, however, the fetal survival rates were 59%, 67% and 56%,
      respectively. The results suggest that progesterone, which is required for
      maintaining pregnancy, may not be essential for survival of fetuses released into
      the abdominal cavity. Progesterone actions unrelated to uterine physical
      environment are likely to be dispensable for fetal survival during late pregnancy
      in rats.

PMID- 10395234
TI  - Contribution of a missense mutation (Trp64Arg) in beta3-adrenergic receptor gene
      to multiple risk factors in Japanese men with hyperuricemia.
AB  - Epidemiological data reveal that hyperuricemia is a risk factor of
      atherosclerosis. The risk is possibly caused by a link between hyperuricemia and
      insulin resistance-related metabolic syndrome. Recently it has been proposed that
      a missense mutation (Trp64Arg) in the beta3-adrenergic receptor (beta3-AR) gene
      may contribute to the accumulation of multiple risk factors related to insulin
      resistance. The present study was undertaken to further clarify an association
      between the Trp64Arg mutation and the metabolic syndrome in 47 Japanese men with
      hyperuricemia, who are substantially at high risk of atherosclerosis. One patient
      (2%) had the homozygous mutation, 12 (26%) were heterozygous for the mutation,
      and 31 (72%) had no mutation found by the PCR-RFLP analysis. The Trp64Arg
      mutation was not related to past maximal body mass index (BMI), BMI and waist/hip
      ratio. The subjects with the heterozygous mutation showed a slightly higher
      incidence of impaired glucose tolerance and diabetes mellitus in the 75 g oral
      glucose challenge (67%), as compared with those without the mutation (39%). Serum
      insulin response at 60 min and the sum of serum insulin in the glucose challenge
      were greater in the former subjects than those in the latter subjects (P=0.041
      and 0.076, respectively). An increase in serum lipoprotein(a) was also observed
      in the subjects with the heterozygous mutation, but the Trp64Arg mutation was not
      associated with other dyslipidemia, blood pressure or ischemic changes on the
      electrocardiogram. These results indicate that the heterozygous mutation of
      Trp64Arg in the beta3-AR gene partly contributes to the accumulation of multiple
      risk factors in male subjects with hyperuricemia. A larger prospective study is
      necessary to elucidate a possible role of the Trp64Arg mutation in
      atherosclerotic diseases in future.

PMID- 10395236
TI  - A missense mutation of C1659 in the fibroblast growth factor receptor 3 gene in
      Russian patients with hypochondroplasia.
AB  - To carry out the genetic screening for the common mutation in the first tyrosine
      kinase domain (TK1) of the fibroblast growth factor receptor 3 gene (FGFR3) in a
      Russian population, a cohort of 16 patients with hypochondroplasia diagnosed
      previously were studied, among them twelve familial cases and four sporadic
      cases. The heterozygous N540K FGFR3 mutation was detected in 9 cases (56.3%) due
      to that C1659A substitution in 6 patients and C1659G substitution in 3 patients,
      respectively. The ratios of familial and sporadic cases among patients which
      carried FGFR3 mutation were similar. Seven (43.7%) patients, negative cases of
      N540K mutation, were all familial cases. Our results support evidence of similar
      frequency of common type N540K mutation of FGFR3 in Russian hypochondroplasia and
      of the genetic heterogeneity of hypochondroplasia, suggesting the need for
      further search for responsible molecular abnormalities for phenotypically similar
      hypochondroplasia patients negative for TK1 domain mutation in FGFR3, reported in
      hypochondroplasia.

PMID- 10395237
TI  - Urinary iodine and thyroid antibodies in Okinawa, Yamagata, Hyogo, and Nagano,
      Japan: the differences in iodine intake do not affect thyroid antibody
      positivity.
AB  - Excess iodine intake may affect the development of Hashimoto's thyroiditis. Kelp
      consumption is very high in Okinawa. We expected a high prevalence of Hashimoto's
      thyroiditis in Okinawa. We studied urinary iodine excretion and the positivities
      of anti-thyroglobulin antibodies (TGAb) and anti-thyroid peroxidase antibodies
      (TPOAb) in the residents of Nishihara in Okinawa, Yamagata in Yamagata, Kobe in
      Hyogo, and Hotaka in Nagano, Japan. TGAb and/or TPOAb were positive in 142
      (13.7%) of 1039 subjects in Nishihara, in 16 (16.0%) of 100 subjects in Yamagata,
      in 31 (13.4%) of 232 subjects in Kobe, and in 35 (13.9%) of 252 subjects in
      Hotaka; TGAb and/or TPOAb positivity was about the same in these 4 areas. One
      tenth of the subjects with positive TGAb and/or TPOAb had hypothyroidism; the
      frequencies of hypothyroidism in those with positive TGAb and/or TPOAb were about
      the same in Nishihara, Yamagata, Kobe, and Hotaka. The iodine concentration in
      samples of morning urine correlated well with the 24-h urine iodine excretion.
      The urinary iodine excretion was 1.5 mg/day in Nishihara. There were no
      differences between Nishihara and Yamagata in the urinary iodine concentration,
      but the urinary iodine concentrations in Kobe and Hotaka were less than those in
      Nishihara or Yamagata. The amounts of iodine excretion in Kobe and Hotaka were
      moderate, and less than those in Nishihara or Yamagata. The amounts of iodine
      intake in Kobe and Hotaka were less than those in Nishihara or Yamagata, but TGAb
      and/or TPOAb positivity was about the same in Nishihara, Yamagata, Kobe, and
      Hotaka. The differences in dietary iodine intake do not affect TGAb and/or TPOAb
      positivity.

PMID- 10395238
TI  - A questionnaire study on outcome of transsphenoidal surgery for Cushing's disease
      in Japan.

PMID- 10395239
TI  - Acute myocardial infarction due to vasospasm in isolated adrenocorticotropin
      deficiency.

PMID- 10395240
TI  - Inappropriate elevation of intact PTH in the presence of normocalcemia after
      successful surgery for primary hyperparathyroidism.
AB  - We describe here a patient with primary hyperparathyroidism who had high serum
      intact PTH levels for over 16 months after parathyroidectomy without signs of
      recurrence or persistence of the disease. The patient was a 48-year-old female
      who appeared well nourished (body mass index, 23.7). She was received subtotal
      gastrectomy as treatment for a duodenal ulcer at 44 years and 5 months old and
      had reached menopaused at 46 years of age. Hypercalcemia and a high serum intact
      PTH level were pointed out three months before admission to our institute. A bone
      densitometric study revealed that the bone mass of the lumbar spine was extremely
      reduced (0.636 g/cm2, Z score, -2.17) preoperatively and had not increased 29.5
      months after parathyroidal adenomectomy (0.656 g/cm2, Z score, -1.97).
      Hyperparathyroidism, menopause and gastrectomy may have together contributed to
      the reduced bone mass. The postoperative persistently increased PTH levels in our
      patient suggest that the remaining parathyroid glands could have been altered
      during hypercalcemia, causing an increase in the set-point of PTH secretion by
      serum calcium or a decrease in the renal responsiveness to PTH during the
      disease.

PMID- 10395242
TI  - Mitochondrial DNA point mutation at nucleotide pair 3316 in a Japanese family
      with heterogeneous phenotypes of diabetes.
AB  - A mitochondrial DNA (mtDNA) point mutation at nucleotide pair (np) 3316 has been
      reported in relation to diabetes. We recently encountered a non-obese family with
      this type of mutation. The proband in the affected family, a 49-year-old woman
      who had been previously diagnosed as having an insulin-requiring non-insulin
      dependent diabetes mellitus (NIDDM), was referred to our hospital for treatment
      of diabetic gangrene in her left foot. Her insulin secretory capacity was
      markedly reduced, but the insulin sensitivity evaluated by the euglycemic
      hyperinsulinemic clamp technique was normal. In addition, her serum lactate level
      was markedly increased after a 5 min ambulation, although her serum pyruvate and
      ketones remained within the normal range. Twenty-year-old twin sons had been
      treated with insulin since the age of 7, when both were diagnosed with insulin
      dependent diabetes mellitus (IDDM). The proband's mother, a 68-year-old, was
      nondiabetic at this time. MtDNA analysis revealed a point mutation at np 3316 in
      all family members, which was homoplasmic for the mutation on a photograph of
      agarose gel electrophoresis containing ethidium bromide under ultraviolet light.
      This mutation seemed to be maternally transmitted in the family, and the onset of
      diabetes was occurring earlier and the insulin secretory capacity was declining
      from generation to generation, so that these findings suggest that the point
      mutation at np 3316 is associated with various phenotypes of diabetes.

PMID- 10395241
TI  - Hypocalcemia due to spontaneous infarction of parathyroid adenoma and
      osteomalacia in a patient with primary hyperparathyroidism.
AB  - A 49 year-old Japanese woman had subjected enlargement of a cervical tumor, and
      also suffered two bone fractures in 2 years. The cervical tumor had enlarged
      further in the month prior to admission, becoming warm and tender.
      Endocrinological examination revealed that the serum intact PTH concentration was
      remarkably high at 400 pg/mL despite the low serum calcium concentration, and
      that the serum vitamin Ds concentration was decreased. Bone roentgenograms
      revealed severe osteolytic changes compatible with osteitis fibrosa cystica and a
      pathologic fracture of the humerus. Under a diagnosis of primary
      hyperparathyroidism, parathyroidectomy was performed, followed by fixation
      surgery for the pathologic fracture. Histologically, the cervical tumor was a
      parathyroid chief-cell adenoma with massive necrosis, and the bone pathology by
      iliac bone biopsy revealed the existence of osteomalacia. She was treated with
      calcium, vitamins D and K2 and calcitonin after the surgery. This case is a rare
      condition manifesting hypocalcemia with catastrophic osteoporosis under the
      coexistence of spontaneous infarction of parathyroid adenoma with osteomalacia,
      suggesting that the clinical features of hyperparathyroidism are modified by both
      the autoparathyroidiectomy and the existence of osteomalacia due to vitamin D
      deficiency.

PMID- 10395243
TI  - Supra- and extrasellar pituitary microadenoma as a cause of Cushing's disease.
AB  - There has been accumulating evidence that pituitary adenomas which cause
      Cushing's disease are located not only in sella turcica but also in various
      extrasellar and intracranial regions. We describe a case of Cushing's disease
      caused by a supra- and extrasellar ACTH-producing microadenoma, which originated
      in the anterior pituitary and extended upward without connecting to the stalk.
      The pituitary microadenoma was identified and removed by transsphenoidal
      microsurgery. After the surgery the patient experienced complete remission. This
      type of pituitary microadenoma is considered to be rare, but in order to
      accomplish successful surgical treatment, it is necessary to consider that
      pituitary adenomas which cause Cushing's disease may be located in such an
      unusual position.

PMID- 10395244
TI  - Familial isolated hyperparathyroidism caused by single adenoma: a distinct entity
      different from multiple endocrine neoplasia.
AB  - Familial hyperparathyroidism (FHPT) is a hereditary disease where
      hyperparathyroidism (HPT) is transmitted in an autosomal dominant fashion. FHPT
      consists of a variety of diseases such as multiple endocrine neoplasia type1 (MEN
      1) and type2 (MEN 2), familial isolated hyperparathyroidism (FIHPT) with single
      adenoma and with multiple adenomas (or hyperplasia), and FHPT with jaw-tumor
      (FHPT-JT). Isolation of the genes responsible for MEN1, and 2, i.e. MEN1 and RET,
      respectively, makes it possible to examine the relations among disorders
      constituting FHPT. We studied germ-line mutations in these 2 genes in a family of
      FHPT with single parathyroid adenoma. The disorder in this family was proved to
      be an entity different from MEN1 because no germ-line mutations in MEN1 gene were
      found in the affected members. The loss of heterozygosity (LOH) at MEN1 gene and
      PYGM were not found in the abnormal parathyroid in this family, supporting the
      above conclusion. No mutations in exons 10, and 11 of RET proto-oncogene was
      found in germ-line DNA of the affected member of the family, suggesting no
      relation to MEN2A. Linkage study excluded the possibility of FHPT-JT syndrome.
      PRAD1 was not overexpressed in the parathyroid tumors in this family. The
      relation of this disorder to FIHPT with multiple enlarged parathyroid glands
      remains to be clarified. A search for the gene(s) predisposing to FIHPT is
      needed.

PMID- 10395245
TI  - Acute and chronic regulation of ob mRNA levels by beta3-adrenoceptor agonists in
      obese Yellow KK mice.
AB  - The inhibitory effect of beta3-adrenoceptor agonists on the ob gene in brown
      adipose tissue (BAT) and white adipose tissue (WAT) is now well documented both
      in vivo in lean animals and in vitro, but the reported effects of beta3
      adrenoceptor agonists on ob gene expression in obese animals remain
      controversial. We investigated whether ob gene expression in BAT and WAT is
      reduced by acute and chronic administrations of a beta3-adrenoceptor agonist,
      CL316,243 (CL). The ob gene mRNA levels in BAT, perimetric and inguinal WAT of
      obese Yellow KK mice were about 4-fold higher than those of lean controls. Acute
      exposure (6 h) to CL decreased ob gene mRNA levels in three fat depots in both
      animals. Chronic exposure (10 days) to CL also decreased ob gene mRNA levels in
      BAT, perimetric, and inguinal WAT in both animals. We concluded that acute and
      chronic regulation by a beta3-adrenoceptor agonist suppressed ob gene expression
      in obese Yellow KK mice and lean controls.

PMID- 10395246
TI  - Detection of a novel nonsense mutation of the MEN1 gene in a familial multiple
      endocrine neoplasia type 1 patient and its screening in the family members.
AB  - We identified a novel nonsense mutation(R29X) of the MEN1 gene in a familial
      multiple endocrine neoplasia type 1 (MEN1) patient. Molecular analysis of the
      MEN1 gene was performed in the family members by a restriction digestion method.
      The same mutation pattern was seen in both the proband's younger brother and
      cousin diagnosed as MEN1, and was also observed in the son of the cousin who
      showed signs of normal levels of serum PTH associated with mild hypercalcemia and
      hypophosphatemia. These findings suggest that mutation analysis of the MEN1 gene
      is very useful in identifying the subclinical state of MEN1 as well as clinical
      MEN1.

PMID- 10395247
TI  - Evaluation of the role of N-linked oligosaccharides in rat placental lactogen
      action by site-directed mutagenesis.
AB  - To evaluate the role of N-linked oligosaccharides in the molecular action of rat
      placental lactogen (PL), recombinant PL-Im (recPL-Im) and three recPL-Im mutants
      were produced in COS-7 cells. The mutants, carrying Gln substitutions of Asn at
      putative N-glycosylation sites, were generated via site-directed mutagenesis,
      i.e. two single mutants (N79Q, N128Q) and one double mutant (N79Q/N128Q). Western
      blot analysis revealed that wild type recPL-Im had a molecular mass of 34 kDa ,
      which was reduced to 29 kDa by tunicamycin present during expression. N79Q and
      N128Q had a lower molecular mass than the wild type, and a further decrease was
      observed for N79Q/N128Q. PL-Im was therefore N-glycosylated at both Asn79 and
      Asn128. Treatment of the wild type with neuraminidase caused a reduction in
      molecular mass, indicating that the N-linked oligosaccharides contained N
      acetylneuraminic acids. In the Nb2 cell bioassay for lactogenic hormones, recPL
      Im and its mutants all had growth-promoting activity but there was a decline in
      the growth-stimulating potency following decreases in N-glycosylation, i.e. the
      order of relative potencies was the wild type>N128Q> N79Q>N79Q/N128Q, suggesting
      that the N-linked oligosaccharides are important in the mitogenic action of the
      PL-Im. Wild type and all mutants had rat PRL receptor (PRL-R)-binding activity in
      radioreceptor assays and stimulated JAK2 phosphorylation in Nb2 cells.
      Interestingly however, the binding activity to PRL-R and phosphorylation of JAK2
      was similar in the wild type and mutants, and these results are not in accord
      with the biological activity. In conclusion, the study suggested that PL-Im has
      two N-linked oligosaccharides which are involved in its biological activity. The
      ability of PL-Im to bind PRL-R and activate JAK2 appears to be independent of the
      N-glycosylation.

PMID- 10395248
TI  - A potential risk for osteomalacia due to sociocultural lifestyle in Turkish
      women.
AB  - Osteomalacia is a metabolic bone disease caused by deficiency of vitamin D or its
      active metabolites. Because poor sunlight exposure is one of the most common
      causes of osteomalacia, the disease seems to be rare in countries with adequate
      sunlight. We report nine Turkish female patients with osteomalacia with ages
      between 21 and 50 years. Osteomalacia was diagnosed on the basis of a history of
      bone aches or pains, muscle weakness, low or low normal serum calcium and urinary
      calcium, decreased concentrations of serum inorganic phosphorus and 25-
      hydroxyvitamin D and increased serum intact PTH and alkaline phosphatase levels.
      Radiographically, pseudo-fractures were present in seven of the patients. The
      patients' symptoms and signs were relieved with the treatment with vitamin D
      analogues and calcium. Their hypovitaminosis D are suggested to be caused by
      excessive clothing in the outdoors due to sociocultural and religious reasons.
      Excessive clothing may be a risk factor for osteomalacia in young to middle-aged
      and otherwise healthy women even in countries with adequate sunlight.

PMID- 10395249
TI  - Bone metabolism after human parturition and the effect of lactation: longitudinal
      analysis of serum bone-related proteins and bone mineral content of the lumbar
      spine.
AB  - A prospective study was performed to investigate postpartum changes in human bone
      metabolism and the effects of lactation on them. The subjects consisted of two
      groups: 13 women who stopped breast-feeding within 3 months postpartum (short
      term group) and 14 women who continued breast-feeding for more than 6 months
      postpartum (long-term group). Serum carboxyl-terminal propeptide of type I
      procollagen (PICP), carboxyl terminal cross-linked telopeptide of type I collagen
      (ICTP), and bone gla protein (BGP) were measured prepartum, and at 5 days, 1
      month, 3 months and 9 months postpartum. Lumbar BMD was measured at 3-7 days, 3
      months and 9 months postpartum. Between prepartum and 3 months postpartum, the
      values and variations in the markers were essentially the same in both groups.
      PICP was maintained at a constant and significantly higher level than the control
      value. In contrast, ICTP had increased markedly at 5 days postpartum, gradually
      decreasing thereafter. BGP was low prepartum and gradually increased. At 9 months
      postpartum, PICP and ICTP decreased to the control values in the short-term
      group. The postpartum time course of lumbar BMD showed a significant decrease in
      both groups at 3 months postpartum. Recovery to the puerperal level was seen at 9
      months postpartum in the short-term group but not in the long-term group. In
      conclusion, bone resorption is stimulated by parturition as well as lactation
      resulting in postpartum loss of lumbar BMD.

PMID- 10395250
TI  - An acromegalic patient with pulsatile secretion of growth hormone (GH) coincident
      with the slow-wave sleep.
AB  - A 43-year-old woman was admitted to our hospital for further treatment of
      acromegaly with high plasma GH and IGF-I levels after transsphenoidal
      adenomectomy and subsequent treatment with bromocriptine. Physical examination
      and magnetic resonance imaging (MRI) showed an active acromegalic appearance with
      residual pituitary macroadenoma. Laboratory findings revealed an increase in
      basal levels of plasma GH (21.3 microg/L) and plasma IGF-I (470 ng/ml). Plasma GH
      levels were suppressed from 21.3 microg/L to 9.9 microg/L following oral
      administration of 75 glucose and did not respond to either TRH or LHRH injection.
      When plasma GH levels were measured after repeated blood sampling every 20 min
      for 24 h and sleep stages were analyzed, there were three GH peaks during the
      night which corresponded to the slow-wave sleep. Mean plasma GH levels which
      corresponded to the slow-wave sleep stages were much greater than those of other
      sleep stages during the night. After the patient was treated with intermittent sc
      injections of octreotide (40 microg/every 2 h, 480 microg/day) in combination
      with oral administration of bromocriptine (15 mg/day, t.i.d.), episodic GH
      release was somewhat suppressed but plasma GH levels were slightly increased,
      corresponding to the slow-wave sleep stage during the night. Mean plasma GH
      levels were much higher during the sleeping period than the waking period for 24
      h before and after the treatment. These findings suggest that GH secretion is
      correlated to the slow-wave sleep in this particular patient with pituitary GH
      producing adenoma.

PMID- 10395251
TI  - Pregnant woman with transient diabetes insipidus resistant to 1-desamino-8-D
      arginine vasopressin.
AB  - We encountered a pregnant woman with transient diabetes insipidus which developed
      during the third trimester. A hypertonic saline infusion study did not
      concentrate the osmolality of urine. Her laboratory data showed hypokalemia,
      hyperreninemia, an increased concentration of plasma aldosterone and an increased
      urinary excretion rate of prostaglandin E2, which resembled hyperprostaglandin E
      syndrome. T1-weighted magnetic resonance imaging of the posterior pituitary gland
      revealed decreased intensity. Polyuria reached 4-6 L daily, and urine osmolality
      remained dilute despite a lapse of four days since treatment with intranasal 1
      desamino-8-D-arginine vasopressin (dDAVP: 10-25 microg every 12 h). The patient
      was conservatively managed without medical treatment, then delivered in the 38th
      week of pregnancy without complication. The osmolality of the patient's urine was
      higher than that of the plasma when tested 3 days postpartum. The abnormality of
      magnetic resonance imaging of the posterior pituitary gland disappeared at 6
      months after delivery. We consider that subclinical nephrogenic diabetes
      insipidus in our patient was exacerbated during pregnancy.

PMID- 10395252
TI  - A case of autoimmune hypophysitis associated with asymptomatic primary biliary
      cirrhosis.
AB  - We report a 61-year old male patient with panhypopituitarism complicated with
      asymptomatic primary biliary cirrhosis (PBC). T1-weighted magnetic resonance
      imaging demonstrated high intensity of the anterior pituitary gland. There was no
      mass lesion or enlargement of the pituitary gland or the stalk. Immunoblot
      analysis of the patient's sera with rat pituitary antigens revealed a band with a
      molecular size of 22 kD. Anti-M2 mitochondrial antibody has been consistently
      positive for five years. Liver biopsy revealed portal hepatitis with periportal
      infiltration of the inflammatory cells. This is the first case report of
      autoimmune hypophysitis complicated with asymptomatic PBC.

PMID- 10395253
TI  - 25th Annual Vascular Surgery Seminar and Meeting of the Society for Military
      Vascular Surgery.
AB  - The 25th Annual (Silver Anniversary) Vascular Surgery Seminar and Meeting of the
      Society for Military Vascular Surgery was held in the Jay P. Sanford Auditorium
      at the F. Edward Hebert School of Medicine, Uniformed Services University of the
      Health Sciences (USUHS), 4-6 December 1997. This highly successful exchange
      included active duty military surgeons, military surgeons in the reserves,
      retired military officers continuing second careers in civilian vascular surgery,
      distinguished visiting professors from the United States and abroad,
      International Guest Scholars, USUHS Faculty as well as colleagues and friends.
      The emphasis continued to be directed to ensuring that military vascular surgery
      remains current, recognizing the rich heritage of contributions to vascular
      surgery in general that have come from surgeons serving on battlefields around
      the world, particularly in this 20th century.

PMID- 10395254
TI  - Restenosis after carotid endarterectomy.

PMID- 10395255
TI  - Five-year experience with endovascular grafts for the treatment of aneurysmal,
      occlusive and traumatic arterial lesions.
AB  - Standard therapy for most aneurysmal, occlusive, and traumatic arterial lesions
      has historically consisted of surgical exposure and repair or placement of an
      interposition bypass graft. Endovascular grafting techniques are an alternative
      treatment. These techniques blend stent and graft technology and enable a
      vascular graft to be placed from a remote access site under fluoroscopic guidance
      to treat a variety of arterial lesions. The major advantage of this approach is
      its less invasive nature. During the last 5 years, 234 endovascular grafts have
      been implanted at Montefiore Medical Center to treat a variety of arterial
      lesions including aneurysms, occlusions and traumatic or iatrogenic injuries.
      Although many of these procedures were complex and difficult, results have
      improved steadily as appropriate devices, techniques and indications have been
      developed. These endovascular grafts have facilitated successful treatment in
      many patients and have permitted correction of limb- or life-threatening lesions
      in some patients who would otherwise be impossible or difficult to treat. Based
      on this 5-year experience, it is likely that endovascular grafts will play an
      important role in the future treatment of various types of arterial pathology.
      Although the value and limitations of endovascular graft for the treatment of
      aneurysmal and occlusive lesions in good-risk patients remains to be precisely
      defined, their usage in high-risk patients and in those with iliac aneurysms and
      central artery traumatic false aneurysms and arteriovenous fistula already
      appears justified.

PMID- 10395256
TI  - Natural history of congenital arteriovenous fistula.
AB  - There is no more difficult lesion to manage than congenital arteriovenous
      fistula. The advanced lesions are extremely vascular and unless they lend
      themselves to total excision, prompt recurrence is the rule. For the same reason,
      embolization is not successful and as the major feeding vessels are occluded,
      access to the tumor becomes more and more limited. In order to obliterate the
      tumor, it must be destroyed at the microvascular level. So far, only ethanol has
      proved effective in this regard, and this agent must be used conservatively to
      avoid excessive destruction of normal tissue and systemic damage.

PMID- 10395257
TI  - Potential of a hand-held ultrasound in assessment of the injured patient.
AB  - Current studies indicate that portable ultrasound used by trained trauma surgeons
      in the emergency room can be performed using the focused abdominal sonogram for
      trauma technique in approximately 2 minutes to evaluate patients with blunt torso
      trauma. It has been shown to be as accurate as DPL and computed tomography (CT)
      in the detection of hemoperitoneum following abdominal trauma. It is also very
      accurate in detecting pericardial fluid and may have a role in the evaluation of
      penetrating injuries of the thorax, either from stab or gunshot wounds. The
      examination is best performed early on in the secondary survey of the injured
      patient. Miniaturization and hand-held ultrasound units are on the horizon. The
      faculty of the University of Washington in Seattle in conjunction with the
      Advanced Technology Laboratories in Seattle and the Advanced Research Project
      Agency of the Department of Defense are producing a battlefield hand-held
      ultrasound with the ultimate goal to have an ultrasound unit that will fit in the
      trauma surgeon's pocket. With the use of this new technology, the potential for
      early diagnosis of victims of trauma and prompt treatment is at hand. One of the
      greatest challenges remaining is that of training surgeons in the use of
      ultrasound. The author's experience in conducting ultrasound courses for surgeons
      at the Uniformed Services University of the Health Sciences is described.

PMID- 10395258
TI  - Arterial reconstruction with vascular clips is safe and quicker than sutured
      repair.
AB  - BACKGROUND: Non-penetrating, arcuate-legged vascular-closure staple clips made of
      titanium were initially developed for microvascular anastomoses with little
      experience of their use in larger vessels. The purpose of this study was to
      compare vascular-closure staple clips to sutured anastomoses in common iliac
      arteries in a porcine model. METHODS: In an experimental study, transected iliac
      arteries on both sides of 11 pigs were randomly assigned to end-to-end
      anastomosis performed with vascular-closure staple clips or interrupted 6-0
      polypropylene sutures. Angiographic, macroscopic and microscopic results were
      assessed after 2 months. RESULTS: There was no significant difference in the
      patency rate, tensile strength of the anastomoses, vessel diameter at the repair
      site, intimal thickness or wall thickness of the arteries after either method of
      closure. The mean (s.d.) clamp time was 19.8 (6.1) minutes for clip repair, and
      36.0 (6.9) seconds for suture repair (P < 0.001). The times required for the
      reconstruction of the anastomoses were 17.4 (6.1) and 35.5 (7.1) minutes,
      respectively (P < 0.001). CONCLUSIONS: Arterial anastomoses performed with
      vascular-closure staple clips are faster than sutured anastomoses, and result in
      comparable wound healing when assessed for patency, tensile strength, degree of
      narrowing and intimal reaction.

PMID- 10395259
TI  - Bilateral internal carotid artery occlusion: natural history and surgical
      alternatives.
AB  - PURPOSE AND BACKGROUND: Bilateral internal carotid artery occlusion is an
      extremely rare entity, therefore, studies of the natural history of this disease
      are lacking in the English literature. The purpose of this study is to analyze
      the natural history and surgical alternatives for patients with bilateral
      internal carotid artery occlusion. PATIENT POPULATION AND METHODS: Twenty-one
      patients with bilateral internal carotid artery occlusion were encountered with a
      mean age of 61 years (range of 48-73 years). Their clinical presentations
      included eight with hemispheric transient ischemic attacks, three with amaurosis
      fugax, five with strokes and five with non-hemispheric transient ischemic attack.
      Diagnosis was confirmed using carotid duplex ultrasound and angiography. The
      majority of patients had more than one risk factor for atherosclerosis: smoking
      in 100%, hyperlipidemia in 14/21 (67%), hypertension in 17/21 (81%), coronary
      artery disease in 15/21 (71%) and diabetes mellitus in 7/21 (33%). In addition to
      the usual medical treatment, 13 patients underwent surgical intervention: eight
      had an external carotid endarterectomy, four had a carotid-subclavian bypass (to
      increase external carotid or vertebral flow for tight stenosis or occlusion of
      the common carotid or subclavian artery) and one patient had an ascending aorta
      to innominate artery bypass. At a mean follow-up of 6 years (range 1-11 years),
      the overall mortality rates were 11/21 (52%), in the surgical group it was 5/13
      (38%) and 6/8 (75%) in the medical group. The causes of death included seven
      myocardial infarctions (four in the surgical group and three in the medical
      group) and four strokes (one in the surgical group and three in the medical
      group). In the surgical group, 2/13 (15%) had late neurological deficits (one
      hemispheric transient ischemic attack and one stroke), in contrast to 6/8 (75%,
      three strokes and three hemispheric transient ischemic attacks) in the medical
      group. CONCLUSIONS: Bilateral internal carotid artery occlusions have grave
      prognoses and should be considered a marker for severe systemic disease. Various
      cerebrovascular reconstructive procedures, if feasible, may be beneficial for
      some of these patients.

PMID- 10395260
TI  - The effect of occult diabetic status and oral glucose intake on brachial artery
      vasoactivity in patients with peripheral vascular disease.
AB  - Brachial artery vasoactivity is a well known non-invasive method of assessing
      arterial endothelial function in vivo. Brachial artery vasoactivity has been
      found to be impaired in overt diabetes and in patients with coronary artery
      disease. Impaired brachial artery vasoactivity is felt to be an early indicator
      of atherosclerosis. The authors identified a group of patients with lower
      extremity peripheral vascular disease, who had normal fasting glucose level and
      were not known to be diabetics. An oral glucose tolerance test was performed in
      this group of patients. Brachial artery vasoactivity was assessed at each step of
      the oral glucose tolerance test to examine their occult diabetic status and
      correlate brachial artery vasoactivity to that status. The authors studied 23
      randomly selected patients from the vascular surgery clinic between the ages of
      50 and 79 years. Serum glucose level was assessed after a 10-h fast and at 30, 60
      and 120 min after a 75-g oral glucose challenge. Any patient with two serum
      glucose values > 140 mg/dl was considered to have a positive oral glucose
      tolerance test. Using duplex ultrasound, the brachial artery diameter (cm) and
      blood volume (ml/min) were assessed before and after tourniquet occlusion at each
      step of the oral glucose tolerance test. Paired and unpaired t-tests were used to
      evaluate the results, P < 0.05 was considered significant. Nine patients had
      abnormal oral glucose tolerance test for a prevalence of 39%. There was no
      significant difference in fasting glucose levels between positive and negative
      oral glucose tolerance test patients (97.4+/-16.7 versus 88.5+/-5.8, P = 0.23).
      Patients with a positive oral glucose tolerance test had impaired vasoactivity at
      fasting and at each step of the test with no significant changes in brachial
      artery diameter or blood flow in response to brachial artery occlusion. Patients
      with a negative oral glucose tolerance test exhibited increased brachial artery
      diameter at fasting in response to brachial artery occlusion (0.43+/-0.02 versus
      0.46+/-0.02, P = 0.03), but not after oral glucose challenge. In patients with a
      negative oral glucose tolerance test, brachial artery flow volume increased
      significantly in response to hyperemia at fasting (240+/-61 versus 578+/-262, P =
      0.001) and at 30 min after glucose intake (260+/-53 versus 358+/-72, P = 0.01).
      At 60 and 120 min after glucose intake, brachial artery flow volume did not
      significantly increase in response to brachial artery occlusion. These results
      indicate that individuals with PVD and normal fasting glucose levels have a high
      prevalence of positive oral glucose tolerance test (39%). Patients with normal
      fasting glucose levels and abnormal oral glucose tolerance test have impaired
      brachial artery vasoactivity at fasting and after oral glucose challenge, this is
      in contrast to patients with normal oral glucose tolerance test who have normal
      fasting hyperemic response to brachial artery occlusion. However, this normal
      brachial artery vasoactivity is lost in the negative oral glucose tolerance test
      group in response to oral glucose load. These results suggest that endothelial
      function in diabetics is impaired in the early stages of the disease even before
      overt hyperglycemia occurs. Tight control of blood glucose level in glucose
      intolerant patients prior to occurrence of overt fasting hyperglycemia may prove
      protective.

PMID- 10395261
TI  - A new accurate, rapid and cost-effective protocol for stroke-prevention
      screening.
AB  - The three immediate causes of stroke are cervical carotid artery disease, atrial
      fibrillation and hypertension. Recognition and appropriate management of these
      causes can prevent the majority of strokes they would have caused. The purpose of
      this study was to develop a new protocol for screening for these causes that is
      more accurate, rapid and cost effective than existing protocols. In this
      protocol, rather than relying on auscultation with a stethoscope, the carotid
      artery was screened with a newly developed and more accurate quick color image
      scan ultrasound technique and a lead 2 EKG rhythm strip was used to find atrial
      fibrillation. The focus in this protocol was on the rapid detection of the three
      immediate causes of stroke and did not include a lengthy questionnaire or long
      counseling. A cholesterol determination was not included and there was little or
      no cost to the participants. In stroke screening trials of the new protocol at
      two institutions, 176 participants were screened at a rate of one every 2.7
      minutes. There were 26 with > 50% carotid stenosis, 16 with previously unknown
      cardiac arrhythmias and 104 had hypertension. It was concluded that this protocol
      provides an accurate, rapid and cost-effective means of screening for the three
      immediate causes of stroke and can on broad application result in significant
      stroke reduction.

PMID- 10395262
TI  - Autogenous common facial vein or external jugular vein patch for carotid
      endarterectomy.
AB  - BACKGROUND: The purpose of this study was to determine whether common facial vein
      or external jugular vein are as good a vein patch as a saphenous vein for carotid
      patch angioplasty. METHOD: Retrospectively, 19 patients who underwent everted
      common facial vein or external jugular vein patch were compared with 199 patients
      who underwent saphenous vein patch carotid endarterectomy during 1989 to 1996.
      The two groups were compared clinically and by sonographic surveillance. The mean
      follow-up was 18+/-4 months for common facial vein/external jugular vein patients
      and 48+/-15 months for saphenous vein patch group. RESULTS: No significant
      differences in mortality or morbidity were observed among patients in whom
      everted common facial vein or external jugular vein was used as compared with
      saphenous vein. No bleeding, thrombotic event, dilation of the patch or
      aneurysmal degeneration and perioperative deaths occurred in either of the two
      groups. Duplex surveillance studies showed no significant difference in recurrent
      moderate (50-79%) and severe (80-99%) stenosis. CONCLUSION: Everted common facial
      vein or external jugular vein patch was comparable to other vein patches. This
      eliminates the comorbidity of groin incision. Also, using everted common facial
      vein or external jugular vein as vein patch saves saphenous vein to be used for
      other vascular procedures, such as coronary artery or lower extremity bypass.

PMID- 10395263
TI  - Symptomatic venous hypertension because of occult iliofemoral deep vein
      thrombosis: a report of two cases.
AB  - Two 25-year-old males with symptomatic venous hypertension (venous claudication,
      n = 1; swollen leg, n = 1) were evaluated for iliofemoral venous occlusive
      disease. One patient had a common femoral vein/external iliac vein occlusion with
      no history of deep vein thrombosis or trauma. The second patient had an acute
      deep vein thrombosis superimposed on a chronic external iliac vein stenosis. No
      source of extrinsic venous compression was identified in either patient. Venous
      reconstruction with vein bypass (patient no. 1) and vein patch angioplasty
      (patient no. 2) led to resolution of their hypertensive symptoms. Intraoperative
      examination of the involved vein segments revealed chronic changes consistent
      with a prior occult deep vein thrombosis in both patients. Occult iliofemoral
      deep vein thrombosis in young healthy males is rarely seen. The acute deep vein
      thrombosis may manifest minimal or no symptoms but it can lead to chronic venous
      occlusive disease and serious post-phlebitic morbidity. In this context, these
      two cases are discussed with a review of the pertinent literature.

PMID- 10395264
TI  - Anterior tibial artery pseudoaneurysm after ankle arthroscopy.
AB  - Arthroscopy of the ankle has dramatically expanded its role in diagnostic and
      therapeutic value afforded to the patient; however, it is not without
      complications. Although the majority of the complications described are
      neurological in origin, vascular injuries can occur. A case of a patient with
      normal coagulation parameters who underwent a purely diagnostic ankle arthroscopy
      and later developed a pseudoaneurysm of her distal anterior tibial artery is
      described. The pseudoaneurysm was resected without complications and early
      postoperative recovery has been uneventful.

PMID- 10395265
TI  - Treatment of May-Thurner syndrome with catheter-directed thrombolysis and stent
      placement, complicated by heparin-induced thrombocytopenia.
AB  - May-Thurner syndrome is an uncommon process in which the right common iliac
      artery compresses the left common iliac vein, resulting in left iliofemoral deep
      vein thrombosis and severe leg edema. We report the case of a 41-year-old female
      who presented with severe left leg edema present for 1 day. One week earlier she
      had experienced acute shortness of breath and pleuritic chest pain. Duplex
      ultrasound revealed a left iliofemoral deep vein thrombosis. A computed
      tomography (CT) scan performed for abdominal pain revealed thrombosis of the
      entire left common and external iliac veins. A ventilation-perfusion scan
      diagnosed a pulmonary embolism. The patient was treated with systemic intravenous
      heparin and catheter-directed thrombolysis of the iliofemoral deep vein
      thrombosis. Complete thrombolysis and iliofemoral vein patency was achieved over
      5 days. A persistent stenosis in the left common iliac vein consistent with May
      Thurner syndrome was alleviated with percutaneous balloon angioplasty and
      placement of a Wallstent. Heparin therapy was terminated at the time of stenting
      because of suspected heparin-induced thrombocytopenia. The patient was started on
      a continuous infusion of 10% dextran 40, and warfarin therapy was initiated.
      Heparin-induced antibodies were confirmed by a C-14 serotonin release assay. The
      endovascular reconstruction remains patent 4 months later. Heparin-induced
      thrombocytopenia complicating endovascular reconstruction of the iliofemoral
      venous system in a patient with May-Thurner Syndrome is an uncommon occurrence.
      This case and a review of the literature are discussed.

PMID- 10395267
TI  - Arresting donor hearts with extracellular-type cardioplegia prevents
      vasoconstriction induced by UW solution.
AB  - The effects of arresting donor hearts with University of Wisconsin solution was
      investigated. Donor dogs were divided into two groups according to the technique
      used for arresting the heart. In group I (n = 6) the heart was arrested with
      University of Wisconsin solution, whereas in group II (n = 6) extracellular-type
      cardioplegia (K+ = 20 mmol/liter) was used to induce cardioplegic arrest. Aortic
      root pressure was measured during the infusion of solution at constant flow. In
      both groups, the hearts were then flushed and stored in cold University of
      Wisconsin solution for 6 h. The hearts were transplanted orthotopically and
      disconnected from cardiopulmonary bypass. Left ventricular function was evaluated
      by pressure-volume relations using a conductance catheter. Peak aortic root
      pressure during the infusion was significantly higher in group I than in group
      II, although post-transplant left ventricular function was similar in both
      groups. Although there was no difference in cardiac function after implantation,
      donor hearts should be arrested by extracellular-type cardioplegia to prevent
      coronary vasoconstriction associated with preservation in University of Wisconsin
      solution.

PMID- 10395266
TI  - Cultured neonatal rat cardiomyocytes and 99mTc-sestamibi to assess the direct
      effects of cardioplegia.
AB  - The efficacy of cardioplegia in neonatal myocardial protection is still a matter
      of debate. 99mTc-sestamibi cellular accumulation reflects sarcolemmal and
      mitochondrial electrical gradients. It was used to monitor the direct effects of
      two cardioplegic solutions, modified St Thomas' Hospital and Bretschneider, on
      normoxic and metabolically-inhibited cultured cells. Cellular accumulation of
      99mTc-sestamibi, expressed by the ratio between intra and extra cellular
      concentrations, was assessed in three different sets of neonatal rat
      cardiomyocytes. Cells were either treated with different concentrations of
      modified St Thomas' solution (50, 75, 100%), they were treated or recovering from
      a treatment with modified St Thomas and Bretschneider solutions at 50%
      concentrations, or were recovering from treatment with modified St Thomas' and
      Bretschneider solution at 50% concentrations mixed with metabolic inhibitors.
      Cardioplegia depressed the tracer accumulation in a concentration-dependent
      manner. This effect was independent of the type of cardioplegia (120-min uptake,
      as a percentage of control values, modified St Thomas' 68+/-12 and Bretschneider
      59+/-7) and was rapidly reversible. Cardioplegia was unable to prevent the
      depression of tracer accumulation induced by metabolic inhibitors and even
      induced a deleterious effect (120-min uptake, as a percentage of control values,
      metabolic inhibitors 69+/-12, metabolic inhibitors + modified St Thomas 38+/-14,
      metabolic inhibitors + Bretschneider 43+/-6) during recovery after 30 min of
      metabolic inhibition. It was concluded that cardioplegia has an apparent
      detrimental effect on neonatal cardiomyocytes accumulation of 99mTc-sestamibi
      during recovery from an ischaemic-like insult.

PMID- 10395268
TI  - Thoracic aortic aneurysm associated with congenital bicuspid aortic valve.
AB  - Congenital bicuspid aortic valve is a relatively rare malformation. It is
      reported that the presence of this anomaly predisposes the patient to development
      of true aortic aneurysms or dissecting aortic aneurysms. Between 1981 and August
      1997, 25 patients with an aneurysm of the thoracic aorta associated with
      congenital bicuspid aortic valve underwent surgical treatment at the authors'
      institution. There were 20 males and five females. The age of the patients ranged
      from 27 to 74 years (mean 53 years). There were 18 patients with true ascending
      aortic aneurysms (of which 10 presented with annulo-aortic ectasia) and seven
      with dissecting aortic aneurysms (four with DeBakey type I dissection, two with
      type II and one with type IIIb). These 25 patients constituted 2.6% (25/973) of
      all cases of surgical operations for aneurysms in the thoracic aorta. Aortic
      valve dysfunction was noted in 20 patients. The authors performed a valved
      conduit operation in nine patients, aortic valve replacement and wrapping of the
      ascending aorta in six, graft replacement of the ascending aorta in five, graft
      replacement of the ascending aorta and aortic arch in four, and graft replacement
      of the descending aorta in one. No hospital deaths occurred in the authors'
      patients. Pathological examination of surgical specimens of the aortic wall
      showed cystic medial necrosis in 11 patients and mucoid degeneration in nine. In
      patients with congenital bicuspid aortic valve, attention should be paid to
      aneurysmal dilatation and aortic dissection as complications in addition to valve
      dysfunction.

PMID- 10395269
TI  - A computer model for the prediction of left epicardial coronary blood flow in
      normal, stenotic and bypassed coronary arteries, by single or sequential
      grafting.
AB  - This article describes a computer model for calculating left epicardial coronary
      blood pressure and flow waveforms of a right dominant coronary circulation. Using
      the geometry of 16 vascular branches and employing the one-dimensional Navier
      Stokes equations the model allows for the prediction of blood pressure and flow
      patterns in normal and stenosed vessels. This model was also used to predict the
      haemodynamic changes observed after insertion of two single saphenous vein bypass
      grafts, as compared with the corresponding changes after insertion of a
      sequential (snake-like) saphenous graft. In normal vessels during systole and
      diastole, the pressure and the flow waveforms obtained showed patterns that
      correlate very well with the findings observed by other investigators using
      intracoronary flowmeter or Doppler velocimeter techniques. In coronary artery
      disease (90% stenoses in LAD and diagonal branch 1), the authors' main
      contribution is the reconfirmation of a previously described finding of systolic
      flow rises in stenotic segments. This finding seems to be an important
      compensatory mechanism, in contrast to normal coronary vessels, which maintain a
      mainly diastolic flow pattern. The introduction of single or sequential bypass
      grafts leads to pressure and flow restoration after graft revascularization.
      Besides this finding, the general concept of a diastolic flow restoration post
      stenotically, in the previously decreased and systolic augmented flow areas, is
      also observed. The two revascularization methods were also compared with regard
      to their specific advantages, disadvantages and indications and were also
      extensively compared with several in vivo studies.

PMID- 10395270
TI  - Long-term patency rates, complications and cost-effectiveness of
      polytetrafluoroethylene (PTFE) grafts for hemodialysis access: a prospective
      study that compares Impra versus Gore-tex grafts.
AB  - Manufacturers of polytetraflouroethylene (PTFE) grafts used for chronic
      hemodialysis access describe specific advantages for their respective grafts,
      which presumably result in greater graft patency rates, reduced complications and
      decreased overall costs. There are few data available in the literature to
      support or contradict these alleged benefits. Therefore, this prospective study
      was undertaken to evaluate and compare patency rates, complications and costs
      between two of the leading brands of PTFE that are currently being marketed for
      use as hemodialysis access grafts. Totals of 190 primary PTFE grafts (100 Gore
      tex (W. L. Gore and Associates, Flagstaff, AZ) and 90 Impra (C. R. Bard Inc.,
      Tempe, AZ)) were implanted in 168 consecutive patients with end-stage renal
      disease. A policy of non-interventions was employed for patent grafts, as no
      attempt was made to assist primary patency. Grafts that occluded during follow-up
      underwent secondary revision to maintain patency. There was no difference in
      primary and secondary patency by life-table analysis between Gore-tex and Impra
      grafts at 2 years (P > 0.53 and P > 0.13, respectively). There was also no
      significant difference between Gore-tex and Impra in the number of days before
      the first thrombectomy or in the number of thrombectomies or revisions per graft
      (P > O.50). Likewise, the incidence of complications was similar between the two
      grafts. The cost of graft implantation and maintenance of patency was not
      significantly different between Gore-tex and Impra grafts. It is concluded that
      either graft can be used for hemodialysis access with similar expected outcomes
      for at least 2 years following implantation.

PMID- 10395271
TI  - Cause and treatment of symptomatic steals following the insertion of
      haemodialysis shunts.

PMID- 10395273
TI  - Feglymycin, a novel inhibitor of the replication of the human immunodeficiency
      virus. Fermentation, isolation and structure elucidation.
AB  - The novel peptide feglymycin has been isolated from cultures of Streptomyces sp.
      DSM 11171 by solid phase extraction, size exclusion chromatography and repeated
      reversed-phase chromatography. The molecular weight was found to be 1900.90 g/mol
      and the molecular formula is C95H97Nl3O30. Feglymycin contains 13 amino acids of
      which four are 3-hydroxyphenylglycine and five are 3,5-dihydroxyphenylglycine
      residues. The structure of the linear peptide has been determined by 1H and 13C
      NMR spectroscopy. The sequence was confirmed by the observed mass spectroscopic
      fragmentation pattern. As well as having weak antibacterial activity, feglymycin
      inhibits the replication of the human immunodeficiency virus (HIV) in vitro.

PMID- 10395272
TI  - Lichenysins G, a novel family of lipopeptide biosurfactants from Bacillus
      licheniformis IM 1307: production, isolation and structural evaluation by NMR and
      mass spectrometry.
AB  - A series of 9 lactonic lipopeptide biosurfactants was isolated from Bacillus
      licheniformis IM 1307 as representatives of the lichenysin group and we propose
      to name them lichenysins G. They were recovered from the culture medium as
      complex mixtures of molecules having different peptide sequences and different
      structures of beta-hydroxy fatty acids. Their separation was achieved by a
      reversed-phase HPLC method leading to eight well-separated compounds. The
      complete structure of individual isoforms was proposed following the results of
      amino acid and fatty acid analysis, LSI-MS and 2D NMR spectroscopies. Compared to
      surfactin, lichenysins G are at least 10 fold more efficient biosurfactants.

PMID- 10395274
TI  - Structure elucidation of Sch 20562, a glucosidic cyclic dehydropeptide lactone-
      the major component of W-10 antifungal antibiotic.
AB  - A novel bacterium designated as Aeromonas sp. W-10 produces the antibiotic W-10
      complex which comprises of two major and several minor components. The two major
      components from this complex, Sch 20562 (1) and Sch 20561 (1a), are of biological
      interest in view of their potent antifungal activity. The chemical degradation
      studies utilized for the assignment of structure 1 for Sch 20562 are described
      here. Some of the noteworthy diversity of structural features in this glucosidic
      cyclic dehydrononapeptide lactone 1 are: an N-terminal (D)-beta-hydroxymyristyl
      unit, three D-amino acid units, two (E)-alpha-aminocrotonyl units, and an O-alpha
      D-glucosyl-N-methyl-L-allo-threonine unit. The structure determination of 1
      utilized the selective cleavage of the dehydropeptide units by ozonolysis to form
      fragments that were sequenced by mass spectrometry. The stereochemistry of the
      amino acid units were assigned by isolation of the free amino acids from the
      hydrolysates of the fragments. The stereochemistry of the alpha-aminocrotonyl
      units and the glucosidic linkage were assigned by nmr spectroscopy and molecular
      rotation data.

PMID- 10395275
TI  - Structure elucidation of Sch 20561, a cyclic dehydropeptide lactone--a major
      component of W-10 antifungal antibiotic.
AB  - Antibiotic W-10 is a fermentation complex produced by the bacterium Aeromonas sp.
      W-10. The cyclic dehydropeptide lactones Sch 20562 (1) and Sch 20561 (2) are the
      major components of this fermentation complex and are of biological interest in
      view of their unique structural features and potent antifungal activity. The
      chemical degradation studies that were utilized in the assignment of structure 2
      for Sch 20561 are described here. The structure determination of 2 made use of
      the ozonolytic cleavage of the dehydropeptide units to form fragments that were
      sequenced by mass spectrometry. The cyclic dehydropeptide lactone Sch 20561 (2)
      was found to be the aglycone of Sch 20562 (1) and these two natural products were
      correlated by a chemical transformation involving the deglucosidation of 1 to
      form 2.

PMID- 10395276
TI  - A new enzyme, edeine B1 amidinohydrolase, from Bacillus brevis TT02-8.
      Purification and determination of the N-terminal amino acid sequence.

PMID- 10395277
TI  - Diazaphilonic acid, a new azaphilone with telomerase inhibitory activity.

PMID- 10395278
TI  - C-1027 enediyne chromophore: presence of another active form and its chemical
      structure.

PMID- 10395279
TI  - Synthesis of an N-methyl-D-aspartate receptor antagonist, ES-242-5, and its
      analogs.

PMID- 10395280
TI  - Inhibition of angiogenesis by a new isocoumarin, NM-3.

PMID- 10395281
TI  - Screening of microbial products modifying the action of leptin (obese gene
      product) by a biosensor.

PMID- 10395282
TI  - Absolute and atropisomeric structure of ES-242s, N-methyl-D-aspartate receptor
      antagonists.

PMID- 10395283
TI  - Functional antagonism between activin and osteogenic protein-1 in human embryonal
      carcinoma cells.
AB  - Activin A and osteogenic protein-1 (OP-1) exerted antagonistic effects on each
      other's responses on the human Tera-2 embryonal carcinoma cell line. OP-1 dose
      dependently inhibited activin A-induced activation of p3TP-Lux transcriptional
      reporter, containing part of the human plasminogen activator inhibitor-1 (PAI-1)
      promoter, while activin A inhibited OP-1-mediated alkaline phosphatase induction.
      Approximately equimolar concentrations of both growth factors resulted in 50%
      inhibition of the respective biological responses. Affinity cross-linking studies
      using 125I-activin A or 125I-OP-1 followed by receptor-immunoprecipitations
      revealed that both ligands bound to the activin type II receptor (ActR-II), but
      recruited different type I receptors. In addition, OP-1 competed with binding of
      125I-activin A, and activin A competed with binding of 125I-OP-1 to ActR-II.
      Transient transfection studies showed that competition between activin A and OP-1
      also occurred at the type I receptor (ActR-1) level; constitutively active (CA)
      ActR-I inhibited CA-ActR-IB-mediated p3TP-Lux reporter induction. There was no
      competition between activin A and OP-1 for availability of Smad4, indicating that
      the concentration of this common signal transducer is not limiting for generating
      the observed biological responses. Overexpression of ActR-II abolished the
      inhibitory effect of OP-1 on activin A-induced p3TP-Lux activation and,
      surprisingly, led to OP-1-induced transcriptional reporter activity. Whereas the
      exact mechanism of competition is unclear, the role of ActR-II in the competition
      between activin A and OP-1 is discussed in light of the observed interference in
      downstream signaling by CA-ActR-I and CA-ActR-IB.

PMID- 10395284
TI  - Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human
      malignant mesothelioma.
AB  - Exposure to the carcinogen asbestos is considered to be a major factor
      contributing to the development of most malignant mesotheliomas (MMs). We
      highlight the role of asbestos in MM and summarize cytogenetic and molecular
      genetic findings in this malignancy. The accumulation of numerous clonal
      chromosomal deletions in most MMs suggests a multistep process of tumorigenesis,
      characterized by the loss and/or inactivation of multiple tumor suppressor genes
      (TSGs). Cytogenetic and loss of heterozygosity (LOH) analyses of MMs have
      demonstrated frequent deletions of specific sites within chromosome arms 1p, 3p,
      6q, 9p, 13q, 15q, and 22q. Furthermore, TSGs within two of these regions, i.e.,
      p16/CDKN2A-p14ARF at 9p21 and NF2 at 22q12, are frequently altered in MMs.
      Homozygous deletion appears to be the major mechanism affecting p16/CDKN2A
      p14ARF, whereas inactivating mutations coupled with allelic loss occur at the NF2
      locus. Finally, recent studies have demonstrated the presence and expression of
      simian virus 40 (SV40) in many MMs. SV40 large T antigen has been shown to
      inactivate the TSG products Rb and p53, suggesting the possibility that asbestos
      and SV40 could act as cocarcinogens in MM. The frequent occurrence of homozygous
      deletions of p16/CDKN2A-p14ARF and the ability of SV40 Tag to bind TSG products
      suggest that perturbations of both Rb- and p53-dependent growth-regulatory
      pathways are critically involved in the pathogenesis of MM.

PMID- 10395286
TI  - New molecular and epidemiological issues in mesothelioma: role of SV40.
AB  - Mesotheliomas are malignant tumors usually associated with occupational asbestos
      exposure. Simian virus 40 (SV40) is a DNA tumor virus that preferentially causes
      mesotheliomas when injected intracardially and/or intrapleurally into hamsters.
      SV40 also transforms human cells in tissue culture, and these cells contain
      extensive DNA damage. In the United States, at least 60% of human mesotheliomas
      contain and express SV40. In these tumor cells, the SV40 tumor antigen binds and
      inhibits the cellular tumor suppressors p53 and Rb. These findings suggest that
      SV40 may contribute to the development of those human mesotheliomas that occur in
      people not exposed to asbestos. SV40 may also facilitate asbestos-mediated
      carcinogenicity. The epidemiological data available are insufficient to address
      the role that SV40 may have played in contributing to the increased incidence of
      mesothelioma in the second half of this century.

PMID- 10395285
TI  - Cellular and molecular mechanisms of asbestos-induced fibrosis.
AB  - Pleural and pulmonary fibrosis (asbestosis) are ramifications of occupational
      exposures to asbestos fibers, a diverse family of ubiquitous, naturally-occurring
      minerals. The pathogenesis of asbestos-associated fibrosis involves the
      participation of a number of cell types and is characterized by an early and
      persistent inflammatory response that involves the generation of oxidants, growth
      factors, chemokines, and cytokines. These mediators may also contribute directly
      to cell injury, proliferation, and fibrogenesis. After interaction with cells,
      asbestos fibers trigger a number of signaling cascades involving mitogen
      activated protein kinases (MAPK) and nuclear factor kappa-B (NF-kappaB).
      Activation of transcription factors such as NF-kappaB and activator protein-1 (AP
      1) may be linked to increases in early response genes (e.g., c-jun and c-fos)
      which govern proliferation, apoptosis, and inflammatory changes in the cells of
      the lung. The goal of this article is to review the cellular and molecular
      mechanisms of asbestos-induced fibrosis that may be critical to the development
      of effective treatment regimens.

PMID- 10395287
TI  - Protein tyrosine phosphatases as negative regulators of mitogenic signaling.
AB  - The regulation of tyrosine phosphorylation represents a key mechanism governing
      cell proliferation. In fibroblasts, inputs from both growth factor and
      extracellular matrix receptors are required for cell division. Triggering such
      receptors induces a wave of tyrosine phosphorylation on key signaling molecules,
      culminating in the activation of cyclin-dependent kinases and cell cycle
      progression. In general, protein tyrosine kinases stimulate, while protein
      tyrosine phosphatases inhibit, such cell proliferation pathways. The role of
      protein tyrosine kinases in mitogenesis has been extensively studied, but the
      identity and targets of the protein tyrosine phosphatases that regulate cell
      growth are not well described. In this review, I will survey recent advances in
      the identification and regulation of protein tyrosine phosphatases that
      downregulate cell proliferation.

PMID- 10395288
TI  - Oxidative stress affects cytoskeletal structure and cell-matrix interactions in
      cells from an ocular tissue: the trabecular meshwork.
AB  - The trabecular meshwork (TM) is a specialized eye tissue that regulates the
      aqueous humor outflow and controls intraocular pressure. Cells in this tissue are
      essential for maintenance of the outflow system. Disturbance of the TM cell
      status by insults such as oxidative stress may lead to elevation of the
      intraocular pressure and development of glaucoma. In the present study, we
      investigated the effect of oxidative stress on the adhesion of human TM cells to
      extracellular matrix (ECM) proteins. Treatment with 1 mM of H2O2 for 10 or 30 min
      did not affect cell viability, whereas the adhesion of TM cells to fibronectin,
      laminin, and collagen types I and IV was significantly reduced. Phalloidin and
      immunostaining also revealed reorganization of actin and vimentin structures. The
      level of integrins alpha5beta1, alphavbeta3, and beta1 was not altered, although
      the distribution of paxillin and focal adhesion kinase in focal contacts was
      reduced. Concomitantly, the level of transcription factor NF-kappaB was enhanced
      by the H2O2 treatment. Nuclear extracts of the treated cells also contained a
      heightened NF-kappaB binding activity. These changes persisted for up to 6 h
      after the H2O2 treatment but were partially recovered by 24 h. We concluded that
      under sublethal oxidative stress conditions, the TM cell adhesion to the ECM was
      impaired. The short-term loss of cell-matrix adhesiveness may be related to the
      rearrangement of cytoskeletal structures. Extensive and repeated oxidative stress
      in vivo may result in reduced TM cell adhesion, leading to cell loss, compromised
      TM integrity, and pathologic consequences.

PMID- 10395289
TI  - Upregulation of selective cholesteryl ester uptake pathway in mice with deletion
      of low-density lipoprotein receptor function.
AB  - This study examines the effect of mutation of the low-density lipoprotein
      receptor (LDLR) on cholesterol metabolism, and especially lipoprotein-derived
      cholesteryl ester uptake, in murine ovarian granulosa cells. Although the tests
      were conducted on cells prepared by two different procedures, the results are
      similar. Deletion of LDLR function did not noticeably affect key enzymes of the
      steroidogenic pathway or affect progestin production and secretion in granulosa
      cells. No change was found in expression of LDL-related protein (LRP). These data
      suggested that cholesterol turnover in cells from the knockout animals is within
      normal limits and that the cells are not stressed to acquire more cholesterol.
      Both biochemical and morphological data indicate that unstimulated granulosa
      cells from LDLR-/- mice are nonetheless programmed to take in double the amount
      of lipoprotein-derived cholesteryl ester (via the selective cholesteryl ester
      uptake pathway) and to process (hydrolyze, re-esterify, or utilize) more than
      twofold the cholesteryl ester processed by cells from wildtype (LDLR+/+) animals.
      Bt2cAMP stimulation of the murine granulosa cells increases the mass of
      cholesteryl ester taken up by the selective pathway by an additional 38%. To
      determine to what extent this increase is related to high-density lipoprotein
      (HDL) scavenger receptor protein (SR-BI) or caveolin function, Western blots and
      immunohistochemical studies were performed under a variety of conditions. SR-BI
      levels are found to be low in unstimulated cells of both LDLR+/+ and LDLR-/-
      animals, but highly expressed (approximately 20-fold increase over basal levels)
      in stimulated (Bt2cAMP) cells of both animal models. Thus, the functional
      relationship between selective cholesteryl ester uptake and SR-BI receptor
      protein is not as tight as in previously reported studies, suggesting a
      requirement for other tissue factors. Caveolin expression did not change under
      any of the conditions tested and appears not to be functionally involved in this
      process.

PMID- 10395290
TI  - Role of diacylglycerol (DAG) in hormonal induction of S phase in hepatocytes: the
      DAG-dependent protein kinase C pathway is not activated by epidermal growth
      factor (EGF), but is involved in mediating the enhancement of responsiveness to
      EGF by vasopressin, angiotensin II, and norepinephrine.
AB  - The role of diacylglycerol (DAG) in hormonal induction of S phase was
      investigated in primary cultures of rat hepatocytes. In this model, several
      agonists that bind to G protein-coupled receptors act as comitogens when added to
      the cells soon after plating (i.e., in Go/early Gl phase), while the cells are
      most responsive to the mitogenic effect of epidermal growth factor (EGF) at 24-48
      h of culturing (i.e., mid/late Gl). It was found that the cellular concentration
      of DAG rose markedly and progressively during the first 24 h of culturing.
      Exposure of the hepatocytes at 3 h to alpha1-adrenergic stimulation
      (norepinephrine with timolol), vasopressin, or angiotensin II further increased
      this rise, producing a sustained increase in the DAG level. Norepinephrine, which
      was the most efficient comitogen, produced the most prolonged DAG elevation. In
      contrast, no significant increase of DAG was found in response to EGF, neither at
      3 nor at 24 h, using concentrations that markedly stimulated the ERK subgroup of
      the mitogen-activated protein kinases (MAPK) and DNA synthesis. Addition of
      Bacillus cereus phosphatidylcholine-specific phospholipase C (PC-PLC) strongly
      elevated DAG, while Streptomyces phospholipase D (PLD) increased phosphatidic
      acid (PA) but not DAG. B. cereus PC-PLC and the protein kinase C (PKC) activator
      tetradecanoyl phorbol-acetate (TPA), like norepinephrine, vasopressin, and
      angiotensin II, stimulated MAPK and enhanced the stimulatory effect of EGF on DNA
      synthesis. The PKC inhibitor GF109203X did not diminish the effect of EGF on MAPK
      or DNA synthesis, but strongly inhibited the effects of norepinephrine,
      vasopressin, angiotensin II, TPA and B. cereus PC-PLC on MAPK and almost
      abolished the enhancement by these agents of EGF-stimulated DNA synthesis. These
      results suggest that although generation of DAG is not a direct downstream
      response mediating the effects of the EGF receptor in hepatocytes, a sustained
      elevation of DAG with activation of PKC markedly increases the responsiveness to
      EGF. Mechanisms involving DAG and PKC seem to play a role in the comitogenic
      effects of various agents that bind to G protein-coupled receptors and activate
      the cells early in Gl, such as norepinephrine, angiotensin II, and vasopressin.

PMID- 10395291
TI  - Basic calcium phosphate crystal induction of collagenase 1 and stromelysin
      expression is dependent on a p42/44 mitogen-activated protein kinase signal
      transduction pathway.
AB  - Synovial fluid basic calcium phosphate (BCP) crystals are markers of severe joint
      degeneration in osteoarthritis. These crystals are mitogenic and induce
      protooncogene expression and matrix metalloproteinase (MMP) synthesis and
      secretion in human fibroblasts, effects that are specifically blocked by
      phosphocitrate (PC). We have recently determined that crystals transduce signals
      to the nucleus via the activation of the p42 and p44 mitogen-activated protein
      (MAP) kinases (Nair et al., 1997, J Biol Chem 272:18920-18925). Treatment of
      human fibroblasts (HF) with BCP induces phosphorylation of p42/44 MAPK, which is
      inhibited by PC in a dose-dependent manner. Blocking of p42/44 MAPK signal
      transduction with an inhibitor (PD98059) of MEK1, an upstream activator of MAPKs,
      reduces crystal-induced p42/44 MAPK activation and significantly inhibits crystal
      induced cell proliferation. Based on these findings, we sought to determine the
      role of the p42/44 MAPK signal transduction pathway in crystal-induced expression
      of matrix MMPs. We demonstrate suppression of crystal-induced MMPs via the
      utilization of two different MEK inhibitors: PD98059 and the recently described
      U0126, a novel inhibitor of MEK1 and MEK2. Treatment of HF with PD98059 blocks
      the induction of crystal-stimulated collagenase 1 (MMP-1) and stromelysin (MMP-3)
      expression. PD98059 and PC reduced the level of crystal-induced MMP-1 and MMP-3
      mRNA expression to that observed in nonstimulated cells. Likewise, PD98059
      treatment of HF blocked the epidermal growth factor (EGF)- and crystal-induced
      increases in MMP-1 and MMP-3 protein expression and secretion as demonstrated by
      Western blotting and zymography. Treatment of HF with U0126 inhibits EGF-induced
      phosphorylation of p42/44 MAPK as well as crystal- and EGF-induced upregulation
      of MMP-1 mRNA. Additionally, we demonstrate that treatment of HF with BCP, EGF,
      or PD98059 does not significantly alter levels of gelatinase A (MMP-2) mRNA and
      protein expression.

PMID- 10395292
TI  - Cellular glycosylphosphatidylinositol-specific phospholipase D regulates
      urokinase receptor shedding and cell surface expression.
AB  - The glycosylphosphatidylinositol (GPI)-anchored, multifunctional receptor for the
      serine proteinase, urokinase plasminogen activator (uPAR, CD87), regulates
      plasminogen activation and cell migration, adhesion, and proliferation. uPAR
      occurs in functionally distinct, membrane-anchored and soluble isoforms (s-uPAR)
      in vitro and in vivo. Recent evidence indicates that s-uPAR present in the
      circulation of cancer patients correlates with tumor malignancy and represents a
      valuable prognostic marker in certain types of cancer. We have therefore analyzed
      the mechanism of uPAR shedding in vitro. We present evidence that uPAR is
      actively released from ovarian cancer cells since the rate of receptor shedding
      did not correlate with uPAR expression. While s-uPAR was derived from the cell
      surface, it lacked the hydrophobic portion of the GPI moiety indicating anchor
      cleavage. We show that uPAR release is catalyzed by cellular GPI-specific
      phospholipase D (GPI-PLD), an enzyme cleaving the GPI anchor of the receptor.
      Thus, recombinant GPI-PLD expression increased receptor release up to fourfold.
      Conversely, a 40% reduction in GPI-PLD activity by GPI-PLD antisense mRNA
      expression inhibited uPAR release by more than 60%. We found that GPI-PLD also
      regulated uPAR expression, possibly by releasing a GPI-anchored growth factor.
      Our data suggest that cellular GPI-PLD might be involved in the generation of
      circulating prognostic markers in cancer and possibly regulate the function of
      GPI-anchored proteins by generating functionally distinct, soluble counterparts.

PMID- 10395293
TI  - Rat skeletal muscle in culture expresses the alpha1 but not the alpha2 protein
      subunit isoform of the Na+/K+ pump.
AB  - Studies from this laboratory have shown that the physiological expression of the
      Na+/K+ pump in primary cultures of rat skeletal muscle increases with
      development. The molecular mechanisms underlying these changes are not known.
      Therefore, we have examined the expression of alpha and beta subunits of the
      Na+/K+ pump at both the protein and mRNA levels during myogenesis of primary
      skeletal muscle cell cultures obtained from newborn rats. Protein isoforms were
      identified by Western blotting techniques with specific monoclonal and polyclonal
      antibodies and subunit mRNA was studied with specific cDNA probes. Freshly
      isolated skeletal muscle from newborn rats expressed both alpha1 and alpha2
      protein subunits. From day 1 after plating, primary cultures expressed only the
      alpha1 protein isoform. In contrast, both beta1 and beta2 isoforms were expressed
      in freshly isolated muscle and in primary cultures, with beta1 expression being
      stronger in both preparations. Studies on RNA expression showed that mRNA for
      alpha1, alpha2, beta1, and beta2 isoforms was identified both in freshly isolated
      muscle and after plating of cells in culture. These findings indicate that the
      lack of alpha2 protein expression in primary muscle cell cultures reflects a form
      of posttranscriptional regulation. There did not appear to be a quantitative
      difference in isoform expression as a function of age or of fusion in spite of
      developmental increases in Na+/K+ pump activity and its dependence on cell
      fusion. The lack of expression of the alpha2 subunit isoform suggests that the
      developmental changes in physiological expression of the Na+/K+ pump in primary
      cultures of skeletal muscle may be attributable either to the changes in activity
      of the alpha1 subunit or to differential activities of alphabeta complexes
      involving either of the beta subunits.

PMID- 10395294
TI  - Magnesium depletion causes growth inhibition, reduced expression of cyclin D1,
      and increased expression of P27Kip1 in normal but not in transformed mammary
      epithelial cells.
AB  - In this study, we have evaluated the effects of extracellular magnesium
      restriction on the growth and cell cycle parameters of normal (HC11) and
      transformed (MCF-7) breast epithelial cell lines. Cells were incubated in medium
      with different concentrations of Mg2+ (from 0.5 to 0 mM) and the growth rates
      were determined by [3H]-thymidine incorporation and cell counting. The growth of
      the HC11 cells was drastically inhibited by Mg2+ depletion whereas the MCF-7
      cells were only slightly inhibited (about 50% and 15%, respectively, after
      incubation in 0.05 mM Mg for 48 h). Cell cycle analyses showed a decrease in the
      percentage of cells in the S phase when both cell lines were incubated at low
      Mg2+ concentration. However, while the percentage of cells in both the G0/G1 and
      G2/M phases was increased in the HC11 cells, only the percentage of cells in the
      G2/M phase was increased in the MCF-7 cell line. Extracellular magnesium
      depletion was associated with increased expression of the cyclin-dependent kinase
      inhibitor p27Kip1 and decreased expression of cyclin D1 in the HC11 but not in
      the MCF-7 cells. We also demonstrated that Mg2+ depletion does not inhibit kinase
      activities in the normal HC11 cells and that Mg2+-restricted HC11 cells are still
      responsive to the epidermal growth factor (EGF)- and insulin-mediated stimulation
      of cell growth. These data suggest that normal but not transformed mammary
      epithelial cells are inhibited by extracellular Mg2+ restriction and that this
      effect might be mediated by changes in the levels of expression of both cyclin D1
      and p27Kip1.

PMID- 10395295
TI  - Differential activation of some transcription factors during rat liver ischemia,
      reperfusion, and heat shock.
AB  - Cells respond to external stimuli by changes in gene expression that are largely
      dependent on transcription factors (TFs). We studied the behavior of some TFs in
      rat liver during ischemia, postischemic reperfusion, and heat shock. Knowledge of
      the conditions at the end of ischemia is essential to understand changes
      occurring at reperfusion. The TFs investigated are known to be typically
      responsive to heat shock (HSF), hypoxia (HIF-1), pro- and antioxidant conditions
      (AP-1), or to various environmental changes (HNF-1 and ATF/CREB family). The most
      relevant new information includes the following: 1) Liver ischemia activates
      extremely rapidly the DNA binding capacity of HSF, soon followed by analogous
      activation of HIF-1 and AP-1. 2) After a certain lag time from the activation of
      HIF-1, mRNAs accumulate for two glycolytic enzymes, in particular Aldolase A and
      Heme Oxygenase 1, which contain HIF-1 sequences in their promoters. 3)
      Reperfusion, which is known to further increase the binding of HSF and to induce
      NFkappaB binding, abrogates or decreases the binding of HIF-1 and AP-1,
      stimulated by ischemia, and activates the binding of ATF/CREB. Later on, a second
      peak of AP-1 binding is induced. 4) Heat shock activates both ischemia-responsive
      and reperfusion-responsive TFs. 5) Preliminary experiments of supergelshift
      reveal that the activation of AP-1 at reperfusion or upon heat shock may result
      from the different involvement of the component subunits.

PMID- 10395296
TI  - Epidermal growth factor inhibits ceramide-induced apoptosis and lowers ceramide
      levels in primary placental trophoblasts.
AB  - The activation of sphingomyelinase and the subsequent generation of ceramide are
      emerging as important components of signaling pathways leading to apoptosis. The
      combination of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN
      gamma) induces apoptosis of primary placental trophoblasts in vitro. This
      apoptosis is inhibited completely by cotreatment with epidermal growth factor
      (EGF). We therefore examined the role of sphingomyelinase and ceramide in
      trophoblast apoptosis and how this may be influenced by EGF. Exogenous C16
      ceramide (20 microM) and acid sphingomyelinase induced trophoblast apoptosis, an
      effect abrogated completely by cotreatment with 10 ng/ml EGF. Neutral
      sphingomyelinase also increased ceramide levels but did not induce apoptosis.
      Treatment with EGF alone decreased cellular ceramide levels. This decrease could
      be blocked by cotreatment with the acid ceramidase inhibitor N-oleoylethanolamine
      (OE). OE alone increased ceramide levels and induced apoptosis that could not be
      blocked by cotreatment with EGF. In contrast, the alkaline ceramidase inhibitor D
      MAPP, although it also increased ceramide levels, did not induce apoptosis nor
      did it affect TNF-alpha/IFN-alpha-induced cell death. These results implicate
      sphingolipids as important mediators in trophoblast apoptosis and suggest that
      the antiapoptotic properties of EGF can in part be explained by its control of
      ceramide concentrations in trophoblasts.

PMID- 10395298
TI  - Evidence for an intracellular barrier to cadmium transport through Caco-2 cell
      monolayers.
AB  - 109Cd transport was studied in the highly differentiated TC7 clone of the
      enterocytic-like Caco-2 cells grown on filters. Accumulation curves for 0.3
      microM 109Cd over 12 h from the apical (AP) or the basal (BL) sides revealed a
      three-step mechanism involving: 1) a zero-time accumulation Ao; 2) a fast process
      Af(t1/2 < or = 10 min); and 3) a slow process of uptake As (5 h < or = t1/2 < or
      = 10 h) responsible for the major cellular levels of 109Cd. The relative
      contribution of adsorption to total accumulation is greater for short exposure
      times (< or = 35%), but is no longer significant after the exposure times needed
      to reach equilibrium. Transepithelial transport was less than 4% of the cellular
      level at 12 h. A negligible but specific binding onto the BL surface of the
      filters was characterized. Saturable systems of accumulation with comparable
      affinities (Km = 2.5+/-0.5 and 5.4+/-0.4 microM) but distinct capacities (Vmax =
      8.9+/-1.2 and 312+/-22 pmol/min/mg protein) were identified at the AP and BL cell
      membranes, respectively. Efflux studies revealed that Cd accumulation is only
      partially reversible, with an exclusive metal release at the same side. A 2-h
      exposure on both sides simultaneously failed to demonstrate any competition for
      cellular accumulation: uptake was additive relative to AP and BL uptake values.
      These data suggest that Af leads to an accumulation of loosely bound Cd, whereas
      As represents irreversible intracellular binding processes. We conclude that Cd
      transport occurs exclusively by a transcellular route and that saturation of the
      intracellular high-capacity binding sites is the rate-limiting step in Cd
      absorption.

PMID- 10395297
TI  - Role of ERK and JNK pathways in regulating cell motility and matrix
      metalloproteinase 9 production in growth factor-stimulated human epidermal
      keratinocytes.
AB  - Invasion is an essential cellular response that plays an important role in a
      number of physiological and pathological processes. Matrix metalloproteinase
      (MMP) production and cell movement are diverse cellular responses integral to the
      process of invasion. The complexity of the invasive process suggests the
      necessity of coordinate activation of more than one signaling pathway in order to
      activate specific factors responsible for regulating these cellular responses. In
      this report, we demonstrate that cell movement and MMP-9 production are both
      directly dependent on the activation of endogenous ERK signaling in hepatocyte
      growth factor (HGF)-or epidermal growth factor (EGF)-stimulated human epidermal
      keratinocytes. The kinetic profiles of endogenous MEK and ERK activity suggest
      that prolonged activation of these signal transducers is an underlying mechanism
      involved in stimulating cell motility and MMP-9 production. In support of this
      finding, a transient MEK/ERK signal elicited by keratinocyte growth factor (KGF)
      or insulin-like growth factor-1 (IGF-1) fails to stimulate these invasion-related
      responses. Specific inhibition of MEK leads to suppression of ERK activation,
      marked reduction in steady-state levels of c-Fos, and inhibition of cell movement
      and MMP-9 production. This occurs despite continued activation of JNK and c-Jun
      signaling in the presence of MEK-specific inhibition. In contrast, when JNK
      activity is specifically inhibited in HGF-stimulated cells, AP-1 activity is
      suppressed but cell motility is not affected. This evidence suggests that while
      ERK and JNK activity are necessary for AP-1 activation, ERK but not JNK is
      sufficient in stimulating cell motility.

PMID- 10395299
TI  - Progesterone stimulates DNA synthesis and lobulo-alveolar development in mammary
      glands in ovariectomized mice.
AB  - The objective of this study was to determine whether sustained progesterone (P)
      use in the absence of estrogen could influence mammary development in mice. Three
      week-old intact or ovariectomized mice were primed with subcutaneous (s.c.)
      cholesterol (C), estrogen (E), P, or estrogen and progesterone (E/P) together.
      Nine days after priming, mammary glands were removed and incubated as a whole
      organ in media supplemented with various combinations of lactogenic hormones.
      After 5 days in whole organ culture, glands were removed and end buds, alveolar
      buds and lobulo-alveoli were quantified. Glands from mice primed with C or E
      developed significantly less lobulo-alveoli than glands from mice primed with P
      or E/P. While the development was greater in animals treated with E/P compared to
      those treated with P, it was clear that P in the absence of E could still induce
      lobulo-alveolar development. We have shown in this paper that P, in the absence
      of E, can stimulate cell proliferation during priming. Subsequently, the P primed
      glands can differentiate in response to lactogenic hormones.

PMID- 10395300
TI  - Does cyclosporin A cause cancer?

PMID- 10395301
TI  - Clinical research, or classical clinical research?

PMID- 10395302
TI  - Oxidative DNA damage and embryo development.

PMID- 10395303
TI  - Conflict-of-interest problems lead to policy changes.

PMID- 10395304
TI  - Local people threaten chimp sanctuary.

PMID- 10395305
TI  - NIH to create PhD program.

PMID- 10395306
TI  - Bioinformatics an NIH priority.

PMID- 10395307
TI  - FDA bans UK blood donation.

PMID- 10395308
TI  - US to make research marijuana more accessible.

PMID- 10395309
TI  - Strategies used by human immunodeficiency virus that allow persistent viral
      replication.

PMID- 10395311
TI  - Cluster headache: phrenology revisited?

PMID- 10395310
TI  - Fighting arthritis with a senescence gene.

PMID- 10395312
TI  - The matrix delivers.

PMID- 10395313
TI  - Heparanase: breaking down barriers in tumors.

PMID- 10395314
TI  - MEK wars, a new front in the battle against cancer.

PMID- 10395315
TI  - Targeting AIDS-Kaposi's sarcoma.

PMID- 10395316
TI  - HIV-1 entry inhibitors: evading the issue.

PMID- 10395317
TI  - Obesity: autonomic circuits versus feeding.

PMID- 10395318
TI  - Integration of endoplasmic reticulum signaling in health and disease.

PMID- 10395319
TI  - Localized, direct plasmid gene delivery in vivo: prolonged therapy results in
      reproducible tissue regeneration.
AB  - The inability to deliver growth factors locally in a transient but sustained
      manner is a substantial barrier to tissue regeneration. Systems capable of
      localized plasmid gene delivery for prolonged times may offer lower toxicity and
      should be well-suited for growth factor therapeutics. We investigated the potency
      of plasmid gene delivery from genes physically entrapped in a polymer matrix
      (gene activated matrix) using bone regeneration as the endpoint in vivo.
      Implantation of gene activated matrices at sites of bone injury was associated
      with retention and expression of plasmid DNA for at least 6 weeks, and with the
      induction of centimeters of normal new bone in a stable, reproducible, dose- and
      time-dependent manner.

PMID- 10395320
TI  - Induction of the p16INK4a senescence gene as a new therapeutic strategy for the
      treatment of rheumatoid arthritis.
AB  - Synovial tissue affected by rheumatoid arthritis is characterized by
      proliferation, which leads to irreversible cartilage and bone destruction.
      Current and experimental treatments have been aimed mainly at correcting the
      underlying immune abnormalities, but these treatments often prove ineffective in
      preventing the invasive destruction. We studied the expression of cyclin
      dependent kinase inhibitors in rheumatoid synovial cells as a means of
      suppressing synovial cell proliferation. Synovial cells derived from hypertrophic
      synovial tissue readily expressed p16INK4a when they were growth-inhibited. This
      was not seen in other fibroblasts, including those derived from normal and
      osteoarthritis-affected synovial tissues. In vivo adenoviral gene therapy with
      the p16INK4a gene efficiently inhibited the pathology in an animal model of
      rheumatoid arthritis. Thus, the induction of p16INK4a may provide a new approach
      to the effective treatment of rheumatoid arthritis.

PMID- 10395321
TI  - Long-term cure of the photosensitivity of murine erythropoietic protoporphyria by
      preselective gene therapy.
AB  - Definitive cure of an animal model of a human disease by gene transfer into
      hematopoietic stem cells has not yet been accomplished in the absence of
      spontaneous in vivo selection for transduced cells. Erythropoietic protoporphyria
      is a genetic disease in which ferrochelatase is defective. Protoporphyrin
      accumulates in erythrocytes, leaks into the plasma and results in severe skin
      photosensitivity. Using a mouse model of erythropoietic protoporphyria, we
      demonstrate here that ex vivo preselection of hematopoietic stem cells transduced
      with a polycistronic retrovirus expressing both human ferrochelatase and green
      fluorescent protein results in complete and long-term correction of skin
      photosensitivity in all transplanted mice.

PMID- 10395322
TI  - CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T
      lymphocyte tolerance and augments anti-tumor vaccine efficacy.
AB  - The outcome of antigen recognition by naive CD8+ cytotoxic T lymphocytes (CTLs)
      in the periphery is orchestrated by CD4+ T-helper cells, and can either lead to
      priming or tolerization. The presence of T-helper cells favors the induction of
      CTL immunity, whereas the absence of T-helper cells can result in CTL tolerance.
      The action of T helper cells in CTL priming is mediated by CD40-CD40 ligand
      interactions. We demonstrate here that triggering of CD40 in vivo can
      considerably enhance the efficacy of peptide-based anti-tumor vaccines. The
      combination of a tolerogenic peptide vaccine containing a minimal essential CTL
      epitope with an activating antibody against CD40 converts tolerization into
      strong CTL priming. Moreover, CD40 ligation can provide an already protective
      tumor-specific peptide vaccine with the capacity to induce therapeutic CTL
      immunity in tumor-bearing mice. These findings indicate that the CD40-CD40 ligand
      pair can act as a 'switch', determining whether naive peripheral CTLs are primed
      or tolerized, and support the clinical use of CD40-stimulating agents as
      components of anti-cancer vaccines.

PMID- 10395323
TI  - Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in
      vivo ligation of CD40.
AB  - Tumor antigen-specific T-cell tolerance limits the efficacy of therapeutic cancer
      vaccines. Antigen-presenting cells mediate the induction of T-cell tolerance to
      self-antigens. We therefore assessed the fate of tumor-specific CD4+ T cells in
      tumor-bearing recipients after in vivo activation of antigen-presenting cells
      with antibodies against CD40. Such treatment not only preserved the
      responsiveness of this population, but resulted in their endogenous activation.
      Established tumors regressed in vaccinated mice treated with antibody against
      CD40 at a time when no response was achieved with vaccination alone. These
      results indicate that modulation of antigen-presenting cells may be a useful
      strategy for enhancing responsiveness to immunization.

PMID- 10395324
TI  - Protective effects of C5a blockade in sepsis.
AB  - Sepsis in humans is a difficult condition to treat and is often associated with a
      high mortality rate. In this study, we induced sepsis in rats using cecal
      ligation and puncture (CLP). In rats depleted of the complement factor C3, CLP
      led to very short survival times (about 4 days). Of the rats that underwent CLP
      ('CLP rats') that were C3-intact and treated with preimmune IgG, most (92%) were
      dead by 7 days. Blood neutrophils from these rats contained on their surfaces the
      powerful complement activation product C5a. This group had high levels of
      bacteremia, and their blood neutrophils when stimulated in vitro had greatly
      reduced production of H2O2, which is known to be essential for the bactericidal
      function of neutrophils. In contrast, when companion CLP rats were treated with
      IgG antibody against C5a, survival rates were significantly improved, levels of
      bacteremia were considerably reduced, and the H2O2 response of blood neutrophils
      was preserved. Bacterial colony-forming units in spleen and liver were very high
      in CLP rats treated with preimmune IgG and very low in CLP rats treated with IgG
      antibody against C5a, similar to values obtained in rats that underwent 'sham'
      operations (without CLP). These data indicate that sepsis causes an excessive
      production of C5a, which compromises the bactericidal function of neutrophils.
      Thus, C5a may be a useful target for the treatment of sepsis.

PMID- 10395325
TI  - Mammalian heparanase: gene cloning, expression and function in tumor progression
      and metastasis.
AB  - Heparan sulfate proteoglycans interact with many extracellular matrix
      constituents, growth factors and enzymes. Degradation of heparan sulfate by
      endoglycosidic heparanase cleavage affects a variety of biological processes. We
      have purified a 50-kDa heparanase from human hepatoma and placenta, and now
      report cloning of the cDNA and gene encoding this enzyme. Expression of the
      cloned cDNA in insect and mammalian cells yielded 65-kDa and 50-kDa recombinant
      heparanase proteins. The 50-kDa enzyme represents an N-terminally processed
      enzyme, at least 100-fold more active than the 65-kDa form. The heparanase mRNA
      and protein are preferentially expressed in metastatic cell lines and specimens
      of human breast, colon and liver carcinomas. Low metastatic murine T-lymphoma and
      melanoma cells transfected with the heparanase cDNA acquired a highly metastatic
      phenotype in vivo, reflected by a massive liver and lung colonization. This
      represents the first cloned mammalian heparanase, to our knowledge, and provides
      direct evidence for its role in tumor metastasis. Cloning of the heparanase gene
      enables the development of specific molecular probes for early detection and
      treatment of cancer metastasis and autoimmune disorders.

PMID- 10395326
TI  - Cloning of mammalian heparanase, an important enzyme in tumor invasion and
      metastasis.
AB  - The endoglycosidase heparanase is an important in the degradation of the
      extracellular matrix by invading cells, notably metastatic tumor cells and
      migrating leukocytes. Here we report the cDNA sequence of the human platelet
      enzyme, which encodes a unique protein of 543 amino acids, and the identification
      of highly homologous sequences in activated mouse T cells and in a highly
      metastatic rat adenocarcinoma. Furthermore, the expression of heparanase mRNA in
      rat tumor cells correlates with their metastatic potential. Exhaustive studies
      have shown only one heparanase sequence, consistent with the idea that this
      enzyme is the dominant endoglucuronidase in mammalian tissues.

PMID- 10395327
TI  - Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.
AB  - The mitogen-activated protein kinase pathway is thought to be essential in
      cellular growth and differentiation. Here we report the discovery of a highly
      potent and selective inhibitor of the upstream kinase MEK that is orally active.
      Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both
      mouse and human origin after treatment with this inhibitor. Efficacy was achieved
      with a wide range of doses with no signs of toxicity, and correlated with a
      reduction in the levels of activated mitogen-activated protein kinase in excised
      tumors. These data indicate that MEK inhibitors represent a promising,
      noncytotoxic approach to the clinical management of colon cancer.

PMID- 10395328
TI  - Interleukin-4 receptor-directed cytotoxin therapy of AIDS-associated Kaposi's
      sarcoma tumors in xenograft model.
AB  - The elusive and enigmatic origin of AIDS-associated Kaposi's sarcoma (AIDS-KS)
      makes it a complex tumor and therefore difficult to treat. Here we demonstrate
      that AIDS-KS cells express surface interleukin-4 (IL-4) receptors, and that IL-4
      toxin (IL-4(38-37)-PE38KDEL) is specifically cytotoxic to these cells.
      Intratumoral, intraperitoneal and intravenous administration of IL-4 toxin in
      nude mice with established subcutaneous AIDS-KS tumors caused considerable anti
      tumor activity in a dose-dependent manner, with highest dose producing durable
      complete responses. Metabolic changes, including cachexia and lymphopenia,
      induced by KS tumors were prevented by IL-4 toxin treatment. This report
      establishes IL-4(38-37)-PE38KDEL as an experimental therapeutic agent for the
      treatment of AIDS-KS.

PMID- 10395329
TI  - Cancer therapy using a self-replicating RNA vaccine.
AB  - 'Naked' nucleic acid vaccines are potentially useful candidates for the treatment
      of patients with cancer, but their clinical efficacy has yet to be demonstrated.
      We sought to enhance the immunogenicity of a nucleic acid vaccine by making it
      'self-replicating'. We accomplished this by using a gene encoding an RNA
      replicase polyprotein derived from the Semliki forest virus, in combination with
      a model antigen. A single intramuscular injection of a self-replicating RNA
      immunogen elicited antigen-specific antibody and CD8+ T-cell responses at doses
      as low as 0.1 microg. Pre-immunization with a self-replicating RNA vector
      protected mice from tumor challenge, and therapeutic immunization prolonged the
      survival of mice with established tumors. The self-replicating RNA vectors did
      not mediate the production of substantially more model antigen than a
      conventional DNA vaccine did in vitro. However, the enhanced efficacy in vivo
      correlated with a caspase-dependent apoptotic death in transfected cells. This
      death facilitated the uptake of apoptotic cells by dendritic cells, providing a
      potential mechanism for enhanced immunogenicity. Naked, non-infectious, self
      replicating RNA may be an excellent candidate for the development of new cancer
      vaccines.

PMID- 10395330
TI  - Mice deficient in tumor necrosis factor-alpha are resistant to skin
      carcinogenesis.
AB  - Given the associations between chronic inflammation and epithelial cancer, we
      studied susceptibility to skin carcinogenesis in mice deficient for the pro
      inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) mice were resistant
      to development of benign and malignant skin tumors, whether induced by initiation
      with DMBA and promotion with TPA or by repeated dosing with DMBA. TNF-alpha(-/-)
      mice developed 5-10% the number of tumors developed by wild-type mice during
      initiation/promotion and 25% of those in wild-type mice after repeated carcinogen
      treatment. TNF-alpha could influence tumor and stromal cells during tumor
      development. The early stages of TPA promotion are characterized by keratinocyte
      hyperproliferation and inflammation. These were diminished in TNF-alpha(-/-)
      mice. TNF-alpha was extensively induced in the epidermis, but not the dermis, in
      TPA-treated wild-type skin, indicating that dermal inflammation is controlled by
      keratinocyte TNF-alpha production. Deletion of a TNF-alpha inducible chemokine
      also conferred some resistance to skin tumor development. TNF-alpha has little
      influence on later stages of carcinogenesis, as tumors in wild-type and TNF
      alpha(-/-) mice had similar rates of malignant progression. These data provide
      evidence that a pro-inflammatory cytokine is required for de novo carcinogenesis
      and that TNF-alpha is important to the early stages of tumor promotion.
      Strategies that neutralize TNF-alpha production may be useful in cancer treatment
      and prevention.

PMID- 10395331
TI  - Inhibition of virus-induced neuronal apoptosis by Bax.
AB  - The Bax protein is widely known as a pro-apoptotic Bcl-2 family member that when
      overexpressed can trigger apoptosis in multiple cell types and is important for
      the developmental cell death of neurons. However, Bax was found here to be a
      potent inhibitor of neuronal cell death in mice infected with Sindbis virus.
      Newborn mice, which are highly susceptible to a fatal infection with neurotropic
      Sindbis virus, were significantly protected from neuronal apoptosis and fatal
      disease when infected with a recombinant Sindbis virus encoding Bax. Deletion of
      the N terminus of Bax, which mimics cleaved Bax, converted Bax into a pro
      apoptotic factor in vivo. As mice mature during the first week after birth, they
      acquire resistance to a fatal Sindbis virus infection. However, Bax-deficient
      mice remained very sensitive to fatal disease compared with their control
      littermates, indicating that endogenous Bax functions as a survival factor and
      contributes to age-dependent resistance to Sindbis virus-induced mortality. The
      protective effects of Bax were reproduced in cultured hippocampal neurons but not
      in cultured dorsal root ganglia neurons. These findings indicate that cell
      specific factors determine the anti-apoptotic versus pro-apoptotic function of
      Bax.

PMID- 10395332
TI  - Correlation between structural and functional changes in brain in an idiopathic
      headache syndrome.
AB  - Fundamental to the concept of idiopathic or primary headache, including migraine,
      tension-type headache and cluster headache, is the currently accepted view that
      these conditions are due to abnormal brain function with completely normal brain
      structure. Cluster headache is one such idiopathic headache with many
      similarities to migraine, including normal brain structure on magnetic resonance
      imaging and abnormal function in the hypothalamic grey matter by positron
      emission tomography. Given the consistency of the positron emission tomography
      findings with the clinical presentation, we sought to assess whether the brains
      of such patients were structurally normal. We used voxel-based morphometry, an
      objective and automated method of analyzing changes in brain structure, to study
      the structure of the brains of patients with cluster headache. We found a co
      localization of structural changes and changes in local brain activity with
      positron emission tomography in the same area of the brain in the same patients.
      The results indicate that the current view of the neurobiology of cluster
      headache requires complete revision and that this periodic headache is associated
      with a hitherto unrecognized brain abnormality in the hypothalamic region. We
      believe that voxel-based morphometry has the potential to change in the most
      fundamental way our concept of primary headache disorders, requiring a radical
      reappraisal of the tenet of structural normality.

PMID- 10395333
TI  - Tetrameric HLA class I-minor histocompatibility antigen peptide complexes
      demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in
      patients with graft-versus-host disease.
AB  - Graft-versus-host disease (GvHD) is a chief complication of allogeneic bone
      marrow transplantation. In HLA-identical bone marrow transplantation, GvHD may be
      induced by disparities in minor histocompatibility antigens (mHags) between the
      donor and the recipient, with the antigen being present in the recipient and not
      in the donor. Cytotoxic T lymphocytes (CTLs) specific for mHags of the recipients
      can be isolated from the blood of recipients with severe GvHD (ref. 3). A
      retrospective study demonstrated an association between mismatch for mHags HA-1, 
      2, -4 and -5 and the occurrence of GvHD in adult recipients of bone marrow from
      HLA genotypically identical donors. Tetrameric HLA-peptide complexes have been
      used to visualize and quantitate antigen-specific CTLs in HIV-infected
      individuals and during Epstein-Barr virus and lymphocytic choriomeningitis virus
      infections. Here we show the direct ex vivo visualization of mHag-specific CTLs
      during GvHD using tetrameric HLA-class and I-mHag HA-1 and HY peptide complexes.
      In the peripheral blood of 17 HA-1 or HY mismatched marrow recipients, HA-1- and
      HY-specific CTLs were detected as early as 14 days after bone marrow
      transplantation. The tetrameric complexes demonstrated a significant increase in
      HA-1- and HY-specific CTLs during acute and chronic GvHD, which decreased after
      successful GvHD treatment. HLA class I-mHag peptide tetramers may serve as
      clinical tools for the diagnosis and monitoring of GvHD patients.

PMID- 10395334
TI  - Gene transfer into CD4+ T lymphocytes: green fluorescent protein-engineered,
      encephalitogenic T cells illuminate brain autoimmune responses.

PMID- 10395335
TI  - A tale of three patients.

PMID- 10395336
TI  - Efficacy of three-phase bone scans in evaluating diabetic foot ulcers.
AB  - To evaluate the utility of bone scans in determining the treatment of diabetic
      patients with foot ulcers, a retrospective study was conducted. Medical records
      were reviewed for clinical signs of infection, laboratory data, and the
      radiologists' interpretations of imaging studies. During the study period, 34
      bone scans were obtained by the treating physicians to evaluate diabetic foot
      ulcers. Among these, 22 of 34 bone scans were markedly confirmatory of being
      "consistent with osteomyelitis," 8 of 34 were moderately confirmatory
      ("indeterminate with regard to osteomyelitis"), and 4 of 34 were not confirmatory
      ("not consistent with osteomyelitis"). Of the 22 patients in the markedly
      confirmatory group, eight patients with clinical findings of uncontrolled
      infection or gangrene were treated with partial or complete amputation, whereas
      all others (14 patients) were treated with local wound care+/-intravenous
      antibiotics. Among the eight bone scans interpreted as indeterminate, three
      patients required partial or complete amputation, whereas the other five patients
      were managed with local wound care. Of the four patients with nonconfirmatory
      bone scans, two patients had evidence of dry gangrene and required amputation,
      whereas the other two patients did not have clinical evidence of infection or
      gangrene and were treated with local wound care. There was no significant
      difference in the amputation rate for patients with confirmatory, indeterminate,
      or nonconfirmatory bone scans for osteomyelitis (36%, 37%, and 50%, respectively)
      (P > 0.5). Therefore, the authors concluded that the ultimate treatment should be
      based on clinical indicators of the presence of uncontrolled infection or
      gangrene rather than on bone scan findings.

PMID- 10395337
TI  - Triple arthrodesis in adults using rigid internal fixation: an assessment of
      outcome.
AB  - The intermediate outcome of patients who underwent a triple arthrodesis for the
      treatment of adult foot disorders was evaluated with an outcome tool to determine
      if their pain and functional status were improved. We evaluated 63 feet in 57
      patients who underwent a triple arthrodesis using rigid internal fixation for the
      treatment of hindfoot deformities associated with symptomatic arthrosis. Twenty
      four men and thirty-three women, with an average age of 54 years, were evaluated.
      The average follow-up was 30 months. Multiple diagnoses contributed to hindfoot
      deformities with secondary arthrosis. Iliac crest bone graft was used in 56 of 63
      cases (89%). Percutaneous heel cord lengthening was done in 53 of 63 cases (84%).
      Twenty-four of the thirty patients (80%) returned to work. Twenty-five patients
      were retired and two were unemployed before surgery. All patients except two
      (97%) were satisfied with the surgery and would have the surgery again. The
      average American Orthopaedic Foot and Ankle Society Ankle-Hindfoot preoperative
      score was 28 points, and the average postoperative score was 81 points (P <
      0.0001). In the radiographic measurements, there was an average improvement of 12
      degrees in the lateral talometatarsal angle, 7 degrees in the lateral
      talocalcaneal angle, and 10 degrees in the AP talometatarsal angle (P < 0.0001).
      Complications experienced included two varus malunions, two valgus malunions, two
      nonunions, two deep vein thromboses, one distal fibula stress fracture, and one
      wound infection. Of the 26 feet in 22 patients with mortise views available, 10
      feet (38%) had evidence of ankle arthrosis and 19 feet (73%) had some degree of
      talar tilt postoperatively.

PMID- 10395338
TI  - Plantar fascia release through a transverse plantar incision.
AB  - A transverse plantar incision for plantar fascial release was assessed for pain
      relief, numbness, and subsequent heel pad symptoms. Twenty-seven feet in 26
      patients who underwent plantar fascia release were reviewed with a minimum follow
      up of 2 years after surgery (average, 37.6 months). Comprehensive data were
      obtained on 25 feet (24 patients) (93% response rate). The plantar fascia origin
      was completely transected in all cases. This led to complete resolution of
      symptoms in 19 feet and residual minor symptoms in six feet. After 2 years, four
      patients had developed recurrent symptoms, two in the area of surgery and two on
      the dorsum of the foot, in association with a pes planus foot. Two patients had
      some continued persistence of heel pain after surgery, although significantly
      less pain than preoperatively.Thus, 76% of patients had complete relieve of there
      symptoms, 12% of patients had mild symptoms not affecting daily activities, and
      12% of patients had moderate symptoms that limited some activities. No patient
      suffered heel pad symptoms or numbness after surgery. It is concluded that
      plantar fascia release through a transverse plantar incision is a successful
      procedure for long-term relief of symptoms which avoids unnecessary heel pad
      numbness and scar morbidity. The benefits of a transverse incision include
      greater intraoperative vision, to ensure adequate release and spur excision, and
      an incision parallel to the medial calcaneal branches of the tibial nerve.

PMID- 10395339
TI  - Open versus arthroscopic ankle arthrodesis: a comparative study.
AB  - A retrospective review was undertaken for 36 patients who underwent ankle
      arthrodesis. Nineteen patients underwent an arthroscopic ankle arthrodesis, and
      17 patients underwent an open arthrodesis. Only patients with limited angular
      deformities were suitable candidates for an arthroscopic arthrodesis. The open
      arthrodesis group inclusion criteria were defined by the maximum coronal and
      sagittal plane deformity in the arthroscopic group. Perioperative parameters were
      compared and analyzed. Arthroscopic ankle arthrodesis yielded comparable fusion
      rates to open ankle arthrodesis, with significantly less morbidity, shorter
      operative times, shorter tourniquet times, less blood loss, and shorter hospital
      stays. Arthroscopic ankle arthrodesis is a valid alternative to traditional open
      arthrodesis of the ankle for selected patients with ankle arthritis.

PMID- 10395341
TI  - External rotation-lateral view of the ankle in the assessment of the posterior
      malleolus.
AB  - Demonstration of a posterior malleolar fragment on a radiograph of an ankle
      fracture is important in the diagnosis and evaluation of posterior malleolus
      fractures. The size and extent of displacement of a posterior malleolar fragment
      can be evaluated. The diagnosis of non-union of the posterior malleolus is also
      important because it can lead to failure of reduction of ankle fractures. The
      authors present a case in which nonunion of the posterior malleolus was diagnosed
      by an external-rotation lateral view of the ankle. This could not be demonstrated
      on the AP or the lateral views. Thirteen cadaver feet were then used to study the
      external-rotation lateral view. A posterior malleolar fracture was created, and
      the borders of the fracture line were marked with solder wire. The average
      external rotation angle required to best demonstrate the posterior malleolar
      fracture was 50 degrees (range, 43 degrees -55 degrees). The actual size of the
      posterior malleolus fragment was measured and compared to the x-ray measurement.
      There was a 0.10 correction for the determination of the actual size of the
      fragment. The unmarked fragment could not be demonstrated on AP and lateral
      views.

PMID- 10395342
TI  - Intraosseous ganglion cysts of the ankle: a report of three cases with long-term
      follow-up.
AB  - Three cases of intraosseous ganglion cysts of the ankle are presented with an
      average follow-up of 68 months (range, 48-78 months). Review of the literature
      revealed 251 cases of intraosseous ganglion cysts, with 75 located in the ankle
      and a recurrence rate of 6.1%. In the three cases presented, a satisfactory long
      term result was obtained with bone graft and curettage in two cases and
      currettage alone in one case. No recurrences or complications occurred.

PMID- 10395344
TI  - Unilateral tibial hemimelia with leg length inequality and varus foot: external
      fixator treatment.
AB  - A 15-year-old girl with type II unilateral hemimelia presented with a 13.5-cm
      shortening of her right leg, absence of the distal half of the tibia,
      tibiofibular synostosis, and medial dislocation of a cavus and varus foot. She
      was treated by means of an external fixator. The shortening was significantly
      corrected, and realignment of the foot with the limb was achieved. An arthrodesis
      of the talus and lower end of the fibula was carried out operatively and
      stabilized with an external fixator. In the same surgical procedure, we performed
      an osteotomy of the tibiofibular synostosis, and progressive distraction was done
      with another external fixator. We emphasize the advantages of progressive
      distraction for the correction of congenital deformities of the limbs.

PMID- 10395343
TI  - Bandage distraction technique for ankle arthroscopy.
AB  - In ankle arthroscopy, the joint space of the talocrural joint is often too narrow
      for insertion of the scope and instruments. Various distraction devices for this
      procedure have been used to widen the joint space. Bandage distraction is
      effective and noninvasive, but it is difficult to extend the posterior joint
      space sufficiently for insertion of the scope. Here we describe a new bandage
      distraction method that can extend the posterior joint space adequately. Using
      our method, the anterior and posterior joint spaces on direct lateral radiographs
      were measured after adding the distraction force in nine healthy volunteers (18
      ankles; three men and 6 women). This was compared to a previously reported
      method. The posterior joint space was widened a greater amount when our new
      bandage distraction technique was used.

PMID- 10395340
TI  - Salvage of tibial pilon fractures using fusion of the ankle with a 90 degrees
      cannulated blade-plate: a preliminary report.
AB  - Six patients with ankle joint destruction and delayed metaphyseal union after
      tibial plafond fracture were surgically treated with tibiotalar arthrodesis and
      metaphyseal reconstruction, using a fixed-angle cannulated blade-plate. The
      procedure was performed through a posterior approach in five cases and a lateral
      approach in one case. The subtalar joint was preserved in all cases. Metaphyseal
      union and a stable arthrodesis were obtained in all cases without loss of
      fixation and with no mechanical failure of the blade-plate. Union was obtained in
      an average of 26 weeks. No secondary procedures were required to obtain union.
      All six patients were ambulatory at last follow-up. Stable internal fixation for
      simultaneous tibiotalar fusion and metaphyseal reconstruction can be achieved
      with a cannulated blade-plate while preserving the subtalar joint in complex
      plafond fractures.

PMID- 10395345
TI  - Intravenous catheter as a wire sleeve during forefoot reconstruction.

PMID- 10395346
TI  - Occult osseous injuries after ankle sprains: incidence, location, pattern, and
      age.

PMID- 10395347
TI  - Detection of acute cardiac rejection by analysis of heart rate variability in
      heterotopically transplanted rats.
AB  - BACKGROUND: A less-invasive method for cardiac allograft surveillance than
      endocardial biopsy is needed. We analyzed heart rate variability of
      heterotopically transplanted rat hearts as a method of detecting rejection of rat
      cardiac allografts. METHODS: Two kinds of heterotopic transplants were performed:
      1) Brown-Norway rats received Brown-Norway rat isografts, and 2) Lewis rats
      received Brown-Norway rat allografts. The electrocardiogram (ECG) of the grafts
      were serially recorded under non-anesthetized and non-restricted conditions using
      a telemetric ECG transmitter implanted in the recipient's abdomen. Frequency
      domain analysis of the ECGs was performed using a fast Fourier algorithm.
      RESULTS: Total power of the heart rate variability in the isograft heart was
      reduced to 1.1%, compared to normal subjects without transplantation (p < .001).
      In the allograft heart, it was also reduced to 1.0% on days 1.5 (rejection score
      0 to 1), but gradually increased thereafter up to 185% on day 6 (rejection score
      3.75+/-0.50). The increase in spectral power was frequency-dependent (i.e.,
      changes in the power in lower frequency range [LF, 0.04 to 0.67 Hz] were
      significantly higher than other ranges). This increase was reversible when
      immunosuppressive therapy was performed with the use of cyclosporine A. In the
      allograft group, peak-to-peak amplitudes of the QRS complex and heart rate were
      significantly decreased on day 5.5 or later, whereas the power of the LF was
      significantly increased by day 3.5 or later. CONCLUSIONS: Our data suggest that
      heart rate variability analysis is a promising noninvasive marker for early
      detection of cardiac allograft rejection. This method may also provide a
      sensitive means of assessing the effects of immunosuppressive therapy.

PMID- 10395348
TI  - Characterization of the natural history of cervical heterotopic heart
      transplantation with echocardiography.
AB  - BACKGROUND: Limitations of the dog model of orthotopic heart transplantation to
      study rejection include the need for extracorporeal circulation and transfusions.
      Heterotopic cervical heart transplantation may improve on these limitations. It
      is not known whether the natural history after heterotopic transplant is similar
      to that after orthotopic grafting. METHODS: Twenty-one dogs underwent cervical
      heterotopic heart transplantation. Serial echocardiographic studies were
      performed 1 to 3 hours after surgery, at 24 hours, 48 hours later, and
      immediately before killing (5 to 7 days). RESULTS: LV diastolic and systolic
      areas were elevated immediately after transplantation (4.95+/- 1.49 cm2 and
      3.36+/-1.18 cm2 respectively) but decreased at 24 hours (3.93+/-1.20 cm2, p =
      0.0003 and 2.44+/-0.96 cm2, p = 0.16). Thereafter, a progressive increase in LV
      diastolic and systolic areas was observed until sacrifice (5.53+/-2.20 cm2 and
      4.59 +/-2.14 cm2, p < 0.001 vs 24 hours). LV fractional area shortening (FAS) and
      fractional volume change were depressed immediately after transplantation (28.2+/
      12.8% and 40.4+/-12.3%, respectively), but increased at 24 hours (35.7+/-10.0%,p
      = 0.11 and 50.3+/-4.0%,p = 0.02). FAS decreased at 48 hours to 19.6+/-11.1% (p =
      0.01 vs 24 hours). The centractility indexes were markedly reduced before killing
      (FAS = 14.0+/-8.2% and LVEF = 18.4+/-1.3%, p < 0.0005 vs 24 hours). The thickness
      of the interventricular septum increased from 11.9+/-2.0 mm at baseline to 14.4+/
      4.2 mm before sacrifice (p = 0.007). CONCLUSION: The evolution of dogs after
      heterotopic cervical heart transplant is comparable to that after the more
      standard orthotopic graft. Considering its multiple practical advantages
      including the easy echocardiographic follow-up, heterotopic transplantation may
      become a very practical model to use for the study of rejection after heart
      transplantation.

PMID- 10395349
TI  - Transforming growth factor-beta (TGF-beta1) genotype and lung allograft fibrosis.
AB  - BACKGROUND: TGF-beta1 is a prosclerotic cytokine implicated in fibrotic
      processes. Fibrosis of the pulmonary parenchyma and airways is a frequent
      presentation in lung transplant recipients before and after transplantation.
      There are two genetic polymorphisms in the DNA sequence encoding the leader
      sequence of the TGF-beta1 protein, located at codon 10 (either leucine or
      proline) and at codon 25 (either arginine or proline). The codon 25 arginine
      allele is associated with higher TGF-beta1 production by cells activated in
      vitro. We tested the hypothesis that inheritance of alleles of the TGF-beta1 gene
      conferring higher production of TGF-beta1 may be responsible for over-expression
      of TGF-beta1 in transplant recipients resulting in lung allograft fibrosis.
      METHODS: We extracted DNA from leukocytes collected from 91 pulmonary transplants
      performed at our centre and 96 normal healthy volunteers between May 1990 and
      September 1995. Part of the first exon was amplified by PCR. Samples were
      genotyped by using sequence specific oligonucleotide probes. RESULT: The
      distribution of codon 10 alleles was similar in a normal healthy control group
      and in lung transplant recipients, regardless of their pretransplant lung
      pathology. By contrast, there was a significant difference in the frequency of
      codon 25 alleles between the control and transplant groups. In the normal control
      group 81% were codon 25 arginine/arginine (A/A) homozygotes, 19% were
      arginine/proline (A/P) heterozygotes and none were proline/proline (P/P)
      homozygotes. The distribution of codon 25 alleles was similar in lung transplant
      recipients who did not have a significant fibrosis in pretransplant pathology,
      but in transplant recipients who came to transplantation with lung fibrosis 98%
      (41 of 42 patients) were homozygous for the codon 25 A/A allele (p < .05). After
      lung transplantation 39 of 91 patients developed lung allograft fibrosis, and of
      these 92.3% (36 of 39 recipients) were of homozygous codon 25 A/A high TGF-beta1
      producer genotype (p < .001). Lung transplant recipients who were homozygous for
      both codon 10 L/L and codon 25 A/A showed poor survival compared with all other
      TGF-beta1 genotypes (p < .03). CONCLUSION: Homozygosity for arginine at codon 25
      of the leader sequence of TGF-beta1 that correlates with higher TGF-b production
      in vitro, is associated with fibrotic lung pathology before lung transplantation
      and with the development of fibrosis in the graft. In combination with the codon
      10 leucine allele, homozygosity for the codon 25arginine allele is a marker for
      poor post-transplant prognosis and recipient survival.

PMID- 10395350
TI  - A new rejection criteria in the heterotopically placed rat heart by non-invasive
      measurement of Dp/Dtmax.
AB  - BACKGROUND: The heterotopic heart of rats has been a useful model in the
      evaluation of immunomodulatory protocols. Graft palpation usually determines the
      day of rejection. We present in this paper an original method of graft monitoring
      in allograft rejection. METHODS: Heterotopic cardiac abdominal transplantation
      was performed in Lewis isografts (n = 15) and in ACI to Lewis allograft (n = 15).
      A balloon connected to a measurement device was inserted in the left ventricle,
      and calculation of Dp/Dtmax was possible by recording the intra-left ventricular
      pressure. A ten-day follow-up was achieved with a daily comparison of palaption,
      ECG, and Dp/Dtmax. RESULTS: In transplanted hearts, Dp/Dtmax did not change in
      isografts but significantly decreased in allograft on posttransplantation Day 5
      (PTD 5) vs PTD 0.1 and 3 (p < .01). Dp/Dtmax values on PTD 5 and 6 were also
      statistically significant in allograft vs isograft group (p < .01). Histological
      analysis at this time showed the occurrence of acute rejection in the allograft
      group. Graft palpation, and ECG remained normal until PTD 10 and no difference
      was observed between iso and allo groups. CONCLUSION: This study shows that daily
      measurement of Dp/Dtmax in heterotopic heart is made possible by our implantable
      system without interrupting the graft, and gives a more accurate definition of
      graft rejection than a combination of palpation and ECG. In addition, this method
      would seem desirable when differences in survival may be expected to be of lesser
      magnitude.

PMID- 10395351
TI  - Mixed hematopoietic chimerism prevents allograft vasculopathy.
AB  - BACKGROUND: Mixed hematopoietic chimerism has been shown to induce long-term
      acceptance of transplant organs. We determined whether mixed chimerism prevented
      allograft vasculopathy, using the rat aortic allograft model. METHODS: Mixed
      chimeras were prepared by reconstituting lethally irradiated (1100 cGy) WF rats
      with a mixture of T-cell depleted (TCD) syngeneic (WF) plus TCD allogeneic (ACI)
      bone marrow. Donor-specific (ACI) or third-party (F344) aortic grafts were
      transplanted into mixed chimeric animals 1 to 2 months after bone marrow
      reconstitution. No immunosuppressive drugs were administered. At 30 days
      postoperatively, aortic allografts were harvested for histology and measurement
      of cytokine mRNA by semiquantitative RT-PCR. Some aortic grafts were harvested at
      90 and 180 days after transplantation for histological analysis. The degree of
      intimal hyperplasia and cytokine gene expression were compared among 4 groups: I
      (syngeneic; ACI donors to ACI recipients), II (allografts; ACI to WF), III (donor
      specific; ACI donor to chimeras) and IV (third-party; F344 to chimeras). RESULTS:
      There was no difference in the degree of intimal hyperplasia (IH) between groups
      I and III. Groups II and IV had significantly more IH than group I. Compared to
      group I, levels of mRNA for IFN-y, IL-2, IL-10 and iNOS in groups II and IV were
      higher, while there was no difference in mRNA levels between group I and III.
      CONCLUSIONS: These data suggest that mixed chimerism prevents allograft
      vasculopathy. Mixed chimerism holds great promise in clinical transplantation as
      a means to prevent allograft vasculopathy.

PMID- 10395353
TI  - Early post-transplant medical compliance and mental health predict physical
      morbidity and mortality one to three years after heart transplantation.
AB  - BACKGROUND: Poor medical compliance has been held responsible for a large
      proportion of deaths occurring subsequent to initial postoperative recovery.
      However, beyond clinical reports, there has been little empirical examination of
      this issue, or of the extent to which major psychiatric disorder and failure to
      adjust to the transplant predict long-term physical morbidity and mortality. We
      prospectively examined whether a full range of compliance behaviors and
      psychiatric outcomes during the first year post-transplant predicted subsequent
      mortality and physical morbidity through 3 years post-transplant. METHODS: A
      total of 145 heart recipients who had received detailed compliance and mental
      health assessments during the first year post-transplant were followed up at 3
      years post-transplant. Interview data and corroborative information from family
      members were used to determine compliance in multiple domains, psychiatric
      diagnoses, and psychiatric symptomatology during the first year post-surgery.
      Medical record reviews were performed to abstract data on acute graft rejection
      episodes, incident cardiac allograft disease (CAD) and mortality from 1 to 3
      years post-transplant. RESULTS: After controlling for known transplant-related
      predictors of outcome, multivariate analyses yielded the following significant (p
      < 0.05) results: (a) risk of acute graft rejection was 4.17 times greater among
      recipients who were not compliant with medications; (b) risk of incident CAD was
      elevated by persistent depression (Odds Ratio, OR = 4.67), persistent anger
      hostility (OR = 8.00), medication noncompliance (OR = 6.91), and obesity (OR =
      9.92); and (c) risk of mortality was increased if recipients met criteria for
      Post-Traumatic Stress Disorder related to the transplant (OR = 13.74).
      CONCLUSIONS: The findings, plus data we have previously reported that showed
      which patients are most likely to have compliance and psychiatric problems early
      post-transplant, suggest that interventions focused on maximizing patients'
      psychosocial status in these areas may further improve long-term physical health
      outcomes in this population.

PMID- 10395352
TI  - Development of obliterative bronchiolitis after allogeneic rat lung
      transplantation: implication of acute rejection and the time point of treatment.
AB  - BACKGROUND: Chronic allograft failure represents the major cause of late
      morbidity and mortality after solid organ transplantation. Despite the
      pathological and clinical changes of this disease being well-described, the
      etiology and the causative factors are still under discussion. Several clinical,
      as well experimental studies, emphasize the significance of acute rejection. In
      rat model of left lung allo-transplantation (F344-to-WKY) the influence of acute
      rejection (AR) on the development of chronic rejection (CR) was studied. METHODS:
      In Group I (n = 25) no immunosuppression was used, while methylprednisolone (MP)
      (10 mg/kg) was applied in Group II (n = 20) in the early phase of AR on
      postoperative Days 9, 10, 11 and in Group III (n = 20) during AR on Day 14, Day
      15, Day 16. The rats were sacrificed on Day 5, Day 15/20, Day 30, Day 60, Day 100
      and following HE-staining the extend of AR as well CR was graded according to the
      working formulation of The International Society of Heart and Lung
      Transplantation. RESULTS: In Group I, AR was found at Day 15 and Day 30 which
      resolved spontaneously and resulted in CR on Day 60 and Day 100. In Group II,
      signs of AR were less evident on Day 20, while mild AR persisted on Day 30 and
      Day 60. On Day 100, normal lung structure was found in all rats. The recipients
      of Group III showed decreased signs of AR in the early course, however, severe CR
      was found on Day 60 and Day 100. Extensive airway inflammation with destruction
      of the subepithelial layer of the smaller airways resulted in severe early
      obliterative bronchiolitis. CONCLUSIONS: Untreated severe AR in the early course
      after lung transplantation results in CR in the F344-to-WKY model. Preventive
      treatment with MP during the early phase of AR clearly diminishes the degree of
      AR and the graft recovers completely without any evidence of CR. Late application
      of steroids during the zenith of AR is successful to control the extent of AR,
      however, it fails to prevent CR.

PMID- 10395355
TI  - Optimized cardiac graft preservation: a comparative experimental study using P-31
      magnetic resonance spectroscopy and biochemical analyses.
AB  - BACKGROUND: The University of Wisconsin (UW), St. Thomas (ST) and Broussais (B)
      solutions were compared to the CRMBM solution, that we developed for long term
      heart preservation. METHODS: Isolated isovolumic rat hearts were arrested with
      each cardioplegic solution (n = 5) to 8 hearts in each group), submitted to 12
      hours of cold storage (4 degrees C) in the same solution and then reperfused for
      60 minutes at 37 degrees C. Function was measured during control and reflow. High
      energy phosphates and intracellular pH were monitored by P-31 magnetic resonance
      spectroscopy. Analyses were performed by biochemical assays and HPLC in coronary
      effluents (CK, Pi, lactate, purines) and in freeze-clamped hearts (amino acids,
      nucleotides, CK, LDH) at the end of reperfusion. RESULTS: Functional recovery was
      significantly improved with the new cardioplegic solution (50+/-12% recovery for
      the rate pressure product at the end of reflow vs 8+/-3% with UW, 0% with B and
      with ST). This result was correlated with the best metabolic and cellular
      protection as assessed in particular by higher PCr levels during reflow (30+/-3%
      vs 10+/-3% with UW, 8+/-4% with B, and 7+/-1% with ST) as well as reduced
      creatine kinase leakage during reflow (110+/-15 IU/60 minute vs 270 +/- 57 IU/60
      minute with UW, 323+/-36 IU/60 minute with Broussais solution and 237+/-18 IU/60
      minute with ST). CONCLUSION: This new solution is more effective in prolonged
      myocardial protection than the three most widely used solutions.

PMID- 10395354
TI  - Lung transplant waiting list: differential outcome of type of end-stage lung
      disease, one year after registration.
AB  - BACKGROUND: Donor lung scarcity, distinct natural courses of the different types
      of end-stage lung diseases, and lung allocation schemes demand appropriate
      candidate acceptance for a lung transplant and time of listing. This study was
      undertaken to investigate the association between type of end-stage lung disease
      and outcome, 1 year after a lung transplant candidate was put on the waiting
      list. METHODS: From 1990 to 1995, 1376 adult patients were registered for a first
      lung (n = 1006) or heart-lung (n = 370) transplantation in Eurotransplant. All
      patients were followed for at least 1 year. For each type of end-stage lung
      disease (cystic fibrosis, pulmonary fibrosis, emphysema, pulmonary hypertension,
      congenital heart disease, and other), chances of transplantation, of death on the
      waiting list, and of removal for other reasons, 1 year after listing, were
      calculated with the competing risks method. A multivariate Cox regression model
      was used to assess the influence of the type of end-stage lung disease on the
      waiting list outflow among other prognostic variables. RESULTS: Lung transplant
      candidates with emphysema and with pulmonary fibrosis had the highest chance of a
      transplant; however, patients with pulmonary fibrosis had also the highest
      probability of dying while waiting, while the emphysema patients and those with
      the type "other" had the lowest probability. In the multivariate analysis, the
      type of end-stage lung disease appeared as an independent prognostic factor for
      both outcomes. Compared to the patients with cystic fibrosis (reference group),
      only patients with pulmonary fibrosis had a significantly higher chance of a
      transplant (RR = 1.50); the lowest chance of death for the emphysema and the
      "other" patients was confirmed (RR = 0.53 and RR = 0.51, respectively). Recipient
      size, ABO blood group, country and epoch of listing also had a significant impact
      on the transplant chance, while country of listing and recipient age were the
      other factors independently influencing the chance of dying on the waiting list.
      On the heart-lung waiting list, the type of end-stage lung disease solely
      affected the chance of death prior to transplant. Compared with cystic fibrosis,
      pulmonary fibrosis had a significantly higher risk (RR = 2.93), closely followed
      by pulmonary hypertension (RR = 2.57). Factors crucial for the chance of a heart
      lung transplant were recipient size, ABO blood group and country of listing.
      CONCLUSIONS: The type of end-stage lung disease is a distinctive factor for
      predicting survival on the lung and heart-lung transplant waiting list, and
      should be taken into account whenever assessing waiting list outcomes. When
      developing lung allocation schemes, it is medically justified to incorporate the
      type of end-stage lung disease.

PMID- 10395356
TI  - Vascular function in the cadaver up to six hours after cardiac arrest.
AB  - BACKGROUND: The aim of the study was to evaluate how well vascular function is
      retained in a cadaver kept in a room with a temperature of 21 degrees C. METHODS:
      The aorta and pulmonary artery of rats were investigated in organ baths as fresh
      controls and after 1, 2, 3, or 6 hours' storage in the cadaver. Six-hour-old
      cadaver aortas were transplanted and investigated after 24 hours and 60 days.
      RESULTS: After 3 hours' storage there was no significant decrease in smooth
      muscle contractile function in either aorta or pulmonary artery. After 6 hours'
      storage both the aorta and the pulmonary artery demonstrated a significant
      decrease in smooth muscle contractile function, 30% (p < 0.05) and 44% (p <
      0.001), respectively, compared to fresh controls. Storing the aorta for 2 hours
      and the pulmonary artery for 6 hours caused no significant decrease in
      endothelium-dependent relaxing function. In aorta segments investigated after 3
      and 6 hours there was a significant decrease in endothelium-dependent relaxation,
      12% (p < 0.05) and 29% (p < 0.001), respectively. Six-hour-old cadaver aortas
      transplanted and investigated after 24 hours or 60 days demonstrated no
      significant changes in endothelium-dependent relaxation and smooth muscle
      function compared to fresh controls. CONCLUSION: The pulmonary artery can
      tolerate 3 hours of warm ischemia in the nonheart-beating cadaver without loss of
      endothelium-dependent relaxation and smooth muscle function. The dysfunction seen
      in 6-hour-old cadaver aortas was normalized after transplantation and 24 hours of
      reperfusion.

PMID- 10395358
TI  - Successful orthotopic pig heart transplantation from non-heart-beating donors.
AB  - BACKGROUND: With the aim to expand the severely limited donor pool by use of non
      heart-beating donors we developed a technique for successful transplantation of
      hearts after 30 minutes of normothermic ischemia without donor pretreatment.
      METHODS: In control groups hearts were transplanted in a conventional fashion
      using crystalloid cardioplegia (Group I, n = 6) or BCP (Group II, n = 8) for
      induction of cardiac arrest. In the ischemic groups hearts were harvested after
      30 minutes of normothermic ischemia, perfused with blood cardioplegia (BCP)
      (Group III, n = 9) or BCP containing the Na(+)-H(+)-exchange inhibitor HOE 642
      (Group IV, n = 8) and transplanted orthotopically. RESULTS: All animals could be
      weaned from cardiopulmonary bypass. Low dose inotropic support was necessary in
      the ischemic groups only. Recovery of the maximal left ventricular stroke work
      index (LVSWImax) in Groups I vs II was 62.6+/-19.6% vs 73.3+/-23.3% (NS), maximal
      right ventricular stroke work index (RVSWImax) averaged 61.1+/-18.8 vs 87.8+/
      31.7% (NS) as compared to the preoperative level. In the ischemic groups (III vs
      IV) LVSWImax was 27.3+/-11.7 vs 59.5+/-32.4% (p = 0.038), RVSWImax was 27.4+/
      20.9 vs 64.2+/-46.6% (NS). CONCLUSIONS: The results indicate that (a) successful
      pig heart transplantation after 30 minutes of normothermic ischemia is possible
      without donor pretreatment, and (b) that HOE 642 improves posttransplant LVSWImax
      significantly.

PMID- 10395357
TI  - Does University of Wisconsin solution harm the transplanted heart?
AB  - BACKGROUND: University of Wisconsin solution (UW) has been shown to be an
      effective preservative for the cardiac allograft. Recently, the high potassium
      content of UW has been implicated in causing coronary endothelial damage,
      allegedly contributing to development of cardiac allograft vasculopathy (CAV) and
      eventually to poorer survival. METHODS: We examined our experience using UW for
      preservation of cardiac allografts between 1990 and 1994 (n = 94), and compared
      these to hearts preserved with the lower potassium-containing Stanford solution
      used at our center between 1986 and 1990 (n = 65). Indices of graft function,
      ischemic injury, CAV incidence, CAV severity, and survival were evaluated.
      RESULTS: The 2 groups were similar in age, gender, diagnosis, donor inotropic
      support, donor-recipient weight ratio, incidence of acute graft failure, and
      cytomegalovirus seroconversion. UW-preserved hearts came from older donors (30.5
      vs 24.1 years, p < .001), and were transplanted into more status 1 recipients
      (56% vs 22%, p < .001), consistent with current trends. Mean ischemic time of UW
      preserved hearts was significantly longer (184 vs 155 minutes, p < .005) although
      time required to wean from bypass was less (45.5 vs 73.8 minutes, p < .001) and
      there was a trend towards less inotropic requirement. CPK-MB release was less
      with UW preservation (63 vs 87 microg/ dL, p = .001). Three years after
      transplantation, both groups were similar in the incidence of CAV (UW, 27.3%;
      STNF, 37.5%; p = 0.27), and also the severity of CAV (p = 0.78). Deaths
      attributed to CAV were equal in each group (UW, 11.4% vs STNF, 10.7%; p = 0.79).
      Kaplan-Meier survival analysis revealed equivalent survival curves (p = 0.26).
      CONCLUSIONS: We conclude that UW is a safe and effective myocardial preservative,
      allowing longer ischemic times with equivalent graft function. Our data suggest
      that when UW is used for cardiac allograft preservation, both CAV and survival
      are comparable to the experience with other preservatives containing lower
      concentrations of potassium.

PMID- 10395360
TI  - Experimentally induced pain perception in men and women in the morning and
      evening.
AB  - The literature regarding whether or not there are diurnal differences in pain
      perception in men and women is equivocal. The purpose of this study was to
      examine the influence of time of day on experimentally induced pain threshold in
      men and women. A secondary purpose was to measure selected psychological and
      physiological responses. Pressure (3000 gm force) was applied to the middle digit
      of the left forefinger for 2-min with the Forgione-Barber pain stimulator. Twenty
      nine volunteers (women = 14; men = 15) completed two randomly assigned sessions
      between 6.00-8.00 in the AM and PM. Selected psychological variables (STAI,POMS)
      and physiological variables (BP, HR, TEMP) were assessed before application of
      the pressure stimulus. Data were analyzed with a 2x2 ANOVA. Results indicated
      that men had significantly higher (p<.05) systolic blood pressure and pain
      thresholds than women however, there was not a significant time of day effect for
      pain threshold. Significant time of day effects (p<.05) were found for systolic
      blood pressure and tympanic temperature. Heart rate, and tympanic temperature
      were found to be significantly higher (p<.05) in women in comparison to men. It
      is concluded that pain threshold did not differ in the AM and PM. Furthermore,
      men were found to have higher pain thresholds compared to the women.

PMID- 10395359
TI  - Hepatitis C virus-related fibrosing cholestatic hepatitis after cardiac
      transplantation: is azathioprine a contributory factor?
AB  - We report a patient who acquired hepatitis C virus (HCV) infection at cardiac
      transplantation, developing fibrosing cholestatic hepatitis (FCH) with early
      liver failure and a fatal outcome. FCH is a recently described
      clinicopathological entity characterized by a cholestatic pattern of serum liver
      enzyme abnormalities, a progressive course leading to liver failure, and a
      pathological picture defined by periportal fibrosis, neutrophilic infiltrates and
      signs of histological cholestasis. Although it was initially described secondary
      to hepatitis B virus infection, it has also been recently related to HCV
      infection. Some histopathological features consistent with azathioprine
      hepatotoxicity like cholestasis, perisinusoidal fibrosis, veno-subocclusive
      lesions and nodular regenerative hyperplasia were also observed in this case.
      Therefore, a direct cytopathic effect of HCV and the concurrent pathogenic role
      of azathioprine hepatotoxicity may be involved in the development of this
      complication of transplantation.

PMID- 10395361
TI  - GABA release mechanism in the golden hamster retina.
AB  - High K+ medium and glutamate elicited a significant [3H]-GABA release in the
      golden hamster retina. High K+ -induced GABA release was largely calcium
      dependent, while the effect of glutamate was Ca2+ -independent. After replacing
      Na+ by Li+, glutamate-evoked [3H]-GABA release was abolished, while high K+ 
      evoked release remained unchanged. The effect of glutamate was completely blocked
      by DNQX but not by APV. Furthermore, kainate induced [3H]-GABA release, whereas
      NMDA was ineffective. Assessment of endogenous GABA efflux further confirmed
      results obtained for [3H]-GABA. GABA-like immunoreactivity was observed in
      amacrine cells, in neurons localized in ganglion cell layer, as well as in fibers
      and terminals at the inner plexiform layer. In addition a few horizontal cells
      showed GABA-like immunolabeling. The present results suggest the existence of at
      least two pools of GABA in the hamster retina, compatible with both vesicular and
      carrier-mediated mechanisms of transmitter release, being the amacrine cells the
      main gabaergic source in this tissue.

PMID- 10395363
TI  - Impairment of depth perception in multiple sclerosis is improved by treatment
      with AC pulsed electromagnetic fields.
AB  - Multiple sclerosis (MS) is associated with postural instability and an increased
      risk of falling which is facilitated by a variety of factors including diminished
      visual acuity, diplopia, ataxia, apraxia of gait, and peripheral neuropathy.
      Deficient binocular depth perception may also contribute to a higher incidence of
      postural instability and falling in these patients who, for example, find it an
      extremely difficult task to walk on uneven ground, over curbs, or up and down
      steps. I report a 51 year old woman with secondary progressive MS who experienced
      difficulties with binocular depth perception resulting in frequent falls and
      injuries. Deficient depth perception was demonstrated also on spontaneous drawing
      of a cube. Following a series of transcranial treatments with AC pulsed
      electromagnetic fields (EMFs) of 7,5 picotesla flux density, the patient
      experienced a major improvement in depth perception which was evident
      particularly on ascending and descending stairs. These clinical changes were
      associated with an improvement in spatial organization and depth perception on
      drawing a cube. These findings suggest that in MS impairment of depth perception,
      which is encoded in the primary visual cortex (area 17) and visual association
      cortex (areas 18 and 19), may be improved by administration of AC pulsed EMFs of
      picotesla flux density. The primary visual cortex is densely innervated by
      serotonergic neurons which modulate visual information processing. Cerebral
      serotonin concentrations are diminished in MS patients and at least some aspects
      of deficient depth perception in MS may be related to dysfunction of serotonergic
      transmission in the primary visual cortex. It is suggested that transcranial AC
      pulsed applications of EMFs improve depth perception partly by augmenting
      serotonergic transmission in the visual cortex.

PMID- 10395362
TI  - Eye tracking in normals: spem asymmetries and association with schizotypy.
AB  - SPEM was recorded electro-oculographically during visual tracking of sinusoidal
      targets oscillating at .4 and .8 cycles per second in one hundred nineteen
      undergraduates. The logarithms of median root mean square values were used to
      assess tracking accuracy for leftward and rightward halfcycles of tracking. Over
      the entire sample, there was a significant superiority of rightward over leftward
      tracking, which, given evidence for the ipsilateral mediation of SPEM at the
      cortical level, suggests a right hemisphere predominance in the control of SPEM
      in normal subjects. Individual tracking asymmetry was associated with overall
      tracking accuracy such that subjects with relatively deficient leftward tracking
      and those with a larger absolute magnitude of asymmetry had poorer overall
      tracking. High scores on an MMPI schizotypy measure (Sum 2-7-8-0) were
      significantly related to poorer overall SPEM accuracy, individual tracking
      asymmetry, the absolute magnitude of tracking asymmetry, and phase lag, though
      the subjects' sex, handedness, and crossed hand-foot dominance were found to
      affect the relationships between schizotypy and tracking accuracy. These findings
      suggest that although control of SPEM may be predominantly right hemispheric, in
      some persons with a vulnerability to schizophrenia spectrum disorders, expressed
      as poorer overall SPEM accuracy and high schizotypy scores, left hemisphere
      mediated (leftward) SPEM may be particularly impaired.

PMID- 10395365
TI  - Development and preliminary validation of a Satz-Mogel short form of the WAIS-III
      in a sample of persons with substance abuse disorders.
AB  - We developed a Satz-Mogel short form of the WAIS-III and evaluated its accuracy
      for predicting IQs of 50 men with substance abuse disorders. Means for age,
      education, and Full Scale IQ were 44.20 years (SD = 7.23), 12.82years (SD =
      1.53), and 98.06 (SD = 11.93). Correlations between the forms were significant
      for the 11 subtests (all rs> or =.79) and three IQs (all rs> or =.93). Short form
      estimated Verbal, Performance, and Full scale IQs were within +/-6 points of the
      WAIS-III 92% 80% and 90% of the time. The abbreviation may be used to estimate
      general intelligence, but interpretation of short-form-based IQ discrepancies
      should be avoided. The short form detected reliable WAIS-III Verbal-Performance
      IQ discrepancies only 67% of the time.

PMID- 10395366
TI  - Internal consistency and discriminant validity of the Luria Nebraska
      Neuropsychological Battery-III.
AB  - This research presents data pertaining to the development of the recently revised
      Luria Nebraska Neuropsychological Battery-III. The final version of this test
      battery consists of 31 clinical scales yielding 35 scores. The battery was given
      to 109 non brain-injured controls and 119 brain-injured subjects. High internal
      consistency was demonstrated for each clinical scale. Results further indicated
      that the test battery was very effective at discriminating between normal and
      brain-injured subjects, as significant between-group differences on 33 of 35
      scores were observed. Significant between-group differences were also observed on
      25 of the 35 scores when age and education were covaried out of the analyses;
      those scales not displaying significant between-group differences generally
      measured very basic over-learned skills.

PMID- 10395364
TI  - Psychoneuroendocrine immunology: perception of stress can alter body temperature
      and natural killer cell activity.
AB  - Psychoimmunology has been credited with using the mind as a way to alter
      immunity. The problem with this concept is that many of the current
      psychoimmunology techniques in use are aimed at alleviating stress effects on the
      immune system rather than at direct augmentation of immunity by the brain.
      Studies in animals provide a model that permits us to approach the difficulties
      associated with gaining an understanding of the CNS-immune system connection. A
      particular advantage of using animals over humans is that psychological and
      social contributions play a less prominent role for animals than for human
      subjects, since the animals are all inbred and reared under identical controlled
      conditions. If the insightful information provided by animal studies is correct,
      then psychotherapy for the treatment of diseases might be made more effective if
      some aspect of this knowledge is included in the design of the treatment. We
      emphasize conditioning as a regimen and an acceptable way to train the brain to
      remember an output pathway to raise immunity. We propose that a specific drug or
      perception (mild stress, represented by rotation, total body heating or handling)
      could substitute and kindle the same output pathway without the need for
      conditioning. If this view is correct, then instead of using conditioning, it may
      be possible to use an antigen to activate desired immune cells, and substitute a
      drug or an external environmental sensory stimulus (perception) to energize the
      output pathway to these cells. Alternatively, monitoring alterations of body
      temperature in response to a drug or perception might allow us to follow how
      effectively the brain is performing in altering immunity. Studies with animals
      suggest that there are alternative ways to use the mind to raise natural or
      acquired immunity in man.

PMID- 10395368
TI  - Gene transfer for therapy or enhancement.

PMID- 10395367
TI  - Intrabodies to human immunodeficiency virus type 1.

PMID- 10395369
TI  - Heat shock protein expression in target cells infected with low levels of
      replication-competent virus contributes to the immunogenicity of adenoviral
      vectors.
AB  - A significant limitation of adenoviral vectors is their associated
      immunogenicity. Since we, and others, have shown that the immunogenicity of cells
      can be increased by the induction of heat shock proteins (hsp), and because
      infection with several viruses induces hsp, we investigated whether the
      immunogenicity of adenoviral gene transfer might be mediated through induction of
      hsp expression. Neither plasmid DNA nor a recombinant retroviral vector induced
      hsp expression in transduced B16 melanoma cells. However, hsp70 was upregulated
      after infection with two of six adenoviral vectors; this induction of hsp70 did
      not correlate with the adenoviral transgene or with the viral backbone (Ad2 or
      Ad5). In previous assays, no replication-competent adenovirus (RCA) had been
      detected in any of these viruses. However, using sensitive assays for RCA,
      induction of hsp70 was found to correlate with the transfer of E1A and low levels
      of RCA. Moreover, target cells expressing hsp70 at levels similar to those
      induced by RCA infection protected syngeneic mice against rechallenge with
      parental cells, demonstrating that cells induced to express hsp70 by inadvertant
      transfer of RCA will become immunogenic. These results reveal a novel mechanism
      contributing to the immunogenicity of adenoviral vectors. If careful screening
      for RCA is not used when using laboratory-prepared viral stocks, the validity of
      the resulting experimental data might be significantly affected, especially when
      the immune stimulatory effects of the transgene are being studied.

PMID- 10395370
TI  - Soluble bone marrow stroma factors improve the efficiency of retroviral transfer
      of the human multidrug resistance 1 gene to human mobilized peripheral blood
      progenitor cells.
AB  - Hematopoietic stem cells (HSCs) are a potential target for the retrovirus
      mediated transfer of chemotherapeutic drug resistance genes. For integration of
      the proviral DNA in the HSC genome cell division is required. In the bone marrow
      (BM) hematopoiesis occurs in the vicinity of stroma cells. Soluble stroma
      components were shown to play a permissive role for the proliferation of lineage
      committed and primitive hematopoietic progenitors in conjunction with cytokines.
      We investigated the effect of stroma-conditioned medium (SCM) of the FBMD1 cell
      line on the gene transfer rate of the human multidrug resistance 1 (MDR1) gene
      contained in the retroviral SF-MDR vector into human mobilized peripheral blood
      progenitor cells (PBPCs) from tumor patients (n = 14) during transwell
      transduction in the presence of the recombinant fibronectin fragment CH-296.
      Addition of SCM during transduction increased the gene transfer efficiency into
      myeloid lineage-committed colony-forming cells by an average of 1.5-fold (p =
      0.02) as detected by an SF-MDR provirus-specific polymerase chain reaction (PCR).
      These data were paralleled by significantly (p = 0.04 to p = 0.007) higher
      proportions of MDR1-expressing myelo-monocytic progeny after transduction in SCM
      plus interleukin 3 (IL-3), IL-3/Flt3 ligand (FL), IL-3/IL-6/FL, or IL-3/IL-6/stem
      cell factor (SCF) when compared with transductions without SCM as measured by
      rhodamine-123 exclusion. A similar trend was observed for SCM employed in
      combination with IL-3/IL-6/SCF/FL or FL/thrombopoietin (TPO)/SCF during
      transduction. The latter combination plus SCM yielded the highest proportion,
      19.16 +/- 3.10% Rh-123dull cells. The beneficial effect of SCM on transduction
      efficiency was confirmed in additional four patients' samples, using a serum-free
      viral supernatant transduction protocol. As soluble BM stroma factors are able to
      increase the efficiency of retrovirus-mediated gene transfer into committed
      progenitor cells, beyond that achieved with fibronectin fragment CH-296, their
      effect on gene transfer into primitive repopulating hematopoietic cells may also
      prove beneficial.

PMID- 10395371
TI  - Inhibition of human immunodeficiency virus type 1 replication in vitro in acutely
      and persistently infected human CD4+ mononuclear cells expressing murine and
      humanized anti-human immunodeficiency virus type 1 Tat single-chain variable
      fragment intrabodies.
AB  - We have previously reported that a murine anti-Tat sFv intrabody, termed
      sFvtat1Ck, directed against the proline-rich N-terminal activation domain of HIV
      1, is a potent inhibitor of HIV-1 replication [Mhashilkar, A. M., et al. (1995).
      EMBO J. 14, 1542-1551]. In this study, the protective effect of sFvtat1Ck
      expression on HIV-1 replication in both acutely infected and persistently
      infected CD4+ cells was examined. Stably transfected CD4+ SupT1 cells were
      resistant to HIV-1 infection at high MOI with both the laboratory isolate HxB2
      and six syncytium-inducing (SI) primary isolates. Persistently infected U1 cells,
      which can be induced to increase HIV-1 mRNA synthesis on addition of PMA or TNF
      alpha, showed decreased production of HIV-1 in the presence of sFvtat1Ck. In
      transduced CD4+-selected, CD8+-depleted, and total PMBCs, the sFvtat1Ck
      expressing cells showed marked inhibition of HIV-1 replication. The anti-Tat sFv
      was subsequently humanized by substituting compatible human framework regions
      that were chosen from a large database of human V(H) and V(L) sequences on the
      basis of high overall framework matching, similar CDR length, and minimal
      mismatching of canonical and V(H)/V(L) contact residues. One humanized anti-Tat
      sFv intrabody, termed sFvhutat2, demonstrated a level of anti-HIV-1 activity that
      was comparable to the parental murine sFv when transduced PBMCs expressing the
      murine or humanized sFv intrabodies were challenged with HxB2 and two SI primary
      isolates. Because Tat is likely to have both direct and indirect effects in the
      pathogenesis of AIDS through its multiple roles in the HIV-1 life cycle and
      through its effects on the immune system, the strategy of genetically blocking
      Tat protein function with a humanized anti-Tat sFv intrabody may prove useful for
      the treatment of HIV-1 infection and AIDS, particularly when used as an adjuvant
      gene therapy together with highly active antiretroviral therapies that are
      currently available.

PMID- 10395372
TI  - Optimizing vascular gene transfer of plasminogen activator inhibitor 1.
AB  - The vessel wall fibrinolytic system plays an important role in maintaining the
      arterial phenotype and in regulating the arterial response to injury. Plasminogen
      activator inhibitor type 1 (PAI-1) regulates tissue fibrinolysis and is expressed
      in arterial tissue; however, its biological role remains uncertain. To help
      elucidate the role of PAI-1 in the artery wall, and to begin to clarify whether
      manipulation of vascular PAI-1 expression might be a target for gene therapy, we
      used adenoviral vectors to increase expression of rat PAI-1 in rat carotid
      arteries. Infusion of an adenoviral vector in which PAI-1 expression was driven
      by a promoter derived from the Rous sarcoma virus (RSV) did not increase PAI-1
      expression above endogenous levels. To improve PAI-1 expression, we modified the
      vector by (1) truncating the 3' untranslated region of PAI-1 to increase the mRNA
      half-life, (2) substituting the SRalpha or the cytomegalovirus (CMV) promoter for
      the RSV promoter, (3) including an intron in the expression cassette, and (4)
      altering the direction of transcription of the transgene cassette. The optimal
      expression vector, revealed by in vitro studies, contained the CMV promoter, an
      intron, and a truncated PAI-1 mRNA. This vector increased PAI-1 expression by 30
      fold over control levels in vitro and by 1.6 to 2-fold over endogenous levels in
      vivo. This vector will be useful for elucidating the role of PAI-1 in arterial
      pathobiology. Because genes that are important in maintaining the vascular
      phenotype are likely to be expressed in the vasculature, the technical issues of
      how to increase in vivo expression of endogenous genes are highly relevant to the
      development of genetic therapies for vascular disease.

PMID- 10395373
TI  - Human cord blood CD34+CD38- cell transduction via lentivirus-based gene transfer
      vectors.
AB  - The efficient transfer and sustained expression of a transgene in human
      hematopoietic cells with in vivo repopulating potential would provide a
      significant advancement in the development of protocols for the treatment of
      hematopoietic diseases. Recent advances in the ability to purify and culture
      hematopoietic cells with the CD34+CD38- phenotype and with in vivo repopulating
      potential from human umbilical cord blood provide a direct means of testing the
      ability of transfer vectors to transduce these cells. Here we demonstrate the
      efficient transduction and expression of enhanced green fluorescent protein
      (EGFP) in human umbilical cord-derived CD34+CD38- cells, without prestimulation,
      using a lentivirus-based gene transfer system. Transduced CD34+CD38- cells
      cultured in serum-free medium supplemented with SCF, Flt-3, IL-3, and IL-6
      maintained their surface phenotype for 5 days and expressed readily detectable
      levels of the transgene. The average transduction efficiency of the CD34+CD38-
      cells was 59 +/- 7% as determined by flow cytometry. Erythroid and myeloid
      colonies derived from transduced CD34+CD38- cells were EGFP positive at a high
      frequency (66 +/- 9%). In contrast, a murine leukemia virus-based vector
      transduced the CD34+CD38- cells at a low frequency (<4%). These results
      demonstrate the utility of lentiviral-based gene transfer vectors in the
      transduction of primitive human hematopoietic CD34+CD38- cells.

PMID- 10395374
TI  - Hormonal and dietary regulation of a mammalian gene introduced into rat liver by
      direct injection.
AB  - The difficulty of introducing foreign genes into a target tissue such as liver
      prompted us to explore the method of direct injection of DNA into this organ. In
      this article we examine whether direct hepatic injection of DNA enables the liver
      to express a transgene controlled by a mammalian promoter. The construct pS14CAT,
      composed of the rat S14 gene promoter coupled to CAT, was directly injected into
      rat liver. Hepatic expression of the pS14CAT transgene mimicked expression of the
      endogenous S14 gene, characterized by a low level of basal expression that
      increased markedly after exposure to thyroid hormone or a high sucrose diet. This
      effect was specific, since similar treatments had no effect on activity of a
      control transgene, pSV2CAT, which is under the direction of the viral SV40
      promoter/enhancer. Dexamethasone treatment enhanced the activity of both pS14CAT
      or pSV2CAT transgenes, an effect likely mediated by both transcriptional and
      nontranscriptional pathways. In summary, our study demonstrates the feasibility
      of using direct DNA injection to study transcriptional regulation of hepatic gene
      promoters in vivo.

PMID- 10395375
TI  - Ligand-dependent regulation of plasmid-based transgene expression in vivo.
AB  - As gene therapy advances, the ability to regulate transgene expression will
      become paramount for safety and efficacy. In this study, we investigate the
      ability of the mifepristone-dependent GeneSwitch system to regulate the
      expression of trangenes delivered to mice by nonviral methods. Two plasmids, one
      encoding the chimeric GeneSwitch protein, the other an inducible transgene for
      secreted human placental alkaline phosphatase (SEAP), were delivered to the hind
      limb muscles of adult mice. Modulation of the level of secretion of the transgene
      product into serum was achieved by intraperitoneal administration of low doses of
      the drug mifepristone (MFP). The EC50 for induction of transgene expression by
      MFP was 0.03 +/- 0.005 mg/kg. The maximal level of transgene expression after
      induction was equal to or higher than that displayed by a plasmid driven by the
      CMV enhancer/promoter. The average magnitude of induction was 14- to 19-fold.
      Multiple rounds of drug-dependent regulation of transgene expression in vivo were
      demonstrated. In BALB/c mice, the ability to regulate transgene expression
      persisted for approximately 3 weeks, until the appearance of neutralizing
      antibodies to the secreted transgene product. In immune-deficient mice, the
      ability to repetitively regulate transgene expression persisted for at least 5
      weeks. Although the dynamic range of regulation needs improvement, the plasmid
      based GeneSwitch system has features that are attractive for gene therapy
      applications.

PMID- 10395376
TI  - Regression of hepatocellular carcinoma in vitro and in vivo by radiosensitizing
      suicide gene therapy under the inducible and spatial control of radiation.
AB  - To improve the efficacy and selectivity of gene therapy for hepatocellular
      carcinoma (HCC), we designed a strategy for suicide gene therapy in conjunction
      with radiation therapy using an HVJ-liposome vector system. The radio-inducible
      suicide gene was constructed by insertion of the early growth response gene 1
      (Egr-1) promoter upstream of the HSV-tk gene (EGF-tk). First, to test the tumor
      specificity of Egr-1, RT-PCR and immunohistochemistry were performed. The Egr-1
      gene was highly expressed in HCC compared with normal liver, where expression was
      barely detectable. Next, radiation-inducible activity of the Egr-1 promoter was
      examined in primary cultured normal hepatocytes and human hepatoma cell lines
      Huh7, HepG2, and PLC/PRF/5 by luciferase assay as a reporter gene system. Egr-1
      promoter activity was markedly increased in hepatoma cell lines in a radiation
      dose-dependent manner, with maximum activation (15- to 28-fold) 12 hr after
      irradiation. In contrast, only a twofold increase in activation was noted in
      normal hepatocytes. An in vitro gene therapy experiment showed that EGR-tk
      transduced hepatoma cells became highly sensitive to ganciclovir (GCV) after
      irradiation, but not without irradiation. GCV with or without irradiation did not
      show any cytotoxic effects against control gene-transfected cells. In addition, a
      "radiosensitization effect" was also demonstrated by combination therapy with the
      HSV-tk/GCV system and irradiation. To examine the efficacy of this EGR-tk/GCV
      gene therapy in vivo, xenografted liver tumors in nude mice were targeted using
      the HVJ-liposome vector system. EGR-tk-transfected tumors regressed significantly
      after a combination therapy of irradiation and GCV in all mice (n = 8), and
      almost disappeared in 3 weeks without any side effects. In comparison, tumors
      continued to grow in all mice (n = 8 in each group) treated by transfer of EGR-tk
      followed by either irradiation without GCV or GCV without irradiation. Our data
      indicate that HSV-tk gene therapy under the control of a radioinducible promoter
      is effective, and might be selective for hepatoma cells because of its inducible
      and radiosensitive capacity after radiation exposure as well as its tumor
      specific activation.

PMID- 10395377
TI  - Gene therapy for canine alpha-L-iduronidase deficiency: in utero adoptive
      transfer of genetically corrected hematopoietic progenitors results in
      engraftment but not amelioration of disease.
AB  - Canine alpha-L-iduronidase (iduronidase) deficiency is a model of the human
      lysosomal storage disorder mucopolysaccharidosis type I (MPS I). We used this
      canine model to evaluate the therapeutic potential of hematopoietic stem cell
      (HSC) gene therapy for enzyme deficiencies. In previous studies, iduronidase
      deficient dogs infused with autologous marrow cells genetically modified to
      express iduronidase had long-term engraftment with provirally marked cells, but
      there was no evidence of proviral iduronidase expression or clinical improvement.
      The presence of humoral and cellular immune responses against iduronidase
      apparently abrogated the therapeutic potential of HSC gene therapy in these
      experiments. To evaluate HSC gene therapy for canine MPS I in the absence of a
      confounding immune response, we have now performed in utero adoptive transfer of
      iduronidase-transduced MPS I marrow cells into preimmune fetal pups. In three
      separate experiments, 17 midgestation fetal pups were injected with 0.5-1.5 x
      10(7) normal or MPS I allogeneic long-term marrow culture (LTMC) cells transduced
      with neo(r)- or iduronidase-containing retroviral vectors. Nine normal and three
      MPS I pups survived the neonatal period and demonstrated engraftment of
      provirally marked progenitors at levels of up to 12% for up to 12 months.
      However, the proportion of provirally marked circulating leukocytes was
      approximately 1%. Neither iduronidase enzyme nor proviral-specific transcripts
      were detected in blood or marrow leukocytes of any MPS I dog. Humoral immune
      responses to iduronidase were not detected in neonates, even after "boosting"
      with autologous iduronidase-transduced LTMC cells. All MPS I dogs died at 8-11
      months of age from complications of MPS I disease with no evidence of
      amelioration of MPS I disease. Our results suggest that iduronidase-transduced
      primitive hematopoietic progenitors can engraft in fetal recipients, contribute
      to hematopoiesis, and induce immunologic nonresponsiveness to iduronidase in MPS
      I dogs. However, the therapeutic potential of HSC gene transfer in this model of
      iduronidase deficiency appears to be limited by poor maintenance of proviral
      iduronidase gene expression and relatively low levels of genetically corrected
      circulating leukocytes.

PMID- 10395378
TI  - Retroviral display of functional binding domains fused to the amino terminus of
      influenza hemagglutinin.
AB  - We have previously shown that retroviral vector particles derived from Moloney
      murine leukemia virus (Mo-MuLV) can efficiently incorporate influenza
      hemagglutinin (HA) glycoproteins from fowl plague virus (FPV), thus conferring a
      broad tropism to the vectors. To modify its host range, we have engineered the
      FPV HA to display four different polypeptides on its N terminus: the epidermal
      growth factor, an anti-human MHC class I molecules scFv (single-chain antibody),
      an anti-melanoma antigen scFv, and an IgG Fc-binding polypeptide. All recombinant
      HA glycoproteins were correctly expressed and processed, and efficiently
      incorporated into Mo-MuLV retroviral particles, indicating that amino-terminal
      insertion of large polypeptides did not alter the conformation of HA chimeras.
      Virions carrying the different chimeras bound specifically to cells expressing
      the targeted cell surface molecules of each ligand. In addition, all virion types
      were infectious but exhibited various degrees of specificity regarding the use of
      the targeted cell surface molecule versus the wild-type FPV HA receptor for cell
      entry and infection. For some ligands tested, infectivity was significantly
      increased on cells that express the targeted receptor, compared with cells that
      express only the wild-type HA receptor. Furthermore, some polypeptides could
      abolish infectivity via the wild-type FPV HA receptor. Our data therefore
      indicate that it is possible to engineer the HA envelope glycoprotein by fusing
      ligands to its amino-terminal end without affecting its fusion activity.

PMID- 10395379
TI  - Liposomal encapsulation of ganciclovir enhances the efficacy of herpes simplex
      virus type 1 thymidine kinase suicide gene therapy against hepatic tumors in
      rats.
AB  - Suicide gene therapy based on ganciclovir (GCV) metabolism by transgene herpes
      simplex thymidine kinase (HSV-1 TK) has been used to selectively kill
      proliferating cells in clinical settings such as cancer, vascular restenosis, and
      immunological disorders. We investigated whether encapsulation of ganciclovir
      (GCV) into liposomes would improve its efficacy, especially against hepatic
      tumors. Large unilamellar liposomes containing GCV were prepared by reversed
      phase evaporation. Pharmacokinetic studies in rats showed that, compared with
      free GCV, the intravenous injection of liposome-encapsulated GCV (lip-GCV) led to
      a faster decrease in GCV plasma concentrations, but higher liver-blood ratios.
      After treatment of syngeneic HSV-1 TK+ liver metastases in rats, histologically
      active tumors were found in 95% of the transplanted lesions when physiological
      saline had been given and in 50% when free GCV had been given at 90.2 microM/kg
      twice daily. This dose is known to be insufficient for the eradication of HSV-1
      TK+ tumors. In contrast, only 5% viable tumors were found in rats receiving lip
      GCV at this same concentration. Average tumor volumes were 19 +/- 15, 7 +/- 9,
      and <1 mm3 for the control, free GCV, and lip-GCV groups, respectively. GCV
      related toxicity was no longer observed. The results demonstrate that liposomal
      encapsulation of GCV is feasible and significantly enhances its efficacy against
      HSV-1 TK+ hepatic tumors.

PMID- 10395380
TI  - Response to "Polarity influences the efficiency of recombinant adenoassociated
      virus infection in differentiated airway epithelia".

PMID- 10395382
TI  - NIH Recombinant DNA Advisory Committee data management report. March 12, 1999.

PMID- 10395381
TI  - Cationic lipid mediated gene transfer of CFTR: safety of a single administration
      to the nasal epithelia.

PMID- 10395383
TI  - Potential risk of inadvertent germ-line gene transmission statement from the
      American Society of Gene Therapy to the NIH Recombinant DNA Advisory Committee,
      March 12, 1999.

PMID- 10395384
TI  - Effects of Laddec on the formation of calcified bone matrix in rat calvariae
      cells culture.
AB  - Osteoblasts from 21 day-old fetal rats calvaria were isolated using a collagenase
      digestion procedure. Cells were cultured in the presence of Laddec (a highly
      purified bovine xenograft) and Bio-Oss (natural bone mineral). Optical
      microscopic observations showed that osteoblasts attached on the plastic culture
      dishes and formed close contact with biomaterial particles. By day 5, the
      osteoblasts formed a confluent monolayer. A cytozymatic method showed intense
      alkaline phosphatase (ALP) staining around and between the substrate granules of
      the two materials. By day 14, inverted phase microscopic observations showed that
      osteoblasts formed bone nodules around and between substrate particles. In
      addition, at this time, the Von Kossa staining was positive. Using a conventional
      assay, ALP specific activity was higher in the presence of Laddec than in the
      presence of Bio-Oss. A quantitative morphological method using image analysis
      showed that the proportion of mineralized bone formed around biomaterial
      particles in relation to total bone was increased with Laddec (15% more than with
      Bio-Oss). Ultrastructural observations by TEM showed the presence of an electron
      dense collagen-free layer at the biomaterial/bone interface and a collagenous
      matrix deposited at the periphery, indicating the bioactivity of the
      biomaterials. These results indicated that Laddec increased the expression of ALP
      in osteoblast cultures and facilitated the formation of multiple cell layers,
      providing a culture environment suitable for mineralization.

PMID- 10395385
TI  - Resurfacing potential of heterologous chondrocytes suspended in fibrin glue in
      large full-thickness defects of femoral articular cartilage: an experimental
      study in the goat.
AB  - A large full-thickness articular-cartilage defect was created in the medial
      femoral condyle of 32 adult goats. The defects were xenografted with isolated
      rabbit chondrocytes suspended in fibrin glue. Sham operated goats, where only a
      standardized defect was created, were used as controls. Results of cartilage
      repair were assessed after 3, 8, 13, 26 and 52 weeks. The repair tissue was
      evaluated macroscopically, histologically and biochemically. Results indicated
      that xenografted rabbit chondrocytes survived the transplantation and maintained
      their potential to produce matrix in fibrin glue, particularly if they were
      located in a non-weight-bearing area. In terms of an immunological reaction to
      xenografted chondrocytes, only mild signs of synovitis were observed in both
      groups and rejection of transplanted cells did not occur. From 3 weeks gradually
      progressive resolvement of the fibrin glue was observed with subsequent
      replacement by fibrous tissue. Initially xenografted defects histologically
      showed better tendency for cartilage regeneration, however, 52 weeks after
      surgery no significant differences could be detected in the repair tissue of both
      groups macroscopically, histologically and on biochemical scoring. The amount of
      collagen type II in the newly synthesized matrix was 75% 1 year after surgery.
      This study shows that isolated heterologous chondrocytes can be used for
      transplantation in articular cartilage defects, however, fibrin glue does not
      offer enough biomechanical support to the cells to maintain its function as a
      three-dimensional scaffold.

PMID- 10395386
TI  - In vitro degradation of a novel poly(lactide-co-glycolide) 75/25 foam.
AB  - Macroporous poly(lactide-co-glycolide) PLGA 75/25 foams were prepared for
      application in bone tissue engineering. Their in vitro degradation behaviour was
      followed over a 30 week period at 37 degrees C and at one of three pHs: (1) pH
      5.0, which mimics the acidic environment produced by activated macrophages, (2)
      pH 7.4, which reproduces normal physiological conditions and (3) an intermediate
      pH 6.4. The degradation of the PLGA 75/25 foams was studied by measuring changes
      in mass, molecular weight and morphology. The degradation profile of foams
      maintained at pH 5.0, 6.4 and 7.4 was similar until week 16, after which foams
      maintained at pH 6.4 and 7.4 had comparable degradation patterns whereas foams
      maintained at pH 5.0 degraded faster. For example, mass loss was less than 3% for
      foams maintained at all three pHs until week 16; however, by week 30, foams
      maintained at pH 6.4 and 7.4 had lost 30% of their mass whereas foams maintained
      at pH 5.0 had lost 90% of their mass. Foams maintained at pH 6.4 and 7.4 showed a
      similar constant decrease in molecular weight over the entire degradation study.
      Foams maintained at pH 5.0 had a similar rate of molecular weight loss as those
      maintained at pH 6.4 and 7.4 until week 16, after which the rate of molecular
      weight loss of foams maintained at pH 5.0 was accelerated. The morphology of the
      foams maintained at pH 6.4 and 7.4 was unchanged for 25 weeks. Foams maintained
      at pH 5.0 collapsed after week 18. Thus the PLGA 75/25 foams, described herein,
      maintained their 3-D morphology at physiological pH for over 6 months, which is
      an important feature for tissue engineering applications.

PMID- 10395387
TI  - Water sorption, solubility and effect of post-curing of glass fibre reinforced
      polymers.
AB  - Different polymer matrices are used for dental glass fibre composites. The aims
      of this study were to determine water sorption and solubility of glass fibre
      composites with different polymer matrices. In addition, the effect of post
      curing of matrix polymers with heat on the water sorption and solubility values
      was investigated. Commercial one-phase and two-phase (powder-liquid) monomer
      systems were used in polymer matrix of E-glass fibre composite. Rhombic
      unreinforced and fibre reinforced test specimens were polymerized by
      autopolymerization or by light only, or additionally post-cured with heat. Water
      sorption and solubility determination method was based on ISO/DIS 1567-1997 draft
      for international standard with 7 d immersion time. In addition, water sorption
      was measured at second time for 30 d immersion time to determine saturation time
      of test specimens by water. Five test specimens of unreinforced polymer and
      reinforced polymer were tested and the quantity of fibres was determined by
      combustion analysis. Water sorption values of different brands of polymer
      matrices ranged from 0.9 to 8.3 wt% (P < 0.001, ANOVA). High sorption values were
      explained by microscopic voids in the polymer matrix and by composition of
      polymer matrix. Solubility values ranged from 0.02 to 2.5 wt% (P < 0.001, ANOVA).
      Generally, fibre inclusion and post-curing of polymer matrix reduced water
      sorption and solubility. The results of this study suggest that the water
      sorption and solubility of fibre composites varies according to the brand of
      polymer matrix and homogenity of polymer matrix. Water sorption of polymer matrix
      might influence hydrolytic stability of polymer-glass fibre composite.

PMID- 10395389
TI  - Adsorption of proteins from plasma at polyester non-wovens.
AB  - Polyester non-wovens in filters for the removal of leukocytes from platelet
      concentrates (PCs) must be platelet compatible. In PC filtration, the adsorption
      of proteins at the plasma-non-woven interface can be of great importance with
      respect to the yield of platelets. Unmodified and radio frequency glow discharge
      (RFGD) treated poly(ethylene terephthalate) non-woven (NW-PET) and two commercial
      surface-modified non-wovens were contacted with human plasma. Protein desorption
      by sodium dodecyl sulphate (SDS) was evaluated by X-ray photoelectron
      spectroscopy (XPS). The desorbed proteins were characterized by gel
      electrophoresis and immunoblotting. Compared to the commercial surface-modified
      non-wovens, unmodified and RFGD-treated NW-PETs adsorbed a relatively high amount
      of protein. Significantly more protein was removed from the hydrophobic NW-PET by
      SDS than from the hydrophilic RFGD-treated non-wovens. RFGD treatment of NW-PET
      reduces the reversibility of protein adsorption. Less albumin and fibrinogen were
      removed from the RFGD-treated non-wovens than from NW-PET. In addition, a large
      amount of histidine-rich glycoprotein was removed from RFGD-treated non-wovens,
      but not from NW-PET. The different behaviour of RFGFD-treated non-wovens towards
      protein adsorption is probably caused by differences in the chemical reactivity
      of the non-woven surfaces.

PMID- 10395388
TI  - Enhanced proliferation and osteocalcin production by human osteoblast-like MG63
      cells on silicon nitride ceramic discs.
AB  - The biocompatibility of silicon nitride (Si3N4) was assessed in an in vitro model
      using the human osteoblast-like MG-63 cell line. Cells were propagated on the
      surface of: reaction-bonded silicon nitride discs, sintered after reaction-bonded
      silicon nitride discs or control polystyrene surface for 48 h. Compared to cells
      propagated on polystyrene surface, cells grown on the surface of unpolished
      silicon nitride discs had significantly lower cell yield and decreased
      osteocalcin production. In contrast, cells on the surface of polished silicon
      nitride discs showed similar proliferative capacity to control cells propagated
      on polystyrene surface. Cells propagated on polished discs also produced higher
      levels of osteocalcin than cells on unpolished discs. SEM analysis showed cells
      with well-delineated morphology and cytoplasmic extensions when propagated on
      polished sintered after reaction-bonded discs. Cells appeared more spherical,
      when grown on polished reaction-bonded discs. The results of this study suggest
      that silicon nitride is a non-toxic, biocompatible ceramic surface for the
      propagation of functional human bone cells in vitro. Its high wear resistance and
      ability to support bone cell growth and metabolism make silicone nitride an
      attractive candidate for clinical application. Further studies are needed to
      explore the feasibility of using silicon nitride clinically as an orthopedic
      biomaterial.

PMID- 10395390
TI  - Biological surface engineering: a simple system for cell pattern formation.
AB  - Biological surface engineering using synthetic biological materials has a great
      potential for advances in our understanding of complex biological phenomena. We
      developed a simple system to engineer biologically relevant surfaces using a
      combination of self-assembling oligopeptide monolayers and microcontact printing
      (muCP). We designed and synthesized two oligopeptides containing a cell adhesion
      motif (RADS)n (n = 2 and 3) at the N-terminus, followed by an oligo(alanine)
      linker and a cysteine residue at the C-terminus. The thiol group of cysteine
      allows the oligopeptides to attach covalently onto a gold-coated surface to form
      monolayers. We then microfabricated a variety of surface patterns using the cell
      adhesion peptides in combination with hexa-ethylene glycol thiolate which resist
      non-specific adsorption of proteins and cells. The resulting patterns consist of
      areas either supporting or inhibiting cell adhesion, thus they are capable of
      aligning cells in a well-defined manner, leading to specific cell array and
      pattern formations.

PMID- 10395391
TI  - Osteoblast adhesion on nanophase ceramics.
AB  - Osteoblast adhesion on nanophase alumina (Al2O3) and titania (TiO2) was
      investigated in vitro. Osteoblast adhesion to nanophase alumina and titania in
      the absence of serum from Dulbecco's modified Eagle medium (DMEM) was
      significantly (P < 0.01) less than osteoblast adhesion to alumina and titania in
      the presence of serum. In the presence of 10% fetal bovine serum in DMEM
      osteoblast adhesion on nanophase alumina (23 nm grain size) and titania (32 nm
      grain size) was significantly (P < 0.05) greater than on conventional alumina
      (177 nm grain size) and titania (2.12 microm grain size), respectively, after 1,
      2, and 4 h. Further investigation of the dependence of osteoblast adhesion on
      alumina and titania grain size indicated the presence of a critical grain size
      for osteoblast adhesion between 49 and 67 nm for alumina and 32 and 56 nm for
      titania. The present study provides evidence of the ability of nanophase alumina
      and titania to simulate material characteristics (such as surface grain size) of
      physiological bone that enhance protein interactions (such as adsorption,
      configuration, bioactivity, etc.) and subsequent osteoblast adhesion.

PMID- 10395392
TI  - Preventing bacterial adhesion onto surfaces: the low-surface-energy approach.
AB  - Good-quality coatings prepared from poly(methylpropenoxyfluoroalkylsiloxane)s or
      poly(perfluoroacrylate)s are capable of inhibiting the bacterial colonisation of
      surfaces.

PMID- 10395393
TI  - Application of an in vitro model to evaluate bioadhesion of fibroblasts and
      epithelial cells to two different dressings.
AB  - The cellular component of a healing wound consists of many cell types and the
      environment in which these cells grow is important to the rate and quality of
      healing which can be influenced by the type of dressing used. The most commonly
      used dressings are traditional gauze-type dressings. In many cases these
      dressings may adhere to the wound surface, and subsequent removal is often
      traumatic, causing pain and tissue reinjury. Some modern gelling dressings have
      been developed to overcome this adherence problem. In order to evaluate in more
      detail cell-dressing interactions, an in vitro model has been developed utilising
      wound fibroblasts and epithelial cells. Quantitative evaluation of adherence of
      cells cultured with a traditional gauze or a new gelling dressing has been
      undertaken using radiolabel and manual counting techniques. Scanning electron
      microscopy has been used to visualise the cells adherent to dressings allowing
      evaluation of their adhesion-morphology. The results show differential attachment
      of cells to viscose and gelling fibres of the dressings; considerably reduced
      cell adhesion to the gelling fibre was evident, and it was apparent that cells
      adhered predominantly to the viscose component of the dressing. This model can be
      used to investigate and compare the adhesion of cells to different dressings and
      their components.

PMID- 10395394
TI  - Effect of the urine conditioning film on ureteral stent encrustation and
      characterization of its protein composition.
AB  - The goal of this study was to characterize the protein composition of the
      conditioning film deposited onto the surface of ureteral stents during in vivo
      implantation and to relate its presence to the precipitation of calcium crystals.
      The protein pattern of the conditioning film of implanted nonencrusted and
      encrusted urological stents was assessed by SDS-PAGE and Western blot of the
      desorbed species. The results obtained highlighted different electrophoresis
      profiles between nonencrusted and encrusted stents. Western blot showed the
      ubiquitous presence of albumin, while Tamm-Horsfall Protein and alpha1
      microglobulin adsorption was limited to nonencrusted devices. By an in vitro
      dynamic model in which artificial urine was flowed through the lumen of control
      and retrieved nonencrusted stents, we demonstrated that the organic layer
      remarkably enhanced crystal precipitation and aggregation events on the surface.

PMID- 10395395
TI  - There is a difference in characteristics and outcome between women and men who
      suffer out of hospital cardiac arrest.
AB  - OBJECTIVE: To evaluate whether there is a difference in characteristics and
      outcome in relation to gender among patients who suffer out of hospital cardiac
      arrest. DESIGN: Observational study. SETTING: The community of Goteborg.
      PATIENTS: All patients in the community of Goteborg who suffered out of hospital
      cardiac arrest between 1980 and 1996, and in whom cardiopulmonary resuscitation
      (CPR) was initiated. MAIN OUTCOME MEASURES: Factors at resuscitation and the
      proportion of patients being hospitalized and discharged from hospital. P values
      were corrected for age. RESULTS: The women were older than the men (median of 73
      vs. 69 years; P < 0.0001), they received bystander-CPR less frequently (11 vs.
      15%; P = 0.003), they were found in ongoing ventricular fibrillation less
      frequently (28 vs. 44%; P < 0.0001), and their arrests were judged to be of
      cardiac origin less frequently. In a multivariate analysis considering age,
      gender, arrest being due to a cardiac etiology, initial arrhythmia and by-stander
      initiated CPR, female gender appeared as an independent predictor for patients
      being brought to hospital alive (odds ratio 1.37; P = 0.001) but not for patients
      being discharged from hospital. CONCLUSION: Among patients who suffer out of
      hospital cardiac arrest with attempted CPR women differ from men being older,
      receive bystander CPR less frequently, have a cardiac etiology less frequently
      and are found in ventricular fibrillation less frequently. Finally female gender
      is associated with an increased chance of arriving at hospital alive.

PMID- 10395396
TI  - Does race or socioeconomic status predict adverse outcome after out of hospital
      cardiac arrest: a multi-center study.
AB  - OBJECTIVE: To assess whether socioeconomic status (SES) or race is associated
      with adverse outcome after an out-of-hospital cardiac arrest (OHCA). METHODS: A
      convenience sample of OHCA of presumed cardiac origin from seven suburban cities
      in Michigan, 1991-1996. Median household income (HHI), utilizing patient home
      address and 1990 census tract data, was dichotomized above and below 1990 state
      median income. Patient race was dichotomized as black or white. Outcome was
      defined as survival to hospital discharge (DC). Multiple logistic regression and
      Pearson's chi2 values were used for analysis. RESULTS: Of 1317 cases with
      complete data for analysis, the average age was 67.3 +/- 16.0, 939 (71.1%) were
      white, 587 (44.4%) arrests were witnessed (WIT), and 65 (4.9%) were DC alive.
      There was no significant difference between races with respect to WIT arrests,
      V(T)/V(F) arrest rhythms, and a small difference in EMS response interval. Whites
      were more likely to be above median HHI (57.1 vs. 26.2%, P < 0.001). Adjusted
      odds ratios for predictors of survival were WIT arrest (OR = 3.76, 95% CI (1.7,
      8.2)), V(T)/V(F) (OR = 8.74, 95% CI (3.7, 10.8), but not race (OR = 0.68, 95% CI
      (0.3, 1.4)) or SES (OR = 1.51, 95% C1 0.8, 2.8). CONCLUSION: In this population,
      neither race nor SES was independently associated with a worse outcome after
      OHCA.

PMID- 10395397
TI  - Training needs and qualifications of anaesthesiologists not exposed to ALS.
AB  - OBJECTIVES: To establish which needs exist for specific training in Advanced
      Cardiac Life Support (ALS) in anaesthesiology residents and interns not exposed
      to structured ALS courses. METHODS: 48 residents, and seven interns accepted for
      training in anaesthesiology, were tested in a spontaneous, blind, cross
      sectional, prospective assessment using a recording manikin with validated
      scoring system, a questionnaire, and 35 multiple-choice questions. RESULTS: 65%
      admitted not having had any CPR training within the last 2 years. The answers
      were correct in 55 +/- 14% of the cases, increasing significantly with the length
      of training (P = 0.001). One-rescuer CPR skills were inadequate: only 13% (n = 7)
      of participants scored within acceptable limits when using the Berden Scoring
      system (Berden et al., Resuscitation 1992;13:31-41), which assigned weighted
      error points to BLS skills. No correlation with skill was noted with increased
      length of residency, confidence, ER or ICU experience, or participation in CPR
      incidents. CONCLUSIONS: Anaesthesiology residents and interns were not able to
      demonstrate BLS skills properly even while in training and did not recognize this
      themselves. CPR-related knowledge is poor and increases only incidentally over
      the years of residency even though participants were frequently confronted with
      seminars and resuscitation situations, and see protocols daily. The use of
      multiple-choice questions and the Berden scoring system avoids difficulties in
      evaluating case-scenario type of tests. We suggest that trainees are motivated to
      take part in standardized, intensive, recognised ALS courses which emphasize BLS
      skills and require (re)certification.

PMID- 10395398
TI  - Inadequate assessment of the airway and ventilation in acute poisoning. A need
      for improved education?
AB  - AIMS AND OBJECTIVES: To analyse the initial management of acute poisoning
      patients, and whether respiratory morbidity was related to inadequate assessment
      of airway and ventilation. METHODS: A retrospective analysis of the assessment
      and resuscitation of a group of acute poisoning patients, as documented in the
      clinical records. SUBJECTS AND SETTING: Forty one patients admitted to either
      Intensive Care or Coronary Care Units in a UK teaching hospital with a diagnosis
      of acute poisoning, between 12 January 1997 and 21 January 1998. STANDARDS:
      Advanced Life Support Guidelines were used to compare initial assessment.
      Criteria for intubation and ventilation described by Gentleman was used as the
      standard for intubation. RESULTS: Thirty seven patients had documented Glasgow
      Coma Scales at the time of admission, 27 were managed appropriately; one
      exhibited signs of aspiration. Ten patients were judged to be managed
      inappropriately; six exhibited clinical signs of aspiration. Four patients had
      unidentified Glasgow Coma Scales. CONCLUSIONS: Increased emphasis on 'Airway and
      Breathing' remains necessary in medical education. Regional recommendations for
      the management of acute poisoning require 'intubation guidelines'. Appropriate
      ward settings for monitoring such patients may pre-empt the onset of major
      respiratory problems.

PMID- 10395399
TI  - The time required to perform different methods for endotracheal drug
      administration during CPR.
AB  - We compared the times necessary to perform different endotracheal drug
      application techniques during CPR. In a simulated CPR situation with a mannequin
      28 paramedics and seven emergency physicians performed different drug
      instillation techniques in a randomized manner: direct injection into the upper
      end of the endotracheal tube (group tube), via a suction catheter placed into the
      bronchial system (group suction catheter), via a flexible venous catheter placed
      into the bronchial system (group venous catheter), using an EDGAR tube (an
      endotracheal tube with an injection channel within the wall of the tube (group
      EDGAR). We measured the time necessary to prepare the drug solution and compared
      the time necessary to prepare and perform each instillation method and the time
      the ventilation was interrupted. Comparison between groups was performed by the
      Kruskal-Wallis test. It took significantly longer to perform the more complicated
      techniques using suction catheters (26; 18 54 s) and venous catheters (30; 22-50
      s) compared to the other two groups (median; min-max) (p < 0.05). No differences
      concerning the application time were found between the group tube (7; 5 14 s) and
      group EDGAR (8; 5-13 s). The time of interruption of chest compression's and
      ventilation: group suction tube (11; 5-19 s) and group catheter (12; 6-18 s) was
      significant longer than in group tube (5; 2-9 s) (p < 0.05). In group EDGAR the
      connection ventilator-tube remained intact due to its concept of drug
      application. The use of special devices such as suction catheters or venous
      catheters for endotracheal instillation during CPR results in significantly
      longer preparation and instillation times with a longer interruption of the
      oxygen supply and chest compression's.

PMID- 10395400
TI  - Improved haemodynamics and restoration of spontaneous circulation with constant
      aortic occlusion during experimental cardiopulmonary resuscitation.
AB  - Continuous balloon occlusion of the descending aorta is an experimental method
      that may improve blood flow to the myocardium and the brain during
      cardiopulmonary resuscitation (CPR). The aim of the present investigation was to
      evaluate the effects of this intervention on haemodynamics and the frequency of
      restoration of spontaneous circulation. Ventricular fibrillation was induced in
      39 anaesthetised piglets, followed by an 8-min non-intervention interval. In a
      haemodynamic study (n = 10), closed chest CPR was performed for 7 min before the
      intra-aortic balloon was inflated. This intervention increased mean arterial
      blood pressure by 20%, reduced cardiac output by 33%, increased coronary artery
      blood flow by 86%, and increased common carotid artery blood flow by 62%. All
      these changes were statistically significant. Administration of epinephrine
      further increased mean arterial blood pressure and coronary artery blood flow,
      while cardiac output and common carotid artery blood flow decreased. In a study
      of short-term survival, nine out of 13 animals (69%) in the balloon group and in
      three out of 13 animals (23%) in the control group had spontaneous circulation
      restored. The difference between these two proportions was 0.46, which was
      statistically significant with a 95% confidence interval from 0.12 to 0.80. In
      conclusion, balloon occlusion of the descending aorta increased coronary and
      common carotid artery blood flow and the frequency of restoration of spontaneous
      circulation. It was also noted that epinephrine appears to augment the
      redistribution of blood flow caused by the aortic occlusion.

PMID- 10395401
TI  - Lack of a neuroprotective effect from N-acetylcysteine after cardiac arrest and
      resuscitation in a canine model.
AB  - OBJECTIVE: Oxygen free radicals cause brain injury following resuscitation from
      cardiac arrest. In preclinical trials, some free radical scavenging drugs reduce
      oxidative neuronal damage after ischemia and reperfusion, but these drugs are
      generally not yet available for clinical testing or use. N-Acetylcysteine (NAC),
      a commonly used antidote in acetaminophen poisoning, is also a potent free
      radical scavenger that can ameliorate oxidative injury following ischemia and
      reperfusion in neuronal cell culture. We hypothesized that treatment with NAC
      would improve neurological outcome after cardiac arrest and resuscitation.
      METHODS: In 16 adult female beagles, 10 min of ventricular fibrillation was
      followed by 3 min of open-chest CPR, and defibrillation. Immediately following
      return of spontaneous circulation, animals randomly received either 150 mg/kg NAC
      (3% solution) (n = 8) or an equivalent volume of normal saline (n = 8). Twenty
      three hours later, neurological deficit was scored (0 = normal, 100 = brain
      death). RESULTS: All animals were successfully resuscitated, and there were no
      apparent adverse effects to the administration of NAC in post resuscitative
      animals. There was, however, no significant difference in neurological deficit in
      the animals receiving NAC (40 +/- 12.9, mean +/- SD) compared to control animals
      (44 +/- 6.5, P = 0.73). CONCLUSION: No neuroprotective effect was found from the
      administration of NAC at currently used clinical dosages, to dogs subjected to 10
      min of global cerebral ischemia from cardiac arrest and resuscitation.

PMID- 10395402
TI  - Awake use of a new laryngeal mask prototype in a non-fasted patient requiring
      urgent peripheral vascular surgery.
AB  - This case illustrates that a new prototype laryngeal mask with high seal
      pressures can be placed in the awake patient with minimal cardiorespiratory
      changes and that it facilitates passage of a nasogastric tube.

PMID- 10395403
TI  - Angiotensin II and nitric oxide: a question of balance.
AB  - The vasoconstrictor peptide angiotensin II (Ang II) and the endogenous
      vasodilator nitric oxide (NO) have many antagonistic effects, as well as
      influencing each other's production and functioning. In the short-term, Ang II
      stimulates NO release, thus modulating the vasoconstrictor actions of the
      peptide. In the long-term, Ang II influences the expression of all three NO
      synthase (NOS) isoforms, while NO downregulates the Ang II Type I (AT1) receptor,
      contributing to the protective role of NO in the vasculature. Within the
      cardiovascular system, Ang II and NO also have antagonistic effects on vascular
      remodeling and apoptosis. In the kidney, the distribution of the NOS isoforms
      coincides with the sites of the components of the renin-angiotensin system. NO
      influences renin secretion from the kidney, and NO-Ang II interactions are
      important in the control of glomerular and tubular function. In the adrenal
      gland, NO has been shown to affect Ang II-induced aldosterone synthesis, while in
      the brain NO appears to influence Ang II-induced drinking behavior, although
      conflicting data have been reported. In this review, we focus on the diverse ways
      in which Ang II and NO interact, and on the importance of maintaining a balance
      between these two important mediators.

PMID- 10395404
TI  - The AT2 receptor: fact, fancy and fantasy.
AB  - The angiotensin AT2 receptor subtype was recently cloned and pharmacologically
      characterized but its function still remains elusive and controversial. It is a
      member of the G-protein coupled receptor superfamily with a minimal sequence
      homology with the AT1 receptor, responsible for the known effect of angiotensin
      II. The AT2 receptor displays a totally different signaling mechanisms from the
      AT1 receptor and involves various phosphatases. It is expressed at low density in
      adult tissues but up-regulated in pathological circumstances. Clearly, the AT2
      receptor has antiproliferative properties and therefore opposes the growth
      promoting effect linked to the AT1 receptor stimulation. It is also reported that
      the AT2 receptor regulates ionic fluxes, affects differentiation and nerve
      regeneration, has anti-angiogenic and anti-fibrotic properties and stimulates
      apoptosis. However, the results, although suggestive, are sometimes equivocal.
      Obviously, the AT2 receptor plays a role in the pathogenesis and remodeling of
      cardiovascular and renal diseases. A more extensive knowledge of the AT2 receptor
      could therefore contribute to the understanding of the clincial beneficial
      effects of the AT1 receptor antagonists.

PMID- 10395405
TI  - Guanylin regulatory peptides: structures, biological activities mediated by
      cyclic GMP and pathobiology.
AB  - The guanylin family of bioactive peptides consists of three endogenous peptides,
      including guanylin, uroguanylin and lymphoguanylin, and one exogenous peptide
      toxin produced by enteric bacteria. These small cysteine-rich peptides activate
      cell-surface receptors, which have intrinsic guanylate cyclase activity, thus
      modulating cellular function via the intracellular second messenger, cyclic GMP.
      Membrane guanylate cyclase-C is an intestinal receptor for guanylin and
      uroguanylin that is responsible for stimulation of Cl- and HCO3- secretion into
      the intestinal lumen. Guanylin and uroguanylin are produced within the intestinal
      mucosa to serve in a paracrine mechanism for regulation of intestinal fluid and
      electrolyte secretion. Enteric bacteria secrete peptide toxin mimics of
      uroguanylin and guanylin that activate the intestinal receptors in an
      uncontrolled fashion to produce secretory diarrhea. Opossum kidney guanylate
      cyclase is a key receptor in the kidney that may be responsible for the diuretic
      and natriuretic actions of uroguanylin in vivo. Uroguanylin serves in an
      endocrine axis linking the intestine and kidney where its natriuretic and
      diuretic actions contribute to the maintenance of Na+ balance following oral
      ingestion of NaCl. Lymphoguanylin is highly expressed in the kidney and
      myocardium where this unique peptide may act locally to regulate cyclic GMP
      levels in target cells. Lymphoguanylin is also produced in cells of the lymphoid
      immune system where other physiological functions may be influenced by
      intracellular cyclic GMP. Observations of nature are providing insights into
      cellular mechanisms involving guanylin peptides in intestinal diseases such as
      colon cancer and diarrhea and in chronic renal diseases or cardiac disorders such
      as congestive heart failure where guanylin and/or uroguanylin levels in the
      circulation and/or urine are pathologically elevated. Guanylin peptides are
      clearly involved in the regulation of salt and water homeostasis, but new
      findings indicate that these novel peptides have diverse physiological roles in
      addition to those previously documented for control of intestinal and renal
      function.

PMID- 10395406
TI  - Histidine decarboxylase in rat stomach ECL cells: relationship between enzyme
      activity and different molecular forms.
AB  - Mammalian HDC mRNA encodes a protein with a molecular mass of 74 kDa. The
      reported molecular mass for the purified HDC subunit is 53-55 kDa. Western blot
      analysis of extracts of rat gastric mucosa and fetal rat liver has revealed the
      presence of at least three different forms of HDC immunoreactivity, having
      molecular masses of about 74, 63 and 53 kDa. There is evidence from previous
      studies that full length rat HDC is enzymatically inactive and that activation
      requires C-terminal truncation. In the present study we examined the various
      immunoreactive HDC forms in rat oxyntic mucosa and their response to treatments
      known to affect the HDC activity. Freely fed rats and hypergastrinemic rats
      (treated with gastrin or the proton pump inhibitor omeprazole) had higher oxyntic
      mucosal HDC activity and HDC mRNA level than fasted or untreated rats. The
      difference in HDC activity was greater than the difference in HDC mRNA level.
      Western blot analysis confirmed the existence of the 74, 63 and 53 kDa HDC forms
      in the oxyntic mucosa. All three forms were more abundant in the oxyntic mucosa
      of freely fed and hypergastrinemic rats than in the mucosa of fasted or untreated
      rats. Of the three HDC forms, the 63 kDa form was the predominant one, the 73 kDa
      form was quantitatively insignificant by comparison and the 53 kDa form was at or
      below the limit of detection in fasted rats. The activity of HDC was well
      correlated to the amount of the 63 kDa HDC form. Administration of cycloheximide
      to hypergastrinemic rats (undergoing omeprazole treatment) resulted in a rapid
      decline of the HDC activity (estimated half-life 1 h and 50 min). The 63 kDa HDC
      form disappeared with a rate that corresponded to the decline in HDC activity.
      The two other HDC forms seemed to have a slower turnover. Our findings suggest
      that the 63 kDa form is enzymatically active. The results do not allow any
      conclusion as to the functional activity of the 74 and 53 kDa forms.

PMID- 10395407
TI  - Effect of nedocromil sodium on non-adrenergic, non-cholinergic neural responses
      in guinea pig bronchi in vitro.
AB  - OBJECTIVE: Nedocromil sodium (nedocromil) improves the clinical condition of
      asthmatic subjects but its mechanism of action is not fully understood. This
      study aimed to determine whether nedocromil alters the ability of contractile and
      relaxant non-adrenergic, non-cholinergic neural (NANC) responses to stabilise
      tone by inhibiting or potentiating these responses in bronchial smooth muscle
      and, if so, whether the action is on a pre- or postjunctional level. RESULTS:
      Nedocromil attenuated contractile but not relaxant NANC responses (elicited by
      electric field stimulation) significantly (P < 0.05) in guinea pig main bronchi
      in vitro. However, the ability of NANC responses to stabilise tone (convergence
      effect) was not significantly impaired by nedocromil. Furthermore, nedocromil did
      not significantly shift the concentration response curve (-log EC50) to
      neurokinin A (NKA), the dominating contractile NANC transmitter, or alter the
      maximum response to NKA (P > 0.05). Submaximum or maximum contractile responses
      to histamine were not markedly affected by nedocromil (P > 0.05). CONCLUSIONS:
      Nedocromil exerts selective neural inhibition of the contractile but not of the
      relaxant NANC responses on a pre-junctional level in bronchial smooth muscle.
      Nedocromil does not, however, markedly impair the ability of NANC response to
      stabilise bronchial smooth muscle tone.

PMID- 10395408
TI  - Identification of the TRH-like peptides pGlu-Glu-Pro amide and pGlu-Phe-Pro amide
      in rat thyroid: regulation by thyroid status.
AB  - Rat thyroid contains thyrotropin-releasing hormone (TRH) and TRH-like peptides
      which react with TRH antisera. We have identified the TRH-like peptides in the
      thyroid and examined whether their levels are influenced by thyroid status. The
      peptides were extracted from the thyroid glands of five hyperthyroid rats and
      purified by ion-exchange chromatography on SP-Sephadex C25 and reversed-phase
      high performance liquid chromatography. The principal TRH-immunoreactive
      component exhibited the same retention on HPLC as synthetic pGlu-Glu-Pro amide
      and a secondary component corresponded to synthetic pGlu-Phe-Pro amide. In
      agreement with these assignments the main peptide was shown to be acidic when
      chromatographed on DEAE-Sephadex A25 and the second peptide neutral. The levels
      of TRH and TRH-like peptides in the thyroid were investigated in hyper-, hypo-
      and euthyroid rats. Hyperthyroidism was induced by chronic subcutaneous
      administration of triiodothyronine (T3) and hypothyroidism was produced by
      addition of propylthiouracil (PTU) to the drinking water. The amounts of the
      peptides were determined by radioimmunoassay with a TRH-antiserum, carried out
      after extraction from the tissues and purification by ion exchange
      chromatography. The mean concentration of TRH-like peptides in the thyroids of
      the hyperthyroid rats was 95.5+/-25.5 pmol/g, the mean concentration in the
      hypothyroid rats was 11.7+/-3.4 pmol/g, and in the euthyroid rats 17.6+/-3.2
      pmol/g. The concentrations of TRH were less influenced by thyroid status: the
      values in hyper-, hypo- and euthyroid rats were 47.5+/-9.4, 42.1+/-6.3, and
      17.2+/-1.6 pmol/g respectively. The results show that the levels of the TRH-like
      peptides in rat thyroid are highly sensitive to thyroid status, suggesting a
      possible involvement in thyroid regulation.

PMID- 10395409
TI  - On the effect of xenin and xenin fragments on exocrine pancreas secretion in
      vivo.
AB  - A stimulatory effect on exocrine pancreas secretion could be demonstrated with
      high concentrations of the 25-amino-acid peptide xenin in non-anesthetized dogs.
      This peptide has been isolated from gastric mucosa and it is part of a structural
      coat protein. It has close structural similarities to neurotensin. The longer C
      terminal fragments xenin-(13--25) and xenin-(18--25) are essential for the
      stimulation of exocrine pancreas secretion in vivo. The smaller peptide fragments
      xenin-(21--25) and xenin-(22--25) failed to stimulate the pancreas as well as the
      N-terminal peptide fragment xenin-(1--23). The stimulatory effects of xenin may
      be mediated via neural neurotensin pathways, because neurotensin receptor
      blockade abolished the stimulatory effect on pancreatic secretion. Cholinergic
      pathways are not involved, because atropine had no inhibiting effect.

PMID- 10395410
TI  - Cysteine residues in a synthetic peptide corresponding to human follicle
      stimulating hormone beta-subunit receptor-binding domain 81-95 [hFSH-beta-(81
      95)] modulate the in vivo effects of hFSH-beta-(81-95) on the mouse estrous
      cycle.
AB  - We have previously reported that synthetic peptide amides corresponding to
      subdomains of the human FSH 3-subunit, hFSH-beta-(33--53) and hFSH-beta-(81--95),
      interact with the external domain of the FSH receptor in two in vitro model
      systems. Consistent with these in vitro observations, we found that
      intraperitoneal (i.p.) administration of each of these peptides prolonged vaginal
      estrus in normally cycling mice in vivo. Both hFSH-beta-(33--53) and hFSH-beta
      (81--95) contain cysteine (Cys) residues with free sulfhydryl groups of potential
      significance in receptor interactions. To assess the possible involvement of
      these groups in the in vivo effects of hFSH-beta-(33--53) and hFSH-beta-(81--95),
      synthetic peptide analogs were prepared in which all Cys residues were replaced
      with serine (Ser). In the present study, we demonstrate that the in vivo effect
      of hFSH-beta-(33--53) on the mouse estrous cycle, extension of vaginal estrus,
      was not changed by substitution of Cys-51 with Ser. In contrast, mice receiving
      the Ser-substituted analog of hFSH-beta-(81--95) had normal estrus stages, but
      were arrested in diestrus. hFSH-beta-(33--53)-(81--95), a linear peptide
      encompassing both domains, also prolonged vaginal estrus. The Ser-substituted
      analog of this peptide, however, prolonged vaginal estrus in some of the mice
      tested and induced cycle arrest at diestrus in others. hFSH-beta-(90--95), the
      active subdomain at the C-terminus of hFSH-beta-(81--95), extended vaginal
      estrus, but diestrus stages were of normal duration. Its Ser-substituted analog,
      however, prolonged the estrus stage of the majority of mice treated, but induced
      diestrus arrest in some. The differing responses to these peptides are presumably
      due to interactions of the synthetic peptides with different regions of the FSH
      receptor. This further suggests that one consequence of ligand interaction with
      multiple receptor binding domains may be variable effects on ovarian function,
      and that Cys to Ser analogs may have value in the design of a novel class of
      synthetic peptides capable of fertility regulation and control.

PMID- 10395411
TI  - Both afferent and efferent nerves are implicated in cholecytokinin motor actions
      in the small intestine of the rat.
AB  - Cholecystokinin (CCK) regulates intestinal motility after being released by
      several luminal nutrients. However the mechanism of action of CCK is still not
      well known. The aim of our study was to establish the mechanism of action of CCK
      in the rat intestine using an in vivo model and focusing on the nervous pathways
      involved in the response as well as type of receptors. Anesthetized rats were
      prepared with two strain-gauges, in duodenum and jejunum, to record circular
      muscle motor activity. A group of animals was also prepared with a catheter to
      infuse capsaicin inside the duodenum. Responses to CCK-octapeptide (CCK-8) as
      well as to CCK agonists were studied. CCK-8 was also infused after CCK
      antagonists, atropine, hexamethonium or L-nitroarginine. Results show that
      duodenal response to CCK-8 is excitatory although inhibitory responses can be
      induced by gastrin. In the jejunum, CCK-8 induces an inhibitory response that is
      mediated by both CCK-A and -B receptors. Excitatory responses to CCK-8 are due to
      stimulation of preganglionic receptors while inhibitory responses are NO mediated
      through stimulation of postganglionic CCK-B receptors. Capsaicin locally applied
      in duodenal mucosa significantly decreased CCK-8 response, whereas mucosal
      exposure to lidocaine completely blocked CCK-8 response. In conclusion our
      results show that CCK response varies along the intestine according to the
      predominance of excitatory or inhibitory efferent innervation. Moreover, CCK-8
      actions are mediated through both extrinsic and intrinsic afferent fibres.

PMID- 10395412
TI  - Cardiorespiratory responses to intracerebroventricular injection of neuropeptide
      Y in anaesthetised dogs.
AB  - Cardiovascular and respiratory effects of intracerebroventricular (icv)
      administration of neuropeptide Y (NPY) and separate, preferential agonists for
      NPY Y1 and Y2 receptors were observed in anaesthetised dogs. Central injections
      of NPY resulted in significant cardiac slowing and decreases in arterial
      pressure. These cardiovascular effects were blocked by central injection of the
      NPY Y1- preferring antagonist 1229U91. Central injection of NPY did not have a
      significant effect on ventilation, but the NPY Y1 antagonist 1229U91 administered
      alone caused a significant increase in ventilation. The NPY Y1-receptor agonist
      [Leu31Pro34] NPY significantly decreased ventilation while the NPY Y2 receptor
      agonist N-acetyl [Leu28Leu31] NPY 24--36 significantly increased it. A similar
      inverse relationship was seen with respect to blood pressure, with the NPY Y1
      receptor agonist [Leu31Pro34] NPY significantly decreasing blood pressure, while
      the NPY Y2 receptor agonist N-acetyl [Leu28Leu31] NPY 24-36 significantly
      increased it. These findings suggest a role for NPY Y1 receptors in pathways
      mediating decreases in ventilation and blood pressure, and for NPY Y2 receptors
      in those mediating increased ventilation and blood pressure.

PMID- 10395413
TI  - Interleukin-1beta potentiates endothelin ET(B) receptor-mediated contraction in
      cultured segments of human temporal artery.
AB  - Segments of human temporal artery were placed in organ culture for up to 4 days
      and examined for endothelin ET(B) receptor activity in the presence and absence
      of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) by in vitro
      pharmacology and reverse transcriptase-polymerase chain reaction (RT-PCR). The
      contractile effect of prostaglandin F2alpha (used as a reference), was not
      significantly altered by culture or IL-1beta. However, the selective ET(B)
      agonist sarafotoxin S6c induced no contraction in fresh arteries, but marked
      contraction after culture. Both maximal contraction and potency to sarafotoxin
      S6c were increased in segments incubated with IL-1beta . The contraction was
      sensitive to BQ 788 (ET(B) antagonist), but not FR 139317 (ET(A) antagonist).
      Actinomycin D abolished the contraction, whereas only the cytokine-induced
      increase in contraction was inhibited by cycloheximide. ET(A) and ET(B) receptor
      mRNAs were detected in all arteries; predominantly for the ET(A) receptor in
      fresh arteries, and for the ET(B) receptor after culture. However, there was no
      change in the ET(A)/ET(B) receptor mRNA ratio after treatment with IL-1beta. This
      suggests de novo synthesis of contractile ET(B) receptors after organ culture and
      that IL- 1beta may further stimulate translation of the mRNA to active receptors.
      The results raise the possibility that contractile ET(B) receptors may be
      implicated in disease states with inflammatory processes.

PMID- 10395415
TI  - In-flight radiation: counseling patients about risk.
AB  - BACKGROUND: At the high altitudes, which are the domain of commercial airliners,
      cosmic-ray exposure rates are hundreds of times greater than at ground level. If
      this radiation originated at a regulated industrial or medical facility, many
      frequent flyers would receive annual exposures in excess of the present legal
      limit applicable to members of the public. For pregnant travelers, the fetus is
      also at risk, with a sensitivity that varies during the course of pregnancy.
      METHODS: Health risks from in-flight radiation exposure are analyzed specifically
      to calculate the likelihood of cancer, birth defects, and genetic damage. A
      literature review was conducted from 1985 to 1998, using the key words "cosmic
      radiation," "aviation medicine," "radiation risk," and "in-flight radiation."
      RESULTS AND CONCLUSIONS: The analysis shows that for the passenger who travels
      only occasionally, the risks are extremely small. For business frequent flyers
      the risks are still small, but not negligible.

PMID- 10395414
TI  - Comparison of ketorolac-chlorpromazine with meperidine-promethazine for treatment
      of exacerbations of chronic pain.
AB  - BACKGROUND: The aim was to compare the efficacy and safety of a combination of
      intramuscular ketorolac and chlorpromazine for the treatment of acute
      exacerbations of chronic pain with the more commonly used regimen of
      intramuscular meperidine and promethazine. METHODS: Use-effective case series
      were drawn from a real-life, rural emergency department practice, in which 200
      consecutive patients coming to a rural emergency department with acute
      exacerbations of chronic pain syndromes were assigned on an every-other basis in
      a single-blind fashion to one of the two treatment conditions. Patients were
      given intramuscular doses of either 60 mg of ketorolac plus 50 mg of
      chlorpromazine (75 mg of chlorpromazine for patients weighing more than 100 kg),
      or 50 mg of meperidine plus 25 mg of promethazine (50 mg of promethazine for
      patients weighing more than 75 kg); patients weighing more than 100 kg were given
      1.5 doses. Patients older than 65 years or whose blood pressure at the time of
      injection was less than 110/70 mmHg were given half-doses. Patients could receive
      one additional half-dose injection if they had no results within 30 to 60 minutes
      after the first injection. Patients were assessed on self-report and on a verbal
      and visual analog scale of pain rating. Temperature, blood pressure, heart rate,
      and respirations were monitored every 15 minutes. RESULTS: Both regimens
      performed well, with more than 90 percent of patients reporting good or excellent
      improvement on acute exacerbations of chronic pain. Ketorolac-chlorpromazine
      offered significant advantages compared with meperidine-promethazine when
      patients rated their pain on a visual analog pain scale (P < 0.05) but not on a
      verbal scale. Adverse reactions were minimal and consisted of more respiratory
      tract depression with meperidine and more vertigo or dizziness with
      chlorpromazine. There was no difference in incidence of hypotension between the
      two groups. CONCLUSIONS: The combination of ketorolac and chlorpromazine is a
      safe and efficacious alternative to meperidine plus promethazine for the
      treatment of exacerbations of chronic pain in the rural emergency department
      setting.

PMID- 10395416
TI  - Cost of medications for patients with ischemic heart disease in a rural family
      practice center.
AB  - BACKGROUND: Cardiovascular disease is the leading cause of death, and multiple
      medications are often needed to control symptoms and risk factors. Little
      research has explored the cost of medications for a typical patient with chronic
      ischemic heart disease. We undertook a study to determine the cost of medications
      and how they are paid for by patients in one rural clinic. METHODS: One hundred
      four patients met criteria for chronic ischemic heart disease. We obtained
      patient information, risk factors, and current medications using retrospective
      chart reviews. We then calculated usual and customary costs per month for each of
      the 355 cardiac and 214 noncardiac prescriptions. After we determined which
      patients qualified for third party reimbursement or the community health center
      medication discount program, we calculated the actual out-of-pocket cost to the
      patient for each prescription. RESULTS: Average monthly medication costs were
      $104.77 for cardiac medications and $115.54 for noncardiac medications, for a
      total of $220.31. Patients were reimbursed for approximately 64 percent of the
      total medications costs, making average out-of-pocket medication costs $41.52 for
      cardiac medications and $36.86 for noncardiac medications, for a total of $78.38.
      Seventy-one percent of patients were reimbursed by their insurance company, 19
      percent qualified for the medication discount program, and 10 percent had no
      assistance. Patient risk factors included positive family history of chronic
      ischemic heart disease (71 percent), hypertension (64 percent), history of
      smoking (61 percent), currently smoking (26 percent), diabetes (25 percent), and
      recently elevated cholesterol levels (67 percent of 76 patients). CONCLUSIONS:
      Medication costs for patients with chronic ischemic heart disease are expensive
      and burdensome. Third party payers and the medication discount program relieved a
      considerable (64 percent) but inadequate amount of prescription costs. Multiple
      risk factors coexist with these medication costs. Patient behavior modification
      and an aggressive approach to risk reduction might reduce these costs.

PMID- 10395417
TI  - What do family physicians believe and value in their work?
AB  - BACKGROUND: Family practice has always valued physician self-awareness. Whereas
      self-awareness has traditionally focused on problem relationships with patients,
      generally unexplored are the physicians' personal beliefs and values that
      strongly influence their routine clinical work and collegial relationships. Thus
      we know little about the nature and scope of these beliefs and values. The
      following study was undertaken to foster a better understanding of beliefs and
      values that residents bring to their clinical practice. METHODS: Applying 13
      years of experience with one method of structured reflection and conversation, I
      was able to perform a cross-set analysis of findings from interactions with 143
      family practice residents. Such dimensions as views of life and death, role of
      physician, and process of healing served as avenues to elicit beliefs and values.
      RESULTS: The residents' responses yielded the following six themes: philosophy
      and spirituality, the nature of suffering, the strains of helping, the healing
      relationship, the coherence of models, and clashes with the models of patients
      and colleagues. CONCLUSION: These conversations with family physicians-in
      training suggest that they bring to their clinical and collaborative
      relationships complex, highly personal models of medicine that emphasize meaning
      and human relationship and serve as a source of strength. To better understand
      these models, future work should investigate the general beliefs and values of
      experienced family physicians in various practice settings, how their models of
      medicine interact and perhaps clash with those of their patients and colleagues,
      and effective methods for helping family physicians articulate their views so
      they can function effectively in their clinical practice.

PMID- 10395418
TI  - Appropriate roles of cardiac troponins in evaluating patients with chest pain.
AB  - BACKGROUND: Diagnosis of acute myocardial infarction relies upon the clinical
      history, interpretation of the electrocardiogram, and measurement of serum levels
      of cardiac enzymes. Newer biochemical markers of myocardial injury, such as
      cardiac troponin I and cardiac troponin T, are now being used instead of or along
      with the standard markers, the MB isoenzyme of creatine kinase (CK-MB) and
      lactate dehydrogenase. METHODS: We performed a MEDLINE literature search (1987 to
      1997) using the key words "troponin I," "troponin T," and "acute myocardial
      infarction." We reviewed selected articles related to the diagnostic and
      prognostic usefulness of these cardiac markers in evaluating patients with
      suspected myocardial infarction. RESULTS: We found that (1) troponin I is a
      better cardiac marker than CK-MB for myocardial infarction because it is equally
      sensitive yet more specific for myocardial injury; (2) troponin T is a relatively
      poorer cardiac marker than CK-MB because it is less sensitive and less specific
      for myocardial injury; and (3) both troponin I and troponin T may be used as
      independent prognosticators of future cardiac events. CONCLUSIONS: Troponin I is
      a sensitive and specific marker for myocardial injury and can be used to predict
      the likelihood of future cardiac events. It is not much more expensive to measure
      than CK-MB. Overall, troponin I is a better cardiac marker than CK-MB and should
      become the preferred cardiac enzyme when evaluating patients with suspected
      myocardial infarction.

PMID- 10395419
TI  - Stridor in a 6-week-old infant caused by right aortic arch with aberrant left
      subclavian artery.
AB  - BACKGROUND: Persistent infant stridor, seal-like cough, and difficulty feeding
      can be the initial signs of right aortic arch with an aberrant left subclavian
      artery. This congenital cardiovascular abnormality results in the development of
      a vascular ring that encircles the trachea and esophagus. METHODS: A case report
      is presented that describes the evaluation and care of a 6-week-old male infant
      whose condition was diagnosed as right aortic arch and aberrant left subclavian
      artery after he was brought to the family practice clinic with a history of
      persistent stridor. This case report involved a patient seen in the author's
      outpatient clinic during a well-child check. Data were obtained from the
      patient's medical record and review of his radiologic diagnostic tests. MEDLINE
      and Index Medicus literature searches were conducted for the years 1966 to the
      present, using the key words "stridor" and "vascular ring," with cross-references
      for earlier articles. RESULTS AND CONCLUSIONS: Persistent or recurrent stridor
      associated with feeding difficulties should prompt an investigation for a
      vascular ring. In general, an anteroposterior and lateral neck radiograph and a
      posteroanterior and lateral chest radiograph are usually the initial diagnostic
      tests to evaluate stridor. Persistent stridor and new-onset regurgitation of
      formula in a 6-week-old infant prompted an escalation of the patient's workup to
      include a barium swallow, which subsequently showed compression of the esophagus
      caused by a vascular ring. In some cases direct observation with a laryngoscope
      or bronchoscope might be necessary to determine the cause of stridor. Indications
      for hospitalization of patients with stridor include stridor at rest, dyspnea,
      actual or suspected epiglottis, repeatedly awakening from sleep with stridor, a
      history of rapid progression of symptoms, toxic appearance, and apneic or
      cyanotic episodes. The primary care provider should be familiar with the
      evaluation and management for patients with the complaint of persistent or
      recurrent stridor.

PMID- 10395420
TI  - Information at the point of care: answering clinical questions.

PMID- 10395421
TI  - Pharmacotherapy of tinea capitis.

PMID- 10395422
TI  - Sulfadiazine-induced crystalluria and renal failure in a patient with AIDS.

PMID- 10395423
TI  - Severe Guillain-Barre syndrome associated with Campylobacter jejuni infection
      with failure to respond to plasmapheresis and immunoglobulin.

PMID- 10395424
TI  - Facial numbness: a manifestation of sarcoidosis.

PMID- 10395425
TI  - Standing ovation.

PMID- 10395426
TI  - Physician, know thyself.

PMID- 10395427
TI  - Treatment of otitis externa.

PMID- 10395428
TI  - Reimbursement for flexible sigmoidoscopy.

PMID- 10395429
TI  - Physician-applied contact pressure and table force response during unilateral
      thoracic manipulation.
AB  - OBJECTIVE: To measure the applied loading to human subjects during the reinforced
      unilateral thoracic manipulation. DESIGN: Biomechanical descriptive study.
      SETTING: The National College of Chiropractic Clinical Biomechanical Laboratory
      in Lombard, Illinois. SUBJECTS: Seven men, ages 24 to 47, with no positive
      responses regarding muscle relaxants or thoracic spinal fractures, surgeries, or
      pain. MAIN OUTCOME MEASURES: We measured the contact pressure distribution at the
      physician-subject contact region and extracted three biomechanical parameters.
      From the measured time-dependent support force magnitudes, we extracted five
      additional biomechanical parameters. RESULTS: In the application of the
      reinforced unilateral manipulative treatment, the physician establishes contact
      and applies a near-static preload force of 250 to 350 N. The dynamic portion of
      the typical thrust is preceded by a 22% decrease in force magnitude, and the peak
      thrust magnitude is linearly related to the preload force magnitude. We estimate
      that the peak contact pressure beneath the chiropractor's pisiform can exceed
      1000 kPa, with the highest pressures transmitted over areas as small as 3.6 cm2,
      depending on manipulative style. CONCLUSIONS: This work represents the first
      attempt at performing simultaneous measurements of the physician-applied loading
      and table force response and measuring the contact pressure distribution at the
      physician-patient contact region during chiropractic manipulation. This type of
      work will lead to a better understanding of the relationship between the dynamic
      physician-applied normal forces and the resulting load response at the table and
      gives us additional outcome parameters to quantify manipulative technique.

PMID- 10395430
TI  - Comparison of work and time estimates by chiropractic physicians with those of
      medical and osteopathic providers.
AB  - BACKGROUND: Resource-based relative value scales (RBRVS) have become a standard
      method for identifying costs and determining reimbursement for physician
      services. Development of RBRVS systems and methods are reviewed, and the RBRVS
      concept of physician "work" is defined. OBJECTIVE: Results of work and time
      inputs from chiropractic physicians are compared with those reported by
      osteopathic and medical specialties. Last, implications for reimbursement of
      chiropractic fee services are discussed. METHODS: Total work, intraservice work,
      and time inputs for clinical vignettes reported by chiropractic, osteopathic, and
      medical physicians are compared. Data for chiropractic work and time reports were
      drawn from a national random sample of chiropractors conducted as part of a 1997
      workers' compensation chiropractic fee schedule development project. Medical and
      osteopathic inputs were drawn from RBRVS research conducted at Harvard University
      under a federal contract reported in 1990. Both data sets used the same or
      similar clinical vignettes and similar methods. Comparisons of work and time
      inputs are made for clinical vignettes to assess whether work reported by
      chiropractors is of similar magnitude and variability as work reported by other
      specialties. RESULTS: Chiropractic inputs for vignettes related to evaluation and
      management services are similar to those reported by medical specialists and
      osteopathic physicians. The range of variation between chiropractic work input
      and other specialties is of similar magnitude to that within other specialties.
      Chiropractors report greater work input for radiologic interpretation and lower
      work input for manipulation services. CONCLUSIONS: Chiropractors seem to perform
      similar total "work" for evaluation and management services as other specialties.
      No basis exists for excluding chiropractors from using evaluation and management
      codes for reimbursement purposes on grounds of dissimilar physician time or work
      estimates. Greater work input by chiropractors in radiology interpretation may be
      related to a greater importance placed on findings in care planning. Consistently
      higher reports for osteopathic work input on manipulation are likely attributable
      to differences in reference vignettes used in the respective populations.
      Research with a common reference vignette used for manipulation providers is
      recommended, as is development of a single generic approach to coding for
      manipulation services.

PMID- 10395431
TI  - A feasibility study of chiropractic spinal manipulation versus sham spinal
      manipulation for chronic otitis media with effusion in children.
AB  - BACKGROUND: Pediatric otitis media with effusion is a common and costly
      condition. Although chiropractors have anecdotally claimed success in treating
      otitis media, there is little research to support their claims. OBJECTIVE: A
      pilot study was undertaken for the purpose of assessing the feasibility of
      conducting a full-scale randomized clinical trial investigating the efficacy of
      chiropractic spinal manipulative therapy (SMT) for children with chronic otitis
      media with effusion. METHODS: This study was a prospective, parallel-group,
      observer-blinded, randomized feasibility study. Twenty-two patients, ages 6
      months to 6 years, received either active chiropractic SMT or placebo
      chiropractic SMT. Otoscopy and tympanometry were used to create a middle ear
      status profile, and daily diaries were collected. RESULTS: Five newspaper
      advertisements over 6 months generated 105 responses. Twenty patients
      subsequently qualified and were randomized into the study. Collection of
      tympanometric and otoscopic data proved to be challenging. Compliance with the
      treatment and evaluation protocols and daily diaries was excellent. There were no
      reports of serious side effects as a result of either the active or placebo
      chiropractic treatments. CONCLUSION: Recruitment for a randomized controlled
      trial is feasible and could be enhanced by medical collaboration. Patients and
      parents are able and willing to participate in a study comparing active SMT and
      placebo SMT. Parents were extremely compliant with the daily diaries, suggesting
      that similar quality-of-life and functional status measures can be successfully
      used in a larger trial. We found the objective outcomes assessment involving
      tympanometry and otoscopy extremely challenging and should be performed by
      experienced examiners in future studies.

PMID- 10395432
TI  - Effective management of spinal pain in one hundred seventy-seven patients
      evaluated for manipulation under anesthesia.
AB  - OBJECTIVE: To demonstrate that manipulation under anesthesia (MUA), a
      conservative treatment modality, is both safe and efficacious in the treatment of
      both acute and chronic spinal pain disorders in appropriately selected patients.
      MUA can be safely used to treat pain arising from the cranial, cervical,
      thoracic, and lumbar spine, as well as the sacroiliac and pelvic region. SETTING:
      An ambulatory surgical center. SUBJECTS: The treatment group consisted of 177
      patients between ages 17 and 65 years. Evaluation followed a treatment algorithm
      created by the authors as a multidisciplinary approach to patient selection,
      evaluation, treatment, and timing of specialized referral, in consideration of
      previously published algorithms. Prior forms of treatment, both conservative and
      surgical in nature, had failed in these patients. INTERVENTION: Patients
      underwent three sequential manipulations under intravenous sedation, followed by
      4 to 6 weeks of skilled spinal manipulation and therapeutic modalities. OUTCOME
      MEASURES: Data regarding changes in Visual Analog Scale (VAS), range of motion,
      medication needs, and return to work status were used to document progress. All
      patients had follow-up for 6 months. RESULTS: On average, VAS ratings improved by
      62.2% in those patients with cervical pain problems. On average, VAS ratings
      improved by 60.1% in those patients with lumbar pain problems. There was a near
      complete reversal in patients out of work before MUA (68.6%) and those returning
      to unrestricted activities at 6 months after MUA (64.1%). There was a 58.4%
      reduction in the percentage of patients requiring prescription pain medication
      from the pre-MUA period to 6 months after MUA. Additionally, 24.0% of the
      treatment group required no medication at 6 months after MUA. CONCLUSION: A
      multidisciplinary approach to evaluation and treatment, including MUA, offers
      patient benefits above and beyond what can be obtained through the individual
      providers working alone.

PMID- 10395434
TI  - Introduction of a new physical examination procedure for the differentiation of
      acromioclavicular joint lesions and subacromial impingement.
AB  - OBJECTIVE: To present a new physical examination procedure that may assist in
      differentiating acromioclavicular joint lesions from subacromial impingement
      lesions. DISCUSSION: The acromioclavicularjoint differential test is performed by
      applying downward pressure over the lateral one third of the clavicle while
      passively inducing slight' adduction, external rotation, and forced forward
      flexion to the humerus while the patient is in the seated position. Although
      similar mechanisms have been described, the acromioclavicular joint differential
      test is a new, previously unreported examination procedure. CONCLUSION: This
      article describes a new test to differentiate between acromioclavicular joint
      lesions and subacromial impingement. On the basis of its mechanism, the
      acromioclavicular joint differential test may provide the examiner with an
      additional tool in the differential diagnosis of acromioclavicularjoint lesions
      and subacromial impingement in the patient with shoulder pain. Although this test
      has been used by the author in a clinical setting, validation data are not yet
      available.

PMID- 10395433
TI  - Chiropractic biophysics digitized radiographic mensuration analysis of the
      anteroposterior lumbopelvic view: a reliability study.
AB  - OBJECTIVE: To investigate the reliability of a radiographic measurement procedure
      that uses a computer and sonic digitizer to determine projected spinal
      displacements from an ideal normal position. DESIGN: A blind, repeated-measure
      design was used. Anteroposterior lumbopelvic radiographs were presented to each
      of 3 examiners in random order. Each film was digitized, and the films were
      randomized for a second run. SETTING: Private, primary-care chiropractic clinic.
      MAIN OUTCOME MEASURES: The angle of the sacral base in comparison to a true
      horizontal line (horizontal base angle), lumbodorsal angle, lumbosacral angle,
      and the thoracic translational displacement from true vertical determined as the
      perpendicular distance from the center of T12 to a vertical axis line drawn from
      the center of the S1 spinous process cephalad and parallel to the lateral edge of
      the x-ray film. RESULTS: Intraexaminer reliability for the (a) horizontal base
      angle was .72 to .94, with confidence intervals included in the range of .52 to
      .97; (b) lumbodorsal angle was .90 to .96, with confidence intervals in the range
      of .82 to .98; (c) lumbosacral angle was .84 to .96, with confidence intervals in
      the range of .72 to .98, and (d) thoracic translational displacement from
      vertical was .95 to.97, with confidence intervals included in the range of .91 to
      .99. Interexaminer reliability for the three examiners ranged from .71 to .97.
      CONCLUSIONS: Measures similar to those described in this study are commonly used
      to measure and categorize spinal displacements from true vertical alignment (ie,
      scoliosis measurements). Most patient assessment methods used in chiropractic
      have poor or unknown reliability. The one possible exception to this rule is
      spinal displacement analysis performed on radiographs. In chiropractic,
      intraclass correlation coefficients values greater than .70 are considered
      accurate enough for use in clinical and research applications. The measures
      tested here would fit within these guidelines of reliability. Establishing
      reliability is an important first step in evaluating these measures so that
      future studies of validity may be undertaken.

PMID- 10395435
TI  - A review of biomechanics of the central nervous system--part II: spinal cord
      strains from postural loads.
AB  - OBJECTIVE: To review spinal cord strains arising from postural loads. DATA
      COLLECTION: A hand search of available reference texts and a computer search of
      literature from the Indexed Medicus sources were collected, with special emphasis
      placed on spinal cord strains caused by various postural rotations and
      translations of the skull, thorax, and pelvis RESULTS: All spinal postures will
      deform the neural elements within the spinal canal. Flexion causes the largest
      canal length changes and, hence, the largest nervous system deformations. Neural
      tissue strains depend on the spinal level, the spinal movement generated, and the
      sequence of movements when more than one spinal area is moved. CONCLUSIONS:
      Rotations of the global postural components (head, thoracic cage, pelvis, and
      legs) cause stresses and strains in the central nervous system and peripheral
      nervous system. Translations of the skull, thorax, and pelvis, as well as
      combined postural loads, need to be studied for their effects on the spinal canal
      and neural tissue deformations. Flexion of any part of the spinal column may
      generate axial tension in the entire cord and nerve roots. Slight extension is
      the preferred position of the spine as far as reducing the magnitude of
      mechanical stresses and strains in the central nervous system is concerned.

PMID- 10395436
TI  - Chiropractic management of a patient with myasthenia gravis and vertebral
      subluxations.
AB  - OBJECTIVE: The chiropractic management of a patient with myasthenia gravis and
      vertebral subluxation is described. We discuss the pathophysiology, clinical
      features, and treatment of patients with these diseases. CLINICAL FEATURES: The
      63-year-old male patient suffered from complaints associated with the disease
      myasthenia gravis along with signs of vertebral subluxation. The patient had an
      initial complaint of dysphagia. In addition, the patient experienced swelling of
      the tongue, nausea, digestive problems, weakness in the eye muscles, difficulty
      breathing, myopia, diplopia, and headaches. Balance and coordination problems
      resulted in walking difficulties. INTERVENTION AND OUTCOME: Contact specific,
      high-velocity, low-amplitude adjustments were applied to sites of patient
      subluxation. Myasthenia gravis is no longer debilitating to the patient; he is
      medication free and has resumed a "normal life." CONCLUSION: The clinical aspects
      of the disease, including the possible role of chiropractic intervention in the
      treatment of patients suffering from myasthenia gravis, are also discussed. This
      case study encourages further investigation into the holistic approach to patient
      management by chiropractors vis-a-vis specific adjustments of vertebral
      subluxation.

PMID- 10395437
TI  - Posterior tibial stress fracture: a report of three cases.
AB  - OBJECTIVE: To discuss the specific clinical and radiographic features of
      posterior tibial stress fracture, as well as appropriate clinical management,
      including imaging and treatment, in the presence of suspected or confirmed tibial
      stress fracture. CLINICAL FEATURES: Three patients suffered from exercise-related
      lower leg pain, clinical features, and risk factors specific for posterior tibial
      stress fracture. Diagnosis was confirmed for all three individuals by
      radiographic imaging. INTERVENTION AND OUTCOME: Treatment included rest and
      modified activity, followed by a graded return to activity commensurate with bony
      healing. This approach was successful for two of the individuals diagnosed with
      posterior tibial stress fracture. In the third individual treatment
      recommendations were not adhered to, resulting in three separate stress fractures
      of the posterior tibia over 27 months. CONCLUSION: Stress fractures may go
      undiagnosed for a long period of time; therefore a high index of suspicion, along
      with knowledge of its clinical and predisposing factors, is necessary for
      recognition. Inappropriate management of individuals with tibial stress fracture
      may result in recurrence or frank fracture. Chiropractors have a role in the
      prevention of stress fractures by identifying and educating patients at risk for
      this condition.

PMID- 10395438
TI  - Commentary: torque misuse revisited.

PMID- 10395439
TI  - Comparative efficacy of conservative medical and chiropractic treatments for
      carpal tunnel syndrome: a randomized clinical trial.

PMID- 10395440
TI  - Active lateral neck flexion range of motion measurements obtained with a modified
      goniometer: reliability and estimates of normal.

PMID- 10395441
TI  - Three-dimensional spinal coupling mechanics: Part I. A review of the literature.

PMID- 10395442
TI  - Three-dimensional spinal coupling mechanics--Part II: implications for
      chiropractic theories and practice.

PMID- 10395443
TI  - Interaction of 3-alkylpyridinium polymers from the sea sponge Reniera sarai with
      insect acetylcholinesterase.
AB  - 3-Alkylpyridinium polymers (poly-APS), composed of 29 or 99 N-butyl-3-butyl
      pyridinium units, were isolated from the marine sponge Reniera sarai. They act as
      potent cholinesterase inhibitors. The inhibition kinetics pattern reveals several
      successive phases ending in irreversible inhibition of the enzyme. To provide
      more information on mechanism of inhibition, interaction of poly-APS and N-butyl
      3-butyl pyridinium iodide (NBPI) with soluble dimeric and monomeric insect
      acetylcholinesterase (AChE) was studied by using enzyme intrinsic fluorescence
      and light scattering, conformational probes ANS and trypsin, and SDS-PAGE. Poly
      APS quenched tryptophan fluorescence emission of AChE more extensively than NBPI.
      Both inhibitors exhibited a pseudo-Lehrer type of quenching. Interaction of poly
      APS with dimeric AChE did not induce significant changes of the enzyme
      conformation as assayed by using the hydrophobic probe ANS and trypsin digestion.
      In contrast to NBPI, titration of both monomeric and dimeric AChE with poly-APS
      resulted in the appearance of large complexes detected by measuring light
      scattering. An excess of poly-APS produced AChE precipitation as proved on SDS
      PAGE. None of the effects were observed with trypsin as a control. It was
      concluded that AChE aggregation and precipitation rather than the enzyme
      conformational changes accounted for the observed irreversible component of poly
      APS inhibition.

PMID- 10395444
TI  - Structure of pyridoxal kinase from sheep brain and role of the tryptophanyl
      residues.
AB  - The primary structure of sheep brain pyridoxal kinase has been determined by
      direct chemical and physical methods. The enzyme contains 312 amino acid residues
      with an acetylated methionine at the N-terminus, yielding a molecular mass of
      34,861 Da. The functional role played by the two tryptophanyl residues in
      positions 52 and 244 of the polypeptide chain has been investigated by
      fluorescence spectroscopy. The tryptophanyl residues are not completely exposed
      to the rapidly relaxing solvent and they are poorly accessible to collisional
      quenchers. Chemical modification with NBS abolishes the catalytic activity of the
      kinase. The amino acid sequence of the sheep brain enzyme shows high similarity
      (86.2% identity) with the human pyridoxal kinase recently reported [Hanna,
      Turner, and Kirkness, (1997), J. Biol. Chem. 272, 10756-10760]. Comparison of the
      mammalian proteins with bacterial and yeast putative pyridoxal kinases retrieved
      from the Swiss-Prot data bank shows a low degree of overall similarity. In
      particular, the putative ATP-binding domain is conserved, whereas the region that
      appears to be crucial in the binding of the pyridoxal substrate is not. Thus, the
      assignment of the bacterial and yeast cDNA-deduced proteins as pyridoxal kinases
      should be taken with caution.

PMID- 10395445
TI  - Spectroscopic characterization of two soluble transducers from the Archaeon
      Halobacterium salinarum.
AB  - In the present study, structural aspects of the two soluble transducers, HtrX and
      HtrXI, from the archaeon H. salinarum have been examined using UV circular
      dichroism and steady-state fluorescence spectroscopies. Circular dichroism (CD)
      data indicate that both HtrX and HtrXI exhibit salt-dependent protein folding.
      Under low-ionic-strength conditions (0.2 M NaCl or KCl) the CD spectra of HtrXI
      is similar to that of the Gdn-HCl- or urea-denatured forms and is indicative of
      random coil structure. In contrast, the CD spectrum of HtrX under low-ionic
      strength conditions contains roughly 85% alpha-helical character, indicating a
      significant degree of folding. Addition of NaCl or KCl to solutions of HtrX or
      HtrXI results in CD features consistent with predominately alpha-helical
      character (>95%) for both proteins. In addition, the transition points (i.e.,
      ionic strengths at which the protein converts from random coil to alpha-helical
      character) are quite distinct and dependent upon the type of salt present (i.e.,
      either NaCl or KCl). Accessibility of tryptophan residues to the solvent was also
      examined for both HtrX and HtrXI in both folded and unfolded states using KI
      quenching. The Stem-Volmer constants obtained suggest that the tryptophans (Trp35
      in HtrX and both Trp47 and Trp74 in HtrXI) are partially exposed to the solvent,
      indicating that they are located near the surface of the protein in all three
      cases. Furthermore, fluorescence quenching with the single Trp mutants Trp74AIa
      and Trp47AIa of HtrXI indicates different environments for these two residues.

PMID- 10395446
TI  - Correlation between self-association modes and GTPase activation of dynamin.
AB  - The GTPase activity of dynamin is obligatorily coupled, by a mechanism yet
      unknown, to the internalization of clathrin-coated endocytic vesicles. Dynamin
      oligomerizes in vitro and in vivo and both its mechanical and enzymatic
      activities appear to be mediated by this self-assembly. In this study we
      demonstrate that dynamin is characterized by a tetramer/monomer equilibrium with
      an equilibrium constant of 1.67 x 10(17) M(-3). Stopped-flow fluorescence
      experiments show that the association rate constant for 2'(3')-O-N
      methylanthraniloyl (mant)GTP is 7.0 x 10(-5) M(-1) s(-1) and the dissociation
      rate constant is 2.1 s(-1), whereas the dissociation rate constant for
      mantdeoxyGDP is 93 s(-1). We also demonstrate the cooperativity of dynamin
      binding and GTPase activation on a microtubule lattice. Our results indicate that
      dynamin self-association is not a sufficient condition for the expression of
      maximal GTPase activity, which suggests that dynamin molecules must be in the
      proper conformation or orientation if they are to form an active oligomer.

PMID- 10395447
TI  - Inhibition of membrane-active peptides by fatty acid-peptide hybrids.
AB  - Nine fatty acid-peptide hybrid molecules were constructed using the general
      formula CH3(CH2)nCO-Phe Asp Cys-amide and tested for their ability to inhibit
      cell lysis induced by the membrane-active peptide melittin. All of these
      molecules, where n = 4-14, inhibited the action of melittin to some extent, but
      the longer carbon chains were most effective. Several potential inhibitors were
      also constructed with conservative substitutions in the peptide portion of the
      molecule. All were effective to varying degrees. We concluded that in the
      hexapeptide inhibitor published by Blondelle et al. (1993), the role of the first
      three residues is only to provide hydrophobic interaction with the melittin and
      has no particular amino acid sequence specificity. Some of these inhibitors were
      found to inhibit the lytic activity of a melittin analogue which had only
      superficial sequence similarity to melittin and also a truncated form of
      melittin, indicating the generality of the action of the inhibitors.

PMID- 10395448
TI  - Kinetics and mechanism of St I modification by peroxyl radicals.
AB  - St I is a toxin present in the Caribbean Sea anemone Stichodactyla helianthus
      which is highly hemolytic in the nanomolar concentration range. Exposure of the
      toxin to free radicals produced in the pyrolysis of 2,2'-azobis(2-amidinopropane)
      hydrochloride leads to a progressive loss of hemolytic activity. This loss of
      hemolytic activity is accompanied by extensive modification of tryptophan
      residues. On the average, three tryptophan residues are modified by each
      inactivated toxin. The loss of hemolytic activity of St I takes place without
      significant changes in the protein structure, as evidenced by the similarity of
      the fluorescence and CD spectra of native and modified proteins. Also, the native
      and modified ensembles present a similar resistance to their denaturation by
      guanidinium chloride. The hemolytic behavior and the performance of the toxin at
      the single-channel level when incorporated to black lipid membranes suggest that
      the modified ensemble can be considered as composed of inactive toxins and active
      toxins whose behavior is similar to that of the native proteins. These results,
      together with the lack of induction time in the activity loss, suggest that the
      fall of hemolytic activity takes place by an all-or-nothing inactivation
      mechanism in which the molecules become inactive when a critical amino acid
      residue is modified.

PMID- 10395449
TI  - Thermodynamics of the binding of chymotrypsin with the black-eyed pea trypsin and
      chymotrypsin inhibitor (BTCI).
AB  - The binding of alpha-chymotrypsin to black-eyed pea trypsin/chymotrypsin
      inhibitor (BTCI) has been studied using the inhibitory activity against the
      enzyme and the formation of the complex enzyme/inhibitor followed by measurements
      of fluorescence polarization. Apparent equilibrium constants were estimated for
      several temperatures and the values obtained range from 0.32 x 10(7) to 1.36 x
      10(7) M(-1). The following values were found from van't Hoff plots: delta H(0)vh
      = 10.8 kcal mol(-1) (from inhibitory assays) and 11.1 kcal mol(-1) (from
      fluorescence polarization); delta S(0) = 67.9 and = 67.8 kcal K(-1) mol(-1),
      respectively. Calorimetric binding enthalpy was determined (corrected for the
      ionization heat of the buffer) and the resulting value was delta H(0)cal = 4.9
      kcal mol(-1). These results indicate that the binding of chymotrypsin to BTCI is
      an entropically driven process.

PMID- 10395450
TI  - Soybean beta-conglycinin alpha subunit is phosphorylated on two distinct serines
      by protein kinase CK2 in vitro.
AB  - Protein kinase CK2 purified from the yeast Yarrowia lipolytica was used to
      phosphorylate soybean beta-conglycinin alpha subunit. CK2 is known to
      phosphorylate serines and threonines in the consensus sequence Ser/Thr-X-X
      Glu/Asp/SerP/TyrP. Beta-conglycinin alpha subunit (68 kDa) presents seven
      consensus sequences, but only 0.5-1 mol P/mol alpha subunit was incorporated by
      CK2. [32P]Phosphorylated beta-conglycinin alpha subunit was cleaved either by
      cyanogen bromide or by trypsin. 32P was incorporated into the largest cyanogen
      bromide fragment only (50 kDa, N-terminal) and only two radiolabeled zones were
      detected after HPLC of the trypsic digest. The corresponding phosphorylated zones
      were collected and further analyzed by RP-HPLC coupled to electrospray ionization
      mass spectrometry (LC-ESMS). Two phosphorylated sites, Ser 75 and Ser 117, were
      determined after MS-MS analysis of three phosphopeptides identified as 70-89, 116
      126, and 116-127 sequences. Over the seven consensus sequences of beta
      conglycinin alpha subunit, Ser 75 is the only one which was phosphorylated. Ser
      117 was phosphorylated although it is not an expected phosphorylation site
      according to the canonical consensus sequence criteria as there is no acidic
      determinant at the +3 position. Both Ser 75 and Ser 117 are located inside very
      acidic sequences, by contrast with the other unphosphorylated potential sites.

PMID- 10395451
TI  - Grafting of aliphatic and aromatic probes on bovine serum albumin: influence on
      its structural and physicochemical characteristics.
AB  - Bovine serum albumin was chosen as a model protein to study the effect of the
      functionalization of the epsilon-NH2 of lysine residues with different carbon
      chains on the physical properties of proteins. Thus, BSA has been acylated and
      sulfonylated by means of anhydrides and sulfonyl chlorides, respectively. The
      secondary structures of modified BSA, studied by far-UV CD, showed very slight
      changes except after sulfamidation. However, near-UV CD and intrinsic
      fluorescence spectra revealed important conformational perturbations for proteins
      bearing long carbon chains. Furthermore, the binding of an apolar probe (ANS) to
      BSA revealed an improvement of surface hydrophobicity after modification.
      Meanwhile, Scatchard plot results indicate that only 20% of the hexanoyl carbon
      chains lie at the surface of the proteins. Solvent conditions should influence
      the exposure of these chains and consequently the surface hydrophobicity of
      proteins.

PMID- 10395452
TI  - Sequencing of gel-isolated proteins using microblotter capillary liquid
      chromatography-electrospray mass spectrometry.
AB  - Enzymatic digests of proteins isolated by sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis (SDS-PAGE) were separated by capillary high-performance
      liquid chromatography (HPLC). The column eluate was split to an electrospray mass
      spectrometer on one side and to both a UV detector and a microblotter on the
      other side. Using the microblotter, the peptides eluted from the column were
      collected directly onto a polyvinylidene difluoride (PVDF) membrane for Edman
      sequencing. Thus, a peptide mass map from the mass spectrometric analysis and a
      prepared PVDF membrane for subsequent Edman sequencing were generated in a single
      experiment. The addition of molecular mass information to the blotted LC eluate
      is useful for determining the most important peaks to undergo Edman sequencing.
      Coupling the capillary HPLC with a microblotter to electrospray mass spectrometry
      provides an integrated system for separation, collection, and structural analysis
      of protein digests. It provides high levels of sensitivity, recovery, and
      convenience for protein characterization. Proteins loaded onto SDS-PAGE at low
      picomole levels can be analyzed by the new integrated system.

PMID- 10395453
TI  - Structural investigations on human erythrocyte acylpeptide hydrolase by mass
      spectrometric procedures.
AB  - The complete primary structure of human erythrocyte acylpeptide hydrolase has
      been determined by using a combination of different mass spectrometric procedures
      and sequencing techniques. These data allowed us to correct the incomplete
      nucleotide sequence of the DNF15S2 locus on the short arm of human chromosome 3
      at region 21, coding for the enzyme. The protein consists of 732 amino acid
      residues and is acetylated at the N-terminus. Alkylation experiments on the
      native enzyme demonstrated that all 17 cysteine residues present in the
      polypeptide chain are in reduced form. Multiple sequence alignment did not reveal
      striking similarity with proteases of known tertiary structure with the exception
      of members of the serine oligopeptidase family. Limited proteolysis experiments
      generated a C-terminal portion, containing all the catalytic triad elements
      responsible for proteolytic activity, and an N-terminal domain of unknown
      function, both still strongly associated in a completely active nicked form. The
      site of tryptic hydrolysis was identified as Arg193. The secondary structural
      organization of the protease domain of the enzyme is consistent with the
      alpha/beta hydrolase fold.

PMID- 10395454
TI  - Denaturation versus unfolding: energetic aspects of residual structure in
      denatured alpha-lactalbumin.
AB  - Denaturational changes in alpha-lactalbumin result in different degrees of
      disordering of the protein molecule. The thermally denatured states have been
      studied to elucidate the energetics of residual structure and its contributions
      to the stability of the native conformation. The value of the heat capacity
      increment of alpha-lactalbumin denaturation correlates closely with the amount of
      residual secondary structure in the denatured protein, therefore reflecting the
      degree of its disordering and accessibility to solvent. As a result of the
      observed correlation, the behavior of protein denaturation functions is
      influenced by the degree of disordering of protein conformation in the denatured
      state. Analysis of the calorimetric data shows that the denaturational transition
      of alpha-lactalbumin is described by different thermodynamic functions when it
      proceeds to an ordered compact denatured state and to the disordered unfolded
      state. This difference is related to unfolding of the compact denatured state
      known as a molten globule state, which is populated differently under different
      denaturing conditions. The enthalpy and entropy of the transition from the native
      to the compact denatured state are always higher in magnitude than the enthalpy
      and entropy of the complete unfolding reaction due to the large negative
      hydration effect upon molten globule unfolding. Since the hydration effect
      increases with decreasing temperature, the gap between the partial denaturing and
      complete unfolding thermodynamic parameters also increases, resulting in a large
      difference at physiological temperatures. The results clearly indicate that a
      degree of residual structure in the denatured state must be taken into account to
      yield a more accurate description of protein structural energetics.

PMID- 10395455
TI  - Purification and amino acid sequence of MP-III 4R D49 phospholipase A2 from
      Bothrops pirajai snake venom, a toxin with moderate PLA2 and anticoagulant
      activities and high myotoxic activity.
AB  - MP-III 4R PLA2 was purified from the venom of Bothrops pirajai venom (Bahia's
      jararacussu) after three chromatographic steps which started with RP-HPLC. The
      complete amino acid sequence of MP-III 4R PLA2 from Bothrops pirajai was
      determined by amino acid sequencing of reduced and carboxymethylated MP-III 4R
      and the isolated peptides from clostripain and protease V8 digestion. MP-III 4R
      is a D49 PLA2 with 121 amino acid residues and has a molecular weight estimated
      at 13,800 Da, with 14 half-cysteines. This protein showed moderate PLA2 and
      anticoagulant activity. This PLA2 does not have a high degree of homology with
      other bothropic PLA2-like myotoxins (approximately 75%) and nonbothropic
      myotoxins (approximately 60%). MP-III 4R is a new PLA2, which was isolated using
      exclusively analytical and preparative HPLC methods. Based on the N-terminal
      sequence and biological activities, MP-III 4R was identified as similar to
      piratoxin-III (PrTX-III), which was isolated by conventional chromatography based
      on molecular exclusion ion exchange chromatography. Clinical manifestations
      indicate that at the site of toxin injection, there may be pain of variable
      intensity, because animals continue to lick the limb. No clinical sign indicating
      general toxicity was noticed. Myotoxicity was observed in gastrocnemius muscle
      cells after exposure to MP-III 4R, with a high frequency (70%) of affected muscle
      fibers.

PMID- 10395456
TI  - Site-directed mutagenesis evidence for arginine-384 residue at the active site of
      maize branching enzyme II.
AB  - Essential arginine residues are suggested to be located at the active sites of
      maize branching enzymes (BE) based on the evidence that two arginine residues are
      conserved in all BE from various species and that as little as one arginine
      residue is located at the active site of maize BE by phenylglyoxal (PGO)
      modification. To determine the exact location of the active-site arginine residue
      in BE, we employed peptide mapping and site-directed mutagenesis approaches. A
      single trypsin-digested, [14C]PGO-labeled peptide was purified from maize BEII by
      two rounds of HPLC separation, but we failed to obtain amino acid sequencing
      information. Site-directed mutagenesis was then used to create one mutant
      (arginine-384 to alanine-384), R384A. Immunoblotting result showed that BEII
      protein was expressed at a similar level in the wild type and the R384A mutant.
      However, BE activity in the R384A mutant was only 1.4% of the wild type. These
      results support the conclusion that the conserved arginine-384 residue is
      important in BEII catalysis.

PMID- 10395458
TI  - Detection of siderophore production from several fungi and bacteria by a
      modification of chrome azurol S (CAS) agar plate assay.
AB  - A well-known and widely used method for detection of siderophore production by
      microorganisms in solid medium is the universal chrome azurol S (CAS)-agar plate
      assay. However, the high toxicity of CAS-blue agar medium caused by the presence
      of a detergent impedes its utilization with many varieties of fungi and Gram
      positive bacteria. To solve this problem, a modification of the CAS-agar plate
      assay was made by incorporating the CAS-blue dye in a medium with no contact with
      the microorganisms tested. Half of each plate used in our experiments was filled
      with the most appropriate culture medium for each type of microorganism and the
      other half with CAS-blue agar. This modification allowed us to study several
      strains of fungi (basidiomycetes, deuteromycetes, ascomycetes and zygomycetes)
      and bacteria (Gram positive and negative), some of them appearing for the first
      time in the literature. All the microorganisms grew properly and reacted in
      different manners to the CAS assay. Some strains of wood-decaying basidiomycetes
      (mainly white-rot fungi) and Aspergillus species produced the fastest color
      change reactions in the CAS-blue agar. This modified method could facilitate
      optimization of culture conditions, since both CAS-blue agar and growth medium
      were prepared and added in the Petri plate separately.

PMID- 10395457
TI  - Nucleotide and Mg2+ induced conformational changes in GroEL can be detected by
      sulfhydryl labeling.
AB  - The accessibility of fluorescein-5-maleimide to sulfhydryl groups in the
      molecular chaperone GroEL was used to follow structural rearrangements in the
      protein triggered by binding Mg2+ and/or adenine nucleotides. Three peptides,
      each containing one of the cysteines of GroEL (C138, C458 and C519) were
      identified. GroEL labeled in 50 mM TrisHCl, pH 7.8, incorporated approximately
      0.3 labels each on C138 and C458. With 10 mM MgCl2, the labeling increased to
      approximately 0.8 labels each on C138 and C458. The increase was partially due to
      a conformational change which occurred upon Mg2+ binding as well as to an
      increase in ionic strength. When ADP, ATP, or AMP-PNP were added to a solution of
      GroEL and Mg2+, C138 incorporated approximately 0.8 labels, while C458
      incorporated approximately 0.1 labels. These results suggest that the binding of
      adenine nucleotides changed the conformation of GroEL and made a previously
      highly exposed sulfhydryl group inaccessible. GroEL slowly dissociated into
      monomers when it was extensively labeled at C458. GroEL labeled with fluorescein
      5-maleimide, under any of the conditions examined, was able to bind but not
      release active rhodanese. The observed variations in sulfhydryl accessibility are
      consistent with mechanisms that suggest binding of GroES to GroEL differs from
      the binding of substrate protein to GroEL, and that the binding of Mg2+ or Mg
      adenine nucleotides results in conformational changes in GroEL.

PMID- 10395459
TI  - Use of fluorescent amplified fragment length polymorphism (fAELP) to characterise
      methicillin-resistant Staphylococcus aureus.
AB  - The new PCR-based genotyping technique, fluorescent amplified fragment length
      polymorphism (fAFLP), was compared for discriminatory power and reproducibility
      with standard phenotypic methods, a coagulase gene (coa) restriction fragment
      length polymorphism (RFLP) method and pulsed-field gel electrophoresis (PFGE), in
      typing 34 isolates and four reference strains of methicillin-resistant
      Staphylococcus aureus (MRSA). The fAFLP showed from 40 to 75 fragments, 50 to 450
      base pairs (bp) in size. Based on replicate studies, the isolates were judged
      indistinguishable when their fAFLP pattern was >93.7% similar. Only two of the
      isolates were indistinguishable by this criterion. Thirty-one MRSA fell into four
      major fAFLP groups (1, 2, 3 and 4) at the level of >79.9% similarity. Three other
      isolates and an EMRSA-16 strain fell outside these major groups. Within both
      fAFLP groups 1 and 2, two subgroups, A and B, could be identified at
      approximately 82.0% similarity. While most isolates within group 1 could also be
      separated by their phenotypic and coagulase gene (coa) RFLP pattern, all the
      isolates within fAFLP groups 2A and 2B were identical on the basis of these
      characters. The MRSA within fAFLP groups 3 and 4 were heterogeneous by their
      phenotypic characteristics and coa gene RFLP patterns. fAFLP was reproducible and
      distinguished between MRSA isolates that appeared identical by other methods. It
      is likely to contribute to the epidemiological analysis of outbreaks of MRSA
      infection.

PMID- 10395460
TI  - Quantification of bacterial lead resistance via activity assays.
AB  - The level of microbial resistance to heavy metals is an important issue for the
      microbial ecology of heavy metal-contaminated habitats. However, assays based
      upon growth in nutrient media will overestimate the resistance level due to metal
      ion interactions with inorganic and organic components. The analysis of Pb
      resistant bacteria isolated from soils containing up to 38 mmol total Pb x kg(-1)
      indicated that PYT80B medium which did not contain inorganic salts, contained low
      amounts of organic matter, and was buffered with a molecule that did not interact
      with metal ions (2-N-morpholinoethanesulfonic acid (MES)) provided the lowest
      estimates of lead resistance. However, better results were obtained by assaying
      metabolic activity (aerobic respiration) of resting cells suspended in 10 mM MES.
      By this criterion, 50% inhibition of Arthrobacter JS7 was found at 37 microM
      Pb(NO3)2. The effects of Pb+2 concentrations upon respiration of resting cells
      and growth rate in PYT80B medium were similar. The activity assay also showed
      that metal resistance was induced to higher levels when Arthrobacter JS7 was
      grown in the presence of Pb.

PMID- 10395461
TI  - A simple extraction procedure for efficient routine detection of pathogenic
      bacteria in plant material by polymerase chain reaction.
AB  - A simple and rapid method for extracting DNA from plants based on the use of an
      extraction buffer and precipitation with isopropanol was assayed to see its
      usefulness in detecting pathogenic bacteria in plant material. The method was
      compared with a phenol-chloroform standard procedure obtaining higher sensitivity
      levels of detection. The protocol developed was efficient for detecting a Gram
      positive bacterium, Clavibacter michiganensis subsp. sepedonicus and several Gram
      negative pathogenic bacteria (Ralstonia solanacearum, Erwinia amylovora,
      Xanthomonas axonopodis pv. citri) with a sensitivity of 10(2)-10(3) cfu/ml in
      spiked samples. It was also efficient to specifically identify such bacteria in
      naturally infected plant material. This procedure is proposed as a routine tool
      for detection of plant pathogenic bacteria, as well as in environmental
      microbiology and biotechnology studies.

PMID- 10395462
TI  - Criteria for evaluation of proposed protozoan detection methods.
AB  - There has been a proliferation of techniques and methods reported for analysis of
      water samples to determine the presence of the protozoan pathogens
      Cryptosporidium parvum and Giardia lamblia. Many of the proposed methods are
      presented as complete procedures, which include sampling, processing, staining,
      or detection steps while other methods are not complete. Some proposed methods
      have been extensively tested in multi-laboratory settings, however, others are
      still in the developmental stage. A set of evaluation criteria has been developed
      to evaluate the many proposed methods. These criteria have been applied as an
      example, to an existing method. These criteria should be useful to individuals
      attempting to evaluate methods developed for detecting protozoa in water, and
      conversely, they should serve as a guideline for individuals interested in
      developing methods, allowing them to gather data with and about their methods,
      and present this data in a manner that is both logical and easily evaluated.

PMID- 10395463
TI  - Hypothetical model for monitoring microbial growth by using capacitance
      measurements--a minireview.
AB  - Microbiological impedance devices are used routinely by food and manufacturing
      industries, and public health agencies to measure microbial growth and
      metabolism. In this paper a hypothetical model explaining the effects of
      microbial growth and metabolism on capacitance at electrode-medium interfaces,
      that can be supported by fundamental theories and principles of electrochemistry,
      is presented. This model provides a framework to interpret changes in capacitance
      during microbial growth and metabolism and can be used to generate and test
      hypotheses on factors (i.e., temperature, microbial cell density, microbial
      growth and medium conductivity) contributing to increases or decreases in
      capacitance.

PMID- 10395464
TI  - Factors influencing capacitance-based monitoring of microbial growth.
AB  - Microbiological impedance devices are routinely used by food and manufacturing
      industries, and public health agencies to measure microbiological growth. Factors
      contributing to increases and decreases in capacitance at the culture medium
      electrode interface are poorly understood. To objectively evaluate the effects of
      temperature, cell density and medium conductivity on capacitance, admittance
      values from an impedance device were standardized; capacitance was converted to
      susceptance to allow unit comparisons with conductance. Although increases in
      temperature increased susceptance, a linear relationship could not be established
      between the change of susceptance with temperature and conductance of the medium.
      Cell density by itself had no measureable effect on susceptance or conductance,
      indicating that cells did not impede the movement of ions in the medium or around
      the electrode. In a low conductivity medium, increases in conductance by the
      addition of ions resulted in a concomitant increase of susceptance values.
      However, in a high conductivity medium, increases in conductance resulted in
      little or no increase of susceptance values because ions saturated the electrode
      surface. Susceptance increased when Escherichia coli, Pseudomonas aeruginosa,
      Alcaligenes faecalis and Staphylococcus aureus were grown in high conductivity
      media because protons produced by metabolically active bacteria balance more
      charge on the electrode than other ions. Increases in susceptance due to
      bacterial growth and metabolism in low conductivity media were attributed to both
      increases in protons and ionic metabolites. These results indicate that
      capacitance may provide a better measure of microbial growth and metabolism than
      conductance.

PMID- 10395465
TI  - NH4+ utilization and regeneration rates in freshwater lakes determined by GC-MS
      of derivatised dihydroindophenol.
AB  - A new gas chromatographic-mass spectrometric method was established that is
      applicable for the determination of NH4+ utilization and regeneration rates in
      freshwater. Hollow-fibre modules were used to stop the biogenic nitrogen-fluxes
      by separating the particulate from the dissolved matter. Incubations were
      performed in Tedlar bags (polyvinylfluoride), which enabled repeated sample
      removals through Teflon tubes, making the calculation of nitrogen-fluxes in
      accordance to Blackburn and Caperon much more reliable. The Berthelot reaction
      was performed with ammonium and a fragment ion (base peak) of tris
      (trifluoroacetyl) 4,4'-dihydroxydiphenylamine was used to determine the at%
      excess 15N by gas chromatography-mass spectrometry. Nitrogen-flux measurements
      were made in the epilimnion of the deep, stratified, mesotrophic Lake Zurich, in
      which the cyanobacterium Planktothrix rubescens was the dominating
      photoautotrophic micro-organism. The size fraction <20 microm that consisted of
      heterotrophic bacterioplankton and nanoflagellates, and photoautotrophic pico-
      and nanoplankton accounted only for a minor part of the ammonium utilization
      (<25%) and regeneration (< or =25%) rates, whereas the size fraction >20 microm
      which primarily consisted of Planktothrix rubescens was responsible for the major
      part. In the eutrophic Lake Au, which is connected to Lake Zurich through a
      canal, utilization and regeneration rates as high as 700 and 482 nM h(-1) were
      measured.

PMID- 10395466
TI  - LIVE/DEAD BacLight : application of a new rapid staining method for direct
      enumeration of viable and total bacteria in drinking water.
AB  - A rapid epifluorescence staining method using the LIVE/DEAD Bacterial Viability
      Kit (BacLight) was applied to estimate both viable and total counts of bacteria
      in drinking water. BacLight is composed of two nucleic acid-binding stains: SYTO
      9 and propidium iodide. SYTO 9 penetrates all bacterial membranes and stains the
      cells green, while propidium iodide only penetrates cells with damaged membranes,
      and the combination of the two stains produces red fluorescing cells. Optimal
      incubation conditions were found to be 15 to 20 min, at room temperature in the
      dark. Total (red + green) and viable (green) cells can hence be counted
      simultaneously. Factors affecting the staining procedure were tested (addition of
      glutaraldehyde, staining time, chlorine impact). In the absence of stress,
      BacLight viable counts were comparable and to 5-cyano-2,3-ditolyl tetrazolium
      (CTC) counts. BacLight total counts were comparable to acridine orange counts
      (differing by <0.1 log/ml). However, the increase in environmental stresses
      (chlorine, growth rate or temperature) induced a decrease in viability that was
      more pronounced for CTC and plate counts than for BacLight viable counts.

PMID- 10395467
TI  - Automated detection of Salmonella spp. in foods.
AB  - An automated method to detect salmonellae in foods was developed and tested in
      food samples intentionally contaminated with the test organisms. Liquid eggs,
      shell eggs, dry eggs, skim milk and chicken were spiked with Salmonella
      enteritidis, S. typhimurium or S. newport to yield 2 to 25 CFU per 25 g or ml of
      sample. Following pre-enrichment in universal pre-enrichment broth at 42 degrees
      C for 6 h (eggs and milk) or 16 h (chicken), Salmonella cells were captured by
      immunomagnetic beads coated with Salmonella antibody (Vicam, Watertown, MA). The
      beads were transferred to selective liquid media containing carbohydrate
      (dulcitol or xylose), amino acid (lysine or ornithine), and H2S indicator, and
      incubated at 42 degrees C in the BioSys instrument (MicroSys, Ann Arbor, MI).
      Salmonella positive samples were identified by black discoloration of the media
      during incubation, while negative samples remained colorless. These color changes
      were recorded by the instrument. All the artificially contaminated samples tested
      positive within 15-18 h, while control samples remained negative during 24 h
      incubation. The results agreed with standard identification procedures. A total
      of 24 h was required to detect 2 to 25 CFU of the pathogen in 25 g or ml of eggs
      and milk, and up to 36 h in chicken, compared to 72 h in the standard methods.

PMID- 10395468
TI  - Identification of phosphate-regulated genes by differential expression in the UV
      irradiated host system.
AB  - The UV-irradiated host system has been used for identifying protein products of
      genes cloned in a phage vector. By starving the host cells for phosphate
      immediately before UV-irradiation, we demonstrate that phosphate-regulated genes
      can be easily identified. By employing this new technique, we also provide
      evidence showing that the gpsA gene might be a new member of the phosphate
      starvation-inducible (psi) genes of E. coli.

PMID- 10395469
TI  - A rapid and efficient method for growth measurement of filamentous fungi.
AB  - Growth of filamentous fungi may be measured very efficiently using 96 well
      microtiter plates and a microplate reader. The relationship between Absorbance
      reading at 630 nm and dry weight is linear. This relationship seems to be similar
      for different fungi with a slope of about 4.2 mg/ml dry weight per Absorbance
      unit. The 8 wells in each column were used as parallels.

PMID- 10395470
TI  - Therapeutic potential and strategies for inhibiting tumor necrosis factor-alpha.

PMID- 10395471
TI  - High-throughput nuclear magnetic resonance-based screening.
AB  - A high-throughput screening strategy is described that involves the acquisition
      of two-dimensional 15N/1H correlation spectra in less than 10 min on 50 microM
      protein samples using cryogenic NMR probe technology. By screening at these
      concentrations, small organic molecules can be tested in mixtures of 100, which
      dramatically increases the throughput of the NMR-based assay. Using this
      strategy, libraries of more than 200 000 compounds can be tested in less than 1
      month. There are many advantages of high-throughput NMR-based screening compared
      to conventional assays, such as the ability to identify high-affinity ligands for
      protein targets with no known function. This suggests that the method will be
      extremely useful for screening the large number of targets derived from genomics
      research.

PMID- 10395472
TI  - Nonapeptide analogues containing (R)-3-hydroxybutanoate and beta-homoalanine
      oligomers: synthesis and binding affinity to a class I major histocompatibility
      complex protein.
AB  - Crystal structures of antigenic peptides bound to class I MHC proteins suggest
      that chemical modifications of the central part of the bound peptide should not
      alter binding affinity to the MHC restriction protein but could perturb the T
      cell response to the parent epitope. In our effort in designing nonpeptidic high
      affinity ligands for class I MHC proteins, oligomers of (R)-3-hydroxybutanoate
      and(or) beta-homoalanine have been substituted for the central part of a HLA-B27
      restricted T-cell epitope of viral origin. The affinity of six modified peptides
      to the B2705 allele was determined by an in vitro stabilization assay. Four out
      of the six designed analogues presented an affinity similar to that of the parent
      peptide. Two compounds, sharing the same stereochemistry (R,R,S,S) at the four
      stereogenic centers of the nonpeptidic spacer, bound to B2705 with a 5-6-fold
      decreased affinity. Although the chiral spacers do not strongly interact with the
      protein active site, there are configurations which are not accepted by the MHC
      binding groove, probably because of improper orientation of some lateral
      substituents in the bound state and different conformational behavior in the free
      state. However we demonstrate that beta-amino acids can be incorporated in the
      sequence of viral T-cell epitopes without impairing MHC binding. The presented
      structure-activity relationships open the door to the rational design of peptide
      based vaccines and of nonnatural T-cell receptor antagonists aimed at blocking
      peptide-specific T-cell responses in MHC-associated autoimmune diseases.

PMID- 10395473
TI  - Potent inhibition of influenza sialidase by a benzoic acid containing a 2
      pyrrolidinone substituent.
AB  - On the basis of the lead compound 4-(N-acetylamino)-3-guanidinobenzoic acid (BANA
      113), which inhibits influenza A sialidase with a Ki of 2.5 microM, several novel
      aromatic inhibitors of influenza sialidases were designed. In this study the N
      acetyl group of BANA 113 was replaced with a 2-pyrrolidinone ring, which was
      designed in part to offer opportunities for introduction of spatially directed
      side chains that could potentially interact with the 4-, 5-, and/or 6-subsites of
      sialidase. While the parent structure 1-(4-carboxy-2-guanidinophenyl)pyrrolidin-2
      one (8) was only a modest inhibitor of sialidase, the introduction of a
      hydroxymethyl or bis(hydroxymethyl) substituent at the C5' position of the 2
      pyrrolidinone ring resulted in inhibitors (9 and 12, respectively) with low
      micromolar activity. Crystal structures of these inhibitors in complex with
      sialidase demonstrated that the substituents at the 5'-position of the 2
      pyrrolidinone ring interact in the 4- and/or 5-subsites of the enzyme.
      Replacement of the guanidine in 12 with a hydrophobic 3-pentylamino group
      resulted in a large enhancement in binding to produce an inhibitor (14) with an
      IC50 of about 50 nM against influenza A sialidase, although the inhibition of
      influenza B sialidase was 2000-fold less. This represents the first reported
      example of a simple, achiral benzoic acid with potent (low nanomolar) activity as
      an inhibitor of influenza sialidase.

PMID- 10395474
TI  - Molecular modeling and synthesis of inhibitors of herpes simplex virus type 1
      uracil-DNA glycosylase.
AB  - We recently reported the properties of the first selective inhibitors of herpes
      simplex virus type 1 (HSV1) uracil-DNA glycosylase (UDG), an enzyme of DNA repair
      that has been proposed to be required for reactivation of the virus from latency.
      6-(4-Octylanilino)uracil (octAU) was the most potent inhibitor among a series of
      6-(4-alkylanilino)uracils, acting in the micromolar range and without effect
      against human UDG. A 28.5-kDa catalytic fragment of HSV1 UDG has been
      crystallized in the presence of uracil, and the structure was recently solved. We
      have used the coordinates of this structure in order to study interaction of our
      inhibitors with the enzyme, and a model of binding between octAU and UDG has been
      derived. Starting with the optimized model, the activity of several octAU
      analogues was predicted, and the values compared favorably with experimental
      results found for the synthetic compounds. Several hydrophilic derivatives were
      predicted and found to be active as UDG inhibitors. These compounds will be
      useful to determine if UDG, like the viral thymidine kinase, is required for
      reactivation of HSV1 from latency in nerve cells.

PMID- 10395475
TI  - Pharmacophore development for corticotropin-releasing hormone: new insights into
      inhibitor activity.
AB  - Corticotropin-releasing hormone (CRH) is an endogenous 41-amino acid peptide
      involved in a wide ranging series of systems including the brain, the
      coordination of the body's overall response to stress, and more recently as a
      crucial initiator in the onset of labor, also known as the placental clock.
      Although more physiological data on CRH is emerging shedding more light on the
      processes involved and their integration, the mode of action of the hormone and
      the postulated binding site(s) remain unknown. Recently, a number of small
      molecular-weight ligands have emerged as potent antagonists but, as therapeutics,
      suffer from a lack of solubility. Additionally, despite a number of exhaustively
      large patents, the lack of structural diversity with these antagonists has
      enabled little scope for comprehensive and wide ranging studies into the
      structure of the binding sites of this hormone. As part of a program
      investigating new, structurally diverse antagonists and agonists of CRH, we have
      developed a preliminary pharmacophore based on the known small-molecular-weight
      ligands as an initial step in our program. This pharmacophore was validated by
      comparison with some of the compounds we postulated to be active.

PMID- 10395476
TI  - Structure-based design, synthesis, and X-ray crystallography of a high-affinity
      antagonist of the Grb2-SH2 domain containing an asparagine mimetic.
AB  - Previous efforts in the search for molecules capable of blocking the associations
      between the activated tyrosine kinase growth factor receptors and the SH2 domain
      of Grb2 had resulted in the identification of 3-amino-Z-pTyr-Ac6c-Asn-NH2, a high
      affinity and selective antagonist of this SH2 domain. In the present paper, we
      report the successful replacement of asparagine in this compound by a beta-amino
      acid mimetic, which brings us closer to our objective of identifying a Grb2-SH2
      antagonist suitable for pharmacological investigations.

PMID- 10395477
TI  - Solution structure of alpha-conotoxin ImI by 1H nuclear magnetic resonance.
AB  - alpha-Conotoxin ImI derives from the venom of Conus imperialis and is the first
      and only small-peptide ligand that selectively binds to the neuronal alpha7
      homopentameric subtype of the nicotinic acetylcholine receptor (nAChR). This
      receptor subtype is a possible drug target for several neurological disorders.
      The cysteines are connected in the pairs Cys2-Cys8 and Cys3-Cys12. To date it is
      the only alpha-conotoxin with a 4/3 residue spacing between the cysteines. The
      structure of ImI has been determined by 1H NMR spectroscopy in aqueous solution.
      The NMR structure is of high quality, with a backbone pairwise rmsd of 0.34 A for
      a family of 19 structures, and comprises primarily a series of nested beta turns.
      Addition of organic solvent does not perturb the solution structure. The first
      eight residues of ImI are identical to the larger, but related, conotoxin EpI and
      adopt a similar structure, despite a truncated second loop. Residues important
      for binding of ImI to the alpha7 nAChR are all clustered on one face of the
      molecule. Once further binding data for EpI and ImI are available, the ImI
      structure will allow for design of novel alpha7 nAChR-specific agonists and
      antagonists with a wide range of potential pharmaceutical applications.

PMID- 10395478
TI  - Structure-activity relationships for 5-substituted 1-phenylbenzimidazoles as
      selective inhibitors of the platelet-derived growth factor receptor.
AB  - Following an earlier discovery of 1-phenylbenzimidazoles as ATP-site inhibitors
      of the platelet-derived growth factor receptor (PDGFR), further structure
      activity relationships for analogues (particularly 5-substituted derivatives) are
      reported. The data are consistent with a binding model (constructed from the
      homology-modeled structure of the catalytic subunit of the PDGFR using protein
      kinase A as the template) in which the ligand binds in the relatively narrow ATP
      site, with the phenyl ring pointing toward the interior of the pocket and the 5
      position of the benzimidazole ring toward the mouth of the pocket. The narrow
      binding pocket allows a maximum torsion angle between the phenyl and
      benzimidazole rings of about 40 degrees, consistent with that calculated (43.6
      degrees) for the minimum-energy conformation of the unsubstituted free ligand.
      The inactivity of 7- or 2'-substituted analogues is consistent with the greater
      torsion angle (and thus larger ligand cross-section) of such substituted
      analogues. There is substantial bulk tolerance for 5-substituents, which protrude
      out of the mouth of the hydrophobic pocket, with the most effective analogues
      being those bearing weak bases. On the basis of this model, 5-OR derivatives
      bearing cationic side chains were prepared as soluble analogues, and these showed
      sub-micromolar potencies against the isolated PDGFR enzyme. They were also
      moderately effective inhibitors of autophosphorylation of PDGFR in rat aortic
      vascular smooth muscle cells, with IC50s in the range 0.1-1 microM.

PMID- 10395479
TI  - Structure-activity relationships for substituted bis(acridine-4-carboxamides): a
      new class of anticancer agents.
AB  - A series of acridine-substituted bis(acridine-4-carboxamides) linked by a
      (CH2)3N(Me)(CH2)3 chain have been prepared by reaction of the isolated
      imidazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3
      aminopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II
      inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), currently in
      clinical trial, show superior potencies to the corresponding monomeric DACA
      analogues in a panel of cell lines, including wild-type (JLC) and mutant (JLA and
      JLD) forms of human Jurkat leukemia. The latter mutant lines are resistant to
      topoisomerase II targeted agents because of lower levels of the enzyme. Analogues
      with small substituents (e.g., Me, Cl) at the acridine 5-position were clearly
      superior, with IC50's as low as 2 nM against the Lewis lung carcinoma and 11 nM
      against JLC. Larger substituents at any position caused a steady decrease in
      potency, likely due to lowering of DNA binding affinity. A small series of
      analogues of the most potent bis(5-methylDACA) compound, with second substituents
      (Me and Cl) in the 1- or 8- position had broadly similar potencies to the 5-Me
      compound, indicating that, while the 1- and 8-substituents are acceptable, they
      add little to the enhancing effect of the 5-methyl group. All of the compounds
      were at least equitoxic (some up to 4-fold more cytotoxic) against the mutant
      Jurkat lines than in the wild-type, consistent with a relatively greater effect
      on topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) compound
      was found to inhibit the action of purified topoisomerase I in a cell-free assay.
      Compounds were on average 10-fold less cytotoxic in an MCF7 breast cancer line
      overexpressing P-glycoprotein than in the wild-type line and showed some
      selectivity for colon tumor lines in the NCI human tumor cell line panel. Several
      analogues produced significant growth delays in the relatively refractory
      subcutaneous colon 38 tumor model in vivo at substantially lower doses than DACA.
      The bis(acridine-4-carboxamides) represent a new and interesting class of potent
      topoisomerase inhibitors.

PMID- 10395480
TI  - Apstatin analogue inhibitors of aminopeptidase P, a bradykinin-degrading enzyme.
AB  - Membrane-bound aminopeptidase P (AP-P) participates in the degradation of
      bradykinin in several vascular beds. We have developed an inhibitor of AP-P
      called apstatin (1) (N-[(2S, 3R)-3-amino-2-hydroxy-4-phenyl-butanoyl]-L-prolyl-L
      prolyl-L-al aninam ide); IC50,human = 2.9 microM. In the rat, apstatin can
      potentiate the vasodilatory effect of bradykinin, reduce blood pressure in an
      aortic-coarctation model of hypertension, and reduce cardiac damage and
      arrhythmias induced by ischemia/reperfusion. In this study, we have determined
      structure-activity relationships for apstatin analogues as well as for other
      chemical classes of inhibitors using AP-P isozymes from different sources. The
      most potent inhibitor was one in which the N-terminal residue of apstatin was
      replaced with a (2S,3R)-3-amino-2-hydroxy-5-methyl-hexanoyl residue (6,
      IC50,human = 0.23 microM). The (2R,3S)-analogue of 6 was equipotent with 6 while
      the (2S,3S)- and (2R,3R)-analogues were considerably less potent. Apstatin
      analogues lacking the L-alanine or having hydroxyproline in place of the proline
      in the second position had reduced affinity. Certain thiol-, carboxylalkyl-, and
      hydroxamate-containing compounds were inhibitory in the low micromolar range.
      Human cytosolic AP-P isozymes and Escherichia coli AP-P exhibited different
      inhibitor profiles than mammalian membrane-bound AP-P isozymes. The effects of
      the compounds on X-Pro dipeptidase (prolidase) and leucyl aminopeptidase are also
      presented.

PMID- 10395481
TI  - gamma-Aminobutyrate-A receptor modulation by 3-aryl-1-(arylsulfonyl)- 1,4,5,6
      tetrahydropyridazines.
AB  - A series of 3-aryl-1-(arylsulfonyl)-1,4,5,6-tetrahydropyridazine allosteric
      modulators of the GABAA receptor was synthesized, and biological activity was
      examined in vitro and in vivo. Beginning with 1a, stepwise modification of the
      substituents and conservation of the scaffold yielded a chemical series in which
      the modulatory activity was enhanced by the presence of GABA. The SAR suggests,
      but does not establish, that the compounds bind to the steroid binding site on
      the GABAA receptor. The GABA shift for each compound indicates that all compounds
      in this series are either agonists or partial agonists.

PMID- 10395482
TI  - Non-peptide GPIIb/IIIa inhibitors. 20. Centrally constrained thienothiophene
      alpha-sulfonamides are potent, long acting in vivo inhibitors of platelet
      aggregation.
AB  - The synthesis and pharmacology of 4, a potent thienothiophene non-peptide
      fibrinogen receptor antagonist, are reported. Compound 4 inhibited the
      aggregation of human gel-filtered platelets with an IC50 of 8 nM and demonstrated
      an 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over
      analogues possessing an isoindolinone backbone. Flow cytometry studies revealed
      that the binding of 4 to resting platelets is a diffusion-controlled process (kon
      = 3.3 x 10(6) M-1 s-1) and that 4 binds to dog and human platelets with
      comparable affinity (Kd = 0.04 and 0.07 nM, respectively). Ex vivo platelet
      aggregation in dogs was completely inhibited by an iv dose of 5 microg/kg
      [corrected], and an oral dose of 50-90 microg/kg [corrected] followed by low
      daily doses of 10 microg/kg [corrected] was sufficient to maintain approximately
      80% inhibition of ex vivo platelet aggregation over several days. Inhibition of
      ADP-induced platelet aggregation in anesthetized dogs at 77 +/- 7% resulted in a
      moderate 2.5-fold increase in bleeding time, while complete inhibition (100%)
      resulted in an approximately 10-min bleeding time. Additional doses were required
      to increase the bleeding time to the maximum time allowed in the protocol (15
      min), thus indicating a potentially useful and safe separation of efficacy and
      bleeding time.

PMID- 10395483
TI  - Structure-activity relationships for a class of inhibitors of purine nucleoside
      phosphorylase.
AB  - Values of inhibition constants, Ki, for a family of structurally related,
      competitive inhibitors of calf spleen purine nucleoside phosphorylase (PNP) have
      been determined employing both inosine as substrate and a manual assay and 2
      amino-6-mercapto-7-methylpurine ribonucleoside (MESG) as substrate and a robot
      based enzyme kinetics facility. Several of the values determined robotically were
      confirmed employing the same substrate and a manual assay. Surprisingly, for many
      of the inhibitors examined, values of Ki determined with MESG as substrate are
      smaller than those obtained employing inosine as substrate by a factor that
      varies from less than 2 to 10. Values of concentrations required for 50%
      inhibition of PNP, IC50, have also been determined for the same family of
      inhibitors employing inosine as substrate. Values of IC50ino and those for Kiino
      and Kimesg for subsets of the inhibitors have been employed as training sets to
      create quantitative structure-activity relationships (QSAR) which have
      substantial power to predict values of IC50 and Ki for inhibitors outside the
      training set. These QSAR models should be useful in guiding future medicinal
      chemistry efforts designed to discover inhibitors of PNP having increased
      potency.

PMID- 10395484
TI  - Effects of C-4 stereochemistry and C-4' hydroxylation on the iron clearing
      efficiency and toxicity of desferrithiocin analogues.
AB  - Additional structure-activity studies of desferrithiocin analogues are carried
      out. The effects of stereochemistry at C-4 on the ligands' iron clearing
      efficiency are reviewed and assessed using the enantiomers 4,5-dihydro-2-(2, 4
      dihydroxyphenyl)thiazole-4(R)-carboxylic acid and 4,5-dihydro-2-(2, 4
      dihydroxyphenyl)thiazole-4(S)-carboxylic acid. The utility of 4'-hydroxylation as
      a method of reducing the toxicity of desazadesferrithiocin analogues is also
      examined further with the synthesis and in vivo comparison of 4, 5-dihydro-2-(2
      hydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, which is the natural
      product 4-methylaeruginoic acid, and 4, 5-dihydro-2-(2,4-dihydroxyphenyl)-4
      methylthiazole-4(S)-carboxylic acid. The stereochemistry at C-4 is shown to have
      a substantial effect on the iron clearing efficiency of desferrithiocin
      analogues, as does C-4'-hydroxylation on the toxicity profile. All of the
      compounds are evaluated in a bile-duct-cannulated rodent model to determine iron
      clearance efficiency and are carried forward to the iron-overloaded primate for
      iron clearing measurements. On the basis of the results of the present work,
      although 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid is
      still the most promising candidate for clinical evaluation, 4,5-dihydro-2-(2, 4
      dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid (4'
      hydroxydesazadesferrithiocin) also merits further preclinical assessment.

PMID- 10395485
TI  - Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di
      , and -trisubstituted aniline-4'-O-demethyl-podophyllotoxin and related compounds
      with improved pharmacological profiles.
AB  - As a continuation of our structure-activity relationship studies, several new 4
      beta-substituted 4'-O-demethyl-4-desoxypodophyllotoxins bearing mono-, di-, or
      trisubstituted anilines have been synthesized and evaluated as inhibitors of DNA
      topoisomerase II and tumor cell growth in tissue culture. Selected compounds were
      further evaluated as cytotoxic agents using a clonogenic survival assay. The
      target compounds include 4'-O-demethyl-4beta-[(4' '-(benzimidazol-2' '
      yl)anilino]-4-desoxypodophyllotoxin (21), 4'-O-demethyl-4beta-(-)-(4' '
      camphanamido-anilino)-4-desoxypodophyllotoxin (25), 4-beta-disubstituted-anilino
      4'-demethyl-4-desoxypodophyllotoxins (18-20, 26), 4-alpha-disubstituted-anilino
      4'-demethyl-4-desoxypodophyllotoxin (27), 4-beta-trisubstituted-anilino-4'
      demethyl-desoxypodophyllotoxin (22, 23), and 4'-O-demethyl-4beta-[4' '
      (benzimidazol-2' '-yl)amino]-4-desoxypodophyllotoxin (24). Among the target
      series, 19, 21, and 24 displayed significant growth inhibitory action against a
      panel of tumor cell lines including human epidermoid carcinoma of the nasopharynx
      (KB) and its etoposide-resistant (KB7B) and vincristine-resistant (vin20c KB)
      subclones, lung carcinoma (A549), human ileocecal carcinoma (HCT-8), human kidney
      carcinoma (CAKI-1), breast adenocarcinoma (MCF-7), and human malignant melanoma
      (SK-MEL-2) cells. Compounds 19, 21, 24, and 25 were "cleavable-complex"-forming
      DNA topoisomerase II inhibitors with either improved or similar activity compared
      with the prototype drug etoposide (VP-16). Compound 21 was the most active
      analogue, being 10-fold more potent than etoposide in both cell killing and
      topoisomerase II inhibition in vitro assays. Using mouse models of antitumor
      activity, 21 was effective against (P388/0) leukemia but not against the growth
      of a (MCF7) mammary tumor.

PMID- 10395486
TI  - Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase inhibitors and
      antitumor agents: synthesis and biological activities of 2,4-diamino-5-methyl-6
      [(monosubstituted anilino)methyl] pyrido[2,3-d]pyrimidines.
AB  - Thirteen 2,4-diamino-5-methyl-6-[(monosubstituted anilino)methyl]pyrido[2,3
      d]pyrimidines 5-17 were synthesized as potential Pneumocystis carinii (pc) and
      Toxoplasma gondii (tg) dihydrofolate reductase (DHFR) inhibitors and as antitumor
      agents. Compounds 5-17 were designed to investigate the structure-activity
      relationship of monomethoxy and monohalide substitution in the phenyl ring and
      N10-methylation of the C9-N10 bridge. The synthetic route to compounds 5-12
      involved the reductive amination of a common intermediate, 2,4-diamino-5
      methylpyrido[2, 3-d]pyrimidine-6-carbonitrile (18), with the appropriate
      anilines. N10-Methylation was achieved by reductive methylation. In contrast to
      previous reports of trimethoprim, the removal of methoxy and chloro groups from
      the phenyl ring in the 2, 4-diamino-5-methyl-6-[(substituted
      anilino)methyl]pyrido[2, 3-d]pyrimidine series generally did not decrease DHFR
      inhibitory activity. The monosubstituted phenyl analogues 5-12 were as potent
      against pcDHFR and tgDHFR as the previously reported disubstituted phenyl
      analogues. N10-Methylation generally resulted in a marginal increase in potency
      against both pcDHFR and tgDHFR. Compounds 5, 7, and 9 were evaluated and shown to
      inhibit the growth of T. gondii cells in culture at nanomolar concentrations.
      Compounds 6-8, 9, 11, and 16 were selected by the National Cancer Institute for
      evaluation in an in vitro preclinical antitumor screening program. All six
      compounds showed GI50 values in the 10(-7)-10(-9) M range in more than 20 cell
      lines.

PMID- 10395487
TI  - Estrogen receptor subtype-selective ligands: asymmetric synthesis and biological
      evaluation of cis- and trans-5,11-dialkyl- 5,6,11, 12-tetrahydrochrysenes.
AB  - We have recently reported that racemic 5,11-cis-diethyl-5,6,11, 12
      tetrahydrochrysene-2,8-diol (THC, rac-2b) acts as an agonist on estrogen receptor
      alpha (ERalpha) and as a complete antagonist on estrogen receptor beta (ERbeta)
      (Sun et al. Endocrinology 1999, 140, 800-804). To further investigate this novel
      ER subtype-selective estrogenic activity, we have synthesized a series of cis-
      and trans-dialkyl THCs. cis-Dimethyl, -diethyl, and -dipropyl THCs 2a-c were
      prepared in a highly enantio- and diastereoselective manner by the acyloin
      condensation of enantiomerically pure alpha-alkyl-beta-arylpropionic esters,
      followed by a Lewis acid-mediated double cyclization under conditions of minimal
      epimerization. ERalpha and ERbeta binding affinity of both cis and trans isomers
      of dimethyl, diethyl, and dipropyl THCs was determined in competitive binding
      assays, and their transcriptional activity was determined in reporter gene assays
      in mammalian cells. Nearly all THCs examined were found to be affinity-selective
      for ERbeta. All these THCs are agonists on ERalpha, and THCs with small
      substituents are agonists on both ERalpha and ERbeta. As substituent size was
      increased, ERbeta-selective antagonism developed first in the (R,R)-cis
      enantiomer series and finally in the trans diastereomer and (S,S)-cis enantiomer
      series. The most potent and selective ligand was identified as (R,R)-cis-diethyl
      THC 2b, which mimicked the ERbeta-selective antagonist character of racemic cis
      diethyl THC 2b. This study illustrates that the antagonist character in THC
      ligands for ERbeta depends in a progressive way on the size and geometric
      disposition of substituent groups and suggests that the induction of an
      antagonist conformation in ERbeta can be achieved with these ligands with less
      steric perturbation than in ERalpha. Furthermore, antagonists that are
      selectively effective on ERbeta can have structures that are very different from
      the typical antiestrogens tamoxifen and raloxifene, which are antagonists on both
      ERalpha and ERbeta.

PMID- 10395488
TI  - Subtype-selective N-methyl-D-aspartate receptor antagonists: synthesis and
      biological evaluation of 1-(arylalkynyl)-4-benzylpiperidines.
AB  - A search of our compound library for compounds with structural similarity to
      ifenprodil (5) and haloperidol (7) followed by in vitro screening revealed that 4
      benzyl-1-(4-phenyl-3-butynyl)piperidine (8) was a moderately potent and selective
      antagonist of the NR1A/2B subtype of NMDA receptors. Substitution on the benzyl
      group of 8 did not significantly affect NR1A/2B potency, while addition of
      hydrogen bond donors in the para position of the phenyl group enhanced NR1A/2B
      potency. Addition of a hydroxyl moiety to the 4-position of the piperidine group
      slightly reduced NR1A/2B potency while reducing alpha-1 adrenergic and dopamine
      D2 receptor binding affinities substantially, resulting in improved overall
      selectivity for NR1A/2B receptors. Finally, the butynyl linker was replaced with
      propynyl or pentynyl. When the phenyl was para substituted with amine or
      acetamide groups, the NR1A/2B potency order was butynyl > pentynyl >> propynyl.
      For the para methanesulfonamide or hydroxyl groups, the order was butynyl
      approximately propynyl > pentynyl. The hydroxyl propyne (48) and butyne (23) were
      among the most potent NR1A/2B antagonists from this study. They both potentiated
      the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of
      Parkinson's disease, dosed at 10 mg/kg ip, but 48 was not active at 30 mg/kg po.

PMID- 10395489
TI  - 4,5-Dihydro-1,2,4-triazolo[1,5-a]quinoxalin-4-ones: excitatory amino acid
      antagonists with combined glycine/NMDA and AMPA receptor affinity.
AB  - A series of 4,5-dihydro-1,2,4-triazolo[1,5-a]quinoxalin-4-ones bearing different
      substituents on the benzo-fused ring and at position 2 were synthesized and
      biologically evaluated for their binding at glycine/NMDA and AMPA receptors. Most
      of the reported compounds show combined glycine/NMDA and AMPA receptor binding
      activity providing further evidences of the structural similarities of the
      binding pockets of both receptor recognition sites. Moreover, this study has
      pointed out some differences for the binding at each receptor type. In
      particular, for the glycine/NMDA receptor-ligand interaction, the presence of a
      free acidic function at position 2 and an electron-withdrawing substituent(s)
      nonbulkier than chlorine atom(s) on the benzo-fused moiety is required.
      Functional antagonism at the NMDA receptor-ion channel complex was also performed
      on some selected compounds.

PMID- 10395491
TI  - Synthesis and biological evaluation of boron-containing polyamines as potential
      agents for neutron capture therapy of brain tumors 

PMID- 10395490
TI  - Self-immolative anthracycline prodrugs for suicide gene therapy.
AB  - Four novel potential prodrugs derived from daunorubicin (8, 10) and doxorubicin
      (12, 14) were designed and synthesized. They are self-immolative prodrugs for
      suicide gene therapy activation by the enzyme carboxypeptidase G2 (CPG2)
      subsequently releasing the corresponding anthracyclines, by a 1,6-elimination
      mechanism. A mammary carcinoma cell line (MDA MB 361) was engineered to express
      CPG2 intracellularly (CPG2) or extracellularly, tethered to the outer cell
      membrane (stCPG2(Q)3). The prodrugs derived from doxorubicin showed prodrug/drug
      cytotoxicity differentials of 21-fold (compound 12) and 23-fold (compound 14).
      Prodrug 12 underwent an 11-fold activation when assayed in the cell line
      expressing externally surface-tethered CPG2.

PMID- 10395492
TI  - Four dimeric aporphine-containing alkaloids from Thalictrum fauriei.
AB  - Four dimeric alkaloids (1-4) containing an aporphine unit and representing unique
      structural features were obtained from Thalictrum fauriei and were characterized
      by spectral and chemical methods. Fauripavine (1), with a munitagine pavine unit,
      is the first such dimer with an aporphine C-1 diphenyl ether connection; although
      fauridine (2), also the first of its class, has codamine, a benzyl
      tetrahydroisoquinoline, linked at the same position. Faurithaline (3) and its 3
      methoxy analogue 4, both with reticuline, a benzyl tetrahydroisoquinoline as the
      second unit, are the first dimers with the diphenyl ether linkage at C-8 of an
      aporphine oxygenated at C-10 and C-11. Oconovine (8) was converted to 8-hydroxy-O
      methyloconovine (12) to determine the effect of oxygenation at C-8 on the proton
      chemical shift of the C-7 hydrogens in a study to support the C-8 ether linkage
      of alkaloids 3 and 4. All the alkaloids have the S-configuration at their
      asymmetric centers as established from their CD spectra when compared with those
      of model compounds.

PMID- 10395493
TI  - Iridoid glycosides of Leonurus persicus.
AB  - Two new iridoid glucosides, 6-O-acetylajugol (1) and 7, 8-epoxy-8-epi-loganic
      acid (2), together with five known iridoid glucosides, galiridoside (3),
      ajugoside (4), 10-deoxygeniposidic acid (5), 7-deoxy-8-epi-loganic acid (6), and
      8-O-acetylharpagide (7), have been isolated from the aerial parts of Leonurus
      persicus. Leucosceptoside A (8), eugenyl beta-rutinoside (9), and kaempferol 3-O
      glucoside (10) were also isolated. The structures of 1 and 2 were elucidated by
      extensive 1D- and 2D-NMR spectroscopy and molecular modeling. The structure of 3
      was confirmed by single-crystal X-ray diffraction. Antimicrobial activity of
      compounds (1-10) was also evaluated against a panel of gram-positive and gram
      negative bacteria and two strains of fungi.

PMID- 10395494
TI  - Lichen metabolites. 1. Inhibitory action against leukotriene B4 biosynthesis by a
      non-redox mechanism.
AB  - Of several lichen metabolites isolated from Parmelia nepalensis and Parmelia
      tinctorum, the didepsides atranorin (4) and diffractaic acid (5), as well as (+)
      protolichesterinic acid (7), inhibited LTB4 biosynthesis in polymorphonuclear
      leukocytes. Ethyl hematommate (3) and (+)-usnic acid (1) were only weak
      inhibitors, while methyl beta-orcinolcarboxylate (2) and gyrophoric acid (6) were
      inactive at concentrations up to 60 microM. Redox properties of the compounds
      were evaluated in terms of inhibition of nonenzymatic lipid peroxidation in model
      membranes, reactivity against the stable free radical 2,2-diphenyl-1
      picrylhydrazyl, and deoxyribose degradation as a measure of hydroxyl-radical
      generation. The results revealed that lichen metabolites neither acted as
      antioxidants against the peroxidation process in model membranes nor did they
      scavenge or produce free radicals, suggesting that the inhibitory effects on LTB4
      biosynthesis was due to specific enzyme interaction rather than a nonspecific
      redox mechanism.

PMID- 10395495
TI  - Lichen metabolites. 2. Antiproliferative and cytotoxic activity of gyrophoric,
      usnic, and diffractaic acid on human keratinocyte growth.
AB  - The sensitivity of the human keratinocyte cell line HaCaT to several lichen
      metabolites isolated from Parmelia nepalensis and Parmelia tinctorum was
      evaluated. The tridepside gyrophoric acid (6), the dibenzofuran derivative (+)
      usnic acid (1), and the didepside diffractaic acid (5) were potent
      antiproliferative agents and inhibited cell growth, with IC50 values of 1.7, 2.1,
      and 2.6 microM, respectively. Methyl beta-orcinolcarboxylate (2), ethyl
      hematommate (3), the didepside atranorin (4), and (+)-protolichesterinic acid (7)
      did not influence keratinocyte growth at concentrations of 5 microM.
      Keratinocytes were further tested for their susceptibility to the action of the
      potent antiproliferative agents on plasma membrane integrity. The release of
      lactate dehydrogenase activity into the culture medium was unchanged as compared
      to controls, documenting that the activity of gyrophoric acid (6), (+)-usnic acid
      (1), and diffractaic acid (5) was due to cytostatic rather than cytotoxic
      effects.

PMID- 10395496
TI  - Synthetic analogues of irlbacholine: a novel antifungal plant metabolite isolated
      from Irlbachia alata.
AB  - Irlbacholine and a series of related analogues were synthesized and their
      antifungal activities against Candida albicans, Cryptococcus neoformans, and
      Aspergillus fumigatus were assessed. The natural bisphosphocholine, irlbacholine,
      was the most potent compound, its 22-carbon chain length appearing to be optimal.

PMID- 10395497
TI  - New pregnane glycosides from Sinomarsdenia incisa.
AB  - Five new pregnane glycosides, sinomarinosides A (1), B (2), C (3), D (4), and E
      (5), have been isolated from Sinomarsdenia incisa (Asclepiadaceae). The
      structures of these compounds were elucidated by NMR and mass spectroscopic
      methods and chemical evidence.

PMID- 10395498
TI  - Chemical constituents and biological activities of the fruit of Zanthoxylum
      integrifoliolum.
AB  - Through continuing studies on the chemical constituents and antiplatelet
      aggregation principles of the fruit of the Formosan Zanthoxylum integrifoliolum,
      four new compounds-including two new lignans, (+)-pinoresinol-di-3,3
      dimethylallyl ether (1), and (+)-pinoresinol-3,3-dimethylallyl ether (2);
      zanthonitrile (3), and one new flavonoid, 3,5-diacetyltambulin (4)-and 18 known
      compounds were isolated from the CHCl3-soluble fraction. Their structures were
      elucidated on the basis of spectral data and chemical evidence. Among the
      isolates, including the previously reported isobutylamides, 13 compounds showed
      strong in vitro antiplatelet aggregation activity, with only (-)
      tetrahydroberberine showing weak vasorelaxing effect in high potassium- or
      norepinephrine-induced contraction of rat aorta.

PMID- 10395499
TI  - Pyrrolidinoindoline alkaloids from Psychotria oleoides and Psychotria lyciiflora.
AB  - The chemical study of two Rubiaceae from New Caledonia, Psychotria lyciiflora and
      Psychotria oleoides, led to the isolation of several pyrrolidinoindoline
      alkaloids. Two dimers, the known meso-chimonanthine (9) and the new Nb-desmethyl
      meso-chimonanthine (5), and a known trimer, hodgkinsine (1), have been isolated
      from P. lyciiflora. Hodgkinsine (1), quadrigemine C (2), isopsychotridine B (3),
      psychotridine (4), and three new alkaloids, quadrigemine I (6), oleoidine (7),
      and caledonine (8), have been isolated from P. oleoides. Structural assignments
      of the compounds were based on mass spectra analysis and 2D NMR experiments. A
      tentative stereochemical determination is made from 2D NMR experiments, circular
      dichroism study and chemical correlations. Some of these compounds are functional
      antagonists of somatostatine (SRIH).

PMID- 10395500
TI  - Glycosyldiacylglycerolipids from the lichen Dictyonema glabratum.
AB  - Three glycolipids (1-3) were isolated from the basidiolichen Dictyonema
      glabratum. Their carbohydrate and lipid components were structurally
      characterized using 1D 1H and 13C and 2D NMR spectroscopy, complemented by mass
      spectrometry, as were the carbohydrate moieties formed on saponification. These
      were O-alpha-D-Galp-(1''-->6')-O-beta-D-Galp-(1'<-->1)-2, 3-diacyl-D-glycerol (2)
      and two others not previously found in lichens, O-beta-D-Galp-(1'<-->1)-2,3
      diacyl-D-glycerol (1) and O-alpha-D-Galp-(1'''-->6'')-O-alpha-D-Galp-(1' '-->6')
      O-beta-D-Galp-(1'<-->1)-2,3-diacyl-D-glycerol (3). Each was saponified to give
      the free carbohydrates and its fatty acid methyl esters. The most abundant fatty
      acid esters in 1-3 was palmitic C16:0, but there was a wide variation of ester
      composition. Others present were C8:0 and C14:0 in 1, C14:0, C15:0, C17:0, C18:0,
      C18:1 (oleic), C18:2 (linoleic), C22:0, and C24:0 in 2, and C8:0, C14:0, C18:0,
      C18:1 (oleic), C18:2 (linoleic), and C18:3 (linolenic) in 3. As in ascolichens,
      the glycolipids appear to arise from the phycobiont.

PMID- 10395501
TI  - Two novel acetogenins, annoglaxin and 27-hydroxybullatacin, from Annona glabra.
AB  - Two new bioactive Annonaceous acetogenins, annoglaxin (1) and 27
      hydroxybullatacin (2), have been isolated from the fractionated ethanolic
      extracts of the leaves of Annona glabra, directing the fractionation with the
      brine shrimp lethality test (BST). The structures of 1 and 2 were elucidated on
      the basis of spectroscopic and chemical methods, and the absolute
      stereochemistries were determined by the advanced Mosher ester method. 1 presents
      unusual features of an OH at C-8 and a carbonyl at C-12 and, while less potent
      than 2, shows interesting selectivity for the human breast carcinoma (MCF-7) cell
      line. Compound 2 was at least 100 000 times more potent than adriamycin against
      the human kidney carcinoma (A-498), prostate carcinoma (PC-3), and pancreatic
      carcinoma (PACA-2) cell lines in our panel of six human solid tumor cell lines.

PMID- 10395502
TI  - Novel isoflavone, cinnamic acid, and triterpenoid glycosides in soybean molasses.
AB  - Seven known isoflavones, genistein (4), daidzein (5), glycitein (6), formononetin
      (7), genistin (8), daidzin (9), and glycitein 7-O-beta-D-(6' '-O
      acetylglucopyranoside) (10), ferulic acid, and two known saponin glycosides,
      soysaponin I (14) and soysaponin A2 (15), were isolated from soybean molasses.
      Several new compounds were also isolated and identified, including three
      isoflavones (1-3), two cinnamic acid ester glycosides (11) and (12), and a new
      saponin hexaglycoside (13). The structures of the new compounds were established
      on the basis of spectral data interpretation.

PMID- 10395503
TI  - Carotenoid glycoside esters from the thermophilic bacterium meiothermusruber 
AB  - The thermophilic bacterium Meiothermus ruber produces a series of carotenoid
      glycoside esters. The major carotenoid has been identified as 1'-beta
      glucopyranosyl-3,4,3',4'-tetradehydro-1', 2'-dihydro-beta,psi-caroten-2-one (1).
      It is acylated at the 6' '-position of the glucose unit by a series of C10-C17
      fatty acids. The structure of 1 was established by spectral means, including
      complete assignment of the 1H and 13C NMR resonances by inverse 2D NMR
      spectroscopy. These carotenoids are thought to play roles in stabilizing
      membranes of this thermophilic organism.

PMID- 10395504
TI  - Structural considerations of NK109, an antitumor benzo[c]phenanthridine alkaloid.
AB  - The antitumor activities of a synthetic benzo[c]phenanthridine, NK109 (7-hydroxy
      2, 3-methylenedioxy-5-methyl-8-methoxybenzo[c]phenanthridinium hydrogensulfate
      dihydrate), and of natural benzo[c]phenanthridines were tested in vitro and in
      vivo. NK109 (3) had the highest activity among them. NK109 is similar in
      structure to fagaronine and fagaridine; however, it has a phenolic-OH at C-7.
      NK109 exists as a resonance hybrid, the keto-amine and zwitterionic forms in
      neutral media. The resonance hybrid is cationic and has molecular planarity;
      these have been considered to be essential for the antitumor activity of the
      benzo[c]phenanthridinium salts. On the other hand, the structurally similar
      benzo[c]phenthridine alkaloids, chelerythrine and sanguinarine, exist as
      pseudobases under the same conditions. The latter do not exhibit antitumor
      activity in vivo, probably because they lose both the immonium region and
      molecular planarity. Thus, 3 may be considered to be novel category of
      benzo[c]phenanthridinium salt from the viewpoint of its structure under
      biological conditions.

PMID- 10395505
TI  - Cytotoxic 3,4-secoapotirucallanes from Aaglaia argentea bark.
AB  - Nine 3,4-secoapotirucallanes, argentinic acids A-I, were isolated from the bark
      of Aglaia argentea and transformed to their methyl esters 1-9. The structures
      were determined by spectral and chemical means. Compounds 1-8 showed moderate
      cytotoxic activity against KB cells (IC50 1.0-3.5 microg/mL).

PMID- 10395506
TI  - Six triterpenoid saponins from Mmaesa laxiflora.
AB  - Six new triterpenoid saponins, maelaxins A-F (1-6), were isolated from a n-BuOH
      extract of the leaves of Maesa laxiflora. They possess 22-O-angeloyl
      camelliagenin A, 16-O-acetyl, 22-O-angeloyl-camelliagenin A, or 22-O-(2Z)
      hexenoyl-camelliagenin A as the aglycon. The pentasaccharide moiety linked to C-3
      of the aglycon consists of D-glucuronic acid, L-rhamnose, D-glucose, and/or D
      galactose. Their structures were elucidated by extensive NMR experiments
      including 1H-1H (COSY, 2D HOHAHA, NOESY) and 1H-13C (HMQC and HMBC) spectroscopy
      and chemical evidence.

PMID- 10395507
TI  - Gleditsiosides N-Q, new triterpenoid saponins from Gleditsia sinensis.
AB  - The structures of gleditsiosides N, O, P, and Q (1-4), isolated from anomalous
      fruits of Gleditsia sinensis, were characterized as novel complex bisdesmosidic
      triterpenoid glycosides acylated with monoterpenoid units, by means of extensive
      1D and 2D NMR studies. The four compounds shared a common structural feature with
      a trisaccharide [(beta-D-xylopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1-->6)
      be ta- D-glucopyranoside)] affixed to C-3 and a tetrasaccharide [(beta-D
      xylopyranosyl-(1-->3)-beta-D-xylopyranosyl-(1-->4)-alpha-L-r hamnopyranosyl-(1-
      >2)-beta-D-glucopyranosyl ester)] attached to C-28. Gleditsioside P (3) is the
      first saponin of this type found to date bearing three monoterpenoid units.

PMID- 10395508
TI  - Two new bromophenols from the red alga odonthalia corymbifera 
AB  - Two novel bromophenols (1 and 2) were isolated from an extract of a red alga,
      Odonthalia corymbifera, together with a known bromophenol (3). The novel
      bromophenols were determined as 4-bromo-2, 3-dihydroxy-6-hydroxymethylphenyl 2, 5
      dibromo-6-hydroxy-3-hydroxymethylphenyl ether (1) and bis(2, 3-dibromo-4,5
      dihydroxybenzyl) ether (2), from spectroscopic evidence. Compounds 1-3 were found
      to be inactivators of alpha-glucosidase.

PMID- 10395509
TI  - A new gypsogenin saponin from arenaria filicaulis 
AB  - The structure elucidation of a new saponin from Arenaria filicaulis (Boiss.),
      Caryophyllaceae, Snatzkein F (1), containing gypsogenin with a tetrasaccharide
      moiety was accomplished by use of 1D and 2D NMR methods.

PMID- 10395510
TI  - Mathemycin B, a new antifungal macrolactone from actinomycete species HIL Y
      8620959.
AB  - A new macrocyclic lactone antibiotic mathemycin B (1) was isolated from the
      fermentation broth of an Actinomycete sp. culture Y-8620959. The structure of 1
      was elucidated by high-resolution MS and interpretation of 2D NMR results.
      Mathemycin B is active against a variety of phytopathogenic organisms.

PMID- 10395511
TI  - New triterpenoids of mallotus repandus 
AB  - Three new triterpenoids-3alpha-hydroxy-13alpha-ursan-28,12beta-olide 3-benzoate
      (1), 3alpha-hydroxy-28beta-methoxy-13alpha-ursan-28, 12beta-epoxide 3-benzoate
      (2), and 3alpha-hydroxy-13alpha-ursan-28-oic acid (3)-and four known compounds
      were isolated from the stem and root bark of Mallotus repandus.

PMID- 10395512
TI  - Novel bromine-containing constituents of the sponge psammaplysilla purpurea1 
AB  - Two new dibromotyrosine-derived metabolites (1 and 2) and the known compounds
      bastadin-6, bastadin-16, purealidin P, purealidin G, and aplysamine-2 and its
      ammonium salt have been isolated from the sponge Psammaplysilla purpurea.
      Compounds 1 and 2 were characterized by interpretation of their spectral data.

PMID- 10395513
TI  - Characterization of 6-epi-3-anhydroophiobolin B from Cochliobolus heterostrophus.
AB  - The new sesterterpenoid 6-epi-3-anhydroophiobolin B (1) and six known ophiobolins
      were isolated from the extracts of the fungus Cochliobolus heterostrophus race O.
      The structure of 6-epi-3-anhydroophiobolin B was deduced from analysis of
      spectral data and the structural characterization of dehydration and dimerization
      products. Ophiobolin A (2) showed potent activity in cytotoxicity assays and
      marginal activity in antimalarial assays.

PMID- 10395514
TI  - Guiaflavine, a new bisindole quaternary alkaloid from the stem bark of Strychnos
      guianensis.
AB  - A reinvestigation of Strychnos guianensis resulted in the isolation of a colored
      quaternary bisindole alkaloid from the stem bark. The structure of this new
      substance, guiaflavine (1), was defined by detailed spectroscopic methods and
      comparison with model compounds.

PMID- 10395515
TI  - Pikuroside: a novel iridoid from Picrorhiza kurroa.
AB  - A new iridoid, pikuroside (1), was isolated from the roots of Picrorhiza kurroa,
      together with three known iridoids, picroside I (2), picroside II (3), and 6
      feruloyl catalpol (4). The structure of 1 was established by interpretation and
      full assignments of NMR spectral data. Pikuroside (1) had no antiinflammatory
      activity, although the crude extract and picroside II (3) demonstrated moderate
      activity.

PMID- 10395516
TI  - Circumdatins D, E, and F: further fungal benzodiazepine analogues from
      aspergillus ochraceus 
AB  - Three new benzodiazepine alkaloids belonging to the circumdatin series have been
      isolated as minor constituents of culture extracts of a terrestrial strain of the
      fungus Aspergillus ochraceus. Their structures were solved by MS and NMR
      comparison with previously reported circumdatin analogues.

PMID- 10395517
TI  - Patulosides A and B, novel xanthone glycosides from cell suspension cultures of
      Hypericum patulum.
AB  - Two new xanthone glycosides, patuloside A (3-beta-D-glucopyranosyloxy-1,5,6
      trihydroxy-9H-xanthene-9-one, 1) and patuloside B [3-(2-O-alpha-L-rhamnopyranosyl
      beta-D-glucopyranosyl)oxy-1,5, 6-trihydroxy-9H-xanthene-9-one, 2], have been
      isolated from cell suspension cultures of Hypericum patulum. Their structures
      were elucidated by spectral techniques.

PMID- 10395518
TI  - Flavones and sesquiterpene lactones from Achillea atrata subsp. multifida:
      antimicrobial activity.
AB  - Four flavones (1-4) and nine sesquiterpene lactones (5-13), one of them (5) a new
      compound, were isolated from the aerial parts of Achillea atrata L. subsp.
      multifida. Although the crude extract demonstrated in vitro inhibitory activity
      against Candida albicans and Bacillus subtilis, all isolated flavones were active
      against B. subtilis. Flavones 1, 2, and 3 were also active against C. albicans,
      while 1 and 3 exhibited activity against E. coli, as well. None of the tested
      lactones (7, 9, 12, and 13) showed any antimicrobial activity.

PMID- 10395519
TI  - Interference of linoleic acid fraction in some receptor binding assays.
AB  - An extract of a suspension culture of Tabernaemontana pandacaqui Poir. was
      fractionated by centrifugal partition chromatography. Aliquots were tested in an
      adenosine A1 receptor binding assay. This led to the isolation and identification
      of linoleic acid, which proved to be a noncompetitive inhibitor. This "false
      positive"effect also extended to some other binding assays.

PMID- 10395520
TI  - Vinylfurans revisited: A new sesquiterpene from euryspongia deliculata 
AB  - A novel furanoterpene (2), iso-dehydrodendrolasin, has been isolated from the
      tropical marine sponge Euryspongia deliculata and characterized by 2D NMR.

PMID- 10395521
TI  - Tetrin C, a new glycosylated polyene macrolide antibiotic produced by
      Streptomyces sp. GK9244.
AB  - A new antifungal 26-membered polyene macrolide, tetrin C (1), has been isolated
      from Streptomyces sp. GK9244. Its structure has been determined by interpretation
      of NMR data. Compound 1 exhibited antifungal activity against Mortierella
      ramannianus (MIC, 5 microg/mL).

PMID- 10395522
TI  - Oxidative transformations of guaia-1(10)-en-12,8-olides into xanthanolides 
AB  - Dihydropsuedoivalin (1) was isolated from Stevia tomentosa, which, when treated
      with base, afforded epidihydropseudoivalin (2). The stereochemistry of 1 and 2
      was established by crystallographic X-ray studies of the two derivatives of
      epidihydropseudoivalin. Treatment of 1 and 2 with Jones's reagent afforded the
      xanthanolides 3 and 4, respectively.

PMID- 10395523
TI  - Biologically active triterpene saponins from callus tissue of Polygala amarella.
AB  - A new bioactive saponin (1), together with a known saponin (polygalasaponin
      XXVIII) has been isolated from the callus tissue culture of Polygala amarella.
      Based on spectroscopic data, especially direct and long-range heteronuclear 2D
      NMR analysis and on chemical transformations, the structure of 1 was elucidated
      as 3-O-beta-D-glucopyranosyl presenegenin-28-O-beta-D-galactopyranosyl-(1 --> 3)
      beta-D-xylopyranosyl-(1 --> 4)-alpha-L-rhamnopyranosyl-(1 --> 2)-[beta-D
      glucopyranosyl-(1 --> 3)]-beta-D-fucopyranoside. Both saponins showed significant
      immunological properties based on the enhancement of granulocyte phagocytosis in
      vitro.

PMID- 10395524
TI  - A new tyrosine kinase inhibitor from the marine brown alga Stypopodium zonale.
AB  - From the lipophilic extract of the marine brown alga Stypopodium zonale
      (Dictyotaceae) the new terpenoid compound stypoquinonic acid (1) together with
      the known compounds taondiol (2) and atomaric acid (3) were isolated. The
      structures of all isolates were determined from their spectroscopic data,
      including 1- and 2-dimensional NMR methods. The new compound, 1, and atomaric
      acid (3), showed inhibition of tyrosine kinase (p56lck).

PMID- 10395525
TI  - Volvatellin, caulerpenyne-related product from the sacoglossan volvatella sp 
AB  - Volvatellin (4) is a highly unstable terpene isolated from the extracts of the
      Indian opisthobranch mollusk Volvatella sp. The structure and the relative
      stereochemistry of 4 were determined by NMR methods. The paper also describes a
      hypothetical biosynthesis of 4 starting from the alga-derived caulerpenyne.

PMID- 10395526
TI  - Madangolide and laingolide A, two novel macrolides from lyngbya bouillonii
      (Cyanobacteria) 
AB  - Two new macrolide derivatives, madangolide (2) and laingolide A (3), have been
      isolated from the cyanobacterium Lyngbya bouillonii, collected in Papua New
      Guinea. Their structures (without stereochemistry) have been established by
      detailed high-field 1D and 2D NMR studies and, in the case of 3, by comparison
      with the spectroscopic data of laingolide (1), previously isolated from the same
      organism.

PMID- 10395527
TI  - Oxidized welwitindolinones from terrestrial fischerella spp 

PMID- 10395528
TI  - Fenestration nodes and the wide submyelinic space form the basis for the
      unusually fast impulse conduction of shrimp myelinated axons.
AB  - Saltatory impulse conduction in invertebrates is rare and has only been found in
      a few giant nerve fibres, such as the pairs of medial giant fibres with a compact
      multilayered myelin sheath found in shrimps (Penaeus chinensis and Penaeus
      japonicus) and the median giant fibre with a loose multilayered myelin sheath
      found in the earthworm Lumbricus terrestris. Small regions of these nerve fibres
      are not covered by a myelin sheath and serve as functional nodes for saltatory
      conduction. Remarkably, shrimp giant nerve fibres have conduction speeds of more
      than 200 m s-1, making them among the fastest-conducting fibres recorded, even
      when compared with vertebrate myelinated fibres. A common nodal structure for
      saltatory conduction has recently been found in the myelinated nerve fibres of
      the nervous systems of at least six species of Penaeus shrimp, including P.
      chinensis and P. japonicus. This novel node consists of fenestrated openings that
      are regularly spaced in the myelin sheath and are designated as fenestration
      nodes. The myelinated nerve fibres of the Penaeus shrimp also speed impulse
      conduction by broadening the gap between the axon and the myelin sheath rather
      than by enlarging the axon diameter as in other invertebrates. In this review, we
      document and discuss some of the structural and functional characteristics of the
      myelinated nerve fibres of Penaeus shrimp: (1) the fenestration node, which
      enables saltatory conduction, (2) a new type of compact multilayered myelin
      sheath, (3) the unique microtubular sheath that tightly surrounds the axon, (4)
      the extraordinarily wide space present between the microtubular sheath and the
      myelin sheath and (5) the main factors contributing to the fastest impulse
      conduction velocity so far recorded in the Animal Kingdom.

PMID- 10395529
TI  - The hippocampus: The shock of the new.
AB  - Recent successes in functional brain imaging have suggested that the hippocampus
      is part of a novelty-detection network; but consideration of the available
      evidence and of the cognitive demands of novelty processing suggests that things
      are not so simple.

PMID- 10395530
TI  - DNA repair: Polymerases for passing lesions.
AB  - Replicative DNA polymerases generally cannot pass lesions in the template strand.
      Now there is accumulating evidence for the widespread existence of a separate
      class of DNA polymerases that can carry out translesion synthesis in both
      mutagenic and error-free ways.

PMID- 10395531
TI  - Sex allocation: At the females' whim.
AB  - Experimental studies of wild birds suggest that females have a previously
      unappreciated ability to control the sex ratio of their offspring in response to
      variation in sex-specific fitness benefits.

PMID- 10395532
TI  - Bacterial evolution: Jittery genomes.
AB  - Recent studies of long-term experimental populations of bacteria have revealed
      the actual progression of evolutionary change and how rates of phenotypic
      evolution can be decoupled from rates of genomic evolution.

PMID- 10395533
TI  - Steroid hormones: Interactions with membrane-bound receptors.
AB  - Steroid hormones are generally thought to pass easily across a plasma membrane
      into a cell, interacting once inside with soluble nuclear receptors, but recent
      experiments have demonstrated the importance of membrane-bound receptors in
      mediating the activity and the metabolism of steroid hormones.

PMID- 10395534
TI  - Pheromone reception: A complex map of activation in the brain.
AB  - Recent studies of the projection pattern made by sensory neurons involved in
      mammalian pheromone reception have shown that there is a map of activation in the
      brain, but this pheromone map appears far more complex than the equivalent map in
      the main olfactory system responsible for the sense of smell.

PMID- 10395535
TI  - Axon guidance: A balance of signals sets axons on the right track.
AB  - Axon guidance depends on the transduction of extracellular guidance cues into
      motile responses by the axonal growth cone. Recent studies in vivo have
      elucidated mechanisms required for this process that involve kinases and
      phosphatases, calcium dynamics and remodeling of the actin cytoskeleton.

PMID- 10395536
TI  - Bacterial cells: The migrating kinase and the master regulator.
AB  - It is becoming clear that, as in eukaryotes, proteins in bacterial cells are
      targeted to specific cellular locations. The most recently discovered example is
      a remarkable histidine kinase that oscillates between polar and global
      distributions while temporally regulating transcription and DNA replication in
      Caulobacter.

PMID- 10395537
TI  - Innate and learned components of human visual preference.
AB  - BACKGROUND: Recent claims in neuroscience and evolutionary biology suggest that
      the aesthetic sense reflects preferences for image signals whose characteristics
      best fit innate brain mechanisms of visual recognition. RESULTS: This hypothesis
      was tested by behaviourally measuring, for a set of initially unfamiliar images,
      the effects of category learning on preference judgements by humans, and by
      relating the observed data to computationally reconstructed internal
      representations of categorical concepts. Category learning induced complex shifts
      in preference behaviour. Two distinct factors - complexity and bilateral symmetry
      - could be identified from the data as determinants of preference judgements. The
      effect of the complexity factor varied with object knowledge acquired through
      category learning. In contrast, the impact of the symmetry factor proved to be
      unaffected by learning experience. Computer simulations suggested that the
      preference for pattern complexity relies on active (top-down) mechanisms of
      visual recognition, whereas the preference for pattern symmetry depends on
      automatic (bottom-up) mechanisms. CONCLUSIONS: Human visual preferences are not
      fully determined by (objective) structural regularities of image stimuli but also
      depend on their learned (subjective) interpretation. These two aspects are
      reflected in distinct complementary factors underlying preference judgements, and
      may be related to complementary modes of visual processing in the brain.

PMID- 10395538
TI  - Comparison of H+-ATPase and Ca2+-ATPase suggests that a large conformational
      change initiates P-type ion pump reaction cycles.
AB  - BACKGROUND: Structures have recently been solved at 8 A resolution for both Ca2+
      ATPase from rabbit sarcoplasmic reticulum and H+-ATPase from Neurospora crassa.
      These cation pumps are two distantly related members of the family of P-type
      ATPases, which are thought to use similar mechanisms to generate ATP-dependent
      ion gradients across a variety of cellular membranes. We have undertaken a
      detailed comparison of the two structures in order to describe their similarities
      and differences as they bear on their mechanism of active transport. RESULTS: Our
      first important finding was that the arrangement of 10 transmembrane helices was
      remarkably similar in the two molecules. This structural homology strongly
      supports the notion that these pumps use the same basic mechanism to transport
      their respective ions. Despite this similarity in the membrane-spanning region,
      the cytoplasmic regions of the two molecules were very different, both in their
      disposition relative to the membrane and in the juxtaposition of their various
      subdomains. CONCLUSIONS: On the basis of the crystallization conditions, we
      propose that these two crystal structures represent different intermediates in
      the transport cycle, distinguished by whether cations are bound to their
      transport sites. Furthermore, we propose that the corresponding conformational
      change (E2 to E1 ) has two components: the first is an inclination of the main
      cytoplasmic mass by 20 degrees relative to the membrane-spanning domain; the
      second is a rearrangement of the domains comprising the cytoplasmic part of the
      molecules. Accordingly, we present a rough model for this important
      conformational change, which relays the effects of cation binding within the
      membrane-spanning domain to the nucleotide-binding site, thus initiating the
      transport cycle.

PMID- 10395539
TI  - Translocation of cyclin B1 to the nucleus at prophase requires a phosphorylation
      dependent nuclear import signal.
AB  - BACKGROUND: At M phase, cyclin B1 is phosphorylated in the cytoplasmic retention
      sequence (CRS), which is required for nuclear export. During interphase, cyclin
      B1 shuttles between the nucleus and the cytoplasm because constitutive nuclear
      import is counteracted by rapid nuclear export. In M phase, cyclin B moves
      rapidly into the nucleus coincident with its phosphorylation, an overall movement
      that might be caused simply by a decrease in its nuclear export. However, the
      questions of whether CRS phosphorylation is required for cyclin B1 translocation
      in mitosis and whether a reduction in nuclear export is sufficient to explain its
      rapid relocalisation have not been addressed. RESULTS: We have used two forms of
      green fluorescent protein to analyse simultaneously the translocation of wild
      type cyclin B1 and a phosphorylation mutant of cyclin B1 in mitosis, and
      correlated this with an in vitro nuclear import assay. We show that cyclin B1
      rapidly translocates into the nucleus approximately 10 minutes before breakdown
      of the nuclear envelope, and that this movement requires the CRS phosphorylation
      sites. A cyclin B1 mutant that cannot be phosphorylated enters the nucleus after
      the wild-type protein. Phosphorylation of the CRS creates a nuclear import signal
      that enhances cyclin B1 import in vitro and in vivo, in a manner distinct from
      the previously described import of cyclin B1 mediated by importin beta.
      CONCLUSIONS: We show that phosphorylation of human cyclin B1 is required for its
      rapid translocation to the nucleus towards the end of prophase. Phosphorylation
      enhances cyclin B1 nuclear import by creating a nuclear import signal. The
      phosphorylation of the CRS is therefore a critical step in the control of
      mitosis.

PMID- 10395540
TI  - A missing metabolic pathway in the cattle tick Boophilus microplus.
AB  - Heme proteins are involved in a wide variety of biological reactions, including
      respiration, oxygen transport and oxygen metabolism [1]. The heme prosthetic
      group is synthesized in almost all living organisms except for a few pathogenic
      bacteria and trypanosomatids that use blood as food [2] [3]. There is a general
      belief that all nucleated animal cells synthesize heme [1] [4]. However, blood
      feeding arthropods ingest enormous amounts of vertebrate blood in a single meal
      and the heme pathway has not been studied in these animals. We have examined heme
      synthesis in two hematophagous arthropods - the blood-sucking bug Rhodnius
      prolixus and the cattle tick Boophilus microplus. We show that R. prolixus makes
      heme and has a fully operative heme biosynthetic pathway, while B. microplus does
      not. To our knowledge, this is the first report of an animal that does not
      synthesize its own heme and relies solely on the recovery of heme present in the
      diet. Because of the inability of Boophilus to synthesize heme and its ability to
      deal efficiently with large amounts of free heme, we propose this organism as a
      good model for studying heme transport and reutilization in animal cells.

PMID- 10395541
TI  - Evidence for functional conservation of a mammalian homologue of the light
      responsive plant protein COP1.
AB  - Identified in Arabidopsis as a repressor of light-regulated development, the COP1
      (constitutively photomorphogenic 1) protein is characterized by a RING-finger
      motif and a WD40 repeat domain [1]. The subcellular localization of COP1 is light
      dependent. COP1 acts within the nucleus to repress photomorphogenic development,
      but light inactivates COP1 and diminishes its nuclear abundance [2]. Here, we
      report the identification of a mammalian COP1 homologue that contains all the
      structural features present in Arabidopsis COP1 (AtCOP1). When expressed in plant
      cells, a fusion protein comprising mammalian COP1 and beta-glucuronidase (GUS)
      responded to light by changing its subcellular localization pattern in a manner
      similar to AtCOP1. Whereas the mammalian COP1 was unable to rescue the defects of
      Arabidopsis cop1 mutants, expression of the amino-terminal half of mammalian COP1
      in Arabidopsis interfered with endogenous COP1 function, resulting in a
      hyperphotomorphogenic phenotype. Therefore, the regulatory modules in COP1
      proteins that are responsible for the signal-dependent subcellular localization
      are functionally conserved between higher plants and mammals, suggesting that
      mammalian COP1 may share a common mode of action with its plant counterpart in
      regulating development and cellular signaling.

PMID- 10395543
TI  - Lead mineral transformation by fungi.
AB  - Pyromorphite (Pb5(PO4)3Cl), the most stable lead mineral under a wide range of
      geochemical conditions [1], can form in urban and industrially contaminated soils
      [2] [3] [4] [5]. It has been suggested that the low solubility of this mineral
      could reduce the bioavailability of lead, and several studies have advocated
      pyromorphite formation as a remediation technique for lead-contaminated land [3]
      [5] [6], if necessary using addition of phosphate [6]. Many microorganisms can,
      however, make insoluble soil phosphate bioavailable [7] [8] [9] [10], and the
      solubilisation of insoluble metal phosphates by free-living and symbiotic fungi
      has been reported [11] [12] [13] [14] [15]. If pyromorphite can be solubilised by
      microbial phosphate-solubilising mechanisms, the question arises of what would
      happen to the released lead. We have now clearly demonstrated that pyromorphite
      can be solubilised by organic-acid-producing fungi, for example Aspergillus
      niger, and that plants grown with pyromorphite as sole phosphorus source take up
      both phosphorus and lead. We have also discovered the production of lead oxalate
      dihydrate by A. niger during pyromorphite transformation, which is the first
      recorded biogenic formation of this mineral. These mechanisms of lead
      solubilisation, or its immobilisation as a novel lead oxalate, have significant
      implications for metal mobility and transfer to other environmental compartments
      and organisms. The importance of considering microbial processes when developing
      remediation techniques for toxic metals in soils is therefore emphasised.

PMID- 10395542
TI  - Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G
      protein-dependent manner.
AB  - In studies of developmental signaling pathways stimulated by the Wnt proteins and
      their receptors, Xenopus Wnt-5A (Xwnt-5A) and a prospective Wnt receptor, rat
      Frizzled 2 (Rfz2), have been shown to stimulate inositol signaling and Ca2+
      fluxes in zebrafish [1] [2] [3]. As protein kinase C (PKC) isoforms can respond
      to Ca2+ signals [4], we asked whether expression of different Wnt and Frizzled
      homologs modulates PKC. Expression of Rfz2 and Xwnt-5A resulted in translocation
      of PKC to the plasma membrane, whereas expression of rat Frizzled 1 (Rfz1), which
      activates a Wnt pathway using beta-catenin but not Ca2+ fluxes [5], did not. Rfz2
      and Xwnt-5A were also able to stimulate PKC activity in an in vitro kinase assay.
      Agents that inhibit Rfz2-induced signaling through G-protein subunits blocked
      Rfz2-induced translocation of PKC. To determine if other Frizzled homologs
      differentially stimulate PKC, we tested mouse Frizzled (Mfz) homologs for their
      ability to induce PKC translocation relative to their ability to induce the
      expression of two target genes of beta-catenin, siamois and Xnr3. Mfz7 and Mfz8
      stimulated siamois and Xnr3 expression but not PKC activation, whereas Mfz3, Mfz4
      and Mfz6 reciprocally stimulated PKC activation but not expression of siamois or
      Xnr3. These results demonstrate that some but not all Wnt and Frizzled signals
      modulate PKC localization and stimulate PKC activity via a G-protein-dependent
      mechanism. In agreement with other studies [1] [2] [3]. [6] [7] these data
      support the existence of multiple Wnt and Frizzled signaling pathways in
      vertebrates.

PMID- 10395544
TI  - Repression by Notch is required before Wingless signalling during muscle
      progenitor cell development in Drosophila.
AB  - The larval muscles of Drosophila arise from the fusion of muscle founder cells,
      which give each individual muscle its identity, with myoblasts (reviewed in [1]).
      Muscle founder cells arise from the asymmetric division of muscle progenitor
      cells, each of which develops from a group of cells in the somatic mesoderm that
      express lethal of scute [2]. All the cells in a cluster can potentially form
      muscle progenitors, but owing to lateral inhibition, only one or two develop as
      such [2] [3] [4] [5]. Muscle progenitors, and the subsequent founder cells, then
      express transcription factors such as Kruppel, S59 and Even-skipped, which confer
      identity on the muscle [6] [7] [8]. Definition of some muscle progenitors,
      including three groups that express S59, depends on Wingless signalling [9].
      Lateral inhibition requires Delta signalling through Notch and the transcription
      factor Suppressor of Hairless [3] [4] [5]. As the Wingless and lateral-inhibition
      signals are sequential [8], one might expect that muscle progenitors would fail
      to develop in the absence of Wingless signalling, regardless of the presence or
      absence of lateral-inhibition signalling. Here, we examine the development of the
      S59-expressing muscle progenitor cells in mutant backgrounds in which both
      Wingless signalling and lateral inhibition are disrupted. We show that progenitor
      cells failed to develop when both these processes were disrupted. Our analysis
      also reveals a repressive function of Notch, required before or concurrently with
      Wingless signalling, which is unrelated to its role in lateral inhibition.

PMID- 10395545
TI  - Identification of a defect in DNA ligase IV in a radiosensitive leukaemia
      patient.
AB  - The major mechanism for the repair of DNA double-strand breaks (DSBs) in
      mammalian cells is non-homologous end-joining (NHEJ), a process that involves the
      DNA-dependent protein kinase [1] [2], XRCC4 and DNA ligase IV [3] [4] [5] [6].
      Rodent cells and mice defective in these components are radiation-sensitive and
      defective in V(D)J-recombination, showing that NHEJ also functions to rejoin DSBs
      introduced during lymphocyte development [7] [8]. 180BR is a radiosensitive cell
      line defective in DSB repair, which was derived from a leukaemia patient who was
      highly sensitive to radiotherapy [9] [10] [11]. We have identified a mutation
      within a highly conserved motif encompassing the active site in DNA ligase IV
      from 180BR cells. The mutated protein is severely compromised in its ability to
      form a stable enzyme-adenylate complex, although residual activity can be
      detected at high ATP concentrations. Our results characterize the first patient
      with a defect in an NHEJ component and suggest that a significant defect in NHEJ
      that leads to pronounced radiosensitivity is compatible with normal human
      viability and does not cause any major immune dysfunction. The defect, however,
      may confer a predisposition to leukaemia.

PMID- 10395546
TI  - Masking of Eph receptors and ephrins.

PMID- 10395548
TI  - How to give a bad talk 

PMID- 10395549
TI  - When a butterfly flaps its wingsellipsis 

PMID- 10395547
TI  - TIP30, a cofactor for HIV-1 Tat-activated transcription, is homologous to short
      chain dehydrogenases/reductases.

PMID- 10395550
TI  - Cytochrome c.

PMID- 10395551
TI  - Guided tours: from precursor snoRNA to functional snoRNP.
AB  - Small nucleolar RNAs (snoRNAs) use base pairing to guide modification of
      conserved nucleotides in functionally important regions of ribosomal RNA. The box
      C/D snoRNAs direct 2'-O-methylation and the box H/ACA snoRNAs direct
      pseudouridylation. Each snoRNA interacts with proteins, many of them newly
      identified. Progress in understanding how snoRNA sequences are stored within
      genomes, liberated from precursor molecules and targeted to the nucleolus has
      begun to elucidate each step in the biogenesis of these critical contributors to
      ribosome formation.

PMID- 10395552
TI  - Transport pathways of macromolecules between the nucleus and the cytoplasm.
AB  - Transport between the nucleus and cytoplasm involves both stationary components
      and mobile factors acting in concert to move macromolecules through the nuclear
      pore complex. Multiple transport pathways requiring both unique and shared
      components have been identified. In the past 18 months, new findings have shed
      light on the nature of some of the mobile components of these pathways. New
      receptor-cargo pairs for both import and export pathways have been identified
      extending the breadth of known transport pathways. Surprising findings on the
      role of Ran and energy in transport have changed our way of thinking about the
      mechanism of movement through the nuclear pore.

PMID- 10395553
TI  - hnRNP complexes: composition, structure, and function.
AB  - Heterogeneous nuclear ribonucleoproteins (hnRNPs) are predominantly nuclear RNA
      binding proteins that form complexes with RNA polymerase II transcripts. These
      proteins function in a staggering array of cellular activities, ranging from
      transcription and pre-mRNA processing in the nucleus to cytoplasmic mRNA
      translation and turnover. Recent studies suggest that several fundamental
      characteristics of hnRNPs account for their involvement in multiple regulatory
      pathways.

PMID- 10395554
TI  - Structure and function of the nucleolus.
AB  - The activity of the ribosomal RNA genes generates a distinct subnuclear
      structure, the nucleolus, which is the site of ribosome biogenesis. The signals
      that target proteins and snoRNAs (small nucleolar RNAs) to the nucleolus, the
      nuclear import of ribosomal proteins, the export of the completed ribosomal
      subunits and the molecular organization of the nucleolus have been the subject of
      intense research during the past year. Evidence is accumulating that nucleoli
      functionally interact with coiled bodies and are also involved in the maturation
      of non-ribosomal RNA species.

PMID- 10395555
TI  - mRNA polyadenylation and its coupling to other RNA processing reactions and to
      transcription.
AB  - Eukaryotic mRNA precursors are processed at their 3' ends by a coupled
      cleavage/polyadenylation reaction. In recent years, most of the factors involved
      in 3'-end processing have been identified and evidence has been presented for the
      coupling of mRNA 3'-end formation to capping, splicing and transcription. These
      links are important for the quality control of the mRNA during synthesis.

PMID- 10395556
TI  - Nuclear organization of pre-mRNA splicing factors.
AB  - The splicing of mRNA precursors (pre-mRNA) in the nucleus is catalyzed by a
      complex machinery termed the spliceosome. In order to understand how it functions
      in vivo, it is essential to complement biochemical analyses with a detailed study
      of how spliceosome components are organized within the nucleus.

PMID- 10395557
TI  - Telomerase and the maintenance of chromosome ends.
AB  - The catalytic subunit of telomerase has recently been identified in diverse
      eukaryotes and shown to be a reverse transcriptase. Ectopic expression of this
      protein in normal human cells leads to lengthened telomeres and an extended in
      vitro life span. Other proteins that modulate telomerase activity in vivo are
      also being identified, including a functionally conserved family of proteins with
      Myb-like DNA-binding domains and proteins that are involved in DNA double-strand
      break repair.

PMID- 10395558
TI  - The nuclear pore complex: from molecular architecture to functional dynamics.
AB  - Toward dissecting the molecular composition and architecture of the nuclear pore
      complex (NPC), over the past 18 months novel nucleoporins and NPC subcomplexes
      were identified and characterized. The three-dimensional structure of isolated
      yeast NPCs was determined by electron cryomicroscopy. New specimen preparation
      and labeling protocols localized a number of nucleoporins and NPC subcomplexes
      within the three-dimensional architecture of the yeast NPC. Structural changes of
      native NPCs mediated by physiological effectors such as calcium or ATP were
      monitored by time-lapse atomic force microscopy, thus revealing a first glimpse
      of the NPC's functional dynamics.

PMID- 10395559
TI  - Activation of RNA polymerase II transcription.
AB  - Multiple alternative interactions between activators and co-activators stimulate
      transcription by RNA polymerase II. In the past two years, multiprotein co
      activator complexes have been characterized and their subunits defined. TATA-box
      binding protein associated factor (TAF) subunits of yeast TFIID were found to be
      generally required for transcription in vivo. Mammalian multisubunit coactivator
      complexes with homologs of the yeast SRB/Mediator subunits have been
      characterized. Structures of nuclear receptor-coactivator complexes have been
      determined.

PMID- 10395561
TI  - Coupling RNA polymerase II transcription with pre-mRNA processing.
AB  - How are transcription and processing of mRNA precursors co-ordinated? The past
      two years has witnessed exciting insights into the mechanism which targets the
      mRNA processing machinery to RNA polymerase II (pol II) transcription complexes
      and closely integrates processing with transcription. Protein-protein contacts
      have been discovered between the pol II transcription machinery and RNA
      processing factors; furthermore, a unique domain of pol II has been identified
      that not only recruits processing factors but also controls their activity.

PMID- 10395560
TI  - Determinants of SR protein specificity.
AB  - The SR (Ser-Arg) proteins are a family of nuclear factors that play multiple
      important roles in splicing of mRNA precursors in metazoan organisms, functioning
      in both constitutive and regulated splicing. Certain of these functions are
      redundant, such that any single SR proteins will suffice, but other functions are
      unique and are specific to a given family member. A number of studies during the
      past year have investigated the basis for SR protein specificity.

PMID- 10395563
TI  - Histone H1: location and role.
AB  - Recent experiments have shown directly that, in bulk chromatin, the globular
      domain of histone H1 is positioned close to the dyad axis and is asymmetrically
      disposed, consistent with a polar arrangement of H1 molecules along the
      nucleosome filament. In addition to a structural role, H1 may also have gene
      specific effects on transcription. The positioning of a core particle relative to
      a transcription factor binding-site may favour either transcription factor
      binding or H1 binding, depending on the location of the site.

PMID- 10395564
TI  - Large-scale chromatin structure and function.
AB  - Recent results in living cells have now established the existence of levels of
      chromatin folding above the 30 nm fiber within interphase chromosomes. We discuss
      the potential functional impact of this large-scale chromatin organization,
      including its possible role in regulating gene expression.

PMID- 10395562
TI  - Mechanism and regulation of transcriptional elongation by RNA polymerase II.
AB  - Over the past few years, biochemical and genetic studies have shed considerable
      light on the structure and function of the RNA polymerase II (pol II) elongation
      complex and the transcription factors that control it. Novel elongation factors
      have been identified and their mechanisms of action characterized in increasing
      detail; new insights into the biological roles of elongation factors have been
      gained from genetic studies of the regulation of mRNA synthesis in yeast; and
      intriguing links between the pol II elongation machinery and the pathways of DNA
      repair and recombination have emerged.

PMID- 10395565
TI  - Gene activation by histone and factor acetyltransferases.
AB  - Persuasive evidence has emerged that acetyltransferases appear to truly function
      to acetylate both histones and transcription factors in vivo to effect gene
      activation. In the cell, acetyltransferases have been identified as components of
      large, multifunctional and evolutionarily conserved macromolecular assemblies,
      whose components and structures suggest complex functions. In addition, the first
      atomic resolution structures of HATs have revealed conserved mechanisms of acetyl
      CoA interaction among the superfamily of GNATs (Gcn5-related N
      acetyltransferases). Finally, enzymatic acetyltransferase activities are
      themselves regulated by phosphorylation and interaction with other proteins.

PMID- 10395566
TI  - V(D)J recombination: on the cutting edge.
AB  - The vertebrate immune system has evolved an elegant mechanism for generating an
      enormous diversity in antigen receptor binding specificity from a limited amount
      of genetic information. Recent advances are rapidly increasing our understanding
      of this unusual site-specific DNA rearrangement that assembles the antigen
      receptor genes during lymphoid development.

PMID- 10395567
TI  - Effects of estrogen in the CNS.
AB  - Awareness of estrogen's effects on neural function is broadening rapidly. Areas
      of recent progress include increased understanding of estrogen signaling through
      both genomic and nongenomic pathways, as well as the mechanisms by which estrogen
      can induce or maintain synapses and protect neurons from a variety of insults.
      Findings in these areas demonstrate a role for estrogen that goes beyond direct
      control of reproductive function.

PMID- 10395568
TI  - Regulation of back-propagating action potentials in hippocampal neurons.
AB  - Protein kinase C has recently been shown to modulate the slow recovery from
      inactivation of Na+ channels in apical dendrites of hippocampal CA1 pyramidal
      neurons. Moreover, dendritic, A-type K+ channels have been found to be modulated
      by protein kinases A and C and by mitogen-activated protein kinase. The
      electrical signalling ability of these dendrites is thus highly regulated by a
      number of neurotransmitters and second-messenger systems.

PMID- 10395569
TI  - Assembly of signaling machinery at the postsynaptic membrane.
AB  - The postsynaptic membrane and the subsynaptic cell compartment are specialized
      for inter- and intracellular signaling. Recent work has focused on the role of
      synaptic activity in regulating the surface distribution of neurotransmitter
      receptors. In addition, several components of secondary signaling pathways
      involved in the long-term regulation of synaptic efficacy have been identified.

PMID- 10395570
TI  - Clearance of glutamate inside the synapse and beyond.
AB  - The heated debate over the level of postsynaptic receptor occupancy by
      transmitter has not been extinguished - indeed, new evidence is fanning the
      flames. Recent experiments using two-photon microscopy suggest that the
      concentration of glutamate in the synaptic cleft does not attain levels
      previously suggested. In contrast, recordings from glial cells and studies of
      extrasynaptic receptor activation indicate that significant quantities of
      glutamate escape from the cleft following exocytosis. Determining the amount of
      glutamate efflux from the synaptic cleft and the distance it diffuses is critical
      to issues of synaptic specificity and the induction of synaptic plasticity.

PMID- 10395571
TI  - The bacterial K+ channel structure and its implications for neuronal channels.
AB  - Voltage-gated K+ (Kv) channels play a central role in generating action
      potentials and rhythmic patterns, as well as in dendritic signal processing in
      neurons. Recently, the first structure of a member of the K+ channel family was
      solved. Although this channel is from bacteria and has a streamlined body plan
      with no voltage gating, it establishes the architecture of the functional core of
      the voltage-gated (K+) channels and their relatives. This architecture explains
      the crucial features of ion permeation and blockade, and gives some strong hints
      about gating. The bacterial K+ channel structure is the central piece in a
      puzzle; it remains to be seen how it will fit together with other domains of the
      Kv channels, with auxiliary subunits, and with other signal transduction
      molecules.

PMID- 10395572
TI  - Synaptic vesicle docking and fusion.
AB  - Neurotransmitter secretion shares many features with constitutive membrane
      trafficking. In both cases, vesicles are targeted to a specific acceptor membrane
      and fuse via a series of protein-protein interactions. Recent work has added to
      the list of protein complexes involved and is beginning to define the order in
      which they act. The rapid fusion, precise regulation and plasticity
      characteristic of synaptic exocytosis probably results from the addition of
      specialized regulators.

PMID- 10395573
TI  - Calcium- and activity-dependent synaptic plasticity.
AB  - Calcium ions play crucial signaling roles in many forms of activity-dependent
      synaptic plasticity. Recent presynaptic [Ca2+]i measurements and manipulation of
      presynaptic exogenous buffers reveal roles for residual [Ca2+]i following
      conditioning stimulation in all phases of short-term synaptic enhancement.
      Pharmacological manipulations implicate mitochondria in post-tetanic
      potentiation. New evidence supports an influence of Ca2+ in replacing depleted
      vesicles after synaptic depression. In addition, high-resolution measurements of
      [Ca2+]i in dendritic spines show how Ca2+ can encode the precise relative timing
      of presynaptic input and postsynaptic activity and generate long-term synaptic
      modifications of opposite polarity.

PMID- 10395574
TI  - Structure, development, and plasticity of dendritic spines.
AB  - Dendritic spines are distinguished by their shapes, subcellular composition, and
      synaptic receptor subtypes. Recent studies show that actin-dependent movements
      take place in spine heads, that spines emerge from stubby and shaft synapses
      after dendritic filopodia disappear, and that spines can form without synaptic
      activation, are maintained by optimal activation, and are lost with excessive
      activation or during degeneration.

PMID- 10395575
TI  - Optical detection of synaptic vesicle exocytosis and endocytosis.
AB  - Recent advances in optical methods have catalyzed a detailed study of individual
      visualized synapses in several model systems. Quantal events at small central
      synapses, as well as single granule exocytosis in secretory cells, have been
      detected using quantitative fluorescence imaging. Sensitive detection of
      exocytosis and endocytosis at individual synapses has advanced our knowledge of
      synaptic vesicle trafficking.

PMID- 10395576
TI  - Signal transduction underlying growth cone guidance by diffusible factors.
AB  - Many diffusible axon guidance cues and their receptors have been identified
      recently. These cues are often found to be bifunctional, acting as attractants or
      repellents under different circumstances. Studies of cytoplasmic signaling
      mechanisms have led to the notion that the response of a growth cone to a
      particular guidance cue depends on the internal state of the neuron, which, in
      turn, is under the influence of other coincident signals received by the neuron.
      Furthermore, many diffusible guidance cues appear to share common cytoplasmic
      signaling pathways.

PMID- 10395577
TI  - Seizure disorders in mutant mice: relevance to human epilepsies.
AB  - The rate at which mutant genes producing an epileptic phenotype in mice have been
      identified over the past few years has been astounding. Manipulating the genome
      of mice has led to identification of a diversity of genes whose absence or
      modification either causes epileptic seizures or, conversely, limits
      epileptogenesis. In addition, positional cloning of genes in which spontaneously
      arising mutations cause epilepsy in mice has led to the identification of genes
      encoding voltage- and ligand-gated ion channels. Finally, engineering a mutation
      that mimics a rare form of human epilepsy has led to a mouse line with a
      phenotype similar to that of the human disease. Taken together, these discoveries
      promise to shed light on the mechanisms underlying genetic control of neuronal
      excitability, suggest candidate genes underlying genetic forms of human epilepsy,
      and provide a valuable model with which to elucidate how the genotype produces
      the phenotype of a rare form of human epilepsy.

PMID- 10395578
TI  - Brain protein serine/threonine phosphatases.
AB  - All of the known protein serine/threonine phosphatases are expressed in the
      brain. These enzymes participate in a variety of signaling pathways that modulate
      neuronal activity. The multifunctional activity of many serine/threonine
      phosphatases is achieved through their association with targeting proteins.
      Identification and analysis of targeting molecules has led to new insights into
      the functions of protein phosphatases in neuronal signaling. The recent use of
      transgenic mice has also increased our understanding of the physiological roles
      of these enzymes in the brain.

PMID- 10395579
TI  - Calcium channelopathies in the central nervous system.
AB  - The recent discovery that familial hemiplegic migraine, episodic ataxia type 2,
      and spinocerebellar ataxia type 6 are allelic disorders caused by different
      mutations in CACNA1A, a calcium-channel-encoding gene, adds to a growing list of
      channelopathies causing paroxysmal neurologic disturbance and progressive
      neurodegeneration. Calcium channelopathies in the central nervous system provide
      a model to study the important roles that calcium channels play in neuronal
      function.

PMID- 10395580
TI  - Roles of metabotropic glutamate receptors in LTP and LTD in the hippocampus.
AB  - Metabotropic L-glutamate receptors are involved in various forms of synaptic
      plasticity in the hippocampus. The use of a new antagonist (LY341495) that blocks
      all known metabotropic L-glutamate receptors in the brain, together with subtype
      selective antagonists, has identified multiple roles both for cloned and novel
      metabotropic L-glutamate receptors in hippocampal long-term potentiation and long
      term depression.

PMID- 10395581
TI  - Axonal atrophy: the retraction reaction.
AB  - Recent studies indicate that morphological alterations of axon branches that are
      removed during normal development are similar to those that occur following
      ablation of postsynaptic cells in adult animals. In both situations, axons
      retract (rather than degenerate), the calibers of withdrawing axon branches are
      markedly reduced, and spherical swellings near (or at) the axon terminations
      appear. The similarity between naturally occurring and target-deprived axon
      withdrawal suggests that both developing and adult axons withdraw from target
      cells that no longer provide support.

PMID- 10395583
TI  - Sphingolipids in food and the emerging importance of sphingolipids to nutrition.
AB  - Eukaryotic organisms as well as some prokaryotes and viruses contain
      sphingolipids, which are defined by a common structural feature, i.e. , a
      "sphingoid base" backbone such as D-erythro-1,3-dihydroxy, 2-aminooctadec-4-ene
      (sphingosine). The sphingolipids of mammalian tissues, lipoproteins, and milk
      include ceramides, sphingomyelins, cerebrosides, gangliosides and sulfatides;
      plants, fungi and yeast have mainly cerebrosides and phosphoinositides. The total
      amounts of sphingolipids in food vary considerably, from a few micromoles per
      kilogram (fruits) to several millimoles per kilogram in rich sources such as
      dairy products, eggs and soybeans. With the use of the limited data available,
      per capita sphingolipid consumption in the United States can be estimated to be
      on the order of 150-180 mmol (approximately 115-140 g) per year, or 0.3-0.4 g/d.
      There is no known nutritional requirement for sphingolipids; nonetheless, they
      are hydrolyzed throughout the gastrointestinal tract to the same categories of
      metabolites (ceramides and sphingoid bases) that are used by cells to regulate
      growth, differentiation, apoptosis and other cellular functions. Studies with
      experimental animals have shown that feeding sphingolipids inhibits colon
      carcinogenesis, reduces serum LDL cholesterol and elevates HDL, suggesting that
      sphingolipids represent a "functional" constituent of food. Sphingolipid
      metabolism can also be modified by constituents of the diet, such as cholesterol,
      fatty acids and mycotoxins (fumonisins), with consequences for cell regulation
      and disease. Additional associations among diet, sphingolipids and health are
      certain to emerge as more is learned about these compounds.

PMID- 10395584
TI  - A delicate balance: homeostatic control of copper uptake and distribution.
AB  - The cellular uptake and intracellular distribution of the essential but highly
      toxic nutrient, copper, is a precisely orchestrated process. Copper homeostasis
      is coordinated by several proteins to ensure that it is delivered to specific
      subcellular compartments and copper-requiring proteins without releasing free
      copper ions that will cause damage to cellular components. Genetic studies in
      prokaryotic organisms and yeast have identified membrane-associated proteins that
      mediate the uptake or export of copper from cells. Within cells, small cytosolic
      proteins, called copper chaperones, have been identified that bind copper ions
      and deliver them to specific compartments and copper-requiring proteins. The
      identification of mammalian homologues of these proteins reveal a remarkable
      structural and functional conservation of copper metabolism between bacteria,
      yeast and humans. Furthermore, studies on the function and localization of the
      products of the Menkes and Wilson's disease genes, which are defective in
      patients afflicted with these diseases, have provided valuable insight into the
      mechanisms of copper balance and their role in maintaining appropriate copper
      distribution in mammals.

PMID- 10395585
TI  - Dietary canola oil alters hematological indices and blood lipids in neonatal
      piglets fed formula.
AB  - This study was undertaken to determine the effects of canola oil on platelet
      characteristics, blood lipids and growth in exclusively formula-fed piglets.
      Piglets were fed from birth to 10 or 18 d with formula containing 51% energy from
      fat, with 100% fat as canola or soybean oil; 26% soybean, 59% high oleic acid
      sunflower and 12% flax oil (canola mimic); or 26% canola (canola blend) or
      soybean (soybean blend) with high oleic acid sunflower, palm and coconut oil. The
      canola mimic provided similar carbon chain 16 and 18 fatty acids without the
      sterol or 20:1 and erucic acid (22:1) of canola oil. The oil blends provided
      formula resembling infant formulas but with higher 16:0 and lower unsaturated
      fatty acid levels than in canola or soybean oil. Body weight, weight gain and
      heart and liver weight were not different after 10 or 18 d feeding canola when
      compared to soybean oil alone or blended oil formulas. Piglets fed formulas with
      100% canola oil had lower platelet counts than piglets fed formula soybean oil or
      the canola oil mimic. Platelet counts were lower, and platelet distribution width
      and volume were higher, when formulas with 100% canola or soybean rather than the
      blended oil formulas were fed. The results show that formula fat composition
      influences the developing hematological system and that canola oil suppresses the
      normal developmental increase in platelet count in piglets by a mechanism
      apparently unrelated to the formula 16:0, 18:1, 18:2(n-6) or 18:3(n-3), or plasma
      phospholipid 20:4(n-6) or 20:5(n-3).

PMID- 10395586
TI  - Tyrosol, the major olive oil biophenol, protects against oxidized-LDL-induced
      injury in Caco-2 cells.
AB  - Experimental and clinical evidence suggest that oxidative stress causes cellular
      damage, leading to functional alterations of the tissue. Free radicals may thus
      play an important role in the pathogenesis of a number of human diseases. Among
      pro-oxidant agents, oxidized LDL lead to the production of cytotoxic reactive
      species, e.g., lipoperoxides, causing tissue injury and various subsequent
      pathologies including intestinal diseases. Thus, to analyze the oxidative damage
      induced by oxidized LDL to intestinal mucosa, we evaluated morphological and
      functional changes induced in the human colon adenocarcinoma cell line, Caco-2.
      In addition, we examined the protective effects exerted by tyrosol, 2-(4
      hydroxyphenyl)ethanol, the major phenolic compound present in olive oil. Caco-2
      cell treatment (24 and/or 48 h) with oxidized LDL (0.2 g/L) resulted in
      cytostatic and cytotoxic effects characterized by a series of morphological and
      functional alterations: membrane damage, modifications of cytoskeleton network,
      microtubular disorganization, loss of cell-cell and cell-substrate contacts, cell
      detachment and cell death. The oxidized LDL-induced alterations in Caco-2 cells
      were almost completely prevented by tyrosol which was added 2 h before and
      present during the treatments. Our results suggest that some biophenols, such as
      those contained in olive oil, may counteract the reactive oxygen metabolite
      mediated cellular damage and related diseases, by improving in vivo antioxidant
      defenses.

PMID- 10395587
TI  - Keratinocyte growth factor enhances glutathione redox state in rat intestinal
      mucosa during nutritional repletion.
AB  - Malnutrition decreases tissue levels of glutathione (GSH), a major endogenous
      antioxidant that detoxifies reactive oxygen species and promotes cell growth.
      This study determined the effects of the gut trophic peptide keratinocyte growth
      factor (KGF) on intestinal mucosal GSH concentrations and redox state in
      malnourished rats. Adult rats were food-deprived for 3 d, then consumed food ad
      libitum or 25% of ad libitum intake for 3 d with daily intraperitoneal
      administration of saline or KGF (5 mg.kg-1.d-1). Mucosal GSH and glutathione
      disulfide (GSSG) concentrations, crypt depth and total mucosal height were
      measured in the jejunum, ileum and colon. In the 25% of ad libitum-refed, saline
      treated group, mucosal GSH was lower in all gut tissues (42% in jejunum, 38% in
      ileum, and 57% in colon), and the GSH/GSSG ratio was lower in the jejunum and
      ileum compared to that in the ad libitum-refed controls. KGF treatment with ad
      libitum refeeding increased GSH/GSSG in the jejunum, ileum and colon.
      Furthermore, in 25% of ad libitum refeeding, KGF normalized jejunal, ileal and
      colonic mucosal GSH content and significantly increased the mucosal GSH/GSSG
      ratio relative to rats treated with saline. Increased crypt depth and total
      mucosal height induced by KGF and feeding could be explained in part by increased
      mucosal GSH content. KGF treatment improved gut mucosal glutathione redox state
      in malnourished, refed rats. These data provide evidence that gut trophic
      hormones and food intake may independently support gut mucosal glutathione
      antioxidant capacity during nutritional repletion.

PMID- 10395588
TI  - Dietary retinol inhibits inflammatory responses of rats treated with
      monocrotaline.
AB  - This study was designed to test the effectiveness of dietary retinol in
      protecting the heart and lung parenchyma in a monocrotaline model for lung injury
      and pulmonary hypertension in rats. Male rats were assigned to three groups. Two
      groups were injected subcutaneously with monocrotaline (17 mg/kg body weight) and
      fed either the control AIN-93G diet (MC) or the control diet supplemented with
      retinol (17 mg retinyl palmitate/kg diet)(MR). The third group was fed the
      control diet and injected with the vehicle only (VC). Four weeks after
      monocrotaline treatment, the MR group had less thickening of the alveolar septal
      wall, less myocardial inflammation and degeneration of the right ventricle, and
      less vascular inflammation in the lung compared with the MC group. The
      supplemented dietary retinol, however, did not prevent development of right
      ventricular hypertrophy and did not affect the synthesis and secretion of
      surfactant phospholipids in type II pneumocytes. The results indicate that
      dietary retinol suppresses the inflammatory responses in the heart and lungs of
      rats treated with monocrotaline.

PMID- 10395589
TI  - Soybean isoflavones, genistein and genistin, inhibit rat myoblast proliferation,
      fusion and myotube protein synthesis.
AB  - The isoflavones, genistein and genistin, are cytotoxic in vitro (e.g. ,
      inhibition of cell proliferation), due in part to inhibition of protein tyrosine
      kinase and DNA topoisomerase activities. Normal cell functions associated with
      these enzymatic activities could potentially be impaired in animals through
      ingestion of soybean products. In this study, cultured rat myogenic cells (L8)
      were used to determine whether genistein or genistin influences myoblast
      proliferation and fusion, and myotube protein synthesis and degradation.
      Genistein or genistin was dissolved in dimethylsulfoxide and included in the
      culture medium at 0, 1, 10 or 100 micromol/L. Myoblast proliferation was measured
      by methyl-3H-thymidine incorporation over 48 h. Myoblast differentiation was
      evaluated by the number of nuclei in multinucleated myotubes. Myotube protein
      synthesis was measured by 2-h 3H-amino acid incorporation into the myosin and
      total protein pools after acute (2 h) or chronic (24 h) exposure to similar
      treatments; protein degradation was measured by measuring radioactivity in
      protein pools following a time course of protein breakdown after myotube proteins
      were prelabeled with 3H-amino acids. Genistein or genistin strongly inhibited in
      vitro myoblast proliferation (P < 0.001) and fusion (P < 0.001) in a dose
      dependent manner with effective genistein concentration as low as 1 micromol/L.
      Genistein or genistin inhibited protein accretion in myotubes (P < 0.001).
      Decreased protein accretion is largely a result of inhibition on cellular
      (myofibrillar) protein synthesis rate. No adverse effect on protein degradation
      was observed. Results suggest that if sufficient circulating concentrations are
      reached in tissues of animals consuming soy products, genistein/genistin can
      potentially affect normal muscle growth and development.

PMID- 10395590
TI  - Glucose and amino acids interact with hormones to control expression of insulin
      like growth factor-I and growth hormone receptor mRNA in cultured pig
      hepatocytes.
AB  - Nutrients and hormones are major determinants of animal growth, but the
      mechanisms of how nutrients influence the growth process are still unclear. A
      primary pig hepatocyte culture system was used to investigate possible direct
      effects of glucose and individual amino acids on the expression of growth hormone
      receptor (GHR) and insulin-like growth factor-I (IGF-I) mRNA. The removal of
      glucose from the culture medium for 40 h resulted in significant reductions (to
      45% of control, P = 0.013) in the expression of GHR in the presence of growth
      hormone (GH), dexamethasone (DEX) and tri-iodothyronine (T3). The decrease in GHR
      expression with removal of glucose from the culture medium resulted in a
      decreased response in class 1 (22% of control, P = 0.011) and 2 (5% of control P
      = 0. 068) transcripts of IGF-I to any GH added. The effects of glucose on GHR and
      IGF-I expression were dose-dependent, appearing to plateau at approximately 1-2
      g/L (P = 0.031, for quadratic trend). Removal of arginine, proline, threonine,
      tryptophan or valine inhibited the stimulation of IGF-I expression that was
      induced by the combination of T3, DEX and GH (to 15, 6, 11, 16 and 16% of
      control, respectively, P < 0.05), with significant decreases in GHR expression
      also observed in some cases. The stimulatory effect of some of these amino acids
      (arginine, proline, threonine and tryptophan) was dose-dependent for expression
      of class 1 transcripts of IGF-I (P = 0. 041, 0.022, 0.016 and 0.097,
      respectively, for linear trends), but there was no effect on GHR or class 2
      transcripts of IGF-I. Whether the observed effects of nutrients on mRNA levels
      are due to direct effects on gene transcription or differences in mRNA stability
      remains to be established. Energy, in the form of glucose, appears to control GHR
      expression, interacting with the effects of glucocorticoids and thyroid hormones,
      whereas protein, in the form of certain individual amino acids, appears to
      control GH-stimulated IGF-I expression.

PMID- 10395591
TI  - Energy metabolism increases and regional body fat decreases while regional muscle
      mass is spared in humans climbing Mt. Everest.
AB  - The objectives of the study were to determine regional changes in body
      composition, energy expenditure by means of doubly labeled water, and net energy
      balance during exposure to high and extreme altitudes (5,300-8,848 m). This study
      focuses on a subset of subjects who consumed the doubly labeled water (three base
      camp personnel and seven climbers). Regional body composition was determined by
      measuring skinfold thicknesses and circumferences at 10 different sites on the
      body. Energy expenditure was measured by doubly labeled water excretion.
      Discrepancies between actual energy expenditure and data obtained from diet
      records and body weight changes suggested a chronic underreporting of dietary
      energy intake, especially by those subjects who reached the highest altitudes.
      This underreporting may be due in part to diminished cognition or to a
      preferential focus on survival, rather than on filling out diet records
      accurately. Mean adjusted dietary intakes were 10.50 +/- 0. 65 MJ/d (2510 +/- 155
      kcal/d) for those who remained at base camp, and 20.63 +/- 6.56 MJ/d (4931 +/-
      1568 kcal/d) for those who climbed above base camp. Energy expenditure averaged
      2.5-3.0 times sea level resting energy expenditure. Differential changes in
      regional body composition suggested a preferential loss of fat mass and a
      relative sparing of muscle mass, despite insufficient energy intake to maintain
      body weight.

PMID- 10395592
TI  - 10-Formyl-dihydrofolic acid is bioactive in human leukemia cells.
AB  - The bioactivity of 10-formyl-7,8-dihydrofolic acid and 10-formyl-folic acid was
      determined in human leukemia (CCRF-CEM) cells grown in a folate-depleted medium
      containing methotrexate. Excess 10-formyl-7,8-dihydrofolic acid, (but not 10
      formyl folic acid) supported the growth of these cells, but it was less potent
      than5-formyl-5,6,7,8-tetrahydrofolic acid (a control). 10-formyl-7, 8
      dihydrofolic acid (not 10-formyl folic acid) was active as substrate for
      aminoimidazole carboxamide ribotide transformylase and dihydrofolate reductase.
      This is the first experimental evidence that 10-formyl-7,8-dihydrofolic acid is a
      bioactive folate in mammalian cells. These experiments and several other lines of
      evidence in the literature suggest that 10-formyl-folic acid must be metabolized
      to bioactive folate by enteric bacteria before it can be utilized by the
      vertebrate host.

PMID- 10395593
TI  - Long-term supplementation with iron does not enhance growth in malnourished
      Bangladeshi children.
AB  - To evaluate the effect of long-term oral iron supplementation on growth, 250
      children aged 6-71 mo were studied in a randomized double-blind controlled trial.
      The intervention group received 125 mg of ferrous gluconate (15 mg elemental
      iron) plus multivitamins (vitamins A, D and C); the comparison group received
      only multivitamins daily for 12 mo. Weight (kg) and height (cm) were measured
      every month. Eighty three percent of the children continued the treatment for one
      year. The weight increment over the 12-mo period was 1.35 +/- 0.65 kg (mean +/-
      SD) in the intervention group and 1.39 +/- 0.54 kg in the comparison group. The
      height increments were 6.01 +/- 1.47 and 6.18 +/- 1.58 cm in the intervention and
      comparison groups, respectively. Mean weight and height increments did not
      differ; in an analysis stratified according to different age and nutritional
      categories, they also did not differ between the two groups, indicating that long
      term iron supplementation does not increase growth in children.

PMID- 10395594
TI  - Hamsters and guinea pigs differ in their plasma lipoprotein cholesterol
      distribution when fed diets varying in animal protein, soluble fiber, or
      cholesterol content.
AB  - There were two objectives to these studies: 1) to compare the lipoprotein
      cholesterol distribution in two animal models in response to different dietary
      treatments and 2) to assess whether the hypercholesterolemia induced by high
      cholesterol intake could be reversed by consumption of vegetable-protein and/or
      dietary fiber. Guinea pigs, which carry the majority of plasma cholesterol in
      LDL, and hamsters, with a higher distribution of cholesterol in HDL, were
      evaluated in three different studies. In Study 1, animals were fed semi-purified
      diets for 4 wk with proportions of 60:40, 20:80 or 0:100 (w/w) of casein/ soybean
      protein. Hamsters and guinea pigs that consumed 100% soybean protein had lower
      plasma total cholesterol (TC) than those fed diets containing casein (P < 0.01).
      In Study 2, three doses of dietary pectin (2.7, 5.4, or 10.7 g/100g) added in
      place of cellulose were tested. Intake of 10.7 g/100 g pectin resulted in the
      lowest plasma TC concentrations for both species (P < 0.01). Although the TC
      lowering was similar in studies 1 and 2, the lipoprotein cholesterol distribution
      differed. Whereas the differences in plasma cholesterol were in LDL in guinea
      pigs, hamsters exhibited differences in both non-HDL and HDL cholesterol. In
      study 3, animals were fed 100% soybean protein, 10.7 g/100 g pectin, and three
      doses of dietary cholesterol: 0.04, 0.08, or 0.16 g/100 g, which is equivalent to
      300, 600, or 1,200 mg/d in humans. Guinea pigs and hamsters had the highest
      plasma LDL and hepatic cholesterol concentrations when they consumed 0.16 g/100 g
      of cholesterol (P < 0.01). However, intake of 0.08 g/100 g of cholesterol
      resulted in lower plasma LDL cholesterol concentrations than did consuming high
      animal protein (60:40 casein/ soy) or low soluble fiber (2.7 g/100 g). Relatively
      high levels of dietary cholesterol combined with vegetable protein and soluble
      fiber resulted in desirable lipoprotein profiles in animal models that
      significantly differ in their lipoprotein cholesterol distribution.

PMID- 10395595
TI  - Oligo-L-methionine and resistant protein promote cecal butyrate production in
      rats fed resistant starch and fructooligosaccharide.
AB  - We examined the role of resistant protein and peptides in promoting cecal
      butyrate production in rats fed rapidly fermentable carbohydrates. Rats were fed
      diets containing raw potato starch (RPS, 200 g/kg diet) or fructooligosaccharide
      (FOS, 60 g/kg diet) with casein, soy or rice protein (250 g/kg diet) for 13 d. In
      rats fed RPS with casein, the major cecal organic acid was acetate (441
      micromol), but lactate and succinate were also found in considerable amounts (324
      micromol). Succinate was the major cecal organic acid (235 micromol) in rats fed
      FOS with casein. When rice protein was fed with RPS, the contribution of lactate
      was significantly lower and that of propionate tended to be higher (P < 0.1) than
      in rats fed casein. In rats fed rice protein with FOS, cecal butyrate and acetate
      were greater and cecal succinate was lower than in rats fed casein with FOS (P <
      0.05). Despite the similar amounts of undigested protein in rice and soy
      proteins, soy protein did not similarly affect cecal butyrate in rats fed FOS or
      RPS. In another experiment, rats were fed diets containing high amylose
      cornstarch (HAS, 200 g/kg diet) with casein, casein + oligo-L-methionine (OM, 3
      g/kg diet), soy protein, soy protein + OM (3 g/kg diet) or rice protein (250 g/kg
      diet) for 10 d. OM (digestibility, 31%) was substituted for the same amount of
      casein. Rats fed rice protein had greater cecal butyrate than rats fed casein (P
      < 0.05). OM supplementation to casein or soy protein increased cecal butyrate
      compared with rats fed casein or soy protein alone (P < 0.05). These data support
      our hypothesis that resistant protein and peptides promote cecal butyrate
      production and suggest that the differing potency of rice and soy proteins in
      promoting cecal butyrate production might be explained in part by the different
      amino acid composition of resistant protein.

PMID- 10395596
TI  - Food deprivation and refeeding influence growth, nutrient retention and
      functional recovery of rats.
AB  - The objective of this work was to determine the effects of starvation and
      refeeding on growth, nutritional recovery and intestinal repair in starved rats.
      Male Wistar rats, weighing 200 g, were starved for 3 d, then refed a soy-based
      diet for another 3 d. Normally fed rats were given the same diet and used as
      controls. The variables assessed were as follows: body weight gain and nitrogen
      retention during recovery after starvation; muscle glutamine concentration;
      tissue protein content; gut mucosa and liver glutathione levels; intestinal
      permeability to ovalbumin, lactulose and mannitol; and intestinal tissue
      apoptosis. Starvation was associated with lower muscle glutamine levels and
      intestinal mucosa impairment, including a lower content of mucosal protein, a
      higher level of oxidized glutathione, enhanced permeability to macromolecules and
      greater numbers of apoptotic cells. Refeeding for 3 d resulted in rapid repair of
      gut atrophy and normalization of not only intestinal permeability but also of the
      majority of metabolic markers assessed in other tissues. In conclusion, with the
      use of severely starved rats, we have established a reversible experimental
      animal model of malnutrition that might prove useful in comparing the
      effectiveness of different enteral diets.

PMID- 10395597
TI  - Dietary protein or arginine deficiency impairs constitutive and inducible nitric
      oxide synthesis by young rats.
AB  - Effects of dietary protein or arginine deficiency on constitutive and
      lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis were determined in
      young rats by quantifying urinary nitrate excretion. In Experiment 1, 30-d-old
      rats (n = 16) were divided randomly into two groups (n = 8/group) and pair-fed on
      the basis of body weight semipurified isocaloric diets containing 20 or 5%
      casein. In Experiment 2, 30-d-old rats (n = 24) were divided randomly into three
      groups (n = 8) and pair-fed on the basis of body weight purified isonitrogenous
      and isocaloric diets (composed of amino acids) containing 0.0, 0.3 or 1.0% L
      arginine. In both experiments, daily collection of urine was initiated 10 d after
      the start of pair-feeding. On d 17 after the pair-feeding was initiated, LPS (1
      mg/kg body wt) was injected intraperitoneally into rats, and urine was collected
      daily for an additional 7 d. In Experiments 3 and 4, activities of constitutive
      and inducible NO synthases were measured in macrophages and various tissues from
      protein- or arginine-deficient rats (n = 6). Body weight was lower in rats fed
      the 5% casein diet or the 0.0 and 0.3% arginine diets than in those fed 20%
      casein or 1% arginine, respectively. Dietary protein or arginine deficiency
      decreased serum concentrations of arginine and urinary nitrate excretion before
      and after LPS treatment, indicating impaired constitutive and inducible NO
      synthesis. Protein malnutrition reduced constitutive and inducible NO synthase
      activities in brain, heart, jejunum, lung, skeletal muscle and spleen, and
      inducible NO synthase activity in macrophages. Because NO is a mediator of the
      immune response and is the endothelium-dependent relaxing factor, impaired NO
      synthesis may help explain immunodeficiency and cardiovascular dysfunction in
      protein- or arginine-deficient subjects.

PMID- 10395598
TI  - All-rac-alpha-tocopherol acetate is a better vitamin E source than all-rac-alpha
      tocopherol succinate for broilers.
AB  - The difference in bioavailabilities of the acetate and succinate esters of all
      rac-alpha-tocopherol was investigated in a feeding experiment with broilers. The
      experiment was initiated with 96 12-d-old male Cobb broilers and lasted for 4 wk.
      The two sources of vitamin E were fed to eight groups of broilers at four
      different dietary levels (50, 100, 150 and 200 mg/kg feed, including the
      naturally occurring alpha-tocopherol). A total collection of droppings for
      determination of apparent tocopherol absorption were performed at two separate
      time periods (d 28-34 and d 35-41). There were no differences among the eight
      experimental groups with respect to animal performance or feed intake. At all
      dietary levels, the apparent absorption coefficient for all-rac-alpha-tocopherol
      succinate was significantly lower than that of the acetate ester. The mean (+/-
      SD) apparent absorption coefficient for all-rac-alpha-tocopherol succinate was
      58.0 +/- 5.4 compared with 70. 8 +/- 5.6 for all-rac-alpha-tocopherol acetate.
      Furthermore, the apparent absorption coefficients for both esters was
      significantly lower in the first collection period (d 28-34) than in the second
      collection period (d 35-41). This difference in the apparent absorption
      coefficient between the succinate and the acetate ester was accompanied by
      significant differences in alpha-tocopherol concentrations in plasma, breast
      muscle, liver and adipose tissue of the broilers, which were lower in those fed
      the succinate ester. Based on a comparison of plasma and tissue responses, the
      succinate ester was utilized only 69-76% as efficiently as the acetate ester. In
      vitro studies showed a significantly higher capacity of pancreatic carboxyl ester
      hydrolase to hydrolyze alpha-tocopherol acetate compared to alpha-tocopherol
      succinate. This difference in intestinal hydrolysis of the two vitamin E sources
      may explain the observed differences in biopotency.

PMID- 10395599
TI  - Teas and other beverages suppress D-galactosamine-induced liver injury in rats.
AB  - We compared the effects of various types of beverages (teas, coffee, and cocoa)
      on D-galactosamine-induced liver injury by measuring plasma alanine
      aminotransferase (ALT) and aspartate aminotransferase (AST) activities in 7-wk
      old male Wistar rats. The effects of five fractions extracted with different
      organic solvents from green tea, different types of dietary fibers, and some
      short chain fatty acids were also investigated. All of the beverages tested
      significantly suppressed D-galactosamine-induced enhancement of plasma enzyme
      activities when powdered beverages were added to the diet (30 g/kg) and fed to
      rats for 2 wk. Plasma ALT activities were 1155 +/- 82 [micromol/(min.L),
      control], 289 +/- 61 (green tea), 626 +/- 60 (roasted green tea), 471 +/- 84
      (puerh tea), 676 +/- 69 (oolon tea), 423 +/- 76 (black tea), 829 +/- 53 (coffee),
      and 885 +/- 89 (cocoa). The profile of AST activities was similar. The caffeine
      containing fraction from green tea had no significant effect, whereas the other
      four fractions, including the soluble fiber fraction, significantly suppressed
      liver injury. In addition to tea fibers, many other types of dietary fiber
      (hemicellulose, chitin, chitosan, alginate, pectin, guar gum, glucomannan, and
      inulin, but not cellulose) had liver injury-preventive effects when added to the
      diet (30 g/kg), suggesting that liver injury-prevention may be one of the general
      effects of dietary fibers. Of three short-chain fatty acids tested (acetate,
      propionate, and butyrate), only acetate prevented liver injury when added to the
      diet (15 g/kg), supporting the possibility that the liver injury-preventive
      effect of dietary fibers may be mediated at least in part by certain organic
      acids. These results suggest that several beverages possess preventive effects on
      certain types of liver injury, such as that induced by D-galactosamine, and that
      different constituents of high and low molecular weights contribute to the liver
      injury-preventive effects of green tea.

PMID- 10395600
TI  - Dietary copper primarily affects antioxidant capacity and dietary iron mainly
      affects iron status in a surface response study of female rats fed varying
      concentrations of iron, zinc and copper.
AB  - This study was designed to examine the interactions among dietary iron (Fe),
      copper (Cu), and zinc (Zn) and their effects on Fe status and oxidative stress in
      female rats. In a three-factor central composite response surface design, rats
      were assigned to 15 groups and fed modified AIN-93G basal diets with varying
      amounts of Fe and Zn (7.0, 15.5, 45.8, 135.6, or 300 micrograms/g diet) and Cu
      (0.5, 1.1, 3.2, 9.2, or 20 micrograms/g diet) for 6 wk. Variations in hemoglobin,
      hematocrit, and serum ferritin were mainly related to dietary Fe. Liver nonheme
      Fe was directly affected by dietary Fe and was slightly attenuated by
      interactions between Cu and Zn, and Zn and Fe. Serum ceruloplasmin activity was
      primarily determined by an interaction between Cu and Zn with substantial
      moderation by the quadratic effect of dietary Cu. Liver and heart total
      superoxide dismutase (SOD) and Cu/Zn SOD activities were directly affected by
      dietary Cu. Dietary Fe was the only significant, yet weak, predictor of liver
      thiobarbituric acid reactive substances (TBARS) and vitamin E content and serum
      triacylglycerols. Variability in serum Cu was mostly determined by the
      interaction between Cu and Fe, with modification from the quadratic effect of
      dietary Cu. Serum Zn varied with dietary Zn with a small negative influence from
      the interaction between Cu and Fe. In summary, Fe status was minimally influenced
      by dietary Zn or Cu, and Fe intakes 10-fold greater than required did not induce
      overt oxidative stress in female rats. In addition, measures of antioxidant
      capacity were primarily influenced by dietary Cu and were optimal at moderate
      intakes of this micronutrient.

PMID- 10395601
TI  - Dietary nucleotides augment dextran sulfate sodium-induced distal colitis in
      rats.
AB  - We have previously shown that enteral and parenteral supplementation of
      nucleotides (NT) accelerates healing of small-bowel ulcers in rats with
      indomethacin-induced ileitis. The purpose of this study was to evaluate whether
      dietary NT supplementation would similarly affect ulcer healing in dextran
      sulfate sodium (DSS)-induced colitis in rats. Male Sprague-Dawley rats were
      randomly assigned to receive either nucleotide-free (NF) or NT-supplemented
      diets. After 2 d of prefeeding, colitis was induced by including 40 g/L of DSS in
      drinking water for 3 d, followed thereafter by tap water. Rats from each group
      were killed at 7 and 12 d after induction of colitis. Additional rats were also
      used for both the groups as controls (untreated groups). The length of colon was
      measured and evaluated by histological score. Colonic myeloperoxidase (MPO)
      activity was assessed. In a separate series of experiments, rats were studied at
      0, 4, 7, and 12 d for interleukin-1beta (IL-1beta) in rectal dialysate and
      plasma. Ulceration predominated in the distal colon in DSS-treated rats. There
      was no significant difference between the histological scores of the NF and NT
      supplemented groups either at 7 or 12 d. MPO activity at 7 and 12 d was
      significantly higher in the NT-supplemented compared to NF group (7 d: 1013 +/-
      172 vs. 409.9 +/- 103.2; 12 d: 471.9 +/- 112.4 vs. 223.6 +/- 21.6 units. min-1. g
      colon-1). IL-1beta concentration in rectal dialysate was significantly higher at
      7 d in both groups compared to 0 and 4 d. At 12 d it continued to be
      significantly elevated in the NT-supplemented group and was greater than in the
      NT-free group. Our data on the proinflammatory cytokine, in conjunction with MPO
      activity, strongly suggest that NT supplementation aggravates the severity of DSS
      induced colitis in rats.

PMID- 10395603
TI  - Comments on LSRO report's recommendations on infant formula nutrient
      requirements.

PMID- 10395602
TI  - High intake of milk fat inhibits intestinal colonization of Listeria but not of
      Salmonella in rats.
AB  - During fat digestion, fatty acids and monoglycerides are liberated in the
      gastrointestinal tract. Generally, these lipids are potent inhibitors of gram
      positive bacteria in vitro but have less effect on gram-negative microbes.
      Considering this, we hypothesized that increased intake of bovine milk fat would
      result in enhanced gastrointestinal killing of Listeria monocytogenes (gram
      positive) but have little effect on infection with Salmonella enteritidis (gram
      negative) in rats. To test this, rats were fed either low milk fat diets (10% of
      energy obtained from milk fat, corresponding to 4. 2 g fat/100 g diet) or high
      milk fat diets (40% of energy obtained from milk fat, corresponding to 19.6 g
      fat/100 g diet). After adaptation to these diets, rats were orally infected with
      Listeria or Salmonella. Greater milk fat consumption in Listeria-infected rats
      diminished intestinal colonization of Listeria (P < 0.05) and reduced diarrhea (P
      < 0.05). Analysis of gastrointestinal contents showed that killing of Listeria
      occurred predominantly in the stomach. High milk fat intake significantly
      augmented this gastric listericidal capacity (P < 0.05) and raised the
      concentration of medium-chain and saturated long-chain free fatty acids and of
      monoglycerides of C12:0, C14:0, C16:0, C18:0, and C18:1 in gastric chyme (P <
      0.05). Considering the in vitro listericidal capacity of these agents, it was
      concluded that particularly the free fatty acids C10:0, C12:0 and C14:0 and the
      monoglycerides of C12:0, C14:0, and C16:0 seem to play a pivotal role in this
      enhanced Listeria killing. In contrast, Salmonella infection was not affected by
      milk fat consumption. In conclusion, high milk fat intake results in higher
      concentrations of gastric bactericidal lipids and thereby protects against
      Listeria infection but not against Salmonella.

PMID- 10395604
TI  - Response to comments on LSRO Report's recommendations 

PMID- 10395605
TI  - Functional foods and health promotion.
AB  - Statements about the ability of selected foods to reduce the risk of diseases and
      to enhance the quality of life continue to captivate, and at times polarize,
      opinions. Interests in these "functional" foods and their active components are
      being propelled by increasing health care cost, recent legislative events and
      mounting scientific evidence. Increasingly, scientists are being asked to clarify
      the precise role that foods have in maintaining and promoting health. Accepting
      this movement as an opportunity to "optimize nutrition" rather than as a way in
      which to endorse good or bad foods or as a marketing gimmick will surely make it
      more acceptable to many scientists. However, the response to functional foods
      depends on several factors, including genetics, physiologic state and the
      composition of the entire diet. Although evaluation of the benefits or risks of
      foods normally does not entail the same extensive examination as that required of
      drugs, this does not negate the need for sound scientific information for making
      recommendations to the consumer. Identification of sensitive and reliable
      biomarkers will be key to adequate assessment of the true effect of foods and
      their components. Inulin and oligofructose are components of the diet that
      deserve added attention for their potential health benefits. Evidence that
      oligofructose and inulin alter several biomarkers, including gastrointestinal
      transit time, experimentally induced neoplasia and colonic microflora, suggests
      that these nondigestible carbohydrates are naturally occurring dietary
      constituents that may improve the quality of life and increase disease resistance
      in both humans and animals.

PMID- 10395606
TI  - Concepts in functional foods: the case of inulin and oligofructose.
AB  - Recent advances in biosciences support the hypothesis that diet modulates various
      body functions. Diet may maintain well-being and reduce the risk of some
      diseases. Such discoveries have led to the concept of "functional food" and the
      development of the new discipline, i.e., "functional food science." A practical
      and simple definition of a "functional food" is a food for which a claim has been
      authorized. The food components to be discussed as potential "functional food
      ingredients" are the inulin-type fructans, i.e., chicory inulin and oligofuctose.
      The targets for their effects are the colonic microflora, the gastrointestinal
      physiology, the immune functions, the bioavailability of minerals, the metabolism
      of lipids and colonic carcinogenesis. Potential health benefits include reduction
      of risk of colonic diseases, noninsulin-dependent diabetes, obesity, osteoporosis
      and cancer. The documentation of such benefits requires scientific evidence that
      must be evaluated in terms of "health claims." Previous assessments have
      concluded that, in terms of "functional claims," strong evidence exists for a
      prebiotic effect and improved bowel habit. The evidence for calcium
      bioavailability is promising, and positive modulation of triglyceride metabolism
      is undergoing preliminary evaluation. Scientific research still must be done to
      support any "disease risk reduction claim," but sound hypotheses do already exist
      for designing the relevant human nutrition trials.

PMID- 10395607
TI  - Inulin and oligofructose: what are they?
AB  - Inulin is a term applied to a heterogeneous blend of fructose polymers found
      widely distributed in nature as plant storage carbohydrates. Oligofructose is a
      subgroup of inulin, consisting of polymers with a degree of polymerization (DP)
      </=10. Inulin and oligofructose are not digested in the upper gastrointestinal
      tract; therefore, they have a reduced caloric value. They stimulate the growth of
      intestinal bifidobacteria. They do not lead to a rise in serum glucose or
      stimulate insulin secretion. Several commercial grades of inulin are available
      that have a neutral, clean flavor and are used to improve the mouthfeel,
      stability and acceptability of low fat foods. Oligofructose has a sweet, pleasant
      flavor and is highly soluble. It can be used to fortify foods with fiber without
      contributing any deleterious organoleptic effects, to improve the flavor and
      sweetness of low calorie foods and to improve the texture of fat-reduced foods.
      Inulin and oligofructose possess several functional and nutritional properties,
      which may be used to formulate innovative healthy foods for today's consumer.

PMID- 10395608
TI  - Presence of inulin and oligofructose in the diets of Americans.
AB  - The U.S. Department of Agriculture 1994-1996 Continuing Survey of Food Intakes by
      Individuals was used to estimate the intake of naturally occurring inulin and
      oligofructose by the U.S. population. Two nonconsecutive 24-h dietary recalls
      from >15,000 Americans of all ages were conducted, and a special database of
      inulin and oligofructose was developed specifically for the analyses. American
      diets provided on average 2.6 g of inulin and 2.5 g of oligofructose. Intakes
      varied by gender and age, ranging from 1.3 g for young children to 3.5 g for
      teenage boys and adult males. When standardized for amount of food consumed, the
      intakes showed little difference across gender and age. Significant differences
      in intake of these components were seen between categories within region of the
      country, season, income, and race and origin; however, the actual differences
      were relatively small. Major food sources of naturally occurring inulin and
      oligofructose in American diets were wheat, which provided about 70% of these
      components, and onions, which provided about 25% of these components. The
      estimation of the presence of inulin and oligofructose in the diets of Americans
      has not been published to date.

PMID- 10395609
TI  - Inulin and oligofructose: safe intakes and legal status.
AB  - Inulin and oligofructose are a significant part of the daily diet of most of the
      world's population. Daily intakes for the U.S. and Europe have been estimated at
      up to 10 g, specifically 1-4 g for the 97th percentile in the U.S. Because both
      inulin and oligofructose are macroingredients, it is difficult to apply classical
      toxicology tests. Although some high dose animal tests have been performed, none
      have revealed any toxic effects. The safety of inulin and oligofructose for use
      in foods was evaluated by many legal authorities worldwide. As a result, both
      inulin and oligofructose are accepted in most countries as food ingredients that
      can be used without restrictions in food formulations. In the U.S., a panel of
      experts performed a generally accepted as safe (GRAS) Self-Affirmation Evaluation
      in 1992 and concluded similarly. At high doses, increased flatulence and osmotic
      pressure can cause intestinal discomfort. These doses vary widely from person to
      person and also depend on the type of food in which inulin or oligofructose is
      incorporated. With regard to labeling, both inulin and oligofructose are
      gradually being accepted as "dietary fibers" in most countries around the world.
      The mention of their "bifidogenic effect" on food labels has also been legally
      accepted in several countries.

PMID- 10395610
TI  - Methods to determine food inulin and oligofructose.
AB  - The fructans, inulin and oligofructose, were known to possess many of the
      physiologic properties of dietary fiber (DF) but were not listed as DF on the
      labels of foods that contained them because they did not precipitate in 78%
      ethanol as prescribed in the AOAC International methods for DF. In the latter
      part of 1995, the Food and Drug Administration (FDA) agreed to consider fructans
      as DF if an AOAC-accepted analytical method could be successfully developed for
      fructans. Six blind duplicate pairs of foods, containing from 4 to 40% of inulin
      or oligofructose, were sent to nine collaborators in five countries for assay.
      These foods included a low fat spread, cheese spread, chocolate, wine gum, dry
      ice mix powder and biscuits. In the proposed method, the samples were treated
      with amyloglucosidase and inulinase, and the sugars released were determined by
      ion-exchange chromatography. The concentration of the fructan was calculated by
      the difference in sugars present in the two enzymic treatments and the initial
      sample. The repeatability standard deviations (RSDr) for the inulin and
      oligofructose ranged from 2.9 to 5.8% and the reproducibility standard deviations
      (RSDR) for these fructans ranged from 4.7 to 11.1%. The method was accepted by
      the AOAC as an official first action.

PMID- 10395611
TI  - Fiber, inulin and oligofructose: similarities and differences.
AB  - The biological, chemical and physical properties of dietary fibers are associated
      with physiologic actions in the small and large intestine that have important
      metabolic implications for health. These properties of fiber include
      dispersibility in water, bulk, viscosity, adsorption and binding of compounds and
      fermentability. Dietary fructans share some of the properties of dietary fiber
      and thus are likely to have similar metabolic effects. Within the small
      intestine, properties such as dispersibility in water, bulking and viscosity are
      associated with slowing the digestion and absorption of carbohydrate and lipid
      and promoting nutrient absorption along a greater length of the small intestine.
      Both of these actions are related to cholesterol reduction and blunting of
      alimentary gylcemia. Although fructans are dispersible in water and will provide
      some bulk because they are nondigestible in the small intestine, they do not
      appear to be associated with significant increases in viscosity. Thus one would
      predict that any immediate effects on alimentary glycemia or on cholesterol
      reduction are likely to be modest compared with more viscous polysaccharides.
      Fermentability and bulking capacity of nondigestible carbohydrates define an
      essential role of fiber in maintaining gastrointestinal health. Within the large
      intestine, carbohydrates that are not digested in the small intestine are
      available for fermentation by the microflora present. Carbohydrates that are
      dispersible in the aqueous phase are more readily digested by microbes. A large
      body of evidence indicates that dietary fructans are digested in the large
      intestine, resulting in an increase in microbial mass and production of short
      chain fatty acids.

PMID- 10395612
TI  - Nondigestibility characteristics of inulin and oligofructose in humans.
AB  - The ileostomy model is considered to be a reliable model to reflect small bowel
      absorption. Studies in ileostomy subjects have shown that inulin and
      oligofructose pass through the small bowel without degradation and without
      influencing the absorption of nitrogen, fat, starch, calcium, magnesium or zinc.
      Inulin and oligofructose do not have any considerable effect on cholesterol
      absorption or bile acid excretion.

PMID- 10395613
TI  - Inulin, oligofructose and intestinal function.
AB  - Inulin and oligofructose have attracted much attention recently as nonabsorbable
      carbohydrates with prebiotic properties. When inulin and oligofructose were added
      to a controlled diet, significant increases were noted in colonic bifidobacterial
      populations, and it has been proposed that these changes promote both colonic and
      systemic health through modification of the intestinal microflora. Inulin and
      oligofructose are rapidly and completely fermented by the colonic microflora with
      the production of acetate and other short-chain fatty acids. As with lactulose,
      they may also result in the growth of the fecal biomass, and in doing so, entrap
      ammonia for bacterial protein synthesis or conversion to the ammonium ion. As
      with dietary fiber and other nonabsorbable carbohydrates, there is also interest
      in inulin and oligofructose from the standpoint of inhibition of colonic
      carcinogenesis, blood cholesterol reduction, immune stimulation and enhanced
      vitamin synthesis. In these areas, the influence of their molecular weight is
      also an issue, with the longer chain length providing a more sustained
      fermentation pattern. More human studies are now required, including studies on
      the long-term effects of inulin and oligofructose consumption on colonic health,
      in particular on markers of cancer risk such as reduction in colonic polyp
      recurrence.

PMID- 10395615
TI  - Caloric value of inulin and oligofructose.
AB  - Dietary carbohydrates, which are absorbed as hexose, (glucose, fructose) have a
      caloric value of 3.9 kcal/g (16.3 kJ/g), and their cellular metabolism produces
      approximately 38 mol ATP/mol. However, chicory inulin and oligofructose resist
      digestion and they are not absorbed in the upper part of the gastrointestinal
      tract. After oral ingestion, they reach the colon intact where they become
      hydrolyzed and extensively fermented by saccharolytic bacteria, which produce
      short-chain carboxylic and lactic acids as electron sinks. Depending on both the
      degree of their colonic fermentation and the assumptions of the model used, the
      caloric value of such nondigested but fermented carbohydrates varies between 0
      and 2.5 kcal/g. Through the catabolism of the absorbed short-chain carboxylic and
      lactic acids, they may produce up to 17 mol ATP/mol of fermented sugar moiety.
      Because the daily intake of these dietary carbohydrates is likely to remain
      relatively small (<10% and probably often not >5% of total daily calorie intake),
      it is of low relevance nutritionally to give them a precise caloric value. On the
      basis of biochemical balance charts for carbon atoms, metabolic pathways and
      energy yields to the host, the caloric value of a fructosyl residue in chicory
      inulin and oligofructose has been calculated to be approximately 25-35% that of a
      fully digested and absorbed fructose molecule. For the purpose of food labeling,
      it is recommended that chicory inulin and oligofructose, like all the other
      carbohydrates that are more or less completely fermented in the human colon,
      should be given a caloric value of 1.5 kcal/g (6.3 kJ/g).

PMID- 10395614
TI  - Nondigestible carbohydrates and mineral bioavailability.
AB  - Generally, fiber and compounds associated with fiber in cereal products (e.g.,
      phytates) have been found to reduce the apparent absorption of minerals (such as
      calcium, magnesium, zinc and manganese) in humans, livestock and animal models.
      The effects of "soluble" forms of fiber (specifically pectins, gums, resistant
      starches, lactulose, oligofructose and inulin) on mineral absorption are more
      difficult to characterize. The addition of these soluble forms of fiber has been
      found in various studies to add viscosity to the gut contents, promote
      fermentation and the production of volatile fatty acids in the cecum, have a
      trophic effect on the ceca of animals and increase serum enteroglucagon
      concentrations. Thus it is not surprising that the addition of soluble forms of
      fiber to diets often has been found to improve absorption of minerals. This may
      reflect absorption of electrolytes from the large intestine. Future work should
      address the mechanisms by which ingestion of nondigestible carbohydrates improves
      mineral absorption in humans.

PMID- 10395616
TI  - Dietary modulation of the human gut microflora using the prebiotics oligofructose
      and inulin.
AB  - Although largely unproven in humans, better resistance to pathogens, reduction in
      blood lipids, antitumor properties, hormonal regulation and immune stimulation
      may all be possible through gut microflora manipulation. One approach advocates
      the oral intake of live microorganisms (probiotics). Although the probiotic
      approach has been extensively used and advocated, survivability/viability after
      ingestion is difficult to guarantee and almost impossible to prove. The prebiotic
      concept dictates that non viable dietary components fortify certain components of
      the intestinal flora (e.g., bifidobacteria, lactobacilli). This concept has the
      advantage that survival of the ingested ingredient through the upper
      gastrointestinal tract is not a prerequisite because it is indigenous bacterial
      genera that are targeted. The feeding of oligofructose and inulin to human
      volunteers alters the gut flora composition in favor of bifidobacteria, a
      purportedly beneficial genus. Future human studies that exploit the use of modern
      molecular-based detection methods for bacteria will determine the efficacy of
      prebiotics. It may be possible to address prophylactically certain
      gastrointestinal complaints through the selective targeting of gut bacteria.

PMID- 10395617
TI  - Dose-response effects of inulin and oligofructose on intestinal bifidogenesis
      effects.
AB  - Recent studies have identified several beneficial attributes of inulin (I) and
      oligofructose (OF) in human health. However, most of the studies pertaining to
      the physiologic role of these compounds have been conducted at higher
      concentrations (8-40 g/d) as a source of dietary fiber. There is growing interest
      in using I and OF as a substrate for the selective growth of beneficial
      gastrointestinal bacteria such as the bifidobacteria. In vitro fermentation
      studies using fecal inoculums have shown that I and OF are utilized rapidly and
      completely by intestinal microflora and that the degree of polymerization of the
      substrate influenced its rate of disappearance. In these and other studies, I and
      OF were shown to be efficient substrates for the growth of most strains of
      bifidobacteria compared with glucose. In vivo studies have also shown that when
      human volunteers ingested I or OF, the number of fecal bifidobacteria increased.
      However, when results from the reported studies are combined and analyzed, a dose
      response relationship in terms of log increases in the count of bifidobacteria
      cannot be demonstrated. Initial numbers of bifidobacteria in the feces,
      independent of the dose of the fructo-oligosaccharides, seem to influence the
      results. Future investigations should consider this relationship carefully.

PMID- 10395618
TI  - The application of ecological principles and fermentable fibers to manage the
      gastrointestinal tract ecosystem.
AB  - Because diet can influence the structure and functions of the gastrointestinal
      tract, there are opportunities for using diet as a "management tool" to affect
      the resident microbiota. Fermentable fibers increase the densities of beneficial
      bacteria and stimulate growth and functions of the healthy intestine. Recent
      findings show that after acute diarrhea, the use of an oral electrolyte solution
      with the fermentable fiber oligofructose accelerates recovery of beneficial
      bacteria, reduces the relative abundance of detrimental bacteria, stimulates
      mucosal growth and enhances digestive and immune functions. This review will
      focus on how the principles of stream ecology can be applied to better understand
      the distribution of bacteria along the length of the gastrointestinal tract, the
      effect of diarrhea on the gastrointestinal ecosystem and how fermentable fibers
      can be used as a "management tool" to promote gastrointestinal health in normal
      states and during recovery from diarrhea.

PMID- 10395619
TI  - Controlled trial of oligofructose in the management of irritable bowel syndrome.
AB  - A double-blind crossover trial of oligofructose (Raftilose P95) 2 g three times
      daily against sucrose (1 g) three times daily was performed in patients suffering
      from irritable bowel syndrome. Each treatment was followed for 4 wk. Patients
      consumed a standardized diet during the last 14 d of each treatment period, and
      symptoms were assessed using a previously validated questionnaire. Fecal weight
      and pH, whole-gut transit time and fasting breath hydrogen concentrations were
      measured at the start of the study and at the end of each treatment period.
      Oligofructose produced no significant change in any of these parameters even when
      patients were divided into those with predominant diarrhea (n = 14) and those
      with predominant constipation (n = 7). Oligofructose at a dose of 6 g/d had no
      therapeutic value in patients with irritable bowel syndrome.

PMID- 10395621
TI  - Impact of nondigestible carbohydrates on serum lipoproteins and risk for
      cardiovascular disease.
AB  - Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in
      the U.S. and in most developed countries. Many nutritional factors contribute to
      risk for ASCVD including total and saturated fat consumption, fruits and
      vegetables in the diet and dietary fiber intake. This review will focus on the
      relationship of dietary fiber intake to risk for coronary heart disease (CHD) and
      ASCVD (which includes, principally, CHD, cerebral vascular disease and peripheral
      vascular disease). Fiber-rich foods such as vegetables, fruits, whole-grain
      cereals and legumes are rich sources of nutrients, phytochemicals and
      antioxidants. For example, most high fiber foods contain soluble and insoluble
      fiber, minerals, vitamins, other micronutrients and phytochemicals. Cereals and
      legumes also contain complex carbohydrates and unsaturated fatty acids. Some high
      fiber foods are rich in monounsaturated fatty acids, whereas others provide (n-3)
      fatty acids. Legumes and certain vegetables provide oligosaccharides. When
      assessing the health benefits of dietary fiber, one should consider the potential
      effects of associated nutrients, micronutrients and phytochemicals. These
      interactions will be reviewed as we discuss relationships of dietary fiber to
      ASCVD.

PMID- 10395620
TI  - Petfood applications of inulin and oligofructose.
AB  - Published data on intestinal microbiota of dogs and cats are limited but suggest
      the presence of a complex and diverse colonic bacterial population (34 genera
      including 129 species) the majority of which are anaerobes. During the colonic
      fermentation of endogenous and undigested amino acids, several putrefactive
      compounds (i.e., ammonia, aliphatic amines, indoles, phenols and volatile sulfur
      containing compounds) are produced and are responsible for the malodor of dog and
      cat feces. These fecal odor components also have been implicated as causes of
      colorectal cancer; therefore, dietary manipulation of gut microbiota towards a
      potentially more remedial community (Bifidobacterium and Lactobacillus) is
      gaining more attention. The health benefits derived from dietary supplementation
      of prebiotics (e.g., oligofructose and inulin) have been documented in humans.
      However, little is known of a potentially similar role in companion animals.
      Feeding another prebiotic (i.e., lactosucrose) to dogs or cats is reported to
      increase the numbers of bifidobacteria and decrease the numbers of pathogens and
      the concentration of fecal odor components. In our laboratory, oligofructose
      supplementation numerically decreased the concentrations of ammonia and amines
      and increased the numbers of bifidobacteria in dog feces.

PMID- 10395622
TI  - Biochemical basis of oligofructose-induced hypolipidemia in animal models.
AB  - Oligofructose (OFS), a mixture of nondigestible/fermentable
      fructooligosaccharides, decreases serum triacylglycerol (TAG) when it is included
      in the standard, fiber-free or high fat diet of rats. This paper summarizes in
      vivo and in vitro data to establish a biochemical mechanism underlying the
      hypolipidemic effect of OFS. When OFS is added to the standard (carbohydrate
      rich) diet of rats at the dose of 10 g/100 g, a TAG-lowering action occurs as a
      consequence of a reduction of de novo liver fatty acid synthesis. The depression
      in the activity of all lipogenic enzymes and fatty acid synthase mRNA suggests
      that OFS modifies the gene expression of lipogenic enzymes. Through its
      modulation of de novo lipogenesis, OFS can protect against liver lipid
      accumulation induced by providing 10% fructose-enriched water for 48 h. OFS also
      significantly decreases serum insulin and glucose, which are both known to
      participate in the nutritional regulation of lipogenesis. It also increases the
      intestinal production of incretins, namely, glucose-dependent insulinotropic
      peptide and glucagon-like peptide 1. This latter phenomenon results mainly from
      promotion of intestinal tissue proliferation by oligofructose fermentation end
      products. Collectively, a link likely exists between the modulation of hormone
      and incretin production by OFS, and its antilipogenic effect.

PMID- 10395623
TI  - Effects of inulin on lipid parameters in humans.
AB  - Convincing lipid-lowering effects of the fructooligosaccharide inulin have been
      demonstrated in animals, yet attempts to reproduce similar effects in humans have
      generated conflicting results. This may be because of the much lower doses used
      in humans as a result of the adverse gastrointestinal symptoms exhibited by most
      subjects consuming daily doses in excess of 30 g. Two studies that fed either
      oligofructose (20 g/d) or inulin (14 g/d) observed no effect on fasting total,
      LDL or HDL cholesterol, or serum triglycerides. Two other studies that fed inulin
      either in a breakfast cereal (9 g/d) or as a powdered addition to beverages and
      meals (10 g/d) reported similar reductions in fasting triglycerides (-27 and 
      19%, respectively). In one of these studies, total and LDL cholesterol
      concentrations were also modestly reduced (5 and 7%, respectively). Because
      animal studies have identified inhibition of hepatic fatty acid synthesis as the
      major site of action for the triglyceride-lowering effects of inulin, and because
      this pathway is relatively inactive in humans unless a high carbohydrate diet is
      fed, future attempts to demonstrate lipid-lowering effects of inulin should
      consider the nature of the background diet as a determinant of response.

PMID- 10395624
TI  - Effects of dietary inulin on serum lipids.
AB  - Inulin is a carbohydrate belonging to a class of compounds known as fructans.
      Because inulin is resistant to digestion in the upper gastrointestional tract it
      reaches the large intestine essentially intact, where it is fermented by
      indigenous bacteria. Thus, it may be classified as a soluble dietary fiber.
      Soluble fibers have been shown to modulate serum lipids. A recent study examined
      the effect of consuming three servings per day of inulin-containing foods,
      compared with the effect of similar foods without inulin, on serum lipid profiles
      among hypercholesterolemic men and women. In addition, the practicality of
      including 18 g/d of inulin in a low fat diet was investigated. The recent study
      randomized, double-blind, crossover trial with two 6-wk treatment periods,
      separated by a 6-wk washout. Men and women (n = 21) with baseline LDL increased
      significantly (7.4 and 12.3%, respectively) during the control phase. There were
      small, nonsignificant declines in total (1.3%) and LDL-C (2.1%) during the inulin
      phase. Thus, differences in response between periods (inulin - control) were
      significant (P < 0.05) for LDL-C (-14.4%) and total cholesterol (-8.7%). Mild
      gastrointestinal discomfort was more common during the inulin than the control
      food phase; however, the gastrointestinal side-effect profile of inulin was
      similar to that of other soluble fibers. Although it was not possible to draw
      firm conclusions, inulin may have blunted the hypercholesterolemic effects
      observed during consumption of control foods. Additional research will be
      required to confirm the possible lipid-modulating properties of dietary inulin in
      humans.

PMID- 10395625
TI  - Possible mechanisms by which pro- and prebiotics influence colon carcinogenesis
      and tumor growth.
AB  - Oligofructose and inulin, selective fermentable chicory fructans, have been shown
      to stimulate the growth of bifidobacteria, which are regarded as beneficial
      strains in the colon. Studies were designed to evaluate inulin (Raftiline) and
      oligofructose (Raftilose) for their potential inhibitory properties against the
      development of colonic aberrant crypt foci (ACF) in rats. ACF are putative
      preneoplastic lesions from which adenomas and carcinomas may develop in the
      colon. The results of this study indicate that dietary administration of
      oligofructose and inulin inhibits the development of ACF in the colon, suggesting
      the potential colon tumor inhibitory properties of chicory fructans. The degree
      of ACF inhibition was more pronounced in animals given inulin than in those fed
      oligofructose. Because these prebiotics selectively stimulate the growth of
      bifidobacteria, ornithine decarboxylase (ODC) activities, ras-p21 ontoprotein
      expressions and tumor inhibitory activity of lyophilized cultures of
      Bifidobacterium longum against chemically induced colon and mammary
      carcinogenesis and against colonic tumor cell proliferation were examined.
      Dietary administration of lyophilized cultures of B. longum strongly suppressed
      colon and mammary tumor development and tumor burden. Inhibition of colon
      carcinogenesis was associated with a decrease in colonic mucosal cell
      proliferation and activities of colonic mucosal and tumor ornithine decarboxylase
      and ras-p21. Human clinical trials are likely to broaden our insight into the
      importance of the pre- and probiotics in health and disease.

PMID- 10395626
TI  - The effect of synbiotics on colon carcinogenesis in rats.
AB  - Evidence indicates that consumption of probiotic microorganisms such as
      bifidobacteria reduces the risk of colon cancer in animal models. Feeding certain
      fructans such as oligofructose and inulin, which are thought to selectively
      increase the growth of intestinal bifidobacteria (i.e., a prebiotic effect), also
      has been shown to reduce colon cancer risk. The objective of our study was
      twofold, i. e., to determine whether the combination of bifidobacteria and
      oligofructose would have an additive effect (i.e., synbiotic) in reducing colon
      cancer risk in rats, and to determine whether other oligosaccharides would also
      be effective as part of a synbiotic combination. The development of colonic
      preneoplastic lesions (aberrant crypts) was used as an index of colon cancer
      risk. In one series of experiments, rats were given the carcinogen 1, 2
      dimethylhydrazine (DMH) and administered one of the following treatments: skim
      milk (control), bifidobacteria (bifido), oligofructose (OF) or bifido + OF.
      Neither bifido nor OF alone significantly reduced aberrant crypt number. Bifido +
      OF reduced aberrant crypt number in five of six experiments, although the
      reduction was significant in only one. However, a paired comparison of the six
      experiments indicated a significant overall reduction in aberrant crypts by
      bifido + OF (P = 0.039). Soybean oligosaccharide (SBO) and wheat bran
      oligosaccharide (WBO) were also fed in combination with bifidobacteria. In two
      other experiments, SBO did not alter the number of aberrant crypts compared with
      the control, whereas WBO reduced aberrant crypt number in one experiment but not
      in another. Of OF, SBO and WBO, only SBO reduced the colonic mucosa proliferation
      compared with the control. These results suggest that the combination of
      bifidobacteria and oligofructose reduces colon cancer risk in carcinogen-treated
      rats, but the effect of other oligosaccharides is uncertain.

PMID- 10395627
TI  - Influence of inulin and oligofructose on breast cancer and tumor growth.
AB  - Because anticarcinogenic and tumor-growth-inhibiting effects of nonsoluble fibers
      have been described, similar actions of soluble fibers appear to merit
      investigation. In a preliminary study on methylnitrosourea-induced mammary
      carcinogenesis in Sprague-Dawley female rats, 15% oligofructose added to the
      basal diet modulated this carcinogenesis in a negative manner. There was a lower
      number of tumor-bearing rats and a lower total number of mammary tumors in
      oligofructose-fed rats than in the group fed the basal diet alone. The effect of
      dietary nondigestible carbohydrates (15% oligofructose, inulin or pectin
      incorporated into the basal diet) on the growth of intramuscularly transplanted
      mouse tumors, belonging to two tumor lines (TLT and EMT6), was also investigated.
      The results were evaluated by regular tumor measurements with a vernier caliper.
      The mean tumor surface in the experimental groups was compared with that in
      animals of the control group fed the basal diet containing starch as the only
      carbohydrate. The growth of both tumor lines was significantly inhibited by
      supplementing the diet with nondigestible carbohydrates. Such nontoxic dietary
      treatment appears to be easy and risk free for patients, applicable as an
      adjuvant factor in the classical protocols of human cancer therapy.

PMID- 10395628
TI  - The influence of chronic yogurt consumption on immunity.
AB  - There has been increased interest in the study of nutrition and immunity. This is
      especially true with respect to the hypothesis that consumption of specific foods
      may reduce an individual's susceptibility to the establishment and/or progression
      of immunologic disease. Although an increased intake of a specific food may
      improve health status in select cases, chronic consumption of large amounts of
      one specific food may in fact be detrimental. The studies described here examined
      the long-term effect of yogurt consumption on two different age populations,
      young adults (20-40 y) and senior adults (55-70 y). There were three study groups
      per age group, live-culture yogurt, pasteurized yogurt and control (no yogurt),
      given 200 g/d of yogurt for 1 y. The subjects completed a questionnaire detailing
      health parameters on a weekly basis and a 4-d food record was taken monthly.
      Blood was taken every 3 mo and complete blood chemistry, blood count, total and
      specific immunoglobulin (Ig)E, and interferon-gamma (IFN-gamma) production
      measured. Yogurt consumption, especially for the live-culture groups, was
      associated with a decrease in allergic symptoms in both age groups. Seniors in
      the control group experienced an increase in both total and LDL cholesterol,
      whereas those in the yogurt groups remained stable during the course of the
      study. There was little effect on IFN-gamma and IgE production, although seniors
      in the yogurt group had lower levels of total IgE throughout the year.

PMID- 10395629
TI  - A comparison of injections of botulinum toxin and topical nitroglycerin ointment
      for the treatment of chronic anal fissure.
AB  - BACKGROUND AND METHODS: Lateral internal sphincterotomy, the most common
      treatment for chronic anal fissure, may cause permanent injury to the anal
      sphincter, which can lead to fecal incontinence. We compared two nonsurgical
      treatments that avert the risk of fecal incontinence. We randomly assigned 50
      adults with symptomatic chronic posterior anal fissures to receive treatment with
      either a total of 20 U of botulinum toxin injected into the internal anal
      sphincter on each side of the anterior midline or 0.2 percent nitroglycerin
      ointment applied twice daily for six weeks. RESULTS: After two months, the
      fissures were healed in 24 of the 25 patients (96 percent) in the botulinum-toxin
      group and in 15 of the 25 (60 percent) in the nitroglycerin group (P=0.005). No
      patient in either group had fecal incontinence. At some time during treatment,
      five patients in the nitroglycerin group had transient, moderate-to-severe
      headaches that were related to treatment. None of the patients in the botulinum
      toxin group reported adverse effects. Ten patients who did not have a response to
      the assigned treatment - 1 in the botulinum-toxin group and 9 in the
      nitroglycerin group - crossed over to the other treatment; the fissures
      subsequently healed in all 10 patients. There were no relapses during an average
      of about 15 months of follow-up. CONCLUSIONS: Although treatment with either
      topical nitroglycerin or botulinum toxin is effective as an alternative to
      surgery for patients with chronic anal fissure, botulinum toxin is the more
      effective nonsurgical treatment.

PMID- 10395630
TI  - Aggressive lipid-lowering therapy compared with angioplasty in stable coronary
      artery disease. Atorvastatin versus Revascularization Treatment Investigators.
AB  - BACKGROUND: Percutaneous coronary revascularization is widely used in improving
      symptoms and exercise performance in patients with ischemic heart disease and
      stable angina pectoris. In this study, we compared percutaneous coronary
      revascularization with lipid-lowering treatment for reducing the incidence of
      ischemic events. METHODS: We studied 341 patients with stable coronary artery
      disease, relatively normal left ventricular function, asymptomatic or mild-to
      moderate angina, and a serum level of low-density lipoprotein (LDL) cholesterol
      of at least 115 mg per deciliter (3.0 mmol per liter) who were referred for
      percutaneous revascularization. We randomly assigned the patients either to
      receive medical treatment with atorvastatin, at 80 mg per day (164 patients), or
      to undergo the recommended percutaneous revascularization procedure (angioplasty)
      followed by usual care, which could include lipid-lowering treatment (177
      patients). The follow-up period was 18 months. RESULTS: Twenty-two (13 percent)
      of the patients who received aggressive lipid-lowering treatment with
      atorvastatin (resulting in a 46 percent reduction in the mean serum LDL
      cholesterol level, to 77 mg per deciliter [2.0 mmol per liter]) had ischemic
      events, as compared with 37 (21 percent) of the patients who underwent
      angioplasty (who had an 18 percent reduction in the mean serum LDL cholesterol
      level, to 119 mg per deciliter [3.0 mmol per liter]). The incidence of ischemic
      events was thus 36 percent lower in the atorvastatin group over an 18-month
      period (P=0.048, which was not statistically significant after adjustment for
      interim analyses). This reduction in events was due to a smaller number of
      angioplasty procedures, coronary-artery bypass operations, and hospitalizations
      for worsening angina. As compared with the patients who were treated with
      angioplasty and usual care, the patients who received atorvastatin had a
      significantly longer time to the first ischemic event (P=0.03). CONCLUSIONS: In
      low-risk patients with stable coronary artery disease, aggressive lipid-lowering
      therapy is at least as effective as angioplasty and usual care in reducing the
      incidence of ischemic events.

PMID- 10395632
TI  - Transplacental transmission of natural-killer-cell lymphoma.

PMID- 10395633
TI  - Images in clinical medicine. Successful treatment of severe thalassemia.

PMID- 10395631
TI  - Cytomegalovirus infection and HIV-1 disease progression in infants born to HIV-1
      infected women. Pediatric Pulmonary and Cardiovascular Complications of
      Vertically Transmitted HIV Infection Study Group.
AB  - BACKGROUND AND METHODS: Cytomegalovirus (CMV) has been implicated as a cofactor
      in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We
      assessed 440 infants (75 of whom were HIV-1-infected and 365 of whom were not)
      who had known CMV status and were born to HIV-1-infected women and who were
      followed prospectively. HIV-1 disease progression was defined as the presence of
      class C symptoms (according to the criteria of the Centers for Disease Control
      and Prevention [CDC]) or CD4 counts of less than 750 cells per cubic millimeter
      by 1 year of age and less than 500 cells per cubic millimeter by 18 months of
      age. RESULTS: At birth the frequency of CMV infection was similar in the HIV-1
      infected and HIV-1-uninfected infants (4.3 percent and 4.5 percent,
      respectively), but the HIV-1-infected infants had a higher rate of CMV infection
      at six months of age (39.9 percent vs. 15.3 percent, P=0.001) and continued to
      have a higher rate of CMV infection through four years of age (P=0.04). By 18
      months of age, the infants with both infections had higher rates of HIV-1 disease
      progression (70.0 percent vs. 30.4 percent, P=0.001), CDC class C symptoms or
      death (52.5 percent vs. 21.7 percent, P=0.008), and impaired brain growth or
      progressive motor deficits (35.6 percent vs. 8.7 percent, P=0.005) than infants
      infected only with HIV-1. In a Cox regression analysis, CMV infection was
      associated with an increased risk of HIV-1 disease progression (relative risk,
      2.59; 95 percent confidence interval, 1.13 to 5.95). Among children infected with
      HIV-1 alone, but not among those infected with both viruses, children with rapid
      progression of HIV-1 disease had higher mean levels of HIV-1 RNA than those with
      slower or no progression of disease. CONCLUSIONS: HIV-1-infected infants who
      acquire CMV infection in the first 18 months of life have a significantly higher
      rate of disease progression and central nervous system disease than those
      infected with HIV-1 alone.

PMID- 10395634
TI  - An increase in the number of deaths in the United States in the first week of the
      month--an association with substance abuse and other causes of death.
AB  - BACKGROUND AND METHODS: There are regular changes in mortality rates, such as
      increased rates of death from influenza in the winter and from motor vehicle
      accidents on long holiday weekends. Previous research has shown that among
      persons with schizophrenia, the rates of cocaine use and hospital admissions
      increase at the beginning of the month, after the receipt of disability payments.
      Using computerized data from all death certificates in the United States between
      1973 and 1988, we compared the number of deaths in the first week of the month
      with the number of deaths in the last week of the preceding month. RESULTS: The
      average number of deaths was about 5500 per day, or about 165,000 in a 30-day
      month. There were 100.9 deaths (95 percent confidence interval, 100.8 to 101.0)
      in the first week of the month for every 100 deaths in the last week of the
      preceding month. This was equivalent to about 4320 more deaths in the first week
      of each month than in the last week of the preceding month in an average year.
      Between 1983 and 1988, for deaths involving substance abuse and an external cause
      (such as suicides, accidents, and homicides), there were 114.2 deaths (95 percent
      confidence interval, 110.5 to 117.9) in the first week of the month for every 100
      in the last week of the preceding month. There were significant increases in the
      number of deaths in the first week of the month for many causes of death,
      including substance abuse, natural causes, homicides, suicides, and motor vehicle
      accidents. CONCLUSIONS: In the United States, the number of deaths is higher in
      the first week of the month than in the last week of the preceding month. The
      increase at the beginning of the month is associated with substance abuse and
      other causes of death.

PMID- 10395635
TI  - The beta-thalassemias.

PMID- 10395636
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 20-1999. A 16-year-old girl with fever, rash, and severe ocular
      disease.

PMID- 10395637
TI  - One man's poison--clinical applications of botulinum toxin.

PMID- 10395638
TI  - Cancer during pregnancy.

PMID- 10395639
TI  - Cutting edge: combined treatment of TNF-alpha and IFN-gamma causes redistribution
      of junctional adhesion molecule in human endothelial cells.
AB  - Proinflammatory cytokines such as TNF-alpha and IFN-gamma induce cell adhesion
      molecules in endothelial cells and promote transmigration of leukocytes across
      endothelial cells. However, when those two were administered together, leukocyte
      transmigration paradoxically decreased. We cloned a human and bovine homologue of
      the junctional adhesion molecule (JAM), a novel molecule at the tight junction,
      and examined the effects of proinflammatory cytokines on JAM in HUVECs. The
      combined treatment of TNF-alpha plus IFN-gamma caused a disappearance of JAM from
      intercellular junctions. However, flow cytometry, cell ELISA, and subcellular
      fractionation analysis demonstrated that the amount of JAM was not reduced. This
      suggested that JAM changed its distribution in response to proinflammatory
      cytokines. This redistribution of JAM might be involved in a decrease in
      transendothelial migration of leukocytes at inflammatory sites.

PMID- 10395640
TI  - Cutting edge: purinergic signaling regulates radical-mediated bacterial killing
      mechanisms in macrophages through a P2X7-independent mechanism.
AB  - Signaling by extracellular nucleotides through P2 purinergic receptors affects
      diverse macrophage functions; however, its role in regulating antimicrobial
      radicals during bacterial infection has not been investigated. Mycobacterium
      tuberculosis-infected macrophages released ATP in a dose-dependent manner, which
      correlated with nitrite accumulation. P2 receptor inhibitors, including oxidized
      ATP, blocked NO synthase (NOSII) up-regulation and NO production induced by
      infection with M. tuberculosis or bacille Calmette-Guerin, or treatment with LPS
      or TNF-alpha. Oxidized ATP also inhibited oxygen radical production and
      activation of NF-kappaB and AP-1 in response to infection and inhibited NO
      dependent killing of bacille Calmette-Guerin by macrophages. Experiments using
      macrophages derived from P2X7 gene-disrupted mice ruled out an essential role for
      P2X7 in NOSII regulation. These data demonstrate that P2 receptors regulate
      macrophage activation in response to bacteria and proinflammatory stimuli, and
      suggest that extracellular nucleotides released from infected macrophages may
      enhance production of oxygen radicals and NO at sites of infection.

PMID- 10395641
TI  - Cas-L is required for beta 1 integrin-mediated costimulation in human Tcells.
AB  - Beta 1 integrins provide a costimulus for TCR/CD3-driven T cell activation and IL
      2 production in human peripheral T cells. However, this beta 1 integrin-mediated
      costimulation is impaired in a human T lymphoblastic line, Jurkat. We studied the
      molecular basis of this impaired costimulation and found that Cas-L, a 105-kDa
      docking protein, is marginally expressed in Jurkat T cells, whereas Cas-L is well
      expressed in peripheral T cells. Cas-L is a binding protein and a substrate for
      focal adhesion kinase and is tyrosine phosphorylated by beta 1 integrin
      stimulation. We here show that the transfection of wild-type Cas-L in Jurkat T
      cells restores beta 1 integrin-mediated costimulation. However, Cas-L
      transfection had no effect on CD28-mediated costimulation, indicating that Cas-L
      is specifically involved in the beta 1 integrin-mediated signaling pathway.
      Furthermore, transfection of the Cas-L Delta SH3 mutant failed to restore beta 1
      integrin-mediated costimulation in Jurkat cells. Cas-L Delta SH3 mutant lacks the
      binding site for focal adhesion kinase and is not tyrosine phosphorylated after
      beta 1 integrin stimulation. These findings strongly suggest that the tyrosine
      phosphorylation of Cas-L plays a key role in the signal transduction in the beta
      1 integrin-mediated T cell costimulation.

PMID- 10395642
TI  - How specific should immunological memory be?
AB  - Protection against infection hinges on a close interplay between the innate
      immune system and the adaptive immune system. Depending on the type and context
      of a pathogen, the innate system instructs the adaptive immune system to induce
      an appropriate immune response. Here, we hypothesize that the adaptive immune
      system stores these instructions by changing from a naive to an appropriate
      memory phenotype. In a secondary immune reaction, memory lymphocytes adhere to
      their instructed phenotype. Because cross-reactions with unrelated Ags can be
      detrimental, such a qualitative form of memory requires a sufficient degree of
      specificity of the adaptive immune system. For example, lymphocytes instructed to
      clear a particular pathogen may cause autoimmunity when cross-reacting with
      ignored self molecules. Alternatively, memory cells may induce an immune response
      of the wrong mode when cross-reacting with subsequent pathogens. To maximize the
      likelihood of responding to a wide variety of pathogens, it is also required that
      the immune system be sufficiently cross-reactive. By means of a probabilistic
      model, we show that these conflicting requirements are met optimally by a highly
      specific memory lymphocyte repertoire. This explains why the lymphocyte system
      that was built on a preserved functional innate immune system has such a high
      degree of specificity. Our analysis suggests that 1) memory lymphocytes should be
      more specific than naive lymphocytes and 2) species with small lymphocyte
      repertoires should be more vulnerable to both infection and autoimmune diseases.

PMID- 10395643
TI  - Immune system development and function in prolactin receptor-deficient mice.
AB  - Prolactin (PRL) is the primary lactogenic pituitary hormone that plays an
      essential role in many aspects of reproduction, from fertilization to mammary
      gland development and maternal behavior. PRL has also been reported to play a
      role in immunoregulation. Because initial observations indicated that
      hypophysectomized rats present abnormalities of the immune system, including
      increased thymic atrophy and lymphopenia, a number of studies have focused on the
      potential immunomodulatory roles of PRL. This hormone exerts its biological
      activities following binding to specific cell surface PRL receptors (PRLRs). In
      this report, we have characterized the development and function of the immune
      system in PRLR-deficient mice. Compared with wild-type control mice, PRLR-/- mice
      demonstrate no alterations in thymic or splenic cellularity or in the composition
      of the lymphocyte subsets present in primary (bone marrow and thymus) or
      secondary (spleen and lymph nodes) lymphoid organs. Lymphocytes from PRLR-/- mice
      are functional in vitro, as they can proliferate normally to mitogens, cytokines,
      and allogeneic cells. PRLR-/- splenocytes display normal NK-mediated cytotoxicity
      to YAC-1 target cells. In vivo studies have revealed that PRLR-/- mice are able
      to 1) generate normal steady-state Ig levels, 2) mount a normal specific Ig
      response following immunization with a T-dependent Ag, 3) eliminate injected
      allogeneic tumor cells, and 4) effectively control Listeria monocytogenes
      infection. Taken together, these results show that immune system development and
      function proceed normally in the absence of PRL-mediated signaling and suggest
      that PRLR pathways are not essential for immunomodulation in vivo.

PMID- 10395644
TI  - Differential antitumor effects of administration of recombinant IL-18 or
      recombinant IL-12 are mediated primarily by Fas-Fas ligand- and perforin-induced
      tumor apoptosis, respectively.
AB  - Systemic administration of rIL-18 protein to mice significantly suppresses the
      growth of murine tumor cell lines. The antitumor effect of IL-18 appears to be
      primarily mediated by asialo GM1+ cells. Since IL-18 enhances Fas ligand (FasL)
      expression on NK cell lines, the IL-18 antitumor effects could be mediated by
      FasL-induced cross-linking of Fas and subsequent tumor apoptosis. To address this
      question, rIL-18 or rIL-12 was administered to animals bearing the CL8-1 melanoma
      inoculated intradermally into wild type (wt), lymphoproliferation gene (lpr) (Fas
      deficient), or generalized lymphoproliferative disease gene (gld) (FasL
      deficient) mice. Although rIL-12 treatment retained significant antitumor effects
      in gld and lpr mice, those of rIL-18 administration were completely abrogated in
      gld but not lpr or wt mice. In vitro cytotoxicity was significantly enhanced
      against NK-sensitive YAC-1 cells and CL8-1 cells by rIL-18 administration to wt
      mice, but not to gld mice. Furthermore, rIL-18 administration augmented the
      cytotoxicity of liver lymphocytes harvested from perforin-deficient mice, whereas
      rIL-12 administration did not. Consistent with the role of this pathway, rIL-18
      administration also up-regulates the expression of FasL mRNA in splenocytes.
      Lysis of CL8-1 cells induced by anti-Fas agonistic Ab was enhanced about 1.4-fold
      by IFN-gamma, a cytokine that is induced by IL-18 in vitro and in vivo. We
      conclude that the antitumor effect of IL-18 is exerted predominantly through a
      Fas-dependent pathway. The perforin pathway, however, appears to be the
      predominant cytolytic pathway mediating IL-12 antitumor effects.

PMID- 10395645
TI  - Inhibition of NF-kappa B activity in human T lymphocytes induces caspase
      dependent apoptosis without detectable activation of caspase-1 and -3.
AB  - NF-kappa B is involved in the transcriptional control of various genes that act
      as extrinsic and intrinsic survival factors for T cells. Our findings show that
      suppression of NF-kappa B activity with cell-permeable SN50 peptide, which masks
      the nuclear localization sequence of NF-kappa B1 dimers and prevents their
      nuclear localization, induces apoptosis in resting normal human PBL. Inhibition
      of NF-kappa B resulted in the externalization of phosphatidylserine, induction of
      DNA breaks, and morphological changes consistent with apoptosis. DNA
      fragmentation was efficiently blocked by the caspase inhibitor Z-VAD-fmk and
      partially blocked by Ac-DEVD-fmk, suggesting that SN50-mediated apoptosis is
      caspase-dependent. Interestingly, apoptosis induced by NF-kappa B suppression, in
      contrast to that induced by TPEN (N,N,N',N'-tetrakis [2
      pyridylmethyl]ethylenediamine) or soluble Fas ligand (CD95), was observed in the
      absence of active death effector proteases caspase-1-like (IL-1 converting
      enzyme), caspase-3-like (CPP32/Yama/apopain), and caspase-6-like and without
      cleavage of caspase-3 substrates poly(ADP-ribose) polymerase and DNA
      fragmentation factor-45. These findings suggest either low level of activation is
      required or that different caspases are involved. Preactivation of T cells
      resulting in NF-kappa B nuclear translocation protected cells from SN50-induced
      apoptosis. Our findings demonstrate an essential role of NF-kappa B in survival
      of naive PBL.

PMID- 10395646
TI  - Differential CD3 zeta phosphorylation is not required for the induction of T cell
      antagonism by altered peptide ligands.
AB  - T cells recognize foreign Ags in the form of short peptides bound to MHC
      molecules. Ligation of the TCR:CD3 complex gives rise to the generation of two
      tyrosine-phosphorylated forms of the CD3 zeta-chain, pp21 and pp23. Replacement
      of residues in MHC-bound peptides that alter its recognition by the TCR can
      generate altered peptide ligands (APL) that antagonize T cell responses to the
      original agonist peptide, leading to altered T cell function and anergy. This
      biological process has been linked to differential CD3zeta phosphorylation and
      generation of only the pp21 phospho-species. Here, we show that T cells
      expressing CD3zeta mutants, which cannot be phosphorylated, exhibit a 5-fold
      reduction in IL-2 production and a 30-fold reduction in sensitivity following
      stimulation with an agonist peptide. However, these T cells are still strongly
      antagonized by APL. These data demonstrate that: 1) the threshold required for an
      APL to block a response is much lower than for an agonist peptide to induce a
      response, 2) CD3zeta is required for full agonist but not antagonist responses,
      and 3) differential CD3zeta phosphorylation is not a prerequisite for T cell
      antagonism.

PMID- 10395647
TI  - Slow accumulation of active mitogen-activated protein kinase during thymocyte
      differentiation regulates the temporal pattern of transcription factor gene
      expression.
AB  - Thymocyte-positive selection is believed to result from low affinity/avidity
      interactions of TCR and MHC proteins, but how these weak interactions translate
      into downstream biochemical signals and how such signals modulate gene expression
      is unknown. Using a culture system where isolated immature thymocytes can be
      induced to differentiate along the CD4 lineage pathway, we show that sustained
      low level mitogen-activated protein/extracellular regulated kinase activity is
      required for cell differentiation and survival. Furthermore, induction of mitogen
      activated protein/extracellular regulated kinase activity is surprisingly slow
      under conditions that induce differentiation. This pattern of kinase activity not
      only selects which genes are expressed but also regulates the temporal pattern of
      expression of transcription factor genes that are induced during double-positive
      thymocyte differentiation.

PMID- 10395648
TI  - Differential involvement of the transcription factor Blimp-1 in T cell
      independent and -dependent B cell differentiation to plasma cells.
AB  - Along humoral immune responses, different stimuli drive the differentiation of B
      lymphocytes to Ig-secreting plasma cells in discrete microenvironments. The Blimp
      1 transcription factor is up-regulated early during the transition of mature B
      cells to IgM-secreting plasma cells. In the present study, we have examined the
      requirement of Blimp-1 in plasma cell formation after both T cell-independent
      (LPS) and -dependent (CD40 + IL-4, Th cell lines) stimulation of spleen B cells.
      B lymphocyte-induced maturation protein (Blimp-1) was expressed early after in
      vitro LPS stimulation, mainly in a population of IgM+Syndecan+CD43+ preplasma
      cells. In contrast, the BSAP transcription factor expressed in mature B cells was
      down-regulated during the differentiation to plasma cells. Treatment of these
      cultures with Blimp-1-specific antisense phosphorothioate oligonucleotides
      suppressed both Blimp-1 protein levels and the emergence of IgM+Syndecan+ cells
      and plasma cells. However, T-B cell cocultures of spleen B cells from C3H/HeJ (H
      2k) mice and syngeneic autoreactive SR.10 Th2 cells submitted to the anti-Blimp-1
      therapy did not show any significant reduction in IgM- and IgG1-secreting plasma
      cell formation. Spleen B cells treated with anti-CD40 mAb + IL-4 differentiated
      to IgG1-secreting cells without significant transcription of the Blimp-1 gene;
      anti-Blimp-1 treatment subsequently did not have any effect in the later
      cultures. Altogether, these results suggest that Blimp-1 transcription factor
      specifically promotes T cell-independent B cell differentiation to plasma cells,
      probably at preplasma cell stages. In contrast, T cell-dependent plasma cell
      formation likely evolves through Blimp-1-independent pathways.

PMID- 10395649
TI  - IgG-mediated enhancement of antibody responses is low in Fc receptor gamma chain
      deficient mice and increased in Fc gamma RII-deficient mice.
AB  - Immunization with IgG/Ag or IgE/Ag complexes leads to a higher production of
      specific Abs than immunization with Ag alone. The enhancing effect of IgE is
      exclusively dependent upon the low-affinity receptor for IgE, Fc epsilon RII,
      whereas the mechanism behind IgG-mediated enhancement is unknown. We have
      investigated whether receptors for the Fc part of IgG are required for responses
      to IgG/Ag. Mice lacking the gamma subunit of Fc receptors (FcRs) (FcR gamma-/-),
      Fc gamma RII (Fc gamma RII-/-), or Fc gamma RIII (Fc gamma RIII-/-) were
      immunized with BSA-2,4,6-trinitrophenyl (TNP) alone or BSA-TNP complexed to
      monoclonal TNP-specific IgG1, IgG2a, or IgG2b. As expected, all subclasses
      enhanced the Ab-response to BSA in wild-type mice. Enhancement was in the same
      order of magnitude in Fc gamma RIII-/- mice (</=177-fold of controls administered
      Ag alone), whereas it was abrogated in FcR gamma-/- mice and augmented in Fc
      gamma RII-/- mice (</=5147-fold of controls). The response to IgE/Ag complexes in
      FcR gamma-/- and Fc gamma RII-/- mice was similar to that se for wild-type mice,
      demonstrating that non-Fc gamma R-dependent responses were normal. Our
      observations suggest that IgG/Ag complexes enhance Ab responses via Fc gamma Rs.
      Moreover, they reveal a strong negative regulation of Ab responses to IgG/Ag
      exerted by Fc gamma RII.

PMID- 10395650
TI  - The transcription factors Elf-1 and GATA-1 bind to cell-specific enhancer
      elements of human high-affinity IgE receptor alpha-chain gene.
AB  - Key regulatory regions necessary for the expression of the gene encoding
      FcepsilonRI alpha-chain, a component of the high-affinity IgE receptor primarily
      responsible for IgE-dependent allergic response, were investigated. Two regions, 
      74/-69 and -55/-47, which contained binding motifs for proteins belonging to the
      Ets family and the GATA family, respectively, were shown to be necessary for the
      activation of the alpha-chain promoter. Both the regulatory elements enhanced the
      promoter activity only in alpha-chain-producing cells PT18 and RBL-2H3 (mast cell
      lines), indicating that the elements required specific trans-acting proteins
      present in the alpha-chain-producing cells. EMSA using nuclear extracts and in
      vitro-translated proteins revealed that Elf-1 and GATA-1 bound to the enhancer
      elements. This is the first report describing the regulation in the expression of
      the FcepsilonRI alpha-chain.

PMID- 10395651
TI  - Differential induction of cytokine genes and activation of mitogen-activated
      protein kinase family by soluble CD40 ligand and TNF in a human follicular
      dendritic cell line.
AB  - Follicular dendritic cells (FDC)3 play crucial roles in germinal center (GC)
      formation and differentiation of GC B cells. Many aspects of FDC function are
      influenced by contact with B or T cells, and by cytokines produced in the GC,
      which involve stimulation of CD40 and TNF-alpha receptors on FDC. In this study,
      using an established FDC line, HK cells, we compared the effects of CD40 and TNF
      receptor triggering on cytokine induction and activation of mitogen-activated
      protein kinase family. We show that HK cells spontaneously produced IL-6, M-CSF,
      and G-CSF mRNA. Both the soluble form of CD40 ligand (sCD40L) and TNF increased
      the level of M-CSF and G-CSF mRNA. While TNF strongly induced IL-6 mRNA, its
      expression was not affected by sCD40L treatment, differing from the strong IL-6
      induction in other cell types upon CD40 stimulation. In addition, sCD40L
      treatment resulted in activation of extracellular signal-related kinase 1 and 2
      (ERK1/2) and p38 without significant increase in c-Jun N-terminal kinase (JNK)
      activity. Lack of JNK activation differs in that most B cells respond to CD40
      stimulation by inducing JNK activity strongly, suggesting distinct
      characteristics of CD40 signaling in FDC. Compared with the effects of sCD40L,
      TNF was capable of inducing JNK activity in addition to the activation of ERK1/2
      and p38. Furthermore, the proximal signaling elements activated by TNF differed
      from those activated by sCD40L, in that TNF did not require PMA-sensitive protein
      kinase C isoforms in the activation of ERK and p38, whereas sCD40L did. However,
      signals activated by these stimuli converged on cytokine gene expression in a
      synergistic manner, which may have implication in augmenting FDC function during
      GC reaction.

PMID- 10395652
TI  - Signaling events induced by lipopolysaccharide-activated toll-like receptor 2.
AB  - Human Toll-like receptor 2 (TLR2) is a signaling receptor that responds to LPS
      and activates NF-kappaB. Here, we investigate further the events triggered by
      TLR2 in response to LPS. We show that TLR2 associates with the high-affinity LPS
      binding protein membrane CD14 to serve as an LPS receptor complex, and that LPS
      treatment enhances the oligomerization of TLR2. Concomitant with receptor
      oligomerization, the IL-1R-associated kinase (IRAK) is recruited to the TLR2
      complex. Intracellular deletion variants of TLR2 lacking C-terminal 13 or 141 aa
      fail to recruit IRAK, which is consistent with the inability of these mutants to
      transmit LPS cellular signaling. Moreover, both deletion mutants could still form
      complexes with wild-type TLR2 and act in a dominant-negative (DN) fashion to
      block TLR2-mediated signal transduction. DN constructs of myeloid differentiation
      protein, IRAK, TNF receptor-associated factor 6, and NF-kappaB-inducing kinase,
      when coexpressed with TLR2, abrogate TLR2-mediated NF-kappaB activation. These
      results reveal a conserved signaling pathway for TLR2 and IL-1Rs and suggest a
      molecular mechanism for the inhibition of TLR2 by DN variants.

PMID- 10395653
TI  - CD4-mediated signals induce T cell dysfunction in vivo.
AB  - Triggering of CD4 coreceptors on both human and murine T cells can suppress
      TCR/CD3-induced secretion of IL-2. We show here that pretreatment of murine CD4+
      T cells with the CD4-specific mAb YTS177 inhibits the CD3-mediated activation of
      the IL-2 promoter factors NF-AT and AP-1. Ligation of CD4 molecules on T cells
      leads to a transient stimulation of extracellular signal-regulated kinase (Erk)
      2, but not c-Jun N-terminal kinase (JNK) activity. Pretreatment with anti-CD4 mAb
      impaired anti-CD3-induced Erk2 activation. Costimulation with anti-CD28 overcame
      the inhibitory effect of anti-CD4 Abs, by induction of JNK activation. The in
      vivo relevance of these studies was demonstrated by the observation that CD4+ T
      cells from BALB/c mice injected with nondepleting anti-CD4 mAb were inhibited in
      their ability to respond to OVA Ag-induced proliferation and IL-2 secretion.
      Interestingly, in vivo stimulation with anti-CD28 mAb restored IL-2 secretion.
      Furthermore, animals pretreated with anti-CD4 elicited enhanced IL-4 secretion
      induced by OVA and CD28. These observations suggest that CD4-specific Abs can
      inhibit T cell activation by interfering with signal 1 transduced through the
      TCR, but potentiate those delivered through the costimulatory molecule CD28.
      These studies have relevance to understanding the mechanism of tolerance induced
      by nondepleting anti-CD4 mAb used in animal models for allograft studies,
      autoimmune pathologies, and for immunosuppressive therapies in humans.

PMID- 10395654
TI  - Hypervariable region 1 variants act as TCR antagonists for hepatitis C virus
      specific CD4+ T cells.
AB  - In various human viral infections, the appearance of mutated epitopes displaying
      TCR antagonistic activity has been correlated with the severity and persistence
      of infection. In hepatitis C virus (HCV) infection, where the virus persistence
      has been associated with the rapid and substantial Ag modifications occurring
      during replication, TCR antagonism has been evidenced in CD8+ T cell responses.
      However, CD4+ T cell antagonism may be another important strategy by which HCV
      eludes a protective response, because sustained Th responses directed against
      several HCV Ags are associated with a self-limited course of infection. The data
      reported here represent the first evidence that variants of the hypervariable
      region (HVR1) of the putative Envelope 2 protein of HCV can act as powerful TCR
      antagonists for HVR1-specific CD4+ T cells isolated from HCV-infected
      individuals. Using classical antagonism assays, we observed strong inhibition of
      cellular proliferation and cytokine production when the agonist and the
      antagonist ligands were simultaneously presented by the same APCs. The presence
      in HVR1 of conserved residues, critical for binding to HLA-DR molecules, supports
      the function of HVR1 variants as TCR antagonists. In conclusion, our data
      evidence an antagonism phenomenon, which was achieved by naturally occurring
      class II-restricted T cell epitopes whose mechanism was addressed in terms of the
      antagonist capacity to inhibit agonist-mediated TCR down-regulation and early
      signal transduction.

PMID- 10395655
TI  - In vivo polysaccharide-specific IgG isotype responses to intact Streptococcus
      pneumoniae are T cell dependent and require CD40- and B7-ligand interactions.
AB  - In vivo Ig responses to soluble, haptenated polysaccharide (PS) Ags are T cell
      independent and do not require CD40 ligand (CD40L). However, little is known
      regarding the regulation of in vivo PS-specific Ig responses to intact bacteria.
      We immunized mice with a nonencapsulated, type 2 Streptococcus pneumoniae (R36A)
      and compared the parameters that regulated in vivo Ig isotype responses to the
      bacterial cell wall C-PS determinant, phosphorylcholine (PC), relative to Ig
      responses to the cell wall protein, pneumococcal surface protein A. Consistent
      with previous reports using soluble PS and protein Ags, the anti-PC and anti
      pneumococcal surface protein A responses differed in that the anti-PC response
      was induced more rapidly, had a distinctive Ig isotype profile, and failed to
      demonstrate boosting upon secondary challenge with R36A. However, in contrast to
      previous studies, the IgG anti-PC response was TCR-alphabeta+ T cell dependent,
      required CD40L, and was blocked by administration of CTLA4 Ig. The nature of the
      T cell help for the anti-PC response had distinct features in that it was only
      partially blocked by CTLA4 Ig and was dependent upon both CD4+ and CD8+ T cells.
      Surprisingly, whereas the IgM anti-PC response was largely T cell independent, a
      strong requirement for CD40L was still observed, suggesting the possibility of an
      in vivo T cell-independent source for CD40L-dependent help. These data suggest
      that the regulatory parameters that govern in vivo Ig responses to purified,
      soluble PS Ags may not adequately account for PS-specific Ig responses to intact
      bacteria.

PMID- 10395656
TI  - ICAM-1-coupled signaling pathways in astrocytes converge to cyclic AMP response
      element-binding protein phosphorylation and TNF-alpha secretion.
AB  - In the CNS, astrocytes play a key role in immunological and inflammatory
      responses through ICAM-1 expression, cytokine secretion (including TNF-alpha),
      and regulation of blood-brain barrier permeability. Because ICAM-1 transduces
      intracellular signals in lymphocytes and endothelial cells, we investigated in
      the present study ICAM-1-coupled signaling pathways in astrocytes. Using rat
      astrocytes in culture, we report that ICAM-1 binding by specific Abs induces TNF
      alpha secretion together with phosphorylation of the transcription factor cAMP
      response element-binding protein. We show that ICAM-1 binding induces cAMP
      accumulation and activation of the mitogen-activated protein kinase extracellular
      signal-regulated kinase. Both pathways are responsible for cAMP response element
      binding protein phosphorylation and TNF-alpha secretion. Moreover, these
      responses are partially dependent protein kinase C, which acts indirectly, as a
      common activator of cAMP/protein kinase A and extracellular signal-regulated
      kinase pathways. These results constitute the first evidence of ICAM-1 coupling
      to intracellular signaling pathways in glial cells and demonstrate the
      convergence of these pathways onto transcription factor regulation and TNF-alpha
      secretion. They strongly suggest that ICAM-1-dependent cellular adhesion to
      astrocytes could contribute to the inflammatory processes observed during
      leukocyte infiltration in the CNS.

PMID- 10395657
TI  - Phenotypic identification of antigen-dependent and antigen-independent CD8 CTL
      precursors in the draining lymph node during acute cutaneous herpes simplex virus
      type 1 infection.
AB  - Optimal immunological control of cutaneous herpes simplex virus type 1 (HSV-1)
      infections initiated in the hind footpad of C57BL/6 (B6, H-2b) mice is dependent
      upon the presence of functional HSV-1-specific T lymphocytes. The class I MHC
      restricted, CD8+ T cell subpopulation is involved in the clearance of infectious
      HSV-1 from the skin and limiting HSV-1 replication and spread within the
      peripheral nervous system. However, the frequency of HSV-1-specific CTL
      precursors (CTLp), as a measure of potential anti-viral CD8+ T cell function, is
      relatively low compared with other acute viral infections. To gain insight into
      the basis for this low functional frequency, changes in the CD8+ T cell
      subpopulation phenotype associated with activation and differentiation were
      investigated. Analysis of the phenotypic changes showed that HSV-1-specific CTLp
      were found predominantly within a subpopulation of CD8+ T cells expressing high
      levels of CD44 (CD44high) and high levels of the IL-2 receptor alpha-chain
      (CD25high). A second activated subpopulation of CD8+ T cells expressing the
      CD44high CD25low phenotype did not contain detectable HSV-1-specific CTLp, even
      after the addition of HSV-1-infected stimulator cells as a source of an exogenous
      Ag. These data suggested that HSV-1-specific CD8+ T cells must increase
      expression of CD25 before attaining the potential to become CTL effector cells.
      These findings also indicated that the up-regulation of CD44 alone is not
      sufficient to identify precisely HSV-1-specific CD8+ T cells.

PMID- 10395658
TI  - A new role for platelet-endothelial cell adhesion molecule-1 (CD31): inhibition
      of TCR-mediated signal transduction.
AB  - Platelet-endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kDa
      transmembrane glycoprotein expressed by endothelial cells, platelets, monocytes,
      neutrophils, and certain T cell subsets. The PECAM-1 extracellular domain has six
      Ig-homology domains that share sequence similarity with cellular adhesion
      molecules. The PECAM-1 cytoplasmic domain contains an immunoreceptor tyrosine
      based inhibitory motif (ITIM) that, when appropriately engaged, becomes
      phosphorylated on tyrosine residues, creating docking sites for nontransmembrane,
      Src homology 2 domain-bearing protein tyrosine phosphatase (SHP)-1 and SHP-2. The
      purpose of the present study was to determine whether PECAM-1 inhibits protein
      tyrosine kinase (PTK)-dependent signal transduction mediated by the
      immunoreceptor tyrosine-based activation motif-containing TCR. Jurkat cells,
      which coexpress PECAM-1 and the TCR/CD3 complex, were INDO-1AM-labeled and then
      incubated with anti-CD3epsilon mAbs, anti-PECAM-1 mAbs, or both, and goat anti
      mouse IgG was used to cross-link surface-bound mAbs. Calcium mobilization induced
      by CD3 cross-linking was found to be attenuated by coligation of PECAM-1 in a
      dose-dependent manner. PECAM-1-mediated inhibition of TCR signaling was
      attributable, at least in part, to inhibition of release of calcium from
      intracellular stores. These data provide evidence that PECAM-1 can dampen signals
      transduced by ITAM-containing receptors and support inclusion of PECAM-1 within
      the family of ITIM-containing inhibitors of PTK-dependent signal transduction.

PMID- 10395659
TI  - Negative selection of T cells occurs throughout thymic development.
AB  - Thymic positive and negative selections govern the development of a self-MHC
      reactive, yet self-tolerant, T cell repertoire. Whether these processes occur
      independently or sequentially remains controversial. To investigate these issues,
      we have employed tetrameric peptide-MHC complexes to fluorescently label and
      monitor polyclonal populations of thymocytes that are specific for moth
      cytochrome c (MCC)/I-Ek. In TCR beta mice tetramer-positive thymocytes are
      detectable even in the most immature TCR-expressing cells. In the presence of MCC
      peptide, thymocytes that bind strongly to MCC/I-Ek tetramers are deleted earlier
      in development and more extensively than cells that bind weakly. This negative
      selection of the MCC/I-Ek-specific cells occurs continuously throughout
      development and before any evidence of positive selection. Thus, positive and
      negative selections are independent processes that need not occur sequentially.

PMID- 10395660
TI  - Induction of antitumor immunity with dendritic cells transduced with adenovirus
      vector-encoding endogenous tumor-associated antigens.
AB  - Dendritic cells (DCs) are professional Ag-presenting cells that are being
      considered as potential immunotherapeutic agents to promote host immune responses
      against tumor Ags. In this study, recombinant adenovirus (Ad) vectors encoding
      melanoma-associated Ags were used to transduce murine DCs, which were then tested
      for their ability to activate CTL and induce protective immunity against B16
      melanoma tumor cells. Immunization of C57BL/6 mice with DCs transduced with Ad
      vector encoding the hugp100 melanoma Ag (Ad2/hugp100) elicited the development of
      gp100-specific CTLs capable of lysing syngeneic fibroblasts transduced with
      Ad2/hugp100, as well as B16 cells expressing endogenous murine gp100. The
      induction of gp100-specific CTLs was associated with long term protection against
      lethal s.c. challenge with B16 cells. It was also possible to induce effective
      immunity against a murine melanoma self Ag, tyrosinase-related protein-2, using
      DCs transduced with Ad vector encoding the Ag. The level of antitumor protection
      achieved was dependent on the dose of DCs and required CD4+ T cell activity.
      Importantly, immunization with Ad vector-transduced DCs was not impaired in mice
      that had been preimmunized against Ad to mimic the immune status of the general
      human population. Finally, DC-based immunization also afforded partial protection
      against established B16 tumor cells, and the inhibition of tumor growth was
      improved by simultaneous immunization against two melanoma-associated Ags as
      opposed to either one alone. Taken together, these results support the concept of
      cancer immunotherapy using DCs transduced with Ad vectors encoding tumor
      associated Ags.

PMID- 10395661
TI  - Diacylglycerol kinase inhibition prevents IL-2-induced G1 to S transition through
      a phosphatidylinositol-3 kinase-independent mechanism.
AB  - Stimulation via IL-2R ligation causes T lymphocytes to transit through the cell
      cycle. Previous experiments by our group have demonstrated that, in human T
      cells, IL-2 binding induces phosphatidic acid production through activation of
      the alpha isoform of diacylglycerol kinase. In this study, using the IL-2
      dependent mouse T cell line CTLL-2, we demonstrate that pharmacological
      inhibition of IL-2-induced diacylglycerol kinase activation is found to block IL
      2-induced late G1 to S transition without affecting cell viability. Herein, we
      demonstrate that diacylglycerol kinase inhibition has a profound effect on the
      induction of the protooncogenes c-myc, c-fos, and c-raf by IL-2, whereas
      expression of bcl-2 and bcl-xL are not affected. When the IL-2-regulated cell
      cycle control checkpoints are examined in detail, we demonstrate that inhibition
      of diacylglycerol kinase activation prevents IL-2 induction of cyclin D3 without
      affecting p27 down-regulation. The strict control of cell proliferation exerted
      by phosphatidic acid through activation of diacylglycerol kinase is independent
      of other well-characterized IL-2R-derived signals, such as the
      phosphatidylinositol-3 kinase/Akt pathway, indicating the existence of a
      different and important mechanism to control cell division.

PMID- 10395662
TI  - Activation of the extracellular signal-related kinase/mitogen-activated protein
      kinase pathway discriminates CD4 versus CD8 lineage commitment in the thymus.
AB  - We have investigated the role of the mitogen-activated protein kinase (MAPK)
      pathway in the differentiation of CD4+ and CD8+ T cells by looking specifically
      at the effects of inhibitors of MAPK-activating enzyme, MAPK/extracellular signal
      related kinase (ERK) kinase (MEK), during the positive selection step from double
      positive to single-positive (SP) thymocytes. Using a variety of
      transgenic/knockout mouse strain combinations that fail to differentiate
      individual lineages of SP thymocytes together with genetically engineered F(ab')2
      reagents that induce maturation preferentially to either the CD4 or CD8
      subpopulations, we show that induction of CD4 differentiation cells is highly
      sensitive to levels of MEK inhibition that have no effect on CD8 maturation. In
      addition, the presence of MEK inhibitor is able to modify signals that normally
      induce CD4 differentiation to instead promote CD8 differentiation. Finally, we
      show that continuous culture in the presence of inhibitor interferes with TCR up
      regulation in SP thymocytes, suggesting that MAPK signaling may be involved in
      final maturation steps for both lineages. These data indicate that there is
      discrimination in the biochemical pathways that are necessary to specify CD4 and
      CD8 lineage commitment and can reconcile previously conflicting reports on the
      influence of MAPK activation in commitment and maturation of thymocytes.

PMID- 10395663
TI  - Antigen concentration and precursor frequency determine the rate of CD8+ T cell
      tolerance to peripherally expressed antigens.
AB  - Expression of transgene-encoded proteins in the pancreatic islets can cause
      peripheral deletion of T cells. However, tolerance has not been observed in all
      transgenic models. It has been proposed that the determining factor for
      successful peripheral tolerance is the amount of Ag cross-presented by quiescent
      APCs. Using InsHA mice, which demonstrate peripheral tolerance to the influenza
      virus hemagglutinin (HA) expressed in the pancreatic islet beta cells, we have
      investigated the consequences when different amounts of HA are expressed. As
      compared with InsHA mice that are heterozygous for the InsHA transgene,
      homozygous InsHA mice demonstrated enhanced activation and proliferation of Kd
      restricted HA-specific CD8+ T cells in the pancreatic lymph nodes. However,
      despite such activation, insulitis was not observed, and the T cells were
      gradually functionally deleted. Deletion of these activated cells occurred much
      more rapidly in homozygous than in heterozygous InsHA mice. These data
      demonstrate that there is a direct correlation between the amount of HA expressed
      in the periphery, and both the degree of T cell proliferation in the pancreatic
      lymph nodes and the rate of tolerance of HA-specific CD8+ T cells. This strongly
      supports the hypothesis that activation of T cells through cross-presentation of
      peripheral Ags in a noninflammatory environment is an important part of the
      normal mechanism of tolerance to Ags expressed in the pancreatic islets.

PMID- 10395664
TI  - TCR and IL-12 receptor signals cooperate to activate an individual response
      element in the IFN-gamma promoter in effector Th cells.
AB  - IFN-gamma is a key regulatory cytokine of the immune system. Reporter transgenic
      mice expressing the luciferase gene under the control of separate TCR-response
      elements (TCR-RE) from the IFN-gamma promoter or expressing the green fluorescent
      protein gene under the control of an IFN-gamma "minigene" were employed to
      explore the basis for IL-12 regulation of IFN-gamma gene transcription. In the
      absence of TCR stimulation, IL-12 did not activate the TCR-REs but did induce
      green fluorescent protein expression. TCR plus IL-12R stimulation of effector Th
      cells resulted in: 1) enhanced activation of the proximal, but not the distal,
      TCR-RE, and 2) increased induction of cJun-proximal TCR-RE complexes and c-Jun
      protein expression. Overexpression of cJun, but not cFos, increased activity of
      the proximal TCR-RE in T cells. These results suggest that IL-12R signaling
      affects IFN-gamma gene transcription by at least two separate mechanisms; IL-12R
      signaling without TCR signaling targets promoter regions outside of the
      approximately 100-bp IFN-gamma TCR-RE, and IL-12R signaling also stimulates TCR
      induced activity of the proximal TCR-RE.

PMID- 10395665
TI  - Functional gene transfer of HIV DNA by an HIV receptor-independent mechanism.
AB  - HIV-1 enters target cells mainly via binding to CD4 and its coreceptors. The
      presence of HIV-1 in CD4- cells suggests, however, that there exist other
      mechanisms for viral entry. Here it is reported that HIV-1 DNA may be transferred
      from one cell to another by uptake of apoptotic bodies in a CD4-independent way.
      This was investigated by coculturing CD4-, chemokine receptor CCR5- and CXCR4-
      human fetal fibroblasts with apoptotic HIV-1-infected HuT78 cells or apoptotic
      PBMC isolated from HIV-1-infected patients. After 2 wk of coculture, fibroblasts
      contained HIV-1 DNA and expressed HIV-1 proteins p24 and gp120. Transfer of HIV-1
      DNA was verified by coculturing fibroblasts with apoptotic bodies derived from
      cells infected with a defective HIV-1 virus. These cells contain one integrated
      copy of a reverse transcriptase (RT)-negative HIV-1 strain (8E5/LAV RT- cells)
      and consequently cannot produce free virus. Intracellular HIV-1 gag DNA was
      detected in both fibroblasts and dendritic cells after coculture with apoptotic
      8E5/LAV RT- cells. Transfer of viral DNA after uptake of apoptotic bodies may
      explain HIV-1 infection of CD4- cells in vivo and furthermore may be relevant for
      Ag presentation.

PMID- 10395666
TI  - I-Ag7-mediated antigen presentation by B lymphocytes is critical in overcoming a
      checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice.
AB  - B cell-deficient nonobese diabetic (NOD) mice are protected from the development
      of spontaneous autoimmune diabetes, suggesting a requisite role for Ag
      presentation by B lymphocytes for the activation of a diabetogenic T cell
      repertoire. This study specifically examines the importance of B cell-mediated
      MHC class II Ag presentation as a regulator of peripheral T cell tolerance to
      islet beta cells. We describe the construction of NOD mice with an I-Ag7
      deficiency confined to the B cell compartment. Analysis of these mice, termed NOD
      BCIID, revealed the presence of functionally competent non-B cell APCs
      (macrophages/dendritic cells) with normal I-Ag7 expression and capable of
      activating Ag-reactive T cells. In addition, the secondary lymphoid organs of
      these mice harbored phenotypically normal CD4+ and CD8+ T cell compartments.
      Interestingly, whereas control NOD mice harboring I-Ag7-sufficient B cells
      developed diabetes spontaneously, NOD BCIID mice were resistant to the
      development of autoimmune diabetes. Despite their diabetes resistance, histologic
      examination of pancreata from NOD BCIID mice revealed foci of noninvasive peri
      insulitis that could be intentionally converted into a destructive process upon
      treatment with cyclophosphamide. We conclude that I-Ag7-mediated Ag presentation
      by B cells serves to overcome a checkpoint in T cell tolerance to islet beta
      cells after their initial targeting has occurred. Overall, this work indicates
      that the full expression of the autoimmune potential of anti-islet T cells in NOD
      mice is intimately regulated by B cell-mediated MHC class II Ag presentation.

PMID- 10395667
TI  - Tumor infiltration by adoptively transferred T cells is independent of
      immunologic specificity but requires down-regulation of L-selectin expression.
AB  - Adoptive immunotherapy with anti-CD3/IL-2 activated tumor-draining lymph node
      (LN) T cells is capable of eradicating tumor established at various histological
      sites. Tumor-specific effector lymphocytes have recently been identified to be LN
      T cells with down-regulated L-selectin (L-selectin-). Using fluorochrome
      labeling, the present study determined the early trafficking pattern of
      systemically transferred cells. In mice with 10-day established pulmonary 3
      methylcholanthrene (MCA) 205 metastases, accumulation of cells in tumors was
      evident as early as 2 h after i.v. cell transfer, and, by 24 h, >50-fold higher
      numbers of cells were seen in metastases than in normal tissues. Similarly,
      transferred cells selectively infiltrated s.c. tumors, albeit at a lower rate.
      Analysis of the transferred cells isolated from recipient mice revealed that
      tumor-infiltrating cells were mostly L-selectin- (>95%). By contrast, only 24%
      and 58% L-selectin- cells were found in the LN and spleen, respectively. The
      ability of L-selectin- cells to accumulate at tumor sites was confirmed by the
      transfer of purified cell populations. Despite this selective tumor infiltration,
      the trafficking pattern did not reflect antigenetic specificity, and tumor
      regression occurred only after the transfer of tumor-specific effector cells.
      These results, thus, suggest that there are two distinct mechanisms operative in
      successful adoptive immunotherapy. Early infiltration of tumors by transferred
      cells is dictated by the physiological properties of cells and is independent on
      their immunologic specificity. Tumor regression, however, requires
      immunologically specific interactions at the site of tumor.

PMID- 10395668
TI  - M1204, a novel 2',5' oligoadenylate synthetase with a ubiquitin-like extension,
      is induced during maturation of murine dendritic cells.
AB  - A novel molecule expressed by spleen dendritic cells (DC) was isolated using a
      subtractive hybridization approach. The full-length M1204 clone has 3063 bp, with
      1415 bp spanning a single open reading frame, coding for a protein of a predicted
      size of about 50 kDa. This sequence has strong homology to 2', 5' oligoadenylate
      synthetase and contains a ubiquitin-like domain. In Northern blot analyses the
      mRNA is strongly expressed in spleen DC, whereas, in bone marrow-derived DC, the
      amount of mRNA increases during the maturation process. None of the other
      leukocytes nor several hemopoietic cell lines tested express this mRNA, but clear
      expression occurs in many organs, the highest levels being in thymus, lung, and
      bone marrow. In situ hybridization, combined with immunocytochemical staining of
      tissue sections of lung and spleen, shows colocalization of M1204 with the 2A1
      and NLDC DC markers. In Western blot experiments, an antiserum raised against the
      recombinant M1204 recognizes a single band in bone marrow-derived DC and in the
      lung. The expressed oligoadenylate synthetase domain is active in synthesizing
      2',5' diadenylate, which by itself may inhibit viral protein synthesis and may
      also function as a substrate for 2',5' oligoadenylate synthetase. Since the
      oligoadenylate/RNase L system provides early protection against virus infection,
      we hypothesize that M1204 prevents virus-induced cell death in DC.

PMID- 10395669
TI  - Determination of residues involved in ligand binding and signal transmission in
      the human IFN-alpha receptor 2.
AB  - The human IFN-alpha receptor (hIFNAR) is a complex composed of at least two
      chains, hIFNAR1 and hIFNAR2. We have performed a structure-function analysis of
      hIFNAR2 extracellular domain regions using anti-hIFNAR2 mAbs (1D3, 1F3, and 3B7)
      and several type I human IFNs. These mAbs block receptor activation, as
      determined by IFN-stimulated gene factor 3 formation, and block the antiviral
      cytopathic effects induced by type I IFNs. We generated alanine substitution
      mutants of hIFNAR2-IgG and determined that regions of hIFNAR2 are important for
      the binding of these blocking mAbs and hIFN-alpha2/alpha1. We further
      demonstrated that residues E78, W101, I104, and D105 are crucial for the binding
      of hIFN-alpha2/alpha1 and form a defined protrusion when these residues are
      mapped upon a structural model of hIFNAR2. To confirm that residues important for
      ligand binding are indeed important for IFN signal transduction, we determined
      the ability of mouse L929 cells expressing hIFNAR2 extracellular domain mutants
      to mediate hIFN signal. hIFN-alpha8, previously shown to signal a response in
      L929 cells expressing hIFNAR1, was unable to signal in L929 cells expressing
      hIFNAR2. Transfected cells expressing hIFNAR2 containing mutations at residues
      E78, W101, I104, or D105 were unresponsive to hIFN-alpha2, but remained
      responsive to hIFN-beta. In summary, we have identified specific residues of
      hIFNAR2 important for the binding to hIFN-alpha2/1 and demonstrate that specific
      regions of the IFNAR interact with the subspecies of type I IFN in different
      manners.

PMID- 10395670
TI  - Expression, linkage, and polymorphism of MHC-related genes in rainbow trout,
      Oncorhynchus mykiss.
AB  - The architecture of the MHC in teleost fish, which display a lack of linkage
      between class I and II genes, differs from all other vertebrates. Because rainbow
      trout have been examined for a variety of immunologically relevant genes, they
      present a good teleost model for examining both the expression and organization
      of MHC-related genes. Full-length cDNA and partial gDNA clones for proteasome
      delta, low molecular mass polypeptide (LMP) 2, TAP1, TAP2A, TAP2B, class Ia, and
      class IIB were isolated for this study. Aside from the expected polymorphisms
      associated with class I genes, LMP2 and TAP2 are polygenic. More specifically, we
      found a unique lineage of LMP2 (LMP2/delta) that shares identity to both LMP2 and
      delta but is expressed like the standard LMP2. Additionally, two very different
      TAP2 loci were found, one of which encodes polymorphic alleles. In general, the
      class I pathway genes are expressed in most tissues, with highest levels in
      lymphoid tissue. We then analyzed the basic genomic organization of the trout MHC
      in an isogenic backcross. The main class Ia region does not cosegregate with the
      class IIB locus, but LMP2, LMP2/delta, TAP1A, and TAP2B are linked to the class
      Ia locus. Interestingly, TAP2A (second TAP2 locus) is a unique lineage in
      sequence composition that appears not to be linked to this cluster or to class
      IIB. These results support and extend the recent findings of nonlinkage between
      class I and II in a different teleost order (cyprinids), suggesting that this
      unique arrangement is common to all teleosts.

PMID- 10395671
TI  - Activation of the Janus kinase 3-STAT5a pathway after CD40 triggering of human
      monocytes but not of resting B cells.
AB  - CD40/CD40 ligand interactions play a key role in the immune responses of B
      lymphocytes, monocytes, and dendritic cells. The signal transduction events
      triggered by cross-linking of the CD40 receptor have been widely studied in B
      cell lines, but little is known about signaling following CD40 stimulation of
      monocytes and resting tonsillar B cells. Therefore, we studied the CD40 pathway
      in highly purified human monocytes and resting B cells. After CD40 triggering, a
      similar activation of the NF-kappaB (but not of the AP-1) transcription factor
      complex occurred in both cell preparations. However, the components of the NF
      kappaB complexes were different in monocytes and B cells, because p50 is part of
      the NF-kappaB complex induced by CD40 triggering in both monocytes and B cells,
      whereas p65 was only induced in B cells. In contrast, although the Janus kinase 3
      tyrosine kinase was associated with CD40 molecules in both monocytes and resting
      B cells, Janus kinase 3 phosphorylation induction was observed only in CD40
      activated monocytes, with subsequent induction of STAT5a DNA binding activity in
      the nucleus. These results suggest that the activation signals in human B cells
      and monocytes differ following CD40 stimulation. This observation is consistent
      with the detection of normal CD40-induced monocyte activation in patients with
      CD40 ligand+ hyper IgM syndrome in whom a defect in CD40-induced B cell
      activation has been reported.

PMID- 10395672
TI  - Discoordinate expression of invariant chain and MHC class II genes in class II
      transactivator-transfected fibroblasts defective for RFX5.
AB  - MHC class II deficiency or bare lymphocyte syndrome is a severe combined
      immunodeficiency caused by defects in MHC-specific transcription factors. In the
      present study, we show that fibroblasts derived from a recently identified bare
      lymphocyte syndrome patient, SSI, were mutated for RFX5, one of the DNA-binding
      components of the RFX complex. Despite the lack of functional RFX5 and resulting
      MHC class II-deficient phenotype, transfection of exogenous class II
      transactivator (CIITA) in these fibroblasts can overcome this defect, resulting
      in the expression of HLA-DR, but not of DP, DQ, and invariant chain. The lack of
      invariant chain expression correlated with lack of CIITA-mediated transactivation
      of the invariant chain promoter in transient transfection assays in SSI
      fibroblast cells. Consequently, these CIITA transfectants lacked Ag-presenting
      functions.

PMID- 10395673
TI  - Tyrosine phosphorylation of Vav stimulates IL-6 production in mast cells by a
      Rac/c-Jun N-terminal kinase-dependent pathway.
AB  - This study investigates whether the guanine nucleotide exchange activity of Vav
      is linked to cytokine production in mast cells. Overexpression of Vav in the RBL
      2H3 mast cell line resulted in the constitutive tyrosine phosphorylation and
      activation of Vav. We analyzed the functional effect of Vav overexpression on
      cytokine production. IL-2 and IL-6 mRNA levels were dramatically increased in Vav
      overexpressing cells and correlated with increased NF-AT activity. Little or no
      effect was observed on the mRNA levels of IL-3, IL-4, GM-CSF, TNF-alpha, and TGF
      beta. FcepsilonRI engagement did not further enhance IL-2 and IL-6 mRNA levels
      and only slightly enhanced NF-AT activity, but dramatically increased the mRNA
      levels of other tested cytokines. To understand the signal transduction required,
      we focused primarily on IL-6 induction by measuring mitogen-activated protein
      kinase activity and analyzing the effects of mutant or dominant negative forms of
      Vav, Rac1, and c-Jun N-terminal kinase-1 (JNK1). Vav overexpression resulted in
      the constitutive activation of JNK1 with little or no effect on p38 mitogen
      activated protein kinase and ERK2. This was dependent on Vav-mediated activation
      of Rac1 as a Dbl domain-mutated Vav, inactive Rac N17, and inactive JNK1 down
      regulated the Vav-induced JNK1 or IL-6 responses. Vav expression, but not
      expression of domain-mutated Vav, increased IL-6 secretion from nonimmortalized
      bone marrow-derived mast cells upon FcepsilonRI engagement. We conclude that Vav
      phosphorylation contributes to IL-6 induction in mast cells.

PMID- 10395674
TI  - Complex regulation of Ly-6E gene transcription in T cells by IFNs.
AB  - The complexity of IFN-mediated regulation of the murine Ly-6E gene in T cell
      lines is highlighted by the following observations: 1) multiple regulatory
      regions are present within different parts of the Ly-6E promoter and are
      necessary for IFN inducibility of the Ly-6E gene, 2) multiple transcription
      factors including Oct-1 and Oct-2 and the high mobility group (HMG) protein
      HMGI(Y) bind to regulatory elements present within the G region required for both
      IFN-alphabeta and IFN-gamma responses, 3) mutational analysis of the G region
      reveals that a complex interaction exists between the factors binding to this
      region as shown by their mutual interdependence for detection in DMSA, and 4)
      inhibition of expression of HMG proteins by antisense HMGI-C RNA in EL4 cells
      causes the loss of IFN-alphabeta and IFN-gamma inducibility of the endogenous Ly
      6 gene. These findings taken together suggest that, in response to IFN treatment,
      an HMG protein-dependent complex involving multiple regulatory factors is
      assembled and is required for IFN inducibility of the Ly-6E gene.

PMID- 10395675
TI  - Conformational epitope of the type III group B Streptococcus capsular
      polysaccharide.
AB  - The protective epitope of the type III group B streptococcal polysaccharide
      (GBSPIII) is length dependent and conformational. To obtain a more accurate
      characterization of the conformational epitope, ELISA inhibition and surface
      plasmon resonance studies were conducted on two GBSPIII-specific mAbs using a
      large panel of oligosaccharide probes. The results of the studies confirmed that
      2 repeating units (RU) is the minimum binding unit and that, while increases in
      chain length from 2 RU to 7 RU caused further optimization of the epitope, it
      remained monovalent. A 3-fold increase in affinity was observed between 7 RU and
      20 RU, which, by surface plasmon resonance studies on a Fab, was shown to be due
      to both further optimization of the individual epitope and the occurrence of
      multivalency of epitope. The data support our hypothesis that the conformational
      epitope is an extended helical segment of the GBSPIII. GBSPIII exists mainly in
      the random coil form, which structurally mimics short oligosaccharide self Ags,
      but it can infrequently and spontaneously form extended helices. Although not
      prevalent in GBSPIII, the immune system preferentially selects these helical
      epitopes because they are unique to the polysaccharide. Contrary to a previously
      proposed model of GBSPIII binding in which the binding of the first Ab propagates
      a continuum of helical epitopes, our binding kinetics are consistent only with
      the helical epitope's being discontinuous and infrequent.

PMID- 10395676
TI  - Peptide ligands that bind IgM antibodies and block interaction with antigen.
AB  - We have selected a peptide-display phage library on IgM Abs and identified a
      panel of phage-expressing peptides that bind to IgM Abs in general, but not to
      Abs of other classes. A synthetic peptide corresponding to one of the displayed
      peptide sequences also binds to IgM Abs. The peptides bind to both soluble
      pentameric Abs and to monomeric cell-surface IgM. The phage-displayed and
      synthetic peptides inhibit the binding of IgM Abs to Ag. These peptides may
      create confounding artifacts when IgM Abs are used for epitope mapping studies.
      Nonetheless, the peptides may have both experimental and therapeutic utility.

PMID- 10395677
TI  - Modulation of terminal deoxynucleotidyltransferase activity by the DNA-dependent
      protein kinase.
AB  - Rare Ig and TCR coding joints can be isolated from mice that have a targeted
      deletion in the gene encoding the 86-kDa subunit of the Ku heterodimer, the
      regulatory subunit of the DNA-dependent protein kinase (DNA-PK). However in the
      coding joints isolated from Ku86-/- animals, there is an extreme paucity of N
      regions (the random nucleotides added during V(D)J recombination by the enzyme
      TdT). This finding is consistent with a decreased frequency of coding joints
      containing N regions isolated from C.B-17 SCID mice that express a truncated form
      of the catalytic subunit of the DNA-PK (DNA-PKCS). This finding suggests an
      unexpected role for DNA-PK in addition of N nucleotides to coding ends during
      V(D)J recombination. In this report, we establish that TdT forms a stable complex
      with DNA-PK. Furthermore, we show that DNA-PK modulates TdT activity in vitro by
      limiting both the length and composition of nucleotide additions.

PMID- 10395679
TI  - Divergence of binding, signaling, and biological responses to recombinant human
      hybrid IFN.
AB  - Three human IFN-alpha hybrids, HY-1 [IFN-alpha21a(1-75)/alpha2c(76-165)], HY-2
      [IFN-alpha21a(1-95)/alpha2c(96-165)], and HY-3 [IFN-alpha2c(1-95)/alpha21a(96
      166)], were constructed, cloned, and expressed. The hybrids had comparable
      specific antiviral activities on Madin-Darby bovine kidney (MDBK) cells but
      exhibited very different antiproliferative and binding properties on human Daudi
      and WISH cells and primary human lymphocytes. Our data suggest that a portion of
      the N-terminal region of the molecule is important for interaction with
      components involved in binding of IFN-alpha2b while the C-terminal portion of IFN
      is critical for antiproliferative activity. A domain affecting the
      antiproliferative activity was found within the C-terminal region from amino acid
      residues 75-166. The signal transduction properties of HY-2 and HY-3 were
      evaluated by EMSA and RNase protection assays. Both HY-2 and HY-3 induced
      activation of STAT1 and 2. However, HY-2 exhibited essentially no
      antiproliferative effects at concentrations that activated STAT1 and 2.
      Additionally, at concentrations where no antiproliferative activity was seen, HY
      2 induced a variety of IFN-responsive genes to the same degree as HY-3. RNase
      protection assays also indicate that, at concentrations where no
      antiproliferative activity was seen for HY-2, this construct retained the ability
      to induce a variety of IFN-inducible genes. These data suggest that the
      antiproliferative response may not be solely directed by the activation of the
      STAT1 and STAT2 pathway in the cells tested.

PMID- 10395678
TI  - TCR and CD28 are coupled via ZAP-70 to the activation of the Vav/Rac-1-/PAK-1/p38
      MAPK signaling pathway.
AB  - CD28 costimulation amplifies TCR-dependent signaling in activated T cells,
      however, the biochemical mechanism(s) by which this occurs is not precisely
      understood. The small GTPase Rac-1 controls the catalytic activity of the mitogen
      activated protein kinases (MAPKs) and cell cycle progression through G1. Rac-1
      activation requires the phospho-tyrosine (p-Tyr)-dependent recruitment of the Vav
      GDP releasing factor (GRF) to the plasma membrane and assembly of GTPase/GRF
      complexes, an event critical for Ag receptor-triggered T cell activation. Here,
      we show that TCR/CD28 costimulation synergistically induces Rac-1 GDP/GTP
      exchange. Our findings, obtained by using ZAP-70-negative Jurkat T cells,
      indicate that CD28 costimulation augments TCR-mediated T cell activation by
      increasing the ZAP-70-mediated Tyr phosphorylation of Vav. This event regulates
      the Rac-1-associated GTP/GDP exchange activity of Vav and downstream pathway(s)
      leading to PAK-1 and p38 MAPK activation. CD28 amplifies TCR-induced ZAP-70
      activity and association of Vav with ZAP-70 and linker for activation of T cells
      (LAT). These results favor a model in which ZAP-70 regulates the intersection of
      the TCR and CD28 signaling pathways, which elicits the coupling of TCR and CD28
      to the Rac-1, PAK-1, and p38 MAPK effector molecules.

PMID- 10395680
TI  - The antiviral activity of HIV-specific CD8+ CTL clones is limited by elimination
      due to encounter with HIV-infected targets.
AB  - Adoptive immunotherapy of virus infection with viral-specific CTL has shown
      promise in animal models and human virus infections and is being evaluated as a
      therapy for established HIV-1 infection. Defining the individual obstacles for
      success is difficult in human trials. We have therefore examined the
      localization, persistence, and antiviral activity of HIV-1 gag-specific CTL
      clones in both HIV-1-infected and uninfected haplotype-matched human (hu)-PBL
      SCID mice. Injection of gag-specific clones but not control CTL into HIV-1
      infected hosts reduced plasma viremia by >10-fold but failed to eliminate the
      virus infection from most treated animals. The failure to eradicate virus did not
      reflect selection of escape variants because the gag epitope remained unmutated
      in virus isolates obtained after CTL therapy. Injection of carboxyfluorescein
      diacetate succinimide ester-labeled CTL demonstrated markedly different fates for
      gag-specific CTL in the presence or absence of HIV-1 infection. HIV-1-specific
      CTL rapidly disappeared in infected recipients, whereas they were maintained at
      high numbers in uninfected mice. By contrast, control CTL were long lived in both
      infected and uninfected recipients. Thus, interaction of CTL with virus-infected
      target cells in vivo leads not only to target destruction but also to the rapid
      disappearance of the infused CTL, and it limits the capacity of CTL therapy to
      eliminate HIV-1 infection.

PMID- 10395681
TI  - Lytic cycle T cell epitopes are expressed in two distinct phases during MHV-68
      infection.
AB  - Murine herpesvirus-68 (MHV-68) is a type 2 gamma herpesvirus that productively
      infects alveolar epithelial cells during the acute infection and establishes long
      term latency in B cells and lung epithelial cells. In C57BL/6 mice, T cells
      specific for lytic cycle MHV-68 epitope p56/Db dominate the acute phase of the
      infection, whereas T cells specific for another lytic cycle epitope, p79/Kb,
      dominate later phases of infection. To further understand this response, we
      analyzed the kinetics of Ag presentation in vivo using a panel of lacZ-inducible
      T cell hybridomas specific for several lytic cycle epitopes, including p56/Db and
      p79/Kb. Two distinct peaks of Ag presentation were observed. The first peak was
      at day 6 in the mediastinal lymph nodes and correlated with the initial pulmonary
      lytic infection. The second peak was at day 18 in both the mediastinal lymph
      nodes and spleen and correlated with the peak of latent infection. Interestingly,
      the p56 epitope was detected only in the mediastinal lymph nodes at day 6 after
      infection whereas the p79 epitope was predominantly presented in the spleen at
      day 18, suggesting that differential epitope presentation drives the switch in T
      cell responses to this virus. Phenotypic analysis of APCs at day 18 postinfection
      revealed that dendritic cells, macrophages, and B cells all presented lytic cycle
      epitopes. Taken together, the data suggest that there is a resurgence of lytic
      cycle Ags in the spleen, which explains the kinetics and specificity of the T
      cell response to MHV-68.

PMID- 10395682
TI  - Delayed clearance of filarial infection and enhanced Th1 immunity due to
      modulation of macrophage APC functions in xid mice.
AB  - Bruton's tyrosine kinase (Btk) mutant CBA/N mice show delayed clearance of
      injected microfilaria (mf) compared with wild-type CBA/J mice. Anti-mf T cells
      from CBA/N mice make relatively more IFN-gamma than those from CBA/J mice. The
      anti-mf T cell proliferative responses are also greater in CBA/N mice. This CBA/N
      immune phenotype is not restricted to filarial Ags, because immunization with
      pure proteins also yields T cell responses of greater proliferative magnitude
      skewed away from Th2 cytokines in CBA/N compared with CBA/J mice. The increased
      magnitude of CBA/N T cell proliferative responses is reflected in increases in
      both precursor frequencies and clonal burst sizes of responding Ag-specific T
      cells, and is independent of the source of re-stimulating APCs. Transfer of CBA/J
      peritoneal resident cells (PRCs) into CBA/N mice before pure protein immunization
      leads to a wild-type immune phenotype in the recipient CBA/N mice, with a
      reduction in the proliferative response and a relative decrease in the IFN-gamma
      produced. When wild-type PRC subpopulations are similarly transferred, the wild
      type immune phenotype is transferred by macrophages rather than by B cells.
      Transfer of wild-type PRCs into CBA/N mice before injection of mf also causes
      similar changes in the anti-mf T cell responses and enhances the clearance of mf.
      Thus, Btk is involved in critical macrophage APC functions regulating priming of
      T cells, and can modulate these responses in pathophysiologically relevant
      fashion in vivo.

PMID- 10395683
TI  - IL-12 and NK cells are required for antigen-specific adaptive immunity against
      malaria initiated by CD8+ T cells in the Plasmodium yoelii model.
AB  - CD8+ T cells have been implicated as critical effector cells in protection
      against preerythrocytic stage malaria, including the potent protective immunity
      of mice and humans induced by immunization with radiation-attenuated Plasmodium
      spp. sporozoites. This immunity is directed against the Plasmodium spp. parasite
      developing within the host hepatocyte and for a number of years has been presumed
      to be mediated directly by CD8+ CTL or indirectly by IFN-gamma released from CD8+
      T cells. In this paper, in BALB/c mice, we establish that after immunization with
      irradiated sporozoites or DNA vaccines parasite-specific CD8+ T cells trigger a
      novel mechanism of adaptive immunity that is dependent on T cell- and non-T cell
      derived cytokines, in particular IFN-gamma and IL-12, and requires NK cells but
      not CD4+ T cells. The absolute requirement for CD8+ T cells to initiate such an
      effector mechanism, and the requirement for IL-12 and NK cells in such vaccine
      induced protective immunity, are unique and underscore the complexity of the
      immune responses that protect against malaria and other intracellular pathogens.

PMID- 10395684
TI  - IL-2 mediates protection against abscess formation in an experimental model of
      sepsis.
AB  - Little is known regarding the mechanism by which T cells control intraabdominal
      abscess formation. Treating animals with polysaccharide A (PS A) from Bacteroides
      fragilis shortly before or after challenge protects against abscess formation
      subsequent to challenge with different abscess-inducing bacteria. Although
      bacterial polysaccharides are considered to be T cell-independent Ags, T cells
      from PS A-treated animals mediate this protective activity. In the present study,
      we demonstrate that CD4+ T cells transfer PS A-mediated protection against
      abscess formation, and that a soluble mediator produced by these cells confers
      this activity. Cytokine mRNA analysis showed that T cells from PS A-treated
      animals produced transcript for IL-2, IFN-gamma, and IL-10, but not for IL-4. The
      addition of IL-2-specific Ab to T cell lysates taken from PS A-treated animals
      abrogated the ability to transfer protection, whereas the addition of Abs
      specific for IFN-gamma and IL-10 did not affect protection. Finally,
      administration of rIL-2 to animals at the time of bacterial challenge prevented
      abscess formation in a dose-dependent manner. These data demonstrate that PS A
      mediated protection against abscess formation is dependent upon a CD4+ T cell
      dependent response, and that IL-2 is essential to this immune mechanism.

PMID- 10395685
TI  - Neonatal exposure to idiotype induces Schistosoma mansoni egg antigen-specific
      cellular and humoral immune responses.
AB  - Exposure of neonatal mice to appropriate, cross-reactive Id (CRI) preparations
      alters immune responsiveness, ameliorates pathology, and prolongs survival of
      animals upon subsequent Schistosoma mansoni infection. However, because
      schistosome infections profoundly affect host immunobiology, which responses are
      effected by neonatal Id exposure alone and which responses are influenced by
      infection is unclear. To directly examine the schistosome soluble egg Ag (SEA)
      specific immune responses altered by CRI exposure, neonatal mice were injected
      with CRI-expressing (CRI+) SEA-specific Ab preparations, SEA-specific Abs that
      did not express CRI (CRI-), or normal mouse Ig. At 9 wk of age, only mice that
      were neonatally exposed to CRI+ anti-SEA Abs displayed significant SEA-specific
      IgG serum levels and spleen cell proliferative responses. SEA-stimulated spleen
      cells from these CRI+-exposed mice also produced IFN-gamma, although not at
      significantly higher levels than mice receiving CRI- Id or normal mouse Ig. If
      CRI+-exposed mice were also injected with SEA at 8 wk of age, the 9-wk IFN-gamma
      responses were significantly higher than those of the other neonatal injection
      groups. The presence of both CRI and anti-CRI in the sera of animals neonatally
      injected with CRI, but receiving no exposure to S. mansoni Ags or infection,
      suggested a functional idiotypic network led to these responses. These data
      demonstrate that appropriate idiotypic exposure induces B and T cell
      responsiveness to the Ag recognized by the Id and support the hypothesis that
      neonatal idiotypic exposure can be an important immunoregulatory factor in
      schistosomiasis.

PMID- 10395686
TI  - Processing, secretion, and anti-HIV-1 activity of IL-16 with or without a signal
      peptide in CD4+ T cells.
AB  - CD4+ T cells transfected with the C-terminal 130 aa of human IL-16 are rendered
      resistant to HIV infection. Whether the constitutively expressed IL-16 acts
      intracellularly, extracellularly, or both is not clear. To address this question
      and to further study the processing of IL-16, new constructs containing either
      the C-terminal 130 aa or the C-terminal 100 aa (PDZ-like motif) were constructed
      with and without a signal peptide. Pulse-chase experiments and treatment of cells
      with brefeldin A and/or tunicamycin showed that IL-16 is secreted despite the
      absence of a signal peptide, but with a signal peptide IL-16 is processed through
      the endoplasmic reticulum-golgi pathway and is glycosylated. Cells expressing IL
      16 linked to a signal peptide secrete considerably more IL-16 into the
      supernatant than cells expressing IL-16 without a signal peptide and are
      considerably more resistant to HIV replication. Resistance extends to almost 25
      days for cells expressing IL-16 with signal peptide as compared with only 15 days
      for cells without signal peptide. Cells expressing the C-terminal 100 aa not
      linked to a signal peptide are poor secretors of IL-16 and show little if any
      resistance to HIV. In contrast, cells expressing the C-terminal 100 aa linked to
      a signal peptide secrete IL-16 and are resistant to HIV replication. It is
      concluded that the secretion of IL-16 is required for HIV inhibition.

PMID- 10395687
TI  - Lack of J chain inhibits the transport of gut IgA and abrogates the development
      of intestinal antitoxic protection.
AB  - Recent publications have provided confusing information on the importance of the
      J chain for secretion of dimeric IgA at mucosal surfaces. Using J chain-deficient
      (J chain-/-) mice, we addressed whether a lack of J chain had any functional
      consequence for the ability to resist challenge with cholera toxin (CT) in
      intestinal loops. J chain-/- mice had normal levels of IgA plasma cells in the
      gut mucosa, and the Peyer's patches exhibited normal IgA B cell differentiation
      and germinal center reactions. The total IgA levels in gut lavage were reduced by
      roughly 90% as compared with that in wild-type controls, while concomitantly
      serum IgA levels were significantly increased. Total serum IgM levels were
      depressed, whereas IgG concentrations were normal. Following oral immunizations
      with CT, J chain-/- mice developed 10-fold increased serum antitoxin IgA titers,
      but gut lavage anti-CT IgA levels were substantially reduced. However, anti-CT
      IgA spot-forming cell frequencies in the gut lamina propria were normal. Anti-CT
      IgM concentrations were low in serum and gut lavage, whereas anti-CT IgG titers
      were unaltered. Challenge of small intestinal ligated loops with CT caused
      dramatic fluid accumulation in immunized J chain-/- mice, and only 20% protection
      was detected compared with unimmunized controls. In contrast, wild-type mice
      demonstrated 80% protection against CT challenge. Mice heterozygous for the J
      chain deletion exhibited intermediate gut lavage anti-CT IgA and intestinal
      protection levels, arguing for a J chain gene-dosage effect on the transport of
      secretory IgA. This study unequivocally demonstrates a direct relationship
      between mucosal transport of secretory SIgA and intestinal immune protection.

PMID- 10395688
TI  - IFN-gamma mediates a novel antiviral activity through dynamic modulation of TRAIL
      and TRAIL receptor expression.
AB  - TNF-related apoptosis-inducing ligand (TRAIL) is able to kill many transformed
      cells of diverse tissue types. We show that TRAIL is inducible by IFN-gamma, by
      TNF-alpha, and by infection with human CMV, and has potent antiviral activity in
      vitro. CMV infection and IFN-gamma also reciprocally modulate TRAIL receptor
      (TRAIL-R) expression. CMV infection increased the expression of TRAIL-R1 and -R2,
      whereas IFN-gamma down-regulated the expression of TRAIL-Rs on uninfected
      fibroblasts. Moreover, IFN-gamma significantly decreased the basal level of NF
      kappaB activation, a known survival factor that inhibits apoptosis. Thus, TRAIL
      selectively kills virus-infected cells while leaving uninfected cells intact, and
      IFN-gamma potentiates these effects by dynamic modulation of TRAIL and TRAIL-R
      expression and by sensitizing cells to apoptosis. The regulation of TRAIL and
      TRAIL-R expression may represent a general mechanism that contributes to the
      control of TRAIL-mediated apoptosis.

PMID- 10395689
TI  - Studies with double cytokine-deficient mice reveal that highly polarized Th1- and
      Th2-type cytokine and antibody responses contribute equally to vaccine-induced
      immunity to Schistosoma mansoni.
AB  - A fundamental obstacle to vaccine development in schistosomiasis mansoni is a
      lack of understanding of what type of an immune response should be invoked. We
      have addressed this central issue by using the radiation-attenuated cercariae
      vaccine in mice genetically engineered to exhibit highly polarized type 1 (IL
      10/IL-4-deficient) or type 2 (IL-10/IL-12-deficient) cytokine and Ab phenotypes.
      Our data show that while significant differences in immunity exist after a single
      vaccination with irradiated cercariae in double cytokine-deficient vs wild-type
      mice, these differences disappear after two vaccinations. The most important
      finding of these studies, however, was revealed in vaccinated IL-10-deficient
      mice. These mice developed a mixed and elevated type 1- and type 2-associated
      immune response and developed anti-schistosome immunity at levels equal to or
      better than those in wild-type mice. This immunity in IL-10-deficient mice
      correlated with higher parasite-specific Ab titers, greater proliferative
      capacity of lymphocytes, increased frequency of IFN-gamma- and IL-4-secreting
      cells, elevated perivascular/peribronchial inflammatory responses in the lung,
      and greater in vitro schistosomulacidal capacity of parasite Ag-elicited cells.
      These results suggest that optimal vaccine-induced immunity against schistosomes
      is linked not to the development of a highly polarized response, but, rather, to
      the induction of both type 1- and type 2-associated immune responses.

PMID- 10395690
TI  - A novel Lyn-binding peptide inhibitor blocks eosinophil differentiation,
      survival, and airway eosinophilic inflammation.
AB  - Receptor antagonists block all receptor-coupled signaling pathways
      indiscriminately. We introduce a novel class of peptide inhibitors that is
      designed to block a specific signal from a receptor while keeping other signals
      intact. This concept was tested in the model of IL-5 signaling via Lyn kinase. We
      have previously mapped the Lyn-binding site of the IL-5/GM-CSF receptor common
      beta (beta c) subunit. In the present study, we designed a peptide inhibitor
      using the Lyn-binding sequence. The peptide was N-stearated to enable cellular
      internalization. The stearated peptide blocked the binding of Lyn to the beta c
      receptor and the activation of Lyn. The lipopeptide did not affect the activation
      of Janus kinase 2 or its association with beta c. The inhibitor blocked the Lyn
      dependent functions of IL-5 in vitro (e.g., eosinophil differentiation from stem
      cells and eosinophil survival). It did not affect eosinophil degranulation. When
      applied in vivo, the Lyn-binding peptide significantly inhibited airway
      eosinophil influx in a mouse model of asthma. The lipopeptide had no effect on
      basophil histamine release or on the proliferation of B cells and T cells. To our
      knowledge, this is the first report on an inhibitor of IL-5 that blocks
      eosinophil differentiation, survival, and airway eosinophilic inflammation. This
      novel strategy to develop peptide inhibitors can be applied to other receptors.

PMID- 10395691
TI  - Neutrophil defensins induce histamine secretion from mast cells: mechanisms of
      action.
AB  - Defensins are endogenous antimicrobial peptides stored in neutrophil granules.
      Here we report that a panel of defensins from human, rat, guinea pig, and rabbit
      neutrophils all have histamine-releasing activity, degranulating rat peritoneal
      mast cells with EC50 ranging from 70 to 2500 nM, and between 45 and 60% of the
      total histamine released. The EC50 for defensin-induced histamine secretion
      correlates with their net basic charge at neutral pH. There is no correlation
      between histamine release and antimicrobial potency. Degranulation induced by
      defensins has characteristics similar to those of activation by substance P. The
      maximum percent histamine release is achieved in <10 s, and it can be markedly
      inhibited by pertussis toxin (100 ng/ml) and by pretreatment of mast cells with
      neuraminidase. These properties differ from those for degranulation induced by
      IgE-dependent Ag stimulation and by the calcium ionophore A23187. GTPase
      activity, a measure of G protein activation, was induced in a membrane fraction
      from mast cells following treatment with defensin. Thus, neutrophil defensins are
      potent mast cell secretagogues that act in a manner similar to substance P and
      48/80, through a rapid G protein-dependent response that is mechanistically
      distinct from Ag/IgE-dependent mast cell activation. Defensins may provide
      important pathways for communication between neutrophils and mast cells in
      defenses against microbial agents and in acute inflammatory responses.

PMID- 10395692
TI  - Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles
      of reactive oxygen intermediates, NF-kappa B, and cyclic AMP response element
      binding protein.
AB  - Acute inflammatory lung injury occurs frequently in the setting of severe
      infection or blood loss. Accumulation of activated neutrophils in the lungs and
      increased pulmonary proinflammatory cytokine levels are major characteristics of
      acute lung injury. In the present experiments, we examined mechanisms leading to
      neutrophil accumulation and activation in the lungs after endotoxemia or
      hemorrhage. Levels of IL-1 beta, TNF-alpha, and macrophage inflammatory protein-2
      mRNA were increased in lung neutrophils from endotoxemic or hemorrhaged mice
      compared with those present in lung neutrophils from control mice or in
      peripheral blood neutrophils from endotoxemic, hemorrhaged, or control mice. The
      transcriptional regulatory factors NF-kappa B and cAMP response element binding
      protein were activated in lung but not blood neutrophils after hemorrhage or
      endotoxemia. Xanthine oxidase inhibition, achieved by feeding allopurinol or
      tungsten-containing diets, did not affect neutrophil trafficking to the lungs
      after hemorrhage or endotoxemia. Xanthine oxidase inhibition did prevent
      hemorrhage- but not endotoxemia-induced increases in proinflammatory cytokine
      expression among lung neutrophils. Hemorrhage- or endotoxemia-associated
      activation of NF-kappa B in lung neutrophils was not affected by inhibition of
      xanthine oxidase. cAMP response element binding protein activation was increased
      after hemorrhage, but not endotoxemia, in mice fed xanthine oxidase-inhibiting
      diets. Our results indicate that xanthine oxidase modulates cAMP response element
      binding protein activation and proinflammatory cytokine expression in lung
      neutrophils after hemorrhage, but not endotoxemia. These findings suggest that
      the mechanisms leading to acute inflammatory lung injury after hemorrhage differ
      from those associated with endotoxemia.

PMID- 10395693
TI  - Lipopolysaccharide modulates cyclooxygenase-2 transcriptionally and
      posttranscriptionally in human macrophages independently from endogenous IL-1
      beta and TNF-alpha.
AB  - The pathogenesis of septicemia can be triggered by LPS, a potent stimulus for PG
      synthesis. The enzyme cyclooxygenase (COX) is a rate-limiting step in PG
      production. COX exists as two isoforms: COX-1, which is constitutively expressed
      in most cell types, and COX-2, which is inducible by LPS and cytokines in a
      variety of cells. In this study we determined the role of the proinflammatory
      cytokines IL-1 beta and TNF-alpha released by LPS-stimulated U937 human
      macrophages in the regulation of COX-2. Macrophages exposed to LPS showed a rapid
      and sustained expression of COX-2 mRNA and protein for up to 48 h, whereas PGE2
      production was notably enhanced only after 12 h. LPS increased COX-2 gene
      transcription and activation of the transcription factor NF-kappa B in a
      transient manner. LPS-treated macrophages produced high levels of TNF-alpha and
      moderate amounts of IL-1 beta protein. However, neutralizing Abs against these
      cytokines had no effect on COX-2 mRNA and protein expression, nor did they affect
      the stability of COX-2 mRNA. Interestingly, in the presence of LPS or exogenous
      IL-1 beta, COX-2 transcripts were stabilized, and actinomycin D inhibited their
      degradation. Only when LPS or IL-1 beta was removed did COX-2 mRNA decay with a
      t1/2 of >/=5 h. In contrast, dexamethasone promoted a faster decay of the LPS
      induced COX-2 transcripts (t1/2 = 2.5 h). These results clearly demonstrate that
      LPS can regulate COX-2 at both transcriptional and posttranscriptional levels
      independently from endogenous IL-1 beta and TNF-alpha in human macrophages.

PMID- 10395694
TI  - Chemotaxis of rat mast cells toward adenine nucleotides.
AB  - Rat mucosal mast cells express P2 purinoceptors, occupation of which mobilizes
      cytosolic Ca2+ and activates a potassium conductance. The primary function of
      this P2 system in mast cell biology remains unknown. Here, we show that
      extracellular ADP causes morphological changes in rat bone marrow-cultured mast
      cells (BMMC) typical of those occurring in cells stimulated by chemotaxins, and
      that the nucleotides ADP, ATP, and UTP are effective chemoattractants for rat
      BMMC. ADP was also a chemotaxin for murine J774 monocytes. The nucleotide
      selectivity and pertussis toxin sensitivity of the rat BMMC migratory response
      suggest the involvement of P2U receptors. Poorly hydrolyzable derivatives of ADP
      and ATP were effective chemotaxins, obviating a role for adenosine receptors.
      Buffering of external Ca2+ at 100 nM or reduction of the electrical gradient
      driving Ca2+ entry (by elevating external K+) blocked ADP-driven chemotaxis,
      suggesting a role for Ca2+ influx in this process. Anaphylatoxin C5a was a potent
      chemotaxin (EC50 approximately 0.5 nM) for J774 monocytes, but it was inactive on
      rat BMMC in the presence or absence of laminin. Ca2+ removal or elevated [K+] had
      modest effects on C5a-driven chemotaxis of J774 cells, implicating markedly
      different requirements for Ca2+ signaling in C5a- vs ADP-mediated chemotaxis.
      This is supported by the observation that depletion of Ca2+ stores with
      thapsigargin completely blocked migration induced by ADP but not C5a. These
      findings suggest that adenine nucleotides liberated from parasite-infested tissue
      could participate in the recruitment of mast cells by intestinal mucosa.

PMID- 10395696
TI  - Selection of a C5a receptor antagonist from phage libraries attenuating the
      inflammatory response in immune complex disease and ischemia/reperfusion injury.
AB  - A C5a-receptor antagonist was selected from human C5a phage display libraries in
      which the C terminus of des-Arg74-hC5a was mutated. The selected molecule is a
      competitive C5a receptor antagonist in vitro and in vivo. Signal transduction is
      interrupted at the level of G-protein activation. In addition, the antagonist
      does not cause any C5a receptor phosphorylation. Proinflammatory properties such
      as chemotaxis or lysosomal enzyme release of differentiated U937 cells, as well
      as C5a-induced changes in intracellular Ca2+ concentration of murine peritoneal
      macrophages, are inhibited. The in vivo efficacy was evaluated in three different
      animal models of immune complex diseases in mice, i.e., the reverse passive
      Arthus reaction in the peritoneum, skin, and lung. The i.v. application of the
      C5a receptor antagonist abrogated polymorphonuclear neutrophil accumulation in
      peritoneum and markedly attenuated polymorphonuclear neutrophil migration into
      the skin and the lung. In a model of intestinal ischemia/reperfusion injury, i.v.
      administration of the C5a receptor antagonist decreased local and remote tissue
      injury: bowel wall edema and hemorrhage as well as pulmonary microvascular
      dysfunction. These data give evidence that C5a is an important mediator
      triggering the inflammatory sequelae seen in immune complex diseases and
      ischemia/reperfusion injury. The selected C5a receptor antagonist may prove
      useful to attenuate the inflammatory response in these disorders.

PMID- 10395695
TI  - Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase.
AB  - Stimulation of the type 1 IL-1R (IL-1R1) and the IL-18R by their cognate ligands
      induces recruitment of the IL-1R-associated kinase (IRAK). Activation of IRAK
      leads in turn to nuclear translocation of NF-kappaB, which directs expression of
      innate and adaptive immune response genes. To study IRAK function in cytokine
      signaling, we generated cells and mice lacking the IRAK protein. IRAK-deficient
      fibroblasts show diminished activation of NF-kappaB when stimulated with IL-1.
      Immune effector cells without IRAK exhibit a defective IFN-gamma response to
      costimulation with IL-18. Furthermore, mice lacking the Irak gene demonstrate an
      attenuated response to injected IL-1. Deletion of Irak, however, does not affect
      the ability of mice to develop delayed-type hypersensitivity or clear infection
      with the intracellular parasite, Listeria monocytogenes. These results
      demonstrate that although IRAK participates in IL-1 and IL-18 signal
      transduction, residual cytokine responsiveness operates through an IRAK
      independent pathway.

PMID- 10395697
TI  - Effects of CD18 deficiency on the emigration of murine neutrophils during
      pneumonia.
AB  - We hypothesized that CD18 deficiency would impair the ability of neutrophils to
      emigrate from pulmonary blood vessels during certain pneumonias. To directly
      compare the abilities of wild-type (WT) and CD18-deficient neutrophils to
      emigrate, mice with both types of leukocytes in their blood were generated by
      reconstituting the hemopoietic systems of lethally irradiated C57BL/6 mice with
      mixtures of fetal liver cells from WT and CD18-deficient mice. Percentages of
      CD18-deficient neutrophils in the circulating and emigrated pools were compared
      during experimental pneumonias. Similar percentages were observed in the blood
      and bronchoalveolar lavage fluid 6 or 24 h after intratracheal instillation of
      Streptococcus pneumoniae, demonstrating that no site on the CD18 molecule was
      required for either its adhesive or its signaling functions during neutrophil
      emigration. However, 6 h after instillation of Escherichia coli LPS or
      Pseudomonas aeruginosa, the percentage of CD18-deficient neutrophils in the
      bronchoalveolar lavage fluid was only about one-fourth of that observed in the
      blood. This difference persisted for at least 24 h after instillation of E. coli
      LPS. Thus, neutrophil emigration elicited by the Gram-negative stimuli E. coli
      LPS or P. aeruginosa was compromised by deficiency of CD18. These data, based on
      comparing WT and gene-targeted CD18-deficient neutrophils within the same
      animals, provide evidence for molecular pathways regulating neutrophil
      emigration, which could not be appreciated in previous studies with
      pharmacological blockade or genetic deficiency of CD18.

PMID- 10395698
TI  - Paradoxical effects of adenovirus-mediated blockade of TNF activity in murine
      collagen-induced arthritis.
AB  - Collagen-induced arthritis (CIA) is an experimental model of arthritis widely
      used to dissect the pathogenesis of human rheumatoid arthritis and to identify
      potential therapeutic targets. Among these, TNF-alpha has been recognized to play
      an important role. Here we investigate the feasibility and therapeutic efficacy
      of prolonged blockade of TNF-alpha activity through the adenovirus-mediated gene
      delivery of a dimeric chimeric human p55 TNFR-IgG fusion protein and compare it
      to protein therapy in established CIA. A single i.v. administration of the
      replication-deficient adenovirus yielded microgram serum levels of the chimeric
      fusion protein and ameliorated CIA for 10 days. Subsequently, benefit was lost
      and a rebound to greater inflammatory activity was observed despite the continual
      presence of bioactive TNFR fusion protein. A similar trend was also observed in
      mice injected directly with comparable amounts of a human TNFR-IgG fusion
      protein, whereas the administration of a control adenovirus-encoding beta
      galactosidase or of a control human IgG1 protein did not significantly affect the
      disease course. The mechanisms of the rebound of CIA were investigated, and
      augmented Ab response to collagen type II and TNFR were identified as potential
      causes. Our results confirm the feasibility of adenovirus-mediated gene delivery
      of cytokine inhibitors in animal models of autoimmune diseases for
      investigational purposes and highlight the importance of prolonged studies.
      Further investigations are needed to optimize ways of exploiting the potential of
      adenoviral gene therapy in RA.

PMID- 10395699
TI  - Alloantibody-mediated class I signal transduction in endothelial cells and smooth
      muscle cells: enhancement by IFN-gamma and TNF-alpha.
AB  - Chronic rejection is the major limiting factor to long term survival of solid
      organ allografts. The hallmark of chronic rejection is transplant
      atherosclerosis, which is characterized by the intimal proliferation of smooth
      muscle cells, endothelial cells, and fibroblasts, leading to vessel obstruction,
      fibrosis, and eventual graft loss. The mechanism of chronic rejection is poorly
      understood, but it is suspected that the associated vascular changes are a result
      of anti-HLA Ab-mediated injury to the endothelium and smooth muscle of the graft.
      In this study we have investigated whether anti-HLA Abs, developed by transplant
      recipients following transplantation, are capable of transducing signals via HLA
      class I molecules, which stimulate cell proliferation. In this report we show
      that ligation of class I molecules with Abs to distinct HLA-A locus and HLA-B
      locus molecules results in increased tyrosine phosphorylation of intracellular
      proteins and induction of fibroblast growth factor receptor expression on
      endothelial and smooth muscle cells. Treatment of cells with IFN-gamma and TNF
      alpha up-regulated MHC class I expression and potentiated anti-HLA Ab-induced
      fibroblast growth factor receptor expression. Engagement of class I molecules
      also stimulated enhanced proliferative responses to basic fibroblast growth
      factor, which augmented endothelial cell proliferation. These findings support a
      role for anti-HLA Abs and cytokines in the transduction of proliferative signals,
      which stimulate the development of myointimal hyperplasia associated with chronic
      rejection of human allografts.

PMID- 10395700
TI  - Identification of pathogenic T cells in patients with beryllium-induced lung
      disease.
AB  - Chronic beryllium disease (CBD) is caused by beryllium exposure and is
      characterized by granulomatous inflammation with accumulation of CD4+ T cells in
      the lung. We analyzed TCR beta-chain and alpha-chain genes expressed by these
      CD4+ T cells. In the lungs of individual patients, as well as among four of five
      CBD patients studied, different oligoclonal expansions within the Vbeta3 subset
      were found to express homologous or even identical CDR3 amino acid sequences.
      These related expansions were specific for CBD patients, were compartmentalized
      to lung, and persisted at high frequency in patients with active disease.
      Limiting dilution cloning and analysis of coexpressed TCR alpha-chain genes
      confirmed that these TCRs were selectively expanded by a common Ag involving
      beryllium. Overall, homologous TCR beta- and alpha-chains showed identical V
      regions and invariant charged residues within the CDR3 but considerable
      variability in TCRJ usage. Remarkably, CBD patients expressing nearly identical
      TCRs did not share common HLA-DRB1 or DQ alleles. These results implicate
      particular CD4+ cells in the pathogenesis of CBD and provide insight into how
      beryllium is recognized in human disease.

PMID- 10395701
TI  - Ig lambda and heavy chain gene usage in early untreated systemic lupus
      erythematosus suggests intensive B cell stimulation.
AB  - To determine the distribution of Vlambda and Jlambda as well as VH and JH gene
      usage in a patient with systemic lupus erythematosus (SLE), productive and
      nonproductive VJ and V(D)J rearrangements were amplified from individual
      peripheral CD19+ B cells and were analyzed. No differences in the Vlambda and
      Jlambda or the VH and JH gene usage in the nonproductive gene repertoire of this
      SLE patient were found compared with the distribution of genes found in normal
      adults, whereas marked skewing of both Vlambda and VH was noted among the
      productive rearrangements. The distribution of productive Vlambda rearrangements
      was skewed, with significantly greater representation of the Jlambda distal
      cluster C Vlambda genes and the Vlambda distal Jlambda7 element, consistent with
      the possibility that there was receptor editing of the Vlambda locus in this
      patient. Significant bias in VH gene usage was also noted with VH3 family members
      dominating the peripheral B cell repertoire of the SLE patient (83%) compared
      with that found in normal subjects (55%; p < 0.001). Notably, a clone of B cells
      employing the VH3-11 gene for the heavy chain and the Vlambda1G segment for the
      light chain was detected. These data are most consistent with the conclusion that
      extreme B cell overactivity drives the initial stages of SLE leading to
      remarkable changes in the peripheral V gene usage that may underlie on fail to
      prevent the emergence of autoimmunity.

PMID- 10395702
TI  - Identification of new HER2/neu-derived peptide epitopes that can elicit specific
      CTL against autologous and allogeneic carcinomas and melanomas.
AB  - Twenty-two new HLA-A2.1-binding peptides derived from the protooncogene HER2/neu
      were identified and analyzed for their capacity to elicit peptide and tumor
      specific CTL responses. We used peptide-pulsed autologous DC from the ascites of
      patients with ovarian carcinomas to induce CTL. Of the 22 tested new HER2/neu
      derived epitopes that could bind HLA-A2 with high (IC50 < 50 nM) or intermediate
      (50 nM < IC50 < 500 nM) affinity, we report the recognition by CTL of at least
      four novel epitopes, including HER2(9435), HER2(9665), HER2(9689), and
      HER2(10952), and confirm that of the known HER2 (9369) epitope. These epitopes
      were able to elicit CTL that specifically killed peptide-sensitized target cells
      and, most importantly, a HER2/neu-transfected cell line and the autologous tumor
      cells. We also confirm that HER2/neu is overexpressed in several melanoma lines,
      and as a new finding, report that some of these lines are sensitive to CTL
      induced by the HER2 (9369), HER2(9435), and HER2(9689) epitopes. Finally, CTL
      clones specific for HER2 (9369), HER2(9435), and HER2(9689) epitopes were
      isolated from tumor-specific CTL lines, further demonstrating the immunodominance
      of these epitopes. These findings broaden the potential application of HER2/neu
      based immunotherapy.

PMID- 10395703
TI  - Intranasal administration of a Schistosoma mansoni glutathione S-transferase
      cholera toxoid conjugate vaccine evokes antiparasitic and antipathological
      immunity in mice.
AB  - Mucosal administration of Ags linked to cholera toxin B subunit (CTB) can induce
      both strong mucosal secretory IgA immune responses and peripheral T cell
      hyporeactivity. In this study, intranasal (i.n. ) administration of CTB
      conjugated Schistosoma mansoni 28-kDa GST (CTB-Sm28GST) was found to protect
      infected animals from schistosomiasis, especially from immunopathological
      complications associated with chronic inflammation. Worm burden and liver egg
      counts were reduced in infected animals treated with the CTB-Sm28GST conjugate as
      compared with mice infected only, or with mice treated with a control (CTB-OVA)
      conjugate. However, a more striking and consistent effect was that granuloma
      formations in liver and lungs of mice treated with CTB-Sm28GST were markedly
      suppressed. Such treatment was associated with reduced systemic delayed-type
      hypersensitivity and lymphocyte proliferative responses to Sm28GST. Production of
      IFN-gamma, IL-3, and IL-5 by liver cells was also markedly reduced after i.n.
      treatment of CTB-Sm28GST, whereas IL-4 production was not impaired. Intranasal
      treatment of infected mice with CTB-Sm28GST increased IgG1-, IgG2a-, IgA-, and
      IgE-Ab-forming cell responses in liver in comparison with treatment with CTB-OVA,
      or free Sm28GST. Most importantly, mucosal treatment with CTB-Sm28GST
      significantly reduced animal mortality when administered to chronically infected
      mice. Our results suggest that it may be possible to design a therapeutic vaccine
      against schistosomiasis that both limits infection and suppresses parasite
      induced pathology.

PMID- 10395704
TI  - Highly Th2-skewed cytokine profile of beta-lactam-specific T cells from nonatopic
      subjects with adverse drug reactions.
AB  - A positive lymphocyte transformation test to beta-lactams (beta-L) was found in
      12 of 29 subjects with adverse drug reaction (ADR) to beta-L, irrespective of
      either the type of clinical manifestation or the presence of specific serum IgE.
      Short-term T cell lines specific for penicillin G, amoxicillin, and ampicillin
      could be generated only from subjects with ADR (eight with positive and one with
      negative lymphocyte transformation test), while streptokinase and
      Dermatophagoides pteronyssinus group 1 (Der p 1)-specific T cells were obtained
      from all these subjects, from 7 atopic Der p-sensitive donors without history of
      ADR and 17 healthy nonatopic donors. Streptokinase-specific T cells from all
      subjects showed intracellular expression of IFN-gamma with poor or no IL-4,
      whereas Der p 1-specific T cells exhibited IFN-gamma but low or no IL-4
      expression in nonatopics, and remarkable IL-4 expression in atopic donors. By
      contrast, all penicillin G-, ampicillin-, and amoxicillin-specific short-term T
      cell lines showed high intracellular expression of IL-4, IL-5, and IL-13, but
      poor or no expression of IFN-gamma, thus exhibiting a clear-cut Th2 profile.
      Accordingly, most penicillin G-specific T cell clones derived from two subjects
      with ADR released high concentrations of IL-4 alone or IL-4 and IFN-gamma. These
      data suggest that cytokines produced by Th2 cells play an important role in all
      beta-L-induced ADR, even when late clinical manifestations occur and an IgE
      mediated mechanism is apparently indemonstrable.

PMID- 10395705
TI  - Anti-human cardiac myosin autoantibodies in Kawasaki syndrome.
AB  - Kawasaki syndrome (KS) is the major cause of acquired heart disease in children.
      Although acute myocarditis is observed in most patients with KS, its pathogenesis
      is unknown. Because antimyosin autoantibodies are present in autoimmune
      myocarditis and rheumatic carditis, the purpose of the current study was to
      determine whether anticardiac myosin Abs might be present during the acute stage
      of KS. Sera from KS patients as well as age-matched febrile controls and normal
      adults were compared for reactivity with human cardiac myosin in ELISAs and
      Western blot assays. A total of 5 of 13 KS sera, as compared with 5 of 8 acute
      rheumatic fever sera, contained Ab titers to human cardiac myosin that were
      significantly higher than those found in control sera. Both cardiac and skeletal
      myosins were recognized in the ELISA by KS sera, although stronger reactivity was
      observed to human cardiac myosin. Only IgM antimyosin Abs from KS sera were
      significantly elevated relative to control sera. KS sera containing antimyosin
      Abs recognized synthetic peptides from the light meromyosin region of the human
      cardiac myosin molecule and had a different pattern of reactivity than acute
      rheumatic fever sera, further supporting the association of antimyosin Ab with
      KS. These Abs may contribute to the pathogenesis of acute myocarditis found in
      patients with KS.

PMID- 10395706
TI  - Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin-1,
      in patients with scleroderma and other connective tissue diseases.
AB  - A duplication in the fibrillin-1 gene has been implicated as the cause of the
      tight skin 1 (tsk1) phenotype, an animal model of scleroderma or systemic
      sclerosis (SSc). In addition to the production of abnormal fibrillin-1 protein,
      the tsk1 mouse also produces autoantibodies to fibrillin-1. Among a population of
      Choctaw Native Americans with the highest prevalence of SSc yet described, a
      chromosome 15q haplotype containing the fibrillin-1 gene has been strongly
      associated with SSc. With a recombinant human fibrillin-1 protein, autoantibodies
      to fibrillin-1 were detected in the sera of Native American SSc patients that
      correlated significantly with disease. Abs to fibrillin-1 also were detected in
      sera from Japanese, Caucasian, and African-American SSc patients. Compared with
      other ethnic groups, Japanese and Native American SSc patients had significantly
      higher frequencies of anti-fibrillin-1 Abs. Sera from patients with diffuse SSc,
      calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, and telangiectasias
      syndrome and mixed connective tissue disease also had significantly higher
      frequencies of anti-fibrillin-1 Abs than sera from controls or patients with
      other non-SSc connective tissue diseases (lupus, rheumatoid arthritis, and
      Sjogren's syndrome). Ab specificity for fibrillin-1 was demonstrated by the lack
      of binding to a panel of other purified autoantigens. The results presented
      demonstrate for the first time the presence of high levels of anti-fibrillin-1
      Abs in a significant portion of patients with SSc.

PMID- 10395707
TI  - Retinal expression of a neo-self antigen, beta-galactosidase, is not tolerogenic
      and creates a target for autoimmune uveoretinitis.
AB  - Recent studies revealing active mechanisms of immune privilege in neural tissues
      have diminished the putative role of passive tolerance. To examine the
      significance of Ag localization in the retina on immune privilege, the immune
      responses of transgenic mice expressing high and low levels of beta-galactosidase
      (beta-gal) in the photoreceptor cells of the retina were compared with those of
      normal mice and those of mice expressing moderate levels of beta-gal
      systemically. Immunization with beta-gal induced experimental autoimmune
      uveoretinitis indistinguishable from that induced by known photoreceptor cell
      autoantigens, including destruction of photoreceptor cells, in transgenic mice
      with high level retinal expression. Retinal expression had no apparent effect on
      the immune responses to beta-gal, showing that tolerance was not elicited by
      levels of retinal beta-gal sufficient to serve as a target for autoimmune
      disease. Mice with systemic expression exhibited reduced lymphoproliferative
      responses following immunization with beta-gal and did not develop autoimmune
      disease. T cells prepared from normal mice immunized with beta-gal transferred
      experimental autoimmune uveoretinitis to the transgenic mice with high level
      retinal beta-gal expression, but no disease was found in mice with systemic
      transgene expression under these conditions. The results of our experiments are
      most consistent with sequestration being the primary mechanism of retinal immune
      privilege. The results also show that beta-gal can serve as an immunopathogenic
      neural autoantigen, and that T cells raised by immunization of normal mice with a
      foreign Ag can be immunopathogenic in certain transgenic recipients.

PMID- 10395709
TI  - Health and human rights.

PMID- 10395710
TI  - The right to health in international human rights law.

PMID- 10395708
TI  - Resistance of Crohn's disease T cells to multiple apoptotic signals is associated
      with a Bcl-2/Bax mucosal imbalance.
AB  - Crohn's disease (CD) is a condition characterized by excessive numbers of
      activated T cells in the mucosa. We investigated whether a defect in apoptosis
      could prolong T cell survival and contribute to their accumulation in the mucosa.
      Apoptotic, Bcl-2+, and Bax+ cells in tissue sections were detected by the TUNEL
      method and immunohistochemistry. T cell apoptosis was induced by IL-2
      deprivation, Fas Ag ligation, and exposure to TNF-alpha and nitric oxide. TUNEL+
      leukocytes were few in control, CD, and ulcerative colitis (UC) mucosa, with
      occasional CD68+ and myeloperoxidase+, but no CD45RO+, apoptotic cells. Compared
      with control and UC, CD T cells grew remarkably more in response to IL-2 and were
      significantly more resistant to IL-2 deprivation-induced apoptosis. CD T cells
      were also more resistant to Fas- and nitric oxide-mediated apoptosis, whereas TNF
      alpha failed to induce cell death in all groups. Compared with control, CD mucosa
      contained similar numbers of Bcl-2+, but fewer Bax+, cells, while UC mucosa
      contained fewer Bcl-2+, but more Bax+, cells. Hence, the Bcl-2/Bax ratio was
      significantly higher in CD and lower in UC. These results indicate that CD may
      represent a disorder where the rate of T cell proliferation exceeds that of cell
      death. Insufficient T cell apoptosis may interfere with clonal deletion and
      maintenance of tolerance, and result in inappropriate T cell accumulation
      contributing to chronic inflammation.

PMID- 10395712
TI  - Rights Violations in the Ecuadorian Amazon: The Human Consequences of Oil
      Development.
AB  - Since 1972, companies have extracted almost two billion barrels of crude oil from
      the Ecuadorian Amazon (Oriente), and in the process have released billions of
      gallons of untreated toxic wastes and oil directly into the environment.
      Indigenous federations and environmental groups in Ecuador have organized in
      opposition to unregulated oil development, charging that contamination has caused
      widespread damage to both people and to the environment. Yet, faced with a weak
      economy and pressure from foreign creditors, the government is rapidly proceeding
      with plans to increase oil production. Little human rights advocacy or scientific
      research has been done on health effects of oil contamination in the Oriente.
      Exposure to crude oil and its constituents is harmful to human health, ranging
      from minor symptoms such as headache, nausea, and dermatitis to cancers and
      adverse effects on reproduction and immune response. This paper is one of the
      first attempts to apply the right to health and a healthy environment in
      assessing the human consequences of a country's development policies.

PMID- 10395711
TI  - Towards the development of a human rights impact assessment for the formulation
      and evaluation of public health policies.

PMID- 10395713
TI  - The World Development Report 1993 and Human Rights.

PMID- 10395714
TI  - A Selected Bibliography of Human Rights and the Right to Health.

PMID- 10395715
TI  - The Opening of a Dialogue.

PMID- 10395716
TI  - Health and Human Rights: An International Crusade.

PMID- 10395717
TI  - From Health or Human Rights to Health and Human Rights: Where Do We Go From Here?

PMID- 10395718
TI  - Health and Human Rights: An Inseparable Synergy.

PMID- 10395719
TI  - Disabled Persons and their Right to Equal Treatment: Allowing Differentiation
      While Ending Discrimination.
AB  - The principle of equality encompasses the right not to be discriminated against.
      It is important to distinguish between discrimination and differentiation when
      seeking to promote and protect the right to equal treatment of disadvantaged or
      otherwise vulnerable groups. The achievement of equality not only prohibits
      abstaining from discrimination, but also entails a positive obligation to rectify
      inequalities. Differentiation may be an adequate means to remedy disadvantages
      and to enhance the equal rights of vulnerable groups. Discrimination against
      disabled people may occur as a result of both differentiation and a lack thereof.
      The admissibility of differentiating between able-bodied and disabled persons
      ultimately depends on the relevance of using disability as a criterion to
      distinguish between individuals or groups. Differentiating is acceptable if the
      absence or presence of an individual quality or group attribute is of paramount
      importance, or when an effort is made to rectify inequalities. Differentiation,
      however, becomes discriminatory when distinctions are made arbitrarily, or when
      they have the purpose or effect of denying or restricting the equal enjoyment and
      exercise of human rights.

PMID- 10395720
TI  - Empirical Dimensions of Discrimination Against Disabled People.
AB  - Where at one time professionals viewed disability as a condition inherent in a
      person, there now is widespread acceptance that, in large measure, disability is
      a social construct with roots in societal attitudes. Specifically, the case has
      been made by disabled people that they are the victims of discrimination. This
      paper reviews some of the empirical evidence of discriminatory practices in the
      areas of: access to education; meaningful participation in the labor force; and,
      physical and sexual assault. There is ample evidence of discriminatory practices
      in education and employment which further disadvantage disabled people. Disabled
      people receive less education and are much less likely to find a job than are non
      disabled people and are much more vulnerable than the non-disabled to sexual or
      physical assault. Promoting and protecting the rights and dignity of disabled
      people will require a combination of legal approaches, attention to the concrete
      realities of disability and societal barriers, and changes in the perception of
      and societal attitudes towards disabled people.

PMID- 10395721
TI  - A Human Rights Approach for Access to Clean Drinking Water: A Case Study.
AB  - In northern and central Israel are some 70 villages that are not recognized by
      the state of Israel. At least half of these villages are not connected to the
      national drinking water networks and lack sufficient quality and quantity of
      water. Outbreaks of diseases associated with contaminated water supply have
      occurred, as well as substantial environmental distress. An outbreak of hepatitis
      A led to the cooperation of a public health physician, a nurse, an environmental
      engineer, and a human rights lawyer in successfully taking a case to the
      International Water Tribunal to get access to safe drinking water for these
      communities. This case study provides a model for cooperation between proponents
      and practitioners of health and human rights.

PMID- 10395722
TI  - A Selected Bibliography of Human Rights and Disability.

PMID- 10395723
TI  - Human rights and the new public health.

PMID- 10395724
TI  - Preventing human rights violations in places of detention: a European initiative.

PMID- 10395726
TI  - Human rights education for Cambodian health professionals.

PMID- 10395727
TI  - Linking health and human rights: a critical legal perspective.

PMID- 10395728
TI  - Monitoring and Protecting Health and Human Rights in Mexico.
AB  - This paper describes a unique system through which health care-related human
      rights are now being monitored and protected in Mexico. Based on the ombudsman
      concept, the system focuses on identifying and responding to violations of human
      rights and dignity which may occur in the context of health care delivery.
      Experience thus far has been encouraging; the Mexican population has identified
      and used the National Commission of Human Rights as a forum for a variety of
      health-related complaints. The Mexican system, while requiring strengthening and
      expansion, is an effort to integrate the monitoring and protection of health
      related human rights into the broader field of human rights work in Mexico.

PMID- 10395729
TI  - Health, Human Rights and Dignity: Reflections from the Mexican Experience.

PMID- 10395730
TI  - Solubilization of liposomes by sodium dodecyl sulfate: new mechanism based on the
      direct formation of mixed micelles.
AB  - The vesicle-to-micelle structural transitions that occurred in the interaction of
      sodium dodecyl sulfate with phosphatidylcholine vesicles were studied at the
      equilibrium by means of dynamic light scattering (at different scattering angles)
      and freeze-fracture electron microscopy techniques. The incorporation of
      surfactant monomers in the bilayers resulted in an initial contraction of the
      mixed vesicles formed up to their saturation (size reduction of about 10%). Then,
      a progressive relaxation of these structures (growth from 170 to 225 nm) and a
      simultaneous formation of mixed micelles (particles of about 6 nm) occurred.
      Hence, in this interval "relaxed mixed vesicles" and mixed micelles coexisted in
      different proportions without formation of intermediate complex aggregates
      (bimodal size distribution curves). Freeze-fracture electron microscopy showed a
      direct formation of mixed micelles within the bilayer and their subsequent
      separation from the vesicle surface without formation of complex intermediate
      aggregates. This simple process progressed up to the complete vesicle
      solubilization.

PMID- 10395731
TI  - A noncatalytic tetrahydrofolate tight binding site is on the small domain of 10
      formyltetrahydrofolate dehydrogenase.
AB  - 10-Formyltetrahydrofolate dehydrogenase has previously been identified as a tight
      binding protein of the polyglutamate forms of tetrahydrofolate (R. J. Cook and C.
      Wagner, Biochemistry 21, 4427-4434, 1982). Each subunit contains two
      independently folded domains connected by a linking peptide. By using the stable
      substrate and product analogs 10-formyl 5,8-dideazafolate and 5, 8-dideazafolate,
      respectively, we have determined that the tight binding folate site is separate
      from the catalytic site and that it is located on the N-terminal domain of the
      protein. This was achieved by cross-linking 10-formyl 5,8-dideazafolate to the
      dehydrogenase through the carboxyl group of the substrate analog. The cross
      linked substrate analog was converted to the cross-linked product complex by
      adding either NADP+ or 2-mercaptoethanol, proving that the 10-formyl 5,8
      dideazafolate was bound at the active site. With the active site cross-linked to
      5,8-dideazafolate and not available for binding, the enzyme still bound 5, 8
      dideazafolate-[3H]tetraglutamate tightly but noncovalently. Separation of the
      large and small domains by limited proteolysis showed that the tightly bound 5,8
      dideazafolate-[3H]tetraglutamate was located on the small domain. The location of
      the cross-linked 10-formyl 5,8-dideazafolate at the active site was determined by
      amino acid sequencing of an isolated tryptic peptide.

PMID- 10395733
TI  - The primary and higher order structures of sea urchin ovoperoxidase as determined
      by cDNA cloning and predicted by homology modeling.
AB  - At fertilization, sea urchin ovoperoxidase (OPO) is incorporated into a nascent
      fertilization envelope in association with proteoliaisin and plays an essential
      role in its hardening. By cDNA cloning based on the previously reported partial
      amino acid sequences of Hemicentrotus pulcherrimus OPO, the cDNA and deduced
      amino acid sequences of the enzyme precursor were determined. Its 814-residue
      sequence consists of 125-residue signal- plus pro-peptides and 689-residue mature
      enzyme and has 92.2 and 81.4% identity with the OPOs of Strongylocentrotus
      purpuratus and Lytechinus variegatus, respectively. Compared with human
      myeloperoxidase, it has 30.3% identity and 9.6% similarity and has an additional
      C-terminal sequence of about 100 residues, suggesting its possible role as the
      site for interaction with proteoliaisin, if not for the entire sequence. The
      linker peptide sequence between L- and H-chains (e.g., ASFVTG and FSFFTG) cleaved
      off upon activation in mammalian promyeloperoxidases is intrinsically lacking in
      OPO, uniquely rendering the single 70K polypeptide a basic unit. The positions of
      distal and proximal histidines, distal arginine, and six disulfide bridges are
      highly conserved among mammalian and sea urchin peroxidases. The secondary
      structure was predicted by EMBL-PHD on the Internet for the whole sequence of
      mature OPO, and both secondary and tertiary structures were predicted by Swiss
      Model for the partial sequences residues 18-65 and 123-570 with canine
      myeloperoxidase as a template. The overall architecture of the OPO molecule is
      close to that of human myeloperoxidase but its secondary structure has some
      differences based on the sequence variation, as depicted by RasMol. Another
      software, Swiss-PdbViewer, produced a slightly but significantly different image
      of the OPO structure for the same predicted atomic coordinates. A discrepancy was
      also found between the secondary structures of human myeloperoxidase in the PDB
      file and in its Swiss-PdbViewer presentation.

PMID- 10395732
TI  - Mutations in the N-terminal regulatory region reduce the catalytic activity of
      Csk, but do not affect its recognition of Src.
AB  - In addition to the C-terminal catalytic domain, Csk is a protein tyrosine kinase
      that has an N-terminal regulatory region that contains SH3 and SH2 domains. The
      role this region plays relative to the function of the catalytic domain is not
      clear. To study its role, we introduced either deletion or site-specific
      mutations within this region and analyzed the effect of such mutations on the
      catalytic activity of Csk and its ability to phosphorylate/inactivate Src protein
      tyrosine kinase, its physiological substrate in the cell. Deletion of the SH3
      domain and the SH2 domain resulted in reductions of kinase activity by 70 and
      96%, respectively. Mutations within the SH2 domain that abolished its ability to
      bind phosphotyrosine did not result in a significant loss of kinase activity.
      Mutation of Ser78 to Asp, located between the SH3 and the SH2 domains, resulted
      in a reduction of over 90% of the catalytic activity. The reduction in specific
      activity is not the result of any apparent physical instability of the mutants.
      Kinetic analyses indicate that the mutations did not affect the Km values for ATP
      Mg or the polypeptide substrate. The ability of the mutants to phosphorylate and
      inactivate Src is directly correlated to their kinase activity. These results
      indicate that the regulatory region is important in optimizing the kinase
      activity of the catalytic domain, but apparently plays no direct or specific role
      in substrate recognition.

PMID- 10395734
TI  - Control of the expression of luteinizing hormone receptor by local factors in rat
      granulosa cells.
AB  - To identify the mechanisms underlying the hormone-dependent induction and
      maintenance of luteinizing hormone receptor (LH-R) in rat granulosa cells, the
      effect of follicle-stimulating hormone (FSH) and local factors on the LH-R mRNA
      levels were studied. LH-R mRNA levels of the cells incubated with FSH decreased
      rapidly after medium removal, and readdition of FSH with the fresh medium did not
      restore these levels. On the other hand, 8-bromoadenosine 3,5-cyclic
      monophosphate significantly enhanced the expression of LH-R mRNA after medium
      removal, while the level of LH-R mRNA was lower than that of the cells replaced
      by original medium including FSH. In addition, the incubation with 8-Br-cAMP
      produced dose-dependent responses for LH-R mRNAs and enhanced the activity of
      1379 bp of the LH-R 5'-flanking region, while the level of LH-R mRNA decreased 3
      days after medium removal. Further studies were undertaken to assess the role of
      factors in maintaining the LH receptor once induced by FSH. Since FSH and cAMP
      increase follistatin production in granulosa cells, we examined the effect of
      follistatin on LH-R induction in the presence of activin and FSH. Activin induced
      LH-R in the presence of FSH significantly, and follistatin antagonized this
      effect in a dose-dependent manner. However, insulinlike growth factor-I (IGF-I)
      induced LH-R mRNA in the presence of FSH even after medium change. IGF-I might be
      one of the important factors that act in the medium to maintain LH-R levels in
      granulosa cells.

PMID- 10395735
TI  - Biochemical characterization of alpha-ketooxadiazole inhibitors of elastases.
AB  - A series of alpha-ketooxadiazole compounds was prepared and evaluated in vitro as
      potential inhibitors of human neutrophil elastase (HNE), proteinase-3 (PR-3), and
      porcine pancreatic elastase (PPE). Several compounds have been found to be very
      potent, fast, reversible, and selective inhibitors of HNE with Ki values below
      100 pM. The highest kon value exceeded 10(7) M(-1) s(-1). Some alpha
      ketooxadiazoles were also very effective against PR-3 and PPE with Ki values in
      the range of 5(-10) nM and 0.1(-2) nM, respectively. The two rings, 1,2,4- and
      1,3,4-oxadiazole, are amenable to substitutions, extending the P' side of the
      inhibitor and allowing additional binding interactions at S' subsites of the
      enzyme. Nonpeptidic HNE inhibitors containing the oxadiazole heterocycle
      displayed promising oral bioavailability.

PMID- 10395736
TI  - The interactions of substituted pyrido[1,2-e]purines with oligonucleotides depend
      on the amphiphilic properties of their side chain.
AB  - Three pyrido[1,2-e]purines of increasing hydrophilicity have been synthesized to
      evaluate as anticancer agents. These drugs interact quite differently with a
      synthetic oligodeoxynucleotide d(CGATCG)2. [1] is very hydrophobic due to a
      phenyl residue in its side chain. It only shows limited interactions with the
      minihelix without any evidence of intercalation. [2] and [3], on the other hand,
      have one ([2]) or two ([3]) hydroxyl groups in their acyl chain and present
      rather amphiphilic properties. The result is a similar intercalation of these
      derivatives between C and G base pairs as revealed by intermolecular nOe, 1H and
      31P chemical shift variations. Models for the intercalation of [2] are proposed
      using energy minimizations and molecular dynamics (MD) calculations subject to
      restraints from nOe connectivities. Simulations and experiments indicate weak
      stability and thus fast exchange of [2] in its intercalation site.

PMID- 10395737
TI  - The role of human glutathione S-transferases hGSTA1-1 and hGSTA2-2 in protection
      against oxidative stress.
AB  - In order to elucidate the protective role of glutathione S-transferases (GSTs)
      against oxidative stress, we have investigated the kinetic properties of the
      human alpha-class GSTs, hGSTA1-1 and hGSTA2-2, toward physiologically relevant
      hydroperoxides and have studied the role of these enzymes in glutathione (GSH)
      dependent reduction of these hydroperoxides in human liver. We have cloned hGSTA1
      1 and hGSTA2-2 from a human lung cDNA library and expressed both in Escherichia
      coli. Both isozymes had remarkably high peroxidase activity toward fatty acid
      hydroperoxides, phospholipid hydroperoxides, and cumene hydroperoxide. In
      general, the activity of hGSTA2-2 was higher than that of hGSTA1-1 toward these
      substrates. For example, the catalytic efficiency (kcat/Km) of hGSTA1-1 for
      phosphatidylcholine (PC) hydroperoxide and phosphatidylethanolamine (PE)
      hydroperoxide was found to be 181.3 and 199.6 s-1 mM-1, respectively, while the
      catalytic efficiency of hGSTA2-2 for PC-hydroperoxide and PE-hydroperoxide was
      317.5 and 353 s-1 mM-1, respectively. Immunotitration studies with human liver
      extracts showed that the antibodies against human alpha-class GSTs
      immunoprecipitated about 55 and 75% of glutathione peroxidase (GPx) activity of
      human liver toward PC-hydroperoxide and cumene hydroperoxide, respectively. GPx
      activity was not immunoprecipitated by the same antibodies from human erythrocyte
      hemolysates. These results show that the alpha-class GSTs contribute a major
      portion of GPx activity toward lipid hydroperoxides in human liver. Our results
      also suggest that GSTs may be involved in the reduction of 5
      hydroperoxyeicosatetraenoic acid, an important intermediate in the 5-lipoxygenase
      pathway.

PMID- 10395738
TI  - Metabolic kinetics of proteoglycans by embryonic chick sternal cartilage in
      culture.
AB  - Explant cultures of embryonic chick sternum have been widely studied, but the
      kinetics of biosynthesis of proteoglycans by this tissue in culture has not been
      characterized. Caudal cartilaginous portions of 16-day-old embryonic chick sterna
      were cultured for 8 days. Histological examination showed that the fresh
      cartilage contained morphologically homogenous chondrocytes, which were embedded
      in a uniform extracellular matrix. After culture for 8 days, the histological
      appearance of the explant remained unchanged but the tissue increased in size
      with time as indicated by a progressive increase in DNA content and in the
      content of glycosaminoglycan and collagen. Rates of degradation and release from
      the tissue of proteoglycans labeled in ovo with 35S were first order during
      culture, as were the unlabeled proteoglycans. Proteoglycan synthesis was high
      during the first 2 days of culture, and this then gradually decreased from this
      high level during the following 2 days. Synthesis was then maintained at a
      constant level for the remainder of the culture period. After culture for 2 and 7
      days, the proteoglycans synthesized by the explants were identical to the
      preexisting proteoglycans in hydrodynamic size, glycosaminoglycan chain size, and
      ability to form aggregates. These findings suggest that the embryonic chick
      sterna maintained a stable cartilage phenotype during the extended culture
      periods. The initial rapid rate of matrix turnover was probably attributable to
      an adaptation of the tissue to ex ovo culture conditions and the subsequent
      maintenance of cellular activities at a lower level indicated the establishment
      of a steady-state rate of metabolism.

PMID- 10395739
TI  - Fas-mediated activation of phospholipase D is coupled to the stimulation of
      phosphatidylcholine-specific phospholipase C in A20 cells.
AB  - The activation of phospholipase D in murine B cell lymphoma A20 cells treated
      with anti-Fas monoclonal antibody has been investigated. Fas cross-linking
      resulted in a both dose- and time-dependent increases in phospholipase D
      activity. There was a nearly maximum saturated rise in phospholipase D activity
      at the dose of 200 ng/ml anti-Fas monoclonal antibody showing a fourfold increase
      within 3 h. Fas activation also caused an approximately twofold increase of
      phosphatidylcholine-specific phospholipase C activity and 1,2-diacylglycerol
      release, which could be blocked by 30 min pretreatment with the
      phosphatidylcholine-specific phospholipase C inhibitor D609 (50 microgram/ml).
      Pretreatment of D609 also effectively inhibited the translocation of protein
      kinase C betaI and betaII from the cytosol to the membrane and the activation of
      phospholipase D induced by Fas cross-linking, suggesting that 1, 2-diacylglycerol
      released from the cellular phosphatidylcholine pool through phosphatidylcholine
      specific phospholipase C plays a major role in protein kinase C/phospholipase D
      activation. Anti-Fas monoclonal antibody failed to elicit phosphoinositide
      specific phospholipase C activation and any changes in the intracellular Ca2+
      level in A20 cells, indicating that the phosphoinositide-mediated pathway is not
      involved in this Fas signaling. Therefore, these results suggest that Fas
      mediated phospholipase D activation may be a consequence of primary stimulation
      of phosphatidylcholine-specific phospholipase C and that phospholipase D may play
      a role in Fas cross-linking signaling downstream from phosphatidylcholine
      specific phospholipase C.

PMID- 10395740
TI  - Probing the affinity and specificity of yeast alcohol dehydrogenase I for
      coenzymes.
AB  - Yeast (Saccharomyces cerevisiae) alcohol dehydrogenase I (SceADH) binds NAD+ and
      NADH less tightly and turns over substrates more rapidly than does horse (Equus
      caballus) liver alcohol dehydrogenase E isoenzyme (EcaADH), and neither enzyme
      uses NADP efficiently. Amino acid residues in the proposed adenylate binding
      pocket of SceADH were substituted in attempts to improve affinity for coenzymes
      or reactivity with NADP. Substitutions in SceADH (Gly202Ile or Ser246Ile) with
      the corresponding residues in the adenine binding site of the homologous EcaADH
      have modest effects on coenzyme binding and other kinetic constants, but the
      Ser246Ile substitution decreases turnover numbers by 350-fold. The Ser176Phe
      substitution (also near adenine site) significantly decreases affinity for
      coenzymes and turnover numbers. In the consensus nucleotide-binding betaalphabeta
      fold sequence, SceADH has two alanine residues (177-GAAGGLG-183) instead of the
      Leu200 in EcaADH (199-GLGGVG-204); the Ala178-Ala179 to Leu substitution
      significantly decreases affinity for coenzymes and turnover numbers. Some NADP
      dependent enzymes have an Ala corresponding to Gly183 in SceADH; the Gly183Ala
      substitution significantly decreases affinity for coenzymes and turnover numbers.
      NADP-dependent enzymes usually have a neutral residue instead of the Asp (Asp201
      in SceADH) that interacts with the hydroxyl groups of the adenosine ribose, along
      with a basic residue (at position 202 or 203) to stabilize the 2'-phosphate of
      NADP. The Gly203Arg change in SceADH does not significantly affect the kinetics.
      The Gly183Ala or Gly203Arg substitutions do not enable SceADH to use NADP+ as
      coenzyme. SceADH with the single Asp201Gly or double Asp201Gly:Gly203Arg
      substitutions have similar, low activity with NADP+. The results suggest that
      several of the amino acid residues participate in coenzyme binding and that
      conversion of specificity for coenzyme requires multiple substitutions.

PMID- 10395741
TI  - Interactions of nuclear receptor coactivator/corepressor proteins with the aryl
      hydrocarbon receptor complex.
AB  - MCF-7 human breast cancer cells express the aryl hydrocarbon receptor (AhR), and
      treatment with AhR agonists such as 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD)
      inhibits estrogen receptor (ER)-mediated responses. This study investigates
      physical and functional interactions of the AhR complex with a prototypical
      coactivator (estrogen receptor associating protein 140, ERAP 140) and corepressor
      (silencing mediator for retinoic acid and thyroid hormone receptor, SMRT) for ER
      and other members of the nuclear receptor superfamily. The AhR, AhR nuclear
      translocator (Arnt), and AhR/Arnt proteins were coimmunoprecipitated with 35S
      ERAP 140 and 35S-SMRT and, in gel mobility shift assays, AhR/Arnt binding to 32P
      dioxin response element (DRE) was enhanced by ERAP-140 and inhibited by SMRT;
      supershifted bands were not observed. In transactivation assays, coactivator and
      corepressor proteins enhanced or inhibited AhR-mediated gene expression; however,
      these responses varied with the amount of coactivator/corepressor expression.
      These results confirmed functional and physical interactions of AhR/Arnt with
      ERAP 140 and SMRT in breast cancer cells.

PMID- 10395742
TI  - Chondrocyte-mediated catabolism of aggrecan: evidence for a
      glycosylphosphatidylinositol-linked protein in the aggrecanase response to
      interleukin-1 or retinoic acid.
AB  - The control of chondrocyte-mediated degradation of aggrecan has been studied in
      rat chondrosarcoma cells and bovine cartilage explants treated with either IL-1
      or retinoic acid. The capacity of glucosamine to inhibit the aggrecanase-mediated
      response (J. D. Sandy, D. Gamett, V. Thompson, and C. Verscharen (1998) Biochem.
      J. 335, 59-66) has been extended to an investigation of the effect of other
      hexosamines. Mannosamine inhibits the aggrecanase response to both IL-1 and RA at
      about one-tenth the concentration of glucosamine in both rat cell and bovine
      explant systems. This effect of mannosamine appears to be due to its capacity to
      inhibit the synthesis of glycosylphosphatidylinositol (GPI)-linked proteins by
      chondrocytes since the GPI synthesis inhibitor 2-deoxyfluoroglucose (2-DFG) also
      inhibited the aggrecanase response to IL-1b and RA in rat cells. Moreover,
      phosphatidylinositol-specific phospholipase C (PIPLC) treatment of rat cells
      markedly inhibited the aggrecanase response to IL-1b and RA. These inhibitory
      effects of mannosamine, 2-DFG, and PIPLC in rat cells did not appear to be due to
      an interference with general biosynthetic activity of the cells as measured by
      [3H]proline incorporation into secreted proteins. We suggest that the aggrecanase
      response by chondrocytes to IL-1 and RA is dependent on the activity of a GPI
      anchored protein on the chondrocyte cell surface.

PMID- 10395743
TI  - Cell-free transfer of the vesicular stomatitis virus G protein from an
      endoplasmic reticulum compartment of baby hamster kidney cells to a rat liver
      Golgi apparatus compartment for Man8-9 to Man5 processing.
AB  - We report the reconstitution of the transfer of a membrane glycoprotein
      (vesicular stomatitis virus glycoprotein, VSV-G protein) from endoplasmic
      reticulum to Golgi apparatus and its subsequent Man8-9GlcNAc2 to Man5GlcNAc2
      processing in a completely cell-free system. The acceptor was Golgi apparatus
      from rat liver immobilized on nitrocellulose. The endoplasmic reticulum donor was
      from homogenates of VSV-G-infected BHK cells. Nucleoside triphosphate plus
      cytosol-dependent transfer and processing of radiolabeled VSV-G protein was
      observed with donor from BHK cells infected at 37 degrees C with wild-type VSV or
      at the permissive temperature of 34 degrees C with the ts045 mutant. With Golgi
      apparatus as acceptor, specific transfer at 37 degrees C in the presence of
      nucleoside triphosphate was eightfold that at 4 degrees C or in the absence of
      ATP. About 40% of the VSV-G protein transferred was processed to the Man5GlcNAc2
      form. Processing was specific for cis Golgi apparatus fractions purified by
      preparative free-flow electrophoresis. Fractions derived from the trans Golgi
      apparatus were inactive in processing. With the ts045 temperature-sensitive
      mutant, transfer and processing were much reduced even in the complete system
      when microsomes were from cells infected with mutant virus and incubated at the
      restrictive temperature of 39.5 degrees C but were able to proceed at the
      permissive temperature of 34 degrees C. Thus, Man8-9GlcNAc2 to Man5GlcNAc2
      processing of VSV-G protein occurs following transfer in a completely cell-free
      system using immobilized intact Golgi apparatus or cis Golgi apparatus cisternae
      as the acceptor and shows temperature sensitivity, donor specificity, requirement
      for ATP, and response to inhibitors similar to those exhibited by transfer and
      processing of VSV-G protein in vivo.

PMID- 10395744
TI  - Hydroperoxidase activity of lipoxygenase in the presence of cyclodextrins.
AB  - The oxidation of xenobiotics by the hydroperoxidase activity of lipoxygenase in
      the presence of cyclodextrins was studied. These produced an inhibitory effect on
      xenobiotics oxidation, based on their degree of hydrophobicity and the charge
      (isoproterenol < 4-methyl-catechol (4MC) < 4-tert-butylcatechol (TBC) < 4-tert
      octylcatechol (TOC)). This inhibitory effect was due to the complexation of
      xenobiotics in the hydrophobic cavity of cyclodextrins. The complexation constant
      Kc was calculated by nonlinear regression of the inhibition curves obtained in
      the presence of cyclodextrins, and the values obtained were 400, 16,250, and
      35,127 M-1 for 4MC, TBC, and TOC, respectively. The validity of these values was
      checked at different points of the Michaelis-Menten saturation curve, and a
      sigmoidal inhibition curve was obtained at the saturating concentration of the o
      diphenol, TBC, with no change in the Kc value. This demonstrates the validity of
      the equations used to calculate Kc for the complete range of the Michaelis-Menten
      equation.

PMID- 10395745
TI  - Characterization of UDP-N-acetylglucosamine:alpha-6-d-mannoside beta-1,6-N
      acetylglucosaminyltransferase V from a human hepatoma cell line Hep3B.
AB  - UDP-N-acetylglucosamine:alpha-6-d-mannoside beta-1, 6-N
      acetylglucosaminyltransferase V (GlcNAcT-V) has been purified from cell extracts
      of the human hepatoma cell line, Hep3B, with 8.7% recovery. The purified enzymes
      had molecular masses of about 67 and 65 kDa on denaturated and natural
      conditions, respectively. The values of pI was 5.9. The GlcNAcT-V, when resolved
      by SDS-PAGE, was positive for Schiff staining, suggesting that the enzyme is
      glycoprotein. When GlcN,GlcN-biant-PA and UDP-GlcNAc were used as substrates, the
      enzyme displayed a temperature optimum of around 50 degrees C and optimum an pH
      of 6.5. The enzyme was stable in response to incubation from pH 4.5 to pH 10.5 at
      4 degrees C for 24 h. The presence of UDP-GlcNAc and GlcN,GlcN-bi-PA protected
      the enzyme from heat inactivation, the extent depending upon the substrate
      concentration. The activity of the enzyme was stimulated by Mn2+ ion; however, it
      was inhibited by Fe3+. The enzyme activity was inhibited by another series of NDP
      sugars including ADP-, CDP-, GDP-, and TDP-GlcNAc. Studies on the activity of the
      enzyme toward a variety of pyridylaminated sugars showed that the enzyme is most
      active toward biantennary (GlcN,GlcN-bi-PA) sugars. The enzymes had apparent Km
      values of 1.28 and 5.8 mM for GlcN,GlcN-bi-PA and UDP-GlcNAc, respectively. In
      order to isolate the GlcNAcT-V gene, PCR primers of GNN-1 and GNN-8 were designed
      and the amplified PCR product carrying the gene was cloned and sequenced.
      Nucleotide sequence analysis showed a 2220-bp open reading frame encoding a 740
      amino-acid protein. This was almost same as the previously reported human
      sequences, except for some sequence differences in three amino acids. The three
      amino acid changes were as follows: 375V --> L, 555T --> R, and 592A --> G. These
      studies represent the detailed characterization of a purified GlcNAcT-V from
      human hepatoma cell Hep3B.

PMID- 10395746
TI  - Reactive oxygen species in the aerobic decomposition of sodium
      hydroxymethanesulfinate.
AB  - Sodium hydroxymethanesulfinate, (HOCH2SO2Na, HMS) is relatively stable in aqueous
      alkaline environments, but rapidly decomposes in acidic medium to give a variety
      of products that include sulfur dioxide. A detailed kinetic and mechanistic study
      of the decomposition of HMS in slightly acidic medium has shown a process that
      produces dithionite, S2O2-4, which is preceded by an induction period which
      persists for as long as molecular oxygen is present in the reaction solution. The
      complete consumption of molecular oxygen is a prerequisite for the formation of
      S2O2-4. Among some of the intermediates detected in the decomposition of HMS is
      the sulfite radical, SO-3. Comparisons are made between the decomposition
      mechanisms of thiourea dioxide (aminoiminomethanesulfinic acid) and HMS.

PMID- 10395747
TI  - Peptide aldehyde inhibitors of bacterial peptide deformylases.
AB  - Bacterial peptide deformylases (PDF, EC 3.5.1.27) are metalloenzymes that cleave
      the N-formyl groups from N-blocked methionine polypeptides. Peptide aldehydes
      containing a methional or norleucinal inhibited recombinant peptide deformylase
      from gram-negative Escherichia coli and gram-positive Bacillus subtilis. The most
      potent inhibitor was calpeptin, N-CBZ-Leu-norleucinal, which was a competitive
      inhibitor of the zinc-containing metalloenzymes, E. coli and B. subtilis PDF with
      Ki values of 26.0 and 55.6 microM, respectively. Cobalt-substituted E. coli and
      B. subtilis deformylases were also inhibited by these aldehydes with Ki values
      for calpeptin of 9.5 and 12.4 microM, respectively. Distinct spectral changes
      were observed upon binding of calpeptin to the Co(II)-deformylases, consistent
      with the noncovalent binding of the inhibitor rather than the formation of a
      covalent complex. In contrast, the chelator 1,10-phenanthroline caused the time
      dependent inhibition of B. subtilis Co(II)-PDF activity with the loss of the
      active site metal. The fact that calpeptin was nearly equipotent against
      deformylases from both gram-negative and gram-positive bacterial sources lends
      further support to the idea that a single deformylase inhibitor might have broad
      spectrum antibacterial activity.

PMID- 10395748
TI  - Light-evoked recovery from wortmannin-induced inhibition of catecholamine
      secretion and synaptic transmission.
AB  - Wortmannin (WT) is known to inhibit catecholamine (CA) secretion in chromaffin
      cells. This effect was found to be sensitive to UV light in experiments designed
      to perform simultaneous monitoring of changes in [Ca2+]i and CA secretion in
      perfused rat adrenal medullas. When the change in [Ca2+]i was measured using
      calcium green-1 (490 nm excitation), a 35-min treatment with 10 microM WT caused
      a 69% inhibition of CA secretion evoked by excess (30 mM) extracellular K+ and a
      moderate inhibition of the [Ca2+]i response. In contrast, the same treatment of
      fura-2-loaded cells with WT caused only an 11% inhibition of the high-K+-evoked
      secretion and no significant attenuation of the [Ca2+]i response. However, during
      interruption of fluorometry with fura-2, the inhibitory effect of WT developed at
      a rate similar to that exhibited in calcium green-1-loaded cells. The WT-induced
      inhibition of high-K+- or bradykinin-evoked secretory responses, which was
      otherwise irreversible, was reversed by exposing WT-treated chromaffin cells to
      380-nm light. When WT was reapplied to the cells of which the secretory ability
      had been restored by light irradiation, the secretory response was inhibited with
      a time course similar to that shown during the initial treatment with WT. The
      photosensitive effect of WT was also demonstrated using bullfrog sympathetic
      ganglia in which WT-induced inhibition of synaptic transmission was reversed by
      irradiation with 380-nm light. These results suggest that UV light removes the
      inhibitory effects of WT by disrupting the covalent bond formed between WT and a
      target molecule which remains to be determined, although myosin light chain
      kinase has been reported as the target molecule in both cases examined in this
      study.

PMID- 10395749
TI  - Reactive oxygen species are partially involved in the bacteriocidal action of
      hypochlorous acid.
AB  - Hypochlorous acid (HOCl) is probably the most widely used disinfectant worldwide
      and has an important role in inflammatory reaction and in human resistance to
      infection. However, the nature and mechanisms of its bactericidal activity are
      still poorly understood. Bacteria challenged aerobically with HOCl concentrations
      ranging from 9.5 to 76 microM exhibit higher ability to form colonies
      anaerobically than aerobically. Conversely, aerobic plating greatly increased
      lethality after an anaerobic HOCl challenge, although anaerobic survival did not
      depend on whether HOCl exposure was aerobic or anaerobic. Even a short transient
      exposure to air after anaerobic HOCl challenge reduced anaerobic survival,
      indicative of immediate deleterious effects of oxygen. Exposure to HOCl can cause
      lethal DNA damage as judged by the fact that recA sensitivity to HOCl was oxygen
      dependent. Antioxidant defenses such as reduced glutathione and glucose-6
      phosphate dehydrogenase were depleted or inactivated at 10 microM HOCl, while
      other activities, such as superoxide dismutase, dropped only above 57 microM
      HOCl. Cumulative deficiencies in superoxide dismutase and glucose-6-phosphate
      dehydrogenase rendered strains hypersensitive to HOCl. This indicates that part
      of HOCl toxicity on Escherichia coli is mediated by reactive oxygen species
      during recovery.

PMID- 10395750
TI  - Expression and processing of a bacterial endoglucanase in transgenic mice.
AB  - The C6.5 endoglucanase from Bacillus subtilis catalyzes the hydrolyses of beta
      glucans. This enzyme, which is also produced by many ruminant microbes, is not
      part of the normal digestive repertoire of monogastric animals. We have generated
      transgenic mice which express the C6.5 endoglucanase gene specifically in the
      pancreas with secretion of the enzyme into the small intestine. The secreted
      enzyme has a molecular mass of 55 kDa which is reduced by protease digestion to
      the principal forms of 37 and 35 kDa. These truncated forms are resistant to
      further protease degradation and exhibit enhanced specific activity compared to
      the native enzyme. These results encourage further investigation of the utility
      of this transgene for enhancing the digestive capability of monogastric animals.

PMID- 10395751
TI  - Methionine S-oxidation in human and rabbit liver microsomes: evidence for a high
      affinity methionine S-oxidase activity that is distinct from flavin-containing
      monooxygenase 3.
AB  - Methionine has previously been shown to be S-oxidized by flavin-containing
      monooxygenase (FMO) forms 1, 2, and 3. The most efficient catalyst was FMO3,
      which has a Km value for methionine S-oxidation of approximately 4 mM, and
      exhibits high selectivity for formation of the d-diastereoisomer of methionine
      sulfoxide. The current studies provide evidence for an additional methionine S
      oxidase activity in liver microsomes. Human and rabbit liver microsomes exhibited
      a biphasic response to methionine at concentrations ranging from 0.05 to 10 mM,
      as indicated by both Eadie-Hofstee plots and nonlinear regression. The low
      affinity component of the biphasic response had Km values of approximately 3 and
      5 mM for humans and rabbits, respectively, as well as high diastereoselectivity
      for methionine sulfoxide formation. The low-affinity activity in rabbit liver
      microsomes was inhibited by methimazole, S-allyl-l-cysteine, and by mild heat
      treatment, suggesting the activity is FMO3. The high-affinity component of the
      biphasic response had Km values of approximately 0.07 and 0.04 mM for humans and
      rabbits, respectively, as well as lower diastereoselectivity for methionine
      sulfoxide formation. Further characterization of the high-affinity activity in
      rabbit liver microsomes indicated lack of involvement of cytochrome P450s or
      reactive oxygen species. The high-affinity activity was inhibited 25% by
      potassium cyanide and greater than 50% by methimazole and S-allyl-l-cysteine.
      Mild heat treatment produced 85% inhibition of the low-affinity activity, but
      only 30% inhibition of the high-affinity activity. Both high- and low-affinity
      activities were decreased by 85% in flavin-depleted microsomes. Because these
      results suggested the additional S-oxidase activity has characteristics of an
      FMO, recombinant human FMO4 was evaluated as a potential catalyst of this
      activity. Recombinant FMO4 catalyzed S-oxidation of both methionine and S-allyl-l
      cysteine, with similar diastereoselectivity to the high-affinity microsomal S
      oxidase; however, the Km values for both reactions appeared to be greater than 10
      mM. In summary, these studies provide evidence for two microsomal methionine S
      oxidase activities. FMO3 is the predominant catalyst at millimolar concentrations
      of methionine. However, at micromolar methionine concentrations, there is an
      additional S-oxidase activity that is distinct from FMO3.

PMID- 10395752
TI  - Guanosine 5'-(3-O-Thio)triphosphate stimulates protein carboxyl methylation in
      cell membranes.
AB  - Using guanosine 5'-(3-O-thio)triphosphate (GTPgammaS), we previously reported
      that protein carboxyl methyltransferase activities in kidney brush border
      membranes were increased by the GTP analog (Arch. Biochem. Biophys. 351, 149-158,
      1998). Here, we investigated the distribution and characterized the effect of
      GTPgammaS on protein carboxyl methylation activity. The analysis of species
      distribution of carboxyl methylation in kidney brush border membranes showed that
      the GTPgammaS strongly stimulated this activity in rat (15.9-fold), mouse (14.7
      fold), human (2.9-fold), and rabbit (2.7-fold). Analysis of GTPgammaS-dependent
      carboxyl methylation in rat tissues and cell fractions indicated that the
      activity was mainly localized in membranes of intestine, lung, and kidney, with
      the highest activity found in liver. To characterize the methyltransferase
      activity modulated by GTPgammaS in liver membranes, their sensitivity to the
      detergent 3-[(3-cholamido)dimethylammonio]-1-propanesulfonic acid (Chaps) was
      used. Methylation of N-acetyl-S-farnesyl cysteine, a prenylated protein
      methyltransferase (PPMT) substrate was strongly inhibited (86%) in the presence
      of Chaps, while the methylation of bovine calmodulin and ovalbumin, both of which
      are substrates for the protein L-isoaspartyl/d-aspartyl methyltransferase (PIMT),
      was slightly reduced by the detergent (0-12%). The GTPgammaS-dependent carboxyl
      methylation of endogenous substrates in liver membranes was decreased by 35% in
      the presence of Chaps, suggesting that PPMT was not the predominant
      methyltransferase involved in the methylation stimulated by GTPgammaS in liver
      membranes. Electrophoretic analysis showed that radioactive methylation of
      several substrates induced by GTPgammaS in liver membranes was reduced by adding
      calmodulin. Interestingly, addition of GTPgammaS partially inhibited the
      methylation of two PIMT substrates, ovalbumin (24%) and bovine calmodulin (19%),
      when incubated with liver membranes. Immunoprecipitation of PIMT from liver and
      lung membranes strongly inhibited (88-94%) the methylation stimulated by
      GTPgammaS. Altogether, these data support the hypothesis that GTPgammaS could
      regulate PIMT activity and may provide new insights into the function of the
      methyltransferase.

PMID- 10395753
TI  - Alanine scanning mutagenesis of oxygen-containing amino acids in the
      transmembrane region of the Na,K-ATPase.
AB  - Oxygen-containing amino acids in the transmembrane region of the Na, K-ATPase
      alpha subunit were studied to identify residues involved in Na+ and/or K+
      coordination by the enzyme. Conserved residues located in the polar face of
      transmembrane helices were selected using helical wheel and topological models of
      the enzyme. Alanine substitution of these residues were introduced into an
      ouabain-resistant sheep alpha1 isoform and expressed in HeLa cells. The capacity
      to generate essential Na+ and K+ gradients and thus support cell growth was used
      as an initial indication of the functionality of heterologous enzymes. Enzymes
      carrying alanine substitution of Ser94, Thr136, Ser140, Gln143, Glu144, Glu282,
      Thr334, Thr338, Thr340, Ser814, Tyr817, Glu818, Glu821, Ser822, Gln854, and
      Tyr994 supported cell growth, while those carrying substitutions Gln923Ala,
      Thr955Ala, and Asp995Ala did not. To study the effects of these latter
      replacements on cation binding, they were introduced into the wild-type alpha1
      sheep isoform and expressed in mouse NIH3T3 cells where [3H]ouabain binding was
      utilized to probe the heterologous proteins. These substitutions did not affect
      ouabain, K+, or Na+ binding. Expression levels of these enzymes were similar to
      that of control. However, the level of Gln923Ala-, Thr955Ala-, or Asp995Ala
      substituted enzyme at the plasma membrane was significantly lower than that of
      the wild-type isoform. Thus, these substitutions appear to impair the maturation
      process or targeting of the enzyme to the plasma membrane, but not cation-enzyme
      interactions. These results complete previous studies which have identified
      Ser755, Asp804, and Asp808 as absolutely essential for Na+ and K+ transport by
      the enzyme. Thus, it is significant that most transmembrane conserved-oxygen
      containing residues in the Na,K-ATPase can be replaced without substantially
      affecting cation-enzyme interactions to the extent of preventing enzyme function.
      Consequently, other chemical groups, aromatic rings or backbone carbonyls, should
      be considered in models of cation-binding sites.

PMID- 10395754
TI  - Pea chloroplast glyceraldehyde-3-phosphate dehydrogenase has uracil glycosylase
      activity.
AB  - Pea (Pisum sativum) chloroplastic glyceraldehyde-3-P dehydrogenase (EC 1.2.1.13)
      was tested for uracil DNA glycosylase activity. It was found that both the
      chloroplast and the recombinant subunit B dehydrogenases remove uracil from
      poly(dA[3H]dU). The glycosylase activity of the recombinant subunit B enzyme and
      that of a truncated form corresponding in length to subunit A were associated
      with the dehydrogenase activity in gel-filtration experiments. Both activities of
      the chloroplast enzyme were inhibited by antisera raised against recombinant
      subunit B, and both activities of the recombinant subunit B enzyme were inhibited
      by antisera raised against pea chloroplast glyceraldehyde-3-P dehydrogenase.
      Antisera raised against Escherichia coli uracil glycosylase did not affect the
      glycosylase activity of the recombinant subunit B enzyme. The glycosylase pH
      activity profile of the chloroplast dehydrogenase was unique. It is distinct from
      the dehydrogenase pH activity profile and from the pH activity profiles of other
      plant glycosylases. The glycosylase activity, but not the dehydrogenase activity,
      of the recombinant subunit B enzyme was inhibited by uracil. Pyridine nucleotides
      stimulated the glycosylase activity. To our knowledge this is the first example
      of a nonhuman glyceraldehyde-3-P dehydrogenase, and of an NADP-dependent
      glyceraldehyde-3-P dehydrogenase, that exhibits uracil glycosylase activity.

PMID- 10395755
TI  - Measurement of Liquid Viscosities in Tapered or Parabolic Capillaries.
AB  - The possibility of using tapered or parabolic capillaries for measurement of
      liquid viscosities is investigated both experimentally and theoretically. It is
      demonstrated that even small deviations in capillary radius from a constant value
      may substantially affect measurement results. Equations are derived which allow
      correct analysis of the measurement results in tapered or parabolic capillaries.
      The following cases are analyzed: a water imbibition into a tapered or parabolic
      capillary and displacement of one liquid by another immiscible liquid in tapered
      or parabolic capillaries. Two possibilities are considered: (a) the narrow end of
      the capillary as capillary inlet and (b) the wide end of the capillary as
      capillary inlet. Copyright 1999 Academic Press.

PMID- 10395756
TI  - Transport Properties for Aqueous Solution of Sodium Sulfonate Surfactants.
AB  - Isothermal mutual diffusion coefficients (D) have been measured for binary
      aqueous solutions of sodium alkylsulfonates at 25 degrees C. The diffusion
      coefficient values drop as the concentration of micelles in the system increases.
      As the length of the hydrocarbon chain increases, the observed drop in D becomes
      increasingly sharp and shifts to lower concentrations. When the micellization
      process is treated as a chemical equilibrium, diffusion coefficients lead to the
      calculation of the thermodynamic parameters association number, n, and the
      equilibrium constant, K. These parameters are briefly discussed in connection
      with the alkyl chain length of the surfactants. Copyright 1999 Academic Press.

PMID- 10395757
TI  - Transport Properties for Aqueous Sodium Sulfonate Surfactants.
AB  - Intradiffusion coefficients of sodium alkylsulfonates [CH3-(CH2)n-1SO-3 Na+,
      CnSNa] (n = 5-9, 11) in mixtures with heavy water were measured by the PGSE-NMR
      technique at 25 degrees C. A slope change in the experimental trends permits the
      determination of the critical micelle concentration (CMC). In the micellar
      composition range, solubilized TMS molecules were used to determine the micelle
      intradiffusion coefficient, from which the micelle radii were obtained. Both the
      monomer surfactant and the micelle intradiffusion coefficients show a sharp
      decrease above the CMC. These results can be interpreted in terms of the
      obstruction effect due to the micelles. The electrostatic repulsion among charged
      particles strongly enhances this effect. A simple approach that permits the
      computation of the Gouy-Chapman layer thickness from the experimental
      coefficients has been proposed and the results are briefly discussed. Copyright
      1999 Academic Press.

PMID- 10395758
TI  - Electrokinetic Behavior of Palm Oil Emulsions in Dilute Electrolyte Solutions.
AB  - The effect of metal cations, both nonhydrolyzable and hydrolyzable, on the zeta
      potential of palm olein emulsions stabilized by the nonionic emulsifier,
      polyoxyethylene nonyl phenyl ether, was investigated as a function of pH and
      cation concentrations, respectively. The oil drops were found to be negatively
      charged in the presence of simple mono- and divalent cations. Charge reversal of
      the oil drops was observed when hydrolyzable cations (Zn2+, Cu2+, Fe3+, and Al3+)
      were used and the behavior is strongly dependent on the type of cation, its
      concentration, and the pH of the dispersion. The results are discussed in terms
      of current theories of electrophoresis and adsorption-precipitation at
      interfaces. The chemical free energies of adsorption of the cations were
      calculated. Copyright 1999 Academic Press.

PMID- 10395759
TI  - A Study of the Temperature-Dependent Micellization of Pluronic F127.
AB  - We have examined the temperature-dependent micellization of the pharmaceutically
      important PEO-PPO-PEO copolymer, Pluronic F127, using static light scattering and
      various aspects of the pyrene fluorescence spectrum (monomer intensity, excimer
      formation and the I1/I3 ratio). All techniques gave essentially the same value
      for the critical micellization temperatures (cmt) of various F127 solutions, and
      our results agreed with those reported in the literature. Cmt values decrease
      with increasing F127 concentration. We observed significant solubilization of
      pyrene in F127 solutions below the cmt, which was also reflected in the measured
      I1/I3 ratios. The thermodynamics of the micellization process were studied and
      gave different results at low and high F127 concentrations. In the low F127
      concentration range (up to approximately 50 mg/mL), we obtain DeltaH = 312 kJ mol
      1 and DeltaS = 1.14 kJ mol-1 K-1. Above 50 mg/mL we obtain DeltaH = 136 kJ mol-1
      and a DeltaS = 0.54 kJ mol-1 K-1. This discontinuity in thermodynamic behavior
      can be due to a change in aggregation number with temperature and/or a change in
      the micellization process at higher concentrations. Copyright 1999 Academic
      Press.

PMID- 10395760
TI  - Structure Effect on Nonideal Mixing of Alkyl Methyl Sulfoxide and
      Alkyldimethylphosphine Oxide in Adsorbed Film and Micelle.
AB  - The surface tension of aqueous solutions of the octylmethylsulfoxide (OMS)
      decyldimethylphosphine oxide (DePO) and decylmethylsulfoxide (DeMS)
      octyldimethylphosphine oxide (OPO) mixtures was measured as a function of the
      total molality of the surfactants and the composition in the surfactants.
      Compositions in the adsorbed film and micelle were thermodynamically evaluated
      from the total molality vs composition and the critical micelle concentration
      (CMC) vs compositon curves, respectively. The phase diagrams of adsorption and
      micelle formation were drawn and compared with those of the DeMS-DePO mixture
      previously studied. A large gap in composition was observed between the adsorbed
      film and the micelle coexisting at the CMC and ascribed to the differences in
      geometric structure between them and the constituent molecules. Negative
      deviation from ideal mixings in adsorbed film and micelle was observed for the
      OMS-DePO mixture, whereas a positive one was observed for the DeMS-OPO. The
      structure effect on the nonideal mixings was clarified by using the excess
      thermodynamic functions of adsorption and micelle formation calculated from the
      activity coefficients in the adsorbed film and micelle. Copyright 1999 Academic
      Press.

PMID- 10395761
TI  - The Applicability of Acoustic Wave Propagation Models to Silica Sols and Gels.
AB  - Acoustic attenuation and phase velocity in the frequency range 2-50 MHz have been
      measured in a series of silica sols and gels with particle sizes in the range 12
      30 nm, and concentrations in the range 5-40% (w/w). Results have been compared
      with both scattering and hydrodynamic models of acoustic propagation in colloids.
      Differences between measured and simulated results indicate that present models
      are inadequate for very small particle sizes and small particle separations (<50
      nm), where very high number concentrations of scatterers are present. Copyright
      1999 Academic Press.

PMID- 10395762
TI  - Low-Temperature Synthesis of Nanometer-Sized Crystalline TiO2 Particles and Their
      Photoinduced Decomposition of Formic Acid.
AB  - Anatase TiO2 particles with an average size of 2.7 nm in an as-grown state were
      obtained below 373 K from an H2O-EtOH mixed solution of TiOSO4 by a facile liquid
      phase method. The volume ratio of H2O to EtOH was revealed to be the key for
      crystallinity of the particles. The as-grown particles prepared from the H2O-EtOH
      solution (H2O/EtOH (mL/mL) = 150/100) showed a high photoreactivity in the TiO2
      photoinduced decarboxylation of HCOOH under a deaerated condition. In contrast,
      under an aerated condition, the rate of the reaction increased with an increase
      in calcining temperature (Tc) due to the improvement of anatase crystallinity,
      going through a maximum at Tc = 873 K. Copyright 1999 Academic Press.

PMID- 10395763
TI  - Kinetics of Adsorption of Diethylene-triaminomethylated Polyacrylamide on
      Dispersed Kaolin Accompanied by Flocculation.
AB  - The kinetics of the adsorption of diethylene-triaminomethylated polyacrylamide on
      kaolin dispersed in water has been investigated. An influence of the flocculation
      of kaolin dispersion on polymer adsorption has been found. The kinetics of
      particle aggregation under the influence of dissolved polymer has been studied.
      Polymer adsorption and particle aggregation proceed simultaneously, accompanied
      by a steady decrease in the amount of adsorbed polymer per unit mass of kaolin. A
      mathematical model of the adsorption process, consistent with the experimental
      data, is described. The rate constants and their ratios have been determined.
      Copyright 1999 Academic Press.

PMID- 10395765
TI  - Competitive Adsorption of Cu(II)-EDTA and Cd(II)-EDTA onto TiO2.
AB  - Cu(II), EDTA, Cu(II)-EDTA, Cd(II)-EDTA, and Cu(II)/Cd(II) and Cu(II)-EDTA/Cd(II)
      EDTA competitive adsorption onto TiO2 has been studied with variation of pH and
      concentration. For Cu(II) and EDTA, typical cationic and anionic types of
      adsorption are noted, respectively. Ligand-type adsorption is found for Cu(II)
      EDTA and Cd(II)-EDTA under both single and competitive conditions. Surface
      complexation modeling considered inner-sphere complexation and the diffuse layer
      model employing MINTEQA2; surface complexes used include Ti-(OH2)O-Cu+, Ti
      (OH)EDTAH-22, Ti-(OH)EDTA-Cu-2, and Ti-(OH)EDTA-Cd-2. Experimental and model
      predictions suggest no competitive adsorption between Cu(II) and Cd(II) at 5 x
      10(-5) M. On the other hand, adsorption data and model predictions indicate that
      Cd(II)-EDTA adsorption is favored over that of Cu(II)-EDTA with some competition
      for adsorption sites. Cd(II)-EDTA adsorption was only slightly affected by the
      presence of Cu(II)-EDTA; however, Cu(II)-EDTA adsorption was strongly influenced
      by the presence of Cd(II)-EDTA, especially as the molar ratio of Cd(II)
      EDTA/Cu(II)-EDTA increased. A modified surface complexation constant for Cd(II)
      EDTA is required to explain the competitive data, suggesting surface site
      heterogeneity. Copyright 1999 Academic Press.

PMID- 10395764
TI  - Filtration of Unipolarly Charged Aerosol Nanoparticles with an Initially
      Discharged Dielectric Screen.
AB  - This paper presents experimental results of penetration of nanometer-sized
      aerosol particles through an initially discharged dielectric screen. Experiments
      have been carried out with two types of monodisperse unipolarly charged particles
      having different dielectric constants (Ag and NaCl) and mobility-equivalent
      particle diameters between 2 and 10 nm (Peclet number between 4 and 80). At the
      very beginning of the process, the screen is uncharged and filtration is
      controlled by particle diffusion. As the number of charges on the screen
      increases due to the diffusional deposition of charged particles, an electric
      field of increasing strength is developed between the dielectric screen and the
      conductive metallic walls of the cylinder where the screen is placed. As a
      result, particles are also driven and lost to the walls and penetration
      decreases. This transient process can be well described by two dimensionless
      parameters, namely the Peclet number and a nondimensional number expressing the
      ratio of the particle drift velocity due to the field to the particle convective
      velocity due to the flowing medium (air). Copyright 1999 Academic Press.

PMID- 10395766
TI  - Dynamic Surface Tension and Adsorption/Desorption Kinetics for Polymer Mixtures
      on Planar Surfaces.
AB  - The adsorption/desorption kinetics for individual polymers and polymer mixtures
      of the water-soluble associative polymers with molecular weights of 12, 62, and
      100 kg/mol onto a SiO2 planar substrate have been studied by ellipsometry at room
      temperature under flow conditions. Equations were derived to predict behaviors of
      the adsorption/desorption kinetics and dynamic surface tension onto planar
      surface for any times. It is shown that the rate of adsorption/desorption
      kinetics under nonflow conditions is significantly less than the one under flow
      conditions due to the convective-diffusive mass transfer to an interface.
      Copyright 1999 Academic Press.

PMID- 10395767
TI  - Complexation of Metal Ions with Amphiphilic o,o'-Dihydroxyazobenzene Derivatives
      at the Air/Water Interface.
AB  - The effect of metal salts (FeCl3, FeCl2, CuCl2, CoCl2, and [Co(NH3)5Cl]Cl2) on
      the surface pressure-area isotherm of an o,o'-dihydroxyazobenzene-containing
      amphiphile was investigated. The isotherm of the amphiphile was little affected
      in the presence of CuCl2 and [Co(NH3)5Cl]Cl2, but the isotherm was greatly
      affected by the presence of FeCl3, FeCl2, and CoCl2, implying the formation of
      certain complexes at the air/water interface. In the presence of salts in the
      water subphase, Y-type Langmuir-Blodgett (LB) multilayers could be readily
      assembled on the arachidic acid precoated solid substrates. From UV/Vis and ATR
      IR spectroscopy, the coordinative polymerization of the azobenzene moieties was
      evidenced to occur when the Fe3+, Fe2+, Cu2+, and Co2+ ions were present in the
      water subphase. The long axis of the azobenzene moiety seemed in all LB films to
      assume a nearly perpendicular orientation with respect to the solid substrate,
      but the orientation of the C&dbond;O bond appeared obviously different between
      the films prepared in the presence of FeCl3 and CuCl2. The IR spectral data
      indicated further that the alkyl chains in the LB film prepared in the presence
      of CuCl2 assumed a more close-packed structure than those prepared in the
      presence of FeCl3, along with an orientation 10 degrees more tilted in the former
      than in the latter with respect to the surface normal. Copyright 1999 Academic
      Press.

PMID- 10395768
TI  - Properties of Goethites Prepared under Acidic and Basic Conditions in the
      Presence of Silicate.
AB  - Goethite in natural environments usually grows in the presence of dissolved
      silicate. To study silicate-associated goethite with specific properties,
      goethite was synthesized in an Fe(III) system at RT under acidic (OH/Fe = 2; pH
      1.6-1.8) and basic (OH/Fe = 4; pH 12-13) conditions at Si concentrations between
      10(-5) and 1 M. The goethites were characterized by transmission (TEM) and
      scanning (SEM) microscopy, X-ray diffraction (XRD), Mossbauer spectroscopy (MS),
      and chemical analyses. Despite large differences in size and morphology, all
      goethite crystals were dominantly bound by 110 and 021 faces. Nanosized crystals
      (ca. 20 nm) were formed at low pH, where the influence of Si was weak. In the
      basic system, where Si retarded crystallization, much larger (tens to hundreds of
      nanometers) crystals were formed whose shape varied from acicular and
      multidomainic at low Si (10(-5) M) to monodomainic, blocky crystals at high (10(
      2) M) Si concentration that had reduced growth along [001] in favor of [100] and
      [010]. The sizes and shapes of the crystals are discussed in terms of nuclei and
      growth unit concentrations in the system. Part of the retained Si could be
      released by phosphate and NaOH (surface-Si), and part was only liberated into HCl
      congruently with Fe (up to 46 and 17 g kg-1 for the acid and basic goethites,
      respectively). Neither XRD nor MS were able to prove structural Si-for-Fe
      substitution, probably because no tetrahedral positions are available to
      accommodate Si in the goethite structure. It is assumed that this nonsurface Si
      fraction is located between the crystal domains. Copyright 1999 Academic Press.

PMID- 10395769
TI  - Incorporation of Aggregate Breakup in the Simulation of Orthokinetic Coagulation.
AB  - The agglomeration and breakup of floc aggregates formed in orthokinetic
      coagulation is examined. By considering local flow strain-rate, a breakup rate
      kernel is derived based on flow-induced normal stresses. The new breakup kernel
      is included in a population size class balance for floc aggregates. The resulting
      population balance was solved numerically over a wide range of parameters to
      obtain a variety of floc size distributions. Results indicate that the inclusion
      of a breakup kernel in orthokinetic coagulation modeling eliminates the
      computational growth to a maximum size class, producing more realistic
      distributions. The breakup kernel was rigorously compared to prior research and
      found to be consistent with the earlier theories of coagulation agglomeration and
      breakup. Copyright 1999 Academic Press.

PMID- 10395770
TI  - SO2-4/TiO2-SiO2 Mixed Oxide Catalyst, I: Synthesis, Characterization, and Acidic
      Properties.
AB  - A series of sulfate-doped titania-silica mixed oxides have been prepared by
      immersing titania-silica gel in the required volume of sulfuric acid, followed by
      drying. The mixed oxide gel is obtained by hydrolyzing an equimolar mixture of
      tetraethylorthosilicate (TEOS) and tetrabutylorthotitanate (TBOT) at pH 3. The
      materials, after calcining at 723 K for 4 h, are characterized by XRD, FT-IR, the
      BET method, and surface acid strength by the Hammett indicator method. The
      catalytic activity tests are carried in a fixed bed catalytic reactor (i.d. = 10
      mm) for alcohol conversion, whereas cumene cracking/dehydrogenation reactions are
      carried out in a micropulse reactor. XRD results shows that the titania-silica
      mixture is amorphous and the crystallization starts with sulfation. The surface
      of the mixed oxide contains both bridged and normal hydroxyl groups, as observed
      from FT-IR data. The surface area of the material is not much altered by
      sulfation and lies within 50 m2/g. The acid strength of 4 wt% SO2-4/TiO2-SiO2 is
      found to be stronger than that of 100% concentrated H2SO4. In the case of 2
      propanol conversion, low acetone selectivity indicates the presence of weak basic
      sites, whereas methanol conversion over all solids shows that dehydration follows
      a parallel and consecutive pathway. A good correlation is found between the
      cumene cracking and the acidity of the catalysts. Copyright 1999 Academic Press.

PMID- 10395771
TI  - 3D Monolayers of 1,4-Benzenedimethanethiol on Au and Ag Clusters: Distinct
      Difference in Adsorption Geometry with the Corresponding 2D Monolayers.
AB  - Au and Ag clusters of 3-nm mean diameter were prepared with 1,4
      benzenedimethanethiol (BDMT) as the capping molecule. In both the monolayer
      capped clusters, BDMT adsorbs in the dithiolate form in contrast to in the 2D
      monolayers, where the dithiolate form exists only in the case of Ag. As a result,
      the molecule lies flat on the cluster surface in both Au and Ag, whereas the
      molecular plane is perpendicular to the surface in the 2D monolayer of Au. This
      difference in adsorbate structure is attributed to the evolution in the cluster
      surface as adsorption occurs. Transmission electron microscopy and X-ray powder
      diffraction suggest that no superlattice of the clusters exists. Mass
      spectrometry suggests the presence of the phase transfer reagent at the surface.
      X-ray photoelectron spectroscopy confirms the chemical similarity of the two
      surfaces and suggests that the thiolate at the surface is susceptible to X-ray
      beam induced damage. Copyright 1999 Academic Press.

PMID- 10395772
TI  - Surface Chemical Studies on the Competitive Adsorption of Poly(acrylic acid) and
      Poly(vinyl alcohol) onto Alumina.
AB  - The adsorption of poly(acrylic acid) (PAA) and poly(vinyl alcohol) (PVA) onto
      alumina has been studied as a function of pH, both individually and in the
      presence of each other. The adsorption density of PAA is found to decrease with
      an increase of pH while that of PVA shows the opposite trend. In a binary system
      containing PAA and PVA, the presence of PVA does not affect the adsorption of PAA
      onto alumina, but the addition of PAA diminishes the adsorption of PVA in the pH
      range investigated. The adsorption isotherm of PAA at acidic pH exhibits high
      affinity Langmuirian behavior. The isotherms for PVA appear rounded and are of
      the low-affinity type. Once again the adsorption isotherms of PAA remain
      unaltered in the presence of PVA whereas those of PVA are significantly affected
      resulting in a lowering of the adsorption density consequent to PAA addition. A
      variation in the sequence of addition of PAA and PVA does not affect the
      adsorption behavior of either of the polymers. The electrokinetic behavior of
      alumina with PAA is hardly influenced by the addition of PVA. On the other hand,
      the electrophoretic mobility of alumina in the presence of PVA is significantly
      altered in the presence of PAA and closely resembles the trend observed with PAA
      alone. Desorption studies reveal that over 80% of PVA could be desorbed in the pH
      range 3-9 whereas in the case of PAA, the percent desorption increases from 20 to
      about 70% as the pH is increased from about 3 to 8. Solution conductivity tests
      confirm interaction of aluminum species and PAA in the bulk solution. FTIR
      spectroscopic data provide evidence in support of hydrogen bonding and chemical
      interaction in the case of the PAA-alumina system and hydrogen bonding with
      respect to the PVA-alumina interaction. Copyright 1999 Academic Press.

PMID- 10395773
TI  - Role of Hydrophobic Effect on the Noncovalent Interactions Between Salicylic Acid
      and a Series of beta-Cyclodextrins.
AB  - The molecular complexation of salicylic acid (o-hydroxybenzoic acid) by beta
      cyclodextrin (beta-CD) and/or two of its most used derivatives, 2,6-di-O-methyl
      beta-cyclodextrin (DIMEB) and hydroxypropyl-beta-cyclodextrin (HPBCD), was
      studied from pH potentiometric measurements. The role of the hydrophobic effect
      was evaluated by studying the influence of the presence of different constant
      amounts of a series of alcohols (methanol, ethanol, propanol, and butanol) on the
      CD:guest interaction at 25 degrees C. The study was carried out by measuring the
      pH of the hydroalcoholic solutions of the guest, whose concentration is kept
      constant, as a function of cyclodextrin concentration. The dissociation constant
      of salicylic acid and the binding constants of the inclusion complexes formed by
      the CD and both the nonionized (HSA) and ionized (SA-) forms of the guest were
      simultaneously determined at all alcohol concentrations by using a model
      previously derived by us. The carboxylic forms were found to bind the CD with
      higher affinities than the carboxylate partners, irrespective of the polarity of
      the medium and the cyclodextrin used. The ratio KCD:HSA/KCD:SA- is a constant
      value characteristic of the cyclodextrin, which points to the hydrophobic effect
      as one of the main forces involved in the association. A clear influence of the
      solvent polarity on the affinity of binding was found, in the sense that, as long
      as the medium becomes more apolar, the interaction between the drug and the
      cyclodextrin is weakened. A phenomenological limit association curve is proposed
      to define the limiting conditions for association in the presence of an alcohol
      as a cosolvent. Copyright 1999 Academic Press.

PMID- 10395774
TI  - A Combined X-Ray Photoelectron and Auger Electron Spectroscopic Study of Cesium
      in Variable-Charge Montmorillonites.
AB  - A combined X-ray photoelectron and Auger electron spectroscopic investigation of
      sorption and characterization of bonding states of Cs in montmorillonite (M) and
      in four reduced-charge montmorillonites (RCMs) were carried out. The
      nondestructive analysis of sorption of Cs in variable-charge montmorillonites
      obtained by XPS is consistent within 4-8% to those obtained by solution analysis
      using AAS. The core-level Cs 3d5/2 photoelectron binding energy was observed to
      be enhanced with the reduction of electron population from higher to lower charge
      montmorillonite. The charge potential model has been used to interpret such core
      level short-range chemical shifts. However, a larger shift in the Auger Cs
      M4N4,5N4,5 line was observed and Cs-Auger kinetic energy was found to decrease
      from higher charge RCM to lower charge RCM, which may be attributed to the effect
      of extra-atomic relaxation from surrounding oxygen atoms; this effect implies
      that the flow of electronic charge to the Cs ion is larger for higher charge RCM
      than for lower charge RCM. However, this effect is enhanced by the extra
      contribution of Li that has migrated. A comparison of Cs 3d binding energies and
      Cs-Auger kinetic energies in a two-dimensional chemical state plot indicates
      multiple bonding states of Cs in variable-charge montmorillonites. The extra
      atomic relaxation energy (DeltaEr) value of each of the Cs-montmorillonites was
      unique, which indicates that this is dependent on the chemical environment and on
      the availability of electron density in montmorillonites. Also, the binding
      energy value of Cs 3d5/2 was found to be nearer to CsOH than to CsCl, which
      reflects that the bonding state of Cs is not as ionic as CsCl. Copyright 1999
      Academic Press.

PMID- 10395775
TI  - Concentration Effects on the Thermophoresis of Aerosol Spheres.
AB  - The thermophoretic motion of a homogeneous suspension of identical spherical
      particles of arbitrary thermal conductivity and surface properties is considered
      under conditions of small Knudsen, Peclet, and Reynolds numbers. The effects of
      interaction of the individual particles are taken into explicit account by
      employing a unit cell model which is known to provide good predictions for the
      sedimentation of monodisperse suspensions of spherical particles. The appropriate
      equations of conservation of energy and momentum are solved for each cell, in
      which a spherical particle is envisaged to be surrounded by a concentric shell of
      suspending fluid, and the thermophoretic migration velocity of the particle is
      calculated for various cases. Analytical expressions of this mean particle
      velocity are obtained in closed form as functions of the volume fraction of the
      particles. Comparisons between the ensemble-averaged thermophoretic velocity of a
      test particle in a dilute suspension and our cell-model results are made. A
      parallel analysis for the sedimentation of aerosol spheres is also presented.
      Copyright 1999 Academic Press.

PMID- 10395776
TI  - Solution-Membrane Equilibrium at Metal-Deposited Cation-Exchange Membranes:
      Chronopotentiometric Characterization of Metal-Modified Membranes.
AB  - Copper- and lead-deposited interpolymer cationic membranes have been prepared by
      electroless plating by an ion-exchange method and characterized by
      chronopotentiometry and cyclic voltammetry. The parameters such as transition
      time (tau), Itau1/2, the potential drop (E0) across these membranes immediately
      after the application of constant current (I), and the height of the potential
      jump (DeltaE) across the membrane at tau have been measured by
      chronopotentiometry and compared with those of plain membranes. The approximate
      percentage of metal coverage and the number of ionic sites masked by the
      deposited metal in terms of NaCl concentration have been estimated from the
      differences in Itau1/2 values of plain and metal-deposited membranes. The
      quantity of metal deposited in a unit area of the membrane surface was measured
      by differential pulse polarography. The oxidation and reduction peak potentials
      corresponding to Cu(0)/Cu(II) and Pb(0)/Pb(II) couples were identified by cyclic
      voltammetry at pH 2.8 and 4.5 of 0.2 M CH3COONa-H2SO4. Copyright 1999 Academic
      Press.

PMID- 10395777
TI  - High-Frequency Viscosity and Shear Modulus of Sterically Stabilized Colloid
      Particles as Probed by Torsional Resonance Oscillation.
AB  - A study of the high-frequency viscosity etainfinity' and of the high-frequency
      shear modulus Ginfinity' of a sterically stabilized latex is presented. The
      experimental measurements have been done using a torsional resonator described
      recently (J. Bergenholtz et al., J. Colloid Interface Sci. 202, 430 (1998)). The
      data of etainfinity' compare favorably with recent theoretical predictions and
      point to a partial draining of the steric layer by the solvent as expected. The
      high-shear modulus, however, is much lower than predicted by theory. The pair
      potential calculated from Ginfinity' by neglect of hydrodynamic interaction has a
      considerably longer range than expected from the structure of the steric layer.
      This points to the fact that hydrodynamic interactions are not negligible for
      these systems and must be included in a quantitative analysis of the high
      frequency shear modulus Ginfinity'. Copyright 1999 Academic Press.

PMID- 10395778
TI  - Surface Modification of a Hydrogen-Bonded Pigment: A Fluorescence Spectroscopy
      Study.
AB  - The effect of hydrogen-bonding additives on the surface modification of a
      hydrogen-bonded organic pigment is studied using absorption and fluorescence
      spectroscopy. Evidence for surface dissolution that occurs during the mixing of
      solids is presented. The spectral signatures of monomers and hydrogen-bonded
      aggregates of the pigment that are present on the surface of crystallites of the
      pigment are quite distinct, as revealed by fluorescence excitation and emission
      spectra. Copyright 1999 Academic Press.

PMID- 10395779
TI  - Convective Sedimentation of Colloidal Particles in a Bowl.
AB  - A physical model, which regards a colloidal dispersion as a single fluid
      continuum, is used to investigate cellular convection accompanying gravitational
      sedimentation in a hemispherical bowl with a thin cylindrical shaft along its
      vertical axis of symmetry. We have adapted the stream-function-vorticity form of
      the Navier-Stokes equations to describe momentum conservation in axially
      symmetric containers. These hydrodynamic equations have been coupled to the mass
      balance equation for binary hydrodynamic diffusion in the presence of a vertical
      gravitational field. Using finite-element software we have solved the equations
      governing coupled diffusive and hydrodynamic flow. A rapidly intensifying
      horizontal toroidal vortex develops around the axis of the bowl. This vortex is
      characterized by downward barycentric flow along the curved surface of the bowl
      and upward flow in the vicinity of its axis. We find that after a short period of
      time this large-scale cellular convection associated with the curved boundary of
      the bowl greatly enhances the rate of sedimentation. Copyright 1999 Academic
      Press.

PMID- 10395780
TI  - Comparative biology of calcium signaling during fertilization and egg activation
      in animals.
AB  - During animal fertilizations, each oocyte or egg must produce a proper
      intracellular calcium signal for development to proceed normally. As a supplement
      to recent synopses of fertilization-induced calcium responses in mammals, this
      paper reviews the spatiotemporal properties of calcium signaling during
      fertilization and egg activation in marine invertebrates and compares these
      patterns with what has been reported for other animals. Based on the current
      database, fertilization causes most oocytes or eggs to generate multiple wavelike
      calcium oscillations that arise at least in part from the release of internal
      calcium stores sensitive to inositol 1,4,5-trisphosphate (IP3). Such calcium
      waves are modulated by upstream pathways involving oolemmal receptors and/or
      soluble sperm factors and in turn regulate calcium-sensitive targets required for
      subsequent development. Both "protostome" animals (e.g., mollusks, annelids, and
      arthropods) and "deuterostomes" (e.g., echinoderms and chordates) display
      fertilization-induced calcium waves, IP3-mediated calcium signaling, and the
      ability to use a combination of external calcium influx and internal calcium
      release. Such findings fail to support the dichotomy in calcium signaling modes
      that had previously been proposed for protostomes vs deuterostomes and instead
      suggest that various features of fertilization-induced calcium signals are widely
      shared throughout the animal kingdom.

PMID- 10395781
TI  - Biphasic dispersion of clones containing Purkinje cells and glia in the
      developing chick cerebellum.
AB  - The cerebellum is a highly conserved structure which exhibits patterns of gene
      expression and axonal connections that are organized into parasagittal domains.
      These aspects of the mature cerebellum are presaged during embryonic development
      by the expression patterns of vertebrate homologs of Drosophila segmentation
      genes. We wished to determine whether the parasagittal domains of gene expression
      are compartments of lineage restriction. To this end, a clonal analysis of the
      chick cerebellum was conducted with a complex retroviral library. From embryonic
      day (E) 8 to E12, clones derived from the more medial portion of the cerebellar
      ventricular zone (VZ) were observed to spread preferentially in the mediolateral
      direction, crossing the boundaries of the parasagittal domains of gene
      expression. In late embryonic and posthatch periods, VZ clones were found to
      comprise Purkinje cells, glial cells, or both types of cells. At these later
      times, clonally related glial cells formed tight parasagittal clusters, while
      clonally related Purkinje cells were scattered extensively in the anteroposterior
      direction. We propose that a subset of the cerebellar VZ clones, those with
      medial origins, undergoes a biphasic dispersion: an early phase of mediolateral
      dispersion and a late phase of anteroposterior dispersion. This novel pattern of
      clonal dispersion suggests that the cerebellar VZ is not partitioned into
      parasagittal domains of lineage restriction. It leaves open the possibility that
      the later dispersion along the anteroposterior axis results from the parasagittal
      patterns of gene expression in the developing cerebellar cortex.

PMID- 10395782
TI  - Expression cloning of an ascidian syndecan suggests its role in embryonic cell
      adhesion and morphogenesis.
AB  - Expression cloning of maternally expressed genes of the ascidian Ciona savignyi
      demonstrated that the overexpression of syndecan, a member of a multigene family
      of integral membrane heparan sulfate proteoglycans, resulted in a disturbance of
      cell adhesion and morphogenesis. The Ciona syndecan gene was expressed both
      maternally and zygotically. The maternal transcript was distributed evenly in
      fertilized eggs and early embryos up to the 32-cell stage without any special
      localization and then became barely detectable in the 64-cell and gastrula
      stages. The zygotic transcription became evident during neurulation, mainly in
      cells of epidermis, the central nervous system, and mesenchyme. Embryos with
      syndecan overexpression via RNA injection cleaved as did normal embryos, but
      showed loose blastomere adhesion after the 32-cell stage. Gastrulation occurred,
      but the closure of the blastopore was markedly delayed, resulting in larvae
      without normal morphology. About half of the syndecan-overexpressing embryos
      hatched, and differentiation of epidermis, endoderm, muscle, and notochord was
      evident. However, the formation of pigment cells of the sensory organs was
      markedly disturbed. These results indicate that an appropriate level of syndecan
      expression is required for normal cell adhesion and morphogenesis of the ascidian
      embryo.

PMID- 10395783
TI  - Morphological domains of Lewis-X/FORSE-1 immunolabeling in the embryonic neural
      tube are due to developmental regulation of cell surface carbohydrate expression.
AB  - The Lewis-X (LeX) carbohydrate epitope, recognized by the FORSE-1 monoclonal
      antibody (mAb), shares expression boundaries with neural regulatory genes and may
      be involved in patterning the neural tube by creating domains of differential
      cell adhesion. The present experiments focus on the question of what determines
      the expression pattern of LeX in embryonic rat brain. Comparisons of FORSE-1
      positive glycolipid and protein antigens in embryonic, early postnatal, and adult
      tissues show that the LeX epitope is carried primarily by glycolipids during
      embryonic development and by a proteoglycan and glycoproteins in postnatal and
      adult tissue. Immunohistochemistry using FORSE-1 and an antibody to the
      proteoglycan phosphacan, which carries LeX, shows that the distribution of LeX is
      more restricted than phosphacan. These observations suggest that the precise
      spatial regulation of FORSE-1 binding in the embryonic forebrain is due to the
      expression pattern of the LeX carbohydrate on glycolipids, rather than to the
      transcriptional regulation of a carrier protein.

PMID- 10395784
TI  - The role of kreisler in segmentation during hindbrain development.
AB  - The mouse kreisler gene is expressed in rhombomeres (r) 5 and 6 during neural
      development and kreisler mutants have patterning defects in the hindbrain that
      are not fully understood. Here we analyzed this phenotype with a combination of
      genetic, molecular, and cellular marking techniques. Using Hox/lacZ transgenic
      mice as reporter lines and by analyzing Eph/ephrin expression, we have found that
      while r5 fails to form in these mice, r6 is present. This shows that kreisler has
      an early role in the formation of r5. We also observed patterning defects in r3
      and r4 that are outside the normal domain of kreisler expression. In both
      heterozygous and homozygous kreisler embryos some r5 markers are induced in r3,
      suggesting that there is a partial change in r3 identity that is not dependent
      upon the loss of r5. To investigate the cellular character of r6 in kreisler
      embryos we performed heterotopic grafting experiments in the mouse hindbrain to
      monitor its mixing properties. Control experiments revealed that cells from even-
      or odd-numbered segments only mixed freely with themselves, but not with cells of
      opposite character. Transposition of cells from the r6 territory of kreisler
      mutants reveals that they adopt mature r6 characteristics, as they freely mix
      only with cells from even-numbered rhombomeres. Analysis of Phox2b expression
      shows that some aspects of later neurogenesis in r6 are altered, which may be
      associated with the additional roles of kreisler in regulating segmental
      identity. Together these results suggest that the formation of r6 has not been
      affected in kreisler mutants. This analysis has revealed phenotypic and
      mechanistic differences between kreisler and its zebrafish equivalent valentino.
      While valentino is believed to subdivide preexisting segmental units, in the
      mouse kreisler specifies a particular segment. The formation of r6 independent of
      r5 argues against a role of kreisler in prorhombomeric segmentation of the mouse
      hindbrain. We conclude that the mouse kreisler gene regulates multiple steps in
      segmental patterning involving both the formation of segments and their A-P
      identity.

PMID- 10395785
TI  - Timp-1 is important for epithelial proliferation and branching morphogenesis
      during mouse mammary development.
AB  - The dynamic process of mammary ductal morphogenesis depends on regulated
      epithelial proliferation and extracellular matrix (ECM) turnover. Epithelial cell
      matrix contact closely dictates epithelial proliferation, differentiation, and
      survival. Despite the fact that tissue inhibitors of metalloproteinases (Timps)
      regulate ECM turnover, their function in mammary morphogenesis is unknown. We
      have delineated the spatiotemporal expression of all Timps (Timp-1 to Timp-4)
      during discrete phases of murine mammary development. Timp mRNAs were abundant in
      mammary tissue, each displaying differential expression patterns with predominant
      localization in luminal epithelial cells. Timp-1 mRNA was unique in that its
      expression was limited to the stage at which epithelial proliferation was high.
      To assess whether Timp-1 promotes or inhibits epithelial cell proliferation we
      manipulated mammary Timp-1 levels, genetically and biochemically. Down-regulation
      of epithelial-derived Timp-1 in transgenic mice, by mouse mammary tumor virus
      promoter-directed Timp-1 antisense RNA expression, led to augmented ductal
      expansion and increased number of ducts (P < 0.004). In these transgenics the
      integrity of basement membrane surrounding epithelial ducts, as visualized by
      laminin-specific immunostaining, was breached. In contrast to these mice, ductal
      expansion was markedly attenuated in the proximity of implanted recombinant Timp
      1-releasing pellets (rTIMP-1), without an increase in basement membrane
      deposition around migrating terminal end buds. Epithelial proliferation and
      apoptosis were measured to determine the basis of altered ductal expansion.
      Luminal epithelial proliferation was increased by 55% (P < 0.02) in Timp-1
      reduced transgenic mammary tissue and, conversely, decreased by 38% (P < 0.02) in
      terminal end buds by implanted rTIMP-1. Epithelial apoptosis was minimal and
      remained unaffected by Timp-1 manipulations. We conclude that Timps have an
      integral function in mammary morphogenesis and that Timp-1 regulates mammary
      epithelial proliferation in vivo, at least in part by maintaining basement
      membrane integrity.

PMID- 10395786
TI  - The transcription factor MEF2C-null mouse exhibits complex vascular malformations
      and reduced cardiac expression of angiopoietin 1 and VEGF.
AB  - The MEF2 family of transcription factors has been implicated in transcriptional
      regulation in a number of different cell types. Targeted deletion of the MEF2C
      gene, in particular, revealed its importance for early cardiogenesis (Q. Lin et
      al., 1997, Science 276, 1404-1407). We report here that this deletion also
      resulted in vascular anomalies characterized by extreme variability in lumen size
      and defects in remodeling. While primary vascular networks formed in the yolk sac
      of the mutants, they failed to remodel into more complex vascular structures.
      Likewise, although the primordia of the dorsal aortae formed normally, anomalies
      were observed in these vessels later in development. Dorsal and anterior to the
      heart, the aortae exhibited abnormally small lumens, as did the anterior cardinal
      veins and intersegmental arteries. In contrast, the dorsal aortae and
      intersegmental arteries caudal to the heart were grossly enlarged. Cranial
      vessels were also enlarged and less branched than normal. Endocardiogenesis in
      the mutant was abnormal with the endothelial cells exhibiting a number of
      aberrant phenotypes. These endocardial defects were accompanied by a notable
      reduction in angiopoietin 1 and VEGF mRNA production by the myocardium,
      indicating that MEF2C is required for myocardial expression of these important
      endothelial-directed cytokines and thus for correct endocardial morphogenesis.

PMID- 10395787
TI  - A common mechanism for antenna-to-Leg transformation in Drosophila: suppression
      of homothorax transcription by four HOM-C genes.
AB  - The Drosophila HOM-C genes encode transcription factors containing the DNA
      binding homeodomain. Mutations in the HOM-C genes can cause specific homeotic
      transformation, suggesting that the HOM-C genes determine segmental identities by
      acting on different target genes. However, misexpression of several HOM-C genes
      in the antenna disc causes similar antenna-to-leg transformations. Here we show
      that the Scr, Antp, Ubx, and abd-A HOM-C genes all exert their effects through a
      common mechanism: suppressing the transcription of the homothorax (hth) homeobox
      gene and thereby preventing the nuclear localization of the Extradenticle
      homeodomain protein. We also show that ectopic hth expression can cause
      duplication of the proximodistal axis of the antenna, suggesting that it is
      involved in proximodistal development of the antenna.

PMID- 10395788
TI  - Target- and maturation-specific membrane-associated molecules determine the
      ingrowth of entorhinal fibers into the hippocampus.
AB  - In this study the role of membrane-associated molecules involved in
      entorhinohippocampal pathfinding was examined. First outgrowth preferences of
      entorhinal neurites were analyzed on membrane carpets obtained from their proper
      target area, the hippocampus, and compared to preferences on control membranes
      from brain regions which do not receive afferent connections from the entorhinal
      cortex. On a substrate consisting of alternating lanes of hippocampal and control
      membranes, entorhinal neurites exhibited a strong tendency to grow on lanes of
      hippocampal membrane. These tissue-specific outgrowth preferences were maintained
      even on membrane preparations from adult brain tissue devoid of myelin. To
      determine the possible maturation dependence of these membranes, we examined
      guidance preferences of entorhinal neurites on hippocampal membranes of different
      developmental stages ranging from embryonic to postnatal and adult. Given a
      choice between alternating lanes of embryonic (E15-E16) and neonatal (P0-P1)
      hippocampal membranes, entorhinal neurites preferred to extend on neonatal
      membranes. No outgrowth preferences were observed on membranes obtained between
      E19 and P10. From P10 onward there was a reoccurrence of a preference for
      postnatal membrane lanes when neurites were presented with a choice between P15,
      P30, and adult membranes (>P60). This choice behavior of entorhinal neurites
      temporally correlates with the ingrowth of the perforant path into the
      hippocampus and with the stabilization of this brain area in vivo. Experiments in
      which postnatal and adult hippocampal membranes were heat inactivated or treated
      to remove molecules sensitive to phosphatidylinositol-specific phospholipase C
      demonstrated that entorhinal fiber preferences were controlled in this assay by
      attractive guidance cues and were independent of phosphatidylinositol-sensitive
      linked molecules. Moreover, entorhinal neurites displayed a positive
      discrimination for membrane-associated guidance cues of their target field, thus
      preferring to grow on membranes from the molecular layer of the dentate gyrus
      compared with CA3 or hilus membranes. Heat-inactivation experiments indicated
      that preferential growth of entorhinal axons is due to a specific attractivity of
      the molecular layer substrate. The data presented demonstrate that outgrowth of
      entorhinal fibers on hippocampal membranes is target and maturation dependent.

PMID- 10395789
TI  - Regulation of dorsal gene expression in Xenopus by the ventralizing homeodomain
      gene Vox.
AB  - Patterning in the vertebrate embryo is controlled by an interplay between signals
      from the dorsal organizer and the ventrally expressed BMPs. Here we examine the
      function of Vox, a homeodomain-containing gene that is activated by the
      ventralizing signal BMP-4. Inhibition of BMP signaling using a dominant negative
      BMP receptor (DeltaBMPR) leads to the ectopic activation of dorsal genes in the
      ventral marginal zone, and this activation is prevented by co-injection of Vox.
      chordin is the most strongly activated of those genes that are up-regulated by
      DeltaBMPR and is the gene most strongly inhibited by Vox expression. We
      demonstrate that Vox acts as a transcriptional repressor, showing that the
      activity of native Vox is mimicked by a Vox-repressor fusion (VoxEnR) and that a
      Vox-activator fusion (VoxG4A) acts as an antimorph, causing the formation of a
      partial secondary axis when expressed on the ventral side of the embryo. Although
      Vox can ectopically activate BMP-4 expression in whole embryos, we see no
      activation of BMP-4 by VoxG4A, demonstrating that this activation is indirect.
      Using a hormone-inducible version of VoxG4A, we find that a critical time window
      for Vox function is during the late blastula period. Using this construct, we
      demonstrate that only a subset of dorsal genes is directly repressed by Vox,
      revealing that there are different modes of regulation for organizer genes. Since
      the major direct target for Vox repression is chordin, we propose that Vox acts
      in establishing a BMP-4 morphogen gradient by restricting the expression domain
      of chordin.

PMID- 10395790
TI  - The forkhead/winged-helix gene, Mf1, is necessary for the normal development of
      the cornea and formation of the anterior chamber in the mouse eye.
AB  - Mf1, which encodes a winged-helix/forkhead transcription factor, is the murine
      homolog of human FKHL7, mutated in individuals with autosomal dominant inherited
      dysgenesis of the anterior segment of the eye (Axenfeld-Reiger anomaly). Mouse
      embryos homozygous for null mutations in Mf1 (Mf1(lacZ) and Mf1(ch)) show
      severely abnormal development of the anterior segment. The cornea fails to
      separate from the lens, resulting in the complete absence of an anterior chamber.
      There is no differentiation of the inner corneal endothelial layer, as judged by
      electron microscopy and by absence of labeling with monoclonal antibody to zonula
      occludens protein 1, a normal component of occluding junctions in wild-type
      endothelial cells. In addition, the mutant corneal stroma is disorganized and the
      epithelium thicker than normal. The Mf1 gene is normally expressed in the
      periocular mesenchyme at E11.5 but is downregulated as the corneal endothelium
      differentiates. In contrast, Mf1(lacZ) expression persists longer in mutant
      corneal mesenchyme, and abnormal expression is also seen in the mutant corneal
      epithelium. Based on classical studies with the chick embryonic eye, a model is
      proposed for the differentiation of the mammalian corneal endothelium from
      mesenchyme in response to putative signals from the lens. Possible roles for Mf1
      in this process are discussed.

PMID- 10395791
TI  - Overexpression of ptc1 inhibits induction of Shh target genes and prevents normal
      patterning in the neural tube.
AB  - Patched (Ptc) is a human tumor suppressor protein and a candidate receptor for
      Hedgehog (Hh) proteins, which regulate growth and patterning in embryos. Ptc
      represses expression of Hh target genes such as Gli1 and ptc1 itself. Localized
      secretion of Hh appears to induce transcription of target genes in specific
      patterns by binding to Ptc and preventing it from functioning in recipient cells.
      People who are heterozygous for PTC1 exhibit a range of developmental defects,
      suggesting that some genes are inappropriately expressed when there is not enough
      Ptc protein. To test the idea that a balance between Hh and Ptc activities is
      essential for normal development, we overexpressed Ptc in the neural tube. We
      find that excess Ptc is sufficient to inhibit expression of Gli1 and ptc1,
      suggesting that Sonic hedgehog (Shh) cannot signal effectively. This leads to
      partial dorsalization of the neural tube and a wide spectrum of neural defects,
      ranging from embryonic lethality to hydrocephaly.

PMID- 10395792
TI  - Cell migration and chick limb development: chemotactic action of FGF-4 and the
      AER.
AB  - Experiments have been carried out to investigate the role of the apical
      ectodermal ridge (AER) and FGF-4 on the control of cell migration during limb bud
      morphogenesis. By coupling DiI cell labeling with ectopic implantation of FGF-4
      microcarrier beads we have found that FGF-4 acts as a potent and specific
      chemoattractive agent for mesenchymal cells of the limb bud. The response to FGF
      4 is dose dependent in both the number of cells stimulated to migrate and the
      distance migrated. The cell migration response to FGF-4 appears to be independent
      of the known inductive activity of FGF-4 on Shh gene expression. We investigated
      the role of the AER in controlling cell migration by characterizing the migration
      pattern of DiI-labeled subapical cells during normal limb outgrowth and following
      partial AER removal. Subapical cells within 75 micrometer of the AER migrate to
      make contact with the AER and are found intermingled with nonlabeled cells. Thus,
      the progress zone is dynamic with cells constantly altering their neighbor
      relationships during limb outgrowth. AER removal studies show that cell migration
      is AER dependent and that subapical cells redirect their path of migration toward
      a functional AER. These studies indicate that the AER has a chemoattractive
      function and regulates patterns of cell migration during limb outgrowth. Our
      results suggest that the chemoattractive activity of the AER is mediated in part
      by the production of FGF-4.

PMID- 10395793
TI  - Integration of cytogenetic with recombinational and physical maps of mouse
      chromosome 16.
AB  - To link the cytogenetic map for mouse chromosome 16 (Chr 16) to the more detailed
      recombinational and physical maps, multiple probes were mapped by fluorescence in
      situ hybridization (FISH). Sixteen large insert clones (YACs, BACs, and PACs)
      containing markers that have been assigned to the Chr 16 recombinational map were
      localized to a cytogenetic band or subband by high-resolution FISH. This linkage
      of the cytogenetic and recombinational maps provides a useful tool for assigning
      new probe locations and for defining breakpoints in mice with chromosomal
      rearrangements. A direct application of these probes is demonstrated by
      identifying mice trisomic for distal Chr 16 using FISH analysis of interphase
      nuclei.

PMID- 10395794
TI  - Induction of erythrocyte protein 4.2 gene expression during differentiation of
      murine erythroleukemia cells.
AB  - Protein 4.2 (P4.2) is an important component in the erythrocyte membrane skeletal
      network that regulates the stability and flexibility of erythrocytes. Recently,
      we provided the evidence for specific P4.2 expression in erythroid cells during
      development (L. Zhu et al., 1998, Blood 91, 695-705). Using dimethyl sulfoxide
      (DMSO)-induced differentiation of murine erythroleukemia (MEL) cells as a model,
      transcription of the P4.2 gene was found to be induced during erythroid
      differentiation. To examine the mechanism for this induction, we isolated the
      mouse P4.2 genomic DNA containing the 5' flanking sequence and defined the
      location of the P4.2 promoter. Transcription of the mouse P4.2 gene initiates at
      multiple sites, with the major initiation site mapped at 174 nucleotides upstream
      of the ATG start codon. The mouse P4.2 promoter is TATA-less and contains
      multiple potential binding sites for erythroid transcription factors GATA-1, NF
      E2, EKLF, and tal-1/SCL. Transient transfection experiments demonstrated that a
      1.7-kb mouse P4.2 promoter fused with the luciferase coding regions was induced
      in DMSO-treated MEL cells. Deletion analysis showed that a 259-bp P4.2 promoter
      DNA (nucleotide position -88 to +171 relative to the major transcription
      initiation site designated +1), containing a GATA-binding site at position -29 to
      -24, could still respond to the induction in differentiated MEL cells.
      Importantly, mutations in the -29/-24 GATA motif rendered the promoter
      unresponsive to DMSO induction. Electrophoretic mobility shift assay revealed
      that GATA-1 could bind to the -29/-24 GATA motif and this was confirmed by the
      observation that the nuclear protein bound to the motif was supershifted by an
      anti-GATA-1 monoclonal antibody. Taken together, these results suggest that the
      erythroid transcription factor GATA-1 plays an important role in the induction of
      P4.2 gene expression during erythroid cell differentiation.

PMID- 10395795
TI  - A human nucleobase transporter-like cDNA (SLC23A1): member of a transporter
      family conserved from bacteria to mammals.
AB  - A family of related polytopic membrane proteins that mediate the transport of
      nucleobases has been extended to Homo sapiens by the cloning of a full-length
      human cDNA that encodes a nucleobase transporter-like protein. The protein is
      predicted to contain 11-14 transmembrane-spanning regions, exhibits 20-28%
      overall sequence identity to fungal and bacterial transporters, and contains a
      conserved signature motif found in this family. Fluorescence in situ
      hybridization localized the gene (HGMW-approved symbol SLC23A1) to human
      chromosome 20p13. Human nucleobase transporter-like mRNA was present in all
      tissues examined, with lower levels found in heart, skeletal muscle, and ovary.
      Expression of the 60-kDa cDNA-encoded protein was demonstrated by an in vitro
      transcription-translation approach. The identification of this nucleobase
      transporter-like protein will allow the further elucidation of the interaction of
      human cells with physiological nucleobases and pharmacologically important drugs
      such as 5-F-uracil, dideoxynucleosides, and acyclic nucleosides.

PMID- 10395796
TI  - Interpolated Markov models for eukaryotic gene finding.
AB  - Computational gene finding research has emphasized the development of gene
      finders for bacterial and human DNA. This has left genome projects for some small
      eukaryotes without a system that addresses their needs. This paper reports on a
      new system, GlimmerM, that was developed to find genes in the malaria parasite
      Plasmodium falciparum. Because the gene density in P. falciparum is relatively
      high, the system design was based on a successful bacterial gene finder, Glimmer.
      The system was augmented with specially trained modules to find splice sites and
      was trained on all available data from the P. falciparum genome. Although a
      precise evaluation of its accuracy is impossible at this time, laboratory tests
      (using RT-PCR) on a small selection of predicted genes confirmed all of those
      predictions. With the rapid progress in sequencing the genome of P. falciparum,
      the availability of this new gene finder will greatly facilitate the annotation
      process.

PMID- 10395797
TI  - Mouse Hus1, a homolog of the Schizosaccharomyces pombe hus1+ cell cycle
      checkpoint gene.
AB  - Cell cycle checkpoints are regulatory mechanisms that arrest the cell cycle or
      initiate programmed cell death when critical events such as DNA replication fail
      to be completed or when DNA or spindle damage occurs. In fission yeast, cell
      cycle checkpoint responses to DNA replication blocks and DNA damage require the
      hus1+ gene. Mammalian homologs of hus1+ were recently identified, and here we
      report a detailed analysis of mouse Hus1. An approximately 4.2-kb full-length
      cDNA encoding the 32-kDa mouse Hus1 protein was isolated. The genomic structure
      and exon-intron boundary sequences of the gene were determined, and mouse Hus1
      was found to consist of nine exons. Mouse Hus1 was mapped to the proximal end of
      chromosome 11 and is therefore a candidate gene for the mouse mutation germ cell
      deficient, which maps to the same genomic region. Finally, mouse Hus1 was found
      to be expressed in a variety of adult tissues and at several stages of embryonic
      development.

PMID- 10395798
TI  - Genomic structure and functional characterization of NBPhox (PMX2B), a
      homeodomain protein specific to catecholaminergic cells that is involved in
      second messenger-mediated transcriptional activation.
AB  - Homeodomain proteins play essential roles in basic processes during embryogenesis
      and development. NBPhox, a vertebrate paired-like homeodomain protein specific to
      catecholaminergic cells, may have a fundamental role in determining and
      maintaining the catecholaminergic phenotype. Here we describe the human and mouse
      genomic structures and the functional characterization of NBPhox. The genomic
      structure of NBPhox is highly conserved at the nucleotide level between human and
      mouse and is also quite similar to that of other paired-like homeodomain
      proteins, Arix/Phox2a, CRX, OTX1, and OTX2. The human NBPhox gene (HGMW-approved
      symbol PMX2B) maps to chromosomal region 5p12-p13. When the NBPhox expression
      plasmid was introduced into PC12h cells, the transcription from the promoter of
      the dopamine beta-hydroxylase (DBH) gene was slightly stimulated. However, NBPhox
      substantially enhances second messenger-mediated activation of the DBH promoter
      by forskolin and/or phorbol ester. Furthermore, we found that NBPhox can also
      enhance second messenger-mediated activation of the c-fos promoter and several
      enhancers, including cyclic AMP-response element, the binding site for activator
      protein 1, and serum-response element. Our findings provide strong evidence that
      a homeodomain protein is involved in the activation of several genetic regulatory
      elements responsive to second messenger-mediated signals. These data suggest that
      this family of proteins may be involved in determining and maintaining a cell
      specific phenotype through regulation of certain genes responsive to second
      messenger-mediated signals.

PMID- 10395799
TI  - Identification and characterization of AFG3L2, a novel paraplegin-related gene.
AB  - We recently identified a gene responsible for an autosomal recessive form of
      hereditary spastic paraplegia (HSP). This gene encodes paraplegin, a
      mitochondrial protein highly homologous to the yeast mitochondrial ATPases Afg3p
      and Rcalp, which have both proteolytic and chaperone-like activities at the inner
      mitochondrial membrane. By screening the Expressed Sequence Tag database, we
      identified and characterized a novel human cDNA, ATPase family gene 3-like 2
      (AFG3L2, Human Gene Nomenclature Committee-approved symbol), which is closely
      related to paraplegin. This cDNA encodes a 797-amino-acid predicted protein
      highly similar to paraplegin as well as to yeast Afg3p and Rca1p.
      Immunofluorescence studies revealed that AFG3L2 and paraplegin share a similar
      expression pattern and the same subcellular localization, the mitochondrial
      compartment. We subsequently mapped AFG3L2 to chromosome 18p11 by radiation
      hybrid analysis. AFG3L2 may represent a candidate gene for other forms of HSPs
      and possibly for other neurodegenerative disorders.

PMID- 10395800
TI  - Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene
      on chromosome 17q21.
AB  - The beclin 1 (BECN1) gene encodes a 60-kDa coiled-coil protein that interacts
      with the prototypic apoptosis inhibitor Bcl-2. Previous studies indicate that
      beclin 1 maps to a region approximately 150 kb centromeric to BRCA1 on chromosome
      17q21 that is commonly deleted in breast, ovarian, and prostate cancer. The
      complete cDNA sequence of beclin 1 encodes a 2098-bp transcript, with a 120-bp 5'
      UTR, 1353-bp coding region, and 625-bp 3' UTR. Hybridization screening of a human
      genomic PAC library identified PAC 452O8, which contains the complete beclin 1
      gene. Determination of the exon-intron structure of beclin 1 reveals 12 exons,
      ranging from 61 to 794 bp, which extend over 12 kb of the human genome. FISH
      analysis of human breast carcinoma cell lines using PAC 452O8 as probe identified
      allelic beclin 1 deletions in 9 of 22 cell lines. Sequencing of genomic DNA from
      10 of these cell lines revealed no mutations in coding regions or splice
      junctions. Additionally, Northern blot analysis of 11 cell lines did not identify
      any abnormalities in beclin 1 transcripts. These results indicate that human
      breast carcinoma cell lines frequently contain allelic deletions of beclin 1, but
      not beclin 1 coding mutations.

PMID- 10395801
TI  - EHD1--an EH-domain-containing protein with a specific expression pattern.
AB  - A cDNA that is a member of the eps15 homology (EH)-domain-containing family and
      is expressed differentially in testis was isolated from mouse and human. The
      corresponding genes map to the centromeric region of mouse chromosome 19 and to
      the region of conserved synteny on human chromosome 11q13. Northern analysis
      revealed two RNA species in mouse. In addition to the high levels in testis,
      expression was noted in kidney, heart, intestine, and brain. In human, three RNA
      species were evident. The smaller one was predominant in testis, while the
      largest species was evident in other tissues as well. The predicted protein
      sequence has an EH domain at its C-terminus, including an EF, a Ca2+ binding
      motif, and a central coiled-coil structure, as well as a nucleotide binding
      consensus site at its N-terminus. As such, it is a member of the EH-domain
      containing protein family and was designated EHD1 (EH domain-containing 1). In
      cells in tissue culture, we localized EHD1 as a green fluorescent protein fusion
      protein, in transferrin-containing, endocytic vesicles. Immunostaining of
      different adult mouse organs revealed major expression of EHD1 in germ cells in
      meiosis, in the testes, in adipocytes, and in specific retinal layers. Results of
      in situ hybridization to whole embryos and immunohistochemical analyses indicated
      that EHD1 expression was already noted at day 9.5 in the limb buds and pharyngeal
      arches and at day 10.5 in sclerotomes, at various elements of the branchial
      apparatus (mandible and hyoid), and in the occipital region. At day 15.5 EHD1
      expression peaked in cartilage, preceding hypertrophy and ossification, and at
      day 17.5 there was no expression in the bones. The EHD1 gene is highly conserved
      between nematode, Drosophila, mouse, and human. Its predicted protein structure
      and cellular localization point to the possibility that EHD1 participates in
      ligand-induced endocytosis.

PMID- 10395802
TI  - Characterization of a novel chromo domain gene in xp22.3 with homology to
      Drosophila msl-3.
AB  - The Drosophila male-specific lethal (MSL) genes regulate transcription from the
      male X chromosome in a dosage compensation pathway that equalizes X-linked gene
      expression in males and females. The members of this gene family, including msl
      1, msl-2, msl-3, mle, and mof, encode proteins with no sequence homology.
      However, mutations in each of these genes produce a similar phenotype: sex
      specific lethality of male embryos caused by the failure of mutants to increase
      transcription from the single male X chromosome. The MSL gene products assemble
      into a multiprotein transcriptional activation complex at hundreds of sites along
      the chromatin of the X chromosome. Here we report the isolation and
      characterization of a human gene, named MSL3L1, that encodes a protein with
      significant homology to Drosophila MSL-3 in three distinct regions, including two
      putative chromo domains. MSL3L1 was identified by database queries with genomic
      sequence from BAC GS-590J6 (GenBank AC0004554) in Xp22.3 and was evaluated as a
      candidate gene for several developmental disorders mapping to this region,
      including OFD1 and SED tarda, as well as Aicardi syndrome and Goltz syndrome.

PMID- 10395803
TI  - Cloning and expression analysis of a novel WD repeat gene, WDR3, mapping to 1p12
      p13.
AB  - WD repeat proteins are components of multiprotein complexes that are involved in
      a wide spectrum of cellular activities, such as cell cycle progression, signal
      transduction, apoptosis, and gene regulation. These proteins are characterized by
      repeat units bracketed by Gly-His and Trp-Asp (GH-WD). We report here the
      isolation of a new member of the WD repeat gene family, WDR3, which encodes a
      putative 943-amino-acid nuclear protein consisting of 10 WD repeat modules. WDR3
      is widely expressed in hematopoietic cell lines and in nonhematopoietic tissues.
      Fluorescence in situ hybridization mapped WDR3 to human chromosome 1p12-p13, a
      region that is affected by chromosomal rearrangements in a number of hematologic
      malignancies and solid tumors.

PMID- 10395804
TI  - Cloning and chromosomal mapping of the human DNA polymerase theta (POLQ), the
      eighth human DNA polymerase.
AB  - We have cloned the cDNA for the eighth human DNA polymerase, DNA polymerase
      &theta;. The human cDNA encodes a putative DNA polymerase of 1762 amino acids
      with a calculated molecular mass of 198 kDa. The derived protein sequence is
      homologous to the Drosophila melanogaster mus308 protein product, a putative DNA
      polymerase-helicase involved in repair of interstrand crosslinks. The C-terminal
      region contains the canonical DNA polymerase motifs A, B, and C found in the
      family A type of DNA polymerases, which includes Escherichia coli polymerase I.
      The N-terminal region contains a putative ATP binding domain but not motifs for a
      helicase. The gene was mapped by radiation hybrid analysis to chromosome 3q
      within an interval flanked by proximal marker D3S1303 and distal marker D3S3576
      and, based on proximity to a gene that has been mapped cytogenetically, within
      band 3q13.31.

PMID- 10395805
TI  - Cloning of a human ortholog (RPH3AL) of (RNO)Rph3al from a candidate 17p13.3
      medulloblastoma tumor suppressor locus.
AB  - Allelic loss of 17p13.3 is observed in approximately 40% of medulloblastomas,
      suggesting the presence of a tumor suppressor gene in this region. Deletion
      mapping has defined a region of common loss flanking the telomeric marker D17S34,
      and a recent report delineated a 9-kb homozygous deletion within the D17S34 locus
      in one such tumor. Using cDNA selection, we have identified a transcript spanning
      this deletion, designated (HSA)RPH3AL (rabphillin-3A-like), based on its 77%
      overall amino acid identity with a recently cloned rat gene, (RNO)Rph3al
      (originally termed Noc2), a gene putatively involved in regulated endocrine
      exocytosis through its interactions with the cytoskeleton. We determined the exon
      intron boundaries of RPH3AL and screened the coding region for mutations by
      direct sequencing in DNA extracted from 33 tumor samples with allelic loss of
      17p13, including 10 medulloblastoma, 14 follicular thyroid cancer (FTC), and 9
      ovarian cancer specimens. No mutations were identified. Thus, despite its
      location in a homozygously deleted 17p13.3 locus, it is unlikely that RPH3AL is a
      gene involved in the oncogenesis of medulloblastoma, FTC, or ovarian cancer.

PMID- 10395806
TI  - Identification, sequence, and mapping of the mouse multiple PDZ domain protein
      gene, Mpdz.
AB  - The PDZ domain gained its name from the three proteins that were first seen to
      have homology by virtue of these domains, the mammalian postsynaptic density
      protein, PSD-95, the Drosophila discs-large septate junction protein, DLG, and
      the mammalian epithelial tight-junction protein zona occludens, ZO-1. Over 50 PDZ
      domain-containing genes have been recognized so far from almost any organism
      subjected to sequencing, including mammals, nematodes, yeast, plants, and
      bacteria. The domain consists of an approximately 90-amino-acid-residue unit,
      which is often repeated in the protein. The majority of residues form a conserved
      spatial structure while a few amino acids in critical positions confer protein
      binding specificity. A subgroup of PDZ domains have been shown to recognize a
      short carboxy-terminal amino acid motif, T/SXV (Ser/Thr-X-Val-COO-), where X is
      any amino acid. We have identified and completely sequenced a gene, Mpdz, that
      encodes a mouse protein containing 13 such domains. We have also mapped the gene
      to a series of overlapping deletions on mouse chromosome 4 and can therefore
      determine that its function is not essential for embryonic development or
      neonatal survival.

PMID- 10395807
TI  - Chromosomal localization of the loci responsible for dystrophic cardiac
      calcinosis in DBA/2 mice.
AB  - Dystrophic cardiac calcinosis (DCC) occurs in certain inbred strains of mice,
      including DBA/2 and C3H/He, and is generally found as an incidental lesion in
      adult animals at necropsy. Preliminary genetic studies into the cause of DCC have
      been performed in DBA/2 mice and suggest that DCC is inherited as an autosomal
      recessive trait involving three or four unlinked genes. To investigate the
      genetics of DCC further, we produced myocardial cell death by freeze-thaw injury
      to induce DCC. Experiments were conducted with three F1 hybrids made using three
      inbred strains of mice (DBA/2J and C3H/HeJ, DCC-susceptible strains; C57BL/6J,
      DCC-resistant strain) to compare the genetic factors in the development of DCC.
      We found that DBA/2 and C3H/He mice share the same gene pattern(s) that is
      responsible for DCC. We determined by backcross linkage analysis in DBA/2 and
      C57BL/6 mice that at least one recessive locus is responsible for DCC. A
      haplotype analysis of the backcross data demonstrated that the recessive locus,
      designated dyscalc1, is located on Chromosome 7, 20.5 cM distal to the
      centromere. The likely candidate genes for dyscalc1 are discussed. Further
      understanding of the structure and function of these mutant genes will be
      beneficial in explaining the molecular pathogenesis of DCC.

PMID- 10395808
TI  - PHTF, a novel atypical homeobox gene on chromosome 1p13, is evolutionarily
      conserved.

PMID- 10395809
TI  - Localization of the human homologue of the Drosophila dachshund gene (DACH) to
      chromosome 13q21.

PMID- 10395810
TI  - A model for dictyostelium slug movement 
AB  - Dictyostelium slug movement results from the coordinated movement of its
      10(5)constituent cells. We have shown experimentally that cells in the tip of the
      slug show a rotational cell movement while the cells in the back of the slug move
      periodically forward (Siegert & Weijer, 1992). We have put forward the hypothesis
      that cell movement in slugs is controlled by chemotaxis to scroll waves generated
      in the tip which convert to twisted scroll or planar waves in the back of the
      slug (Bretschneider et al., 1995). The coordinated movement of all individual
      cells in response to these waves could then result in forward movement of the
      slug. We now test this hypothesis by extending our model for mound formation
      (Bretschneider et al., 1997) to include two cell types with different signalling
      and movement properties. All cells are able to relay cAMP and move
      chemotactically in response to cAMP gradients. Cells interact by adhesion,
      pressure and friction with neighbouring cells and the extracellular matrix. The
      model can generate stable scroll waves propagating from the tip to the back of a
      slug which coordinate forward cell movement and result in slug migration. We use
      the model to investigate the influence of cell type specific differences in
      excitability, adhesion and cell interactions on slug motion. Copyright 1999
      Academic Press.

PMID- 10395811
TI  - Aspects of fluid dynamics applied to the larger arteries.
AB  - A review is given of some of the ideas from fluid mechanics which are considered
      essential background for researchers in cardiovascular flows. The paper links the
      topics discussed at a fundamental level with real problems which, in the
      experience of the author, occur in research. In particular, approximate equations
      governing the principal phenomena, and which help with understanding, are
      introduced. A description is given of the equations of motion and the
      significance of similarity parameters is discussed: it is shown how Reynolds
      number and the Womersley parameter arise from dimensionless forms of the
      equations. Steady flow equations and approximations are commented on, including
      illustrations of their use. Unsteady flow phenomena are introduced and it is
      shown how Stokes' first and second problems illustrate key aspects of unsteady
      viscous diffusion and boundary layers in the circulation. Important features of
      pulsatile pipe flow, as analysed by both Uchida and Womersley, are discussed and
      linked to Stokes' two-dimensional results. Entrance effects in steady and
      unsteady pipe flow are compared and contrasted. Other phenomena discussed include
      the effects of bends in vessels, transition to turbulence and the different time
      scales associated with unsteady flows. Computational methods, which are assuming
      increasing importance in biological fluid mechanics, also receive a brief
      description. Finally, comments are made on pressure and other measurements and
      the need for an understanding of various fluid flow phenomena when planning
      measurements and interpreting the resulting data.

PMID- 10395812
TI  - Stabilizing function of skeletal muscles: an analytical investigation.
AB  - Stability is the ability of a system to return to its original state after a
      disturbance. Taking vertical oscillations of the centre of mass of a human
      bending his legs as an example we prove that the intrinsic mechanical properties
      of musculature can stabilize the oscillatory movement (preflex) without reflexive
      changes in activation. The human is represented by a model consisting of a
      massless two-segment linkage system (knee) topped by a point mass. Conditions for
      stability are calculated analytically based on the theory of Ljapunov and the
      results are illustrated by numerical examples. In order to guarantee a self
      stabilizing ability of the muscle-skeletal system, the muscle properties such as
      force-length relationship, force-velocity relationship and the muscle geometry
      must be tuned to the geometric properties of the linkage system.

PMID- 10395813
TI  - The physical basis of transparency in biological tissue: ultrastructure and the
      minimization of light scattering 
AB  - In the open ocean, many animals are highly transparent, some achieving near
      invisibility. However, little is known about how this transparency is attained.
      The effects of cellular ultrastructure on tissue transparency were mathematically
      modeled. Given a specific constant volume or surface area of a higher refractive
      index material (e.g. protein, lipid, etc.), within a lower refractive index
      cytoplasm or other matrix, the model calculates the total amount of light
      scattered as a function of how the volume or surface area is subdivided. Given a
      constant volume, the scattering peaks strongly when the volume is divided into
      spheres of critical radii. The critical radii depend upon the refractive index of
      the material relative to its surroundings. Similarly, given a constant surface
      area, the scattering increases rapidly with sphere size until critical radii
      (approximating the critical radii for constant volume) are reached, after which
      the scattering is relatively constant. Under both constraints, refractive index
      is critical when the particles are small, but becomes progressively less
      important as particle size increases. When only forward scattering is considered,
      the results are essentially similar to those found for total scattering. When
      scattering at only larger angles is considered, the critical radii are
      independent of refractive index, and the scattered radiance depends critically on
      refractive index at all particle sizes. The effects of particle shape on
      scattering depend on the geometric constraint and particle size. Under constant
      volume constraints, small particles of any shape scatter light equally, but large
      spheres scatter less light than other larger shapes. Under constant surface area
      constraints, small spheres scatter more light than any small shape, but large
      particles of any shape scatter equally. The effects of crowding and the
      refractive index of the surrounding medium on these predictions are discussed.
      Copyright 1999 Academic Press.

PMID- 10395814
TI  - A model for circular dichroism monitored dimerization and calcium binding in an
      EF-hand synthetic peptide.
AB  - EF-hand peptides have been shown to bind calcium and dimerize to form an intact
      protein domain [Shaw, G.S., Hodges, R.S. & Sykes, B.D. (1990). Science, 249, 280
      283]. A synthetic 33-residue EF-hand peptide with the sequence of carp
      parvalbumin CD site demonstrated a seven-fold increase in the apparent calcium
      dissociation constant with a eight-fold decrease in peptide concentration when
      fit to a single-site calcium-binding model. This observation is consistent with
      EF-hand dimerization. This paper describes a method to determine the dimerization
      dissociation constant and the calcium dissociation constants for both the monomer
      and dimer forms of this EF-hand peptide using circular dichroism techniques. By
      monitoring the increase in negative molar ellipticity at 222 nm with increasing
      peptide concentration under calcium-saturating conditions the dimerization
      dissociation constant for the synthetic parvalbumin CD site was determined to be
      55.68+/-10.76 microM. Using the dimerization constant, the calcium dissociation
      constants for both the monomer and dimer forms of this peptide were determined by
      monitoring the change in ellipticity of peptide solutions on addition of
      increasing amounts of calcium. A fit of this data to a mathematical model that
      takes into account dimerization results in calcium dissociation constants of
      421.3+/-21.56 and 47.06+/-6.72 microM for the monomer and dimer forms,
      respectively.

PMID- 10395815
TI  - Attachment of the chromosome to the cell poles: the strategy for the growth of
      bacteria in two and three dimensions.
AB  - Bacteria such as Staphylococcus, Lampropedia, and Sarcina develop in
      characteristic two-or three-dimensional groups of cells. We propose here a model
      of how bacteria may generate such groupings by an extension of an earlier model
      for rod-shaped bacteria. No other mechanism for forming two- or three-dimensional
      structures of groups of cells has been proposed. Our earlier model for division
      of rod-shaped bacteria into nearly equal-sized daughters assumed that the origin
      and terminus DNA were attached at a critical time to polar wall sites. While such
      binding was speculative 20 years ago, it has now been established that the DNA
      for the origin of replication, at least during some part of the cell cycle is
      located in the pole for several different bacteria. Evidence is also building
      showing that the terminus DNA region is sometimes located at a position in the
      cell that will develop into two new poles. Here, a new extension of the concept
      that polar sites bind specifically origin and terminus DNA of the chromosome is
      presented that can explain how division takes place in one and then in another
      dimension to form two-dimensional tablets of four cells or large planar arrays. A
      further possible extension to three dimensions to generate octets of cells is
      proposed.

PMID- 10395816
TI  - Finishing the cell cycle.
AB  - The eukaryotic cell division cycle consists of two characteristic states: G1,
      when replication origins of chromosomes are in a pre-replicative state, and
      S/G2/M, when they are in a post-replicative state (Nasmyth, 1995). Using
      straightforward biochemical kinetics, we show that these two states can be
      created by antagonistic interactions between cyclin-dependent kinases (Cdk) and
      their foes: the cyclin-degradation machinery (APC) and a stoichiometric inhibitor
      (CKI). Irreversible transitions between these two self-maintaining steady states
      drive progress through the cell cycle: at "Start" a cell leaves the G1 state and
      commences chromosome replication, and at "Finish" the cell separates the products
      of replication to the incipient daughter cells and re-enters G1. We propose that
      a protein-phosphatase, by up-regulating the APC and by stabilizing the CKI, plays
      an essential role at Finish. The phosphatase acts in parallel pathways; hence,
      cells can leave mitosis in the absence of cyclin degradation or in the absence of
      the CKI.

PMID- 10395817
TI  - Processing of the N termini of nascent polypeptide chains requires deformylation
      prior to methionine removal.
AB  - N-formyl-methionine termini are formed in the initiation reaction of bacterial
      protein synthesis and processed during elongation of the nascent polypeptide
      chain. We report that the formyl group must be removed before the methionine
      residue can be cleaved by methionine aminopeptidase. This has long been
      implicitly assumed, but that assumption was based on inconclusive data and was in
      apparent conflict with more recently published data. We demonstrate that the
      Salmonella typhimurium methionine aminopeptidase is totally inactive on an N
      formyl-methionyl peptide in vitro, and present a detailed characterization of the
      substrate specificity of this key enzyme by use of a very sensitive and
      quantitative assay. Finally, a reporter protein expressed in a strain lacking
      peptide deformylase was shown to retain the formyl group confirming the
      physiological role of the deformylase.

PMID- 10395818
TI  - Mutational analysis of Phe160 within the "palm" subdomain of human
      immunodeficiency virus type 1 reverse transcriptase.
AB  - The highly conserved Phe160 residue is located in the "palm" subdomain of human
      immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), and makes
      contact with Tyr115, a residue which is involved in deoxynucleoside triphosphate
      (dNTP) binding and fidelity of DNA synthesis. Five mutant RTs having Tyr, Trp,
      Ile, Ala or Gln instead of Phe160 were obtained by site-directed mutagenesis.
      F160Y and F160W retained substantial DNA polymerase activity, whereas the
      catalytic efficiency of nucleotide incorporation of mutants F160I, F160A and
      F160Q was less than 10 % that of the wild-type RT, using poly(rA).oligo(dT)20 as
      the template-primer. The low catalytic efficiency of mutants F160I, F160A and
      F160Q was due to their lower affinity for the dNTP substrate. F160Y displayed
      similar kinetic parameters as the wild-type RT in nucleotide insertion assays
      carried out with heteropolymeric DNA/DNA template-primers. However, nucleotide
      affinity was two- to sixfold reduced in the case of mutant F160W. Fidelity assays
      revealed similar misinsertion and mispair extension ratios for the three enzymes,
      although F160W showed a slightly higher accuracy of DNA synthesis, particularly
      in the presence of high concentrations of dNTP. When introduced in an infectious
      proviral clone, mutations F160I, F160A and F160Q rendered non-viable virus. The
      importance of Phe160 for polymerase function and viral replication could be
      mediated by its interaction with Tyr115, as suggested by the analysis of the
      available crystal structures of HIV-1 RT.

PMID- 10395819
TI  - The F plasmid centromere, sopC, is required for full repression of the sopAB
      operon.
AB  - The SopB protein of the F plasmid has a dual role in the partition of F plasmid
      copies to daughter cells prior to division. It binds to the sopC centromere site
      to form the partition complex needed for stabilizing the plasmid, and it
      interacts with SopA to repress transcription of the sopAB operon, thus preventing
      the destabilization that results from excess SopB. We have isolated sop mutants
      by screening for unstable inheritance of mutagenized mini-F DNA. Four of the
      mutants resulted from different missense mutations in sopB. All four were
      deficient, to varying degrees, in autoregulation of Sop protein synthesis. The
      mutant proteins showed diminished capacity for reducing the linking number of
      mini-F and for destabilizing a plasmid carrying sopC, indicating that reduced
      ability to form a normal complex with sopC might underlie the autoregulation
      defect. Repression of the transcription of a sop promoter- lacZ fusion by SopA
      and SopB was strongly enhanced in the presence of sopC, in cis or in trans, and
      the enhancement was reduced or nullified when wild-type sopB was replaced by the
      mutant sopB alleles. A single 43 bp unit of sopC was almost as effective as sopC
      itself in enhancing repression. The results show that sopC is necessary for full
      repression of the sop promoter. They thus indicate a previously unsuspected role
      for this centromere site, and suggest that autoregulation and partition might
      normally be coordinated processes.

PMID- 10395820
TI  - Initiation of DNA replication in a eukaryotic rolling-circle replicon:
      identification of multiple DNA-protein complexes at the geminivirus origin.
AB  - The mechanism of initiation of DNA replication in eukaryotic rolling- circle
      replicons is still poorly understood in molecular terms. Geminiviruses, a family
      of plant DNA viruses, which use this strategy during part of their replicative
      cycle, replicate in the nucleus and are amenable to molecular studies. Except for
      the virally encoded initiator protein (Rep), geminivirus DNA replication relies
      on cellular factors, likely interfering with cell cycle regulation of the
      infected cell. Here, we report the identification of three distinct DNA-protein
      complexes of the DNA replication initiator protein encoded by wheat dwarf
      geminivirus (WDV) within viral regulatory sequences controlling DNA replication
      and transcription. We have mapped the WDV Rep binding sites by combining gel
      shift assays, electron microscopy and DNase I footprinting. Two of the Rep-DNA
      complexes (C and the V) are high-affinity complexes, located in the proximity of
      the two divergent TATA boxes, at 150 and 90 bp, respectively, from the DNA
      replication initiation site. The third one, the O-complex, is a low-affinity
      complex, which can assemble under conditions supporting the DNA cleavage
      reaction. This suggests that it might be responsible for initiation of rolling
      circle DNA replication in WDV and other members of the Mastrevirus genus.

PMID- 10395821
TI  - Dimerisation mutants of Lac repressor. I. A monomeric mutant, L251A, that binds
      Lac operator DNA as a dimer.
AB  - Dimer formation between monomers of the Escherichia coli Lac repressor is
      substantially specificed by the interactions between three alpha-helices in each
      monomer which form a hydrophobic interface. As a first step in analysing the
      specificity of this interaction, we examined the mutant L251A. LacR bearing this
      mutation in a background lacking the C-terminal heptad repeats is completely
      incapable of forming dimers in solution, with a dimer-monomer equilibrium
      dissociation constant, or Kd, higher than 10(-5)M. This correlates with a 200
      fold decrease in its ability to repress the lac operon in vivo compared to
      dimeric LacR. Surprisingly, the mutant is still capable of forming dimers upon
      binding to short operator DNA in vitro. Analysis of the kinetic parameters of
      binding of the mutant to operator DNA reveals a 2000 to 3000-fold increase in the
      equilibrium dissociation constant (Kd) of the mutant-DNA complex in comparison to
      dimeric LacR-operator complexes, with the change almost entirely due to a greater
      than 1000-fold decrease in association rate. The dissociation rate varies only by
      a factor of about two, in comparison to dimeric LacR. This change reflects a
      kinetic pathway in which dimer formation, in solution or on DNA, is the rate
      limiting step. These findings have implications for the specificity and stability
      of the protein-protein interface in question.

PMID- 10395822
TI  - In vitro repair of synthetic ionizing radiation-induced multiply damaged DNA
      sites.
AB  - When ionizing radiation traverses a DNA molecule, a combination of two or more
      base damages, sites of base loss or single strand breaks can be produced within 1
      4 nm on opposite DNA strands, forming a multiply damaged site (MDS). In this
      study, we reconstituted the base excision repair system to examine the processing
      of a simple MDS containing the base damage, 8-oxoguanine (8-oxoG), or an abasic
      (AP) site, situated in close opposition to a single strand break, and asked if a
      double strand break could be formed. The single strand break, a nucleotide gap
      containing 3' and 5' phosphate groups, was positioned one, three or six
      nucleotides 5' or 3' to the damage in the complementary DNA strand. Escherichia
      coli formamidopyrimidine DNA glycosylase (Fpg), which recognizes both 8-oxoG and
      AP sites, was able to cleave the 8-oxoG or AP site-containing strand when the
      strand break was positioned three or six nucleotides away 5' or 3' on the
      opposing strand. When the strand break was positioned one nucleotide away, the
      target lesion was a poor substrate for Fpg. Binding studies using a reduced AP
      (rAP) site in the strand opposite the gap, indicated that Fpg binding was greatly
      inhibited when the gap was one nucleotide 5' or 3' to the rAP site. To complete
      the repair of the MDS containing 8-oxoG opposite a single strand break,
      endonuclease IV DNA polymerase I and Escherichia coli DNA ligase are required to
      remove 3' phosphate termini, insert the "missing" nucleotide, and ligate the
      nicks, respectively. In the absence of Fpg, repair of the single strand break by
      endonuclease IV, DNA polymerase I and DNA ligase occurred and was not greatly
      affected by the 8-oxoG on the opposite strand. However, the DNA strand containing
      the single strand break was not ligated if Fpg was present and removed the
      opposing 8-oxoG. Examination of the complete repair reaction products from this
      reaction following electrophoresis through a non-denaturing gel, indicated that a
      double strand break was produced. Repair of the single strand break did occur in
      the presence of Fpg if the gap was one nucleotide away. Hence, in the in vitro
      reconstituted system, repair of the MDS did not occur prior to cleavage of the 8
      oxoG by Fpg if the opposing single strand break was situated three or six
      nucleotides away, converting these otherwise repairable lesions into a
      potentially lethal double strand break.

PMID- 10395823
TI  - An antibody single-domain phage display library of a native heavy chain variable
      region: isolation of functional single-domain VH molecules with a unique
      interface.
AB  - To develop very small antibody-derived recognition units for experimental,
      medical, and drug design purposes, a heavy chain variable region (VH) single
      domain phage-display library was designed and constructed. The scaffold that was
      used for library construction was a native sequence of a monoclonal antibody with
      a unique VH/VL interface. There was no need to modify any residues in the VL
      interface to avoid non-specific binding of VH domain. The library repertoire,
      consisting of 4x10(8)independent clones, was generated by the randomization of
      nine amino acid residues in complementary determining region 3. The library was
      screened by binding to protein antigens, and individual clones were isolated. The
      VH genes encoding for specific binding clones were rescued and large amounts of
      soluble and stable single-domain VH protein were made from insoluble inclusion
      bodies by in vitro refolding and purification. Biochemical and biophysical
      characterization of the VH protein revealed a highly specific, correctly folded,
      and stable monomeric molecule. Binding studies demonstrated an affinity of 20 nM.
      The properties of these molecules make them attractive for clinical, industrial,
      and research applications, as well as a step toward improvement in the design of
      small molecules that are based on the hypervariable loops of antibodies.

PMID- 10395824
TI  - Structure, dynamics and hydration of the nogalamycin-d(ATGCAT)2Complex determined
      by NMR and molecular dynamics simulations in solution.
AB  - The structure of the 1:1 nogalamycin:d(ATGCAT)2 complex has been determined in
      solution from high-resolution NMR data and restrained molecular dynamics (rMD)
      simulations using an explicit solvation model. The antibiotic intercalates at the
      5'-TpG step with the nogalose lying along the minor groove towards the centre of
      the duplex. Many drug-DNA nuclear Overhauser enhancements (NOEs) in the minor
      groove are indicative of hydrophobic interactions over the TGCA sequence. Steric
      occlusion prevents a second nogalamycin molecule from binding at the symmetry
      related 5'-CpA site, leading to the conclusion that the observed binding
      orientation in this complex is the preferred orientation free of the complication
      of end-effects (drug molecules occupy terminal intercalation sites in all X-ray
      structures) or steric interactions between drug molecules (other NMR structures
      have two drug molecules bound in close proximity), as previously suggested.
      Fluctuations in key structural parameters such as rise, helical twist, slide,
      shift, buckle and sugar pucker have been examined from an analysis of the final
      500 ps of a 1 ns rMD simulation, and reveal that many sequence-dependent
      structural features previously identified by comparison of different X-ray
      structures lie within the range of dynamic fluctuations observed in the MD
      simulations. Water density calculations on MD simulation data reveal a time
      averaged pattern of hydration in both the major and minor groove, in good
      agreement with the extensive hydration observed in two related X-ray structures
      in which nogalamycin is bound at terminal 5'-TpG sites. However, the pattern of
      hydration determined from the sign and magnitude of NOE and ROE cross-peaks to
      water identified in 2D NOESY and ROESY experiments identifies only a few "bound"
      water molecules with long residence times. These solvate the charged
      bicycloaminoglucose sugar ring, suggesting an important role for water molecules
      in mediating drug-DNA electrostatic interactions within the major groove. The
      high density of water molecules found in the minor groove in X-ray structures and
      MD simulations is found to be associated with only weakly bound solvent in
      solution.

PMID- 10395826
TI  - Conformational multiplicity of the antibody combining site of a monoclonal
      antibody specific for a (6-4) photoproduct.
AB  - The antigen binding site of monoclonal antibody 64M5, which possesses a high
      degree of affinity for DNA containing pyrimidine (6-4) pyrimidone photoproducts,
      were investigated by use of stable-isotope-assisted NMR spectroscopy. A variety
      of 64M5 Fab fragments specifically labeled with 13C and 15N at backbone amide
      groups were prepared. Extensive assignments of amide resonances originating from
      the variable region of 64M5 were made by using 2D-HN(CO) measurements along with
      recombination of the heavy and light chains of 64M5. On the basis of chemical
      shift changes of the amide resonances caused upon addition of d(T[6-4]T) and
      d(GTAT[6-4]TATG), the binding sites of 64M5 Fab for the (6-4) photodimer and for
      the oligodeoxynucleotides flanking it were identified. It was revealed that the
      L1 and L3 segments, which are responsible for the binding to (6-4) photodimer,
      exhibit conformational multiplicities in the absence of antigens, and take
      different conformations between the d(T[6-4]T) and d(GTAT[6-4]TATG)-bound forms.
      On the basis of spectral comparison with another Fab fragment with a similarity
      in the amino acid sequence of the VL domain of 64M5, we suggest that the
      conformational multiplicities observed in the present study is caused by a
      substitution of an amino acid residue at the position of a key residue in L3
      canonical structure, which leads to a preferable effect on the antigen binding,
      and by a specific combination of L1 and L3 canonical structures.

PMID- 10395827
TI  - Structural predictions of AgfA, the insoluble fimbrial subunit of Salmonella thin
      aggregative fimbriae.
AB  - The unusually stable and multifunctional, thin aggregative fimbriae common to all
      Salmonella spp. are principally polymers of the fimbrin subunit, AgfA. AgfA of
      Salmonella enteritidis consists of two domains: a protease-sensitive, 22 amino
      acid residue N-terminal region and a protease-resistant, 109 residue C-terminal
      core. The unusual amino acid sequence of the AgfA core region comprises two-,
      five- and tenfold internal sequence homology patterns reflected in five
      conserved, 18-residue tandem repeats. These repeats have the consensus sequence,
      Sx5QxGx2NxAx3Q and are linked together by four or five residues, (x)xAx2. The
      predicted secondary structure for this unusual arrangement of tandem repeats in
      AgfA indicates mainly extended conformation with the beta strands linked by four
      to six residues. Candidate proteins of known structure with motifs of alternating
      beta strands and short loops were selected from folds described in SCOP as a
      source of coordinates for AgfA model construction. Three all-beta class motifs
      selected from the Serratia marcescens metalloprotease, myelin P2 protein or
      vitelline membrane outer protein I were used for initial AgfA homology build-up
      procedures ultimately resulting in three structural models; beta barrel, beta
      prism and parallel beta helix. The beta barrel model is a compact, albeit
      irregular structure, with the beta strands arranged in two antiparallel beta
      sheet faces. The beta prism model does not reflect the 5 or 10-fold symmetry of
      the AgfA primary sequence. However, the favored, parallel beta helix model is a
      compact coil of ten helically arranged beta strands forming two parallel beta
      sheet faces. This arrangement predicts a regular, potentially stable, C-terminal
      core region consistent with the observed tandem repeat sequences, protease
      resistance and strong tendency of this fimbrin to oligomerize and aggregate.
      Positional conservation of amino acid residues in AgfA and the Escherichia coli
      AgfA homologue, CsgA, provides strong support for this model. The parallel beta
      helix model of AgfA offers an interesting solution to a multifunctional fimbrin
      molecular surface having solvent exposed areas, regions for major and minor
      subunit interactions as well as fiber-fiber interactions common to many bacterial
      fimbriae.

PMID- 10395825
TI  - Molecular and cellular analysis of Grb2 SH3 domain mutants: interaction with Sos
      and dynamin.
AB  - Quantitative analysis of Grb2/dynamin interaction through plasmon resonance
      analysis (BIAcore) using Grb2 mutants showed that the high affinity measured
      between Grb2 and dynamin is essentially mediated by the N-SH3 domain of Grb2. In
      order to study the interactions between Grb2 and either dynamin or Sos in more
      detail, Grb2 N-SH3 domains containing different mutations have been analysed. Two
      mutations were located on the hydrophobic platform binding proline-rich peptides
      (Y7V and P49L) and one (E40T) located in a region that we had previously shown to
      be essential for Grb2/dynamin interactions. Through NMR analysis, we have clearly
      demonstrated that the structure of the P49L mutant is not folded, while the other
      E40T and Y7V mutants adopt folded structures that are quite similar to that
      described for the reference domain. Nevertheless, these point mutations were
      shown to alter the overall stability of these domains by inducing an equilibrium
      between a folded and an unfolded form. The complex formed between the peptide
      VPPPVPPRRR, derived from Sos, and the E40T mutant was shown to have the same 3D
      structure as that described for the wild-type SH3 domain. However, the VPPPVPPRRR
      peptide adopts a slightly different orientation when it is complexed with the Y7V
      mutant. Finally, the affinity of the proline-rich peptide GPPPQVPSRPNR, derived
      from dynamin, for the Grb2 N-SH3 domain was too low to be analyzed by NMR. Thus,
      the interaction between either Sos or dynamin and the SH3 mutants were tested on
      a cellular homogenate by means of a far-Western blot analysis. In these
      conditions, the P49L mutant was shown to be devoid of affinity for Sos as well as
      for dynamin. The Y7V SH3 mutant displayed a decrease of affinity for both Sos and
      dynamin, while the E40T mutant exhibited a decrease of affinity only for dynamin.
      These results support the existence of two binding sites between dynamin and the
      Grb2 N-SH3 domain.

PMID- 10395828
TI  - Protein threading by recursive dynamic programming.
AB  - We present the recursive dynamic programming (RDP) method for the threading
      approach to three-dimensional protein structure prediction. RDP is based on the
      divide-and-conquer paradigm and maps the protein sequence whose backbone
      structure is to be found (the protein target) onto the known backbone structure
      of a model protein (the protein template) in a stepwise fashion, a technique that
      is similar to computing local alignments but utilising different cost functions.
      We begin by mapping parts of the target onto the template that show statistically
      significant similarity with the template sequence. After mapping, the template
      structure is modified in order to account for the mapped target residues. Then
      significant similarities between the yet unmapped parts of the target and the
      modified template are searched, and the resulting segments of the target are
      mapped onto the template. This recursive process of identifying segments in the
      target to be mapped onto the template and modifying the template is continued
      until no significant similarities between the remaining parts of target and
      template are found. Those parts which are left unmapped by the procedure are
      interpreted as gaps. The RDP method is robust in the sense that different local
      alignment methods can be used, several alternatives of mapping parts of the
      target onto the template can be handled and compared in the process, and the cost
      functions can be dynamically adapted to biological needs. Our computer
      experiments show that the RDP procedure is efficient and effective. We can thread
      a typical protein sequence against a database of 887 template domains in about 12
      hours even on a low-cost workstation (SUN Ultra 5). In statistical evaluations on
      databases of known protein structures, RDP significantly outperforms competing
      methods. RDP has been especially valuable in providing accurate alignments for
      modeling active sites of proteins.RDP is part of the ToPLign system (GMD Toolbox
      for protein alignment) and can be accessed via the WWW independently or in
      concert with other ToPLign tools at http://cartan.gmd.de/ToPLign.html.

PMID- 10395829
TI  - Characterisation of the dominant oxidative folding intermediate of hen lysozyme.
AB  - Reduced denatured lysozyme has been oxidised and refolded at pH values close to
      neutral in an efficient way by dilution from buffers containing 8.0 M urea, and
      refolding intermediates were separated by reverse-phase HPLC at pH 2. By using
      peptic digestion in combination with high-resolution Fourier transform ion
      cyclotron resonance (FT-ICR) mass spectrometry (MS) and tandem MS/MS the dominant
      intermediate was identified to be des-[76-94]. This species has three of the four
      native disulphide bonds, but lacks the Cys76-Cys94 disulphide bond which connects
      the two folding domains in the native protein. Characterisation of des-[76-94] by
      2D1H NMR shows that it has a highly native-like structure. This provides an
      explanation for the accumulation of this species during refolding as direct
      oxidation to the fully native protein will be restricted by the burial of Cys94
      in the protein interior.

PMID- 10395830
TI  - Role of the salt-bridge between switch-1 and switch-2 of Dictyostelium myosin.
AB  - Motifs N2 and N3, also referred to as switch-1 and switch-2, form part of the
      active site of molecular motors such as myosins and kinesins. In the case of
      myosin, N3 is thought to act as a gamma-phosphate sensor and moves almost 6 A
      relative to N2 during the catalysed turnover of ATP, opening and closing the
      active site surrounding the gamma-phosphate. The closed form seems to be
      necessary for hydrolysis and is stabilised by the formation of a salt-bridge
      between an arginine residue in N2 and a glutamate residue in N3. We examined the
      role of this salt-bridge in Dictyostelium discoideum myosin. Myosin motor domains
      with mutations E459R or R238E, that block salt-bridge formation, show defects in
      nucleotide-binding, reduced rates of ATP hydrolysis and a tenfold reduction in
      actin affinity. Inversion of the salt-bridge in double-mutant M765-IS eliminates
      most of the defects observed for the single mutants. With the exception of a
      2,500-fold higher KMvalue for ATP, the double-mutant displayed enzymatic and
      functional properties very similar to those of the wild-type protein. Our results
      reveal that, independent of its orientation, the salt-bridge is required to
      support efficient ATP hydrolysis, normal communication between different
      functional regions of the myosin head, and motor function.

PMID- 10395832
TI  - Surgery in limited stage small cell lung cancer.
AB  - The role of surgery in small cell lung cancer (SCLC) is controversial. Surgery
      has several potential advantages because it may reduce the frequency of local
      relapses, it does not impede the intensity of chemotherapy, it does not affect
      the bone marrow, and surgical staging may be of prognostic significance. Several
      smaller retrospective studies which focus on surgery alone, surgery with adjuvant
      chemotherapy or radiotherapy, or chemotherapy followed by adjuvant surgery have
      been reported. Five-year survival data have ranged from 10-50% according to
      stage, both T-status and nodal status appearing to be significant prognostic
      factors. Only one prospective randomized trial has been reported concerning the
      addition of surgery to chemotherapy alone. This trial does not favour surgery.
      The reason for this could be a selection bias in the smaller non-randomized
      studies or a result of stage migration. Nevertheless, surgery may yet play an
      important role in SCLC, especially in diagnosis and staging, and with new
      improved non-invasive staging procedures, such as positron emission tomography,
      resection may lead to cure in selected patients. Prospective randomized studies
      are needed to settle this issue.

PMID- 10395831
TI  - Experimental study of the protein folding landscape: unfolding reactions in
      cytochrome c.
AB  - Hydrogen exchange results for cytochrome c have been interpreted in terms of
      transient hydrogen bond-breaking reactions that include large unfolding reactions
      and small fluctuational distortions. The differential sensitivity of these
      opening reactions to denaturant, temperature, and protein stability makes it
      possible to distinguish the different opening reactions and to characterize their
      structural and thermodynamic parameters. The partially unfolded forms (PUFs)
      observed are few and discrete, evidently because they are produced by the
      reversible unfolding of the protein's several intrinsically cooperative secondary
      structural elements. The PUFs are robust, evidently because the structural
      elements do not change over a wide range of conditions. The discrete nature of
      the PUFs and their small number is as expected for classical folding
      intermediates but not for theoretically derived folding models apparently because
      the simplified non-protein models usually analyzed in theoretical studies
      encompass only a single cooperative unit rather than multiple separable units.

PMID- 10395833
TI  - Interleukin 2 (IL-2) therapy: potential advantages of locoregional versus
      systemic administration.
AB  - There has been an apparent discrepancy between the results obtained with IL-2
      based immunotherapy in animal tumour models, including veterinary cancer
      patients, and human cancer patients. We argue that this is due to differences in
      the therapeutic regimens used to treat human and veterinary cancer patients. The
      main differences are systemic therapy and surgical removal of the primary tumour
      in case of human cancer patients, whereas these treatment modalities are not used
      in IL-2 treated veterinary cancer cases. We have developed a treatment protocol,
      in which IL-2 is applied locally, that has been successful against transplanted
      tumours as well as spontaneous tumours of varying origin and immunogenicity. In
      view of immunobiological considerations we conclude that local treatment of
      cancer with IL-2 makes more sense than systemic treatment, as usually applied in
      the clinic, and that surgical removal of tumours may be detrimental to successful
      IL-2 therapy.

PMID- 10395834
TI  - Clinical pharmacology of anticancer agents in relation to formulations and
      administration routes.
AB  - In the past years, alternative administration routes and pharmaceutical
      formulations of anticancer agents have been investigated in order to improve
      conventional chemotherapy treatment. The impact of these adjustments on the
      pharmacokinetics and pharmacodynamics is discussed. A review of the literature
      shows many examples of alternative administration forms of anticancer agents with
      improved pharmacokinetics. Local administration routes have been investigated in
      order to reduce the systemic toxicity and to enhance the local efficacy of
      conventional chemotherapy. Oral administration of anticancer agents is preferred
      by patients for its convenience and its potential for outpatient treatment. In
      addition, oral administration facilitates a prolonged exposure to the cytotoxic
      agent. However, poor bioavailability and substantial interpatient variability are
      noted as limitations for oral chemotherapy. Increased tumour selectivity can also
      be achieved by the use of specific pharmaceutical formulations, such as liposomes
      and macromolecular drug conjugates. The composition of these formulations often
      determine the pharmacokinetic behaviour of the formulated drug. In conclusion,
      several alternative administration forms of anticancer agents have been designed
      in the past years, with the potential for improvement of conventional
      chemotherapy, however, more extensive clinical evaluation of these novel
      strategies is warranted to prove their real clinical value.

PMID- 10395835
TI  - Leptomeningeal carcinomatosis.
AB  - Leptomeningeal carcinomatosis occurs in approximately 5% of patients with cancer.
      This disorder is being diagnosed with increasing frequency as patients live
      longer and as neuro-imaging studies improve. The most common cancers to involve
      the leptomeninges are breast cancer, lung cancer, and melanomas. Tumour cells
      reach the leptominges by hematogenous spread or by direct extension from pre
      existing lesions and are then disseminated throughout the neuroaxis by the flow
      of the cerebrospinal fluid. Patients present with signs and symptoms from injury
      to nerves that traverse the subarachnoid space, direct tumour invasion into the
      brain or spinal cord, alterations in blood supply to the nervous system,
      obstruction of normal cerebrospinal fluid (CSF) flow pathways, or general
      interference with brain function. The diagnosis is most commonly made by lumbar
      puncture although the CSF cytology is persistently negative in about 10% of
      patients with leptomeningeal carcinomatosis. Radiologic studies may reveal
      subarachnoid masses, diffuse contrast enhancement of the meninges, or
      hydrocephalus without a mass lesion. Without treatment, the median survival of
      patients with this disorder is 4-6 weeks and death occurs from progressive
      neurologic dysfunction. Early diagnosis and therapy is critical to preserving
      neurologic function. Radiation therapy to symptomatic sites and disease visible
      on neuroimaging studies and intrathecal chemotherapy increases the median
      survival to 3-6 months. The major favorable prognostic factors include excellent
      performance status, absence of serious fixed neurologic deficits, normal CSF flow
      scans, and absent or responsive systemic tumour. Aggressive therapy for this
      disorder is often accompanied by a necrotizing leukoencephalopathy which becomes
      symptomatic months after treatment with radiation and intrathecal methotrexate.
      As currently available therapies are toxic and provide limited benefits, novel
      approaches are being studied. Further information on the mechanisms of
      neurotoxicity from antineoplastic agents is critical to providing better outcomes
      for this increasing common complication of cancer.

PMID- 10395836
TI  - Cytomegalovirus (CMV)-specific T cell immunity after renal transplantation
      mediates protection from CMV disease by limiting the systemic virus load.
AB  - The role of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTLs) and T
      helper cells (Th) in controlling CMV infection, as detected by antigenemia assay
      and polymerase chain reaction (PCR) in blood leukocytes, and CMV disease was
      investigated in 20 renal transplant recipients. Within 3 months after transplant,
      CMV-specific CTL and Th responses were demonstrable in 11 (55%) and 15 (75%)
      patients, respectively; CMV infection was detected by antigenemia and PCR in 19
      (95%) patients each. During the month of first CMV detection, there was an
      inverse correlation between CTL response and antigenemia at >/=20 positive
      cells/105 leukocytes (P=.007) but no association with lower antigenemia levels or
      PCR positivity. CMV disease developed in 7 (35%) patients and was associated with
      high-level antigenemia but was inversely correlated with detection of CTLs
      (P=.04). After renal transplantation, CMV-specific CTLs limit the systemic virus
      load as reflected by antigenemia levels and thereby mediate protection from CMV
      disease.

PMID- 10395837
TI  - Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of
      influenza A and B virus infections.
AB  - The efficacy and safety of zanamivir, administered 2x or 4x daily over 5 days,
      was evaluated in the treatment of influenza infections. A total of 1256 patients
      entered the study; 57% of those randomized had laboratory-confirmed influenza
      infection. The primary end point, "alleviation of major symptoms," was created to
      evaluate differences in clinical impact. In the overall population with or
      without influenza infection, zanamivir reduced the median number of days to reach
      this end point by 1 day (P=.012 2x daily vs. placebo; P=.014 4x daily vs.
      placebo). The reduction was greater in patients treated within 30 h of symptom
      onset, febrile at study entry, and in defined high-risk groups. Zanamivir reduced
      nights of disturbed sleep, time to resumption of normal activities, and use of
      symptom relief medications. It was well tolerated. These results suggest that
      zanamivir can significantly reduce the duration and overall symptomatic effect of
      influenza.

PMID- 10395838
TI  - In vivo and in vitro induction of MxA protein in peripheral blood mononuclear
      cells from patients chronically infected with hepatitis C virus.
AB  - To test whether (HCV) persistence is related to interferon (IFN)
      hyporesponsiveness, peripheral blood monuclear cells from 29 patients and 11
      controls were studied for MxA protein expression. In vitro, only IFN-alpha
      (P<.001) and interleukin-2 (P<.05) induced MxA protein expression above
      unstimulated levels. Forty patients were treated with IFN-alpha2b. Patients
      showed higher basal levels of MxA protein (P<.02) and 2',5'-oligoadenylate
      synthase (2-5A) activity (P<.05) than controls. During therapy, MxA protein
      levels (P<.001) and 2-5A activity (P<.05) increased; after 1 month, MxA levels
      remained high, whereas 2-5A activity declined to initial levels. Increases in MxA
      were inversely correlated with decreases in serum alanine aminotransferase
      levels, and MxA induction was greater among virological responders. Thus, the IFN
      system seems to be activated in chronic HCV infection, but HCV appears to
      modulate these two components of the IFN system differentially. These results
      suggest that an inefficient response may contribute to virus persistence and
      affect the therapeutic outcome.

PMID- 10395840
TI  - Early and persistent human immunodeficiency virus type 1 (HIV-1)-specific T
      helper dysfunction in blood and lymph nodes following acute HIV-1 infection.
AB  - Without potent antiretroviral therapy, most human immunodeficiency virus type 1
      (HIV-1)-infected persons experience a progressive decline in CD4+ T cells and
      impairment in T helper function. It is unclear how soon after infection T cell
      dysfunction occurs. T helper responses were examined in blood and lymphoid tissue
      of 39 untreated patients with acute HIV-1 infection. Within the first 3 months,
      lymphoproliferative responses to mitogen, recall antigens, and HIV-1 antigens
      were impaired. After 6-9 months, responses to phytohemagglutinin and recall
      antigens improved. However, HIV-1-specific lymphoproliferation remained largely
      undetectable throughout 2 years of infection, and results were similar upon
      evaluation of lymphoid cells. Rare patients with HIV-1-specific responses had
      significantly lower plasma HIV-1 RNA levels than did nonresponders. These results
      indicate that T helper dysfunction occurs early after HIV-1 acquisition and that
      untreated individuals rarely recover HIV-specific helper responses; these
      findings lend support for early therapeutic intervention to prevent the
      destruction and further impairment of the T helper cells.

PMID- 10395839
TI  - Human monoclonal antibodies isolated from spontaneous Epstein-Barr virus
      transformed tumors of Hu-SPL-SCID mice and specific for fusion protein display
      broad neutralizing activity toward respiratory syncytial virus.
AB  - Two human monoclonal antibodies, RF-1 and RF-2, specifically recognize the fusion
      protein of the human respiratory syncytial virus (RSV). These were isolated from
      spontaneous tumors in SCID mice reconstituted with human splenocytes and boosted
      with fusion protein. The tumors consisted of Epstein-Barr virus-transformed human
      B cells in animals with antigen-specific antibody titers>105. The binding
      affinity of RF-1 and RF-2 to the fusion protein is 1010 and 109 M-1,
      respectively. The antibodies bind specifically to a conformational epitope of the
      fusion protein on RSV-infected HEp-2 cells. Both antibodies display virus
      neutralizing properties in vitro at concentrations varying between 8 and 1000
      ng/mL. Virus neutralization applies to a broad variety of wild and laboratory
      adapted virus strains belonging to both virus types A and B. These antibodies are
      potential candidates for passive immunotherapy of severe RSV infections.

PMID- 10395841
TI  - Identification of two distinct subsets of long-term nonprogressors with divergent
      viral activity by stromal-derived factor 1 chemokine gene polymorphism analysis.
AB  - Stromal-derived factor (SDF)-1, the natural ligand for CXCR4, is present in a
      common polymorphic variant defined by a G-->A transition in the 3' untranslated
      region of the gene. In persons infected with human immunodeficiency virus type 1
      (HIV-1), the homozygous genotype (SDF1-3'A/3'A) has been postulated to interfere
      with the appearance of T-tropic syncytium-inducing strains. The polymorphism of
      SDF1 was correlated with HIV-1 phenotype, plasma viremia, and unspliced and
      multiply spliced specific transcripts in 158 virologically characterized HIV-1
      infected patients (39 recent seroconverters, 75 typical progressors, and 44 AIDS
      patients) and in 42 HIV-1-infected long-term nonprogressors (LTNPs). Analysis of
      SDF1 allele distribution revealed that SDF1-3'A/3'A status is associated with low
      CD4 cell count (P=.0449) but not with a specific HIV-1 phenotype. In LTNPs, SDF1
      +/+ condition defined a subset of persons with lower HIV-1 replication than in
      heterozygous subjects. The low viral activity in SDF1-+/+ LTNPs suggests that
      other factors play a major role in vivo in determining the course of HIV-1
      infection.

PMID- 10395842
TI  - A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes
      given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte
      responses in seronegative volunteers.
AB  - Induction of CD8+ cytotoxic T cells is considered one of the important correlates
      for the protective efficacy of candidate human immunodeficiency virus type 1 (HIV
      1) vaccines. To induce CD8+ cytotoxic T lymphocytes (CTLs) along with
      neutralizing antibody and CD4+ T cell help, a live canarypox virus construct
      expressing gp120, transmembrane gp41, the gag and protease genes, and sequences
      containing CTL epitopes in nef and pol was given simultaneously with, or followed
      by, rgp120 SF2. CD8+ CTLs were detected in 61% of volunteers at some time during
      the trial. Three to 6 months after the last immunization, the gene-specific
      responses were gag, 26/81; env, 17/77; nef, 12/77; and pol, 3/16. Simultaneous
      immunization with the canarypox vector and the subunit, beginning with the
      initial immunization, resulted in earlier antibody responses. In summary, a
      strategy of immunization with a canarypox vector expressing multiple genes of HIV
      1 given with gp120 results in durable CD8+ CTL responses to a broad range of
      epitopes.

PMID- 10395844
TI  - Cerebrospinal fluid beta chemokine concentrations in neurocognitively impaired
      individuals infected with human immunodeficiency virus type 1.
AB  - Macrophages express the chemokine receptor CCR-5, a coreceptor for human
      immunodeficiency virus (HIV) entry. This receptor is ligated by beta chemokines,
      which influence HIV type 1 (HIV-1) replication in CCR-5-bearing cells in vitro
      and could influence the course of infection in the central nervous system.
      Cerebrospinal fluid (CSF) samples from 73 HIV-infected men were assayed for
      macrophage inflammatory protein-1 alpha (MIP-1alpha), MIP-1beta, and regulated
      upon activation, normal T cell expressed and secreted (RANTES). Distributions of
      all three were positively skewed. CSF chemokine concentrations were correlated
      with each other and were higher in demented patients. In a multivariate analysis,
      demented subjects were more likely to have detectable CSF MIP-1alpha, elevated
      CSF HIV RNA levels, and lower CD4+ cell counts. However, among those with
      detectable CSF MIP-1alpha, levels were lower in demented patients. CSF beta
      chemokine elevation is consistent with the macrophage activation known to occur
      in dementia and with studies of beta chemokine mRNA expression in the brain. Low,
      but detectable, levels of CSF MIP-1alpha were strongly associated with dementia,
      suggesting that higher levels may have neuroprotective effects.

PMID- 10395843
TI  - Consistent associations of HLA class I and II and transporter gene products with
      progression of human immunodeficiency virus type 1 infection in homosexual men.
AB  - Polymorphic products of genes in the HLA region contributing to variability in
      the course of human immunodeficiency virus type 1 (HIV-1) infection were
      identified by screening 375 Caucasian seroconverters who were aggregated from 3
      cohorts. AIDS-free time was related to numerous (15) class I alleles, alone or in
      conjunction with transporter protein variants, to homozygosity at the A or B
      locus, and to alleles of two class II haplotypes. A prognostic scoring algorithm
      derived from the 3 cohorts captured multiple HLA contributions to protection or
      to risk (relative hazard=0.57-60 per unit increase in score, all P<<.001). The
      impact of HLA was strong and appeared independent of the effects of chemokine
      receptor/ligand polymorphisms and antiretroviral treatment. The algorithm also
      predicted divergent rates of CD4+ cell decline in 2 other groups, totaling 227
      seropositive persons (P=.06 - <.001). Confirmation of these relationships should
      encourage investigation of HIV-1 antigen processing and presentation mediated by
      polymorphisms in the HLA region.

PMID- 10395845
TI  - Potent antiretroviral therapy of primary human immunodeficiency virus type 1 (HIV
      1) infection: partial normalization of T lymphocyte subsets and limited reduction
      of HIV-1 DNA despite clearance of plasma viremia.
AB  - Antiretroviral therapy commenced during primary human immunodeficiency virus type
      1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent
      early loss of HIV-specific CD4 lymphocyte function. We studied the effect of
      current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16
      patients with symptomatic PHI. In the 13 patients who completed 1 year of
      treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were
      comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed
      (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However,
      HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore,
      CD8 cell counts remained elevated, including activated (CD38+HLA-DR+),
      replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion,
      early antiretroviral therapy resulted in clearance of viremia and prevented loss
      of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8
      T lymphocyte turnover and activation indicate continued expression of viral
      antigens.

PMID- 10395846
TI  - Effect of circumcision on incidence of human immunodeficiency virus type 1 and
      other sexually transmitted diseases: a prospective cohort study of trucking
      company employees in Kenya.
AB  - To determine the effect of circumcision status on acquisition of human
      immunodeficiency virus (HIV) type 1 and other sexually transmitted diseases, a
      prospective cohort study of 746 HIV-1-seronegative trucking company employees was
      conducted in Mombasa, Kenya. During the course of follow-up, 43 men acquired HIV
      1 antibodies, yielding an annual incidence of 3.0%. The annual incidences of
      genital ulcers and urethritis were 4.2% and 15.5%, respectively. In multivariate
      analysis, after controlling for demographic and behavioral variables,
      uncircumcised status was an independent risk factor for HIV-1 infection (hazard
      rate ratio [HRR=4.0; 95% confidence interval [CI], 1.9-8.3) and genital ulcer
      disease (HRR=2.5; 95% CI, 1.1-5.3). Circumcision status had no effect on the
      acquisition of urethral infections and genital warts. In this prospective cohort
      of trucking company employees, uncircumcised status was associated with increased
      risk of HIV-1 infection and genital ulcer disease, and these effects remained
      after controlling for potential confounders.

PMID- 10395847
TI  - High rates of transmission of subtype E human immunodeficiency virus type 1 among
      heterosexual couples in Northern Thailand: role of sexually transmitted diseases
      and immune compromise.
AB  - The heterosexual transmission of subtype E human immunodeficiency virus type 1
      (HIV-1) infection was evaluated in 467 couples in Thailand in whom the man was
      HIV-1 positive and the woman had no risk factors for HIV other than sex with her
      infected partner. At baseline, 216 (46.3%) of the 467 women were positive for HIV
      1; prevalence of HIV among women was 52.2% when their male partners had CD4+
      lymphocyte counts of <200 cells/microL, 45.9% in women whose partners had counts
      of 200-499 micro/L, and 39.2% in women whose partners had counts of
      >/=500/microL. Women were twice as likely to be HIV positive if their partners
      had a history of a sexually transmitted disease (STD); however, their HIV
      prevalence was 29% among couples who had no STD history. It appears that female
      partners of men infected with subtype E HIV-1 are at high risk of infection even
      when the man's CD4+ cell count is relatively high. A high rate of STDs may
      contribute significantly to this risk [corrected].

PMID- 10395849
TI  - The ALBI trial: a randomized controlled trial comparing stavudine plus didanosine
      with zidovudine plus lamivudine and a regimen alternating both combinations in
      previously untreated patients infected with human immunodeficiency virus.
AB  - A total of 151 previously untreated patients infected with human immunodeficiency
      virus type 1 (HIV-1) with CD4 cell counts >/=200/microL and plasma HIV-1 RNA
      levels of 10,000-100,000 copies/mL were randomly assigned to 24 weeks of open
      labeled stavudine plus didanosine (group 1), zidovudine plus lamivudine (group
      2), or stavudine plus didanosine followed by zidovudine plus lamivudine (group
      3). The mean decrease in HIV-1 RNA level was greater in group 1 (2.26 log10
      copies/mL) than in groups 2 (1.26 log10 copies/mL) or 3 (1.58 log10 copies/mL;
      P<.0001). The mean increase in CD4 cell counts was greater in groups 1 (124
      cells/microL) and 3 (118 cells/microL) than in group 2 (62 cells/microL; P=.02).
      All regimens were generally well tolerated. The combination of stavudine plus
      didanosine reduced plasma HIV-1 RNA concentrations and increased CD4 cell counts
      more effectively than did the combination of zidovudine plus lamivudine or the
      regimen alternating both combinations.

PMID- 10395848
TI  - Lack of autologous neutralizing antibody to human immunodeficiency virus type 1
      (HIV-1) and macrophage tropism are associated with mother-to-infant transmission.
AB  - To investigate factors that affect mother-to-infant transmission of human
      immunodeficiency virus type 1 (HIV-1), autologous neutralizing antibody, viral
      load, and viral tropism were evaluated in 28 pregnant women infected with HIV-1,
      of whom 8 were transmitters and 20 nontransmitters. One (12%) of 8 transmitters
      versus 11 (55%) of 20 nontransmitters had autologous neutralizing antibody
      (P=.04). Plasma levels of HIV-1 RNA and infectious HIV-1 titers (mean+/-SD) in
      peripheral blood mononuclear cells (PBMC) at delivery did not differ
      significantly between transmitters and nontransmitters (24, 266+/-10,101 vs.
      31,589+/-9128 copies/mL and 29+/-12 vs. 42+/-17 infected cells per 106 PBMC,
      respectively). However, only transmitters (4 [50%] of 8) were HIV p24 antigen
      positive. The ability of HIV-1 strains to induce syncytium did not differ between
      groups (P=.6); however, only non-syncytium-inducing isolates were transmitted.
      Isolates from 4 (80%) of 5 transmitters versus 2 (18%) of 12 nontransmitters
      (P=.03) demonstrated increasing replication in macrophages. Thus, lack of
      autologous neutralizing antibody and increased replication in macrophages were
      significantly associated with mother-to-infant transmission. In addition,
      autologous neutralizing antibody was associated with reduced viral load.

PMID- 10395850
TI  - Changes in frequency of HIV-1-specific cytotoxic T cell precursors and
      circulating effectors after combination antiretroviral therapy in children.
AB  - Combination antiretroviral therapy has had a major role in reducing human
      immunodeficiency virus type 1 (HIV-1) plasma viral loads in HIV-1-infected adults
      but a variable effect in infants, in whom complete viral suppression appears to
      be less readily achieved. In adults, after the reduction in plasma viremia, there
      is a decrease in the numbers of circulating cytotoxic T cell (CTL) effectors and
      precursors in the majority of patients. This longitudinal study assessed the
      effect of combination drug therapy on the frequency of HIV-1-specific CTL
      responses in 8 HIV-1-infected children. Following treatment, the frequency of HIV
      1-specific CTL responses initially increased, especially in children with
      incomplete viral suppression but with increasing CD4+ cell counts. In children
      with complete viral suppression, the frequency of HIV-1-specific CTL responses
      decreased, suggesting that viral replication is required to maintain CTL
      responses in the systemic circulation.

PMID- 10395851
TI  - Atovaquone suspension compared with aerosolized pentamidine for prevention of
      Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects
      intolerant of trimethoprim or sulfonamides.
AB  - Atovaquone suspensions (750 mg and 1500 mg once a day) were compared with
      aerosolized pentamidine (300 mg once a month) for the prevention of Pneumocystis
      carinii pneumonia (PCP) in subjects with human immunodeficiency virus (HIV)
      infection who were intolerant to trimethoprim or sulfonamides (or both). Median
      time using the assigned therapy was 6.6 months, and the median follow-up was 11.3
      months. Intent-to-treat analyses (n=549) showed no statistically significant
      differences among subjects with regard to the incidence of PCP (26%, 22%, and
      17%, respectively) or mortality (20%, 13%, and 18%, respectively). The incidence
      of treatment-limiting adverse events with atovaquone was significantly higher
      (P<.01). There was, however, no significant difference in the time using therapy.
      Incidences of PCP and death were higher in subjects receiving 750 mg of
      atovaquone than in subjects receiving 1500 mg. Atovaquone suspension at 1500 mg
      once a day has an efficacy similar to that of aerosolized pentamidine for
      prevention of PCP in HIV-infected subjects and is a safe, effective alternative
      in those who are intolerant to trimethoprim or sulfonamides.

PMID- 10395853
TI  - Effect of parenteral antibiotic administration on persistence of vancomycin
      resistant Enterococcus faecium in the mouse gastrointestinal tract.
AB  - A mouse model of vancomycin-resistant Enterococcus faecium (VRE) intestinal
      colonization was used to study the effect of different subcutaneous antibiotics
      on persistence and density of VRE colonization. Gastric inoculation of a clinical
      VanB VRE isolate, in conjunction with oral vancomycin in drinking water (250
      microgram/mL), resulted in high-level VRE colonization (mean, 9.5 log10 cfu/g) in
      all 169 experimental mice. After discontinuation of oral vancomycin, the level of
      VRE in the stool specimens of mice receiving subcutaneous saline steadily
      decreased (mean, 3.59 log10 cfu/g at day 19). Subcutaneous vancomycin,
      clindamycin, piperacillin-tazobactam, ticarcillin-clavulanic acid, metronidazole,
      cefotetan, ampicillin, and ampicillin-sulbactam all promoted persistent high
      levels of stool VRE. Subcutaneous ceftriaxone, cefepime, ciprofloxacin, and
      aztreonam promoted increased VRE density to a lesser degree or not at all. Thus,
      in a mouse model, vancomycin and antibiotics with potent antianaerobic activity
      promoted persistent high-density intestinal VRE colonization, whereas antibiotics
      lacking potent antianaerobic activity did not.

PMID- 10395852
TI  - Successful treatment of Lyme encephalopathy with intravenous ceftriaxone.
AB  - The efficacy of intravenous ceftriaxone, 2 g per day for 30 days, was evaluated
      in a case series of 18 consecutive patients who met strict criteria for Lyme
      encephalopathy. Months to years after classic manifestations of Lyme disease, the
      18 patients presented with memory difficulty, minor depression, somnolence, or
      headache. Sixteen (89%) had abnormal memory scores; 16 (89%) had cerebrospinal
      fluid (CSF) abnormalities, and all 7 patients tested had frontotemporal perfusion
      defects on single photon emission computed tomographic (SPECT) imaging. Six
      months after treatment, memory scores in the 15 patients who completed the study
      according to protocol were significantly improved (P<.01). In the 10 patients who
      had follow-up CSF analyses, total protein levels were significantly lower
      (P<.05). In the 7 patients who had SPECT imaging, posttreatment perfusion was
      significantly better (P<.01). Twelve to 24 months after treatment, all 18
      patients rated themselves as back to normal or improved. We conclude that Lyme
      encephalopathy can be treated successfully with ceftriaxone.

PMID- 10395854
TI  - Regional dissemination of vancomycin-resistant enterococci resulting from
      interfacility transfer of colonized patients.
AB  - During early 1997, the Siouxland District Health Department (SDHD; Sioux City,
      IA) reported an increased incidence of vancomycin-resistant enterococcal (VRE)
      isolates at area health care facilities. To determine the prevalence and risk
      factors for colonization with VRE strains at 32 health care facilities in the
      SDHD region, a prevalence survey and case-control study were performed. Of 2266
      patients and residents, 1934 (85%) participated, and 40 (2.1%) were positive for
      (gastrointestinal) VRE colonization. The prevalence of VRE isolates was
      significantly higher in acute care facilities (ACFs) than in long-term care
      facilities (LTCFs) (10/152 [6.6%] vs. 30/1782 [1.7%]; odds ratio [OR], 4.1; 95%
      confidence interval [CI], 1.8-9.0). LTCF case patients were significantly more
      likely than controls to have been inpatients at any ACF (19/30 vs. 12/66; OR,
      8.0; 95% CI, 2.7-23.8). Of 40 VRE isolates, 34 (85%) were a related strain. The
      predominant strain was present in all 12 LTCFs that had at least 1 case patient
      in each facility. Soon after the introduction of VRE isolates into this region,
      dissemination to multiple LTCFs resulted from resident transfer from ACFs to
      LTCFs.

PMID- 10395855
TI  - A randomized clinical trial of acellular pertussis vaccines in healthy adults:
      dose-response comparisons of 5 vaccines and implications for booster
      immunization.
AB  - The safety and immunogenicity of 5 acellular pertussis vaccines (ACVs) were
      compared in a multicenter, randomized, double-blind trial. A total of 481 healthy
      adults were given a single intramuscular booster dose of ACV or placebo. Three
      different dose levels were tested for 4 ACVs: full strength (the dose level
      proposed for infant immunization), one-third strength, and one-tenth strength.
      For 1 multicomponent vaccine, only the pertussis toxoid dose level varied. Minor
      injection site reactions were common and similar in frequency among vaccinated
      groups. Late-onset injection site reactions were seen in all ACV groups. Dose
      related increases in mean antibody titers against vaccine antigens were seen
      after immunization with all ACVs. Antibody responses against antigens not known
      to be present in the vaccines were detected after immunization with 4/5 ACVs.
      Antibody levels fell significantly during the year after immunization. These data
      support evaluation of ACVs for broader use among adolescents and adults.

PMID- 10395856
TI  - Simultaneous respiratory tract colonization by multiple strains of nontypeable
      haemophilus influenzae in chronic obstructive pulmonary disease: implications for
      antibiotic therapy.
AB  - Nontypeable Haemophilus influenzae often causes exacerbations of chronic
      obstructive pulmonary disease (COPD), and these exacerbations are frequently
      treated with oral antibiotics. The goals of this study were to determine the
      frequency of the simultaneous presence of multiple strains of H. influenzae in
      sputum and to measure the MICs of antibiotics for the isolates. In a prospective
      study, adults with COPD were seen monthly. Sputum cultures were obtained, and
      individual colonies were subjected to genomic DNA typing and MIC determinations.
      Multiple strains of H. influenzae were present simultaneously in the sputum of
      26.3% of adults with COPD. In 64.5% of these, MICs of >/=1 antibiotic varied by
      >/=4-fold among the strains. Therefore, multiple strains of H. influenzae are
      frequently present simultaneously in the sputum of adults with COPD, and the
      antimicrobial susceptibility of different strains in the same sputum sometimes
      differs.

PMID- 10395857
TI  - Invasive group A streptococcal infections: T1M1 isolates expressing pyrogenic
      exotoxins A and B in combination with selective lack of toxin-neutralizing
      antibodies are associated with increased risk of streptococcal toxic shock
      syndrome.
AB  - Analysis of 132 group A streptococcal (GAS) isolates from 151 invasive episodes,
      including streptococcal toxic shock syndrome (STSS), from 1983 to 1995 showed
      great genetic variation by use of T serotyping in combination with restriction
      fragment length polymorphism. In contrast, genetically homogenous T1M1 isolates
      appeared in epidemic patterns with significantly increased risk of STSS. The speA
      gene, with the allelic variants speA2 and speA3 carried by the T1M1 and T3M3
      serotypes, respectively, was strongly associated with STSS. Infection with a GAS
      isolate carrying speA, alcohol abuse, and malignancy recently treated with
      cytostatic drugs were factors independently related to STSS. Neutralization of
      SpeA lymphocyte mitogenicity was totally absent in sera from patients with STSS
      and low in sera from persons with uncomplicated bacteremia compared with levels
      in sera from uncomplicated erysipelas. Neutralization of SpeB was significantly
      lower in sera of patients with STSS than in sera from persons with bacteremia or
      erysipelas.

PMID- 10395858
TI  - Participation of ABH glycoconjugates in the secretory response to Escherichia
      coli heat-labile toxin in rabbit intestine.
AB  - The ability of membrane ABH blood group-active glycoconjugates to act as
      receptors of the heat-labile enterotoxin of Escherichia coli (LTh) was studied in
      vitro and in vivo when GM1 was blocked by the cholera toxin B subunit. Rabbits
      were classified as AB or H based on intestinal ABH-antigenic activities. Brush
      border membranes from AB rabbits contained 4 times more LTh binding sites than
      the H ones. LTh interaction could be inhibited by lectins that recognize ABH
      determinants. LTh induced a similar dose-dependent secretory response in ligated
      ileal loops of both types of animals. Anti-AB antibodies and Ulex europaeus I
      lectin could significantly reduce the fluid accumulation in AB and H rabbits,
      respectively. LTh caused adenylate cyclase activation even when GM1 was blocked,
      and this effect was abolished by the addition of specific ABH ligands. These
      results suggest that ABH glycoconjugates are involved in the host secretory
      response to LTh in rabbit intestine.

PMID- 10395859
TI  - The effects of three nonoxynol-9 preparations on vaginal flora and epithelium.
AB  - To evaluate the effects of nonoxynol-9 (N-9) on the vaginal flora and epithelium,
      48 women (16 in each group) were evaluated by use of quantitative vaginal
      cultures and colposcopy. at baseline and at 0.5, 4, 24, 48, and 72 h after
      insertion of one of three N-9 preparations (4% gel [Conceptrol], 3.5% gel
      [Advantage-24], or a 28% vaginal contraceptive film). The proportion positive for
      H2O2+ or H2O2- lactobacilli did not change significantly with any of the
      preparations, but lactobacilli concentrations decreased transiently. Both the
      proportion of women with Gardnerella vaginalis and the concentration of G.
      vaginalis decreased transiently. The proportion of women with Escherichia coli
      increased with the 4% gel, and the concentration increased with all preparations.
      The number with anaerobic gram-negative rods increased, although the
      concentrations decreased. Symptoms and colposcopic abnormalities were rare.
      Changes in levels of vaginal bacteria were transient after single applications of
      N-9, but adverse effects may be enhanced with frequent, chronic use.

PMID- 10395860
TI  - Correlation of quantitative bone marrow and blood cultures in AIDS patients with
      disseminated Mycobacterium avium complex infection.
AB  - The relationship between Mycobacterium avium complex (MAC) infection of blood and
      bone marrow was studied in human immunodeficiency virus-infected patients before
      and during treatment. Quantitative cultures were obtained at baseline from 17
      persons with newly detected MAC bacteremia. Serial blood cultures were obtained,
      and a second bone marrow sample was obtained at 4 or 8 weeks. At baseline, the
      median MAC load in bone marrow core samples was 3 log10 higher than in blood.
      Bone marrow MAC loads ranged widely (866-847,315 cfu/g), and no significant
      correlation was found between MAC load in blood and that in bone marrow core
      samples. MAC loads in bilateral bone marrow biopsy samples from 7 subjects were
      highly correlated. MAC loads declined in blood and bone marrow at similar rates
      during therapy, but blood was sterilized before bone marrow. Length of survival
      was inversely associated with initial bone marrow core MAC load but not with
      blood MAC load. Initiation of treatment when tissue MAC load is low may increase
      the likelihood of favorable clinical outcome.

PMID- 10395861
TI  - In vitro and in vivo anticandidal activity of human immunodeficiency virus
      protease inhibitors.
AB  - Highly active antiretroviral therapy that includes human immunodeficiency virus
      (HIV) aspartyl protease inhibitors (PIs) causes a decline in the incidence of
      some opportunistic infections in AIDS, and this decline is currently attributed
      to the restoration of specific immunity. The effect of two PIs (indinavir and
      ritonavir) on the enzymatic activity of a secretory aspartyl protease (Sap) of
      Candida albicans (a major agent of mucosal disease in HIV-infected subjects) and
      on growth and experimental pathogenicity of this fungus was evaluated. Both PIs
      strongly (>/=90%) and dose dependently (0.1-10 microM) inhibited Sap activity and
      production. They also significantly reduced Candida growth in a nitrogen-limited,
      Sap expression-dependent growth medium and exerted a therapeutic effect in an
      experimental model of vaginal candidiasis, with an efficacy comparable to that of
      fluconazole. Thus, besides the expected immunorestoration, patients receiving PI
      therapy may benefit from a direct anticandidal activity of these drugs.

PMID- 10395862
TI  - Control of schistosomiasis pathology by combination of Sm28GST DNA immunization
      and praziquantel treatment.
AB  - Today the control of schistosomiasis infection relies only on the use of
      praziquantel (PZQ) chemotherapy. However, PZQ treatment cannot prevent
      reinfection and progressive development of the pathology. We assessed in a mouse
      model the efficiency of a combined therapy, based on the combination of PZQ
      chemotherapy with Schistosoma mansoni 28-kDa glutathion S-transferase (Sm28GST)
      DNA vaccination, designed to limit the pathology. Following this combined
      therapy, the long-term survival of the mice was significantly enhanced in
      comparison with the survival of mice either vaccinated only or treated with PZQ
      only. In addition, the development of the pathology observed in the control
      groups was almost completely prevented in the vaccinated-PZQ-treated mice and was
      associated with a dramatic reduction of egg deposition in the tissues. We showed
      that PZQ treatment induced the unmasking of the native GST enzyme at the surface
      of the worms, thus permitting its neutralization by the antibodies raised by DNA
      immunization. This study provides insights into the synergistic mechanisms
      involved in an immunointervention strategy associated with chemotherapy for the
      control of a chronic infection and its associated pathology.

PMID- 10395864
TI  - Plasmodium falciparum-infected erythrocytes and oxidized low-density lipoprotein
      bind to separate domains of CD36.
AB  - The cytoadherence of erythrocytes (red blood cells) infected with Plasmodium
      falciparum (pRBCs) to endothelial cells and the uptake of oxidized low-density
      lipoprotein (oxLDL) by macrophages are both mediated, in part, by the
      glycoprotein receptor CD36. The interaction of lipoproteins and pRBCs competing
      for the human CD36 receptor was examined by use of Chinese hamster ovary cells
      expressing human CD36. OxLDL competitively inhibits the adherence of pRBCs to
      CD36, but native LDL and high-density lipoprotein do not. Modification of Lys
      residues in CD36 inhibits both oxLDL and pRBC binding; however, only oxLDL
      binding is inhibited by receptor iodination, and only pRBC binding is influenced
      by pH variations and receptor reduction. Furthermore, peptide inhibitors of the
      pRBC/CD36 interaction do not influence oxLDL binding. These results suggest that,
      although oxLDL competitively inhibits the adherence of pRBCs, these ligands
      interact with distinct domains on the CD36 receptor.

PMID- 10395863
TI  - Plasmodium falciparum isolates from infected pregnant women and children are
      associated with distinct adhesive and antigenic properties.
AB  - Plasmodium falciparum malaria during pregnancy is an important cause of maternal
      and infant morbidity and mortality. Accumulation of large numbers of P.
      falciparum-infected erythrocytes in the maternal blood spaces of the placenta may
      be mediated by adhesion of infected erythrocytes to molecules presented on the
      syncytiotrophoblast surface. In this study, isolates from placentas and
      peripheral blood of infected pregnant women and from children were tested for
      binding to purified receptors and for agglutination with adult sera. Results
      suggest that adhesion to chondroitin sulfate A may be involved in placental
      parasite sequestration in most cases, but other factors are also likely to be
      important. Agglutination assay results suggest that parasites infecting pregnant
      women are antigenically distinct from those common in childhood disease. The
      prevalence of agglutinating antibodies to pregnancy isolates was generally low,
      but it was highest in multigravidae who are likely to have had the greatest
      exposure.

PMID- 10395865
TI  - Parasite persistence correlates with disease severity and localization in chronic
      Chagas' disease.
AB  - The protozoan parasite Trypanosoma cruzi infects up to 20 million people in Latin
      America, and the resulting disease (Chagas' disease) is a leading cause of heart
      disease and death in young adults in areas endemic for the parasite. The clinical
      symptoms of Chagas' disease have been attributed to autoimmune reactivity to
      antigens shared by the parasite and host muscle or neuronal tissue. In the
      present study, in situ polymerase chain reaction analysis was used in murine
      models of Chagas' disease to demonstrate an absolute correlation between the
      persistence of parasites and the presence of disease in muscle tissue. Clearance
      of parasites from tissues, presumably by immunologic mechanisms, correlated with
      the abatement of inflammatory responses and the resolution of disease. These data
      provide strong evidence for parasite persistence as a primary cause of Chagas'
      disease and argue for efforts to eliminate T. cruzi from the host as a means for
      prevention and treatment of Chagas' disease.

PMID- 10395866
TI  - Characterization of the DNA polymerase and thymidine kinase genesof herpes
      simplex virus isolates from AIDS patients in whom acyclovirand foscarnet therapy
      sequentially failed.
AB  - Herpes simplex virus (HSV) isolates were characterized from 8 AIDS patients in
      whom acyclovir and foscarnet therapy sequentially failed. The 6 postacyclovir
      (prefoscarnet) HSV isolates were resistant to acyclovir and susceptible to
      foscarnet. Of the 9 postfoscarnet isolates, 8 were foscarnet-resistant and
      acyclovir-susceptible, 1 was resistant to both drugs. Acyclovir- or foscarnet
      resistant isolates retained susceptibility to cidofovir. The acyclovir-resistant
      isolates contained single-base substitutions or frameshift mutations in G or C
      homopolymer nucleotide repeats of the thymidine kinase gene. In contrast, the
      foscarnet-resistant strains contained single-base substitutions in conserved (II,
      III, or VI) or, more rarely, nonconserved (between I and VII) regions of the DNA
      polymerase (pol) gene. The single isolate exhibiting resistance to acyclovir and
      foscarnet contained mutations in both genes. In this study of clinical HSV
      isolates, DNA pol mutations conferring foscarnet resistance were not associated
      with decreased acyclovir or cidofovir susceptibility.

PMID- 10395867
TI  - Comprehensive restriction analysis of the UL97 region allows early detection of
      ganciclovir-resistant human cytomegalovirus in an immunocompromised child.
AB  - Children with innate immunodeficiencies may be at high risk for early development
      of ganciclovir-resistant human cytomegalovirus (HCMV) infection after bone marrow
      transplantation (BMT). For early and frequent monitoring of the occurrence of
      ganciclovir resistance-associated mutations in codons of the UL97 gene, a panel
      of previously described restriction assays was expanded for use on codons 591,
      592, and 603. This technique enabled detection of suddenly emerging ganciclovir
      resistant HCMV after BMT in a 7-year-old child with a T cell defect. Resistance
      emerged among the isolation of a ganciclovir-sensitive HCMV strain 32 days after
      transplantation, the first detection of genotypical resistance at day 44, and the
      isolation of resistant HCMV (ID50>12 microM) at day 54. Simple and yet
      comprehensive methods for therapy surveillance may be important in this patient
      group, in which the restriction assays proved useful.

PMID- 10395868
TI  - Polymorphism of the interleukin-10 gene is associated with susceptibility to
      Epstein-Barr virus infection.
AB  - There are indications that the cytokine interleukin (IL)-10 has a regulatory role
      in Epstein-Barr virus (EBV)-induced infections. Because the human IL-10 gene
      demonstrates polymorphism resulting in interindividual differences in cytokine
      production, the frequencies of the alleles defined by the base exchange
      polymorphism at the position -1082 (allele 1=G, allele 2=A) were analyzed in EBV
      seronegative adults, seropositive adults, and in patients hospitalized because of
      a severe EBV infection. The frequencies of allele 1 were 0.80, 0.46, and 0.29,
      respectively. Because this allele is associated with a high IL-10-producing
      capability, these data suggest that high IL-10 levels protect against EBV
      infection and, conversely, that low IL-10-producing capability makes individuals
      more susceptible to a severe EBV infection.

PMID- 10395869
TI  - Prevalence of antibodies to human parvovirus B19 nonstructural protein in persons
      with various clinical outcomes following B19 infection.
AB  - Persistent infections with human parvovirus B19 (B19) associated with
      debilitating chronic disease have been described, although evidence linking B19
      to these more unusual clinical outcomes has been inconclusive. Recent reports
      have suggested that the development of antibodies to the B19 nonstructural
      protein (NS1) following B19 infection might be linked to development of severe
      arthropathy and chronic infection. To confirm these findings, the C-terminal
      region of the NS1 protein was expressed for use in Western blot assays for
      detection of anti-NS1 IgG antibodies in human serum. Among 91 persons tested, 0
      of 20 not previously infected with B19, 9(36%) of 25 with past B19 infection, and
      5 (12.5%) of 40 with recent B19 infection, had detectable anti-NS1 antibodies. Of
      6 persons with chronic B19 infection, 2 had detectable antibodies to NS1. The
      presence of anti-NS1 antibodies did not appear to correlate with unusual clinical
      outcomes or chronic B19 infection.

PMID- 10395870
TI  - Case-control study of risk factors for avian influenza A (H5N1) disease, Hong
      Kong, 1997.
AB  - In May 1997, a 3-year-old boy in Hong Kong died of a respiratory illness related
      to influenza A (H5N1) virus infection, the first known human case of disease from
      this virus. An additional 17 cases followed in November and December. A case
      control study of 15 of these patients hospitalized for influenza A (H5N1) disease
      was conducted using controls matched by age, sex, and neighborhood to determine
      risk factors for disease. Exposure to live poultry (by visiting either a retail
      poultry stall or a market selling live poultry) in the week before illness began
      was significantly associated with H5N1 disease (64% of cases vs. 29% of controls,
      odds ratio, 4.5, P=.045). By contrast, travel, eating or preparing poultry
      products, recent exposure to persons with respiratory illness, including persons
      with known influenza A (H5N1) infection, were not associated with H5N1 disease.

PMID- 10395871
TI  - The epidemiology of viral hepatitis in children in South Texas: increased
      prevalence of hepatitis A along the Texas-Mexico border.
AB  - An initial retrospective study of 194 children demonstrated a high prevalence of
      hepatitis A but not hepatitis B or C infection among children living along the
      Texas-Mexico border. A larger prospective study of hepatitis A was conducted with
      285 children (aged 6 months to 13 years) living in 3 sociodemographically
      dissimilar areas of South Texas. Children living in colonias along the border had
      a significantly higher prevalence of hepatitis A virus infection (37%) than
      children living in urban border communities (17%) or in a large metropolitan area
      (San Antonio [6%]). Independent risk factors for hepatitis A infection included
      increased age, colonia residence, and history of residence in a developing
      country. Use of bottled water (vs. municipal or spring/well water) and years of
      maternal secondary education were protective. Improved sanitation or routine
      hepatitis A vaccination in early childhood may reduce the prevalence of hepatitis
      A in these areas.

PMID- 10395872
TI  - Molecular epidemiology of childhood astrovirus infection in child care centers.
AB  - This study assessed the role of human astrovirus (HAstV) in outbreaks and
      sporadic cases of diarrhea among children attending child care centers (CCCs) and
      determined the infecting astrovirus antigenic types by reverse transcriptase
      polymerase chain reaction (RT-PCR) and sequence analysis. Eight astrovirus
      outbreaks occurred in 6 CCCs. Of 179 children with diarrhea, 36 (20%) had
      astrovirus-associated diarrhea. Diarrhea stools obtained during diarrhea
      outbreaks were more likely to contain astrovirus (40/476) than were samples not
      associated with a diarrhea outbreak (14/452) (P<.001). Type-specific RT-PCR and
      DNA sequencing identified 5 outbreaks associated with HAstV-1 and 3 outbreaks
      with HAstV-2. Sequential outbreaks in 2 CCCs occurred with a different type in
      the same year. Phylogenetic analysis identified 6 clades of HAstV-1 and 2 clades
      of HAstV-2 during this 1-year surveillance. Astrovirus was a significant cause of
      diarrhea outbreaks, and 2 antigenic types were present in the community during 1
      diarrhea season.

PMID- 10395873
TI  - Late increase of serum S100 beta protein levels in hamsters after oral or
      intraperitoneal infection with scrapie.
AB  - Following recent reports of elevated serum S100 beta protein (S100 beta) levels
      in patients with genetic and sporadic Creutzfeldt-Jakob disease and in rodents
      parenterally infected with scrapie, the suitability of serum S100 beta as a
      preclinical marker for transmissible spongiform encephalopathies was assessed in
      time-course studies. Syrian hamsters were orally and intraperitoneally challenged
      with scrapie and assayed for serum S100 beta levels at various times after
      infection. Although elevated serum S100 beta levels were consistently observed in
      terminally ill animals for both routes of infection, the experiments failed to
      detect significantly increased S100 beta serum concentrations prior to the
      manifestation of clinical symptoms. Thus, in this animal model, serum S100 beta
      does not appear to be an appropriate marker for the preclinical detection of
      scrapie, but it may provide a convenient laboratory aid for the diagnosis of
      transmissible spongiform encephalopathy in naturally or accidentally infected
      animals and humans.

PMID- 10395874
TI  - The mumps virus neurovirulence safety test in Rhesus monkeys: a comparison of
      mumps virus strains.
AB  - Wild type mumps viruses are highly neurotropic and a frequent cause of aseptic
      meningitis in unvaccinated humans. To test whether attenuated mumps viruses used
      in the manufacture of mumps vaccines have neurovirulent properties, a monkey
      neurovirulence safety test (MNVT) is performed. However, results with several
      mumps virus MNVTs have raised questions as to whether the test can reliably
      discriminate neurovirulent from nonneurovirulent mumps virus strains. Here,
      various mumps virus strains representing a wide range of neuropathogenicity were
      tested in a standardized MNVT. A trend of higher neurovirulence scores was
      observed in monkeys inoculated with wild type mumps virus versus vaccine strains,
      although differences were not statistically significant. Results indicated the
      need for further examination and refinement of the MNVT or for development of
      alternative MNVTs.

PMID- 10395875
TI  - Plasma human immunodeficiency virus RNA below 40 Copies/mL is rare in untreated
      persons even in the first years of infection.
AB  - To clarify the frequency and prognostic significance of a plasma human
      immunodeficiency virus (HIV) RNA load below the detection threshold during the
      natural history of infection, an ultrasensitive assay was used to identify
      persons with low virus loads in a cohort of 111 untreated subjects with a known
      date of seroconversion. Six persons had HIV RNA loads <40 viral copies (VC)/mL
      during the first years of HIV infection. The probability of meeting the criteria
      for long-term nonprogression was higher in these subjects (P=.043). However, a
      virus load <40 VC/mL was rare during the natural history of infection, even
      during the first years of symptomless HIV carriage. Such data confirm the general
      trend of disease progression in the entire population of HIV carriers.

PMID- 10395876
TI  - CD4 lymphocyte count as a predictor of the duration of highly active
      antiretroviral therapy-induced suppression of human immunodeficiency virus load.
AB  - The association between CD4 cell count and duration of virus load suppression was
      investigated in 558 patients in the Frankfurt HIV Clinic Cohort who had begun
      highly active antiretroviral therapy and who had virus load declines to </=500
      copies/mL. The Kaplan-Meier method estimated viral rebound in 42.5% of patients
      by 24 weeks and in 64.3% by 84 weeks. Risk of viral rebound was independently
      associated with baseline and changes from baseline CD4 cell count. The achieved
      CD4 cell count was the most important factor for prediction of viral rebound
      (relative hazard, 5.4 for an updated CD4 cell count of <20 vs. >500 copies/mL;
      P=.0001). Baseline virus load was not associated with virus load rebound. Lower
      baseline CD4 cell counts were associated with increased risk of viral rebound;
      however, this risk was significantly reduced in persons with low baseline CD4
      cell counts who experienced substantial increases in CD4 cell counts during
      follow-up.

PMID- 10395877
TI  - Association of plasma levels of human immunodeficiency virus type 1 RNA and
      oropharyngeal Candida colonization.
AB  - The pathophysiology of oropharyngeal candidiasis in patients infected with human
      immunodeficiency virus (HIV) type 1 is poorly understood. Association between
      oropharyngeal yeast carriage and various clinical factors in HIV-1-infected
      patients was studied in 83 patients with no clinical evidence of thrush and no
      recent antifungal use. Of the clinical factors measured, the only correlate of
      yeast colonization was with plasma HIV-1 RNA levels (P=.001), whereas the
      correlation with CD4 cell count was poor (P=.36). By multivariable regression
      modeling, plasma HIV-1 RNA was the only parameter that correlated with the extent
      of colonization with Candida infection (P=.003). These data indicate that the
      presence and amount of asymptomatic oropharyngeal yeast carriage in persons with
      HIV-1 infection is more significantly correlated with plasma HIV-1 RNA levels
      than with CD4 cell count. Further studies on the effect of HIV-1 on oropharyngeal
      yeast colonization, infection, and local immunity are warranted.

PMID- 10395878
TI  - The induction of immunologic memory after vaccination with Haemophilus influenzae
      type b conjugate and acellular pertussis-containing diphtheria, tetanus, and
      pertussis vaccine combination.
AB  - The significance of reduced antibody responses to the Haemophilus influenzae type
      b (Hib) component of acellular pertussis-containing combination vaccines (DTaP
      Hib) is unclear. A DTaP-Hib vaccine evaluated in infants vaccinated at ages 2, 3,
      and 4 months showed reduced anti-Hib polysaccharide IgG (geometric mean
      concentration [GMC], 1.23 microgram/mL; 57%, >1.0 microgram/mL).
      Polyribitolribosyl phosphate (PRP) and Hib conjugate (PRP-T) vaccine given as a
      booster during the second year of life was evaluated for the presence of
      immunological memory. After boosting, most children achieved anti-PRP IgG >1.0
      microgram/mL, although the GMC was higher with PRP-T (88.5 microgram/mL) than
      with PRP vaccine (7.86 microgram/mL, P<.001). The GMC of the PRP group was higher
      than anticipated for naive PRP recipients of the same age. PRP-specific IgG
      avidity was significantly higher after boosting than after priming, providing
      further evidence for the generation of memory. Despite reduced immunogenicity,
      DTaP-Hib combination vaccines appear to prime for immunologic memory.

PMID- 10395879
TI  - Increased nitric oxide in infective gastroenteritis.
AB  - Nitric oxide (NO) production is increased in several inflammatory disorders,
      although the role of this gas is not clear. The purpose of this study was to
      determine whether luminal NO in the intestine is increased in infective
      gastroenteritis. Rectal gas was sampled in 17 patients with gastroenteritis and
      10 healthy volunteers, with balloon catheters made of 100% silicone and analyzed
      for NO by chemiluminescence. Plasma nitrate and nitrite levels were determined by
      capillary electrophoresis. Rectal NO was (mean+/-SEM) 9441+/-3126 parts per
      billion (ppb) in the patients and 74+/-13 ppb in controls (P<.0001). There was no
      individual overlap. Plasma nitrite but not nitrate was significantly increased in
      patients compared with controls. These data indicate that luminal NO is greatly
      increased in gastroenteritis. The high levels of NO are easily measurable by
      rectal sampling, and measurement of luminal NO seems to be useful for evaluating
      local NO production in the gut in health and disease.

PMID- 10395880
TI  - Development and distribution of pathologic lesions are related to immune status
      and tissue deposition of human granulocytic ehrlichiosis agent-infected cells in
      a murine model system.
AB  - To evaluate pathology and the role of immune status in a murine model system of
      human granulocytic ehrlichiosis (HGE), C3H/HeJ, C3H-SCID, and Peromyscus leucopus
      mice were infected with an HGE agent. All mice remained healthy. Ehrlichemia was
      not detected after day 14 in P. leucopus and C3H/HeJ mice but increased between
      days 14 and 90 in C3H-SCID mice. In tissues examined at day 21 and later,
      infection was rarely detected in immunocompetent mice but was present in all C3H
      SCID mice and included pulmonary endothelialitis and hepatic mononuclear cell
      aggregates with apoptoses. HGE agent was demonstrated in mature and immature
      myeloid cells in hematopoietic tissues and infrequently in lung and liver lesions
      with deposition of infected cells. HGE agent infection in immunocompromised mice
      progresses slowly, has a higher infectious burden and more tissue pathology and
      is persistent. A murine model for HGE may be useful to assess pathologic lesions,
      transmission, and persistence.

PMID- 10395881
TI  - Elderly humans show prolonged in vivo inflammatory activity during pneumococcal
      infections.
AB  - Levels of circulating cytokines were measured in 22 hospitalized patients with
      pneumococcal infections during the first week after admission, to test for age
      associated differences. Twenty-two healthy age- and sex-matched subjects were
      included as controls. Concentrations of tumor necrosis factor (TNF)-alpha,
      interleukin (IL)-1beta, IL-6, IL-1 receptor antagonist, soluble TNF receptor I
      (sTNFR-I), and IL-10 were increased on admission (P<.05), but macrophage
      inflammatory protein (MIP)-1beta was not. Whereas levels of cytokines were
      similar on admission, levels of TNF-alpha and sTNFR-I after 1 week were higher
      (P<.05) in elderly (68-91 years) than in young (37-55 years) patients.
      Furthermore, plasma levels of IL-10 and sTNFR-I after 1 week were positively
      correlated with age, and the declines in sTNFR-I and in the TNFalpha/IL-10 ratio
      from day 0 to day 7 were correlated with age. Thus, aging was associated with
      prolonged inflammatory activity. This may reflect decreased ability to control
      the infection or a dysregulated cytokine response.

PMID- 10395882
TI  - In vitro exchange of fluoroquinolone resistance determinants between
      Streptococcus pneumoniae and viridans streptococci and genomic organization of
      the parE-parC region in S. mitis.
AB  - Transfer of fluoroquinolone (FQ) resistance determinants between Streptococcus
      pneumoniae and viridans streptococci was explored by transformation in vitro. One
      step FQ-resistant parC mutants were selected, and resistance could be transferred
      from DNA from S. oralis, S. mitis, S. sanguis, and S. constellatus to S.
      pneumoniae, with frequencies of 10(-3) to <10(-7) in correlation with the
      homologies of their quinolone resistance determining region sequences (95%, 91%,
      85%, and 81%, respectively). Reciprocal transfers of mutated parC from DNA from
      S. pneumoniae to S. mitis and S. oralis were also observed. Simultaneous transfer
      of mutated parC and gyrA genes from S. mitis to S. pneumoniae yielded high-level
      resistant pneumococcal transformants in one step at low frequencies. The parE
      parC region of the type strain S. mitis 103335T had >90% homology with that of S.
      pneumoniae. The efficient interspecific transfer of quinolone resistance
      determinants in vitro leads us to anticipate their dissemination in the clinical
      setting.

PMID- 10395883
TI  - Effect of immune activation induced by Cryptosporidium parvum whole antigen on in
      vitro human immunodeficiency virus type 1 infection.
AB  - Previous epidemiologic investigations have suggested that persons with AIDS who
      are infected with Cryptosporidium parvum have a shorter survival time than those
      with other opportunistic infections. In this study, the effect of immune
      activation by a crude Cryptosporidium whole antigen on human immunodeficiency
      virus type 1 (HIV-1) infection was evaluated. Peripheral blood mononuclear cells
      from healthy persons without HIV-1 infection had increased proliferative and
      cytokine (interleukin-4, interferon-gamma, and tumor necrosis factor [TNF]-alpha)
      responses to stimulation with the crude Cryptosporidium whole antigen. This
      stimulation increased HIV-1 p24 antigen production in in vitro infection by>30
      fold. A similar increase in p24 production was also seen when stimulation was
      done after cells were infected with HIV-1. Neutralization of TNF-alpha reduced
      Cryptosporidium antigen-induced p24 production by >50%. Results of this study
      suggest that Cryptosporidium-induced immune activation may be a cofactor in
      regulating HIV-1 production.

PMID- 10395884
TI  - Evidence that the high incidence of treatment failures in Indian kala-azar is due
      to the emergence of antimony-resistant strains of Leishmania donovani.
AB  - The possibility that the high frequency of treatment failures in Indian kala-azar
      might be due to infection with antimony-resistant strains of Leishmania donovani
      has not been experimentally addressed. L. donovani isolates were obtained from
      splenic aspiration smears of 24 patients in Bihar, India, who either did not
      respond (15) or did respond (9) to 1 or more full courses of treatment with
      sodium antimony gluconate (SAG). A strong correlation (P<.001) between clinical
      response and SAG sensitivity in vitro was observed only when strains were assayed
      as intracellular amastigotes: responsive isolates ED50=2.4+/-2.6, ED90=6.4+/-7.8
      microgram SAG/mL; unresponsive isolates ED50=7.4+/-3.7 microgram SAG/mL,
      ED90=29.1+/-11.1 SAG/mL. No correlation with clinical response was found by use
      of extracellular promastigotes (ED50=48+/-22 vs. 52+/-29 microgram/mL). The
      emergence of antimony-resistant L. donovani strains appears to be a cause of
      treatment failures in India.

PMID- 10395885
TI  - Highly active antiretroviral therapy failure and protease and reverse
      transcriptase human immunodeficiency virus type 1 gene mutations.

PMID- 10395886
TI  - Reply 

PMID- 10395887
TI  - Does high-dose prophylactic acyclovir add benefit in allogeneic marrow transplant
      recipients receiving prophylactic or preemptive ganciclovir?

PMID- 10395888
TI  - Reply 

PMID- 10395889
TI  - Sustained disappearance of hepatitis C viremia in patients receiving protease
      inhibitor treatment for human immunodeficiency virus infection.

PMID- 10395891
TI  - The essence of SNPs.
AB  - Single nucleotide polymorphisms (SNPs) are an abundant form of genome variation,
      distinguished from rare variations by a requirement for the least abundant allele
      to have a frequency of 1% or more. A wide range of genetics disciplines stand to
      benefit greatly from the study and use of SNPs. The recent surge of interest in
      SNPs stems from, and continues to depend upon, the merging and coincident
      maturation of several research areas, i.e. (i) large-scale genome analysis and
      related technologies, (ii) bio-informatics and computing, (iii) genetic analysis
      of simple and complex disease states, and (iv) global human population genetics.
      These fields will now be propelled forward, often into uncharted territories, by
      ongoing discovery efforts that promise to yield hundreds of thousands of human
      SNPs in the next few years. Major questions are now being asked, experimentally,
      theoretically and ethically, about the most effective ways to unlock the full
      potential of the upcoming SNP revolution.

PMID- 10395892
TI  - Initiation of translation in prokaryotes and eukaryotes.
AB  - The mechanisms whereby ribosomes engage a messenger RNA and select the start site
      for translation differ between prokaryotes and eukaryotes. Initiation sites in
      polycistronic prokaryotic mRNAs are usually selected via base pairing with
      ribosomal RNA. That straightforward mechanism is made complicated and interesting
      by cis- and trans-acting elements employed to regulate translation. Initiation
      sites in eukaryotic mRNAs are reached via a scanning mechanism which predicts
      that translation should start at the AUG codon nearest the 5' end of the mRNA.
      Interest has focused on mechanisms that occasionally allow escape from this first
      AUG rule. With natural mRNAs, three escape mechanisms - context-dependent leaky
      scanning, reinitiation, and possibly direct internal initiation - allow access to
      AUG codons which, although not first, are still close to the 5' end of the mRNA.
      This constraint on the initiation step of translation in eukaryotes dictates the
      location of transcriptional promoters and may have contributed to the evolution
      of splicing.The binding of Met-tRNA to ribosomes is mediated by a GTP-binding
      protein in both prokaryotes and eukaryotes, but the more complex structure of the
      eukaryotic factor (eIF-2) and its association with other proteins underlie some
      aspects of initiation unique to eukaryotes. Modulation of GTP hydrolysis by eIF-2
      is important during the scanning phase of initiation, while modulating the
      release of GDP from eIF-2 is a key mechanism for regulating translation in
      eukaryotes. Our understanding of how some other protein factors participate in
      the initiation phase of translation is in flux. Genetic tests suggest that some
      proteins conventionally counted as eukaryotic initiation factors may not be
      required for translation, while other tests have uncovered interesting new
      candidates. Some popular ideas about the initiation pathway are predicated on
      static interactions between isolated factors and mRNA. The need for functional
      testing of these complexes is discussed. Interspersed with these theoretical
      topics are some practical points concerning the interpretation of cDNA sequences
      and the use of in vitro translation systems. Some human diseases resulting from
      defects in the initiation step of translation are also discussed.

PMID- 10395893
TI  - Molecular cloning of a cDNA encoding 14-3-3 protein from the protozoan
      Tetrahymena pyriformis and its mRNA expression during synchronous division.
AB  - The 14-3-3 proteins have been identified in a wide variety of eukaryotic cells
      and diverse biochemical properties have been ascribed to them. Here we have
      cloned a cDNA encoding 14-3-3 protein from a cDNA library of Tetrahymena
      pyriformis. This cDNA (Tp14-3-3) encoded an open reading frame consisting of 244
      amino acids with predicated molecular mass as 28.1kDa. The predicted protein
      shares 59.2%, 56.5% and 59.2% identity to Entamoeba histolytica 14-3-3-1,
      Schizosaccharomyces pombe Rad 24 and human 14-3-3 zeta/delta respectively. On the
      basis of comparison with other 14-3-3 proteins, two of the putative functional
      domains (dimerization domain and annexin-similarity domain) were found in Tp14-3
      3. In order to know the role of Tp14-3-3 in Tetrahymena, its mRNA levels during
      synchronous division were examined by Northern blot analysis. There was a marked
      increase in Tp14-3-3 mRNA level at 45min after the end of heat treatment,
      followed by a gradual decrease. These results suggest that the Tp14-3-3 mRNA
      level might vary during the cell cycle. The accumulation of Tp14-3-3 mRNA before
      cell division was assumed to be a prerequisite for the initiation of synchronous
      cell division.

PMID- 10395894
TI  - Characterization of the human glycogenin-1 gene: identification of a muscle
      specific regulatory domain.
AB  - The de-novo synthesis of glycogen is now known to involve a novel class of self
      glucosylating protein primers. In mammalian skeletal muscle, glycogenin-1 is the
      protein responsible for this initiation step. Northern blot analysis revealed
      that glycogenin-1 gene transcription is differentially regulated in the C2C12
      mouse muscle cell line. To define the regulatory elements that control expression
      of the glycogenin-1 gene, we have cloned and characterized the genomic structure
      of the human glycogenin-1 gene and its promoter region. This gene consists of
      seven exons and six introns, and spans over 13kb. Transcription of human
      glycogenin-1 is initiated at two major sites, 80 and 86bp upstream from the
      initiation of translation codon. Nucleotide sequence analysis of 2.1kb of the 5'
      flanking region revealed the proximal promoter contains both a TATA box and two
      putative Sp1 binding sites located in a CpG island. There are numerous binding
      sites for developmental and cell-type-specific transcription factors, including
      AP-1, AP-2, GATA, and several potential Oct 1 binding domains. There are also
      nine consensus E-boxes that bind the basic helix-loop-helix family of muscle
      specific transcription factors. The transcriptional activity of the glycogenin-1
      gene was investigated by transient transfection of the 5'-flanking region in
      HepG2 cells and C2C12 myoblasts and myotubes. These results permitted the
      definition of a minimal 232bp promoter fragment that is responsible for basal
      level transcription in a cell-type-independent manner. Furthermore, we have
      identified a regulatory region located between -2076 and -1736 of the 5'-flanking
      region of the human glycogenin-1 gene that allows myotube-specific expression in
      C2C12 cells.

PMID- 10395896
TI  - Genome engineering of Toxoplasma gondii using the site-specific recombinase Cre.
AB  - Site-specific DNA recombinases from bacteriophage and yeasts have been developed
      as novel tools for genome engineering both in prokaryotes and eukaryotes. The
      38kDa Cre protein efficiently produces both inter- and intramolecular
      recombination between specific 34bp sites called loxP. We report here the in vivo
      use of Cre recombinase to manipulate the genome of the protozoan parasite
      Toxoplasma gondii. Cre catalyzes the precise removal of transgenes from T. gondii
      genome when flanked by two directly repeated loxP sites. The efficiency of
      excision has been determined using LacZ as reporter and indicates that it can
      easily be applied to the removal of undesired sequences such as selectable marker
      genes and to the determination of gene essentiality. We have also shown that the
      reversibility of the recombination reaction catalyzed by Cre offers the
      possibility to target site-specific integration of a loxP-containing vector in a
      chromosomally placed loxP target in the parasite. In mammalian systems, the Cre
      recombinase can be regulated by hormone and is used for inducible gene targeting.
      In T. gondii, fusions between Cre recombinase and the hormone-binding domain of
      steroids are constitutively active, hampering the utilization of this mode of
      post-translational regulation as inducible gene expression system.

PMID- 10395895
TI  - Identification of four novel ADAMs with potential roles in spermatogenesis and
      fertilization.
AB  - The ADAM (A Disintegrin And Metalloprotease) family is known to have important
      roles in various developmental systems, e.g., myogenesis and neurogenesis. In
      this study, we searched for ADAMs that may function in spermatogenesis or
      fertilization, and have cloned and sequenced four new mouse ADAM cDNAs: ADAM 24,
      ADAM 25, ADAM 26 and ADAM 27. The deduced amino acid sequences show that all four
      contain the complete domain organization common to ADAM family members. Messenger
      RNA for each of the four ADAMs was found only in the testis. The conserved zinc
      dependent metalloprotease active site HEXGHXXGXXHD was found in the
      metalloprotease domain of three of the novel ADAMs, suggesting that they are
      testis-specific proteases, to which we give the alternative names: testase 1,
      ADAM 24; testase 2, ADAM 25; and testase 3, ADAM 26. Using RNA extracted from
      testes of pre-pubertal males of increasing age (8-40days), we found that adult
      levels of transcription, assessed in Northern blots, are reached by day 20 (ADAM
      27), day 25 (ADAMs 24 and 25) and in the range day 25-50 (ADAM 26). These results
      suggest that each ADAM is transcribed in spermatogenic cells in a regulated
      pattern at a specific developmental stage.

PMID- 10395898
TI  - Starts of bacterial genes: estimating the reliability of computer predictions.
AB  - Exact mapping of gene starts is an important problem in the computer-assisted
      functional analysis of newly sequenced prokaryotic genomes. We describe an
      algorithm for finding ribosomal binding sites without a learning sample. This
      algorithm is particularly useful for analysis of genomes with little or no
      experimentally mapped genes. There is a clear correlation between the ribosomal
      binding site (RBS) properties of a given genome and the potential gene start
      prediction accuracy. This correlation is of considerable predictive power and may
      be useful for estimating the expected success of future genome analysis efforts.
      We also demonstrate that the RBS properties depend on the phylogenetic position
      of a genome.

PMID- 10395897
TI  - Mouse leukotriene A4 hydrolase is expressed at high levels in intestinal crypt
      cells and splenic lymphocytes.
AB  - LTA4 hydrolase (EC 3.3.2.6) is a dual-function enzyme that is essential for the
      conversion of leukotriene A4 (LTA4) to leukotriene B4 (LTB4) and also possesses
      an aminopeptidase activity. To characterize the expression of this unusual
      enzyme, we have cloned the mouse LTA4 hydrolase cDNA. The deduced amino acid
      sequence revealed 92% identity with the human sequence. Cloning and analysis of
      genomic sequences of mouse LTA4 hydrolase indicated that it is a single-copy gene
      spanning over 40kb and containing 20 exons. LTA4 hydrolase is widely expressed,
      with the highest levels of expression occurring in the small intestine, followed
      by the spleen. In situ hybridization revealed that LTA4 hydrolase is localized in
      the crypt cells of the small intestine, white pulp of the spleen, bronchiolar
      epithelium of the lung, myocardium, adrenal cortex, epithelium of the seminal
      vesicles, proximal tubules and the collecting ducts of the kidney, and occasional
      hepatocytes. Thus the widespread distribution of LTA4 hydrolase in various cell
      types in the tissues suggests that LTB4 may possess biological activities other
      than those known at present. It is also plausible that the widespread occurrence
      of LTA4 hydrolase in various tissues may correspond more with its function as an
      aminopeptidase than its function as an LTA4 hydrolase.

PMID- 10395899
TI  - Identification and characterization of a new member of the gas3/PMP22 gene family
      in C. elegans.
AB  - The Gas3/PMP22 protein family is characterized by tetraspan transmembrane
      proteins. The gas3/PMP22 gene is highly expressed in Schwann cells of the
      peripheral nervous system, and different alterations of this gene are associated
      with hereditary demyelinating neuropathies, such as the Charcot-Marie-Tooth type
      1A, the Dejerine-Sottas syndrome and the Hereditary Liability to Pressure Palsies
      (HNPP).Here, we report on the identification of at least one member of the
      Gas3/PMP22 family in the nematode C. elegans (C01C10.1b). C01C10.1b shares 36% of
      identical amino acids with the human Gas3/PMP22 and is characterized by four
      hydrophobic putative transmembrane domains. It lacks the typical N-linked
      glycosylation consensus in the first extracellular loop. C01C10.1b is transcribed
      as an operon downstream to the gene C01C10.1a, which encodes for a putative
      tetraspan protein with less conserved homology with the Gas3/PMP22 family.
      Interestingly, C01C10.1a contains three N-glycosylation sites at the C-terminus.
      Both genes are expressed in different nematode developmental stages and in the
      adults. The characterization of one member of the gas3/PMP22 family in C. elegans
      gives the opportunity to use this model organism to investigate the role of
      gas3/PMP22 in the regulation of cell proliferation and differentiation and its
      relation to the hereditary neurodegenerative diseases in humans.

PMID- 10395900
TI  - Expression of plastocyanin and cytochrome f of the cyanobacterium Phormidium
      laminosum in Escherichia coli and Paracoccus denitrificans and the role of leader
      peptides.
AB  - The gene for plastocyanin from the cyanobacterium Phormidium laminosum was
      successfully expressed in Escherichia coli. Expression of the gene for cytochrome
      f resulted in the production of holocytochrome f in the periplasmic space of E.
      coli, but the yield was low. Expression in Paracoccus denitrificans yielded no
      holoprotein. When the region encoding the cytochrome f leader sequence was
      replaced with more typical bacterial leader sequences (those from the P.
      laminosum plastocyanin gene and the Paracoccus versutus cytochrome c-550 gene),
      much higher yields were consistently obtained in both species. Overexpressed
      proteins were compared to those isolated from P. laminosum and found to be
      identical in mass, isoelectric point, redox midpoint potential and (for
      plastocyanin) 1H-NMR spectrum.

PMID- 10395901
TI  - Yeast tom1 mutant exhibits pleiotropic defects in nuclear division, maintenance
      of nuclear structure and nucleocytoplasmic transport at high temperatures.
AB  - A tom1-1 mutant was isolated from Saccharomyces cerevisiae. At high temperatures,
      60% of the cells were arrested as dumbbell forms with a single large nucleus
      containing duplicated DNA and a short spindle. Electron-microscopy showed
      electron-dense structures scattered within the nucleus. Indirect
      immunofluorescent microscopy revealed these structures to be fragmented nucleoli
      since the dotted structures were stained with anti-Nop1(fibrillarin) antibody in
      large regions of the nuclei. Fluorescent in situ hybridization analysis using
      oligo(dT) revealed nuclear accumulation of poly(A)+RNA. We cloned TOM1 which
      encodes a large protein (380kDa) with a hect (homologous to E6-AP C terminus)
      domain at its C terminus. Deletions of either this hect-region or the entire gene
      made cellular growth temperature-sensitive. Site-directed mutagenesis of the
      conserved cysteine residue (tom1C3235A) in the hect-domain, supposed to be
      necessary for thioester-bond formation with ubiquitin, abolished the gene
      function. When a functional glutathione S-transferase (GST)-tagged hect protein
      was overproduced, it facilitated the protein conjugation with a myc-tagged
      ubiquitinRA, while this was not seen when GST-hectC3235A was overproduced. The
      protein conjugation with a hemagglutinin-tagged Smt3 was not affected by the
      overproduction of GST-hect. Taken together, we suggest that Tom1 is a ubiquitin
      ligase. As a multi-copy suppressor of tom1, we isolated STM3/NPI46/FPR3 which
      encodes a nucleolar nucleolin-like protein. We discuss possible functions of Tom1
      with respect to the pleiotropic defects of nuclear division, maintenance of
      nuclear structure, and nucleocytoplasmic transport.

PMID- 10395902
TI  - Molecular cloning and characterization of the rat inducible nitric oxide synthase
      (iNOS) gene.
AB  - We have cloned and characterized the rat inducible nitric oxide synthase (iNOS)
      gene. It spans approx. 36kb and is divided into 27 exons and 26 introns. The
      distribution and length of exons are similar to those in the human iNOS gene. In
      the 5' flanking regulatory region of the rat iNOS gene, there are a number of
      putative transcription factor binding sites (>20), many of them probably
      indispensable for the gene's nuclear factor kappaB (NFkappaB)-dependent
      induction, but also many which may have a role in its NFkappaB-independent
      induction pathway. These include cyclic adenosine 3', 5'-monophosphate (cAMP)
      response elements (CRE), hypoxia responsive element (HRE) and GATA-core elements.
      Rat models are powerful tools in studies of neurological diseases. Because iNOS
      is most likely responsible for the harmful consequences of nitric oxide (NO) in
      general, the cloned rat iNOS gene will further reveal the mechanisms of iNOS
      inducibility in different cell types during development and disease, including
      brain diseases, and to promote studies of pharmacological intervention in cases
      where extensive NO production plays a critical role.

PMID- 10395903
TI  - Characterization of dentin matrix protein 1 gene in crocodilia.
AB  - Several clones containing DMP1 cDNA were isolated from a caiman tooth library by
      screening with a platypus DMP1 probe. The caiman DMP1 shows little amino acid
      sequence similarity to mammalian DMP1s for much of its length. A few highly
      conserved regions can, however, be identified that correspond to the slowly
      evolving parts of the corresponding mammalian genes. Southern blot analysis using
      probes comprising either conserved regions or longer segments of the gene
      indicates that only a single DMP1 locus exists. In coding regions, exon-intron
      boundaries and reading frames are shared by caiman and mammalian genes with the
      exception of exons 1 and 5, which are longer in the caiman. The repetitive
      sequence of the last exon is shared by mammals and caiman as are the high Ser
      content and acidity due to a high proportion of Asp and Glu residues. The
      conserved mammalian cell-attachment signal Arg-Gly-Asp is absent in the caiman
      DMP1. In contrast to the amelogenin gene, the DMP1 gene appears to evolve rapidly
      in vertebrates.

PMID- 10395904
TI  - Enhanced expression of a nuclease gene in leaves of barley plants under salt
      stress.
AB  - We isolated a cDNA clone, Bnuc1, encoding a nuclease I from leaves of salt
      stressed barley (Hordeum vulgare L. cv. Haruna-nijyo) by the differential display
      method. Northern blot analysis revealed that the transcript of Bnuc1 gene was
      increased dramatically in barley leaves under salt stress. The expression of
      Bnuc1 gene was also increased by exogenously applied abscisic acid (ABA) in
      leaves, but not by gibberellic acid (GA) during seed germination. Furthermore,
      Bnuc1 gene was expressed more in old leaves than in young leaves during both salt
      stress and natural senescence. Salt-inducible nuclease activity possibly
      corresponding to the Bnuc1 gene was detected, and was much higher in old leaves
      than in young leaves under salt stress.

PMID- 10395905
TI  - Imprinted methylation and its effect on expression of the mouse Zfp127 gene.
AB  - The Zfp127 gene is located on mouse chromosome 7 in an imprinted region that is
      homologous to the 2-Mb Prader-Willi and Angelman Syndromes region on human
      chromosome 15q11-q13. Here, we show that the gene is differentially methylated,
      the maternal allele being methylated and the paternal allele being unmethylated.
      This maternal methylation is established promptly after fertilization prior to
      syngamy. We also provide data that demonstrate the significance of methylation in
      the paternal expression of the gene. The expression of the Zfp127 gene in
      methyltransferase-deficient mice is significantly higher, suggesting that the
      gene is biallelically expressed in these mice. The data presented here will help
      to understand the mechanism by which the monoallelic expression of the entire 2
      Mb Prader-Willi and Angelman Syndrome region is regulated.

PMID- 10395906
TI  - The alpha1-microglobulin/bikunin gene: characterization in mouse and evolution.
AB  - The 129Sv mouse gene coding for the alpha1-microglobulin/bikunin precursor has
      been isolated and characterized. The 11kb long gene contains ten exons, including
      six 5'-exons coding for alpha1-microglobulin and four 3'-exons encoding bikunin.
      Exon 7 also codes for the tribasic tetrapeptide RARR which connects the alpha1
      microglobulin and bikunin parts. The sixth intron, which separates the alpha1
      microglobulin and bikunin encoding parts, was compared in the human, mouse and a
      fish (plaice) gene. The size of this intron varies considerably, 6.5, 3.3 and
      0.1kb in man, mouse and plaice, respectively. In all three genes, this intron
      contains A/T-rich regions, and retroposon elements are found in the first two
      genes. This indicates that this sixth intron is an unstable region and a hotspot
      for recombinational events, supporting the concept that the alpha1-microglobulin
      and bikunin parts of this gene are assembled from two ancestral genes. Finally,
      the nonsynonymous nucleotide substitution rate of the gene was determined by
      comparing coding sequences from ten vertebrate species. The results indicate that
      the alpha1-microglobulin part of the gene has evolved faster than the bikunin
      part.

PMID- 10395907
TI  - Characterization of the murine gene encoding 1-Cys peroxiredoxin and
      identification of highly homologous genes.
AB  - A new type of peroxiredoxin, named 1-Cys peroxiredoxin (1-Cys Prx), reduces
      hydrogen peroxide with the use of electrons from unidentified electron donor(s).
      We have isolated the mouse gene encoding 1-Cys Prx (CP-3) and shown that it is
      comprised of five exons and four introns. Analysis of 5' flanking regions
      revealed binding sequences of several putative transcription factors such as Sp1,
      Pit-1a, c-Jun, c-Myc and YY1. It is noticeable that several potential Sp1 binding
      sites assigned the -60 through -96bp from putative transcription initiation site.
      The gel shift assays showed that Sp1 and Pit-1a bind specifically to each binding
      site in 1-Cys Prx promoter. We also isolated two highly related genes such as CP
      2 and CP-5. These genes are encoded by single exons, and show 85% of nucleotide
      sequence homology with the CP-3. The structural features of these genes suggest
      that they might be intronless genes derived from the CP-3 by the mechanism
      involving retrotransposition. In addition, our data suggest that they are
      inserted to a specific site of the mouse L1 repetitive element. The 1-Cys Prx was
      actively transcribed in a variety of adult tissues as well as in the developing
      embryos. These results suggest that only the 1-Cys Prx gene might be relevant for
      studying the function of the 1-Cys Prx in the murine system.

PMID- 10395908
TI  - A sequence with homology to human HPFH-linked enhancer elements and to a family
      of G-protein linked membrane receptor genes is located downstream of the chicken
      beta-globin locus.
AB  - We report 5805bp of novel sequence (GenBank/EMBL Accession No. AJ012570) from a
      region starting approx. 11.5kb downstream of the chicken beta-globin locus (map
      position approx. +30.8 to +36.6kb), which contains a 945bp open reading frame
      (map position approx. +33 to +33.9kb). This is predicted to encode a 315-residue
      protein containing seven hydrophobic helical regions and a 17 amino acid motif
      characteristic of the R7G family of G-protein coupled membrane-bound receptors.
      The open reading frame and some surrounding sequence also have significant
      homology with the breakpoint enhancer elements, which also contain open reading
      frames, implicated in the HPFH-1/2 and HPFH-6 deletional forms of the human
      syndrome, hereditary persistence of foetal haemoglobin (HPFH). The existence of
      similar sequences at similar distances downstream of the beta-globin genes in
      chickens and HPFH patients is intriguing.

PMID- 10395909
TI  - The Drosophila ortholog of the human XPG gene.
AB  - Xeroderma pigmentosum complementation group G (XPG) protein is a junction
      specific endonuclease which is indispensable for nucleotide excision repair (NER)
      of DNA in eukaryotes. Recent studies have hinted at a second, essential function
      for the XPG protein in higher eukaryotes. We undertook a comparison of the amino
      acid sequences of multiple XPG orthologs to determine if a motif or domain could
      be identified that is conserved uniquely in higher eukaryotes. A search of
      current databases allowed us to retrieve complete amino acid sequences for the
      human, mouse and Xenopus XPG proteins, and for two yeast orthologs. We also
      identified an incomplete Drosophila open reading frame (ORF) that was a good
      candidate for the XPG protein. We cloned a complete Drosophila cDNA for this ORF
      and examination of the primary amino acid sequence suggests that this cDNA
      encodes the Drosophila ortholog of XPG. A comparison of all six orthologous
      polypeptides reveals the presence of two previously unidentified conserved
      domains. One of these is unique to all four higher eukaryotic sequences.
      Conceivably this domain evolved to support the essential function of XPG protein.

PMID- 10395910
TI  - Structure analysis of a class II transposon encoding the mercury resistance of
      the Gram-positive Bacterium bacillus megaterium MB1, a strain isolated from
      minamata bay, Japan.
AB  - A unique transposon was found in the chromosome of Bacillus megaterium MB1, a
      Gram-positive bacterium isolated from mercury-polluted sediments of Minamata Bay,
      Japan. The transposon region of a 14.5kb DNA fragment was amplified by PCR using
      a single PCR primer designed from the nucleotide sequence of an inverted repeat
      of class II transposons. The molecular analysis revealed that the PCR-amplified
      DNA fragment encodes a transposition module similar to that of Tn21. The
      transposon also encodes a broad-spectrum mercury resistance region having a
      restriction endonuclease map identical to that of Bacillus cereus RC607, a strain
      isolated from Boston Harbor, USA. The result of a phylogenetic analysis of the
      amino acid sequence of putative resolvase of the transposon showed that the
      transposon is phylogenetically closer to the transposons of Gram-positive
      bacteria than those of Gram-negative bacteria. Besides the transposition module
      and mer operon, the transposon encodes a mobile genetic element of bacterial
      group II introns between the resolvase gene and mer operon. The intron, however,
      does not intervene in any exon gene. The discovery of this newly found
      combination of the complex mobile elements may offer a clue to understanding the
      horizontal dissemination of broad-spectrum mercury resistance among microbes.

PMID- 10395911
TI  - Transcriptional regulatory sequences within the first intron of the chicken
      apolipoproteinAI (apoAI) gene.
AB  - Previous studies demonstrated that the -82 to +87 nucleotides (nt) 5'-upstream
      region of the chicken apolipoprotein (apoAI) gene are necessary for maximum
      reporter chloramphenicol acetyl transferase (cat) gene activation in chicken
      hepatocarcinoma (LMH) cells [Bhattacharyya, N., Chattapadhyay, R., Oddoux, C.,
      Banerjee, D., 1993. Characterisation of the chicken apolipoprotein A-I gene 5'
      flanking region. DNA Cell Biol. 12, 597-604]. The -82 to +87nt contain the 5'
      untranslated nt, part of the first intron, and the upstream regulatory sequences.
      In this study, we examined the role of the first intron in the transcriptional
      regulation of the chicken apoAI gene. Six different reporter cat gene constructs
      with or without part of the first intron were prepared and transfected into LMH,
      normal rat kidney (NRK) and human hepatocarcinoma (HepG2) cells. Cell extracts
      were prepared from each transfected cell line, and CAT activities were measured.
      All three cell-lines readily expressed CAT, indicating that transcriptional
      regulatory sequences are present within the first intron region of the chicken
      apoAI gene. In an enhancer assay, the first intron containing cat construct
      exhibited a 5.4-fold increase of reporter activity in NRK cells when compared to
      a SV 40 promoter containing cat plasmid, suggesting the presence of a moderate
      enhancer element within +29 to +87nt of the first intron. DNase I protection
      assays, electrophoretic mobility shift assays and binding experiments with
      nuclear proteins isolated from different chicken tissues and LMH cells showed
      interaction with +29 to +87nt. Nuclear proteins isolated from tissues like liver
      and intestine, that actively express apoAI gene, failed to interact with +29 to
      +87nt, whereas nuclear proteins isolated from tissues that are less active in
      apoAI gene expression readily interacted with this region. To show the binding of
      the LMH-specific trans-acting factors to the +50 to +68nt intron region, DNA
      affinity chromatography step was performed by using 3H-labeled nuclear proteins.
      These studies demonstrate that the first intron region of the apoAI gene
      interacts with trans-acting proteins and plays an important role in
      transcriptional regulation of the apoAI gene.

PMID- 10395912
TI  - A variety of RNA polymerases II and III-dependent promoter classes is repressed
      by factors containing the Kruppel-associated/finger preceding box of zinc finger
      proteins.
AB  - KRAB/FPB (Kruppel-associated/finger preceding box) domains are small, portable
      transcriptional repression motifs, encoded by hundreds of vertebrates C2-H2-type
      zinc finger genes. We report that KRAB/FPB domains feature an unprecedented,
      highly promiscuous DNA-binding dependent transcriptional repressing activity.
      Indeed, template bound chimeric factors containing KRAB/FPB modules actively
      repress in vivo the transcription of distinct promoter classes that depend on
      different core elements, recruit distinct basal transcriptional apparatuses and
      are transcribed either by RNA polymerase II or III. The promoter types repressed
      in transient assays in a dose- and DNA-binding dependent, but position- and
      orientation-independent manner, by GAL4-KRAB/FPB fusions include an RNA
      polymerase II-dependent small nuclear RNA promoter (U1) as well as RNA polymerase
      III-dependent class 2 (adenovirus VA1), class 3 (human U6) and atypical (human
      7SL) promoters. Down-modulation of all of these templates depended on factors
      containing the A module of the KRAB/FPB domain. Data provide further insights
      into the properties and mode of action of this widespread repression motif, and
      support the notion that genes belonging to distinct classes may be repressed in
      vivo by KRAB/FPB containing zinc finger proteins. The exquisitely DNA-binding
      dependent transcriptional promiscuity exhibited by KRAB/FPB domains may provide a
      unique model system for studying the mechanism by which a promoter recruited
      repression motif can down-modulate a large variety of promoter types.

PMID- 10395913
TI  - Gene expression during gonadogenesis in the chicken embryo.
AB  - Genes implicated in vertebrate sex determination and differentiation were studied
      in embryonic chicken gonads using reverse transcription and the polymerase chain
      reaction (RT-PCR). Expression profiles were obtained during gonadal sex
      differentiation for AMH, SOX9, SOX3, the Wilm's Tumour gene, WT1, and the orphan
      nuclear receptor genes, SF1 and DAX1. Some of these genes showed sexually
      dimorphic expression profiles during gonadal development, whereas others were
      expressed at similar levels in both sexes. The gene encoding Anti-Mullerian
      hormone (AMH) was expressed in both sexes prior to and during sexual
      differentiation of the gonads, with levels of expression consistently higher in
      males than in females. SOX9 expression was male-specific, and was up-regulated
      after the detection of AMH transcripts. SOX3 expression was observed prior to
      clear SOX9 expression and was up-regulated in both sexes at the onset of gonadal
      sex differentiation (but declined later in development). The WT1 gene was highly
      expressed in both sexes, whereas SF1 expression was clearly higher in developing
      ovaries compared to testes. DAX1 transcripts were observed in both sexes at all
      stages examined, but expression appeared somewhat higher in developing ovaries.
      These expression profiles are analysed in terms of current theories of vertebrate
      sex determination.

PMID- 10395915
TI  - Dissimilatory nitrate reductases in bacteria.

PMID- 10395914
TI  - Characterization of mouse Trip6: a putative intracellular signaling protein.
AB  - Trip6 is a human LIM domain-containing protein that has been identified in yeast
      two-hybrid screens as interacting with a variety of proteins. Trip6 has been
      proposed to transport signals from the cell surface to the nucleus. In this
      report, we have characterized a mouse cDNA encoding Trip6. Mouse Trip6 is highly
      similar to human Trip6, especially in the C-terminal LIM domain region, and the
      in vitro and in vivo mouse Trip6 cDNA directs the synthesis of a polypeptide with
      a relative mobility of approx. 57kDa on SDS-polyacrylomide gels. Full-length
      Trip6 localizes to discrete cytoplasmic patches when overexpressed in chicken
      embryo fibroblasts, consistent with localization to focal adhesion plaques.
      However, deletion of the N-terminal 115 amino acids allows Trip6 to enter the
      nucleus of CEF. A GAL4 fusion protein containing the LIM domain region of mouse
      Trip6 can activate transcription in yeast and chicken fibroblasts. Our results
      indicate that the functional domains and properties of mouse Trip6 are highly
      conserved between humans and mice, and are consistent with a model in which Trip6
      relays signals from the cell surface to the nucleus.

PMID- 10395916
TI  - The mouse neurotrophin receptor trkB gene is transcribed from two different
      promoters.
AB  - We have analysed a 7-kb region upstream of the mouse trkB coding sequence. The
      region showed promoter activity in transient transfection experiments and
      conferred tissue-specific expression to a reporter gene. Deletion analysis of
      this region demonstrated the presence of two alternative promoters named P1 and
      P2 that have been mapped by RNase protection. P1 has been located to 1.8 kb and
      P2 to 0.5 kb upstream of the trkB translation start site. From the P1 promoter,
      alternative splicing generates various transcripts. Interestingly, P2 is located
      in an intron of the transcripts produced from the P1 promoter. This peculiar
      arrangement results in different mRNA species that encode the same protein(s) but
      differ in their 5'-untranslated regions. In addition, transcription of the trkB
      locus results in two different trkB isoforms (kinase and truncated receptors)
      originated by alternative splicing of the mRNA, that possess differential spatial
      and temporal expression patterns. Using RT-PCR, we demonstrated that there was no
      linkage between promoter usage and alternative splicing, since transcripts
      initiated from each promoter encoded both kinase and truncated receptor proteins.

PMID- 10395917
TI  - Cathepsin expression during skeletal development.
AB  - Cysteine proteinases, cathepsins B, H, K, L and S, have been implicated in
      several proteolytic processes during development, growth, remodeling and aging,
      as well as in a variety of pathological processes. For systematic analysis of
      cathepsin gene expression we have produced cDNA clones for mouse and human
      cysteine cathepsins. Northern analysis of a panel of total RNAs isolated from 16
      19 different human and mouse tissues revealed the presence of mRNAs for cathepsin
      B, H, K, L and S in most tissues, but each with a distinct profile. Of the
      different cathepsin mRNAs, those for cathepsin K were clearly the highest in bone
      and cartilage. However, relatively high mRNA levels for the other cathepsins were
      also present in these tissues. To better understand the roles of different
      cathepsins during endochondral ossification in mouse long bones, cathepsin mRNAs
      were localized by in situ hybridization. Cathepsin K mRNAs were predominantly
      seen in multinucleated chondroclastic and osteoclastic cells at the osteochondral
      junction and on the surface of bone spicules. The other cathepsin mRNAs were also
      seen in osteoclasts, and in hypertrophic and proliferating chondrocytes. These
      observations were confirmed by immunohistochemistry and suggest that all cysteine
      cathepsins are involved in matrix degradation during endochondral ossification.

PMID- 10395918
TI  - Regulation of gamma-glutamylcysteine synthetase regulatory subunit (GLCLR) gene
      expression: identification of the major transcriptional start site in HT29 cells.
AB  - gamma-Glutamylcysteine synthetase (GCS) is of major importance in glutathione
      homeostasis. The GCS heterodimer is composed of catalytic (heavy subunit, GCSh)
      and regulatory (light subunit, GCSl) subunits. Regulation of the human GCSl
      subunit gene (GLCLR) expression was studied as GCSl has a critical role in
      glutathione synthesis. The minimal basal expression of GLCLR was found to be
      mediated by a region between nt -205 and -318. The major transcriptional start
      site in HT29 cells was located within this region at nt -283. A region between nt
      -411 and -447 was identified as having a potential involvement in the negative
      regulation of GLCLR expression. In order to study the transcriptional regulation
      of GCSl by oxidant stress, HepG2 cells were treated with sodium nitroprusside
      (SNP). SNP (1.5 mM) was found to increase glutathione levels by 2-fold, as well
      as GCS activity by 6-fold. This is accompanied by a co-ordinate increase in the
      levels of the both the GCSl and GCSh subunits, each by approximately 2-fold. The
      transcriptional activity of the GLCLR gene was increased by approximately 2.5
      fold in SNP-treated cells.

PMID- 10395919
TI  - A novel subgroup of class I G-protein-coupled receptors.
AB  - Based on structural similarities of an expressed sequence tag with the platelet
      activating factor (PAF) receptor a cDNA clone encoding a novel G-protein-coupled
      receptor (GPCR), named GPR34, was isolated from a human fetal brain cDNA library.
      Genomic DNA analyses revealed the receptor to be encoded by an intronless single
      copy gene at Xp11. 3-11.4. The predicted 381-amino-acid protein disclosed all
      structural features characteristic of a member of the class I GPCR family. Except
      an obvious sequence homology in transmembrane domain 6, no further similarities
      to the PAF receptor or any other known GPCR were found. The corresponding mouse
      receptor DNA was isolated from a genomic P1 library displaying a 90% amino acid
      identity compared to the human receptor. Phylogenetic studies showed that GPR34
      is preserved among vertebrates, and the existence of GPR34 subtypes was
      demonstrated. The receptor mRNA is abundantly expressed in human and mouse
      tissues. In addition to the major 2-kb transcript, a 4-kb transcript was found
      only in mouse liver and testis. Expression of the human GPR34 in COS-7 cells
      followed by Western blot studies revealed specific bands of a highly glycosylated
      protein between 75 and 90 kDa. A number of potential ligands including
      phospholipids, leukotrienes, hydroxy-eicosatetraenoic acids, nucleotides and
      peptides were tested in functional assays. Since none of the applied substances
      led to significant changes in second messenger levels (cAMP and inositol
      phosphates), the natural ligand and coupling profile of this novel GPCR subgroup
      remains unknown.

PMID- 10395921
TI  - c-Myb protein binds to the EP element of the HBV enhancer and regulates
      transcription in synergy with NF-M.
AB  - The hepatitis B virus (HBV) enhancer contains multiple active elements, one of
      which is the EP element, a 15 bp site important for its regulation by acting on
      other functional elements like the E site. The EP element, in the HBV enhancer
      context, contains two putative binding sites for c-myb family gene products.
      Electrophoretic mobility shift assays showed that the minimal c-Myb DNA-binding
      domain binds to the EP sequence. DNase I footprinting experiments revealed that
      only one consensus binding site was effectively protected. We found that c-Myb
      down-regulates transcription driving by the HBV enhancer in CAT assays performed
      in a haematopoietic (K562) and in a hepatic (HepG2) cell line. Interestingly, co
      expression of both c-Myb and NF-M, a C/EBPbeta homologue which recognises the E
      element of the HBV enhancer, showed a synergistic transactivation of the HBV
      enhancer while, separately, each of them had an inhibitory effect on
      transcription in HepG2 and K562 cell lines, two cell types potentially infected
      by the hepatitis B virus.

PMID- 10395920
TI  - Identification of a novel transcriptional regulatory element within the promoter
      region of the keratinocyte growth factor gene that mediates inducibility to
      cyclic AMP.
AB  - Keratinocyte growth factor (KGF) plays a critical role for the normal development
      and morphogenesis of many different tissues and organs. Furthermore, its
      expression is induced during wound healing and in various chronic inflammatory
      diseases. To determine the molecular mechanisms which regulate KGF gene induction
      at the transcriptional level, we carried out in vitro studies using the human KGF
      promoter. We have identified a novel regulatory element, TGAGGTCAG, located
      between -39 and -46 bp (relative to the transcription start site) in the KGF
      basal promoter region, which binds to inducible transcription factors as
      determined by electrophoretic mobility shift assay. When cloned in front of a
      heterologous SV40 promoter this region conferred inducibility to forskolin, a
      stimulator of adenylate cyclase. In contrast, various mutated forms of this
      region were either partially or completely impaired in their ability to mediate
      induction to forskolin. The TGAGGTCAG sequence shared homology to both the cAMP
      responsive element (CRE) and CCAAT/enhancer binding protein (C/EBP) consensus
      binding sites. An oligonucleotide comprising a consensus CRE binding site
      partially competed for the nuclear protein binding to the TGAGGTCAG site. Gel
      mobility supershift assays indicated that two members of the activating
      transcription factor (ATF) family of CRE binding proteins, ATF1 and ATF2, were
      part of the nuclear protein complex bound to this regulatory region. Furthermore,
      purified recombinant ATF2 was able to directly recognize and bind the TGAGGTCAG
      sequence. In contrast, no evidence was obtained for C/EBP transcription factors
      being part of the complex. These results suggest that members of the ATF family
      are involved in mediating the transcriptional regulation of the KGF gene in
      response to extracellular stimuli via a novel CRE regulatory element.

PMID- 10395922
TI  - Isolation of a novel gene, moc2, encoding a putative RNA helicase as a suppressor
      of sterile strains in Schizosaccharomyces pombe.
AB  - A novel gene designated moc2, which encodes a putative RNA helicase, was isolated
      from Schizosaccharomyces pombe on the basis of its suppression of the sterility
      of two different mutant strains, one of which had elevated levels of cAMP and the
      other deregulated Ras functioning as a result of an ectopic expression of
      dominant negative RAS2. Moc2 is highly homologous to the RNA helicase DED1 of
      Saccharomyces cerevisiae (58% identity) and PL10 of mouse (50% identity).
      Disruption of the moc2 gene indicated that moc2 is essential for cell growth. The
      moc2 gene seems to have roles in both sexual differentiation and cell growth.

PMID- 10395923
TI  - Effects of domain exchanges between Escherichia coli and mammalian mitochondrial
      EF-Tu on interactions with guanine nucleotides, aminoacyl-tRNA and ribosomes.
AB  - Escherichia coli elongation factor (EF-Tu) and the corresponding mammalian
      mitochondrial factor, EF-Tumt, show distinct differences in their affinities for
      guanine nucleotides and in their interactions with elongation factor Ts (EF-Ts)
      and mitochondrial tRNAs. To investigate the roles of the three domains of EF-Tu
      in these differences, six chimeric proteins were prepared in which the three
      domains were systematically switched. E. coli EF-Tu binds GDP much more tightly
      than EF-Tumt. This difference does not reside in domain I alone but is regulated
      by interactions with domains II and III. All the chimeric proteins formed ternary
      complexes with GTP and aminoacyl-tRNA although some had an increased or decreased
      activity in this assay. The activity of E. coli EF-Tu but not of EF-Tumt is
      stimulated by E. coli EF-Ts. The presence of any one of the domains of EF-Tumt in
      the prokaryotic factor reduced its interaction with E. coli EF-Ts 2-3-fold. In
      contrast, the presence of any of the three domains of E. coli EF-Tu in EF-Tumt
      allowed the mitochondrial factor to interact with bacterial EF-Ts. This
      observation indicates that even domain II which is not in contact with EF-Ts
      plays an important role in the nucleotide exchange reaction. EF-Tsmt interacts
      with all of the chimeras produced. However, with the exception of domain III
      exchanges, it inhibits the activities of the chimeras indicating that it could
      not be productively released to allow formation of the ternary complex. The
      unique ability of EF-Tumt to promote binding of mitochondrial Phe-tRNAPhe to the
      A-site of the ribosome resides in domains I and II. These studies indicate that
      the interactions of EF-Tu with its ligands is a complex process involving cross
      talk between all three domains.

PMID- 10395924
TI  - Characterisation of the enzymatic and RNA-binding properties of the Rhodobacter
      sphaeroides 2.4.1. Rho homologue.
AB  - The Escherichia coli Rho is a transcription termination factor with complex
      enzymatic properties. Rho is a near-universal prokaryotic transcription factor,
      but very few non-enteric Rho factors have been studied. The expression and
      enzymatic activity of Rho from the GC-rich, Gram-negative bacterium Rhodobacter
      sphaeroides was characterised. Poly(C)-activated ATP hydrolysis, multimerisation
      and the abundance of the R. sphaeroides Rho were similar to the E. coli Rho. The
      R. sphaeroides Rho was a DNA:RNA helicase. The R. sphaeroides Rho was unique in
      Rho factors characterised to date in that it did not interact with the lambdatR1
      terminator transcript and ATP hydrolysis was unusually weakly activated by
      poly(U) RNA. A chimeric Rho (RhoER), with the RNA-binding domain from the E. coli
      Rho and the ATPase domain of the R. sphaeroides Rho, was activated by RNA co
      factors in a similar fashion to the E. coli Rho. The activity of RhoER suggests
      functional interactions between the N- and C-terminal domains of Rho monomers are
      highly conserved between Rho factors. The main differences between Rho factors
      from different bacteria is in the specificity of RNA binding although this does
      not appear to be necessarily dependent on the GC bias of target RNA as has been
      previously suggested.

PMID- 10395926
TI  - Comparison of CMV, RSV, SV40 viral and Vlambda1 cellular promoters in B and T
      lymphoid and non-lymphoid cell lines.
AB  - Determining the activity of viral and cellular regulatory elements in B or T
      lymphoid cell lines would facilitate appropriate utilization of the regulatory
      sequences for gene transfer- and expression-dependent applications. We have
      compared the activity of the CMV, RSV and SV40 viral promoter/enhancers as well
      as the Vlambda1 cellular promoter, in three B cell lines (REH, SMS-SB, C3P),
      three T cell lines (CEM, Jurkat, ST-F10), and two non-lymphoid cell lines (K-562,
      HeLa) using the luciferase reporter gene. In B cell lines, the activity of the
      CMV promoter/enhancer construct was the highest ranging from 10- to 113-fold
      greater than that of SV40. In contrast, in T cell lines the RSV promoter/enhancer
      activity was 11-65-fold higher than that of SV40. The Vlambda1 promoter activity
      was close to that of SV40 promoter/enhancer in most of the cell lines tested. We
      conclude that CMV and RSV promoter/enhancers contain stronger regulatory elements
      than do the SV40 and Vlambda1 for expression of genes in lymphoid cell lines.

PMID- 10395925
TI  - Mitochondrial DNA replication in human T lymphocytes is regulated primarily at
      the H-strand termination site.
AB  - The most unique feature in the replication of mitochondrial DNA (mtDNA) is that
      most of the newly synthesized heavy strands (H-strands) terminate prematurely,
      resulting in the formation of displacement loop (D-loop) strands. Only the H
      strand which proceeds past the termination site is a true nascent H-strand
      leading to the overall replication on a circular mtDNA molecule. The
      physiological significance of the D-loop formation has long been unclear. To
      examine the role of premature termination in mtDNA replication, we therefore
      developed a method for selectively measuring both the total amount of nascent H
      strands and the amount of true nascent H-strands using ligation-mediated
      polymerase chain reaction, which, for the first time, enabled us to estimate the
      frequency of premature termination. The stimulation of cell proliferation with
      interleukin 2 and phytohemagglutinin in human peripheral T lymphocytes caused an
      increase in the net replication rate of mtDNA. In stimulated cells, in comparison
      to resting ones, the amount of true nascent H-strands increased approx. 2.6-fold
      while the total amount of nascent H-strands remained unchanged, indicating that
      premature termination decreased while the initiation of replication remained the
      same. Our findings thus demonstrate the first clear example that premature
      termination plays a primary role in the up-regulation of the net rate of mtDNA
      replication in human cells.

PMID- 10395927
TI  - Interferon regulatory factor 1 tryptophan 11 to arginine point mutation abolishes
      DNA binding.
AB  - Interferon regulatory factor-1 (IRF-1) is a transcriptional activator of genes
      induced by a variety of cytokines and growth factors. Defects in IRF-1 occur
      frequently in human cancers and may contribute to tumorigenesis. The IRF family
      of transcription factors share invariant tryptophan residues that have been
      proposed to function by orienting the DNA contacting residues of IRF-1 with the
      DNA core sequence of the IRF element. Here we describe a point mutation in IRF-1
      that converts the tryptophan at codon 11 to arginine (W11R). The IRF-1 (W11R)
      mutation abolishes IRF-1 DNA binding and transactivating activities demonstrating
      the critical role of this invariant tryptophan in IRF-1 function.

PMID- 10395928
TI  - Eubacterial tmRNAs: everywhere except the alpha-proteobacteria?
AB  - Eubacterial tmRNAs mediate, at least in Escherichia coli, recycling of ribosomes
      stalled at the end of terminatorless mRNAs. A tmRNA-encoded peptide tag is added
      to abnormal protein products of truncated mRNAs. This tag is a specific signal
      for proteolysis of the aberrant protein. To obtain further sequence information,
      PCR was used to amplify more Eubacterial genes for tmRNA. Fifty-eight new tmDNA
      sequences including from members of nine additional phyla were determined.
      Remarkably, tmDNA sequences could be amplified from all species tested apart from
      those in the alpha-Proteobacteria, raising evolutionary implications.

PMID- 10395929
TI  - Molecular cloning and expression of the Na+/H+ exchanger gene in Oryza sativa.
AB  - Na+/H+ exchanger catalyzes the countertransport of Na+ and H+ across membranes.
      We isolated a rice cDNA clone the deduced amino acid sequence of which had
      homology with a putative Na+/H+ exchanger in Saccharomyces cerevisiae, NHX1. The
      sequence contains 2330 bp with an open reading frame of 1608 bp. The deduced
      amino acid sequence is similar to that of NHX1 and NHE isoforms in mammals, and
      shares high similarity with the sequences within predicted transmembrane segments
      and an amiloride-binding domain. The expression of the gene was increased by salt
      stress. These results suggest that the product of the novel gene, OsNHX1,
      functions as a Na+/H+ exchanger, and plays important roles in salt tolerance of
      rice.

PMID- 10395930
TI  - Characterization of two zebrafish cDNA clones encoding egg envelope proteins ZP2
      and ZP3.
AB  - Two zebrafish cDNA clones encoding homologs of mammalian zona pellucida proteins
      ZP2 and ZP3 were isolated from a whole adult cDNA library. The ZP2 clone encodes
      a protein of 428 amino acids. Unlike other teleost ZP2s that contain an N
      terminal repetitive domain enriched with prolines and glutamines, the zebrafish
      ZP2 has no such repetitive domain. In the C-terminal non-repetitive domain, the
      zebrafish ZP2 shares 55-76% sequence identity with other teleost ZP2s. The ZP3
      cDNA clone encodes a protein of 431 amino acids, which shares 61% sequence
      identity with a carp ZP3. Similar to mammalian ZP proteins, both zebrafish ZP2
      and ZP3 contain several potential phosphorylation sites. However, unlike
      mammalian ZP proteins, both zebrafish ZP proteins contain almost no glycosylation
      site, which has been proposed to be important for interaction with sperm; thus,
      the ZP proteins may behave differently in mammals and teleosts. Northern blot
      analysis indicated that both zebrafish ZP2 and ZP3 mRNAs were expressed
      exclusively in the ovary and hence the ovary is likely the only site for ZP2 and
      ZP3 biosynthesis.

PMID- 10395931
TI  - Identification, cloning and analysis of expression of a new alternatively spliced
      form of the metabotropic glutamate receptor mGluR1 mRNA1.
AB  - We have applied quantitative RT-PCR analysis to characterise relative levels of
      expression of the alternatively spliced mGluR1 mRNAs. This has also allowed us to
      identify and clone a new alternatively spliced form of the mGluR1 mRNA. The newly
      identified mGluR1f mRNA is expressed at moderate levels in rat brain, reaching
      its maximum in cortex. mGluR1f differs from the mGluR1a mRNA by deletion of a 35
      bp fragment of the mGluR1a/alpha coding sequence and insertion of an 85-bp
      fragment, found only in mGluR1b/beta mRNA.

PMID- 10395932
TI  - Genomic organization, sequence and transcriptional regulation of the human CXCL
      11(1) gene.
AB  - CXCL 11, encoded by the cDNA sequences designated beta-R1, H-174, or I-TAC, is a
      CXC chemokine ligand for CXCR3 and assumed to be involved in inflammatory
      diseases characterized by the presence of activated T-cells. We here describe the
      genomic organization (four exons interrupted by three introns of 585, 98 and 230
      bp) and sequence including 960 bp from the immediate 5'-upstream region of the
      human CXCL 11 gene. Within the promoter region, consensus sequences for
      regulatory elements (ISRE, GAS, NF-kappaB) important for cytokine-induced gene
      transcription were identified. The effect of (pro)inflammatory cytokines on CXCL
      11 mRNA expression in monocytic cell lines (THP-1, U937) and primary cultures of
      dermal fibroblasts and endothelial cells were examined using Northern blot
      analysis. For these cell types, IFN-gamma was a potent inducer of CXCL 11
      transcription, which was synergistically enhanced by TNF-alpha.

PMID- 10395933
TI  - Membrane traffic and the cellular uptake of cholera toxin.
AB  - In nature, cholera toxin (CT) and the structurally related E. coli heat labile
      toxin type I (LTI) must breech the epithelial barrier of the intestine to cause
      the massive diarrhea seen in cholera. This requires endocytosis of toxin-receptor
      complexes into the apical endosome, retrograde transport into Golgi cisternae or
      endoplasmic reticulum (ER), and finally transport of toxin across the cell to its
      site of action on the basolateral membrane. Targeting into this pathway depends
      on toxin binding ganglioside GM1 and association with caveolae-like membrane
      domains. Thus to cause disease, both CT and LTI co-opt the molecular machinery
      used by the host cell to sort, move, and organize their cellular membranes and
      substituent components.

PMID- 10395934
TI  - Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type.
AB  - A multigenic family of Ca2+-binding proteins of the EF-hand type known as S100
      comprises 19 members that are differentially expressed in a large number of cell
      types. Members of this protein family have been implicated in the Ca2+-dependent
      (and, in some cases, Zn2+- or Cu2+-dependent) regulation of a variety of
      intracellular activities such as protein phosphorylation, enzyme activities, cell
      proliferation (including neoplastic transformation) and differentiation, the
      dynamics of cytoskeleton constituents, the structural organization of membranes,
      intracellular Ca2+ homeostasis, inflammation, and in protection from oxidative
      cell damage. Some S100 members are released or secreted into the extracellular
      space and exert trophic or toxic effects depending on their concentration, act as
      chemoattractants for leukocytes, modulate cell proliferation, or regulate
      macrophage activation. Structural data suggest that many S100 members exist
      within cells as dimers in which the two monomers are related by a two-fold axis
      of rotation and that Ca2+ binding induces in individual monomers the exposure of
      a binding surface with which S100 dimers are believed to interact with their
      target proteins. Thus, any S100 dimer is suggested to expose two binding surfaces
      on opposite sides, which renders homodimeric S100 proteins ideal for
      crossbridging two homologous or heterologous target proteins. Although in some
      cases different S100 proteins share their target proteins, in most cases a high
      degree of target specificity has been described, suggesting that individual S100
      members might be implicated in the regulation of specific activities. On the
      other hand, the relatively large number of target proteins identified for a
      single S100 protein might depend on the specific role played by the individual
      regions that in an S100 molecule contribute to the formation of the binding
      surface. The pleiotropic roles played by S100 members, the identification of S100
      target proteins, the analysis of functional correlates of S100-target protein
      interactions, and the elucidation of the three-dimensional structure of some S100
      members have greatly increased the interest in S100 proteins and our knowledge of
      S100 protein biology in the last few years. S100 proteins probably are an example
      of calcium-modulated, regulatory proteins that intervene in the fine tuning of a
      relatively large number of specific intracellular and (in the case of some
      members) extracellular activities. Systems, including knock-out animal models,
      should be now used with the aim of defining the correspondence between the in
      vitro regulatory role(s) attributed to individual members of this protein family
      and the in vivo function(s) of each S100 protein.

PMID- 10395935
TI  - 3'-Azido-3'-deoxythymidine reduces the rate of transferrin receptor endocytosis
      in K562 cells.
AB  - K562 cells, exposed for at least 24 h to 5 microM 3'-azido-3'-deoxythymidine
      (AZT), gave rise to an overall increase in the number of cell surface transferrin
      binding receptors (18-20%). This effect was ascertained either with binding
      experiments by using 125I-transferrin and with immunoprecipitation by using a
      specific monoclonal antibody against the transferrin receptor. At higher AZT
      concentrations (20 and 40 microM), a further increase was found, that is, up to
      23% by binding experiments and up to 110% by immunoprecipitation. However,
      Scatchard analysis of the binding data indicated that although the number of cell
      surface transferrin receptors increased, the affinity of transferrin for its
      receptor did not change (Ka=4.0x108 M). Surprisingly, immunoprecipitation of
      total receptor molecules showed that the synthesis of receptor was not enhanced
      by the drug treatment. The effect of AZT on transferrin internalization and
      receptor recycling was also investigated. In this case, data indicated that the
      increase in the number of receptors at the cell surface was probably due to a
      slowing down of endocytosis rate rather than to an increased recycling rate of
      the receptor to cell surface. In fact, the time during which half the saturated
      amount of transferrin had been endocytosed (t1/2) was 2.15 min for control cells
      and 3.41, 3.04, and 3.74 min for 5, 20, and 40 microM AZT-treated cells,
      respectively. Conversely, recycling experiments did not show any significant
      differences between control and treated cells. A likely mechanism through which
      AZT could interfere with the transferrin receptor trafficking, together with the
      relevance of our findings, is extensively discussed.

PMID- 10395936
TI  - Protein kinase C stimulates PtdIns-4,5-P2-phospholipase C activity.
AB  - The tumour promoter, phorbol ester 12,13-dibutyrate (PDBu), acts on rectal
      palisadic epithelial cells and mimics the effects of neuroparsin, an antidiuretic
      neuronal hormone isolated from nervous lobes of the African locust corpora
      cardiaca. PDBu stimulated Ca2+-dependent phospholipase C (PLC) activity resulting
      in inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) production, increased cytosolic
      free calcium (monitored with the probe indo-1) and rectal fluid resorption. A 15
      min pre-treatment with polymyxin B (PMXB), a protein kinase C (PKC) inhibitor
      acting at the phosphatidylserine (PS) binding site, suppressed PDBu stimulatory
      effects on free calcium entry and fluid resorption but not on
      phosphatidylinositol 4, 5-bisphosphate (PtdIns-4,5-P2) breakdown. On the
      contrary, bisindolylmaleimide Ro 32-0432 (which inhibits PKC at its ATP binding
      site) abolished entirely PDBu-stimulated PLC activity. It was concluded that two
      PKC are involved in transduction of the antidiuretic signal of neuroparsin. One
      PKC is PMXB sensitive and stimulates biological response after cytosolic free
      Ca2+ increase, while another PKC, insensitive to the PKC inhibitor, regulates the
      processes induced by the former PKC. Since PMXB-insensitive PKC exerts a
      stimulatory effect on PtdIns-4,5-P2-PLC production, this original mechanism may
      be considered as a new signalling pathway under control of PKC.

PMID- 10395937
TI  - Expressed sequence tag (EST) phenotyping of HT-29 cells: cloning of ser/thr
      protein kinase EMK1, kinesin KIF3B, and of transcripts that include Alu repeated
      elements.
AB  - To study the mechanisms that control epithelial commitment and differentiation we
      have used undifferentiated HT-29 colon cancer cells and a subpopulation of mucus
      secreting cells obtained by selection of HT-29 cells in 10-6 M methotrexate (M6
      cells) as experimental models. We isolated cDNAs encoding transcripts
      overexpressed in early confluent M6 cells regarding steady-state levels in HT-29
      cells by subtractive hybridisation. Fifty-one cDNA clones, corresponding to 34
      independent transcripts, were isolated, partially sequenced by their 5' end, and
      classified into four groups according to their identity: transcripts that
      included a repeated sequence of the Alu family (10 clones, among them those
      encoding ribonucleoprotein RNP-L and E-cadherin), transcripts encoded by the
      mitochondrial genome (nine clones), transcripts encoding components of the
      protein synthesis machinery (23 clones, including the human ribosomal protein L38
      not previously cloned in humans) and nine additional cDNAs that could not be
      classified in the previous groups. These last included ferritin, cytokeratin 18,
      translationally controlled human tumour protein (TCHTP), mt-aldehyde
      dehydrogenase, as well as unknown transcripts (three clones), and the human
      homologues of the molecular motor kinesin KIF3B and of the ser/thr protein kinase
      EMK1. Spot dot and Northern blot analyses showed that ser/thr protein kinase EMK1
      was differentially expressed in M6 cells when compared with parental HT-29 cells.
      Steady-state levels of EMK1 were higher in proliferating, preconfluent, M6 and HT
      29 cells than in 2 days post confluence (dpc) and 8dpc M6 and HT-29 cells.
      Transcripts that included an Alu repeat were also shown to be differentially
      expressed and accumulated in differentiating M6 cells when analysed by Northern
      blot. The significance of the transcripts cloned is discussed in the context of
      the commitment and differentiation of the M6 cells to the mucus secreting lineage
      of epithelial cells.

PMID- 10395939
TI  - Enzyme distributions in subcellular fractions of BHK cells infected with Semliki
      forest virus: evidence for a major fraction of sphingomyelin synthase in the
      trans-golgi network.
AB  - BHK cells either untreated or infected with Semliki Forest virus have been
      fractionated on sucrose density gradients. Virus infection caused an increase in
      density of a membrane fraction enriched in sphingomyelin (SM), cholesterol, SM
      synthase and sialyltransferase activity. This increase in density was related to
      incorporation of viral proteins into this fraction, which is likely to contain
      trans-Golgi network (TGN) membranes. In contrast, glucosylceramide synthase and
      galactosyltransferase activities (markers for cis/medial and trans-Golgi
      respectively) underwent no density shift and alkaline phosphodiesterase, a plasma
      membrane marker, was only slightly density-shifted in infected cells. When cells
      were incubated with NBD-ceramide to enable them to synthesise NBD-SM and then
      washed with albumin to remove surface label, fluorescence in untreated cells was
      concentrated in a single juxtanuclear spot but in infected cells this region of
      bright fluorescence was larger and extended around the nucleus. After
      fractionation of these cells, NBD-SM (but only a small proportion of the NBD
      ceramide) was found to be shifted into the higher density fraction in infected
      cells. This work provides further evidence that SM synthase is not mainly
      localised in the early Golgi cisternae as previously thought, but is associated
      more with a cholesterol-rich compartment which could be the TGN.

PMID- 10395938
TI  - PAR1 activation initiates integrin engagement and outside-in signalling in
      megakaryoblastic CHRF-288 cells.
AB  - To better understand the means by which cells such as human platelets regulate
      the binding of the integrin alphaIIbbeta3 to fibrinogen, we have examined agonist
      initiated inside-out and outside-in signalling in CHRF-288 cells, a
      megakaryoblastic cell line that expresses alphaIIbbeta3 and the human thrombin
      receptor, PAR1. The results show several notable similarities and differences.
      (1) Activation of PAR1 caused CHRF-288 cells to adhere and spread on immobilized
      fibrinogen in an alphaIIbbeta3-dependent manner, but did not support the binding
      of soluble fibrinogen or PAC-1, an antibody specific for activated alphaIIbbeta3.
      (2) Direct activation of protein kinase C with PMA or disruption of the actin
      cytoskeleton with low concentrations of cytochalasin D also caused CHRF-288 cells
      to adhere to fibrinogen. (3) Despite the failure to bind soluble fibrinogen,
      activation of PAR1 in CHRF-288 cells caused phosphoinositide hydrolysis,
      arachidonate mobilization and the phosphorylation of p42MAPK, phospholipase A2
      and the Rac exchange protein, Vav, all of which occur in platelets. PAR1
      activation also caused an increase in cytosolic Ca2+, which, when prevented,
      blocked adhesion to fibrinogen. (4) Finally, as in platelets, adhesion of CHRF
      288 cells to fibrinogen was followed by a burst of integrin-dependent ('outside
      in') signalling, marked by FAK phosphorylation and a more prolonged
      phosphorylation of p42MAPK. However, in contrast to platelets, adhesion to
      fibrinogen had no effect on Vav phosphorylation. Collectively, these observations
      show that signalling initiated through PAR1 in CHRF-288 cells can support
      alphaIIbbeta3 binding to immobilized ligand, but not the full integrin activation
      needed to bind soluble ligand. This would suggest that there has been an increase
      in integrin avidity without an accompanying increase in affinity. Such increases
      in avidity are thought to be due to integrin clustering, which would also explain
      the results obtained with cytochalasin D. The failure of alphaIIbbeta3 to achieve
      the high affinity state in CHRF-288 cells was not due to the failure of PAR1
      activation to initiate a number of signalling events that normally accompany
      platelet activation nor did it prevent at least some forms of outside-in
      signalling. However, at least one marker of outside-in signalling, the
      augmentation of Vav phosphorylation seen during platelet aggregation, did not
      occur in CHRF-288 cells.

PMID- 10395940
TI  - Coupling of thromboxane A2 receptor isoforms to Galpha13: effects on ligand
      binding and signalling.
AB  - Previous subtyping of thromboxane A2 (TXA2) receptors in platelets and vascular
      smooth muscle cells was based on pharmacological criteria. Two distinct carboxy
      terminal splice variants for TXA2 receptors exist and they couple to several
      different G protein alpha subunits including Galpha13, but it has not been
      established whether either or both isoforms interact with and signal through it.
      We sought to determine: (1) which TXA2 receptor isoforms exist in vascular smooth
      muscle, (2) if Galpha13 is present in vascular smooth muscle and (3) if Galpha13
      interacts with either or both of the two TXA2 receptor isoforms as determined by
      changes in ligand binding properties and generation of intracellular signals.
      Both TXA2 receptor isoforms and Galpha13 were found in vascular smooth muscle
      cells. Both the alpha and beta isoforms of the TXA2 receptors were transiently
      transfected with or without Galpha13 into COS-7 (radioligand binding assays) or
      CHO cells (agonist induced Na+/H+ exchange). Co-expression of each receptor
      isoform with Galpha13 significantly (P<0.05) increased the affinity of each
      receptor for the two agonists, I-BOP and ONO11113, and decreased the affinity of
      the receptor for the antagonists, SQ29,548 and L657,925. I-BOP stimulated Na+/H+
      exchange in vascular smooth muscle cells. Co-expression of Galpha13 with each
      TXA2 receptor isoform in CHO cells resulted in a significant (P<0.04) agonist
      induced increase in Na+/H+ exchange compared to cells not transfected with
      Galpha13. The results support the possibility that the previous classification of
      TXA2 receptor subtypes based on pharmacological criteria reflect unique
      interactions with specific G protein alpha subunits.

PMID- 10395941
TI  - Delayed labelling of brain glutamate after an intra-arterial [13C]glucose bolus:
      evidence for aerobic metabolism of guinea pig brain glycogen store.
AB  - Glycogen in glial cells is the largest store of glucose equivalents in the brain.
      Here we describe evidence that brain glycogen contributes to aerobic energy
      metabolism of the guinea pig brain in vivo. Five min after an intra-arterial
      bolus injection of d-[U-14C]glucose, 28+/-11% of the radioactivity in brain
      tissue was associated with the glycogen fraction, indicating that a significant
      proportion of labelled glucose taken up by the brain is converted to glycogen
      shortly after bolus infusion. Incorporation of 13C-label into lactate generated
      by brains made ischaemic after d-[1-13C]glucose injection confirms that these
      glucose equivalents can be mobilised for anaerobic glucose metabolism. Aerobic
      metabolism was monitored by following the time course of 13C-incorporation into
      glutamate in guinea pig cortex and cerebellum in vivo. After an intra-arterial
      bolus injection of d-[1-13C]glucose, glutamate labelling reached a maximum 40-60
      min after injection, suggesting that a slowly metabolised pool of labelled
      glucose equivalents was present. As the concentration of 13C-labelled glucose in
      blood was shown to decrease below detectable levels within 5 min of bolus
      injection, this late phase of glutamate labelling must occur with mobilisation of
      a brain storage pool of labelled glucose equivalents. We interpret this as
      evidence that glucose equivalents in glycogen may contribute to energy metabolism
      in the aerobic guinea pig brain.

PMID- 10395942
TI  - Retinoic acid repressed the expression of c-fos and c-jun and induced apoptosis
      in regenerating rat liver after partial hepatectomy.
AB  - Retinoic acid (RA), which was injected within 4 h after partial hepatectomy (PH),
      inhibited DNA synthesis in regenerating liver. The inhibition was accompanied by
      apoptosis, evidenced by in situ end labeling and gel electrophoresis of DNA
      fragmentation. Characteristic DNA fragmentation was obvious at 4 h and reached a
      maximum at 8 h after injection. Northern blot analysis revealed that RA repressed
      the expression of c-fos and c-jun at 15 and 30 min with the up-regulation of
      retinoic acid receptor gamma (RARgamma) and RARbeta at 2 h after PH. The
      transglutaminase II mRNA level and activity were increased by RA injection at 4 h
      and 8 h after PH, respectively. The mRNA levels of thymidylate synthase and
      thymidine kinase, which are rate determining enzymes of DNA synthesis, decreased
      in RA injected rats. No change was seen in the expression of p53 and p21WAF1/CIP1
      which have been suggested to participate in the apoptosis process. These results
      suggest that RA exerts the antiproliferative activity only on the early stage of
      liver regeneration accompanied by the repression of c-fos and c-jun expression
      and induction of apoptosis.

PMID- 10395943
TI  - Signal transduction in the vomeronasal organ of garter snakes: ligand-receptor
      binding-mediated protein phosphorylation.
AB  - The vomeronasal (VN) system of garter snakes plays an important role in several
      species-typical behaviors, such as prey recognition and responding to courtship
      pheromones. We (X.C. Jiang et al., J. Biol. Chem. 265 (1990) 8736-8744 and Y. Luo
      et al., J. Biol. Chem. 269 (1994) 16867-16877) have demonstrated previously that
      in the snake VN sensory epithelium, the chemoattractant ES20, a 20-kDa
      glycoprotein derived from electric shock-induced earthworm secretion, binds to
      its receptor which is coupled to PTX-sensitive G-proteins. Such binding results
      in elevated levels of IP3. We now report that ES20-receptor binding regulates the
      phosphorylation of two membrane-bound proteins with molecular masses of 42- and
      44-kDa (p42/44) in both intact and cell-free preparations of the VN sensory
      epithelium. ES20 and DAG regulate the phosphorylation of p42/44 in a similar
      manner. ES20-receptor binding-mediated phosphorylation of p42/44 is rapid and
      transient, reaching a peak value within 40 seconds and decaying thereafter.
      Phosphorylation of p42/44 appears to be regulated by the countervailing actions
      of a specific membrane-bound protein kinase and a protein phosphatase. The
      phosphorylation of these membrane-bound proteins significantly reduces the
      activity of G-proteins as evidenced by a decrease in GTPase activity, but has
      little effect on ligand-receptor binding. These findings suggest that p42/44 play
      a role in modulating the signal transduction induced by ES20 in the vomeronasal
      system.

PMID- 10395944
TI  - Transcriptional regulation of a receptor protein tyrosine phosphatase gene hPTP-J
      by PKC-mediated signaling pathways in Jurkat and Molt-4 T lymphoma cells.
AB  - The recently cloned type II receptor protein tyrosine phosphatase (RPTP) gene
      hPTP-J is a new member of the MAM (meprin, A5, PTPmicro) domain subfamily. We
      previously reported that hPTP-J mRNA was detected significantly in Jurkat T
      lymphoma cells and its expression was completely down-regulated by phorbol
      myristate acetate (PMA). In this study, we investigated what signaling
      pathways/molecules are involved in the transcriptional regulation of hPTP-J
      expression in Jurkat and Molt-4 T cell lines. The hPTP-J transcription was
      transiently up-regulated 20 min after the addition of PMA (20 ng/ml) to the
      Jurkat culture, followed by the complete down-regulation in 8 h after PMA
      addition. The transient up-regulation and the complete down-regulation induced by
      PMA was blocked by a PKC-specific inhibitor, GF109203X, suggesting that the
      regulatory effect of PMA on the hPTP-J transcription depends on protein kinase C
      activation. hPTP-J transcription was down-regulated not only by PMA but also by
      several signaling modulators including 1-oleoyl-2-acetylglycerol, forskolin,
      orthovanadate, manumycin and okadaic acid. Therefore, several signaling molecules
      such as protein tyrosine phosphatases, PP2A/CaMKIV and Ras are required for hPTP
      J transcription in Jurkat and Molt-4 cells.

PMID- 10395945
TI  - Enhancement of tyrosyl phosphorylation and protein expression of eps8 by v-Src.
AB  - Two eps8 isoforms, p97eps8 and p68eps8, were previously identified as substrates
      for receptor tyrosine kinases. Analysis of eps8 phosphotyrosine content in v-Src
      transformed cells (IV5) revealed that both isoforms were highly tyrosyl
      phosphorylated and their readiness to be phosphorylated by Src in vitro further
      indicated that they were putative Src substrates as well. Indeed, the enhancement
      of tyrosyl phosphorylation of p97eps8 detected in cells coexpressing both p97eps8
      and active Src relative to that in cells expressing p97eps8 alone supported our
      hypothesis. The existence of common phosphotryptic peptides between in vitro 32P
      labeled p97eps8 and p68eps8 indicated that these two proteins shared the same Src
      mediated sites. Further in vitro binding assays demonstrated that p68eps8 was the
      major eps8 isoforms that could be precipitated by bacterial fusion protein
      containing Src SH3. Interestingly, both p68eps8 and p97eps8 were preferentially
      expressed in v-Src transformed cells and the presence of p68eps8 appeared to
      depend on Src. Since p97eps8 has been implicated in mitogenesis and
      tumorigenesis, its readiness to be phosphorylated and induced by v-Src might
      attribute to v-Src-mediated transformation.

PMID- 10395946
TI  - Expression and localization of Rab3D in rat parotid gland.
AB  - Rab3 proteins (isoforms A, B, C and D) are low molecular weight GTP-binding
      proteins proposed to be involved in regulated exocytosis. In the present study,
      Rab3 protein expression and localization was examined in rat parotid gland by
      reverse transcription (rt) PCR, Western blotting and immunocytochemistry. An
      approximately 200 bp PCR product was obtained from parotid RNA by rtPCR and this
      fragment was cloned and sequenced. Nucleotide and deduced amino acid sequences
      obtained from five clones were identical to rab3D. Membrane and cytosolic
      fractions prepared from parotid acini were immunoblotted with antisera specific
      for each of the four Rab3 isoforms. A 28 kDa protein was detected with Rab3D
      specific antisera in both fractions with staining being more intense in the
      membrane fraction. No other Rab3 isoforms were detected by immunoblotting, a
      result consistent with those obtained by rtPCR. Rab3D was enriched in zymogen
      granule membranes and Triton X-114 extraction revealed that this isoform is
      predominantly lipid-modified in parotid. Localization of Rab3D was done on frozen
      sections of parotid gland by immunofluorescence microscopy. Staining was observed
      primarily in the acinar cells and was adjacent to the acinar lumen. Incubation of
      dispersed acini with isoproterenol and substance P stimulated amylase secretion 4
      and 2-fold above basal, respectively. Isoproterenol, but not substance P,
      induced redistribution of Rab3D from the cytosol to the membrane fraction in
      dispersed parotid acini. Consistent with these findings, isoproterenol injections
      into fasted rats also resulted in increased membrane-associated Rab3D in the
      parotid acini. These results indicate that Rab3D is: (1) the major Rab3 isoform
      expressed in rat parotid gland; (2) localized to zymogen granule membranes; and
      (3) involved with regulated enzyme secretion in acinar cells.

PMID- 10395948
TI  - Correlation between the kinetics of anthracycline uptake and the resistance
      factor in cancer cells expressing the multidrug resistance protein or the P
      glycoprotein.
AB  - Multidrug resistance (MDR) in model systems is known to be conferred by two
      different integral proteins, the 170-kDa P-glycoprotein (Pgp) and the 190-kDa
      multidrug resistance-associated protein (MRP1). One possible pharmacological
      approach to overcome drug resistance is the use of specific inhibitors, which
      enhance the cytotoxicity of known antineoplastic agents. However, while many
      compounds have been proven to be very efficient in inhibiting Pgp activity only
      some of them are able to inhibit MRP1. The other likely approach is based on the
      design and synthesis of new non-cross-resistant drugs with physicochemical
      properties favoring the uptake of the drug by the resistant cells. The
      intracellular drug retention influences its cytotoxic effect. The level of the
      intracellular drug content is a function of the amount of drug transported inside
      the cell (influx) and the amount of drug expelled from the cell (efflux). In this
      work, the kinetics of drug uptake and the kinetics of active efflux of several
      anthracycline derivatives in both Pgp expressing K562/Adr cells and MRP1
      expressing GLC4/Adr cells was determined. Our data have shown that in both cell
      lines there is no correlation between the resistance factor and the kinetics of
      drug efflux by these pumping systems. However, a very good correlation between
      the resistance factor and the kinetics of drug uptake has been established in
      both cell lines: the resistance factor decreases when the kinetics of drug uptake
      increases. This work has clearly shown that when the rate of transmembrane
      transport of anthracycline is high enough, the efflux mediated by the protein
      transporter is not able to pace with it. The protein transporter essentially
      operates in a futile cycle and the resistance factor is tending to one. It does
      not mean, however, that when the resistance factor is close to one the
      anthracycline is not transported by the pump.

PMID- 10395947
TI  - Differential expression of the RTP/Drg1/Ndr1 gene product in proliferating and
      growth arrested cells.
AB  - Using a differential display method to identify differentiation-related genes in
      human myelomonocytic U937 cells, we cloned the cDNA of a gene identical to Drg1
      and homologous to other recently discovered genes, respectively human RTP and
      Cap43 and mouse Ndr1 and TDD5 genes. Their open reading frames encode proteins
      highly conserved between mouse and man but which do not share homology with other
      know proteins. Conditions in which mRNAs are up-regulated suggest a role for the
      protein in cell growth arrest and terminal differentiation. We raised antibodies
      against a synthetic peptide reproducing a characteristic sequence of the putative
      polypeptide chain. These antibodies revealed a protein with the expected 43 kDa
      molecular mass, up-regulated by phorbol ester, retinoids and 1,25-(OH)2 vitamin
      D3 in U937 cells. It was increased in mammary carcinoma MCF-7 cells treated by
      retinoids and by the anti-estrogen ICI 182,780 but not by 4-hydroxytamoxifen. The
      mouse Drg1 homologous protein was up-regulated by retinoic acid in C2 myogenic
      cells. The diversity of situations in which expression of RTP/Drg1/Ndr1 has now
      been observed shows that it is widely distributed and up-regulated by various
      agents. Here we show that ligands of nuclear transcription factors involved in
      cell differentiation are among the inducers of this novel protein.

PMID- 10395949
TI  - Possible mechanism for the decrease of mitochondrial aspartate aminotransferase
      activity in ischemic and hypoxic rat retinas.
AB  - Glutamate is believed to be an excitatory amino acid neurotransmitter in the
      retina. Enzymes for glutamate metabolism, such as glutamate dehydrogenase,
      ornithine aminotransferase, glutaminase, and aspartate aminotransferase (AAT),
      exist mainly in the mitochondria. The abnormal increase of intracellular calcium
      ions in ischemic retinal cells may cause an influx of calcium ions into the
      mitochondria, subsequently affecting various mitochondrial enzyme activities
      through the activity of mitochondrial calpain. As AAT has the highest level of
      activity among enzymes involved in glutamate metabolism, we investigated the
      change of AAT activity in ischemic and hypoxic rat retinas and the protection
      against such activity by calpain inhibitors. We used normal RCS (rdy+/rdy+) rats.
      For the in vivo studies, we clamped the optic nerve of anesthetized rats to
      induce ischemia. In the in vitro studies, the eye cups were incubated with
      Locke's solution saturated with 95% N2/5% CO2. The activity of cytosolic AAT
      (cAAT) was about 20% of total activity, whereas mitochondrial AAT (mAAT) was
      about 75% in rat retina. Ninety minutes of ischemia or hypoxia caused a 20%
      decrease in mAAT activity, whereas cAAT activity remained unchanged. To examine
      the contribution of intracellular calcium ions to the degradation of mAAT, we
      used Ca2+-free Locke's solution containing 1 mM EGTA, ryanodine (Ca2+ channel
      blocker), and thapsigargin (Ca2+-ATPase inhibitor). In the present study,
      thapsigargin in Ca2+-free Locke's solution, but not ryanodine in this solution,
      was found to prevent AAT degradation. AAT degradation was also prevented by
      calpain inhibitors (Ca2+-dependent protease inhibitor) such as calpeptin at 1 nM,
      10 nM, 0.1 microM, 1 microM and 10 microM, and by calpain inhibitor peptide, but
      not by other protease inhibitors (10 microM leupeptin, pepstatin, chymostatin).
      Additionally, we determined the subcellular localization of calpain activity and
      examined the change of calpain activity in ischemic rat retinas. Our results
      suggest that decreased activity of mAAT in ischemic and hypoxic rat retinas might
      be evoked by the degradation by calpain-catalyzed proteolysis in mitochondria.

PMID- 10395950
TI  - Expression of CCAAT/enhancer binding protein C/EBPalpha, beta and delta in rat
      adipose stromal-vascular cells in vitro.
AB  - Stromal-vascular (S-V) cells from rat inguinal fat depots were isolated and
      cultured in medium containing fetal bovine serum (FBS) and differentiated in
      defined medium until lipid accumulation was apparent. C/EBPalpha, beta and delta
      levels were evaluated for different growth conditions and at different times
      using Western blots. Immediately after isolation C/EBPalpha, beta and delta could
      not be detected in S-V cells. After seeding for 24 h in Dulbecco's modified
      Eagle's medium (DMEM) with FBS, C/EBPalpha, beta and delta could all be detected.
      Cells at day 1 of culture in insulin, transferrin, triiodothyronine and selenium
      (ITTS) had increased levels of C/EBPalpha and continued steady high levels to day
      6 of culture. Cultures grown in DMEM alone, with no ITTS, showed C/EBPalpha
      levels similar to ITTS cultures at day 1 and day 3; however, levels diminished
      after day 3. DMEM cultures also showed lipid accumulation at day 6; however, the
      number of cells and the amount of lipid cell were reduced from levels observed in
      ITTS cultures. C/EBPbeta was expressed uniformly throughout the culture period in
      either DMEM or ITTS cultures while C/EBPdelta expression was higher with DMEM
      treatment than with ITTS. Treatment of 2 day DMEM cultures with FBS increased
      levels of C/EBPbeta and delta but significantly reduced levels of C/EBPalpha.
      Immunocytochemical analysis of S-V cells at day 1 of culture showed a similar
      percentage of cells stained in DMEM cultures and ITTS cultures. However, by day 6
      of culture the percentage of cells staining positively for C/EBPalpha in DMEM had
      been reduced by one half while in ITTS the percent positive cells remained about
      the same. Our results indicate that ITTS is not necessary for the induction of
      C/EBPalpha and accumulation of lipid in S-V cells. However, ITTS is responsible
      for maintaining C/EBPalpha and enhanced lipid accumulation. Because C/EBPalpha,
      beta and delta expression occurs very early in cell culture and C/EBPalpha and
      delta expression continues to increase in DMEM without any apparent inducing
      agents, our results suggest that these factors may be expressed by the same cells
      in vivo before being placed in culture. Thus, a large fraction of S-V cells may
      be further along in the differentiation program than 3T3 cells are when they
      begin differentiation.

PMID- 10395951
TI  - Nitric oxide can function as either a killer molecule or an antiapoptotic
      effector in cardiomyocytes.
AB  - Caspase enzymes are a family of cysteine proteases that play a central role in
      apoptosis. Recently, it has been demonstrated that caspases can be S-nitrosylated
      and inhibited by nitric oxide (NO). The present report shows that in chick embryo
      heart cells (CEHC), NO donor molecules such as S-nitroso-N-acetylpenicillamine
      (SNAP), S-nitrosoglutathione, spermine-NO or sodium nitroprusside inhibit caspase
      activity in both basal and staurosporine-treated cells. However, the inhibitory
      effect of NO donors on caspase activity is accompanied by a parallel cytotoxic
      effect, that precludes NO to exert its antiapoptotic capability. N-Acetylcysteine
      (NAC) at a concentration of 10 mM blocks depletion of cellular glutathione and
      cell death in SNAP-treated CEHC, but it poorly affects the ability of SNAP to
      inhibit caspase activity. Consequently, in the presence of NAC, SNAP attenuates
      not only caspase activity but also cell death of staurosporine-treated CEHC.
      These data show that changes in the redox environment may inhibit NO-mediated
      toxicity, without affecting the antiapoptotic capability of NO, mediated by
      inhibition of caspase enzymes. NO may thus be transformed from a killer molecule
      into an antiapoptotic agent.

PMID- 10395952
TI  - Expression of constitutive nitric oxide synthase in rat and human
      gastrointestinal tract.
AB  - The aim of this study was to determine the expression of constitutive NO
      synthases (ecNOS and bNOS) at the protein level in rat and human gastrointestinal
      tract. We established a quantitative Western blotting method for detection and
      quantification of ecNOS and bNOS in both species. Human gastric fundus was
      further analyzed by immunohistochemistry. EcNOS expression at the protein level
      could be quantified in different organs of the rat gastrointestinal tract and in
      human gastric mucosal biopsies. Immunohistochemistry of gastric fundus revealed
      that immunoreactivity for ecNOS was localized mainly in the endothelium of small
      vessels. In rats, expression of bNOS at the protein level was highest in
      esophagus. By means of immunohistochemistry of human gastric fundus,
      immunoreactivity was detected mainly in the plexus of Auerbach. We conclude that
      isoforms of constitutive nitric oxide synthase can be identified and quantified
      at the protein level both in rat and human gastrointestinal tract. The presence
      of bNOS in nerve tissue supports previous observations that NO serves as a
      transmitter in non-adrenergic, non-cholinergic nerves in human esophagus and
      stomach. The observation that ecNOS has been found mainly in endothelial cells
      suggests the involvement of NO in the regulation of mucosal blood flow.

PMID- 10395953
TI  - Conformational changes induced in troponin I by interaction with troponin T and
      actin/tropomyosin.
AB  - Troponin I (TnI) is the inhibitory component of the striated muscle Ca2+
      regulatory protein troponin (Tn). The other two components of Tn are troponin C
      (TnC), the Ca2+-binding component, and troponin T (TnT), the tropomyosin-binding
      component. We have used limited chymotryptic digestion to probe the local
      conformation of TnI in the free state, the binary TnC*TnI complex, the ternary
      TnC*. TnI*TnT (Tn) complex, and in the reconstituted Tn*tropomyosin*F-actin
      filament. The digestion of TnI alone or in the TnC*TnI complex produced initially
      two major fragments via a cleavage of the peptide bond between Phe100 and Asp101
      in the so-called inhibitory region. In the ternary Tn complex cleavage occurred
      at a new site between Leu140 and Lys141. In the absence of Ca2+ this was followed
      by digestion of the 1-140 fragment at Leu122 and Met116. In the reconstituted
      thin filament the same fragments as in the case of the ternary complex were
      produced, but the rate of digestion was slower in the absence than in the
      presence of Ca2+. These results indicate firstly that in both free TnI and TnI
      complexed with TnC there is an exposed and flexible site in the inhibitory
      region. Secondly, TnT affects the conformation of TnI in the inhibitory region
      and also in the region that contains the 140-141 bond. Thirdly, the 140-141
      region of TnI is likely to interact with actin in the reconstituted thin filament
      when Ca2+ is absent. These findings are discussed in terms of the role of TnI in
      the mechanism of thin filament regulation, and in light of our previous results
      [Y. Luo, J.-L. Wu, J. Gergely, T. Tao, Biochemistry 36 (1997) 13449-13454] on the
      global conformation of TnI.

PMID- 10395954
TI  - The role of phosphatidylinositol 3-kinase in the regulation of cell response to
      steroid hormones.
AB  - Phosphatidylinositol 3-kinase (PI-3 kinase) has been implicated in the regulation
      of many cellular processes, including growth and transformation. We describe the
      effect of glucocorticoids on cell growth, phosphoinositide formation and PI-3
      kinase activity in Rous sarcoma virus-transformed hamster fibroblasts (HET-SR).
      Using a prolonged dexamethasone treatment of HET-SR cells we have selected a new
      glucocorticoid receptor-positive cell subline, HET-SR(h), that was resistant to
      growth inhibitory action of dexamethasone and/or non-hormonal drugs (vinblastine,
      adriamycin) and was characterized by higher levels of phosphoinositide formation
      and increased PI-3 kinase activity. Study of the short-term hormone action has
      shown that both dexamethasone-sensitive and -resistant sublines responded to
      hormone by a decrease in phospholipid turnover rate. At the same time, in both
      cell lines activation of PI-3 kinase after dexamethasone addition was revealed.
      Dexamethasone-dependent activation of PI-3 kinase was more significant and
      maintained for a longer period in HET-SR(h) cells than in parent HET-SR cells.
      Finally, by transfecting p110*, a constitutively active catalytic subunit of PI-3
      kinase, into hormone-sensitive HET-SR cells, we have found a marked increase in
      cell resistance to growth inhibitory dexamethasone action. These results suggest
      that PI-3 kinase may serve as one of the factors providing cell resistance to
      cytostatic drugs.

PMID- 10395955
TI  - Prostaglandin E2 regulates macrophage colony stimulating factor secretion by
      human bone marrow stromal cells.
AB  - Bone marrow stromal cells regulate marrow haematopoiesis by secreting growth
      factors such as macrophage colony stimulating factor (M-CSF) that regulates the
      proliferation, differentiation and several functions of cells of the mononuclear
      phagocytic lineage. By using a specific ELISA we found that their constitutive
      secretion of M-CSF is enhanced by tumour necrosis factor-alpha (TNF-alpha). The
      lipid mediator prostaglandin E2 (PGE2) markedly reduces in a time- and dose
      dependent manner the constitutive and TNF-alpha-induced M-CSF synthesis by bone
      marrow stromal cells. In contrast, other lipid mediators such as 12-HETE, 15
      HETE, leukotriene B4, leukotriene C4 and lipoxin A4 have no effect. EP2/EP4
      selective agonists (11-deoxy PGE1 and 1-OH PGE1) and EP2 agonist (19-OH PGE2)
      inhibit M-CSF synthesis by bone marrow stromal cells while an EP1/EP3 agonist
      (sulprostone) has no effect. Stimulation with PGE2 induces an increase of
      intracellular cAMP levels in bone marrow stromal cells. cAMP elevating agents
      (forskolin and cholera toxin) mimic the PGE2-induced inhibition of M-CSF
      production. In conclusion, PGE2 is a potent regulator of M-CSF production by
      human bone marrow stromal cells, its effects being mediated via cAMP and PGE
      receptor EP2/EP4 subtypes.

PMID- 10395956
TI  - Molecular cloning and characterization of the chicken pro-opiomelanocortin (POMC)
      gene.
AB  - The gene for pro-opiomelanocortin (POMC), a common precursor of melanocortins,
      lipotropins and beta-endorphin, was isolated in the chicken first among avian
      species. The chicken POMC gene was found to be a single copy gene and appeared to
      show the same structural organization as that of other species of different
      classes. The predicted POMC displayed the highest identity to Xenopus POMC(A)
      (60. 1%), and consisted of 251 amino acid residues with nine proteolytic cleavage
      sites, suggesting that it could be processed to give rise to all members of the
      melanocortin family, including adrenocorticotropic hormone and alpha-, beta- and
      gamma-melanocyte-stimulating hormones, as well as the other POMC-derived
      peptides. RT-PCR analysis detected the POMC mRNA in the brain, adrenal gland,
      gonads, kidney, uropygial gland and adipose tissues, each of which has been
      demonstrated to express melanocortin receptors. These results suggest that
      melanocortins act in a paracrine and/or autocrine manner to control a variety of
      functions both in the brain and in the peripheral tissues in the chicken.

PMID- 10395957
TI  - Glyoxalase I from Brassica juncea is a calmodulin stimulated protein.
AB  - Brassica juncea glyoxalase I (S-lactoylglutathione-lyase, EC 4.4.1. 5) is a 56
      kDa, heterodimeric protein. It requires magnesium (Mg2+) for its optimal
      activity. In this report we provide biochemical evidence for modulation of
      glyoxalase I activity by calcium/calmodulin (Ca2+/CaM). In the presence of Ca2+
      glyoxalase I showed a significant (2.6-fold) increase in its activity. It also
      showed a Ca2+ dependent mobility shift on denaturing gels. Its Ca2+ binding was
      confirmed by Chelex-100 assay and gel overlays using 45CaCl2. Glyoxalase I was
      activated by over 7-fold in the presence of Ca2+ (25 microM) and CaM (145 nM) and
      this stimulation was blocked by the CaM antibodies and a CaM inhibitor,
      trifluroperazine (150 microM). Glyoxalase I binds to a CaM-Sepharose column and
      was eluted by EGTA. The eluted protein fractions also showed stimulation by CaM.
      The stimulation of glyoxalase I activity by CaM was maximum in the presence of
      Mg2+ and Ca2+; however, magnesium alone also showed glyoxalase I activation by
      CaM.

PMID- 10395958
TI  - Perinatal PTX-sensitive G-protein expression and regulation of conductive 22Na+
      transport in lung apical membrane vesicles.
AB  - Using apical membrane vesicles (AMV) prepared from mature foetal and early
      neonatal guinea pig lung we show that pertussis toxin (PTX)-sensitive G-protein
      regulation of conductive 22Na+ uptake undergoes rapid changes following birth.
      Thus, G-protein activation by intravesicular incorporation of 100 microM
      GTPgammaS into vesicles resuspended in NaCl, which in late gestation stimulated
      uptake, consistently induced inhibition of conductive Na+ uptake into AMV
      prepared from neonatal lung at 4 days of age (N4) (52+/-9%, n=8, P<0.05). This
      response was not significantly different in the presence of the relatively
      impermeant anion isethionate (Ise-) (69+/-9%, n=7, P<0.05). Changes in the
      regulation of uptake were already detectable on the day of birth (N0) in AMV
      resuspended in NaCl, with GTPgammaS inducing both stimulatory and inhibitory
      responses. These data indicate that the processes by which 22Na+ uptake into AMV
      is regulated by G-proteins undergoes a change at birth and by 4 days of age, G
      protein regulation of uptake occurs predominantly via modulation of co-localised
      Na+ channels. Intravesicular incorporation of GDPbetaS or pre-treatment with PTX
      did not significantly alter conductive 22Na+ uptake in the presence of NaCl or
      NaIse suggesting that constitutively active G-proteins are not involved in this
      process. Pre-treatment of AMV with PTX prevented the inhibition of conductive
      22Na+ uptake by GTPgammaS (105+/-16% n=7) indicating that a PTX-sensitive G
      protein mediates the inhibition of channels in neonatal AMV. Western blotting
      demonstrated enrichment of Gialpha1, Gialpha2, Gialpha3 and Goalpha in the apical
      membrane preparations. We also show that there is a significant rise in the
      levels of Gialpha3 during the early neonatal period providing a potential
      candidate for the G-protein mediated changes in regulation of conductive 22Na+
      uptake in neonatal AMV.

PMID- 10395960
TI  - Sequence and expression of a cDNA encoding the red seabream androgen receptor.
AB  - The cDNA of the androgen receptor (AR) has been isolated from the ovary of red
      seabream, Pagrus major, and sequenced. The amino acid sequence of red seabream AR
      (rsAR) shows about 45% identity with those of Xenopus, rat, mouse, and human ARS.
      It is shown that rsAR has the ability to trans-activate the responsive gene
      depending on the presence of androgen.

PMID- 10395961
TI  - Mammalian lysophospholipases.

PMID- 10395962
TI  - Use of sphingolipid analogs: benefits and risks.

PMID- 10395963
TI  - Microsomal long-chain acyl-CoA thioesterase (carboxylesterase ES-4) is regulated
      by thyroxine.
AB  - Long chain acyl-CoA thioesterase activity is mainly located in microsomes after
      subcellular fractionation of liver from untreated rats. The physiological
      function and regulation of expression of this activity is not known. In the
      present study we have investigated the effect of thyroxine on expression of
      carboxylesterase ES-4, the major acyl-CoA thioesterase of liver microsomes.
      Thyroidectomy of rats decreased the palmitoyl-CoA thioesterase activity to about
      25% of normal activity. This decrease was accompanied by similar decreases at the
      protein and mRNA levels (31% and 57%, respectively, of controls). Treatment with
      thyroxine completely reversed the effect of thyroidectomy and resulted in
      elevated levels in both thyroidectomized and control rats. For reasons of
      comparison we also studied the possibility that ES-10 and ES-2, two other members
      of the same gene family, are affected by thyroxine. ES-10 was not changed at the
      protein or mRNA level by any of the treatments, while ES-2 expression in liver
      was decreased by thyroxine treatment. The data shows that changes in activity and
      expression of ES-4 correlate to thyroxine status in the rat suggesting a
      physiological regulatory role by this hormone. Since thyroxine regulates the
      expression of lipogenic enzymes, these results are consistent with a function for
      this microsomal acyl-CoA thioesterase in fatty acid synthesis and/or secretion,
      rather than in oxidative degradation of fatty acids.

PMID- 10395964
TI  - Synthesis of azidophospholipids and labeling of lysophosphatidylcholine
      acyltransferase from developing soybean cotyledons.
AB  - A photoreactive substrate analog of lysophosphatidylcholine (LPC), 1-([(4
      azidosalicyl)-12-amino)]dodecanoyl-sn-glycerol-3-phospho cholin e (azido-LPC) was
      synthesized. Fast atom bombardment mass spectrometry was employed to confirm the
      structures of azido-LPC and its intermediates. Azido-LPC was used to label
      putative acyl-CoA:LPC acyltransferase from microsomal membranes of developing
      soybean cotyledons. The synthesized substrate analog acts as a substrate for the
      target acyltransferases and phospholipases in the dark. When the microsomal
      membranes were incubated with the acyl acceptor analog and immediately
      photolyzed, LPC acyltransferase was irreversibly inhibited. Photoinactivation of
      the enzyme by the photoprobe decreased in the presence of LPC. Microsomal
      membranes were photolyzed with 125I-labeled azido-LPC and analyzed by SDS-PAGE
      followed by autoradiography. These revealed that the analog preferentially
      labeled 54- and 114-kDa polypeptides. Substrate protected the labeling of both
      the polypeptides. In our earlier report, the same polypeptides were also labeled
      with photoreactive acyl-CoA analogs, suggesting that these polypeptides could be
      putative LPC acyltransferase(s). These results demonstrated that the
      photoreactive phospholipid analog could be a powerful tool to label
      acyltransferases involved in lipid biosynthesis.

PMID- 10395965
TI  - Functional analysis of genes from Streptomyces griseus involved in the synthesis
      of isorenieratene, a carotenoid with aromatic end groups, revealed a novel type
      of carotenoid desaturase.
AB  - The biosynthesis of the aromatic carotene isorenieratene is restricted to green
      photosynthetic bacteria and a few actinomycetes. Among them Streptomyces griseus
      has been used to study the genes involved in this pathway. Five genes out of
      seven of two adjacent operons in one cluster could be identified to be sufficient
      for the synthesis of isorenieratene. Stepwise deletions of these genes
      demonstrated their participation in phytoene synthesis, phytoene desaturation and
      lycopene cyclization. The novel gene crtU was assigned to encode a unique
      desaturase responsible for the conversion of beta-carotene via beta
      isorenieratene to isorenieratene by a desaturation/methyltransferation mechanism.
      Sequence analysis of crtU revealed two conserved regions, one at the N-terminus
      and the other at the C-terminus of the protein which is universal to different
      types of carotene desaturases. In addition, the sequence comprises a motif
      typically found in methyltransferases. The deletion of the two remaining genes of
      the cluster left the carotenoid biosynthetic pathway unaffected.

PMID- 10395966
TI  - Phospholipid transfer protein enhances removal of cellular cholesterol and
      phospholipids by high-density lipoprotein apolipoproteins.
AB  - High-density lipoprotein (HDL) apolipoproteins remove excess cholesterol from
      cells by an active transport pathway that may protect against atherosclerosis.
      Here we show that treatment of cholesterol-loaded human skin fibroblasts with
      phospholipid transfer protein (PLTP) increased HDL binding to cells and enhanced
      cholesterol and phospholipid efflux by this pathway. PLTP did not stimulate lipid
      efflux in the presence of albumin, purified apolipoprotein A-I, and phospholipid
      vesicles, suggesting specificity for HDL particles. PLTP restored the lipid
      efflux activity of mildly trypsinized HDL, presumably by regenerating active
      apolipoproteins. PLTP-stimulated lipid efflux was absent in Tangier disease
      fibroblasts, induced by cholesterol loading, and inhibited by brefeldin A
      treatment, indicating selectivity for the apolipoprotein-mediated lipid removal
      pathway. The lipid efflux-stimulating effect of PLTP was not attributable to
      generation of prebeta HDL particles in solution but instead required cellular
      interactions. These interactions increased cholesterol efflux to minor HDL
      particles with electrophoretic mobility between alpha and prebeta. These findings
      suggest that PLTP promotes cell-surface binding and remodeling of HDL so as to
      improve its ability to remove cholesterol and phospholipids by the apolipoprotein
      mediated pathway, a process that may play an important role in enhancing flux of
      excess cholesterol from tissues and retarding atherogenesis.

PMID- 10395967
TI  - Regulation of phosphatidylcholine homeostasis by calcium-independent
      phospholipase A2.
AB  - Phosphatidylcholine (PtdCho) is the most abundant phospholipid in mammalian cell
      membranes and is essential for cell viability. The levels of this lipid must be
      tightly controlled to maintain homeostasis. Therefore, changes in the rate of
      PtdCho synthesis are generally balanced by changes in PtdCho catabolism and vice
      versa. It is commonly accepted that the rate of PtdCho synthesis is regulated by
      CTP:phosphocholine cytidylyltransferase (CT). However, it is not certain if
      PtdCho mass is regulated by specific catabolic enzyme(s). Our goal is to
      determine if PtdCho homeostasis is regulated by a phospholipase A2 (PLA2). To
      this end, we have prepared Chinese hamster ovary (CHO) cell lines that
      overexpress CT. CT activity is 7-10-fold higher in the transfected cells than in
      parental CHO cells. This increase in CT activity is associated with increases in
      both PtdCho synthesis and PtdCho catabolism. Glycerophosphocholine is the PtdCho
      catabolite that accumulates in the transfected cells, which suggests that PtdCho
      turnover is mediated by a phospholipase A2 (PLA2). Indeed, higher levels of
      calcium-independent PLA2 activity are measured in the cytosols of the CHO cells
      that overexpress CT, compared to parental CHO cells. The elevated calcium
      independent PLA2 activity is associated with increases in the expression of the
      80-kDa calcium-independent PLA2 (iPLA2). Together, these data suggest that the 80
      kDa iPLA2 may be modulated in response to changes in PtdCho levels and therefore
      is involved in the regulation of PtdCho homeostasis in CHO cells.

PMID- 10395968
TI  - Identification and characterization of the mouse cDNA encoding acyl
      CoA:dihydroxyacetone phosphate acyltransferase.
AB  - We used the amino acid sequence of human acyl-CoA:dihydroxyacetone phosphate
      acyltransferase (DHAPAT) as bait to screen the database of expressed sequence
      tags (dbEST) and identified several partial mouse cDNA clones showing high
      identity. Primers were selected based on the dbEST sequences and used for
      amplification of this transcript from cDNA prepared from mouse skin fibroblasts.
      The complete nucleotide sequence was then determined and revealed an open reading
      frame (ORF) of 2034 bp encoding a protein consisting of 678 amino acids with a
      calculated molecular mass of 76870. The deduced amino acid sequence showed high
      identity (80%) with that of human DHAPAT and also revealed a typical peroxisomal
      targeting signal type 1 (PTS1) at its extreme carboxy-terminus (alanine-lysine
      leucine, AKL). Definitive evidence that this cDNA indeed codes for DHAPAT was
      obtained by heterologous expression in the yeast Saccharomyces cerevisiae.
      Northern blot analysis revealed high expression of DHAPAT especially in mouse
      heart, liver and testis.

PMID- 10395969
TI  - Role of lecithin-cholesterol acyltransferase in the metabolism of oxidized
      phospholipids in plasma: studies with platelet-activating factor-acetyl hydrolase
      deficient plasma.
AB  - To determine the relative importance of platelet-activating factor
      acetylhydrolase (PAF-AH) and lecithin-cholesterol acyltransferase (LCAT) in the
      hydrolysis of oxidized phosphatidylcholines (OXPCs) to lyso-phosphatidylcholine
      (lyso-PC), we studied the formation and metabolism of OXPCs in the plasma of
      normal and PAF-AH-deficient subjects. Whereas the loss of PC following oxidation
      was similar in the deficient and normal plasmas, the formation of lyso-PC was
      significantly lower, and the accumulation of OXPC was higher in the deficient
      plasma. Isolated LDL from the PAF-AH-deficient subjects was more susceptible to
      oxidation, and stimulated adhesion molecule synthesis in endothelial cells, more
      than the normal LDL. Oxidation of 16:0-[1-14C]-18:2 PC, equilibrated with plasma
      PC, resulted in the accumulation of labeled short- and long-chain OXPCs, in
      addition to the labeled aqueous products. The formation of the aqueous products
      decreased by 80%, and the accumulation of short-chain OXPC increased by 110% in
      the deficient plasma, compared to the normal plasma, showing that PAF-AH is
      predominantly involved in the hydrolysis of the truncated OXPCs. Labeled sn-2
      acyl group from the long-chain OXPC was not only hydrolyzed to free fatty acid,
      but was preferentially transferred to diacylglycerol, in both the normal and
      deficient plasmas. In contrast, the acyl group from unoxidized PC was transferred
      only to cholesterol, showing that the specificity of LCAT is altered by OXPC. It
      is concluded that, while PAF-AH carries out the hydrolysis of mainly truncated
      OXPCs, LCAT hydrolyzes and transesterifies the long-chain OXPCs.

PMID- 10395970
TI  - The fatty acid distribution in low density lipoprotein in diabetes.
AB  - Atherosclerosis is commonly found in diabetes. There is an association between
      small dense low density lipoprotein (LDL) phenotype, which is more prevalent in
      the diabetic state, and atherosclerosis. Small dense LDL is more easily oxidised
      and it is possible that fatty acid compositional changes, particularly an
      increase in polyunsaturated fatty acids, could underlie this association.
      However, there is little information about fatty acids in the different LDL
      phenotypes in the literature. This study examined LDL subfraction composition in
      18 non-insulin-dependent diabetic (NIDDM) patients and 11 control subjects. LDL
      was isolated and fractionated into LDL 1, 2 and 3 by density gradient
      ultracentrifugation. NIDDM patients had significantly more fatty acids in all LDL
      subfractions than control subjects (P<0.01). Palmitic and linoleic acid were
      significantly greater in all subfractions in the diabetic patients compared to
      control subjects (P<0.01) and palmitoleic and oleic acids were also greater in
      LDL1 and LDL2 in diabetic patients (P<0.01). We conclude that in NIDDM fatty
      acids are increased in all LDL subfractions and this may be the reason for the
      increased atherosclerosis in diabetes irrespective of phenotype.

PMID- 10395972
TI  - Adipose tissue as an endocrine organ regulating growth, puberty, and other
      physiological functions.
AB  - There are reports on some patients with clearly manifested specific features of
      genotype and phenotype similar to those of ob/ob and db/db mice. Three patients
      from Turkey were described who had a homozygous mutation in the gene of leptin
      identical to the mutation in C57BL6J ob/ob mice. This mutation is a C --> T
      substitution in codon 105 of the amino acid sequence of leptin. In mice this
      mutation generates a stop-codon; in humans it substitutes Arg-105 with Trp. The
      mutant human leptin cannot be secreted by the cells and thus has no effect on the
      hypothalamus. Patients with a homozygous mutation of the leptin receptor
      resulting in the G --> T substitution in the splice donor site of exon 16 were
      studied in a family of Kabilian origin. Exon 16 was not included in the mature
      mRNA molecule, and a truncated leptin receptor was synthesized which lacked the
      transmembrane and intracellular domains; this receptor was unable to transduce
      the hormonal signal. Both groups of patients suffered from obesity, delayed
      linear growth, infertility, increased blood insulin level, and other disorders.
      Leptin influences lipid metabolism by stimulating the expression of the
      proopiomelanocortin (POMC) gene in melanocortinergic neurons of the hypothalamus.
      POMC is the precursor of alpha-melanocyte-stimulating hormone (alpha-MSH), which
      binds to the melanocortin receptor MC4-R in the brain, decreases appetite, and
      activates lipid metabolism. Patients with mutations in MC4-R suffered only from
      obesity, but their growth and puberty were not affected. Thus, leptin apparently
      stimulates growth and puberty not through its binding to the receptors on
      melanocortinergic neurons, but through its binding to receptors on other
      hypothalamic neurons; this effect of leptin is not affected by mutations in the
      MC4-R gene.

PMID- 10395973
TI  - Lag phase of CO2-dependent O2 evolution by illuminated Anabaena variabilis cells.
AB  - The steady-state rate of CO2-dependent O2 evolution by Anabaena variabilis cells
      in response to illumination was established after a lag phase. The lag phase was
      shortened (1) in cells incubated with glucose as an oxidizable substrate and (2)
      upon an increase in light intensity. The lag phase was absent during electron
      transfer from H2O to p-benzoquinone (in combination with ferricyanide) involving
      Photosystem II. A lag was observed during electron transfer from H2O to methyl
      viologen involving Photosystems II and I, but not for electron transfer from
      N,N,N',N'-tetramethyl-p-phenylenediamine (in combination with ascorbate) to
      methyl viologen involving only Photosystem I. The lag phases of the light-induced
      H2O --> CO2 and H2O --> methyl viologen electron transfer reactions showed the
      same temperature dependences at 10-30 degrees C. The lag was prevented by 3-(3,4
      dichlorophenyl)-1,1-dimethylurea at concentrations that caused partial inhibition
      of photosynthetic O2 evolution. Retardation of cell respiration by a combination
      of CN- and benzylhydroxamate shortened the lag phase of the H2O --> methyl
      viologen electron transfer. It is concluded that the lag phase is associated with
      the electron transfer step between Photosystem II and Photosystem I common for
      the photosynthetic and respiratory chains and is due to the stimulation of cell
      respiration during the initial period of illumination as a consequence of an
      increase in the reduced plastoquinone pool and to subsequent retardation of
      respiration resulting from the transition of the electron transfer chain to the
      competitive pathway involving Photosystem I.

PMID- 10395974
TI  - Gadolinium chloride-induced Kupffer cell blockade increases uptake of oxidized
      low-density lipoproteins by rat heart and aorta.
AB  - Oxidized low-density lipoproteins (LDL) play a key role in the formation of
      atherosclerotic lesions of arteries. We analyzed the effect of hepatic resident
      macrophage (Kupffer cell) blockade on oxidized [125I]LDL accumulation in
      different organs and tissues of the rat. Kupffer cell blockade was induced by
      gadolinium chloride (GdCl3) which was injected intravenously 24 h prior to
      injection of oxidized [125I]LDL into the rats. Ten minutes after administration
      to intact animals, oxidized [125I]LDL was accumulated in the liver (86.8% of the
      dose administered), muscles (4.7%), spleen (2.1%), lungs (0.8%), kidney (0.6%),
      adrenal glands (0.2%), heart (0.15%), and thymus (0.04%). Kupffer cell blockade
      significantly decreased the clearance rate of oxidized [125I]LDL from the blood.
      Specific radioactivity (per g tissue) decreased in the liver (1.3-fold compared
      to control), but increased in the aorta (2.5-fold), heart (2-fold), lungs (1.6
      fold), and kidney (1.3-fold). The results indicate that the accumulation of
      oxidized LDL in heart and aorta significantly depends on the functional state of
      the mononuclear phagocyte system in the liver.

PMID- 10395975
TI  - Purification and characterization of maleylacetate reductase from Nocardioides
      simplex 3E utilizing phenoxyalcanoic herbicides 2,4-D and 2,4,5-T.
AB  - Maleylacetate reductase was isolated and purified from the Gram-positive strain
      Nocardioides simplex 3E which is able to utilize the phenoxyalcanoic herbicides
      2,4-D and 2,4,5-T. Cells were grown on 2,4-D as the sole carbon source. The
      enzyme was purified by 380-fold with 3.0% yield. The purified maleylacetate
      reductase is a homodimer with subunit molecular mass of 37 kD. The enzyme
      required NADH as a cofactor; the Km for maleylacetate is 25 microM; Vmax (with
      NADH as cofactor) and kcat are 185 U/mg and 6845 min-1, respectively. The enzyme
      is very unstable; its pH and temperature optima are at 7.0-7.1 and 50 degrees C,
      respectively.

PMID- 10395976
TI  - Mechanisms of interaction of a plasmalogenic analog of platelet-activating factor
      with human platelets.
AB  - The interaction of a plasmalogenic analog of platelet-activating factor (1-O-alk
      1;-enyl-2-acetyl-sn-glycero-3-phosphocholine; 1-alkenyl-PAF) with human platelets
      was studied. 1-Alkenyl-PAF induced an increase in intracellular Ca2+
      concentration and inhibition of adenylate cyclase at significantly higher
      concentrations than PAF. 1-Alkenyl-PAF inhibits PAF-induced platelet aggregation
      but has no effect on ADP- or thrombin-induced aggregation of human platelets. In
      contrast to PAF, 1-alkenyl-PAF increases [3H]PGE1 binding with human platelets.
      The properties of 1-alkenyl-PAF as an agonist or antagonist of PAF receptors
      apparently depend on its concentration in the cell medium. Under physiological
      conditions 1-alkenyl-PAF might be a natural PAF antagonist acting in the human
      cardiovascular system.

PMID- 10395977
TI  - Algorithmic rules for determination of subgraph contributions considering the
      application of bigraphs in the kinetics of biological processes.
AB  - Algorithmic rules for the determination of subgraph contribution considering the
      application of bigraphs in the kinetics of biological and chemical processes are
      proposed. An example of the use of these rules for investigation of a model
      system by the bigraph method is presented.

PMID- 10395978
TI  - Single-step sandwich immunoassay of myoglobin with bifunctional monoclonal
      antibodies.
AB  - Two protocols for sandwich antigen-capture ELISA of human myoglobin were
      compared. In the first (routine) variant, 14D6 monoclonal antibodies conjugated
      to horseradish peroxidase were used as the secondary antibodies. Bifunctional
      antibodies specific for myoglobin/peroxidase were used as the secondary
      antibodies in the second variant. The myoglobin-binding site of the bifunctional
      antibodies was similar to that of the 14D6 antibodies, and the second antigen
      binding site of the bifunctional antibodies was bound to horseradish peroxidase.
      When comparing standard calibration curves, the effective concentration of the
      bifunctional antibodies and that of antibodies conjugated to horseradish
      peroxidase were made equal. It is shown that the use of bispecific antibodies as
      the secondary antibodies does not improve the quality of the parameters tested,
      i.e., the sensitivity of the assay does not increase and the slope of the
      calibration curve remains constant.

PMID- 10395979
TI  - Purine biosynthesis de novo in bovine retina: purification and characterization
      of amidophosphoribosyl transferase and phosphoribosyl pyrophosphate synthetase.
AB  - The ability of bovine retina to synthesize purines de novo is shown for the first
      time. Amidophosphoribosyl transferase (EC 2.4.2.14), the enzyme controlling the
      rate of the process, and phosphoribosyl pyrophosphate synthetase (EC 2.7.6.1),
      the enzyme regulating the intracellular contents of phosphoribosyl pyrophosphate
      (PRPP), were purified and characterized. The molecular masses of the enzyme
      subunits are similar to those of the purified enzyme from the liver. The
      molecular masses of amidophosphoribosyl transferase, PRPP synthetase catalytic
      subunit, and two PRPP synthetase-associated proteins are 50, 34, 39, and 41 kD,
      respectively. The apparent Km values of the enzymes and coenzymes are similar to
      those of the purified enzymes from the liver. For amidophosphoribosyl
      transferase, the apparent Km for Gln and PRPP are 0.75 +/- 0.05 and 0.66 +/- 0.09
      mM, respectively (the corresponding Vmax values are 59 +/- 3 and 136 +/- 12
      nmoles PPi/min per mg protein). For PRPP synthetase, the apparent Km for ribose-5
      phosphate and ATP are 37.9 +/- 0.5 and 53 +/- 7 microM, respectively (the
      corresponding Vmax values are 61 +/- 4 and 52 +/- 3 nmoles PRPP/min per mg
      protein). The sensitivity of the retinal PRPP synthetase to inhibition by ADP and
      AMP was significantly lower than that of the enzyme from the liver.

PMID- 10395980
TI  - Metabolic features of the adaptive effect of delta-sleep inducing peptide and
      piracetam under hyperoxic conditions.
AB  - Adaptive effects of delta-sleep inducing peptide (DSIP, 12 microgram/100 g body
      weight, single intraperitoneal injection) and piracetam (3 mg/100 g body weight,
      daily intraperitoneal injection for 3 days) are manifested via differential
      changes in neurotransmitter amino acids (GABA, glutamate, aspartate), modulation
      of transport ATPase activity, and decreased accumulation of lipid peroxidation
      products (conjugated dienes, malonic dialdehyde, Schiff bases) in various
      fractions of neuronal membranes (myelin, synaptic and mitochondrial membranes) in
      the sensomotor cortex of rat brain. Under hyperbaric oxygenation (0.3 MPa for 2
      h), the combination of DSIP and piracetam enhanced the protective effect of each
      compound.

PMID- 10395981
TI  - Modulation of mast cell activity by a peptide agonist of the thrombin receptor:
      role of nitric oxide.
AB  - The effect of a thrombin receptor agonist peptide (TRAP-6) on the release of
      nitric oxide (NO) and platelet activating factor (PAF) from resting and calcium
      ionophore (A23187)-activated rat peritoneal mast cells (RPMC) was studied using a
      platelet aggregation bioassay. RPMC spontaneously released NO, which inhibited
      TRAP-6-, ADP-, and PAF-stimulated platelet aggregation. This effect of NO was
      abolished by the addition of an NO binding agent, oxyhemoglobin (oxyHb), to the
      platelet suspension. The RPMC-induced suppression of platelet aggregation was
      completely inhibited by the NO-synthase inhibitor L-NAME. TRAP-6 and its high
      affinity analog haTRAP stimulated the rapid release of NO from RPMC. The effect
      of TRAP-6 was inhibited by pretreatment of the RPMC with L-NAME or with the
      inhibitor of the constitutive NO-synthase isoform (cNOS) calmidazolium. TRAP-6
      inhibited PAF release from A23187-activated RPMC via an NO-dependent mechanism.
      Platelet aggregation induced by PAF release from activated RPMC was also
      confirmed in experiments using the PAF receptor antagonist ginkgolide B. Thus,
      TRAP-6 is a rapidly acting modulator of mast cell reactivity; it stimulates NO
      release and inhibits PAF secretion.

PMID- 10395982
TI  - Using hydrated reversed micelles to evaluate the dimensions of polymer-protein
      adducts.
AB  - Hydrolysis of N-trans-cynnamoylimidazole catalyzed by conjugates and complexes of
      alpha-chymotrypsin (ChT) with poly(ethylene glycol) (PEG) of different molecular
      mass (from 300 to 5000 daltons) was studied in the system of the hydrated
      reversed micelles of aerosol OT (AOT) in octane at 25 degrees C. The plot of the
      deacylation constant k3 for PEG--ChT conjugates and complexes versus the degree
      of hydration of reversed micelles (w0 = [H2O]/[AOT]) was studied. These plots are
      bell-shaped with maxima shifted to higher degrees of micelle hydration compared
      to the corresponding value of the shift for ChT. As for PEG--ChT conjugates, the
      value of the shift of w0 increases with increasing of molecular mass of the
      attached PEG and/or with the number of polymer chains per ChT molecule. Another
      picture was observed for PEG--ChT complexes for which the position of the maximum
      on k3 versusw0 curves was practically the same for all compounds. The values of
      the thickness of the polymer layer for PEG--ChT conjugates and complexes were
      calculated. Thus, polymer chains in conjugates placed in hydrated micelles are
      highly packed, whereas in the case of complexes they form a flat layer on the
      surface of the protein.

PMID- 10395983
TI  - Anionic carbohydrate-containing polymers of cell walls in two streptoverticille
      genospecies.
AB  - The cell walls of two streptoverticille genospecies which belong to a
      historically isolated group of the genus Streptomyces contain anionic polymers of
      different structure. Streptomyces hachijoensis VKM Ac-191T and Streptomyces
      cinnamoneus subsp. azacoluta VKM Ac-606T assigned to one genospecies on the basis
      of DNA--DNA hybridization [5] contain 37% of an identical sugar-1-phosphate
      polymer. The repeating disaccharide units of the polymer, 2-amino-2-deoxy-alpha-D
      glucopyranosyl-(1-->6)-2-acetamido-2-deoxy-al pha-D-glucopyranose, are linked at
      C-1 and C-6' by phosphodiester bonds. The cell walls of Streptomyces
      biverticillatus VKM Ac-891T and Streptomyces baldaccii VKM Ac-821T, members of
      another genospecies, contain about 30% 1,3-poly(glycerol phosphate) completely
      substituted by 2-amino-2-deoxy-alpha-D-glucopyranosyl residues at C-2. Due to the
      presence of an amino sugar with a free amino group in the repeating unit, the
      polymers exhibit neutral properties. Polymer structures were determined by
      chemical methods and NMR spectroscopy. The data indicate taxonomic specificity of
      anionic polymers in streptoverticille cell walls.

PMID- 10395984
TI  - A sequence of the U5 region of Drosophila 1731 retrotransposon long terminal
      repeat (LTR) trans-represses the LTR-directed transcription.
AB  - Transcription of retrotransposons is modulated by various upstream and downstream
      regulatory sites and, as in retroviruses, the majority of these sites are in long
      terminal repeats (LTRs). Also, various mechanisms of positive or negative
      regulation have been shown in the LTR of 1731, a Drosophila melanogaster
      retrotransposon. Here we describe experiments investigating the possible
      mechanism of action of a region localized in the U5 region of the 1731-LTR, which
      has been considered as a silencer. Using cotransfection experiments, we have been
      able to show that this region is implicated in trans-transcriptional repression
      of the 1731 promoter in Schneider's Drosophila cells (S2). However,
      cotransfections have no effect on the UV-B upregulation of the 1731-LTR. Also, in
      spite of the fact that previous experiments have shown that UV-B irradiation
      activation of the 1731-LTR requires the same short sequence of U3 region both in
      drosophila cells and in a human colonic carcinoma cell line (HT29),
      cotransfection experiments showed that the silencer of the U5 region has no
      significant effect in human cells. Analysis of the U5 region shows the presence
      of a short open reading frame which could encode a 26 amino acid polypeptide.
      Furthermore, computer assisted sequence comparisons suggest a possible role for
      this putative peptide in the repression of transcription since this peptide has
      sequence similarities with some of the members of a family of inhibitors of
      transcriptional factor (Rox and Mnt proteins). Interestingly, the 1731-LTR
      contains the sequence CACGCG that is identical to the non-canonical E-box
      recognized by the Rox--Max heterodimer.

PMID- 10395985
TI  - Histones evoke thymocyte death in vitro; histone-binding immunoglobulins decrease
      their cytotoxicity.
AB  - Effects of various histones, poly-L-lysine, spermine, and the synthetic peptide
      Arg-Lys-Asn-Val-Tyr-Arg (thymohexine) on intact rat thymocytes were studied.
      Histones and poly-L-lysine displayed cytotoxicity, causing disorders in the
      membrane permeability of thymocytes and their death. The dose and time
      dependences of the effects of histones on thymocytes were determined.
      Preparations of normal human immunoglobulins bound histones but displayed neither
      cytotoxicity nor interaction with intact thymocytes. The immunoglobulins
      significantly decreased the number of dead thymocytes in the presence of total
      histones. However, the number of cells with detectable immunoglobulin molecules
      was increased in the presence of histone in the incubation medium. It is
      suggested that cytotoxicity depends on the number of epitopes on the cell
      membrane available for interaction with positively charged protein molecules.

PMID- 10395986
TI  - Regulation of delta-aminolevulinate synthase activity during the development of
      oxidative stress.
AB  - Activities of rat liver delta-aminolevulinate synthetase (delta-ALAS),
      glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH), GSH
      content in the liver, and the absorption spectrum of blood serum were
      investigated after CoCl2, HgCl2, or beta-adrenoblocker (propranolol) injection
      and after CoCl2 and propranolol co-administration. Inhibition of the activity of
      the key heme biosynthesis enzyme delta-ALAS was most pronounced and prolonged
      during the first hours after CoCl2 and CoCl2 plus propranolol injections; this
      was associated with accumulation of Co2+--protoporphyrin-containing products of
      hemolysis. Inhibition of delta-ALAS after propranolol injection is not mediated
      by hemolysis. A decrease in GSH content precedes the induction of heme
      biosynthesis only in the case of HgCl2 administration, and this was associated
      with inhibition of GR and G6PDH. The decreased GSH content during the first hours
      after injection of propranolol and co-administration of CoCl2 and propranolol was
      not followed by increase in delta-ALAS activity 24 h after the injection. The
      mechanisms of the increase in the free heme content in the liver during the early
      stages of oxidative stress and the regulation of the key heme biosynthesis enzyme
      are discussed.

PMID- 10395987
TI  - Characteristics of the interaction of melittin with sarcoplasmic reticulum
      membranes.
AB  - Addition of an amphipathic bee venom peptide, melittin, to sarcoplasmic reticulum
      (SR) vesicles isolated from rabbit skeletal muscles resulted in a fast (<1 min)
      blue shift in the fluorescence maximum of the melittin--SR membrane complex. Over
      the following 45 min the position of the fluorescence maximum did not change, but
      the fluorescence intensity of the melittin--SR membrane complex decreased by
      approximately 35% with rate constant 0.14 min-1. Melittin rapidly quenched the
      isotropic signal in the EPR spectrum of spin-labeled stearic acid added to SR
      membranes. Further changes in the spectral parameters of the spin probe bound to
      SR membranes in the presence of melittin indicated an increase of the viscosity
      of the probe microenvironment (empiric parameter T/eta was decreased by
      approximately 35% with rate constant 0.11 min-1). The surface potential of SR
      membranes measured using a pH-sensitive dye, neutral red, decreased after
      melittin addition from -60 to -30 mV. It was demonstrated with the use of a cross
      linking agent, cupric o-phenanthroline, that melittin induced slow aggregation of
      Ca-ATPase protein in SR membranes; the content of enzyme in the monomeric form
      decreased with rate constant 0.14 min-1. It is concluded that melittin binds
      rapidly to SR membranes, inducing slow changes in Ca-ATPase conformation and
      oligomeric state as well as structural transitions in the lipid bilayer of SR
      membranes.

PMID- 10395988
TI  - Adenosine transport in liver before and after organ preservation.
AB  - The effect of 24-h cold storage of liver on nucleoside transport was
      investigated. Nucleoside transport was estimated under conditions when both known
      types of nucleoside transport, facilitated diffusion and Na+/nucleoside
      cotransport, were active and when one of these transport mechanisms was
      inhibited. The rate of adenosine transport was not decreased after long-term cold
      storage of the liver. Inhibition of one of the transport systems decreased the
      rate of adenosine uptake before and after preservation of the liver to about the
      same extent. The adenosine transport rate was maintained during long-term (100
      min) liver perfusion ex vivo. Slight activation of energy-dependent transport in
      the beginning of reperfusion and the slower recovery of this transport after the
      second transition from Na+-free to Na+-containing perfusion are not regarded as
      physiologically important because they were observed after changing the ionic
      content of the extracellular medium. We conclude that the nucleoside transport
      systems in liver are quite well preserved after 24-h cold storage of the organ.

PMID- 10395989
TI  - Cellulase and xylanase activities in higher basidiomycetes.
AB  - Extracellular carboxymethylcellulase, xylanase, beta-glucosidase, and beta
      xylosidase activities of four cultures of higher basidial fungi were studied in
      relation to the source of carbon in the nutrient medium. It was shown that beta
      glucosidases and beta-xylosidases of all basidiomycetes and cellulases and
      xylanases of Pholiota aurivella IBR437 and Gloeophyllum saepiarium IBR155, the
      causal agents of wood brown rot, are constitutive enzymes; however, their
      activities depend on the source of carbon in the growth medium. Cellulases and
      xylanases of Coriolus pubescens IBR663 and Lentinus tigrinus IBR100 degrading
      wood through white rot are inducible enzymes. The synthesis of cellulases and
      xylanases was induced upon fungal growth on media containing crystalline
      cellulose and plant raw materials; carboxymethylcellulose and xylan were less
      effective. The induction of C. pubescens IBR663 cellulase and xylanase was
      observed when avicel was added to the culture growing on a mannitol-containing
      medium. Glucose at a concentration of 0.2-0.8% caused catabolite repression of C.
      pubescens IBR663 cellulase and xylanase. After utilization of glucose, leading to
      a decrease in its concentration below 0.1%, the synthesis of enzymes was resumed.
      These data indicate that the synthesis of cellulases and xylanases in the
      examined macromycetes is under common regulatory control.

PMID- 10395990
TI  - Risk factors associated with hypertensive nephrosclerosis.

PMID- 10395991
TI  - Effects of Mediterranean diet on lipid levels and cardiovascular risk in renal
      transplant recipients.
AB  - BACKGROUND: Renal transplant recipients have an increased incidence of
      cardiovascular disease. These patients present abnormalities of lipoprotein
      profile which are persistent and involve an increasing number of individuals,
      suggesting the opportunity of an early therapeutic intervention. METHODS: We
      evaluated the effects of a 10- to 12-week diet based on the American Heart
      Association step-one diet criteria, modified with an increased intake of
      monounsaturated fats and alimentary fibers, on lipid profile and lipid-related
      cardiovascular risk in 78 normolipidemic and hyperlipidemic renal transplant
      recipients. RESULTS: Diet led to a significant reduction in total cholesterol
      levels by 10%, triglycerides by 6.5%, low-density lipoprotein (LDL)-cholesterol
      by 10.4% and LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol ratio by
      10%, whereas HDL-cholesterol levels remained unchanged. Dividing renal transplant
      recipients into risk classes according to the National Cholesterol Expert Program
      guidelines and LDL-cholesterol levels, we observed a progressively increasing
      reduction in total cholesterol and LDL-cholesterol levels among 'desirable LDL
      cholesterol', 'borderline high-risk LDL-cholesterol' and 'high-risk LDL
      cholesterol' patients, while HDL-cholesterol levels did not change in any group
      and the LDL-cholesterol/HDL-cholesterol ratio significantly decreased in
      'borderline high-risk LDL-cholesterol' and in 'high-risk LDL-cholesterol'
      patients (respectively by 6.8%, p < 0.05, and by 21.1%, p < 0.0001). Reduction in
      triglyceride levels was statistically significant only in subjects with
      'desirable LDL-cholesterol' (by 12.3%, p < 0.01). Patients in the 'desirable LDL
      cholesterol' class increased from 28 (35.9% of total patients) before diet to 45
      (57.7% of total patients, p < 0.01), while subjects in the 'high-risk LDL
      cholesterol' class reduced from 24 (30.8% of total patients) to 8 (10.2% of total
      patients, p < 0.005). CONCLUSION: These data suggest the possibility of a
      nutritional hypolipidemic approach in renal transplant recipients, even if
      normolipidemic. Dietetic treatment determined an inversion in the typical trend
      of renal transplant recipients, reducing instead of increasing the number of
      subjects with hypercholesterolemia, permitting the selection of individual
      candidates for further pharmacological treatment by carefully evaluating
      risk/benefit costs.

PMID- 10395992
TI  - Nationwide and long-term survey of primary glomerulonephritis in Japan as
      observed in 1,850 biopsied cases. Research Group on Progressive Chronic Renal
      Disease.
AB  - Primary chronic glomerulonephritis is the most common cause of end-stage renal
      failure in Japan. The incidence in dialysis patients in Japan is about four times
      higher than in the United States for reason which are unclear. We conducted a
      nationwide survey on the natural history and treatment of primary
      glomerulonephritis under a program project from the Ministry of Health and
      Welfare of Japan entitled 'Progressive Chronic Renal Disease'. We analyzed
      patient characteristics, disease onset, clinical data, and histological findings
      in 1,850 patients with primary glomerulonephritis from 53 institutions in 1985
      who underwent renal biopsy at least 5 years ago, and the follow-up study was
      carried out 8 years after registration. The incidence of diffuse-mesangial
      proliferative glomerulonephritis is 41.9%, that of minor glomerular abnormalities
      17.5%, and that of focal-mesangial proliferative glomerulonephritis 13.0%. Of
      1,045 biopsy specimens that were examined by immunofluorescence microscopy, 47.4%
      showed IgA nephropathy. Half of all cases with primary chronic glomerulonephritis
      were asymptomatic and were detected on routine health examination. The survival
      rates at 20 years from the apparent onset or earliest known renal abnormality
      are: focal glomerular sclerosis 49%, membranoproliferative glomerulonephritis
      58%, diffuse-mesangial proliferative glomerulonephritis 66%, focal-proliferative
      glomerulonephritis 81%, membranous nephropathy 82%, minor glomerular
      abnormalities 94%, and IgA nephropathy 61%. In conclusion, a high incidence of
      IgA nephropathy and a better renal survival of membranous nephropathy are the
      features of primary chronic glomerulonephritis in Japan. This high incidence of
      IgA nephropathy together with its poor prognosis is probably the reason for the
      increased incidence of primary chronic glomerulonephritis in dialysis patients in
      Japan. In addition, the importance of routine health examination including
      urinalysis is demonstrated.

PMID- 10395993
TI  - Hemodialysis neutropenia correlates with a decreased filterability and an
      increase in the number of cytoplasmic actin filaments in peripheral blood
      neutrophils, which is preceded by a decrease in the number of surface expression
      of L-selectin.
AB  - In order to clarify the precise cellular mechanism of hemodialysis neutropenia,
      we examined the changes in the viscoelasticity of peripheral blood neutrophils
      using both the micropore and the microchannel filtration methods, and the changes
      in the neutrophil surface expression of Mac-1, L-selectin and sialyl Lewis X and
      the cytoplasmic expression of the actin filaments using a flow cytometric
      analysis during a dialysis session. Five patients with chronic renal failure were
      selected who showed a nadir leukocyte count in peripheral blood at 30 min after
      the initiation of the dialysis session. The neutrophil count also reached a nadir
      at 30 min and thereafter returned to almost the predialysis level by 180 min.
      Both the micropore filtration time and the microchannel passage time, which
      reflect the viscoelasticity of the peripheral blood neutrophils, correlated
      inversely with the neutrophil count. At the nadir of neutropenia, the neutrophils
      were observed to have become both adhesive and viscoelastic. The actin filaments
      in the neutrophil cytoplasm gradually increased in number from the start of
      dialysis, reaching a peak level at 30 min, and thereafter decreasing to
      predialysis levels. The Mac-1 expression continuously increased up from 30 min
      until the end of dialysis. The L-selectin expression first decreased at 15 min,
      but thereafter returned to predialysis levels within 60 min. The SLex expression
      did not change throughout the course of the session. These results thus indicated
      the neutrophil counts during a dialysis session to inversely correlate with the
      viscoelasticity of the neutrophils expressed by the micropore filtration time or
      microchannel passage time, which possibly depends on the contents of cytoplasmic
      actin filaments. In addition, the shedding of L-selectin from neutrophil surface
      may also be involved in the first step of hemodialysis neutropenia.

PMID- 10395994
TI  - IgM/IgA nephropathy in callitrichids: antigen studies.
AB  - Renal tissues of callitrichids with IgM nephropathy were immunohistochemically
      examined for the participation of IgA in pathogenesis. In 58 histopathologically
      nephropathy-positive kidneys, IgM predominated in 20 cases and IgA in 7 cases,
      and in 31 cases both immunoglobulins were rated to be approximately equally
      involved. The disease, therefore, might be described as IgM/IgA nephropathy. The
      renal tissues and sera were also tested for nutritional antigens or
      antinutritional antigen antibodies, using immunohistochemistry and Western blots
      (tissues) and enzyme-linked immunosorbent assay (sera). Evidences of nutritional
      antigens in the renal tissues were inconclusive, although circulating IgG class
      antibodies against cereals, milk, and egg proteins were present in quite a number
      of sera. Particular consideration was paid to IgA-antigliadin antibodies, which
      were statistically significantly associated with nephropathy as were IgA
      rheumatoid factors. The findings are discussed in relation to human IgA and IgM
      nephropathies.

PMID- 10395995
TI  - Decrease of apoptosis rate in patients with renal transplantation treated with
      mycophenolate mofetil.
AB  - BACKGROUND/AIMS: Mycophenolate mofetil (MMF) is a powerful immunosuppressant that
      inhibits the proliferation of lymphocytes by blocking the enzyme inosine
      monophosphate dehydrogenase. MMF prevents acute graft rejection in organ
      transplants. The aim of this investigation is to study whether MMF has any
      influence on apoptosis and proliferation rates of cells other than lymphocytes.
      METHODS: We conducted a retrospective study of renal allograft biopsies taken
      during the 1st week after transplantation in 25 patients receiving triple therapy
      with prednisone, ciclosporin and azathioprine 75 mg/day and in 25 patients
      treated with MMF at a dose of 2 g/day instead of azathioprine, in order to
      investigate the differences in the proliferation and apoptosis rates of the
      glomerular, tubular, interstitial and endothelial cells of the kidney. Twelve
      normal kidneys were used as controls. Conventional histopathological techniques
      were applied as usual for pathological diagnosis. Proliferative activity was
      assessed by use of MIB-1 antibody. Sections of formalin-fixed, paraffin-embedded
      tissue blocks were stained for the presence of apoptotic cells by TUNEL assay.
      Evaluation of proliferative or apoptotic rates was made by counting the number of
      positive cells in 10 glomeruli and in 10 transversely cut tubuli in each biopsy.
      The positive cells in the interstitium were counted in ten high-power fields.
      Positive cells in the endothelium were scored semiquantitatively from 0 to 3: 0 =
      none, 1 = isolated cells, 2 = small groups of cells, 3 = most endothelial cells.
      Mann-Whitney U and chi-square tests were used for intergroup comparisons.
      RESULTS: All biopsies were normal or had borderline (Banff classification) acute
      rejection. MIB-1 rates were similar in both groups, without statistical
      differences (p > 0.05) between them. Significantly lower apoptotic rates were
      found in the group treated with MMF in tubular epithelium (23.41 +/- 8.86 vs.
      57.4 +/- 13.42; p = 0.021), in glomerular (1.25 +/- 0.78 vs. 5.3 +/- 1.66; p =
      0.027), and interstitial cells (1.58 +/- 0.6 vs. 5.8 +/- 1.54; p = 0.043).
      Apoptosis in endothelial cells (p > 0.05) was similar in both groups. CONCLUSION:
      We conclude that treatment with MMF of kidney transplant patients does not affect
      the proliferative rate of cells of the allograft, but decreases the number of
      apoptotic cells in tubular epithelium.

PMID- 10395996
TI  - Control of cytomegalovirus disease in renal transplant patients treated with
      prednisone, azathioprine and cyclosporine using intensive monitoring and
      decreased immunosuppression.
AB  - BACKGROUND: The aim of this trial was to study the effectiveness of intensive
      monitoring, together with an early decrease in immunosuppression, in reducing the
      prevalence of CMV disease in renal transplant recipients treated with prednisone,
      azathioprine and cyclosporine. METHODS: From 1/95 to 11/97 a prospective,
      longitudinal study was conducted among 146 consecutive, unselected, renal
      transplant patients in our unit. Only 96 patients whose immunosuppressive
      regimens consisted of prednisone, azathioprine and cyclosporine and whose follow
      up period was greater than 4 months were included in the study. Preemptive
      therapy was administered to 27 high-risk patients. CMV antigenemia (CMV-AG) and
      other virological tests were performed weekly for the first 4 posttransplant
      months. The immunosuppression was decreased when the first positive CMV-AG was
      detected. Azathioprine was completely withdrawn when the CMV-AG count was greater
      than 10 cells per 10(5) PBLs. The cyclosporine dose was gradually decreased in
      the next 4 weeks, but it was not withdrawn in any patient. The prednisone dose
      was modified according to the immunosuppressive protocol. RESULTS: 53% (51/96) of
      the patients had positive CMV-AG on at least one occasion. The dose of
      azathioprine was decreased after CMV-AG detection in 41/51 (80.4%) patients and
      it was completely withdrawn in 23 of these (45%). The mean decrease in the dose
      of azathioprine was 73 +/- 31 (25-175) mg, a mean percentage decrease of 76 +/-
      27% (25-100%). The dose of cyclosporine was progressively decreased during the 4
      weeks after detection of the first CMV-AG (mean cyclosporine levels: 210 +/- 66,
      196 +/- 54 and 164 +/- 36 ng/ml at the time of first CMV-AG detection, 2 and 4
      weeks respectively, p < 0.0001, repeated measures analysis of variance). None of
      the 45 patients without CMV-AG and only 2 of 51 (3.9%) patients with CMV-AG
      developed symptomatic CMV disease (2% of the total). CMV disease was of moderate
      intensity in both patients. Only 3/51 (5.8%) patients developed acute rejection
      after the first CMV-AG detection in the 4 posttransplant months. CONCLUSION: The
      results of this study suggest that intensive monitoring and an early reduction of
      immunosuppression, together with preemptive therapy in high-risk patients, is
      effective in diminishing the prevalence and severity of CMV disease.

PMID- 10395997
TI  - Induction of transient proteinuria, hematuria, and glucosuria by ethanol
      consumption in Japanese alcoholics.
AB  - Urinalysis was carried out in 231 inpatients with alcohol dependence syndrome
      (215 males and 16 females). Fifty-nine patients (25.5%) showed proteinuria, 97
      (42.0%) showed glucosuria, and 62 patients (26.8%) showed hematuria on admission.
      A total of 135 out of 231 patients (58.4%) showed abnormal urinalysis.
      Proteinuria was related to high blood pressure, high serum glutamic-oxaloacetic
      transaminase, glutamic-pyruvic transaminase, lactate dehydrogenase, uric acid,
      and triglyceride levels, and high urinary amylase concentration. Glucosuria was
      related to high serum glutamic-oxaloacetic transaminase concentration and a
      history of gastrectomy. Hematuria was related to high age and high urinary
      amylase levels. By chi-square test, there was a significant correlation between
      proteinuria and hematuria (p < 0.001) and between hematuria and glucosuria (p <
      0.001), but no correlation was found between proteinuria and glucosuria. The
      incidence of diabetes mellitus was 10.8% (25 out of 231 patients), but transient
      hyperglycemia was observed in some patients without diabetes mellitus on
      admission. Elevated hemoglobin A1, hemoglobin A1c, and fructosamine
      concentrations were observed in patients with either impaired glucose tolerance
      or transient hyperglycemia, which suggested the presence of persistent
      hyperglycemia before admission. On discharge, only 12 out of 198 patients (6.1%)
      showed abnormal urinalysis. We report that heavy ethanol consumption induces
      transient abnormal urinalysis results in Japanese alcoholics.

PMID- 10395998
TI  - Expression and localization of the neuronal glycine receptor beta-subunit in
      human, rabbit and rat kidneys.
AB  - The glycine receptor (GlyR) is a ligand-gated Cl- channel composed of two
      transmembrane subunits, alpha and beta, and gephyrin. The goal of this study was
      to determine whether the alpha- and/or beta-subunits of the GlyR are expressed in
      human, rabbit and/or rat kidneys. Screening of human and rat kidney cortex cDNA
      libraries identified polymerase chain reaction products that were identical to
      the neuronal GlyR beta-subunit. Sequencing revealed that rat kidney cortex and
      neuronal GlyR beta-subunits were identical. RNA isolated from the S2 segment of
      rabbit renal proximal tubules (RPT) and rat and rabbit kidney cortex was
      amplified following reverse transcription and gave similar results to that of
      human and rat kidney cDNA libraries. Degenerate primers against all GlyR alpha
      subunits did not yield a product from rat and rabbit kidney cortex RNA, or from
      human and rat kidney cortex cDNA libraries. Immunofluorescence studies localized
      the beta-subunit and gephyrin to the basolateral membrane of rabbit RPT. These
      results provide compelling evidence for the GlyR beta-subunit, but not the alpha
      subunit, in human, rabbit and rat kidney cortex.

PMID- 10395999
TI  - Abnormal tenascin expression in murine autosomal recessive polycystic kidneys.
AB  - The mechanisms responsible for renal cyst formation in congenital polycystic
      kidney disease (PKD) remain unknown. Changes in extracellular matrix (ECM) are
      regarded as an important pathogenic factor in PKD. Tenascin, an ECM glycoprotein
      implicated in abnormal growth in adult organs, has not been systematically
      evaluated in PKD. In this study, tenascin expression was studied by
      immunohistochemistry in the autosomal recessive polycystic kidneys of C57BL/6J
      (cpk/cpk) mice. Scanning electron microscopy was performed to determine the cyst
      types and their temporal evolution, and to establish correlations with the
      immunohistochemistry observations. Cystic lesions evolved in three main stages.
      Initially, the cysts appeared as segmental dilatations of both proximal and
      collecting ducts. In the second stage, the collecting duct cysts (CDCs) underwent
      rapid growth that led to the destruction of all other kidney elements. In the
      final stage, the CDCs reached their maximum size and the PKD mice died. Normal
      differentiated principal cells and three types of intercalated cells were present
      in the CDC epithelium. In all three stages an intense tenascin expression was
      detected selectively in the basement membranes of the cysts. In the last stage,
      an intense tenascin immunoreactivity was also observed in the interstitial
      fibrotic tissue. The abnormal presence of tenascin in the basement membranes of
      the cysts suggests that this glycoprotein is implicated in the pathogenesis of
      the cysts, possibly by stimulating cell proliferation.

PMID- 10396000
TI  - Focal segmental glomerulosclerosis in a 32-year-old kidney allograft after 7
      years without immunosuppression.
AB  - In kidney allografts, focal segmental glomerulosclerosis (FSGS) has been
      described as recurrent, de novo, or a histological variant of chronic transplant
      glomerulopathy. We describe a unique case of de novo FSGS in a renal transplant
      not accompanied by any feature of rejection in a patient who had not been
      immunosuppressed for several years. A 58-year-old woman received a histoidentical
      living-related kidney transplant for end-stage renal disease due to chronic
      pyelonephritis. Twenty-four years after the transplant she voluntarily
      discontinued all immunosuppressive medication. Seven years later she presented
      with nephrotic syndrome, mild renal failure, and positive serology for hepatitis
      C virus (HCV) antibody. The kidney transplant biopsy disclosed de novo FSGS.
      Features of acute or chronic rejection, including chronic transplant
      glomerulopathy, were not seen. The pathogenesis of this lesion is probably
      related to sustained and prolonged glomerular hyperfiltration; alternatively, HCV
      infection may have triggered or accelerated the appearance of FSGS.

PMID- 10396001
TI  - Hyponatremia-associated rhabdomyolysis.
AB  - BACKGROUND: Hyponatremia is the most frequent electrolyte disorder. However,
      hyponatremia rarely results from excessive water intake, unless the kidney is
      unable to excrete free water, such as in patients on thiazide diuretics; in
      addition, hyponatremia is an uncommon cause of rhabdomyolysis. METHODS: We
      present a 51-year-old hypertensive woman on chronic hydrochlorothiazide therapy
      who developed acute water intoxication and severe myalgias. RESULTS: The patient
      developed acute hypotonic hyponatremia and subsequent rhabdomyolysis. We discuss
      the mechanisms responsible for the development of hyponatremia and its
      association with rhabdomyolysis. CONCLUSION: Muscle enzymes should be monitored
      in patients with acute hyponatremia who develop muscle pain, and hyponatremia
      induced rhabdomyolysis must be considered in patients with myalgias receiving
      thiazide diuretics.

PMID- 10396002
TI  - Q-T interval dispersion and its arrhythmogenic potential in hemodialyzed
      patients: methodological aspects.

PMID- 10396003
TI  - Serum laminin P1 fragment and procollagen III in patients with kidney diseases.

PMID- 10396004
TI  - End-stage chronic renal failure secondary to cisplatin and ifosfamide combination
      chemotherapy.

PMID- 10396005
TI  - Postdialysis serum albumin is more rational than predialysis value.

PMID- 10396006
TI  - Effects of conventional heparin and low-molecular-weight heparin treatment on
      lipid metabolism during a single hemodialysis session.

PMID- 10396007
TI  - Well-being therapy: conceptual and technical issues.
AB  - Well-being therapy is a short-term, well-being-enhancing psychotherapeutic
      strategy. It is based on Carol D. Ryff's multidimensional model of psychological
      well-being, encompassing environmental mastery, personal growth, purpose in life,
      autonomy, self-acceptance and positive relations with others. Its conceptual and
      technical issues are described. It may be applied as a relapse-preventive
      strategy in the residual phase of affective (mood and anxiety) disorders, as an
      additional ingredient of cognitive behavioral packages, in patients with
      affective disorders who failed to respond to standard pharmacological and
      psychotherapeutic treatments, in body image disorders and in psychosomatic
      medicine. The first validation studies appeared to be promising. The technique is
      in its preliminary stage of development and may undergo major changes in the next
      years. It is hoped it may herald a new trend of psychotherapy research and
      practice in the current symptom-oriented settings.

PMID- 10396008
TI  - Combined treatment for patients with double depression.
AB  - BACKGROUND: Patients with double depression (major depression + dysthymia) have a
      particularly chronic course of illness, yet few studies have investigated
      treatments for these patients. METHODS: 26 inpatients with double depression were
      assigned to two types of treatment: (1) pharmacotherapy and (2) combined
      treatment (pharmacotherapy + cognitive-behavioral psychotherapy). Treatment began
      while the patients were in the hospital and continued for 20 weeks after
      discharge. Comprehensive assessments were conducted at the end of treatment as
      well as at 6- and 12-month follow-up assessments. RESULTS: The results indicated
      that double-depressed patients who received the combined treatment had
      significantly lower levels of depression and higher social functioning at the end
      of treatment. However, no significant differences between groups were found at
      the follow-up assessments. CONCLUSIONS: These results suggest that the addition
      of cognitive-behavioral psychotherapy may produce an improved short-term outcome
      for patients with double depression.

PMID- 10396009
TI  - High-density exposure therapy for obsessive-compulsive inpatients: a 1-year
      follow-up.
AB  - BACKGROUND: This study evaluates the effects of individual high-density exposure
      (2-3 weeks, all day) plus response prevention therapy on 85 unselected inpatients
      suffering from obsessive-compulsive disorder (OCD). METHODS: Twenty-eight
      therapist practitioners performed treatment. RESULTS: At 1-year follow-up, self
      ratings indicated that patients on average felt much improved. Impairment by both
      obsessions and compulsions was significantly reduced (p < 0.001 in each case),
      and OCD symptoms as assessed by two OCD questionnaires had also decreased
      significantly, as had depressiveness and overall symptomatology (all p < 0.001).
      Defining improvements as >30% successes, as done in other OCD treatment outcome
      studies, success rates were 68 and 69%, respectively, for the two OCD
      questionnaire scores, 75% for self-rated impairment by obsessions and 84.5% for
      compulsions, 85.6% for overall psychopathology (General Symptom Index), and 75%
      for depressiveness (Beck Depression Inventory). Effect sizes were >1 SD for all
      of the measures included. CONCLUSIONS: We conclude that long-term effects for
      high-density treatment of unselected OCD patients bring about as good results as
      treatments with exposure and response prevention performed with selected patient
      samples in a research context.

PMID- 10396010
TI  - Evaluation of some criteria used to select patients for brief psychodynamic
      therapy.
AB  - BACKGROUND AND OBJECTIVES: The effectiveness of brief psychotherapy is
      established, but criteria for the selection of patients remain elusive. This
      study examines the usefulness of some widely used criteria for the selection of
      patients for brief psychodynamic therapy (BPT). METHODS: A checklist of 39
      criteria often used in a teaching hospital to screen patients for BPT was
      constructed. Scores derived from a principal components analysis of this
      checklist provided one set of predictor criteria. A second measure was derived
      from the consensual agreement of the independent ratings by 3 prominent advocates
      of BPT. A third predictor was derived from a similar analysis of items from the
      checklist on which consensual agreement for their relevance was obtained from the
      independent ratings of 23 BPT teachers in 16 university-affiliated hospitals.
      Reliable chart-based ratings of improvement in symptoms, increased insight, and
      improvement in general functioning of a convenience sample of 43 patients treated
      with BPT in the outpatient clinic of a teaching hospital served as outcome
      measures. RESULTS: No correlation between any of the derived predictors and any
      of the measures of outcome was significant after a Bonferroni correction.
      CONCLUSION: Teachers and clinicians still do not have good criteria for the
      selection of patients who will benefit from BPT. Exclusion of severe behavior
      disorders may, however, improve outcome rates by more than 15%.

PMID- 10396011
TI  - Measuring psychotherapeutic change with the symptom checklist SCL 90 R.
AB  - BACKGROUND: Despite a long tradition of discussions on the evaluation of
      psychotherapy, there is still a lack of agreement for measuring change after
      psychological treatment. In this paper we describe the concept of statistical and
      clinical significance of change. We use the Symptom Checklist 90 R as a commonly
      administered instrument to propose conventions and cutoff points for
      psychological symptoms and their change after therapy. METHOD: A German norm
      population and several psychotherapy samples have been aggregated to calculate
      cutoffs and confidence intervals (reliable change indices) for statistically and
      clinically significant changes after psychotherapy. RESULTS: The cutoff point
      between a 'functional' and a 'dysfunctional' population was calculated as C =
      0.57 (Global Severity Index, GSI). Patients above this score need a change of at
      least RCI = 0.43 (GSI difference) for a statististically significant change.
      Below this score the RCI = 0.16. The use of multiple clinical groups (e.g.
      inpatients and outpatients) for a more realistic determination of a 'stepwise'
      clinically significant change, as proposed by Tingey et al. in the USA, is not
      possible in the German samples collected so far. Initial SCL 90-R scores in these
      groups do not show enough differences to call a move from one group to the other
      a clinically significant change. CONCLUSION: In the German samples investigated
      the move from a 'functional' to a 'dysfunctional' population and vice versa has
      to be taken as the criterion for a clinically significant change up to now.

PMID- 10396012
TI  - Psychophysiological correlates of relaxation induced by standard autogenic
      training.
AB  - BACKGROUND: The present study aimed to determine the psychophysiological changes
      induced in subjects by standard autogenic training (AT). Physiological
      measurements were taken under strict experimental conditions. METHODS: Thirty-one
      healthy students were divided randomly into two groups: the AT group and the
      control group. In the first session, the physiological variables were measured
      for all students before and after all were asked to relax in their own way. The
      AT group were then taught AT for 3 months, after which time the measurements were
      repeated. In the second session, the AT group practised the standard AT exercise,
      while the control group repeated their own form of simple relaxation.
      Electrocardiogram, plethysmogram (PTG) and blood pressure (BP) were measured
      while the students carried out a breathing rate of 15 cycles/min. The R-R
      intervals and BP were analysed by an autoregressive model for spectral analysis,
      and the data were compared by repeated-measures ANOVA. RESULTS: The AT group had
      a significant increase in the mean R-R interval and a significant decrease in the
      baseline deflection of the PTG in the second session. There were no significant
      changes in sympathetic activity except for the change in the PTG, although low
      frequency amplitude of systolic BP decreased slightly. CONCLUSIONS: AT was found
      to induce significant changes that were independent of respiration in healthy
      students, although paced breathing might have operated as a mental stress. The
      increase in mean R-R interval and the decrease in baseline deflection of the PTG
      were the most robust correlates of AT.

PMID- 10396014
TI  - A pilot study of hypnosis in the treatment of patients with psoriasis.
AB  - BACKGROUND: The use of psychological therapies for patients with psoriasis has
      been proposed based on observations that the severity of their disease may
      correlate with emotional stress. The aim of this pilot study was to evaluate the
      effect of hypnosis as a treatment modality for patients with psoriasis. METHODS:
      We performed a 3-month randomized, single-blind, controlled trial of the use of
      hypnosis in adults with stable, chronic, plaque-type psoriasis. Highly or
      moderately hypnotizable subjects were randomized to receive either hypnosis with
      active suggestions of improvement (5 patients) or neutral hypnosis with no
      mention of their disease process (6 patients). After this period, the study was
      unblinded, and all the patients were treated for an additional 3 months with
      hypnosis with active suggestions of improvement. RESULTS: Highly hypnotizable
      subjects showed significantly greater improvement than did moderately
      hypnotizable subjects, independent of treatment group assignment (active
      suggestion or neutral hypnosis). CONCLUSION: Although this study included a very
      limited number of patients, the results suggest that hypnosis may be a useful
      therapeutic modality for highly hypnotizable subjects with psoriasis, and merits
      further testing in a larger patient population.

PMID- 10396013
TI  - Cognitive change following cognitive behavioural therapy for non-cardiac chest
      pain.
AB  - BACKGROUND: Seventeen to 43% of patients with non-cardiac chest pain suffer from
      anxiety/panic disorders. Cognitive behavioural therapy (CBT) is effective in
      reducing non-cardiac chest pain. However, no data are available indicating that
      pain reduction following CBT may be cognitively mediated or whether success of
      CBT is dependent on the presence of panic. The aim of the study was threefold:
      (1) does CBT have a differential effect on cognitive measures; (2) does a
      relationship exist between improvement in non-cardiac chest pain and changes in
      cognitive measures, and (3) can panic be established as a moderator of the effect
      of treatment? METHODS: Sixty-five patients with non-cardiac chest pain completed
      a randomised trial comparing study CBT with 'care as usual'. Dependent measures
      were: frequency of chest pain, anxiety, the fear of bodily sensations,
      attributions and catastrophic cognitions. RESULTS: CBT had a differential effect
      on most of the cognitive measures. Pain reduction was associated with the
      development of more adequate cognitions with respect to chest pain, independent
      of anxiety reduction. Although panic patients reported higher baseline scores on
      the cognitive measures, no differences in treatment results were found between
      panic and no-panic patients. CONCLUSIONS: Pain reduction following CBT may be
      cognitively mediated. The presence of panic did not affect the outcome of
      treatment, implying a broad applicability of the cognitive model for treatment of
      patients with non-cardiac chest pain.

PMID- 10396015
TI  - Using skeletal muscle as an artificial endocrine tissue.
AB  - Gene transfer into muscle tissue is currently being developed as a method for the
      production, secretion and delivery of therapeutic proteins. This methodology has
      been used to produce a variety of physiologically active proteins and may
      ultimately be applied to the treatment of several diseases. In this review, we
      consider several applications of this methodology and discuss approaches for
      modulating therapeutic protein production and secretion from muscle, using growth
      hormone as an example. In addition, factors limiting the effectiveness of muscle
      gene transfer are also discussed, as these shall determine the efficacy of muscle
      gene transfer when applied to humans.

PMID- 10396017
TI  - Effects of prolonged infusion of basic fibroblast growth factor and IGF-I on
      adrenocortical differentiation in the autotransplanted adrenal: an
      immunohistochemical study.
AB  - Adrenocortical regeneration after adrenal autotransplantation provides a model
      for the study of local autocrine/paracrine mechanisms involved in the growth and
      differentiation of the adrenal cortex. To study the possible involvement of some
      growth factors, namely basic fibroblast growth factor (bFGF, FGF-2) and insulin
      like growth factor I (IGF-I), in cell differentiation, immunohistochemical and
      ultrastructural studies were carried out on adrenal autotransplants in adult male
      rats. To distinguish between fasciculata and glomerulosa-like cells with
      accuracy, tissue sections were immunostained with IZAb, which recognizes the
      inner zone antigen (IZAg) present in fasciculata and reticularis cells but absent
      from the glomerulosa, and by electron microscopy. IGF-I-treated animals exhibited
      a clear glomerulosa-like zone that was devoid of IZAb immunostaining. In this
      outer subcapsular area, ultrastructural examination showed cells containing
      mitochondria with irregular cristae resembling those of the fetal or immature
      glomerulosa cells. In contrast, no significant morphological differences were
      observed in bFGF-treated animals when compared with those from saline-treated
      controls, in both of which, IZAb immunostaining occurred in almost all
      adrenocortical cells, with no clear zonation or glomerulosa, as seen in the
      intact animal. Plasma aldosterone and corticosterone concentrations were lower in
      autotransplanted control animals than in intact controls, although plasma renin
      activities were similar. IGF-I treatment significantly increased aldosterone
      concentrations, whereas corticosterone and plasma renin activity were reduced.
      bFGF infusion further reduced plasma aldosterone, although plasma renin activity
      and corticosterone were unaffected. These results suggest that the two growth
      factors have different effects on zonal differentiation and function in the
      autotransplanted gland. In particular, bFGF, by reducing glomerulosa function,
      appears partly to replicate the actions of ACTH in normal animals. In contrast,
      IGF-I enhances the glomerulosa secreting phenotype and diminishes that of the
      fasciculata/reticularis, possibly replicating the actions of angiotensin II or a
      low sodium diet.

PMID- 10396016
TI  - Ovarian steroids regulate 24p3 expression in mouse uterus during the natural
      estrous cycle and the preimplantation period.
AB  - We examined 24p3 expression in the mouse uterus at various stages of the natural
      estrous cycle and during the preimplantation period. The level of 24p3 mRNA
      appeared intensively in proestrus and estrus, then declined sharply from
      metestrus to diestrus. Consistent with this observation, 24p3 protein was
      abundant in proestrus, decreased from estrus to metestrus and declined to a very
      low level in diestrus. The uterine 24p3 expression closely overlapped with the
      estradiol (E2) surge in proestrus and estrus but it was suppressed when
      progesterone (P4) rose to a high level during the reproductive cycle. Neither the
      protein nor its message was detected in the uteri of immature mice or
      ovariectomized adult animals. While an injection of P4 to these animals was
      unable to initiate uterine 24p3 expression, administration of estrogenic steroids
      to these animals markedly stimulated the gene expression. Treatment of these
      animals with E2 together with P4, on the other hand, did not stimulate the gene
      expression. In pregnant animals (day 1 (D1)=day of vaginal plug), 24p3 mRNA
      remained at a high level on D1 and D2 but dropped to an almost undetectable level
      on D3 and D4. This was accompanied by a decrease in 24p3 protein from D1 to D2
      and a decline in the protein to undetectable levels from D3 to D4. The staining
      patterns of both the immunohistochemical localization of 24p3 protein and in situ
      hybridization for the detection of 24p3 mRNA in the uterine sections showed that
      24p3 expression took place mainly in the luminal and glandular epithelial cells
      of the endometrium. This together with our previous observation that 24p3 protein
      is found in uterine luminal fluid indicates that the protein is secreted
      primarily from these cells to their respective luminal surfaces during proestrus
      and estrus.

PMID- 10396018
TI  - Cell-specific localization of G protein alpha-subunits in the islets of
      Langerhans.
AB  - G protein alpha-subunits are involved in the transduction of receptor-mediated
      regulation of insulin and glucagon secretions. To get further insight into the
      status of G proteins in alpha- and beta-cells of the Langerhans islets, we have
      used immunohistochemistry to study the distribution of alpha-subunits in pancreas
      sections from the rat. Our results show that only insulin-immunoreactive beta
      cells display immunoreactivity for selective antibodies directed against the
      different members of the Galphas and Galpha12-families (alphas, alphaolf, and
      alpha12, alpha13 respectively). Immunoreactivities for antibodies directed
      against members of the Galphaq- and Galphai-families showed a more diverse
      localization: alpha11 and alphao2 were only detected in glucagon-immunoreactive
      alpha-cells, whereas alphai1 was detected in all beta-cells but only in a few
      alpha-cells. Even though beta-cells showed immunoreactivities for alphao-non
      isoform-selective antibodies, we could not identify the isoform(s) present using
      selective alphao1 and alphao2 antibodies. Other members of the Galphai- and
      Galphaq-families (alphai3, alphat2, alphaz and alphaq) were detected in both
      alpha- and beta-cells. In conclusion, our findings demonstrate a clear difference
      in the localization of G protein alpha-subunits between alpha- and beta-cells,
      suggesting the involvement of specific receptor transduction pathways for the
      neuronal/hormonal regulation of alpha- and beta-cell functions.

PMID- 10396019
TI  - Morphometric studies of neonatal estrogen imprinting in the mature mouse
      prostate.
AB  - Estrogens play an important role in prostate physiology and neonatal exposure to
      estrogens has profound effects on the mature structure and hormonal sensitivity
      of rodent prostate. We aimed to determine the long-term effects of neonatal
      estrogens on the ductal architecture, morphology and hormonal sensitivity of the
      mature mouse prostate. Newborn mice (day 1-2) were administered a single
      injection (s.c.) of estrogens (estradiol benzoate (EB), diethylstilbestrol (DES))
      with or without concomitant anti-estrogens (tamoxifen (TAM) or ICI 182 780 (ICI))
      TAM or ICI alone, GnRH-antagonist (GnRH-A) or vehicle. At 7 weeks of age, ventral
      prostates (VP) were microdissected to estimate branch tip numbers and processed
      for stereologic analysis of volume fractions and diameters of various tissue
      components. Estrogens induced permanently reduced branching morphogenesis leading
      to reduced VP weights and these effects were fully reproduced by GnRH-A,
      consistent with an indirect effect. Stereologically, neonatal estrogens induced
      epithelial and stromal hyperplasia and significantly reduced (P<0.05) the
      diameters of VP glandular tubules and lumen compared with controls and these
      regressive effects were not reversed either by TAM or ICI. These studies confirm
      that a single neonatal dose of both DES and EB produces imprinting in the mature
      mouse prostate and indicate that neonatal estrogen effects involve both direct as
      well as indirect effects. In addition, both TAM and ICI act as partial agonists
      to the estrogen receptor in the ventral prostate of neonatal mouse.

PMID- 10396020
TI  - Characterization and hormonal modulation of immunoreactive thiamin carrier
      protein secreted by adult rat Leydig cells in vitro.
AB  - Leydig cells isolated from adult rats and maintained under defined conditions in
      culture secrete a protein of molecular weight (Mr) 70 000 which is
      immunologically similar to chicken thiamin carrier protein (TCP). Synthesis of
      immunoreactive TCP by these cells is demonstrated by immunoprecipitation of
      [35S]methionine incorporated, newly synthesized proteins with monoclonal and
      polyclonal antibodies to chicken TCP. The amount of immunoreactive TCP secreted
      into the culture supernatant is quantitated by using a specific radioimmunoassay.
      Under the influence of LH, secretion of immunoreactive TCP is enhanced 3-fold and
      can be inhibited by up to 70% with aromatase inhibitor (1,4,6-androstatrien-3,17
      dione). Cyclic AMP acts as a second messenger in the sequence of events involved
      in LH-induced elevation of immunoreactive TCP in Leydig cells. The effects of
      exogenous estradiol-17beta and diethylstilbestrol are comparable in terms of
      stimulation of secretion of immunoreactive TCP by these cells. Tamoxifen brought
      about a 70% decrease in the elevated levels of immunoreactive TCP. These results
      suggest that estrogen mediates immunoreactive TCP induction in hormonally
      stimulated adult rat Leydig cells.

PMID- 10396021
TI  - Up-regulation of clusterin (sulfated glycoprotein-2) in pancreatic islet cells
      upon streptozotocin injection to rats.
AB  - Clusterin is a heterodimeric glycoprotein which has been shown to play important
      roles in programmed cell death and/or in tissue reorganization not only during
      embryonic development but also in damaged tissues. Recently, we reported the
      transient induction of clusterin in pancreatic endocrine cells during early
      developmental stages of islet formation. In the present study, we have
      investigated the expression of clusterin in pancreatic tissue of streptozotocin
      treated rats which were undergoing extensive islet tissue reorganization due to
      degeneration of insulin beta cells. Clusterin was found in endocrine cells
      identified as glucagon-secreting alpha cells at the periphery of the islet. Using
      immunoelectron microscopy, clusterin-positive cells showed the typical
      ultrastructural features of pancreatic alpha cells. In addition, colocalization
      of clusterin and glucagon in the same secretory granules was shown by double
      immunogold labeling. These results imply that clusterin is a secretory molecule
      having endocrine and/or paracrine actions in parallel with glucagon. Further, we
      noted that clusterin expression was increased in pancreatic alpha cells during
      the process of beta cell death upon streptozotocin injection. The increase was
      significant as early as 1-3 h after streptozotocin treatment prior to any
      morphological alteration of islet beta cell and any manifestation of
      hyperglycemia. The expression of clusterin was steady-stately up-regulated during
      the process of islet reorganization caused by streptozotocin-induced cytotoxic
      injury. Therefore, we suggest that clusterin might be considered as a molecule
      induced by both embryonic development and drug-induced reorganization of the
      endocrine pancreas. Since clusterin expression is up-regulated in alpha cells,
      but not in beta cells undergoing degeneration, it may play a protective role
      against the cytotoxic insult.

PMID- 10396023
TI  - Glucocorticoid-induced insulin resistance of protein synthesis is independent of
      the rapamycin-sensitive pathways in rat skeletal muscle.
AB  - This study was designed to evaluate the role of p70 S6 kinase (p70(S6K) ), p90 S6
      kinase (p90(RSK)) and mitogen-activated protein (MAP) kinase pathways in the
      insulin resistance of muscle protein synthesis observed during glucocorticoid
      treatment. Dexamethasone treatment decreased the effect of insulin on protein
      synthesis (-35. 2%) in epitrochlearis muscle incubated in vitro. This resistance
      is associated with a total blockage of the stimulation of p70(S6K) by insulin
      without any significant decrease in the amount of the kinase. However, the effect
      of rapamycin (inhibitor of several intracellular pathways including p70(S6K)
      pathways) on muscle protein synthesis was not modified by dexamethasone in rat
      muscles. This suggested that 'rapamycin-sensitive pathways' associated with the
      insulin stimulation of protein synthesis were not altered by glucocorticoids and
      thus are not responsible for the insulin resistance observed. As incubation of
      muscles with a MAP kinase inhibitor (PD98059) did not modify the stimulation of
      protein synthesis by insulin and as glucocorticoids did not alter the effect of
      insulin on p90(RSK )activity, our results provide evidence that glucocorticoid
      induced alterations in muscle protein synthesis regulation by insulin do not
      involve factors or kinases that are dependent on MAP kinase and/or p90(RSK).

PMID- 10396022
TI  - Corticosterone alters insulin signaling in chicken muscle and liver at different
      steps.
AB  - Chronic treatment with corticosterone evokes insulin resistance in chickens, a
      species which is already resistant to insulin compared with mammals. The in vivo
      effects of corticosterone on insulin signaling were investigated in chicken liver
      and thigh muscle in two nutritional states: basal (overnight fasted) and
      stimulated (30 min refeeding). Corticosterone significantly decreased specific
      insulin binding in liver and the amount of insulin receptor substrate-1 (IRS-1)
      and p85 (regulatory subunit of phosphatidylinositol (PI) 3'-kinase) in both
      tissues. Insulin receptor (IR) and IRS-1 mRNAs generally varied accordingly. Src
      homology and collagen protein (Shc) and messenger were not altered. In liver, in
      the basal state, the tyrosine phosphorylation of IR, IRS-1 and Shc, and the IR
      associated PI 3'-kinase activity were largely decreased by corticosterone.
      Following refeeding the cascade was activated in control but totally inhibited in
      treated chickens. In muscle, as previously observed, IR and IRS-1 phosphorylation
      and PI 3'-kinase were not stimulated by refeeding in controls. Only the
      phosphorylation of Shc was increased. On this background, corticosterone
      decreased the basal PI 3'-kinase activity and prevented the phosphorylation of
      Shc in response to refeeding. In conclusion, corticosterone largely impaired
      insulin signaling in liver and to some extent in muscle. This should contribute
      to the large impairment of growth. In addition, the present studies further
      emphasize the peculiarities of insulin signaling in chicken muscle, which needs
      further investigation.

PMID- 10396024
TI  - The role of growth hormone and glucocorticoid in glucose handling in vivo.
AB  - Growth hormone (GH) can oppose the catabolic effects of glucocorticoids. However,
      both hormones have adverse effects on carbohydrate metabolism. Here we examined
      the interactive effects of GH and the glucocorticoid methylprednisolone (MP) on
      glucose tolerance, insulin resistance and [3H]2,6-deoxyglucose uptake of
      peripheral tissues in rats. Female Wistar rats received either saline, GH (2.7
      mg/kg), MP (5.0 mg/kg) or GH+MP. After 7 days treatment, animals were subjected
      to an i.v. glucose tolerance test. In a second experiment, animals treated as
      above were anesthetized and injected with human insulin (0.5 U/kg), [3H]2,6
      deoxyglucose (500 microCi/kg), and [14C]mannitol (25 microCi/kg), to estimate
      insulin resistance and [3H]2,6-deoxyglucose uptake in fat and muscle. Weight gain
      in controls was 7.6+/-1.7 g, while GH treatment increased the mean body weight by
      18.7+/-2.2 g (P<0.0002) and MP inhibited weight gain down to 0.0+/-1.0 g
      (P<0.004). This drop in weight gain was reversed back to normal when GH was given
      in combination with MP. After a glucose tolerance test no significant differences
      in glucose area under the curve were detected when comparing individual groups
      with the control group, but samples taken just before this test revealed that
      basal insulin was significantly elevated in the group treated with GH (174+/-27
      pM, P<0.008), or GH+MP (209+/-21 pM, P<0.004), when compared with controls (107+/
      17 pM). MP alone had no effect (122+/-19, P<0.3). After an i.v. bolus of insulin
      the group receiving GH+MP had a significantly (P<0.007) higher level of
      circulating glucose compared with controls (6.5+/-0.3 mM vs 4.4+/-0.7 mM).
      Despite this, there were no differences in peripheral glucose uptake between the
      two groups. In conclusion this study shows that a combined administration of GH
      and MP decreases the potency by which insulin decreases circulating glucose
      levels, but that peripheral tissues are not primarily involved in this insulin
      resistance.

PMID- 10396025
TI  - Leptin regulates GH secretion in the rat by acting on GHRH and somatostatinergic
      functions.
AB  - Leptin is a hormonal product of adipose tissue whose expression reflects the body
      state of nutritional reserves. Previous experiments have demonstrated that leptin
      is one of the metabolic signals capable of regulating GH secretion. The aim of
      the present study was to evaluate whether CNS-mediated mechanisms underlie the GH
      releasing activity of leptin. Freely moving mature male rats were injected i.c.v
      with leptin or isovolumetric amounts of diluent once daily for 3 days and were
      killed 2 h after the last administration. Central injection of leptin increased
      pituitary GH mRNA levels by 53. 2% and hypothalamic GHRH mRNA by 61.8%, and
      reduced somatostatin mRNA levels by 41.5%. To evaluate the direct effect of
      leptin on the pituitary, it was added alone or in combination with GHRH to
      primary cultures of anterior pituitary cells. Addition of leptin (10(-11)-10(-7)
      M) did not alter basal GH release nor the GH-releasing activity of GHRH. These
      results demonstrate that leptin is a metabolic signal that regulates GH secretion
      in the rat by acting on hypothalamic GH-regulatory hormones.

PMID- 10396026
TI  - The de novo synthesis of numerous proteins is decreased during vitamin D3
      deficiency and is gradually restored by 1, 25-dihydroxyvitamin D3 repletion in
      the islets of langerhans of rats.
AB  - Since both the release and de novo biosynthesis of insulin are severely decreased
      by vitamin D3 deficiency and improved by 1, 25-dihydroxyvitamin D3 (1,25(OH)2D3)
      repletion following a 6-h delay in the rat, the present experiments investigated
      the effects of vitamin D3 deficiency on the biosynthesis of heavier molecular
      weight proteins using electrophoretic separation. Gel protein staining by
      Coomassie blue showed very different profiles for islets protein production from
      4-week vitamin D3-deficient rats compared with normal islets. The pattern was
      characterised by a decrease in high molecular weight proteins, concomitantly
      accompanied by an increase in low molecular weight proteins. This tendency was
      partially reversed in vivo by 1,25(OH)2D3 repletion treatment for 7 days and was
      evident after only 16 h of treatment. In parallel with these in vivo
      observations, which represent a static index of islets protein production, a
      kinetic study was performed in vitro by a double-labelling method allowing us to
      measure the de novo synthesis of proteins in islets during a strong 16.7 mM
      glucose stimulation. Comparison of 3H and 14C labelled samples was achieved via
      coelectrophoresis to avoid experimental artefacts. The study of the ratio of
      d.p.m. 3H/d.p.m. 14C for each molecular weight protein in islets stimulated by
      16.7 mM glucose (versus basal 4.2 mM glucose) showed an increase in the height of
      certain peaks: 150, 130 and 8.5 kDa. Under the same conditions, islets from 4
      week vitamin D3-deficient rats (versus normal islets) presented a large deficit
      of numerous newly synthesised proteins and particularly those implicated in the
      response to glucose stimulation. In vitro repletion of 1,25(OH)2D3 tended to
      reverse, at least in part, the deleterious effect of vitamin D3 deficiency on the
      de novo protein synthesis of islets but these effects were gradual. Indeed, there
      was no detectable effect at 2 h incubation, but 1,25(OH)2D3 increased the 60 to
      65 kDa, 55 kDa, and 9 to 8 kDa molecular mass proteins at 4 h, and increased the
      level of most newly synthesised proteins at 6 h. These data support the
      hypothesis of a beneficial genomic influence of 1,25(OH)2D3 that occurs
      progressively within the islets of Langerhans and which may prepare the beta
      cells for an enhanced response to glucose stimulation.

PMID- 10396027
TI  - A sensitive and specific in vitro bioassay for activin using a mouse plasmacytoma
      cell line, MPC-11.
AB  - A new in vitro bioassay for activin was developed using the mouse plasmacytoma
      cell line, MPC-11. Human recombinant (hr) activin A dose-dependently inhibited
      the proliferation of these cells, whereas a range of other factors, including
      inhibin, follistatin and transforming growth factor-beta1, -beta2 and -beta3 had
      no effect. Conditioned medium containing activin B induced an inhibition similar
      to hr-activin A. The inhibitory influence of activin A could be blocked by
      follistatin, but not by hr-inhibin A. This bioassay had a sensitivity for activin
      A of around 0.4 ng/ml, an ED50 response of 3.5 ng/ml, and an intra-assay
      coefficient of variation of <11%. It offers substantial advantages over existing
      in vitro activin bioassays in terms of ease of use, specificity and throughput.
      The utility of the MPC-11 bioassay was demonstrated in the purification of
      activin from amniotic fluid, where an almost identical profile of bioactive
      activin A was detected compared with the pituitary cell bioassay of activin.
      Bioactive activin could also be detected in unpurified ovine allantoic and
      amniotic fluids and bovine follicular fluid. Measuring activin in untreated and
      heat-treated human sera or seminal plasma was hampered by a non-specific
      inhibitory effect, so that several serum samples did not run parallel with the hr
      activin A standard. This inhibitory effect by serum could not be overcome by
      addition of follistatin, suggesting it is not activin-like bioactivity. This new
      bioassay for activin demonstrates widespread applicability for monitoring of
      purified or partially purified samples during purification procedures,
      bioactivity measurements, receptor-binding studies and assays of cell culture
      medium.

PMID- 10396028
TI  - A novel human GnRH receptor homolog gene: abundant and wide tissue distribution
      of the antisense transcript.
AB  - Gonadotropin releasing hormone (GnRH) regulates the reproductive system through a
      specific G-protein-coupled receptor (GPCR) in pituitary gonadotropes. The
      existence of two (or more) forms of GnRH in most vertebrates suggested the
      existence of GnRH receptor subtypes (I and II). Using sequence information for
      extracellular loop 3 of a putative Type II GnRH receptor from a reptile species,
      we have looked for a Type II GnRH receptor gene in the human genome EST
      (expressed sequence tag) database. A homolog was identified which has 45% and 41%
      amino acid identity with exons 2 and 3 of the known human GnRH pituitary receptor
      (designated Type I) and much lower homology with all other GPCRs. A total of 27
      contiguous ESTs was found and comprised a continuous sequence of 1642
      nucleotides. The EST sequences were confirmed in the cloned human gene and in PCR
      products of cDNA from several tissues. All EST transcripts detected were in the
      antisense orientation with respect to the novel GnRH receptor sequence and were
      highly expressed in a wide range of human brain and peripheral tissues. PCR of
      cDNA from a wide range of tissues revealed that intronic sequence equivalent to
      intron 2 of the Type I GnRH receptor was retained. The failure to splice out
      putative intron sequences in transcripts which spanned exon-intron boundaries is
      expected in antisense transcripts, as candidate donor and acceptor sites were
      only present in the gene when transcribed in the orientation encoding the GnRH
      receptor homolog. No transcripts extended 5' to the sequence corresponding to
      intron 2 of the Type I GnRH as the antisense transcripts terminated in poly A due
      to the presence of a polyadenylation signal sequence in the putative intron 2
      when transcribed in the antisense orientation. These findings suggest that a Type
      II GnRH receptor gene has arisen during vertebrate evolution and is also present
      in the human. However, the receptor may have become vestigial in the human,
      possibly due to the abundant and universal tissue transcription of the opposite
      DNA strand to produce antisense RNA.

PMID- 10396029
TI  - Endocrine control of Na+,K+-ATPase and chloride cell development in brown trout
      (Salmo trutta): interaction of insulin-like growth factor-I with prolactin and
      growth hormone.
AB  - A 2-factorial (3x3) injection experiment was used to investigate the effect and
      interaction between different hormones on the initial phase of seawater (SW)
      acclimation in brown trout (Salmo trutta). Each fish was given 4 injections on
      alternate days in freshwater (FW). Factor 1 was either saline, 2 micrograms ovine
      prolactin (oPRL)/g, or 2 micrograms ovine growth hormone (oGH)/g. Factor 2 was
      either 0, 0. 01, or 0.1 mirograms recombinant human insulin-like growth factor-I
      (rhIGF-I)/g. In each of the 9 treatment groups, half of the fish were subjected
      to a 48-h SW-challenge test, and the remaining fish were sham-transferred to FW
      one day after the last injection. Hypo-osmoregulatory performance was increased
      by GH and impaired by PRL treatment as judged by changes in plasma osmolality,
      [Na+], [Cl-], total [Mg] and muscle water content (MWC) after SW transfer. IGF-I
      reduced plasma osmolality after transfer to SW but had no effect on plasma total
      [Mg] or MWC. The effects of the two factors on plasma osmolality, [Na+], [Cl-],
      and MWC were additive. In sham-transferred fish, GH and IGF-I, alone and in
      combination, stimulated Na+,K+-ATPase alpha-subunit mRNA (alpha-mRNA) content in
      the gill. This was paralleled by an overall increase in gill Na+, K+-ATPase
      activity in fish treated with 0.01 micrograms IGF-I/g. Simultaneous
      administration of PRL completely inhibited the increase in gill alpha-mRNA
      observed in the IGF-I-injected groups. Combination of GH and IGF-I did not
      further affect the alpha-mRNA level relative to the single hormone-injected
      groups. There was an overall decrease in Na+,K+-ATPase activity in pyloric caeca
      and middle intestine by the low dose and both doses of IGF-I respectively. No
      effect was observed in the posterior intestine. PRL and GH treatments did not
      affect enzyme activity in any intestinal segment. Both doses of IGF-I increased
      Na+,K+-ATPase-immunoreactive (NKIR) cell density in gill primary filaments. PRL
      and GH had no effect on primary filament NKIR cell density. GH and both doses of
      IGF-I reduced secondary lamellar NKIR cell density, whereas PRL had no effect.
      The main conclusion is that IGF-I and GH induce an overall redistribution of NKIR
      cells away from the secondary lamella onto the primary filament of FWacclimated
      trout. This is associated with an overall increased alpha-mRNA level in the gill,
      which may reflect an increased expression within individual NKIR cells in the
      primary filament. PRL completely abolished the IGF-I stimulation of alpha-mRNA
      levels, suggesting a desensitisation of the gill tissue to IGF-I, which may
      explain the overall anti-SW adaptive effect of PRL.

PMID- 10396030
TI  - Evidence that the CAG repeat in the androgen receptor gene is associated with the
      age-related decline in serum androgen levels in men.
AB  - In men over 30 years old, serum levels of testosterone (T) decrease with age. A
      shorter polymorphic CAG repeat length in exon 1 of the androgen receptor (AR)
      gene is associated with higher transcription activation by the AR. We determined
      the number of CAG repeats for 882 men aged between 40 and 70 years from the
      Massachusetts Male Aging Study (MMAS). MMAS is a population-based random sample
      survey of men for whom baseline (1987-1989, mean age 53+/-8 years) and follow-up
      (1995-1997, mean age 61+/-8 years) serum hormone levels were available. Multiple
      linear regression was used to determine if CAG repeat length would be predictive
      of hormone levels at follow-up. Hormone levels measured included T, free T,
      albumin-bound T, dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG)
      and luteinizing hormone (LH). The CAG repeat length was significantly associated
      with T (P=0.041), albumin-bound T (P=0.025) and free T (P=0.003) when controlled
      for age, baseline hormone levels and anthropometrics. Follow-up levels of T
      decreased by 0.74%+/-0.36 per CAG repeat decrement. Likewise, the percentages of
      free and albumin-bound T decreased by 0.93%+/-0.31 and 0.71%+/-0.32 per CAG
      repeat decrement respectively. These results suggest that androgen levels may be
      modulated by AR genotype.

PMID- 10396031
TI  - Evidence for enhanced rates of complement activation in serum from patients with
      newly diagnosed insulin-dependent diabetes mellitus exposed to rat islet cells
      and complement-dependent induction of islet cell apoptosis.
AB  - In this paper we report the concentration of terminal complement complexes (TCCs,
      SC5b-9, an index of complement activation) in newly diagnosed insulin-dependent
      diabetes mellitus (IDDM) patient serum and normal human serum. In the nine
      patients studied, levels of serum soluble TCCs were approximately 1.6-fold higher
      than in sera obtained from normal control individuals. On incubation of rat islet
      cells with diluted serum (10%, v/v, concentration), complement activation was
      increased at a significantly faster rate and the total TCC concentration was
      significantly higher in culture medium containing IDDM patient serum than in
      medium containing control serum. The concentration of anti-(glutamic acid
      decarboxylase) autoantibodies in newly diagnosed IDDM patient serum was on
      average 60-fold higher than in normal human control serum. IDDM patient serum
      (10%, v/v) induced apoptosis in islet cells, as determined by islet cell density
      changes and DNA fragmentation patterns. However, serum from IDDM patients was not
      able to induce apoptosis of the cells when complement components (C1q and C3) or
      antibodies were depleted. In addition, glutamine and the potent antioxidant 1
      pyrrolidinecarbodithioic acid partially reversed cell death induced by IDDM
      patient serum in a concentration-dependent manner. The ATP concentration in islet
      cells incubated for 24 h in the presence of diluted IDDM patient serum was
      reduced to 4.4% of that observed in islet cells incubated in fetal calf serum or
      7.3% of that observed in islet cells incubated in normal human serum. On the
      basis of these observations, we suggest that the pathway of IDDM patient serum
      induced islet cell apoptosis may involve antibody-dependent complement
      activation, free radical generation and a precipitous fall in ATP levels.

PMID- 10396032
TI  - The influence of plasma on basal and ACTH-stimulated in vitro adrenocortical
      steroidogenesis.
AB  - Early descriptions of in vitro ACTH bioassays all emphasised the need to use
      extracted plasma samples due to interference by an unidentified component. The
      aim of these studies was to elucidate the effects of whole plasma on ACTH
      steroidogenic activity in vitro and to identify the responsible factor. A
      sensitive in vitro dispersed bovine adrenocortical cell bioassay was established.
      The addition of 10% ACTH-depleted human pooled plasma to the incubation media
      resulted in basal steroidogenesis equivalent to that achieved with 10(-9) M ACTH1
      24 and potentiated the steroidogenic activity of 10(-9) M ACTH1-24 by 7.8-fold.
      This potentiation was dependent on the concentration of both ACTH and plasma in
      the media, but did not result from the mitogenic effect of plasma. A pituitary
      source was excluded and the potentiating activity was not extractable by Vycor
      glass. Column chromatography demonstrated two peaks of activity corresponding to
      molecular weights of 650 and 220x10(3) Da. These peaks did not correspond to the
      plasma binding of 125I-ACTH which resulted from non-specific binding to albumin.
      Lipoprotein-deficient serum had no effect on either basal or ACTH-stimulated
      steroidogenesis, but both were restored by the addition of purified lipoproteins.
      However, novel findings demonstrated a differential effect of low (LDL) and high
      (HDL) density lipoproteins on basal and ACTH-stimulated steroid production; thus,
      LDL exerted a greater effect on the former, whilst HDL potentiated the
      steroidogenic activity of added ACTH more than LDL. The addition of the
      lipoproteins to lipoprotein-deficient serum restored its basal and ACTH
      potentiating effects, the cholesterol concentrations of the chromatographic
      fractions exactly paralleling their ACTH potentiating effect. These findings
      suggest that not only are lipoproteins the plasma factor(s) which potentiates
      ACTH steroidogenic activity in in vitro bioassays, but also that they exert
      differential effects on basal and ACTH-stimulated steroid production.

PMID- 10396033
TI  - The formation and selection of cells expressing preB cell receptors and B cell
      receptors.

PMID- 10396034
TI  - Fetal liver organ cultures as a tool to study selection processes during B cell
      development.

PMID- 10396035
TI  - Negative selection of self-reactive B lymphocytes involves complement.

PMID- 10396037
TI  - The transition from immature to mature B cells.

PMID- 10396036
TI  - Cross-talk between CD44 and c-Met in B cells.

PMID- 10396038
TI  - CD21high IgMhigh splenic B cells enriched in the marginal zone: distinct
      phenotypes and functions.
AB  - Collectively, these findings suggest that MZ B cells have unique signaling and
      subsequent differentiative capabilities that permit them to react much more
      vigorously than the majority of splenic B cells (FO) in the earliest stages of an
      in vivo immune response. This is particularly evident with limiting T cell help,
      low concentration of thymus-independent mitogens or low amounts of particulate
      blood-borne antigen in the spleen (Fig. 4). They are uniquely situated adjacent
      to the marginal sinuses and a rich array of antigen trapping macrophages. Because
      of this location the MZ B cells are ideally positioned for immediate exposure to
      blood-borne antigens. In contrast, the FO B cells are in juxtaposition to the
      PALS which may expedite the interactions of FO B cells with T cells and antigen
      presenting cells. Collectively these properties point to a role for FO B cells in
      antibody responses to T dependent antigens generated in germinal centers. These
      responses occur temporally later in immune responses and may be involved
      principally in the response to protein antigens. [figure: see text].

PMID- 10396040
TI  - Role of complement receptors CD21/CD35 in B lymphocyte activation and survival.
AB  - In summary, the complement system has evolved an important function in regulation
      of humoral immunity to T-dependent antigens. Covalent attachment of activated C3
      to antigen alters its fate by enhancing uptake on the surface of FDC via
      CD21/CD35; and by enhancing signal transduction via the B cell coreceptor
      CD21/CD19/Tapa-1. In the absence of complement receptors CD21/CD35 or C3 ligand,
      naive B cells bearing low affinity BCR fail to effectively survive within the
      lymphoid follicle following contact with antigen and death is mediated by a Fas
      dependent mechanism. Alternatively, B cells sufficiently activated to initiate a
      GC reaction fail to survive in the absence of CD21-CD21L interaction.

PMID- 10396039
TI  - Do germinal centers have a role in the generation of lymphomas?

PMID- 10396041
TI  - Long-lived plasma cells survive independent of antigen.

PMID- 10396042
TI  - Regulation of expression of chemokine receptor BLR1/CXCR5 during B cell
      maturation.

PMID- 10396043
TI  - Chemokines and B-cell homing to follicles.

PMID- 10396044
TI  - A novel CC chemokine ABCD-1, produced by dendritic cells and activated B cells,
      exclusively attracts activated T lymphocytes.

PMID- 10396045
TI  - Human macrophage-derived chemokine (MDC) is strongly expressed following
      activation of both normal and malignant precursor and mature B cells.

PMID- 10396046
TI  - Susceptibility genes for AIDS and AIDS-related lymphoma.

PMID- 10396047
TI  - Molecular mechanisms of T helper cell differentiation and tissue-specific
      migration.

PMID- 10396048
TI  - The role of chemokine receptors in directing traffic of naive, type 1 and type 2
      T cells.

PMID- 10396049
TI  - A lymphoid tissue-specific receptor, EDG6, with potential immune modulatory
      functions mediated by extracellular lysophospholipids.

PMID- 10396050
TI  - Phenotypic and molecular characterization of human peripheral blood B-cell
      subsets with special reference to N-region addition and J kappa-usage in V kappa
      J kappa-joints and kappa/lambda-ratios in naive versus memory B-cell subsets to
      identify traces of receptor editing processes.
AB  - We identified a population of IgM+IgD+ B-cells in the peripheral blood (PB) of
      humans that express somatically mutated V-region genes like classical class
      switched or IgM-only memory B-cells and comprise around 15% of PB B-cells in
      adults. Mutated IgM+IgD+ cells differ from unmutated naive IgM+IgD+ cells in that
      they express the CD27 cell surface antigen. In addition, a very small subset of
      IgD-only B-cells was identified in the PB that carried rearranged VH-genes with
      an extremely high load of somatic mutations (up to 60 mutations per gene). A
      common characteristic of the four somatically mutated subsets, which altogether
      comprise 40% of PB B-lymphocytes in adults, is the surface expression of CD27.
      This antigen may thus represent a general marker for memory B-cells in the human.
      Somatically mutated and unmutated PB B-cell subsets were analyzed for N-region
      addition and J kappa-usage in V kappa J kappa-joints, and in addition for the
      respective kappa/lambda-ratios: N-nucleotides could be identified in a large
      fraction of V kappa-regions of all B-cell subsets, indicating that N-region
      insertion already occurs in the pre-germinal center (GC) phase of B-cell
      development. Both the J kappa-usage in expressed V kappa J kappa-joints and the
      kappa/lambda-ratio from somatically mutated B-cells do not differ substantially
      from those of the unmutated cells, so that in terms of these parameters, a
      contribution of secondary V kappa J kappa-rearrangements in shaping the memory B
      cell repertoire is not detectable.

PMID- 10396051
TI  - Tuning somatic hypermutation by transcription.
AB  - The dependence of somatic hypermutation on transcription was studied in three
      mutant immunoglobulin heavy chain (IgH) insertion mice in which a targeted non
      functional VHB1-8 passenger transgene was either placed under the transcriptional
      control of a truncated DQ52 promoter (p delta), its own RNA polymerase II
      dependent IgH promoter (pII) or a RNA polymerase I dependent promoter (pI). The
      relative mutation-frequency of the VHB1-8 passenger transgene in memory B cells
      of p delta, pI and pII mice (7%, 60% and 100%) correlated with the relative
      levels of transgene-specific pre-mRNA expressed in germinal center B cells
      isolated from the mutant mice (8%, 72% and 100%, respectively). These data
      indicate that the mutation load of rearranged Ig genes can be tuned by
      transcription. The question, whether somatic hypermutation requires transcription
      per se or a specific component of the RNA polymerase II complex, is under
      investigation.

PMID- 10396052
TI  - Immunoglobulin gene associated chromosomal translocations in B-cell derived
      tumors.

PMID- 10396053
TI  - Analysis of B-cell neoplasias by spectral karyotyping (SKY).
AB  - B-cell neoplasias represent a heterogeneous group of diseases, including acute
      lymphocytic leukemia (ALL) and the broad spectrum of non-Hodgkin's lymphomas
      (NHL). Conventional cytogenetic analysis has revealed specific chromosomal
      aberrations in ALL as well as in NHL. Spectral karyotyping (SKY) is a novel
      molecular cytogenetic technique which allows the visualization of all human
      chromosomes in different colors, therefore greatly facilitating the recognition
      of chromosomal aberrations. The potential of SKY is exemplified by the fact that
      in our experience, 70% of the cases analyzed resulted in karyotypes where the
      majority of aberrations were either refined or new aberrations were detected when
      compared to their G-banding karyotypes. This also applies to the analysis of B
      cell neoplasias. In hematologic malignancies, especially acute leukemias,
      specific chromosomal aberrations are of etiologic as well as diagnostic and
      prognostic importance. The identification of new recurrent chromosomal
      aberrations could therefore lead to a better characterization of disease entities
      or subgroups in ALL and NHL and further improve diagnosis, treatment
      stratification and ultimately prognosis. Interestingly, the comparison of the
      pattern of chromosomal aberrations in hematological neoplasias and carcinomas
      revealed striking differences. While about 50% of the aberrations in
      hematological malignancies are balanced translocations, such aberrations are
      exceedingly rare in epithelial cancers in which unbalanced structural and
      numerical aberrations prevail.

PMID- 10396054
TI  - Recurrent non-reciprocal translocations of chromosome 5 in primary T(12;15)
      positive BALB/c plasmacytomas.
AB  - The majority of inflammation-induced peritoneal BALB/c plasmacytomas
      (approximately 90%) harbor a balanced T(12;15) chromosomal translocation that
      deregulates the expression of the proto-oncogene c-myc. Recent evidence suggests
      that the T(12;15) is an initiating tumorigenic mutation that occurs in early
      plasmacytoma precursor cells. However, plasmacytomas take a long time to develop
      (average tumor latency approximately 220 days), which suggests that additional
      tumor progression events may be required to complete oncogenesis. We hypothesized
      that such tumor progression events may take the form of secondary chromosomal
      aberrations that can be detected by spectral karyotyping (SKY). We screened the
      entire chromosome complement of 18 primary BALB/c plasmacytomas carrying the
      T(12;15) and found in nine tumors (50% recurrence) secondary cytogenetic
      aberrations that involved bands D, E and F chromosome (Chr) 5. The Chr 5D-F
      rearrangements were manifested predominantly as unbalanced translocations with
      various partner chromosomes. This finding led us to propose the existence of an
      important plasmacytoma progression locus in the central region of Chr 5, which
      presumably becomes involved in peritoneal plasmacytoma development by promiscuous
      chromosomal translocations.

PMID- 10396055
TI  - Myc-induced cyclin D2 genomic instability in murine B cell neoplasms.

PMID- 10396057
TI  - Chromosome 13 deletion in myeloma.

PMID- 10396056
TI  - The role of somatic hypermutation in the generation of deletions and duplications
      in human Ig V region genes and chromosomal translocations.

PMID- 10396058
TI  - Unusual immunoglobulin and T-cell receptor gene rearrangement patterns in acute
      lymphoblastic leukemias.
AB  - Immunoglobulin (Ig) and T-cell receptor (TCR) genes are rearranged in virtually
      all acute lymphoblastic leukemia (ALL) cases. However, the recombination patterns
      display several unusual features as compared to normal lymphoid counterparts.
      Cross-lineage gene rearrangements occur in more than 90% of precursor-B-ALL and
      in approximately 20% of T-ALL, whereas they are rare in normal lymphocytes.
      Approximately 25-30% of the Ig and TCR gene rearrangements at diagnosis are
      oligoclonal, and can undergo continuing or secondary recombination events during
      the disease course. Based on our extensive molecular studies we hypothesize that
      the unusual Ig and TCR gene rearrangements in ALL occur as an early postoncogenic
      event resulting from the continuing V(D)J recombinase activity on accessible gene
      loci. This hypothesis is on the one hand supported by the virtual absence of
      cross-lineage gene rearrangements in normal lymphocytes and mature lymphoid
      malignancies and on the other hand by the presence of oligoclonality and
      secondary Ig and TCR gene rearrangements in ALL.

PMID- 10396059
TI  - Analysis of variable heavy and light chain genes in follicular lymphomas of
      different heavy chain isotype.

PMID- 10396061
TI  - Epidemiology of B-cell lymphomas.

PMID- 10396060
TI  - Regulation of c-myc and immunoglobulin kappa gene transcription by promoter
      proximal pausing of RNA polymerase II.
AB  - In normal cells, the proto-oncogene c-myc is regulated by promoter-proximal
      pausing of RNA polymerase II (pol II). In Burkitt lymphoma cells, c-myc is
      chromosomally translocated to one of the three immunoglobulin (Ig) gene loci and
      its transcription is driven constitutively by Ig enhancers. Promoter-proximal
      pausing of pol II is abolished on the translocated c-myc allele. This raised the
      question whether induction of Ig gene transcription also involves activation of
      promoter-proximal paused pol II. Here we have studied the transcriptional
      activation of a functionally rearranged Ig kappa gene in the mouse pre B cell
      line 70Z/3. We show that pol II pauses approximately 50 bp downstream of the
      transcriptional start site of the uninduced Ig kappa gene.

PMID- 10396062
TI  - Alternative splicing of CD79a (Ig alpha) and CD79b (Ig beta) transcripts in human
      B-CLL cells.

PMID- 10396063
TI  - Novel aspects of murine B cell lymphomas.

PMID- 10396064
TI  - Molecular pathogenesis of B cell malignancy: the role of BCL-6.

PMID- 10396065
TI  - ATM and lymphoid malignancies; use of oriented peptide libraries to identify
      novel substrates of ATM critical in downstream signaling pathways.

PMID- 10396067
TI  - The adaptor protein SLP-65/BLNK controls the calcium response in activated B
      cells.

PMID- 10396066
TI  - MHC-linked control of murine SLE.

PMID- 10396068
TI  - Involvement of the SHP-1 tyrosine phosphatase in regulating B lymphocyte antigen
      receptor signaling, proliferation and transformation.

PMID- 10396069
TI  - Antigen receptor signaling induces differential tyrosine kinase activation and
      population stability in B-cell lymphoma.

PMID- 10396070
TI  - Importance of CD44 variant isoforms in mouse models for inflammatory bowel
      disease.

PMID- 10396071
TI  - EBNA2 and c-myc in B cell immortalization by Epstein-Barr virus and in the
      pathogenesis of Burkitt's lymphoma.

PMID- 10396072
TI  - The control of proliferation, survival and apoptosis in human multiple myeloma
      cells in vitro.

PMID- 10396073
TI  - Activation molecules on human myeloma cells.

PMID- 10396074
TI  - Peritoneal B-1 cells switch in vivo to IgA and these IgA antibodies can bind to
      bacteria of the normal intestinal microflora.

PMID- 10396075
TI  - Inhibition of pristane-induced peritoneal plasmacytoma formation.
AB  - While the mechanism of how Indo inhibits PCTGEN is not established, Several
      hypothetical explanations provide new potential experimental approaches. Indo may
      block production of cytokines such as Il-6 in accessory cells that are critical
      for B-cell growth, viability and maturation, or it may directly target B cells
      via PPAR-gamma receptors. The latter mode of action is described in other cell
      types but not yet defined in B cells.

PMID- 10396076
TI  - The role of p16INK4a (Cdkn2a) in mouse plasma cell tumors.

PMID- 10396077
TI  - Transgenic shuttle vector assays for assessing oxidative B-cell mutagenesis in
      vivo.
AB  - The recent development of transgenic mutagenicity assays provides new
      opportunities for evaluating mutagenic processes in vivo. To asses mutant
      frequencies in tissue B cells, we decided to take advantage of two such assays
      that utilize the transgenic shuttle vectors, lambda LIZ and pUR288. Our main
      interest in this research is to test two basic premises of inflammation-induced
      plasmacytoma development in genetically susceptible BALB/c mice; i.e., the
      possibility that plasmacytoma precursor cells may become targets of phagocyte
      mediated oxidative mutagenesis in situ and the prospect that plasmacytoma
      susceptibility/resistance genes may contribute to these phenotypes by
      enhancing/reducing oxidative mutagenesis in B cells. Based on our preliminary
      experience with the lambda LIZ and pUR288 transgenic in vivo mutagenicity tests,
      we propose to employ these assays as broadly applicable tools for assessing
      overall mutagenesis during normal and aberrant (malignant) B-cell development.
      Furthermore, transgenic shuttle vector assays appear to lend themselves as ideal
      methods to associate general B-cell mutagenesis with the peculiar, B cell-typical
      somatic hypermutation processes that target the V(D)J gene segment, the proto
      oncogene bcl-6 and perhaps other, still unknown loci.

PMID- 10396078
TI  - Plasmacytoma induction in specific pathogen-free (SPF) bcl-2 transgenic BALB/c
      mice.
AB  - Germ-free (GF) and specific pathogen free (SPF) BALB/c mice are refractory to
      plasmacytoma induction by pristane (McIntire and Princler, 1969, Byrd et al
      1991). It was therefore suggested that MPC development may depend on antigenic
      stimulation. If so, it may conceivably act by preventing the apoptotic
      elimination of tumor precursor cells. We have tested this idea by elevating the
      apoptotic threshold by the introduction of a bcl-2 transgene. We have found that
      MPCs could be induced by pristane oil in transgene carrying SPF mice. An E mu
      activated bcl-2 transgene was introduced into SPF BALB/c mice. The mice were used
      after two backcrosses (BC-2). Pristane oil treatment was started at 4 to 6 weeks
      of age (3 x 0.3 ml via i.p. at monthly intervals). For each transgene carrier a
      transgene negative littermate was used as control. Fifteen of 24 (63%) transgene
      carriers developed plasmacytomas after latency periods between 67 and 146 days
      (mean = 112 +/- 30 days) after the first pristane injection. Five additional
      transgene carriers developed lymphoma (3 cases) or mixed MPC and lymphoma (2
      cases). In contrast, no tumors developed in 16 transgene negative littermates
      that were kept > 300 days under observation. Karyotyping showed that 10/15 (66%)
      of the MPCs carried a T(12;15) translocation, 4/15 (27%) carried both T(12;15)
      and T(6;15) translocations in the same metaphase plate, and 1/15 (7%) was
      translocation free. A T(12;15) translocation was also detected in one of the 2
      mice with mixed tumor type. Pristane treated bcl-2 transgenic C57B1/6 mice
      remained tumor free, although T(12;15) translocation carrying cells were found in
      the peritoneal fluid of 4/20 mice 176 days after pristane.

PMID- 10396079
TI  - Induction of B cell autoimmunity by pristane.

PMID- 10396080
TI  - Cytokine network imbalances in plasmacytoma-regressor mice.

PMID- 10396082
TI  - [Mathematical models for the epidemiologic study of infectious diseases].

PMID- 10396081
TI  - The role of human herpesvirus-8, (HHV-8), in multiple myeloma pathogenesis.

PMID- 10396083
TI  - [Comparative study of three systems for in vitro activity investigation of
      fluconazole against yeast isolates of clinical interest].
AB  - BACKGROUND: Study of antifungal sensitivity can help in treatment screening and
      evaluation of patients suffering from some fungal infections. The purpose of this
      study is to compare fluconazole MICs obtained by E-test and agar dilution with
      the NCCLS method. MATERIAL AND METHODS: The in vitro activity of fluconazole
      against 158 yeast strains by three systems: E-test, agar dilution and the
      microbroth NCCLS M27P method. RESULTS AND CONCLUSION: A correlation between 84 to
      100% was observed the degree varying in the result among different species. The E
      test was found to be comparable to the NCCLS M27P microbroth method, was easier
      to perform and provides MIC result for Candida species within 24 h.

PMID- 10396084
TI  - [Prospective study of 198 community acquired pneumonias in a general hospital].
AB  - BACKGROUND: Pneumonia is a common medical problem with a significant mortality
      and morbidity. It is the leading infectious disease in hospital admissions. We
      conducted a one year prospective study of the patients over 14 years of age that
      had been diagnosed of community-acquired pneumonia in our institution. The
      objective was to determinate the clinical characteristics and the aetiological
      agents of pneumonia in our geographic area and to know which factors are related
      with the evolution and prognosis of this disease. PATIENTS AND METHODS: A medical
      team evaluated and followed-up all the patients diagnosed of community-acquired
      pneumonia. Epidemiological, clinical, radiological and laboratory data were
      recorded. An attempt to obtain an aetiological diagnosis was done by means of
      sputum, blood cultures and serologic studies at admission and between third and
      fourth week later. In individualized patients invasive techniques were performed.
      We classified the patients in five groups according to previous criteria defined
      in the guidelines of our hospital based in age, the presence of an underlying
      disease and the severity in the initial presentation. RESULTS: 274 patients
      received an initial diagnosis of pneumonia, in 76 (28%) this initial diagnosis
      was not confirmed. The mean age of the remaining 198 was 55 years. 62% were men.
      40% had an identifiable microbiological etiology. The main causal microorganism
      was Streptococcus pneumoniae followed by Mycoplasma pneumoniae. Gram stain and
      sputum culture were the most useful laboratory tests for the aetiological
      diagnosis. Blood cultures and serological test had a lower efficiency. There was
      no relationship between the clinical presentation, typical or atypical pneumonia,
      and the causal microorganism. Complications developed in 11% of the patients and
      the mortality rate was of 3%. CONCLUSIONS: There was a high rate of initial
      erroneous diagnoses of pneumonia. The epidemiological, clinical and
      roentgenographic characteristics were similar to other studies conducted in our
      country with a lower number of microbiological agents identified. Patients who
      were admitted at hospital only because their age or the presence of chronic
      disease had a good evolution. In this series patients with severe presentation
      also had a good prognosis. It would be interesting to investigate about which
      parameters could be useful as indicators of prognosis and evolution at initial
      presentation of pneumonia.

PMID- 10396085
TI  - [Clinical, epidemiological and microbiological aspects of Mobiluncus sp. in
      bacterial vaginosis].
AB  - BACKGROUND: In this paper, our goal was to determine the optimal isolation
      conditions, biochemical characterization, and preservation of species of the
      genus Mobiluncus, associated with bacterial vaginosis in patients attending the
      family planning clinic. Also, we tried to relate its presence with demographic
      variables and criteria used in the clinical diagnosis of bacterial diagnosis.
      METHODS: The specimen from the posterior fornix were collected and transported to
      the laboratory in a Stuart medium, one at room temperature and the other at 4
      degrees C. These samples were inoculated in anaerobic culture media. RESULTS: Of
      a total of 92 patients studied, 61 (66.3%) were normal, 28 (30.4%) bacterial
      vaginosis, and 3 (3.3%) had intermediate vaginosis. There was statistically
      significant relationship only with intrauterine device use (p = 0.00499). The
      presence of curved rod, using Gram's method, was significantly related with pH (p
      = 0.00000) positive amines test (p = 0.00000), and the presence of clue cells (p
      = 0.00000). Mobiluncus was observed in 23 samples (82%), and the majority (15)
      using RLK agar (cold enrichment technique). With conventional techniques, we
      identified 12 strains as Mobiluncus curtisii and 3 strains as Mobiluncus
      mulieris. The strains of Mobiluncus sp. grew better from litmus milk conserved at
      -30 degrees C. CONCLUSION: Isolating Mobiluncus sp. is fairly easy, if the right
      media and the techniques are used.

PMID- 10396086
TI  - [Infection by Staphylococcus lugdunensis: clinico-microbiologic characterization
      of 25 cases].
AB  - INTRODUCTION: S. lugdunensis is a recently described staphylococcal species with
      morphologic characteristic similar to those of S. aureus. It has been associated
      to a variety of clinical infections. In this paper we present the clinical and
      microbiological features of S. lugdunensis isolates from 25 patients. MATERIALS
      AND METHODS: We have studied the S. lugdunensis isolates obtained from clinical
      specimens in our laboratory over a three-year period, 1994-96. For all isolates
      we determined the presence of clumping factor, Dnase, free coagulase in tube and
      ornithine decarboxylase (ODC). Full identification was performed with API ID32
      Staph strips (bioMerieux) and antimicrobial susceptibility with commercial broth
      microdilution MIC panels (PASCO System, Difco). RESULTS: We obtained 38 S.
      lugdunensis isolates from 25 patients. The clinical specimens were: breast
      exudate/pus (8), blood (5), surgical wound (2), urine (2), nasal exudate (2),
      peritoneal fluid (1), pleural fluid (1), venous catheter (1), Tenckoff catheter
      (1), bartholin pus (1), ulcer (1). The isolates were considered clinically
      significant in 20 patients, whereas those of the remaining 5 patients were
      considered mere colonizers. All isolates were clumping factor (+), ODC (+), Dnase
      (-) and free coagulase (-). 16/23 (69.5%) were susceptible to penicillin and only
      one isolate was methicillin-resistant. CONCLUSIONS: We have isolated S.
      lugdunensis from a great variety of clinical specimens (blood, sterile body
      fluids, urine, skin, abscesses and nasal mucosa). It is specially remarkable the
      association with non-puerperal mastitis. The presence of clumping factor in all
      isolates can easily lead to misidentification as S. aureus. The ODC test appears
      as a good screening method for detecting S. lugdunensis. S. lugdunensis shows a
      good susceptibility to betalactamic an other antimicrobial agents.

PMID- 10396087
TI  - [The importance of polymerase chain reaction in the diagnosis of enterovirus
      infections of the central nervous system in children. Clinico-epidemiologic
      characteristics].
AB  - BACKGROUND: To compare the diagnosis utility of a reverse transcription
      polymerase chain reaction (RT-PCR) for detection of enteroviral RNA in
      cerebrospinal fluid (CSF) in comparison to viral culture for central nervous
      system infections in pediatric population and to know the clinic epidemiological
      characteristics of this infection. METHODS: From June to December of 1997, 116
      CSF samples of children were included in the study. The samples were inoculated
      in MRC-5 and HEP-2 and the enterovirus RNA was detected with AMPLICOR-Enterovirus
      (Roche Diagnostic System). The virus were typed by neutralization. RESULTS: 36
      samples were positive (30 were positive for RT-PCR and 6 for RT-PCR and viral
      culture). The media time in detect the CPE was 4.8 days. The viruses found were
      four echovirus 6, one echovirus 30 and one echovirus 7. Fifteen children were
      under 6 months (93.3% under two months) and 21 children over 6 months with a
      media age of 81 months (range, 38-160 months). In over 6 months old children, the
      most frequent clinical presentation was meningitis aseptic syndrome with
      pleocytosis and in under 6 months old ones was fever and only 60% of these
      children had pleocytosis. The evolution was good in all the cases. CONCLUSIONS:
      AMPLICOR-Enterovirus is a sensitive method for the diagnosis of enteroviral
      meningitis. The clinical manifestations are different with the age and due to the
      absence of neurological symptoms and pleocytosis in the patients under two
      months, we think that it is necessary to study the presence of enterovirus with
      genetic amplification methods in this population of patients.

PMID- 10396088
TI  - [The management and information technology applicable to clinical microbiology
      laboratories].

PMID- 10396089
TI  - [Otomycosis of uncommon etiology].

PMID- 10396090
TI  - [49 Year-old woman with cutaneous lesion, hypoxemia and pulmonary mass].

PMID- 10396091
TI  - [Primary meningococcal arthritis: two adult cases].

PMID- 10396092
TI  - [Acute rhabdomyolysis by Q fever].

PMID- 10396093
TI  - [Out of hospital pneumonia by Morganella morganii].

PMID- 10396094
TI  - [Nitric oxide levels in cephalorhachidian++ fluid in patients with HIV
      infection].

PMID- 10396095
TI  - [Venous and right atrial ventricular septic thrombosis by Candida albicans].

PMID- 10396096
TI  - [Bacteremia by Stomatococcus mucilaginosus in leukemic patients].

PMID- 10396097
TI  - [Disseminated cutaneous involvement by cytomegalovirus and high levels of
      antigenemia in a patient with HIV infection].

PMID- 10396099
TI  - [Pulmonary infection by Nocardia farcinica].

PMID- 10396098
TI  - [Cerebral abscess by Staphylococcus aureus secondary to infectious aortic
      endocarditis. The usefulness of stereotaxic surgery].

PMID- 10396100
TI  - [The effects of an oral calcium overload on the rat exocrine pancreas].
AB  - AIM: The possible induction of functional or morphologic changes in the exocrine
      pancreas of the rat by oral calcium overload was studied to determine the
      possible relationship to predisposition of acute pancreatitis over the acinar
      theory. MATERIALS AND METHODS: Oral chloride calcium (0.45 and 0.25 g/kg body
      weight/day) plus cholelecalciferol (300,000 UI/kg i.m.) were administered to male
      Wistar rats over 1 to 3 months. Half of each group, including a control were
      submitted to cholinergic stimulation with carbamylcholin. After anesthesia, blood
      and pancreatic tissue and duodenal fluid were extracted for enzymatic and
      ultrastructural studies. RESULTS: In the rats treated with high doses of calcium
      for 1 month greater tissue concentrations of amylase, lipase and trypsin were
      observed. Moreover, there was a greater trend to the presence of dilated
      ergastoplasm. In the rats treated with high doses over 3 months a lower enzyme
      concentration was observed in the animals not stimulated that in the control
      group. On stimulation with carbamylcholin, higher concentrations of enzymes were
      observed in tissue than in those not stimulated. This was accompanied by a lower
      number of exocytosis in this experimental group that in the control. CONCLUSIONS:
      A possible increase in the calcium concentration in the acinar cell may lead to
      dysfunction in the secretory mechanisms favoring the intracellular accumulation
      of digestive enzymes, predisposing intracellular activation, in the context of
      the acinar or lysosomal hypothesis of acute pancreatitis.

PMID- 10396101
TI  - [The predictive factors of a good response to the transfusion of erythrocyte
      concentrates in patients with controlled digestive hemorrhage].
AB  - INTRODUCTION: Not all patients respond the same to the transfusion of erythrocyte
      concentrates (EC) after achieving the control of gastrointestinal bleeding. AIM:
      The aim of the present study was to analyze the predictive factors of good
      response to EC transfusion in patients with controlled gastrointestinal
      hemorrhage and determine the stability of transfusion performance. PATIENTS AND
      METHODS: A prospective study was carried out in 61 patients with controlled
      gastrointestinal bleeding. The epidemiologic data were compared and prior to
      transfusion different analytical and hemodynamic variables were compared basally.
      On completion of the transfusion analytical controls were performed at 4 and 24
      hours. The response was considered as optimum when pretransfusional basal
      hemoglobin (Hb) increased at least 1 g and the hematocrit (HCT) rose 3 points for
      each EC administered. RESULTS: The response to transfusion was optimum in 29
      patients and bad in 32. The women responded significantly better than the men (p
      < 0.05), as did patients with lower weight (p < 0.05) and body surface (p <
      0.05). The mean age of the responding patients was greater (p = 0.06) and the
      height, to the contrary, lower (p = 0.09). No significant differences were
      observed in the presence or not of associated disease, type of lesion causing the
      hemorrhage, or number of EC transfused. Likewise, no differences were found with
      regard to the pretransfusional values of TAM, TAS, FC, PVC, Hb, HCT, VCM, HCM,
      urea and creatinine. The only variables with independent predictive value of good
      response were female sex and low body surface. The difference between the Hb and
      HCT values at 4 and 24 h after transfusion did not achieve statistical
      significance. CONCLUSIONS: 1. The hemodynamic state and the degree of basal
      anemia do not condition response to EC transfusion in controlled gastrointestinal
      bleeding. 2. The response to the administration of EC is better in women and
      subjects of lower body surface. 3. Postransfusional analytical control at 4 hours
      allows early evaluation of the effects of the transfusion in patients at risk of
      recurrent hemorrhage.

PMID- 10396102
TI  - [The diagnosis and preoperative location of digestive endocrine tumors by
      endoscopic ultrasonography].
AB  - Around 30% of the gastroenteropancreatic endocrine tumors (GPET) cannot be
      preoperatively identified by the common diagnostic imaging techniques. The aim of
      this retrospective study was to present our experience in the diagnosis and
      localization of GPET by endoscopic ultrasonography (EUS) performed prior to
      surgery and compare this with a review of the literature. PATIENTS AND METHODS:
      Twenty patients suspected of having specific hormonal syndromes were
      correlatively explored with US, CT, MR, angiography, octreoscan and radial EUS
      with Olympus GFUM3/EUM3 and GF-UM20/EUM 20 and 30. Eleven cases were males (55%)
      and 9 (45%) females with a mean age of 60 years (range: 40-80 years). Of the 20
      patients, 14 had endocrine 16 tumors in the pancreas and 6 tumors in the
      gastrointestinal tract. In 6 patients no tumors were found and were therefore
      used as a control group. Of the 20 patients, 14 underwent surgery confirming the
      existence of GPET in 12 cases. RESULTS: The diagnostic sensitivity and precision
      of the EUS were of 75 and 78%, respectively, with these percentages being higher
      to those obtained with other imaging techniques. The specificity was 83%. All
      these values were slightly lower than the mean obtained on review of the
      literature. Two pancreatic tumors of less than or equal to 1 cm were detected
      which had not been previously diagnosed with US, CT and MR. In two cases the
      exact situation was not determined. Echo-endoscopic exploration of the pancrease
      could not be completely performed in two cases (10%), one pancreatic carcinoma
      and one double pancreatic gastrinoma which was gastrectomized. Endoscopic
      ultrasonography is a good preoperative technique for detecting GPET and in the
      evaluation of small sized tumors it may surpass other imaging techniques. The
      usefulness of EUS as a second exploration following US has been suggested for the
      diagnosis and localization prior to surgery.

PMID- 10396103
TI  - [Pyoderma gangrenosum with an atypical location and a rapid response to
      cyclosporin A].
AB  - Pyoderma gangrenosum is an unusual neutrophilic dermatosis associated to
      different rheumatologic, haematologic and inflammatory bowel diseases which
      generally responds to the therapy of the underlying disease. We report a case of
      pyoderma in a 44-years-old woman with paucisymptomatic, distal, ulcerative
      colitis which appeared simultaneously in her forehead and hands. We think it of
      general interest because of its localization, its importance, the failure of
      response to steroids and the need of cyclosporine A for regression.

PMID- 10396104
TI  - [Cytomegalovirus granulomatous hepatitis in an immunocompetent patient].
AB  - A case of granulomatous hepatitis induced by cytomegalovirus in a 34-year-old
      immunocompetent male with no other history of interest is presented. The clinical
      severity of the picture with progressive cholestasis, evening fever peaks and the
      development of echographic signs of portal hypertension led to treatment with
      high doses of intravenous ganciclovir. Rapid clinical improvement was observed
      with normalization of the analytical parameters after 15 days of treatment. The
      pathologic, clinical and therapeutic aspects of the liver infection by
      cytomegalovirus in an immunocompetent patient are discussed.

PMID- 10396105
TI  - [An ileal ulcer and diaphragm-type colonic stenosis due to diclofenac].
AB  - Nonsteroidal anti-inflammatory drugs (NSAID) are used extensively in the general
      population. It's well known the adverse effects of NSAID over the upper
      gastrointestinal tract and small intestine. Enteric-coated and slow release
      preparations were created in order to prevent those effects. We describe a woman
      case who took diclofenac for many years and developed both ileal ulceration and
      diaphragm-like colonic structure. Lesions in lower gastrointestinal tract were
      infrequent but severe; the lesion were seen on colonoscopy but not on barium
      studies; the physiopathology of these lesions remains uncertain; and the most
      efficacy attitude is the suppression of diclofenac.

PMID- 10396106
TI  - [Severe hepatitis from therapeutic doses of paracetamol in an alcoholic patient].
AB  - The case of a 36-year-old chronic alcoholic patient who came to the hospital for
      presenting general bad shape, arthromyalgia and jaundice and who developed severe
      hepatitis with an extreme elevation in the transaminase levels following the
      consumption of therapeutic doses of paracetamol (3 g/day for 4 days). The
      possibility of other causes of hepatitis were duly discarded. Liver biopsy showed
      confluent centrolobular necrosis compatible with the diagnosis of toxic
      hepatitis. The patient was discharged from hospital in stable condition and with
      a slight alteration in the transaminase levels. Recognizing hepatotoxicity by
      paracetamol in alcoholics is simple if the clinical history, the marked
      transaminase elevation and the history of paracetamol intake are adequately
      evaluated. Lower doses of paracetamol or even avoidance of this drug is
      recommended in circumstances in which the toxicity of the drug may be potentiated
      by chronic alcohol consumption or by the lack of appetite associated with
      deficient alimentation.

PMID- 10396107
TI  - [Progression and the clinical implications of metaplasia and dysplasia in the
      stomach].

PMID- 10396108
TI  - [The benefits of computed tomography in the study of Crohn disease and its
      complications].

PMID- 10396109
TI  - [The pathogenesis of hepatic encephalopathy].

PMID- 10396110
TI  - [Crohn disease with recurrent free intestinal perforation].

PMID- 10396111
TI  - [Terlipressin in the treatment of portal hypertension].

PMID- 10396112
TI  - [The percutaneous drainage with a pigtail catheter of multiple pyogenic liver
      abscesses in a 7-year-old girl].

PMID- 10396113
TI  - [Acute flutamide-induced hepatitis].

PMID- 10396114
TI  - Socioeconomics and politics affecting the Japanese neurosurgeon.

PMID- 10396115
TI  - High incidence of persistent primitive arteries in moyamoya and quasi-moyamoya
      diseases.
AB  - This study investigated the incidences of persistent primitive arteries in
      patients with moyamoya disease, unilateral moyamoya disease, and quasi-moyamoya
      disease. Cerebral angiograms of 50 patients (39 moyamoya disease patients, 6
      unilateral moyamoya disease patients, and 5 quasi-moyamoya disease patients) were
      retrospectively reviewed. There were 35 females and 15 males, aged from 3 to 63
      years (mean 27.4 years). Persistent primitive carotid-basilar artery anastomoses
      were observed in three patients: primitive hypoglossal artery in one moyamoya
      disease patient, primitive trigeminal artery variant in one unilateral moyamoya
      disease patient, and an anastomosis between the accessory meningeal artery and
      the anterosuperior cerebellar artery in one quasi-moyamoya disease patient. The
      ophthalmic artery originated from the middle meningeal artery in three moyamoya
      and two quasi-moyamoya disease patients. The incidence of the persistent
      primitive arteries is significantly higher in patients with moyamoya disease
      (10.7%) and quasi-moyamoya disease (60%) than in patients with other disease
      (0.67%) (p < 0.001), so congenital factors may be important in the pathogenesis
      of moyamoya disease.

PMID- 10396116
TI  - Reduction of operating time and blood transfusion for craniosynostosis by
      simulated surgery using three-dimensional solid models.
AB  - Preoperative planning of craniofacial synostosis can be achieved through the use
      of two- or three-dimensional (3D) computed tomography (CT) images and by 3D solid
      models. The advantage of using 3D models was evaluated by calculating the amount
      of blood transfused and the operating time for 36 craniosynostosis procedures, 21
      planned with 3D models and 15 with CT images performed in the past 7 years. The
      use of 3D models reduced both blood loss and operating time for fronto-orbital
      advancement with reshaping, LeFort III advancement, and LeFort IV minus Glabellar
      advancement; blood loss for fronto-orbital advancement without reshaping; and
      operating time for total cranial reshaping.

PMID- 10396117
TI  - Sternal splitting approach to upper thoracic lesions located anterior to the
      spinal cord.
AB  - The sternal splitting approach for upper thoracic lesions located anterior to the
      spinal cord is described. The sternal splitting approach can be effectively
      applied to lesions from the T-1 to T-3 levels. The aortic arch prevents
      procedures below this level. The approach is straight toward the T1-3 vertebral
      bodies and provides good surgical orientation. The sternal splitting approach was
      applied to five patients with metastatic spinal tumors at the C7-T3 levels and
      three patients with ossification of the posterior longitudinal ligament at the T1
      3 levels. No postoperative neurological deterioration occurred. Two patients had
      postoperative hoarseness. The sternal splitting approach to the upper thoracic
      spine is recommended for hard lesions, extensive lesions requiring radical
      resection, and lesions requiring postoperative stabilization with spinal
      instrumentation.

PMID- 10396118
TI  - Spinal instrumentation for unstable C1-2 injury.
AB  - Seventeen patients with unstable C1-2 injuries were treated between 1990 and
      1997. Various methods of instrumentation surgery were performed in 16 patients,
      excluding a case of atlantoaxial rotatory fixation. Posterior stabilization was
      carried out in 14 cases using Halifax interlaminar clamp, Sof'wire or Danek
      cable, or more recently, transarticular screws. Transodontoid anterior screw
      fixation was performed in four cases of odontoid process fractures, with
      posterior instrumentation in two cases because of malunion. Rigid internal
      fixation by instrumentation surgery for the unstable C1-2 injury avoids long-term
      application of a Halo brace and facilitates early rehabilitation. However, the
      procedure is technically demanding with the risk of neural and vascular injuries,
      particularly with posterior screw fixation. Sagittal reconstruction of thin
      sliced computed tomography scans at the C1-2 region, neuronavigator, and
      intraoperative fluoroscopy are essential to allow preoperative surgical planning
      and intraoperative guidance.

PMID- 10396119
TI  - Subarachnoid hemorrhage from intracranial dissecting aneurysms of the anterior
      circulation. Two case reports.
AB  - Two rare cases of intracranial dissecting aneurysms of the anterior circulation
      associated with subarachnoid hemorrhage (SAH) are described. A 56-year-old female
      presented with a dissecting aneurysm in the proximal segment of the left middle
      cerebral artery. Proximal occlusion of the affected artery and a superficial
      temporal artery-middle cerebral artery anastomosis were performed, but the
      outcome was poor. A 61-year-old male presented with a dissecting aneurysm in the
      proximal segment of the left anterior cerebral artery. Clipping was enhanced by a
      piece of fascia lata, allowing patency of the affected artery with a satisfactory
      outcome. Dissecting aneurysm of the carotid system should be considered in a
      patient with SAH but no evidence of berry aneurysm.

PMID- 10396120
TI  - Removal of petrous apex meningioma and microvascular decompression for trigeminal
      neuralgia through the anterior petrosal approach. Case report.
AB  - A 64-year-old female presented with right trigeminal neuralgia. Computed
      tomography and magnetic resonance (MR) imaging demonstrated a tumor attached to
      the right petrous apex. MR imaging also revealed that the trigeminal nerve was
      compressed and distorted by the tumor. Tumor removal and microvascular
      decompression (MVD) were performed via the anterior petrosal approach. The
      trigeminal nerve was distorted by the tumor and the superior cerebellar artery
      compressed the medial part of the root entry zone of the trigeminal nerve. The
      surgery resulted in complete relief of the trigeminal neuralgia. Posterior fossa
      tumors causing ipsilateral trigeminal neuralgia are not rare, and are often
      removed via the suboccipital retromastoid approach, as MVD for trigeminal
      neuralgia is usually performed through the retromastoid approach. The advantages
      of the anterior petrosal approach are shorter access to the lesion and direct
      exposure without interference from the cranial nerves, and that bleeding from the
      tumors is easily controlled as the feeding arteries can be managed in the early
      stage of the surgery. We conclude that the anterior petrosal approach is safe and
      advantageous for the removal of petrous apex tumor associated with trigeminal
      neuralgia.

PMID- 10396121
TI  - Primary central nervous system T-cell lymphoma. Case report.
AB  - A 46-year-old male presented with a rare primary non-Hodgkin's lymphoma of the
      central nervous system of T-cell lineage, localized primarily in the right
      parietal region. There was no evidence of acquired immunodeficiency syndrome.
      Biopsy of the tumor allowed immunohistochemical confirmation of the diagnosis.
      Irradiation and chemotherapy were given, and the patient has remained well for 24
      months. The clinical manifestations, management, and outcome of T-cell lymphoma
      are very similar to those of B-cell lymphoma.

PMID- 10396122
TI  - Reduction cranioplasty for macrocephaly. Two case reports.
AB  - Multi-stage reduction cranioplasty was performed on two children with severe
      macrocephaly secondary to hydrocephalus. One patient underwent a four-stage
      operation, and the other underwent a two-stage operation. The postoperative
      course of both patients was uneventful. Reduction cranioplasty improved quality
      of life for both patients, and good cosmetic results were achieved. Reduction
      cranioplasty is effective for the treatment of macrocephaly, and multi-stage
      surgery can reduce the associated risks.

PMID- 10396123
TI  - Large empty sella with an intrasellar herniation of an elongated third ventricle.
      Case report.
AB  - A 73-year-old female presented with a large empty sella with herniation of an
      elongated third ventricle concomitant with herniation of the surrounding
      subarachnoid space into the sella, manifesting as visual impairment and
      amenorrhea without galactorrhea. Magnetic resonance imaging and computed
      tomography cisternography clearly showed the large empty sella, without evidence
      of either hydrocephalus or benign intracranial hypertension, which is extremely
      rare.

PMID- 10396124
TI  - Hypothermia bed system for stroke patients. Technical note.
AB  - A new hypothermia bed system was used to induce mild hypothermia (33-35 degrees
      C) in six patients with stroke due to subarachnoid hemorrhage, hypertensive
      intracerebral hemorrhage, or embolic internal carotid artery occlusion. The
      system bed contained all necessary equipment including a respirator, a cooling
      unit, physiological monitors, and a storage battery. Surface cooling of the
      patients was performed using water-circulating blankets, and core temperature was
      maintained based on bladder temperature and a feedback computer program. During
      hypothermic therapy, patient transfer and radiological examination including
      computed tomography and positron emission tomography could be easily and safely
      performed. Differences between the measured bladder temperature and the target
      temperature were approximately +/- 0.1 degree C. The proposed hypothermia system
      bed may be useful for serial radiological examination of patients with stroke.

PMID- 10396125
TI  - Recent advances in immunosuppressants.
AB  - In recent years, a large number of structurally diverse immunosuppressants have
      been discovered that are effective for the treatment of organ transplantation.
      Some of them are undergoing clinical trials and may soon enter into routine
      clinical practice. These compounds are either chemical entities obtained from
      natural sources/synthetic means or biomaterials such as monoclonal
      antibodies/gene products/proteins. They have been found to interfere at different
      stages of T cell activation and proliferation, and can be identified as
      inhibitors of nucleotide synthesis, growth factor signal transduction and
      differentiation. Newer strategies involving combination of new agents with
      traditional immunosuppressants, monoclonal antibodies and gene therapy offer
      enormous potential, not only for the investigation of mechanisms pertaining to
      graft rejection, but also for its therapeutic prevention.

PMID- 10396126
TI  - Present status of hepatoprotectants.
AB  - Perpetual exposure of liver to xenobiotics and therapeutic agents leads to toxic
      manifestations of a complex and diverse nature. Not a single curative therapeutic
      agent has been found so far which could provide lasting remedy to patients
      suffering from hepatic disorders. In fact, the remedies available in the modern
      system of medicine provide only symptomatic relief without any significant
      changes on the disease process. Moreover, their use is associated with severe
      side effects and chances of relapses. Except some natural products claimed to be
      effective, no safe synthetic product is yet available for the management of
      hepatic disorders. Lack of effective, least toxic and curative hepatoprotectants
      made the task difficult to discover newer drugs. This review is an attempt to
      provide an overall view of the development of synthetic and natural products as
      hepatoprotective agents.

PMID- 10396127
TI  - The 5-HT1A receptor and its ligands: structure and function.
AB  - An overview is presented on progress made in research on 5-HT1A receptors and
      their ligands since their discovery in 1983. Molecular biology has offered new
      tools, for example cloned 5-HT1A receptors, their mutants and chimeras to study
      structure and function. Many compounds, belonging to different chemical classes,
      display high affinity and selectivity for 5-HT1A receptors. The majority of these
      compounds are agonists or partial agonists, full antagonists are still scarce.
      Agonists and partial agonists are active in various animal models of anxiety and
      depression. Partial receptor agonists have been proven to be effective in general
      anxiety disorder and depression in man. Potential therapeutic applications for 5
      HT1A receptor antagonists are evaluated, for example, in cognition disorders.

PMID- 10396128
TI  - U-50,488 and the kappa receptor: a personalized account covering the period 1973
      to 1990.
AB  - All clinically significant analgesics for severe pain derive from the morphine
      model. Morphine has provided a fertile area for medicinal chemistry research and
      received an additional stimulus in the 1970s with the appearance of the opioid
      receptors. The background for the birth of U-50,488 is described herein. It
      occurred before the discovery of the kappa receptor and, thus, U-50,488 was
      classified originally as a non-mu compound, and only later as a kappa agonist. U
      50,488 provided a succinct template for structural modifications and they are
      described for the period up to 1990. A description of the structural classes of
      kappa agonists is provided including a summary of kappa recognition sites based
      on known agonists.

PMID- 10396129
TI  - Protease inhibitors as potential antiviral agents for the treatment of
      picornaviral infections.
AB  - The picornavirus family contains several human pathogens including human
      rhinovirus (HRV) and hepatitis A virus (HAV). In the case of HRVs, these small
      single-stranded positive-sense RNA viruses translate their genetic information
      into a polyprotein precursor which is further processed mainly by two viral
      proteases designated 2A and 3C. The 2A protease (2Apro) makes the first cleavage
      between the structural and non-structural proteins, while 3C protease (3Cpro)
      catalyzes most of the remaining internal cleavages. It has been shown that both
      2Apro and 3Cpro are cysteine proteases but their overall protein folding is more
      like trypsin-type serine proteases. Due to their unique protein structure and
      essential roles in viral replication, 2Apro and 3Cpro have been viewed as
      excellent targets for antiviral intervention. In recent years, considerable
      efforts have been made in the development of antiviral compounds targeting these
      proteases. This article summarizes the recent approaches in the design of novel
      2A and 3C protease inhibitors as potential antiviral agents for the treatment of
      picornaviral infections.

PMID- 10396131
TI  - [The Dusseldorf short-term dynamic psychotherapy project (DKZP)].
AB  - Time-limited psychodynamic therapies in the outpatient setting are offered for a
      broad spectrum of psychogenic disorders. Meta-analyses prove their effectiveness
      mainly for neurotic disorders. We are interested in the suitability of the here
      applied CMP/SASB model (Tress et al. 1996) of psychodynamic short-term therapy
      for patients with psychosomatic and severe personality disorders. We extensively
      present the concept of Cyclic Mal-adaptive Pattern (CMP) in its clinically
      relevant parts as the core of psychogenic pathological developments. Particularly
      the introject, as the patient's attitude towards him- or herself, is of great
      importance for therapeutic change and its follow-up development. Within the DKZP
      (Duesseldorf Short-Term Psychotherapy Project), 36 male and female therapists,
      mostly interns at the local university clinic, treated 82 patients (m: 23/f: 59)
      with personality disorders (n = 26) and psychosomatic disorders (n = 31) as
      research groups and, in comparison, neurotic patients (n = 25) in a naturalistic
      design. 68 treatments have been completed so far, 11 patients have dropped out,
      the remaining 3 are still in therapy. Relevant research instruments are the
      Beeintrachtigungsschwere Score (BSS, an impairment score), Global Assessment of
      Functioning Scale (GAF), Cyclic Maladaptive Pattern (CMP), Symptom Check List
      (SCL-90-R), and Structural Analysis of Social Behavior (SASB) including process
      and content ratings, as well as the Intrex questionnaire. The treatments last 25
      sessions. We carried out follow-up examinations after 6 months, 1 year, 2, and 5
      years. Effect sizes for the whole sample by BSS and GAF are remarkably high, with
      further increase at follow-up interviews. Psychosomatic patients came off best,
      but personality disorders in comparison to neurotic patients profited
      surprisingly well. Effect sizes in self-rating (SCL and Intrex) were less high.
      However, in self-rating the changes of social functions are not sufficiently
      addressed. As a result, our form of focal therapy is well suited not only for
      neuroses, but also for psychosomatic disorders and personality disorders. An
      enlargement of the indication spectrum for this form of psychodynamic therapy to
      include these disorders is well founded and promising.

PMID- 10396133
TI  - [Use and costs of psycho-oncological liaison services].
AB  - The extent to which patients took advantage of psychosocial consultation services
      in two clinics for internal and oncological disorders was documented over a
      period of four and a half years to establish, for the sake of future planning,
      whether there was a demand for psychosocial intervention. During the first year
      of treatment, consultations between a member of the psychosocial staff and any
      one patient averaged a total of 13 hours (2 sessions a week, each lasting 28
      mins). The number of sessions depended most of all on objectifiable stress
      factors related to the course of disease or treatment. From records of both
      directly patient-oriented and team-oriented staff activities, we calculated the
      staffing requirements and costs of offering a psychosomatic consultation service
      within the framework of intensive internal-oncological medical care.

PMID- 10396132
TI  - [Psychosocial risk factors for Alzheimer's disease].
AB  - Psychosocial stress has been shown to contribute to neurodegenerative changes and
      has been discussed as a pathogenic element in Alzheimer's disease (AD). However,
      studies investigating this aspect are rare. We performed a case-control study on
      50 clinically diagnosed probable AD patients and 90 controls consisting of
      surgical patients. Interviews were performed by trained personnel, using a
      questionnaire, a semi-structured interview, and a psychosocial risk list
      protocol. Findings are presented as marginal and partial odds ratio from linear
      logistic regressions. Adapting to an active but unproductive working style as
      well as living with a dominant spouse is associated with significant risk for AD.
      Protective factors are high self-esteem and working in one's desired job. Our
      results indicate psychosocial factors as a possible agent in the latent
      development of AD and may shift the focus from more traditional risk factors to
      hitherto almost neglected psychosocial factors in a disease of still unknown
      etiology.

PMID- 10396134
TI  - [Four minutes for the patient and one minute for the families. Physician-patient
      family communication in medical departments].
AB  - Facing the changes in working situation of hospital doctors, the question is
      raised as show how much time is spent on communication with patients and their
      families. The daily working time, including the time spent on communication with
      patients and their families, of 24 ward doctors (junior and senior house
      officers) from 5 medical departments at general hospitals, were assessed by means
      of questionnaires and time measurements. An average daily working time of 8.6
      hours, yielding an average of 4 minutes for communication with each patient and 1
      minute with his family.

PMID- 10396135
TI  - [Problem-based teaching and learning. An opportunity for medical psychology,
      psychosomatic medicine and psychotherapy?].
AB  - All proposals for a reform of the study of medicine recommend problem-based
      teaching and learning methods. The rapid increase in the number of medical
      faculties abroad offering experimental courses along these lines is an indicator
      of their usefulness. The results of empirical research also suggest that
      departments of medical psychology, psychosomatic medicine and psychotherapy
      should participate more closely in the introduction and exploration of the
      advantages of this didactic approach.

PMID- 10396136
TI  - Comparative aspects of muscle elastic proteins.

PMID- 10396137
TI  - The titin cDNA sequence and partial genomic sequences: insights into the
      molecular genetics, cell biology and physiology of the titin filament system.

PMID- 10396138
TI  - The physiological role of titin in striated muscle.

PMID- 10396139
TI  - Control of sarcomeric assembly: the flow of information on titin.

PMID- 10396140
TI  - The elastic filament system in myogenesis.

PMID- 10396141
TI  - Structure and assembly of the sarcomeric M band.

PMID- 10396143
TI  - The genetics and molecular biology of the titin/connectin-like proteins of
      invertebrates.

PMID- 10396142
TI  - The C-protein (myosin binding protein C) family: regulators of contraction and
      sarcomere formation?

PMID- 10396144
TI  - [Is gastric adenocarcinoma in a phase of retreat?].

PMID- 10396145
TI  - [Cancer of the operated stomach: a descriptive study on the experience of the
      last 12 years].
AB  - BACKGROUND: The incidence of gastric remnant carcinoma ranges between 1% and 9%.
      We report here our experience in a sanitary area in which, on account of
      different social and working reasons, the surgical indication for treatment of
      peptic disease was very common in previous decades. PATIENTS AND METHODS: An
      analysis was made of the 52 cases of patients operated over the last 12 years,
      which represents 7.13% of 729 gastric cancers operated over the same time period.
      RESULTS: In 67% of cases the carcinoma sat on a type-II stump, in 25% on a B-I
      type stump, and in the remaining 8% on stomachs with vagotomy and pyloroplasty.
      Seventy-five percent of patients had two characteristics: to be older than 60
      years and to have undergone primary surgery at least 15 years before. Over half
      of patients were admitted on an emergency basis with no diagnosis and had
      received prolonged symptomatic therapies without previous examinations. The
      carcinoma involved the anastomotic mouth in 56% of cases and the histologic
      intestinal type predominated. Twenty-seven percent of patients had stages I and
      II, whereas almost half of patients had stage IV. Surgical resection was feasible
      in 42 cases (81%), with a surgical mortality rate of 21% for resections. The
      overall survival rate estimated at 5 years was 23%. CONCLUSIONS: The possibility
      of performing surgery with a curative aim is the main prognostic factor for the
      gastric remnant carcinoma. The endoscopic study of patients at risk allows for
      diagnosis in earlier stages and therefore and improvement in results.

PMID- 10396146
TI  - [Glucocorticoid treatment improves glucose tolerance in patients with temporal
      arteritis or polymyalgia rheumatica].
AB  - BACKGROUND: Corticosteroid therapy has been shown to improve glucose tolerance in
      some connective tissue diseases. This fact has been inadequately investigated in
      vasculitis. OBJECTIVE: To evaluate the effect of glucocorticoid therapy on
      glucose tolerance in patients with temporal arteritis (TA) or polymyalgia
      rheumatica (PR). MATERIALS AND METHODS: An oral test with glucose overload (OGO)
      was performed before and after one month of initiating therapy with
      corticosteroids in 14 patients with TA or PR (TA/PR group) and in nine patients
      with other chronic inflammatory diseases (control group). RESULTS: After
      treatment, patients with TA/PR experienced a decrease in the area under the
      glucose curve and in serum glucose values at minutes 0, 90, and 120 of the OGTT.
      Also, a decrease was observed for the area under the insulin curve and for plasma
      insulin levels at minutes 90 and 120 after OGO. CONCLUSIONS: Therapy with
      corticosteroids improves glucose tolerance in TA/PR with no increase in insulin
      secretion.

PMID- 10396147
TI  - [The cost effectiveness of the study of the familial contacts of tuberculosis
      patients coinfected with the human immunodeficiency virus].
AB  - The investigation of contacts of patients with tuberculosis is a highly cost
      effective measure to detect new cases of disease and infected individuals;
      nevertheless, its efficacy has not been contrasted with persons living with
      patients with tuberculosis (TB) coinfected with HIV. A total of 152 family
      contacts were studied corresponding to 84 HIV-positive tuberculosis patients. As
      a control group, 516 persons living with HIV-negative TB patients were included.
      Contacts were classified according to the bacteriologic status of the index case
      (IC): group I, contacts of patients with negative bacterioscopy and positive
      culture of respiratory specimens; group II, contacts of patients with negative
      bacterioscopy and positive culture of respiratory specimens, and group III,
      contacts of pulmonary and/or extrapulmonary TB patients with negative
      bacterioscopy and culture. Among IC coinfected with HIV there was a higher
      percentage of extrapulmonary clinical forms and therefore a lower proportion of
      bacillary forms, which accounted for a lower rate of infection among contacts of
      HIV-positive patients than among contacts of HIV-negative patients (20.4% vs
      48.8%; OR: 3.7; 95% CI: 2.4-5.9). After controlling for bacteriologic status of
      the IC, differences remained when bacillary (group I) of HIV-coinfected patients
      were compared with those of patients not coinfected with HIV (35.9% vs 52.3%; OR:
      2.1%; 95% CI: 1.2-5.9). Overall, 28 new TB cases were detected (4.2% of the total
      of studied persons living with TB patients) with no differences among contacts of
      both groups. The lower rate of infections among persons living with HIV-positive
      patients might be due not only to a lower number of pulmonary forms in HIV
      coinfected IC and therefore less bacillary forms but also to a lower degree of
      crowding and a higher protection against exposure to their contacts.

PMID- 10396148
TI  - [Lung transplantation in cystic fibrosis. The results of the Clinica Puerta de
      Hierro (Madrid) and the Hospital La Fe (Valencia)].
AB  - Retrospective analysis of cystic fibrosis patients who underwent pulmonary
      transplantation at Clinica Puerta de Hierro, Madrid, and at Hospital La Fe,
      Valencia. Since the beginning of the programme and until March 1998, a total of
      63 patients with cystic fibrosis were studied. Among transplanted patients, 18
      were males and 16 females, with a mean age of 18.9 years. All patients underwent
      sequential bilateral pulmonary transplantation. After transplantation, the most
      common complication was bacterial pneumonia which affected all patients. Six
      patients had dehiscence or stenosis of the bronchial suture. Other specific
      complications of this condition by frequency were intestinal obstruction and
      diabetes mellitus. Six patients developed obliterans bronchiolitis and one of
      them underwent a repeat transplantation. Three out of the 34 patients died, and
      the likelihood of survival after one and three years was 94%. Respiratory
      function tests and PaO2 peaked at sixth post-transplantation month. CONCLUSION:
      Pulmonary transplantation is a therapeutic option to be considered for the
      patient with cystic fibrosis and severe involvement of his/her pulmonary disease.

PMID- 10396149
TI  - [Thyrotropin-producing hypophyseal adenomas].
AB  - Thyrotropin (TSH)-producing adenoma or TSH-oma is an uncommon entity. Most cases
      correspond to macroadenomas, and microadenomas are exceptional. The differential
      diagnosis should include mainly hypophyseal resistance to thyroid hormones, which
      can be difficult because of normal findings of imaging studies of the pituitary
      gland in some cases of TSH-oma and also because of the clinical and biochemical
      heterogeneity of both entities. Hypophyseal surgery is the treatment of choice
      for TSH-omas, although clinical and biochemical recovery of hyperthyroidism is
      not achieved in a considerable proportion of cases. When surgery fails or is
      contraindicated, radiotherapy and somatostatine analogues are therapeutic
      alternatives. We report here two cases of TSH-producing microadenoma which were
      confirmed after hypophyseal surgery.

PMID- 10396150
TI  - [Cystic neoplasms of the pancreas: a review of the literature apropos 5 cases].
AB  - Cystic neoplasms of the pancreas make up a group of uncommon tumors. Their
      relevance lies upon their favorable prognosis after resection and the fact of
      being commonly mistaken with pseudocysts. Based on five patients treated at our
      hospital in the last few years we make an update review of the literature on
      these tumors. To note the role that imaging and puncture-aspiration techniques
      can play for diagnosis. We conclude that when a cystic lesion of the pancreas is
      found, the diagnosis of cystic neoplasm must be considered, thus avoiding delays
      in surgical resections which may condition the patient's prognosis.

PMID- 10396151
TI  - [Thyrotoxic crisis].

PMID- 10396152
TI  - [Myxedematous coma].

PMID- 10396153
TI  - [A man of 60 with a constitutional syndrome, abdominal pain and heart failure].

PMID- 10396155
TI  - [Stridor in a female patient who underwent pneumonectomy. A postpneumonectomy
      syndrome].

PMID- 10396154
TI  - [A man of 53 with a cervical mass. Cervical actinomycosis].

PMID- 10396156
TI  - [Sudden aphasia in a young woman].

PMID- 10396157
TI  - [Hemoptysis in a male ex-smoker. Hemoptysis in relation to the aspiration of a
      foreign body (a metal bracelet)].

PMID- 10396158
TI  - [The association between cocaine consumption and lupus anticoagulant as the
      probable cause of ischemic stroke].

PMID- 10396160
TI  - [Endocarditis of the native aortic valve due to Propionibacterium acnes].

PMID- 10396159
TI  - [Bordetella bronchiseptica pneumonia and the acquired immunodeficiency syndrome].

PMID- 10396161
TI  - [Gastric leishmaniasis associated with human immunodeficiency virus infection].

PMID- 10396162
TI  - [Non-bacteremic ecthyma gangrenosum in a patient with human immunodeficiency
      virus infection].

PMID- 10396163
TI  - [The treatment of human fascioliasis with triclabendazole].

PMID- 10396164
TI  - The epidemiology of antisocial personality disorder.
AB  - This paper reviews the current state of knowledge about the frequency, natural
      history, risk factors and associations of antisocial personality disorder.
      Important recent developments are discussed, and where possible, findings have
      been tabulated Epidemiological surveys have shown that antisocial personality
      disorder is a common disorder, with a prevalence rate of between 2 and 3% among
      community samples, rising to 60% among male prisoners. Antisocial personality
      disorder is a chronic condition, and is associated with a multitude of medical
      and social problems. These include substance abuse, deliberate self harm and
      crime. Genetic and environmental factors have been implicated in the aetiology of
      the disorder. However, despite the large amount of research into antisocial
      personality disorder, longitudinal data are missing and the validity of the
      diagnosis, therefore, remains questionable. The paper concludes with
      recommendations for future research.

PMID- 10396165
TI  - The feasibility of routine outcome measures in mental health.
AB  - BACKGROUND: Standardised outcome measures are not being used in routine mental
      health care. METHOD: The importance of routine use of standardised outcome
      measures is argued, and reasons for their lack of use suggested. RESULTS: One
      reason for standardised outcome measures not being used routinely is the lack of
      appropriate instruments. This property of being suitable for routine use is often
      called feasibility, but there is no consensus about the meaning of feasibility,
      or how it should be measured. We propose a definition of feasibility as a
      psychometric property of a standardised outcome measure, provide criteria for
      assessing feasibility, and then present a framework for changing practice to
      increase the routine use of standardised outcome measures. CONCLUSIONS: If mental
      health care is to maximise outcome, then more attention needs to be paid both to
      the process of developing and to facilitating the routine clinical use of
      feasible outcome measures.

PMID- 10396167
TI  - A pilot study evaluating the effectiveness of individual inpatient cognitive
      behavioural therapy in early psychosis.
AB  - BACKGROUND: Recent research indicates that cognitive-behaviour therapy (CBT) can
      be effective in ameliorating persistent positive symptoms in chronic psychotic
      patients. The effectiveness of CBT in acute and recent-onset psychosis has been
      little explored, although a recent pilot study indicated that CBT could
      significantly improve recovery in acutely psychotic inpatients. METHOD: Short
      term individual CBT was compared to supportive counselling/psychoeducation (SC)
      as an adjunct to standard inpatient hospital care and medication in 21 inpatients
      experiencing a recent-onset acute schizophrenic episode. RESULTS: Both groups
      showed significant reductions in Brief Psychiatric Rating Scale (BPRS) scores
      following treatment, although there were no group differences. Time to discharge
      did not differ significantly between the groups, although there was a greater
      variance for the SC patients. Two-year follow-up showed no significant
      differences between the groups, although the number of patients who relapsed, the
      number of relapses and the time to recurrence of psychotic symptoms was lower in
      the CBT group than the SC group. Interestingly, the time to readmission was
      shorter in the CBT group. CONCLUSIONS: CBT and SC are acceptable treatments for
      recent-onset acutely psychotic inpatients. A larger randomised controlled trial
      over multiple hospital sites is warranted.

PMID- 10396166
TI  - A randomised controlled trial of home-based rehabilitation versus outpatient
      based rehabilitation for patients suffering from chronic schizophrenia.
AB  - BACKGROUND: Outpatient-based treatments for patients suffering from chronic
      schizophrenia inadvertently exclude a significant proportion of subjects because
      they are often too poorly motivated to attend for treatment. In addition there
      are also concerns about whether the skills that are learnt in a hospital setting
      will generalize to situations when the individuals are at home. This study
      attempted to redress some of these potential deficiencies and followed on from an
      earlier local study which found that a community-based team met more of the needs
      of patients suffering from chronic schizophrenia. METHOD: Seventy-five patients
      suffering from chronic schizophrenia were allocated randomly to receive
      traditional outpatient-based or home-based rehabilitation from a clinical
      psychologist and an occupational therapist. They were assessed before and after 9
      months of treatment on a range of clinical, social and quality of life outcomes.
      Distress to carers was also assessed. Readmission to hospital was recorded for
      each subject. RESULTS: There were significant reductions in socially embarrassing
      behaviour (SBS), increases in interpersonal functioning and recreational
      activities and a trend for quality of life to improve in the home-based group.
      There were fewer admissions in the home-based group but the differences, although
      financially substantial, were not statistically significant. CONCLUSIONS: The
      home-based rehabilitation service was well received by the majority of patients
      suffering from chronic schizophrenia and led to some improvement in social
      behaviour, interpersonal functioning, recreational activities and quality of
      life.

PMID- 10396168
TI  - Prescribing patterns for analgesics in relation to underprivileged area (UPA)
      score, mortality and suicide in 33 municipalities in the province of Skane,
      southern Sweden.
AB  - BACKGROUND: Although it is well known that analgesics contribute to suicide,
      there is little knowledge about how much of the mortality and suicide can be
      explained by socioeconomic deprivation or by sales of analgesics. METHODS: This
      ecological study analyses the relationships between the sales (defined daily
      doses per 1000 inhabitants per day) of dextropropoxyphene, dextropropoxyphene
      combinations, paracetamol, codeine and paracetamol combinations, and other
      codeine combinations and the Swedish UPA (underprivileged area) score, mortality
      and suicide rates in 33 municipalities in Skane in 1987 and 1994 for people aged
      20-64 years. The association of each of the subgroups of analgesics with all
      cause mortality, and with standardised mortality rates for suicide, adjusted for
      UPA score, was investigated by using weighted (by population size) regression
      analysis. RESULTS: In 1994 there was a moderate to strong significant correlation
      between sales of analgesics and UPA scores, mortality and suicide (r = 0.49
      0.78). Although UPA score explained 68.9% and 67.4% respectively of the variance
      between the analgesics and all-cause mortality and suicide, codeine and
      paracetamol combinations explained a further 10.1% of the variance in suicide.
      Dextropropoxyphene and codeine and paracetamol combinations explained an
      additional 3.8% and 2.9% respectively of the variance in mortality. CONCLUSIONS:
      Local prescription rates for analgesics were associated with mortality and
      suicide, when adjusted for socioeconomic deprivation defined as UPA score.

PMID- 10396169
TI  - The War Events Questionnaire.
AB  - BACKGROUND: The measurement of exposure to war in large epidemiological studies
      necessitates the use of easily administered and reliable questionnaires that
      cover a range of war events. The War Event Questionnaire (WEQ) was designed by
      our group to address these issues and has proved to be quite easy to administer.
      The aim of this study is to establish the inter-rater reliability of the WEQ.
      METHOD: Two trained interviewers alternated in administering parts I and II of
      the WEQ. RESULTS: The Kappa statistics used to calculate the degree of agreement
      between the two raters ranged from 0.281 to 0.774 for part I events and from
      0.189 to 1.000 for part II events. CONCLUSION: The WEQ has proved to be a useful
      instrument that addresses both objective and the subjective war experiences; it
      is a fairly reliable instrument and has helped us avoid tautological assessment
      of the mental health effects of war.

PMID- 10396170
TI  - Lay beliefs about mental disorders: a comparison between the western and the
      eastern parts of Germany.
AB  - BACKGROUND: Since the end of the Second World War the western and eastern parts
      of Germany have been exposed to very different social and cultural influences. It
      was our assumption that this should also be reflected in the beliefs about mental
      disorders held by the general public. METHODS: In autumn 1990, immediately after
      German reunification, a representative survey on lay concepts of schizophrenia
      and depression was carried out in both parts of Germany. In all, 2118 personal,
      fully structured interviews resulted in the West, 980 in the East. RESULTS: In
      general, there were more similarities than differences between West and East,
      particularly as concerns causal attributions (with psychosocial stress being most
      frequently seen as etiologically relevant) and treatment recommendations (with
      psychotherapy clearly favored over drug treatment). However, there were also some
      differences, most notably a stronger tendency in the West to define depressive
      behavior in psychiatric terms and to recommend established forms of psychiatric
      treatment for its management. CONCLUSIONS: Our assumption that the exposure to
      different cultural influences should have led to discrepant beliefs about mental
      disorders was only partly confirmed. Especially with regard to schizophrenia, the
      prevalence of the dominant stereotype hardly differed between West and East.

PMID- 10396171
TI  - Psychopathology in the Dogon Plateau: an assessment using the QDSM and principal
      components analysis.
AB  - BACKGROUND: The present paper reports the findings of principal components
      analysis performed on the basis of answers to the Questionnaire pour le Depistage
      en Sante Mentale (QDSM) administered to subjects from the Bandiagara plateau
      (Mali), who had been evaluated in a previously published report. METHODS: The
      study sample was made up of 466 subjects (253 males, 213 females), 273 of whom
      belonged to the Dogon ethnic group, 163 were Peul and the remaining 30 belonged
      to other groups (Sonrai, Bozo, Tuareg, Bambara). All subjects were submitted to
      QDSM, a structured interview derived from the Self Reporting Questionnaire. Data
      obtained were processed by means of principal components analysis, in order to
      obtain syndromic aggregations. RESULTS: Eight factors with an Eigen value greater
      than 1 were extracted, which provided sufficient explanation for the overall
      variance observed among the 23 items. These factors may be termed as follows:
      Sadness (factor 1); Dysphoria (factor 2); Nightmares (factor 3); Persecution
      (factor 4); Somatic symptoms (factor 5); Special powers (factor 6); Hopelessness
      (factor 7); Loss of Interest (factor 8). CONCLUSIONS: The findings from this
      study support the hypothesis of an independence of "psychosomatic" from
      depressive symptoms. In particular, contrary to some evidence derived from other
      African studies, the present research appears to suggest a possible
      counterposition of these two ways of expressing depression, commonly considered
      as autonomous.

PMID- 10396172
TI  - Provider profiles on-line--making health care choices easier for consumers.

PMID- 10396173
TI  - Rising health care costs: is this the turning point?

PMID- 10396174
TI  - Poverty and health: a simple matter of money?

PMID- 10396175
TI  - Loss prevention case of the month. Teamwork missing.

PMID- 10396176
TI  - Perceived barriers to childhood immunization: a physician and parent survey in a
      southeastern urban/rural community.
AB  - PURPOSE: To identify physicians' and parents' perceptions of barriers to
      completing the immunization process by age 24 months. METHODS: A questionnaire
      hand-delivered to 110 physicians who treat children yielded a response rate of
      83%. A telephone survey conducted with parents of a random sample of 2,100
      children younger than three years of age selected from the county birth records
      yielded an adjusted response rate of 87%. RESULTS: Physicians' response fell into
      two categories: those with more and less than 90% up-to-date immunizations. Those
      with less than 90% indicated that parental knowledge is the primary reason. Those
      with more than 90% reported telephone follow-up for missed appointments. The top
      three barriers reported by parents; (1) waiting time at the clinic (33%), (2)
      child too ill at time of appointment (21%), and (3) insurance does not cover
      immunizations (16%). CONCLUSIONS: There is an opportunity for education
      intervention with physicians, policy makers, and parents in several key areas:
      (1) fact-based contraindications to immunizations, (2) effective means of follow
      up, (3) accessibility to immunization for the under-insured, and (4) parental
      responsibility.

PMID- 10396177
TI  - Bursal cyst: an unusual axillary mass.
AB  - We discuss an unusual case of a bursal cyst presenting as an axillary mass in a
      previously healthy individual. Although both bursal and ganglion cysts not
      uncommonly arise from other joints, they also rarely occur in the axilla as well.
      Clinicians should include cysts in their differential of diagnoses when examining
      axillary masses and deciding on their appropriate treatment.

PMID- 10396178
TI  - A 57-year-old man with a stroke.

PMID- 10396179
TI  - A 29-year-old woman with crampy abdominal pain.

PMID- 10396180
TI  - Immunization program update.

PMID- 10396181
TI  - Building large trees by combining phylogenetic information: a complete phylogeny
      of the extant Carnivora (Mammalia).
AB  - One way to build larger, more comprehensive phylogenies is to combine the vast
      amount of phylogenetic information already available. We review the two main
      strategies for accomplishing this (combining raw data versus combining trees),
      but employ a relatively new variant of the latter: supertree construction. The
      utility of one supertree technique, matrix representation using parsimony
      analysis (MRP), is demonstrated by deriving a complete phylogeny for all 271
      extant species of the Carnivora from 177 literature sources. Beyond providing a
      'consensus' estimate of carnivore phylogeny, the tree also indicates taxa for
      which the relationships remain controversial (e.g. the red panda; within canids,
      felids, and hyaenids) or have not been studied in any great detail (e.g.
      herpestids, viverrids, and intrageneric relationships in the procyonids). Times
      of divergence throughout the tree were also estimated from 74 literature sources
      based on both fossil and molecular data. We use the phylogeny to show that some
      lineages within the Mustelinae and Canidae contain significantly more species
      than expected for their age, illustrating the tree's utility for studies of
      macroevolution. It will also provide a useful foundation for comparative and
      conservational studies involving the carnivores.

PMID- 10396182
TI  - Tunicate tails, stolons, and the origin of the vertebrate trunk.
AB  - Tunicates are primitive chordates that develop a transient 'tail' in the larval
      stage that is generally interpreted as a rudimentary version of the vertebrate
      trunk. Not all tunicates have tails, however. The groups that lack them, salps
      and pyrosomes, instead have a trunk-like reproductive stolon located
      approximately where the tail would otherwise be. In salps, files of blastozooids
      are formed along the sides of the stolon. The tail and caudal trunk in more
      advanced chordates could have evolved from a stolon of this type, an idea
      referred to here as the 'stolon hypothesis'. This means the vertebrate body could
      be a composite structure, since there is the potential for each somite to
      incorporate elements originally derived from a complete functional zooid. If
      indeed this has occurred, it should be reflected in some fashion in gene
      expression patterns in the vertebrate trunk. Selected morphological and molecular
      data are reviewed to show that they provide some circumstantial support for the
      stolon hypothesis. The case would be stronger if it could be demonstrated that
      salps and/or pyrosomes are ancestral to other tunicates. The molecular
      phylogenies so far available generally support the idea of a pelagic ancestor,
      but offer only limited guidance as to which of the surviving pelagic groups most
      closely resembles it. The principal testable prediction of the stolon hypothesis
      is that head structures (or their homologues) should be duplicated in series in
      the trunk in advanced chordates, and vice versa, i.e. trunk structures should
      occur in the head. The distribution of both rhabdomeric photoreceptors and
      nephridia in amphioxus conform with this prediction. Equally striking is the
      involvement of the Pax2 gene in the development of both the inner ear and nephric
      ducts in vertebrates. The stolon hypothesis would explain this as a consequence
      of the common origin of otic capsules and excretory ducts from atrial rudiments:
      from the paired rudiments of the parent oozooid in the case of the otic capsule
      (these express Pax2 according to recent ascidian data), and from tubular
      rudiments in the stolon in the case of the excretory ducts.

PMID- 10396183
TI  - Metabolic depression in animals: physiological perspectives and biochemical
      generalizations.
AB  - Depression of metabolic rate has been recorded for virtually all major animal
      phyla in response to environmental stress. The extent of depression is usually
      measured as the ratio of the depressed metabolic rate to the normal resting
      metabolic rate. Metabolic rate is sometimes only depressed to approx. 80% of the
      resting value (i.e. a depression of approx. 20% of resting); it is more commonly
      5-40% of resting (i.e. a depression of approx. 60-95% of resting); extreme
      depression is to 1% or less of resting, or even to an unmeasurably low metabolic
      rate (i.e. a depression of approx. 99-100% of resting). We have examined the
      resting and depressed metabolic rate of animals as a function of their body mass,
      corrected to a common temperature. This allometric approach allows ready
      comparison of the absolute level of both resting and depressed metabolic rate for
      various animals, and suggests three general patterns of metabolic depression.
      Firstly, metabolic depression to approx. 0.05-0.4 of rest is a common and
      remarkably consistent pattern for various non-cryptobiotic animals (e.g.
      molluscs, earthworms, crustaceans, fishes, amphibians, reptiles). This extent of
      metabolic depression is typical for dormant animals with 'intrinsic' depression,
      i.e. reduction of metabolic rate in anticipation of adverse environmental
      conditions but without substantial changes to their ionic or osmotic status, or
      state of body water. Some of these types of animal are able to survive anoxia for
      limited periods, and their anaerobic metabolic depression is also to approx. 0.05
      0.4 of resting. Metabolic depression to much less than 0.2 of resting is apparent
      for some 'resting', 'over-wintering' or diapaused eggs of these animals, but this
      can be due to early developmental arrest so that the egg has a low 'metabolic
      mass' of developed tissue (compared to the overall mass of the egg) with no
      metabolic depression, rather than having metabolic depression of the entire cell
      mass. A profound decrease in metabolic rate occurs in hibernating (or
      aestivating) mammals and birds during torpor, e.g. to less than 0.01 of pre
      torpor metabolic rate, but there is often no intrinsic metabolic depression in
      addition to that reduction in metabolic rate due to readjustment of
      thermoregulatory control and a decrease in body temperature with a concommitant
      Q10 effect. There may be a modest intrinsic metabolic depression for some species
      in shallow torpor (to approx. 0.86) and a more substantial metabolic depression
      for deep torpor (approx. 0.6), but any energy saving accruing from this intrinsic
      depression is small compared to the substantial savings accrued from the
      readjustment of thermoregulation and the Q10 effect. Secondly, a more extreme
      pattern of metabolic depression (to < 0.05 of rest) is evident for cryptobiotic
      animals. For these animals there is a profound change in their internal
      environment--for anoxybiotic animals there is an absence of oxygen and for
      osmobiotic, anhydrobiotic or cryobiotic animals there is an alteration of the
      ionic/osmotic balance or state of body water. Some normally aerobic animals can
      tolerate anoxia for considerable periods, and their duration of tolerance is
      inversely related to their magnitude of metabolic depression; anaerobic metabolic
      rate can be less than 0.005 of resting. The metabolic rate of anhydrobiotic
      animals is often so low as to be unmeasurable, if not zero. Thus, anhydrobiosis
      is the ultimate strategy for eggs or other stages of the life cycle to survive
      extended periods of environmental stress. Thirdly, a pattern of absence of
      metabolism when normally hydrated (as opposed to anhydrobiotic or cryobiotic) is
      apparently unique to diapaused eggs of the brine-shrimp (Artemia spp., an
      anostracan crustacean) during anoxia. The apparent complete metabolic depression
      of anoxic yet hydrated cysts (and extreme metabolic depression of normoxic,
      hypoxic, or osmobiotic, yet hydrated cysts), is an obvious exception to the above
      patterns. (ABST

PMID- 10396184
TI  - The "thin man" phenomenon: imperfect filling in of visual space.

PMID- 10396185
TI  - The healing optic nerve in glaucoma: transforming growth factor beta and optic
      nerve head remodelling.

PMID- 10396186
TI  - Distribution of azithromycin for the treatment of trachoma.

PMID- 10396187
TI  - The "thin man" phenomenon: a sign of cortical plasticity following inferior
      homonymous paracentral scotomas.
AB  - AIM: To investigate an image distortion, experienced by patients with homonymous
      paracentral scotomas. METHODS: Two consecutive patients with right inferior
      homonymous paracentral scotomas resulting from ischaemic brain insults were
      examined. Neuro-ophthalmological examination included tangent screen and Amsler
      grid evaluation. In addition, the patients were asked to describe a figure
      showing two vertical lines, identical in length and symmetrically located on
      either side of a fixation point. This figure was presented in such a way that
      when the subject looked at the fixation point the right line crossed the scotoma.
      Finally, the patients were asked whether, when looking at the face of an
      interlocutor, both sides of the body looked the same. RESULTS: In both patients
      field defects were markedly smaller when delineated with Amsler grids than using
      a tangent screen. With the parallel line test, the right line appeared
      uninterrupted in patient 1, whereas in patient 2 it looked slightly blurred in a
      two degree long segment corresponding to the middle of the scotoma. To both
      subjects the right line appeared shorter than the left line. Finally both
      subjects indicated that, after steadily fixating their interlocutor's face or
      neck for 5-10 seconds, the left shoulder appeared narrower than the right one,
      which made him look surprisingly thin. This perceptual alteration was called the
      "thin man" phenomenon. CONCLUSIONS: Paracentral homonymous scotomas can be
      associated with perceptual completion and shape distortion, owing to apparent
      displacement of images adjacent to the scotoma towards the field defect.
      Occurrence of such a perceptual change should alert one to the possibility of
      paracentral homonymous scotomas, which often go undetected when using routine
      visual field testing procedures.

PMID- 10396188
TI  - Ophthalmological follow up of preterm infants: a population based, prospective
      study of visual acuity and strabismus.
AB  - BACKGROUND/AIMS: Prematurely born infants are known to have an increased rate of
      ophthalmological morbidity. The aim of the present study was to investigate
      visual acuity and ocular alignment in a population of preterm infants in a
      geographical area, in infants with and without retinopathy of prematurity (ROP).
      METHODS: A prospective population based study of ophthalmological status of
      preterm infants with a birth weight of 1500 g or less was performed during 3.5
      years, with examinations at 6, 18, 30, and 42 months of corrected age. Visual
      acuity was tested using linear optotypes. Multiple regression analyses were used
      to analyse independent risk factors for poor vision and strabismus. RESULTS: Poor
      vision (< 0.3) was detected in 2.5% (6/237) of the children. Of these, only two
      (0.8%) had a severe visual impairment (< 0.1). Strabismus occurred in 13.5%
      (31/229). Children with cryotreated ROP and neurological complications ran the
      highest risk of poor vision and strabismus, according to multiple regression
      analysis. Among children without a history of ROP or neurological complications,
      34% had a visual acuity < 0.7 and 5.9% had strabismus, compared with 61% and 22%,
      respectively, among the children with ROP or neurological complications.
      CONCLUSIONS: The overall incidence of subnormal vision and strabismus in children
      born prematurely was higher than in a full term population of the same age. On
      the basis of this study, follow up of all preterm infants screened for ROP is
      recommended and general guidelines are suggested.

PMID- 10396189
TI  - Filtration procedures supplemented with mitomycin C in the management of
      childhood glaucoma.
AB  - AIMS: To evaluate the outcome of filtering procedures supplemented with mitomycin
      C in children with glaucoma. METHODS: All patients aged 17 or younger with
      glaucoma who underwent filtering surgery supplemented with mitomycin C at a
      tertiary care centre (n = 21) during a 5 year interval (1992 and 1996) were
      included. One eye for each patient was entered into the analysis. The
      postoperative intraocular pressure (IOP), use of antiglaucoma medications,
      clinical stability of glaucoma, complications, and visual acuity were
      retrospectively evaluated. Kaplan-Meier survival curves were used to estimate the
      probability of success. RESULTS: At the time of surgery mean age was 5.7 (SD 5.0)
      years. The most common diagnoses were trabeculodysgenesis (n = 6) and aphakic
      glaucoma (n = 8). Mean IOP before surgery was 35.7 (10.5) mm Hg. Average length
      of follow up was 18.6 (14.7) months. The probability of having IOP less than 21
      mm Hg with no antiglaucoma medications and with clinically stable glaucoma 1 year
      after surgery was 76.9% in phakic eyes (n = 13) and 0% in aphakic eyes (n = 8). A
      phakic patient with Sturge-Weber's syndrome had choroidal effusion after surgery
      that resolved spontaneously. In the aphakic group one patient had retinal
      detachment and another developed an encapsulated bleb. Visual acuity deteriorated
      in one patient. CONCLUSION: A guarded filtration procedure with mitomycin C is
      relatively successful in phakic children with glaucoma, but unsuccessful in
      aphakic ones.

PMID- 10396190
TI  - Screening for refractive errors in children: accuracy of the hand held refractor
      Retinomax to screen for astigmatism.
AB  - AIMS: To assess the reliability of the hand held automated refractor Retinomax in
      measuring astigmatism in non-cycloplegic conditions. To assess the accuracy of
      Retinomax in diagnosing abnormal astigmatism in non-cycloplegic refractive
      screening of children between 9 and 36 months. METHODS: Among 1205 children
      undergoing a non-cycloplegic refractive screening with Retinomax, 299 (25%) had
      repeated non-cycloplegic measurements, 302 (25%) were refracted under cycloplegia
      using the same refractor, and 88 (7%) using retinoscopy or an automated on table
      refractor. The reproducibility of non-cycloplegic cylinder measurement was
      assessed by comparing the cylindrical power and axis values in the 299 repeated
      measurements without cycloplegia. The influence of the quick mode on cylinder
      measurement was analysed by comparing the cylinder and axis value in 93 repeated
      measurements without cycloplegia where normal mode was used in one measurement
      and quick mode in the other. Predictive values of the refractive screening were
      calculated for three different thresholds of manifest astigmatism (> or = 1.5, >
      or = 1.75, and > or = 2 D) considering as a true positive case an astigmatism >
      or = 2 D under cycloplegic condition (measured by retinoscopy, on table, or hand
      held refractor). RESULTS: The 95% limits of agreement between two repeated
      manifest cylinder measurements with Retinomax attained levels slightly less than
      plus or minus 1 D. The 95% limits of agreement for the axis were plus or minus 46
      degrees. The comparison of non-cycloplegic measurements in the quick and normal
      mode showed no significant difference and 95% limits of agreement plus or minus
      0.75 D. The mean difference between non-cycloplegic and cycloplegic cylinder
      values measured by Retinomax reached 0.17 D and was statistically significant.
      Manifest thresholds of > or = 1.5 D, > or = 1.75 D, > or = 2 D cylinder value
      diagnosed 2 D of astigmatism under cyclplegia respectively with 71-84%, 59-80%,
      51-54% of sensitivity (right eye-left eye) and 90-92%, 95%, 98% of specificity.
      CONCLUSION: Without cycloplegia, Retinomax is able to measure cylinder power with
      the same reproducibility as cycloplegic retinoscopy. No significant difference
      was found in the cylinder values obtained with the quick and the normal modes.
      Therefore, the quick mode of measurement is recommended as it is more feasible in
      children. No difference, which is significant from a screening point of view,
      exists between the non-cycloplegic and the cycloplegic cylinder value (< 0.25 D).
      Retinomax diagnoses abnormal astigmatism (> or = 2 D) in a non-cycloplegic
      refractive screening at preschool ages with 51-84% sensitivity rates and 98-90%
      specificity rates, depending on the chosen threshold of manifest astigmatism. If
      2 D of manifest astigmatism is chosen as a positive test, the positive predictive
      value of the screening reaches 81-84% and the negative predictive value 91-90%
      (right eye-left eye).

PMID- 10396191
TI  - Effect of isosorbide mononitrate on the human optic nerve and choroidal
      circulations.
AB  - AIMS: To assess the effects of the nitric oxide donor 5-isosorbide mononitrate
      (ISMO) on blood flow in the optic nerve head (ON flow) and choroid (Ch flow).
      METHODS: Laser Doppler flowmetry was used to measure ON flow and Ch flow in 12
      normal subjects by aiming the laser beam at the fovea and at the temporal rim,
      respectively. In a double masked, randomised, crossover design, each subject
      received orally on separate days either 20 mg of 5-isosorbide mononitrate (ISMO)
      or placebo. Ch flow and ON flow were determined monocularly at baseline and 1
      hour after dosing. In the last six subjects, additional measurements were
      obtained at 3 hours. Mean arterial blood pressure (BPm), heart rate, and
      intraocular pressure (IOP) were monitored, and ocular perfusion pressure (PP) was
      estimated. RESULTS: No significant changes in ON flow, PP, IOP, or BPm were
      observed following placebo. Following ISMO, ON flow increased from baseline by
      19.8% (SEM 9.3%) at 1 hour (paired t test, p = 0.058) and by 33.1% (7.5%) at 3
      hours (p = 0.007). Compared with the changes following placebo, statistically
      significant increases in ON flow were observed both at 1 (p = 0.050) and 3 hours
      (p = 0.041) after ISMO treatment. Compared with placebo, PP decreased
      significantly 1 hour after ISMO dosing (p = 0.039), mainly as a function of
      reduced BPm. A significant inverse correlation (R = -0.618; p = 0.032) was
      observed between the percentage changes in PP and ON flow 1 hour following ISMO
      administration, but not after placebo. No significant change in foveal Ch flow
      was documented. CONCLUSIONS: These results suggest that, in normal subjects, ISMO
      increases significantly ON flow but not Ch flow. The inverse correlation observed
      between PP and ON flow suggests that the same mechanism(s) responsible for
      systemic vasodilatation and blood pressure decrease may also cause the ON flow
      increase.

PMID- 10396193
TI  - Infectious keratitis in leprosy.
AB  - AIM: To describe leprosy characteristics, ocular features, and type of organisms
      that produce infective corneal ulcers in leprosy patients. METHOD: The records of
      all leprosy patients admitted for treatment of corneal ulcers between 1992 and
      1997 were reviewed. RESULTS: 63 leprosy patients, 53 males and 10 females, are
      described. 16 were tuberculoid and 47 lepromatous. 25 patients had completed
      multidrug therapy. 10 patients had face patches, eight had type I reaction, and
      10 had type II reaction. 43 (68%) patients had hand deformities. In 54% of
      patients pain was absent as a presenting symptom. 19 patients gave a history of
      trauma. In 15 patients ulcers had also occurred on the other eye, five of them
      having occurred during the study period and the rest before 1992. Of the 68 eyes
      with corneal ulcers, 28 had madarosis, 34 had lagophthalmos, nine had ectropion,
      three had trichiasis, six had blocked nasolacrimal ducts, and 39 decreased
      corneal sensation. In 14 eyes, a previous lagophthalmos surgery had been done. 16
      patients were blind at presentation. 32% of ulcers were located centrally. After
      treatment only 18% of the eyes showed visual improvement. Five types of fungus
      were cultured, two of them rare ocular pathogens. CONCLUSIONS: Corneal ulcers
      occur more in males and in the lepromatous group of patients. Decreased corneal
      sensation, lagophthalmos and hand deformity are closely associated. Indigenous
      treatment and late presentations were notable in many patients. Visual outcome is
      not good. There is increased risk of developing an ulcer in the other eye. Fungal
      corneal ulcers are not uncommon.

PMID- 10396192
TI  - Indocyanine green guided laser photocoagulation in patients with occult choroidal
      neovascularisation.
AB  - AIMS: To determine whether indocyanine green (ICG) guided laser photocoagulation
      of occult choroidal neovascularisations (OCNV) is beneficial for patients with
      occult choroidal neovascularisation secondary to age related macular degeneration
      (AMD). METHODS: A prospective pilot study was performed in 21 eyes with OCNV
      secondary to AMD that could be identified extrafoveolarly or juxtafoveolarly in
      an early ICG angiographic study. Laser photocoagulation was applied to the
      neovascular membrane identified in the early ICG angiographic study. RESULTS:
      Visual acuity ranged from 20/400 to 20/20 (logMAR 0.54 (SD 0.29) before and hand
      movements and 20/30 (logMAR 0.81 (0.69)) at the last follow up after laser
      photocoagulation. During the follow up (30 (13) months) vision improved in four
      eyes (two lines), in seven eyes the initial visual acuity could be stabilised
      (two lines), in five eyes vision dropped moderately (three to five lines), and in
      five eyes vision decreased severely (six or more lines). Recurrences (seven
      patients) or persistent CNV (six patients) was observed in 13 patients.
      CONCLUSION: This preliminary study of ICG guided laser photocoagulation of occult
      extrafoveal and juxtafoveal choroidal neovascularisations suggests that this
      technique may improve the visual prognosis of these patients. Further prospective
      controlled studies are necessary to confirm these data.

PMID- 10396194
TI  - Conjunctival squamous cell carcinoma in Tanzania.
AB  - AIMS: To assess changes in incidence of conjunctival squamous cell carcinoma over
      a 22 year period in Tanzania and to analyse possible reasons for change. METHODS:
      Retrospective analysis of records from a Tanzanian pathology department serving
      north and central Tanzania from 1976 to 1997; medical record analysis of cases of
      conjunctival squamous cell carcinoma presenting in the last 2 years of the study.
      RESULTS: There was a sharp rise in the incidence of conjunctival squamous cell
      carcinoma in the last 3 years of the study (1995-7). The mean age of patients
      presenting with the condition over the full period was 44.7 years (95% confidence
      interval 42.4-46.9 years). In the final 2 years of the study the mean length of
      history on presentation was 3.1 months (2.1-4.0 months). Several patients had a
      previous history of chronic conjunctival disease such as allergic conjunctivitis
      and trachoma; one had had a conjunctival papilloma excised previously. Only five
      patients had been tested for HIV status, but of these four were positive.
      CONCLUSION: Tanzania is experiencing an epidemic of conjunctival squamous cell
      carcinoma similar to that seen in other African countries. Often the tumours are
      aggressive and occur in patients of relatively young age. The epidemic appears to
      be related to HIV infection, on a background of ultraviolet light exposure.
      Previous chronic conjunctival disease and exposure to human papillomavirus may
      also have a role.

PMID- 10396196
TI  - Confocal microscopy in cornea guttata and Fuchs' endothelial dystrophy.
AB  - AIMS: To report the appearances of cornea guttata and Fuchs' endothelial
      dystrophy from white light confocal microscopy. METHODS: Seven eyes of four
      consecutive patients with cornea guttata were prospectively examined. Of the
      seven eyes, three also had corneal oedema (Fuchs' dystrophy). In vivo white light
      tandem scanning confocal microscopy was performed in all eyes. Results were
      compared with non-contact specular microscopy. RESULTS: Specular microscopy was
      precluded by corneal oedema in one eye. In the remaining six eyes, it
      demonstrated typical changes including pleomorphism, polymegathism, and the
      presence of guttae appearing as dark bodies, some with a central bright reflex.
      In all seven eyes, confocal microscopy revealed the presence of round
      hyporeflective images with an occasional central highlight at the level of the
      endothelium. Changes in cell morphology and size were readily appreciated.
      CONCLUSION: By comparison with specular microscopy, the hyporeflective images
      with an occasional central highlight seen on confocal microscopy are consistent
      with the presence of guttae. Confocal microscopy may confirm the diagnosis of
      cornea guttata and Fuchs' endothelial dystrophy by demonstrating the presence of
      guttae. This technique is especially valuable in cases of corneal oedema, where
      specular microscopy may fail to visualise the endothelium. However, specular
      microscopy should remain the method of choice to evaluate the endothelium,
      principally because it is easier to use.

PMID- 10396195
TI  - Efficacy of nedocromil 2% versus fluorometholone 0.1%: a randomised, double
      masked trial comparing the effects on severe vernal keratoconjunctivitis.
AB  - AIMS: To compare the efficacy of topical nedocromil 2% with fluorometholone 0.1%
      in vernal keratoconjunctivitis (VKC). METHODS: In a double masked random design,
      24 patients with severe vernal keratoconjunctivitis were placed at random on
      nedocromil 2% eye drops in one eye and fluorometholone 0.1% in the fellow eye. At
      the end of the 2 week treatment period, the patient crossed over the eye drops
      (if asymptomatic in one eye), or continued with nedocromil sodium in both eyes
      (if asymptomatic in both eyes). All patients were examined weekly and ocular
      surface temperature recorded for a period of 6 weeks. RESULTS: Improvement in the
      watering, discharge, conjunctival hyperaemia, papillary hypertrophy, and Trantas'
      dots was noted in both groups, but overall fluorometholone was significantly more
      effective than nedocromil. Eyes treated with fluorometholone showed a significant
      decrease in ocular surface temperature compared with nedocromil treated eyes (p =
      0.03). CONCLUSIONS: Both nedocromil and fluorometholone were effective in
      ameliorating the signs and symptoms of vernal keratoconjunctivitis. No adverse
      effects were noted in the nedocromil group.

PMID- 10396197
TI  - Cone and rod dysfunction in the NARP syndrome.
AB  - AIMS: Description of the ophthalmic manifestations of the NARP (neuropathy,
      ataxia, retinitis pigmentosa) syndrome that is associated with a point mutation
      in position 8993 of the mitochondrial DNA (mtDNA). METHODS: A mother and her two
      children, all carrying the 8993 mtDNA mutation, were examined. Two had
      manifestations of the NARP syndrome. A complete ocular and systemic examination
      was performed on all three patients. RESULTS: The clinical examination,
      electroretinogram, and visual fields revealed a typical cone-rod dystrophy in the
      son, and a typical cone dystrophy in the daughter. The mother had no ocular
      manifestations of the disease. CONCLUSIONS: NARP is a recently described,
      maternally inherited mitochondrial syndrome in which a retinal dystrophy, among
      other abnormalities, is related to a mutation of the mtDNA at nucleotide 8993.
      This study demonstrates the great variability of the ocular manifestations in the
      NARP syndrome. It also indicates that the retinal dystrophy in at least some NARP
      patients affects primarily the cones.

PMID- 10396198
TI  - Ring melanoma--a rare cause of refractory glaucoma.
AB  - BACKGROUND: Ring melanoma of the ciliary body and iris is extremely rare and
      often has adverse histology. This tumour may cause raised intraocular pressure.
      METHODS: A review of four cases of ring melanomas with insidious presentations
      seen in the ocular oncology service over a 12 month period. RESULTS: All four
      patients presented with unilateral anterior segment abnormalities and refractory
      glaucoma. The misdiagnoses of the causes of the glaucoma included angle recession
      from previous blunt trauma (patient 1); iridocorneal endothelial (ICE) syndrome
      supported by endothelial specular microscopy (patients 2 and 3); and melanocytoma
      on ciliary body biopsy (patient 4). Two patients were treated by several
      cyclodiode ciliary body ablation treatments and the other two underwent
      trabeculectomies and Molteno tubes. Two of the four patients have since died from
      their disease. CONCLUSION: The ophthalmologist should re-evaluate the diagnosis
      in patients with anterior segment abnormalities and refractory ipsilateral
      glaucoma. Endothelial specular microscopy and biopsy of the suspicious lesion may
      give misleading reassurance. The potential presence of an anterior uveal melanoma
      must always be considered.

PMID- 10396199
TI  - Temporal contrast sensitivity with peripheral and central stimulation in glaucoma
      diagnosis.
AB  - AIMS: To evaluate temporal contrast sensitivity with full field, peripheral, and
      central stimulation and to determine the most sensitive corresponding retinal
      area for glaucoma damage. METHODS: Temporal contrast sensitivity was determined
      either with a full field, a peripheral annular area from 30 degrees to 90
      degrees, or a central area from 0 degree to 30 degrees at a frequency of 37.1 Hz.
      232 eyes of 232 subjects were included. They were classified into four groups:
      eyes with ocular hypertension (OHT, n = 54), "preperimetric" glaucomas (n = 73)
      with glaucomatous optic disc abnormalities but no visual field loss, "perimetric"
      glaucomas (n = 53) with visual field loss, and 52 normals. RESULTS: In all four
      groups, temporal contrast sensitivity was almost equal with full field and
      peripheral, but significantly higher than with central stimulation (p < 0.001).
      With regard to the diagnostic power of the three different stimulus areas, OHTs
      and glaucomas were found to be best discriminated from normals by peripheral
      stimulation. CONCLUSIONS: According to these results, temporal contrast
      sensitivity seems to be determined by peripheral retinal areas. As the diagnostic
      power of the three different stimulus areas was best with the peripheral
      stimulation, this condition should be used for early glaucoma diagnosis.

PMID- 10396200
TI  - Comparison of inferior oblique muscle weakening by anterior transposition or
      myectomy: a prospective study of 20 cases.
AB  - BACKGROUND/AIMS: Among the various weakening techniques of inferior oblique
      muscle overaction, the most commonly used techniques include myectomy, recession,
      and anterior transposition. Anterior transposition and myectomy were compared to
      evaluate the surgical results in inferior oblique overaction. METHODS: 20
      children with bilateral +3 overacting inferior oblique muscles underwent a
      prospective randomised study by which the anterior transposition procedure in one
      eye was compared with the myectomy procedure in the other eye. RESULTS:
      Postoperative follow up averaged 2 years. The success rates in two surgical
      procedures were 85% for the anterior transposition and 25% for the myectomy
      (standard of success was based on zero inferior oblique overaction). In only one
      case did the anterior transposition tend to limit the elevation of the eye in the
      midline, adduction, and abduction. Anterior transposition produced hypotropia at
      the primary position in only one case. Most eyes that underwent myectomy (75%)
      showed apparent residual overaction. CONCLUSION: The anterior transposition
      appeared to be more effective in eliminating the overaction of inferior oblique
      muscle than the myectomy.

PMID- 10396201
TI  - Transforming growth factor beta isoforms in human optic nerve heads.
AB  - AIM: To determine if the isoforms of transforming growth factor beta (TGF-beta)
      are present in fetal, normal adult, and glaucomatous optic nerve heads. METHODS:
      To localise cells synthesising TGF-beta, optic nerve heads were stained using
      antibodies to TGF-beta 1, TGF-beta 2, and TGF-beta 3. To demonstrate synthesis,
      human optic nerve heads from fetal, glaucomatous, and normal age matched subjects
      were explanted, cultured overnight, and the culture supernatant was assayed for
      the presence of TGF-beta 1 and TGF-beta 2 by bioassay. In addition,
      semiquantitative RT-PCR was performed to determine the gene expression pattern of
      TGF-beta 2. RESULTS: Immunohistochemistry of glaucomatous samples revealed the
      presence of intense staining for TGF-beta 2 primarily in astrocytes, whereas TGF
      beta 1 was localised to blood vessels. No TGF-beta 3 immunoreactivity was
      observed. There was little or no expression of TGF-beta in normal optic nerve
      heads. Optic nerve heads from glaucomatous eyes released 70-100-fold more TGF
      beta 2 than normal age matched optic nerve heads. Fetal optic nerve heads
      released 90-100-fold more TGF-beta 2 than normal adult optic nerve heads. TGF
      beta 1 was undetectable by bioassay in all samples tested. There was no apparent
      increase in TGF-beta 2 gene expression in glaucomatous and fetal eyes, suggesting
      post-transcriptional regulatory mechanisms. CONCLUSIONS: These results
      demonstrate that TGF-beta 2 is produced in high levels in the fetal and
      glaucomatous optic nerve heads, perhaps by a mechanism of post-transcriptional
      regulation. TGF-beta may be important during development of the optic nerve head
      and, in glaucoma, TGF-beta 2 may be a mediator of astrocyte reactivation and
      extracellular matrix remodelling in the lamina cribrosa.

PMID- 10396202
TI  - Long-term ultrastructural changes in human corneas after tattooing with non
      metallic substances.
AB  - AIM: To investigate the ultrastructural appearance and the deposition pattern of
      dye particles in long term non-metallic corneal tattooing. METHODS: Two tattooed
      human corneas were obtained by keratoplasty. One corneal button was fixed in
      Karnovsky's solution and the other in Trumps' solution. Both corneas were divided
      and processed for conventional light (LM) and transmission electron microscopy
      (TEM). Five additional formalin fixed corneas with tattoos were retrieved from
      paraffin for TEM. The time between tattoo and removal of the corneal
      button/enucleation ranged from 7 to 61 years. All seven corneas were examined
      using a Jeol JCXA733 microprobe for wave length dispersive analysis in order to
      exclude any presence of metallic salts in the tattooed area. RESULTS:
      Histologically, clumps of brown-blackish granules were present mainly in the mid
      stroma, but also in anterior and partially in the posterior half of the stroma.
      On TEM, numerous round and oval electron dense particles were seen in the
      cytoplasm of keratocytes arranged as clusters or large islands. The larger
      particles appeared black, while the smaller particles were grey. In well fixed
      tissue a unit membrane was observed around these clusters. No granules were
      detected in the extracellular matrix. CONCLUSIONS: Keratocytes can actively
      ingest and retain tattooing particles of non-metallic dyes within their cell
      membrane for very long periods of time.

PMID- 10396203
TI  - Differential induction of proto-oncogene expression and cell death in ocular
      tissues following ultraviolet irradiation of the rat eye.
AB  - BACKGROUND/AIMS: Ultraviolet (UV) irradiation of mammalian cells in culture
      evokes the transcriptional activation of different proto-oncogenes, among them
      members of the fos/jun family which are known to play an important role in cell
      proliferation and differentiation. To investigate in vivo UV induced proto
      oncogene expression of irradiated ocular cells, the expression of JunB, JunD, and
      Egr-1 was analysed in the cornea, lens, and retina. Furthermore, UV radiation is
      known to induce pleiotrophic events in irradiated cells which include growth
      arrest, inflammation, and even cell death. In order to determine the type of cell
      death--for example, apoptosis versus necrosis, sections of UV irradiated rat eyes
      were further examined for distinct ultrastructural morphology of cell death and
      DNA fragmentation. METHODS: Eyes of anaesthetised rats were exposed to 1.5 J/cm2
      of ultraviolet radiation (280-380 nm). Animals were perfused 6 and 16 hours after
      irradiation and tissue sections of enucleated bulbi were processed for light and
      electron microscopy. RESULTS: Under control conditions, Jun B was constitutively
      expressed in numerous superficial cells but also in scattered basal cells of the
      corneal epithelium. After UV exposure JunB expression was massively upregulated
      in many cells of the basal cell layers of the corneal epithelium, although during
      the entire experiment, both the corneal stroma and endothelium were JunB
      negative. In contrast, Egr-1 was expressed exclusively in lens epithelium showing
      only a faint expression pattern under control conditions. However, Egr-1
      expression increased after UV exposure, so that many Egr-1 positive cells of the
      lens epithelium could be found several hours after UV illumination. JunD was
      expressed in single cells of both the ganglion cell layer and the inner nuclear
      layer of the retina, a pattern of expression which did not change after UV
      exposure. Regarding the type of cell death, features of apoptosis were only
      occasionally present in scattered superficial cells of the corneal epithelium of
      control eyes. After UV exposure, however, morphological signs of apoptosis and
      TUNEL positive cells were visible both in the stroma and epithelium of the rat
      cornea. In contrast, UV irradiated lens epithelial cells exhibited features
      typical of necrosis. The corneal endothelium and the retina did not show any
      indications of morphological changes indicative of cell death after UV
      irradiation. CONCLUSION: Each proto-oncogene encoded protein was found to be
      expressed in a tissue specific manner and UV irradiation differentially modulates
      the expression pattern of these transcriptional regulatory proteins. This
      temporospatial expression pattern of these proteins is accompanied by two
      morphologically distinct types of cell death in the cornea and lens after UV
      irradiation.

PMID- 10396204
TI  - Histochemical localisation of mitochondrial enzyme activity in human optic nerve
      and retina.
AB  - AIMS: To demonstrate the quantitative distribution of mitochondrial enzymes
      within the human optic nerve and retina in relation to the pathogenesis of
      ophthalmic disease. METHODS: Enucleations were performed at the time of multiple
      organ donation and the optic nerve and peripapillary retina immediately excised
      en bloc and frozen. Reactivities of the mitochondrial enzymes cytochrome c
      oxidase and succinate dehydrogenase were demonstrated in serial cryostat sections
      using specific histochemical assays. RESULTS: In the optic nerve the unmyelinated
      prelaminar and laminar regions were rich in both cytochrome c oxidase and
      succinate dehydrogenase. Myelination of fibres as they exited the lamina cribrosa
      was associated with an abrupt reduction in enzyme activity. Within the retina,
      high levels of enzyme activity were found localised within the retinal ganglion
      cells and nerve fibre layer, the outer plexiform layer, inner segments of
      photoreceptors, and the retinal pigment epithelium. CONCLUSIONS: Mitochondrial
      enzyme activity is preserved in human optic nerve and retina retrieved at the
      time of multiple organ donation. The distribution of enzyme activity within the
      eye has implications for the understanding of the pattern of ophthalmic
      involvement seen in mitochondrial diseases and the site of ganglion cell
      dysfunction in those patients with optic nerve involvement.

PMID- 10396205
TI  - Human retina contains polyamine sensitive [3H]-ifenprodil binding sites:
      implications for neuroprotection?
AB  - AIMS: This study characterised the pharmacology of [3H]-ifenprodil binding to the
      polyamine binding sites (PBS) on the N-methyl-D-aspartate (NMDA) receptor channel
      complex on human retinas. These data were correlated with the known
      neuroprotective effects of ifenprodil and eliprodil. METHODS: Specific binding of
      [3H]-ifenprodil (under sigma site blockade) was investigated using human retinal
      homogenates and radioligand binding techniques. Scatchard and competition
      analyses were utilised to define the pharmacology of the [3H]-ifenprodil binding
      sites. RESULTS: Specific binding of [3H]-ifenprodil comprised 73% (SEM 3%) of
      total and reflected interaction with two affinity sites (Kds = 0.39 and 4.3
      microM) of different densities (Bmax = 14.4 and 105 pmol/mg protein) (n = 5). The
      rank order of affinity of compounds competing for [3H]-ifenprodil binding to the
      high affinity PBS was: ifenprodil > eliprodil > arcaine > spermine >
      diaminodecane > spermidine > putrescine >> MK-801 (n = 3-7). However, [3H]
      ifenprodil binding was minimally inhibited by glutamate, NMDA, and kainate.
      CONCLUSION: These studies have shown, for the first time, the presence of
      specific [3H]-ifenprodil binding sites in the human retina with pharmacological
      characteristics of PBS associated with the NMDA receptor ionophore complex. The
      neuroprotective effects of eliprodil and ifenprodil may, in part, be mediated via
      these [3H]-ifenprodil labelled sites.

PMID- 10396207
TI  - A case of reversible blindness in maple syrup urine disease.

PMID- 10396206
TI  - Birdshot retinochoroidopathy.

PMID- 10396208
TI  - Measurement of optic disc size.

PMID- 10396209
TI  - Elevated serum levels of soluble ICAM-1 in uveitis patients predict underlying
      systemic disease.

PMID- 10396210
TI  - Do patients with age related maculopathy and cataract benefit from cataract
      surgery?

PMID- 10396211
TI  - Imaging of patients with severe emphysema considered for lung volume reduction
      surgery.
AB  - Lung volume reduction surgery has recently been reintroduced as a palliative
      treatment for patients with severe emphysema. Selection criteria vary between
      centres and imaging is extensively used, but the exact role of individual
      techniques in the selection process is still emerging.

PMID- 10396212
TI  - Estimation of breast volume and its variation during the menstrual cycle using
      MRI and stereology.
AB  - Unbiased estimates of breast volume may be obtained in vivo from systematic
      series of MR images acquired in accordance with the Cavalieri method of modern
      design-based stereology. The method does not require any assumptions to be made
      regarding breast shape. If point counting techniques are used to obtain the
      required breast section areas estimates, 10-15 min analysis (i.e. counting about
      250 points on 12 to 16 images) ensures that the contribution of sectioning and
      point counting to the coefficient of error (CE) on the volume estimate is less
      than 3%. The methods were applied to measure breast volume in 15 healthy females
      aged between 22 and 44 years (mean 31.7 years; SD 8.2 years). One subject was
      studied on every fourth day during two consecutive cycles. The other 14 subjects
      were studied on three occasions corresponding to menses, ovulation and pre-menses
      during a single menstrual cycle. Repeat imaging after repositioning on three
      occasions within a period of 30 min and also at three different times of day for
      a single subject, both yielded a coefficient of variation (CV) of less than 3% in
      the estimation of breast volume. ANOVA indicates that there is no significant
      difference between the mean volume of the left and the right breast (p = 0.294).
      The mean volume of the left breast is 561 ml (95% confidence interval (CI): 553
      ml, 569 ml) and the mean volume of the right breast is 567 ml (95% CI: 559 ml,
      576 ml). There are highly significant differences between the three named stages
      of the menstrual cycle (p < 0.0005), whereby the mean volume at ovulation is 5.5%
      less than the mean volume at menses (95% CI: 3.0%, 7.9%) and the mean volume pre
      menses is 8.1% greater than the mean volume at menses (95% CI: 5.3%, 10.9%).
      Overall, the volume of each breast varies by an average of 76 ml (95% CI: 61 ml,
      92 ml) during the menstrual cycle, which corresponds to 13.6% of the volume at
      menses (95% CI: 13.3%, 13.8%). No significant interaction was found between the
      relative volumes of the left and right breast and the stage of the menstrual
      cycle (p = 0.277), nor between subjects and stages of cycle (p = 0.296). However,
      a significant interaction was observed between the volume of the left and right
      breasts in different subjects (p < 0.005). The average difference in the volume
      of the left and right breasts of all 15 subjects is 39.7 ml (95% CI: 21.3 ml,
      58.1 ml), which is 7% of average breast volume and approximately 50% of the
      average variation in the volume of the breast during the menstrual cycle.

PMID- 10396213
TI  - Does resection of small liver metastases from colorectal cancer improve survival
      of patients?
AB  - Because the size of metastases greatly affects their detection, we
      retrospectively investigated the influence of the size of liver metastases on
      survival after hepatic surgery. The subject group study consisted of 77 patients
      who underwent liver surgery for metastases from colorectal cancer. The survival
      rate after hepatic surgery was analysed using multivariate Cox's proportional
      hazards model with the following variables: (1) size of dominant metastases
      (Small: < 3 cm; Medium: > or = 3 cm and < 6 cm; Large: > or = 6 cm); (2)
      synchronous versus metachronous resection; (3) solitary versus multiple
      metastases. The size of dominant metastases (p = 0.035) and synchronous versus
      metachronous resection (p = 0.0009) were independently associated with survival
      after liver resection. No association was found, however, for solitary versus
      multiple metastases. The survival of the Large group was much poorer than that of
      the Small group (p = 0.0168) and that of the Medium group (p = 0.0205), with
      statistically significant differences. No statistically significant difference
      was seen between the Small and the Medium groups (p = 0.7963). This study showed
      that long-term survival following resection of metastases was much poorer when
      metastases were 6 cm or greater in diameter. With regard to metastases less than
      6 cm in diameter, resection of the smallest of these (less than 3 cm) did not
      appear to improve survival.

PMID- 10396214
TI  - MRI appearances of the axilla in treated breast cancer.
AB  - Differentiation between recurrent axillary disease and changes due to
      radiotherapy or surgery has major implications for management in patients
      following breast cancer treatment, but clinical examination of the axilla may be
      difficult. This study was undertaken to correlate the MRI appearances of the
      axilla following breast cancer treatment with clinical outcome. 74 women with
      treated breast cancer were evaluated by MRI (0.5 T) and the appearances defined
      by consensus. Outcome was assessed by long-term clinical follow-up. 62 women had
      symptoms related to the axilla while 12 were scanned to stage the axilla. None of
      the axillary staging group had abnormal MRI appearances and none of these
      subsequently developed recurrence. The 62 symptomatic women were subdivided
      according to MRI appearances. 22 had normal axillary appearances, 18 had an
      axillary mass and 22 women had abnormal axillary appearances (rated mild,
      moderate and severe) in the absence of a mass. Normal axillary appearances on MRI
      excluded recurrent disease as the cause of symptoms with a specificity of 94.7%
      and a positive predictive value (PPV) of 95.5%. The presence of an axillary mass
      was commonly but not exclusively due to recurrent disease (sensitivity 68.4%,
      specificity 88.4%, PPV 72.2%). Sensitivity for diagnosis of axillary recurrence
      was increased to 89.5% with a specificity of 76.7% if the criteria for recurrent
      disease were taken as either the presence of an axillary mass or severe axillary
      changes in the absence of a mass lesion.

PMID- 10396215
TI  - A comparison of MRI and echocardiography in hypertrophic cardiomyopathy.
AB  - This study compares MRI and echocardiography as imaging modalities in
      hypertrophic cardiomyopathy, with particular reference to measurement of left
      ventricular wall thickness and mass. 10 subjects underwent echocardiography and
      MRI. Contiguous 10 mm short axis 35 degrees flip angle cine gradient recalled
      echo MR images were acquired from the apex to the base of the left ventricle at
      1.5 tesla. Standard M-mode and cross-sectional echocardiographic views of the
      left ventricle were obtained. Excellent agreement between measurements occurred
      with MRI and M-mode echocardiographic assessment of the thickness of the anterior
      interventricular septum (95% limits of agreement -1.5 to +1.5 mm). Other
      comparisons of MRI vs M-mode echocardiographic measurements had the following
      limits of agreement: posterior free wall -3.3 to +2.9 mm; end-diastolic dimension
      -5 to +8 mm, left ventricular mass -291 to +55.5 g. Comparing MRI with cross
      sectional echocardiographic measurements, the limits of agreement were: anterior
      interventricular septum -2.4 to +1.7 mm, posterior interventricular septum -2.4
      to +2.9 mm, posterior free wall -3.4 to +2.5 mm, anterior free wall -2.4 to +1.7
      mm, end-diastolic dimension -4.1 to +8 mm. MRI estimates of LVM in systole vs
      diastole showed good agreement with 95% limits of agreement of -20 to +17 g, with
      excellent interobserver variability in diastole (-9 to +5 g) and in systole (-7
      to +12 g). In conclusion, MRI is superior to echocardiography for the
      quantification of ventricular mass in the abnormal left ventricle because it does
      not make invalid geometrical assumptions. Comparisons of wall thickness show
      greater discrepancy with increasing distance from the echocardiographic
      transducer. This study suggests that sequential echocardiography could
      rationalize the need for MRI in left ventricular hypertrophy. A change in
      anterior septal thickness of > or = 3 mm on echocardiography merits a further MRI
      study.

PMID- 10396216
TI  - The 4 year outcome following the demonstration of bilateral renal pelvic
      dilatation on pre-natal renal ultrasound.
AB  - There is little in the literature regarding long-term prognosis in cases of fetal
      pyelectasis and calyceal dilatation. The aim of this study was to correlate
      antenatal ultrasound findings with outcome in a large group of children, most of
      whom had routine antenatal mid-trimester scans. 75 babies with bilateral
      pyelectasis and calyceal dilatation in the pre-natal period and complete
      radiological and clinical data were identified over a 3 year period. Pre-natal
      ultrasound was correlated with results of post-natal investigation and the
      frequency of post-natal surgery was established. Follow-up was documented to
      discharge or to at least 4 years of age. Prognosis was related to the degree of
      pelvic dilatation, but neonatal morbidity was much more likely to be associated
      with pre-natal calyceal dilatation and/or hydroureter. 68% (51 of 75) of babies
      had insignificant abnormalities on post-natal investigation, defined as either
      transient fetal pyelectasis and calyceal dilatation, extrarenal pelves, or
      transient neonatal pyelectasis and calyceal dilatation. Five babies died in the
      neonatal period, all classified as either moderate or severe disease. Of the
      surviving 70 cases (93.3%), 27% had renal anomalies that required treatment by
      prophylactic antibiotics or surgery. The remaining babies were conservatively
      managed and followed as outpatients. One child required transplantation and a
      further two had a severe degree of chronic renal failure by the age of 4 years.
      These data will be of value in prospective counselling.

PMID- 10396217
TI  - CT findings in involvement of the paranasal sinuses by lepromatous leprosy.
AB  - The role of nasal infection in the transmission of leprosy has been extensively
      studied. Leprosy can affect the paranasal sinuses due to mucosal continuity and
      bacillaemia. This prospective study was performed on 25 untreated patients with
      lepromatous leprosy. 5 mm contiguous axial and coronal CT sections of paranasal
      sinuses, on soft tissue and bone windows, were obtained in all patients. Each
      sinus was examined for mucosal thickening, soft tissue densities and bony
      outlines. Representative biopsies were taken from ethmoid sinus to confirm the
      radiological diagnosis in 12 patients with multiple paranasal sinus involvement.
      Ethmoid aircells were involved in 20 patients (80%). Maxillary, frontal and
      sphenoid sinuses showed abnormalities in 12, four and three patients,
      respectively. The ethmoid biopsy showed involvement by lepromatous leprosy in
      seven of 12 patients (58.3%). Involvement of paranasal sinuses is common in
      lepromatous leprosy and is of considerable epidemiological significance.

PMID- 10396218
TI  - Brain radiotherapy during pregnancy: an analysis of conceptus dose using
      anthropomorphic phantoms.
AB  - The aims of this study were: (a) to determine conceptus dose resulting from brain
      radiotherapy; (b) to investigate the necessity of using shielding devices over
      patient's abdomen during treatment; and (c) to estimate the components of
      conceptus dose. Radiation doses received by conceptus were measured using
      anthropomorphic phantoms simulating pregnancy at 4, 12 and 24 weeks gestation and
      thermoluminescent dosemeters. All irradiations were performed with two lateral
      and opposed fields approximating the minimum, medium and maximum field size used
      during treatment of brain malignancies. For a treatment course delivering 65 Gy
      to tumour without using shielding equipment, conceptus dose never exceeded 100
      mGy. Appropriate positioning of 5.1 cm of lead over the phantom's abdomen
      provided reduction of conceptus dose from 26% to 71%, depending upon gestational
      age, field size and distance from the field isocentre. The contribution of
      scatter arising from within the phantom to the conceptus dose was small compared
      with that from head leakage and collimator scatter. Our dosimetric results
      indicate that the construction of special shielding equipment is not a
      prerequisite for treating brain malignancies during pregnancy. However, based on
      the concept that exposures in women of childbearing age should be kept as low as
      reasonably achievable, we suggest that shielding devices should be used whenever
      possible.

PMID- 10396219
TI  - Use of dose-volume histograms and biophysical models to compare 2D and 3D
      irradiation techniques for non-small cell lung cancer.
AB  - For non-small cell lung cancer (NSCLC), unsatisfactory local control (LC) still
      remains an important cause of failure. It has been suggested that improved LC can
      be achieved with both higher radiation dosage and adequate target coverage.
      Modern three-dimensional treatment planning systems (3D-TPSs) offer many tools
      for planning optimization. Biophysical models, which estimate the normal tissue
      complication probability (NTCP), are gaining in importance in comparing plans.
      This study compares conventional two-dimensional (2D) with 3D irradiation
      techniques using parameters related to volumetric dose distribution and two
      different biophysical models predicting normal tissue tolerance to radiotherapy
      (RT). Nine patients with inoperable locally advanced NSCLC were treated with a
      beam's eye view-based 3D technique. For the same patients, a conventional
      treatment was simulated; the irradiation geometry and beam contour were fully
      defined at the simulator and then transferred to the 3D-TPS to calculate the dose
      distribution. Both techniques gave the same prescribed dose at the reference
      point. Dose-volume histograms (DVHs) and dose statistics of organs at risk (OARs)
      (heart, lung(s), parenchyma lung, spinal cord and oesophagus) were analysed. The
      probability of side effects was estimated using two different biophysical models:
      the integrated normal ("empirical") model and the relative seriality model. Apart
      from contralateral lung, the 3D irradiation technique significantly reduced the
      average mean doses to all OARs. The current analysis suggests that in the
      treatment of locally advanced NSCLC, the use of 3D irradiation techniques allows
      a large sparing of OARs; this advantage is confirmed by both dose statistics
      analysis and NTCP values.

PMID- 10396220
TI  - Volumetric assessment of carotid artery bifurcation using freehand-acquired,
      compound 3D ultrasound.
AB  - The aim of this study was to establish the reproducibility of sequential three
      dimensional (3D) ultrasound reconstructions of an identified segment of the
      carotid artery bifurcation in asymptomatic subjects. A freehand acquisition,
      compound reconstruction, 3D ultrasound system was used on three occasions, over a
      period of 1 year. The lumen of the vessel was reconstructed to provide a volume
      measurement and a rotatable 3D structure representation that could be examined
      for geometrical correspondence. The four subjects differed significantly in the
      visualized 3D geometry of the vessel bifurcation. There was good correspondence
      in the sequential reconstructions for each individual in both the 3D geometry and
      in the measured lumen volume, with an overall coefficient of variation of 5% and
      no evidence of deterioration in correlation with time.

PMID- 10396221
TI  - A model simulator for radiotherapy treatment planning and checking.
AB  - For a linear accelerator the direction and orientation of a beam is specified
      uniquely by a set of gantry, turntable and collimator angles. Sometimes,
      particularly for 3D planning, it is very difficult for the planner or plan
      checker to visualize the set-up of the treatment machine from the angles
      specified for each beam. This note describes a simple line-of-sight model that
      can be used for planning and checking the radiotherapy geometry prior to
      simulator verification.

PMID- 10396222
TI  - Pre-surgical localization of ectopic parathyroid glands using three-dimensional
      CT imaging, 99Tcm sestamibi, and 99Tcm tetrofosmin imaging.
AB  - We describe two patients with ectopic parathyroid glands evaluated with 99Tcm
      sestamibi, 99Tcm tetrofosmin, and three-dimensional computed tomography (3D-CT).
      Radionuclide images of the neck were acquired at 10 min, and at 2-3 h after
      radiopharmaceutical injection, and showed intense uptake in the ectopic
      parathyroid tissue. These patients also underwent contrast enhanced CT imaging
      with 3D reconstructions which were evaluated for ability to visualize critical
      anatomical structures, e.g. blood vessels and parathyroid glands. Based on 3D-CT
      images, surgical planning was altered in one of the two patients studied. In
      conclusion, reconstructed 3D-CT images provided useful anatomical localization of
      ectopic parathyroid glands identified on 99Tcm sestamibi and 99Tcm tetrofosmin
      imaging. This anatomical information aided surgical planning of gland resection.

PMID- 10396223
TI  - MR findings in ovarian granulocytic sarcoma.
AB  - Granulocytic sarcoma (chloroma) is a mass of malignant myeloid precursor cells in
      an extramedullary location. The female genital tract, including the ovary, may be
      the first site for clinical manifestation of granulocytic sarcoma. The MR
      findings are reported in a case of ovarian granulocytic sarcoma which preceded
      acute myelogenous leukaemia. Granulocytic sarcoma shows a mixed cystic and solid
      adnexal mass with intermediate signal intensity on T1 weighted images and
      hypointensity on T2 weighted images.

PMID- 10396224
TI  - Spontaneous regression of pulmonary metastases demonstrated by CT.
AB  - Two cases of disappearing or spontaneous regression of pulmonary metastases on CT
      are presented. In both cases, cytological proof was obtained by radiologically
      guided fine needle aspiration. The lesions subsequently regressed on follow-up CT
      studies without recognized systemic treatment.

PMID- 10396225
TI  - Thallium-201 scintigraphy in malignant mesothelioma.
AB  - A patient with malignant pleural mesothelioma was investigated using 201Tl
      scintigraphy. There was diffuse pleural tumour accumulation on planar
      scintigraphy. Single photon emission computed tomography (SPECT) demonstrated
      exact tumour location. It is concluded that planar scintigraphy using 201Tl may
      be useful in detecting mesothelioma. Clearer tumour localization is possible with
      SPECT.

PMID- 10396227
TI  - CT of unusual nasal masses.
AB  - This pictorial review illustrates the CT appearances of unusual nasal masses and
      the possibility of offering a correct diagnosis in some cases but a reliance on
      histology in others where radiology can only offer a differential diagnosis.

PMID- 10396226
TI  - Embolization of iatrogenic venous pseudoaneurysm.
AB  - A case is described where a patient on long-term anticoagulation developed a
      venous pseudoaneurysm in the antecubital fossa following venepuncture. This
      venous pseudoaneurysm was successfully treated with coil embolization.

PMID- 10396228
TI  - A complication following a total knee arthroplasty.

PMID- 10396229
TI  - Testing automatic exposure control devices used in diagnostic radiology.

PMID- 10396230
TI  - Routine use of CT prior to lumbar puncture.

PMID- 10396231
TI  - How to test for antineutrophil cytoplasmic antibodies--evidence based immunology?

PMID- 10396232
TI  - Gynaecological effects of tamoxifen.

PMID- 10396234
TI  - The effect of specimen processing delay on borate urine preservation.
AB  - AIM: To investigate the effect on urine culture results and their clinical
      interpretation of delaying the processing of urine samples in which boric acid
      had been used as a preservative. METHODS: 792 mid-stream specimens of urine from
      patients attending their general practitioner were received in borate containing
      plastic jars. The specimens were cultured upon receipt, stored at room
      temperature, and then recultured the following morning. RESULTS: After overnight
      delayed culture, the results were altered in 16% of samples and the clinical
      interpretation of these findings differed in 8% of specimens. In 28 samples
      (3.5%) the bacterium isolated on initial culture was not the same as that
      obtained by culture after overnight storage. CONCLUSIONS: Boric acid urine
      preservation used for overnight delayed processing of samples is associated with
      a significant alteration in culture results and the attendant clinical
      interpretation of such specimens. Rapid transportation/processing of urine
      specimens must remain the optimum procedure.

PMID- 10396233
TI  - Recent advances in antiviral therapy.
AB  - In the early 1980s many institutions in Britain were seriously considering
      whether there was a need for specialist departments of virology. The arrival of
      HIV changed that perception and since then virology and antiviral chemotherapy
      have become two very active areas of bio-medical research. Cloning and sequencing
      have provided tools to identify viral enzymes and have brought the day of the
      "designer drug" nearer to reality. At the other end of the spectrum of drug
      discovery, huge numbers of compounds for screening can now be generated by
      combinatorial chemistry. The impetus to find drugs effective against HIV has also
      stimulated research into novel treatments for other virus infections including
      herpesvirus, respiratory infections, and hepatitis B and C viruses. The need to
      understand the function of the immune system during HIV infection has brought
      virologists and immunologists together into new partnerships. The huge increase
      in activity in antiviral research is reflected in the frequency with which these
      drugs are now being licensed: in 1985 there were two licensed antiviral drugs for
      systemic use. Since then approximately 20 compounds have been licensed and more
      are being submitted to the regulatory authorities on a regular basis.

PMID- 10396235
TI  - The species specificity of the microimmunofluorescence antibody test and
      comparisons with a time resolved fluoroscopic immunoassay for measuring IgG
      antibodies against Chlamydia pneumoniae.
AB  - AIMS: To examine the species specificity of the microimmunofluorescence test
      (MIF) and assess a time resolved fluoroscopic immunoassay (TRIA) for measuring
      IgG antibodies to C pneumoniae. METHODS: Sera from 1020 subjects were tested by
      MIF for IgG, IgM, and IgA antibodies to C pneumoniae, C trachomatis, and C
      psittaci; 501 serum samples were also tested by TRIA for IgG antibodies to C
      pneumoniae. RESULTS: C pneumoniae antibody titres as measured by MIF were
      correlated with those for C psittaci and trachomatis. It was estimated that on
      average, one third of the twofold dilution steps that make up the final C
      pneumoniae antibody titre may be due to cross reacting genus specific antibody.
      The results of TRIA correlated well with those of MIF. In 75% of cases, the TRIA
      result predicted a three titre range within which the actual MIF result would
      fall. CONCLUSIONS: MIF does not appear to be as species specific as claimed. TRIA
      is unlikely to be as specific but as it is completely objective, easier to
      perform, amenable to automation, and gives reproducible results, it is a rapid
      and useful method for comparing populations.

PMID- 10396236
TI  - Detection of human papillomavirus DNA in urinary bladder carcinoma by in situ
      hybridisation.
AB  - AIMS: To investigate the sensitivity of an in situ hybridisation system to detect
      human papillomavirus (HPV) infection in transitional cell bladder cancer and to
      evaluate the advantages of analysing multiple biopsies; to examine the
      correlation between HPV tumour infection detected by in situ hybridisation and
      the presence of serum anti-HPV antibodies detected by enzyme linked immunosorbent
      assay (ELISA); and to relate the presence of viral infection to grade, stage, and
      follow up in cases of bladder cancer. METHODS: The in situ hybridisation
      technique was used with broad spectrum and type specific (6/11, 16/18, 31/33/35)
      probes against HPV DNA in formalin fixed, paraffin embedded tissues from 43 cases
      of bladder cancer. The results were analysed for the presence and type of
      papillomavirus and correlated with clinicopathological variables. RESULTS: The
      presence of HPV DNA was identified by the in situ hybridisation technique in 17
      of 43 cases of bladder cancer; 12 of these were serum antibody positive and 10
      had had multiple biopsies. Fifteen of the cases that were negative for HPV DNA by
      in situ hybridisation had positive serum serology when tested by ELISA. In 14
      cases, the HPV was either types 16/18 or types 31/33/35, both of which carry high
      oncogenic risk. The stage (p < 0.05) and grade (NS) of the tumour and the outcome
      on follow up (p < 0.05) were correlated with the presence of HPV infection.
      CONCLUSIONS: ELISA is not useful in identifying patients with HPV positive
      bladder cancer, but the use of several probes and multiple biopsies increases the
      detection rate of HPV in neoplastic tissues. The association between tumour virus
      infection and high grade/high stage tumours and worse outcome suggests that HPV
      infection of neoplastic tissue has a negative effect on the behaviour and
      evolution of transitional cell bladder carcinoma.

PMID- 10396237
TI  - Ki-67 labelling index and invasiveness among anterior pituitary adenomas:
      analysis of 103 cases using the MIB-1 monoclonal antibody.
AB  - AIMS: To investigate the relation between proliferative activity of anterior
      pituitary adenomas, quantified by the Ki-67 labelling index, and their invasive
      behaviour. METHODS: Expression of Ki-67 was evaluated in 103 anterior pituitary
      adenomas consecutively operated on in a 36 month period and correlated with
      surgical evidence of invasiveness. RESULTS: Non-invasive (n = 65) and invasive (n
      = 38) adenomas were identified from surgically verified infiltration of sellar
      floor dura and bone. The wall of the cavernous sinus was infiltrated in 16 cases.
      Forty one adenomas were non-functioning and 62 functioning (24 prolactin, 21
      growth hormone, 10 ACTH, seven mixed). The overall mean (SD) Ki-67 labelling
      index was 2.64 (3.69) per cent (median 1.5). The mean index was 3.08 (4.59) per
      cent in functioning and 1.97 (1.78) per cent in non-functioning tumours; 5.47
      (9.52) per cent in ACTH adenomas and 2.33 (2.42) per cent in others (p = 0.01);
      3.71 (5.17) per cent in invasive and 2.01 (2.45) per cent in non-invasive
      adenomas (p = 0.027); and 5.58 (7.24) per cent in cavernous sinus infiltrating v
      2.10 (2.39) per cent in cavernous sinus non-infiltrating adenomas (p = 0.0005).
      To identify a value of labelling index beyond which adenomas should be considered
      invasive and another beyond which cavernous sinus infiltration should be
      suspected, normality Q-Q plots were obtained: a threshold labelling index of 3.5%
      for invasive adenomas and of 5% for cavernous sinus infiltrating adenomas was
      defined, with statistically significant differences (p = 0.02 and p = 0.004,
      respectively). CONCLUSIONS: The Ki-67 labelling index can be considered a useful
      marker in determining the invasive behaviour of anterior pituitary adenomas.

PMID- 10396239
TI  - An assessment of the histological criteria used to diagnose infection in hip
      revision arthroplasty tissues.
AB  - AIM: To characterise the number and nature of the inflammatory cells seen in
      cases of septic or aseptic loosening of hip arthroplasty, and to establish
      reliable histological criteria to distinguish between these two conditions.
      METHODS: Histological examination of paraffin sections of periprosthetic tissues
      (pseudocapsule, femoral and acetabular pseudomembranes) of 523 cases of aseptic
      loosening and 79 cases of microbiology culture proven septic loosening. The
      cellular composition of the inflammatory cell infiltrate was determined
      semiquantitatively. RESULTS: The finding of a 2+ or greater neutrophil polymorph
      infiltrate (one or more cells per high power field (x400) on average after
      examination of 10 fields) in arthroplasty tissues correlated strongly with the
      microbiological diagnosis of septic loosening: diagnostic sensitivity 100%,
      specificity 97%, accuracy 99%, positive predictive value 92%, negative predictive
      value 100%. The finding of a 3+ neutrophil polymorph infiltrate (five or more
      cells on average per high power field) had a diagnostic sensitivity of 72%,
      specificity 100%, accuracy 98%, positive predictive value 100%, and negative
      predictive value 97%. In some cases of septic loosening the finding of a heavy
      lymphocytic and plasma cell infiltrate was of low diagnostic sensitivity. A
      neutrophil polymorph infiltrate (generally less than one cell per 10 high power
      fields) was also seen in cases of aseptic loosening. CONCLUSIONS: The presence of
      2+ or more (more than one neutrophil polymorph per high power field (x400) on
      average after examination of at least 10 high power fields) in periprosthetic
      tissues provides the most sensitive and accurate histopathological criterion for
      distinguishing between septic and aseptic loosening of hip arthroplasty.

PMID- 10396238
TI  - Relation of cervical glandular intraepithelial neoplasia to microinvasive and
      invasive adenocarcinoma of the uterine cervix: a study of 121 cases.
AB  - AIMS: To examine the relation between invasive adenocarcinoma and its alleged
      precursor, cervical glandular intraepithelial neoplasia (CGIN), and to assess the
      management and outcome of CGIN and the validity of using the term "microinvasive
      adenocarcinoma." METHODS: The clinical and pathological features of 121 cases of
      glandular neoplasia of the cervix diagnosed between the years 1990 to 1995 were
      examined for the following: histological diagnosis, smear records, type of
      treatment, the association between the precursor lesions and invasive disease,
      and follow up. RESULTS: 27 cases were identified as low grade CGIN (L-CGIN) and
      38 as high grade CGIN (H-CGIN), 10 as microinvasive adenocarcinoma (less than 5
      mm in depth), and 46 as invasive adenocarcinoma. The ratio of non-invasive to
      invasive disease was 1.12:1. The mean age of women was 39, 43, 43, and 48 years
      for L-CGIN, H-CGIN, microinvasive, and invasive adenocarcinoma, respectively. L
      CGIN was seen in 13% and 18% of H-CGIN and microinvasive disease, respectively. H
      CGIN was seen in 100% of microinvasive and 26% of invasive adenocarcinomas. The
      available smears before diagnosis predicted 59% of L-CGIN, 70% of H-CIGN, 100% of
      microinvasive adenocarcinoma, and 32% of invasive adenocarcinomas. Treatment of
      74% of L-CGIN, 52% of H-CIGN, and 10% of microinvasive adenocarcinoma was by
      diathermy loop excision only. The remaining cases had hysterectomy. Residual
      disease was found in 43%, 50%, and 33% of hysterectomies for L-CGIN, H-CGIN, and
      microinvasive adenocarcinoma, respectively. This is correlated with positive
      margins, or disease within 3 mm of margins on loop specimens. Cervical smear
      follow up for two to seven years revealed no recurrence of glandular lesions in
      any of the cases of CGIN or microinvasive adenocarcinoma. CONCLUSIONS: Precursor
      glandular lesions tend to progress to invasive carcinoma. There is a progressive
      increase in age of patients from L-CGIN to invasive disease, a span of
      approximately 10 years. There is a high association between H-CGIN and invasive
      disease. In the management of such alleged precursors, it is important to ensure
      adequate free margins of at least 3 mm. Microinvasive adenocarcinoma appears to
      have an excellent prognosis if treated by hysterectomy.

PMID- 10396240
TI  - Diagnostic value of classical and atypical antineutrophil cytoplasmic antibody
      (ANCA) immunofluorescence patterns.
AB  - BACKGROUND: The "classical" antineutrophil cytoplasmic antibody (C-ANCA) pattern
      seen on indirect immunofluorescence (IIF) is characterised by granular
      cytoplasmic staining showing central or interlobular accentuation, and is
      strongly associated with antiproteinase-3 antibodies (PR3-ANCA) and Wegener's
      granulomatosis. However, many laboratories report C-ANCA in the presence of any
      cytoplasmic IIF staining, regardless of pattern, which risks reducing the
      diagnostic value of this pattern. AIMS: To classify different cytoplasmic ANCA
      patterns and thus determine whether stringent application of the classical
      criteria for C-ANCA would produce better correlation between C-ANCA and (1) PR3
      ANCA enzyme linked immunosorbent assay (ELISA) results; (2) a diagnosis of
      systemic vasculitis (including Wegener's granulomatosis). METHODS: 72 sera with
      cytoplasmic IIF collected over a two year period were analysed by IIF and a
      commercial PR3-ANCA ELISA kit. RESULTS: Three IIF patterns were defined:
      "classical/true" C-ANCA as described above (n = 27 (37.5%)); "flat" ANCA with
      homogeneous cytoplasmic staining (n = 21 (29%)); and "atypical" ANCA which
      included all other cytoplasmic patterns (n = 24 (33.5%)). Twenty five of the 27
      true C-ANCA sera (92.5%) contained PR3-ANCA (p < 0.0001), but none of the 21 with
      flat ANCA and only one of the 24 with atypical ANCA. From clinical data on 23 of
      the 27 true C-ANCA positive patients, 20 (87%) had evidence of Wegener's
      granulomatosis or systemic vasculitis (p < 0.0001 v the other two patterns).
      However, none of 19 sera with flat ANCA and clinical data had evidence of
      systemic vasculitis. CONCLUSIONS: Restricting the term "c-ANCA" to the
      "classical" description of central/interlobular accentuation on IIF, will improve
      its correlation with PR3-ANCA positivity and a diagnosis of systemic vasculitis.

PMID- 10396241
TI  - A cytotoxic phenotype does not predict clinical outcome in anaplastic large cell
      lymphomas.
AB  - AIM: To investigate whether anaplastic large cell lymphomas (ALCL) expressing
      cytotoxic proteins have a relatively worse clinical outcome compared with ALCL
      lacking a cytotoxic phenotype. METHODS: 59 primary cases of ALCL originating from
      different sites were investigated by immunohistochemistry for the presence of the
      cytotoxic proteins T cell intracytoplasmic antigen (TIA-1) and granzyme B in the
      neoplastic cells. Since site of origin and expression of anaplastic lymphoma
      kinase (ALK) strongly influence prognosis, the presence of a cytotoxic phenotype
      was also investigated in relation to the primary site of origin (lymph node, gut,
      or skin) and ALK expression. The prognostic value was investigated by analysis of
      overall and relapse-free survival time, including Cox regression analysis.
      RESULTS: 39 of 59 ALCL (66%) appeared to have a cytotoxic phenotype as shown by
      expression of TIA-1 or granzyme B or both in the neoplastic cells. The presence
      of a cytotoxic phenotype did not have any influence on prognosis. Even when the
      survival data were corrected for site of origin and stage at presentation or were
      analysed separately for ALK positive and negative cases, no prognostic influence
      of a cytotoxic phenotype was observed. CONCLUSIONS: In primary biopsies of
      patients with ALCL, the presence of a cytotoxic phenotype is not related to
      clinical outcome of the disease.

PMID- 10396242
TI  - Sulphomucins favour adhesion of Helicobacter pylori to metaplastic gastric
      mucosa.
AB  - AIMS: To assess the influence of sulphomucin secretion on Helicobacter pylori
      colonisation and adhesion to metaplastic gastric cells. METHODS: Gastric biopsies
      from 230 H pylori positive patients with intestinal metaplasia were analysed.
      Sulphated mucins and H pylori were visualised using a new technique combining
      high iron diamine-alcian blue mucin stains with the Steiner silver stain for the
      bacteria. RESULTS: Sulphomucin secretion anywhere in the mucosa and a
      histological diagnosis of dysplasia increase the risk of H pylori adhesion to
      metaplastic cells (odds ratios 19.9 and 4.3, respectively). However, only 9.4% of
      cases showing sulphomucin secretion and 10.8% of cases with dysplasia had
      evidence of adhesion of H pylori bacteria to metaplastic cells. CONCLUSIONS: The
      findings suggest that H pylori may play a role in the advanced stages of
      carcinogenesis. It will be of interest to investigate if the relative small
      proportion of type III metaplasias that actually progress to carcinoma show
      persistence of H pylori.

PMID- 10396243
TI  - Use of alcohol fixed cytospins protected by 10% polyethylene glycol in
      immunocytology external quality assurance.
AB  - AIMS: To provide cytospins as a means of external quality assurance (EQA), while
      maintaining antigen expression integrity and achieving uniformity of material for
      all participating laboratories. METHODS: Cells were collected from two
      adenocarcinoma and one reactive pleural effusion specimens. Lymphoid cells were
      also collected through aspiration of a resected tonsil specimen. All cells were
      collected in Hanks balanced salt solution (HBSS); cytospins were made and fixed
      in methanol or acetone alone or protected using a layer of 10% polyethylene
      glycol (PEG) in 50% methanol. Two laboratories participated (RGHT and UCL).
      RESULTS: Cytokeratin expression detected using either CAM5.2 or AE1/AE3
      antibodies was sensitive to temperature. Without PEG, unacceptable or negative
      staining was seen within six weeks of preparation. LCA was not sensitive to
      temperature, with good staining scores being achieved after eight weeks following
      preparation. CONCLUSIONS: It is possible to send alcohol fixed, air dried
      cytospins to laboratories participating as part of an EQA scheme for
      immunocytology. Some antigens will require protection from temperature variations
      during transit. A layer of 10% PEG in 50% methanol, allowed to air dry, is
      suitable for this purpose. Participating laboratories will only have to remove
      this layer using methanol before their localisation technique for assessment.

PMID- 10396244
TI  - Calcium oxalate crystals (Weddellite) within the secretions of ductal carcinoma
      in situ--a rare phenomenon.
AB  - A case is described in which calcium oxalate (Weddellite) crystals were
      identified in an area of ductal carcinoma in situ of the breast. Seventy other
      cases were examined but no evidence of Weddellite was detected. This is evidently
      a rare phenomenon in carcinoma in situ.

PMID- 10396245
TI  - Metastatic endometrial stromal sarcoma masquerading as pulmonary
      lymphangioleiomyomatosis.
AB  - A 39 year old female presented with bilateral pneumothoraces and interstitial
      shadowing on chest x ray. A diagnosis of lymphangioleiomyomatosis was made
      following an open lung biopsy. Over the next eight years she developed
      respiratory failure leading to single lung transplantation but she died in the
      immediate postoperative period. Necropsy examination and review of the previous
      open lung biopsy revealed multiple pulmonary metastases from a low grade
      endometrial stromal sarcoma of the uterus. This case high-lights the importance
      of an accurate diagnosis before transplantation.

PMID- 10396246
TI  - A comparison of three methods of orienting cervical punch biopsies.
AB  - AIMS: To compare methods of orienting cervical punch biopsies, since well
      oriented biopsies are needed to optimise the diagnosis and grading of cervical
      intraepithelial neoplasia. METHODS: The orientation, the presence and
      preservation of the squamocolumnar junction, and the presence or absence of the
      surface layers of the squamous epithelium were compared in 345 cervical biopsies
      that had either been attached to paper (n = 112), floated directly into 10%
      formalin (n = 107), or floated into a solution of 10% formalin including 0.05%
      eosin (n = 126) in the colposcopy clinic. RESULTS: When the specimens were
      mounted on filter paper before fixation, they were more likely to be optimally
      oriented, to have a preserved squamocolumnar junction, and to have intact surface
      epithelium than specimens that were handled using the other methods, even when
      the specimens floated off the paper in transit. CONCLUSIONS: Cervical biopsy
      specimens should be mounted on paper before fixation and submission to the
      laboratory.

PMID- 10396247
TI  - Adrenocortical oncocytoma.
AB  - The histopathology and ultrastructural features of an adrenocortical oncocytoma
      are reported. The tumour was discovered incidentally during investigation for
      hypertension in a 72 year old female. Oncocytic tumours of the adrenal cortex are
      rare, with only 20 examples described in English language reports. Most have been
      non-functioning and benign, like the present example. Molecular studies may help
      assess the significance of oncocytic change in the pathogenesis and behaviour of
      oncocytic neoplasms.

PMID- 10396248
TI  - Trained nurses can obtain satisfactory bone marrow aspirates and trephine
      biopsies.
AB  - AIMS: To assess the feasibility of training nurse practitioners to perform bone
      marrow aspiration and trephine biopsy, and to compare the quality of these
      samples with those obtained by medical staff. METHODS: A retrospective audit was
      undertaken of nurse practitioner and medical staff performance in bone marrow
      procedures in a busy haematology day unit. RESULTS: Nurse practitioners fared
      favourably in comparison with medical staff in performing bone marrow trephine
      biopsies, with mean biopsy lengths of 11 mm and 10.7 mm respectively. However,
      only 78% of the smears obtained by the nurses were judged technically
      satisfactory, compared with 91% prepared by doctors. This discrepancy was thought
      to be due largely to the quality of slide spreading. CONCLUSIONS: With motivated
      staff and a structured educational and training programme it is possible for
      nurse practitioners to perform the techniques of bone marrow aspiration and
      biopsy, and obtain specimens of satisfactory quality, thus improving efficiency
      of the haematology day unit and increasing quality of patient care.

PMID- 10396249
TI  - Hypokalaemic paralysis revealing Sjogren syndrome in an elderly man.
AB  - A 73 year old white man presented with life threatening hypokalaemic paralysis
      requiring admission to an intensive care unit. Biochemical investigations showed
      severe hypokalaemia with hyperchloraemic metabolic acidosis, a spot urine pH of
      6.5, and a positive urinary anion gap, establishing the diagnosis of distal renal
      tubular acidosis. Autoimmune tests revealed Sjogren syndrome as the underlying
      cause of the distal renal tubular acidosis. Full recovery followed potassium and
      alkali replacement. This dramatic presentation of Sjogren syndrome has not
      previously been reported in an elderly man.

PMID- 10396250
TI  - Tuberculosis and the poverty-disease cycle.

PMID- 10396251
TI  - Artificial intelligence for clinicians.

PMID- 10396252
TI  - Drug abusers who die during arrest or in custody.

PMID- 10396253
TI  - Reducing non-attendance at outpatient clinics.
AB  - Outpatient non-attendance is a common source of inefficiency in a health service,
      wasting time and resources and potentially lengthening waiting lists. A
      prospective audit of plastic surgery outpatient clinics was conducted during the
      six months from January to June 1997, to determine the clinical and demographic
      profile of non-attenders. Of 6095 appointments 16% were not kept. Using the
      demographic information, we changed our follow-up guidelines to reflect risk
      factors for multiple non-attendances, and a self-referral clinic was introduced
      to replace routine follow-up for high risk non-attenders. After these changes, a
      second audit in the same six months of 1998 revealed a non-attendance rate of 11%
      -i.e. 30% lower than before. Many follow-up appointments are sent inappropriately
      to patients who do not want further attention. This study, indicating how risk
      factor analysis can identify a group of patients who are unlikely to attend again
      after one missed appointment, may be a useful model for the reduction of
      outpatient non-attendance in other specialties.

PMID- 10396254
TI  - Artificial neural networks: a potential role in osteoporosis.
AB  - Artificial neural networks are computer software systems that recognize patterns
      in complex data sets. A recent development in neural computing, multiversion
      systems (MVS), has led to enhanced analytical power, and this was harnessed to
      demonstrate the value of risk factors in predicting the result of osteoporosis
      investigations by quantitative ultrasound. 274 women were screened in an open
      access osteoporosis service. A conventional risk factor questionnaire was
      completed for each patient by the osteoporosis specialist nurse. An MVS was
      trained on 180 randomly selected data sets and tested on the remaining 94. The
      results were compared with those from logistic regression analysis in predictive
      power, both from the selected 20-item questionnaire and for a limited 5-item
      questionnaire comprising age, height, height loss, weight and years since the
      menopause. The MVS approach predicted the T-score categorization of the patients
      from the 20-item questionnaire with 83.0% accuracy, whereas logistic regression
      yielded an accuracy of only 72.8% (P = 0.04). From the 5-item database the MVS
      yielded a best prediction accuracy of 73.1%, whereas the logistic regression
      prediction accuracy was 60% (P = 0.04). These results suggest that 20 risk
      factors can be used by an MVS to predict the outcome of osteoporosis
      investigations with a power that outperforms conventional statistical methods.
      Use of this system may improve the selection of patients for osteoporosis
      investigations, since even with only 5 risk factors the system performs nearly as
      well as that based on the full 20 factors.

PMID- 10396256
TI  - Where do UK health services researchers publish their findings?
AB  - Health services research has emerged as the third vital requirement for
      understanding and improving health care, alongside basic science and clinical
      research. This has coincided with more stringent management of research, in
      particular by funding bodies. The latter are seeking to use bibliographic
      databases to aid the monitoring of the output of their investments. The principal
      source of data in the UK is the Research Outputs Database (ROD) set up by the
      Wellcome Trust primarily to monitor basic and clinical research. Health services
      researchers' output is difficult to monitor in view of the large number and wide
      variety of journals in which they publish. In addition, nearly half the journals
      (representing 35% of the articles) are not currently covered by the ROD. Funding
      bodies will underestimate the quantity of health services researchers' output
      unless they take these findings into account.

PMID- 10396255
TI  - Misuse of correlation and regression in three medical journals.
AB  - Errors relating to the use of the correlation coefficient and bivariate linear
      regression are often to be found in medical publications. This paper reports a
      literature search to define the problems. All the papers and letters published in
      the British Medical Journal, The Lancet and the New England Journal of Medicine
      during 1997 were screened for examples. Fifteen categories of errors were
      identified of which eight were important or common. These included: failure to
      define clearly the relevant sample number; the display of potentially misleading
      scatterplots; attachment of unwarranted importance to significance levels; and
      the omission of confidence intervals for correlation coefficients and around
      regression lines.

PMID- 10396258
TI  - Trauma care and the pitfalls of diaphragmatic rupture.

PMID- 10396257
TI  - Issues of consent in colonoscopy: if a patient says 'stop' should we continue?
AB  - Colonoscopy is generally performed under intravenous sedation, which may alter a
      patient's responses and perception. What should be done if, during the procedure,
      a patient withdraws the consent previously given? The views of
      gastroenterologists and patients were ascertained by mailing questionnaires to
      100 members of the British Society of Gastroenterology and to 100 patients who
      had undergone colonoscopy with intravenous sedation. Only 1 of 59 eligible
      consultants who replied said they would stop the procedure after a single
      request, but a further 51 would stop if repeatedly asked to do so. Of the
      remaining 7 who would complete the procedure, 1 nevertheless believed that a
      sedated patient is capable of making a rational decision. Of the 51 patients who
      returned a usable questionnaire, 25 thought that the procedure should be stopped
      immediately following a request, while 26 felt that the doctor should continue.
      The divergent and sometimes inconsistent views found in this study highlighted
      the need for further clarification of the issue of informed consent for
      procedures conducted with the patient under sedation.

PMID- 10396259
TI  - Small-bowel adhesions long after blast injury.

PMID- 10396260
TI  - Lymphoedema and Crohn's disease.

PMID- 10396262
TI  - Senile squalor syndrome: two unusual cases.

PMID- 10396261
TI  - Metastases or mesothelioma?

PMID- 10396263
TI  - Life-threatening Capnocytophaga canimorsus infection after dog bite.

PMID- 10396264
TI  - The National Health Service: doctors and society beyond 2000.

PMID- 10396265
TI  - Post-traumatic stress disorder.

PMID- 10396266
TI  - Post-traumatic stress disorder.

PMID- 10396267
TI  - Complementary medicine.

PMID- 10396268
TI  - Complementary medicine.

PMID- 10396269
TI  - Stigma in mental illness.

PMID- 10396270
TI  - Telespirometry for home monitoring of pulmonary function.

PMID- 10396271
TI  - Renal carcinoma with acute mastoiditis.

PMID- 10396272
TI  - Lost ear wicks.

PMID- 10396273
TI  - Five-minute neurology.

PMID- 10396274
TI  - Methylphenidate role in Tourette syndrome prevalence.

PMID- 10396275
TI  - Psychopharmacology and the human condition.

PMID- 10396276
TI  - Antioxidants in wine and tea.

PMID- 10396277
TI  - Specialist palliative care and general practice.

PMID- 10396278
TI  - Ethics of human reproductive cloning.

PMID- 10396279
TI  - Statin therapy in nephrotic syndrome.

PMID- 10396280
TI  - Are we failing in molecular genetic testing?

PMID- 10396281
TI  - Frequency of problems during clinical molecular-genetic testing.
AB  - Concerns have been raised about the quality of DNA-based genetic testing, but few
      data are available on the problems that occur during clinical genetic testing. We
      sought to determine the frequency and severity of such problems in US
      laboratories. Problems were defined as events that could or did impair patient
      care significantly. Data on the frequency and severity of adverse events during
      genetic testing were collected from laboratories by anonymous mail questionnaire
      and detailed on-site inspection. The surveyed laboratories (n = 42) reported
      significant problems in 0.33% of tests performed; the corresponding value in the
      inspected laboratories (n = 2) was 0.38%. Sixty percent of problems occurred in
      the pretest phase, 32% in the laboratory phase, and 8% in the posttest phase or
      multiple phases. The average level of actual harm resulting from these problems
      was low. Moderate or high levels of harm occurred in only 0.008% of total cases.
      No lawsuits, judgments, or disciplinary actions were taken against the
      laboratories in 277,000 tests performed. The overall frequency of problems in a
      given laboratory did not correlate with laboratory age, test volume,
      accreditation status, proficiency testing performance, or institution type
      (academic, private nonprofit, private for profit). In conclusion, significant
      problems during genetic testing occur infrequently (< 0.5% in most laboratories),
      and problems resulting in moderate or high levels of harm to patients are rare
      (0.008%).

PMID- 10396282
TI  - Evaluation of Sysmex UF-100 urine flow cytometer vs chamber counting of
      supravitally stained specimens and conventional bacterial cultures.
AB  - We evaluated the Sysmex UF-100 urine flow cytometer (TOA Medical Electronics,
      Kobe, Japan) with 269 uncentrifuged urine specimens by comparing it with
      Sternheimer staining and particle counting in 1-microL disposable chambers with
      both brightfield and phase-contrast microscopy (the reference method). Results of
      routine test strip analysis, sediment microscopy (182 specimens), and bacterial
      culture (204 specimens) were also available. Detection of urinary WBCs and RBCs
      was highly reliable with the UF-100 compared with manual chamber counting (r =
      .98 and .88, respectively). Identification of bacteria was equal to that with
      visual microscopy of uncentrifuged specimens; sensitivity was 55%, and
      specificity 90%, compared with bacterial cultures at a cutoff of > 10(3) colony
      forming units per milliliter. Renal damage was difficult to evaluate even with
      manual methods because of the low counts of renal tubular cells and casts; with
      standard manual Sternheimer-stained sediment analysis, sensitivity was 65% to 69%
      and specificity 66% to 91%, compared with the uncentrifuged chamber method at a
      cutoff of 3 and 10 particles per microliter, respectively. Renal damage was
      demonstrated with the UF-100 with a sensitivity of 26% to 69% and specificity 92%
      to 94%, compared with chamber counts. Automated urinalysis with the UF-100 urine
      flow cytometer offers considerable savings in time and labor. When high
      sensitivity is needed, visual microscopic review should be performed to detect
      renal disease.

PMID- 10396283
TI  - Use of polymerase chain reaction for citrate synthase gene to diagnose Bartonella
      quintana endocarditis.
AB  - We describe aortic valve endocarditis caused by Bartonella quintana in a 31-year
      old man. The diagnosis was made on the basis of polymerase chain reaction
      amplification of the B quintana citrate synthase gene from cardiac valve tissue,
      the compatibility of histochemical stains of cardiac valve tissue, and serologic
      studies.

PMID- 10396284
TI  - Absence of SYT-SSX fusion products in soft tissue tumors other than synovial
      sarcoma.
AB  - The chromosomal translocation t(X;18), which generates SYT-SSX1 and SYT-SSX2
      fusion products, is a sensitive marker for synovial sarcoma; most synovial
      sarcomas test positive for this marker. However, few studies have addressed the
      presence of t(X;18) or its fusion products in spindle cell sarcomas in the
      differential diagnosis of synovial sarcoma. We studied the presence of the SYT
      SSX fusion products with reverse transcriptase polymerase chain reaction on
      frozen tissue samples of 24 synovial sarcomas and 24 other spindle cell sarcomas,
      including 12 malignant peripheral nerve sheath tumors. In cases
      histopathologically diagnosed as synovial sarcoma, SYT-SSX fusion products were
      detected in 21 of 24 (87%) lesions. No evidence of these fusions was found in 12
      malignant peripheral nerve sheath tumors, 2 hemangiopericytomas, 3
      leiomyosarcomas, 2 fibrosarcomas, 1 poorly differentiated sarcoma (malignant
      fibrous histiocytoma), 1 sarcoma with rhabdoid features, and 2 sarcomas not
      otherwise specified. One lesion with histologic, immunohistologic, and
      ultrastructural features indeterminate for a diagnosis of synovial sarcoma or
      malignant peripheral nerve sheath tumor was studied and was positive for SYT
      SSX1. The SYT-SSX fusion products appear specific for synovial sarcoma and are
      not seen in other spindle cell lesions in its differential diagnosis.

PMID- 10396286
TI  - Long-term outcome and relative risk in women with atypical squamous cells of
      undetermined significance.
AB  - Few studies have compared long-term follow-up and risk for invasive cancer in
      women with atypical squamous cells of undetermined significance (ASCUS). We
      conducted a 6-year review of pathology files for 651 women in whom ASCUS had been
      diagnosed in 1992. Data collected included patient demographics, follow-up
      diagnoses, time between follow-up examinations, and procedures performed. At
      follow-up, high-grade squamous intraepithelial lesions (HSIL) had developed in
      9.0% of the women, and invasive cancer in none. Previous cervical history did not
      affect risk for an HSIL. Although the average time to first follow-up was 6.18
      months, in 20.9% of the women the diagnosis of HSIL was not established until
      after 2.0 years. For individual pathologists, the percentage of HSILs ranged from
      0% to 18.8%. Thus women with ASCUS who are followed up regularly are at low risk
      for development of invasive cancer.

PMID- 10396285
TI  - Estrogen and progesterone receptor contents in ThinPrep-processed fine-needle
      aspirates of breast.
AB  - This study was undertaken to assess the potential value of ThinPrep-processed
      (Cytyc, Boxborough, MA) smears from malignant breast fine-needle aspirates (FNAs)
      for the determination of estrogen receptor (ER) and progesterone receptor (PR)
      status. The ER and PR content of 142 malignant FNAs were compared with the
      results of the surgically excised tumors in which the assay was done by enzyme
      immunoassay in 97 cases or by immunohistochemistry in 45 cases. Monoclonal
      antibodies directed against ER-1D5 (Dako, Carpinteria, CA) and PR-1A6 (Dako) were
      used with the antigen retrieval technique. By using enzyme immunoassay and
      immunohistochemistry as standards, the overall accuracy for ER was 97% and for PR
      was 89%. The results of this study show that the ThinPrep smear with microwave
      antigen retrieval pretreatment is a reliable method and a suitable alternative
      for hormone receptor analysis in breast carcinoma.

PMID- 10396287
TI  - Granulomatous myositis. Clinicopathologic study of 12 cases.
AB  - Granulomatous inflammation is infrequently encountered in skeletal muscle biopsy
      material. Of 2,985 muscle biopsy specimens reviewed over 12 years, 12 (0.4%) with
      granulomatous inflammation were identified. The patients included 9 women who
      ranged in age from 24 to 76 years (mean 50.3 years). The most common clinical
      findings included decreased strength or weakness in the extremities (n = 8),
      muscle pain (n = 5), and weight loss (n = 3). All muscles exhibited
      nonnecrotizing granulomas; an associated vasculitic process was identified in 2.
      Endomysial chronic inflammation consisting primarily of lymphocytes and plasma
      cells was present in 10 muscles, and perivascular chronic inflammation in 8.
      Degenerating muscle fibers were noted in 10 cases, and regenerating fibers in 11.
      Evidence of neurogenic atrophy was seen in 8 muscles. Increased endomysial
      fibrosis was observed in 5 muscles, and type II muscle fiber atrophy in 5
      muscles. Stains for acid-fast bacilli and Gomori methenamine silver stain were
      performed in all but 2 cases and failed to demonstrate organisms. In 3 cases,
      concomitant sural nerve biopsies were performed, and granulomas were identified
      in 2 of those cases. Clinicopathologic diagnoses included sarcoidosis (n = 6),
      vasculitis (n = 2), and granulomatous myositis not otherwise specified (n = 2).
      In 2 cases, there was insufficient clinical information or follow-up data to
      determine a cause. In conclusion, granulomatous myositis is infrequently found in
      muscle biopsy specimens (0.5% of all biopsies in this series); most muscles
      demonstrate evidence of chronic endomysial or perivascular inflammation
      accompanied by muscle fiber degeneration and regeneration; and the most common
      cause for granulomatous myositis was sarcoidosis in this series.

PMID- 10396288
TI  - Cytokeratin 34 beta E-12 immunoreactivity in benign prostatic acini.
      Quantitation, pattern assessment, and electron microscopic study.
AB  - Because of the widespread use of keratin 34 beta E-12 to assist in the
      distinction between benign acini and malignant glands, the lack of
      immunoreactivity of benign prostatic acini are important issues. We studied
      midprostate whole-mount sections from 21 low-volume adenocarcinoma radical
      prostatectomy specimens with keratin 34 beta E-12. We marked out benign 0.25-cm2
      areas in the peripheral and transition zones and counted the number of small
      acini immunoreactive with keratin 34 beta E-12 to a total of 50 acini within each
      area. Small benign acini from nonatrophic peripheral zone lobules of 3 prostate
      specimens were examined by electron microscopy. The median number of
      immunoreactive acini in each region was 49. The nonreactive acini were always the
      most peripheral acini in a lobule, a small cluster of outpouched acini furthest
      from a large duct, or the terminal end of a large duct. More proximal acini had a
      discontinuous pattern of immunoreactivity. Electron microscopy showed occasional
      acini with luminal cells abutting the basement membrane, without the
      interposition of basal cell cytoplasm, and other acini with extremely attenuated
      basal cell cytoplasmic processes containing sparse bundles of intermediate
      filaments. The basal cell layer becomes attenuated toward the periphery of some
      lobules and duct outpouchings, producing nonreactive acini adjacent to
      discontinuously reactive acini.

PMID- 10396289
TI  - Role of immunohistochemistry in differentiating epithelial mesothelioma from
      adenocarcinoma. Review and update.

PMID- 10396290
TI  - Clonality analysis using X-chromosome inactivation at the human androgen receptor
      gene (Humara). Evaluation of large cohorts of patients with chronic
      myeloproliferative diseases, secondary neutrophilia, and reactive thrombocytosis.
AB  - Chronic myeloproliferative diseases (MPDs) are not associated with consistent
      cytogenetic or molecular abnormalities. Demonstration of clonal cell growth by
      analysis of X-chromosome inactivation (XCI) patterns in females provides a
      promising tool for diagnosis. However, this technique can be complicated by
      excessive lyonization of normal cells mimicking clonal cell growth: We analyzed
      XCI patterns at the human androgen receptor (HUMARA) locus in 146 healthy
      females, 65 women with secondary neutrophilia, 31 women with reactive
      thrombocytosis, and 86 women with chronic MPDs. A skewed XCI pattern with greater
      than 75% amplification of 1 allele (allele ratio > 3:1) was found in 22 (9.1%) of
      242 control subjects. The incidence of skewing was statistically significantly
      lower in women younger than 30 years (2/73) compared with women older than 60
      years (10/53). Of 86 patients with a chronic MPD, 71 (82%) exhibited an allele
      ratio greater than 3:1, whereas only 10 (12%) of 86 age-matched control subjects
      showed a skewed XCI pattern. Although statistical evaluation of the data showed a
      significant difference between patients with a chronic MPD and control subjects,
      proof of clonality in individual, especially elderly, patients is difficult.

PMID- 10396291
TI  - Bcl-6 protein expression by follicle center lymphomas. A marker for
      differentiating follicle center lymphomas from other low-grade
      lymphoproliferative disorders.
AB  - Low-grade lymphoproliferative disorders are a heterogeneous group of lymphoid
      neoplasms with wide variation in histologic features, immunologic phenotype, and
      molecular abnormalities. Subclassification of these disorders with small
      lymphocytic proliferation may be difficult on the basis of morphologic findings
      alone. The bcl-6 gene, originally cloned from a tumor with 3q27 translocation, is
      commonly expressed in large cell lymphomas. In humans, bcl-6 encodes for a
      Kruppel-type zinc finger protein and is believed to be important in germinal
      center formation. Bcl-6 protein is expressed mainly by follicle center cells and
      a few interfollicular T lymphocytes. We analyzed Bcl-6 expression with
      immunologic methods in common low-grade lymphoproliferative disorders as an aid
      to differentiation of tumors with follicle center origin. We analyzed Bcl-6
      staining of formalin-fixed paraffin-embedded tissue from 72 indolent lymphomas
      including 31 grade I and II follicle center lymphomas (FCL). 13 small lymphocytic
      lymphomas (SLL), 12 mantle cell lymphomas (MCL), and 16 marginal zone lymphomas
      (MZL) including lymphomas of mucosa-associated lymphoid tissue and spleen. All of
      31 FCL were positive for Bcl-6 expression. One of 13 SLL and 1 of 12 MCL were
      positive, whereas none of 16 MZL were positive. Bcl-6 was also detected in 5 of 5
      FCL and 1 of 3 MZL but in no SLL or MCL by Western blot analysis in 14 cases with
      lymphoid disorders. Our study demonstrates that Bcl-6 expression is common in low
      grade FCL but is rare in other indolent B-cell lymphoid disorders, and may be a
      useful adjunct in classification of indolent lymphomas.

PMID- 10396292
TI  - Cytomegalovirus-infected cells in routinely prepared peripheral blood films of
      immunosuppressed patients.
AB  - We describe 4 patients identified over 5 years with large atypical cells on the
      feathered edge of routinely prepared peripheral blood films. Films were reviewed
      either as part of a blood film consultation or a bone marrow examination. The
      cells were 50 to 60 microns in diameter, with granular eosinophilic cytoplasmic
      inclusions and eccentric enlarged nuclei. Additional studies including buffy coat
      preparations and immunohistochemistry revealed that these were circulating
      cytomegalovirus (CMV)-infected cells, most likely of endothelial origin. All
      patients were immunocompromised (3 had HIV infection, and 1 was an organ
      transplant recipient) and had clinical evidence of CMV infection. The unique
      appearance of these cells at Wright-Giemsa staining, and their possible
      misidentification as malignant cells or other cells, highlights the need for
      pathologists to be aware of their morphologic features and possible clinical
      implication.

PMID- 10396293
TI  - Acute promyelocytic leukemia with additional chromosomal abnormalities and
      absence of Auer rods.
AB  - We report 4 acute promyelocytic leukemia cases that demonstrated karyotypic
      abnormalities in addition to the classic t(15;17) translocation and did not
      contain any Auer rods in leukemic blasts and dysplastic promyelocytes, either in
      the peripheral blood or in the bone marrow. Morphologically, 2 cases were
      characterized as the common or hypergranular type, and 2 were otherwise typical
      of the microgranular variant. Three patients had typical clinical and laboratory
      signs of disseminated intravascular coagulation. Immunophenotypic analysis of the
      blasts and dysplastic promyelocytes by dual-color flow cytometry revealed an
      immunoprofile consistent with acute promyelocytic leukemia. Cytogenetic analysis
      of the bone marrow revealed the following karyotypes: case 1,
      [47,XY,t(15;17)(q22;q12),+21]; case 2, [47,XY,t(15;17)(q22;q12),-16,+2 mar]; case
      3, [47,XX,t(15;17)(q22;q12)ider(17)(q10),+8]; and case 4,
      [47,XY,der(5)t(5;?9)(p15;q12).t(15;17)(q22;q12]. Review of an additional 7 cases
      with t(15;17) as the sole cytogenetic abnormality revealed Auer rods in all
      cases. Our findings emphasize the importance of cytogenetics in evaluating acute
      myeloid leukemias. Acute promyelocytic leukemia without Auer rods, which may be
      morphologically confused with other types of leukemia (in particular, acute
      myeloblastic leukemia, type M2 or M5) or agranulocytosis with maturation arrest,
      appears to be associated with additional chromosomal abnormalities and possibly a
      poorer prognosis.

PMID- 10396294
TI  - Myeloperoxidase detection by three-color flow cytometry in acute lymphoblastic
      leukemia.

PMID- 10396295
TI  - Frozen section? Just do it.

PMID- 10396296
TI  - Economic, regulatory, and practice issues in molecular pathology and diagnostics.
AB  - This issue of Pathology Patterns presents a series of review articles in
      molecular pathology and molecular diagnostics that cover a wide variety of
      applications of new technologies recently integrated into many clinical
      laboratories and pathology departments. In order for the benefits of molecular
      pathology to outweigh its inherent costs, these new procedures must be integrated
      into the assessment of total disease management to fully observe how the benefits
      outweigh the costs and effects on patient outcome. Major financial benefits can
      be achieved with molecular testing because of ability to reduce the use of less
      sensitive and specific tests, and unnecessary diagnostic procedures and
      ineffective therapies.

PMID- 10396297
TI  - DNA in situ hybridization as an adjunct in tumor diagnosis.
AB  - DNA in situ hybridization (ISH) methods, particularly fluorescence in situ
      hybridization, have gained broad acceptance in the clinical cytogenetic and
      research communities, but are used less frequently by noncytogenetic diagnostic
      pathology services. This review discusses tumor-related ISH, including the
      advantages and limitations of enzymatic detection ("insituhistochemistry"). The
      ISH applications are categorized with respect to diagnostic capabilities, ease of
      use, and cost.

PMID- 10396298
TI  - Molecular testing for inherited diseases.
AB  - Technological advances in molecular biology, coupled with the Human Genome
      Project, has led to the isolation and characterization of thousands of human
      genes. Subsequently, many of these discoveries have been promptly translated into
      clinical assays by DNA laboratories for immediate patient evaluation and
      management. Since a variety of mutation detection techniques exist, the technique
      most appropriate for clinical testing of a particular disease is determined by:
      both the type and number of different mutations associated with the disease; the
      frequency of referrals; and the required turn-around time for appropriate patient
      management. This review discusses some of the more commonly inherited diseases
      for which molecular testing is available. It describes and illustrates the
      techniques used for direct mutation analysis of expanded trinucleotide repeats,
      point mutations, deletions, gene rearrangements, uniparental disomy, and linkage
      analysis.

PMID- 10396299
TI  - Molecular diagnostics for existing and emerging infections. Complementary tools
      for a new era of clinical microbiology.
AB  - Diagnostic molecular methods have had a large effect on diagnosis and management
      of infectious diseases. These tools have been developed in response to diagnostic
      methods that lack sensitivity, specificity, or rapid turnaround time, to assist
      with identification of agents that are difficult to cultivate or classify or as
      methods for assessing the effects of antiviral or antimicrobial agents in chronic
      infection. Molecular methods have also enabled microbiologists to define disease
      by the presence of virulence, toxin, or antimicrobial resistance genes and to
      identify potentially important clones of organisms responsible for outbreaks of
      infection. Early outcome-based studies suggest that molecular methods may provide
      substantial reductions in per patient costs. Nucleic acid diagnostic methods will
      continue to be used in infectious disease and microbiology, and increasingly
      appear to be complementary tools with important diagnostic, patient management,
      and health care cost benefits for the laboratory and health care systems.

PMID- 10396300
TI  - Abnormal cell cycle regulation in malignancy.
AB  - The cell cycle consists of an initial growth phase (G1), DNA replication (S), a
      gap phase (G2), and mitosis (M), after which the cell may differentiate or enter
      the resting state (G0). The cycle is driven by a number of positive and negative
      regulatory phosphorylation and dephosphorylation events, involving protein
      kinases, protein phosphatases, cyclins, cyclin-dependent kinases, and cyclin
      dependent kinase inhibitors, that ultimately impinge on the activity of
      transcription factors. Unreplicated or damaged DNA blocks the progression of the
      cell cycle at checkpoints, including a late G1 checkpoint regulated by the
      dephosphorylated retinoblastoma protein and a late G2 checkpoint regulated by the
      phosphorylation of cyclin-dependent kinase 1 complexed with cyclin B. Many cell
      cycle regulator genes may be considered proto-oncogenes or tumor suppressor
      genes, and point mutations, amplifications, deletions, or rearrangements
      involving their loci, particularly those in the "RB pathway," are associated with
      various tumors. A number of molecular techniques may be used to detect genomic
      alterations or posttranscriptional modifications, but immunohistochemistry
      remains the most common method to determine expression levels of a regulatory
      protein. Multivariate analysis of the usefulness in prognosis has been applied
      most often for the general proliferation antigen Ki-67.

PMID- 10396301
TI  - HER-2/neu (c-erb-B2) gene and protein in breast cancer.
AB  - The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with
      extensive homology to the epidermal growth factor receptor. The association of
      HER-2/neu gene and protein abnormalities with prognosis in breast cancer is
      presented by considering a series of 52 published studies including more than
      16,000 patients. The relative advantages and disadvantages of Southern blot
      testing, polymerase chain reaction amplification, and fluorescence in situ
      hybridization assays designed to detect HER-2/neu gene amplification are compared
      with HER-2/neu protein overexpression assays performed with immunohistochemical
      techniques applied to frozen and paraffin-embedded tissues and enzyme
      immunoassays performed on tumor cytosols. The importance of HER-2/neu protein
      overexpression in ductal carcinoma in situ, and HER-2/neu protein status in
      uncommon breast diseases in female patients and breast cancer in male patients
      are also considered. The potential value of HER-2/neu protein status for the
      prediction of response to therapy in breast cancer is presented for standard
      hormonal therapy, cytotoxic chemotherapy, and radiation therapy. Also evaluated
      is the status of serum-based testing for circulating HER-2/neu receptor protein
      and its ability to predict disease outcome and therapy response. Finally,
      preliminary data concerning use of antibody-based therapies directed against HER
      2/neu protein and their potential use in breast cancer treatment are considered.

PMID- 10396302
TI  - Telomerase activity in human solid tumors. Diagnostic utility and clinical
      applications.
AB  - Telomerase is expressed in almost all human malignant processes but not in benign
      and normal tissues, with the exception of germline and stem cells. Because of its
      prevalent expression and potential as a target for cancer therapy, telomerase is
      the subject of intense investigation, and numerous papers have been published. We
      present the most recent findings on the association between telomerase activity
      and human malignancies, recent developments in methods of telomerase detection,
      telomerase utility in monitoring of patients with cancer for residual or
      recurrent disease, and potential usefulness of telomerase in treatment of cancer.

PMID- 10396303
TI  - Molecular pathology of leukemia and lymphoma.
AB  - Molecular dissection of physiologic and pathologic genetic phenomena in
      hematologic malignancy has provided the pathologist with a broad menu of new
      assays. By integrating the data gleaned from these techniques we can formulate
      more rational and biologically based diagnoses, which should lead to the ultimate
      goal of targeted therapy for these specific entities. We summarize some of the
      more relevant molecular genetic assays and present an overview of those genetic
      mechanisms usually evaluated in the current practice of hematopathology. The
      usefulness of such assays extends beyond refining diagnoses in that they also
      provide relevant prognostic information. Moreover, since most are based on the
      polymerase chain reaction and reverse transcriptase polymerase chain reaction, we
      are more sensitively able to monitor for residual disease after attempts at
      curative therapy, and our definition of remission has been dramatically altered.
      However, molecular genetic tests are not without limitations, and we must remain
      cognizant of their cost effectiveness and be aware of current deficiencies in
      standardization. The challenge will be to meaningfully and economically harness
      and integrate the information we obtain from these and future technologies into
      appropriate clinical practice.

PMID- 10396304
TI  - Applications of forensic identity testing in the clinical laboratory.
AB  - DNA analysis is becoming routine in the clinical laboratory for the diagnosis of
      human diseases using various tissue sources. Most clinical specimens are followed
      by tracking forms that include patient demographic data, accession number, and
      date and time of collection. As part of a thorough quality assurance program,
      proper documentation of test requisitions and tracking forms is mandatory.
      Despite these efforts, specimen mislabeling or other mix-ups can, and do, occur.
      We demonstrate the utility of the PM + DQA1 typing kit and STR analysis using the
      Visible Genetics automated DNA sequencing system in the proper identification of
      such clinical specimens as urine, blood, and paraffin-embedded tissues. In each
      case, sufficient DNA was extracted from these specimen types using a nonorganic
      extraction protocol for typing purposes. We conclude that DNA typing methods are
      feasible for distinguishing clinical laboratory specimens of questionable
      identity and compliment existing quality assurance techniques.

PMID- 10396305
TI  - [Motherhood and fatherhood after liver transplantation].
AB  - BACKGROUND AND OBJECTIVE: Liver transplantation for terminal liver failure
      enables patients to look forward to many years of good quality life. As a result,
      more and more of the often still relatively young transplant recipients inquire
      about the possible risks to a child procreated after transplantation. PATIENTS
      AND METHODS: During 9.5 years (between September 1988 and April 1998) 1000 liver
      transplantations were performed on 911 patients (374 females, 537 males) at our
      hospital. The potential for parenthood existed for 163 women (aged between 16 an
      46 years) and 520 men. 14 children were born of 14 women, six pregnancies ended
      in spontaneous abortion or miscarriage and three other women are now pregnant.
      Seven men reported paternity of eight children after transplantation. All data
      were collected prospectively. RESULTS: Six of the 14 births (42.9%) proceeded
      normally, but up to three complications developed in the other eight (57.1%). Six
      women (35.7%) developed hypertension during the pregnancy. There was no case of
      transplant dysfunction or toxaemia of pregnancy. Half the births were by
      caesarean section. Premature births occurred in two women (14.3%); four children
      were underweight (< 2500 g) at birth (28.6%). The seven men, at a mean age of 44
      (7-75) months after transplantation, fathered eight children, at present aged
      between 11 months and 6 years, all of whom have developed normally. The 13
      children of the post-transplantation mothers are also without malformation or
      abnormal development. One child's development is retarded due to a fetal alcohol
      syndrome resulting from the mother's post-transplantation alcohol abuse during
      pregnancy. All the patients are well at present and live with their children.
      CONCLUSIONS: Both men and women can procreate at a relatively low risk to the off
      spring. But for this to happen, an informed decision for parenthood must be made
      by the prospective parent together with her/his partner and the doctor in charge,
      she/he must be in good physical condition with stable transplant function, and
      there must be frequent interdisciplinary monitoring during any post
      transplantation pregnancy.

PMID- 10396306
TI  - [A 51-year-old patient with arterial hypertension, respiratory insufficiency and
      polycythemia--an unusual cause of nocturnal sleep-associated breathing disorder].
AB  - HISTORY AND ADMISSION FINDINGS: A 51-year-old man without significant previous
      illness presented with treatment-resistant arterial hypertension, dyspnoea,
      increased fatigue and headaches. Except for a florid face and fine tremor the
      physical examination was unremarkable. INVESTIGATIONS: The chest x-ray showed
      pulmonary congestion. Blood gas analysis indicated respiratory alkalosis and
      hypoxaemia (pO2 65.2 mm Hg, pCO2 33.9 mm Hg, pH 7.46) and polycythaemia
      (haemoglobin 18.1 g/dl, haematocrit 53.5%). There was no evidence of an
      underlying cardiopulmonary disease. Sleep apnoea screening with an 8-channel
      recorder was compatible with the central sleep apnoea syndrome (apnoea/hypopnoea
      index 38/h). TREATMENT AND COURSE: In the absence of neurological findings and an
      underlying medical condition the patient was again questioned. This revealed that
      in the previous 3 months he had been living and working as a waiter at a height
      of 3029 m above sea-level, without prior acclimatization. The symptoms and
      abnormal findings cleared up after a 6-week stay at 800 m. CONCLUSION: At a time
      when people often quickly move between different altitudes, high-altitude
      sickness should be included in the differential diagnosis of respiratory failure
      and the central sleep apnoea syndrome.

PMID- 10396308
TI  - [Current therapy for unstable angina pectoris].

PMID- 10396307
TI  - [Skin necrosis in the front foot area during anticoagulation with phenprocoumon].
AB  - HISTORY AND ADMISSION FINDINGS: A 52-year-old woman was admitted because of pain
      for several days in the lower left leg and increasing pretibial swelling with
      livid discoloration. Six months before she had undergone a bilateral adnexectomy
      with removal of the omentum and subsequent chemotherapy for ovarian cancer.
      INVESTIGATIONS: Duplex sonography on the day of admission revealed thrombosis of
      the left popliteal vein with an unobstructed femoral vein. Both the quick value
      (89%) and partial thromboplastin time (PTT, 35.9 s) were within normal limits.
      Computed tomography and sonography were highly suspicious of a local recurrence
      of the ovarian cancer with peritoneal carcinomatosis. TREATMENT AND COURSE: PTT
      effective heparinization (heparin-Na) was initiated together with overlapping
      anticoagulation with phenprocoumon (thromboplastin time 20-30%). On the 9th day
      after starting phenprocoumon painful, black necrotic changes began to appear on
      the skin of the left first to fourth toes. Assuming these to be due to
      phenprocoumon, anticoagulation was switched to low-molecular heparin
      (Enoxaparin), and antithrombin III and protein C were administered. A few days
      later thrombosis of the right iliac vein occurred, probably caused by local
      recurrence of the ovarian cancer. No palliative chemotherapy was undertaken in
      view of the thrombotic complications. The patient died a few months later from
      the cancer. CONCLUSION: If there is an underlying malignancy, chemotherapy and
      therapeutic vitamin-K antagonism in the presence of thromboembolic complications
      increases the risk of lowering protein C activity and may cause the rare
      complication of skin necrosis, induced by phenprocoumon.

PMID- 10396309
TI  - [Diagnosis and therapy of acquired factor inhibitors].

PMID- 10396310
TI  - [Death due to liver hemorrhage after infarct lysis].

PMID- 10396311
TI  - [Isolated falling out of upper eyelid hair].

PMID- 10396312
TI  - [Hormone replacement therapy and breast cancer].
AB  - An evaluation of the role of estrogen and progesterone in hormone replacement
      therapy (HRT) as a cause and promotor of breast cancer should begin with a study
      of the effect of these hormones on normal breast tissue. Cyclic alterations in
      the histologic changes of the breast in relation to menstruation have been
      confirmed in some papers. However, the histological influence on the breast of
      the use of exogenous estrogen and progestin in postmenopausal women remains very
      controversial. There has been little consistency with regard to the relative risk
      of HRT and breast cancer in many epidemiological studies. However, the
      Collaborative. Group on Hormonal Factors in Breast Cancer has brought together
      and reanalyzed about 90% of the international epidemiological evidence on the
      relation between risk of breast cancer and use of HRT. These analyses revealed
      that the risk of breast cancer in HRT users was significantly increased. However,
      whether HRT affects mortality from breast cancer is unknown.

PMID- 10396313
TI  - [Clinical development in gemcitabine and its clinical pharmacological profile].
AB  - Gemcitabine Hydrochloride (hereafter: Gemcitabine) is a new anti-tumor agent
      being widely used in other countries for treatment of non-small cell lung cancer
      was recently approved in Japan. The profile of Gemcitabine is considered to be
      the following 2 points both for non-small cell lung cancer and for pancreatic
      cancer, of which the study is currently conducted in Japan: high efficacy as
      foreign data indicate prolongation of survival time and less frequency of serious
      adverse reactions than other conventional anti-tumor agents. According to the
      results of Japanese and foreign phase I studies, as clinical pharmacological
      profile of Gemcitabine, its elimination half-life is rather short such as 20
      minutes. Weekly administration by injection over 30 minutes is appropriate since
      bone marrow suppression and hepatic disorder were frequently observed in case of
      administration twice a week or injection for more than 60 minutes. Also,
      population pharmacokinetics results showed a tendency that blood plasma clearance
      of Gemcitabine was lower in women and aged patients. Dose adjustment depending on
      gender is not considered to be necessary because the blood plasma clearance
      amount of Gemcitabine is large enough itself. However, influence caused by aging
      must be observed continuously in the future. For its profile of mild adverse
      reactions of Gemcitabine mentioned above, concomitant chemotherapy with other
      anti-tumor agents is expected be widely conducted in the future, therefore,
      clinically pharmacological observation of Gemcitabine is important for its
      appropriate use as well.

PMID- 10396314
TI  - [Phase II studies of gemcitabine for non-small cell lung cancer in Japan].
AB  - To determine the activity and toxicity of gemcitabine in non-small cell lung
      cancer, three phase II studies of single agent gemcitabine have been conducted
      between 1990 and 1994. In an early phase II study, gemcitabine was administered
      of 800 mg/m2 on day 1, 8, 15 every four weeks (step I), and 1,000 mg/m2 (step
      II). Response was observed in 3 of 13 patients with previously untreated non
      small cell lung cancer, although there was no responders in the previously
      treated patients. Late phase II studies were performed at 20 (group A) and 24
      (group B) Japanese institutions to confirm the efficacy and safety of gemcitabine
      administered alone in patients with non-small cell lung cancer. Seventy-three
      patients (group A) and 67 patients (group B) were entered into these studies. All
      patients had no previous chemotherapy and had measurable disease. Gemcitabine was
      administered at a starting dose of 1,000 mg/m2/wk for 3 weeks followed by a week
      of rest. The dose was escalated to 1,250 mg/m2 if severe toxicity was not seen in
      the previous course. Nineteen of 73 patients (26%) had a partial response in
      group A. Of 67 patients, 14 (20.9%) showed a partial response in group B. Grade 3
      or greater toxicities included anemia (20.5%) and leukopenia (9.6%) in group A,
      and in 13.4% and seven 10.4% in group B, respectively. And grade 3
      thrombocytopenia was observed in 1.4%. Other toxicities including hepatic
      toxicity, fatigue, nausea/vomiting, and fever were mild and transient. Pulmonary
      toxicity was observed in five patients, two of whom died of ARDS. The median
      durations of response were 19.6 weeks in group A and 20 weeks in group B, and
      median survival times were 44 and 39 weeks, respectively. In conclusion,
      gemcitabine is an active agent against non-small cell lung cancer with very mild
      toxicities. These results suggest that gemcitabine has potential utility in
      advanced non-small cell lung cancer on an outpatient basis. Further trials in
      combination with other active agents are warranted.

PMID- 10396315
TI  - [Gemcitabine in the treatment of non-small cell lung cancer for elderly
      patients].
AB  - Among all 140 eligible cases in the two late phase II studies of gemcitabine
      monotherapy for advanced non-small cell lung cancer, response rate was 26.3% in
      57 elderly patients group who were older than 70 and 21.7% in 83 non-elderly
      patients group who were blow 69. Median survival was 9.8 months and 9.3 months
      for elderly and non-elderly respectively, 1 year survival rate was 35.1% for
      elderly and 38.6% for non-elderly, and both groups showed good efficacy. Among
      elderly group, one case died from septic shock accompanied with grade 4 of
      leukopenia, neutropenia and thrombocytopenia, and two cases developed
      interstitial pneumonitis. Of these two cases, one with mild pulmonary fibrosis
      died of respiratory failure due to aggravation of interstitial pneumonitis. Grade
      3 or more anemia was occurred significantly more often in elderly group (elderly:
      24.6%, non-elderly: 12.0%). There was no significant difference between both
      groups in the incidence of grade 3 or more of leukopenia and gastrointestinal
      toxicity, which were relatively low. No significant difference between both
      groups was found in total gemcitabine doses, average of single dose and the
      number of administration. Gemcitabine can be administered in elderly cases as
      well as in non-elderly cases. The results suggested that this agent is well
      tolerated and effective for elderly patients with normal organ functions.

PMID- 10396316
TI  - [Phase I study of gemcitabine hydrochloride (LY 188011) combination therapy with
      cisplatin in the patients with non-small cell lung cancer].
AB  - The combination Phase I study of gemcitabine hydrochloride with cisplatin was
      conducted in the patients with non-small cell lung cancer (NSCLC) at 5
      investigation sites. Gemcitabine was administrated on day 1, 8 and 15 and
      cisplatin on day 1 of each 28-day cycle. The dosage of cisplatin was fixed to 80
      mg/m2 and the dosage of Gemcitabine was gradually escalated in 3 dosing level
      from 600, 800 to 1,000 mg/m2. The maximum tolerated dose (MTD) and the
      recommended dose was determined with Continual Reassessment Method. For each dose
      level, 6 cases, 3 cases and 6 cases were registered respectively and all 15 cases
      were evaluable. In the dose level 3 with 1,000 mg/m2 of gemcitabine and 80 mg/m2
      of cisplatin, grade 4 neutropenia was observed as DLT in 3 out of 6 cases, thus
      dose level 3 was considered as MTD and the recommended dose. Major adverse events
      were leukopenia, neutropenia, nausea/vomiting and anorexia. The incidence of such
      adverse events seemed to be dose-dependent and especially the grade of
      neutropenia seemed to be more serious as the dose increased. Also, the grade of
      liver function tests abnormal seemed to be more serious as the dose increased but
      the incidence as well as the grade did not have tendency of dose-dependent in
      another events including renal function tests abnormal. On the other hand, as to
      the efficacy PR was observed in 4 out of 15 cases. Based upon the results, it is
      necessary to discuss further the efficacy in the recommended dose in the
      combination therapy of gemcitabine and cisplatin.

PMID- 10396317
TI  - [Gemcitabine hydrochloride is a new anti-cancer agent which will be available in
      the patients with non-small cell lung cancer (NSCLC) in Japan].
AB  - Gemcitabine hydrochloride is a novel anti-cancer drug which is marketed as an
      indication for non-small cell lung cancer (NSCLC). This drug is already on the
      market and has been done many clinical trials. In order to evaluate its efficacy
      in treating NSCLC, many studies of gemcitabine by combination chemotherapy using
      agents such as cisplatin, which is a key drug in treating NSCLC, and paclitaxel,
      docetaxel and vinorelbine, which are novel anti cancer agents, were conducted.
      Although the efficacy of this drug was confirmed in terms of the combination
      therapy from the results, the optimal dosage schedule of this drug was not
      established because each study showed a different result in terms of the dosage
      as well as the dosage interval, thus, it is necessary to discuss and establish
      the optimal dosage schedule. Also comparative studies between the single therapy
      of gemcitabine and the existing combination therapy were conducted and it was
      reported that the single therapy was as effective as the conventional combination
      therapy. Based upon the results, it is considered that gemcitabine is a potential
      option in the chemotherapy for NSCLC. Gemcitabine has been already approved as
      indications for NSCLC as well as pancreatic cancer abroad and now there have been
      discussions on its efficacy against other kinds of cancer such as breast cancer.
      Clinical trials in order to evaluate its efficacy for pancreatic cancer have been
      conducted here in Japan and it is also expected to expand develop the efficacy
      against other kinds of cancer.

PMID- 10396318
TI  - [Results of questionnaire to 56 medical institutions about clinical trials of
      cancer chemotherapy].
AB  - From the stand point of investigators doing clinical trials of anti-cancer drugs,
      a questionnaire to survey of the current status of clinical trials concerning on
      the reactions of medical institutions to the new GCP started in April 1997, sent
      to 75 institutions all over the Japan. 56 institutions (75%) gave answers to the
      questionnaire, in August 1998. As the results, apparent decrease of Phase II &
      III trials were noticed compared the numbers before March 1997. IRB with one or
      two outside members are well functioned in these institutions. But, training
      related doctors, nurses (especially CRC) are nowadays most important problems,
      which are strongly expected to Ministry of Health and Welfare and related medical
      societies, for instance Japan Society of Clinical Oncology.

PMID- 10396319
TI  - [Evaluation of chemotherapy with docetaxel and cisplatin in advanced non-small
      cell lung cancer].
AB  - Clinical study has been conducted to evaluate the efficacy of chemotherapy with
      docetaxel and cisplatin in six patients with advanced non-small cell lung cancer.
      Treatment schedule consisted of docetaxel 60 mg/m2 and cisplatin 80 mg/m2 on day
      1 and repeated every 4 weeks. Eligible patients had histologically proven locally
      advanced or metastatic non-small cell lung cancer, PS < or = 2, age < or = 74,
      normal hematological, hepatic and renal functions and informed consent in
      writing. Six patients have been included; all were males, median age 64 (range 47
      74), histology; adenocarcinoma 4, squamous cell carcinoma 2, stage III B 4, stage
      IV 2. Among these 6 patients, 3 PR (50%) were observed. Neutropenia was the most
      common adverse event (83%). The lowest granulocyte counts were most frequently
      seen on day 9.4 (range: 6-14). Non hematologic adverse events included alopecia
      (6 cases), general fatigue (5 cases), anorexia (5 cases) and emesis (3 cases).
      These events were recovered rapidly with no therapy. The results suggest that
      combination chemotherapy of docetaxel and cisplatin will be effective and safe
      under careful observation.

PMID- 10396321
TI  - [Antitumor effect of 5'-DFUR and PyNPase activity in colorectal cancer].
AB  - Following preoperative administration of 5'-deoxy-5-fluorouridine (5'-DFUR) in
      patients with colorectal cancer, histologic antitumor effects as well as
      pyrimidine nucleoside phosphorylase (PyNPase) activities in cancerous tissues
      were examined. Fifty-five patients were randomly divided into two groups: Twenty
      five patients received 5'-DFUR orally at a daily dose of 800 mg for 3 weeks
      before operation (Group A) and twenty-nine received no medication (Group B).
      PyNPase activities in cancerous tissues obtained from resected specimens in Group
      A and B were 49.7 +/- 21.6 and 66.6 +/- 40.0 U/mg prot, respectively, which were
      significantly higher than 25.5 +/- 14.1 and 22.1 +/- 11.2 U/mg prot in normal
      colorectal tissues. No significant difference was observed in PyNPase activities
      in cancerous tissues between Group A and B. PyNPase activities in cancerous
      tissues in Group A were no different either from 59.2 +/- 40.0 U/mg prot in
      biopsy specimens before administration of 5'-DFUR. Histologic anti-tumor effects
      were as follows: Grade 2, 1 case Grade 1b, 5; Grade 1a, 10; and Grade 0, 9.
      Although no correlation was observed between antitumor effects and PyNPase
      activities in cancerous tissues, antitumor effects of 2 cases in which PyNPase
      activities in cancerous tissues before administration of 5'-DFUR showed more than
      100 U/mg prot were Grade 2 and 1b, respectively.

PMID- 10396320
TI  - [Chemotherapy with low-dose CDDP and continuous 5-FU for the treatment of
      advanced gastric cancers].
AB  - INTRODUCTION: 5-fluorouracil (5-FU) has been widely used for the treatment of
      gastrointestinal cancers. On the basis of recent findings, low-dose Cisplatin
      (CDDP) and continuous venous infusion of 5-FU have shown additive or synergistic
      antitumor effects in experimental models. We evaluated clinical effects of low
      dose CDDP and 5-FU (low-dose FP therapy) in patients with advanced gastric
      cancers. PATIENTS AND METHODS: In December 1993 and June 1998, 52 patients with
      advanced gastric cancer were entered in this study. Patients were considered
      eligible if they had a bidimensionally measurable tumor. 5-FU (160 mg/m2/day) was
      continuously infused over 24 hours using an implantable port, and CDDP (3
      mg/m2/day) was infused for half an hour. The administration schedule consisted of
      5-FU for 7 consecutive days and CDDP for 5 days followed by a 2-day rest every
      four weeks according to response and tolerance. RESULTS: Low-dose FP therapy was
      given 44 patients (85%). The response rate was 65.9% and median survival time was
      249 days. The responder group showed good survival compared with the non
      responder group. The regimen was tolerable, and the most common toxicity was
      anorexia (40.3%). Three patients suffered from grade 3 anorexia, leukopenia and
      mucositis. On the other hand, renal dysfunction occurred in 50% (two of four
      patients administered over 1,000 mg CDDP). These results raise the possibility
      that the dose-limiting factor of low-dose FP therapy may account for the total
      dosage of CDDP. CONCLUSION: Low-dose FP therapy promises to be effective in the
      clinical management of advanced gastric cancer.

PMID- 10396322
TI  - [Treatment for advanced colorectal carcinoma with 5-fluorouracil plus low-dose
      leucovorin].
AB  - From July 1992 to May 1996, 16 patients with non-curative postoperative or
      recurrent colorectal carcinomas were treated with 5-fluorouracil (5-FU) plus
      leucovorin (LV) systemic chemotherapy. LV was given at a dose of 20 mg/m2/d
      immediately followed by 5-FU at 370 mg/m2/d. LV was given by rapid intravenous
      (i.v.) injection and 5-FU by rapid or drip i.v. for 5 consecutive days. Courses
      were repeated once every 4 weeks for two months and then once every 5 weeks. All
      patients took 3 or more courses. The toxicity was tolerable, but one patient
      needed hospitalization because of severe gastro-intestinal toxicity. We observed
      3 PR cases, no CR and an overall response rate of 19%. The response duration was
      6 to 8 months, averaging 7.3 months, and median survival was 12 months. It was
      possible to perform this chemotherapy on an outpatient basis, so we think this
      chemotherapy is superior to in-hospital chemotherapy considering the issue of
      quality of life. However, the response rate was low and its duration was short.
      We must investigate chemotherapy further with new and more powerful chemical
      modulations to increase the response rate and to prolong the response duration.

PMID- 10396323
TI  - [Usefulness of low dose 5'-DFUR (5'-deoxy-5-fluorouridine) for advanced or
      recurrent breast cancer].
AB  - The usefulness of low dose (600 mg/day) 5'-DFUR for advanced or recurrent breast
      cancer was evaluated. Eight patients out of 38 showed a partial response
      (response rate 21.1%), 22 patients had no change, and 8 patients had progressive
      disease. The response rate was 31.0% in soft tissue and 9.1% in bone, both of
      which were slight. In both one-shot (200 mg) and continuous (1-4 months)
      administration of 5'-DFUR (600 mg/day), the concentration of 5'-DFUR of 5-FU in
      sera reached a plateau from 30 minutes to 2 hours after administration of 5'
      DFUR, and disappeared after 3 hours. There were no significant differences in the
      concentration of 5'-DFUR of 5-FU in sera between one-shot and continuous
      administration. It is concluded that there was no accumulation of the drug after
      continuous administration of 5'-DFUR, and that low dose 5'-DFUR is a useful
      therapy for advanced or recurrent breast cancer.

PMID- 10396324
TI  - [Clinical trial of fadrozole hydrochloride for postmenopausal patients with
      recurrent breast cancer].
AB  - Eleven recurrent postmenopausal breast cancer patients with osseous or lung
      metastases were received fadrozole hydrochloride at a dose of 1 mg twice a day
      for more than 8 weeks. The median disease-free interval of these 11 patients with
      metastasis was 74 months. Out of 11 evaluable cases, 2 PR, 6 long-NC and 3 PD
      were observed. The overall response rate was 18.2% and the long-NC rate was
      54.5%. The average overall duration of responses and long-NC were 567 days and
      573 days, respectively. There was no adverse drug reaction. A combination therapy
      with fadrozole hydrochloride 2 mg daily and cyclophosphamide 100 mg orally on
      days 1-14 was given to 14 postmenopausal patients with recurrent breast cancer.
      The median disease-free interval of these 14 patients with metastasis was 33
      months. There were 2 CR, 3 PR, 4 long-NC, 2 NC and 3 PD. The overall response
      rate and long-NC rate were 35.8% and 28.6%, respectively. The average overall
      duration of responses and long-NC were 700 days and 443 days, respectively. The
      adverse drug reactions were anorexia (Grade 2) and neutropenia (Grade 1 and 2).
      These results suggested that a combination therapy with fadrozole hydrochloride
      and cyclophosphamide can be effective and contribute to survival time in the
      treatment of postmenopausal breast cancer.

PMID- 10396325
TI  - [Superselective intra-arterial infusion chemotherapy of high-dose cisplatin for
      advanced paranasal sinus carcinomas].
AB  - Eighteen patients with advanced paranasal sinus carcinomas were treated by "two
      route" intra-arterial chemotherapy using cis-diamminedichloroplatinum (CDDP) and
      sodium thiosulfate (STS) to preserve the hard palate and the eye. In these
      patients, 100 mg/m2 of CDDP was administered weekly through each feeding artery
      of the tumor superselectively at 5 mg/min. During infusion of CDDP, STS at a two
      hundred fold dose of CDDP was injected through a catheter placed in the
      brachiocephic vein introduced via the subclavian vein. The complete and partial
      response rates were 14/18 (78%) and 4/18 (22%), respectively. None of the nine
      patients following operation showed residual tumors histologically. The peak of
      the mean total plasma platinum concentration was 5.5 micrograms/ml, and this
      concentration was rapidly reduced to 1.5 micrograms/ml in 5 hours. The peak of
      the plasma protein unbound platinum was 3.9 micrograms/ml. This concentration
      rapidly decreased to almost zero within 5 hours after IA infusion. The mean tumor
      platinum content achieved by superselective IA infusion was as high as 6.0
      micrograms/g tumor, and this decreased rapidly to 2.4 micrograms/g tumor on the
      5th day after the 1st intra-arterial infusion. All patients were free from
      chemotoxicity such as renal, hematological dysfunctions, or gastrointestinal
      symptoms. Each chemotherapy treatment could be done weekly on schedule. All but
      one patient was alive for 5-40 months. This new method of chemotherapy appears
      very effective for advanced paranasal sinus carcinomas.

PMID- 10396326
TI  - [A case of type 4 gastric cancer with peritoneal dissemination treated with intra
      aortic chemotherapy].
AB  - A 45-year-old woman was admitted to our hospital because of lower abdominal pain
      and anorexia. A barium gastrography and gastroscopy showed a type 4 gastric
      cancer in the upper gastric body. Histologic study on biopsy specimens from the
      tumor revealed poorly differentiated adenocarcinoma. Computed tomography revealed
      bilateral hydronephrosis, and barium enema showed diffuse stenosis of the sigmoid
      colon because of peritoneal dissemination. This patient was treated by intra
      aortic infusion therapy with sequential MTX and 5-FU. After five courses of the
      administration, barium enema revealed reexpansion of the lumen of sigmoid colon
      with normalization of the tumor markers. The patient was discharged without
      symptoms. Intra-aortic infusion therapy with sequential MTX and 5-FU was
      considered an effective treatment for unresectable gastric cancer.

PMID- 10396327
TI  - [Combination of 5'-DFUR and MMC for recurrent rectal cancer with pulmonary
      metastasis].
AB  - We report a 68-year-old man with rectal cancer and recurrent pulmonary metastasis
      treated with concomitant 5'-DFUR + MMC, which resulted in an extreme reduction of
      the lesion. The initial pulmonary metastases were treated by pneumonectomy, but
      32 months later the patient again showed a pulmonary metastasis. Thus, from July
      1997, he was treated with 5'-DFUR (800 mg/day) + MMC (4 mg/2 weeks). After 3
      months of therapy, the chest CT examination showed an extreme reduction of the
      pulmonary lesion, and at 5 months the lesion was even smaller. Presently, after 7
      months of therapy, the lesion remains stable. His CEA level is 1.0-2.6 ng/ml.
      After 4 months of treatment he had mild anorexia, which was alleviated by
      reducing the 5'-DFUR to 600 mg/day. No other adverse reaction was observed; the
      therapy was safely conducted on an outpatient basis.

PMID- 10396328
TI  - [Effective chemo-endocrine combination therapy for obstructive-jaundice caused by
      multiple liver metastasis of recurrent breast cancer--a case report].
AB  - A 68-year-old woman complained of obstructive jaundice 9 years after a radical
      mastectomy. CT scan demonstrated multiple metastasis of the liver and two coin
      lesions of the right lung. The biliary tract was completely obstructed at the
      portal fissure. Multiple liver and lung metastasis of breast cancer were
      diagnosed because of high CA 15/3 serum levels and normal gastrointestinal study.
      Following unsuccessful treatment with tamoxifen (TAM), we used toremifene (TORE)
      and 5'-deoxy-5-fluorouridine (5'-DFUR) followed by percutaneous transhepatic
      cholangiodrainage (PTCD). The biliary tract was reopening and jaundice
      disappeared with improvement of the general condition. Then endocrine therapy
      with medroxy progesterone acetate and UFT and chemotherapy with CAF
      (Cyclophosphamide, Adriamycin, 5-FU) were begun. A partial response (PR) was
      obtained with the disappearance of liver metastasis and two coin lesions of the
      lung 5 months after the first treatment. The effect of chemo-endocrine
      combination therapy continued for 5 months. Survival time from recurrence was 13
      months. In our case, PR was obtained by using chemo-endocrine combination
      therapy, although a poor prognosis has been reported in patients with obstructive
      jaundice caused by multiple liver metastasis of recurrent breast cancer.

PMID- 10396330
TI  - [Low-dose weekly administration of docetaxel for metastatic breast cancer].

PMID- 10396329
TI  - [Endocrine chemotherapy (high-dose toremifene + 5'-DFUR) found markedly effective
      for 2 cases of metastatic breast cancer].
AB  - Two cases of metastatic breast cancer are reported in which endocrine
      chemotherapy with Toremifene + 5'-DFUR proved markedly effective. Case 1: A 69
      year-old female. After CAF therapy as a adjuvant chemotherapy, Tamoxifen and
      Tegafur had been administered. At the 5th postoperative year, multiple metastases
      to lung and a rise in the tumor marker were found. Since the patient was not
      desirous of intensive chemotherapy, administration of Toremifene 120 mg/day and
      5'-DFUR 800 mg/day was initiated. The patient showed PR 9 months after and
      achieved CR 14 months later. Case 2: A 48-year-old female. CAF therapy for a
      total of 6 cycles was performed as adjuvant chemotherapy. The patient was
      administered Tamoxifen and followed. On bone scintigrams 3.5 years after surgery,
      an abnormal accumulation appeared in the left sternoclavicular joint, and an
      infiltrative tumor mass was formed in the skin of that region. Administration of
      Toremifene + 5'-DFUR was initiated. After 6 months, the infiltrative mass
      disappeared. These findings are suggestive of the effectiveness of this combined
      chemotherapy.

PMID- 10396331
TI  - [Pharmacokinetics of azasetron (Serotone), a selective 5-HT3 receptor
      antagonist].
AB  - 5-HT3 receptor antagonists have been established in a number of clinical trials
      as effective agents in the management of nausea and vomiting induced by cancer
      chemotherapy including cisplatin. Azasetron (Serotone) is a potent and selective
      5-HT3 receptor antagonist, and classified as benzamide derivative. It has a
      different chemical structure from indole-type 5-HT3 receptor antagonists such as
      granisetron, ondansetron, ramosetron and tropisetron. The major difference is
      found in the pharmacokinetic profiles. Approximately 60-70% of azasetron
      administered i.v. and orally is excreted in urine as the unmetabolized form.
      Also, orally-administered azasetron has shown to be absorbed and/or secreted by
      the saturable transport mechanism in the small intestine, resulting in good
      bioavailability as approximately 90%. In this report, the relationship between
      the structure of 5-HT3 receptor antagonists (especially azasetron) and their
      pharmacokinetics were described.

PMID- 10396332
TI  - [Assay and detection methods for urokinase-type plasminogen activator and its
      related-factors].
AB  - The urokinase-type plasminogen activator (u-PA) has been implicated in invasion
      and metastasis of various cancers including lung, breast, gastric and colon
      cancers. The u-PA system consists of plasmin, u-PA, specific u-PA receptor and
      the serpins, PAI-1 and PAI-2. It has been demonstrated that the reciprocal
      actions among the components of the u-PA system are much important for regulating
      u-PA activity. Recent studies are focusing on the interaction between the u-PA
      system and cell adhesion molecules such as integrins, and the physiological
      significance in vivo of u-PA system-related proteins. We introduce here the
      useful methods to examine the u-PA enzyme activity and the expression of proteins
      and genes related with the u-PA system for clinical cancer specimens.

PMID- 10396333
TI  - [Nonspecific symptoms due to gastrointestinal stromal tumors].
AB  - Three patients, two women aged 64 and 52 years and one man aged 78 years, had non
      specific symptoms and they had signs of a tumour at imaging examination.
      Immunohistochemical study of operation preparations led to the diagnosis of
      'gastrointestinal stromal tumour' (GIST). It is important to consider the
      possibility of a GIST at surgery, because the potential malignancy requires a
      resection with free margins.

PMID- 10396334
TI  - [Electrophysiology of the atrioventricular node during atrial fibrillation. I.
      Ventricular rhythm].
AB  - Atrial fibrillation (AF) occurs in 0.9% of the population, in 6% of persons over
      65 and in 10% of persons over 80. It is an important independent risk factor for
      thromboembolism, especially cerebral infarctions. The functions of the
      atrioventricular (AV) node are: (a) optimal adjustment of the time between the
      contractions of atria and ventricles; (b) protection of the ventricles against
      excessively high frequencies of atrial tachycardia; (c) a pacemaker function in
      case of atrial arrest. AF is an irregular, disorganized electrical activity of
      the atria. On the ECG, P waves are absent and the baseline shows wavelets
      constantly changing in shape, duration, amplitude and direction. Development and
      existence of AF are correlated with a sufficiently large number of myocardial
      cells and a sufficient degree of difference between the electrical properties of
      the myocardial cells. In the absence of an AV conduction block, the resulting
      ventricular rhythm is completely irregular. The constant irregularity of the
      ventricular rhythm is independent of ventricular frequency and independent of
      cardiac and other characteristics of the patient. Electrical stimulation of the
      right ventricle leads to complete AV block.

PMID- 10396335
TI  - [Electrophysiology of the atrioventricular node during atrial fibrillation. II.
      The influence of atrial impulses].
AB  - An atrial impulse that is not conducted to the ventricle may slow down the
      conduction of the next atrial impulse. A ventricular extrasystole may also affect
      the conduction through the AV node. This phenomenon is called 'concealed
      conduction'. At least three mechanisms are possible to explain concealed
      conduction, but neither weakening of the impulse as the conduction proceeds nor
      electrotonic modulation of the pacemaker function of the AV node is in accordance
      with the observed constant irregularity of atrial fibrillation. The most probable
      mechanism to explain the ventricular rhythm during atrial fibrillation is the
      electrotonic change (inhibition) by atrial impulses of the conduction properties
      of the AV node.

PMID- 10396336
TI  - [Clinical thinking and decision making in practice: a full-term neonate with
      misunderstood respiratory insufficiency].
AB  - A fullterm newborn boy developed severe respiratory insufficiency, multiple air
      leaks and severe pulmonary hypertension, leading to his death on the third day of
      life. Family history revealed that a sister of the patient had died earlier after
      a similar course with respiratory problems. The most common causes of respiratory
      insufficiency could be subsequently excluded. After extensive postmortem
      investigation alveolar proteinosis was found in the lung tissue. DNA
      investigation was then performed in the parents, and both appeared to be
      heterozygotic for the 121ins2 mutation. This finding suggests both children in
      this family to have been homozygotic for the 121ins2 mutation resulting in a lack
      of synthesis of surfactant protein B (SP-B). Homozygotic SP-B deficiency in the
      newborn is a fatal disease with no curative perspectives, except for lung
      transplantation and gene therapy.

PMID- 10396337
TI  - [Epidemic of respiratory tract infections by Mycoplasma pneumoniae in an
      institute for mentally disabled, investigated with polymerase chain reaction of a
      throat swab specimen].
AB  - OBJECTIVE: To determine the spread of respiratory infection with Mycoplasma
      pneumoniae in an institute for mentally disabled persons. DESIGN: Descriptive.
      METHODS: In the period from mid-April to mid-September in a certain year the
      transmission of M. pneumoniae in the facility was evaluated using questionnaires
      and laboratory investigations. The laboratory investigations consisted of an M.
      pneumoniae specific polymerase chain reaction (PCR) on throat swab specimens and
      detection of antibodies in serum. RESULTS: 21 Residents and 26 staff members from
      2/36 units were involved in the initial investigation. 17 Persons had complaints
      of a (recent) respiratory infection (cough, malaise and fever). In 9 cases an M.
      pneumoniae infection was confirmed, in 5 cases by PCR and in 4 cases by serology.
      Two PCR positive persons had only complaints of coughing. During the
      investigation period 2 more persons were diagnosed with a respiratory infection
      due to M. pneumoniae. No new cases were found by investigation of contacts
      outside the facility. CONCLUSION: M. pneumoniae can cause an outbreak of M.
      pneumoniae respiratory infection in an institute for mentally disabled persons.
      Rapid detection of this pathogen is possible by PCR and is important for proper
      antibiotic therapy and epidemic-control measures.

PMID- 10396338
TI  - [Rubberband ligation of hemorrhoids: symptoms almost gone after 6 weeks, but many
      patients need retreatment in the long run].
AB  - OBJECTIVE: To assess the short and middle-long term results of outpatient
      treatment of internal haemorrhoids by rubber band ligation. DESIGN: Prospective.
      METHODS: The results and the complications of rubber band ligation were assessed
      in a group of consecutive patients treated for internal haemorrhoids by one
      surgeon in March 1995-September 1997 in the Laurentius Hospital Roermond, the
      Netherlands. Middle-long term results were assessed by an independent examiner
      who questioned the patients by phone. RESULTS: Ninety-four patients were treated:
      43 women and 51 men, with a mean age of 51 years (range: 23-80). After 6-18 weeks
      80 out of 90 accessible patients (89%) were symptom-free, 71 (79%) of them after
      one treatment. Serious complications were not reported. However, the days after
      treatment mild complaints of anal urgency and pain were present in 16 patients
      (20%). Twenty-three patients underwent sigmoidoscopy. In 10 patients (43%)
      adenomatous polyps (in 9 patients) or diverticulosis (in 1 patient) were found.
      After a mean of 18 months (range: 6-31) 32 patients (41%) (still) had anal
      complaints compatible with haemorrhoids. CONCLUSION: Rubber band ligation is an
      easy and safe outpatient treatment of internal haemorrhoids. Most patients become
      symptom-free, often after one treatment. However, about 40% of the patients have
      recurrent symptoms within a few years after initial treatment.

PMID- 10396339
TI  - [Legal representatives of the child with respect to the Act on Consent to Medical
      Treatment (WGBO): more representatives possible the under the new family law].
AB  - The possibilities to exercise family authority over minors have been extended
      drastically since 1998. This has its consequences for the doctor with respect to
      medical treatment. According to the Dutch act on agreement concerning medical
      treatment the minor up to the age of fifteen needs his tutor in deciding about
      medical treatment. From the age of sixteen the child decides for himself. New
      family law offers the doctor many more representatives of the child.
      Representatives may be parents, tutors of special curators. Main changes in the
      family law are that since 1998 the partner of a parent or of a tutor may be given
      family authority. Furthermore this is now also possible for a parent or tutor
      living together with a partner of the same sex. The central issue is that the
      best interests of the child always prevail and that the physician has the legal
      obligation to act as a good assistant. This may entail the physician's
      ascertaining who represents the child and who is allowed to decide and to be
      informed. This is not necessarily the person accompanying the child.

PMID- 10396340
TI  - [Interaction between breast cancer, psychosocial stress and the immune response].

PMID- 10396341
TI  - [Imported skin diseases].

PMID- 10396342
TI  - Influence of a past history of Gambian sleeping sickness on physical growth,
      sexual maturity and academic performance of children in Fontem, Cameroon.
AB  - Little has been published on the long-term complications of Gambian sleeping
      sickness (GSS) following treatment. A case-control study to compare physical
      growth, sexual maturity and academic performance of children with and without a
      past history of GSS was therefore conducted. The study took place over a period
      of 6 months, in the 10 villages of the Fontem GSS focus, which is known to be
      very endemic for the disease. Overall, 100 young subjects (aged 6-20 years) with
      a past history of GSS were pair-matched for age (+/- 5 months), sex, place of
      residence, and socio-economic and cultural backgrounds with 100 other, control
      subjects who had no history of GSS and who were sero-negative for GSS when
      checked with a card agglutination test (Testryp-CATT). On average, the cases
      weighed 4.25 kg less, were 3 cm shorter and had 1.15-cm smaller mid-upper-arm
      circumferences than the controls (P < 0.05 for each). The mean sexual-maturity
      rating of the two groups was similar but the controls tended to have attained
      puberty earlier than the cases. When the cases were subdivided into those treated
      with melarsoprol and those given pentamidine, only the melarsoprol-treated sub
      group was significantly different from the corresponding controls in terms of
      physical growth and sexual maturity.

PMID- 10396343
TI  - A multi-centre evaluation of the card indirect agglutination test for
      trypanosomiasis (TrypTect CIATT).
AB  - A version of the card indirect agglutination test for trypanosomiasis, the
      TrypTect CIATT, was evaluated for the diagnosis of Trypanosoma brucei gambiense
      and T. b. rhodesiense sleeping sickness. The results of this antigen-detection
      test indicated high relative sensitivity (99.3%) and specificity (99.4%), and
      also much higher prevalences of infection in the general population of endemic
      foci (27.9% for T. b. gambiense and 21.8% for T. b. rhodesiense) than detected by
      parasitological diagnosis (1.6% and 1.1%, respectively). TrypTect CIATT detected
      (and could therefore be used for the diagnosis of) non-patent infections. Among
      the suspected cases (i.e. those initially found to be parasite-negative but to be
      antigen-positive), trypanosomes were detected in 29 (4.2%) of those checked at a
      3-month follow-up, and 17 more such suspects when they were followed up at 6-18
      months. Moreover, a high proportion of blood samples from a random sample of the
      rest of the suspects tested positive for trypanosome-specific DNA by PCR (79.9%
      for T. b. gambiense and 13.9% for T. b. rhodesiense). ELISA also demonstrated the
      presence of anti-trypanosome antibodies in many of the suspects tested (63%, 38%,
      24% and 66.9% of those in Cameroon, Cote d'Ivoire, Tanzania, and Malawi,
      respectively). A follow-up of 164 patients treated with melarsoprol revealed
      that, by 9 months post-treatment, 113 (69.0%) had no detectable trypanosome
      antigens in their peripheral blood. The test could therefore be used for
      evaluating chemotherapeutic cure, as well as for diagnosis.

PMID- 10396344
TI  - Parasitological detection of Trypanosoma brucei gambiense in serologically
      negative sleeping-sickness suspects from north-western Uganda.
AB  - Forty-five parasitologically confirmed cases of sleeping sickness were diagnosed
      in north-western Uganda using a combination of two or three techniques. Forty of
      the cases were positive by the card agglutination test for trypanosomiasis
      (CATT), four were negative and one was not screened by the CATT. Trypanosomes
      isolated from the four CATT-negative but parasitologically positive cases were
      propagated for detailed biochemical genetic analysis. The aim was to demonstrate
      whether these four stocks lacked the LiTat 1.3 gene which encodes the antigen on
      which the CATT is based. All the DNA extracts isolated from these CATT-negative
      stocks and from six CATT-positive stocks of Trypanosoma brucei gambiense were
      targeted for amplification by the three variable-surface-glycoprotein genes
      thought to be ubiquitous in T. b. gambiense. The LiTat 1.3 gene was shown to be
      present in all 10 stocks. Trypanosome carriers may be CATT-negative because the
      CATT is not sensitive enough, because their parasites lack the LiTat 1.3 gene, or
      because their parasites have this gene but do not express it. The four sleeping
      sickness cases who gave negative CATT results in the present study have very
      important implications in the diagnosis of T. b. gambiense infections using the
      CATT. Following treatment of the CATT-positive cases, the CATT-negative carriers
      of the trypanosomes remain as human reservoir hosts for continuous infection of
      the population. Because CATT-negative individuals are rarely examined further,
      the general prevalence of parasitologically positive but CATT-negative cases is
      unclear. This study demonstrates the value of co-ordinated use of serological and
      parasitological techniques in the diagnosis of Gambian sleeping sickness.

PMID- 10396345
TI  - The relationship between Schistosoma haematobium infection and school performance
      and attendance in Bamako, Mali.
AB  - Schistosomiasis due to Schistosoma haematobium was the most common helminth
      infection in school-age children from a poor area in Bamako, Mali. Almost half
      (47%) of the boys and 40% of the girls were infected, 18% of the children being
      heavily infected. There was a significant decline in academic performance and in
      school attendance with increasing intensity of infection. When all sources of
      variation were taken into consideration, absenteeism was the main factor
      explaining the variation in academic performance, although a significant effect
      of infection remained. School-based delivery of chemotherapeutic interventions is
      currently promoted by several international organizations. However, rates of
      school attendance are low in some areas and it is the absentees who appear to be
      at relatively high risk of ill health. Novel ways of reaching this elusive subset
      of the population are required.

PMID- 10396346
TI  - The selection and validation of indicators for monitoring progress towards self
      sustainment in community-directed, ivermectin-treatment programmes for
      onchocerciasis control in Uganda.
AB  - A retrospective analysis was made of quantitative data on coverage obtained over
      4 years of annual ivermectin treatment of the eligible populations (approximately
      56,000 individuals) of 71 communities with endemic onchocerciasis in the Kabale,
      Kisoro and Rukungiri districts of Uganda. The objective was to formulate methods
      for defining sustainability in community-directed, ivermectin-treatment
      programmes (CDITP). Three dependent-variable scales of programme sustainability
      (PS), PS1, PS2, and PS3, were tested for statistical significance by analysis of
      variance. The inhabitants of a random sample of 230 households drawn from 23
      communities [each containing one community leader and one community-based
      distributor (CBD)] were then invited to answer a questionnaire covering seven
      independent variables. These variables were analysed in regression and
      correlation models, with the PS scales as dependent variables. In the regression
      model, only one variable, selection of CBD by community members (P = 0.038),
      which scored 100% on the scale of programme-indicator sensitivity, passed as a
      useful indicator for predicting the sustainability and monitoring the sustainment
      of CDITP at the community level. The same variable was also selected in the
      correlation model (P = 0.028). Although two other variables--involvement of CBD
      in other primary-health-care activities (P = 0.0594) and provision of incentives
      for the CBD (P = 0.0558)--showed weak negative associations with sustainability
      in the correlation model, they did not exhibit a linear relationship with it and
      cannot therefore be used as valid indicators for predicting sustainability or
      monitoring sustainment.

PMID- 10396347
TI  - Behaviour of Lutzomyia longipalpis in an area of southern Honduras endemic for
      visceral/atypical cutaneous leishmaniasis.
AB  - The predominant sandfly in Las Maria de Pavana, Choluteca, Honduras, was found to
      be Lutzomyia longipalpis, most (69%) of the 791 specimens of this species caught
      being male. When local Lu. longipalpis were studied over 1 year (1986-1987) using
      CDC traps, peaks in the size of the adult population were observed in December
      and July, each after a period of rain. Most [51% (24/47)-67% (97/144)] of the
      flies caught inside houses were female whereas most [55% (6/11)-56% (37/66)] of
      those caught outside were male. Far more Lu. longipalpis of both sexes were
      collected, per h of collection, from cattle and horses than from dogs or pigs,
      the vast majority (83%-93%) of the flies caught on each type of animal being
      male. The males may benefit from resting on the mammals because the females with
      which they mate come to the same animals for blood. The females may benefit by
      the presence of the males, not only by the increased chance of finding a mate but
      also because pheremones from the males may attract the females both to the males
      and to a bloodmeal source. The adult Lu. longipalpis only appeared to be active
      during the hours of darkness, none alighting in the twilight of dawn (04.00-06.00
      hours) or dusk (18.00-20.00 hours) on the large mammals investigated.

PMID- 10396348
TI  - Environmental determinants of the distribution of Phlebotomus orientalis in
      Sudan.
AB  - Despite its importance as a vector of visceral leishmaniasis in Sudan, the
      ecology of Phlebotomus orientalis is still poorly understood. The results of a
      ground-based survey and a geographical-information-system (GIS) study, carried
      out to investigate the environmental determinants of the distribution of P.
      orientalis in the wooded areas of the central savannah belt of Sudan, are
      described here. The survey, carried out in April-June 1996, consisted of a
      collection of sandflies over two consecutive nights at each of 44 study sites,
      using three CDC, miniature, light traps at each site. During the survey, the
      ecology of each site was described. Phlebotomus orientalis was caught at 17 of
      the sites. Environmental data on the collection sites (rainfall, minimum and
      maximum temperatures, soil class, vegetation and land-surface-temperature
      indices) were extracted from a range of sources of digital data collected by
      satellites in the National Ocean and Atmospheric Administration's series. These
      data were then analysed, to ascertain which variables were significantly
      associated with sites positive for P. orientalis. In line with the results of
      previous studies, P. orientalis was found to have a significant association with
      the presence of the tree species Acacia seyal and Balanites aegyptiaca and with
      the black cotton (vertisolic) soils of eastern Sudan. The positive sites were
      found to have significantly higher annual mean maximum and minimum daily
      temperatures than the negative sites and the annual mean maximum normalized
      difference vegetation index (NDVI) value was also found to be significantly
      higher in these sites than in sites where no P. orientalis were found.

PMID- 10396349
TI  - Estimation of Plasmodium falciparum oocyst survival in Anopheles arabiensis.

PMID- 10396350
TI  - Where do most mosquitoes acquire their malarial (Plasmodium falciparum)
      infection? From adults or from children?

PMID- 10396351
TI  - Circulating immune complexes in Mansonella ozzardi infection.

PMID- 10396352
TI  - Genetic confirmation of the specific status of Triatoma petrochii (Hemiptera:
      Reduviidae: Triatominae).

PMID- 10396353
TI  - Investigation protocol: adrenal enlargement.

PMID- 10396354
TI  - Thyroid hormones and neurodevelopment.

PMID- 10396355
TI  - Low maternal free thyroxine concentrations during early pregnancy are associated
      with impaired psychomotor development in infancy.
AB  - BACKGROUND: Maternal thyroid function during early pregnancy is an important
      determinant of early fetal brain development because the fetal thyroid is unable
      to produce any T4 before 12-14 weeks' gestation. Overt maternal hypothyroidism as
      seen in severe iodine-deficient areas is associated with severely impaired
      neurological development of the offspring. At present, it is not known whether
      low free T4 (fT4) levels during pregnancy in healthy women from iodine sufficient
      areas may affect fetal neurodevelopment. METHODS: Neurodevelopment was assessed
      at 10 months of age in a cohort of 220 healthy children, born after uncomplicated
      pregnancies and deliveries, using the Bayley Scales of Infant Development.
      Maternal TSH, fT4 and TPO antibody status were assessed at 12 and 32 weeks'
      gestation. Maternal gestational fT4 concentration was defined as an independent
      parameter for child development. RESULTS: Children of women with fT4 levels below
      the 5th (< 9.8 pmol/l, n = 11) and 10th (< 10.4 pmol/l, n = 22) percentiles at 12
      weeks' gestation had significantly lower scores on the Bayley Psychomotor
      Developmental Index (PDI) scale at 10 months of age, compared to children of
      mothers with higher fT4 values (t test, mean difference: 14.1, 95% confidence
      interval (CI): 5.9-22 and 7.4, 95% CI: 1.1-13.9, respectively). At 32 weeks'
      gestation, no significant differences were found. In the group of women with the
      lowest 10th percentile fT4 concentrations at 12 weeks' gestation, a positive
      correlation was found between the mothers' fT4 concentration and children's PDI
      scores (linear regression, R: 0.46, P = 0.03). After correction for confounding
      variables, a fT4 concentration below the 10th percentile at 12 weeks' gestation
      was a significant risk factor for impaired psychomotor development (RR): 5.8, 95%
      CI: 1.3-12.6). CONCLUSIONS: Low maternal plasma fT4 concentrations during early
      pregnancy may be an important risk factor for impaired infant development.

PMID- 10396356
TI  - An atypical contiguous gene syndrome: molecular studies in a family with X-linked
      Kallmann's syndrome and X-linked ichthyosis.
AB  - BACKGROUND AND OBJECTIVE: Kallmann's syndrome (KS) is characterized by
      hypogonadotrophic hypogonadism in association with anosmia or hyposmia. This
      entity can be associated with X-linked ichthyosis (XLI) in a contiguous gene
      syndrome. Genetic defects have been demonstrated on the Xp22.3 region explaining
      the presence of one or both entities in affected individuals. In this report we
      describe the molecular findings in four patients, pertaining to a three
      generation family, with KS which was associated with XLI in two of them.
      MEASUREMENTS: Enzymatic activity of steroid sulphatase was measured in
      leucocytes. Polymerase chain reaction of the 14 exons of the Kallmann gene (KAL)
      and of the 5' and 3' extremes of the steroid sulphatase gene was performed in
      genomic DNA. PCR products of the 14 exons of the KAL gene were purified and
      sequenced. RESULTS: Absence of steroid sulphatase activity and a complete
      deletion of the STS gene were demonstrated in both patients with XLI. In all
      subjects, the 14 KAL gene exons amplified in a normal fashion; no mutation was
      documented after sequencing all exons. CONCLUSIONS: Although it has been proposed
      recently that the X-linked form of the disease accounts for the minority of
      patients with Kallman's syndrome, the pedigree chart of this family demonstrates
      this inheritance pattern. Various possibilities are mentioned in order to explain
      the absence of mutation in the KAL gene. The coexistence, in this family, of
      Kallman's syndrome individuals and patients with Kallman's syndrome and X-linked
      ichthyosis is discussed.

PMID- 10396357
TI  - Hyperleptinaemia in young adults following cranial irradiation in childhood:
      growth hormone deficiency or leptin insensitivity?
AB  - OBJECTIVE: In order to explore the mechanism of obesity in long-term survivors of
      childhood leukaemia, fat mass, lean body mass and serum leptin were assessed in a
      cohort of 32 (17 males) adults who had received cranial irradiation (XRT) in
      childhood as part of their treatment for acute lymphobiastic leukaemia (ALL), and
      compared with 35 age and body mass index (BMI) matched young adults (18 male).
      DESIGN: Thirty-one patients and 18 controls had fat mass and lean body mass
      assessed by dual x-ray absorptiometry (DEXA), using a lunar DPX-L scanner. Serum
      leptin concentrations were also measured in 27 patients and all controls. Growth
      hormone status had previously been determined using an insulin tolerance test and
      arginine stimulation test. Nine patients were classified as severe growth hormone
      (GH) deficient (group 1), 12 patients as GH insufficient (group 2) and 11
      patients as normal (group 3). RESULTS: BMI and absolute fat mass were not
      significantly different between the patients and controls regardless of their
      gender (P = 0.1 and P = 0.14 respectively). In contrast, absolute lean mass was
      significantly reduced (P < 0.01) and leptin concentrations were significantly
      increased (P < 0.001) in patients compared with controls. BMI, fat mass and
      leptin concentrations but not lean mass were significantly different between the
      three GH status groups (P < 0.01, P < 0.01, P = 0.004, and P = 0.67
      respectively). When leptin concentrations were expressed per unit of fat mass,
      they were increased in the patients compared with the controls (P = 0.03) with
      significant differences between the GH status groups (P = 0.004), being
      significantly higher in the severe GH deficient group. CONCLUSIONS: Young adults
      who receive cranial irradiation in childhood are prone to GH deficiency and
      hyperleptinaemia. The pathophysiological significance of the hyperleptinaemia
      remains to be established but it has occurred either as a consequence of
      radiation induced hypothalamic damage or GH deficiency.

PMID- 10396358
TI  - Bone turnover and cortical bone mineral density in the distal radius in patients
      with hyperthyroidism being treated with antithyroid drugs for various periods of
      time.
AB  - OBJECTIVE: Whether patients, who have lost bone mass, can be restored to age
      matched control levels by some means is still controversial. We investigated how
      the thyroid status after antithyroid drug therapy for various periods of time
      affects bone metabolism in patients with hyperthyroidism by assessing currently
      used biochemical markers of bone turnover and distal radius bone mineral density
      (BMD). DESIGN AND PATIENTS: The biochemical markers of bone turnover and BMD at
      the distal one third of the radius were measured in 79 women with hyperthyroidism
      treated with antithyroid drugs for various periods of time. The patients were
      divided into two groups according to thyroid function at the time of study: a
      hyperthyroid group (serum thyroid stimulating hormone (TSH) < 0.4 mU/l) and an
      euthyroid group (TSH 0.4-4.0 mU/l). Second, each group was further divided
      according to the duration of therapy: short-term (less than 3 years) and long
      term (3 or more years). MEASUREMENTS: Urinary type I collagen degradation
      products (CTx) were measured by the CrossLapsTM ELISA kit. Urinary pyridinoline
      (Pyr) and deoxypyridinoline (Dpyr) were measured by high performance liquid
      chromatography (HPLC) after acid hydrolysis. Serum N-mid osteocalcin (OCN-mid)
      was measured by a recently developed enzyme-linked immunosorbent assay. Serum
      alkaline phosphatase (ALP) was determined by routine laboratory methods. Bone
      mineral density (BMD) at the distal one third of the radius was measured using
      dual energy X-ray absorptiometry (DEXA; DCS-600EX, Aloka, Tokyo). RESULTS: There
      were statistically significant positive correlations of FT3 and FT4 with the
      biochemical markers of bone turnover. There were significant negative
      correlations between the biochemical markers and BMD only in patients undergoing
      long-term therapy. In a comparison between hyperthyroid and euthyroid groups
      based on duration of treatment (long-term and short-term), and in a comparison
      without regard for length of treatment (all patients), it was evident that ALP
      and CTx levels were significantly higher in the hyperthyroid than in the
      euthyroid groups. Significantly lower BMD Z-scores in the hyperthyroid group
      compared to those in the euthyroid group were observed only in patients
      undergoing long-term therapy. CONCLUSIONS: Urinary type I collagen degradation
      products were a sensitive marker for evaluating the bone turnover in patients
      with hyperthyroidism. Our data suggested that it might be important to control
      the levels of TSH within normal ranges during long-term antithyroid drug therapy
      in order to prevent bone loss.

PMID- 10396359
TI  - Cord blood leptin concentrations in relation to intrauterine growth.
AB  - OBJECTIVE: Leptin, a hormone that signals the amount of energy stores to the
      brain, has recently been shown to play a role in the regulation of several
      hypothalamic pituitary axes, including the growth hormone axis. To investigate a
      potential association between cord blood leptin concentrations and intrauterine
      growth we measured leptin concentrations in the cord blood of small for
      gestational age (SGA), appropriate for gestational age (AGA) and large for
      gestational age (LGA) healthy newborns. PATIENTS AND MEASUREMENTS: Cord blood
      leptin concentrations were evaluated in 25 SGA, 100 AGA, and 45 LGA, neonates.
      RESULTS: Leptin was detectable in all newborns in concentrations comparable with
      those found in adults. Moreover, SGA newborns had lower leptin concentrations
      (3.70 +/- 1.81 micrograms/l) than AGA (5.65 +/- 4.98 micrograms/l) and LGA
      newborns (11.99 +/- 7.06 micrograms/ l)(P < 0.01). Cord blood leptin
      concentrations were significantly associated with ponderal index, cord blood
      insulin concentrations, placental weight and maternal serum leptin
      concentrations. Importantly, the association between cord blood leptin
      concentrations and intrauterine growth status persisted after adjusting for
      adiposity, placental weight, maternal serum leptin concentrations and cord blood
      insulin concentrations. CONCLUSIONS: Cord blood leptin concentrations are
      independently associated with intrauterine growth. Future studies are needed to
      elucidate the underlying mechanism and clarify the role of leptin in regulating
      growth and controlling appetite in newborns.

PMID- 10396360
TI  - Comparison of serum thyrotrophin concentrations determined by a third generation
      assay in patients with various types of overt and subclinical thyrotoxicosis.
AB  - OBJECTIVE: Recent increases in the sensitivity of methods used to measure TSH,
      especially third generation assays, have enabled separation of partial from
      complete pituitary suppression in patients with thyrotoxicosis. We have
      investigated the use of a sensitive chemiluminescent enzymeimmunoassay in the
      differential diagnosis of thyrotoxicosis. DESIGN AND PATIENTS: Serum TSH
      concentrations were determined by chemiluminescent enzymeimmunoassay in patients
      with various types of overt and subclinical thyrotoxicosis. RESULTS: The assay
      was highly sensitive with an analytical sensitivity of 0.0016 mU/l. Among 45
      hyperthyroid patients with untreated Graves' disease, 37 (82.2%) showed
      undetectably low levels (< 0.002 mU/l). Serum TSH in the remaining 8 patients
      (17.8%) was 0.003-0.005 mU/l. In contrast, TSH was undetectably low in only 5
      (20.0%) of 20 patients with painless thyroiditis and in 2 (12.5%) of 16 patients
      with subacute thyroiditis. Eleven (55.0%) with painless thyroiditis and 12
      (75.0%) with subacute thyroiditis had TSH values greater than 0.005 mU/l (0.006
      0.032 and 0.006-0.228 mU/l, respectively; normal range 0.5-5.0 mU/l). Serum TSH
      levels were subnormal in 10 of 12 patients with euthyroid ophthalmic Graves'
      disease, including 4 with undetectably low levels. Among 11 patients with an
      autonomously functioning thyroid nodule 6, including 1 with normal free T4 and
      free T3 and 2 with normal free T3, showed TSH values less than 0.002 mU/l. No
      significant correlation was observed between serum free T4 or free T3 and TSH
      concentrations in thyrotoxic patients. Together with the incomplete suppression
      of TSH observed in those with destructive thyroiditis, this suggests that the
      grade of TSH suppression was influenced by the duration of illness at the time of
      blood sampling. CONCLUSION: The third-generation TSH assay is useful for the
      differential diagnosis of various types of thyrotoxicosis, especially between
      Graves' disease and destructive thyroiditis.

PMID- 10396361
TI  - Genetic studies of a family with hereditary hyperparathyroidism-jaw tumour
      syndrome.
AB  - BACKGROUND AND OBJECTIVES: Familial hyperparathyroidism may occur as familial
      isolated hyperparathyroidism (FIHP) or as part of an inherited syndrome, in
      particular multiple endocrine neoplasia types 1 and 2A (MEN1, MEN2A) and
      hyperparathyroidism-jaw tumour (HPT-JT) syndrome. The localization of the genes
      responsible for these syndromes has enabled genetic screening of families with
      primary hyperparathyroidism (PHPT) to be carried out. This has important clinical
      implications in terms of individual follow-up and management. We previously
      reported a large FIHP family with an increased risk of parathyroid cancer and
      excluded its linkage to MEN1, MEN2 and PTH genes. Here we re-analysed this family
      and performed genetic linkage to the HPT-JT locus in chromosome 1q21-q32. Loss of
      heterozygosity studies of 1q21-q32, 11q13 and X chromosome were also performed.
      PATIENTS AND DESIGN: We studied 19 family members, aged 6-63 years. High
      molecular weight DNA was isolated from peripheral blood samples from 17 family
      members. For the two deceased individuals, DNA was extracted from normal paraffin
      embedded tissues. MEASUREMENTS: All individuals (except two deceased patients)
      had serum corrected calcium, inorganic phosphate, intact PTH, prolactin and
      various pancreatic hormones, measured on fasting blood samples. Twenty
      microsatellite markers were examined for the 1q21-q32 region, the locus for the
      HPT-JT gene. Genetic polymorphisms were determined by polymerase chain reaction
      amplification of genomic DNA and genetic linkage analysis was performed. Loss of
      heterozygosity studies were performed using paraffin-embedded parathyroid tissues
      from four affected members. RESULTS: Seven of the eight affected family members
      included in this study had biochemical evidence of PHPT and surgically proven
      parathyroid tumours. Indication of linkage of the disease to the HPT-JT locus was
      demonstrated with a maximum lod score of 2.32 by two-points linkage analysis.
      Linkage data were supported by multi-point analysis which gave a maximum lod
      score of 2.7. Meiotic recombinations detected in one affected individual narrowed
      the region to 26 cM. As a result of the genetic findings, we re-screened the
      living family members by orthopantomograph and renal ultrasound, and identified
      two jaw lesions in two gene carriers. One affected family member demonstrated
      polycystic kidney disease, thus establishing the association between the two
      conditions. A reduced penetrance of HPT in females was evident, in agreement with
      our previous study. No allelic deletion was detected in any tumour at 1q21-q32,
      11q13 or X chromosome. CONCLUSIONS: This study illustrates the usefulness and
      importance of genetic studies in familial isolated hyperparathyroidism families.
      Our clinical and genetic findings indicate that this previously reported familial
      isolated hyperparathyroidism family has hyperparathyroidism-jaw tumour syndrome.

PMID- 10396362
TI  - Long-term effect of radioactive iodine on thyroid function and size in patients
      with solitary autonomously functioning toxic thyroid nodules.
AB  - OBJECTIVE: To investigate the long-term effects of radioiodine (131I) on thyroid
      function and size in patients with a solitary toxic thyroid nodule. DESIGN:
      Prospective study of patients treated for a solitary autonomous toxic nodule,
      followed by evaluation of thyroid volume and function. PATIENTS: Sixty-two
      consecutive patients followed for a minimum of 12 months (range 12-168, median
      60). Seventeen patients received antithyroid drug treatment before 131I.
      MEASUREMENTS: Standard thyroid function variables and ultrasonically determined
      thyroid volume before as well as 0.75, 1.5, 3, 6 and 12 months after treatment,
      and then once a year were investigated. RESULTS: 131I treatment (3.7 MBq/g
      thyroid tissue corrected to a 100% 24-h 131I uptake) was given as a single dose
      in 53 patients; six needed two doses and another three were given 3-5 131I
      treatments. The median initial dose was 310 MBq (140-666) and the median total
      dose was 332 MBq (148-1576). In patients receiving one 131I treatment (n = 53)
      the total thyroid volume decreased significantly from a median of 40 ml (range 19
      77) to 24 ml (8-50) within 3 months. This represented a median reduction of 35%.
      A further significant decrease was seen after 24 months to a total reduction of
      45%. In patients given more than one dose the thyroid volume was reduced from a
      median of 45 ml (19-104) before treatment to 30 ml (14-50) after a follow-up of
      60 months (9-132) after the last 131I treatment. Patients without antithyroid
      pretreatment, receiving one 131I treatment (n = 39) became euthyroid after a
      median of 1.5 months (0.75-9) after treatment. Seventy-five per cent were
      euthyroid within 3 months. In patients pretreated with antithyroid drugs and
      treated with one dose of 131I (n = 14) euthyroidism was achieved after a median
      of 12 months (0.75-24) after 131I treatment. Hypothyroidism developed in five
      patients (8%) after a median of 36 months (6-60) after 131I treatment.
      CONCLUSION: A cure-rate of 75% within 3 months is seen when treating autonomous
      solitary toxic thyroid nodules with 131I. The thyroid volume is reduced by 35%
      within 3 months and 45% after 2 years. Side-effects are few and consist of
      hypothyroidism in less than 10% with a median follow-up of 5 years. This
      treatment should be regarded as the standard treatment for this condition until
      prospective comparisons with surgery and ethanol injection therapy have been
      performed.

PMID- 10396363
TI  - Serum prostate specific antigen, sex hormone binding globulin and free androgen
      index as markers of pubertal development in boys.
AB  - OBJECTIVE: Prostate specific antigen (PSA) expression in the prostate gland is
      regulated by androgens. Serum levels of PSA are undetectable by routine assays in
      normal boys. Measurable values could serve as a marker for pubertal development.
      In order to explore this question, we measured serum PSA levels in normal boys
      throughout puberty and examined the interrelationships with various hormonal and
      physical developmental changes. DESIGN: Sera from 77 normal boys in Tanner stages
      I to V (T-I to T-V) were analysed for PSA levels by a sensitive time-resolved
      fluoro-immunometric assay (sensitivity: 0.012 microgram/l). In addition, sex
      hormone binding globulin (SHBG), insulin like growth factor I (IGF-I), IGF
      binding protein 3(IGFBP-3) and testosterone were measured. RESULTS: PSA was
      detectable in 0% of Stage T-I (n = 16), 33% of T-II (n = 18), 65% of T-III (n =
      17) and 100% of T-IV (n = 10) and T-V (n = 16) boys. PSA levels rose
      significantly according to stage (P < 0.05). Also, there were significant (P <
      0.05) increments in serum testosterone, IGF-I and IGFBP-3 levels from stages T-I
      to T-IV. PSA showed a positive correlation with testosterone (r = 0.86, P <
      0.001), IGF-I (r = 0.66, P < 0.001), and IGFBP-3 (r = 0.34, P = 0.004) levels.
      Both PSA and these analytes, however, showed significant overlap between stages T
      I and T-II with only 6/18 (33%) and 12/18 (66%) of T-II subjects having PSA and
      testosterone levels, respectively, above the T-I range. In contrast, serum SHBG
      levels decreased markedly from stages I to II (P < 0.001). At the calculated best
      cut-off point for SHBG of 50 nmol/l, 16/18 T-II subjects had values below the T-I
      range (sensitivity = 89%). Because of this decrement of SHBG and the increasing
      testosterone secretion in early puberty, the Free Androgen Index (FAI =
      Testosterone/SHBG) could even better differentiate the onset of puberty with all
      except one of the T-II subjects having FAI levels above the T-I range
      (sensitivity = 94.4%). The decrease of SHBG in T-II subjects coincided with an
      increase in total body weight (P = 0.001) and body mass index (BMI, P = 0.0003).
      Despite the continuing pubertal rise in testosterone, SHBG levels showed a
      rebound increment from T-II-T-III subjects (P = 0.02) with a concomitant decrease
      in BMI (P = 0.0014). CONCLUSIONS: Prostate specific antigen closely reflects
      serum free androgen activity during puberty. However, it was unable to
      differentiate the earliest pubertal development. In comparison, SHBG levels and
      Free Androgen Index are more sensitive markers for the onset of puberty in boys.
      The inverse association between SHBG levels and BMI in pubertal stages Tanner
      stages, I to III suggests that body fatness, via its effect on insulin
      sensitivity, may play an important role in the regulation of SHBG production
      during early pubertal development.

PMID- 10396364
TI  - Serum leptin levels in women throughout pregnancy and the postpartum period and
      in women suffering spontaneous abortion.
AB  - OBJECTIVE: In pregnancy, important changes occur in the body weight of the
      mother, caused by sodium and water retention and by an increase in body fat
      tissue, but the mechanisms that regulate maternal and foetal changes in fat mass
      are poorly understood. Leptin is a hormone produced by adipocytes in order to
      regulate food intake and energy expenditure at the hypothalamic level in man. In
      order to verify whether leptin participates in the changes in body composition
      during pregnancy and postpartum, 630 healthy women were studied at specific time
      periods and leptin and auxological parameters were determined. DESIGN: A cross
      sectional study in which leptin levels were measured in women at specific time
      periods related to pregnancy. Each woman was assessed only once. PATIENTS: 630
      women participated in the study, and were divided into categories as follows:
      Group A, 29 internal controls, with no previous or current pregnancy; Group B, 73
      women in the first trimester of pregnancy; Group C, 60 women in the 24 h before
      delivery; Group D, 212 women in the 24 h postpartum; Group E, 93 women in the
      eightH postpartum week (2 months group); Group F, 71 women in the sixteenth
      postpartum week (4 months group); Group G, 20 women in the sixth month
      postpartum; Group H, 23 women one year postpartum; Group I, 20 women two years
      postpartum; finally Group J, of 29 women who had suffered spontaneous abortion in
      the first trimester of pregnancy and were studied in the 24 h after the stillborn
      delivery. MEASUREMENTS: Serum leptin levels were measured in duplicate by
      radioimmunoassay using commercial kits. Height and weight was measured and BMI
      (kg/m2) calculated. RESULTS: Compared with serum leptin in the control group
      (11.7 +/- 1.0 micrograms/l), a non significant (NS) increase was observed in the
      first trimester of pregnancy (14.3 +/- 1.4 micrograms/l), with no parallel
      changes in body weight. A reduction in leptin occurred in the 24 h after delivery
      (9.4 +/- 1.4 micrograms/l, P = 0.02). After delivery a progressive increase in
      leptin concentrations was observed, 13.3 +/- 1.5 micrograms/l at two months (NS)
      and 17.4 +/- 2.6 micrograms/l at four months (P = 0.035 vs controls). Afterwards
      leptin values decreased towards normal values at 6, 12 and 24 months after
      delivery 14.4 +/- 1.8 micrograms/l; 12.9 +/- 1.6 micrograms/l; and 10.1 +/- 1.1
      micrograms/l respectively (all NS). With the exception of the postpartum group, a
      significant correlation was observed between leptin concentrations and body
      weight or BMI in each group of women studied. In the women who suffered
      spontaneous abortion in the first trimester of pregnancy a reduction in leptin
      levels occurred (8.8 +/- 1.0 micrograms/l, P = 0.001 vs first trimester group).
      CONCLUSION: Serum leptin concentrations rose slightly during pregnancy, fell
      following delivery and subsequently increased during the first six months
      postpartum. These variations were unrelated to changes in body composition, and
      may be responsible for the postpartum weight gain observed in some women.
      Abnormally low serum leptin levels were observed in women suffering spontaneous
      abortion in the first trimester of pregnancy.

PMID- 10396365
TI  - The prevalence of subclinical hypothyroidism at different total plasma
      cholesterol levels in middle aged men and women: a need for case-finding?
AB  - OBJECTIVE: In order to determine whether screening of thyroid function is
      justified in patients with hypercholesterolaemia, we determined the prevalence of
      subclinical hypothyroidism at different levels of total plasma cholesterol in
      middle-aged men and women. DESIGN AND METHODS: 1200 participants were selected
      from a population based cross sectional study on risk factors for cardiovascular
      diseases. The participants were divided into three groups: total plasma
      cholesterol < 5 mmol/l, total plasma cholesterol 5-8 mmol/l, total plasma
      cholesterol > 8 mmol/l. Each group was comparable in size and sex distribution.
      Subclinical hypothyroidism was defined as plasma TSH levels higher than 4 mU/l,
      in the presence of normal free thyroxine (FT4(4)) concentration. RESULTS: Plasma
      samples of a total of 1191 participants were analyzed. The overall prevalence of
      subclinical hypothyroidism was 1.9% in men and 7.6% in women of middle age. In
      women the prevalence of subclinical hypothyroidism increased from 4.0 percent in
      the lowest, to 10.3 percent in the highest cholesterol stratum (P = 0.02). In
      men, the mean prevalence was 1.8 percent and roughly similar in the various
      strata. After age correction, an increase of 1 mU/l TSH in women was associated
      with an increase of 0.09 mmol/l total plasma cholesterol (95% confidence interval
      (CI) 0.02-0.16 mmol/l). A similar trend was found in men (0.16 mmol/l, 95% CI 
      0.02-0.34 mmol/l). CONCLUSIONS: In the population, the prevalence of subclinical
      hypothyroidism is up to 10 percent in middle aged women with high levels of total
      plasma cholesterol and may justify case-finding. In these women approximately 0.5
      mmol/l of total plasma cholesterol can be attributed to the subclinical thyroid
      dysfunction. In men a similar correlation between thyroid dysfunction and total
      plasma cholesterol is seen, but the prevalence of thyroid dysfunction is
      considerably lower.

PMID- 10396366
TI  - Insulin-like growth factor binding protein-1 in NIDDM: relationship with the
      insulin resistance syndrome.
AB  - OBJECTIVE: In order to examine the role of insulin-like growth factors in the
      pathogenesis of accelerated macrovascular disease in noninsulin-dependent
      diabetes mellitus (NIDDM), we investigated the relationship between the insulin
      resistance syndrome and the IGF axis. DESIGN: Cross-sectional analysis of the
      relationship between insulin resistance syndrome variables and concentrations of
      IGF-1, IGF-2, IGFBP-1 and IGFBP-3 in 80 subjects with NIDDM. RESULTS: After
      correcting for age, sex and body mass index, concentrations of IGFBP-1,
      correlated with those of HDL-cholesterol (r = 0.40; P < 0.001), triglycerides (r
      = -0.24; P = 0.04), insulin (r = -0.39; P < 0.001), intact proinsulin (r = -0.32;
      P = 0.006), des 31,32 proinsulin (r = -0.40; P = 0.001), and with insulin
      sensitivity (r = 0.38; P = 0.001) and PAI-1 activity (r = -0.24; P = 0.05); IGF-1
      levels only correlated with those of HDL-cholesterol (r = -0.33; P = 0.005), and
      this was not explained by IGFBP-1 or insulin sensitivity. With additional
      correction for insulin, concentrations of IGFBP-1 still correlated with HDL
      cholesterol (r = 0.40; P < 0.001), but not those of triglycerides or PAI-1
      activity. There were no significant relationships between levels of IGF-2 and any
      of the variables investigated, and IGFBP-3 levels only correlated with those of
      total cholesterol (r = 0.24, P = 0.04). CONCLUSIONS: In NIDDM, concentrations of
      IGFBP-1 are related to those of insulin, insulin sensitivity, serum lipoproteins
      and PAI-1 activity. The relationship between concentrations of IGFBP-1 and HDL
      cholesterol is not explained by insulin. Concentrations of IGF-1 are linked to
      HDL-cholesterol, and this is not explained by levels of IGFBP-1. IGFBP-1
      concentrations were related to PAI-1 activity, and this may be explained by
      insulin, which regulates the production of IGFBP-1 and PAI-1.

PMID- 10396368
TI  - Bone mineral density and markers of bone turnover in young adult survivors of
      childhood lymphoblastic leukaemia.
AB  - OBJECTIVE: In order to determine if a serious disease like childhood acute
      lymphoblastic leukaemia (ALL) and the treatment necessary to cure the patients
      has long term effects on bone mass, we assessed bone mineral density (BMD) and
      several parameters involved in bone formation in a group of young adult survivors
      of ALL. DESIGN AND PATIENTS: Fourteen male and ten female survivors, treated for
      ALL in childhood, were cross-sectionally studied, at a mean age of 25.1 years
      (range 20.1-34.9). All patients, except for two, had received cranial irradiation
      as part of their treatment (mean radiation dose 2460 cGy). MEASUREMENTS: Height
      and weight were measured. Bone mineral density (BMD) was assessed using dual
      energy X-ray absorptiometry in the lumbar spine, femoral neck, femoral trochanter
      and at 1/3 distal and ultradistal in the radius. Early morning serum levels of
      LH, FSH, oestradiol or testosterone, IGF-1 and IGF-BP3 were determined as well as
      several specific markers of bone turnover. RESULTS: Mean height, expressed as
      standard deviation score (SDS) was -1.12, significantly reduced. BMD in the
      lumbar spine, femoral neck and at 1/3 distal and ultradistal in the radius, was
      significantly lower compared to the reference population (P < 0.05). No
      correlation was found between the BMD values and the cumulative dose of
      administered cytotoxic drugs, the age at diagnosis of ALL or the duration of
      follow-up. Mean IGF-1 and IGF-BP3 SDS-scores were -1.24 and -0.78 respectively,
      significantly reduced. GH stimulation tests performed in a subgroup of 9 patients
      showed an insufficient peak GH response in at least one test in all tested
      patients. The values of LH, FSH oestradiol or testosterone were within the normal
      adult range. Serum markers of bone formation and bone resorption were in the
      normal range, indicating that bone turnover was normal at the time of the study.
      CONCLUSIONS: Bone development in patients cured of acute lymphoblastic leukaemia
      is disturbed, resulting in a significantly reduced bone mineral density. Impaired
      growth hormone activity, as a long term effect of cranial irradiation, may be one
      of the underlying causes as well as the illness itself and the administered
      cytotoxic drugs. Since a reduced bone mineral density predispose patients to
      osteoporosis, intervention in order to improve bone mass should be considered.

PMID- 10396369
TI  - Comparison of monthly intramuscular injections of Sandostatin LAR with multiple
      subcutaneous injections of octreotide in the treatment of acromegaly; effects on
      growth hormone and other markers of growth hormone secretion.
AB  - OBJECTIVE: To compare the effects of monthly intra-muscular injections of a long
      acting preparation of octreotide, Sandostatin LAR, with multiple daily
      subcutaneous injections of octreotide and to study the interrelationships between
      mean 24 h growth hormone profile, serum total and free IGF-1 levels, 24 h urinary
      growth hormone levels and serum IGFBP-3. DESIGN: Patients were assessed by 24 h
      GH profile off octreotide or any other GH modifying drug therapy; on subcutaneous
      octreotide (200-600 micrograms daily in divided doses for six weeks); and 28 days
      after the second of two injections of Sandostatin LAR (20 mg by intra-muscular
      injection) administered 28 days apart. Serum total and free IGF-1, serum IGFBP-3
      and 24 h urinary GH were also measured on each occasion. RESULTS: Sandostatin LAR
      was well tolerated. None of the patients reported any adverse effect and all
      completed the study uneventfully. Mean GH off treatment was 10.1 +/- 3.0
      micrograms/l falling equally significantly (P < 0.05) during therapy with
      subcutaneous octreotide to 3.0 +/- 0.7 micrograms/l and Sandostatin LAR to 2.8 +/
      0.7 micrograms/l. Fasting 0900 h GH was significantly reduced (P < 0.05) on
      Sandostatin LAR (3.0 +/- 0.7 micrograms/l) compared with subcutaneous octreotide
      (5.1 +/- 1.2 micrograms/l). Mean total IGF-1 off treatment was 658.6 +/- 56.1
      micrograms/l and was reduced to a comparable extent with subcutaneous octreotide
      and Sandostatin LAR (466.0 +/- 59.7 and 448.6 +/- 59.5 micrograms/l respectively;
      both P < 0.05). Free IGF-1 off treatment was 3.1 +/- 0.6 micrograms/l and was
      reduced equally by subcutaneous octreotide and Sandostatin LAR (1.2 +/- 0.2 and
      1.2 +/- 0.2 micrograms/l; both P < 0.05). IGFBP-3 was reduced to a greater extent
      during Sandostatin LAR than during subcutaneous octreotide (4518.2 +/- 247.3 vs
      5132.8 +/- 280.7 micrograms/l; P < 0.05). Twenty-four hour urinary GH excretion
      was reduced to a comparable extent with both therapies. Highly significant
      positive correlations were found between mean 24 h GH levels and free IGF-1 (r =
      0.66, P < 0.0001) and 24 h urinary GH excretion (r = 0.94, P < 0.0001). The
      relationships between mean 24 h GH levels and total IGF-1 and IGFBP-3 although
      significant showed less powerful correlations. CONCLUSIONS: These results suggest
      that Sandostatin LAR is well tolerated and as effective as subcutaneous
      octreotide. In addition, urinary growth hormone and serum free IGF-1 may prove
      valuable for outpatient follow-up of acromegalic patients, as both correlate well
      with mean 24 h serum growth hormone levels.

PMID- 10396367
TI  - Functional hypothalamic amenorrhoea: a partial and reversible gonadotrophin
      deficiency of nutritional origin.
AB  - OBJECTIVE: Functional hypothalamic amenorrhoea (FHA) is a consequence of low
      dietary intake as observed in two major pathophysiological conditions, anorexia
      nervosa and/or intensive physical exercise. The aim of the present study was to
      assess in women with FHA and normal body mass index (BMI) and apparently normal
      daily activities, the degree of impairment of GnRH secretion, its nutritional
      origin and its reversibility. PATIENTS: Twelve women (22-35 years) with FHA not
      related with exercise and 12 age and BMI matched menstruating controls (NC) were
      studied. Six women with congenital hypothalamic hypogonadism (CHH),
      representative of complete gonadotrophin deficiency, were also enrolled for
      comparison. DESIGN: Plasma oestradiol (E2) and androstenedione (A) levels were
      measured and the pulsatile profile of LH was studied. A GnRH agonist test, using
      100 micrograms S/C of DTrp6 GnRH (Triptorelin) was performed (sampling every 2 h
      for 24 h). Dietary intake, body composition and nutritional markers (FT3,
      ferritin, retinol binding protein (RBP), SHBG, IGF-1 and leptin) were measured.
      All the women with FHA were advised to normalize their diet during four months.
      The same studies were performed if nutritional markers and body composition were
      normalized. RESULTS: In FHA, mean plasma E2 and A levels were low. LH pulse
      frequency and amplitude were significantly reduced compared to NC (P < 0.005).
      FSH/LH ratio increased rapidly after triptorelin with a significant increase in
      plasma E2 levels between 18 and 24 h. In contrast, no response to triptorelin was
      observed in women with CHH. The fat body mass was lower and the lean body mass
      higher in FHA than in NC. Marked differences in nutritional intake were
      identified, with altered dietary composition. FHA consumed significantly less fat
      (P < 0.001) and less carbohydrate (P = NS) than the BMI-matched controls. Mean
      plasma levels of SHBG were increased whereas mean plasma levels of FT3, ferritin,
      RBP, IGF-1, and leptin were significantly decreased. Only three patients with FHA
      kept a balanced diet and improved their body composition after 4 months. LH
      pulsatile profile and response to triptorelin challenge were normalized in these
      patients. CONCLUSION: Mild dieting, close to normal but prolonged and
      characterized by an important fat restriction, is able to interfere with
      gonadotrophin secretion. Assessment of nutritional markers allows recognition of
      mild nutritional insufficiency as a common cause of FHAs. The gonadotrophin
      deficiency is partial and may be reversible after improvement of nutritional
      intake and body composition.

PMID- 10396371
TI  - A comparison of the naloxone test with the insulin stress test in patients
      following transsphenoidal surgery.
AB  - OBJECTIVE: To study the reliability of the naloxone test in assessing the
      hypothalamic-pituitary-adrenal (HPA) axis in patients following transsphenoidal
      pituitary surgery, by comparison with the insulin stress test (IST). Also, to
      establish a normal range for the response to naloxone in healthy controls.
      DESIGN: All patients had the IST performed, soluble insulin 0.1-0.3 U/kg (usually
      0.15 U/kg) being administered intravenously, followed by venous sampling for
      plasma glucose and serum cortisol at 0, 15, 30, 45, 60, 75 and 90 minutes.
      Naloxone (125 micrograms/kg body weight) was similarly administered to all
      patients 6 days later, with sampling at -15, 0, 15, 30, 45, 60, 90 and 120
      minutes for plasma glucose, serum cortisol and plasma ACTH. The naloxone test was
      also performed on control subjects using an identical protocol. SUBJECTS: Twenty
      patients (11F/9M) aged 48.8 +/- 2.8 years (mean +/- SE) 4-6 weeks following
      transsphenoidal pituitary surgery. Twelve normal healthy control subjects (6F/6M)
      aged 31.5 +/- 3.0 years. MEASUREMENTS: Serum cortisol was measured by
      radioimmunoassay and plasma ACTH by immunoradiometric assay. RESULTS: Adequate
      hypoglycaemia (< or = 2.0 mmol/l) was achieved in all patients. Peak cortisol was
      > 550 nmol/l in 17 subjects (range: 572-867 nmol/l) and a subnormal response
      observed in 3 (peak cortisol 163-498 nmol/l). In the 17 patients with a normal
      cortisol response to hypoglycaemia the response to naloxone was extremely
      variable, with serum cortisol falling in 4 and an increment of < or = 100 nmol/l
      in 6 others. In the 3 patients who failed the IST, two responded to naloxone and
      one did not. In normal controls, 3 of the 12 had little or no response to
      naloxone. CONCLUSIONS: As the naloxone test fails to produce a response in all
      normal subjects it is impossible to define a 'normal' response. The numerous
      discrepancies with the IST in patients are further evidence of the test's lack of
      reliability in assessing the HPA-axis and it is consequently not a viable
      alternative to traditional dynamic methods such as the IST.

PMID- 10396370
TI  - Plasma oestrone-fatty acid ester levels are correlated with body fat mass in
      humans.
AB  - OBJECTIVE: The metabolites of steroidal hormones, including sulphate,
      glucuronide, and fatty acid (FA) ester derivatives, have received little
      attention, although these steroid derivatives are essential components in the
      global assessment of steroid metabolism. The study of FA-derivatives could, in
      obesity, contribute some insights into factors modulating steroid metabolism and
      their plasma levels. In a recent study we found that, in rats, an oestrone-fatty
      acid ester (E1-FA) was produced by white adipose tissue and released into
      lipoproteins in the blood-stream. We have examined whether E1-FA levels correlate
      with body fat and insulin sensitivity in humans. SUBJECTS: A sample of 20 men and
      22 women with varying levels of total body fat (mean body mass index (BMI) 29.2
      +/- 4.7, range 22.2-35.8 in men; mean BMI 27.6 +/- 6.3, range 16.8-37.9 in
      women). All participants were healthy. MEASUREMENTS: We measured oestrone fatty
      acid esters (E1-FA), body fatness, and body fat distribution variables, as well
      as insulin sensitivity through a frequently sampled intravenous glucose tolerance
      test. Plasma E1-FA and serum leptin levels were measured by radioimmunoassay.
      RESULTS: E1-FA levels strongly correlated with BMI (r = 0.69, P = 0.001 in men; r
      = 0.75, P < 0.0001, in women) percent body fat (PBF, r = 0.52. P = 0.018 in men;
      and r = 0.69, P < 0.0001, in women) and with the sum of 4 fat skinfolds (sigma
      skinfolds). E1-FA level was significantly and positively associated with fasting
      insulin (r = 0.62, P = 0.003 in men, and r = 0.48, P = 0.023 in women) but not
      with fasting glucose levels. E1-FA correlated with insulin sensitivity (SI, r = 
      0.72 in men; and -0.76, in women, both P < 0.0001). In men, E1-FA levels also
      correlated with systolic blood pressure (r = 0.59, P = 0.01), total triglycerides
      (r = 0.63, P = 0.003), VLDL-triglycerides (r = 0.62, P = 0.004) and VLDL
      cholesterol (r = 0.48, P = 0.03), but not with diastolic blood pressure, serum
      total or LDL-cholesterol, or total and HDL2 and HDL3 subfractions of HDL
      cholesterol. After controlling for fat mass, only the correlation between VLDL
      triglycerides and E1-FA levels remained significant. In women, E1-FA levels
      correlated with total triglycerides (r = 0.66, P = 0.001), VLDL-triglycerides (r
      = 0.65, P = 0.001), VLDL-cholesterol (r = 0.63, P = 0.002), LDL-cholesterol (r =
      0.57, P = 0.005) and total and HDL2 and HDL3 subfractions of HDL cholesterol (r =
      -0.58, -0.48, -0.61, P = 0.004, 0.02 and 0.002, respectively), but not with
      systolic or diastolic blood pressure or total cholesterol. However, covariance
      analysis revealed that controlling for the concomitant variation in body fat mass
      eliminated all these associations. Fasting plasma E1-FA concentration correlated
      with serum leptin (r = 0.60, P = 0.005 in men; r = 0.75, P = 0.0001, in women).
      However, these correlations no longer persisted after controlling for fat mass (r
      = 0.33 and 0.36, P = NS). Stepwise regression analysis models were tested, with
      E1-FA as the dependent variable, and sigma skinfolds and SI as independent
      covariables. Both the sigma skinfolds (P = 0.03) and SI (P = 0.01) entered the
      equation at a statistically significant level in men. Therefore, insulin
      sensitivity was related to E1-FA independently of fat in men. In women only sigma
      skinfolds (P = 0.04) entered the regression model at a statistically
      significantly level. Fifty-seven percent of the variance in plasma E1-FA levels
      in men, and 50% in women, was accounted for using a regression model that
      combined these variables. CONCLUSIONS: Oestrone-fatty acid esters circulate in
      human blood in proportion to body fat, independently of gender. Plasma oestrone
      fatty acid ester levels are associated with insulin sensitivity in men,
      independently of body fat. These findings may widen our perspective on the
      regulation of insulin action and control of body weight.

PMID- 10396373
TI  - Hyperprolactinaemia as a reversible cause of weight gain in male patients?

PMID- 10396372
TI  - Apparent cure of Graves-Basedow disease after sibling allogeneic bone marrow
      transplantation.
AB  - Evidence that allogeneic bone marrow transplantation (BMT) can cure or alter the
      course of intractable autoimmune diseases comes from both extensive experimental
      work in animal models and anecdotal case reports in humans. We describe a female
      patient diagnosed as having severe aplastic anaemia (SAA), hyperthyroidism and
      ophthalmopathy of Graves-Basedow disease who received a BMT from her
      histocompatible sister. Fifty-three months after BMT, complete remission of
      hyperthyroidism and ocular signs persists. The SAA is cured and she is free of
      any chronic graft-versus-host disease (GVHD). In the early post-BMT period, PCR
      analysis of bone marrow and peripheral blood cells confirmed a complete chimerism
      of donor origin. Thus, it is plausible to attribute the resolution of the
      patient's thyroid hyperfunction and opththalmopathy to the replacement of the
      host immune system.

PMID- 10396374
TI  - Prevalence of MEN 1 in patients with prolactinoma. MEN1 Study Group of the
      Hospital de la Santa Creu i Sant Pau of Barcelona.

PMID- 10396375
TI  - The effectiveness of surgery for congenital nystagmus.
AB  - Many individuals with CN cope remarkably well. With several different surgical
      approaches available, there needs to be reasonable certainty that a chosen
      treatment is the best for an individual patient. It is hoped that continued
      research into the mechanisms underlying CN will deliver a deeper understanding of
      exactly how extraocular surgery brings about an improvement in some cases while
      still being less than perfectly reliable in others.

PMID- 10396376
TI  - Child abuse and the eye. The Ophthalmology Child Abuse Working Party.

PMID- 10396377
TI  - Surgical treatment in nystagmus.
AB  - PURPOSE: To evaluate the effect of symmetric recession surgery on all four
      horizontal rectus muscles in the treatment of patients with congenital motor
      nystagmus and sensory nystagmus secondary to albinism, dyschromatopsia and
      degenerative myopia. METHODS: Prospectively, four patients with a diagnosis of
      congenital motor nystagmus and eight patients with sensory nystagmus were
      operated on. The amount of recession was determined according to the ocular
      alignment of the patients. Electronystagmographic recordings were conducted in
      every patient pre-operatively and post-operatively, as well as an
      ophthalmological examination. RESULTS: Mean age of the patients at the time of
      the first visit was 6.7 +/- 4.2 years (range 9 months to 14 years) and mean age
      at the time of operation was 8.3 +/- 2.7 years (range 6-14 years). In 8 cases an
      equal amount of weakening of the four horizontal recti was done, whereas in 2
      cases more recession on the lateral recti due to exotropia and in 2 cases more
      recession on the medial recti due to esotropia was performed. Mean follow-up time
      was 15.8 months (min. 6 months, max. 28 months). Improvement in visual function
      was achieved in 7 patients. Amplitude decreased in 9 patients. One patient had a
      decrease in visual acuity due to progression of her primary macular degeneration.
      Improvement in head posture was seen in 3 patients and there was no change in the
      head posture in 2 patients. One patient acquired head posture after surgery.
      Restriction of motility was seen in none of the patients after surgery in spite
      of large amounts of recession. Recession of horizontal recti decreased nystagmus
      amplitude and frequency in 81.8% of patients. Improvement in visual function,
      measured as an increase in visual acuity in terms of Snellen lines, was achieved
      in 63.6% of patients. CONCLUSION: Symmetric recession of the horizontal rectus
      muscles is shown to be a successful procedure to perform in nystagmus patients,
      resulting in an increase in visual acuity and a decrease in nystagmus amplitude
      and frequency. It is a reliable alternative to the Kestenbaum operation and is
      easier to perform surgically.

PMID- 10396378
TI  - Sorsby's fundus dystrophy: a case report of 24 years follow-up with
      electrodiagnostic tests and indocyanine green angiography.
AB  - PURPOSE: Five families with dominantly inherited macular dystrophy were
      originally described by Sorsby et al. in 1949. Key features include early
      bilateral central visual loss secondary to either choroidal neovascularisation or
      central geographical atrophy and late progressive chorioretinal atrophy. We
      report a member of one of the original families who has been studied with a
      series of investigations over a long time, providing important information on
      differences in the phenotype and natural history of a rare genetically determined
      macular dystrophy. METHODS: The patient has been followed up for the last 24
      years, from asymptomatic to full manifestation of Sorsby's fundus dystrophy.
      Series of fundus photographs, colour vision, dark adaptation and
      electrodiagnostic tests were performed. The disease was also studied with fundus
      fluorescein angiography and indocyanine green angiography. RESULTS: Unlike her
      other family members, who were reported in other studies as all having rapid loss
      of vision secondary to disciform macular disease, our patient has a unique
      clinical course in that she has a progressive bilateral central and generalised
      chorioretinal atrophy with a well-preserved minute central island of fovea.
      Nyctalopia was her early and only symptom. There was evidence of central scotoma,
      tritanopia and mild abnormality in dark adaptation. Rod function was affected
      earlier and to a larger degree than cone function. CONCLUSIONS: The overall
      features suggest phenotypic variability within a family in this autosomal
      dominant macular dystrophy. The findings from indocyanine green angiography and a
      consecutive series of electrodiagnostic tests in this condition support the
      theory of partial choroidal hypoperfusion and an interesting progressive rod-cone
      dystrophy as part of the pathophysiology.

PMID- 10396379
TI  - Limited argon laser peripheral iridoplasty as immediate treatment for an acute
      attack of primary angle closure glaucoma: a preliminary study.
AB  - PURPOSE: To study the efficacy and safety of limited (180 degrees) argon laser
      peripheral iridoplasty (ALPI) as a first-line treatment for acute primary angle
      closure glaucoma (PACG) without the use of systemic anti-glaucomatous
      medications. METHODS: Ten consecutive patients with PACG were recruited into the
      study. Each patient received topical pilocarpine (4%) and timolol (0.5%), and
      immediate limited ALPI as primary treatment. The intraocular pressures at 15, 30
      and 60 min after ALPI were documented by Goldmann applanation tonometry. RESULTS:
      The mean intraocular pressure (IOP) of this group of patients was reduced from
      57.9 +/- 10.6 mmHg to 39.0 +/- 10.9 mmHg at 15 min, 28.3 +/- 9.1 mmHg at 30 min
      and 20.4 +/- 9.0 mmHg at 60 min after ALPI. No complications were encountered. In
      8 of the 10 patients the corneal oedema cleared 1 h after ALPI. In the remaining
      2 patients the corneal oedema cleared 2 h after ALPI. CONCLUSION: Immediate
      limited ALPI, without adjunctive systemic anti-glaucomatous medications, appeared
      to be effective and safe in controlling the IOP in treating acute PACG with a
      duration of attack < or = 48 h. It may be as effective as 360 degrees ALPI, and
      therefore has a role in those patients in whom 360 degrees treatment is not
      possible.

PMID- 10396380
TI  - The effect of once-daily latanoprost on intraocular pressure and pulsatile ocular
      blood flow in normal tension glaucoma.
AB  - PURPOSE: To determine the effect of once-daily 0.005% latanoprost on intraocular
      pressure (IOP) and pulsatile ocular blood flow (POBF) in patients with normal
      tension glaucoma (NTG). METHODS: The diurnal IOP and sitting POBF were determined
      for 32 eyes of 19 NTG patients after a washout period. The subjects were treated
      with 0.005% latanoprost for 3-4 weeks and the measurements repeated. Statistical
      analysis was performed using the Wilcoxon signed rank test. RESULTS: Median IOP
      before and after treatment were 19 and 15 mmHg respectively (p < 0.001). The IOP
      reduction correlated with the initial IOP before treatment (p < 0.01) and was
      accompanied by an increase in median POBF from 656 to 796 microliters/min (p <
      0.001). CONCLUSIONS: Once-daily treatment with 0.005% latanoprost provides a
      significant and stable IOP reduction in the majority of NTG patients after short
      term treatment. This is accompanied by a significant increase in POBF.

PMID- 10396381
TI  - Tono-Pen tonometer and corneal thickness.
AB  - PURPOSE: To compare the intraocular pressure (IOP) measurements taken at the
      central cornea with those taken at the mid-peripheral cornea using the Tono-Pen
      tonometer. METHODS: Forty-eight normal human subjects had their IOP measurements
      taken (i) with the Goldmann tonometer, (ii) with the Tono-Pen at the central
      cornea and (iii) with the Tono-Pen at the mid-peripheral cornea. The central and
      mid-peripheral corneal thickness at the site of IOP measurements were then
      determined by ultrasonic pachymetry. RESULTS: The mean IOP with the Goldmann
      tonometer was 15.7 +/- 3.1 mmHg. The mean Tono-Pen IOPs at the central and
      midperipheral cornea were 15.2 +/- 3.2 mmHg and 15.7 +/- 3.3 mmHg respectively.
      The mean midperipheral corneal thickness (578 microns) was significantly higher
      than the mean central thickness (538 microns) (p < 0.001). CONCLUSION: There was
      no significant difference between the IOP taken with the Tono-Pen and with the
      Goldmann tonometer. In addition, no clinically significant difference was
      observed between the IOP readings of central and mid-peripheral cornea measured
      by the Tono-Pen.

PMID- 10396382
TI  - Primary orbital Ewing's sarcoma: report of a case and review of the literature.
AB  - Primary orbital Ewing's sarcoma is a very rare condition. Since the first case
      was reported in 1950, only 7 other cases have been reported in the English
      literature. Herein we describe the ninth, the only bilateral and the youngest
      case of primary orbital Ewing's sarcoma occurring in a 2-year-old boy, who
      presented to us with bilateral painless proptosis. Tissue biopsy of the tumour
      was obtained through the nasal sinus. Immunohistological studies of the biopsy
      tissue confirmed the diagnosis of Ewing's sarcoma. No distant site of the tumour
      was found so this was considered a primary orbital tumour. Combined chemotherapy
      and radiotherapy without surgical resection achieved an encouraging result in
      that the patient has remained in remission for 30 months after completion of
      treatment. The successful use of combined chemotherapy and radiotherapy, without
      surgery, adds further support to evidence that surgical excision may be avoided
      in selected cases of primary orbital Ewing's sarcoma.

PMID- 10396383
TI  - Genetic predisposition to ocular melanoma.
AB  - Uveal melanoma is the most common primary intraocular malignancy, with an annual
      incidence of 6 per million. The environmental factors known to increase the risk
      of cutaneous melanoma appear to be less important in ocular melanoma and it is
      conceivable that host factors have a greater impact. The coexistence of ocular
      and cutaneous melanoma in some patients suggests a predisposition to both types
      and implicates mutations in the CDKN2A gene in a proportion of these cases. An
      association between ocular melanoma and breast and/or ovarian cancer has also
      been reported and recent studies of breast cancer families strongly implicate
      BRCA2 as a predisposition gene. Other more common genes predisposing to ocular
      melanoma may be of low penetrance. An example of a gene in this class is MC1R,
      which affects host response to ultraviolet radiation. Identification of genes
      conferring an increased risk of ocular melanoma should provide insights into the
      pathogenesis of this tumour. Furthermore, it offers an opportunity to identify
      individuals at a high risk who may benefit from targeted surveillance. At present
      the identification of such individuals is restricted to the small number
      belonging to BRCA2 families and those with the atypical mole syndrome.

PMID- 10396384
TI  - ERG and VEP follow-up study in children with Leber's congenital amaurosis.
AB  - PURPOSE: Our prospective clinical and electrophysiological study of children
      suspected of Leber's congenital amaurosis (LCA) was aimed to follow-up the course
      of their visual dysfunction. METHODS: Electroretinography (ERG) and visual evoked
      potentials (VEP) to white flash stimulation were simultaneously recorded in 9
      children at least twice. RESULTS: The first flash ERG and flash VEP recordings
      were performed when children were 3-17 months old (mean age 7.6 months). Flash
      ERG was not recordable in 8 children; flash VEP to binocular stimulation could
      not be detected in 3, was delayed in 2, attenuated in 2, both attenuated and
      delayed in 1, and without evident abnormality in 1 of the 9 children. On the last
      examination (mean age 33.8 months) flash VEP activity was recordable in all
      children, while flash ERG was recordable in 1. Electrophysiological follow-up
      (mean duration 26.2 months) showed no deterioration of flash VEP in 8 children.
      CONCLUSION: In children of LCA simultaneous recording of flash ERG and flash VEP
      in alert children was helpful to indicate the nature of the visual problem for
      diagnostic and follow-up purposes.

PMID- 10396385
TI  - Changes in anterior chamber depth and axial length measurements after radial
      keratotomy.
AB  - PURPOSE: To evaluate the changes that occur in anterior chamber depth and globe
      axial length after radial keratotomy (RK) surgery in cases with different degrees
      of myopia. METHODS: One hundred and twelve eyes that underwent RK were studied.
      The eyes were divided into two groups: 70 eyes with a correction of myopia of
      4.00 D and under after RK (group 1) and 42 eyes with a correction of myopia of
      more than 4.00 D (group 2). Routine examinations were done in all cases.
      Ultrasonic biometry and central anterior chamber depth and axial length were
      measured pre-operatively and on the third day, second week, third month and sixth
      month post-operatively. RESULTS: Pre-operatively the average globe axial length
      was longer in group 2 than group 1. When all post-operative measurements were
      compared with pre-operative measurements in group 1, there was a decrease in
      anterior chamber depth and globe axial length, but no significant difference was
      found except on the third day (t = 3.15, p = 0.003). In group 2 there was an
      insignificant decrease in axial length but the decrease in anterior chamber depth
      was significant at all measurement times except for the sixth month. CONCLUSIONS:
      Refractive changes related to biometric changes after RK are not important
      compared with the total refractive corrections of RK. These changes should be
      considered, however, when planning RK procedures.

PMID- 10396386
TI  - Changing trends in cytomegalovirus retinitis with triple therapy.
AB  - PURPOSE: Cytomegalovirus retinitis (CMVR) has been the most common cause of
      visual loss in AIDS patients. We investigate whether the pattern of disease has
      changed since the introduction of triple therapy. METHODS: We reviewed the
      records of all patients with CMVR in one teaching hospital HIV unit over a 2 year
      period (n = 24). This included the opthalmic and systemic findings, HIV and CMV
      treatment, survival after diagnosis and CD4 results. RESULTS: There has been a
      marked decrease in the number of patients developing new CMVR: from 21 eyes (15
      patients) to 4 eyes (4 patients) in two consecutive 12 month periods between
      January 1996 and December 1997, coinciding with the introduction of triple
      therapy in October 1996. Median survival has increased from 376 days in the
      deceased patients to 598 days in the survivors on triple therapy. Median time to
      CMVR relapse has lengthened from 79 to 179 days in the triple therapy cohort. The
      pattern of ocular morbidity in the 11 eyes of the 7 surviving patients is also
      changing, with no new zone 1 disease, and a marked rise in the incidence of
      uveitis, maculopathy and cataracts. CONCLUSION: Results suggest that triple
      therapy is associated with an increase in survival, a decrease in CMVR relapse
      and changes in ocular features. This transition has implications for current
      screening and treatment protocols.

PMID- 10396387
TI  - Childhood blindness in Uzbekistan.
AB  - PURPOSE: To elucidate the aetiology of childhood blindness in the Republic of
      Uzbekistan and to assess the needs for future provision of ophthalmic services
      for children. METHODS: Six hundred and seventy-one children in seven schools for
      the blind and visually impaired throughout Uzbekistan were examined using the
      WHO/PBL (World Health Organization Prevention Of Blindness) childhood blindness
      proforma. The locations were chosen to give a representation of the major areas
      of population within the country. RESULTS: Of the 671 children examined, 506
      (75.4%) were blind or severely visually impaired (corrected visual acuity of less
      than 6/60 (20/200) in the better eye). Cataract-related blindness (35%), retinal
      dystrophies (24%) and microphthalmos (23%) formed the three largest diagnostic
      categories. CONCLUSIONS: The commonest avoidable cause of blindness was found to
      be cataract; the cause of poor vision may be due to unoperated cataract, aphakia,
      amblyopia or post-operative capsular fibrosis. The high proportion of retinal
      dystrophies may be related to the common practice of consanguineous marriage. The
      frequent finding of microphthalmos is discussed and compared with findings from
      other surveys. Glaucoma accounted for approximately 5% of the avoidable
      blindness.

PMID- 10396389
TI  - Is sphenoid sinus opacity significant in patients with optic neuritis?
AB  - PURPOSE: Optic neuritis secondary to sinus disease is an infrequent but well
      documented association. When a patient presents with signs of optic nerve
      dysfunction and orbital inflammation the significance of widespread sinus disease
      on radiology is clear and the management is straightforward. We present a group
      of patients with isolated optic neuritis and radiological evidence of spheno
      ethmoiditis and discuss the clinical relevance of this finding. METHODS: We
      reviewed the notes of 11 patients with optic neuritis who, because of atypical
      headache, underwent neuroimaging revealing sphenoid sinus opacity. Six patients
      had endoscopic drainage of the sphenoid sinus; 4 were treated medically. RESULTS:
      Sinus contents included fungal infection (2), mucopurulent material (5), polyps
      (1) and necrotic tumour (1). Narrowing of the optic canal due to chronic
      osteomyelitis was found in 1 patient with irreversible optic atrophy. Visual loss
      was reversible in 6 patients. Four patients had normal radiological findings
      after treatment. Two patients had recurrent optic neuritis with sphenoid
      sinusitis on MRI scan, resolving on treatment, during the 4 year follow-up
      period. CONCLUSIONS: Possible mechanisms of nerve damage in this situation
      include direct spread of infection, occlusive vasculitis and bony deficiency in
      the wall of the sinus. Patients presenting with isolated optic neuritis and
      atypical headache should be scanned; an opaque sphenoid sinus in the context of
      visual loss should not be dismissed as coincidental but assumed to be
      pathological and the patient referred for drainage. Sphenoid sinusitis is an
      uncommon but treatable cause of optic neuritis.

PMID- 10396388
TI  - Management of day-surgery patients with cataract attending a peripheral
      ophthalmic clinic.
AB  - PURPOSE: To compare two organisational models of management for patients with
      cataract referred to a peripheral ophthalmic clinic who underwent day-surgery at
      a main eye hospital. METHOD: Patients were randomised into two groups. The
      experimental group (n = 25) received pre-operative assessment by a trained
      ophthalmic nurse at the peripheral clinic immediately following diagnosis of
      cataract and diary-booking for surgery. The control group (n = 24) received a
      separate appointment for pre-operative assessment at the main hospital. For all
      patients, the first review appointment (3 or 5 days post-operatively) and all
      subsequent review was at the peripheral clinic. Outcome measures included: visual
      acuity, subjective visual function (VF-14), anxiety and depression (HADS), semi
      structured interviews to ascertain patient satisfaction, and a cost-benefit
      analysis. RESULTS: There were no significant differences at any time between the
      experimental and control groups with respect to visual acuity, subjective visual
      function or anxiety and depression. The experimental model was found to be more
      cost-effective and provided a less fragmented means of care delivery. The
      majority of patients in both groups expressed satisfaction with their care but,
      overall, the experimental model was preferred. CONCLUSIONS: Nurse-led pre
      operative assessment of patients with cataract at a peripheral ophthalmic clinic
      is safe, cost-effective and is preferred by patients.

PMID- 10396390
TI  - The development and maintenance of emmetropia.
AB  - The human eye is programmed to achieve emmetropia in youth and to maintain
      emmetropia with advancing years. This is despite the changes in all eye
      dimensions during the period of growth and the continuing growth of the lens
      throughout life. The process of emmetropisation in the child's eye is indicated
      by a shift from the Gaussian distribution of refractive errors around a
      hypermetropic mean value at birth to the non-Gaussian leptokurtosis around an
      emmetropic mean value in the adult. Emmetropisation is the result of both passive
      and active processes. The passive process is that of proportional enlargement of
      the eye in the child. The proportional enlargement of the eye reduces the power
      of the dioptric system in proportion to the increasing axial length. The power of
      the cornea is reduced by lengthening of the radius of curvature. The power of the
      lens is reduced by lengthening radii of curvature and the effectivity of the lens
      is reduced by deepening of the anterior chamber. Ametropia results when these
      changes are not proportional. The active mechanism involves the feedback of image
      focus information from the retina and consequent adjustment of the axial length.
      Defective image formation interferes with this feedback and ametropia then
      results. Heredity determines the tendency to certain globe proportions and
      environment plays a part in influencing the action of active emmetropisation. The
      maintenance of emmetropia in the adult in spite of continuing lens growth with
      increasing lens thickness and increasing lens curvature, which is known as the
      lens paradox, is due to the refractive index changes balancing the effect of the
      increased curvature. These changes may be due to the differences between nucleus
      and cortex or to gradient changes within the cortex.

PMID- 10396391
TI  - Reliability of drop size from multi-dose eye drop bottles: is it cause for
      concern?
AB  - PURPOSE: Responses to topically applied ocular drugs vary between patients. The
      volume of drug instilled is of particular importance as one of many sources of
      response variation, but the reliability of drop volume from eye drop bottles is
      unknown. Hence, the repeatability of drop volume and factors affecting this for a
      variety of drug manufacturers were considered in this study. METHODS: Nineteen
      bottles, one from each primary manufacturer in the UK, were examined. The mass of
      all drops expelled from each bottle was measured with respect to the bottle type,
      handling angle, drop number, drug and concentration. The accuracy (repeatability
      and trueness) of drops from each bottle was also evaluated. RESULTS: Drop volume
      varied significantly between drug manufacturers, ranging from 33.8 microliters to
      63.4 microliters. The handling angle of the bottle also influenced drop volume,
      with angles less than 60 degrees giving smaller drops. Drop number exhibited no
      significant effect upon drop volume. However, the drug type and its concentration
      did significantly affect the volume of the drop expelled from the bottle, with
      higher concentrations giving rise to larger drops. Repeatability coefficients
      across the range of bottles varied between +/- 2.24 microliters and +/- 10.76
      microliters (mean +/- 5.07 microliters). CONCLUSIONS: It is well reported that
      drug volume instilled has a significant effect on the degree of response.
      However, there are currently no official regulations concerning eye drop volume
      in either the UK or the USA. Since drop volume has been shown to vary
      significantly depending upon a variety of factors, it may be appropriate that the
      regulatory bodies consider the consequences of variable drop size.

PMID- 10396392
TI  - Red blood cell membrane integrity in primary open angle glaucoma: ex vivo and in
      vitro studies.
AB  - PURPOSE: There is increasing evidence that abnormal perfusion of the optic nerve
      head is an important factor involved in the pathophysiology of glaucoma.
      Transport and distribution of oxygen to the tissues takes place through the
      erythrocyte membrane. Red blood cell (RBC) acetylcholinesterase (AChE) is a
      marker of RBC membrane integrity. The aim of this study was to find out whether
      RBC membrane integrity is preserved in primary open angle glaucoma (POAG), and
      whether it is modified by the use of topical timolol maleate and pilocarpine.
      METHOD: RBC AChE activity was determined ex vivo by Kaplan's spectrophotometric
      method in 19 POAG patients undergoing topical treatment for glaucoma with
      timolol, pilocarpine or a combination of the two drugs, and compared with that in
      20 controls. To assess the effect of antiglaucomatous therapy in our findings, we
      carried out an in vitro study in 26 non-glaucomatous patients in which we
      measured RBC AChE activity after incubation of blood with either timolol maleate,
      pilocarpine or a combination of the two drugs, using the same spectrophotometric
      method. RESULTS: There was a significant increase in RBC AChE enzyme activity in
      POAG patients compared with the control group (p < 0.002). However, timolol and
      pilocarpine, individually or in combination, have the opposite effect,
      significantly decreasing RBC AChE activity (p < 0.05). CONCLUSION: This change in
      RBC AChE enzyme activity could suggest alterations in RBC membrane integrity in
      primary open angle glaucoma. Whether or not this finding has implications
      regarding the microcirculation at the optic nerve head needs to be investigated
      further.

PMID- 10396393
TI  - Dimorphic immunohistochemical staining in ocular sebaceous neoplasms: a useful
      diagnostic aid.
AB  - PURPOSE: We studied whether patterns of immunostaining in formalin-fixed,
      paraffin-embedded tissue could help to distinguish between sebaceous neoplasms of
      the eyelid and other eyelid neoplasms. METHODS: We applied antibodies to human
      milk fat globule-1 (HMFG1), cytokeratins (PKK1 and MNF116), epithelial membrane
      antigen (EMA) and carcino-embryonic antigen (CEA) to normal eyelid tissue and to
      a range of sebaceous lesions of the eyelid; these included sebaceous hyperplasia,
      sebaceous adenoma and sebaceous epithelioma, in addition to well to poorly
      differentiated sebaceous carcinoma. RESULTS: The central and peripheral cellular
      components of normal sebaceous glands and neoplastic sebaceous lesions showed a
      distinctive dimorphic staining pattern with the antibody panel used. The central
      foamy 'sebaceous' cells expressed HMFG1 and EMA, but not PKK1 or MNF116, whereas
      the smaller, peripheral basal and ductal cells expressed PKK1 or MNF116 but not
      HMFG1 or EMA. CEA expression in sebaceous cells was unhelpful diagnostically.
      CONCLUSION: Normal sebaceous glands and all sebaceous neoplasms show a dimorphic
      cell population that can be identified using a small panel of antibodies on
      formalin-fixed, paraffin-embedded tissue. This distinctive staining pattern can
      be assessed retrospectively, even in small biopsies, and largely removes the need
      for fat stains on frozen sections to differentiate sebaceous lesions from other
      ocular neoplasms. The results also support the suggestion that ocular sebaceous
      neoplasms arise from a common stem cell, rather than from either sebaceous or
      basal/ductal cells.

PMID- 10396394
TI  - Sebaceous gland carcinoma of the eyelid seventeen years after irradiation for
      bilateral retinoblastoma.

PMID- 10396395
TI  - Use of ganciclovir implants for CMV retinitis in an 18-month-old child with AIDS.

PMID- 10396396
TI  - Peripapillary subretinal neovascular complex complicating papillitis.

PMID- 10396397
TI  - Endogenous fungal endophthalmitis caused by Paecilomyces variotii.

PMID- 10396398
TI  - Endogenous endophthalmitis due to group G streptococcus.

PMID- 10396399
TI  - Combined limbal and corneal autograft transplantation.

PMID- 10396400
TI  - Actinic keratoconjunctivitis and minocycline.

PMID- 10396401
TI  - Chiasmal apoplexy, an unusual complication of cerebral glioblastoma.

PMID- 10396402
TI  - Local anaesthesia for vitreoretinal surgery: a case-control study of 200 cases.

PMID- 10396403
TI  - The effect of intracameral, per-operative antibiotics on microbial contamination
      of anterior chamber aspirates during phacoemulsifaction.

PMID- 10396405
TI  - Hospital radiology: today and tomorrow.

PMID- 10396404
TI  - The role of radiofrequency ablation in the treatment of cardiac arrhythmias.

PMID- 10396406
TI  - Current issues in mammographic breast cancer screening.
AB  - Mammographic screening for the early detection of breast cancer is widely
      accepted as the most effective means currently available to reduce breast cancer
      deaths. However, evidence shows that to maximize benefits and minimize harm,
      mammographic screening must be of high quality.

PMID- 10396407
TI  - Imaging and stenting for renal artery stenosis.
AB  - Renal artery stenosis is a potentially correctable cause of hypertension and
      renal failure, using endoluminal or, less commonly, surgical techniques. A number
      of imaging techniques can be used to diagnose renal artery stenosis, all with
      similar accuracy.

PMID- 10396408
TI  - Central venous catheter placement.
AB  - Central venous access has become a vital element of medical care. Fraught with
      significant complications, traditional surgical approaches have yielded image
      guided techniques. This article reviews clinical aspects and devices used, and
      compares surgical and interventional radiological approaches. It also looks at
      complications and their management, and aspects of patient care.

PMID- 10396409
TI  - Magnetic resonance imaging and ischaemic stroke.
AB  - Recent successes in the management of acute ischaemic stroke have emphasized the
      importance of early diagnosis and treatment. Patients with a 'brain attack' are
      best managed as a medical emergency. Imaging is vital in identifying infarct as
      well as tissue at risk and is best done with ultrafast magnetic resonance
      imaging.

PMID- 10396410
TI  - The adverse effects of drugs.
AB  - Adverse drug reactions vary in presentation and severity, and can mimic almost
      any disease. The article explores the importance of adverse drug reactions in
      modern clinical practice, highlighting the mechanisms and how to manage patients.

PMID- 10396411
TI  - Paroxetine and its uses in psychiatry.
AB  - Paroxetine is one of the specific serotonin-reuptake inhibitor antidepressants
      which is used in a variety of psychiatric disorders. It has recently gained
      considerable publicity because of its use in social anxiety disorder and its
      subsequent labelling by the media as a 'lifestyle drug'. This review summarizes
      current indications for paroxetine and outlines doses and duration of treatment
      for each condition.

PMID- 10396412
TI  - Combination therapy for chronic hepatitis C: interferon and ribavirin.
AB  - Hepatitis C virus (HCV) infection is one of the commonest causes of liver
      cirrhosis and hepatocellular carcinoma. This review deals with treatment of
      chronic HCV infection with a combination of interferon and ribavirin. Recent
      trials have shown that approximately 40% of patients will clear HCV with
      combination treatment. This is an important advance in the treatment of this
      serious viral infection.

PMID- 10396413
TI  - Clopidogrel: a novel antiplatelet agent.
AB  - Clopidogrel is a novel antiplatelet agent that has a different mechanism of
      action to aspirin. Clopidogrel is chemically related to ticlopidine, both of
      which are more effective than aspirin in preventing some thrombotic events, but
      it has a safer side-effect profile than ticlopidine. It is likely to add to the
      antithrombotic armoury and reduce vascular mortality and morbidity more than
      current therapies.

PMID- 10396414
TI  - Immunosuppressive agents in organ transplantation.
AB  - This article reviews current and future immunosuppressive strategies in organ
      transplantation. Recently introduced drugs are lowering the rates of acute
      rejection and allowing more individualized management of transplanted patients.

PMID- 10396415
TI  - Using the Internet for postgraduate medical education.
AB  - Obtaining information from the Internet can be fun. As the Internet is
      unregulated, the quality of this information can vary enormously and time can be
      wasted searching poor quality websites. Despite this, use of the Internet for
      postgraduate medical education is increasing.

PMID- 10396416
TI  - The junior doctor manager.
AB  - Several organizations are employing junior doctor managers to help them implement
      and maintain controls on the hours worked by their colleagues, and to improve
      conditions. A person who has worked as a junior doctor is in a good position to
      understand these issues.

PMID- 10396417
TI  - Lumbar puncture in subarachnoid haemorrhage: a necessary evil?

PMID- 10396418
TI  - The changing face of endocarditis: report of a series of cases.

PMID- 10396419
TI  - Interferon-alpha induced 'tertiary mania'.

PMID- 10396420
TI  - Spontaneous oesophageal rupture.

PMID- 10396421
TI  - Infective endocarditis.

PMID- 10396422
TI  - Local anaesthetics.

PMID- 10396423
TI  - Euthanasia: who needs it?

PMID- 10396424
TI  - A labouring opera singer with idiopathic thrombocytopenia: 'its not over 'til the
      fat lady sings'.

PMID- 10396425
TI  - Screening for genital chlamydial infection.

PMID- 10396426
TI  - Effective gynaecological practice and evidence-based medicine.

PMID- 10396428
TI  - HELLP syndrome: mechanisms and management.
AB  - Effective management of HELLP syndrome depends on swift recognition of a
      condition which often masquerades as other pathology. This article reviews
      clinical aspects of HELLP syndrome and outlines recent advances in our
      comprehension of what may be the underlying pathophysiology.

PMID- 10396427
TI  - Osteoporosis and its management.
AB  - Osteoporosis is a common systemic disease leading to premature fractures. This
      article reviews the state of the art of assessing the risk of future osteoporotic
      fracture and summarizes the prevention and treatment of the condition.

PMID- 10396429
TI  - Recurrent cervical smear abnormalities following treatment.
AB  - The cervical screening programme has had a dramatic impact on the incidence of
      invasive cervical cancer and preinvasive disease can be effectively treated in
      the majority of cases. However, recurrent abnormalities after treatment pose
      management dilemmas which are considered in this overview of the topic.

PMID- 10396430
TI  - Pruritus in pregnancy and obstetric cholestasis.
AB  - Pruritus is often considered a common but minor symptom of pregnancy. However,
      pruritus caused by obstetric cholestasis is increasingly being recognized as a
      cause of so-called 'unexplained' stillbirths. This article reviews recent
      literature and outlines possible management strategies with the aim of reducing
      maternal morbidity and improving perinatal outcome.

PMID- 10396431
TI  - Tracheostomy management in ordinary wards.
AB  - Tracheostomy is more commonplace, particularly since the introduction of
      percutaneous techniques performed at the patient's bedside in the intensive care
      unit. Subsequent care and management within ordinary wards causes anxiety among
      staff. This review identifies some of the problems encountered and discusses
      their potential management.

PMID- 10396432
TI  - Asthma management with HFA-BDP (Qvar).
AB  - This report reviews the role of hydrofluoroalkane-beclomethasone dipropionate
      (HFA-BDP; Qvar, 3M, Laughborough) in the management of asthma, based on
      pharmacokinetic, efficacy and safety clinical trial data presented at a satellite
      symposium to the European Respiratory Society in 1998. Qvar provides equivalent
      efficacy and safety to chlorofluorocarbon-BDP at about half the dose.

PMID- 10396433
TI  - Carotid endarterectomy under local anaesthesia.
AB  - Carotid endarterectomy has been widely used for the surgical treatment of carotid
      stenosis, and may be performed under either general or local anaesthesia. This
      article examines the relative merits of both techniques for carotid
      endarterectomy, and describes the local anaesthetic technique used by the authors
      for this procedure.

PMID- 10396434
TI  - Migraine: which triptan?
AB  - A wide variety of drugs are now available for the acute treatment of migraine
      attacks. Although the new triptans are expensive, clinical trials have shown them
      to be highly effective, and they are the treatment of choice for disabling
      attacks unresponsive to cheaper medication. This article discusses the different
      clinical circumstances in which each preparation may prove the most effective.

PMID- 10396435
TI  - The role of laboratory investigations in identifying body fluids.
AB  - In diverse clinical situations it may be important to establish the nature and
      origin of fluid samples. This article sets out to provide some practical guidance
      on the role of laboratory investigations in this process.

PMID- 10396436
TI  - Flexible specialist training compared with full-time training.
AB  - The educational and training quality of flexible training posts compared very
      well and in some instances was better than that obtained in full-time training.
      The hours of work were fewer, but as a proportion not as small as is sometimes
      recognized by the Colleges and is comparable with many full-time training
      programmes in other European Union countries.

PMID- 10396437
TI  - Specialist registrar training in obstetrics and gynaecology: have we got it
      wrong?
AB  - The introduction of the Calman proposals for radical reform of the training of
      young doctors is now nearly 3 years past. Obstetrics and gynaecology was one of
      the first major specialties to go through the convulsions of transition and it
      has emerged on the other side well organized and in tune with the requirements of
      the reforms, but just how are they perceived by the trainees and trainers?

PMID- 10396438
TI  - Confounded by confounding: separating association from causation.
AB  - Health-care professionals need to be able to distinguish causal relationships
      from simple associations in two main areas: when unravelling the aetiology of
      diseases, and when assessing the effects of therapies. In each of these the
      presence of confounding can seriously mislead. This short report explains the
      nature of confounding and outlines criteria that can be applied to help
      distinguish causality from mere statistical associations.

PMID- 10396439
TI  - Treatment of hyperlipidaemia as a risk factor for coronary heart disease: the
      role of fibrates.

PMID- 10396440
TI  - Giant cell arteritis as a cause of intermittent claudication.

PMID- 10396441
TI  - Thyrotoxicosis and abdominal pain: atypical presentation in a middle-aged man.

PMID- 10396442
TI  - Tachycardia-induced cardiomyopathy caused by atrial flutter responding to DC
      cardioversion.

PMID- 10396443
TI  - New quinolones in clinical practice.

PMID- 10396444
TI  - Local anaesthetics: the debate continues.

PMID- 10396445
TI  - Acute myocardial infarction: failed thrombolysis.

PMID- 10396446
TI  - Coexisting allergies to latex and to muscle relaxants in a primigravida.

PMID- 10396448
TI  - Subcellular membrane impairment and application of phospholipase A2 inhibitors in
      endotoxic shock.
AB  - The study aims at elucidating the mechanism involved in the cell dysfunction or
      impairment and the protective effects of phospholipase A2 (PLA2) inhibitors in
      endotoxin shock. Thirty-four rabbits were divided randomly into four groups: (1)
      normal control group (NC, n = 6), receiving saline intravenously; (2) endotoxin
      shock group (ES, n = 12), receiving 3 mg/kg of E. coli endotoxin; (3) chloroquine
      pretreated group (CQ, n = 8), receiving 3 mg/kg of chloroquine 3 min before
      endotoxin injection and (4) chlorpromazine pretreated group (CPZ, n = 8),
      receiving 0.3 mg/kg of chlorpromazine 30 min before endotoxin injection. Hepatic
      mitochondria were extracted either 8 h after commencement of the experiment or
      when the animals died for detecting PLA2 activity, membrane fluidity, membrane
      bound succinate dehydrogenate (SDH) and malondialdehyde (MDA). Mitochondria of
      the lung, heart and kidney were also used for detection of the membrane fluidity.
      It was revealed that the survival rate of 8 h was 100% (NC), 58% (ES), 87.5% (CQ)
      and 75% (CPZ), respectively. Mean arterial pressure (MAP) dropped soon after
      endotoxin injection and descended continuously afterwards in the ES group (P <
      0.01). Fluorescence polarization, microviscosity and anisotrophy with a DPH probe
      were elevated above control levels (P < 0.01). SDH was decreased obviously
      following endotoxin infusion (P < 0.01). Chloroquine and chlorpromazine, serving
      as PLA2 inhibitors, could abate cellular dysfunction and increase survival rate.
      It is proposed that PLA2 plays a pivotal role in cellular injury in endotoxin
      shock. PLA2 inhibitor might serve as a useful adjunct in combating sepsis and
      shock.

PMID- 10396447
TI  - A review of the quality of trauma protocols on the Internet.
AB  - A review of trauma protocols found on the Internet was performed in September
      1997 to evaluate the content, presentation and usefulness of these resources. A
      wide variation was found in the nature of these 'protocols', the educational
      content and the academic strengths of the web pages. We attempted to define a
      protocol and a scoring system to assess these documents and reviewed each
      accordingly.

PMID- 10396449
TI  - Missile injuries of the sciatic nerve.
AB  - Missile injuries of the sciatic nerve are not common in civil practice. We
      analysed a war series of 55 cases operated on in a period from 1991 to 1995.
      Nerve continuity was preserved at least partially in 76.4% of cases, but only
      13.3% of cases had preserved some nerve function. Surgical results were analysed
      in 45 cases followed for more than two years. The rates of useful functional
      recovery were 86.7% for tibial division, 53.3% for peroneal division and 86.7%
      for the sciatic nerve complex. On the basis of the obtained results we were able
      to make the following conclusions: (1) missile injuries to the sciatic nerve are
      characterised by partially preserved nerve continuity and complete functional
      loss in the majority of cases, (2) surgery should be performed 3 to 6 months
      after injury, (3) reconstruction of tibial division is the major goal of surgical
      repair, (4) the extent and severity of nerve damage and the type of surgical
      procedure are the main prognostic factors and (5) failures of surgical repair are
      usually related to nerve grafting at gluteal level.

PMID- 10396450
TI  - Percutaneous intramedullary elastic wiring of displaced diaphyseal forearm
      fractures in children. A modified technique.
AB  - Under the age of 11 years there are specific anatomic considerations which favour
      intramedullary wiring of displaced forearm fractures. The isthmus of radius and
      ulna is narrow (range = 3-6 mm). The medulla is at its widest proximally in the
      (ulna) and distally in the radius. These are the optimum entry points for
      intramedullary progression of the wire. At these points there is a low stress
      raising effect minimising the risk of iatrogenic fracture. A 1.6 mm Kirschner
      wire is elastic enough to be prebent into a large radius. It is strong enough to
      resist deformity on entry, though elastic enough to achieve stability by
      intramedullary three-point contact. The tip of the wire is prebent to 30 degrees
      aiding closed reduction of displaced fractures. An oblique 4.5 mm drill hole is
      made through a < 2 cm skin incision avoiding the epiphysis. This allows the wire
      to be introduced into the intramedullary canal at an optimum angle of 30 degrees.
      A smaller hole would not allow intramedullary progression e.g.; in a 2.5 mm hole
      the angle of insertion would be 55 degrees. Wire is now held with a cannulated T
      handle, which is tapped with a hammer thus bouncing the wire of the side wall
      into the medulla. Rotating the handle aids reducing of displaced fractures. There
      are advantages to this method over other methods of intramedullary fixation e.g.;
      Steinman pins, Rush pins, or Nancy nails. Also holds advantage over plating. Over
      the last 12 months 11 cases were treated by the above methods without significant
      complications.

PMID- 10396451
TI  - Do axial dynamic fixators really produce axial dynamization?
AB  - The use of dynamic external fixators for the treatment of long bone fracture is
      widespread and well accepted. It is claimed that dynamization, i.e. small
      micromovements of compression/distraction at the fracture site, can be produced
      by allowing sliding of an inner rod within an outer housing. However, as the
      forces on the fixator are not direct but transferred from the bone via bone pins,
      there is a bending moment on the fixator. This produces "self-locking" and
      effectively prevents axial movements. We have studied the effect of this moment
      on the binding properties of the Orthofix system. The amount of movement at a
      simulated fracture site allowed before this locking occurs was measured and its
      implications discussed. It would appear that true axial dynamization does not
      take place using this system.

PMID- 10396452
TI  - Fatal falls down stairs.
AB  - Fatal falls down stairs in south-east Scotland were studied using prospectively
      collected data between 1992 and 1997. 51 individuals, comprising 27 men and 24
      women with mean age 68.9 years, died following falls down stairs, 30 (59%) of
      which were unwitnessed. 43 (84%) individuals died following falls within their
      own homes. Overall, 27 (53%) fatal falls resulted in death at the scene of the
      accident. Analysis of injuries according to the Abbreviated Injury Scale yielded
      injury severity scores (ISS) of between 5 and 75, but only four individuals had
      injuries recognised to be unsurvivable (ISS = 75). Injury to the brain and/or
      spinal cord was responsible for the vast majority of most severe injuries. The
      results demonstrate that stairs represent a significant hazard for the elderly.
      Most of the deaths in the pre-hospital setting appeared to be more the result of
      the fact that the victim was alone and unable to summon assistance, rather than
      as a result of unsurvivable injuries. Consideration needs to be given to both how
      the safety of stairs can be improved and whether a particular elderly person can
      safely cope with stairs.

PMID- 10396453
TI  - Can we evaluate the pressure of perihepatic packing? Results of a study on dogs.
AB  - The pressure of perihepatic packing can cause organ perfusion disturbances. The
      problem is to determine the pressure applied during the operative procedure. The
      objective of this animal study was to assess the perihepatic packing pressure and
      its effect on the pressure in the inferior vena cava (IVC). In order to assess
      the pressure in the IVC a catheter was introduced through the femoral vein. A
      rearranged tourniquet for blood pressure measurement was placed on the dog liver
      and with various perihepatic pressures the resulting pressures in the IVC were
      assessed. It was established, that by applying pressure of 30 mm Hg to the liver,
      the pressure in the IVC did not exceed 10 cm of water. Two clinical cases are
      reported where the method was shown to be crucial for the management. The first
      one is related to haemodynamic instability after successful perihepatic packing
      for grade V injury. In the second case, an otherwise stable patient had
      significantly elevated pressure in the IVC, which crucially influenced the
      treatment. The introduction of a catheter into the IVC to monitor the pressure in
      patients with liver injuries is useful.

PMID- 10396454
TI  - Treatment of distal femoral fractures with intramedullary supracondylar nails in
      elderly patients.
AB  - 30 acute fractures of the distal femur in 29 elderly patients were treated with a
      Russell-Taylor intramedullary supracondylar nail (IMSC). 26 of the 30 fractures
      (87%) united in 2-8 months. Two patients died before fracture union for reasons
      unrelated to the fracture. Two patients were reoperated upon, in one case the
      fracture was not adequately reduced at the first operation; in the other patient
      the nail broke 4 months after operation. In all patients knee flexion reached at
      least 90 degrees. No infections or thromboembolic complications were seen. The
      IMSC nail provided the necessary stable fixation with only a few complications in
      this group of elderly patients without the need to prolonged immobilisation.

PMID- 10396455
TI  - Snowboarding injuries of the abdomen: comparison with skiing injuries.
AB  - A retrospective study was conducted to identify the characteristics of
      snowboarding injury of the abdomen in comparison with those of alpine skiing
      injuries. Between December 1988 and April 1997, 1579 patients were treated for
      snowboarding injuries and 9108 patients were treated after skiing accidents. 19
      patients (1.2%) in snowboarding and 64 (0.7%) in skiing had abdominal injuries.
      The abdominal injury rate in snowboarders was significantly higher than that in
      skiers. Snowboarders with abdominal injuries were similar to skiers with respect
      to epidemiology but the patterns of injury in the two groups showed several
      distinct differences. Riding mistakes after jumping for the snowboarders (31.6%)
      was significantly higher than that for the skiers (0%). The main organs involved
      in snowboarding and skiing injuries were kidney, liver and spleen. The incidence
      of solitary renal injury in snowboarding (68.4%) was significantly higher than
      that in skiing (29.7%).

PMID- 10396456
TI  - Revascularization of subtotal amputation at the ankle in children following
      motorcycle-spoke injury.
AB  - A prospective study of subtotal amputation of the ankle following motorcycle
      spoke injury was carried out to define the mechanism of the injury and results of
      revasculization. Between 1990 to 1995, there were 42 patients with this type of
      injury. They were 31 boys and 11 girls. All sustained severe skin lacerations,
      medial, posterior, lateral and anterior to the ankle joint. All tendons and
      neurovascular bundles medial, lateral and anterior to the ankle were completely
      torn, leaving tendons of anterior tibial, extensor hallucis longus and extensor
      digitorum communis intact. Revascularization was performed successfully in 38
      patients. All had good functional outcome although varus of the distal tibia,
      limitation of ankle motion, shortening of the foot and limb length discrepancy
      were observed. The motorcycle wheel needs to be redesigned.

PMID- 10396457
TI  - Anchoring the diaphragm after blunt trauma.

PMID- 10396458
TI  - Ultrasonic diagnosis of interosseous ligament failure in radioulnar dissociation.

PMID- 10396459
TI  - A rare and dangerous cause of chest pain.

PMID- 10396460
TI  - Supracondylar stress fracture of the femur.

PMID- 10396461
TI  - Post traumatic large bowel stricture.

PMID- 10396462
TI  - Rupture of the triceps muscle at its attachments.
AB  - A case of rupture of the triceps muscle at both the origin and insertion is
      presented and no similar case has been reported in the literature, to the best of
      our knowledge.

PMID- 10396463
TI  - The use of the ankle arthroscopy strap during intramedullary tibial nailing.

PMID- 10396464
TI  - Salvaging a stripped drive connection when removing screws.

PMID- 10396465
TI  - Are X-rays useful in the treatment of fractures of the fourth and fifth
      metacarpals?

PMID- 10396466
TI  - Relative importance of heritable characteristics and lifestyle in the development
      of maternal obesity.
AB  - STUDY OBJECTIVE: To assess the relative importance of heritable characteristics
      and lifestyle in the development of "maternal obesity" after pregnancy. SETTING:
      South east London, in the homes of mothers who had delivered their babies at
      either Guy's, Lewisham or St Thomas's hospitals. PARTICIPANTS: Seventy four
      mothers of low antenatal risk who had been enrolled in the Antenatal Care (ANC)
      Project (a previous trial of antenatal care) during the first trimester of
      pregnancy, and who had subsequently been followed up 2.5 years after delivery.
      DESIGN: Information on parental obesity, psychosocial and sociodemographic
      factors as well as lifestyle, was gathered during a semi-structured interview at
      each mother's home. Additional anthropometric and psychosocial data were taken
      from the existing ANC Project database. These data were used to assess the
      relative importance of heritable characteristics and lifestyle on changes in
      maternal body weight from the beginning of pregnancy to the follow up interview.
      MAIN RESULTS: After adjusting for the effects of potential confounders and known
      risk factors for maternal obesity, women who selected larger silhouettes to
      represent their biological mothers were significantly more likely to have higher
      long term weight gains than those who selected thinner maternal silhouettes (r =
      0.083, p = 0.004). Women who were less satisfied with their bodies postpartum had
      significantly greater long term weight gains than those women who displayed no
      increase in dissatisfaction with their bodies after pregnancy (r = 0.067, p =
      0.010). CONCLUSIONS: A heritable predisposition to gain weight together with
      changing attitudes to body size, both had an independent role in the development
      of maternal body weight after pregnancy. Differences in each woman's heritable
      predisposition to gain weight and any changes in body image that occur after
      pregnancy might explain why some women gain weight in association with pregnancy.

PMID- 10396467
TI  - Association between educational level and health related quality of life in
      Spanish adults.
AB  - OBJECTIVE: To analyse differences in health by educational level in Spanish
      adults by comparing the health dimensions of the SF-36 Heath Survey. DESIGN: Data
      were taken from the National Survey on Drug Use carried out in February 1996. The
      information was collected by home personal interview. In addition to measuring
      the use of legal and illegal drugs and their associated health risks, the health
      status of the Spanish population was analysed using the Spanish version of the SF
      36 Health Survey. MAIN OUTCOME MEASURE: Absolute and standardised differences
      between mean score on each dimension of the SF-36 Health Survey in each
      educational group with respect to the group with the highest educational level.
      RESULTS: Perceived health status declines with decreasing educational level,
      except in women with second level education who have a higher mean rating than
      women with third level education on various health dimensions. The absolute
      differences in perceived health between the different categories of educational
      level and the reference category become larger with increasing age. The greatest
      differences by educational level in both men and women were found in mental
      health and general health among persons 25 to 44 years of age, and in physical
      function and general health among those 45 to 64 years. In persons aged 65 or
      older, the greatest differences are seen in physical function and vitality in
      men, and in bodily pain and emotional role in women. CONCLUSIONS: The influence
      of educational level on the different dimensions of perceived health may vary by
      sex.

PMID- 10396468
TI  - Health, cognitive, and psychosocial factors as predictors of mortality in an
      elderly community sample.
AB  - STUDY OBJECTIVE: To examine whether cognitive and psychosocial factors predict
      mortality once physical health is controlled. DESIGN: A prospective study of
      community dwelling elderly. Mortality was assessed over a period of 3-4 years
      after the baseline assessment of predictors. The data were analysed using the Cox
      proportional hazards model. SETTING: Canberra and Queanbeyan, Australia.
      PARTICIPANTS: A sample of 897 people aged 70 or over and living in the community,
      drawn from the compulsory electoral roll. RESULTS: For the sample as a whole, the
      significant predictors of mortality were male sex, poor physical health, poor
      cognitive functioning, and low neuroticism. Men had an adjusted relative risk of
      mortality of 2.5 compared with women. For the male sub-sample, poor self rated
      health and a poor performance on a speeded cognitive task were significant
      predictors, while for women, greater disability, low systolic blood pressure, and
      a low score on a dementia screening test were the strongest predictors.
      CONCLUSIONS: Mortality was predicted by physical ill health and poor cognitive
      functioning. Psychosocial factors such as socioeconomic status, psychiatric
      symptoms, and social support did not add to the prediction of mortality, once
      sex, physical health, and cognitive functioning were controlled. Mortality among
      men was more than twice that of women, even when adjusted for other predictors.

PMID- 10396469
TI  - Trends in coronary heart disease in two Belgian areas: results from the MONICA
      Ghent-Charleroi Study.
AB  - SETTING: As part of the WHO-MONICA study, acute coronary events have been
      registered from 1983 until 1992 in the general population aged 25-69 years in two
      Belgian cities--Ghent in the northern Dutch speaking part of Belgium and
      Charleroi in the southern French speaking part. Registration of events was done
      according to an international standard protocol. OBJECTIVE: To study trends in
      total, fatal and non-fatal event rates and trends in case fatality rates in these
      two cities. MAIN RESULTS: Incidence of CHD was on average 50% higher in Charleroi
      compared with Ghent in both men and women (attack rate ratio Charleroi/Ghent was
      1.5 in both sexes). In both men and women, diverging trends were observed between
      the two cities for total and non-fatal event rates, while parallel declining
      trends were observed in fatal event rates and in case fatality rates. In both
      sexes, total attack rates showed a significant decrease in Ghent and a
      significant increase in Charleroi. Also in the two sexes, attack rates of non
      fatal events increased significantly in Charleroi and remained stable in Ghent.
      Attack rates of fatal events decreased significantly in men and women in Ghent
      and in men in Charleroi. Both "total" and "in hospital" case fatality rates
      declined significantly in both sexes in the two cities. CONCLUSIONS: Important
      differences in coronary heart disease (CHD) incidence and CHD trends between
      Ghent and Charleroi were observed. These differences and trends are interpreted
      in the context of existing and still growing differences in the overall
      socioeconomic situation between the north and the south of the country. On the
      other hand, the efficacy of medical treatment of CHD is comparable in the two
      regions, as reflected by similar figures and trends for case fatality rates.

PMID- 10396470
TI  - Towards a philosophy of public health.

PMID- 10396471
TI  - DISCERN: an instrument for judging the quality of written consumer health
      information on treatment choices.
AB  - OBJECTIVE: To develop a short instrument, called DISCERN, which will enable
      patients and information providers to judge the quality of written information
      about treatment choices. DISCERN will also facilitate the production of new, high
      quality, evidence-based consumer health information. DESIGN: An expert panel,
      representing a range of expertise in consumer health information, generated
      criteria from a random sample of information for three medical conditions with
      varying degrees of evidence: myocardial infarction, endometriosis, and chronic
      fatigue syndrome. A graft instrument, based on this analysis, was tested by the
      panel on a random sample of new material for the same three conditions. The panel
      re-drafted the instrument to take account of the results of the test. The DISCERN
      instrument was finally tested by a national sample of 15 information providers
      and 13 self help group members on a random sample of leaflets from 19 major
      national self help organisations. Participants also completed an 8 item
      questionnaire concerning the face and content validity of the instrument.
      RESULTS: Chance corrected agreement (weighted kappa) for the overall quality
      rating was kappa = 0.53 (95% CI kappa = 0.48 to kappa = 0.59) among the expert
      panel, kappa = 0.40 (95% CI kappa = 0.36 to kappa = 0.43) among information
      providers, and kappa = 0.23 (95% CI kappa = 0.19 to kappa = 0.27) among self help
      group members. Higher agreement levels were associated with experience of using
      the instrument and with professional knowledge of consumer health information.
      Levels of agreement varied across individual items on the instrument, reflecting
      the need for subjectivity in rating certain criteria. The trends in levels of
      agreement were similar among all groups. The final instrument consisted of 15
      questions plus an overall quality rating. Responses to the questionnaire after
      the final testing revealed the instrument to have good face and content validity
      and to be generally applicable. CONCLUSIONS: DISCERN is a reliable and valid
      instrument for judging the quality of written consumer health information. While
      some subjectivity is required for rating certain criteria, the findings
      demonstrate that the instrument can be applied by experienced users and providers
      of health information to discriminate between publications of high and low
      quality. The instrument will also be of benefit to patients, though its use will
      be improved by training.

PMID- 10396472
TI  - Tuberculosis infection and disease among schoolchildren: the influence of the HIV
      epidemic and of other factors.
AB  - BACKGROUND: The HIV/AIDS epidemic has caused an excess of tuberculosis cases in
      Spain and in other countries, but its impact on tuberculosis infection is less
      well understood. This study presents a massive screening undertaken to estimate
      the prevalence of tuberculous infection in a cohort of primary school entrants.
      The evolution of the risk of infection is studied by comparison with previous
      data in the same population. METHODS: Tuberculin skin test screening with 2TU of
      PPD RT 23 of first grade students in the primary schools of Barcelona, in the
      1994-95 school year (cohort born in 1988). Information was also sought from
      families of unscreened children. Contacts of PPD+ children were traced to locate
      index cases. The results were also linked to the case registry of the
      tuberculosis control programme. RESULTS: The prevalence of tuberculin reactors
      free of BCG vaccination among the 11,080 schoolchildren screened belonging to the
      1988 cohort was 0.76%. A 3% annual decline in the annual risk of infection is
      estimated by comparison with previous data. The identification of 24 cases with a
      previous history of tuberculosis disease and of 13 cases with active disease
      diagnosed after the screening was possible by the follow up of these tuberculin
      positive children and of the information provided by families of unscreened
      pupils. The screening detected 1.5 new cases of tuberculosis per 1000 tuberculin
      tests performed. Tuberculosis infection could be traced to HIV infected
      tuberculosis cases for at least 6% of the positive schoolchildren. CONCLUSIONS:
      The decline of the annual risk of infection continues in Barcelona, although at a
      slower pace than before the HIV/AIDS epidemic, probably attributable to the
      influence of injecting drug users with smear positive tuberculosis and HIV/AIDS.

PMID- 10396474
TI  - Review of the "City Health Profiles" produced by WHO-Healthy Cities--do they
      present information on health and its determinants and what are their perceived
      benefits?

PMID- 10396473
TI  - Is follow up by specialists routinely needed after elective surgery? A controlled
      trial.
AB  - STUDY OBJECTIVE: To assess the benefit of planned specialist follow up
      appointments after elective inpatient surgery. DESIGN: This was a controlled
      trial, using repeated alternate allocation of time periods to the two study
      groups. Group 1: Planned outpatient follow up 6-12 weeks after surgery. Group 2:
      No planned follow up: additional written information for patients and general
      practitioners. SETTING: A district general hospital in the north west of England.
      PARTICIPANTS: 264 patients listed for one of: transurethral resection of the
      prostate, varicose vein surgery, cholecystectomy (open or laparoscopic), inguinal
      herniorraphy (open or laparoscopic). MAIN OUTCOME MEASURES: Health status,
      complications, return to normal activity, patient satisfaction, use and costs of
      primary and secondary care in the 12 weeks after surgery. MAIN RESULTS: Data were
      available for 212 (80%) of eligible patients. Thirty eight per cent of patients
      in the "no planned follow up" group were in fact seen in outpatients after their
      discharge. Intention to treat analysis showed that there were no significant
      differences between the groups for health status, complications, or time to
      return to normal activity. Patients in the "no planned follow up" group had
      significantly fewer hospital visits and costs (mean difference in visits 0.51,
      95% confidence intervals 0.39 to 0.69; mean difference in hospital costs 12.75
      Pounds, 9.75 Pounds to 15.50 Pounds). There were fewer primary care staff
      contacts and costs in the "no planned follow up" group, although this difference
      was not significant (mean difference = 0.61 visits, -0.13 to 1.33 visits; primary
      care costs difference 8.37 Pounds, -1.31 Pounds to 18.73 Pounds). Patients in the
      "no planned follow up group" had significantly reduced patient travel costs (mean
      difference 4.84 Pounds, 3.44 Pounds to 6.22 Pounds). Eighty nine (42%) patients
      would prefer to be followed up by both their hospital doctor and GP; 53 (25%)
      patients would prefer to be followed up by the hospital doctor only. There were
      no significant differences between the two groups in their preferences for follow
      up. The majority of GPs agreed with the statement that a policy of no follow up
      at hospital outpatients for each of the six surgical procedures would increase
      their workload. CONCLUSIONS: Planned outpatient appointments after uncomplicated
      surgery seem to be neither necessary nor cost effective. A policy of "no planned
      follow up" results in no increase in primary care costs, and savings in hospital
      and patient costs. However, many patients expected and wanted to be seen again by
      their surgeon and GPs were concerned that a "no follow up" policy would result in
      an increase in workload.

PMID- 10396475
TI  - The fate of non-medics working in public health.

PMID- 10396476
TI  - The Acheson report: beyond parenthood and apple pie?

PMID- 10396477
TI  - High rates and a healthy city.

PMID- 10396478
TI  - Poverty, time, and place: variation in excess mortality across selected US
      populations, 1980-1990.
AB  - STUDY OBJECTIVE: To describe variation in levels and causes of excess mortality
      and temporal mortality change among young and middle aged adults in a regionally
      diverse set of poor local populations in the USA. DESIGN: Using standard
      demographic techniques, death certificate and census data were analysed to make
      sex specific population level estimates of 1980 and 1990 death rates for
      residents of selected areas of concentrated poverty. For comparison, data for
      whites and blacks nationwide were analysed. SETTING: African American communities
      in Harlem, Central City Detroit, Chicago's south side, the Louisiana Delta, the
      Black Belt region of Alabama, and Eastern North Carolina. Non-Hispanic white
      communities in Cleveland, Detroit, Appalachian Kentucky, South Central Louisiana,
      Northeastern Alabama, and Western North Carolina. PARTICIPANTS: All black
      residents or all white residents of each specific community and in the nation,
      1979-1981 and 1989-1991. MAIN RESULTS: Substantial variability exists in levels,
      trends, and causes of excess mortality in poor populations across localities.
      African American residents of urban/northern communities suffer extremely high
      and growing rates of excess mortality. Rural residents exhibit an important
      mortality advantage that widens over the decade. Homicide deaths contribute
      little to the rise in excess mortality, nor do AIDS deaths contribute outside of
      specific localities. Deaths attributable to circulatory disease are the leading
      cause of excess mortality in most locations. CONCLUSIONS: Important differences
      exist among persistently impoverished populations in the degree to which their
      poverty translates into excess mortality. Social epidemiological inquiry and
      health promotion initiatives should be attentive to local conditions. The
      severely disadvantageous mortality profiles experienced by urban African
      Americans relative to the rural poor and to national averages call for
      understanding.

PMID- 10396479
TI  - Unemployment, depression, and health: a look at the African-American community.
AB  - OBJECTIVES: While the unemployment rate of African-American people is more than
      twice that of the white population, the research on the impact of unemployment on
      the health of this population is scarce. This study analysed the impact of
      unemployment on depression and well being among African-American people, and the
      factors associated with well being. METHODS: Logistic and multiple regression
      models were used to analyse panel data collected in the National Survey of
      Families and Households 1987-1992. African-American (1369) and white (6660)
      respondents were analysed separately. Outcome variables included an index of
      depression and self reported health status. MAIN FINDINGS: Differences between
      employment and unemployment groups were less significant for African-Americans
      than for the white population in predicting depression and well being. Health
      enhancing factors such as education and wealth were significantly associated with
      better health and lower depression indices among the white population but not
      consistently so among African-Americans. Satisfaction with personal relationships
      was the strongest predictor of well being for both groups. CONCLUSION: Research
      should focus on the special needs and circumstances of African-Americans, because
      protective factors may not have the same impact in different groups of the
      population.

PMID- 10396480
TI  - Mental distress and risk of hip fracture. Do broken hearts lead to broken bones?
AB  - OBJECTIVE: Mental distress may entail increased risk of hip fracture, but it is
      uncertain whether the effect consists solely of an indirect effect through use of
      medication, or whether it is also mediated through other mechanism. The purpose
      of this study was to examine the association between mental distress and risk of
      hip fracture in women, adjusted for medication (that is, use of
      tranquillisers/sedatives or hypnotics). DESIGN: A three year follow up of hip
      fracture was conducted on 18,612 women, consisting of 92.5% of all women aged 50
      years or older in a Norwegian county. Three hundred and twenty nine suffered a
      hip fracture. A mental distress index was based on questions about life
      dissatisfaction, nervousness, loneliness, sleep disorders, troubled and uneasy
      feelings, depression and impairment attributable to psychological complaints.
      Relative risk with 95% confidence intervals (CI) of hip fracture with respect to
      mental distress were controlled for medication, age, body mass index (BMI),
      smoking, physical inactivity, and physical illness by means of Cox regression.
      RESULTS: The 10% of women with the highest mental distress had more than twofold
      increased risk of hip fracture compared with the 10% of women with the lowest
      mental distress, after adjustment for age and medication. The relative risk was
      1.95 (95% CI 1.2, 3.3) after additional control for BMI, smoking, physical
      inactivity, and physical illness. The relative risk of hip fracture for daily
      users of medication compared with never users was 2.1 (95% CI 1.6, 2.9). After
      adjusting for mental distress it was 1.5 (95% CI 1.0, 2.2). CONCLUSIONS: Risk of
      hip fracture was positively related to mental distress, also after adjustment for
      medication use. The effect of tranquillisers/sedatives or hypnotics on hip
      fracture risk may be overestimated in studies with no adjustments for mental
      distress.

PMID- 10396482
TI  - Inequalities in low birth weight: parental social class, area deprivation, and
      "lone mother" status.
AB  - OBJECTIVE: To describe the extent of socioeconomic inequalities in low birth
      weight. To assess the relative benefits of measuring socioeconomic status by
      individual occupation, socioeconomic deprivation status of area of residence, or
      both, for describing inequalities and targeting resources. DESIGN: Analysis of
      birth registrations by registration status: joint compared with sole registrants
      ("lone mothers"), routinely recorded parental occupation (father's for joint
      registrants), and census derived enumeration district (ED) deprivation. SETTING:
      England and Wales, 1986-92. SUBJECTS: 471,411 births with coded parental
      occupation (random 10% sample) and birth weight. MAIN OUTCOME MEASURES:
      Proportion of low birth weight (< 2500 g) RESULTS: 34% of births to joint
      registrants in social classes IV and V, and 45% of births to sole registrants,
      were in the quintile of most deprived EDs. It was found that 6.8% of births were
      of low birth weight. Sole registrants were at higher risk (9.3% overall) than
      joint registrants, across all deprivation quintiles. For joint registrants, the
      socioeconomic risk gradient was similar by social class or area deprivation, but
      a greater gradient from 4.7% to 8.7% was found with combined classification.
      CONCLUSIONS: Up to 30% of low birth weight can be seen as being associated with
      levels of socioeconomic deprivation below that of the most affluent group, as
      measured in this study. Caution is needed when targeting interventions to high
      risk groups when using single indicators. For example, the majority of births to
      lone mothers and to joint registrants in social classes IV and V would be missed
      by targeting the most deprived quintile. There is a high degree of inequality in
      low birth weight according to social class, area deprivation and lone mother
      status. When using routinely recorded birth and census data, all three factors
      are important to show the true extent of inequalities.

PMID- 10396481
TI  - Association between job characteristics and plasma fibrinogen in a normal working
      population: a cross sectional analysis in referents of the SHEEP Study. Stockholm
      Heart Epidemiology Program.
AB  - STUDY OBJECTIVE: To explore the association between job characteristics and
      plasma fibrinogen concentrations. DESIGN: Cross sectional design. SETTING: The
      Greater Stockholm area. SUBJECTS: A total of 1018 men and 490 women aged 45-70
      who were randomly selected from the general population during 1992-1994. They
      were all employed and had no history of myocardial infarction. MAIN RESULTS: The
      self reported job characteristics were measured by a Swedish version of the
      Karasek demand-control questionnaire. For inferred scoring of job
      characteristics, psychosocial exposure categories (job control and psychological
      demands) were assigned by linking each subject's occupational history with a work
      organisation exposure matrix. Job strain was defined as the ratio between demands
      and control. In univariate analyses, expected linear trends were found in three
      of four tests of association between high plasma fibrinogen and low control (the
      self reported score for women and the inferred score for both sexes), in one of
      four tests of association between high plasma fibrinogen and high demands (the
      inferred score for women) and in two of four tests of association between high
      plasma fibrinogen and job strain (the inferred score for both sexes). Multiple
      logistic regression analyses showed that men in the inferred job strain group
      have an increased risk of falling into the increased plasma fibrinogen
      concentration group (above median level of the distribution) (odds ratio (OR)
      1.2; 95% CI 1.0, 1.5) after adjustment for the variables that were associated
      with plasma fibrinogen in the univariate analyses. In women, low self reported
      control, high inferred demand, and inferred job strain were significantly
      associated with increased plasma fibrinogen concentration (OR 1.3; 95% CI 1.0,
      1.8, OR 1.5; 95% CI 1.0, 2.2, OR 1.5; 95% CI 1.1, 2.2, respectively).
      CONCLUSIONS: These results indicate that adverse job characteristics may be
      related to plasma fibrinogen concentrations and this relation is more relevant in
      female workers. The clearest evidence for psychosocial effects on plasma
      fibrinogen seems to be with job control and the associations are clearer for the
      objective than for the self report variables.

PMID- 10396483
TI  - Overtime, psychosocial working conditions, and occurrence of non-insulin
      dependent diabetes mellitus in Japanese men.
AB  - OBJECTIVES: To ascertain the effects of overtime and psychosocial job conditions
      on the occurrence of non-insulin dependent diabetes mellitus (NIDDM) in Japan.
      DESIGN: An eight year prospective cohort study. SETTING: An electrical company in
      Japan. PARTICIPANTS: In 1984, a mailed questionnaire was sent to industrial
      workers of an electrical company in Japan. After excluding those who had a
      history of diabetes mellitus or other chronic diseases, 2597 male respondents
      were prospectively followed up for the succeeding eight years. Data from 2194
      (84%) who were completely followed up were analysed. The occurrence of NIDDM
      during the follow up period was assessed according to the WHO criteria on the
      basis of an annual screening programme. MAIN RESULTS: The age adjusted incidence
      of NIDDM was significantly higher in those who worked overtime more than 50 hours
      per month than in those who worked 25 hours or less per month (p < 0.05). It was
      significantly higher in those who worked with new technology at baseline than in
      those who did not (p < 0.05). Cox's proportional hazard model indicated that
      those who worked overtime more than 50 hours per month had 3.7 times higher risk
      of NIDDM after controlling for known risk factors (p < 0.01) and those who worked
      with new technology had 2.4 times higher risk of NIDDM (p < 0.05). CONCLUSIONS:
      It is suggested that longer overtime and use of new technology are risk factors
      of NIDDM in Japanese men.

PMID- 10396484
TI  - Family, religion, and depressive symptoms in caregivers of disabled elderly.
AB  - STUDY OBJECTIVE: To explain the variations in depressive symptomatology among
      primary caregivers of community dwelling activities of daily living disabled
      elderly and to evaluate the role of family and religiosity on the mental health
      consequences of caregiving in Spain. DESIGN: Cross sectional study. SETTING: City
      of Leganes in the metropolitan area of Madrid, Spain. PARTICIPANTS: All
      caregivers of a representative sample of community dwelling activities of daily
      living disabled persons, aged 65 and over were approached. The response rate was
      85% (n = 194). Depression was assessed by the Center for Epidemiologic Studies
      Depression (CES-D) Scale. MAIN RESULTS: Controlling for caregivers' income,
      education, health status, and caregiving stress, religiosity was associated with
      more depressive symptoms among children caregivers while for spouses the
      association was negative. Emotional support was negatively associated with
      depression, but instrumental support was not significant. CONCLUSIONS: Depressive
      symptomatology is frequent among Spanish caregivers of disabled elderly. This
      study concludes that religiosity and family emotional support play an important
      part in the mental health of Spanish caregivers. The role of religiosity may be
      different according to kinship tie and needs further investigation.

PMID- 10396485
TI  - 1997 Chadwick Lecture--is a healthy north west region achievable in the 21st
      century.

PMID- 10396486
TI  - Non-Hodgkin's lymphoma and nitrate in drinking water: a study in Yorkshire,
      United Kingdom.

PMID- 10396487
TI  - Public health issues in Hong Kong and China.

PMID- 10396488
TI  - Fertility and infant mortality trends in Nicaragua 1964-1993. The role of women's
      education.
AB  - OBJECTIVES: To assess trends in fertility and infant mortality rates (IMR) in
      Leon, Nicaragua, and to examine the effect of women's education on these trends
      during 1964-1993, a period of rapid social change. DESIGN: Cross sectional
      survey, based on random cluster sampling. A retrospective questionnaire on
      reproductive events was used. SETTING: The municipality of Leon, which is the
      second largest city in Nicaragua, with a total population of 195,000 inhabitants.
      SUBJECTS: 10,867 women aged 15-49 years, corresponding to 176,281 person years of
      reproductive life. Their children contributed 22,899 person years under 12 months
      of age to the IMR analysis. MAIN OUTCOME MEASURES: Fertility rate (number of
      pregnancies per 1000 person years) for specific age groups and calendar periods,
      total fertility rate, and IMR. RESULTS: Fertility rates and IMR declined in
      parallel, especially during the 1980s. However, education specific fertility
      rates did not decline, but the proportion of educated young women increased from
      20% to 46%. This had also an impact on the overall IMR decline, although IMR
      reduction mainly took place among infants of women without formal education,
      decreasing from 118 to 69 per 1000 during the observation period. CONCLUSIONS: In
      this demographic transition over three decades, fertility and IMR declined
      simultaneously. The decreasing trend in fertility was mainly explained by an
      increase in women's education, while the IMR decline seemed to be the result of
      health interventions, specially targeted to poorer groups of women and their
      infants. Thus, social differences in fertility rates remained unchanged, while
      equity in chances of child survival increased.

PMID- 10396489
TI  - Social prognostic factors of mortality in a random cohort of Geneva subjects
      followed up for a period of 12 years.
AB  - STUDY OBJECTIVE: To analyse the relative risk (RR) of mortality related to social
      factors independent of health status and occupational category. SETTING: Subjects
      were Swiss men and women aged 40-65 years. DESIGN: A random sample of 820 people
      living in Geneva were followed up prospectively between 1984 and 1996. The
      social, occupational, and health data were gathered at subjects' homes in 1984
      using a standardised questionnaire. Information about deaths and the
      corresponding dates were obtained from updated files of the Swiss Federal Office
      of Statistics (OFS). Risk of mortality was examined according to a Cox model.
      MAIN RESULTS: There were several social prognostic factors of mortality with
      relative risks greater than 3.0 (RR > 3.0) independent of health and occupational
      status. These factors were: a period of unemployment during life time, the
      feeling of not demonstrating initiative in the occupational setting, and not
      having participated in social activities. CONCLUSION: The results suggest that
      differential mortality determined by occupational status can be explained in part
      by factors that are characteristic of "life style", social dynamics, occupational
      context, and ruptures during the course of occupational life.

PMID- 10396490
TI  - Association of sexual problems with social, psychological, and physical problems
      in men and women: a cross sectional population survey.
AB  - STUDY OBJECTIVE: To investigate the association of sexual problems with social,
      physical, and psychological problems. DESIGN: An anonymous postal questionnaire
      survey. SETTING: Four general practices in England. PARTICIPANTS: 789 men and 979
      women responding to a questionnaire sent to a stratified random sample of the
      adult general population (n = 4000). MAIN RESULTS: Strong physical, social, and
      psychological associations were found with sexual problems. In men, erectile
      problems and premature ejaculation were associated with increasing age. Erectile
      problems were most strongly associated with prostate trouble, with an age
      adjusted odds ratio of 2.6 (95% confidence intervals 1.4, 4.7), but hypertension
      and diabetes were also associated. Premature ejaculation was predominantly
      associated with anxiety (age adjusted odds ratio 3.1 (95% confidence intervals
      1.7, 5.6)). In women, the predominant association with arousal, orgasmic, and
      enjoyment problems was martial difficulties, all with odds ratios greater than
      five. All female sexual problems were associated with anxiety and depression.
      Vaginal dryness was found to increase with age, whereas dyspareunia decreased
      with age. CONCLUSIONS: This study indicates that sexual problems cluster with
      self reported physical problems in men, and with psychological and social
      problems in women. This has potentially important consequences for the planning
      of treatment for sexual problems, and implies that effective therapy could have a
      broad impact on health in the adult population.

PMID- 10396491
TI  - Prevalence of varicose veins and chronic venous insufficiency in men and women in
      the general population: Edinburgh Vein Study.
AB  - STUDY OBJECTIVE: To determine the prevalence of varicose veins and chronic venous
      insufficiency (CVI) in the general population. DESIGN: Cross sectional survey.
      SETTING: City of Edinburgh. PARTICIPANTS: Men and women aged 18-64 years selected
      randomly from age-sex registers of 12 general practices. MAIN RESULTS: In 1566
      subjects examined, the age adjusted prevalence of trunk varices was 40% in men
      and 32% in women (p < or = 0.01). This sex difference was mostly a result of
      higher prevalence of mild trunk varices in men. More than 80% of all subjects had
      mild hyphenweb and reticular varices. The age adjusted prevalence of CVI was 9%
      in men and 7% in women (p < or = 0.05). The prevalence of all categories of
      varices and of CVI increased with age (p < or = 0.001). No relation was found
      with social class. CONCLUSIONS: Approximately one third of men and women aged 18
      64 years had trunk varices. In contrast with the findings in most previous
      studies, mainly conducted in the 1960s and 1970s, chronic venous insufficiency
      and mild varicose veins were more common in men than women. No evidence of bias
      in the study was found to account for this sex difference. Changes in lifestyle
      or other factors might be contributing to an alteration in the epidemiology of
      venous disease.

PMID- 10396492
TI  - An assessment of spatial clustering of leukaemias and lymphomas among young
      people in New Zealand.
AB  - STUDY OBJECTIVE: To assess spatial clustering of childhood leukaemias and
      lymphomas in New Zealand, using a national dataset from a country with no nuclear
      installations. DESIGN: New Zealand Map Grid coordinates, derived from the birth
      addresses of cases and controls were used in clustering analyses that applied
      Cuzick and Edwards' method. SETTING: The whole of New Zealand. PARTICIPANTS: The
      cases were ascertained from the New Zealand Cancer Registry. They were diagnosed
      with leukaemia or lymphoma at ages 0-14 years during the period 1976 to 1987. For
      Hodgkin's disease, the age range was extended to include those aged from 0-24
      years. The cancer registrations were linked with national birth records, to
      obtain the birth addresses of the cases. The controls were selected at random
      from birth records, with matching to cases (1:1) on age and sex. The analyses
      included 600 cases and 600 controls. MAIN RESULTS: There was no statistically
      significant spatial clustering for any tumour group overall, including acute
      lymphoblastic leukaemia, acute nonlymphoblastic leukaemia, other leukaemias, non
      Hodgkin's lymphomas, Hodgkin's disease, and all these combined. Significant
      clustering was found in a sub-analysis for one of three age specific subgroups of
      acute lymphoblastic leukaemia (ages 10-14 years, p = 0.003). CONCLUSION: The
      subgroup finding may have been real or a chance association, as several
      comparisons were made. This study found little evidence for spatial clustering of
      leukaemias or lymphomas in a population with no nuclear installations.

PMID- 10396493
TI  - Validation of the University of Manchester Drug Misuse Database.
AB  - OBJECTIVE: The study was conducted to assess the validity and quality of data
      held by one of the UK regional drug misuse databases (DMD). DESIGN: The research
      was multi-centred and used retrospective analysis to assess the validity of data
      held on the database. SETTING: The Regional Database is managed at the University
      of Manchester Drug Misuse Research Unit and uses data returned by medical and non
      medical services within the UK's former North Western Regional Health Authority.
      MATERIAL: The research was largely based on analysis of the reporting or non
      reporting to DMD of 1526 presentations by drug users to four community drug teams
      (CDTs) during the course of 1993. Two datasets were used: the DMD dataset, based
      on returns to the regional database from the agencies in question; and agency
      client records. Additionally the data included on a random sample of 300 database
      forms returned by these CDTs were compared with information contained in client
      records. MAIN OUTCOME MEASURES: The study reports on how well DMD is functioning
      in relation to the correct reporting of episodes of problem drug use and the
      quality of data held. RESULTS: A very high level of agreement (0.875 +/- 0.017,
      95% CI, kappa coefficient 0.728) was established between reports sent in to the
      database and those expected by examination of agency records. The database
      figures underestimated the total number of episodes that should have been
      reported by a factor of 0.008. It was also established that 0.906 (+/- 0.018, 95%
      CI) of the reports made to the database were made correctly, that 0.178 (+/-
      0.030, 95% CI) of eligible presentations were not reported, and that 0.166 (+/-
      0.030, 95% CI) of ineligible presentations were mistakenly reported. Lastly, it
      was established that data were unnecessarily missing or inaccurately recorded in
      0.027 of cases and that data entry errors occurred in 0.015 of cases.
      CONCLUSIONS: The validation project showed that the DMD system is very reliable,
      providing accurate measures of the extent and nature of presenting problem drug
      use in the region under study.

PMID- 10396494
TI  - The validity of dietary assessment in general practice.
AB  - OBJECTIVE: To validate a range of dietary assessment instruments in general
      practice. METHODS: Using a randomised block design, brief assessment instruments
      and more complex conventional dietary assessment tools were compared with an
      accepted "relative" standard--a seven day weighed dietary record. The standard
      was checked using biomarkers, and by performing test-retest reliability in
      additional subjects (n = 29). OUTCOMES: Agreement with weighed record. Percentage
      agreement with weighed record, rank correlation from scatter plot, rank
      correlation from Bland-Altman plot. Reliability of the weighed record. SETTING:
      Practice nurse treatment room in a single suburban general practice. SUBJECTS:
      Patients with risk factors for cardiovascular disease (n = 61) or age/sex
      stratified general population group (n = 50). RESULTS: Brief self completion
      dietary assessment tools based on food groups caten during a week show reasonable
      agreement with the relative standard. For % energy from fat and saturated fat,
      non-starch polysaccharide, grams of fruit and vegetables and starchy foods
      consumed the range of agreement with the standard was: median % difference -6% to
      12%, rank correlation 0.5 to 0.6. This agreement is of a similar order to the
      reliability of the weighed record, as good as or better than test standard
      agreement for more time consuming instruments, and compares favourably with
      research instruments validated in other settings. Under-reporting of energy
      intake was common (40%) and more likely if subjects were obese (body mass idex
      (BMI) > or = 30 60% under-reported; BMI < 30 29%, p < 0.001). CONCLUSION: Under
      reporting of absolute energy intake is common, particularly among obese patients.
      Simple self assessment tools based on food groups, designed for practice nurse
      dietary assessment, show acceptable agreement with a standard, and suggest such
      tools are sufficiently accurate for clinical work, research, and possibly
      population dietary monitoring.

PMID- 10396495
TI  - Twice vaccinated recipients are better protected against epidemic measles than
      are single dose recipients of measles containing vaccine.
AB  - OBJECTIVE: To study measles risk after revaccination. DESIGN: A population-based
      case-control study during an epidemic season. MAIN OUTCOME MEASURE: Relative
      serologically confirmed measles risk. PARTICIPANTS AND METHODS: 153 vaccinated
      cases, mostly from rural areas, were serologically confirmed as measles at the
      central laboratory in 1988-89. A randomly selected group of 453 controls from
      either municipalities of vaccinated cases or from areas where measles attack rate
      was > 600/10(5), was identified via the population registry. Vaccination and
      measles histories of cases and controls were determined from official vaccination
      cards. RESULTS: Once and twice vaccinated had crude relative risk 15.6 and 2.3
      compared with thrice vaccinated. When cases who had received their first
      vaccination at less than 14 months of age were omitted from analysis, once
      vaccinated had 4.0 (95% CI 1.2, 16.6) times higher age adjusted measles risk
      compared with twice vaccinated. When, omission was extended to cases from one
      particular municipality where even revaccinees had high measles risk during an
      explosive outbreak the corresponding risk ratio was 17.8 (2.8, 67.8).
      CONCLUSIONS: Twice vaccinated have better protection against epidemic measles
      compared with single dose recipients.

PMID- 10396496
TI  - Secondary analysis of economic data: a review of cost-benefit studies of neonatal
      screening for phenylketonuria.
AB  - STUDY OBJECTIVE: To estimate the net financial benefit of neonatal screening for
      phenylketonuria (PKU): by a simple pooling of cost data from the literature; and
      by a more complex modelling approach. DESIGN: A systematic literature review was
      conducted to identify papers containing data on the monetary costs and benefits
      of neonatal screening for PKU. The methodological quality of the studies was
      appraised, and data were extracted on resource use and expenditure. Monetary data
      were converted to common currency units, and standardised to UK incidence rates.
      Net benefits were calculated for median, best case and worst case scenarios, and
      the effect of excluding poor quality studies and data was tested. The net benefit
      was also estimated from a model based on data from the literature and assumptions
      appropriate for the current UK situation. Extensive sensitivity analysis was
      conducted. MAIN RESULTS: The direct net benefit of screening based on the median
      costs and benefits from the 13 studies identified was 143,400 Pounds per case
      detected and treated (39,000 Pounds and 241,800 Pounds for worst case and best
      case scenarios respectively). The direct net benefit obtained by the modelling
      approach was lower at 93,400 Pounds per case detected and treated. Screening
      remained cost saving under sensitivity analysis, except with low residential care
      costs (less than 12,300 Pounds per annum), or very low incidence rates (less than
      1 in 27,000). CONCLUSIONS: The economic literature on PKU screening is of
      variable quality. The two methods of secondary analysis lead to the same
      conclusion: that neonatal PKU screening is worthwhile in financial terms alone in
      the UK, and that it justifies the infrastructure for collecting and testing
      neonatal blood samples. This result cannot necessarily be extrapolated to other
      countries.

PMID- 10396497
TI  - Operationalisation of a demand/resource model of health: an explorative study.

PMID- 10396498
TI  - The choice of deprivation in measuring poorer health in Northamptonshire.

PMID- 10396500
TI  - Being prepared to protect the public health. Information for thinking the
      unthinkable and doing the essential.

PMID- 10396499
TI  - Barriers to physical activity and socioeconomic position: implications for health
      promotion.

PMID- 10396501
TI  - Health impact assessment--theory into practice.

PMID- 10396502
TI  - Coronary heart disease epidemiology: a look towards the south.

PMID- 10396503
TI  - High prevalence of cardiovascular risk factors in Gerona, Spain, a province with
      low myocardial infarction incidence. REGICOR Investigators.
AB  - STUDY OBJECTIVE: To establish the prevalence of main cardiovascular risk factors
      in the province of Gerona, where the incidence of myocardial infarction is known
      to be low. DESIGN: This was a cross sectional study of prevalence of
      cardiovascular risk factors conducted on a large random population sample.
      SETTING: The province of Gerona, Spain. PARTICIPANTS: Two thousand four hundred
      and four eligible inhabitants of Gerona aged between 25 and 74 years were
      randomly selected for a multi-stage sample stratified by age and sex. The
      following were standardly measured: lipids (total cholesterol, high density, low
      density, lipoprotein (a) and triglycerides), fibrinogen, basal glycaemia,
      arterial pressure, anthropometric variables, smoking, history of angina (Rose
      questionnaire), and a medical history questionnaire. Population measurements were
      standardised for the world population of 24 to 74 years of age. RESULTS: The
      participation rate was 72.7% (1748). Total mean cholesterol was 5.69 mmol/l in
      men and 5.61 mmol/l in women and mean high density cholesterol was 1.22 mmol/l
      and 1.47 mmol/l, respectively. Median lipoprotein (a) was 0.22 g/l. These three
      lipids increased significantly with age. Mean fibrinogen was 2.92 g/l in men and
      3.09 g/l in women, and was higher in smokers. The prevalence of hypertension
      (systolic arterial tension > or = 140 mm Hg or diastolic > or = 90 mm Hg or drug
      treatment) was 31.3% in men and 27.7% in women. The proportion of male smokers
      was 33.8% and female smokers 22.7%. The proportion of female smokers in the 25-34
      year age group exceeded that of the remaining age groups for both men and women.
      CONCLUSIONS: The prevalence of cardiovascular risk factors in Gerona is
      relatively high for the low myocardial infarction incidence typical of the area,
      although similar to that of other Spanish areas. The factors that confer
      sufficient protection to compensate for the effect of the prevalence of these
      risk factors remain to be elucidated.

PMID- 10396504
TI  - Migration patterns of children with cancer in Britain.
AB  - OBJECTIVES: To investigate the early migration patterns of children who later
      developed cancer. To test a prior hypothesis that some cancers are initiated by
      early exposures to toxic atmospheric pollutants from point sources. DESIGN:
      Address changes in children dying from cancer are examined in relation to
      potentially hazardous sites of several different types. The relative proximities
      of birth addresses and death addresses to these sites, are compared. The approach
      is based upon the premise that a local exposure, effective only at an early age,
      must be preferentially linked with an early address. SETTING AND SUBJECTS:
      Records of 22,458 children dying from leukaemia or other cancer under the age of
      16 years in Great Britain between 1953 and 1980: including 9224 who moved house
      between birth and death. The migration analysis was based upon birth and death
      addresses, converted first to postcodes and thence to map coordinates. The
      geographical locations of potentially toxic industrial sites were obtained
      through direct map searches and from commercial directories. RESULTS: Systematic
      asymmetries were found between measured distances from birth and death addresses
      to sources emitting volatile organic compounds, or using large scale combustion
      processes. The children had more often moved away from these hazards than towards
      them. Many of the sources had already been identified as hazardous using other
      methods. There was also a birth association with areas of dense habitation;
      possibly because of unidentified toxic sources contained within them. All forms
      of cancer were involved although some effluents were associated preferentially
      with specific types. CONCLUSIONS: The main findings of an earlier study, based
      upon a different and independent method, were confirmed. Proximities to several
      types of industrial source, around the time of birth, were followed by a raised
      risk of childhood cancer. Combustion products and volatile organic compounds were
      especially implicated. Within the 16 year limit of the study, the increased risk
      did not decay with advancing age. Low atmospheric concentrations of many
      carcinogenic substances suggest that the mother acts as a cumulative filter and
      passes them to the fetus across the placenta or in breast milk.

PMID- 10396505
TI  - Measuring social class differences in cancer patient survival: is it necessary to
      control for social class differences in general population mortality? A Finnish
      population-based study.
AB  - STUDY OBJECTIVES: Estimation of cancer patient survival by social class has been
      performed using observed, corrected (cause specific), and relative (with expected
      survival based on the national population) survival rates. Each of these measures
      are potentially biased and the optimal method is to calculate relative survival
      rates using social class specific death rates to estimate expected survival. This
      study determined the degree to which the choice of survival measure affects the
      estimation of social class differences in cancer patient survival. SETTING AND
      PARTICIPANTS: All Finnish residents diagnosed with at least one of 10 common
      malignant neoplasms during the period 1977-1985 were identified from the Finnish
      Cancer Registry and followed up for deaths to the end of 1992. DESIGN: Survival
      rates were calculated by site, sex, and age at 5, 10, and 15 years subsequent to
      diagnosis for each of three measures of survival; relative survival, corrected
      (cause specific) survival, and relative survival adjusted for social class
      differences in general mortality. Regression models were fitted to each set of
      rates for the first five years of follow up. MAIN RESULTS: The degree of
      variation in relative survival resulting from social class decreased, although
      did not disappear, after controlling for social class differences in general
      mortality. The results obtained using corrected survival were close to those
      obtained using relative survival with a social class correction. The differences
      between the three measures were largest when the proportion of deaths from other
      causes was large, for example, in cancers with high survival, among older
      patients, and for longer follow up times. CONCLUSIONS: Although each of the three
      measures gave comparable results, it is recommended that relative survival rates
      are used with expected survival adjusted for social class when studying social
      class variation in cancer patient survival. If this is not an available option,
      it is recommended that corrected survival rates are used. Relative survival rates
      without the social class correction overestimate social class differences and
      should be used with caution.

PMID- 10396506
TI  - Perinatal death in ethnic minorities in The Netherlands.
AB  - OBJECTIVES: To investigate differences in perinatal death rate and associated
      obstetric risk factors between ethnic groups in the Netherlands. DESIGN:
      Retrospective cohort study based on the 1990-1993 birth cohorts in the National
      Obstetric Registry. SUBJECTS: 569,743 births of which 85,527 were for women
      belonging to ethnic minorities. MAIN OUTCOME MEASURES: Perinatal death occurring
      between 16th week of pregnancy and 24 hours after birth. METHOD: Bivariate and
      multivariate analysis of perinatal death rate per ethnic group. A total of 42,282
      women living in the three main cities of the Netherlands were classified on the
      basis of postal code districts into four socioeconomic (SES) classes for analysis
      of the relation between SES, perinatal death, and preterm birth. RESULTS: Black
      mothers had the highest perinatal death rate compared with indigenous Dutch (odds
      ratio 2.2, 95% CI 1.9, 2.4) followed by a group "others", consisting of women of
      mixed or unknown ethnicity (odds ratio 1.8, 95% CI 1.5, 2.0), Hindustani (odds
      ratio 1.4, 95% CI 1.2, 1.6), and Mediterraneans (odds ratio 1.3, 95% CI 1.2,
      1.4). Asians (excluding West Indian Asians) and non-Dutch Europeans did not have
      higher rates than Dutch women. The increased rates of black and Hindustani women
      could be explained fully and that of the group "others" partially by higher rates
      of preterm birth. Controlling for age and parity lowered the odds ratio of the
      Mediterraneans slightly. The risk of ethnicity was independent of SES.
      CONCLUSION: Ethnic minorities in the Netherlands except immigrants from Asia and
      other European countries have higher rates of perinatal death than indigenous
      Dutch women. With a twofold increase, black women had the highest rate, which was
      related to an equally large increased rate of preterm birth.

PMID- 10396507
TI  - Hospitalisation of the elderly during the last year of life: an application of
      record linkage in Western Australia 1985-1994.
AB  - STUDY OBJECTIVE: To measure the trend, pattern, and cost of time spent in
      hospital during the last year of life in Western Australia and to identify trends
      in the place of death. The results were compared with those reported from the
      Oxford Record Linkage Study. DESIGN: Mortality records for those aged 65 years
      and over were linked to inpatient hospital morbidity records with a date of
      separation within one year before death. Comparative inpatient resource
      utilisation was estimated using ANDRG 3.0 cost weights for Australian public
      hospitals. SETTING: Western Australia. PARTICIPANTS: All 68,875 persons aged 65
      years and over who died between 1 January 1985 and 31 December 1994. MAIN
      RESULTS: Increasing proportions of all age groups (65-74, 75-84, and 85+ years)
      were admitted to hospital at least once in the year before death during 1985-94,
      but the chance of admission decreased with age. There was a trend towards a
      greater number of shorter admissions per person. Total bed days per person showed
      no significant increase, except at ages 65-74 years. Total inpatient resource
      utilisation during the last year of life was lowest and remained constant in
      those aged 85 years and over, while increasing gradually (3.7% per annum) in the
      younger elderly. The Western Australian population spent more time in hospital in
      the last year of life at ages 65-74 years, but the advanced elderly spent less
      time in hospital, when compared with the Oxford Region. CONCLUSIONS: Recent gains
      in life expectancy and higher per capita health expenditure have not been
      accompanied by more time spent in hospital during the last year of life at ages
      75+ years. International differences between Western Australia and Oxford can be
      explained by differences in aged care provision.

PMID- 10396508
TI  - Food safety knowledge and practice among elderly people living at home.
AB  - OBJECTIVE: To assess the food storage knowledge and practice of elderly people
      living at home. METHODS: Three phase survey data collection: face to face
      interviews; dietary diaries with a food frequency questionnaire; and follow up
      interviews. SETTING: Urban Nottingham. PARTICIPANTS: 809 elderly people (aged
      65+) randomly selected from general practitioner lists. MAIN OUTCOME MEASURES:
      Respondent's refrigerator temperature; knowledge of freezer star rating;
      understanding of "use by" and "sell by" dates; reported ability to read food
      product safety labels. RESULTS: From a weighted total of 645 refrigerators
      measured, 451 (70%) were too warm for the safe storage of food (> or = 6 degrees
      Celsius). Only 41% of respondents (n = 279) knew the star rating of their
      freezer. Within a smaller sub-sample knowledge of the "use by" and "sell by"
      dates was good, but 45% of these respondents reported difficulty reading food
      labels. The storage of foods at inappropriate temperatures was not independent of
      socioeconomic or demographic status, and tended to be more likely among the
      poorer and those not living alone. CONCLUSIONS: Food storage practices among the
      majority of elderly people interviewed in this study do not meet recommended
      safety standards to minimise the risk of food poisoning.

PMID- 10396510
TI  - Religious circumcision on the NHS: opinions of Pakistani people in Middlesbrough,
      England.

PMID- 10396509
TI  - Effect of a transient, geographically localised economic recovery on community
      health and income studied with longitudinal household cohort interview method.
AB  - STUDY OBJECTIVE: The main purpose of the study was to determine whether the
      health or economic status of a cohort of residents in an economically troubled
      geographical area changed between 1990 and 1993. DESIGN: Longitudinal, single
      cohort, interview survey method with the key variables of health status and
      economic status. Quasi-experimental pre-post design with economic rebound as the
      intervention. SETTING: A relatively low income geographical area in a rural,
      mountainous region before and after an economic rebound. In 1990, the local
      economy and health care system collapsed because of the closure of a series of
      manufacturing plants; outward migration from the area peaked. Between 1990 and
      1993, new industries opened, and state and private community assistance
      programmes intervened, resulting in an economic rebound, migration into the area,
      and marked growth of the health service sector. PARTICIPANTS: A 2% sample of
      residents of households, using a combination of random, stratified, and clustered
      sampling. Residents included in the study had lived within the area throughout
      the 1990-1993 period of the study. MAIN RESULTS: Stable, non-migrating residents
      had a statistically significant 7% reduction in health status between 1990 and
      1993, as measured by a composite of subjective and objective measures. The non
      migrating residents also had a significant decrease in average household income
      ($14,700 in 1990 and $12,400 in 1993 in constant 1990 dollars) during the strong
      economic expansion, and therefore did not participate in or receive direct
      economic benefit from the expansion. There was a rapid population increase during
      the expansion, attributable to inward migrants who were younger and healthier
      than existing residents. The decline in health for the non-migrating residents
      was tentatively attributed to either direct or indirect effects of the decline in
      family income. CONCLUSIONS: Local economic development accompanied by expanded
      health care services availability can leave existing area residents poorer and
      less healthy, and this problem may be masked by an abundance of healthier,
      wealthier inward migrants.

PMID- 10396511
TI  - Smoke alarm ownership and house fire death rates in children.

PMID- 10396512
TI  - "Late presenters" after paracetamol self poisoning.

PMID- 10396514
TI  - Alcohol and health: what is good for the French may not be for the Russians.

PMID- 10396513
TI  - Public health surveys in Singapore.

PMID- 10396515
TI  - Health sector reform.

PMID- 10396516
TI  - The onward march of European public health.

PMID- 10396517
TI  - Alcohol and cardiovascular mortality in Moscow; new evidence of a causal
      association.
AB  - BACKGROUND: In explaining recent trends in Russian mortality, alcohol drinking
      has often been put forward as a major factor. However, cardiovascular disease
      remains the major cause of death in Russia and alcohol is currently viewed as
      having a protective effect on heart disease. This study explores this apparent
      paradox by examining daily trends in deaths from cardiovascular disease in
      Moscow. SUBJECTS: Those dying in Moscow in the years 1993-1995. METHODS: Analysis
      of daily variation in deaths based on data from Moscow City death certificates.
      RESULTS: There is a significant increase in deaths from alcohol poisoning,
      accidents, and violence and cardiovascular diseases on Saturdays, Sundays, and
      Mondays. This is especially marked for sudden deaths. This pattern is consistent
      with the known pattern of drinking in Russia, which is more likely to take place
      in binges than is the case in other countries. CONCLUSION: A possible causative
      role for alcohol in sudden cardiovascular death is suggested as there are no
      other obvious explanations for this pattern, which cannot be accounted for by
      daily variations in traditional risk factors such as smoking or lipids. Although
      this is inconsistent with the prevailing view in the West that alcohol is seen as
      cardioprotective, there is considerable supporting evidence from a necropsy study
      and from studies in other places with a similar pattern of drinking. In countries
      such as Russia, where patterns of drinking differ considerably from that in the
      West, binge drinking can be an important cause of sudden cardiac death. This has
      important implications for estimates of the amount of mortality worldwide
      attributable to specific risk factors and thus for national and international
      policy.

PMID- 10396518
TI  - Combined oral contraceptives, smoking, and cardiovascular risk.
AB  - STUDY OBJECTIVE: To assess age specific incidence and mortality of stroke, acute
      myocardial infarction (AMI), and idiopathic venous thromboembolism (VTE)
      associated with use of modern low dose combined oral contraceptives (OCs) and the
      interaction with smoking. DESIGN: Hospital-based case-control study. SETTING:
      Hospitals in Oxford region in the United Kingdom, which covered a defined
      population, during the period 1989-1993. METHODS: Relative risk estimates from
      the WHO Collaborative Study and observed incidence rates from the Oxford region
      were used to estimate age specific incidence of each disease among women without
      cardiovascular risk factors and model total cardiovascular incidence and
      mortality. RESULTS: Among women who did not use OCs, smoke nor had any other
      cardiovascular risk factors, total incidence of stroke and AMI were less than 2
      events per 100,000 woman years in those aged 20-24 years and rose exponentially
      with age to 8 events per 100,000 among women aged 40-44 years. Incidence of
      idiopathic VTE among women who did not use OCs rose linearly with age (from 3.3
      per 100,000 at ages 20-24 years to 5.8 per 100,000 at ages 40-44 years). The
      increased risk of idiopathic VTE associated with OC use among non-smokers
      constituted over 90% of all cardiovascular events for women aged 20-24 years and
      more than 60% in those aged 40-44 years. Fatal cardiovascular events were
      dominated by haemorrhagic stroke and AMI, and among OC users who smoked these two
      diseases accounted for 80% of cardiovascular deaths among women aged 20-24 years,
      rising to 97% among those aged 40-44 years. Cardiovascular mortality associated
      with smoking was greater than that associated with OC use at all ages.
      Attributable risk associated with OC use was 1 death per 370,000 users annually
      among women aged 20-24 years, 1 per 170,000 at ages 30-34 years, and 1 per 37,000
      at ages 40-44 years. Among smokers, the cardiovascular mortality attributable to
      OC use was estimated to be about 1 per 100,000 users annually among women aged
      less than 35 years, and about 1 per 10,000 users annually among those above the
      age of 35 years. CONCLUSION: The incidence of fatal cardiovascular events among
      women aged less than 35 years is low. The VTE risk associated with OC use is the
      largest contributor to OC induced adverse effects. The potentially avoidable
      excess VTE risk associated with the newer progestogens desogestrel and gestodene
      would account for a substantial proportion of total cardiovascular morbidity in
      this age group. For women over age 35 years the absolute risks associated with OC
      use and smoking are greater because of the steeply rising incidence of arterial
      diseases. The combination of smoking and OC use among such women is associated
      with particularly increased risks. Any potential reduction in AMI or stroke risk
      with use of third generation OCs would be a more important consideration among
      older compared with younger women, particularly if they smoke. However, the
      mortality associated with smoking is far greater than that associated with OC use
      (of any type) at all ages.

PMID- 10396519
TI  - Accumulation of factors influencing children's middle ear disease: risk factor
      modelling on a large population cohort.
AB  - STUDY OBJECTIVES: Data were analysed from a large national birth cohort to
      examine cumulative and interactive prediction from various risk factors for
      childhood middle ear disease, and to resolve conflicting evidence arising from
      small and incompletely controlled studies. The large sample size permitted
      appropriate covariate adjustment to give generality, and permit demographic
      breakdown of the risk factors. SETTING: A large multi-purpose longitudinal birth
      cohort study of all births in the UK in one week in 1970, with multiple
      questionnaire sweeps. PARTICIPANTS: Over 13,000 children were entered into the
      original cohort. Data on over 12,000 children were available at the five year
      follow up. MAIN OUTCOME MEASURES: For children at 5 years, parent reported data
      were available on health and social factors including data on two markers for
      middle ear disease: the occurrence of purulent (nonwax) ear discharge and
      suspected or confirmed hearing difficulty. MAIN RESULTS: In those children who
      had ever had reported hearing difficulty (suspected or confirmed), after control
      for socioeconomic status, three of the classic factors (male sex, mother's
      smoking habits since birth, and attending day care) were significantly more
      frequent. In those who had ever had ear discharge reported, only mother's smoking
      habit since birth was significantly more frequent. However, it showed an orderly
      dose response relation. In addition, a derived general child health score was
      found to be significantly associated with both the middle ear disease markers.
      Control for this variable in the analysis of those having reported hearing
      difficulty reduced the effect size of mother's smoking habit, but it remained
      statistically significant. For reported ear discharge, even after control for the
      general health score and social index, mother's smoking habits and day care
      attendance were both significant predictors. Mother's (but not father's) smoking
      habits and day care attendance were found to be significant risk factors for
      middle ear disease. Breast feeding effects were weak and did not generally
      survive statistical control. CONCLUSIONS: A child having all three risk factors
      (attends day care, a mother who smokes, and male sex) is 3.4 times more likely to
      have problems with hearing than a child who has none, based on cumulative risk.
      Further studies should focus on preventative risk modification and well specified
      intervention.

PMID- 10396520
TI  - Health related lifestyle in adolescence predicts adult educational level: a
      longitudinal study from Finland.
AB  - OBJECTIVE: To assess the relative importance of perceived health and health
      related lifestyle in adolescence in the production of educational differences.
      DESIGN: A longitudinal study: survey data from 1981 and 1985 linked with
      Educational Registry data from 1993. SETTING: The whole of Finland. PARTICIPANTS:
      A representative sample of 4761, 16 and 18 year olds. The follow up rate was 82%.
      MEASUREMENTS AND MAIN RESULTS: The outcome variable was the attained educational
      level at age 24 to 30. Predictive variables described health related lifestyle
      and health at the age of 16 and 18. Those whose educational level was low at
      follow up, had in adolescence, a more health compromising lifestyle than those
      who had reached higher levels. They had placed less emphasis on health promoting
      behaviours like not smoking, physical exercise, good diet, and dental hygiene.
      Smoking was the outstanding predictor of attained educational level. Among the
      health variables, only psychosomatic symptoms predicted high educational levels
      in girls, and both psychosomatic symptoms and height in boys. CONCLUSION: Those
      who reach a high level of education in adulthood, have had a health enhancing
      lifestyle already in adolescence, while those reaching only a low level, have had
      a health compromising lifestyle. Health plays only a small part in the prediction
      of adult educational level. The results suggest that a health compromising
      lifestyle, adopted already in adolescence, is an important mechanism from which
      educational health differences originate.

PMID- 10396521
TI  - A randomised controlled trial of postal versus interviewer administration of a
      questionnaire measuring satisfaction with, and use of, services received in the
      year before death.
AB  - STUDY OBJECTIVES: To develop a short form of an interview schedule used
      successfully in previous national surveys of care for the dying, and to
      investigate the effect of administering it by post on response rate, response
      bias and on the nature of responses to questions. DESIGN: Randomised controlled
      trial. SETTING: An inner London health authority. PARTICIPANTS: Informants
      (person registering death) of random sample of cancer deaths between June 1995
      and July 1996. MAIN RESULTS: The shortened questionnaire (VOICES) has 158
      questions. Response rate did not differ significantly between postal and
      interview groups (interview; 56% (69 of 123), postal: 52% (161 of 308).
      Responders in the two groups did not differ in terms of their sociodemographic
      characteristics. Postal questionnaires had significantly more missing data,
      particularly on questions about service provision and satisfaction with services.
      Responses to questions differed between the groups on 11 of 158 questions.
      Interview group respondents were more likely to give top ranking responses to
      questions on service satisfaction and symptom control. CONCLUSIONS: Postal
      questionnaires are an acceptable alternative to interviews in retrospective post
      bereavement surveys of care for the dying, at least in terms of response rate and
      response bias. However, the increased costs of interview surveys need to be
      balanced against the fact that postal questionnaires result in more missing data,
      and possibly less reliable answers to some questions. Caution is needed in
      combining results from the two data collection methods as interview respondents
      gave more positive answers to some questions.

PMID- 10396522
TI  - How many lives is equity worth? A proposal for equity adjusted years of life
      saved.
AB  - STUDY OBJECTIVE: To present a formula for equity adjusted years of life saved
      (EYLS). DESIGN: A mailed questionnaire. The survey participants were given a
      scenario describing a trade off between a health maximization programme and a
      programme that is less efficient, but eliminates social inequalities. SETTING:
      Swedish politicians responsible for health care in the county councils.
      PARTICIPANTS: A sample of 449 Swedish politicians responsible for health care in
      the county councils. MAIN RESULTS: The principle of health maximization was
      rejected. Under certain conditions, the Swedish politicians are prepared to
      sacrifice 15 of 100 preventable deaths to achieve equity. Based on the results a
      formula for EYLS is presented. CONCLUSIONS: An equity adjusted formula for years
      of life saved has been proposed, but must be developed and revised according to
      each country's specific conditions and value premises. In the future, such
      formulas could serve the purpose of incorporating explicit considerations of
      equity into cost effectiveness analyses.

PMID- 10396523
TI  - Should we be frightened of bracken? A review of the evidence.
AB  - OBJECTIVE: To assess the risk to human health of the plant bracken (Pteridium
      sp). DESIGN: An evaluation of studies of human and animal populations exposed to
      bracken, together with a review of expert reports and advice to the public. MAIN
      RESULTS: Bracken induced disease has been demonstrated in animals in both
      laboratory and field studies. Depending on the species, diseases in animals
      associated with the plant have included; cancers of the alimentary and urogenital
      tract, lung and breast; haematuria; retinal degeneration; and, thiamine
      deficiency. Potential exposure of human populations is through: food either
      directly (people in some parts of the world eat bracken as a traditional dish) or
      indirectly by consuming animals fed on bracken; milk; water; inhalation and
      ingestion of spores; and insect vectors. Four studies of human populations (two
      analytical and two observational) failed to assess adequately confounding factors
      and other sources of bias, so that conclusions about a risk to human health from
      bracken cannot firmly be drawn. Establishing exposure is also extremely difficult
      in populations (such as the United Kingdom) where direct consumption of bracken
      is rare. CONCLUSION: Bracken is a common plant worldwide. It is toxic to many
      animal species and to several organ systems. There is no tumour (or other
      disease) that is pathognomic of exposure in animals, though cancers of the
      alimentary and urogenital tract seem to be the most commonly associated. It is
      not possible to extrapolate from animal models to humans. Studies of human
      populations, do not establish a clear risk of bracken to human health, largely
      because of methodological problems. Testing the evidence against traditional
      criteria of causality only fulfils the criterion of biological plausibility.
      Despite this, current public information implies a serious risk to human health
      from bracken, and increasing media coverage of the subject is likely to lead to
      greater public concern. Further epidemiological studies are required.

PMID- 10396524
TI  - Colorectal cancer prevention. An approach to increasing compliance in a faecal
      occult blood test screening programme.
AB  - STUDY OBJECTIVE: The assessment of the uptake of colorectal cancer screening
      offered in a workplace setting. DESIGN: Employees were offered a free faecal
      occult blood test (Haemoccult). A repeat letter was sent two months later to non
      responders. Those with positive tests were invited for colonoscopy. Compliance
      was measured according to age, sex, and occupational group and the effects of
      reinviting non-compliers investigated. SETTING: Leicester General Hospital, a
      large university teaching hospital. PARTICIPANTS: 990 employees aged 41 to 65
      years. MAIN RESULTS: Total compliance was 46% with women participating more than
      men (49% v 34%, chi 2 = 12.2, p < 0.001). The difference was mostly because of
      women aged 41 to 50 years complying more than their male counterparts (48% v 24%,
      chi 2 = 15.5, p < 0.0001). Participation was highest in clinical support staff
      (56%), nurses (52%), and clerical workers (46%). Uptake by doctors (26%) and
      managers (26%) was significantly lower than by clinical support staff and nurses
      (chi 2 > 5.5, p < 0.02). Remailing raised compliance slightly from 43.6% to
      46.3%. Four employees (1%) had positive faecal occult blood tests but three were
      negative on repeat testing with dietary restrictions. CONCLUSIONS: The government
      favours the development of health promotion programmes as stated in its document
      "Health at work in the NHS". The response in this study, showed methods to
      increase compliance must be developed if such programmes are to be successful. As
      uptake was similar to that in several community based programmes in general
      practice, workplace based programmes could offer a complementary method of
      delivering screening.

PMID- 10396526
TI  - Thirty year trend (1967-1996) in prevalence of poliomyelitis and vaccine coverage
      in Ballabgarh, Haryana, India.

PMID- 10396525
TI  - Strong correlation between Helicobacter pylori seropositivity and Chlamydia
      pneumoniae IgG concentrations.

PMID- 10396527
TI  - Periconceptional folic acid in The Netherlands in 1995. Socioeconomic
      differences.

PMID- 10396528
TI  - Type 3 errors, pill scares, and the epidemiology of oral contraception and
      health.

PMID- 10396529
TI  - The covert influence of the tobacco industry on research and publication: a call
      to arms.

PMID- 10396530
TI  - Models: instruments for evidence based policy.

PMID- 10396531
TI  - An inverse relation between blood pressure and birth weight among 5 year old
      children from Soweto, South Africa.
AB  - STUDY OBJECTIVE: To examine the relation between birth weight and blood pressure
      at 5 years in a cohort of South African children. DESIGN: Prospective cohort
      study. PARTICIPANTS: 849 five year old children. SETTING: Soweto, a sprawling
      urban area close to Johannesburg, South Africa, which was a designated
      residential area for people classified as "black" under apartheid legislation.
      MAIN RESULTS: Systolic blood pressure at 5 years was inversely related to
      birthweight (r = -0.05, p = 0.0007), independent of current weight, height,
      gestational age, maternal age or socioeconomic status at 5 years. There was no
      relation between birth weight and diastolic blood pressure. After adjusting for
      current weight and height, there was a mean decline in systolic blood pressure of
      3.4 mm Hg (95% confidence intervals 1.4, 5.3 mm Hg) for every 1000 g increase in
      birth weight. CONCLUSIONS: These data from a disadvantaged urbanised community in
      Southern Africa extend the reported observations of an inverse relation between
      birth weight and systolic blood pressure. The study adds to the evidence that
      influences in fetal life and early childhood influence systolic blood pressure.
      Further research is required to assess whether efforts to reduce the incidence of
      low birthweight babies will attenuate the prevalence of hypertension in future
      generations.

PMID- 10396533
TI  - Patterns of smoking in the Baltic Republics.
AB  - BACKGROUND: Tobacco is a leading cause of avoidable death in the Baltic Republics
      but there is, as yet, relatively little information in the public domain on who
      is smoking and how this is changing. This information is important for those
      seeking to develop effective policies to tackle this issue. OBJECTIVE: To
      determine the pattern of smoking in Estonia, Latvia, and Lithuania. METHODS:
      Analysis of data on patterns of tobacco consumption from representative surveys
      of approximately 3000 adults aged under 65 in each country undertaken in 1997.
      RESULTS: The prevalence of smoking among men is 53.9%, 56.0%, and 53.2%
      respectively in Estonia, Latvia, and Lithuania. The corresponding figures for
      women are 24.1%, 10.9%, and 7.6%. For both sexes, current smoking rates are
      consistently lowest in the age group 50 to 64 and highest in the age group 35 to
      49. Education and income are determinants of smoking rates among men but much
      less so among women. Russian men are more likely to smoke than are men from the
      majority group in each country. Smoking rates among women are much lower in rural
      than in urban areas of Latvia and Lithuania but this is not so in Estonia.
      CONCLUSIONS: Smoking rates among men in the Baltic Republics are already very
      high. Among women, they still vary considerably. Each country has implemented
      some measures to reduce smoking. These seem to have been especially effective in
      Lithuania but, overall, much more action is needed.

PMID- 10396532
TI  - Familial predisposition and susceptibility to the effect of other risk factors
      for myocardial infarction.
AB  - STUDY OBJECTIVES: To assess if familial predisposition to myocardial infarction
      (MI) is an indicator of increased susceptibility to the effect of other
      established risk factors. The study assessed whether a family history of MI
      modifies the effect of arterial blood pressure, plasma cholesterol, high and low
      density lipoprotein cholesterol, % triglycerides, diabetes mellitus, body mass
      index, height, smoking habits, alcohol intake, physical activity level, and
      educational level on the incidence of MI. DESIGN: Prospective population based
      cohort study of cardiovascular risk and risk factors with follow up of MI by
      record linkage with the Cause of Death Register and The National Hospital
      Discharge Register until 1994. SETTING: The Copenhagen Centre for Prospective
      Population Studies, where data from three Danish studies are integrated.
      PARTICIPANTS: Subjects were 24,664 people aged 20-93, examined between 1976 and
      1987. MAIN RESULTS: A total of 1763 new cases of MI occurred during 293,559
      person years of observation. All risk factors, including family history of MI
      reported by 4012 subjects, were, as expected, associated with incidence of MI.
      With a few inconsistent exceptions we found no significant interactions between
      family history of MI and cardiovascular risk factors in their effect on MI.
      CONCLUSIONS: The familial predisposition to MI does not consistently modify the
      effect of other risk factors on the risk of MI. However, subjects with a family
      history of MI may still be regarded as an appropriate target group for screening
      for cardiovascular risk and intervention against other risk factors.

PMID- 10396534
TI  - Lymphatic and haematopoietic cancer mortality in a population attending school
      adjacent to styrene-butadiene facilities, 1963-1993.
AB  - STUDY OBJECTIVE: To evaluate the risk of mortality from lymphatic and
      haematopoietic cancers and other causes among students. DESIGN: The study used
      school records, yearbooks, and Texas Department of Health records for the school
      years 1963-64 to 1992-93 to construct a cohort of 15,403 students. Three
      mortality databases were searched to identify deaths, and mortality rates in the
      cohort were compared with mortality rates from the United States and Texas.
      Computed standardised mortality ratios and 95% confidence intervals were used.
      SETTING: Eastern Texas high school adjacent to facilities that have been
      producing synthetic styrene-butadiene since 1943. MAIN RESULTS: 338 deaths were
      identified. The all causes standardised mortality ratio was 0.84 (95% confidence
      intervals 0.74, 0.95) for men and 0.89 (0.73, 1.09) for women. The standardised
      mortality ratio for all lymphatic and haematopoietic cancers was 1.64 (95%
      confidence intervals 0.85, 2.87) for men and 0.47 (0.06, 1.70) for women. The
      slight male excess in lymphatic and haematopoietic cancers was stronger among men
      who attended school for two years or less. CONCLUSIONS: The overall mortality
      from lymphatic and haematopoietic cancer among the students was little different
      from that of the United States as a whole. A moderate excess for men,
      predominantly among the shorter-term students, was offset by a deficit among
      women. These variations are compatible with random fluctuations; the overall
      pattern is not indicative of an effect of environmental exposure sustained while
      attending the high school.

PMID- 10396535
TI  - The magnitude of differences in perceived general health associated with
      educational level in the regions of Spain.
AB  - STUDY OBJECTIVE: To examine and compare the relation between inequalities in
      perceived general health and education in the 17 regions of Spain. DESIGN AND
      METHODS: Data were taken from the 1993 Spanish Health Interview Survey. For each
      region we calculated the magnitude of inequality in perceived general health in
      association with educational level by a measure of association or effect and by a
      relative index of inequality. Both measures are odds ratios and were estimated by
      logistic regression. The first is an odds ratio associated with one year less
      education, while the second represents the inequality in perceived general health
      between those at the bottom and those at the top of the educational hierarchy.
      MAIN RESULTS: The six regions with the highest relative indices of inequality
      also have the highest odds ratios associated with one year less education, and
      five of the six regions with the lowest relative indices of inequality have the
      lowest odds ratios associated with one year less education. Pearson's correlation
      coefficient between the odds ratio and the relative index of inequality is 0.94.
      CONCLUSIONS: Regional differences in levels of inequality in perceived general
      health are attributable exclusively to the effect of education on health and not
      to the distribution of the population among the different educational levels. It
      is not known why the magnitude of this effect of education on health varies from
      one area to another.

PMID- 10396536
TI  - The Health Education Authority's health and lifestyle survey 1993: who are the
      low fruit and vegetable consumers?
AB  - STUDY OBJECTIVE: Firstly, to determine the demographic and behavioural
      characteristics of low fruit and vegetable consumers. Secondly, to investigate
      whether knowledge and attitudes are barriers to consumption of fruit and
      vegetables. DESIGN: Cross sectional survey: an interviewer administrated
      questionnaire was used to assess the demographic, knowledge, attitude, and
      behavioural characteristics of the respondents. SETTING: England. PARTICIPANTS:
      Random sample of 5553 men and women aged between 16 and 74 years. Response rate
      70%. MAIN RESULTS: The main demographic characteristics of the respondents
      identified as low consumers of fruit and vegetables (less than daily consumption
      of either fruit or vegetables) were age, sex, and smoking status. The adjusted
      odds ratios were 2.59 for those aged 16-24 years compared with those aged 45-74
      years, 2.17 for men compared with women, and 1.77 for current smokers compared
      with never smokers. The most important knowledge and attitude statements after
      adjusting for the demographic variables were disagreeing with the statement
      "healthy foods are enjoyable" (odds ratio 1.90) and agreeing with the statement
      "I don't really care what I eat" (odds ratio 1.76). The impact of knowledge
      seemed less important than attitudes about a healthy diet in characterising a low
      fruit and vegetable consumer. CONCLUSIONS: These findings are relevant to future
      strategies for improving intake of fruit and vegetables, but demonstrate the
      complexity of interventions required, and the dangers inherent in assuming
      simplistic relations between psychosocial factors and behaviour.

PMID- 10396537
TI  - How good is the Prevent model for estimating the health benefits of prevention?
AB  - STUDY OBJECTIVE: Prevent is a public health model for estimating the effect on
      mortality of changes in exposure to risk factors. When the model is tested by
      simulating a development that has already taken place, the results may differ
      considerably from the actual situation. The purpose of this study is to test the
      Prevent model by applying it to a synthetic cohort in which the development is
      unaffected by concealed factors. DESIGN: A micro-simulation model was developed
      to create basic data for Prevent and give "exact" results as to changes in risk
      factor prevalences and mortality. The estimates of Prevent simulations were
      compared with the "exact" results. MAIN RESULTS: Modelling one risk factor
      related to a cause specific mortality gave fairly similar results by the two
      methods. Including two risk factors Prevent tends slightly to overestimate the
      health benefits of prevention. CONCLUSIONS: The differences between the "exact"
      mortality and the Prevent estimates will be small for realistic scenarios and
      Prevent provide reasonable estimates of the health benefits of prevention.

PMID- 10396538
TI  - Acute health effects of the Sea Empress oil spill.
AB  - STUDY OBJECTIVE: To investigate whether residents in the vicinity of the Sea
      Empress tanker spill suffered an increase in self reported physical and
      psychological symptoms, which might be attributable to exposure to crude oil.
      DESIGN: Retrospective cohort study; postal questionnaire including demographic
      details, a symptom checklist, beliefs about health effects of oil and the
      Hospital Anxiety and Depression and SF-36 mental health scales. SETTING:
      Populations living in four coastal towns on the exposed south Pembrokeshire coast
      and two control towns on the unexposed north coast. PATIENTS: 539 exposed and 550
      unexposed people sampled at random from the family health services authority age
      sex register who completed questionnaires. MAIN RESULTS: Adjusted odds ratios for
      self reported physical symptoms; scores on the Hospital Anxiety and Depression
      and SF-36 mental health scales, in 1089 people who responded out of a possible
      1585 (69%). CONCLUSIONS: Living in areas exposed to the crude oil spillage was
      significantly associated with higher anxiety and depression scores, worse mental
      health; and self reported headache (odds ratio = 2.35, 95% CI 1.56, 3.55), sore
      eyes (odds ratio = 1.96, 95% CI 1.06, 3.62), and sore throat (odds ratio = 1.70,
      95% CI 1.12, 2.60) after adjusting for age, sex, smoking status, anxiety, and the
      belief that oil had affected health. People living in exposed areas reported
      higher rates of physical and psychological symptoms than control areas. Symptoms
      significantly associated with exposure after adjustment for anxiety and health
      beliefs were those expected from the known toxicological effect of oil,
      suggesting a direct health effect on the exposed population.

PMID- 10396540
TI  - Geographical clustering of acute adult leukaemia in the East Anglian region of
      the United Kingdom: a registry-based analysis.

PMID- 10396539
TI  - Nutritional counselling in general practice: a cost effective analysis.
AB  - STUDY OBJECTIVE: To study the clinical and cost outcomes of providing nutritional
      counselling to patients with one or more of the following conditions: overweight,
      hypertension and type 2 diabetes. DESIGN: The study was designed as a random
      controlled trial. Consecutive patients were screened opportunistically for one or
      more of the above conditions and randomly allocated to one of two intervention
      groups (doctor/dietitian or dietitian) or a control group. Both intervention
      groups received six counselling sessions over 12 months from a dietitian.
      However, in the doctor/dietitian group it was the doctor and not the dietitian
      who invited the patient to join the study and the same doctor also reviewed
      progress at two of the six counselling sessions. SETTING: The study was conducted
      in a university group general practice set in a lower socioeconomic outer suburb
      of Perth, Western Australia. PATIENTS: Of the 273 patients randomly allocated to
      a study group, 198 were women. Age ranged from 25 to 65 years. Seventy eight per
      cent of patients resided in the lower two socioecnomic quartiles, 56 per cent
      described their occupation as home duties and 78 per cent were partnered.
      RESULTS: Both intervention groups reduced weight and blood pressure compared with
      the control group. Patients in the doctor/dietitian group were more likely to
      complete the 12 month programme than those in the dietitian group. Patients in
      the doctor/dietitian group lost an average of 6.7 kg at a cost of $A9.76 per
      kilogram, while the dietitian group lost 5.6 kg at a cost of $A7.30 per kilogram.
      CONCLUSION: General practitioners, in conjunction with a dietitian, can produce
      significant weight and blood pressure improvement by health promotion methods.

PMID- 10396541
TI  - Assessment of differential item functioning in the Perceived Stress Scale-10.

PMID- 10396542
TI  - On editorial freedom: implications of the JAMA affair.

PMID- 10396543
TI  - Social capital: is it good for your health? Issues for a public health agenda.

PMID- 10396544
TI  - Are risk factors for atherothrombotic disease associated with back pain sickness
      absence? The Whitehall II Study.
AB  - STUDY OBJECTIVE: To explore the previously stated hypothesis that risk factors
      for atherothrombotic disease are associated with back pain. DESIGN: Prospective
      (mean of four years of follow up) and retrospective analyses using two main
      outcome measures: (a) short (< or = 7 days) and long (> 7 days) spells of
      sickness absence because of back pain reported separately in men and women; (b)
      consistency of effect across the resulting four duration of spell and sex cells.
      SETTING: 14 civil service departments in London. PARTICIPANTS: 3506 male and 1380
      female white office-based civil servants, aged 35-55 years at baseline. MAIN
      RESULTS: In age adjusted models, low apo AI was associated with back pain across
      all four duration-sex cells and smoking was associated across three cells. Six
      factors were associated with back pain in two cells: low exercise and high BMI,
      waist-hip ratio, triglycerides, insulin and Lp(a). On full adjustment (for age,
      BMI, employment grade and back pain at baseline), each of these factors retained
      a statistically significant effect in at least one duration-sex cell.
      Triglycerides were associated with short and long spells of sickness absence
      because of back pain in men in fully adjusted models with rate ratios (95%
      confidence intervals) of 1.53 (1.1, 2.1) and 1.75 (1.0, 3.2) respectively. There
      was little or no evidence of association in age adjusted models with: fibrinogen,
      glucose tolerance, total cholesterol, apoB, hypertension, factor VII, von
      Willebrand factor, electrocardiographic evidence of coronary heart disease and
      reported angina. CONCLUSIONS: In this population of office workers, only modest
      support was found for an atherothrombotic component to back pain sickness
      absence. However, the young age of participants at baseline and the lack of
      distinction between different types of back pain are likely to bias the findings
      toward null. Further research is required to ascertain whether a population sub
      group of atherothrombotic back pain can be identified.

PMID- 10396546
TI  - Social mobility and health related behaviours in young people.
AB  - STUDY OBJECTIVE: To assess the influences related to social mobility,
      particularly health related behaviours, as one potential explanation for the
      social class variation in health among adults. DESIGN: The study is based on
      questionnaire data from the Adolescent Health and Lifestyle Surveys of 1985,
      1987, and 1989. SETTING: The whole of Finland. PARTICIPANTS: A representative
      sample of 8355 adolescents. The response rate was 79%. MEASUREMENT AND MAIN
      RESULTS: The relation between social mobility and health related behaviours among
      16 and 18 year old young people was studied. The measure of social mobility was
      based on a combination of the social class of origin and achieved social position
      measured by the present educational status, educational attainment, and labour
      market position. Three mobility groups were constructed: the downwardly mobile,
      the upwardly mobile and the stable. Health related behaviours in an upwardly or
      downwardly mobile group were compared with a stable group from the same social
      class of origin by calculating relative risks (RR). RRs were assessed by
      calculating age and sex adjusted rate ratios approximating a Mantel-Haenszel
      estimate. In logistic regression analyses the independent effects of the social
      class of origin and the achieved social position were investigated. Most of the
      nine behaviours studied (smoking, alcohol use, heavy intoxication, coffee
      drinking, tooth brushing, consumption of sweets, lack of physical exercise,
      choice of bread spread, and consumption of milk) were related to the direction of
      mobility so that health compromising behaviours were more frequent among
      downwardly mobile and less frequent among upwardly mobile young people than their
      stable peers. Achieved social position proved to determine health related
      behaviours more strongly than class of origin, thus emphasising the way education
      facilitates both health values and behaviours as well as the future social
      position. CONCLUSIONS: The close relation between social mobility and health
      related behaviours is concluded to be a part of an explanation of social class
      differences in health observed among adults.

PMID- 10396545
TI  - Suicide, religion, and socioeconomic conditions. An ecological study in 26
      countries, 1990.
AB  - STUDY OBJECTIVE: Relative risks are frequently assumed to be stable across
      populations but this may not apply in psychiatric epidemiology where
      sociocultural context may modify them. Such ecological effect modification will
      give curved associations between aggregated risk factor and outcome. This was
      examined in connection with the ecological association between suicide rates and
      an aggregate index of religiosity. DESIGN: Ecological study of associations
      between suicide rates and an index of religiosity, adjusted for socioeconomic
      variation. The effect of stratification of the study sample according to levels
      of religiosity, was examined. SETTING: 26 European and American countries.
      SUBJECTS: Interview data from 37,688 people aggregated by country. OUTCOME
      MEASURES: Age and sex specific (1986-1990) suicide rates. MAIN RESULT: Adjusted
      for socioeconomic variation, negative associations of male suicide rates with
      religiosity were apparent in the 13 least religious countries only (test for
      interaction F (1, 25) = 5.6; p = 0.026). Associations between religiosity and
      female suicide rates did not vary across countries. CONCLUSION: The bent
      ecological association was apparent only after adjustment for socioeconomic
      variation suggesting that, rather than confounding, ecological modification of
      individual level links between religion and male (but not female) suicide risk is
      the responsible mechanism. This concurs with micro-level findings suggesting that
      suicide acceptance depends not only on personal but also on contextual levels of
      religious belief, and that men are more sensitive to this phenomenon than women.
      In psychiatric epidemiology, relative risks vary with the exposure's prevalence.
      This has important implications for research and prevention.

PMID- 10396548
TI  - Longitudinal, population-based study of self reported alcohol habits, high levels
      of sickness absence, and disability pensions.
AB  - STUDY OBJECTIVE: To analyse the relation between self reported hazardous drinking
      on the one hand and high sickness absence and/or disability pensions in both
      sexes on the other hand. DESIGN: The study is based on data from a health survey,
      Stockholm Health of the Population Study, conducted in 1984. The mailed
      questionnaire covered alcohol consumption. Three different measures of alcohol
      habits were used: usual alcohol consumption, consumption during the previous
      week, and answers to the four CAGE questions on problem drinking. Information
      from the health survey and data from a subsequent health examination were related
      to information from the National Swedish Social Insurance Board for the year 1984
      and the years 1986 to 1991 concerning sick leave and disability pensioning.
      SETTING: Four primary health care districts in Stockholm County. PARTICIPANTS:
      The study group included persons who were aged 20 to 52 years in 1984, who
      answered the questionnaire (by mail or by telephone), and who participated in the
      health examination. The study group comprised 985 women and 870 men fulfilling
      the criteria for inclusion out of 6217 subjects aged 18 years and over randomly
      drawn. MAIN RESULTS: In both sexes, a consistent pattern of increased sickness
      absence was seen for high consumers and for those with indications of problem
      drinking. In most comparisons, a clearly increased relative risk, although not
      always statistically significant, for an average of at least 60 sick days per
      year or for a disability pension during follow up was found. In multivariate
      analysis, controlling for age, socioeconomic group, smoking habits, and self
      reported health, a small reduction in the relative risks was found, suggesting
      that these factors could explain only a small part of the relative risks. The
      risks for abstainers were higher than for low and moderate consumers.
      CONCLUSIONS: The effects of alcohol on subsequent high levels of sickness absence
      five to seven years after baseline as well as on the occurrence of disability
      pensions suggested that there is an effect on working incapacity independent of
      baseline health status, smoking, and socioeconomic group.

PMID- 10396547
TI  - Gender inequalities in health and health care services use in Catalonia (Spain).
AB  - BACKGROUND AND OBJECTIVES: While socio-economically derived differences in health
      and health services use have long been a subject of study, differences based on
      gender, considered as the explicative variable, have scarcely been quantified
      from population-based data. The aim of this investigation was to analyse
      inequalities in health and health care services utilisation between men and women
      in Catalonia (Spain). DESIGN, SETTING, PARTICIPANTS, AND MEASURES: Data from the
      Catalan Health Interview Survey, a cross sectional survey conducted in 1994, were
      used. A total of 6604 women and 5641 men aged 15 years or over were included for
      analysis. Health related variables studied were self perceived health,
      restriction of activity (past two weeks), and presence of chronic conditions;
      health services use variables analysed were having visited a health professional
      (past two weeks), an optometrist (12 months), or a dentist (12 months); and
      hospitalisation (past 12 months). Age standardised proportions were computed
      according to gender, and prevalence odds ratios (OR) were derived from logistic
      regression equations. MAIN RESULTS: Women more frequently rated their health as
      fair or poor than men (29.8% v 21.4%; OR = 1.22; 95% CI: 1.10, 1.34). More women
      than men reported having restricted activity days (OR = 1.86; 95% CI: 1.59, 2.18)
      and chronic conditions (OR = 1.74; 95% CI: 1.60, 1.89). The proportion of women
      visiting a health professional was slightly greater than that for men (OR = 1.20;
      95% CI: 1.09, 1.31), as was the proportion of women visiting an optometrist (OR =
      1.21; 95% CI: 1.11, 1.33), and a dentist (OR = 1.43; 95% CI: 1.31, 1.55). The
      proportion of hospitalisation was lower in women (6.6%) than in men (7.7%; OR =
      0.73; 95% CI: 0.63, 0.85). When health services use was analysed according to
      self perceived health, women declaring good health reported a greater probability
      of consulting a health professional (OR = 1.35; 95% CI: 1.20, 1.52). There were
      no differences in respect to hospitalisation, visits to the optometrist and to
      the dentist. CONCLUSIONS: These results indicate a pattern close to the inverse
      care law, as women, who express a lower level of health and thus would need more
      health care, are not, however, using health services more frequently than men.

PMID- 10396549
TI  - Decline in lung function and mortality: the Busselton Health Study.
AB  - BACKGROUND: There is a direct association between level of lung function,
      measured by forced expiratory volume in 1 second (FEV1) and mortality rates. A
      low FEV may result from an increased decline in FEV1 with age, which may be an
      independent predictor of mortality. OBJECTIVE: To examine the association between
      decline in FEV1 and mortality in a cohort from a community health study. SETTING
      AND METHODS: From five cross sectional studies in Busselton between 1969 and 1981
      a cohort of 751 men and 940 women was identified who had three assessments of
      lung function over a six year period and had other health related data collected.
      Each subject's average FEV1 and decline in FEV1 (litre/year) were calculated from
      these three measurements. Mortality follow up to December 1995 was obtained.
      Cause of death was taken as the certified cause of death from the death
      certificate using ICD9 categories. RESULTS: The average decline in FEV1 was 0.04
      litre per year (SD = 0.07) for men and 0.03 litre per year (SD = 0.06) for women.
      Average FEV1 was significantly associated with all cause and cardiovascular
      disease mortality in both sexes. In women there was a significant association
      between decline in FEV1 and death from all causes, after adjusting for average
      FEV1, age, smoking, coronary heart disease, and cardiovascular disease risk
      factors; a 0.05 litre per year increase in the rate of decline of FEV1 increased
      the risk of death for all causes by 1.23 (95% confidence interval 1.06, 1.44). In
      men the effect of decline in FEV1 on death rate was less; for all men the hazard
      ratio for a 0.05 litre/year greater decline in FEV1 was 1.19 (0.99, 1.21).
      CONCLUSION: Decline in lung function, measured by FEV1 is a predictor of death,
      independent of average FEV1 and risk factors for cardiovascular disease.

PMID- 10396550
TI  - Studying seasonality by using sine and cosine functions in regression analysis.
AB  - STUDY OBJECTIVE: A statistical test that allows for adjustment of confounding can
      be helpful for the study of seasonal patterns. The aim of this article is to
      supply a detailed description of such a method. An example of its application is
      given. DESIGN: A statistical test is presented that retains the information on
      the connection of time periods by describing the seasonal pattern as one sine and
      one cosine function. Such functions can be included into a regression model. The
      resulting form of the seasonal pattern follows a cosine function with variable
      amplitude and shift. MAIN RESULTS: The test is shown to be applicable to test for
      seasonality. Not only one cosine function per time period, but also a mixture of
      cosine functions can be used to describe the seasonal pattern. Adjustment for
      confounding effects is possible. CONCLUSIONS: This method for studying seasonal
      patterns can be applied easily in a regression model. Adjusted prevalences and
      odds ratios can be calculated.

PMID- 10396551
TI  - Smoking habits among pregnant Danish women: reliability of information recorded
      after delivery.
AB  - STUDY OBJECTIVE: To compare recall of smoking habits during pregnancy 0.5-3 years
      after delivery across groups defined by recall time (5 six month periods) and
      pregnancy outcome (pre-eclampsia, pregnancy induced hypertension, intrauterine
      growth retardation, preterm or post-term delivery compared with controls).
      DESIGN: Case-control nested in cohort study. SETTING AND PARTICIPANTS: A
      subsample of 503 women from a cohort of 6347 women established between 1989 and
      1991 in Aarhus University Hospital. MAIN RESULTS: Measures of agreement between
      concurrent and retrospective data on smoking status varied between 0.93 and 1.0
      (sensitivity), 0.90 and 0.98 (specificity), and 0.79 and 0.98 (kappa). Spearman's
      correlation coefficients for number of cigarettes smoked/day varied between 0.87
      and 0.97; mean differences were all close to zero. Accuracy of recall tended to
      diminish with increasing alcohol intake, particularly among women smoking > or =
      10 cigarettes/day. CONCLUSIONS: Information on smoking habits could be accurately
      obtained retrospectively independent of recall time and the pregnancy outcomes
      studied here. Accuracy diminished with increasing alcohol intake, particularly
      among heavy smokers.

PMID- 10396552
TI  - Shifting the distribution of risk: results of a community intervention in a
      Swedish programme for the prevention of cardiovascular disease.
AB  - STUDY OBJECTIVE: To examine the impact of a systematic risk factor screening and
      counselling carried out by family physicians and family nurses within the larger
      framework of a community intervention programme for the prevention of
      cardiovascular disease (CVD). DESIGN: Quasi-experimental study comparing trends
      in an intervention area with those in a reference area. SETTING: A Northern
      Sweden municipality (5500 inhabitants) constituted the intervention area while
      the Northern Sweden region (510,000 inhabitants) served as the reference area.
      PARTICIPANTS: All 30, 40, 50, and 60 year old inhabitants were invited each year
      from 1985 to 1992. Among 2046 eligible 1893 participated (92.5%), which formed
      eight independent cross sections. One cross section, 1986, was re-surveyed
      forming a panel. MAIN RESULTS: In the cross sections, mean total cholesterol was
      reduced from 7.09 to 6.27 mmol/l for men (p < 0.001) and from 7.13 to 5.89 mmol/l
      for women (p < 0.001) and mean systolic blood pressure from 132.2 to 123.7 mm Hg
      for men (p < 0.05) and from 129.2 to 122.0 mm Hg for women (p < 0.001) during the
      eight years. Body mass index (BMI) increased from 25.6 to 26.2 for men (p < 0.05)
      and from 25.0 to 25.5 for women (NS). A corresponding reduction in cholesterol
      and blood pressure (for women) occurred in the panel, while BMI was unchanged.
      The risk for CVD, using the Framingham equation, was estimated to be reduced
      overall by 19% (p = 0.0021) when comparing early cross sections (1985/86) with
      the later cross sections (1990/91). CONCLUSIONS: It was concluded that a long
      term community based CVD prevention programme that combines population and
      individual strategies can substantially promote a health shift in CVD risk in a
      high risk rural population. The individual attention and evaluation provided by
      the health provider survey seem to accelerate, but not increase the amount of,
      risk reduction.

PMID- 10396553
TI  - Social deprivation and patterns of consultation for respiratory symptoms: a
      population-based cohort study.

PMID- 10396554
TI  - The life span of Methodist ministers: an example of the use of obituaries in
      epidemiology.

PMID- 10396555
TI  - Multiple myeloma in south Cumbria: prediction fulfilled.

PMID- 10396556
TI  - Weight gain and relation to maternal smoking.

PMID- 10396557
TI  - Minimizing complications in neck dissection.

PMID- 10396558
TI  - Effects of capsaicin pre-treatment in experimentally-induced secretory otitis
      media.
AB  - Neurogenic inflammation may play a role in the aetiology of secretory otitis
      media (SOM). The strongest candidate that initiates the characteristic symptoms
      of neurogenic inflammation is supposed to be substance P. Capsaicin is a specific
      antagonist of substance P. The effects of capsaicin on middle ear mucosa have not
      been studied yet. In an attempt to investigate the effect of pre-treatment with
      capsaicin on the development of SOM an experimental study was performed. Fourteen
      Wistar rats were divided into two groups. Seven rats were pre-treated with
      capsaicin (Group 1) and the others were administered isotonic saline solution
      (Group 2). Seven days after the third injection rats were operated on and the
      right tympanal orifice of the Eustachian tube was obstructed. Animals were
      sacrificed seven days after the operation. Their bullas were excised bilaterally
      and were studied by light microscopic technique. In Group 1 there was no effusion
      except for one case. The subepithelial layer was thickened by fibroblast
      proliferation. Capillary proliferation and some glandular atrophy were observed.
      In Group 2 the middle ear lumens were filled with effusion. Oedema with
      dilatation in capillaries and medium-sized vessels of lamina propria was observed
      as a common feature of the group. Subepithelial fibrosis was found in one case.
      Capsaicin pre-treatment prevented the formation of effusion in the middle ear
      lumen in spite of tuba occlusion. The results of this preliminary study lead us
      to consider that an imbalance in the autonomic innervation of the mucosa of the
      middle ear may play a role in the aetiology of SOM as in vasomotor rhinitis, and
      capsaicin may be an alternative in the treatment.

PMID- 10396559
TI  - An adequate parameter evaluating the galvanic body sway test: comparison with the
      caloric test in patients with vestibular schwannomas.
AB  - It has been reported that the galvanic body sway test does not correlate with the
      caloric test. We evaluated the galvanic body sway test in patients with
      vestibular schwannomas using three parameters: the angle of deviation response
      onset, the maximum value of the deviation response, and the area of deviation.
      These parameters reflect velocity, position, and locus of the centre of pressure,
      respectively. Among these parameters, only the angle of deviation response onset
      showed unilateral weakness of the response correlating with the canal paresis
      value, which indicates that velocity is responsible for conduction in the
      vestibular nerve. However, the galvanic body sway test is apt to be preferred to
      the caloric test. This might be attributed to the decreased sensitivity of this
      test.

PMID- 10396560
TI  - Endoscopic anatomy of the sphenoid sinus.
AB  - The anatomy of the sphenoid sinus, as it relates to endoscopic sinus surgery, was
      studied in 93 cadaver heads (186 sphenoid sinuses) using endoscopic dissections
      as well as sagittal sections. The relationship of the sphenoid sinuses to the
      carotid artery, optic nerve, floor of sella turcica, as well as other important
      structures, were verified and discussed. The recesses of the sinus as well as its
      ostium and accessory septa and crests were described and their clinical
      importance was discussed. Pertinent measurements were included wherever
      appropriate.

PMID- 10396561
TI  - Juvenile angiofibroma: the lessons of 20 years of modern imaging.
AB  - Seventy-two patients with juvenile angiofibroma have been investigated by
      computerized tomography (CT) and/or magnetic resonance imaging (MRI) over a
      period of 20 years. The evidence from these studies indicates that angiofibroma
      takes origin in the pterygo-palatine fossa at the aperture of the pterygoid
      (vidian) canal. An important extension of the tumour is posteriorly along the
      pterygoid canal with invasion of the cancellous bone of the pterygoid base, and
      greater wing of the sphenoid (60 per cent of patients). Distinctive features of
      angiofibroma are the high recurrence rate, and the rapidity with which many
      tumours recur. It is postulated that the principal determinant of recurrence is a
      high tumour growth rate at the time of surgery coupled with incomplete surgical
      excision. The inability to remove the tumour in toto is principally due to deep
      invasion of the sphenoid, as described above. In this series 93 per cent of
      recurrences occurred with this type of tumour extension. A contributory cause in
      these patients is the use of pre-operative embolization. The treatment
      implications of these findings are examined.

PMID- 10396562
TI  - Tonsillectomy: assessment of quality by consultation rate after discharge.
AB  - The aim of this prospective study was to establish a measure of short-term
      quality of treatment after tonsillectomy/adenotonsillectomy. One hundred and
      thirty-four questionnaires, returned after 14 days, from 41 children and 93
      adults were analysed. Forty-seven per cent had one or more consultations with
      health-care professionals. Eighty-three consultations by telephone and 33
      consultations in person were made. Two recent studies reported higher
      consultation rates in person to doctors compared to this study. The predominant
      reason for consulting health-care professionals was pain. Maximum pain scores
      were significantly higher among those with consultations vs. no consultations (p
      = 0.0001). Additionally, the intensity as well as the duration of maximal pain
      increased with the number of contacts per patient (p = 0.0001, p = 0.0045). Sixty
      four per cent felt relieved after consultation by telephone and 83 per cent felt
      relieved after consultation in person. The present study suggests consultation
      rate as a parameter of quality of treatment and quality of information.

PMID- 10396563
TI  - Functional results after CO2 laser surgery compared with conventional
      phonosurgery.
AB  - Treatment of benign vocal fold lesions by the use of the CO2 laser is discussed
      critically. The aim of the present prospective randomized study was to examine
      the post-operative functional results after laser phonosurgery in comparison to
      those after cold phonosurgery. In total, 44 patients with benign vocal fold
      lesions underwent surgery. Conventional cold phonosurgery was performed in 23
      patients, and 21 patients were treated by laser phonosurgery. To determine vocal
      function, examinations were performed pre-operatively, on the second post
      operative day, and one and four months post-operatively. The examinations
      included direct videolaryngoscopy, determination of maximal phonation, speech
      voice field as well as singing voice field. The results four months after surgery
      showed an improvement of vocal function in both treatment groups in comparison to
      the pre-operative findings. The improvement is only statistically significant
      after cold surgery.

PMID- 10396564
TI  - Reconstructive techniques currently used following resection of hypopharyngeal
      carcinoma.
AB  - There is no general consensus as to the best method of reconstruction following
      total laryngopharyngectomy for hypopharyngeal carcinoma. The aim of this study is
      to attempt to establish the current practice amongst British ENT Consultants and
      to ascertain the reasons for their choice of reconstructive technique. An
      anonymous questionnaire was sent to 546 consultants in the UK and the results of
      363 (66.5 per cent) were analysed. One hundred and twenty-eight (35.3 per cent)
      consultants replied that they performed surgery for hypopharyngeal carcinoma.
      Sixty-five (50.8 per cent) performed a stomach pull-up procedure, 23 (18 per
      cent) used a jejunal free flap, 36 (28.1 per cent) used both and four (3.1 per
      cent) used other techniques. In the stomach pull-up group, the main reasons given
      for their choice were because there was no lower resection margin (48 out of 65)
      and because of tradition in the way they were trained (37 out of 65). In the
      group using the jejunal free flap, lower morbidity (18 out of 23) and mortality
      (14 out of 23) were the main reasons for their choice. The questionnaire also
      found that amongst the 60 consultants who would consider using a jejunal free
      flap, the majority (39) aimed for a lower clearance margin of 2-4 cm, while 17
      aimed for > 4 cm clearance. This study provides a good indication of the current
      practice in the UK of reconstruction following resection for hypopharyngeal
      carcinoma. It appears that the stomach pull-up remains the most commonly used
      method of reconstruction, but the jejunal free flap is becoming increasingly more
      popular because of its lower morbidity and mortality.

PMID- 10396565
TI  - Surgical simulation: an animal tissue model for training in therapeutic and
      diagnostic bronchoscopy.
AB  - A series of surgical simulation exercises has been developed using an animal
      model to allow trainees to practise basic instrument handling and develop
      psychomotor skills in bronchoscopy, without risk to patients. A pig model was
      found to be most suitable. After suitable preparation the model can be used for
      diagnostic and therapeutic exercises in bronchoscopy, including lavage, biopsy
      and the removal of various foreign bodies. The model is a safe, inexpensive and
      convenient means of bronchoscopic training for otolaryngology trainees. For the
      trained specialist who has to remove bronchial foreign bodies infrequently, the
      model is a useful way of maintaining skills.

PMID- 10396566
TI  - Radiological staging of the chest and abdomen in head and neck squamous cell
      carcinoma--are computed tomography and ultrasound necessary?
AB  - The need for, and choice of, radiological staging investigations for distant
      metastases in the management of head and neck squamous cell carcinoma is a
      contentious issue. To address this problem a retrospective audit of routine
      computerized tomography (CT) and ultrasound scanning of the chest and abdomen
      respectively was undertaken. The records of 103 patients who, over a six and a
      half year period, underwent major surgery for head and neck squamous cell
      carcinoma were reviewed. A total of 57 patients (59 per cent) had CT scanning of
      the chest of whom two were identified as having synchronous tumours. In both
      cases, the lesions were identified on chest X-ray prior to scanning. Seventy
      patients (68 per cent) had routine ultrasound scanning of the abdomen. In none of
      these was metastatic disease identified. As a result of the audit findings
      routine CT and ultrasound scanning of the chest and abdomen has been
      discontinued.

PMID- 10396567
TI  - Solitary adult myofibroma of the pinna.
AB  - Solitary myofibroma is a recently described benign neoplasm of the skin or
      superficial soft tissue and it represents the adult counterpart of infantile
      myofibromatosis. This new clinicopathological entity is being recognized
      increasingly. A case of solitary myofibroma occurring in the pinna of a 50-year
      old woman is presented. Such a lesion occurring in the pinna of an adult has not
      been reported in the literature.

PMID- 10396568
TI  - Otological findings in idiopathic hyperphosphatasia.
AB  - A 17-year-old male patient was admitted because of progressive hearing loss since
      the age of six. His former blood and radiology investigation had revealed
      idiopathic hyperphosphatasia. On ENT examination bilateral thickened tympanic
      membranes with severe mixed-type hearing loss was diagnosed. Computerized
      tomography (CT) demonstrated expansion of the calvarial bones, including the
      temporal bones, except for the otic capsule. Middle-ear exploration revealed
      thickened middle-ear mucosa and a stone hard, immobile bony mass instead of the
      normal ossicular chain at the posterior superior part of the mesotympanum. No
      ossicular reconstruction could be attempted and the patient was rehabilitated
      with a hearing aid.

PMID- 10396569
TI  - Auditory rehabilitation in neurofibromatosis type 2: a case for cochlear
      implantation.
AB  - Cochlear implantation has a limited but definite role in the rehabilitation of
      certain neurofibromatosis type 2 (NF2) patients. The presence of a dead ear
      either before, or after, tumour removal does not necessarily imply loss of
      function in the eighth nerve; in some instances the hearing loss will be
      cochlear. Promontory or round window electrical stimulation may help to identify
      those individuals with surviving eighth nerve function. In such patients
      multichannel cochlear implantation promises a better level of audition than the
      auditory brain stem implant. This paper highlights such a case and the management
      problems are discussed.

PMID- 10396570
TI  - Solitary plasmacytoma of the skull base presenting with unilateral sensorineural
      hearing loss.
AB  - Solitary plasmacytoma of the skull base is a rare entity with only a few reported
      cases in the literature. We review the literature and present our experience with
      this lesion that produced ipsilateral sensorineural hearing loss, vertigo and
      ipsilateral sixth nerve palsy.

PMID- 10396571
TI  - Leiomyosarcoma of the larynx.
AB  - Tumours of smooth muscle origin are extremely rare in the upper aerodigestive
      tract. Immunohistochemical studies are helpful for accurate diagnosis of
      leiomyosarcoma. Here, we report a case of well-differentiated laryngeal
      leiomyosarcoma that showed rapid local growth but no metastasis. Diagnosis and
      treatment of leiomyosarcoma are discussed.

PMID- 10396572
TI  - Goitre presenting as an oropharyngeal mass: an unusual finding in the elderly.
AB  - Thyroid goitre presentation in the neck with extension inferiorly to the
      mediastinum is well-known. Extension superiorly into the retropharyngeal space is
      very rare and may be accompanied by change in voice and/or airway compromise. A
      case is described of a patient with change in voice and mild airway compromise
      secondary to a goitre presenting in the oropharynx. Computed tomography (CT) and
      physical findings are discussed with the need to recognize this rare entity.

PMID- 10396573
TI  - Pharyngo-oesophageal haemangioma with a positive cough impulse.
AB  - Benign tumours of both the pharynx and oesophagus are rarely seen, cavernous
      haemangiomas even less so. We present a case in which a large lesion was the
      cause of non-specific symptoms but which only appeared intermittently on
      nasendoscopic examination of the pharynx.

PMID- 10396574
TI  - Dercum's disease (adiposis dolorosa).
AB  - Dercum's disease (adiposis dolorosa) is a rare condition characterized by
      progressively painful fatty deposits, usually, in menopausal women with obesity,
      asthenia and mental phenomena. We report a case of a 48-year-old woman with
      recurrent neck swelling and pain in the neck and parotid region, and a review of
      management of this uncommon problem.

PMID- 10396575
TI  - Paranasal sinus enlargement in Sturge-Weber syndrome.
AB  - A case of Sturge-Weber syndrome is described in which all paranasal sinuses were
      grossly enlarged. The mastoid, petrous and squamous portions of the temporal bone
      on both sides were fully pneumatized and the right orbit was distorted. There was
      resistant infection in the left maxillary sinus. These unusual features were well
      demonstrated by computed tomographic scans.

PMID- 10396576
TI  - A parapharyngeal myxoid liposarcoma.
AB  - We present a case of a parapharyngeal space myxoid liposarcoma. This case
      highlights the importance of wide surgical resection margins, and the difficult
      histological diagnosis.

PMID- 10396577
TI  - Tall cell variant of papillary carcinoma arising from ectopic thyroid tissue in
      the trachea.
AB  - Ectopic thyroid tissue within the submucosa of the trachea is a rare cause of
      upper airway obstruction. Primary neoplasms arising from such thyroid nests are
      rare. This report describes a case of tall cell variant of papillary carcinoma
      arising from ectopic thyroid tissue in the trachea.

PMID- 10396578
TI  - Management of non-Hodgkin's lymphomas.
AB  - The non-Hodgkin's lymphomas (NHL) are a heterogeneous group of disorders
      characterised by malignant proliferation of lymphoid cells. The cellular origin
      is relatively well established with subtypes corresponding to the various stages
      of lymphocyte differentiation. The term encompasses a hotchpotch of conditions
      with very different morphological appearance, behaviour and clinical outcome. NHL
      comprise 2.4% of all cancers, with incidence increasing with age. The commonest
      presentation is with progressive lymphadenopathy, though extranodal
      manifestations are present in a significant proportion. The clinical behaviour
      ranges from a benign, indolent course to rapidly progressive disease; prognosis
      varies from weeks to many years. Treatment is correspondingly diverse, from
      'watchful waiting' to high-dose chemotherapy with bone marrow stem cell
      transplantation. Cure is possible in an increasing number of patients and much
      interest currently lies in identifying patients with high-risk disease
      necessitating the use of intensive treatment regimens.

PMID- 10396579
TI  - Treatment for morbid obesity.
AB  - There is no single unifying theory to explain the aetiology of obesity but
      several environmental factors, such as decreased physical activity and increased
      fat intake may contribute to its development in genetically predisposed
      individuals. Dietary and pharmacological treatments of morbid obesity have been
      proven to be unsuccessful. Modern surgical treatments have been shown to be
      effective in achieving significant weight loss with consequent reduction in
      morbidity. Despite the fact that surgical treatment of morbid obesity is the only
      therapeutic form that has stood the test of time, it still remains a crisis
      driven form of therapy in the UK. It is probable that a better understanding of
      the aetiology and physiology of obesity may lead to the development of an
      effective pharmacological treatment of obesity in the future. However, until
      then, surgical treatment of morbid obesity should be considered as an effective
      and efficient way of treatment in selected cases.

PMID- 10396580
TI  - Alterations in enzymatic antioxidant defence in diabetes mellitus--a rational
      approach.
AB  - Defence against the reactive oxidants produced during aerobic metabolism is a
      complex process and is provided by a system of enzymes and antioxidant compounds
      capable of preventing excess radical production, neutralising free radicals and
      repairing the damage caused by them. Regulation of the antioxidant system must
      provide sufficient, properly located, antioxidant compounds and enzymes. Damage
      to this system has been proved to play a role in various disorders. Long-term
      complications of diabetes mellitus are supposed to be partially mediated by
      oxidative stress. The authors summarise experimental and clinical investigations
      in this field and analyse the possible importance of the changes in the
      antioxidant system in the development of diabetic vascular complications.

PMID- 10396581
TI  - Why do Italian stroke patients receive CT scans earlier than UK patients?
      International Stroke Trial Collaborators in Italy and the UK.
AB  - Computed tomography (CT) scanning is important prior to acute stroke treatment.
      We wished to identify factors associated with being able to obtain a CT scan
      quickly, from a recent large stroke treatment trial. A questionnaire survey on
      the organisation of CT scanning services for stroke was sent to 179 UK and
      Italian hospitals who had randomised patients into the International Stroke Trial
      and performed at least one pre-randomisation CT scan. Data from the questionnaire
      were analysed in conjunction with other patient data. Italian doctors expected
      the CT scans to be done more quickly than UK doctors, their hospitals were more
      likely to have a CT scanner operating all the time, and a porter was used less
      frequently to take the patient to the CT scanner. A few simple changes in the way
      CT scanning is organised for stroke patients in the UK could speed access to CT
      considerably.

PMID- 10396582
TI  - Outcome of oesophagogastric carcinoma in young patients.
AB  - The survival of young patients (< or = 50 years of age) with carcinoma of the
      oesophagus or stomach has been reported to be poorer than that of their older
      counterparts. The aim of the current study was to review the outcome of such
      young patients with oesophagogastric cancer and to compare the outcome in
      patients with carcinoma of the oesophagus/cardia with patients with carcinoma of
      the more distal stomach. The study population was 50 patients. Tumour location
      was oesophagus/cardia (n = 33) and gastric body/antrum (n = 17). The most common
      presenting symptoms were weight loss (66%), epigastric pain (54%), dysphagia
      (50%), and heartburn (40%). Seventeen patients had experienced foregut symptoms
      for a period of > or = 6 months. These patients were more likely to have symptoms
      of gastro-oesophageal reflux disease and to have received acid suppression
      therapy than patients with shorter symptom durations. Only 20 patients underwent
      a potentially curative resection, while 10 underwent open and close laparotomy.
      The overall median survival was 7 months and the 5-year survival was 8%.
      Multivariate analysis revealed that surgical resection and UICC stage were the
      only factors that significantly influenced survival. There was no difference in
      the survival of patients with proximally situated tumours compared to those with
      distally located tumours. Wide variations in clinical practice were seen between
      different surgeons. Consequently, a multidisciplinary team designed to manage all
      patients with oesophagogastric cancer according to nationally agreed protocols
      has been established in our hospital. Earlier diagnosis of these tumours is to be
      encouraged, even if this necessitates the more liberal use of endoscopy in the
      evaluation of young patients with persistent foregut symptoms.

PMID- 10396584
TI  - Hyponatraemia and seizures after ecstasy use.
AB  - A patient presented to our unit with seizures and profound hyponatraemia after
      ingestion of a single tablet of ecstasy. The seizures proved resistant to therapy
      and ventilation on the intensive care unit was required. Resolution of the
      seizures occurred on correction of the metabolic abnormalities. The pathogenesis
      of seizures and hyponatraemia after ecstasy use is discussed. Ecstasy use should
      be considered in any young patient presenting with unexplained seizures and
      attention should be directed towards electrolyte levels, particularly sodium.

PMID- 10396583
TI  - Evolution of insulin resistance in coronary artery disease patients on four
      different pharmacological therapies.
AB  - The objective of the study was to examine the evolution of insulin sensitivity in
      a group of patients with stable coronary artery disease receiving one of four
      different pharmacological therapies. Insulin sensitivity was evaluated using an
      insulin suppression test in 40 newly diagnosed patients with coronary artery
      disease and no previous history of metabolic disorders, who were not taking any
      medication which might affect insulin sensitivity. The insulin suppression test
      consisted of a constant infusion of glucose, insulin and somatostatin for 150
      min; insulin resistance was estimated by determining the steady-state plasma
      glucose concentrations during the last 60 minutes of the test. The insulin
      sensitivity index was calculated by the formula: insulin sensitivity index =
      (glucose infusion rate/steady state plasma glucose concentrations) x 10(3). A
      second insulin suppression test was performed after 6 months' therapy with either
      isosorbide mononitrate, atenolol, diltiazem or captopril in 30 of the 40
      patients. There were no differences between any of the groups before therapy was
      initiated. After 6 months, patients treated with captopril and, to a lesser
      extent, those treated with diltiazem showed statistically significantly decreased
      steady state plasma glucose concentrations and increased insulin sensitivity
      index compared to basal values. No statistically significant differences were
      found in the other two groups. We conclude that captopril and, to a lesser
      extent, diltiazem improve insulin sensitivity in patients with stable coronary
      artery disease.

PMID- 10396585
TI  - Gangrenous cystitis: a rare cause of colovesical fistula.
AB  - A case of gangrenous cystitis presenting as a colovesical fistula in an elderly
      woman is described. The literature on this rare condition is reviewed.

PMID- 10396586
TI  - Intra-operative localisation of skull base tumours. A case report using the ISG
      viewing wand in the management of trigeminal neuroma.
AB  - Deep-seated skull base tumours provide as much a challenge to the surgeons'
      skills of localisation as to his technical abilities during the resection. These
      lesions are frequently inaccessible and lie adjacent to vital structures
      requiring extensive cerebral retraction for adequate exposure and direct
      visualisation. The ISG viewing wand is a newly developed image guidance system to
      aid direction of the operative approach and localisation of intracerebral
      pathology. We discuss its use in the management of a trigeminal neuroma.

PMID- 10396587
TI  - A case of ureteric obstruction, retroperitoneal fibrosis, and carcinoid tumour.
AB  - We report the incidental finding at surgery for retroperitoneal fibrosis of a
      carcinoid tumour causing complete right ureteric obstruction. Retroperitoneal
      fibrosis is an uncommon inflammatory disease that leads to extensive fibrosis
      throughout the retroperitoneum. It can occur at any age, peak incidence being in
      patients between 40 and 60 years of age. Carcinoid tumours arise from
      enterochromaffin or amine precursor uptake and decarboxylation cells that occur
      in gastrointestinal tract. Carcinoid tumours are an uncommon clinical entity and
      incidence varies with gender and age. No association between retroperitoneal
      fibrosis and carcinoid tumour has been previously reported in the English
      literature, although one case has been reported in a French journal.

PMID- 10396588
TI  - Red-man syndrome after vancomycin: potential cross-reactivity with teicoplanin.
AB  - We report a patient with infective endocarditis who developed a severe form of
      Red-man syndrome after vancomycin. On substituting the antibiotic to teicoplanin,
      the patient went on to develop a dramatic pyrexia which settled only after the
      teicoplanin was discontinued. This suggested that there may be an element of
      cross-reactivity between teicoplanin and vancomycin in such patients and that
      teicoplanin may not be the most appropriate substitute in all cases of vancomycin
      induced Red-man syndrome.

PMID- 10396589
TI  - Cushing's disease masking coincidental steroid-responsive diseases.
AB  - Two cases of Cushing's disease are presented. In both cases successful treatment
      was followed by the development of a steroid-responsive disease condition, a
      seronegative arthritis in the first case and retinal vasculitis in the second. It
      is likely that both these conditions were unmasked by the fall in the endogenous
      steroid levels following the successful treatment of the Cushing's disease by
      trans-sphenoidal hypophysectomy.

PMID- 10396590
TI  - Recurrent thrombo-embolic episodes: the association of cholangiocarcinoma with
      antiphospholipid syndrome.
AB  - Antiphospholipid syndrome is a disorder of recurrent vascular thrombosis,
      pregnancy loss and thrombocytopenia associated with persistently elevated levels
      of antiphospholipid antibodies. It was first described in a group of patients
      with systemic lupus erythematosus but has since been associated with a wide range
      of conditions, including other autoimmune disorders and malignancy. It can also
      occur in isolation, the so-called primary antiphospholipid syndrome. We describe
      an elderly woman with the antiphospholipid syndrome thought to be associated with
      a cholangiocarcinoma.

PMID- 10396591
TI  - An adolescent Pakistani girl with chronic meningitis.

PMID- 10396592
TI  - Infected lung cysts.

PMID- 10396593
TI  - Back pain and fever.

PMID- 10396594
TI  - A rare case of radiculopathy.

PMID- 10396595
TI  - Polyuria in a patient with fibrosing alveolitis.

PMID- 10396596
TI  - Hyperamylasaemia: an unusual cause.

PMID- 10396597
TI  - Postoperative back pain.

PMID- 10396598
TI  - An unusual tumour in a post-partum woman.

PMID- 10396599
TI  - Perception of dietary fat: ingestive and metabolic implications.

PMID- 10396600
TI  - Molecular inroads into the regulation and metabolism of fatty acids, lessons from
      bacteria.

PMID- 10396601
TI  - Structure and functional properties of diacylglycerols in membranes.
AB  - 1. 1,2-Diacyl-sn-glycerols (DAG) are minor components of cell membranes (about 1
      mole% of the lipids) and yet they are potent regulators of both the physical
      properties of the lipid bilayer and the catalytic behaviour of several membrane
      related enzymes. 2. In the pure state DAG's present a considerable polymorphism,
      with several crystalline phases in addition to the neat fluid phase. The most
      stable crystalline phase is the so-called beta' phase, a monoclinic crystalline
      form with orthorhombic perpendicular subcell chain packing, in which both acyl
      chains lie parallel to each other in a hairpinlike configuration about the sn-1
      and sn-2 glycerol carbon atoms. The molecules are organized in a bilayer, with
      the glycerol backbone roughly parallel to the plane of the bilayer, and the acyl
      chains tilted at approximately 60 degrees with respect to that plane. Acyl chain
      unsaturation, and particularly a single cis unsaturation, impairs chain packing
      in mixed-chain DAG's, and this results in an increased number of metastable
      crystalline phases. 3. DAG's mix with phospholipids in fluid bilayers when their
      melting temperature is below or close enough to the melting temperature of the
      bilayer system. When incorporated in phospholipid bilayers, the conformation of
      DAG is such that the glycerol backbone is nearly perpendicular to the bilayer,
      with the sn-1 chain extending from the glycerol Cl carbon into the hydrophobic
      matrix of the bilayer and the sn-2 chain first extending parallel to the bilayer
      surface, then making a 90 degrees bend at the position of the sn-1 carbonyl to
      become parallel to the sn-1 chain. DAG's are located in phospholipid bilayers
      about two CH2 units deeper than the adjacent phospholipids. DAG's mix nonideally
      with phospholipids, giving rise to in-plane separations of DAG-rich and -poor
      domains, even in the fluid state. DAG molecules also increase the separation
      between phospholipid headgroups, and decrease the hydration of the bilayer
      surface. Also, because the transversal section of the DAG headgroup is small when
      compared to that of the acyl chains, DAG favours the (negative) curvature of the
      lipid monolayers, and DAG-phospholipid mixtures tend to convert into inverted
      nonlamellar hexagonal or cubic phases. 4. A number of membrane enzyme activities
      are modulated (activated) by DAG, most notably protein kinase C, phospholipases
      and other enzymes of lipid metabolism. Protein kinase C activation (and perhaps
      that of other enzymes as well) occurs as the combined result of a number of DAG
      induced modifications of lipid bilayers that include: changes in lipid headgroup
      conformation, interspacing and hydration, changes in the bilayer propensity to
      form inverted nonlamellar phases, and lateral phase separations of DAG-rich and 
      poor domains. Among the DAG-activated enzymes, phospholipases C show the
      peculiarity of yielding the activator DAG as their reaction product, and this
      allows the self-induced transition from a low- to a high-activity status. 5.
      DAG's induce or enhance membrane fusion in a number of ways, mainly through
      partial dehydration of the bilayer surface, increase in lipid monolayer curvature
      and perhaps lateral phase separation. DAG-increased fusion rates have been
      demonstrated in several instances of cation-induced fusion of model membranes, as
      well as in Ca(2+)-induced fusion of chromaffin granules with plasma membrane
      vesicles. Also phospholipase C has been shown to induce vesicle aggregation and
      fusion through the catalytic generation of DAG in the bilayers. A rather general
      property of DAG is that it promotes vesicular or interparticle aggregation. 6. In
      the living cell, DAG is often generated through phospholipid degradation in
      response to an extracellular agonist binding a specific receptor in the cell
      surface. DAG is said to act as an intracellular second messenger. (ABSTRACT
      TRUNCATED)

PMID- 10396602
TI  - Heterogeneous N-terminal acylation of retinal proteins.

PMID- 10396603
TI  - Molecular interactions and kinetic properties of fats.
AB  - This article has reviewed the recent work on the molecular interactions and
      kinetic properties of the polymorphic transformations of the TAGs in the single
      and mixed states. Progress has recently been made in the molecular-level
      understanding of the polymorphic transformations of the TAGs. Particularly, the
      use of the time-resolved X-ray diffraction with Synchrotron radiation (SR-XRD)
      has provided precise information of the structural changes of the fat crystals at
      a time scale of 10 sec. Therefore, fruitful information was obtained on the
      kinetic and molecular aspects of crystallization and mixing processes of the
      various types of mixed-acid TAGs, which were not obtained with the traditional
      thermal and structural techniques because of their complicated structural
      properties. One may anticipate that, although the experimental sites and machine
      times are limited, the SR-XRD techniques will be more applied to the fat systems
      involving the following materials and systems; (a) multicomponent natural fats
      with and without additives of emulsifiers, proteins and carbohydrates, (b) fats
      in dispersed phases such as oil-in-water (O/W) and water-in-oil (W/O) emulsions,
      (c) crystallization and transformation processes under external influences of
      hydrostatic pressure and shear stress [68].

PMID- 10396604
TI  - Mendel and his legacy.

PMID- 10396605
TI  - The management of hypertensive disease in black patients.
AB  - The ethnic differences in the incidence, pathophysiology and management of
      hypertensive disease, are particularly pertinent to the Black or Afro-Caribbean
      populations, who have a high prevalence of hypertension and associated
      complications, such as strokes and renal impairment. Our understanding of the
      underlying pathophysiology of hypertensive disease and the optimal treatment of
      hypertension in Black patients continues to evolve, especially with the
      introduction of new drugs and the need for prognostic data in this ethnic
      population. We review the management of hypertensive disease in the black
      population, emphasizing race-related differences in the pathophysiology of
      hypertension and the importance of tailored management in this group of patients,
      including sensible application of non-pharmacological measures with effective
      antihypertensive agents. For example, diuretics and calcium antagonists are
      suitable first-line agents in black hypertensives, whilst beta-blockers and the
      ACE inhibitors tend to be less effective at lowering blood pressure, due to the
      low renin state in these patients.

PMID- 10396606
TI  - Improved antioxidative protection in winter swimmers.
AB  - Adaptation to oxidative stress is an improved ability to resist the damaging
      effects of reactive oxygen species, resulting from pre-exposure to a lower dose.
      Changes in uric acid and glutathione levels during ice-bathing suggest that the
      intensive voluntary short-term cold exposure of winter swimming produces
      oxidative stress. We investigated whether the repeated oxidative stress in winter
      swimmers results in improved antioxidative adaptation. We obtained venous blood
      samples from winter swimmers and determined important components of the
      antioxidative defense system in the erythrocytes or blood plasma: reduced and
      oxidized glutathione (GSH and GSSG), and the activities of superoxide dismutase
      (SOD), glutathione peroxidase (GPx) and catalase (Cat). The control group
      consisted of healthy people who had never participated in winter swimming. The
      baseline concentration of GSH and the activities of erythrocytic SOD and Cat,
      were higher in winter swimmers. We interpret this as an adaptative response to
      repeated oxidative stress, and postulate it as a new basic molecular mechanism of
      increased tolerance to environmental stress.

PMID- 10396607
TI  - The winter bed crisis--quantifying seasonal effects on hospital bed usage.
AB  - Winter bed crises are a common feature in NHS hospitals, and have given rise to
      great concern. We set out to determine the relative contribution of seasonal
      effects and other factors to bed occupancy in a large teaching hospital over one
      year. There were 190,804 occupied bed-days, which we analysed by specialty
      groupings. There was considerable variability in bed occupancy in each specialty.
      A significant winter peak occurred for general medicine and orthopaedics together
      with a significant increase on 'take-in' days. Virtually all specialties showed a
      significant variation in occupancy between weekdays. Geriatric Medicine had a
      high and fairly constant occupancy, with some seasonal effect. We conclude that
      seasonal trends in bed occupancy occur in 'front door' specialties and are
      predictable. In these specialties, admission policies also make a contribution to
      bed usage and are amenable to modification. There is no surge in occupancy in the
      immediate post-Christmas period, except that attributable to the seasonal trend.
      In the 'elective' specialties, bed occupancy fluctuates widely, with reduced
      occupancy at weekends and at Christmas. These differences are entirely amenable
      to modification. More effective bed management would make a very significant
      contribution to avoiding winter bed crises.

PMID- 10396608
TI  - Fasting plasma glucose and subsequent macrovascular disease after 10 years follow
      up: a collaborative study on two populations.
AB  - The American Diabetes Association recently proposed a new, lower, cut-point of
      7.0 mmol/l for diagnosis of diabetes mellitus. We examined data from the
      Caerphilly and Speedwell cohorts to determine possible cut-points of fasting
      plasma glucose for increased risk of subsequent ischaemic heart disease (IHD).
      Men (n = 4860) from the general population of a town in South Wales and a
      practice-based population in Bristol aged 45-63 years were first examined in 1979
      83, and re-examined at intervals, and these data relate to follow-up at about 10
      years (120 months, Caerphilly) (112 months, Speedwell). Clinically recognized
      diabetics (n = 94) experienced a higher mortality rate and an excess number of
      major IHD events. Among non-diabetics, mean blood glucose was 5.0 mmol/l and a
      significant excess of major IHD events occurred above this point even when the
      data were fully adjusted for all other IHD risk factors. Risk of major IHD was
      greatest for non-diabetic men with plasma glucose levels between 7.0 and 7.7
      mmol/l. Under 7.0 mmol/l, the excess event rate was modest, however. Glucose
      levels were not associated with excess all-cause mortality among these non
      diabetic men. These data, based on the excess risk of macrovascular disease
      experienced by a British cohort of non-diabetic men, accord with the proposals to
      base the diagnosis of diabetes on a cut point of 7.0 rather than 7.8 mmol/l.

PMID- 10396609
TI  - The very long-term prognosis and complications of lupus nephritis and its
      treatment.
AB  - Although the short- and medium-term (5-10 years) outcome of patients with lupus
      nephritis has been studied extensively, there are very few data on the second and
      subsequent decades. We studied outcome in 110 local patients investigated at a
      single centre before 1986, who all had potential follow-up of more than 10 years
      (actual 2-31 years, median 15.5 years). At last follow-up, 40 patients were dead
      and 70 alive, nine of whom were on maintenance dialysis or transplanted,
      actuarial survivals being 84%, 72%, 62%, 61% and 54% at 5, 10, 15, 20 and 25
      years for the group as a whole. Survival was better in the cohort 1976-86 (n =
      60) than in that from 1963-75 (n = 50) (90, 81 and 76% vs. 78, 56 and 43% at 5,
      10 and 15 years, p < 0.001). Sepsis (12) and myocardial infarction (8) were the
      principal causes of death. Of living patients with renal function, 38% had normal
      urine and renal function, 11 were off all treatment (19%), 62% had persistent
      proteinuria and 18% had reduced but generally stable renal function. Renal
      failure, in those patients who developed it, occurred during the first decade and
      none of 67 patients actually followed more than 10 years subsequently went into
      renal failure. Induction treatment was with prednisolone, combined with
      azathioprine in more severe forms of nephritis, and from the middle 1970s to
      1986, 30 with methylprednisolone and in 12 cases plasma exchange. Seventeen other
      patients were treated using oral cyclophosphamide during the 1960s. No patient
      received i.v. cyclophosphamide as induction therapy, although nine patients had
      this form of treatment later, largely because of non-compliance. Serious
      complications of lupus and/or its treatment occurred in 49%: sepsis in 32,
      ischaemic heart disease in 20, thrombosis in one and avascular necrosis of bone
      in eight. In contrast, fracturing osteoporosis occurred in only three, and
      cataracts requiring surgery and diabetes mellitus in none. The very long-term
      outlook of lupus nephritis, especially its more severe forms, has improved, but
      that with current management strategies only a minority of patients are able to
      stop treatment altogether, and the incidence of serious complications is high.

PMID- 10396610
TI  - Cholesterol in peripheral vascular disease--a suitable case for treatment?
AB  - We assessed the prevalence of conventional risk factors for ischaemic heart
      disease in patients with peripheral vascular disease, and the scope for
      preventative treatment with lipid-lowering therapy in this group, by
      retrospectively reviewing 299 patients who had undergone peripheral angiography
      in 1996. A total of 278 patients had severe peripheral vascular disease; 44% were
      current smokers at the time of their angiogram, and 36% had a history of coronary
      artery disease (either myocardial infarction, coronary artery bypass surgery,
      coronary angioplasty or angina). Cholesterol had been measured in 80 (27%)
      patients, of whom 26 (9%) were receiving treatment for hypercholesterolaemia.
      Patients with a history of ischaemic heart disease were more likely to have had
      their cholesterol measured (50% vs. 15%; p < 0.001). Hypertension (defined as
      systolic > 160 mmHg or diastolic > 90 mmHg) was present in 44%. There was no
      difference in the distribution of risk factors between those with and those
      without known ischaemic heart disease. There is a high prevalence of modifiable
      risk factors for coronary disease in patients with severe peripheral vascular
      disease. Effective prevention is available for coronary artery disease, but we
      found low levels of treatment. There is considerable scope for intervention to
      reduce the risk of coronary disease in such patients.

PMID- 10396611
TI  - Genetic markers to predict polygenic disease: a new problem for social genetics.
AB  - Many genetic markers that relate to common multifactorial disease in adults have
      been identified during the past 15 years. Their use as adjuncts for the
      diagnosis, prognosis, prediction of disease or targeting therapy for these
      disorders has begun, good examples being the Factor V Leiden mutation for venous
      thromboembolism, lipoprotein lipase mutations for hypertriglyceridaemia and the
      apolipoprotein E4 variant for Alzheimer's dementia. However, extensive gene-gene
      and gene-environment interactions make their use more complex than markers for
      the simpler monogenic disorders (such as cystic fibrosis, or Duchenne's muscular
      dystrophy). Possible misapplication of the genetic markers for multifactorial
      disease in the fields of risk prediction, direct sales to the public, life
      assurance, employment rights, and legislation for regulation of their use are
      discussed.

PMID- 10396612
TI  - Cerebellar syndrome in Plasmodium falciparum malaria.

PMID- 10396613
TI  - Retinal development, degeneration and functional restitution.

PMID- 10396614
TI  - Morphological changes in the retina of Aequidens pulcher (Cichlidae) after
      rearing in monochromatic light.
AB  - We investigate the processing of chromatic information in the outer retina of a
      cichlid fish, Aequidens pulcher. The colour opponent response characteristics of
      some classes of cone-specific horizontal cells in the fish retina are the result
      of feedforward-feedback loops with cone photoreceptors. To interfere with the
      reciprocal transmissions of signals, animals were reared in monochromatic lights
      which preferentially stimulated the spectrally different cone types. Here we
      report the effects on the cones. Their absorbance spectra were largely
      unaffected, indicating no change in photopigment gene expression. Significant
      changes were observed in the cone outer segment lengths and the frequencies of
      spectral cone types. Quantum catch efficiency and survival of cones appear to be
      controlled in a spectrally selective way. Our results suggest that the retina
      responds to spectral deprivation in a compensatory fashion aimed at balancing the
      input from the different cone types to second order neurons.

PMID- 10396615
TI  - The feedback pathway from horizontal cells to cones. A mini review with a look
      ahead.
AB  - The feedback pathway from HCs to cones forms the basis of the surround responses
      of the bipolar cells and is essential for the spectral opponency of horizontal
      cells. The nature of this feedback pathway is an issue of debate. Three
      hypothesis are presented in literature: (1) a GABAA-ergic feedback pathway; (2) a
      GABA-independent feedback pathway that modulates the Ca-current in cones; and (3)
      an electrical feedback pathway. In this review the evidence for the various
      pathways will be discussed. The conclusion is that the available evidence favors
      the hypothesis that feedback modulates the Ca-current in the cones in a GABA
      independent way. An alternative role of GABA in the outer plexiform layer is
      discussed and finally the functional consequences of the negative feedback
      pathway from horizontal cells to cones are presented.

PMID- 10396616
TI  - Synaptic mechanisms of bipolar cell terminals.
AB  - Giant synaptic terminals of goldfish bipolar neurons allow direct studies of
      presynaptic mechanisms underlying neurotransmitter release and its modulation.
      Calcium influx via L-type calcium channels of the terminal triggers synaptic
      vesicle exocytosis, which can be monitored in isolated terminals by means of the
      associated changes in membrane capacitance. Information about the kinetics and
      calcium dependence of synaptic exocytosis has been obtained from capacitance
      measurements in these ribbon-type synaptic terminals.

PMID- 10396617
TI  - Maturation of intrinsic membrane properties in rat retinal ganglion cells.
AB  - In view of the prominent role of voltage-activated conductances in both neuronal
      differentiation and signal transmission, the present study describes
      developmental alterations of ion channel properties during the functional
      maturation of rat RGCs, i.e., between embryonic day 15 when RGCs start to
      differentiate (E15) and postnatal day 35 (P35) when the retina is fully developed
      and the animals had already visual input for about 2 weeks. While the sodium
      system seems to reach maturity already at the end of the second postnatal week,
      significant alterations in the potassium system were found only from postnatal
      day 10 on. The functional implications of these alterations are discussed.

PMID- 10396618
TI  - Synchronous oscillations in the cat retina.
AB  - Retinal ganglion cells exhibit oscillatory responses which are precisely
      synchronized over large distances. Here we examined, with multi-electrode
      recordings, the time course of synchronization during spontaneous and stimulus
      driven oscillatory activity. Spontaneous discharges showed synchronized
      oscillations at approximately 30 Hz, which were occasionally associated with
      slower superimposed oscillations in the range of 1-5 Hz. Stationary stimuli or
      moving gratings induced synchronous oscillations at higher frequencies (mean of
      79.0 +/- 20.0 Hz for OFF- and 91.7 +/- 11.7 Hz for ON-responses), with time lags
      of a few milliseconds. At response onset, the first few oscillatory cycles were
      occasionally time locked to the stimulus. Thereafter, synchronization became
      independent of stimulus coordination and was exclusively due to neuronal
      interactions. Oscillatory modulation emerged rapidly and was sustained throughout
      the responses while oscillation frequency decreased gradually. This periodic
      patterning of responses persisted despite brief and local occlusion of stimuli,
      suggesting that synchronous oscillations emerge from population dynamics and
      entrain cells even if they are intermittently silenced.

PMID- 10396619
TI  - Long-term changes in retinal contrast sensitivity in chicks from frosted
      occluders and drugs: relations to myopia?
AB  - Experiments in animal models have shown that the retinal analyzes the image to
      identify the position of the plane of focus and fine-tunes the growth of the
      underlying sclera. It is fundamental to the understanding of the development of
      refractive errors to know which image features are processed. Since the position
      of the image plane fluctuates continuously with accommodative status and viewing
      distance, a meaningful control of refractive development can only occur by an
      averaging procedure with a long time constant. As a candidate for a retinal
      signal for enhanced eye growth and myopia we propose the level of contrast
      adaptation which varies with the average amount of defocus. Using a behavioural
      paradigm, we have found in chickens (1) that contrast adaptation (CA, here
      referred to as an increase in contrast sensitivity) occurs at low spatial
      frequencies (0.2 cyc/deg) already after 1.5 h of wearing frosted goggles which
      cause deprivation myopia, (2) that CA also occurs with negative lenses (-7.4D)
      and positive lenses (+6.9D) after 1.5 h, at least if accommodation is paralyzed
      and, (3) that CA occurs at a retinal level or has, at least, a retinal component.
      Furthermore, we have studied the effects of atropine and reserpine, which both
      suppress myopia development, on CA. Quisqualate, which causes retinal
      degeneration but leaves emmetropization functional, was also tested. We found
      that both atropine and reserpine increase contrast sensitivity to a level where
      no further CA could be induced by frosted goggles. Quisqualate increased only the
      variability of refractive development and of contrast sensitivity. Taken
      together, CA occurring during extended periods of defocus is a possible candidate
      for a retinal error signal for myopia development. However, the situation is
      complicated by the fact that there must be a second image processing mode
      generating a powerful inhibitory growth signal if the image is in front of the
      retina, even with poor images (Diether, S., & Schaeffel, F. (1999).

PMID- 10396620
TI  - Differential DNA binding activities of the transcription factors AP-1 and Oct-1
      during light-induced apoptosis of photoreceptors.
AB  - The activity of transcription factors like AP-1 and Oct-1 is critical for the
      regulation of gene expression. Whereas Oct-1 mainly regulates the expression of
      housekeeping genes, AP-1 is often involved in cellular responses to external
      stimuli and plays an essential role in the regulation of light-induced apoptosis
      of mouse retinal photoreceptors. In this study, we investigated AP-1 and Oct-1
      DNA binding activity and AP-1 complex composition in the mouse retina during
      light-induced photoreceptor apoptosis. AP-1 DNA binding activity was low in dark
      adapted animals but was transiently elevated within 12 h after exposure of mice
      to apoptosis-inducing levels of white fluorescent light. Maximal AP-1 activity
      was found 6 h after light-exposure. Antibody interference analysis at 6 h after
      damaging light exposure and under normal light conditions revealed that the major
      fraction of AP-1 consists of c-Fos/JunD heterodimers in both situations. In
      contrast to AP-1, Oct-1 DNA binding activity was maximal in dark-adapted animals
      and was reduced during photoreceptor apoptosis. Transient induction of AP-1 (c
      Fos/JunD) and inactivation of Oct-1 may be crucial events for light-mediated
      apoptosis of retinal photoreceptors.

PMID- 10396621
TI  - The purine nucleoside adenosine in retinal ischemia-reperfusion injury.
AB  - Adenosine, an intercellular messenger that is a product of the metabolism of ATP,
      plays a major role in neuronal and vascular responses of the retina to
      alterations in oxygen delivery. Significant changes in adenosine concentration
      have been measured in the retina during both ischemia and during the subsequent
      reperfusion period which result in important, but complex, functional effects.
      Adenosine A1 receptor stimulation produces a protective effect during ischemia,
      whereas overstimulation of the A2a receptor has deleterious effects. The
      mechanisms underlying these findings have not been completely determined, but
      most likely are the result of alterations in excitotoxicity, gene expression, and
      blood flow. Paradoxically, prolonged increases in adenosine concentration may be
      injurious to the retina, a consequence of superoxide radical formation secondary
      to adenosine catabolism. Adenosine is a critical mediator of blood flow changes
      in response to ischemia. It is a significant component of the retina's
      compensatory hyperemic response to ischemia, hypoxia, and hypoglycemia.
      Increasing endogenous adenosine concentrations may be useful in ameliorating post
      ischemic hypoperfusion. Overall, current evidence suggests that adenosine is a
      vital component of the endogenous retinal response to substrate deprivation.
      Additionally, in vitro studies provide strong evidence that adenosine is a
      mediator of the formation and effects of vascular endothelial growth factor,
      which in turn promotes neovascularization. Finally, the ability of the retina to
      develop an ischemia-tolerant state by ischemic preconditioning is an intriguing
      phenomenon that reveals yet another essential role for adenosine in the retina's
      endogenous response to ischemia. The experimental results described in this
      review suggest that continued investigation into the role of adenosine in the
      retina may lead to important clinical applications for adenosine-based therapies
      that could decrease the incidence of retinal damage in ischemic vasculopathies
      such as diabetes, glaucoma, and retinal vascular occlusion.

PMID- 10396622
TI  - The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal
      disease: from monogenic to multifactorial.
AB  - The ABCR gene encodes a rod photoreceptor specific ATP-binding cassette
      transporter. Mutations in ABCR are associated with at least four inherited
      retinal dystrophies: Stargardt disease, Fundus Flavimaculatus, cone-rod
      dystrophy, and retinitis pigmentosa. A statistically significant increase in
      heterozygous ABCR alterations has been identified in patients with age-related
      macular degeneration (AMD). A pedigree is described which manifests both
      Stargardt disease and AMD in which an ABCR mutation cosegregates with both
      disease phenotypes. These data from this case report support the hypothesis that
      ABCR is a dominant susceptibility locus for AMD. Recent work regarding ABCR is
      reviewed and a model is presented in which decreased ABCR function correlates
      with severity of retinal disease.

PMID- 10396623
TI  - Persistent transgene product in retina, optic nerve and brain after intraocular
      injection of rAAV.
AB  - Recombinant adeno-associated virus (rAAV) is a promising vector for retinal
      application as it transduces photoreceptors and retinal pigment epithelium cells
      efficiently and in a stable fashion. Because rAAV also transduces retinal
      ganglion cells, we reasoned that ocular application of rAAV might result in
      delivery of transgenic protein to the CNS. Here we describe high levels of green
      fluorescent protein (GFP) persisting at least 6 months in optic nerves and brains
      of mice and dogs after intravitreal delivery of rAAV-GFP. There was no clinical
      or histological evidence of inflammatory response although a mild humoral Th-2
      response to viral capsid proteins was detected. These findings have important
      implications with respect to therapeutic applications of rAAV.

PMID- 10396624
TI  - Can subretinal microphotodiodes successfully replace degenerated photoreceptors?
AB  - The idea of implanting microphotodiode arrays as visual prostheses has aroused
      controversy on its feasibility from the moment it appeared in print. We now
      present results which basically support the concept of replacing damaged
      photoreceptors with subretinally implanted stimulation devices. Network activity
      in degenerated rat retinae could be modulated through local electrical
      stimulation in vitro. We also investigated the long term stability and
      biocompatibility of the subretinal implants and their impact on retinal
      physiology in rats. Ganzfeld electroretinograms and histology showed no
      significant side effect of subretinal implants on retinal function or the
      architecture of the inner retina.

PMID- 10396625
TI  - Pattern electrical stimulation of the human retina.
AB  - Experiments were conducted to study if electrical stimulation of the retinal
      surface can elicit visual sensation in individuals blind from end-stage retinitis
      pigmentosa (RP) or age-related macular degeneration (AMD). Under local
      anesthesia, different stimulating electrodes were inserted through the eyewall
      and positioned over the surface of the retina. Subjects' psychophysical responses
      to electrical stimulation were recorded. Subjects perceived simple forms in
      response to pattern electrical stimulation of the retina. A non-flickering
      perception was created with stimulating frequencies between 40 and 50 Hz. The
      stimulation threshold was dependent on the targeted retinal area (macular versus
      extramacular).

PMID- 10396626
TI  - A neural interface for a cortical vision prosthesis.
AB  - The development of a cortically based vision prosthesis has been hampered by a
      lack of basic experiments on phosphene psychophysics. This basic research has
      been hampered by the lack of a means to safely stimulate large numbers of
      cortical neurons. Recently, a number of laboratories have developed arrays of
      silicon microelectrodes that could enable such basic studies on phosphene
      psychophysics. This paper describes one such array, the Utah electrode array, and
      summarizes neurosurgical, physiological and histological experiments that suggest
      that such an array could be implanted safely in visual cortex. We also summarize
      a series of chronic behavioral experiments that show that modest levels of
      electrical currents passed into cortex via this array can evoke sensory percepts.
      Pending the successful outcome of biocompatibility studies using such arrays,
      high count arrays of penetrating microelectrodes similar to this design could
      provide a useful tool for studies of the psychophysics of phosphene perception in
      human volunteers. Such studies could provide a proof-of-concept for cortically
      based artificial vision.

PMID- 10396627
TI  - Photoreceptor function of retinal transplants implicated by light-dark shift of S
      antigen and rod transducin.
AB  - The aim was to demonstrate functional properties of transplanted histologically
      normal photoreceptors. Subretinal intact-sheet transplants of fetal E17-E20 rat
      retinas to light-damaged albino rat eyes were fixed in light or dark, 2 to 42
      weeks after transplantation, and stained immunohistochemically for certain
      phototransduction proteins. In light adapted transplants, transducin was
      predominantly found in inner segments of parallel-organized photoreceptors.
      Transducin shifted to the outer segments with dark-adaptation. S-antigen
      distribution was opposite to transducin. Rhodopsin distribution did not change.
      The shift of signal transduction proteins correlated to the light conditions
      indicates that normal phototransduction processes were established in
      photoreceptors of transplanted retinal sheets.

PMID- 10396628
TI  - Organ culture of chicken bursa as a model to study the pathogenicity of
      infectious bursal disease virus isolates.
AB  - In vitro study with chicken bursal organ culture was attempted to assess the
      pathogenicity of locally isolated infectious bursal disease virus (IBDV)
      initially isolated from the bursa of naturally infected birds. In bursal organ
      culture, lymphoblastic transformation was noticed as early as 24 hr
      postinoculation and reached maximum at 72 hr postinoculation. The other
      microscopic changes were increased number of macrophages and formation of plasma
      cells. The IBDV antigen was detected 24 hr onward by coagglutination test with
      antibody coated Staphylococcus aureus strain Cowan I. On the basis of lesion
      score, the three isolates of IBDV (A, B, and C) were graded as virulent (B
      isolate) and moderately virulent (A and C isolates). A similar pattern of
      pathogenicity was also observed in the in vivo pathogenicity studies in chicken
      based on bursa: body weight ratio and histopathologic lesion score. The bursal
      organ culture thus provides a useful experimental model to differentiate the IBDV
      isolates on the basis of their virulence.

PMID- 10396629
TI  - An evaluation of the mitogenic reactivity of intestinal intraepithelial
      lymphocytes of chickens.
AB  - A colorimetric assay employing MTT (3-[4,5-dimethylthiazole-2-yl], 2-5
      diphenyltetrazolium bromide) was used to determine the mitogenic response of
      intestinal intraepithelial lymphocytes (i-IELs) of chickens to T- and B-cell
      mitogens. Comparisons between mitogenic responses of i-IELs and peripheral blood
      lymphocytes (PBLs) were made to examine potential relationships. The results from
      this study indicated that T-cell mitogens, concanavalin A (Con A), and
      phytohemagglutinin-P (PHA-P) induced mitogenic stimulation in i-IELs. Although
      stimulation indexes of both i-IELs and PBLs were similar, the optical densities
      (ODs) of i-IEL cultures containing Con A or PHA-P were 20- to 50-fold lower than
      the ODs of PBL cultures containing the same mitogen. The lower conversion of MTT
      to formazan resulting in lower ODs in i-IEL cultures indicated a lower level of
      cellular activity in the i-IELs than in the PBLs. The mitogenic responses of both
      i-IELs and PBLs to Con A and PHA-P were dose dependent. The responsive
      concentration of Con A for i-IELs was within the range of 25-50 micrograms/ml,
      whereas the responsive concentration of PHA-P for i-IELs was 50 micrograms/ml.
      Three days of incubation was found to be adequate to induce a significant (P <
      0.05) mitogenic response for both T-cell mitogens. Lipopolysaccharide was unable
      to induce a mitogenic response in i-IELs, which was attributed to the lack of B
      cells in the i-IEL population. This technique may prove useful in evaluating and
      studying the role of i-IELs in local cell-mediated immune responses of the
      gastrointestinal tract.

PMID- 10396630
TI  - Genome analysis of Marek's disease virus strain CVI-988: effect of cell culture
      passage on the inverted repeat regions.
AB  - The genomes of different derivatives of Marek's disease virus (MDV) strain CVI
      988, a low oncogenic isolate of a serotype 1 MDV, were analyzed by restriction
      enzyme analyses to detect whether alterations occurred after passages in cell
      culture. DNA molecules of strain 988 isolated directly from blood cells contained
      mainly two copies of the 132-bp repeat sequence previously reported within BamH1
      H and -D fragment as previously reported for more virulent MDV strains. Although
      a minority of virus particles showed repeat amplification was already at the
      fifth passage level, amplification mainly occurred between passages 17 and 34 in
      cell culture. In addition, a 400-bp deletion was detected within the BamH1-A
      fragment of two derivatives of CVI-988, 988C and 988C/R6.

PMID- 10396631
TI  - Correlation of enzyme-linked immunosorbent assay titers with protection against
      infectious bursal disease virus.
AB  - We examined the utility of baculovirus-expressed infectious bursal disease virus
      (IBDV) proteins to act as antigens in the enzyme-linked immunosorbent assay
      (ELISA). The three IBDV protein antigens tested included 1) a truncated VP2, 2)
      whole VP2, and 3) the polyprotein products VP2, VP3, and VP4. Serum samples from
      2-wk-old commercially reared broilers were collected and tested in the three
      ELISAs. Serum samples were obtained from 34 different commercial broiler flocks.
      An average of 14 serum samples (range = 11-17) were tested for each flock. The
      ELISA results were compared with the percentage of protection of these birds
      following challenge with IBDV. Fifty 2-wk-old chicks from each of the 34 broiler
      flocks were challenged with STC classic virus or Del-E variant virus. At 7 days
      postchallenge, the bursa from each of the birds was removed and bursa/body
      weights were recorded. Percentage of protection was determined by the number of
      birds in each challenge group that had normal relative bursal weights compared
      with unchallenged controls. No evidence was found of a relationship between ELISA
      data generated with the polyprotein antigen (VP2, VP3, VP4) and percentage of
      protection observed in the STC and Del-E challenged birds. A significant
      relationship was found between ELISA data and percentage of protection to STC and
      Del-E when the truncated VP2 or whole VP2 antigens were used in the ELISA. The
      results of this study indicate that predicting the percentage of protection
      against classic or variant IBDV strains in broilers from vaccinated breeder
      flocks can be improved when VP2 is used as the only antigen in the ELISA.

PMID- 10396632
TI  - Antigenic and molecular characterization of three infectious bursal disease virus
      field isolates.
AB  - Three infectious bursal disease field viruses, identified as U28, 3212, and MISS
      and isolated in the early 1980s from the southeastern United States, were
      characterized both antigenically and genotypically. A panel of monoclonal
      antibodies (MAbs) was utilized in an antigen-capture enzyme-linked immunosorbent
      assay (ELISA) for antigenic characterization. The ELISA data indicated that U28
      and the Delaware variants are antigenically related. The 3212 and the GLS
      variants were more closely related antigenically to each other than to other
      viruses analyzed. However, the MISS isolate reacted with MAbs that were specific
      for both classic and variant strains of infectious bursal disease virus (IBDV).
      Reverse transcription-polymerase chain reaction (RT-PCR) was used to amplify
      nucleotide sequences from the genome coding for the variable region of VP2 from
      IBDV field isolates U28, 3212, and MISS. Phylogenetic analysis of the deduced
      amino acid sequences revealed that U28 was most similar (98.3%) to the IBDV
      Delaware variants and that 3212 was most similar (97.1%) to the GLS variant. The
      MISS isolate was most similar (97.4%) to the classic 52/70 strain. Positive
      correlation occurred with the use of different methods to characterize IBDV
      isolates.

PMID- 10396633
TI  - Genetic diversity in twenty variants of the avian polyomavirus.
AB  - To determine if different pathotypes of the avian polyomavirus (APV) exist and to
      compare the genomes of APVs originating from different geographic areas, dates,
      and species of birds, the partial sequences of 18 APVs were determined. New viral
      sequences were compared with three published APV sequences. Two of the new
      viruses had identical sequences. Forty point mutations were found at 31 loci. A
      27-bp deletion was found in the VP2 and VP3 open reading frames of one virus. A
      duplication of the putative origin of replication and adjacent enhancer region
      was previously reported in one APV. Smaller duplications involving the origin in
      one APV and a second enhancer region in another were discovered. All duplications
      were in tissue culture-adapted viruses, suggesting they occurred during the
      isolation process. Excluding duplications and the deletion, maximum variation
      between viruses was small (11 bp). A maximum parsimony tree was constructed that
      contained three major branches. The three earliest isolates were on separate
      branches. The European viruses were confined to branch I, but APVs from the
      United States were on all three branches. Lovebird, budgerigar, and macaw APVs
      were also on each of the three branches, suggesting that species-specific
      pathotypes have not developed. Most nonsynonymous mutations occurred in a small
      portion of the VP2 and VP3 open reading frames, demonstrating a selection for
      these mutations. That a glycine at VP2 221 will inhibit virus replication in
      chicken embryo fibroblasts (CEFs) has been previously reported. In contrast, six
      of seven of the new APVs isolated in CEFs had a glycine at VP2 221.

PMID- 10396634
TI  - Characterization of the genome of avian encephalomyelitis virus with cloned cDNA
      fragments.
AB  - cDNA fragments were generated from RNA extracted from preparations of avian
      encephalomyelitis virus (AEV) by a reverse transcription-polymerase chain
      reaction (RT-PCR) strategy, which exploited the probability that AEV is a
      picornavirus. Rapid amplification of the 3' cDNA ends, which utilized an oligo
      d(T)-based primer that hybrizes to the putative Poly (A) tract at the 3' terminus
      of picornavirus RNA, produced a 3.8-kbp fragment (3.8-kbp 3' RACE fragment), from
      which a 2.5-kbp cDNA fragment specific to the extreme 3' terminal region of the
      AEV genome was cloned. Positive hybridization reactions between RNA from gradient
      purified virus and radiolabeled probes confirmed that the cloned 2.5-kbp fragment
      was AEV specific. The success of the RT-PCR amplification strategy adopted and
      the results of northern blotting hybridization experiments indicated that the AEV
      genome is a polyadenylated, single-stranded RNA, approximately 7.5 kb in size.
      Sequence analysis of a 869-base region at the 3' terminal of the genome indicated
      that this region encoded a protein with close homologies to picornaviral RNA
      polymerase proteins. On the basis that the highest levels of protein homologies
      were observed with hepatitis A virus, it is likely that AEV will be reassigned to
      a genus other than the enterovirus genus within the virus family Picornaviridae.
      The AEV-specific cloned DNA fragments and nucleotide sequence information
      resulting from this investigation may facilitate the development of in situ
      hybridization and RT-PCR methods that will be useful in AEV diagnosis.

PMID- 10396635
TI  - Effect of hydrogen peroxide disinfection during incubation of chicken eggs on
      microbial levels and productivity.
AB  - Hatchery sanitation has a significant impact on chick quality. The proper use of
      disinfectants is essential. Aerosol bacterial counts, egg moisture loss,
      hatchability, chick quality, and broiler productivity were measured in eggs
      exposed to hydrogen peroxide fogging and compared with eggs not exposed to
      disinfectant during the incubation period. Hydrogen peroxide was also evaluated
      in the presence of a severe challenge with Staphylococcus aureus-contaminated
      eggs. A significant reduction was found in aerosol bacterial counts within the
      hatcher when incubators were fogged with 3% hydrogen peroxide when compared with
      water-fogged machines even in the face of high bacterial challenge. Eggs exposed
      to hydrogen peroxide lost a significantly greater amount of moisture during
      incubation, but hatchability was not affected. The use of hydrogen peroxide as a
      hatchery sanitizer did not affect broiler livability, body weight, or feed
      conversion but did reduce the incidence of retained yolk sacs in 42-day-old
      chickens.

PMID- 10396636
TI  - Protection of turkeys from hemorrhagic enteritis with a recombinant fowl poxvirus
      expressing the native hexon of hemorrhagic enteritis virus.
AB  - Hemorrhagic enteritis (HE) is an economically important disease of turkeys caused
      by a type II aviadenovirus, hemorrhagic enteritis virus (HEV). The vaccines
      currently available to the commercial poultry producer are highly effective in
      preventing disease outbreaks; however, they are immunosuppressive. A recombinant
      fowl poxvirus (rFPV) expressing the native hexon of HEV has been shown to induce
      an anti-HEV humoral immune response in turkeys. In this study, the rFPV
      expressing the native hexon of HEV was compared with a commercial HEV vaccine
      (vxHEV) for its ability to protect turkeys from virulent HEV challenge. Complete
      protection from the enteritis of HE was achieved in experimental groups
      vaccinated with either the rFPV or the vxHEV. Lymphocyte stimulation was measured
      in turkeys inoculated with rFPV, vxHEV, or a sublethal dose of HEV or not
      inoculated. No statistically significant immunodepression was observed in turkeys
      receiving the rFPV.

PMID- 10396637
TI  - Inhibition of Salmonella typhimurium in the chicken intestinal tract by a
      transformed avirulent avian Escherichia coli.
AB  - An avirulent, wild-type avian Escherichia coli (E. coli Av) was
      electrotransformed with a plasmid coding for the production of microcin 24
      (pGOB18) and was designated E. coli AvGOB18. The transformant inhibited the
      growth of seven serotypes of Salmonella commonly associated with colonization and
      contamination of poultry products and seven strains of E. coli O157:H7 in the in
      vitro colicin/microcin assay. The transformant did not inhibit the replication of
      multiple isolates of Listeria monocytogenes or Campylobacter jejuni in similar
      assays. The transformant is nonconjugative, indicating that the plasmid would not
      be transmitted to other intestinal microflora in the environment. The
      transformant also survived in sterile tap and deionized water incubated at 25 C
      and 37 C in the laboratory for 30 days and was recovered from drinkers and birds
      in in vivo floor pen studies. In in vivo studies, E. coli AvGOB18 did not
      colonize the intestinal tract of broiler chicks when given as a single or
      multiple dose and did not reduce the Salmonella load in the broilers. But
      Salmonella typhimurium was reduced significantly in the intestinal tracts of
      broiler chickens when E. coli AvGOB18 was administered continually in the water
      supply.

PMID- 10396638
TI  - Factors associated with virulence of Mycoplasma synoviae.
AB  - Virulence mechanisms of six isolates of Mycoplasma synoviae (MS), previously
      classified as pathogenic (K1968), moderately pathogenic (WVU 1853, K1858,
      92D8034, and F10-2AS), and mildly pathogenic (FMT) in chickens, were examined.
      The most virulent isolate, K1968, had been found to invade systematically and
      produce lesions following eye-drop inoculation. In the present study, all
      isolates were evaluated for presence of a possible cytadhesin and for functional
      attachment to host cells as indicated by hemagglutination and hemadsorption.
      Three representative isolates, K1968, 92D8034, and FMT, were evaluated for
      attachment and colonization in cultured chick tracheal rings and tendon cell
      monolayers by direct transmission electron microscopic examination and by
      quantitative polymerase chain reaction assay. Ciliostasis was compared in
      tracheal organ culture. Previously found differences in pathogenicity of these
      isolates for chickens could not be explained as differences in attachment and
      were only partially explained by differences in colonization. Pathogenicity of
      the most virulent isolate of MS was suspected to be multifactorial, involving
      attachment and colonization of the upper respiratory tract plus additional
      unidentified factors associated with systemic invasion and lesion production.

PMID- 10396639
TI  - Characterization of fowl adenoviruses from outbreaks of inclusion body
      hepatitis/hydropericardium syndrome in Chile.
AB  - Three fowl adenovirus (FAV) isolates (341, 344, and 215) obtained during 1996-97
      from field outbreaks of inclusion body hepatitis/hydropericardium syndrome
      (IBH/HPS) affecting broilers and broiler breeders in Chile were characterized by
      virus neutralization tests (VNTs) and restriction enzyme analysis of a DNA
      fragment. Furthermore, the pathologic characteristics of one of these FAV
      isolates (FAV 341) was studied in experimentally infected chickens. The VNTs
      conducted with isolates 341 and 344 against reference strains and antisera
      belonging to each of 12 FAV serotypes demonstrated a close antigenic relationship
      with strain KR5 of the FAV serotype 4. Polymerase chain reaction using the
      primers H3/H4 and subsequent HpaII digestion was used for serotype identification
      of isolates 341 and 215. The length of the PCR products and the restriction
      profiles of isolates 341, 215, and the reference strain KR5 (FAV4) were
      identical. The present results confirmed the classification of all three isolates
      as FAV4. The pathogenicity test with 1000 mean tissue infectious dose of isolate
      341 inoculated intramuscularly in 20-day-old specific-pathogen-free chickens
      resulted in the death of 9% (two birds) six days postinoculation (PI). Both birds
      showed characteristic IBH/HPS gross and microscopic lesions; the remaining birds,
      sacrificed at day 10 PI, showed less severe lesions. On the basis of
      epidemiologic and experimental data of the virulence of Chilean FAV isolates, and
      the pathogenicity results with isolate 341, we speculate that Chilean FAV strains
      may require an association with other agents (immunosuppressive agents) to induce
      IBH/HPS outbreaks in the field.

PMID- 10396640
TI  - Reovirus serology in broiler parents and their progeny and its correlation with
      performance.
AB  - An intensive vertically integrated monitoring program for broiler breeders and
      their offspring was set up in a Belgian poultry integration between 1993 and
      1997. Serology for anti-reovirus antibodies was performed by enzyme-linked
      immunosorbent assay on blood samples taken from the broiler parents throughout
      rearing and production and also on blood samples taken at day-old and at
      slaughter from the broilers. Furthermore, production parameters of the birds were
      registered. All data were used two by two in a simple correlation study to
      calculate the degree to which these variables were linearly correlated. The
      reovirus antibody pattern indicated frequent field infections breaking through
      vaccinal immunity in the broiler parents. Under the epidemiologic conditions of
      this study, high antibody titers in the parents or in the broilers at day-old
      were significantly correlated with poor feed conversion, increased mortality,
      increased slaughterhouse condemnation, and low production score in the broilers.
      These correlations strongly support the view that reovirus infections can be
      economically important under European conditions of broiler production.
      Improvement of reovirus vaccines or the vaccination scheme in broiler parents or
      both may lead to better production results in the broiler offspring.

PMID- 10396641
TI  - Virulence of raptor-origin Pasteurella multocida in domestic chickens.
AB  - Pasteurella multocida belonging to somatic serotype 1 and capsular type A has
      been known to cause avian cholera in domestic poultry. Pasteurella multocida
      serotype 1 has also been isolated from raptorial birds. However, the capsular
      type for these raptorial isolates remains unknown. Moreover, the virulence of
      these raptorial isolates for domestic poultry has not been determined. The
      objectives of this study were to determine the capsular type of raptorial P.
      multocida serotype 1 isolates and to determine if these isolates were virulent
      for domestic chickens. Study chickens were inoculated with one of three P.
      multocida isolates. Isolate WESO-1 was obtained from a western screech owl (Otus
      kennicottii) and isolates RTHA-2 and RTHA-4 were isolated from two red-tailed
      hawks (Buteo jamaicensis). These isolates were given by either the oral,
      intravenous, or intraocular route. Control birds were given brain-heart infusion
      broth. The capsular serotypes of three isolates were also determined. The RTHA-2
      and RTHA-4 isolates belonged to P. multocida capsular type A. The WESO-1 isolate
      belonged to capsular type F. Results also demonstrated that, for the isolates
      examined, the intraocular route did not cause mortality in chickens. There was
      mortality in all groups for the intravenous route. However, various mortality
      patterns were observed when P. multocida was given orally for the three different
      isolates. The RTHA-4 isolate (serotype 1:A) was the most virulent for domestic
      chickens. The WESO-1 isolate (serotype 1:F) was the least virulent for chickens
      among the raptorial isolates examined.

PMID- 10396642
TI  - Response of turkeys to simultaneous vaccination with hemorrhagic enteritis and
      Newcastle disease viruses.
AB  - The effects of single and combined vaccination of turkeys against hemorrhagic
      enteritis virus (HEV) and Newcastle disease virus (NDV) were investigated. Dual
      vaccination of turkeys with NDV-B1 and HEVp30 or marble spleen disease virus
      (MSDV) enhanced white mottling of the spleens and the apoptosis rate in spleen
      cells (P < 0.05). In addition, simultaneously vaccinated turkeys had fewer HEV
      infected spleen cells at 4 days postvaccination than turkeys given HEVp30 or MSDV
      alone. The anti-HEV antibody response was significantly reduced at 14 days
      postvaccination (P < 0.05), whereas the anti-NDV antibody response was enhanced
      (P < 0.05) in turkeys vaccinated with HEVp30 + NDV-B1. Further, the effect of
      dual vaccination on macrophage function was studied. Spleen cells from NDV-B1
      vaccinated turkeys were primed to produce nitric oxide (NO) after stimulation in
      vitro with lipopolysaccharide. Spleen cells from HEVp30- or MSDV-vaccinated
      turkeys did not produce NO after in vitro stimulation. In dual-vaccinated
      turkeys, the priming effect of NDV-B1 was reduced in comparison with single
      inoculated birds.

PMID- 10396643
TI  - In ovo vaccination of specific-pathogen-free chickens with vaccines containing
      multiple agents.
AB  - We used in ovo technology to protect chickens against multiple diseases by
      inoculating vaccines containing mixtures of live viral agents. A single in ovo
      injection of a vaccine containing serotypes 1, 2, and 3 of Marek's disease virus
      (MDV), a vaccine strain of serotype 1 infectious bursal disease virus (IBDV), and
      recombinant fowl pox vaccine with HN and F genes of Newcastle disease virus (rFP
      NDV) induced protection against virulent MDV, IBDV, Newcastle disease virus, and
      fowl poxvirus. The multiple-agent vaccine induced specific antibodies against the
      viral agents present in the mixture and did not adversely affect the survival of
      hatched chickens. Inoculation of a vaccine containing serotypes 1, 2, and 3 of
      MDV and IBDV did not affect hatchability of eggs, although the addition of rFP
      NDV to the mixture reduced hatchability by 23%-26%. In ovo vaccination with a
      vaccine containing MDV and IBDV vaccine viruses did not exacerbate the inhibitory
      effect of individual viral agents on humoral and cellular immune competence.

PMID- 10396644
TI  - Contamination of Salmonella blockley in the environment of a poultry farm.
AB  - Cecal and environmental samples were collected and examined for the presence of
      Salmonella on a farm where a high prevalence of Salmonella blockley in chickens
      was observed. Of 895 cecal and 525 environmental samples examined, 242 (27.0%)
      and 202 (38.5%) samples, respectively, yielded S. blockley. From the analysis of
      plasmid profile patterns, 11 different plasmid profile patterns were found among
      444 isolates, with plasmid patterns c and d the most frequent among the isolates
      from ceca and the environment. Salmonella blockley was isolated from
      environmental samples such as floor litter, walls, drinking water, waste water,
      dust, and soil collected when barns were occupied and was positive in drinking
      water, waste water, and soil when samples were collected from empty barns with
      occupied neighboring barns, but it was negative in all environmental samples with
      the exception of soil when the environmental samples were collected from empty
      barns with empty neighboring barns.

PMID- 10396646
TI  - A descriptive analysis of the potential association between migration patterns of
      bean and white-fronted geese and the occurrence of Newcastle disease outbreaks in
      domestic birds.
AB  - The sightings and migration patterns of 65 bean (Anser fabalis) and 65 white
      fronted geese (Anser albifrons) are reported. In the past, these geese were
      serologically screened for the occurrence of Newcastle disease virus (NDV) and
      other avian viral diseases by Hlinak et al. (3). Of the 130 birds originally
      tagged and serologically screened in 1991, 53 birds were resighted between 1991
      and 1996. Most of the sightings were reported from main wintering and resting
      sites in Germany and The Netherlands. It is noteworthy that 19 of the 53 birds
      sighted had serologic evidence that they had been exposed to NDV before the time
      of marking in 1991. Although the origin of these infections in bean geese and
      white-fronted geese is still unknown, the sightings reported in this study
      indicate that, once infected, wild geese may be involved in the dissemination and
      spread of avian viral diseases, specifically Newcastle disease. The migration
      patterns of the wild geese provided further evidence that the main resting and
      wintering areas of migratory waterfowl are likely to be important for the inter-
      and intraspecies transmission of avian diseases, thereby representing risk areas
      for the poultry industry.

PMID- 10396645
TI  - Restriction fragment length polymorphisms in the VP2 gene of infectious bursal
      disease viruses from outside the United States.
AB  - Infectious bursal disease viruses (IBDVs) were identified in bursa samples from
      chickens reared outside the United States. All samples were obtained from
      commercially reared chicken flocks experiencing signs typical of infectious
      bursal disease. The reverse transcriptase/polymerase chain reaction (RT/PCR)
      technique was used to detect the viruses and restriction fragment length
      polymorphism (RFLP) was used to compare a 743-bp region of the VP2 gene among the
      viruses detected. The 81 IBDVs detected were from 16 different countries and were
      assigned to molecular groups on the basis of their RFLP following digestion with
      the restriction enzymes BstNI and MboI. The presence of an SspI site in the 743
      bp RT/PCR fragment was used to predict the very virulent (vv) phenotype. Almost
      half (49%) of the viruses detected had the same RFLP with the BstNI and MboI
      enzymes. These viruses were placed into a new molecular group, designated group
      6, that was exemplified by the RS593 vaccine strain of IBDV, which also had this
      molecular RFLP pattern. Some viruses detected had RFLP patterns similar to
      molecular groups 2, 3, and 4, previously described in our laboratory. Sixteen
      RFLP patterns were observed that did not match RFLP results we previously
      obtained for vaccine IBDV strains. The SspI restriction site was found in 46% of
      the viruses detected, predicting that these viruses have the vvIBDV phenotype.
      The SspI site was not observed in viruses from Central and South America.

PMID- 10396647
TI  - Evaluation of scratches as an essential element in the development of avian
      cellulitis in broiler chickens.
AB  - Currently, the published cellulitis models do not adequately address the actual
      pathogenesis as seen in the commercial broiler industry. In this model, small
      dermal scratches were made on the skin of broiler chickens, which were then
      placed on litter seeded with avian cellulitis-associated Escherichia coli. The
      research confirms scratches are required for the induction of avian cellulitis.
      The research also confirms that "type I" cellulitis lesions or those previously
      thought to be due to hatchery-borne infections can be induced with scratches. The
      described methods provide a realistic model for cellulitis development that will
      improve the reliability of prophylactic and therapeutic-regimen efficacy testing
      data, thereby providing information more directly useful to the commercial
      broiler industry.

PMID- 10396648
TI  - The effects of F strain Mycoplasma gallisepticum, Mycoplasma synoviae, and the
      dual infection in commercial layer hens over a 44-week laying cycle when
      challenged before beginning of lay. II. Egg size distribution.
AB  - In each of two trials, 160 commercial pullets were separated into four treatments
      with four replicates of 10 chickens in each treatment. Forty pullets were
      designated as controls and received no inoculation; 40 pullets received F strain
      Mycoplasma gallisepticum (FMG); an additional 40 pullets received Mycoplasma
      synoviae (MS); and the final 40 pullets were inoculated with both FMG and MS
      (dual). All inoculations occurred at 10 wk of age. Eggs from all treatments were
      collected daily, Monday-Thursday, and individually weighed. No significant
      difference was observed among the treatments for percentages of jumbo, extra
      large, medium, small, peewee, or undergrade eggs. As a percentage of eggs laid
      for the 4 days of each week over the 44-wk laying cycle of each trial, the FMG
      hens laid significantly fewer large size eggs (43.2%) as compared with either
      controls (51.17%) or dual-infected hens (49.95%). No significant difference was
      found in percentage of large eggs laid by FMG hens when compared with MS hens.

PMID- 10396649
TI  - Pathogenicity of Mycoplasma synoviae in chicken embryos.
AB  - Pathogenicity of Mycoplasma synoviae (MS) was examined in specific-pathogen-free
      (SPF) white leghorn chicken embryos. Six isolates of MS were inoculated into 7
      day embryos via the yolk sac. Isolates were evaluated for gross and microscopic
      lesions through 19 days' incubation and for embryo lethality through 20 days'
      incubation. Isolates in decreasing order of lethality, from lowest to highest 50%
      embryo lethal dose, were WVU 1853, K1968, K1858, FMT, 92D8034, and F10-2AS.
      Embryo lethality was consistent with lesion incidence and severity. Embryo
      lethality did not correlate with previous results regarding pathogenicity of
      these same six isolates in SPF broiler chickens.

PMID- 10396650
TI  - Erysipelas in a free-ranging Hawaiian crow (Corvus hawaiiensis).
AB  - We describe a case of erysipelas in a free-ranging endangered Hawaiian crow. The
      partially scavenged carcass exhibited gross emaciation and petechial hemorrhages
      in both lungs. Microscopy revealed multiple necrotic foci associated with gram
      positive rods in the liver and adrenal, diffuse acute proximal tubular necrosis
      of kidney, diffuse necrosis and inflammation of proventricular mucosa associated
      with gram-positive rods, and multiple intravascular aggregates of gram-positive
      rods associated with thrombi. Culture of the kidney revealed the bacterium to be
      Erysipelothrix rhusiopathiae. The implications of this finding to free-ranging
      crows remain unclear.

PMID- 10396651
TI  - An outbreak of histomoniasis in turkeys infected with a moderate level of
      Ascaridia dissimilis but no Heterakis gallinarum.
AB  - Histomoniasis was diagnosed in a commercial turkey flock. All morbidity and
      mortality occurred in one house. Birds exhibited lesions characteristic for
      histomoniasis, and the diagnosis was confirmed by histopathologic examination.
      Affected turkeys were infected with moderate levels of Ascaridia dissimilis but
      not Heterakis gallinarum. Compression smears of hepatic tissues showed typical
      histotrophic phase Histomonas meleagridis, whereas cecal smears exhibited large
      numbers of Trichomonas gallinarum. A challenge experiment was conducted in which
      turkey poults were placed on contaminated litter. Although histomoniasis was not
      reproduced in the experiment, the birds did become infected with low numbers of
      A. dissimilis.

PMID- 10396653
TI  - Needle-stick injuries and HIV infection.

PMID- 10396652
TI  - Exotic Newcastle disease in a game chicken flock.
AB  - A sudden increase in mortality, preceded by a short history of respiratory signs
      and diarrhea, occurred in a backyard flock of 48 game chickens in the Central
      Valley of California. Necropsy findings included severe generalized linear
      hemorrhages and/or ulcers in the digestive tract, larynx, and trachea. Histology
      revealed severe multifocal hemorrhages and necrosis in the mucosa of the
      respiratory and digestive tracts, vasculitis, and necrosis of lymphoid tissue.
      The birds were serologically negative to Newcastle disease virus; this was
      consistent with an acute infection. The avian paramyxovirus type 1 isolated was
      characterized as velogenic viscerotropic Newcastle disease virus. A thorough
      epidemiologic investigation was carried out, and no other premises were found to
      have birds with clinical signs or evidence of exposure. The entire outbreak was
      limited to the original backyard flock and resolved within 14 days of the onset
      of clinical signs.

PMID- 10396654
TI  - Update in cornea and external disease: solving the mystery of "sands of the
      Sahara" syndrome (diffuse lamellar keratitis).

PMID- 10396655
TI  - Needle-stick injuries and HIV infection: a surgeon's personal experience and
      review of postexposure prophylaxis. St. Paul's Ocular AIDS Group.

PMID- 10396656
TI  - Corneal endothelial deposits in patients with HIV infection or AIDS:
      epidemiologic evidence of the contribution of rifabutin.
AB  - BACKGROUND: We noted a number of patients with unusual fine, stellate corneal
      endothelial deposits. The distribution of the deposits appeared to be concentric,
      involving mostly the periphery. We postulated that the changes might be related
      to the use of rifabutin rather than to cytomegalovirus (CMV) retinitis. We
      conducted a study among patients infected with HIV to assess the factors
      associated with these corneal changes. METHODS: All patients with HIV infection
      or AIDS who presented to an ocular AIDS clinic in Vancouver between May 16 and
      July 4, 1996, were examined for the presence of corneal endothelial deposits. The
      clinical history was noted in a masked fashion. RESULTS: Of the 162 patients
      examined, 25 showed fine, diffuse, white, stellate corneal endothelial deposits
      occurring predominantly in the periphery. The presence of the deposits was
      associated with rifabutin use (odds ratio 5.6, 95% confidence interval 2.5 to
      12.9) independent of the presence of CMV retinitis, the CD4 count, the presence
      of uveitis and use of other medications. INTERPRETATION: Corneal endothelial
      deposits found in patients with HIV infection are associated with rifabutin use
      independent of the presence of CMV retinitis. The deposits should be monitored to
      determine their clinical significance.

PMID- 10396657
TI  - The prognosis of amaurosis fugax and hemispheric transient ischemic attacks.
AB  - BACKGROUND: The natural history of amaurosis fugax and of hemispheric transient
      ischemic attacks (TIAs) may be different. We analysed the ischemic risk factors,
      carotid status and prognosis with respect to future ischemic events in a cohort
      of patients who presented with either of these transient ischemic episodes.
      METHODS: The charts of patients who presented to our institution between February
      1983 and April 1995 with amaurosis fugax or hemispheric TIAs were reviewed.
      Patients under the age of 45 years with a history of migraine or previous carotid
      surgery were excluded. Follow-up by a clinical visit or telephone interview was
      performed. Information was obtained regarding demographic features, presenting
      symptoms, ischemic risk factors, carotid status (as measured by duplex
      ultrasonography), type of medical treatment prescribed and occurrence of
      subsequent ischemic events. Outcome ischemic events were graded as major
      (myocardial infarction, cerebrovascular accident or death due to either of these)
      or minor (recurrent amaurosis fugax or hemispheric TIA). RESULTS: A total of 141
      patients were followed for a mean of 47 months. Risk factors were more prevalent
      in patients with hemispheric TIAs than in those with amaurosis fugax. Most
      patients had a low degree of carotid stenosis. There was no statistically
      significant difference in the occurrence of major outcome events between the two
      groups. Kaplan-Meier survival curves were similar for the two groups.
      INTERPRETATION: Amaurosis fugax and hemispheric TIA both carry a risk for future
      ischemic events. However, we did not find a statistically significant difference
      in prognosis between the two groups.

PMID- 10396658
TI  - Use of topical steroid therapy in the management of nonnecrotizing anterior
      scleritis.
AB  - BACKGROUND: Nonnecrotizing anterior scleritis may be treated with a variety of
      therapies, including topical steroid therapy, systemic therapy with nonsteroidal
      antiinflammatory drugs (NSAIDs) and systemic steroid therapy. This study was
      carried out to determine the efficacy of topical steroid therapy in treating
      diffuse and nodular scleritis. METHODS: A phase I/II descriptive study was
      conducted. Thirty-two consecutive patients with nonnecrotizing anterior scleritis
      referred to a tertiary care ophthalmology cornea and uveitis practice in Ottawa
      were enrolled between September 1995 and February 1997. The patients received 1%
      prednisolone acetate, administered topically every 2 hours for at least 2 weeks.
      The drug was tapered off thereafter based on the clinical response. A successful
      treatment outcome was defined as resolution of scleritis without the need for
      systemic steroid or NSAID therapy by 2 months after initial presentation.
      RESULTS: The 2-month success rate was 47%. Of the 17 patients in whom treatment
      failed, 5 (29%) still had some evidence of scleritis at 2 months despite systemic
      treatment with steroids. There was no difference between the two groups in the
      rate of first recurrence of scleritis (log-rank test). INTERPRETATION: Although
      topical steroid therapy failed in over half of the patients, a significant number
      were spared systemic steroid therapy with its potential side effects. Despite the
      moderately high failure rate, topical steroid therapy could be considered as
      first-line treatment for nonnecrotizing anterior scleritis, especially in cases
      in which the likelihood of complications from systemic steroid or NSAID therapy
      is high.

PMID- 10396659
TI  - Glaucoma secondary to topical use of steroid cream.

PMID- 10396660
TI  - Ocular Munchausen's syndrome, a costly disorder.

PMID- 10396661
TI  - Saccharomyces keratitis and endophthalmitis.

PMID- 10396662
TI  - Surgical correction for complete cryptophthalmos: case report and review of the
      literature.

PMID- 10396663
TI  - Functionally significant versus intriguingly different coronary artery anatomy:
      anatomo-clinical correlations in coronary anomalies.

PMID- 10396664
TI  - Myocardial revascularization without cardiopulmonary bypass.

PMID- 10396665
TI  - Left ventricular opacification by intravenous contrast echocardiography.
AB  - BACKGROUND: The present study was undertaken in order to evaluate the efficacy of
      the intravenous administration of Albunex in obtaining left ventricular
      opacification and the relationship between left ventricular opacification and
      pulmonary pressures and cardiac function. METHODS: Fifty-two adult patients,
      mostly affected by ischemic heart disease, were enrolled in the study. In 37 of
      these patients, a complete right heart hemodynamic study was performed after Swan
      Ganz catheterization. Albunex was administered in three randomized doses (0.10,
      0.15 and 0.20 ml/kg) to all the patients. Left ventricular opacification was
      assessed both visually and using videodensitometric analysis. RESULTS: Left
      ventricular opacification was obtained in 93% of all the injections and an
      intermediate or strong opacification was obtained in 68%, while absent
      opacification was observed in 6% of the injections, irrespective of the contrast
      dose. An incremental opacification efficacy trend was observed from the lower to
      the higher dose, with an intermediate or strong opacification in 58 and in 77% of
      0.10 and 0.20 ml/kg injections, respectively. Irrespective of the contrast dose,
      an enhancement of the endocardial borders was observed in 61% of the wall
      segments suboptimally visualized in basal conditions. The endocardial borders
      enhancement was obtained in 39 and in 79% of segments using the 0.10 and the 0.20
      ml/kg doses, respectively. No statistically significant differences were observed
      between the videodensitometric parameters obtained using the three contrast
      doses. Finally, a significant relationship was observed between left ventricular
      opacification parameters and pulmonary pressures and left ventricular functional
      parameters, irrespective of the contrast doses considered. CONCLUSIONS: The
      results we obtained demonstrate the good overall efficacy of Albunex administered
      intravenously in order to obtain left ventricular opacification in a clinical
      population of cardiac patients. Moreover, they suggest that the dosage to be used
      clinically should preferably be at least 0.20 ml/kg, although no significant
      influence of contrast dosage on videodensitometric parameters has been observed.
      Finally, irrespective of the contrast dosage, the magnitude of left ventricular
      opacification appears to be influenced by the hemodynamic status of the patient.

PMID- 10396666
TI  - Safety and feasibility of coronary stenting during rescue PTCA: in-hospital
      outcome.
AB  - BACKGROUND: Rescue PTCA is still a debatable procedure and the results published
      in the literature may not justify routine application of this strategy. AIM: To
      evaluate the hospital outcome of patients undergoing rescue PTCA with the aim of
      achieving a complete recanalization of the infarct-related artery (IRA)--residual
      stenosis assessed with QCA < 30% and TIMI 3 forward flow--obtained with adjuvant
      coronary stenting when needed. METHOD: From April 1993 to December 1997, 59
      consecutive patients underwent rescue PTCA after thrombolysis failure (SK or
      front-loaded r-tPA, UK) within 6 hours of chest pain onset. All patients had a
      pre-procedure TIMI 0-1 flow. IRA was the right coronary artery in 23 cases (39%),
      the left anterior descending in 26 (44%), the left circumflex in 9 (15.3%) and a
      saphenous vein graft in 1 case (1.7%). In 2 (3.3%) patients, PTCA was not
      performed (impossibility of crossing the stenosis with the guide-wire). Fifteen
      patients (26.3%) had a successful procedure (TIMI 3 flow, residual stenosis <
      30%) with lone PTCA. Forty-two patients (73.6%) had an intracoronary stent placed
      (Palmaz-Schatz, Micro-Stent, Multilink, IRIS III): 24 patients (57.1%) for
      suboptimal angiographic result (TIMI 2 flow, residual stenosis > 30%), 11
      patients (26.2%) for dissection, 7 patients (16.7%) for intracoronary thrombosis.
      All 57 patients had a TIMI 3 flow and a residual stenosis < 30% at the end of the
      procedure. Mean vessel diameter was 3.22 +/- 0.4 mm, mean balloon size 3.3 +/-
      0.4 mm, mean inflation pressure 12 +/- 4 atm, mean residual stenosis 8 +/- 9%.
      RESULTS: The overall procedure success rate was 96.6%. During hospitalization,
      three patients (5.1%) suffered subacute reocclusion managed conservatively in one
      case, with CAGB in another and with re-PTCA in the last one. Three patients
      (5.1%) had minor vascular complications (groin hematoma) not requiring surgical
      correction or blood transfusion. No patients died, suffered reinfarction or
      stroke. All patients were discharged alive and free of angina or clinical heart
      failure. CONCLUSIONS: Coronary stenting performed in the setting of rescue PTCA
      leads to a good procedural success rate allowing TIMI 3 flow and low residual
      stenosis (< 30%). Therefore, when conventional balloon angioplasty is unable to
      achieve an optimal angiographic result, stenting can be accomplished safely,
      thereby improving the procedural success rate and allowing a bright event-free
      survival rate.

PMID- 10396667
TI  - Mortality and cause of death in patients with chronic non-rheumatic atrial
      fibrillation after a two-year follow-up.
AB  - BACKGROUND: Non-rheumatic atrial fibrillation (NRAF) is a very common arrhythmia
      but its role in the prognosis and cardiovascular mortality is controversial. In
      particular, cause and predictors of death are not completely known. METHODS: We
      analyzed the cause of death and the possible predictors of cardiovascular
      mortality in 664 outpatients (mean age 72 +/- 9 years old) enrolled in the
      "Trieste Area Study on Non-Rheumatic Atrial Fibrillation" (TASAF), a prospective
      community study, after a follow-up of 27 +/- 9 months. The mean duration of the
      arrhythmia at enrollment was 59 months (range 1-360 months). Only 42 patients
      (6.3%) were on anticoagulants by general practitioners and 205 (30.8%) were on
      antiplatelet drugs. RESULTS: Of these patients, 110 (16.5%) died: 28 (25.5%) due
      to a cerebral or peripheral thromboembolism, 10 (8.2%) of sudden death, 46
      (42.7%) of expected cardiac death and 25 (22.7%) of non-cardiac causes. In one
      patient, the cause of death was uncertain. Sixty-nine patients underwent
      postmortem examination. In univariate analysis, left ventricular dysfunction (p =
      0.03) and an enlarged left atrium (p = 0.03) proved to be directly related to
      increased cardiovascular mortality. Both in univariate and Cox proportional
      hazards model analysis, aging (odds ratio 1.09, IC 95% 1.05-1.12, p = 0.00001),
      history of heart failure (odds ratio 1.27, IC 95% 1.01-1.60, p = 0.036),
      cardiomegaly (odds ratio 1.35, IC 95% 1.01-1.81, p = 0.040), diabetes mellitus
      (odds ratio 1.35, IC 95% 0.99-1.84, p = 0.058) and previous myocardial infarction
      (odds ratio 1.56, IC 95% 1.20-2.03, p = 0.0007) were all independent risk factors
      for cardiovascular mortality. A history of cerebral or systemic embolism (23
      versus 12%, p = 0.09) and, above all, one or more recurrences before enrollment
      (11 versus 2.3%, p = 0.04), were associated with embolic mortality. CONCLUSIONS:
      Patients with NRAF have an increased risk of cardiovascular death. Aging, the
      presence of diabetes, cardiomegaly on chest x-ray, heart failure and a previous
      myocardial infarction were independent risk factors for cardiovascular mortality.
      A history of embolism at enrollment significantly conditioned the embolic
      mortality rate but above all, embolic events during follow-up determined a very
      high percentage of total deaths (25.5% of all causes). A proper anticoagulant
      therapy should strongly be advised to all patients with no contraindications.

PMID- 10396668
TI  - Is the shortening of the QTc interval in Q-wave leads showing ST segment shift
      during exercise testing a new ECG marker of myocardial ischemia and viability in
      patients with previous anterior myocardial infarction?
AB  - PURPOSE: To evaluate whether the shortening of the QTc-interval, measured in Q
      wave leads showing ST segment elevation during exercise testing may be a marker
      of stress-induced transmural ischemia (and indirectly of myocardial viability) in
      the infarct zone in patients with prior Q-wave anterior myocardial infarction.
      METHODS: We evaluated 15 consecutive patients (Group A) with previous anterior
      myocardial infarction presenting these peculiarities: 1) ST segment elevation
      over Q waves during exercise testing; 2) critical (> 75%) stenosis of LAD; 3)
      evidence by echocardiography and stress-redistribution-reinjection 201thallium
      myocardial scintigraphy (SRR201TIMS) of viable myocardium in the infarct zone
      (akinetic segments with normal echo-reflectivity plus > 7 mm end-diastolic wall
      thickness and significant 201thallium redistribution after reinjection). The
      study control group (Group B) consisted of 15 patients with previous myocardial
      infarction, critical stenosis of LAD and evidence of scarring by imaging
      techniques (increased echo-reflectivity associated with an end-diastolic wall
      thickness < 6 mm and no 201thallium redistribution in infarcted areas). The QTc
      interval was measured at rest and at peak stress in all leads, and particularly
      in infarct-related leads showing ST-T changes, and the lead-by-lead fractional
      difference percentage between the QTc intervals (delta QTc) was calculated. The
      delta QTc was measured again during exercise testing in 11 patients from Group A
      (Group A1) who showed significant contractility recovery three months after
      complete myocardial revascularization. A delta QTc shortening < -10% was
      considered "significant". RESULTS: In 14/15 patients from Group A, a significant
      delta QTc shortening was measured, while in 14/15 patients from Group B no
      significant delta QTc shortening was detected (sensitivity = 93.3%; specificity =
      93.3%) (p < 0.0001). The mean delta QTc in Group A was -18.1 +/- 8.5%; the mean
      delta QTc in Group B was -4.2 +/- 7.8% (p < 0.0001). No patient from Group A1
      showed a significant delta QTc shortening in Q-wave leads (mean delta QTc group
      A1 = +6.9 +/- 14.8%). CONCLUSIONS: delta QTc shortening in infarct-related leads
      during exercise testing is a simple ECG marker of transmural ischemia and,
      indirectly, of myocardial-viability. This sign is no more evident after
      myocardial revascularization and may be useful in identifying "hibernating
      myocardium".

PMID- 10396670
TI  - [Heart rupture in acute myocardial infarct: the advantages of using M-2D color
      Doppler echocardiography in a coronary intensive therapy unit].
AB  - BACKGROUND: Free-wall rupture of the heart is the second most common cause of
      death in acute myocardial infarction (AMI), following pump failure. Acute rupture
      is more common and rapidly fatal, while subacute rupture, which accounts for
      about 30% of total cases of mortality in AMI, can be diagnosed early by clinical
      signs with the support of echocardiography in coronary intensive care units.
      METHODS: From March 1996 to December 1997, 293 patients diagnosed with acute
      myocardial infarction were admitted to the coronary intensive care unit of our
      hospital. Of these patients, 71 (23.8%) were treated with thrombolysis within 6
      hours of onset of symptoms. All patients were observed daily with M-2D color
      Doppler echocardiography and in the event of renewed chest pain,
      electrocardiogram changes, abrupt hypotension, syncope or clinical signs of low
      output syndrome. RESULTS: We observed 11 cases (3.8%) of free-wall rupture of the
      heart in acute myocardial infarction with echocardiography, 6 females and 5
      males, with a mean age of 74.2 +/- 7.8 years (min. 56-max 84), none of whom had
      prior AMI. Six of them received thrombolytic therapy, six were hypertensive
      (54.5%) and three were diabetics (27.2%). Surgical repair was performed in two
      patients with subacute rupture, but one died a few days later. The
      echocardiography data at bedside for diagnosis of cardiac rupture were confirmed
      in 5 patients with autopsy and intraoperatively in two of them. CONCLUSIONS:
      Routine use of echocardiography in coronary intensive care units allows prompt
      diagnosis of cardiac rupture in acute myocardial infarction, and in the event of
      subacute rupture it can accelerate surgical decision-making.

PMID- 10396669
TI  - [Coronary disease in patients with an abdominal aortic aneurysm].
AB  - The presence of coronary artery disease (CAD) evaluated with coronary angiography
      and eventual correction of CAD in abdominal aortic aneurysm (AAA) patients has
      been considered the main determinant of early and late outcome after AAA repair.
      This study reports our experience in CAD and AAA patients in terms of diagnosis
      and therapy of CAD. In a population of 126 patients (122 males, 4 females, mean
      age 67.5 years, range 37-81) who were candidates to elective repair for AAA with
      a diameter > or = 5 centimeters, we included coronary arteriography in 1)
      patients who were symptomatic for angina (15.9%); 2) patients with previous
      myocardial infarction (33.3%); 3) patients with previous coronary artery bypass
      (4%). We identified a group of 45 patients (35.7%) with significant CAD who had
      been treated before AAA surgery by coronary artery bypass grafting (CABG) in 37
      cases or percutaneous coronary angioplasty (PTCA) in 8 cases. AAA repair was
      performed during the same hospital stay or at a later date. We did not report any
      morbidity and mortality related to cardiac or vascular procedures. We believe
      that among patients reporting cardiac symptoms (previous myocardial infarction,
      angina) the incidence of surgically-correctable CAD is not negligible (45/67,
      67.2%). Therefore, invasive coronary study is strongly suggested in such cases to
      reveal and treat an eventual coronary artery stenosis prior to AAA repair. The
      absence of cardiac morbidity and mortality related to cardiac and vascular
      procedures supports this approach.

PMID- 10396671
TI  - [Variation in the evoked ventricular potentials after the implantation of an
      endocardiac catheter; the correlation with stimulation thresholds].
AB  - BACKGROUND: The drop in T wave amplitude of the ventricular pace-evoked response
      (VER) is a well-recognized and reliable mean of detecting localized conditions of
      myocardial hypoxia. In patients who undergo pacemaker implantation, the post
      implant change at the electrode-tissue interface consists of an early
      inflammatory reaction. The aim of this study was to establish whether the extent
      of the inflammatory reaction following an endocardial lead can be assessed by the
      changes in the T wave amplitude of VER. METHODS: Modifications in VER amplitude
      and the correlation between these changes and pacing threshold time-course were
      evaluated in 30 patients receiving an endocardial catheter. Telemetered
      endocardial recordings of T wave amplitude and pacing thresholds were measured at
      the time of implant and after 1, 2, 3, 7, 14 and 30 days. RESULTS: A biphasic
      time-course was observed for T wave, characterized by reduction in amplitude of
      48% (p < 0.005) from baseline at day 3 and subsequent increment up to 84% (p =
      ns) of the baseline value at day 30. By using a linear regression analysis, a
      significant correlation between T wave changes and increment in pacing threshold
      was found (r = 0.81; p < 0.002). A higher pacing threshold increment was observed
      in patients having a decrease in VER amplitude > or = 1 mV at 3rd in comparison
      with patients with a decrease in VER amplitude < 1 mV (1.1 +/- 0.4 vs 0.2 +/- 0.2
      V; p < 0.001). CONCLUSIONS: VER recordings during the first days after
      endocardial lead implantation may be a valuable means of assessing the extent of
      the inflammatory reaction developing at the electrode-tissue interface. This
      method may be useful for early identification of patients at risk of increases in
      pacing threshold and for evaluation of the biocompatibility of different leads.

PMID- 10396673
TI  - The influence of socioeconomic status on cardiovascular diseases.
AB  - In the first half of this century, cardiovascular diseases were more prevalent in
      individuals belonging to the richest social class. Later on, their prevalence
      became higher in individuals belonging to the lowest socioeconomic level. In
      developed countries, this phenomenon is common and independent of traditional
      risk factors. This paper reviews some factors claimed to explain the differences
      due to social class: eating habits, living condition at birth and during
      childhood (the Forsdahl-Baker hypothesis), the genetic susceptibility of the
      population, self-perceived health as a consequence of the social hierarchy. These
      factors, beyond the traditional risk factors, may explain the independent role of
      socioeconomic status on cardiovascular diseases development.

PMID- 10396672
TI  - [QT dispersion in insulin-dependent diabetics].
AB  - BACKGROUND: The measurement of the dispersion of the QT interval reflects
      regional repolarization differences in the heart which in turn can elicit the
      onset of arrhythmias by means of re-entry mechanism. Therefore, inter-lead QT
      dispersion has been proposed as novel indicator of arrhythmogenic risk that can
      predict severe ventricular arrhythmias or sudden death. The present study was
      conducted to evaluate QT dispersion in diabetic insulin-dependent patients with
      autonomic neuropathy. METHODS: We recruited three groups of 10 patients with the
      same age, sex, body weight distribution: 1) group DAN+ (diabetics with
      neuropathy); 2) group DAN- (diabetics without neuropathy); and 3) group CTRL
      (healthy control group). The patients underwent two-dimensional color-Doppler
      echocardiography and 12-lead electrocardiogram, 25 and 50 mm/s paper speed (gain
      10 mm/mU). The QTc dispersion was determined as the difference between the
      maximum and the minimum value of the QTc interval in different leads of the ECG
      recording. QT interval was corrected (QTc) by heart rate according to the
      Bazett's formula. Cardiovascular autonomic function was evaluated by Ewing's
      tests (heart rate and blood pressure measurement during lying to standing, deep
      breathing, hand-grip isometric stress test and Valsalva's maneuver). RESULTS: QT
      dispersion was significantly greater (p < 0.01) in the patients with autonomic
      neuropathy (51 +/- 10 ms) than in the patients without autonomic neuropathy (29
      +/- 6 ms) or in healthy control subjects (26 +/- 5 ms). CONCLUSIONS: Our data
      suggest that diabetic neuropathy, associated with an increased QT dispersion,
      shows a higher risk for serious ventricular arrhythmias and sudden cardiac death.

PMID- 10396675
TI  - [Cardiovascular risk and social classes: a comparison between adult female
      populations in rural and urban areas].
AB  - The distribution of cardiovascular risk factors and the prevalence of several
      risk conditions are analysed in two female cohorts in southern-central Italy, one
      living in an urban area (the city of Naples) and the other in a rural area (the
      province of Latina). Analysis of different social classes identified through the
      level of education was also performed. The distribution of risk factors is
      different in the two areas (body mass index, systolic and diastolic blood
      pressure are higher in the province of Latina, while serum total and HDL
      cholesterol are higher in Naples) as well as the prevalence of several risk
      conditions (the prevalence of hypertension is higher in the province of Latina,
      whereas hypercholesterolemia and smoking are more prevalent in Naples).
      Cardiovascular risk factors are unevenly distributed in the different social
      classes: body mass index and systolic and diastolic blood pressure decrease as
      the educational level increases in both cohorts; in the city of Naples, serum
      total and HDL cholesterol increase with the increase in educational level. An
      awareness of these differences is crucial to targeting primary prevention
      campaigns in specific social classes.

PMID- 10396674
TI  - [Social inequalities in the mortality due to cardiovascular diseases in Italy].
AB  - Social inequalities in cardiovascular disease mortality are described in this
      paper focusing on the results of the Studio Longitudinale Torinese (SLT), an
      investigation that links census data with the statistical data that are currently
      available. The overall results confirm that cardiovascular disease mortality is
      higher in less-advantaged socioeconomic groups, irrespectively of the social
      indicator used: education, social class, housing quality, job security.
      Stratified data shows less important inequalities among ischemic heart disease as
      compared to cerebrovascular mortality. The differences are even more complex when
      the age groups in the two genders are analyzed, revealing cohort effects.
      Overall, the results agree with the previous survey carried out by ISTAT on 1981
      Italian mortality, which confirmed the variations in inequalities according to
      geographical areas, gender and age. Differences in access to the health system
      are likely to be related to the differences detected for geographical areas,
      while differences in personal history and attitude towards health-associated
      behavior should explain age and gender variations in inequalities. Equity must be
      included in the evaluation of preventive programs and health-care models.
      Epidemiological and social research should be encouraged to better understand the
      factors that influence inequalities in cardiovascular disease mortality and in
      the health status of the population at large.

PMID- 10396676
TI  - [Socioeconomic indicators and mortality for ischemic cardiopathy in the RIFLE
      population. The RIFLE Group. Risk Factors and Life Expectancy].
AB  - The aim of this paper was to evaluate the relationship between socioeconomic
      indicators (education, occupation and residence) and short-term CHD mortality in
      an Italian population sample. Socioeconomic indicators and major CHD risk factors
      (BMI, SBP, DBP, TOT-CH, HDL-CH and TRIG) were measured in 15,315 males aged 40-69
      years; mortality data by cause were collected for the next six years. CHD
      mortality risk ratio (RR) in the different educational and occupational levels
      and by residence was computed by Cox proportional hazards models. The association
      between socioeconomic indicators and CHD risk factors was explored by covariance
      and logistic regression analysis. After six years, 632 men died, 181 of whom
      because of coronary fatalities. No association with educational level was found
      for CHD mortality (RR = 1.00 high, 0.69 intermediate, 0.92 low), nor did
      occupational level show a significant association. Urban vs rural residence (RR =
      1.00) showed a RR for CHD mortality of 1.35. Adjustment for bio-behavioral risk
      factors did not change the above results; only mortality for CHD of urban vs
      rural residents increased (RR = 1.63, p < 0.003). By considering the interaction
      between schooling and occupation, it was found that education appropriated to
      occupational level was a protective factor. The study does not indicate any
      association between education/occupational level and CHD mortality in male RIFLE
      population samples. The mean level of major CHD risk factors within different
      educational/occupational levels supports these results. Status incongruity as
      well as residence in an urban environment proved to be risk conditions for CHD
      mortality.

PMID- 10396678
TI  - [Idiopathic left fascicular ventricular tachycardia: the evidence for a
      "bystander" bundle of His participation].
AB  - Idiopathic left ventricular tachycardia is a rare arrhythmia whose
      electrophysiological basis is not yet well-defined. We report a case of
      idiopathic left ventricular tachycardia caused by a reentrant circuit limited
      exclusively to the two fascicles of the left bundle branch.

PMID- 10396677
TI  - [Myocardial infarct with ST segment depression: an absolute contraindication to
      thrombolytic therapy?].
AB  - The benefit of thrombolytic reperfusion has been demonstrated widely in patients
      who present with ST segment elevation and develop myocardial infarction. Instead,
      the role of thrombolytic therapy in patients who present with ST segment
      depression and develop myocardial infarction is still unresolved. The purpose of
      this paper is to review the literature on the subject and give rise to
      reconsideration of thrombolytic therapy in this subgroup of patients who are
      usually excluded from receiving thrombolytic agents because of the absence of
      indications and the presence of contraindications.

PMID- 10396679
TI  - [OTTO: the Intra-Hospital Organization of and Time to the Treatment of Acute
      Myocardial Infarct. A regional multicenter observational study. ANMCO Regionale
      Piemonte e Valle d'Aosta].

PMID- 10396680
TI  - Pathomorphological aspects of arrhythmogenic right ventricular cardiomyopathy.

PMID- 10396681
TI  - [Echocardiography in the localization of the anomalous pathway in ventricular pre
      excitation. Technics, usefulness and limits].

PMID- 10396682
TI  - [The biochemical markers of myocardial damage. The Intersociety Interdisciplinary
      Study Group of the ANMCO-SIBioC-SIMeL, Markers of Myocardial Lesions.
      Associazione Nazionale Medici Cardiologi Ospedalieri-SIBioC-Societa Italiana di
      Medicina di Laboratorio].

PMID- 10396684
TI  - [A forum on forensic cardiology?].

PMID- 10396683
TI  - Severe non-obstructive hypertrophic cardiomyopathy in a pediatric patient.

PMID- 10396686
TI  - [Antimicrobial activities of beta-lactam antibiotics against clinically isolated
      Haemophilus influenzae].
AB  - Antimicrobial activities of oral beta-lactam antimicrobial agents against
      clinically isolated 131 strains of Haemophilus influenzae were studied. The peak
      of MICs of ampicillin (ABPC) was 0.20 microgram/ml. Those of cefaclor (CCL),
      cefotiam (CTM), cefteram (CFTM), cefpodoxime (CPDX), cefdinir (CFDN), cefditoren
      (CDTR), cefcapene (CFPN), and faropenem (FRPM) were 1.56, 0.39, 0.013, 0.05,
      0.20, 0.013, 0.013, and 0.39 microgram/ml, respectively. The antimicrobial
      activities of CFTM, CDTR and CFPN were superior to those of others. There was
      74.8% of ABPC-sensitive strains, of which the MICs were below 0.78 microgram/ml.
      The percentages of beta-lactamase-positive strains and beta-lactamase-negative
      ABPC-resistant H. influenzae (BLNAR) were 14.5% and 14%, respectively.

PMID- 10396685
TI  - [Survey of the sensitivities of clinical isolates to antibacterial agents (annual
      report)].
AB  - Research groups were formed in 21 institutions nationwide to investigate
      carbapenem resistance. The activities of various antibacterial agents,
      principally carbapenems, were tested against clinical isolates collected from
      these institutions. The broth microdilution method was used to determine the
      minimum inhibitory concentrations (MIC) of 17 antibacterial agents for 1,241
      strains of 11 bacterial species isolated at all institutions between October and
      December 1996. The results were as follows: Carbapenems exhibited strong
      antibacterial activities against MSSA and Streptococcus pneumoniae and showed low
      activities against MRSA. Their activities against Enterococcus faecalis were
      comparable to that of ampicillin and piperacillin. The carbapenems showed high
      activities against Haemophilis influenzae, Escherichia coli, Klebsiella
      pneumoniae. Enterobacter cloacae. Serratia marcescens and Bacteroides fragilis
      group. Their activities were greater than that exhibited by other beta-lactam
      antibacterial agents, but some resistant strains of Serratia marcescens were
      detected. The antibacterial activity of carbapenems against Pseudomonas
      aeruginosa was comparable to that of CAZ, and there were some resistant strains.

PMID- 10396687
TI  - [Susceptibilities of Enterococcus faecium, PRSP and MRSA to RP59500 and their
      correlations with those to other drugs].
AB  - Investigations on emergence of vancomycin-resistant Enterococcus faecium (VREF)
      which has recently been attracting attention, especially in the Western
      countries, have been conducted in Japan. A total of 1,239 isolates of E. faecium
      were collected from 19 institutions during the period of April 1995 and June
      1996, in the purpose of evaluating susceptibilities to variety of antimicrobial
      agents, including RP59500 and vancomycin (VCM), and detecting vancomycin
      resistant genes (van genes). Susceptibilities of penicillin-resistant
      Streptococcus pneumoniae (PRSP) and methicillin-resistant Staphylococcus aureus
      (MRSA) were also studied. As a result, 2 isolates of E. faecium were found to be
      moderately resistant to VCM showing MIC of 8 micrograms/ml though the final
      identification in species level and the detection of van genes by PCR method have
      not been completed. On the other hand there detected no MRSA nor PRSP showing
      moderately resistant or resistant to VCM. It was concluded that RP59500 and VCM
      possessed favorable activity against clinically isolated E. faecium, PRSP and
      MRSA. Among other species of enterococci, moderately resistant strains to VCM
      showing MIC of 8 micrograms/ml were detected; 10 isolates of E. gallinarum, 4 of
      E. casseliflavus and 2 of E. flavescens. In those isolates, vanC1 and vanC2 were
      detected by PCR, and vanB was also detected in a isolates of E. gallinarum
      simultaneously.

PMID- 10396688
TI  - [Epidemiological studies on drug-resistance patterns, coagulase types, and MRSA
      phage types of MRSA isolates during 1990-1994].
AB  - We examined drug-resistance patterns, coagulase types, and MRSA-phage types of
      125 MRSA strains isolated from clinical specimens during the period of January
      1990 and December 1994. No vancomycin-resistant strain was isolated. Twenty one
      antibiotics were divided into three classes, low-intermediate- and high-isolation
      frequency class, based on isolation frequencies of resistant strains.
      Minocycline, chloramphenicol, streptomycin, and imipenem were found to be
      included in low-isolation-frequency class (16.8-40%). In intermediate-isolation
      frequency class (45.6-62.9%), cefmetazole, amikacin, gentamicin, and tetracycline
      were included. Oxacillin, ampicillin, piperacillin, ceftizoxime, cefoperazone,
      cefazolin, erythromycin, oleandomycin, kitasamycin, clindamycin, kanamycin,
      tobramycin, and ofloxacin belonged to high-isolation-frequency class (97.6-100%).
      MIC90s of vancomycin and minocycline (1.56 and 25 micrograms/ml) were lower than
      that of other 13 drugs. Comparing medical ward with dental ward, imipenem-,
      gentamicin-, and minocycline-resistant strains at medical ward, chloramphenicol-
      and streptomycin-resistant strains at dental ward were isolated dominantly on
      each ward, MRSA isolates were classified to 39 types by drug-resistance patterns.
      The isolation frequencies of coagulase type II and type IV strains were 65.6% and
      29.6%, respectively. At dental ward, the isolation frequency of coagulase type IV
      strains was higher than that of coagulase type II strains during 1990-1992.
      However, coagulase type II strains were isolated considerably more than type IV
      strains during 1993-1994. By MRSA-phage typing, MRSA isolates were grouped into
      18 MRSA-phage types. One hundred and twenty five MRSA isolates were divided into
      56 types by using drug-resistance patterns, coagulase typing, and MRSA-phage
      typing. It was considered that such classification in combination of three
      methods is useful to make decision of epidemic by the same MRSA strain.

PMID- 10396689
TI  - [Clinical and bacteriological evaluation of ceftriaxone (CTRX) dosed once daily
      in children with community-acquired pneumonia].
AB  - Clinical and bacteriological evaluation was performed as follows on ceftriaxone
      (CTRX) at a dose of 50 mg/kg once daily to pediatric patients with community
      acquired pneumonia. Of 48 subject patients, CTRX was markedly effective in 36
      (75.0%), effective in 9 (18.7%), slightly effective in 2 (4.2%), and failure in 1
      (2.1%), indicating the overall effective rate of 93.7%. In 47 (97.9%) patients
      with the exception of 1, it was observed during the period of administration that
      fever was resolved and clinical symptoms as well as radiographically abnormal
      shadows were found relieved or improved. Patients infected by an isolated strain
      accounted for 34 (70.8%), while those by multiple strains 14 (29.2%), indicating
      that either Streptococcus pneumoniae or Haemophilus influenzae, or both were
      detected in almost all patients (45 cases). Of the 48 patients, bacteriological
      effect was eliminated in 44 (91.7%), and replacement of the bacteria in the
      remaining 4 (8.3%). MIC90 of CTRX against detected bacteria was 0.2 microgram/ml
      with H. influenzae, < or = 0.025 microgram/ml with PSSP, 0.1 microgram/ml with
      PISP, and 0.39 microgram/ml with PRSP. Blood concentration of CTRX at 50 mg/kg
      upon completion of 1-hour drip intravenous infusion was 89.7 +/- 25.2
      micrograms/ml, and 6.6 +/- 0.9 micrograms/ml at 24 hours after the completion,
      indicating that the concentrations had been well above the levels of MIC90
      throughout the 24 hours. Abnormal symptoms, which were most likely adverse drug
      reactions, were not observed in any patients, and no abnormal changes were noted
      in patients, whose clinical lab values were taken before or after the
      administration. Situations may differ by region in Japan, however, infants under
      3 are generally exempted from medical payment regardless of inpatients or
      outpatients. When hospitalized, psychological burden upon pediatric patients
      without guardians attended must be enormous. If they are over 3, there is a
      difference in medical costs between inpatients and outpatients, with greater
      economic burden on inpatients. Thus, it was considered worth attempting the
      outpatient treatment as one of new therapies for community-acquired pneumonia,
      though the outpatient treatment should not be encouraged without due
      consideration. Based on these results, CTRX dosed once daily to pediatric
      patients with community-acquired pneumonia is clinically and bacteriologically
      superior in usefulness. Further review may be necessary, however, it is
      considered that outpatient treatment can also serve as one of the options, if
      safety of once-a-day administration of CTRX can be established.

PMID- 10396690
TI  - [A consideration on the results of nationwide surveillance of antimicrobial
      susceptibilities--gram-negative bacilli].
AB  - The results of the semi-annual nationwide surveillance of antimicrobial
      susceptibilities, conducted by the Japanese Ministry of Health and Welfare during
      the period of January 1993 to July 1995, were analyzed for typical Gram-negative
      bacilli in the purpose of provision of an index for antimicrobial selection.
      During these 3 years, Escherichia coli, Citrobacter freundii, Enterobacter
      aerogenes and Proteus mirabilis showed slightly increasing tendency in
      susceptibility to fosfomycin (FOM) and Citrobacter freundii. Klebsiella
      pneumoniae and Enterobacter aerogenes showed slightly increasing tendency to
      minocycline (MINO). While Haemophilus influenzae and Haemophilus parainfluenzae
      showed slightly decreasing tendency to cefmetazole (CMZ). However, these annual
      changes were almost negligible. Generally, these microorganisms showed relatively
      good susceptibilities, every year, to the principal antimicrobial agents being
      approved for use against Gram-negative bacilli. However, Enterobacter cloacae,
      Enterobacter aerogenes, Serratia marcescens and Pseudomonas aeruginosa showed
      tendencies of decreased susceptibility to some of the antimicrobial agents. On
      the other hand, sulfamethoxazole-trimethoprim (ST), CMZ, latamoxef (LMOX),
      gentamicin (GM) and amikacin (AMK) showed good activities against some of the
      Gram-negative bacilli to which no indications are approved. In conclusion,
      bedside the identification of the causative microorganisms and the performance of
      antimicrobial susceptibility testing, such analyses (graphics of susceptibility
      tendency of clinical isolates to variety of antimicrobial agents) could be used
      as an index for selection of antimicrobial agents, when emergent and urgent
      selection of antimicrobial agents is necessary.

PMID- 10396691
TI  - A numerical study of blood flow patterns in anatomically realistic and simplified
      end-to-side anastomoses.
AB  - PURPOSE: Recently, some numerical and experimental studies of blood flow in large
      arteries have attempted to accurately replicate in vivo arterial geometries,
      while others have utilized simplified models. The objective of this study was to
      determine how much an anatomically realistic geometry can be simplified without
      the loss of significant hemodynamic information. METHOD: A human femoral
      popliteal bypass graft was used to reconstruct an anatomically faithful finite
      element model of an end-to-side anastomosis. Nonideal geometric features of the
      model were removed in sequential steps to produce a series of successively
      simplified models. Blood flow patterns were numerically computed for each
      geometry, and the flow and wall shear stress fields were analyzed to determine
      the significance of each level of geometric simplification. RESULTS: The removal
      of small local surface features and out-of-plane curvature did not significantly
      change the flow and wall shear stress distributions in the end-to-side
      anastomosis. Local changes in arterial caliber played a more significant role,
      depending upon the location and extent of the change. The graft-to-host artery
      diameter ratio was found to be a strong determinant of wall shear stress patterns
      in regions that are typically associated with disease processes. CONCLUSIONS: For
      the specific case of an end-to-side anastomosis, simplified models provide
      sufficient information for comparing hemodynamics with qualitative or averaged
      disease locations, provided the "primary" geometric features are well replicated.
      The ratio of the graft-to-host artery diameter was shown to be the most important
      geometric feature. "Secondary" geometric features such as local arterial caliber
      changes, out-of-plane curvature, and small-scale surface topology are less
      important determinants of the wall shear stress patterns. However, if patient
      specific disease information is available for the same arterial geometry,
      accurate replication of both primary and secondary geometric features is likely
      required.

PMID- 10396692
TI  - Quantification of mitral regurgitation using corrected Doppler measurements.

PMID- 10396693
TI  - Catheter obstruction effect on pulsatile flow rate--pressure drop during coronary
      angioplasty.
AB  - The coupling of computational hemodynamics to measured translesional mean
      pressure gradients with an angioplasty catheter in human coronary stenoses was
      evaluated. A narrowed flow cross section with the catheter present effectively
      introduced a tighter stenosis than the enlarged residual stenoses after balloon
      angioplasty; thus elevating the pressure gradient and reducing blood flow during
      the measurements. For resting conditions with the catheter present, flow was
      believed to be about 40 percent of normal basal flow in the absence of the
      catheter, and for hyperemia, about 20 percent of elevated flow in the patient
      group. The computations indicated that the velocity field was viscous dominated
      and quasi-steady with negligible phase lag in the delta p(t)-u(t) relation during
      the cardiac cycle at the lower hydraulic Reynolds numbers and frequency
      parameter. Hemodynamic interactions with smaller catheter-based pressure sensors
      evolving in clinical use require subsequent study since artifactually elevated
      translesional pressure gradients can occur during measurements with current
      angioplasty catheters.

PMID- 10396694
TI  - An in vitro study of implant--tooth-supported connections using a robot test
      system.
AB  - Many unsolved problems in dental implant research concern the interfacial stress
      distributions between the implant components, as well as between the implant
      surface and contacting bone. To obtain a mechanical understanding of how vertical
      and horizontal occlusal forces are distributed in this context, it is crucial to
      develop in vitro testing systems to measure the force transmission between dental
      implants and attached prostheses. A new approach to such testing, involving a
      robotic system, is described in this investigation. The system has been designed
      to produce simulated mandibular movements and occlusal contact forces so that
      various implant designs and procedures can be thoroughly tested and evaluated
      before animal testing or human clinical trials. Two commonly used fixed
      prosthesis designs used to connect an implant and a tooth, a rigid connection and
      a nonrigid connection, were fabricated and used for experimental verification.
      The displacement and force distributions generated during simulated chewing
      activities were measured in vitro. Force levels, potentially harmful to human
      bone surrounding the connected dental implant and tooth, were analyzed. These
      results are useful in the design of prostheses and connecting components that
      will reduce failures and limit stress transfer to the implant/bone interface.

PMID- 10396695
TI  - Estimation of in vivo bone mineral density (BMD) and shape characterization for
      diagnosing osteoporosis by ultrasonic inspection.
AB  - A new method for estimating in vivo bone mineral density (BMD) and characterizing
      the shape of cancellous bone has been proposed using the results of ultrasonic
      inspection for the diagnosis of osteoporosis. The method is based on two
      dimensional bone area fraction S (percent bone area between bone and bone marrow)
      calculated from the difference in the speed of ultrasonic wave propagation
      through cancellous bone. It was shown that the two-dimensional area fraction of a
      heel bone gives a good relationship to the BMD by DXA (dual energy x-ray
      absorptiometry) testing of human heel bone (calcaneus) and spine (vertebrae
      lumbar), as expressed by the relation, BMD (g/cm2) = 0.0167S for heel bone (r =
      0.83), and BMD (g/cm2) = 0.0254S + 0.123 for the spine (r = 0.77). Shape
      characterization is based on the image simulation procedure employing eight
      random variables from a computer and the statistical results of fractal analysis
      for numerous cancellous bone patterns. We also demonstrate the validity of the
      shape characterization using autopsy specimens as a diagnostic tool for
      osteoporosis.

PMID- 10396696
TI  - Robust optimization of total joint replacements incorporating environmental
      variables.
AB  - Direct search techniques for the optimal design of biomechanical devices are
      computationally intensive requiring many iterations before converging to a global
      solution. This, along with the incorporation of environmental variables such as
      multiple loading conditions and bone properties, makes direct search techniques
      infeasible. In this study, we introduced new methods that are based on the
      statistical design and analysis of computer experiments to account efficiently
      for environmental variables. Using data collected at a relatively small set of
      training sites, the method employs a computationally inexpensive predictor of the
      structural response that is statistically motivated. By using this predictor in
      place of the simulator (e.g., finite element model), a sufficient number of
      iterations can be performed to facilitate the optimization of the complex system.
      The applicability of these methods was demonstrated through the design of a
      femoral component for total hip arthroplasty incorporating variations in joint
      force orientation and cancellous bone properties. Beams on elastic foundation
      (BOEF) finite element models were developed to simulate the structural response.
      These simple models were chosen for their short computation time. This allowed us
      to represent the actual structural response surface by an exhaustive enumeration
      of the design and environmental variable space, and provided a means by which to
      validate the statistical predictor. We were able to predict the structural
      response and the optimal design accurately using only 16 runs of the computer
      code. The general trends predicted by the BOEF models were in agreement with
      previous three-dimensional finite element computer simulations, and experimental
      and clinical results, which demonstrated that the important features of
      intramedullary fixation systems were captured. These results indicate that the
      statistically based optimization methods are appropriate for optimization studies
      using computationally demanding models.

PMID- 10396697
TI  - An analytical approach to determine the in situ forces in the glenohumeral
      ligaments.
AB  - The purpose of this study was to use an analytical approach to determine the
      forces in the glenohumeral ligaments during joint motion. Predictions from the
      analytical approach were validated by comparing them to experimental data. Using
      a geometric model, the lengths of the four glenohumeral ligaments were determined
      during anterior-posterior loading simulations and forward flexion-extension. The
      corresponding force in each structure was subsequently calculated based on length
      data via load-elongation curves obtained experimentally. During the anterior
      loading simulation at 0 deg of abduction, the superior glenohumeral ligament
      carried up to 71 N at the maximally translated position. At 90 deg of abduction,
      the anterior band of the inferior glenohumeral ligament had the highest force of
      45 N during anterior loading. These results correlated well with those found in
      previous experimental studies. We believe that this validated analytical approach
      can be used to predict the forces in the glenohumeral ligaments during more
      complex joint motion as well as assist surgeons during shoulder repair
      procedures.

PMID- 10396698
TI  - Prediction of antagonistic muscle forces using inverse dynamic optimization
      during flexion/extension of the knee.
AB  - This paper examined the feasibility of using different optimization criteria in
      inverse dynamic optimization to predict antagonistic muscle forces and joint
      reaction forces during isokinetic flexion/extension and isometric extension
      exercises of the knee. Both quadriceps and hamstrings muscle groups were included
      in this study. The knee joint motion included flexion/extension, varus/valgus,
      and internal/external rotations. Four linear, nonlinear, and physiological
      optimization criteria were utilized in the optimization procedure. All
      optimization criteria adopted in this paper were shown to be able to predict
      antagonistic muscle contraction during flexion and extension of the knee. The
      predicted muscle forces were compared in temporal patterns with EMG activities
      (averaged data measured from five subjects). Joint reaction forces were predicted
      to be similar using all optimization criteria. In comparison with previous
      studies, these results suggested that the kinematic information involved in the
      inverse dynamic optimization plays an important role in prediction of the
      recruitment of antagonistic muscles rather than the selection of a particular
      optimization criterion. Therefore, it might be concluded that a properly
      formulated inverse dynamic optimization procedure should describe the knee joint
      rotation in three orthogonal planes.

PMID- 10396699
TI  - Biomechanical studies of the rabbit patellar tendon after removal of its one
      fourth or a half.
AB  - Effects of the overstressing induced by the harvest of grafts from the patellar
      tendon on the mechanical properties and morphometry of remaining tendon were
      studied using a rabbit model. The width of the patellar tendon was reduced by one
      fourth or one-half equally removing the medial and lateral portions; by this
      surgery, the cross-sectional area was decreased by 25 or 50 percent from the
      original area. After all the rabbits were allowed unrestricted activities in
      cages for 3 to 12 weeks, their patellar tendons were harvested for mechanical and
      histological studies. The one-fourth removal induced no significant changes in
      the mechanical properties, but significantly increased the cross-sectional area.
      In the case of one-half removal, tensile strength and tangent modulus did not
      change in some tendons, although the cross-sectional area increased
      significantly. In the other central half tendons, mechanical strength decreased
      markedly, while the cross-sectional area increased; hypercellular areas and
      breakage of collagen bundles were observed in these tendons. These results
      indicate that the patellar tendon has an ability of functionally adapting to
      overstressing by changing the cross-sectional area, while keeping the mechanical
      properties unchanged, if the extent of overstressing is less than 30 percent.

PMID- 10396700
TI  - Extraction of quasi-linear viscoelastic parameters for lower limb soft tissues
      from manual indentation experiment.
AB  - A manual indentation protocol was established to assess the quasi-linear
      viscoelastic (QLV) properties of lower limb soft tissues. The QLV parameters were
      extracted using a curve-fitting procedure on the experimental indentation data.
      The load-indentation responses were obtained using an ultrasound indentation
      apparatus with a hand-held pen-sized probe. Limb soft tissues at four sites of
      eight normal young subjects were tested in three body postures. Four QLV model
      parameters were extracted from the experimental data. The initial modulus E0
      ranged from 0.22 kPa to 58.4 kPa. The nonlinear factor E1 ranged from 21.7 kPa to
      547 kPa. The time constant tau ranged from 0.05 s to 8.93 s. The time-dependent
      materials parameter alpha ranged from 0.029 to 0.277. Large variations of the
      parameters were noted among subjects, sites, and postures.

PMID- 10396701
TI  - A fibril-network-reinforced biphasic model of cartilage in unconfined
      compression.
AB  - Cartilage mechanical function relies on a composite structure of a collagen
      fibrillar network entrapping a proteoglycan matrix. Previous biphasic or
      poroelastic models of this tissue, which have approximated its composite
      structure using a homogeneous solid phase, have experienced difficulties in
      describing measured material responses. Progress to date in resolving these
      difficulties has demonstrated that a constitutive low that is successful for one
      test geometry (confined compression) is not necessarily successful for another
      (unconfined compression). In this study, we hypothesize that an alternative
      fibril-reinforced composite biphasic representation of cartilage can predict
      measured material responses and explore this hypothesis by developing and solving
      analytically a fibril-reinforced biphasic model for the case of uniaxial
      unconfined compression with frictionless compressing platens. The fibrils were
      considered to provide stiffness in tension only. The lateral stiffening provided
      by the fibril network dramatically increased the frequency dependence of disk
      rigidity in dynamic sinusoidal compression and the magnitude of the stress
      relaxation transient, in qualitative agreement with previously published data.
      Fitting newly obtained experimental stress relaxation data to the composite model
      allowed extraction of mechanical parameters from these tests, such as the
      rigidity of the fibril network, in addition to the elastic constants and the
      hydraulic permeability of the remaining matrix. Model calculations further
      highlight a potentially important difference between homogeneous and fibril
      reinforced composite models. In the latter type of model, the stresses carried by
      different constituents can be dissimilar, even in sign (compression versus
      tension) even though strains can be identical. Such behavior, resulting only from
      a structurally physiological description, could have consequences in the efforts
      to understand the mechanical signals that determine cellular and extracellular
      biological responses to mechanical loads in cartilage.

PMID- 10396702
TI  - Reduced gap strains induce changes in bone regeneration during distraction.
AB  - A bilateral New Zealand white rabbit model of distraction osteogenesis (DO) was
      used to investigate the relationship between strain environment and bone
      regeneration during limb lengthening. In seven (n = 7) rabbits, a stiffener was
      applied to the fixator on one side to reduce strains within the gap tissue after
      lengthening was completed. Animals were euthanized six days later and their
      distraction zones were harvested and analyzed for changes in new bone volume and
      architecture. Nonlinear finite element analyses (FEA) were performed to predict
      changes in the gap strain environment. FEA results predicted a nearly uniform
      sevenfold decrease in average strain measures within the distraction zone. No
      change in total average new bone volume and significant decreases in both bone
      volume fraction (BV/TV) and trabecular thickness (Tb.Th) were observed in tibiae
      in which gap strains were reduced experimentally, compared to contralateral
      controls. These results suggest that fixator stiffening influenced the
      architecture but not the amount of newly formed bone. This animal model of
      distraction might be used to study the mechanisms by which strain fields affect
      events in bone repair and regeneration, such as cell proliferation, precursor
      tissue differentiation, and altered growth factor and nutrient delivery to
      tissues.

PMID- 10396703
TI  - [Estimation of left internal thoracic artery flow reserve after coronary artery
      bypass grafting using Doppler flow wire].
AB  - The usefulness of the left internal thoracic artery (LITA) for aortocoronary
      bypass grafting is now established. Reports of variation in LITA graft function
      are rare. Graft flow was measured using a Doppler flow wire to estimate graft
      function in 27 patients (24 males, 3 females) who underwent LITA grafting to the
      left anterior descending artery. Patients were classified into the following 3
      groups: Group A consisted of 9 patients with normal left ventricular function and
      no native flow; Group B consisted of 11 patients with normal ventricular function
      and good native flow; Group C consisted of 7 patients with abnormal left
      ventricular function and no native flow. LITA graft function was also estimated 1
      year after operation in 12 of these 27 patients (4 in each group).
      Diastolic/systolic velocity ratio (DSVR) and flow reserve were determined in the
      proximal, middle, and distal portions of the LITA graft and native left anterior
      descending artery before and after papaverine administration (8-10 mg). DSVR was
      significantly higher in the distal portion than in the proximal portion (p <
      0.01), but this value did not change after papaverine administration. After 1
      year, DSVR in the proximal portion was significantly higher in Group C than in
      Groups A or B (p < 0.05 for both). Four weeks after operation, the flow reserve
      of the distal portion was significantly higher in Group A than in Group C (p <
      0.001). After 1 year, this value was significantly higher in Group A than in
      either Groups B or C (p < 0.01, p < 0.001, respectively). The rate of increase in
      flow reserve in the distal portion was significantly greater in Group A (23.4%)
      than in groups B (2.53%) or C (1.94%; p < 0.05 for both). The distal portion of
      the LITA was the best measurement site, since the flow pattern in the LITA graft
      varied throughout all portions. Diastolic flow velocity in the LITA graft was
      dominant in patients with myocardial damage. The results indicate that flow
      reserve of the LITA graft depends on antegrade native coronary flow and distal
      myocardial damage.

PMID- 10396704
TI  - [Significance of angiographic haziness at the distal stent edge: analysis by
      intravascular ultrasound and quantitative coronary angiography].
AB  - Haziness on coronary angiograms has been interpreted as thrombogenic morphologies
      such as dissection or thrombus. Haziness is often seen at distal sites following
      stent deployment. To clarify the pathophysiology of distal haziness of coronary
      stenting, we performed intravascular ultrasonography (3.5F, 30 MHz) after
      implantation of 48 Palmaz-Schatz stents in 45 patients. Haziness was defined
      visually as a reduction in contrast density or an indistinct vessel border. The
      luminal diameter and videodensitometry score were measured at the distal edge of
      the stent and distal adjacent segment by quantitative coronary angiography.
      Luminal diameter and lumen area were measured by intravascular ultrasound. The
      distal/in-stent ratio was calculated for each measurement to assess the magnitude
      of the vessel tapering and the reduction in contrast density. Haziness was found
      in 18 vessels. Qualitative intravascular ultrasound determined dissections (n =
      5) and irregular shapes of the lumen compressed by heavy calcium (n = 3) in the
      hazy vessels. There were no specific morphologies in the other 10 cases.
      Distal/in-stent ratio of the videodensitometry score was significantly smaller in
      hazy vessels, but quantitative coronary angiography could not distinguish hazy
      arteries with dissection or calcium from arteries without specific morphologies.
      The distal/in-stent ratio of the lumen area (< 0.8) and lumen area at the distal
      segment (< 5 mm2) were markedly smaller in the 'hazy' group without specific
      morphologies. Dissection, heavy calcium, and luminal reduction can cause a hazy
      appearance at the distal stent edge. Quantitative coronary angiography could
      quantify the haziness, but could not distinguish the morphologies of the vessel
      wall. Only intravascular ultrasound could assess the pathophysiology of hazy
      vessels after coronary stenting.

PMID- 10396705
TI  - Effects of long-term treatment with pimobendan on neurohumoral factors in
      patients with non-ischemic chronic moderate heart failure.
AB  - To evaluate the effects of the addition of pimobendan to an optimal basic regimen
      on plasma levels of neurohumoral factors in patients with non-ischemic, moderate
      heart failure during 2-year follow-up. This prospective, observational study
      involved 16 patients with non-ischemic, moderate heart failure [New York Heart
      Association (NYHA) functional class IIM-III] receiving an optimal basic regimen
      of digitalis, diuretics and angiotensin-converting enzyme inhibitor. Eight
      patients (Group P) were also administered pimobendan at a dose of 2.5 or 5 mg
      daily, while the other 8 served as controls (Group C). After 3 months of
      pimobendan administration, the plasma levels of norepinephrine and atrial
      natriuretic peptide and brain natriuretic peptide decreased and left ventricular
      ejection fraction improved. After 1 year, the cardiac symptoms, assessed using
      the Specific Activity Scale as well as the NYHA functional class, improved and
      the left ventricular end-diastolic diameter decreased. These improvements in
      Group P were maintained for 2 years. However, in Group C, the cardiac symptoms
      and the neurohumoral factor levels remained unchanged or deteriorated during this
      study, and one patient died of heart failure. Long-term combination therapy with
      the optimal basic regimen and pimobendan has potentially beneficial effects on
      neurohumoral factor levels and cardiac symptoms in patients with non-ischemic,
      chronic moderate heart failure.

PMID- 10396706
TI  - Responsiveness to a self-administered diet history questionnaire in a work-site
      dietary intervention trial for mildly hypercholesterolemic Japanese subjects:
      correlation between change in dietary habits and serum cholesterol levels.
AB  - Modification of lifestyle, especially of diet, is considered important for
      prevention of cardiovascular disease. Dietary assessment is generally too
      troublesome to use in a large number of subjects for prevention. We have
      therefore developed a self-administered diet history questionnaire (DHQ), an
      easier dietary assessment method than conventional methods, with reasonable
      validity for use in dietary intervention studies. Responsiveness, i.e.,
      sensitivity to a change in a target variable, is one type of validity required
      for a dietary assessment method which is used for the evaluation of the effect of
      dietary interventions. We examined the responsiveness of the DHQ using the data
      from a 12-week work-site dietary intervention trial including 63(54 men and 9
      women) mildly hypercholesterolemic Japanese (age range: 22-59 years, serum
      cholesterol > or = 200 mg/dl). Dietary habits were assessed by the DHQ before and
      after the trial. Pearson's correlation coefficients between the change in serum
      cholesterol and Keys score calculated from the dietary data were 0.33 and 0.32 (p
      < 0.01) with and without adjustment for possible confounding factors,
      respectively. Forty-two percent of the total variation of serum cholesterol
      change was explained by the initial serum cholesterol level, the change in body
      mass index, and the Keys score. The results suggest that the DHQ showed adequate
      responsiveness to the serum cholesterol change resulting from dietary
      intervention.

PMID- 10396708
TI  - [A 71-year-old man complaining of subcutaneous and oral mucosal bleeding].

PMID- 10396707
TI  - [Hypertensive heart disease with left ventricular diastolic dysfunction
      demonstrating restrictive hemodynamics: a case report].
AB  - A 47-year-old man with hypertensive heart disease and left heart failure due to
      left ventricular diastolic dysfunction was admitted to our hospital because of
      emergent hypertension. Chest radiography on admission showed slight cardiomegaly
      and mild pulmonary congestion with right pleural effusion Echocardiography showed
      concentric hypertrophy and normal contraction of the left ventricular wall Pulsed
      Doppler left ventricular inflow velocity wave and pulmonary venous flow velocity
      wave disclosed restrictive filling patterns. After Ca antagonist, nitrate, and
      diuretics were administered, blood pressure was normalized, and left ventricular
      inflow velocity wave showed the relaxation abnormality pattern and pulmonary
      venous flow velocity wave showed the normal pattern. Radioiodinated iodine-123
      metaiodobenzyl guanidine (123I-MIBG) imaging in the state of normalized blood
      pressure showed decreased heart to mediastinum ratio and increased washout rate.
      Left heart catheterization and angiography revealed normal end-diastolic pressure
      and coronary arteries, but coronary flow reserve evaluated with Doppler flow wire
      and intracoronary adenosine triphosphate administration was impaired: Plasma
      level of atrial and brain natriuretic peptides, which were markedly elevated on
      admission, decreased with the improvement of heart failure. Doppler flow velocity
      patterns, plasma levels of atrial natriuretic peptide and brain natriuretic
      peptide, cardiac sympathetic nerve activity, and coronary flow reserve might be
      useful for evaluating the severity of left ventricular diastolic dysfunction in
      patients with hypertensive heart disease.

PMID- 10396709
TI  - [Myocardial contrast echocardiography in a 38-year-old woman complaining of chest
      pain].

PMID- 10396710
TI  - From economics to ethics: values-based anesthesia.

PMID- 10396711
TI  - The effect of a dissociative dose of ketamine on the bispectral index (BIS)
      during propofol hypnosis.
AB  - STUDY OBJECTIVE: To compare the effect of a standardized stimulus during propofol
      only hypnosis on the bispectral index (BIS) value with the effect of the
      injection of local anesthesia for surgery during ketamine plus propofol hypnosis
      (dissociative monitored anesthesia care). To determine whether ketamine increases
      the level of propofol hypnosis when used in dissociative doses. DESIGN:
      Descriptive case study. SETTING: Private practice office plastic surgery suites.
      PATIENTS: 30 nonpremedicated ASA physical status I and II adult female (23) and
      male (7) patients scheduled for elective cosmetic surgery. INTERVENTIONS:
      Hypnosis was induced via slow (60 to 80 drops [gtts]/min), dilute (5 mg/ml)
      propofol solution. Hypnosis was induced using the BIS monitor as an adjunct to
      traditional vital signs and verbal contact. Patients were engaged in conversation
      and note was taken of the BIS value when verbal contact was lost and when BIS
      appeared to stabilize (BIS1). A standardized stimulus (0.3 ml 1% lidocaine plain
      via 30-gauge needle) was applied to the area of the supraorbital nerve. Note was
      taken of the highest BIS value (BIS2) in the patient response. The BIS returned
      to baseline hypnosis (BIS1) and a 50-mg dissociative dose (independent of body
      weight) of ketamine was administered. Two minutes were allowed to elapse and then
      the surgeon was allowed to inject the local anesthesia for the proposed surgery.
      Note was taken of the BIS value (BIS3) in response to the surgeon's injection.
      MEASUREMENTS AND MAIN RESULTS: The average delta (BIS2 - BIS1) was 9.5 + 6.9.
      Patients did not move in response to the surgeon's injection: BIS3 = BIS1. When
      movement occurred, the injection was terminated and additional ketamine was given
      before resuming the injection. Sixteen patients received ketamine 50 mg, 12
      received ketamine 100 mg, one received ketamine 150 mg, and one received ketamine
      200 mg. Men required an average 19% less propofol than women in this group.
      CONCLUSION: This study demonstrated a positive BIS response to a standardized
      local anesthetic stimulus during propofol-only hypnosis and a zero response
      during ketamine plus propofol hypnosis (dissociative anesthesia). Ketamine
      administered in dissociative doses does not deepen the level of propofol
      hypnosis. Hypnosis alone does not imply general anesthesia. Patients move in
      response to inadequate local anesthesia. Because the ketamine analgesia is only
      transitory and the primary analgesia is not given intravenously, propofol
      ketamine technique is not a total intravenous anesthetic technique (TIVA).
      Instead, propofol-ketamine technique may be classified as a form of monitored
      anesthesia care (MAC).

PMID- 10396712
TI  - The effect of propofol and thiamylal on hypertensive responses to a rapid
      increase in isoflurane concentration.
AB  - STUDY OBJECTIVE: To compare the effects of propofol and thiamylal on the
      hyperdynamic circulatory response caused by a rapid increase in isoflurane
      concentration. DESIGN: Prospective, randomized, double-blind study. SETTING:
      Operating rooms of a university hospital. PATIENTS: 30 ASA physical status I
      adult patients scheduled for elective surgery with general anesthesia.
      INTERVENTIONS: Patients were anesthetized with either propofol 2 mg/kg (propofol
      group, n = 15) or thiamylal 4 mg/kg (thiamylal group, n = 15). Two minutes after
      anesthesia induction, the inspired isoflurane concentration was rapidly increased
      from 0.5% to 5% and maintained for 5 minutes. MEASUREMENTS AND MAIN RESULTS: Mean
      arterial pressure significantly increased after the increase in isoflurane
      concentration in the thiamylal group, but it did not change in the propofol
      group. The isoflurane-induced increase in rate-pressure product was significantly
      greater in the thiamylal group than in the propofol group. CONCLUSION: Propofol
      induction of anesthesia more effectively attenuates the circulatory responses to
      a sudden increase in isoflurane concentration than does thiamylal.

PMID- 10396713
TI  - Comparison of the analgesic effects of intrabursal oxycodone and bupivacaine
      after acromioplasty.
AB  - STUDY OBJECTIVES: To compare the peripheral analgesic effect of oxycodone, an
      opioid agonist, to the effect of bupivacaine infiltration and parenteral
      oxycodone administration in conjunction with shoulder surgery. DESIGN:
      Prospective, randomized, double-blind study. SETTING: University teaching
      hospital. PATIENTS: 42 ASA physical status I and II patients scheduled for
      shoulder surgery with general anesthesia. INTERVENTIONS: Patients were randomized
      to three study groups: at the end of the surgery patients received either 10 ml
      of 0.5% bupivacaine (group BIB) or 5 mg of oxycodone in 10 ml of saline (group
      OIB) in the subacromial bursa; or 5 mg of oxycodone intramuscularly (group OIM).
      Postoperative analgesia was provided by patient-controlled analgesia (PCA).
      MEASUREMENTS AND MAIN RESULTS: The fentanyl requirements were recorded for the 24
      hour postoperative period and the total perioperative period. Postoperative pain
      was assessed by visual analog scale for pain (VASP). Plasma oxycodone
      concentrations were measured in groups OIB and OIM. The total perioperative
      fentanyl consumption was significantly lower in groups BIB (0.97 +/- 0.09 mg) and
      OIB (1.23 +/- 0.12 mg) than in group OIM (1.61 +/- 0.12 mg) (p = 0.01 and 0.048,
      respectively). Groups BIB and OIB were similar (p = 0.34). The absorption of
      oxycodone was significantly lower after subacromial than after intramuscular
      administration. CONCLUSION: Intrabursal oxycodone and intrabursal bupivacaine
      reduced perioperative analgesic requirements similarly. Intrabursal oxycodone may
      offer an effective, simple, and safe method for postoperative analgesia after
      shoulder surgery.

PMID- 10396715
TI  - Prevention or treatment of postoperative vomiting using ondansetron? A
      mathematical assessment.
AB  - STUDY OBJECTIVES: To assess the effectiveness of ondansetron versus placebo when
      used as prophylaxis of postoperative vomiting compared to its use for the
      treatment of established postoperative vomiting. DATA SOURCES: All prospectively
      randomized controlled trials, identified using the MEDLINE database and which had
      been included in two previously published meta-analyses. MEASUREMENTS AND MAIN
      RESULTS: The effectiveness of ondansetron (1, 4, and 8 mg) used for prevention
      (28 studies) or treatment (two studies) of postoperative vomiting was compared
      using odds ratios and number needed to treat (NNT) scores. NNT values were
      extrapolated to a similar incidence of vomiting in the placebo groups. The
      effectiveness equivalence between both meta-analyses was compared by assessing
      the degree of coincidence between the respective 95% confidence intervals (CI).
      The 1-mg dose was superior in treatment than in prophylaxis, odds ratios (95%
      CI): 2.73 (1.81-4.11) versus 1.34 (1.04-1.74), respectively (p < 0.05), although
      this difference did not reach statistical significance when the NNT values were
      compared. For the 4-mg dose, a near congruence was observed in the odds ratios;
      3.34 (2.22-5.03) versus 2.61 (2.24-3.05) as well as in the NNT values: 3.90 (2.97
      5.78) versus 3.40 (2.93-4.07). For the 8-mg dose, there were equivalent NNT
      values: 4.10 (3.08-6.23) versus 4.08 (3.28-5.43), and with respect to the odds
      ratios: 3.18 (2.11-4.81) versus 2.42 (1.95-2.99). The differences were not
      statistically significant. CONCLUSIONS: For the usual doses recommended for
      postoperative emesis, there was equivalent effectiveness of ondansetron whether
      administered as prophylaxis or as a treatment of established vomiting.

PMID- 10396714
TI  - Individualized outcome feedback produces voluntary antiemetic prescribing
      practice changes.
AB  - STUDY OBJECTIVE: To determine the impact of individualized outcome feedback on
      antiemetic prescribing practices and compare outcomes of a cost-effective,
      standardized antiemetic protocol (PROT) to that of customized antiemetic therapy
      (NONPROT). DESIGN: Prospective, observational study with randomized component.
      SETTING: Postanesthesia care unit (PACU) of an academic medical center. PATIENTS:
      3027 consecutive ASA physical status I, II, and III patients receiving general
      anesthesia. INTERVENTIONS: Patients were randomized to receive 0.625 mg
      droperidol or 4 mg ondansetron for postoperative nausea and/or vomiting (PONV)
      from a protocol, or received customized antiemetic therapy. MEASUREMENTS AND MAIN
      RESULTS: Incidence of PACU PONV, selection of PROT versus NONPROT, patient
      satisfaction, and use of PONV prophylaxis were measured and indexed by an
      attending anesthesiologist in a monthly report for 4 months. Monthly expenditures
      for antiemetic therapy prior to, during, and after the study were collected.
      Literature on PONV outcomes, appropriate timing, and selection of PONV
      prophylaxis was distributed. The NONPROT group was slightly older than the PROT
      group; otherwise, demographics were similar between all groups. The incidence of
      PONV did not differ between the PROT and NONPROT groups (11% vs. 10%), and the
      incidence of PONV in patients receiving prophylaxis was higher in both groups
      (17% PROT vs. 15% NONPROT). Patients receiving ondansetron as a first-line drug
      required rescue therapy less often (5%) than those receiving droperidol (14%);
      however, patient satisfaction was indistinguishable among all groups. During the
      study, the use of prophylaxis decreased 47% without an increase in PONV, and PROT
      selection increased 54%. CONCLUSIONS: Individualized outcome feedback produced a
      48% reduction in monthly expenditures for ondansetron and droperidol, which was
      sustained after the study. Patients satisfaction between ondansetron 4 mg and
      droperidol 0.625 mg given in the PACU did not differ in spite of a slightly
      greater efficacy of ondansetron as a first-line drug.

PMID- 10396716
TI  - Transesophageal echocardiographic assessment of right heart hemodynamics during
      high-frequency jet ventilation.
AB  - STUDY OBJECTIVE: To evaluate right ventricular dimensions and function by
      echocardiography in anesthetized patients during superimposed high-frequency jet
      ventilation (HFJV). DESIGN: Prospective clinical study. SETTING: University
      hospital operating room. PATIENTS: 20 ASA physical status I patients undergoing
      elective minor otorhinolaryngological surgery, and undergoing conventional
      mechanical ventilation with subsequent superimposed HFJV. INTERVENTIONS: Two
      dimensional transesophageal echocardiography with a 5-MHz multiplane transducer
      to determine right ventricular dimensions and function from a mid-esophageal
      view. Insertion of a radial artery catheter for monitoring blood pressure and
      blood gases. MEASUREMENTS AND MAIN RESULTS: Heart rate, mean arterial blood
      pressure, and right ventricular end-diastolic and end-systolic volumes determined
      by echocardiography, stroke volume, and ejection fraction. Measurements were
      performed after 10 minutes of conventional positive pressure ventilation
      (control) and after 10 minutes of subsequent superimposed HFJV at similar peak
      and positive end-expiratory airway pressures. Right ventricular systolic and
      diastolic volumes, stroke volume, and ejection fraction did not reveal
      statistical significant differences after transition to HFJV. Interventricular
      septum did not show any abnormalities in motion. In contrast, interatrial septum
      demonstrated momentary mid-systolic bows toward the left atrium in 9 of 17
      patients (53%) during conventional ventilation, but in 15 of 17 patients (88%)
      during jet ventilation. Heart rate and mean arterial blood pressure remained
      unchanged, but arterial oxygen tension values were higher and arterial carbon
      dioxide tension values lower during HFJV. CONCLUSION: Transesophageal
      echocardiographic evaluation of right heart hemodynamics did not show any
      significant difference after transition of ventilation to superimposed HFJV
      applying similar airway pressures. Furthermore, superimposed HFJV was safe and
      effective, it improved oxygenation, and it facilitated carbon dioxide
      elimination.

PMID- 10396717
TI  - Outpatient preoperative evaluation clinic can lead to a rapid shift from
      inpatient to outpatient surgery: a retrospective review of perioperative setting
      and outcome.
AB  - STUDY OBJECTIVE: To report the rapid shift from inpatient to outpatient surgery
      that occurred after opening an outpatient preoperative evaluation clinic and the
      perioperative complications and mortality rates before and after this
      intervention. DESIGN: Monthly variations of total volume of procedures and
      percentages of outpatient procedures were analyzed retrospectively using control
      charts over two consecutive 10-month periods before and after the intervention.
      For each type of procedure (inpatient vs. outpatient), the perioperative
      complications and 30-day mortality rates were compared between periods. SETTING:
      The Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
      PATIENTS: Patients who underwent 3,159 inpatient or outpatient procedures in the
      main operating room suite during the control period were compared with patients
      who underwent 3,190 procedures in the same operating room suite during the
      intervention period. INTERVENTION: The establishment of an outpatient
      preoperative evaluation clinic. MEASUREMENTS AND MAIN RESULTS: For each period,
      the total monthly surgical volume (inpatient and outpatient), perioperative
      complications, deaths within 30 days of surgery, and the number of procedures
      performed on patients classified as ASA physical status III, IV, or V were
      analyzed. The monthly total number of procedures was stable over both periods,
      but the monthly percentage of outpatient procedures departed from its baseline
      immediately after establishing the clinic (control period: 24.7%; study period:
      45.4%; p << 0.0001). Finally, the perioperative complication rate did not change
      for outpatient procedures but increased for inpatient procedures (control period:
      2.31%; study period: 3.50%; p < 0.05). The 30-day mortality rate remained
      unchanged for inpatient and outpatient procedures. CONCLUSIONS: Establishing an
      outpatient preoperative evaluation clinic can lead to a rapid shift from
      inpatient to outpatient surgery at a government funded hospital without a
      concomitant increase in perioperative morbidity or mortality.

PMID- 10396719
TI  - Lidocaine and bupivacaine exert differential effects on whole blood coagulation.
AB  - STUDY OBJECTIVES: To compare bupivacaine to lidocaine's effects on blood clotting
      at two concentrations, and to characterize and determine relative effects of two
      equianalgesic bupivacaine and lidocaine concentrations. DESIGN: Prospective, dual
      controlled, whole blood equal volume admixture thrombelastographic (TEG) study.
      SETTING: University of Pennsylvania Medical Center operating rooms. PATIENTS: 20
      ASA physical status I and II patients' blood comprised control groups and
      anesthetic groups. INTERVENTIONS: Analysis of whole blood clotting used six TEG
      channels for untreated and saline controls and four final concentrations (1.0%
      lidocaine, 0.5% lidocaine, 0.25% bupivacaine, and 0.125% bupivacaine) of local
      anesthetics. Saline control and the local anesthetic-treated specimens underwent
      8.3% hemodilution. MEASUREMENTS AND MAIN RESULTS: Blood was studied. Saline
      control or four anesthetic solutions (30 microliters) were added in random order
      two 5 TEG cuvettes. Whole blood (330 microliters) was mixed ex vivo at 37 degrees
      C. A sixth channel with untreated whole blood (360 microliters) acted as an
      undiluted control. Data for four TEG parameters [reaction time (r), angle
      (alpha), maximum amplitude (MA), and percent decrease in TEG amplitude from MA 30
      minutes after MA acquisition (Lysis 30)] for undiluted control and saline
      volumetric controls were compared to each other using Student's t-test for paired
      observations. Lidocaine and bupivacaine groups' TEGs were compared to the paired
      saline control analysis of variance for repeated measures. A p-value less than
      0.05 was considered significant. There was no difference between whole blood and
      saline control TEGs. All local anesthetics produced significant hypocoagulable
      changes from control. Angle alpha and MA were significantly decreased in all
      local anesthetic groups. Ther time was prolonged only in the high lidocaine
      treated blood. Lysis was a feature of the low lidocaine and bupivacaine
      solutions. Equianalgesic lidocaine produced more profound hypocoagulable effects
      than did bupivacaine. CONCLUSIONS: Lidocaine and bupivacaine both significantly
      impaired TEG coagulation in a concentration-dependent manner. Lidocaine was
      significantly more hypocoagulable than bupivacaine at two similarly analgesic
      concentrations.

PMID- 10396718
TI  - The effect of repeated epidural sympathetic nerve block on "failed back surgery
      syndrome" associated chronic low back pain.
AB  - STUDY OBJECTIVE: To assess the therapeutic benefits of repeated epidural local
      anesthetic administration on pain perception and straight leg raise (SLR) in
      patients suffering from chronic low back pain. DESIGN: Prospective, randomized,
      controlled, single-blind study protocol. PATIENTS: 50 ASA physical status I, II,
      and III patients at least 18 years of age, who had previously undergone spine
      surgery. INTERVENTIONS: All participants were admitted to hospital for the 5-day
      duration of the study. Following epidural catheterization, fluoroscopy was
      performed to verify correct placement of the epidural catheter. On the first
      study day, all patients received depomedrol 80 mg, in 10-ml 1% lidocaine,
      epidurally. Thereafter, patients were randomized into two equal groups. In Group
      Bupivacaine (B) 10-ml 0.125% bupivacaine was administered. In Group Saline (S),
      an equal volume of saline was administered. Epidural injections were performed
      twice daily (09H00 and 14H00) for 4 days. Sympathetic blockade was confirmed by
      the presence of peripheral vasodilatation. Sensory blockade was assessed using
      loss of pin prick and temperature sensation. SLR as well as patient-generated 100
      mm visual analog score (VAS) for pain were performed prior to each injection, at
      15 minutes after injection, and hourly for 2 hours thereafter. Similar parameters
      were measured 1 week, 1 month, and 3 months after discharge. MEASUREMENTS AND
      MAIN RESULTS: 46 patients completed the study. VAS for pain was marginally lower
      in Group B. However, statistical significance was not demonstrated. During the
      hospitalization period, the SLR in both study groups significantly (0.008)
      improved with time. However, no difference between the groups was demonstrated.
      In both groups, 1 week, 1 month, and 3 months after discharge, the SLR was
      comparable to prestudy recordings. In Group B, at 1 week, 1 month, and 3 months
      after discharge, patient-generated VAS for pain were significantly (p = 0.002)
      higher when compared to pain scores at the time of patient discharge.

PMID- 10396720
TI  - Preoperative pregnancy testing in a tertiary care children's hospital: a medico
      legal conundrum.
AB  - STUDY OBJECTIVES: To track physician and nursing practice regarding preoperative
      pregnancy screening and testing in a setting where testing is the established
      policy. DESIGN: Prospective study. SETTING: University-affiliated, urban,
      tertiary care pediatric hospital. PATIENTS: 261 menarcheal patients, aged 10 to
      34 years, presenting for ambulatory surgery in a 15-month period. INTERVENTIONS:
      None. MEASUREMENTS AND MAIN RESULTS: Of 235 routine pregnancy tests performed,
      three were positive (1.3%). All patients denied the possibility of pregnancy; all
      reported last menstrual period less than 3 weeks prior to their scheduled
      surgery. Two of the three patients whose pregnancy tests were positive were
      adults. Only two study patients were unsure about the possibility of pregnancy;
      both patients tested negative. No patient younger than 15 years tested positive
      (0 of 107). History was an unreliable marker for pregnancy. CONCLUSIONS: Medical
      history alone may be an unreliable marker for ruling out pregnancy in patients
      presenting for outpatient surgery in an urban pediatric hospital. The policy for
      preoperative pregnancy screening adopted by a hospital or health care facility
      should be predicated on the principle of "best interest of the patient."
      Considerations must include local law, ethical responsibility, and the balance
      between cost and risk based on the best and most current scientific information.

PMID- 10396721
TI  - Remifentanil for conscious sedation and analgesia during awake fiberoptic
      tracheal intubation: a case report with pharmacokinetic simulations.
AB  - We report a case of awake, fiberoptic tracheal intubation of a difficult airway
      (Ludwig's angina) using remifentanil as part of the sedation-analgesia regimen.
      Remifentanil's rapid onset-rapid offset pharmacokinetic profile enabled precise
      control of the level of opioid effect. In combination with other drugs,
      remifentanil may offer some clinical advantages compared to the other fentanyl
      congeners in providing the opioid component of conscious sedation-analgesia for
      awake tracheal intubation in patients with difficult airways.

PMID- 10396722
TI  - Newborn resuscitation and anesthesia responsibility post-cesarean section.

PMID- 10396723
TI  - The ethics of cost containment from the anesthesiologist's perspective.
AB  - Cost containment, as an essential part of current effort to manage health care,
      has been examined thoroughly from the perspectives of finance and patient care.
      In this article, the ethics of cost containment are discussed from the vantage
      point of the health care provider. Cost-cutting initiatives, however necessary
      and sound, nevertheless may place anesthesiologists in situations of ethical
      conflict and ultimately interfere with their rights as workers and professionals.
      The anesthesiology community is encouraged to investigate the effect of cost
      cutting measures on patients and physicians alike.

PMID- 10396724
TI  - Criteria for fast-tracking outpatients after ambulatory surgery.

PMID- 10396725
TI  - A smaller double-lumen tube for older children.

PMID- 10396726
TI  - Mendelson's syndrome: a contrarian perspective.

PMID- 10396727
TI  - Late intraoperative hypoglycemia in a patient with Russell-Silver syndrome.

PMID- 10396728
TI  - [Essays on modern molecular genetic. Essay 8. Genomic diseases and new molecular
      genetics. Part 2. Cancer--a genomic disease. "Cancer genes" and signal
      transduction in the cell].

PMID- 10396729
TI  - [Participation of mobile elements in formation of properties of pathogenic
      bacteria].
AB  - Published reports about structural organization of genes coding for pathogenicity
      factors are reviewed. Many of such genes are often united into "virulence blocks"
      or "pathogenicity islands" and are surrounded by mobile genetic elements,
      promoting their transposition between related bacteria genomes and leading to
      changes in virulence in the course of evolution. Data on the similarity of
      nucleotide sequences of virulence genes in different bacteria are presented,
      despite differences in their localization in the relevant genomes. The role of
      rRNA genes in dissemination of virulence genes among different bacteria during
      transduction or conjugation is shown.

PMID- 10396730
TI  - Staphylococcus aureus isolated from Kawasaki disease patients hyper-releases
      extracellular protein A.
AB  - S. aureus isolates from patients with Kawasaki disease (KD) release high levels
      of extracellular protein A (SpA), as compared to S. aureus in other diseases. The
      molecular weight of this released protein A is about 70 kDa. Extracellular KD SpA
      purified by affinity chromatography possessed the same amino acid sequence at the
      NH2-terminal IgG binding region and the same antigenic specificity as recombinant
      and cell-wall-bound SpA preparations. The size of DNA fragments containing the
      spa gene from S. aureus KD strains was 160-165 kb. All of these DNA fragments
      contained the igb portion encoding the IgG-binding region of KD SpA.
      Significantly higher molecular size of the SpA molecules hyper-released in the
      stationary-phase culture and the lack of production of other exo-proteins allow
      us to speculate that S. aureus isolated from patients with KD have mutations
      occurring in the agr locus.

PMID- 10396731
TI  - [Genetic characteristics of the KC vaccine strain of hog cholera virus:
      comparative analysis of the primary sequence of surface glycoprotein E(rns), E1,
      and E2 genes].
AB  - Primary structure of a genome fragment of attenuated strain CS of hog cholera
      virus (HCV) coding for three surface glycoproteins Erns, E1, and E2 (fragment
      size 2379 nucleotides) is analyzed. By the nucleotide sequence the homology
      between strain CS and ten other virulent and attenuated HCV strains in this area
      is 84.9-94.6%, 87.2-94.6% in gene Erns, 84.6-96.9% in gene E1, and 83.3-94.3% in
      gene E2. By amino acid sequence the homology is 90.9-94.3%, 92.9-95.0%, 92.3
      95.6%, and 88.9-94.1%, respectively. Computer analysis demonstrated philogenetic
      ratios between these strains and other HCV strains and the areas of potential
      antigenic differences between CS strain and other HCV strains. The data indicate
      that strain CS used as live vaccine protecting from HCV contains unique
      nucleotide and amino acid positions and its evolution history is different from
      that of analyzed reference strains. The data will be further used for detecting
      the fine antigenic structure of strain CS surface glycoproteins with the aim of
      disclosing unique antigenic markers.

PMID- 10396732
TI  - [Brain infarction and apoptosis].

PMID- 10396733
TI  - [Surgery of malignant tumors affecting the skull base].

PMID- 10396734
TI  - [Surgical indication and problems of patients aged over 70 years with unruptured
      aneurysms].
AB  - Surgical indication and problems of patients aged over 70 years with unruptured
      aneurysms were investigated. Clinical features of eighteen cases of unruptured
      cerebral aneurysms were analyzed. The location of the cerebral aneurysms were in
      the internal carotid artery in five cases, in the middle cerebral artery in ten
      cases, in the anterior cerebral artery in 2 cases and in the basilar artery in 1
      case. The size of the aneurysms was less than 10 mm in diameter in 17 cases and
      giant in one case. Treatment of these aneurysms was classified into two groups as
      follows; the conservative treatment group (four cases) and the surgical treatment
      group (14 cases). The therapeutic results of the conservative group were good
      recovery in 2 cases, and death in 2 cases. On the other hand, the results of
      surgical group were good recovery in 12 cases and fair in 2 cases. Operative
      complications were recognized in two cases. Consciousness disturbance and left
      hemiparesis was recognized in one case. Right hemiparesis was recognized in the
      another case. Postoperative MR imagings or CT scan presented small cerebral
      infarctions in the corona radiata in both cases. The cause of infarction was
      thought to be the occlusion of lenticulostriate arteries. From these data, in
      patients aged over 70 years with unruptured cerebral aneurysms, surgery should be
      considered not only from the aspect of aneurysmal size and its site, but also
      from the aspect of cerebral blood flow of the patient.

PMID- 10396735
TI  - [Surgical technique and long-term follow-up of laminoplasty using titanium
      miniplates].
AB  - Problems concerning a spinal deformity due to simple laminectomy and the
      usefulness of laminoplasty are often reported recently. In our hospital,
      laminoplasty with titanium miniplates for spinal operations has been used in all
      cases since 1992. We started to use this method after we encountered several
      cases of post-operative spinal deformity following multiple-level laminectomy. We
      reviewed two different subgroups of patients. Group A consisted of 38 cases who
      were operated on using simple laminectomy. Group B consisted of 32 cases who were
      operated on using laminoplasty with titanium miniplates. Postoperative spinal
      deformity occurred in 5 patients of Group A (13%), and in none of Group B (0%).
      In particular, postoperative spinal deformity occurred in one child case of Group
      A (33%), and in none of Group B (0%). Laminoplasty is a very simple and efficient
      technique, and advantages are the presentation of stability of the posterior
      column and curvature of the laminae, as well as protection of the spinal cord.
      Compatibility with magnetic resonance imaging (MRI) is another advantage of
      titanium miniplates, because long follow-up using MRI is always necessary in
      these cases. In conclusion, laminoplasty with titanium miniplates for spinal
      operations are a very useful and safe technique.

PMID- 10396736
TI  - [Analysis of spinal cord hemangioblastoma in von Hippel-Lindau disease].
AB  - Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary disorder
      showing various clinical features. We analyzed 6 patients with spinal cord
      hemangioblastoma associated with VHL disease in four families. All patients had
      cerebellar hemangioblastomas. Four cases carried retinal hemangioblastoma and 5
      cases showed visceral lesions; renal cell carcinoma (2 cases), renal cyst (2
      cases), pancreas cyst (2 cases) and paraovarian tumor. In four cases, spinal cord
      hemangioblastomas were multiple. Ten symptomatic or rapidly growing lesions in 5
      patients were surgically resected. Two of these lesions were extramedullary
      spinal root hemangioblastoma. Operative results were good except for a case of
      ventrally placed thoracic spinal intramedullary hemangioblastoma who showed
      paraparesis postoperatively. One patient who suffered from complete paraplegia
      preoperatively did not recover after surgery. In two patients, renal cell
      carcinoma was detected and nephrectomy was undergone. It was noteworthy that
      metastasis of renal cell carcinoma to the hemangioblastoma was histologically
      proved with anti-cytokeratin immunostaining in two patients with VHL-associated
      renal cell carcinoma. Molecular genetic analysis showed a missence mutation in
      one family and possible intragenic deletion in another family. However, two
      families showed no VHL gene mutation with single strand conformational
      polymorphism or Southern blot analyses. Spinal cord hemangioblastomas in VHL
      disease are often multiple and located at various sites and seem to be
      underestimated. Surveillance should start in childhood and requires annual follow
      up with imaging of the central nervous system and abdominal viscera.
      Presymptomatic diagnosis by gene analysis can be very useful for early detection
      of this disease.

PMID- 10396737
TI  - [Pathological features of dysembryoplastic neuroepithelial tumor (DNT): study of
      five surgical cases with intractable epilepsies].
AB  - The dysembryoplastic neuroepithelial tumor (DNT), characterized by its favorable
      prognosis, must be precisely differentiated from other gliomas to prevent
      overtreatment by radio/chemotherapy. We studied, here, pathological features of
      five surgical cases of DNT with intractable epilepsies. There were two males and
      three females with a median age of 20.4 years (range 12-41). We evaluated
      lesional topography, gross appearances and microscopic findings including
      immunohistochemical data. One tumor was located in the temporal lobe, another two
      in the parietal lobe, another in the occipital lobe, and the other one in the
      occipito-parietal junction. The lesions were predominantly intracortical in all
      cases. Macroscopically, two tumors were grayish-soft, another two were yellowish
      elastic, and the other one was resected as soft-mucinous fragments.
      Microscopically, the main glial components were oligodendrocyte-like cells (OLCs)
      in all cases, except for one case in which atypical glial cells were also
      prominent. Histopathological characteristics of the DNTs included the specific
      glioneuronal elements (the mixture of OLCs and neurons) in four cases, alveolar
      pattern (all cases), microcystic degeneration (all cases), multinodular
      architecture (four cases), and adjacent cortical dysplasia (all cases).
      Immunohistochemically, Ki-67 labelling indices ranged from 0 to 0.8%. OLCs were
      positive for glial fibrillary acidic protein in two cases, for S-100 protein in
      all cases, for synaptophysin in two cases, and for class III beta tubulin in all
      cases. Pathological features of our cases were characterized by its heterogeneous
      histological appearances and divergent cellular differentiation.

PMID- 10396738
TI  - [Subependymal giant cell astrocytoma associated with tuberous sclerosis
      exhibiting rapid regrowth after 17 years: a case report].
AB  - A 17-year-follow-up case of subependymal giant cell astrocytoma (SGCA) is
      reported. In 1979, when aged 28 years, the patient first presented obstructive
      hydrocephalus caused by a tumor in the right lateral ventricle close to the
      foramen of Monro. It was partially removed by a transcallosal approach.
      Pathological examinations showed gemistocytic astrocytoma or SGCA associated with
      tuberous sclerosis. A ventriculo-peritoneal shunt was carried out and 36Gy of
      radiation therapy was administered. Eight months later, the patient suffered from
      an intraventricular hemorrhage originating from SGCA, but he responded to
      conservative therapy. He was followed-up by CT scans over 17 years. In 1996,
      because of rapid regrowth of the tumor, total removal was performed by a
      transcortical approach via the right frontal horn. The pathological diagnosis was
      SGCA. The greater part of the recurrent tumor was composed of blood vessels. The
      tumor cells were grouped into two morphological types, large cells and spindle
      cells. We compared the tumor in 1996 with that in 1979, each revealing
      immunohistochemical stainability for glial fibrillary acidic protein (GFAP),
      neuron specific enolase (NSE) and S-100 protein (S-100). The large cells in 1979
      were negative for GFAP, NSE and S-100, but were positive for NSE and S-100 in
      1996. The spindle cells in 1979 were positive for GFAP, NSE and S-100, but were
      negative for GFAP in 1996. The pathological origin of SGCA remains a subject of
      controversy. These results suggest that the origin of SGCA could be variably
      differentiated cells like the germinal matrix cells.

PMID- 10396739
TI  - [Crushing head injuries: report of six cases].
AB  - We report 6 cases of crushing head injuries produced by static loading forces,
      which are defined as those that occur over a longer period of time (> 200 ms) and
      are applied over a large area. Patients ranged in age from 4 to 53 years. There
      were five male and one female. The causes of injuries in 5 cases were industrial
      accidents. In one case, the patient's head was run over by a motor vehicle in a
      parking lot. Glasgow Coma Scale scores ranged from 3 to 12. Three patients had
      cerebrospinal fluid otorrhea and rhinorrhea. Computed tomograms showed multiple
      calvarial and basilar cranial fractures, as well as intracranial hematomas,
      pneumocephalus and diffuse cerebral swelling. In 4 cases, fatal compressive brain
      damage occurred. Compression of the skull beyond a certain degree causes damages
      to the brain itself and the great vessels through cerebral compression. We
      consider that this damage may contribute to mortality in such injuries.

PMID- 10396740
TI  - [The natural history of a dural arteriovenous fistula associated with sinus
      thrombosis: a case report].
AB  - The patient, a 52-year-old man, complained of vertigo. CT scan revealed right
      cerebellar infarction and he was admitted to our hospital. MRI revealed a fresh
      thrombus in the right transverse sinus and angiography revealed the occlusion of
      the right transverse-sigmoid sinus. He complained of vertigo again and he was re
      admitted to our hospital 4 months after the first admission. Angiography revealed
      a dural arteriovenous fistula (DAVF) of the right transverse-sigmoid sinus fed by
      the right occipital artery and the right transverse-sigmoid sinus was found to be
      recanalized. The angiography which was carried out one year after the second
      admission, revealed also an enlarged DAVF fed by the left occipital artery and
      the right transverse sinus was occluded again. There are two theories about the
      pathogenesis of DAVF. One is that it is congenital and the other that it is
      acquired, but it is still controversial. Our case suggested that sinus thrombosis
      induced DAVF initially and the DAVF induced sinus thrombosis secondarily. The
      causal relations between DAVF and sinus thrombosis probably changed inversely
      over a long term and, when we discuss the pathogenesis of DAVF, we must
      understand the natural history of DAVF starting from the occurrence of sinus
      thrombosis.

PMID- 10396741
TI  - [Atypical neuroradiological features of microcystic meningioma: case report].
AB  - We report a rare case of microcystic meningioma presenting with atypical
      neuroradiological features. A 76-year-old woman was admitted to our hospital in
      October, 1996 because of head heaviness without obvious neurological deficits.
      Previous CT scan in 1989 revealed no abnormality, but a subsequent scan in 1992
      showed a low-density area in the right frontal region. Since then the patient has
      been followed up as a case of cerebral infarction. At the time of the current
      admission, CT scan disclosed the low-density area as having grown to the size of
      4 cm and heterogeneously enhanced after injection of contrast medium. On MRI the
      mass lesion was depicted as low-intensity on T1-weighted image and high-intensity
      on T2-weighted image. The mass was heterogeneously enhanced after administration
      of Gd-DTPA. Right internal and external carotid angiograms revealed neither tumor
      feeder nor tumor stain. Craniogram showed neither hyperostosis nor bone erosion,
      and yet bone scintigram demonstrated markedly increased uptake involving the
      right frontal bone near the tumor. At surgery the tumor was found to have
      originated from the dura in the right frontal convexity, which was well
      demarcated and separated from the surrounding brain tissue. Total removal
      designated as Simpson grade I procedure was accomplished. Light microscopy
      revealed abundant microcysts of varied size throughout the tumor tissue with the
      presence of whorl formation and psammoma body, but no malignancy was indicated.
      Electron microscopy further demonstrated interdigitation of the neighboring cell
      membranes, desmosomes, and intracytoplasmic filaments, which are pathognomonic
      findings of meningiomas. The microcysts were seen to reside in the extracellular
      spaces rather than in the cytoplasm. With these pathological findings, the tumor
      was finally diagnosed as microcystic meningioma.

PMID- 10396742
TI  - [A case of traumatic dissecting aneurysm of the C1-2 portion of the internal
      carotid artery].
AB  - The authors report a case of traumatic dissecting aneurysm of the C1-2 portion of
      the internal carotid artery (ICA) in a 54-year-old woman. She suffered from
      traumatic SAH due to closed head trauma as a result of a motor vehicle accident.
      Twenty-five days after this accident, traumatic dissecting aneurysm of the C1-2
      portion of the ICA that was caused by closed head trauma was ruptured and
      increased in size, as revealed by serial angiographic studies. In intraoperative
      finding, dissection involved the entire circumference of the C1-2 portion of the
      ICA. Clipping procedures were impossible, so internal carotid ligation and STA
      MCA anastomosis was performed. To our knowledge, this traumatic dissecting
      aneurysm of the C1-2 portion of the ICA was the first case that presented with
      SAH. We discussed the mechanism of dissection of the ICA and operative strategy
      suitable for this aneurysm.

PMID- 10396743
TI  - [A case of a traumatic anterior cerebral artery aneurysm following the
      penetration of the skull base by an iron rod].
AB  - A 61-year-old male fell from a position 1 m high when building a house. An iron
      rod, which protruded upward from a solid base in cement, penetrated this
      patient's neck 15 cm to the head and was successfully extracted by himself. On
      admission, he complained of headache and vomiting. General examination disclosed
      nasal bleeding, intraoral bleeding, and L figured skin laceration in the left
      side of his neck at the level of the thyroid cartilage. Mild disorientation
      (JCS2) was noted. Otolaryngological examination disclosed hyperemia on the left
      side of the vocal cord as well as at the dome of the superior pharynx. Plain
      skull film disclosed pneumocephalus and that a piece of bone fragment of the
      planum sphenoidale had penetrated the brain. CT demonstrated air in the
      subarachnoid space, ventricular hemorrhage, intracerebral hematoma in the right
      frontal lobe, and subarachnoid hemorrhage in the anterior interhemispheric
      fissure. CAG detected neither cerebral vascular abnormalities nor cerebral
      aneurysm. While staying in our department, he developed mild fever and CSF
      rhinorrhea. The diagnosis of bacterial meningitis was made from the CSF finding
      and was well controlled with conservative therapy. CSF rhinorrhea stopped
      spontaneously with conservative treatment. Sagittal MRI continuously demonstrated
      contusional hematoma in the base of the right frontal lobe just above the
      fractured planum sphenoidale and genu of the corpus callosum following the course
      of the intracranially invading iron rod. The right CAG on Day 10 demonstrated
      vasospasm on the A1 and a 1 cm sized saccular cerebral aneurysm at the proximal
      right fronto-polar artery. CAG on Day 17 again showed the persistent presence of
      the aneurysm. For the purpose of preventing delayed rupture of the aneurysm,
      radical surgical treatment was planned. Microsurgical dissection disclosed that
      the aneurysm was located just behind the elevated fracture of the planum
      sphenoidale. Severe arachnoid adhesion was noted around the aneurysm. The
      aneurysm was successfully clipped with preservation of the parent artery without
      inducing new neurological deficits. From the general, otolaryngological,
      neuroradiological, and operative findings, this aneurysm was diagnosed as a
      traumatic cerebral artery aneurysm following the penetration of the skull base by
      the iron rod. The CAG performed at 8 months postoperatively demonstrated the
      patency of the parent artery and that there was no recurrence of the aneurysm. An
      unusual case of a traumatic cerebral artery aneurysm following the penetration of
      the skull base by an iron rod was thus reported.

PMID- 10396744
TI  - [Pathophysiology and clinic of idiopathic dystonia].

PMID- 10396745
TI  - [Angiogenic factor of brain tumor].

PMID- 10396746
TI  - [Comparison of electrophysiological findings between CIDP and HMSN-1].
AB  - Chronic inflammatory demyelinating polyneuropathy (CIDP) and hereditary motor
      sensory neuropathy type 1 (HMSN-1) are representative myelinopathies. In order to
      differentiate changes in acquired and congenital demyelinating neuropathies, we
      studied electrophysiologically 9 patients with active phase of CIDP (36.0 +/-
      17.6 years old; mean +/- SD) and 7 patients with genetically-proven HMSN-1 A
      (56.0 +/- 13.6 years old). Motor conduction studies demonstrated longitudinal
      uniformity in HMSN-1, contrariwise focal conduction block or conduction delay in
      CIDP. The mean median nerve conduction velocity in the forearm segment and the
      mean CMAP amplitude stimulated at the wrist were not different between CIDP and
      HMSN-1 group; 31.8 +/- 7.2 m/sec and 5.6 +/- 2.8 mV in CIDP, and 26.7 +/- 9.8
      m/sec and 3.2 +/- 2.6 mV in HMSN-1, respectively. Upper extremity polyneuropathy
      index (PNI), a mean percentage of normal for 6 indices concerning to the velocity
      and latency over two nerves obtained by motor conduction studies, was equal and
      around 50% on the average in each group. Conduction blocks were presented in 7
      patients with CIDP and only one patient with HMSN-1. No sensory nerve action
      potential was recorded in 6 out of 9 patients with CIDP, and in 6 out of 7
      patients with HMSN-1. Intrafascicular neurography of the median nerve, stimulated
      at the wrist and recorded from intrafascicularly inserted microelectrode at the
      elbow, revealed irregular multiphasic waves which signify severe temporal
      dispersion. Maximum conduction velocity was similarly reduced to 48 m/sec in CIDP
      and 44 m/sec in HMSN-1 on the average, but in one patient with HMSN-1 it was
      maintained to 63 m/sec with conspicuous temporal dispersion of the waveform.
      Amplitude of the compound nerve action potential (CNAP) decreased more (p < 0.01)
      in HMSN-1 (26 +/- 11 micro V) than in CIDP (72 +/- 25 micro V). Temporal
      dispersion of CNAP was prominent in HMSN-1 than in CIDP. In conclusion,
      electrophysiological changes were more homogeneous in the longitudinal
      distribution but more heterogeneous in the cross-sectional distribution in HMSN-1
      than in CIDP.

PMID- 10396747
TI  - [Incidence of diabetic neuropathy which fulfills electrophysiologic criteria of
      CIDP].
AB  - In order to examine the specificity of the diagnostic criteria of CIDP, we
      studied 543 patients with diabetic neuropathy without clinical evidence of CIDP
      (307 men and 236 women, aged 60.4 +/- 11.1 years old). Moderate or severe
      neuropathy patients, whose polyneuropathy index (PNI) was below 80% of the
      normal, counted 169. Twenty out of 169 diabetic patients fulfilled the
      electrophysiologic criteria of CIDP. This number corresponded to more than 3.7%
      of the total diabetics. Motor conduction velocity category was fulfilled in 90%,
      conduction block in 65%, distal motor latency in 70% and F-wave latency category
      in 90% of 20 patients. Incomplete conduction block in the peroneal nerve and
      abnormally prolonged distal latency in the median nerve were frequent. These
      findings may reflect an overlaying focal compression. Decreased motor conduction
      velocity or prolonged F-wave latency were observed almost equally in every nerve.
      Electrophysiologic diagnostic criteria of CIDP was prepared to confirm the
      demyelinating nature of the neuropathy, and other demyelinating diseases should
      be ruled out. Diabetic patient who fulfilled this criteria was not rare. This
      fact is important, because clinical and CSF criteria of CIDP will be cleared in
      most of the diabetic patients; some diabetic neuropathy can be diagnosed as
      probable CIDP.

PMID- 10396748
TI  - [Analysis of dynamic CT functional imaging parameters in patients with acute
      basilar artery occlusion].
AB  - It is very important to make a prompt and accurate diagnosis and to commence
      pertinent treatment for patients suffering from acute cerebrovascular occlusive
      disease. Thirteen patients (mean age: 67.1 years) with basilar artery occlusion
      (BAO) were enrolled in this study. Dynamic computed tomography functional images
      (FID-CT) were analysed to determine whether this method could diagnose BAO in the
      acute phase. The functional images were categorized into 3 groups: (1) group A (n
      = 5) showed abnormalities on corrected mean transit time (cMTT) images and time
      to-peak (TP) images in the territory of the posterior cerebral artery (PCA) and
      in the thalamus, (2) group B (n = 6) only showed abnormalities on TP images, and
      (3) group C (n = 2) had no abnormalities on either cMTT or TP images. The group C
      patients had poor time-density curves because of heart disease. Although the
      results may sometimes be false negative and this limitation should be kept in
      mind, FID-CT seem to be useful not only for defining patients who need
      angiography but also those who need thrombolytic therapy for acute BAO.

PMID- 10396749
TI  - [Treatment of hemifacial spasm with type A botulinum toxin (AGN 191622): a dose
      finding study and the evaluation of clinical effect with electromyography].
AB  - Forty-one patients with hemifacial spasm had an injection of type A botulinum
      toxin (AGN 191622; Allergan Co. Ltd., Irvine, CA). Patients were randomly divided
      into 3 groups by the injection dose: group L (1 unit; 14 patients), group M (5
      units; 14 patients), and group H (10 units; 13 patients). Half of the dose was
      injected into the orbicularis oculi and the rest into the zygomaticus major
      muscles on the affected side. The clinical effect and electromyogram were
      evaluated at 2 weeks after the injection. The clinical benefit was dependent on
      the injection dose, and group H showed the highest rate of improvement (84.6%).
      No adverse effect related to the toxin was demonstrated except one patient in
      group H who showed mild and transient lagophthalmos. For 81.8% of group H
      patients, the final judgement was "useful" or "very useful", which was 9.1% for
      group L and 50.0% for group M. On the other hand, electromyography disclosed no
      consistent dose-finding relationship. We conclude that at least 10 (preferably
      more) units of botulinum toxin are necessary for effectively treating hemifacial
      spasm. Electromyography has only limited value for the evaluation of clinical
      effect.

PMID- 10396750
TI  - [Occurrence of argyrophilic grains in multiple system atrophy: histopathological
      examination of 26 autopsy cases].
AB  - Argyrophilic grain disease (AGD) is a progressive disorder producing dementia in
      elderly individuals characterized by the presence of numerous AGs in the limbic
      system. However, the occurrence of AGs has been reported in other
      neurodegenerative conditions including Alzheimer's disease, Pick's disease,
      progressive supranuclear palsy and corticobasal degeneration, all of which show
      tau-positive cytoskeletal abnormalities. We examined the brains of 26 patients
      with multiple system atrophy (MSA), a neurodegenerative disorder fundamentally
      lacking tau pathology, histologically and immunocytochemically. Numerous AGs were
      found in the limbic system in 5 patients, of whom two had shown mild dementia.
      Immunocytochemically, these AGs were labeled with antibodies against
      phosphorylation-dependent and -independent tau protein, but not alpha-synuclein,
      whereas oligodendroglial cytoplasmic inclusions found exclusively in MSA were
      immunoreactive for alpha-synuclein and, less consistently, for phosphorylation
      independent tau but not for phosphorylation-dependent tau protein. Furthermore,
      many phosphorylation-dependent tau-positive neurons and significant numbers of
      ballooned neurons (BNs) were found in the limbic system in all of the 5 patients
      with AGs. These findings suggest that AGs can occur with relatively high
      frequency in the limbic system of MSA patients, and that as in AGD, they may be
      accompanied by tau-positive neurons and BNs.

PMID- 10396751
TI  - [Primary progressive limb-kinetic apraxia: a case report with an
      electrophysiological study].
AB  - We report a 53-year-old right handed woman with a 5-year history of slowly
      progressive clumsiness of her right hand. Neurologic symptoms was otherwise
      unremarkable except for mild dysarthria. Brain CT and MRI revealed a focal
      atrophic change in the left precentral gyrus. She was thought to have the primary
      progressive limb-kinetic apraxia. Electrophysiological studies were performed to
      explore physiologic mechanism of her apraxia. Surface EMG revealed co-contraction
      of antagonistic muscles in her right upper extremity with rhythmic myoclonic
      discharges. C-reflex was positive after median nerve stimulation only on the
      affected side. SEPs elicited by the median nerve stimulation were not enlarged
      and the SEP recovery curves showed no abnormal facilitation or inhibition. In
      addition, the premyoclonus spike was demonstrated by Jerk-locked averaging.
      Transcranial magnetic stimulation using double pulse paradigm revealed a decrease
      in the level of cortico-cortical inhibition on the motor cortex in the affected
      side. Median nerve stimulation given prior to the transcortical magnetic
      stimulation on the size of the magnetic evoked potential (MEP) revealed abnormal
      facilitations on the affected side, especially at conditioning-test interval of
      60-80 ms. Therefore, our results indicate increase in the excitability of motor
      cortical neurons in primary progressive limb-kinetic apraxia, likely due to a
      decreased excitability of cortico-cortical inhibitory mechanism as a result of
      focal degeneration of cortical neurons.

PMID- 10396752
TI  - [A case of hypertensive intracerebral hemorrhage associated with ipsilateral
      internal carotid artery occlusion].
AB  - We report a case of intracerebral hemorrhage associated with ipsilateral internal
      carotid artery occlusion. The patient was a 54-year-old man, who developed a
      small cerebral hemorrhage in the left internal capsule. He was admitted with mild
      right hemiparesis to out hospital. Left carotid angiography showed an occlusion
      at the origin of the internal carotid artery. Right cerebral angiography revealed
      the slow filling of cerebral arteries of left hemisphere by the cross flow. He
      was treated conservatively. Two days after admission, the neurological
      examination revealed no notable abnormalities. The etiology of hemorrhage of this
      case is presumed as the arterial necrosis due to hypertension. There has been no
      report on the intracerebral hemorrhage associated with ipsilateral internal
      carotid artery occlusion. Our case suggests that the volume and enlargement of
      cerebral hemorrhage may be influenced by cerebral perfusion pressure.

PMID- 10396753
TI  - [Double cortex syndrome].

PMID- 10396754
TI  - [One-and-a-half syndrome].

PMID- 10396755
TI  - [An autopsy case with lower motor neuron disease showing a transient-appearance
      of anti-GM1 antibody and an improvement of conduction block after gamma-globulin
      administration].
AB  - We report a 63-year-old man who died of respiratory failure. He was well until
      1992 (57 years of his age), when he had an onset of progressive weakness of the
      bilateral upper limbs. He showed no improvement with TRH administration in other
      hospital. On January 12, 1994, he admitted to our department because of the
      progressive muscle weakness. Neurologic examination revealed a muscular atrophy
      associated with severe weakness and hyporeflexia in both upper limbs, and
      fasciculation were seen in his tongue. Electrophysiological studies revealed mild
      conduction block in the left medial nerve, and F-waves were not evoked in the
      left ulnar nerve and bilateral median nerves. After an administration of 25 g/day
      of human gamma-immunoglobulin for 5 days, conduction block as well as F-wave
      abnormalities in the left median and left ulnar nerve were improved, yet no
      improvement of muscle weakness was seen. The anti-GM1 IgG titer was transiently
      elevated in the patient's serum after gamma-immunoglobulin therapy. On September
      8, 1994, subtotal gastrectomy was performed because of the early stage gastric
      cancer. Histological examination showed poorly differentiated adenocarcinoma
      (signet-ring cell carcinoma). His muscle weakness had been gradually extended to
      the lower limbs and he couldn't walk himself on January, 1998. On March, 1998, he
      developed tetraplegia, mild dysphagia, dysuria and the respiratory disturbance.
      On April 12, 1998, he admitted to our department for the second time. Neurologic
      examination revealed a muscular atrophy and fasciculation associated with severe
      weakness in all of his limbs, tongue and musclus masseter. Neither deep tendon
      reflex nor pathologic reflex was evoked in his upper and lower extremities. His
      ocular movements and sensations were well preserved. He died of respiratory
      failure on May 1, 1998. The patient was presented in a neurological CPC.
      Neurological and laboratory findings suggested a spinal progressive muscular
      atrophy (SPMA). However, there were several unusual points as a typical SPMA in
      this case, that is, an improvement of the electrophysiological abnormalities by
      gamma-globulin treatment, as well as transient elevation of anti-GM1 antibody.
      The clinical neurologists have arrived at the conclusion that the patient had
      lower motor neuron syndrome associated with anti-ganglioside antibody and cause
      of death was ascribed to the respiratory failure. We discussed whether this case
      was SPMA or multifocal motor neuropathy. Postmortem examination revealed numerous
      diverticulums in the ascending colon and lymphothyroiditis. No recurrent
      carcinoma was detected. Neuropathologically, both severe atrophy of the anterior
      spinal roots, and severe gliosis and neuronal loss in the anterior horn of the
      spinal cord were observed. Onuf nuclei were not affected. Neurogenic muscular
      atrophy was detected in the tongue, diaphragm, and limb muscles. Motor neurons of
      the brainstem were relatively preserved, but skein-like inclusions as detected by
      anti-ubiquitin antibody, were present in the facial and hypoglossal nuclei.
      Neither motor cortex nor cortico-spinal tracts were affected. Demyelination,
      remyelination or cellular infiltrations were not apparent in the right median
      nerve and sciatic nerves. The neuropathologic features were compatible with SPMA.

PMID- 10396756
TI  - The epidemiology of rabies in Zimbabwe. 1. Rabies in dogs (Canis familiaris).
AB  - The epidemiology of rabies in dogs in Zimbabwe is described using data from 1950,
      when rabies was re-introduced after a 37-year absence, to 1996. Dogs constituted
      45.7% of all laboratory-confirmed rabies cases and were the species most
      frequently diagnosed with the disease. Slightly more cases were diagnosed from
      June to November than in other months. From 1950 to the early 1980s, most dog
      cases were recorded from commercial farming areas, but since the early 1980s most
      have been recorded from communal (subsistence farming) areas. This change appears
      to be due to improved surveillance in communal areas and not to any change in the
      prevalence of rabies. Dog rabies therefore appears to be maintained mainly in
      communal area dog populations, particularly the large communal area blocks. Urban
      rabies was not important except in the city of Mutare. Where dog rabies
      prevalence was high, the disease was cyclic with periods between peak prevalence
      ranging from 4-7 years. Dog rabies cases were, on the whole, independent of
      jackal rabies and rabies in other carnivores. There was a significant negative
      relationship between the annual number of rabies vaccine doses administered
      nationally to dogs and the annual number of dog rabies cases lagged by one year,
      indicating that the past levels of immunisation coverage have had a significant
      effect on the number of rabies cases. However, dog vaccination coverage has
      clearly not been adequate to prevent the regular occurrence of rabies in dogs.

PMID- 10396757
TI  - The epidemiology of rabies in Zimbabwe. 2. Rabies in jackals (Canis adustus and
      Canis mesomelas).
AB  - The epidemiology of rabies in Canis adustus (the side-striped jackal) and Canis
      mesomelas (the black-backed jackal) in Zimbabwe is described using data collected
      from 1950-1996. Cases in the two species made up 25.2% of all confirmed cases,
      second only to domestic dogs. Since the species of jackal cases was not recorded
      on rabies submission forms, the country was divided into areas according to
      species dominance and jackal cases were assigned to either C. adustus or C.
      mesomelas dominant zones or a sympatric zone where the relative status of the
      species is not known. Jackal rabies in both species is maintained in the
      commercial farming sector. Jackal rabies in the C. adustus zone occurs as dense
      epidemics, which begin at a single focus and spread centrifugally. The foci were
      initiated by rabid dogs, but once initiated the epidemic is maintained by C.
      adustus independently of other species. The extent of outbreaks in the C. adustus
      zone was limited by geographical (landuse type and jackal species interface)
      boundaries. Jackal rabies in C. adustus zones showed two seasonal peaks with the
      main peak occurring during late summer and the second peak during winter. In the
      C. mesomelas zone jackal rabies was more sparse but it occurred during most
      years. C. mesomelas is also able to maintain rabies independently of other
      species, although the epidemiology of the disease in this species is unclear.
      Transmission of rabies cycles between the two jackal species zones does not
      appear to occur as epidemics terminate when crossing the C. adustus and C.
      mesomelas interface boundaries.

PMID- 10396758
TI  - The use of chicken IgY in a double antibody sandwich ELISA for detecting African
      horsesickness virus.
AB  - An indirect sandwich ELISA that can detect as little as 8 ng of African
      horsesickness virus (AHSV) was developed. Viral antigen was captured from
      suspension using an immobilized monoclonal antibody specific for an epitope on
      VP7, a protein that is a major constituent of the virus core. Egg-yolk derived
      chicken IgY directed against AHSV (serotype 3) was used as the secondary
      antibody. Since IgY and mouse IgG do not cross-react serologically, the secondary
      antibody was not labelled, but was instead detected with enzyme-coupled sheep
      antibodies directed against avian immunoglobulins. The assay recognized all nine
      AHSV serotypes, but not the Cascara isolate of equine encephalosis virus, a
      related orbivirus that also infects horses. In addition to being able to detect
      and quantify whole AHSV, the ELISA could show the presence of VP7 produced by
      recombinant baculoviruses.

PMID- 10396759
TI  - Haemoproteus columbae in domestic pigeons in Sebele, Gaborone, Botswana.
AB  - Mature and immature stages of Haemoproteus columbae gametocytes, an avian
      haemosporidian protozoan parasite were found in 75% of blood smears prepared from
      30 healthy domestic pigeons in Sebele location, Gaborone, Botswana. Parenteral
      administration of an immuno-suppressive dose of dexamethasone, lowered the level
      of parasitaemia, the packed cell volume and the heterophil:lymphocyte ratio in
      the test pigeons. However, both the dexamethasone-treated and the control pigeons
      remained clinically normal.

PMID- 10396760
TI  - Parasites of domestic and wild animals in South Africa. XXXVI. Arthropod
      parasites of yellow mongooses, Cynictis penicillata (G. Cuvier, 1829).
AB  - Eighty yellow mongooses, Cynictis penicillata, from five localities in South
      Africa were examined for arthropod parasites. Ten ixodid tick species, of which
      Haemaphysalis zumpti was the most abundant, prevalent and widely distributed,
      were collected. The mongooses were also infested with two mite species.
      Echidnophaga gallinacea was the most abundant of the eight flea species
      collected. It and Ctenocephalides connatus were present at every locality. A
      single biting louse species, Felicola cynictis, was recovered and it was the most
      prevalent ectoparasite on the mongooses.

PMID- 10396761
TI  - Electron microscopy of Cowdria-infected macrophages suggests that in the absence
      of binary fission a mosaic of organisms develops from an amorphous electron dense
      matrix.
AB  - Electron microscopy of mouse peritoneal macrophages infected with the Kumm stock
      of Cowdria ruminantium suggests that in the final stage of intracellular growth,
      a mosaic of organisms develops from an amorphous matrix of varying electron
      density by a process in which double unit membranes portion off the Cowdria
      particles. This stage is preceded by inclusions consisting of a network of
      aggregated electron dense granules and these in turn by homogeneous dense bodies.
      The study failed to show how these dense bodies develop from internalized Cowdria
      particles introduced in the infective inoculum. The replication of the heartwater
      agent in macrophages differs from that in vascular endothelial cells in two
      important respects. First, at no stage during the course of development in
      macrophages is binary fission in evidence and second, in the absence of a
      limiting membrane the inclusions and colonies of organisms throughout the cycle
      of development in macrophages are in intimate contact with the host cell
      cytoplasm.

PMID- 10396762
TI  - A comparison of serum biochemical changes in two breeds of sheep (Red Masai and
      Dorper) experimentally infected with Fasciola gigantica.
AB  - Twelve Red Masai and 12 Dorper sheep aged between 6 and 9 months, were acquired
      from a fluke-free area and sheep of each breed divided into two equal groups of
      six. Each animal in one group of each breed was experimentally infected with 400
      viable metacercariae of Fasciola gigantica. The other groups acted as uninfected
      controls. Blood samples were taken at weekly intervals for the determination of
      serum bilirubin, albumin, and gamma glutamyl transferase levels. Following the
      establishment of infection, albumin levels declined in both breeds of infected
      animals without any significant difference between the two breeds. However, serum
      bilirubin and gamma glutamyl transferase (GGT) in the infected animals were
      elevated significantly more in the Dorper than in the Red Masai sheep. Based on
      these findings, it would appear that Dorper sheep are more susceptible to the
      infection than Red Masai sheep.

PMID- 10396763
TI  - Could bats act as reservoir hosts for Rift Valley fever virus?
AB  - The inter-epizootic reservoir host of Rift Valley fever virus (RVFV) remains
      unknown, although the namaqua rock rat, Aethomys namaquensis, as well as bats
      have been implicated. Bats can be asymptomatically infected with rabies, as well
      as several arboviruses; the possibility that they can act as host for RVFV
      therefore exists. To examine this possibility, 350 different samples (brain,
      liver, salivary glands and brown fat) obtained from 150 bats (comprising seven
      species) were tested for RVFV antigen using an enzyme linked immunosorbent assay
      (ELISA). None of the samples tested positive, but the ELISA proved to have
      limited sensitivity (> or = 10(3) TCID50/ml). In order to determine whether bats
      could be infected with RVFV, one Miniopterus schreibersii and two Eptesicus
      capensis bats were inoculated by the oral or intramuscular route with 100 ml and
      30 ml, respectively, of a RVFV suspension with a titre of 10(6) TCID50/ml. None
      of the bats developed any clinical signs. A low concentration of RVFV antigen was
      found in the liver and urine of M. schreibersii, but not in brain tissue. A third
      E. capensis bat was inoculated by the intramuscular route and sacrificed on day
      18. A low level of antigen was detected in the brown fat. These results
      demonstrate that bats can be infected with RVFV, and that further studies should
      be done to determine the potential of different bat species to act as reservoir
      hosts for RVFV during inter-epizootic periods.

PMID- 10396764
TI  - Confirmation that PCR can be used to identify NAD-dependent and NAD-independent
      Haemophilus paragallinarum isolates.
AB  - Seventy five bacteria tentatively identified as Haemophilus paragallinarum (the
      causative agent of infectious coryza), eight identified as Ornithobacterium
      rhinotracheale and 13 identified as NAD-independent Pasteurella species were
      isolated from chickens with respiratory infection in various provinces in South
      Africa. The isolates were characterized by conventional biochemical and
      serological methods. A polymerase chain reaction (PCR) assay specific for H.
      paragallinarum was used to identify the cultures directly from colonies. The PCR
      assay gave positive results for all isolates that were identified by conventional
      methods as H. paragallinarum, irrespective of whether they were nicotinamide
      adenine dinucleotide (NAD)-dependent (43 isolates) or NAD-independent (32
      isolates). The eight isolates that were identified by conventional methods as O.
      rhinotracheale and the 13 isolates identified as various Pasteurella species gave
      negative results in the PCR assay. This study has demonstrated that colony PCR is
      a rapid method for uniquely identifying both NAD-dependent and NAD-independent
      strains of H. paragallinarum and distinguishing them from other bacteria, such as
      O. rhinotracheale and Pasteurella species.

PMID- 10396765
TI  - Effect of an aqueous extract of Azadirachta indica on the immune response in
      mice.
AB  - Because of the very wide spectrum of infectious and non-infectious diseases for
      which preparations from Azadirachta indica are said to be efficacious, it was
      suspected that a general immunopotentiating ability could be part of the
      mechanisms by which it ameliorates so many disease conditions. Using the
      haemolytic plaque technique, an aqueous extract of Azadirachta indica stem bark
      was shown to enhance the immune response of BALB/C mice to sheep red blood cells
      in vivo.

PMID- 10396766
TI  - DRO contingencies: an analysis of variable-momentary schedules.
AB  - We conducted several comparative analyses to determine the relative effectiveness
      of variable-momentary differential-reinforcement-of-other-behavior (VM DRO)
      schedules. Three individuals who had been diagnosed with mental retardation
      participated. Results of functional analyses indicated that their self-injurious
      behavior (SIB) was maintained by social-positive reinforcement. Two individuals
      participated in a two-stage comparative analysis within multielement and multiple
      baseline designs. Fixed-interval (FI) and variable-interval (VI) DRO were
      compared in the first stage; VI DRO and VM DRO were compared in the second. All
      three schedules effectively reduced the participants' SIB. Treatment for the 3rd
      individual was conducted in a reversal design to examine the effects of VM DRO
      when it was implemented in isolation, and results indicated that the procedure
      was effective in reducing SIB. These findings suggest that VM DRO schedules may
      represent attractive alternatives to traditional FI schedules because momentary
      schedules do not require continuous monitoring and may result in higher rates of
      reinforcement.

PMID- 10396767
TI  - Reducing indices of unhappiness among individuals with profound multiple
      disabilities during therapeutic exercise routines.
AB  - A program was developed to reduce indices of unhappiness that accompanied
      therapeutic exercise routines among people with profound multiple disabilities.
      Indices of unhappiness were recorded, using an observation system that had been
      validated through previous research involving happiness-related variables, while
      support personnel conducted exercises with 3 participants. A multicomponent
      program was then implemented that involved presenting highly preferred stimuli
      before, during, and after each exercise session. Results indicated that the
      program was accompanied by reduced indices of unhappiness for each participant
      relative to the traditional method of conducting the exercises, although changes
      in the preferred stimuli used with 1 participant were required before consistent
      reductions occurred. Results are discussed regarding the importance of reducing
      unhappiness indices as a means of enhancing aspects of the daily quality of life
      for people with profound multiple disabilities. Areas for future research are
      also discussed, focusing on expanding the unhappiness-reduction procedures to
      other routine events that may occasion indices of unhappiness.

PMID- 10396768
TI  - Correspondence between outcomes of brief and extended functional analyses.
AB  - We compared results obtained from 50 sets of functional analysis data from
      assessments of self-injurious behavior (SIB), 35 of which showed clear response
      patterns and 15 of which were undifferentiated, with those obtained from two
      abbreviated methods of assessment: (a) a brief functional analysis, consisting of
      the first session of each condition from the full functional analysis, and (b) a
      within-session analysis, in which data from the brief analysis were regraphed to
      show minute-by-minute changes in response rates during a session. Results
      indicated that outcomes of the brief and within-session analyses corresponded
      with those of the full functional analyses in 66.0% and 68.0% of the cases,
      respectively. Further examination of results indicated a tendency for the brief
      analysis to identify a large proportion of positive cases (both true and false
      positives) and for the within-session analysis to identify a large proportion of
      negative cases (true and false negatives).

PMID- 10396769
TI  - A comparison of presession and within-session reinforcement choice.
AB  - Single- and concurrent-operants procedures were used to evaluate the effects of
      two reinforcement conditions on the free-operant responding of 3 individuals with
      developmental disabilities and 1 with attention deficit disorder. In the
      presession choice condition, prior to each session the participant chose one item
      from an array of three different highly preferred stimuli. This item was
      delivered by the experimenter on each reinforcer delivery during that session. In
      the within-session choice condition, each reinforcer delivery consisted of
      placing an array of three different highly preferred stimuli in front of the
      participant, who was allowed to select one. Only one of the two reinforcement
      conditions was in effect for any particular session in single-operant phases.
      Buttons associated with each reinforcement condition were present, and the
      participant could allocate responses to one or the other in concurrent-operants
      phases. Data showed substantially more responding to the button associated with
      within-session choice than presession choice during concurrent-operants phases.
      This effect was not as apparent during single-operant phases, suggesting that a
      concurrent-operants procedure provided the more sensitive evaluation of within
      session and presession reinforcer choice effects.

PMID- 10396770
TI  - Effects of session duration on functional analysis outcomes.
AB  - We examined the extent to which variations in session duration affected the
      outcomes of functional analyses. Forty-six individuals, all diagnosed with mental
      retardation and referred for assessment and treatment of self-injurious or
      aggressive behavior, participated in functional analyses, consisting of repeated
      exposure to multiple test conditions during 15-min sessions. For each set of
      assessment data, new data sets based on session durations of 10 and 5 min were
      prepared by deleting data from the last 5 and 10 min, respectively, of each
      session. Each graph (N = 138) was then reviewed individually by graduate students
      who had previous experience conducting and interpreting functional analyses, but
      who were blind to both participant identity and session duration. Interpretations
      of behavioral function based on the 10- and 5-min data sets were then compared
      with those based on the 15-min data sets. All of the 10-min data sets yielded
      interpretations identical to those based on 15-min data sets. Interpretations
      based on the 5-min and 15-min data sets yielded three discrepancies, all of which
      were the result of increased response rates toward the latter parts of sessions.
      These results suggest that the efficiency of assessment might be improved with
      little or no loss in clarity by simply reducing the duration of assessment
      sessions.

PMID- 10396771
TI  - The impact of functional analysis methodology on treatment choice for self
      injurious and aggressive behavior.
AB  - Self-injurious behavior (SIB) and aggression have been the concern of researchers
      because of the serious impact these behaviors have on individuals' lives. Despite
      the plethora of research on the treatment of SIB and aggressive behavior, the
      reported findings have been inconsistent regarding the effectiveness of
      reinforcement-based versus punishment-based procedures. We conducted a literature
      review to determine whether a trend could be detected in researchers' selection
      of reinforcement-based procedures versus punishment-based procedures,
      particularly since the introduction of functional analysis to behavioral
      assessment. The data are consistent with predictions made in the past regarding
      the potential impact of functional analysis methodology. Specifically, the
      findings indicate that, once maintaining variables for problem behavior are
      identified, experimenters tend to choose reinforcement-based procedures rather
      than punishment-based procedures as treatment for both SIB and aggressive
      behavior. Results indicated an increased interest in studies on the treatment of
      SIB and aggressive behavior, particularly since 1988.

PMID- 10396772
TI  - Effects of reinforcement magnitude on spontaneous recovery.
AB  - Extinction of operant behavior has been associated with a number of undesirable
      effects. One such effect is the temporary reappearance of behavior after
      responding appears to be completely extinguished, known as spontaneous recovery.
      In this report, the occurrence of spontaneous recovery and its attenuation with
      large amounts of reinforcement were examined during the treatment of disruption.

PMID- 10396773
TI  - False-positive maintenance of self-injurious behavior by access to tangible
      reinforcers.
AB  - Results of a functional analysis indicated that the hand mouthing of a woman with
      developmental disabilities was maintained by multiple sources of control (sensory
      stimulation and access to a leisure item). Further assessment revealed that
      access to several other items also produced high rates of hand mouthing. However,
      direct observation conducted in the woman's home indicated that none of these
      items was delivered contingent upon hand mouthing. When the consequence observed
      most frequently in the home was incorporated into the functional analysis, rates
      of hand mouthing were no higher than they were during an alone condition. We
      concluded that hand mouthing, although maintained by automatic reinforcement, was
      also susceptible to social contingencies when exposed to them during assessment,
      thereby producing a partially false-positive outcome.

PMID- 10396774
TI  - Increasing accuracy and decreasing latency during clean intermittent self
      catheterization procedures with young children.
AB  - We examined the effects of simulation training on performance of clean
      intermittent self-catheterization procedures with 2 young girls. Simulation
      training was conducted, after which independent performance was assessed within a
      multiple baseline design. The training resulted in increased accuracy and
      decreased latency for both girls.

PMID- 10396775
TI  - Improving staff nutritional practices in community-based group homes: evaluation,
      training, and management.
AB  - We evaluated the effectiveness of a staff training and management package on
      nutritional practices in two community-based group homes serving adults with
      developmental disabilities. Food storage, menu development, and meal preparation
      were trained in a multiple baseline format, followed by supervisor feedback. All
      staff behaviors increased after training and were maintained for up to 1 year.
      Biological indices reflected collateral improvements in the health of consumers,
      and surveys of staff and parents established social validity.

PMID- 10396776
TI  - Reduction of unsafe eating in a patient with esophageal stricture.
AB  - Previous research has demonstrated the efficacy of behavioral interventions in
      teaching self-feeding skills as well as in reducing inappropriate self-feeding
      behavior. The purpose of this study was to extend previous research on the use of
      prompting and reinforcement in reducing unsafe eating behaviors to the treatment
      of an adolescent with developmental disabilities and esophageal stricture. A
      behavioral assessment and treatment using prompting and reinforcement were shown
      to be effective in decreasing bite rate, decreasing bite size, and increasing the
      number of chews per bite.

PMID- 10396777
TI  - Functional analysis and treatment of problem behavior exhibited by elementary
      school children.
AB  - A functional analysis involving antecedent events was conducted with 4 students
      who had been identified as having behavior problems. Off-task behavior was
      measured while task difficulty and level of adult attention were manipulated
      during analogue sessions. Results revealed two patterns: Three students displayed
      higher rates of off-task behavior during difficult tasks, and 1 displayed higher
      rates of off-task behavior during sessions with low attention. Improved behavior
      was observed when students were taught an alternative behavior that matched the
      assessment results.

PMID- 10396779
TI  - Death of a vaccine?

PMID- 10396780
TI  - Stem cells come of age.

PMID- 10396778
TI  - Reinforcement of compliance with respiratory treatment in a child with cystic
      fibrosis.
AB  - An 8-year-old boy with cystic fibrosis (CF), mental retardation, and autism
      exhibited noncompliance with respiratory treatments that were essential for the
      management of his CF. A treatment involving shaping cooperation while still
      allowing escape for aggression and avoidance behavior resulted in increases
      compliance with respiratory treatments and decreases in problem behavior.
      Treatment gains were maintained over 3 months.

PMID- 10396781
TI  - Parsing cells.

PMID- 10396783
TI  - Review papers in substance abuse research.

PMID- 10396782
TI  - Genetic vaccines.

PMID- 10396784
TI  - Substance abuse studies and prevention efforts among Arabs in the 1990s in
      Israel, Jordan and the Palestinian Authority--a literature review.
AB  - This paper is the result of a collaborative project of Israeli, Jordanian and
      Palestinian scientists gathered to reveal the current extent of substance abuse
      and efforts at prevention among Arabs in Israel, Jordan and the Palestinian
      Authority territories, in order to identify needs and suggest future
      collaborative activities and directions for regional cooperation. The article
      provides data and covers the current state of substance abuse prevention and
      research among Moslems, Christians and Druze in the trilateral region in the
      1990s by reviewing prevention materials and studies published in the professional
      literature, as well as in reports and Doctoral and Master's theses in Arabic,
      which have been located in academic libraries and other institutions, in the
      framework of a comprehensive search. This manuscript is the first to summarize
      Jordanian and Palestinian findings in the substance abuse domain. The review
      shows that most of the Israeli research in the Arab sector deals with alcohol use
      among youth, that the majority of Jordanian studies focus on illicit drug use,
      that the research among Palestinians is in its infancy, and that comprehensive
      prevention programs are lacking in the trilateral region. It describes the key
      results of most of the 12 Israeli studies among Arabs, 11 Jordanian studies and
      four Palestinian studies. It reveals that drug abuse among Israeli Arab students
      is probably more prevalent than among Jewish adolescents, that the typical
      Jordanian drug addict has a higher level of education than the typical
      Palestinian drug addict, and that the Palestinian is more likely to be a multiple
      drug user. Recommendations for future activities include organization of a
      regional collaborative workshop in order to establish data collection systems for
      basic statistics relevant to drug abuse and development of comprehensive
      prevention programs, as well as studies in the substance abuse domain concerning
      knowledge, attitudes and behavior among the general Arab population.

PMID- 10396785
TI  - Preventing opiate overdose fatalities with take-home naloxone: pre-launch study
      of possible impact and acceptability.
AB  - AIMS: Before proceeding with the introduction of an overdose fatality prevention
      programme including teaching in cardio-pulmonary resuscitation and distribution
      of naloxone, a pre-launch study of treatment and community samples of injecting
      drug misusers has been undertaken to establish (i) the extent of witnessing
      overdoses, (ii) the acceptability of naloxone distribution and training; and
      (iii) the likely impact of such measures. DESIGN AND SETTING: Structured
      interview of two samples: (a) a community sample of injecting drug misusers
      recruited by selected privileged access interviewers (PAI) and interviewed by
      them in community settings and (b) a treatment sample of opiate addicts recruited
      from our methadone maintenance clinic (interviewed by in-house research staff).
      PARTICIPANTS: (a) Three hundred and twelve injecting drug misusers with a history
      of having injected and currently still using injectable drugs; and (b) 142 opiate
      addicts in treatment at our local catchment area methadone maintenance clinic in
      South London. FINDINGS: History of personal overdose was found with 38% of the
      community sample and 55% of the treatment sample--mainly involving opiates and in
      the company of friends. Most (54% and 92%, respectively) had witnessed at least
      one overdose (again mostly involving opiates), of whom a third had witnessed a
      fatal overdose. Only a few (35%) already knew of the existence and effects of
      naloxone. After explanation to the treatment sample, 70% considered naloxone
      distribution to be a good proposal. Of the 13% opposed to the proposal, half
      thought it may lead them to use more drugs. Eighty-nine per cent of those who had
      witnessed an overdose fatality would have administered naloxone if it had been
      available. We estimate that at least two-thirds of witnessed overdose fatalities
      could be prevented by administration of home-based supplies of naloxone.
      CONCLUSIONS: Substantial proportions of both community and treatment samples of
      drug misusers have witnessed an overdose death which could have been prevented
      through prior training in resuscitation techniques and administration of home
      based supplies of naloxone. Such a new approach would be supported by most drug
      misusers. On the basis of these findings, we conclude that it is appropriate to
      proceed to a carefully constructed trial of naloxone distribution.

PMID- 10396786
TI  - Attacking overdose on the home front.

PMID- 10396787
TI  - A project which deserves support.

PMID- 10396789
TI  - Balancing on the edge of death: suicide attempts and life-threatening overdoses
      among drug addicts.
AB  - AIMS: Assessment of prevalence of non-fatal overdoses and suicide attempts and
      predictors of and co-variation between such behaviours among drug addicts.
      DESIGN: Cross-sectional survey. SETTING: Inpatient and outpatient treatment units
      in Norway. PARTICIPANTS: National sample of 2051 drug addicts admitted to
      treatment in Norway in 1992-93. MEASUREMENTS: Self-reports of suicide attempts
      and of life-threatening overdoses from structured interviews with therapists.
      FINDINGS: Almost half (45.5%) the clients reported having experienced one or more
      life-threatening overdoses. A third (32.7%) reported one or more suicide
      attempts. Suicide attempts were more often reported among those who had overdosed
      (odds ratio (OR) = 6.3), and the number of life-threatening overdoses and number
      of suicide attempts were positively and moderately associated (Pearson's r =
      0.39). Drug addicts who had exhibited both life-threatening behaviours were
      characterized by polydrug use, poor social functioning and HIV risk-taking
      behaviour. Suicide attempters were also characterized by psychiatric problems.
      CONCLUSIONS: The substantial co-variation between suicide attempts and drug
      overdose suggests some common underlying causal factors. These seem to be related
      to heavy drug use and poor social integration.

PMID- 10396790
TI  - The quantification of mortality resulting from the regular use of illicit
      opiates.
AB  - AIMS/DESIGN: Estimates of mortality associated with illicit opiate use provide
      useful information to those directing and monitoring local, national and
      international policies and programmes. Most studies investigating the association
      have, however, been small with imprecise estimates of increased mortality. The
      current study combines data from a number of international studies in a meta
      analysis to estimate more precisely mortality associated with illicit opiate use.
      Because HIV infection among injecting drug users differs dramatically between
      countries and localities, we excluded studies where AIDS was a major contributor
      to mortality. Studies were included only where AIDS-specific mortality accounted
      for less than 2% of total mortality. FINDINGS: Our results show a mortality rate
      for people regularly using illicit opiates, which is more than 13 times greater
      than that observed for the general community. It is estimated that 9.4% of total
      mortality in Australians aged 15-39 years of age can be attributed to regular use
      of illicit opiates. Application of this aetiological fraction to Australian
      mortality data for 1992 indicate that approximately 401 male and 161 female
      deaths occurred as a result of opiate use. This represents some 15,429 and 6261
      person-years of life lost (to age 70) for males and females, respectively.
      CONCLUSIONS: The mortality rate for illicit opiate users is approximately 13
      times greater than for the general population. The large number of years of life
      lost is reflective of the relatively young population (15-39 years of age) in
      which opiate-related mortality occurs. Relative risk estimates can also be
      applied to data on the prevalence of illicit opiate use in other countries to
      produce locally based aetiological fractions and estimates of person-years of
      life lost.

PMID- 10396791
TI  - Comparison of methadone and slow-release morphine maintenance in pregnant
      addicts.
AB  - AIMS: To investigate whether the neonatal abstinence syndrome (NAS) is different
      in children born to women maintained on slow-release morphine, compared with
      those maintained on methadone, and to compare additional drug consumption in
      these groups of women. DESIGN, SETTING AND PARTICIPANTS: An open, randomized
      trial was conducted in an established clinic. Forty-eight pregnant women who
      presented to the clinic as opiate or polysubstance abusers were enrolled and
      maintained on either methadone (24 women) or slow-release morphine (24 women) up
      to and following delivery. The programme included psychosocial therapy and
      support for their opiate-addicted partners. MEASUREMENTS: Standard urinalysis
      methods were used to measure consumption of cocaine and benzodiazepines during
      pregnancy. Injection sites were monitored to indicate additional opiate use. NAS
      was measured according to Finnegan score and the amount of phenobarbiturates
      prescribed to alleviate the symptoms. FINDINGS: No difference was found in the
      number of days that NAS was experienced by neonates born to methadone or morphine
      maintained mothers (mean = 16 and 21 days, respectively). All children were born
      healthy and no serious complications arose. Fewer benzodiazepines (p < 0.05) and
      fewer additional opiates (p < 0.05) were consumed by the morphine-maintained
      women compared with those who took methadone, but no difference was seen in
      cocaine consumption. Nicotine consumption was reduced significantly in both
      groups during pregnancy (p < 0.02). CONCLUSIONS: Both methadone and morphine are
      suitable maintenance agents for pregnant opiate addicts. Maintenance agents that
      result in a less prolonged NAS should be studied in further trials.

PMID- 10396792
TI  - An experimental intervention with families of substance abusers: one-year follow
      up of the focus on families project.
AB  - AIMS: Children whose parents abuse drugs are exposed to numerous factors that
      increase the likelihood of future drug abuse. Despite this heightened risk, few
      experimental tests of prevention programs with this population have been
      reported. This article examines whether intensive family-focused interventions
      with methadone treated parents can reduce parents' drug use and prevent
      children's initiation of drug use. DESIGN: Parents were assigned randomly into
      intervention and control conditions and assessed at baseline, post-test, and 6
      and 12 months following the intervention. Children were assessed at baseline, and
      6- and 12-month follow-up points. SETTING: Two methadone clinics in Seattle,
      Washington. PARTICIPANTS: One hundred and forty-four methadone-treated parents,
      and their children (n = 178) ranging in age from 3 to 14 years old. INTERVENTION:
      The experimental intervention supplemented methadone treatment with 33 sessions
      of family training combined with 9 months of home-based case management. Families
      in the control condition received no supplemental services. MEASUREMENT: Parent
      measures included: relapse and problem-solving skills, self-report measures of
      family management practices, deviant peer networks, domestic conflict and drug
      use. Child measures included self-report measures of rules, family attachment,
      parental involvement, school attachment and misbehavior, negative peers,
      substance use and delinquency. FINDINGS: One year after the family skills
      training, results indicate significant positive changes among parents, especially
      in the areas of parent skills, parent drug use, deviant peers and family
      management. Few changes were noted in children's behavior or attitudes.
      CONCLUSIONS: Programs such as this may be an important adjunct to treatment
      programs, helping to strengthen family bonding and to reduce parents' drug use.

PMID- 10396793
TI  - The identification of alcohol dependence criteria in the general population.
AB  - AIMS: To assess the criteria used to identify alcohol dependence in the general
      population. DESIGN AND SETTING: Two independent probability surveys of the US
      household population 18 years of age and older were analyzed: the 1994 National
      Telephone Survey (NTS-94), which interviewed 637 respondents, and the 1988
      National Household Interview Survey (NHIS-88) which interviewed 43,809
      respondents in their homes. PARTICIPANTS: The analyses of the NHIS-88 dataset
      focused on drinkers who consumed at least 12 drinks of alcohol in the 12 months
      prior to the survey interview (N = 22,102). The analyses of the NTS-94 dataset
      focused on drinkers who consumed at least one drink in the 12 months prior to the
      survey interview (N = 637). MEASUREMENTS: Criteria for DSM-IV alcohol dependence
      were operationalized using 15 items from a standardized questionnaire. FINDINGS:
      Analyses suggested that normal drinking behavior can be misidentified as
      dependence criteria. Results for men who drank up to two drinks per day suggest
      that if the dependence criteria were invalid, reductions in the prevalence of
      specific indicators of alcohol dependence would range from 0.3% to 5.2%.
      Correcting for the misidentification of alcohol dependence diagnosis would reduce
      the overall prevalence of alcohol dependence by 0.5%. Up to 7% of the men could
      have been diagnosed as alcohol-dependent and could have provided invalid reports.
      CONCLUSIONS: The identification of alcohol dependence in general population
      samples must include careful probing of the nature of drinking-related behavior
      reported by respondents. This will decrease misidentification of dependence
      criteria, increasing the validity of dependence diagnosis in survey research.

PMID- 10396795
TI  - Predictors of smoking cessation during pregnancy.
AB  - AIMS: The purpose of this study was to determine predictors of smoking cessation
      from a sample of pregnant Medicaid recipients. Of special interest was whether
      patient stage of change, based on the transtheoretical model, was predictive of
      smoking behavior change during pregnancy. PARTICIPANTS/SETTING: The sample was
      drawn from a cohort of pregnant smokers who were participants in a prospective,
      randomized clinical trial conducted in four public health maternity clinics in
      Birmingham, Alabama, USA. DESIGN/MEASUREMENTS: The 435 participants entered
      prenatal care on or before their 24th week of gestation and had saliva collected
      for cotinine assays at baseline and follow-up. In this secondary analysis,
      descriptive statistics defined the sample, cross-tabulation procedures identified
      a preliminary set of predictor variables, and discriminant function analyses
      predicted group membership--quitter or smoker. FINDINGS/CONCLUSIONS: Discriminant
      function analyses revealed that patient baseline cotinine value, duration of
      smoking habit, self-efficacy, exposure to environmental tobacco smoke, and
      exposure to patient education methods were predictive of non-smoking status
      assessed during the third trimester of pregnancy.

PMID- 10396794
TI  - Validity of the Fagerstrom test for nicotine dependence and of the Heaviness of
      Smoking Index among relatively light smokers.
AB  - AIMS: To assess the validity of the Fagerstrom test for nicotine dependence
      (FTND, six items) and of a short-form of this questionnaire, the Heaviness of
      Smoking Index (HSI, two items), in a population of relatively light smokers.
      DESIGN: Comparison of item content with published definitions of addiction. Test
      retest reliability and multiple tests of construct validity, based on a secondary
      analysis of a cohort study conducted between November 1995 and June 1996.
      SETTING: University of Geneva, Switzerland. PARTICIPANTS: Students (82%),
      academic (12%) and administrative staff (6%): 643 smokers at baseline and 482
      smokers at follow-up. MEASUREMENTS: French-language versions of the FTND and HSI,
      smoking status, saliva cotinine level, self-efficacy for quitting smoking and
      other variables related to addiction with cigarettes. FINDINGS: A literature
      review showed that both composite scales fail to assess several recognised
      aspects of tobacco dependence. In this population of relatively light smokers
      (average: 12 cigarettes per day), both tests had important floor effects with,
      respectively, 55% and 63% of participants with scores equal to 0 or 1 on these
      scales. In addition, two of the FTND items (Difficult-to-refrain and Hate-most-to
      give-up) had poor psychometric properties. Even though FTND and HSI correlated
      about as expected with criterion variables, the number of cigarettes smoked per
      day performed better than either composite scale on most validation criteria.
      CONCLUSION: In a population of relatively light smokers, FTND and HSI seem to
      measure little more than the number of cigarettes per day. Designing a new and
      more broadly applicable test of addiction to cigarettes is a research priority.

PMID- 10396796
TI  - Physico-chemical characterization of liposomes with covalently attached hepatitis
      A VP3(101-121) synthetic peptide.
AB  - The covalent conjugation of a 20-mer peptide belonging to the VP3 capsid protein
      of hepatitis A virus to the surface of preformed liposomes was investigated.
      Three different bonds (disulfide, thioether and amide) were established between
      the peptide sequence and liposomes bearing at their surface appropriate reactive
      groups. The effect of the relative concentration of the N-[4-(p
      maleimidophenyl)butyryl]dipalmitoylphosphatidylethanolamine anchor in liposomes
      on stability during coupling of the peptide sequence was studied. The interaction
      of the three liposomal preparations with phospholipids in a biomembrane model
      system, monolayers at the air-water interface, is also reported. The results
      showed that although the peptides associate with liposomes in similar yields for
      the three strategies studied, differences can be observed when their interaction
      with phospholipid monolayers composed of dipalmitoylphosphatidylcholine is
      analysed.

PMID- 10396797
TI  - Comparison of HPLC, capillary electrophoretic and direct spectrofluorimetric
      methods for the determination of temoporfin-poly(ethylene glycol) conjugates in
      plasma.
AB  - High-performance liquid chromatographic (HPLC), capillary electrophoretic (CE)
      and direct spectrofluorimetric methods for the determination of temoporfin
      poly(ethylene glycol) 2000 conjugate (m-THPC-PEG 2000) in plasma are described
      and compared. m-THPC-PEG 2000 in plasma was quantitatively extracted (recovery
      101-107%) with CH3OH-DMSO (4 + 1 v/v). The supernatant after centrifugation was
      used for HPLC, CE or direct spectrofluorimetric determination. The major drawback
      of the HPLC method was that it gave a broad and split peak even under gradient
      elution conditions, resulting in difficulty in detection and quantification. This
      is because m-THPC-PEG 2000 consists of a group of compounds with an average
      molecular mass of approximately 8680 Da owing to the wide molecular mass
      distribution of PEG 2000 used in the synthesis of the drug. m-THPC-PEG 2000 gave
      a single and relatively sharp peak when separated by CE with sodium tetraborate
      buffer (pH 9.45) in the presence of sodium dodecyl sulfate as the running buffer.
      However, this method lacks the necessary sensitivity for detecting the drug in
      plasma extract because of the limited sample volume that can be injected. Direct
      spectrofluorimetry is the method of choice because of its simplicity, specificity
      and sensitivity. Using an excitation wavelength of 423 nm and the specific
      emission maximum of 657 nm, the fluorescence intensity could be sensitively
      measured. The calibration curve constructed by plotting fluorescence intensity
      against concentration was linear within the range 1.32-1056 ng ml-1. The
      detection limit (S/N = 3) was 1.32 ng ml-1 and the limit of quantification (S/N =
      10) was 2.24 ng ml-1. The precision and reproducibility were assessed by repeated
      analysis (n = 24) of spiked plasma samples at 350.8 and 699.3 ng ml-1. The RSD
      was 4.5% and 1.6%, respectively.

PMID- 10396798
TI  - pH-induced destabilization of lipid bilayers by a peptide from the VP3 protein of
      the capsid of hepatitis A virus.
AB  - The membrane destabilizing and fusogenic properties of the synthetic peptide
      VP3(110-121), corresponding to an immunogenic sequence of the hepatitis A virus
      (HAV) VP3 capsid protein, were studied. By tryptophan fluorescence and acryalmide
      quenching it was demonstrated that the peptide binds liposomes of POPC-SM-DPPE
      (47 + 39 + 14) and POPC-SM-DPPE-DOTAP (40 + 33 + 12 + 15) and penetrates the
      membrane, at both neutral and acidic pH (POPC = 1-palmitoyl-2-oleoylglycero-sn-3
      phosphocholine; SM = sphingomyelin; DPPE = 1,2
      dipalmitoylphosphatidylethanolamine; DOTAP = 1,2-dioleoyl-3
      trimethylammoniumpropane). VP3(110-121) did not have membrane-destabilizing
      properties at neutral pH. Acid-induced destabilization of the vesicles was
      demonstrated by fluorescence techniques and dynamic light scattering. VP3(110
      121) induced aggregation of POPC-SM-DPPE-DOTAP (40 + 33 + 12 + 15) vesicles,
      lipid mixing and leakage of vesicle contents, all consistent with fusion of
      vesicles. In POPC-SM-DPPE (47 + 39 + 14) vesicles, at acidic pH, VP3(110-121)
      induced membrane destabilization with leakage of contents but without aggregation
      of vesicles or lipid mixing. The peptide only showed fusogenic properties when
      bound to the vesicles at neutral pH before acidification to pH below 6.0, and no
      effect was seen if the peptide was added to vesicles already set at acidic pH.
      These results may have physiological significance in the mechanism of infection
      of host hepatic cells by HAV.

PMID- 10396799
TI  - Spectrofluorimetric study of the degradation of alpha-amino beta-lactam
      antibiotics catalysed by metal ions in methanol.
AB  - The alpha-aminopenicillins ampicillin and amoxicillin and a cephalosporin,
      cephalothin, give rise to a fluorescent product when their methanolic solutions
      are incubated for prolonged time periods. The process also occurs in the presence
      of the metal ions Cd2+, Co2+ and Zn2+. The effects of the different ions on the
      emission and excitation wavelengths and the appearance rate of the fluorophore
      were studied. The appearance of the fluorescent product was zero order for
      ampicillin and amoxicillin in metal ion-free solution and solutions with Cd2+ and
      Zn2+, whereas in the presence of Co2+ ion it was first order under the
      experimental conditions used; for cephalothin it was first order in all cases.
      Apparent fluorescent compound formation rates were calculated in the zero-order
      reactions and rate constants in the first-order reactions. The activation energy
      of the formation reaction of the fluorescent products of amoxicillin and
      ampicillin was calculated from a study of the reactions at four temperatures; all
      the values recorded were between 34 and 118 kJ mol-1. As a possible mechanism for
      the formation of these products, cyclization of the penamaldic derivative of the
      antibiotic, which is formed in the first stage of the methanolytic reaction, is
      proposed.

PMID- 10396800
TI  - Photochemically induced fluorimetric detection of tianeptine and some of its
      metabolites. Application to pharmaceutical preparation.
AB  - The photochemically induced fluorescence (PIF) properties of tianeptine and some
      of its metabolites were investigated in acidic (pH 2.3) water-alcohol mixtures at
      room temperature. Two PIF methods were developed, including bulk solution and
      flow injection analysis (FIA). Linear calibration plots were established over a
      concentration range of more than one order of magnitude. Limits of detection
      ranged from 15 ng ml-1 for FIA-PIF to 25 ng ml-1 in bulk solution. The RSDs were
      between 3 and 5%. The PIF methods were applied to the determination of tianeptine
      in a pharmaceutical preparation with recoveries varying from 96 to 106% in bulk
      solutions and from 98 to 106% for FIA-PIF.

PMID- 10396801
TI  - Development of solid-phase chemiluminescence immunoassays for digoxin comparing
      flow injection and sequential injection techniques.
AB  - The development of a competitive solid-phase immunoassay for digoxin making use
      of the acridinium chemiluminescence system is described. Two different
      instrumental approaches are compared. One is based on a continuous flow system
      using a peristaltic flow injection analysis pump; the other uses a new sequential
      injection technique. In both systems a flow cell, consisting of transparent PTFE
      tubing packed with immobilized antibodies, acts as an immunoreactor. The entire
      assay, including both the immunoreaction and the chemiluminescence reaction,
      takes place in this immunoreactor cell. Compared with the flow injection
      technique, the sequential injection mode showed higher precision, ranging from
      2.16 to 5.5% RSD depending on concentration. The total assay time, including
      regeneration, is less than 8 min with the sequential injection technique. The
      detection limit for both techniques is in the low femtomole range.

PMID- 10396802
TI  - Determination of alternariol in tomato paste using solid phase extraction and
      high-performance liquid chromatography with fluorescence detection.
AB  - Alternaria spp. produce a wide variety of toxic metabolites with different
      chemical structures. Tomato products have been considered a likely source of
      Alternaria toxins in the human diet because Alternaria is an important spoilage
      mold of tomatoes. A new method for the determination of these mycotoxins in
      tomato paste, involving solid phase cartridges for extraction before HPLC
      fluorescence detection with a reversed phase column and isocratic elution, was
      developed. The method was demonstrated to be linear in the range 5.2-196 ppb of
      alternariol (AOH) in tomato paste. Good recoveries were obtained for AOH at all
      levels assayed (minimum 77.2%). The detection limit of the AOH toxin in real
      samples of tomato paste was low, 1.93 ppb. The precision of the method was
      demonstrated with a good repeatability (RSD = 2.98%) and reproducibility (RSD =
      9.35%).

PMID- 10396803
TI  - HPLC with fluorescence detection of urinary phenol, cresols and xylenols using 4
      (4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride as a fluorescence labeling
      reagent.
AB  - A simple and sensitive HPLC method for the determination of phenolic compounds,
      i.e., phenol (Phe), cresols (Cres) and xylenols (Xyls), was developed. After a
      pre-column fluorescence derivatization of these compounds with 4-(4,5-diphenyl-1H
      imidazol-2-yl)benzoyl chloride (DIB-Cl) at 60 degrees C for 30 min, 11 DIB
      derivatives were successfully separated within 50 min with an ODS column using
      CH3CN-H2O-CH3OH (25 + 22 + 53, v/v) as the eluent. The detection limits of DIB
      derivatives at a signal-to-noise ratio of 3 ranged from 0.15 to 1.09 microM (0.2
      1.6 pmol per 20 microliters). The precision of the proposed method for both
      within- and between-day assays of free and total phenol related compounds was
      satisfactory (RSD < 9.5%). By the proposed method, Phe and p-Cre could be
      detected in normal urine samples, and the calculated concentrations of free Phe
      and p-Cre in unhydrolysed urine samples were 1.5 +/- 1.3 and 23.9 +/- 24.3 microM
      and those of total Phe and p-Cre in hydrolysed urine samples were 87.3 +/- 81.2
      and 200.7 +/- 195.4 microM (n = 21), respectively.

PMID- 10396804
TI  - Determination of nafronyl in pharmaceutical preparations by means of stopped-flow
      micellar-stabilized room temperature phosphorescence.
AB  - The stopped-flow mixing technique was applied to micellar-stabilized room
      temperature phosphorimetry by measuring the fast appearance of the phosphorescent
      signal yielded by nafronyl in the presence of sodium dodecyl sulfate and thallium
      nitrate. This mixing system diminishes the time required for the deoxygenation of
      micellar medium by sodium sulfite, allowing a kinetic curve that levels off
      within only 5 s to be obtained. Phosphorescence enhancers thallium(I) nitrate,
      sodium dodecyl sulfate and sodium sulfite were optimized to obtain maximum
      sensitivity and selectivity. A pH value of 10.5 was selected as adequate for
      phosphorescence development. Two rapid, straightforward and automatic methods
      were proposed using the slope and amplitude of the kinetic curve, which are
      directly proportional to the nafronyl concentration, as analytical parameters.
      Calibration graphs were linear for the concentration range from 30 to 600 ng ml
      1. Praxilene, the only commercial formulation containing nafronyl, was analysed
      by both proposed methodologies. Suitable recovery values were obtained.

PMID- 10396805
TI  - Neural networks in multivariate calibration.

PMID- 10396806
TI  - The application of multiple linear regression to the measurement of the median
      particle size of drugs and pharmaceutical excipients by near-infrared
      spectroscopy.
AB  - A number of powdered drugs and pharmaceutical excipients were used to demonstrate
      the ability of near-infrared spectroscopy to measure median particle size (d50).
      Sieved fractions and bulk samples of aspirin, anhydrous caffeine, paracetamol,
      lactose monohydrate and microcrystalline cellulose were particle sized by forward
      angle laser light scattering (FALLS) and scanned by fibre-optic probe FT-NIR
      spectroscopy. Two-wavenumber multiple linear regression (MLR) calibrations were
      produced using: NIR reflectance; absorbance and Kubelka-Munk function data with
      each of median particle size, reciprocal median particle size and the logarithm
      of median particle size. Best calibrations were obtained using reflectance data
      versus the logarithm of median particle size (NIR predicted lnd50 versus ln(FALLS
      d50) for microcrystalline cellulose and lactose monohydrate sieve fraction
      calibrations: r = 0.99 in each case). Working calibrations for lactose
      monohydrate (median particle size range: 19.2-183 microns) and microcrystalline
      cellulose (median particle size range: 24-406 microns) were set-up using
      combinations of machine sieve-fractions and bulk samples. This approach was found
      to produce more robust calibrations than just the use of sieved fractions. The
      method has been compared with single wavenumber quadratic least squares
      regression using reflectance and mean-corrected reflectance data with median
      particle size. Correlation between NIR predicted and FALLS values was
      significantly better using the MLR method.

PMID- 10396808
TI  - Near-infrared analytical control of pharmaceuticals. A single calibration model
      from mixed phase to coated tablets.
AB  - A new method for analysis of the active compound in a commercial pharmaceutical
      formulation in different steps of the production cycle, based on near-infrared
      diffuse reflectance spectroscopy, is proposed. The analysis includes three
      different steps of the production cycle: granules ready for compression (mixed
      phase), cores (intermediate) and coated tablets (final product). Satisfactory
      predictive results for production samples, independently of its origin in the
      production cycle, require calibration with laboratory-made samples covering the
      concentration range involved in the manufacturing process, and also production
      samples from various production batches and different steps, which introduce the
      variation sources inherent in such a process. A global and sole model was found
      to determine the active compound during the production cycle, with errors of
      prediction less than 1.8% in all cases. Tablets can be individually analysed with
      high accuracy and precision, so a content uniformity analysis may be performed.

PMID- 10396807
TI  - Quantification of paracetamol in intact tablets using near-infrared transmittance
      spectroscopy.
AB  - Production batch samples of paracetamol tablets and specially prepared out-of
      specification batches covering the range 90-110% of the stated amount (500 mg)
      were analysed by the BP official UV assay and by NIR transmittance spectroscopy.
      NIR measurements were made on 20 intact tablets from each batch, scanned five
      times each (10 min measurement time per batch) over the spectral range 6000
      11,520 cm-1. An average spectrum was calculated for each batch. Partial least
      squares (PLS) regression models were set up using a calibration set (20 batches)
      between the NIR response and the reference tablet paracetamol content (UV).
      Various pre-treatments of the spectra were examined; the smallest relative
      standard error of prediction (0.73%) was obtained using the first derivative of
      the absorbance over the full spectrum. Only two principal components were
      required for the PLS model to give a good relationship between the spectral
      information and paracetamol content. Applying this model to the validation set
      (15 batches) gave a mean bias of -0.08% and a mean accuracy of 0.59% with
      relative standard deviations of 0.75 and 0.44%, respectively. The proposed method
      is non-destructive and therefore lends itself to on-line/at-line production
      control purposes. The method is easy to use and does not require a knowledge of
      the mass of the tablets.

PMID- 10396809
TI  - Near infrared reflectance spectroscopy in the study of atopy. Part 3.
      Interactions between the skin and fomblins.
AB  - The near infrared reflectance spectra of the skin of atopic and normal subjects
      were compared after topical application of perfluorinated polyethers (fomblins)
      of different molecular weight and viscosity. It was possible to distinguish the
      two classes of subjects and the different fomblins applied, by principal
      components analysis.

PMID- 10396810
TI  - Enantioselective high-performance liquid chromatography with fluorescence
      detection of methamphetamine and its metabolites in human urine.
AB  - A simple, rapid and highly sensitive high-performance liquid chromatographic
      method with fluorescence detection for determining the enantiomers of
      methamphetamine and its major metabolites, amphetamine and p
      hydroxymethamphetamine, in urine samples was developed. Using a newly developed
      reagent for amines, namely, 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride,
      six enantiomers were derivatized under mild conditions (i.e., 10 min at room
      temperature, pH 9.0) and separated isocratically on a cellulose tris(3,5
      dimethylphenylcarbamate) coated silica gel column following a pre-separation on
      an ODS column within 42 min, and the effluent was monitored at 440 nm (lambda ex
      330 nm). Calibration curves for these derivatives using spiked human urine were
      linear in the range 0.05-100 mumol dm-3 with correlation coefficients > or =
      0.999. The detection limits at a signal-to-noise ratio of 3 were 2.8-8.8 fmol per
      5 microliters injection. The relative standard deviations of within- (n = 6) and
      between-day (n = 5) variations were < or = 7.4%. The method was successfully
      applied to discriminate between (S)-(+)-methamphetamine and its corresponding
      metabolites found in abusers' urine and their antipodes in a sample taken from a
      Parkinsonian patient on selegiline (Deprenyl) therapy.

PMID- 10396811
TI  - Determination of progesterone and 17-hydroxyprogesterone by high performance
      liquid chromatography after pre-column derivatization with 4,4-difluoro-5,7
      dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionohydra zide.
AB  - Progesterone, 17-hydroxyprogesterone and four other 3-keto steroids were
      determined by high performance liquid chromatography with fluorescence detection.
      Each steroid was derivatized with 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s
      indacene++ +-3- propionohydrazide (BODIPY FL hydrazide) and separated on a
      Wakosil 5C4 column with acetonitrile-water (7 + 3) as mobile phase. The limits of
      detection of progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone,
      androstenedione, testosterone and 17-methyltestosterone were 550-3700 fmol per 10
      microliters injection (signal-to-noise ratio = 5) serum. The calibration curves
      were linear up to 1000 ng/ml serum. The proposed method was most sensitive among
      the available high performance liquid chromatographic methods after fluorescence
      and chemiluminescence pre-labeling with dansylhydrazine.

PMID- 10396812
TI  - Development of an automated measurement system using a diffusion scrubber and
      high-performance liquid chromatography for the monitoring of formaldehyde and
      acetaldehyde in automotive exhaust gas.
AB  - An automated measurement system for monitoring formaldehyde (HCHO) and
      acetaldehyde (CH3CHO) in automotive exhaust gas by using a diffusion scrubber in
      combination with high-performance liquid chromatography (HPLC) was developed.
      HCHO and CH3CHO are effectively collected by the diffusion scrubber, which
      consists of a hydrophobic porous PTFE tube disposed concentrically within a Pyrex
      glass tube and a scrubbing solution. 2,4-Dinitrophenylhydrazine is used as the
      scrubbing solution for trapping HCHO and CH3CHO, which are derivatized to
      formaldehyde 2,4-dinitrophenylhydrazone (DNPH-HCHO) and acetaldehyde 2,4
      dinitrophenylhydrazone (DNPH-CH3CHO), respectively, with phosphoric acid as an
      acid catalyst. After the collection of the gas sample, the sample solution in the
      diffusion scrubber is injected into the HPLC system and DNPH-HCHO and DNPH-CH3CHO
      are separated and determined. All measurement operations are sequenced by a
      programmable controller and an automated continuous measurement can be performed
      at 10 min intervals. The collection efficiencies of HCHO and CH3CHO were higher
      than 97% at a gas flow rate of 0.21 min-1. The detection limit (3 sigma of the
      blank value) was 0.001 ppm v/v for HCHO and CH3CHO for a 1.61 gas sample volume.
      No interference of co-existing nitrogen dioxide (NO2) in the collection of HCHO
      and CH3CHO was observed. The average concentration of HCHO in the exhaust gas
      from methanol-fueled vehicles was 77.3 ppm v/v (n = 5) in the cold-phase mode
      when engines were first started. In the hot-phase mode, the average concentration
      of HCHO was 3.3 ppm v/v (n = 15). The concentrations of HCHO measured by this
      automated measurement system were in good agreement with those obtained using the
      impinger-HPLC method.

PMID- 10396813
TI  - Determination of sulfadiazine and sulfamethoxazole by capillary electrophoresis
      with end-column electrochemical detection.
AB  - Capillary electrophoresis (CE) with end-column electrochemical detection (EC) of
      sulfadiazine (SDZ) and sulfamethoxazole (SMZ) is described. Under the optimum
      conditions, SDZ and SMZ were separated satisfactorily, and a highly sensitive and
      stable response was obtained at a potential of 1.1 V versus Ag/AgCl. Optimized
      end-column detection provides detection limits as low as 0.1 microM for both
      compounds, which corresponds to 0.024 and 0.021 fmol with peak efficiencies of
      394,000 and 335,000 theoretical plates for SDZ and SMZ, respectively. The
      calibration graph was linear over three order of magnitude. The relative standard
      deviations (n = 12) of peak currents and migration times were 2.3 and 2.7%, and
      0.8 and 1.3%, respectively, for the two compounds. The proposed method was
      applied to the analysis of tablets and human urine samples with satisfactory
      results.

PMID- 10396814
TI  - Detection of antibiotics in muscle tissue with microbiological inhibition tests:
      effects of the matrix.
AB  - The effects of the tissue matrix on detection limits of antibiotics with
      microbiological inhibition tests, intended for muscle tissue, were measured.
      Pieces of frozen meat were laid directly on top of paper disks impregnated with
      aqueous antibiotic solutions. Inhibition zones were compared with those obtained
      by the same standard solution without tissue. Only tetracyclines were detected as
      efficiently with as without muscle tissue. Inhibition zones of the beta-lactam
      antibiotics ampicillin and penicillin G, and the fluoroquinolone antibiotics
      enrofloxacin and ciprofloxacin were smaller when muscle tissue was added to low
      levels of standard solution. At higher levels the differences were not
      substantial. Inhibition zones of tylosin were smaller and irregular or had
      disappeared completely, while ceftiofur, sulfadimidine, erythromycin, lincomycin,
      and streptomycin were not detected in spiked muscle tissue at concentrations
      fivefold higher than the detection limits without tissue. These results indicate
      that ceftiofur, sulfonamides, streptomycin and some macrolide antibiotics cannot
      be detected in intact meat with the plates and bacterial strains prescribed in
      the European Four Plate Test, a test which was initially intended as a multi
      residue method for muscle tissue. Two plates of this system are not suitable for
      screening purposes; a third one detects tetracyclines and beta-lactam antibiotics
      in spiked tissue; the fourth one is sensitive for beta-lactam antibiotics and for
      some but not all macrolides. Samples spiked with the fluoroquinolones
      enrofloxacin and ciprofloxacin can be detected with an additional plate, not
      included in the Four Plate Test.

PMID- 10396815
TI  - Sensitive determination of paraquat and diquat at the sub-ng ml-1 level by
      continuous amperometric flow methods.
AB  - Two methodologies are described for the determination of paraquat and diquat. The
      first is based on the pre-treatment of an electrode with a surfactant solution,
      which improves the electrochemical determination of the herbicides. Linear
      calibration graphs were obtained in the ranges 10-80 and 10-100 ng ml-1 for
      paraquat and diquat, respectively. The limits of detection were 6.32 for paraquat
      and 4.80 ng ml-1 for diquat. The method was applied to the determination of the
      herbicides in synthetic water samples. The second methodology is based on the
      preconcentration of paraquat and diquat in a minicolumn packed with a cation
      exchange material. The determination ranges and detection limits depend on the
      sample volume used (5-50 ml). Thus, 50 ml of sample provides limits of detection
      of 0.016 and 0.020 ng ml-1 for paraquat and diquat, respectively. The
      applicability of the method was demonstrated with the determination of the
      herbicides in both synthetic and real water samples.

PMID- 10396817
TI  - Apparatus to measure simultaneously 14 isometric leg joint moments. Part 2: Multi
      moment chair system.
AB  - An apparatus has been developed that measures isometrically the 14 lower limb
      joint moments corresponding to the degrees of freedom of the hips, knees and
      ankles. This is the second of two papers describing the development of the multi
      moment chair system (MMCS). It presents the overall design and changes that were
      implemented to compensate for problems. These were primarily to improve the
      accuracy of hip joint moments; a compromise between accuracy and practicalities,
      because of force-moment responses being measured at the ankles. All joint moment
      errors have been calculated to be of the order of a few newton metres. Since
      these represent errors of less than 10% when considering peak joint moment
      responses, this is considered sufficiently accurate for the proposed application.
      The MMCS is being used in a programme to investigate the restoration of lower
      limb functions, principally standing, in paraplegics by electrical stimulation of
      the lumbosacral anterior roots.

PMID- 10396816
TI  - Apparatus to measure simultaneously 14 isometric leg joint moments. Part 1:
      Design and calibration of six-axis transducers for the forces and moments at the
      ankle.
AB  - An apparatus has been developed for making isometric measurements of the joint
      moments corresponding to the 14 degrees of freedom of the legs, in postures
      ranging between sitting and near full extension. The apparatus is called the
      multi-moment chair system (MMCS) and is described in the companion paper. This
      paper describes the most critical components of the MMCS, which are the six-axis
      transducers for measuring the force and moment components on the plantar-flexion
      axis of each ankle while the feet are laced into fixed shoes. The transducers are
      made of steel bars, on which strain gauges are mounted, joined by clamps. The
      design of the transducer and methods of calibration and error estimation are
      described. The RMS errors are less than 2 N for the forces and 1 Nm for the
      moments, but these may be correlated. A method for error reduction that
      compensates for the finite compliance of the transducer does not reduce the
      measured errors.

PMID- 10396819
TI  - An implantable impedance pneumograph monitor for detection of diaphragm
      contraction and airway obstruction during diaphragm pacing.
AB  - Impedance pneumography signals were characterised during diaphragm pacing using
      stimulating and recording electrodes placed on the abdominal surface of the
      diaphragm. These measurements were useful for the detection of muscle contraction
      without confounding effects from stimulus artifacts. Impedance pneumography
      signals were measured using 23 epimysial electrodes implanted in seven dogs with
      1-5 experiments on each electrode. The polarity of the change in impedance
      associated with diaphragm pacing differed for each recording electrode and its
      configuration. Thirty-four of 57 cases produced increased impedance, 11 produced
      decreased impedance and the remaining 12 depended on the level of diaphragm
      activation. Impedance pneumography signals were useful for detecting complete
      airway obstruction. The mean difference between the impedance measured during
      open and obstructed airway conditions was 80% of the open airway impedance
      signal. The difference between open and obstructed airway impedance measurements
      was a mean of 2.3 times larger with a recording electrode on the same
      hemidiaphragm as the stimulating electrode, compared to an electrode placed on
      the opposite hemidiaphragm (p < 0.05, paired t test, four dogs). In addition, the
      differences between open and completely obstructed airways were a mean of 2.8
      times larger when the second recording electrode was placed on the thorax at the
      fifth intercostal space, compared to the ninth intercostal space (p < 0.05, two
      factor ANOVA, one dog, two replicates). It was concluded that impedance
      pneumograph circuitry could be incorporated into an existing diaphragm pacer
      using electrodes placed on the diaphragm to provide valuable measurements of the
      function of the device.

PMID- 10396818
TI  - Pelvis and lower limb anatomical landmark calibration precision and its
      propagation to bone geometry and joint angles.
AB  - Human movement analysis using stereophotogrammetry is based on the reconstruction
      of the instantaneous laboratory position of selected bony anatomical landmarks
      (AL). For this purpose, knowledge of an AL's position in relevant bone-embedded
      frames is required. Because ALs are not points but relatively large and curved
      areas, their identification by palpation or other means is subject to both intra-
      and inter-examiner variability. In addition, the local position of ALs, as
      reconstructed using an ad hoc experimental procedure (AL calibration), is
      affected by photogrammetric errors. The intra- and inter-examiner precision with
      which local positions of pelvis and lower limb palpable bony ALs can be
      identified and reconstructed were experimentally assessed. Six examiners and two
      subjects participated in the study. Intra- and inter-examiner precision (RMS
      distance from the mean position) resulted in the range 6-21 mm and 13-25 mm,
      respectively. Propagation of the imprecision of ALs to the orientation of bone
      embedded anatomical frames and to hip, knee and ankle joint angles was assessed.
      Results showed that this imprecision may cause distortion in joint angle against
      time functions to the extent that information relative to angular movements in
      the range of 10 degrees or lower may be concealed. Bone geometry parameters
      estimated using the same data showed that the relevant precision does not allow
      for reliable bone geometry description. These findings, together with those
      relative to skin movement artefacts reported elsewhere, assist the human movement
      analyst's consciousness of the possible limitations involved in 3D movement
      analysis using stereophotogrammetry and call for improvements of the relevant
      experimental protocols.

PMID- 10396820
TI  - Parallel conductance determination in cardiac volumetry using dilution
      manoeuvres: theoretical analysis and practical implications.
AB  - Left ventricular volume calibration based on the conductance catheter depends on
      the correct determination of the parallel conductance (Gp). Baan's saline
      manoeuvre procedure leads to Gp by finding the end-systolic (Ges) and end
      diastolic (Ged) conductances, for each beat of the dilution curve rising limb.
      After plotting such values in an xy-system, their linear regression is back
      projected to intersect the identity line, so yielding an estimated Gp. The
      objective is to theoretically analyse all possible lines, Ges = aGed + b (Baan's
      line) and, based on experimental results, to establish their limitations. This
      was attained by calculating the regression lines using, first Ged = f1(Ges) and
      thereafter, Ges = f2(Ged), which led to two values, Gp2 and Gp1, for the parallel
      conductance. The morphology of the saline curve was also modified to assess its
      effect on the extrapolation. Multiple dilutions were recorded in eight
      experimental dogs injecting different concentrations. Each curve was classified
      according to the maximum change (VAR) reached by the total average conductance.
      Over 138 manoeuvres, 276 regressions were processed yielding correlations higher
      than 0.65. Of this total, 92.4% gave positive parallel conductances. The rest
      produced negative values and, thus, were neglected. If the two (Ged, Ges)
      statistical relationships were ideal, they should yield Gp = Gp1 = Gp2; however,
      there were differences which, when Gp1 was studied against Gp2, led to: Gp1 =
      0.97 Gp2 + 0.055, with r = 0.9476, and n = 85. The remaining 53 were discarded
      because either some Gp values were negative, or the correlation of Ges which Ged
      (or vice versa) was < 0.85, and/or VAR < 15%; the two latter conditions were
      found necessary for reliable calibration. Baan's line high correlation is not a
      unique condition to ensure the accuracy and precision of Gp determination because
      the slope a depends on VAR and, thus, different intersections with the identity
      line may be obtained. Its recommended that manoeuvres be used with at least eight
      data points, with VAR > 15% and, finally, with (Ges, Ged) correlation better than
      0.85. Theoretical analysis of Baan's line offers a reference frame, which
      contains only a limited number of practical possibilities.

PMID- 10396821
TI  - Analysis of the ST-T complex of the electrocardiogram using the Karhunen--Loeve
      transform: adaptive monitoring and alternans detection.
AB  - The Karhunen-Loeve transform (KLT) is applied to study the ventricular
      repolarisation period as reflected in the ST-T complex of the surface ECG. The
      KLT coefficients provide a sensitive means of quantitating ST-T shapes. A
      training set of ST-T complexes is used to derive a set of KLT basis vectors that
      permits representation of 90% of the signal energy using four KLT coefficients.
      As a truncated KLT expansion tends to favor representation of the signal over any
      additive noise, a time series of KLT coefficients obtained from successive ST-T
      complexes is better suited for representation of both medium-term variations
      (such as ischemic changes) and short-term variations (such as ST-T alternans)
      than discrete parameters such as the ST level or other local indices. For
      analysis of ischemic changes, an adaptive filter is described that can be used to
      estimate the KLT coefficient, yielding an increase in the signal-to-noise ratio
      of 10 dB (u = 0.1), with a convergence time of about three beats. A beat spectrum
      of the unfiltered KLT coefficient series is used for detection of ST-T alterans.
      These methods are illustrated with examples from the European ST-T Database.
      About 20% of records revealed quasi-periodic salvos of ischemic ST-T change
      episodes and another 20% exhibit repetitive, but not clearly periodic patterns of
      ST-T change episodes. About 5% of ischemic episodes were associated with ST-T
      alterans.

PMID- 10396822
TI  - Evaluation of a lumped parameter model for isolated working rat hearts.
AB  - When a mechanical model of the rat aortic input impedance is perfused with a
      pulsatile pump, the computed values of the impedance components vary linearly
      with flow rate and are interactive. When the model is perfused by an isolated rat
      heart, the total load upon the left ventricle consists of the model and coronary
      impedances in parallel. Adenosine triphosphate induces changes in coronary
      impedance, and the redistribution of cardiac output from the model to the
      coronary circulation causes flow-related changes in the model impedance. Thus,
      the mechanical model does not provide a constant load for the isolated heart,
      because of variations in both the model and coronary impedances.

PMID- 10396823
TI  - Consequences of static and pulsatile pressure on transmembrane exchanges during
      in vitro microdialysis: implication for studies in cardiac physiology.
AB  - Microdialysis is an established technique for measuring the kinetics of various
      neurotransmitters within the extracellular space in the field of neurochemistry.
      Recently, its use has been extended to sampling in other tissues, including
      liver, kidney and the heart. A persistent problem in cardiac microdialysis
      concerns two parameters related to myocardial function: pressure and frequency
      (heart rate). The aim of the study is to evaluate the consequences of pressure
      and frequency on transmembrane exchanges. Linear flexible microdialysis probes
      (membrane length: 12 mm, outside diameter: 390 microns, MWCO 50,000 Daltons) were
      designed in our laboratory. The probes, perfused at 2 microL/min with sterile
      water, were placed in a system filled with a glucose solution (2 g/L) and able to
      generate either static: 0 to 400 mmHg (0 to 53.31 kPa) or pulsatile pressure: 0
      100; 0-200; 0-300 mmHg (0-13.32; 0-26.65; 0-39.98 kPa) at different frequencies:
      1, 2 and 3 Hz. At 2 mu litre min-1 perfusion rate, the pressure inside the probe
      is estimated to be 80 mmHg (10.66 kPa). Under static pressure conditions, the
      glucose recovery rate can be expressed as an exponential function, and the
      outflow rate can be expressed as a linear function of the external pressure
      level. Under dynamic conditions, the external mean pressure must be accounted
      for. When external mean pressure exceeds 80 mmHg (10.66 kPa) (pressure generated
      by the flow rate of perfusion inside the probe), the recovery rate increases with
      frequency. Conversely, if the outer mean pressure is lower than 80 mmHg (10.66
      kPa), the recovery rate decreases with frequency. Theoretical and experimental
      modelling results in a nomogram that can be used to estimate in vivo recovery. In
      conclusion, mass transfer across a microdialysis membrane is dependent on the
      direction of the transmembrane pressure gradient and increases with heart rate.
      These findings must be taken into account when in vivo recovery rates during
      cardiac microdialysis are determined.

PMID- 10396824
TI  - One-dimensional experimental mechanical characterisation of porcine aortic root
      wall.
AB  - The human aortic valve, in cases of disease, can be substituted with a stentless
      biological prosthesis that is made of both porcine aortic root and leaflets. In
      particular, the aortic root plays a very important part in the opening mechanics
      of the valve. Therefore, to understand the behaviour of the prosthesis, a
      knowledge of the mechanical characteristics of each element constituting the
      system is useful. For a structural and mechanical characterisation of the porcine
      aortic root wall tissue, specific measuring devices are made. A uni-axial tensile
      apparatus, operating in a temperature-controlled saline bath, is equipped with
      special pneumatic clamps. A test rig for the measurement of the specimen cross
      sectional area is developed. To determine the porcine aortic root wall mechanical
      properties, 189 tensile tests are carried out. Specimens of both natural and
      chemically fixed tissue are used to consider the conditions of both natural
      valves and prostheses. Tensile tests are carried out on both axial and
      circumferential specimens taken from 12 areas of one-sixth of the entire aortic
      root, with the aim of identifying the anisotropic and non-homogeneous behaviour
      of the tissue. The behavior changes considerably depending on the direction in
      which the specimen is strained, the chemical treatment and the zone from which it
      has been taken. The paper presents the stress-strain characteristics of fresh and
      fixed tissue in all zones of the aortic wall, both in circumferential and axial
      directions.

PMID- 10396825
TI  - Application of correlation dimension and pointwise dimension for non-linear
      topographical analysis of focal onset seizures.
AB  - For many patients who are candidates for epilepsy surgery, non-invasive
      evaluation fails to provide sufficient information to permit surgical treatment.
      Since there are also definite risks and considerable costs associated with
      invasive procedures, new (non-invasive) techniques are required. This study
      provides empirical evidence that a non-linear approach applied to ictal surface
      electroencephalograms (EEGs) can help to delineate the area of seizure onset and
      may prove useful in complementing visual analysis of the EEG. Multichannel EEGs,
      recorded from eight patients with different drug-resistant localisation-related
      epilepsies, were analysed using the concept of correlation dimension and two
      extensions based on the pointwise dimension. The latter also provided results in
      cases where assessment of the correlation dimension was not feasible. Comparative
      values between 2 and 6 were accepted as the result of the algorithms, mostly 3-4
      for the EEG channels strongly reflecting epileptic activity, and 4-6 for the
      other signals. The proportion of accepted pointwise values was usually 200-800%
      for strong epileptic EEG activity compared to the other data. The approach
      permitted the characterisation of the scalp area reflecting epileptic activity.
      The results obtained were in perfect concordance with those obtained during pre
      surgical work-up and confirmed by the post-operative outcome.

PMID- 10396826
TI  - A tracing evoked potential estimator.
AB  - The paper presents an adaptive Gaussian radial basis function neural network
      (RBFNN) for rapid estimation of evoked potential (EP). Usually, a recorded EP is
      severely contaminated by background ongoing activities of the brain. Many
      approaches have been reported to enhance the signal-to-noise ratio (SNR) of the
      recorded signal. However, non-linear methods are seldom explored due to their
      complexity and the fact that the non-linear characteristics of the signal are
      generally hard to determine. An RBFNN possesses built-in non-linear activation
      functions that enable the neural network to learn any function mapping. An RBFNN
      was carefully designed to model the EP signal. It has the advantage of being
      linear-in-parameter, thus a conventional adaptive method can efficiently estimate
      its parameters. The proposed algorithm is simple so that its convergence
      behaviour and performance in signal-to-noise ratio (SNR) improvement can be
      mathematically derived. A series of experiments carried out on simulated and
      human test responses confirmed the superior performance of the method. In a
      simulation experiment, an RBFNN having 15 hidden nodes was trained to approximate
      human visual EP (VEP). For detecting human brain stem auditory EP (BAEP), the
      approach (40 hidden nodes and convergence rate = 0.005) speeded up the estimation
      remarkably by using only 80 ensembles to achieve a result comparable to that
      obtained by averaging 1000 ensembles.

PMID- 10396827
TI  - A model of the electrical behaviour of myelinated sensory nerve fibres based on
      human data.
AB  - Calculation of the response of human myelinated sensory nerve fibres to spinal
      cord stimulation initiated the development of a fibre model based on
      electrophysiological and morphometric data for human sensory nerve fibres. The
      model encompasses a mathematical description of the kinetics of the nodal
      membrane, and a non-linear fibre geometry. Fine tuning of only a few, not well
      established parameters was performed by fitting the shape of a propagating action
      potential and its diameter-dependent propagation velocity. The quantitative
      behaviour of this model corresponds better to experimentally determined human
      fibre properties than other mammalian, nonhuman models do. Typical
      characteristics, such as the shape of the action potential, the propagation
      velocity and the strength-duration behaviour show a good fit with experimental
      data. The introduced diameter-dependent parameters did not result in a noticeable
      diameter dependency of action potential duration and refractory period. The
      presented model provides an improved tool to analyse the electrical behaviour of
      human myelinated sensory nerve fibres.

PMID- 10396828
TI  - Automated prostate recognition: a key process for clinically effective robotic
      prostatectomy.
AB  - Clinical trials of PROBOT, a robotic system for prostate surgery, have shown that
      robotic surgery of soft tissue can be successful. Monitoring of the progress of
      the resection has shown to be a necessary feature of an effective robotic system
      for prostate surgery. It should provide the surgeon with a reliable method of
      assessing the cavity during resection. An automatic system for intraoperative
      monitoring of the progress of the resection during robotic prostatectomy consists
      of two subsystems: real-time intraoperative imaging of the prostate and automatic
      identification of the contour of the gland on each image. The development of a
      fully automatic scheme for prostate recognition on transurethral ultrasound scans
      is reported. A genetic algorithm has been developed to automatically adjust a
      model of the prostate boundary until an optimum fit to the prostate in a given
      image is obtained. An analysis of its performance on 22 different ultrasound
      images showed an average error of 6.21 mm. Use of a genetic algorithm and a
      constrained prostate model have shown to be a robust way to automatically
      identify the prostate in ultrasound images. The scheme is able to produce
      approximate prostate boundaries, without any human intervention, on ultrasound
      scans of varying quality. In addition to soft tissue robotic surgery, the genetic
      algorithm technique is also applicable to a wide range of computer assisted
      surgical techniques.

PMID- 10396829
TI  - Improving the detection of low concentration metabolites in magnetic resonance
      spectroscopy by digital filtering.
AB  - In vivo detection and quantitation of metabolites is often limited by their low
      concentration. As far as magnetic resonance spectroscopy (MRS) is concerned,
      detection and quantitation can be significantly improved by reduction of the
      observed spectral width (SW). The reduction is limited to the spreading of
      resonances in the bandwidth unless high performance digital filters are used.
      Indeed, these filters avoid the folding of unwanted resonances such as water peak
      into the main frequency spectrum and therefore allow reduction of the spectral
      width to its optimal value. These filters are now available on most MRS systems
      but their use is not common even if, as we show in the particular case of proton
      MRS, a significant increase in signal-to-noise ratio (two-fold factor for SW
      reduction from 5000 Hz to 1351 Hz) can be achieved. This signal-to-noise
      improvement allows better quantitation accuracy.

PMID- 10396830
TI  - Mechanical and electromotile characteristics of auditory outer hair cells.
AB  - The passive and active properties of the cochlear outer hair cell are studied.
      The outer hair cell is currently considered the major candidate for the active
      component of mammalian hearing. Understanding of its properties may explain the
      amplification and sharp frequency selectivity of the ear. To analyse the cell
      behaviour, a model of a nonlinear anisotropic electro-elastic shell is used.
      Using the data from three independent experiments, where the mechanical strains
      of the cell are measured, estimates of the cell wall in-plane Young's moduli and
      Poisson's ratios are given, as well as estimates of three modes of bending
      stiffness. Based on these estimates and data from the microchamber experiment,
      where the cell is under the action of transmembrane potential changes, the
      characteristics of the outer hair cell active behaviour are found. These
      characteristics include the coefficients of the active force production per unit
      of the transmembrane potential change and limiting parameters of the
      electromotile response for extreme hyperpolarisation and depolarisation of the
      cell. The obtained estimates provide important information for the modelling of
      organ-level cochlear mechanics.

PMID- 10396831
TI  - Mechanical and dimensional adaptation of rabbit carotid artery cultured in vitro.
AB  - The effects of the mechanical environment on arterial walls were investigated in
      rabbit common carotid arteries, cultured for six days under three different
      intraluminal pressures (0, 80 and 160 mmHg) in a perfusion culture system. The
      mechanical responses following the culture were examined using a quasi-static
      pressure-diameter test. Specimen viability was determined by smooth muscle
      contraction induced with KCl. Eighteen out of 21 cultured segments showed a peak
      reduction in diameter of more than 10% and were used for the analysis. The
      arterial segments cultured at 0 mmHg had a significantly smaller diameter than
      those cultured at other pressures. The segments cultured at higher pressure had
      lower incremental elastic moduli at 20 and 80 mmHg and higher moduli at 160 mmHg.
      The walls of the cultured segments were thicker in groups with higher pressure.
      These results indicate that, even in culture, the mechanical environment is a
      major determinant for the mechanical property and dimensions of the arterial
      wall. Arterial walls may respond to their mechanical environment even if other
      factors, such as hormonal environment and nervous stimuli, are kept unchanged.

PMID- 10396832
TI  - Flow-mediated cell stress induction in adherent leukocytes is accompanied by
      modulation of morphology and phagocytic function.
AB  - Leukocytes adherent to the surfaces of both vascular biomaterials and normal
      blood vessels experience blood flow induced shear stress. The goal of the
      reported studies was to investigate the effect of fluid flow on the morphology,
      phagocytic function and stress response induction in adherent immune cells. Shear
      approximating arterial, venous and intermediate levels were applied onto glass
      adherent IC21 macrophages in a temperature-controlled parallel plate flow system.
      The results indicate that fluid flow induces a shear-dependent physiological
      stress response in adherent macrophages and that significant morphological
      changes accompany macrophage responses to shear stress. In addition, arterial
      flow conditions induce not only significant cell polarisation, but also enhanced
      phagocytic ingestion in glass-adherent IC21 macrophages. These findings suggest
      that blood flow induced shear stress may not only be consequent to adherent
      leukocyte activation, but may also be integral to the regulation of adherent
      leukocyte behaviour in vivo.

PMID- 10396833
TI  - Dielectric single particle spectroscopy for measurement of dispersion.
AB  - Measuring the frequency-dependent behaviour of single particles or biological
      cells in inhomogeneous and/or rotating electric fields is a sensitive method for
      characterising their dielectric properties. This technique is able to detect
      broad dispersion in the megahertz range of homogeneous artificial Sephadex G15
      spheres. Recent progress has opened up the possibility of carrying out dielectric
      spectroscopy in cell culture media. Dielectrophoretic and electrorotational
      spectra of different cells in media of varying conductivity can only be explained
      by the introduction of dispersive cell compartments. The cytoplasm of animal
      cells typically exhibits a broad dispersion around 15 MHz and there is evidence
      for membrane dispersion around 50 MHz.

PMID- 10396834
TI  - Multichannel magnetocardiographic measurements with a physical thorax phantom.
AB  - Artificial dipolar sources were applied inside a physical thorax phantom to
      experimentally investigate the accuracy obtainable for non-invasive
      magnetocardiographic equivalent current dipole localisation. For the
      measurements, the phantom was filled with saline solution of electrical
      conductivity 0.21 S m-1. A multichannel cardiomagnetometer was employed to record
      the magnetic fields generated by seven dipolar sources at distances from 25 mm to
      145 mm below the surface of the phantom. The inverse problem was solved using an
      equivalent current dipole in a homogeneous boundary element torso model. The
      dipole parameters were determined with a non-linear least squares fitting
      algorithm. The signal-to-noise ratio (SNR) and the goodness of fit of the
      calculated localisations were used in assessing the quality of the results. The
      dependence between the SNR and the goodness of fit was derived, and the results
      were found to correspond to the model. With SNR between 5 and 10, the average
      localisation error was found to be 9 +/- 8 mm, while for SNR between 30 and 40
      and goodness of fit between 99.5% and 100%, the average error reduced to 3.2 +/-
      0.3 mm. The SNR values obtained in this study were also compared with typical
      clinical values of SNR.

PMID- 10396835
TI  - Technique of distortion correction in endoscopic images using a polynomial
      expansion.
AB  - A new technique to correct non-linear distortion of endoscopic images based on L2
      norm approximation is proposed. A mathematical model is defined that maps the
      endoscopic images from the distorted image plane onto an undistorted image plane.
      A set of model parameters is defined, consisting of the image distortion centre,
      corrected centre and expansion polynomial coefficients representing radial
      distortion correction. A new method to find the image distortion centre based on
      a curvature criterion is also developed. The expansion coefficients are estimated
      on the basis of the degree of straightness of the grid lines in an image of a
      test grid consisting of dots in a rectangular pattern. The corrected image centre
      is computed by ensuring that the distances between neighbouring test dots of
      different grid lines in the corrected image are the same. The quantitative data
      providing the results and errors of the expansion characteristics are presented.
      The performance of the proposed distortion correction algorithm is validated with
      grid patterns of different orientations. The algorithm is also applied to typical
      endoscopic images, and the results are presented. The high-speed response of the
      proposed technique is a key step towards on-line camera calibration.

PMID- 10396836
TI  - Application of dynamic computed tomography for measurements of local aortic
      elastic modulus.
AB  - A novel computed tomographic (CT) technique used for the instantaneous
      measurement of the dynamic elastic modulus of intact excised porcine aortic
      vessels subjected to physiological pressure waveforms is described. This system
      was comprised of a high resolution X-ray image intensifier based computed
      tomographic system with limiting spatial resolution of 3.2 mm-1 (for a 40 mm
      field of view) and a computer-controlled flow simulator. Utilising cardiac gating
      and computer control, a time-resolved sequence of 1 mm thick axial tomographic
      slices was obtained for porcine aortic specimens during one simulated cardiac
      cycle. With an image acquisition sampling interval of 16.5 ms, the time sequences
      of CT slices were able to quantify the expansion and contraction of the aortic
      wall during each phase of the cardiac cycle. Through superficial tagging of the
      adventitial surface of the specimens with wire markers, measurement of wall
      strain in specific circumferential sectors and subsequent calculations of
      localised dynamic elastic modulus were possible. The precision of circumferential
      measurements made from the CT images utilising a cluster-growing segmentation
      technique was approximately +/- 0.25 mm and allowed determination of the dynamic
      elastic modulus E(dyn) with a precision of +/- 8 kPa. Dynamic elastic modulus was
      resolved as a function of the harmonics of the physiological pressure waveform
      and as a function of the angular position around the vessel circumference.
      Application of this dynamic CT (DCT) technique to seven porcine thoracic aortic
      specimens produced a circumferential average (over all frequency components)
      E(dyn) of 373 +/- 29 kPa. This value was not statistically different (p < 0.05)
      from the values of 430 +/- 77 and 390 +/- 47 kPa obtained by uniaxial tensile
      testing and volumetric measurements respectively.

PMID- 10396837
TI  - A method for determining the information capacity of x-ray imaging scintillator
      detectors by means of luminescence and modulation transfer function measurements.
AB  - A method to determine the information capacity of x-ray phosphor screens used in
      the detectors of medical imaging systems is described. Information capacity was
      determined via x-ray luminescence efficiency (XLE), modulation transfer function
      (MTF) and emission spectrum measurements. The method was applied to laboratory
      prepared screens from commonly employed phosphor materials. The screen coating
      weight varied from 50 mg cm-2 to 140 mg cm-2. Results indicated that information
      capacity decreased with screen coating thickness but also depended on intrinsic
      phosphor properties (density, effective atomic number, intrinsic conversion
      efficiency, light wavelength). The Gd2O2S:Tb phosphor, exhibiting high density
      and effective atomic number, was found to be superior to La2O2S:Tb and Y2O2S:Tb.

PMID- 10396838
TI  - Measurement of forces associated with compression therapy.
AB  - Compression therapy is the principal treatment for leg ulcers associated with
      venous disease. The efficacy of compression therapy can be variable, which may in
      part be owing to the degree of compression applied. However, if the mechanism of
      action of this treatment could be better understood, it might be possible to
      improve its efficacy. It is not clear whether assessment of the degree of
      compression should be made under static or dynamic conditions, or both. A review
      of methods used previously suggests the need for a new method of assessment
      allowing continuous monitoring, even during movement. A system for continuous
      static and dynamic measurements of compression is described. Using an air chamber
      and manometer to test the system, agreement within +/- 3 mmHg is observed. The
      system is applied to investigate changes in forces, expressed as pressure, under
      bandages and compression stockings. Application of five bandage systems by
      experienced nurses to a volunteer shows a marked variation in applied pressure.
      During short periods of walking, rapid changes in pressure under compression
      stockings are observed, including some transients of less than 0.25 s. The method
      is simple to apply and may help to understand further the mechanism of action of
      compression therapy.

PMID- 10396839
TI  - Gait control system for functional electrical stimulation using neural networks.
AB  - In functional electrical stimulation (FES) systems for restoring walking in
      spinal cord injured (SCI) individuals, hand switches are the preferred method for
      controlling stimulation timing. Through practice the user becomes an 'expert' in
      determining when stimulation should be applied. Neural networks have been used to
      'clone' this expertise but these applications have used small numbers of sensors,
      and their structure has used a binary output, giving rise to possible controller
      oscillations. It was proposed that a three-layer structure neural network with
      continuous function, using a larger number of sensors, including 'virtual'
      sensors, can be used to 'clone' this expertise to produce good controllers. Using
      a sensor set of ten force sensors and another of 13 'virtual' kinematic sensors,
      a good FES control system was constructed using a three-layer neural network with
      five hidden nodes. The sensor set comprising three sensors showed the best
      performance. The accuracy of the optimum three-sensor set for the force sensors
      and the virtual kinematic sensors was 90% and 93%, respectively, compared with
      81% and 77% for a heel switch. With 32 synchronised sensors, binary neural
      networks and continuous neural networks were constructed and compared. The
      networks using continuous function had significantly fewer oscillations.
      Continuous neural networks offer the ability to generate good FES controllers.

PMID- 10396841
TI  - Estimation of respiratory volumes from the photoplethysmographic signal. Part 2:
      A model study.
AB  - A Windkessel model has been constructed with the aim of investigating the
      respiratory-volume dependence of the photoplethysmographic (PPG) signal.
      Experimental studies show a correlation between respiratory volume and the peak
      to-peak value of the respiratory-induced intensity variations (RIIV) in the PPG
      signal. The model compartments are organised in two closed chambers, representing
      the thorax and the abdomen, and in a peripheral part not directly influenced by
      respiration. Cardiac pulse and respiration are created by continuous adjustment
      of the pressures in the affected compartments. Together with the criteria for
      heart and venous valves, the model is based on a set of 17 differential
      equations. These equations are solved for varying thoracic and abdominal
      pressures corresponding to different respiratory volumes. Furthermore, a
      sensitivity analysis is performed to evaluate the properties of the model. The
      PPG signals are created as a combination of peripheral blood flow and pressure.
      From these signals, the respiratory synchronous parts are extracted and analysed.
      To study some important limitations of the model, respiratory type and rate are
      varied. From the simulations, it is possible to verify our earlier experimental
      results concerning the relationship between respiratory volume and the peak-to
      peak value of the RIIV signal. An expected decrease in the amplitude of the
      respiratory signal with increased respiratory rate is also found, which is due to
      the lowpass characteristics of the vessel system. Variations in the relationship
      between thoracic and abdominal respiration also affect the RIIV signal. The
      simulations explain and verify what has been found previously in experimental
      studies.

PMID- 10396840
TI  - Estimation of respiratory volumes from the photoplethysmographic signal. Part I:
      Experimental results.
AB  - To evaluate the possibility of respiratory-volume measurement using
      photoplethysmography (PPG), PPG signals from 16 normal volunteers are collected,
      and the respiratory-induced intensity variations (RIIV) are digitally extracted.
      The RIIV signals are studied while respiratory volume is varied. Furthermore,
      respiratory rate, body posture and type of respiration are varied. A Fleisch
      pneumotachograph is used as the inspired volume reference. The RIIV and
      pneumotachograph signals are compared, and a statistical analysis is performed
      (linear regression and t-tests). The key idea is that the amplitude of the RIIV
      signal is related to the respiratory volume. The conclusion from the measurements
      is that there exists a relationship between the amplitude of the RIIV signal and
      the respiratory volume (R = 0.842, s = 0.428, p < 0.005). Absolute measurements
      of the respiratory volume are not possible from the RIIV signal with the present
      set-up. The RIIV signal also seems to be affected by respiratory rate and type.
      More knowledge about respiratory parameters and improved sensor and filter design
      are required to make absolute measurements of volumes possible.

PMID- 10396842
TI  - Very low frequency variability in arterial blood pressure and blood volume pulse.
AB  - Several parameters of the cardiovascular system fluctuate spontaneously owing to
      the activity of the autonomic nervous system. In the study, the simultaneous very
      low frequency (VLF) fluctuations of the arterial blood pressure, the tissue blood
      content and the tissue blood volume pulse are investigated. The latter two
      parameters are derived from the baseline BL and the amplitude AM of the
      photoplethysmographic (PPG) signal, measured on the fingertips of 20 healthy male
      subjects: the changes in the PPG parameters AM and BV, defined by BV = const.-BL,
      are related to the change in the tissue blood volume pulse and the total tissue
      blood volume, respectively. The VLF fluctuations in BV and AM are directly
      correlated, those of AM preceding those of BV by 4-13 heart-beats. The VLF
      fluctuations in the systolic (SBP) and the diastolic (DBP) blood pressure are
      inversely correlated to those of AM and BV, those of AM preceding those of SBP
      and lagging behind those of DBP by about one heart-beat. For most subjects, the
      period P of the PPG pulse, which is equal to the cardiac cycle period, directly
      correlates with AM and BV and inversely correlates with DBP and SBP. On average,
      the fluctuations of P precede those of AM by more than three heart-beats. The
      measurement of the VLF fluctuations in tissue blood volume, systolic blood volume
      pulse, diastolic and systolic blood pressure, and heart period, together with
      their interrelationship, can provide a better understanding of the autonomic
      nervous control of the peripheral circulation and a potential tool for the
      evaluation of its function.

PMID- 10396843
TI  - Computer modelling of the cerebrospinal fluid flow dynamics of aqueduct stenosis.
AB  - As the craniospinal space is a pressure loaded system it is difficult to
      conceptualize and understand the flow dynamics through the ventricular system.
      Aqueduct stenosis compromises flow, increasing the pressure required to move
      cerebrospinal fluid (CSF) through the ventricles. Under normal circumstances,
      less than one pascal (1 Pa) of pressure is required to move a physiological flow
      of CSF through the aqueduct. This is too small to measure using clinical pressure
      transducers. A computational fluid dynamics (CFD) program, CFX, has been used to
      model two forms of aqueduct stenosis: simple narrowing and forking of the
      aqueduct. This study shows that with mild stenoses, the increase in pressure
      required to drive flow becomes significant (86-125 Pa), which may result in an
      increased transmantle pressure difference but not necessarily an increased
      intraventricular pressure. Severe stenoses will result in both. Wall shear
      stresses increase concomitantly and may contribute to local damage of the
      aqueduct wall and further gliosis with narrowing.

PMID- 10396844
TI  - Study of catheter designs and drug mixing processes using 2D steady numerical
      simulations.
AB  - The effectiveness of substance delivery through catheters is an important issue
      in interventional radiology, especially for infusion therapies where the
      pharmacokinetic advantage of local intra-arterial drug administration has been
      firmly established. In principle, the procedure is used to provide appropriate
      local concentrations while maintaining low systemic values so as to minimise the
      global effect and toxicity of the intervention. However, poor drug mixing may
      produce excessive local concentrations potentially damaging for the surrounding
      tissues and may lead to unsuccessful therapies. These phenomena have been
      observed in the infusion therapies of liver cancers through the hepatic artery
      and with brain tumour therapies through the carotid artery. Many aspects of the
      drug delivery methodology have been explored in order to determine the infusion
      conditions that would provide optimal mixing: the catheter tip design is
      considered one of the most important characteristics to be investigated for this
      purpose. Interestingly, it turns out that angiographic procedures could also
      benefit from this, because better mixing properties are associated with designs
      that provide potentially less harmful flow conditions such as jets, whipping and
      recoil of the catheter on the vascular wall. A 2D steady numerical model is
      proposed, to simulate the main physical processes occurring during catheter
      substance infusion: blood dynamics is taken into account with the Navier-Stokes
      equations and substance dispersion by the flowing blood with the advection
      diffusion equation. The model is used to evaluate mixing properties of certain
      catheter designs in different flow conditions. In particular, two types of side
      hole catheter are compared in the context of water bath injection and in the
      context of vessel injection. The simulations suggest that the improved mixing
      reported with water bath experiments would not be maintained in the clinical
      context of arterial circulation.

PMID- 10396845
TI  - QT interval analysis on ambulatory electrocardiogram recordings: a selective beat
      averaging approach.
AB  - A computerised method for the analysis of QT intervals in ambulatory ECG
      recordings is presented. This approach is based on selective beat averaging which
      allows one to process P-QRS-T complexes together with the environment that
      characterises them. Long-term autonomic nervous system influences are accounted
      for by separating the analysis over different circadian periods. Effects of QT
      recovery time are taken into account by requiring a stable heart rate preceding
      each beat to be averaged. Before averaging, beats are resampled and realigned
      with respect to the R-wave peak estimated by parabolic interpolation. Averaged
      ECG templates are then analysed with an algorithm which automatically detects QRS
      complex and T-wave features. Repolarisation analysis is based on first and second
      derivatives of lowpass filtered ECG (recursive Butterworth filter). The QT/RR
      relationship and the circadian QT variation at identical heart rate were analysed
      in 14 normal individuals. When performed at stable heart rate conditions and when
      confined to well-defined circadian periods, the QT/RR relationship was strongly
      linear (r = 0.95 +/- 0.06); in addition, the slope of this relation changed
      between day and night (respectively, 0.197 +/- 0.07 and 0.139 +/- 0.03, p <
      0.01). The range of circadian QT variation at identical heart rate was
      approximately 20 ms for both males and females.

PMID- 10396847
TI  - Artefact cancellation in motor-sensory evoked potentials: two approaches using
      adaptive filtration and exponential approximation.
AB  - Adaptive filtering for artefact cancellation in motor-sensory evoked potentials
      using signals obtained by subtraction methods (double-stimulus, off-nerve and
      subthreshold) is proposed. This is advantageous as inherent non-linear
      distortions can be overcome in an easier way by adaptive filtering. Efficiency is
      assessed with reference signals synthesised by varying the shape and reducing the
      amplitude of a 'pure' evoked potential in the range from 10% to 50%. The
      experiments show virtually identical shapes of the 'pure' and the filtered
      signal. The time shift between them is insignificant if a causal filter and small
      number of Widrow coefficients, e.g. N = 8, are used. Further, two-exponential
      artefact approximation is applied with subsequent direct subtraction from the
      contaminated signal by a specially designed PC-controlled system for data
      acquisition and processing. For a fast procedure convergence, one-parametric
      optimisation of the time-constant tau is used, starting with tau = 0.5 ms. The
      results obtained with artefact-corrupted evoked potentials from several subjects
      prove the efficiency of the approach. It has the substantial advantage of
      avoiding the need for reference signals. Both methods have advantages compared
      with other known software techniques.

PMID- 10396846
TI  - Blind separation of multichannel electrogastrograms using independent component
      analysis based on a neural network.
AB  - The electrogastrogram (EGG) is an abdominal surface measurement of gastric myo
      electrical activity which regulates gastric contractions. It is of great clinical
      importance to record and analyse multichannel EGGs, which provide more
      information on the propagation and co-ordination of gastric contractions. EGGs
      are, however, contaminated by myo-electric interference from other organs and
      artefacts such as motion and respiration. The aim of the study is to separate the
      gastric signal from noisy multichannel EGGs without any information on the
      interference, using independent component analysis. A neural-network model is
      proposed, and corresponding unsupervised learning algorithms are developed to
      achieve the separation. The performance of the proposed method is investigated
      using artificial data simulating real EGG signals. Experimental EGG data are
      obtained from humans and dogs. The processed results of both simulated and real
      EGG data show the following: first, the proposed method is able to separate
      normal gastric slow waves from respiratory artefacts and random noises. It is
      also able to extract gastric slow waves, even when the EGG is contaminated by
      severe respiratory and ECG artefacts. Secondly, when the stomach contains various
      gastric electric signals with different frequencies, the proposed method is able
      to separate these different signals, as illustrated by simulations. These data
      suggest that the proposed method can be used to separate gastric slow waves,
      respiratory and motion artefacts, and intestinal myo-electric interference that
      are mixed in the EGG. It can also be used to detect gastric slow-wave uncoupling,
      during which the stomach has multiple gastric signals with different frequencies.
      It is believed that the proposed method may also be applicable to other
      biomedical signals.

PMID- 10396849
TI  - A fast recursive-least-squares adaptive notch filter and its applications to
      biomedical signals.
AB  - A fast recursive-least-squares (FRLS) adaptive notch filter (ANF) for
      cancellation of sinusoidal interference from recorded biomedical signals is
      investigated. The FRLS ANF is derived by making an approximation to the
      conventional recursive-least-squares (RLS) ANF for computation economy. It
      outperforms the commonly adopted least-mean-squares (LMS) ANF, demonstrating a
      rapid and bandwidth-insensitive initial convergence. A novel application of the
      FRLS ANF is for the elimination of the tonal artefact in distortion product
      otoacoustic emission (DPOAE) signals.

PMID- 10396848
TI  - Temporal and spatial complexity measures for electroencephalogram based brain
      computer interfacing.
AB  - There has been much interest recently in the concept of using information from
      the motor cortex region of the brain, recorded using non-invasive scalp
      electrodes, to construct a crude interface with a computer. It is known that
      movements of the limbs, for example, are accompanied by desynchronisations and
      synchronisations within the scalp-recorded electroencephalogram (EEG). These
      event-related desynchronisations and synchronisations (ERD and ERS), however,
      appear to be present when volition to move a limb occurs, even when actual
      movement of the limb does not in fact take place. The determination and
      classification of the ERD/S offers many exciting possibilities for the control of
      peripheral devices via computer analysis. To date most effort has concentrated on
      the analysis of the changes in absolute frequency content of signals recorded
      from the motor cortex. The authors present results which tackle the issues of
      both the interpretation of changes in signals with time and across channels with
      simple methods which monitor the temporal and spatial 'complexity' of the data.
      Results are shown on synthetic and real data sets.

PMID- 10396850
TI  - Computerised volumetric analysis of lesions in multiple sclerosis using new semi
      automatic segmentation software.
AB  - The paper describes the application of new semi-automatic segmentation software
      to the task of detection of anatomical structures and lesion and their three
      dimensional (3D) visualisation in 23 patients with secondary progressive multiple
      sclerosis (MS). The purpose is to study the correlation between magnetic
      resonance imaging (MRI) parameters (volumes of plaques and cerebrospinal fluid
      spaces) and clinical deficits (neurological deficits in the form of EDSS and RFSS
      scores, and neuropsychological deficits). The software operates in PC/Windows and
      PC/NeXTstep environments and utilises graphical user interfaces. Quantitative
      accuracy is measured by performing segmentation of fluid-filled syringes
      (relative error of 1.5%), and reproducibility is measured by intra- and inter
      observer studies (3% and 7% variability, respectively). The mean volumes of MS
      plaques show significant correlations with the total RFSS scores (p = 0.04).
      Relative intracranial cerebrospinal fluid (CSF) space volumes show statistically
      significant correlation with EDSS scores (p = 0.01). The mean volume of MS
      plaques shows a significant correlation with the overall neuropsychological
      deficits (p = 0.03). 3D visualisation helps to understand the relationship of
      lesions to the surrounding brain structures. The use of semiautomatic
      segmentation techniques is recommended in the clinical diagnosis of MS patients.

PMID- 10396851
TI  - Dependence of cardiac strength-interval curves on pacing rate.
AB  - The purpose of the research is to determine how the pacing rate affects the
      strength-interval curve in cardiac tissue. Computer simulations are used to
      calculate the cathodal and anodal strength-interval curves. The tissue is
      represented by the bidomain model with Beeler-Reuter membrane properties. The
      strength-interval curves shift to shorter intervals as the pacing rate increases.
      However, the shape of the strength-interval curve, including the separation into
      'make' and 'break' sections and the presence of a 'dip', is insensitive to pacing
      rate.

PMID- 10396852
TI  - Microstructures for studies of cultured neural networks.
AB  - A description is given of a functional silicon micromachined device that permits
      non-invasive, bidirectional, highly specific communication with cultured
      mammalian neurons. The heart of the system is a well structure that holds the
      cell in close proximity to a metal extracellular electrode while permitting
      normal outgrowth of axons and dendrites. An iterative approach is used to create
      a design that allows normal growth of the neurons while preventing their escape.
      An array of 16 such neurowells makes it possible to perform studies of biological
      neural network development and function with unprecedented detail.

PMID- 10396853
TI  - Computer modelling of the adsorption of proteins on solid surfaces under the
      influence of double layer and van der Waals energy.
AB  - The study of protein interactions with surfaces is important in many branches of
      biomedical engineering. A computer model has been set up in order to aid the
      understanding and prediction of the likelihood of protein adsorption at a surface
      and of coagulation between two proteins. In this model, a protein is represented
      as a hard sphere, neglecting conformation changes which may occur during the
      adsorption process. The sphere is assumed to be in a medium whose properties are
      described by the ionic strength, the pH and the dielectric permittivity. It is
      considered to interact both with an infinite plane, representing the surface, and
      with another sphere, representing another protein. The model focuses on the total
      interaction energy between a protein and a surface and between two proteins. The
      energy is expressed according to the DLVO theory of colloidal stability, which
      assumes that the adsorption behaviour of proteins at a surface depends, first, on
      the van der Waals interactions energy and, second, on the electrostatic double
      layer interaction energy. The conditions under which adhesion is prevented
      correspond to the presence of local extremes of the energy function, whereas the
      conditions under which adhesion is likely to take place correspond to absence of
      local extremes.

PMID- 10396854
TI  - Amphiphile-induced spherical microexovesicle corresponds to an extreme local area
      difference between two monolayers of the membrane bilayer.
AB  - It is shown that an increase of the area difference between the outer and the
      inner membrane lipid layers of the skeleton-free membrane segment as a result of
      exogenously added amphiphilic molecules results in budding of the segment. The
      process reaches its final point when the segment attains the shape of the local
      maximal area difference, corresponding to formation of a spherical
      microexovesicle.

PMID- 10396856
TI  - [Hospital pharmacy service].

PMID- 10396855
TI  - N,N-dicarboxymethyl chitosan as delivery agent for bone morphogenetic protein in
      the repair of articular cartilage.
AB  - Bone morphogenetic protein (BMP), associated with N,N-dicarboxymethyl chitosan,
      is used to induce or facilitate the repair of articular cartilage lesions. This
      association is intended for the synergistic potentiation of the respective
      biological effects. Data show that BMP-7 enhances the in vivo proliferation of
      cells with chondrocytes phenotype in the articular environment, leading to
      partial healing of the articular surface of the lesions. N,N-dicarboxymethyl
      chitosan is found to be useful as a molecular carrier or drug delivery agent.

PMID- 10396858
TI  - [Transcutaneous radiotherapy after thyroidectomy for differentiated thyroid
      carcinoma].
AB  - PURPOSE: To compare the results, in terms of 10-year actuarial survival, between
      I-131-therapy and I-131-therapy + external beam radiotherapy (RT) in patients
      operated on for differentiated thyroid carcinoma. PATIENTS AND METHODS: Over a
      period of 13 years (1982-1995) 408 patients underwent thyroidectomy with or
      without linphoadenectomy for pT0/T4 Nx or pN0, pN1a, pN1b thyroid carcinoma. In
      all cases, thyroidectomy was radical. Patients were divided into two groups,
      which were comparable according to several prognostic factors: group A composed
      of 165 patients (surgery + I-131) and group B, 243 patients (surgery + I-131 +
      RT). RESULTS: The percentage of deaths related to relapsed or metastatic thyroid
      carcinoma was 6.25%. In the group treated with adjuvant radiotherapy, 14.8% of
      the patients experienced acute tracheal or esophageal side effects. Late toxicity
      (mouth dryness, skin and/or muscle fibrosis) was recorded only in a small
      percentage of the patients (2.4%). CONCLUSIONS: Adjuvant RT resulted in a
      statistically significant improvement (p < 0.01) in survival of patients with
      extracapsular diffusion of the cancer, especially those with pT4 N1b tumors or
      tumors involving the trachea.

PMID- 10396857
TI  - [IX. International Congress on cancer treatment. 2-5 February 1999, Paris,
      France].

PMID- 10396859
TI  - [Chemotherapy of advanced stage melanoma using cisplatin, epirubicin and alpha
      interferon].
AB  - PURPOSE: To evaluate the activity and toxicity of cisplatin (DDP), epirubicin
      (EPI) and interferon alfa-2a (a-IFN) in patients (pts) with metastatic melanoma.
      PATIENTS AND METHODS: Thirty-seven pts with histologically-proven metastatic
      melanoma were treated with DDP 75 mg/m2 e.v. and EPI 90 mg/m2 e.v. on day 1 +
      alpha-IFN 9 MUI/die s.c. on days 4 to 8 and 18 to 22. Cycles were repeated every
      4 weeks. RESULTS: Characteristics of the patients were the following: median age
      55 years (range, 24-75), median WHO performance status 1 (range, 0-2), prior
      chemotherapy 9, prior immunotherapy 16 (adjuvant/advanced 11/5), sites of
      disease: soft tissue only 10, lung 22, liver 11, bone 1, brain 3. In 35 evaluable
      patients we have obtained 3 complete and 10 partial responses, for an overall
      response rate of 37%. Dose-limiting toxicity was myelosuppression with grade (G)
      4 neutropenia in 59.5% of patients and G4 thrombocytopenia in 11% of patients.
      Other toxicities were generally mild to moderate with nausea and vomiting in
      67.5% of patients, flu-like syndrome in 78.5% and fatigue in 48.5% of the
      patients. Median time to response, median time to progression and survival were 3
      (range, 2-6), 7 (range, 2-45+) and 10 months (range, 4-45+), respectively.
      CONCLUSION: This combination is active and well tolerated in metastatic melanoma.
      Toxicity was manageable and has enabled us to conduct this trial on an outpatient
      basis.

PMID- 10396860
TI  - Hunger sensation in Graves' disease before and after pharmacological therapy.
AB  - PURPOSE: Hunger sensation (HS) provides information about the need of eating in
      order to counterbalance the energy expenditure (EE). HS was, thus, investigated
      in patients affected by Graves' disease (PAGD), a clinical condition
      characterized by excessive EE. MATERIALS AND METHODS: Ten newly diagnosed PAGD
      were investigated before and after therapy. Thirty clinically healthy subjects
      (CHS) were investigated as controls. The investigated subjects were asked to
      provide the 24-h profile of their HS by subjectively self-rating (from 1 to 10
      hunger units) their orectic perception (OP) at regular intervals of 30 minutes
      (orexigram). The orexigrams were investigated via the conventional descriptive
      statistics as well as the Single-Cosinor method. RESULTS: PAGD were found to show
      a very consistent increase of their HS (hyperorexia), whose day-night variability
      was, still, the expression of a circadian rhythm, characterized by an elevation
      in its oscillatory level and extent. Interestingly, the pre-treatment hyperorexia
      was seen to show a normalization (eurexia) after pharmacological therapy.
      CONCLUSIONS: According to these results, it can be affirmed that hyperorexia is a
      clinical sign of Graves' disease, which is obtained via mechanisms of tonic and
      amplitude modulation of the HS circadian rhythm. Because of the eurexia after
      remission, it can be argued that the hyperorexia is a theleological response
      really aimed at increasing food intake in order to counterbalance the excessive
      EE which characterizes the thyrotoxicosis.

PMID- 10396861
TI  - [Evaluation study of the opinion on Di Bella's multimodal therapy of patients
      with tumors. 2].
AB  - PURPOSE: To evaluate the opinion of patients with tumors who chose spontaneously
      to undergo the traditional anti-cancer treatment about Di Bella's therapy after
      the negative results of the experimental trial. MATERIALS AND METHODS: From
      November 23rd, 1998 to December 10th, 1998 a questionnaire was distributed among
      50 patients with tumors. The questionnaire was anonymous, self-administered and
      included 9 questions. The data were compared, when possible, with those obtained
      in a previous study. RESULTS: Overall, 40 (70%) patients accepted favourably the
      conventional therapy; 27 (54%) patients did not believe in the experimental
      trial, as it was performed; 34 (68%) patients think the experimental trial should
      be repeated. CONCLUSIONS: The negative results of the experimental trial caused a
      distrustful feeling towards the Di Bella multi-therapy; but there is much
      confusion. There is a strong feeling that the conventional medicine is linked to
      powerful interests of the international pharmaceutical firms.

PMID- 10396862
TI  - [Virtual reality: a simple joke or therapeutic instrument?].
AB  - Virtual reality is a relatively new application for rehabilitative neurology, and
      achieve many successes in assessment and treatment of CNS damages. The Authors
      describe a prototype computer simulation for virtual environment reconstruction
      to assess the fundamental living skills of every day dedicated to persons in
      which CNS injury was occurred.

PMID- 10396863
TI  - Cell cycle and cancer.
AB  - PURPOSE: To evaluate the link between cell cycle dysfunctions and tumor
      formation. DESIGN: A review of the cell cycle mechanism and its regulatory
      factors which are involved in carcinogenesis. RESULT: Cell duplication is
      directed by a precise cellular machine. The engine of this machine is composed of
      the cyclin-dependent kinases (Cdks). Their function mainly consists of
      phosphorylating the pRb family of proteins to conduct the cell towards a series
      of events that end in generating two sister cells from one mother cell. The
      regulation of Cdk activity depends on several cellular proteins that are part of
      a major system that is able to sense extracellular factors and intracellular
      signals. Abnormalities in cell cycle regulation and in its checkpoints lead to
      development of malignant cells. Various components of the cell cycle machinery
      are mutated, overexpressed or eliminated in several human cancers. Some of them
      can be even classified as oncogenes or tumor suppressor genes. CONCLUSIONS: It is
      necessary to design new antitumoral strategies able to target cells harboring
      such alterations, in order to understand the events that regulate the cell cycle
      and its disruption during oncogenesis.

PMID- 10396864
TI  - [The role of MRI in the diagnosis and evaluation of extension of the disease and
      condition of patients with neurofibromatosis].
AB  - Neurofibromatosis 1 (NF 1) and Neurofibromatosis 2 (NF 2) have been recently
      recognized to be distinct disorders through genetic linkages. MR imaging can be
      used to identify abnormalities of the head and spine in patients with these
      disorders. This review highlights some important but lesser known aspects of the
      two more common phakomatoses. The role of newer imaging technique such as
      contrast-enhanced MR imaging in the evaluation of these disorders also are
      discussed.

PMID- 10396865
TI  - [Metaplastic tumors of the breast: a case of primary squamous cell carcinoma].
AB  - We report a case of primary squamous cell carcinoma of the breast in a 58 years
      old woman. The diagnosis of this rare tumor is possible after excluding a skin
      primary lesion or an epidermoid cancer of a distant site. In reviewing the
      reported cases we didn't find any significant prognostic difference between this
      form and the breast adenocarcinoma with squamous metaplasia.

PMID- 10396866
TI  - [Evolution of cancer chemotherapy. Discovery of new active drugs. III].

PMID- 10396867
TI  - [Evaluation of dermatological symptoms of Yusho patients in the annual
      examination in 1997-1998].
AB  - We analyzed the severity grades of the skin symptoms of Yusho patients who
      visited the annual examinations in 1997 and 1998. The severity grades of the skin
      symptoms clearly improved. The patients graded as 0 I-II increased and those
      graded as II III-III decreased as compared to the data in 1993 and 1994. The skin
      severity scores did not change much, although the patients who showed 0 or 1
      reached more than 60% in both 1997 and 1998. The blood PCB concentration of Yusho
      patients also clearly decreased, especially in the patients who showed "A"
      pattern.

PMID- 10396868
TI  - [Serum immunoglobulin concentrations and autoantibodies in patients with Yusho].
AB  - To evaluate chronic immune effects of polychlorinated biphenyl (PCB), serum
      immunoglobulin concentrations and autoantibodies were studied in 79 patients with
      Yusho in 1997. Serum levels of immunoglobulin A (IgA), immunoglobulin G (IgG) and
      immunoglobulin M (IgM) were elevated in 10 cases (12.7%), 19 cases (24.1%) and 7
      cases (8.9%), respectively. Autoatibodies were present in some patients of Yusho;
      10 cases (12.7%) for rheumatoid factor and 36 cases (45.6%) for antinuclear
      antibody. LE factor was not detected. There were no significant correlations
      between blood PCB concentrations and serum immunoglobulin concentrations, or
      presence of autoantibodies. We conclude that antinuclear antibody in patients
      with Yusho is frequent, although it may not be associated with blood PCB
      concentration.

PMID- 10396869
TI  - [An epidemiologic examination on the prevalence of the periodontal diseases and
      oral pigmentation in Yusho patients in 1998].
AB  - An epidemiologic examination was carried out to reveal the prevalence of the
      periodontal diseases and oral pigmentation in patients with Yusho 30 years after
      PCBs exposure. The results obtained were as follows. 1) 69 patients out of 71
      patients with Yusho, who were measured periodontal pocket depth using Ramfjord'
      methods, had at least one tooth with periodontal pocket deeper than 3 mm.
      Similarly, 241 teeth out of a total 348 examined teeth showed periodontal pocket
      with more than 3 mm depth. 2) Oral pigmentation was observed in 46 out of 79
      patients with Yusho. In this study, gingival pigmentation was most predominant
      among oral pigmentation. In addition, it is of particular interest that oral
      pigmentation tended to be observed at a much higher frequency in younger patients
      with Yusho.

PMID- 10396870
TI  - [Site specific difference of PCB concentration in the skin derived sebum and
      collection of excreted sebum with commercial sebum-remover sheet].
AB  - The PCB concentrations in the sebum of Yusho patients showed a site specific
      difference. It was higher in the sebum derived from the chest (1128.0 +/- 374.1
      ng/g), the upper arm (1460.0 +/- 350.7 ng/g) and the femur (1456.0 +/- 488.5
      ng/g) than from the forehead (758.0 +/- 233.7 ng/g) and the upper back skin
      (638.0 +/- 165.3 ng/g). To remove PCB in the sebum, a sebum-remover sheet was
      applied on the femur of two patients. During the four times of application, the
      mean amounts of removed sebun was 10.5 mg and 28.3 mg respectively. These results
      are unsatisfactory for practical treatment of Yusho patient. However, this
      approach seems to be safe and convenient and modification to collect large scale
      of sebum from the skin is required.

PMID- 10396871
TI  - [Association between the results of blood test and blood PCB level of chronic
      Yusho patients twenty five years after the outbreak].
AB  - A cross-sectional study on the association between the results of blood test and
      the blood concentration of PCB was conducted on the chronic Yusho patients. The
      subjects were 265 Yusho patients (134 men and 131 women) who received the annual
      nationwide health examination for Yusho in 1993. The results of the blood test
      and questionnaire survey at the annual health examination were used for the
      analyses using ANCOVA. Serum levels of triglycerides, total cholesterol, GOT,
      GPT, gamma-GTP, total bilirubin, and conjugated bilirubin were associated with
      the blood concentration of PCB adjusting for sex, age, drinking habit, smoking
      habit and body mass index (BMI). Because the distribution of the serum levels was
      strongly skewed to the right except that of serum concentration of total
      cholesterol, they were log transformed to approximate to the Normal distribution.
      The association between age and the blood concentration of PCB was significant (P
      < 0.001), although the associations of sex, drinking habit, smoking habit and BMI
      to the blood concentration of PCB were not significant. With the adjustment for
      sex, age, drinking habit, smoking habit and BMI, the serum concentrations of
      triglycerides and total cholesterol were significantly associated with the blood
      PCB level expressed by loge (blood concentration of PCB in ppb-1) (P = 0.02 and P
      < 0.001, respectively). The associations of serum levels of GOT, GPT, gamma-GTP,
      total bilirubin and conjugated bilirubin to the PCB level were not significant.
      The results of this study suggests the need of careful observation on the serum
      lipids of Yusho patients, especially those with high concentration of blood PCB,
      because the serum concentrations of total cholesterol and triglycerides are
      prominent risk factors of heart diseases.

PMID- 10396872
TI  - [Effect of protoporphyrin on digestive tract absorption of dioxins in rats].
AB  - This paper presents the fecal excretion of polychlorinated dibenzo-p-dioxin
      (PCDD) congeners, and polychlorinated dibenzofuran (PCDF) congeners in male rats
      fed a diet containing 0.5% disodiumprotoporphyrin (PPNa) or 0.5% hemin. The
      animals were administered 4 g of 0.5% PPNa or 0.5% hemin diet containing 0.5 ml
      of the causal rice-bran oil of Yusho that had occurred in the Southwest part of
      Japan in 1968 and kept on the same diet for five days. The fecal excretion of
      2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed with 0.5% PPNa were 2.1 and
      1.9 times higher, respectively, than that in the group fed with a control diet.
      Hemin did not show any significant effect on the inhibition of absorption of
      dioxins. Next, the rats were given a diet containing 0.5% PPNa or 0.5% Hemin for
      four weeks after a week interval from the day of the causal rice-bran oil
      administration. The fecal excretion of 2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the
      group fed with 0.5% PPNa were stimulated 2.1 times higher, respectively, than
      that in the group fed with a control diet. Hemin did not show any significant
      effect on the inhibition of re-absorption of dioxins.

PMID- 10396873
TI  - [Effect of green vegetable on digestive tract absorption of polychlorinated
      dibenzo-p-dioxins and polychlorinated dibenzofurans in rats].
AB  - The effect green vegetable on fecal excretion of polychlorinated dibenzo-p-dioxin
      (PCDD) congeners and polychlorinated dibenzofuran (PCDF) congeners was examined
      in male rats. The rats were administered 10% vegetable diets or a basal diet
      containing 0.2 ml of the causal rice-bran oil of Yusho that had occurred in the
      Southwest part of Japan in 1968 and kept on the same diet for five days. The
      fecal excretion of 2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed with
      Komatsuna, Mitsuba, Spinach and Perilla were 7.6-11.6 and 6.5-9.4 times higher,
      respectively, than that in the group fed with a basal diet. The fecal excretion
      of 2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed with Kale, Chinese chive,
      Shungiku, Chingentsuai, Green lettus and Sweet pepper were 3.3-4.8 and 4.3-4.5
      times higher, respectively, than that in the basal group. The fecal excretion of
      2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed with Chinese cabbage,
      Broccoli, Onion, Welsh onion, Cabbage and Celery were 1.6-3.0 and 1.2-1.3 times
      higher, respectively, than that in the basal group. A correlation between
      Chllophyll consumption and fecal excretion of PCDD and PCDF congeners was highly
      significant (p < 0.01). Next, we investigated the fecal excretion of PCDD and
      PCDF congeners from day 8 to day 35 in rats administered with 0.5 ml of the rice
      oil. The fecal excretion of 2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed
      with Perilla, Kale and Spinach were 3.1-4.9 and 3.0-3.6 times higner,
      respectively, than that in the basal group. The presents results suggest that the
      green vegetables might be useful in treatment of humans exposed to PCDD and PCDF
      congeners.

PMID- 10396874
TI  - [Blood PCB analysis by capillary column-gas chromatograph/quadruple mass
      spectrometer--comparison with packed column-electron capture detector/gas
      chromatograph].
AB  - The contents of polychlorinated biphenyls (PCBs) in the blood of Yusho patients
      (Y) and normal subjects (N) were analyzed, using a gas-chromatograph equipped
      with a capillary column/quadruple mass spectrometer (capillary column GC/MS).
      While the average of the content of blood PCBs was 679 ppt in N, those were 2960,
      1480 and 1090 ppt in Y diagnosed previously as A, B and C patterns, respectively.
      The contents of non-ortho coplanar PCBs (3,3',4,4' Tetra-, 3,3',4,4',5-Penta-
      plus 3,3',4,4',5,5'-Hexa-CB) were 0.9-2.1 ppt in Y, and 0.8 ppt in N. The
      contents of eight mono-ortho coplanar PCBs having the toxic equivalency factors
      (TEFs) were 118-424 (Y) and 78 ppt (N), respectively. The differences between Y
      and N in the species of mono-ortho coplanar PCBs contained were observed as
      follows: 2,3,3',4,4',5- and 2,3,3',4,4',5'-Hexa-CB were predominant in Y, whereas
      2,3,4,4',5-Penta-CB was a major congener in N. The levels of di-ortho coplanar
      PCBs (2,2',3,4,4',5,5' plus 2,2',3,3',4,4'5-Hepta-CB) were determined to be 195
      608 and 98 ppt in Y and N, respectively. In both groups, the content of the
      former isomer was greater than the latter. Total TEQ values were 0.214-1.226 ppt
      in Y, and 0.148 ppt in N. The analyses were also performed by a conventional
      method in which a GC equipped with a packed column/electron capture detector
      (packed column GC/ECD) was used, and the results obtained were compared with
      those by capillary column GC/MS method. The results showed that the total PCB
      levels obtained by capillary column GC/MS method were 56-61% in Y and 67% in N of
      those obtained by packed column GC/ECD method.

PMID- 10396875
TI  - [Analysis of 209 PCB congeners by high separation gas chromatography/low
      resolution mass spectrometer].
AB  - All PCB congeners were analyzed by high separation gas chromatography/low
      resolution mass spectrometer, using 209 PCB congeners as standards. They were
      separated into 169 peaks, including 28 peaks containing 2 PCBs and 8 peaks
      containing 3 PCBs. The rice oil samples of Fukuoka and Taiwan Poisonings were
      analyzed for PCB congeners. They showed 115 separated peaks of PCB congeners.
      Total PCB concentrations were 879 and 769 ppm in 2 samples of Fukuoka rice oil
      and 57 and 83 ppm in 2 samples of Taiwan rice oil.

PMID- 10396876
TI  - [Analysis of all PCB congeners in breast milk and blood of Yusho patients].
AB  - Breast milk and blood of Yusho patients were analyzed for polychlorinated
      biphenyl (PCB) congeners by High separation gas chromatography/Low resolution
      mass spectrometer. Seventy-one and forty-nine PCB congeners were identified and
      quantified in the breast milk and blood, respectively. Total PCB concentrations
      (Whole base) in breast milk of 2 Yusho patients were 69.9 and 15.1 ppb,
      respectively, being 11.6 and 2.5 times higher than those of 4 control breast
      milk. Average total PCB concentration of 5.0 ppb in whole blood of 13 Yusho
      patients was 3.6 times higher than those of control persons. Fourteen PCB
      congeners, such as 99, 117, 130, 137, 138, 156, 157, 164, 170, 171, 172, 189, 191
      and 195, were particularly higher concentration in breast milk and blood of Yusho
      patients than in those of control persons. Polychlorinated dibenzo-p-dioxins
      (PCDDs) and dibenzofurans (PCDFs) and coplanar PCBs were also analyzed in the
      breast milk of Yusho patients and control persons. Large portions, 83 and 74%, of
      Dioxin toxic equivalency (TEQ) in the 2 Yusho breast milk were consisted of TEQ
      of 2,3,4,7,8-pentaCDF only, while total TEQ in the breast milk of control persons
      was consisted of PCDFs 48%. PCDDs 29% and coplanar PCBs 23%.

PMID- 10396877
TI  - [Metabolism of 3,3',4,4',5-penta- and 2,2',3,3',4,4'-hexachlorobiphenyls in
      rats].
AB  - Following the i.p. administration of 3,3',4,4',5-pentachlorobiphenyl (CB126) and
      2,2',3,3',4,4'-hexachlorobiphenyl (CB128) to rats, blood, liver, lung, kidney,
      adipose tissue and feces were analyzed for the metabolites. CB126 was
      biotransformed to three hydroxylated metabolites identified as 4-OH-3,3',4',5'
      tetraCB, 4-OH-3,3',4',5,5'-pentaCB and 5-OH-3,3',4,4',5'-pentaCB at about 1:7:2
      ratio, whereas to two methylthio metabolites as 5-MeS- and 6-MeS-3,3',4,4',5'
      pentaCBs at 1:2 ratio. Among the metabolites, only 4-OH-3,3',4',5,5'-pentaCB was
      detected in all tissues and blood. The ratio of metabolite/unchanged CB126 was
      1:1.3 in blood and 1:162 in liver, indicating the high blood affinity of this
      metabolite. Trace amounts of 5-methylsulfonyl-3,3',4,4',5'-pentaCB was also
      detected in the liver. CB128 was biotransformed to 5-OH-, 5-MeS- and 6-MeS
      2,2',3,3',4,4' hexaCBs which were excreted to feces in about 5:5:1 ratio. No
      metabolites were detected in blood and any tissues except for liver where trace
      amounts of 5-hydroxylated metabolite was present, indicating the low tissue
      affinity of hydroxylated metabolites from CB128.

PMID- 10396878
TI  - [Comparative study on metabolism of three tetrachlorobiphenyls with animal liver
      microsomes].
AB  - In vitro metabolism of 3,5,3',4'-, 3,5,3',5'- and 2,4,3',4'-tetrachlorobiphenyls
      (TCBs) was studied using liver microsomes from rats, guinea pigs and hamsters.
      3,5,3',4'-TCB was metabolized to 4-hydroxy-3,5,3',4'-TCB with liver microsomes of
      3-methyl-cholanthrene (MC)- and 3,4,5,3',4'-pentachlorobiphenyl (PenCB)-treated
      rats but not of phenobarbital (PB)-treated ones. This result suggests that a MC
      inducible cytochrome P450 isoform, probably CYP1A1, is more important in the in
      vitro metabolism of 3,5,3',4'-TCB in rat liver and that the isoform attacks the
      3,5-dichloro-substituted phenyl ring more predominantly than 3,4-dichloro
      substituted one. In 3,5,3',5'-TCB metabolism, liver microsomes from MC- and
      3,4,5,3',4'-PenCB-treated hamsters formed 4-hydroxy-3,5,3',5'-TCB to a similar
      extent to rats reported previously. Guinea pig liver microsomes formed no
      metabolite. In 2,4,3',4'-TCB metabolism, PB accelerated 3-, 5- and 4
      hydroxylations in guinea pigs and also 3- and 5-hydroxylations in hamsters,
      suggesting the involvement of a PB-inducible P450 isoform, presumably P450GP-1
      and P450HPB-1, respectively. On the other hands, MC- and 3,4,5,3',4'-PenCB
      treatment resulted in the marked increase of 4-hydroxylation in hamsters, but in
      the suppression of 4-hydroxylation in guinea pigs. From these results, it is
      suggested that the hydroxylation of coplanar TCBs such as 3,5,3',4'- and
      3,5,3',5'-TCB is catalyzed by a MC-inducible P450 in rats and hamsters, whereas
      non-coplanar TCBs such as 2,4,3',4'-TCB which possesses both PB- and MC-like
      inducing ability of liver enzymes are metabolized by one or more kinds of P450
      isoform induced by PB and MC.

PMID- 10396880
TI  - Induction of sister chromatid exchanges in cultured human lymphocytes with
      methylsulphonyl PCB congeners.
AB  - Methylsulphonyl polychlorinated biphenyls (MSF-PCBs) have already contaminated at
      relatively high concentration in the lungs and blood of Yusho patients and
      healthy Japanese people. Therefore, we should give due attention to their
      biological and toxicological effects to man. In this study, in order to evaluate
      S-dependent genotoxicity of five MSF-PCB congeners, namely, 3-MSF-4,5,3',4'
      tetrachlorobiphenyl (TCB), 3-MSF-4,5,2',3'-TCB, 3-MSF-2,5,2',4',5'
      pentachlorobiphenyl (PenCB), 4-MSF-2,5,2',3',4'-PenCB and 4-MSF-2,5,2',3',5',6'
      hexachlorobiphenyl (HCB), we have examined their effects on the induction of
      sister chromatid exchanges (SCEs), which has been frequently used to estimate the
      dose of S-dependent clastogens, in cultured human lymphocytes in the absence or
      presence of 2,3,4,7,8-pentachlorodibenzofuran (PenCDF), 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD) or 3,4,5,3',4'-pentachlorobiphenyl (Co-PenCB)
      and the following results were obtained. 1) 4 x 10(-5)M, 7,8-benzoflavone (ANF)
      and two of the five MSF-PCB congeners, namely, 3-MSF-2,5,2',4',5'- and 4-MSF
      2,5,2',3',4'-PenCB at respective doses of 5.2 and 5.8 ppm, which were about
      35,000 times higher than the concentrations in the lungs and adipose tissue of
      healthy Japanese people, significantly enhanced the frequency of SCEs. 2) In the
      simultaneous treatment of one of the five MSF-PCB congeners and PenCDF (3.9 ppb),
      TCDD (1.5 ppb) or Co-PenCB (8.8 ppb), the combination of 3-MSF-4,5,3',4'-TCB (6.8
      ppb) or 4-MSF-2,5,2',3',5',6'-HCB and one of the three highly toxic chemicals
      significantly promoted the formation of SCEs. We have already studied whether
      these MSF-PCBs are non-S-dependent genotoxic compounds or not and have obtained
      the results that they seemed not to be or very weak ones. Therefore, based on the
      results of this and our former studies, the five MSF-PCB congeners examined are
      considered rather potent S-dependent genotoxic chemicals than non-S-dependent
      ones.

PMID- 10396879
TI  - [Effect of PCBs on mouse lung tumorigenesis induced by 1-nitropyrene: a
      preliminary report].
AB  - We have analyzed the effect of polychlorinated biphenyls (PCB, Kanechlor-400) on
      1-nitropyrene (1-NP) induced lung tumor. Male A/J mice (6 weeks old) were used
      for the experiment. A total of 2.5 mg/kg PCB was administered intraperitoneally
      (PCB group), a total of 0.38 mmol/kg 1-NP was administered intraperitoneally for
      17 times (1-NP group), PCB was administered followed by i.p. injection of 1-NP
      (PCB + 1-NP group), and only vehicle was administered (control group). The lung
      lesions induced were examined 18 weeks after the final treatment with 1-NP or
      vehicle. In control group, no neoplastic lesion in the lung was induced. In PCB
      group, only one lesion with adenoma was induced. In 1-NP group, various kinds of
      lung neoplastic lesions including hyperplasia, adenoma and adenocarcinoma were
      induced. In PCB + 1-NP group, both the number and size of tumors induced were
      significantly more than those in 1-NP group. In addition, the number of
      adenocarcinoma formed was more in PCB + 1-NP group than in 1-NP group. Each
      lesion was microdissected to collect and analyze DNA of the targeted tissue. K
      ras gene mutation was detected in part of adenoma lesions and all the carcinoma
      lesions. The mutation was found in either 1-NP or PCB + 1-NP group, but not in
      control and PCB group. The pattern of K-ras mutation was CAA to CGA in codon 61
      or GGT to GAT in codon 12. There was no difference in the pattern of K-ras
      mutation despite of the pretreatment with PCB. Although the present data are from
      small sample size, it was suggested that PCB may promote (but not initiate) 1-NP
      induced lung tumorigenesis, and may not induce K-ras mutation directly in the
      experimental system.

PMID- 10396881
TI  - [Influential factors in elevation of serum creatine phosphokinase for the
      patients with Kanemi Yusho].
AB  - We studied the etiology of the elevation of serum creatin phosphokinase (CK)
      using the data from routine medical checkup of Kanemi Yusho patients during 1995
      and 1997. We also studied the serum CK and blood urea nitrogen (BUN) in rats
      given the polychlolinated biphenyls as well as controls, and conducted optical
      microscopic observation of muscle tissue in rats given the polychlolinated
      biphenyls and control. The patients with elevation of serum creatine
      phosphokinase also showed the elevation of BUN and polychlolinated biphenyls in
      their serum. These are thought to be triggers of the elevation of CK in the
      serum. However, animal experiments failed to yield the same results as human. The
      rats given polycholorinated biphenyls showed atrophy of muscle fibers.
      Accordingly, we were unable to clarify the etiology of CK elevation in humans and
      muscle atrophy in rats.

PMID- 10396882
TI  - [Suppression of stress proteins in endoplasmic reticulum in liver cytosol of rats
      treated with a highly toxic coplanar PCB].
AB  - The present study was addressed on the effect of 3,3',4,4',5-pentachlorobiphenyl
      (PenCB) to the expression of glucose regulated protein (GRP) 78 and GRP94 in
      liver endoplasmic reticulum of rat by treatment with the schedule after acute or
      subacute exposure. In the acute exposure, male Wistar rats received PenCB in corn
      oil at once a dose of 25 mg/kg i.p., then at 5 days after treatment the
      microsomes were prepared. Free- and pair-fed control groups were given the
      vehicle. The microsomal proteins were separated on SDS-PAGE, transferred to
      membrane and blotted using anti-sera to the GRPs. The reduction of GRP78 and
      GRP94 was associated significantly with the acute exposure. In subacute exposure,
      the rats received PenCB in corn oil at once a dose of 0.1 or 1.0 mg/kg i.p. At 4
      weeks after treatment, liver microsomes were obtained. The expression level of
      GRP78 and GRP94 are also decreased at 1.0 mg PenCB/kg treatment as similar as the
      acute exposure. But the reduction was not notable at 0.1 mg PenCB/kg treatment.
      GRP78 and GRP94 are a member of GRPs and the expression is regulated by glucose
      in cells as stress proteins. GRP78 and GRP94 have also the function for chaperone
      protein. Chaperone proteins have important physiological functions against
      synthesized and/or denatured proteins, which include assembling, folding of
      proteins. Our results suggested that a part of the toxicity of PenCB is
      associated to significant decrease of the chaperone proteins in the endoplasmic
      reticulum.

PMID- 10396883
TI  - [Induction of molecular chaperones HSP70 and HSP90 in rat liver cytosol by a
      highly toxic coplanar PCB].
AB  - We report here that a highly toxic coplanar polychlorinated biphenyl (PCB),
      3,3',4,4',5-pentachlorobiphenyl (PenCB) induces molecular chaperones, HSP70 and
      HSP90 in liver cytosol of rats. Male Wistar rats received PenCB in corn oil once
      at a dose of 25 mg/kg i.p. Pair-fed control groups were treated with the vehicle
      and given the amount of chow matched with that taken by the PenCB-treated
      animals, and free-fed controls were given the vehicle. The liver cytosolic HSP70
      level in rats treated with PenCB was 5-fold higher than those in free-fed
      controls, though that for pair-fed controls was approximately 2-fold higher than
      that in free-fed controls. The liver cytosolic HSP90 alpha and HSP90 beta levels
      were also higher in PenCB-treated rats than in both control groups, but the
      induction extent was lesser than that for HSP70. Inductive effect on the
      chaperones was examined with a single different dose of PenCB 0, 0.5, 1.0, 5.0,
      10 and 25 mg/kg. Marked induction of the HSP70 level was observed with a minimum
      dose of PenCB 0.5 mg/kg. The HSP90 alpha level was induced with PenCB-dose
      dependent manner although the HSP90 beta induction was greatest with a dose of
      PenCB 5.0 mg/kg. HSP70 and HSP90 are essential for cells under normal conditions
      and act as molecular chaperones. HSP90 is well known to modulate the function of
      sex steroid hormone or aromatic hydrocarbon receptors while HSP70 is required for
      receptor-HSP90 heterocomplex assembly. The role of molecular chaperones may be
      involved in the endocrine disrupting properties of coplanar PCB and dioxins.

PMID- 10396884
TI  - Types of conflicts and tensions between older parents and adult children.
AB  - What are the most common themes of conflict between aging parents and their adult
      children? Six types emerged in a qualitative analysis of Longitudinal Study of
      Generations survey data: conflicts over (1) communication and interaction style;
      (2) habits and lifestyle choices; (3) child-rearing practices and values; (4)
      politics, religion, and ideology; (5) work habits and orientations; and (6)
      household standards or maintenance. There were generational differences: parents
      most often listed conflicts over habits and lifestyle choices, whereas children
      cited communication and interaction style. These results suggest a new agenda for
      gerontological research: intergenerational conflict in the context of solidarity
      within aging families.

PMID- 10396885
TI  - Relationship between age and patients' current health state preferences.
AB  - This article explores age differences in preferences for current health states,
      which is one way to measure trade-offs between "quantity of life" and the
      "quality" of those health states. Data are from 17,707 adult outpatients visiting
      46 primary care, managed care practices. Patient preferences (utility) for their
      current health were assessed by standard gamble and time trade-off methods.
      Although older primary care patients' utility measurements for their current
      health were lower than other patient groups, most of the difference in value
      measurements was attributable to differences in health. Health providers should
      take care to assess individual preferences from all patients regardless of age.

PMID- 10396886
TI  - Hospice in nursing homes: a facility-level analysis of the distribution of
      hospice beneficiaries.
AB  - Since 1989, the Medicare hospice benefit has been available to terminally ill
      individuals residing in nursing homes. We first describe the evolution and nature
      of hospice care for nursing home residents. We then utilize recent On-line Survey
      and Certification of Automated Records data on a national sample of
      Medicare/Medicaid certified nursing homes, merged with hospice Provider of
      Service and Area Resource File information, to examine the distribution of
      hospice beneficiaries in nursing homes. Bivariate analyses provide descriptive
      comparisons of homes with 0%, 0.1-4.9%, and 5%+ residents on the hospice benefit.
      Multinomial logistic regression reveals the influence of organizational, market,
      and environmental factors on the proportion of beneficiaries in nursing homes.
      Results indicate that significant numbers of homes have hospice patients and that
      these institutions may have strong incentives to convert residents to the
      Medicare hospice benefit.

PMID- 10396887
TI  - The role of depression in the association between self-rated physical health and
      clinically defined illness.
AB  - We enrolled 543 elderly participants of a managed care organization in a cross
      sectional study to test whether the association between self-rated physical
      health and clinically defined illness differs for persons who are not depressed
      compared with persons with minor or serious depression. Depression was measured
      with the Diagnostic Interview Schedule (DIS). Clinically defined illness was
      measured with the Chronic Disease Score (CDS), a pharmacy-based measure.
      Additional variables included age, sex, and self-reported pain and physical
      function. Self-rated physical health was associated with both minor and serious
      depression, independent of clinically defined illness; minor depression was no
      longer significant when self-reported pain and physical function were added to
      the model. A significant negative correlation between self-rated physical health
      and clinically defined illness was observed for minor and no depression, but no
      correlation was seen for serious depression. These results confirm the
      association between depression and self-rated physical health and emphasize that,
      for persons with serious depression, self-rated health provides a less accurate
      picture of clinically defined illness at both ends of the spectrum. Also, a
      diagnosis of minor depression should not forestall investigation of
      inconsistencies between patient report and clinical evidence.

PMID- 10396888
TI  - Reducing caregiver burden: a randomized psychoeducational intervention for
      caregivers of persons with dementia.
AB  - This 3-year randomized clinical trial tested the effectiveness of an
      interdisciplinary psychoeducational family group intervention in decreasing the
      caregivers' perceptions of the frequency and severity of behavioral problems in
      persons with dementia and their reactions to those problems, and in decreasing
      caregiver burden and depression. The intervention consisted of seven weekly, 2
      hour multimedia training sessions that included education, family support, and
      skills training for 94 primary caregivers and their families. Repeated measures
      ANOVA was used to test for significant differences between the intervention and
      waiting list control groups over a 5-month period. The intervention was
      successful in reducing caregivers' negative reactions to disruptive behaviors and
      in reducing caregiver burden over time.

PMID- 10396889
TI  - English language proficiency among older Hispanics in the United States.
AB  - Hispanics will constitute a growing part of the older population well into the
      21st century. Accompanying this growth, we can expect that challenges associated
      with a large bilingual and non-English speaking older population may become more
      pronounced. The purpose of this research was to examine the level and
      determinants of English proficiency among older Hispanics in the United States.
      Data from the 1990 Census indicate that a third of the older Hispanic population
      in the United States speaks English poorly or not at all. This group includes a
      sizable number who are "linguistically isolated" in that they either live alone
      or with other nonproficient speakers of English. Using multivariate logistic
      regression techniques, it is shown that immigrant status and timing,
      socioeconomic status, geographic concentration, and national origin are key
      determinants of English proficiency.

PMID- 10396890
TI  - Gender differences in pension wealth: estimates using provider data.
AB  - Information from pension providers was examined to investigate gender differences
      in pension wealth at midlife. For full-time wage and salary workers approaching
      retirement age who had pension coverage, median pension wealth on the current job
      was 76% greater for men than women. Differences in wages, years of job tenure,
      and industry between men and women accounted for most of the gender gap in
      pension wealth on the current job. Less than one third of the wealth difference
      could not be explained by gender differences in education, demographics, or job
      characteristics. The less-advantaged employment situation of working women
      currently in midlife carries over into worse retirement income prospects.
      However, the gender gap in pensions is likely to narrow in the future as married
      women's employment experiences increasingly resemble those of men.

PMID- 10396891
TI  - Elders' preferences for care setting in short- and long-term disability
      scenarios.
AB  - Preference for long-term care (LTC) location among community-dwelling elders was
      assessed using short- and long-term disability scenarios (N = 537). Using
      Wilcoxon rank sum tests, we assessed differences in perceptions of financial
      difficulty, family strain, and personal stress by predisposing, enabling, and
      need factors. Using logistic regression we determined which factors were
      predictive of preference for LTC location. Frail and poor elders and those who
      lived alone had more financial and familial concerns; elders of higher social
      class anticipated more personal stress; elders with negative attitudes toward LTC
      facilities, who had fewer financial, familial and personal concerns, and who were
      married were more likely to prefer home care.

PMID- 10396893
TI  - An integrated program for dementia evaluation and care management.
AB  - The growth of the geriatric population and the emergence of managed care dictate
      new approaches to dementia care. Management of Alzheimer's disease (AD) is a
      critical issue for health care policy as well as quality of life for patients and
      caregivers. The Alzheimer's Disease Education Program (ADEP) seeks to improve the
      quality of care for individuals with AD and to reduce the burden of caregiving
      experienced by families. Objectives of ADEP include early detection of AD through
      dementia screening followed by caregiver education and support. This article
      outlines an effective method of dementia evaluation and management.

PMID- 10396892
TI  - Strategies to measure nursing home residents' satisfaction and preferences
      related to incontinence and mobility care: implications for evaluating
      intervention effects.
AB  - This study compared four different interview strategies to measure 111
      incontinent nursing home residents' "met need" related to incontinence and
      mobility care. Strategies were compared on criteria related to ceiling effects
      and stability. Four methods were used: questions that used the term
      "satisfaction" and direct questions about preferences that did not use the term
      "satisfaction" and which could be translated into three indirect measures of met
      need. To facilitate a comparison among the four methods, a statement of
      satisfaction was interpreted as met need. All of these measures were then
      compared to direct observations of care processes. Residents were more stable in
      their reports indicating that their care needs were met than they were in their
      reports that their needs were not met. The direct satisfaction questions produced
      information most characterized by ceiling effects compared to information
      elicited by the preference questions. Despite high reported rates of met need as
      assessed by two of the four methods, direct observations revealed low frequencies
      of care provision.

PMID- 10396894
TI  - Improving a system of care for elderly persons in rural areas.
AB  - This article describes a community initiative to improve the care of elders in
      largely rural areas. An organization development framework guided pilot projects
      in two communities, with support from a regional geriatric program. Two
      interdisciplinary teams, representing primary service agencies in the
      communities, have been trained to serve as local resources in geriatric
      assessment and intervention. Through the resource teams, the communities are
      developing a more integrated and coordinated approach to care for the elderly
      population. The process has yielded valuable insights into the implementation of
      system change.

PMID- 10396895
TI  - Anode/cathode make and break phenomena in a model of defibrillation.
AB  - The goal of this simulation study is to examine, in a sheet of myocardium, the
      contribution of anode and cathode break phenomena in terminating a spiral wave
      reentry by the defibrillation shock. The tissue is represented as a homogeneous
      bidomain with unequal anisotropy ratios. Two case studies are presented in this
      article: tissue that can electroporate at high levels of transmembrane potential,
      and model tissue that does not support electroporation. In both cases, the spiral
      wave is initiated via cross-field stimulation of the bidomain sheet. The
      extracellular defibrillation shock is delivered via two small electrodes located
      at opposite tissue boundaries. Modifications in the active membrane kinetics
      enable the delivery of high-strength defibrillation shocks. Numerical solutions
      are obtained using an efficient semi-implicit predictor-corrector scheme that
      allows one to execute the simulations within reasonable time. The simulation
      results demonstrate that anode and/or cathode break excitations contribute
      significantly to the activity during and after the shock. For a successful
      defibrillation shock, the virtual electrodes and the break excitations restrict
      the spiral wave and render the tissue refractory so it cannot further maintain
      the reentry. The results also indicate that electroporation alters the
      anode/cathode break phenomena, the major impact being on the timing of the
      cathode-break excitations. Thus, electroporation results in different patterns of
      transmembrane potential distribution after the shock. This difference in patterns
      may or may not result in change of the outcome of the shock.

PMID- 10396896
TI  - The use of the spatial covariance in computing pericardial potentials.
AB  - This paper investigates the incorporation of the spatial covariance of the
      pericardial potentials, assumed known a priori as a regularization function, when
      computing the pericardial potential distribution from observed body surface
      potentials. The resulting inverse solutions are compared with those using as a
      regularization function: 1) the norm of the solution, 2) the norm of the surface
      Laplacian of the solution, as well as with those based on using the truncated
      singular value decomposition. The study uses a realistic source model to simulate
      potentials throughout the QRS-interval. This source is placed in an anatomically
      accurate inhomogeneous volume conductor model of the torso. The use of a single
      value of the regularization parameter is shown to be feasible: for data
      incorporating 2% noise, the use of the spatial covariance is demonstrated to
      result in a relative error over the entire QRS interval as low as 10%. Major
      errors are demonstrated to result if the effect of the inhomogeneity of the lungs
      is ignored. The spatial covariance based inverse is shown to be more robust with
      respect to the perturbations (noise; inhomogeneity) than the other estimators
      included in this study.

PMID- 10396897
TI  - Canine sternal force-displacement relationship during cardiopulmonary
      resuscitation.
AB  - A viscoelastic model developed to model human sternal response to the cyclic
      loading of manual cardiopulmonary resuscitation (CPR) [8] was used to evaluate
      the properties of canine chests during CPR. Sternal compressions with
      ventilations after every fifth compression were applied to supine canines (n = 7)
      with a mechanical resuscitation device. The compressions were applied at a
      nominal rate of 90/min with a peak force near 400 N. From measurements of sternal
      force, sternal displacement, and tracheal airflow, model parameters were
      estimated and their dependence on time and lung volume evaluated. The position to
      which the chest recoiled between compressions changed with time at a mean rate of
      1.0 mm/min. Within each ventilation cycle (five compressions) the sternal recoil
      position decreased by 2.0 cm for each liter of decrease in lung volume. The
      elastic force and damping decreased with time and decreasing lung volume. Canine
      and human [8] model parameters were found to be similar despite the notable
      differences in thoracic anatomy between the species, supporting the continued use
      of canines as models for human CPR. These parameters may be useful in the
      development of a model relating sternal compression forces to blood flow during
      CPR.

PMID- 10396898
TI  - Gait phase information provided by sensory nerve activity during walking:
      applicability as state controller feedback for FES.
AB  - In this study, we extracted gait-phase information from natural sensory nerve
      signals of primarily cutaneous origin recorded in the forelimbs of cats during
      walking on a motorized treadmill. Nerve signals were recorded in seven cats using
      nerve cuff or patch electrodes chronically implanted on the median, ulnar, and/or
      radial nerves. Features in the electroneurograms that were related to paw contact
      and lift-off were extracted by threshold detection. For four cats, a state
      controller model used information from two nerves (either median and radial, or
      ulnar and radial) to predict the timing of palmaris longus activity during
      walking. When fixed thresholds were used across a variety of walking conditions,
      the model predicted the timing of EMG activity with a high degree of accuracy
      (average error = 7.8%, standard deviation = 3.0%, n = 14). When thresholds were
      optimized for each condition, predictions were further improved (average error =
      5.5%, standard deviation = 2.3%, n = 14). The overall accuracy with which EMG
      timing information could be predicted using signals from two cutaneous nerves for
      two constant walking speeds and three treadmill inclinations for four cats
      suggests that natural sensory signals may be implemented as a reliable source of
      feedback for closed-loop control of functional electrical stimulation (FES).

PMID- 10396899
TI  - Modeling of surface myoelectric signals--Part I: Model implementation.
AB  - The relationships between the parameters of active motor units (MU's) and the
      features of surface electromyography (EMG) signals have been investigated using a
      mathematical model that represents the surface EMG as a summation of
      contributions from the single muscle fibers. Each MU has parallel fibers
      uniformly scattered within a cylindrical volume of specified radius embedded in
      an anisotropic medium. Two action potentials, each modeled as a current tripole,
      are generated at the neuromuscular junction, propagate in opposite directions and
      extinguish at the fiber-tendon endings. The neuromuscular junctions and fiber
      tendon endings are uniformly scattered within regions of specified width. Muscle
      fiber conduction velocity and average fiber length to the right and left of the
      center of the innervation zone are also specified. The signal produced by MU's
      with different geometries and conduction velocities are superimposed. Monopolar,
      single differential and double differential signals are computed from electrodes
      placed in equally spaced locations on the surface of the muscle and are displayed
      as functions of any of the model's parameters. Spectral and amplitude variables
      and conduction velocity are estimated from the surface signals and displayed as
      functions of any of the model's parameters. The influence of fiber-end effects,
      electrode misalignment, tissue anisotropy, MU's location and geometry are
      discussed. Part II of this paper will focus on the simulation and interpretation
      of experimental signals.

PMID- 10396900
TI  - Modeling of surface myoelectric signals--Part II: Model-based signal
      interpretation.
AB  - Experimental electromyogram (EMG) data from the human biceps brachii were
      simulated using the model described in [10] of this work. A multichannel linear
      electrode array, spanning the length of the biceps, was used to detect monopolar
      and bipolar signals, from which double differential signals were computed, during
      either voluntary or electrically elicited isometric contractions. For relatively
      low-level voluntary contractions (10%-30% of maximum force) individual firings of
      three to four-different motor units were identified and their waveforms were
      closely approximated by the model. Motor unit parameters such as depth, size,
      fiber orientation and length, location of innervation and tendonous zones,
      propagation velocity, and source width were estimated using the model. Two
      applications of the model are described. The first analyzes the effects of
      electrode rotation with respect to the muscle fiber direction and shows the
      possibility of conduction velocity (CV) over- and under-estimation. The second
      focuses on the myoelectric manifestations of fatigue during a sustained
      electrically elicited contraction and the interrelationship between muscle fiber
      CV, spectral and amplitude variables, and the length of the depolarization zone.
      It is concluded that a) surface EMG detection using an electrode array, when
      combined with a model of signal propagation, provides a useful method for
      understanding the physiological and anatomical determinants of EMG waveform
      characteristics and b) the model provides a way for the interpretation of fatigue
      plots.

PMID- 10396901
TI  - Parallel conductance estimation by hypertonic dilution method with conductance
      catheter: effects of the bolus concentration and temperature.
AB  - The conductance catheter has gained momentum since its introduction in
      cardiovascular dynamics back in 1980. However, measuring errors are still
      blurring its clinical acceptance. The main objective here was to study the
      effects of the injected saline concentration and temperature on the evaluation of
      the parallel conductance, Gp, and thus, on the correction volume Vp. That
      conductance, Gp, and its associated volume, Vp, were computed using 167 saline
      dilution curves obtained with boluses at different concentrations and
      temperatures, injected in seven anesthetized closed-chest dogs. The excursion of
      the total conductance relative to the steady-state value during a saline maneuver
      showed good correlation with the injected concentration at both studied
      temperatures. The reference parallel volume (one reference per dog) was defined
      as the average value obtained with three successive maneuvers, at 6-M
      concentration and at body temperature; therefore, the method acted as its own
      reference. The variation of Vp relative to the reference value was clearly
      dependent on the injected concentration and on its temperature; dispersion was
      greater at 22 degrees C than at 40 degrees C. The variability would recognize
      also other causes, such as uncertainty of the extrapolation procedure and the
      thoracic redistribution of electrical field lines. As conclusion, it is
      recommended to characterize each maneuver by its concentration and temperature.
      Body temperature and 6-M concentration appear as the most recommendable
      combination for the injectate in most animals. Finally, these results intend to
      characterize the Vp estimation procedure in order to minimize errors. The
      variability of Vp, in different experimental conditions, demonstrated that both
      concentration and temperature are additional parameters that may modify the Gp
      estimate.

PMID- 10396902
TI  - Wavelet transform-based QRS complex detector.
AB  - In this paper, we describe a QRS complex detector based on the dyadic wavelet
      transform (Dy WT) which is robust to time-varying QRS complex morphology and to
      noise. We design a spline wavelet that is suitable for QRS detection. The scales
      of this wavelet are chosen based on the spectral characteristics of the
      electrocardiogram (ECG) signal. We illustrate the performance of the Dy WT-based
      QRS detector by considering problematic ECG signals from the American Heart
      Association (AHA) data base. Seventy hours of data was considered. We also
      compare the performance of Dy WT-based QRS detector with detectors based on
      Okada, Hamilton-Tompkins, and multiplication of the backward difference
      algorithms. From the comparison, results we observed that although no one
      algorithm exhibited superior performance in all situations, the Dy WT-based
      detector compared well with the standard techniques. For multiform premature
      ventricular contractions, bigeminy, and couplets tapes, the Dy WT-based detector
      exhibited excellent performance.

PMID- 10396903
TI  - Subspace regularization method for the single-trial estimation of evoked
      potentials.
AB  - A method for the single-trial estimation of the evoked potentials is proposed.
      The method is based on the so-called subspace regularization approach in which
      the second-order statistics of the set of the measurements is used to form a
      prior information model for the evoked potentials. The method is closely related
      to the Bayesian estimation. The performance of the proposed method is evaluated
      using realistic simulations. As a specific application the method is applied to
      the estimation of the target responses in the P300 test.

PMID- 10396904
TI  - Multiple window time-frequency distribution and coherence of EEG using Slepian
      sequences and hermite functions.
AB  - Multiple window (MW) time-frequency analysis (TFA) is a newly developed technique
      to estimate a time-varying spectrum for random nonstationary signals with low
      bias and variance. In this paper, we describe the application of MW-TFA
      techniques to electroencephalogram (EEG) and compare the results with those of
      the conventional spectrogram. We find that the MW-TFA provide us with not only
      low bias and variance time-frequency (TF) distribution for EEG but also TF
      coherence estimation between a single realization of EEG recorded from two sites.
      We also compare the performance of the MW-TFA using two sets of windows, Slepian
      sequences, and Hermite functions. If care is taken in matching the two windows,
      we find no noticeable difference in the resulting TF representations.

PMID- 10396905
TI  - Single-sweep analysis of event-related potentials by wavelet networks-
      methodological basis and clinical application.
AB  - OBJECTIVE: Trial-to-trial variabilities in event-related potentials (ERP's),
      which are neglected by investigating averaged ERP's, can be important to
      establish group-specific effects in clinical studies. Single ERP responses have
      to be analyzed to quantify these variations. In order to overcome the
      disadvantages of existing single-sweep estimators, we have developed a new
      procedure based on wavelet networks (WN's) and applied this novel approach in a
      study concerning attention deficit hyperactivity disorder (ADHD) in children.
      METHOD: WN's represent signals as a linear combination of wavelet nodes, i.e.,
      components characterized by time-frequency features related to the wavelet
      transformation. In single-sweep analysis, each wavelet node is restricted to a
      specific region of the time-frequency plane during the recursive WN training
      process. This is achieved by means of tapering and bandpass filtering with
      Gaussian functions which are automatically adapted and closely related to the
      Morlet basis wavelet. The time course of a single event-related response can be
      reliably estimated. Furthermore, the WN method automatically provides well
      defined parameters for single event-related responses, respectively ERP trial-to
      trial variabilities. RESULTS: In a psychophysiological study on ADHD using
      auditory evoked potentials (AEP's), latency and amplitude parameters extracted
      from averaged ERP's did not reveal any significant differences between 25 control
      and 25 ADHD boys. In contrast, interesting group-specific differences could be
      established by WN single-sweep analysis. CONCLUSION: WN single-sweep analysis can
      be recommended as a sensitive tool for clinical ERP studies which should be
      applied in addition to the investigation of averaged responses. INDEX TERMS:
      Attention deficit hyperactivity disorder (ADHD), event-related potentials, single
      sweep estimation, single-sweep parameterization, time-frequency method, wavelet
      networks.

PMID- 10396906
TI  - Arrays of multielement ultrasound applicators for interstitial hyperthermia.
AB  - Arrays of multielement ultrasound applicators for interstitial hyperthermia have
      been developed and tested both in vitro and in vivo. The system includes
      multielement applicators, a 64 channel RF driving unit, a power measuring unit, a
      112 channel multisensor temperature measuring unit, and a water cooling unit.
      Ninety-five arrays of single-element and nine arrays of three-element ultrasound
      applicators were designed, built, and characterized by measuring transducer
      efficiency and ultrasound field distribution. Improved uniformity in the
      azimuthal direction was achieved by using multiple driving frequencies. In
      addition, production of ultrasound in a desired sector of the transducer was
      possible by selecting a suitable frequency. Both in vitro and in vivo experiments
      showed that 92% of monitored temperature points within the target volume of 30 mm
      x 30 mm x 35 mm achieved a therapeutic temperature rise (above 5 degrees C) when
      an array of five three-element applicators were used. These results indicated
      that the arrays of multielement ultrasound applicators have distinct advantages
      over present interstitial hyperthermia modalities in terms of the capability to
      control the temperature distribution with a large catheter spacing. As a
      conclusion, the feasibility of a practical arrays of multielement ultrasound
      applicators for interstitial hyperthermia was demonstrated.

PMID- 10396907
TI  - Measurement of the force required to move a neurosurgical probe through in vivo
      human brain tissue.
AB  - The advent of high-precision magnetic and robotic computer-controlled
      neurosurgery systems makes it necessary to determine the range of forces that
      will be encountered by the probes of such devices as they are guided through the
      brain tissues to intraparenchymal targets. We have measured the penetration
      forces on 2.5-mm spheres and the drag forces on 3.0-mm ventricular shunt
      catheters advanced 2.0-3.5 cm deep into in vivo human brain tissues (in patients
      about to have those tissues resected during epilepsy surgery) at rates of
      approximately 0.33 mm s-1. Penetration forces of (8 +/- 2) grams were found for
      the spherical probe once it passed 0.5 cm below the cortical surface, and
      frictional drags of (2.8 +/- 0.3) grams cm-1 were exerted on the catheters. The
      variable nature of these forces is discussed and the results are compared with
      earlier studies on experimental animal tissues and brain phantom gelatins. The
      implications of these results for magnetic and robotic surgery systems are
      considered.

PMID- 10396908
TI  - Indexes for identification of abnormal tremor using computer tremor evaluation
      systems.
AB  - We consider methods of formulating indexes to identify abnormalities in tremor
      appropriate for computerized tremor analysis systems. Characterization of
      amplitude, frequency, and "harmonicity" are considered as well as how to combine
      several such characteristics into a single index to discriminate normal from
      abnormal tremor effectively. The methodological issues discussed here should be
      of interest to researchers and clinicians working with tremor in general and to
      both users and developers of computer tremor analysis systems.

PMID- 10396909
TI  - Quantification of injury-related EEG signal changes using distance measures.
AB  - Novel indicators based on distance measures are developed and compared to
      quantify changes in electroencephalogram signal resulting from hypoxic-asphyxic
      injury. An injury index is derived based on the measures. The Itakura distance
      based index is found to have the highest correlation with the long-term outcome
      as measured by the neurological deficit scores.

PMID- 10396910
TI  - A new formulation of death and its relevance to medical law.

PMID- 10396911
TI  - Medical responsibility and air transport.
AB  - When a medical emergency occurs during a flight operated by a commercial airline,
      the assistance of a physician-passenger fortuitously present aboard may be
      requested. This physician becomes bound by both his professional and civil
      responsibilities. However, in the case of a serious problem, he would usually
      ignore the question of the jurisprudence of the country where the emergency
      occurs. In discussing this issue, this paper analyses different situations and
      risks that the physician may incur and points out various defects in the law not
      currently covered by existing international conventions.

PMID- 10396912
TI  - Introduction of a new medical procedure: a novel approach.
AB  - Before it is permitted for general use, a newly developed drug or medical device
      must undergo a series of pre-clinical testing and clinical trials to prove safety
      and efficacy. However, new medical procedures--even highly sophisticated and
      ethically controversial ones, such as organ transplants and I.V.F. do not require
      any clearance from regulatory authorities. This is an undesirable situation,
      which can be corrected by limiting legal liability for those who opt to perform
      new medical procedures as part of clinical trials. By this means we shall
      encourage a more prudent and better regulated introduction of new technologies
      into medical practice.

PMID- 10396914
TI  - The hospital doctor in legislation and medical deontology: tension between
      profession and institution.
AB  - 1. Every health policy should make clear the organization of its offer of care;
      also, more particularly, the role of the individual professionals and their
      groups, as well as the role of the services and institutions, all within the
      chosen private, public or mixed framework. 2. Both in public law and in private
      law as well as in deontology, clear rules will have to be formulated concerning
      the relationship of doctor-patient and institution-patient; therefore also
      concerning the relationship of hospital-doctor. 3. It is evident that the lack of
      clarity frequently encountered in the Belgian and many other national legal
      systems with respect to these matters is unfortunately also reflected in
      international health law. 4. The issue of the legal relationships in the patient
      doctor-hospital triangle should no longer be delayed until the catastrophic
      moment when medical liability should be considered. 5. Can we indeed speak of
      integral quality of a hospital, when it is anything but clear whether it concerns
      a single integrated enterprise or a roof under which two or more enterprises or
      entrepreneurs organize their own separate services to the clients? 6. Although
      the decision is a societal matter, the organisations of institutions and
      professionals should (continue to) play an important role in the preparation of
      this debate, which must bring the necessary clarity to the present relations and
      preferably also about the future options with respect to these relations. 7. A
      fundamental question, which remains to be solved for the future health policy,
      appears to be whether hospitals can be integrated institutions and, in the
      affirmative, whether they should be so. 8. The law, with priority to deontology,
      should formulate basic rules to clarify all possibilities in the patient-hospital
      doctor triangle relationship--which is evolving into a polygon through fusion and
      group practices--and especially to trace out the consequences of health policy
      options with regard to the integrated hospital formula, also for patients, and to
      enhance its chances of success. 9. Will the professionals succeed in convincing
      the hospital responsibles that the integrated hospital itself is already a far
      too traditional construction to offer a valuable answer to the future needs of
      the patients?

PMID- 10396915
TI  - Approaches to managed care in Germany.
AB  - The economic burden of growing health care expenses requires self-sustaining
      limitations to spending on health care all over the world. Germany is no
      exception. In the search for solutions different managed care systems are being
      introduced into the German public and private health care system commencing in
      1996. The gatekeeper project of the largest German public health care corporation
      and the Berlin network project of a competing public health care corporation are
      described and evaluated. Managed care as a concept of techniques limiting health
      care spending will thoroughly change the German health care system within the
      next decade.

PMID- 10396916
TI  - Ethical practice in the management of impaired neonates--a Chinese viewpoint.
AB  - In recent years, the issue of whether medical care should be given to impaired
      neonates has given rise to widely divergent views among practitioners of
      medicine, law and ethics. The general public also holds wide-ranging opinions on
      this subject. The divergence centres on whether medical care should be given to
      seriously impaired neonates, on whom should make decisions in these matters, and
      who should perform acts of euthanasia, in accordance with the current climate of
      opinion in China. This opinion has been focused both on ethical principles and on
      relevant precepts relevant to the "value of life." The author presents his
      opinions and explanations on the rights of impaired neonates, the rights and
      duties of parents and medical staff, and his views on the application of
      beneficence relative to this subject.

PMID- 10396913
TI  - Informed consent. Evaluation of the information provided to patients before
      anaesthesia and surgery.
AB  - The procedure for obtaining informed consent is often poorly appreciated by
      patients. The aim of this paper is to evaluate the verbal information given as
      part of the informed consent process before anaesthesia and surgery. A total of
      300 randomly chosen patients (141 male and 159 female) were asked their opinion
      between 1993 and 1995 at the University of Murcia Hospital (Murcia, Spain). One
      hundred and fifty of these patients received scheduled surgery and the other 150
      received emergency surgery. In general, the patients were not happy with the
      information they had received concerning their pathology and treatment. Although
      they had signed the consent documents, the patients did not feel they had really
      understood the risks involved in the surgery they had undergone.

PMID- 10396917
TI  - Quality of life decisions at the beginning of life: ethical considerations.
AB  - The burdens of life with treatment may outweigh the benefits. Under which set of
      circumstances and to what extent a neonate should receive medical intervention is
      a difficult ethical issue involving principles and cultural aspects which may be
      in conflict. The nature of the disease, the risks involved in treatment or non
      treatment, the degree to which therapy will extend life, the discomfort
      associated with therapy, the anticipated quality of life, the wishes of
      surrogates, and national cultural mores are the important considerations in
      determination of the neonate's best interest in order to arrive at ethically
      defensible decisions. These decisions are not necessarily cross-culturally
      uniform.

PMID- 10396918
TI  - Law and mental health--on the role of lawmaking in the process of developing
      psychiatric care.
AB  - Mental health (as well as somatic health) depends on individual biological,
      psychological and social factors as well as more general societal factors. If one
      wishes to promote health, it is necessary to work in many different fields
      hopefully in a synergistic way. As a psychiatrist and clinician one is inclined
      to believe that developments in psychiatric science and practice are the most
      important activities to improve the mental health situation in a population. But,
      at the same time it is apparent that societal processes of social, political and
      economic nature also play a decisive role. One of the most important factors in
      the development of society is lawmaking by which its nature is setting the norms
      in a society and which is also usually combined with some kind of sanction system
      to support the norms. Lawmakers also have the possibility to interfere in the
      process of developing knowledge and practice in different fields, for example
      through supporting treatment and research of a special kind or even to forbid
      special kinds of treatment and research in certain areas. Lawmakers are also
      inclined to believe that if there is a law this will be enough to answer these
      challenges. I think it is extremely important that lawmaking in the field of
      mental health is in broad agreement with the development in the scientific and
      practical field of psychiatry and other mental health disciplines. This is the
      subject of this paper.

PMID- 10396919
TI  - The right to die and physician-assisted suicide: medical, legal, and ethical
      aspects (Part II).

PMID- 10396920
TI  - Freedom of choice in birth, abortion and the place of conscientious objection.
AB  - The Constitution of the Republic of Slovenia includes two statutes: (a) the
      freedom to decide about the birth of one's own child (freedom of birth-decision),
      and (b) the right of conscientious objection, including the right to abortion.
      This discussion focuses on the principles of "free choice and womens'reproductive
      freedom". The right of conscientious objection in relation to the right to
      abortion is also discussed.

PMID- 10396921
TI  - Battered women: dilemmas and care.
AB  - Domestic violence is a complex problem, and its victims are women from all social
      classes and positions. The "cycle of beating" where tension accumulates, and then
      assault is followed by excuses and reconciliation, puts the battered women in
      dilemma. One conflict is that of exposure of intimate family details, and the
      other the guilt for the consequences of external intervention in family
      situations. The modern society has several tools to treat domestic violence and
      to assist battered wives. They include the police, legislation, courts and
      probation officers, besides shelters, legal aid and social services. Specific
      training of nursing and medical personnel is pivotal for the proper
      identification of women is such distress.

PMID- 10396922
TI  - Bio-ethical and legal issues in relation to HIV/AIDS: the Uganda experience.
AB  - In Uganda, as in many other countries, there is a vacuum regarding an appropriate
      legal and ethical response to the HIV/AIDS pandemic. Whereas much has been done
      to address the HIV/AIDS pandemic in a multidisciplinary way, very little has been
      done regarding legal and ethical issues. Hence, cases of claimants to have cures
      for AIDS, spiritual healers and sale of fake drugs plus unauthorized vaccine and
      drug trials are on the increase. The rights and needs of people infected with
      HIV/AIDS are not adequately addressed. The property rights of those affected by
      the pandemic continue to be abused. Therefore there is need to mobilize doctors,
      lawyers and human rights activists who should advocate and address these issues.
      This paper therefore highlights the critical bio-ethical and legal issues in
      relation to HIV/AIDS.

PMID- 10396923
TI  - Employment outcomes of regular versus extended outpatient alcohol and drug
      treatment.
AB  - In a study on treatment duration, alcohol and drug patients were placed in two
      groups, one receiving regular (3 months) and the other extended (6 months)
      outpatient treatment. The objective was to determine differences in outcomes at 3
      and 6 months post-treatment. Most patients received 30 days of inpatient
      treatment before outpatient treatment.

PMID- 10396924
TI  - Law, blood transfusions and Jehovah's Witnesses.
AB  - Jehovah's Witnesses respect divine law. Where secular law is in conflict with
      divine law, they prefer God's law to man's law. They accept all medical treatment
      except where blood is involved. Doctors worldwide have come to respect their
      conscientious stand on blood and many doctors have successfully invented and
      applied techniques of bloodless surgery.

PMID- 10396925
TI  - The West Coast Study. I: Self-reported dental health and the use of dental
      services.
AB  - This study examined self-reported dental health and the use of dental services in
      a sample of the population of the West Coast of the South Island of New Zealand.
      The study differs from previous national surveys in that it provides a regional
      focus in a relatively remote area of the country; it provides an estimate of the
      prevalence and severity of dental anxiety among New Zealanders, using an
      instrument with a long history of use and validation; and it estimates the social
      impact of oral conditions. A questionnaire was mailed to 450 adult members of the
      population chosen at random from the electoral roll. The overall response rate
      was 76.6 percent. A dental check-up was the most commonly reported reason for the
      last visit to the dentist, although presentation for a specific problem accounted
      for 63 percent of all dental visits. Some 78.8 percent of the respondents
      described themselves as dentate, and episodic dental visiting was reported by 53
      percent of that group. Higher proportions of episodic use of dental services were
      observed among beneficiaries, those on low incomes, and those who were classified
      as dentally anxious. Six percent of respondents had their last dentally treatment
      funded by public monies, and a further 3.6 percent did not have to pay.
      Beneficiaries and Community Services Cardholders were more likely to make up
      these groups. While public funding ensures access to care for a substantial
      number of individuals. West Coast dentists are supplementing this care by
      providing treatment without charge for a small number of people. Various adverse
      impacts of oral conditions were reported by up to 8.6 percent of respondents;
      more Community Cardholders reported feeling self-conscious or embarrassed than
      non-Community Cardholders. Geographic isolation and lack of choice of dental
      practitioner did not appear to be factors in determining utilisation. The two
      characteristics associated with poorer self-reported dental health and infrequent
      use of dental services were lower socio-economic status and self-reported dental
      anxiety. The findings of this study provide regional-level confirmation of the
      general findings of the 1976 and 1988 national studies.

PMID- 10396926
TI  - The West Coast Study. II: Dental anxiety and satisfaction with dental services.
AB  - Dental anxiety is common, and is a notable factor in the avoidance of dental
      care. The dental satisfaction of users is an important indicator of the quality
      of dental care. A postal survey (response rate 76.6 percent) was used to
      investigate dental anxiety and dental satisfaction among a representative sample
      of 249 dentate adults living on the West Coast of the South Island of New
      Zealand. Dental anxiety was reported by 20.8 percent of respondents, and was more
      prevalent among beneficiaries (individuals in receipt of a Social Welfare
      benefit) and younger people. Dental satisfaction was lower among younger people
      and those who were dentally anxious, and was higher among people with a tertiary
      education. Differences in consumers' expectations were considered responsible for
      the latter findings. Where appropriate, dentists should be prepared to adapt
      their manner of communicating with patients.

PMID- 10396927
TI  - Orthodontics and orthognathic surgery in the combined treatment of an excessively
      "gummy smile".
AB  - This report highlights the benefits that can be achieved with the combined
      orthodontic and orthognathic surgical approach where the presenting malocclusion
      is related primarily to an underlying skeletal malrelationship. The patient
      experienced a dramatic improvement in her facial form and occlusion, and a
      reduction of her excessively "gummy smile".

PMID- 10396928
TI  - Dental programme for smoke-free promotion: attitudes and activities of dentists,
      hygienists, and therapists at training and 1 year later.
AB  - Dentists, hygienists, and therapists in Auckland, who had attended a training
      programme designed to discourage smoking in their patients, were surveyed to
      determine their current anti-smoking activities. After the training course, those
      surveyed were more aware of the importance of smoking-cessation counselling, and
      were taking a much more active role in such activities. The activities of dental
      therapists with child patients indicate that this is a potentially important
      addition to their health education role.

PMID- 10396929
TI  - Drug addiction and dental care.
AB  - Patients who are addicted to drugs, or are being treated for drug addiction,
      present a variety of management issues when they attend for dental care. A number
      of factors are related to the treatment planning and clinical management.
      Dentists should be aware of these factors in order to manage these patients
      sensitively and effectively. Important management issues include medical problems
      associated with drug abuse, dental problems and how drug abuse and its subsequent
      treatment affect the dentition, behavioural disorders, pain management, and
      control of cross-infection. People who have recovered from chemical dependency to
      opiates have special needs, especially in pain management. Establishing a good
      pre-treatment rapport with the patient will assist the dentist in reducing the
      need for postoperative analgesics, and will encourage this group of patients to
      return and obtain needed dental care. The more dental practitioners know about
      types and patterns of drug abuse and recovery programmes, the more safely this
      group of patients with special needs can be managed.

PMID- 10396930
TI  - Dental injury claims.

PMID- 10396931
TI  - Epidemiology in practice.

PMID- 10396932
TI  - [Portal hypertensive gastropathy].

PMID- 10396933
TI  - [Helicobacter pylori and gastric cancer].

PMID- 10396934
TI  - [Helicobacter pylori infection and histological types of gastric cancer].
AB  - The relationship between Helicobacter pylori (H. pylori) infection and gastric
      cancer was evaluated clinicopathologically by histological types of gastric
      cancer (intestinal or diffuse type). Histological findings of resected stomach
      tissues and serum anti-H. pylori IgG antibody titers obtained in patients with
      early gastric cancer revealed H. pylori infection and associated inflammatory
      changes in all cases, irrespective of histological types of cancer, and suggested
      that diffuse type cancer occurs in the mucosa with marked inflammation at a
      relatively early stage of H. pylori infection, while intestinal type cancer
      occurs at a relatively late stage of infection in parallel with the progression
      of mucosal atrophy and intestinal metaplasia. Results of immunohistochemical
      staining showed high incidence of secretory components in and around cancer foci,
      suggesting that immunological mechanisms for H. pylori infection play a role in
      the development of gastric cancer regardless of its histological type.

PMID- 10396935
TI  - [Usefulness of DIC-CT in choledocholithiasis].
AB  - In order to assess the efficacy of helical CT in drip-infusion cholangiography
      (DIC-CT) for diagnosis of choledocholithiasis, 82 patients with biliary diseases,
      including 25 patients with a definite diagnosis of choledocholithiasis obtained
      by direct cholangiography, were investigated by DIC-CT and EUS. Comparative
      investigation showed that, of the 25 cases, 94.7% could be imaged by DIC-CT and
      87.5% by EUS, with respective sensitivities of 94.7% and 87.5%. The specificities
      in both cases were 100% and accuracies were 97.8% with DIC-CT and 96% with EUS
      respectively. Therefore, in diagnosis the choledocholithiasis, DIC-CT displays
      similar diagnostic efficiency as EUS or ERC, and can be recognized as the non
      invasive and useful procedure for pre-operative diagnosis of cholecystolithiasis.

PMID- 10396936
TI  - [A case of primary carcinoma of the vermiform appendix associated with Bowen's
      disease and early gastric carcinoma].

PMID- 10396937
TI  - [A case of well differentiated adenocarcinoma with ulcerative colitis resembling
      colitis cystica profunda].

PMID- 10396938
TI  - [An adult case of colonic duplication with recurrent abdominal pain: CT scan
      reveals fluctuation of the cyst].

PMID- 10396939
TI  - [A case of low-grade fibromyxoid sarcoma of the small bowel mesentery].

PMID- 10396940
TI  - [A case of advanced hepatocellular carcinoma treated by repeated arterial
      infusion chemotherapy of 5-FU, LV, CDDP with an implanted reservoir].

PMID- 10396941
TI  - [A case of gallbladder carcinoma with regional metastasis to the cystic vein
      perfusion area of the liver].

PMID- 10396942
TI  - [A case report of pancreatic mucinous cystadenocarcinoma with penetration to the
      stomach].

PMID- 10396943
TI  - [Histological concepts on clinico-pathological features of Kaposi sarcoma].

PMID- 10396944
TI  - [Comparison between aspirates (cytology and histology) and biopsy (cytology and
      histology) in bone marrow evaluation in simple peripheral cytopenia].
AB  - In order to assess a "basic" comparison between needle biopsy (B) and aspirate
      (A) in terms of diagnostic efficacy two hundred consecutive samples of bone
      marrow from 180 patients with simple (non neoplastic) peripheral cytopenia were
      examined. Both B and A from the identical anatomical site (posterior superior
      iliac spine) were performed in every case. Histology (I) and cytology (C) were
      systematically prepared from B (IB and CB) and from A (IA and CA). The cases were
      subdivided in 7 groups according to the type of cytopenia (mono-bi-trilinear).
      From a nosologic point of view these corresponded to common hematological
      disorders. As far as myelodysplasia (MD) is concerned only refractory anemia (RA)
      and refractory anemia with ring sideroblasts (RARS) were included. MD represented
      28.6% of anemias which in turn covered 63.0% of all the cases. The diagnostic
      significance of I and C referred to the final diagnosis (A + B). In each group
      were compared (vs) A (CA + IA) vs B (IB + CB), IB vs CA, CA vs IA,IB vs CB and IB
      vs IA. The results were expressed by putting each related case into one of the
      following three cathegories: equivalence, superiority, inferiority. Equivalence
      could be diagnostically significant or non significant. Combination I + C was
      diagnostic in 100% of cases for A + B and IB + CA, in 96.5% for CA + IA, in 92.5%
      for IB + CB. Combination IB + IA was significant in 99.5% of samples, similarly
      supported by IB and IA respectively accounting for 91.0% and 90.0 of diagnoses.
      Individually CA was diagnostic in 92.0% and CB in 80.5% of cases. In some
      istances uneffective CA was implemented by IA (4.5%) and analogously IB by CB
      (1.5%). Within A CA gave little more significance than IA (only +2.0%). The
      different rates of I + C coincident diagnostic significance were: 97.5% (A + B),
      85.5% (CA + IA), 83.0% (IB + CA), 79.0% (IB + CB). In 25.0% of MD cases diagnosis
      was assured by A only. In case of diagnostic discrepancy the classical
      morphologic parameters as cellularity, linearity and cytological details were
      also comparatively analysed. CONCLUSIONS: 1) the data above mentioned measure the
      diagnostic efficacy of the various procedures, individually or in association,
      with reference to the examined area, but they can be "basically" significant in
      the perspective of other comparisons; 2) as a whole B and A showed diagnostic
      equivalence, but A was more contributory in RA and RARS; this methologically
      means that CA needs to be reappraised and that IA is very reliable; 3)
      association I + C seems to be the best procedural approach in order to provide
      complementary morphology and amplified availability of material for examination,
      diagnosis and further study; 4) the performance of histopathologist can be
      improved by simultaneous cytological evaluation.

PMID- 10396945
TI  - [Metastatic brain tumors].
AB  - 211 patients operated on for brain metastases have been selected through a review
      of specimens from the Department of Pathology of the University of Florence
      covering the period between 1980 to 1995. 140 patients (66%) are males and 71
      (34%) are females. Average age is 59 years ranging from 33 to 79 years of age.
      Lung tumours (47%) and breast cancer (9%) are most frequently responsible for
      brain metastases. In 17% of the patients, the primary lesion was unknown. The
      average survival was 14 months and in 8 patients (4%) it was more 5 years. In 36
      cases (17%) recurrence appeared 8 months after the first operation. Survival in
      these patients averaged 20 months from the diagnosis of brain metastases and 11
      months after the discovery of the relapses. It is not significantly different
      from that of patients without evidence of relapsed metastases in the brain (13
      months). Prognostically renal carcinoma behaves more favourably, average survival
      (27 months); on the contrary prognosis of metastatic melanoma is ominous (7
      months). Metastases from unknown primaries do not have a significant different
      prognosis from all the other lesions.

PMID- 10396946
TI  - [Helicobacter heilmannii: anatomo-clinical study of 14 new cases].
AB  - INTRODUCTION: Helicobacter pylori is one of the most common causes of human
      gastritis. Recently, a new agent has been isolated, which also causes a
      gastritis. It has been initially named Gastrospirillum hominis and renamed
      Helicobacter heilmannii (Hh). Hh is extremely rare. In spite of the rarity it is
      important to recognize and diagnose it, as it requires a proper therapy,
      different from Hp therapy. Clinical presentation and serological results of Hh
      are superimposable to those of HP. Therefore differential diagnosis resides on
      histological grounds. PURPOSE of the present paper is to report 14 new cases of
      Hh gastritis, which constitutes the first italian series. RESULTS: Cases
      constituted 0.01% of all gastric biopsies seen in the period 1994-1998. Nine
      patients were male and five were female; age ranged from 32 to 76 years (50 years
      on average). All patients presented a mild to moderate gastritis. Hh is a spiral
      bacterium, being about 10 micra in length, localized in single or small groups in
      the glandular mucus. Two cases were associated with Hp. One case was associated
      with gastric adenocarcinoma. Two cases were diagnosed during the follow-up of
      duodenal ulcer. In CONCLUSION, the incidence of Hh gastritis in the present
      series seems consistent with that from other European countries. In all cases the
      presence of Hh was associated with features of gastritis. This confirms the
      pathogenetic role of Hh.

PMID- 10396947
TI  - [Meconium peritonitis and feto-fetal transfusion syndrome].
AB  - A case of twin-to-twin transfusion syndrome with intrauterine death of one twin
      and meconium peritonitis and intravascular disseminated coagulation in the other
      twin is reported. Meconium peritonitis follows to bowel perforation, caused by
      segmental severe hypoplasia of muscular layer. The Authors suggest that this
      structural alteration of bowel wall could be an expression of inequal
      distribution of some cells between the two twins, during embrional development.

PMID- 10396948
TI  - [Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid:
      description of a case].
AB  - INTRODUCTION: A case of sclerosing mucoepidermoid carcinoma with eosinophilia of
      the thyroid gland is described. RESULTS: The patient, a 32 year-old female with
      Hashimoto's thyroiditis, presented with a 4 cm nodule of the right lobe of the
      thyroid gland. The tumour was constituted by squamoid cords infiltrating a dense
      fibro-jaline stroma rich in eosinophils. The patient is alive and well 14 months
      after surgery. DISCUSSION: The literature is briefly reviewed and the
      differential diagnosis is discussed. In the Author's opinion, sclerosing
      mucoepidermoid carcinoma with eosinophilia of the tyroid is a well defined
      clinicopathological entity.

PMID- 10396949
TI  - [How technology and vaccination have changed the Pap test].

PMID- 10396951
TI  - [Mitochondrial diseases].

PMID- 10396950
TI  - [Guidelines for the anatomopathological diagnosis of chronic idiopathic
      inflammatory bowel disease].

PMID- 10396952
TI  - Prognostic factors of epithelial tumours of the kidney.

PMID- 10396953
TI  - [How a university professor should be: Giovanni Capellini, geologist,
      paleontologist and paleoanthropologist (1833-1922)].

PMID- 10396954
TI  - [On the latest case of renal carcinoma associated with GIST].

PMID- 10396955
TI  - [Pathology and the movies].

PMID- 10396956
TI  - [Methodological questions in resolving the problem of determining the time of
      death].
AB  - Presents the modern concept of evaluating the time of death, the philosophy of
      solving this problem, and approaches to its solution. Analyzes the procedure and
      choice of correct approach to problem solution from methodological viewpoint and
      as a problem at the interface of medicine and technology.

PMID- 10396957
TI  - [The morphofunctional changes in the internal organs in the modelling of
      poisonings by psilocybine-containing mushrooms].
AB  - Histological analysis of the viscera in experimental poisoning with psilocybin
      containing mushrooms showed nonspecific changes in all examined organs,
      presenting as expressed hemocirculatory disorders and intracellular dystrophy.
      Quantitative histochemical analysis showed appreciable shifts in the activities
      of enzymes involved in the cytoplasmic and mitochondrial redox processes and of
      specific enzymes involved in nerve tissue metabolism. This may reflect some
      features in the direct effects of narcotic alkaloids contained in psilocybin
      producing mushrooms.

PMID- 10396958
TI  - [The expert assessment of the damages to the teeth resulting from an operation
      for their removal].
AB  - Evaluates the causes and mechanisms of tooth fractures occurring during tooth
      removal, using mathematical simulation methods. Most common sites of tooth
      destruction during tooth removal are noted. The authors emphasize obligatory
      thorough examination of a patient before the operation, a detailed description of
      the status of oral tissues and teeth in the case history, rational choice of
      instruments, and strict adherence to the protocol of intervention.

PMID- 10396959
TI  - [The intergroup variability and sex dimorphism in the size of the human dental
      arches in personal identification].
AB  - The morphology of dental arch has been studied in representatives of 11 contrast
      (by anthropological characteristics) ethnic groups from regions of their compact
      residence. The sampling from each ethnic group consisted of 200 subjects (100
      male and 100 female) aged 13-20 years. A total of 4,500 plaster models of dental
      arches were examined. The results were statistically processed using factor,
      canonical, discriminant analyses, and multidimensional scanning. The data on the
      variability and sex dimorphism in the size and shape of dental arches in subjects
      belonging to different ethnic groups may be practically significant in forensic
      medical personality identification.

PMID- 10396960
TI  - [The incidence of finding ABO system antigens in the population of the Russian
      Federation].
AB  - A total of 48,744 blood specimens collected in various regions of the Russian
      Federation are analyzed. There is no correlation between the incidence of this or
      that AB0 blood group and geographic position of a region. Blood group A is the
      most prevalent. In women the predominance of blood group A is the most
      pronounced.

PMID- 10396961
TI  - [Testing problems regarding narcotic substances in hair analysis].
AB  - The authors discuss legal, ethic, and technological problems associated with
      introduction of drug testing by analysis of hair in Russia. There are
      sufficiently reliable methods of hair analysis, but lack of legal basis and poor
      equipment of forensic chemical departments impede the introduction and wide use
      of these methods in Russia. The authors propose certification of the best
      equipped departments and render them the legal status of regional centers for
      tests for narcotics and psychotropic agents.

PMID- 10396962
TI  - [The forensic chemical analysis of cadaveric material for the presence of drug
      and narcotic compounds].
AB  - The authors consider that the list of drugs and narcotics which can be reliably
      identified in a general forensic chemical analysis of cadaveric material (not a
      purposeful screening) should be changed. Isolation by acidified water,
      hydrochloric acid hydrolysis, and by acetonitrile should be used for isolation of
      drugs and narcotic compounds in forensic chemical analysis of cadaveric material.

PMID- 10396963
TI  - [The analysis of the methylenedioxy derivatives of amphetamine].
AB  - Methods for analysis of narcotics belonging to amphetamine methylene dioxy
      derivatives (MDD) are reviewed. The characteristics of these agents, their
      metabolism, and methods used for their detection and identification (TLC, GC,
      HPLC, GC/MS) are described. Methods for their extraction from biological objects
      (human urine and hair) are described. Efficacy of MDMA and MDEA from the urine by
      different extractants is assessed. The data demonstrate different potentialities
      for detection and identification of amphetamine MDD, including those in
      biological specimens (human urine and hairs), by numerous chromatographic
      methods.

PMID- 10396964
TI  - [The current methods for determining the time of death].

PMID- 10396965
TI  - [Fatal dipyridamole poisonings].

PMID- 10396966
TI  - [Multiple injuries from the action of the explosive gas wave from a detonator].

PMID- 10396967
TI  - [The detection of Brilliant Green in cadaveric material].

PMID- 10396968
TI  - [Membrane lipid signaling system participating in intracellular signal
      transduction--General concept].

PMID- 10396969
TI  - [Phosphatidylinositol kinase: functional roles for PI4-kinase and PIP kinase in
      signal transduction].

PMID- 10396970
TI  - [Phosphoinositide 3-kinase].

PMID- 10396971
TI  - [The role of phosphatidylinositol turnover in nuclear].

PMID- 10396972
TI  - [Diacylglycerol kinase: molecular diversity and gene expression in central
      nervous system].

PMID- 10396973
TI  - [Phosphatidic acid phosphatase].

PMID- 10396974
TI  - [Phospholipase C].

PMID- 10396975
TI  - [Roles of phospholipase D in signal transduction].

PMID- 10396976
TI  - [Mechanism of phospholipase D regulation].

PMID- 10396977
TI  - [Phospholipase A2].

PMID- 10396978
TI  - [Structure and function of phospholipase A2 receptor].

PMID- 10396979
TI  - [Phospholipase B/lipase belonging to a new lipase family].

PMID- 10396980
TI  - [Structure and function of phosphatidylserine-specific phospholipase A1: PS
      PLA1].

PMID- 10396981
TI  - [Structure and function of animal lysophospholipase].

PMID- 10396982
TI  - [Implications of "ceramide-regulating biostat system" from the discovery of
      "sphingomyelin cycle"].

PMID- 10396983
TI  - [Recent development of sphingosin 1-phosphate studies as a second messenger or a
      second agonist in cell signaling].

PMID- 10396985
TI  - [Platelet-activating factor (PAF) receptor-related pathophysiology].

PMID- 10396986
TI  - [PAF acetylhydrolase].

PMID- 10396984
TI  - [Bio-active lipids].

PMID- 10396987
TI  - [Leukotriene receptors].

PMID- 10396988
TI  - [Structure and function of prostaglandin receptors].

PMID- 10396989
TI  - [Prostanoid synthases].

PMID- 10396990
TI  - [2-Arachidonoylglycerol: an endogenous cannabinoid receptor agonist].

PMID- 10396991
TI  - [Function of sterylglucoside in cell differentiation and stress responses].

PMID- 10396992
TI  - [Occurrence, metabolism and bioactions of lysophosphatidic acid and cyclic
      phosphatidic acid as lysophospholipid mediators].

PMID- 10396993
TI  - [Induction of tumor invasion by lysophosphatidic acid and inhibition of tumor
      invasion by cyclic phosphatidic acid].

PMID- 10396994
TI  - [Lipoxygenases].

PMID- 10396995
TI  - [Anandamide and its related compounds].

PMID- 10396996
TI  - [Functional coupling between phospholipase A2 and cyclooxygenase].

PMID- 10396997
TI  - [Cell biological studies on intracellular trafficking of lipids].

PMID- 10396998
TI  - [Phosphatidylserine biosynthesis and its regulation in mammalian cells].

PMID- 10396999
TI  - [Biosynthesis and function of phosphatidylglycerol and cardiolipin in animal
      cells].

PMID- 10397000
TI  - [Role of membrane phospholipid dynamics in cell division].

PMID- 10397001
TI  - [Cell biology of lysobisphosphatidic acid].

PMID- 10397002
TI  - [Role of mammalian phosphatidylinositol transfer proteins in signal transduction
      and vesicle traffic].

PMID- 10397003
TI  - [Inositol phospholipid function in yeast].

PMID- 10397004
TI  - [Biosynthesis and intracellular trafficking of sphingolipids in mammalian cells].

PMID- 10397005
TI  - [Biosynthesis of triacylglycerol and related intracellular lipid transport in
      fungi and yeasts].

PMID- 10397007
TI  - [Physiological function of alpha-tocopherol transfer protein].

PMID- 10397006
TI  - [Niemann-Pick disease type C and cholesterol].

PMID- 10397008
TI  - [Imaging of endosome traffic in cells].

PMID- 10397009
TI  - [Recent progress of oxidized lipid].

PMID- 10397010
TI  - [Structure and function of phospholipid hydroperoxide glutathione peroxidase].

PMID- 10397011
TI  - [Oxidized lipoproteins and diseases].

PMID- 10397012
TI  - [Mechanism for the production of lipid peroxides].

PMID- 10397013
TI  - [Atherosclerosis and lipids: overview].

PMID- 10397014
TI  - [Macrophage scavenger receptor class A].

PMID- 10397016
TI  - [Lipid metabolism in Tangier disease].

PMID- 10397015
TI  - [Scavenger receptor class B].

PMID- 10397017
TI  - [Structure and function of a novel scavenger receptor expressed in human
      endothelial cells].

PMID- 10397019
TI  - [Lipoprotein lipase and atherosclerosis].

PMID- 10397018
TI  - [ApoE receptors].

PMID- 10397020
TI  - [Cholesteryl ester transfer protein].

PMID- 10397021
TI  - [CD36 as an oxidized LDL receptor].

PMID- 10397022
TI  - [Roles of acyl-coenzyme A: cholesterol acyltransferase (ACAT) isozymes].

PMID- 10397023
TI  - [Regulation of protein function by lipid modifications].

PMID- 10397024
TI  - [GPI-anchored proteins].

PMID- 10397025
TI  - [Biosynthesis of GPI-anchored proteins and its deficiency].

PMID- 10397026
TI  - [Regulation of protein functions by fatty acid acylation and isoprenylation].

PMID- 10397027
TI  - Functional foods: a prescription for health?

PMID- 10397028
TI  - Medical allies against alcoholism.

PMID- 10397029
TI  - The great debate over drug ads.

PMID- 10397030
TI  - Leery of liposuction.

PMID- 10397031
TI  - Food bargains: too much of a good thing.

PMID- 10397032
TI  - New papilloma test.

PMID- 10397033
TI  - Night lights to blame for vision problems?

PMID- 10397034
TI  - Rising PSA after prostate surgery may guide subsequent treatment.

PMID- 10397035
TI  - Hepatitis C home test.

PMID- 10397036
TI  - Investigate anemia in older adults.

PMID- 10397037
TI  - [Allogenic transplantation of blood stem cells: status quo and perspectives].

PMID- 10397038
TI  - Parasitic meningitis.

PMID- 10397039
TI  - Primary stenting in acute myocardial infarction: paving the way to arterial
      patency.

PMID- 10397040
TI  - Australians with renal disease: a new national survey.

PMID- 10397041
TI  - Living from day to day--or generation to generation.

PMID- 10397042
TI  - Hormone replacement therapies in women at risk of cardiovascular disease and
      osteoporosis in South Australia in 1997.
AB  - OBJECTIVE: To describe changes in use of hormone replacement therapy (HRT) in an
      Australian population and to determine HRT use in women at risk of cardiovascular
      disease and osteoporotic fracture. DESIGN: Data were derived from the 1997 South
      Australian Health Omnibus Survey (a representative population survey) and
      compared with data from 1991, 1993 and 1995 Omnibus Surveys. SETTING: South
      Australia, 1997. PARTICIPANTS: 1049 women aged 40 years and over from a random
      selection of 4400 households. RESULTS: Among women aged 55-64 years (and thus
      likely to be postmenopausal), 60% had used HRT (ever use). Nearly two-thirds of
      these women used it currently. In this age group, mean length of HRT use had
      increased to 70 months (median, 60 months). Rates of HRT use had not changed
      significantly between 1991 and 1997 in women under 55 years, but had increased
      significantly in women aged 55 years or over (P < or = 0.01). Among women
      currently using HRT, 5.4% had used testosterone therapy, while 4% used
      unregistered products purported to contain hormones. Rates of ever use of HRT in
      women with zero, one, two, or three or more cardiovascular risk factors were 33%,
      37%, and 45%, respectively. Among women with a diagnosis of osteoporosis, 52% had
      used HRT, with a mean length of use of 86 months (median, 60 months). CONCLUSION:
      HRT use is increasing in older-age groups. Longer-term therapy with potential for
      primary prevention is now occurring, but half of those with osteoporosis and more
      than half of those with risk factors for cardiovascular disease have not used
      HRT.

PMID- 10397043
TI  - Why do preterm infants die in the 1990s?
AB  - OBJECTIVES: To describe the mortality rate for preterm infants (born 23-36
      completed weeks' gestational age) and to determine the causes of death, focusing
      on avoidable causes. DESIGN AND SETTING: Prospective cohort study of preterm
      infants born at Royal Women's Hospital, Melbourne (a tertiary referral hospital
      with a neonatal intensive care unit and a special care nursery) from January 1994
      to December 1996. SUBJECTS: 2475 consecutive liveborn infants with gestational
      ages from 23 to 36 weeks. MAIN OUTCOME MEASURES: Mortality rate during the
      primary hospitalisation, and causes of death. RESULTS: The total mortality rate
      was 4.8% (118/2475). The mortality rate declined with increasing maturity. The
      decrease in mortality was rapid between 23 and 28 weeks' gestational age, from
      64.5% at 23 weeks to 4.0% at 28 weeks, then slower, falling to 0.4% at 36 weeks.
      Fifty of the 118 infants who died had lethal congenital anomalies. Lethal
      anomalies accounted for three-quarters of deaths in infants aged 28-36 weeks. The
      mortality rate in infants free of lethal anomalies was 2.8% (68/2425) and only
      0.2% (4/1759) for infants aged 32-36 weeks. In the 68 infants without lethal
      anomalies who died, few obvious preventable causes were identified. CONCLUSIONS:
      Mortality rates fell rapidly between 23 and 28 weeks' gestational age. Survival
      rates for preterm infants born after 31 weeks' gestational age approached the
      survival rates of term infants. Lethal congenital anomalies were the most common
      cause of death; preventable causes of death were rare.

PMID- 10397044
TI  - Japanese encephalitis in north Queensland, Australia, 1998.
AB  - OBJECTIVE: To describe the circumstances of two cases of Japanese encephalitis
      (JE) in north Queensland in 1998, including one acquired on the Australian
      mainland. DESIGN: Serological surveillance of sentinel pigs for JE virus
      activity; serological surveys of humans and pigs and viral cultures of mosquito
      collections. SETTING: Islands in the Torres Strait and communities in the
      Northern Peninsula Area (NPA) and near the mouth of the Mitchell River in Cape
      York, Queensland, in the 1998 wet season (December 1997-May 1998). RESULTS:
      Sentinel pigs in the Torres Strait began to seroconvert to JE virus in February
      1998, just before onset of JE in an unvaccinated 12-year-old boy on Badu island.
      By mid-April, most sentinel pigs had seroconverted. Numerous JE viruses were
      isolated from Culex annulirostris mosquitoes collected on Badu. In early March, a
      person working at the mouth of the Mitchell River developed JE. Serological
      surveys showed recent JE virus infection in 13 young pigs on a nearby farm, but
      not in 488 nearby residents. In NPA communities, sentinel pigs seroconverted
      slowly and JE viruses were isolated from three, but none of 604 residents showed
      evidence of recent infection. Nucleotide sequencing showed that 1998 JE virus
      isolates from the Torres Strait were virtually identical not only to the 1998
      isolate from an NPA pig, but also to previous (1995) Badu isolates. CONCLUSIONS:
      JE virus activity was more widespread in north Queensland in the 1998 wet season
      than in the three previous wet seasons, but ecological circumstances (e.g., less
      intensive pig husbandry, fewer mosquitoes) appear to have limited transmission on
      the mainland. Nucleotide sequencing indicated a common source for the 1995 and
      1998 JE viruses. Circumstantial evidence suggests that cyclonic winds carried
      infected mosquitoes from Papua New Guinea.

PMID- 10397045
TI  - A primary stenting strategy as an alternative to fibrinolytic therapy in acute
      myocardial infarction. An analysis of results in hospital and at 6 weeks and 6
      months.
AB  - OBJECTIVE: To report the feasibility and results to 6 months of a primary
      stenting strategy in patients with acute myocardial infarction (AMI). DESIGN:
      Prospective, single-centre, observational study. SETTING: A tertiary referral
      teaching hospital (Royal North Shore Hospital, Sydney), July 1997 to November
      1998. SUBJECTS: 102 (of 194) consecutive patients presenting to the emergency
      department with AMI who were eligible for fibrinolytic therapy, and for a primary
      stenting strategy. The first 50 patients were under 70 years of age, and had not
      had previous coronary artery bypass grafting (CABG). The following 52 patients
      included patients up to 80 years and with previous CABG. OUTCOME MEASURES: Major
      adverse cardiac and cerebrovascular events: death, reinfarction, cerebrovascular
      accident (CVA) and repeat target lesion revascularisation, in hospital, and at 6
      weeks and 6 months. Minor in-hospital adverse events: bleeding requiring blood
      transfusion, vascular complications and new-onset heart failure. Time delays to
      treatment, and duration of hospital stay. RESULTS: Normal flow was established in
      the infarct-related artery in 97/102 patients (95%). Stenting, percutaneous
      transluminal coronary angioplasty (PTCA), CABG or medical therapy was performed
      in 74, 11, 9 and 8 patients, respectively. Minor in-hospital events, time delays
      and hospital stay were similar to those reported previously. At 6 weeks, major
      adverse cardiac and cerebrovascular events had occurred in 5% of patients (four
      repeat target lesion revascularisation and one reinfarction). By 6 months, repeat
      target lesion revascularisation had been performed in an additional 10% of
      patients. No deaths had occurred. CONCLUSIONS: A primary stenting strategy can be
      performed safely, without significant delays and with excellent short and
      intermediate term outcomes.

PMID- 10397046
TI  - A fatal case of angiostrongyliasis in an 11-month-old infant.
AB  - An 11-month-old boy developed flaccid quadriparesis after two months in Fiji, and
      was transferred to Australia, where a diagnosis of postinfectious myelitis was
      made. Despite peripheral blood eosinophilia, eosinophils were not detected in the
      cerebrospinal fluid, and an infective aetiology was not identified. The patient
      died of progressive bulbar dysfunction. At autopsy, numerous nematodes,
      identified as Angiostrongylus cantonensis, were seen in vessels of the lungs,
      brain and spinal cord, associated with pulmonary abscesses and eosinophilic
      meningitis. A notable feature was the presence of adult nematodes in the lung.

PMID- 10397047
TI  - Androgen treatment in women.
AB  - Many women, both before and after menopause, may have symptoms of androgen
      deficiency: unexplained fatigue, lack of well-being and diminished libido. If
      plasma levels of bioavailable testosterone are low, these symptoms will mostly be
      relieved by judicious administration of testosterone. The addition of
      testosterone to postmenopausal hormone replacement regimens is becoming more
      widespread, and other potential uses include prevention and treatment of bone
      loss, treatment of spontaneous or iatrogenic androgen deficiency in premenopausal
      women, and, possibly, management of the premenstrual syndrome.

PMID- 10397048
TI  - Lipovac v Black: was Dr Black negligent?

PMID- 10397049
TI  - The slow pulse: is a pacemaker necessary?

PMID- 10397050
TI  - Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised
      controlled clinical trial. Unfortunate methodological flaws.

PMID- 10397051
TI  - Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised
      controlled clinical trial. Was the neuropsychological testing appropriate?

PMID- 10397052
TI  - Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised
      controlled clinical trial. Some evidence at last.

PMID- 10397053
TI  - Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised
      controlled clinical trial. Was the best treatment protocol used?

PMID- 10397054
TI  - Treatment of glucocorticoid-dependent Takayasu's arteritis with cyclosporin.

PMID- 10397055
TI  - Heparin in acute ischaemic stroke.

PMID- 10397056
TI  - Routine coagulation tests.

PMID- 10397057
TI  - Clinical pathways.

PMID- 10397058
TI  - Alternative neutering technique for consideration.

PMID- 10397059
TI  - Appreciates historical perspective on urinary tract disease.

PMID- 10397060
TI  - What is your diagnosis? Mycoplasma arthritis in a cat.

PMID- 10397061
TI  - Animal behavior case of the month. A dog was evaluated because of extreme fear.

PMID- 10397062
TI  - Control of fleas on pets and in homes by use of imidacloprid or lufenuron and a
      pyrethrin spray.
AB  - OBJECTIVE: To evaluate imidacloprid and the combination of lufenuron and
      pyrethrin to control flea infestations in households with pets. ANIMALS: 37 dogs
      and 19 cats in 34 flea-infested households. PROCEDURE: Households were assigned
      randomly to 1 of 2 groups. Pets in group 1 were treated topically with
      imidacloprid on day 0, then once a month for 90 days. Pets in group 2 were given
      lufenuron orally on day 0 and at monthly intervals for 90 days and also were
      treated topically with a pyrethrin spray every 1 to 2 weeks throughout the study.
      Flea numbers in homes were assessed by use of intermittent light traps, and flea
      burdens on pets were assessed using visual area counts done once a week during
      the first month, then every other week. RESULTS: One application of imidacloprid
      reduced flea burdens on pets by 96 and 93.5% on days 7 and 28, respectively,
      compared with day-0 burdens. Following 3 applications, flea burdens on pets and
      in homes were reduced by 98.8 and 99.9%, respectively. Lufenuron and pyrethrin
      spray reduced flea numbers on pets by 48.9 and 91.1% on days 7 and 28,
      respectively. By the end of the study, this combination reduced flea burdens on
      pets and in homes by 99.2 and 99.7%, respectively. CONCLUSIONS AND CLINICAL
      RELEVANCE: Imidacloprid applied topically or lufenuron administered orally along
      with a topically applied pyrethrin spray were effective in eliminating fleas on
      pets and in homes. Flea control can be achieved with topical application of
      adulticides or oral administration of insect growth regulators without
      concomitant treatment of the surroundings.

PMID- 10397063
TI  - Evaluation of the association between medial patellar luxation and hip dysplasia
      in cats.
AB  - OBJECTIVE: To investigate the association between hip dysplasia (HD) and medial
      patellar luxation (MPL) in cats. DESIGN: Cross-sectional prevalence study.
      ANIMALS: 78 cats. PROCEDURE: A complete history was obtained. Cats were examined
      to detect MPL and HD. Radiographs of the stifle and hip joints were obtained. Hip
      joints were evaluated by use of Norberg angle, distraction index, and scoring
      consistent with that established by the Orthopedic Foundation for Animals.
      RESULTS: There were 43 male and 35 female cats mean age, 2.5 years). Eleven cats
      had clinical signs of disease in the pelvic limbs. Medial subluxation of the
      patella (subgrade 1) was seen in 31 of 33 cats with otherwise normal stifle
      joints. Medial patellar luxation was found in 45 of 78 (58%) cats, and 35 of 45
      (78%) had grade-1 MPL. Bilateral MPL was seen in 32 of 45 (71%) cats. A weak
      association existed between MPL and HD, because cats were 3 times more likely to
      have HD and patellar luxation than to have either condition alone. Concurrent MPL
      and HD were detected in 19 of 78 (24%) cats, and HD was diagnosed
      radiographically in 25 of 78 (32%) cats (19 mild, 4 moderate, 2 severe). Eighteen
      of the 25 cats with HD had bilateral HD. CONCLUSIONS AND CLINICAL RELEVANCE:
      Clinically normal cats may have a certain degree of laxity in the stifle joint,
      evident as medial patellar subluxation (< grade 1). There is a weak association
      between MPL and HD, and both conditions may develop, alone or in combination,
      more frequently than has been reported.

PMID- 10397064
TI  - Introduction of an endocardial pacing lead through the costocervical vein in six
      dogs.
AB  - Lead dislodgement is one of the most common complications of endocardial pacing
      lead implantation in dogs. Incidence of lead displacement appears to be higher in
      large-breed, compared with small-breed, dogs, suggesting that excessive neck
      movements may be a contributing factor. To avoid introducing pacing leads through
      a vein in the neck, we developed a technique for implantation of endocardial
      pacing leads through the right costocervical vein. A right second intercostal
      space thoracotomy was performed to expose the vein, and the pacing generator was
      placed in the musculature over the lateral aspect of the thorax. The technique
      was performed in 6 dogs, 5 of which had had an endocardial pacing lead dislodge.
      None of the dogs had problems with lead dislodgement during follow-up periods of
      15 to 20 months. Implantation of endocardial pacing leads through the
      costocervical vein should not be considered a replacement for implantation
      through the jugular vein. However, we believe that this technique is indicated
      for large dogs in which endocardial pacing leads implanted through the jugular
      vein have dislodged.

PMID- 10397065
TI  - Plasma lactate concentration as a predictor of gastric necrosis and survival
      among dogs with gastric dilatation-volvulus: 102 cases (1995-1998).
AB  - OBJECTIVE: To determine relationships between plasma lactate concentration and
      gastric necrosis and between plasma lactate concentration and outcome for dogs
      with gastric dilatation-volvulus. DESIGN: Retrospective study. ANIMALS: 102 dogs.
      PROCEDURE: Information on signalment, history, plasma lactate concentration,
      medical and surgical treatment, cost of hospitalization, and outcome was
      retrieved from medical records. RESULTS: 69 of 70 (99%) dogs with plasma lactate
      concentration < 6.0 mmol/L survived, compared with 18 of 31 (58%) dogs with
      plasma lactate concentration > 6.0 mmol/L (1 dog euthanatized for economic
      reasons was not included). Gastric necrosis was identified in 38 (37%) dogs.
      Median plasma lactate concentration in dogs with gastric necrosis (6.6 mmol/L)
      was significantly higher than concentration in dogs without gastric necrosis (3.3
      mmol/L). Specificity and sensitivity of using plasma lactate concentration (with
      a cutoff of 6.0 mmol/L) to predict which dogs had gastric necrosis were 88 and
      61%, respectively. Sixty-two of 63 (98%) dogs without gastric necrosis survived,
      compared with 25 of 38 (66%) dogs with gastric necrosis. CONCLUSIONS AND CLINICAL
      RELEVANCE: Preoperative plasma lactate concentration was a good predictor of
      gastric necrosis and outcome for dogs with GDV. Preoperative measurement of
      plasma lactate concentration may assist in determining prognosis of dogs with
      GDV.

PMID- 10397066
TI  - Dietary and other management factors associated with colic in horses.
AB  - OBJECTIVE: To determine whether dietary and other management factors were
      associated with development of colic in horses. DESIGN: Prospective matched case
      control study. POPULATION: 2,060 horses examined by veterinarians in private
      practice in Texas for colic and noncolic emergencies. PROCEDURE: Each month for
      12 months, participating veterinarians were sent forms to collect information on
      1 horse with colic and 1 horse that received emergency treatment for a condition
      other than colic, information collected included signalment, farm management and
      characteristics, diet, medical and preventive medical factors, transport, and
      activity or use. Case and control horses were compared by means of conditional
      logistic regression to identify factors associated with colic. RESULTS: Recent
      change in diet, recent change in type of hay, history of previous episode of
      colic, history of abdominal surgery for colic, recent change in weather
      conditions, recent change in housing, Arabian breed, administration of an
      anthelmintic during the 7-day period prior to examination, failure to receive
      regular deworming, age > 10 years, and regular exercise (vs pastured at all
      times) were associated with increased risk of colic. CONCLUSIONS AND CLINICAL
      RELEVANCE: Results suggest that changes in diet (particularly in type of hay fed)
      contribute to increased risk of colic. A regular program for administration of
      anthelmintics may reduce the overall frequency at which colic develops, but
      recent administration of anthelmintics may predispose some horses to colic.
      Arabian horses may have an increased risk of colic, and horses at pasture may
      have a decreased risk of colic.

PMID- 10397067
TI  - Efficacy of a commercial vaccine for preventing disease caused by influenza virus
      infection in horses.
AB  - OBJECTIVE: To evaluate efficacy of a commercial vaccine for prevention of
      infectious upper respiratory tract disease (IURD) caused by equine influenza
      virus. DESIGN: Double-masked, randomized, controlled field trial. ANIMALS: 462
      horses stabled at a Thoroughbred racetrack. PROCEDURE: Vaccine or saline solution
      placebo was administered 4 times in the population at 6-week intervals. The
      vaccine contained 3 strains of inactivated influenza virus, and inactivated
      equine herpesvirus type 4. Horses received 1 or 2 doses of vaccine or placebo
      prior to onset of a natural influenza epidemic, and were examined 5 d/wk to
      identify and monitor horses with IURD. Serum antibody concentrations were
      determined, and virus isolation was performed. RESULTS: Vaccination of horses
      prior to the influenza epidemic did not result in significant decrease in risk of
      developing respiratory tract disease. Severity of clinical disease was not
      different between affected vaccinated horses with IURD and controls with IURD,
      but median duration of clinical disease was 3 days shorter in vaccinated horses.
      Serum concentrations of antibodies to H3N8 influenza viruses were lower prior to
      initial vaccination in horses that were sick during the epidemic, and did not
      increase in these horses in response to vaccination. On arrival at the racetrack,
      young horses had lower antibody concentrations than older horses, and did not
      respond to vaccination as well. CONCLUSIONS AND CLINICAL RELEVANCE: Vaccination
      was of questionable benefit. A greater degree of protection must be obtained for
      influenza vaccines to be effective in protecting horses from IURD. Objective
      field evaluations of commercial vaccines are needed to adequately document their
      efficacy.

PMID- 10397068
TI  - Effects of blood contamination of cerebrospinal fluid on western blot analysis
      for detection of antibodies against Sarcocystis neurona and on albumin quotient
      and immunoglobulin G index in horses.
AB  - OBJECTIVE: To determine effects of blood contamination on western blot (WB)
      analysis of CSF samples for detection of anti-Sarcocystis neurona antibodies, and
      on CSF albumin and IgG concentrations, albumin quotient (AQ), and IgG index in
      horses. DESIGN: Prospective in vitro study. SAMPLES: Blood with various degrees
      of immunoreactivity against S neurona was collected from 12 healthy horses.
      Cerebrospinal fluid without immunoreactivity against S neurona was harvested from
      4 recently euthanatized horses. PROCEDURE: Blood was serially diluted with pooled
      nonimmunoreactive CSF so that final dilutions corresponded to 10(-3) to 100
      microliters of blood/ml CSF, and WB analysis was performed on contaminated CSF
      samples. Number of RBC, albumin and IgG concentrations, AQ, and IgG index were
      also determined. RESULTS: Antibodies against S neurona were detected in CSF
      contaminated with 10(-3) microliters of strongly immunoreactive blood/ml. In CSF
      samples contaminated with 10 microliters of blood/ml, AQ remained within
      reference range. Volume of blood required to increase IgG index varied among
      blood samples and was primarily influenced by serum IgG concentrations. Number of
      RBC in contaminated samples was correlated with volume of blood added, but not
      with degree of immunoreactivity detected in contaminated CSF samples. CONCLUSIONS
      AND CLINICAL RELEVANCE: During collection of CSF from horses, contamination with
      blood may introduce serum antibodies against S neurona at concentrations
      sufficient for detection by WB analysis, thus yielding false-positive results.
      When blood is moderately or strongly immunoreactive, the amount of contaminating
      albumin may be small enough as to not increase AQ above reference range. In these
      cases, AQ and IgG index should be interpreted with caution.

PMID- 10397069
TI  - Effect of oral administration of a calcium chloride gel on blood mineral
      concentrations, parturient disorders, reproductive performance, and milk
      production of dairy cows with retained fetal membranes.
AB  - OBJECTIVE: To assess the effect of oral administration of CaCl2 gel on blood
      mineral concentrations, parturient disorders, reproductive performance, and milk
      production of dairy cows with retained fetal membranes (RFM). DESIGN: Randomized
      field trial. ANIMALS: 20 cows that calved normally and were not treated with
      CaCl2 gel (group 1), 20 cows with RFM that were treated with CaCl2 gel (group 2),
      and 20 cows with RFM that were not treated with CaCl2 gel (group 3). PROCEDURE:
      Group-2 cows were treated orally with CaCl2 gel (54 g of calcium) 24 and 48 hours
      after parturition. RESULTS: Administration of CaCl2 gel 24 and 48 hours after
      parturition did not have a significant effect on serum normalized calcium, total
      calcium, magnesium, or phosphorus concentrations or on incidence of metritis or
      left displacement of the abomasum, days to first insemination, pregnancy status
      after first insemination, or milk production. CONCLUSIONS AND CLINICAL RELEVANCE:
      Administration of CaCl2 gel 24 and 48 hours after parturition did not have
      significant effect on blood mineral concentrations, parturient disorders,
      reproductive performance, and milk production in dairy cows with RFM.

PMID- 10397070
TI  - Calcium oxalate crystalluria in a goat.
AB  - As part of a routine health evaluation of an 8-month-old female Nubian goat,
      serum biochemical analyses and urinalysis were performed. Most serum biochemical
      values including concentrations of blood calcium and indicators of urinary system
      dysfunction, such as blood urea nitrogen, creatinine, and phosphorous
      concentrations, were within reference ranges. An aliquot of voided urine was
      hypersthenuric and acidic and contained numerous typical cuboidal-bipyramidal
      calcium oxalate dihydrate crystals and unique rectangular parallelepiped crystals
      that were confirmed by energy dispersive X-ray microanalysis as being of calcium
      oxalate dihydrate composition. We hypothesize that the calcium oxalate crystals
      resulted from a diet containing calcium and oxalic acid. Treatment was not
      administered, and the goat remained healthy during the ensuing year.

PMID- 10397071
TI  - Anticentromere antibodies and vascular diseases.

PMID- 10397072
TI  - The role of antidiuretic hormone in hyponatremia in adrenal insufficiency--is the
      guideline for the diagnosis of syndrome of inappropriate secretion of the
      antidiuretic hormone appropriate?

PMID- 10397073
TI  - Chronic inflammatory demyelinating polyneuropathy: treatable hypertrophic
      neuropathy.

PMID- 10397074
TI  - Mixed connective tissue disease.
AB  - Mixed connective tissue disease deserves to be a distinct disease entity due to
      the persistent citation of this disease in the literature since the original
      description by Sharp in 1972, in spite of the presence of several criticisms
      against the independency of this disease. The characteristic features of mixed
      connective tissue disease are: 1) the presence of anti-U1snRNP antibody with high
      titers in sera, 2) an increased frequency of HLA-DR4 in the leukocytes, and 3)
      death due to pulmonary hypertension.

PMID- 10397075
TI  - The role of nitric oxide in bradykinin-induced dilation of coronary resistance
      vessels in patients with hypercholesterolemia.
AB  - OBJECT: In hypercholesterolemic patients, acetylcholine- and substance P-mediated
      endothelium-dependent dilation of the coronary resistance vessels is impaired due
      to decreased nitric oxide production. However, it is not clear if bradykinin
      induced coronary vasodilation is impaired in these patients. We investigated
      whether the endothelium-dependent dilation of coronary resistance vessels
      mediated by bradykinin is impaired in patients with hypercholesterolemia and, if
      so, whether this impairment is caused by a decreased production of nitric oxide.
      METHODS: We examined the coronary vascular responses to acetylcholine and
      bradykinin. The vascular responses to bradykinin were also assessed after N(G)
      monomethyl-L-arginine was infused to inhibit nitric oxide production. Drugs were
      infused into the left coronary ostium and coronary blood flow (CBF) and coronary
      vascular resistance were evaluated by quantitative angiography and Doppler flow
      velocity measurements. PATIENTS: Twelve hypercholesterolemic patients and 11
      control patients with angiographically normal coronary arteries were studied.
      RESULTS: The vasodilator responses to acetylcholine and bradykinin were reduced
      in hypercholesterolemic patients compared with control patients (p<0.005 and
      p<0.04, respectively, by two-way analysis of variance (ANOVA)). The CBF responses
      to acetylcholine and bradykinin were significantly correlated (r=0.56; p<0.01).
      Bradykinin-induced dilation was similar in hypercholesterolemic patients and
      control patients after inhibition of nitric oxide. CONCLUSION: These results
      suggest that the bradykinin-mediated endothelium-dependent dilation of coronary
      resistance vessels may be impaired due to depressed nitric oxide production in
      patients with hypercholesterolemia.

PMID- 10397076
TI  - Branched-chain amino acid therapy for spinocerebellar degeneration: a pilot
      clinical crossover trial.
AB  - OBJECT: The potential effects of branched-chain amino acids (BCAAs) on
      spinocerebellar degeneration (SCD) were explored in eleven patients. METHODS: The
      patients received 200 ml of BCAA-rich solution, 2 mg of thyrotropin-releasing
      hormone (TRH; protirelin), or a placebo daily for 7 days each in a random order.
      An SCD score was used to quantify the severity of symptoms. PATIENTS: Eleven
      patients with SCD (7 male, 4 female; mean age 60+/-11; mean disease duration 5.5
      years) participated in this study. RESULTS: The mean SCD score of the eleven
      patients improved significantly by the BCAA treatment compared with the baseline.
      The conditions of five of the eleven patients (45%) were clearly improved by the
      BCAA treatment. All of the responders manifested predominantly cerebellar
      symptoms, but no prominent parkinsonian symptoms. Two patients with marked
      rigidity and akinesia did not respond to the treatment. CONCLUSION: We concluded
      that BCAAs do have a beneficial effect on functional improvement in patients with
      SCD, and that further large scale studies are needed.

PMID- 10397077
TI  - Analysis of the CAG repeat number in a patient with Huntington's disease.
AB  - This study was performed to confirm 1) the difference in the trinucleotide CAG
      repeat number among tissues, 2) somatic mosaicism in each tissue, 3) the
      correlation of the repeat number with pathological severity in Huntington's
      disease. The CAG repeat number was determined by analysis of the polymerase chain
      reaction (PCR) product in various tissues, including central nervous system (CNS)
      tissues and non-CNS tissues. We also determined the pathological severity grade
      in each brain section and compared this with the results of CAG repeat analyses.
      The patient was a Japanese male with Huntington's disease who died at 62 years of
      age. Genomic DNA was extracted from 10 parts of the central nervous system and 6
      parts of other tissues from the patient. Each part of the formalin-fixed brain
      was subjected to gross and microscopic pathological assessment. The main peaks of
      CAG repeat in all tissues were 22 and 44. In analysis of somatic mosaicism, high
      degrees of mosaicism were obtained in the caudate nucleus, putamen and cerebral
      cortex, in which more severe degeneration was observed by pathological
      examination. These results, although this is a single case study, indicated that
      pathological severity did not correlate with the CAG repeat number, but it did
      relate to the degree of somatic mosaicism. Somatic mosaicism might reflect region
      specific neuronal degeneration in Huntington's disease.

PMID- 10397078
TI  - Statistically significant differences in the number of CD24 positive muscle
      fibers and satellite cells between sarcoglycanopathy and age-matched Becker
      muscular dystrophy patients.
AB  - OBJECT: The aim of this study was to reveal variations in the patterns of
      expression of the cell surface proteins in regenerating fibers and those in the
      number of satellite cells to gain an understanding of the pathological processes
      involved in sarcoglycanopathy. METHODS: We have reported that there is a
      reduction of the beta-1 subunit of laminin, heparan sulfate proteoglycan (HSPG),
      and HCAM (CD44) in Japanese patients with sarcoglycanopathy. Here, we
      investigated immunohistochemically the expression of the neural cell adhesion
      molecule (NCAM), which is a marker for human regenerating muscle and satellite
      cell, and CD24, which appears to be expressed in the early stages of the
      regeneration process. PATIENTS: We investigated six Japanese patients with
      sarcoglycanopathy, and compared to age-matched Becker muscular dystrophy.
      RESULTS: We found that the incidences of muscle fibers with increased NCAM were
      not statistically different between the two groups. However, the incidences of
      muscle fibers with increased CD24 and those of NCAM positive satellite cells were
      very low in sarcoglycanopathy and were statistically different between
      sarcoglycanopathy and age-matched Becker muscular dystrophies. CONCLUSION: The
      poor expression of CD24 and the fewer satellite cells in sarcoglycanopathy
      without significant difference in the number of total regenerating fibers suggest
      that a different regeneration process is involved in sarcoglycanopathy compared
      to that in other types of muscular dystrophy.

PMID- 10397079
TI  - Phlebosclerosis of the colon with positive anti-centromere antibody.
AB  - A 56-year-old woman with symptoms of chronic bowel disease presented a peculiar
      calcification of the mesenteric vein of the ascending to transverse colon on
      barium enema study. The resected colon was hard and black. Histo-pathologic
      examinations demonstrated fibrous change of the colon with a calcified and
      hyaline-deposited mesenteric vein. No cell infiltration was observed. These
      findings were compatible with phlebosclerosis and also with systemic sclerosis.
      Positive anti-centromere antibody and Raynaud's phenomenon, hallmarks of a
      variant systemic sclerosis, the CREST syndrome were observed. We therefore
      speculated that the pathogenesis of the phlebosclerosis of the colon is related
      to the CREST syndrome.

PMID- 10397080
TI  - An aged male patient with autoimmune hepatitis complicated by hepatocellular
      carcinoma.
AB  - An 82-year-old male patient was admitted for liver dysfunction. Laboratory test
      showed the following data; aspartate aminotransferase (AST) 79 IU/l, alanine
      aminotransferase (ALT) 28 IU/l, total bilirubin (T. Bil) 0.9 U, zinc sulfate
      turbidity test (ZTT) 48.9 U, gamma-globulin 4.9 g/dl, immunoglobulin G (IgG)
      5,046 mg/dl, anti-nuclear antibodies x 320, anti-mitochondrial antibodies (-),
      hepatitis B virus surface antigen (HBsAg) (-), HBcAb (-), anti-hepatitis C virus
      (anti-HCV) (-), hepatitis C virus (HCV-RNA) (-), anti-hepatitis G virus (anti
      HGV) (-), alpha-fetoprotein 306.8 ng/ml, carcinoembryonic antigen (CEA) 2.3
      ng/ml, carbohydrate antigen (CA) 19-9 77.2 U/ml. Abdominal ultrasonography and
      computed tomography showed a large mass occupying most of the right lobe and
      portal thrombosis in the liver. Liver biopsy revealed cirrhosis with inactive
      hepatitis in the nontumorous lesion and well-differentiated hepatocellular
      carcinoma in the tumorous lesion. We report a rare case of an aged male patient
      with autoimmune hepatitis complicated by hepatocellular carcinoma.

PMID- 10397081
TI  - Severe hyponatremia caused by hypothalamic adrenal insufficiency.
AB  - A 60-year-old woman was admitted with severe hyponatremia. Basal values of
      adrenocorticotropic hormone (ACTH), thyroid hormone and cortisol were normal on
      admission. Impairment of water diuresis was observed by water loading test.
      Initially, we diagnosed her condition as the syndrome of inappropriate secretion
      of antidiuretic hormone (SIADH). By provocation test, we finally confirmed that
      the hyponatremia was caused by hypothalamic adrenal insufficiency. The basal
      values of ACTH and cortisol might not be sufficient to exclude the possibility of
      adrenal insufficiency. Therefore, it is necessary to evaluate adrenal function by
      provocation test or to re-evaluate it after recovery from hyponatremia.

PMID- 10397082
TI  - Palliative chemotherapy for malignant pheochromocytoma: symptomatic palliation of
      two cases.
AB  - Malignant pheochromocytoma is a rare tumor with a poor prognosis because excess
      production of catecholamines leads to potentially lethal complications. Several
      chemotherapy regimens have been reported to be effective against this tumor, but
      a standard form of chemotherapy has not been established. We treated two patients
      with histologically confirmed pheochromocytoma after surgical removal of the
      primary lesion. Non-cardiogenic pulmonary edema was resolved and bone metastases
      were controlled by individualized chemotherapy that decreased the catecholamine
      levels, and the performance status was improved in both cases. Palliative
      chemotherapy should be designed to improve the quality of life of cancer
      patients.

PMID- 10397083
TI  - Vasospastic angina likely related to cisplatin-containing chemotherapy and
      thoracic irradiation for lung cancer.
AB  - Vasospastic angina is rarely observed during cancer treatment. The present report
      describes two males with lung cancer, aged 73 and 61, who developed vasospastic
      angina during combination treatment of cisplatin-containing chemotherapy and
      thoracic irradiation. As both patients have smoked and their ages are typical for
      patients with coronary artery disease, such events may be incidental. However,
      oncologists should be aware of the possible development of myocardial ischemia
      during or following administration of antineoplastic agents, especially in
      elderly patients with pre-existing coronary risk factors or a history of thoracic
      radiotherapy.

PMID- 10397084
TI  - Spontaneous regression of a bulla with the development of adenocarcinoma of the
      lung.
AB  - Spontaneous regression of a bulla in the lung is rare. We describe a case of
      spontaneous regression associated with the development of adenocarcinoma of the
      lung in a 59-year-old male smoker. The bulla had begun to regress spontaneously
      at least six months before lung cancer was detected on a chest radiograph. He
      underwent left upper lobe lobectomy with mediastinal node dissection. The tumor
      arose within the bulla, extending along the bulla wall. He has been alive for
      more than eight years with no evidence of recurrence. This case suggests that
      spontaneous regression of a bulla should be recognized as one of the early
      radiographic signs of the development of lung cancer in patients with bullous
      lung disease.

PMID- 10397085
TI  - Mucosa-associated lymphoid tissue type lymphoma of the gallbladder associated
      with acute myeloid leukemia.
AB  - We describe a patient with mucosa-associated lymphoid tissue (MALT) type lymphoma
      of the gallbladder who developed concurrent acute myeloid leukemia (M2). She was
      admitted because of progressive jaundice and underwent cholecystectomy.
      Histologic examination of the gallbladder showed diffuse proliferation of
      atypical lymphoid cells and a formed lymphoepithelial lesion. Because of
      progressive thrombocytopenia, a bone marrow tap was performed 25 days after the
      operation. Bone marrow contained 65.5% blasts, and was positive for peroxidase,
      CD33 and HLA-DR, and negative for lymphoid markers. We discuss the rare
      association of these disorders.

PMID- 10397086
TI  - Chronic inflammatory demyelinating polyneuropathy with multiple hypertrophic
      nerves in intracranial, and intra- and extra-spinal segments.
AB  - Hypertrophic nerves have occasionally been seen in chronic inflammatory
      demyelinating polyneuropathy (CIDP), but most are in the cauda equina. We report
      a case with CIDP in whom magnetic resonance imaging (MRI) with gadolinium
      diethylene triamine penta-acetic acid (Gd-DTPA) enhancement demonstrated
      hypertrophy of various peripheral nerves including multiple cranial nerves.
      Interestingly, none showed neurological signs corresponding to the lesions,
      except for clinical signs consistent with CIDP. MRI can be useful for the
      detection of silent, but abnormal nerve involvement in CIDP.

PMID- 10397087
TI  - Eosinophilic pneumonia with eosinophilic gastroenteritis.
AB  - A 48-year-old man was admitted to our hospital with cough, fever and dysphagia.
      He had a past history of bronchial asthma and surgery for nasal polyp. Chest
      radiograph and computed tomography showed atelectasis in the right lower field
      and infiltrative shadow in the left lower field and overall thickening of the
      esophageal wall. Transbronchial lung biopsy (TBLB) specimens revealed
      infiltration of eosinophils and lymphocytes under the bronchial mucosa.
      Gastrointestinal tract biopsy specimens showed submucosal infiltration of
      eosinophils. These findings led to a definite diagnosis of eosinophilic pneumonia
      associated with eosinophilic gastroenteritis, a disease which has been rarely
      reported.

PMID- 10397088
TI  - Clinicopathological study on liver dysfunction in measles.
AB  - We analyzed the clinical course of eight patients with liver dysfunction in
      measles. All of the patients showed an elevation of aspartate aminotransferase
      (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), but no
      jaundice. These levels returned to normal about 3 weeks after the onset of the
      rash. A percutaneous liver biopsy was done in two cases. Histological examination
      showed slight necrosis of liver cells but no significant changes in portal area.
      On electron microscopy, virus particles were not detected. We detected measles
      virus RNA in the liver specimen by RT-PCR, which suggests that the measles virus
      affects liver cells directly in measles.

PMID- 10397089
TI  - Screening versus diagnostic mammography.

PMID- 10397090
TI  - Applicability of American College of Radiology appropriateness criteria in a
      general internal medicine clinic.
AB  - OBJECTIVE: The American College of Radiology (ACR) Appropriateness Criteria for
      Imaging and Treatment Decisions are intended to help radiologists and referring
      physicians use imaging procedures appropriately and cost-effectively, but these
      criteria have not undergone empirical testing. To assess how readily the ACR
      appropriateness criteria can be applied to clinical practice, we retrospectively
      examined their applicability in a general ambulatory care setting. MATERIALS AND
      METHODS: From all requests during an 8-month period for noninterventional CT,
      sonography, MR imaging, and nuclear medicine imaging procedures received from a
      general internal medicine clinic, we excluded cases for which relevant clinic
      notes were unavailable or incomplete. Three experienced radiologists classified
      cases by consensus, using data from radiology requests and clinic notes. Cases
      were classified as a "complete match" if the features matched a clinical
      condition and variant included in the ACR appropriateness criteria; as a "partial
      match" if the features matched a clinical condition but did not match all
      features of a variant; or as "unmatched." RESULTS: Of 316 cases, there were 202
      complete matches (64%) and 37 partial matches (12%). Of the 77 unmatched cases
      (24%), 14 pertained to asymptomatic patients. CONCLUSION: The ACR appropriateness
      criteria could be applied to 76% of the imaging procedure requests that we
      received from a general internal medicine clinic. These results suggest that the
      ACR appropriateness criteria can be applied to diagnostic imaging in a general
      ambulatory-care setting.

PMID- 10397091
TI  - Methemoglobin suppression in T2-weighted pulse sequences: an adjunctive technique
      in MR imaging of hemorrhagic tumors.

PMID- 10397092
TI  - Characterization of adrenal masses using MR imaging with histopathologic
      correlation.
AB  - OBJECTIVE: The purpose of this study was to evaluate the sensitivity,
      specificity, and accuracy of MR imaging in the characterization of adrenal masses
      by correlating imaging findings with histopathologic results. In addition,
      adrenal tumors that were of an indeterminate nature on MR imaging were analyzed.
      SUBJECTS AND METHODS: For 114 patients with 134 adrenal masses, MR findings were
      compared with histologic results. In all patients, MR imaging was performed using
      T2-weighted fast spin-echo imaging and unenhanced and gadolinium-enhanced T1
      weighted spin-echo imaging. Chemical-shift imaging was performed in 92 patients
      and dynamic gadolinium-enhanced studies in 108 patients. Chemical-shift images
      were analyzed quantitatively and qualitatively, and dynamic gadolinium-enhanced
      studies were qualitatively assessed. RESULTS: The sensitivity of MR imaging in
      differentiating between benign and malignant adrenal masses was 91%, the
      specificity was 94%, and the accuracy was 93%. The diagnosis at MR imaging
      differed from that at histology in 12 (9%) of 134 patients. Results of
      quantitative analyses of chemical-shift imaging techniques showed significant
      differences between adenomas and nonadenomas (-36.0% versus -3.7%; p < .001).
      Qualitative analysis provided a similar diagnostic confidence compared with
      quantitative analysis. Both chemical-shift and dynamic gadolinium-enhanced
      studies proved to be unreliable in characterizing borderline tumors (epithelial
      tumors with high malignant potential). Moreover, such imaging failed to allow
      correct diagnosis of adenomas in two patients. CONCLUSION: The characterization
      of an adrenal mass can be made with high sensitivity and specificity using MR
      imaging. The increased reliance on MR imaging seems to be based mainly on
      findings from chemical-shift and dynamic gadolinium-enhanced studies. The need to
      perform histologic sampling of incidentally discovered adrenal masses may be
      reduced to some problematic lesions, which will remain during the era of MR
      imaging.

PMID- 10397093
TI  - Medical research: an important addition to the literature and a reminder of our
      obligation to the public.

PMID- 10397094
TI  - Imaging of adrenal tumors using FDG PET: comparison of benign and malignant
      lesions.
AB  - OBJECTIVE: The aim of this study was to differentiate benign from malignant
      adrenal tumors using positron emission tomography (PET) with 18F
      fluorodeoxyglucose (FDG) in patients with unilateral adrenal masses originally
      detected by CT or MR imaging. CONCLUSION: PET imaging with FDG can metabolically
      characterize adrenal masses. Abnormally increased FDG uptake in adrenal
      malignancies allows one to differentiate these abnormalities from benign lesions.
      Whole-body PET can also reveal extraadrenal tumor sites in patients with
      malignant tumors, using a single imaging technique for accurate disease staging.

PMID- 10397095
TI  - Female pelvic organ prolapse: diagnostic contribution of dynamic
      cystoproctography and comparison with physical examination.
AB  - OBJECTIVE: The aim of this study was to assess the contribution of dynamic
      cystoproctography to the evaluation of female pelvic organ prolapse and to
      compare this contribution with that of physical examination. MATERIALS AND
      METHODS: The presence or absence of rectocele, enterocele, sigmoidocele, and
      cystocele on physical examination and on cystoproctography was retrospectively
      analyzed in 170 consecutive patients. For each of these diagnostic methods, organ
      prolapse was graded as small, moderate, or large on the basis of specific,
      defined measurements. RESULTS: A rectocele was detected by proctography in 155
      patients (91%); 119 (77%) of these rectoceles were also found on physical
      examination. Barium trapping at proctography was related to rectocele size.
      Proctography showed an enterocele in 47 patients (28%); 24 (51%) of these
      enteroceles were also found on physical examination. Physical examination also
      found 44 enteroceles that could not be corroborated radiologically. At
      proctography, the enteroceles were relatively large, extending an average of 7.3
      cm below the vaginal apex. Eight patients had sigmoidoceles, none of which were
      found on physical examination. A cystocele was shown by cystoproctography in 159
      patients (94%); 132 (83%) of these cystoceles were also found on physical
      examination. CONCLUSION: The correlation between finding prolapsed pelvic organs
      on dynamic cystoproctography and finding them on physical examination varies.
      Most radiographically detected rectoceles and cystoceles are found on physical
      examination, whereas the correlation for enteroceles and sigmoidoceles is poor.
      Dynamic cystoproctography provides direct visualization and quantification of
      female pelvic organ prolapse, information that usually can only be inferred by
      physical examination.

PMID- 10397096
TI  - Advantages of performing sonourethrography with lidocaine hydrochloride jelly in
      a prepackaged delivery system.

PMID- 10397097
TI  - Power Doppler imaging: evaluation of vascular complications after renal
      transplantation.

PMID- 10397098
TI  - Bronchiectasis: accuracy of high-resolution CT in the differentiation of specific
      diseases.
AB  - OBJECTIVE: The aim of the study was to determine whether various causes of
      bronchiectasis can be differentiated by the pattern and distribution of
      abnormalities seen on high-resolution CT. MATERIALS AND METHODS: The
      retrospective study included 82 consecutive patients who had a specific diagnosis
      of bronchiectasis proven by appropriate clinical and laboratory criteria. All
      patients underwent high-resolution CT scanning (1- to 1.5-mm collimation). The CT
      scans were assessed for the presence, extent, type, and anatomic distribution of
      bronchiectasis by two independent observers who were not aware of the clinical
      data. The observers recorded their most likely diagnosis and the degree of
      confidence in that diagnosis. RESULTS: The two independent observers made a
      correct diagnosis in 61% of cases (100/164 interpretations). On average, a
      correct diagnosis was made in 19 (68%) of 28 cases of cystic fibrosis, 16 (67%)
      of 24 cases of previous tuberculosis, six (43%) of 14 cases of previous childhood
      infection, five (56%) of nine cases of allergic bronchopulmonary aspergillosis,
      and four (57%) of seven cases of other causes of bronchiectasis. We found
      moderate agreement between the observers for the correct diagnosis (kappa = .53)
      and good agreement for the presence or absence of bronchiectasis in each lobe
      (kappa = .71). CONCLUSION: The pattern and distribution of abnormalities revealed
      by high-resolution CT in patients with bronchiectasis are influenced by the
      underlying cause. Bilateral, predominantly upper lobe, bronchiectasis is seen
      most commonly in patients with cystic fibrosis and allergic bronchopulmonary
      aspergillosis, unilateral upper lobe predominance in patients with tuberculosis,
      and lower lobe predominance in patients after childhood viral infection.

PMID- 10397099
TI  - Correlation of CT findings with clinical evaluations in 261 patients with
      symptomatic bronchiectasis.
AB  - OBJECTIVE: In a multicenter study, we evaluated the relationships between the
      extent and severity of bronchiectasis on CT and clinical symptoms, spirometric
      abnormality, and sputum characteristics. SUBJECTS AND METHODS: The study
      population included 261 patients with symptomatic, physiologically significant
      bronchiectasis, who were enrolled in another study evaluating the clinical
      efficacy of deoxyribonudease in treatment of bronchiectasis. Patients with cystic
      fibrosis, allergic bronchopulmonary aspergillosis, and fungal or mycobacterial
      infection were excluded. In addition to high-resolution CT scanning, all patients
      underwent clinical evaluation, spirometry, and sputum culture. CT features scored
      by consensus of two observers included the extent of bronchiectasis, type of
      bronchiectasis (cylindric, varicose, or cystic), extent of mucoid impaction, and
      degree of bronchial wall thickening. RESULTS: Scores for the severity and extent
      of bronchiectasis correlated with the forced expiratory volume in 1 sec (FEV1) (r
      = -.362, p < .0001) and with the forced vital capacity (FVC) (r = -.362, p <
      .0001). Scores for bronchial wall thickening correlated with the FEV1 (r = -.367,
      p < .0001) and FVC (r = -.239, p < .001). Patients with cystic bronchiectasis
      were significantly more likely to grow Pseudomonas from their sputa and to have
      purulent sputa than were patients with cylindric or varicose bronchiectasis.
      Patients with cystic bronchiectasis had significantly lower FEV1 and FVC values
      than did patients with cylindric or varicose bronchiectasis. CONCLUSION: In this
      patient population, we found weak but significant correlations between the degree
      of morphologic abnormality on CT and the extent of physiologic impairment. Cystic
      bronchiectasis was associated with sputum purulence and with the growth of
      Pseudomonas. CT classification of the type of bronchiectasis may be useful as an
      index of severity of disease.

PMID- 10397100
TI  - Chronic pulmonary paracoccidioidomycosis (South American blastomycosis): high
      resolution CT findings in 41 patients.
AB  - OBJECTIVE: To assess the pulmonary parenchymal findings on high-resolution CT in
      41 patients with the chronic form of paracoccidioidomycosis (South American
      blastomycosis). SUBJECTS AND METHODS: The study included 41 consecutive patients
      in whom chronic paracoccidioidomycosis had been proven. All patients underwent
      high-resolution CT (1-mm collimation, high-spatial-frequency reconstruction
      algorithm) at 12 equally spaced intervals through the chest. The images were
      analyzed by two radiologists, and each final decision was reached by consensus.
      RESULTS: Thirty-eight (93%) of the 41 patients had CT scans with abnormal
      findings. The findings included interlobular septal thickening in 36 patients
      (88%), 1-25 mm diameter nodules in 34 (83%), peribronchovascular interstitial
      thickening in 32 (78%), centrilobular opacities in 26 (63%), intralobular lines
      in 24 (59%), ground-glass opacities in 14 (34%), cavitation in seven (17%), air
      space consolidation in five (12%), traction bronchiectasis in 34 (83%), and
      paracicatricial emphysema in 28 (68%). In approximately 90% of patients, the
      abnormalities were bilateral and symmetrical and involved all lung zones.
      CONCLUSION: High-resolution CT findings of paracoccidioidomycosis consist
      predominantly of interstitial abnormalities and nodules associated with traction
      bronchiectasis and paracicatricial emphysema in a bilaterally symmetrical
      distribution.

PMID- 10397101
TI  - Right paratracheal air cysts in the thoracic inlet: clinical and radiologic
      significance.
AB  - OBJECTIVE: The purpose of our study was to determine the CT appearance and
      clinical significance of a right paratracheal air cyst at the level of the
      thoracic inlet. MATERIALS AND METHODS: Sixty-five consecutive patients with
      paratracheal air cysts were included in this study. The location, level, size,
      and shape of the paratracheal air cysts on CT were analyzed. The spirometric
      data, tracheal indexes, and CT-determined emphysema scores of these patients were
      compared with those of 60 consecutive patients in a control group. RESULTS: The
      air cysts were located at the right posterolateral aspect of the trachea in 64
      (98%) of 65 patients and at T1-T2 vertebral levels in 57 (88%) of 65 patients.
      The mean diameter of the right paratracheal cysts was 10 mm in the axial plane
      and 14 mm in the vertical plane. CT showed a communicating channel with the
      trachea in five patients. The ratio of forced expiratory volume obtained in 1 sec
      to forced vital capacity, and forced expiratory flow between 25% and 75% of vital
      capacity in patients with paratracheal air cysts, were significantly lower than
      those of the control group (p < .05). Differences in the tracheal indexes and CT
      determined emphysema scores between the study group and the control group were
      found to be statistically significant (p = .001). CONCLUSION: The most probable
      nature of a right paratracheal cyst in the thoracic inlet is tracheal
      diverticulum with a narrow stalk. The presence of a right paratracheal air cyst
      on CT could be a sign of obstructive lung disease clinically and of the presence
      of emphysema radiologically.

PMID- 10397102
TI  - Differential diagnosis of lymphocytic interstitial pneumonia and malignant
      lymphoma on high-resolution CT.
AB  - OBJECTIVE: Lymphoproliferative disorders span a spectrum from inflammatory
      lesions to malignant neoplasms. The purpose of this study was to compare high
      resolution CT findings of lymphocytic interstitial pneumonia with those of
      malignant lymphoma of the chest. MATERIALS AND METHODS: The study included 17
      patients with lymphocytic interstitial pneumonia and 44 patients with malignant
      lymphoma (35 with non-Hodgkin's lymphoma and nine with Hodgkin's disease).
      Without knowledge of the pathologic diagnosis, two chest radiologists evaluated
      the frequency and distribution of high-resolution CT findings in both groups of
      patients. RESULTS: Cysts were more common in patients with lymphocytic
      interstitial pneumonia (14/17, 82%) than in patients with malignant lymphoma
      (1/44, 2%) (p < .0001). Air-space consolidation was more commonly seen in
      patients with malignant lymphoma (29/44, 66%) than in patients with lymphocytic
      interstitial pneumonia (3/17, 18%) (p < .001). Large nodules (11-30 mm in
      diameter) were more common in patients with malignant lymphoma (41%) than in
      patients with lymphocytic interstitial pneumonia (6%). Pleural effusions (25%)
      were seen only in patients with malignant lymphoma. We found no statistically
      significant difference in the distribution of lung lesions between patients with
      lymphocytic interstitial pneumonia and patients with malignant lymphoma.
      CONCLUSION: On high-resolution CT, cysts are characteristic in patients with
      lymphocytic interstitial pneumonia, whereas consolidation, large nodules, and
      pleural effusions are characteristic in patients with malignant lymphoma. These
      findings on high-resolution CT help differentiate lymphocytic interstitial
      pneumonia from malignant lymphoma.

PMID- 10397103
TI  - The subtypes of localized bronchioloalveolar carcinoma: CT-pathologic correlation
      in 18 cases.
AB  - OBJECTIVE: The purpose of this study was to correlate thin-section CT findings
      with histologic findings for the three histopathologic subtypes of localized
      bronchioloalveolar carcinoma. CONCLUSION: Thin-section CT can be used to predict
      the histologic subtype of bronchioloalveolar carcinoma.

PMID- 10397104
TI  - Evolution of CT findings in patients with cystic fibrosis.
AB  - OBJECTIVE: The aim of our study was to assess the evolution of pulmonary CT
      findings in cystic fibrosis patients. MATERIALS AND METHODS: Serial CT
      examinations were performed in four different follow-up periods on 107 patients
      with cystic fibrosis. Lung images of the initial and follow-up CT were reviewed
      and scored for specific morphologic findings. CT findings were correlated with
      the results of the pulmonary function tests and clinical (Shwachman-Kulczycki)
      scores. RESULTS: Morphologic changes were minor within the first 18 months of
      follow-up compared with the period after 18 months. The increase of the overall
      score was significantly higher in groups with follow-up periods longer than 18
      months compared with groups with follow-up periods shorter than 18 months.
      Various components of morphologic changes contributed to the sequential changes
      seen on the CT scans. All morphologic changes and the CT scores correlated
      significantly (p < .0001) with pulmonary function tests and clinical score.
      CONCLUSION. Serial CT scans allow assessment of the evolution of pulmonary
      abnormalities in patients with cystic fibrosis. CT seems to have advantages over
      pulmonary function tests and clinical scoring in the depiction of pulmonary
      changes over time.

PMID- 10397105
TI  - Electron beam CT features of the pulmonary artery in Takayasu's arteritis.
AB  - OBJECTIVE: Pulmonary artery involvement in Takayasu's arteritis is suggestive of
      the disease. Our aim was to use electron beam CT to study pulmonary artery
      changes in patients with Takayasu's arteritis. CONCLUSION: Diffuse wall
      thickening and dilatation or stenosis were significantly more frequent on CT in
      patients with Takayasu's arteritis than in the control subjects. Knowledge of
      these findings may be of value when assessing pulmonary artery involvement and
      thus may be helpful for the diagnosis of Takayasu's arteritis.

PMID- 10397106
TI  - Parathyroid adenoma of the mediastinum.

PMID- 10397107
TI  - Navigator echo-based respiratory gating for three-dimensional MR coronary
      angiography: results from healthy volunteers and patients with proximal coronary
      artery stenoses.
AB  - OBJECTIVE: The purpose of our study was to investigate the value of respiratory
      gated three-dimensional (3D) MR angiography in identifying coronary arteries in
      healthy volunteers and in patients with proximal coronary artery stenosis and to
      compare the results with those of conventional coronary angiography. SUBJECTS AND
      METHODS: Twenty healthy volunteers and 20 patients with coronary artery stenosis
      were examined on a 1.5-T scanner with a retrospectively respiratory-gated 3D
      gradient-echo sequence. Visualization of the main coronary arteries was analyzed
      after curved multiplanar reconstructions. A six-point grading system was used to
      evaluate 400 vessel segments. The assessment of stenosis was performed by two
      observers who were unaware of the results of conventional coronary angiography.
      RESULTS: The proximal, middle, and distal segments of the coronary arteries were
      completely identified with or without luminal irregularities in 55%, 47%, and
      20%, respectively, of the healthy volunteers. For the 20 patients, results were
      69%, 44%, and 20%, respectively. For the assessment of coronary artery stenoses
      (n = 53), sensitivity was 73% and specificity was 50% after evaluation of the MR
      angiograms of all patients. A sensitivity of 79% and a specificity of 54% were
      found for evaluation of the MR coronary angiograms, with an image quality score
      of at least 3 (i.e., artery segments completely identified with major luminal
      irregularities). CONCLUSION: With the navigator echo MR imaging technique, a
      complete 3D visualization of the main coronary arteries was possible in cases
      with high image quality. However, further experience with and improvement of the
      navigator echo technique we used is necessary for reliable assessment of coronary
      artery stenosis.

PMID- 10397108
TI  - MR angiography versus color Doppler sonography in the evaluation of renal vessels
      and the inferior vena cava in abdominal masses of pediatric patients.
AB  - OBJECTIVE: Involvement of renal vessels and the inferior vena cava (IVC) plays a
      decisive role during operative planning for removal of abdominal masses in
      pediatric patients. Advantages and limitations of MR angiography and color
      Doppler sonography for determining these factors were evaluated. MATERIALS AND
      METHODS: MR angiography and color Doppler sonography were performed
      preoperatively in 42 neonates, infants, and children with abdominal masses and
      were compared with spin-echo MR imaging and with surgical findings. Variables
      evaluated were anatomic variants, vessel displacement, patency of vessels,
      collateral circulation, and intravascular tumor extension. Quality of vessel
      visualization was assessed in vessels not affected by tumor. RESULTS: In 88% of
      unaffected renal vessels, the entire vessel course could be visualized on MR
      angiography compared with 58% on color Doppler sonography and 43% on spin-echo MR
      imaging. In four of nine cases, color Doppler sonography revealed an accessory
      renal artery, whereas MR angiography revealed these variants in seven of nine
      cases. MR angiography showed 79% and color Doppler sonography 66% of displaced
      vessels. Unlike MR angiography, color Doppler sonography did not reveal five
      stenotic renal veins because they could not be completely imaged. In two cases,
      however, MR angiography falsely indicated an occlusion of the IVC, whereas color
      Doppler sonography showed residual flow. CONCLUSION: Anatomic variants, vessel
      displacement, collateral circulation, and neoplastic vessel infiltration were
      revealed more accurately by MR angiography than by color Doppler sonography. In
      cases in which patency of the IVC is unclear on MR angiography, color Doppler
      sonography should also be performed.

PMID- 10397109
TI  - Three-dimensional helical CT of pulmonary arteries in infants and children with
      congenital heart disease.
AB  - OBJECTIVE: The purpose of our study was to determine the value of three
      dimensional reconstructed helical CT in the assessment of the pulmonary arteries
      in infants and children with complex congenital heart disease. MATERIALS AND
      METHODS: Twenty patients were examined with contrast-enhanced helical CT. Three
      dimensional reconstructions were performed with multiplanar reformations, maximum
      intensity projection, and shaded-surface display. Correlation was made with 19
      echocardiograms and 14 cineangiocardiograms. All imaging studies were reviewed
      independently for the following parameters: the caliber of the main and branch
      pulmonary arteries and their confluence, the presence of stenosis, the number and
      caliber of aortopulmonary collaterals, and the patency of vascular shunts and
      conduits. Surgical confirmation, which was used as the reference standard, was
      available in all patients. RESULTS: Helical CT was as accurate as
      angiocardiography in revealing stenotic and nonconfluent central pulmonary
      arteries and in revealing aortopulmonary collaterals (overall CT test parameters:
      sensitivity, 90%; specificity, 100%; accuracy, 93%).Three-dimensional rendition
      did not improve the accuracy of CT. The patency of shunts was shown equally well
      with CT as with angiography, but CT showed thrombosis more directly.
      Echocardiography was the least accurate technique in revealing pulmonary artery
      anatomy (accuracy, 65%), primarily because a relatively large number of studies
      were technically unsatisfactory to assess the study parameters. CONCLUSION:
      Helical CT angiocardiography with three-dimensional reconstruction is superior to
      echocardiography for the noninvasive assessment of pulmonary artery anatomy in
      patients with complex congenital heart disease. Helical CT may be used as a
      complementary technique and occasionally as a substitute for the diagnostic
      imaging portion of cardiac catheterization with cineangiocardiography.

PMID- 10397110
TI  - Non-Hodgkin's lymphoma in a patient with Diamond-Blackfan anemia.

PMID- 10397111
TI  - Clinical impact of MR spectroscopy when MR imaging is indeterminate for pediatric
      brain tumors.
AB  - OBJECTIVE: We undertook this study to determine if single-voxel proton (hydrogen)
      MR spectroscopy could have clinical impact on the management of pediatric brain
      tumors when MR findings were indeterminate. SUBJECTS AND METHODS: Eleven children
      (mean age, 9 years) being examined for brain tumors underwent MR imaging that
      revealed indeterminate criteria of enhancement, mass effect, and prolonged T1 and
      T2 signal. MR spectroscopy was then used to distinguish radiation necrosis from
      tumor in one patient, differentiate residual tumor from scarring in two patients,
      document early treatment response in three patients, and discriminate benign from
      malignant masses in five patients. RESULTS: In 10 of the 11 patients, spectra
      were successfully acquired. Based on the chemical analysis of the indeterminate
      area shown on MR imaging, clinical impact was achieved in these 10 patients.
      Clinical impact included treatment modification in five patients, follow-up
      studies replacing further treatment in three patients, and tumor characterization
      in the remaining two patients. Confirmation was by histology in four patients and
      by follow-up MR imaging and MR spectroscopy for up to 30 months in the remaining
      six patients. CONCLUSION: When MR imaging is indeterminate in evaluating
      pediatric brain tumors, MR spectroscopy can provide objective neurochemical
      information, thereby altering treatment.

PMID- 10397112
TI  - Prospective analysis of CT of the sinuses in acute asthma.
AB  - OBJECTIVE: Asthma and sinusitis are both inflammatory diseases of the respiratory
      epithelium, but to our knowledge no prospective analyses of CT of the sinuses in
      patients with acute asthma have been performed. The purpose of this study was to
      investigate the type and extent of abnormalities found on CT of the sinuses in
      patients with acute asthma. SUBJECTS AND METHODS: Sixty-five patients with acute
      asthma and 62 age-, race-, and sex-matched control subjects were enrolled in the
      emergency department. Limited coronal sinus CT was performed and scans were
      interpreted by a radiologist who was unaware of the patient's clinical condition.
      Scans were analyzed for the presence of mucosal thickening in the sinuses,
      ostiomeatal complexes, and nasal cavities. Scans were also assigned a CT score
      for total mucosal thickening. A CT score of 12 or more points indicated extensive
      disease. RESULTS: Mucosal thickening in the nasal passages (p < .001),
      ostiomeatal complexes (p < .05), and ethmoidal (p < .05) and sphenoidal sinuses
      (p < .05) was associated with acute asthma, but maxillary mucosal thickening was
      not (p = .44). CT scores differed significantly between asthmatic patients (7.7
      +/- 0.8 points) and control subjects (4.1 +/- 0.4 points) (p < .001). Nineteen of
      the 65 asthmatic patients had extensive disease compared with two of the 62
      control subjects (p < .001). Thirteen asthmatic patients with extensive disease
      underwent follow-up CT 5 months later, and 11 of the 13 patients showed
      improvement in CT score without having undergone specific therapy for sinusitis.
      CONCLUSION: Mucosal thickening in the nasal passages and sphenoidal, ethmoidal,
      and frontal sinuses is more common in patients with acute asthma than in control
      subjects. However, maxillary sinus mucosal thickening is no more common in
      asthmatic patients than in control subjects.

PMID- 10397113
TI  - MR angiography and surgery for unruptured familial intracranial aneurysms in
      persons with a family history of cerebral aneurysms.
AB  - OBJECTIVE: We used MR angiography to determine prevalence of unruptured familial
      intracranial aneurysms in a prepaid medical care program. We compared surgical
      outcomes and the cost of treating unruptured versus ruptured aneurysms. We
      compared the cost of MR angiography with the cost of screening mammography and
      with the cost of surgically treating a ruptured aneurysm. SUBJECTS AND METHODS:
      During a 30-month period, we performed MR angiography to show cerebral aneurysms
      in 63 surgical candidates who had one or more first-degree relatives with an
      aneurysm. Unruptured aneurysms seen on MR angiography were evaluated by digital
      subtraction angiography (DSA) and treated surgically. RESULTS: MR angiography
      showed nine unruptured aneurysms in six patients. Eight aneurysms were seen on MR
      angiography and nine were seen on DSA. Seven unruptured aneurysms were treated
      surgically. The mean treatment cost was 50% lower for an unruptured aneurysm than
      that for a ruptured aneurysm. No patient surgically treated for an unruptured
      aneurysm required rehabilitation, unlike 25% of patients with ruptured aneurysms.
      The annual total cost of MR angiography was equivalent to 2.9% of the annual cost
      of screening mammography. The annual cost of MR angiography equaled half the cost
      of treating one patient after aneurysm rupture. CONCLUSION: MR angiography showed
      a 9.5% prevalence of unruptured aneurysms among persons who had one or more first
      degree relatives with a cerebral aneurysm. DSA confirmed 88% of aneurysms found
      on MR angiography. Persons with unruptured aneurysms had better treatment
      outcomes at lower cost than did patients treated for aneurysm rupture. The annual
      MR angiography cost was low compared with the cost of screening mammography and
      with the cost of treating one patient with aneurysm rupture.

PMID- 10397114
TI  - Dissections of the internal carotid artery: three-dimensional time-of-flight MR
      angiography and MR imaging features.

PMID- 10397115
TI  - Orbital assault with a pencil: evaluating vascular injury.

PMID- 10397116
TI  - Thoracic aorta: comparison of single-dose breath-hold and double-dose non-breath
      hold gadolinium-enhanced three-dimensional MR angiography.
AB  - OBJECTIVE: The purpose of this study was to compare single-dose (0.1 mmol/kg)
      breath-hold gadolinium-enhanced three-dimensional (3D) MR angiography and double
      dose (0.2 mmol/kg) non-breath-hold 3D MR angiography for evaluation of thoracic
      aortic disease. MATERIALS AND METHODS: Twenty-five patients referred for MR
      evaluation of the thoracic aorta underwent non-breath-hold gadolinium-enhanced 3D
      MR angiography on a 1.5-T scanner with standard gradients (TR/TE, 21/6; flip
      angle, 30 degrees) during slow infusion of a double dose of gadopentetate
      dimeglumine using a body coil. Subsequently, the same patients underwent breath
      hold MR imaging with high-performance gradients (TR/TE, 5/2; flip angle, 30
      degrees-50 degrees), a timing examination, and power injection of a single dose
      of gadolinium. For both studies, quantitative signal-to-noise measurements were
      obtained for the ascending thoracic, descending thoracic, and abdominal aorta.
      Three observers retrospectively evaluated each examination for degree of
      enhancement of the aorta, pulmonary arteries, and systemic veins; motion
      artifacts; and overall image quality. RESULTS: Single-dose breath-hold gadolinium
      enhanced 3D MR angiography showed greater signal-to-noise ratio, fewer motion
      artifacts, and better overall image quality (p < .05) than the non-breath-hold
      double-dose technique. The single-dose technique also showed significantly better
      qualitative enhancement of the aortic root and ascending aorta (p < .05) and less
      enhancement of the pulmonary arteries, renal veins, and left internal jugular
      vein (p < .05). CONCLUSION: Optimized single-dose breath-hold gadolinium-enhanced
      3D MR angiography is superior to double-dose non-breath-hold 3D MR angiography
      for evaluation of thoracic aortic disease.

PMID- 10397117
TI  - Imaging of penetrating atherosclerotic ulcers of the aorta.

PMID- 10397118
TI  - Exchange of poorly functioning tunneled permanent hemodialysis catheters.
AB  - OBJECTIVE: The usefulness of exchanging poorly functioning tunneled permanent
      hemodialysis catheters in patients with end-stage renal disease was evaluated.
      MATERIALS AND METHODS: We retrospectively reviewed case histories of 51
      consecutive patients who underwent 88 catheter exchanges because of poor flow
      rates. All hemodialysis catheters were initially placed by the radiology service
      using image guidance. Catheter exchanges were performed through the existing
      subcutaneous tract over two stiff hydrophilic guidewires and without additional
      interventions such as fibrin sheath stripping or venoplasty. Life table analysis
      was performed to evaluate catheter patency rates after initial placement (primary
      patency) and after multiple exchanges (secondary patency). RESULTS: The technical
      success rate for hemodialysis catheter exchange was 100%. Primary catheter
      patency was 42% at 60 days and 16% at 120 days. Secondary patency was 92% at 60
      days and 82% at 120 days. The cumulative infection rate was 1.1 per 1000 catheter
      days. No complications from the procedure occurred. CONCLUSION: Catheter exchange
      is an effective means of prolonging catheter patency in patients with end-stage
      renal disease and limited central venous access.

PMID- 10397119
TI  - Subacute and chronic benign superior vena cava obstructions: endovascular
      treatment with self-expanding metallic stents.
AB  - OBJECTIVE: Our purpose is to report our clinical experience with patients who
      underwent endovascular treatment with Wallstents for subacute or chronic benign
      obstruction of the superior vena cava (SVC). SUBJECTS AND METHODS: Twelve
      patients who were an average of 54 +/- 12 years old were referred for treatment
      of severe SVC syndrome related to implanted central venous catheters (n = 8),
      postradiation fibrosis (n = 2), a permanent pacemaker (n = 1), or a benign tumor
      (n = 1). Symptoms were present for an average of 16 weeks (range, 4-48 weeks)
      before treatment. Diagnosis of SVC obstruction was confirmed with helical CT and
      pretherapeutic phlebography. Four patients had Stanford's type II stenosis; two,
      type III; and six, type IV. The mean clinical and radiologic follow-up intervals
      were 11 months (range, 1-36 months) and 7 months (range, 1 week to 32 months),
      respectively. RESULTS: Recanalization was successful in all patients. Fifteen
      stents were implanted in the 12 patients. Stents were placed after percutaneous
      balloon angioplasty in nine patients, and primary stent placement was attempted
      in three patients. We immediately achieved a satisfactory SVC diameter in all
      patients, whose symptoms were relieved completely within 1 week of stent
      placement. No technical or clinical complications occurred. SVC syndrome recurred
      in one patient 2 months after stent placement and was treated by placing a second
      stent. CONCLUSION: Endovascular treatment with stent placement should be
      considered relevant and safe for refractory benign SVC syndrome. However, a
      larger series and a longer follow-up period are needed to define the role of
      stent placement for this syndrome.

PMID- 10397120
TI  - Combined preoperative embolization of the right portal vein and hepatic artery
      for hepatic resection in a high-risk patient.

PMID- 10397121
TI  - The usefulness of glucagon hydrochloride for colonic distention in CT
      colonography.
AB  - OBJECTIVE: The purpose of this study was to compare colonic distention with and
      without glucagon hydrochloride during CT colonography. SUBJECTS AND METHODS: CT
      colonography using single breath-hold, thin-section helical technique was
      performed on 60 patients who were in the supine and prone positions. Magnesium
      citrate and polyethylene glycol were used for bowel preparation. Colonic air
      insufflation averaged 30 bulb compressions. Thirty-three patients received IV
      glucagon (1 mg), and 27 patients did not. The colon was divided into eight
      segments, and the adequacy of the distention of each segment was evaluated.
      Overall colonic distention scores, defined as the number of inadequately
      distended segments (0-8), were recorded for the supine, prone, and combined
      positions. In the combined position, inadequate distention was defined as
      identical segments that were inadequately distended in both positions. RESULTS: A
      total of 960 segments were evaluated: 528 segments in the glucagon group and 432
      segments in the nonglucagon group. In the glucagon group, 444 segments (84.1%)
      were adequately distended. In the nonglucagon group, 365 segments (84.5%) were
      adequately distended. The median and range for overall colonic distention scores
      in the supine, prone, and combined positions were 1 (0-3), 1 (0-3), and 0 (0),
      respectively, for the glucagon group and 1 (0-6), 1 (0-6), and 0 (0-1),
      respectively, for the nonglucagon group. We found no statistically significant
      difference in overall colonic distention between the glucagon group and the
      nonglucagon group for the supine (p = .84), prone (p = .15), or combined (p =
      .28) positions. CONCLUSION: Glucagon administration before CT colonography does
      not improve colonic distention.

PMID- 10397123
TI  - Transvaginal sonography of the anal sphincter: reliable, or not?
AB  - OBJECTIVE: The purpose of this study was to validate the use of transvaginal
      sonography for anal sphincter evaluation, compare this technique with the more
      commonly used transanal technique, and explain a publication that suggested that
      transvaginal sonography is unreliable. SUBJECTS AND METHODS: The study population
      consisted of 50 women, of whom 44 prospectively underwent transanal and
      transvaginal sonography. The six remaining patients with surgical confirmation
      underwent only transvaginal sonography. All images were interpreted by the
      examining radiologist and then reviewed by a second radiologist who was unaware
      of the first radiologist's interpretations. Defects in the external and internal
      anal sphincters, the status of the perineal body, and any perianal collections or
      fistulas were documented. RESULTS: Twenty-five of the 50 patients showed
      sphincteric defects. Twenty-two had a defect in the external anal sphincter, of
      whom 16 had a matching internal anal sphincter defect. Four patients had an
      isolated internal anal sphincter defect. Surgery in nine of these 22 patients
      confirmed the defects seen on sonography. The 10th patient who underwent surgery
      had scar tissue rather than a tear in the external anal sphincter that
      corresponded with the defect seen on sonography. Defects were identified in all
      patients presenting with fecal incontinence who had undergone either a primary
      repair or an anterior sphincteroplasty. Of the 25 patients with intact sphincters
      on both transvaginal and transanal sonography, four had other significant
      findings including two perianal abscesses and two T3 rectal carcinomas. In 40 of
      the 44 patients who were prospectively imaged using both techniques, the
      sonographic findings were in agreement. Review, performed by a second radiologist
      who was unaware of the first radiologist's interpretations, verified the findings
      resulting in an 88.6% interobserver agreement. In all patients, perineal body
      assessment and assessment of perianal inflammatory disease was more accurate with
      the transvaginal technique. CONCLUSION: Transvaginal sonography is a reliable
      method for evaluating the anal sphincter, with an accuracy equivalent to that of
      the transanal technique. Transvaginal sonography is preferable for evaluation of
      the perineal body and perianal inflammatory processes.

PMID- 10397122
TI  - Comparative efficacy of and sequence choice for two oral contrast agents used
      during MR imaging.
AB  - OBJECTIVE: Our objective was to compare the efficacy of a positive and a negative
      oral contrast agent and to determine the optimal sequence choice for use in
      pelvic MR imaging. SUBJECTS AND METHODS: We undertook a prospective randomized
      trial of 57 patients with pelvic cancer who were examined with MR imaging after
      oral administration of a positive contrast agent (27 patients) or a negative
      contrast agent (30 patients). T1- and T2-weighted breath-hold and non-breath-hold
      gradient-recalled echo and turbo spin-echo sequences were obtained. Using the
      hard-copy images, we graded filling and distention of the small bowel, bowel wall
      conspicuity, delineation of normal and pathologic structures, and artifacts.
      RESULTS: Good or excellent small-bowel filling and distention was obtained in 17
      patients (63%) receiving the positive agent and in 26 patients (87%) receiving
      the negative agent, and bowel wall conspicuity was graded good or excellent in 19
      patients (70%) and 20 patients (67%), respectively. Normal and pathologic
      structures were better delineated with the negative agent (20 patients [74%] and
      27 patients [90%], respectively; p = .02). Breath-hold gradient-recalled echo T1
      weighted images were preferred for the positive agent (78%), and breath-hold T2
      weighted images were preferred for the negative agent (93%). Contrast artifacts
      were more frequently seen with the negative agent (11% and 93%, respectively; p =
      .0001), and such artifacts were eliminated using T2-weighted sequences.
      CONCLUSION: Both contrast agents were effective in pelvic MR imaging, but
      delineation of normal and pathologic structures was better with the negative
      agent. Gradient-recalled echo T1-weighted sequences are recommended for positive
      contrast agents, and breath-hold T2-weighted sequences are recommended for
      negative contrast agents.

PMID- 10397125
TI  - Pancreas divisum: implications for diagnostic and therapeutic pancreatography.
AB  - OBJECTIVE: The purpose of our study was to determine the prevalence,
      distribution, and clinical significance of pancreatic ductal changes due to
      pancreatitis on ERCP in patients with pancreas divisum. MATERIALS AND METHODS:
      From January 1993 through December 1997, 1714 patients underwent 2469 ERCP
      studies. Ninety-four patients (5.5%) had pancreas divisum. Retrospective review
      of the spot radiographs was performed to establish the presence and location of
      pancreatitis. Clinical indications for and therapy during ERCP were correlated
      with radiographic findings. RESULTS: Of the 94 patients with pancreas divisum, 54
      (57%) had radiographic evidence of pancreatitis. Of these 54 patients, 44 had at
      least one episode of clinically documented pancreatitis, seven had recurrent
      abdominal pain, and three underwent ERCP for biliary indications. In 76% of the
      54 patients with radiographic evidence of pancreatitis, only the dorsal system
      showed irreversible inflammatory change (p < .0001). Acute recurrent pancreatitis
      was the most common indication for ERCP in divisum patients and was statistically
      more common than in pancreatitis patients with normal anatomy (p < .0001). Sixty
      two (66%) of the 94 patients with pancreas divisum underwent endoscopic
      pancreatic intervention, most commonly minor papilla sphincterotomy or stenting
      or both. Eleven patients with clinically documented pancreatitis had no
      abnormalities revealed by ERCP. CONCLUSION: In our population of patients
      referred for ERCP and found to have pancreas divisum, the prevalence of
      pancreatitis was very high and usually was limited to a dorsal distribution.

PMID- 10397124
TI  - MR imaging of pancreatic changes in patients with transfusion-dependent beta
      thalassemia major.
AB  - OBJECTIVE: The aim of this study was to evaluate MR imaging changes of the
      pancreas in patients with transfusion-dependent beta-thalassemia major. SUBJECTS
      AND METHODS: Twenty patients with transfusion-dependent beta-thalassemia major
      were examined using MR imaging at 0.5 T, with spin-echo T1-weighted, fast spin
      echo T2-weighted, and gradient-echo T2*-weighted sequences. Image analysis was
      performed to assess pancreas-to-fat signal intensity ratios for all pulse
      sequences. Pancreatic exocrine and endocrine function and serum ferritin levels
      were assessed. Twenty healthy volunteers underwent MR imaging with the same three
      sequences and served as a control group. RESULTS: The pancreas-to-fat signal
      intensity ratio was significantly decreased in 17 (85%) of the 20 patients on
      spin-echo T1-weighted images (p < .05), fast spin-echo T2-weighted images (p <
      .01), and gradient-echo T2*-weighted images (p < .01) when compared with the 20
      volunteers in the control group. The pancreas-to-fat signal intensity ratio was
      significantly increased in three (15%) of the 20 patients on spin-echo T1
      weighted images (p < .01) and fast spin-echo T2-weighted images (p < .05). In
      addition, in the 20 patients, we found a significant correlation between
      increased pancreas-to-fat signal intensity ratios and decreased serum trypsin
      levels (r = -.77, p < .01 for spin-echo T1-weighted sequences; r = -.75, p < .05
      for fast spin-echo T2-weighted sequences; and r = -.74, p < .05 for gradient-echo
      T2*-weighted sequences). Likewise, for the 20 patients, we found a significant
      correlation between decreased pancreas-to-fat signal intensity ratios and
      increased serum ferritin levels for gradient-echo T2*-weighted images (r = -.65,
      p < .01). No correlation was found for the other clinical parameters evaluated.
      CONCLUSION: MR imaging revealed signal intensity changes in the pancreas of
      patients with transfusion-dependent beta-thalassemia major. Patients with a major
      impairment of the exocrine pancreatic function had higher signal intensity of the
      pancreas because of fatty replacement of the parenchyma.

PMID- 10397126
TI  - Torricelli-Bernoulli sign in an ulcerating gastric leiomyosarcoma.

PMID- 10397127
TI  - Hepatic sonography: comparison of tissue harmonic and standard sonography
      techniques.
AB  - OBJECTIVE: This study was performed to compare tissue harmonic sonography of the
      liver with conventional sonography of the liver. SUBJECTS AND METHODS: Forty
      eight patients underwent tissue harmonic and conventional sonography of the
      liver, using a randomized imaging sequence. Imaging parameters were standardized,
      but gain varied. Techniques were compared using predetermined impact analysis
      categories. If a finding was revealed by only one sonographic technique,
      additional confirmation was obtained by another imaging technique or by surgery.
      In a separate image quality analysis, masked images were reviewed by two
      experienced radiologists to evaluate fluid-solid differentiation, near-field, far
      field, and overall image quality. Rankings were correlated with field of view of
      images and body habitus of patients as determined by body mass index. RESULTS:
      Tissue harmonic sonography provided the same information as conventional
      sonography in 34 patients (71%) and added information in 14 patients (29%). The
      findings from tissue harmonic sonography resulted in altered treatment in five
      patients (10%). Eight patients (17%) had lesions revealed by tissue harmonic
      sonography only. Four patients (8%) had inadequate far-field visualization by
      both techniques. Both observers ranked tissue harmonic sonography the same as or
      better than standard sonography in 46 patients (96%) for fluid-solid
      differentiation, in 46 patients (96%) for near-field image quality, and in 45
      patients (94%) for overall image quality. For far-field image quality, one
      observer ranked tissue harmonic sonography the same as or better than
      conventional sonography in 40 patients (83%), and the second observer, in 41
      patients (85%). Image quality ratings showed no correlation with body habitus of
      the patients or field of view of images. CONCLUSION: Tissue harmonic sonography
      of the liver provides more information and better image quality than does
      conventional sonography of the liver.

PMID- 10397128
TI  - Perfusion MR imaging with a superparamagnetic iron oxide using T2-weighted and
      susceptibility-sensitive echoplanar sequences: evaluation of tumor vascularity in
      hepatocellular carcinoma.
AB  - OBJECTIVE: The study purpose was to examine the usefulness of perfusion
      echoplanar MR imaging with a superparamagnetic iron oxide (SHU-555A) for
      evaluating the vascularity of hepatocellular carcinomas. SUBJECTS AND METHODS:
      Twenty-two patients with 32 hepatocellular carcinomas underwent perfusion imaging
      with bolus injection (0.7-1.1 ml) of SHU-555A. Echoplanar sequences included
      multishot spin-echo (17 patients) and single-shot gradient-echo (five patients)
      imaging. Image acquisition was repeated every 30 sec for 3 min with the multishot
      spin-echo sequence and every 2 sec for 100 sec with the single-shot gradient-echo
      sequence. Lesion signal intensity versus time curves were created for
      quantitative analysis. RESULTS: Transient decreases in tumor signal intensity
      (28.8% with multishot spin-echo and 63.3% with the single-shot gradient-echo)
      were seen in the perfusion phase. These decreases in signal intensity were
      statistically significantly (p < .01) different for each histologic type of
      hepatocellular carcinoma (poorly differentiated, 43.3%; well differentiated,
      18.4%; and moderately differentiated, 24.8%). After the perfusion phase, the
      tumor signal intensities rapidly recovered. The multishot spin-echo sequence
      could detect some signal changes even in lesions smaller than 1 cm. CONCLUSION:
      Hepatocellular carcinoma vascularity can be evaluated with perfusion echoplanar
      imaging with SHU-555A. Because of its excellent temporal resolution, the single
      shot gradient-echo echoplanar sequence detects the transient signal decrease in
      most lesions. The high image quality of the multishot spin-echo echoplanar
      sequence allows evaluation of the vascularity of even very small lesions.

PMID- 10397129
TI  - The role of imaging in the diagnosis and management of biliary complications
      after liver transplantation.

PMID- 10397130
TI  - Initial experience with the advanced breast biopsy instrumentation device.
AB  - OBJECTIVE: The Advanced Breast Biopsy Instrumentation (ABBI) device (United
      States Surgical; Norwalk, CT) is designed to percutaneously excise nonpalpable
      breast lesions. Because this is a new technique, we report our initial experience
      with regard to technical success, complications, and histologic margins for
      malignancies. SUBJECTS AND METHODS: From May 14, 1997, until March 4, 1998, 89
      consecutive patients elected to undergo the ABBI procedure. Preprocedure imaging
      included screening mammography and additional mammographic and sonographic
      studies when deemed necessary. Lesions were targeted by the surgeons. Specimen
      radiography was performed for all lesions, and the images were interpreted by
      radiologists. Pathologic analysis was provided or reviewed by a dedicated breast
      pathologist. Parameters analyzed included technical success, complications,
      lesion size, histologic diagnosis, and margin status for malignant lesions.
      RESULTS: There were 29 patients with 30 noncalcified masses, 53 patients with
      clustered calcifications, three patients with masses and calcifications, three
      patients with asymmetric densities, and one patient with architectural
      distortion. Eighteen ABBI procedures were aborted, converted to core biopsy, or
      failed to remove the targeted lesion. Fifteen patients experienced a total of 19
      complications; 10 of the complications required treatment and follow-up after the
      biopsy. Of 11 malignant tumors revealed by ABBI, four had negative margins. Seven
      of these 11 malignant tumors had positive margins. CONCLUSION: The ABBI procedure
      had a high number of complications and technical failures and did not reliably
      provide cancer-free margins for malignant tumors. Women with nonpalpable breast
      lesions that need a tissue diagnosis are better treated by stereotactic or
      sonographically guided needle biopsy.

PMID- 10397131
TI  - Stereotactic biopsy of ductal carcinoma in situ of the breast using an 11-gauge
      vacuum-assisted device: persistent underestimation of disease.
AB  - OBJECTIVE: The purpose of this study was to compare the diagnostic accuracy of 14
      gauge automated gun and 11-gauge directional vacuum-assisted biopsy techniques in
      the diagnosis of ductal carcinoma in situ of the breast. MATERIALS AND METHODS:
      We retrospectively reviewed 41 consecutive lesions that had been diagnosed as
      ductal carcinoma in situ using stereotactic needle biopsy. The first 21 lesions
      had been biopsied using a 14-gauge automated gun; the remaining 20 lesions, using
      an 11-gauge vacuum-assisted device. Surgical histopathologic results at
      lumpectomy were compared with the findings at needle biopsy and defined as either
      concordant, when only ductal carcinoma in situ (i.e., no evidence of invasive
      carcinoma) was evident at surgery, or discordant, when invasive carcinoma was
      found. One patient from the automated gun group was lost to follow-up and was not
      included in the analysis. RESULTS: Invasive carcinoma was found at surgery in
      seven (35%) of the 20 cases diagnosed using the automated gun compared with three
      (15%) of the 20 cases diagnosed using the vacuum-assisted device (p = .13). In
      all three of these discordant vacuum-assisted cases, only microinvasive disease
      was found at surgery. However, in only two of the seven discordant automated gun
      cases was only microinvasive disease found at surgery. CONCLUSION: The 11-gauge
      directional vacuum-assisted biopsy technique may improve the accuracy of ductal
      carcinoma in situ diagnosis. Underestimation of disease still occurs, however.

PMID- 10397132
TI  - Fat suppression using direct phase encoding: musculoskeletal applications using
      MR imaging.

PMID- 10397133
TI  - The use of fat suppression in gadolinium-enhanced MR imaging of the
      musculoskeletal system: a potential source of error.

PMID- 10397134
TI  - Effects of injection rates of contrast material on arterial phase hepatic CT.

PMID- 10397135
TI  - Observations on the standard of care.

PMID- 10397136
TI  - Addendum report when prior films sought.

PMID- 10397137
TI  - Unenhanced helical CT of ureteral stones in planning treatment: patient selection
      criteria.

PMID- 10397138
TI  - Patient intolerance of CO2 angiography.

PMID- 10397140
TI  - Quality, around the clock.

PMID- 10397139
TI  - Reinterpreting imaging examinations performed at other institutions.

PMID- 10397141
TI  - Beware the stronger magnet.

PMID- 10397142
TI  - Displacement of extrapleural fat with extrapleural hematoma.

PMID- 10397143
TI  - Aspiration of gastric contents.

PMID- 10397144
TI  - MR appearance of non-Hodgkin's lymphoma of the ovary.

PMID- 10397145
TI  - Inconspicuous path of an aortic bypass straight through the urinary bladder.

PMID- 10397146
TI  - Synovial sarcoma arising from the pericardium: radiographic and CT findings.

PMID- 10397147
TI  - Juvenile xanthogranuloma with tracheal and bronchial involvement.

PMID- 10397148
TI  - Diffuse necrosis of the thyroid presenting as hypothyroidism after laryngectomy.

PMID- 10397149
TI  - Diagnosis of familial adenomatous polyposis using two-dimensional and three
      dimensional CT colonography.

PMID- 10397150
TI  - Immunoreceptor tyrosine-based inhibition motif-bearing receptors regulate the
      immunoreceptor tyrosine-based activation motif-induced activation of immune
      competent cells.
AB  - ITIM-bearing receptors, a family which only recently has been recognized, play a
      key role in the regulation of the ITAM-induced activation of immune competent
      cells. The mechanism of ITM-mediated regulation in various cells was recently
      clarified. The present review focuses on ITIM bearing membrane proteins that
      negatively regulate the activation of cells when co-crosslinked with ITAM
      containing receptors, illustrates the inhibitory processes by the negative
      regulation of B-, NK-, T-cells and mast cells and summarizes current views on the
      mechanism of ITIM-mediated inhibition.

PMID- 10397151
TI  - Biochemical analysis and crystallisation of Fc gamma RIIa, the low affinity
      receptor for IgG.
AB  - Fc gamma RIIa is one of a family of specific cell surface receptors for
      immunoglobulin. Fc gamma RIIa, which binds immune complexes of certain IgG
      isotypes, plays important roles in immune homeostasis. However, the precise
      characteristics of IgG binding and three-dimensional structure of Fc gamma RIIa
      have not been reported. This study describes the affinity of the Fc gamma
      RIIa:IgG interaction as well as biochemical characterisation of recombinant Fc
      gamma RIIa that has been used to generate high quality crystals. Equilibrium
      binding analysis of the Fc gamma RII:IgG interaction found, IgG3 binds with an
      affinity of K(D) = 0.6 microM, as expected. Unlike other Fc gamma R, IgG4 also
      bound to Fc gamma RIIa, K(D) = 3 microM, clearly establishing Fc gamma RIIa as an
      IgG4 receptor. Biochemical analysis of mammalian and insect cell derived Fc gamma
      RIIa established the genuine N-terminus with Q being the first amino acid in the
      sequence Q, A, A, A, P... extending the N-terminus further than previously
      thought. Furthermore, both potential N-linked glycosylation sites are occupied.
      Electrospray ionisation mass spectrometry (ESMS) indicate that the N-glycans of
      baculovirus derived Fc gamma RIIa are core mannose oligosaccharide side chains.
      Finally, we describe the first crystallisation of diffraction quality crystals of
      soluble Fc gamma RIIa. Orthorhombic crystals diffract X-rays beyond 2.1 A
      resolution in the space group P2(1)2(1)2 with cell dimensions a = 78.8 A, b =
      100.5 A, c = 27.8 A. This marks a significant advance towards understanding the
      three-dimensional structure of Fc gamma RIIa and related FcR proteins that share
      high amino acid identity with Fc gamma RIIa.

PMID- 10397152
TI  - Cooperation between SHP-2, phosphatidyl inositol 3-kinase and phosphoinositol 5
      phosphatase in the Fc gamma RIIb mediated B cell regulation.
AB  - Co-clustering B cell receptors (BCR) and type II receptors binding the Fc part of
      IgG (Fc gamma RIIb) inhibits B cell activation and antibody production. Tyrosine
      phosphorylation of an intracellular motif of Fc gamma RIIb has been shown to be a
      prerequisite of the inhibition. After being phosphorylated by BCR-activated
      tyrosine kinases, the immunoreceptor tyrosine-based inhibitory motif (P-ITIM) of
      Fc gamma RIIb recruits SH2 domain containing protein tyrosine phosphatase(s)
      (PTPs) and polyphosphoinositol 5-phosphatase (SHIP) to the vicinity of BCR, which
      in turn dephosphorylate their specific substrates. This leads to the interruption
      of signal transduction, consequently to the anergy and/or apoptosis of the cell.
      The downstream signaling pathways affected by Fc gamma RIIb-BCR co-clustering are
      not clarified yet, neither the substrates of PTPs are known. We have studied the
      Fc gamma RIIb mediated B cell inhibition on human Burkitt lymphoma cell line
      (BL41). From the lysates of BL41 cells SHP-2 and phosphatidylinositol 3-kinase
      (PI3-K), as well as the protein tyrosine kinase (PTK) Lyn bind both to the BCR-co
      clustered Fc gamma RIIb and to its P-ITIM peptide. Lyn hyperphosphorylates the P
      ITIM associated molecules, including SHIP in the in vitro protein tyrosine kinase
      activity assay. The P-ITIM-compelled multi-phosphoprotein complex binds to and
      activates SHP-2, which in turn dephosphorylates SHIP and Shc and probably other
      substrates. Subcellular localisation of these signaling molecules is regulated by
      the phosphotyrosine-SH2 domain interactions, thus dephosphorylation may result in
      the re-direction of Shc and SHIP within the cell, consequently, in the modulation
      of their activity. Finally, co-clustering Fc gamma RIIb and BCR or Fc gamma RIIb
      and CD19 on the intact cells inhibited PI3-K activity as detected in the anti
      phosphotyrosine (anti-PY) precipitates. The results indicate that SHP-2 bound to
      and activated by the BCR co-clustered Fc gamma RIIb, may down-regulate PI3-K
      activity by dephosphorylating a yet unidentified regulatory molecule, which
      recruits PI3-K to the cell membrane.

PMID- 10397153
TI  - Unique features of SHIP, SHP-1 and SHP-2 binding to FcgammaRIIb revealed by
      surface plasmon resonance analysis.
AB  - A growing family of inhibitory receptors characterized by content of one or more
      immunoreceptor tyrosine-based inhibitor motif (ITIM), I/V xYxxL/V, has been shown
      to regulate activation and effector function of immune system cells. The
      inhibitory activity of these receptors is mediated in large part by tyrosyl
      phosphorylated ITIM (pITIM) interactions with cytoplasmic effectors.
      Interestingly, different members of the family utilize partially distinct subsets
      of effectors from a group that includes SHP-1, SHP-2 and SHIP, an inositol 5'
      phosphatase. For example, while killer inhibitory receptors bind only SHP-1 and
      SHP-2, FcgammaRIIB bind SHIP, SHP-1 and SHP-2. The basis of selectivity of ITIMs
      for effectors is unclear. In this study surface plasmon resonance has been used
      to characterize the binding of phosphorylated FcgammaRIIB ITIM peptides to SHP-1,
      SHP-2 and SHIP derived Src-homology 2 (SH2) domains. SHIP was found to bind with
      highest affinity with intermediate on and off rates. SHP-1 bound with lowest
      affinity with slow on and slow off kinetics, and only its C-terminal SH2 domain
      exhibited binding activity. Both C- and N-terminal SH-2 domains of SHP-2 bound
      the pITIM. The affinity of these interactions were similar, however, they
      exhibited relatively fast on fast off and slow on slow off kinetics respectively.
      Interestingly, removal of the Ala-Glu-Asn sequence which lies immediately N
      terminal from the ITIM in FcR ablated binding to SHP-1 and SHP-2 but not to SHIP.
      These results reveal a previously unrecognized level of complexity of effector
      binding to pITIM, including dependence of optimal SHP-1 and SHP-2 binding on
      residues N-terminal from the ITIM.

PMID- 10397154
TI  - Antibody feedback suppression: towards a unifying concept?
AB  - IgG antibodies can negatively regulate antibody responses. When IgG anti-sheep
      erythrocytes (SRBC) is administered to an animal together with SRBC, the response
      against SRBC will frequently be less than 1% of the response in animals immunized
      with SRBC alone. The mechanism behind this phenomenon is not fully understood. It
      has been suggested that suppression is caused by masking of epitopes by IgG, thus
      preventing B cells from recognizing the antigen. Other possible explanations are
      that IgG/antigen complexes are eliminated via Fc-receptor dependent phagocytosis
      or that the complexes inhibit B cell activation by co-crosslinking the B cell
      receptor for antigen and the inhibitory Fc-receptor, FcgammaRIIB, expressed by B
      cells. Whereas the first mechanism would operate independently of the Fc-portion
      of IgG, the two latter would be Fc-dependent. In the literature data has been
      presented supporting both Fc-dependence and Fc-independence of suppression. It
      has recently been shown that IgG suppresses more than 90% of the antibody
      response in gene targeted mice lacking the known Fc-receptors for IgG and that
      F(ab')2 fragments as well as IgE are efficient suppressors. These findings
      strongly suggest that IgG is able to efficiently suppress antibody responses
      independently of the Fc-part and favor the model of epitope masking. Here, a way
      of interpreting available experimental data which can explain many of the
      discrepancies in the literature, is presented.

PMID- 10397155
TI  - Glycosylation of human IgG-Fc: influences on structure revealed by differential
      scanning micro-calorimetry.
AB  - Glycosylation of the Fc region of IgG (IgG-Fc) is essential for the full
      expression of Fc effector functions. The profound differences in functional
      activity observed between glycosylated and aglycosylated IgG have not previously
      been paralleled by the demonstration of large-scale structural changes. In the
      present study differential scanning microcalorimetry (DSMC) was used to
      investigate IgG-Fc glycoprotein stability and to determine the thermodynamic
      parameters for thermal unfolding, which will include a contribution from the
      intra-molecular oligosaccharide-protein interactions. The thermogram obtained for
      glycosylated IgG1-Fc yielded two clearly defined transitions whilst the
      glycosylated IgG4-Fc exhibited a single transition. The methodology was also able
      to reveal measurable differences in the stability of IgG4-Fc glycoforms differing
      by the presence or absence of terminal galactose residues; deglycosylated IgG4-Fc
      exhibited two transitions with evidence for destabilisation of the C(H)2 domain.

PMID- 10397156
TI  - A quantitative approach to signal transduction.
AB  - The high affinity receptor for IgE (FcepsilonRI), is one of a family of
      immunoreceptors whose antigen-induced clustering leads to a variety of cellular
      responses. The signaling pathways are enormously complex but by focusing on only
      the most initial steps, it is now possible to sketch plausible molecular models
      that relate the interaction of multivalent antigens with the receptor-bound IgE
      to the earliest cellular events. In this paper, we describe how we have combined
      quantitative experimentation and mathematical modeling to probe this system
      further. We also discuss some of the formidable challenges that remain before we
      can claim reasonably complete understanding of even these early events.

PMID- 10397157
TI  - Parameters determining the stimulatory capacity of the type I Fc epsilon
      receptor.
AB  - Several experiments and theoretical considerations aimed at obtaining the
      parameters which determine the capacity of type I Fc epsilon-receptors to
      stimulate the secretion of mast cells are reviewed. Earlier studies have
      established that secretion requires Fc epsilon RI clustering at least two dimers.
      The roles of such clusters lifetimes and configuration requires a detailed and
      quantitative analysis of Fc epsilon RI clustering and stimulus secretion.
      Different approaches to these issues are described and discussed. We especially
      address the relevance of the general concept of kinetical proof reading (T.W.
      McKeithan, Proc. Natl. Acad. Sci. USA 92 (1995) 5042) which is based on the
      assumption that the stimulating receptors must stay in an active state
      sufficiently long to bridge the time interval between initiation and termination
      of cell activation. For mast cells which generally secrete upon clustering of
      type I Fc epsilon-receptors, this implies that effective stimulation requires a
      sufficiently long lifetime of such clusters. This notion is corroborated by
      results obtained from several experiments performed in the last 20 years which
      are briefly described and compared in this review.

PMID- 10397158
TI  - Mast cell stimulation by co-clustering the type I Fc epsilon-receptors with mast
      cell function-associated antigens.
AB  - The secretory response of rat mucosal-type mast cells (line RBL 2H3) to stimuli
      produced by clustering or co-clustering two of its membranal components; the type
      I Fc epsilon receptor and the mast cell function associated antigen (MAFA) was
      investigated. The primary reagents employed for this purpose were Fab fragments
      of the monoclonal antibodies J17 and G63 specific to the above respective
      proteins. The Fabs were then aggregated by F(ab')2 fragments of mouse IgG
      specific goat antibodies. This reaction was assumed to yield predominantly three
      different bivalent clustering reagents. Namely, dimers of the Fc epsilon RI
      specific (J17-Fab)2; dimers of the MAFA specific, (G63-Fab)2 and bispecific (J17
      Fab-G63-Fab) dimers. The observed cellular secretory response was analyzed by
      employing a model which accounts for the clustering and co-clustering of Fc
      epsilon RIs and MAFAs by the above protocols. Results of this analysis provided
      evidence that at least some of the MAFA molecules are physically associated with
      the Fc epsilon RI. As a consequence, clustering of MAFA and Fc epsilon RI by
      bispecific J17-Fab-G63-Fab dimers induces secretion at comparatively low
      concentrations of these reagents, though with a significantly lower maximal
      response than that caused by the respective monospecific reagent (J17-Fab)2. This
      result most likely reflects the inhibitory capacity of MAFA-Fc epsilon RI
      interaction.

PMID- 10397159
TI  - Inhibition of IgE-mediated triggering of mast cells by complement-derived
      peptides interacting with the Fc epsilon RI.
AB  - Mucosal type mast cells, in contrast to the serosal type ones, do not respond to
      cationic agents, or to the complement-derived peptides C3a and C5a. Earlier we
      have found that while C3a does not activate the rat mucosal type mast cells (line
      RBL-2H3), it strongly inhibits the IgE-mediated triggering of these cells, by
      interfering with the Fc epsilon RI-initiated signaling pathway. In the present
      study we further investigated the mechanism of this process. It is shown, that
      C3a interacts with the beta-chain of the Fc epsilon RI complex. Binding of the
      complement peptide to the cells apparently causes a decrease in the proximity of
      the IgE-binding Fc epsilon RI. Investigating certain sequences of C3a we found
      that the inhibition is caused by the C-terminal sequences of the complement
      peptide, ranging from positions 56 to 77 and also by a shorter sequence, ranging
      from positions 56 to 64. The inhibitory effect of these peptides was observed
      both in the case of RBL-2H3 cells and mouse bone marrow derived mast cells.

PMID- 10397160
TI  - The human Fc receptor for IgA (Fc alpha RI, CD89) on transgenic peritoneal
      macrophages triggers phagocytosis and tumor cell lysis.
AB  - Even though IgA is considered to play an important role in immunity, surprisingly
      little is known about the presence of IgA Fc receptor (Fc alpha R)-expressing
      effector cells in tissues. Difficulties in obtaining human tissue macrophages,
      led us to study peritoneal macrophages in a human Fc alpha RI transgenic (Tg)
      mouse model. Naive peritoneal macrophages did not express hFc alpha RI.
      Expression, however, could be induced by overnight culture, and was upregulated
      by GM-CSF. In addition, the receptor proved functional since macrophage-mediated
      phagocytosis and tumor cell kill were effectively triggered via hFc alpha RI. To
      assess necessity of the FcR gamma-chain signaling molecule for hFc alpha RI
      function in macrophages, Tg mice were crossed with mice deficient in FcR gamma
      chain (gamma-/-). Tg, gamma-/- macrophages were unable to kill tumor cells. This,
      because Tg macrophages failed to express hFc alpha RI in the absence of FcR gamma
      chain, and overnight culture did not overcome this lack of expression. Further
      studies with the transgenic mouse model presented in this study will help to
      define the precise conditions under which Fc alpha RI is expressed on
      macrophages. It will, furthermore, represent a useful tool to study Fc alpha RI
      function in immune defense.

PMID- 10397161
TI  - B cell development in the mouse from early progenitors to mature B cells.

PMID- 10397162
TI  - Characterization of the B cell-specific adaptor SLP-65 and other protein tyrosine
      kinase substrates by two-dimensional gel electrophoresis.
AB  - The identification of substrates for protein tyrosine kinases in B cells is a
      critical step to a better understanding of the molecular mechanism(s) of
      lymphocyte activation through the antigen receptor. The substrate proteins were
      immunopurified from stimulated B cells and separated by two-dimensional gel
      electrophoresis techniques using either the isoelectric focussing (IEF)/SDS-PAGE
      or the non-equilibrium PH gradient electrophoresis (NEPHGE)/SDS-PAGE method. The
      biochemical characteristics of the proteins (isoelectric point and relative
      molecular mass) obtained and the subsequent use of antibodies that are specific
      for different cellular proteins confirmed the participation of HS1, Vav, Ig
      alpha, Lyn and Btk in antigen receptor-mediated signal transduction. The heat
      shock cognate protein HSC70 was identified as a novel substrate protein in
      activated B cells. An important signaling function has previously been suggested
      for a 65-kDa protein (p65), whose phosphorylation can be detected before that of
      other substrate proteins. The analysis identified p65 as a so far unknown
      protein. Based on p65 peptide sequences, the full length cDNA was isolated and
      found to encode a B cell-specific adaptor protein, called SLP-65.

PMID- 10397163
TI  - Signaling complex formation of CD44 with src-related kinases.
AB  - The complex formation of murine CD44 with the src-like protein tyrosine kinases,
      lck and lyn, was investigated. In accordance with previous observations, stable
      CD44-lck and CD44-lyn complexes were detected in nonstimulated lymphoid T- and B
      cells, respectively. In addition, a direct modulation of lck and lyn by CD44 was
      observed as revealed by the CD44-dependent translocation of these enzymes to the
      Triton X-100 resistant cell fraction. To clarify which receptor domain is
      responsible for the association, peptide binding assays were performed.
      Interestingly, the synthetic peptide pCD44 (ILAVCIAVNSRRR), which corresponds to
      the plasma membrane-cytoplasmic interface region of murine CD44, exhibited a high
      capacity to bind lck and lyn. A single amino acid modification in the position of
      the cysteine residue completely abolished this interaction, while the truncation
      of the three tandem arginines significantly decreased it. Remarkably, similar
      sequences were found in a number of other molecules including subunits of
      receptors recognizing antigens, immunoglobulins, extracellular matrix components,
      accessory molecules, cytokines and also in certain viral gene products. Synthetic
      peptides corresponding to the homologous regions found in CD28 and
      FcepsilonRIbeta were also studied and comparable lck-lyn-binding potentials were
      detected. These data suggest a novel interaction between src-family kinases and
      CD44, CD28, FcepsilonRIbeta, and provide a simple model for the association of
      src-like kinases with transmembrane proteins.

PMID- 10397164
TI  - A regulatory role for Fc gamma receptors (CD16 and CD32) in hematopoiesis.
AB  - Progenitor cells of the T- and B-lineages in mice express (CD32) and Fc gamma
      RIII (CD16) but as the developing lymphocytes begin to express clonal antigen
      receptors, CD16 and CD32 are downregulated in T-cells, and CD16 is downregulated
      in B-cells. Considering that counter-receptors for Fc gamma R occur on thymic and
      bone marrow stromal cells, the possibility exists that Fc gamma R might
      participate in some aspect of T- and B-lineage development prior to the stage of
      antigen receptor expression. Previous studies provided evidence that Fc gamma R
      can influence murine T-lineage development. In the present studies we found that
      anti-Fc gamma RII/III mAb accelerated B-lineage development in bone marrow
      cultures from normal mice, but not in cultures from CD16-/- or CD32-/- mice.
      Similar results were observed when FACS-purified B-progenitor cells were co
      cultured with BMS2, a bone marrow stromal cell line. Fresh bone marrow from CD32
      /- mice contained about two-fold more B-lineage cells compared to bone marrow
      from normal or CD16-/- mice. These studies indicate that the Fc gamma R on B
      lineage progenitor cells can influence their further development and add to a
      growing body of evidence that implicates Fc gamma R as regulatory elements in
      hematopoiesis.

PMID- 10397165
TI  - TCR specificity in infection induced granulomas.
AB  - Granuloma formation is an essential host response to many intracellular pathogens
      and some particulate antigens. T lymphocytes, especially CD4+ T-cells, are
      required for the initial formation and ongoing maintenance of the inflammatory
      response. In the absence of CD4+ T-cells, most infections which normally provoke
      a granulomatous response are more widely disseminated or lethal since the
      protective lesions are either malformed or absent. The role of T-cell receptor
      mediated antigen specificity in infectious states is reviewed with a special
      emphasis upon recent work on S. mansoni induced granulomas.

PMID- 10397166
TI  - Generation of 'truncated' interleukin-6 receptor (IL-6R) mRNA by alternative
      splicing; a possible source of soluble IL-6R.
AB  - Receptors for interleukin-6 (IL-6) occur in body fluids in soluble form, as well.
      This is an approx. 50 kDa protein with the ability to bind IL-6. The soluble IL-6
      receptor (sIL-6R)/IL-6 complex can attach to membrane anchored gp130, a molecule
      associated with the signal transduction induced by IL-6 and by other related
      cytokines. Earlier we described the appearance of sIL-6R in various body fluids
      of autoimmune patients. In this study using reverse transcriptase polymerase
      chain reaction (RT-PCR) we isolated and characterised a truncated form of
      amplified cDNA reverse-transcribed from IL-6 receptor mRNA both from human
      hepatoma cell line HepG2 and mononuclear cells from inflammatory bowel disease
      (IBD) patients. Using digestion by Pvu II restriction endonuclease and direct
      nucleotide sequencing we conclude that alternative splicing is likely involved in
      generation of sIL-6R. Our further experiments suggest that IL-6 and recombinant
      sIL-6R themselves do not influence the alternative splicing of IL-6 receptor
      gene.

PMID- 10397167
TI  - Regulation of production of soluble Fc gamma receptors type III in normal and
      pathological conditions.
AB  - CD16 (Fc gamma R type III), a low affinity IgG Fc receptor, is found in two
      forms, a transmembrane Fc gamma RIIIa expressed by NK cells and monocytes and a
      phosphatidylinositol-linked Fc gamma RIIIb present on neutrophils. Exposure of
      neutrophils to inflammatory signals induces a rapid loss of CD16 expression and
      release of a soluble form of CD16 (sCD16). Soluble CD16 circulates in plasma,
      levels being reduced in sera from patients with multiple myeloma. In the present
      manuscript the authors summarize work that aimed to better understand: (i) the
      role of proteinases in sCD16 production and CD16 membrane shedding; and (ii) the
      regulation of sCD16 levels in multiple myeloma patients and the possible
      biological consequences of its decrease in this disease. Soluble CD16 was
      purified from human serum. Its N-terminal sequencing demonstrated that it
      originates from neutrophil CD16 and its C-terminal sequencing showed that the
      cleavage site was between Val 196 and Ser 197, close to the membrane anchor.
      Analysis of the effect of protease inhibitors revealed that the cleavage leading
      to sCD16 production by PMA-activated neutrophils was metalloproteinase-dependent.
      In addition, membrane and sCD16 were sensitive to serine proteinases released by
      azurophil granules or added under purified form. The reduction of sCD16 levels
      that occurs in patients with multiple myeloma was associated with a slight
      decrease in circulating neutrophils, but not with a significant defect in sCD16
      production by neutrophils, as detected in vitro. Moreover, addition of a
      recombinant sCD16 to plasmocytoma lines did not significantly modify their
      proliferation and Ig secretion.

PMID- 10397168
TI  - Control of tumor development by intratumoral cytokines.
AB  - The local immune reactions may influence the clinical outcome of human tumors. In
      carcinoma of the cervix, high gene expression of IL6 with tumor invasiveness
      whereas lack of gene expression of IFNbeta is correlated with poor prognosis. In
      colorectal cancer, lack of expression of IFNbeta is associated with the presence
      of distant metastasis and poor survival. The production of IL17 and IL18,
      inducers of IL6 and IFNbeta respectively is regulated in these tumors and may
      control the levels of the effector cytokines, i.e. IL6 and IFNbeta. The
      mechanisms by which these cytokines act are linked to the recruitment of effector
      cells such as macrophages.

PMID- 10397169
TI  - MCP-1 expression as a potential contributor to the high malignancy phenotype of
      murine mammary adenocarcinoma cells.
AB  - The search for mechanisms that regulate tumor progression has motivated the
      authors' laboratory to establish a unique murine model system, consisting of two
      lines of DA3 mammary adenocarcinoma cells that were derived originally from a
      common ancestor but differed in their malignant potential. Studies indicated that
      the highly malignant phenotype manifested by one of the cell lines (termed Ly-6hi
      DA3 cells) was associated with high expression of the Ly-6E.1 antigen. To
      characterize the mechanisms controlling the high malignancy phenotype expressed
      by Ly-6hi DA3 cells, the study was focussed on the potential contribution of
      tumor-derived factors to the high malignancy phenotype expressed by these cells.
      To this end, the expression of CC chemokines, major chemoattractants of monocytes
      and T cells, by the highly malignant Ly-6hi DA3 cells as compared to the low
      malignancy Ly-6lo DA3 cells was evaluated. The results indicate that the highly
      malignant cells express higher levels of factors that induce monocyte migration
      than the low malignancy cells. Two CC chemokines were shown to be highly produced
      by Ly-6hi DA3 cells, MIP-1alpha and MCP-1, of which only the latter was shown to
      contribute to the high migratory activity expressed by the high malignancy Ly-6hi
      DA3 cells. Since MCP-1 may attract monocytes to tumor sites, these findings
      suggest that monocyte-derived mediators, such as growth factors or angiogenic
      cytokines, have pro-malignancy effects that contribute to the high malignancy
      phenotype expressed by Ly-6hi DA3 cells.

PMID- 10397170
TI  - LMP-1, the Epstein-Barr virus-encoded oncogene with a B cell activating mechanism
      similar to CD40.
AB  - Many details in the expression pattern of Epstein-Barr virus (EBV)-encoded
      proteins, their role in blast and growth transformation in infected B lymphocytes
      are known, but 'black holes' still exist. The two main types of virus-B
      lymphocyte interactions are denoted as Type I and Type III. These are
      characterized by the difference in the EBV protein expression which is related to
      the phenotype of the cell. The difference was first detected in comparisons
      between Burkitt lymphoma cells (BL) and lymphoblastoid cell lines, LCLs, which
      arise from normal B lymphocytes after experimental infection and are growth
      transformed by EBV. A third type of interaction can be seen in B-CLL cells which
      carry the EBV receptor CD21 and can be thus infected with the virus in vitro. The
      infected cells express the EBV-encoded proteins with a pattern which is different
      from the above mentioned two types, in that they express the nuclear proteins but
      not the membrane localized LMP-1. Importantly, the infected B-CLL cells do not
      enter DNA synthesis and they do not growth transform. Normal B lymphocytes with
      similar expression pattern have been seen in analysis of the lymphoreticular
      tissues of patients which responded to the primary EBV infection with development
      of the infectious mononucleosis symptoms.

PMID- 10397171
TI  - Demonstration of the interaction of thioredoxin with p40phox, a phagocyte oxidase
      component, using a yeast two-hybrid system.
AB  - Thioredoxin (TRX) has disulfide reducing activity and is reported to be involved
      in various cellular functions including the promotion of cell growth and
      apoptosis. To help understand the molecular mechanism through which TRX is
      involved in immunological systems, we screened a cDNA library derived from a B
      cell population of Epstein-Barr virus-transformed human peripheral blood
      lymhocyte for TRX binding proteins by use of a yeast two-hybrid system. Among
      plasmids from positive clones, a plasmid contained an insert which has homology
      with human p40phox, a cytosolic component of phagocyte oxidase. This insert
      sequence extended from the base + 181 to the stop codon of p40phox. The entire
      coding region of p40phox was shown to interact with TRX both in assays of
      histidine prototrophy and beta-galactosidase activity; in contrast, no
      interaction was observed with substituted mutant TRX (C32S/C35S), which lacks
      reducing activity. These results showed that p40phox interacts with TRX and
      indicated the possibility of TRX-dependent regulation of phagocyte oxidase
      activity.

PMID- 10397172
TI  - Cell-mediated suppression of human interleukin-2 gene expression at splicing of
      mRNA.
AB  - Human IL-2 gene expression is regulated by cell-mediated suppression. Mitogenic
      stimulation of PBMC induces transient activation of CD8 cells that inhibit
      expression of this gene. Depletion of CD8 cells elicits marked superinduction of
      IL-2 mRNA; reintroduction of CD8 cells causes severe inhibition. Moreover, during
      IL-2 gene induction, splicing of IL-2 precursor transcripts becomes inhibited,
      resulting in a transient mRNA wave. This block in IL-2 mRNA splicing is relieved
      by the translation inhibitor, cycloheximide (CHX), which does not stimulate
      transcription [Gerez et al., J. Biol. Chem. 270, 15569 (1995)]. We show that
      suppression of IL-2 mRNA expression, whether by CD8 cells, soluble mediators
      derived from them, or IL-10, is relieved completely by CHX. Hence, suppression
      involves a CHX-sensitive step. Response to CHX, manifested in superinduction of
      IL-2 mRNA, is enhanced 10-fold during suppression. Suppression by CD8 cells or
      soluble mediators leads to rapid degradation of precursor transcripts while
      relief from suppression leads to a significant rise in precursor RNA. These
      changes precede effects at the mRNA level. We conclude that suppression induces a
      block in mRNA splicing and degradation of blocked precursor transcripts. The near
      complete absence of IL-2 mRNA superinduction by CHX in Jurkat Th cells, lacking
      cells with suppressive capacity, supports this interpretation.

PMID- 10397173
TI  - Thirty years with Fc(sigma)R.
AB  - In his talk Henry Metzger [H. Metzger et al., Immunol. Lett. 68 (1999) 53-57]
      referred to a view recently expressed in an article by Koshland [D.E. Koshland
      Jr., Science 280 (1998) 852-853], that there are three stages in the study of
      biological systems: firstly, to describe what's happening; secondly, to define
      the molecules involved and what they are doing; thirdly, to quantitate these
      processes.

PMID- 10397174
TI  - Revision of the functional analysis and structural features of immortalized
      dendritic cell lines derived from mice lacking both type I and type II interferon
      receptors.
AB  - Cell lines with dendritic morphology were obtained from several organs of mice
      lacking both type I and II interferon receptors after a retroviral
      immortalization procedure. Their surface antigen phenotype was analyzed by flow
      cytometry with monoclonal antibodies and their functional capabilities to induce
      antigen dependent specific immune response was also determined. Two
      representative cell lines called AG101 (skin-derived) and AG116 (brain-derived)
      were cloned and analyzed in more detail. Cytometric analysis showed that they
      constitutively expressed the cell surface markers CD45, CD1 1b, MHC class II,
      F4/80, N418, B7-2 and ICAM1. Despite both cell lines expressing Thy-1 only, the
      AG116 show CD4 but both were negative for CD8 and B220. The functional analysis
      showed that the cell lines were capable and very efficient at actively taking up,
      processing and presenting soluble antigens like Ovalbumin (OVA). The processed
      protein was presented by both cell lines to the OVA-peptide-specific T cell
      hybridoma BO97.105, which responded specifically with the production of IL-2. In
      addition AG101 and AG116 cells were able to induce in naive allogeneic T cells, a
      mixed lymphocyte reaction, determined by T cell proliferation and T cell
      dependent L-2 production. Moreover, the capability to prime naive syngeneic T
      cells was also demonstrated by loading AG101 and AG116 cells with soluble
      antigens, then co-culturing with naive T cells which yielded both T cell
      proliferation and IL-2 production. The cell lines priming capability was shown to
      be quite similar, as freshly isolated and cultured cutaneous dendritic cells from
      129Sv/Lv mice (wtDCs) to prime naive T cells. In addition to a basal production
      of IL-6, the cell lines were found to increase their synthesis of IL-6 and IL-12
      p40 after interaction with T cells in a similar way as mature wtDCs. Also it was
      determined that DC cell lines devoid of functional IFN system allow the
      replication of infectious agents like BDV and even are able to induce in vivo a
      specific humoral response against proteins of the BDV. Therefore, the cell lines
      AG101 and AG116 show structural and functional features of DCs. They are able to
      take up, process and present antigens as well as prime naive T cell in a similar
      manner as nontransformed DC. Therefore, these cell lines will be useful for
      studying the interactions between DC and the effectors cells of the immune
      response at the clonal level and in the absence of functional interferon
      receptors.

PMID- 10397175
TI  - Signalling mechanisms and the role of calcineurin in erythropoiesis.
AB  - Erythropoietin (Epo) is the principal regulator of the production of circulating
      erythrocytes by controlling the proliferation, the differentiation and the
      survival of the erythroid progenitor cells. Early down-regulation of c-myb
      expression in erythroleukemia cells is a common feature of the action of Epo and
      chemical inducers of differentiation such as DMSO. Previously we have shown that
      in our Epo-responsive murine erythroleukemia cell line ELM-I-1, [Ca2+]i
      increasing agents can mimic the effect of Epo on c-myb expression and activate
      nuclear signal transduction processes involved in the induction of hemoglobin
      synthesis. These results also indicated that the Ca2+-induced down-regulation of
      c-myb expression and hemoglobin synthesis are mediated by the Ca2+/calmodulin
      dependent serine/threonine-specific protein phosphatase PP2B, calcineurin, but
      the Epo induced processes are not mediated by PP2B. In spite of this, we
      demonstrated in this paper that in ELM-I-1 cells the Epo-induced down-regulation
      of c-myb expression and hemoglobin production can be effectively enhanced by the
      simultaneously added [Ca2+]i-increasing agent, cyclopiazonic acid (CPA). This
      observation further supports the existence of at least two independent signalling
      pathways in the mechanism of Epo and [Ca2+]i increasing agents and the strong
      correlation between c-myb expression and hemoglobin production in differentiating
      cells. Although the c-AMP-response element binding protein (CREB) could be the
      common target of both calcium-dependent and -independent dephosphorylation, our
      results do not support the involvement of CREB in the regulation of c-myb gene
      expression. In addition to the calcineurin mediated down-regulation of c-myb
      expression, we have found a negative regulatory effect in the Ca2+-mediated
      transcriptional activation of certain genes. In response to [Ca2+]i-increasing
      agents in ELM-I-1 cells, both, egr-1 and c-fos mRNA expression increased
      significantly after the inhibition of calcineurin by cyclosporine A. Cyclosporin
      A exerted stimulatory effects on the egr-1 and c-fos expression also at lower
      (150-400 nM) intracellular Ca2+ levels. This potential co-regulation of c-myb,
      egr-1 and c-fos expression by calcineurin suggests that the negative modulation
      of egr-1 and c-fos expression may also be important for the induction of
      erythroid differentiation by [Ca2+]i-increasing agents. This negative modulation
      may also contribute to the Epo-induced differentiation in the case of a moderate
      increase of [Ca2+]i.

PMID- 10397176
TI  - Caries detector dyes--an in vitro assessment of some new compounds.
AB  - Previous studies have shown that the caries detector dyes, basic fuchsin and acid
      red, lack specificity. Accordingly, their clinical use can lead to the
      unnecessary removal of sound tissue. In the present study, the specificity of
      three further dyes, Carbolan Green, Coomassie Blue and Lissamine Blue was
      studied. Carious dentine was removed in vitro by means of rotary instruments
      until the cavities were deemed caries free by conventional clinical criteria.
      Experimental dyes were applied to the cavity floors, all of which became stained.
      Stained dentine was removed from half the cavity by means of a burr, the other
      half remaining as a control. Further stain was then applied and the procedure
      repeated until no further reduction of the staining of the cavity floor could be
      achieved. Light microscopy of ground sections of experimental teeth showed that
      sound tissue had been removed unnecessarily from the experimental half of the
      cavity due to the lack of specificity of these dyes. This lack of specificity of
      staining was similar to basic fuchsin and acid red. Only Carbolan Green showed
      possible differential staining between control and experimental sites, but this
      was not caries specific. If a clinically useful dye is to be developed, it would
      need to specifically stain either bacteria in infected dentine and/or the carious
      degradation products of dentine matrix.

PMID- 10397177
TI  - Effect of water storage on the silanization in porcelain repair strength.
AB  - This study examined the long-term water storage affect of silanization on shear
      bond strength of composite resin to porcelain. One hundred and sixty square
      shaped specimens were fabricated and sanded flat sequentially with silicone
      carbide papers. The specimens were then placed into four groups and 16 subgroups
      of 10 specimens each randomly. Four commercially available silane systems, two
      one-mix and two two-mix, were tested in this study. Teflon tubes with an internal
      diameter of 2.97 mm and 2 mm in height were filled with a dual cure composite
      resin (Mirage FLC), placed on the silanated surfaces and light-cured for 120 s.
      Specimens were stored in room temperature water and subjected to shear bond
      strength testing after 24 h, 1 week, 1 month and 3 month periods of immersion. An
      Instron Universal testing machine with a crosshead speed of 0.5 mm/min was used
      for the testing. The mean values of the shear bond strengths ranged from 4.38 MPa
      (24-h period) to 23.90 MPa (3-month period). ANOVA and Scheffe' tests were used
      to analyse data with confidence level at 95%. All groups recorded an increase in
      bond strength after one week as compared with the 24-h period (P<0.05). With the
      exception of a one-mix system, all systems showed significantly higher bond
      strength at 3 weeks as compared with the 24-h and 1-week water storage periods.
      In conclusion, bond strength of composite resin to porcelain resulting from
      silanization of porcelain increased during the experimental period. The bond
      strength also varied for different silanes used in this study.

PMID- 10397178
TI  - Peri-implant tissue health in reconstructed atrophic maxillae--report of 88
      patients and 470 implants.
AB  - The aim of this study was to evaluate the soft-tissue health around 470 implants
      placed in the upper jaw of 88 patients with severe maxillary atrophy. All
      patients underwent a reconstruction procedure which included a composite bone
      grafting from the iliac crest to the maxillary sinus. Evaluation was performed at
      a mean implant lifetime of 21.6+/-10.9 months. The following parameters were
      used: probing depth, plaque-, gingival-, bleeding index and width of the buccal
      keratinized mucosa. They were calculated as means for each implant and related to
      the type of superstructure and the thickness of the original sinus floor. (higher
      or lower than 5 mm). A high percentage of bleeding on probing was observed in
      obviously clinically healthy peri-implant pockets. Bleeding on probing and deeper
      probing depth were especially observed in the group with severe maxillary atrophy
      (less than 5 mm initial height of the sinus floor.) There was a significant
      increase in mean peri-implant probing depth and gingiva index in overdentures
      versus fixed bridges. No differences were observed with respect to the width of
      the keratinized buccal mucosa. It was concluded that implants in the
      reconstructed maxilla and supporting overdentures had a higher risk for bone
      loss, based on the worse peri-implant tissue health observed.

PMID- 10397179
TI  - Adhesive primers for bonding cobalt-chromium alloy to resin.
AB  - This study evaluated the effect of five adhesive primers on the shear bond
      strength of a self-curing resin to cobalt-chromium (Co-Cr) alloy. The adhesive
      primers Acryl Bond (AB, Shofu), Cesead Opaque Primer (COP, Kuraray), Metacolor
      Opaque Bonding Liner (MOBL, Sun-Medical), Metal PrimerII (MPII, GC) and MR. Bond
      (MRB, Tokuyama) were used. A brass ring which was placed over the casting alloy
      disk surface non-primed or primed with each primer was filled with the self
      curing MMA-PMMA resin. The specimens were stored in water at 37 degrees C for 24
      h and then immersed alternately in water baths at 4 C and 60 degrees C for 1 min
      each for up to 50000 thermal cycles before shear mode testing at a crosshead
      speed of 0.5 mm/min. All of the primers examined, except MOBL, improved the shear
      bond strength between the resin and Co-Cr alloy compared with nonprimed specimens
      prior to thermal cycling. Regardless of which primer was used, the shear bond
      strength significantly differed between thermal cycles 0 and 50000. However,
      after 50000 thermal cycles, the bond strengths of resin to Co-Cr alloy primed
      with COP or MPII were significantly greater than those of specimens primed with
      AB, MOBL or MRB and non-primed controls. This study indicated that COP and MPII
      are effective primers to obtain higher bond strength between resin and Co-Cr
      alloy.

PMID- 10397180
TI  - The study of jaw reflexes evoked by electrical stimulation of the lip: the
      importance of stimulus intensity and polarity.
AB  - The aim of this study was to investigate whether reported differences in the
      patterns of jaw reflexes which can be evoked by electrical stimulation of the lip
      might be related to the intensity or polarity of the stimuli. Constant-current
      stimuli were applied through bipolar electrodes clipped across the lower lip of
      14 subjects while EMG recordings were made from a masseter muscle. During
      stimulation, the subjects sustained a level of masseter activity equivalent to
      10% of their maximum. The stimuli were applied as multiples of sensory threshold.
      The EMGs were analysed following rectification, averaging and smoothing. A
      sequence of inhibitory, excitatory, inhibitory and excitatory responses could be
      produced in the muscle by both polarities of stimuli. The latencies of these four
      responses were generally in the ranges 10-20, 25-40, 40-55 and 80-100 ms,
      respectively. These latencies, particularly for the last two responses, tended to
      decrease at higher intensities of stimulation. The threshold for the long-latency
      inhibition was significantly lower than that for the short-latency inhibition
      when the cathode was outside the mouth but not when it was inside the mouth. In
      addition, the long-latency excitation had the lowest threshold of the four
      responses regardless of stimulus polarity. Since nerves are excited particularly
      around a cathode, we interpret these results as showing that stimulation of
      nerves supplying the skin outside the mouth evokes predominately long-latency jaw
      reflexes whereas shorter latency responses can be evoked by stimulating nerves
      supplying oral mucosa. Furthermore, long latency excitatory reflexes seem to be
      the most easily evoked by stimulation of the lip.

PMID- 10397181
TI  - Comparison of the retentive and photoelastic properties of two prefabricated
      endodontic post systems.
AB  - This in vitro study compared the retention and photoelastic stress patterns from
      two loading conditions, vertical (133.2 N, 30 pounds) and oblique at a 26 degrees
      angle (133.2 N, 30 pounds) for two prefabricated post systems. The post studied
      were: (1) Flexi-Post (a split-shank threaded post) and (2) C-Post (a carbon fibre
      bound in an epoxy resin, passive double taper tier post). Two groups with 10
      specimens per group were subjected to retentive forces with a universal testing
      machine (MTS 810 Material Testing Machine). In addition, two photoelastic test
      blocks were prepared with simulated root canals for each post studied. After
      cementation the photoelastic blocks were photographed before vertical and oblique
      loading and after loading. One-way analysis of variance (ANOVA) for retention
      data revealed a highly significant difference (P<0.0001) between groups. The
      Flexi-Post had a statistically higher mean retention force of 1180.6 N (265.9
      pounds), while the C-Post had a mean of 171.8 N (38.7 pounds). Photoelastic
      analysis indicated minimal stresses for both the Flexi-Post and C-Post in the
      unloaded state. The C-Post showed asymmetrical apically stress patterns, while
      loaded in both states. The multi-tiered system of the Flexi-Post clearly
      distributes stress symmetrically, while the C-Post distributes stresses
      asymmetrically. The symmetric, even stresses and statistically higher retentive
      strength for Flexi-Post are more favourable than the asymmetric, uneven stresses
      and relatively low retentive strength for the C-Post.

PMID- 10397182
TI  - Polymetallism and osseointegration in oral implantology: pilot study on primate.
AB  - In oral implantology, successful results in osseointegration are obtained in the
      medium term (6-12 months) with commercially pure titanium implants. However,
      current superstructures can be of a different nature (precious metal or titanium)
      and of different manufacture (cast or machine-produced). Polymetallism between
      the implant and the superstructure may lead to conditions of galvanic corrosion,
      and influence osseointegration. The study described establishes, on the one hand,
      the procedures of animal experimentation in primates and on the other, the
      techniques of analysis of histological sections. The first technique of analysis
      is based on histomorphometry and leads to the definition of an osseointegration
      index. The second technique of analysis consists of X spectrometry by dispersion
      of energy which enables a spectral analysis of selected points below the crestal
      neck of the implant (vulnerable area in the case of corrosive attack) to be
      obtained. It is noted that after 6months, two of which were of activation,
      osseointegration did not vary according to the nature of the superstructure
      (precious alloy or titanium). After 2 months, the presence of a precious alloy
      superstructure lead to titanium migration towards the area around the cervical
      region of the implant (10-50 microm). This phenomenon did not occur with a
      titanium implant. It can therefore be presumed that polymetallism leads to
      detectable corrosion after 2 months but without apparent modification of
      osseointegration.

PMID- 10397183
TI  - Electromyographic study of the activity of jaw depressor muscles before
      initiation of opening movements.
AB  - The authors attempted to clarify the primary factors affecting the timing of the
      initial electromyographic discharges in the jaw depressor muscles (EMG onset).
      The changes in EMG onset in the inferior head of the lateral pterygoid (Lpt) and
      the anterior belly of the digastric muscles (Dig) were measured by varying
      duration of the open-close movement or occlusal force during the open-close
      clench cycle (OCC). EMG onset tended to precede the beginning of the opening
      movement during OCC. The duration of opening and closing phase and the duration
      of occluding phase showed no significant correlation with the time-lag between
      EMG onset and the beginning of the opening movement (onset time). The mean EMG
      activity of the masseter muscle (Mm), corresponding to the occlusal force, showed
      a highly significant correlation with the onset time. The maximal opening
      velocity was highly correlated with the mean EMG activity of the jaw depressors
      before jaw opening. In conclusion, it was found that occlusal force is a major
      factor in EMG onset in the jaw depressors. It is suggested that smooth opening
      needs tooth contact with some degree of occlusal force.

PMID- 10397184
TI  - The effect of head posture on direction and stability of mandibular closing
      movement.
AB  - This study investigated the effects of head posture on mandibular habitual
      closing movement. Ten healthy subjects were examined. Head posture was evaluated
      as a sagittally viewed inclination of the head, and was changed from 25 degrees
      forward bending up to 30 degrees backward bending in 5 degrees increments. The
      mandibular opening and closing movement was measured at each head posture. As the
      head bended forward, the closing path approached the maximum intercuspal position
      from the anterior region, and as the head was bent backward, the closing path
      approached the maximum intercuspal position from the posterior region. However,
      the limit of this relationship was found when the head was bent forward to some
      extent. There was also a correlation between the head posture and the stability
      of the closing movement. The forward bending of the head decreased the stability
      of the closing path, and conversely, the backward bending increased the stability
      of the closing path. It was concluded that the head posture affects the direction
      and stability of the mandibular closing movement. Possible underlying reasons for
      these findings are masticatory muscle activity and the tension and resistance of
      inframandibular soft tissue varying with the change of head posture.

PMID- 10397185
TI  - Effect of fluorosis on etching of human enamel.
AB  - To investigate the effect of fluorosis on the pattern and depth of etch of human
      enamel, 420 enamel specimens classified according to the Thylstrup and Fejerskov
      index (TFI) were etched with 37% phosphoric acid for varying times. The mean
      depths of etch for mildly fluorosed enamel (TFI = 1-3) were generally dependent
      on etching time (r = 0.55-0.76), and were not significantly different from the
      depth obtained for non-fluorosed (TFI = 0) specimens. The enamel specimens with
      more severe fluorosis (TF = 4) required longer etching time which showed little
      correlation with the mean depth of etch (r = 0.15-0.16). Furthermore, the etched
      specimens showed typical enamel etching patterns, independent of the severity of
      fluorosis. When the specimens with TFI = 4 were etched for 45 s, the subsurface
      organic network was evident, but this disappeared and typical etching patterns
      could be seen again when etching time was increased to 75-90 s. It is therefore
      concluded that the diagnosis of the severity of fluorosis must first be made
      whenever etching of fluorosed enamel is contemplated.

PMID- 10397186
TI  - Investigation of microleakage between titanium and porcelain.
AB  - Porcelain was applied to 30 titanium and 30 Remanium CS disc-shaped frameworks in
      order to investigate the microleakage. Each group was divided to three subgroups
      each containing 10 specimens and representing the different firing cycles (10
      specimens for opaque + dentine; 10 specimens for opaque + dentine + enamel; and
      10 specimens for opaque + dentine + enamel porcelain + glaze application). All
      the specimens were stored in 37 degrees C distilled water for 2 weeks and
      subjected to 100 thermocycles between 5 and 55 degrees C with 30 s dwell time.
      The specimens were then stored in 5% basic fuchsin dye for 2 days. The washed,
      rinsed and air dried specimens were embedded in autopolymerizing resin and
      sectioned diametrically. The stereoptical investigations were performed by three
      independent investigators. The data were analysed by the Mann-Whitney U-test. The
      statistical analysis revealed that the different number of firings does not
      affect the amount of microleakage. However, it should be emphasized that the use
      of titanium would be beneficial regarding the relatively lower values obtained
      from the titanium-porcelain group.

PMID- 10397187
TI  - A mouth opening index for patients with temporomandibular disorders.
AB  - Limitation of mouth opening is an important sign of temporomandibular disorders.
      It is usually measured linearly from the incisal edge of the maxillary incisors
      to the incisal edge of the mandibular incisors. This measurement has been
      queried. A new measure of mouth opening, the opening index is suggested. It was
      shown that the mean opening index differs for groups of patients with a myogenous
      or arthrogenous temporomandibular joint problem.

PMID- 10397188
TI  - An in vitro investigation into the wear effects of glazed, unglazed and
      refinished dental porcelain on an opposing material.
AB  - A machine designed to simulate the physical parameters of masticatory function
      was used to investigate the amount of wear produced on perspex plates opposing
      discs of porcelain which were glazed, unglazed or finished to varying stages of a
      polishing sequence recommended with a proprietary finishing kit. The perspex
      specimens were abraded, under water at 37 degrees C for a total of 800000
      contacts using a contact time of 0.2 s, a sliding distance of 15 mm and a
      constant load of 0.19 N/mm2. Assessments of the wear of the perspex were based
      upon depth measurements of the wear track recorded on surfometric tracings.
      Further measurements of the cross-sectional area of the wear track were made
      using an image analysing computer. The investigation confirmed that the best
      finish and least abrasive surface was produced by glazing of porcelain. The
      finish produced by intermediate components of the proprietary finishing kit did
      not reduce the abrasiveness of the porcelain surface. It was necessary to
      complete the polishing sequence with diamond paste to achieve a surface which
      approached the wear characteristics of glazed porcelain. It is recommended that
      any adjusted porcelain restoration should be re-glazed or subjected to a
      finishing sequence which is followed through to a final stage of polishing with a
      diamond paste.

PMID- 10397189
TI  - Preventing intra-abdominal candidiasis in surgical patients.

PMID- 10397190
TI  - Rapid diagnosis of acute myocardial infarction: is sooner better?

PMID- 10397191
TI  - Multiresistance of gram-negative bacteria in intensive care units: bad news from
      without.

PMID- 10397192
TI  - Pneumatic compression stockings increase the variability of thermodilution
      cardiac output measurements: do they truly affect cardiac output?

PMID- 10397193
TI  - Hypernatremia in the intensive care unit: instant quality--just add water.

PMID- 10397194
TI  - Acquired immunodeficiency syndrome, Pneumocystis carinii pneumonia, and the
      danger of prognostication: apples to apples.

PMID- 10397195
TI  - Do-not-resuscitate orders in the face of patient and family opposition.

PMID- 10397196
TI  - Low systemic vascular resistance after cardiopulmonary bypass: are we any closer
      to understanding the enigma?

PMID- 10397197
TI  - Antimicrobial-bonded catheters: Important aspects.

PMID- 10397198
TI  - Liquid ventilation: more than "PEEP in a bottle"?

PMID- 10397199
TI  - Intraosseous vascular access: from the archives to the ABC.

PMID- 10397200
TI  - Bacterial peritonitis: innovative experimental treatment.

PMID- 10397201
TI  - Divalent cations and bronchodilation in asthma.

PMID- 10397202
TI  - The effect of 21-aminosteroids on endotoxin-induced TNF-alpha release.

PMID- 10397203
TI  - NO good--or not?

PMID- 10397204
TI  - Reversal of fortune? Respiratory failure after bone marrow transplantation.

PMID- 10397205
TI  - Nitric oxide production in neonatal and pediatric sepsis.

PMID- 10397206
TI  - Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk
      surgical patients.
AB  - OBJECTIVE: To evaluate the efficacy and safety of intravenous fluconazole for the
      prevention of intra-abdominal Candida infections in high-risk surgical patients.
      DESIGN: Randomized, prospective, double-blind, placebo-controlled study. SETTING:
      Two university-affiliated hospitals in Switzerland. PATIENTS: Forty-nine surgical
      patients with recurrent gastrointestinal perforations or anastomotic leakages.
      INTERVENTIONS: Prophylaxis with intravenous fluconazole (400 mg per day) or
      placebo continued until resolution of the underlying surgical condition.
      MEASUREMENTS AND MAIN RESULTS: Patients were evaluated daily, and specimens for
      culture were obtained three times per week during prophylaxis. The primary study
      end points were the frequency of and the time to intra-abdominal Candida
      infections. Secondary end points were the frequency of candidiasis (intra
      abdominal and extra-abdominal) and the emergence or persistence of Candida
      colonization. Among patients who were not colonized at study entry, Candida was
      isolated from surveillance cultures during prophylaxis in 15% of the patients in
      the fluconazole group and in 62% of the patients in the placebo group (relative
      risk, 0.25; 95% confidence interval, 0.07 to 0.96; p = .04). Candida peritonitis
      occurred in one of 23 patients (4%) who received fluconazole and in seven of 20
      patients (35%) who received placebo (relative risk, 0.12; 95% confidence
      interval, 0.02 to 0.93; p = .02). In addition, one catheter-related Candida
      albicans sepsis occurred in a fluconazole-treated patient. Thus, overall,
      candidiasis developed in two fluconazole patients and seven placebo patients
      (relative risk, 0.25; 95% confidence interval, 0.06 to 1.06; p = .06). C.
      albicans accounted for 87% of the Candida species isolated before or during
      prophylaxis, and all C. albicans strains were susceptible to fluconazole.
      Fluconazole was well tolerated, and adverse events occurred at similar
      frequencies in both treatment groups. CONCLUSIONS: Fluconazole prophylaxis
      prevents colonization and invasive intra-abdominal Candida infections in high
      risk surgical patients.

PMID- 10397207
TI  - Evaluation of triage decisions for intensive care admission.
AB  - OBJECTIVE: To assess physician decision-making in triage for intensive care and
      how judgments impact on patient survival. DESIGN: Prospective, descriptive study.
      SETTING: General intensive care unit, university medical center. INTERVENTIONS:
      All patients triaged for admission to a general intensive care unit were studied.
      Information was collected for the patient's age, diagnoses, surgical status,
      admission purpose, Acute Physiology and Chronic Health Evaluation (APACHE) II
      score, and mortality. The number of available beds at the time of triage and
      reasons for refused admission were obtained. MEASUREMENTS AND MAIN RESULTS: Of
      382 patients, 290 were admitted, 92 (24%) were refused admission, and 31 were
      admitted at a later time. Differences between admission diagnoses were found
      between patients admitted or not admitted (p < .001). Patients refused admission
      had higher APACHE II scores (15.6+/-1.5 admitted later and 15.8+/-1.4 never
      admitted) than did admitted patients (12.1+/-.4; p < .001). The frequency of
      admitting patients decreased when the intensive care unit was full (p < .001).
      Multivariate analysis revealed that triage to intensive care correlated with age,
      a full unit, surgical status, and diagnoses. Hospital mortality was lower in
      admitted (14%) than in refused patients (36% admitted later and 46% never
      admitted; p < .01) and in admitted patients with APACHE II scores of 11 to 20 (p
      = .02). The 28-day survival of patients was greater for admitted patients
      compared with patients never admitted (p = .01). CONCLUSIONS: Physicians triage
      patients to intensive care based on the number of beds available, the admission
      diagnosis, severity of disease, age, and operative status. Admitting patients to
      intensive care is associated with a lower mortality rate, especially in patients
      with APACHE scores of 11 to 20.

PMID- 10397208
TI  - Impaired inducibility of heat shock protein 70 in peripheral blood lymphocytes of
      patients with severe sepsis.
AB  - OBJECTIVE: To determine the extent of the potentially protective heat shock
      protein 70 response in peripheral blood lymphocytes of patients with severe
      sepsis after ex vivo lipopolysaccharide stimulation. DESIGN: Entry study of
      consecutive patients with severe sepsis, those who were critically ill or
      nonseptic after major surgery, and healthy blood donors. SETTING: Surgical
      intensive care unit in a university hospital. PATIENTS: Ten patients with
      diagnoses of severe sepsis; ten critically ill, nonseptic patients after major
      surgery; and ten healthy blood donors. INTERVENTIONS: None. MEASUREMENTS AND MAIN
      RESULTS: We investigated the ex vivo endotoxin-inducible expression of heat shock
      protein 70 in peripheral blood lymphocytes of patients with severe sepsis by
      means of flow cytometry. Only negligible amounts of inducible intracellular heat
      shock protein 70 accumulation (<4.2% of lymphocytes) could be detected in
      peripheral blood lymphocytes without lipopolysaccharide stimulation. The
      proportion of cells accumulating heat shock protein 70 after treatment with
      lipopolysaccharide was distinctly lower in patients with severe sepsis (p < .05)
      than in critically ill, nonseptic patients after major surgery and healthy blood
      donors (38.3+/-3.3%, 82.2+/-4.5%, and 70.9+/-3.9%, respectively; mean +/- SEM; n
      = 10). Patients with clinical signs of recovery from severe sepsis showed an
      increase in heat shock protein 70 expression. CONCLUSIONS: Inducibility of ex
      vivo heat shock protein 70 was impaired in peripheral blood lymphocytes of
      patients with severe sepsis. The impaired expression of the potentially
      protective heat shock protein 70 may contribute in vivo to immune dysfunction,
      because intact functioning of T and B lymphocyte responses is of central
      importance in resisting infection in severe sepsis. Monitoring of inducible heat
      shock protein 70 in peripheral blood lymphocytes may contribute to the evaluation
      of the immune consequences of severe sepsis.

PMID- 10397209
TI  - Assessment of a creatine kinase-MB/myoglobin kit in the prehospital setting in
      patients presenting with acute nontraumatic chest pain: the "Shahal" experience.
AB  - OBJECTIVES: To evaluate the usefulness of a novel qualitative, rapid, bedside
      immunoassay device for the detection of elevated creatine kinase MBmass (CK-MB)
      and myoglobin as a supportive tool for decision-making by the physician who is
      evaluating patients who present with chest pain. DESIGN: Prospective study.
      SETTING: Prehospital (mobile intensive care units). PATIENTS: Three hundred
      twenty-eight consecutive patients, age 71+/-13 yrs (64% males), who were admitted
      to the hospital via Shahal's mobile intensive care units. INTERVENTION: During a
      6-month period, based on clinical presentations and electrocardiograms, the
      mobile's physicians classified patients into groups of high or low probability of
      having an acute myocardial infarction and, thereafter, used a rapid bedside
      STATus kit (Spectral Diagnostics, Toronto, Ontario, Canada) to determine blood
      creatine kinase/MB and myoglobin. MEASUREMENTS AND MAIN RESULTS: Myocardial
      infarction was confirmed in 59 (18%) patients. If measured >2 hrs after onset,
      diagnostic sensitivities, specificities, and positive and negative predictive
      values for physicians were as follows: 71%, 90%, 46%, and 96%, respectively,
      compared with 100%, 85%, 44%, and 100%, respectively, if assessed by the kit.
      CONCLUSIONS: If used 2 to 12 hrs from the onset of symptoms, this device is a
      convenient diagnostic aid to prevent a misdiagnosis of acute myocardial
      infarction or unnecessary hospitalization to exclude infarction. This tool may be
      a promising cost-cutting factor in these days of escalating expenses and
      dwindling resources.

PMID- 10397210
TI  - Colonization with broad-spectrum cephalosporin-resistant gram-negative bacilli in
      intensive care units during a nonoutbreak period: prevalence, risk factors, and
      rate of infection.
AB  - OBJECTIVE: To define the epidemiology of broad-spectrum cephalosporin-resistant
      gram-negative bacilli in intensive care units (ICUs) during a nonoutbreak period,
      including the prevalence, the risk factors for colonization, the frequency of
      acquisition, and the rate of infection. DESIGN: Prospective cohort study.
      SETTING: Tertiary care hospital. PATIENTS: Consecutive patients admitted to two
      surgical ICUs. MAIN OUTCOME MEASUREMENTS: Serial patient surveillance cultures
      screened for ceftazidime (CAZ) resistance, antibiotic and hospital exposure, and
      infections. RESULTS: Of the 333 patients enrolled, 60 (18%) were colonized with
      CAZ-resistant gram-negative bacilli (CAZ-RGN) at admission. Clinical cultures
      detected CAZ-RGN in only 5% (3/60) of these patients. By using logistic
      regression, CAZ-RGN colonization was associated with duration of exposure to
      cefazolin (odds ratio, 10.3; p < or = .006) and to broad-spectrum
      cephalosporins/penicillins (odds ratio, 2; p < or = .03), Acute Physiology and
      Chronic Health Evaluation III score (odds ratio, 1.2; p < or = .008), and
      previous hospitalization (odds ratio, 3.1; p < or = .006). Of the 100 patients
      who remained in the surgical ICU for > or = 3 days, 26% acquired a CAZ-RGN. Of
      the 14 infections caused by CAZ-RGN, 11 (79%) were attributable to the same
      species present in surveillance cultures at admission to the surgical ICU.
      CONCLUSIONS: Colonization with CAZ-RGN was common and was usually not recognized
      by clinical cultures. Most patients colonized or infected with CAZ-RGN had
      positive surveillance cultures at the time of admission to the surgical ICU,
      suggesting that acquisition frequently occurred in other wards and institutions.
      Patients exposed to first-generation cephalosporins, as well as broad-spectrum
      cephalosporins/penicillins, were at high risk of colonization with CAZ-RGN.
      Empirical treatment of nosocomial gram-negative infections with broad-spectrum
      cephalosporins, especially in the critically ill patient, should be reconsidered.

PMID- 10397211
TI  - Influence of lower limb pneumatic compression on pulmonary artery temperature:
      effect on cardiac output measurements.
AB  - OBJECTIVES: To characterize the decreases in pulmonary artery temperature that
      coincide with the inflation cycle of pneumatic calf compression stockings and to
      examine their effects on the thermodilution measurement of cardiac output.
      DESIGN: Three-part observational study. SETTING: University hospital surgical
      intensive care unit. PATIENTS: Postoperative patients with indwelling pulmonary
      artery catheters. INTERVENTION: Thermodilution cardiac output measurements with
      and without pneumatic calf compression. MEASUREMENTS AND MAIN RESULTS: Phase 1 (n
      = 18) examined the effects of pneumatic compression on pulmonary artery
      temperature. There was no effect on pulmonary artery temperature (device off,
      37.468+/-0.008 degrees C; device on, 37.458+/-0.014 degrees C), but the
      difference between the maximum and minimum pulmonary artery temperatures was
      increased (off, 0.031+/-0.006 degrees C; on, 0.055+/-0.012 degrees C [p < .001]).
      Phase 2 (n = 12) found that the mean thermodilution cardiac output with 10 mL of
      cold (0-5 degrees C) injectate was unchanged by pneumatic compression (off,
      7.00+/-2.28 L/min; on, 6.89+/-2.22 L/min). However, when the compression devices
      were operating, the variability between the individual measurements was
      increased, as reflected by larger coefficients of variation (off, 3.19+/-1.96;
      on, 8.72+/-6.56 [p < .02]). Similar results were obtained during phase 3 (n = 5),
      when cardiac output was measured with room temperature Injectate. CONCLUSIONS:
      Intermittent pneumatic calf compression increased lower limb venous return,
      causing acute but transient decreases in pulmonary artery blood temperature. This
      did not affect the accuracy of thermodilution cardiac output measurements that
      were made using 10 mL of either cold or room temperature injectate.

PMID- 10397212
TI  - N-Acetylcysteine treatment to prevent the progression of multisystem organ
      failure: a prospective, randomized, placebo-controlled study.
AB  - OBJECTIVES: To investigate whether prolonged infusion of N-acetylcysteine (NAC)
      that is commenced immediately after admission to the intensive care unit could
      ameliorate the development or progression of multisystem organ failure and
      improve mortality. DESIGN: Prospective, randomized, double-blinded clinical
      trial. SETTING: Six-bed intensive care unit in a teaching hospital. PATIENTS: Of
      the 100 patients recruited (14 withdrew), 86 patients were studied.
      INTERVENTIONS: After randomization, the treatment group (n = 41) received NAC
      (150 mg/kg bolus followed by a continuous infusion of 12 mg/kg/hr) and the
      placebo group (n = 45) received 5% dextrose, from a minimum of 3 days up to a
      maximum of 5 days. MEASUREMENTS AND MAIN RESULTS: There was no statistically
      significant difference between the two groups regarding outcome as indicated by
      mortality and the required days of inotropic support, mechanical ventilation, and
      intensive care. The time interval between hospital and intensive care unit
      admission showed great variability, with a median of 24 hrs for the whole sample.
      By splitting the groups with this median value, the effect of NAC was examined on
      patients admitted within 24 hrs and after 24 hrs of arrival to the hospital.
      There was a nonsignificant difference in mortality in favor of NAC. Patients
      admitted after 24 hrs of hospital admission had a significantly worse mortality
      in the NAC-treated group (61% vs. 32% for controls; p = .05). CONCLUSIONS: We
      found a nonsignificant difference in outcome between NAC and placebo-treated
      patients. Our results suggest that the initiation of NAC treatment >24 hrs after
      hospital admission may potentially be harmful, and further studies should be
      undertaken to investigate the clinical use of the early application of NAC in
      critically ill patients.

PMID- 10397213
TI  - Hypernatremia in the intensive care unit: an indicator of quality of care?
AB  - OBJECTIVE: To assess the frequency of hypernatremia in patients who were admitted
      to an intensive care unit (ICU) and to determine the correlation of hypernatremia
      with the clinical outcomes, durations of the patients' stays in the ICU, and
      other clinical variables. DESIGN: Retrospective survey. SETTING: University
      teaching hospital. PATIENTS: All patients (total, 389) who were admitted to the
      medical ICU of the department of internal medicine during 1 yr. MEASUREMENTS: The
      database of our hospital's mainframe computer was searched for sodium values > or
      = 150 mmol/L that were registered in the year 1995. These data were then matched
      with the registration numbers of all patients who were admitted to our medical
      ICU between January 1 and December 31, 1995. In this way, we identified all
      patients in whom hypernatremia was present at admission or those who developed
      hypernatremia in the course of their stay in our ICU. The prevalence and duration
      of hypernatremia (defined as a serum sodium concentration of > or = 150 mmol/L or
      more) were determined; the correlation of hypernatremia with clinical outcome,
      duration of ICU stay, Acute Physiology and Chronic Health Evaluation II scores,
      and other clinical variables were evaluated; and changes in fluid administration
      in response to hypernatremia and fluid regimens in the period preceding
      hypernatremia were examined. MAIN RESULTS: Of a total of 389 patients who were
      admitted in 1995, hypernatremia was present at admission in 34 patients (8.9%).
      The average duration of hypernatremia in these patients was 16.2 (range, 4-56)
      hrs. A total of 22 patients (5.7%) developed hypernatremia in the course of their
      stay in the ICU. The average duration of hypernatremia in this group was 34.7
      (range, 4-89) hrs. Moderately elevated levels of sodium had been detected in most
      of these patients (n = 21) in the days before the development of severe
      hypernatremia; however, adjustments in fluid infusion aimed at preventing the
      occurrence of hypernatremia were either lacking (n = 7) or inadequate (n = 11).
      Hospital-acquired hypernatremia vs. hypernatremia present at admission to the ICU
      was associated with a higher mortality rate (32% vs. 20.3%, respectively; p <
      .01). CONCLUSIONS: Despite frequent measurement of sodium levels in patients in
      the ICU, hypernatremia is a relatively common occurrence. Initial treatment of
      hypernatremia is often inadequate, and sometimes treatment is delayed. The
      development of hypernatremia is associated with adverse outcomes for patients
      developing hypernatremia in the ICU. Hypernatremia could potentially be used as
      an indicator of quality of care in the medical ICU.

PMID- 10397214
TI  - Pneumocystis carinii pneumonia requiring intensive care management: survival and
      prognostic study in 110 patients with human immunodeficiency virus.
AB  - OBJECTIVE: To perform a descriptive study of patients with acute respiratory
      failure secondary to acquired immunodeficiency syndrome-related Pneumocystis
      carinii pneumonia and to identify variables that are predictive of death within 3
      months. DESIGN: Case series study. SETTING: Infectious disease intensive care
      unit (ICU) in a university hospital. PATIENTS: Detailed clinical, laboratory, and
      ventilatory data were collected prospectively within 48 hrs of admission and
      during the ICU stay in 110 consecutive human immunodeficiency virus-infected
      patients requiring ICU management with or without mechanical ventilation for P.
      carinii pneumonia-related acute respiratory failure. MEASUREMENTS AND MAIN
      RESULTS: Continuous positive airway pressure was used initially in 66 (60%)
      patients. Among the 34 patients (31%) who required mechanical ventilation,
      including 12 at admission and 22 after failure of continuous positive airway
      pressure, 76% died. The 3-month mortality rate after ICU admission was estimated
      at 34.6% (95% confidence interval [CI], 25%-44%). The 1-yr survival rate was
      estimated at 47% (95% CI, 36%-58%). With successive multiple logistic regression
      models analyzing the relative prognostic importance of baseline clinical and
      laboratory tests variables, ventilation variables, and events in the ICU, only
      delayed mechanical ventilation after 3 days (odd ratio [OR], 6.7; 95% CI, 1.9
      23.9), duration of mechanical ventilation of > or = 5 days (OR, 2.8; 95% CI, 1.1
      6.9), nosocomial infection (OR, 5.2; 95% CI, 2.1-12.9), and pneumothorax (OR, 5;
      95% CI, 1.7-14.7) were predictive of death within 3 months of ICU admission.
      Among patients with delayed mechanical ventilation on day 3 or later and with a
      pneumothorax associated or not associated with a nosocomial infection, the
      predicted probability of 3-month death was close to 100%. CONCLUSIONS: Our data
      suggest that the most significant predictive factors of death were identifiable
      during the course of P. carinii pneumonia-related acute respiratory failure
      rather than at admission and can help in bedside decisions to withdraw intensive
      care support in such patients.

PMID- 10397215
TI  - Unilateral do-not-attempt-resuscitation orders and ethics consultation: a case
      series.
AB  - OBJECTIVE: To describe the role of an ethics consultation service in unilaterally
      withholding cardiopulmonary resuscitation. DESIGN: Retrospective case series of
      31 ethics consultations regarding unilateral do-not-attempt-resuscitation orders
      between 1992 and 1996. SETTING: A large, urban, academic medical center.
      MEASUREMENTS AND MAIN RESULTS: Patient characteristics, physicians' rationale for
      withholding cardiopulmonary resuscitation, ethics consultants' recommendations,
      and patient outcomes were measured. The consultation service agreed with the
      medical team's intent to withhold cardiopulmonary resuscitation in 25 cases, but
      a unilateral do-not-attempt-resuscitation order was written in only seven of
      these. In 17 cases, the disagreement between the physician and the patient or
      surrogate over code status was resolved in a conference organized by the ethics
      service. CONCLUSIONS: The process of ethics consultation is useful in resolving
      disagreements over withholding cardiopulmonary resuscitation and other treatment
      and can frequently result in a consensus. Hospital policies that permit
      unilateral treatment limitation should be based on a model that is process-based
      and that encourages interdisciplinary participation in decision-making, such as
      that recently proposed by the Houston Task Force.

PMID- 10397216
TI  - Low systemic vascular resistance state in patients undergoing cardiopulmonary
      bypass.
AB  - OBJECTIVE: To determine the prevalence, hemodynamic characteristics, and risk
      factors for the low systemic vascular resistance (SVR) state in patients who have
      undergone cardiopulmonary bypass. DESIGN: Prospective cohort study. SETTING: The
      intensive care unit of a tertiary care hospital. PATIENTS: Seventy-nine
      consecutive patients who underwent coronary artery bypass graft, mitral valve, or
      aortic valve procedures. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Low
      SVR was defined as an indexed systemic vascular resistance (SVRi) of <1800 dyne x
      sec/cm5 x m2 at two consecutive times postoperatively. SVRi, cardiac index, mean
      arterial pressure, temperature, and central venous pressure were recorded before
      bypass and at 0, 1, 2, 4, 8, and 16 hrs after bypass. We recorded age, gender,
      urgency of operation, use of angiotensin-converting enzyme inhibitors and calcium
      channel blockers, ejection fraction, pump time, cross-clamp time, use of
      antifibrinolytics, type of oxygenator, amrinone use, postoperative biochemical
      and hematologic values, medication use, fluid balance, intensive care unit
      admission duration, and hospital admission duration. We assessed the role of
      diabetes mellitus, current smoking, and systemic hypertension. The incidence of
      the low-SVR state was 35 of 79 patients during a 3-month period (44%). At 8 hrs
      postoperatively, the SVRi in low-SVR and non-low-SVR patients was 1594+/-50 (SEM)
      and 2103+/-56 (SEM) dyne x sec/cm5 x m2, respectively (p < .001). In low-SVR
      patients, there was an initial and sustained increase in cardiac index and
      central venous pressure that preceded the decrease in mean arterial pressure. The
      decrease in mean arterial pressure was maximal at 8 hrs postoperatively. Patients
      with low SVR were more likely to have longer cross-clamp times, to be male, and
      to have lower postoperative platelet counts (p < .05 for all). Low-SVR patients
      were less likely to require dobutamine in the first 4 hrs postoperatively.
      CONCLUSIONS: Low SVR, a probable manifestation of systemic inflammatory response
      syndrome, is common in patients after cardiopulmonary bypass. These patients may
      respond better to a vasopressor to restore vascular tone than to volume loading
      to further increase cardiac index.

PMID- 10397217
TI  - The ex vivo antimicrobial activity and colonization rate of two antimicrobial
      bonded central venous catheters.
AB  - OBJECTIVE: Catheter-related sepsis is an important complication associated with
      the use of central venous catheters. Recent studies have suggested that
      antimicrobial-bonded catheters may reduce catheter colonization and catheter
      related sepsis. The aim of this study was to determine the relationship between
      the antimicrobial activity and the colonization rate of two commercially
      available antimicrobial-bonded central venous catheters. DESIGN: Prospective,
      randomized, controlled, nonblinded study. SETTING: Medical intensive care unit of
      a university-affiliated teaching hospital. PATIENTS: One hundred twenty
      consecutive medical intensive care unit patients requiring new central venous
      catheters (fresh stick). INTERVENTIONS: Patients were randomized to receive a) a
      Standard Arrow; b) an ARROWgard; or c) a Cook Bio-Guard Spectrum central venous
      catheter. Central venous catheters were removed when they were no longer required
      or when catheter-related sepsis was suspected. Under aseptic conditions, the
      distal 12 cm of the removed catheters were cut into six 2-cm segments.
      Semiquantitative culture was performed (by roll technique) on the distal segment.
      Colonization was defined as >15 colony-forming units. Using a modified Kirby
      Bauer technique, the zone of inhibition of the remaining five segments was
      determined against the following organisms: methicillin-resistant Staphylococcus
      aureus (MRSA), Staphylococcus epidermidis, Enterococcus faecalis, Acinetobacter
      baumannii, and Candida albicans Catheters that were removed within 24 hrs of
      insertion were excluded from the analysis. MEASUREMENTS AND MAIN RESULTS: Seven
      patients were not assessable. The baseline clinical and demographic
      characteristics were similar among the three groups of patients. Eleven Standard
      Arrow (28%), seven ARROWgard (19%), and four Bio-Guard (11%) catheters were
      colonized (p = .05 for Bio-Guard vs. control). Staphylococci were the most common
      colonizing organisms. Two patients with Standard Arrow catheters (5%) and one
      patient with an ARROWgard catheter (3%) developed catheter-related sepsis.
      Antibiotic-coated catheters significantly inhibited the growth of all test
      organisms except C. albicans (p < or = .05). Zones of inhibition were
      significantly larger for the Bio-Guard compared with the ARROWgard catheter when
      tested against MRSA, S. epidermidis, and E. faecalis (p < or = .002). CONCLUSION:
      The Bio-Guard central venous catheter had greater ex vivo antimicrobial activity
      against MRSA, S. epidermidis, and E. faecalis compared with the ARROWgard
      catheter, and this was associated with a significantly lower rate of catheter
      colonization.

PMID- 10397218
TI  - Quality of life after prolonged intensive care.
AB  - OBJECTIVE: To assess the subjective health status, quality of life, and
      functional ability of patients whose intensive care stay was prolonged and to
      compare their quality of life with that of the general population. DESIGN:
      Inception cohort study. SETTING: Twenty-three-bed multidisciplinary intensive
      care unit (ICU) in a tertiary care center. PATIENTS: A consecutive sample of 718
      patients aged > or = 18 yrs who required intensive care > or = 4 days.
      INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The Nottingham Health Profile
      was used to compare the ICU patients with a random sample (n = 2,595) of the
      general population. The quality of life and functional ability of 368 respondents
      (78.3% of 470 survivors) were assessed at 6 months after ICU admission. The
      length of the ICU stay was 13.6+/-11.8 (median, 9; maximum, 81) days. The quality
      of life and its various dimensions were influenced by the diagnosis for ICU
      admission and age. Although problems in physical mobility and energy were
      prevalent among all patient groups, only a small proportion was dependent on
      others for the management of daily activities. Patients with trauma or
      respiratory failure experienced the most limitations. The quality of life of
      elderly patients and patients who had undergone cardiac surgery was comparable
      with the general population regarding emotional reactions, social isolation, and
      pain. CONCLUSIONS: The quality of life of survivors after a prolonged intensive
      care stay is fairly good, although not comparable with that of the general
      population. The psychosocial aspects of the quality of life are restored more
      rapidly than physical performance.

PMID- 10397219
TI  - Optimizing liquid ventilation as a lung protection strategy for neonatal
      cardiopulmonary bypass: full functional residual capacity dosing is more
      effective than half functional residual capacity dosing.
AB  - OBJECTIVE: To evaluate and compare the protective effects of two different
      perflubron doses on hemodynamics and lung function in a neonatal animal model of
      cardiopulmonary bypass-induced lung injury. DESIGN: Prospective, randomized,
      controlled study. SETTING: Animal laboratory of the Department of Surgery, Duke
      University Medical Center. SUBJECTS: Twenty-one neonatal swine. INTERVENTIONS:
      One-wk-old swine (2.2-3.2 kg) were randomized to receive cardiopulmonary bypass
      with full functional residual capacity perflubron (n = 7), cardiopulmonary bypass
      with half functional residual capacity perflubron (n = 7), or cardiopulmonary
      bypass alone (n = 7). This last group served as control animals, receiving
      cardiopulmonary bypass with conventional ventilation. Liquid lung ventilation
      animals received perflubron via the endotracheal tube at either full functional
      residual capacity (16-20 mL/kg) or half functional residual capacity (10 mL/kg)
      before the initiation of cardiopulmonary bypass. Each animal was placed on
      nonpulsatile cardiopulmonary bypass and cooled to a nasopharyngeal temperature of
      18 degrees C (64.4 degrees F). Low-flow cardiopulmonary bypass (35 mL/kg/min) was
      instituted for 90 mins. The blood flow rate was then returned to 100 mL/kg/min.
      The animals were warmed to 36 degrees C (96.8 degrees F) and separated from
      cardiopulmonary bypass. Data were obtained at 30, 60, and 90 mins after
      separation from cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS:
      Cardiopulmonary bypass without liquid lung ventilation resulted in a significant
      decrease in cardiac output and oxygen delivery and a significant increase in
      pulmonary vascular resistance in the post-bypass period. Full functional residual
      capacity liquid lung ventilation administered before bypass resulted in no change
      in cardiac output and oxygen delivery after bypass. Full functional residual
      capacity liquid lung ventilation resulted in lower pulmonary vascular resistance
      after bypass compared with both control and half functional residual capacity
      liquid lung ventilation animals. CONCLUSIONS: These data suggest that liquid lung
      ventilation dosing at full functional residual capacity before bypass is more
      effective than half functional residual capacity in minimizing the lung injury
      associated with neonatal cardiopulmonary bypass. Full functional residual
      capacity dosing may optimize alveolar distention and lung volume, as well as
      improve oxygen delivery compared with half functional residual capacity dosing.

PMID- 10397220
TI  - Use of intraosseous blood to assess blood chemistries and hemoglobin during
      cardiopulmonary resuscitation with drug infusions.
AB  - OBJECTIVE: To compare intraosseous with central venous blood samples for
      biochemical analyses and hemoglobin levels during cardiopulmonary resuscitation
      (CPR) and during cardiopulmonary resuscitation with infusion of sodium
      bicarbonate, epinephrine, and saline boluses through the intraosseous site.
      DESIGN: Prospective, complete repeated measures study. SETTING: An animal
      laboratory at a university medical center. SUBJECTS: Thirty-two piglets (mean
      weight, 30 [range, 24-35] kg). INTERVENTIONS: Animals were anesthetized,
      instrumented, and subjected to hypoxic cardiac arrest. An intraosseous cannula
      was inserted into the tibia, and animals were randomly assigned to one of five
      groups: heparinized saline (n = 6), epinephrine infusions only (n = 6), saline
      infusions only (n = 6), sodium bicarbonate infusions only (n = 8), and
      epinephrine, saline, and sodium bicarbonate infusions through the same site (n =
      6). CPR (chest compressions and mechanical ventilation) was performed in all
      groups. Simultaneous blood samples were taken from the central venous and
      intraosseous sites before arrest and after 5 and 30 mins of CPR. MEASUREMENTS AND
      MAIN RESULTS: There were no differences (p < .05) in sodium, potassium,
      magnesium, lactate, and calcium values of intraosseous and central venous blood
      at the baseline and during 5 mins of CPR with infusions through the intraosseous
      cannula. At 30 mins, differences were apparent in magnesium, potassium, and
      sodium values between groups when the intraosseous cannula was used for infusions
      as well as sampling. Intraosseous potassium, glucose, and magnesium values were
      lower and sodium values were higher than central venous blood levels. No
      differences were seen at all sampling intervals if small-volume heparinized
      saline was given through the intraosseous site. Hemoglobin values were lower in
      the intraosseous group after 30 mins of CPR and infusions through the
      intraosseous site. After 30 mins of CPR, all hemoglobin values from the
      intraosseous site were <10 g/100 mL. CONCLUSION: Intraosseous and central venous
      blood biochemical and hemoglobin values were similar during hemodynamic stability
      and throughout 30 mins of resuscitation if no drugs were given through the
      intraosseous site. However, differences existed after 30 mins of CPR and
      infusions through the intraosseous site. Laboratory values may be erroneous when
      intraosseous blood is used during periods of resuscitation of >5 mins if drugs
      and fluid boluses have also been infused through the site. For reliable values,
      an intraosseous site for sampling only may be reasonable.

PMID- 10397221
TI  - Efficacy of liposomal antibiotic therapy in a rat infusion model of Escherichia
      coli peritonitis.
AB  - OBJECTIVE: To compare the potential therapeutic effect of liposomal vs. free
      cefoxitin. DESIGN: Randomized, controlled study, using a rat model of
      peritonitis. SETTING: Government research facility. SUBJECTS: Male Sprague-Dawley
      rats. INTERVENTIONS: Rats were infused intraperitoneally with 6.5 x 10(8) colony
      forming units of Escherichia coli over 12 hrs. Animals were then randomized to
      receive intravenous saline, free cefoxitin, liposomal cefoxitin, or plain
      liposomes twice daily until they were killed. MEASUREMENTS AND MAIN RESULTS: Free
      cefoxitin significantly reduced the number of E. coli after 24 hrs compared with
      saline treatment in both liver and spleen. However, liposomal cefoxitin further
      decreased the bacterial content by five-fold to ten-fold in these organs. Minimal
      bactericidal effect was observed in animals injected with plain liposomes.
      Although administration of liposomal cefoxitin for 7 days further reduced
      bacterial counts in liver and spleen, there was no apparent beneficial
      bactericidal effect of free cefoxitin over saline at 7 days. There was
      approximately a ten-fold reduction in bacterial content in the lungs after 24 hrs
      in all three treatments, but no further reduction was observed after 7 days.
      There was no difference in 7-day survival rate in animals treated with plain
      liposomes or saline (45% vs. 39%). Although survival tended to increase with free
      cefoxitin treatment (64%), this outcome was significantly improved with the use
      of liposomal cefoxitin (82%). CONCLUSIONS: Liposomal cefoxitin enhanced bacterial
      killing in liver and spleen in this model of E. coli peritonitis. It also
      improved survival outcome relative to no treatment but not compared with free
      cefoxitin.

PMID- 10397222
TI  - Relaxant effect of magnesium and zinc on histamine-induced bronchoconstriction in
      dogs.
AB  - OBJECTIVE: Magnesium sulfate (MgSO4) has been reported to produce bronchodilation
      in asthmatic patients. In vitro studies have suggested that divalent cations
      inhibit L-type voltage-sensitive calcium ion (Ca2+) channels in cardiac and
      smooth muscles. In this study, we evaluated the in vitro and in vivo effects of
      magnesium ion (Mg2+) and zinc ion (Zn2+) on the airway contracted by histamine.
      SETTING: A university research laboratory. SUBJECTS:  IN VITRO: Tracheal smooth
      muscle from guinea pigs. IN VIVO: Mongrel dogs. MEASUREMENTS AND MAIN RESULTS: 
      IN VITRO STUDY: The tension of isolated guinea pig tracheal strips was measured
      isometrically with a force displacement transducer. The specimen was contracted
      with histamine (10 microM). Then, MgSO4 (n = 6), zinc sulfate (ZnSO4, n = 6), or
      sodium sulfate (Na2SO4, n = 6) was cumulatively added to the organ bath. IN VIVO
      STUDY: The bronchial cross-sectional area of mongrel dogs was measured by a
      direct visualization method demonstrated previously. The dogs were randomly
      assigned to three groups: group Mg (n = 7), group Zn (n = 7), and group Na (n =
      7). Bronchoconstriction was elicited with histamine (10 microg/kg plus 500
      microg/kg/hr iv). Thirty minutes after the start of histamine infusion, 0
      (saline), 1, 10, and 100 micromol/kg ZnSO4 or 1, 10, 100, and 1000 micromol/kg
      MgSO4 or Na2SO4 were administered intravenously in group Zn, Mg, or Na,
      respectively. The bronchial cross-sectional area was assessed before (basal) and
      30 mins after the start of histamine infusion and 5 mins after each dose of
      ZnSO4, MgSO4, or Na2SO4. Arterial blood was also obtained to measure plasma
      levels of epinephrine and norepinephrine by gas chromatography-mass spectrometry.
      All data are expressed as mean +/- SEM. The doses of the divalent cations that
      reversed histamine-induced contraction by 50% were calculated by GraphPad Prism.
      MgSO4 and ZnSO4 (9.38+/-0.28 and 1.84+/-0.30 mM, respectively) relaxed histamine
      contracted tracheal strip in a concentration-dependent manner, whereas Na2SO4 did
      not. Similarly, the in vivo study showed that MgSO4 and ZnSO4 dose-dependently
      reversed histamine-induced bronchoconstriction (potency, ZnSO4 > MgSO4), whereas
      Na2SO4 did not. In groups Mg and Zn, the plasma catecholamine levels also dose
      dependently increased except when 1000 micromol/kg MgSO4 was administered.
      CONCLUSION: Because the divalent cations tested produced a spasmolytic effect on
      the contracted airway, infusion of divalent cations might be effective against
      asthmatic attack. However, high concentrations of these cations produce
      significant toxicity, so dosage will be an important concern in development of
      these agents.

PMID- 10397223
TI  - Inhibition of tumor necrosis factor-alpha release in rat experimental endotoxemia
      by treatment with the 21-aminosteroid U-74389G.
AB  - OBJECTIVE: To determine the effect of the 21-aminosteroid U-74389G on tumor
      necrosis factor (TNF)-alpha release in experimental endotoxemia. DESIGN:
      Prospective, randomized, controlled animal study. SETTING: Experimental
      laboratory. SUBJECTS: Twenty-one male Wistar rats weighing 190+/-40 g.
      INTERVENTIONS: The rats were divided equally into 3 groups: a) control; b)
      endotoxemia (5 mg/kg lipopolysaccharide [LPS] from Escherichia coli 055:B5); and
      c) endotoxemia and U-74389G administration 30 mins before (3 mg/kg) and 60 mins
      after (1.5 mg/kg) endotoxin challenge. MEASUREMENTS AND MAIN RESULTS: At 0, 120,
      and 240 mins, serum levels of TNF-alpha were measured using a specific rat TNF
      alpha ELISA kit. U-74389G-treated endotoxemic animals showed significantly
      reduced TNF-alpha release 120 mins after endotoxin challenge (control, 2.5+/-2.1
      pg/mL; LPS, 4041+/-871 pg/mL; U-74389G, 1627+/-474 pg/mL [p < .05]). Two hundred
      forty minutes after LPS administration, TNF-alpha levels decreased, whereas
      values in the untreated LPS group remained twice as high as those in the U-74389G
      group (LPS, 863+/-182 pg/mL; U-74389G, 369+/-54 pg/mL [p < .05]). CONCLUSIONS:
      The study demonstrated that administration of U-74389G, which has radical
      scavenging and membrane-stabilizing properties, decreased TNF-alpha release
      during endotoxemia. Thus, 21-aminosteroids may lend themselves to evaluation in
      the treatment of septic states.

PMID- 10397224
TI  - Combined effects of inhaled nitric oxide and hyperoxia on pulmonary vascular
      permeability and lung mechanics.
AB  - OBJECTIVE: To determine whether inhaled nitric oxide (NO) may alter pulmonary
      vascular permeability and respiratory function in an in vivo model. DESIGN:
      Prospective, randomized, controlled, experimental study. SETTING: University
      experimental pharmacology laboratory. SUBJECTS: Mechanically ventilated newborn
      piglets, 1 to 2 days old, exposed to 100% oxygen for 76 hrs. INTERVENTIONS: The
      piglets were randomly assigned either to a treatment group receiving 20 ppm
      inhaled NO from the onset of ventilation (n = 5) or to a control group (n = 6)
      receiving no treatment. MEASUREMENTS AND MAIN RESULTS: The main variables studied
      were gas exchange (PaO2/F(IO2) ratio, lung diffusing capacity), respiratory
      mechanics (static compliance of the respiratory system, stat, quasi-static
      hysteresis area, functional residual capacity), and pulmonary vascular
      permeability assessed by simultaneous intravenous administration of iodine-125
      labeled albumin and chromium-51-labeled red blood cells. Extravascular albumin
      space of the lung and dry lung weight were significantly higher in the NO group
      vs. the control group (albumin space, 1.08+/-0.16 vs. 0.70+/-0.26 [SD] mL/kg body
      weight [p < .05]; dry lung weight, 3.20+/-0.34 vs. 2.66+/-0.14 g/kg body weight
      [p < .05]). Moreover, the hysteresis area was higher from 24 hrs of NO exposure.
      Conversely, NO inhalation altered neither the extravascular lung water content
      (12.98+/-2.79 mL/kg body weight in the NO group vs. 12.18+/-2.26 mL/kg body
      weight in the control group [not significant]) nor the main respiratory
      mechanical variables (static compliance, functional residual capacity) and gas
      exchange (lung diffusing capacity, PaO2/F(IO2) ratio). CONCLUSION: These results
      do not support the hypothesis that NO inhalation combined with hyperoxia can
      alter the main lung-function variables in neonates. However, it may induce an
      increase in lung vascular protein leakage. The pathophysiologic consequences of
      this finding remain to be elucidated.

PMID- 10397225
TI  - Does splanchnic ischemia occur in isolated neurotrauma? A prospective
      observational study.
AB  - OBJECTIVE: To characterize the incidence and severity of splanchnic ischemia, as
      defined by gastric tonometry, in patients with isolated severe head injury and to
      examine the relationship between cerebral hemodynamics and splanchnic ischemia.
      DESIGN: Prospective observational study. SETTING: Neurosurgical intensive care
      unit in a tertiary referral center. PATIENTS: Ten patients with severe
      neurotrauma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean
      arterial pressure, intracranial pressure, and gastric mucosal P(CO2) measurements
      were recorded at 15-min intervals. Intramucosal pH was calculated every 3 hrs.
      All patients received stress ulcer prophylaxis. Nine patients received
      noradrenaline infusions to maintain a target cerebral perfusion pressure of 70 mm
      Hg. The mean baseline gastric mucosal P(CO2) and intramucosal pH were 38+/-10
      torr and 7.38+/-0.1 pH units, respectively. Nine patients manifested low
      intramucosal pH during the study period. Gastric mucosal P(CO2) values ranged
      from 36 to 132 torr. Intramucosal pH measurements ranged from 6.9 to 7.47. The
      mucosal gap ranged from -12 to +93 torr (mean +/- SD, 17+/-17 torr). The pH gap
      ranged from -0.1 to +0.54 pH units (mean +/- SD, 0.14+/-0.11 pH units). There was
      no statistically significant relationship between cerebral hemodynamics, the use
      of inotropes, and gastric mucosal P(CO2), or intramucosal pH. CONCLUSIONS:
      Splanchnic ischemia (intramucosal pH, <7.3) occurs commonly in isolated
      neurotrauma, with a statistically nonsignificant trend toward development of
      mucosal ischemia with decreased cerebral perfusion.

PMID- 10397226
TI  - Prognosis of pediatric bone marrow transplant recipients requiring mechanical
      ventilation.
AB  - OBJECTIVES: To assess the prognosis of pediatric bone marrow transplant
      recipients requiring mechanical ventilation and to identify risk factors for
      mortality. DESIGN: Retrospective chart review. SETTING: Pediatric intensive care
      unit (PICU), tertiary care center. PATIENTS: Inclusion criteria were endotracheal
      intubation and mechanical ventilation after bone marrow transplantation; patients
      with perioperative ventilation were excluded. Outcome measures were extubation,
      PICU discharge, and 6-month survival. The 39 patients who met the inclusion
      criteria were ventilated on 41 occasions. INTERVENTIONS: None. MEASUREMENTS AND
      MAIN RESULTS: Overall survival rate to PICU discharge was 44% (17 of 39
      patients). Six months after PICU discharge, 14 of these children were still
      alive, for a medium-term survival rate of 36%. Preexisting conditions (primary
      disease, bone marrow engraftment, or graft-vs.-host disease) had no significant
      effect on survival. Multiple organ failure, especially pulmonary failure and
      neurologic deterioration, were significant determinants of patient survival.
      CONCLUSIONS: The observed prognosis is improved over previous reports. Early
      initiation of aggressive intensive care treatment is warranted in this patient
      group. Decisions regarding intensity of treatment must be based on aspects of the
      acute illness rather than on the primary conditions.

PMID- 10397228
TI  - Accuracy of methemoglobin measurements: comparison of six different commercial
      devices and one manual method.
AB  - OBJECTIVE: During nitric oxide inhalation, methemoglobinemia needs to be
      monitored. We compared six commercially available instruments and one manual
      method for methemoglobin measurements. In addition, we studied whether and to
      what degree methylene blue interferes with methemoglobin measurements. DESIGN: In
      vitro methodologic study. SETTING: Research laboratory in a university hospital.
      PATIENTS: Five healthy volunteers from whom red blood cells were obtained.
      INTERVENTIONS: Methemoglobinemia was generated in a red blood cell suspension by
      nitric oxide; methemoglobin was measured with six commercial instruments and one
      manual photometric method to calculate variation coefficients and to determine
      the differences between the devices. Methemoglobin was measured with and without
      the addition of methylene blue with two instruments. Measurements were performed
      immediately after the addition of methylene blue. MEASUREMENTS AND MAIN RESULTS:
      All six commercially available instruments had variation coefficients of <0.1 at
      methemoglobin concentrations of 5%, whereas the manual photometric method did not
      reach a variation coefficient of <0.1 at 8% of methemoglobin. Apart from two
      devices that measured slightly but significantly higher methemoglobin levels, all
      instruments measured similar values of methemoglobin when the same samples were
      determined simultaneously. Higher concentrations of methylene blue (10, 40, 100
      microM) reduced substantially the apparent concentrations of methemoglobin.
      Interference by methylene blue was most pronounced at low methemoglobin levels.
      CONCLUSIONS: With some limitations, all commercial instruments that were tested
      performed adequately for the monitoring of methemoglobinemia. Methylene blue
      interferes with the methemoglobin measurements in a dose-dependent manner.

PMID- 10397227
TI  - Nitric oxide production in meningococcal disease is directly related to disease
      severity.
AB  - OBJECTIVES: Meningococcal disease is a homogeneous and well-characterized form of
      sepsis. Cardiovascular collapse is prominent in severe meningococcal disease.
      Nitric oxide overproduction may be a mediator of cardiovascular collapse. We
      relate the level of nitric oxide metabolites, nitrates and nitrites, to disease
      severity in meningococcal disease. DESIGN: Prospective, nonrandomized study.
      SETTING: Tertiary referral pediatric intensive care unit. PATIENTS: Children
      admitted with a clinical diagnosis of meningococcal disease. INTERVENTIONS: Blood
      was sampled from children with meningococcal disease. Disease severity was scored
      using the Glasgow meningococcal septicemia prognostic score and pediatric risk of
      mortality score. Plasma nitrates and nitrites were measured in stored plasma
      using the Greiss reaction after conversion of all the nitrate to nitrite.
      MEASUREMENTS AND MAIN RESULTS: Twenty-two children were studied. In 19, the final
      diagnosis was meningococcal disease. Of the 19 children with meningococcal
      disease, 7 had a Glasgow meningococcal septicemia prognostic score of <8 (mild)
      and 12 had a Glasgow meningococcal septicemia prognostic score > or = 8 (severe).
      Three children died, all of these being in the severely affected group. Higher
      levels of nitrates and nitrites were seen in the more severely affected children
      (median admission nitrates and nitrites, 27.5 vs. 59.7 nmol/mL; p = 0.063; median
      peak nitrates and nitrites, 49.9 vs. 114 nmol/mL; p = .01) or those with an
      increased predicted mortality using pediatric risk of mortality (Spearman's p
      0.742; p = .0003). CONCLUSIONS: Higher levels of nitrates and nitrites are seen
      in sicker children with meningococcal disease.

PMID- 10397229
TI  - How to use the results of an economic evaluation.
AB  - BACKGROUND: Given the high costs of delivering care to critically ill patients,
      practitioners and policymakers are beginning to scrutinize the costs and outcomes
      associated with intensive care. Health economics is a discipline concerned with
      determining the best way of using resources to maximize the health of the
      community. This involves addressing questions such as which procedure, test,
      therapy, or program should be provided, and to whom, given available resources.
      PURPOSE: The purpose of this article is to review general economic principles
      that will help intensivists to better interpret published economic evaluations.
      DATA SOURCES: Selected articles from the health economics and critical care
      literature. RESULTS: In this article, we use an economic evaluation that examines
      sedation strategies in critically ill patients. We discuss how learning to
      critically appraise an economic evaluation is only part of the task for end
      users. Determining whether and how to apply the results of economic evaluations
      to local settings presents bigger challenges and remains largely a matter of
      judgment. CONCLUSIONS: Economic evaluations use analytic techniques to
      systematically consider all possible costs and consequences of clinical actions.
      Although they should never form the sole basis for clinical decisions for
      individual patients, economic evaluations offer potentially useful information at
      different levels of decision-making.

PMID- 10397230
TI  - A meta-analysis of three decades of validating thoracic impedance cardiography.
AB  - OBJECTIVE: To provide a meta-analysis of current literature concerning the
      validation of thoracic impedance cardiography (TIC) and to explain the variations
      in the reported results from the differences in the studies. DATA SOURCES: A
      computer-assisted search of English-language, German, and Dutch literature was
      performed for the period January 1966 to April 1997. Moreover, references from
      review articles were obtained. STUDY SELECTION: A total of 154 studies comparing
      measurements of cardiac output or related variables obtained from TIC and a
      reference method were analyzed. DATA EXTRACTION: Articles were classified by
      differences in TIC methodology, reference method, and subject characteristics.
      Fisher's Zf transformed correlation coefficients were used to compare results.
      Data were pooled using the random-effects method. DATA SYNTHESIS: An overall
      pooled r2 value of .67 (95% confidence interval, 0.64-0.71) was found. However,
      the correlation was higher in repeated-measurement designs than in single
      measurement designs (r2 = .53; 95% confidence interval, 0.43-0.62). Further
      research using analysis of variance revealed a significant influence of the
      reference method and the subject characteristics on the correlation coefficient.
      The correlation was significantly better in animals than in cardiac patients.
      Subgroup analysis revealed that TIC correlated significantly better to the
      indirect Fick method than to echocardiography in healthy subjects. No significant
      influence of the applied TIC methodology was found. DISCUSSION: The overall r2
      value of .67 indicates that TIC might be useful for trend analysis of different
      groups of patients. However, for diagnostic interpretation, a r2 value of .53
      might not meet the required accuracy of the study. Great care should be taken
      when TIC is applied to the cardiac patient. However, because the applied
      reference method was of significant influence, differences between TIC and the
      reference method are incorrectly attributed to errors in TIC alone.

PMID- 10397231
TI  - Erythema nodosum after smoke inhalation-induced bronchiolitis obliterans
      organizing pneumonia.
AB  - Bronchiolitis obliterans organizing pneumonia and erythema nodosum are
      immunologic diseases that have not been reported to occur together. We report the
      case of a lady who developed bronchiolitis obliterans organizing pneumonia and
      erythema nodosum simultaneously, several weeks after smoke inhalation in a house
      fire.

PMID- 10397232
TI  - Efficacy of antibiotic-coated central venous catheters.

PMID- 10397233
TI  - Predicting body water changes with bioimpedance using equations derived from
      mixture theory.

PMID- 10397234
TI  - Iliac venous pressure predicts central venous pressure in spontaneously breathing
      patients.

PMID- 10397235
TI  - Primary surfactant deficiency.

PMID- 10397237
TI  - Mammaglobin expression in primary, metastatic, and occult breast cancer.
AB  - The mammaglobin gene encodes a novel, breast cancer-associated glycoprotein. In
      this study, we have evaluated the frequency with which mammaglobin expression can
      be detected in primary and metastatic breast tumors and in breast tumor cells
      present in the peripheral circulation. Of 100 primary human breast tumors
      examined, 81 were strongly immunopositive for mammaglobin protein. Staining was
      independent of tumor grade and histological type. Ten of 11 lymph nodes from
      patients with metastatic breast cancer contained detectable mammaglobin mRNA,
      whereas mammaglobin expression in uninvolved lymph nodes was undetectable. Using
      a nested reverse transcription-PCR assay, mammaglobin mRNA was also detected in 9
      of 15 products (60%) used for autologous stem cell transplant. These results
      suggest that larger clinical studies are warranted to investigate the full
      clinical utility of mammaglobin as a tool for breast cancer patient management.

PMID- 10397236
TI  - Apoptosis induced by overexpression of hMSH2 or hMLH1.
AB  - Mutations of the mismatch repair genes hMSH2 and hMLH1 have been found in a high
      proportion of individuals with hereditary nonpolyposis colon cancer (HNPCC),
      establishing the link between mismatch repair and cancer. Tumor cell lines that
      are deficient in mismatch repair develop a mutator phenotype that appears to
      drive the accumulation of mutations required for tumor development. However,
      mutations of other mismatch repair genes such as hPMS2 can lead to a mutator
      phenotype, although inherited mutations of these genes are rare in HNPCC
      families. Here, we show that overexpression of hMSH2 or hMLH1 but not of hMSH3,
      hMSH6, or hPMS2 induces apoptosis in either repair-proficient or -deficient
      cells. Furthermore, primary mouse embryo fibroblasts derived from Msh2-deficient
      mice lose their ability to undergo apoptosis after treatment with N-methyl-N'
      nitro-N-nitrosoguanidine. These results suggest that the mismatch repair proteins
      hMSH2 and hMLH1 may be components of a pathway that influences apoptosis. We
      consider the possibility that loss of apoptosis as a result of hMSH2 or hMLH1
      deficiency may be an additional factor in cancer predisposition in HNPCC.

PMID- 10397238
TI  - Allelotype of posterior uveal melanoma: implications for a bifurcated tumor
      progression pathway.
AB  - To further elucidate the somatic genetic alterations leading to acquired
      choroidal and ciliochoroidal melanoma, we screened every autosomal arm and the X
      chromosome of 50 primary posterior melanomas (31 choroidal tumors and 19
      ciliochoroidal tumors). A minimum of two microsatellite markers were used to
      achieve at least 90% informativity (excluding X). Twenty-eight of 47 informative
      tumors (59%) showed allelic loss of all informative markers on chromosome 3,
      consistent with monosomy 3 (M3). Allelic imbalance of 8q was observed in 60% of
      tumors. A total of 28% of tumors displayed allelic loss of 6p. We then compared
      these genetic alterations with the status of chromosome 3 and found a relative
      absence of 6p alteration in tumors with M3 (P = 0.0005). Additionally, all
      observed 8q imbalance was associated with either M3 or alteration of 6p,
      suggesting that 8q alterations occur later in tumor progression. The mutual
      exclusivity of M3 and 6p alterations suggests a bifurcated tumor progression
      model. In this model, M3 or 6p loss identify distinct pathways, both followed by
      8q loss in tumor progression.

PMID- 10397239
TI  - N-acetyltransferase 2 influences cancer prevalence in hMLH1/hMSH2 mutation
      carriers.
AB  - Hereditary nonpolyposis colorectal cancer (HNPCC), an inherited cancer
      predisposition syndrome, has been associated with germline mutations in DNA
      mismatch repair (MMR) genes. Because a deficiency in MMR does not predict a
      specific cancer phenotype, modifying genes may account in part for the variation
      in disease expression. We determined the N-acetyltransferase 2 (NAT2) genotype in
      26 unaffected and 52 cancer-affected hMLH1/hMSH2 mutation carriers coming from 21
      Swiss HNPCC families. Slow acetylators were found to be significantly (P < 0.03)
      more prevalent in the group of affected mutation carriers. Our results suggest a
      protective effect of the NAT2 rapid acetylator phenotype, an observation that
      could have implications for genetic counseling and management of MMR gene
      mutation carriers.

PMID- 10397240
TI  - Clinical implication of expression of platelet-derived endothelial cell growth
      factor (PD-ECGF) in metastatic lesions of uterine cervical cancers.
AB  - The platelet-derived endothelial cell growth factor (PD-ECGF) level was
      significantly (P < 0.05) increased in 8 of 40 metastatic lymph node lesions of
      uterine cervical cancers. The prognosis of the eight patients with high PD-ECGF
      (>10,000 pg/mg protein) in metastatic lymph node lesions was extremely poor. On
      the other hand, the 24-month survival rate of the 32 patients with low PD-ECGF
      (<10,000 pg/mg protein) in metastatic lymph node lesions was 75%. This indicates
      that PD-ECGF may contribute to the advancement of metastatic lesions, and that
      the PD-ECGF level in metastatic lesions may be a prognostic indicator.

PMID- 10397241
TI  - Association of the NAD(P)H:quinone oxidoreductase 609C-->T polymorphism with a
      decreased lung cancer risk.
AB  - The NAD(P)H:quinone oxidoreductase gene, NQO1, often carries a C-->T transition
      at bp 609, which has been associated with a reduced enzymatic activity and which
      may result in altered metabolic activation of tobacco smoke procarcinogens. We
      tested the association of this polymorphism with lung cancer risk in a population
      based case-control study of 327 cases and 440 controls of Caucasian, Japanese, or
      Native Hawaiian ancestry in Hawaii. We found a notable difference in the
      frequency of the variant allele among Japanese (38%), Caucasians (20%), and
      Hawaiians (22%). Overall, the variant allele was less frequent in cases than in
      controls (P = 0.03). A significant inverse association was found in Japanese,
      with adjusted odds ratios of 0.8 (95% confidence interval, 0.4-1.5) and 0.3 (0.1
      0.7) for the heterozygous and homozygous variant genotypes, respectively,
      compared with the homozygous wild-type genotype (P for genetic trend, 0.02). The
      association did not reach statistical significance in Caucasians and Hawaiians
      but was in the same direction.

PMID- 10397242
TI  - Enhanced efficacy of transcriptionally targeted suicide gene/prodrug therapy for
      thyroid carcinoma with the Cre-loxP system.
AB  - Our recent study demonstrates the feasibility of the thyroglobulin (TG) promoter
      in transcriptionally targeted gene therapy for thyroid carcinomas expressing TG,
      albeit less effectively than the constitutive viral promoter. The present study
      was, therefore, designed to enhance the activity of the TG promoter with the Cre
      loxP system. Our data demonstrate that the in vitro cytotoxic effect of herpes
      simplex virus thymidine kinase/ganciclovir obtained with the TG promoter and the
      Cre-loxP system is approximately 5-10-fold higher than that with the TG promoter
      alone. Enhanced tumor growth inhibition was also observed in in vivo tumor
      models. These data indicate the usefulness of the Cre-loxP system to enhance the
      activity of a tissue (or tumor)-specific promoter in transcriptionally targeted
      cancer gene therapy.

PMID- 10397243
TI  - Arsenic induces apoptosis through a c-Jun NH2-terminal kinase-dependent, p53
      independent pathway.
AB  - Arsenic has been used as an effective chemotherapy agent for some human cancers,
      such as acute promyelocytic leukemia. In this study, we found that arsenic
      induces activation of c-Jun NH2-terminal kinases (JNKs) at a similar dose range
      for induction of apoptosis in JB6 cells. In addition, we found that arsenic did
      not induce p53-dependent transactivation. Similarly, there was no difference in
      apoptosis induction between cells with p53 +/+ or p53 -/-. In contrast, arsenic
      induced apoptosis was almost totally blocked by expression of a dominant-negative
      mutant of JNK1. These results suggest that the activation of JNKs is involved in
      arsenic-induced apoptosis of JB6 cells. Taken together with previous findings
      that p53 mutations are involved in approximately 50% of all human cancers and
      nearly all chemotherapeutic agents kill cancer cells mainly by apoptotic
      induction, we suggest that arsenic may be a useful agent for the treatment of
      cancers with p53 mutation.

PMID- 10397244
TI  - Role of O6-alkylguanine-DNA alkyltransferase in protecting against
      cyclophosphamide-induced toxicity and mutagenicity.
AB  - Cyclophosphamide is used to treat a wide range of human malignancies. However, it
      is also a known carcinogen associated with induction of therapy-related leukemia
      and bladder cancer. The DNA repair protein, O6-alkylguanine-DNA alkyltransferase
      (AGT), protects cells from the toxic and mutagenic effects of O6-alkylating
      agents. We report here the contribution of AGT in protecting against the toxic
      and mutagenic effects of cyclophosphamide. CHO cells transduced with wild-type
      human AGT (CHO(AGT)) and pcDNA3 (CHOpcDNA3) were treated with activated
      cyclophosphamide derivatives, 4-hydroperoxycyclophosphamide (4-HC), 4
      hydroperoxydidechlorocyclophosphamide (4-HDC), a progenitor of acrolein, and
      phosphoramide mustard (PM). The results show that CHO(AGT) is 7- or 20-fold less
      sensitive to the toxic effects of 30 microM 4-HC or 300 microM 4-HDC,
      respectively, than CHOpcDNA3 cells as measured by cell survival using a colony
      forming assay. CHO(AGT) cells treated with 20 microM 4-HC or 200 microM 4-HDC
      produced 4- or 7-fold lower mutation frequency as measured at the HPRT locus than
      CHOpcDNA3 cells treated with the same dose of drugs. At 30 microM acrolein, the
      cell survival for CHO(AGT) was 30% compared with 18.7% for CHOpcDNA3. The
      mutation frequency of acrolein at the same dose was 57 mutants/10(6) cells in
      CHOpcDNA3 compared with no mutants in CHO(AGT). In contrast, CHO(AGT) and
      CHOpcDNA3 cells treated with PM had similar survival curves and exhibited no
      difference in mutation frequency. The present study demonstrates that AGT plays
      an important role in protecting against the toxic and mutagenic effect of
      cyclophosphamide and suggests that acrolein, not PM, is responsible for
      generating the toxic and mutagenic lesion(s) protected by the AGT protein.

PMID- 10397245
TI  - Alpha-fetoprotein-specific genetic immunotherapy for hepatocellular carcinoma.
AB  - The majority of human hepatocellular carcinomas overexpress alpha-fetoprotein
      (AFP). Two genetic immunization strategies were used to determine whether AFP
      could serve as a target for T-cell immune responses. Dendritic cells engineered
      to express AFP produced potent T-cell responses in mice, as evidenced by the
      generation of AFP-specific CTLs, cytokine-producing T cells, and protective
      immunity. AFP plasmid-based immunization generated less potent responses. These
      novel observations demonstrate that this oncofetal antigen can serve as an
      effective tumor rejection antigen. This provides a rational, gene therapy-based
      strategy for this disease, which is responsible for the largest number of cancer
      related deaths worldwide.

PMID- 10397246
TI  - Alterations of Fas (APO-1/CD95) gene in transitional cell carcinomas of urinary
      bladder.
AB  - Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling. The
      key role of the Fas system in negative growth regulation has been studied mostly
      within the immune system, and somatic mutations of Fas in cancer patients have
      been described solely in lymphoid-lineage malignancies. We analyzed somatic
      mutations and loss of heterozygosity of Fas gene in 43 transitional cell
      carcinomas of urinary bladder. Overall, 12 tumors (28%) were found to have Fas
      mutations, including 11 missense mutations and 1 frameshift mutation. Ten of the
      12 mutations were located in the death domain known to be involved in the
      transduction of an apoptotic signal, and 8 of these 10 mutations showed an
      identical G to A transition at bp 993, indicating a potential hotspot in bladder
      cancers. Three of eight (38%) informative tumors carrying Fas mutations showed
      LOH at polymorphic sites in the promoter region. This is the first report on the
      Fas gene mutations in nonlymphoid malignancies, and our data suggest that
      alterations of the Fas gene might lead to the loss of its apoptotic function and
      contribute to the pathogenesis of some bladder cancers.

PMID- 10397247
TI  - Radiation-induced mutations at the autosomal thymidine kinase locus are not
      elevated in p53-null cells.
AB  - To explore further the possibility that some forms of mutated p53 may increase
      mutagenesis in a positive manner, a double p53 knockout cell line was created,
      using a promoterless gene targeting approach. The identity of these p53-null
      cells was confirmed by Southern blot and Western blot analyses. Radiation-induced
      toxicity and mutagenicity was then compared among p53-null cells, TK6 cells with
      wild-type p53, and WTK1 cells with a p53 point mutation in codon 237. At the
      autosomal, heterozygous thymidine kinase locus, p53-null cells had equivalent
      background mutation frequencies and were approximately equally mutable as TK6,
      whereas WTK1 was much more sensitive to spontaneously arising and X-ray-induced
      mutation. Thus, these results indicate that the lack of wild-type p53 did not
      lead to increased mutagenesis.

PMID- 10397248
TI  - Cisplatin-induced apoptosis proceeds by caspase-3-dependent and -independent
      pathways in cisplatin-resistant and -sensitive human ovarian cancer cell lines.
AB  - We have assessed in detail the effect of cisplatin-activated programmed cell
      death in the cisplatin-sensitive human ovarian cancer cell line A2780 and two
      drug-resistant subclones, CP70 and C30. To determine whether the differential
      extent of apoptosis observed between the sensitive and resistant ovarian cancer
      cell lines was the result of dissimilar upstream signaling events, we assessed
      the execution of apoptotic events that precede target protein proteolysis and
      subsequent chromosomal DNA degradation. Proteolytic degradation of procaspase-3
      was observed in both the CP70 and C30 cells following IC50 cisplatin treatment,
      whereas no proteolyzed caspase-3 subunits were detected in the A2780 cells.
      However, using a direct enzymatic assay measuring cleavage of the synthetic
      peptide substrate (N-acetyl-Asp-Glu-Val-Asp-p-nitroanilide), activity was
      detected in extracts prepared from A2780 cells treated at the IC90 level of
      cisplatin and was 2-3-fold less than that of extracts prepared from CP70 and C30
      cells. Because the activation of procaspase-3 by caspase-9 requires the release
      of cytochrome c into the cytoplasm, we determined the level of cytoplasmic
      cytochrome c in each cell line in response to cisplatin treatment. Consistent
      with the caspase-3 activation data, a very small increase in cytoplasmic
      cytochrome c was observed in A2780 cells following cisplatin treatment, whereas
      dramatic increases were evident in both the CP70 and C30 cell lines. The
      expression of the mitochondrial factors Bcl-2, Bcl-x, and Bax was determined
      because each has been implicated in the regulation or release of cytochrome c at
      the level of the mitochondria. Bcl-2 and Bcl-xL proteins remained relatively
      unchanged in expression for over 48 h after exposure to cisplatin in the A2780
      cell lines. However, within the same time period, expression of Bcl-2 decreased
      in the CP70- and C30-resistant cell lines, whereas an increase in Bcl-xL
      expression was observed. Expression of the proapoptotic Bcl-xS protein was
      observed in only the resistant CP70 and C30 cell lines independent of cisplatin
      treatment. A change in the expression of Mr 24,000 Bax to a Mr 21,000 isoform was
      evidenced in the A2780 cells within 48 h of cisplatin treatment and, to a greater
      extent, in the CP70 and C30 cells, which also expressed a Mr 16,000 Bax variant.
      Evidence for an alternative apoptotic pathway in A2780 cells was obtained by
      demonstrating increased FADD expression in response to cisplatin treatment. These
      results support a model in which cisplatin-induced programmed cell death in the
      cisplatin-sensitive A2780 and -resistant CP70 and C30 cells proceeds via caspase
      3-independent and -dependent pathways, respectively.

PMID- 10397249
TI  - Chemoprevention of rat prostate carcinogenesis by early and delayed
      administration of dehydroepiandrosterone.
AB  - Two in vivo bioassays were conducted to evaluate the efficacy of
      dehydroepiandrosterone (DHEA) as an inhibitor of prostate carcinogenesis in rats.
      Prostate adenocarcinomas were induced in male Wistar-Unilever rats by a
      sequential regimen of cyproterone acetate and testosterone propionate, followed
      by a single i.v. injection of N-methyl-N-nitrosourea (MNU) and chronic androgen
      stimulation. In the first experiment, DHEA (1000 or 2000 mg/kg diet) was
      administered continuously to rats beginning 1 week before MNU exposure. In the
      second experiment, continuous administration of DHEA (2000 mg/kg diet) was begun
      either 1 week before, 20 weeks after, or 40 weeks after MNU exposure. Controls
      received basal diet without added DHEA. Studies were terminated at 13 months
      after MNU administration, and prostate cancer incidence was determined by
      histopathological evaluation of step sections of accessory sex glands. In the
      first study, continuous dietary administration of DHEA beginning 1 week before
      MNU resulted in a dose-related inhibition of prostate cancer induction. In the
      second experiment, comparable reductions in prostate cancer incidence were
      observed in groups exposed to DHEA beginning 1 week before, 20 weeks after, and
      40 weeks after carcinogen exposure. These data demonstrate that nontoxic doses of
      DHEA confer significant protection against prostate carcinogenesis in rats. The
      efficacy of delayed administration of DHEA suggests that the compound confers
      protection against later stages of prostate cancer induction and can suppress the
      progression of existing preneoplastic lesions to invasive disease.

PMID- 10397250
TI  - Estrogen receptor activation via activation function 2 predicts agonism of
      xenoestrogens in normal and neoplastic cells of the uterine myometrium.
AB  - The possible contribution of endocrine disrupters to human disease, particularly
      those compounds that modulate the estrogen receptor (ER), has recently drawn
      considerable attention. The tissue specificity of effects mediated by the ER is
      well recognized, although the mechanism of this specificity is not understood
      sufficiently to predict the effects of a particular ligand in different target
      tissues. Although the divergence of ER-mediated effects in the breast, bone, and
      uterine endometrium has been described, a frequently overlooked site of estrogen
      action is the smooth muscle of the uterus. The uterine myometrium is the tissue
      of origin of an extremely common hormone-responsive tumor, uterine leiomyoma, a
      tumor with a significant impact on women's health and a possible environmental
      influence. This report describes an in vitro/in vivo system for identifying the
      effects of ER ligands in the myometrium and elucidating their mechanism of
      action. Several natural and synthetic xenoestrogens were evaluated at the
      cellular and molecular level for their ability to mimic estrogen action in
      uterine myometrial tissues. Diethylstilbestrol, coumestrol, genistein,
      naringenin, and endosulfan were able to activate the AF2 function of the ER in
      vitro and demonstrated agonist activity in estrogen-responsive myometrial cells,
      as determined by induction of proliferation and increased message levels of
      progesterone receptor. Compounds that could not activate AF2 function (4-hydroxy
      tamoxifen, LY117018, and LY317783) did not act as estrogen agonists. For
      agonists, rank order of potency was predicted by receptor affinity; however,
      endosulfan displayed a surprising degree of activity, despite negligible receptor
      binding. Additionally, diethylstilbestrol and tamoxifen demonstrated prototypical
      agonist and antagonist effects, respectively, in the intact myometrium of
      sexually mature rats. The results presented here suggest that some exogenous ER
      ligands may mimic the effects of endogenous estrogens on uterine leiomyoma and
      may contribute to a complex hormonal milieu that impacts both normal and
      neoplastic myometrium.

PMID- 10397251
TI  - Use of the glucose starvation-inducible glucose-regulated protein 78 promoter in
      suicide gene therapy of murine fibrosarcoma.
AB  - A new strategy in anticancer gene therapy uses stress-responsive cellular
      promoters that offer the advantage of enhanced gene expression in a variety of
      tumors. Although the feasibility of their selective expression has been
      demonstrated, functional evidence of their ability to activate therapeutic agents
      within the tumor environment leading to tumor eradication has not been
      established. Glucose deprivation, chronic anoxia, and acidic pH known to persist
      in poorly vascularized solid tumors strongly induce the transcription of the
      glucose-regulated protein 78 (grp78) gene, which encodes an Mr 78,000 stress
      inducible protein. In this report, we tested directly the efficacy of the grp78
      promoter in a retroviral system to drive the expression of the herpes simplex
      virus-thymidine kinase (HSVtk) suicide gene, using a murine fibrosarcoma model,
      in the context of their syngeneic, immunocompetent hosts. Our results showed that
      under glucose starvation conditions, the expression of HSVTK was enhanced in
      tumor cells where the HSVtk gene was driven by the internal grp78 promoter, in
      contrast to the Moloney murine leukemia virus long terminal repeat, where
      suppression was observed. We further demonstrated that in vivo, HSVTK expression
      was elevated to much higher levels inside tumors when driven by the internal
      grp78 promoter, resulting in complete eradication of sizable tumor mass, with no
      recurrence of tumor growth. Our study suggests that the glucose starvation
      inducible grp78 promoter could be useful for enhanced expression of a variety of
      therapeutic agents within the solid tumor environment.

PMID- 10397253
TI  - In vivo antitumor activity of choline kinase inhibitors: a novel target for
      anticancer drug discovery.
AB  - Transformation by some oncogenes is associated with increased activity of choline
      kinase (ChoK), resulting in elevated constitutive levels of phosphorylcholine, a
      proposed second messenger required for DNA synthesis induced by growth factors.
      Here we describe the characterization of ChoK inhibitors with antiproliferative
      properties against human tumor-derived cell lines. The new molecules were
      tolerated in mice at doses that showed in vivo antitumor activity against human
      tumor xenografts derived from HT-29 and A431 cell lines implanted s.c. in nude
      mice. This first generation of inhibitors provides in vivo evidence that blockade
      of phosphorylcholine production is a valid strategy for the development of new
      anticancer agents, opening a new avenue for the development of antitumor drugs
      with a novel mechanism of action.

PMID- 10397252
TI  - Fas-FasL-mediated CD4+ T-cell apoptosis following stem cell transplantation.
AB  - We report the preferential expression of Fas on CD4+ T cells and Fas ligand
      (FasL) on monocytes and their potential role in the selective loss of CD4+ T
      cells in breast cancer patients undergoing high-dose chemotherapy and peripheral
      blood stem cell transplantation (PSCT). A high frequency of apoptotic CD4+ T
      cells (28-51%) is observed during the first 100 days after PSCT concomitant with
      a significant increase in monocyte frequency and FasL expression (11.6-23%) on
      monocytes. The preferential expression of Fas on CD4+ T cells (73-92%) in the
      peripheral blood (PB) of these patients is associated with a significantly higher
      frequency of CD4+ T-cell apoptosis compared with CD8+ T cells (28-47%) and CD4+ T
      cells (46 +/- 5.7%) in normal PB. These data suggest that "primed" Fas+ CD4+
      lymphocytes interact with activated monocytes that express FasL, resulting in
      apoptosis, leading to deletion of CD4+ T cells, an inversion in the CD4:CD8 T
      cell ratio, and immune dysfunction. The prevention of CD4+ T-cell apoptosis and
      improved immune reconstitution by the manipulation of PB stem cell products,
      blockade of Fas-FasL interactions, or cytokine support after transplantation may
      be important adjuvant immunotherapeutic strategies in patients undergoing high
      dose chemotherapy and PSCT.

PMID- 10397254
TI  - GD3 ganglioside antibody augments tumoricidal capacity of canine blood
      mononuclear cells by induction of interleukin 12.
AB  - Monoclonal antibody R24 recognizes ganglioside GD3 expressed on the cell surfaces
      of some tumor cells and on a subset of human T lymphocytes. Binding of R24 to
      these lymphocytes induces proliferation, cytokine production, and activation of
      intracellular signaling pathways. In the current report, we investigated
      expression of gangliosides by canine mononuclear immune cells and studied the
      ability of antiganglioside antibody to activate these cells using tumor cell
      killing as a measure of activation. A subset of canine monocytes, but not
      lymphocytes, was found to express gangliosides GD3 and GD2 as determined by the
      binding of monoclonal antibodies R24 and 14.G2a, respectively. Only R24 augmented
      the tumoricidal potential of fresh canine peripheral blood mononuclear cells
      (PBMCs) against tumor cell lines that did not express surface gangliosides GD3 or
      GD2. The augmenting effect of R24 on PBMC-mediated tumor cytotoxicity required
      cooperation between monocytes and lymphocytes because there was no enhancement of
      cytotoxicity mediated by R24 combined with either monocytes or lymphocytes
      individually. The enhancing effect of R24 on canine PBMC-mediated tumor
      cytotoxicity was blocked by anti-interleukin (IL)-12 neutralizing antibody,
      suggesting that R24 binding to monocytes triggered IL-12 release, contributing to
      the observed tumor killing effects. Reverse transcription-PCR confirmed that the
      binding of R24 to canine monocytes induced transcription of mRNA for canine IL
      12. These data indicate that monocytes can be activated for tumoricidal responses
      through a membrane structure associated with ganglioside GD3 triggered by the
      binding of R24 and that the mechanism for enhanced cytotoxicity is due to the
      production and secretion of IL-12.

PMID- 10397255
TI  - Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor
      alpha) monoclonal antibody.
AB  - Immune regulation has been shown to be involved in the progressive growth of some
      murine tumors. In this study, we demonstrated that a single in vivo
      administration of an amount less than 0.125 mg of anti-CD25 interleukin 2
      receptor alpha monoclonal antibody (mAb; PC61) caused the regression of tumors
      that grew progressively in syngeneic mice. The tumors used were five leukemias, a
      myeloma, and two sarcomas derived from four different inbred mouse strains. Anti
      CD25 mAb (PC61) showed an effect in six of the eight tumors. Administration of
      anti-CD25 mAb (PC61) caused a reduction in the number of CD4+ CD25+ cells in the
      peripheral lymphoid tissues. The findings suggested that CD4+ CD25+
      immunoregulatory cells were involved in the growth of those tumors. Kinetic
      analysis showed that the administration of anti-CD25 mAb (PC61) later than day 2
      after tumor inoculation caused no tumor regression, irrespective of depletion of
      CD4+ CD25+ immunoregulatory cells. Two leukemias, on which the PC61-treatment had
      no effect, seemed to be incapable of eliciting effective rejection responses in
      the recipient mice because of low or no antigenicity.

PMID- 10397256
TI  - Generation of human T-cell responses to an HLA-A2.1-restricted peptide epitope
      derived from alpha-fetoprotein.
AB  - Alpha-fetoprotein (AFP) is often derepressed in human hepatocellular carcinoma.
      Peptide fragments of AFP presented in the context of major histocompatibility
      molecules could serve as potential recognition targets by CD8 T cells, provided
      these lymphocytes were not clonally deleted in ontogeny. We therefore wished to
      determine whether the human T-cell repertoire could recognize AFP-derived peptide
      epitopes in the context of a common class I allele, HLA-A2.1. Dendritic cells
      genetically engineered to express AFP were capable of generating AFP-specific T
      cell responses in autologous human lymphocyte cultures and in HLA-A2.1/Kb
      transgenic mice. These T cells recognize a 9-mer peptide derived from the AFP
      protein hAFP(542-550) (GVALQTMKQ). Identified as a potential A2.1-restricted
      peptide epitope from a computer analysis of the AFP sequence, hAFP(542-550)
      proved to have low binding affinity to A2.1, but slow off-kinetics. AFP-specific
      CTL- and IFN-gamma-producing cells recognize hAFP(542-550)-pulsed targets.
      Conversely, hAFP(542-550) peptide-generated T cells from both human lymphocyte
      cultures and A2.1/Kb transgenic mice recognized AFP-transfected targets in both
      cytotoxicity assays and cytokine release assays. These lines of evidence clearly
      demonstrate that AFP-reactive clones have not been deleted from the human T-cell
      repertoire and identify one immunodominant A2.1-restricted epitope. These
      findings also clearly establish AFP as a potential target for T-cell-based
      immunotherapy.

PMID- 10397257
TI  - The cancer antiapoptosis mouse survivin gene: characterization of locus and
      transcriptional requirements of basal and cell cycle-dependent expression.
AB  - Survivin is the first apoptosis inhibitor described to date to be expressed in G2
      M in a cell cycle-dependent manner and to directly associate with mitotic spindle
      microtubules. To gain additional insights into this novel apoptotic checkpoint,
      we have now characterized the mouse survivin locus. Hybridization screening of
      mouse BAC libraries identified a survivin gene containing four exons and three
      introns, spanning >50 kb on the telomere of chromosome 11E2 and generating a 0.85
      kb mRNA versus the 1.9-kb human transcript. A mouse survivin protein of 140 amino
      acids (Mr approximately 16,200) was 84% identical to its human orthologue and
      contained a structurally unique single baculovirus iap repeat (BIR) and a -COOH
      terminus coiled domain instead of a RING finger. Analysis of the 5'-flanking
      region of the mouse survivin gene revealed a TATA-less promoter containing a
      canonical CpG island, numerous Sp1 sites, two cell cycle-dependent elements
      (CDEs), and one cell cycle gene homology region (CHR), typically found in G2-M
      expressed genes. Primer extension and S1 nuclease mapping identified three
      transcription start sites at position -32, -36, and -40 from the initiating ATG.
      Transfection of survivin promoter-luciferase constructs identified a minimal
      promoter region within the most proximal 174 bp upstream of the first ATG.
      Mutagenesis of the CDE/CHR elements and Sp1 sites in this region, alone or in
      combination, reduced transcriptional activity by 40-60% in asynchronously growing
      cells and abolished cell cycle periodicity in G2-M-synchronized cells. These data
      demonstrate that cell cycle expression of survivin requires integration of
      typical CDE/CHR G1 repressor elements and basal transcriptional activity by Sp1.
      Disruption of these transcriptional requirements may provide an alternative
      strategy to block the overexpression of survivin in cancer.

PMID- 10397258
TI  - hSNF5/INI1 inactivation is mainly associated with homozygous deletions and
      mitotic recombinations in rhabdoid tumors.
AB  - The chromatin-remodeling hSNF5/INI1 gene has recently been shown to act as a
      tumor suppressor gene in rhabdoid tumors (RTs). In an attempt to further
      characterize the main chromosomal mechanisms involved in hSNF5/INI1 inactivation
      in RTs, we report here the molecular cytogenetic data obtained in 12 cell lines
      harboring hSNF5/INI1 mutations and/or deletions in relation to the molecular
      genetic analysis using polymorphic markers extended to both extremities of
      chromosome 22q. On the whole, mitotic recombination occurring in the proximal
      part of chromosome 22q, as demonstrated in five cases, and
      nondisjunction/duplication, highly suspected in two cases (processes leading
      respectively to partial or complete isodisomy), appear to be major mechanisms
      associated with hSNF5/INI1 inactivation. Such isodisomy accompanies each of the
      RTs exhibiting two cytogenetically normal chromosomes 22. This results in
      homozygosity for the mutation at the hSNF5/INI1 locus. An alternate mechanism
      accounting for hSNF5/INI1 inactivation observed in these tumors is homozygous
      deletion in the rhabdoid consensus region. This was observed in each of the four
      tumors carrying a chromosome 22q abnormality and, in particular, in the three
      tumors with chromosomal translocations. Only one case of our series illustrates
      the mutation/deletion classical model proposed for the double-hit inactivation of
      a tumor suppressor gene.

PMID- 10397260
TI  - Telomerase activity and human telomerase reverse transcriptase mRNA expression in
      soft tissue tumors: correlation with grade, histology, and proliferative
      activity.
AB  - Telomerase activity (TA) is detected in most human cancers but, with few
      exceptions, not in normal somatic cells. Little is known about TA in soft tissue
      tumors. We have examined a series of benign and malignant soft tissue tumors for
      TA using the telomerase repeat amplification protocol assay. Analysis of the
      expression of the human telomerase reverse transcriptase was also carried out
      using RT-PCR. TA was undetectable in benign lesions (15 of 15) and low-grade
      sarcomas (6 of 6) and was detectable in 50% (19 of 38) of intermediate-/high
      grade sarcomas. Although the presence of TA in soft tissue tumors is synonymous
      with malignancy, it is neither a reliable method in making the distinction
      between reactive/benign and malignant (especially low-grade) lesions nor a
      reliable marker of tumor aggressiveness. Leiomyosarcomas and
      storiform/pleomorphic malignant fibrous histiocytomas rarely showed TA,
      irrespective of their grade. A strong correlation between human telomerase
      reverse transcriptase mRNA expression and TA was observed, supporting the close
      relationship between both parameters. No significant relationship was observed
      between proliferative activity (as assessed by MIB-1 immunolabeling) and TA. We
      verified that the absence of telomerase expression was not due to the presence of
      telomerase inhibitors and therefore alternative mechanism(s) for cell
      immortalization, yet to be determined, seem to be involved in the development
      and/or maintenance of some soft tissue sarcomas.

PMID- 10397261
TI  - LightCycler technology for the quantitation of bcr/abl fusion transcripts.
AB  - Quantifying bcr/abl fusion transcripts in chronic myelogenous leukemia is thought
      to serve as a powerful parameter for monitoring the kinetic nature of this clonal
      disease in vivo and in vitro. Recently, we demonstrated the technical advantages
      as well as the clinical relevance of quantitating bcr/abl fusion mRNA using the 5
      nuclease assay and a real-time fluorescence reverse transcriptase-PCR (RT-PCR)
      detection system (ABI PRISM 7700 SDS). Meanwhile, another technique was
      introduced (LightCycler technology) that may be used for the same purpose. To
      investigate whether this method may be an appropriate alternative to the
      described procedure, we have established bcr/abl LightCycler RT-PCR for major and
      minor bcr/abl fusion transcripts. We found that, with only minor modifications,
      TaqMan RT-PCR and fluorescent probe design can be used to obtain comparable
      results in the LightCycler system. The developed method could quantitate as
      little as 10 bcr/abl copies per 100 ng cDNA and was as safe and reproducible as
      the previously described technique. Because reaction efficiency was identical
      within different bcr/abl major fusions, one single RT-PCR could be established
      that simultaneously detects b2a3, b2a2, b3a2, and b3a3 fusion RNA with equal
      specificity and sensitivity. Compared to results generated by the ABI PRISM 7700
      SDS, absolute amounts of bcr/abl did not differ significantly, and there was a
      linear correlation between the respective values. We conclude that TaqMan
      chemistry can be used in the LightCycler and that both real-time fluorescence PCR
      detection systems equally fulfill the criteria for the safe and reliable
      quantitation of bcr/abl fusion RNA in clinical samples. This may be of help for
      further standardization of quantitative bcr/abl RT-PCR, which, again, is
      necessary for the comparison of results generated by different investigators.

PMID- 10397259
TI  - Characterization of the GAGE genes that are expressed in various human cancers
      and in normal testis.
AB  - The GAGE-1 gene was identified previously as a gene that codes for an antigenic
      peptide, YRPRPRRY, which was presented on a human melanoma by HLA-Cw6 molecules
      and recognized by a clone of CTLs derived from the patient bearing the tumor. By
      screening a cDNA library from this melanoma, we identified five additional,
      closely related genes named GAGE-2-6. We report here that further screening of
      this library led to the identification of two more genes, GAGE-7B and -8. GAGE-1,
      -2, and -8 code for peptide YRPRPRRY. Using another antitumor CTL clone isolated
      from the same melanoma patient, we identified antigenic peptide, YYWPRPRRY, which
      is encoded by GAGE-3, -4, -5, -6, and -7B and which is presented by HLA-A29
      molecules. Genomic cloning of GAGE-7B showed that it is composed of five exons.
      Sequence alignment showed that an additional exon, which is present only in the
      mRNA of GAGE-1, has been disrupted in gene GAGE-7B by the insertion of a long
      interspersed repeated element retroposon. These GAGE genes are located in the
      p11.2-p11.4 region of chromosome X. They are not expressed in normal tissues,
      except in testis, but a large proportion of tumors of various histological
      origins express at least one of these genes. Treatment of normal and tumor
      cultured cells with a demethylating agent, azadeoxycytidine, resulted in the
      transcriptional activation of GAGE genes, suggesting that their expression in
      tumors results from a demethylation process.

PMID- 10397262
TI  - The human p53 negative regulatory domain mediates inhibition of reporter gene
      transactivation in yeast lacking thioredoxin reductase.
AB  - Stimulation of target gene transcription by human p53 is inhibited in budding
      yeast lacking the TRR1 gene encoding thioredoxin reductase. LexA/p53 fusion
      proteins were used to study the basis for thioredoxin reductase dependence. A
      fusion protein containing all 393 of the residues of p53 efficiently and
      specifically stimulated transcription of a LexOP-LacZ reporter gene in wild-type
      yeast but was several-fold less effective in delta trr1 yeast lacking the
      thioredoxin reductase gene. Thus, even when p53 was tethered to a reporter gene
      by a heterologous DNA-binding domain, reporter gene transactivation remained
      dependent on thioredoxin reductase. A fusion protein containing only the
      activation domain of p53 stimulated reporter gene transcription equally in wild
      type and delta trr1 cells, suggesting that p53 residues downstream from the
      activation domain created the requirement for thioredoxin reductase. Experiments
      using additional LexA/p53 truncation mutations indicated that the p53 negative
      regulatory domain, rather than the DNA-binding or oligomerization domains,
      created the requirement for thioredoxin reductase. The fusion protein results
      suggested that, under oxidative conditions, the negative regulatory domain
      inhibited the ability of DNA-bound p53 to stimulate transcription. However,
      deletion of the negative regulatory domain did not alleviate the requirement of
      non-LexA-containing p53 for thioredoxin reductase. The results, thus, suggest
      that oxidative conditions inhibit both DNA binding and transactivation by p53,
      and that inhibition of the latter requires the negative regulatory domain.

PMID- 10397263
TI  - The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor
      cell proliferation and poor clinical outcome.
AB  - Cytogenetically, synovial sarcoma (SS) is characterized by the translocation
      t(X;18)(p11.2;q11.2), resulting in a fusion between the SYT gene on chromosome 18
      and SSX1 or SSX2 on the X chromosome and the formation of new chimeric genes, SYT
      SSX1 or SYT-SSX2. We examined the potential clinical relevance of SYT-SSX1 and
      SYT-SSX2 fusion transcripts together with tumor proliferation. In a series of 33
      patients with primary SS, the type of fusion transcript was assessed by reverse
      transcription-PCR and sequence analysis. The proliferation rate was analyzed
      using anti-Ki-67 antibodies. One case carrying an atypical transcript with a 57
      bp insert was excluded, leaving 13 SYT-SSX1 and 19 SYT-SSX2 cases for analysis.
      The hazard ratio (with respect to metastasis-free survival for patients with SYT
      SSX1 versus patients with SYT-SSX2 fusion transcripts was 7.4 (95% confidence
      interval, 1.5-36; log-rank P = 0.004). There was also an association with reduced
      overall survival for patients with SYT-SSX1 compared to patients with SYT-SSX2
      (hazard ratio, 8.5; 95% confidence interval, 1.0-73; log-rank P = 0.02). The 5
      year metastasis-free survival for patients with SYT-SSX1 was 42% versus 89% for
      patients with SYT-SSX2. There was a significant association between SYT-SSX1 and
      a high tumor proliferation rate (P = 0.02). We conclude that the findings suggest
      that the type of SYT-SSX fusion transcript determines the proliferation rate and
      is an important predictor of clinical outcome in patients with SS.

PMID- 10397264
TI  - Two independent mechanisms essential for tumor angiogenesis: inhibition of human
      melanoma xenograft growth by interfering with either the vascular endothelial
      growth factor receptor pathway or the Tie-2 pathway.
AB  - Protein ligands and receptor tyrosine kinases that specifically regulate
      endothelial cell function are mainly involved in physiological as well as in
      disease-related angiogenesis. These ligand/receptor systems include the vascular
      endothelial growth factor (VEGF) and the angiopoietin (Ang) families, and their
      receptors, the VEGF receptor family and the tyrosine kinase with immunoglobulin
      like and epidermal growth factor homology domains (Tie) family. In the present
      study, the contribution of these endothelium-specific ligand/receptor systems to
      tumor angiogenesis was evaluated. A375v human melanoma cells, which express at
      least the angiogenic growth factors VEGF, VEGF-C, and Ang-1, were stably
      transfected to overexpress the extracellular ligand-binding domains of the
      endothelium-specific receptor tyrosine kinases fms-like tyrosine kinase-1 (Flt
      1), Flt-4, Tie-1, and Tie-2, respectively. In vitro proliferation and colony
      formation assays confirmed that expression of the extracellular receptor domains
      inhibited neither tumor cell mitogenesis nor the ability to produce anchorage
      independent growth. Nude mouse xenografts revealed that interference with either
      the VEGF receptor pathway or the Tie-2 pathway resulted in a significant
      inhibition of tumor growth and tumor angiogenesis. In contrast, interference with
      the Flt-4 pathway or the Tie-1 pathway was without significant effect. Our
      results show that both the VEGF receptor pathway and the Tie-2 pathway are
      essential for A375v melanoma xenograft growth. The inhibition of the VEGF
      receptor pathway cannot be compensated by the Tie-2 pathway, nor vice versa.
      These findings suggest that the VEGF receptor pathway and the Tie-2 pathway have
      to be considered as two independent mediators essential for the process of in
      vivo angiogenesis.

PMID- 10397265
TI  - Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm
      PSMA expression in tumor-associated neovasculature.
AB  - Prostate-specific membrane antigen (PSMA) is a type II integral membrane
      glycoprotein that was initially characterized by the monoclonal antibody (mAb)
      7E11. PSMA is highly expressed in prostate secretory-acinar epithelium and
      prostate cancer as well as in several extraprostatic tissues. Recent evidence
      suggests that PSMA is also expressed in tumor-associated neovasculature. We
      examined the immunohistochemical characteristics of 7E11 and those of four
      recently developed anti-PSMA mAbs (J591, J415, and Hybritech PEQ226.5 and
      PM2J004.5), each of which binds a distinct epitope of PSMA. Using the
      streptavidin-biotin method, we evaluated these mAbs in viable prostate cancer
      cell lines and various fresh-frozen benign and malignant tissue specimens. In the
      latter, we compared the localization of the anti-PSMA mAbs to that of the anti
      endothelial cell mAb CD34. With rare exceptions, all five anti-PSMA mAbs reacted
      strongly with the neovasculature of a wide spectrum of malignant neoplasms:
      conventional (clear cell) renal carcinoma (11 of 11 cases), transitional cell
      carcinoma of the urinary bladder (6 of 6 cases), testicular embryonal carcinoma
      (1 of 1 case), colonic adenocarcinoma (5 of 5 cases), neuroendocrine carcinoma (5
      of 5 cases), glioblastoma multiforme (1 of 1 cases), malignant melanoma (5 of 5
      cases), pancreatic duct carcinoma (4 of 4 cases), non-small cell lung carcinoma
      (5 of 5 cases), soft tissue sarcoma (5 of 6 cases), breast carcinoma (5 of 6
      cases), and prostatic adenocarcinoma (2 of 12 cases). Localization of the anti
      PSMA mAbs to tumor-associated neovasculature was confirmed by CD34
      immunohistochemistry in sequential tissue sections. Normal vascular endothelium
      in non-cancer-bearing tissue was consistently PSMA negative. The anti-PSMA mAbs
      reacted with the neoplastic cells of prostatic adenocarcinoma (12 of 12 cases)
      but not with the neoplastic cells of any other tumor type, including those of
      benign and malignant vascular tumors (0 of 3 hemangiomas, 0 of 1
      hemangioendothelioma, and 0 of 1 angiosarcoma). The mAbs to the extracellular
      PSMA domain (J591, J415, and Hybritech PEQ226.5) bound viable prostate cancer
      cells (LNCaP and PC3-PIP), whereas the mAbs to the intracellular domain (7E11 and
      Hybritech PM2J004.5) did not. All five anti-PSMA mAbs reacted with fresh-frozen
      benign prostate secretory-acinar epithelium (28 of 28 cases), duodenal columnar
      (brush border) epithelium (11 of 11 cases), proximal renal tubular epithelium (5
      of 5 cases), colonic ganglion cells (1 of 12 cases), and benign breast epithelium
      (8 of 8 cases). A subset of skeletal muscle cells was positive with 7E11 (7 of 7
      cases) and negative with the other four anti-PSMA mAbs. PSMA was consistently
      expressed in the neovasculature of a wide variety of malignant neoplasms and may
      be an effective target for mAb-based antineovasculature therapy.

PMID- 10397266
TI  - Testisin, a new human serine proteinase expressed by premeiotic testicular germ
      cells and lost in testicular germ cell tumors.
AB  - We have cloned and characterized a cDNA encoding a new human serine proteinase,
      testisin, that is abundantly expressed only in the testis and is lost in
      testicular tumors. The testisin cDNA was identified by homology cloning using
      degenerate primers directed at conserved sequence motifs within the catalytic
      regions of serine proteinases. It is 1073 nucleotides long, including 942
      nucleotides of open reading frame and a 113-nucleotide 3' untranslated sequence.
      Northern and dot blot analyses of RNA from a range of normal human tissues
      revealed a 1.4-kb mRNA species that was present only in testis, which was not
      detected in eight of eight testicular tumors. Testisin cDNA is predicted to
      encode a protein of 314 amino acids, which consists of a 19-amino acid (aa)
      signal peptide, a 22-aa proregion, and a 273-aa catalytic domain, including a
      unique 17-aa COOH-terminal hydrophobic extension that is predicted to function as
      a membrane anchor. The deduced amino acid sequence of testisin shows 44% identity
      to prostasin and contains features that are typical of serine proteinases with
      trypsin-like substrate specificity. Antipeptide antibodies directed against the
      testisin polypeptide detected an immunoreactive testisin protein of Mr 35,000
      39,000 in cell lysates from COS-7 cells that were transiently transfected with
      testisin cDNA. Immunostaining of normal testicular tissue showed that testisin
      was expressed in the cytoplasm and on the plasma membrane of premeiotic germ
      cells. No staining was detected in eight of eight germ cell-derived testicular
      tumors. In addition, the testisin gene was localized by fluorescence in situ
      hybridization to the short arm of human chromosome 16 (16p13.3), a region that
      has been associated with allellic imbalance and loss of heterozygosity in
      sporadic testicular tumors. These findings demonstrate a new cell surface serine
      proteinase, loss of which may have a direct or indirect role in the progression
      of testicular tumors of germ cell origin.

PMID- 10397267
TI  - Contribution of c-erbB-2 and topoisomerase IIalpha to chemoresistance in ovarian
      cancer.
AB  - Overexpression of the c-erbB-2 (HER-2/neu) oncogene, which encodes a
      transmembrane receptor tyrosine kinase, has been shown to be associated with poor
      prognosis in ovarian and breast cancer. Recent studies indicate that c-erbB-2 may
      also be involved in determining the chemosensitivity of human cancers. In the
      present study, we examined the role of c-erbB-2 for chemoresistance in ovarian
      cancer. Overexpression of c-erbB-2 mRNA in tumor tissue was associated with a
      shorter survival of patients with primary ovarian cancer (P = 0.0001; n = 77) and
      was an independent prognostic factor in the proportional-hazard model adjusted
      for International Federation of Gynecologists and Obstetricians stage, residual
      disease, chemotherapy, and age (P = 0.035). A significant association between
      expression of c-erbB-2 mRNA and survival was obtained for the subgroup of
      patients who received a standard chemotherapy with carboplatin or cisplatin and
      cyclophosphamide (P = 0.0003), whereas only a nonsignificant trend was observed
      for patients who did not receive a standard chemotherapy (P = 0.124). In
      addition, the application of a standard chemotherapy improved the survival of
      patients with relatively low c-erbB-2 expression (P = 0.013) but not of patients
      with overexpression of c-erbB-2 (P = 0.359). Expression of c-erbB-2 mRNA
      correlated with expression of topoisomerase IIalpha mRNA determined by a reverse
      semiquantitative PCR technique (P = 0.009), whereas expression of c-erbB-2 and
      topoisomerase IIbeta mRNA did not correlate (P = 0.221). To examine the
      hypothesis that coamplified and/or coregulated topoisomerase IIalpha contributes
      to the resistance of c-erbB-2-overexpressing carcinomas, we established a
      chemosensitivity assay using primary cells from an ovarian carcinoma that
      overexpressed both c-erbB-2 and topoisomerase IIalpha. The combination of
      carboplatin with nontoxic concentrations of the topoisomerase II inhibitors
      etoposide or novobiocin enhanced the toxicity of carboplatin. In contrast, the
      tyrosine kinase inhibitor emodin exhibited no chemosensitizing effect in cells of
      this individual carcinoma. In conclusion, overexpression of c-erbB-2 was
      associated with poor prognosis and poor response to chemotherapy. The data
      suggest that topoisomerase IIlalpha, which correlates with c-erbB-2 expression,
      contributes to the resistance of c-erbB-2-overexpressing carcinomas.

PMID- 10397268
TI  - Isolation of a novel gene, TSP50, by a hypomethylated DNA fragment in human
      breast cancer.
AB  - A novel gene, testes-specific protease 50 (TSP50), was isolated from a human
      testes cDNA library by using a genomic DNA probe, BR50. BR50 was isolated by a
      modified representational difference analysis (RDA) technique due to its
      hypomethylated feature in a breast cancer biopsy. This altered DNA methylation
      status was also detected by BR50 in other breast and some ovarian cancer tissues.
      The TSP50 gene product is a homologue to several human proteases, which indicates
      that it may encode a protease-like protein. Northern analysis of 16 different
      types of normal human tissues suggests that TSP50 was highly and specifically
      expressed in human testes, which indicates that it might possess a unique
      biological function(s) in that organ. Methylation status analysis in normal human
      testes and other tissues showed a correlation between DNA methylation and gene
      expression. Most importantly, reverse transcription-PCR analysis of 18 paired
      breast cancer tissues found that in 28% of the cancer samples, the TSP50 gene was
      differentially expressed. The possibility that TSP50 may be an oncogene is
      presently under investigation.

PMID- 10397269
TI  - Progranulin gene expression regulates epithelial cell growth and promotes tumor
      growth in vivo.
AB  - Progranulin is a 593-amino acid glycoprotein, the mRNA of which is expressed by
      many epithelial cells both in vitro and in vivo, but the biological significance
      of this expression is unclear. In this study, we demonstrate that overexpression
      of the progranulin gene in SW-13 adrenal carcinoma cells and MDCK nontransformed
      renal epithelia results in the transfection-specific secretion of progranulin,
      acquired clonogenicity in semisolid agar, and increased mitosis in monolayer
      culture, whereas diminution of progranulin gene expression impairs growth of
      these cells. Purified recombinant progranulin reproduces the effects of forced
      progranulin expression, being clonogenic in soft agar and mitogenic in monolayer
      culture to SW-13 and MDCK cells and other epithelia of various origins such as
      GPC16 colonic epithelium and A549 lung carcinoma cells. Progranulin
      overproduction in SW-13 cells markedly increases its tumorigenicity in nude mice,
      demonstrating that it can regulate epithelial proliferation in vivo. We propose
      that the rate of growth for some epithelia, such as SW-13 and MDCK, is
      proportional to the level of intrinsic progranulin gene expression, and that
      elevated progranulin gene expression confers a transformed phenotype on
      epithelial cells including anchorage independence in vitro and growth as tumors
      in nude mice.

PMID- 10397270
TI  - Protein kinase C delta involvement in mammary tumor cell metastasis.
AB  - Metastasis requires cytoskeletal remodeling for migration, adhesion, and
      extravasation of metastatic cells. Although protein kinase C (PKC) is involved in
      tumor promotion/progression and cytoskeletal remodeling, its role in metastasis
      has not been defined. PKCdelta levels are increased in highly metastatic 13762NF
      mammary tumor cells (MTLn3) compared with less metastatic, parental cell lines.
      To determine whether the increase in endogenous PKCdelta is functionally related
      to their increased metastatic potential, we prepared MTLn3 cells that express the
      inhibitory regulatory domain fragment of PKCdelta (RDdelta) under the control of
      a tetracycline-inducible promoter. RDdelta expression attenuated endogenous
      PKCdelta activity, as demonstrated by decreased phosphorylation of the PKCdelta
      substrate adducin in migrating cells. Thus, in MT cells, RDdelta appears to
      primarily influence cytoskeleton-dependent processes rather than cell cycle
      progression. To determine whether RDdelta expression influenced metastatic
      potential in vivo, MTLn3/RDdelta cells were either grown in the mammary fat pad
      or injected into the tail vein of syngeneic rats, and effects of doxycycline
      induced RDdelta expression on pulmonary metastases were studied. Consistent with
      the in vitro data, induction of RDdelta significantly reduced the number of lung
      metastases without affecting growth of the primary tumor. These results suggest
      that interfering with endogenous PKCdelta activity by expressing the inhibitory
      RDdelta fragment inhibits cytoskeleton-regulated processes important for MTLn3
      cell metastasis.

PMID- 10397271
TI  - Nitric oxide is an initiator of intercellular signal transduction for stress
      response after hyperthermia in mutant p53 cells of human glioblastoma.
AB  - Nitric oxide is known to be a multifunctional physiological substance. Recently,
      it was suggested that nitric oxide is involved in p53-dependent response to many
      kinds of stress, such as heat shock and changes in cellular metabolism. To verify
      this hypothesis, we examined the effect of nitric oxide produced endogenously by
      heat-shocked cells on nonstressed cells using a human glioblastoma cell line, A
      172, and its mutant p53 (mp53) transfectant (A-172/mp53). The accumulation of
      inducible nitric oxide synthase was caused by heat treatment of the mtp53 cells
      but not of the wild-type p53 (wtp53) cells. The accumulation of heat shock
      protein 72 (hsp72) and p53 was observed in nontreated mtp53 cells cocultivated
      with heated mp53 cells, and the accumulation of these proteins was suppressed by
      the addition of a specific inducible nitric oxide synthase inhibitor,
      aminoguanidine, to the medium. Furthermore, the accumulation of these proteins
      was observed in the wtp53 cells after exposure to the conditioned medium by
      preculture of the heated mp53 cells, and the accumulation was completely blocked
      by the addition of a specific nitric oxide scavenger, 2-(4-carboxyphenyl)-4,4,5,5
      tetramethyl-imidazoline-1-oxyl-3-oxide, to the medium. In addition, the
      accumulation of hsp72 and p53 in the wtp53 cells was induced by the
      administration of an nitric oxide-generating agent, S-nitroso-N
      acetylpenicillamine, to the medium. Finally, the thermosensitivity of the wtp53
      cells was reduced in the conditioned medium by preculture of the heated mp53
      cells as compared with conventional fresh growth medium. Our finding of the
      accumulation of hsp72 and p53 in nitric oxide-recipient cells cocultivated with
      heated nitric oxide-donor cells provides the first evidence for an intercellular
      signal transduction pathway via nitric oxide as intermediate without cell-to-cell
      interactions such as gap junctions.

PMID- 10397273
TI  - Presence of tumor DNA in plasma of breast cancer patients: clinicopathological
      correlations.
AB  - Using different molecular techniques, DNA has been detected in the plasma of
      cancer patients with various types of tumors. We undertook the present study to
      investigate the presence of plasma DNA, before mastectomy, in patients with
      breast cancer at diagnosis and to analyze the clinicopathological spectrum of
      this subgroup of patients with respect to patients without DNA with tumor
      characteristics. We studied 62 patients with breast cancer, who were selected
      sequentially after mastectomy and diagnosis of breast carcinomas. Genomic DNA
      extracted from tumor and normal tissues, normal blood cells, and plasma was used
      for molecular studies. Alterations in polymorphic markers selected because they
      had been found to show a high rate of alterations in breast cancer in previous
      studies (D17S855, D17S654, D16S421, TH2, D10S197, and D9S161), as well as
      mutations in the p53 gene and aberrant methylation at the first exon of p16INK4a,
      were used to identify and characterize tumor and plasma DNA. Thirteen
      clinicopathological parameters were analyzed in each patient. We identified 56
      cases (90%) with at least one molecular event in tumor DNA, and 41 cases (66%)
      with a similar alteration in plasma DNA. Comparison of the clinicopathological
      parameters between patients with and without plasma DNA revealed significant
      differences in the axillary involvement, rate of invasive ductal carcinoma, high
      proliferative index, and the parameter comprised of lymph node metastases,
      histological grade II, and peritumoral vessel involvement. A high proportion of
      breast cancer patients exhibited plasma DNA at diagnosis similar to tumor DNA,
      and its presence correlated significantly with pathological parameters associated
      with a poor prognosis.

PMID- 10397272
TI  - Loss of P27Kip1 expression correlates with tumor grade and with reduced disease
      free survival in primary superficial bladder cancers.
AB  - p27Kip1 is a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors
      and is a potential tumor suppressor gene. We previously reported a deregulated
      expression of p27Kip1 in a series of human cancer cell lines and in primary
      breast and colon cancers. Moreover, p27Kip1 has been reported as an important
      prognostic factor in primary lung, breast, colon, and prostate cancers. In this
      study, we evaluated the prognostic value of p27Kip1 in a series of 96 superficial
      (pTa-1) human bladder carcinomas. High (>50% positive cells), moderate (25-50%),
      and low (<25%) p27Kip1 staining was observed in 39 (41%), 19 (20%), and 38 (39%)
      of the 96 primary superficial bladder cancers, respectively. No significant
      association was found between the expression level of p27Kip1 and tumor stage.
      Decreased p27Kip1 staining correlated with higher tumor grade (P = 0.001).
      Interestingly, a significant association was observed between increased
      expression of p27Kip1 and positivity for p53 (>20% positive cells; P < 0.001). A
      significant correlation was also observed between low expression of p27Kip1 and
      decreased disease-free survival (P = 0.0003 by log-rank test) and overall
      survival (P = 0.01 by log-rank test). Furthermore, on multivariate analysis, low
      p27Kip1 protein expression was an independent predictor of reduced disease-free
      survival (P = 0.018; relative risk = 1.95) second only to tumor stage. These data
      indicate that p27Kip1 protein is frequently expressed at low level in poorly
      differentiated tumors and suggest that this protein might represent a useful
      prognostic marker for disease recurrence and overall survival in superficial
      bladder carcinomas.

PMID- 10397274
TI  - Overexpression of the wild type p73 gene in breast cancer tissues and cell lines.
AB  - The p73 gene is a structural and, in overexpression systems, functional p53
      homologue. Ectopic p73 expression can activate a broad subset of p53-responsive
      genes, induce apoptosis, and act as a growth suppressor. Yet, viral oncoproteins
      that antagonize p53 (adenovirus E1B 55K, SV40 large T, and human papillomavirus
      E6) do not antagonize p73. This could suggest that inactivation of p73, in
      contrast to p53, is not required for tumorigenesis. Also, p73 is not activated by
      DNA damage. Because intragenic p73 mutations in tumors have not been reported and
      imprinting is idiosyncratic, tumor-specific changes in wild-type p73 expression
      levels become the most reliable guide toward identifying the normal function of
      p73 and its role in tumorigenesis. We analyzed 77 invasive breast cancers and 7
      breast cancer cell lines for p73 mRNA expression levels, allelic origin,
      intragenic mutations, and COOH-terminal splice variants. A range of normal
      tissues, including breast, showed very low p73 expression, with little variation
      from tissue to tissue. In contrast, 38% (29 cases) of breast cancers had elevated
      p73 mRNA ranging from 5-25-fold above normal, with the remaining tumors (64%)
      falling within the normal range. Moreover, five of seven cell lines (71%) also
      exhibited p73 overexpression (13-73-fold). Yet, no correlation with p21 mRNA and
      protein levels was present, although four of the five lines were mutant for p53.
      Mutation analysis of the eight highest expressers showed wild type status. Eight
      of 14 informative samples were biallelic, whereas the remaining 6 samples showed
      monoallelic expression. Tumors and cell lines with p73 overexpression tended to
      exhibit a complex profile of up to six different COOH-terminal splice variants,
      whereas normal and transformed tissues with low p73 mRNA predominantly expressed
      p73 alpha. We confirm the previously described variants p73 gamma and delta in
      breast tissue and describe two novel isoforms, p73 epsilon and phi, thereby
      further enlarging combinatorial possibilities. Together, our in vivo data show
      that p73 does not have a role as a classic Knudson-type tumor suppressor in
      breast cancer.

PMID- 10397275
TI  - The insulin-like growth factor 1 receptor induces transformation and
      tumorigenicity of ovarian mesothelial cells and down-regulates their Fas-receptor
      expression.
AB  - Cell proliferation and papillogenesis are growth factor-sensitive events in the
      ovarian mesothelium, the tissue source of ovarian epithelial cancer. To further
      investigate the regulation of cell proliferation in this tissue, rabbit ovarian
      mesothelial cells (OMC) were transfected in vitro with a CVN expression vector
      carrying the human gene for insulin-like growth factor 1 receptor (IGF-1R). The
      growth characteristics of IGF-1R transfectants (OMIR) and their response to IGF-1
      were then compared with those of OMC in serumless HL-1 cultures. OMIR cells
      formed epithelial-like colonies and, even when nonconfluent, produced
      tridimensional structures reminiscent of papillae seen in ovarian serous
      epithelial tumors. After 3 and 7 days of exposure to IGF-1, OMIR cells grew
      approximately 20-fold (P < 0.05), and papillogenesis was 15- to 25-fold over
      similar events in OMC, respectively. Exposure to treatment with antisense
      oligonucleotides against IGF-1R mRNA inhibited OMIR growth rate by 70%. Western
      immunoblotting and flow cytometry revealed higher expression of IGF-1R in OMIR
      cells than in OMC. The reverse was true when Fas-receptor expression was
      evaluated. OMIR cells were clonogenic in 15% serum-rich soft agar assay (OMIR:OMC
      colony-forming ratio 150-200:1), and tumorigenic in nude mice in which high-grade
      carcinomas with occasional lung metastases were observed. These data suggest that
      IGF-1R plays a role in ovarian epithelial carcinogenesis. The overexpression of
      this receptor induces transformation and morphogenesis of OMCs via an autocrine
      mechanism. IGF-1R may down-regulate the Fas expression rendering transformed
      ovarian mesothelial cells resistant to apoptosis.

PMID- 10397276
TI  - Tenth Annual Pezcoller Symposium: the genetics of cancer susceptibility.

PMID- 10397277
TI  - Regulation of alcohol and aldehyde dehydrogenase activity: a metabolic balancing
      act with important social consequences.

PMID- 10397278
TI  - A novel polymorphism (-357 G/A) of the ALDH2 gene: linkage disequilibrium and an
      association with alcoholism.
AB  - BACKGROUND: Human mitochondrial aldehyde dehydrogenase (ALDH2) is a major enzyme
      responsible for the oxidation of acetaldehyde derived from ethanol metabolism.
      The human ALDH2 gene shows genetic polymorphism at position 1510 with a G to A
      transition in exon 12. This mutation leads to ALDH2 enzyme deficiency and
      protection against alcoholism. As yet, no polymorphism for the promoter region of
      the ALDH2 gene has been reported. METHODS: We analyzed 600 nucleotides of the
      promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar,
      60 Mongolians, and 82 North-American Caucasians using single-strand
      conformational change polymorphism (SSCP) analysis and the polymerase chain
      reaction (PCR). PCR products that showed an aberrant banding pattern detected by
      the SSCP analysis were subjected to PCR direct sequencing. RESULTS: A novel
      polymorphism at -357 with a G to A substitution was found in all the population
      groups, including North-American Caucasians. In addition, the polymorphic status
      in the promoter and exon 12 suggested linkage disequilibrium between the two
      loci, which indicated that among Japanese, the ALDH2*2 allele is linked to the G
      promoter allele, and theALDH2*1 allele is linked to the A allele. A total of 206
      healthy male controls and 185 alcoholic male patients with the homozygous ALDH2*1
      genotype were analyzed for the polymorphism in the promoter. Genotypic
      frequencies of GG, GA, and AA for alcoholics were 54.1%, 44.3%, and 1.6%, and
      those for controls were 52.9%, 40.3%, and 6.8%, respectively. The A allele
      frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A chi2
      test for the entire 3 x 2 table indicated significant variations in the three
      genotypes (chi2 = 6.40, p < 0.05). However, no significant difference in allelic
      frequencies between the two groups was observed. CONCLUSION: This new
      polymorphism in the ALDH2 promoter is present in all populations studied. Further
      analysis in other ethnic groups is necessary to establish this as an additional
      risk factor for alcoholism.

PMID- 10397280
TI  - Total body water and peak alcohol concentration: a comparative study of young,
      middle-age, and older females.
AB  - A search of the alcohol research literature reveals that very little experimental
      work has been done to describe the effects of alcohol in older females. In the
      present study, the effects of age and body water volume on the resultant peak
      alcohol concentration were observed for females ranging in age from 21 to 81. The
      peak alcohol concentration was estimated by breath testing in three groups of
      female volunteer subjects: young (21 to 25 years old), middle-age (35 to 47 years
      old), and older (>60 years old) after ingestion of 30 g of alcohol. Bioelectrical
      impedance analysis and anthropometric equations were used to estimate total body
      water, percent body water, and percent body fat for each subject. Significantly
      higher blood alcohol concentrations were obtained in older females [mean blood
      alcohol concentration (+/-SD) = 0.0975+/-0.018], compared with younger females
      (0.0818+/-0.016 and 0.0811+/-0.012). The results suggest, however, that this
      effect cannot be fully explained by the notion that older persons have a smaller
      body water volume. Particular attention is paid to the difference between total
      body water in liters and body water expressed as a percentage of body weight.
      Evidence is offered to demonstrate that percent body fat is not a determinant of
      the blood alcohol level an individual will attain. The findings are discussed
      with particular reference to the lack of experimental work involving older
      females and alcohol.

PMID- 10397279
TI  - An A/G polymorphism in the promoter of mitochondrial aldehyde dehydrogenase
      (ALDH2): effects of the sequence variant on transcription factor binding and
      promoter strength.
AB  - INTRODUCTION: The strong protective effect of the ALDH2*2 mutation on risk of
      alcoholism suggests that other mutations that reduce mitochondrial aldehyde
      dehydrogenase (ALDH) activity in the liver might also deter drinking. This study
      describes a polymorphic locus found in the promoter of the ALDH2 gene that
      affects expression of reporter constructs. METHODS: Polymerase chain reaction
      (PCR)-based sequencing was used to search for polymorphisms. The ability of the
      promoter variants to bind transcription factors apolipoprotein A regulatory
      protein 1 (ARP-1) and chicken ovalbumin upstream promoter-transcription factor
      (COUP-TF) was tested in gel retardation assays using in vitro synthesized
      transcription factors. The variant promoters were tested for transcriptional
      activity using a heterologous promoter system and transient transfection assays.
      RESULTS: A common polymorphism (A or G) in the human ALDH2 promoter region was
      found at -361 base pair (bp) from the translation start site. This polymorphism
      was found at different frequencies in African Americans, Caucasians, and Asians.
      The polymorphism occurs adjacent to the core binding motif for the transcription
      factors COUP-TF and ARP-1. Competition and binding affinity determinations did
      not show differences in the ability of these two sequences to bind the factors.
      Reporter genes containing these elements upstream of a basal thymidine kinase
      promoter had similar activity when transfected into a fibroblast (CV-1) cell
      line. However, the reporter containing the G allele was more active than that
      containing the A allele in hepatoma (H4IIEC3) cells. CONCLUSIONS: The -361 bp A/G
      polymorphism is common in all racial groups tested. The G allele was more active
      than the A allele in a transfection assay. The basis for this difference is not
      known. If the differences in activity of the promoter constructs were paralleled
      by differences in ALDH2 enzyme activity in the liver, this polymorphism could
      affect risk of alcoholism.

PMID- 10397281
TI  - Acute effect of alcohol on estradiol, estrone, progesterone, prolactin, cortisol,
      and luteinizing hormone in premenopausal women.
AB  - BACKGROUND: Heavy alcohol consumption is associated with menstrual
      irregularities, including anovulation, luteal-phase dysfunction, recurrent
      amenorrhea, and early menopause. In addition, moderate to heavy alcohol intake
      has been found to increase the risk of spontaneous abortions and breast cancer.
      These adverse effects could at least in part originate from alcohol-mediated
      changes in hormone levels. METHODS: The acute effect of alcohol on the hormone
      balance in women using oral contraceptives (OC+) and also in nonusers (OC-), was
      evaluated in 30 OC- and 31 OC+ subjects, representing the whole period of the
      menstrual cycle. It was also evaluated in 40 OC- and 47 OC+ subjects during the
      midcycle phase and in 10 OC+ subjects with unknown cycle phase. RESULTS: We found
      that among subjects who used oral contraceptives, estradiol levels increased and
      progesterone levels decreased after intake of alcohol (0.5 g/kg). No dose effect
      (0.34-1.02 g/kg) on progesterone was observed in a substudy on 10 OC+ subjects.
      With regard to estrone levels, no effect was observed, although a significant
      increase was found in the estradiol-to-estrone ratio. Among subjects not using
      oral contraceptives, progesterone levels decreased after intake of alcohol (0.5
      g/kg). No effect was found in estradiol, estrone, or the estradiol-to-estrone
      ratio during midcycle in this study group. A transient elevating effect of
      alcohol (0.5 g/kg) on prolactin levels was observed in both study groups. We
      found that alcohol (0.5 g/kg) had no significant effect on luteinizing hormone
      (LH) levels among subjects not using oral contraceptives, and observed a decline
      among subjects using oral contraceptives at midcycle. CONCLUSIONS: We suggest
      that the estradiol and progesterone effects are related to decreased steroid
      catabolism, resulting from the alcohol-mediated increase in the hepatic NADH-to
      NAD ratio. The transient effect on prolactin levels may reflect acute changes in
      opioid and dopamine levels in the hypothalamus. The present findings regarding
      female sex steroids may be of relevance in the association between moderate to
      heavy alcohol consumption and the development of breast cancer.

PMID- 10397282
TI  - Action of ethanol on responses to nicotine from cerebellar interneurons and
      medial septal neurons: relationship to methyllycaconitine inhibition of nicotine
      responses.
AB  - BACKGROUND: A majority of alcoholics also smoke, suggesting that alcohol and
      nicotine share a common action on nicotinic cholinergic receptors. METHODS:
      Extracellular single-unit recording was used to investigate the effects of
      ethanol on responses to nicotine from rat cerebellar interneurons and medial
      septal neurons. RESULTS: Nicotine produced inhibition from medial septal neurons,
      but increased neural activity of cerebellar interneurons. When ethanol was
      applied locally to cerebellar interneurons, the excitatory response to nicotine
      was enhanced in a dose-related manner. Nicotine-induced inhibition from medial
      septal neurons was reduced by ethanol from the majority of neurons, but a dose
      relationship for this inhibition by ethanol was not observed. Ethanol affected
      responses to nicotine from over 90% of all neurons investigated at these sites.
      Initially, it was established that the nicotinic antagonists, methyllycaconitine
      (MLA) and alpha-bungarotoxin, which affect a nicotinic cholinergic (nACh)
      receptor with an alpha7 subunit, had similar actions on responses to nicotine
      from individual medial septal cells and cerebellar interneurons. When MLA was
      tested against responses to nicotine from neurons in the two brain regions, MLA
      antagonized responses to nicotine from only 27% of the neurons rather than the
      90% found for ethanol. This latter observation provided evidence that ethanol was
      affecting neurons with MLA-insensitive receptors. When the actions of ethanol on
      responses to nicotine were compared directly with the action of MLA on the same
      medial septal neurons, both ethanol and MLA caused a greater than 50% antagonism
      of the response to nicotine, indicative that nACh receptors with the alpha7
      subunit were sensitive to ethanol. CONCLUSIONS: Collectively, these data provide
      evidence that ethanol affects responses to nicotine not only from nACh receptors
      on medial septal cells and cerebellar interneurons containing an alpha7 subunit
      (i.e., MLA-sensitive receptors), but also from nACh receptor subtypes without
      this specific nACh receptor subunit (i.e., MLA-insensitive receptors).

PMID- 10397283
TI  - Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998)--a
      review.
AB  - Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic
      effects of ethanol but does not account for the tolerance and a number of
      associated disorders that develop in the alcoholic. These were elucidated by the
      discovery of the microsomal metabolism of ethanol. The physiologic role of this
      system comprises gluconeogenesis from ketones, fatty acid metabolism, and
      detoxification of xenobiotics, including ethanol. After chronic ethanol
      consumption, the activity of the microsomal ethanol-oxidizing system (MEOS)
      increases, with an associated rise in cytochromes P-450, especially CYP2E1. This
      induction is associated with proliferation of the endoplasmic reticulum, both in
      experimental animals and in humans. The role of MEOS in vivo and its increase
      after chronic ethanol consumption was shown most conclusively in alcohol
      dehydrogenase-negative deer mice. Enhanced ethanol oxidation is associated with
      cross-induction of the metabolism of other drugs, resulting in drug tolerance.
      Furthermore, there is increased conversion of known hepatotoxic agents (such as
      CCl4) to toxic metabolites, which may explain the enhanced susceptibility of
      alcoholics to the adverse effects of industrial solvents. CYP2E1 also has a high
      capacity to activate some commonly used drugs, such as acetaminophen, to their
      toxic metabolites, and to promote carcinogenesis (e.g., from
      dimethylnitrosamine). Moreover, catabolism of retinol is accelerated and there
      also is induction of microsomal enzymes involved in lipoprotein production,
      resulting in hyperlipemia. Contrasting with the chronic effects of ethanol
      consumption, acute ethanol intake inhibits the metabolism of other drugs through
      competition for the at least partially shared microsomal pathway. In addition,
      metabolism by CYP2E1 results in a significant free radical release and
      acetaldehyde production which, in turn, diminish reduced glutathione (GSH) and
      other defense systems against oxidative stress. Acetaldehyde also forms adducts
      with proteins, thereby altering the functions of mitochondria and of repair
      enzymes. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the
      area of maximal liver damage. CYP1A2 and CYP3A4, two other perivenular P-450s,
      can also sustain the metabolism of ethanol, thereby contributing to MEOS activity
      and possibly liver injury. By contrast, CYP2E1 inhibitors oppose alcohol-induced
      liver damage, but heretofore available compounds were too toxic for clinical use.
      Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of
      polyunsaturated lecithins extracted from soybeans, was discovered to decrease
      CYP2E1 activity. PPC (and its active component dilinoleoylphosphatidylcholine)
      also oppose hepatic oxidative stress and fibrosis. PPC is now being tested
      clinically for the prevention and treatment of liver disease in the alcoholic.

PMID- 10397284
TI  - Ethanol consumption by Fawn-Hooded rats following abstinence: effect of
      naltrexone and changes in mu-opioid receptor density.
AB  - BACKGROUND: Relapse after abstinence can be modelled in rats using an alcohol
      deprivation effect (ADE) of enhanced ethanol consumption after a period of
      enforced abstinence from ethanol; however, not all rat strains display such an
      effect. We wanted to examine the effect of naltrexone on ethanol consumption by
      ethanol-preferring Fawn-Hooded (FH) rats using such a model. METHODS: FH rats
      were given continual free-choice access to a 5% ethanol solution or water (4
      weeks) followed by 2 weeks of water alone. At the end of this abstinence period,
      osmotic minipumps were implanted subcutaneously to deliver saline (n = 4) or
      naltrexone (n = 4; 8.4 mg/kg/day for 4 weeks). After recovery from surgery, the
      rats were again given access to 5% ethanol under the same free-choice conditions
      (4 weeks). A third group of age-matched controls drank only water during the
      behavioral trial. At the end of the behavioral trial, the rats were decapitated
      and an autoradiographic examination was made of micro-opioid receptor density
      through the forebrain using the ligand [125I]FK-33824. RESULTS: First, a period
      of enforced abstinence from ethanol consumption caused a significant (p < 0.05)
      and prolonged increase in ethanol preference (+18%) and decrease in water
      consumption (-53%), although the volume of ethanol consumed (ml/day) did not
      vary, indicating an atypical ADE in this rat strain. Second, naltrexone
      significantly (p < 0.05) decreased ethanol consumption by the FH rats in terms of
      absolute amount of ethanol consumed and preference for ethanol solution, but this
      effect of naltrexone diminished over time, concurrent with a robust and
      significant elevation in micro-opioid receptor density in all brain regions
      examined (p < 0.05). Finally, ethanol consumption alone also upregulated micro
      opioid receptor density relative to nondrinking controls in a number of brain
      regions, which included the nucleus accumbens (+29%) and caudate-putamen (+15%,p
      < 0.05), but decreased micro-opioid receptor density in other regions including
      the substantia nigra pars reticulata, which was suggestive of an indirect effect
      on micro-opioid receptors. CONCLUSIONS: The data suggest that continual long-term
      naltrexone treatment may not be effective in the treatment of alcoholism,
      possibly because of the induced increase in micro-opioid receptor density.

PMID- 10397285
TI  - Limited access alcohol drinking in high- and low-alcohol preferring selected
      lines of mice.
AB  - BACKGROUND: Selection studies and genetic analyses of drinking behavior in
      rodents often involved unlimited access to alcohol over a period of weeks, with
      water and food freely available. Most studies investigating the pharmacology of
      alcohol drinking, on the other hand, use procedures in which access to alcohol is
      limited to a particular time each day. Reconciliation of findings between these
      two conditions likely depends on their sharing common genetic mechanisms as
      indicated, for example, by covariation in response to selection. To this end,
      high- and low-alcohol preferring (HAP and LAP, respectively) mice, selected for
      differences in 24-hr access alcohol drinking over a 4-week period, were subjected
      to a limited access alcohol drinking protocol. METHODS: During 2-hr sessions,
      mice had access to various concentrations of alcohol (7-15%, v/v) in the home
      cage for 2 hr a day, with ad libitum access to food and water. Additional
      sessions were conducted with no food present. RESULTS: Although both strains
      consumed alcohol and water during these sessions, HAP mice drank far more alcohol
      than did LAP mice. HAP but not LAP mice drank alcohol at a high rate early in the
      session compared with later in the session. Additionally, HAP mice responded to
      changes in alcohol concentration, whereas LAP mice did not. Removal of food did
      not influence alcohol drinking, although water drinking decreased following food
      removal. HAP mice reached appreciable blood alcohol concentrations after limited
      access. CONCLUSIONS: These findings indicate that in these selectively bred mice,
      alcohol drinking during limited and unlimited access may be genetically related,
      and that drinking during limited access sessions in HAP mice is likely for the
      pharmacological properties of alcohol.

PMID- 10397287
TI  - Alcoholics' deficits in the decoding of emotional facial expression.
AB  - The present study investigated emotional facial expression decoding in
      alcoholics. Twenty-five alcoholic patients at the end of the detoxification
      process were compared with 25 volunteers matched for age, sex, and education.
      They were presented with facial expressions of neutral, mild, moderate, or strong
      emotional intensity. Results indicate that alcoholics overestimate the intensity
      of emotional expressions and make more errors in their decoding with a special
      bias for anger and contempt. Moreover, this decoding deficit is not perceived by
      the alcoholic patients. A general model is proposed that links visuospatial
      deficits, abnormal processing of social information, interpersonal stress, and
      alcohol abuse.

PMID- 10397286
TI  - Innate differences of neuropeptide Y (NPY) in hypothalamic nuclei and central
      nucleus of the amygdala between selectively bred rats with high and low alcohol
      preference.
AB  - BACKGROUND: Neuropeptide Y (NPY) is a neuropeptide that has been demonstrated to
      produce anxiolytic effects when administered centrally. To examine the hypothesis
      that NPY might play a role in alcohol-seeking behavior, this study took advantage
      of the genetic differences of the alcohol-preferring (P) rats and alcohol
      nonpreferring (NP) rats, as well as the high alcohol-drinking (HAD) rats and low
      alcohol-drinking (LAD) rats, in voluntary alcohol consumption to examine if NPY
      neurons in the brains differ between these selected lines. METHODS: The NPY
      immunoreactivity (NPY-I) was measured using an established
      radioimmunohistochemical assay in discrete brain structures including the
      paraventricular hypothalamic nucleus (PVN), arcuate nucleus (ARC), and central
      nucleus of the amygdala (CeA). RESULTS: The quantitative data indicated that
      there was more NPY-I in the PVN and ARC of P rats than NP rats, whereas there was
      less NPY-I in the PVN and ARC of HAD rats than LAD rats. However, the NPY-I in
      the CeA was less in both the P and HAD rats than in the NP and LAD rats,
      respectively. Therefore, the data indicate that there are innate differences in
      the NPY-I in the brain between selectively bred rats with high and low alcohol
      preference. CONCLUSION: Because both P rats and HAD rats have high alcohol
      preference, the disparate finding between these two lines of rats suggests that
      the hypothalamic NPY neurons are probably not associated with alcohol preference.
      In contrast, consistent findings in the CeA of both P rats and HAD rats suggest
      that NPY in the CeA of P and HAD rats may contribute to the regulation of alcohol
      consumption. This is substantiated by a recent report showing that NPY-knockout
      mice drink significantly more ethanol, and transgenic mice that overexpress the
      NPY gene drink less alcohol, than wild-type mice. Together, the findings support
      the notion that NPY agonists that would enhance NPY function in the amygdala
      might be useful for the treatment of anxiety and alcoholism.

PMID- 10397288
TI  - Sialic acid: new potential marker of alcohol abuse.
AB  - BACKGROUND: A number of laboratory markers are suggested for the detection and
      monitoring of alcohol abuse. However, there is still a need to find better
      indicators of alcohol abuse. Sialic acid (SA) is the name for a series of acyl
      derivatives of neuraminic acids that occur as nonreducing terminal residues of
      glycoproteins or glycolipids in biological fluids and cell membranes. In this
      study, we investigated the diagnostic value of SA as a marker of alcohol abuse.
      METHODS: Sera from social drinkers (n = 38) and alcoholics (n = 77) were analyzed
      for sialic acid by a colorimetric assay and for carbohydrate-deficient
      transferrin (CDT) by a radioimmunoassay method. Mean corpuscular volume (MCV),
      gamma-glutamyltransferase (GGT), aspartate aminotransferase (ASAT), and alanine
      aminotransferase (ALAT) were determined by using routine methods. RESULTS: The
      sialic acid levels of both female and male subjects were significantly (p <
      0.001) increased among alcoholic subjects when compared with social drinkers. SA
      levels were decreased after 3 weeks of treatment. The sensitivity and specificity
      for SA, respectively, were 57.7 and 95.5 for women and 47.8 and 81.3 for men. The
      respective values for CDT were 57.7 and 95.5 for women and 78.3 and 100.0 for
      men; for GGT, 60.0 and 95.5 for women and 60.9 and 87.5 for men; for MCV, 52.4
      and 95.5 for women and 47.8 and 100.0 for men; for ASAT, 53.8 and 95.5 for women
      and 43.5 and 100.0 for men; and for ALAT, 38.5 and 90.9 for women and 39.1 and
      87.5 for men. Among women, SA and GGT, and among men CDT, showed the largest area
      under receiver operation curve. CONCLUSION: This study indicated that sialic acid
      levels were elevated by high alcohol consumption and reduced during abstinence,
      especially among women. Thus, sialic acid seems to be an interesting marker that
      needs further evaluation as a diagnostic tool for alcohol abuse.

PMID- 10397289
TI  - Impaired sleep in alcohol misusers and dependent alcoholics and the impact upon
      outcome.
AB  - BACKGROUND: There is very little work that has investigated the self-reported
      sleep status of alcohol misusers. This study addressed that imbalance. METHODS:
      The study consisted of two parts: 1) the outpatient study, a sample of DSM-IV
      alcohol-dependent subjects who were referred to an outpatient clinic and were
      given a series of questionnaires, including the Pittsburgh Sleep Quality Index
      (PSQI); and 2) the inpatient study, a group of DSM-IV alcohol-dependent subjects
      whose sleep was assessed by the Nottingham Health Profile (NHP) sleep subscore at
      the start of the study and again at the 12-week follow-up. Both the PSQI and NHP
      are self-report indices whereby higher scores indicate a poor sleep quality.
      RESULTS: In the outpatient study, the PSQI scores were significantly higher in
      the alcoholics (n = 31) compared with the controls (n = 49). There were no
      differences in the PSQI scores among mildly (n = 11), moderately (n = 10), and
      severely (n = 11) dependent drinkers. The PSQI total scores correlated with the
      Beck Depression Index but not with severity of dependence or alcohol problem
      scores. Sleep latency emerged as the most significant predictor of relapse, and
      sleeping badly was associated with poor outcome at the 12-week follow-up in the
      inpatient study. CONCLUSION: Self-reported sleep disturbance can provide
      clinicians with information to plan better treatment for alcohol misusers.

PMID- 10397290
TI  - Comparing the diagnostic accuracy of carbohydrate-deficient transferrin, gamma
      glutamyltransferase, and mean cell volume in a general practice population.
AB  - In certain populations, the biological alcohol marker carbohydrate-deficient
      transferrin (CDT) is known to have a high diagnostic accuracy. The aim of this
      study was to compare the diagnostic accuracy of CDT, gamma-glutamyltransferase
      (gamma-GT), and mean cell volume (MCV) in a general practice population; more
      specifically, to ascertain whether CDT is a better tool than gamma-GT and MCV for
      (early) recognition of excessive alcohol use. To represent the general practice
      situation as realistically as possible, three different drinking patterns are
      defined: irregular excessive, regular excessive, and very excessive. From a
      sample of 524 men from seven general practices, sensitivity, specificity, and
      predictive values of the three markers for the three drinking patterns were
      compared, and receiver-operating characteristic analysis was used to compare
      differences between the markers. The results indicate that drinking patterns do
      influence the (difference in) diagnostic accuracy. CDT has a higher diagnostic
      accuracy for all three drinking patterns than gamma-GT and higher predictive
      values for hazardous [(ir)regular excessive] drinking patterns than MCV. However,
      receiver-operating characteristic analyses failed to demonstrate a significant
      difference between these patterns. It is concluded that the performance of all
      tests is too low to be useful for screening procedures in a general population;
      however, some tests may be useful for case finding. CDT seems to be the best
      alcohol marker available, although the difference between CDT and MCV is small.

PMID- 10397291
TI  - Serum and saliva levels of sialic acid are elevated in alcoholics.
AB  - BACKGROUND AND METHODS: Recently, sialic acid has been suggested as a potential
      marker for alcohol abuse. In this study, social drinkers and alcoholics were
      analyzed with a modified version of Warren's method for sialic acid and
      traditional markers of alcohol abuse in serum (n = 38; n = 87), saliva (n = 36; n
      = 29), and urine (n = 37; n = 83), respectively. The alcoholics were
      participating in an alcohol dependency treatment program and were followed in
      this study for 5 weeks. RESULTS: The sialic acid concentrations in female and
      male alcoholics were significantly higher in serum (p < 0.001;p < 0.001
      respectively) and saliva (p < 0.05; p < 0.05) but not in urine, compared with
      social drinkers. The diagnostic efficiency of serum sialic acid was higher than
      that for traditional markers: 77% for female subjects and 64% for male subjects.
      The corresponding results for saliva were 72% and 53%. The sialic acid
      concentrations were significantly decreased during the alcohol dependency
      treatment program (after 5 weeks of treatment) in both females and males.
      CONCLUSIONS: This study confirms that serum sialic acid is a valuable marker for
      detecting and monitoring alcohol abuse. This work also indicates that sialic acid
      in saliva could be used possibly as a noninvasive marker for alcohol abuse.

PMID- 10397292
TI  - Self-reported alcohol-associated symptoms and drinking behavior in three ALDH2
      genotypes among Japanese university students.
AB  - BACKGROUND: Alcohol abuse is one of the most serious health problems among young
      adults. Nearly half of the Japanese population is sensitive to alcohol due to a
      genetic polymorphism in low K(m) aldehyde dehydrogenase (ALDH2). In the present
      study, we investigated the effects of the ALDH2 genotype on both self-reported
      alcohol-associated symptoms and alcohol drinking behavior among Japanese
      university students. METHODS: The study subjects were 423 (389 males and 34
      females) university students in a medical university. The subjects completed a
      questionnaire regarding self-reported alcohol-associated symptoms and alcohol
      drinking behavior. The ALDH2 genotype was determined through digestion of
      polymerase chain reaction (PCR) products by a restriction enzyme Ksp632I. The
      frequency of alcohol-associated symptoms generally increased in the order
      ALDH2*1/*1, ALDH2*1/*2, ALDH2*2/*2 among males. The frequency of those who drink
      > or = 5 days/week was less than 10% in all genotype groups. However, the
      frequency of those who drink 1-4 days/week was significantly higher in ALDH2*1/*1
      than that in ALDH2*1/*2 and in ALDH2*2/*2. A similar tendency also was observed
      in females. Mean amounts of alcohol consumption per occasion in the three ALDH2
      genotypes stratified by drinking frequency generally increased significantly in
      the order ALDH2*2/*2, ALDH2*1/*2, ALDH2*1/*1 in both sexes. The proportion of
      binge drinkers defined by those who drink ethanol of > or = 75 ml per occasion on
      average also increased in the order ALDH2*2/*2 (0.0%), ALDH2*1/*2 (9.8%),
      ALDH2*1/*1 (22.1%) among male drinkers (> or = 1 day/month). CONCLUSIONS: We for
      the first time demonstrated clear associations between the ALDH2 genotype, self
      reported alcohol-associated symptoms, and alcohol drinking behavior among
      Japanese university students.

PMID- 10397293
TI  - Behavioral and psychosocial profiles of alcohol-exposed children.
AB  - BACKGROUND: It is widely known that prenatal alcohol exposure is related to
      cognitive and behavioral deficits throughout childhood and adolescence. Much
      research has focused on understanding and quantifying the cognitive profile of
      children with fetal alcohol syndrome (FAS) with relatively less empirical
      research on behavioral or psychosocial adjustment. The primary purpose of this
      study was to examine the behavioral and psychosocial profile of children exposed
      to heavy amounts of alcohol prenatally. METHOD: Two groups of subjects were
      evaluated: an alcohol-exposed group (ALC) and a nonexposed control group (NC)
      each made up of 32 subjects matched for age, gender, and ethnicity. The alcohol
      exposed group consisted of children heavily exposed to alcohol in utero,
      including 19 children diagnosed with FAS. The Personality Inventory for Children
      (PIC) was completed by the caretaker of each child. Four validity/screening
      scales and 12 clinical scales were scored for all subjects. RESULTS: Analyses
      revealed significant group differences on four validity/screening scales and 12
      substantive scales. Within the ALC group, the profile of children without FAS was
      similar to that of children with FAS, with the exception that their profiles were
      consistent with less cognitive impairment. CONCLUSIONS: These findings indicate
      that in addition to previously reported cognitive impairments, heavy prenatal
      alcohol exposure is related to significant impairments in psychosocial
      functioning. Even children without alcohol-related physical anomalies suffer from
      impaired psychosocial functioning. Because impairments of this nature can
      interfere with functioning across multiple domains, effective early intervention
      programs should be considered for families of alcohol-exposed children.
      Furthermore, given the similarities of alcohol-exposed children with and without
      FAS, it is imperative to obtain prenatal alcohol exposure histories on all
      children experiencing cognitive or psychosocial deficits.

PMID- 10397294
TI  - Multiple previous alcohol detoxifications are associated with decreased medial
      temporal and paralimbic function in the postwithdrawal period.
AB  - BACKGROUND: Functional neuroimaging studies after alcohol cessation have
      demonstrated that chronic alcohol use globally reduces neuronal activity for
      several weeks. Less is known about the effects of previous alcohol use patterns
      on regional brain activity. Multiple previous alcohol detoxifications are
      associated with a worse clinical course and increased risk of seizures, perhaps
      due to sensitization of key brain structures. We performed the following imaging
      study in alcoholics in the postwithdrawal period to determine if blood flow in
      medial temporal structures would differ as a function of previous alcohol use
      (i.e., whether regions were kindled or sensitized due to multiple
      detoxifications). METHODS: Fourteen adults meeting DSM-IV criteria for alcohol
      dependence (mean age 35, 8 SD; 10 men) and participating in a double-blind
      detoxification medication study underwent a brain perfusion Tc99 m-ECD
      (Neurolite) single photon emission computed tomography scan on days 7 through 9
      (mean 7.6, .5 SD) after their last drink and 2 to 3 days since their last
      detoxification medication. Seven nonpsychiatrically ill, nonalcohol-dependent
      healthy adults were scanned as control subjects. RESULTS: Alcoholics compared
      with controls had widely reduced relative activity in cortical secondary
      association areas and relatively increased activity in the medial temporal lobes
      (p < 0.01). Five alcoholic patients with > or = 2 previous detoxifications were
      compared with five patients in their first detoxification (age and detoxification
      medication matched). Multiple detoxification patients had significantly lower
      relative activity in bilateral anterior temporal poles and medial temporal lobes
      and in visual cortex (p < 0.01) compared with first episode patients.
      CONCLUSIONS: These studies are consistent with other studies comparing alcoholics
      and controls. They also suggest that on day 7 of detoxification, alcoholic
      subjects with multiple previous detoxifications have decreased visual cortex,
      medial temporal lobes, and anterior paralimbic blood flow, compared with those in
      their first detoxification. Further studies seem warranted to confirm these
      initial exploratory results.

PMID- 10397295
TI  - Effects of early postnatal alcohol exposure on learning in the developing rat:
      replication with intubation method of delivery.
AB  - Early postnatal exposure to alcohol during early development produces deficits in
      learned persistence, as reflected in the partial reinforcement extinction effect
      (PREE) in weanling rats, and deficits memory-based learning, as shown by
      patterned single alternation (PSA) discrimination learning in preweanling rats.
      We report a partial replication of these effects using the intubation method
      instead of artificial rearing. Rat pups were intubated once per day with 4.5
      g/kg/day alcohol in a milk-based diet or control diet on postnatal days (PNDs) 4
      to 9, and then assessed for the PREE on PNDs 20 and 21 or PSA learning on PNDs 17
      and 18. Compared with previous artificial rearing reports, the intubation method
      produced healthier and heavier pups, and yielded a consistently lower and less
      variable blood alcohol levels. Even with the lower alcohol levels, intubation
      with alcohol eliminated the PREE. Intubation with alcohol had a weaker but still
      detrimental effect on PSA learning. These results suggest that alcohol exposure
      during development can produce behavioral deficits in the absence of the more
      severe effects on brain and body growth typically associated with fetal alcohol
      syndrome.

PMID- 10397296
TI  - Reversal of a postnatal alcohol-induced deficit in learned persistence in the rat
      by d-amphetamine.
AB  - Periodic (high peak) exposure to alcohol during early infancy in the rat has been
      shown to disrupt the partial reinforcement extinction effect (PREE), a measure of
      persistence learning, when rats were tested at weaning age. The current study
      examined the effects of d-amphetamine (0.3 mg/kg, i.p.) on the PREE after early
      postnatal exposure to alcohol (4.5 mg/kg) delivered in a milk-based diet or an
      isocaloric control diet via oral intubation once a day on postnatal days 4 to 9.
      On postnatal days 20 and 21, rats were trained on either a continuously
      reinforced or partially reinforced schedule of food reward, followed by
      extinction. Rats were randomly assigned to eight conditions, depending on diet,
      drug, and reward schedule. The results were (1) a replication of the finding that
      periodic (high peak) exposure to alcohol diminishes the PREE, and (2) that
      amphetamine restores the PREE to normal levels in alcohol-treated animals, and
      may reduce the PREE in control subjects. The possible role of noradrenergic and
      dopaminergic systems in situations of extinction and nonreward are discussed.

PMID- 10397297
TI  - Effects of ethanol treatment of proliferation and differentiation in a head and
      neck squamous cell carcinoma cell line.
AB  - INTRODUCTION: Epidemiologic studies have provided evidence that chronic ethanol
      consumption is an independent risk factor in upper aerodigestive tract cancer,
      but the underlying mechanisms are largely unknown. METHODS: To examine ethanol
      effects on mucosal keratinocytes in vitro, we used a squamous cell carcinoma of
      the head and neck (SCCHN) cell line as a model and, to exclude line specific
      effects, two other cell lines. The influence of ethanol on proliferation (using
      [3H]thymidine uptake/cell number), cell cycle distribution, cytokeratin pattern,
      and growth factor receptor expression (using FACS analyses) was investigated.
      RESULTS: Ethanol increased in a dose dependent manner (tested range 10(-3) M to
      10(-10) M) the [3H]thymidine uptake and cell number, with unaltered viability
      (>95%) in all concentrations. In all tested cell lines, addition of 10(-3) M
      ethanol caused: (a) a significant increase of cells in the S-phase of the cell
      cycle; (b) a shift of cytokeratin pattern that suggested inhibition of
      differentiation; and (c) significant upregulation of EGF, IL-4, and PDGF
      receptors. CONCLUSIONS: Our results demonstrated an increased proliferation and
      reduced differentiation induced by ethanol in mucosa derived neoplastic cells,
      which may enhance further growth of neoplastic cells. These effects may also be
      involved in the carcinogenesis of upper aerodigestive tract malignancies.

PMID- 10397298
TI  - Molecular mechanisms underlying alcohol-induced cardioprotection: contribution of
      hemostatic components. Introduction to the symposium.

PMID- 10397299
TI  - Blood coagulation.

PMID- 10397300
TI  - Effect of ethanol on platelet function.
AB  - Epidemiological studies have linked an inhibition of platelet function by
      ethanol, among other factors, to the cardioprotective effects of moderate ethanol
      consumption. Platelet defects have been noted in alcoholics and in human
      experimental studies. Importantly, in in vivo experimental settings, ethanol
      diminishes thrombus formation on damaged arterial walls. Ethanol inhibits
      platelet activation in vitro in response to diverse agonists. Phospholipase A2 is
      a major site for ethanol inhibition, corresponding to a reduction in the
      formation of stimulatory arachidonate metabolites. Additional signal transduction
      pathways are likely targets for ethanol including phosphoinositide-specific
      phospholipase C and cyclic AMP. The role of additional cofactors in the
      inhibition of platelet responses by ethanol is discussed.

PMID- 10397301
TI  - Endothelial cell fibrinolysis: transcriptional regulation of fibrinolytic protein
      gene expression (t-PA, u-PA, and PAI-1) by low alcohol.
AB  - Epidemiological studies have associated moderate alcohol consumption with a
      reduced risk for coronary artery disease (CAD) and myocardial infarction (MI).
      This cardioprotection may be attributed to alcohol-induced changes in a variety
      of cellular functions, including increased fibrinolysis. Fibrinolysis is
      important in regulating normal hemostasis. Endothelial cells (ECs) synthesize
      fibrinolytic proteins, t-PA, u-PA, and PAs inhibitor, PAI-1. Systemic factors,
      i.e., alcohol, that affect one or more of these components, resulting in
      increased EC fibrinolysis, will reduce the risk for thrombosis, CAD, and MI and
      afford cardioprotection. These studies will identify/define the effects of low
      ethanol (< 0.1%, v/v) on the expression of PAs, PAI-1, and surface-localized
      fibrinolytic activity in cultured ECs. Low ethanol exerted a short-term time- and
      dose-dependent increase (approximately 5- to 8-fold) in activity at approximately
      20 min and 0.05% ethanol, which was sustained for approximately 1 hr. On the
      other hand, a single brief exposure to low ethanol (< 0.1%, < 120 min), followed
      by 4-24 hr incubation in the absence of ethanol, showed a time- and dose
      dependent increase (approximately 2- to 3-fold) in PAs antigen/mRNA and a
      concomitant approximately 2- to 3-fold sustained increase (approximately 24 hr)
      in fibrinolytic activity. Further nuclear transcription run-on assays and
      transient transfection experiments, using pPAs/luc and pPAI-1/luc promoter
      constructs, demonstrated that low ethanol transcriptionally upregulates t-PA and
      u-PA gene expression and downregulates PAI-1 gene expression. These combined
      studies have described a feasible molecular mechanism by which low ethanol can
      induce and sustain increased surface-localized EC fibrinolysis that may underlie
      and contribute, in part, to the cardioprotective benefit associated with moderate
      alcohol consumption.

PMID- 10397302
TI  - An intelligent framework for the classification of the 12-lead ECG.
AB  - An intelligent framework has been proposed to classify an unknown 12-Lead
      electrocardiogram into one of a possible number of mutually exclusive and
      combined diagnostic classes. The framework segregates the classification problem
      into a number of bi-dimensional classification problems, requiring individual bi
      group classifiers for each individual diagnostic class. The bi-group classifiers
      were generated employing Neural Networks (NN), combined with a combination
      framework containing an Evidential Reasoning framework to accommodate for any
      conflicting situations between the bi-group classifiers. A number of different
      feature selection techniques were investigated with the aim of generating the
      most appropriate input vector for the bi-group classifiers. It was found that by
      reducing the original input feature vector, the generalisation ability of the
      classifiers, when exposed to unseen data, was enhanced and subsequently this
      reduced the computational requirements of the network itself. The entire
      framework was compared with a conventional approach to NN classification and a
      rule based classification approach. The framework attained a significantly higher
      level of classification in comparison with the other methods; 80.0% compared with
      66.7% for the rule based technique and 68.00% for the conventional neural
      approach.

PMID- 10397303
TI  - A framework for building cooperative software agents in medical applications.
AB  - Exploiting the information technology may have a great impact on improving
      cooperation and interoperability among the different professionals taking part to
      the process of delivering health care services. New paradigms are therefore being
      devised considering software systems as autonomous agents able to help
      professionals in accomplishing their duties. To this aim those systems should
      encapsulate the skills for solving a given set of tasks and possess the social
      ability to cooperate in order to fetch the required information and knowledge.
      This paper illustrates a methodology facilitating the development of
      interoperable intelligent software agents for medical applications and proposes a
      generic computational model for implementing them. That model may be specialized
      in order to support all the different information and knowledge related
      requirements of a Hospital Information System. The architecture is being tested
      for implementing a prototype system able to coordinate the joint efforts of the
      professionals involved in managing patients affected by Acute Myeloid Leukemia.

PMID- 10397304
TI  - Formal description of temporal knowledge in case reports.
AB  - Patient case analysis is an elementary and crucial process which clinicians are
      daily confronted with. The importance and complexity is reflected in the need to
      discuss cases in clinicopathological conferences and the documentation of more
      than 70,000 patient cases in MEDLINE. This paper introduces a generic patient
      case report language (PCRL) based on general medical temporal concepts to
      formalise temporal knowledge as present in case descriptions. The lack of such a
      generic technique is reflected by the fact that computers are very restrictive in
      accepting patient specific temporal information. Acceptance is almost always
      controlled and guided by specific predefined disease or treatment models. We
      strive for a case library consisting of unambiguous patient case descriptions
      formulated independent from future use.

PMID- 10397305
TI  - Feature selection for optimized skin tumor recognition using genetic algorithms.
AB  - In this paper, a new approach to computer supported diagnosis of skin tumors in
      dermatology is presented. High resolution skin surface profiles are analyzed to
      recognize malignant melanomas and nevocytic nevi (moles), automatically. In the
      first step, several types of features are extracted by 2D image analysis methods
      characterizing the structure of skin surface profiles: texture features based on
      cooccurrence matrices, Fourier features and fractal features. Then, feature
      selection algorithms are applied to determine suitable feature subsets for the
      recognition process. Feature selection is described as an optimization problem
      and several approaches including heuristic strategies, greedy and genetic
      algorithms are compared. As quality measure for feature subsets, the
      classification rate of the nearest neighbor classifier computed with the leaving
      one-out method is used. Genetic algorithms show the best results. Finally, neural
      networks with error back-propagation as learning paradigm are trained using the
      selected feature sets. Different network topologies, learning parameters and
      pruning algorithms are investigated to optimize the classification performance of
      the neural classifiers. With the optimized recognition system a classification
      performance of 97.7% is achieved.

PMID- 10397306
TI  - Use of artificial neural networks in modeling associations of discriminant
      factors: towards an intelligent selective breast cancer screening.
AB  - In order to improve the costs/benefits ratio of breast cancer (BC) screenings,
      the author evaluated the performance of a back-propagation artificial neural
      network (ANN) to predict an outcome (cancer/not cancer) to be used as
      classificator. Networks were trained on data from familial history of cancer, and
      sociodemographic, gynecoobstetric and dietary variables. The ANN achieved up to
      94.04% of positive predictive value and 97.60% of negative predictive value.
      Results could operate as guidelines for preselecting women who would be
      considered as a BC high-risk subpopulation. The procedure--not only based on age
      factor, but on a multifactorial basis--appears to be a promising method of
      achieving a more efficient detection of preclinical, asymptomatic BC cases.

PMID- 10397307
TI  - Clostridia and clostridioses.

PMID- 10397308
TI  - Phylogenetic basis for a taxonomic dissection of the genus Clostridium.
AB  - The 16S rDNA-based phylogenetic analysis of the genus Clostridium has been
      completed by determination of the phylogenetic position of the type strains of 15
      species and two non-validated species. These strains are members of phylogenetic
      clusters I, III, IV, V, IX, XIVa and XVIII as defined previously by Collins et
      al. [Int. J. Syst. Bacteriol. 44 (1994) 812-826]. Members of the genus
      Clostridium span a large evolutionary distance and the genus is not a
      phylogenetically coherent taxon but is intermixed with members of different
      genera, exhibiting a combination of Clostridium- and non-Clostridium-type
      properties. Anaerobacter polyendosporus, Syntrophococcus sucromutans and
      Acetivibrio multivorans also cluster within the radiation of Clostridium species.
      Although several taxa have been described for former Clostridium species with
      distinct phenotypic properties, the majority of Clostridium species, which are
      not members of the core cluster I, can at present not be reclassified as long as
      taxon-specific, phenotypic properties are not available.

PMID- 10397309
TI  - Typing of sheep clinical isolates and identification of enterotoxigenic
      Clostridium perfringens strains by classical methods and by polymerase chain
      reaction (PCR).
AB  - A simple procedure was developed to identify toxitypes of Clostridium perfringens
      of different origins. Ninety strains of C. perfringens were identified by
      classical bacteriological methods, typing of the strains was done by a
      seroneutralisation test on mice. Production of enterotoxin was tested and all
      strains were analysed by PCR using gene of toxin alpha, gene of toxin E, gene of
      toxin beta and gene of enterotoxin. Simple amplification (amplifying one gene),
      and duplex and triplex amplification (amplifying two and three genes
      simultaneously) were performed. In the conditions of the experiment, the PCR
      method has proved efficacious. The specificity and sensitivity are excellent and
      superior to those of the classical methods. The prophylaxis of enterotoxaemia in
      animals is achieved by vaccination, the PCR technique can thus become a first
      choice tool for the identification and typing of the C. perfringens strains which
      initiate these diseases. In turn, this would simplify the development of vaccines
      adapted to the epidemiological situation.

PMID- 10397310
TI  - Identification of Clostridium botulinum with API 20 A, Rapid ID 32 A and RapID
      ANA II.
AB  - Three commercially available test systems for the identification of anaerobic
      bacteria were evaluated for the identification of 18 proteolytic group I and 69
      non-proteolytic group II Clostridium botulinum, four Clostridium sporogenes and
      18 non-toxigenic group II C. botulinum-like strains. All proteolytic C. botulinum
      strains were misidentified by the Rapid ID 32 A and RapID ANA II, while 14
      strains and all C. sporogenes strains were identified as C. botulinum or C.
      sporogenes by the API 20 A. Reversely, all non-proteolytic C. botulinum strains
      were misidentified by the API 20 A while the Rapid ID 32 A recognized 67 and
      RapID ANA II 68 strains. All C. sporogenes strains were recognized by the RapID
      ANA II, while the Rapid ID 32 A recognized one strain. All non-proteolytic non
      toxigenic strains were identified as C. botulinum group II by the Rapid ID 32 A,
      17 strains by the RapID ANA II, and one strain by the API 20 A. The results show
      that these test systems do not provide a reliable method for identification of C.
      botulinum.

PMID- 10397311
TI  - Detection of Clostridium novyi type B alpha toxin by cell culture systems.
AB  - Ten permanent cell lines were examined for their reaction to the Clostridium
      novyi alpha toxin. The action of the toxin was determined after 3 days by
      microscopic examination and the MTT assay. The alpha toxin exhibited the
      strongest effect on ESH-L cells rather than other cell lines. Vero and SFT-R
      cells reacted in a comparable way, but less sensitively. We were able to show
      that the cytopathic effect on the three types of cells was neutralised by the
      international standard for gas gangrene antitoxin (C. novyi) but in no case by
      heterologous antisera. Our results have shown that the three cell lines were
      specific indicators for the detection of the cytopathic effect of alpha toxin.
      The cytopathic effect can be measured reproducibly by the cell culture assay
      used. These results are suitable as the starting point for the development of the
      neutralisation test using cell cultures.

PMID- 10397313
TI  - Short protocol for pulsed field gel electrophoresis of a variety of Clostridia
      species.
AB  - While pulsed field gel electrophoresis has become an important tool for
      genotyping of bacteria, one of its drawbacks is that standard methods are rather
      time-consuming. In order to overcome this problem, shortened procedures for DNA
      preparation have been developed for some bacterial species. The aim of this study
      was to examine if a short procedure used for pulsed field gel electrophoresis of
      Clostridium botulinum could be applied to other Clostridia species. For this, the
      protocol was modified and used to prepare the DNA of 34 strains of 25 different
      Clostridia species. In contrast to a standard procedure, which takes at least 5
      days from DNA extraction to completion of the electrophoresis, this protocol
      yielded results within 2 days. In order to directly compare the results of the
      short protocol with those of the standard, long procedure, parallel DNA
      preparations were performed using both methods and the two DNA samples thus
      obtained per strain were then run on the same gel. Briefly, the procedure was as
      follows. After embedding the bacterial cells in agarose, the agarose blocks were
      incubated for 1 h in lysis solution containing lysozyme, mutanolysin, lysostaphin
      and RNase. This was followed by a 1-h proteinase K treatment. Then, slices were
      cut from the agarose blocks and washed for 15 min in TE buffer, these washes were
      repeated four times with fresh TE. After a 2-h restriction with SmaI,
      electrophoresis was carried out overnight.

PMID- 10397312
TI  - Molecular methods for the analysis of Clostridium perfringens relevant to food
      hygiene.
AB  - Clostridium perfringens continues to be a common cause of food-borne disease. It
      produces an enterotoxin (CPE) which is released upon lysis of the vegetative cell
      during sporulation in the intestinal tract. Catering premises with insufficient
      cooling and reheating devices often seem to be the cause of outbreaks of C.
      perfringens food poisoning. Typing of C. perfringens is of great importance for
      investigating sources of food poisoning cases and for studying the epidemiology
      of this microorganism. This report describes the examination of 155 C.
      perfringens isolates by molecular methods. Isolates were taken from 10 food
      poisoning outbreaks and cases (n = 34, food and fecal isolates) and from meat and
      fish pastes (n = 121). Isolates were characterized by plasmid profiling,
      ribotyping, and/or macrorestriction analysis by pulsed-field gel electrophoresis
      (PFGE). Results show that all three methods are suitable for classifying C.
      perfringens isolates below the species level. Ribopatterns and PFGE patterns can
      be interpreted more easily than plasmid profiling results and can be recommended
      for contamination studies and epidemiologic investigation of food poisonings
      associated with C. perfringens.

PMID- 10397314
TI  - Development and evaluation of various enzyme-linked immunosorbent assays for the
      detection of Clostridium perfringens beta anti-toxins.
AB  - The aim of our work was to develop an enzyme-linked immunosorbent assay for the
      detection of antibodies against the Clostridium perfringens beta toxin. For this
      purpose, five different ways of performing an enzyme-linked immunosorbent assay
      were investigated. Positive and negative sera of different animals and partially
      purified beta toxin were used. In all enzyme-linked immunosorbent assay tests,
      microplates were first coated with monoclonal antibodies against the C.
      perfringens beta toxin. Actually, the first three ways of performing enzyme
      linked immunosorbent assay proved to be an inhibition or a blocking enzyme-linked
      immunosorbent assay. In the first of these modifications, the examined serum was
      added on a microplate after the toxin. In the second two tests, they were added
      simultaneously after they were incubated together (60 min at room temperature or
      overnight at 4 degrees C, respectively). An anti-toxin conjugate was used for the
      detection. It was also used in a competitive enzyme-linked immunosorbent assay,
      where it was added together with the examined serum on the microplate, to which
      the toxin was already bound. The fifth way of performing an enzyme-linked
      immunosorbent assay differed from others by the use of conjugated anti-species
      immunoglobulin for the detection. The biggest differences in absorbances between
      positive and negative sera were found in the blocking enzyme-linked immunosorbent
      assay, where the mixture of the toxin and the examined serum were previously
      incubated overnight at 4 degrees C. The smallest differences in absorbance were
      found when anti-species conjugates were used.

PMID- 10397315
TI  - Development and prevalidation of two different ELISA systems for the potency
      testing of Clostridium perfringens beta and epsilon-toxoid containing veterinary
      vaccines.
AB  - The potency testing of Clostridium perfringens mono- and multicomponent
      veterinary vaccines is currently performed with the mouse neutralisation test
      (MNT) to estimate levels of C. perfringens beta- and epsilon-antitoxin levels in
      the sera of rabbits immunised with the vaccine. Two in vitro methods based on
      monoclonal antibodies (mAb) have been developed for the determination of specific
      antibodies against C. perfringens beta-toxin (capture ELISA) and epsilon-toxin
      (competitive ELISA) in these sera. Both test systems show high specificity and
      good reproducibility. These ELISA procedures were used in addition to the routine
      batch potency test in mice (MNT) to determine beta- and epsilon-antitoxin levels
      in 523 samples of rabbit serum. There was good agreement between the rank order
      of sera determined in vivo and the rank order determined in vitro. Linear
      regression analysis gave correlation coefficients of 0.88 for the capture ELISA
      and 0.41 for the competitive ELISA, with a significance level of P < 0.01 in both
      cases. Furthermore, a prevalidation study was carried out in four laboratories to
      evaluate the transferability of the ELISA procedures and the interlaboratory
      reproducibility of the results. Three coded serum samples were tested several
      times. The results indicated that both ELISA systems are suitable candidates to
      replace the MNT used for the potency testing of beta- and epsilon-toxoid in mono-
      and multicomponent veterinary vaccines. However, these assays still need to be
      validated in an international collaborative study.

PMID- 10397316
TI  - Quantitation of commercial equine tetanus antitoxin by competitive enzyme-linked
      immunosorbent assay.
AB  - In the USA, the potency of commercially prepared equine tetanus antitoxin is
      determined by the method outlined in the Code of Federal Regulations, Title 9,
      Part 113.451. In the current test, commercial equine tetanus antitoxin is tested
      by a toxin neutralization test in guinea pigs. The in vivo test measures
      antitoxin content through effectiveness of protection of guinea pigs injected
      with diluted mixtures of antitoxin and a standard toxin. A competitive enzyme
      linked immunosorbent assay, designed as an in vitro alternative to the in vivo
      test, measures antitoxin content based on a competitive reaction between standard
      or unknown serum and murine monoclonal antibody specific for tetanus toxin. The
      monoclonal antibody used in the assay delayed death in mouse passive protection
      studies and reacted with the C fragment of tetanus toxin. No cross-reaction was
      observed when the antibody was tested with the toxins of Clostridium chauvoei, C.
      novyi, C. perfringens, or C. sordellii. The in vitro test will measure the
      antitoxin content of serum samples containing 100-1500 units of antitoxin.
      Tetanus antitoxin titers obtained by the competitive enzyme-linked immunosorbent
      assay compared favorably with the toxin neutralization test conducted in guinea
      pigs. The in vitro assay serves as a feasible alternative to the in vivo test
      because it can be completed in less time, is reproducible, and eliminates the use
      of test animals.

PMID- 10397317
TI  - Development of in vitro assays for the detection of botulinum toxins in foods.
AB  - Currently the only accepted method for the detection of botulinum neurotoxin in
      contaminated samples is the mouse bioassay. Although highly sensitive this test
      has a number of drawbacks: it is expensive to perform, lacks specificity and
      involves the use of animals. With increasing resistance to such animal tests
      there is a need to replace the bioassay with a reliable in vitro test. Over the
      past six years it has been demonstrated that all the botulinum neurotoxins act
      intracellularly as highly specific zinc endoproteases, cleaving proteins involved
      in the control of secretion of neurotransmitters. In the work described, this
      enzymatic activity has been utilised in assay formats for the detection in foods
      of neurotoxin of the serotypes involved in food-borne outbreaks in man. These
      assays have been shown to have a greater sensitivity, speed and specificity than
      the mouse bioassay. It is envisaged that such assays will prove realistic
      alternatives to animal-based tests.

PMID- 10397318
TI  - Detection of the beta2 toxin gene of Clostridium perfringens in diarrhoeic
      piglets in The Netherlands and Switzerland.
AB  - The two studies presented here were done to determine the prevalence of the
      alpha, beta, epsilon and enterotoxin genes and the novel beta2 toxin gene of
      Clostridium perfringens in neonatal or pre-weaned piglets with diarrhoea or
      necrotic enteritis. All C. perfringens isolates were positive for the alpha and
      negative for the epsilon and enterotoxin gene, implying that only non
      enterotoxigenic type A and C strains were detected. The most important findings
      were the relatively high prevalence of the beta2 toxin gene in isolates from
      diarrhoeic piglets in both studies, and, in one of the two studies, absence of
      strains with only the alpha and beta toxin gene. These data are supportive for
      the suggestion of a causal relationship of beta2 toxin-producing strains with
      digestive tract diseases in piglets.

PMID- 10397319
TI  - The control of necrotic enteritis in sucking piglets by means of a Clostridium
      perfringens toxoid vaccine.
AB  - Necrotic enteritis in sucking piglets constitutes a serious problem in piglet
      rearing units because of the high morbidity and mortality associated with the
      disease. The primary causal agent is Clostridium perfringens type C. The beta
      toxin plays a decisive role in the pathogenesis of this disease. A toxoid vaccine
      for use in sows has been developed and studied in field trials. The European
      Pharmacopoeia Monograph on vaccines for use in animals lays down a method of the
      efficacy testing based on the immunization of rabbits, the collection of pooled
      sera and the subsequent assay of anti-toxin antibodies in mice using an
      appropriate test toxin. The vaccine is regarded as effective if it induces a
      minimum of 10 IU of beta-anti-toxin per ml of rabbit serum. We have established a
      range of 17.14-98.23 IU beta-anti-toxin per ml rabbit serum induced by a sample
      of C. perfringens toxoid vaccine. The vaccine has been used under field
      conditions in different rearing units at the same time, mostly in the form of
      emergency vaccinations following the outbreak of disease. The outcome of
      vaccination was evaluated by recording the total numbers of piglets born alive
      and the piglet losses. Use of the vaccine, coupled with other measures, resulted
      in an approximately 30% reduction in the number of losses.

PMID- 10397320
TI  - Necrotic enteritis challenge models with broiler chickens raised on litter:
      evaluation of preconditions, Clostridium perfringens strains and outcome
      variables.
AB  - The effect of Clostridium perfringens challenge, number of challenge days, and
      pre-challenge antibiotic treatment on the induction of necrotic enteritis in
      broiler chickens raised on litter was studied, and the relationship between
      bacterial counts and frequency of gut lesions was evaluated. Specific intestinal
      lesions in randomly selected birds were present despite a lack of disease
      specific mortality. Challenge, number of challenge days and frequency of lesions
      were associated with median counts of C. perfringens. The effect of pre-challenge
      C. perfringens counts and antibiotics cannot be evaluated unless procedures for
      the control of pre-challenge infection and methods for the differentiation
      between wild-type and challenge strains are established.

PMID- 10397321
TI  - Liver lesions seen at slaughter as an indicator of necrotic enteritis in broiler
      flocks.
AB  - Historical data of necrotic enteritis incidence and carcass condemnations owing
      to liver lesions in south-eastern Norway during 1978-1998 revealed covariance in
      the occurrence of the two variables. In histological examination during the first
      half of 1998, 33 of 45 sampled carcasses condemned owing to liver lesions showed
      histopathological changes consistent with earlier described Clostridium
      perfringens-associated hepatitis. The results suggest that the occurrence of
      necrotic enteritis in broiler flocks may be monitored by using meat inspection
      data on liver lesions.

PMID- 10397322
TI  - Detection of neutralizing antibodies against alpha-toxin of different Clostridium
      septicum strains in cell culture.
AB  - Clostridium septicum, a ubiquitious organism, is the pathogen which causes the
      classical malignant edema after injuries. Because of its strong cytotoxic alpha
      toxin, infections are often lethal. To prevent losses in animals, vaccination
      with alpha-toxoid vaccines is carried out. Quality control of the vaccines is
      done by a neutralization test in mice. A cytotoxin test and as an alternative
      method to detect neutralizing antibodies, a cytotoxin inhibition test was
      standardized. In the studies, alpha-toxin of the C. septicum reference strain (NC
      547) from the National Collection of Type Cultures was compared with alpha-toxin
      of a field strain from an outbreak in Germany. Sera from five heterologous
      polyvalent and three monovalent vaccines from eight rabbit groups were available.
      Each vaccination had been carried out according to the procedure of the German
      Pharmacopoeia. In three out of the five sera of the groups vaccinated with the
      heterologous polyvalent vaccine, cytotoxin neutralizing antibodies were detected.
      High antibody titers were observed in sera of rabbits vaccinated with a vaccine
      of strain NC 547, lower titers in the sera of rabbits vaccinated with a vaccine
      of the field strain. No cytotoxin neutralizing antibodies could be found in the
      sera of rabbits vaccinated with the monovalent C. chauvoei vaccine. The toxins of
      all strains showed the same ranking of the vaccines. Vaccines which caused high
      antibody titers in the animals were detected by all toxins as such, as well as
      vaccines which had medium or low antibody inducing capacity. The results were
      independent of the C. septicum strain used for the production of alpha-toxin.

PMID- 10397323
TI  - Production and purification of Clostridium botulinum type C and D neurotoxin.
AB  - Neurotoxins of Clostridium botulinum are needed in basic neurologic research, but
      as therapeutic agent for certain neuromuscular disorders like strabism as well. A
      method for the production and purification of botulinum neurotoxins C and D is
      reported using a two-step hollow-fiber cross flow filtration and a newly
      developed chromatographic purification procedure. Hollow-fiber filtration proved
      to be a rapid and safe concentration and pre-purification step, which can easily
      be scaled up. The chromatographic purification included hydrophobic interaction,
      anion exchange and size exclusion chromatography runs. Botulinum neurotoxins C
      and D could be recovered with an overall yield of 12.6% and 10.6%, respectively.
      A specific toxicity of 1.86 x 10(7) minimal lethal dose mg(-1) (type C) and 5.26
      x 10(7) minimal lethal dose mg(-1) (type D) was determined in the mouse bioassay.

PMID- 10397324
TI  - In vitro evaluation methods for Clostridium botulinum type C and D vaccines.
AB  - Reagents were prepared for use in ELISAs to determine the concentration of the
      antigenic components of Clostridium botulinum type C and D. The results obtained
      were compared with the L+dose assay and a good correlation was found between the
      two assays for measurement of the C and D neurotoxin concentration. These ELISAs
      were also used to determine the concentration of the neurotoxins in toxoid form.
      The relationship between the C neurotoxin dose, in toxoid form, and the immune
      response in guinea pigs could be deduced from the data obtained. The relationship
      for the D neurotoxin was not that clear, as the same concentration of the antigen
      resulted in variable potency values. However, these ELISAs can be used to
      formulate the concentration of the C and D components in the final bivalent
      vaccine. Replacement of the preliminary potency assay on the monovalent
      components after production with the in vitro assays will shorten the total
      production time of the vaccine by about 60 days. The economical and ethical
      implications are the reduction in the use of animals to evaluate the vaccine.

PMID- 10397325
TI  - Detection of the etx gene (epsilon-toxin inducer) in plasmids of high molecular
      weight in Clostridium perfringens type D.
AB  - The purpose of this work is to correlate the production of epsilon-toxin in a set
      of strains of Clostridium perfringens type D with the presence of the etx gene,
      either genomic or in plasmids. Total DNA obtained from strains with a different
      level of toxin production was explored by PCR and all the strains showed the
      amplification signal. Different methods were used to obtain plasmid profiles and
      all of the bands were assayed by PCR. The detection of the etx gene was only
      shown in several high molecular plasmids. These results were confirmed by a
      Southern blot. We suggest that the localization of the etx gene in different
      plasmids could be associated with the epsilon-toxin production level.

PMID- 10397326
TI  - Study of the presence of the spores of Clostridium botulinum in honey in Brazil.
AB  - The isolation of Clostridium botulinum from honey samples is described. Botulism
      is characterized as an intoxication provoked by ingestion of contaminated foods
      with this toxin. Infant botulism happens by the ingestion of spores of C.
      botulinum together with food that in special conditions of the intestinal tract,
      such as those present in babies of less than 1 year old, will allow the
      germination and colonization of the intestine with production and absorption of
      botulinic toxin. The samples were subjected to dilution and to a thermal shock
      and cultivated in modified CMM (Difco). Cultures were subjected to Gram smears
      and toxicity tests in mice. The toxic cultures were purified in RFCA (Oxoid)
      plates and incubated in anaerobic jars. Positive samples were typed using the
      mouse assay neutralization test. From the 85 honey samples analyzed, six were
      positive for C. botulinum (7.06%), and identified as producers of type A, B, and
      D toxins.

PMID- 10397328
TI  - CD79a detected by ZL7.4 separates chronic lymphocytic leukemia from mantle cell
      lymphoma in the leukemic phase.
AB  - Both B-cell chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are
      characterized by a lymphoproliferation of neoplastic CD5+ B-cells, but an
      accurate differential diagnosis between these two malignancies is vitally
      important for guiding treatment options. Because CD79a has been identified as a
      pan-B marker, we intended to use it in place of CD19 to identify B-cells and to
      use CD23 to distinguish between CLL and MCL in the leukemic phase. Anti-CD79a
      (clone ZL7.4) was used to detect the Igalpha/mb1 protein in fresh CD5+ B
      lymphocytes by dual-channel flow cytometry. Expression of CD19 and CD23 were
      similarly assessed. As expected, CD19 was expressed in all specimens, whereas
      CD23 expression was zero in 3/4 MCLs, weak in 1/4 MCLs, and 2/8 CLLs (10-19%) and
      stronger in 6/8 CLLs (> or =45%). However, although all the CD19+/CD5+ cells of
      MCL expressed high CD79a levels, CD79a expression was negligible or absent in 8/8
      CLL specimens (mean positivity for CD79a = 2.41 +/- 2.71%). CD79a (ZL7.4) levels
      may provide a more reliable distinction than CD23 levels between CLL and MCL. If
      these results hold up in a larger series, we recommend that the ZL7.4 antibody
      should be considered in routine marker panels for CLL and low-grade lymphoma.

PMID- 10397327
TI  - Induction of CD69 antigen on normal CD4+ and CD8+ lymphocyte subsets and its
      relationship with the phenotype of responding T-cells.
AB  - We evaluated phenotype and apoptotic status of normal CD4+CD69+ and CD8+CD69+
      peripheral blood T-lymphocytes after short-term challenge with escalating
      concentrations of phytohemagglutinin (PHA). The frequency of CD69-coexpressing
      CD4+ and CD8+ T-cells and CD69 staining intensity increased following T-cell
      mitogenic stimulation; these changes were proportional to PHA concentration in
      culture medium. A considerable fraction of lymphocytes underwent blast
      transformation, displaying increased forward and side scatter signals.
      Interestingly enough, PHA-responsive T-cells exhibited a predominantly
      CD25negCD38negTCRalphabetapos phenotype; APO-1/Fas antigen (CD95) could be
      detected on a minority of activated CD69+ T-cells. A considerable proportion of
      CD69+ lymphocytes expressed intracellular perforin; in addition, an average 16+/
      6% CD69+ T-lymphocytes were apoptotic after 4 h of stimulation, as evaluated by 7
      amino-actinomycin-D staining and by annexin-V binding. CD69+ activated
      lymphocytes comprise phenotypically heterogeneous cell subpopulations potentially
      devoted to diverse immunological functions, i.e., proliferation, apoptosis, or
      cell cytotoxicity; moreover, our findings indicate that CD69 expression is
      proportional to the intensity of the activating stimulus and that the capacity to
      upregulate CD69 antigen following short-term mitogenic challenge may be
      restricted to unactivated CD38negCD25negTCRalphabetapos T-lymphocytes.

PMID- 10397329
TI  - Analysis of cells in cerebrospinal fluid from patients with neurocysticercosis by
      means of flow cytometry.
AB  - The events of the cellular immune response in neurocysticercosis (NC) are not
      fully understood. Studies of the CD3, CD3/CD4, CD3/CD8, CD45/CD19, and CD45/CD56
      molecules and activation-related CD69 molecule in cells from the cerebrospinal
      fluid (CSF) and peripheral blood (PB) of patients with NC may provide a better
      elucidation of the inflammatory and immunological events occurring in this
      disease. Seven patients with NC and 3 individuals with other disorders were
      evaluated by a three-color flow cytometric method. CD69 was detected in a higher
      percentage of cells in all CSF samples from patients, but not in PB or CSF from
      the control group. The percentage of CD3+ cells did not differ significantly in
      CSF and PB cells from patients and controls. The predominance of CD3+CD8+ cells
      was observed in CSF from one patient and in PB from 2 patients, who were in stage
      III of the disease (inflammatory process). The percentage of CD45+CD19+ cells was
      higher in CSF than in PB from patients who presented anti-cysticercus antibodies
      in CSF. The percentage of CD45+CD56+ cells in CSF was higher than in PB, but this
      rate was similar to reference values reported by other authors. Our data suggest
      that the cytometric method applied to a larger number of CSF samples may provide
      a better understanding of the cell-mediated immune response involved in NC.

PMID- 10397330
TI  - Role of DNA aneuploidy, overexpression of p53 gene product, and cellular
      proliferation in the progression of gastric cancer.
AB  - DNA aneuploidy, p53 overexpression, and high cell proliferation frequently occur
      in gastric cancer. However, little is known about the time of their appearance
      throughout cancer progression. Therefore, the objective of the present study was
      to determine when such abnormalities occur during gastric cancer progression. We
      classified the gastric cancers examined into intestinal (n = 65) and diffuse (n =
      34) types. DNA ploidy was examined using flow cytometry and expression of MIB-1
      and p53 immunoreactivity were studied using the avidin-biotin complex method in
      three stages of gastric cancer (mucosal, submucosal, deeply invasive cancer,
      i.e., advanced cancer). The incidence of DNA aneuploidy in intestinal-type
      mucosal cancers (15/27, 55.6%) was lower than that of submucosal invasive cancers
      (14/16, 87.5%) or advanced cancers (19/22, 86.4%), while a low incidence of DNA
      aneuploidy was observed in each diffuse-type cancer group (mucosal, 1/12, 8.3%;
      submucosal invasive, 3/9, 33.3%; advanced, 8/14, 57.1%). Although overexpression
      of the p53 gene in intestinal-type cancer was found in early stage, that in
      diffuse-type cancer was observed in advanced stage. Among the intestinal-type
      mucosal cancers, the MIB-1 percent positive was higher in aneuploid tumors than
      diploid ones. DNA aneuploidy and overexpression of the p53 gene may play an
      important role in the early tumorigenesis of intestinal-type gastric cancer and
      in the late event of tumorigenesis of diffuse-type gastric cancer.

PMID- 10397331
TI  - Proportion of S-phase tumor cells measured by flow cytometry is an independent
      prognostic factor in meningioma tumors.
AB  - Meningiomas are tumors in arachnoid cells which represent up to one fifth of all
      intracranial tumors and up to a quarter of spinal neoplasias. Although
      meningiomas have classically been considered to be benign tumors, it has also
      been well-established that they show a heterogeneous clinical outcome. To the
      best of our knowledge no study has yet been performed in which the independent
      prognostic value of both DNA ploidy and cell cycle has been simultaneously
      assessed in a large series of meningioma tumors. The aim of the present study was
      to prospectively explore the prognostic value of DNA ploidy status and the
      proliferative rate of tumor cells in a series of 105 consecutive meningioma
      patients studied at diagnosis. Both the presence of DNA aneuploidy and the
      proportion of S-phase tumor cells were analyzed in all cases in fresh tumors
      obtained during diagnostic surgery. From the technical point of view, we followed
      the recommendations of the Consensus Conference on Flow Cytometry DNA Analysis
      held in October 1992. Our results show that meningioma tumors display a
      relatively low incidence of DNA aneuploidy (14%), and they usually show a low
      proliferative rate (mean percentage of S-phase cells of 1.3 +/- 0.3%). The
      presence of DNA aneuploidy was associated with a higher incidence of aggressive
      histopathologic subtypes (P = 0.045), a greater age (P = 0.009), location at the
      cerebral convexity (P = 0.004), and a greater proportion of S-phase cells (P =
      0.005). In contrast, no significant association between the DNA ploidy status of
      meningioma patients and their disease-free survival was found (P = 0. 1).
      Regarding the proliferative activity of neoplastic cells, we found that a high
      proportion of S-phase cells (>1.8%) was associated with a significantly lower
      mean age (P = 0.007), aggressive histopathologic subtypes (P = 0.03), a higher
      incidence of DNA aneuploidy (P = 0.004), and a significantly shorter disease-free
      survival (P < 0.004). Multivariate analysis of prognostic factors showed that the
      proportion of S-phase tumor cells was the most powerful independent prognostic
      factor in meningioma patients (P = 0.02). In summary, we conclude that the
      proportion of S-phase tumor cells represents the individual parameter with the
      highest value for predicting disease-free survival in meningioma patients.

PMID- 10397332
TI  - Multicenter study of reference stabilized human blood for lymphocyte
      immunophenotyping quality control in flow cytometry. GEIL.
AB  - The development of automated methods and normative rules, as well as the
      dependence of some therapeutic approaches on lymphocyte subsets counts, has led
      to the appearance of calibration reagents. Such reagents are expected to perform
      equally well in very different settings. We developed a multicenter trial to
      evaluate the performance of a new quality control reagent, i.e., stabilized blood
      to be used in immunophenotyping laboratories. Aliquots of the same batch of
      stabilized blood were shipped to 45 French and Belgian laboratories on a Monday
      and had to be tested for percentages and absolute counts of at least CD3-, CD4-,
      and CD8-positive lymphocytes on 4 consecutive days. The percentages and absolute
      counts obtained on each assay were recorded, as well as the type of lysis used,
      the trademark of reagents, and the brand of flow cytometer. The mean values
      collected did not differ significantly from those expected by the manufacturer.
      Absolute counts generated through one-step techniques displayed lower CVs. This
      new reagent therefore appears to be a robust product, liable to yield consistent
      results in the array of different conditions represented by routine laboratories,
      and it could be useful for quality control procedures.

PMID- 10397333
TI  - Age-related changes of immunophenotypically immature lymphocytes in normal human
      peripheral blood.
AB  - The presence of phenotypically immature lymphocytes in umbilical cord blood has
      been a controversial topic. Moreover, their changes with age have not been
      systematically evaluated. In the present study, relative and absolute numbers of
      CD34+, CD10+CD19+, and CD4+CD8+ cell subsets were determined in umbilical cord
      blood from 12 full-term normal newborns, 43 children aged 1 month to 6 years, and
      10 young adults. The samples were processed by whole-blood lysis and monoclonal
      antibody staining, and cells were analyzed by flow cytometry. Immature cells were
      present in cord blood and progressively declined in both absolute and percentage
      numbers with age, each according to a particular curve, reaching youth values
      roughly at age 2-4 years. These results demonstrate that phenotypically immature
      cells normally circulate at low levels in peripheral blood, mostly at birth and
      during infancy, but also during youth.

PMID- 10397335
TI  - Recognition of the 5' splice site by the spliceosome.
AB  - The splicing of nuclear pre-mRNAs is catalyzed by a large, multicomponent
      ribonucleoprotein complex termed the spliceosome. Elucidation of the molecular
      mechanism of splicing identified small nuclear RNAs (snRNAs) as important
      components of the spliceosome, which, by analogy to the self-splicing group II
      introns, are implicated in formation of the catalytic center. In particular, the
      5' splice site (5'SS) and the branch site, which represent the two substrates for
      the first step of splicing, are first recognized by U1 and U2 snRNPs,
      respectively. This initial recognition of splice sites is responsible for the
      global definition of exons and introns, and represents the primary target for
      regulation of splicing. Subsequently, pairing interaction between the 5'SS and U1
      snRNA is disrupted and replaced by a new interaction of the 5'SS with U6 snRNA.
      The 5'SS signal contains an invariant GU dinucleotide present at the 5' end of
      nearly all known introns, however, the mechanism by which the spliceosome
      recognizes this element is not known. We have identified and characterized a
      specific UV light-induced crosslink formed between the 5'SS RNA and hPrp8, a
      protein component of U5 snRNP in the spliceosome that is likely to reflect a
      specific recognition of the GU dinucleotide for splicing. Because recognition of
      the 5'SS must be linked to formation of the catalytic site, the identification of
      a specific and direct interaction between the 5'SS and Prp8 has significant
      implications for the role of this protein in the mechanism of mRNA splicing.

PMID- 10397334
TI  - RNA recombination in brome mosaic virus, a model plus strand RNA virus.
AB  - Studies on the molecular mechanism of genetic recombination in RNA viruses have
      progressed at the time when experimental systems of efficient recombination
      crossovers were established. The system of brome mosaic virus (BMV) represents
      one of the most useful and most advanced tools for investigation of the molecular
      aspects of the mechanism of RNA-RNA recombination events. By using engineered BMV
      RNA components, the occurrence of both homologous and nonhomologous crosses were
      demonstrated among the segments of the BMV RNA genome. Studies show that the two
      types of crossovers require different RNA signal sequences and that both types
      depend upon the participation of BMV replicase proteins. Mutations in the two BMV
      encoded replicase polypeptides (proteins 1a and 2a) reveal that their different
      regions participate in homologous and in nonhomologous crossovers. Based on all
      these data, it is most likely that homologous and nonhomologous recombinant
      crosses do occur via two different types of template switching events (copy
      choice mechanism) where viral replicase complex changes RNA templates during
      viral RNA replication at distinct signal sequences. In this review we discuss
      various aspects of the mechanism of RNA recombination in BMV and we emphasize
      future projections of this research.

PMID- 10397336
TI  - Possible evolution of factors involved in protein biosynthesis.
AB  - The elongation factors of protein biosynthesis are well preserved through out
      evolution. They catalyze the elongation phase of protein biosynthesis, where on
      the ribosome amino acids are added one at a time to a growing peptide according
      to the genetic information transcribed into mRNA. Elongation factor Tu (EF-Tu)
      provides the binding of aminoacylated tRNA to the ribosome and protects the
      aminoester bond against hydrolysis until a correct match between the codon on
      mRNA and the anticodon on tRNA can be achieved. Elongation factor G (EF-G)
      supports the translocation of tRNAs and of mRNA on the ribosome so that a new
      codon can be exposed for decoding. Both these factors are GTP binding proteins,
      and as such exist in an active form with GTP and an inactive form with GDP bound
      to the nucleotide binding domain. Elongation factor Ts (EF-Ts) will catalyze the
      exchange of nucleotide on EF-Tu. This review describes structural work on EF-Tu
      performed in our laboratory over the last eight years. The structural results
      provide a rather complete picture of the major structural forms of EF-Tu,
      including the so called ternary complex of aa-tRNA:EF-Tu:GTP. The structural
      comparison of this ternary complex with the structure of EF-G:GDP displays an
      unexpected macromolecular mimicry, where three domains of EF-G mimick the shape
      of the tRNA in the ternary complex. This observation has initiated much
      speculation on the evolution of all factors involved in protein synthesis, as
      well as on the details of the ribosomal function in one part of elongation.

PMID- 10397337
TI  - Cyclases of the 3'-terminal phosphate in RNA: a new family of RNA processing
      enzymes conserved in eucarya, bacteria and archaea.
AB  - The 2',3'-cyclic phosphate termini are produced, as either intermediates or final
      products, during RNA cleavage by many different endoribonucleases. Likewise,
      ribozymes such as hammerheads, hairpins, or the hepatitis delta ribozyme,
      generate 2',3'-cyclic phosphate ends. Discovery of the RNA 3'-terminal phosphate
      cyclase has indicated that cyclic phosphate termini in RNA can also be produced
      by an entirely different mechanism. The RNA 3'-phosphate cyclase converts the 3'
      terminal phosphate in RNA into the 2',3'-cyclic phosphodiester in the ATP
      dependent reaction which involves formation of the covalent cyclase-AMP and the
      RNA-N3' pp5' A intermediates. The findings that several eukaryotic and
      prokaryotic RNA ligases require the 2',3'-cyclic phosphate for the ligation of
      RNA molecules raised a possibility that the RNA 3'-phosphate cyclase may have an
      anabolic function in RNA metabolism by generating terminal cyclic groups required
      for ligation. Recent cloning of a cDNA encoding the human cyclase indicated that
      genes encoding cyclase-like proteins are conserved among Eucarya, Bacteria, and
      Archaea. The protein encoded by the Escherichia coli gene was overexpressed and
      shown to have the RNA 3'-phosphate cyclase activity. This article reviews
      properties of the human and bacterial cyclases, their mechanism of action and
      substrate specificity. Possible biological functions of the enzymes are also
      discussed.

PMID- 10397338
TI  - Some aspects of oligoribonucleotides synthesis via the H-phosphonate approach.
AB  - This review gives a short account of selected aspects of oligoribonucleotide
      synthesis via the H-phosphonate method. It includes: (i) recent methods for the
      preparation of suitably protected ribonucleoside 3'-H-phosphonates (the
      phosphonylation step), (ii) some chemical and stereochemical features of the
      formation of H-phosphonate internucleosidic linkages, and (iii) stereoselective
      synthesis of oligoribonucleoside phosphorothioates using chemo-enzymatic
      approach.

PMID- 10397339
TI  - Molecular recognition motifs in cytidinium and 2'-deoxycytidinium salts with
      composite anions.
AB  - In the crystal structures of N3-protonated cytidinium and 2'-deoxycytidinium
      salts with composite XYn anions capable of accepting hydrogen bonds through their
      Y atoms, the dominating motif of cytosinium...anion interactions consists of a
      pair of hydrogen bonds donated from the N3+ -H protonation site and from the
      exoamino N4-H41 group cis to N3, and accepted by two Y centers of one anion. This
      multipoint recognition pattern is stable and robust and thus can be classified as
      a supramolecular synthon. In a broader group of N3-protonated, N1-substituted
      cytosinium salts with composite anions it occurs with 70% frequency. The C5 side
      of the cytosine ring mimics the N3+ -H type synthon and shows a propensity to
      form an analogous motif in which a C5-H5...Y hydrogen bond replaces the strong
      N3+ -H...Y interaction. Since the C-H...Y bond is much weaker, the secondary
      motif shows higher deformability and is less frequent (44%).

PMID- 10397340
TI  - New experimental and computational approaches to the analysis of gene expression.
AB  - Public and private EST (Expressed Sequence Tag) programs provide access to a
      large number of ESTs from a number of plant species, including Arabidopsis, corn,
      soybean, rice, wheat. In addition to the homology of each EST to genes in
      GenBank, information about homology to all other ESTs in the data base can be
      obtained. To estimate expression levels of genes represented in the DuPont EST
      data base we count the number of times each gene has been seen in different cDNA
      libraries, from different tissues, developmental stages or induction conditions.
      This quantitation of message levels is quite accurate for highly expressed
      messages and, unlike conventional Northern blots, allows comparison of expression
      levels between different genes. Lists of most highly expresses genes in different
      libraries can be compiled. Also, if EST data is available for cDNA libraries
      derived from different developmental stages, gene expression profiles across
      development can be assembled. We present an example of such a profile for soybean
      seed development. Gene expression data obtained from Electronic Northern analysis
      can be confirmed and extended beyond the realm of highly expressed genes by using
      high density DNA arrays. The ESTs identified as interesting can be arrayed on
      nylon or glass and probed with total labeled cDNA first strand from the tissue of
      interest. Two-color fluorescent labeling allows accurate mRNA ratio measurements.
      We are currently using the DNA array technology to study chemical induction of
      gene expression and the biosynthesis of oil, carbohydrate and protein in
      developing seeds.

PMID- 10397342
TI  - Acid promoted transformations of fluorescent luminarosine and its 2'-modified
      analogues.
AB  - The susceptibility of highly fluorescent luminarine nucleosides to acid promoted
      anomerization reactions has been studied in order to select a derivative with
      suitable properties for chemical synthesis of luminarine-labeled
      oligo(deoxy)ribonucleotides. Both O-acetylated derivatives Ia-c and parent
      luminarosine IIa, as well as 2'-O-methylluminarosine IIb, and 2'
      deoxyluminarosine IIc undergo anomerization at pH = 4 however, at considerably
      different velocities. In the case of O-protected nucleosides (Ia-c), the
      anomerization leads to an equilibrium mixture of respective beta and alpha
      furanosides, the rate and extent of anomerization decreasing in the following
      order: Ic >> Ia > Ib. Parent nucleosides (IIa-c) bearing free hydroxyls are
      generally more susceptible to anomerization than the O-acetylated derivatives but
      a similar order of reactivity (IIc >> IIa > IIb) is observed. In each case, a
      complex mixture containing both beta and alpha ribopyranosyl and -furanosyl forms
      is formed. Their structure and anomeric configuration have been proved by 1H and
      13C NMR spectroscopy. The results point to 2'-O-methylluminarosine as the
      fluorophore of choice for further derivatization and chemical introduction into
      oligo(deoxy)ribonucleotides.

PMID- 10397341
TI  - Yeast nuclear PET127 gene can suppress deletions of the SUV3 or DSS1 genes: an
      indication of a functional interaction between 3' and 5' ends of mitochondrial
      mRNAs.
AB  - Saccharomyces cerevisiae nuclear genes SUV3 and DSS1 encode putative RNA helicase
      and RNase II, respectively, which are subunits of the mitochondrial degradosome
      (mtEXO): a three-protein complex which has a 3' to 5' exoribonuclease activity
      and plays a major role in regulating stability of mitochondrial RNA. Lack of
      either of the two gene products results in a respiratory negative phenotype,
      while on the molecular level it causes a total block of mitochondrial
      translation, loss of the in vitro exoribonuclease activity and changes in
      stability and processing of many mtRNAs. We have found that the yeast nuclear
      gene PET127 present on a low or high copy number vector can effectively suppress
      the effects of the SUV3 or DSS1 gene disruptions. Since the product of the PET127
      gene is involved in processing of the 5' ends of mitochondrial mRNAs, we suggest
      that there is a functional coupling between the 5' and 3' ends of mitochondrial
      mRNAs.

PMID- 10397343
TI  - Oligonucleotide synthesis using the 2-(levulinyloxymethyl)-5-nitrobenzoyl group
      for the 5'-position of nucleoside 3'-phosphoramidite derivatives.
AB  - A comparative study on the utility of 2-(levulinyloxymethyl)-5-nitrobenzoyl
      (LMNBz) and 2-(levulinyloxymethyl)benzoyl (LMBz) protecting groups for the 5'
      positions of nucleoside 3'-phosphoramidite derivatives in the oligonucleotide
      synthesis is presented in terms of the syntheses of TpTpT, TpTpTpT, and
      UpCpApGpUpUpGpG. In addition we describe the synthesis, using the LMNBz
      protecting group, of the CpCpA terminus triplet of tRNAs bearing exocyclic amino
      groups with 15N-labeling, and the trimer Gp[A*]pG containing 2'-O-(beta-D
      ribofuranosyl)adenosine ([A*]), the latter of which is found at position 64 in
      the yeast initiator tRNA(Met).

PMID- 10397344
TI  - Hydration of C-H groups in natural dithymidine nucleotide and its
      methylphosphonate analogues.
AB  - In this paper we report our preliminary studies on the hydration pattern of
      selected C-H groups in natural thymidyl(3'-5)thymidine and its Rp and Sp
      methylphosphonate analogues using Molecular Dynamic simulations in aqueous
      solutions. The methyl groups attached to the phosphorus center (P-Me) in
      methylphosphonate analogues are hydrated by water molecules as efficiently as the
      hydrophilic P=O group in the natural dithymidine nucleotide and better than the
      neutral P=O functions in these compounds, although the nature of the hydration is
      different. The C5-Me centers of the 3'-yl units seem to be better hydrated in the
      methylphosphonate analogues than in the natural dithymidine phosphate and than
      other centers of the thymine bases in methylphosphonate analogues. Due to
      chirality of the phosphorus center, the C5-Me group of the 5'-yl unit in the Sp
      diastereomer coordinates more water than that in the Rp diastereomer. The C6-H
      group in the 5'-yl unit of the Sp diastereomer exhibits a specific interaction
      with water.

PMID- 10397345
TI  - Matrix-assisted laser desorption ionization time-of-flight mass spectrometric
      analysis of glycosphingolipids including gangliosides.
AB  - Long chain base compositions of gangliosides containing mainly stearic acid could
      be determined without any chemical modification by matrix-assisted laser
      desorption ionization time-of-flight mass spectrometry with delayed ion
      extraction (DE MALDI-TOF MS). The analytical results for the long chain base
      compositions of various samples of GM1 from the brain tissues of patients with
      different diseases at different ages confirmed that the proportion of d20:1
      (icosasphingosine) and d20 (icosa-sphinganine) of the total sphingosine bases
      increased quickly until adolescent or adult age and then remained constant
      slightly exceeding 50%; this value was evidently higher than the proportion of
      d20:1 and d20 of GM1 in various adult mammalian brains. A long chain base
      composition of GM1 from the brain tissue of a patient with infantile type of GM1
      gangliosidosis at 4y2m was abnormal and so was in two sibling patients with
      Spielmeyer-Vogt type of juvenile amaurotic idiocy at 19y and 21y in spite of that
      in the latter there was no accumulation of GM1 in the brain tissue. On the other
      hand, a patient with adult type of GM1 gangliosidosis at 66y showed a local
      accumulation of GM1 in the putamen and caudate nucleus, but its long chain base
      composition was found to be normal. It was of interest that the white matter of
      Eker rat with hereditary renal carcinoma contained a large amount of
      plasmalocerebroside as compared with the amount of cerebroside and sphingomyelin.
      The individual molecular species of plasmalocerebroside were identified by DE
      MALDI-TOF MS.

PMID- 10397346
TI  - Occurrence of lipopolysaccharide alterations among Tn5 mutants of Rhizobium
      leguminosarum bv. trifolii strain 24.1 with altered colony morphology.
AB  - Transposon mutants of Rhizobium leguminosarum bv. trifolii 24.1 showing less
      glossy or smaller colonies were screened for properties usually associated with
      lipopolysaccharide (LPS) defects in R. leguminosarum, i.e. motility, growth rate,
      tendency to agglutination in liquid media and symbiotic efficiency. Neither any
      of the above mutants nor the earlier isolated 24.12 strain, defective in LPS,
      showed all these properties changed simultaneously. According to PAGE/sodium
      deoxycholate analysis the mutant 24.12 was the only one producing defective
      lipopolysaccharide. GC-MS analysis revealed in this mutant qualitative changes in
      composition of its LPS in comparison with LPS isolated from the parent strain.
      Other Tn5 mutants produced LPSs similar in composition, however the proportion
      between LPS I and LPS II differed from that in the parent strain.

PMID- 10397347
TI  - Immunochemical studies on R mutants of Yersinia enterocolitica O:3.
AB  - Three mutants of Yersinia enterocolitica O:3, namely: YeO3-R1, YeO3-RfbR7 and
      YeO3-c-trs8-R were classified on the basis of sodium dodecyl
      sulphate/polyacrylamide gel electrophoresis (SDS/PAGE) profile of isolated
      lipopolysaccharides (LPS) as belonging to the Ra- (the first) and the Rc-type
      (the other two mutants). Methylation analysis, in addition to 13C and 1H NMR
      studies of purified core oligosaccharides revealed structures similar to those
      established previously for the full core of Y. enterocolitica O:3 in the case of
      the Ra mutant, and identical to that reported for the Rc mutant Ye75R, in the
      case of the two other mutants. The O-specific sugar, 6d-L-altrose, which forms a
      homopolymeric O-chain, was present in small amounts in all three LPS
      preparations, as well as in the core oligosaccha ride preparations along with the
      Ra and the Rc sugars, characteristic of the Y. enterocolitica O:3 core. This
      result is in line with genetic data, indicating that it is the inner core region
      which is the receptor for the O-specific chain in Y. enterocolitica O:3. This
      region seems likewise to be the anchoring region for the enterobacterial common
      antigen (ECA), as shown by SDS/PAGE/Western blot analysis with monoclonal
      antibodies against ECA. In addition, we also demonstrated that the Ye75R mutant
      Rc and its parental strain Ye75S, both were ECA-immunogenic strains. So far, ECA
      immunogenic strains, i.e. those with LPS-linked ECA, were only identified in E.
      coli mutants of the R1, R4 and K-12 serotype.

PMID- 10397348
TI  - Dolichyl sulphate and H-phosphonate: enzymatic reactions with activated sugars.
AB  - Two phosphate-modified analogues of dolichyl phosphate were evaluated as
      substrates or inhibitors of the reactions catalyzed by mammalian microsomal
      enzymes. Dolichyl H-phosphonate could serve as an efficient acceptor for mannosyl
      and glucosyl transfer. The reaction products were chromatographically different
      from those formed from dolichyl phosphate. Lower activity of the H-phosphonate
      was observed for the reaction of N-acetylglucosaminyl phosphate transfer from UDP
      GlcNAc. Dolichyl sulphate was shown not to serve as a substrate for the transfer
      of mannosyl (from GDP-Man), glucosyl (from UDP-Glc) or N-acetylglucosaminyl
      phosphate (from UDP-GlcNAc) residues in the presence of rat liver microsomes.
      Weak inhibitory properties of this analogue were demonstrated.

PMID- 10397349
TI  - Chemical modification of lysine and arginine residues of bovine heart 2
      oxoglutarate dehydrogenase: effect on the enzyme activity and regulation.
AB  - Chemical modification of arginine and lysine residues of bovine heart 2
      oxoglutarate dehydrogenase with phenylglyoxal and pyridoxal 5'-phosphate
      inactivated the enzyme, indicating the importance of these residues for the
      catalysis. Inactivation caused by pyridoxal 5'-phosphate was prevented in the
      presence of thiamine pyrophosphate and Mg2+ allowing the assumption that lysine
      residues participate in binding of the cofactor.

PMID- 10397350
TI  - Collagenous constituents of amniotic fluid.
AB  - The amniotic fluid (AF) was fractionated by dialysis, gel filtration and
      SDS/PAGE, and submitted to the assay of collagenous constituents. The collagenous
      character of peptides and proteins of amniotic fluid was confirmed by
      hydroxyproline (Hyp) assay and treatment with bacterial collagenase followed by
      electrophoresis and gel filtration of the digestion products. It was found that
      AF contains collagen degradation products but the classical method of Hyp
      determination described by Woessner (Arch. Biochem. Biophys., 1961, 93, 440-447)
      gives overestimated values due to the interference with other AF components.
      Fractionation of AF on Sephadex G-100 column allowed to remove the interfering
      material and to estimate the actual Hyp content which equals to approx. 6.2
      microg/ml. About 70% of Hyp was found in low molecular dialyzable products and
      the rest (about 30%) appears to be a constituent of nondialyzable collagenous
      polypeptides of the molecular mass of about 7.9-26.3 kDa. It is suggested that
      such collagenous polypeptides may be the products of proteolytic conversion of
      collagen precursor (procollagen) into the monomeric form of this protein. No high
      molecular forms of collagen, corresponding to alpha-subunits, were found.

PMID- 10397351
TI  - Uptake of acridinecarboxamide derivatives by L1210 cells.
AB  - The uptake of six 9-aminoacridinecarboxamide derivatives by L1210 cells in
      relation to their lipophilicity and cytotoxic activity was studied. The amount of
      acridines taken up by cells was estimated by fluorimetric measurements. It was
      found that the uptake efficiency of this class of compounds by cells depends on
      the size of carboxamide residue as well as on position of the substituent. The
      increase of size of carboxamide chain resulted in the loss of capability of
      acridines to penetrate cell membrane. Cytotoxic effects of acridines were well
      correlated with the level of drugs accumulated by cells, whereas no clear
      correlation between uptake and lipophilicity was observed. It is concluded that
      uptake of 9-aminoacridinecarboxamides is the most important factor determining
      their antiproliferative activity.

PMID- 10397352
TI  - Functional role of rRNAs in plant translation system tested with antisense
      strategy.
AB  - There are regions in rRNA which are evolutionary conserved and exposed on
      ribosomal surface. We selected in plant material (Lupinus luteus) two of them:
      the alpha-sarcin domain of 26S rRNA (L-rRNA) and C loop of 5S rRNA, to be further
      investigated using antisense oligomers as research tools. We found inhibition of
      the model polypeptide biosynthesis (up to 80%) due to specific hybridization of
      oligomers addressed to alpha-sarcin domain and loop C. Based on our results we
      present the evidence for the key role played by these regions of rRNAs during
      protein biosynthesis in plant system. According to our hypothesis, conformational
      changes of these two regions are synchronised and cooperative during transition
      of pre- to post-translocation state of the ribosome. The correlation of structure
      and activity of rRNA domains in translation is shown.

PMID- 10397353
TI  - Molecular characterization and symbiotic importance of prsD gene of Rhizobium
      leguminosarum bv. trifolii TA1.
AB  - The prsD, prsE and orf3 genes of Rhizobium leguminosarum bv. trifolii strain TA1
      encode the proteins which are significantly related to the family of bacterial
      ABC transporters type I secretion systems. The prsD:Km(r) mutant of strain TA1
      induced non-nitrogen-fixing nodules on Trifolium pratense. Microscopic analysis
      of the nodules induced by prsD mutant did not reveal major abberations in the
      bacteroid appearance. The exopolysaccharide of prsD mutant was produced in
      increased amount and its level of polymerization was changed. SDS/PAGE of the
      proteins from the culture supernatants showed a lack of the 47-kDa protein in the
      culture of prsD mutant. Thus, PrsD may play a role in the export of this protein.

PMID- 10397355
TI  - The so-called transcerebral veins: appearance in three different cases.
AB  - The radiologic findings in three patients with dilated transcerebral (medullary)
      veins detected on routine computed tomography and/or magnetic resonance imaging
      were reviewed. Sectional imaging showed the dilatation of transcerebral veins as
      well as the dilated superior ophthalmic veins in all patients. It also
      demonstrated the primary pathology: vein of Galen aneurysmal malformation; dural
      sinus fistula with varix; and dural arteriovenous fistula. All three patients had
      both arteriovenous fistula and sinovenous occlusion. We concluded that the
      dilated transcerebral veins developing secondary to elevation of the cerebral
      venous pressure, might be the useful radiologic finding of some dural vascular
      pathologies on sectional imaging.

PMID- 10397354
TI  - Ultrafast FLAIR imaging with single-shot echo-planar technique in evaluation of
      intracranial lesions.
AB  - We evaluated the detection of the brain lesions with single-shot echo-planar
      FLAIR imaging (EP-FLAIR) relative to fast spin-echo FLAIR imaging (fast-FLAIR).
      In 30 patients with variety of intracranial lesions, a prospective comparison of
      EP-FLAIR and fast-FLAIR was performed. Data acquisition time per image was 0.1 s
      with EP-FLAIR. Quantitative and qualitative criteria as well as lesion
      detectability were evaluated. EP-FLAIR provided almost same tissue contrast and
      CSF suppression as fast-FLAIR did. In the quantitative analysis, contrast and
      contrast-to-noise ratio (C/N) of EP-FLAIR were comparable to those of fast-FLAIR,
      and there was no significant difference between them. The increased magnetic
      susceptibility effect was useful in screening for subtle hemorrhage. However, EP
      FLAIR was degraded by susceptibility artifacts at the skull base and posterior to
      the frontal sinuses. Motion artifacts were not encountered owing to the very
      short imaging time, and EP-FLAIR was particularly useful in screening for the
      lesions in uncoorporative patients.

PMID- 10397356
TI  - Self-calibration of a biplane X-ray imaging system for an optimal three
      dimensional reconstruction.
AB  - The purpose of this paper is to elaborate a three dimensional (3D) reconstruction
      method, using biplane X-ray angiograms acquired daily by the clinician, without
      any special calibration procedure during the X-ray examination. The absolute
      geometry of the X-ray imaging system is determined by an iterative procedure
      based on the minimization of the mean square distance between observed and
      analytical projections of a set of reference points identified by the clinician
      on the simultaneous pair of images. Once the geometry of the imaging system is
      found the 3D structure of interest is retrieved from classical methods of
      binocular stereovision. This 3D information is a prerequisite for an accurate
      evaluation of the degree of severity of a vascular structure or motion anomaly
      and therefore, for establishing an appropriate diagnosis. The proposed 3D
      reconstruction method is validated on synthetic and real data and is shown to
      perform robustly and accurately in the presence of noise. The method should be
      particularly useful in clinical applications as it needs very little intervention
      from the clinician.

PMID- 10397357
TI  - Pitfalls in image reconstruction of helical CT angiography: an experimental
      study.
AB  - This study was undertaken to evaluate the effects of the object related factors:
      background tissue and the direction of vessels on the morphological
      reproducibility of helical CT angiography. Cylindrical tubes filled with a
      diluted contrast medium were prepared to obtain vascular phantoms. The scan was
      performed within various background tissues. For the evaluation of the direction
      of the vessels, two types of vascular phantoms were prepared. The phantoms were
      scanned by varying beam collimations and scan pitches. Reconstructed CT images
      were markedly affected by the background tissue. The reconstructed images were
      also affected by the direction of vessels.

PMID- 10397358
TI  - Correlative CT, MRI and histological findings of hepatic Echinococcus alveolaris:
      a case report.
AB  - Diagnosis of liver infestation by Echinococcus alveolaris (EA) is based on
      serologic, sonographic and CT findings. Literature review yielded only one report
      discussing the MRI findings of hepatic EA infestation. In this report, we present
      a case of hepatic EA infestation with its correlative CT, MRI and histological
      findings. CT showed hypodense mass involving more than half of the liver with rim
      and central calcifications. MRI revealed hypointense signal of the infiltrative
      mass on both T1- and T2-weighted images. On MRI, the portal vein branches were
      seen coursing through the lesion. Neither CT nor MRI demonstrated any contrast
      enhancement of the mass. On the histological examination, abundant fibrous and
      hyalinized tissue surrounding multiple small cysts were observed. MRI may provide
      invaluable information in the diagnosis of EA infestation of the liver, either by
      disclosing the infiltrative pattern of infestation without significant effect to
      vascular structures, or by the signal characteristics.

PMID- 10397359
TI  - Intradural-extramedullary spinal cysticercosis: MR imaging findings.
AB  - A rare case with intradural-extramedullary cysticercosis is presented here. MR
      imaging with and without gd-DTPA were performed. There were multiple cysts in the
      basal cistern, cisterna magna, and cervical subarachnoid space which were
      isointense with cerebrospinal fluid both on T2- and T1-weighted images. Swelling
      and increased signal intensity in the cord parenchyma were detected on T2
      weighted images. Gadolinium enhanced studies showed rim-shaped enhancement in the
      cysts and irregular, diffuse enhancement in the meninges.

PMID- 10397360
TI  - Massive pneumatosis intestinalis: CT diagnosis.
AB  - Pneumatosis cystoides intestinalis is a rare condition characterized by multiple
      subserosal or submucosal gas filled cysts within the wall of a segment of bowel.
      It is associated with numerous conditions, both intra and extraabdominal in
      nature. The condition may be asymptomatic or may present clinically as nausea,
      vomiting, diarrhea or other signs of intestinal obstruction. With rupture of the
      cysts, pneumoperitoneum may be a finding. In a patient with vague clinical
      presentation, this finding radiographically may lead to a clinical dilemma as
      many of these patients have comorbid conditions which are also associated with
      intestinal perforation. The authors present the case of a 47-year-old obese black
      female found to have massive pneumatosis intestinalis of the tranverse colon with
      a small amount of free intraperitoneal air. This case highlights the importance
      of recognizing pneumatosis intestinalis as a possible mimic of free
      intraabdominal air as well as a possible cause of benign pneumoperitoneum.

PMID- 10397361
TI  - Leukoencephalopathy with a mild clinical course: a case report.
AB  - Infantile-onset leukoencephalopathy of van der Knaap type is manifested by
      initially normal or near normal neurological findings despite infantile-onset
      megalencephaly and magnetic resonance imaging evidence of severe white matter
      affection. Until this entity was recently described, these cases were usually
      presented under the heading of atypical variants of Alexander disease. To date 63
      individuals have been reported in English literature. We report a four-year-old
      boy presented in the first months of life with progressive megalencephaly, delay
      in walking, clumsiness, convulsions and magnetic resonance imaging evidence of
      diffuse swelling of white matter, cystic cavitations in frontal, temporal and
      parietal lobes.

PMID- 10397362
TI  - Recent advances in GABA research.
AB  - In this article I throw attention on to this GABA issue by outlining several
      aspects of current interest in the field of GABA research. The theme was selected
      in association with the Pharmacology and Therapeutical Potential of the GABA
      System symposium of the Second European Congress of Pharmacology held in July
      1999 in Budapest, Hungary. A wide range of topics relating to the GABA system
      were outlined, including new members of the GABAA receptor gene family, subunit
      composition of native GABA(A) receptors, surface expression and clustering of
      GABA(A) receptor subunits, allosteric modulation of GABA(A) receptors,
      localization of agonist binding sites, GABA release, GABA(A)-GABA(B) receptor
      crosstalk, GABA(A) and GABA(B) receptor functions in different brain areas,
      altered transport and GABA(A) receptor pattern in different models of epilepsy.

PMID- 10397363
TI  - Structural basis of the cholinergic and serotonergic modulation of GABAergic
      neurons in the hippocampus.
AB  - Ascending subcortical pathways effectively modulate hippocampal information
      processing. Two components, the cholinergic and serotonergic pathways have been
      demonstrated to play an important role in the generation of behaviour-dependent
      hippocampal EEG patterns. Several findings suggest that the above projections
      influence the activity of hippocampal interneurons. Here we review the available
      data from physiological, pharmacological and receptor localization experiments,
      drawing attention to the crucial role of interneurons in the transfer and
      amplification of subcortical effects on cortical information processing. We
      hypothesize that, by exerting diverse actions on different subsets of
      interneurons, the cholinergic and serotonergic systems might change the balance
      of somatic and dendritic inhibition, and consequently change the integrative
      properties of hippocampal principal cells.

PMID- 10397364
TI  - Pharmacologic and therapeutic aspects of the developmentally regulated expression
      of GABA(A) and GABA(B) receptors: cerebellar granule cells as a model system.
AB  - Cerebellar granule neurons can be conveniently kept in culture. They constitute a
      useful model to study regulation of glutamatergic activity, in particular the
      inhibitory action of GABA (7-aminobutyrate). GABA exerts an inhibitory action on
      evoked transmitter release acting on both GABA(A) and GABA(B) receptors. The
      functional properties of these receptors are dependent upon the environment of
      the neurons during early development in culture as the expression of both
      receptor subtypes is enhanced by exposure of the neurons to GABA(A) receptor
      agonists. Thus, the inducible GABA(A) receptors are of low affinity and lack
      benzodiazepine sensitivity, and the G-protein coupling differs among the native
      and the inducible GABA(B) receptors. Moreover, the GABA(A) and the GABA(B)
      receptors are functionally coupled, leading to a disinhibitory action of GABA.
      Therefore drugs exhibiting selective agonist or antagonist action on subclasses
      of GABA(A) and GABA(B) may be of potential use as regulators of glutamatergic
      excitatory activity.

PMID- 10397365
TI  - Structure and subunit composition of GABA(A) receptors.
AB  - GABA(A) receptors are the major inhibitory neurotransmitter receptors in the
      brain and are the site of action of many clinically important drugs. These
      receptors are composed of five subunits that can belong to eight different
      subunit classes. If all GABA(A) receptor subunits could randomly combine with
      each other, an extremely large number of GABA(A) receptor subtypes with distinct
      subunit composition and arrangement would be formed. Depending on their subunit
      composition, these receptors would exhibit distinct pharmacological and
      electrophysiological properties. Recent evidence, however, indicates that not all
      subunits can assemble efficiently with each other and form functional homo- or
      hetero-oligomeric receptors. In addition, the efficiency of formation of hetero
      oligomeric assembly intermediates determines the subunit stoichiometry and
      subunit arrangement for each receptor and thus further reduces the possible
      heterogeneity of GABA(A) receptors in the brain. Studies investigating the
      subunit composition of native GABA(A) receptors support this conclusion, but also
      indicate that receptors composed of one, two, three, four, or five different
      subunits might exist in the brain. Using a recently established immunodepletion
      technique, the subunit composition and quantitative importance of native GABA(A)
      receptor subtypes can be determined. This information, together with studies on
      the regional, cellular and subcellular distribution of these receptor subtypes,
      will be the basis for a rational development of drugs that specifically affect
      the GABAergic system.

PMID- 10397366
TI  - The GABA-A receptor gene family: new targets for therapeutic intervention.
AB  - Until 1987, when the first GABA-A receptor subunit cDNAs were cloned and
      sequenced, it was thought that there were perhaps two subtypes of receptor in the
      brain. These were defined by the fact that benzodiazepines, which act through the
      GABA-A receptor, had two binding sites with different affinities. By 1991 it was
      known that the GABA-A receptor family existed as a family of subunits which
      coassembled to form a family of receptor subtypes in the brain. More recently,
      two additional GABA-A receptor subunits have been identified, epsilon and theta.
      The identification of these new members of the gene family, and the
      characterisation of the receptor subtypes into which they are incorporated, is
      reviewed.

PMID- 10397367
TI  - Effect of CGP 36742 on the extracellular level of neurotransmitter amino acids in
      the thalamus.
AB  - We have evaluated the effect of the brain penetrating GABAb antagonist, CGP 36742
      on GABAb receptors using in vivo microdialysis in the ventrobasal thalamus of
      freely moving rat. When a solution of 1 mM CGP 36742 in ACSF was dialyzed into
      the ventrobasal thalamus, 2-3-fold increases of extracellular Glu, Asp and Gly
      running parallel with significant decreases of contralateral extracellular Asp
      and Gly were observed. Unilateral applications of Glu receptor antagonists (0.5
      mM MK801, 0.1 mM CNQX) evoked 2-3-fold decreases of CGP 36742-specific elevations
      of extracellular Asp, Glu and Gly. Administration of CNQX and MK801 in the
      absence of CGP 36742 did not alter the extracellular Glu and Gly concentrations
      whereas extracellular Asp concentrations diminished by 42-45% at both sides. By
      contrast, no changes of extracellular Gly accompanied the 5-10-fold enhancements
      of extracellular Asp and Glu, observed during application of the Glu uptake
      inhibitor, tPDC (1mM). Suspensions of resealed plasmalemma fragments from the rat
      thalamus were mixed rapidly with the membrane impermeant form of the fluorescence
      indicator, bis-fura-2 and the changes in fluorescence intensity in response to
      CGP 36742 (0.5 mM), and the GABAb agonist, baclofen (0.1 mM), were monitored on
      the time scale of 0.04 ms(-10)s. Progress of CGP 36742-mediated influx, and
      baclofen-mediated efflux of Ca++ ion, antagonized by CGP 36742, was observed in
      the 1 ms(-10s) period of time. These data support the hypothesis that background
      ventrobasal activities and thalamocortical signaling are under the control of
      inhibitory GABAb receptors in the ventrobasal thalamus.

PMID- 10397368
TI  - Differential effects of zinc on native GABA(A) receptor function in rat
      hippocampus and cerebellum.
AB  - Hippocampal noradrenergic and cerebellar glutamatergic granule cell axon
      terminals possess GABA(A) receptors mediating enhancement of noradrenaline and
      glutamate release, respectively. The hippocampal receptor is benzodiazepine
      sensitive, whereas the cerebellar one is not affected by benzodiazepine agonists,
      indicating the presence of an alpha6 subunit. We tested here the effects of Zn2+
      on these two native GABA(A) receptor subtypes using superfused rat hippocampal
      and cerebellar synaptosomes. In the cerebellum, zinc ions strongly inhibited
      (IC50 approximately 1 microM) the potentiation of the K(+)-evoked [3H]D-aspartate
      release induced by GABA. In contrast, the GABA-evoked release of
      [3H]noradrenaline from hippocampal synaptosomes was much less sensitive to Zn2+
      (IC50 > 30 microM). The effects of Zn2+ were then studied in two rat lines
      selected for high (ANT) and low (AT) alcohol sensitivity because granule cell
      GABA(A) receptors in ANT, but not AT, rats respond to benzodiazepine agonists due
      to a critical mutation in the alpha6 subunit. GABA increased the K(+)-evoked
      release of [3H]DCNS REGIONS-aspartate from cerebellar synaptosomes of AT and ANT
      rats, an effect prevented by the GABAA selective antagonist bicuculline. In AT
      rat cerebellum, the effect of GABA was strongly inhibited by Zn2+ (IC50 < or = 1
      microM), whereas in ANT rats, the divalent cation was about 100-fold less potent.
      Thus, native benzodiazepine-sensitive GABAA receptors appear largely insensitive
      to functional inhibition by Zn2+ and vice versa. Changes in sensitivity to Zn2+
      inhibition consequent to mutations in cerebellar granule cell GABA(A) receptor
      subunits may lead to changes in glutamate release from parallel fibers onto
      Purkinje cells and may play important roles in cerebellar dysfunctions.

PMID- 10397369
TI  - Separation of carrier mediated and vesicular release of GABA from rat brain
      slices.
AB  - In this study the temperature dependence of [3H]GABA release from brain slices
      evoked by electrical field stimulation and the Na+/K+ ATPase inhibitor ouabain
      was investigated. [3H]GABA has been taken up and released from hippocampal slices
      at rest and in response to electrical field stimulation (20 V, 10 Hz, 3 msec, 180
      pulses) at 37 degrees C. When the bath temperature was cooled to 7 degrees C,
      during the sample collection period, the tissue uptake and the resting outflow of
      [3H]GABA were not significantly changed. In contrast, the stimulation-induced
      tritium outflow increased both in absolute amount (Bq/g) and in fractional
      release and the S2/S1 ratio was also higher at 7 degrees C. Perfusion of the
      slices with tetrodotoxin (TTX, 1 microM) inhibited stimulation-induced [3H]GABA
      efflux indicating that exocytotic release of vesicular origin is maintained under
      these conditions. 15 min perfusion with ouabain (10-20 microM) induced massive
      tritium release both in hippocampal and in striatal slices. However, the fraction
      of [3H]GABA outflow evoked by ouabain was much higher in the hippocampus than in
      the striatum. Sequential lowering the bath temperature from 37 degrees C to 17
      degrees C completely abolished ouabain-induced [3H]GABA release in both brain
      regions, indicating that it is a temperature-dependent, carrier-mediated process.
      When the same experiments were repeated under Ca2+ free conditions, cooling the
      bath temperature to 17 degrees C, although substantially decreased the release
      but failed to completely abolish the tritium outflow evoked by ouabain, a
      significant part was maintained. Our results show that vesicular (field
      stimulation-evoked) and carrier-mediated (ouabain-induced) release of GABA is
      differentially affected by low temperature: while vesicular release is
      unaffected, carrier-mediated release is abolished at low bath temperature.
      Therefore, lowering the temperature offers a reliable tool to separate these two
      kinds of release and makes possible to study exclusively the pure neuronal
      release of GABA of vesicular origin.

PMID- 10397370
TI  - GABA release and uptake measured in crude synaptosomes from Genetic Absence
      Epilepsy Rats from Strasbourg (GAERS).
AB  - GABA release and uptake were examined in Genetic Absence Epilepsy Rats from
      Strasbourg and in non-epileptic control animals, using crude synaptosomes
      prepared from the cerebral cortex and thalamus. Uptake of [3H]GABA over time was
      reduced in thalamic synaptosomes from epileptic rats, compared to controls. The
      affinity of the uptake process in thalamic synaptosomes was lower in epileptic
      animals. NNC-711, a ligand for the GAT-1 uptake protein, reduced synaptosomal
      uptake by more than 95%; beta-alanine, an inhibitor selective for the uptake
      proteins GAT-2 and -3, did not significantly reduce synaptosomal uptake.
      Autoradiography studies using [3H]tiagabine, a ligand selective for GAT-1,
      revealed no differences between the strains in either affinity or levels of
      binding. Ethanolamine O-sulphate (100 microM), a selective inhibitor of GABA
      transaminase, did not affect uptake levels. Aminooxyacetic acid (10-100 microM),
      an inhibitor of GABA-transaminase and, to a lesser extent, glutamate
      decarboxylase, caused an increase in measured uptake in both thalamic and
      cortical synaptosomes, in both strains. We found no difference in in vitro basal
      or KCl-stimulated endogenous GABA release between epileptic and control rats.
      These results indicate that GABA uptake in the thalamus of Genetic Absence
      Epilepsy Rats from Strasbourg was reduced, compared to control animals. The lower
      uptake affinity in the epileptic animals probably contributed to the reduction in
      uptake over time. Uptake appeared to be mediated primarily by the 'neuronal'
      transporter GAT-1. Autoradiography studies revealed no differences in the number
      or affinity of this uptake protein. It is therefore possible that altered
      functional modulation of GAT-1 caused the decrease in uptake shown in the
      epileptic animals. Inhibition of GABA-transaminase activity had no effect on
      measured GABA uptake, whereas a reduction in glutamate decarboxylase activity may
      have affected measured uptake levels.

PMID- 10397371
TI  - Equilibrium binding characteristics of [3H]thiomuscimol.
AB  - The equilibrium binding characteristics of the tritiated GABAA agonist, 5
      aminomethyl-3-isothiazolol (thiomuscimol) are described. Using the filtration
      technique to separate bound- from free-ligand, [3H]thiomuscimol was shown to bind
      to the GABA(A) receptor site(s) in a saturable manner with a Kd value of 28+/-6.0
      nM and a Bmax value of 50+/-4.0 fmol/mg original tissue. In parallel binding
      experiments, the Kd and Bmax values for [3H]muscimol were determined to be 5.4+/
      2.8 nM and 82+/-11 fmol/mg original tissue, respectively. In binding assays using
      the centrifugation technique, Kd and Bmax values for [3H]thiomuscimol were found
      to be 116+/-22 nM and 154 13 fmol/mg original tissue, respectively, whereas a Kd
      value of 16+/-1.8 nM and a Bmax value of 155+/-8.0 fmol/mg original tissue were
      determined for [3H]muscimol. In comparative inhibition studies using the GABA(A)
      antagonist SR 95531 and a series of specific GABAA agonists, the binding sites
      for [3H]thiomuscimol and [3H]muscimol were shown to exhibit similar
      pharmacological profiles. Autoradiographic studies disclosed similar regional
      distribution of [3H]thiomuscimol and [3H]muscimol binding sites in rat brain.
      Highest densities of binding sites were detected in cortex, hippocampus, and
      cerebellum, whereas low densities were measured in the midbrain structures of rat
      cortex. In conclusion, the equilibrium GABA(A) receptor binding characteristics
      of [3H]thiomuscimol are very similar to those of [3H]muscimol.

PMID- 10397372
TI  - GABAergic neurons and GABA(A)-receptors in temporal lobe epilepsy.
AB  - Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of epilepsy,
      characterized by recurrent complex partial seizures and hippocampal sclerosis.
      The pathophysiology underlying this disorder remains unidentified. While a loss
      of benzodiazepine binding sites is a key diagnostic feature of MTLE, experimental
      studies have shown enhanced inhibitory transmission and increased expression of
      GABA(A)-receptors, suggesting that compensatory mechanisms are operative in
      epileptic hippocampus. In the present study, changes in the expression and
      cellular distribution of major GABA(A)-receptor subunits were investigated in the
      hippocampus of pilocarpine-treated rats during the phase of spontaneous recurrent
      seizures. A uniform decrease in GABA(A)-receptor subunit-immunoreactivity was
      observed in regions of extensive neuronal death (i.e. CA1, CA3, hilus). whereas a
      prominent increase occurred in the dentate gyrus (DG). Most strikingly, the
      increase was largest for the alpha3- and alpha5-subunits, which are expressed at
      very low levels in the DG of control rats, suggesting the formation of novel
      GABA(A)-receptor subtypes in epileptic tissue. Furthermore, an extensive loss of
      interneurons expressing the alpha1-subunit, representing presumptive basket
      cells, was seen in the DG. These changes were very similar to those reported in a
      novel mouse model of MTLE, based on the unilateral injection of kainic acid into
      the dorsal hippocampus (Bouilleret et al., 1999). This indicates that the
      regulation of GABA(A)-receptor expression is related to chronic recurrent
      seizures, and is not due to the extrahippocampal neuronal damage affecting
      pilocarpine-treated rats. These results allow causal relationships in the
      induction and maintenance of chronic recurrent seizures to be distinguished. The
      loss of a critical number of interneurons in the DG is a possible cause of
      seizure initiation, whereas the long-lasting upregulation of GABA(A)-receptors in
      granule cells represents a compensatory response to seizure activity.

PMID- 10397373
TI  - The interaction of general anaesthetics and neurosteroids with GABA(A) and
      glycine receptors.
AB  - The positive allosteric effects of four structurally distinct general
      anaesthetics (propofol, pentobarbitone, etomidate and 5alpha-pregnan-3alpha-ol-20
      one [5alpha3alpha]) upon recombinant GABA(A) (alpha6beta3gamma2L), invertebrate
      GABA (RDL) and glycine (alpha1) receptors expressed in Xenopus laevis oocytes
      have been determined. Propofol and pentobarbitone enhanced agonist (GABA or
      glycine as appropriate) evoked currents at GABA(A), glycine, and RDL receptors,
      whereas etomidate and 5alpha3alpha were highly selective for the GABA(A)
      receptor. Utilizing site-directed mutagenesis, we demonstrate that the nature of
      the interaction of propofol, pentobarbitone and etomidate (but not 5alpha3alpha)
      with mammalian and invertebrate ionotropic GABA receptors depends critically upon
      the nature of a single amino acid located in the second transmembrane region
      (TM2) of these receptors. These data are discussed in relation to the specificity
      of action of general anaesthetics.

PMID- 10397374
TI  - Identification of subunits mediating clustering of GABA(A) receptors by rapsyn.
AB  - Human embryonic kidney 293 cells transfected with alpha1beta1gamma2,
      alpha1beta2gamma2, alpha1beta3gamma2, alpha1beta1, alpha1beta2, alpha1beta3,
      beta3gamma2, or beta3 subunits formed gamma-aminobutyric acidA receptors on the
      cell surface that could be clustered by rapsyn. In contrast, alpha1, beta1,
      beta2, or gamma2 subunits, or alpha1gamma2 subunit combinations could not be
      detected on the surface of transfected cells and could not be clustered by
      rapsyn. Experiments investigating the ability of rapsyn to cluster chimeras
      consisting of the N-terminus of the beta3 subunit and the remaining part of the
      alpha1, beta2 or gamma2 subunits indicated that the intracellular domains of
      beta1, beta2, beta3 or gamma2 subunits, but not those of alpha1 subunits are able
      to form sites mediating clustering by rapsyn. These results demonstrate that
      rapsyn has the potential to cluster the majority of GABA(A) receptor subtypes via
      beta or gamma2 subunits. Further experiments will have to clarify the
      physiological importance of this observation.

PMID- 10397375
TI  - Comparison of the in vitro activity of and pathogen responses to sparfloxacin
      with those of other agents in the treatment of respiratory tract, urinary tract,
      and skin and skin-structure infections.
AB  - The in vitro activity of and pathogen responses to sparfloxacin were compared
      with those of standard therapies for the treatment of patients with community
      acquired pneumonia, complicated skin or skin-structure infections, urinary tract
      infections, acute bacterial exacerbations of chronic bronchitis, and acute
      maxillary sinusitis in 7 multicenter controlled trials in North America.
      Sparfloxacin was administered orally as a 400-mg loading dose followed by 200 mg
      once daily for up to 10 days. The bacteriologic efficacy of sparfloxacin (84% to
      95%) was comparable to that of comparator drugs (77% to 100%). Sparfloxacin was
      generally 2 to 8 times more active (minimum inhibitory concentration for 90% of
      strains tested [MIC90]: 0.03 to 0.5 microg/mL) than comparators against common
      pathogens isolated in community-acquired infections, especially Streptococcus
      pneumoniae, including penicillin-resistant strains; Moraxella catarrhalis;
      Haemophilus influenzae; Streptococcus pyogenes; and Staphylococcus aureus.
      Sparfloxacin was also effective against Chlamydia and Mycoplasma species. The
      emergence of resistance was uncommon during sparfloxacin therapy (0.3% of 1100
      cases). Higher area under the plasma concentration-time curve/MIC and maximum
      plasma concentration/MIC ratios for sparfloxacin were associated with clinical
      and bacteriologic efficacy, whereas lower ratios were associated with clinical
      and bacteriologic failure. The clinical efficacy of sparfloxacin (80% to 95%) was
      comparable to that obtained with the comparator drugs (71% to 92%). In addition,
      sparfloxacin was well tolerated and had an overall frequency of related adverse
      events similar to that of the comparators. There was a higher frequency of
      photosensitivity reactions but a lower level of digestive adverse events with
      sparfloxacin compared with comparators. Sparfloxacin is a suitable therapeutic
      alternative for the empiric treatment of respiratory tract infections owing to
      its favorable pharmacokinetic profile and activity against typical and atypical
      respiratory tract pathogens, even in geographic areas with a high incidence of
      penicillin resistance.

PMID- 10397376
TI  - Switching from therapy with typical antipsychotic agents to risperidone: long
      term impact on patient outcome.
AB  - This paper reports the results of a retrospective, open-label study in 31
      schizophrenic patients who had been switched from therapy with a typical
      antipsychotic agent to risperidone, a novel antipsychotic agent, in the course of
      their treatment in an outpatient/community program. The study was based on both a
      review of all 31 patients' charts and a structured interview of 26 of the
      patients. The change to risperidone had been made because of lack of efficacy or
      intolerance to typical antipsychotic agents after a mean of 3.5 years of therapy.
      Patients had been maintained on risperidone for a mean of 1.7 years at the time
      of the review. The impact of switching to risperidone was assessed by comparing
      clinical variables for the patients with their own historic control data. The
      current levels of symptoms, side effects, and social functioning were also
      assessed by means of the Interview for Retrospective Assessment of Onset of
      Schizophrenia and rating scales. Seventy-one percent and 81% of the patients
      exhibited a positive response, as measured by a 30% reduction in psychotic and
      disorganization syndromes, respectively. After the switch, significant declines
      were noted in service utilization; the level of psychotic, disorganization, and
      negative symptom dimensions; and the use of anticholinergic drugs (P < 0.01 for
      all). Assessments conducted at the time of the review revealed a low level of
      psychotic (mean, 3.5) and disorganization (mean, 3.0) symptoms, a moderate level
      of negative symptoms (mean, 19.5), and a low level of extrapyramidal symptoms
      (total mean parkinsonism score, 6.0). No significant changes were seen in the
      level of employment or in living conditions. Results of this study suggest that a
      switch to risperidone therapy because of the inefficacy of typical antipsychotic
      agents or patients' inability to tolerate them may lead to sustained and
      significant improvement in a substantial proportion of patients with
      schizophrenia.

PMID- 10397377
TI  - Effect of single ascending, supratherapeutic doses of sparfloxacin on cardiac
      repolarization (QTc interval).
AB  - This double-masked, randomized, placebo-controlled study was conducted in healthy
      adult male and female volunteers with no clinically relevant baseline
      electrocardiographic (ECG) abnormalities to assess the cardiac tolerability
      margin of sparfloxacin (as measured by the effect on QTc interval) under
      conditions of potential overdose at up to 4 times the usual therapeutic loading
      dose. The 23 enrolled volunteers received a sequence of single doses of
      sparfloxacin (400, 800, 1200, and 1600 mg), 1 dose in each of 4 study periods.
      Six volunteers received placebo during each period. A 14-day washout separated
      the periods. Serial blood samples and ECG measurements were collected in each
      period to determine the pharmacokinetic and pharmacodynamic characteristics of
      sparfloxacin. The area under the concentration-time curve from time zero to
      infinity (AUC0-infinity) exhibited dose proportionality. The maximum plasma
      concentration (Cmax) after the 1200- and 1600-mg doses was lower than would be
      expected for a linear dose relationship. This was also the case with the mean
      increase and mean maximum increase in QTc interval. Increases in the QTc interval
      correlated well with Cmax but not with AUC0-infinity. The time to reach Cmax
      showed a slight tendency to increase with dose, as did the terminal elimination
      half-life. Changes in QTc-interval dispersion were similar for both placebo
      recipients and sparfloxacin-treated volunteers and were of no clinical
      consequence. At supratherapeutic doses, the extent of sparfloxacin's absorption
      (AUC0-infinity) was dose independent; however, the rate of absorption was dose
      dependent, with Cmax increasing substantially less than proportionally to the
      administered dose. This limited the Cmax of sparfloxacin at supratherapeutic
      doses and thus the increase in QTc interval. Rechallenge demonstrated that only 2
      of 8 subjects had the same degree of QTc-interval prolongation, emphasizing the
      marked variability in the QTc interval.

PMID- 10397379
TI  - Atovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of
      acute falciparum malaria in Zambia.
AB  - Atovaquone and proguanil hydrochloride are blood schizonticides that demonstrate
      in vitro synergy against drug-resistant strains of Plasmodium falciparum. When
      coadministered, they may therefore be effective for the treatment of malaria in
      regions where there is known or suspected drug resistance. In an open-label,
      randomized, parallel-group, clinical trial conducted in Zambia, 163 patients (age
      range, 14 to 54 years) with acute P falciparum malaria were randomly assigned to
      receive treatment with atovaquone and proguanil hydrochloride (1000 and 400 mg,
      respectively, administered orally at 24-hour intervals for 3 doses; n = 82) or
      pyrimethamine/sulfadoxine (75/1500 mg administered orally as a single dose; n =
      81). Efficacy was assessed by cure rate (the percentage of patients in whom
      parasitemia was eliminated and did not recur during 28 days of follow-up),
      parasite clearance time (PCT), and fever clearance time (FCT). Safety was
      determined by sequential clinical and laboratory assessments over 28 days. Cure
      rates did not differ significantly between patients treated with atovaquone and
      proguanil (100%) and those treated with pyrimethamine/sulfadoxine (98.8%).
      Patients in the atovaquone and proguanil group had a significantly shorter FCT
      than patients in the pyrimethamine/sulfadoxine group (mean, 30.4 vs 44.9 hours; P
      < 0.05) but a longer PCT (mean, 64.0 vs 51.4 hours; P < 0.05). Both treatments
      were well tolerated; adverse events and laboratory abnormalities were typical of
      those normally observed in patients with malaria. In this study, the combination
      of atovaquone and proguanil was equally effective and as well tolerated as
      pyrimethamine/sulfadoxine for the treatment of acute, uncomplicated, drug
      resistant falciparum malaria in Zambia.

PMID- 10397378
TI  - Pharmacokinetics and pharmacodynamics of clomethiazole after oral and rectal
      administration in healthy subjects.
AB  - Clomethiazole, a sedative-hypnotic and anticonvulsant drug, has been successfully
      administered orally and intravenously, but in cases where either of these methods
      presents complications, rectal administration may represent a practical
      alternative. We sought to compare the single-dose pharmacokinetics and
      pharmacodynamics of clomethiazole after oral and rectal administration. Ten
      healthy adult volunteers were given 600 mg clomethiazole edisylate (corresponding
      to 390 mg clomethiazole base) in 2 capsules as a single oral or rectal dose in a
      double-masked, double-dummy, crossover fashion. Serum concentrations were
      measured up to 10 hours after administration using a specific high-performance
      liquid chromatography method. Computerized reaction-time measurement and visual
      analogue scales (VAS) were used to assess drug effects. Peak serum concentrations
      were significantly higher after oral administration (mean +/- SEM, oral 1.76 +/-
      0.47 microg/mL vs rectal 0.48 +/- 0.14 microg/mL; P = 0.03) and appeared earlier
      (55 +/- 12 vs 89 +/- 11 min; P = 0.04). Area under the concentration-time curve
      values were similar after administration by both routes (oral 116 +/- 20.6 vs
      rectal 105 +/- 36.0 microg x min/mL), with a relative rectal bioavailability of
      90% compared with oral administration. The objective pharmacodynamic effects on
      reaction time (increase of 104 +/- 26 vs 66 +/- 22 ms, oral vs rectal) and
      working speed (decrease of 132 +/- 38 vs 97 +/- 32 ms, oral vs rectal) were not
      significantly different. Subjective pharmacodynamic effects, as measured on the
      VAS, were comparable with both routes of administration. Clomethiazole was well
      tolerated, with a similar adverse effect profile for both routes of
      administration. The effects of rectal dosing of clomethiazole were similar to
      those of oral dosing but appeared to occur later. Our results suggest that rectal
      administration of a single 600-mg clomethiazole edisylate dose bears no safety
      risk. Therefore, rectal administration could be considered when neither oral nor
      parenteral administration is possible and a later onset of effect is not
      critical.

PMID- 10397380
TI  - A pharmacoeconomic assessment of torsemide and furosemide in the treatment of
      patients with congestive heart failure.
AB  - The management of patients with congestive heart failure (CHF) can place a
      significant economic burden on managed care organizations, leading providers to
      seek treatments that are cost-effective. Diuretics play a significant role in the
      treatment of edema associated with CHF. We evaluated the use of 2 loop diuretics,
      torsemide and furosemide, in patients with CHF in a managed care setting. This
      prospective study compared clinical, economic, and quality-of-life outcomes in
      240 patients randomized to the 2 drugs. Patients with New York Heart Association
      (NYHA) class II or class III CHF requiring loop diuretic treatment, either alone
      or in conjunction with other therapy, were eligible. Patients were told about the
      study during an office visit, and those with an interest in participating and who
      met the eligibility criteria were given further information and the opportunity
      to participate. After investigators obtained informed consent, patients were
      enrolled, randomized to either treatment, and followed for 6 months. Outcomes
      included CHF/cardiovascular (CV)-related medical costs, change in NYHA class,
      change in sodium retention score, hospitalizations, physician visits, medication
      use, adverse events, and change in quality of life. A total of 103 patients were
      randomized to torsemide, and 137 patients were randomized to furosemide. Except
      for body weight, patient demographic characteristics did not differ between
      groups at baseline; patients in the torsemide group were significantly heavier (P
      = 0.004). The results showed that mean total CHF/CV-related medical costs did not
      differ between groups (torsemide, $1520.07; furosemide, $1503.26; P = 0.975),
      despite higher mean drug-acquisition costs for torsemide patients ($121.01 vs
      $42.95; P < 0.0001). Mean costs were similar for CHF/CV-related hospitalizations
      (torsemide, $845.84; furosemide, $893.33; P = 0.918) and CHF-related physician
      visits (torsemide, $138.80; furosemide, $164.09; P = 0.288). Quality of life was
      significantly better for patients in the torsemide group at month 4 (P = 0.017),
      but not at month 2 (P = 0.059) or month 6 (P = 0.269). The number of adverse
      events did not differ significantly between groups (torsemide, 221; furosemide,
      287; P = 0.916). The results of this study appear to indicate that in a
      representative cross-section of managed care patients, those who received
      torsemide, despite higher drug-acquisition costs, had similar CHF/CV-related
      management costs compared with furosemide recipients.

PMID- 10397381
TI  - Treatment of urge incontinence in Veterans Affairs medical centers.
AB  - Urinary incontinence has far-reaching medical, psychological, social, and
      economic effects. The objectives of this descriptive study were to examine
      utilization patterns and discontinuation rates of various pharmacologic agents
      used to treat symptoms of overactive bladder, primarily urge incontinence (UI),
      and to estimate the prevalence of urinary incontinence in the study population.
      Patient-level data regarding specific drugs used to treat UI and the use of
      diapers or pads over a 9-month period from October 1995 to May 1996 were
      retrospectively extracted from the medication databases of 9 Department of
      Veterans Affairs medical centers. A total of 2233 male patients were included in
      the analyses. Most patients were receiving oxybutynin chloride (39.8%),
      dicyclomine hydrochloride (16.0%), or imipramine hydrochloride (13.9%), and the
      remaining 30.3% were using flavoxate hydrochloride, propantheline bromide,
      hyoscyamine sulfate, and adult diapers or pads. Overall, 72.1% of patients had
      been prescribed daily dosages within the recommended dosing ranges for these
      medications. The majority (91.3%) of patients had not switched to another UI
      medication during the study period. Based on a chronic disease index, 47.6% of
      patients had 2 or fewer chronic diseases. Using pooled prevalence estimates, the
      estimated percentage of patients who had ever experienced UI in this population
      ranged from 7.4% to 20.8%; however, a considerably smaller percentage were taking
      medications for the treatment of UI. The results of this study suggest that
      oxybutynin, dicyclomine, and imipramine are the agents most commonly used to
      treat urinary incontinence within Veterans Affairs medical centers. The majority
      of patients who received a prescription for one of these drugs did not routinely
      refill the medication over the course of the study. There are many reasons for
      patients not to refill a prescription (eg, ineffectiveness, side effects,
      complications, obtaining the drug from another source), but the present study did
      not address the causes.

PMID- 10397382
TI  - Assessment of asthma patients' willingness to pay for and give time to an asthma
      self-management program.
AB  - Despite the success of health education programs for patients with asthma,
      several researchers have found that patients are reluctant to enroll in and
      complete a program designed to help them manage their condition. The purpose of
      this study was to identify factors that influence asthma patients' willingness to
      pay (WTP) for and willingness to give time (WTGT) to an asthma self-management
      program. The patient sample consisted of 116 adult asthma patients (age range, 18
      to 34 years) from 2 affiliated sites: a county teaching hospital with ambulatory
      clinics and a staff-model health maintenance organization. To determine WTP and
      WTGT, patients were presented with a scenario in which the components of an 8
      week asthma management program were described. Patients were then asked how much
      they would be willing to pay for and how much time they would be willing to spend
      on the program. Regression analyses were used to determine what effect the
      following factors had on WTP and WTGT with respect to an asthma self-management
      program: sociodemographic factors; predisposing, enabling, and reinforcing
      factors; level of asthma self-management; and health care utilization. Mean
      patient WTP was $29.50 for an 8-week asthma education program. Several factors
      appeared to influence this amount. Patients who were willing to pay more for a
      program that would help them manage their asthma exhibited suboptimal behaviors
      during asthma attacks, had greater perceived access to health care resources,
      received less educational information from health care providers, had previously
      participated in a self-management program, and had indicated an interest in
      participating in a self-management program. This model was statistically
      significant (P < 0.0001), with 35% of the variation in WTP scores explained by
      the independent variables. Patients reported that they were willing to spend a
      mean of 5.8 hours per week on an 8-week asthma self-management program. Patients
      who were willing to spend more time on an asthma self-management program had
      indicated an interest in participating in such a program, had a higher number of
      comorbidities, or had more emergency department visits. This model was
      statistically significant (P = 0.0018), with 18% of the variance explained. This
      study identified several factors that may affect WTP and WTGT in relation to an
      asthma self-management program. This information may be helpful in identifying
      candidates for educational programs.

PMID- 10397383
TI  - Modeling economic evaluations of pharmaceuticals: manipulation or valuable tool?
AB  - Controversy surrounds the use of models in economic evaluations of
      pharmaceuticals. Many believe that modeling is a way of manipulating results and
      is not credible, whereas others consider modeling a valuable tool in economic
      evaluations. The purpose of this article is to provide a historical perspective
      on modeling, focus on the controversy and policy implications of using models,
      and review the suggested framework and guidelines for modeling practices. Models
      can be used to extrapolate beyond intermediate end points, predict costs and
      consequences of alternative therapies, generalize data to other settings, pose
      questions instead of providing answers when no data exist, design an evaluation
      to reduce uncertainty, and perform direct comparisons that are not currently
      available. We believe that a useful model should document the detailed inner
      workings, assumptions, and inherent bias during production (and at publication
      time), so that its reviewers and users can evaluate the appropriateness of the
      model's outcomes. The acceptability of models in the future rests with the
      researchers constructing them. If constructed appropriately, modeling economic
      evaluations is not a manipulation but rather a valuable tool.

PMID- 10397384
TI  - Pharmacoeconomics and policy decisions: the Australian health care system.
AB  - This paper provides an overview of the use of pharmacoeconomic analysis in the
      process that governs drug reimbursement decisions in Australia. It discusses the
      methods by which drugs are evaluated, both clinically and economically, and the
      means by which these 2 facets are amalgamated; the types of pharmacoeconomic data
      submitted in support of requests for reimbursement; the methods and standards
      used to assess these data; some of the more commonly encountered flaws in the
      data submitted; and how the different types of data influence reimbursement
      decisions.

PMID- 10397385
TI  - Drug utilization patterns and outcomes associated with in-hospital treatment with
      risperidone or olanzapine.

PMID- 10397386
TI  - The use of biological therapy in cancer of the head and neck.
AB  - Exciting progress, in the molecular and cell biology of head and neck cancer has
      provided us with new ways to target cancer cells more specifically. The
      possibility now exists with gene therapy of targeting specific genetic defects
      found in certain tumor types using any one of a number of possible gene delivery
      systems. Although specific problems with currently existing gene therapy
      strategies remain to be addressed, encouraging preclinical and clinical data
      indicate that this is a very promising area. In addition, the exquisite
      sensitivity of anti/bodies directed at specific molecular targets should make
      antibody-conjugated toxins, radioimmunoconjugates, and antibodies alone viable
      therapeutic options. Finally, increased understanding of the antitumor immune
      response has yielded more rationally designed cytokine as well as cellular-based
      immunologic treatments for cancer. During the next several years, physicians and
      scientists alike will need to critically appraise the results of clinical trials
      of some of these novel treatment approaches and determine how they will fit in
      with the existing options for the treatment of patients with head and neck
      cancer. Given that these tumors arise from multiple molecular aberrations, it is
      likely that biological therapies will be used in combination with other
      biological approaches or more conventional treatment modalities.

PMID- 10397387
TI  - Apoptosis in dendritic cell biology.
AB  - Apoptosis or programmed cell death regulates many aspects in immunological
      homeostasis and, thus, controls the initiation, magnitude, duration, and
      termination of immune responses. Recent studies on dendritic cells (DC),
      including Langerhans cells (LC), have reinforced this concept by documenting that
      these antigen presenting cells express surface receptors and ligands that are
      known to mediate apoptotic cell death and that they are highly susceptible to
      apoptotic signals. In this review article, four major topics concerning apoptosis
      in the biology of DC will be overviewed: (a) molecular mechanisms of apoptosis;
      (b) DC apoptosis induced by various stimuli; (c) regulation of DC apoptosis; and
      (d) cross-priming and cross-tolerance induced by DC ingesting apoptotic bodies.

PMID- 10397389
TI  - An immunohistochemical study of beta1,4-galactosyltransferase in human skin
      tissue.
AB  - An immunohistochemical investigation of beta1,4-galactosyltransferase (beta1,4
      GalT) on human skin tissue was performed on formalin-fixed paraffin-embedded
      sections using a monoclonal antibody, MAb8628, which specifically recognizes a
      protein moiety of human beta1,4-GalT. Distribution of the galactose beta1,4-N
      acetylglucosamine (Gal beta1,4GlcNAc)-R epitope was also detected by staining
      with Ricinus communis agglutinin (RCA) 120. The beta1,4-GalT was observed to be
      localized at the perinuclear region of epidermal keratinocytes. The fine
      localization was also observed at the supranuclear region in the cells of
      apocrine glands, eccrine ducts and glands. The positive staining with RCA 120 was
      well colocalized with the cells expressing the beta1,4-GalT. An electron
      microscopic study revealed that positive signals of beta1,4-GalT definitely
      reside in the Golgi apparatus. No immunoreactivity was observed in any other
      intracellular structure or on the cell surface. These findings strongly indicated
      that the beta1,4-GalT is the major enzyme responsible for the Gal beta1,4GlcNAc-R
      epitope synthesis in human skin tissue.

PMID- 10397388
TI  - Artificial human skin: cytokine, prostaglandin, Hsp70 and histological responses
      to heat exposure.
AB  - Artificial human skin, Skin2 (keratinocytes and fibroblasts) and EpiDerm
      (keratinocytes), was used to determine heat-induced release/accumulation of
      mediators of injury and repair. Skin2 was exposed to 37 or 41-45 degrees C for 90
      min, followed by 37 degrees C for 22.5 h. Media were analyzed for interleukin
      1alpha (IL-1alpha), prostaglandin-E2 (PGE2), thromboxane-B2 (TxB2) and nuclear
      matrix apparatus protein (NMAP, viability). Specimens were taken for microscopy.
      Media and lysates from Skin2 and EpiDerm (37 and 45 degrees C) were analyzed for
      IL-1alpha, its soluble receptor (sIL-1RII), receptor antagonist (IL-1Ra),
      interleukin-6 (IL-6) and heat shock protein-70A (lysates only). Significant
      release of IL-1alpha and PGE2 was detected only above 43 degrees C, where
      viability deteriorated and histological damage (especially to keratinocytes) was
      observed. With both skin products, sIL-1RII release was heat-depressed. IL-1alpha
      and IL-1Ra were elevated in media and IL-1Ra appeared to lower the bioactivity of
      IL-1alpha. Heat depressed IL-6 release from Skin2 fibroblasts. IL-6 production
      and release were negligible with EpiDerm. Heat increased Hsp-70A in both
      products. We conclude keratinocytes and fibroblasts are not primary cytokine and
      prostaglandin sources in heatstroke (< 44 degrees C) but could be in evaporative
      cooling failure, focal hot spots, or systemic responses. Levels of IL-1Ra, PGE2
      and Hsp70A may be important markers of cell status.

PMID- 10397390
TI  - Influences of keratinocyte-fibroblast interaction on the expression of epimorphin
      by fibroblasts in vitro.
AB  - Epimorphin was demonstrated to be a mesenchymal signal factor modulating
      epithelial morphogenesis of skin, lung and liver in vitro. Most of the previous
      studies were performed biochemically and functionally. In the present study,
      expression of epimorphin was immunohistochemically compared between cultured
      fibroblasts and cocultured fibroblasts with keratinocytes obtained from normal
      skin. Cultured fibroblasts revealed a low level of epimorphin expression. In
      contrast, the expression by fibroblasts was greatly enhanced in skin explant
      culture where both fibroblasts and keratinocytes were present. In three
      dimensional coculture of fibroblasts and keratinocytes, the expression of
      epimorphin was enhanced. The staining pattern of epimorphin in three-dimensional
      coculture was similar to that in human skin. These results suggest that dermal
      fibroblasts are manufacturers of epimorphin, and keratinocyte-fibroblast
      interaction may play important roles in the expression of epimorphin in vitro.

PMID- 10397391
TI  - Peripheral distribution of presynaptic sites of abdominal motor and modulatory
      neurons in Manduca sexta larvae.
AB  - Insect muscle fibers are commonly innervated by multiple motor neurons and
      efferent unpaired median (UM) neurons. The role of UM neurons in the modulation
      rather than rapid activation of muscle contraction (Evans and O'Shea [1977]
      Nature 270:257-259) suggests that their terminal varicosities may differ
      structurally and functionally from the presynaptic terminals of motor neurons.
      Furthermore, differences in the characteristics of UM neuron terminal
      varicosities may be correlated with functional differences among their diverse
      target muscles. Larval abdominal body wall muscles in the hawkmoth, Manduca
      sexta, consist of large, elongated fibers that are multiterminally innervated by
      one and occasionally two motor neurons (Levine and Truman [1985] J. Neurosci.
      5:2424-2431). The fibers are also innervated by one of two efferent UM neurons
      that bifurcate to innervate targets on both sides of the abdomen (Pfluger et al.
      [1993] J. Comp. Neurol. 335:508-522). In this study, the intracellular tracer
      biocytin was used to identify the targets of the UM neurons and to distinguish
      their terminal axonal varicosities on the muscle fibers. An antiserum to the
      synaptic vesicle protein, synaptotagmin, was used to label synaptic vesicles, and
      the styryl dye FM1-43 was used to demonstrate release and recycling. Most of the
      abdominal muscles in a given hemisegment were found to be supplied by one of the
      two UM neurons. Terminal varicosities of the excitatory motor neurons were large
      (3-7 pm) and were found in rows of rosettes that extended to every aspect of the
      muscle fiber; these varicosities were designated as type I terminals. The UM
      neuron terminal varicosities also occupied every aspect of the fiber but were
      smaller (1-3 microm) and more separated from each other; these were designated as
      type II terminals. Both type I and type II terminals are synaptotagmin
      immunoreactive and, as shown by FM1-43 staining, are sites of synaptic vesicle
      recycling. The excitatory motor neuron terminals (type I) could easily be loaded
      and unloaded with FM1-43, which indicates their capacity for repeated vesicular
      exocytosis and recycling. In contrast, the dye could not as readily be unloaded
      from UM neuron terminals (type II), which may indicate that they have a slower
      turnover of synaptic vesicles.

PMID- 10397392
TI  - Errors in lamina growth of primary olfactory axons in the rat and mouse olfactory
      bulb.
AB  - In the adult olfactory nerve pathway of rodents, each primary olfactory axon
      forms a terminal arbor in a single glomerulus in the olfactory bulb. During
      development, axons are believed to project directly to and terminate precisely
      within a glomerulus without any exuberant growth or mistargeting. To gain insight
      into mechanisms underlying this process, the trajectories of primary olfactory
      axons during glomerular formation were studied in the neonatal period.
      Histochemical staining of mouse olfactory bulb sections with the lectin Dolichos
      biflorus-agglutinin revealed that many olfactory axons overshoot the glomerular
      layer and course into the deeper laminae of the bulb in the early postnatal
      period. Single primary olfactory axons were anterogradely labelled either with
      the lipophilic carbocyanine dye, 1,1'-dioctodecyl-3,3,3',3'
      tetramethylindocarbocyanine perchlorate (DiI), or with horse-radish peroxidase
      (HRP) by localized microinjections into the nerve fiber layer of the rat
      olfactory bulb. Five distinct trajectories of primary olfactory axons were
      observed in DiI-labelled preparations at postnatal day 1.5 (P1.5). Axons either
      coursed directly to and terminated specifically within a glomerulus, branched
      before terminating in a glomerulus, bypassed glomeruli and entered the underlying
      external plexiform layer, passed through the glomerular layer with side branches
      into glomeruli, or branched into more than one glomerulus. HRP-labelled axon
      arbors from eight postnatal ages were reconstructed by camera lucida and were
      used to determine arbor length, arbor area, and arbor branch number. Whereas
      primary olfactory axons display errors in laminar targeting in the mammalian
      olfactory bulb, axon arbors typically achieve their adult morphology without
      exuberant growth. Many olfactory axons appear not to recognize appropriate cues
      to terminate within the glomerular layer during the early postnatal period.
      However, primary olfactory axons exhibit precise targeting in the glomerular
      layer after P5.5, indicating temporal differences in either the presence of
      guidance cues or the ability of axons to respond to these cues.

PMID- 10397393
TI  - Synaptic targets of cholinergic terminals in the cat lateral posterior nucleus.
AB  - We examined profiles in the neuropil of the lateral division of the lateral
      posterior (LP) nucleus of the cat stained with antibodies against choline acetyl
      transferase (ChAT) or gamma-aminobutyric acid (GABA), and several differences in
      the synaptic circuitry of the lateral LP nucleus compared with the pulvinar
      nucleus and lateral geniculate nucleus (LGN) were identified. In the lateral LP
      nucleus, there are fewer glomerular arrangements, fewer GABAergic terminals, and
      fewer cholinergic terminals. Correspondingly, the neuropil of the lateral LP
      nucleus appears to be composed of a higher percentage of small type I cortical
      terminals (RS profiles). Similar to the pulvinar nucleus and the LGN, the
      cholinergic terminals present in the lateral LP nucleus contact both GABA
      negative profiles (thalamocortical cells; 74%) and GABA-positive profiles
      (interneurons; 26%). However, in contrast to the pulvinar nucleus and the LGN,
      the majority of cholinergic terminals in the lateral LP nucleus contact small
      caliber dendritic shafts outside of glomeruli (60 of 82; 73%). Consequently, most
      cholinergic terminals are in close proximity to RS profiles. Therefore, whereas
      the cholinergic input to the LGN and pulvinar nucleus appears to be positioned to
      selectively influence the response of thalamocortical cells to terminals that
      innervate glomeruli (retinal terminals or large type II cortical terminals), the
      cholinergic input to the lateral LP nucleus may function primarily in the
      modulation of responses to terminals that innervate distal dendrites (small type
      I cortical terminals).

PMID- 10397394
TI  - Axonal regeneration from injured dorsal roots into the spinal cord of adult rats.
AB  - Injury to the central processes of primary sensory neurons produces less profound
      changes in the expression of growth-related molecules and less vigorous axonal
      regeneration than does injury to their peripheral processes. The left L4, L5, and
      L6 dorsal roots of deeply anaesthetized adult Sprague-Dawley rats were severed
      and reanastomosed, and in some animals, the ipsilateral sciatic nerve was crushed
      to increase the expression of growth-related molecules. After between 28 days and
      three months, the sciatic nerve of most animals was injected with transganglionic
      tracers and the animals were killed 2-3 days later. Other animals were perfused
      for electron microscopy. Very few regenerating axons entered the spinal cord of
      the rats without sciatic nerve injuries. Labelled axons, however, were always
      found in the spinal cord of rats with sciatic nerve injuries. They often entered
      the cord around blood vessels, ran rostrally within the superficial dorsal horn,
      and avoided the degenerating white matter. The animals with a conditioning
      sciatic nerve crush had many more myelinated axons around the dorsal root entry
      zone (DREZ) and on the surface of the cord. Thus, a conditioning lesion of their
      peripheral processes increased the ability of the central processes of myelinated
      A fibres to regenerate, including to sites (such as lamina II) they do not
      normally occupy. Astrocytes, oligodendrocytes, and meningeal fibroblasts in and
      around the DREZ may have inhibited regeneration in that region, but growth of the
      axons into the deep grey matter and degenerated dorsal column was also blocked.

PMID- 10397395
TI  - Cortical organization in shrews: evidence from five species.
AB  - Cortical organization was examined in five shrew species. In three species,
      Blarina brevicauda, Cryptotis parva, and Sorex palustris, microelectrode
      recordings were made in cortex to determine the organization of sensory areas.
      Cortical recordings were then related to flattened sections of cortex processed
      for cytochrome oxidase or myelin to reveal architectural borders. An additional
      two species (Sorex cinereus and Sorex longirostris) with visible cortical
      subdivisions based on histology alone were analyzed without electrophysiological
      mapping. A single basic plan of cortical organization was found in shrews,
      consisting of a few clearly defined sensory areas located caudally in cortex. Two
      somatosensory areas contained complete representations of the contralateral body,
      corresponding to primary somatosensory cortex (S1) and secondary somatosensory
      cortex (S2). A small primary visual cortex (V1) was located closely adjacent to
      S1, whereas auditory cortex (A1) was located in extreme caudolateral cortex,
      partially encircled by S2. Areas did not overlap and had sharp, histochemically
      apparent and electrophysiologically defined borders. The adjacency of these areas
      suggests a complete absence of intervening higher level or association areas.
      Based on a previous study of corticospinal connections, a presumptive primary
      motor cortex (M1) was identified directly rostral to S1. Apparently, in shrews,
      the solution to having extremely little neocortex is to have only a few small
      cortical subdivisions. However, the small areas remain discrete, well organized,
      and functional. This cortical organization in shrews is likely a derived
      condition, because a wide range of extant mammals have a greater number of
      cortical subdivisions.

PMID- 10397396
TI  - Intraspinal and behavioral consequences of nerve growth factor-induced
      nociceptive sprouting and nerve growth factor-induced hyperalgesia compared in
      adult rats.
AB  - Intraspinal and behavioral events were studied in adult rats with nociceptive
      nerves that were undergoing collateral sprouting into adjacent denervated skin.
      This sprouting, which is driven by endogenous nerve growth factor (NGF), did not
      cause hyperalgesia. For comparison, we studied an exogenous NGF administration
      that induced hyperalgesia but was too brief to evoke sprouting. When nociceptive
      nerves sprouted in skin, back-labeling with wheat germ agglutinin-conjugated
      horseradish peroxidase revealed that their projections sprouted in the cord. The
      sprouted peripheral nerves now activated more c-Fos-containing interneurons,
      which stimulus-response studies showed was not due to an increased afferent
      discharge. We attribute the interneuron recruitment to synaptogenesis following
      the intraspinal sprouting. Nociceptive stimulation of dorsal skin reflexly
      activates underlying cutaneous trunci muscle (CTM). When a nociceptive field
      expanded by nerve sprouting, so did the area of the evoked CTM reflex: this
      implies a recruitment of CTM motoneurons. We interpret this "matching" of
      response to stimulus as an adaptive phenomenon ensured by an adaptive intraspinal
      sprouting of the nociceptive projections. Neither the intraspinal changes nor the
      reflex changes occurred if peripheral sprouting was blocked by systemic anti-NGF
      treatment, indicating that the role of endogenous NGF was only in that sprouting.
      No comparable adaptive events occurred during NGF-induced hyperalgesia. Neither
      nociceptive fields nor CTM reflexes were affected; however there was a
      recruitment of c-Fos-expressing interneurons. This recruitment was not explained
      by peripheral sensitization, and, because sprouting was not involved here, we
      attribute the recruitment to "synaptic unmasking," i.e., an increased
      effectiveness of the preexisting excitatory circuitry.

PMID- 10397397
TI  - Acetylcholinesterase-positive innervation is present at undifferentiated stages
      of the sea turtle Lepidochelis olivacea embryo gonads: implications for
      temperature-dependent sex determination.
AB  - In embryos of different reptile species, incubation temperature triggers a
      cascade of endocrine events that lead to gonad sex differentiation. The cellular
      and molecular mechanisms by which temperature sets in motion this process are
      still controversial. Here, we begin evaluating the possible participation of the
      nervous system in temperature-dependent sex determination by showing the
      existence and origin of acetylcholinesterase (AchE)-positive nerve fibers in
      undifferentiated gonads of the Lepidochelys olivacea (L. olivacea) sea turtle
      putative male and female embryos, along the thermosensitive period for sex
      determination (TPSD; stages 20-27). AChE-positive nerve bundles and fibers were
      readily visualized until developmental stage 24 and thereafter. DiI injections
      and confocal imaging showed that some of these gonadal nerves arise from the
      lower thoracic and upper lumbar spinal cord levels, and might thus be sensory in
      nature. Because the vertebrate spinal cord is capable of integrating by itself
      thermoregulatory responses with no intervention of uppermost levels of the
      central nervous system, we also evaluated spinal cord maturation during the TPSD.
      The maturation of the spinal cord was more advanced in putative female than in
      male embryos, when sex determination is taking place for each sex; this process
      starts and ends earlier in male than in female embryos. Together these
      observations open the possibility that the spinal cord and the innervation
      derived from it could play a direct role in driving or modulating the process of
      temperature-dependent gonad sex determination and/or differentiation,
      particularly in female L. olivacea embryos.

PMID- 10397398
TI  - Motor effects and mapping of cerebral alterations in animal models of Parkinson's
      and Huntington's diseases.
AB  - Changes in stimulant-induced behavioral effects and subcortical c-Fos expression
      were compared between rodent models of Parkinson's disease (PD) and Huntington's
      disease (HD). Rats received either a unilateral 6-hydroxydopamine (6-OHDA)
      induced lesion of the nigrostriatal dopamine pathway (PD model) or a unilateral
      infusion of antisense oligodeoxynucleotides targeting c-fos into the striatum (HD
      model). Dopamine-lesioned animals received intraperitoneal injections of either d
      amphetamine (6-OHDAamp group) or apomorphine (6-OHDAapo group), whereas all
      animals that received antisense infusions received d-amphetamine (ASF group). All
      groups exhibited robust circling behavior upon stimulant challenge. Changes in
      subcortical activation, as assessed by the induction of Fos-like immunoreactivity
      (Fos-LI), were examined in several brain regions. The 6-OHDAamp and ASF groups
      exhibited robust, ipsiversive circling behavior, with similar changes in Fos-LI
      in the striatum, entopeduncular nucleus, superior colliculus, and ventromedial
      thalamus. The 6-OHDAapo group exhibited contraversive rotation and had reciprocal
      patterns of Fos-LI in these regions. Despite exhibiting the same direction of
      rotation, the 6-OHDAamp and ASF groups had markedly different patterns of Fos-LI
      in the globus pallidus and the pontine reticular formation. These results suggest
      that the globus pallidus may undergo distinct alterations in PD and HD and that
      the pontine reticular formation is particularly susceptible to changes in
      mesencephalic dopamine sources.

PMID- 10397399
TI  - Different polysialic acid-neural cell adhesion molecule expression patterns in
      distinct types of mossy fiber boutons in the adult hippocampus.
AB  - Dentate granule cells continue to be generated in the adult hippocampus, and the
      newly generated granule cells express the highly polysialylated neural cell
      adhesion molecule (PSA-NCAM), which has been shown to be important in neural
      development and plasticity. In the present study, the PSA-NCAM expression pattern
      in morphologically distinct types of mossy fiber boutons in adult rats was
      examined by immunoelectron and confocal laser scanning microscopy. Although many
      unmyelinated axons within the mossy fiber bundles expressed PSA-NCAM, most of the
      mature type of mossy fiber boutons were negative for polysialic acid (PSA) but
      positive for NCAM peptides, suggesting that NCAM is less polysialylated in the
      mature mossy fiber boutons. On the other hand, PSA was expressed by small round
      varicosities, irregularly shaped boutons, and the presumptive immature type of
      mossy fiber boutons. The PSA-positive small boutons were found to make synaptic
      contacts with CA3 pyramidal cells and nonpyramidal cells. The PSA-expressing
      presumptive immature boutons contained fewer clear synaptic vesicles and
      mitochondria, and, in some instances, they were invaginated by the PSA-positive,
      finger-like dendritic outgrowths arising from the dendritic shafts of the
      pyramidal cells, which are known to develop into a mossy fiber bouton-thorny
      excrescence complex. These findings indicate that distinct types of the mossy
      fiber boutons possess different PSA expression patterns in the adult hippocampus,
      and they also imply that PSA expression allows the mossy fibers to have the
      ability to regulate the bouton formation and remodeling that accompany synapse
      formation at the contact sites with pyramidal cells and nonpyramidal cells.

PMID- 10397401
TI  - Increased corticofugal plasticity after unilateral cortical lesions combined with
      neutralization of the IN-1 antigen in adult rats.
AB  - If damage to the central nervous system (CNS) occurs early in life, extensive
      rearrangements of the remaining fiber systems as well as regeneration of lesioned
      fibers take place. In the rat or hamster, newly grown projections have been
      described only if the lesion occurred within the first two weeks postnatally.
      This decreasing growth ability correlates with CNS maturation and the progression
      of myelination. Myelin contains the potent neurite growth inhibitors NI-35/250
      that are crucially involved in the failure of long-distance regeneration and the
      lack of compensatory structural plasticity after adult CNS lesions. In this
      study, we show that extensive remodeling occurs well after the termination of the
      growth permissive period in the adult rat if we neutralize the inhibitory
      properties of myelin with the monoclonal antibody IN-1. After ablation of one
      motor cortex and treatment with the antibody IN-1, we observed that the remaining
      corticospinal tract (CST) from the spared hemisphere sprouted into the
      denervated, contralateral red nucleus and pons. In the pons, these fibers
      terminated in a typical somatotopic pattern. For comparison with neonatal
      plasticity, we performed the same lesion in two-day-old rats (no antibody). This
      lesion led as well to sprouting of the remaining CST into denervated brainstem
      nuclei, resulting in a bilateral corticofugal projection. Our results show that
      neutralization of myelin-associated neurite-growth inhibitors after CNS lesions
      leads to a structural remodeling of the spared corticofugal fibers in adult rats,
      a process normally restricted to a short postnatal period.

PMID- 10397400
TI  - Development of layer I of the human cerebral cortex after midgestation:
      architectonic findings, immunocytochemical identification of neurons and glia,
      and in situ labeling of apoptotic cells.
AB  - The development of layer I was studied in the human frontal cortex from 21 weeks
      of gestation (GW) to 2.5 postnatal months in series of adjacent sections
      processed for thionin staining, Bodian silver staining, and immunocytochemical
      labeling of neurons and glia. In addition, the terminal dUTP nick-end labeling
      (TUNEL) method was used to label in situ DNA fragmentation. A progressive
      decrease of cell density and the disappearance of the subpial granular layer
      (SGL) appeared as distinctive developmental features of human layer I,
      consistently with previous investigations. The neuronal antigen microtubule
      associated protein2 was found to label preferentially Cajal-Retzius cells and
      dendritic processes extending from the cortical plate. At midgestation, the
      calcium binding protein calretinin stained in the marginal zone numerous neurons,
      including the Cajal-Retzius cells and their processes. Calretinin-immunoreactive
      neurons decreased during the subsequent maturation: such decline was abrupt in
      the SGL, whereas bipolar calretinin-immunopositive cells accumulated in the inner
      marginal zone to be presumably incorporated into the cortical plate. Cajal
      Retzius cells expressed calretinin throughout the examined developmental stages.
      The glial antigen vimentin was already expressed at midgestation, and vimentin
      immunopositivity decreased progressively in cell bodies and fibers of layer I
      during development. Glial fibrillary acidic protein-positive elements gradually
      matured, and the positive cell bodies displayed the features of mature astrocytes
      at the end of gestation. Moreover, a decrease of free glial cells was observed in
      layer I, suggesting their progressive incorporation into the cortical plate.
      TUNEL-positive cells were detected at midgestation in the marginal zone, and they
      were concentrated in the SGL until its disappearance; their number decreased
      dramatically throughout layer I after 30 gestational weeks. TUNEL-positive nuclei
      or regressive changes were not detected in Cajal-Retzius cells throughout the
      examined developmental stages. Thus, our data point out that naturally occurring
      cell death is an active mechanism contributing to the disappearance of the SGL
      but not to the subsequent developmental reshaping of human layer I, in which,
      instead, migratory phenomena should play a major role. In addition, our findings
      argue against a disappearance of Cajal-Retzius cells due to regressive processes.

PMID- 10397402
TI  - Relationships between sex and the size and number of forebrain gonadotropin
      releasing hormone-immunoreactive neurones in the ballan wrasse (Labrus
      berggylta), a protogynous hermaphrodite.
AB  - This study is the first to examine the brain gonadotropin-releasing hormone
      (GnRH) cell population phenotype in a protogynous and monandric sequentially
      hermaphroditic fish. Male ballan wrasse (Labrus berggylta) had on average higher
      numbers of GnRH-immunoreactive (GnRH-ir) cells within the brain preoptic area
      (POA) than females, a difference not found in GnRH-ir cells in other brain
      regions. Furthermore, in males, but not females, the number of these POA GnRH-ir
      cells correlated with body size. Maturational state (prespawning or postspawning)
      had marked effects on mean profile sizes (but not numbers) of both GnRH-ir cell
      bodies and cell nuclei, even when existing differences in body size and
      allometric relationships had been taken into account. Postspawning males tended
      to have larger GnRH-ir profiles in all brain regions relative to both prespawning
      males and females. Moreover, the GnRH-ir cell number in POA, and the cell body
      profile size in both POA and at the level of the anterior commissure, correlated
      with gonad size in spermiated prespawning males, indicating a relationship
      between both size and number of GnRH cells and male gonadal development. These
      results suggest that temporary changes in the size of brain GnRH-ir neurones are
      coupled to the male spawning cycle, and that permanent POA GnRH-ir cell number
      changes are involved in the process of sex change in sequential hermaphrodites.
      However, smaller males had no more preoptic GnRH-ir cells than equally sized
      females, which may argue against a proximate inducing role of GnRH cell number
      changes in naturally occurring sex reversal.

PMID- 10397403
TI  - Depression and bipolar disorder: relationships to impaired fatty acid and
      phospholipid metabolism and to diabetes, cardiovascular disease, immunological
      abnormalities, cancer, ageing and osteoporosis. Possible candidate genes.
AB  - Depression and bipolar disorder are two of the commonest illnesses in the
      developed world. While some patients can be treated effectively with available
      drugs, many do not respond, especially in the depression related to bipolar
      disorder. Depression is associated with diabetes, cardiovascular disease,
      immunological abnormalities, multiple sclerosis, cancer, osteoporosis and ageing:
      in each case depressed individuals have a worse outcome than non-depressed
      individuals. In all of these conditions there is now evidence of impaired
      phospholipid metabolism and impaired fatty acid-related signal transduction
      processes. Impaired fatty acid and phospholipid metabolism may be a primary cause
      of depression in many patients and may explain the interactions with other
      diseases. Several novel gene candidates for involvement in depression and bipolar
      disorder are proposed.

PMID- 10397404
TI  - Concentration- and time-dependent effects of gamma-linolenic acid supplementation
      to tumor cells in culture.
AB  - Gamma-linolenic acid (GLA) supplemented to neuroblastoma SK-N-BE, tubal carcinoma
      TG and colon carcinoma SW-620 cells was incorporated into phospholipids in all
      the cell lines (although to different extents), in a concentration- and time
      dependent manner. All the cell lines were able to metabolize GLA to arachidonic
      acid, SK-N-BE being the most active. Supplementation with low GLA concentrations
      for short periods was not sufficient to impair cell proliferation; only higher
      amounts of GLA had an anti-proliferative effect also in short times. In these
      conditions, the antiproliferative effect of GLA is probably due to cellular
      dysfunction caused by fatty acid modifications.

PMID- 10397405
TI  - Cyclic AMP response element mediates dexamethasone induced suppression of
      prostaglandin H synthase-2 gene expression in human amnion derived WISH cells.
AB  - A human PGHS-2 promoter fragment (300 BP) linked to the luciferase reporter was
      used to study the regulation of PGHS-2 gene expression in human amnion-derived
      WISH cells. A cyclic AMP (cAMP) response element (CRE) was found to be important
      in the induction of PGHS-2 gene expression. This was demonstrated by showing that
      coexpression of CREB stimulated native but not CRE mutant promoter and that IL
      1beta and PMA induced less activity with the mutant promoter as compared to the
      native promoter. The effect of dexamethasone on IL-1beta and PMA induced promoter
      activities was further examined. IL-1beta or PMA induced activity was blocked by
      dexamethasone, whereas IL-1beta or PMA induced mutant activity was not responsive
      to dexamethasone. Direct activation of CRE by a cAMP elevating agent,
      isoproterenol, was found to be inhibited significantly dexamethasone. These
      results suggest that CRE may mediate the induction of PGHS-2 by IL-1beta and PMA
      as well as the suppression of expression by dexamethasone in amnion-derived
      cells.

PMID- 10397406
TI  - Role of centrally administered melatonin and inhibitors of COX and NOS in LPS
      induced hyperthermia and adipsia.
AB  - In the present study we have examined the effect of centrally administered non
      steroidal anti-inflammatory drugs (NSAIDS), nitric oxide synthase (NOS) inhibitor
      and melatonin on lipopolysaccharide (LPS)-induced hyperthermia and its anti
      dipsogenic effect. Intracerebroventricular (i.c.v.) administration of LPS (100
      200 ng/rat) induces a dose dependent elevation in body temperature and decreases
      water consumption in 24 h water deprived rats. Coadministration of NSAIDS
      (indomethacin and nimesulide: 10 nM/rat each) with LPS (100 ng) reversed, whereas
      NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME: 10-20 microg/rat)
      enhanced LPS-induced hyperthermia. In contrast L-NAME reversed the LPS-induced
      anti-dipsogenic effect in a dose dependent manner, whereas NSAIDS showed no
      change in the effect of LPS. Further, centrally administered prostaglandin E2
      (PGE2, 0.5-1 microg/rat) produced hyperthermia without affecting the drinking
      behavior, suggesting that two independent mechanisms operate in LPS-induced
      hyperthermia and in the anti-dipsogenic effect. The pineal hormone melatonin is
      known to inhibit cellular damage caused by LPS, produced dose dependent (5-10 nM
      i.c.v.) inhibition of LPS-induced hyperthermia and adipsia, but failed to reverse
      the PGE2-induced hyperthermia, shows reversal of LPS-induced hyperthermia by
      melatonin is due to inhibition of prostaglandin synthesis rather than antagonism
      of prostaglandin action. The overall study reveals that inhibition of both NO and
      prostaglandin production by melatonin might be responsible for its reversal of
      LPS-induced hyperthermia and adipsia.

PMID- 10397407
TI  - Interleukin-4 differentially regulates prostaglandin production in amnion-derived
      WISH cells stimulated with pro-inflammatory cytokines and epidermal growth
      factor.
AB  - Cytokines and growth factors have been proposed to act as in vivo modulators of
      amnion prostaglandin production at parturition. To characterize the effects of
      the 'anti-inflammatory' cytokine interleukin (IL)-4 on amnion prostaglandin
      production, amnion epithelium-derived WISH cells were treated with IL-4 in the
      presence/absence of IL-1beta, tumour necrosis factor-alpha (TNF-alpha) or
      epidermal growth factor (EGF). IL-4 (0.08-10 ng/ml) potently inhibited cytokine
      stimulated PGE2 production over 16 h (maximal inhibition approximately 66% at 2.0
      ng/ml IL-4). Delaying addition of IL-4 (1 ng/ml) by up to 8 h after IL-1beta
      addition only slightly attenuated its inhibitory effects, from approximately 65%
      to approximately 50%. EGF-stimulated PGE2 production was either not inhibited or
      slightly stimulated by IL-4. Immunoblotting studies revealed that IL-4 (10 ng/ml)
      significantly suppressed prostaglandin-H synthase-2 (PGHS-2) levels in cells
      stimulated with IL-1beta and TNF-alpha over 16 h, but had no consistent effects
      on cytosolic phospholipase A2 (cPLA2) levels under any condition. In the presence
      of arachidonic acid (10 microM), IL-4 again inhibited cytokine-stimulated, but
      not EGF-stimulated, PGE2 production. The presence of IL-4 also failed to alter
      the amount of arachidonic acid released in response to EGF. These findings
      suggest a role and potential therapeutic application for IL-4 in inhibiting
      amnion PGHS-2 expression and hence prostaglandin production in infection-driven
      preterm labour, but not labour in the absence of inflammatory initiators.

PMID- 10397408
TI  - Endothelin-induced prostacyclin production in rat aortic endothelial cells is
      mediated by protein kinase C.
AB  - Endothelin (ET) is a vasoconstrictor peptide released from endothelial cells that
      is known to cause prostaglandin (PG) release. The mechanism remains unclear. To
      determine whether the protein kinase C (PKC) signaling pathway is stimulated by
      endothelin, we pretreated rat aortic endothelial cells with either PKC activator
      or inhibitors and measured the release of prostacyclin (PGI2) by
      radioimmunoassay. ET (10(-9) M) produced a 10-fold increase in PGI2 release.
      Pretreatment with 10(-9) M of three different PKC inhibitors: 1-(5
      isoquinolinesulfonyl) piperazine (CL), staurosporine, and 1-(5
      isoquinolinesulfonyl-methyl) piperazine (H7) blocked ET induced PGI2 release. ET
      induced prostacyclin release was also blocked by pretreatment with inhibitors of
      either phospholipase A2 (7,7,dimethyleicosadienoic acid or trifluoromethyl ketone
      analogue) (10(-9) M) or cyclooxygenase (indomethacin) (10(-9) M). We conclude
      that ET activates PKC which activates phospholipase A2 which liberates
      arachidonic acid which increases PGI2 production and release.

PMID- 10397409
TI  - Time-course of the alterations in prostanoid production and in contractile
      responses of mesenteric beds isolated from streptozotocin diabetic rats.
AB  - The prostanoid production and the effect of indomethacin on the noradrenaline
      induced contractions were studied in the mesenteric bed of rats at different
      times (1-8 weeks) after the administration of streptozotocin (STZ). The
      production of prostacyclin (measured as 6-keto-PGF1alpha) and prostaglandin (PG)
      E2 was unchanged one week after STZ, but it was reduced to 50% of control values
      4 weeks after STZ without further changes 8 weeks after the treatment. The
      release of thromboxane (TX) A2 (measured as TXB2) and PGF2alpha, increased by
      100% one week after STZ and returned to basal values at 3 weeks. TX release was
      below control values 8 weeks after STZ. The ratio 6-keto-PGF1alpha/TXB2 was
      reduced one week after STZ, recovered to control values at 4 weeks and augmented
      at 8 weeks. Indomethacin (10 microM) reduced the contractile responses to
      noradrenaline in the controls, whereas in STZ-treated rats this effect was
      observed solely 8 weeks after the treatment. Since this recovery coincided with
      an increase of the vasodilator/vasoconstrictor prostanoid ratio, a time-dependent
      compensation of the vascular alterations caused by STZ can be proposed from the
      present results.

PMID- 10397410
TI  - Thromboxane A2 fails to induce proliferation of smooth muscle cells enriched with
      eicosapentaenoic acid and docosahexaenoic acid.
AB  - Thromboxane A2 (TXA2) released from aggregating platelets and injured vessel wall
      stimulates smooth muscle cell proliferation, which may contribute to the
      development of vascular lesion formation after percutaneous transluminal coronary
      angioplasty. Polyunsaturated fatty acids (n-3) present in the fish oils have been
      shown to have anti-atherosclerotic effects. In view of this, we examined the
      effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the active
      ingredients of fish oils on TXA2 induced smooth muscle cell proliferation. To
      find out the specificity of these fatty acids we used gamma-linolenic acid (n-6)
      and oleic acid (n-9) as controls. It was found that TXA2 failed to stimulate
      proliferation of smooth muscle cells preloaded with EPA or DHA but not with gamma
      linolenic acid or oleic acid. Further, when smooth muscle cells were preloaded
      with both EPA and DHA, they acted together in preventing the TXA2 induced smooth
      muscle cell proliferation. These results demonstrate that one of the mechanisms
      by which fish oils may prevent neointima formation is by making smooth muscle
      cells less responsive to TXA2 induced proliferation of smooth muscle cells.

PMID- 10397411
TI  - Panic induced by carbon dioxide inhalation and lack of hypothalamic-pituitary
      adrenal axis activation.
AB  - It has been hypothesized that spontaneous panic is distinct from anticipatory
      anxiety, which activates the hypothalamic-pituitary-adrenal (HPA) axis. Panic
      attacks characterized by prominent respiratory symptoms, such as those induced by
      sodium lactate, are not associated with increases in cortisol. We examined blood
      cortisol responses to CO2-induced panic. Cortisol levels did not increase and
      actually decreased significantly in 10 panicking subjects with panic disorder. No
      reductions were noted after 20 min of CO2 inhalation in either eight normal
      comparison subjects or six non-panicking panic disorder patients. These results
      lend support to the hypothesis that the pathophysiological mechanism underlying
      CO2-induced panic is different from that underlying general or anticipatory
      anxiety.

PMID- 10397412
TI  - Clinical, demographic and social characteristics of psychotic depression.
AB  - The goal of this study was to compare the clinical, demographic and social
      characteristics of psychotic and non-psychotic depression in the elderly and
      younger age groups. Depressed patients (n = 674) meeting DSM-III-R criteria for
      major depressive episode were classified into two groups, psychotic and non
      psychotic, based on the presence of delusions or hallucinations. The patients
      with psychotic and non-psychotic depression were compared on clinical,
      demographic, and social characteristics. Bivariate analyses revealed that younger
      age, psychomotor retardation, guilt, feelings of worthlessness, history of
      delusions in the past, and increased suicidal ideation and intent were found more
      commonly in psychotic as compared to non-psychotic depression. A fully adjusted
      logistic regression model also confirmed younger age, history of past delusions,
      and increased feelings of worthlessness to be associated more with psychotic than
      with non-psychotic depression. Trends were observed for psychotic depression to
      be associated with poor subjective social support and with bipolar illness.
      Cerebrovascular risk factors and gender composition did not differ significantly
      in the psychotic vs. non-psychotic groups. The study confirms previously
      described findings such as increased guilt, increased psychomotor retardation and
      increased suicidality in psychotic depression in a large sample of depressed
      patients. The study also introduces the concept of age as an important variable
      influencing psychotic depression. The limitation of this finding is that it is
      applicable to tertiary care samples. Further studies are needed to confirm this
      finding in other subgroups.

PMID- 10397413
TI  - Reproducibility of in vivo measures of platelet membrane phospholipids in human
      subjects.
AB  - Membrane phospholipid abnormalities in the brain neurons may be implicated in the
      pathophysiology of neuropsychiatric disorders. In the absence of methods to
      directly examine the levels of brain membrane phospholipids in vivo in human
      subjects, peripheral cells and platelets have been used as models in this field.
      We previously reported a method to determine the relative amounts of eight
      individual platelet membrane phospholipid classes using two-dimensional thin
      layer chromatography, and scanning-laser densitometry (Mallinger et al., 1993).
      Here we report the test/retest reproducibility of these platelet membrane
      phospholipid measures in healthy human subjects (n = 12) who were studied on two
      different occasions separated by a 3-week interval. The mean intra-subject
      coefficients of variation were 3.1-18%, and the intra-class correlation
      coefficients (ICCs) were 0.41-0.68. These findings are consistent with a low to
      moderate variability, and moderate reliability of these individual platelet
      membrane phospholipid measures over the period studied. When this method is
      applied for longitudinal studies of psychiatric populations, the degree of
      variability has to be considered in the interpretation of the results.

PMID- 10397415
TI  - Predicting quality of life from symptomatology in schizophrenia at exacerbation
      and stabilization.
AB  - There has been little research investigating how symptoms of schizophrenia and
      changes in symptomatology across the course of the illness relate to measures of
      quality of life in patients. We examined this issue in 45 patients assessed at
      hospital admission for illness exacerbation, at stabilization (prior to
      discharge) and at follow-up (5-9 months post-discharge). Symptom ratings at each
      time period consisted of the Brief Psychiatric Rating Scale (BPRS) and the
      Negative Symptom Assessment (NSA). The Heinrichs-Carpenter Quality of Life Scale
      (QLS) was administered upon admission to the hospital (assessing the 3 months
      prior to admission) and again at follow-up. Correlational analyses revealed
      relationships of both positive and negative symptoms with quality of life. These
      relationships are particularly strong at stabilization. Stepwise regression
      analyses revealed changes in the NSA motivation component to be most important in
      predicting quality of life for the patients at follow-up. BPRS psychosis and
      paranoia components are important predictors of quality of life at stabilization
      (but not during acute exacerbation). These results are important in terms of
      understanding the impact of changes in symptomatology on the quality of life for
      patients with schizophrenia as well as in targeting specific symptom clusters for
      treatment to maximize quality of life post-hospitalization.

PMID- 10397414
TI  - Neurological signs and psychomotor performance in patients with schizophrenia,
      their relatives and healthy controls.
AB  - Schizophrenic patients (DSM-III-R) were consecutively recruited and 39 were
      included. Twenty-one were first-episode and 18 were chronic schizophrenic
      patients. Thirty of the patients were on neuroleptic medication. Thirty-three
      parents were included, of whom nine were classified as 'family history positive'
      and 22 as 'family history negative' of a disposition to psychosis. Fifty-five
      healthy controls volunteered. The subjects were investigated according to a
      protocol divided into neurological signs and psychomotor performance (finger
      tapping rate, Purdue pegboard test, pronation-supination test, gait and hand
      grasp strength). Seventy-eight percent of the patients and 7% of the controls
      were classified as globally aberrant in signs. The patients and their parents,
      classified as 'family history positive', exhibited a similar laterality pattern
      in a finger-tapping test improving performance with the preferred hand,
      significantly different from the performance of the 'family history negative'
      parents and normal subjects. Duration of illness, neuroleptic medication and
      negative symptoms were not related to the occurrence of neurological signs and
      psychomotor performance. These findings indicate that neurological aberrations
      are present at the onset of illness and that hereditary factors are associated
      with motor laterality.

PMID- 10397416
TI  - Increased olfactory sensitivity in first episode psychosis and the effect of
      neuroleptic treatment on olfactory sensitivity in schizophrenia.
AB  - Olfactory sensitivity to two odorants, isoamyl acetate and androstenone, was
      assessed in 19 male schizophrenic patients and 10 control subjects. Tests were
      performed during a drug-free period and 2-3 weeks after initiation of neuroleptic
      drug therapy. Olfactory sensitivity in schizophrenic patients was significantly
      impaired during the drug-free period and neuroleptic treatment further reduced
      olfactory sensitivity in these patients. The same olfactory tests were
      administered to 22 first-episode-psychosis patients, 12 first-episode
      schizophrenia and 10 brief-psychotic-disorder patients, as well as to 20 age
      matched control subjects. The first-episode-psychosis patients had significantly
      higher sensitivity to isoamyl acetate and to androstenone, but the incidence of
      anosmia to androstenone was not higher in the first episode patient group as
      compared to the control group. We conclude that olfactory dysfunction in
      schizophrenic patients, and possibly other forms of psychosis, is mainly due to
      long-term effects of commonly used neuroleptic drugs.

PMID- 10397417
TI  - Self-report and objective measures of cognitive deficit in patients entering
      substance abuse treatment.
AB  - The relationship between self-reported cognitive deficits and objectively
      measured cognitive performance was examined in 86 patients entering substance
      abuse treatment. Self-ratings of cognitive impairment were strongly correlated
      with indices of depression and vulnerability to stress, but not with objective
      cognitive performance. Confirming the lack of relationship between self-report
      and objective cognitive measures, cognitive performance did not differ between
      patients at the extremes of the cognitive-complaint distribution; and cognitively
      impaired patients did not differ from cognitively intact patients in their self
      ratings of impairment.

PMID- 10397419
TI  - Correspondence of emotional self-rating with facial expression.
AB  - Emotional processing abilities are difficult to measure psychometrically.
      Ultimately their quantification has to rely on 'subjective' judgment thereby
      leaving open the problem of response biases. Assessments of autonomic arousal
      similarly provide a mere unspecified measurement of a specific emotion. A
      standardized mood induction procedure capable of obtaining reliable happy and sad
      mood changes in healthy subjects was used to demonstrate the effectiveness of
      this procedure. We performed a two-part experiment using a rater-based analysis
      of facial expressions. This entailed analyzing the emotion portrayed in the
      faces. The faces of 24 healthy subjects were videotaped during the mood induction
      procedure of happiness and sadness, respectively. A group of 20 raters naive to
      the experimental task and conditions rated the facial expressions on six basic
      emotions. Results showed that ratings corresponded with the facial expressions,
      which were reflecting the mood of the task condition. Subjects' facial
      expressions together with self-ratings demonstrate the successful applicability
      of this standardized mood induction procedure for eliciting happy and sad mood.

PMID- 10397418
TI  - Impulsive and premeditated aggression: a factor analysis of self-reported acts.
AB  - Although aggression research in general has been hampered by a lack of objective
      measurements of aggressive acts, two types of aggressive acts, impulsive vs.
      premeditated, have been studied extensively in recent years. These two types of
      aggression have been primarily measured by structured or semi-structured
      interviews. The current study was designed to assess the construct validity of
      these two types of aggression using a self-report questionnaire which included
      items gleaned from the content of interviews used in past studies. For this
      study, 216 college students assessed their own aggressive acts rather than
      answering general questions about aggression. The students were not significantly
      different from normative sample groups on self-report measures of impulsiveness,
      aggression, and anger/hostility. A PCA factor analysis with a promax rotation of
      the items on the self-report questionnaire identified four factors: impulsive
      aggression; mood on the day the act occurred; premeditated aggression; and
      agitation. Thus, impulsive and premeditated aggression are independent constructs
      which exist in varying degrees among these 'normal' persons in a non-clinical
      sample. Impulsive aggression was characterized in part by feelings of remorse
      following the acts and by thought confusion. Premeditated aggression was related
      to social gain and dominance.

PMID- 10397420
TI  - Integrating psychological therapies: processes of meaning transformation.
AB  - We review the role played by meaning in different schools of psychotherapy, and
      propose that the systematic study of meaning transformation has the potential to
      unify understanding of the scientific basis of psychotherapy. We describe some of
      the most important innate and social origins of meaning, and identify seven major
      themes that characterize the thinking of people with psychological disorders. We
      also describe how these themes are processed cognitively on multiple levels, and
      propose common change processes that are consistent with research in cognitive
      psychology. These core sets of themes and processes are offered as a first step
      toward a systematic study of meaning and psychotherapeutic change.

PMID- 10397421
TI  - Stress and intervention strategies in mental health professionals.
AB  - There is growing evidence to show that mental health professionals by the nature
      of their work are particularly vulnerable to stress with all its detrimental
      effects on service delivery and quality of care. This comes at a time when mental
      health services in many countries are under considerable strain. The present
      paper examines the multifaceted stressors encountered by the mental health team
      and recommends possible ways of reducing burnout through innovative intervention
      strategies. The detection of emotional distress and psychological dysfunctioning
      in mental health providers is outlined and their management carefully considered.

PMID- 10397422
TI  - Some psychometric properties of the Texas Grief Inventory adjusted for
      miscarriage.
AB  - The psychometric properties of an adjusted version of the Texas Grief Inventory
      (Zisook, Devaul & Click, 1982) were evaluated in a sample of 207 women following
      an early pregnancy loss. Factor structure of the Inventory was examined, and the
      validity was assessed by comparing the level of grief in women who became
      pregnant following a miscarriage and those who did not. Factor analysis resulted
      in a three-factor solution that was theoretically interpretable. The identified
      subscales were: pure grief, grief-related emotions and perceived adjustment and
      functioning since miscarriage. Significantly lower levels of grief-related
      behaviours and feelings were reported in women who became pregnant, which was
      suggestive of the construct validity of the Inventory. The high reliability
      coefficient (Cronbach's alpha = .90) obtained with this 17-item version of the
      Grief Inventory suggests it to be a reliable instrument for the assessment of
      grief after early miscarriage.

PMID- 10397423
TI  - Dialogical engagement with voices: a single case study.
AB  - This paper raises the possibility that a dialogical, or discursive, model of
      human experience may be useful in helping someone who experiences verbal
      hallucinations. The model regards verbal hallucinations as a variety of inner
      speech with dialogical properties. The explication of these properties in the
      context of a personal narrative allowed the individual to engage in dialogue with
      the voices, through the medium of a new, supportive and positive voice. This
      process made it possible to introduce moral responses to distressing and
      potentially dangerous imperative verbal hallucinations, through the mediation of
      the new voice. Her dialogical engagement with this voice enabled her to deal
      effectively with troublesome voices, and was a powerful source of self-esteem. We
      briefly present the theoretical perspective underlying this approach, and compare
      and contrast the approach with cognitive-behavioural techniques.

PMID- 10397424
TI  - Mother and caregiver representations of toddlers in a kibbutz setting.
AB  - Seventy-seven mother-caregiver pairs were interviewed by a 10-item instrument in
      order to evaluate their perception of children which they cared for, and their
      dyadic relationships with him or her. Children's ages ranged between 16-38
      months. Results indicated that mothers presented more elaborated and more
      positive descriptions of their children, and perceived them as more developed as
      compared with caregivers. Mothers' emotional tone in describing the child was
      more ambivalent, namely more anxious and at the same time also more enthusiastic,
      as compared with the caregivers. Results are discussed in terms of the
      distinction between the meaning attributed by mothers and caregivers to their
      respective experiences of caregiving role-relations with the same child, and
      their different representations of the same child.

PMID- 10397425
TI  - Brains, minds and selves: changing conceptions of the losses involved in
      dementia.
AB  - Until the last 10 years or so, dementia research had been dominated by the
      psychiatric or medical approach to dementia. However, increasing numbers of new
      psychological and social psychological approaches to dementia have begun to
      emerge. Consequently, there has been a significant change in the descriptions of
      the losses involved in the dementing process: from being represented in terms of
      brain functioning, they have become repositioned as occurring within both
      personal and social contexts. We elaborate these frameworks and apply them to
      three phenomena associated with dementia--depressions, delusions and denial.
      While these conceptualizations are limited by a number of difficulties, they
      nevertheless represent a significant change in approaches to dementia care and
      allow the potential for positive change through psychological as well as chemical
      means. The emergence of these new accounts of the losses involved in dementia
      needs to be matched by the equivalent development of effective psychosocial
      interventions to maintain individuals within their own homes.

PMID- 10397426
TI  - Phasic influences on psychometric measures during the menstrual cycle:
      implications for the construct integrity of the locus of control dimension.
AB  - Thirty healthy female volunteers with normal menstrual cycles participated in a
      study to examine the influence of menstrual cycle phase on locus of control (LC)
      orientation. LC measures were taken on the follicular, luteal and premenstrual
      phase of the cycle. It was found that menstrual cycle phase had little effect on
      LC orientation suggesting that previously observed LC differences across the
      cycle in dysmenorrhea and premenstrual syndrome sufferers cannot be generalized
      to a normal non-clinical population. Surprisingly, it was further found that no
      significant statistical relationship was found between the two LC measures used,
      in spite of the finding that, individually, each LC measure intercorrelated
      highly significantly across the menstrual cycle. Since one of the LC scales was
      derived theoretically, and the other LC scale used was derived from clinical
      practice, the findings are discussed in relation to the theory-practice divide
      and the prima facie value of self-report LC measures.

PMID- 10397427
TI  - The helping process in couples during recovery from heart attack: a single case
      study.
AB  - This single case study aimed to illustrate help-intended communication in
      couples, in particular how a husband and wife attempted to help each other with
      adjusting to the husband's recent myocardial infarction. The study employed a
      semi-structured communication task to gather samples of the couple's helping
      interactions: the couple had two conversations in which they alternated helper
      and discloser roles. Quantitative and qualitative data were obtained from the
      couple and from expert raters (observers) about their perspectives of the
      conversations. The observers' ratings and verbal response mode patterns indicated
      that the conversations were characterized by low levels of empathy and
      exploration of feelings and relatively high levels of helper disclosure and
      advice; overall, the observers found the conversations to be somewhat unhelpful.
      In contrast, the couple rated the conversations more positively; the 'helpful
      events' they identified consisted of their partner disclosing a new piece of
      information and giving advice. The results were discussed in terms of the unique
      features of helping in close relationships.

PMID- 10397428
TI  - Absolutist thinking and health.
AB  - Absolutist thinking has been identified in therapeutic studies as a style of
      thinking which is believed to promote emotional distress, particularly anger,
      when people are confronted by situations which do not conform to their demands
      concerning what ought to happen. It is not a discrete thought process, however,
      but a key aspect of a framework of beliefs and reactions which are thought to
      make people vulnerable to poor psychological and physical health when faced with
      personal, domestic or work problems. This thinking style was assessed in a study
      of the coping behaviour of headteachers to examine associations between
      absolutist thinking, coping behaviour and health. The headteachers were
      classified as absolutist (N = 49) or non-absolutist (N = 31) in the ways they
      handled two work problems, one with a 'successful' outcome, the other with an
      'unsuccessful' outcome. In line with predictions, statistically significant
      differences were found between the two groups when using multivariate and
      univariate analyses. Absolutist headteachers experienced their job demands as
      less pleasant, and perceived themselves to be less effective at managing their
      emotions for both problems; they perceived themselves as producing less
      'successful' outcomes for the successful problem, as handling this problem less
      effectively, and as having poorer psychological and physical health.

PMID- 10397429
TI  - Emotional and behavioural problems in adolescents/young adults receiving
      treatment at a community-based psychotherapy centre for young people: a
      preliminary study of the correspondence among adolescent/young adult and
      significant other reports.
AB  - The present study examined the correspondence among adolescent/young adult and
      parental figure, professional, peer and partner reports, in their rating of
      emotional and behavioural problems of 195 young people aged between 12 and 25
      years who attended a community-based psychotherapy centre. Data from young people
      were obtained at intake by participants completing the Youth Self Report Form and
      from significant others by them completing the Significant Other version of the
      Teacher's Report Form. Professionals rated internalizing (emotional) problems
      lower than peers, partners or parental figures. Externalizing (disruptive)
      problems were rated lowest by professionals, highest by partners with parental
      figures and peers in between. Agreement for internalizing problems was highest
      between self and professionals and lowest for partners and peers; parental
      figures were in between these two extremes. For externalizing problems, agreement
      was highest between self and friends but very low for partners. Professionals'
      ratings of internalizing problems showed a strong association with clinicians'
      assessment of global functioning and there was a strong association between
      partner ratings of total problems and clinicians' ratings of global functioning.
      The study showed the value of using a wider range of informants for assessing
      emotional and behavioural problems presented by young people seeking treatment
      than used in the assessment of pre-adolescents.

PMID- 10397430
TI  - Does 'denial' really cover our everyday experiences in clinical oncology? A
      critical view from a psychoanalytic perspective on the use of 'denial'.
AB  - The concept of 'denial' emanates from psychoanalytic psychology. Within this
      framework it is regarded as a primitive defence mechanism related to personality
      disorder. The concept has been adopted by coping research but invested with quite
      other implications. Different researchers operationalize 'denial' in different
      ways which contributes to this confusion. This paper views 'denial' from the
      different perspectives of psychoanalysis and coping research and, based on a
      previous qualitative study, it proposes a reconceptualization which distinguishes
      between three different processes: 'avoidance', 'disavowal' and 'denial'.
      'Disavowal', self-deception in the face of accurate perception, is, more than
      'denial', regarded as the appropriate concept covering everyday experiences of
      patients dealing mentally with their strain.

PMID- 10397431
TI  - Selective hypothermia in repair of aneurysms of the descending aorta.
AB  - Since 1991, we have used a simple, single-clamp technique with open distal
      anastomosis to repair aneurysms of the descending aorta. To enhance the results
      of the single-clamp technique in a recent high-risk patient, we used selective
      hypothermia, cooling primarily the tissues and organs supplied by the aorta and
      tributaries distal to the left subclavian artery. This preliminary report
      describes the technique and gives the rationale for its use.

PMID- 10397433
TI  - Low-energy internal cardioversion of atrial fibrillation after failed external
      cardioversion: Texas Heart Institute experience and review of the literature.
AB  - In patients with atrial fibrillation, low-energy internal cardioversion may be
      used to restore sinus rhythm after external cardioversion fails. We used this
      method in 8 consecutive patients with a mean age of 69.5+/-8.3 (SD) years, 7
      (87.5%) of whom were successfully treated with a mean 9.1 J (range, 4 to 14 J).
      No patient had ventricular arrhythmias at the time of cardioversion, or local
      groin complications afterward. One patient had recurrent atrial fibrillation the
      morning after cardioversion, and another patient had an embolus to the renal
      artery 20 days posttreatment. After 1 month, 5 patients were still in sinus
      rhythm, and 1 patient was lost to follow-up. This study confirms the efficacy of
      internal cardioversion in this setting and stresses the importance of a standard
      anticoagulation protocol before and after cardioversion.

PMID- 10397432
TI  - The Vineberg legacy: internal mammary artery implantation from inception to
      obsolescence.
AB  - At a time when cardiac surgery was still approached with hesitation, Arthur M.
      Vineberg developed the procedure of direct implantation of the internal mammary
      artery into the left ventricle for the relief of myocardial ischemia. The
      Vineberg operation, as it became known, had merit but never received broad
      endorsement from the medical and surgical communities. Its physiologic benefits
      were inconsistent and for years were documented by little more than anecdotal
      evidence, until coronary angiography (newly developed by Mason Sones) was able to
      demonstrate that the procedure did in fact increase perfusion in the diseased
      heart. This supporting evidence came rather late, for within the next decade
      direct aortocoronary artery bypass grafting overtook the Vineberg operation as a
      more efficient means of revascularizing the myocardium. Thousands of patients,
      however, had benefited from internal mammary artery implantation at a time when
      options were few; and the procedure was an aggressive move towards current (and
      similarly aggressive) treatments for myocardial ischemia. Moreover, the
      characteristics of the myocardium that Vineberg sought to exploit may form the
      basis for future therapy. A reappraisal of the implant is warranted, as today's
      physicians and surgeons inherit the last remaining recipients of Vineberg
      implants.

PMID- 10397434
TI  - Endoscopic harvesting of the greater saphenous vein for aortocoronary bypass
      grafting.
AB  - We conducted an observational study to evaluate the effectiveness of an
      endoscopic technique for harvesting the greater saphenous vein for aortocoronary
      bypass grafting. We hypothesized that the endoscopic technique would minimize the
      risk of postoperative wound complications. From May 1997 to July 1998, we used an
      endoscopic technique to harvest the greater saphenous vein in 50 patients who
      underwent aortocoronary artery bypass grafting. Twenty-five of the patients had
      an increased risk for wound complications due to preexisting diabetes, obesity,
      peripheral vascular disease, or lymphedema. The average duration of the procedure
      was 39 minutes (range, 11 to 70 minutes). The average length of the harvested
      vein was 58 cm (range, 25 to 85 cm). We made an average of 2.5 incisions per
      patient (range, 1 to 5 incisions), and the average incision length was 7 cm
      (range, 3 to 10 cm). Two patients (4%) required conversion to an open technique
      using 5 small incisions. Postoperative complications included 1 wound infection
      (2%) and 1 small hematoma (2%). Two patients (4%) had minor erythema at the
      incision site, and 5 patients (10%) had postoperative lymphedema. The most common
      problem, ecchymosis, was seen in 6 patients (12%). None required repeat
      hospitalization or reoperation for wound complications. In our study, the
      endoscopic approach yielded superior cosmetic results, and reduced wound
      complications and discomfort, compared with traditional methods of vein
      harvesting. After gaining expertise with this minimally invasive method of vein
      harvesting, a surgeon can safely remove the saphenous vein in 20 to 30 minutes.

PMID- 10397435
TI  - Open-heart surgery in 48 patients via a small right anterolateral thoracotomy.
AB  - To limit the trauma to the chest and to achieve a pleasing cosmetic result, we
      used 2 types of right anterolateral thoracotomy in 48 patients who required open
      heart surgery: 1 was a curved incision along the lower edge of the right breast
      in women with developed breasts; the other was a slanted incision for men and
      children. These surgical procedures took place between July 1996 and November
      1997. Intraoperatively, a right atriotomy was used to repair 11 atrial septal
      defects and 11 ventricular septal defects, 2 combined atrial and ventricular
      septal defects, 1 case of a single atrium, and 1 partial atrioventricular canal.
      A right ventricular outflow tract incision was used to repair 7 ventricular
      septal defects and 7 ruptured aortic sinus aneurysm. A combination of a right
      atriotomy and right ventricular outflow tract incision was used for 2 repairs of
      combined atrial and ventricular septal defects, 3 radical corrections of
      tetralogy of Fallot, and 2 radical corrections of trilogy of Fallot. A combined
      right and interatrial septal incision was used for 6 mitral valve replacements
      and 1 mitral valvuloplasty. Smooth bypass cannulation and satisfactory
      intracardiac exposure were achieved with the right anterolateral thoracotomy.
      There was no complication or mortality directly related to the incision. We
      believe that the right anterolateral thoracotomy is safer and more effective than
      the median sternotomy for many common congenital and acquired heart diseases. The
      thoracotomy causes less trauma and results in a cosmetic appearance that is more
      acceptable to the patient.

PMID- 10397436
TI  - The use of subcutaneous drains to manage subcutaneous emphysema.
AB  - Subcutaneous emphysema is a frequent complication of thoracic and cardiac
      surgical procedures, and emergency tracheostomy is often advocated as the
      treatment for this complication. However, we report the case of a patient in whom
      massive subcutaneous emphysema, which had developed after emergent replacement of
      the aortic root, was relieved using subcutaneous drains and suction, instead of a
      tracheostomy. We found that the subcutaneous drains provided effective
      decompression of the head and neck areas, and markedly reduced airway pressure
      and subcutaneous air. We recommend subcutaneous drains for safe, effective, and
      inexpensive management of massive subcutaneous emphysema.

PMID- 10397437
TI  - Successful reoperation after Batista partial left ventriculectomy demonstrates
      patient's hemodynamic recovery.
AB  - We report an emergency reoperation due to mechanical valve thrombosis following a
      Batista partial left ventriculectomy and mitral valve replacement with a St. Jude
      prosthesis. We re-replaced the valve with an identical St. Jude device and
      counseled the patient on the importance of routine anticoagulation. To the best
      of our knowledge, this is the 1st reported case of a patient who has survived
      cardiac reoperation after a Batista partial left ventriculectomy. Moreover, our
      report demonstrates that the hemodynamic recovery achieved after a Batista
      operation can enable a patient to tolerate reoperation on cardiopulmonary bypass,
      even in the presence of acute pulmonary edema and cardiogenic shock.

PMID- 10397438
TI  - Treatment of congenital aneurysms of the left atrium and left atrial appendage.
AB  - We report 2 cases of congenital aneurysm, 1 of the left atrium and 1 of the left
      atrial appendage. The patients were 14 and 27 years of age, respectively. Their
      common symptoms were paroxysmal palpitations and dyspnea. Diagnoses were
      suggested by chest radiographic films that revealed prominent convexity at the
      upper left border of the heart and were confirmed by echocardiography, which
      demonstrated a large cystic mass attached to the left atrium in each case.
      Aneurysmectomy was performed through a median sternotomy or a left thoracotomy,
      with cardiopulmonary bypass in 1 patient and without it in the other. Both
      patients were discharged, free of symptoms, in sinus rhythm. We conclude that
      echocardiography can provide a clear diagnosis and that aneurysmectomy is the
      treatment of choice.

PMID- 10397439
TI  - Aorto-right ventricular fistula: a late complication of aortic valve replacement.
AB  - We report the case of a patient who was found to have an aorto-right ventricular
      fistula 17 years after receiving a Bjork-Shiley prosthetic aortic valve. A
      pseudoaneurysm had formed at the aortotomy suture line, and it had extended into
      the interventricular septum and had eventually opened into the right ventricle.
      Using transesophageal echocardiography, we identified the defect in the ascending
      aorta, and a left-to-right shunt. Aortography was used to confirm these findings.
      The pseudoaneurysm was successfully resected and the ascending aorta was replaced
      with a Dacron graft. To the best of our knowledge, no similar late complication
      of aortic valve replacement has been reported in the medical literature.

PMID- 10397440
TI  - Stent implantation in an adult with coarctation of the aorta in the presence of
      advanced secondary heart failure.
AB  - We report the case of a 56-year-old woman with congenital coarctation of the
      aorta, who presented in critical clinical condition with advanced secondary
      cardiomyopathy and heart failure. We successfully applied an unusual technique to
      pass the aortic obstruction, and then implanted a PALMAZ stent. The procedure
      resulted in prompt clinical improvement and completely resolved the coarctation.
      The patient's improved clinical condition was still evident 11 months after the
      procedure.

PMID- 10397441
TI  - Right iliac vein agenesis, varicosities, and widespread hemangiomas: report of a
      rare case.
AB  - We present a probable variant of the Klippel-Trenaunay syndrome with the clinical
      features of capillary hemangiomas, varicosities, and agenesis of the right iliac
      venous system, but without limb hypertrophy. To our knowledge, this is the 1st
      such case reported in the medical literature.

PMID- 10397442
TI  - Cardiovascular sequelae of fetal twin-to-twin transfusion syndrome: an
      echocardiographic perspective.

PMID- 10397443
TI  - Congestive heart failure arising from diastolic dysfunction in the presence of
      normal left-ventricular systolic function.

PMID- 10397444
TI  - Wenckebach, Dock, and Willie Sutton.

PMID- 10397445
TI  - Should surgeons and anesthesiologists auscultate?

PMID- 10397446
TI  - K-ras mutations in 239PuO2 canine lung neoplasms.
AB  - Single-strand conformational polymorphism (SSCP) analysis and direct sequencing
      methods were used to examine lung tumors derived from a cohort of beagle dogs
      with inhalational exposures to 239PuO2. These exposures were done at Pacific
      Northwest Laboratories where 18-month-old beagle dogs were given 239PuO2 by
      single-dose inhalation and allowed to live out their life-spans. Formalin-fixed
      paraffin-embedded blocks of tissues from 25 dogs exposed to 239PuO2 by aerosol
      inhalation which later developed lung tumors were available for this study. Two
      of 25 tumors had mutations within exon 1 of K-ras detected by SSCP analysis. Both
      mutations were GGT to GAT transitions at codon 12 confirmed by direct sequencing
      experiments. One was an adenocarcinoma from the medium-high exposure group and
      the other was a broncheolo-alveolar carcinoma from the medium-low exposure group.
      The rate of K-ras mutations in plutonium-induced lung tumors described herein
      (8%) was greater than previously described in canine plutonium-induced lung
      tumors (0%), but was less than that which we have described in spontaneous canine
      lung cancer (16%), less than that reported for human spontaneous non-small cell
      lung cancer (13-36%) and less than that described in rats with spontaneous lung
      cancer (40%) or lung tumors following 239Pu inhalation exposure (46%).

PMID- 10397447
TI  - Room temperature-induced apoptosis of Jurkat cells sensitive to both caspase-1
      and caspase-3 inhibitors.
AB  - We recently reported that HL-60 cells underwent apoptosis when exposed to room
      temperature (RT) (21 degrees C). RT-induced apoptosis of HL-60 cells is inhibited
      by the caspase-1 inhibitor (YVAD-CMK), but not by the caspase-3 inhibitor (DEVD
      CHO). In this study, we studied RT-induced apoptosis in 15 human cell lines of
      hematopoietic lineage and found that the Jurkat cell line also responded to RT by
      a different apoptotic process. RT-induced apoptosis of Jurkat cells was
      attenuated by YVAD-CMK as well as DEVD-CHO. Increased caspase activity on DEVD
      AMC, which was inhibited by both YVAD-CMK and DEVD-CHO added to the cell culture,
      was also detected. The involvement of caspase-3 itself, however, was not
      recognized by Western blot analysis. In contrast, the processing of caspase-3 was
      observed in the apoptotic HL-60 cells. These data implicate the presence of the
      redundant processes of apoptosis induced by RT treatment.

PMID- 10397448
TI  - Prostaglandin E2 levels in human brain tumor tissues and arachidonic acid levels
      in the plasma membrane of human brain tumors.
AB  - Arachidonic acid is stored in the cell membrane and released when the cell is
      activated by appropriate stimuli. It is the substrate for prostaglandins. Both
      experimental and human tumors often synthesize high levels of prostaglandins,
      most notably prostaglandin E2 (PGE2). Some experiments suggest that these
      compounds increase tumor growth through their actions on host immunocytes. In
      this study, 22 patients with various brain tumors and 12 control brain tissues
      were studied. PGE2 levels in tissue samples were measured by ELISA. Arachidonic
      acid levels in the plasma membrane of tissue samples were analyzed by capillary
      gas chromatography. The levels of PGE2 were significantly higher in gliomas (n =
      10) and meningiomas (n = 7) compared with control tissues (P = 0.000 and P =
      0.000, respectively). Also, PGE2 levels in meningiomas were significantly higher
      than in gliomas (P = 0.000). Arachidonic acid levels in the plasma membrane of
      gliomas (n = 9) and meningiomas (n = 6) were significantly higher than in the
      control tissues (P = 0.000 and P = 0.000, respectively). These results suggest
      that the increased production of PGE2 may suppress the immune system and play an
      important role in tumor growth.

PMID- 10397449
TI  - Docosahexaenoic acid in phosphatidylcholine mediates cytotoxicity more
      effectively than other omega-3 and omega-6 fatty acids.
AB  - We reported previously that docosahexaenoic acid (22:6)-containing
      phosphatidylcholine (PC), but not oleic acid-containing PC nor 22:6-containing
      phosphatidylethanolamine, is toxic to tumor cells in vitro. To test whether other
      polyunsaturated fatty acids share 22:6's cytotoxic activity, we treated cultured
      T27A murine leukemia cells with PC liposomes composed of stearic acid in the sn-1
      position and alpha-linolenic acid (alpha-18:3), arachidonic acid (20:4), or
      eicosapentaenoic acid (20:5) in the sn-2 position. PC containing 22:6 in both
      positions was also tested. Following treatment, the cells were monitored for
      fatty acid composition, liposome uptake and viability. Here we demonstrate that
      cytotoxicity is unique to 22:6-containing PCs and is not shared by PCs with other
      polyunsaturated omega-3 and omega-6 fatty acids. Because PCs with fatty acids
      other than 22:6 were taken up by cells but did not kill the cells, we propose
      that 22:6-containing PCs incorporated into cellular membranes produce unique
      changes in the membrane structure incompatible with cell survival. PC liposomes
      containing 22:6 are potential drug delivery vehicles that may, by virtue of their
      cytotoxicity, serve concomitantly as adjunct cancer therapy.

PMID- 10397450
TI  - Maternal or paternal exposure to radiation increases susceptibility to the
      induction of glutathione S-transferase-positive hepatic foci in offspring rats.
AB  - Experiments were conducted to determine whether gamma-ray-induced genetic damage
      in parental rats can lead to the development of cancer in their offspring rats
      using glutathione S-transferase-positive (GST-P+) hepatic foci with or without
      the addition of diethylnitrosamine (DEN), a carcinogen. A single 1 Gy whole-body
      exposure of gamma-rays was given to pregnant rats at day 14 and during postnatal
      week 3, DEN was intraperitoneally injected twice in 1 week. Female pups from
      irradiated maternal and paternal rats were also used. Twelve weeks after birth,
      the rats were sacrificed. GST-P+ foci in animals subjected only to radiation were
      not different to those of normal control pups, but the incidence of GST-P+ foci
      was 2.4 times higher in pups treated with DEN alone at 3 weeks after birth than
      in those irradiated after the onset of pregnancy. In DEN-combined groups,
      irradiation of post-pregnant or maternal and paternal rats with gamma-rays before
      mating significantly increased both the incidence and area of GST-P+ foci when
      compared to those of rats treated with DEN alone. The proliferating cell nuclear
      antigen (PCNA) labeling index was significantly higher in the offspring of rats
      subjected to radiation alone or radiation combined with DEN than in normal
      control pups. Using a rat-liver model, the results of this study indicate that
      although the dose did not induce phenotypic malformation, exposure to radiation
      during the embryonic or pre-embryonic stage increases susceptibility to
      carcinogens.

PMID- 10397451
TI  - Expression of hMSH2 correlates with in vitro chemosensitivity to CDDP
      cytotoxicity in oral and oropharyngeal carcinoma.
AB  - We investigated the expression of hMSH2, a human mutS homologue from chromosome
      2p, in oral and oropharyngeal squamous cell carcinoma (SCC) by an
      immunohistochemical technique and performed tumor in vitro chemosensitivity
      testing. In 58 oral and oropharyngeal SCC, the hMSH2 positive score was inversely
      associated with tumor size, but not with other clinical parameters. Among five
      anticancer drugs (cisplatin (CDDP), 5-FU, peplomycin, mitomycin C and
      doxorubicin), only for CDDP was sensitivity to cytotoxicity correlated with the
      hMSH2 positive score. The susceptibility of hMSH2-positive tumors to CDDP killing
      was significantly higher than that of hMSH2-negative tumors. Immunohistochemical
      results regarding hMSH2 are promising in the evaluation of the sensitivity of
      cancer cells to CDDP cytotoxicity and enable one to select patients for adjuvant
      chemotherapy for oral and oropharyngeal SCC.

PMID- 10397452
TI  - Reversal of P-glycoprotein-mediated multidrug resistance in vitro by AV200, a new
      ardeemin derivative.
AB  - The activity of AV200, a synthetic ardeemin derivative, in reversing the
      multidrug resistance phenotype has been investigated. At non-toxic doses, AV200
      was able to completely restore vincristine and paclitaxel toxicities and
      partially restore that of doxorubicin in multidrug-resistant cells. The potency
      of AV200 as a modulator of the resistance to doxorubicin, vincristine and
      paclitaxel resulted to be seven-, 59 and 12-fold, respectively, higher than that
      of verapamil. In vitro measurements of rhodamine 123 accumulation in human
      resistant cells suggest that AV200 reverses multidrug resistance by directly
      inhibiting the P-glycoprotein-mediated drug efflux. This work underscores the
      possibility of utilizing ardeemin derivatives as a source of non-toxic modulators
      of the multidrug resistance phenotype.

PMID- 10397453
TI  - Detection of tumor promoters by early antigen expression of EB virus in Raji
      cells using a fluorescence microplate-reader.
AB  - As an in vitro assay for possible tumor promoters, we designed a quantitative
      immunofluorometric method to detect Epstein-Barr virus early antigen (EBV-EA)
      expression in Raji cells. In this method, anti-EBV-EA monoclonal antibody, a
      fluorogenic substrate and a fluorescence microtiterplate-reader were employed. 12
      O-Tetradecanoylphorbol-13-acetate (TPA) was shown to be a potent inducer. EBV-EA
      induction by TPA was related to the activation of protein kinase C and
      phospholipase A2. The chemicals that reacted positively were okadaic acid,
      diethylstilbestrol, progesterone, sodium phenobarbital, aldrin and dieldrin.
      Lithocholic acid, testosterone and DDT were equivocal in the present experiments.
      Eight other chemicals tested did not react.

PMID- 10397454
TI  - Paraffin section immunocytochemistry and cytosol-based ligand-binding assays for
      ER and PR detection in breast cancer: the time has come for more objectivity.
AB  - The importance of the receptor level in breast cancer as an indicator of hormone
      response has been extensively studied for more than 20 years. Besides cytosol
      based ligand-binding assays (dextran-coated charcoal assay, DCC), new methods
      using monoclonal antibodies raised against estrogen and progesterone receptors
      allow for the detection of receptors both in cytosol extracts (enzyme
      immunoassay, EIA) and in tissue sections (immunocytochemical assay, ICA). The
      biochemical assays (DCC and EIA) as well as the immunochemical detection (ICA)
      have specific qualities and produce original information which is useful for the
      therapeutic decision. While DCC gives a measure of the receptor level, whatever
      the real source of synthesis (normal and/or neoplastic tissue), ICA locates the
      positive cells and their relative proportion in the tumor. Both methods present
      their own advantages and disadvantages which are summarized in this study.

PMID- 10397455
TI  - Reduced p27Kip1 expression in hepatocellular carcinomas.
AB  - This study was designed to determine whether changes in p27Kip1 expression are
      involved in human hepatocarcinogenesis. We examined the p27Kip1 mRNA expression
      in hepatocellular carcinomas and surrounding non-cancerous liver tissue samples
      from 21 patients using a reverse-transcriptase polymerase chain reaction assay.
      The mean p27Kip1 mRNA expression levels (ratio of p27Kip1/beta-actin mRNA) were
      significantly lower in hepatocellular carcinomas than in non-cancerous liver
      tissues (0.49 +/- 0.24 versus 0.57 +/- 0.22, P < 0.05). p27Kip1 mRNA expression
      was reduced in 11 (52%) of the 21 hepatocellular carcinomas when compared with
      the surrounding non-cancerous liver tissues. These findings suggest that reduced
      p27Kip1 expression may be at least partly responsible for human
      hepatocarcinogenesis.

PMID- 10397456
TI  - Evidence for mRNA expression of vascular endothelial growth factor by X-ray
      irradiation in a lung squamous carcinoma cell line.
AB  - Vascular endothelial growth factor (VEGF) is a multipotent cytokine which plays
      an important role in various angiogenic conditions as well as in some tumor
      behaviors. Here we examined the induction of VEGF mRNA by X-ray irradiation in a
      lung squamous cell carcinoma cell line (RERF-LC-AI). Irradiating the cells with
      15 Gy X-rays significantly increased the mRNA expression up to 2.5-fold of
      control at a post-irradiation time of 16-24 h. The induction of VEGF mRNA by X
      ray irradiation was completely blocked by treating cells with either genistein
      (Src tyrosine kinase inhibitor) or H7 (protein kinase C inhibitor). This suggests
      that the mechanism of induction might be concerned with the pathway which
      triggers Src tyrosine kinase of the cell surface and the protein kinase C
      pathway.

PMID- 10397457
TI  - Inversion of genetic predisposition to carcinogenesis in liver of two lines of
      mice selected for resistance (Car-R) or susceptibility (Car-S) to skin
      carcinogenesis.
AB  - Two lines of mice, one resistant (Car-R) and one susceptible (Car-S) to skin
      carcinogenesis, were produced by bi-directional selective breeding. To see
      whether the characteristics of susceptibility or resistance to tumorigenesis were
      also expressed in the liver and lung, the two lines were submitted comparatively
      to treatment with 5,9-dimethyl dibenzo[c,g]carbazole (DiMeDBC), a potent
      hepatocarcinogenic derivative of the ubiquitous heterocyclic carcinogenic
      pollutant, 7H-dibenzo[c,g]-carbazole (DBC). An inversion of genetic
      predisposition to carcinogenesis in liver was observed. Car-R animals displayed
      rapid tumorigenesis in 100% of cases while Car-S mice were remarkably less
      sensitive, showing a 4-fold lower mean tumor multiplicity and a 4-month longer
      latency time. In parallel adduct formation by DiMeDBC and DBC in liver DNA was
      analyzed by the 32P-postlabeling method, showing a remarkably higher level in Car
      R mice than in Car-S animals. These data indicate that tissue-specific
      sensibility in carcinogenesis may involve gene expression at various levels.

PMID- 10397458
TI  - c-erbB-2 oncoprotein assay in ovarian carcinoma and its clinical correlation with
      prognostic factors.
AB  - Overexpression of the c-erbB-2 oncoprotein has been detected in human
      adenocarcinoma of the breast, cervix and salivary gland, in all of which an
      association between the overexpression of the c-erbB-2 and a poor prognosis of
      the disease has been reported. However, the prognostic role of c-erbB-2
      oncoprotein in ovarian carcinoma remains controversial. We measured c-erbB-2
      oncoprotein with an enzyme-linked immunosorbent assay (ELISA). Patients with
      invasive ovarian cancer were found to have significantly higher median c-erbB-2
      oncoprotein expression than patients with either benign ovarian cyst (P = 0.002)
      or control groups (P = 0.001). Overexpression of c-erbB-2 oncoprotein was found
      in seven (21.9%) of 32 epithelial ovarian cancers. Our results suggest that
      quantitative analysis of c-erbB-2 oncoprotein may be used to define the
      prognostic significance of ovarian carcinoma.

PMID- 10397459
TI  - Activation of NF-kappaB mediates the PMA-induced differentiation of K562 cells.
AB  - The role of NF-kappaB during the PMA-induced megakaryocytic differentiation of
      K562 cells was investigated using K562 cells transfected with each or both
      subunits of NF-kappaB. The NF-kappaB subunit-transfected cells have shown much
      higher sensitivity to PMA-induced differentiation than their parental cells. This
      result was consistent with the findings that PMA-stimulated activities of NF
      kappaB were markedly increased in the NF-kappaB subunit-transfected cells in
      comparison with their parental cells and PMA-induced differentiation was enhanced
      by pretreatment with IkappaB-alpha antisense oligonucleotide in the NF-kappaB
      subunit-transfected cells. Meanwhile, there were basically no difference in the
      basal and PMA-stimulated MAP kinase activities among the parental and NF-kappaB
      subunit-transfected cells, respectively. However, PMA-induced differentiation was
      blocked by pretreatment with PD98059, a specific inhibitor of MEK, in both
      parental and NF-kappaB-transfected cells. Therefore, these results suggest that
      during the PMA-induced megakaryocytic differentiation of K562 cells, NF-kappaB
      works downstream of MAP kinase, or that activation of both NF-kappaB and MAP
      kinase pathways is involved.

PMID- 10397460
TI  - Enhanced angiogenesis and growth of 12-lipoxygenase gene-transfected MCF-7 human
      breast cancer cells in athymic nude mice.
AB  - Transfection of the estrogen-dependent and poorly invasive MCF-7 human breast
      cancer cell line so that it stably overexpressed 12-lipoxygenase and secreted
      high levels of 12-hydroxyeicosatetraenoic acid when cultured with arachidonate
      resulted in rapid growth in athymic nude mice when compared with the parental
      line. This enhanced acquisition of tumor mass was a result of both increased cell
      proliferation and reduced apoptotic cell death and was accompanied by high
      angiogenic activity.

PMID- 10397461
TI  - Xanthones as inhibitors of Epstein-Barr virus activation.
AB  - To search for possible antitumor promoters, we carried out a primary screening of
      20 xanthones isolated from plants of the Guttiferae family, using their possible
      inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation
      induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Some of
      these xanthones, namely 1,3,7-trihydroxy-2-(3-methyl-2-butenyl)xanthone (8),
      dulxanthone-B (10) and latisxanthone-C (15), were observed to significantly
      inhibit the EBV-EA activation. The investigation indicated that 8, 10 and 15
      might be valuable antitumor promoters.

PMID- 10397462
TI  - Mutations of the adenomatous polyposis coli and p53 genes in a child with
      Turcot's syndrome.
AB  - Turcot's syndrome is a rare heritable complex that is characterized by an
      association between a primary neuroepithelial tumor of the central nervous system
      and multiple colonic polyps. The aim of this study was to analyze genetic
      alterations in a case of Turcot's syndrome in a 10.5-year-old boy in whom a
      colorectal tumor developed 3.5 years following astrocytoma. An APC germline non
      sense mutation at codon 1284 leading to a truncated protein was identified, as
      was a somatic p53 mutation in the colorectal carcinoma in exon 7, codon 244. The
      latter was not identified in the primary astrocytoma. However,
      immunohistochemistry revealed high p53 protein expression in both tumors,
      suggesting an additional p53 mutation in the primary astrocytic tumor. The
      diverse p53 mutations observed in this unique syndrome in two different sites and
      stages of the disease may shed light on the multistep progression of the
      malignant events.

PMID- 10397463
TI  - Orthotopic implantation of colon carcinoma cells provides an experimental model
      in the rat that replicates the regional spreading pattern of human colorectal
      cancer.
AB  - Our goal was to develop an experimental model of colon adenocarcinoma based on
      the orthotopic implantation of tumour cells in syngenic rats which would
      replicate the pattern of regional spreading of human colorectal adenocarcinoma.
      We used cell line DHD/K12-PROb and 62 BD-IX rats with intra-caecal injection of 1
      x 10(6) cells. Macroscopic and histological examinations were made at different
      times after injection (from 1 to 16 weeks) with particular emphasis on caecal
      lesions and tumours were classified according to the TNM system (UICC, 1987). Our
      results suggest that this model provides a step-by-step reproduction of the
      development of human colorectal adenocarcinoma. It also allows us to predict how
      long it will take to achieve a certain degree of local spreading, which is
      essential for the design of cancer-related experiments. Moreover, our model has
      the advantage that it uses immunocompetent rats, which facilitates its
      application.

PMID- 10397464
TI  - Effects of pycnogenol on the microsomal metabolism of the tobacco-specific
      nitrosamine NNK as a function of age.
AB  - NNK is a potent environmental carcinogen to which smokers and non-smokers are
      exposed. The response to NNK can be altered by various factors including
      nutrition. In this study, we examined the effects of pycnogenol on the in vitro
      metabolism of the tobacco-specific nitrosamine NNK by liver and lung microsomes
      from 6- and 20-month-old male F344 rats. The major NNK metabolic pathway in liver
      microsomes was carbonyl reduction, while alpha-hydroxylation was the major
      pathway in lung microsomes irrespective of age. Pycnogenol (40 and 120 microg/ml)
      exhibited a statistically significant inhibition of carbonyl reduction and alpha
      hydroxylation pathways in liver microsomes from both age groups and in addition
      to these pathways, pycnogenol inhibited the N-oxidation pathway in lung
      microsomes. The liver and lung microsomes from 20-month-old rats were less active
      than from 6-month-old rats although the difference was not statistically
      significant.

PMID- 10397465
TI  - Increased phospholipase D activity in butyrate-induced differentiation of HT-29
      cells.
AB  - Phospholipids are important constituents of biomembrane components and are
      supposed to function as enzyme activators or precursors of bioactive substances.
      Our earlier work has shown an increased esterification of neutral lipids of HT-29
      cells during butyrate-induced differentiation (M. Madesh, O. Benard, K.A.
      Balasubramanian, Butyrate-induced alteration in lipid composition of human colon
      cell line HT-29, Biochem. Mol. Biol. Int. 38 (1996) 659-664). In this report we
      show that there is an increase in phospholipase D (PLD) activity during butyrate
      induced differentiation of HT-29 cells as indicated by the formation of
      phosphatidic acid (PA). When the control and butyrate-treated cell homogenates
      were incubated in vitro with 1 mM Ca2+, the increase in PA formation was higher
      than in butyrate-treated cells. This PA was formed due to PLD activity that was
      confirmed by the generation of phosphatidylethanol by in vitro incubation of HT
      29 cell homogenates in the presence of ethanol. The formation of PA was
      associated with a decrease in phosphatidylcholine (PC) and
      phosphatidylethanolamine (PE). This study has shown an increase in PLD activity
      associated with the differentiation of HT-29 cells.

PMID- 10397466
TI  - Effects of glutathione S-transferase (GST) M1 and GSTT1 genotypes on urothelial
      cancer risk.
AB  - The M1 member of the mu class of the glutathione S-transferase (GSTM1) gene is
      present in about 50% of individuals. GSTT1, a member of the theta class, which
      has been recently shown to be polymorphic, is expressed in 35-90% of individuals.
      In this study, 145 Japanese patients with urothelial transitional cell carcinoma
      and 145 healthy controls, frequency-matched for age and gender, were compared for
      frequencies of GSTM1 and GSTT1 genotypes. The urothelial cancer risk increased
      due to the GSTM1 null genotype (odds ratio (OR) 1.71, 95% confidence interval
      (CI) 1.05-2.79). On the other hand, the OR tended to decrease due to the GSTT1
      null genotype, although not significantly. Among individuals of the GSTM1 null
      genotype, those of the GSTT1-positive genotype had a two-fold risk (OR 2.62, 95%
      CI 1.36-5.05) compared with the GSTT1 null genotype (OR 1.25, 95% CI 0.62-2.51).
      A significant interaction between the GSTM1 genotype and smoking status was
      found; the GSTM1 null genotype was associated with an increased risk of
      urothelial cancer among smokers (OR 1.98, 95% CI 1.10-3.57).

PMID- 10397467
TI  - Morphology and function of human benign tumors and normal thyroid tissues
      maintained in severe combined immunodeficient mice.
AB  - In the improved SCID (severe combined immunodeficient) mice, various human benign
      tumors of the head and neck region were well maintained morphologically and
      functionally for 3 years until the experiments were terminated, e.g. transplanted
      parathyroid adenoma secreted parathyroid hormone (PTH) in the SCID mice for more
      than 1 year. Normal human thyroid tissue was also well maintained in the SCID
      mice for 3 years. Rapid and high uptake of radioiodine into the transplanted
      human thyroid tissue was observed. Furthermore, transplanted human thyroid tissue
      secreted thyroid hormone (T3) and T3 secretion was stimulated by the injection of
      human thyroid stimulating hormone (TSH). These findings suggest that the improved
      SCID mice will provide an invaluable experimental system for investigating the
      function of normal human tissues and the influence of endogenous and exogenous
      factors on human tissues.

PMID- 10397468
TI  - Opposite effects of TPA on G1/S transition and on cell size in the low metastatic
      B16F1 with respect to high metastatic BL6 murine melanoma cells.
AB  - Phorbol esters, known activators of c- and n-protein kinase C (PKC) isoforms,
      play a pivotal role in tumor promotion. In order to better understand the
      relationships between PKC activation, the metastatic potential and the
      proliferative capacity, we have analyzed the effect of 12-O-tetradecanoylphorbol
      13-acetate (TPA) treatment on the proliferative as well as on the cell cycle
      distribution and on the cell size of low and high metastatic murine B16F1 and B16
      BL6 (BL6) melanoma cells, respectively. TPA-treated B16F1 cells showed an
      increased proliferative capacity up to 72 h, the cytofluorimetric analysis
      revealing an increased number of cells in the S + G2-M phase of the cell cycle.
      In contrast, TPA-treated BL6 cells reached a plateau at 48 h and showed an
      increased cell volume in the G1 and S phases of the cell cycle, with a reduction
      in the percentage of cells in the S + G2-M phase. Taken together, our results
      indicate opposite effects of TPA treatment in murine melanoma cells of different
      metastatic potential. TPA could cause a block in the G1 phase of the cell cycle
      with enhanced cell volume in high metastatic BL6 cells. The same treatment, on
      the contrary, induced an increased entry into the cell cycle of low metastatic
      B16F1 cells, suggesting a relationship between cell proliferation and the
      metastatic potential of B16 murine melanoma cells. Moreover, under the present
      conditions, classical PKC isoforms were inactivated, suggesting the involvement
      of the TPA-dependent novel PKCs.

PMID- 10397469
TI  - Putrescine and chlorpheniramine inhibit Ehrlich ascites tumor cell plasma
      membrane ferricyanide reductase activity.
AB  - The presence of putrescine or chlorpheniramine in the incubation medium of
      Ehrlich ascites tumor cells starved for 1 h significantly inhibits the rate of
      ferricyanide reduction by their plasma membrane redox system. Freshly harvested
      cells, without depletion of their intracellular pools of polyamines, and cells
      preincubated under conditions arranged to increase ornithine decarboxylase
      activity also reduced externally added ferricyanide at a lower rate than those
      cells starved for 1 h. All these data seems to indicate that the presence of
      putrescine is enough to significantly inhibit Ehrlich cell plasma membrane redox
      system activity.

PMID- 10397470
TI  - Oxidative DNA base damage in cancerous tissues of patients undergoing
      brachytherapy.
AB  - This aim of this study was to measure the typical free radical-induced products
      of DNA bases in cellular DNA of cervical cancer tissues directly irradiated by
      applying brachytherapy to the patients. Significant increases in the amounts of
      modified bases over the control level were observed in the samples isolated after
      irradiation for all patients. These increases differed among patients and among
      products. The repair capacity and/or the amount of hypoxic cells inside the tumor
      may account for the different levels of modified bases. It is possible that the
      observed variabilities may account for the differences in clinical responses to
      brachytherapy.

PMID- 10397471
TI  - The kinetics and cytotoxicity of cisplatin and its monohydrated complex.
AB  - This paper examines the monohydrated complex of cisplatin (MHC) with respect to
      kinetics and cytotoxicity. Equilibrium mixtures of cisplatin and hydrated species
      have been used in previous studies of a similar nature. To our knowledge, this is
      the first paper examining MHC after isolation and quantification. This was
      accomplished using liquid chromatography with porous graphitic carbon. MHC and
      cisplatin were quantified over time in a suspension of the small-cell lung cancer
      cell line U-1285. Cytotoxicity was evaluated using the fluorescent microculture
      cytotoxicity assay. MHC was significantly more cytotoxic than cisplatin at the
      high end of the drug concentrations tested. In culture media with low chloride
      ion concentrations, the stability of MHC was related to changes in pH. At a pH of
      between 6.0 and 7.2, MHC was rapidly converted to cisplatin. In culture media
      with a pH above 7.2, MHC was considerably more stable. These findings might have
      clinical significance given that MHC circulates in the blood stream of patients
      receiving cisplatin infusions and that solid tumours often have environments that
      are extremely acidotic.

PMID- 10397472
TI  - Increased levels of CSF soluble CD27 in patients with primary central nervous
      system lymphoma.
AB  - The aim of this study is to determine the diagnostic value of cerebrospinal fluid
      (CSF) soluble CD27 (sCD27) as a tumor marker for primary central nervous system
      lymphoma (PCNSL). We examined sCD27 levels in CSF obtained from various types of
      brain tumor patients. Forty-two patients were studied (including 12 PCNSL
      patients) who had not received any therapy for their tumors. In all PCNSL cases,
      CSF sCD27 levels were more than 15 U/ml (median 84.5 U/ml, range 17-484 U/ml) and
      in other brain tumor cases, CSF sCD27 levels were all less than 15 U/ml. Our data
      suggest that CSF sCD27 levels are useful to distinguish PCNSL from other brain
      tumors.

PMID- 10397473
TI  - Tumor growth and food intake in interleukin-6 gene knock-out mice.
AB  - Interleukin (IL)-6 has potential antitumor activity and at the same time is
      responsible for tumor-derived cachexia. Using IL-6 gene knock-out (GKO) mice, we
      investigated the effect of IL-6 deficiency on the survival time, tumor growth and
      daily food intake of mice inoculated with Ehrlich ascites carcinoma. IL-6 GKO
      mice gained weight due to tumor growth more rapidly than the wild-type mice. The
      daily food intake of wild-type mice declined on day 2 after tumor inoculation and
      was only 37% on day 8. In contrast, the daily food intake of IL-6 GKO mice was
      constant for the first 7 days after tumor inoculation. Although wild-type mice
      suffered from cachexia, their survival time was significantly longer than that of
      IL-6 GKO mice. We propose that both IL-6 secretion and cancer cachexia syndrome
      may be involved in the defense mechanism against tumor progression.

PMID- 10397474
TI  - Loss of p120ctn in human colorectal cancer predicts metastasis and poor survival.
AB  - The p120ctn protein (formerly p120CAS) is an armadillo family member that
      associates directly with the cytoplasmic tail of E-cadherin and participates in
      the junctional complex responsible for cell-cell adhesion. Since reduced cell
      cell adhesion is associated with metastasis in colorectal cancer and other
      neoplasms, we hypothesize that reduced expression of p120ctn may be related to
      metastasis in colorectal tumors. Here we describe a study of p120ctn expression
      in 44 primary human colorectal adenocarcinomas. As detected by
      immunohistochemical methods, we find altered p120ctn staining patterns in 86% of
      the cases. Regional complete loss of expression is seen in 18% of the cases, and
      it correlates with high stage disease and nodal metastasis as well as decreased
      survival. Although this is a preliminary study, it suggests that downregulation
      of p120ctn in colon cancer may be associated with metastasis and poor clinical
      outcome.

PMID- 10397475
TI  - Random integration of HTLV-1 provirus: increasing chromosomal instability.
AB  - Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of mature helper (CD4) T
      lymphocytes. Human T-cell lymphotropic virus type-I (HTLV-I) is etiologically
      considered to cause ATLL. It has been suggested that HTLV-I integrates its
      provirus into random sites in host chromosomal DNA after infection. Clonal
      integration has been observed in patients with ATLL, including smoldering,
      chronic and acute leukemia states. Almost all cases with ATLL demonstrate clonal
      chromosome abnormalities, with karyotypes being very complicated in both number
      and structure. However, there are no specific karyotype abnormalities in ATLL. In
      order to examine the role of HTLV-I in the pathogenesis of ATLL, we investigated
      whether or not HTLV-I randomly integrates and whether the integration site in the
      human genome is associated with any chromosomal abnormality. We analyzed 18 cases
      with ATLL, which included 15 cases with acute states, two cases with chronic
      states and one case with a smoldering state. In four of the 18 cases, the HTLV-I
      provirus integrated into the 9th chromosome, while in three cases, it integrated
      into the 1st or 10th chromosome. However, the integrated site in the chromosome
      varied in each case and the random integration was considered to be true. All 15
      cases with acute ATLL had complicated chromosomal abnormalities and two cases
      with chronic and smoldering ATLL showed simple abnormal karyotypes, while one
      case with chronic ATLL showed a normal karyotype. In 15 of the 18 cases, the
      chromosomes with HTLV-I integration showed abnormalities. In particular, in two
      cases with simple chromosome abnormalities, HTLV-I integrated into the abnormal
      chromosome, but not into the normal chromosome. The HTLV-I proviral integration
      thus seems to be associated with chromosome abnormalities. In the multistage
      leukemogenesis of ATLL, these findings indicate that HTLV-I integration might
      play an important role in the induction of chromosomal instability.

PMID- 10397476
TI  - Expression of vascular endothelial growth factor in cerebellar hemangioblastomas
      does not correlate with tumor angiogenesis.
AB  - The relation between angiogenesis and tissue expression of vascular endothelial
      growth factor (VEGF) was studied in a series of 14 capillary cerebellar
      hemangioblastomas. In the present series, the number of intratumoral
      microvessels, identified by the endothelial marker CD34, does not correlate with
      the degree of VEGF expression. This finding suggests that endothelial growth
      factors other than VEGF may regulate tumor angiogenesis in these neoplasms.

PMID- 10397477
TI  - Inhibition of oxidative DNA damage, 8-OHdG, and carbonyl contents in smokers
      treated with antioxidants (vitamin E, vitamin C, beta-carotene and red ginseng).
AB  - The chemopreventive effects of antioxidants (vitamin E, beta-carotene, vitamin C
      and red ginseng) on oxidative DNA and protein (globin) damages were comparatively
      investigated in the peripheral blood of smokers (> or = 20 cigarettes/day).
      Smokers showed a lower baseline level of plasma micronutrients (vitamin C and
      beta-carotene) (P < 0.01) and higher baseline level of oxidative DNA or protein
      damage than non-smokers (N = 5; P < 0.05). During daily supplementation of
      antioxidants (200 IU vitamin of E, 9 mg of beta-carotene, 500 mg of vitamin C, or
      1.8 g of red ginseng) for 4 weeks, smokers plasma antioxidant concentrations
      increased linearly, while their mean levels of 8-hydroxydeoxyguanosine (8-OHdG)
      and carbonyl contents decreased compared with those in smokers supplemented with
      a placebo (P < 0.05). Levels of urinary and plasma cotinine remained steady in
      smokers regardless of supplementation with antioxidants. 8-OHdG and carbonyl
      content decreased in a time-dependent manner (as the total intake dose increased)
      after supplementation with vitamin E (8-OHdG, 33.8%; carbonyl content, 43.6%) or
      red ginseng (8-OHdG, 31.7%; carbonyl content, 21.3%). These preliminary data
      suggest that supplementation with antioxidants might protect smokers from
      oxidative damages and could reduce cancer risk or other diseases caused by free
      radicals associated with smoking.

PMID- 10397478
TI  - L-Canavanine modulates cellular growth, chemosensitivity and P-glycoprotein
      substrate accumulation in cultured human tumor cell lines.
AB  - L-Canavanine (L-CAV) is a naturally occurring L-arginine analog that induces the
      formation of non-functional proteins in a variety of organisms. Previous studies
      have shown that L-CAV is cytotoxic for several human tumor cell lines. In this
      study, we have evaluated the cytotoxicity of L-CAV for both parental and multi
      drug resistant (MDR) human tumor cells. We have also determined the effect of L
      CAV exposure on cellular expression and activity of the MDR P-glycoprotein (P-gp)
      membrane efflux pump, and the effect of L-CAV on cellular accumulation of P-gp
      substrates. The effect of pre-treatment with non-cytotoxic doses of L-CAV on
      cellular sensitivity to ten standard antineoplastic agents was also evaluated, in
      order to assess the chemosensitization potential of L-CAV. 3-(4,5-Dimethylthiazol
      )2,5-diphenyl tetrazolium bromide (MTT) cytotoxicity assays revealed that the MDR
      variants of human uterine sarcoma and leukemic cells were equally sensitive to L
      CAV as compared with their respective parental controls. Although the presence of
      free L-CAV in the uptake media did not influence cellular accumulation of P-gp
      substrates, cells cultured for 72 h in 250 microM L-CAV accumulated from 16 to
      23% less P-gp substrate than untreated controls. Although L-CAV-cultured sarcoma
      cells accumulated 17% less doxorubicin (DOX) than untreated controls, they were
      three times more sensitive to its cytotoxic effects. L-CAV-treated cells were
      also significantly more sensitive to cisplatin, 5-fluorouracil, mitoxantrone and
      bleomycin than were untreated controls. Indirect immunofluorescence revealed that
      72-h exposure to as much as 1000 microM L-CAV did not alter cellular expression
      of P-gp. These studies suggest that L-CAV may be equally cytotoxic for both
      parental and MDR tumor cells, and that L-CAV neither induces the expression of,
      nor is a substrate for, P-gp. The observation that L-CAV pre-treatment reduces
      cellular accumulation of DOX, yet sensitizes tumor cells to DOX and other DNA
      targeting antineoplastic drugs, suggests a role for L-CAV as a chemosensitizer
      for the chemotherapy of cancer.

PMID- 10397479
TI  - Cancer survivors as standardized patients: an innovative program integrating
      cancer survivors into structured clinical teaching.
AB  - BACKGROUND: Increasingly, standardized patients are involved in medical
      education; however, reports of cancer survivors functioning as standardized
      patients have not been available. This study describes the participation of
      cancer survivors as standardized patients in structured clinical teaching.
      METHODS: Forty-two cancer survivors, 354 trainees, and 54 faculty members took
      part in the structured clinical instruction modules (SCIMs) at five academic
      institutions. After completing the SCIMs, the cancer survivors answered
      evaluation questionnaire items concerning their perceptions of the course, and
      all participants (cancer survivors, faculty members, medical students, and
      residents) rated the benefit of the participation of cancer survivors. The
      evaluation items were rated on a five-point scale ranging from 1 = "strongly
      disagree" to 5 = "strongly agree. RESULTS: The evaluation responses were very
      positive, and the cancer survivors expressed a strong willingness to participate
      in future courses. Faculty members, residents, and medical students all rated the
      benefit of using cancer survivors highly. CONCLUSIONS: The participation of
      cancer survivors in structured clinical teaching was considered beneficial not
      only by the cancer survivors themselves, but also by the faculty members,
      residents, and medical students who were involved in the educational program. The
      role of cancer survivors in the education of physicians needs to be expanded.

PMID- 10397480
TI  - Medical students' knowledge, attitudes, skills, and practices of cancer
      prevention and detection.
AB  - BACKGROUND: Surveys of U.S. physicians show deficiencies in cancer detection and
      counseling skills. Thus, there is a compelling need to provide skills teaching
      during medical school for cancers with preventable mortality and for counseling
      techniques for smoking prevention and cessation. METHODS: In advance of the
      integration of initiatives for cancer education into the medical school
      curriculum, the authors conducted a baseline survey of students' knowledge,
      attitudes, skills, practices, observation, and training (KASPOT) related to
      cancer education. Eighty-one percent of Boston University School of Medicine
      students (n = 499) completed surveys. RESULTS: The students reported higher
      levels of KASPOT for breast and cervical cancers, compared with skin cancer
      examination or tobacco use cessation or prevention counseling. More than half of
      third- and fourth-year students reported that too little emphasis was given to
      cancer control education. CONCLUSIONS: It appears that students' practice and
      skills for detection of the most common cancer (skin cancer), and for cancers
      with the greatest mortality (tobacco-related cancers) are deficient. Revisions in
      medical students' curricula should seek to address these shortcomings.

PMID- 10397481
TI  - A multifaceted educational approach to increasing awareness and use of physician
      data query (PDQ).
AB  - BACKGROUND: PDQ is a database developed by the National Cancer Institute that
      provides state-of-the-art information about cancer. A study was conducted to
      raise healthcare professionals' and patients'/families' awareness and use of
      PDQ's patient information file (PIF). METHODS: Educational presentations and
      poster displays were presented for health care staff to inform them of PDQ/PIF's
      attributes and how to access it. To expand awareness among patients and families,
      poster displays were presented in high-traffic areas; PDQ/PIF statements were
      redesigned and displayed in patient information racks. RESULTS: Among health care
      professionals, a 54% increase was observed in awareness of the PIF. A ninefold
      increase in the number of PDQ/PIF statements distributed to patients/families was
      reported. CONCLUSIONS: To maintain a level of awareness among health care
      professionals, a consistent educational strategy should be implemented. The
      number of PDQ/PIF statements distributed to patients and families increased,
      especially those redesigned for visual appeal.

PMID- 10397483
TI  - Social factors affecting interest in participating in a prostate cancer
      chemoprevention trial.
AB  - PURPOSE: A sample survey was conducted to assess the feasibility of recruiting
      participants, specifically African Americans, and to determine social factors
      influencing participation in a prostate cancer chemoprevention trial. METHODS: A
      convenience sample of adults visiting a hospital was identified and asked to
      participate in the survey. The survey included brief background information about
      prostate cancer and questions concerning four independent (age, marital status,
      race, insurance status) and three dependent (willingness to join a trial,
      involvement in long-term drug intake, interest in receiving more information)
      variables. RESULTS: The study analyzed 165 responses. Of the 165 respondents, 67%
      were African American. Marital status was a significant predictor of general
      willingness to participate (p = 0.047) for male respondents. No significant
      predictor was found for female respondents. Furthermore, for men, ethnicity/race
      showed a significant difference (30% white men vs 70% of minority men) for
      willingness to take the pills. CONCLUSION: The results suggest that African
      Americans are receptive to participating in chemopreventive trials. Thus, future
      studies exploring chemoprevention trials as an effective tool for reaching
      African Americans are warranted.

PMID- 10397482
TI  - Perceived benefits of and barriers to participation in a phase I/II colon cancer
      chemoprevention trial.
AB  - METHOD: A questionnaire was administered to 42 subjects completing a one-year
      cancer chemoprevention trial (response rate = 69%, n = 29). The questionnaire
      assessed subjects' 1) previous study participation, 2) perceived
      benefits/barriers of participation, 3) likelihood of participating in future
      trials, 4) willingness to pay out-of-pocket expenses for trial participation, and
      5) interest in post-trial continuation of the drug. RESULTS: The most highly
      rated benefits of trial participation were the possibility of reducing one's
      chance of getting cancer and the possibility of preventing others from getting
      cancer in the future. Barriers considered to be the most troublesome were billing
      problems and having colonoscopies done. Only 29% would have joined the trial had
      they been required to pay for trial-related costs. CONCLUSION: Results of this
      study may be used to educate potential participants about the benefits
      of/barriers to trial participation. Additionally, by learning from the
      experiences of trial participants, investigators can improve the execution of
      clinical trials, increasing participant satisfaction.

PMID- 10397484
TI  - A new cancer education mission: managed care and clinical trials.
AB  - BACKGROUND: The traditional support for clinical research, teaching, and indigent
      patient care is being seriously compromised by the growth of managed care in the
      United States. Educational initiatives are needed to ensure the incorporation of
      clinical trials into the optimal care of cancer patients. METHODS: The Cancer
      Clinical Trials Task Force of Colorado was established in 1995 to find a
      collaborative and non-legislative solution to the uncertainty of coverage by
      third-party payers for cancer patients participating in clinical trials. RESULTS:
      This program has served to heighten the awareness of the crucial role of clinical
      trials in defining new treatment strategies among third-party payers.
      CONCLUSIONS: The Task Force and similar regional and national efforts have begun
      to provide needed information and education about the importance of clinical
      trials to the managed care industry; however, much remains to be done to ensure
      access to and coverage for clinical trials.

PMID- 10397485
TI  - Development of a patient information packet for veterans with cancer receiving
      chemotherapy.
AB  - BACKGROUND: Patient education is an important part of caring for cancer patients.
      Providing educational materials suitable to the particular patient population is
      crucial. Veterans with cancer represent a population that requires special
      educational materials. METHODS: A patient information packet (PIP) was developed
      for veteran cancer patients receiving chemotherapy. The PIP contains information
      about chemotherapy side effects, when to call for help, available resources, and
      information about support groups. RESULTS: The PIP was distributed by the
      oncology pharmacist to 96 newly diagnosed cancer patients. One-month evaluation
      of 85 patients revealed that 83 had utilized the materials. Thirty-four patients
      had read the PIP once; 32, twice; ten, three times; and six, four or more times.
      The PIP had helped 13 patients decide to call the VA Hospital and had helped 16
      patients decide whom to call. CONCLUSION: The PIP, developed to meet the specific
      needs of this patient population, was well received and utilized.

PMID- 10397486
TI  - Risk beliefs and interest in counseling: focus-group interviews among first
      degree relatives of breast cancer patients.
AB  - BACKGROUND: First-degree relatives (FDRs) of breast cancer patients are at
      potential genetic risk for developing breast cancer. Although FDRs are being
      targeted for screening and counseling, few studies have explored their beliefs
      about risk modification or preferences for risk counseling. METHODS: To learn
      more about these beliefs, the authors conducted four focus groups among FDRs (n =
      29). RESULTS: Findings indicate misunderstanding about risk and interest in more
      information. For instance, the participants confused risk factors with causes,
      discounting scientific validity of risk-factor information if they knew a breast
      cancer victim without risk factors or with protective factors. Most FDRs thought
      lifestyle factors contributed to risk. The overwhelming majority thought they
      could reduce personal risk by lifestyle modifications. Most were not interested
      in genetic testing for breast cancer susceptibility, saying they would worry too
      much if they learned they had a mutated gene. According to the participants, lack
      of primary prevention techniques negates the value of genetic testing.
      CONCLUSION: If risk counseling for FDRs is to become more widespread, these
      exploratory findings should be addressed in research and program development.

PMID- 10397487
TI  - You're never too old: a cancer education and risk reduction program for the
      elderly.
AB  - BACKGROUND: Although age is the most significant risk factor for cancer, older
      adults are less likely to be informed about and to follow through with screening
      procedures. METHODS: The University of Chicago Cancer Research Center, working in
      collaboration with health educators and city elderly organizations, developed a
      carefully scripted, hour-long presentation on cancer awareness and screening,
      designed specifically for older adults. The program was designed to be delivered
      in the community by trained graduate students. Pre-post-program surveys were used
      to evaluate the program's effectiveness in increasing cancer awareness. RESULTS:
      The presentation was delivered 40 times at Chicago nutrition sites, regional
      senior centers, retirement homes, and community clinics, reaching close to 1,000
      individuals. Responses to revised surveys showed improvements of an average of 22
      (ranging from one to 41) percentage points per question. CONCLUSIONS: This
      program gives older adults the basic knowledge and tools they need to take more
      active roles in their health care, follow healthier lifestyles, and reduce cancer
      risk.

PMID- 10397488
TI  - Bridging cultures through the development of a cervical cancer screening video
      for Cambodian women in the United States.
AB  - BACKGROUND: Southeast Asian women have higher invasive cervical cancer rates than
      any other U.S. racial/ethnic population subgroup, and their levels of Pap testing
      do not even approach the year 2000 goals. Video is a particularly useful medium
      for cancer education in Cambodian refugee communities because of low literacy
      levels and high rates of VCR ownership. METHODS: The authors produced a
      motivational Pap-testing video for Cambodian American women. The 18-minute Khmer
      language video is entitled "The Preservation of Traditions." Content, with
      respect to cervical cancer screening barriers and facilitators, was guided by
      intensive qualitative data collection. Barriers addressed were: beliefs that
      traditional postpartum practices protect against cervical disease, Cambodians do
      not get cervical cancer, and screening is unnecessary; fear of cancer as well as
      surgery; lack of understanding about preventive concepts and familiarity with the
      Pap test; concerns about embarrassment and pain; and problems with transportation
      and child care. Facilitators included the availability of female physicians and
      interpreters. A community coalition of Cambodian women and two community advisors
      participated in all aspects of the video development and production. Video
      techniques frequently used in American productions were adapted to the target
      audience. For example, cultural context was provided, use of biomedical
      terminology minimized, role modeling emphasized, and testimonial accounts
      avoided. CONCLUSION: The processes used to translate empirical evidence into
      meaningful educational messages, and to adapt American behavioral change
      techniques to Cambodian cultural norms, are generalizable to other less
      acculturated immigrant groups and cancer education topics.

PMID- 10397489
TI  - The benefits of group music at the 1996 music weekend for women with cancer.
AB  - BACKGROUND: Music therapy has been proven to benefit cancer patients physically
      and emotionally. The Music Weekend for Women with Cancer was developed as a novel
      opportunity for participants to experience the healing powers of music amidst
      others who had a shared understanding of their illness. MATERIALS AND METHODS:
      Fourteen female mixed cancer patients, three spouses, and one daughter attended
      the weekend from Friday evening through Sunday afternoon. Workshops and events
      centered on the use of music as a vehicle for expression of emotions, reflection,
      relaxation, communication, and enjoyment. Questionnaires were collected before
      the weekend to describe our population as well as three months after the weekend
      to assess any changes in their utilization of music and mood state. RESULTS:
      Although insufficiency of post-weekend data limited the potential for assessing
      the effects of the weekend on the participants' utilization of music and mood
      state, the extremely positive evaluations supported the role music can play in
      helping patients and families explore their reactions to cancer. CONCLUSIONS:
      Events such as this answer the call in the literature for more opportunities to
      use music and the arts in cancer education. The authors hope this weekend will
      serve as a prototype for future events that aim to offer the benefits of music.

PMID- 10397490
TI  - A novel approach toward bacteriochlorophylls-e and f.
AB  - Methyl bacteriopheophorbide-f was prepared from methyl bacteriopheophorbide-d
      with retention of the 3(1)-chirality. The transformation of the methyl to the
      formyl group at the 7-position of the chlorin moiety will provide an alternative
      route for the synthesis of bacteriochlorophylls-e and f.

PMID- 10397491
TI  - Novel C-ring analogues of 20(S)-camptothecin-part-2: synthesis and in vitro
      cytotoxicity of 5-C-substituted 20(S)-camptothecin analogues.
AB  - A series of 5-C-substituted 20(S)-camptothecin analogues were synthesised and
      evaluated their in vitro anti-cancer activity. Several of these analogues have
      showed excellent activity against human tumor cell lines.

PMID- 10397492
TI  - Synthesis of taxoids 5. Synthesis and evaluation of novel water-soluble prodrugs
      of a 3'-desphenyl-3'-cyclopropyl analogue of docetaxel.
AB  - A novel 3'-desphenyl-3'-cyclopropyl analogue of docetaxel was synthesized from 10
      deacetyl-baccatin III. The cytotoxicity of the new taxoid was evaluated against
      several human tumor cell lines, and it had ca. 20 times stronger activity against
      human colon cancer cell lines (WiDr and Colon 320) than that of docetaxel. This
      taxoid was converted to its water-soluble prodrugs that have 2'-substituted amino
      acid derivatives with spacer. The prodrugs had good solubility in saline and
      showed more potent antitumor activity against B 16 melanoma in mice than that of
      docetaxel.

PMID- 10397493
TI  - Derivation of a possible transition-state for the reaction catalysed by the
      enzyme estrone Sulfatase (ES).
AB  - We have determined a possible transition-state for the reaction catalysed by the
      enzyme Estrone Sulfatase (ES) - as a representation of the active site. Using the
      derived structure, we have superimposed several steroidal and non-steroidal
      inhibitors in an attempt to rationalise the inhibitory activity of a number of
      potent inhibitors.

PMID- 10397494
TI  - Nitroquinolones with broad-spectrum antimycobacterial activity in vitro.
AB  - During search on quinolonecarboxylic acids we used a facile, convenient two- or
      three-step procedure to synthesize new quinolone analogs, bearing at the C-7
      position alkylamino substituents, and at the C-6 position a fluorine or
      alternatively a nitro group. The new derivatives were tested against both Gram
      positive and Gram-negative bacteria and against a number of different
      mycobacteria. In vitro assays showed 1-tert-butyl-7-tert-butylamino-6-nitro-1,4
      dihydro-4-quinolone-3-carboxy lic acid to be a potent inhibitor of Streptococcus
      and Staphylococcus with potencies superior to those of ofloxacin and
      ciprofloxacin, used as reference drugs. Some 6-nitroquinolones were found to
      exert good inhibiting activities against Mycobacterium tuberculosis and various
      atypical mycobacteria, whereas the 6-fluoro counterparts showed poor or no
      activity against this bacterium.

PMID- 10397495
TI  - Thrombin inhibitors based on [5,5] trans-fused indane lactams.
AB  - A series of trans-fused lactams containing the indane nucleus has been prepared.
      Compound 19 has much enhanced plasma stability compared with its lactone
      counterpart and shows appreciable in vitro anticoagulant activity.

PMID- 10397496
TI  - Landomycin A inhibits DNA synthesis and G1/S cell cycle progression.
AB  - Landomycin A was found to inhibit the uptake of [3H]thymidine into DNA in murine
      smooth muscle cells indicating decreased DNA synthesis. Subsequent studies showed
      that landomycin A inhibits cell cycle progression.

PMID- 10397497
TI  - A substrate combinatorial array for caspases.
AB  - An efficient strategy for the synthesis of a tetrapeptidyl substrate
      combinatorial array directed toward the caspases is described. Testing of this
      array with caspases 1 and 4 gave substrate hydrolytic profiles characteristic of
      each caspase, and permitted the identification of efficiently processed
      substrates. A comparison of this approach to that using a positional scanning
      library is presented.

PMID- 10397498
TI  - Synthesis of reduced collagen crosslinks.
AB  - A new synthetic route to reduced collagen crosslinks (LNL and HLNL) is described
      in this report. It enables an enantioselective synthesis of LNL. HLNL was
      obtained as a mixture of two diastereoisomers. This method also provides the
      possibility to introduce radio-labels during the synthesis.

PMID- 10397499
TI  - Interaction of cyanine dyes with nucleic acids. XII.beta-substituted
      carbocyanines as possible fluorescent probes for nucleic acids detection.
AB  - Results of investigations of fluorescent properties of a beta-substituted
      carbocyanine and its complexes with nucleic acids in comparison with those for
      the unsubstituted dye are presented. Carbocyanine substituted in polymethine
      chain has shown promising properties for use as a fluorescent probe in
      homogeneous systems of nucleic acids detection.

PMID- 10397501
TI  - Binding and catalysis by yeast aldose reductase: a substrate-analog approach with
      new aldose derivatives.
AB  - 5-Deoxy-D-xylofuranose derivatives and a range of new 5,6-dideoxy analogs of D
      glucofuranose bearing azido or fluoro substituents were synthesised and employed
      as substrates of the NADH-dependent aldehyde reduction catalysed by yeast aldose
      reductase. In terms of catalytic efficiencies, these products proved to be
      superior to the parent compounds.

PMID- 10397500
TI  - Design and synthesis of 2-[4-[4-(m-(ethylsulfonamido)-phenyl) piperazin-1
      yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole (EF-7412) using neural
      networks. A selective derivative with mixed 5-HT1A/D2 antagonist properties.
AB  - A test series of 32 phenylpiperazines III with affinity for 5-HT1A and alpha1
      receptors was subjected to QSAR analysis using artificial neural networks (ANNs),
      in order to get insight into the structural requirements that are responsible for
      5-HT1A/alpha1 selectivity. Good models and predictive power were obtained for 5
      HT1A and alpha1 receptors. A comparison of these models gives information for the
      design of the new ligand EF-7412 (5-HT1A:Ki(nM)= 27; alpha1: Ki(nM) > 1000). This
      derivative displayed affinity for dopamine D2 receptor (Ki = 22 nM) and is
      selective for all other receptor examined (5-HT2A, 5-HT3, 5-HT4 and Bz). EF-7412
      acts an antagonist in vivo in pre- and postsynaptic 5-HT1A receptor sites and as
      an antagonist in dopamine D2 receptor.

PMID- 10397502
TI  - Selective binding of bryostatin analogues to the cysteine rich domains of protein
      kinase C isozymes.
AB  - Designed bryostatin analogues are assayed for binding affinity to individual
      cysteine rich domains of several protein kinase C (PKC) isozymes. These analogues
      exhibit significant selectivity for the PKCdelta-C1B peptide in terms of absolute
      affinity and the PKCdelta-C1A peptide in terms of relative affinity when compared
      to phorbol-12,13-dibutyrate.

PMID- 10397503
TI  - Picking the S1, S1' and S2' pockets of matrix metalloproteinases. A niche for
      potent acyclic sulfonamide inhibitors.
AB  - A series of acyclic hydroxamic acids harboring strategically placed alpha
      arylsulfonamido and thioether groups was synthesized and found to be potent
      inhibitors of various MMPs. An unprecedented cleavage of t-butyl hydroxamates to
      hydroxamic acids was found.

PMID- 10397504
TI  - Synthesis and evaluation of 1-position-modified inositol 1,4,5-trisphosphate
      analogs.
AB  - IP3 analogs were synthesized by the modification of phosphate at the 1-position,
      and their affinity for the IP3 receptor was analyzed by means of surface plasmon
      resonance measurements. Our results suggest that a hydrophobic and charged moiety
      linked to this position enhances the affinity for the IP3 receptor.

PMID- 10397505
TI  - Photoinduced cross-linking of RNA by cis-Rh(phen)2Cl2+ and cis-Rh(phen)(phi)Cl2+:
      a new family of light activatable nucleic acid cross-linking agents.
AB  - The metal complexes, cis-Rh(phen)2Cl2+ and its more hydrophobic analog cis
      Rh(phen)(phi)Cl2+, have been shown to photocross-link the 120-base phi29-encoded
      pRNA. Primer extension on the cis-Rh(phen)(phi)Cl2(+)-photocross-linked RNA
      revealed that guanines are responsible for the interstrand cross-links.

PMID- 10397506
TI  - Synthesis of spermidine and norspermidine dimers as high affinity polyamine
      transport inhibitors.
AB  - A series of novel spermidine and sym-norspermidine dimers was synthesized by
      crosslinking the polyamine backbones via alkylation of their secondary amino
      groups to butyl, trans-2-butenyl, 2-butynyl or p-xylyl bridges. The resulting
      hexamines behaved as high-affinity antagonists of polyamine uptake, with a
      relative potency that was dependent on the geometry of the linker structure.

PMID- 10397507
TI  - 2-heterosubstituted-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl pyridines as
      selective and orally active cyclooxygenase-2 inhibitors.
AB  - A series of novel 2-alkoxy, 2-thioalkoxy and 2-amino-3-(4
      methylsulfonyl)phenylpyridines has been synthesized and shown to be highly potent
      and selective cyclooxygenase-2 (COX-2) inhibitors. Structure-activity
      relationship studies have demonstrated that central pyridine ring substituents
      play an important role in the COX-2 potency, selectivity vs the COX-1 enzyme, and
      oral activity.

PMID- 10397508
TI  - 1-amino-APDC, a partial agonist of group II metabotropic glutamate receptors with
      neuroprotective properties.
AB  - The synthesis of the 1-amino derivative of (2R,4R)-4-aminopyrrolidine-2,4
      dicarboxylic acid (1-amino-APDC), a selective metabotropic glutamate ligand, is
      disclosed. This compound acts as a partial agonist of the group II mGluRs and
      shows pronounced neuroprotective properties in the NMDA model of cell toxicity.

PMID- 10397509
TI  - Synthesis and biological activity of anthelmintic thiadiazoles using an AF-2
      receptor binding assay.
AB  - Following our discovery of the strong binding of thiadiazole 1 to the AF-2
      neuropeptide receptor of gastrointestinal nematodes (e.g., Ascaris suum), we
      prepared two series of analogs. Only the series containing the thiadiazole ring
      had potencies comparable to that of compound 1. Analog 50 exhibited an apparent
      potency in the AF-2 binding assay 300 times that of compound 1.

PMID- 10397510
TI  - The influence of interleukin gene polymorphism on expression of interleukin-1beta
      and tumor necrosis factor-alpha in periodontal tissue and gingival crevicular
      fluid.
AB  - BACKGROUND: A specific composite genotype of the polymorphic interleukin-1 (IL-1)
      gene cluster has recently been associated with severe periodontitis. One
      polymorphism of the composite periodontitis-associated genotype (PAG) has been
      functionally linked with expression of high levels of IL-1. The purpose of this
      study was to test whether gingival crevicular fluid (GCF) levels of IL-1beta and
      tumor necrosis factor-alpha (TNFalpha), and gingival tissue levels of IL-1alpha,
      IL-1beta, and TNFalpha correlate with PAG, and to examine the effect of
      conservative periodontal therapy on these levels. METHODS: Twenty-two adults with
      moderate to advanced periodontal disease were enrolled. Polymerase chain reaction
      amplification and restriction enzymes were used to identify specific
      polymorphisms from peripheral blood samples. GCF samples were collected at
      baseline and 3 weeks following conservative treatment and analyzed by ELISA for
      IL-1beta and TNFalpha. An interproximal gingival biopsy was collected at baseline
      and follow-up and analyzed for IL-1alpha, IL-1beta, and TNFalpha by ELISA.
      RESULTS: The genotyping identified 7 as PAG(+) and 15 as PAG(-). The 2 groups
      were comparable in terms of existing periodontitis and age. In shallow sites (<4
      mm), total IL-1beta in GCF was 2.5 times higher for PAG(+) patients prior to
      treatment (P=0.03), and 2.2 times higher after treatment (P=0.04), while
      differences were less apparent in deeper sites. Following treatment, a reduction
      in IL-1beta concentration in GCF was seen for PAG(-) but not for PAG(+) patients.
      While not statistically significant, a trend was observed in mean tissue levels
      of IL-1beta which were 3.6 times higher in PAG(+) versus PAG(-) patients
      (P=0.09). CONCLUSIONS: These data suggest that PAG(+) patients may demonstrate
      phenotypic differences as indicated by elevated levels of IL-1beta in GCF.

PMID- 10397511
TI  - Effect of initial periodontal therapy on the frequency of detecting Bacteroides
      forsythus, Porphyromonas gingivalis, and Actinobacillus actinomycetemcomitans.
AB  - BACKGROUND: Porphyromonas gingivalis, Bacteroides forsythus, and Actinobacillus
      actinomycetemcomitans have been described as periodontopathic bacteria, and their
      presence in subgingival pockets can lead to development of periodontal disease.
      Until now, clinical parameters have been used to evaluate the effect of
      conventional periodontal treatment without microbiological parameters. The
      present study examined the microbiological effects of initial periodontal therapy
      using DNA probes and the polymerase chain reaction (PCR). METHODS: Twenty-six
      patients with periodontitis, 10 males and 16 females, were given instructions
      regarding oral hygiene, then thoroughly treated by conventional scaling and root
      planing. Bacterial samples were collected on paper points from 4 sites per
      patient at baseline and after initial therapy (total: 104 sites). Clinical
      parameters including probing depth, attachment level, and bleeding on probing
      were also recorded for each site at baseline and after therapy. A DNA probe kit
      was used to monitor the frequency of B. forsythus, P. gingivalis, and A.
      actinomycetemcomitans, the last of which was identified by PCR. RESULTS: At
      baseline, B. forsythus was the bacterium most frequently detected. DNA probe
      analysis also showed that more than half of the sites were colonized by both B.
      forsythus and P. gingivalis. Initial therapy resulted in significant clinical
      improvement such as significant reduction in the frequency of B. forsythus and P.
      gingivalis detected using the DNA probe. A. actinomycetemcomitans was difficult
      to detect using the DNA probe, but PCR indicated that levels of A.
      actinomycetemcomitans did not significantly decrease. CONCLUSIONS: These results
      indicate that initial conventional therapy can eliminate B. forsythus and P.
      gingivalis, but not A. actinomycetemcomitans. When levels of these bacteria
      decreased to below-detectable levels, clinical improvement was significant. These
      results indicate that monitoring levels of these three periodontopathic bacteria
      may render periodontal therapy more effective and accurate.

PMID- 10397513
TI  - Clinical effects of periodontal therapy on the severity of cyclosporin A-induced
      gingival hyperplasia.
AB  - BACKGROUND: Gingival hyperplasia (GH) is a major side effect associated with
      cyclosporin A (CsA) therapy. The condition is further augmented due to the
      gingival inflammation. In this study, the effects of initial periodontal therapy
      and gingival curettage are analyzed in a group of patients with clinically
      significant (>30%) CsA-induced gingival hyperplasia. METHODS: The test group of
      15 patients received oral hygiene instructions, supra- and subgingival scaling,
      polishing, and gingival curettage only oral hygiene instructions were given to 16
      control subjects. Plaque index (PI), gingival index (GI), calculus index (CI),
      periodontal probing depth (PD), and gingival hyperplasia were recorded at
      baseline and repeated 8 weeks after treatment. Current doses of immunosuppressive
      agents, serum concentrations of CsA, and duration of CsA therapy were recorded as
      the pharmacological parameters. RESULTS: Statistical evaluation revealed that all
      clinical variables showed statistical decreases compared to baseline in the
      treated patients, while none of the parameters changed significantly in the
      control group. Initial GH scores of 53.63% in controls and 53.40% in the treated
      patients were 52.83% and 32.13% following treatment, respectively. A difference
      of 21.27% in the severity of treated GH was accompanied by a 0.56 decrease in GI
      scores in the test group. CONCLUSIONS: Compared to the initial observations, the
      results suggested that nearly 60% of the condition could be of fibrotic origin.
      Initial periodontal therapy and curettage resulted in the resolution of the
      inflammation in CsA-induced GH. Further investigation of the treated patients has
      shown that 7 out of 15 patients (47%) in the test group responded well and their
      GH scores decreased below 30% at the end of the study. The treatment in this
      study was effective in eliminating the necessity of more extensive surgical modes
      of treatment, such as gingivectomy, in 47% of cases.

PMID- 10397512
TI  - Expression of p53 protein and Ki-67 antigen in gingival hyperplasia induced by
      nifedipine and phenytoin.
AB  - BACKGROUND: Although it has been thought that drug-induced gingival hyperplasia
      is not related to tumorigenesis, recent case reports have shown that squamous
      cell carcinomas may arise in gingival hyperplasia induced by cyclosporin and
      phenytoin. The possible implications between the pathogenesis of this disease and
      tumorigenesis have not been elucidated and remain to be studied. METHODS: We
      immunohistochemically examined the expression of tumor-related markers such as
      p53 protein and Ki-67 antigen in 11 hyperplastic gingival tissues induced by
      nifedipine and phenytoin, as well as 5 control tissues using an avidin-biotin
      peroxidase complex method. RESULTS: Two specimens out of 4 nifedipine-induced and
      4 out of 7 phenytoin-induced hyperplastic gingival tissues revealed the
      expression of p53 protein in the nuclei of epithelial cells, while no expression
      of p53 protein was observed in the epithelia of the 5 non-hyperplastic control
      tissues. The immunoreactions against p53 protein showed sporadic distribution in
      the suprabasal layers of hyperplastic epithelia. The mean percentage of
      epithelial cells expressing Ki-67 antigen in the hyperplastic gingival tissues
      was more than 10% higher than that in the controls. The expression of Ki-67
      antigen was suppressed in the typical rete pegs deeply elongated into lamina
      propria of hyperplastic gingival tissues. Intense immunostaining of Ki-67 antigen
      was found in fibroblasts of hyperplastic gingival tissues, while that of the
      control tissues was negligible. CONCLUSIONS: The expression of p53 protein in
      gingival hyperplasia suggests that the pathogenesis of this disease is involved
      with impaired DNA, while the growth arrest observed in the hyperplastic epithelia
      with typically elongated rete pegs as expressed with Ki-67 antigen may prevent
      the invasive expansion of epithelial cells undergoing DNA damage within gingival
      tissues and may consequently suppress tumorigenic progression.

PMID- 10397514
TI  - In vitro stimulation of human gingival epithelial cell attachment to dentin by
      surface conditioning.
AB  - BACKGROUND: Chemical root conditioning is widely used to improve the outcome of
      regenerative periodontal therapies by favoring the attachment of the regenerated
      periodontal structures. Although the effect of root conditioning on periodontal
      mesenchymal cells is well documented, very little is known about its potential
      effect on the re-formation of the junctional epithelium, a crucial event for the
      protection of the wound. The goal of the present study was to test in vitro the
      consequences of dentin conditioning with citric acid or minocycline on the
      attachment kinetics and morphology of human gingival keratinocytes (HGK).
      METHODS: The attachment kinetics of HGK to samples of powdered human dentin
      (particle size 44 to 76 microm) were examined by use of 3H-labeled cells. The
      morphology of attached epithelial cells was then determined by scanning electron
      microscopy (SEM). RESULTS: When the initial adhesion kinetics of cells on
      untreated dentin were tested, the percentage of attached HGK proved to be
      dependent on the number of plated cells and the time of incubation (from 0 to 12
      hours). Conditioning the dentin by 3% citric acid or by minocycline-HCl (at 0.01,
      0.1, or 2.5%) significantly increased (P <0.005) keratinocyte attachment beyond 6
      hours, without notable differences between the 2 substances at any concentration.
      The attachment kinetics of HGK preincubated for 24 hours by 10 microg/ml
      minocyline-HCl on untreated dentin was found to be similar to that observed for
      non-preincubated cells. These results are in agreement with the SEM observations:
      indeed, the surface conditioning of dentin significantly modified the morphology
      of attached HGK, whereas the preincubation of these cells with minocyline-HCl did
      not. CONCLUSIONS: These results suggest that minocycline-HCl does not exert a
      direct effect on human gingival epithelial cells. In contrast, conditioning the
      dentin by citric acid or by minocycline stimulates the attachment of HGK, which
      could lead to a rapid periodontal healing by favoring the re-formation of a
      junctional epithelium.

PMID- 10397515
TI  - Androgens modulate interleukin-6 production by gingival fibroblasts in vitro.
AB  - BACKGROUND: Pregnancy and puberty gingivitis have been attributed to increased
      concentrations of circulating sex hormones. This inflammatory gingival condition
      is accompanied by the local production of cytokines. The aims of this in vitro
      study were to assess, in the presence or absence of testosterone (T) or
      dihydrotestosterone (DHT), the production of interleukin-6 (IL-6) by human
      gingival fibroblasts (hGF), and to evaluate the effects of flutamide (a common
      anti-androgen) in this system. METHODS: The effects of the androgens, T and DHT,
      on IL-6 production were measured in vitro in serum-free, phenol red-free medium.
      Cells were incubated with or without androgens for 72 hours; the concentration of
      IL-6 secreted into the medium after an additional 24-hour challenge with IL-1beta
      plus hormones was estimated by radioimmunoassay. The reverse transcription
      polymerase chain reaction was used to examine hGF and periodontal ligament cells
      (PDL) for the presence of androgen receptor. RESULTS: In serum-free medium, T and
      DHT at concentrations of 5 x 10(-8) to 10(-7)M significantly (P <0.05) inhibited
      IL-6 production by hGF. Flutamide, up to concentrations of 2 x 10(-5)M, did not
      reverse this inhibition. The androgen receptor was identified in both hGF and
      PDL. CONCLUSIONS: We concluded that elevated levels of androgens, specifically
      testosterone and dihydrotestosterone, could affect the stromal cell response to
      an inflammatory challenge by downregulation of IL-6 production. This in vitro
      study lends support to the hypothesis that increased hormones during pregnancy or
      puberty could modulate the development of localized inflammation.

PMID- 10397516
TI  - Opsonophagocytic effect of antibody against recombinant conserved 40-kDa outer
      membrane protein of Porphyromonas gingivalis.
AB  - BACKGROUND: Porphyromonas gingivalis is associated with the initiation and
      progression of adult periodontitis. The outer membrane proteins of the bacteria
      are potentially important targets for interaction with host defense systems. A 40
      kDa outer membrane protein (40-kDa OMP) is conserved among many strains of P.
      gingivalis. We have cloned the gene for 40-kDa OMP from P. gingivalis 381 and
      produced a recombinant protein. For the development of recombinant 40-kDa OMP as
      a component of a vaccine for passive immunization, the elucidation of the roles
      of the anti-recombinant 40-kDa OMP antibody in the host defense against P.
      gingivalis is essential. The objective of this study was to determine the opsonic
      capacity of the antibody for phagocytosis by neutrophils which play a key role in
      the immune response to microbial infections. METHODS: To test the opsonic
      activity of a rabbit polyclonal antibody against r40-kDa OMP (r40-kDa OMP Ab) on
      human neutrophils to phagocytize P. gingivalis, we constructed a reproducible in
      vitro model of P. gingivalis-neutrophil interaction using the human promyelocytic
      cell line HL-60. RESULTS: We demonstrated that r40-kDa OMP Ab in the presence of
      human complement successfully opsonized [3H]-thymidine-labeled P. gingivalis as a
      target for phagocytosis by HL-60 cells differentiated with dimethyl sulfoxide.
      The phagocytized bacteria were then intracellularly killed and lysed, and the
      radioactive degradation debris egested into the culture medium. CONCLUSIONS: We
      conclude that antibody against r40-kDa OMP has opsonic activity on human
      neutrophil function for phagocytosis of P. gingivalis. Subgingival bacteria are
      coated in vivo with immunoglobulin and complement. When the antibody is specific
      for crevicular bacteria, immunological interactions can be expected in the
      crevice. Our observations suggest that the anti-recombinant 40-kDa OMP antibody
      in concert with the crevicular complement may prevent P. gingivalis colonization
      r40-kDa OMP may contribute to the development of a local immunotherapy when
      applied to the crevice of a patient with P. gingivalis-related periodontitis
      which relates to susceptibility for certain systemic diseases such as diabetes
      mellitus, cardiovascular disease, and preterm labor.

PMID- 10397517
TI  - Comparison of fluorescence microscopy and culture assays to quantitate adhesion
      of Porphyromonas gingivalis to mono- and multi-layered pocket epithelium
      cultures.
AB  - BACKGROUND: The present study compared 2 different methods (direct versus
      indirect evaluation) for the quantification of the adhesion of Porphyromonas
      gingivalis strains to in vitro cultured mono-layers of pocket epithelium.
      METHODS: The indirect culture viability assay (calculation of colony forming
      units) was compared to a direct microscopic evaluation using a novel fluorescent
      stain. The fluorescent kit was found to stain both bacteria and epithelial cells
      and enabled a differentiation between dead and living cells. RESULTS: Comparing
      the visual to the culture data, a high and significant correlation was found
      (Pearson's correlation = 0.75; P <0.001). The adhesion capacity was in general
      higher for dead epithelial cells than for living cells (P <0.01). Although
      comparable numbers of bacteria of 2 P. gingivalis strains (Pg 4 and Pg 5) were
      applied, Pg 4 showed a significantly lower adhesion capacity. This intra-strain
      variability was observed by the culture assay (2.3 x 10(6) versus 7.8 x 10(6)+/
      2.7 x 10(6); P <0.01) and by the direct microscopy (P <0.01) for both live and
      dead epithelial cells. A second goal was to see whether there was a difference in
      the amount of bacterial adherence to mono- and multi-layers of in vitro cultured
      epithelium. No significant differences were found for the 5 examined P.
      gingivalis strains. However, interstrain differences in adhesion capacity were
      evident for both tissues. CONCLUSIONS: This study highlights the reproducibility
      of a direct microscopic evaluation of bacterial adhesion to in vitro cultured
      epithelial cells, and suggests both intrastrain (P. gingivalis) and inter-cell
      (live versus dead) variation in adhesion capacity. Studies are needed to
      determine the extent to which P. gingivalis strain variation is reflected in
      variation of other strains in humans.

PMID- 10397518
TI  - Acoustic microstreaming: detection and measurement around ultrasonic scalers.
AB  - BACKGROUND: Acoustic microstreaming (AMS) may be useful to the clinician when
      using the ultrasonic scaler to remove particulate matter from the teeth. The aim
      of this study was to detect and measure the effects of AMS produced by ultrasonic
      scalers. METHODS: For the study, an ultrasonic generator was selected with 4
      differently shaped scaling tip inserts (TFI-3, TFI-9, TFI-1, and P-12). A plaque
      substitute (0.2 mm thick soft cream cheese) was coated onto a microscope slide
      and immersed in water. The ultrasonic scaler tip was placed in the water and
      orientated either perpendicular or parallel to the slide. The instrument was
      operated both contacting the slide under a load of 0.3 N and non-contacting at
      various distances from the slide surface. This was repeated with the tip parallel
      to the slide. The area of medium removed was quantified by digital image
      analysis. RESULTS: It was found that AMS removed the plaque substitute from
      around the tip. The TFI-9 insert significantly removed more material with
      increasing displacement amplitude (P <0.05). Significantly larger areas of plaque
      substitute were removed when the tips of the TFI-3, TFI-9, and P-12 inserts were
      orientated perpendicularly to the slide compared to the parallel orientation (P
      <0.05). Of the 4 inserts used, the TFI-9 insert removed the most material while
      the straight tip produced no apparent removal. Removal by AMS required the
      presence of a water medium and such forces were found to decrease with distance
      from the scaling tip. No plaque substitute removal was seen at a distance of 7 mm
      for the TFI-9 insert at 37.5 microm displacement with the tip orientation
      parallel to the slide. CONCLUSIONS: It is concluded that AMS occurs around
      ultrasonic scalers and this depends on the displacement amplitude, tip
      orientation, and presence of a water medium. AMS may play a role in disruption of
      subgingival biofilms associated with periodontal disease.

PMID- 10397519
TI  - One stage full- versus partial-mouth disinfection in the treatment of chronic
      adult or generalized early-onset periodontitis. I. Long-term clinical
      observations.
AB  - BACKGROUND: A standard treatment strategy for periodontal infections often
      consists of 4 consecutive sessions of scaling and root planing (per quadrant, at
      1- to 2-week intervals), without proper disinfection of the remaining intra-oral
      niches for periodontopathogens. This could theoretically lead to a reinfection of
      previously disinfected pockets by bacteria from an untreated region/niche. This
      study aimed to investigate, over an 8-month period, the clinical benefits of a
      one stage full-mouth disinfection in the control of severe periodontitis.
      METHODS: Sixteen patients with early-onset periodontitis and 24 patients with
      severe adult periodontitis were randomly assigned to test and control groups. The
      control group was scaled and root planed, per quadrant, at 2-week intervals and
      given standard oral hygiene instructions. A one stage full-mouth disinfection
      (test group) was sought by scaling and root planing the 4 quadrants within 24
      hours in combination with the application of chlorhexidine to all intra-oral
      niches for periodontopathogens. Besides oral hygiene, the test group also rinsed
      twice daily with a 0.2% chlorhexidine solution and sprayed the tonsils with a
      0.2% chlorhexidine spray, for 2 months. The plaque index, gingival index, probing
      depth, bleeding on probing, gingival recession, and clinical attachment level
      were recorded at baseline and at 1, 2, 4, and 8 months afterwards. RESULTS: The
      one stage full-mouth disinfection resulted, in comparison to the standard
      therapy, in a significant (P <0.001) additional probing depth reduction and gain
      in attachment up to 8 months. For initial pockets > or =7 mm, the "additional"
      probing depth reduction at the 8 month follow-up was 1.2 mm for single-rooted and
      0.9 mm for multi-rooted teeth, with corresponding additional gains in attachment
      of 1.0 mm and 0.8 mm, respectively. The additional improvements were observed for
      all subgroups (adult periodontitis, generalized early-onset cases, smokers), with
      the largest differences in the non-smoking adult periodontitis patients.
      CONCLUSIONS: These findings suggest that a one stage full-mouth disinfection
      results in an improved clinical outcome for the treatment of chronic adult or
      early-onset periodontitis as compared to scaling and root planing per quadrant at
      2-week intervals.

PMID- 10397520
TI  - One stage full- versus partial-mouth disinfection in the treatment of chronic
      adult or generalized early-onset periodontitis. II. Long-term impact on microbial
      load.
AB  - BACKGROUND: Recent studies showed the clinical benefits of a one stage full-mouth
      disinfection, when compared to the worldwide standard treatment strategy of
      consecutive root planings per quadrant without proper disinfection of the
      remaining intraoral niches. The purpose of this study was to investigate the
      microbiological benefits of such a one stage full-mouth disinfection with special
      attention to all intraoral niches for periodontopathogens and to evaluate the
      perception by the patients of the new treatment strategy. METHODS: Sixteen
      patients with early-onset periodontitis and 24 patients with severe adult
      periodontitis were randomly assigned to test and control groups. The control
      group was scaled and root planed, per quadrant, at 2-week intervals and given
      oral hygiene instructions. The test group received the one stage full-mouth
      disinfection treatment. At baseline and after 1, 2, 4, and 8 months,
      microbiological samples were taken from all niches (tongue, mucosa, saliva, and
      pooled samples from single- and multi-rooted teeth). The samples were cultured on
      selective and non-selective media. Patient perception of the treatment was
      evaluated using a questionnaire. RESULTS: In comparison to the standard therapy,
      the one stage full-mouth disinfection resulted in significant additional
      microbial improvements. The test group showed larger reductions in the
      proportions of spirochetes and motile organisms in the subgingival flora, and
      more significant reductions in the density of key pathogens, with even the
      eradication of P. gingivalis. The beneficial effects in the other niches were
      primarily restricted to the number of colony-forming units/ml of black-pigmented
      bacteria, especially on the mucosa and in the saliva and to a lesser extent on
      the tongue. Both treatments were well tolerated by the patients and the overall
      severity rating for both therapies was comparable, although 4 quadrants were
      treated within 24 hours in the test group versus only 1 in the control group. The
      full-mouth disinfection approach resulted more frequently in a slight increase of
      body temperature, especially after the second day. CONCLUSIONS: These findings
      support the benefit of a one stage full-mouth disinfection in the treatment of
      patients with either chronic adult or early-onset periodontitis.

PMID- 10397521
TI  - A 15-month evaluation of the effects of repeated subgingival minocycline in
      chronic adult periodontitis.
AB  - BACKGROUND: A double-blind, randomized, parallel, comparative study was designed
      to evaluate the long-term safety and efficacy of subgingivally administered
      minocycline ointment versus a vehicle control. METHODS: One hundred four patients
      (104) with moderate to severe adult periodontitis (34 to 64 years of age; mean 46
      years) were enrolled in the study. Following scaling and root planing, patients
      were randomized to receive either 2% minocycline ointment or a matched vehicle
      control. Study medication was administered directly into the periodontal pocket
      with a specially designed, graduated, disposable applicator at baseline; week 2;
      and at months 1, 3, 6, 9, and 12. Scaling and root planing was repeated at months
      6 and 12. Standard clinical variables (including probing depth and attachment
      level) were evaluated at baseline and at months 1, 3, 6, 9, 12, and 15.
      Microbiological sampling using DNA probes was done at baseline; at week 2; and at
      months 1, 3, 6, 9, 12, and 15. RESULTS: Both treatment groups showed significant
      and clinically relevant reductions in the numbers of each of the 7 microorganisms
      measured during the entire 15-month study period. When differences were detected,
      sites treated with minocycline ointment always produced statistically
      significantly greater reductions than sites which received the vehicle control.
      For initial pockets > or =5 mm, a mean reduction in probing depth of 1.9 mm was
      seen in the test sites, versus 1.2 mm in the control sites. Sites with a baseline
      probing depth > or =7 mm and bleeding index >2 showed an average of 2.5 mm
      reduction with minocycline versus 1.5 mm with the vehicle. Gains in attachment
      (0.9 mm and 1.1 mm) were observed in minocycline-treated sites, with baseline
      probing depth > or =5 mm and > or =7 mm, respectively, compared with 0.5 mm and
      0.7 mm gain at control sites. Subgingival administration of minocycline ointment
      was well tolerated. CONCLUSIONS: Overall, the results demonstrate that repeated
      subgingival administration of minocycline ointment in the treatment of adult
      periodontitis is safe and leads to significant adjunctive improvement after
      subgingival instrumentation in both clinical and microbiologic variables over a
      15-month period.

PMID- 10397522
TI  - Multi-layered periodontal pocket epithelium reconstituted in vitro: histology and
      cytokeratin profiles.
AB  - BACKGROUND: In order to study inter-individual differences in bacterial
      adhesion/invasion of periodontal tissues, an in vitro model for culturing multi
      layered pocket epithelium without feeder layers or stromal equivalents (including
      the evaluation of their cytokeratin profiles) was developed. METHODS: Pocket
      epithelium was collected and grown until confluent in Falcon flasks using
      keratinocyte-serum free medium (KSFM), without a feeder layer. In the second
      passage, oral keratinocytes were re-grown in a 2 compartment system using either
      a clear polyester (transwell-clear [TCL]) or a collagen (transwell-col [TCO])
      membrane as culture surface. After the first week, the calcium concentration was
      raised to 1.2 mM and in half the wells, the KSFM was supplemented with 10% fetal
      calf serum (FCS). Histology and immunohistochemistry were performed after 1, 2,
      and 3 weeks of additional growth. RESULTS: In general, all conditions resulted in
      a structured epithelium consisting of 3 to 5 layers, but important differences
      were observed between the membrane types and between the media. CK4 was rarely
      and only lightly expressed while CK18 and 19 (characteristic of junctional
      epithelium) were very strongly expressed in the older (2 and 3 weeks) cultures.
      CK13 and 14 (characteristic of any stratifiable epithelial cell) also tended to
      increase over time; CK13 seemed to be stronger in KSFM with FCS while the
      contrary was true for CK14. The multi-layer created by the combination TCL/KSFM +
      10% FCS resembled a junctional epithelium most, while that grown on TCO without
      FCS mimicked the sulcular epithelium. CONCLUSIONS: It seems possible to create a
      histiotypic culture resembling either periodontal pocket or junctional epithelium
      without the use of stromal equivalents or feeder layers which make this approach
      more cumbersome. This multi-layered culture offers a model to investigate the
      permeability of pocket epithelium and the adhesion and penetration of bacteria
      under well-defined environmental conditions.

PMID- 10397523
TI  - Compliance with supportive periodontal therapy. Part 1. Risk of non-compliance in
      the first 5-year period.
AB  - BACKGROUND: Supportive periodontal therapy (SPT) is needed for the success of
      periodontal therapy; however, patient compliance is poor. This study evaluates
      records from non-compliant patients in an attempt to identify a profile of
      patients with a higher risk of becoming non-compliant. METHODS: Data on 874
      patients who had completed active periodontal treatment up to 5 years earlier and
      who had begun SPT were analyzed for risk of non-compliance. The factors evaluated
      were gender (326 males and 548 females); type of therapy (surgical or non
      surgical) and age (< or =20; 21 to 30; 31 to 40; 41 to 50; and > or =51 years)
      and the relationships among them. RESULTS: The overall rate of non-compliance was
      46.8%, and the relative risk for non-compliance was greater in the younger age
      groups (< or =40 years old) when compared to the older groups. Gender, age, and
      type of therapy as independent factors were not significant risk factors for non
      compliance, but the association of the 3 factors produced interesting results.
      CONCLUSIONS: This study suggests that certain patient groups have a higher risk
      of non-compliance and that clinicians should intensify their efforts in
      motivating and instructing these patient groups in the importance of SPT.

PMID- 10397524
TI  - Myoepithelioma of the gingiva. Report of a case.
AB  - Myoepithelioma is a rare form of salivary gland tumor composed entirely of
      myoepithelial cells. It represents about 1 to 1.5% of all salivary gland tumors
      and is most frequently located in the parotid. The authors present a case of
      myoepithelioma of the gingiva. The tumor presented a focal strong positivity for
      cytokeratins, a diffuse positivity for S-100 protein, and a rare focal positivity
      for actin. No duct formation was observed. Myoepithelioma must be differentiated
      from several benign and malignant epithelial and mesenchymal tumors.

PMID- 10397525
TI  - Molecular diagnosis of hypophosphatasia with severe periodontitis.
AB  - Hypophosphatasia (HOPS) is an inherited disorder characterized by the defect of
      skeletal mineralization due to tissue-nonspecific alkaline phosphatase (TNSALP)
      deficiency. In this study we analyzed the TNSALP gene from a Japanese patient
      with HOPS, his parents, his brother, and unrelated normal controls. The proband
      is a 25-year-old Japanese male diagnosed with childhood hypophosphatasia. The
      patient reported premature exfoliation of the deciduous teeth and severe
      periodontal destruction of the permanent dentition. Genomic DNA was extracted
      from peripheral leukocytes of subjects. Eleven pairs of the polymerase chain
      reaction (PCR) primers were used to amplify the coding exons according to the
      published sequence data of the TNSALP gene. The PCR amplified samples were
      subjected to PCR-single strand conformation polymorphism (SSCP) analysis and PCR
      allele specific oligonucleotide (ASO) analysis. In PCR-SSCP analysis of the
      patient's genomic DNA, the fragments containing exons 9 and 10 revealed abnormal
      mobilities. These abnormal mobilities (exons 9 and 10) were also found from his
      mother and father's genomic DNA, respectively. The sequencing analysis of the
      abnormal bands extracted from the SSCP gel showed a T to C transition at
      nucleotide position 1155 (T1155C) in exon 9 and G1320A in exon 10. PCR-ASO
      analysis confirmed these missense point mutations. PCR-ASO analysis also
      confirmed that mutation-specific oligonucleotides corresponded to the new
      mutations and did not hybridize with PCR products from normal control genomic
      DNAs. These results indicated that the proband was a compound heterozygote who
      inherited T1155C mutation in exon 9 from the mother and G1320A mutation in exon
      10 from the father. Both of them are new missense point mutations and appear to
      cause significant changes in the structure and function of TNSALP.

PMID- 10397526
TI  - A classification system for sinus membrane perforations during augmentation
      procedures with options for repair.
AB  - A classification system for sinus membrane perforations encountered during a
      sinus augmentation procedure is presented. Five of the perforations are
      discussed, as are the therapeutic options for their repair. Class I and Class II
      perforations are most easily repaired, while Class IV is the most difficult to
      successfully treat. In addition, the effect of the sinus membrane perforation on
      the course of proposed therapy is discussed. When classified and managed
      appropriately, sinus membrane perforations are not an absolute indication for
      aborting the augmentation procedure which is in progress. This paper provides a
      system of classification that can be used by clinicians to collect data on
      membrane perforations and repair results.

PMID- 10397527
TI  - Clinical versus statistical significance.

PMID- 10397528
TI  - Introduction of HIV drug-resistance testing in clinical practice.

PMID- 10397529
TI  - CD4 T cells remain the major source of HIV-1 during end stage disease.
AB  - OBJECTIVE: To assess the source of HIV-1 production in lymphoid tissue biopsies
      from HIV-infected patients, with no prior anti-retroviral protease inhibitor
      treatment, with a CD4 cell count > 150 x 10(6)/l (group I) or < 50 x 10(6)/l
      (group II), co-infected with Mycobacterium tuberculosis or Mycobacterium avium
      complex. DESIGN AND METHODS: Lymphoid tissue biopsies from 11 HIV-1-infected
      patients, taken for diagnostic purposes, were studied by HIV-1 RNA in situ
      hybridization and immunohistochemistry. RESULTS: Patients of group I showed well
      organized granulomas, in contrast with patients of group II, in which granuloma
      formation was absent. HIV-1 RNA-positive cells in group I patients were found
      mainly around the granulomas, whereas in group II HIV-1-producing cells were
      confined to areas with remaining intact lymphoid tissue. Despite the abundant
      presence of macrophages, the productively infected HIV-1-positive cells in both
      groups were almost exclusively CD4 T cells. CONCLUSION: In contrast with
      previously published data, CD4 T cells appear to remain the major source of HIV-1
      production in end-stage disease.

PMID- 10397530
TI  - The C domain of HIV-1 gp41 binds the putative cellular receptor protein P62.
AB  - OBJECTIVE: To characterize the binding of gp41 with the putative receptor protein
      P62. DESIGN: HIV-1 gp41 binds several cellular proteins by two binding sites, one
      of which has been shown to bind to a putative receptor protein P45 (45 kDa).
      Based on this, an attempt was made to determine the relationship between the two
      binding sites and P62 (62 kDa). METHODS: Using surface plasmon resonance (SPR)
      measurement, the interaction was measured between recombinant soluble gp41
      (rsgp41, Env aa539-684) and protein P62. Inhibition of this interaction was
      attempted by the use of synthetic peptides (P1, aa583-599; P2, aa646-674)
      corresponding to the two binding sites in gp41. In addition, the direct binding
      of P62 to peptide P2 was examined in an enzyme-linked immunosorbent assay.
      RESULTS: Using SPR measurement, the interaction between P62 and rsgp41 was
      confirmed, and the interaction was found to be inhibited by only the synthetic
      peptide P2 sequence that corresponds to the C domain of gp41; neither P1 nor a
      control peptide inhibited the interaction. Moreover, like rsgp41, P2 was able to
      bind P62 whereas P1 and another recombinant gp41 (aa567-648 that does not include
      the C domain) were not. CONCLUSIONS: P62 bound rsgp41 and the synthetic peptide
      P2. This interaction could be inhibited only by P2. These results indicate that
      the C domain of HIV-1 gp41 binds P62.

PMID- 10397531
TI  - Protection against parenteral HIV-1 infection by homozygous deletion in the C-C
      chemokine receptor 5 gene.
AB  - OBJECTIVES: To investigate the role of the CC chemokine receptor 5 (CCR5) for
      parenteral transmission of HIV-1. DESIGN: The prevalence of the delta32 deletion
      within the CCR5 gene was determined in a cohort of 207 patients, who had received
      documented amounts of non-antibody-tested and non-inactivated clotting factor
      concentrate. METHODS: Chromosomal DNA of haemophiliacs was isolated from whole
      blood. A portion of the CCR5 gene spanning the delta32 deletion was amplified by
      PCR. The resulting DNA fragments were analysed by agarose gel electrophoresis.
      RESULTS: The rate of HIV-1 infection was correlated strongly with increasing
      amounts of inoculated clotting factor concentrate. None of the HIV-positive
      patients (n = 129) had the delta32/delta32 genotype, whereas 12 out of 78 HIV
      negative haemophiliacs had the homozygous delta32 deletion. CONCLUSIONS: The
      delta32/delta32 genotype was highly protective against HIV-1 infection, even in
      patients who had received millions of non-inactivated clotting factor units. As
      it is likely that in the early 1980s plasma pools were contaminated not only with
      monocyte-tropic HIV-1 strains, CCR5 appears to be the major mediator of HIV-1
      infection. Furthermore, we conclude that there must be other protective
      mechanisms in multiply exposed non-infected haemophiliacs who have wild-type
      CCR5.

PMID- 10397532
TI  - HIV-specific cytotoxic T lymphocyte precursors exist in a CD28-CD8+ T cell subset
      and increase with loss of CD4 T cells.
AB  - OBJECTIVES: To determine whether the CD28-CD8+ T cells that develop during HIV
      infection contain HIV-specific cytotoxic precursor cells. DESIGN: CD8
      subpopulations from six asymptomatic HIV-positive adults, with varying degrees of
      CD4 T cell loss, were sorted by flow cytometry and HIV-specific precursor
      cytotoxic T lymphocyte frequencies were measured. Three populations of CD8 T
      cells were tested: CD28+CD5-- T cells, CD28-CD57+ T cells (thought to be memory
      cells) and CD28-CD57- T cells (function unknown). METHODS: Sorted CD8 subsets
      were stimulated with antigen presenting cells expressing HIV-1 Gag/Pol molecules.
      Cytotoxic T cell assays on Gag/Pol expressing 51Cr-labeled Epstein-Barr virus
      transformed autologous B cells lines or control targets were performed after 2
      weeks. Specific lysis and precursor frequencies were calculated. RESULTS: Both
      CD28 positive and CD28-CD57+ populations contained appreciable numbers of
      precursors (9-1720 per 10(6) CD8+ T cells). However, the CD28-CD57- population
      had fewer precursors in five out of six people studied. More CD28 positive HIV
      specific cytotoxic T lymphocyte precursors were found in patients with CD4:CD8
      ratios > 1, whereas more CD28-CD57+ precursors were found in patients whose
      CD4:CD8 ratios were < 1 (r2, 0.68). CONCLUSIONS: Memory HIV-specific precursor
      cytotoxic T lymphocytes are found in both CD28 positive and CD28-CD8+ cells,
      however, a CD28-CD57- subpopulation had fewer. Because CD28-CD57+ cells are
      antigen-driven with limited diversity, the loss of CD28 on CD8 T cells during
      disease progression may reduce the response to new HIV mutations; this requires
      further testing.

PMID- 10397533
TI  - Joint effects of HIV-1 RNA levels and CD4 lymphocyte cells on the risk of
      specific opportunistic infections.
AB  - OBJECTIVES: To evaluate the predictive value of baseline plasma HIV-1 RNA levels
      and CD4 lymphocyte counts and early changes in these markers after initiating
      antiretroviral therapy on the risk of development of specific opportunistic
      infections (OIs). DESIGN: Patient data from four antiretroviral therapy studies
      were combined for a retrospective analysis. The analysis included 842
      participants from the virology substudies of these trials who had baseline
      measurements for both HIV-1 RNA levels and CD4 cell counts. METHODS: Cox
      proportional hazards models were used to assess the joint effects of baseline CD4
      cell count and HIV-1 RNA level and early treatment-associated changes in these
      values on the risk of development of Pneumocystis carinii pneumonia (PCP),
      cytomegalovirus (CMV), or Mycobacterium avium complex (MAC). The effects of
      potential confounders such as prior prophylaxis and previous OIs were also
      addressed. RESULTS: Baseline CD4 cell counts and HIV-1 RNA measurements showed
      significant associations with the risk of PCP, CMV, and MAC. Patients with higher
      levels of HIV-1 RNA were estimated to have three to six times the risk of these
      OIs than those with lower levels. Reductions in viral load were linked to
      significantly reduced risks of PCP, CMV, and MAC. Early decreases in RNA were
      generally more predictive of risk than were early increases in CD4 cell counts.
      CONCLUSIONS: Baseline viral load and reductions in viral load during therapy
      appeared to influence the risk of these OIs independently of the CD4 cell count.
      Future guidelines for the initiation of prophylaxis for these OIs may be improved
      by incorporating information on viral load.

PMID- 10397534
TI  - Quantification of integrated and total HIV-1 DNA after long-term highly active
      antiretroviral therapy in HIV-1-infected patients.
AB  - OBJECTIVE: To assess the impact of long-term virus suppression on the peripheral
      blood CD4 T cells integrated and total HIV-1 DNA loads in patients receiving
      highly active antiretroviral therapy (HAART). METHODS: A total of 10 HIV-1
      infected patients receiving a triple combination therapy (two nucleoside
      analogues and one protease inhibitor) were longitudinally studied to compare
      integrated and total HIV-1 DNA loads. HIV-1 DNA quantification was performed
      using a quantitative nested polymerase chain reaction (PCR) on genomic peripheral
      blood mononuclear cell (PBMC) DNA obtained at baseline and at 48 weeks of HAART.
      RESULTS: All the study patients showed an early and sustained decrease in plasma
      HIV-1 RNA to below the limit of detection (200 copies/ml). Concordant with the
      plasma viral decline, a significant increase in the CD4 T cell count was observed
      (P = 0.007). A statistically significant fivefold decrease in total HIV-1 DNA was
      detected after 48 weeks of HAART (P = 0.005). However, no statistically
      significant change was noted after the therapy when the integrated HIV-1 DNA copy
      number was compared (P = 0.333). Taken together, these results suggest that in
      the patients analysed the integrated HIV-1 DNA does not decay rapidly after
      HAART. CONCLUSION: Within the study cohort the total amount of PBMC HIV-1 DNA
      decreased drastically after 48 weeks of HAART. Nevertheless, the integrated HIV-1
      DNA did not significantly decay during this period. Although the data presented
      here are limited by the number of patients analysed, our findings suggest that 48
      weeks of HAART does not significantly reduce the integrated HIV-1 proviral DNA
      load in the latently infected CD4 T cell reservoir.

PMID- 10397535
TI  - Time course of cerebrospinal fluid responses to antiretroviral therapy: evidence
      for variable compartmentalization of infection.
AB  - OBJECTIVES: To compare the kinetics and magnitude of HIV-1 RNA responses to
      antiretroviral therapy (ART) in the cerebrospinal fluid (CSF) and plasma. DESIGN:
      Repeated lumbar punctures (LPs) were performed after the initiation or change in
      ART in 15 HIV-1-infected subjects, with the focus on two phases of response: an
      acute phase within the first 11 days, for which crude estimates of viral RNA half
      lives and decay rates were derived and CSF:plasma relative decay ratios
      quantitatively analysed; and a longer-term phase beyond 4 weeks that was
      descriptively assessed. RESULTS: In 13 subjects studied during the acute phase,
      the crude HIV-1 RNA half-life was longer (median 2.0 compared with 1.9 days), the
      decay rate slower (median 0.13 compared with 0.16 log10 copies/day) and, most
      notably, the variability greater (intraquartile range of half-life 1.8-4.3
      compared with 1.7-2.1 days) in the CSF than in the plasma. A slower decay in the
      CSF correlated with lower initial blood CD4 T lymphocyte counts (P = 0.001).
      Seven of 11 subjects studied at 4 weeks or later, including some with slower
      acute-phase CSF responses, showed greater or more durable viral suppression in
      the CSF. CONCLUSION: Divergent acute-phase viral kinetics in the CSF and plasma,
      and proportionally greater long-term decrements in CSF HIV-1 RNA in slow early
      responders or poor overall plasma responders indicate variable
      compartmentalization of CSF infection, consistent with a model of two prototypes
      of CSF infection: short-lived, transitory infection that predominates in early
      HIV-1 infection and longer-lived, more autonomous CSF infection predominating in
      late HIV-1 infection. Additional studies will be needed to define more precisely
      the acute and longer-term CSF kinetics in different clinical settings and to
      assess this model.

PMID- 10397536
TI  - Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial
      comparing meglumine antimoniate with amphotericin B. Spanish HIV-Leishmania Study
      Group.
AB  - BACKGROUND: Visceral leishmaniasis is common in patients with HIV infection
      living in endemic areas, but the most effective and safe treatment remains
      unknown. OBJECTIVE: To compare the efficacy and safety of meglumine antimoniate
      versus amphotericin B in HIV-infected patients with first episodes of visceral
      leishmaniasis (VL). DESIGN: An open, multicentre, prospective and randomized
      trial. SETTING: Twelve tertiary hospitals. PATIENTS: Eighty-nine consecutive HIV
      infected patients diagnosed with VL. Patients were randomly assigned to treatment
      with either meglumine antimoniate (20 mg pentavalent antimony per kilogram of
      body weight per day) or amphotericin B (0.7 mg/kg per day) both for 28 days.
      Treatment was considered successful if a bone marrow aspirate performed 1 month
      after the end of therapy did not detect parasites. Relapse was defined as the
      reappearance of parasites after an initial cure. RESULTS: An initial cure was
      attained in 29 of 44 patients (65.9%) randomly assigned to treatment with
      meglumine antimoniate and 28 of 45 (62.2%) randomly assigned to treatment with
      amphotericin B. The incidence of moderate to severe adverse events was similar in
      both groups. The patients treated with meglumine antimoniate had higher
      incidences of cardiotoxicity (14 versus 0%, P = 0.02) and chemical pancreatitis
      (30 versus 0%, P < 0.01). However, in the amphotericin B group, nephrotoxicity
      was more frequent (36 versus 5%, P < 0.01). There was no difference in survival
      or relapse-free interval according to the allocated group of therapy. CONCLUSION:
      Treatment of VL with meglumine antimoniate or amphotericin B was shown to have
      similar efficacy and toxicity rates in Spanish HIV-infected patients. The
      differences in the toxicity patterns could be useful in choosing one of these
      agents as first-line treatment.

PMID- 10397537
TI  - BK virus as the cause of meningoencephalitis, retinitis and nephritis in a
      patient with AIDS.
AB  - BACKGROUND: The two widely spread human polyomaviruses, BK virus (BKV) and JC
      virus (JCV) establish latency in the urinary tract, and can be reactivated in
      AIDS. JCV might cause progressive multifocal leucoencephalopathy, but although up
      to 60% of AIDS patients excrete BKV in the urine there have been few reports of
      BKV-related renal and/or neurological disease in AIDS. OBJECTIVE: To report on an
      AIDS patient with progressive renal and neurological symptoms involving the
      retina. DESIGN: Case report. SETTING: Venhalsan, Soder Hospital, Stockholm,
      Sweden. METHODS: The brain, eye tissue, cerebrospinal fluid, urine and peripheral
      blood mononuclear cells were analysed by nested PCR for polyoma-virus DNA.
      Macroscopical and microscopical examination were performed of the kidney and
      brain post mortem. Immunohistochemical stainings for the two BKV proteins, the
      VP1 and the agnoprotein, were performed on autopsy material and virus infected
      tissue culture cells. RESULTS: BKV could be demonstrated in the brain,
      cerebrospinal fluid, eye tissues, kidneys and peripheral blood mononuclear cells.
      CONCLUSION: During 6 years, approximately 400 cerebrospinal fluid samples from
      immunosuppressed individuals with neurological symptoms have been investigated by
      PCR for the presence of polyomaviruses. BKV DNA has, so far, only been found in
      the case reported here. Although reports of BKV infections in the nervous system
      are rare, there is now evidence for its occurrence in immunocompromised patients
      and the diagnosis should be considered in such patients with neurological
      symptoms and signs of renal disease. The diagnosis is simple to verify and is
      important to establish.

PMID- 10397538
TI  - T cell changes after combined nucleoside analogue therapy in HIV primary
      infection.
AB  - OBJECTIVE: To characterize the immune changes after treatment of acute HIV-1
      infection with triple nucleoside analogue therapy. DESIGN: Immunological and
      virological parameters were monitored from day 0 to weeks 36-44 in eight patients
      [median CD4 cells = 451 cells/microl (range: 149-624), viral load = 4.8 log10
      copies/ml (range: 6.5-3.3)] who started at time of primary HIV infection (PHI) a
      therapy including zidovudine (ZDV), didanosine (ddl), and lamivudine (3TC).
      METHODS: Lymphoid subsets were evaluated on peripheral blood lymphocytes by four
      colour flow cytometry using a panel of mAbs directed against differentiation and
      activation markers. RESULTS: We observed a median -2.1 (range: -1; -3.3) log10
      copies/ml viral load decrease and a median +158 cells/microl (range: +7 to +316)
      CD4 cell count increase at week 4 reaching normal CD4 cell count values of 761
      CD4 cells/microl (range: 389-1153) at weeks 36-44. Virus undetectability was
      obtained at week 24 for all subjects. A rapid CD4 T cell amplification involved
      both memory and naive CD4 T cells. This was associated with a very rapid and
      significant decrease in activation markers [human leukocyte antigen-DR (HLA-DR),
      CD38] on both CD4 and CD8 T cell subsets together with a CD8+CD28+ cell increase
      as early as week 4. CONCLUSIONS: These results show that early therapy with
      nucleoside analogues can correct the immunological abnormalities observed in CD4
      and CD8 T cell subsets at the time of PHI. This early kinetics in T cell recovery
      appears to be faster than in established disease.

PMID- 10397539
TI  - Rates of HIV-1 transmission within marriage in rural Uganda in relation to the
      HIV sero-status of the partners.
AB  - OBJECTIVE: To assess the efficacy of transmission of HIV-1 within married couples
      in rural Uganda according to the sero-status of the partners. DESIGN: Estimation
      of HIV incidence rates for 2200 adults in a population cohort followed for 7
      years comparing male-to-female with female-to-male transmission and sero
      discordant with concordant sero-negative couples. METHODS: Each year, adults
      (over 12 years of age) resident in the study area were linked to their spouses if
      also censused as resident. The HIV sero-status was determined annually. RESULTS:
      At baseline 7% of married adults were in sero-discordant marriages and in half of
      these the man was HIV-positive. Among those with HIV-positive spouses, the age
      adjusted HIV incidence in women was twice that of men (rate ratio (RR) = 2.2 95%
      confidence interval (CI) 0.9-5.4) whereas, among those with HIV-negative spouses,
      the incidence in women was less than half that of men (RR = 0.4, 95% CI 0.2-0.8).
      The age-adjusted incidence among women with HIV-positive spouses was 105.8 times
      (95% CI 33.6-332.7) that of women with HIV-negative spouses, the equivalent ratio
      for men being 11.6 (95% CI 5.8-23.4). CONCLUSION: Men are twice as likely as
      women to bring HIV infection into a marriage, presumably through extra-marital
      sexual behaviour. Within sero-discordant marriages women become infected twice as
      fast as men, probably because of increased biological susceptibility. Married
      adults, particularly women, with HIV-positive spouses are at very high risk of
      HIV infection. Married couples in this population should be encouraged to attend
      for HIV counselling together so that sero-discordant couples can be identified
      and advised accordingly.

PMID- 10397540
TI  - Reversal in mortality trends: evidence from the Agincourt field site, South
      Africa, 1992-1995.
AB  - OBJECTIVE: To examine changes in mortality in rural South Africa over the period
      1992-1995 by age, sex and cause of death. DESIGN: As with much of sub-Saharan
      Africa, South Africa lacks effective vital registration and information on
      mortality is lacking. The Agincourt demographic and health surveillance system
      was established to inform health policy and practice with regard to rural
      subdistrict populations. METHODS: Prospective community-based study involving
      annual update of a household census with enquiry into all birth, death and
      migration events. All reported deaths (n = 1001) are the subject of a verbal
      autopsy. RESULTS: An increasing trend in overall mortality relative to general
      population growth in the study area is apparent. There is evidence for a reversal
      in the previously declining trend in mortality among women 20-44 years. A
      comparison of 1992-1993 with 1994-1995 shows that most of the increase in
      mortality is concentrated in the younger adult (20-49 year) age group. AIDS and
      related diseases, particularly tuberculosis, appear primarily responsible.
      Injuries and violence (especially homicide) and circulatory disease are
      important, under-recognized causes of death, although their levels have remained
      constant over the period. CONCLUSIONS: Mortality from AIDS and related diseases
      appears responsible for the probable reversal in mortality emerging in South
      Africa's rural northeast. Findings carry implications for the emerging system of
      decentralized health care.

PMID- 10397541
TI  - The value of patient-reported adherence to antiretroviral therapy in predicting
      virologic and immunologic response. California Collaborative Treatment Group.
AB  - OBJECTIVE: To correlate self-reported antiretroviral adherence with virologic
      suppression. DESIGN: Prospective observational study of adherence to therapy
      nested in a randomized comparative trial of frequent versus infrequent monitoring
      of plasma HIV RNA. SETTING: Five university-affiliated HIV clinics. PATIENTS: A
      group of 173 HIV-infected patients with a mean baseline CD4 count of 142 x 10(6)
      cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2
      and 6 months, respectively. INTERVENTION: Individualized, unrestricted
      antiretroviral therapy. MEASUREMENTS: Patients were classified into four groups
      by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%).
      Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. RESULTS:
      Recreational drug or alcohol use was associated with decreased adherence, whereas
      frequency of HIV RNA monitoring, demographic variables, (age, gender, education,
      and risk group) and stage of disease had no effect. Greater HIV suppression at 6
      months was seen across four categories of increasing adherence (P = 0.009 for
      linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log10
      copies/ml increase in HIV RNA and a loss of 19 x 10(6) CD4 cells/l compared with
      a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72 x 10(6) CD4
      cells/l in those reporting 100% adherence (P = 0.02). CONCLUSION: Self-reported
      poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA
      at 6 months of antiretroviral therapy.

PMID- 10397542
TI  - The impact of the 1993 AIDS case definition on the completeness and timeliness of
      AIDS surveillance.
AB  - OBJECTIVE: To assess the impact of the 1993 change in the AIDS case definition on
      the completeness and timeframe of AIDS case reporting in San Francisco. DESIGN:
      Retrospective review of records: billing records, list of selected diagnostic
      codes, radiology logs, ophthalmology clinic records, and patient registries at a
      selection of hospitals, clinics, and physician offices. SETTING: Hospitals,
      public/community health clinics, and physician offices. MAIN OUTCOME MEASURES:
      The completeness of reporting and the median reporting delay was calculated for
      hospitals, clinics, and physician offices. RESULTS: Reporting was 97% complete.
      Reporting from physician offices was less complete (75%) than from other
      facilities. The median reporting delay was 1 month and was shorter for persons
      who met the 1993 AIDS case definition (1 month) than for persons who met the 1987
      case definition (3 months). CONCLUSIONS: AIDS case reporting in San Francisco is
      highly complete but less so for persons diagnosed at physician offices. The 1993
      AIDS case definition has resulted in more timely reporting. Health departments
      should consider efforts to improve reporting from private physician offices and
      should evaluate the use of laboratory-initiated CD4 reporting.

PMID- 10397543
TI  - Cost effectiveness of highly active antiretroviral therapy in HIV-infected
      patients. Swiss HIV Cohort Study.
AB  - BACKGROUND: Highly active antiretroviral therapy (HAART) has become the most
      important strategy for treating HIV infection in developed countries; however,
      access to HAART might vary under different funding policies. The Swiss health
      care system provides unrestricted access to HAART for all patients who need these
      newer combination therapies. This study investigated the impact of this funding
      policy on the society and health care system. METHODS: A cost-effectiveness
      analysis with natural history data and productivity estimates was based on the
      Swiss HIV Cohort Study. A random sample of patient charts was used to estimate
      health care costs. In addition to a base-case scenario, a pessimistic and an
      optimistic scenario of natural disease history was developed. Costs were
      expressed in 1997 Swiss francs (100 CHF correspond to about US$67) and effects as
      projected years of life gained. RESULTS: In the analysis limited to health care
      costs, on the basis of projected survival in each scenario, the cost
      effectiveness ratio was 33,000 CHF (base case), 14,000 CHF (optimistic), and
      45,000 CHF (pessimistic) per year of life gained. When changes in productivity
      were included, cost savings occurred in the base-case and optimistic scenarios.
      The cost-effectiveness ratio was 11,000 CHF per year of life gained in the
      pessimistic scenario. CONCLUSIONS: HAART increases expected survival and health
      care costs. However, when productivity gains are included, society will probably
      save costs or pay a low price for substantial health benefits. The study provides
      strong arguments, from a societal perspective, to continue the current policy of
      providing unrestricted access to HAART in Switzerland. The presented results also
      suggest that this policy could be of interest for other developed countries.
      Decision makers in developed countries where access to HAART is limited should re
      evaluate their policy for the benefit of the society at large.

PMID- 10397544
TI  - The quality of patient-doctor communication about end-of-life care: a study of
      patients with advanced AIDS and their primary care clinicians.
AB  - OBJECTIVE: To assess prevalence and quality of end-of-life communication between
      persons with advanced AIDS and their clinicians and to identify patient and
      clinician characteristics associated with this communication. DESIGN: Prospective
      cohort study of 57 patients with AIDS and their primary care clinicians. SETTING:
      University-based and private clinics in Seattle, Washington. PATIENTS: Patients
      had a prior AIDS-defining illness and a CD4 cell count of less than 100 x 10(6)
      cells/l. MAIN OUTCOME MEASURES: Quality of patient-clinician communication about
      end-of-life care, validated against patient satisfaction and patient-clinician
      concordance on advance directives and treatment preferences. RESULTS: Patients
      reported they had communication about end-of-life care with their clinician in 31
      of 57 cases (54%) while clinicians reported they had this discussion in 36 of 57
      cases (64%). Patients and clinicians gave concordant answers in 42 patient
      clinician pairs. In 15 pairs (26%), patients and clinicians disagreed about
      whether end-of-life communication had occurred. African-American and Hispanic
      patients were less likely to report having communication than non-Hispanic white
      patients (chi-square analysis: chi2 = 4.67; P < 0.05); injection drug users and
      women with high-risk sexual partners were less likely to report communication
      than homosexual or bisexual men (chi2 = 4.67; P < 0.05). A four-item measure of
      patients' assessment of the quality of communication about end-of-life care had
      good internal consistency (Cronbach's alpha 0.81) and was significantly
      correlated with overall satisfaction with medical care (r2 = 0.76; P < 0.0001).
      Patients with lower income reported lower quality of communication (chi2 = 5.82;
      P = 0.05). If patients assessed quality of communication as high, their
      clinicians were more likely to know if the patient had a durable power of
      attorney for health care (chi2 = 4.95; P = 0.03) but were not more likely to
      predict patients' preferences for life-sustaining treatments. CONCLUSIONS:
      Quality of patient-clinician communication about end-of-life care can be measured
      in a brief questionnaire; higher quality of this communication is associated with
      higher satisfaction with care and increased clinician knowledge of patients'
      advance directives. Since socioeconomic status and ethnicity are associated with
      both the occurrence and quality of this communication, future interventions in
      end-of-life care should assess the effect of these variables. Given the important
      and independent goals of improving patient-clinician communication about end-of
      life care and improving the quality of care at the end of life, future studies
      should test interventions to improve the quality of communication and determine
      whether improving this communication improves the quality of care at the end of
      life.

PMID- 10397545
TI  - Mother-to-child transmission of HIV-1: the 'all mucosal' hypothesis as a
      predominant mechanism of transmission.

PMID- 10397546
TI  - Expansion of the CD57 subset of CD8 T cells in HIV-1 infection is related to CMV
      serostatus.

PMID- 10397547
TI  - Inverse proportions of activated and CD4 circulating lymphocytes in AIDS
      patients.

PMID- 10397548
TI  - Low seroincidence and decrease in seroprevalence of HIV among female prostitutes
      in Madrid.

PMID- 10397550
TI  - Plasma HIV viral load in relation to season and to Plasmodium falciparum
      parasitaemia.

PMID- 10397549
TI  - Effective inhibition of HIV-1 isolated from patients with acute primary HIV-1
      infection by aminooxypentane-RANTES.

PMID- 10397551
TI  - Pulmonary tuberculosis with normal radiographs in HIV-immunodeficient patients.

PMID- 10397552
TI  - Osteonecrosis of the femoral head in patients receiving HIV protease inhibitors.

PMID- 10397553
TI  - Complete regression of AIDS-related Kaposi's sarcoma in a child treated with
      highly active antiretroviral therapy.

PMID- 10397554
TI  - Response to: Early regression of cervical lesions in HIV-seropositive women
      receiving highly active antiretroviral therapy, by Heard et al. AIDS 1998,
      12:1459-1464.

PMID- 10397556
TI  - Do needle exchange programmes increase the spread of HIV among injection drug
      users?: an investigation of the Vancouver outbreak.
AB  - OBJECTIVE: An association between needle exchange attendance and higher HIV
      prevalence rates among injecting drug users (IDU) in Vancouver has been
      interpreted by some to suggest that needle exchange programmes (NEP) may
      exacerbate HIV spread. We investigated this observed association to determine
      whether needle exchange was causally associated with the spread of HIV. DESIGN
      AND METHOD: Prospective cohort study of 694 IDU recruited in the downtown
      eastside of Vancouver. Subjects were HIV-negative at the time of recruitment and
      had injected illicit drugs within the previous month. RESULTS: Of 694 subjects,
      the 15-month cumulative HIV incidence was significantly elevated in frequent NEP
      attendees (11.8+/-1.7 versus 6.2+/-1.5%; log-rank P = 0.012). Frequent attendees
      (one or more visits per week) were younger and were more likely to report:
      unstable housing and hotel living, the downtown eastside as their primary
      injecting site, frequent cocaine injection, sex trade involvement, injecting in
      'shooting galleries', and incarceration within the previous 6 months. The Cox
      regression model predicted 48 seroconversions among frequent attendees; 47 were
      observed. Although significant proportions of subjects reported obtaining
      needles, swabs, water and bleach from the NEP, only five (0.7%) reported meeting
      new friends or people there. When asked where subjects had met their new sharing
      partners, only one out of 498 respondents cited the needle exchange. Paired
      analysis of risk variables at baseline and the first follow-up visit did not
      reveal any increase in risk behaviours among frequent attendees, regardless of
      whether they had initiated drug injection after establishment of the NEP.
      CONCLUSIONS: We found no evidence that this NEP is causally associated with HIV
      transmission. The observed association should not be cited as evidence that NEP
      may promote the spread of HIV. By attracting higher risk users, NEP may furnish a
      valuable opportunity to provide additional preventive/support services to these
      difficult-to-reach individuals.

PMID- 10397555
TI  - HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban
      AIDS clinic: response to both initial and salvage therapy.
AB  - OBJECTIVE: To determine the HIV RNA and CD4 cell response to both initial and
      salvage therapy with protease inhibitor-based therapy, and to examine the
      relationship between the virological response and pre-therapy characteristics.
      DESIGN: Observational cohort. SETTING: University-based public hospital AIDS
      clinic. PATIENTS: HIV-infected adults who received at least 16 continuous weeks'
      therapy with a potent protease inhibitor (indinavir, ritonavir or nelfinavir)
      based regimen, and who have had at least 48 weeks of follow-up. MAIN OUTCOME
      MEASURES: Plasma HIV RNA and CD4 cell count response at week 48 of therapy for
      patients receiving their first protease inhibitor-containing regimen, and at week
      24 of therapy with a salvage regimen. RESULTS: Of the 337 patients analysed, 170
      (50.2%) had a successful outcome (HIV RNA <500 copies/ml after 48 weeks of
      treatment). Independent predictors of virological failure were higher baseline
      HIV RNA level, lower baseline CD4 cell count and failure to initiate at least one
      new nucleoside analog simultaneously at the time protease inhibitor therapy was
      initiated. The risk of failure increased incrementally across most HIV RNA and
      CD4 cell strata, with significant increases as the HIV RNA increased above 4.5
      log10 copies/ml and the CD4 cell count fell below 100 cells/mm3 (P< or =0.01).
      The CD4 cell count remained above baseline to week 48 in most patients,
      regardless of the HIV RNA response. Of the 99 patients who experienced
      virological failure and switched to a salvage regimen, only 22 (22%) achieved an
      undetectable HIV RNA level 24 weeks after initiating salvage therapy. Independent
      predictors of failure with salvage therapy included an HIV RNA greater than 4.0
      log10 RNA copies/ml at the time of the switch and failure to use a non-nucleoside
      reverse transcriptase inhibitor (NNRTI) in the salvage regimen. CONCLUSION:
      Failure of potent protease inhibitor therapy to suppress HIV RNA levels below
      detectable levels is common in clinical practice, and can often be explained by
      their suboptimal use. CD4 T cell counts remain above baseline for at least one
      year in most patients experiencing virological failure. Successful salvage
      therapy, which was uncommon, was associated with a low plasma HIV RNA at the time
      of the switch and the use of a new class of antiretroviral agents (NNRTI) in the
      salvage regimen.

PMID- 10397557
TI  - Granulocyte-macrophage colony-stimulating factor: potential therapeutic,
      immunological and antiretroviral effects in HIV infection.

PMID- 10397558
TI  - Evaluation of sperm washing as a potential method of reducing HIV transmission in
      HIV-discordant couples wishing to have children.
AB  - OBJECTIVE: A number of discordant couples, in whom the man is HIV positive and
      the woman is HIV negative, wish to have children. To conceive they must abandon
      protected sex, posing a risk of HIV transmission to the woman and so to the
      child. In such circumstances purification of spermatozoa ('sperm-washing') to
      inseminate the woman artificially has been proposed as a method of reducing the
      risk of transmission. Here we evaluate whether this does represent a true risk
      reduction. METHODS: Semen samples from HIV-positive patients were separated into
      spermatozoa, non-sperm cells (NSCs) and plasma fractions. The amount of viral RNA
      present in each fraction was measured and compared with the level in the
      peripheral blood. Each fraction was also assessed for the presence of proviral
      DNA. The ability of spermatozoa to be infected was assessed by evaluating for the
      presence of HIV receptors, i.e. CD4, CCR5 and CXCR4 on the surface of the sperm,
      by flow cytometry. RESULTS: A poor correlation was found between the levels of
      HIV in blood and semen. Within the semen the virus was restricted to the plasma
      and/or NSCs. All spermatozoa were negative for viral RNA or proviral DNA.
      Spermatozoa did not express significant levels of CD4, CCR5 or CXCR4, suggesting
      that they are unlikely to be major targets for HIV infection. CONCLUSIONS: These
      data suggest that spermatozoa are not major targets of HIV infection. Purifying
      spermatozoa reduced the level of HIV RNA and proviral DNA to below the detection
      limit of the assays irrespective of the amount of virus present in the
      unfractionated semen. On the basis of these data we would recommend 'sperm
      washing' followed by insemination as a safer alternative to natural conception
      for HIV-discordant couples wishing to have children.

PMID- 10397559
TI  - Antibody to capsular polysaccharide enhances the function of neutrophils from
      patients with AIDS against Cryptococcus neoformans.
AB  - OBJECTIVE: To determine the contribution of anti-glucuronoxylomannan monoclonal
      antibody (MAb18B7) to the fungicidal capacity of polymorphonuclear leukocytes
      (PMNL) from HIV-infected patients towards Cryptococcus neoformans. DESIGN:
      Killing activity and superoxide anion generation were evaluated in the presence
      or absence of MAb18B7 in an in vitro system. METHODS: Killing activity was
      determined by colony forming unit inhibition assay. Superoxide generation was
      measured in the presence or absence of zymosan, C. neoformans, or Candida
      albicans. CD16, CD32, and CD64 molecules on PMNL were evaluated by
      cytofluorometric analysis. RESULTS: MAb18B7 strongly influenced the phagocytic
      and killing activities against encapsulated C. neoformans and consistently
      enhanced superoxide anion generation. Expression of CD16, and to a lesser extent
      CD64, on PMNL was required for MAb18B7-induced superoxide generation. By blocking
      CD16 and CD64 molecules with anti-CD16 and anti-CD64 MAb, a significant down
      regulation of MAb18B7-induced fungicidal activity was observed. CONCLUSIONS: Our
      results demonstrate that MAb18B7 selectively enhances the killing mechanisms of
      PMNL from HIV-infected patients against encapsulated C. neoformans. The
      availability of CD16 and CD64 molecules on PMNL plays a critical role.

PMID- 10397561
TI  - Determinants of paradoxical CD4 cell reconstitution after protease inhibitor
      containing antiretroviral regimen.
AB  - OBJECTIVES: We evaluated the parameters influencing CD4 cell reconstitution after
      the introduction of highly active antiretroviral therapies in real life, as well
      as the frequency and the determinants of the discrepancies occurring between
      virus and CD4 cell count evolution. DESIGN AND METHODS: A total of 317 pre
      treated patients starting a protease inhibitor (PI)-containing regimen were
      prospectively followed for 2 years on an intent-to-treat basis for CD4 cell
      counts and viral loads. RESULTS: The CD4 cell counts rapidly increased from
      baseline (50/mm3) by a median of 50/mm3 at month 2 (+0.72 CD4 cells/mm3/day) and
      up to 137/mm3 at the last follow-up (second slope: +0.16 CD4 cells/mm3/day). Two
      independent major factors among five parameters tested significantly affected the
      first phase, which was negatively correlated to the slope of CD4 cell decline
      before PI initiation, and was positively correlated to baseline CD4 cell counts
      (P = 0.0001); the second phase was mostly affected by the mean viral load
      reduction over time (P = 0.0001). Paradoxical CD4 cell reconstitution (15% of
      cases) was defined by a rapid or slow CD4 cell increase contrasting with a minor
      or strong viral reduction, respectively. The role of previous CD4 cell decline
      and the low effect of viral load reduction during the first 2 months explain the
      early paradoxical CD4 cell responses. The major influence of viral load reduction
      on the long-term reconstitution, however, reduces such paradoxical responses at 2
      years. CONCLUSIONS: Early paradoxical CD4 cell reconstitution after the
      introduction of a PI are explained by the major influence of previous disease
      progression on the early CD4 cell increase, whereas the magnitude of viral load
      reduction over time reduces such paradoxical evolutions in the long term.

PMID- 10397560
TI  - Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many
      antiretroviral compounds in current clinical development.
AB  - OBJECTIVES: To assess the in-vitro drug susceptibility of a panel of five well
      characterized drug-resistant HIV variants to recently developed anti-HIV
      compounds including seven reverse transcriptase (RT) inhibitors and seven
      protease inhibitors. METHODS: Drug-resistant viral strains were selected on the
      basis of the prevalence of these mutants in patient samples from local area HIV
      clinics. The isolates included one multinucleoside-resistant virus containing the
      Q151M mutation, and four clinical isolates containing multiple RT and protease
      resistance mutations. The activity of the experimental compounds against these
      isolates was determined using drug susceptibility assays and measuring the viral
      antigen p24 end-point. RESULTS: These clinically relevant highly drug-resistant
      viruses were resistant to many of the new compounds in clinical development. In
      most cases the resistance mutations of the clinical isolate were different from
      those selected in vitro for the particular experimental compound. CONCLUSIONS: It
      is critical to expand the preclinical development of new drugs to include the
      assessment of their activity against currently circulating highly drug-resistant
      clinical strains, in order to develop appropriate salvage therapies for patients
      harboring resistant strains.

PMID- 10397563
TI  - Lamivudine in combination with zidovudine, stavudine, or didanosine in patients
      with HIV-1 infection. A randomized, double-blind, placebo-controlled trial.
      National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group
      Protocol 306 Investigators.
AB  - OBJECTIVE: To study the antiviral activity of lamivudine (3TC) plus zidovudine
      (ZDV), didanosine (ddl), or stavudine (d4T). DESIGN: Randomized, placebo
      controlled, partially double-blinded multicenter study. SETTING: Adult AIDS
      Clinical Trials Units. PATIENTS: Treatment-naive HIV-infected adults with 200
      600x10(6) CD4 T lymphocytes/l. INTERVENTIONS: Patients were openly randomized to
      a d4T or a ddl limb, then randomized in a blinded manner to receive: d4T (80
      mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching
      placebos; or ddl (400 mg/day), ddl plus 3TC (300 mg/day), or ZDV (600 mg/day)
      plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients
      assigned to the monotherapy arms. MAIN OUTCOME MEASURE: The reduction in plasma
      HIV-1 RNA level at weeks 24 and 48. RESULTS: Two hundred ninety-nine patients
      were enrolled. After 24 weeks the mean reduction in plasma HIV-1 RNA copies/ml
      from baseline was 0.49 log10 (d4T monotherapy) versus 1.03 log10 (d4T plus 3TC; P
      = 0.001), and 0.68 log10 (ddl monotherapy) versus 0.82 log10 (ddl plus 3TC;
      P>0.22). After 48 weeks the mean reduction was 1.08 log10 (d4T plus 3TC) versus
      1.01 log10 (ZDV plus 3TC) in the d4T limb (P = 0.66), and 0.94 log10 (ddl plus
      3TC) versus 0.88 log10 (ZDV plus 3TC; P = 0.70) in the ddl limb. CONCLUSIONS: 3TC
      added significantly to the virologic effects of d4T, but not ddl, in treatment
      naive patients. 3TC plus d4T produced virologic changes comparable to those of
      3TC plus ZDV. These results support the use of 3TC with either ZDV or d4 as a
      component of initial combination antiretroviral therapy.

PMID- 10397562
TI  - HIV-1 rebound during interruption of highly active antiretroviral therapy has no
      deleterious effect on reinitiated treatment. Comet Study Group.
AB  - BACKGROUND: Potent antiretroviral therapy (ART) with a protease inhibitor-based
      regimen is commonly used to treat HIV-1-infected patients. Transient treatment
      interruptions because of drug intolerance or other reasons are not uncommon. HIV
      1 dynamics during therapy interruption and its consequences for the subsequent
      reinitiation of therapy have not been properly studied. METHODS: Ten
      antiretroviral-naive, HIV-1-infected subjects (mean baseline CD4 cell count of
      414 cells/mm3 and plasma viral load of 4.8 log10 copies/ml) were treated with the
      triple drug ART regimen indinavir/zidovudine/lamivudine for 28 days. Therapy was
      then interrupted for 28 days, after which the same ART regimen was re-started.
      RESULTS: HIV-1 in plasma declined during the first 7 days of therapy with T1/2 of
      1.5 days, and during days 7-28 with T1/2 of 8.9 days. Once therapy was
      interrupted, a delay of 4-7 days was observed in all subjects, preceding a rapid
      viral rebound with a mean doubling time of 1.6 days. Mean viral load after 28
      days of interruption was 96% of baseline. Upon reinitiation of the same ART
      regimen, viral load declined at rates similar to those observed during the
      initial therapy (T1/2 of 1.6 and 8.0 days, respectively). No resistance
      conferring mutations were observed in the HIV-1 reverse transcriptase (RT) and
      protease regions after the interruption of therapy. Plasma viral loads were
      maintained below 200 copies/ml in subjects continuing therapy for 4 (n = 9) to 12
      (n = 5) months, with a mean CD4 cell count increase of 145 cells/mm3.
      CONCLUSIONS: The reintroduction of efficient ART therapy after a 1 month
      interruption shows viral kinetics similar to that of naive patients, and is not
      associated with the development of resistance. No deleterious effect on the
      reinitiated therapy was observed in patients who temporarily discontinued ART
      therapy. Nevertheless, because viral load rebounds back to baseline during
      treatment interruption, viral suppression is in effect put off by that period of
      time.

PMID- 10397564
TI  - Lack of protection against HIV-1 infection among women with HIV-2 infection.
AB  - OBJECTIVE: To assess whether HIV-2 infection protects against HIV-1 infection by
      comparing the rate of HIV-1 seroconversion among HIV-negative and HIV-2
      seropositive women followed in a cohort study in Abidjan, Cote d'Ivoire. DESIGN:
      Prospective cohort study METHODS: HIV seroconversion was assessed in 266 HIV
      seronegative, 129 HIV-1-seropositive, and 127 HIV-2-seropositive women
      participating in a closed cohort study of mother-to-child transmission of HIV
      conducted during 1990-1994. Participants were seen every 6 months, and blood
      samples were obtained. All blood samples were screened for HIV antibodies by
      enzyme immunoassay (EIA) and confirmed by line immunoassay (LIA) and Western
      blot. Among women who were HIV-seronegative at enrolment, seroconversion was
      defined as new EIA-reactivity confirmed on LIA and Western blot. Among HIV-1- or
      HIV-2-seropositive women, seroconversion to dual reactivity was defined as new
      dual reactivity on the LIA that was confirmed by reactivity on both HIV-1- and
      HIV-2-monospecific EIA. RESULTS: Five HIV-seronegative women became HIV-1
      seropositive [seroconversion rate, 1.1 per 100 person-years; 95% confidence
      interval (CI), 0.3-2.5), and none became HIV-2-seropositive. No HIV-1
      seropositive women became HIV-1/2 dually reactive, whereas six HIV-2-seropositive
      women acquired HIV-1 seroreactivity and thus became HIV-1/2 dually reactive
      (seroconversion rate 2.9 per 100 person-years; 95% CI, 1.1-6.3). HIV-2
      seropositive women were more likely to acquire HIV-1 seroreactivity than were HIV
      seronegative women (rate ratio, 2.7; 95% CI, 0.7-11.2), but this difference was
      not statistically significant (P>0.15). CONCLUSION: HIV-2 infection does not
      appear to protect against HIV-1 infection.

PMID- 10397565
TI  - Trends and interaction of HIV-1 and HIV-2 in Guinea-Bissau, west Africa: no
      protection of HIV-2 against HIV-1 infection.
AB  - OBJECTIVES: To study trends in the prevalence and incidence of HIV-1 and HIV-2
      infections in Guinea-Bissau over the last 7 years, and to evaluate the protective
      effect of HIV-2 against HIV-1 infection. DESIGN: Prospective follow-up of a
      cohort of police officers in Guinea-Bissau, and sentinel surveillance of pregnant
      women in Bissau. METHODS: Participants in the police cohort were tested regularly
      for antibodies to HIV and Treponema pallidum, and information about sexual risk
      behaviour and a history of sexually transmitted diseases was obtained.
      Simultaneously, pregnant women at the maternity wards at the National Hospital in
      Bissau were screened annually for HIV antibodies. To evaluate changes in
      prevalence and incidence of HIV in the police cohort, the study period was
      divided into three time strata with 2-3 years in each stratum. For the evaluation
      of a protective effect of HIV-2 on subsequent HIV-1 infection, two multivariate
      Poisson regression models were constructed, adjusting for different selected
      confounding variables. RESULTS: Between 1990 and 1997, 2637 police officers were
      included in the cohort study, 90.7% of whom were male. The overall prevalence of
      HIV-1 was 0.9%, of HIV-2 it was 9.7% and of HIV-1 and HIV-2 dual reactivity it
      was 0.5%. For pregnant women the prevalence rates were 0.9, 5.5 and 0.2% for HIV
      1, HIV-2 and dual reactivity respectively. The prevalence of HIV-1 increased
      significantly whereas the prevalence of HIV-2 declined significantly during the
      study period, among both police officers and pregnant women. The total incidence
      of HIV-1 and HIV-2 was 0.74 and 0.83 per 100 person-years respectively in the
      police cohort. The incidence of HIV-1 increased slightly from 0.62 to 0.78 per
      100 person-years (not significant), whereas the incidence of HIV-2 declined
      significantly from 0.90 to 0.35 per 100 person-years over the study period. Seven
      police officers seroconverted from HIV-2 to dual reactivity (1.22 per 100 person
      years). The adjusted incidence ratio of acquiring HIV-1 infection among HIV-2
      positive subjects compared with HIV-negative subjects was 1.65 [95% confidence
      interval (CI), 0.73-3.74] and 1.98 (95% CI, 0.80-4.87), depending on the
      confounding variables included. CONCLUSIONS: Our study shows an increasing
      prevalence of HIV-1 and a decreasing prevalence of HIV-2 in Guinea-Bissau. The
      incidence of HIV-2 declined significantly whereas the incidence of HIV-1 was
      relatively stable over the study period. No protective effect of HIV-2 against
      subsequent HIV-1 infection was observed, instead HIV-2-positive subjects had a
      tendency towards higher risk of acquiring HIV-1 infection compared with
      seronegative subjects.

PMID- 10397566
TI  - Self-reported sexual behaviour and HIV risk taking among men who have sex with
      men in Fortaleza, Brazil.
AB  - OBJECTIVES: To describe and identify sociodemographic and behavioural
      characteristics and other factors related to high-risk behaviour for HIV
      infection of men who have sex with men (MSM) living in Fortaleza, Brazil.
      METHODS: A survey was carried out among 400 MSM aged 14-65 years and recruited
      through the snowball technique or in gay-identified venues. A semi-structured
      questionnaire was conducted among them. Logistic regression analysis was used to
      model the dichotomous outcome (high risk or low risk). RESULTS: Forty-four per
      cent of the participants reported engaging in high-risk sexual behaviour in the
      previous year. MSM less informed about AIDS, reporting more sexual partners,
      reporting at least one female partner in the previous year, having anal sex as
      the favourite way to have sex, and having great enjoyment of unprotected anal sex
      were more likely to be engaged in risky behaviour. Twenty-three per cent of
      participants reported at least one sexual contact with women during the previous
      year. Two-thirds of men who had unprotected sex with their female partners also
      had unprotected anal sex with their male partners. CONCLUSIONS: A large
      proportion of MSM in Fortaleza still remain at elevated risk for contracting HIV
      infection. The factors predictive of high-risk sexual behaviour are significant
      in spreading HIV infection among the MSM population and also among their female
      partners. The lifestyles of these men are different to those of men from other
      parts of Brazil or outside the country. Preventive interventions need to be
      culturally and socially specific in order to be effective.

PMID- 10397568
TI  - Inaccurate HIV-1 viral load quantification by three major commercially available
      methods.

PMID- 10397567
TI  - Predictors of visits to commercial sex workers by male attendees at sexually
      transmitted disease clinics in southern Vietnam.
AB  - OBJECTIVES: To determine the HIV/sexually transmitted disease (STD) status of
      male patients at STD clinics and factors associated with frequent visits to
      commercial sex workers (CSW) in southern Vietnam. DESIGN: Cross-sectional survey.
      METHODS: Confidential interviews and physical and laboratory evaluation of 804
      male patients at STD clinics in two semi-rural provinces in the Mekong delta.
      RESULTS: HIV seroprevalence was 0.5%. The prevalence of urethritis syndrome was
      19.3%, gonorrhea 10.2% (Gram-stain positive) and syphilis 2% (reactive rapid
      plasma reagin test). All the men had visited CSW in the past and 58% had their
      first sexual experience with a CSW; 73% had visited a CSW in the last 3 years.
      Married men were equally as likely as single men to have casual partners or to
      have visited a CSW. The men recruited CSW more from the streets (45%) than from
      brothels (38%). Factors independently associated with visiting a CSW in the last
      3 years included being single [odds ratio (OR), 2.2], age under 20 years (OR,
      1.9), having first sexual intercourse with a CSW (OR, 2.1), not having a current
      girlfriend (OR, 2.1), using alcohol before sex (OR, 2.7) and drug use (OR, 1.8).
      Only 7% of men used condoms consistently; 70% had never used them. Only 37% had
      used a condom last time they had intercourse with a CSW. CONCLUSIONS: Prevention
      programs for men in Vietnam, particularly those who are young or single, need to
      focus on reducing drug and alcohol consumption and improving condom use with
      CSWs.

PMID- 10397569
TI  - Sweet's syndrome in an HIV-infected patient.

PMID- 10397570
TI  - Reappearance of HIV antibody in an infected, seronegative individual after
      treatment with highly active antiretroviral therapy.

PMID- 10397571
TI  - Prolonged fever revealing disseminated infection due to Penicillium marneffei in
      a French HIV-seropositive patient.

PMID- 10397572
TI  - HIV-associated non-Hodgkin's lymphoma: highly active antiretroviral therapy
      improves remission rate of chemotherapy.

PMID- 10397573
TI  - Cryptosporidiosis: eradication or suppression with combination antiretroviral
      therapy?

PMID- 10397574
TI  - Lipodystrophy in patients naive to HIV protease inhibitors.

PMID- 10397575
TI  - Oral sex and HIV transmission.

PMID- 10397576
TI  - The message not heard: myth and reality in discussions about syringe exchange.

PMID- 10397577
TI  - Continued explosive rise in HIV prevalence among pregnant women in rural South
      Africa.

PMID- 10397578
TI  - Chronic environmental arsenic poisoning.

PMID- 10397579
TI  - Solar urticaria: the annoying photodermatosis.

PMID- 10397580
TI  - Cutaneous manifestations due to Pseudomonas infection.

PMID- 10397581
TI  - The saga of ectoparasitoses: scabies and pediculosis.

PMID- 10397582
TI  - Myotonic dystrophy (Steinert disease): a morphologic and biochemical hair study.
AB  - BACKGROUND: Myotonic dystrophy is a systemic genetic disorder, with dominant
      transmittance. It is characterized by generalized progressive muscular
      abnormality. Although frontoparietal alopecia is one of the most common symptoms
      in myotonic dystrophy, it has not received much attention. METHODS: We examined
      25 subjects from two families: 10 patients were affected by Steinert disease and
      15 were not. The various morphologic and biochemical hair alterations are
      reported. RESULTS: All investigated subjects (affected or not) presented the same
      type of morphologic and biochemical hair alterations. CONCLUSIONS: These findings
      could be used to construct a hypothesis to explain the cause of the disease.

PMID- 10397583
TI  - Lipid profile in actinic keratosis and basal cell carcinoma.
AB  - BACKGROUND: The lipid content of the skin and its changes are important in the
      pathogenesis of many disorders affecting the skin, particularly actinic keratosis
      (AK) and basal cell carcinoma (BCC). METHODS: Cholesterol, phospholipid,
      triglyceride, and total lipid levels were studied in paired lesional (AK and BCC)
      and nonlesional intact skin of 13 patients with AK and 12 patients with BCC.
      Serum concentrations of the same lipid fractions studied in the skin were
      investigated in AK and BCC patients and in 11 healthy, age-matched controls.
      RESULTS: Levels of all lipid fractions were increased in both AK and BCC skin.
      When AK and BCC skin were compared with each other, a significant increase in
      phospholipids (p < 0.02) and total lipids (p < 0.01) was found in BCC. Serum
      cholesterol (p < 0.001), phospholipid (p < 0.001), triglyceride (p < 0.05), and
      total lipid (p < 0.001) concentrations of AK patients were significantly higher
      than those of the control group. When BCC and controls were compared, a
      significant increase in phospholipids and total lipids (p < 0.001) was seen.
      Serum cholesterol in BCC patients was significantly lower (p < 0.001) and serum
      phospholipid levels were significantly higher (p < 0.05) than those in the AK
      group. CONCLUSIONS: An increase in the metabolically active serum phospholipid
      fraction is reflected in elevated neoplastic tissue phospholipid. This produces
      altered proportions between lipid fractions in tumorous areas and may result in
      changes in the intact nature of the cellular membrane, spread, and malignant
      proliferation.

PMID- 10397584
TI  - Computerized system to enhance the clinical diagnosis of pigmented cutaneous
      malignancies.
AB  - BACKGROUND: An increase in the incidence of cutaneous malignant melanoma in
      recent years has not been accompanied by satisfactory progress in diagnostic
      methods. This study was carried out to evaluate a specially designed computerized
      image analysis system, called Derma Vision, to aid in the differentiation between
      malignant and benign cutaneous pigmented lesions. METHODS: Seventy-one lesions
      were photographed with a digital camera and the data were analyzed by the Derma
      Vision system. The system assessed the variation of hues in each image,
      calculated the mean standard deviation of the hues, and produced a value that
      expressed the range of hues in the lesion. The lesions were then excised and
      examined histologically. The computer-assisted clinical diagnosis was correlated
      with the histologic diagnosis to determine the accuracy of the former. RESULTS:
      Derma Vision predicted the malignant character of a lesion with 92% precision,
      compared with 87% accuracy based only on the clinical features. CONCLUSIONS: This
      simple, inexpensive device can boost the accuracy of clinical diagnosis and
      provide a useful tool to the physician faced increasingly with having to
      determine whether pigmented lesions are malignant or benign.

PMID- 10397585
TI  - Occupational allergic contact dermatitis from unsaturated polyester resin in a
      car repair putty.
AB  - BACKGROUND: Unsaturated polyester (UP) resins are widely used as cements in car
      repair painting to produce a smooth surface before the final painting. We report
      two car painters with hand and face dermatitis who were sensitized to a UP resin
      used for car repair cements. METHODS: Patch testing with commercial substances
      and ingredients and extracts from UP resins was used to verify the sensitivity.
      RESULTS: Both patients showed an allergic patch test reaction to a UP resin. They
      also had an allergic patch test reaction to diethyleneglycol maleate (DEGM), an
      extract of a UP resin. CONCLUSIONS: Both patients had been patch tested elsewhere
      with negative results because UP resins had not been used for patch testing.
      Accordingly, patients with dermatitis who have been exposed to UP resins need to
      be patch tested with UP resins. The specific chemical causing allergic contact
      dermatitis in our patients was DEGM.

PMID- 10397587
TI  - Mucocutaneous manifestations of HIV infection: a retrospective analysis of 145
      cases in a Chinese population in Malaysia.
AB  - BACKGROUND: Mucocutaneous lesions directly related to human immunodeficiency
      virus (HIV) infection usually present as initial manifestations of immune
      deficiency. The most common mucocutaneous lesions are Kaposi's sarcoma,
      histoplasmosis, oro-esophageal candidiasis, oral hairy leukoplakia, and, in Asia,
      Penicillium marneffei infection. Non-HIV-related skin lesions, such as psoriasis,
      seborrheic dermatitis, and nodular prurigo, may be the initial presentation among
      HIV infected patients attending outpatient clinics. METHODS: A retrospective
      analysis was performed on 145 HIV-positive Malaysians of Chinese descent from two
      centers at the University Hospital Kuala Lumpur (UHKL) and the General Hospital
      Kuala Lumpur (GHKL) from March 1997 to February 1998. Demographic data and
      clinical data were analyzed. RESULTS: The analysis showed that 104 out of 145
      patients had mucocutaneous disorders (71.7%). In the study, there were 100 men
      (96.2%) and four women (3.8%). The majority of patients were in the age group 20
      50 years. The patients who presented with mucocutaneous disease also had low CD4+
      T-lymphocyte counts and most had acquired immunodeficiency syndrome (AIDS)
      defining illness. The number of cases with generalized hyperpigmentation was very
      high in the group (35.9%), followed by nodular prurigo (29.7%) and xerosis
      (27.6%). Seborrheic dermatitis was seen in 20.7% of cases, with psoriasis in
      8.3%. The most common infections were oral candidiasis (35.9%), tinea corporis
      and onychomycosis (9.7%), and herpes infection (5.5%); however, mucocutaneous
      manifestations of Kaposi's sarcoma were rare. CONCLUSIONS: The results suggest
      that mucocutaneous findings are useful clinical predictors of HIV infection or
      signs of the presence of advanced HIV infection.

PMID- 10397586
TI  - An epidemic outbreak of Malassezia folliculitis in three adult patients in an
      intensive care unit: a previously unrecognized nosocomial infection.
AB  - BACKGROUND: Malassezia is a lipophilic fungus commonly found in normal human
      skin. Infection of the hair follicle by Malassezia furfur occurs in patients with
      predisposing factors such as diabetes or immunosuppression, or who are undergoing
      antibiotic treatment. Malassezia furfur folliculitis is an infrequent nosocomial
      infection which may be associated with fomite transmission. METHODS: We reviewed
      the clinical files of three adult patients from an intensive care unit (ICU) who
      simultaneously developed folliculitis through Malassezia infection. We
      specifically analysed predisposing factors, possible transmission modes,
      characteristics of skin lesions, results of biopsies and cultures, treatment, and
      patient outcome. RESULTS: The three male patients were in neighboring beds and
      they all had factors that predisposed them to underlying immunosupression.
      Simultaneously, and within hours of each other, they developed erythematous
      follicular papules and pustules on the face and chest. The skin biopsies revealed
      an acute folliculitis with abundant round to oval yeasts of up to 5 microm in
      diameter. Stains for fungi (Schiff's peryodic acid, Grocott and silver
      methenamine) revealed numerous unipolar budding yeasts without hyphae, consistent
      with M. furfur. Conventional cultures were negative. The diagnosis of
      folliculitis by M. furfur was established and antifinigal treatment initiated,
      with adequate outcome of the dermatosis. After this outbreak, the aseptic and
      hygienic measures of the health care personnel of the ICU were reviewed and
      corrected. CONCLUSIONS: The simultaneous emergence of this superficial infection
      by M. furfur suggests fomite participation. This dermatomycosis is an infrequent
      nosocomial infection in adults, which to our knowledge has not been previously
      reported.

PMID- 10397588
TI  - Kikuchi disease associated with Still disease.

PMID- 10397590
TI  - Atypical acral persistent papular mucinosis.

PMID- 10397589
TI  - Pyloric atresia with junctional epidermolysis bullosa (PA-JEB) syndrome: absence
      of detectable beta4 integrin and reduced expression of epidermal linear IgA
      dermatosis antigen.

PMID- 10397591
TI  - Unilateral transient forehead paralysis following injury to the temporal branch
      of the facial nerve.
AB  - BACKGROUND: Cutaneous surgery in the temporal region of the forehead can lead to
      injury to the superficial temporal branch of the facial nerve. A flattened
      forehead and with ipsilateral forehead paralysis can occur with damage to this
      nerve. METHODS: A case is presented of transient forehead paralysis resulting
      from Mohs' micrographic surgery with reconstruction of the defect. The paralysis
      resolved over a period of fifteen months. RESULTS: The anatomy of the nerve makes
      it susceptible to injury during cutaneous surgery. The area of danger is the area
      superior to the zygomatic arch and lateral to the lateral eyebrow where the nerve
      is closest to the skin. CONCLUSIONS: Restoration of motor function usually occurs
      without intervention, but may take several months. Should motor function not
      recur, nerve grafting of a repair of the ptotic brow may be needed. The anatomy
      of the nerve is reviewed and brow lifting options are discussed.

PMID- 10397592
TI  - Chromosome damage in a young woman with generalized morphea: cause or effect?

PMID- 10397593
TI  - Rosacea-like tinea faciei.

PMID- 10397594
TI  - From the National Institute of General Medical Sciences. Learning the system:
      changes pending in peer review and around the NIH.

PMID- 10397595
TI  - An interview with a distinguished pharmaceutical scientist. William E. Evans.

PMID- 10397597
TI  - Reversibility of heat-induced denaturation of the recombinant human megakaryocyte
      growth and development factor.
AB  - PURPOSE: The present study was performed to examine the effect of solution
      conditions on the reversibility of the thermal denaturation of megakaryocyte
      growth and development factor (rHuMGDF). METHODS: Changes in the far UV CD
      spectra of rHuMGDF with temperature were used to monitor the thermal denaturation
      of the protein, and the recovery of folded protein following a return to room
      temperature. The effect of protein concentration, scan rate, and buffer
      composition on thermal denaturation and on the reversibility were determined.
      Surface tension measurements were used to determine the effect of this unfolding
      reaction on the surface adsorption of the protein. Sedimentation velocity was
      used to assess recovery of native monomer and the size of soluble aggregates. In
      addition, monomeric protein remaining in solution after incubation at 37 degrees
      C for 2 weeks in either 10 mM imidazole of 10 mM phosphate was determined.
      RESULTS: In phosphate buffer the rHuMGDF irreversibly precipitates upon unfolding
      under all the conditions examined. In imidazole the unfolding is at least
      partially reversible, with no visible precipitate seen; the degree of
      reversibility increased by lowering both protein and salt concentrations, and the
      amount of time spent at elevated temperature. In order to compare thermal
      unfolding occuring with different degrees of reversibility, the melting
      temperature was defined as the temperature at which melting begins. The melting
      temperature itself is relatively independent of the buffer composition, or
      experimental conditions. At low protein concentrations the protein stabilizer
      sucrose had a marginal effect on the thermal transition of rHuMGDF, while at
      protein concentrations of about 2 mg/ml the inclusion of sucrose increased the
      apparent melting temperature by about 4 degrees C, to that seen at low protein
      concentrations, but had little effect on the reversibility of denaturation.
      Inclusion of 1 or 2 M urea did not affect the reaction. Surface tension
      measurements of rHuMGDF solutions showed little difference before and after
      melting, and in the presence or absence of sucrose. When unfolding is
      irreversible, the MGDF appears to form soluble aggregates of tetramers to 14
      mers, while under reversible conditions native monomer is recovered. More
      monomeric MGDF remained in solution following storage for 2 weeks at 37 degrees C
      in imidazole than in phosphate, in both the presence and absence of sucrose.
      CONCLUSIONS: These results can be explained by assuming that thermal denaturation
      proceeds as a two-step reaction, the first step being the equilibrium between
      folded and unfolded states, while the second step is a slow irreversible
      aggregation. The different buffer systems affect the rate of the aggregation
      step, but not the intrinsic thermal stability nor the rate of the unfolding step.

PMID- 10397598
TI  - Investigation of protein-surfactant interactions by analytical
      ultracentrifugation and electron paramagnetic resonance: the use of recombinant
      human tissue factor as an example.
AB  - PURPOSE: The purpose of this work is to utilize electron paramagnetic resonance
      (EPR) spectroscopy in conjunction with analytical ultracentrifugation (AUC) to
      investigate the binding of surfactants to proteins with a transmembrance domain.
      As an example these methods have been used to study the interaction of a nonionic
      surfactant, C12E8, to recombinant human tissue factor (rhTF) in liquid
      formulations. The complementary nature of the two techniques aids in data
      interpretation when there is ambiguity using a single technique. In addition to
      binding stoichiometries, the possibility of identifying the interacting domains
      by using two forms of rhTF is explored. METHODS: Two recombinant, truncated forms
      of human tissue factor were formulated in the absence of phospholipids. Neither
      of the recombinant proteins, produced in E. coli, contains the cytoplasmic
      domain. Recombinant human tissue factor 243 (rhTF 243) consists of 243 amino
      acids and includes the transmembrane sequences. Recombinant human tissue factor
      220 (rhTF 220), however, contains only the first 221 amino acids of the human
      tissue factor, lacking those of the transmembrane region. EPR and AUC were used
      to investigate the interactions between these two forms of rhTF and
      polyoxyethylene 8 lauryl ether, C12E8. RESULTS: Binding of C12E8 to rhTF 243 is
      detected by both EPR spectroscopy and AUC. Although a unique binding
      stoichiometry was not determined, EPR spectroscopy greatly narrowed the range of
      possible solutions suggested by the AUC data. Neither technique revealed an
      interaction between rhTF 220 and C12E8. CONCLUSIONS: The complementary nature of
      EPR spectroscopy and AUC make the combination of the two techniques useful in
      data interpretation when studying the interactions between rhTF and C12E8. By
      utilizing these techniques in this study, the binding stoichiometry of rhTF 243
      to C12E8 ranges from 1.2:1 to 1.3:0.6 based on an aggregation number of 120. This
      binding is consistent with previously reported activity data that showed an
      increase in clotting rate when rhTF 243 is in the presence of C12E8 micelles.
      From the rhTF 220 data, it can further be concluded that the transmembrane domain
      of rhTF is necessary for interactions with C12E8.

PMID- 10397596
TI  - Pharmacodynamics and toxicodynamics of drug action: signaling in cell survival
      and cell death.
AB  - In therapeutic response to drugs, the plasma concentration range leads to the
      establishment of a safe and effective dosage regimen. Our hypothesis is that by
      studying drug concentration-dependent effect on signal transduction mechanisms, a
      better understanding of the beneficial pharmacodynamic and adverse toxicodynamic
      responses elicited by the drug may be achieved. Using two classes of
      chemopreventive compounds (phenolic antioxidants and isothiocyanates), we
      illustrate the potential utility of two signal transduction pathways elicited by
      these agents to predict the pharmacodynamic effect (induction of Phase II drug
      metabolizing enzymes) and the potential toxicodynamic response (stimulation of
      caspase activity and cytotoxic cell death). At lower concentration, phenolic
      antioxidants and isothiocyanates activate mitogen-activated protein kinase (MAPK;
      extracellular signal-regulated protein kinase 2, ERK2; and c-Jun N-terminal
      kinase 1, JNK1) in a concentration-and time-dependent manner. The activation of
      MAPK by these compounds may lead to the induction of cell survival/protection
      genes such as c-jun, c-fos, or Phase II drug metabolizing enzymes. However, at
      higher concentrations, these agents activate another signaling molecule, ICE/Ced3
      cysteine protease enzymes (caspases) leading to apoptotic cell death. The
      activation of these pathways may dictate the fate of the cells/tissues upon
      exposure to drugs or chemicals. At lower concentrations, these compounds activate
      MAPK leading to the induction of Phase II genes, which may protect the
      cells/tissues against toxic insults and therefore may enhance cell survival. On
      the other hand, at higher concentrations, these agents may activate the caspases,
      which may lead to apoptotic cell death, and have toxicity. Understanding the
      activation of these and other signal transduction events elicited by various
      drugs and chemicals may yield insights into the regulation of gene expression of
      drug metabolizing enzymes and cytotoxicity. Thus, the study of signaling events
      in cell survival (hemeostasis) and cell death (cytotoxicity) may have practical
      application during pharmaceutical drug development.

PMID- 10397599
TI  - Isolation, characterization, and stability of positional isomers of mono
      PEGylated salmon calcitonins.
AB  - PURPOSE: To separate and characterize the different positional isomers of mono
      PEGylated salmon calcitonins (mono-PEG-sCTs) and to evaluate the effects of the
      PEGylation site on the stability of different mono-PEG-sCTs in rat kidney
      homogenate. METHODS: Mono-PEG-sCTs were prepared using succinimidyl carbonate
      monomethoxy polyethylene glycol (5,000 Da) and separated by gel-filtration HPLC
      followed by reversed-phase HPLC. To characterize PEGylated sCTs, matrix-assisted
      laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) and
      reversed-phase HPLC of the trypsin digested samples were performed. Mono-PEG-sCTs
      and sCT in rat kidney homogenates were measured by column-switching reversed
      phase HPLC with on-line detection of the radioiodinated samples using a flow
      through radioisotope detector. RESULTS: Three different mono-PEGylated sCTs were
      separated by reversed-phase gradient HPLC. From the MALDI-TOF MS analysis, the
      average molecular weight of mono-PEG-sCTs was confirmed as around 8650 Da. The
      presence of PEG moiety in the mono-PEG-sCTs was also manifested by the fact that
      the distance between two adjacent mass spectum lines was 44 Da which corresponds
      to PEG monomer unit. Tryptic digestion analysis demonstrated that these mono-PEG
      sCTs are 3 positional isomers of N-terminus, Lys18- and Lys11-residue modified
      mono-PEGylated sCTs. The degradation half-life of these 3 positional isomers in
      rat kidney homogenates significantly increased in order of the N-terminus (125.5
      min), Lys11- (157.3 min), and Lys18 residue modified mono-PEGylated sCT (281.5
      min) over the native sCT (4.8 min). CONCLUSION: Three positional isomers of mono
      PEGylated sCTs were purified and characterized. Of these, the resistance to
      proteolytic degradation was highest for the Lys18-residue modified mono-PEG-sCT.
      These studies demonstrate that the in vivo stability of PEGylated sCTs is highly
      dependent on the site of PEG molecule attachment.

PMID- 10397600
TI  - Polymer molecular weight alters properties of pH-/temperature-sensitive polymeric
      beads.
AB  - PURPOSE: To study the physical and release properties of different molecular
      weight (MW) pH- and temperature-responsive statistical terpolymers and beads of N
      isopropylacrylamide (NIPAAm), butylmethacrylate (BMA) and acrylic acid (AA).
      METHODS: Random terpolymers of varying MW were synthesized with NIPAAm/BMA/AA of
      feed mol ratio 85/5/10. Polymeric beads were formed by dropping a polymer
      solution into an oil bath kept at a temperature above the lower critical solution
      temperature (LCST) of the polymer. The release profile of cytochrome c was
      investigated as a function of the polymer MW and pH of the release medium at 37
      degrees C. RESULTS: The weight average MW ranged between 49,000 and 3 million.
      The LCST at pH 2.0 and pH 7.4 was 22 degrees C and 60 degrees C respectively. SEM
      studies showed that the size of the pores decreased as the MW increased.
      Irrespective of MW, the polymeric beads did not swell or dissolve at pH 2.0 and
      37 degrees C and showed minimal drug release. At pH 7.4 and 37 degrees C, the
      rate of bead dissolution/swelling decreased as the MW of the polymer increased.
      CONCLUSIONS: By modulating polymer MW, it was possible to vary the physical
      properties of beads. Dissolution/swelling characteristics were dependent on the
      MW of the polymer. Such unique dissolution/swelling properties are useful for
      delivering drugs to different sites in the intestine.

PMID- 10397601
TI  - Pharmaceutical dry powder aerosols: correlation of powder properties with dose
      delivery and implications for pharmacodynamic effect.
AB  - PURPOSE: Efficient dispersion of bulk solids is critical for dry powder aerosol
      production which can be viewed as a sequence of events from stationary through
      dilated, flowing and finally dispersed particulates. The purpose of this study
      was to test the hypothesis that numerical descriptors of powder flow properties
      predict aerosol dispersion and pharmacodynamic effect. METHODS: Drug and
      excipient particles were prepared in size ranges suitable for inhalation drug
      delivery, and their physico-chemical properties were evaluated. Novel techniques
      (chaos analysis of dynamic angle of repose and impact force separation) were
      developed and utilized to measure and characterize powder flow and particle
      detachment from solid surfaces, respectively. Dry powder aerosol dispersion was
      evaluated using inertial impaction. Pharmacodynamic evaluations of
      bronchodilation were performed in guinea pigs, for selected formulations.
      RESULTS: We observed a direct correlation of powder flow with ease of particle
      separation (r2=0.9912) and aerosol dispersion (r2= 0.9741). In vivo evaluations
      indicated that formulations exhibiting a higher in vitro dose delivery resulted
      in a greater reduction in pulmonary inflation pressure. CONCLUSIONS: These
      results integrate powder behavior at various levels and indicate that numerical
      descriptors of powder flow accurately predict dry powder aerosol dispersion. A
      proportionality between aerosol dispersion and pharmacodynamic effect was
      observed in preliminary in vivo evaluations, which demonstrates the potential of
      these techniques for correlation studies between in vitro powder properties and
      in vivo effect.

PMID- 10397602
TI  - Differences in crystallization behavior between quenched and ground amorphous
      ursodeoxycholic acid.
AB  - PURPOSE: To study the crystallization of ground and quenched ursodeoxycholic acid
      (UDCA) and to characterize their amorphous states. METHODS: Amorphous UDCA was
      prepared by grinding and also by rapid cooling of the melt. These samples were
      characterized by powder X-ray diffraction (XRD), near IR spectra and dynamic
      water sorption. The heat associated with crystallization was measured in an
      isothermal microcalorimeter at 25 degrees C at various relative humidities (RH)
      (50%-100%) and, in the presence of the vapour from a mixed solvent of ethanol and
      water (ethanol conc. 10%-100%). The specific surface area was calculated from
      krypton adsorption. Contact angles were measured by using a Wilhelmy plate to
      calculate the surface energy of the samples. RESULTS: Ground and quenched samples
      yielded amorphous XRD patterns. Differential scanning calorimetry thermographs of
      the milled sample revealed that crystallization occurred at around 80 degrees C,
      whereas the quenched sample did not crystallize. Exposure to humid air did not
      result in crystallization of either amorphous sample during the microcalorimetric
      experiments. In the presence of ethanol vapour, the ground sample did, but the
      quenched sample did not, crystallize. The amount of water sorption into the
      quenched sample was larger than that of the ground sample at low RH. The surface
      energy of the quenched material was different to that of the ground. Peak shifts
      were observed in the NIR spectra at around 1450, 2100 nm, allowing
      differentiation between the ground and quenched samples. CONCLUSIONS: It can be
      concluded that different molecular states of amorphous UDCA were obtained
      depending on the preparation method. The crystallisation of amorphous UDCA was
      related to the molecular state of disorder.

PMID- 10397603
TI  - Reduced UV-induced degradation of doxorubicin encapsulated in polyethyleneglycol
      coated liposomes.
AB  - PURPOSE: The aim of this study was to investigate the stability of doxorubicin
      encapsulated in polyethyleneglycol-coated liposomes (Doxil) under UV-A light.
      METHODS: High performance liquid chromatography and a fluorimetric method were
      used to quantify doxorubicin in bulk solution and doxorubicin in Doxil
      formulation. RESULTS: The photodegradation of Doxil was significantly lower in
      comparison to the photodegradation of the free drug and showed no concentration
      dependency at the measured concentration range of 5-50 microg/ml. During and
      after UV-A irradiation, there was no leakage of the drug from liposomes to the
      medium. After induced leakage of doxorubicin from the liposomes by the ionophore
      nigericin, the degradation kinetics of Doxil were identical to that of free
      doxorubicin. CONCLUSIONS: High intraliposomal doxorubicin concentration and
      intraliposomal acidic pH are the two critical factors that protect DXR in Doxil
      from UV-A degradation.

PMID- 10397604
TI  - pH and osmotic pressure inside biodegradable microspheres during erosion.
AB  - PURPOSE: To measure changes in pH as well as osmotic pressure in aqueous pores
      and cavities inside biodegradable microspheres made from polymers such as
      poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acid -co- glycolic acid) (PLGA).
      METHODS: The internal osmotic pressure inside eroding PLA microspheres was
      analyzed with differential scanning calorimetry (DSC) in a temperature range of
      10 to--25 degrees C. The osmotic pressure was calculated from the melting peaks
      of the aqueous phase using purity analysis. For pH determination, PLGA
      microspheres were loaded with a pH-sensitive spin probe which allowed the
      determination of pH by electron paramagnetic resonance (EPR). RESULTS: The
      osmotic pressure in PLA microspheres increased to 600 mOsm within four days and
      decreased to 400 mOsm after two weeks. The pH in PLGA microspheres in this study
      was < or =4.7. Basic drugs such as gentamicin free base or buffering additives
      led to a pH increase. In no case, however, did the internal pH exceed a value of
      6 within 13 hours. CONCLUSIONS: DSC and EPR are useful techniques to characterize
      the chemical microenvironment inside eroding microspheres. This data in
      combination with detailed information on peptide and protein stability could
      allow in the future to predict the stability of such compounds within degradable
      polymers.

PMID- 10397605
TI  - Cyclodextrins as diethylstilbestrol carrier system: characterization of
      diethylstilbestrol-cyclodextrins complexes.
AB  - PURPOSE: The in vitro formation of DES-cyclodextrins inclusion complexes was
      characterized using lipoxygenase as enzymatic system. METHODS: DES-cyclodextrins
      complexes were obtained in aqueous solution. RESULTS: The addition of
      cyclodextrins to the reaction medium had an inhibitory effect on DES oxidation by
      lipoxygenase due to the drug's complexation into the cyclodextrin cavity. This
      inhibitory effect depends on the complexation constant between DES and the
      cyclodextrins type used. In this case, beta-, 2-hydroxypropyl-beta- and gamma
      cyclodextrins have similar complexation constants and therefore produce the same
      inhibitory effect. Moreover, depending on the type of cyclodextrins used, the
      solubility of DES can be enhanced up to 956 times, while the lipoxygenase
      activity remains constant. CONCLUSIONS: These results suggest that the system
      described may be used as a controlled-release delivery system for DES, since it
      may diminish the local and systemic adverse side effects caused by high
      concentrations of the drug.

PMID- 10397606
TI  - Formulation and lyoprotection of poly(lactic acid-co-ethylene oxide)
      nanoparticles: influence on physical stability and in vitro cell uptake.
AB  - PURPOSE: To investigate the feasibility of producing freeze-dried poly(ethylene
      oxide) (PEO)-surface modified nanoparticles and to study their ability to avoid
      the mononuclear phagocytic system (MPS), as a function of the PEO chain length
      and surface density. METHODS: The nanoparticles were produced by the salting-out
      method using blends of poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acidco
      ethylene oxide) (PLA-PEO) copolymers. The nanoparticles were purified by cross
      flow filtration and freeze-dried as such or with variable amounts of trehalose as
      a lyoprotectant. The redispersibility of the particles was determined immediately
      after freeze-drying and after 12 months of storage at -25 degrees C. The uptake
      of the nanoparticles by human monocytes was studied in vitro by flow cytometry.
      RESULTS: PLA-PEO nanoparticles could be produced from all the polymeric blends
      used. Particle aggregation after freeze-drying was shown to be directly related
      to the presence of PEO. Whereas this problem could be circumvented by use of
      trehalose, subsequent aggregation was shown to occur during storage. These
      phenomena were possibly related to the specific thermal behaviours of PEO and
      trehalose. In cell studies, a clear relationship between the PEO content and the
      decrease of uptake was demonstrated. CONCLUSIONS: The rational design of freeze
      dried PEO-surface modified nanoparticles with potential MPS avoidance ability is
      feasible by using the polymer blends approach combined with appropriate
      lyoprotection and optimal storage conditions.

PMID- 10397607
TI  - Enzymatic degradation of epichlorohydrin crosslinked starch microspheres by alpha
      amylase.
AB  - PURPOSE: The influence of chemical parameters on the sensitivity to enzymatic
      degradation by alpha-amylase of starch microspheres cross-linked by
      epichlorohydrin was studied. METHODS: Starch microspheres were prepared using
      epichlorohydrin as a crosslinking agent. Their swelling degree, reflecting the
      number of glycerol diether bridges in the polymeric network, and the number of
      non-crosslinking monoglycerol ether groups corresponding to a side-reaction of
      epichlorohydrin with starch were determined. Degradation rates of the
      microspheres in presence of porcine alpha-amylase were determined by a
      microvolumetric method. RESULTS: Degradation by alpha-amylase was surface
      controlled and could be modulated by the introduction in the polymeric network
      of: (i) non-hydrolysable alpha-1,6 bonds related to the presence of amylopectin
      in the raw starch, (ii) glycerol diether and, (iii) monoether groups, all of
      these being likely to block the activity of alpha-amylase. In the case of highly
      cross-linked microspheres, the number of glycerol monoether pendent chains had a
      predominant effect on the degradation rate which ranged between 10(-2) and 10(-5)
      min(-1). CONCLUSIONS: It was possible to modulate simultaneously the swelling
      degree and the enzymatic degradability of starch microspheres by adjusting the
      chemical parameters during the crosslinking reaction.

PMID- 10397608
TI  - Polymers with thiol groups: a new generation of mucoadhesive polymers?
AB  - PURPOSE: To improve the mucoadhesive properties of polycarbophil by the
      introduction of sulfhydryl groups. METHODS: Mediated by a carbodiimide, cysteine
      was covalently bound to polycarbophil (PCP) forming amide bonds between the
      primary amino group of the amino acid and the carboxylic acid moieties of the
      polymer. The amount of covalently attached cysteine and the formation of
      disulfide bonds within the modified polymer were determined by quantifying the
      share of thiol groups on the polymer conjugates with Ellman's reagent. The
      adhesive properties of polycarbophil-cysteine conjugates were evaluated in vitro
      on excised porcine intestinal mucosa by determining the total work of adhesion
      (TWA). RESULTS: Depending on the weight-ratio of polycarbophil to cysteine at the
      coupling reaction, e.g., 16:1 and 2:1, 0.6+/-0.7 micromole and 5.3+/-2.4
      micromole cysteine, respectively, were covalently bound per g polymer. The
      modified polymer displayed improved internal cohesive properties due to the
      formation of interchain disulfide bonds within the polymer in aqueous solutions
      at pH-values above 5. Adhesion studies revealed strongly improved adhesive
      properties. Whereas the TWA was determined to be 104+/-21 microJ for the
      unmodified polymer, it was 191+/-47 microJ for the polymer-cysteine conjugate
      16:1 and 280+/-67 microJ for the polymer-cysteine conjugate 2:1. CONCLUSIONS:
      Polymers with thiol groups might represent a new generation of mucoadhesive
      polymers displaying comparatively stronger adhesive properties.

PMID- 10397609
TI  - Drug liposome partitioning as a tool for the prediction of human passive
      intestinal absorption.
AB  - PURPOSE: Appropriate physicochemical parameters are desired for the prediction of
      passive intestinal drug absorption during lead compound selection and drug
      development. METHODS: Liposome distribution coefficients measured titrimetrically
      and solubility data at pH 6.8 were used to characterize 21 structurally diverse
      ionizable drugs covering a range from <5% to almost complete absorption. RESULTS:
      A sigmoidal relationship was found between the percentage of human passive
      intestinal absorption and a new absorption potential parameter calculated from
      liposome distribution data and the solubility-dose ratio. In contrast, the human
      absorption data did not correlate with an octanol-based absorption potential or
      partitioning data alone. Poor correlations were found between liposome and
      octanol partitioning of ionic species or nonionic bases indicating the profound
      differences of the partitioning systems. CONCLUSIONS: Liposome distribution
      coefficients of ionizable drugs derived by a pH-metric titration were
      successfully used to calculate a parameter that correlates with the percentage of
      passive intestinal absorption in humans. Profound differences between liposome
      and octanol partitioning were found for a highly diverse set of species. This
      titration technique may serve to generate liposome partitioning data for the
      selection and optimization of lead compounds and in drug development.

PMID- 10397610
TI  - Synergistic effect of formulated plasmid and needle-free injection for genetic
      vaccines.
AB  - PURPOSE: A plasmid-based gene expression system was complexed with protective,
      interactive, and non-condensing (PINC) polymer system and administered with Medi
      Jector, a needle-free injection device (NFID), to achieve high and sustained
      levels of antigen-specific antibodies in blood circulation. METHODS: Human growth
      hormone (hGH) or bacterial beta-galactosidase gene expression plasmids driven by
      a cytomegalovirus (CMV) promoter were formulated in saline or complexed with a
      PINC polymer, polyvinylpyrrolidone (PVP), and intramuscularly or subcutaneously
      administered into dogs and pigs using a 22-gauge needle or a NFID. The hGH
      specific IgG titers in serum were measured by an ELISA. Beta-galactosidase
      expression was measured in injected muscles by an enzymatic assay or
      immunohistochemistry. The effect of NFID on DNA stability and topology was
      assessed by gel electrophoresis. RESULTS: Intramuscular (i.m.) or subcutaneous
      (s.c.) injection of a hGH expression plasmid pCMV-hGH (0.05-0.5 mg/kg) in dogs
      and pigs elicited antigen-specific IgG antibody titers to expressed hGH. With
      both routes of injection, pDNA delivery by a NFID was superior to pDNA injection
      by needle. The magnitude of hGH-specific IgG titers with NFID was 15-20-fold
      higher than needle injection when pDNA was complexed with PVP, and only 3-4-fold
      higher with pDNA in saline. The transfection efficiency in the injected muscle,
      as measured by beta-galactosidase expression, following i.m. injection of pCMV
      betagalactosidase/PVP, was not significantly different between needle and NFID
      injected groups. CONCLUSIONS: These data demonstrate that the combination of
      pDNA/ PVP complexes and a NFID act synergistically to achieve high and sustained
      levels of antigen-specific IgG response to expressed antigen. This gene delivery
      approach may offer advantage over needle injection of naked DNA for the
      development of genetic vaccines.

PMID- 10397611
TI  - Lipid association increases the potency against primary medulloblastoma cells and
      systemic exposure of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats.
AB  - PURPOSE: To reduce the systemic toxicity and prolong the systemic presence of 1
      (2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), a lipid-based drug carrier was
      designed and characterized. METHODS: The degree of CCNU association with lipid
      vesicles composed of 1, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2
      dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) (1:1, m/m) was characterized and
      the drug decomposition rates of lipid-drug complexes were monitored. Effects of
      lipid association on drug potency against medulloblastoma cells and total
      systemic drug exposure in rats were determined. RESULTS: At a CCNU:lipid molar
      ratio greater than 1:5, more than 90% of the drug was associated with the lipid
      vesicles. In aqueous suspensions, lipid association significantly reduced the
      first-order drug decomposition rate. In addition, lipid-associated CCNU exhibited
      a 4-fold increase in drug sensitivity with medulloblastoma cells. IC50 values for
      CCNU admixed and encapsulated with lipid vesicles were 18+/-4.9 and 14.0+/-2.2
      microM, respectively, compared to 83+/-11.0 microM for free CCNU. When
      administered to rats, lipid-associated CCNU increased the AUC (area under the
      concentration-time curve) of CCNU by approximately 2-fold (20.46+/-2.15 compared
      to 39.59+/-1.87 microg x min/ml), and the terminal half-life (t1/2beta) by almost
      9-fold (17+/-9 compared to 147+/-48 min) over free CCNU. Despite the increase in
      total systemic drug exposure, rats treated with lipid-associated CCNU exhibited a
      significantly lower frequency of acute neurotoxicity. CONCLUSIONS: These data
      indicate that CCNU associated with lipid vesicles may increase drug stability,
      potency, and systemic exposure in rats.

PMID- 10397612
TI  - Pravastatin, an HMG-CoA reductase inhibitor, is transported by rat organic anion
      transporting polypeptide, oatp2.
AB  - PURPOSE: We previously demonstrated the HMG-CoA reductase inhibitor, pravastatin,
      is actively taken up into isolated rat hepatocytes through multispecific organic
      anion transporters. The present study examined whether a newly cloned organic
      anion transporting polypeptide (oatp2) transports pravastatin. METHODS: We
      investigated functional expression of oatp2 in Xenopus laevis oocytes, to examine
      [14C] pravastatin uptake. RESULTS: [14C] Pravastatin (30 microM) uptake into
      oatp2 cRNA-injected oocytes was 40 times higher than that of water-injected
      control oocytes. The oatp2-mediated pravastatin uptake was Na+-independent and
      saturable. The Michaelis-Menten constant was 37.5+/-9.9 microM, a level
      comparable to that obtained in isolated rat hepatocytes in our previous study. As
      is the case with rat hepatocytes, the uptake of pravastatin (30 microM) was
      inhibited by 300 microM concentrations of taurocholate, cholate,
      bromosulfophthalein, estradiol-17beta-glucuronide, and simvastatin acid, but not
      by para-aminohippurate. On the other hand, [14C] simvastatin acid (30 microM)
      uptake of oatp2 cRNA-injected oocytes was not significantly different from that
      of water-injected oocytes. CONCLUSIONS: The cloned oatp2 was identified as the
      transporter responsible for the active hepatocellular pravastatin uptake.

PMID- 10397613
TI  - Effect of concentration and degree of saturation of topical fluocinonide
      formulations on in vitro membrane transport and in vivo availability on human
      skin.
AB  - PURPOSE: The thermodynamic activity of drugs in topical vehicles is considered to
      significantly influence topical delivery. In vitro diffusion across a synthetic
      membrane was shown to be correlated to the degree of saturation of the drug in
      the applied vehicle and therefore offers a potential for increased topical drug
      delivery. Fluocinonide a topical corticosteroid, was chosen as a model compound
      to investigate in vitro and in vivo availability from formulations with different
      degrees of saturation. METHODS: Sub-, as well as, supersaturated drug solutions
      were prepared using PVP as an antinucleant agent. In vitro membrane diffusion
      experiments across silicone membrane and in vivo pharmacodynamic activity
      assessments, using the human skin blanching assay, were carried out. RESULTS:
      Over the concentration range studied, the in vitro membrane transport of
      fluocinonide was proportional to the degree of saturation of the respective
      formulations. The in vivo pharmacodynamic response in the human skin blanching
      assay was related to the concentration of the drug in the vehicle irrespective of
      the degree of saturation. CONCLUSIONS: From the membrane permeation experiment it
      can be concluded, that the drug flux might be increased supra-proportionally with
      increasing donor concentration, drug (super-)saturation (proportional), beyond
      what would be anticipated based on ideal donor concentration and partition
      coefficient considerations only. These findings could not be confirmed in the in
      vivo investigation, probably due to additional vehicle effects (e.g.,
      enhancement, irritation, drug binding) which have to be expected and could have
      altered the integrity of the stratum corneum and therewith topical
      bioavailability of the drug.

PMID- 10397614
TI  - Interaction between two dicarboxylate endogenous substances, bilirubin and an
      uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, on human serum
      albumin.
AB  - PURPOSE: Two dicarboxylate endogenous substances, bilirubin (BR) and 3-carboxy-4
      methyl-5-propyl-2-furanpropanoic acid (CMPF), have a very high affinity to human
      serum albumin (HSA). This study was undertaken to clarify the existence of a
      dicarboxylate binding site on HSA. METHODS: Chemical modification, pH dependent
      binding and X-ray crystallographic analysis were performed to characterize these
      dicarboxylate binding sites. RESULTS: It was found the binding behavior for
      dicarboxylates was different from typical site I ligands such as warfarin (WF)
      and phenylbutazone (PB) and that electrostatic interaction was an important
      factor for their binding to HSA. Moreover, His residues were considered to play
      an important role in pH dependent binding of dicarboxylic acids but in a
      different manner from the site I ligands. X-ray crystallography of CMPF and BR
      revealed the distances between the two carboxyl groups in their chemical
      structures were 5.854 A and 9.979 A, respectively. This difference may be
      reflected in pH dependent binding. Using fluorescent probe displacement, we
      attempted to identify the binding site for monocarboxylate derivatives of CMPF
      and investigated the role of individual carboxyl group in the recognition of the
      binding site. The results suggested two carboxyl groups were important for the
      specific binding of CMPF to site I. CONCLUSIONS: The binding site for
      dicarboxylic acids is located in subdomain IIA, which includes site I, on the HSA
      molecule. Electrostatic interaction is an important driving force for binding to
      HSA.

PMID- 10397615
TI  - Relationship between etomidate plasma concentration and EEG effect in the rat.
AB  - PURPOSE: The effect-plasma concentration relationship of etomidate was studied in
      the rat using electroencephalographic changes as a pharmacodynamic parameter.
      METHODS: Etomidate was infused (50 mg/kg/h) in chronically instrumented rats
      (n=6) until isoelectric periods of 5 s or longer were observed in the
      electroencephalogram (EEG). The EEG was continuously recorded during the
      experiment and frequent arterial blood samples were taken for determination of
      etomidate plasma concentrations. The changes observed in the raw EEG signal were
      quantified using aperiodic analysis in the 2.5-7.5 Hz frequency band. The return
      of the righting reflex was used as another parameter of anesthesia. RESULTS: A
      mean dose of 8.58+/-0.41 mg/kg needed to be infused to reach the end point of 5 s
      isoelectric EEG. The plasma concentration time profiles were most adequately
      fitted using a three-exponential model. Systemic clearance, volume of
      distribution at steady-state and elimination half-life averaged 93+/-6 ml/min/kg,
      4.03+/-0.24 l/kg and 59.4+/-10.7 min respectively. The EEG effect-plasma
      concentration relationship was biphasic exhibiting profound hysteresis. Semi
      parametric minimization of this hysteresis revealed an equilibration half-life of
      2.65+/-0.15 min, and the biphasic effect-concentration relationship was
      characterized nonparametrically by descriptors. The effect-site concentration at
      the return of the righting reflex was 0.44+/-0.03 microg/ml. CONCLUSIONS: The
      results of the present study show that the concentration-effect relationship of
      etomidate can be characterized in individual rats using aperiodic analysis in the
      2.5-7.5 Hz frequency band of the EEG. This characterization can be very useful
      for studying the influence of diseases on the pharmacodynamics of etomidate in
      vivo.

PMID- 10397616
TI  - Venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats
      following intravenous administration of a novel supersaturated submicron lipid
      emulsion.
AB  - PURPOSE: To compare the venous irritation, pharmacokinetics, and tissue
      distribution of tirilazad in rats after intravenous administration of a submicron
      lipid emulsion with that of an aqueous solution. METHODS: Venous irritation was
      determined by microscopic evaluation of injury to the lateral tail veins of rats.
      Pharmacokinetic parameters were determined by following plasma concentrations of
      drug. Tissue distribution of [14C]-tirilazad was determined by quantitative whole
      body autoradiography. RESULTS: Single dose injections of tirilazad as an emulsion
      at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution
      was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not
      statistically different between the emulsion and the solution (p > 0.2) at doses
      of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6)
      (4-fold) and lower V(ss), (18-fold) and CL(5-fold) were observed for the lipid
      emulsion as compared to the solution (p < 0.05). Tissue distribution showed
      higher initial concentrations (two fold or more) in most tissues for the
      solution. These values, however, equilibrated by 4 h and AUC(0,4) differences
      were less than two fold in most tissues. CONCLUSIONS: Formulating tirilazad in
      the lipid emulsion significantly reduces the venous irritation without changing
      the pharmacokinetics and tissue distribution at low doses.

PMID- 10397617
TI  - Evaluation of truncated areas in the assessment of bioequivalence of immediate
      release formulations of drugs with long half-lives and of Cmax with different
      dissolution rates.
AB  - PURPOSE: To Evaluate truncated AUC in place of AUCt or extrapolated AUCinf, for
      drugs with long half-lives and to study the relationship between Cmax and in
      vitro dissolution rates. METHODS: Monte-Carlo simulations were conducted using
      actual mean plasma concentrations of five long half-life drug products. The
      simulations were based on a catenary pharmacokinetic system in which the drug
      disposition in the body was represented by a one-or two-compartment model,
      characterizing the observed mean profiles. The influence of dramatic changes in
      the in vitro dissolution rate constant 'kd', was simulated in scenarios
      consisting of 20 crossover trials with 24 subjects per trial, comparing a fast
      dissolving reference and a hypothetical, slow dissolving test formulation.
      RESULTS: The AUC's truncated after the completion of distribution phase were
      found surrogate to the AUCt or AUCinf measures. Except for Phenylbutazone, the
      Cmax measure was insensitive to the changes in the in vitro dissolution rate. The
      Cmax measure was found to be useful in the bioequivalence assessment since it
      reflected both the rate and extent of absorption. (Cmax/AUCt) measure was
      specific to absorption rate. CONCLUSIONS: For the bioequivalence determination of
      long half-life drug products, (1) the use of truncated AUC's after completion of
      the distribution phase instead of AUCinf, appears feasible. (2) Cmax measure may
      be insensitive to input rate changes, if the absorption rate is not constrained
      by the input rate in relation to the distribution or elimination rate. (3)
      (Cmax/AUCt) may be more specific to 'ka' differences, but Cmax reflects
      differences in both rate and extent of absorption.

PMID- 10397618
TI  - Prediction of pharmacokinetic parameters and the assessment of their variability
      in bioequivalence studies by artificial neural networks.
AB  - PURPOSE: The methodology of predicting the pharmacokinetic parameters (AUC, cmax,
      tmax) and the assessment of their variability in bioequivalence studies has been
      developed with the use of artificial neural networks. METHODS: The data sets
      included results of 3 distinct bioequivalence studies of oral verapamil products,
      involving a total of 98 subjects and 312 drug applications. The modeling process
      involved building feedforward/backpropagation neural networks. Models for
      pharmacokinetic parameter prediction were also used for the assessment of their
      variability and for detecting the most influential variables for selected
      pharmacokinetic parameters. Variables of input neurons based on logistic
      parameters of the bioequivalence study, clinical-biochemical parameters, and the
      physical examination of individuals. RESULTS: The average absolute prediction
      errors of the neural networks for AUC, cmax, and tmax prediction were: 30.54%,
      39.56% and 30.74%, respectively. A sensitivity analysis demonstrated that for
      verapamil the three most influential variables assigned to input neurons were:
      total protein concentration, aspartate aminotransferase (AST) levels, and heart
      rate for AUC, AST levels, total proteins and alanine aminotransferase (ALT)
      levels, for cmax, and the presence of food, blood pressure, and body-frame for
      tmax. CONCLUSIONS: The developed methodology could supply inclusion or exclusion
      criteria for subjects to be included in bioequivalence studies.

PMID- 10397619
TI  - Dipeptide derivatives of primaquine as transmission-blocking antimalarials:
      effect of aliphatic side-chain acylation on the gametocytocidal activity and on
      the formation of carboxyprimaquine in rat liver homogenates.
AB  - PURPOSE: Dipeptide derivatives of primaquine (PQ) with reduced oxidative
      deamination to the inactive metabolite carboxyprimaquine were synthesized and
      evaluated as a novel class of transmission-blocking antimalarials. METHODS;
      Antimalarial activity was studied using a model consisting of mefloquine
      resistant Plasmodium berghei ANKA 25R/10, Balb C mice, and Anopheles stephensi
      mosquitoes. Metabolic studies were performed with rat liver homogenates, and the
      incubates were analyzed by HPLC. RESULTS: All dipeptide derivatives and glycyl-PQ
      completely inhibited the appearance of oocysts in the midguts of the mosquitoes
      at 15 mg/ kg, while N-acetylprimaquine was not active at this dose. However, none
      of the title compounds were able to block oocyst production at 3.75 mg/kg, in
      contrast with primaquine. Exception for sarc-gly-PQ, all remaining compounds
      prevented sporozoite formation in the salivary glands of mosquitoes at a dose of
      3.75 mg/kg. Simultaneous hydrolysis to primaquine and gly-PQ ocurred with the
      following order of Vmax/Km: for primaquine formation. L-ala-gly-PQ > L-phe-gly-PQ
      > gly-gly-PQ; and for gly-PQ formation, L-phe-gly-PQ > L-ala-gly-PQ > gly-gly-PQ.
      In contrast, primaquine was not released from D-phe-gly-PQ, sarc-gly-PQ, and N
      acetylprimaquine. Neither carboxyprimaquine nor 8-amino-6-methoxyquinoline were
      detected in any of the incubation mixtures. CONCLUSIONS: The title compounds
      prevent the development of the sporogonic cycle of Plasmodium berghei.
      Gametocytocidal activity is independent of the rate and pathway of primaquine
      formation. Acylation of the aliphatic side-chain effectively prevents the
      formation of carboxyprimaquine, but the presence of a terminal amino group
      appears to be essential for the gametocytocidal activity.

PMID- 10397620
TI  - NO donor and biological properties of different benzofuroxans.
AB  - PURPOSE: To investigate the effect of benzofusion on NO donor properties and
      related biological activities of the furoxan system. The biological properties
      considered were the ability to increase the cytosolic levels of cGMP in C6 cells
      and vasodilation. METHODS: NO donor properties were investigated either in the
      presence or the absence of cysteine by using the Griess reaction,
      chemiluminescence, and gas chromatography. Increase of cytosolic cGMP levels were
      evaluated by radioimmunoassay. Vasodilating activity was assessed on rat aorta
      strips precontracted with noradrenaline, in the presence and the absence of
      oxyhemoglobin (HbO2) and methylene blue (MB), respectively. RESULTS: Benzofuroxan
      and its methyl and cyano derivatives were unable to release NO under the
      experimental conditions. Generally these compounds displayed feeble vasodilating
      properties and were able to weakly stimulate soluble guanylate cyclase (sGC). By
      contrast, benzodifuroxan and benzotrifuroxan were able to produce both NO* and
      its reduced form NO- , the nitroxyl anion. They displayed potent vasodilating
      properties and were able to increase cytosolic levels of cGMP in a concentration
      dependent manner. CONCLUSIONS: The simple benzofuroxans considered here are
      devoid of the capability to release NO, they weakly stimulate sGC as well as
      manifest feeble vasodilating properties by a mechanism that does not involve a
      thiol-induced NO production. By contrast, benzodifuroxan and benzotrifuroxan
      behave as typical NO donor furoxans.

PMID- 10397621
TI  - Soft drugs based on hydrocortisone: the inactive metabolite approach and its
      application to steroidal antiinflammatory agents.
AB  - PURPOSE: The soft drug approach was applied to the design of analogs of highly
      potent synthetic steroids but with a metabolically labile ester group which at
      the same time served as an activating group. METHODS: Several structural
      modifications of soft antiinflammatory steroids were synthesized and tested in
      several assays of biological activity. The hydrolytic stability of the compounds
      was also determined. RESULTS: One of the compounds synthesized was determined to
      be a very potent steroid and had a highly significant separation of topical from
      systemic activity. However, the compound demonstrated greater than expected
      stability in the hydrolysis studies. CONCLUSIONS: The goal of the soft drug
      approach has been achieved with the development of a highly potent drug which
      displays little or no systemic activity as measured in the tests presented here.
      The anticipated hydrolytic instability of the compounds was not corroborated;
      however, in view of other results, the interpretation is allowed that the rapid
      hydrolysis of the unbound fraction of the drug is an important factor in its lack
      of systemic effects.

PMID- 10397622
TI  - Use of 1-methyl-pyrrolidone as a solubilizing agent for determining the uptake of
      poorly soluble drugs.

PMID- 10397624
TI  - The validation of the Psychological Maltreatment of Women Inventory.
AB  - To evaluate the validity of the Psychological Maltreatment of Women Inventory
      (PMWI), 100 women were interviewed. Both PMWI subscales (dominance/isolation and
      emotional/verbal) successfully discriminated among three groups: physically
      abused women (BW) scored significantly higher than both relationship
      distressed/nonabused (RD) and relationship satisfied/nonabused women (RS). Both
      subscales of the PMWI were highly correlated with the nonphysical abuse subscale
      of the Index of Spouse Abuse (ISA). A 14-item short version of the PMWI also
      successfully discriminated between the BW and RD groups. When the battered women
      were divided into service seeking (SB) and nonservice seeking battered women
      (CB), a more complex picture emerged. The SB group scored significantly higher
      than the RD and RS group on all PMWI long and short subscales. However, the CB
      group differed from the RD group only on the short dominance/isolation subscale.

PMID- 10397623
TI  - Psychological abuse: a variable deserving critical attention in domestic
      violence.
AB  - Policy makers and researchers give psychological abuse considerably less
      attention than physical abuse in the partner abuse area. One reason for the
      relative neglect of psychological abuse is that there are difficulties in
      arriving at a common definition of psychological abuse that might be useful to
      both the mental health and legal professions. Another reason for the relative
      neglect of psychological abuse has been an implicit assumption that physical
      abuse exacts a greater psychological toll on victims than does psychological
      abuse. At the extreme level of physical abuse, this assumption seems defensible,
      but at levels of physical aggression that are most common in marriage and long
      term relationships, psychological abuse appears to have as great an impact as
      physical abuse. Even direct ratings of psychological and physical abuse by women
      in physically abusive relationships indicate that psychological abuse has a
      greater adverse effect on them than physical abuse. Retrospective reports,
      longitudinal research, and treatment dropout research all provide evidence that
      psychological abuse can exact a negative effect on relationships that is as great
      as that of physical abuse. Finally, psychological abuse almost always precedes
      physical abuse, so that prevention and treatment efforts clearly need to address
      psychological abuse. Eight measures of various forms of psychological abuse that
      have reasonable psychometric properties and considerable construct validity are
      reviewed and a definition of psychological abuse in intimate relations is
      provided.

PMID- 10397625
TI  - Measuring emotional abuse in dating relationships as a multifactorial construct.
AB  - Initial investigations of a multifactorial approach to the measurement of
      emotional abuse in dating relationships are presented. A set of 54 items was
      generated to assess 4 rationally derived subscales measuring Restrictive
      Engulfment, Hostile Withdrawal, Denigration, and Dominance/Intimidation. An
      exploratory factor analysis on reports of partner behavior by 157 female
      undergraduate students in dating relationships provided support for the
      hypothesized subscales. Denigration and Dominance/Intimidation had consistently
      higher correlations with physical aggression than did the other two forms of
      emotional abuse. Further evidence for discriminant and convergent validity was
      apparent in correlations with the circumplex scales of the Inventory of
      Interpersonal Problems, and with self-reported attachment variables. The results
      support the assessment of emotional abuse in dating relationships as a
      multifactorial construct.

PMID- 10397626
TI  - Psychological abuse: implications for adjustment and commitment to leave violent
      partners.
AB  - The contribution of psychological abuse, beyond that of physical abuse, to
      battered women's psychological adjustment and their intentions to terminate their
      abusive relationships was examined. Sixty-eight battered women residing in
      shelters for battered women provided information on their: (1) physical and
      psychological abuse; (2) psychological symptomatology; (3) strategies for coping
      with and perceptions of control over partner violence; and (4) intentions to
      return to their abusive partners. Multiple regression analyses indicated that
      frequency and severity of physical abuse was not a significant predictor of
      posttraumatic stress disorder (PTSD) symptomatology nor of women's intentions to
      terminate their abusive relationships. However, psychological abuse was a
      significant predictor of both PTSD symptomatology and intentions to permanently
      leave abusive partners even after controlling for the effects of physical abuse.
      PTSD symptomatology moderated the relationship between psychological abuse and
      intentions to terminate the abusive relationships: resolve to leave the abusive
      partner as a function of level of psychological abuse was significant only among
      women characterized by low levels of PTSD symptomatology. Greater use of emotion
      focused coping strategies, absolutely and relative to problem-focused coping, had
      direct effects on PTSD symptomatology. However, neither coping nor perceptions of
      control moderated the effects of psychological abuse on psychological adjustment.
      The results of the investigation suggested that psychological abuse and ensuing
      PTSD symptomatology are important variables to assess among physically battered
      women.

PMID- 10397627
TI  - Effects of men's subtle and overt psychological abuse on low-income women.
AB  - A social influence approach to the psychological abuse of women (Marshall, 1994;
      1996) was expanded and tested. Distinctions are made between obvious acts (e.g.,
      verbal aggression, controlling behaviors), overt acts which are easily recognized
      and described, and subtle acts which are least likely to be recognized as
      psychologically abusive. Men's violence and sexual aggression, and overt
      (dominating acts, indifference, monitoring, discrediting) and subtle
      (undermining, discounting, isolating) psychological abuse were examined as they
      related to women's psychological and emotional state and perceptions of their
      relationship. Results of regression equations with 834 low-income women in long
      term heterosexual relationships are reported. In general, subtle psychological
      abuse had stronger and more consistent associations with women's state and
      relationship perceptions than did their partners' overt psychological abuse,
      violence, or sexual aggression. The importance of extending research beyond
      obvious acts was underscored by findings showing that subtle psychological abuse
      accounted for a small but significant proportion of the variance in outcome
      variables even after the effects of violence and sexual aggression (Step 1) and
      overt psychological abuse (Step 2) were controlled in eight of the nine
      regression equations. In contrast, when subtle and overt psychological abuse were
      entered first (in Steps 1 and 2, respectively), violence and sexual aggression
      (Step 3) made significant contributions in only two of the nine equations.

PMID- 10397628
TI  - Court-involved battered women's responses to violence: the role of psychological,
      physical, and sexual abuse.
AB  - Failure to understand the importance of psychological abuse as a component of
      domestic violence can result in little appreciation for the complexity of
      victims' experience and thus a failure to provide the most effective
      intervention. This study examined the role of psychological abuse, physical
      violence, injury, and sexual abuse in predicting court-involved women's (1) prior
      attempts to seek help from the justice system and to leave the battering
      relationship, (2) use of criminal prosecution and civil protection orders, and
      (3) traumatic stress reactions. At the univariate level, each abuse variable was
      significantly associated with at least one strategic response and all traumatic
      responses to violence. Multivariate analyses revealed that strategic responses
      were largely predicted by injury and physical assault, whereas traumatic
      responses were mainly predicted by psychological abuse. Taken together, these
      findings demonstrate the important role of both physical and psychological abuse
      in shaping women's responses to domestic violence.

PMID- 10397629
TI  - The impact of different forms of psychological abuse on battered women.
AB  - Battered women receiving either shelter (n = 30) or nonshelter services (n = 30)
      from a domestic violence agency were interviewed regarding psychological abuse
      and its aftermath. Four types of abuse were derived from factor analysis:
      ridiculing of traits, criticizing behavior, ignoring, and jealous control.
      Sheltered women experienced ridicule and jealous/control more often than
      nonsheltered women. For the entire sample, ridiculing of traits was rated as the
      most severe form. Ignoring was the strongest predictor of low self-esteem. Both
      psychological abuse and physical abuse contributed independently to depression
      and low self-esteem. However, fear of being abused was uniquely predicted by
      psychological abuse. Implications for practice and research are discussed.

PMID- 10397630
TI  - Differential effects of Bcl-2 overexpression on hippocampal CA1 neurons and
      dentate granule cells following hypoxic ischemia in adult mice.
AB  - In contrast to its known anti-apoptotic activity in sympathetic neurons, immortal
      neuronal cell lines, and primary cultured immature neurons of the central nervous
      system (CNS), the role of Bcl-2 in CNS neurons in the adult brain is poorly
      understood. In the present study, we examined effects of overexpression of Bcl-2
      on selective neuronal death of the hippocampal CA1 neurons and the dentate
      granule cells induced by hypoxic ischemia in adult transgenic mice overexpressing
      human Bcl-2 under the control of neuron-specific enolase (NSE-hbcl-2). At the
      light microscopic level, numbers of TUNEL-positive cells with pyknotic nuclei
      were observed in the CA1 subfield of NSE-hbcl-2 transgenic mice, as well as that
      of wild-type mice, after hypoxic ischemic insult, although the onset of neuronal
      death was apparently delayed in NSE-hbcl-2 transgenic mice. The electron
      microscopic studies showed that morphological changes of the degenerating CA1
      neurons from both groups were clearly distinct from ordinary apoptosis. In
      contrast, a significant amount of degenerating dentate granule cells from wild
      type but not from transgenic mice had typical apoptotic nuclei by the treatment.
      The activation of caspase-3 was detected in the dentate granule cells but not
      that of the CA1 neurons. These results indicate that the overexpression of Bcl-2
      effectively suppressed dentate granule cell apoptosis but only delayed cell death
      of the CA1 neurons induced by hypoxic ischemia, suggesting the occurrence of a
      non-apoptotic, caspase-3-independent mechanism for neuronal death in the CA1
      subfield.

PMID- 10397631
TI  - Conserved and divergent expression patterns of the proteolipid protein gene
      family in the amphibian central nervous system.
AB  - The recent discovery of a proteolipid protein gene family has revealed that its
      members are in fact widely distributed and are not exclusively associated with
      myelination. To date, three different gene products, DMalpha/DM-20/PLP,
      DMbeta/M6a, and DMgamma/M6b, have been isolated from certain primitive fish
      species, mouse, and human central nervous system (CNS). We cloned Xenopus laevis
      orthologues of DMbeta/M6a and DMgamma/M6b and investigated the expression
      patterns of these gene transcripts as well as that of PLP in developing Xenopus
      CNS. As is the case in shark and mouse, the mRNA encoding the major myelin
      integral protein, PLP, is first detected at stage 42/43 in tadpoles and is
      exclusively found in morphologically recognizable oligodendrocytes throughout the
      brain, while DMbeta mRNA is solely expressed in young presumptive neurons in the
      gray matter. There exist two distinct DMgamma mRNAs and, in contrast to these
      evolutionarily conserved expression patterns, DMgamma mRNAs distribute uniquely
      within the ventricular zone in young tadpoles (stage 25) through maturity.
      Furthermore, both DMbeta and DMgamma are expressed in the developing retina, and
      their distributions are different from one other. In Xenopus CNS, therefore, the
      expression patterns of three proteolipid proteins, PLP, DMbeta, and DMgamma, are
      distinct from each other, implying very different roles for their protein
      products within the cell populations in which they are expressed.

PMID- 10397632
TI  - Mice with disrupted midsized and heavy neurofilament genes lack axonal
      neurofilaments but have unaltered numbers of axonal microtubules.
AB  - Mammalian neurofilaments are assembled from the light (NF-L), midsized (NF-M),
      and heavy (NF-H) neurofilament proteins. While NF-M and NF-H cannot self-assemble
      into homopolymers, the data concerning NF-L has been more contradictory. In vitro
      bovine, porcine, and murine NF-L can homopolymerize in the absence of other
      subunits. However, in vivo studies suggest that neither rat nor mouse NF-L can
      form filaments when transfected alone into cells lacking endogenous intermediate
      filaments. By contrast, human NF-L forms homopolymers in similar cell lines.
      Recently we generated mice with null mutations in the NF-M and NF-H genes. To
      determine if mouse NF-L can homopolymerize in mouse axons, NF-M and NF-H null
      mutants were bred to create a line of double mutant animals. Here we show that
      axons in NF-M/H double mutant animals are largely devoid of 10-nm filaments.
      Instead, the axoplasm is transformed to a microtubule-based cytoskeleton-although
      the lack of any increase in tubulin levels per unit length of nerve or of
      increases in microtubule numbers relative to myelin sheath thickness argues that
      microtubules are not increased in response to the loss of neurofilaments. Thus in
      vivo rodent neurofilaments are obligate heteropolymers requiring NF-L plus either
      NF-M or NF-H to form a filamentous network.

PMID- 10397633
TI  - Expression and translocation of protein kinase C isoforms in rat microglial and
      astroglial cultures.
AB  - Cellular distribution and activation by phorbol myristate acetate (PMA) of
      classical (alpha, betaI, betaII,gamma), novel (delta, epsilon, theta, eta), and
      atypical (zeta, iota) protein kinase C (PKC) isoforms were studied in cultured
      rat neonatal microglial and astroglial cells by Western blot analysis. Among the
      classical isoforms, only betaII was expressed in microglia and astrocytes in the
      same abundance. The expression of betaI in microglia was less abundant, while
      PKCalpha was not detectable in this cell type. PKCgamma was absent in both cell
      populations. A different pattern of expression was also found for novel and
      atypical isoenzymes: Both cell types expressed delta, theta, eta, zeta, and iota
      isoforms, but PKCepsilon was absent in microglia and the expression of PKCzeta
      and PKCiota in these cells was low compared to astrocytes. The pattern of PKC
      distribution in cytosolic and particulate fractions as well as activation by
      short (10 min) and prolonged (4 hr) PMA treatment in both cell types were
      similar. On the whole, in comparison with astrocytes, PKC in microglial cells was
      less expressed, both in terms of number of isoforms and level of expression. The
      microglial profile of PKC isoforms differed from that of rat peritoneal
      macrophages, which did express PKCalpha. Preliminary evidence suggests that the
      ability of PMA to enhance cyclic AMP responses in astrocytes, but not in
      microglia, is related to the different pattern of expression of PKCalpha and
      PKCepsilon in the two cell types.

PMID- 10397634
TI  - Sodium channel expression in NGF-overexpressing transgenic mice.
AB  - Dorsal root ganglion (DRG) neurons depend on nerve growth factor (NGF) for
      survival during development, and for the maintenance of phenotypic expression of
      neuropeptides in the adult. NGF also plays a role in the regulation of expression
      of functional sodium channels in both PC12 cells and DRG neurons. Transgenic mice
      that overexpress NGF under the keratin promoter (hyper-NGF mice) show increased
      levels of NGF in the skin from embryonic day 11 through adulthood, hypertrophy of
      the peripheral nervous system and mechanical hyperalgesia. We show here that mRNA
      levels for specific sodium channel isotypes are greater in small (< 30 microm
      diameter) DRG neurons from hyper-NGF mice compared to wild-type mice.
      Hybridization signals for sodium channel subunits alphaII and beta2 displayed the
      most substantial enhancement in hyper-NGF mice, compared to wild-type mice DRG,
      and mRNA levels for alphaI, NaG, Na6, SNS/PN3, NaN, and beta1 were also greater
      in hyper-NGF DRG. In contrast, the levels of alphaII and PN1 mRNAs were similar
      in neurons from hyper-NGF and wild-type DRG. Whole-cell patch-clamp studies
      showed no significant differences in the peak sodium current densities in hyper
      NGF vs. wild-type DRG neurons. These data demonstrate that DRG neurons in wild
      type mice have a heterogeneous pattern of sodium channel expression, which is
      similar to that previously described in rat, and suggest that transcripts of
      some, but not all, sodium channel mRNAs can be modulated by long-term
      overexpression of NGF.

PMID- 10397635
TI  - 2-Deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative
      injury: evidence for the involvement of stress proteins.
AB  - Food restriction can extend life span in rodents and was recently reported to
      increase the resistance of neurons in the brain to excitotoxic and metabolic
      insults. In principle, administration to ad libitum fed rodents of an agent that
      reduces glucose availability to cells should mimick certain aspects of food
      restriction. We now report that administration of 2-deoxy-D-glucose (2DG), a non
      metabolizable analog of glucose, to adult rats results in a highly significant
      reduction in seizure-induced spatial memory deficits and hippocampal neuron loss.
      Pretreatment of rat hippocampal cell cultures with 2DG decreases the
      vulnerability of neurons to excitotoxic (glutamate) and oxidative (Fe2+) insults.
      The protective action of 2DG is associated with decreased levels of cellular
      oxidative stress and enhanced calcium homeostasis. 2DG treatment increased levels
      of the stress-responsive proteins GRP78 and HSP70 in hippocampal neurons, without
      affecting levels of Bcl-2 or GRP75, suggesting that mild reductions in glucose
      availability can increase neuronal resistance to oxidative and metabolic insults
      by a mechanism involving induction of stress proteins. Our findings establish
      cell culture and in vivo models of "chemical food restriction" which may prove
      useful in elucidating mechanisms of neuroprotection and in developing preventive
      approaches for neurodegenerative disorders that involve oxidative stress and
      excitotoxicity.

PMID- 10397636
TI  - Identification of PSF, the polypyrimidine tract-binding protein-associated
      splicing factor, as a developmentally regulated neuronal protein.
AB  - The polypyrimidine tract-binding protein-associated splicing factor (PSF), which
      plays an essential role in mammalian spliceosomes, has been found to be expressed
      by differentiating neurons in developing mouse brain. The sequence of a fragment
      of mouse PSF was found to be remarkably similar to that of human PSF. Both the
      expression of PSF mRNA in cortex and cerebellum and PSF immunoreactivity in all
      brain areas were high during embryonic and early postnatal life and almost
      disappeared in adult tissue, except in the hippocampus and olfactory bulb where
      various neuronal populations remained PSF-immunopositive. Double-labeling
      experiments with anti-PSF antibody and anti-neurofilaments or anti-glial
      fibrillary acidic protein antibodies on sections of cortex, hippocampus, and
      cerebellum indicate that PSF is expressed by differentiating neurons but not by
      astrocytic cells. In vitro, mouse PSF was found to be expressed by
      differentiating cortical and cerebellar neurons. Radial glia or astrocyte nuclei
      were not immunopositive; however, oligodendrocytes differentiating in vitro were
      found to express PSF. The restricted expression of PSF suggests that this
      splicing factor could be involved in the control of neuronal-specific splicing
      events occurring at particular stages of neuronal differentiation and maturation.

PMID- 10397637
TI  - In vivo actions of fibroblast growth factor-2 and insulin-like growth factor-I on
      oligodendrocyte development and myelination in the central nervous system.
AB  - The in vivo effects of fibroblast growth factor-2 (FGF-2) and insulin-like growth
      factor-I (IGF-I) on oligodendrocytes and CNS myelination were determined in the
      postnatal rat anterior medullary velum (AMV) following injection of both
      cytokines into the cerebrospinal fluid. Either FGF-2, IGF-I, or saline were
      administered via the lateral ventricle, twice daily commencing at postnatal day
      (P) 6. At P9, AMV were immunohistochemically labeled with the Rip antibody, to
      enable analysis of the numbers of myelin sheaths and of promyelinating and
      myelinating oligodendrocytes; promyelinating oligodendrocytes are a recognisable
      immature phenotype which express myelin-related proteins prior to forming myelin
      sheaths. In parallel experiments, AMV were treated for Western blot analysis to
      determine relative changes in expression of the myelin proteins 2', 3'-cyclic
      nucleotide 3'-phosphohydrolase (CNP) and myelin oligodendrocyte glycoprotein
      (MOG), which, respectively, characterise early and late stages of myelin
      maturation. In FGF-2-treated AMV, the number of promyelinating oligodendrocytes
      increased by 87% compared to saline-injected controls. The numbers of myelinating
      oligodendrocytes and myelin sheaths were not decreased, but conspicuous
      unmyelinated gaps within fibre tracts were indications of retarded myelination
      following FGF-2 treatment. Western blot analysis demonstrated decreased
      expression of CNP and a near-total loss of MOG, confirming that FGF-2 decreased
      myelin maturation. In contrast, IGF-I had no effect on the number of
      promyelinating oligodendrocytes, but increased the numbers of myelinating
      oligodendrocytes and myelin sheaths by 100% and 93%, respectively. Western blot
      analysis showed that the amount of CNP was increased following IGF-I treatment,
      correlating with the greater number of oligodendrocytes, but that MOG expression
      was lower than in controls, suggesting that the increased number of myelin
      sheaths in IGF-I was not matched by increased myelin maturation. The results
      provide in vivo evidence that FGF-2 and IGF-I control the numbers of
      oligodendrocytes in the brain and, respectively, retard and promote myelination.

PMID- 10397638
TI  - Two distinct mechanisms are involved in 6-hydroxydopamine- and MPP+-induced
      dopaminergic neuronal cell death: role of caspases, ROS, and JNK.
AB  - In this study, we examined the possibility that MPTP and 6-hydroxydopamine (6
      OHDA) act on distinct cell death pathways in a murine dopaminergic neuronal cell
      line, MN9D. First, we found that cells treated with 6-OHDA accompanied
      ultrastructural changes typical of apoptosis, whereas MPP+ treatment induced
      necrotic manifestations. Proteolytic cleavage of poly-(ADP-ribose)polymerase by
      caspase was induced by 6-OHDA, whereas it remained uncleaved up to 32 h after
      MPP+ treatment and subsequently disappeared. Accordingly, 6-OHDA- but not MPP(+)
      induced cell death was significantly attenuated in the presence of a broad
      spectrum caspase inhibitor, N-benzyloxy-carbonyl-Val-Ala-Asp-fluomethylketone (Z
      VAD-fmk). As measured by fluorometric probes, the level of reactive oxygen
      species (ROS) significantly increased after 6-OHDA treatment. In contrast, the
      level of dihydroethidium-sensitive ROS following MPP+ treatment remained
      unchanged while a slight increase in dichlorofluorescin-sentive ROS was
      temporarily observed. As demonstrated by immunoblot analysis, the level of
      superoxide dismutase was down-regulated following 6-OHDA treatment, whereas it
      remained unchanged after MPP+ treatment. Cotreatment of cells with antioxidants
      such as N-acetylcysteine or Mn(III)tetrakis(4-benzoic acid)porphyrin chloride
      (MnTBAP, cell-permeable superoxide dismutase mimetic) rescued 6-OHDA- but not
      MPP(+)-induced cell death, whereas inclusion of catalase or N(G)-nitro-L-arginine
      had no effect in both cases. In addition, 6-OHDA induced ROS-mediated c-Jun N
      terminal kinase (JNK) activation that was attenuated in the presence of N
      acetylcysteine or MnTBAP but not catalase or Z-VAD-fmk. In contrast, MPP+ has
      little effect on JNK activity, indicating that ROS and/or ROS-induced cell death
      signaling pathway seems to play an essential role in 6-OHDA-mediated apoptosis
      but not in MPP(+)-induced necrosis in a mesencephalon-derived, dopaminergic
      neuronal cell line.

PMID- 10397639
TI  - Effects of the conformationally restricted GABA analogues, cis- and trans-4
      aminocrotonic acid, on GABA neurotransmission in primary neuronal cultures.
AB  - The effects of the GABA analogues, cis- and trans-4-aminocrotonic acid (ACA) on
      GABA(A) receptor function and GABA uptake, together with the presence of p-1
      subunit mRNA and putative GABAc receptors, were studied in primary cultures of
      neocortical neurons and cerebellar granule cells. Both isomers induced a Cl-
      influx, which was inhibited by bicuculline, t-butylbicyclophosphorothionate
      (TBPS), picrotoxinin (PTX), and gamma-hexachlorocyclohexane (gamma-HCH or
      lindane). [3H]-flunitrazepam binding was also increased by both isomers and this
      increase was inhibited by bicuculline. In neocortical neurons, the transisomer
      completely inhibited the [3H]GABA uptake, whereas the cis-isomer produced only a
      25% inhibition at the highest concentration used. The possible presence of GABAc
      receptors was investigated only in neocortical cultures by using RT-PCR in order
      to detect the presence of the mRNA encoding the p-1 subunit which assembles to
      form homooligomeric Cl-channels. The results presented here show that p-1
      subunits, and thus GABAc receptors, may represent a very minor population of GABA
      receptors in these neuronal preparations. We conclude that both GABA analogues
      may act as agonists at the GABA(A) receptors, although with very different
      potencies.

PMID- 10397640
TI  - Long-term variations in cyclic light intensity and dietary vitamin A intake
      modulate lipofuscin content of the retinal pigment epithelium.
AB  - Experiments were conducted to determine whether the intensity of cyclic light
      exposure to the retina over a long period of time affects retinoid-dependent
      accumulation of lipofuscin in the retinal pigment epithelium (RPE). Albino rats
      were maintained from weaning on diets either containing (+A) or lacking (-A)
      retinyl palmitate, which can be metabolized to the retinoids involved in the
      visual cycle. Animals in each dietary group were divided between bright (L) and
      dim (D) cyclic light treatments. Thus, the experiments employed the following
      four treatment groups: +A/D, +A/L, -A/D, and -A/L. After 6, 12, and 15 months
      from the start of the treatments, animals in each group were killed for
      quantitative determination of: 1) retinal photoreceptor densities; 2) RPE
      lipofuscin content; and 3) RPE lipofuscin fluorescence intensity. Animals in the
      L groups had a lower volume of RPE lipofuscin than those in the D groups fed the
      same diet. Among the -A rats, this reduced lipofuscin volume could be attributed
      to a light-enhanced depletion of vitamin A from the retina and an accompanying
      loss of photoreceptor cells. In the +A animals, however, there were no
      differences in photoreceptor densities between the D and L groups. In the -A
      rats, the volume of RPE lipofuscin decreased between 6 and 15 months of age,
      whereas it increased in the +A animals. In contrast, lipofuscin fluorescence
      intensity increased between 6 and 15 months of age in all four treatment groups.
      However, in the +A rats, the fluorescence intensity was lower in the L than in
      the D group at all three ages. In the -A groups, light level had no effect on
      lipofuscin fluorescence intensity. At all three ages, fluorescence intensity was
      lower in the -A animals than in +A rats. Thus, at light intensities below those
      that induce acute retinal degeneration, long-term exposure to higher intensity
      light inhibits the age-related increase in RPE lipofuscin volume. A decrease in
      the volume of RPE lipofuscin after the retina is depleted of vitamin A suggests
      that lipofuscin is turned over, and that RPE lipofuscin content is determined by
      a balance between the rates at which lipofuscin is formed and at which it is
      eliminated from the RPE. An age-related increase in lipofuscin-specific
      fluorescence intensity after vitamin A depletion from the retina suggests that
      lipofuscin fluorophores may continue to form slowly from retinoids that have been
      modified such that they can no longer enter the visual cycle.

PMID- 10397641
TI  - Embryonic raphe neurons grafted in vitro on fetal spinal cord slices recognize
      specific target areas.
AB  - To investigate the characteristics of neurotropic signaling involved in specific
      target recognition by grafted embryonic serotonergic cells, we have developed an
      in vitro grafting model. Specific raphe nuclei (B1/B2 and B3) were respectively
      dissected from 14-day-old rat embryos, and partially dissociated cells were
      cocultured on spinal cord slices from 20-day-old fetuses. After serotonin
      immunodetection, neurite growth patterns were analyzed by standard photonic or
      confocal scanning microscopy. Computer reconstruction (maximal signal projection)
      was used to track individual neurites in spite of their changing depth levels.
      Whereas the direction and branching of the initial neurite segments did not seem
      to be significantly influenced by any specific environment, specific growth
      patterns were developed at some distance from the cell bodies, indicating that
      neurites are able to recognize their specific targets.

PMID- 10397642
TI  - Estrogen and progesterone stimulate Schwann cell proliferation in a sex- and age
      dependent manner.
AB  - The effects of estrogen and progesterone on Schwann cell proliferation were
      studied in cultured segments of the rat sciatic nerve from adult male, female,
      and newborn rats, by measurement of [3H thymidine incorporation or bromo-deoxy
      uridine- (BrdU)-labelling and immunocytochemistry. Estrogen (100 nM-500 nM)
      enhanced [3H] thymidine incorporation in segments from male and newborn rats,
      while it had no effect on segments from female rats. Progesterone stimulated
      thymidine incorporation in segments from female and newborn rats (100 nM-500 nM),
      but caused only a small proliferative response in Schwann cells from male rats at
      high concentrations. The proliferative effects of estrogen and progesterone were
      blocked when the segments were cultured in the presence of inhibitors of their
      respective receptors, ICI 128 780 and zk 112994. The data suggest that Schwann
      cells possess distinct receptors for estrogen and progesterone and that these
      receptors may be involved in the control of Schwann cell proliferation. It also
      shows that the response of Schwann cells to sex hormones varies with sex and
      perhaps also with age.

PMID- 10397643
TI  - Acetylcholine and acetyl-CoA metabolism in differentiating SN56 septal cell line.
AB  - The rate of acetylcholine (ACh) synthesis was found to depend on the activity of
      choline acetyltransferase (ChAT) and on the concentrations of the two substrates
      of this enzyme, choline and acetyl-CoA. In SN56 cells treated for 3 days with 1
      mM dbcAMP activities of ChAT and acetylcholinesterase (AChE) were elevated. It
      was accompanied by an increased activity of ATP-citrate lyase (ACL)-an enzyme
      responsible for provision of part of acetyl-CoA for ACh synthesis in cholinergic
      neurons. In contrast lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH)
      activities were reduced by dbcAMP. Treatment with 0.001 mM all-trans retinoic
      acid (RA) elevated ChAT and LDH activities but reduced the activities of AChE and
      ACL. The combined treatment with db-cAMP and tRA increased ChAT activity in supra
      additive fashion. The effects of these two compounds on the other enzymes were
      not additive. Neither compound altered the activities of carnitine acetyl
      transferase, acetyl-CoA synthase, or acetyl-CoA hydrolase. On the other hand,
      they decreased acetyl-CoA content and rate of ACh release. Overall, the results
      indicate that tRA upregulates only ChAT expression, whereas dbcAMP upregulates
      several features of cholinergic neurons including ChAT, AChE, and ACL. Low levels
      of acetyl-CoA in differentiated cells may result in a low rate of ACh release and
      resynthesis during their depolarization.

PMID- 10397644
TI  - Recombinant adeno-associated virus (AAV) drives constitutive production of
      glutamate decarboxylase in neural cell lines.
AB  - Many neurological disorders result directly or indirectly from the loss of
      inhibitory function. Engineering the production of GABA, an inhibitory
      neurotransmitter, may therefore be able at least partly to restore the lost
      inhibition seen in epilepsy, Parkinson's disease, or Huntington's disease. In
      this article, we describe a set of recombinant adeno-associated viruses (AAVs)
      that can deliver cDNAs encoding the GABA-producing enzyme, glutamate
      decarboxylase (GAD), directly into neural cells. We have characterized these
      recombinant AAVs in several cell lines derived from the CNS. These recombinant
      AAVs effectively transduced all neural cell lines, although with different
      efficiencies. Transduction occurred in both proliferating and nonproliferating
      cells, but actively proliferating cell lines had approximately six times greater
      transduction efficiency than nonproliferating cells. Furthermore, these AAVs
      maintained long-term expression of GAD in an astrocytic cell line for at least
      seven passages. These recombinant AAVs are promising vehicles for investigating
      the potential therapeutic effects of GABA in animal models of epilepsy and
      neurodegenerative diseases.

PMID- 10397645
TI  - Am I my brother's keeper?

PMID- 10397646
TI  - To biopsy or not.

PMID- 10397647
TI  - To biopsy or not.

PMID- 10397648
TI  - To biopsy or not.

PMID- 10397649
TI  - To biopsy or not.

PMID- 10397650
TI  - The osteoplastic flap for access to the oral and maxillofacial region.

PMID- 10397651
TI  - A 5-year comparison of hydroxyapatite-coated titanium plasma-sprayed and titanium
      plasma-sprayed cylinder dental implants.
AB  - OBJECTIVE: A preliminary report from this study showed that hydroxyapatite-coated
      (HA) titanium plasma-sprayed (TPS) cylinder implants had fewer failures than TPS
      cylinder implants before prosthetic loading. The purpose of this article is to
      report the long-term success associated with the 2 systems. In addition, local
      and systemic factors that may influence the success or failure of the implants
      were analyzed. STUDY DESIGN: Each of 65 subjects was randomized to either HA
      coated TPS or TPS cylinder implants. Loss of an implant was considered a failure.
      Failures were analyzed in terms of the coating of the implant, age and gender of
      the patient, location and length of the implant, opposing dentition, and smoking
      status. Data were statistically analyzed through use of chi-square tests.
      RESULTS: Of 351 implants that were placed, 13 were lost before prosthetic loading
      and 17 were lost after prosthetic loading. The overall success rate was 92.8%.
      Three hundred thirty-eight implants were prosthetically loaded. The implant
      success rate after prosthetic loading was 95.3%. There was an overall
      nonsignificant higher failure rate for the TPS implants (8.0%). Patient age and
      patient gender were nonsignificant variables. Ten-mm implants had a significantly
      higher failure rate (17.4%; chi-square, 1.00; P = .39). Before prosthetic
      loading, more implants failed in the posterior mandible; after prosthetic
      loading, more implants failed in the anterior maxilla (chi-square, 8.97; P =
      .03). More implants failed when they were opposed by natural dentition or hybrids
      (chi-square, 7.36; P = .007). Smoking history was a significant factor (chi
      square, 5.2; P = .002). CONCLUSIONS: Statistically, there is little difference
      between the 2 systems. Local and systemic factors appear to play a greater role
      in implant failure than does the surface of the implant.

PMID- 10397652
TI  - Prevalence of temporomandibular disorders associated with whiplash injury in
      Lithuania.
AB  - OBJECTIVE: The purpose of this study was to ascertain the prevalence of symptoms
      of temporomandibular disorders in whiplash victims in Lithuania and compare it
      with the prevalence in otherwise healthy control subjects. STUDY DESIGN: In a
      controlled historical cohort study in Lithuania, we asked each of 210 victims of
      vehicular rear-end collisions (at 14-27 months after the accident) to report the
      presence and frequency of a number of temporomandibular disorder symptoms. The
      results were compared with those for an age-matched and gender-matched control
      group, sampled randomly from the local population. RESULTS: In the accident
      group, 2.4% of subjects (4/165) reported jaw pain for 1 day or more per month;
      this compared with 3.3% of the controls (6/180). One (0.6%) of the accident
      victims and 2 (1.1%) of the controls had daily jaw pain. In both groups there was
      a low prevalence of jaw sounds, pain in or near the ear(s), jaw locking,
      tinnitus, and facial pain. CONCLUSIONS: Unlike whiplash claimants in many Western
      societies, Lithuanian accident victims do not appear to report the chronic
      symptoms of temporomandibular disorders despite their acute whiplash injuries.

PMID- 10397654
TI  - Vasovagal syncope in heart transplant patients during dental surgery.
AB  - The pathogenesis of vasovagal syncope during emotional stress is controversial.
      Several authors have postulated that the vasodepressor response in humans may be
      initiated by C-fiber mechanoreceptors situated in the heart and connected via
      cardiac vagal afferents to the medullary center for cardiovascular control. It
      has been argued that heart transplant patients cannot show any vasovagal reaction
      because the donor heart is transplanted completely deprived of any vagal or
      sympathetic innervation. In this report, however, 3 episodes of vasovagal syncope
      are documented in 3 heart transplant patients undergoing periodontal surgery.
      During vasovagal syncope in each of these patients, a dramatic fall in systolic
      blood pressure (from 137 +/- 5 mmHg to 76 +/- 3.6 mmHg) was detected, but, in
      contrast to what is observable in normal subjects, the heart rate did not show
      any relevant change (from 96.7 +/- 4.5 beats per minute to 102.6 +/- 7.6 beats
      per minute). These unexpected findings emphasize the marginal role of the heart
      on the pathogenesis of the vasovagal syncope and underline the fact that a
      vasovagal reaction can develop even in the absence of the bradycardia that is the
      primary symptom usually reported in the literature.

PMID- 10397653
TI  - The use of ultrasound for guiding needle placement for inferior alveolar nerve
      blocks.
AB  - OBJECTIVE: The degree of pulpal anesthesia obtained with an ultrasound-assisted
      inferior alveolar nerve block was compared to that obtained with a conventional
      inferior alveolar nerve block for mandibular teeth to determine whether needle
      placement assisted by ultrasound results in more successful anesthesia. STUDY
      DESIGN: Through use of a repeated-measures design, each of 40 subjects randomly
      received an ultrasound-assisted inferior alveolar nerve block and a conventional
      inferior alveolar nerve block at 2 separate appointments. Mandibular anterior and
      posterior teeth were blindly tested by means of a pulp tester at 4-minute cycles
      for 60 minutes postinjection. Anesthesia was considered successful when 2
      consecutive readings of 80 were obtained. RESULTS: One hundred percent of the
      subjects had profound lip numbness with both the ultrasound-assisted inferior
      alveolar nerve block and the conventional inferior alveolar nerve block. For
      these 2 techniques, anesthetic success rates for individual teeth ranged from 38%
      to 92%. There were no significant differences (P > .05) between the 2 techniques.
      CONCLUSIONS: It was concluded that accurate needle placement with ultrasound for
      the inferior alveolar nerve block did not result in more successful pulpal
      anesthesia in the mandible. Therefore, accuracy of needle placement is not the
      primary reason for pulpal anesthetic failure with this block.

PMID- 10397655
TI  - Conveying diagnosis of cancer.
AB  - Conveying news of cancer is stressful for the doctor, as receiving such news is
      for the patient. A patient may not perceive the news in the same way that the
      doctor does. Regular incorporation of the suggestions made in this article will
      advance the doctor's confidence, communication skills, and relationships with
      patients.

PMID- 10397656
TI  - Use of a parotid fascia flap to prevent postoperative fistula.
AB  - OBJECTIVE: The purpose of this study was to investigate the usefulness of a
      fascia flap technique designed to improve the post-operative results of regional
      excision in cases of benign tumor in the superficial lobe of the parotid gland
      and to reduce formation of postoperative fistula. STUDY DESIGN: During surgery in
      each of 32 patients with benign tumor in the superficial lobe of the parotid
      gland, a fascia flap was raised from beneath the ear lobe, placed in its original
      position, and firmly sutured after regional resection of the tumor. The results
      were compared with those in a control group of 30 patients, whose operations were
      the same as those of the experimental group except for the fact that the fascia
      overlying the tumor was excised with the tumor in the controls. RESULTS: The
      wounds of the 32 patients repaired with the fascia flap healed well without any
      complication. Among the 30 patients in the control group, fistula occurred in 4
      patients (13.3%). The difference was significant when the 2 groups were compared
      (chi2 test: P = .049 , P < .05). CONCLUSIONS: Use of a parotid fascia flap in
      partial parotidectomy for benign tumors in the superficial lobe holds promise for
      the prevention of postoperative fistula formation.

PMID- 10397657
TI  - Unique inflammatory features noted in intraorally transferred skin flaps:
      correlation with Candida albicans infection.
AB  - OBJECTIVE: The purpose of this study was to evaluate how well intraorally
      transferred skin flaps endure their new surroundings. STUDY DESIGN: Biopsy
      specimens were taken from 20 patients who had undergone microsurgical
      reconstruction and as pretransferred skin from 5 of these patients at the time of
      surgery. The study used immunohistochemistry for immunocompetent cells,
      differentiation markers for the epidermis and desmosomal proteins, and
      immunoelectron microscopy for desmosomal protein, in addition to routine
      histologic examination, including Sudan IV, periodic acid Schiff, and Grocott
      stains. We also measured the thickness of the epidermis and stratum corneum. Oral
      swabs from the skin flaps were examined for the presence of yeasts, particularly
      Candida albicans, by means of a culture method. RESULTS: According to the results
      of periodic acid-Schiff and Grocott staining, 20 cases were divided into 2
      groups: fungal element-positive cases (n = 15) and fungal element-negative cases
      (n = 5). All swabs from the former were positive for Candida albicans. In these
      fungus-positive cases, histopathologic evaluation revealed marked diminution of
      stratum corneum and pronounced epidermal hyperplasia. Immunohistochemistry
      demonstrated the dermal infiltration of numerous immunocompetent cells-CD4+,
      CD8+, CD20+, CD68+, neutrophil elastase+, and HLA-DR+ cells-and the scarce
      infiltration of IgA+ and IgG+ cells. There were scattered CD1a+, CD4+, CD8+, and
      HLA-DR+ cells and elastase+ neutrophils in the epidermis. Expression of
      cytokeratin subtypes (10, 14, 16, and 19), involucrin, and tenascin showed the
      characteristic features of epidermal proliferation. Enumeration of Ki-67+
      keratinocytes showed an increase, indicating epidermal proliferation. Expression
      of desmoglein 1 and desmocollin 1 in the epidermal keratinocytes was decreased in
      comparison with that in the pretransferred skin. Immunoelectron microscopy for
      desmoglein 1 confirmed the reduced immunoreactive deposits along the desmosomal
      plaques. In the fungus-negative cases, all such changes were a great deal milder.
      CONCLUSIONS: Taken together, our results demonstrate that most intraorally
      transferred flaps are affected by an inflammatory process that is induced by the
      influence of the wet oral environment. They present psoriasiform tissue reactions
      characterized by epidermal hyperproliferation that are mostly due to Candida
      albicans infection.

PMID- 10397658
TI  - Idiopathic maxillary pain: prevalence of maxillary sinus hyperreactivity in
      relation to allergy, chronic mucosal inflammation, and eosinophilia.
AB  - OBJECTIVE: In patients with chronic orofacial pain, an underlying sinus
      hyperreactivity may contribute to the clinical symptoms of a diagnosis of
      atypical odontalgia, trigeminal neuralgia, or temporomandibular disorders. The
      purpose of this study was to assess the prevalence of histamine-related maxillary
      sinus hyperreactivity in patients manifesting signs and symptoms of idiopathic
      maxillary pain and to correlate the respective findings with the presence or
      absence of chronic maxillary sinusitis-related diagnoses such as allergy, chronic
      mucosal inflammation, and eosinophilia. STUDY DESIGN: Fifty patients who had been
      assigned a diagnosis of idiopathic maxillary pain underwent skin allergy tests,
      maxillary sinus histamine provocation tests, and maxillary sinus mucosa biopsy.
      Histamine challenge to a selected area was performed during transoral sinuscopy
      of the maxillary sinus; a positive test result was defined as the development of
      a significant local mucosa response such as reddening and swelling. RESULTS:
      Comparison of the data showed most patients (38%) to have an absence of chronic
      maxillary sinusitis-related diagnoses, whereas the most common multiple diagnosis
      was found to be chronic mucosal inflammation in combination with eosinophilia
      (22%). Regarding the prevalence rates of positive histamine provocation test
      outcomes, a significant difference was found between the diagnostic subgroup
      "absence of chronic maxillary sinusitis-related diagnoses" (36.9%) and the
      diagnostic subgroups "chronic mucosal inflammation" (20%; P< .05), "chronic
      mucosal inflammation in combination with eosinophilia" (18.2%; P< .05), and
      "chronic mucosal inflammation in combination with eosinophilia and allergy"
      (14.3%; P < .01). An analysis of the distribution of chronic maxillary sinusitis
      related diagnoses revealed absence of chronic mucosal inflammation-related
      diagnoses to be significantly more frequently associated with positive histamine
      provocation test outcomes than with negative histamine provocation test outcomes
      (41.2% vs 19.7%; P< .01), whereas chronic maxillary sinusitis (41.0% vs 29.4%),
      eosinophilia (26.2% vs 17.6%), and allergy (13.1% vs 11.8%) were found to be more
      prevalent in patients with negative histamine provocation test outcomes.
      CONCLUSIONS: The findings of this study suggest patients with idiopathic
      maxillary pain to be associated with a low rate of sinus hyperreactivity, whereas
      a positive test outcome with histamine provocation may not be linked to the
      presence of chronic maxillary sinusitis-related diagnoses such as allergy,
      chronic mucosal inflammation, and eosinophilia. Further investigations using a
      larger sample size of patients with idiopathic maxillary pain and nonidiopathic
      maxillary pain are necessary to demonstrate the presence or absence of an
      idiopathic maxillary pain-specific prevalence of maxillary sinus hyperreactivity.

PMID- 10397659
TI  - Leukocyte adhesion deficiency in a child with severe oral involvement.
AB  - Leukocyte adhesion deficiency is a rare inherited defect of phagocytic function
      resulting from a lack of leukocyte cell surface expression of beta2 integrin
      molecules (CD11 and CD18) that are essential for leukocyte adhesion to
      endothelial cells and chemotaxis. A small number of patients with leukocyte
      adhesion deficiency-1 have a milder defect, with residual expression of CD18.
      These patients tend to survive beyond infancy; they manifest progressive severe
      periodontitis, alveolar bone loss, periodontal pocket formation, and partial or
      total premature loss of the primary and permanent dentitions. We report on a 13
      year-old boy with moderate leukocyte adhesion deficiency-1 and severe prepubertal
      periodontitis. This case illustrates the need for the dentist to work closely
      with the pediatrician in the prevention of premature tooth loss and control of
      oral infection in these patients.

PMID- 10397660
TI  - Effects of the common cold and intranasal fluticasone propionate treatment on
      mucosal host defense assessed by human saliva.
AB  - OBJECTIVE: The purpose of this investigation was to study the effect of a potent
      topical steroid, fluticasone propionate, on patients with early signs and
      symptoms of the common cold. To characterize the mucosal inflammatory response,
      salivary defense factors and flow rate in these patients were analyzed. STUDY
      DESIGN: Forty patients with symptoms of the common cold were randomized into 2
      groups to receive either high-dose fluticasone propionate (100 microg per
      nostril) or placebo 4 times daily for 6 days. Paraffin-stimulated whole saliva
      was collected on day 1 (before the onset of medication), day 7 (posttreatment),
      and day 21 (follow-up). RESULTS: Salivary flow rate, innate host defense factors,
      and total protein content were not affected by the common cold. IgA increased
      between day 7 and day 21 (P < or = .01; Student 2-tailed t test), and the
      relative proportions of salivary peroxidase and IgA increased on day 7 (P = .01)
      and day 21 (P= .05). In patients receiving fluticasone, saliva flow rate was
      lower on day 21 (P < or = .05) than on days 1 and 7. The innate salivary defense
      factors were not affected, but IgA increased both on day 7 (P < or = .001) and on
      day 21 (P < or = .001) in comparison with day 1. CONCLUSIONS: Of the oral mucosal
      defense factors, only IgA is activated during the common cold. Intranasally
      administrated fluticasone propionate does not have a suppressive effect on
      salivary antimicrobial capacity.

PMID- 10397661
TI  - A clinical evaluation of a novel liposomal carrier for acyclovir in the topical
      treatment of recurrent herpes labialis.
AB  - In a 2-armed, double-blind, randomized clinical study, the efficacy in the
      treatment of recurrent herpes labialis of 5% acyclovir in a novel liposomal
      carrier (ethosome) was evaluated in comparison with that of a commercial 5%
      acyclovir cream (Zovirax cream) and that of a drug-free vehicle. Data were based
      on 61 herpetic episodes in 40 subjects. In a crossover arm in which the 2 active
      preparations were compared, the time to crusting of lesions was significantly
      shorter (P < .025) with the ethosomal acyclovir (1.8 days) than with the cream
      (3.5 days). Time to loss of crust was also significantly shorter (4.2 vs 5.9
      days; P < .05). In a parallel arm in which all 3 preparations were compared, the
      time to crusting with the ethosomal acyclovir (1.6 days) was significantly
      shorter than the time with the acyclovir cream (4.3 days; P < .02) and the time
      with the drug-free vehicle (4.8 days; P < .005); in this arm, the shorter time to
      loss of crust for the ethosome (3.5 days), in comparison with the times for the
      cream (6.4 days) and the drug-free vehicle (6.1 days), did not reach statistical
      significance. Approximately 30% of all episodes treated with the ethosome were
      clinically abortive; this compared with 10% of those treated with the cream or
      the drug-free vehicle. No adverse effects were reported, other than minor burning
      sensations at the application site that lasted a few seconds after application
      and were evenly distributed between the investigated preparations. This pilot
      study suggests the improved clinical efficacy of the new liposomal preparation in
      comparison with Zovirax cream in the treatment of recurrent herpes labialis.

PMID- 10397662
TI  - Nicorandil-induced severe oral ulceration: a newly recognized drug reaction.
AB  - Nicorandil, a potassium-channel activator used for the long-term treatment of
      ischemic heart disease, has been recently implicated as having a drug side effect
      of recurrent aphthous stomatitis. Three patients are reported with drug-induced
      aphthouslike ulceration secondary to nicorandil.

PMID- 10397663
TI  - Factors associated with utilization of care for oral lesions in HIV disease.
AB  - OBJECTIVES: The purpose of this study was to examine factors associated with
      utilization of care for oral lesions in people with HIV disease. STUDY DESIGN:
      The data were derived from 1424 adults who participated in a series of up to 4
      interviews as part of the AIDS Cost and Service Utilization Survey. Treatment for
      thrush, oral sores, and other conditions was evaluated through use of logistic
      regression, with generalized estimating equations being applied. RESULTS: In all,
      9.1% of those in the study sample reported being treated. After adjusting for CD4
      cell count and other variables, regression analyses indicated that blacks (odds
      ratio [OR], 0.54; 95% confidence interval [CI], 0.32-0.91) and Hispanics (OR,
      0.59; 95% CI, 0.36-0.98) had significantly lower odds of reporting being treated.
      Respondents with more than a high school education (OR, 1.64; 95% CI, 1.08-2.51),
      clinical trial participants (OR, 1.92; 95% CI, 1.27-2.90), and those receiving
      counseling (OR, 2.22; 95% CI, 1.60-3.09) were more likely to report being
      treated. CONCLUSIONS: Utilization of care for oral lesions is very low.
      Educational and racial differences exist among those respondents who received
      care for HIV-associated oral lesions.

PMID- 10397664
TI  - Primary failure of tooth eruption: a unique case.
AB  - Primary failure of tooth eruption rarely occurs. This case represents a rare
      clinical situation and appears to reflect a generalized disturbance in the
      eruptive process, inasmuch as (1) deciduous and permanent dentition are affected,
      (2) incisors, molars, and premolars are involved in all quadrants, (3) skeletal
      and craniofacial growth are within normal limits, and (4) no systemic/genetic
      anomalies were detected. This is the first such case reported in the literature;
      diagnosis and management are discussed.

PMID- 10397665
TI  - Benign lymphoepithelial lesion of the parotid gland with sebaceous
      differentiation.
AB  - The salivary duct system in the setting of chronic sialadenitis is predisposed to
      undergo a variety of cellular modifications. This report documents a rare type of
      metaplasia of a parotid benign lymphoepithelial lesion. Epimyoepithelial islands
      showing focal sebaceous differentiation and pure sebaceous cell nests in addition
      to their usual histologic appearance were noted throughout the lesion. The
      possible pathogenesis is discussed through a review of the literature.

PMID- 10397666
TI  - Tumoral calcinosis in the premaxillary region.
AB  - Tumoral calcinosis, an uncommon pathologic condition that manifests itself in
      many forms, has rarely been described in the craniofacial region. This report
      describes a case of tumoral calcinosis affecting the premaxillary region.

PMID- 10397667
TI  - Oral plasmablastic lymphoma in previously undiagnosed HIV disease.
AB  - Non-Hodgkin's lymphoma is the second most common HIV-associated malignancy. This
      report details a case of the recently described entity plasmablastic lymphoma of
      the mouth in a patient who was later found to have severe HIV disease. The tumor
      manifested as a large ulcerated mass of the left maxillary alveolus, causing bony
      destruction and tooth mobility. Histologic examination of lesional tissue
      revealed a lymphoid tumor with a high proliferation rate containing
      lymphoplasmacytoid cells that were reactive to the plasma cell marker VS38c but
      not to CD20 or CD79a; these are features of the recently reported non-Hodgkin's
      lymphoma termed plasmablastic lymphoma. This is only the second report of an
      unusual tumor that has a predilection for the orofacial tissues.

PMID- 10397668
TI  - Synchronous pleomorphic adenomas of the major salivary glands: a case report.
AB  - The presentation of multiple distinct tumors in major salivary glands is rare.
      Although the most common tumor with bilateral synchronous or metachronous
      development is the Warthin tumor, pleomorphic adenomas have been diagnosed
      simultaneously as well. We report the case of a female patient who was diagnosed
      with pleomorphic adenomas in the right parotid and submandibular glands,
      concomitant with sialolithiasis affecting the submandibular gland. This patient
      had been exposed to head and neck radiotherapy in childhood, which may have
      played a role in the development of her tumors. A review of the relevant
      literature is included.

PMID- 10397669
TI  - Angiomyolipoma of the parotid gland: a case report.
AB  - Angiomyolipoma is a hamartomatous process that most frequently occurs as a single
      lesion or multiple foci in the kidneys of patients affected by tuberous
      sclerosis. Angiomyolipoma can also arise in extrarenal sites, among which the
      liver is the most frequently recorded. Only rare cases of angiomyolipoma located
      in the head and neck region (ear and oral and nasal cavity) have been described.
      The purpose of the present article is to report a case of angiomyolipoma of the
      parotid gland. A 68-year-old woman appeared for treatment with a slow-growing
      nodule located in her right parotid gland. Ultrasound examination revealed a
      heterogeneous nodule with well-defined margins. The nodule was surgically removed
      by total parotidectomy and showed the characteristic appearance of
      angiomyolipoma, with an admixture of fat smooth muscle cells, and tortuous, thick
      walled blood vessels. Careful physical examination of the patient failed to
      reveal features of tuberous sclerosis. Angiomyolipoma should be considered in the
      differential diagnosis of mesenchymal lesions involving the salivary gland.

PMID- 10397670
TI  - Reliability of laser Doppler flowmetry in a 2-probe assessment of pulpal blood
      flow.
AB  - OBJECTIVE: The reliability of using 2 probes with laser Doppler signals when
      adjacent teeth are being measured simultaneously to determine pulpal blood flow
      is unknown. The purpose of this study was to determine whether 2 probes are more
      reliable than 1 in a single-tool assessment. STUDY DESIGN: Tooth pulp vitality
      was studied in 19 adults through use of laser Doppler flowmetry tests. In each
      subject, testing was carried out on 2 successive occasions with 2 probes
      positioned on the maxillary central incisors. RESULTS: Significant mean
      differences of 31% for blood flux and 96% for concentration were found between
      the 2 probes, although they shared equal coefficients of variation. The
      reproducibility for each probe was found to be consistent, and the probes were
      highly correlated with each other. Flux and concentration, however, were not
      systematically correlated. CONCLUSIONS: Simultaneous measurements with 2 probes
      were clearly more reliable. The necessity for a calibration control was evident.

PMID- 10397671
TI  - Pulp stones throughout the dentition of monozygotic twins: a case report.
AB  - Pulpal calcifications are relatively common. However, their occurrence in the
      entire dentition is relatively infrequent. The presence of such calcification
      arouses suspicion of systemic or hereditary origin. This case report describes
      twin sisters with pulpal calcifications in their entire dentitions. No systemic
      cause was detected. The pattern of calcification was partially consistent with
      the hereditary condition of dentinal dysplasia.

PMID- 10397672
TI  - Dentin dysplasia, type II: report of 2 new families and review of the literature.
AB  - Dentin dysplasia, type II, is an inherited autosomal dominant disorder in which
      primary teeth are amber and translucent, with pulp chambers obliterated by
      abnormal dentin. The permanent teeth have a normal coronal morphologic character
      and coloration but exhibit "thistle tube"-shaped pulp chambers as well as
      numerous pulpal calcifications. The disorder has traditionally been thought to be
      somewhat rare; however, this article presents 2 new families in which several
      generations with the disorder were reported to the authors within a 1-year
      period. It also includes a review of the literature documenting a total of 17
      previously reported families.

PMID- 10397673
TI  - Eosinophilic granuloma: a case report with pathologic fracture.
AB  - Approximately 10% to 20% of all cases of eosinophilic granuloma occur in the
      jaws. A palpable mass with or without pain is the most frequent presenting
      clinical feature. Less common clinical signs include gingivitis, loose teeth, and
      oral ulceration with poor healing. We report a case of monostotic mandibular
      eosinophilic granuloma in a 38-year-old woman that initially manifested
      mandibular body fracture, an unusual and poorly documented clinical sign for this
      disease. The clinical and radiographic features, differential diagnosis, and
      treatment plan of the case are presented.

PMID- 10397674
TI  - Smooth muscle cell origin and its relation to heterogeneity in development and
      disease.

PMID- 10397675
TI  - Cross-sectional study of soluble intercellular adhesion molecule-1 and
      cardiovascular risk factors in apparently healthy men.
AB  - An elevated plasma concentration of the soluble intercellular adhesion molecule-1
      (sICAM-1) is associated with increased risk for future coronary events. However,
      data exploring the interrelations of sICAM-1 with known cardiovascular risk
      factors are sparse. We determined sICAM-1 levels in 948 middle-aged men with no
      prior history of cardiovascular disease. sICAM-1 levels increased with age
      (P<0.001) and were significantly associated with smoking (P<0.001), hypertension
      (P<0.05), and frequent alcohol consumption (P=0.006). Positive correlations were
      observed between sICAM-1 and triglycerides (r=0.15; P<0.001), fibrinogen (r=0.21;
      P<0.001), tissue-type plasminogen activator antigen (r=0.17; P<0.001), and total
      homocysteine (r=0.09; P=0.02); whereas a negative correlation was observed for
      high density lipoprotein cholesterol (r=-0.15; P<0. 001). Overall, plasma
      concentrations of sICAM-1 increased with increasing prevalence of usual
      cardiovascular risk factors; mean plasma concentrations were 231, 236, 245, 257,
      and 312 ng/mL for those subjects with 0, 1, 2, 3, and >4 risk factors,
      respectively (P<0.01 for trend). In multivariate analysis, age, smoking status,
      diabetes, systolic blood pressure, positive family history of coronary disease,
      and serum levels of total homocysteine and fibrinogen were all independently
      associated with sICAM-1 levels (all P</=0.05). sICAM-1 levels are associated with
      several established cardiovascular risk factors. Further studies will be needed
      to evaluate whether these associations reflect the role of sICAM-1 as a marker of
      preclinical atherosclerosis, and whether such interrelations might have a causal
      basis.

PMID- 10397676
TI  - Oxidized LDL-containing immune complexes induce Fc gamma receptor I-mediated
      mitogen-activated protein kinase activation in THP-1 macrophages.
AB  - Our previous studies have shown that Fc gamma receptor (FcgammaR)-mediated uptake
      of LDL-containing immune complexes (oxLDL-ICs) by human monocyte-derived
      macrophages leads to not only transformation of macrophages into foam cells but
      also macrophage activation and release of cytokines. It has been shown that cross
      linking of FcgammaR triggers activation of signal transduction pathways that
      alter gene expression in macrophages. In this study, we determined whether
      engagement of FcgammaR by oxLDL-ICs leads to activation of mitogen-activated
      protein (MAP) kinase pathway, a signaling cascade serving many important
      functions, including the regulation of gene expression, in THP-1 macrophage-like
      cells. Our results from immunoblotting, using specific anti-phosphorylated MAP
      kinase antibodies, showed that oxLDL-ICs induced extracellular signal regulated
      kinase 2 (ERK2) MAP kinase phosphorylation in THP-1 macrophage-like cells in time
      and dose-dependent manners. Cholesterol loading before stimulation led to a
      longer phosphorylation of ERK2. Nuclear translocation of phosphorylated ERK was
      markedly increased after the stimulation. Moreover, our data showed that oxLDL-IC
      induction of MAP kinase was prevented by human monomeric IgG1, suggesting that
      the specific engagement of type I FcgammaR by oxLDL-IC is responsible for the MAP
      kinase activation. Finally, we showed that human anti-oxLDL autoantibody
      containing immune complexes immobilized on type I collagen induced MAP kinase
      activation in THP-1 cells. These results strongly suggest that oxLDL-IC, which
      has been detected in atherosclerotic plaques, may play an important role in
      macrophage activation and atherogenesis.

PMID- 10397677
TI  - Protein kinase C mediates basic fibroblast growth factor-induced proliferation
      through mitogen-activated protein kinase in coronary smooth muscle cells.
AB  - Proliferation of coronary smooth muscle cells (cSMCs) contributes to the
      pathogenesis of arteriosclerosis and restenosis after angioplasty, and basic
      fibroblast growth factor (bFGF) is a powerful mitogen for cSMCs. In this study,
      we investigated the involvement of mitogen-activated protein kinase (MAPK),
      protein kinase C (PKC), and the transcription factor c-myc in bFGF-stimulated
      mitogenesis, as well as the functional relationship between these factors. cSMC
      stimulation with bFGF resulted in phosphorylation of p42 MAPK, as well as the
      phosphorylation and increased expression of c-myc. The MAPK kinase (MEK)
      inhibitor PD98059 blocked bFGF-stimulated MAPK phosphorylation and resulted in
      both a decrease of c-myc expression and inhibition of bFGF-stimulated DNA
      synthesis in cSMCs. bFGF also increased PKC activity in cSMCs in a time-dependent
      manner. The inhibition of PKC by chelerythrine or its downregulation by phorbol
      12-myristate 13-acetate (PMA) inhibited bFGF-induced DNA synthesis and blocked
      the phosphorylation of MAPK and c-myc expression in response to bFGF. This
      indicates an involvement of phorbol ester-sensitive PKC isoforms in MAPK
      activation and mitogenic signaling by bFGF. Western blot analysis revealed the
      presence of the phorbol ester-sensitive isoforms PKC alpha, epsilon, and gamma as
      well as the PKC isoforms iota, lambda, micro, and zeta in cSMCs. In this study,
      we show that the MAPK cascade is required for bFGF-induced proliferation and that
      phorbol ester-sensitive PKC isoforms contribute to the bFGF-induced cSMC
      mitogenesis in cSMCs.

PMID- 10397678
TI  - Aortic connexin43 is decreased during hypertension induced by inhibition of
      nitric oxide synthase.
AB  - Connexin43 (Cx43), the predominant gap junction protein in vessels and heart, is
      involved in the control of cell-to-cell communication and is thought to modulate
      the contractility of the vascular wall and the electrical coupling of cardiac
      myocytes. We have investigated the effects of arterial hypertension induced by
      inhibition of nitric oxide synthase on the expression of Cx43 in aorta and heart
      as well as on the distensibility of the carotid artery. Administration of 0.4 g/L
      NG-nitro-L-arginine methyl ester (L-NAME) to rats in their drinking water for 4
      weeks increased intra-arterial mean blood pressure, wall thickness of aorta and
      carotid artery (25%), and heart weight (17%). Analysis of heart mRNA demonstrated
      increased expression of the fetal skeletal alpha-actin and of atrial natriuretic
      peptide but not of Cx43. In contrast, Cx43 mRNA and protein were decreased by 50%
      in the aortas of L-NAME-treated rats that did not show increased carotid
      distensibility. Because these data contrasted with those obtained in the 2
      kidney, 1 clip model of rat hypertension, which is characterized by increased
      arterial distensibility and Cx43 expression in aorta, we investigated by Western
      blot analysis the posttranslational modifications of Cx43. We found that Cx43 was
      more phosphorylated in the aorta of 2-kidney, 1 clip rats than in that of L-NAME
      or control rats, which indicated a differential regulation of Cx43 in different
      models of hypertension. The data suggest that the cell-to-cell communication
      mediated by Cx43 channels may help regulate the elasticity of the vascular wall.

PMID- 10397679
TI  - Angiotensin induces inflammatory activation of human vascular smooth muscle
      cells.
AB  - Multiple data suggest that the renin-angiotensin system contributes to the
      pathogenesis of atherosclerosis. The atherogenic effect of the renin-angiotensin
      system can only in part be explained by the influence of its effector angiotensin
      II on blood pressure, smooth muscle cell (SMC) growth, or antifibrinolytic
      activity. Because chronic inflammation of the vessel wall is a hallmark of
      atherosclerosis, we hypothesized that angiotensin II may elicit inflammatory
      signals in vascular SMCs. Human vascular SMCs were stimulated with angiotensin.
      Inflammatory activation was assessed by determination of interleukin-6 (IL-6)
      release into the culture medium, detection of IL-6 mRNA by RT-PCR, and
      demonstration of activation of nuclear factor-kappaB in electrophoretic mobility
      shift assays. Angiotensin II concentration-dependently (1 nmol/L to 1 micromol/L)
      stimulated IL-6 production by SMCs via activation of the angiotensin II type 1
      receptor (demonstrated by the inhibitory action of the receptor antagonist
      losartan). Angiotensin I increased IL-6 production by SMCs, too. This effect was
      inhibited by captopril and ramiprilat, suggesting conversion of angiotensin I to
      angiotensin II by angiotensin-converting enzyme in SMCs. Steady-state mRNA for IL
      6 was augmented after stimulation with angiotensin II, suggesting regulation of
      angiotensin-induced IL-6 release at the pretranslational level. Moreover, the
      proinflammatory transcription factor nuclear factor-kappaB, which is necessary
      for transcription of most cytokine genes, was also activated by angiotensin II.
      Pyrrolidine dithiocarbamate suppressed angiotensin II-induced IL-6 release, a
      finding compatible with involvement of reactive oxygen species as second
      messengers in cytokine production mediated by angiotensin. The data demonstrate
      the ability of angiotensin to elicit an inflammatory response in human vascular
      SMCs by stimulation of cytokine production and activation of nuclear factor
      kappaB. Inflammatory activation of the vessel wall by a dysregulated renin
      angiotensin system may contribute to the pathogenesis of atherosclerosis.

PMID- 10397680
TI  - Versican/PG-M isoforms in vascular smooth muscle cells.
AB  - The expression of increased amounts of proteoglycans in the extracellular matrix
      may play a role in vascular stenosis and lipid retention. The large chondroitin
      sulfate proteoglycan versican is synthesized by vascular smooth muscle cells
      (SMCs), accumulates during human atherosclerosis and restenosis, and has been
      shown to bind LDLs. We recently demonstrated that adult rat aortic SMCs express
      several versican mRNAs. Four versican splice variants, V0, V1, V2, and V3, have
      recently been described, which differ dramatically in length. These variants
      differ in the extent of modification by glycosaminoglycan chains, and V3 may lack
      glycosaminoglycan chains. In this study, we characterized versican RNAs from rat
      SMCs by cloning, sequencing, and hybridization with domain-specific probes. DNA
      sequence was obtained for the V3 isoform, and for a truncated V0 isoform. By
      hybridization of polyadenylated RNA with domain-specific probes, we determined
      that the V0, V1, and V3 isoforms are present in vascular SMCs. We confirmed the
      presence of the V3 isoform in polyadenylated RNA and in RT-PCR products by
      hybridization with an oligonucleotide that spans the splice junction between the
      hyaluronan-binding domain and the epidermal growth factor-like domain. In
      addition, a novel splice variant was cloned by PCR amplification from both rat
      and human SMC RNA. This appears to be an incompletely spliced variant, retaining
      the final intron. PCR analysis shows that this intron can be retained in both V1
      and V3 isoforms. The predicted translation product of this variant would have a
      different carboxy-terminus than previously described versican isoforms.

PMID- 10397681
TI  - Increased secretion of basement membrane-degrading metalloproteinases in pig
      saphenous vein into carotid artery interposition grafts.
AB  - Late saphenous vein bypass graft failure in humans involves medial and neointimal
      thickening as the result of migration and proliferation of vascular smooth muscle
      cells (SMCs). Recent work on angioplasty indicates that basement membrane
      degrading metalloproteinases (MMPs) cooperate with growth factors to mediate SMC
      migration and proliferation. We sought evidence here for a similar role in
      experimental vein grafts in pigs. Tissue levels and secretion of MMP-2 and MMP-9
      were compared by quantitative zymography in veins and grafts removed 2 to 168
      days after implantation. Pro and active forms of MMP-2 were present in veins, but
      levels were increased in vein grafts after 7 days (4- and 6-fold, respectively)
      and 28 days (3-fold for both), returning to values in veins after 168 days. MMP-9
      was not detected in veins, was increased in grafts after 2 days, further
      increased after 7 days (6-fold) and 28 days (15-fold), and declined to
      undetectable levels by 168 days. Immunocytochemistry detected increased
      expression of MMP-2 and MMP-9 with the same time course. MMP-2 was widely
      distributed, whereas MMP-9 was concentrated in highly proliferative SMCs at the
      superficial layers of the thickened neointima. We conclude that increased
      production of the basement membrane-degrading MMP-2 and MMP-9 spanned the period
      of neointima formation and SMC proliferation in experimental vein grafts. MMPs
      therefore constitute new therapeutic targets for reducing late vein graft
      failure.

PMID- 10397682
TI  - Identification and cloning of a new gene (2A3-2), homologous to human
      translational elongation factor, upregulated in a proliferating rat smooth muscle
      cell line and in carotid hyperplasia.
AB  - Smooth muscle cells (SMCs), before migration and proliferation in the intima of
      the vessel wall, change from a normal contractile to a pathological proliferating
      phenotype. The molecular regulatory mechanisms implicated in such phenotypic
      changes remain poorly understood. In this study, using differential display, we
      have isolated for the first time a new gene (2A3-2) that is overexpressed in a
      rapidly proliferating, but not synthetic, rat SMC line. This was further
      confirmed by northern blot performed on the 2 cell types. Moreover, balloon
      catheter injury of rat carotids showed, by a virtual northern technique, an
      upregulation of this new gene in hyperplasia vessels. This new gene (2A3-2, 1.2
      kb) was present in skeletal muscle, heart, aorta, lung, liver, kidney, and
      spleen. In addition, 5' rapid amplification of cDNA ends (5' RACE) allowed the
      cloning and sequencing of this 1.2-kb gene. Comparison of this newly identified
      gene sequence with data banks showed a strong homology to human and bovine
      mitochondrial translational elongation factor. The 2A3-2 gene, identified in this
      study, may play a vital role in the cascade of events implicated in switching SMC
      phenotype from a quiescent to a proliferate one.

PMID- 10397683
TI  - Granulocyte-macrophage colony-stimulating factor (GM-CSF) modulates the
      expression of type VIII collagen mRNA in vascular smooth muscle cells and both
      are codistributed during atherogenesis.
AB  - The expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and
      type VIII collagen was studied in human arteries. GM-CSF and type VIII collagen
      were codistributed in all layers of the walls of nondiseased arteries and during
      early atherogenesis with up to type V lesions. The number of cells expressing
      both mRNAs increased during the development of advanced atherosclerotic lesions.
      Whereas type VIII collagen expression increased further in complicated lesions,
      GM-CSF was downregulated. During early atherogenesis smooth muscle cells (SMC)
      and endothelial cells were the principal GM-CSF and type VIII collagen mRNA
      expressing cell types. In advanced lesions monocytes/macrophages also expressed
      the mRNAs. In complicated lesions the number of GM-CSF mRNA-expressing SMC was
      markedly reduced. In in vitro experiments transforming growth factor-beta1,
      platelet-derived growth factor, and GM-CSF, but not basic fibroblast growth
      factor, stimulated the expression of type VIII collagen mRNA by SMC. GM-CSF
      transiently stimulated type VIII collagen transcription. Thus GM-CSF is a
      prominent component of the regulatory network influencing collagen metabolism
      during atherogenesis. By modulating the synthesis of type VIII collagen in SMC,
      GM-CSF may influence the course of plaque development and may govern processes
      such as cell movement, plaque stability, and thrombus organization.

PMID- 10397684
TI  - Differential expression of connexin43 and desmin defines two subpopulations of
      medial smooth muscle cells in the human internal mammary artery.
AB  - Upregulation of connexin43-gap junctions is associated with transition of
      contractile vascular smooth muscle cells (SMCs) to the synthetic state. To
      determine whether phenotypically distinct subpopulations of medial SMCs
      differentially express connexin43, we investigated the human distal internal
      mammary artery, a structurally heterogeneous vessel with features ranging from
      elastic to elastomuscular to muscular. Immunoconfocal microscopy combined with
      quantitative analysis and complemented by in situ hybridization showed that SMCs
      in the elastic medial regions expressed high levels of connexin43 but low levels
      of desmin, whereas those of muscular medial regions expressed low levels of
      connexin43 but high levels of desmin. Ultrastructurally, SMCs of both regions
      were of the contractile phenotype, but the former cells were irregular in shape
      with relatively prominent synthetic organelles whereas the latter were spindle
      shaped with fewer synthetic organelles. Vimentin, smooth muscle alpha-actin,
      calponin, h-caldesmon, and myosin heavy chains (SM1 and SM2) were equally highly
      expressed by most cells in both subpopulations. The connexin43/desmin expression
      pattern of SMCs in regions of intimal thickening resembled those of elastic
      medial regions. These findings refine the view suggested from previous studies
      that high levels of connexin43 expression are associated with SMCs of a less
      contractile/more synthetic phenotype. In the internal mammary artery, the 2
      subpopulations of SMCs with markedly different connexin43 expression levels both
      represent a differentiated contractile phenotype, but the subpopulation showing
      high levels of connexin43-gap junctions is characterized by low levels of desmin
      and structural features that reflect a more synthetic tendency.

PMID- 10397685
TI  - The effect of supplementation with omega-3 fatty acids on soluble markers of
      endothelial function in patients with coronary heart disease.
AB  - During progression of atherosclerosis the overlying endothelial cells alter their
      expression of some surface molecules. Circulating levels of such molecules may be
      quantified. We investigated the effect of omega-3 fatty acids (n-3 FA) on the
      levels of tissue plasminogen activator antigen, von Willebrand factor, and the
      soluble forms of thrombomodulin, P-selectin, E-selectin, and vascular cell
      adhesion molecule-1 in 54 patients with coronary heart disease. Twenty-three of
      the patients had taken 5.1 g/d n-3 FA for 6 months (group I) and 31 were given
      corn oil as placebo (group II). For another 4 weeks ("the study period") they all
      got 5.1 g/d of n-3 FA. Compliance was confirmed by demonstration of changes in
      relevant fatty acids in serum phospholipids. At baseline, significant differences
      between the groups were found with lower median values of von Willebrand factor
      (128% versus 147%) and soluble thrombomodulin (24.9 versus 32.5 ng/mL) and higher
      median values of soluble E-selectin (41.4 versus 35.5 ng/mL) and soluble vascular
      cell adhesion molecule-1 (573 versus 473 ng/mL) in group I. During the study
      period differences in changes between the groups were found; tissue plasminogen
      activator antigen and soluble thrombomodulin decreased (P for difference between
      the groups 0.001 and 0.015, respectively), whereas soluble E-selectin and soluble
      vascular cell adhesion molecule-1 increased (P for difference between the groups
      <0.01 for both) in group II relative to group I. Our results indicate that n-3 FA
      supplementation decreases hemostatic markers of atherosclerosis, whereas markers
      of inflammation may be increased. The latter may be the result of lipid
      peroxidation as a simultaneous decrease of vitamin E and increase in
      thiobarbituric acid-reactive substances were observed.

PMID- 10397686
TI  - Effect of cyclosporine on arterial balloon injury lesions in cholesterol-clamped
      rabbits: T lymphocyte-mediated immune responses not involved in balloon injury
      induced neointimal proliferation.
AB  - Restenosis after balloon dilatation of stenosed coronary arteries is a major
      clinical problem. Because T lymphocytes occur in neointima and because
      cyclosporine inhibits T-lymphocyte proliferation, we tested the hypothesis that
      cyclosporine would attenuate neointimal proliferation after balloon dilation
      injury. Rabbits with a balloon-injured aorta, randomized to cyclosporine in the
      human therapeutic range (n=13) or vehicle (n=14) were followed up for 5 weeks; as
      a control for the effect of cyclosporine, half the rabbits received in addition
      an aorta allograft. Rabbits were clamped at a human plasma cholesterol level of 5
      to 7 mmol/L. Cyclosporine did not affect aorta cholesterol accumulation or
      neointimal proliferation in balloon-injured aortas; however, it attenuated both
      in transplanted aortas. Likewise, cyclosporine had no effect on endothelial cells
      at balloon-injured sites, but protected these cells in the transplanted aortas.
      Infiltration of smooth muscle cells, T lymphocytes, and macrophages were
      unaffected by cyclosporine in balloon-injured aortas; however, in transplanted
      aortas, cyclosporine reduced the relative number of T lymphocytes and macrophages
      but increased the relative number of smooth muscle cells. Finally, in balloon
      injured aortas, cyclosporine did not affect expression of vascular adhesion
      molecule-1, intercellular adhesion molecule-1, or major histocompatibility
      complex II, but all these cellular activation markers were attenuated by
      cyclosporine in transplanted aortas. These results suggest that cyclosporine does
      not attenuate neointimal proliferation after balloon dilatation, and that T
      lymphocyte--mediated immune responses are not involved in neointimal
      proliferation after balloon dilatation.

PMID- 10397688
TI  - Increased secretion of tissue inhibitors of metalloproteinases 1 and 2 from the
      aortas of cholesterol fed rabbits partially counterbalances increased
      metalloproteinase activity.
AB  - The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of
      MMPs (TIMPs) plays an important role in extracellular matrix turnover and thereby
      modulates atherosclerotic plaque development. MMP-1, -2, -3, and -9 activity is
      increased by atherosclerosis, but the status of TIMPs is less clear. We therefore
      compared secretion of TIMPs-1 and -2 from cultured aortic explants derived from
      arch, middle, and distal portions of thoracic aortas of normal rabbits and
      rabbits fed a 1% cholesterol diet for 8 weeks, using reverse zymography of
      conditioned media. Cholesterol feeding significantly increased secretion of TIMP
      1 from arch and middle portions (both 2.6-fold), accompanied by 2.0- and 2.7-fold
      increases in TIMP-2, respectively. Atherosclerotic aortas exhibited increased
      immunoreactive TIMP-1 and TIMP-2 in endothelial cells, smooth muscle cells, and
      macrophages. Staining of extracellular matrix was also prominent within the
      noncellular boundary region between fibrous cap and the lipid core, and within
      the lipid core. Increased TIMP-2 staining was also found in the media subjacent
      to the lipid core. In situ gelatin zymography demonstrated excess MMP activity
      within the plaque with partial inhibition in the lipid core base and subjacent
      media, consistent with the distribution of TIMPs. Casein zymography and in situ
      zymography demonstrated that increased caseinolytic activity was confined to the
      pericellular zones of macrophages within the lipid core, again consistent with
      its restriction by TIMPs. In summary, atherosclerosis increases TIMP expression,
      which counterbalances, in part, increased MMP activity.

PMID- 10397687
TI  - Plasma concentrations of interleukin-6 and abdominal aortic diameter among
      subjects without aortic dilatation.
AB  - Previous studies suggest that cytokine-induced tissue inflammation may
      participate in the pathogenesis of abdominal aortic aneurysms. Serum inflammatory
      markers may reflect arterial inflammation in asymptomatic phases of the
      aneurysmal disease. We studied 120 outpatients (62 men; age, 65+/-9 years) by
      ultrasound evaluation of the abdominal aorta to evaluate the association of
      circulating levels of interleukin-6 (IL-6) with abdominal aortic diameter in
      subjects with normal aortic size. Aortic diameter was measured at the infrarenal
      level and indexed for body surface area. Seven patients with abdominal aortic
      dilatation (indexed aortic diameter, >1.3 cm/m2) were also identified. Plasma
      concentrations of IL-6, serum amyloid A (SAA), C-reactive protein (CRP), total
      homocysteine, and lipids were measured. Among the 113 subjects without aortic
      dilatation, indexed aortic diameter was positively associated with serum levels
      of IL-6 (P<0.01), SAA (P<0.01), and total homocysteine (P=0.01). IL-6 levels
      increased in a stepwise fashion among dichotomized groups of aortic size (low and
      high aortic diameters) and peaked in patients with aortic dilatation (2.3+/-1.2
      versus 2. 7+/-0.9 versus 3.2+/-0.9 pg/mL, respectively; P for trend=0.039). None
      of the serum lipid measurements correlated with abdominal aortic diameter.
      Although CRP levels were associated with SAA levels (r=0.60; P<0.001),
      associations between CRP and aortic diameter were nonsignificant. In multivariate
      analysis, levels of IL-6 (P=0.02), SAA (P=0.001), and total homocysteine
      (P<0.001) were independent correlates of indexed aortic diameter. In conclusion,
      circulating levels of IL-6, SAA, and total homocysteine may reflect processes
      involved in the early phases of abdominal aortic aneurysm formation, before
      dilation of the abdominal aorta is established. These data support a role for
      chronic inflammation in the progression of asymptomatic aortic disease.

PMID- 10397689
TI  - Coexistence of oxidized lipids and alpha-tocopherol in all lipoprotein density
      fractions isolated from advanced human atherosclerotic plaques.
AB  - After investigation of the contents and redox status of antioxidants and lipids
      in homogenates of both normal artery and atherosclerotic plaque, we now
      investigated them in the density fractions (very low, low, high, and protein
      fractions) of atherosclerotic plaque freshly obtained from carotid
      endarterectomy. By using the optimum extraction method (homogenization in
      carbonate buffer) and after density gradient ultracentrifugation, we isolated and
      characterized density fractions of plaque for apolipoproteins, size and contents
      of alpha-tocopherol (alpha-TOH), unesterified cholesterol, cholesteryl linoleate
      (Ch18:2), and hydroxides and hydroperoxides of Ch18:2, ie, Ch18:2-O(O)H. The
      distribution of apolipoproteins was more heterogeneous than that in the
      corresponding lipoproteins isolated from blood, and the majority of material in
      all plaque density fractions was present in large particles eluting in the void
      volume of gel-filtration columns. The content of unesterified cholesterol per
      unit of protein in low- and high-density fractions was 10-fold that in
      corresponding plasma lipoproteins. Low- and very-low-density fractions contained
      most of the lesion lipids and alpha-TOH. Two to five percent of lesion Ch18:2 was
      present as Ch18:2-O(O)H and distributed more or less equally among all density
      fractions, yet the content of alpha-TOH per unit of Ch18:2 was higher than that
      in corresponding plasma lipoproteins. These results demonstrate that alpha-TOH
      and oxidized lipids coexist in all lesion density fractions, further supporting
      the notion that large proportions of lipids in lipoproteins of advanced stages of
      atherosclerosis are oxidized. However, although not ruling it out, our results do
      not support the suggestion that advanced stages of atherosclerosis are associated
      with gross deficiencies in the lipoproteins' vitamin E content.

PMID- 10397690
TI  - Oxidized low density lipoprotein suppresses expression of inducible
      cyclooxygenase in human macrophages.
AB  - Atherogenesis involves several aspects of chronic inflammation and wound healing.
      Indeed, the atheroma is considered a special case of tissue response to injury.
      Injurious stimuli may include lipoproteins trapped within lesions where protein
      and lipid moieties have undergone chemical modifications. We have studied the
      effect of oxidized low density lipoproteins (ox-LDL) on inducible cyclooxygenase
      (Cox-2) in human monocyte-derived macrophages exposed to bacterial
      lipopolysaccharide (LPS). Levels of both Cox-2 and constitutive cyclooxygenase
      (Cox-1) were assessed using Western blot analysis. Prior incubation of
      macrophages with ox-LDL resulted in a strong inhibition of Cox-2 induced by LPS,
      without effect on Cox-1. The inhibitory effect was dependent on ox-LDL
      concentration and its onset was early in time (already detectable 1 hour after
      macrophage exposure to ox-LDL). Native LDL, and other forms of modified LDL, were
      without effect. The inhibition was dependent on endocytosis of ox-LDL and could
      be reproduced using the lipid extract from ox-LDL. Lysophosphatidylcholine, 7beta
      hydroxycholesterol, and 7-oxocholesterol failed to mimic the inhibition, but
      oxidized arachidonic acid-containing phospholipids, produced by autoxidation of 1
      palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine, markedly inhibited Cox-2.
      The observation that ox-LDL downregulates Cox-2 in human macrophages may explain
      the fact that, within atheromata, the transformation of macrophages into foam
      cells results in attenuation of the inflammatory response, thus contributing to
      progression of atherogenesis.

PMID- 10397692
TI  - Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and
      body mass index in a white population.
AB  - The scavenger receptor class B type I (SR-BI) is a lipoprotein receptor that has
      been shown to be important in high density lipoprotein cholesterol (HDL-C)
      metabolism in mice. To determine its role in humans, we have characterized the
      human SR-BI gene and investigated its genetic variation in 489 white men and
      women. Five variants were demonstrated: 2 in introns (3 and 5) and 3 in exons (1,
      8, and 11). Three variants at exons 1 and 8 and intron 5 with allele frequencies
      >0.1 were used to examine associations with lipid or anthropometric variables.
      The exon 1 variant was significantly (P<0.05) associated with increased HDL-C and
      lower low density lipoprotein cholesterol (LDL-C) values in men, but no
      associations were observed in women. The exon 8 variant was associated in women
      with lower LDL-C concentrations (3.05+/-0.98 mmol/L and 3.00+/-0.93 mmol/L for
      heterozygotes and homozygotes, respectively) compared with women homozygous for
      the common allele (3.39+/-1.09 mmol/L, P=0. 043). No associations for this
      variant were observed in men. Women carriers of the intron 5 variant showed a
      higher body mass index (23. 8+/-3.8 kg/m2, P=0.031) than those women homozygous
      for the common allele (22.4+/-3.4 kg/m2). Similar results were observed after
      haplotype analysis. Multiple regression analysis using HDL-C, LDL-C, and body
      mass index as dependent variables and age, sex, and each of the genetic variants
      as predictors also provided similar results. The associations found with both LDL
      C and HDL-C suggest that SR-BI may play a role in the metabolism of both
      lipoprotein classes in humans.

PMID- 10397691
TI  - Glucocorticoid inhibits oxidized LDL-induced macrophage growth by suppressing the
      expression of granulocyte/macrophage colony-stimulating factor.
AB  - Glucocorticoid, an anti-inflammatory agent, inhibits the development of
      atherosclerosis in various experimental animal models. This is partially
      explained by its ability to inhibit smooth muscle cell migration and
      proliferation in the intima and to reduce chemotaxis of circulating monocytes and
      leukocytes into the subendothelial spaces. We have recently demonstrated that
      oxidized LDL (Ox-LDL) has a mitogenic activity for macrophages in vitro in which
      Ox-LDL-induced granulocyte/macrophage colony-stimulating factor (GM-CSF)
      production plays an important role. Proliferation of cellular components is one
      of the characteristic events in the development and progression of
      atherosclerotic lesions. In the present study, we investigated the effects of
      glucocorticoids on Ox-LDL-induced macrophage growth. Dexamethasone, prednisolone,
      and cortisol inhibited Ox-LDL-induced thymidine incorporation into macrophages by
      85%, 70%, and 50%, respectively. Ox-LDL induced a significant production of GM
      CSF by macrophages, which was effectively inhibited by dexamethasone,
      prednisolone, and cortisol by 80%, 65%, and 50%, respectively. Dexamethasone
      mediated inhibition of Ox-LDL-induced GM-CSF mRNA expression and macrophage
      growth was significantly abrogated by RU-486, a glucocorticoid receptor
      antagonist. Our results suggest that the inhibitory effects of glucocorticoids on
      macrophage growth may be due to the inhibition of Ox-LDL-induced GM-CSF
      production through transactivation of the glucocorticoid receptor.

PMID- 10397693
TI  - Impaired anticoagulant response to infusion of thrombin in atherosclerotic
      monkeys associated with acquired defects in the protein C system.
AB  - To examine the effects of atherosclerosis on the protein C anticoagulant pathway
      in vivo, we measured anticoagulant responses to intravenous administration of
      human alpha-thrombin or activated protein C (APC) in cynomolgus monkeys. Two
      groups of monkeys were fed either a control diet (n=18) or an atherogenic diet
      (n=12) that produces both hypercholesterolemia and moderate
      hyperhomocyst(e)inemia. A third group (n=8) was fed an atherogenic diet for 15
      months, and then fed the atherogenic diet supplemented with B vitamins for 6
      months to correct the hyperhomocyst(e)inemia. The plasma homocyst(e)ine level was
      higher in monkeys fed the atherogenic diet (9.6+/-1.0 micromol/L) than in monkeys
      fed the control diet (3.7+/-0.2 micromol/L) or the atherogenic diet with B
      vitamins (3.6+/-0.2 micromol/L) (P<0.001). Infusion of thrombin produced a much
      greater prolongation of the activated partial thromboplastin time in monkeys fed
      the control diet (52+/-10 seconds) than in monkeys fed the atherogenic diet
      either with (24+/-4 seconds) or without (27+/-5 seconds) supplemental B vitamins
      (P<0.02). Thrombin-dependent generation of circulating APC was higher in control
      (294+/-17 U/mL) than in atherosclerotic (240+/-14 U/mL) monkeys (P<0.05),
      although levels of fibrinogen, plasminogen, D-dimer, and thrombin-antithrombin
      complexes were similar in each group. Injection of human APC produced a similar
      prolongation of the activated partial thromboplastin time in control (31+/-3
      seconds) and atherosclerotic (29+/-2 seconds) monkeys. These findings provide
      evidence for impaired anticoagulation, due partly to decreased formation of APC,
      in atherosclerosis. The blunted anticoagulant response to thrombin in
      hypercholesterolemic monkeys was not corrected by supplementation with B
      vitamins.

PMID- 10397694
TI  - Inherited prothrombotic conditions and premature ischemic stroke: sex difference
      in the association with factor V Leiden.
AB  - At a young age, ischemic stroke is an uncommon event in which prothrombotic
      factors are likely to play an important role. In 202 referred cases, 105 men and
      97 women, median age 39 years (range, 3 to 50), with a history of ischemic stroke
      and in 1036 age frequency-matched apparently healthy individuals from the same
      ethnic background, we have investigated whether inherited prothrombotic
      conditions increase the risk of ischemic stroke. Neither abnormal plasma levels
      of natural anticoagulants and fibrinogen nor significant increase of the
      prothrombin A20210 allele was found in stroke cases compared with controls.
      Hypertension (odds ratio [OR], 22.61), male sex (OR, 2.30), smoking (OR, 2.78)
      and alcohol habits (OR, 0.14), a personal history of venous thromboembolism (OR,
      4.53), a family history of stroke (OR, 1.93), high circulating levels of
      fibrinogen (P=0.0190), and total cholesterol (P=0.101) were all independently
      associated with ischemic stroke. Compared with noncarriers, carriers of the
      factor V (FV) Leiden mutation (OR, 2.56), and to a lesser extent, of the
      methylenetetrahydrofolate reductase (MTHFR) TT genotype (OR, 1.60), had an
      independent higher estimated risk of having a history of ischemic stroke. The
      relationship with the FV Leiden mutation was greater in women (OR, 3.95). Thus,
      in addition to established determinants, FV Leiden mutation is independently
      associated with the occurrence of ischemic stroke in this setting. The greater
      association in women suggests the possibility of an interaction of this genotype
      with female hormones.

PMID- 10397696
TI  - Low folate levels and thermolabile methylenetetrahydrofolate reductase as primary
      determinant of mild hyperhomocystinemia in normal and thromboembolic subjects.
AB  - Several studies have indicated that mild to moderate hyperhomocystinemia is a
      common cause of arterial occlusive disease. Whether hyperhomocystinemia per se is
      an independent risk factor for vein thromboembolism (VTE) is still somewhat
      controversial. Both genetic and nutritional factors influence plasma homocysteine
      levels. Therefore, we evaluated plasma total homocysteine (tHcy), folate, and
      vitamin B12 levels and established, by polymerase chain reaction, the presence of
      the C677T mutation (A223V) in the methylenetetrahydrofolate reductase (MTHFR)
      gene in 220 cases with VTE without well-established prothrombotic defects. As a
      control group, 220 healthy subjects from the same geographic area as the cases
      were investigated. Hyperhomocystinemia was defined as a plasma tHcy level above
      the 95th percentile in the controls (18.05 micromol/L). Hyperhomocystinemia was
      found in 16% of cases (odds ratio=3.59; P<0.001); deficiencies of folate (<2.47
      ng/mL) or vitamin B12 (<165 pg/mL), defined as values below the 5th percentile in
      controls, were found in 17.7% (P<0.001) and 12.3% (P=0.015) of cases,
      respectively. The homozygous condition for the MTHFR mutation (VV) was present in
      28.2% of cases and 17.7% of controls (odds ratio=1.82; P=0.013). Comparing only
      the idiopathic forms of VTE (n=80/220; 36.3%) with normal controls, individuals
      with hyperhomocystinemia, or individuals homozygous for MTHFR mutation increased
      the odds ratios to 4.03 (P=0.005) and 2.11 (P=0.018), respectively. No
      statistically significant difference was observed in the MTHFR genotype
      distribution of cases and controls with hyperhomocystinemia (P=0.386); however,
      the normal MTHFR genotype (AA) appeared in control subjects only when tHcy levels
      were below the 80th percentile (10.57 micromol/L) of the distribution, whereas in
      case patients, it was present at the highest tHcy levels. A strong association
      between mutated homozygosity (VV), low folate levels, and hyperhomocystinemia was
      found in both groups. We conclude that in patients with VTE who do not have
      coexisting prothrombotic defects, hyperhomocystinemia increases the risk of
      developing idiopathic and venous thrombosis; the homozygous condition for the
      MTHFR mutation confers a moderate risk but, together with low folate levels, it
      is the main determinant of mild hyperhomocystinemia in normal and thromboembolic
      populations.

PMID- 10397695
TI  - Large amounts of vascular endothelial growth factor at the site of hemostatic
      plug formation in vivo.
AB  - Vascular endothelial growth factor (VEGF) is important for the proliferation,
      differentiation, and survival of microvascular endothelial cells. It is a potent
      angiogenic factor and a specific endothelial cell mitogen that increases
      fenestration and extravasation of plasma macromolecules. Recently, large
      quantities of VEGF were detected in human megakaryocytes. Incubation of human
      platelets with thrombin in vitro resulted in the release of large amounts of
      VEGF. To investigate whether VEGF is released from platelets during coagulation
      activation in vivo, we measured in human subjects VEGF at the site of plug
      formation, ie, in blood emerging from a standardized injury made to determine
      bleeding time (shed blood). VEGF was also determined in the same volunteers after
      treatment with the specific thrombin inhibitor recombinant hirudin (r-hirudin).
      In a double-blind, randomized, crossover study, 17 healthy male volunteers (aged
      20 to 35 years) were investigated. VEGF concentrations were measured in venous
      blood and in shed blood by the use of an immunoassay 10 minutes after intravenous
      administration of r-hirudin (0.35 mg/kg of body weight) or physiological saline.
      Prothrombin fragment f1.2 (f1.2) and beta-thromboglobulin (beta-TG) were
      determined as indicators of coagulation and platelet activation, respectively.
      Concentrations of VEGF, f1.2, and beta-TG in shed blood 4 minutes after injury
      were significantly higher than in venous blood (VEGF, 55.8+/-9.2 versus <20
      pg/mL, P<0.001; f1.2, 71.3+/-10.4 versus 0.78+/-0.03 nmol/L, P<0. 001; beta-TG,
      2290+/-170 versus 53.2+/-14.0 ng/mL, P<0.001). Administration of r-hirudin caused
      a >50% inhibition of the beta-TG and f1.2 levels in shed blood. In a similar
      manner, much lower amounts of VEGF were detectable at the site of plug formation
      after r-hirudin treatment (69.0+/-9.5 versus 37.8+/-2.6 pg/mL per minute;
      P=0.0015). Our data indicate that substantial quantities of VEGF are released
      from platelets during the interaction with the injured vessel wall in vivo. This
      finding may be relevant with respect to wound healing and tissue repair, tumor
      vascularization, or arterial thrombus formation.

PMID- 10397697
TI  - Endothelin-1 enhances plasminogen activator inhibitor-1 production by human brain
      endothelial cells via protein kinase C-dependent pathway.
AB  - The effects of endothelin-1 (ET-1) on the production of plasminogen activator
      inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA) by human brain
      derived endothelial cells in culture were studied. At 100 nmol/L, ET-1 increased
      PAI-1 production by 88+/-6% within 72 hours, and increased PAI-1 mRNA expression
      within 1 hour of stimulation; there was no significant effect on t-PA production.
      PAI-1 activity was also examined and found to increase with ET-1 treatment.
      Suboptimal concentrations of ET-1 and tumor necrosis factor-alpha (TNF-alpha)
      acted synergistically to increase PAI-1 production. ET-1 activated protein kinase
      C and cAMP-dependent protein kinase pathways within 3 to 5 minutes of treatment,
      with the peak at 10 minutes. Activation of protein kinase C by phorbol-12
      myristate-13-acetate (PMA) resulted in increased PAI-1 production, whereas
      activation of the cAMP-dependent protein kinase by forskolin or dibutyryl cAMP
      (dBu-cAMP) significantly decreased PAI-1 production. However, simultaneous
      activation of protein kinase C by PMA and cAMP-dependent protein kinase by dBu
      cAMP only slightly attenuated PMA-induced PAI-1 increase. Inhibition of protein
      kinase C by GF-109213X abolished the effects of ET-1. These results demonstrate
      that ET-1 and TNF-alpha function synergistically to induce procoagulant activity
      of brain endothelial cells in a process that involves a protein kinase C
      dependent pathway.

PMID- 10397698
TI  - The relationship of fibrinogen and factors VII and VIII to incident
      cardiovascular disease and death in the elderly: results from the cardiovascular
      health study.
AB  - Little is known about the prospective associations of fibrinogen, factor VII, or
      factor VIII with cardiovascular disease (CVD) and mortality in the elderly. At
      baseline in the Cardiovascular Health Study (5888 white and African American men
      and women; aged >/=65 years), we measured fibrinogen, factor VIII, and factor
      VII. We used sex-stratified stepwise Cox survival analysis to determine relative
      risks (RRs) for CVD events and all-cause mortality (up to 5 years of follow-up),
      both unadjusted and adjusted for CVD risk factors and subclinical CVD. After
      adjustment, comparing the fifth quintile to the first, fibrinogen was
      significantly associated in men with coronary heart disease events (RR=2.1) and
      stroke or transient ischemic attack (RR=1.3), and also with mortality within 2.5
      years of follow-up (RR=5.8) and later (RR=1.7). Factor VIII was significantly
      associated in men with coronary heart disease events (RR=1.5) and mortality
      (RR=1.8), and in women with stroke/transient ischemic attack (RR=1.4). For both
      factors, values were higher in those who died, whether causes were CVD-related or
      non-CVD-related, but highest in CVD death. Factor VII exhibited associations with
      incident angina (RR=1.44) in men and with death in women (RR, middle quintile
      compared with first=0.66). However, in general, factor VII was not consistently
      associated with CVD events in this population. We conclude that, if confirmed in
      other studies, the measurement of fibrinogen and/or factor VIII may help identify
      older individuals at higher risk for CVD events and mortality.

PMID- 10397699
TI  - Comparison of the inhibitory effects of ApoB100 and tissue factor pathway
      inhibitor on tissue factor and the influence of lipoprotein oxidation.
AB  - The procoagulant activity of tissue factor is regulated by circulating inhibitors
      such as tissue factor pathway inhibitor (TFPI) and LDL. These 2 inhibitors also
      readily associate making the distinction between their activities difficult. We
      have examined the relative contributions of intact and C-terminal truncated TFPI
      and ApoB100. By following the inhibitory potential of the preparations, over a
      period of 120 minutes, it was demonstrated that TFPI and LDL-resembling particles
      inhibited tissue factor at different rates. TFPI was found to be a short, fast
      acting inhibitor, whereas the action of LDL-resembling particles was more
      prolonged but slower. The oxidation of LDL has been closely associated with the
      development of cardiovascular disease, including atherosclerosis and thrombosis.
      Positively charged amino acids, particularly lysine residues, are prone to
      alterations via the formation of adducts by lipid peroxidation products. These
      residues are important in the inhibition of tissue factor activity by ApoB100.
      They also play an important role in the inhibitory Kunitz domains of TFPI. We
      have shown that the decline in the ability of LDL to inhibit tissue factor was as
      a result of modifications in LDL arising from oxidation. By examining the effects
      of oxidation on full-length and C-terminal truncated TFPI bound to LDL-resembling
      particles, we found that TFPI is only affected when in close association with
      ApoB100. C-terminal truncated TFPI was not affected significantly by oxidation.
      Finally, chemical modification of lysine and arginine residues reduced the
      overall inhibition of tissue factor by TFPI. We propose that TFPI and LDL act
      separately to inhibit tissue factor in vivo. However, the oxidation of LDL can
      alter both the endogenous activity of ApoB100 and reduce that of closely
      associated TFPI, compromising normal hemostasis.

PMID- 10397700
TI  - Storage of tissue-type plasminogen activator in Weibel-Palade bodies of human
      endothelial cells.
AB  - Tissue-type plasminogen activator (t-PA) is acutely released by endothelial
      cells. Although its endothelial storage compartment is still not well defined, t
      PA release is often accompanied by release of von Willebrand factor (vWf), a
      protein stored in Weibel-Palade bodies. We investigated, therefore, whether t-PA
      is stored in these secretory organelles. Under basal culture conditions, a
      minority of human umbilical vein endothelial cells (HUVEC) exhibited
      immunofluorescent staining for t-PA, which was observed only in Weibel-Palade
      bodies. To increase t-PA expression, HUVEC were infected with a t-PA recombinant
      adenovirus (AdCMVt-PA). Overexpressed t-PA was detected in Weibel-Palade bodies
      and acutely released together with endogenous vWf by thrombin or calcium
      ionophore stimulation. In contrast, plasminogen activator inhibitor type 1 and
      urokinase were not detected in Weibel-Palade bodies after adenovirus-mediated
      overexpression. Infection of HUVEC with proinsulin recombinant adenovirus
      resulted in the storage of insulin in Weibel-Palade bodies, indicating that these
      organelles can also store nonendothelial proteins that show regulated secretion.
      Infection of AtT-20 pituitary cells, a cell type with regulated secretion, with
      AdCMVt-PA resulted in the localization of t-PA in adrenocorticotropic hormone
      containing granules, indicating that t-PA can be diverted to secretory granules
      independently of vWf. Coinfection of AtT-20 cells with AdCMVt-PA and proinsulin
      recombinant adenovirus resulted in the colocalization of t-PA and insulin in the
      same granules. Taken together, these results suggest that HUVEC have protein
      sorting mechanisms similar to those of other regulated secretory cells. Although
      the results did not exclude an alternative storage site for t-PA in HUVEC, they
      established that t-PA can be stored in Weibel-Palade bodies. This finding may
      explain the acute coordinate secretion of t-PA and vWf.

PMID- 10397701
TI  - A transcriptional repressor of the tissue factor gene in endothelial cells.
AB  - Tissue factor, the high-affinity receptor and cofactor for the plasma serine
      protease VII/VIIa, is the primary cellular initiator of the blood coagulation
      cascade. Inside the vasculature, expression of the tissue factor gene must be
      tightly controlled. Whereas the endothelium normally does not express tissue
      factor, on stimulation with inflammatory cytokines or endotoxin the gene is
      transcriptionally upregulated leading to a procoagulant state. We have now
      detected a repressive cis-acting element in the tissue factor promoter that
      downmodulates tissue factor transcription in endothelial cells. In reporter gene
      assays, deletion of this element leads to an increase of tissue factor
      transcription and insertion of a trimerized site reduces transcription. Specific
      protein/DNA complexes are formed on the element with nuclear extracts in
      electrophoretic mobility shift assays and cross-linking of the proteins followed
      by SDS-PAGE detects the presence of at least 2 subunits of approximately 40 and
      60 kDa, respectively. After transfection of different cell types with the
      reporter genes, the suppressive effect of the element can only be revealed in
      endothelial cells. These data suggest that this element represents a novel
      transcription factor target sequence that functions to suppress expression of the
      tissue factor gene, preferentially in endothelial cells thereby supporting a
      noncoagulant state.

PMID- 10397702
TI  - Platelet deposition on eroded vessel walls at a stenotic shear rate is inhibited
      by lipid-lowering treatment with atorvastatin.
AB  - Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase are widely used in
      the treatment of dyslipemias and have shown beneficial effects in the primary and
      secondary prevention of cardiovascular diseases. However, regression studies with
      lipid-lowering drugs have not shown significant lesion reduction associated with
      the improvement in clinical events. Therefore, our objective has been to study
      whether treatment with a lipid-lowering drug of this family, atorvastatin, could
      reduce platelet deposition on the damaged vessel wall at different shear stress
      conditions, simultaneously with retardation of the development of atherosclerotic
      lesions. Using cholesterol-fed swine as the model, we found that atorvastatin
      significantly diminished platelet deposition on the mildly damaged vessel wall at
      high shear rates (50%, P<0.01), but it did not have any effect in preventing
      platelet deposition triggered by a severely injured vessel wall. Development of
      coronary lesions was also reduced by treatment. These findings suggest that
      atorvastatin may prevent platelet attachment to eroded vessels and hence,
      contribute to reducing the thrombotic risk associated with the erosions of the
      luminal surface and the platelet-dependent progression of atherosclerotic
      plaques.

PMID- 10397703
TI  - Choosing the source of stem cells for allogeneic transplantation: no longer a
      peripheral issue.

PMID- 10397704
TI  - The risk of residual molecular and cytogenetic disease in patients with
      Philadelphia-chromosome positive first chronic phase chronic myelogenous leukemia
      is reduced after transplantation of allogeneic peripheral blood stem cells
      compared with bone marrow.
AB  - The detection of residual molecular and cytogenetic disease was prospectively
      compared in patients with Philadelphia-chromosome (Ph1) positive first chronic
      phase chronic myelogenous leukemia (CML) who underwent allogeneic transplantation
      of unmanipulated peripheral blood stem cells (PBSCT) (n = 29) or bone marrow (BM)
      (n = 62) using genotypically HLA-identical sibling donors or partially HLA
      matched extended family donors. A molecular relapse (MR), as defined by two
      consecutive positive polymerase chain reaction (PCR) assays for the detection of
      M-bcr-abl transcripts in a 4-week interval, was found in two of 29 (7%) patients
      after PBSCT compared with 20 of 62 (32%) patients after bone marrow
      transplantation (BMT). This corresponds to a 4-year molecular relapse estimate
      (+/- standard error) of 7% +/- 5% after PBSCT and of 44% +/- 8% after BMT (P
      <.009). With identical follow-up periods of survivors in both patient subsets
      between 6 and 55 months (median, 28 months), 14 of the 20 patients with MR after
      BMT progressed to an isolated cytogenetic (n = 10) or a hematologic (n = 4)
      disease recurrence, resulting in a 4-year cytogenetic relapse estimate of 47% +/-
      11%, while none of the patients after PBSCT has so far relapsed (P <.006).
      Multivariate analysis including all potential influencial factors of
      posttransplant disease recurrence identified the source of stem cells (P <.02) as
      the only independent predictor of molecular relapse. In conclusion, this
      prospective comparison of molecular and cytogenetic residual disease demonstrates
      that peripheral blood stem cell transplants have a more pronounced activity
      against residual CML cells than bone marrow transplants. Prospective randomized
      trials comparing PBSCT and BMT in patients with first chronic phase Ph1-positive
      CML are strictly required to further substantiate differences in the antileukemic
      activity of the two stem cell sources.

PMID- 10397705
TI  - Massive activation-induced cell death of alloreactive T cells with apoptosis of
      bystander postthymic T cells prevents immune reconstitution in mice with graft
      versus-host disease.
AB  - After hematopoietic stem cell transplantation, the persistence and expansion of
      grafted mature postthymic T cells allow both transfer of donor immunologic memory
      and generation of a diverse T repertoire. This thymic-independent process, which
      is particularly important in humans, because most transplant recipients present
      severe thymus atrophy, is impaired by graft-versus-host disease (GVHD). The goal
      of this study was to decipher how GVHD influences the fate of grafted postthymic
      T cells. Two major findings emerged. First, we found that, after a brisk
      proliferation phase, alloreactive antihost T cells underwent a massive activation
      induced cell death (AICD). For both CD4(+) and CD8(+) T cells, the Fas pathway
      was found to play a major role in this AICD: alloreactive T cells upregulated Fas
      and FasL, and AICD of antihost T cells was much decreased in the case of lpr (Fas
      deficient) donors. Second, whereas non-host-reactive donor T cells neither
      upregulated Fas nor suffered apoptosis when transplanted alone, they showed
      increased membrane Fas expression and apoptosis when coinjected with host
      reactive T cells. We conclude that GVHD-associated AICD of antihost T cells
      coupled with bystander lysis of grafted non-host-reactive T cells abrogate immune
      reconstitution by donor-derived postthymic T lymphocytes. Furthermore, we
      speculate that massive lymphoid apoptosis observed in the acute phase of GVHD
      might be responsible for the occurrence of autoimmunity in the chronic phase of
      GVHD.

PMID- 10397706
TI  - Efficient gene delivery to quiescent interleukin-2 (IL-2)-dependent cells by
      murine leukemia virus-derived vectors harboring IL-2 chimeric envelope
      glycoproteins.
AB  - Interleukin-2 (IL-2) is a cytokine that induces the proliferation of certain IL-2
      receptor expressing quiescent cells. Human IL-2 was fused to the amino-terminus
      of amphotropic murine leukemia virus (MLV) envelope glycoproteins. Retroviral
      vectors were pseudotyped with both the IL-2 chimeric envelope and the wild-type
      amphotropic MLV envelope. The chimeric IL-2 glycoproteins were incorporated on
      retroviral vectors and the IL-2-displaying vector particles could bind
      specifically to cell surface IL-2 receptors. In addition, the IL-2-displaying
      vectors could infect proliferating cells through amphotropic receptors
      irrespective of whether the cells expressed the IL-2 receptor. IL-2-displaying
      vector particles could also transiently stimulate the cell cycle entry and
      proliferation of several IL-2-dependent cell lines. Finally, retroviral vectors
      displaying IL-2 could efficiently transduce G0/G1-arrested cells expressing the
      IL-2 receptor at a 34-fold higher efficiency compared with vectors with
      unmodified envelopes. This new strategy, whereby C-type retroviral vector
      particles display a ligand that activates the cell cycle of the target cells at
      the time of virus entry, may represent an alternative to lentivirus-derived
      retroviral vectors for the infection of quiescent cells. In addition, upon
      infection of an heterogeneous population of nonproliferating cells, MLV
      retroviral vectors that display cytokines/growth factors will allow the transgene
      of interest to be integrated specifically in quiescent cells expressing the
      corresponding cytokine/growth factor receptor.

PMID- 10397707
TI  - Reed-Sternberg cell genome expression supports a B-cell lineage.
AB  - The malignant Reed-Sternberg cell of Hodgkin's disease, first described a century
      ago, has resisted in-depth analysis due to its extreme rarity in lymphomatous
      tissue. To directly study its genome-wide gene expression, approximately
      11,000,000 bases (27,518 cDNA sequences) of expressed gene sequence was
      determined from living single Reed-Sternberg cells, Hodgkin's tissue, and cell
      lines. This approach increased the number of genes known to be expressed in
      Hodgkin's disease by 20-fold to 2,666 named genes. The data here indicate that
      Reed-Sternberg cells from both nodular sclerosing and lymphocyte predominant
      Hodgkin's disease were derived from an unusual B-cell lineage based on a
      comparison of their gene expression to approximately 40,000,000 bases (10(5)
      sequences) of expressed gene sequence from germinal center B cells (GCB) and
      dendritic cells. The data set of expressed genes, reported here and on the World
      Wide Web, forms a basis to understand the genes responsible for Hodgkin's disease
      and develop novel diagnostic markers and therapies. This study of the rare Reed
      Sternberg cell, concealed in its heterogenous cellular context, also provides a
      formidable test case to advance the limit of analysis of differential gene
      expression to the single disease cell.

PMID- 10397708
TI  - Chromatin remodeling and leukemia: new therapeutic paradigms.

PMID- 10397709
TI  - Whole-body positron emission tomography using 18F-fluorodeoxyglucose for
      posttreatment evaluation in Hodgkin's disease and non-Hodgkin's lymphoma has
      higher diagnostic and prognostic value than classical computed tomography scan
      imaging.
AB  - A residual mass after treatment of lymphoma is a clinical challenge, because it
      may represent vital tumor as well as tissue fibrosis. Metabolic imaging by 18F
      fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) offers the
      advantage of functional tissue characterization that is largely independent of
      morphologic criteria. We compared 18F-FDG PET to computed tomography (CT) in the
      posttreatment evaluation of 54 patients with Hodgkin's disease (HD) or
      intermediate/high-grade non-Hodgkin's lymphoma (NHL). Residual masses on CT were
      observed in 13 of 19 patients with HD and 11 of 35 patients with NHL. Five of 24
      patients with residual masses on CT versus 1 of 30 patients without residual
      masses presented a positive 18F-FDG PET study. Relapse occurred in all 6 patients
      (100%) with a positive 18F-FDG PET, 5 of 19 patients (26%) with residual masses
      on CT but negative 18F-FDG PET, and 3 of 29 patients (10%) with negative CT scan
      and 18F-FDG PET studies (P </=.0001). We observed a higher relapse and death rate
      in patients with residual masses at CT compared with patients without residual
      masses at CT (progression-free survival at 1 year: 62 +/- 10 v 88 +/- 7%, P =.
      0045; overall survival at 1 year: 77 +/- 5 v 95 +/- 5%, P =.0038). A positive 18F
      FDG PET study was even more consistently associated with poorer survival:
      compared with patients with a negative 18F-FDG PET study, the 1-year progression
      free survival was 0% versus 86% +/- 5% (P <.0001) and the 1-year overall survival
      was 50% +/- 20% versus 92% +/- 4% (P <.0001). The detection of vital tumor by 18F
      FDG PET after the end of treatment has a higher predictive value for relapse than
      classical CT scan imaging (positive predictive value: 100% v 42%). This could
      help identify patients requiring intensification immediately after completion of
      chemotherapy. However, 18F-FDG PET mainly predicts for early progression but
      cannot exclude the presence of minimal residual disease, possibly leading to a
      later relapse.

PMID- 10397711
TI  - Effect of Epstein-Barr virus infection on response to chemotherapy and survival
      in Hodgkin's disease.
AB  - We have analyzed paraffin sections from 190 patients with histologically
      confirmed Hodgkin's disease (HD) for the presence of Epstein-Barr virus (EBV)
      using in situ hybridization to detect the EBV-encoded Epstein-Barr virus early
      RNAs (EBERs) and immunohistochemistry to identify latent membrane protein-1
      (LMP1) expression. EBV was present in the tumor cells in 51 HD cases (27%) and
      was mainly confined to the mixed cellularity and nodular sclerosis subtypes.
      There was no difference between EBV-positive and EBV-negative HD patients with
      regard to age, clinical stage, presentation, and the number of alternating
      chemotherapy cycles of ChIVPP and PABIOE received. The complete remission rate
      after study chemotherapy was 80% in EBV-positive patients versus 69% in EBV
      negative patients (P =.05). The 2-year failure-free survival rate was
      significantly better for EBV-positive patients when compared with the EBV
      negative HD group (P =.02). Although 2-year and 5-year overall survival rates
      were better for EBV-positive HD patients, the differences were not statistically
      significant (P =.18 and P =.40, respectively). In conclusion, the results confirm
      the favorable prognostic value of EBV in the tumor cells of HD patients and
      suggest important differences in response to chemotherapy between EBV-positive
      and EBV-negative patients.

PMID- 10397712
TI  - Clinical characteristics and outcome of young chronic lymphocytic leukemia
      patients: a single institution study of 204 cases.
AB  - A retrospective analysis on chronic lymphocytic leukemia (CLL) patients </=55
      years observed at a single institution was performed with the purpose of
      characterizing the clinical features and outcome of young CLL and of identifying
      patients with different prognostic features. Over the period from 1984 to 1994,
      1,011 CLL patients (204 [20%] </=55 years of age and 807 [80%] >55 years of age)
      were observed. At diagnosis, younger and older patients displayed a similar
      distribution of clinical features, except for a significantly higher male/female
      ratio in younger patients (2.85 v 1. 29; P <.0001). Both groups showed an
      elevated rate of second primary cancers (8.3% v 10.7%), whereas the occurrence of
      Richter's syndrome was significantly higher in younger patients (5.9% v 1.2%; P
      <. 00001). Younger and older patients showed a similar overall median survival
      probability (10 years) but were characterized by a different distribution of
      causes of deaths: CLL unrelated deaths and second primary malignancies
      predominated in the older age group, whereas the direct effects of leukemia were
      prevalent in the younger age group. Although younger and older patients displayed
      a similar survival, the evaluation of the relative survival rates showed that the
      disease had a greater adverse effect on the expected survival probability of the
      younger population. Multivariate analysis showed that for young CLL patients only
      dynamic parameters, such as lymphocyte doubling time and other signs of active
      disease, were the independent factors that significantly influenced survival
      probability (P =.00001). A prolonged clinico-hematologic follow-up allowed us to
      identify two subsets of young CLL patients with a different prognostic outcome: a
      group of patients (40%) with long-lasting stable disease without treatment and an
      actuarial survival probability of 94% at 12 years from diagnosis and another
      group (60%) with progressive disease and a median survival probability of 5 years
      after therapy. For the latter patients, the therapeutic effect of innovative
      therapies with curative intents needs to be investigated in prospective,
      comparative clinical trials.

PMID- 10397710
TI  - T-cell depletion plus salvage immunotherapy with donor leukocyte infusions as a
      strategy to treat chronic-phase chronic myelogenous leukemia patients undergoing
      HLA-identical sibling marrow transplantation.
AB  - T-cell depletion (TCD) of the donor marrow graft has been shown to reduce the
      severity of graft-versus-host disease (GVHD) in patients with chronic-phase (CP)
      chronic myelogenous leukemia (CML) undergoing HLA-identical sibling allogeneic
      marrow transplantation. However, there has been a corresponding reduction in the
      graft-versus-leukemia effect so that any decrease in GVHD-related mortality has
      been offset by an increased rate of disease relapse. Therapy of recurrent disease
      with donor leukocyte infusions (DLI) has been proven to be effective salvage
      therapy for the majority of patients who relapse after allogeneic BMT with CP
      CML. However, the overall impact of salvage DLI therapy on the survival of CP CML
      patients initially transplanted with TCD marrow grafts is not defined. To address
      this question, we have evaluated a clinical strategy of TCD followed by targeted
      adoptive immunotherapy with DLI in 25 CP CML patients undergoing allogeneic BMT
      from HLA-identical siblings. All patients received a standardized preparative
      regimen along with ex vivo TCD and posttransplant cyclosporine as GVHD
      prophylaxis. Durable engraftment was observed in all 25 patients. The incidence
      of grade II to IV acute GVHD was 8%. The cumulative incidence of transplant
      related mortality (TRM) was 4%, and the 1-year probability of overall survival
      was 96%. The 3-year cumulative relapse incidence was 49%. All relapsed patients
      received DLI to reinduce remission. The total T-cell dose administered to these
      patients varied from 0.1 to 5.0 x 10(8) T cells/kg. Complete responses were
      observed in 12 of 14 patients, with 1 additional patient still too early to
      evaluate. Three patients died of GVHD after DLI, and 1 relapsed into blast crisis
      after a transient cytogenetic remission. Of the remaining 10 patients, 8 are in
      molecular remission, 1 is alive in relapse, and 1 is receiving DLI treatment. The
      median follow-up after infusion of surviving DLI patients in remission is 5.3
      years. The probability of overall 5-year survival for the entire population is
      80%, with a median follow-up of 6.4 years. We conclude that the clinical strategy
      of TCD followed by targeted adoptive immunotherapy with DLI for those patients
      with evidence of recurrent disease is a viable transplant strategy for CP CML,
      resulting in 80% survival and a low risk of acute GVHD and transplant-related
      mortality.

PMID- 10397713
TI  - Peripheral blood stem cell transplantation from unrelated donors: a comparison
      with marrow transplantation.
AB  - Peripheral blood stem cell (PBSC) transplants from HLA-A, -B, and -DR compatible
      unrelated donors (n = 45) were compared with bone marrow (BM; BM group, n = 45).
      Eighteen patients received CD34-selected PBSC (CD34 group). The PBSCs contained
      more mononuclear cells, CD34(+), CD3(+), and CD56(+) cells compared with marrow
      (P <.001). Engraftment was achieved in all 45 patients in the BM group, in 43 of
      45 (95%) in the PBSC group, and in 14 of 18 (78%) in the CD34 group (P <.01). In
      multivariate analysis, a short time to absolute neutrophil count (ANC) equal to
      0.5 x 10(9)/L was associated with the PBSC/CD34 groups (P <.001) and granulocyte
      colony-stimulating factor (G-CSF) treatment (P =.017). A short time to platelets
      equal to 50 x 10(9)/L was associated with PBSC (P =. 003) and no methotrexate (P
      =.015). Grades II-IV acute graft-versus-host disease (GVHD) was 20% in the BM
      controls, 30% in the PBSC group, and 18% in the CD34 group (not significant
      [NS]). The probability of chronic GVHD was 85% in the BM group, 59% in the PBSC
      group, and 0% in the CD34 group (P <.01). One-year transplant-related mortality
      was 21% and 27% and survival was 53% and 54% in the BM and PBSC groups,
      respectively (NS). The 2-year relapse-free survival was 41% and 46% in the two
      groups, respectively.

PMID- 10397714
TI  - Correction of uroporphyrinogen decarboxylase deficiency (hepatoerythropoietic
      porphyria) in Epstein-Barr virus-transformed B-cell lines by retrovirus-mediated
      gene transfer: fluorescence-based selection of transduced cells.
AB  - Hepatoerythropoietic porphyria (HEP) is an inherited metabolic disorder
      characterized by the accumulation of porphyrins resulting from a deficiency in
      uroporphyrinogen decarboxylase (UROD). This autosomal recessive disorder is
      severe, starting early in infancy with no specific treatment. Gene therapy would
      represent a great therapeutic improvement. Because hematopoietic cells are the
      target for somatic gene therapy in this porphyria, Epstein-Barr virus-transformed
      B-cell lines from patients with HEP provide a model system for the disease. Thus,
      retrovirus-mediated expression of UROD was used to restore enzymatic activity in
      B-cell lines from 3 HEP patients. The potential of gene therapy for the metabolic
      correction of the disease was demonstrated by a reduction of porphyrin
      accumulation to the normal level in deficient transduced cells. Mixed culture
      experiments demonstrated that there is no metabolic cross-correction of deficient
      cells by normal cells. However, the observation of cellular expansion in vitro
      and in vivo in immunodeficient mice suggested that genetically corrected cells
      have a competitive advantage. Finally, to facilitate future human gene therapy
      trials, we have developed a selection system based on the expression of the
      therapeutic gene. Genetically corrected cells are easily separated from deficient
      ones by the absence of fluorescence when illuminated under UV light.

PMID- 10397715
TI  - Developmental expression of plasminogen activator inhibitor-1 associated with
      thrombopoietin-dependent megakaryocytic differentiation.
AB  - Plasminogen activator inhibitor-1 (PAI-1) is present in the platelet alpha
      granule and is released on activation. However, there is some debate as to
      whether the megakaryocyte and platelet synthesize PAI-1, take it up from plasma,
      or both. We examined the expression of PAI-1 in differentiating megakaryocytic
      progenitor cells (UT-7) and in CD34(+)/CD41(-) cells from cord blood. UT-7 cells
      differentiated with thrombopoietin (TPO) resembled megakaryocytes (UT-7/TPO) with
      respect to morphology, ploidy, and the expression of glycoprotein IIb-IIIa. PAI-1
      messenger RNA (mRNA) expression was upregulated and PAI-1 protein synthesized in
      the UT-7/TPO cells accumulated in the cytoplasm without being released
      spontaneously. In contrast, erythropoietin (EPO)-stimulated UT-7 cells (UT-7/EPO)
      did not express PAI-1 mRNA after stimulation with TPO because they do not have
      endogenous c-Mpl. After cotransfection with human wild-type c-mpl, the cells (UT
      7/EPO-MPL) responded to phorbol 12-myristate 13-acetate (PMA), tumor necrosis
      factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) with enhanced PAI-1
      mRNA expression within 24 to 48 hours. However, induction of PAI-1 mRNA in UT
      7/EPO-MPL cells by TPO required at least 14-days stimulation. UT-7/EPO cells
      expressing c-Mpl changed their morphology and the other characteristics similar
      to the UT-7/TPO cells. TPO also differentiated human cord blood CD34(+)/CD41(-)
      cells to CD34(-)/CD41(+) cells, generated morphologically mature megakaryocytes,
      and induced the expression of PAI-1 mRNA. These results suggest that both PAI-1
      mRNA and de novo PAI-1 protein synthesis is induced after differentiation of
      immature progenitor cells into megakaryocytes by TPO.

PMID- 10397716
TI  - All-trans retinoic acid delays the differentiation of primitive hematopoietic
      precursors (lin-c-kit+Sca-1(+)) while enhancing the terminal maturation of
      committed granulocyte/monocyte progenitors.
AB  - All-trans retinoic acid (ATRA) is a potent inducer of terminal differentiation of
      malignant promyelocytes, but its effects on more primitive hematopoietic
      progenitors and stem cells are less clear. In this study, we investigated the
      effect of ATRA on highly enriched murine hematopoietic precursor cells (lin-c
      kit+Sca-1(+)) grown in liquid suspension culture for 28 days. ATRA initially
      slowed the growth of these hematopoietic precursors but prolonged and markedly
      enhanced their colony-forming cell production compared with the hematopoietic
      precursors cultured in its absence. At 7 and 14 days of culture, a substantially
      greater percentage of cells cultured with ATRA did not express lineage-associated
      antigens (55.4% at day 7 and 68.6% at day 14) and retained expression of Sca-1
      (44.7% at day 7 and 79.9% at day 14) compared with cells grown in its absence
      (lin- cells: 31.5% at day 7 and 4% at day 14; Sca-1(+): 10.4% at day 7 and 0.7%
      at day 14). Moreover, a marked inhibition of granulocyte production was observed
      in cultures continuously incubated with ATRA. Significantly, ATRA markedly
      prolonged and enhanced the production of transplantable colony-forming unit
      spleen (CFU-S) during 14 days of liquid suspension culture. In contrast with its
      effects on primitive lin-c-kit+Sca-1(+) hematopoietic precursors, ATRA did not
      exert the same effects on the more committed lin-c-kit+Sca-1(-) progenitor cells.
      Moreover, the late addition of ATRA (7 days post-culture initiation) to cultures
      of primitive hematopoietic precursors resulted in a marked decrease in colony
      forming cell production in these cultures, which was associated with enhanced
      granulocyte differentiation. These observations indicate that ATRA has different
      effects on hematopoietic cells depending on their maturational state, preventing
      and/or delaying the differentiation of primitive hematopoietic precursors while
      enhancing the terminal differentiation of committed granulocyte/monocyte
      progenitors.

PMID- 10397718
TI  - The thrombocytopenia of Wiskott Aldrich syndrome is not related to a defect in
      proplatelet formation.
AB  - The Wiskott-Aldrich syndrome (WAS) is an X-linked hereditary disease
      characterized by thrombocytopenia with small platelet size, eczema, and increased
      susceptibility to infections. The gene responsible for WAS was recently cloned.
      Although the precise function of WAS protein (WASP) is unknown, it appears to
      play a critical role in the regulation of cytoskeletal organization. The platelet
      defect, resulting in thombocytopenia and small platelet size, is a consistent
      finding in patients with mutations in the WASP gene. However, its exact mechanism
      is unknown. Regarding WASP function in cytoskeletal organization, we investigated
      whether these platelet abnormalities could be due to a defect in proplatelet
      formation or in megakaryocyte (MK) migration. CD34(+) cells were isolated from
      blood and/or marrow of 14 WAS patients and five patients with hereditary X-linked
      thrombocytopenia (XLT) and cultured in serum-free liquid medium containing
      recombinant human Mpl-L (PEG-rHuMGDF) and stem-cell factor (SCF) to study in
      vitro megakaryocytopoiesis. In all cases, under an inverted microscope, normal MK
      differentiation and proplatelet formation were observed. At the ultrastructural
      level, there was also no abnormality in MK maturation, and normal filamentous MK
      were present. Moreover, the in vitro produced platelets had a normal size, while
      peripheral blood platelets of the same patients exhibited an abnormally small
      size. However, despite this normal platelet production, we observed that F-actin
      distribution was abnormal in MKs from WAS patients. Indeed, F-actin was regularly
      and linearly distributed under the cytoplasmic membrane in normal MKs, but it was
      found concentrated in the center of the WAS MKs. After adhesion, normal MKs
      extended very long filopodia in which WASP could be detected. In contrast, MKs
      from WAS patients showed shorter and less numerous filopodia. However, despite
      this abnormal filopodia formation, MKs from WAS patients normally migrated in
      response to stroma-derived factor-1alpha (SDF-1alpha), and actin normally
      polymerized after SDF-1alpha or thrombin stimulation. These results suggest that
      the platelet defect in WAS patients is not due to abnormal platelet production,
      but instead to cytoskeletal changes occuring in platelets during circulation.

PMID- 10397717
TI  - Interleukin-6 directly modulates stem cell factor-dependent development of human
      mast cells derived from CD34(+) cord blood cells.
AB  - In the present study, we attempted to clarify the effects of interleukin-6 (IL-6)
      on the growth and properties of human mast cells using cultured mast cells
      selectively generated by stem cell factor (SCF) from CD34(+) cord blood cells.
      The addition of IL-6 to cultures containing mast cells resulted in a substantial
      reduction of the number of progenies grown by SCF in the liquid culture. This IL
      6-mediated inhibition of mast cell growth may be due in part to the suppression
      at the precursor level, according to the results of a clonal cell culture assay.
      Moreover, a flow cytometric analysis showed that the cultured mast cells grown in
      the presence of SCF+IL-6 had decreased c-kit expression. The exposure of cultured
      mast cells to SCF+IL-6 also caused substantial increases in the cell size,
      frequency of chymase-positive cells, and intracellular histamine level compared
      with the values obtained with SCF alone. The flow cytometric analysis showed low
      but significant levels of expression of IL-6 receptor (IL-6R) and gp130 on the
      cultured mast cells grown with SCF. The addition of either anti-IL-6R antibody or
      anti-gp130 antibody abrogated the biological functions of IL-6. Although IL-4
      exerted an effect similar to that of IL-6 on the cultured mast cells under
      stimulation with SCF, the results of comparative experiments suggest that the two
      cytokines use different regulatory mechanisms. Taken together, the present
      findings suggest that IL-6 modulates SCF-dependent human mast cell development
      directly via an IL-6R-gp130 system.

PMID- 10397719
TI  - Constitutive HOXA5 expression inhibits erythropoiesis and increases myelopoiesis
      from human hematopoietic progenitors.
AB  - The role of the homeobox gene HOXA5 in normal human hematopoiesis was studied by
      constitutively expressing the HOXA5 cDNA in CD34(+) and CD34(+)CD38(-) cells from
      bone marrow and cord blood. By using retroviral vectors that contained both HOXA5
      and a cell surface marker gene, pure populations of progenitors that expressed
      the transgene were obtained for analysis of differentiation patterns. Based on
      both immunophenotypic and morphological analysis of cultures from transduced
      CD34(+) cells, HOXA5 expression caused a significant shift toward myeloid
      differentiation and away from erythroid differentiation in comparison to CD34(+)
      cells transduced with Control vectors (P =.001, n = 15 for immunophenotypic
      analysis; and P <.0001, n = 19 for morphological analysis). Transduction of more
      primitive progenitors (CD34(+)CD38(-) cells) resulted in a significantly greater
      effect on differentiation than did transduction of the largely committed CD34(+)
      population (P =.006 for difference between HOXA5 effect on CD34(+) v CD34(+)CD38(
      ) cells). Erythroid progenitors (burst-forming unit-erythroid [BFU-E]) were
      significantly decreased in frequency among progenitors transduced with the HOXA5
      vector (P =.016, n = 7), with no reduction in total CFU numbers. Clonal analysis
      of single cells transduced with HOXA5 or control vectors (cultured in erythroid
      culture conditions) showed that HOXA5 expression prevented erythroid
      differentiation and produced clones with a preponderance of undifferentiated
      blasts. These studies show that constitutive expression of HOXA5 inhibits human
      erythropoiesis and promotes myelopoiesis. The reciprocal inhibition of
      erythropoiesis and promotion of myelopoiesis in the absence of any demonstrable
      effect on proliferation suggests that HOXA5 diverts differentiation at a
      mulitpotent progenitor stage away from the erythroid toward the myeloid pathway.

PMID- 10397720
TI  - Murine stromal cells counteract the loss of long-term culture-initiating cell
      potential induced by cytokines in CD34(+)CD38(low/neg) human bone marrow cells.
AB  - Evidence has been provided recently that shows that high concentrations of
      cytokines can fulfill functions previously attributed to stromal cells, such as
      promote the survival of, and led to a net increase in human primitive progenitors
      initiating long-term cultures in vitro (LTC-IC) or engrafting NOD-SCID (nonobese
      diabetic severe-combined immunodeficient) recipients in vivo. These data prompted
      us to re-evaluate whether stromal cells will further alter the properties of
      primitive progenitor cells exposed to cytokines. Single CD34(+)CD38(low) and
      CD38(neg) cells were incubated 10 days in serum-containing or serum-free medium
      in the presence or in the absence of murine marrow-derived stromal cells (MS-5).
      Recombinant human cytokines stem cell factor (SCF), pegylated-megakaryocyte
      growth and differentiation factor (PEG-MGDF), FLT3-L, Interleukin (IL)-3, IL-6,
      and granulocyte-macrophage colony-stimulating factor (GM-CSF) were systematically
      added at various concentrations (10 to 300 ng/mL). Cell proliferation and LTC-IC
      potential were evaluated in each clone after 10 days. A striking and consistent
      observation was the retention of a high LTC-IC potential in clones exposed to
      cytokines in the presence of stromal feeders, whereas clones exposed to cytokines
      alone in the absence of stromal feeders rapidly lost their LTC-IC potential as
      they proliferated. This was reflected both by the higher proportion of wells
      containing LTC-IC and by the high numbers of CFC produced after 5 weeks in clones
      grown with MS-5 during the first 10 days. We further showed by analyzing multiple
      replicates of a single clone at day 10 that MS-5 cells promoted a net increase in
      the LTC-IC compartment through self-renewal divisions. Interestingly, these
      primitive LTC-IC were equally distributed among small and large clones, as
      counted at day 10, indicating that active proliferation and loss of LTC-IC
      potential could be dissociated. These observations show that, in primitive cells,
      stromal cells counteract differentiation events triggered by cytokines and
      promoted self-renewal divisions. Furthermore, the almost identical distribution
      of the size of the clones with or without MS-5 suggests that proliferation and
      function of human primitive cells may be independently regulated by external
      signals, and that the former is primarily under the control of cytokines.

PMID- 10397721
TI  - The receptor protein tyrosine phosphatase, PTP-RO, is upregulated during
      megakaryocyte differentiation and Is associated with the c-Kit receptor.
AB  - We have recently isolated a cDNA encoding a novel human receptor-type tyrosine
      phosphatase, termed PTP-RO (for a protein tyrosine phosphatase receptor omicron),
      from 5-fluorouracil-treated murine bone marrow cells. PTP-RO is a human homologue
      of murine PTPlambda and is related to the homotypically adhering kappa and mu
      receptor-type tyrosine phosphatases. PTP-RO is expressed in human megakaryocytic
      cell lines, primary bone marrow megakaryocytes, and stem cells. PTP-RO mRNA and
      protein expression are upregulated upon phorbol 12-myristate 13-acetate (PMA)
      treatment of the megakaryocytic cell lines CMS, CMK, and Dami. To elucidate the
      function of PTP-RO in megakaryocytic cells and its potential involvement in the
      stem cell factor (SCF)/c-Kit receptor pathway, COS-7 and 293 cells were
      cotransfected with the cDNAs of both the c-Kit tyrosine kinase receptor and PTP
      RO. PTP-RO was found to be associated with the c-Kit receptor in these
      transfected cells and the SCF/Kit ligand induced a rapid tyrosine phosphorylation
      of PTP-RO. Interestingly, these transfected cells demonstrated a decrease in
      their proliferative response to the SCF/Kit ligand. In addition, we assessed the
      association of PTP-RO with c-Kit in vivo. The results demonstrated that PTP-RO
      associates with c-Kit but not with the tyrosine kinase receptor FGF-R and that
      PTP-RO is tyrosine-phosphorylated after SCF stimulation of Mo7e and CMK cells.
      Antisense oligonucleotides directed against PTP-RO mRNA sequences significantly
      inhibited megakaryocyte progenitor proliferation. Therefore, these data show that
      the novel tyrosine kinase phosphatase PTP-RO is involved in megakaryocytopoiesis
      and that its function is mediated by the SCF/c-Kit pathway.

PMID- 10397722
TI  - The glucocorticoid receptor cooperates with the erythropoietin receptor and c-Kit
      to enhance and sustain proliferation of erythroid progenitors in vitro.
AB  - Although erythropoietin (Epo) is essential for the production of mature red blood
      cells, the cooperation with other factors is required for a proper balance
      between progenitor proliferation and differentiation. In avian erythroid
      progenitors, steroid hormones cooperate with tyrosine kinase receptors to induce
      renewal of erythroid progenitors. We examined the role of corticosteroids in the
      in vitro expansion of primary human erythroid cells in liquid cultures and colony
      assays. Dexamethasone (Dex), a synthetic glucocorticoid hormone, cooperated with
      Epo and stem cell factor to induce erythroid progenitors to undergo 15 to 22 cell
      divisions, corresponding to a 10(5)- to 10(6)-fold amplification of erythroid
      cells. Dex acted directly on erythroid progenitors and maintained the colony
      forming capacity of the progenitor cells expanded in liquid cultures. The hormone
      delayed terminal differentiation into erythrocytes, which was assayed by
      morphology, hemoglobin accumulation, and the expression of genes characteristic
      for immature cells. Sustained proliferation of erythroid progenitors could be
      induced equally well from purified erythroid burst-forming units (BFU-E), from
      CD34(+) blast cells, and from bone marrow depleted from CD34(+) cells.

PMID- 10397724
TI  - Interleukin-1 (IL-1) inhibits growth of cytomegalovirus in human marrow stromal
      cells: inhibition is reversed upon removal of IL-1.
AB  - A Toledo strain cytomegalovirus (CMV) containing the gene for green fluorescent
      protein (GFP) under the control of elongation factor-1 promoter was used to study
      infection of human marrow stromal cells. Two stromal cell lines were used: HS-5,
      which secretes copious amounts of known cytokines and interleukins; and HS-27a,
      which does not secrete these activities. CMV growth and spread was monitored by
      counting green plaques and quantitating GFP intensity. Initial studies indicated
      that, whereas HS-5 and 27a have similar susceptibilities to infection, as
      evidenced by the same number of GFP+ cells at day 2, HS-5 appears more resistant
      to growth and spread of CMV. Furthermore, conditioned media from HS-5 (HS-5 CM)
      inhibited CMV plaque formation in HS-27a, suggesting that factors secreted by HS
      5 are responsible for limiting CMV growth. Neutralizing antibodies against
      interleukin-1alpha (IL-1alpha) and IL-1beta completely blocked the ability of HS
      5 CM to limit viral growth, suggesting that IL-1, which is known to be present in
      HS-5 CM, is responsible for this effect. When exogenous IL-1beta was added to CMV
      infected HS-27a, both the number of plaques and the intensity of GFP was
      significantly reduced in IL-1-treated HS-27a compared with untreated HS-27a (the
      number of plaques by day 18 was 20 +/- 3 v 151 +/- 12/well, respectively; GFP
      intensity was 535 +/- 165 v 6,516 +/- 652/well, respectively, in 4 separate
      experiments). At day 21, when IL-1beta-treated, CMV-infected cultures were
      passaged and then cultured in the absence of IL-1beta, CMV growth progressed with
      the kinetics of the original untreated culture, indicating that the IL-1beta
      effect is reversible. Because HS-27a expresses the type I IL-1 receptor, we
      speculate that the antiviral effects are mediated through IL-1-induced changes in
      cellular gene expression. DNA chip analysis of mRNA from IL-1beta-treated and
      nontreated HS-27a cells has identified some candidate molecules.

PMID- 10397723
TI  - C/EBPalpha bypasses granulocyte colony-stimulating factor signals to rapidly
      induce PU.1 gene expression, stimulate granulocytic differentiation, and limit
      proliferation in 32D cl3 myeloblasts.
AB  - Within hematopoiesis, C/EBPalpha is expressed only in myeloid cells, and PU.1 is
      expressed mainly in myeloid and B-lymphoid cells. C/EBPalpha-deficient mice lack
      the neutrophil lineage and retain monocytes, whereas PU.1-deficient mice lack
      monocytes and have severely reduced neutrophils. We expressed a C/EBPalpha
      estrogen receptor ligand-binding domain fusion protein, C/EBPalphaWT-ER, in 32D
      cl3 myeloblasts. 32D cl3 cells proliferate in interleukin-3 (IL-3) and
      differentiate to neutrophils in granulocyte colony-stimulating factor (G-CSF). In
      the presence of estradiol, C/EBPalphaWT-ER induced morphologic differentiation
      and the expression of the myeloperoxidase, lactoferrin, and G-CSF receptor mRNAs.
      C/EBPalphaWT-ER also induced a G1/S cell cycle block, with induction of p27 and
      Rb hypophosphorylation. bcr-ablp210 prevented 32D cl3 cell differentiation.
      Activation of C/EBPalpha-ER in 32D-bcr-ablp210 or Ba/F3 B-lymphoid cells induced
      cell cycle arrest independent of terminal differentiation. C/EBPalphaWT-ER
      induced endogenous PU.1 mRNA within 8 hours in both 32D cl3 and Ba/F3 cells, even
      in the presence of cycloheximide, indicating that C/EBPalpha directly activates
      the PU.1 gene. However, activation of a PU.1-ER fusion protein in 32D cl3 cells
      induced myeloperoxidase (MPO) RNA but not terminal differentiation. Thus,
      C/EBPalpha acts downstream of G-CSF and upstream of PU.1, p27, and potentially
      other factors to induce myeloblasts to undergo granulocytic differentiation and
      cell cycle arrest.

PMID- 10397725
TI  - Regulation of tissue factor pathway inhibitor expression in smooth muscle cells.
AB  - Tissue factor pathway inhibitor (TFPI) is the primary physiological inhibitor
      that regulates tissue factor-induced blood coagulation. TFPI is thought to be
      synthesized, in vivo, primarily by microvascular endothelial cells. Little is
      known about how TFPI is regulated under pathophysiological conditions. In this
      study, we determined mechanisms by which TFPI expression is regulated by human
      pulmonary artery smooth muscle cells (PASMC), because these cells contribute to
      remodeling of the pulmonary vasculature in disease. PASMC in culture
      constitutively synthesize and secrete TFPI. Exposure of PASMC to phorbol
      myristate acetate, lipopolysaccharide, tumor necrosis factor alpha, thrombin,
      interleukin-1, and transforming growth factor-beta had no significant effect on
      expression of TFPI by PASMC. By contrast, treatment of PASMC with serum and basic
      fibroblast growth factor (bFGF)/heparin markedly upregulated the expression of
      TFPI activity and antigen. On Western blot analysis, a protein consistent with
      full-length TFPI (42 kD) was identified in the conditioned media of PASMC, and
      the levels of the protein were much higher in the conditioned media of serum and
      bFGF/heparin-treated cells. Northern blot analysis showed that PASMC
      constitutively express TFPI mRNA, and treatment of cells with serum and
      bFGF/heparin had a minimal effect on the steady-state levels of TFPI mRNA.
      Nuclear run-on analysis did not show a significant increase in the
      transcriptional rate of TFPI gene in PASMC treated with serum or bFGF/heparin.
      Cycloheximide, but not actinomycin-D, treatment inhibited the serum and
      bFGF/heparin-induced increase in TFPI activity in PASMC. In conclusion, our data
      demonstrate that PASMC constitutively synthesize and secrete TFPI and serum or
      bFGF upregulate its expression, suggesting that growth factors that can stimulate
      the vessel wall in vivo might locally regulate TFPI expression. Our study also
      suggests that control of TFPI expression by serum or bFGF occurs via
      translational rather than transcriptional regulation.

PMID- 10397726
TI  - Fibrinogen receptor antagonist-induced thrombocytopenia in chimpanzee and rhesus
      monkey associated with preexisting drug-dependent antibodies to platelet
      glycoprotein IIb/IIIa.
AB  - Most clinical trials with fibrinogen receptor antagonists (FRAs) have been
      associated with thrombocytopenia. This report describes the occurrence of
      thrombocytopenia in one chimpanzee and one rhesus monkey upon administration of
      potent FRAs. Chimpanzee A-264 experienced profound thrombocytopenia on two
      occasions immediately upon intravenous administration of two different potent
      FRAs, L-738, 167 and L-739,758. However, an equally efficacious antiaggregatory
      dose of another potent antagonist, L-734,217, caused no change in platelet count.
      These compounds did not affect platelet count in five other chimpanzees or
      numerous other nonhuman primates. Flow cytometric analysis showed drug-dependent
      antibodies (DDAbs) in the plasma of chimpanzee A-264 that bound to platelets of
      chimpanzees, humans, and all other primates tested only in the presence of the
      compounds that induced thrombocytopenia. Rhesus monkey 94-R021 experienced
      thrombocytopenia upon administration of a different antagonist, L-767,679, and
      several prodrugs that are converted into the active form, L-767,679, in the
      blood. More than 20 other FRAs, including those that induced thrombocytopenia in
      chimpanzee A-264, had no effect on platelet count in this monkey. Flow cytometric
      measurements again identified DDAbs that reacted with platelets of all primates
      tested and required the presence of L-767,679. Screening for DDAbs in the plasma
      of 1,032 human subjects with L-738, 167 and L-739,758 demonstrated that the
      incidence of these preexisting antibodies in this population was 0.8% +/- 0.6%
      and 1.1% +/- 0.6%, respectively.

PMID- 10397727
TI  - P-selectin expression by endothelial cells is decreased in neonatal rats and
      human premature infants.
AB  - Decreased adhesion of neutrophils to endothelial cells and delayed
      transendothelial cell migration of neutrophils have been consistently reported in
      neonatal animals and humans and contribute to their susceptibility to infection.
      The delayed transmigration of neutrophils is especially prevalent in premature
      neonates. To define the nature of this defect, we used an in vivo animal model of
      inflammation and found that radiolabeled leukocytes from adult rats transmigrated
      into the peritoneum of other adult rats 5 times more efficiently than they did in
      neonatal rats (P =.05). This indicated that defects in neonatal neutrophils could
      not completely account for the delayed transmigration. Delayed transmigration in
      the neonatal rats correlated with a defect in the expression of P-selectin on the
      surface of their endothelial cells. We found a similar P-selectin deficiency in
      endothelial cells lining mesenteric venules and umbilical veins of human
      premature infants when compared with term human infants. The decreased P-selectin
      in premature infants was associated with decreased numbers of P-selectin storage
      granules and decreased P-selectin transcription. Decreased P-selectin expression
      on the surface of endothelial cells in preterm infants may contribute to delayed
      neutrophil transmigration and increased susceptibility to infection.

PMID- 10397728
TI  - Increased fragmentation of von Willebrand factor, due to abnormal cleavage of the
      subunit, parallels disease activity in recurrent hemolytic uremic syndrome and
      thrombotic thrombocytopenic purpura and discloses predisposition in families. The
      Italian Registry of Familial and Recurrent HUS/TTP.
AB  - We investigated here the changes in von Willebrand factor (vWF) multimers in
      recurrent, sporadic and familial forms of hemolytic uremic syndrome
      (HUS)/thrombotic thrombocytopenic purpura (TTP) to see whether they are actually
      proteolyzed in vivo in these patients. Molecular determinants of fragments in vWF
      were also characterized to identify possible sites of cleavage of the subunit.
      Unusually large vWF multimers were found in blood of 8 of 10 patients with
      recurrent HUS/TTP, both in the acute phase and in remission, but never in
      familial and sporadic cases. Instead, all of the groups showed evidence of
      enhanced fragmentation of vWF multimers during the acute phase. Increased
      fragmentation was also shown by decrease in native 225-kD vWF subunit. In
      recurrent and sporadic HUS/TTP, enhanced fragmentation normalized at remission,
      but the abnormality persisted in familial HUS/TTP patients. The latter findings
      suggest that patients with familial HUS/TTP may have a congenital abnormality in
      vWF processing. Analysis with specific monoclonal antibodies showed the presence
      of the normal vWF fragments with apparent molecular mass of 189, 176, and 140 kD
      in all patients; however, in 6 recurrent and in 5 familial cases, novel fragments
      that differed in size from normal ones were found. The size of these abnormal
      fragments differed from one patient to another and none of them was ever found in
      normal plasma. These results documented, for the first time in HUS/TTP, an
      abnormal cleavage of the vWF subunit that might account for the increased
      fragmentation observed in these patients.

PMID- 10397729
TI  - Amino acid sequence of trocarin, a prothrombin activator from Tropidechis
      carinatus venom: its structural similarity to coagulation factor Xa.
AB  - Among snake venom procoagulant proteins, group II prothrombin activators are
      functionally similar to blood coagulation factor Xa. We have purified and
      partially characterized the enzymatic properties of trocarin, the group II
      prothrombin activator from the venom of the Australian elapid, Tropidechis
      carinatus (rough-scaled snake). Prothrombin activation by trocarin is enhanced by
      Ca2+, phospholipids, and factor Va, similar to that by factor Xa. However, its
      amidolytic activity on peptide substrate S-2222 is significantly lower. We have
      determined the complete amino acid sequence of trocarin. It is a 46,515-Dalton
      glycoprotein highly homologous to factor Xa and shares the same domain
      architecture. The light chain possesses an N-terminal Gla domain containing 11
      gamma-carboxyglutamic acid residues, followed by two epidermal growth factor
      (EGF)-like domains; the heavy chain is a serine proteinase. Both chains are
      likely glycosylated: the light chain at Ser 52 and the heavy chain at Asn 45.
      Unlike other types of venom procoagulants, trocarin is the first true structural
      homologue of a coagulation factor. It clots snake plasma and thus may be similar,
      if not identical, to snake blood coagulation factor Xa. Unlike blood factor Xa,
      it is expressed in high quantities and in a nonhepatic tissue, making snake venom
      the richest source of factor Xa-like proteins. It induces cyanosis and death in
      mice at 1 mg/kg body weight. Thus, trocarin acts as a toxin in venom and a
      similar, if not identical, protein plays a critical role in hemostasis.

PMID- 10397730
TI  - Structural and functional implications of the intron/exon organization of the
      human endothelial cell protein C/activated protein C receptor (EPCR) gene:
      comparison with the structure of CD1/major histocompatibility complex alpha1 and
      alpha2 domains.
AB  - The endothelial cell protein C/activated protein C receptor (EPCR) is located
      primarily on the surface of the large vessels of the vasculature. In vitro
      studies suggest that it is involved in the protein C anticoagulant pathway. We
      report the organization and nucleotide sequence of the human EPCR gene. It spans
      approximately 6 kbp of genomic DNA, with a transcription initiation point 79 bp
      upstream of the translation initiation (Met) codon in close proximity to a TATA
      box and other promoter element consensus sequences. The human EPCR gene has been
      localized to 20q11.2 and consists of four exons interrupted by three introns, all
      of which obey the GT-AG rule. Exon I encodes the 5' untranslated region and the
      signal peptide, and exon IV encodes the transmembrane domain, the cytoplasmic
      tail, and the 3' untranslated region. Exons II and III encode most of the
      extracellular region of the EPCR. These exons have been found to correspond to
      those encoding the alpha1 and alpha2 domains of the CD1/major histocompatibility
      complex (MHC) class I superfamily. Flanking and intervening introns are of the
      same phase (phase I) and the position of the intervening intron is identically
      located. Secondary structure prediction for the amino acid sequence of exons II
      and III corresponds well with the actual secondary structure elements determined
      for the alpha1 and alpha2 domains of HLA-A2 and murine CD1.1 from crystal
      structures. These findings suggest that the EPCR folds with a beta-sheet platform
      supporting two alpha-helical regions collectively forming a potential binding
      pocket for protein C/activated protein C.

PMID- 10397731
TI  - Thrombospondin-1 acts via IAP/CD47 to synergize with collagen in alpha2beta1
      mediated platelet activation.
AB  - Integrin-associated protein (IAP; or CD47) is a receptor for the cell binding
      domain (CBD) of thrombospondin-1 (TS1). In platelets, IAP associates with and
      regulates the function of alphaIIbbeta3 integrin (Chung et al, J Biol Chem
      272:14740, 1997). We test here the possibility that CD47 may also modulate the
      function of platelet integrin alpha2beta1, a collagen receptor. The CD47 agonist
      peptide, 4N1K (KRFYVVMWKK), derived from the CBD, synergizes with soluble
      collagen in aggregating platelet-rich plasma. 4N1K and intact TS1 also induce the
      aggregation of washed, unstirred platelets on immobilized collagen with a rapid
      increase in tyrosine phosphorylation. The effects of TS1 and 4N1K on platelet
      aggregation are absolutely dependent on IAP, as shown by the use of platelets
      from IAP-/- mice. Prostaglandin E1 (PGE1) prevents 4N1K-dependent aggregation on
      immobilized collagen but does not inhibit the 4N1K peptide stimulation of
      alpha2beta1-dependent platelet spreading. Finally, a detergent-stable, physical
      association of IAP and alpha2beta1 integrin is detected by coimmunoprecipitation.
      These results imply a role for IAP and TS1 in the early activation of platelets
      upon adhesion to collagen.

PMID- 10397732
TI  - Src-dependence and pertussis-toxin sensitivity of urokinase receptor-dependent
      chemotaxis and cytoskeleton reorganization in rat smooth muscle cells.
AB  - The catalytically inactive precursor of urokinase-type plasminogen activator (pro
      u-PA) induced a chemotactic response in rat smooth muscle cells (RSMC) through
      binding to the membrane receptor of urokinase (u-PA receptor [u-PAR]). A soluble
      form of u-PAR activated by chymotrypsin cleavage as well as a peptide located
      between domain 1 and 2 of u-PAR reproduced the effect of pro-u-PA on cell
      migration. The chemotactic pro-u-PA effect correlates with a dramatic
      reorganization of actin cytoskeleton, of adhesion plaques, and with major cell
      shape changes in RSMC. Pro-u-PA induced a decrease in stress fiber content,
      membrane ruffling, actin ring formation, and disruption leading to the
      characteristic elongated cell shape of motile cells with an actin semi-ring
      located close to the leading edge of cells. u-PAR effects on both chemotaxis and
      cytoskeleton were sensitive to pertussis toxin and, hence, possibly require G
      proteins. u-PAR effects are accompanied by a relocation of u-PAR, vitronectin
      receptor (VNR) alphavbeta3, beta1 integrin subunit, and Src tyrosine kinase to
      the leading membrane of migrating cells. In conclusion, our data show that pro-u
      PA, via binding to u-PAR, controls a signaling pathway, regulated by tyrosine
      kinases and possibly G proteins, leading to cell cytoskeleton reorganization and
      cell migration.

PMID- 10397733
TI  - The Tat protein of human immunodeficiency virus type-1 promotes vascular cell
      growth and locomotion by engaging the alpha5beta1 and alphavbeta3 integrins and
      by mobilizing sequestered basic fibroblast growth factor.
AB  - The Tat protein of human immunodeficiency virus type-1 (HIV-1) has been shown to
      be released during acute infection of T cells by HIV-1 and to promote
      angiogenesis and Kaposi's sarcoma (KS) development in infected individuals. In
      this study, we investigated the molecular mechanisms responsible for the
      angiogenic effects of Tat. The results shown herein indicate that two different
      Tat domains cooperate to induce these effects by different pathways. The arginine
      glycine-aspartic acid (RGD) sequence present at the carboxyterminal of Tat
      mediates vascular cell migration and invasion by binding to the alpha5beta1 and
      alphavbeta3 integrins. This interaction also provides endothelial cells with the
      adhesion signal they require to grow in response to mitogens. At the same time,
      the Tat basic sequence retrieves into a soluble form extracellular basic
      fibroblast growth factor (bFGF) bound to heparan sulfate proteoglycans by
      competing for heparin-binding sites. This soluble bFGF mediates Tat-induced
      vascular cell growth. These effects resemble those of extracellular matrix
      proteins, suggesting that Tat enhances angiogenesis and promotes KS progression
      by a molecular mimicry of these molecules.

PMID- 10397735
TI  - Acute systemic reaction and lung alterations induced by an antiplatelet integrin
      gpIIb/IIIa antibody in mice.
AB  - Shock is frequently accompanied by thrombocytopenia. To investigate the
      pathogenic role of platelets in shock, we examined the in vivo effects of
      monoclonal antibodies (MoAbs) against mouse platelet membrane proteins. Injection
      of the platelet-specific MoAb MWReg30 to the fibrinogen receptor (gpIIb/IIIa)
      rendered mice severely hypothermic within minutes. Isotype-matched control
      antibodies, even if they also recognized platelet surface antigens, did not
      induce comparable signs. MWReg30 induced early signs of acute lung injury with
      increased cellularity in the lung interstitium and rapid engorgement of alveolar
      septal vessels. Despite this in vivo activity, MWReg30 inhibited rather than
      stimulated platelet aggregation in vitro. MWReg30-binding to platelets led to
      phosphorylation of gpIIIa, but did not induce morphological signs of platelet
      activation. The MWReg30-induced reaction was abolished after treatment with MoAbs
      2.4G2 to FcgammaRII/III and was absent in FcgammaRIII-deficient mice, clearly
      demonstrating the requirement for FcgammaRIII on involved leukocytes.
      Simultaneous administration of tumor necrosis factor exacerbated, whereas a
      tolerizing regimen of tumor necrosis factor or bacterial lipopolysaccharide
      completely prevented the reaction. These data suggest that platelet surface
      deposited MWReg30-immune complexes lead to an acute Fc-mediated reaction with
      pulmonary congestion and life-threatening potential that could serve as an in
      vivo model of acute lung injury.

PMID- 10397734
TI  - Idiotype vaccination in human myeloma: generation of tumor-specific immune
      responses after high-dose chemotherapy.
AB  - Igs contain unique portions, collectively termed idiotypes (Id), that can be
      recognized by the immune system. Id expressed by tumor cells in B-cell
      malignancies can be regarded as tumor-specific antigens and a target for vaccine
      immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using
      Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens
      and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor
      (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had
      previously been treated with high-dose chemotherapy followed by peripheral blood
      progenitor cell (PBPC) transplantation entered this study from August 1995 to
      January 1998. All patients were in first remission at the time of vaccination.
      They received subcutaneous injections of Id vaccines and immunoadjuvants in an
      outpatient setting. The generation of Id-specific T-cell proliferative responses
      was documented in 2 patients, whereas a positive Id-specific delayed-type
      hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH
      specificity was confirmed in 1 patient by investigating the reactivity to
      synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy
      chain. None of the patients generated soluble immune responses to Id, whereas the
      generation of soluble and cellular immune responses to KLH was observed in 100%
      and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient
      failed to finish owing to progression of disease. Freedom from disease
      progression (FFDP), measured from the date of first Id/KLH injection to the date
      of first treatment after vaccination or last follow-up, ranged from 9 to 36
      months. These data indicate that the immune competence status of MM patients is
      still susceptible to specific immunization after high-dose chemotherapy and PBPC
      transplantation. It remains to be determined whether generation of Id-specific
      immune responses can reduce the relapse rate of patients with minimal residual
      disease.

PMID- 10397736
TI  - Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia.
AB  - Genetic and environmental factors play an interactive role in the development of
      childhood acute lymphoblastic leukemia (ALL). Since the demonstration of a major
      histocompatibility complex (MHC) influence on mouse leukemia in 1964, an HLA
      association has been considered as a possible genetic risk factor. Despite
      extensive efforts, however, no strong evidence comparable to the H-2(k) influence
      on mouse leukemia has been shown. The number of negative serological studies
      resulted in a loss of interest and consequently, no molecular HLA-DR association
      study has been published to date. We reconsidered the HLA-DR association in
      childhood ALL in 114 patients from a single center and 325 local newborn controls
      by polymerase chain reaction (PCR) analysis of the HLA-DRB1/3/4/5 loci. With
      conventional analysis, there was a moderate allelic association with the most
      common allele in the HLA-DR53 group, HLA-DRB1*04, in the whole group that was
      stronger in males (P =.0005, odds ratio = 2.9). When the other expressed HLA-DRB
      loci were examined, homozygosity for HLA-DRB4*01, encoding the HLA-DR53
      specificity, was increased in patients (21.1% v 8.3%; odds ratio = 2.9, P
      =.0005). Consideration of gender showed that all of these associations were
      reflections of a male-specific increase in homozygosity for HLA-DRB4*01 (32.8% v
      4. 0%; odds ratio = 11.7, 95% confidence interval [CI] = 4.9 to 28.0; P = 3 x 10(
      8)). This highly significant result provided the long-suspected evidence for the
      HLA-DR influence on the development of childhood ALL while confirming the
      recessive nature of the MHC influence on human leukemogenesis as in experimental
      models. The cross-reactivity between HLA-DR53 and H-2Ek, extensive mimicry of the
      immunodominant epitope of HLA-DR53 by several carcinogenic viruses, and the extra
      amount of DNA in the vicinity of the HLA-DRB4 gene argue for the case that HLA
      DRB4*01 may be one of the genetic risk factors for childhood ALL.

PMID- 10397737
TI  - Reactive plasmacytoses are expansions of plasmablasts retaining the capacity to
      differentiate into plasma cells.
AB  - Circulating plasma cells in 10 cases of reactive plasmacytosis had a shared
      phenotype with early plasma cell (CD19(+) CD38(+) CD138(+) CD40(+) CD45(+) CD11a+
      CD49e- CD56(-)). In most cases, a minor subpopulation of CD28(+) plasma cells was
      also detected. Reactive plasma cells were highly proliferative, suggesting the
      presence of circulating progenitors (plasmablasts). After CD138(+) plasma cell
      removal, highly proliferative CD138(-) plasmablasts differentiated into CD138(+)
      plasma cells within a few days. This differentiation, which was associated with
      increased CD38 and decreased HLA-DR expression, was further confirmed by a large
      increase in intracellular Ig content (associated with Ig secretion) and was
      concomitant with extensive secretion of interleukin-6 (IL-6). The addition of
      neutralizing anti-IL-6 and anti-CD126 (IL-6 receptor) monoclonal antibodies
      totally prevented Ig secretion and cell differentiation by inducing apoptosis of
      plasmablasts, which indicates that IL-6 is an essential survival factor for
      plasmablasts. This report provides the first characterization of normal
      plasmablasts and shows that their phenotype is not exactly that of multiple
      myeloma cells.

PMID- 10397738
TI  - Loss of c-kit accompanies B-lineage commitment and acquisition of CD45R by most
      murine B-lymphocyte precursors.
AB  - Using surface markers, we identified two bone marrow (BM) subsets enriched for
      TdT+ cells on the brink of CD45R acquisition. These two populations, Lin-c-kitLo
      and Lin-c-kit-, consisting of 35.4% and 7. 4%, respectively, TdT+ cells,
      generated B-lineage cells in overnight cultures. Approximately half of the c
      kitLo B-lineage precursors were bipotential, yielding myeloid and lymphoid
      progeny, whereas most that were c-kit- gave rise only to lymphocytes. Analysis of
      B-lineage progression during a finite culture period showed that the most mature
      precursors were concentrated in the Lin-c-kit- population. Moreover, a majority
      of the earliest CD45R+ pro-B cells in BM, identified as CD45R+ CD43(+) BP-1(-)
      CD25(-) natural killer (NK)1.1(-) sIgM-, were also c-kit-. These c-kit- cells,
      like their c-kitLo counterparts, expressed TdT, proliferated in response to
      interleukin (IL)-7, and generated sIgM+ cells. These data suggest that TdT
      expression is initiated as c-kit downregulation begins in Lin- cells, with
      progressive loss of c-kit during B-lineage differentiation. CD45R expression is
      initiated during the transition from c-kitLo to c-kit- with many cells losing c
      kit before acquiring CD45R. The ability to isolate highly enriched populations of
      viable CD45R- precursors will be instrumental in characterizing the earliest B
      lineage cells.

PMID- 10397739
TI  - Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by
      double-color fluorescent in situ hybridization.
AB  - Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus
      at chromosome 14q32 represent a common mechanism of oncogene activation in
      lymphoid malignancies. In multiple myeloma (MM), variable chromosome partners
      have been identified by conventional cytogenetics, including the 11q13, 8q24,
      18q21, and 6p21 loci. We and others have recently reported a novel,
      karyotypically undetectable chromosomal translocation t(4;14)(p16. 3;q32) in MM
      derived cell lines, as well as in primary tumors. The 4p16.3 breakpoints are
      relatively scattered and located less than 100 kb centromeric of the fibroblast
      growth factor receptor 3 (FGFR3) gene or within the recently identified WHSC1
      gene, both of which are apparently deregulated by the translocation. To assess
      the frequency of the t(4;14)(p16.3;q32) translocation in MM, we performed a
      double-color fluorescent in situ hybridization (FISH) analysis of interphase
      nuclei with differently labeled probes specific for the IGH locus (a pool of
      plasmid clones specific for the IGH constant regions) or 4p16.3 (yeast artificial
      chromosome (YAC) 764-H1 spanning the region involved in breakpoints). Thirty MM
      patients, the MM-derived cell lines KMS-11 and OPM2, and six normal controls were
      examined. The identification of a t(4;14) translocation, evaluated as the
      presence of a der(14) chromosome, was based on the colocalization of signals
      specific for the two probes; a cutoff value of 15% (mean + 3 standard deviation
      [SD]) derived from the interphase FISH of the normal controls (range, 5% to 11%;
      mean +/- SD, 8.16 +/- 2.2) was used for the quantification analysis. In
      interphase FISH, five patients (one in clinical stage I, two in stage II, one in
      stage III, and a plasma cell leukemia) were found to be positive (approximately
      15%). FISH metaphases with split or colocalized signals were detected in only two
      of the translocated cases and confirmed the pattern found in the interphase
      nuclei. Furthermore, in three of the five cases with the translocation, FISH
      analysis with the IGH joining probe (JH) showed the presence of the reciprocal
      product of the translocation [der(4) chromosome]. Overall, our study indicates
      that the t(4;14)(p16. 3;q32) chromosomal translocation is a recurrent event in MM
      tumors and may contribute towards the detection of this lesion and our
      understanding of its pathogenetic and clinical implications in MM.

PMID- 10397740
TI  - Microsatellite instability and p53 mutations are associated with abnormal
      expression of the MSH2 gene in adult acute leukemia.
AB  - Microsatellite instability (MSI) and p53 mutations have been reported to occur in
      a significant proportion of patients with therapy-related acute myeloid leukemia
      (AML). MSH2 is one of the genes involved in DNA mismatch repair to maintain
      fidelity of genomic replication, and defects of MSH2 are directly involved in MSI
      in hereditary nonpolyposis colorectal tumors and other human tumors. We have
      examined the expression of MSH2 protein by Western blotting in 43 adult leukemia
      samples, including 42 AML and 1 acute lymphoblastic leukemia (ALL) using the
      antibody MSH2 (Ab-1) (Calbiochem, La Jolla, CA). Abnormal expression of MSH2
      protein was found in 14 of 43 (32.6%) cases; a control antibody to actin was
      always positive. Of the 14 patients that had abnormal expression of MSH2, 2 had
      therapy-related acute leukemia and 9 were elderly patients (>60 years of age).
      Expression of MSH2 mRNA was further examined by reverse transcriptase-polymerase
      chain reaction (RT-PCR). Deletion of MSH2 mRNA was found in 1 of 14 cases with
      deficient MSH2 protein expression. This group of patients was also screened for
      loss of heterozygosity (LOH) at the MSH2 locus using a panel 4 microsatellite
      markers (D2S367, D2S288, D2S391, and D2S2294). LOH was found in 5 of 11 cases
      examined. There was no evidence of LOH in 14 patients with normal MSH2 expression
      who were examined using the same markers. Functional evidence for defective DNA
      mismatch repair in leukemic cells lacking MSH2 as manifest by MSI was found in 7
      of 11 cases studied. Mutations of the p53 gene in these 43 samples were also
      investigated by direct sequencing of full-length p53 cDNA. Mutations of p53 were
      found in 6 of 43 cases, including 5 of the 14 (35.7%) cases that did not express
      MSH2 protein. In contrast, mutation of p53 was only found in 1 of 29 (3.4%) cases
      with normal MSH2 protein expression (chi2 = 5.720, P <.02). These results suggest
      that abnormalities of DNA mismatch repair due to defective MSH2 expression could
      play a key role in leukemogenesis, in particular in AML arising in elderly
      patients or secondary to previous chemotherapy.

PMID- 10397741
TI  - NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with
      chromosome translocation t(1;11)(q23;p15).
AB  - The nucleoporin gene NUP98 was found fused to the HOXA9, HOXD13, or DDX10 genes
      in human acute myelogenous leukemia (AML) with chromosome translocations
      t(7;11)(p15;p15), t(2;11)(q35;p15), or inv(11)(p15;q22), respectively. We report
      here the fusion between the NUP98 gene and another homeobox gene PMX1 in a case
      of human AML with a t(1;11)(q23;p15) translocation. The chimeric NUP98-PMX1
      transcript was detected; however, there was no reciprocal PMX1-NUP98 fusion
      transcript. Like the NUP98-HOXA9 fusion, NUP98 and PMX1 were fused in frame and
      the N-terminal GLFG-rich docking region of the NUP98 and the PMX1 homeodomain
      were conserved in the NUP98-PMX1 fusion, suggesting that PMX1 homeodomain
      expression is upregulated and that the fusion protein may act as an oncogenic
      transcription factor. The fusion to NUP98 results in the addition of the strong
      transcriptional activation domain located in the N-terminal region of NUP98 to
      PMX1. These findings suggest that constitutive expression and alteration of the
      transcriptional activity of the PMX1 homeodomain protein may be critical for
      myeloid leukemogenesis.

PMID- 10397742
TI  - Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic
      lymphocytic leukemia.
AB  - Deletion in chromosome bands 11q22-q23 is one of the most common chromosome
      aberrations in B-cell chronic lymphocytic leukemia (B-CLL). It is associated with
      extensive lymph node involvement and poor survival. The minimal consensus
      deletion comprises a segment, which contains the ATM gene presenting an
      interesting candidate gene, as mutations in ATM predispose A-T patients to
      lymphoid malignancies. To investigate a potential pathogenic role of ATM in B
      cell tumorigenesis, we performed mutation analysis of ATM in 29 malignant
      lymphomas of B-cell origin (B-CLL = 27; mantle cell lymphoma, [MCL] = 2). Twenty
      three of these carried an 11q22-q23 deletion. In five B-CLLs and one MCL with
      deletion of one ATM allele, a point mutation in the remaining allele was
      detected, which resulted in aberrant transcript splicing, alteration, or
      truncation of the protein. In addition, mutation analysis identified point
      mutations in three cases without 11q deletion: two B-CLLs with one altered allele
      and one MCL with both alleles mutated. In four cases analyzed, the ATM
      alterations were not present in the germ line indicating a somatic origin of the
      mutations. Our study demonstrates somatic disruption of both alleles of the ATM
      gene by deletion or point mutation and thus its pathogenic role in sporadic B
      cell lineage tumors.

PMID- 10397744
TI  - Anomalous high p27/KIP1 expression in a subset of aggressive B-cell lymphomas is
      associated with cyclin D3 overexpression. p27/KIP1-cyclin D3 colocalization in
      tumor cells.
AB  - p27 cyclin-dependent kinase inhibitor downregulation is essential for transition
      to the S phase of the cell cycle. Thus, proliferating cells in reactive lymphoid
      tissue show no detectable p27 expression. Nevertheless, anomalous high p27
      expression has been shown to be present in a group of aggressive B-cell lymphomas
      with high proliferation index and adverse clinical outcome. This suggests that
      abnormally accumulated p27 protein has been rendered functionally inactive. We
      analyzed the causes of this anomalous presence of p27 in a group of aggressive B
      cell lymphomas, including 54 cases of diffuse large B-cell lymphomas and 20
      Burkitt's lymphomas. We simultaneously studied them for p27, cyclin D3, cyclin
      D2, cyclin D1, and cyclin E expression, because it has been stated that high
      levels of expression of cyclin D1 or E lead to increased p27 levels in some cell
      types. A statistically significant association between p27 and cyclin D3
      expression was found for the group as a whole. Additionally, when dividing the
      cases according to the level of expression of cyclin D3 by reactive germinal
      centers, it was observed that cases with stronger cyclin D3 expression also show
      higher p27 expression. The relationship between both proteins was also shown at a
      subcellular level by laser confocal studies, showing that in cases with high
      expression of both proteins there was a marked colocalization. Additional
      evidence in favor of p27 sequestration by cyclin D3 was provided by
      coimmunoprecipitation studies in a Burkitt's cell line (Raji) showing the
      existence of cyclin D3/p27 complexes and the absence of CDK2/p27 complexes. These
      results could support the hypothesis that there are cyclin D3/p27 complexes in a
      subset of aggressive B-cell lymphomas in which p27 lacks the inhibitory activity
      found when it is bound to cyclin E/CDK2 complexes. This interaction between both
      proteins could lead to an abnormal nuclear accumulation, detectable by
      immunohistochemical techniques.

PMID- 10397743
TI  - High frequency of adhesion defects in B-lineage acute lymphoblastic leukemia.
AB  - Aberrant proliferation, differentiation, and/or migration of progenitors observed
      in various hematological malignancies may be caused by defects in expression
      and/or function of integrins. In this study, we have developed a new fluorescent
      beads adhesion assay that facilitates flow cytometric investigation of lymphocyte
      function-associated antigen 1 (LFA-1)- and very late activation antigen-4 (VLA-4)
      mediated functional adhesion in B-lineage acute lymphoblastic leukemia (ALL) of
      both the CD10(-) and CD10(+) (leukemic) cell population within one blood or bone
      marrow sample. Surprisingly, of the 20 B-lineage ALL patients investigated, 17
      contained a leukemic cell population with LFA-1- and/or VLA-4-mediated adhesion
      defects. Five patients contained CD10(+) cells that did not exhibit any LFA-1
      mediated adhesion due to the lack of LFA-1 surface expression. The CD10(+) cells
      from 10 ALL patients expressed LFA-1 that could not be activated by the phorbol
      ester phorbol 12-myristate 13-acetate (PMA), whereas the CD10(-) cells expressed
      a functional LFA-1. Seven patients contained CD10(+) cells that expressed a PMA
      unresponsive form of VLA-4. The PMA unresponsiveness of the integrins LFA-1 and
      VLA-4 expressed by the CD10(+) cells may be due to mutations in the integrins
      itself, in protein kinases, or in other intracellular molecules involved in
      integrin adhesion. These data clearly demonstrate the importance of investigating
      integrin function in addition to integrin surface expression. The strikingly high
      frequency (85%) of adhesion defects in ALL could suggest a causal relationship
      between integrin-mediated adhesion and B-lineage ALL.

PMID- 10397745
TI  - A new recurrent translocation, t(5;11)(q35;p15.5), associated with del(5q) in
      childhood acute myeloid leukemia. The UK Cancer Cytogenetics Group (UKCCG)
AB  - Partial deletion of the long arm of chromosome 5, del(5q), is the cytogenetic
      hallmark of the 5q-syndrome, a distinct subtype of myelodysplastic syndrome
      refractory anemia (MDS-RA). Deletions of 5q also occur in the full spectrum of
      other de novo and therapy-related MDS and acute myeloid leukemia (AML) types,
      most often in association with other chromosome abnormalities. However, the loss
      of genetic material from 5q is believed to be of primary importance in the
      pathogenesis of all del(5q) disorders. In the present study, we performed
      fluorescence in situ hybridization (FISH) studies using a chromosome 5-specific
      whole chromosome painting probe and a 5q subtelomeric probe to determine the
      incidence of cryptic translocations. We studied archival fixed chromosome
      suspensions from 36 patients with myeloid disorders (predominantly MDS and AML)
      and del(5q) as the sole abnormality. In 3 AML patients studied, this identified a
      translocation of 5q subtelomeric sequences from the del(5q) to the short arm of
      an apparently normal chromosome 11. FISH with chromosome 11-specific subtelomeric
      probes confirmed the presence of 11p on the shortened 5q. Further FISH mapping
      confirmed that the 5q and 11p translocation breakpoints were the same in all 3
      cases, between the nucleophosmin (NPM1) and fms-related tyrosine kinase 4 (FLT4)
      genes on 5q35 and the Harvey ras-1-related gene complex (HRC) and the radixin
      pseudogene (RDPX1) on 11p15.5. Importantly, all 3 patients with the cryptic
      t(5;11) were children: a total of 3 of 4 AML children studied. Two were
      classified as AML-M2 and the third was classified as M4. All 3 responded poorly
      to treatment and had short survival times, ranging from 10 to 18 months. Although
      del(5q) is rare in childhood AML, this study indicates that, within this
      subgroup, the incidence of cryptic t(5;11) may be high. It is significant that
      none of the 24 MDS patients studied, including 11 confirmed as having 5q
      syndrome, had the translocation. Therefore, this appears to be a new nonrandom
      chromosomal translocation, specifically associated with childhood AML with a
      differentiated blast cell phenotype and the presence of a del(5q).

PMID- 10397746
TI  - The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as
      effective antiproliferative agents III: the effect of the ligands on molecular
      targets involved in proliferation.
AB  - We have identified specific iron (Fe) chelators of the pyridoxal isonicotinoyl
      hydrazone (PIH) class that are far more effective ligands than desferrioxamine
      (DFO; Richardson et al, Blood 86:4295, 1995; Richardson and Milnes, Blood
      89:3025, 1997). In the present study, we have compared the effect of DFO and one
      of the most active chelators (2-hydroxy-1-naphthylaldehyde isonicotinoyl
      hydrazone; 311) on molecular targets involved in proliferation. This was
      performed to further understand the mechanisms involved in the antitumor activity
      of Fe chelators. Ligand 311 was far more active than DFO at increasing Fe release
      from SK-N-MC neuroepithelioma and BE-2 neuroblastoma cells and preventing Fe
      uptake from transferrin. Like DFO, 311 increased the RNA-binding activity of the
      iron-regulatory proteins (IRPs). However, despite the far greater Fe chelation
      efficacy of 311 compared with DFO, a similar increase in IRP-RNA binding activity
      occurred after 2 to 4 hours of incubation with either chelator, and the binding
      activity was not inhibited by cycloheximide. These results suggest that,
      irrespective of the Fe chelation efficacy of a ligand, an increase IRP-RNA
      binding activity occurred via a time-dependent step that did not require protein
      synthesis. Further studies examined the effect of 311 and DFO on the expression
      of p53-transactivated genes that are crucial for cell cycle control and DNA
      repair, namely WAF1, GADD45, and mdm-2. Incubation of 3 different cell lines with
      DFO or 311 caused a pronounced concentration- and time-dependent increase in the
      expression of WAF1 and GADD45 mRNA, but not mdm-2 mRNA. In accordance with the
      distinct differences in Fe chelation efficacy and antiproliferative activity of
      DFO and 311, much higher concentrations of DFO (150 micromol/L) than 311 (2.5 to
      5 micromol/L) were required to markedly increase GADD45 and WAF1 mRNA levels. The
      increase in GADD45 and WAF1 mRNA expression was seen only after 20 hours of
      incubation with the chelators and was reversible after removal of the ligands. In
      contrast to the chelators, the Fe(III) complexes of DFO and 311 had no effect on
      increasing GADD45 and WAF1 mRNA levels, suggesting that Fe chelation was
      required. Finally, the increase in GADD45 and WAF1 mRNAs appeared to occur by a
      p53-independent pathway in SK-N-MC and K562 cells, because these cell lines lack
      functional p53. Our results suggest that GADD45 and WAF1 may play important roles
      in the cell cycle arrest observed after exposure to these chelators.

PMID- 10397747
TI  - Overexpression of wild-type retinoic acid receptor alpha (RARalpha) recapitulates
      retinoic acid-sensitive transformation of primary myeloid progenitors by acute
      promyelocytic leukemia RARalpha-fusion genes.
AB  - Retinoic acid receptor alpha (RARalpha) is the target of several chromosomal
      translocations associated with acute promyelocytic leukemias (APLs). These
      rearrangements fuse RARalpha to different partner genes creating the chimeric
      proteins: PML-RARalpha, PLZF-RARalpha, and NPM-RARalpha. Although the vast
      majority of APLs respond to retinoic acid therapy, those associated with PLZF
      RARalpha are resistant. We have used retroviruses to express PML-RARalpha, PLZF
      RARalpha, NPM-RARalpha, RARalpha403 (a dominant negative mutant of RARalpha), and
      wild-type RARalpha in murine bone marrow progenitors and found that all of these
      constructs blocked differentiation and led to the immortalization of myeloid
      progenitors. This cellular transformation is specific to an alteration of the
      RARalpha pathway because overexpression of RARbeta, RARgamma, or RXRalpha did not
      result in similar growth perturbations. Pharmacological doses of RA induced
      differentiation and inhibited proliferation of cells transformed with either of
      the APL fusion genes, including PLZF-RARalpha, whereas physiological retinoic
      acid concentrations were sufficient to reverse the phenotype of cells transformed
      with wild-type RARalpha. The cellular responses to retinoic acid were accompanied
      by a sharp decrease in the amount of the RARalpha-fusion proteins expressed in
      the cells. Our findings suggest that the oncogenicity of RARalpha-fusion proteins
      results from their nature to behave as unliganded RARalpha in the presence of
      physiological concentrations of retinoic acid.

PMID- 10397748
TI  - Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:quinone
      oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid
      leukemia.
AB  - NAD(P)H:quinone oxidoreductase (NQO1) converts benzene-derived quinones to less
      toxic hydroquinones and has been implicated in benzene-associated hematotoxicity.
      A point mutation in codon 187 (Pro to Ser) results in complete loss of enzyme
      activity in homozygous subjects, whereas those with 2 wild-type alleles have
      normal activity. The frequency of homozygosity for the mutant allele among
      Caucasians and African Americans is 4% to 5% but is higher in Hispanics and
      Asians. Using an unambiguous polymerase chain reaction (PCR) method, we assayed
      nonmalignant lymphoblastoid cell lines derived from 104 patients with myeloid
      leukemias; 56 had therapy-related acute myeloid leukemia (t-AML), 30 had a
      primary myelodysplastic syndrome (MDS), 9 had AML de novo, and 9 had chronic
      myelogenous leukemia (CML). All patients had their leukemia cells karyotyped.
      Eleven percent of the t-AML patients were homozygous and 41% were heterozygous
      for the NQO1 polymorphism; these proportions were significantly higher than those
      expected in a population of the same ethnic mix (P =.036). Of the 45 leukemia
      patients who had clonal abnormalities of chromosomes 5 and/or 7, 7 (16%) were
      homozygous for the inactivating polymorphism, 17 (38%) were heterozygous, and 21
      (47%) had 2 wild-type alleles for NQO1. Thus, NQO1 mutations were significantly
      increased compared with the expected proportions: 5%, 34%, and 61%, respectively
      (P =.002). An abnormal chromosome no. 5 or 7 was observed in 7 of 8 (88%)
      homozygotes, 17 of 45 (38%) heterozygotes, and 21 of 51 (41%) patients with 2
      wild-type alleles. Among 33 patients with balanced translocations [14 involving
      bands 11q23 or 21q22, 10 with inv(16) or t(15;17), and 9 with t(9;22)], there
      were no homozygotes, 15 (45%) heterozygotes, and 18 (55%) with 2 wild-type
      alleles. Whereas fewer than 3 homozygotes were expected among the 56 t-AML
      patients, 6 were observed; 19 heterozygotes were expected, but 23 were observed.
      The gene frequency for the inactivating polymorphism (0. 31) was increased
      approximately 1.4-fold among the 56 t-AML patients. This increase was observed
      within each of the following overlapping cohorts of t-AML patients: the 43 who
      had received an alkylating agent, the 27 who had received a topoisomerase II
      inhibitor, and the 37 who had received any radiotherapy. Thus, the frequency of
      an inactivating polymorphism in NQO1 appears to be increased in this cohort of
      myeloid leukemias, especially among those with t-AML or an abnormality of
      chromosomes 5 and/or 7. Homozygotes and heterozygotes (who are at risk for
      treatment-induced mutation or loss of the remaining wild-type allele in their
      hematopoietic stem cells) may be particularly vulnerable to leukemogenic changes
      induced by carcinogens.

PMID- 10397749
TI  - The FcgammaRIa (CD64) ligand binding chain triggers major histocompatibility
      complex class II antigen presentation independently of its associated FcR gamma
      chain.
AB  - Within multi-subunit Ig receptors, the FcR gamma-chain immunoreceptor tyrosine
      based activation motif (ITAM) plays a crucial role in enabling antigen
      presentation. This process involves antigen-capture and targeting to specific
      degradation and major histocompatibility complex (MHC) class II loading
      compartments. Antigenic epitopes are then presented by MHC class II molecules to
      specific T cells. The high-affinity receptor for IgG, hFcgammaRIa, is exclusively
      expressed on myeloid lineage cells and depends on the FcR gamma-chain for surface
      expression, efficient ligand binding, and most phagocytic effector functions.
      However, we show in this report, using the IIA1.6 cell model, that hFcgammaRIa
      can potentiate MHC class II antigen presentation, independently of a functional
      FcR gamma-chain ITAM. Immunoelectron microscopic analyses documented hFcgammaRIa
      alpha-chain/rabbit IgG-Ovalbumin complexes to be internalized and to migrate via
      sorting endosomes to MHC class II-containing late endosomes. Radical deletion of
      the hFcgammaRIa alpha-chain cytoplasmic tail did not affect internalization of
      rabbit IgG-Ovalbumin complexes. Importantly, however, this resulted in diversion
      of receptor-ligand complexes to the recycling pathway and decreased antigen
      presentation. These results show the hFcgammaRIa cytoplasmic tail to contain
      autonomous targeting information for intracellular trafficking of receptor
      antigen complexes, although deficient in canonical tyrosine- or dileucine
      targeting motifs. This is the first documentation of autonomous targeting by a
      member of the multichain FcR family that may critically impact the
      immunoregulatory role proposed for hFcgammaRIa (CD64).

PMID- 10397750
TI  - Expression of the Fanconi anemia group A gene (Fanca) during mouse embryogenesis.
AB  - About 80% of all cases of Fanconi anemia (FA) can be accounted for by
      complementation groups A and C. To understand the relationship between these
      groups, we analyzed the expression pattern of the mouse FA group-A gene (Fanca)
      during embryogenesis and compared it with the known pattern of the group-C gene
      (Fancc). Northern analysis of RNA from mouse embryos at embryonic days 7, 11, 15,
      and 17 showed a predominant 4.5 kb band in all stages. By in situ hybridization,
      Fanca transcripts were found in the whisker follicles, teeth, brain, retina,
      kidney, liver, and limbs. There was also stage-specific variation in Fanca
      expression, particularly within the developing whiskers and the brain. Some
      tissues known to express Fancc (eg, gut) failed to show Fanca expression. These
      observations show that (1) Fanca is under both tissue- and stage-specific
      regulation in several tissues; (2) the expression pattern of Fanca is consistent
      with the phenotype of the human disease; and (3) Fanca expression is not
      necessarily coupled to that of Fancc. The presence of distinct tissue targets for
      FA genes suggests that some of the variability in the clinical phenotype can be
      attributed to the complementation group assignment.

PMID- 10397751
TI  - Keratinocyte growth factor separates graft-versus-leukemia effects from graft
      versus-host disease.
AB  - The major obstacles to successful outcome after allogeneic bone marrow
      transplantation (BMT) for leukemia remain graft-versus-host disease (GVHD) and
      leukemic relapse. Improved survival after BMT therefore requires more effective
      GVHD prophylaxis that does not impair graft-versus-leukemia (GVL) effects. We
      studied the administration of human recombinant keratinocyte growth factor (KGF)
      in a well- characterized murine BMT model for its effects on GVHD. KGF
      administration from day -3 to +7 significantly reduced GVHD mortality and the
      severity of GVHD in the gastrointestinal (GI) tract, reducing serum
      lipopolysaccharide (LPS) and tumor necrosis factor (TNF)alpha levels, but
      preserving donor T-cell responses (cytotoxic T lymphocyte [CTL] activity,
      proliferation, and interleukin [IL]-2 production) to host antigens. When mice
      received lethal doses of P815 leukemia cells at the time of BMT, KGF treatment
      significantly decreased acute GVHD compared with control-treated allogeneic mice
      and resulted in a significantly improved leukemia-free survival (42% v 4%, P
      <.001). KGF administration thus offers a novel approach to the separation of GVL
      effects from GVHD.

PMID- 10397752
TI  - Tissue-specific expression of dominant negative mutant Drosophila HSC70 causes
      developmental defects and lethality.
AB  - The Drosophila melanogaster HSC3 and HSC4 genes encode Hsc70 proteins homologous
      to the mammalian endoplasmic reticulum (ER) protein BiP and the cytoplasmic
      clathrin uncoating ATPase, respectively. These proteins possess ATP
      binding/hydrolysis activities that mediate their ability to aid in protein
      folding by coordinating the sequential binding and release of misfolded proteins.
      To investigate the roles of HSC3 (Hsc3p) and HSC4 (Hsc4p) proteins during
      development, GAL4-targeted gene expression was used to analyze the effects of
      producing dominant negatively acting Hsc3p (D231S, K97S) and Hsc4p (D206S, K71S)
      proteins, containing single amino acid substitutions in their ATP-binding
      domains, in specific tissues of Drosophila throughout development. We show that
      the production of each mutant protein results in lethality over a range of
      developmental stages, depending on the levels of protein produced and which
      tissues are targeted. We demonstrate that the functions of both Hsc3p and Hsc4p
      are required for proper tissue establishment and maintenance. Production of
      mutant Hsc4p, but not Hsc3p, results in induction of the stress-inducible Hsp70
      at normal temperatures. Evidence is presented that lethality is caused by tissue
      specific defects that result from a global accumulation of misfolded protein
      caused by lack of functional Hsc70. We show that both mutant Hsc3ps are defective
      in ATP-induced substrate release, although Hsc3p(D231S) does undergo an ATP
      induced conformational change. We believe that the amino acid substitutions in
      Hsc3p interfere with the structural coupling of ATP binding to substrate release,
      and this defect is the basis for the mutant proteins' dominant negative effects
      in vivo.

PMID- 10397753
TI  - The C-terminal domain of p21 inhibits nucleotide excision repair In vitro and In
      vivo.
AB  - The protein p21(Cip1, Waf1, Sdi1) is a potent inhibitor of cyclin-dependent
      kinases (CDKs). p21 can also block DNA replication through its interaction with
      the proliferating cell nuclear antigen (PCNA), which is an auxiliary factor for
      polymerase delta. PCNA is also implicated in the repair resynthesis step of
      nucleotide excision repair (NER). Previous studies have yielded contradictory
      results on whether p21 regulates NER through its interaction with PCNA.
      Resolution of this controversy is of interest because it would help understand
      how DNA repair and replication are regulated. Hence, we have investigated the
      effect of p21 on NER both in vitro and in vivo using purified fragments of p21
      containing either the CDK-binding domain (N terminus) or the PCNA binding domain
      (C terminus) of the protein. In the in vitro studies, DNA repair synthesis was
      measured in extracts from normal human fibroblasts using plasmids damaged by UV
      irradiation. In the in vivo studies, we used intact and permeabilized cells. The
      results show that the C terminus of the p21 protein inhibits NER both in vitro
      and in vivo. These are the first in vivo studies in which this question has been
      examined, and we demonstrate that inhibition of NER by p21 is not merely an
      artificial in vitro effect. A 50% inhibition of in vitro NER occurred at a 50:1
      molar ratio of p21 C-terminus fragment to PCNA monomer. p21 differentially
      regulates DNA repair and replication, with repair being much less sensitive to
      inhibition than replication. Our in vivo results suggest that the inhibition
      occurs at the resynthesis step of the repair process. It also appears that
      preassembly of PCNA at repair sites mitigates the inhibitory effect of p21. We
      further demonstrate that the inhibition of DNA repair is mediated via binding of
      p21 to PCNA. The N terminus of p21 had no effect on DNA repair, and the
      inhibition of DNA repair by the C terminus of p21 was relieved by the addition of
      purified PCNA protein.

PMID- 10397754
TI  - Role of the box C/D motif in localization of small nucleolar RNAs to coiled
      bodies and nucleoli.
AB  - Small nucleolar RNAs (snoRNAs) are a large family of eukaryotic RNAs that
      function within the nucleolus in the biogenesis of ribosomes. One major class of
      snoRNAs is the box C/D snoRNAs named for their conserved box C and box D sequence
      elements. We have investigated the involvement of cis-acting sequences and
      intranuclear structures in the localization of box C/D snoRNAs to the nucleolus
      by assaying the intranuclear distribution of fluorescently labeled U3, U8, and
      U14 snoRNAs injected into Xenopus oocyte nuclei. Analysis of an extensive panel
      of U3 RNA variants showed that the box C/D motif, comprised of box C', box D, and
      the 3' terminal stem of U3, is necessary and sufficient for the nucleolar
      localization of U3 snoRNA. Disruption of the elements of the box C/D motif of U8
      and U14 snoRNAs also prevented nucleolar localization, indicating that all box
      C/D snoRNAs use a common nucleolar-targeting mechanism. Finally, we found that
      wild-type box C/D snoRNAs transiently associate with coiled bodies before they
      localize to nucleoli and that variant RNAs that lack an intact box C/D motif are
      detained within coiled bodies. These results suggest that coiled bodies play a
      role in the biogenesis and/or intranuclear transport of box C/D snoRNAs.

PMID- 10397755
TI  - Assembly of a novel cartilage matrix protein filamentous network: molecular basis
      of differential requirement of von Willebrand factor A domains.
AB  - Cartilage matrix protein (CMP) is the prototype of the newly discovered matrilin
      family, all of which contain von Willebrand factor A domains. Although the
      function of matrilins remain unclear, we have shown that, in primary chondrocyte
      cultures, CMP (matrilin-1) forms a filamentous network, which is made up of two
      types of filaments, a collagen-dependent one and a collagen-independent one. In
      this study, we demonstrate that the collagen-independent CMP filaments are
      enriched in pericellular compartments, extending directly from chondrocyte
      membranes. Their morphology can be distinguished from that of collagen filaments
      by immunogold electron microscopy, and mimicked by that of self-assembled
      purified CMP. The assembly of CMP filaments can occur from transfection of a wild
      type CMP transgene alone in skin fibroblasts, which do not produce endogenous
      CMP. Conversely, assembly of endogenous CMP filaments by chondrocytes can be
      inhibited specifically by dominant negative CMP transgenes. The two A domains
      within CMP serve essential but different functions during network formation.
      Deletion of the A2 domain converts the trimeric CMP into a mixture of monomers,
      dimers, and trimers, whereas deletion of the A1 domain does not affect the
      trimeric configuration. This suggests that the A2 domain modulates
      multimerization of CMP. Absence of either A domain from CMP abolishes its ability
      to form collagen-independent filaments. In particular, Asp22 in A1 and Asp255 in
      A2 are essential; double point mutation of these residues disrupts CMP network
      formation. These residues are part of the metal ion-dependent adhesion sites,
      thus a metal ion-dependent adhesion site-mediated adhesion mechanism may be
      applicable to matrilin assembly. Taken together, our data suggest that CMP is a
      bridging molecule that connects matrix components in cartilage to form an
      integrated matrix network.

PMID- 10397756
TI  - In vitro studies with purified components reveal signal recognition particle
      (SRP) and SecA/SecB as constituents of two independent protein-targeting pathways
      of Escherichia coli.
AB  - The molecular requirements for the translocation of secretory proteins across,
      and the integration of membrane proteins into, the plasma membrane of Escherichia
      coli were compared. This was achieved in a novel cell-free system from E. coli
      which, by extensive subfractionation, was simultaneously rendered deficient in
      SecA/SecB and the signal recognition particle (SRP) components, Ffh (P48), 4. 5S
      RNA, and FtsY. The integration of two membrane proteins into inside-out plasma
      membrane vesicles of E. coli required all three SRP components and could not be
      driven by SecA, SecB, and DeltamicroH+. In contrast, these were the only
      components required for the translocation of secretory proteins into membrane
      vesicles, a process in which the SRP components were completely inactive. Our
      results, while confirming previous in vivo studies, provide the first in vitro
      evidence for the dependence of the integration of polytopic inner membrane
      proteins on SRP in E. coli. Furthermore, they suggest that SRP and SecA/SecB have
      different substrate specificities resulting in two separate targeting mechanisms
      for membrane and secretory proteins in E. coli. Both targeting pathways intersect
      at the translocation pore because they are equally affected by a blocked
      translocation channel.

PMID- 10397759
TI  - Effects of genome position and the DNA damage checkpoint on the structure and
      frequency of sod2 gene amplification in fission yeast.
AB  - The Schizosaccharomyces pombe sod2 gene, located near the telomere on the long
      arm of chromosome I, encodes a Na+ (or Li+)/H+ antiporter. Amplification of sod2
      has previously been shown to confer resistance to LiCl. We analyzed 20
      independent LiCl-resistant strains and found that the only observed mechanism of
      resistance is amplification of sod2. The amplicons are linear, extrachromosomal
      elements either 225 or 180 kb long, containing both sod2 and telomere sequences.
      To determine whether proximity to a telomere is necessary for sod2 amplification,
      a strain was constructed in which the gene was moved to the middle of the same
      chromosomal arm. Selection of LiCl-resistant strains in this genetic background
      also yielded amplifications of sod2, but in this case the amplified DNA was
      exclusively chromosomal. Thus, proximity to a telomere is not a prerequisite for
      gene amplification in S. pombe but does affect the mechanism. Relative to wild
      type cells, mutants with defects in the DNA damage aspect of the rad checkpoint
      control pathway had an increased frequency of sod2 amplification, whereas mutants
      defective in the S-phase completion checkpoint did not. Two models for generating
      the amplified DNA are presented.

PMID- 10397757
TI  - Isolated mammalian and Schizosaccharomyces pombe ran-binding domains rescue S.
      pombe sbp1 (RanBP1) genomic mutants.
AB  - Mammalian Ran-binding protein-1 (RanBP1) and its fission yeast homologue, sbp1p,
      are cytosolic proteins that interact with the GTP-charged form of Ran GTPase
      through a conserved Ran-binding domain (RBD). In vitro, this interaction can
      accelerate the Ran GTPase-activating protein-mediated hydrolysis of GTP on Ran
      and the turnover of nuclear import and export complexes. To analyze RanBP1
      function in vivo, we expressed exogenous RanBP1, sbp1p, and the RBD of each in
      mammalian cells, in wild-type fission yeast, and in yeast whose endogenous sbp1
      gene was disrupted. Mammalian cells and wild-type yeast expressing moderate
      levels of each protein were viable and displayed normal nuclear protein import.
      sbp1(-) yeast were inviable but could be rescued by all four exogenous proteins.
      Two RBDs of the mammalian nucleoporin RanBP2 also rescued sbp1(-) yeast. In
      mammalian cells, wild-type yeast, and rescued mutant yeast, exogenous full-length
      RanBP1 and sbp1p localized predominantly to the cytosol, whereas exogenous RBDs
      localized predominantly to the cell nucleus. These results suggest that only the
      RBD of sbp1p is required for its function in fission yeast, and that this
      function may not require confinement of the RBD to the cytosol. The results also
      indicate that the polar amino-terminal portion of sbp1p mediates cytosolic
      localization of the protein in both yeast and mammalian cells.

PMID- 10397758
TI  - Mapmodulin, cytoplasmic dynein, and microtubules enhance the transport of mannose
      6-phosphate receptors from endosomes to the trans-golgi network.
AB  - Late endosomes and the Golgi complex maintain their cellular localizations by
      virtue of interactions with the microtubule-based cytoskeleton. We study the
      transport of mannose 6-phosphate receptors from late endosomes to the trans-Golgi
      network in vitro. We show here that this process is facilitated by microtubules
      and the microtubule-based motor cytoplasmic dynein; transport is inhibited by
      excess recombinant dynamitin or purified microtubule-associated proteins.
      Mapmodulin, a protein that interacts with the microtubule-associated proteins
      MAP2, MAP4, and tau, stimulates the microtubule- and dynein-dependent
      localization of Golgi complexes in semi-intact Chinese hamster ovary cells. The
      present study shows that mapmodulin also stimulates the initial rate with which
      mannose 6-phosphate receptors are transported from late endosomes to the trans
      Golgi network in vitro. These findings represent the first indication that
      mapmodulin can stimulate a vesicle transport process, and they support a model in
      which the microtubule-based cytoskeleton enhances the efficiency of vesicle
      transport between membrane-bound compartments in mammalian cells.

PMID- 10397760
TI  - BiP and immunoglobulin light chain cooperate to control the folding of heavy
      chain and ensure the fidelity of immunoglobulin assembly.
AB  - The immunoglobulin (Ig) molecule is composed of two identical heavy chains and
      two identical light chains (H2L2). Transport of this heteromeric complex is
      dependent on the correct assembly of the component parts, which is controlled, in
      part, by the association of incompletely assembled Ig heavy chains with the
      endoplasmic reticulum (ER) chaperone, BiP. Although other heavy chain-constant
      domains interact transiently with BiP, in the absence of light chain synthesis,
      BiP binds stably to the first constant domain (CH1) of the heavy chain, causing
      it to be retained in the ER. Using a simplified two-domain Ig heavy chain (VH
      CH1), we have determined why BiP remains bound to free heavy chains and how light
      chains facilitate their transport. We found that in the absence of light chain
      expression, the CH1 domain neither folds nor forms its intradomain disulfide bond
      and therefore remains a substrate for BiP. In vivo, light chains are required to
      facilitate both the folding of the CH1 domain and the release of BiP. In
      contrast, the addition of ATP to isolated BiP-heavy chain complexes in vitro
      causes the release of BiP and allows the CH1 domain to fold in the absence of
      light chains. Therefore, light chains are not intrinsically essential for CH1
      domain folding, but play a critical role in removing BiP from the CH1 domain,
      thereby allowing it to fold and Ig assembly to proceed. These data suggest that
      the assembly of multimeric protein complexes in the ER is not strictly dependent
      on the proper folding of individual subunits; rather, assembly can drive the
      complete folding of protein subunits.

PMID- 10397761
TI  - Nuclear import of sterol regulatory element-binding protein-2, a basic helix-loop
      helix-leucine zipper (bHLH-Zip)-containing transcription factor, occurs through
      the direct interaction of importin beta with HLH-Zip.
AB  - The sterol regulatory element-binding protein-2 (SREBP-2) is produced as a large
      precursor molecule attached to the endoplasmic reticulum membrane. In response to
      the sterol depletion, the N-terminal segment of the precursor, which contains a
      basic helix-loop-helix-leucine zipper domain, is released by two sequential
      cleavages and is translocated to the nucleus, where it activates the
      transcription of target genes. The data herein show that released SREBP-2 uses a
      distinct nuclear transport pathway, which is mediated by importin beta. The
      mature form of SREBP-2 is actively transported into the nucleus when injected
      into the cell cytoplasm. SREBP-2 binds directly to importin beta in the absence
      of importin alpha. Ran-GTP but not Ran-GDP causes the dissociation of the SREBP-2
      importin beta complex. G19VRan-GTP inhibits the nuclear import of SREBP-2 in
      living cells. In the permeabilized cell in vitro transport system, nuclear import
      of SREBP-2 is reconstituted only by importin beta in conjunction with Ran and its
      interacting protein p10/NTF2. We further demonstrate that the helix-loop-helix
      leucine zipper motif of SREBP-2 contains a novel type of nuclear localization
      signal, which binds directly to importin beta.

PMID- 10397762
TI  - Pleiotropic alterations in lipid metabolism in yeast sac1 mutants: relationship
      to "bypass Sec14p" and inositol auxotrophy.
AB  - SacIp dysfunction results in bypass of the requirement for phosphatidylinositol
      transfer protein (Sec14p) function in yeast Golgi processes. This effect is
      accompanied by alterations in inositol phospholipid metabolism and inositol
      auxotrophy. Elucidation of how sac1 mutants effect "bypass Sec14p" will provide
      insights into Sec14p function in vivo. We now report that, in addition to a
      dramatic accumulation of phosphatidylinositol-4-phosphate, sac1 mutants also
      exhibit a specific acceleration of phosphatidylcholine biosynthesis via the CDP
      choline pathway. This phosphatidylcholine metabolic phenotype is sensitive to the
      two physiological challenges that abolish bypass Sec14p in sac1 strains; i.e.
      phospholipase D inactivation and expression of bacterial diacylglycerol (DAG)
      kinase. Moreover, we demonstrate that accumulation of phosphatidylinositol-4
      phosphate in sac1 mutants is insufficient to effect bypass Sec14p. These data
      support a model in which phospholipase D activity contributes to generation of
      DAG that, in turn, effects bypass Sec14p. A significant fate for this DAG is
      consumption by the CDP-choline pathway. Finally, we determine that CDP-choline
      pathway activity contributes to the inositol auxotrophy of sac1 strains in a
      novel manner that does not involve obvious defects in transcriptional expression
      of the INO1 gene.

PMID- 10397763
TI  - The plant vesicle-associated SNARE AtVTI1a likely mediates vesicle transport from
      the trans-Golgi network to the prevacuolar compartment.
AB  - Membrane traffic in eukaryotic cells relies on recognition between v-SNAREs on
      transport vesicles and t-SNAREs on target membranes. Here we report the
      identification of AtVTI1a and AtVTI1b, two Arabidopsis homologues of the yeast v
      SNARE Vti1p, which is required for multiple transport steps in yeast. AtVTI1a and
      AtVTI1b share 60% amino acid identity with one another and are 32 and 30%
      identical to the yeast protein, respectively. By suppressing defects found in
      specific strains of yeast vti1 temperature-sensitive mutants, we show that
      AtVTI1a can substitute for Vti1p in Golgi-to-prevacuolar compartment (PVC)
      transport, whereas AtVTI1b substitutes in two alternative pathways: the vacuolar
      import of alkaline phosphatase and the so-called cytosol-to-vacuole pathway used
      by aminopeptidase I. Both AtVTI1a and AtVTI1b are expressed in all major organs
      of Arabidopsis. Using subcellular fractionation and immunoelectron microscopy, we
      show that AtVTI1a colocalizes with the putative vacuolar cargo receptor AtELP on
      the trans-Golgi network and the PVC. AtVTI1a also colocalizes with the t-SNARE
      AtPEP12p to the PVC. In addition, AtVTI1a and AtPEP12p can be
      coimmunoprecipitated from plant cell extracts. We propose that AtVTI1a functions
      as a v-SNARE responsible for targeting AtELP-containing vesicles from the trans
      Golgi network to the PVC, and that AtVTI1b is involved in a different membrane
      transport process.

PMID- 10397764
TI  - Sla2p is associated with the yeast cortical actin cytoskeleton via redundant
      localization signals.
AB  - Sla2p, also known as End4p and Mop2p, is the founding member of a widely
      conserved family of actin-binding proteins, a distinguishing feature of which is
      a C-terminal region homologous to the C terminus of talin. These proteins may
      function in actin cytoskeleton-mediated plasma membrane remodeling. A human
      homologue of Sla2p binds to huntingtin, the protein whose mutation results in
      Huntington's disease. Here we establish by immunolocalization that Sla2p is a
      component of the yeast cortical actin cytoskeleton. Deletion analysis showed that
      Sla2p contains two separable regions, which can mediate association with the
      cortical actin cytoskeleton, and which can provide Sla2p function. One
      localization signal is actin based, whereas the other signal is independent of
      filamentous actin. Biochemical analysis showed that Sla2p exists as a dimer in
      vivo. Two-hybrid analysis revealed two intramolecular interactions mediated by
      coiled-coil domains. One of these interactions appears to underlie dimer
      formation. The other appears to contribute to the regulation of Sla2p
      distribution between the cytoplasm and plasma membrane. The data presented are
      used to develop a model for Sla2p regulation and interactions.

PMID- 10397765
TI  - Functional and biochemical analysis of the C2 domains of synaptotagmin IV.
AB  - Synaptotagmins (Syts) are a family of vesicle proteins that have been implicated
      in both regulated neurosecretion and general membrane trafficking. Calcium
      dependent interactions mediated through their C2 domains are proposed to
      contribute to the mechanism by which Syts trigger calcium-dependent
      neurotransmitter release. Syt IV is a novel member of the Syt family that is
      induced by cell depolarization and has a rapid rate of synthesis and a short half
      life. Moreover, the C2A domain of Syt IV does not bind calcium. We have examined
      the biochemical and functional properties of the C2 domains of Syt IV. Consistent
      with its non-calcium binding properties, the C2A domain of Syt IV binds syntaxin
      isoforms in a calcium-independent manner. In neuroendocrine pheochromocytoma
      (PC12) cells, Syt IV colocalizes with Syt I in the tips of the neurites.
      Microinjection of the C2A domain reveals that calcium-independent interactions
      mediated through this domain of Syt IV inhibit calcium-mediated neurotransmitter
      release from PC12 cells. Conversely, the C2B domain of Syt IV contains calcium
      binding properties, which permit homo-oligomerization as well as hetero
      oligomerization with Syt I. Our observation that different combinatorial
      interactions exist between Syt and syntaxin isoforms, coupled with the calcium
      stimulated hetero-oligomerization of Syt isoforms, suggests that the secretory
      machinery contains a vast repertoire of biochemical properties for sensing
      calcium and regulating neurotransmitter release accordingly.

PMID- 10397766
TI  - The movement of coiled bodies visualized in living plant cells by the green
      fluorescent protein.
AB  - Coiled bodies are nuclear organelles that contain components of at least three
      RNA-processing pathways: pre-mRNA splicing, histone mRNA 3'- maturation, and pre
      rRNA processing. Their function remains unknown. However, it has been speculated
      that coiled bodies may be sites of splicing factor assembly and/or recycling,
      play a role in histone mRNA 3'-processing, or act as nuclear transport or sorting
      structures. To study the dynamics of coiled bodies in living cells, we have
      stably expressed a U2B"-green fluorescent protein fusion in tobacco BY-2 cells
      and in Arabidopsis plants. Time-lapse confocal microscopy has shown that coiled
      bodies are mobile organelles in plant cells. We have observed movements of coiled
      bodies in the nucleolus, in the nucleoplasm, and from the periphery of the
      nucleus into the nucleolus, which suggests a transport function for coiled
      bodies. Furthermore, we have observed coalescence of coiled bodies, which
      suggests a mechanism for the decrease in coiled body number during the cell
      cycle. Deletion analysis of the U2B" gene construct has shown that the first RNP
      80 motif is sufficient for localization to the coiled body.

PMID- 10397767
TI  - Polymerizing microtubules activate site-directed F-actin assembly in nerve growth
      cones.
AB  - We identify an actin-based protrusive structure in growth cones termed
      "intrapodium." Unlike filopodia, intrapodia are initiated exclusively within
      lamellipodia and elongate in a continuous (nonsaltatory) manner parallel to the
      plane of the dorsal plasma membrane causing a ridge-like protrusion. Intrapodia
      resemble the actin-rich structures induced by intracellular pathogens (e.g.,
      Listeria) or by extracellular beads. Cytochalasin B inhibits intrapodial
      elongation and removal of cytochalasin B produced a burst of intrapodial
      activity. Electron microscopic studies revealed that lamellipodial intrapodia
      contain both short and long actin filaments oriented with their barbed ends
      toward the membrane surface or advancing end. Our data suggest an interaction
      between microtubule endings and intrapodia formation. Disruption of microtubules
      by acute nocodazole treatment decreased intrapodia frequency, and washout of
      nocodazole or addition of the microtubule-stabilizing drug Taxol caused a burst
      of intrapodia formation. Furthermore, individual microtubule ends were found near
      intrapodia initiation sites. Thus, microtubule ends or associated structures may
      regulate these actin-dependent structures. We propose that intrapodia are the
      consequence of an early step in a cascade of events that leads to the development
      of F-actin-associated plasma membrane specializations.

PMID- 10397768
TI  - Muscle LIM proteins are associated with muscle sarcomeres and require dMEF2 for
      their expression during Drosophila myogenesis.
AB  - A genetic hierarchy of interactions, involving myogenic regulatory factors of the
      MyoD and myocyte enhancer-binding 2 (MEF2) families, serves to elaborate and
      maintain the differentiated muscle phenotype through transcriptional regulation
      of muscle-specific target genes. Much work suggests that members of the cysteine
      rich protein (CRP) family of LIM domain proteins also play a role in muscle
      differentiation; however, the specific functions of CRPs in this process remain
      undefined. Previously, we characterized two members of the Drosophila CRP family,
      the muscle LIM proteins Mlp60A and Mlp84B, which show restricted expression in
      differentiating muscle lineages. To extend our analysis of Drosophila Mlps, we
      characterized the expression of Mlps in mutant backgrounds that disrupt specific
      aspects of muscle development. We show a genetic requirement for the
      transcription factor dMEF2 in regulating Mlp expression and an ability of dMEF2
      to bind, in vitro, to consensus MEF2 sites derived from those present in Mlp
      genomic sequences. These data suggest that the Mlp genes may be direct targets of
      dMEF2 within the genetic hierarchy controlling muscle differentiation. Mutations
      that disrupt myoblast fusion fail to affect Mlp expression. In later stages of
      myogenic differentiation, which are dedicated primarily to assembly of the
      contractile apparatus, we analyzed the subcellular distribution of Mlp84B in
      detail. Immunofluorescent studies revealed the localization of Mlp84B to muscle
      attachment sites and the periphery of Z-bands of striated muscle. Analysis of
      mutations that affect expression of integrins and alpha-actinin, key components
      of these structures, also failed to perturb Mlp84B distribution. In conclusion,
      we have used molecular epistasis analysis to position Mlp function downstream of
      events involving mesoderm specification and patterning and concomitant with
      terminal muscle differentiation. Furthermore, our results are consistent with a
      structural role for Mlps as components of muscle cytoarchitecture.

PMID- 10397769
TI  - UNC-11, a Caenorhabditis elegans AP180 homologue, regulates the size and protein
      composition of synaptic vesicles.
AB  - The unc-11 gene of Caenorhabditis elegans encodes multiple isoforms of a protein
      homologous to the mammalian brain-specific clathrin-adaptor protein AP180. The
      UNC-11 protein is expressed at high levels in the nervous system and at lower
      levels in other tissues. In neurons, UNC-11 is enriched at presynaptic terminals
      but is also present in cell bodies. unc-11 mutants are defective in two aspects
      of synaptic vesicle biogenesis. First, the SNARE protein synaptobrevin is
      mislocalized, no longer being exclusively localized to synaptic vesicles. The
      reduction of synaptobrevin at synaptic vesicles is the probable cause of the
      reduced neurotransmitter release observed in these mutants. Second, unc-11
      mutants accumulate large vesicles at synapses. We propose that the UNC-11 protein
      mediates two functions during synaptic vesicle biogenesis: it recruits
      synaptobrevin to synaptic vesicle membranes and it regulates the size of the
      budded vesicle during clathrin coat assembly.

PMID- 10397770
TI  - Characterization of Mayven, a novel actin-binding protein predominantly expressed
      in brain.
AB  - The cytoskeleton plays an important role in neuronal morphogenesis. We have
      identified and characterized a novel actin-binding protein, termed Mayven,
      predominantly expressed in brain. Mayven contains a BTB (broad complex,
      tramtrack, bric-a-brac)/POZ (poxvirus, zinc finger) domain-like structure in the
      predicted N terminus and "kelch repeats" in the predicted C-terminal domain.
      Mayven shares 63% identity (77% similarity) with the Drosophila ring canal
      ("kelch") protein. Somatic cell-hybrid analysis indicated that the human Mayven
      gene is located on chromosome 4q21.2, whereas the murine homolog gene is located
      on chromosome 8. The BTB/POZ domain of Mayven can self-dimerize in vitro, which
      might be important for its interaction with other BTB/POZ-containing proteins.
      Confocal microscopic studies of endogenous Mayven protein revealed a highly
      dynamic localization pattern of the protein. In U373-MG astrocytoma/glioblastoma
      cells, Mayven colocalized with actin filaments in stress fibers and in patchy
      cortical actin-rich regions of the cell margins. In primary rat hippocampal
      neurons, Mayven is highly expressed in the cell body and in neurite processes.
      Binding assays and far Western blotting analysis demonstrated association of
      Mayven with actin. This association is mediated through the "kelch repeats"
      within the C terminus of Mayven. Depolarization of primary hippocampal neurons
      with KCl enhanced the association of Mayven with actin. This increased
      association resulted in dynamic changes in Mayven distribution from uniform to
      punctate localization along neuronal processes. These results suggest that Mayven
      functions as an actin-binding protein that may be translocated along axonal
      processes and might be involved in the dynamic organization of the actin
      cytoskeleton in brain cells.

PMID- 10397771
TI  - Yeast Dam1p is required to maintain spindle integrity during mitosis and
      interacts with the Mps1p kinase.
AB  - We have identified a mutant allele of the DAM1 gene in a screen for mutations
      that are lethal in combination with the mps1-1 mutation. MPS1 encodes an
      essential protein kinase that is required for duplication of the spindle pole
      body and for the spindle assembly checkpoint. Mutations in six different genes
      were found to be lethal in combination with mps1-1, of which only DAM1 was novel.
      The remaining genes encode a checkpoint protein, Bub1p, and four chaperone
      proteins, Sti1p, Hsc82p, Cdc37p, and Ydj1p. DAM1 is an essential gene that
      encodes a protein recently described as a member of a microtubule binding
      complex. We report here that cells harboring the dam1-1 mutation fail to maintain
      spindle integrity during anaphase at the restrictive temperature. Consistent with
      this phenotype, DAM1 displays genetic interactions with STU1, CIN8, and KAR3,
      genes encoding proteins involved in spindle function. We have observed that a
      Dam1p-Myc fusion protein expressed at endogenous levels and localized by
      immunofluorescence microscopy, appears to be evenly distributed along short
      mitotic spindles but is found at the spindle poles at later times in mitosis.

PMID- 10397772
TI  - Saccharomyces cerevisiae MPS2 encodes a membrane protein localized at the spindle
      pole body and the nuclear envelope.
AB  - The MPS2 (monopolar spindle two) gene is one of several genes required for the
      proper execution of spindle pole body (SPB) duplication in the budding yeast
      Saccharomyces cerevisiae (). We report here that the MPS2 gene encodes an
      essential 44-kDa protein with two putative coiled-coil regions and a hydrophobic
      sequence. Although MPS2 is required for normal mitotic growth, some null strains
      can survive; these survivors exhibit slow growth and abnormal ploidy. The MPS2
      protein was tagged with nine copies of the myc epitope, and biochemical
      fractionation experiments show that it is an integral membrane protein.
      Visualization of a green fluorescent protein (GFP) Mps2p fusion protein in living
      cells and indirect immunofluorescence microscopy of 9xmyc-Mps2p revealed a
      perinuclear localization with one or two brighter foci of staining corresponding
      to the SPB. Additionally, immunoelectron microscopy shows that GFP-Mps2p
      localizes to the SPB. Our analysis suggests that Mps2p is required as a component
      of the SPB for insertion of the nascent SPB into the nuclear envelope.

PMID- 10397773
TI  - A role for Tlg1p in the transport of proteins within the Golgi apparatus of
      Saccharomyces cerevisiae.
AB  - Members of the syntaxin protein family participate in the docking-fusion step of
      several intracellular vesicular transport events. Tlg1p has been identified as a
      nonessential protein required for efficient endocytosis as well as the
      maintenance of normal levels of trans-Golgi network proteins. In this study we
      independently describe Tlg1p as an essential protein required for cell viability.
      Depletion of Tlg1p in vivo causes a defect in the transport of the vacuolar
      protein carboxypeptidase Y through the early Golgi. Temperature-sensitive (ts)
      mutants of Tlg1p also accumulate the endoplasmic reticulum/cis-Golgi form of
      carboxypeptidase Y at the nonpermissive temperature (38 degrees C) and exhibit
      underglycosylation of secreted invertase. Overexpression of Tlg1p complements the
      growth defect of vti1-11 at the nonpermissive temperature, whereas incomplete
      complementation was observed with vti1-1, further suggesting a role for Tlg1p in
      the Golgi apparatus. Overexpression of Sed5p decreases the viability of tlg1 ts
      mutants compared with wild-type cells, suggesting that tlg1 ts mutants are more
      susceptible to elevated levels of Sed5p. Tlg1p is able to bind His6-tagged Sec17p
      (yeast alpha-SNAP) in a dose-dependent manner and enters into a SNARE complex
      with Vti1p, Tlg2p, and Vps45p. Morphological analyses by electron microscopy
      reveal that cells depleted of Tlg1p or tlg1 ts mutants incubated at the
      restrictive temperature accumulate 40- to 50-nm vesicles and experience
      fragmentation of the vacuole.

PMID- 10397774
TI  - Functional characterization of the interaction of Ste50p with Ste11p MAPKKK in
      Saccharomyces cerevisiae.
AB  - The Saccharomyces cerevisiae Ste11p protein kinase is a homologue of mammalian
      MAPK/extracellular signal-regulated protein kinase kinase kinases (MAPKKKs or
      MEKKs) as well as the Schizosaccharomyces pombe Byr2p kinase. Ste11p functions in
      several signaling pathways, including those for mating pheromone response and
      osmotic stress response. The Ste11p kinase has an N-terminal domain that
      interacts with other signaling molecules to regulate Ste11p function and direct
      its activity in these pathways. One of the Ste11p regulators is Ste50p, and
      Ste11p and Ste50p associate through their respective N-terminal domains. This
      interaction relieves a negative activity of the Ste11p N terminus, and removal of
      this negative function is required for Ste11p function in the high-osmolarity
      glycerol (HOG) pathway. The Ste50p/Ste11p interaction is also important (but not
      essential) for Ste11p function in the mating pathway; in this pathway binding of
      the Ste11p N terminus with both Ste50p and Ste5p is required, with the Ste5p
      association playing the major role in Ste11p function. In vitro, Ste50p disrupts
      an association between the catalytic C terminus and the regulatory N terminus of
      Ste11p. In addition, Ste50p appears to modulate Ste11p autophosphorylation and is
      itself a substrate of the Ste11p kinase. Therefore, both in vivo and in vitro
      data support a role for Ste50p in the regulation of Ste11p activity.

PMID- 10397778
TI  - Honorary members elected to the AAA in 1999 

PMID- 10397777
TI  - ANATOMY WEB: new interconnectedness for new anatomists.

PMID- 10397776
TI  - Biogenesis of Tim proteins of the mitochondrial carrier import pathway:
      differential targeting mechanisms and crossing over with the main import pathway.
AB  - Two major routes of preprotein targeting into mitochondria are known. Preproteins
      carrying amino-terminal signals mainly use Tom20, the general import pore (GIP)
      complex and the Tim23-Tim17 complex. Preproteins with internal signals such as
      inner membrane carriers use Tom70, the GIP complex, and the special Tim pathway,
      involving small Tims of the intermembrane space and Tim22-Tim54 of the inner
      membrane. Little is known about the biogenesis and assembly of the Tim proteins
      of this carrier pathway. We report that import of the preprotein of Tim22
      requires Tom20, although it uses the carrier Tim route. In contrast, the
      preprotein of Tim54 mainly uses Tom70, yet it follows the Tim23-Tim17 pathway.
      The positively charged amino-terminal region of Tim54 is required for membrane
      translocation but not for targeting to Tom70. In addition, we identify two novel
      homologues of the small Tim proteins and show that targeting of the small Tims
      follows a third new route where surface receptors are dispensable, yet Tom5 of
      the GIP complex is crucial. We conclude that the biogenesis of Tim proteins of
      the carrier pathway cannot be described by either one of the two major import
      routes, but involves new types of import pathways composed of various features of
      the hitherto known routes, including crossing over at the level of the GIP.

PMID- 10397779
TI  - The 1999 Henry Gray Award.

PMID- 10397775
TI  - Rho-dependent regulation of cell spreading by the tetraspan membrane protein
      Gas3/PMP22.
AB  - Gas3/PMP22 plays a crucial role in regulating myelin formation and maintenance,
      and different genetic alterations in gas3/PMP22 are responsible for a set of
      human peripheral neuropathies. We have previously demonstrated that Gas3/PMP22
      could regulate susceptibility to apoptosis in NIH3T3 cells but not in REF 52
      cells. In this report we demonstrate that when the apoptotic response triggered
      by gas3/PMP22 was counteracted by Bcl-2 coexpression, morphological changes were
      observed. Time-lapse analysis confirmed that Gas3/PMP22 can modulate cell
      spreading, and this effect was strengthened after inhibition of phosphoinositide
      3-kinase. Using the active form of the small GTPase RhoA, we have been able to
      dissect the different Gas3/PMP22 biological activities. RhoA counteracted the
      Gas3/PMP22-dependent morphological response but was unable to neutralize the
      apoptotic response. Treatment of NIH3T3 cells with cytotoxic necrotizing factor
      1, which activates endogenous Rho, also counteracted Gas3/PMP22-mediated cell
      shape and spreading changes. Treatment of REF 52 cells, which are unresponsive to
      Gas3/PMP22 overexpression, with the C3 exoenzyme, inhibiting Rho activity,
      renders REF 52 cells responsive to Gas3/PMP22 overexpression for cell shape and
      spreading changes. Finally, assembly of stress fibers and focal adhesions
      complexes, in response to lysophosphatidic acid-induced endogenous Rho
      activation, was impaired in Gas3/PMP22-overexpressing cells. We hypothesize that
      cell shape and spreading regulated by Gas3/PMP22 through the Rho GTPase might
      have an important role during Schwann cells differentiation and myelinization.

PMID- 10397780
TI  - The A.J. Ladman AAA/Wiley Exemplary Service Award.

PMID- 10397781
TI  - Huxley's bulldog: the battles of E. Ray Lankester (1846-1929).

PMID- 10397782
TI  - The standard medical microscopic anatomy course: histology circa 1998.

PMID- 10397783
TI  - Diffusion magnetic resonance imaging: its principle and applications.
AB  - Diffusion magnetic resonance imaging (MRI) is one of the most rapidly evolving
      techniques in the MRI field. This method exploits the random diffusional motion
      of water molecules, which has intriguing properties depending on the
      physiological and anatomical environment of the organisms studied. We explain the
      principles of this emerging technique and subsequently introduce some of its
      present applications to neuroimaging, namely detection of ischemic stroke and
      reconstruction of axonal bundles and myelin fibers.

PMID- 10397784
TI  - Biomechanics of total hip arthroplasty.
AB  - The biomechanics of the hip joint provide an understanding of the development,
      evolution, and treatment of many disabling conditions of this joint. The
      available methods of biomechanical analysis include in vitro studies, in vivo
      studies, and theoretical mathematic analyses. The information obtained from these
      analyses have enabled the design of therapeutic programs to alleviate the
      symptoms of, and possibly delay the progression of, hip disease. The design of
      surgical procedures has been based on alterations of the biomechanics of the hip.
      These procedures have proven useful for treating pathologies such as
      osteoarthritis, hip dysplasia, and hip fractures. The study of biomechanics and
      biomaterials are integral to the current success of total hip arthroplasty in
      achieving pain relief and functional restoration.

PMID- 10397785
TI  - Forthcoming topics 

PMID- 10397786
TI  - Dielectric properties of alginate beads and bound water relaxation studied by
      electrorotation.
AB  - The electrical and dielectric properties of Ba2+ and Ca2+ cross-linked alginate
      hydrogel beads were studied by means of single-particle electrorotation. The use
      of microstructured electrodes allowed the measurements to be performed over a
      wide range of medium conductivity from about 5 mS/m to 1 S/m. Within a
      conductivity range, the beads exhibited measurable electrorotation response at
      frequencies above 0.2 MHz with two well-resolved co- and antifield peaks. With
      increasing medium conductivity, both peaks shifted toward higher frequency and
      their magnitudes decreased greatly. The results were analyzed using various
      dielectric models that consider the beads as homogeneous spheres with conductive
      loss and allow the complex rotational behavior of beads to be explained in terms
      of conductivity and permittivity of the hydrogel. The rotation spectra could be
      fitted very accurately by assuming (a) a linear relationship between the internal
      hydrogel conductivity and the medium conductivity, and (b) a broad internal
      dispersion of the hydrogel centered between 20 and 40 MHz. We attribute this
      dispersion to the relaxation of water bound to the polysaccharide matrix of the
      beads. The dielectric characterization of alginate hydrogels is of enormous
      interest for biotechnology and medicine, where alginate beads are widely used for
      immobilization of cells and enzymes, for drug delivery, and as microcarriers for
      cell cultivation.

PMID- 10397788
TI  - Structure and dynamics of alpha-MSH using DRISM integral equation theory and
      stochastic dynamics.
AB  - The structural and dynamical features of the hormone alpha-MSH in solution have
      been examined over a 100 ns time scale by using free energy molecular mechanics
      models at room temperature. The free energy surface has been modeled using
      methods from integral equation theory and the dynamics by the Langevin equation.
      A modification of the accessible surface area friction drag model was used to
      calculate the atomic friction coefficients. The molecule shows a stable beta-turn
      conformation in the message region and a close interaction between the side
      chains of His6, Phe7, and Trp9. A salt bridge between Glu5 and Arg8 was found not
      to be a preferred interaction, whereas a Glu5 and Lys11 salt bridge was not
      sampled, presumably due to relatively high free energy barriers. The message
      region was more conformationally rigid than the N-terminal region. Several
      structural features observed here agree well with experimental results. The
      conformational features suggest a receptor-hormone interaction model where the
      hydrophobic side chains of Phe7 and Trp9 interact with the transmembrane portion
      of the MC1 receptor. Also, the positively charged side chain of Arg8 and the
      imidazole side chain of His6 may interact with the negatively charged portions of
      the receptor which may even be on the receptor's extracellular loops.

PMID- 10397787
TI  - Orientation and immersion depth of a helical lipopeptaibol in membranes using
      TOAC as an ESR probe.
AB  - Trichogin GA IV is a lipopeptaibol antibiotic characterized by the sequence nOct
      Aib1-Gly-Leu-Aib4-Gly-Gly-Leu-Aib8-Gly-Ile- Lol (nOct: n-octanoyl; Aib: alpha
      aminoisobutyric acid; Lol, leucinol), which exhibits membrane-modifying
      properties. We synthesized step-by-step by solution methods three trichogin
      analogues, each with a single Aib --> 2,2,6,6-tetramethylpiperidin-1-oxyl-4-amino
      4-carboxylic acid (TOAC) substitution. The similarity in the conformational
      propensities of the Calpha-tetrasubstituted alpha-amino acids Aib and TOAC
      allowed us to exploit these analogues to investigate the orientation and
      therefore the mechanism of action of trichogin in the membranes by the electron
      spin resonance (ESR) technique. A conformational analysis by Fourier transform ir
      absorption and CD in different organic solvents and in a membrane-mimetic
      environment indicated that the conformation of the natural lipopeptaibol remains
      almost unchanged in the three analogues. Moreover, for all of the analogues
      permeability measurements revealed membrane-modifying properties comparable to
      those of trichogin. Our ESR investigation demonstrated that, in liposomes based
      on phosphatidylcholine, trichogin lays parallel to the membrane surface with its
      hydrophobic face oriented toward the membrane interior. These results suggest
      that trichogin might modify membrane permeability via a carpet-like mechanism, at
      least in liposomes and in the absence of a transmembrane potential.

PMID- 10397789
TI  - Addition of positively charged tripeptide to N-terminus of the Fos basic region
      leucine zipper domain: implications on DNA bending, affinity, and specificity.
AB  - GKH-Fos(139-211)/Jun(248-334) (GKH: glycine-lysine-histidine) is a modified
      Fos/Jun heterodimer designed to contain a metal binding motif in the form of a
      GKH tripeptide at the amino terminus of Fos bZIP domain dimerized with the Jun
      basic region leucine zipper (bZIP) domain. We examined the effect of the addition
      of positively charged GKH motif to the N-terminus of Fos(139-211) on the DNA
      binding characteristics of the Fos(139-211)/Jun(248-334) heterodimer. Binding
      studies indicate that while the nonspecific DNA binding affinity of the GKH
      modified heterodimer increases 4-fold, it specifically binds the activating
      protein-1 (AP-1) site 6-fold less tightly than the control unmodified
      counterpart. Furthermore, helical phasing analysis indicates that GKH-Fos(139
      211)/Jun(248-334) and control Fos(139-211)/Jun(248-334) both bend the DNA at the
      AP-1 site toward the minor groove. However, due to the presence of the positively
      charged GKH motif on Fos, the degree of the induced bend by GKH- Fos(139
      211)/Jun(248-334) is greater than that induced by the unmodified Fos/Jun
      heterodimer. Our results suggest that the unfavorable energetic cost of the
      increased DNA bending by GKH-Fos(139-211)/Jun(248-334) results in a decrease in
      both specificity and affinity of binding of the heterodimer to the AP-1 site.
      These findings may have important implications in protein design as well in our
      understanding of DNA bending and factors responsible for the functional
      specificity of different members of the bZIP family of transcription factors.

PMID- 10397790
TI  - A molecular dynamics simulation of the flavin mononucleotide-RNA aptamer complex.
AB  - We report on an unrestrained molecular dynamics simulation of the flavin
      mononucleotide (FMN)-RNA aptamer. The simulated average structure maintains both
      cross-strand and intermolecular FMN-RNA nuclear Overhauser effects from the nmr
      experiments and has all qualitative features of the nmr structure including the
      G10-U12-A25 base triple and the A13-G24, A8-G28, and G9-G27 mismatches. However,
      the relative orientation of the hairpin loop to the remaining part of the
      molecule differs from the nmr structure. The simulation predicts that the
      flexible phosphoglycerol part of FMN moves toward G27 and forms hydrogen bonds.
      There are structurally long-lived water molecules in the FMN binding pocket
      forming hydrogen bonds within FMN and between FMN and RNA. In addition, long
      lived water is found bridging primarily RNA backbone atoms. A general feature of
      the environment of long-lived "structural" water is at least two and in most
      cases three or four potential acceptor atoms. The 2'-OH group of RNA usually acts
      as an acceptor in interactions with the solvent. There are almost no intrastrand
      O2'H(n) vertical ...O4'(n + 1) hydrogen bonds within the RNA backbone. In the
      standard case the preferred orientation of the 2'-OH hydrogen atoms is
      approximately toward O3' of the same nucleotide. However, a relatively large
      number of conformations with the backbone torsional angle gamma in the trans
      orientation is found. A survey of all experimental RNA x-ray structures shows
      that this backbone conformation occurs but is less frequent than found in the
      simulation. Experimental nmr RNA aptamer structures have a higher fraction of
      this conformation as compared to the x-ray structures. The backbone conformation
      of nucleotide n + 1 with the torsional angle gamma in the trans orientation leads
      to a relatively short distance between 2'-OH(n) and O5'(n + 1), enabling hydrogen
      bond formation. In this case the preferred orientation of the 2'-OH hydrogen atom
      is approximately toward O5'(n + 1). We find two relatively short and dynamically
      stable types of backbone-backbone next-neighbor contacts, namely C2'(H)(n)
      vertical ...O4'(n + 1) and C5'(H)(n + 1) vertical ...O2'(n). These interactions
      may affect both backbone rigidity and thermodynamic stability of RNA helical
      structures.

PMID- 10397791
TI  - High-resolution calorimetric and optical melting profiles of DNA plasmids:
      resolving contributions from intrinsic melting domains and specifically designed
      inserts.
AB  - We demonstrate that differential scanning calorimetry (DSC) can be used to yield
      high-resolution melting profiles for DNA plasmids that agree in all major
      features with the corresponding plasmid melting profiles derived using more
      traditional optical techniques. We further demonstrate that by combining
      information derived from both calorimetric and optical melting profiles one can
      glean insights that are unavailable from either melting curve alone. By using
      both optical and calorimetric observables, we show how one can resolve, identify,
      and measure the thermodynamic properties of particular sequences/domains of
      interest within a plasmid. We also show that complementary DSC and optical
      melting studies on plasmids with and without specifically designed inserts can
      provide fundamental advantages over the corresponding melting studies on other
      model system constructs for thermodynamically characterizing nucleic acid
      sequences/structures.

PMID- 10397792
TI  - Docking of 4-oxalocrotonate tautomerase substrates: implications for the
      catalytic mechanism.
AB  - The enzyme 4-oxalocrotonate tautomerase catalyzes the ketonization of dienols,
      which after further processing become intermediates in the Krebs cycle. The
      enzyme uses a general acid-base mechanism for proton transfer: the amino-terminal
      proline has been shown to function as the catalytic base and Arg39 has been
      implicated as the catalytic acid. We report the results of molecular docking
      simulations of 4-oxalocrotonate tautomerase with two substrates, 2
      hydroxymuconate and 5-carboxymethyl-2-hydroxymuconate. pKa calculations are also
      performed for the free enzyme. The predicted binding mode of 2-hydroxymuconate is
      in agreement with experimental data. A model for the binding mode of 5
      carboxymethyl-2-hydroxymuconate is proposed which explains the lower catalytic
      efficiency of the enzyme toward this substrate. The pKa predictions and docking
      simulations support residue Arg39 as the general acid for the enzyme catalysis.

PMID- 10397795
TI  - Editorial: peptide structure and bioactivity 

PMID- 10397793
TI  - Free energy based populations of interconverting microstates of a cyclic peptide
      lead to the experimental NMR data.
AB  - Analysis of nuclear Overhauser enhancement (NOE) intensities data of
      interconverting microstates of a peptide is a difficult problem in nmr. A new
      statistical mechanics methodology has been proposed recently, consisting of
      several steps: (1) potential energy wells on the energy surface of the molecule
      are identified (the corresponding regions are called wide microstates); (2) each
      wide microstate is then spanned by a Monte Carlo (MC) or molecular dynamics
      simulation starting from a representative structure, and the corresponding
      relative populations are obtained from the free energy calculated with the local
      states method; and (3) the overall NOEs and 3J coupling constants are obtained as
      averages over the corresponding contributions of the samples, weighted by the
      populations. Extending this methodology to cyclic peptides, we are treating here
      the hexapeptide cyclo(D-Pro1-Phe2-Ala3-Ser4-Phe5-Phe6) in DMSO, which was studied
      by Kessler et al. using nmr (Journal of the American Chemical Society, 1992, Vol.
      114, pp. 4805-4818). They found that at least two structures are required to
      explain their NOE data, a conclusion also corroborated by our analysis (Journal
      of the American Chemical Society, 1998, Vol. 120, pp. 800-812) and led to a novel
      derivation of atomic solvation parameters (ASPs) for DMSO. Thus, the overall
      interactions within the peptide-solvent system are described approximately by
      Etot = EGRO + summation operator sigmaiAi, where EGRO is the energy of the GROMOS
      force field, Ai is the solvent-accessible surface area of atom i, and sigmai is
      the ASP. In the present paper the validity of these ASPs within the framework of
      the entire methodology is verified. This requires taking into account 23
      microstates. A very good agreement is obtained between experimental and
      calculated NOEs and 3J coupling constants. The free energy based populations lead
      to the best results, which means that entropic effects should not be ignored. We
      have also studied the behavior of the internal angular fluctuations of the proton
      proton vectors and discovered that they have a negligible effect on the
      calculated NOEs; this is due to the relatively concentrated wide microstates
      spanned by the MC simulations. The applicability of our ASPs to other cyclic
      peptides in DMSO is being studied in another work and preliminary results are
      discussed.

PMID- 10397796
TI  - Pseudo-prolines: induction of cis/trans-conformational interconversion by
      decreased transition state barriers.
AB  - Molecular events such as cis/trans isomerization of Xaa-Pro tertiary amide bonds
      in peptides and proteins are slow on the overall time scale of the formation of a
      final biostructure and are, therefore, rate limiting. In order to pursue a better
      understanding of the molecular events underlying such slow interconversions, we
      applied the recently introduced pseudo-proline (PsiPro) concept as a tool to
      study the dynamics of Xaa-Pro bonds by determining the kinetics and
      thermodynamics of cis/trans isomerism. We show that enhanced isomerization rates
      of tertiary amide bonds prior to a PsiPro unit in short model peptides is due to
      lowered transition state barriers. In addition, pronounced effects upon the
      dynamics of the reversible transition between helix I and II of oligoprolines
      containing one or several PsiPro units were observed.

PMID- 10397797
TI  - Gramicidin D conformation, dynamics and membrane ion transport.
AB  - The linear pentadecapeptide antibiotic, gramicidin D, a heterogeneous mixture of
      six components, is a naturally occurring product of Bacillus brevis known to form
      ion channels in synthetic and natural membranes. The conformation of gramicidin A
      in the solid state, in organic solvents, and in planar lipid bilayers and the
      relationship between the composition and the conformation of gramicidin and its
      selective transport of ions across membranes has been the subject of intense
      investigation for over 50 years. The x-ray crystal structure and nmr solution
      spectroscopy agree fully with one another and reveal that entirely different
      conformations of gramicidin are present in uncomplexed and ion complexed forms.
      Precise refinements of the three-dimensional structures of naturally occurring
      gramicidin D in crystals obtained from methanol, ethanol, and n-propanol
      demonstrate the unexpected presence of stable left-handed antiparallel double
      helical heterodimers that vary with the crystallization solvent. The side chains
      of Trp residues in the three structures exhibit sequence-specific patterns of
      conformational preference. Tyr substitution for Trp at position 11 appears to
      favor beta ribbon formation and stabilization of the antiparallel double helix.
      This conformation acts as a template for gramicidin folding and nucleation of the
      different crystal forms. The fact that a minor component in a heterogeneous
      mixture influences aggregation and crystal nucleation has potential applications
      to other systems in which anomalous behavior is exhibited by aggregation of
      apparently homogeneous materials, such as the enigmatic behavior of prion
      proteins. The crystallographically determined structures of cesium, potassium,
      rubidium, and hydronium ion complexes of gramicidin A are in excellent agreement
      with the nmr structure determination of the cesium ion gramicidin complex in a
      methanol chloroform mixture (50 : 50). The right-handed antiparallel double
      stranded double helical structures (DSDHR) also exhibit geometric features
      compatible with the solid-state 15N and 2H nmr data recorded for gramicidin in
      planar lipid bilayers and attributed to the active form of gramicidin A. The
      DSDHR crystal structures reveal an ion channel with a single partially solvated
      cation distributed over three ion binding sites. The channel lumen is relatively
      smooth and electrostatically negative as required for cation passage, while the
      exterior is electrostatically neutral, a requirement for membrane insertion. The
      "coordination" of the Cs+ ion is achieved by interaction with the pi orbitals of
      the carbonyls which do not point toward the ions. The K+ binding sites, which are
      similar in position to Cs+ binding sites, are shifted off center slightly toward
      the wall of the channel.

PMID- 10397798
TI  - Peptides and proteins in neurodegenerative disease: helix propensity of a
      polypeptide containing helix 1 of the mouse prion protein studied by NMR and CD
      spectroscopy.
AB  - Transmissible spongiform encephalopathies (TSE) or "prion diseases" have been
      related to the "protein-only hypothesis", which suggests that the "scrapie form
      (PrPSc)" of the prion protein (PrP) is the TSE infectious agent. The nmr
      structure of the ubiquitous benign cellular form of PrP (PrPC) consists of a
      globular domain of residues 126-231 with three alpha-helices and a short beta
      sheet, and a flexible extended "tail" of residues 23-125. The peptide segment of
      helix 1 has been implicated in various stages of hypothetical pathways to prion
      pathology on the basis of the protein-only idea, including that it takes part in
      the conformation change that leads from PrPC to PrPSc. In this paper we describe
      solution nmr and circular dichroism studies of the synthetic hexadecapeptide
      mPrP(143-158), with the sequence H-NDWEDRYYRENMYRYP-NH2, where the bold letters
      represent the segment that forms helix 1 in murine PrPC. In both H2O and a 1:1
      mixture of H2O and trifluoroethanol this polypeptide segment shows high helix
      propensity, which is a key issue in discussions on potential roles of this
      molecular region in conformational transitions of PrP.

PMID- 10397799
TI  - Novel RNA-binding motif: the KH module.
AB  - The KH motif has recently been identified in single or multiple copies in a
      number of RNA associated proteins. Here we review the current knowledge
      accumulated about the sequence, structure, and functions of the KH. The
      multidomain architecture of most of the KH-containing proteins inspired an
      approach based on the production of peptides spanning the sequence of an isolated
      KH motif. Correct identification of the minimal length necessary for producing a
      folded peptide has had a number of important consequences for interpreting
      functional data. The presence of the KH motifs in fmr1, the protein responsible
      for the fragile X syndrome, and their possible role in the fmr1 functions are
      also discussed.

PMID- 10397800
TI  - Binding of phenol to R6 insulin hexamers.
AB  - Small amounts of phenolic compounds are being used as preservatives in
      pharmaceutical insulin preparations. It has been shown previously that these
      compounds bind to specific sites on the insulin hexamer and act as allosteric
      effectors, inducing a transformation of the T6 hexamer to the R6 hexamer, via a
      T3R3 intermediate. In this article, the crystal structures of eight different
      insulin derivatives, all in the phenol-containing R6 form, are analyzed with
      respect to their phenol-binding sites. While six phenol molecules are normally
      bound per insulin hexamer, one of the engineered insulins appears to contain only
      three phenols but yet exists in an R6 conformation. This observation provides
      additional evidence for an inherent nonequivalence of the two trimers in the
      insulin hexamer. The unusual observation of a seventh phenol molecule bound to
      the hexamer of crystalline A21Gly-B31,B32Arg2 insulin (HOE 901), a long-acting
      derivative currently undergoing phase III clinical trials, provides a partial
      explanation for its protracted activity.

PMID- 10397801
TI  - Semi-automated high throughput combinatorial solid-phase organic synthesis.
AB  - A semi-automated technique for massive parallel solid-phase organic synthesis
      based on a "split only" strategy is described. Two different types of purpose
      oriented reaction vessels are used. The initial steps are performed in domino
      blocks, and the resin-bound intermediates then split into wells of a micro plate
      for the last combinatorial step. The domino block is a reaction block for manual
      and semi-automatic parallel solid-phase organic synthesis that simplifies liquid
      exchange and integrates common synthetic steps. The synthesis in micro plates
      does not use any filter for separation of resin beads from the supernatant
      liquid, and allows high throughput parallel synthesis on solid phase to be
      performed. This technique, documented on examples of diverse disubstituted
      benzenes, includes the use of gaseous cleavage in the last synthetic step and
      allows the synthesis of thousands of compounds per day in mg quantities.

PMID- 10397802
TI  - Solid-phase synthesis of a library of functionalized aminodiol scaffolds.
AB  - A combinatorial library motif has been developed based on orthogonally protected
      aminodiol scaffolds. Amine functionality was derivatized by commercially
      available electrophiles including carboxylic acids, sulfonyl chlorides,
      isocyanates, and aldehydes. A hydroxyl moiety was converted to a carbamate
      linkage, allowing a variety of amines to be incorporated. The scaffold was
      anchored to TentaGel at the second hydroxyl via a succinyl linker, which was
      hydrolyzed by mild aqueous basic conditions. The method was used to make a
      library of about 17,000 different members in mixtures of 5 per sample.

PMID- 10397804
TI  - Monitoring solution-phase combinatorial library synthesis by capillary
      electrophoresis.
AB  - Capillary electrophoresis has been applied to monitor model reactions in solution
      phase combinatorial chemistry. In particular, the simultaneous alkylation
      reactions of secondary amines with a series of benzyl halides has been
      investigated. Reactant and product concentrations were monitored using capillary
      electrophoresis in a non-aqueous buffer system. The simplified sample preparation
      was a key feature making this an attractive method of analysis. The results
      demonstrate that capillary electrophoresis is a useful tool for monitoring
      reactions to determine initial rates, rate constants, and extinction correlation
      coefficients for quantitative analysis in combinatorial chemistry, and is a
      broadly applicable technique for the analysis of a variety of organic and
      bioorganic transformations.

PMID- 10397803
TI  - Rational optimization of a HIV-1 Tat inhibitor: rapid progress on combinatorial
      lead structures.
AB  - Lead molecules identified by combinatorial chemistry approaches are preferred
      starting points for straightforward improvements of compound profiles. Structure
      guided rationales can be supported and complemented by systematic variations
      based on the modular nature of the molecules. A peptoidic compound (CGP 64222),
      previously identified from a sequential unrandomization process, was shown to
      specifically inhibit the interaction between the HIV-1 trans-activator Tat and
      its RNA response element TAR. To improve the compound's pharmaceutical
      attractiveness an approach to reduce both, size and number of charges was
      pursued. Because this resulted in activity decrease, parallel synthesis with
      variations on one rationally defined position aimed at the identification of
      structural determinants was undertaken to regain in vitro activity in biochemical
      and cellular Tat-TAR interaction assays. As a result CGP74026 was identified, a
      drastically simplified but highly active Tat antagonist, which is able to block
      HIV-1 replication even in primary human cells.

PMID- 10397805
TI  - The use of optical spectroscopy in combinatorial chemistry.
AB  - Infrared and Raman spectroscopy allow direct spectral analysis of the solid
      phase, thus avoiding the tedious cleavage of compounds from the solid support.
      With diagnostic bands in starting materials or products, infrared and Raman
      spectroscopy are efficient in monitoring each reaction step directly on the solid
      phase. Consequently, infrared and Raman spectroscopy have evolved as the premier
      analytical methodology for direct analysis on the solid support. While infrared
      transmission spectroscopy is a general analytical method for resin samples,
      internal reflection spectroscopy is especially suited for solid polymer
      substrates known as "pins" or "crowns." Single bead analysis is done best by
      infrared microspectroscopy, whereas photoacoustic spectroscopy allows totally
      nondestructive analysis of resin samples. With an automated accessory, diffuse
      reflection spectroscopy provides a method for high throughput on-bead monitoring
      of solid-phase reactions. Providing identification based on molecular structure,
      HPLC-FTIR is, therefore, complementary to LC-MS. Additionally, Raman spectroscopy
      as a complement to infrared spectroscopy can be applied to resin samples and
      using a Raman microscope-to single beads. Fluorometry as an extremely sensitive
      spectroscopic detection method allows rapid quantification of organic reactions
      directly on the resin.

PMID- 10397806
TI  - Quarterly U.S. patent review: first quarter, 1999.
AB  - The following are among the U.S. patents, issued in the first quarter of 1999,
      directed to combinatorial chemistry and related technologies. Patent issuances in
      the field are growing in number. Additionally, patents claiming libraries
      themselves, as opposed to synthetic methodologies, are becoming more common. It
      is impossible to be comprehensive. The author would be pleased to recognize
      additional patents and invites the use of his e-mail address for this purpose.

PMID- 10397807
TI  - Anaerobic phosphate release from activated sludge with enhanced biological
      phosphorus removal. A possible mechanism of intracellular pH control 
AB  - The biochemical mechanisms of the wastewater treatment process known as enhanced
      biological phosphorus removal (EBPR) are presently described in a metabolic
      model. We investigated details of the EBPR model to determine the nature of the
      anaerobic phosphate release and how this may be metabolically associated with
      polyhydroxyalkanoate (PHA) formation. Iodoacetate, an inhibitor of glycolysis,
      was found to inhibit the anaerobic formation of PHA and phosphate release,
      supporting the pathways proposed in the EBPR metabolic model. In the metabolic
      model, it is proposed that polyphosphate degradation provides energy for the
      microorganisms in anaerobic regions of these treatment systems. Other
      investigations have shown that anaerobic phosphate release depends on the
      extracellular pH. We observed that when the intracellular pH of EBPR sludge was
      raised, substantial anaerobic phosphate release was caused without volatile fatty
      acid (VFA) uptake. Acidification of the sludge inhibited anaerobic phosphate
      release even in the presence of VFA. From these observations, we postulate that
      an additional possible role of anaerobic polyphosphate degradation in EBPR is for
      intracellular pH control. Intracellular pH control may be a metabolic feature of
      EBPR, not previously considered, that could have some use in the control and
      optimisation of EBPR. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397808
TI  - Dose-dependent reduction of apoptosis in nutrient-limited cultures of NS/0
      myeloma cells transfected with the E1B-19K adenoviral gene.
AB  - It is now well documented that apoptosis represents the prevalent mode of death
      in lymphoid cultures and occurs spontaneously in late-exponential phase of batch
      cultures following nutrient exhaustion. In an attempt to enhance the cell
      survival of these cell lines, we have initially engineered nonproducing NS/0
      myeloma cells with a vector expressing the adenoviral E1B-19K protein. NS/0 cells
      transfected with E1B-19K were found to be more resistant to apoptosis occurring
      in the late phase of batch culture and under stressful conditions such as
      cultivation in glutamine-free medium or following heat shock. In this study, we
      have characterised a number of NS/0 subclones constitutively expressing different
      levels of E1B-19K, as well as several subclones in which the expression of E1B
      19K was regulated by a tetracycline-controllable gene switch. We have found that
      a threshold E1B-19K level was required in order to achieve protection against
      apoptosis. The extent of resistance against cell death induced by nutrient
      deprivation in glutamine-free medium and in the late phase of batch cultures
      correlated with the level of E1B-19K expression up to an optimal level where
      further increases in E1B-19K levels did not result in significant additional
      protection. To assess the effects of E1B-19K on antibody productivity, an
      apoptosis-resistant NS/0 clone was then transfected with a chimeric antibody
      construct. Despite their improved viability, the antibody productivity of E1B-19K
      clones in batch culture was not significantly improved. Moreover, while the use
      of E1B-19K considerably delayed cell death, cells eventually died by apoptosis.
      Surprisingly, E1B-19K had no beneficial effect on the efficiency of fusion of
      NS/0 myelomas and splenocytes for the generation of hybridoma cells. Furthermore,
      the resulting hybridomas, although expressing E1B-19K at levels comparable to the
      myeloma parent, were no longer resistant to apoptosis. This indicates that the
      ability of E1B-19K to prevent apoptosis is not only dose-dependent but also seems
      to be cell-type dependent.

PMID- 10397809
TI  - Apoptosis-resistant E1B-19K-expressing NS/0 myeloma cells exhibit increased
      viability and chimeric antibody productivity under perfusion culture conditions.
AB  - We have shown previously that recombinant NS/0 myelomas expressing sufficient
      amounts of E1B-19K were resistant to apoptosis occurring in the late phase of
      batch culture and under stressful conditions such as cultivation in glutamine
      free medium or following heat shock. However, no significant increase in
      monoclonal antibodies (MAb) was observed during the prolonged stationary phase of
      these batch cultures. Here, we show that E1B-19K can enhance cell survival and
      improve MAb productivity in high cell density perfusion culture. Typically,
      lymphoid cells grown under steady state in perfusion exhibit decreasing
      viabilities with concomitant accumulation of apoptotic cells. By modulating the
      ability of these cells to resist to induction of apoptosis in low nutrient
      environment, a 3-fold decrease in specific death rate from 0.22 day-1 for NS/0
      control to 0.07 day-1 for E1B-19K cells was achieved, resulting in a significant
      improvement in cell viability throughout perfusion. E1B-19K cells at the
      perfusion plateau phase also exhibited a 3-fold reduction in specific growth rate
      concomitant with a lower percentage of S and higher percentage of G1 phase cells.
      This was associated with a 40% decrease in specific oxygen consumption rate,
      likely related to a reduction in the specific consumption rates of limiting
      nutrient(s). Expression of E1B-19K consequently had a significant impact on the
      steady-state viable cell density, allowing maintenance of 11.5 x 10(6) E1B-19K
      cells/mL versus 5.9 x 10(6) control NS/0 cells/mL for the same amount of fresh
      medium brought into the system (half a volume per day). Whereas MAb
      concentrations found in perfusion culture of control NS/0 myelomas were almost 3
      fold higher than those found in batch culture; in the case of E1B-19K-expressing
      myelomas, the MAb concentration in perfusion was more than 7-fold higher than in
      batch. This was attributable to the 2-fold increase in viable cell plateau and to
      a 40% increase in the perfusion to batch ratio of specific MAb productivity (2.2
      fold for E1B-19K myelomas versus 1.6-fold for NS/0 control).

PMID- 10397810
TI  - Tuning biphenyl dioxygenase for extended substrate specificity.
AB  - Highly substituted polychlorinated biphenyls (PCBs) are known to be very
      resistant to aerobic biodegradation, particularly the initial attack by biphenyl
      dioxygenase. Functional evolution of the substrate specificity of biphenyl
      dioxygenase was demonstrated by DNA shuffling and staggered extension process
      (StEP) of the bphA gene coding for the large subunit of biphenyl dioxygenase.
      Several variants with an extended substrate range for PCBs were selected. In
      contrast to the parental biphenyl dioxygenases from Burkholderia cepacia LB400
      and Pseudomonas pseudoalcaligenes KF707, which preferentially recognize either
      ortho- (LB400) or para- (KF707) substituted PCBs, several variants degraded both
      congeners to about the same extent. These variants also exhibited superior
      degradation capabilities toward several tetra- and pentachlorinated PCBs as well
      as commercial PCB mixtures, such as Aroclor 1242 or Aroclor 1254. Sequence
      analysis confirmed that most variants contained at least four to six template
      switches. All desired variants contained the Thr335Ala and Phe336Ile
      substitutions confirming the importance of this critical region in substrate
      specificity. These results suggest that the block-exchange nature of gene
      shuffling between a diverse class of dioxygenases may be the most useful approach
      for breeding novel dioxygenases for PCB degradation in the desired direction.

PMID- 10397811
TI  - Hydrostatic pressure rescues native protein from aggregates.
AB  - Misfolding and misassembly of proteins are major problems in the biotechnology
      industry, in biochemical research, and in human disease. Here we describe a novel
      approach for reversing aggregation and increasing refolding by application of
      hydrostatic pressure. Using P22 tailspike protein as a model system,
      intermediates along the aggregation pathway were identified and quantitated by
      size-exclusion high-performance liquid chromatography (HPLC). Tailspike
      aggregates were subjected to hydrostatic pressures of 2.4 kbar (35,000 psi). This
      treatment dissociated the tailspike aggregates and resulted in increased
      formation of native trimers once pressure was released. Tailspike trimers
      refolded at these pressures were fully active for formation of infectious viral
      particles. This technique can facilitate conversion of aggregates to native
      proteins without addition of chaotropic agents, changes in buffer, or large-scale
      dilution of reagents required for traditional refolding methods. Our results also
      indicate that one or more intermediates at the junction between the folding and
      aggregation pathways is pressure sensitive. This finding supports the hypothesis
      that specific determinants of recognition exist for protein aggregation, and that
      these determinants are similar to those involved in folding to the native state.
      An increased understanding of this specificity should lead to improved refolding
      methods.

PMID- 10397812
TI  - Constraints on the transport and glycosylation of recombinant IFN-gamma in
      Chinese hamster ovary and insect cells.
AB  - In this study we compare intracellular transport and processing of a recombinant
      glycoprotein in mammalian and insect cells. Detailed analysis of the N
      glycosylation of recombinant human IFN-gamma by matrix-assisted laser-desorption
      mass spectrometry showed that the protein secreted by Chinese hamster ovary and
      baculovirus-infected insect Sf9 cells was associated with complex sialylated or
      truncated tri-mannosyl core glycans, respectively. However, the intracellular
      proteins were predominantly associated with high-mannose type oligosaccharides
      (Man-6 to Man-9) in both cases, indicating that endoplasmic reticulum to cis
      Golgi transport is a predominant rate-limiting step in both expression systems.
      In CHO cells, although there was a minor intracellular subpopulation of
      sialylated IFN-gamma glycoforms identical to the secreted product (therefore
      associated with late-Golgi compartments or secretory vesicles), no other
      intermediates were evident. Therefore, anterograde transport processes in the
      Golgi stack do not limit secretion. In Sf9 insect cells, there was no direct
      evidence of post-ER glycan-processing events other than core fucosylation and de
      mannosylation, both of which were glycosylation site-specific. To investigate the
      influence of nucleotide-sugar availability on cell-specific glycosylation, the
      cellular content of nucleotide-sugar substrates in both mammalian and insect
      cells was quantitatively determined by anion-exchange HPLC. In both host cell
      types, UDP-hexose and UDP-N-acetylhexosamine were in greater abundance relative
      to other substrates. However, unlike CHO cells, sialyltransferase activity and
      CMP-NeuAc substrate were not present in uninfected or baculovirus-infected Sf9
      cells. Similar data were obtained for other insect cell hosts, Sf21 and Ea4. We
      conclude that although the limitations on intracellular transport and secretion
      of recombinant proteins in mammalian and insect cells are similar, N-glycan
      processing in Sf insect cells is limited, and that genetic modification of N
      glycan processing in these insect cell lines will be constrained by substrate
      availability to terminal galactosylation.

PMID- 10397813
TI  - Influence of low temperature on productivity, proteome and protein
      phosphorylation of CHO cells.
AB  - Proliferation of mammalian cells can be controlled by low cultivation
      temperature. However, depending on cell type and expression system, varying
      effects of a temperature shift on heterologous protein production have been
      reported. Here, we characterize growth behavior and productivity of the Chinese
      hamster ovary (CHO) cell line XM111-10 engineered to synthesize the model-product
      secreted alkaline phosphatase (SEAP). Shift of cultivation temperature from 37
      degrees C to 30 degrees C caused a growth arrest mainly in the G1 phase of the
      cell cycle concomitant with an up to 1.7-fold increase of specific productivity.
      A low temperature cultivation provided 3.4 times higher overall product yield
      compared to a standard cultivation at 37 degrees C. The cellular and molecular
      mechanisms underlying the effects of low temperature on growth and productivity
      of mammalian cells are poorly understood. Separation of total protein extracts by
      two-dimensional gel electrophoresis showed altered expression levels of CHO-K1
      proteins after decrease in cultivation temperature to 30 degrees C. These changes
      in the proteome suggest that mammalian cells respond actively to low temperature
      by synthesizing specific cold-inducible proteins. In addition, we provide the
      first evidence that the cold response of mammalian cells includes changes in
      postranslational protein modifications. Two CHO proteins were found to be
      phosphorylated at tyrosine residues following downshift of cultivation
      temperature to 30 degrees C. Elucidating cellular events during cold exposure is
      necessary for further optimization of host-cell lines and expression systems and
      can provide new strategies for metabolic engineering.

PMID- 10397814
TI  - Integrated reversed micellar extraction and stripping of alpha-amylase 
AB  - In this work the possibility of integrating the two process steps-extraction of
      an enzyme from its source aqueous solution into an organic solvent containing
      reversed micelles and its stripping into another aqueous medium of appropriate
      composition is studied. The kinetics of enzyme mass transfer during the
      integrated process is investigated using a stirred cell with two separated
      compartments. The enzyme/surfactant system chosen consisted of alpha-amylase and
      the cationic surfactant CTAB (cetyl trimethyl ammonium bromide). Comparison
      between the classical extraction process and the "integrated reversed micellar
      extraction-stripping" is made. The enzyme activity changes during the transfer
      process are followed, and the registered tendencies are discussed. Copyright 1999
      John Wiley & Sons, Inc.

PMID- 10397815
TI  - Studies on the respiration rate of free and immobilized cells of cephalosporium
      acremonium in cephalosporin C production 
AB  - Bioprocesses using filamentous fungi immobilized in inert supports present many
      advantages when compared to conventional free cell processes. However, assessment
      of the real advantages of the unconventional process demands a rigorous study of
      the limitations to diffusional mass transfer of the reagents, especially
      concerning oxygen. In this work, a comparative study was carried out on the
      cephalosporin C production process in defined medium containing glucose and
      sucrose as main carbon and energy sources, by free and immobilized cells of
      Cephalosporium acremonium ATCC 48272 in calcium alginate gel beads containing
      alumina. The effective diffusivity of oxygen through the gel beads and the
      effectiveness factors related to the respiration rate of the microorganism were
      determined experimentally. By applying Monod kinetics, the respiration kinetics
      parameters were experimentally determined in independent experiments in a
      complete production medium. The effectiveness factor experimental values
      presented good agreement with the theoretical values of the approximated zero
      order effectiveness factor, considering the dead core model. Furthermore,
      experimental results obtained with immobilized cells in a 1.7-L tower bioreactor
      were compared with those obtained in 5-L conventional fermentor with free cells.
      It could be concluded that it is possible to attain rather high production rates
      working with relatively large diameter gel beads (ca. 2.5 mm) and sucrose
      consumption-based productivity was remarkably higher with immobilized cells,
      i.e., 0.33 gCPC/kg sucrose/h against 0.24 gCPC/kg sucrose/h in the aerated
      stirred tank bioreactor process. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397816
TI  - Epoxidation of 1,7-octadiene by pseudomonas oleovorans in a membrane bioreactor 
AB  - A growing cell culture of Pseudomonas oleovorans was used to biotransform 1,7
      octadiene to 1,2-epoxy-7,8-octene in a continuous-flow bioreactor with an
      external membrane module. A dense silicone rubber membrane was used to contact an
      organic phase, containing both the reactant (1,7-octadiene) and the growth
      substrate (heptane), with an aqueous biomedium phase containing the biocatalyst.
      Heptane and octadiene delivery to the aqueous phase, and epoxide extraction into
      the solvent, occurred by diffusion across the dense membrane under a
      concentration-driving force. In addition, a liquid feed of heptane and octadiene
      was pumped directly into the bioreactor to increase the rate of delivery of these
      compounds to the aqueous phase. In this system 1,2-epoxy-7,8-octene accumulated
      in a pure solvent phase, thus, product recovery problems associated with emulsion
      formation were avoided. Furthermore, no phase breakthrough of either liquid
      across the membrane was observed. In this system, the highest volumetric
      productivity obtained was 30 U.L-1, and this was achieved at a dilution rate of
      0.07 h-1, 70 m2. m-3 of membrane area, and a steady-state biomass concentration
      of 2. 5 g.L-1. The system was stable for over 1250 h. Decreasing the dilution
      rate led to an increased biomass concentration, however, the specific activity
      was significantly reduced, and therefore, an optimal dilution rate was determined
      at 0.055 h-1. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397817
TI  - Recombinant protein synthesis in Trichoplusia ni BTI-Tn-5B1-4 insect cell
      aggregates.
AB  - The Trichoplusia ni BTI-Tn-5B1-4 (Tn-5B1-4) insect cell line has received
      considerable attention as a host for the baculovirus expression vector system. In
      the present study, suspension cultures were used to compare Tn-5B1-4 cell
      aggregates and cells selected to grow predominantly as individual cells. No
      significant difference was found between cell aggregates and cells growing
      predominantly individually in regard to cell growth rate, glucose consumption and
      lactate accumulation, and specific recombinant protein synthesis levels. In
      addition, the levels of recombinant protein synthesis were considerably higher
      than those produced by the commonly used Spodoptera frugiperda Sf-9 insect cell
      line.

PMID- 10397818
TI  - Regional heparinization via simultaneous separation and reaction in a novel
      Taylor-Couette flow device.
AB  - The development of a safe and efficient bioreactor design has remained a
      challenge for the clinical application of immobilized enzymes. Specifically, the
      use of immobilized heparinase I has been the target of many studies to make
      heparin anticoagulation therapy safer for the critically ill patient with kidney
      failure or heart disease. We have investigated the use of Taylor-Couette flow for
      a novel type of bioreactor. In a previous study, we showed that the fluidization
      of agarose immobilized heparinase within Taylor vortices in whole blood can lead
      to extensive blood damage in the form of cell depletion and hemolysis. Based on
      these findings, we designed and developed a reactor, referred to as vortex-flow
      plasmapheretic reactor (VFPR), that incorporated plasmapheresis and fluidization
      of the agarose in the reactive compartment, separate from the whole-blood path.
      In the present study, immobilized heparinase I was tested as a means of achieving
      regional heparinization of a closed circuit. This is a method in which heparin is
      infused into the extracorporeal circuit predialyzer and neutralized postdialyzer.
      Saline studies were performed with an immobilized heparinase I-packed bed and
      with the VFPR. An in vitro feasibility study was performed with the VFPR using
      human blood. The VFPR achieved heparin conversions of 44 +/- 0.5% and 34 +/- 2%
      in saline and blood, respectively. In addition, the VFPR caused no blood damage.
      We report a novel method to achieve fluidization which depended on secondary,
      circumferencial flow, and was independent of the primary flow through the device.

PMID- 10397819
TI  - Diffusion in cell-free and cell immobilising kappa-carrageenan gel beads with and
      without chemical reaction 
AB  - Diffusion into and from kappa-carrageenan gel beads was studied, both in the
      absence and presence of bacterial cells, both with and without biochemical
      reaction. The solutes were indole, L-serine, and L-tryptophan. The reaction was
      that of indole and L-serine to give L-tryptophan. Established theory concerning
      diffusion of a single solute in cell-free gels was found to describe well the
      effect of the gel on diffusivity. Simultaneous diffusion of the three solutes
      resulted in lower diffusivities than those for individual solutes, suggesting the
      need to use multicomponent diffusion theory. The effect of cells on diffusion
      could only be accounted for by models assuming permeable cells. Diffusion with
      chemical reaction was reasonably well described by an effectiveness factor
      calculated using an effective diffusivity estimated from diffusion data without
      reaction. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397820
TI  - Affinity chromatographic screening of soluble combinatorial peptide libraries.
AB  - Affinity chromatography using immobilized S-protein was used for the screening of
      affinity peptide ligands from two soluble peptide libraries. Peptide library I
      consisted of octamers with glycine (G) at both termini of each peptide, i.e.
      GXXXXXXG. The six center positions were constructed using random sequences of six
      L-amino acids (Y, N, F, E, V, and L). Peptide library II also consisted of
      octamers but with glycine and valine (V) at both termini of each peptide
      (GVZZZZVG). The four variable center positions of peptide library II were random
      sequences of 18 L-amino acids. Peptides that were retained specifically on the
      immobilized S-protein column were eluted by 2% acetic acid. The peptides in the
      acid eluate were further separated using reversed-phase HPLC. Each separated
      peptide fraction was collected and the peptide sequences deconvoluted by mass
      spectrometry (MS/MS). The screenings of peptide libraries I and II resulted in 12
      and 7 affinity peptides, respectively. Eight out of the twelve peptides from
      peptide library I contained the clear consensus sequence NFEV. Peptide library II
      resulted in affinity peptides with the sequences GVNFEVVG, GVNFTVVG and
      GVFFEL(I)VG. The advantages and limitations of affinity chromatography in peptide
      library screening are discussed.

PMID- 10397821
TI  - Kinetic analysis of simultaneous 2,4-dinitrotoluene (DNT) and 2, 6-DNT
      biodegradation in an aerobic fluidized-bed biofilm reactor.
AB  - We previously reported on the mineralization of 2,4-dinitrotoluene (2,4-DNT) and
      2,6-dinitrotoluene (2,6-DNT) in an aerobic fluidized-bed bioreactor (FBBR)
      (Lendenmann et al. 1998 Environ Sci Technol 32:82-87). The current study examines
      the kinetics of 2, 4-DNT and 2,6-DNT mineralization at increasing loading rates
      in the FBBR with the goal of obtaining system-independent kinetic parameters. At
      each steady state, the FBBR was subjected to a set of transient load experiments
      in which substrate flux in the biofilm and bulk substrate concentrations were
      measured. The pseudo-steady-state data were used to estimate the biokinetic
      parameters for 2,4-DNT and 2,6-DNT removal using a mechanistic mathematical
      biofilm model and a routine that minimized the sum of the squared residuals
      (RSS). Estimated kinetic parameters varied slightly for each steady-state;
      retrieved parameters for qm were 0. 83 to 0.98 g DNT/g XCOD d for 2,4-DNT removal
      and 0.14 to 0.33 g DNT/g XCOD d for 2,6-DNT removal. Ks values for 2,4-DNT
      removal (0. 029 to 0.36 g DNT/m3) were consistently lower than Ks values for 2, 6
      DNT removal (0.21 to 0.84 g DNT/m3). A new approach was introduced to estimate
      the fundamental biofilm kinetic parameter S*b,min from steady-state performance
      information. Values of S*b,min indicated that the FBBR performance was limited by
      growth potential. Adequate performance of the examined FBBR technology at higher
      loading rates will depend on an improvement in the growth potential. The obtained
      kinetic parameters, qm, Ks, and S*b,min, can be used to aid in the design of
      aerobic FBBRs treating waters containing DNT mixtures.

PMID- 10397823
TI  - Controlled shear filtration: A novel technique for animal cell separation.
AB  - A novel rotary microfiltration technique specifically suited for the separation
      of animal cells has been developed. The concept allows the independent adjustment
      of wall shear stress, transmembrane pressure, and residence time, allowing
      straightforward optimization of the microfiltration process. By using a smooth,
      conically shaped rotor, it is possible to establish a controlled shear field in
      which animal cells experience a significant hydrodynamic lift away from the
      membrane surface. It is shown in preliminary experiments that shear-induced cell
      rupture speeds up membrane clogging and that cell debris poses the most
      significant problem in harvesting of BHK cell cultures by dynamic
      microfiltration. However, a threshold value of shear stability exists which
      depends on the frequency of passing the shear field, the residence time in the
      shear field, as well as on cell status. By operating close to this threshold
      value, cell viability can be maintained while concentration polarization is
      efficiently minimized. By applying this concept, it is possible to attain flux
      rates several times higher compared to conventional crossflow filtration.
      Controlled shear filtration (CSF) can be used for batch harvesting as well as for
      cell retention in high cell density systems. In batch harvesting of hIL-2 from
      rBHK cell culture, a constant flux rate of 290 L h-1 m-2 has been adjusted
      without indication of membrane clogging or fouling.

PMID- 10397822
TI  - Kinetics of retrovirus production and decay.
AB  - There has been only limited success in using recombinant retroviruses to transfer
      genes for the purposes of human gene therapy, in part because the average number
      of genes delivered to the target cells (transduction efficiency) is often too low
      to achieve the desired therapeutic effect [Miller, AD. 1990. Blood 76:271-278;
      Mulligan RC. 1993. Science 260:926-932; Orkin SH, Motulsky AG. 1995. Report and
      recommendations of the panel to assess the NIH investment in research on gene
      therapy. Bethesda, MD: National Institutes of Health.]. One strategy to improve
      transduction efficiency is to focus on understanding and improving the processes
      used to produce recombinant retroviruses. In this report, we characterized the
      dynamics of retrovirus production and decay in batch cultures of virus producer
      cells using a simple mathematical model, a recombinant retrovirus encoding the
      Escherichia coli lacZ gene, and quantitative assays for virus activity and
      number. We found that the rate at which recombinant retroviruses spontaneously
      lose their activity (decay) is a strong function of temperature, decreasing
      roughly 2-fold for every 5 degrees C reduction in temperature, whereas the rate
      at which retroviruses are produced is only weakly affected by temperature,
      decreasing about 10% for every 5 degrees C reduction in temperature. In addition,
      we developed a simple mathematical model of virus production and decay that
      predicted that the virus titer in batch cultures of virus producer cells would
      reach a maximum steady-state at a rate that is inversely proportional to the
      virus decay rate and to a level that is proportional to the ratio of the virus
      production rate to the virus decay rate. Consistent with the model, we observed
      that the steady-state levels of virus titer increased more than 3-fold when the
      cell culture temperature was reduced from 37 to 28 degrees C. Despite their
      higher titers, virus stocks produced at 28 degrees C, when used in undiluted form
      so as to mimic human gene transfer protocols, did not transduce substantially
      more cells than virus stocks produced at 37 degrees C. The implications of our
      findings on the production of retroviruses for use in human gene therapy
      protocols are discussed.

PMID- 10397824
TI  - Metabolic flux analysis of hybridoma continuous culture steady state
      multiplicity.
AB  - Physiological state multiplicity was observed in continuous cultures of the
      hybridoma cell line ATCC CRL-1606 cultivated in glutamine-limited steady state
      chemostats. At the same dilution rate (0.04 h-1), two physiologically different
      cultures were obtained which exhibited similar growth rates and viabilities but
      drastically different cell concentrations (7.36 x 10(5) and 1.36 x 10(6)
      cells/mL). Metabolic flux analysis conducted using metabolite and gas exchange
      rate measurements revealed a more efficient culture for the steady state with the
      higher cell concentration, as measured by the fraction of pyruvate carbon flux
      shuttled into the TCA cycle for energy generation. The low-efficiency steady
      state was achieved after innoculation by growing the cells in a nutrient rich
      environment, first in batch mode followed by a stepwise increase of the dilution
      rate to its set point at 0.04 h-1. The high-efficiency steady state was achieved
      by reducing the dilution rate to progressively lower values to 0.01 h-1 resulting
      in conditions of stricter nutrient limitation. The high energetic efficiency
      attained under such conditions was preserved upon increasing the chemostat
      dilution rate back to 0.04 h-1 with a higher nutrient consumption, resulting in
      approximate doubling of the steady state cell concentration. This metabolic
      adaptation is unlikely due to favorable genetic mutations and could be
      implemented for improving cell culture performance by inducing cellular metabolic
      shifts to more efficient flux distribution patterns.

PMID- 10397825
TI  - Near-infrared spectroscopy for bioprocess monitoring and control.
AB  - This article describes the calibration of a spectroscopic scanning instrument for
      the measurement of selected contaminants in a complex biological process stream.
      Its use is for the monitoring of a process in which contaminants are to be
      removed selectively by flocculation from yeast cell homogenate. The main
      contaminants are cell debris, protein, and RNA. A low-cost instrument has been
      developed for sensitivity in the region of the NIR spectrum (from 1900 to 2500
      nm) where preliminary work found NIR signatures from cell debris, protein, and
      RNA. Calibration models have been derived using a multivariate method for
      concentrations of these contaminants, such as would be found after the
      flocculation process. Two strategies were compared for calibrating the NIR
      instrument. In one case, samples were prepared by adding materials representative
      of the contaminants to clarified yeast homogenate so the contaminant levels were
      well known but outside the range of interest. In the other case, where samples
      were like those from the process stream after flocculation and floc removal,
      there was uncertainty of analysis of contaminant level, but the calibration was
      in the range of interest. Calibration using process stream samples gave results
      close to those derived from traditional assays. When the calibration models were
      used to predict the contaminant concentrations in previously unseen samples, the
      correlation coefficients between measurements and predictions were above 90% in
      all cases but one. The prediction errors were similar to the errors in the
      traditional assays.

PMID- 10397826
TI  - Kinetics and performance of a co-immobilised system of amyloglucosidase and
      Zymomonas mobilis.
AB  - High operational stability and productivity of co-immobilised systems are
      important aspects for their successful application in industrial processes. A
      dynamic model is required to describe artificially co-immobilised systems because
      the time needed to reach steady state normally exceeds the operational life span
      of these systems. Time dependent intraparticle concentration profiles and
      macroscopic conversion were modelled to study the operational stability and
      productivity of these systems theoretically. The model was used to describe
      experimental results of ethanol production from maltose by a co-immobilised
      system of amyloglucosidase and Zymomonas mobilis. Furthermore, the influence of
      the immobilisation procedure with glutaraldehyde and polyethyleneimine could also
      be studied with and incorporated in the model. From the model it could be derived
      that co-immobilised systems performing a consecutive reaction evolve towards a
      steady state, characterised by a constant concentration of the intermediate in
      the particle if product inhibition is neglected. Such a situation develops
      independently of the biomass concentration and the radial position, and has
      important consequences for co-immobilised systems. When the concentration of the
      intermediate in the bulk liquid is lower than this constant value in the
      biocatalyst particle, two regions may be distinguished in the particle: an
      inactive peripheral region without biomass and an active core with a biomass
      concentration depending on the substrate and immobilised enzyme concentration.
      Unlike immobilised single cell systems, it is possible to obtain a real steady
      state and therefore a stable situation for co-immobilised systems. However, a
      high operational life time could only be achieved at the expense of the
      productivity of the biocatalyst particle. A stability criterion is derived which
      agrees very well with the simulation results.

PMID- 10397827
TI  - Use of multi-staining flow cytometry to characterise the physiological state of
      Escherichia coli W3110 in high cell density fed-batch cultures.
AB  - High cell density fed-batch fermentations of Escherichia coli W3110 have been
      carried out at specific growth rates of less than 0.3 h-1, to investigate the
      effect of glucose limitation on the physiological state of individual cells.
      After an initial exponential batch phase, the feed rate was held constant and a
      final dry cell weight of approximately 50 g per litre was achieved. The
      fermentations were monitored by mass spectrometry whilst measurements of pH, DOC,
      CFU/mL, TCN, OD500nm and residual glucose concentrations were made. Satisfactory
      and reproducible results were obtained. Flow cytometric analysis of cells in
      broth samples, based on either of two multi-staining protocols, revealed a
      progressive change in cell physiological state throughout the course of the
      fermentations. From these measurements it was concluded that the loss in
      reproductive viability towards the end of the fed-batch process is due to cell
      death and not due to the formation of a "viable but nonculturable state" as had
      previously been reported. Since the presence of a high proportion of dead or
      dying cells at any time during a fermentation has a detrimental effect on the
      synthesis of any desired product it is proposed that an on-line flow cytometric
      analysis and control strategy could be used as a means of increasing overall
      process efficiency.

PMID- 10397829
TI  - Chimeric infectious bursal disease virus-like particles expressed in insect cells
      and purified by immobilized metal affinity chromatography.
AB  - Chimeric virus-like particles (VLPs) of infectious bursal disease virus (IBDV)
      were produced by coinfecting Spodoptera frugiperda (Sf-9) insect cells with two
      recombinant baculoviruses, vIBD-7 and vEDLH-22. vIBD-7 encodes VP2, VP3, and VP4
      of the IBDV structural proteins. vEDLH-22 encodes VP2 with five histidine
      residues at the carboxy-terminus (VP2H). Coinfection produced hybrid VLPs
      composed of VP2, VP2H, and VP3. The additional histidine residues on VP2H enabled
      the efficient purification of VLPs based on immobilized metal affinity
      chromatography (IMAC). These results demonstrated that the VLPs formed are
      comprised of chimeric subunits with attached affinity ligands, and further, that
      sufficient His5 ligand was available for binding to the IMAC metal-chelating
      resin. Additionally, these novel particles were fully characterized for
      antigenicity by a series of monoclonal antibodies, and appeared identical to the
      two wild-type IBDV strains contributing subunits to the chimeric VLP. IMAC
      purification provides a promising low-cost and simple scheme to purify VLPs as
      vaccines.

PMID- 10397828
TI  - Effects of pulse addition of carbon sources on continuous cultivation of
      Escherichia coli containing a recombinant E. coli gapA gene.
AB  - At high glucose concentrations, Escherichia coli produces acetate (Crabtree
      effect). To look for the influence of glucose and/or acetate in the medium on the
      expression of a recombinant gene in E. coli, the effect of a pulse addition of
      glucose, on transcription of a cloned E. coli gapA gene and the resulting
      glyceraldehyde-3P-dehydrogenase activity (GAPDH), was tested during continuous
      cultivation of E. coli HB101 transformed with the plasmid pBR::EcogapA. Stable
      continuous cultures were established in a semi-synthetic medium supplemented with
      5 g/L of glucose. After the addition of 7 g of glucose within a few seconds, gapA
      gene expression was strongly and very rapidly induced. As shown by primer
      extension analysis, promoter P1, one of the four transcriptional promoters of the
      gapA gene, was strongly activated, and GAPDH activity increased. However, after
      rapid glucose consumption, acetate was produced and acetate concentrations above
      2 g/L induced stress conditions. This is shown by a strong activation of promoter
      P2, that is recognized by the stress specific Esigma32 RNA polymerase. During
      this period, the total cellular RNA content was strongly diminished. Later, when
      acetate was partially consumed a high level of total RNA was restored,
      translation was efficient and a regular increase of the GAPDH-specific activity
      was observed. The transitions between glucose metabolism, acetate production and
      the end of acetate consumption, were marked by large increases in RNase and
      protease activities. For comparison, pulse-addition experiments were also
      performed with serine and alanine. A transient increase of GAPDH production
      associated with an increase in biomass was also found for serine that can be
      utilized as an energy source, whereas the addition of alanine, which is only
      incorporated into newly synthesized proteins, did not increase GAPDH production.
      The implication of these data for overproduction of recombinant proteins in E.
      coli is discussed.

PMID- 10397830
TI  - Enzymatic synthesis of unsaturated fatty acid glucoside esters for dermo-cosmetic
      applications.
AB  - Unsaturated fatty acid alpha-butylglucoside esters were prepared by enzymatic
      esterification of alpha-butylglucoside in nonaqueous media. Conditions were
      firstly optimized using oleic acid as acyl group. Synthesis was possible in
      several solvents but the presence of water co-product in the medium limited the
      reaction to a thermodynamic equilibrium corresponding to a maximal conversion
      yield of 62%. In pure molten substrates, the removal of water under reduced
      pressure enabled yields superior to 95% to be obtained. Product profiles depended
      on enzyme origin : whatever the support, immobilized lipase B from Candida
      antarctica proved to be far more regioselective for the primary hydroxyl group of
      glucose than immobilized lipase from Rhizomucor miehei. Results obtained could be
      easily transposed to the acylation of alpha-butylglucoside with a commercial
      mixture of unsaturated fatty acids containing more than 60% of linoleic acid. The
      biocatalyst could be recycled more than ten times without any significant
      activity loss.

PMID- 10397831
TI  - Metabolic flux analysis of Escherichia coli expressing the Bacillus subtilis
      acetolactate synthase in batch and continuous cultures.
AB  - Metabolically engineered Escherichia coli expressing the B. subtilis acetolactate
      synthase has shown to be capable of reducing acetate accumulation. This reduction
      subsequently led to a significant enhancement in recombinant protein production.
      The main focus of this study is to systematically examine the effect of ALS in
      the metabolic patterns of E. coli in batch and continuous culture. The specific
      acetate production rate of a strain carrying the B. subtilis als gene is 75%
      lower than that of the control strain (host carrying the control plasmid
      pACYC184) in batch cultures. The ALS strain is further demonstrated to be capable
      of maintaining a reduced specific acetate production rate in continuous cultures
      at dilution rates ranging from 0.1 to 0.4 h-1. In addition, this ALS strain is
      shown to have a higher ATP yield and lower maintenance coefficient. The metabolic
      flux analysis of carbon flux distribution of the central metabolic pathways and
      at the pyruvate branch point reveals that this strain has the ability to channel
      excess pyruvate to the much less toxic compound, acetoin.

PMID- 10397832
TI  - Cloning and characterization of the astaxanthin biosynthetic gene encoding
      phytoene desaturase of Xanthophyllomyces dendrorhous.
AB  - The first carotenoid biosynthetic gene from the basidiomycetous yeast
      Xanthophyllomyces dendrorhous was isolated by heterologous complementation in
      Escherichia coli. The isolated gene, denominated as crtI, was found to encode for
      phytoene desaturase. The coding region is interrupted by 11 introns. The deduced
      amino acid sequence showed significant homology with its bacterial and eukaryotic
      counterparts, especially those of fungal origin. A plasmid containing the
      geranylgeranyl diphosphate synthase and phytoene synthase encoding genes from
      Erwinia uredovora was introduced in E. coli together with the phytoene desaturase
      encoding cDNA from X. dendrorhous. As a result, lycopene accumulation was
      observed in these transformants. We conclude that in X. dendrorhous the four
      desaturase steps, by which phytoene is converted into lycopene, are carried out
      by a single gene product.

PMID- 10397833
TI  - Cometabolism of chlorinated solvents by nitrifying bacteria: kinetics, substrate
      interactions, toxicity effects, and bacterial response 

PMID- 10397835
TI  - Characterization of bimodal cell death of insect cells in a rotating-wall vessel
      and shaker flask 
AB  - In previous publications, we reported the benefits of a high-aspect rotating-wall
      vessel (HARV) over conventional bioreactors for insect-cell cultivation in terms
      of reduced medium requirements and enhanced longevity. To more fully understand
      the effects that HARV cultivation has on longevity, the present study
      characterizes the mode and kinetics of Spodoptera frugiperda cell death in this
      quiescent environment relative to a shaker-flask control. Data from flow
      cytometry and fluorescence microscopy show a greater accumulation of apoptotic
      cells in the HARV culture, by a factor of at least 2 at the end of the
      cultivation period. We present a kinetic model of growth and bimodal cell death.
      The model is unique for including both apoptosis and necrosis, and further,
      transition steps within the two pathways. Kinetic constants reveal that total
      cell death is reduced in the HARV and the accumulation of apoptotic cells in this
      vessel results from reduced depletion by lysis and secondary necrosis. The ratio
      of early apoptotic to necrotic cell formation is found independent of cultivation
      conditions. In the model, apoptosis is only well represented by an integral term,
      which may indicate its dependence on accumulation of some factor over time; in
      contrast, necrosis is adequately represented with a first-order term. Cell-cycle
      analysis shows the percent of tetraploid cells gradually decreases during
      cultivation in both vessels. For example, between 90% and 70% viability,
      tetraploid cells in the HARV drop from 43 +/- 1% to 24 +/- 4%. The data suggests
      the tetraploid phase as the likely origin for apoptosis in our cultures. Possible
      mechanisms for these changes in bimodal cell death are discussed, including
      hydrodynamic forces, cell-cell interactions, waste accumulation, and mass
      transport. These studies may benefit insect-cell cultivation by increasing our
      understanding of cell death in culture and providing a means for further
      enhancing culture longevity. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397834
TI  - Efficiency of physical (light) or chemical (ABA, tetracycline, CuSO4 or 2-CBSU)
      stimulus-dependent gus gene expression in tobacco cell suspensions.
AB  - In this study, the efficiency of inducible promoters to switch on gene expression
      in the presence of inducer or to switch it off in its absence was evaluated in
      tobacco cell suspensions transformed with the gus gene coding sequence. Either
      plant (pats1A, pSalT, pIn2-2) or microbial (pMre, pTet) inducible promoters were
      used to drive gus expression. The inducers were light, abscisic acid, 2-CBSU,
      CuSO4, tetracycline, respectively. For each construct (inducible promoter-gus
      coding sequence), the optimal induction conditions were determined (inducer
      concentration, induction time, and age of cells in culture cycle before
      induction). The efficiency of the inducible promoter was then evaluated under
      optimal induction conditions. GUS-expression levels obtained under non-inducing
      and inducing conditions were systematically compared. Thirty or forty percent of
      the clones transformed with the pSalT-gus or pTet-gus construct, respectively,
      showed high induction rates (>1000) and GUS activities of the same order as those
      obtained with a constitutive system. However, basal GUS levels were always high
      for the pTet-gus cell lines. Seventy or eighty-five percent of the cell lines
      transformed with the pMre-gus or pln2-2-gus construct, respectively, had
      induction rates of 1.5 to 1000. The pats1A-gus construct gave very low induction
      rates-55% of cell lines had induction rates less than 1.5. Only the pSalt-gus
      construct gave both the highest induction rates and basal GUS-levels equivalent
      to the endogenous GUS background.

PMID- 10397836
TI  - Effect of solution pH on protein transport through ultrafiltration membranes 
AB  - Although a number of previous studies have demonstrated that solution pH can have
      a dramatic effect on protein transport through ultrafiltration membranes, the
      exact origin of this behavior has been unclear. Experimental data were obtained
      for the transport of a broad range of proteins with different surface charge and
      molecular weight. The effective hydrodynamic size of the proteins was evaluated
      using size-exclusion chromatography. The membrane charge, both before and after
      exposure to a given protein, was evaluated using streaming potential
      measurements. In most cases, the electrostatic interactions were dominated by the
      distortion of the electrical double layer surrounding the protein, leading to a
      distinct maximum in protein transmission at the protein isoelectric point.
      Attractive electrostatic interactions did occur when the protein and membrane had
      a large opposite charge, causing a second maximum in transmission at a pH between
      the isoelectric points of the protein and membrane. The sieving data were in good
      agreement with theoretical calculations based on available models for the
      partitioning of charged solutes in cylindrical pores. Copyright 1999 John Wiley &
      Sons, Inc.

PMID- 10397837
TI  - Expression, reactivation, and purification of enzymes from Haloferax volcanii in
      Escherichia coli.
AB  - Enzymes from extreme halophiles have potential as catalysts in
      biotransformations. We have developed methods for the expression in Escherichia
      coli and purification of two enzymes from Haloferax volcanii: dihydrolipoamide
      dehydrogenase and citrate synthase. Both enzymes were expressed in E. coli using
      the cytoplasmic expression vectors, pET3a and pET3d. Citrate synthase was soluble
      and inactive, whereas dihydrolipoamide dehydrogenase was expressed as inclusion
      bodies. Citrate synthase was reactivated following overnight incubation in 2 M
      KCl, and dihydrolipoamide dehydrogenase was refolded by solubilisation in 8 M
      urea followed by dilution into a buffer containing 2 M KCl, 10 microM FAD, 1 mM
      NAD, and 0.3 mM GSSG/3 mM GSH. Maximal activity was obtained after 3 days
      incubation at 4 degrees C. Purification of the two active enzymes was carried out
      using high-resolution methods. Dihydrolipoamide dehydrogenase was purified using
      copper-based metal ion affinity chromatography in the presence of 2 M KCl.
      Citrate synthase was recovered using dye-affinity chromatography in the presence
      of salt. A high yield of active enzyme was obtained in both cases. Following
      purification, characterisation of both recombinant proteins showed that their
      kinetics and salt-dependence were comparable to those of the native enzymes.
      Expression of active protein was attempted both by growth of E. coli in the
      presence of salt and betaine, and also by using periplasmic expression vectors in
      combination with a high salt growth media. Neither strategy was successful.

PMID- 10397839
TI  - Production of S-lactoylglutathione by high activity whole cell biocatalysts
      prepared by permeabilization of recombinant saccharomyces cerevisiae with
      alcohols 
AB  - The permeabilization of yeast cells with methanol, ethanol, and isopropyl alcohol
      under various conditions was studied to develop the preparation method of high
      activity whole cell biocatalysts. Recombinant Saccharomyces cerevisiae, which
      intracellularly overexpresses glyoxalase I and catalyzes the conversion of
      methylglyoxal to S-lactoylglutathione in the presence of glutathione, was used as
      the model system. The permeabilization treatments with alcohols significantly
      enhanced the activities of yeast cells. Especially, the initial S
      lactoylglutathione production rates of cells permeabilized with 40% ethanol and
      isopropyl alcohol solutions for 10 min at 4 degrees C were high and were 364 and
      582 times larger than those of untreated cells, respectively. These permeabilized
      yeast cells retained high activities during repeated batch reactions. Even in
      third batch reaction, they showed approximately 70-80% of the activity in the
      first batch. The plasma membrane of S. cerevisiae cells was damaged by the
      treatment with alcohol solutions in such a way that leakage of glyoxalase I from
      the cells is rather small and that both substrate and product show very high
      permeability. The initial S-lactoylglutathione production rates of these
      permeabilized cells were 1.5-2.5 times larger than those of glyoxalase I in cell
      extracts prepared by ethyl acetate method from the same amount of cells. These
      results demonstrate that the recombinant S. cerevisiae cells permeabilized with
      alcohol solutions under the optimum condition are very effective whole cell
      biocatalysts. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397838
TI  - Effect of glutamine limitation on the death of attached Chinese hamster ovary
      cells.
AB  - The effect of glutamine depletion on the death of attached Chinese hamster ovary
      (CHO) cells was investigated. Experiments were performed using an anchorage
      dependent CHO cell line expressing gamma-IFN and a second cell line obtained by
      transfection of that cell line with the human bcl-2 (hbcl-2). Either cell line
      could grow in media devoid of glutamine with minimal cell death due to endogenous
      glutamine synthetase activity that allowed cells to synthesize glutamine from
      glutamic acid in the medium. However, compared to control cultures in glutamine
      containing media, the cell growth rate in glutamine-free media was slower with an
      increased fraction of cells distributed in the G0/G1 phase. The slower rate of
      cell cycling apparently protected the cells from entering apoptosis when they
      were stimulated to proliferate in an environment devoid of other protective
      factors, such as serum or over-expressed hbcl-2. The depletion of both glutamine
      and glutamic acid did cause cell death, which could be mitigated by hbcl-2 over
      expression.

PMID- 10397840
TI  - Fed-batch fermentor synthesis of 3-dehydroshikimic acid using recombinant
      Escherichia coli.
AB  - 3-Dehydroshikimic acid (DHS), in addition to being a potent antioxidant, is the
      key hydroaromatic intermediate in the biocatalytic conversion of glucose into
      aromatic bioproducts and a variety of industrial chemicals. Microbial synthesis
      of DHS, like other intermediates in the common pathway of aromatic amino acid
      biosynthesis, has previously been examined only under shake flask conditions. In
      this account, synthesis of DHS using recombinant Escherichia coli constructs is
      examined in a fed-batch fermentor where glucose availability, oxygenation levels,
      and solution pH are controlled. DHS yields and titers are also determined by the
      activity of 3-deoxy-D-arabino-heptulosonic acid 7-phosphate (DAHP) synthase. This
      enzyme's expression levels, sensitivity to feedback inhibition, and the
      availability of its substrates, phosphoenolpyruvate (PEP) and D-erythrose 4
      phosphate (E4P), dictate its in vivo activity. By combining fed-batch fermentor
      control with amplified expression of a feedback-insensitive isozyme of DAHP
      synthase and amplified expression of transketolase, DHS titers of 69 g/L were
      synthesized in 30% yield (mol/mol) from D-glucose. Significant concentrations of
      3-dehydroquinic acid (6.8 g/L) and gallic acid (6.6 g/L) were synthesized in
      addition to DHS. The pronounced impact of transketolase overexpression, which
      increases E4P availability, on DHS titers and yields indicates that PEP
      availability is not a limiting factor under the fed-batch fermentor conditions
      employed.

PMID- 10397841
TI  - Thermodynamic analysis of growth of methanobacterium thermoautotrophicum 
AB  - Growth of Methanobacterium thermoautotrophicum, an anaerobic archaebacterium
      using methanogenesis as the catabolic pathway, is characterized by large heat
      production rates, up to 13 W g-1, and low biomass yields, in the order of 0.02 C
      mol mol-1 H2 consumed. These values, indicating a possibly "inefficient" growth
      mechanism, warrant a thermodynamic analysis to obtain a better understanding of
      the growth process. The growth-associated heat production (DeltarHX0, min) and
      the growth-associated Gibbs energy dissipation per mol biomass formed
      (DeltarGXmin) were -3730 kJ C-mol-1 and -802 kJ C-mol-1, respectively. The Gibbs
      energy change found in this study is indeed unusually high as compared to aerobic
      methylotrophes, but not untypical for methanogens grown on CO2. It explains the
      low biomass yield. Based on the information available on the energetic metabolism
      and on an ATP balance, the biomass yield can be predicted to be approximately in
      the range of the experimentally determined value. The fact that the exothermicity
      exceeds vastly even the Gibbs energy change can be explained by a dramatic
      entropy decrease of the catabolic reaction. Microbial growth characterized by
      entropy reduction and correspondingly by unusually large heat production may be
      called entropy-retarded growth. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397842
TI  - Fermentation seed quality analysis with self-organising neural networks 
AB  - Industrial fermentation processes operate under well defined operating conditions
      to attempt to minimise production variability. Variability occurs for many
      reasons but a long held belief is that variation in the state of the seed is
      highly influential. In this paper a seed stage (a batch process) of an industrial
      antibiotic fermentation is considered and the performance of the main production
      fermentations is correlated with the quality of the seed using an unsupervised
      Kohonen self-organising feature map (SOM). It is shown that using only seed
      information poor performance in the final stage fermentations can be predicted.
      Data from industrial penicillin G fermenters is used to demonstrate the
      procedure. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397843
TI  - Medium optimization for spore production of coniothyrium minitans using
      statistically-based experimental designs 
AB  - Statistically-based experimental designs were used to optimize a chemically
      defined solid medium for the spore production of Coniothyrium minitans. In the
      first optimization step the influence of starch, urea, phosphate, magnesium,
      calcium, thiamin and trace elements on spore production was evaluated using a
      fractional factorial design. Starch and trace elements influenced spore
      production positively while urea affected spore production negatively. The other
      components had no significant influence on spore production. In the second and
      third steps the concentrations of starch, urea and trace elements were further
      optimized using central composite designs and response surface analysis. This
      optimization strategy allowed the spore production to be increased by a factor 7
      from 4 x 10(9) to almost 3 x 10(10) spores per Petri dish of 9 cm diameter.
      Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397844
TI  - Can the combination of electrochemical regeneration of NAD+, selectivity of L
      alpha-amino-acid dehydrogenase, and reductive amination of alpha-keto-acid be
      applied to the inversion of configuration of a L-alpha-amino-acid? 
AB  - The inversion of configuration of L-alanine can be carried out by combining its
      selective oxidation in the presence of NAD+ and L-alanine dehydrogenase,
      electrochemical regeneration of the NAD+ at a carbon felt anode, and reductive
      amination of pyruvate, i.e., reduction of its imino derivative at a mercury
      cathode, the reaction mixture being buffered with concentrated ammonium/ammonia
      (1.28M / 1. 28M). The dehydrogenase exhibits astonishing activity and stability
      under such extreme conditions of pH and ionic strength. The main drawback of the
      process is its slowness. At best, the complete inversion of a 10 mM solution of L
      alanine requires 140 h. A careful and detailed quantitative analysis of each of
      the key steps involved shows that the enzyme catalyzed oxidation is so
      thermodynamically uphill that it can be driven efficiently to completion only
      when both the coenzyme regeneration and the pyruvate reduction are very
      effective. The first condition is easily fulfilled. Under the best conditions, it
      is the rate of the chemical reaction producing the imine which controls the whole
      process kinetically. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397846
TI  - Lipase-catalyzed dynamic resolution of naproxen 2,2,2-trifluoroethyl thioester by
      hydrolysis in isooctane 
AB  - A lipase-catalyzed enantioselective hydrolysis process under continuous in situ
      racemization of substrate by using trioctylamine as an organic base was developed
      for the production of (S)-naproxen from racemic naproxen thioesters in isooctane.
      Naproxen 2,2, 2-trifluoroethyl thioester and 45 degrees C were selected as the
      best substrate and temperature, respectively, by comparing the time-course
      variations for the racemization of (S)-naproxen thioesters containing an electron
      withdrawing group. A detailed investigation of the effect of trioctylamine
      concentration on the kinetic behaviors of the thioester in racemization and
      enzymatic reaction was conducted, in which more than 70% conversion of the
      racemate (or 67.2% yield of (S)-naproxen) with eep value higher than 92% was
      obtained. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397845
TI  - Serum protects protein-free competent Chinese hamster ovary cells against
      apoptosis induced by nutrient deprivation in batch culture.
AB  - The development of serum- and protein-free Chinese hamster ovary (CHO) cell
      cultures is a high priority for the production of biopharmaceuticals. Protein
      free competent CHO cells lines have been previously constructed by two different
      methods-metabolic engineering with cell-cycle regulatory proteins and long-term
      selective adaptation. Apoptosis was present in both cell lines during protein
      free, static-batch culture as a result of nutrient deprivation, and glucose
      deprivation alone was a potent inducer of apoptosis compared to the depletion of
      other nutrients such as amino acids. By adding back serum to the cultures during
      batch growth or nutrient deprivation, it was shown that unidentified survival
      factors in serum can greatly reduce apoptosis in protein-competent cell lines in
      all phases of the culture. Both observations contrast to previous reports for
      hybridoma cells, in which amino acids were the key determinants of apoptosis and
      serum had no additional antiapoptotic effect. Serum's protective effect against
      CHO cell death in batch culture was multifaceted and complex: (1) 10% FBS
      increased cell viability to >99% during exponential growth from roughly 75-90%,
      (2) 5-10% fetal bovine serum (FBS) reduced specific glucose consumption rates in
      both cell lines by 40%, thereby delaying the onset of apoptosis caused by glucose
      deprivation, and (3) 5% FBS reduced the specific cell death rate by 65% during a
      3-d lactate-consumption phase characterized by substantial abortive
      proliferation, in which the cells both proliferated and died at a constant rate.
      The benefit of serum on cell production over the various phases of batch growth
      was combined into a single parameter by integrating the viable cell concentration
      vs. time profile (termed here as cumulative volumetric viable cell-time, VCTvol).
      Despite the ability of both cell lines to grow indefinitely without any exogenous
      growth factors, the addition of serum resulted in a 2. 3-fold increase in the
      VCTvol. Thus, it is clear that there is much room for improvement of protein-free
      CHO cell lines despite their adequate growth competence, and new strategies
      different from those successfully used for hybridomas may be necessary to combat
      CHO cell apoptosis.

PMID- 10397847
TI  - The expression of recombinant genes from bacteriophage lambda strong promoters
      triggers the SOS response in escherichia coli 

PMID- 10397848
TI  - Metabolic fluxes, pools, and enzyme measurements suggest a tighter coupling of
      energetics and biosynthetic reactions associated with reduced pyruvate kinase
      flux.
AB  - In this study, it is found that, for Bacillus subtilis, citrate-glucose
      cometabolism leads to zero acid production over a wide range of growth rates and
      nearly theoretical carbon yield. Experimental results are presented that point to
      pyruvate kinase (PYK) as a site of citrate-mediated glycolytic flux attenuation.
      First, the measured fluxes show that, compared with cultures grown on glucose,
      the PYK flux drops by more than tenfold when citrate is added. Second, relative
      to cultures metabolizing glucose, the phosphoenolpyruvate (PEP) pool elevates
      substantially, whereas the pyruvate pool drops, when citrate is present. Finally,
      our modeling results indicate that maximizing carbon yield corresponds to nearly
      eliminating pyruvate kinase (PYK) flux and that the pyruvate supplied by the PEP
      consuming glucose transport system can supply the biosynthetic requirements. A
      literature review suggests some mechanisms for how PYK attenuation by citrate
      addition can occur. At this juncture, we hypothesize that direct PYK inhibition
      occurs which, in turn, also leads to phosphofructokinase inhibition via the
      elevated PEP pool. These two inhibition events combine to throttle glycolytic
      flux; minimize acid formation; and substantially increase cellular, product, and
      energetic yields.

PMID- 10397849
TI  - Production of a diagnostic monoclonal antibody in perennial alfalfa plants.
AB  - The increasing use of monoclonal antibodies (mAbs) in diagnostic reagents
      necessitates efficient and cost-effective mAb production methods. In blood banks,
      one of the most routinely used reagents is the anti-human IgG reagent used for
      the detection of non-agglutinating antibodies. Here we report the production of a
      functional, purified anti-human IgG, through the expression of its encoding genes
      in perennial transgenic alfalfa. Transgenic plants expressing the light- and
      heavy-chain encoding mRNAs were obtained, and plants from crosses were found to
      express fully assembled C5-1. The purification procedure yielded mainly the H2L2
      form with specificity and affinity identical to those of hybridoma-derived C5-1.
      The ability to accumulate the antibody was maintained both in parental F1 lines
      during repeated harvesting and in clonal material; the antibody was stable in the
      drying hay as in extracts made in pure water. Also, plant and hybridoma-derived
      C5-1 had similar in vivo half-lives in mice. These results indicate that plant C5
      1 could be used in a diagnostic reagent as effectively as hybridoma-derived C5-1,
      and demonstrates the usefulness of perennial systems for the cost-effective,
      stable, and reliable production of large amounts of mAbs.

PMID- 10397850
TI  - Protein solubility modeling.
AB  - A thermodynamic framework (UNIQUAC model with temperature dependent parameters)
      is applied to model the salt-induced protein crystallization equilibrium, i.e.,
      protein solubility. The framework introduces a term for the solubility product
      describing protein transfer between the liquid and solid phase and a term for the
      solution behavior describing deviation from ideal solution. Protein solubility is
      modeled as a function of salt concentration and temperature for a four-component
      system consisting of a protein, pseudo solvent (water and buffer), cation, and
      anion (salt). Two different systems, lysozyme with sodium chloride and
      concanavalin A with ammonium sulfate, are investigated. Comparison of the modeled
      and experimental protein solubility data results in an average root mean square
      deviation of 5.8%, demonstrating that the model closely follows the experimental
      behavior. Model calculations and model parameters are reviewed to examine the
      model and protein crystallization process.

PMID- 10397851
TI  - Metabolic flux analysis for serine alkaline protease fermentation by Bacillus
      licheniformis in a defined medium: effects of the oxygen transfer rate.
AB  - The metabolic fluxes through the central carbon pathways in the bioprocess for
      serine alkaline protease (SAP) production by Bacillus licheniformis were
      calculated by the metabolic flux-based stoichiometric model based on the proposed
      metabolic network that contains 102 metabolites and 133 reaction fluxes using the
      time profiles of citrate, dry cell, organic acids, amino acids, and SAP as the
      constraints. The model was solved by minimizing the SAP accumulation rate in the
      cell. The effects of the oxygen-transfer rate (OTR) on the metabolic fluxes were
      investigated in a defined medium where citrate was used as the sole carbon
      source. The central pathways were active for the growth and the SAP synthesis in
      all the periods of the bioprocess at low (LOT), medium (MOT), and high (HOT)
      oxygen-transfer conditions. The flux partitioning in the TCA cycle at alpha
      ketoglutarate towards glutamate group and at oxalacetate (OA) toward aspartic
      acid group amino acids were dependent on the OTR. The flux of the anaplerotic
      reaction that connects the TCA cycle either from malate or OA to the
      gluconeogenesis pathway via the main branch point pyruvate (Pyr) was also
      influenced by the OTR. With the decrease in the OTR, the intracellular flux
      values after glycerate 3-phosphate (PG3) in the gluconeogenesis pathway and the
      specific growth rate decreased. The total ATP-generation rate increased with the
      increase in OTR. The pathway towards the aspartic acid family amino acids which
      is important for sporulation that precedes the SAP synthesis were all active
      throughout the bioprocess. Metabolic flux analysis results at LOT, MOT, and HOT
      conditions encourage the design of an oxygen-transfer strategy in the bioreactor;
      moreover, asparagine synthetase or aspartate kinase could be the potential
      metabolic engineering sites due to the low value of the flux from the branch
      point aspartate toward asparagine.

PMID- 10397852
TI  - Application of factorial designs for optimization of cyclodextrin
      glycosyltransferase production from Klebsiella pneumoniae pneumoniae AS-22.
AB  - Production of cyclodextrin glycosyltransferase (CGTase) from Klebsiella
      pneumoniae pneumoniae AS-22 was optimized in shake flasks using a statistical
      experimental design approach. Effect of various components in the basal medium,
      like carbon, nitrogen, phosphorus, and mineral sources as well as initial pH and
      temperature, were tested on enzyme production. The optimum concentrations of the
      selected media components were determined using statistical experimental designs.
      Two level fractional factorial designs in five variables, namely, dextrin,
      peptone, yeast extract, ammonium dihydrogen orthophosphate, and magnesium
      sulphate concentrations were constructed. The optimum medium composition thus
      found consisted of 49.3 g/L dextrin, 20.6 g/L peptone, 18.3 g/L yeast extract,
      6.7 g/L ammonium dihydrogen orthophosphate, and 0.5 g/L magnesium sulphate. The
      maximum CGTase activity obtained was 21.4 U/mL in 28 h of incubation. The cell
      growth and CGTase production profiles were studied with the optimized medium in
      shake flasks and in 1-L fermenters. It was observed that the enzyme production
      was growth associated both in shake flask and in fermenter, although it was
      slower in shake flask. The maximum CGTase activity obtained in the fermenter was
      32.5 U/mL in 16 h. The optimized medium resulted in about 9-fold increase in the
      enzyme activity as compared to that obtained in the basal medium in shake flask
      as well as in fermenter.

PMID- 10397853
TI  - Bcl-2 over-expression reduces growth rate and prolongs G1 phase in continuous
      chemostat cultures of hybridoma cells.
AB  - Recent studies have suggested that Bcl-2 can affect cell cycle re-entry by
      inhibiting the transition from G0/G1 to S phase. In this study, we have taken a
      novel route to the study of the relationship between Bcl-2 expression and cell
      cycle progression. Continuous cultures of pEF (control) and Bcl-2 transfected
      murine hybridoma cells were operated at a range of dilution rates from 0.8 day-1
      down to 0.2 day-1. The specific growth rate of the pEF cell line was the same as
      the dilution rate down to a value of 0.6 day-1. However, as the dilution rate was
      reduced stepwise to 0.2 day-1, the growth rate levelled-off at approximately 0.55
      day-1 and this coincided with a fall in culture viability. By contrast, the
      specific growth rate of the Bcl-2 transfected cell line followed the dilution
      rate down to a value of 0.3 day-1 with high levels of cell survival. At high
      dilution rates, the cell cycle distributions were very similar for both cell
      lines. However, the distributions diverged as the dilution rate was reduced and,
      at a rate of 0.2 day-1, the percentage of G1 cells in the Bcl-2 culture was 80%,
      compared to only 56% in the pEF cell population. This corresponded with a greater
      extension in the duration of the G1 phase in the Bcl-2 cells, which was 1.7 days
      at the lowest dilution rate tested, compared to only 0.6 day for the pEF cell
      line. The durations of the G2/M and S phases remained constant throughout the
      culture. The maximum doubling time was 1.2 days in the pEF culture compared to
      2.3 days in the Bcl-2 culture. Analysis of amino acids, ammonia and lactate
      concentrations indicated that the observed effects on cell cycle dynamics were
      probably not due to differences in the culture environment. It is suggested that
      the expression of Bcl-2 can effect G1 to S phase transition in continuously
      cycling cells, but this is only apparent at suboptimal growth rates.

PMID- 10397854
TI  - Pilot scale production and isolation of recombinant NAD+- and NADP+-specific
      formate dehydrogenases.
AB  - The expression of the recombinant wild-type NAD+- and mutant NADP+-dependent
      formate dehydrogenases (EC 1.2.1.2., FDH) from the methanol-utilizing bacterium
      Pseudomonas sp. 101 in Escherichia coli cells has been improved to produce active
      and soluble enzyme up to the level of 50% of total soluble proteins. The
      cultivation process for E. coli/pFDH8a and E. coli/pFDH8aNP cells was optimized
      and scaled up to a volume of 100 L. A downstream purification process has been
      developed to produce technical grade NAD+- and NADP+-specific formate
      dehydrogenases in pilot scale, utilizing extraction in aqueous two-phase systems.

PMID- 10397855
TI  - Efficient coupled transcription/translation from PCR template by a hollow-fiber
      membrane bioreactor.
AB  - A novel bioreactor using a hollow-fiber membrane was developed for the coupled
      transcription/translation system using T7 RNA polymerase and Escherichia coli S30
      extract. The large surface area per the reaction volume of the reactor assured
      rapid mass transfers of substrates into the reaction mixture and of wastes out
      from it across the membrane by their molecular diffusion. The flux was large
      enough to maintain nucleotide concentrations for more than 3 h, which increased
      the protein synthesis greatly. In addition, the T7 terminator sequence downstream
      from the reporter genes was found to increase the synthesized protein
      significantly, especially when the product of polymerase chain reaction (PCR) was
      used as a template. Implementation of this finding and use of the bioreactor
      developed multiplied the productivity of protein by the in vitro direct
      expression from PCR template.

PMID- 10397856
TI  - In vivo nuclear magnetic resonance studies of glycolytic kinetics in Lactococcus
      lactis.
AB  - The metabolism of glucose by nongrowing cells of L. lactis strain MG5267 was
      studied under controlled conditions of pH, temperature, and gas atmosphere
      (anaerobic and aerobic) using a circulating system coupled to nuclear magnetic
      resonance (NMR) detection that allowed a noninvasive determination of
      intracellular pools of intermediate metabolites by 13C-NMR with a time resolution
      of 30 seconds. In addition, intracellular parameters, such as pH, NTP levels, and
      concentration of inorganic phosphate in the cytoplasm, could be monitored on-line
      by 31P-NMR with a time resolution of approx. 3 min. The time course for the
      concentrations of intracellular fructose 1,6-bisphosphate (FBP), 3
      phosphoglycerate (3-PGA), and phosphoenolpyruvate (PEP), together with kinetic
      measurements of substrate consumption and endproducts formation, were used as a
      basis for the construction of a mechanistic model for glycolysis. In vivo
      measurements were complemented with determinations of phosphorylated metabolites
      in perchloric acid extracts. A top-down model was developed by simplifying the
      metabolism to the resolution allowed by the experimental data collected by in
      vivo NMR (grouped in seven metabolic steps). This simplified mechanistic model
      was adjusted to the metabolite concentrations determined by in vivo NMR. The
      results obtained led to the rationalization of the dynamics of glucose metabolism
      as being driven largely by ATP surplus. This excess causes accumulation of FBP
      due to NAD+ limitation, whose regeneration is dependent on downstream pyruvate
      reduction. The model was capable of predicting qualitative shifts in the
      metabolism of glucose when changing from anaerobic to aerobic conditions.

PMID- 10397857
TI  - Optimizing lipase activity, enantioselectivity, and stability with medium
      engineering and immobilization for beta-blocker synthesis.
AB  - Lipase from Pseudomonas cepacia showed poor activity and moderate
      enantioselectivity (E) in pure aqueous systems for hydrolysis of a racemic
      mixture (+/-)-1-chloro-2-acetoxy-3-(1-naphthyloxy)-propane, which is a potential
      intermediate for beta-blocker synthesis. However, addition of polar organic
      solvents to the reaction can change both the activity and the enantioselectivity
      for this chiral reaction significantly. It was observed, in general, that the
      activity increases and the enantioselectivity decreases with the increase in the
      polarity of the organic solvent added to the medium. Among the six solvents
      chosen (i.e., dimethylsulfoxide [DMSO], 1, 4-dioxane, dimethylformamide [DMF],
      acetone, 1-propanol, and tetrahydrofuran [THF]), maximum activity and minimum
      enantioselectivity was obtained with DMSO, whereas minimum activity and maximum
      enantioselectivity was obtained with THF as the cosolvents. In the subsequent
      studies, native or polyethylene glycol (PEG)-modified lipase was immobilized by
      entrapping in Caalginate gel beads. In a fixed-bed continuous reactor containing
      these catalyst beads, the enzyme was found to be at least three times more
      enantioselective than the native form in a batch reactor. This fixed-bed reactor
      with the beads could be operated with high concentration of acetone (33% v/v) for
      about 1 month without a significant loss of enzyme activity and
      enantioselectivity.

PMID- 10397858
TI  - Biodegradation of neutralized sarin.
AB  - This research investigated the biotransformation of IMPA, the neutralization
      product of the nerve agent Sarin, by a microbial consortia. As mandated by the
      Chemical Weapons Convention signed by 132 countries in 1993, all chemical warfare
      agents are to be destroyed within ten years of ratification. Technologies must be
      developed to satisfy this commitment. This paper presents data from a
      biodegradation kinetics study and background information on the biological
      transformation of IMPA. Microbial transformation of organophosphate nerve agents
      and organophosphate pesticide intermediates can be incorporated into a treatment
      process for the fast and efficient destruction of these similar compounds. Sarin
      (isopropyl methylphosphonofluoridate), also known as GB, is one of several highly
      neurotoxic chemical warfare agents that have been developed over the past 50 to
      60 years. Four mixed cultures were acclimated to the Sarin hydrolysis product,
      isopropyl methylphosphonic acid (IMPA). Two of these cultures, APG microorganisms
      and SX microorganisms, used IMPA as the sole phosphorus source. Extended exposure
      to IMPA improved the cultures' abilities to degrade IMPA to form methylphosphonic
      acid (MPA) and inorganic phosphate. The presence of free phosphate in the reactor
      suppressed the degradation of IMPA. IMPA did not inhibit either cultural
      consortia within the tested concentration range (0 to 1250 mg/L). The numax was
      120.9 mg/L/day for the SX microorganisms and 118.3 mg/L/day for the APG
      microorganisms. Initial IMPA concentrations of 85 to 90 mg/L were degraded to
      nondetectable levels within 75 h. These results demonstrate the potential for
      biodegradation to serve as a complementary treatment process for the destruction
      of stockpiled Sarin.

PMID- 10397859
TI  - Imprinted polymers as tools for the recovery of secondary metabolites produced by
      fermentation 
AB  - Imprinted polymers were synthesized using a mixture of pigments, N-glutamyl
      rubropuctamine, and N-glutamyl-monascorubramine (I) as the template, and 2
      methacrylamido-6-picoline or 4-aminostyrene as functional monomers, to obtain
      recognition materials capable of forming hydrogen bonds and charge interactions,
      respectively, with carboxyl groups of target I in the binding sites. The polymers
      were prepared thermally at a template loading of 5 mol% using ethylene-glycol
      dimethacrylate or trimethylolpropane trimethacrylate as crosslinkers and
      acetonitrile or tetrahydrofuran as porogens. The selective binding of I to both
      types of polymer was demonstrated, although aminostyrene-based materials showed
      higher overall adsorption and were studied in more detail. It was shown that the
      kinetics of binding of I from ethyl-acetate extracts of fermented Monascus sp.
      was very rapid and virtually all the pigment adsorbed can be released by washing
      the polymer with ethanol-water mixtures. The feasibility of reusing imprinted
      polymer in consecutive adsorption/desorption cycles was also demonstrated.
      Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397860
TI  - Use of exogenous specialised bacteria in the biological detoxification of a dump
      site-polychlorobiphenyl-contaminated soil in slurry phase conditions 
AB  - The possibility of biologically detoxifying a contaminated soil from an Italian
      dump site containing about 1500 mg/kg (in dry soil) of polychlorinated biphenyls
      was studied in the laboratory in this work. The soil, which contained indigenous
      aerobic bacteria capable of growing on biphenyl or on monochlorobenzoic acids at
      concentration of about 300 CFU per g of air-dried soil, was amended with
      inorganic nutrients, saturated with water and treated in aerobic 3-L batch slurry
      reactors (soil suspension at 20% w/v). Either Pseudomonas sp. CPE1 strain,
      capable of cometabolising low-chlorinated biphenyls into chlorobenzoic acids, or
      a bacterial co-culture capable of aerobically dechlorinating polychlorobiphenyls
      constituted by this bacterium and the two chlorobenzoic acid degrading bacteria
      Pseudomonas sp. CPE2 strain and Alcaligenes sp. CPE3 strain, were used as inocula
      (final concentration of about 10(8) CFU/mL for each bacterium), in the absence
      and in the presence of biphenyl (4 g/kg of air dried soil). Significant soil
      polychlorobiphenyl depletions were observed in all the reactors after 119 days of
      treatment. The soil inoculation with the sole CPE1 was found to slightly enhance
      the polychlorobiphenyl depletions (about 20%) and the soil detoxification; the
      effect was higher in the presence of biphenyl. The use of the polychlorobiphenyl
      mineralising bacterial co-culture as inoculum resulted in a strong enhancement of
      the depletions of both the soil polychlorobiphenyls (from 50 to 65%) and of the
      original soil ecotoxicity. The bacterial biomass inoculated was found to implant
      into the soil; the higher specialised biomass availability thus reached in the
      inoculated soil was probably responsible of a more extensive biodegradation of
      polychlorobiphenyls and therefore of the higher detoxification yields observed in
      the inoculated reactors. The soil ecotoxicity, measured through two different
      soil contact assays, i.e., the Lepidium sativum germination test and the
      Collembola mortality test, was often found to decrease proportionally with the
      soil polychlorobiphenyl concentration. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397861
TI  - Increasing the tolerance of organophosphorus hydrolase to bleach 
AB  - Organophosphorus hydrolase (OPH) has been incorporated within polyurethane foams
      during polymer synthesis as a means of reducing the enzyme's environmental
      sensitivity to alterations in pH and bleach-induced enzyme denaturation.
      Unfavorable losses of enzyme activity upon altered pH are reduced by covalently
      incorporating OPH within polyurethane matrices. Also, the stability of the
      immobilized enzyme under alkaline conditions is significantly enhanced. The
      bleach compatibility of OPH is also increased upon enzyme polymerization.
      Although a fraction of the increased bleach compatibility results from
      polyurethane oxidation, the covalent linkages between OPH and polyurethane
      directly enhance enzyme stability in buffered solutions of calcium hypochlorite
      bleach. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397862
TI  - Bubble rise velocities and drag coefficients in non-Newtonian polysaccharide
      solutions.
AB  - Microbially produced polysaccharides have properties which are extremely useful
      in different applications. Polysaccharide producing fermentations start with
      liquid broths having Newtonian rheology and end as highly viscous non-Newtonian
      solutions. Since aerobic microorganisms are used to produce these
      polysaccharides, it is of great importance to know the mass transfer rate of
      oxygen from a rising air bubble to the liquid phase, where the microorganisms
      need the oxygen to grow. One of the most important parameters determining the
      oxygen transfer rate is the terminal rise velocity of air bubble. The dynamics of
      the rise of air bubbles in the aqueous solutions of different, mostly microbially
      produced polysaccharides was studied in this work. Solutions with a wide variety
      of polysaccharide concentrations and rheological properties were studied. The
      bubble sizes varied between 0.01 mm3 and 10 cm3. The terminal rise velocities as
      a function of air bubble volume were studied for 21 different polysaccharide
      solutions with different rheological properties. It was found that the terminal
      velocities reached a plateau at higher bubble volumes, and the value of the
      plateau was nearly constant, between 23 and 27 cm/s, for all solutions studied.
      The data were analyzed to produce the functional relationship between the drag
      coefficient and Reynolds number (drag curves). It was found out that all the
      experimental data obtained from 21 polysaccharide solutions (431 experimental
      points), can be represented by a new single drag curve. At low values of Reynolds
      numbers, below 1.0, this curve could be described by the modofoed Hadamard
      Rybczynski model, while at Re > 60 the drag coefficient was a constant, equal to
      0.95. The latter finding is similar to that observed for bubble rise in Newtonian
      liquids which was explained on the basis of the "solid bubble" approach.

PMID- 10397863
TI  - Synthesis of sugar fatty acid esters by modified lipase.
AB  - A simple synthesis of sugar fatty acid esters was developed in a nonaqueous
      solution using lipase modified by synthetic detergent. Esterification of sugar
      was accelerated by continuous removal of water from the reaction mixture with a
      molecular sieve. When glucose and palmitic acid (1:1 by mole) were used as the
      starting substrates, more than 90% of glucose was converted to its ester in this
      system. The resultant product was 6-O-palmitoylglucose. Other mono- or
      disaccharides were also esterified by the modified lipase with high yield. It was
      shown that the modified lipase might act as a catalyst for the synthesis of sugar
      fatty acid esters.

PMID- 10397864
TI  - Modeling, simulation, and kinetic analysis of a heterogeneous reaction system for
      the enzymatic conversion of poorly soluble substrate.
AB  - We developed a kinetic model that describes a heterogeneous reaction system
      consisting of a solid substrate suspension for the production of D-amino acid
      using D-hydantoinase. As a biocatalyst, mass-produced free and whole cell enzymes
      were used. The heterogeneous reaction system involves dissolution of a solid
      substrate, enzymatic conversion of the dissolved D-form substrate, spontaneous
      racemization of an L-form substrate to D-form, and deactivation of the enzyme. In
      the case of using whole cell enzymes, transfer of the dissolved substrate and
      product through the cell membrane was considered. The kinetic parameters were
      determined from experiments, literature data, and by using Marquardt's method of
      nonlinear regression analysis. The model was simulated using the kinetic
      parameters and compared with experimental data, and a good agreement was observed
      between the experimental results and the simulation ones. Factors affecting the
      kinetics of the heterogeneous reaction system were analyzed on the basis of the
      kinetic model, and the efficiency of the reaction systems using free and whole
      cell enzymes was also compared.

PMID- 10397865
TI  - Fermentability of the hemicellulose-derived sugars from steam-exploded softwood
      (douglas fir) 
AB  - Steam explosion ofDouglas fir wood chips under low-severity conditions (log Ro =
      3.08 corresponding to 175 degrees C, 7.5 min, and 4.5% SO2) resulted in the
      recovery of around 87% of the original hemicellulose component in the water
      soluble stream. More than 80% of the recovered hemicellulose was in a monomeric
      form. As the pretreatment severity increased from 3.08 to 3.76, hemicellulose
      recovery dropped to 43% of the original hemicellulose found in Douglas fir chips
      while the concentration of glucose originating from cellulose hydrolysis
      increased along with the concentration of sugar degradation products such as
      furfural and hydroxymethylfurfural. Despite containing a higher concentration of
      hexose monomers (mainly glucose originating from cellulose degradation), the
      water-soluble fraction prepared under high-severity conditions (log Ro = 3.73
      corresponding to 215 degrees C, 2.38 min, and 2.38% SO2) was not readily
      fermented. Only the two hydrolyzates obtained at low and medium (195 degrees C,
      4.5 min, and 4.5% SO2) severities were fermented to ethanol using a spent sulfur
      liquor adapted strain of Saccharomyces cerevisiae. High ethanol yields were
      obtained for these two hydrolyzates with 0.44 g of ethanol produced per gram of
      hexose utilized (86% of theoretical). However, the best results of hemicellulose
      recovery and fermentability were obtained for the low-severity water-soluble
      fraction which was fermented significantly faster than the fraction obtained
      after medium-severity treatment probably because it contained higher amounts of
      fermentation inhibitors. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397866
TI  - Poly(ethylene glycol)-modified ligninase enhances pentachlorophenol
      biodegradation in water-solvent mixtures 
AB  - Polychlorinated hydrocarbons are prevalent environmental contaminants whose rates
      of biodegradation are limited by their minimal solubilities in aqueous solutions
      where the biological reactions take place. In this study, ligninase (LiP) from
      Phanerochaete chrysosporium was modified by poly(ethylene glycol) to enhance its
      activity and stability for the biodegradation of pentachlorophenol (PCP) in the
      presence of acetonitrile (MeCN), a water-miscible solvent. The modified enzyme
      retained 100% of its activity in aqueous solutions and showed enhanced tolerance
      against the organic solvent. The activity of the modified enzyme was found to be
      over twice that of the native enzyme in the presence of 10% (v/v) MeCN. The
      solubility of PCP was enhanced significantly by the addition of MeCN to aqueous
      solutions, such that it was over 10-fold more soluble in the presence of 15%
      (v/v) MeCN than in pure aqueous buffer solution (from 0.06 to 0.65 mM).
      Capitalizing on the enhanced substrate solubility and the increased activity of
      the modified enzyme, the catalytic efficiency of the modified LiP in solutions
      containing 15% MeCN was over 11-fold higher than that of the native enzyme in
      buffer solutions (pH 4.2) in unoptimized reactor systems (from 44 to 480 mol
      PCP/mol LiP.h). Continued research both in the use of organic solvents to
      increase the availability of recalcitrant contaminants and in the modification of
      enzymes to enhance their activity and stability in such solvents promises to
      dramatically affect our ability to remediate contaminated sites. Published by
      John Wiley & Sons.

PMID- 10397868
TI  - Process intensification by direct product sequestration from batch fermentations:
      application of a fluidised bed, multi-bed external loop contactor 
AB  - A critical comparison has been made of the relative efficacy of the primary
      purification of an extracellular acid protease produced by the yeast Yarrowia
      lipolytica. The performance of conventional, discrete sequences of fermentation,
      broth clarification and fixed bed, anion exchange chromatography has been
      compared with fluidised bed adsorption directly interfaced with post-term
      fermentation broth and fluidised bed adsorption directly integrated with
      productive fermentations (so-called direct product sequestration; DPS).
      Advantages of the latter, in terms of the improved yield and molecular quality of
      the protease end product are discussed in terms of the design, assembly and
      operation of component parts of DPS devices and their generic application to
      other extracellular bioproducts of microbial fermentations. Copyright 1999 John
      Wiley & Sons, Inc.

PMID- 10397867
TI  - The adaptation of BHK cells to a non-ammoniagenic glutamate-based culture medium.
AB  - Although glutamine is a major carbon source for mammalian cells in culture, its
      chemical decomposition or cellular metabolism leads to an undesirable excess of
      ammonia. This limits the shelf-life of glutamine-supplemented media and may
      reduce the cell yield under certain conditions. We have attempted to develop a
      less ammoniagenic medium for the growth of BHK-21 cells by a mole-to-mole
      substitution of glutamine by glutamate. This results in a medium that is
      thermally stable but unable to support an equivalent growth yield. However,
      supplementation of the glutamate-based medium with asparagine (3 mM) and a
      minimal level of glutamine (0.5 mM) restored the original growth capacity of the
      cultures. Substitution of the low level of glutamine with the glutamine
      dipeptides, ala-gln (1 mM), or gly-gln (3 mM) resulted in an equivalent cell
      yield and in a thermally stable medium. The ammonia accumulation in cultures with
      glutamate-based medium was reduced significantly (>60%). Factors mediating growth
      and adaptation in medium substituted with glutamate were also investigated. The
      maximum growth capacity of the BHK-21 cells in glutamate-based medium (without
      glutamine) was achieved after a period of adaptation of 5 culture passages from
      growth in glutamine-based cultures. Adaptation was not influenced by increases in
      glutamate uptake which was constitutively high in BHK cells. Adaptation was
      associated with changes in the activities of enzymes involved in glutamate or
      glutamine metabolism. The activities of glutamine synthetase (GS) and alanine
      aminotransferase (ALT) increased significantly and the activity of phosphate
      activated glutaminase (PAG) decreased significantly. The activity of glutamate
      dehydrogenase (GDH) showed no significant change after adaptation to glutamate.
      These changes resulted in an altered metabolic profile which included a reduced
      ammonia production but an increased alanine production. Alanine production is
      suspected of being an alternative route for removal of excess nitrogen.

PMID- 10397869
TI  - Development of an ultra-high-temperature process for the enzymatic hydrolysis of
      lactose. I. The properties of two thermostable beta-glycosidases.
AB  - Recombinant beta-glycosidases from hyperthermophilic Sulfolobus solfataricus
      (SsbetaGly) and Pyrococcus furiosus (CelB) have been characterized with regard to
      their potential use in lactose hydrolysis at about 70 degrees C or greater.
      Compared with SsbetaGly, CelB is approximately 15 times more stable against
      irreversible denaturation by heat, its operational half-life time at 80 degrees C
      and pH 5.5 being 22 days. The stability of CelB but not that of SsbetaGly is
      decreased 4-fold in the presence of 200 mM lactose at 80 degrees C. CelB displays
      a broader pH/activity profile than SsbetaGly, retaining at least 60% enzyme
      activity between pH 4 and 7. Both enzymes have a similar activation energy for
      lactose hydrolysis of approximately 75 kJ/mol (pH 5.5), and this is constant
      between 30 and 95 degrees C. D-Galactose is a weak competitive inhibitor against
      the release of D-glucose from lactose (Ki approximately 0.3 M), and at 80 degrees
      C the ratio of Ki, D-galactose to Km,lactose is 2.5 and 4.0 for CelB and
      SsbetaGly, respectively. SsbetaGly is activated up to 2-fold in the presence of D
      glucose with respect to the maximum rate of glycosidic bond cleavage, measured
      with o-nitrophenyl beta-D-galactoside as the substrate. By contrast, CelB is
      competitively inhibited by D-glucose and has a Ki of 76 mM. The transfer of the
      galactosyl group from lactose to acceptors such as lactose or D-glucose rather
      than water is significant for both enzymes and depends on the initial lactose
      concentration as well as the time-dependent substrate/product ratio during
      batchwise lactose conversion. It is approximately 1.8 times higher for SsbetaGly,
      compared with CelB. Overall, CelB and SsbetaGly share their catalytic properties
      with much less thermostable beta-glycosidases and thus seem very suitable for
      lactose hydrolysis at >/=70 degrees C.

PMID- 10397870
TI  - Controlled regioselectivity of fatty acid oxidation by whole cells producing
      cytochrome P450BM-3 monooxygenase under varied dissolved oxygen concentrations.
AB  - Utilising whole cells of recombinant Escherichia coli K27 (pCYP102, pGEc47)
      containing active cytochrome P450BM-3 monooxygenase [E.C. 1. 14.14.1], multiple
      oxidations of saturated and unsaturated fatty acids were performed by the enzyme
      under conditions of excess oxygen. The amount of oxygen dissolved in the culture
      medium strongly influenced the regioselectivity of the reaction, as reflected in
      the distribution and amount of oxidised products. We have verified by gas
      chromatography/mass spectrometry that the products of in vivo biotransformation
      of pentadecanoic acid by cytochrome P450BM-3 are identical to those formed in
      cell-free extracts containing the enzyme. The formation of keto- and dihydroxy
      acids, side products which are characteristic for in vitro conversions with
      purified cytochrome P450BM-3 in the presence of excess oxygen, has been observed
      as well. Thus, by varying the oxygen concentration, we could control the
      regioselectivity of oxidation and the number of products made. Under oxygen
      limiting conditions, only monooxidised 12-, 13-, and 14-hydroxy-pentadecanoic
      acids were obtained. Consequently, unwanted side products could be excluded by
      modulating the amount of oxygen used in the bioconversion. Furthermore, whole
      cell oxidation of two unsaturated long-chain fatty acids, cis-pentadec-10-enoic
      and cis-hexadec-9-enoic acid, resulted in the production of epoxides, various
      subterminal hydroxyalkenoic acids and keto- and hydroxyalkanoic acids. Although
      we obtained higher activities of C15:0 conversion in vitro, the whole cell
      biocatalyst proved to be useful for specific oxidations of long-chain fatty acids
      since there is no need to add the costly cofactor NADPH. This biooxidation by E.
      coli K27 (pCYP102, pGEc47) under oxygen limitation has been demonstrated at the 2
      L scale, showing that 12-, 13-, and 14-hydroxypentadecanoic acids can be produced
      in the g L-1 range.

PMID- 10397871
TI  - Biotransformation of carbon tetrachloride by various acetate- and nitrate-limited
      denitrifying consortia 
AB  - Fed-batch experiments were performed to determine the carbon tetrachloride (CT)
      degrading ability of three denitrifying consortia cultured from sites not
      contaminated with CT. A mathematical model was used to quantify the rates of CT
      transformation by the consortia under both acetate-limiting and nitrate-limiting
      conditions. A rate constant for CT transformation on a cellular protein basis and
      the fraction of degraded CT transformed to chloroform (CF) were determined for
      each consortium by optimizing the model to fit the experimental data. The
      parameters for these experiments were statistically compared to those obtained
      for previous experiments with a denitrifying consortium cultured from an aquifer
      soil sample from the US Department of Energy Hanford site in southeastern
      Washington state. Results of F-test analysis indicated the rate of CT
      transformation and the production of CF both were functions of the limiting
      nutrient. Under nitrate-limited conditions, the rate constant for CT
      transformation for all four consortia was about 30 L/gmol/min and approximately
      50% of the CT transformed was converted to CF. When acetate was the limiting
      nutrient, the rate constant for CT transformation was approximately 8 L/gmol/min
      and the CF yield decreased to about 25%. These results imply the ability to
      degrade CT may be inherent to some denitrifying organisms, regardless of previous
      exposure to CT. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397872
TI  - Effects of cell density and temperature on oxygen consumption rate for different
      mammalian cell lines.
AB  - Oxygen consumption rates were measured in a respirometer for different mammalian
      cell lines (BHK, murine hybridoma, and CHO), and the effects of cell density (1
      20 million cells/mL) and temperature (6 to 37 degrees C) on specific oxygen
      consumption rate were investigated. The specific oxygen consumption was cell line
      dependent. For a given temperature, the murine hybridoma cells had the lowest and
      the CHO cells had the highest oxygen consumption rate. The specific oxygen
      consumption rate was not affected by the cell concentration for cell densities
      between 1 and 20 million cells/mL. However, artificial trends implicating the
      effects of cell density were obtained when traditional analysis was used and the
      probe response time was neglected. A detailed mathematical analysis was presented
      to investigate the magnitude of errors originating from neglecting the probe
      response time for the calculation of oxygen consumption rate. The error was
      significant, especially when the probe response was slow and/or the oxygen
      consumption was fast. Temperature influenced the specific oxygen consumption rate
      similarly for the cells studied, and about 10% decrease was observed in specific
      oxygen consumption by 1 degrees C decrease in the temperature. Between 6 and 37
      degrees C, the effect of temperature on oxygen consumption rate could be
      described using an Arrhenius model, i.e., qO2 = qoO2. e-E/RT. The activation
      energy, E, in this equation was similar for different cells (between 80 and 90
      kJ/mol), indicating the action of a similar mechanism for the effect of
      temperature on oxygen consumption.

PMID- 10397873
TI  - Monitoring of intracellular ribonucleotide pools is a powerful tool in the
      development and characterization of mammalian cell culture processes.
AB  - Efficient cell culture process development for the industrial production of
      recombinant therapeutics is characterized by constraints which pertain to issues
      such as costs, competitiveness and the meeting of project timelines. These
      constraints require tools which can help the developer learn as much as possible
      as quickly as possible about the cell at hand and identify features of a
      particular culture which are amenable to improvement. Current on- and off-line
      monitoring parameters, however useful, provide only late indications (cell
      concentration, viability) and circumstantial evidence (lactate, ammonia, etc.)
      with regard to the physiologic status of cells at the time of sampling. The
      relative intracellular content of purine to pyrimidine nucleotide triphosphates
      as well as the ratio of UTP to UDP-N-acetylhexosamines have been previously
      described as sensitive indicators of a cell's metabolic status, growth potential,
      and overall physiological condition. The sensitivity of such nucleotide ratios
      and their usefulness in commercially relevant process development and
      characterization were tested at Boehringer Ingelheim Pharma KG in a large number
      of fermentations (>80) with a variety of culture modes, cells, and products in
      scales up to 10,000 litres. Monitoring of these intracellular parameters allows a
      timely and reliable assessment of cell state and growth potential, which is
      possible neither by classical cell number and viability measurements nor by a
      variety of fermentation data typically monitored. The view inside the cell
      afforded by nucleotide monitoring enables prediction of the behavior of a culture
      up to 2 days before any hint of physiological changes is given by cell number and
      viability estimation. In this paper, data relating the growth behavior of CHO and
      hybridoma cell lines to their nucleotide pools are shown. Two very different
      processes for the production of recombinant tPA in 10,000-litre bioreactors are
      compared and characterized with respect to their nucleotide profiles. Examples
      from industrial process development cases in which intracellular nucleotide
      information is used to advantage are also presented and discussed.

PMID- 10397874
TI  - pH regulation of recombinant glucoamylase production in Fusarium venenatum JeRS
      325, a transformant with a Fusarium oxysporum alkaline (trypsin-like) protease
      promoter.
AB  - Fusarium venenatum (formerly Fusarium graminearum) JeRS 325 produces heterologous
      glucoamylase (GAM) under the regulation of a Fusarium oxysporum alkaline (trypsin
      like) protease promoter. The glucoamylase gene was used as a reporter gene to
      study the effects of ammonium and pH on GAM production under the control of the
      alkaline protease promoter. Between pH 4.0 and 5.8, GAM production in glucose
      limited chemostat cultures of JeRS 325 grown at a dilution rate of 0.10 h-1
      (doubling time, 6.9 h) on (NH4)2SO4 medium increased in a linear manner with
      increase in pH. However, at pH 4.0 and below GAM production was almost completely
      repressed in glucose-limited chemostat cultures grown on (NH4)2SO4 or NaNO3
      medium. Thus GAM production in JeRS 325 is regulated by culture pH, not by the
      nature of the nitrogen source in the medium. The difficulty of using unbuffered
      medium when investigating putative ammonium repression is also shown. The study
      demonstrates the potential for use of the alkaline protease promoter in F.
      graminearum for the production of recombinant proteins in a pH dependent man ner.

PMID- 10397875
TI  - Activity losses among T4 lysozyme charge variants after adsorption to colloidal
      silica.
AB  - Enzyme structure and function depend to some extent on enzyme net charge and
      charge location. Altering the charge of even a single residue may affect the
      interaction between enzyme and substrate such that all catalytic activity is
      lost. In this study we investigated the effect of net charge and charge location
      on the enzymatic activity of synthetic mutants of bacteriophage T4 lysozyme in
      the presence of colloidal silica. Enzymatic activity decreased upon adsorption,
      and these changes were variant-specific. Results were interpreted with reference
      to differences in adsorbed enzyme structure and orientation, and electrostatic
      effects. By exploring the effects of enzyme charge on adsorption, it may be
      possible to gain a better understanding of how enzyme structure influences
      adsorption and function at an interface.

PMID- 10397876
TI  - Stability of native and cross-linked crystalline glucose isomerase.
AB  - Stabilities of native and cross-linked crystalline forms of Streptomyces
      rubiginosus glucose isomerase were compared in buffer and in 45% glucose/fructose
      solutions. The cross-linked crystalline form of the enzyme was more stable in the
      presence of substrate while in a buffer solution the native enzyme was more
      stable. Inactivation of native enzyme in buffer did not obey first-order kinetics
      but proceeded with a rapid first phase followed by a stable phase. This
      stabilization is interpreted to be a result of a conformational change in the
      protein structure. Inactivation of the native enzyme in buffer was directly
      related to protein precipitation. In the presence of high substrate
      concentration, the inactivation was related to browning reactions between the
      enzyme and the reactive sugar, resulting in soluble sugar-protein complexes.

PMID- 10397877
TI  - Electrically immobilized enzyme reactors: bioconversion of a charged substrate.
      Hydrolysis Of penicillin G by penicillin G acylase.
AB  - The possibility of using the multicompartment immobilized enzyme reactor (MIER)
      in presence of a charged substrate is here explored. Penicillin G acylase is used
      to convert penicillin G (a free acid, with a pK of 2.6) into two charged
      products: phenyl acetic acid (PAA, with a pK of 4.2) and 6-aminopenicillanic acid
      (6-APA, a zwitterion with a pI of 3.6). The enzyme is trapped by an isoelectric
      mechanism in a chamber of the electrolyzer delimited by a pI 5.0 and a pI 9.0
      amphoteric, isoelectric membranes. Under normal operating conditions (continuous
      substrate feeding in the presence of an electric field), only a low substrate
      conversion can be achieved, due to rapid electrophoretic transport of unreacted
      penicillin G out of the reaction chamber towards the anode. Excellent conversion
      rates (>96%) are obtained under a "doubly-discontinuous" operation mode: a time
      lapse substrate feeding, accompanied by short times (4-8 min) of electric field
      interruption. The product of interest (6-APA, a precursor of semisynthetic
      penicillins), by virtue of its amphoteric nature, is trapped in a chamber
      delimited by a pI 3.5 membrane and a pI 5.5 membrane, adjacent to the reaction
      chamber on its anodic side. The other contaminant product (PAA) first accumulates
      in the same chamber and then progressively vacates it to collect in the anodic
      reservoir, leaving behind a pure 6-APA solution. In this operation mode,
      vanishing amounts of unreacted substrate (penicillin G) leave the reaction
      chamber to contaminate the adjacent, anodic chambers. A novel class of
      zwitterionic buffers is additionally reported, able to cover very thoroughly any
      pH value along the pH 3-10 interval: polymeric, zwitterionic buffers, synthesized
      with the principle of the Immobiline (acrylamido weak acids and bases) chemicals.
      Enhanced enzyme reactivity is found in this macromolecular buffers as compared to
      conventional ones.

PMID- 10397878
TI  - Extractive fermentation of aroma with supercritical CO2 
AB  - This work deals with the feasibility of achieving an extractive fermentation of 2
      phenylethyl alcohol, the rose aroma, coupling fermentation with Kluyveromyces
      marxianus and supercritical carbon dioxide (SCCO2) extraction. The extractive
      process is, in this case, of special interest due to the strong yeast inhibition
      by 2-phenylethyl alcohol. First results confirmed that direct SCCO2 extraction is
      not possible, due to a drastic CO2 effect on cell viability. It is therefore
      necessary to perform cell separation prior to the extraction. Aroma extraction
      conditions from a synthetic mixture were then optimized, a pressure of 200 bar
      and a temperature in the range 35-45 degrees C being chosen. Under these
      conditions, the distribution coefficient Kd is 2 times higher than during the
      extraction using a conventional organic solvent, n-hexane. Using a simple model
      of aroma partition between aqueous and SCCO2 phases, the parameters of a
      continuous extraction from a synthetic broth were defined. The two substrates,
      glucose and phenylalanine, are not extracted whatever the conditions. As
      predicted by the model, more than 90% of 2-phenylethyl alcohol can be extracted,
      while the extraction of ethanol, the second main product, can be easily tuned
      with respect to operating conditions, as a function of its influence on the
      fermentation. Finally, the feasibility of the aroma recovery using two
      depressurization steps at the outflow of the extraction vessel was demonstrated;
      97% of the extracted aroma was recovered, and a mass purity of 91% was achieved.
      Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397879
TI  - Incorporation of ammonium into intracellular UDP-activated N-acetylhexosamines
      and into carbohydrate structures in glycoproteins.
AB  - The negative effects of ammonia on animal cells, especially in vitro cultures,
      are well known, but the mechanism of how ammonia inhibits cell growth and
      influences the glycosylation of proteins is not completely understood. We
      investigated the ammonium action on the synthesis of the intracellular UDP-N
      acetylhexos- amines (UDPGNAc), which are precursors of glycosylation as well as
      on N-linked oligosaccharides of a recombinant human IL-2 mutant variant model
      glycoprotein expressed in BHK-21 cells under defined and controlled culture
      conditions in a continuously perfused bioreactor. The examinations were based on
      our previous observations that increased ammonia concentrations in the medium
      lead to the intracellular formation and accumulation of UDPGNAc (Ryll et al.,
      1994). The kinetics of formation of the UDPGNAc pool after adding ammonia and its
      reconstitution to normal conditions are shown. To study the pathway leading to
      the intracellular increase of UDPGNAc, the uptake and incorporation of 15NH4+ was
      confirmed by the detection of 15N in UDP-N-acetylglucosamine (UDP-GlcNAc). UDP
      GlcNAc was purified using high pH anion-exchange chromatography with pulsed
      amperometric detection and analyzed by GC/MS. The proportion of UDP-GlcNAc
      containing 15N was approximately 60% and corresponds quantitatively to the
      increased intracellular concentration of UDP-GlcNAc. In order to confirm the
      direct influence of ammonia on protein glycosylation, the human IL-2 mutant
      glycoprotein variant IL-Mu6, bearing a novel N-glycosylation site, has been
      produced under defined protein-free medium conditions in the presence of 15NH4Cl.
      IL-Mu6 glycoprotein was purified and N-glycans released were analyzed by matrix
      assisted laser desorption ionization time of flight mass spectroscopy. Maximally
      60-80% of N-acetylated sugars in N-glycan structures contained 15N indicating
      that ammonium is used as a building block during synthesis of the carbohydrate
      structures expressed from in vitro cultivated mammalian cells.

PMID- 10397880
TI  - Enhancing ligand-protein binding in affinity thermoprecipitation: elucidation of
      spacer effects 
AB  - Copolymers of N-isopropylacrylamide and N-acryloyl amino acid spacers of varying
      chain length were synthesized. p-Aminobenzamidine (PABA) was chemically linked to
      the pendant carboxyl groups of these polymers to obtain thermoprecipitating
      affinity polymers. The inhibition constant (Ki) of these polymers for trypsin
      decreased, i. e., the efficiency of PABA-trypsin binding increased with increase
      in the spacer chain length. The polymer to which PABA was linked through a spacer
      of five methylene groups exhibited eleven times lower Ki than that of the polymer
      containing PABA without a spacer. Investigations on model inhibitors N-acyl-p
      aminobenzamidines showed that this enhancement in trypsin binding by the polymers
      was due to the spacer as well as to microenvironmental effects. Recovery and
      specific activity of the trypsin recovered increased with the spacer chain
      length. Separation of trypsin from a mixture of trypsin and chymotrypsin was also
      enhanced with the spacer chain length. The inhibition constants of these affinity
      polymers were not adversely affected by the crowding effect. Copyright 1999 John
      Wiley & Sons, Inc.

PMID- 10397881
TI  - Transformed Lepidopteran insect cells: new sources of recombinant human tissue
      plasminogen activator.
AB  - Stable transformation was used to generate a cloned insect cell line (Bm5
      silkmoth cells) over-expressing human tissue plasminogen activator (tPA). This
      cell line expressed 135 microg/mL single chain tPA in serum-free medium in static
      culture with a maximum specific activity of 120 IU/microg. In serum-containing
      medium, this line expressed 160 microg/mL of combined single-chain tPA, two-chain
      tPA, and a higher molecular weight SDS-stable tPA complex in suspension cultures
      with a maximum specific activity of 255 IU/microg. Approximately 100 copies of
      the tPA cDNA were randomly integrated into each Bm5 cell. For secretion of
      recombinant tPA from Bm5 cells, the native human tPA signal peptide is as
      effectively recognized as an insect specific signal peptide derived from a
      silkmoth chorion gene. Finally, stably transformed polyclonal populations of Bm5,
      High Five, and Sf21 cells expressing tPA were generated and compared for relative
      tPA expression.

PMID- 10397882
TI  - Transmembrane distribution of substrate and product during the bioreduction of
      acetophenone with resting cells of Saccharomyces cerevisiae.
AB  - The average volumetric intracellular concentrations of acetophenone and phenethyl
      alcohol were determined during the bioreduction of acetophenone using resting
      cells of Saccharomyces cerevisiae in aqueous solutions at 30 degrees C. The
      behavior of their distribution coefficients (ratio of intracellular to
      extracellular concentrations) during the bioreduction process was evaluated with
      different cell preparation and extracellular conditions. The distribution
      coefficient of acetophenone was found to be in the range of 2.3-4.0. The
      distribution coefficient of phenethyl alcohol was found to be in the range of 1.3
      1.8. Both the distribution coefficients were correlated significantly only with
      the physiological state of the resting cells as reflected by the relative cell
      mass (0.65-1.09). The correlation is approximately linear with the largest slope
      for the toxic reagent, acetophenone. No significant effects on the distribution
      coefficients were experimentally observed or were present in a regression
      analysis for the concentrations of acetophenone (0-0.30% v/v), phenethyl alcohol
      (0-0.20% v/v), ethanol (1.60-2.25% v/v), the extracellular pH (pH 2-7), or the
      presence of the salts: KCl, KH2PO4, MgSO4, NaCl, and CaCl2 (each 0-0.1 M) in the
      medium. Different cell initialization times (0-6 days) and initialization
      conditions were also included.

PMID- 10397883
TI  - A predictive thermodynamic model for the bioreduction of acetophenone to
      phenethyl alcohol using resting cells of Saccharomyces cerevisiae.
AB  - Equilibrium conversions were observed in the range of 60.2-76.0% with different
      initial compositions of reaction media for the bioreduction of acetophenone using
      resting cells of Saccharomyces cerevisiae in aqueous solutions at 30 degrees C.
      The reduction of acetophenone in the cells under anaerobic conditions is
      considered to be coupled with the oxidation of ethanol to acetate in the
      cytoplasm. A biphasic thermodynamic model is proposed which includes a nonuniform
      distribution of reagents across the cell membrane, a transmembrane pH gradient,
      ideal and nonideal solution models, and a basic reaction stoichiometry (ACP +
      (1/2) EtOH + (1/2)H2O <--> PEA + (1/2)Ac- + (1/2)H+). The intracellular activity
      coefficients were based on the Lewis-Randall rule for acetophenone, phenethyl
      alcohol, and H2O and Henry's law for ethanol, acetate anion, and H+. The overall
      standard Gibbs free energy was estimated to be -0.11 kcal/mol at a pH 7, 25
      degrees C, and 1 atm. The intracellular thermodynamic activity coefficients of
      acetophenone and phenethyl alcohol were predicted to be 471.2 and 866.4,
      respectively, using the measured initial distribution coefficients and calculated
      extracellular activity coefficients. The model reflected a zero Gibbs free energy
      change at calculated conversions within 4% of the measured equilibrium
      conversions. The analysis verified the effect of the concentration ratio of the
      substrate acetophenone to the co-substrate ethanol on the conversion efficiency
      and suggested that the intracellular pH and the pH gradient across the cell
      transmembrane significantly affect the predicted equilibrium conversion. The
      intracellular pH of resting, viable cells of Bakers' yeast at the bioconversion
      conditions was determined experimentally to be 5.77.

PMID- 10397884
TI  - Membrane sparger in bubble column, airlift, and combined membrane-ring sparger
      bioreactors 
AB  - The bubble column and the two internal loop airlift reactors (riser/downcomer
      area ratios of 0.11 and 0.58) characterized in this study were equipped with a
      rubber membrane sparger, which produced small bubbles, giving high mass transfer
      coefficients. The low mixing intensity in the bubble column was increased by an
      order of magnitude in the airlift reactors. We designed a novel aeration and
      mixing system by adding a ring sparger to the membrane sparger in the bubble
      column and maintained the advantages of both airlift configuration (good mixing
      properties) and bubble column configuration (efficient aeration, without any
      internal constructions). The combined membrane-ring sparger system has unique
      features with respect to the efficiency of utilization of substrate gasses and
      energy. Model experiments showed that the small bubbles from the membrane sparger
      do not coalesce with the large bubbles from the ring sparger. If different gases
      were added through the two spargers it was possible to transfer a hazardous or
      expensive gas quantitatively to the liquid through the membrane sparger (dual
      sparging mode). In the combined membrane-ring sparger system the energy input for
      mixing and mass transfer is divided. Therefore, the energy consumption can be
      minimized if the flow distribution of air through the membrane and ring sparger
      is controlled by the oxygen demand and the inhomogeneity of the culture,
      respectively (split sparging mode). The dual sparging mode was used for mass
      production of the alga Rhodomonas sp. as the first step in aquatic food chains.
      Avoiding mechanical parts removes an important risk of malfunction, and a
      continuous culture could be maintained for more than 8 months. Copyright 1999
      John Wiley & Sons, Inc.

PMID- 10397885
TI  - Integrated two-liquid phase bioconversion and product-recovery processes for the
      oxidation of alkanes: process design and economic evaluation 
AB  - Pseudomonas oleovorans and recombinant strains containing the alkane oxidation
      genes can produce alkane oxidation products in two-liquid phase bioreactor
      systems. In these bioprocesses the cells, which grow in the aqueous phase,
      oxidize apolar, non-water soluble substrates. The apolar products typically
      accumulate in the emulsified apolar phase. We have studied both the bioconversion
      systems and several downstream processing systems to separate and purify alkanols
      from these two-liquid phase media. Based on the information generated in these
      studies, we have now designed bioconversion and downstream processing systems for
      the production of 1-alkanols from n-alkanes on a 10 kiloton/yr scale, taking the
      conversion of n-octane to 1-octanol as a model system. Here, we describe overall
      designs of fed-batch and continuous-fermentation processes for the oxidation of
      octane to 1-octanol by Pseudomonas oleovorans, and we discuss the economics of
      these processes. In both systems the two-liquid phase system consists of an
      apolar phase with hexadecene as the apolar carrier solvent into which n-octane is
      dissolved, while the cells are present in the aqueous phase. In one system,
      multiple-batch fermentations are followed by continuous processing of the product
      from the separated apolar phase. The second system is based on alkane oxidation
      by continuously growing cultures, again followed by continuous processing of the
      product. Fewer fermentors were required and a higher space-time-yield was
      possible for production of 1-octanol in a continuous process. The overall
      performance of each of these two systems has been modeled with Aspen software.
      Investment and operating costs were estimated with input from equipment
      manufacturers and bulk-material suppliers. Based on this study, the production
      cost of 1-octanol is about 7 US$kg-1 when produced in the fed-batch process, and
      8 US$kg-1 when produced continuously. The comparison of upstream and downstream
      capital costs and production costs showed significantly higher upstream costs for
      the fed-batch process and slightly higher upstream costs for continuous
      fermentation. The largest cost contribution was due to variable production costs,
      mainly resulting from media costs. The organisms used in these systems are P.
      putida alk+ recombinants which oxidize alkanes, but cannot oxidize the resulting
      alkanols further. Hence, such cells need a second carbon source, which in these
      systems is glucose. Although the continuous process is about 10% more expensive
      than the fed-batch process, improvements to reduce overall cost can be achieved
      more easily for continuous than for fed-batch fermentation by decreasing the
      dilution rate while maintaining near constant productivity. Improvements relevant
      to both processes can be achieved by increasing the biocatalyst performance,
      which results in improved overall efficiency, decreased capital investment, and
      hence, decreased production cost. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397886
TI  - Inhibitory effect of iron-oxidizing bacteria on ferrous-promoted chalcopyrite
      leaching 
AB  - It is generally accepted that iron-oxidizing bacteria, Thiobacillus ferrooxidans,
      enhance chalcopyrite leaching. However, this article details a case of the
      bacteria suppressing chalcopyrite leaching. Bacterial leaching experiments were
      performed with sulfuric acid solutions containing 0 or 0.04 mol/dm3 ferrous
      sulfate. Without ferrous sulfate, the bacteria enhance copper extraction and
      oxidation of ferrous ions released from chalcopyrite. However, the bacteria
      suppressed chalcopyrite leaching when ferrous sulfate was added. This is mainly
      due to the bacterial consumption of ferrous ions which act as a promoter for
      chalcopyrite oxidation with dissolved oxygen. Coprecipitation of copper ions with
      jarosite formed by the bacterial ferrous oxidation also causes the bacterial
      suppression of copper extraction. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397887
TI  - The influence of complex biological feedstock on the fluidization and bed
      stability in expanded bed adsorption 
AB  - The stability of expanded bed adsorption systems (EBA) was studied in biomass
      containing culture broth by residence time distribution (RTD) experiments, using
      pulse inputs of fluorescent molecules as tracers. Different commercial adsorbents
      (Streamline DEAE, SP, Phenyl, Chelating, and AC) were tested at various biomass
      concentrations (2.5-12 %, wet weight) of whole (Saccharomyces cerevisiae) yeast,
      yeast cell homogenate, and Escherichia coli homogenate. Analyzing the RTD
      according to the PDE model (PDE: axially dispersed plug-flow exchanging mass with
      stagnant zones) allowed the calculation of three parameters: the number of
      transfer units for mass exchange between mobile and stagnant fraction (N), the
      Peclet number for overall axial dispersion (P), and the mobile fraction of the
      liquid in axially dispersed plug flow (varphi). When fluidization was performed
      in particle-free buffer the normalized response signal (after perfect input
      pulse) was symmetric (N:0; P: 50-100; varphi: 1), thus, demonstrating the
      formation of a homogeneous fluidized (expanded) bed. Upon application of
      suspended biomass the RTD was skewed, depending on the adsorbent used and the
      type and level of biomass present in the sample. This situation leads to three
      different characteristic pictures: the well-fluidized system (N: >/= 7-10; P: >/=
      40; varphi: 0.80-0.90), the system exhibiting bottom channeling (N: < 1-2; P: >/=
      40; varphi: 0.5-0.7) and, the system where extensive agglomeration develops (N: 4
      7; P: 20-40; varphi: < 0.5). These results demonstrate that changes in the
      hydrodynamics of EBA already take place in the presence of moderate
      concentrations of biomass. Furthermore, those changes can be quantitatively
      described mainly in terms of the fraction of stagnant zones in the system, which
      are formed due to the interaction of biomass and adsorbent. The technique
      described here can be used to evaluate a certain combination of adsorbent and
      biomass with regard to its suitability for expanded bed adsorption from whole
      broth. Copyright 1999 John Wiley & Sons, Inc. Biotechol Bioeng 64: 484-496, 1999.

PMID- 10397888
TI  - Improvement of red pigment/citrinin production ratio as a function of
      environmental conditions by monascus ruber 
AB  - The growth and metabolic behaviour of the filamentous fungus Monascus ruber were
      studied in submerged cultures under various aeration and agitation conditions.
      Improving the oxygen supply, by increasing either the air input or the agitation
      speed, resulted in modified metabolism: the biomass yield, the consumption of the
      nitrogen source (monosodium glutamate), and the production of secondary
      metabolites (red pigment and citrinin) all increased. However, the citrinin
      production increased more than that of the red pigment. In consequence, a low
      oxygen transfer coefficient was required to improve the red pigment/citrinin
      production ratio. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397889
TI  - Surfactant-histidine-heme ternary complex as a simple artificial heme enzyme in
      organic media 
AB  - A surfactant-heme complex which shows peroxidase activity in organic media has
      been prepared by a method utilizing water-in-oil (W/O) emulsions. Both the
      aqueous phase pH and the type of surfactant appeared to have prominent effect on
      the catalytic activity of the heme complex in benzene. The catalytic efficiency
      of the heme complex was enhanced more than ten times by adding histidine to the
      aqueous phase of W/O emulsions in the preparation process. The enhancement of
      peroxidase activity was observed only in a nonaqueous medium due to the increase
      of the effective concentration of histidine as an activator. In the present
      study, we propose a simple preparation method for an artificial heme enzyme which
      works in nonaqueous media. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10397890
TI  - Editorial note: linda spear appointed to state university of new york
      distinguished professorship 

PMID- 10397891
TI  - Olfactory alliesthesia in human neonates: prandial state and stimulus familiarity
      modulate facial and autonomic responses to milk odors.
AB  - This study examines the effects of a shift in the motivational state (from hunger
      to satiety) of human neonates on their behavioral and autonomic responsiveness to
      artificial and food-related odors as a function of stimulus familiarity. In
      Experiment 1, videotaped facial movements and autonomic (respiration rate: RR,
      heart rate: HR) responses to five olfactory stimuli (familiar regular formula,
      unfamiliar regular formula, protein hydrolysate formula, vanillin, control) are
      recorded in 3-day-old neonates (n = 14) during episodes of irregular sleep. The
      infants are tested on average 50 min. before and after bottle feeding. RR
      discriminates the odor stimuli from the control stimulus, indicating clear
      olfactory detection. Furthermore, neonates react with higher HR change only when
      exposed to their familiar formula milk during the postprandial condition. The
      measurement of facial movements with the Baby-Facial Action Coding System
      indicates that disgust and aversive actions are more often evoked by the odor of
      regular formulas (familiar or unfamiliar) than by the other olfactory stimuli
      during the postprandial condition. In Experiment 2, untrained adult observers,
      presented with the videotapes of the infants' facial responses to the odors, are
      able to decode differential hedonic signals from the sender faces as a function
      of the infants' motivational states. The present findings are in line with the
      concept of olfactory alliesthesia as defined in adults.

PMID- 10397892
TI  - Spontaneous motor activity in the perinatal infant before and after birth:
      stability in individual differences.
AB  - This study was undertaken to determine if a relationship existed between the
      duration of spontaneous general movements before and after birth. Twenty-two
      infants were examined three times as fetuses between 38 and 40 weeks gestational
      age and three times as neonates between 2 and 4 weeks postnatal age. Motor
      activity level during active sleep periods was quantified by direct sonographic
      visualization for fetuses and by videotaped images of trunk movement for
      neonates. We found that both fetuses and neonates exhibited stable individual
      differences in motor activity level. In addition, infants who moved at a certain
      rate as fetuses generally moved at the same relative rate as neonates up to 4
      weeks postnatal age. Our findings suggested that individual differences in motor
      activity level in the 1st month following birth probably arise during fetal life.

PMID- 10397893
TI  - High vagal tone is associated with more efficient regulation of homeostasis in
      low-risk human fetuses.
AB  - Homeostasis is maintained primarily by the parasympathetic nervous system and is
      thought to provide a physiological substrate for the development of complex
      behaviors. This investigation was undertaken to test the hypothesis that infants
      with high parasympathetic tone are more efficient regulators of homeostasis than
      infants with low parasympathetic tone. Respiratory sinus arrhythmia (RSA) was
      used as a measure of parasympathetic tone, and the efficiency of homeostatic
      control was quantified, for each infant, by the slope (SRSA) and correlation
      coefficient (RRSA) of the regression line relating fluctuations in heart period
      and fluctuations in RSA. To test our hypothesis, we examined the relationship
      between RSA and both SRSA and RRSA in 34 low-risk human fetuses between 36 and 40
      weeks gestation. We found that fetuses who were parasympathetic-dominated had
      larger SRSA and RRSA values, and hence were more efficient regulators of
      homeostasis, than fetuses who were sympathetic-dominated. The results of our
      analyses are important because they establish, very early in development, a
      physiological basis for the relationship between vagal tone and the development
      of complex behaviors.

PMID- 10397894
TI  - Geotaxis in 2-week-old Norway rats (Rattus norvegicus): A reevaluation.
AB  - In 1926, Crozier and Pincus first reported that 2-week-old rats placed head-down
      on an inclined plane orient in a head-up direction; this response is called
      negative geotaxis. In Experiment 1, we replicated this finding by testing 12- to
      14-day-old rats on an inclined plane covered with wire mesh. Pups oriented in a
      head-up direction and avoided the head-down direction at inclines of 45 degrees
      but not 30 degrees. Because pups in Experiment 1 appeared to grasp the wire mesh
      with their claws, pups in Experiment 2 were now tested on a smooth but high
      friction substrate. At inclines of 30 degrees, 35 degrees, and 40 degrees, pups
      did not exhibit significant tendencies to orient in a head-up direction or avoid
      a head-down direction. Finally, in Experiment 3, the effect of substrate on
      geotaxis was tested further by comparing pups' behaviors at 40 degrees with the
      inclined plane covered with either wire mesh or the high-friction substrate.
      Pups' orientation behaviors differed on the two substrates. Taken together, these
      data suggest that testing substrate affects the orientation behaviors of young
      rats and raise questions about the plausibility of applying the concept of
      geotaxis to young mammals, at least when tested on an inclined plane.

PMID- 10397896
TI  - A lack of evidence in 4-month-old human infants for paternal voice preference.
AB  - Several studies have found that human infants recognize the sight, sound, smell,
      and touch of their mothers. Maternal recognition occurs early in development,
      often being influenced by prenatal experiences. In contrast, the development of
      infants' recognition of their fathers is not understood. We investigated whether
      4-month-old human infants preferred their fathers' voices, in two different
      speaking contexts. In both Experiments 1 and 2, infants were tested with fathers'
      adult-directed (AD) or infant-directed (ID) speech. In all experiments, infants
      were allowed to listen to recordings of either father's or other's voice
      contingent on their visual attention. Results from the first two experiments
      showed that infants did not prefer their fathers' voices over unfamiliar male
      voices. However, in Experiment 3, 4-month-olds showed that they could
      discriminate the male voices heard in the previous studies. These data were
      interpreted as supporting the hypothesis that the experiences necessary for the
      development of maternal preferences are different from those supporting paternal
      preferences, and that perhaps multimodal cues are necessary for father
      recognition in infancy.

PMID- 10397895
TI  - A comparative study of quiet sleep, active sleep, and waking on the first 2 days
      of life.
AB  - Direct behavioral observation and motility monitoring procedures provide reliable
      data, and both are appropriate for sleep/wake state measurements starting
      immediately after birth. Using these procedures, newborn rats, rabbits, and
      humans were found to have a greater amount of quiet sleep on the day of birth
      rather than 24 hr later. Changes in active sleep and wake were inconsistent
      across the 2 days. The quiet sleep findings are contrary to the developmental
      course which increases with age. The findings are interpreted as a temporary
      adaptive response to the stress of the birth process.

PMID- 10397897
TI  - Activational and organizational actions of gonadal hormones and the sex-specific
      effects of prolactin on food intake by rats.
AB  - Results of previous studies indicate that there is a sex-specific feeding
      response to prolactin (PRL) by rats: Only female rats significantly increase
      their food intake. The possible roles of the activational and/or organizational
      actions of the gonadal hormones in this sex difference were explored. In the
      first experiment, activational hormone exposure was manipulated in adult male and
      female rats. The results suggest that the activational actions of estrogen are
      not necessary for, and that testosterone does not block, PRL-induced increases in
      food intake by female rats. In a second experiment, organizational hormone
      exposure was manipulated in male and female rats during the early postnatal
      period. Genetic male rats organized as females by postnatal Day-1 castration
      significantly increased their food intake, while genetic female rats organized as
      males by postnatal androgen treatment maintained baseline levels of food intake.
      Overall, these experiments suggest that organizational, but not activational,
      gonadal hormone exposure plays a critical role in the development of this sex
      specific response to PRL.

PMID- 10397898
TI  - Fetal behavior in diabetic and nondiabetic pregnant women: An exploratory study.
AB  - To characterize differential behavior and the relationship between maternal blood
      glucose levels and behavior in fetuses of diabetic (n = 10) and nondiabetic (n =
      20) women at 33 and 36 weeks gestational age (GA), spontaneous changes in fetal
      heart rate (FHR), body and breathing movements, and vibroacoustic stimulus
      elicited (3 stimulus/3 no-stimulus control trials) FHR changes and body movements
      were compared. Measures of maternal blood glucose levels were obtained
      immediately following testing; measures varied within normal range. Spontaneous
      behaviors showed no differences between groups and no relationship to maternal
      blood glucose levels. Sensory stimulation elicited similar average peak FHR
      accelerations (M = 17. 1/20.0 BPM) and average movement scores (2.0/2.6) across
      groups. In the diabetic group at 33 weeks GA, the nature of the FHR change over
      time, showed more varied patterns of response, a shorter latency to peak
      acceleration, was less organized, and less mature; as average maternal blood
      glucose levels increased, elicited body movements decreased. These findings
      suggest immaturity and differential functional development of sensory-motor
      response systems in fetuses of diabetic mothers.

PMID- 10397899
TI  - Attachment of cultured human bone cells to novel polymers.
AB  - The initial attachment of human bone-derived cells (HBDC) to several polymer
      systems has been studied in vitro. A novel polymer system based on poly(ethyl
      methacrylate) polymer and tetrahydrofurfuryl methacrylate monomer (PEMA/THFMA)
      was compared with a variant in which THFMA was replaced by 2-hydroxyethyl
      methacrylate (PEMA/HEMA). Tissue culture polystyrene (TCPS) and polystyrene (PS)
      were used as reference materials. The ability of the substrates to adsorb the
      attachment glycoproteins fibronectin (Fn) and vitronectin (Vn) from serum and the
      subsequent effect on radiolabeled HBDC attachment were examined. Initial cell
      attachment from the medium containing 10% (v/v) serum was highest on TCPS; on
      PEMA/THFMA and PEMA/HEMA substrates it was about 25% of this level, and on PS it
      was only 10% of that on TCPS. Attachment of HBDC to all substrates was dependent
      on the presence of Vn, which, unlike Fn, was able to adsorb in the face of
      competition from other serum components. Both Vn and Fn were able to support cell
      attachment when precoated onto all substrates. In comparison to TCPS, PEMA/THFMA
      did not show enhanced adsorption of either Fn or Vn from serum, and this was
      reflected in the level of cell attachment. Interestingly, the potency of
      preadsorbed Fn for cell attachment was much higher on this substrate than on any
      other: 45 ng/cm2 Fn when adsorbed to PEMA/THFMA gave a level of cell attachment
      1.6-fold higher than the same density of Fn on PS or TCPS. The maximum Fn surface
      density achieved on HEMA/PEMA was 16 ng/cm2. Cells on PEMA/THFMA showed typical
      clustering of the alpha5 beta1 Fn receptor, but this was not evident in cells
      attached to PEMA/HEMA even when precoated with Fn. This study indicates that the
      initial attachment of HBDC to all substrates was Vn dependent. It also indicates
      that on PEMA/THFMA the favorable presentation of subsequently adsorbed Fn may
      assist matrix assembly.

PMID- 10397900
TI  - Calcium phosphate formation on porous sol-gel-derived SiO2 and CaO-P2O5-SiO2
      substrates in vitro.
AB  - Sol-gel-derived SiO2 and CaO-P2O5-SiO2 have been shown to be bioactive and bone
      bonding. In this study bioactive sol-gel-derived SiO2 and CaO-P2O5-SiO2 systems
      were tested for in in vitro bioactivity. The calcined ceramic monoliths were
      immersed in a simulated body fluid and analyzed to follow the hydroxyapatite
      formation on the ceramic surface. Apatite-forming ability was investigated in
      terms of structural changes by changing the composition and the preparation
      method. The role of Ca and P dopants in the substrate structure is complicated,
      and careful characterization is needed. The composition and structure together
      determine the in vitro bioactivity. The pore structure was analyzed using N2
      adsorption/desorption isotherms. The results indicate that a great mesopore
      volume and a wide mesopore size distribution favor hydroxycarbonate apatite
      nucleation and a great surface area is not needed. The performed preparation
      process for silica in a basic environment provides a convenient way to prepare a
      mesoporous material.

PMID- 10397901
TI  - Enhanced growth of human vascular endothelial cells on negative ion (Ag-)
      implanted hydrophobic surfaces.
AB  - Silver negative ions (Ag-) were implanted to an insulator, polystyrene, in a
      relatively low ion energy ranging from 5 to 30 keV, and in a dose ranging from
      10(14) to 6 x 10(16) ions. cm-2. Surfaces of Ag--implanted polystyrene were
      studied by means of secondary ion mass spectrometry, X-ray photoelectron
      spectroscopy, Fourier transform infrared spectroscopy, and micro-Raman
      spectroscopy, and contact angle measurement. As a result of Ag- implantation, the
      polystyrene surfaces underwent degradation, thereby becoming more hydrophilic
      with increasing dose and ion energy except an ion energy of 30 keV. The Ag-
      implantation in polystyrene led to enhanced growth of human vascular endothelial
      cells, which grew to more extent with increased hydrophilicity of Ag--implanted
      surfaces except an ion energy of 30 keV. Polystyrene surfaces on which Ag- were
      implanted up to an ion energy of 30 keV caused the same hydrophobic level as
      polystyrene surface itself. Nevertheless, the Ag--implanted polystyrene showed
      relatively good biocompatibility different from polystyrene. Such an improvement
      in cell adhesion may be related to the formation of a graphite-like structure on
      polystyrene surfaces by a Ag--implanted process. Moreover, upon plating in a high
      cell density, human vascular endothelial cells survived even on the polystyrene
      region of Ag--implanted polystyrene for longer than 1.5 months, while the cells
      did not grow on untreated polystyrene in the same culture conditions.

PMID- 10397902
TI  - Comparative bone growth behavior in granules of bioceramic materials of various
      sizes.
AB  - Various bioceramic materials were implanted into 6-mm-diameter holes made in the
      femoral condyles of mature Japanese white rabbits using different-sized granules
      to find an optimal material and granule diameter for use as a bone graft.
      Bioceramics include a bioinert ceramic (Alumina), surface-bioactive ceramics
      [hydroxyapatite (HAp) and Bioglass(R)], and resorbable bioactive ceramics
      [alphatricalcium phosphate (alpha-TCP), beta-TCP, tetracalcium phosphate (TeCP),
      Te. DCPD, Te. DCPA, and low-crystalline HAp]. Granule sizes were 100-300, 10, and
      1-3 microm. Bone growth behavior varied with the kind of bioceramic and the size
      used. For surface-bioactive ceramics, 45S5 Bioglass(R) led to more rapid bone
      proliferation than synthetic HAp. In resorbable bioactive ceramics, the order of
      resorption was: low-crystalline HAp and OCP > TeCP, Te DCPD, Te DCPA > alpha-TCP,
      beta-TCP. In terms of biocompatibility, alpha-TCP was better than beta-TCP.

PMID- 10397903
TI  - Signal transduction and cytoskeletal reorganization are required for cell
      detachment from cell culture surfaces grafted with a temperature-responsive
      polymer.
AB  - We have developed a new cell culture substrate grafted with a temperature
      responsive polymer, poly(N-isopropylacrylamide) (PIPAAm) using an electron beam
      irradiation method. These surfaces are hydrophobic in culture at 37 degrees C due
      to the hydration/dehydration changes intrinsic to PIPAAm at 32 degrees C, and
      they become highly hydrophilic below 32 degrees C. At 37 degrees C grafted and
      ungrafted surfaces showed no difference with regard to attachment, spreading,
      growth, confluent cell density, and morphology of bovine aortic endothelial
      cells. Stress fibers, peripheral bands, and focal contacts were established in
      similar ways. After the medium temperature was decreased to 20 degrees C, spread
      cells lost their flattened morphology, acquiring a rounded cell appearance
      similar to that of cells immediately after plating. After mild agitation cells
      floated free from the dish surface without trypsin treatment. Neither cell
      morphological changes nor cell detachment occurred on ungrafted surfaces. An ATP
      synthesis inhibitor, sodium azide, and a tyrosine kinase inhibitor, genistein,
      suppressed cell morphological changes and cell detachment while a protein
      synthesis inhibitor, cycloheximide, slightly enhanced cell detachment. An actin
      filament stabilizer, phalloidin, and its depolymerizer, cytochalasin D, also
      inhibited cell detachment. These findings suggest that cell detachment on grafted
      surfaces is mediated by intracellular signal transduction and reorganization of
      the cytoskeleton. While trypsinization causes damage to the cell membrane surface
      and extracellular matrix proteins, this alternative low temperature treatment is
      exceptionally noninvasive. The temperature-responsive cell culture surface also
      should prove useful for investigating the molecular machinery involved in cell
      surface detachment.

PMID- 10397904
TI  - Synthesis of superporous hydrogels: hydrogels with fast swelling and
      superabsorbent properties.
AB  - We have been interested in the synthesis of hydrogels with fast swelling kinetics
      and superabsorbent properties. To increase the water absorption rate,
      interconnected pores were introduced to the hydrogels. Since the pore size in the
      dried hydrogels is in the order of hundreds of micrometers, these hydrogels are
      called "superporous" hydrogels. Superporous hydrogels were synthesized by
      crosslinking polymerization of various vinyl monomers in the presence of gas
      bubbles formed by the chemical reaction of acid and NaHCO3. The polymerization
      process was optimized to capture the gas bubbles inside the synthesized
      hydrogels. The use of the NaHCO3/acid system allowed easy control of timing for
      gelation and foam formation. We found that PF127 was the best foam stabilizer for
      most of the monomer systems used in our study. Scanning electron microscope (SEM)
      pictures showed interconnected pores forming capillary channels. The capillary
      channels, which were critical for fast swelling, were preserved during drying by
      dehydrating water-swollen hydrogels with ethanol before drying. The ethanol
      dehydrated superporous hydrogels reached equilibrium swelling within minutes. The
      equilibrium swelling time could be reduced to less than a minute with the use of
      a wetting agent. In our study, water moisture was used as a wetting agent since
      the amount of moisture content in the dried hydrogels easily could be controlled.
      Preparation of superporous hydrogels using the right blowing system, foam
      stabilizer, drying method, and wetting agent makes it possible to reduce the
      swelling time to less than a minute regardless of the size of the dried gels. The
      superporous hydrogels can be used where fast swelling and superabsorbent
      properties are critical.

PMID- 10397905
TI  - Effects of heparan-like polymers associated with growth factors on osteoblast
      proliferation and phenotype expression.
AB  - Heparan-like polymers derived from dextran, named RGTA, were shown to stimulate
      bone repair in different bone defect models. Like heparin and heparan sulfates,
      RGTA potentiate in vitro the biological activities of heparin-binding growth
      factors (HBGFs), such as fibroblast growth factor (FGF), by stabilizing them
      against denaturations and by enhancing their binding with cellular receptors.
      RGTA were postulated to stimulate bone healing by interacting with HBGFs released
      in the wound site and, subsequently, by promoting the proliferation and/or
      differentiation of cells implicated in this process. We examined the effects of
      RGTA alone and associated with HBGFs on MC3T3-E1 osteoblastic cell proliferation
      and differentiation. RGTA inhibited cell proliferation, as measured by [3H]
      thymidine incorporation into DNA. They enhanced the inhibition of DNA synthesis
      caused by transforming growth factor-beta (TGF-beta1) and bone morphogenetic
      protein-2 (BMP-2). RGTA alone increased the alkaline phosphatase and parathyroid
      hormone-responsive adenylate cyclase activities in MC3T3. RGTA enhanced the
      stimulation of the alkaline phosphatase activity induced by BMP-2 and decreased
      or suppressed the inhibition caused by TGF-beta1 and FGF-2. Furthermore, RGTA
      increased the response to parathyroid hormone stimulated by BMP-2. In conclusion,
      RGTA stimulate the expression of osteoblast phenotype features alone or in
      association with HBGFs. The ability to promote the differentiation of bone
      forming cells is a potential explanation of the stimulating effect of RGTA on
      bone repair.

PMID- 10397906
TI  - Variability of cytotoxicity and leaching of substances from four light-curing pit
      and fissure sealants.
AB  - It was the aim of our study to investigate the composition and cytotoxicity of
      aqueous extracts of four light-curing pit and fissure sealants. Water extracts
      were analyzed by gas chromatography/mass spectrometry (GC/MS), and relative
      quantities of identified compounds were compared by means of an internal caffeine
      standard [%CF]. Cytotoxic effects due to medium extracts were determined by means
      of permanent 3T3 fibroblasts. All light-curing pit and fissure sealants
      segregated different ingredients into water, such as co-monomers (mainly ethylene
      glycol compounds) and initiating substances (e.g., camphorquinone). Bisphenol-A,
      however, which is easily detected by GC/MS, was not found in any of the analyzed
      eluates. The extracts of three sealants inhibited monolayer growth only
      moderately whereas the eluate of one product inhibited cell proliferation
      significantly. In the extracts of this sealant high quantities [%CF] of the co
      monomer TEGDMA were detected. Our results indicate that light-curing pit and
      fissure sealants release substances into aqueous media that may induce cytotoxic
      effects. However, no concerns about potential estrogenic effects of Bisphenol-A
      are supported by our results.

PMID- 10397907
TI  - Degradation of calcium phosphate ceramics.
AB  - Degradation of three types of sintered calcium phosphate ceramic spheres was
      investigated in vitro at low pH conditions (LPC) and in an in vivo model, that
      is, injection into a mouse peritoneal cavity. Degradation was observed under both
      conditions. The rate of degradation depended on the type of ceramic, with beta
      TCP degrading faster than HA and HA degrading faster than FA. Degradation was
      characterized by dissolution of the necks and the formation of cracks and
      irregularities in the grains. Intraperitoneal injection of the spheres into a
      mouse peritoneal cavity led to the formation of foreign body granulomas in which
      degradation could be observed. The in vivo degradation pattern was similar to
      that observed in vitro, but longer implantation times resulted in a further
      degradation. Small fragments rich in Ca and P were present in inclusion bodies.
      Calcium phosphate crystals sometimes also were observed in mitochondria, many of
      which were subject to lysis. We observed that ceramic type and implantation
      period also were related to the number of dead cells in the granulomas.
      Furthermore, extracellular deposits were seen between cells and ceramic spheres.
      Ca and P and also Fe were detected in these deposits. The presence of Fe is
      indicative of a lysosomal origin and thus of exocytotic activity.

PMID- 10397908
TI  - Cyclic-strain-induced endothelial cell expression of adhesion molecules and their
      roles in monocyte-endothelial interaction.
AB  - Vascular endothelial cells (ECs) are constantly subjected to hemodynamic forces
      that may regulate monocyte-endothelial interaction in vivo. To examine the
      effects of cyclic strain on endothelial expression of monocyte adhesion
      molecules, E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular
      cell adhesion molecule-1 (VCAM-1) ECs were exposed to physiologically relevant
      levels of cyclic strain. When ECs were under 25% maximal strain at 30 cycles/min
      for 24 h, the expression of E-selectin significantly (p<0.05) increased, by 83%,
      compared to control ECs under static conditions. Similarly, monocyte adhesion to
      ECs under strain (maximum of 15 or 25% at 30 and 60 cycles/min for 24 h) also
      significantly (p<0.05) increased, by >82%. This cyclic-strain-induced monocyte
      adhesion was substantially inhibited (83.5%) by anti-E-selectin antibody. ICAM-1
      expression also significantly increased, by 62%, when ECs were under 25% maximal
      strain at 30 cycles/min for 3 h whereas VCAM-1 expression by ECs under strain
      (for 0.5, 3, and 24 h) did not change compared to static ECs. When ECs were
      treated with anti-ICAM-1 antibody and monocytes with anti-VLA-4 antibody, an
      increase in monocyte adhesion to ECs under cyclic strain was reduced
      significantly. These results demonstrate that cyclic strain can induce EC
      expression of monocyte adhesion molecules E-selectin, ICAM-1, and VCAM-1 in a
      time-dependent manner and thus can mediate monocyte adhesion.

PMID- 10397909
TI  - Osteogenic potential in vitro of human bone marrow cells cultured on macroporous
      biphasic calcium phosphate ceramic.
AB  - Calcium phosphate ceramics are synthetic bone substitutes that promote bone
      formation by osteoconduction. However, they have shown an osteogenic potential in
      vivo in animal models when associated with bone marrow cells. In order to develop
      an osteogenic human "hybrid material," we studied the in vitro osteogenic
      potential of human bone marrow cells cultured on macroporous biphasic calcium
      phosphate (BCP) pellets in the presence of dexamethasone with or without
      1alpha,25 dihydroxyvitamin D3. We were examining, in particular, their
      mesenchymal stem cell proliferation and hematopoietic potential. Osteogenic
      differentiation was evaluated in terms of alkaline phosphatase activity and
      immunological characterization of the extracellular matrix formed by these cells.
      The specimens were observed by scanning and transmission electron microscopy.
      Human mesenchymal stem cells proliferated on macroporous BCP ceramic, with a
      doubling time delayed at the beginning of the culture as compared to the cultures
      realized on plastic. These cells maintained a hematopoietic activity identical to
      that of cultures performed in plastic wells. The proliferating mesenchymal stem
      cells expressed an osteoblastic phenotype, as shown by alkaline phosphatase
      activity and the synthesis in ceramic macropores of an extracellular matrix
      composed of fibronectin, osteocalcin, and collagen I (but not collagen III). In
      addition, numerous microcrystals of apatite precipitated on the extracellular
      matrix, producing a mineralized fibrillar network within the ceramic not observed
      with cell cultures realized on plastic. These results demonstrate that human
      mesenchymal stem cells cultured on macroporous BCP ceramic express and conserve
      their osteoblastic phenotype even after one month of culture and that these
      osteogenic cells are able to form new bone matrix in a BCP ceramic in vitro.

PMID- 10397910
TI  - MPEO-PLA nanoparticles: effect of MPEO content on some of their surface
      properties.
AB  - Nanoparticles of poly(lactic acid) (PLA) and of blends of PLA and
      monomethoxypoly(ethylene oxyde) (MPEO-PLA) were prepared by the double emulsion
      method. Sucrose was added to overcome nanoparticle aggregation with freeze
      drying. Whereas PLA nanoparticles rapidly are phagocytosed by the mononuclear
      phagocyte system cells, the uptake of MPEO-PLA nanoparticles is delayed.
      Opsonization is one of the steps of phagocytosis, and serum complement is a major
      component of the opsonin system. The in vitro complement consumption of the
      prepared nanoparticles was evaluated as a function of time and of their surface
      area. To avoid the aggregation of MPEO-PLA nanoparticles due to MPEO
      crystallization, sucrose was necessary, and its concentration was dependent on
      MPEO proportion in the nanoparticle suspension. As expected, the complement
      consumption for PLA nanoparticles is faster and more important than for PLA/MPEO
      PLA blends. The complement consumption decreases with the increase in MPEO
      surface density. Complement is less consumed with the lower surface density
      provided by a higher molecular weight than by the higher surface density provided
      by a lower molecular weight MPEO. The complement consumption seems to be
      dependent on the number of nanoparticles in contact with human serum. Finally,
      the model of steric repulsion of MPEO towards proteins and the importance of the
      surface density of MPEO were emphasized.

PMID- 10397911
TI  - Studies on small (<350 microm) alginate-poly-L-lysine microcapsules. III.
      Biocompatibility Of smaller versus standard microcapsules.
AB  - Microencapsulation of islets of Langerhans has been proposed as a means of
      preventing their immune destruction following transplantation. Microcapsules of
      diameters <350 microm made with an electrostatic pulse system present many
      advantages relative to standard microcapsules (700-1500 microm), including
      smaller total implant volume, better insulin kinetics, better cell oxygenation,
      and accessibility to new implantation sites. To evaluate their biocompatibility,
      200, 1000, 1120, 1340, or 3000 of these smaller microcapsules (<350 microm) or 20
      standard microcapsules (1247+/-120 microm) were implanted into rat epididymal fat
      pads, retrieved after 2 weeks, and evaluated histologically. The average
      pericapsular reaction increased with the number of small microcapsules implanted
      (p<0.05; 3000 vs. 200, 3000 vs. 1000, and 1000 vs. 200 microcapsules). At equal
      volume and alginate content, standard microcapsules caused a more intense
      fibrosis reaction than smaller microcapsules (p<0.05). In addition, 20 standard
      microcapsules elicited a stronger pericapsular reaction than 200 and 1000 smaller
      microcapsules (p<0.05) although the latter represented a 3.4-fold larger total
      implant surface exposed. We conclude that microcapsules of diameters <350 microm
      made with an electrostatic pulse system are more biocompatible than standard
      microcapsules.

PMID- 10397913
TI  - Human plasma fibrinogen adsorption and platelet adhesion to polystyrene.
AB  - The purpose of this study was to further investigate the role of fibrinogen
      adsorbed from plasma in mediating platelet adhesion to polymeric biomaterials.
      Polystyrene was used as a model hydrophobic polymer; i.e., we expected that the
      role of fibrinogen in platelet adhesion to polystyrene would be representative of
      other hydrophobic polymers. Platelet adhesion was compared to both the amount and
      conformation of adsorbed fibrinogen. The strategy was to compare platelet
      adhesion to surfaces preadsorbed with normal, afibrinogenemic, and fibrinogen
      replenished afibrinogenemic plasmas. Platelet adhesion was determined by the
      lactate dehydrogenase (LDH) method, which was found to be closely correlated with
      adhesion of 111In-labeled platelets. Fibrinogen adsorption from afibrinogenemic
      plasma to polystyrene (Immulon I(R)) was low and <10 ng/cm2. Platelet adhesion
      was absent on surfaces preadsorbed with afibrinogenemic plasma when the residual
      fibrinogen was low enough (<60 microg/mL). Platelet adhesion was restored on
      polystyrene preadsorbed with fibrinogen-replenished afibrinogenemic plasma.
      Addition of even small, subnormal concentrations of fibrinogen to afibrinogenemic
      plasma greatly increased platelet adhesion. In addition, surface-bound
      fibrinogen's ability to mediate platelet adhesion was different, depending on the
      plasma concentration from which fibrinogen was adsorbed. These differences
      correlated with changes in the binding of a monoclonal antibody that binds to the
      Aalpha chain RGDS (572-575), suggesting alteration in the conformation or
      orientation of the adsorbed fibrinogen. Platelet adhesion to polystyrene
      preadsorbed with blood plasma thus appears to be a strongly bivariate function of
      adsorbed fibrinogen, responsive to both low amounts and altered states of the
      adsorbed molecule.

PMID- 10397912
TI  - Polypyrrole-heparin composites as stimulus-responsive substrates for endothelial
      cell growth.
AB  - Heparin is a potent anticoagulant which can be immobilized on biomaterial
      surfaces to increase their hemocompatability. In the present work, we have
      electrochemically synthesized composites comprising heparin and the electrically
      conducting polymer polypyrrole. The incorporation and exposure of heparin were
      controlled by varying key conditions of polymer synthesis (i.e., applied current
      and synthesis time). The resulting composite polymers were electroactive after
      synthesis and the amount of heparin exposed in the polymer could be increased (up
      to threefold) by switching the polymers from their oxidized to reduced states.
      Polymer reduction was achieved by either application of negative potentials (-0.4
      to -0.7 V for 90 s) or exposure to aqueous reductant (0.1M sodium dithionite for
      30 min). Heparin-polypyrrole composites remained stable after autoclaving,
      displaying no significant loss of electroactivity, and had a shelf life of at
      least 2 years postautoclaving. Finally, the composites were found to be excellent
      substrates for the growth of human endothelial cells.

PMID- 10397914
TI  - Liposomes coated with chemically modified dextran interact with human endothelial
      cells.
AB  - Some liposomal formulations are now in clinical use. New applications in biology
      and medicine using targeted liposomes remain an intensive research area. In this
      context, liposomes constituted of phosphatidylcholine (PC),
      phosphatidylethanolamine (PE), and cholesterol (70/10/20 mol %) were prepared by
      detergent dialysis and coated with dextran (Dx) or functionalized dextran (FDx),
      both hydrophobized by a cholesterol anchor which penetrates the lipid bilayer
      during the vesicle formation. The coating of liposomes with these polysaccharides
      was performed because chemically modified dextran but not native Dx interacted
      with vascular cells. The liposome uptake by human endothelial cells was followed
      using uncoated and coated liposomes radiolabeled with a neutral lipid (3H
      cholesterol) and a polar phospholipid (14C-PC). The results indicated for both
      radiolabels a preferential uptake by endothelial cells of FDx-coated liposomes
      compared to uncoated or Dx-coated liposomes. Addition to the culture medium of
      calcium up to 10 mM further enhanced the level and rate of incorporation of FDx
      coated liposomes, whereas interaction of endothelial cells with uncoated
      liposomes or liposomes coated with Dx was poorly affected. Liposome membranes
      were then labeled with N-(lissamine rhodamine B sulfonyl)diacyl-PE and liposome
      uptake by endothelial cells was observed by fluorescence microscopy. The punctate
      intracellular fluorescence of cells incubated at 37 degrees C with fluorolabeled
      liposomes is indicative of the liposome localization within the endocytotic
      pathway of the cells. Altogether, these data demonstrate that coating of
      liposomes with FDx enable specific interactions with human endothelial cells in
      culture. Consequently, these liposomes coated with bioactive polymers represent
      an attractive approach as materials for use as drug delivery vehicles targeting
      vascular cells.

PMID- 10397915
TI  - Retention of hyaluronic acid in alginate beads: aspects for in vitro cartilage
      engineering.
AB  - Alginate has been used successfully for three-dimensional chondrocyte cultures
      and may be important for cartilage transplant formation. However, alginate is not
      a natural component of the cartilage matrix. The aim of this study was (a) to
      supplement alginate with the extracellular matrix component hyaluronic acid; and
      (b) to analyze the hyaluronic acid retention in different alginate gels.
      Hyaluronan is assumed to improve proteoglycan retention and may be important for
      in vitro matrix formation, tissue turgor, and biomechanical quality. Alginate and
      hyaluronan were mixed with chondrocytes and polymerized as were alginate,
      hyaluronan, and fibrinogen. [3H]hyaluronan was used to quantitate the leakage of
      hyaluronan from the gel beads. After 28 days in culture, 1.2% alginate beads
      supplemented with 0.26% hyaluronan contained only 9% of the initial amount of
      hyaluronan whereas 2.4% alginate beads still contained about 55% of the initial
      0.22% hyaluronan. Release of hyaluronan from the beads was significantly lower if
      the beads additionally contained fibrin. Alginate beads supplemented with
      hyaluronan or fibrin showed increased chondrocyte proliferation compared to
      controls. Supplemented hyaluronan greatly diffuses out of alginate gels of lower
      densities. It must be assumed also that most of the hyaluronan newly synthesized
      by chondrocytes in these cells diffuses into the surrounding culture medium. The
      in vitro development of a sufficiently hygroscopic cartilage ground substance
      therefore may be very limited. Sufficient hyaluronic acid retention can be
      achieved in alginate gels with concentrations above 1.2% or by addition of
      fibrin.

PMID- 10397916
TI  - Enhanced expression of P-selectin (CD62P) by endothelial cells seeded onto
      synthetic arterial prostheses (PET, Dacron) is correlated with leukocyte
      interactions.
AB  - This study evaluated the expression by seeded endothelial cells (S-EC) of P
      selectin (CD62P/GMP-140/PADGEM), an adhesion molecule implicated in endothelial
      leukocyte interactions. Endothelial cells were seeded onto knitted polyethylene
      terephthalate (PET, Dacron(R)) prostheses and compared with control endothelial
      cells (C-EC) cultured in flasks to the same stage. Using flow cytometry
      techniques, we observed that CD62P expression by PET S-EC was significantly
      increased (p<0.05) compared to C-EC. Moreover, RT PCR techniques showed that the
      CD62P RNA level was higher on S-ECs compared to C-ECs. Following adhesion assays,
      increased polymorphonuclear neutrophil (PMN) attachment to the PET-seeded
      prostheses as compared to control cultures (p<0.001) was observed. PMN adherence
      was enhanced by TNFalpha activation. PMN adhesion was decreased significantly
      (p<0.001) after the incubation of resting EC or TNFalpha-activated EC-seeded
      prostheses with a blocking monoclonal antibody (LYP20) directed against the P
      selectin. Such results suggest that: (1) PET prosthetic material may induce the
      expression of P-selectin by S-EC; (2) seeding conditions provoke an increase in
      PMN adhesion; (3) increased PMN interactions with seeded PET material is
      partially dependent upon P-selectin expression by the S-EC.

PMID- 10397917
TI  - Sol-gel-processed sintered silica xerogel as a carrier in controlled drug
      delivery.
AB  - Sol-gel-processed sintered silica xerogel was studied as a controllable,
      dissolvable, implantable material. The erosion of the matrix and the release of
      the preadsorbed drug toremifene citrate was investigated both in vitro and in
      vivo using mice. In an in vitro dissolution study, 50 to 60% of the drug was
      released after 24 h, according to the square root of time kinetics, and the
      weight loss of the silica was 24 wt %. Silica xerogel with tritium-labeled
      toremifene was implanted subcutaneously in mice for 56 days. To determine the
      amount of tritiated drug remaining in the silica disks at the implantation site,
      the disks were excised periodically and the radioactivity measured. About 40% of
      the radioactivity was released during the first 4 days and all of it within 28
      days. Radioactivity also was measured in the liver, lungs, kidneys, uterus, and
      blood. The radioactivity reached a maximum level after 4 days in the liver,
      kidneys, and lungs and slowly decreased until all of the drug had been released
      from the matrix after 28 days. After release of the drug (28 days) the amount of
      remaining silica xerogel implant was 45 wt %, and at the end of the study (56
      days) it was 24 wt %. In the histopathological study, sintered silica xerogel did
      not show any tissue toxicity at the site of the implantation, in the liver, or in
      the kidneys. It was concluded that sintered silica xerogel is a biocompatible and
      controllably resorbable material and therefore is a promising matrix for use in
      the sustained delivery of drugs.

PMID- 10397918
TI  - Healing of segmental bone defects in rats induced by a beta-TCP-MCPM cement
      combined with rhBMP-2.
AB  - A beta-tricalcium phosphate-monocalcium phosphate monohydrate (beta-TCP-MCPM)
      cement was evaluated as an effective carrier of recombinant human bone
      morphogenetic protein-2 (rhBMP-2) in rat femoral critical-size defects. Hard
      cement cylinders (4 x 5 mm) impregnated with two different doses of rhBMP-2 (1.26
      or 6.28 microg) were implanted into each defect, and the results were compared
      with those in rats that had implantations of cylinders only. Implantation of the
      6.28 microg dose of rhBMP-2 caused a large bone shell to form around the defect,
      resulting in osseous union in all cases within 3 weeks. Except for beta-TCP
      granules, the cement was resorbed and replaced by bone tissue at 6 weeks. A
      torsion test at 9 weeks showed that the failure torque and bone stiffness had
      recovered 99% and 141%, respectively, compared with the intact contralateral
      femur. The defects that received 1.26 microg of rhBMP-2 resulted in 40% union and
      41% of the failure torque at 9 weeks. However, no instances of union were
      observed in the defects implanted with cylinders only. In conclusion, the beta
      TCP-MCPM cement was shown to be effective as a rhBMP-2 carrier. Combined with
      rhBMP-2, this cement was rapidly resorbed and completely healed the defects.

PMID- 10397919
TI  - In vitro osteoblastic differentiation of human bone marrow cells in the presence
      of metal ions.
AB  - For periods up to 21 days human bone marrow was cultured in control conditions
      that favor the proliferation and differentiation of osteoblastic cells. The
      effect of AISI 316L corrosion products and the corresponding major separate metal
      ions (Fe, Cr, and Ni) were studied in three different phases of the culture
      period in order to investigate the effects of metal ions in cell populations
      representative of osteoblastic cells in different stages of differentiation.
      Toxicity consequences of the presence of metal ions in bone marrow cultures were
      evaluated by biochemical parameters (enzymatic reduction of MTT, alkaline
      phosphatase activity, and total protein content), histochemical assays
      (identification of ALP-positive cells and Ca and phosphates deposits), and
      observation of the cultures by light and scanning electron microscopy. Culture
      media were analyzed for total and ionized Ca and P and also for metal ions (Fe,
      Cr, and Ni). The presence of AISI 316L corrosion products and Ni salt in bone
      marrow cultures during the first and second weeks of culture significantly
      disturbs the normal behavior of these cultures, interfering in the lag phase and
      exponential phase of cell growth and ALP expression. However, the presence of
      these species during the third week of culture, when expression of osteoblastic
      functions occurs (mineralization process), did not result in any detectable
      effect. Fe salt also disturbs the behavior of bone marrow cell cultures when
      present during the lag phase and proliferation phase, and a somewhat compromised
      response between the normal pattern (control cultures) and intense inhibition
      (AISI 316L corrosion products and Ni salt-added cultures) was observed. Fe did
      not affect the progression of the mineralization phase. Osteogenic cultures
      exposed to Cr salt (Cr3+) presented a pattern similar to the controls, indicating
      that this element does not interfere, in the concentration studied, in the
      osteoblastic differentiation of bone marrow cells. Quantification of metal ions
      in the culture media showed that Cr (originated from AISI 316L corrosion products
      but from not Cr3+ salt) and Ni (originated from AISI 316L corrosion products and
      Ni salt) appear to be retained by the bone marrow cultures.

PMID- 10397920
TI  - Mechanical and morphological variation of the human lumbar vertebral cortical and
      trabecular bone.
AB  - The nanoindentation technique was used to characterize the variation in the
      elastic modulus and hardness of human lumbar vertebral cortical and trabecular
      bone. The elastic modulus (and in most cases, the hardness as well) of axially
      aligned trabeculae cut in the transverse direction was significantly greater than
      in other orientations of vertebral cortical and trabecular bone. In all cases,
      the elastic modulus and hardness of bone in the load-bearing direction was
      greater than in corresponding bone types cut in the other directions. Scanning
      electron micrographs of cortical shell revealed the Haversian-like canal systems
      expected in secondary cortical bone, but it was difficult to differentiate by
      morphology cortical from trabecular bone in the human lumbar vertebrae.

PMID- 10397921
TI  - Investigation of the mechanism of the bioacoustic effect.
AB  - Bacterial biofilms growing on implanted medical devices are difficult to
      eradicate, even with aggressive antibiotic therapy. However, application of
      ultrasound enhances the effectiveness of the antibiotic. The possible mechanisms
      of this phenomenon were explored in light of the observed influence of various
      ultrasonic parameters on the enhanced action of gentamicin against biofilms of
      Pseudomonas aeruginosa. It is postulated that ultrasound increases the transport
      of gentamicin through the cell membranes, which is the proposed rate determining
      step in killing by gentamicin. It is possible that the ultrasound perturbs the
      cell membrane and stimulates active uptake or permits passive uptake by
      temporarily disrupting the membrane or other structural cell components. The cell
      membrane disruption could be caused by high pressure, high shear stress, or
      cavitation. The dependence upon peak power density suggests that acoustic
      pressure plays a significant role. There is also a strong frequency component
      that causes the killing effect to decrease as frequency increases. A mathematical
      analysis of oscillatory shear stress on the cell shows that the magnitude of
      stress increases with frequency; thus, the hypothesis of oscillatory shear
      inducing antibiotic uptake is discounted. In addition, the shear displacement
      caused by shear forces is very small, so the shear disruption caused by
      oscillatory flow in an acoustic field has minimal impact. The experimental data
      also rule out the existence of transient cavitation in the bioacoustic effect. It
      is possible that stable cavitation and the accompanying microstreaming contribute
      to the bioacoustic effect.

PMID- 10397922
TI  - Effects of surface-coupled polyethylene oxide on human macrophage adhesion and
      foreign body giant cell formation in vitro.
AB  - Surface immobilized polyethylene oxide (PEO) has been shown to efficiently reduce
      protein adsorption and cellular adhesion, resulting in a biologically passive
      surface. To explore the in vitro effects of surface immobilized PEO on the human
      inflammatory cells, macrophages, and foreign body giant cells (FBGCs), we
      developed a diisocyanate-based method for coupling PEO to amine-modified glass, a
      surface previously shown to enhance macrophage adhesion and FBGC formation.
      Contact angle analysis and X-ray photoelectron spectroscopy confirmed the
      presence of PEO molecules bound to the surface and revealed that PEO molecular
      weight significantly influenced the efficiency of PEO coupling. We used a 10-day
      human monocyte culture protocol to demonstrate that the presence of surface
      coupled PEO molecules does not significantly decrease initial monocyte density or
      monocyte-derived macrophage density after 3 days. However, PEO-coupled surfaces
      significantly reduced long-term monocyte-derived macrophage density and virtually
      eliminated interleukin-4-induced FBGC formation observed at day 10. The cellular
      response to these PEO-coupled surfaces was related to the molecular weight of the
      PEO chains, which was varied between 200 Da and 18.5 kDa. These results suggest
      that an optimized PEO surface treatment may be effective in reducing inflammatory
      cell adhesion and possible degradation during the inflammatory response to an
      implanted biomedical device.

PMID- 10397923
TI  - Morphology and mechanical function of long-term in vitro engineered cartilage.
AB  - Cartilage tissue can be engineered in vitro with articular chondrocytes and
      poly(glycolic acid) nonwoven scaffolds as previously shown over 12 weeks in
      vitro. This study addressed whether engineered cartilage would further evolve and
      approach natural cartilage in extracellular matrix organization and biomechanical
      properties, especially aggregate modulus through longer term in vitro
      cultivation. Cellularity, cell size, compressive modulus, and permeability of the
      in vitro engineered cartilage stabilized within the 12-week cultivation time and
      remained at the same levels as those of natural cartilage thereafter. The linear
      range of the stress-strain curve was from 0 to a strain value between 5 and 10%
      for all the engineered cartilage tissues that were in vitro cultured for longer
      than 2 weeks, which was the same linear range for natural cartilage. The
      aggregate modulus further increased from week 12 to week 20 and remained
      approximately the same value thereafter during a 25-week in vitro cultivation.
      The aggregate modulus of the engineered cartilage reached 179+/-9 kPa after 20
      weeks of in vitro cultivation, which was 40% that of natural articular cartilage.
      To our knowledge this is the highest aggregate modulus value yet reported of any
      in vitro engineered cartilage tissue.

PMID- 10397924
TI  - Ellipsometric studies in vitro on kinetics of rat complement activation.
AB  - The role of complement activation may be important during the early interactions
      between implantable materials and blood and during the acute inflammatory phase,
      but it is not well understood. This applies especially to rats that are
      extensively used in in vivo animal models for materials and surface testing.
      Features of the kinetics of rat complement activation were studied and compared
      with human complement by the ellipsometry and antibody techniques. The results
      indicate that the rat classical pathway is rapidly activated, but it is not as
      fast as the human system. The activation of the alternative pathway was observed
      within 5 min in the rat system and within 15 min for the human. Thus, the
      observations indicate substantial differences in the kinetics between the two
      species. This may influence the choice of the rat experimental model and the
      tissue response to materials during in vivo conditions.

PMID- 10397925
TI  - Adsorption and coadsorption of water and glycine on TiO2.
AB  - Adsorption of water, ions, and biomolecules constitutes the first events
      occurring at biomaterial-biosystem interfaces. In this work, the adsorption and
      coadsorption of water and glycine on TiO2 were studied by thermal desorption
      spectroscopy (TDS). The first water monolayer desorbs in three peaks around 180K,
      300K, and 400K, which are assigned to water molecularly adsorbed at oxygen sites,
      at Ti4+ sites, and to recombination of dissociated water, respectively. A fourth
      desorption peak (160K), appearing at coverages > 0.8 monolayer, is attributed to
      water clusters and multilayers. The water-TiO2 interaction is changed if the
      surface is annealed in vacuum, which leads to increased hydroxylation. Desorption
      spectra from glycine overlayers evaporated on TiO2 in situ show that around 40%
      of the first monolayer desorbs as intact molecules ( approximately 300-450 K) and
      the remainder as dissociation fragments and surface reaction products around 600
      K. At coverages > 0.6 monolayers, intact molecules desorbing from cluster
      multilayers at 310 K are detected. The glycine desorption spectra are unaffected
      by coadsorbed water. In contrast, coadsorption of glycine displaces water from
      more strongly bound states in the monolayer to more weakly bound states and
      clusters, making the surface more hydrophobic. The study shows that TDS is a
      powerful method for characterizing biomaterial surfaces with regard to their
      interaction with biologically relevant molecules.

PMID- 10397926
TI  - Adhesion of new bioactive glass coating.
AB  - A valuable alternative to the existing biomedical implant coatings is a bioactive
      glass (BAG) coating that is produced by reactive plasma spraying. A mechanical
      performance requirement that is of the utmost importance is the adhesion strength
      of the coating. Considering the application as dental implant, a new adhesion
      test (shear test), which was close to the service conditions, was designed. A
      Ti6Al4V rod (3 mm) with a sprayed BAG coating of 50 microm was glued with an
      epoxy glue to a hollow cylindrical counterpart and was used as such in the
      tensile machine. This test was evaluated by finite element analysis (FEA).
      Preliminary experiments showed that a conversion from shear to tensile adhesion
      strength is possible by using the Von Mises criterion (sigma = 3(1/2)tau),
      indicating that thin coatings of brittle materials can behave as a ductile
      material. The new coating technique was proved to produce a high quality coating
      with an adhesion strength of 40.1 +/- 4.8 MPa in shear and 69.4 +/- 8.4 MPa in
      tension. The FEA revealed that no one homogeneously distributed shear stress is
      present but several nonhomogeneously distributed stress components (shear and
      tensile) are present in the coating. This analysis indicated that real service
      conditions are much more complicated than standard adhesion tests.

PMID- 10397927
TI  - Residence-time dependent changes in fibrinogen adsorbed to polymeric
      biomaterials.
AB  - It has generally been accepted that biomaterials adsorbing the least amount of
      the plasma protein fibrinogen following exposure to blood will support less
      platelet adhesion and therefore exhibit less thrombogenicity. Several studies
      suggest, however, that the conformation or orientation of immobilized fibrinogen
      rather than the total amount adsorbed plays an important role in determining the
      blood compatibility of biomaterials. The purpose of this study was to investigate
      time-dependent functional changes in fibrinogen adsorbed to
      polytetrafluoroethylene (PTFE), polyethylene (PE), and silicone rubber (SR).
      Fibrinogen was adsorbed to these materials for 1 min and then allowed to 'reside"
      on the surfaces for up to 2 h prior to assessing its biological activity. Changes
      in fibrinogen reactivity were determined by measuring the adhesion of 51Cr
      labeled platelets, the binding of a monoclonal antibody (mAb) directed against an
      important functional region of the fibrinogen molecule (the gamma-chain
      dodecapeptide sequence 400-411), and the ability of blood plasma to displace
      previously adsorbed fibrinogen. Platelet adhesion differed among the polymeric
      materials studied, and PTFE and PE samples exhibited a small decrease in adhesion
      with increasing fibrinogen residence time. Platelet adhesion to SR was the least
      among all materials studied and showed no variation with residence time. When
      using PTFE and SR as substrates, mAb recognition of adsorbed fibrinogen did not
      change with residence time whereas that on PE decreased slightly. The mAb binding
      was least to fibrinogen adsorbed to SR, which is in agreement with the platelet
      adhesion results. Finally, the ability of plasma to displace previously adsorbed
      fibrinogen decreased dramatically with increasing residence time on all
      materials. These in vitro studies support the hypothesis that fibrinogen
      undergoes biologically significant conformational changes upon adsorption to
      polymeric biomaterials, a phenomenon that may contribute to the hemocompatibility
      of the materials following implantation in the body.

PMID- 10397928
TI  - Tissue colonization from implantable biomaterials with low numbers of bacteria.
AB  - This study was undertaken to evaluate the risk of infection (defined as the
      recovery of the relevant organism from the implant site) in a mouse model when
      low numbers of bacteria were present on an implanted biomaterial. Segments of
      different types of suture with adherent bacteria were implanted subcutaneously
      into mice. The infection risk with Staphylococcus aureus was greater than with
      Staphylococcus epidermidis RP62A or Candida albicans. The infection risk with the
      implantation of multifilament sutures was significantly greater than with
      monofilament sutures. When <10 colony forming units (cfu) of S. aureus were
      present on monofilament suture material, the infection rate was 3%. When <10 cfu
      of S. aureus were present on multifilament suture material, the infection rate
      was 7%. An infection rate of 15% occurred with <10 cfu of S. aureus on
      multifilament nylon sutures. When >10 but <20 cfu of S. aureus were present, the
      infection rates were 4 and 51%, respectively. These data confirm that the
      infection rate with multifilament sutures (or porous materials) is greater than
      with monofilament sutures (or solid materials) when the organisms are encountered
      at implantation (acute model) and indicate that a significant risk of infection
      may occur when only a few organisms are on a device at implantation.

PMID- 10397929
TI  - Characterization of hydroxyapatite and titanium coatings sputtered on Ti-6Al-4V
      substrate.
AB  - A series of thin (<10 microm), single-layered HA/Ti coatings were deposited on Ti
      6Al-4V substrate using a radio frequency magnetron-assisted sputtering system.
      The adhesion strength, microstructure, and chemistry of the coatings were
      characterized. Experimental results showed that higher Ti contents in targets or
      coatings resulted in higher deposition rates. When Ti was added the highly
      crystalline structure of monolithic HA coating was largely disrupted and the
      coating became amorphous-like. The highly crystalline structure of the monolithic
      Ti coating was also disrupted by introducing small amounts of Ca, P, and O into
      the coating. The HA/Ti coatings had quite uniform thicknesses and appeared
      smooth, dense, and well bonded to the substrate. A scanning electron microscope
      with an energy dispersive spectroscopy system showed that monolithic HA,
      95HA/5Ti, 25HA/75Ti, and 50HA/50Ti coatings had the lowest Ca/P ratios while the
      75HA/25Ti coating had the highest. The adhesion strengths of all coatings were
      between 60 and 80 MPa.

PMID- 10397930
TI  - Bioengineering of elastic cartilage with aggregated porcine and human auricular
      chondrocytes and hydrogels containing alginate, collagen, and kappa-elastin.
AB  - Transplantation of isolated chondrocytes has long been acknowledged as a
      potential method for rebuilding small defects in damaged or deformed cartilages.
      Recent advances in tissue engineering permit us to focus on production of larger
      amounts of cartilaginous tissue, such as might be needed for reconstructive
      surgery of the entire auricle. In this report we describe modification of the
      basic techniques that lead to production of a large amount of elastic cartilage
      originated from porcine and human isolated chondrocytes. Small fragments of
      auricular cartilage were harvested from children undergoing ear reconstruction
      for microtia or extirpation of preauricular tags and from ears of juvenile pigs.
      Enzymatically isolated elastic chondrocytes were then agitated in suspension to
      form the chondronlike aggregates, which were further embedded in molded hydrogel
      constructs made of alginate and type I collagen augmented with kappa-elastin. The
      constructs were then implanted in nude mice and harvested 4 and 12 weeks after
      heterotransplantation. The resulting neocartilage closely resembled native
      auricular cartilage at the gross, microscopic, and ultrastructural levels.
      Immunohistochemistry and electron microscopy additionally confirmed that the
      newly produced cartilage contained the major components of the elastic cartilage
      specific matrix, including collagen type II, proteoglycans, and well-assembled
      elastic fibers.

PMID- 10397931
TI  - Flow cytometric study of in vitro neutrophil activation by biomaterials.
AB  - Neutrophil activation for adherent and nonadherent cells, as measured by flow
      cytometry, was not strongly dependent on material surface chemistry. We had
      hypothesized that material-induced neutrophil activation was an important
      parameter associated with material failure. All materials tested [cellophane, an
      acrylonitrile copolymer (AN69), Pellethane, nylon, polyethylene terephthalate,
      low density polyethylene, and polydimethylsiloxane] activated isolated human
      neutrophils, which were resuspended in plasma or serum, to similar extents based
      on L-selectin shedding, CD11b upregulation, and stimulation of the oxidative
      burst after 30-min exposure. Inhibition of complement activation by sCR1
      unexpectedly had little effect if any on nonadherent neutrophils. However,
      neutrophil adhesion, but not the level of activation of the adherent cells, was
      strongly dependent on complement activation. Pretreatment with albumin did not
      inhibit adhesion or reduce neutrophil activation, but plasma pretreatment
      resulted in increased activation for nonadherent and adherent cells. More
      adhesion and a higher level of activation of adherent cells was observed
      following pretreatment with fibrinogen, a ligand of CD11b. Taken together these
      results suggest that upon contact with a material, neutrophil activation may
      occur though mechanisms that are not mediated by complement. For example, the
      presence of plasma proteins such as fibrinogen at the interface may trigger
      activation and the release of other activating agents. Although the material
      differences are small, the extent of activation may be significant and warrant
      further study of the mechanism and consequences of that activation.

PMID- 10397932
TI  - Effects of photochemically immobilized polymer coatings on protein adsorption,
      cell adhesion, and the foreign body reaction to silicone rubber.
AB  - Photochemical immobilization technology was utilized to covalently couple
      polymers to silicone rubber either at multiple points along a polymer backbone or
      at the endpoint of an amphiphilic chain. The coating variants then were tested in
      vitro and in vivo for improvement of desired responses compared to uncoated
      silicone rubber. All coating variants suppressed the adsorption of fibrinogen and
      immunoglobulin G, and most also inhibited fibroblast growth by 90-99%. None of
      the coating variants inhibited monocyte or neutrophil adhesion in vitro. However,
      the surfaces that supported the highest levels of monocyte adhesion also elicited
      the lowest secretion of pro-inflammatory cytokines. None of the materials
      elicited a strong inflammatory response or significantly (p< 0.05) reduced the
      thickness of the fibrous capsule when implanted subcutaneously in rats. Overall,
      the most passivating coating variant was an endpoint immobilized polypeptide that
      reduced protein adsorption, inhibited fibroblast growth by 90%, elicited low
      cytokine secretion from monocytes, and reduced fibrous encapsulation by 33%. In
      general, although some coating variants modified the adsorption of proteins and
      the behavior of leukocytes or fibroblasts in vitro, none abolished the
      development of a fibrous capsule in vivo.

PMID- 10397933
TI  - Attachment of periosteal grafts to articular cartilage with fibrin sealant.
AB  - Favorable results using fibrin sealants in vascular surgery and soft tissue
      reconstruction have prompted investigation of these biologic adhesives for
      orthopedic applications. One important recent application was as a sealant for
      periosteal grafts applied to defects in articular surfaces, a procedure that
      contained injected chondrocytes cultured in vitro. The low and variable adhesive
      strength of autologous fibrin substances prompted our investigation of allogeneic
      fibrin. An in vitro test method was developed to investigate the use of a fibrin
      sealant for attaching periosteal (bovine) patches to articular cartilage
      (bovine). Dermis-dermis (porcine) adhesion also was evaluated. In tests of the
      periosteum-to-cartilage bond performed in a physiological environment, we
      determined the effects of the following variables on the adhesive shear strength:
      set time, source of fibrinogen (bovine versus human), and fibrinogen
      concentration. A specially designed test rig was developed to avoid nonshear
      force components. Adhesive shear strength increased with fibrin set time for both
      fibrinogen concentrations and sources (p <.03). The 30-min set time yielded data
      with less variance than the 5-min set time in all cases except with the higher
      human fibrinogen concentration (50-80 mg/mL). While there was a trend at each set
      time towards greater shear strength with increased protein concentration (50-80
      mg/mL versus 25-40 mg/mL), only the 5-min trial of the bovine product provided a
      significant advantage (p <.006). There was no significant difference in adhesive
      strength between the fibrin products produced with human and bovine fibrinogen.
      The periosteum-cartilage adhesive strengths obtained in our model were comparable
      to values recorded for the dermis-dermis bonding. The greater strength at the 30
      min set time suggests that a certain time period of joint immobilization might be
      beneficial in procedures in which grafts are glued to articular cartilage. This
      study has shown that adhesive strengths achieved with fibrin glues in treating
      skin wounds also can be achieved in the attachment of periosteal grafts to
      articular cartilage.

PMID- 10397934
TI  - Crosslinking characteristics of an injectable poly(propylene fumarate)/beta
      tricalcium phosphate paste and mechanical properties of the crosslinked composite
      for use as a biodegradable bone cement.
AB  - We investigated the crosslinking characteristics of an injectable composite paste
      of poly(propylene fumarate) (PPF), N-vinyl pyrrolidinone (N-VP), benzoyl peroxide
      (BP), sodium chloride (NaCl), and beta-tricalcium phosphate (beta-TCP). We
      examined the effects of PPF molecular weight, N-VP/PPF ratio, BP/PPF ratio, and
      NaCl weight percent on the crosslinking temperature, heat release upon
      crosslinking, gel point, and the composite compressive strength and modulus. The
      maximum crosslinking temperature did not vary widely among formulations, with the
      absolute values falling between 38 degrees and 48 degrees C, which was much lower
      than that of 94 degrees C for poly(methyl methacrylate) bone cement controls
      tested under the same conditions. The total heat released upon crosslinking was
      decreased by an increase in PPF molecular weight and a decrease in N-VP/PPF
      ratio. The gel point was affected strongly by the PPF molecular weight, with a
      decrease in PPF molecular weight more rapidly leading to a gel point. An increase
      in initiator concentration had the same effect to a lesser degree. The time frame
      for curing was varied from 1-121 min, allowing the composite to be tailored to
      specific applications. The compressive strength and compressive modulus values
      increased with decreasing N-VP/PPF, increasing NaCl content, and increasing
      BP/PPF ratio. For all formulations, the compressive strength values fell between
      1 and 12 MPa, and the compressive modulus values fell between 23 and 265 MPa.
      These data suggest that injectable PPF/beta-TCP pastes can be prepared with
      handling characteristics appropriate for clinical orthopedic applications and
      that the mechanical properties of the cured composites are suitable for
      trabecular bone replacement.

PMID- 10397935
TI  - Effects of neutral sodium hydrogen phosphate on setting reaction and mechanical
      strength of hydroxyapatite putty.
AB  - The setting reaction and mechanical strength in terms of diametral tensile
      strength (DTS) of hydroxyapatite (HAP) putty made of tetracalcium phosphate,
      dicalcium phosphate anhydrous, and neutral sodium hydrogen phosphate
      (Na1.8H1.2PO4) solution containing 8 wt % sodium alginate were evaluated as a
      function of the Na1.8H1.2PO4 concentration. In one condition, HAP putty was
      placed in an incubator kept at 37 degrees C and 100% relative humidity. In the
      other condition, immediately after mixing HAP putty was immersed in serum kept at
      37 degrees C. Longer setting times and lower DTS values were observed when HAP
      putty was immersed in serum regardless of the Na1.8H1.2PO4 concentration. The
      setting times of the HAP putty in both conditions became shorter with an increase
      in the Na1. 8H1.2PO4 concentration, reaching approximately 7-13 min when the Na1.
      8H1.2PO4 concentration was 0.6 mol/L or higher. The DTS value of HAP putty was
      relatively constant (10 MPa) regardless of the Na1.8H1. 2PO4 concentration (0.2
      1.0 mol/L) when HAP putty was kept in an incubator. In contrast, when HAP putty
      was immersed in serum, the DTS value was dependent on the Na1.8H1.2PO4
      concentration. It increased with the Na1.8H1.2PO4 concentration and reached
      approximately 5 MPa when the Na1.8H1.2PO4 concentration was 0.6 mol/L, after
      which it showed a relatively constant DTS value. We therefore would recommend a
      HAP putty that uses 0.6 mol/L Na1.8H1. 2PO4 since at that concentration the
      putty's setting time (approximately 10 min) is proper for clinical use and it
      shows good DTS value (approximately 5 MPa) even when it is immersed in serum
      immediately after mixing.

PMID- 10397936
TI  - Proliferation of endothelial cells on surface-immobilized albumin-heparin
      conjugate loaded with basic fibroblast growth factor.
AB  - Seeding of endothelial cells (ECs) on the luminal surface of small-diameter
      vascular grafts is a promising method to avoid occlusion of these prostheses.
      Immobilization of basic fibroblast growth factor (bFGF) to substrates used to
      coat or fill porous prostheses may enhance the formation of a confluent monolayer
      of ECs. Human umbilical vein endothelial cells (HUVECs) were grown on bFGF-loaded
      albumin-heparin conjugate bound to CO2 gas-plasma-treated polystyrene. In the
      order of 2-3 ng/cm2 bFGF had to be immobilized to form a confluent monolayer of
      HUVECs. The most prominent effect of surface-immobilized bFGF was stimulation of
      the proliferation shortly after seeding, resulting within 3 days in confluent
      cell monolayers with high density. In contrast, in cultures with 0.3 ng/mL bFGF
      in the medium instead of bFGF bound to the surface, it took almost a week before
      the cell layers reached confluency. Binding of bFGF to heparin and the biological
      activity of bFGF towards ECs were not influenced by the (radio-)labeling of bFGF
      with iodine. However, only a minor part of the bFGF used in this study displayed
      heparin affinity. Furthermore, degradation and multimerization of labeled bFGF in
      time occurred when the growth factor was stored at 20 degrees -37 degrees C. This
      limits the use of labeled bFGF to short-term (hours) experiments. In conclusion,
      bFGF loading of vascular graft surfaces through complexation of bFGF with a
      heparin-containing matrix probably will lead to more rapid formation of a
      confluent monolayer of ECs on graft surfaces upon seeding of the cells.

PMID- 10397937
TI  - Altered vitronectin receptor (alphav integrin) function in fibroblasts adhering
      on hydrophobic glass.
AB  - Function of integrins is crucial for adhesion, movement, proliferation, and
      survival of cells. In a recent study we found impaired fibronectin receptor
      function on hydrophobic substrata (G. Altankov et al. J Biomater Sci Polym Edn
      1997;8:712-740). Here, we have studied the distribution and function of the
      vitronectin receptor (alphav integrin) in fibroblasts adhering on hydrophilic
      glass and hydrophobic octadecyl glass (ODS). The morphology of fibroblasts and
      the organization of actin cytoskeleton were studied and found to be altered on
      ODS, where the cells did not spread and possessed condensed actin. Pretreatment
      of the surfaces with serum or pure vitronectin improved cell morphology on both
      substrata, resulting in the development of longitudinal actin stress fibers. It
      was found with biotinylated vitronectin that comparable quantities of vitronectin
      were adsorbed from single vitronectin solutions or serum on glass and on
      hydrophobic ODS. The organization of the vitronectin receptors on the ventral
      cell surface was investigated in permeabilized cells showing normal focal
      adhesions in fibroblasts plated on glass but none of these structures on ODS. The
      distribution of alphav integrin on the dorsal cell surface was studied on
      nonpermeabilized living cells after antibody tagging. While fibroblasts adhering
      on plain or serum-treated glass developed a linear organization of alphav
      integrin, cells on plain and serum-treated ODS were not able to reorganize the
      vitronectin receptor. Studies on signal transduction with antiphosphotyrosine
      antibodies revealed co-localization of alphav integrin and phosphotyrosine in
      focal adhesions on glass and serum-treated glass. However, signaling was almost
      absent on plain ODS and weak on serum-treated ODS. It was concluded that
      alterations in vitronectin receptor function on the ventral cell surface caused
      by the hydrophobic material surface inhibit signal transfer and subsequent
      intracellular events that are important for the organization and function of
      integrins.

PMID- 10397938
TI  - Early bone formation around calcium-ion-implanted titanium inserted into rat
      tibia.

PMID- 10397940
TI  - An investigation of the in vivo stability of poly(ether urethaneurea) blood sacs.
AB  - In this paper we investigate the biostability of a series of Biolon blood sacs
      that were utilized in electric total artificial hearts for time periods of up to
      19 weeks. A battery of experimental probes, including scanning electron
      microscopy (SEM) and X-ray photoelectron spectroscopy (XPS), were used to
      characterize the bulk and surface properties of explanted and control blood sacs.
      Gel permeation chromatography (GPC) experiments showed that generally there was a
      dramatic increase in average molecular weight at longer implantation times.
      However, SEM and GPC observations suggest significant deterioration of the flex
      regions of right blood sacs after 17 weeks of service. XPS experiments indicated
      appreciable silicon and hydrocarbon concentrations on blood-contacting surfaces
      both before and after implantation, and we speculate as to their origin.

PMID- 10397939
TI  - Control of attachment, morphology, and proliferation of skeletal myoblasts on
      silanized glass.
AB  - Generating skeletal muscle in vitro is an attractive approach to overcome
      problems associated with autologous transfer of muscle and donor site morbidity
      during plastic surgery. Such tissue engineering requires application of
      biomaterials that selectively control the attachment, morphology, and
      proliferation of muscle progenitor ("satellite") cells. This study examined the
      initial attachment, morphological characteristics, and proliferative behavior of
      murine C2C12 myoblasts on glass substrata derivatized with self-assembled
      monolayers (SAMs) of the organosiloxanes N-(2-aminoethyl)(3
      aminopropyl)trimethoxysilane (EDA) and tridecafluoro-1,1,2,2-tetrahydrooctyl-1
      dimethylchlorosil ane (13F). The fraction of myoblasts resisting detachment upon
      rinsing was greater on EDA than on 13F. Application of a quantitative moments
      based analysis of cell morphology demonstrated that projected area and two size
      invariant metrics of shape (extension and dispersion) for these cells were
      greater for EDA than for 13F. Myoblasts also proliferated faster on EDA than on
      13F. These data indicate that EDA-derivatized glass provides a superior
      substratum for myoblast culture compared to 13F-derivatized glass. Understanding
      myoblast behavior on these biomaterials that promotes contrasting cellular
      responses is the first step toward using patterned SAMs to control myotube
      alignment for tissue engineering skeletal muscle.

PMID- 10397941
TI  - Al2O3 doped apatite-wollastonite containing glass ceramic provokes osteogenic
      differentiation of marrow stromal stem cells.
AB  - Fresh marrow cells were obtained from femora of Fischer rats and cultured in a
      medium containing 15% fetal calf serum (FCS) until confluence. After
      trypsinization, cells were subcultured at a cell density of 100 x 10(3)/35-mm
      well in the presence of FCS, beta-glycerophosphate, and ascorbic acid phosphate
      on four different culture substrata. The period of subculture was 2 weeks; the
      substrata used were the culture dish, apatite-wollastonite containing glass
      ceramic (AW), hydroxyapatite coated AW (HA/AW), and Al2O3 doped AW (Al/AW). The
      HA coating was attained by the incubation of AW in simulated physiological
      solution. The glass matrix of AW and HA/AW contained MgO, CaO, P2O5, and SiO2;
      Al/AW contained Al2O3 in addition to these components. The subculture on Al/AW
      substratum showed many alkaline phosphatase (ALP) positive nodules and the
      highest ALP activity. On a Northern blot analysis the housekeeping gene of beta
      actin mRNA was evenly detected from the cells cultured on all substrata; however,
      bone-specific osteocalcin mRNA was only detected from the cells on Al/AW. These
      results indicate that Al/AW provokes the osteoblastic differentiation of marrow
      stromal stem cells.

PMID- 10397942
TI  - Effect of surface chemical modification of bioceramic on phenotype of human bone
      derived cells.
AB  - In the search for methods to improve the biocompatibility of prosthetic
      materials, attention has recently been directed toward the potential use of
      surface chemical modification and its influence on cellular behavior. This in
      vitro study investigates the effect of surface chemistry modification of
      bioceramics on human bone-derived cells (HBDCs) grown on biomaterial surfaces for
      2 weeks. Cells were cultured on either alumina (Al2O3), alumina doped with
      magnesium ions ([Mg]-Al2O3), or hydroxyapatite (HAP), as well as tissue culture
      polystyrene (TCPS). Expression of alkaline phosphatase (ALP), thrombospondin
      (Tsp), osteopontin (OP), osteocalcin (OC), osteonectin (ON/SPARC), type I
      collagen (Col I), and bone sialoprotein (BSP) were determined in terms of mRNAs
      and proteins. Protein levels for ALP, OP, OC, and BSP were significantly (p < 0.
      05) greater at day 5 in HBDCs cultured on [Mg]-Al2O3 compared to those cells
      grown on Al2O3. At day 14 the levels of ALP, Tsp, Col I, OP, ON/SPARC, and BSP
      rose significantly (p < 0.05) above those occurring in HBDCs grown on Al2O3, HAP,
      and TCPS. This suggests that HBDCs from the same patient respond to differences
      in the surface chemical groups. This study confirms that the chemistry of a
      substratum, which facilitates cellular adhesion, will enhance cellular
      differentiation.

PMID- 10397943
TI  - Crystallization of beta-estradiol in an acrylic transdermal drug delivery system.
AB  - Transdermal drug delivery systems are pharmaceutical products that can deliver
      controlled doses of drugs from polymeric patches applied on the human skin. The
      long-term stability of these patches is a critical issue relative to their
      performance in delivering drugs at a constant rate. Where a drug has been
      dissolved in the polymeric adhesive patch, crystallization has been reported in
      several systems. This study uses a variety of characterization tools to determine
      the physical and chemical nature of the precipitates formed in situ in estradiol
      patches. Optical microscopy revealed that crystals were formed in a single layer
      inside the adhesive matrix and that there were two distinctly different
      morphologies: needle-like crystals and aggregates around the needles. From IR
      measurements it was evident that estradiol probably was present in more than one
      crystal form in these patches. Raman microscopy showed that the needle-like
      crystals contain the adhesive component and the aggregates some modified crystal
      form of estradiol, indicating that in addition to the drug, the polymeric
      adhesive also crystallizes during storage.

PMID- 10397944
TI  - Three-dimensional nano-HAp/collagen matrix loading with osteogenic cells in organ
      culture.
AB  - Transplantation of osteogenic cells with a suitable matrix is one strategy for
      engineering bone tissue. Three-dimensional distribution and growth of cells
      within the porous scaffold are of clinical significance for the repair of large
      bony defects. A nano-HAp/collagen (nHAC) composite that mimics the natural bone
      both in composition and microstructure to some extent was employed as a matrix
      for the tissue engineering of bone. A porous nHAC composite was produced in sheet
      form and convolved to be a three-dimensional scaffold. Using organ culture
      techniques and the convolving method, we have developed three-dimensional
      osteogenic cells/nHAC constructs in vitro. Scanning electron microscopic and
      histological examination has demonstrated the development of the cells/material
      complex. Spindle-shaped cells migrating out of bone fragments continuously
      proliferated and migrated throughout the network of the coil. The porous nHAC
      scaffold provided a microenvironment resembling that seen in vivo, and cells
      within the composite eventually acquired a tridimensional polygonal shape. In
      addition, new bone matrix was synthesized at the interface of bone fragments and
      the composite.

PMID- 10397945
TI  - XRD, SEM-EDS, and FTIR studies of in vitro growth of an apatite-like layer on sol
      gel glasses.
AB  - A glass with a composition (in mole %) of: SiO2 (70), CaO (26), and P2O5 (4) was
      obtained using a sol-gel method. The in vitro bioactivity of the glass was
      assessed by determining the changes in surface morphology and composition after
      soaking in simulated body fluid (SBF) for periods of up to 14 days at 37 degrees
      C. X-ray diffraction, scanning electron microscopy, X-ray energy dispersive
      spectroscopy, and FTIR analyses of the glass surface after different soaking
      periods in SBF demonstrated the growth of an apatite-like layer on the glass
      surface. In the first stage, an amorphous calcium phosphate layer was formed;
      after 7 days this surface consisted of spheres, with diameters ranging between 2
      and 15 microm, composed of needle-like apatite crystallites (250 x 100 nm) with a
      crystallinity similar to that of a biological apatite.

PMID- 10397946
TI  - Chemical characterization of silicon-substituted hydroxyapatite.
AB  - Bioceramic specimens have been prepared by incorporating a small amount of
      silicon (0.4 wt %) into the structure of hydroxyapatite [Ca10(PO4)6(OH)2, HA] via
      an aqueous precipitation reaction to produce a silicon-substituted hydroxyapatite
      (Si-HA). The results of chemical analysis confirmed the proposed substitution of
      the silicon (or silicate) ion for the phosphorus (or phosphate) ion in
      hydroxyapatite. The Si-HA was produced by first preparing a silicon-substituted
      apatite (Si-Ap) by a precipitation process. A single-phase Si-HA was obtained by
      heating/calcining the as-prepared Si-Ap to temperatures above 700 degrees C; no
      secondary phases, such as tricalcium phosphate (TCP), tetracalcium phosphate
      (TeCP), or calcium oxide (CaO), were observed by X-ray diffraction analysis.
      Although the X-ray diffraction patterns of Si-HA and stoichiometric HA appeared
      to be identical, refinement of the diffraction data revealed some small
      structural differences between the two materials. The silicon substitution in the
      HA lattice resulted in a small decrease in the a axis and an increase in the c
      axis of the unit cell. This substitution also caused a decrease in the number of
      hydroxyl (OH) groups in the unit cell, which was expected from the proposed
      substitution mechanism. The incorporation of silicon in the HA lattice resulted
      in an increase in the distortion of the PO4 tetrahedra, indicated by an increase
      in the distortion index. Analysis of the Si-HA by Fourier transform infrared
      (FTIR) spectroscopy indicated that although the amount of silicon incorporated
      into the HA lattice was small, silicon substitution appeared to affect the FTIR
      spectra of HA, in particular the P-O vibrational bands. The results demonstrate
      that phase-pure silicon-substituted hydroxyapatite may be prepared using a simple
      precipitation technique.

PMID- 10397947
TI  - Polymorphonuclear cell apoptosis in exudates generated by polymers.
AB  - Flow cytometry was used to quantify apoptotic and necrotic polymorphonuclear
      (PMN) cells in an exudate generated by biomaterials, and the results were
      compared with determinations of spontaneous apoptosis and necrosis in PMN cells
      from the bloodstream. The exudate formed inside cylindrical tubes subcutaneously
      implanted in the dorsal region of rats was collected over a 1-week period. A
      rapid and simple staining procedure based on the spectral properties of the
      bisbenzemide Hoechst 33342 was used to identify apoptotic PMN cells.
      Quantification of permeabilized PMN cells stained by propidium iodide was
      possible in the same unfixed specimens. The percentages of apoptotic and
      permeabilized PMN cells in peripheral rat blood were low (1.8 +/-0 0.5% and 1.7
      +/- 0.7%, respectively), similar to results found in humans. In exudates
      generated by polyvinyl chloride (PVC), the percentages of apoptotic and
      permeabilized PMN cells were higher than in the blood. The percentage of PMN
      cells undergoing apoptosis progressively increased with time and reached a
      maximum at day 2 (27% +/- 6%). The percentage of permeabilized cells
      progressively increased with time and was much higher than the percentage of
      apoptotic cells on days 4 and 8. Apoptosis and necrosis of PMN cells at day 2
      were inhibited when tubes were filled with 10% serum. Selective inhibition of
      apoptosis with a caspase inhibitor in vivo indicated that apoptosis and necrosis
      are two separate pathways leading to the death of PMN cells in the exudate. At
      day 2, polyurethane (PU) was associated with a lower rate of apoptosis than PVC
      or a random copolymer of trimethylene carbonate (TMC) and epsiloncaprolactone
      (ECL). Apoptosis was interpreted as an organized cell removal process that limits
      inflammation. Apoptosis was the natural route of PMN cell death at the early
      stage of inflammation.

PMID- 10397948
TI  - ESR study of MMA polymerization by a peroxide/amine system: bone cement
      formation.
AB  - Electron spin resonance (ESR) spectroscopy was used to gain insight at the
      molecular level into the curing of bone cement. Methyl methacrylate was
      polymerized using a N,N-dimethyl-p-toluidine (TD)/benzoyl peroxide (BPO) redox
      system in the presence of polymethyl methacrylate (PMMA) powder. The conventional
      nine-line ESR spectrum for the growing polymer radical was detected at the gel
      stage of polymerization. While the optimum free radical concentration was
      observed near the equimolar amine/BPO concentration, excess amine led to a change
      in the chemical structure of the trapped radical and inhibited the polymerization
      process. At a high amine/BPO ratio the nine-line signal disappeared and a three
      line nitroxide-based radical appeared. The appearance of this nitroxide signal
      seems to depend on the amine/BPO molar ratio and on the presence of PMMA. An
      excess amount of amine with respect to BPO was found to inhibit the
      polymerization process. When BPO was removed, the system still polymerized but
      with a longer gelation time and a lower radical concentration. These results
      demonstrate that trapped free radicals in the bulk polymerization of MMA convert
      to polymeric peroxides that act as initiators in bone cement. When the
      accelerator 4-dimethylamino phenethyl alcohol (TDOH) was used, a higher radical
      concentration was observed in the polymerizing system. TDOH shows potential for
      being a more effective accelerator than TD for bone cement curing.

PMID- 10397949
TI  - Poly(alpha-hydroxyl acids)/hydroxyapatite porous composites for bone-tissue
      engineering. I. Preparation and morphology.
AB  - Tissue engineering has shown great promise for creating biological alternatives
      for implants. In this approach, scaffolding plays a pivotal role. Hydroxyapatite
      mimics the natural bone mineral and has shown good bone-bonding properties. This
      paper describes the preparation and morphologies of three-dimensional porous
      composites from poly(L-lactic acid) (PLLA) or poly(D,L-lactic acid-co-glycolic
      acid) (PLGA) solution and hydroxyapatite (HAP). A thermally induced phase
      separation technique was used to create the highly porous composite scaffolds for
      bone-tissue engineering. Freeze drying of the phase-separated polymer/HAP/solvent
      mixtures produced hard and tough foams with a co-continuous structure of
      interconnected pores and a polymer/HAP composite skeleton. The microstructure of
      the pores and the walls was controlled by varying the polymer concentration, HAP
      content, quenching temperature, polymer, and solvent utilized. The porosity
      increased with decreasing polymer concentration and HAP content. Foams with
      porosity as high as 95% were achieved. Pore sizes ranging from several microns to
      a few hundred microns were obtained. The composite foams showed a significant
      improvement in mechanical properties over pure polymer foams. They are promising
      scaffolds for bone-tissue engineering.

PMID- 10397950
TI  - Short-term effects of bisphosphonates on the biomechanical properties of canine
      bone.
AB  - Periprosthetic osteolysis and aseptic loosening of total joint replacements are
      believed to be initiated often by abnormal bone resorption induced by prosthetic
      wear debris. Bisphosphonates can inhibit bone resorption and have been
      successfully used clinically to treat osteoporosis and Paget's disease. In a
      recent study it also was shown that a third generation bisphosphonate
      (alendronate) is effective in preventing wear debris-induced periprosthetic
      osteolysis. Since inhibition of bone resorption by alendronate may disrupt the
      delicate balance between bone resorption and formation in normal bone remodeling,
      it is possible that continuous alendronate therapy may have an adverse effect on
      the biomechanical properties of bone. Thus the purpose of the present study was
      to examine the effects of systemic alendronate administration on the
      biomechanical properties of normal bone using a canine total hip arthroplasty
      model. We evaluated the biomechanical properties of femora from canines that had
      received total hip replacements on one side and had been given oral alendronate
      daily for 23 weeks. The biomechanical properties assessed were fracture
      toughness, elastic modulus, tensile strength, microhardness, porosity, and weight
      fractions of the mineral and organic phases of bone. Also, bone microstructure
      was examined using optical microscopy. Our results indicate that in the short
      term alendronate therapy does not have any adverse effects on the intrinsic
      biomechanical properties of canine bone. However, the long-term effects of
      alendronate therapy still need to be investigated.

PMID- 10397951
TI  - Implant-borne suture expansion in rabbits: a histomorphometric study of the
      supporting bone.
AB  - Osseointegrated implants have a large potential for diverse clinical
      applications, including support for sutural expansion and facial prostheses. The
      objectives of this study were to evaluate: (1) the histomorphometric response of
      thin cortical bone to implant placement and (2) whether loading of the bone
      surrounding these implants affects osseointegration as evaluated by
      histomorphometry. Eighteen New Zealand White rabbits had two titanium implants
      placed bilaterally in the anterior surface of their nasal bones. The rabbits were
      divided into an unloaded control group, one experimental group loaded at 1 Newton
      (N), and another loaded at 3 N. Fluorescent labels were used to mark areas of
      active bone formation. All rabbits were euthanized after 12 weeks of loading.
      Stereological point-hit and line-intercept methods were used to measure bone
      volume, direct bone-implant contact, new bone volume, and bone turnover rate in
      the bone surrounding the implants. All the implants remained stable during the
      loading period. A factorial ANOVA with repeated measures was used to compare the
      variables. The only significant difference among the three groups was a higher
      bone volume in the lateral coronal far region in the control group (p < 0. 05).
      Within all groups, bone volume (p < 0.002), turnover rate (p < 0.001), and
      percent of new bone (p < 0.05) were higher within 1 mm of the implant compared to
      1-3 mm away. This may be due to the increased stress and strain in the bone
      adjacent to the implant. This study indicates that there are no detrimental
      effects of loading on osseointegration when implants placed in the thin facial
      cortices are used as anchors for sutural expansion.

PMID- 10397952
TI  - Solution ripening of hydroxyapatite nanoparticles: effects on electrophoretic
      deposition.
AB  - Electrophoretic deposition is a low-cost, simple, and flexible coating method for
      producing hydroxyapatite (Hap) coatings on metal implants. However, densification
      requires heating the coated metal to high temperatures, which, for commercial HAp
      powders, generally means at least 1200 degrees C. At such temperatures, the metal
      tends to react with the HAp coating, inducing decomposition, and the strength of
      titanium and stainless steel implants is severely degraded. With the use of raw
      uncalcined nanoparticulate Hap, densification can occur at 900 degrees -1050
      degrees C; however, such coatings are prone to cracking due to the high drying
      shrinkage. This problem was solved by precipitating nanoparticulate HAp by the
      metathesis process [10Ca(NO3)2 + 6NH4H2PO4 + 8NH4OH] and optimizing the
      approximately 30 nm of nanoprecipitates by an Ostwald ripening approach, that is,
      by boiling and/or ambient aging in the mother liquor. While the as-precipitated
      nanoparticles produced severely cracked coatings, 2 h of boiling or 10 days of
      ambient aging ripened the "gel-like" mass into unagglomerated nanoparticles,
      which produced crack-free coatings. Since boiling enhanced particle size but
      ambient aging did not, crack elimination probably was due to the transition from
      the highly agglomerated gel-like state to the dispersed nanoparticulate state
      rather than to particle growth. Furthermore, boiling only reduced the amount of
      cracking whereas aging completely eliminated cracking.

PMID- 10397953
TI  - Bioadhesion of gelatin films crosslinked with glutaraldehyde.
AB  - The present study was carried out in an attempt to make a gelatin film strongly
      bioadhesive by introducing free dangling aldehyde groups. When gelatin films were
      treated with 0.5M of glutaraldehyde (GA) solution at 60 degrees C, free aldehyde
      groups (up to 150 micromol/g) were introduced in the film. The bonding strength
      of GA-crosslinked gelatin films (GA gelatin films) with biological tissue was
      assessed using porcine skins. It was found that bonding strength increased with
      increasing aldehyde content in the film. The GA gelatin films had bonding
      strength as high as 250 gf/cm2 whereas the native gelatin film (before GA
      treatment) showed bonding strength of 40 gf/cm2. When the aldehyde groups
      introduced in the gelatin films were quenched with glycine or reduced by NaBH4,
      the films no longer demonstrated such high bonding strength. These facts suggest
      that a Schiff base was formed between the free dangling aldehyde in the GA
      gelatin films and the amino groups of the natural tissue, which strongly
      contributed to a marked bioadhesion.

PMID- 10397954
TI  - Experimental study of ectopic-free tissue transfer of rabbit epigastric flap
      using small-caliber vascular grafts.
AB  - Ectopic intraperitoneal free-tissue grafting using small-caliber artificial
      vascular grafts is reported. The vascular grafts were polyurethane tubes (inner
      diameter 1.4 mm; outer diameter 1.9 mm; length 15 mm) with a coating of the
      antithrombotic agents argatroban and 2-hydroxyethylmethacrylate-styrene block
      copolymer (HS)on the inner surface. The patency of the artificial vessels was
      investigated in an ectopic-free rabbit epigastric flap in which grafts were used
      for anastomosis between the femoral and renal vessels. The mean patent duration
      of uncoated controls (n = 10) was 128 +/- 37 min. Flap viability after one week
      (n = 17) and the patency of the coated grafts were investigated histologically.
      The flap take rate was 65%, the arterial graft patency rate 41%, and the venous
      graft patency rate 24%. The HS-treated surface combined with the argatroban slow
      release system exhibited improvement of flap survival in an intraperitoneal
      ectopic -free grafting model.

PMID- 10397955
TI  - The role of recombinant human bone morphogenetic protein-2 in PLGA capsules at an
      extraskeletal site of the rat.
AB  - Bone morphogenetic protein-2 (BMP-2) is a member of the transforming growth
      factor-beta (TGF-beta) superfamily and has strong bone-inductive activity in
      vivo. To examine the role of BMP-2 in an extraskeletal site of rat using a
      controlled release system of peptides, we encapsulated the recombinant human BMP
      2 (rhBMP-2) with poly(DL-lactide-co-glycolide) (PLGA) and implanted the rhBMP
      2/PLGA capsules in the subcutaneous area of rats. Upon histochemical examination,
      it was found that bone-inducing cells having alkaline phosphatase (ALP) activity
      appeared around the capsules by the suitably released rhBMP-2. In addition, the
      temporal histological examination showed that direct bone formation without
      cartilage occurred in the process of this ectopic bone induction. These data
      indicate that the role of rhBMP-2 in the extraskeletal site of rats is to induce
      the differentiation of mesenchymal cells into the osteoblasts.

PMID- 10397956
TI  - Effect of nitinol implant porosity on cranial bone ingrowth and apposition after
      6 weeks.
AB  - The present study addresses two aspects of the use of nitinol in cranial bone
      defect repair. The first is to verify that there is substantial bone ingrowth
      into the implant after 6 weeks; the second is to determine the effect of pore
      size on the ability of bone to grow into the implant during the early (6-week)
      postoperative period. Porous equiatomic (equal atomic masses of titanium and
      nickel) nickel-titanium (nitinol) implants with three different morphologies
      (differing in pore size and percent porosity) were implanted for 6 weeks in the
      parietal bones of New Zealand White rabbits. Ingrowth of bone into the implants
      and apposition of bone along the exterior and interior implant surfaces were
      calculated. The mean pore size (MPS) of implant type #1 (353 +/- 74 microm)
      differed considerably from implant types #2 (218 +/- 28 microm) and #3 (178 +/-
      31 microm). There was no significant difference among implant types in the
      percentages of bone and void/soft tissue composition of the aggregate implants.
      The amount of bone ingrowth also was not significantly different among the
      implant types. Implant #1 was significantly higher in pore volume and thus had a
      significantly higher volume of ingrown bone (2.59 +/- 0.60 mm3) than implant #3
      (1. 52 +/- 0.66 mm3) and a greater amount, but not significantly greater, than
      implant #2 (1.76 +/- 0.47 mm3). Pore size does not appear to affect bone ingrowth
      during the cartilaginous period of bone growth in the implant. This implies that
      within the commonly accepted range of implant porosities (150-400 microm), at 6
      weeks bone ingrowth near the interface of nitinol implants is similar.

PMID- 10397957
TI  - Elastic properties of microstructural components of human bone tissue as measured
      by nanoindentation.
AB  - The elastic properties of several microstructural components of dry human
      vertebrae (T-12 and L-1) and tibiae have been investigated in the longitudinal
      and transverse directions using nanoindentation. The largest Young's modulus was
      that for the interstitial lamellae in the longitudinal direction (25.7 +/- 1.7
      GPa). This was followed in decreasing order by osteons in the longitudinal
      direction (22.4 +/- 1.2 GPa), trabeculae in the longitudinal direction (19.4 +/-
      2.3 GPa), an average over osteons and interstitial lamellae in the transverse
      direction [16.6 +/- 1.1 GPa (it was difficult to microstructurally distinguish
      osteons from interstitial lamellae in the transverse direction)], and trabeculae
      in the transverse direction (15.0 +/- 2.5 GPa). An ANOVA statistical analysis
      revealed that the values all are significantly different (p < 0.05). Since the
      elastic moduli in the longitudinal direction are all greater than in the
      transverse, measurable elastic anisotropies exist in the components. The
      hardnesses also varied among the microstructural components in the range 0.52
      0.74 GPa.

PMID- 10397958
TI  - Fibrinogen adsorbs from aqueous media to microscopic droplets of
      poly(dimethylsiloxane) and remains coagulable.
AB  - Fibrinogen binds from aqueous media containing it to droplets of linear
      trimethylsilyl-terminated poly(dimethylsiloxane) (PDMS) dispersed in those same
      media. Once bound, fibrinogen elutes from emulsified droplets of PDMS only very
      slowly, even when incubated in buffer that contains a physiologic concentration
      of the protein. The bound fibrinogen is coagulable, as indicated by the thrombin
      dependent agglutination of droplets. Thus fibrinogen bound to droplets of PDMS
      renders an adhesive potential to the surface of the droplets, a potential that
      may have relevance to the biologic processing of the polymer in vivo.

PMID- 10397959
TI  - Synergistic effects of oxidative environments and mechanical stress on in vitro
      stability of polyetherurethanes and polycarbonateurethanes.
AB  - The in vitro structural stability of polyetherurethanes (PEUs) and
      polycarbonateurethanes (PCUs and PCUUs) was examined under strong oxidative
      conditions (0.5N HNO3, pH 0.3; and NaClO, 4% Cl2 available, pH approximately 13)
      and in the presence of a constant strain state. Solvent-cast dog-bone shaped
      specimens were strained at 100% uniaxial elongation over extension devices and
      completely immersed in the oxidative solutions at 50 degrees C for 15 days.
      Unstrained polyurethane (PU) samples were treated in the same way for comparison.
      The modification of the PU molecular structure was determined by DSC, GPC, ATR
      FTIR, static contact angle, and surface roughness analyses. The incubation in
      nitric acid and sodium hypochlorite brought about a greater degradation of
      samples tested under the applied strain with the exception of PEU treated with
      nitric acid. PEU was the most affected material, showing bulk deterioration in
      NaClO and significant modifications in nitric acid, with the appearance of new IR
      bands, which were assigned to oxidation products. A higher phase separation
      between soft and hard domains occurred in PCUs upon incubation in nitric acid,
      the treatment with NaClO gave rise to new bands in the IR spectra, denoting the
      presence of oxidation products at the surface. The surface roughness greatly
      increased in strained PCUs with SEM evidence of deep cracks and holes or ragged
      and stretched fractures perpendicular to the direction of stress. PCUU underwent
      complex chemical modifications with a marked decrease of N-H and urea IR
      absorptions and showed a lower degradation than PEU and PCUs under mechanical
      constraint. From these results, sodium hypochlorite appears to be able to create
      an ESC-like degradation for PUs that are resistant to other aggressive chemical
      environments.

PMID- 10397960
TI  - Interface shear strength of titanium implants with a sandblasted and acid-etched
      surface: a biomechanical study in the maxilla of miniature pigs.
AB  - The purpose of the present study was to evaluate the interface shear strength of
      unloaded titanium implants with a sandblasted and acid-etched (SLA) surface in
      the maxilla of miniature pigs. The two best documented surfaces in implant
      dentistry, the machined and the titanium plasma-sprayed (TPS) surfaces served as
      controls. After 4, 8, and 12 weeks of healing, removal torque testing was
      performed to evaluate the interface shear strength of each implant type. The
      results revealed statistically significant differences between the machined and
      the two rough titanium surfaces (p <.00001). The machined surface demonstrated
      mean removal torque values (RTV) between 0.13 and 0.26 Nm, whereas the RTV of the
      two rough surfaces ranged between 1.14 and 1.56 Nm. At 4 weeks of healing, the
      SLA implants yielded a higher mean RTV than the TPS implants (1.39 vs. 1. 14 Nm)
      without reaching statistical significance. At 8 and 12 weeks of healing, the two
      rough surfaces showed similar mean RTVs. The implant position also had a
      significant influence on removal torques for each implant type primarily owing to
      differences in density in the periimplant bone structure. It can be concluded
      that the interface shear strength of titanium implants is significantly
      influenced by their surface characteristics, since the machined titanium surface
      demonstrated significantly lower RTV in the maxilla of miniature pigs compared
      with the TPS and SLA surfaces.

PMID- 10397961
TI  - Comparative experimental study of esophageal wall regeneration after prosthetic
      replacement.
AB  - This study compares three prosthetic materials for potential use in patching and
      bridging congenital and acquired esophageal defects. The study was divided into
      two parts. In the first part, full-thickness, 6-cm2 cervical esophageal defects
      were induced in three groups of young mongrel dogs and were replaced with patches
      of lyophilized dura mater (Lyodura), polyethylene terephthalate (Dacron), or
      expanded polytetrafluoroethylene (PTFE). The dogs in the Lyodura subgroup were
      scheduled to be sacrificed after 1, 2, 4, 8, and 12 weeks and the dogs in the
      PTFE and Dacron subgroups were sacrificed after 1, 2, 3, 4, 6, and 7 months. The
      patched esophagus was removed for gross and microscopic examination. In the
      second part of the study a segment of the esophagus was excised in another three
      groups of dogs and replaced with 3 x 2 cm tubes of Lyodura, Dacron, or PTFE. Here
      the follow-up was prolonged and included radiological, endoscopic, and
      histological assessment. The dogs of each subgroup were scheduled to be
      sacrificed after 6, 8, and 12 months. Results indicated that lyophilized dura
      mater covered and neoepithelialized the patched area within the shortest period
      of time without foreign body reaction and with only slight collagen deposit,
      resulting in a ductile repaired esophageal wall. Therefore, its use may be
      considered for replacement of partial esophageal defects. For complete
      circumferential defects, the present study and our review of the literature
      showed that there is as yet no ideal prosthetic material that promotes good
      incorporation but is not prone to stenosis. Further studies in this area are
      required.

PMID- 10397962
TI  - Dissolution of synthetic hydroxyapatite in the presence of acidic polypeptides.
AB  - This article deals with the effect of two acidic polypeptides [polyaspartic acid
      (PA) and polyglutamic acid (PG)] onto hydroxyapatite (HAP) dissolution by
      separately considering their influence when they are present only at the HAP
      interface and when they are both adsorbed and present in the bulk solution. We
      first determined the amount of adsorbed PA and PG at pH 7.0 and 5.0 onto 10 mg of
      HAP. Dissolution experiments were performed at pH 5.0 under pH stat conditions by
      continuously following the consumed protons and released calcium versus time with
      the aid of specific electrodes. The released phosphate ions were determined by
      spectrophotometric analysis. The data show that, because of their calcium
      chelating properties, the polypeptides act as a driving force for HAP dissolution
      when PA and PG remain present in solution and the interfacial beneficial effect
      of the adsorbed peptides is erased by the chelating properties of PA and PG
      present in the solution. When the polypeptides are only adsorbed at the
      interface, even if a partial PA or PG desorption occurs, HAP dissolution
      inhibition is still observed.

PMID- 10397963
TI  - Graded surface structure of bioactive titanium prepared by chemical treatment.
AB  - An NaOH treatment of pure titanium (Ti) forms a sodium titanate hydrogel surface
      layer with a smooth graded interface structure to the Ti metal substrate.
      Subsequent heat treatment at 600 degrees C of the NaOH-treated Ti forms an
      amorphous sodium titanate surface layer with a smooth graded interface structure
      similar to the Ti metal substrate. These treated Ti metals both form an apatite
      surface layer with a smooth graded interface structure to the Ti metal substrates
      in simulated body fluid (SBF). The smooth graded interface structures give a
      tight bond of the apatite layer to the substrates. Heat treatment at 800 degrees
      C of the NaOH-treated Ti forms crystalline sodium titanate and a rutile surface
      layer with a graded interface structure to the Ti metal substrate, which is
      intervened by a thick titanium oxide. This substrate forms an apatite layer with
      a graded interface structure to the Ti metal substrate, which is intervened by a
      thick titanium oxide in SBF. This irregular graded structure gives a less tight
      bond of the apatite layer to the substrate.

PMID- 10397964
TI  - The role of collagen in the declining mechanical properties of aging human
      cortical bone.
AB  - The importance of the mechanical role of collagen in bone is becoming
      increasingly more clear as evidence mounts on the detrimental effects of altered
      collagen on the mechanical properties of bone. We previously examined a set of
      mechanical properties (material stiffness, strength, and toughness) of human
      femoral bone (ages 35-92) and found that a gradual deterioration in these
      properties occurs with age. The present study examines the collagen of the same
      specimens and relates the collagen properties to the mechanical ones. In the
      collagen we measured the concentration of stable mature crosslinks, the shrinkage
      temperature, and the rate of contraction during isometric heating. The changes in
      the concentration of mature (pyridinium and deoxypyridinium) crosslinks showed no
      clear relationship to age nor did they correlate with the mechanical properties.
      The shrinkage temperature declined with age and correlated with a bone's
      toughness. The maximum rate of contraction was strongly correlated with three
      different measures of tissue toughness, but much less to stiffness and strength.
      Our results reinforce speculation regarding the toughening role of collagen in
      bone mechanics and suggest that the fragility of aging bone may be related to
      collagen changes.

PMID- 10397965
TI  - Characterization of cellular response to thiol-modified gold surfaces implanted
      in mouse peritoneal cavity.
AB  - The early inflammatory reaction in vivo to three well defined surfaces-gold, gold
      coated with glutathione (GSH), and 3-mercapto-1, 2-propanediol (MG)-was assessed
      as manifested by the adherence and activation of inflammatory cells during
      implantation intraperitoneally in mice. Evaluation of cell adhesion and
      activation was done by immunohistochemistry using specific monoclonal antibodies
      directed against cell differentiation antigens CD11b/CD18, CD74, and CD25 or by
      measurement by chemoluminescence of reactive oxygen radical species produced by
      adhering cells. Cell recruitment and activation was slow on the GSH-coated gold
      surfaces. These surfaces also had the highest percentage of adhering cells with
      an intact cell membrane. The MG-coated surfaces, on the other hand, rapidly
      recruited and activated cells and also caused cell membrane leakage to propidium
      iodide, suggesting cell membrane damage or cell death. The respiratory burst of
      adhering cells was stimulated by phorbol-myristate acetate on the GSH-coated
      surface but not on the MG-coated surface and by opsonized zymosan on the Mg
      coated surface but only to a small degree on the GSH-coated surface. The
      respiratory burst following zymosan activation of cells adhering to the MG-coated
      surface was inhibited by treatment with 2. 3-diphosphoglycerate, a phospholipase
      D inhibitor. The presented data suggest that peritoneal leukocytes adhering to
      foreign materials may raise a respiratory burst response via a phospholipase D
      dependent and protein kinase C-independent pathway.

PMID- 10397966
TI  - Preparation and characterization of alpha-amylase-immobilized thermal-responsive
      composite hydrogel membranes.
AB  - Composite hydrogel membranes of crosslinked poly(N-isopropylacrylamide-co-N
      acryloxysuccinimide-co-2-hydroxyet hyl methacrylate) [P(NIPAAm-NAS-HEMA)] with
      starch, as a macropore forming agent, on nonwoven polyester was prepared. The
      membranes could swell and de-swell around the characteristic lower critical
      solution temperature (LCST) of poly(N-isopropylacrylamide) (PNIPAAm). It was
      demonstrated that the presence of macropores in the membranes could improve the
      immobilization efficiency as well as lead to a short responding time upon
      temperature change across the LCST. Immobilized alpha-amylase could retain as
      high as 33% of the activity of the free enzyme with a loading level of 0.60-0.65
      mg/cm2 when the membrane preparation and enzyme immobilization conditions were
      optimized. The half time (T0.5) for the swelling or de-swelling response of the
      gel phase within the membranes was less than 2 min, and the 90% time (T0.9) was
      less than 6 min. The permeability for maltose through the membranes could change
      as much as 4.9-fold when the temperature was raised above or reduced below the
      LCST.

PMID- 10397967
TI  - Preparation of poly(acrylic acid) modified polyurethane membrane for biomaterial
      by UV radiation without degassing.
AB  - Poly(acrylic acid) modified polyurethane (AA/PU) membranes were prepared by UV
      radiation without degassing. The chemical composition of the AA/PU membrane was
      studied by IR spectroscopy. In addition to those absorption peaks associated with
      pure PU, the absorption peak at 2400 cm-1 of poly(AA) was also found. The
      morphology of AA/PU membrane was studied by optical polarizing microscopy. We
      also measured the glass transition temperature and the decomposition temperature
      of the AA/PU membrane by differential scanning calorimetry and thermogravimetric
      analysis. A significant domain was found in the AA/PU membrane, which resulted in
      different glass transition temperature and decomposition temperature between
      AA/PU and pure PU membrane. The effect of AA content on the contact angle and
      water absorption of the AA/PU membrane was determined. It was found that the
      water content of AA/PU membrane increased with increasing AA content, whereas the
      contact angle decreased. By using Kaeble's equation and the contact angle data,
      the surface free energy of AA/PU membrane was determined. The increase of surface
      free energy resulted from the increase of the dispersion (gammad) term and polar
      (gammap) term. In order to evaluate the biocompatibility of these membranes, a
      cytotoxicity test and a cell adhesion and proliferation assay were conducted in
      cell culture. Immortal cells and primary lymphocytes were both used in this
      study. The results showed that these AA/PU membranes exhibited very low
      cytotoxicity and could support cell adhesion and growth. An animal primary test
      was also done in this study. It was found that the AA/PU membrane could possibly
      be employed in the treatment of bowel defect.

PMID- 10397968
TI  - Osteoclast adhesion and activity on synthetic hydroxyapatite, carbonated
      hydroxyapatite, and natural calcium carbonate: relationship to surface energies.
AB  - This study investigates the adhesion, cytoskeletal changes, and resorptive
      activity of disaggregated rat osteoclasts cultured on polished slices of three
      biomaterials: crystalline synthetic hydroxyapatite (HA), carbonated
      hydroxyapatite (C-HA), and natural calcium carbonate (C). The surface chemistry
      of each substrate was defined by X-ray diffraction and IR spectroscopy, surface
      wettability by the dispersive, and the polar components of the surface energies.
      Osteoclast adhesion was modulated by the polar component of the surface energy:
      fewer (p < 0.01) osteoclasts adhered to C-HA (97 +/- 20/slice, surface energy 9
      +/- 5 mJ/m2) than to HA (234 +/- 16/slice, surface energy 44 +/- 2 mJ/m2) or to C
      (268 +/- 37/slice, surface energy 58 +/- 0.5 mJ/m2). Actin rings, which are the
      cytoskeletal structure essential for resorption, developed on all three
      materials. The area of the actin ring, which is resorbed by local acidification,
      and the osteoclast area, which reflects osteoclast spreading, were both greater
      in osteoclasts cultured on HA and C-HA than in those cultured on C. C was
      resorbed, but HA and C-HA were not. Thus, the surface energy plays an essential
      role in osteoclast adhesion, whereas osteoclast spreading may depend on the
      surface chemistry, especially on protein adsorption and/or on newly formed
      apatite layers. Resorption may be limited to the solubility of the biomaterial.

PMID- 10397969
TI  - Spatial regulation and surface chemistry control of monocyte/macrophage adhesion
      and foreign body giant cell formation by photochemically micropatterned surfaces.
AB  - A long-standing goal of biomedical device development has been the generation of
      specific, desired host blood and tissue responses. An approach to meeting this
      design criteria is precise surface modification that creates micropatterns of
      distinct physicochemical character to direct cell adhesion and behavior. For this
      study, poly(ethylene terephthalate) films were coated with poly(benzyl N, N
      diethyldithiocarbamate-co-styrene) and sequentially exposed to monomer solutions
      for photoirradiation. A photomask was placed over different regions to generate
      micropatterned surfaces with graft polymer stripes of three distinct ionic
      characters. Human monocytes were cultured on these surfaces to ascertain whether
      adhesion and fusion of monocytes/macrophages could be controlled. Nonionic
      polyacrylamide greatly inhibited adhesion and induced clumping of the few
      monocytes that did adhere. Macrophage adhesion and spreading led to high degrees
      of interleukin-13 induced foreign body giant cell formation on both the anionic
      poly(acrylic acid), sodium salt, and benzyl N,N-diethyldithiocarbamate portions
      of the culture surface. In spite of the highest observed levels of
      monocyte/macrophage adhesion on cationic poly(dimethylaminopropylacrylamide),
      methiodide, the adherent cells were not competent to undergo fusion to form
      foreign body giant cells. These results suggest that inflammatory cell responses
      may be spatially controlled in a manner that may be ultimately exploited to
      improve the biocompatibility of medical devices.

PMID- 10397970
TI  - Blood compatibility of TiO films.

PMID- 10397971
TI  - alpha-smooth muscle actin and contractile behavior of bovine meniscus cells
      seeded in type I and type II collagen-GAG matrices.
AB  - Many types of injuries to the meniscus of the knee joint result in defects that
      do not heal, leading to pain and dysfunction. Several ongoing investigations are
      developing porous absorbable matrices to be used alone or seeded with cultured
      cells to facilitate regeneration of this tissue. The objective of this study was
      to evaluate in vitro the contractile behavior of meniscal cells seeded in type I
      and type II collagen matrices. In many connective tissues, fibroblasts that have
      assumed a contractile phenotype (myofibroblasts) have been found to play an
      important role in healing and in pathological conditions. This phenotype, if
      expressed by meniscal cells, could affect their behavior in cell-seeded matrices
      developed for tissue engineering. In this study, the presence of a contractile
      actin isoform, alpha-smooth muscle (alpha-SM) actin, was assessed by
      immunohistochemistry in normal calf meniscal tissue and in meniscal cells in 2-
      and 3-dimensional culture. Calf meniscus cells were seeded in type I and type II
      collagen-glycosaminoglycan (GAG) matrices. The diameter of the matrices was
      measured every 2-3 days. Immunohistochemical staining of the 2-dimensional
      cultures for alpha-SM actin was performed after 1, 3, and 7 days and the staining
      of the seeded matrices was at 1, 7, 14, and 21 days. Transmission electron
      microscopy (TEM) was performed on selected samples. After 3 weeks the seeded type
      I matrices displayed a significant shrinkage of almost 50% whereas the type II
      matrix and both types of unseeded controls showed almost no contraction over the
      same time period. Positive staining for the alpha-SM actin phenotype was seen in
      10% of the cells of the normal tissue but was present in all cells seeded in
      monolayer and in both types of matrices. TEM of representative cell-seeded
      matrices showed microfilaments approximately 7 nm thick, consistent with the
      myofibroblast phenotype. This is the first report of alpha-SM actin containing
      cells in the knee meniscus. The finding that, under certain conditions, meniscal
      cells can express the myofibroblast phenotype warrants study of their role in
      meniscal healing and the tissue response to implants to facilitate tissue
      regeneration.

PMID- 10397972
TI  - Intermolecular force mapping of platelet surfaces on collagen substrata.
AB  - The interactions between plasma proteins and platelets are responsible for
      surface adsorption and activation of platelets, which leads to initiation of
      platelet-mediated thrombotic events at biomaterial surfaces. We are seeking to
      gain a fundamental understanding of these interactions. The atomic force
      microscope (AFM) has been used to create force maps across platelets adsorbed
      onto collagen substrata using peptide-modified probes. Combining the imaging and
      force-measuring capabilities of AFM, the force-mapping mode has been used to
      measure interactions of peptide-modified AFM probes with the surface. Observed
      differences in the force of adhesion are clearly evident in the platelet samples
      fixed in air, proving the ability of the AFM system to map adhesion. When this
      system is changed to a fluid environment we are no longer able to see such
      evident adhesion because of the membrane flexibility; instead the deformability
      of the surface is mapped. The specific interaction between the peptide sequence
      RGD and platelets was measured in a non-mapping mode of the AFM. Although this
      does not provide a force map, we can see significant differences between the
      forces measured on the substrate and those measured with a control hexapeptide.

PMID- 10397973
TI  - Matrix metalloproteinases and tissue inhibitors of metalloproteinases in joint
      fluid of the patients with loose artificial hip joints.
AB  - The pseudojoint cavity formed in patients undergoing total hip arthroplasty (THA)
      is later remodeled to synovial membrane-like tissue, which produces
      pseudosynovial fluid. This pseudosynovium also is an important source of matrix
      metalloproteinases (MMPs). As it is widely speculated that synovial fluid MMPs
      may contribute to local tissue degradation in rheumatoid arthritis (RA) and
      osteoarthritis (OA), we hypothesize that locally produced MMPs are found in the
      pseudosynovial fluid, via which they have access to the implant-host interface,
      and that if they retain their proteolytic potential, they might contribute to
      aseptic loosening. Enzyme-linked immunosorbent assay (ELISA), immunoblotting, and
      zymography were used to analyze MMPs and tissue inhibitors of metalloproteinases
      (TIMPs) in synovial fluid in aseptic loosening, which was compared to RA and OA.
      Pseudosynovial THA fluid was characterized using low levels of MMP-1 but moderate
      levels of MMP-13 and MT1-MMP (MMP-14). Due to the lack of an appropriate assay,
      MMP-13 and MT1-MMP were not similarly assessed, but the immunoblotting indicated
      that they were in the 56 kD intermediate proteolytically processed forms. The MMP
      9 level was intermediate between RA and OA. MMP-2 was on a significant level, but
      there were no differences among study groups. The THA group also was
      characterized using relatively high levels of TIMP-1 and TIMP-2. Accordingly, MMP
      9 and MMP-2 were found to occur in the 92 kD and 72 kD proenzyme form,
      respectively, with full activity retained in all study groups. The data suggest
      that proMMP-2-TIMP-2 and proMMP-9-TIMP-1 complexes are formed in the
      pseudosynovial fluid due to the excess of TIMPs over MMPs in aseptic loosening of
      THA. TIMP-complexed MMPs are resistant to MMP-mediated proteolytic activation,
      which may explain their latency and proenzyme zymogen form. Thus, formation of
      stabilizing proMMP-TIMP complexes enable transportation of proMMPs far from their
      original site of production. Due to motion-associated cyclic changes of the intra
      articular pressure, fluid-phase MMPs stabilized by TIMPs might be absorbed to
      implant surfaces and interface tissues and help to dissect the implant/cement-to
      bone interface in situ. Consequently, they may contribute to local
      proteolytic/tissue destructive events and aseptic loosening.

PMID- 10397974
TI  - Hydrophilic acrylic biomaterials derived from vitamin E with antioxidant
      properties.
AB  - Hydrogels based on polymeric derivatives of vitamin E for biomedical purposes
      have been prepared by copolymerization reaction of the alpha-tocopheryl
      methacrylate (V) with 2-hydroxyethyl methacrylate (H) in a range of composition
      between 5-20 wt % of V. The swelling behavior of the hydrogels in water,
      alkaline, and acidic media showed a slight decrease in the equilibrium water
      content with the content of V in the copolymer although in all cases it was
      superior to an EWC > 20%. The diffusion mechanism followed a Fickian behavior in
      all media. The values of the diffusion coefficients were in the range 2.5-1.6 10(
      7) cm2/s. The states of water in the hydrogels were determined by DSC. A decrease
      in the content of freezing water was obtained with the V content for all media,
      and for all compositions lower values of freezing water were obtained in acidic
      or basic pHs than in distilled water. The copolymeric xerogels, analyzed by
      contact angle measurements, deviated from those expected taking into
      consideration those of the homopolymers and the average fraction of the monomers
      in the copolymer. The polar contribution dropped with the introduction of a small
      content (4 wt %) of the vitamin E-containing monomer, and it reached a value
      similar to that of poly-V for a composition of 49 wt % of V in the copolymer.
      This behavior is accounted for by the segregation of the macromolecular chains of
      both kinds of monomers, due mainly to differences in their polarity, molecular
      weights, and the reactivity of both monomers. Finally, thermogravimetric analysis
      showed a higher thermal (antioxidant) stability of the poly-V with respect to
      poly-H, giving rise to a residue of 18 wt %. The V-containing copolymers also
      showed an improved stability (antioxidant behavior), indicating the possibility
      of the V unit's interfering with the oxidative process, based on free-radical
      species, and, therefore, with the aging process at the cellular level.

PMID- 10397975
TI  - Estrogenicity of bisphenol A and bisphenol A dimethacrylate in vitro.
AB  - Although pit and fissure sealants have been utilized extensively in dentistry as
      a way of preventing occlusal caries, results described by Olea et al. (1996)
      raised concerns about the safety of sealants and other resin-based dental
      materials due to the reported presence of bisphenol A (BPA) and its
      dimethacrylate ester (BPA-DM). Although the release of these compounds from
      dental materials has not been substantiated by two subsequent studies, we
      believed it was important to confirm or refute the report that BPA and BPA-DM
      have estrogenic activity in vitro. We grew breast cancer cells (MCF-7, T-47D, ZR
      75-1) known to proliferate under estrogenic stimulation in phenol red-free DMEM
      containing human serum and concentrations of BPA or BPA-DM ranging from 10(-8)M
      to 5 x 10(-6)M. After 1 week, plates were harvested for crystal violet or
      sulforhodamine-B assays, and the optical densities of groups of treated cells
      were compared with values from control cells. At concentrations at or above 10(
      6)M, both BPA and BPA-DM significantly increased cell proliferation (p < 0.05),
      comparable to the increase seen with 10(-9)M of estrogen. Flow cytometric methods
      demonstrated that these mitogenic effects occurred within 24 h of exposure to
      estrogen, BPA, or BPA-DM. The increase in DNA synthesis was analogous to that
      seen with estrogen stimulation. Thus, we confirmed that BPA and BPA-DM cause cell
      proliferation at micromolar concentrations that exceed the effective
      concentrations of estrogen by 1 to 10,000-fold.

PMID- 10397976
TI  - The structural characteristics and mechanical behaviors of nonstoichiometric
      apatite coatings sintered in air atmosphere.
AB  - Two types of nonstoichiometric apatite coatings on Ti6Al4V substrates were
      prepared in our laboratory by electrodeposition and hydrothermal synthesis. One
      was composed of highly pure needle-like calcium-deficient hydroxyapatite, and the
      other consisted of needle-like calcium-deficient hydroxyapatite and plate-like
      brushite. In this paper, the morphology, phase transition, and bonding strength
      of these coatings sintered at 450( degrees ) approximately 980 degrees C in an
      air atmosphere were studied. In addition, the residual stresses in pure calcium
      deficient hydroxyapatite coatings and coatings sintered at 800 degrees C were
      measured by a hole-drilling method. The results show that after being sintered at
      a higher temperature, the coating/Ti6Al4V samples exhibited structural
      characteristics such as biphasic [hydroxyapatite + beta-Ca3(PO4)2] coatings and
      dense TiO2 film/Ti6Al4V in which the residual stresses in the coatings slightly
      increased. In addition, the results indicate that bonding strength was improved.

PMID- 10397978
TI  - Mineralization of glutaraldehyde-fixed porcine aortic valve cusps in the
      subcutaneous rat model: analysis of variations in implant site and cuspal
      quadrants.
AB  - When evaluating the efficacy of new antimineralization treatments for
      bioprosthetic heart valves, subcutaneous implantation in a rat model often is
      used as an initial test. Although this model is widely used, there still are many
      aspects of its implementation that have not been investigated. To further
      investigate several parameters that may affect mineralization in the subcutaneous
      rat model, portions of glutaraldehyde-treated porcine aortic valve cusps were
      implanted both ventrally and dorsally into 21-day-old male Sprague-Dawley rats.
      Cusp quadrants were explanted at 1,2, and 3 weeks postimplantation and the
      calcium levels determined by atomic absorption spectroscopy. The objective of
      this study was to determine whether or not different implant locations and/or
      regions of the cusps affect the degree to which tissue mineralizes in the
      subcutaneous rat model. A total of 270 tissue specimens were examined. While the
      specific portion of the cusp implanted did not significantly affect the degree of
      mineralization, dorsal implantation resulted in significantly more mineralization
      than abdominal implantation (p = 0.007). As expected, longer implantation time
      was associated with greater calcification (p = 0.0001). The results of this study
      indicate that inconsistent placement of tissues in the rat subcutaneous implant
      model can result in significant differences in the degree of mineralization.

PMID- 10397977
TI  - Effect of hydroxyapatite content on physical properties and connective tissue
      reactions to a chitosan-hydroxyapatite composite membrane.
AB  - The present study investigated the effect on certain physical properties of
      adding various amounts of hydroxyapatite (HAP) to chitosan sol. Also investigated
      were connective tissue reactions to a composite membrane that is being developed
      for possible use in guided tissue regeneration and for the limitation of HA
      particle migration at sites of implantation. The physical properties evaluated
      were shrinkage, tensile strength, hardness, calcium ion release, and morphology.
      Assessment of physical properties indicated that a ratio of HA to chitosan sol of
      4/11 by weight is optimal in the preparation of the composite membrane.
      Subperiosteal implantation of the membranes over rat calvaria revealed that the
      membranes were well tolerated, with fibrous encapsulation and occasional areas of
      osteogenesis. Increasing the hydroxyapatite content seems to enhance membrane
      degradation.

PMID- 10397979
TI  - Cytotoxicity tests of in situ polymerized resins: methodological comparisons and
      introduction of a tissue culture insert as a testing device.
AB  - The in vitro cytotoxic potential of six commonly used methacrylate polymers was
      evaluated using human oral fibroblast cultures with different cell-material
      contact systems. A tissue culture insert was introduced to test resin-released
      components. Both acute and delayed cytotoxic effects of resin were quantified by
      cellular enzymatic and DNA synthetic activities of fibroblasts over a 6-day
      exposure period. Resin toxicity was material-dependent. Statistical analysis
      showed that the experimental conditions significantly contributed to the overall
      toxicity and the cytotoxicity pattern for a given material. DNA synthesis
      activity of human oral fibroblasts assayed by 3H-thymidine incorporation was more
      sensitive to resins than cellular enzyme activity, as determined by tetrazolium
      bromide reduction. However, extended exposure increased the cytotoxicity of all
      resins, as measured by tetrazolium bromide reduction, which seemed to be a better
      indicator of the development of resin toxicity than 3H-thymidine incorporation.
      Removal of the oxygen inhibition layer on resin specimens partially enhanced cell
      viability, indicating that this surface layer together with other unknown factors
      contributed to resin toxicity.

PMID- 10397980
TI  - Alginate-poly-L-lysine microcapsule biocompatibility: a novel RT-PCR method for
      cytokine gene expression analysis in pericapsular infiltrates.
AB  - Transplantation of microencapsulated islets of Langerhans is impaired by a
      pericapsular host reaction that eventually induces graft failure. We are studying
      the role of cytokines in the pathogenesis of this reaction, using the model of
      alginate-polylysine microcapsule implantation in rat epididymal fat pads. The
      objectives were: (1) to develop a method to measure, by semiquantitative PCR, TGF
      beta1 gene expression in fat pad pericapsular infiltrates, and (2) to use this
      method to evaluate TGF-beta1 gene expression 14 days after microcapsule
      implantation. TGF-beta1 mRNA level was significantly higher in pericapsular
      infiltrate cells than in nonimplanted tissue cells and saline-injected tissue
      cells (p < 0.0001 and p < 0.01, respectively). There was no significant
      difference between the TGF-beta1 mRNA levels of the two types of controls (p =
      0.0945). These results suggest that TGF-beta1 plays a role in the pathogenesis of
      the pericapsular reaction. The method developed can be used to study the role of
      other fibrogenic cytokines potentially involved. This will shed light on the
      mechanisms underlying the pericapsular reaction and will serve as a basis for the
      development of strategies to control this reaction.

PMID- 10397981
TI  - Biocompatibility of a biodegradable in situ forming implant system in rhesus
      monkeys.
AB  - Formulations of a polymeric delivery system containing a 75/25 poly(DL-lactide-co
      caprolactone dissolved in either N-methyl-2-pyrrolidone or dimethyl sulfoxide
      were injected both subcutaneously (SC) and intramuscularly (IM) into rhesus
      monkeys. Each monkey received an SC and IM injection of each of the two
      formulations, for a total injection volume of 4 mL. The monkeys were observed
      daily for overt signs of toxicity, and after 4 weeks biopsies of each implant
      site were fixed, stained, and evaluated histologically for tissue reaction to the
      polymer system. Tissue response was graded upon the presence and level of fibrous
      connective tissue and inflammatory cell infiltrate. The polymer formulations
      appeared to be safe, as the animals remained healthy and active throughout the
      study with no changes in food or water consumption, weight loss, or abnormal
      behavior observed. Tissue response to both formulations was considered mild and
      similar to that for other biodegradable polymers, in that the reaction was
      limited to tissue immediately adjacent to the residual polymer fragments and
      consisted of a mild fibroplasia with the presence of a few lymphocytes and
      macrophages. There were no differences between the two formulations in tissue
      response, and both formulations were considered acceptable for use as injectable
      implant systems.

PMID- 10397982
TI  - Sheep, pig, and human platelet-material interactions with model cardiovascular
      biomaterials.
AB  - The relationship between cardiovascular device performance in animals and humans
      is not straightforward. As the principal formed element in a thrombus, platelets
      play a major role in determining the hemocompatibility of mechanical heart valves
      and other high-shear-rate cardiovascular devices. Since larger animals are
      required to test many such devices, sheep and porcine platelet responses were
      compared to humans. Adhesion, spreading, and the formation of thrombilike
      structures were examined in vitro on pyrolytic carbon mechanical heart valve
      leaflets, National Institutes of Health-reference polyethylene and silicone
      rubber, and Formvar. Principal findings were that platelet responses are strongly
      dependent upon the biomaterial and the species: Porcine and human platelets
      spread extensively on pyrolytic carbon, formed thrombuslike structures on
      Formvar, and were least active on silicone rubber. Human and porcine platelets
      responded differently to polyethylene: Human platelets spread extensively, while
      porcine platelets remained pseudopodial. In contrast, sheep platelets attached
      much less, never reached fully spread shapes, and were far less active overall.
      Since porcine responses were generally similar to humans, pigs may be a useful
      predictor of in vivo platelet-biomaterial interaction in humans. Conversely, as
      ovine platelets were much less active, this must be accounted for in the
      evaluation of cardiovascular devices tested in sheep.

PMID- 10397983
TI  - Ability of Ni-containing biomedical alloys to activate monocytes and endothelial
      cells in vitro.
AB  - Nickel-containing alloys commonly are used in medical and dental applications
      that place them into long-term contact with soft tissues. The release of Ni ions
      from these alloys is disturbing because of the toxic, immunologic, and
      carcinogenic effects that have been documented for some Ni compounds. In
      particular, Ni ions in solution recently have been shown to cause expression of
      inflammatory mediators, such as interleukin-1beta (IL-1beta), tumor necrosis
      factor-alpha (TNF-alpha), and intercellular adhesion molecules (ICAMs) from
      keratinocytes, monocytes, and endothelial cells. However, the ability of the
      solid alloys themselves to induce these inflammatory effects has not been
      demonstrated. An in vitro system was used to determine if Ni-containing
      biomedical alloys could cause secretion of either IL-1beta or TNF-alpha from
      monocytes or expression of ICAMs on endothelial cells. Pure nickel, titanium, and
      three biomedical alloys-18-8 stainless steel, NiTi, and Rexillium III-were
      evaluated. First, it was determined whether or not the alloys or pure metals
      could cause cytotoxicity to THP-1 human monocytes or human microvascular
      endothelial cells (HMVECs) by measuring the succinic dehydrogenase (SDH) activity
      of the cells. Then, using identical conditions of exposure, the secretion of IL
      1beta or TNF-alpha from monocytes or ICAM-1 expression on the HMVECs was
      determined. Only pure nickel suppressed (by 48% compared to Teflon controls) the
      SDH activity of the HMVECs or THP-1 monocytes. No alloy or metal caused the
      HMVECs to express ICAM-1, but the NiTi alloy caused a significant (ANOVA/Tukey)
      secretion of IL-1beta from the THP-1 monocytes. Secretion of TNF-alpha induced by
      NiTi was detectable but not statistically significant. The levels of IL-1beta
      secretion from monocytes were sufficient to induce ICAM-1 expression on HMVECs.
      The release of Ni from the NiTi was a logical suspect in causing the IL-1beta
      secretion by monocytes, but its role was not confirmed since other alloys, such
      as Rexillium III, released the same quantities of Ni yet did not activate the THP
      1 monocytes. Within the limitations of in vitro conditions, our results indicate
      that NiTi alloys pose a risk of promoting an inflammatory response in soft
      tissues by activating monocytes. Further study is needed to substantiate this
      finding in vivo.

PMID- 10397984
TI  - Ricinoleic acid-based biopolymers.
AB  - Polyanhydrides synthesized from pure ricinoleic acid half-esters with maleic and
      succinic anhydrides possess desired physicochemical and mechanical properties for
      use as drug carriers. Ricinoleic acid maleate or succinate diacid half-esters
      were prepared from the reaction of crude ricinoleic acid (85% content) with
      succinic or maleic anhydride. The pure diacid monomers were obtained by
      chromatography purification through silica gel using petroleum ether/ethyl
      acetate/acetic acid (80/30/1 v/v/v) mixture as eluent. The pure diacid monomers
      (>99%) were polymerized by melt condensation to yield film-forming polymers with
      molecular weights exceeding 40,000 with a polydispersity of 2. Extensive
      biocompatibility study demonstrated their toxicological inertness and
      biodegradability. Their rate of elimination from rats in the course of about 4-6
      weeks was faster than that found for similar fatty acid-based polyanhydrides
      previously tested. In vitro studies showed that these polymers underwent rapid
      hydrolytic degradation in 10 days. Methotrexate release from the polymers was not
      affected by the initial polymer molecular weight in the range of 10,000-35,000.
      The in vitro drug release correlated with the degradation of the polymers. The
      fatty acid ester monomers were further degraded to its counterparts, ricinoleic
      acid and succinic or maleic acid.

PMID- 10397985
TI  - Size matters: molecular weight affects the efficiency of poly(ethylenimine) as a
      gene delivery vehicle.
AB  - Poly(ethylenimine) (PEI) samples of various molecular weights and pHs were used
      to transfect endothelial cells to achieve levels of gene expression for
      comparison. PEIs with nominal molecular weights of 600, 1200, 1800, 10,000, and
      70,000 Da were examined at pHs of 5. 0, 6.0, 7.0, and 8.0, and the results were
      recorded in terms of transfection efficiencies at 24, 48, 68, 92, and 120 h post
      transfection. Trials were performed on the human endothelial cell-derived cell
      line EA.hy 926. We found that, for the polymers tested, transfection efficiency
      increased as the molecular weight of PEI increased. Representative values of PEIs
      at pH 6 and molecular weight 70,000 produced average transfection efficiencies of
      25.6 +/- 7.9% (n = 8) at the greatest average expression levels, while PEI of
      molecular weight 10,000 yielded efficiencies of only 11.4 +/- 1.7% (n = 6).
      Transfection efficiencies for molecular weight 1,800 PEI were essentially zero,
      and PEIs of lower molecular weights produced no transfection at all. In contrast,
      the pH of the PEI solutions had no discernible effect on transfection. Optimal
      expression of the green fluorescent protein reporter occurred between 2 and 3
      days post-transfection. The amount of reporter expression also was noted, as
      determined by the brightness of fluorescing cells under UV. The data obtained
      demonstrate that the molecular weight of the PEI carrier has an effect on
      transfection efficiency while the pH of the PEI solutions prior to DNA
      complexation has no such effect.

PMID- 10397986
TI  - Plasmin degradation of fibrin coatings on synthetic polymer substrates.
AB  - The goal of this research was to evaluate the in vitro stability of fibrin
      coatings on polymeric materials in the presence of plasmin. Factor XIIIa
      crosslinked and noncrosslinked fibrin layers were coated on three different
      polyurethane substrates: Corethane, Tegaderm, and a biodegradable polyurethane,
      PCL/HDI/Phe. Degradation assays indicated that crosslinking the fibrin coatings
      enhanced the stability of the coatings on both Tegaderm and PCL/HDI/Phe; however,
      the persistence of the coating on the woven Corethane was not influenced by
      crosslinking. Degradation assay results also showed that the fibrin coating on
      the Corethane was significantly less stable than the fibrin coatings on the
      Tegaderm and PCL/HDI/Phe films. The chromogenic substrate assay data showed
      crosslinking did not affect the specific plasmin activity on the coatings;
      therefore, the increased stability resulting from crosslinking was not achieved
      through a reduction of fibrinolysis. The plasmin activity on the coated Corethane
      samples was much greater than that on either of the coated flat wound dressing
      materials. The large surface area of Corethane, a porous woven vascular graft
      material, may have had a direct influence on the fibrinolysis of its coatings by
      providing a large number of tissue-type plasminogen activator (tPA) binding
      sites. A thin, crosslinked, fibrin-coated polyurethane provides a theoretically
      attractive biomaterial for use in a wound dressing application and should be
      subject to ongoing research.

PMID- 10397987
TI  - Field emission in-lens SEM study of enamel and dentin.
AB  - This investigation used field emission in-lens scanning electron microscopy
      (FEISEM) for the study of tooth surfaces, with particular reference to adhesive
      bonding and acid conditioning. Dentin wafers with an intact enamel periphery were
      treated by either ethylenediaminetetraacetic acid (EDTA) (pH 7.4) or phosphoric
      acid (pH 0.7). The samples were then fixed, sequentially dehydrated in alcohol,
      and either air- or critical point-dried. After coating, surfaces were examined by
      FEISEM. For enamel, intraprismatic crystals were clearly recognizable, with the
      crystals showing both a longitudinal and parallel orientation to the long axis of
      the prisms. For dentin, the surface ultrastructure (mineral crystals and collagen
      banding) for the both untreated and treated samples was observed. Fine structures
      measuring on the order of 6 nm were also observed on samples treated by EDTA. We
      conclude that FEISEM can routinely provide high-resolution images of enamel and
      dentin, and that it has the capability of revealing the defined distribution of
      crystals and collagen fibers in dental tissues.

PMID- 10397988
TI  - Tumor necrosis factor (TNFalpha) production by rat peritoneal macrophages is not
      polyacrylate surface-chemistry dependent.
AB  - Polyacrylate films in the absence of added endotoxin caused rat peritoneal
      macrophages to secrete a small amount of TNFalpha. There was little difference,
      if any, among the materials, which included various co- or ter-polymers of
      hydroxyethyl methacrylate, dimethylaminoethyl methacrylate, methacrylic acid,
      methyl methacrylate, and butyl methacrylate. The materials were surface
      characterized and endotoxin cleaned prior to testing. Equivalent endotoxin levels
      associated with the material were <0.03 EU/mL for all materials but two; for
      polyHEMA, the most contaminated material, it was 0.23 EU/mL. Films of the
      materials were incubated with freshly isolated rat peritoneal macrophages for 6
      to 24 h before the TNFalpha levels in the supernatant were analyzed for
      biological activity, using L929 cells as a target. When endotoxin was added, far
      greater quantities of TNFalpha were generated at 24 h compared to 6 h, but still
      there was little effect with regard to material chemistry. Such an in vitro assay
      proved not to be useful for the screening of potential microencapsulation
      materials for peritoneal biocompatibility.

PMID- 10397989
TI  - Interaction of a plasma-sprayed hydroxyapatite coating in contact with human
      osteoblasts and culture medium.
AB  - The loss of calcium from plasma-sprayed calcium phosphate ceramics (CPCs) on
      bioinert metal substrate (Ti-6Al-4V) immersed in cell culture medium with or
      without human osteoblast culture was measured. The ceramics were a CPC and a
      duplex system composed of a CPC layer on an alumina coating. The dissolution of
      calcium compounds was monitored by measuring the calcium leaked from the coatings
      into the culture medium in 15 days. Calcium was measured by flame photometry. The
      surfaces of the ceramics exposed to the culture medium and in contact with
      osteoblasts were analysed by X-ray diffraction (XRD). The dissolution process
      occurred in the first 6 days of contact, but the calcium released into the
      culture medium was only a small fraction of the calcium content of the coatings.
      The presence or absence of osteoblasts on the surface of the ceramics did not
      make significant difference for the calcium release. The XRD spectra of the
      ceramics before and after immersion and in contact with cells did not show a
      significant change in the compounds of the coatings.

PMID- 10397990
TI  - Chondrocyte aggregation and reorganization into three-dimensional scaffolds.
AB  - Articular cartilage has a very limited self-repairing capacity; thus, chondral
      lesions normally result in chronic degeneration and, eventually, osteoarthritis
      development. Currently, tissue engineering offers a new tool for the clinical
      treatment of osteochondral defects. The present investigation aimed to develop an
      in vitro engineered cartilage using a new class of semisynthetic scaffolds. Two
      nonwoven meshes of hyaluronan esters (Hyaff(R) derivatives) were seeded with
      sternal chick embryo chondrocytes cultured for up to 21 days, after which time
      they were assessed for both the cellular growth profile and histological
      features. Avian chondrocytes easily adhered and proliferated onto hyaluronan
      based scaffolds, demonstrating a significant preference for the fully esterified
      benzylic form. Histochemical staining revealed the presence of a neosynthesized
      glycosaminoglycan-rich extracellular matrix, and immunohistochemistry confirmed
      the deposition of collagen type II. Moreover, ultrastructural observations
      supported evidence that chondrocytes grown onto a hyaluronan-derived three
      dimensional scaffold maintained their unique phenotype and organization in a
      cartilage-like extracellular matrix. These findings support the further pursuit
      of a transplantable engineered cartilage using human chondrocytes for the
      regeneration of chondral lesions.

PMID- 10397991
TI  - Evaluation of teflon-coated intraocular lenses in an organ culture method.
AB  - An amorphous and transparent form of Teflon is proposed as a coating of
      polymethylmethacrylate (PMMA) intraocular lenses (IOLs), rendering them highly
      hydrophobic. We used an organ culture method to evaluate cell adhesion,
      proliferation, and migration on Teflon-coated IOLs. Corneal explants from 14-day
      old chicken embryos were placed on a semisolid culture medium and covered with
      uncoated PMMA (n = 36) and Teflon-coated PMMA (n = 36) IOLs and two controls,
      Thermanox (n = 84) and latex (n = 36). After incubation (7 days at 37 degrees C),
      a digital imaging system was used to measure the areas of the cell migration
      layers on the materials. The cells were then removed with tripsin
      ethylenediaminetetraacetic acid and the cells detached at times up to 75 min were
      counted (Coulter(R) Multisizer System). The values were used to construct a cell
      disconnecting curve for each material. The areas of cell migration layers on
      uncoated and Teflon-coated IOLs were significantly different (p <.05). Cell
      disconnecting curves demonstrated that cells adhered less strongly to Teflon
      coated IOLs than to the other materials. This organ culture method demonstrated
      that the coating of PMMA IOLs with Teflon AF(R) is correlated with antiadhesive
      and antiproliferative properties.

PMID- 10397992
TI  - Human serum albumin and fibrinogen interactions with an adsorbed RGD-containing
      peptide.
AB  - The modification of polyethylene terephthalate (PET) and polytetrafluoroethylene
      (PTFE) with an arginine-glycine-aspartic acid cell adhesion peptide, RGD peptide
      (PepTite Adhesive Coating; Telios Pharmaceuticals, San Diego, CA) has been
      previously investigated. Initial animal studies showed this RGD peptide to
      accelerate healing and assist in the formation of an endothelial cell lining of
      the lumenal side of PET and PTFE fabrics in a cardiovascular application. It is
      of interest to determine how this RGD peptide is able to influence cellular
      events through intervening layers of plasma proteins that spontaneously adsorb
      upon implantation. This study examined the interaction of predeposited RGD
      containing peptide with human serum albumin (HSA) or fibrinogen that was
      characterized using multiple attenuated internal reflection infrared (MAIR-IR)
      spectroscopy, ellipsometry, and contact angle analysis. It was determined that
      fibrinogen-containing films consistently exhibited more mass than films of the
      RGD peptide, HSA, or HSA adsorbed onto RGD peptide-containing films. MAIR-IR
      spectra of RGD peptide films before and after HSA adsorption were similar in
      absorption and intensity; however, ellipsometry indicated HSA introduction had
      created thicker, less dense films. Fibrinogen, on the other hand, when adsorbed
      onto RGD peptide films provided increased relative mass in a more compact
      arrangement. Contact angle analyses of each of the dried films showed their
      surface energies to remain high, but the polar components of RGD peptide films
      were reduced after either serum protein adsorption. These phenomena may be
      related to the minimal thrombus accumulation that was noted during the initial
      animal studies, that promoted subsequent healing.

PMID- 10397994
TI  - Development of RGD peptides grafted onto silica surfaces: XPS characterization
      and human endothelial cell interactions.
AB  - The attachment of human umbilical vein endothelial cells (HUVECs) on substrates
      that had been covalently grafted with the cell adhesion peptides Arg-Gly-Asp
      (RGD) was investigated. This approach was used to provide substrates that are
      adhesive to cells even in the absence of serum proteins and to cells that have
      had no prior treatment of the surface with proteins that promote cell adhesion.
      We wanted to improve control of cellular interactions with cell-adhesive
      materials by providing fixedly bound adhesion ligands. Silica was examined as a
      model surface. The peptides were grafted using three different steps: grafting of
      aminosilane molecules; reaction with a maleimide molecule; and immobilization of
      cell-binding peptides containing the RGD sequence. The RGD-grafted surface was
      characterized by X-ray photoelectron spectroscopy (XPS) and contact-angle
      measurements.

PMID- 10397993
TI  - Behavior of blood cells in contact with water-soluble phospholipid polymer.
AB  - Omega-Methacryloyloxyalkyl phosphorylcholine (MAPC) polymer, which has various
      methylene chain lengths between the phosphorylcholine group and the backbone, was
      synthesized with attention to formation of the biomembrane. The effect of water
      soluble poly(MAPC) on the function and activation of blood cells was evaluated to
      determine the interaction between blood cells and the MAPC polymer. The
      poly(MAPC) and the MAPC copolymer with a small amount of fluorescent units were
      synthesized by a conventional radical polymerization technique. Using a
      fluorescence spectrometer, it was determined that the MAPC polymer was adsorbed
      on the plasma membrane of platelets when the platelets were suspended in an
      aqueous solution of the MAPC copolymer. The hemolytic activity of poly(MAPC) was
      less than that of other water-soluble polymers, such as poly(ethylene glycol) and
      poly(1-vinyl-2-pyrrolidone) (PVPy). The change in the plasma membrane fluidity of
      platelets on contact with poly(MAPC) was determined with 1,6-diphenyl-1,3,5,
      hexatriene. The plasma membrane fluidity of platelets decreased with an increase
      in the methylene chain length of the MAPC unit. The aggregation activity of
      platelets after contact with poly(MAPC) was also evaluated, but no significant
      difference between that of polymer-contacted platelets and native platelets was
      observed. Finally, the activity of platelets on contact with poly(MAPC) was
      determined by measuring the cytoplasmic calcium ion concentration ([Ca2+]i) in
      platelets. The increase in [Ca2+]i in the platelets after contact with poly(MAPC)
      was similar to that of native platelets. We conclude that the poly(MAPC) reduced
      platelet activation even though the poly(MAPC) adsorbed on the membrane surface
      of the platelets. In particular, poly(10-methacryloyloxydecyl phosphorylcholine)
      significantly reduced platelet activation compared with PVPy.

PMID- 10397995
TI  - Bovine serum albumin adsorption on titania surfaces and its relation to
      wettability aspects.
AB  - The adsorption of bovine serum albumin (BSA) from sodium chloride solution and
      Hanks' balanced salt solution (HBSS) onto TiO2-silicon surfaces is studied by
      reflectometry in stagnation point flow. The results are compared with those
      obtained by dynamic contact-angle (DCA) analysis of titanium substrates. The
      adsorption isotherms show that the adsorbed amount of protein always is lower in
      HBSS, that is, in the presence of calcium and phosphate ions. This may be related
      to the increase in surface hydrophilicity caused by these ions, as suggested by
      the authors in previous works. The rate of adsorption also is lower in HBSS
      solutions. Comparison of the initial adsorption rates with the rate of mass
      transfer to the surface reveals that in both solvents only a small fraction of
      the protein that arrives at the surface adsorbs onto it. Electrostatic and/or
      conformational effects can explain the energy barrier to adsorption. The DCA
      analysis of high concentration (4 mg/mL) protein solutions shows a strong
      reduction of the contact-angle hysteresis, both in HBSS and in NaCl solutions,
      which confirms that the immediate adsorption of the protein to the surface forms
      a stable, hydrophilic film.

PMID- 10397996
TI  - In vitro evaluation of the inflammatory potential of the silk fibroin.
AB  - Silk fibroin membranes recently have been suggested as matrices for biomedical
      applications, such as guided tissue regeneration and burn wound dressings. The
      aim of this study was to evaluate the inflammatory potential of fibroin films and
      to compare the fibroin films with two model materials with completely different
      physico-chemical properties: poly(styrene) and poly(2-hydroxyethyl methacrylate).
      Fibroin bound lower levels of fibrinogen than did the two synthetic polymers
      while the same amounts of adsorbed human plasma complement fragment C3 and IgG
      were detected. Studies of the binding strength of C3 to fibroin, evaluated by a
      novel experimental procedure, indicated the occurrence of strong hydrophobic
      interactions at the interface. The activation of the mononuclear cells by
      fibroin, measured as interleukin 1beta production, was lower than the reference
      materials. Adhesion experiments showed the ability of the macrophages to adhere
      to fibroin by filopodia without a complete spreading of the cells. The results
      achieved in this study demonstrate that the interactions of fibroin with the
      humoral components of the inflammatory system were comparable with those of the
      two model surfaces while the degree of activation and adhesion of the
      immunocompetent cells appeared more limited.

PMID- 10397997
TI  - Modulation of marrow stromal cell function using poly(D,L-lactic acid)-block
      poly(ethylene glycol)-monomethyl ether surfaces.
AB  - The adhesion of marrow stromal osteoblasts and the adsorption of fetal bovine
      serum (FBS) proteins to end-capped poly(D,L-lactic acid) 50:50 (PLA50) of
      molecular weight 17,000 (PLA5017), non-end-capped PLA50 of molecular weight
      11,000 (PLA5011h), and a diblock copolymer made of poly(ethylene glycol)
      monomethyl ether of molecular weight 5,000 and PLA50 of molecular weight 20,000
      (Me. PEG5-PLA20) were investigated. Cell attachment and proliferation on both
      PLA50 polymers were equally good. The block copolymer did not allow the
      proliferation of cells. However, the attached cells were highly differentiated
      and metabolically active in contrast to the cells on PLA50. Moreover, surface
      analysis studies using electron spectroscopy revealed that FBS proteins adsorbed
      well from aqueous solutions to the PLA50 surfaces while they adsorbed
      substantially less to the block copolymer. These results suggest that Me.PEG-PLA
      block copolymers may be used to regulate protein adsorption and, therefore, cell
      adhesion by varying the block composition of the copolymer.

PMID- 10397998
TI  - The cytotoxic effect of titanium particles phagocytosed by osteoblasts.
AB  - The cytotoxic effect of different concentrations of titanium particles on
      osteoblasts was studied in vitro. It was found that the viability of the
      osteoblasts was inversely proportional to the particle concentration.
      Phagocytosis of particles by the osteoblasts was evident and was demonstrated to
      be responsible for cell necrosis. Moreover, during and after phagocytosis, the
      osteoblasts released products that were cytotoxic for other osteoblasts, as
      established with a conditioned medium assay. The titanium particles thus had both
      a direct and an indirect effect on osteoblast viability. It also was observed
      that the titanium particles induced a process of programmed cell death
      (apoptosis) when co-cultured with osteoblasts. The results of this study suggest
      that not only is the amount of wear debris generated important, but the local
      accumulation of the debris also may have a significant impact on bone cell
      function.

PMID- 10397999
TI  - Hydroxyapatite thin films deposited onto uncoated and (Ti,Al, V)N-coated Ti
      alloys.
AB  - Plasma-sputtered hydroxyapatite (HA) thin coatings ( approximately 1 microm) were
      deposited onto uncoated and (TiAlV)N-coated Ti-6Al-4V-alloy substrates at low
      temperatures. The (TiAlV)N coating interlayer was deposited by reactive
      sputtering. Depositions were achieved by utilizing unbalanced and balanced
      magnetrons in a capacitively coupled RF plasma. Characterization of the
      thermostability, bioerosion resistance, and chemical composition of the coating
      layer was examined by scanning electron microscopy (SEM), energy-dispersive X-ray
      analysis (EDX), and Fourier transform infrared spectroscopy (FTIR). The results
      show that for deposition temperatures as low as 67 degrees C, the crystalline
      phase of the HA coating still is clearly detectable and that the underlying
      (TiAlV)N coating can increase the crystallinity and thermostability of the HA
      coating before and after heat treatment. The thin ( approximately 1 microm)
      sputtered HA coating shows strong HA characteristic peaks in the FTIR spectra
      even after a 30-day dissolution test. The experimental results show that a
      multilayer structure comprised of a bioinert (TiAlV)N and bioactive HA coating
      has the potential to improve the biocompatibility of implant materials. The
      bioinert (TiAlV)N coating also may provide a long-term stable interface between
      bone tissue and an alloy implant after the bioactive HA coating is remodeled by
      the surrounding tissue.

PMID- 10398000
TI  - Histopathological and immunohistochemical studies of membranes of deacetylated
      chitin derivatives implanted over rat calvaria.
AB  - Membranes made of 65, 70, 80, 94, and 100% deacetylated chitin (chitosan) were
      implanted subperiosteally over the calvaria of 100 rats. Reactions were studied
      at 1, 2, 4, and 8 weeks after implantation. Membranes prepared with 65, 70, and
      80% deacetylated chitin initially elicited marked inflammatory reactions that
      subsided in time with granulation tissue formation and osteogenesis. Osteocalcin
      positive cells were detected immunohistochemically in the granulation tissue. On
      the other hand, membranes made of 94% deacetylated chitin and chitosan showed
      mild inflammation and minimal osteogenesis. The results indicate that membranes
      made of 65, 70, and 80% deacetylated chitin enhance osteogenesis at the site of
      their implantation. However, the initially severe inflammatory reaction
      associated with these materials needs to be controlled before the materials would
      be suitable for clinical application.

PMID- 10398001
TI  - Crosslinking and modification of dermal sheep collagen using 1, 4-butanediol
      diglycidyl ether.
AB  - Crosslinking of dermal sheep collagen (DSC) was accomplished using 1, 4
      butanediol diglycidyl ether (BDDGE). At pH values > 8.0, epoxide groups of BDDGE
      will react with amine groups of collagen. The effects of BDDGE concentration, pH,
      time, and temperature were studied. Utilization of a 4-wt % BDDGE instead of 1-wt
      % resulted in a faster reaction. Whereas similar values of shrinkage temperature
      were obtained, fewer primary amine groups had reacted at a lower BDDGE
      concentration, which implies that the crosslinking reaction had a higher
      efficacy. An increase in pH from 8.5 to 10.5 resulted in a faster reaction but
      reduced crosslink efficacy. Furthermore, an increase in reaction temperature
      accelerated the reaction without changing the crosslink efficacy. Crosslinking
      under acidic conditions (pH < 6.0) evoked a reaction between epoxide groups and
      carboxylic acid groups of collagen. Additional studies showed that no oligomeric
      crosslinks could be formed. However, hydrolysis of the epoxide groups played a
      role in the crosslink mechanism especially under acidic reaction conditions. The
      macroscopic properties of these materials were dependent on the crosslinking
      method. Whereas a flexible and soft tissue was found if crosslinking was
      performed at pH < 6.0, a stiff sponge was obtained under alkaline conditions.
      Reaction of DSC with a monofunctional compound (glycidyl isopropyl ether) led to
      comparable trends in reaction rate and in similar macroscopical differences in
      materials as observed with BDDGE.

PMID- 10398002
TI  - Decontaminating particles exposed to bacterial endotoxin (LPS).
AB  - Lipopolysaccharide (LPS), which comes from the cell wall of gram-negative
      bacteria, can stimulate murine macrophage cells to produce nitric oxide (NO),
      cytokines, such as tumor necrosis factor-alpha, and interleukins, such as IL-6.
      When examining the biological effects of particles on macrophages, it is
      important to have no contaminating LPS associated with the particles and none
      with any cell culture media or supplies since even very low levels of LPS are
      stimulatory. The presence or absence of LPS was observed in two ways: (1) the
      amount of NO produced by RAW 264.7 murine macrophage cells, and (2) the Limulus
      amebocyte lysate (LAL) test. Treating particles with 70% ethanol at room
      temperature for 48 h, followed by washing the polymethylmethacrylate (PMMA)
      particles with endotoxin-free phosphate-buffered saline three times,
      decontaminated LPS and LPS-treated PMMA particles. When given LPS that had been
      treated with 70% ethanol for 48 h at room temperature or at 37 degrees C, cells
      did not produce NO above control levels. Negative LAL tests indicated the
      presence of extremely low levels or the complete absence of LPS in 70% ethanol
      treated LPS.

PMID- 10398004
TI  - Nucleation and growth of hydroxyapatite on titanium pretreated in NaOH solution:
      experiments and thermodynamic explanation.
AB  - Titanium was submitted to chemical attack with sodium hydroxide solution under
      hydrothermal (SBF) conditions and then kept for 4 weeks in simulated body fluid
      after heat treatment. The resultant coating titanium samples were characterized
      regarding nucleation and growth of hydroxyapatite on their surfaces using
      scanning electron microscopy and energy dispersive spectroscopy, as well as low
      angle X-ray diffraction. In order to obtain a thermodynamic explanation of same
      results, Eh-pH diagrams of Na-Ti-H2O and Ca-Ti-H2O systems at 25, 100, 200, and
      300 degrees C were built for selected activities of the species in aqueous
      solutions. Values of pairs corresponding to the predominance limit of the species
      in solution at equilibrium with 0.21 atm of oxygen pressure were taken from these
      Eh-pH diagrams for subsequent building of the pNa-pH and pCa-pH diagrams of the
      same systems at each referred temperature (pi = -log10ai). In addition, the
      titanate-apatite free energy of formation was estimated and then a pCa-pH diagram
      of the Ca-P-Ti-H2O system at 25 degrees C was built. Examination of the resultant
      diagrams could elucidate the thermodynamic viability of the process.

PMID- 10398005
TI  - Effect of bioactive filler content on mechanical properties and osteoconductivity
      of bioactive bone cement.
AB  - We took three types of bioactive bone cement (designated AWC, HAC, and TCPC),
      each with a different bioactive filler, and evaluated the influence of each
      filler on the mechanical properties and osteoconductivity of the cement. The
      cements consisted of bisphenol-a-glycidyl methacrylate-based (Bis-GMA based)
      monomers as an organic matrix, with a bioactive filler of apatite/wollastonite
      containing glass-ceramic (AW-GC) or sintered hydroxyapatite (HA) or beta
      tricalcium phosphate (beta-TCP) powder. Each filler was mixed with the monomers
      in proportions of 50, 70, and 80% (w/w), giving a total of nine cement subgroups.
      The nine subgroups were designated AWC50, AWC70, AWC80, HAC50, HAC70, HAC80,
      TCPC50, TCPC70, and TCPC80. The compressive and bending strengths of AWC were
      found to be higher than those of HAC and TCPC for all bioactive filler contents.
      We also evaluated the cements in vivo by packing them into the intramedullary
      canals of rat tibiae. To compare the osteoconductivity of the cements, an
      affinity index was calculated for each cement; it equaled the length of bone in
      direct apposition to the cement, expressed as a percentage of the total length of
      the cement surface. Microradiographic examination up to 26 weeks after
      implantation revealed that AWC showed a higher affinity index than HAC and TCPC
      for each filler content although the affinity indices of all nine subgroups
      (especially the AWC and HAC subgroups) increased with time. New bone had formed
      along the AWC surface within 4 weeks, even in the cement containing AW-GC filler
      at only 50% (w/w); observation of the cement-bone interfaces using a scanning
      electron microscope showed that all the cements had directly contacted the bone.
      At 4 weeks the AWC had bonded to the bone via a 10 micron-thick reactive layer;
      the width of the layer, in which partly degraded AW-GC particles were seen,
      became slightly thicker with time. On the other hand, in the HAC- and TCPC
      implanted tibiae, some particles on the cement surface were surrounded by new
      bone and partly absorbed or degraded. The results suggest that the stronger
      bonding between the inorganic filler and the organic matrix in the AWC cements
      gave them better mechanical properties. The results also indicate that the higher
      osteoconductivity of AWC was caused by the higher reactivity of the AW-GC powder
      on the cement surface.

PMID- 10398006
TI  - Reactive capsule formation around soft-tissue implants is related to cell
      necrosis.
AB  - Low-density polethylene disks with smooth or course surfaces were implanted in
      the abdominal wall of rats, and the tissue response was evaluated after 1, 6, or
      12 weeks. Cell damage was detected by two different methods. Cells with increased
      membrane permeability could be identified using fluorescence microscopy by
      injection of propidium iodide prior to the killing of the rats. Second, cell
      death was verified by detection of DNA fragmentation. At 1 week a considerable
      number of the interfacial cells was stained with propidium iodide. Propidium
      iodide-positive cells also were enriched at the edges of the disks irrespective
      of surface texture. The numbers of positive interfacial cells decreased markedly
      over time. Cells with DNA fragmentation initially displayed a scattered
      distribution; at later time points they appeared mainly in the outer portion of
      the enveloping capsule. The reactive capsule was thicker for the smooth surface,
      and there was a positive correlation between capsule thickness and propidium
      iodide-positive cells at earlier implantation periods. The results suggest that
      the thickness of the reactive capsule is related to the extent of cell necrosis.
      It is suggested that the major initiator for this cell necrosis is mechanical
      shear since cell necrosis was found mainly in areas where mechanical shear could
      be expected.

PMID- 10398007
TI  - Influence of synthetic polymers on neutrophil migration in three-dimensional
      collagen gels.
AB  - In vitro studies of cell migration within three-dimensional polymeric materials
      are essential for understanding cell behavior and for developing new biomedical
      materials. Human neutrophil motility was examined in hydrated collagen gels
      containing various synthetic polymers. Physical mixtures of collagen and certain
      water-soluble polymers formed stable gels that were good substrates for cell
      migration. Addition of either polyethylene glycol (PEG) or the pluronictrade mark
      copolymer F68 did not change the morphological or mechanical properties of
      collagen gels, as determined by SEM and oscillatory rheometry; however, addition
      of either polymer significantly inhibited cell motility in both a modified 96
      well chemotaxis chamber assay and a direct visual assay. Although the mechanism
      for this observed polymer inhibition of neutrophil migration is not yet clear,
      these results suggest that PEG and F68, two widely used biomedical polymers that
      are considered to be relatively "inert," may cause significant inhibition of cell
      motility.

PMID- 10398008
TI  - In vitro modulation of macrophage phenotype and inhibition of polymer degradation
      by dexamethasone in a human macrophage/Fe/stress system.
AB  - A new in vitro accelerated biological model, the macrophage-FeCl2-stress system
      was used for the evaluation of dexamethasone (DEX)-polymer formulations. This
      model combines the effects of cells (macrophages), transition metal ions (Fe2+),
      and polymer stress to promote material biodegradation. The cell and material
      effects of DEX, either in solution or incorporated into a polyetherurethane
      matrix (DEX/PEU), were monitored. Cell morphology and hydroperoxide formation in
      the polymer during cell culturing were characterized. After a subsequent
      treatment with FeCl2 the development of environmental stress cracking in the
      polymer was evaluated. We attempted to duplicate the biodegradation of PEU in
      terms of environmental stress cracking (ESC). Our results support the direct
      involvement of macrophages in polyetherurethane oxidation, probably by inducing
      hydroperoxide formation in the polymer structure. Under the influence of stress
      or strain, polymers with sufficient hydroperoxides degrade in the presence of
      Fe2+ metal ions in a manner that closely resembles the stress cracking that is
      observed in vivo. By contrast, polymers treated with either agents that inhibit
      cell activation and/or the oxidative burst, or with cells with no oxidative burst
      did not show signs of the biodegradative process. We demonstrated a reduction in
      hydroperoxide formation and no later ESC development in macrophage-cultured PEU
      in the presence of DEX in solution or in DEX-loaded PEU. We believe the
      prevention of initial polymer oxidation by reducing the cell's potential to
      produce oxidative stress at the tissue-biomaterial interface can directly inhibit
      the ESC degradation of chronically implanted polymers. The in vitro macrophage-Fe
      stress system is a valuable tool for reliable assessment and cost-effective
      evaluation of biomaterials.

PMID- 10398009
TI  - Persistent adhesion of epithelial tissue is sensitive to polymer topography.
AB  - The persistent adhesion of corneal epithelial tissue to the surface of a porous
      polymer is of interest in the development of a corneal onlay. Using an in vitro
      model system, this study examined the effect of polymer surface topography on the
      assembly of basement membrane and hemidesmosomes. Corneal epithelial tissue was
      grown on polycarbonate surfaces with a range of pore sizes (0.1-3.0 micron, pore
      diameter) and an equivalent nonporous surface. The ultrastructure of the tissue
      polymer interface was evaluated using electron microscopy. On the porous
      surfaces, the tissue responded to a balance between the size of the discontinuity
      (pores) and the amount of polymer surface between the pores. Continuous basement
      membrane and a regular pattern of hemidesmosomal plaque occurred only on the 0.1
      micron surface, where both the pores and the total surface area covered by pores
      were relatively small. The assembly of adhesive structures on surfaces with pore
      diameters between 0.4-2.0 microns was restricted to regions of polymer between
      pores. No adhesive structures assembled on the nonporous or on the 3.0-micron
      surface. These results demonstrate that, in addition to porosity, surface
      topography is a significant factor in the formation of structures involved in the
      persistent adhesion of stratified epithelial tissue on a polymer.

PMID- 10398010
TI  - Sulbactam-cefoperazone polyhydroxybutyrate-co-hydroxyvalerate (PHBV) local
      antibiotic delivery system: in vivo effectiveness and biocompatibility in the
      treatment of implant-related experimental osteomyelitis.
AB  - In this study, a novel antibiotic carrier system for use in the treatment of
      implant-related and chronic osteomyelitis was developed. Sulbactam-cefoperazone
      was introduced to rods of polyhydroxybutyrate-co-hydroxyvalerate (22 mol % HV,
      w/w), a member of a family of microbial-origin polymer that is biodegradable,
      biocompatible, and osteoconductive due to its piezoelectric property. The
      antibiotic-loaded carrier was implanted into the infection site that was induced
      by Staphylococcus aureus inoculation into the rabbit tibia. The effectiveness of
      this was assessed macroscopically, radiographically, bacteriologically, and
      histopathologically. Findings of infection subsided on day 15 and almost complete
      remission was observed on day 30. The control side that contained antibiotic-free
      rods, however, worsened. These findings prompted us to conclude that the novel
      biodegradable antibiotic carrier developed in the present study seems to be a
      promising candidate for use in the treatment of severe bone infection.

PMID- 10398011
TI  - Reaction of calcium phosphate cements with different amounts of tetracalcium
      phosphate and dicalcium phosphate anhydrous.
AB  - Calcium phosphate cements (CPCs) with different amounts of tetracalcium phosphate
      (TTCP) and dicalcium phosphate anhydrous (DCPA) (TTCP/DCPA molar ratio from 0.25
      to 2.00) were prepared to further understand the setting reaction and the factors
      that could influence the properties of CPCs. Quantitative X-ray diffraction
      patterns, Fourier transform IR spectra, and diametral tensile strength of the set
      mass were measured along with pH measurements of the CPC suspension. Calcium
      deficient hydroxyapatite (d-HAP) with a calcium to phosphate molar ratio of
      approximately 1.5 was formed initially in the CPC setting consisting of an
      equimolar mixture of TTCP and DCPA. This gradually transformed into
      stoichiometric HA (s-HA) with increasing incubation time. The s-HA was formed in
      the initial stage when the CPC contained an excess amount of TTCP. In contrast,
      maturation to s-HAP was slow when the CPC contained excess amounts of DCPA. The
      highest mechanical strength of set CPC was associated with an equimolar mixture
      of TTCP and DCPA, and the mechanical strength decreased as the TTCP/DCPA molar
      ratio deviated from 1.00. We concluded, therefore, that the setting reaction and
      the nature of the resulting set mass are dependent on the molar ratios of TTCP
      and DCPA.

PMID- 10398012
TI  - Shear stress effects on bacterial adhesion, leukocyte adhesion, and leukocyte
      oxidative capacity on a polyetherurethane.
AB  - Infection of implanted cardiovascular biomaterials still occurs despite inherent
      host defense mechanisms. Using a rotating disk system, we investigated
      Staphylococcus epidermidis and polymorphonuclear leukocyte (PMN) adhesion to a
      polyetherurethane urea (PEUU-A') under shear stress (0-17.5 dynes/cm2) for time
      periods up to 6 h. In addition, the superoxide (SO) release capacity of PMNs
      after transient exposure to PEUU-A' under shear stress was determined. Bacterial
      adhesion in phosphate-buffered saline (PBS) showed a linear shear dependence,
      decreasing with increasing shear stress. Overall adhesion in PBS decreased with
      time. However, bacterial adhesion in 25% human serum was similar for all time
      points up to 360 min. Adhesion was observed at all shear levels, displaying no
      shear dependence. In contrast, PMN adhesion demonstrated a strong shear
      dependence similarly for times up to 240 min, decreasing sharply with increasing
      shear stress. Although PMNs preexposed to shear stress showed a slightly
      diminished SO release response compared to fresh cells for all stimuli, it was
      not statistically significant regardless of the stimulus. We conclude that
      circulating leukocytes are unable to adhere in regions of high shear which may
      contain adherent bacteria. In addition, exposure to PEUU-A' and shear stress (in
      the range 0-18 dynes/cm2) is insufficient to cause a depression in the oxidative
      response of PMNs.

PMID- 10398015
TI  - Maturation-dependent durability of spontaneous cartilage repair in rabbit knee
      joint.
AB  - The spontaneous healing of osteochondral defects in the knee joints of immature
      rabbits within the first 12 weeks after surgery showed a faster filling and
      earlier tissue specialization than in adult animals. The purpose of the present
      study was to investigate whether the better short-term quality of spontaneous
      repairs in immature animals lasted over a period of 48 weeks. A full-thickness
      osteochondral defect was created on the medial femoral condyle in both knees of
      10 young, 10 adolescent, and 10 adult rabbits. Equal numbers of animals were
      evaluated after 24 and 48 weeks. At both time intervals, bonding to adjacent
      cartilage and proteoglycan content of the matrix were better in the repairs of
      young than in adult animals. Repairs in the former had cellularity similar to the
      adjacent cartilage and were composed of 90% hyaline-like cartilage, which did not
      decrease with time. In contrast, repairs in older animals formed less hyaline
      like cartilage and had a lower cellularity than the adjacent cartilage. However,
      the surface of the repaired tissue was similarly disrupted in all age groups, and
      the mechanical properties remained inferior to adjacent or normal cartilage.
      Repairs in older animals showed signs of degeneration with time. The initial
      better repair quality in a young, growing animal remained up to 48 weeks when the
      animal had already reached maturity, indicating that successful initial promotion
      of cartilage repair may even lead to better results in the long term. However, it
      has to be pointed out that the morphologically good repairs with hyaline-like
      cartilage appearance, normal cellularity, and durability of up to 48 weeks were
      unable to reestablish and maintain a cartilage-like mechanical function.

PMID- 10398014
TI  - Thermal analysis characterization of aortic tissues for cardiac valve
      bioprostheses.
AB  - Two multistep extractions were achieved on porcine aortic tissues to obtain
      acellular matrices used for cardiac bioprostheses. The evaluation of structural
      modifications and the possible damage of extracellular matrix fibrous proteins
      were investigated by means of thermogravimetric analysis (TGA) and differential
      scanning calorimetry (DSC). Protein-water interactions and degradation
      temperatures were determined by TGA. DSC was used to characterize protein thermal
      transitions (glass transition and denaturation), which provided information on
      the dynamic structure of the aortic tissue components. Sodium dodecyl sulfate
      (SDS) extraction had a destructuring effect, while Triton and cholate treatments
      did not affect the structural integrity of either elastin and collagen. A DSC
      comparison showed that SDS destabilizes the collagen triple helical domain and
      swells the elastin network.

PMID- 10398013
TI  - Evaluation of gelatin hydrogel crosslinked with various crosslinking agents as
      bioadhesives: in vitro study.
AB  - Bioadhesives are used for tissue adhesion and hemostasis in surgery. A gelatin
      resorcinol mixture crosslinked with formaldehyde (GRF glue) and/or glutaraldehyde
      (GRG) is used for this purpose. Although the bonding strength of the GRF glue to
      tissue is satisfactory, concerns about the cytotoxicity of formaldehyde are
      reported in the literature. It was suggested that the cytotoxicity problem of the
      GRF glue may be overcome by changing its crosslinking method. The study was
      therefore undertaken to assess the feasibility of using an epoxy compound (GRE
      glue), a water-soluble carbodiimide (GAC glue), or genipin (GG glue) to crosslink
      with a gelatin hydrogel as new bioadhesives. GRF glue and GRG glue were used as
      controls. The results of our cytotoxicity study suggested that the cellular
      compatibility of the GAC and GG glues was superior to the GRF, GRG, and GRE
      glues. The gelation time for the GG glue was relatively longer than the GRF and
      GRG glues, while no gelation time could be determined for the GAC glue.
      Additionally, it took approximately 17 h for the GRE glue to become adhesive. The
      GRF and GRG glues had the greatest bonding strengths to tissue among all test
      adhesives, while the bonding strengths of the GAC and GG glues were comparable.
      In contrast, there was almost no bonding strength to tissue for the GRE glue.
      However, the GRF and GRG glues were less flexible than the GAC and GG glues.
      Subsequent to the bonding strength measurement, each test adhesive was found to
      adhere firmly to the tissue surface and underwent cohesive failure during the
      bond breaking. In conclusion, the GRF and GRG glues may be used as tissue
      adhesives when their ability to bind tissue rapidly and tightly is required; the
      GAC and GG glues are preferable when the adhesive action must be accompanied with
      minimal cytotoxicity and stiffness; and the GRE glue is not suitable for
      bioadhesion in clinical applications.

PMID- 10398016
TI  - Glass-based coatings for titanium implant alloys.
AB  - Glass coatings on Ti6Al4V were prepared using a simple enameling technique. The
      composition of the glasses was tailored to match the thermal expansion of
      Ti6Al4V. By controlling the firing atmosphere, time, and temperature, it was
      possible to control the reactivity between the glass and the alloy and to
      fabricate coatings (25-150 micron thick) with excellent adhesion to the
      substrate. The optimum firing temperatures ranged between 800 and 840 degrees C
      at times up to 1 min in air or 15 min in N2. The same basic technique was used to
      prepare multilayered coatings with graded composition or with hydroxyapatite (HA)
      particles embedded in the outer layer. Some of these coatings presented excellent
      adhesion to the substrate and were able to form HA during in vitro tests in
      simulated body fluid.

PMID- 10398017
TI  - Influence of P2O5 on crystallinity of apatite formed in vitro on surface of
      bioactive glasses.
AB  - Two sol-gel glasses with 80 mol % SiO2 were prepared in the system SiO2-CaO-P2O5;
      the first one had 3 mol% P2O5 in its composition, and the second one was P2O5
      free. The in vitro behavior of glasses was studied by soaking them in simulated
      body fluid for 7 days at 37 degrees C. After the in vitro test, the study by
      Fourier transform infrared spectroscopy, scanning electron microscopy, energy
      dispersive spectroscopy, electron diffraction, and transmission electron
      microscopy showed an apatite-like layer had formed on the surface of both
      glasses. However, for identical soaking time, the apatite crystals formed on the
      surface of the glass containing P2O5 in the composition were larger. Therefore,
      the presence of P2O5 in the sol-gel glass composition promotes the crystal growth
      of the apatite.

PMID- 10398018
TI  - Electrochemical method for entrapment of oligonucleotides in polymer-coated
      electrodes.
AB  - Oligonucleotides were incorporated into conducting films of poly(3, 4-ethylene
      dioxythiophene) by an electrochemical method that involves two steps. The
      electrode is first coated with the polymer film by electropolymerization followed
      by electrooxidation of the formed polymer in the presence of the oligonucleotide.
      Neutral water soluble polymers such as poly(vinylpyrrolidone) or poly(ethylene
      glycol) were added to the polymerizing medium resulting in higher incorporation
      yields of oligonucleotides. The results showed that a payload of about 1.5
      nmol/cm2 can be achieved in an 8 micron thick film for an oligomer concentration
      of about 70 microM in the working solution. Various physical methods were used to
      analyze the surface of the polymer-coated electrodes. Results showed the presence
      of domains of varying sizes at the film surface, corresponding to the insertion
      of the hydrophilic polymer within the matrix of the conductive polymer. The
      release of entrapped oligonucleotides from the coated film exhibited a three-step
      profile: a "burst" period during the first 5 min followed by an intermediate and
      a very slow release period lasting several days. Such polymer films could be
      exploited as useful reservoirs of biologically active substances for in vivo
      delivery to targeted tissues. For example, coated stents that can release
      antiproliferative agents such as antisense oligonucleotides at the site of
      balloon dilatation may be of interest in the treatment of postangioplasty
      restenosis.

PMID- 10398019
TI  - Study of fatigue resistance of chemical and radiation crosslinked medical grade
      ultrahigh molecular weight polyethylene.
AB  - The aim of this work is to understand the role of chemical and radiation induced
      crosslinking on the fatigue crack propagation resistance of medical grade
      ultrahigh molecular weight polyethylene (UHMWPE). In recent years, the need to
      improve the tribological performance of UHMWPE used in total joint replacements
      has resulted in the widespread utilization of crosslinking as a method to improve
      wear resistance. Although crosslinking has been shown to drastically improve the
      wear resistance of the polymer, the potential trade-off in fatigue properties has
      yet to be addressed. Fatigue crack propagation resistance is a concern in tibial
      inserts where large cyclic stresses are sufficient to drive the growth of
      subsurface cracks that potentially contribute to delamination wear mechanisms.
      For clinical relevance, the combined effects of sterilization and aging are
      examined in two commercially available crosslinked resins. Nonsterile and unaged
      resins serve as a control. To evaluate the effect of crosslinking, a comparison
      is made to uncrosslinked resins. Scanning electron microscopy is used to provide
      an understanding of fatigue fracture mechanisms in the crosslinked polymers. The
      results of this study show that the current level of crosslinking used in
      orthopedic resins for enhanced wear resistance is not beneficial for fatigue
      crack propagation resistance.

PMID- 10398020
TI  - Surface characterization, protein adsorption, and initial cell-surface reactions
      on glutathione and 3-mercapto-1,2,-propanediol immobilized to gold.
AB  - Monolayers of glutathione (GSH) and 3-mercapto-1,2-propanediol (MG) on gold were
      tested for their bioreactivity by assessing the degree of inflammatory reaction
      as manifested by the adherence and activation of platelets and white blood cells
      (wbc) after exposure to blood ex vivo. Surface composition was characterized by
      XPS, and noncontact optical profilometry was used to determine surface roughness.
      The thickness and composition of the adsorbed protein layers were measured by
      ellipsometry/antibody techniques in vitro. Cell adhesion and activation were
      quantified by acridine orange staining, fluorescein-diacetate staining, and by
      specific antibodies against cell membrane antigens. Distinct differences among
      the surfaces were observed relative to the amounts and composition of adsorbed
      plasma proteins and the adhesion and activation of platelets (CD62P-exposure) and
      wbc (CD11b/CD18-exposure). GSH surfaces, which adsorbed the least amount of
      plasma protein, caused the least adherence and activation of platelets (CD62P),
      followed by the highest activation of wbc (CD11b/18). The MG surfaces caused a
      rapid recruitment and activation of platelets (CD62P), followed by a lower
      activation of wbc (CD11b/18). Thus it appears that measurements of the initial
      adsorption of plasma protein from anticoagulated plasma and of the adhesion and
      activation of platelets after 8 min of exposure to whole blood cannot be used to
      predict accurately the adhesion and activation behavior of inflammatory cells
      after longer periods (2 h) of exposure on different surfaces.

PMID- 10398022
TI  - Physeal response to absorbable polydioxanone bone pins in growing rabbits.
AB  - Absorbable fixation materials would seem especially useful for treating
      transphyseal fractures in growing children, but their degradation products may
      affect physeal growth. The histologic response of an open physis to placement of
      transphyseal, polydioxanone (PDS), bioabsorbable pins was studied in skeletally
      immature New Zealand White rabbits. A 1.3-mm PDS pin was inserted across the
      right femoral physis, and a 1.3-mm empty drill hole across the left femoral
      physis served as a control. The animals were sacrificed at 3, 6, 9, and 12 weeks
      postsurgery. Biplanar radiographs, bone length measurements, and histology
      sections of the physis and adjacent bone were made. Three independent observers
      graded the histologic response of the physis to the drilling and implant. There
      was no evidence of inflammation, foreign body reaction, or distortion of the
      growth plate during the entire growth period. This suggests bioabsorbable pins do
      not cause any appreciable inflammatory response or adverse effect on physeal
      function during active longitudinal growth of the bone.

PMID- 10398021
TI  - Potential errors in FTIR measurement of oxidation in ultrahigh molecular weight
      polyethylene implants.
AB  - Potential sources of error in the use of FTIR to measure the level of oxidation
      in ultrahigh molecular weight polyethylene acetabular cups were evaluated using
      cups from a hip simulator wear study with and without artificial aging, as well
      as cups retrieved from clinically failed hip prostheses. Oxidation was measured
      as a function of depth below the bearing surface using transmission FTIR on
      microtomed sections of the cups. To account for the variation of the thickness of
      the microtomed sections, oxidation was plotted as the ratio of the absorbance of
      the carbonyl groups to the absorbance of a reference band at 2022 cm-1. Overnight
      soaking in hexane reduced the apparent levels of oxidation, presumably due to the
      extraction of absorbed contaminants. In cups with low to moderate levels of
      oxidation, the reference absorption was relatively independent of the level of
      oxidation and was linearly proportional to the thickness of the specimens,
      providing reproducible oxidation ratios. However, the scatter in the reference
      absorption and in the apparent oxidation ratio increased with increasing levels
      of oxidation and was greatest for the thickest (400 microm) microtomed sections.
      The profiles of the oxidation ratios for a given specimen that were plotted by
      the present study method could be numerically adjusted to coincide with the
      ratios plotted using the methods of two previous investigators, providing
      conversion factors that are useful for comparing results among the studies.

PMID- 10398023
TI  - Measurement of insertion torque of tapered external fixation pins: A comparison
      between two experimental models.
AB  - The aim of this study was to compare an in vitro versus an ex vivo experimental
      model to test the insertion torque of two different types of external fixation
      pins. A torque measuring machine was developed in order to perform accurate
      measurements. Forty tapered pins made of stainless steel were utilized. Half of
      the pins were plasma-spray coated with hydroxyapatite (HA) and the other half
      remained uncoated. For the in vitro model 20 cylinders were used that were made
      of synthetic polymer according to ASTM standards. For the ex vivo model 10 fresh
      femora harvested from adult sheep were used. All the pins were implanted after
      predrilling, and insertion torque was measured. Statistical analysis of the in
      vitro versus the ex vivo model showed significant differences in both coated (p <
      0. 0005) and uncoated (p = 0.002) external fixation pins. These results may be
      due to the surface roughness that caused significant friction between the HA
      coating and the polyvinylchloride in the in vitro model. The significant
      difference between the in vitro and ex vivo results lead us to state that the in
      vitro model does not realistically simulate the behavior of external fixation
      pins implanted in bone.

PMID- 10398024
TI  - Fabrication of submicron titanium-alloy particles for biological response
      studies.
AB  - Biologic response to generated wear particles and subsequent aseptic loosening is
      a critical factor limiting the long-term survival of total hip replacements. To
      better understand the sequence of events leading to aseptic loosening and the
      role of the individual material components, fabricating metal particles similar
      to those present clinically is very important. We describe a simple milling
      technique to generate significant amounts of fine titanium-alloy (TiAlV) debris.
      A TiAlV rod was milled against a TiAlV plate in distilled water supplemented with
      antibiotics. The resulting debris were sedimented in alcohol and the fine debris
      were separated. Scanning electron microscopy analysis and particle size analysis
      demonstrated that the mean size of particles was 1.1 +/- 0.9 microm (range 0.2
      4.2 microm). Sixty-two percent were smaller than 1.0 microm, and 85% were smaller
      than 2.0 microm. The particles generated had varying shapes, including angular or
      shard-like shapes with jagged and irregular outlines.

PMID- 10398025
TI  - Degradation of hydroxylapatite, fluorapatite, and fluorhydroxyapatite coatings of
      dental implants in dogs.
AB  - Calcium phosphate coatings on dental implants enhance integration of the
      material. Resorption of the ceramic coatings has raised some concern about the
      behavior of the bone-implant interfaces after the coating disappearance.
      Substitution of the OH- ions by fluoride in the hydroxylapatite (HA) lattice
      makes the calcium phosphate more stable. We investigated the degradation rate of
      dental implants with 50- and 100-microm coatings of HA, fluorapatite (FA), or
      fluorhydroxylapatite (FHA). The implants were inserted in dog jaws and retrieved
      for histological analysis after 3, 6, and 12 months. The thickness of the calcium
      phosphate coatings was evaluated using an image analysis device. A relative
      resorption index and its standard deviation were studied. HA and FA coatings
      (even at 100-microm thickness) were almost totally degraded within the
      implantation period. In contrast, the FHA coatings did not show significant
      degradation during the same period. The standard deviation showed that the
      resorption process for FHA with thicknesses of 50 or 100 microm was the same.
      Such a difference was not observed between the 50- and 100-microm thick coatings
      of FA and HA. In conclusion, the FHA coatings showed good integration in the bone
      tissue and lasted much longer than classic calcium phosphate coatings.

PMID- 10398026
TI  - Microporous segmented polyetherurethane vascular graft: I. Dependency of graft
      morphology and mechanical properties on compositions and fabrication conditions.
AB  - The influence of polyurethane compositions and fabrication conditions on the pore
      morphology and mechanical properties of microporous segmented polyetherurethane
      (SPEU) grafts, which were produced by the coagulation technique, were carefully
      investigated in this article. SPEU resins based on polytetramethylene oxide
      (PTMO) were synthesized by the solution polymerization method. Different types of
      coagulant were adapted to examine the feasibility of producing a microporous SPEU
      graft with good structural regularity. The experimental results indicate that a
      microporous SPEU graft with a uniform pore structure can be fabricated quite
      conveniently by using a proper concentration of water and ethanol mixed
      coagulant. Tensile tests demonstrated that the fabricated microporous SPEU grafts
      possess high mechanical strengths and satisfy the requirements as vessel
      replacements. The burst strength test also revealed that the SPEU graft can
      sustain extremely high internal pressure. Furthermore, a high compliant SPEU
      (high porosity) graft can be obtained by blending a proper amount of "soluble
      filler" (i.e., free PTMO polyol in this study) into the SPEU resin.

PMID- 10398027
TI  - Chemotaxis and activation of particle-challenged human monocytes in response to
      monocyte migration inhibitory factor and C-C chemokines.
AB  - Cytokines that regulate monocyte migration were found in membrane tissue
      surrounding loosened prosthetic implants. Monocyte migration inhibition factor
      (MIF) is able to inhibit macrophage migration. Monocyte chemoattractant protein
      (MCP) and macrophage inflammatory protein (MIP) are potent macrophage
      chemoattractants. These cytokines may be expressed as part of the foreign body
      response to prosthetic particulate debris. Chemotaxis analysis and macrophage
      activation experiments were performed to determine the effects of MIF, MCP-1, and
      MIP-1alpha on macrophage migration and activation in vitro. We demonstrated that
      MIF had its maximal migration inhibitory effect for unchallenged and particle
      challenged macrophages at 1 ng/mL. MCP-1 and MIP-1alpha stimulated macrophage
      chemotaxis maximally at 1 to 10 ng/mL. Dose-response studies with MIF, MCP-1, and
      MIP-1alpha demonstrated that these cytokines did not modulate activation of
      unchallenged or particle challenged macrophages as evaluated by IL-6 and TNF
      alpha release. However, these cytokines do not appear to affect macrophage
      release of proinflammatory mediators in vitro.

PMID- 10398028
TI  - Quantitative, low cycle, crack initiation fatigue testing of fine wires and
      CENELEC standard pacing coil.
AB  - Uniaxial fatigue testing was performed on different diameters of fine wires made
      from MP35N. The fatigue limits of the wires differed from each other based on the
      diameter of the wire. Multiaxial (shear) fatigue testing was also performed on a
      benchmark coil used to evaluate the fatigue life of all modern pacemaker leads
      (the CENELEC standard coil). A computer algorithm was used to quantify the
      maximum shear stress and strain on the coil. The bend radius, coil diameter, wire
      diameter, and pitch of the coil all affect the shear stress and strain and
      therefore the fatigue properties of conductor coils. Based on the analysis
      presented, it was determined that the portion of the CENELEC standard dealing
      with fatigue, when used in its present format, is not a valid fatigue test for
      pacemaker leads.

PMID- 10398029
TI  - Thermal creep analysis of noble metal alloys for the ceramic-fused-to-metal
      technique.
AB  - Distortion of metal frameworks for the ceramic fused to metal technique during
      firing is attributed to thermal creep of the alloys. Usually thermal creep
      measurements are performed at constant load and constant temperature over varying
      time periods. Because metal frameworks for the ceramic-fused-to-metal technique
      are cyclically stressed, a three-point bending test for dynamic measurement of
      creep in a modified dilatometer was developed. Bending of 14 commercially
      available noble metal alloys was determined in the as-cast state, as well as
      after simulation of the firing process. The sag at 950 degrees C, which is the
      firing temperature of the ceramic, was chosen as an indicator for creep. No
      correlation of this value to other technical data of the alloys was observed, but
      it was found that sag correlates with the sum of the Au and Ag content of the
      alloys. A strong sag was observed with high (Au + Ag) content. The lowest sag
      values were found with a content in the range of 50 atom % (Au + Ag). At lower
      (Au + Ag) content Pd becomes the main component in the alloys, and the values for
      sag increased slightly. The method for dynamic measurement of creep gave
      reproducible results and offers a possible test for rapid qualitative creep
      assessment.

PMID- 10398030
TI  - Osteoconductivity and bone-bonding strength of high- and low-viscous bioactive
      bone cements.
AB  - A study was conducted to evaluate the osteoconductivity and bone-bonding ability
      of two types of bioactive bone cement, both consisting of apatite and
      wollastonite containing glass-ceramic powder (AW-P), fused silica glass powder
      (SG-P), submicron fumed silica as an inorganic filler, and bisphenol-a-glycidyl
      methacrylate (Bis-GMA) based resin as an organic matrix. The cements had two
      kinds of formulas: one (dough-type cement; designated DTC) composed of 85% (w/w)
      filler and 15% resin, which was developed for fixation of the acetabular
      component in total hip arthroplasty and could be handled manually; and one
      (injection-type cement; designated ITC) composed of 79% (w/w) filler and 21%
      resin. ITC was developed for fixation of the femoral component and, because it
      had a lower viscosity than DTC, could be injected. The DTC and ITC both contained
      73% AW-P, 25% SG-P, and 2% fumed silica in the weight ratio of the filler
      component. Two other types of cement, both of which consisted of 83.3% AW-P or SG
      P, 1.7% fumed silica, and 15% resin, were used as reference material (designated
      AWC or SGC) for a detaching test. Following the packing of bone defects in the
      rat tibiae with either DTC or ITC, histological examination revealed that the DTC
      and ITC had both directly contacted the bone and were almost completely
      surrounded by bone by 16 weeks after the surgery and that no marked
      biodegradation had occurred at 52 weeks postimplantation. Rectangular plates (2 x
      10 x 15 mm) of AWC, DTC, ITC, and SGC were implanted into the metaphysis of the
      tibia of male rabbits and the failure load was measured by a detaching test at 10
      and 25 weeks after implantation. The failure loads of AWC, DTC, ITC, and SGC were
      3.65, 2.21, 2.44, and 0.04 kgf at 10 weeks and 4.87, 2. 81, 2.82, and 0.13 kgf at
      25 weeks, respectively. Observation of the bone-implant interface by scanning
      electron microscopy and energy dispersive X-ray microanalysis revealed that all
      the samples except SGC formed direct contact with the bone and that only AWC
      implanted tibiae had a layer of a low calcium and phosphorus level at the bone
      implant interface. Results showed that DTC and ITC have excellent
      osteoconductivity and bone-bonding ability under non-weight-bearing conditions.

PMID- 10398031
TI  - Factors responsible for pulp cell cytotoxicity induced by resin-modified glass
      ionomer cements.
AB  - Resin-modified glass ionomer cements (RM-GICs) are the last generation of GICs
      commonly used in restorative dentistry. They contain various resins that improve
      their mechanical properties. These modifications, however, may also affect their
      biocompatibility. We compared the cytotoxicity of seven biomaterials (five RM
      GICs, one metal-reinforced GIC (M-GIC), and a zinc-oxyphosphate cement) using an
      assay of pulp cell viability in vitro (MTT assay). The most toxic materials
      appeared to be the M-GIC Hi-Dense and the RM-GIC Vitremer. The less toxic ones
      appeared to be the RM-GICs Compoglass and Photac-Fil. Attempts made to identify
      the factors responsible for their cytotoxicity indicated that in vitro
      cytotoxicity did not seem to be caused by any change in pH of the biomaterial
      eluates. Adsorption of biomaterial eluates on dentin powder significantly reduced
      the cytotoxicity of all biomaterials. The concentration of F-, Sr2+, and Al3+
      (major ionic elements present in GICs) in the eluate of six glass ionomer
      containing biomaterials was too low to be cytotoxic. However, Cu2+ and Ag+
      (present in alloys of M-GIC) were present in toxic concentrations in Hi-Dense
      eluates. Unpolymerized monomers leached from resins were identified by Fourier
      transform IR spectroscopy in biomaterial eluates. The monomers hydroxyethyl
      methacrylate (HEMA), triethylene glycol dimethacrylate (TEGDMA), and
      poly(acrylic) acid were identified in eluates of Vitremer, Compoglass, and Hi
      Dense, respectively. After ethanol elution of HEMA and TEGDMA from Vitremer and
      Compoglass, respectively, the cytotoxicity of these two RM-GICs was drastically
      reduced. Our results suggest that the principal compounds responsible for
      cytotoxicity are unpolymerized resin monomers in the two RM-GICs and Cu2+ and Ag+
      in the M-GIC.

PMID- 10398032
TI  - Interaction between carbon composites and bone after intrabone implantation.
AB  - Candidate carbon fiber reinforced carbon (CFRC) porous implant materials were
      evaluated for tissue compatibility in a rat model. Six different CFRCs of
      constant pore size (about 30 microm) were fabricated that had 9, 12, and 17%
      porosity with 2-nm3 matrix crystallites and 6, 12, and 20% at 25 nm3. They were
      implanted as femoral transverse diaphyseal pins that were 1.5 mm in diameter. At
      5 and 45 weeks, implant and bone histologic specimens were evaluated
      histologically and by a scanning electron microscope and an electron microprobe.
      Also, regional lymph nodes and spleens were examined. By 45 weeks, direct implant
      bone contact was observed over most of the interface in most specimens. At the
      implant surface, there was partial replacement of CFRC with host tissue. However,
      the microprobe showed that the implant-bone interface was chemically abrupt with
      no cross-diffusion of ionic species. Besides the surface effects, there was
      partial filling of the implant pores with tissue, including bone organized de
      novo deep within. This was observed histologically and confirmed by microprobe.
      Lymph nodes and spleens were histologically normal, and no carbon particles were
      found. None of the results were influenced by porosity or matrix crystallite size
      over the ranges studied. In summary, these porous CFRCs are partially degraded
      when in contact with bone and appear substantially tissue compatible. They may be
      useful as scaffolds for regrowth of bone.

PMID- 10398033
TI  - A simple multi-specimen apparatus for fixed stress fatigue testing.
AB  - To cope with the time-consuming characteristics of fatigue tests, a multi
      specimen fatigue testing apparatus, which could test 10 specimens at a time, was
      designed, constructed, and tested. The specimens are fixed around a rotating
      axis, and the required stresses are applied by weights attached on the other end
      of each specimen. The test mode can be categorized as a stress-controlled
      flexural fatigue test. Its performance was tested by comparing it with a
      commercial three-point bending fatigue testing apparatus. The stress versus
      number of cycles to failure curves of poly(methylmethacrylate) (PMMA), which were
      obtained from both fatigue testing equipment, showed results that were similar to
      each other. The fatigue test results of acrylic bone cement in a fixed-stress
      mode also showed good agreement between the data obtained from the new apparatus
      and the commercial apparatus. The test results seem quite reliable and show
      feasibility of significantly reducing the overall test periods. It may be
      valuable, especially for the fatigue tests, which must be done with a low
      frequency and a low applied stress level such as a fatigue test of bone cements.

PMID- 10398034
TI  - The wear of a polyethylene socket articulating with a zirconia ceramic femoral
      head in canine total hip arthroplasty.
AB  - Wear of yttria-zirconia (zirconia) in the femoral head was investigated in mature
      mongrel dogs weighing 10 to 13 kg. Two dogs, which were used as a control group,
      were sacrificed 18 months after implantation of the uncemented modular hip system
      with an alumina ceramic (alumina) femoral head. A zirconia femoral head was
      implanted in five dogs: one was sacrificed 12 months after implantation, two at
      18 months, and two at 24 months. In each femoral head and polyethylene (PE)
      socket, the surface was observed by means of scanning electron microscopy (SEM);
      the mean articulation surface roughness on the femoral head and PE socket and the
      thickness of the PE socket were measured. Wear was not seen on the surface of
      either the zirconia or the alumina heads. In both groups, minute white spots on
      the smooth surface of the PE socket were visible by SEM. In the alumina and
      zirconia groups the mean roughness was 0.1 microm. The mean thickness of the PE
      socket was reduced by 0.2 mm in the alumina group. In the zirconia group it was
      reduced by 0.2 to 0.3 mm. However, the mechanical strength of zirconia is known
      to be greater than that of alumina and it may be possible to reduce the diameter
      of the femoral head. The smaller zirconia head may contribute to the reduction of
      the wear of the PE socket in an uncemented modular total hip system.

PMID- 10398035
TI  - Biocompatibility and degradation of collagen bone anchors in a rabbit model.
AB  - Bone anchors are used to fasten tendons and ligaments to bone during
      reconstructive surgery. Although metal anchors are often used, an anchor that
      could resorb and permit normal bone regeneration would be advantageous. The
      objective of the study was to evaluate the biocompatibility and degradation of
      bone anchors that consist of collagen-based bodies, ceramic washers, and
      polyester sutures. Eighteen rabbits underwent bilateral implantations in the
      distal femoral condyles. Nine animals received glutaraldehyde-crosslinked
      fibrillar collagen bone anchors (FC) and nine received glutaraldehyde-crosslinked
      fibrillar collagen bone anchors containing tricalcium phosphate (FC-TCP). Three
      animals per group were sacrificed at postimplantation weeks 1, 6, and 12. One
      femur from each rabbit was evaluated histologically, and the contralateral side
      underwent biomechanical pull-out testing. Histological evaluation of the implant
      site indicated that the FC and FC-TCP bone anchors were both biocompatible. The
      FC-TCP formulation degraded earlier than the FC formulation, and FC-TCP showed
      significant degradation at 6 weeks; the FC and FC-TCP formulations both showed
      similar amounts of degradation at 12 weeks. The degrading anchor bodies appeared
      to be osteoconductive as evidenced by new bone ingrowth into the degrading
      collagen matrices without a fibrous interface. These results suggest that
      collagen-based bone anchors have potential as bioresorbable orthopedic implants.

PMID- 10398036
TI  - Evaluation of fibrin sealants in cutaneous wound closure.
AB  - Human fibrin sealant (HFS) and bovine fibrin sealant (BFS) were delivered as
      preformulated fibrinogen-thrombin mixtures that are light activated. These
      formulations were evaluated in the healing of incised cutaneous wounds in beagle
      dogs. Four groups were differentiated by sealant type and study duration with
      group: BFS for 10 days, HFS for 10 days, BFS for 30 days, and HFS for 30 days.
      Healing was evaluated by noting incidences of open wounds, laser Doppler
      perfusion imaging (LDPI), planimetry, breaking strength, and histopathology. In
      the absence of tension, both sealants tended to hold wound edges together;
      however, HFS tended to be better than its controls and BFS. Both sealants
      augmented suture closure, necessitating fewer sutures for wound closure. At 5 and
      30 days BFS wounds had more perfusion than HFS wounds, indicating more
      inflammation. At 10 and 30 days BFS wounds had larger scar areas than their
      controls, while scar areas of HFS wounds were smaller than either BFS wounds or
      controls. Breaking strengths indicated that HFS wounds were stronger than their
      controls and BFS wounds. Histologically, mild to moderate chronic-active
      inflammation was observed in wounds receiving either sealant, and this persisted
      longer in BFS wounds. Overall, HFS had positive qualities, thus showing potential
      for functional and cosmetic wound closure.

PMID- 10398037
TI  - Proliferation, morphology, and protein expression by osteoblasts cultured on
      poly(anhydride-co-imides).
AB  - In vitro cell biocompatibility models are crucial in the study of any newly
      synthesized material. Our focus has been on the development of a new class of
      biocompatible, degradable, high-strength polymeric materials, the poly(anhydride
      co-imides), for use in bone regeneration. This study examined osteoblast cell
      adherence, proliferation, viability, and phenotypic preservation on the surface
      of the poly(anhydride-co-imide) poly[pyromellitylimidoalanine (PMA-ala):1,6
      bis(carboxyphenoxy) hexane (CPH)] over a period of time. Cell proliferation on
      PMA-ala:CPH degradable matrices over 21 days was examined. Throughout the 21-day
      period of study, osteoblast proliferation was similar on PMA-ala:CPH and on
      tissue culture polystyrene controls. Osteoblasts maintained their characteristic
      morphology as demonstrated by both scanning electron microscopy and
      immunofluorescence studies. Alkaline phosphatase activity for cells grown on PMA
      ala:CPH was confirmed. Retention of the osteoblastic phenotype was demonstrated
      using immunofluorescence techniques and staining with antibodies against
      osteocalcin (an extracellular matrix protein of bone) and osteopontin (a marker
      of cell adhesion). Radioimmunoassay results provided evidence that levels of
      osteocalcin production by osteoblasts were similar when cells were cultured on
      PMA-ala:CPH and on tissue culture polystyrene controls. The present study
      provided evidence of normal osteoblast function on PMA-ala:CPH surfaces. PMA
      ala:CPH may therefore be useful as a synthetic material for orthopedic
      applications.

PMID- 10398038
TI  - Polyethylene oxide additive-entrapped polyvinyl chloride as a new blood bag
      material.
AB  - Until now, most widely used blood bag material has been a plasticized polyvinyl
      chloride (PVC) because it has many desirable properties as a blood bag material.
      One of main concerns of using plasticized PVC as a blood bag material is the
      toxicity of the plasticizers that are leached out of the material. We tried to
      solve this problem by the addition of polyethylene oxide (PEO)-containing
      amphiphilic block copolymers as additives in the PVC. The PEO additives may play
      two roles: they can act as nontoxic plasticizers to PVC, and they can also act as
      blood-compatible surface modifiers. In this study, PEO additive-entrapped PVC
      films were prepared by the addition (up to 30 wt%) of PEO-alkyl carbon block
      copolymers or PEO-polypropylene oxide (PPO)-PEO triblock copolymers with
      different PEO chain lengths in the PVC. The prepared PEO additive-containing PVC
      films were characterized by the measurements of water contact angle, Fourier
      transform IR spectroscopy in the attenuated total reflectance mode, mechanical
      properties (tensile strength and elongation at break), water absorption, and
      stability of the PEO additives entrapped in the films. It was observed that the
      PEO additive-entrapped PVC films were flexible and transparent. It seems that the
      PEO additives are surface active, resulting in the considerable change of surface
      characteristics without a significant change of the mechanical properties of the
      films compared to the control PVC without any additives or a commercial blood
      bag. The adhesion of platelets on the film surfaces was significantly reduced by
      the addition of PEO additives. It seems that 10% addition of PEO additives is
      enough for the suppression of platelet adhesion on the surfaces. This study
      demonstrated that the use of PEO-containing block copolymers as additives to the
      PVC can be a feasible approach to prepare a new type of blood bag.

PMID- 10398039
TI  - A bibliography of monographic works on biomaterials and biocompatibility: update
      II.
AB  - This bibliography includes monographs published from 1996 to 1998 and serves to
      update two previous bibliographies by the same title that together covered the
      years 1973 to 1995. All three bibliographies are indexed as a combined work by
      conference titles, series titles, and names of associated corporate bodies
      including professional society, research institute, and government agency names.

PMID- 10398040
TI  - Hydrolytic degradation characteristics of aliphatic polyesters derived from
      lactic and glycolic acids.
AB  - During the past decade, important advances have been made in the understanding of
      the hydrolytic degradation characteristics of aliphatic polyesters derived from
      lactic acid (LA) and glycolic acid (GA). Degradation of large poly(LAGA) (PLAGA)
      polymers is autocatalyzed by carboxyl end groups initially present or generated
      upon ester bond cleavage. Faster internal degradation and degradation-induced
      morphological and compositional changes are three of the most important findings
      deduced from the behaviors of various PLAGA polymers. This review presents the
      state of the art in this domain. The research efforts are focused on detailing
      the degradation mechanism and the effects of various factors on the degradation
      of PLAGA polymers. An attempt is also made to elaborate a scheme that can be used
      to predict degradation characteristics of these polymers from their initial
      composition and morphology.

PMID- 10398041
TI  - Silicone gel breast implant failure and frequency of additional surgeries:
      analysis of 35 studies reporting examination of more than 8,000 explants.
AB  - Although it is well known that silicone gel breast implants (SGBIs) produce many
      "local" complications (i.e., pain, hard fibrous capsules, disfigurement, chronic
      inflammation, implant shell failure) and necessitate frequent surgical revisions,
      no large cohort retrospective quantitative analysis of clinical data has been
      reported to date, especially for the prevalence of failures and additional
      surgeries. Data from 35 different studies that encompass more than 8000 explanted
      SGBIs have now been analyzed and are reported here. Because examination of a
      prosthesis when explanted is the definitive method for determining shell
      integrity, the only studies that were used were ones that reported implant
      duration, the total number of SGBIs explanted, and the number of SGBIs for which
      shell rupture or failure ("not intact") was confirmed upon surgical removal. An
      exponential regression plot of data indicated a direct correlation of implant
      duration with percent shell failure (r2 = 0. 63 and r = 0.79 ). SGBI failure was
      found to be 30% at 5 years, 50% at 10 years, and 70% at 17 years. The failure
      rate was 6% per year during the first 5 years following primary implant surgery.
      ANOVA comparison of three implant age groups (mean implant durations of 3. 9,
      10.2, and 18.9 years) indicated a highly significant statistical correlation of
      percent failure with implant duration (p < 0.001). Complications necessitating at
      least one additional surgery occurred for 33% of implants within 6 years
      following primary implant surgery. Shell failure was found to be an order of
      magnitude greater than the 4 to 6% rupture prevalence suggested by the AMA
      Council on Scientific Affairs in 1993, the 0.2 to 1.1% cited by manufacturers at
      that time, and the 5% rupture that was stated to be "not a safety standard that
      the FDA can accept."

PMID- 10398042
TI  - Multitechnique characterization of articular surfaces of retrieved ultrahigh
      molecular weight polyethylene acetabular sockets.
AB  - The articular surfaces of 10 retrieved ultrahigh molecular weight polyethylene
      acetabular sockets were studied by optical microscopy, X-ray fluorescence
      spectrometry, multiple internal reflectance FTIR spectroscopy, scanning electron
      microscopy, and wavelength dispersive X-ray microanalysis. The results revealed
      characteristic wear patterns including polishing, scratching, pitting, cratering,
      folding, shredding, burnishing, cracking, embedding of particles, and development
      of acquired biofilms with various degrees of mineralization. The biofilms formed
      were mainly of proteinaceous origin, and mineralized regions were composed of
      calcium phosphates with carbonate impurities. The crystallinity of the
      polyethylene at the articular surfaces was enhanced compared to the bulk, which
      was possibly due to the cold work produced in vivo. The mineralized regions were
      classified into two groups based on the grey levels of the backscattered images
      obtained. The high-contrast regions that were mainly composed of Ca and P with
      traces of Al and Si were associated with bone fragments; the low-contrast regions
      composed of K, Na, Ca, Mg, Si, Al, Fe, Cl, and P were associated with acquired
      biofilm calcification, which implies the active engagement of biofilms in the
      long term performance of acetabular sockets in vivo.

PMID- 10398043
TI  - Clinical wear of 63 ultrahigh molecular weight polyethylene acetabular
      components: effect of starting resin and forming method.
AB  - This study compares the clinical wear rates and implant characteristics of 63
      surgically retrieved acetabular components. All components were made by the same
      manufacturer, implanted by the same surgeon, in articulation against the same
      type of femoral component, and revised for the same reason; 19 were made from
      directly compression molded, calcium stearate free, ultrahigh molecular weight
      polyethylene (UHMWPE) and 44 were made from machined, ram extruded, calcium
      stearate containing UHMWPE. There were significant differences in wear, duration,
      and wear rate between the molded (type I) and machined (type II and III)
      components. Most importantly, the wear rates of type I (molded) components were
      significantly (p < 0.0001) lower than the wear rates of type II, type III, and
      type II and III components as a group (all machined). The machined components had
      wear rates 2.3 times greater than the molded components. The wear rates between
      the two different groups of machined components (type II and III) were not
      significantly different. The scanning electron microscope observations did not
      reveal any major differences in wear mechanisms between the three types of
      components, although the machined components did show more evidence of
      brittleness. The molded components were better consolidated (or had less fusion
      defects) than the ram extruded components.

PMID- 10398044
TI  - Postmortem retrieval of total joint replacement components.
AB  - Improved understanding of the clinical outcomes of orthopedic implants requires
      the study of implants at the end of their service life. Previous studies focused
      on the retrieval of so-called failed implants during surgical revision. Interest
      is now moving to the study of successful implants, which are those still in place
      at the patient's death. A procedure was developed for recruitment of implant
      patients and their families and for safe and effective device and tissue
      retrieval after death. More than 50 retrievals were performed to support various
      research efforts.

PMID- 10398045
TI  - Regional differences in the sympathetic innervation of the guinea pig large
      intestine by neuropeptide Y- and tyrosine hydroxylase-immunoreactive nerves of
      divergent extrinsic origin.
AB  - Region-specific patterns of nerves with immunoreactivity to neuropeptide Y (NPY)
      have been described previously in the submucous plexus of guinea pig large
      intestine. Because these may have functional significance, the possibility of
      similar, characteristic variations of NPY-like immunoreactivity (NPY-ir) in the
      myenteric plexus was explored. Regional differences were found in the occurrence
      and pattern of distribution of NPY-ir in the myenteric plexus of the guinea pig
      large intestine. NPY-ir was present rarely within neuron somata in any region of
      the large intestine, and NPY-ir nerve fibers were present only within the distal
      large intestine, increasing progressively in density from the distal spiral to
      the rectum. Lesion of the colonic nerves, but not the hypogastric,
      intermesenteric, or lumbar splanchnic nerves, resulted in a loss of NPY-ir in the
      distal spiral and transverse colon but not in the descending colon or rectum.
      Ring myotomies in the descending colon resulted in a loss of NPY-ir proximal to
      the lesion. Dual-labeling immunohistochemical studies revealed that the NPY-ir
      nerve fibers rarely contained immunoreactivity for tyrosine hydroxylase (TH).
      Extrinsic nerve lesions resulted in an unequivocal reduction in NPY-ir in
      intraganglionic fibers of the submucosal plexuses of the transverse colon and a
      partial loss in the distal spiral and descending colon: the rectum was
      unaffected; in only a minority of guinea pigs, however, was any decrease in the
      NPY-ir innervation of submucosal blood vessels detected. The principal
      projections of NPY-ir nerves were from and through the inferior mesenteric
      ganglion; however, NPY-ir was not colocalized with TH-ir. It is proposed that
      nonnoradrenergic, NPY-containing neurons located in the inferior mesenteric
      ganglion project through the colonic nerves and that these proximally directed
      fibers innervate the transverse colon and the distal spiral. Nonnoradrenergic,
      NPY-ir neurons lying in the pelvic ganglia or sacral sympathetic chain may make
      an important contribution to the innervation of the myenteric plexus of the
      rectum and the descending colon.

PMID- 10398046
TI  - Expression and localisation of dynamin and syntaxin during neural development and
      neuromuscular synapse formation.
AB  - The expression and subcellular localisation of dynamin and syntaxin were examined
      during the periods of motor neuron development and neuromuscular synaptogenesis
      in the mouse embryo. Both dynamin and syntaxin could be detected by
      immunoblotting in the spinal cord at embryonic day 10 (E10; 2 days before axon
      outgrowth) and at all subsequent ages examined. Reverse transcription and
      polymerase chain reaction (RT-PCR) identified low levels of all three carboxy
      terminal splicing forms of dynamin I in spinal cord from as early as E10. During
      the period of maturation of spinal neurons, from E10 to the first postnatal day
      (P0), the short carboxy-terminal splicing form of dynamin I (dynamin I*b) was up
      regulated, as was dynamin III, relative to dynamin II mRNA. Syntaxin
      immunostaining became colocalized with the synaptic vesicle protein, SV2, at
      neuromuscular synapses within 12 hours of the commencement of synapse formation
      and throughout subsequent development. In contrast, dynamin, which is important
      for activity-dependent synaptic vesicle recycling and, thus, sustained
      neurotransmission, could not be detected at most newly formed synapses until
      several days after synapse formation. The delayed appearance of dynamin at the
      synapse, thus, heralds the neonatal development of robust synaptic transmission
      at the neuromuscular junction.

PMID- 10398047
TI  - Responses of neurons in the region of human thalamic principal somatic sensory
      nucleus to mechanical and thermal stimuli graded into the painful range.
AB  - The role of the region of the principal somatic sensory nucleus of the human
      thalamus (ventral caudal - Vc) in signaling painful sensations is unclear. We
      have now studied the response of cells (n = 57) in this region to both thermal
      and mechanical stimuli graded into the painful range during surgeries (n = 24)
      for treatment of movement disorders. Fifteen cells had a graded response to
      mechanical stimuli extending into the painful range and, thus, were classified in
      the wide dynamic range (WDR) category. The mean stimulus-response function of
      cells in the WDR class, normalized to baseline, showed a fourfold mean increase
      in firing rate above baseline across the mechanical series of stimuli. Seven of
      these cells responded to heat stimuli (WDR-H) and two responded to cold stimuli
      (WDR-C). Twenty-five cells were in a class (multiple receptive - MR) that showed
      a response to both brush and compressive stimuli, although the responses were not
      graded into the painful range. Three of these cells (MR-H) had a response to heat
      stimuli and five cells responded to cold stimuli (MR-C). Nine cells responded to
      brushing without a response to the compressive stimuli (low threshold - LT).
      Cells responsive to painful mechanical and thermal stimuli were located
      throughout the thalamic region where cells responded to nonpainful cutaneous
      stimulation. These results show that cells in the region of the human thalamic
      principal somatic sensory nucleus respond to mechanical and thermal stimuli
      extending into the painful range.

PMID- 10398048
TI  - Expression of presenilin 1 in nervous system during rat development.
AB  - Alzheimer's disease (AD) is a polygenic disorder involving at least four
      different genes. Among them, missense mutations in the presenilins segregate with
      the vast majority of early onset cases of familial AD. To elucidate possible
      function(s) of presenilin 1 (PS1), we have studied its expression during the
      development of the rat nervous system. Analysis by in situ hybridization showed
      expression of PS1 in a variety of cell types and tissues during development, with
      prominent expression in the nervous system. During late embryogenesis, the
      ventricular zone presented the highest levels of expression, paralleling the
      pattern previously reported for Notch. Later, during postnatal development, we
      observed a peak of PS1 expression at postnatal day 10, particularly in the
      cerebellum and hippocampus, a time when proliferation and migration are still
      ongoing and synapse formation is being completed. We propose that presenilins
      participate in at least two different developmental processes: (1) one involved
      in neurogenesis and skeleton formation during embryonic development, probably
      involving coordinate expression with Notch, and (2) a second one in the postnatal
      central nervous system, perhaps involved in neuritogenic and/or synaptogenic
      stages, most likely playing a role in amyloid precursor protein processing and
      amyloid beta production.

PMID- 10398049
TI  - Projections from the lateral vestibular nucleus to the upper cervical spinal cord
      of the cat: A correlative light and electron microscopic study of axon terminals
      stained with PHA-L.
AB  - Vestibulospinal axon collaterals in C1 and C2 were stained following injections
      of Phaseolus vulgaris leucoagglutinin (PHA-L) into the lateral vestibular nucleus
      (LVN). The distribution and geometry of collaterals within three regions of the
      ventral horn were determined at the light microscopic level. These processes were
      subsequently examined at the electron microscopic level to define the
      relationship between their ultrastructural characteristics and their geometry and
      location. All round or elliptical varicosities, whose diameters exceeded the
      diameter of the adjacent axon shaft by a factor of two, as measured at the light
      microscopic level, contained synaptic vesicles and contacted dendrites or somata.
      These varicosities accounted for 82% of labelled axon terminals found at the
      electron microscopic level. Thus, axon terminals stained with PHA-L can be
      identified reliably at the light microscopic level, but synaptic density will be
      slightly underestimated. One-hundred and thirty-eight axon terminals were
      classified as excitatory or inhibitory on the basis of well-established
      morphological criteria (e.g., vesicle shape). Placed in the context of previous
      physiological observations describing the excitatory or inhibitory actions of
      medial and lateral vestibulospinal tract (MVST and LVST) neurons, our results
      suggest that projections from the LVN to the ipsilateral ventral horn originate
      primarily from the LVST. These connections are excitatory. Ipsilateral
      connections via the MVST are inhibitory and are largely confined to a region near
      the border of laminae VII and VIII. Most axon terminals in the contralateral
      ventral horn were inhibitory. This result indicates that the LVN is the source of
      a specific subset of crossed MVST axons with inputs from the posterior
      semicircular canal.

PMID- 10398050
TI  - Median raphe serotonergic innervation of medial septum/diagonal band of broca
      (MSDB) parvalbumin-containing neurons: possible involvement of the MSDB in the
      desynchronization of the hippocampal EEG.
AB  - Activation of median raphe serotonergic neurons results in the desynchronization
      of hippocampal electroencephalographic (EEG) activity. This could be a direct
      effect, because serotonin (5-HT) fibers terminate on a specific population of
      hippocampal interneurons. On the other hand, it could be an indirect action
      through the medial septum/diagonal band of Broca (MSDB) pacemaker cells, because,
      in addition to previously described inhibitory effects, excitatory actions of 5
      HT have been demonstrated on MSDB gamma-aminobutyric acid (GABA)-containing
      neurons through 5-HT2A receptors. Electron microscopic double immunostaining for
      Phaseolus vulgaris-leucoagglutinin (PHA-L) injected into the median raphe (MR)
      and parvalbumin, choline acetyltransferase, or calretinin as well as double
      immunostaining for 5-HT and parvalbumin, and colocalization for parvalbumin and 5
      HT2A receptors were done in rats. The results demonstrated that: 1) MR axons form
      perisomatic and peridendritic baskets and asymmetric synaptic contacts on MSDB
      parvalbumin neurons; 2) these fibers do not terminate on septal cholinergic and
      calretinin neurons; 3) 5-HT fibers form synapses identical to those formed by PHA
      L-immunolabeled axons with parvalbumin neurons; and 4) MSDB parvalbumin cells
      contain 5-HT2A receptors. These observations indicate that 5-HT has a dual action
      on the activity of hippocampal principal cells: 1) an inhibition of the input
      sector by activation of hippocampal GABA neurons that terminate exclusively on
      apical dendrites of pyramidal cells, and 2) a disinhibition of the output sector
      of principal neurons. MSDB parvalbumin-containing GABAergic neurons specifically
      innervate hippocampal basket and chandelier cells. Thus, 5-HT-elicited activation
      of MSDB GABAergic neurons will result in a powerful inhibition of these GABA
      neurons.

PMID- 10398051
TI  - Expression of NR2 receptor subunit in rat somatic sensory cortex: synaptic
      distribution and colocalization with NR1 and PSD-95.
AB  - Functional N-methyl-D-aspartate (NMDA) receptors comprise heteromeric
      combinations of NR1 and NR2 subunits. In the present study, we employed light and
      electron microscopic immunocytochemistry to study the expression of NR2A and NR2B
      (NR2A/B) protein in somatic sensory cortex of adult rats. To relate this
      distribution to that of NR1 and to the NMDA receptor anchoring protein PSD-95, we
      documented extensive cellular colocalization of NR2A/B with NR1 at the light
      microscopic level. In contrast, PSD-95 exhibited little somatic staining, being
      restricted mainly to dendrites and neuropil. We employed postembedding
      immunocytochemistry to study the ultrastructural expression of NR2A/B. Labeling
      in neuronal perikarya was associated with rough endoplasmic reticulum and Golgi
      apparatus; in dendrites, gold particles labeled microtubules. The preponderance
      of labeling was associated with asymmetric synapses. Double immunolabeling
      revealed that NR2 colocalized in many synapses with NR1 and with PSD-95.
      Quantitative measurements revealed that density of gold particles coding for both
      NR2 and PSD-95 was highest just inside the postsynaptic membrane. Tangentially
      along the membrane, gold particles were concentrated at the synaptic
      specialization. These data provide structural evidence in neocortex for
      heteromeric NMDA receptors anchored at the postsynaptic membrane.

PMID- 10398052
TI  - Axonal regeneration of descending brain neurons in larval lamprey demonstrated by
      retrograde double labeling.
AB  - In larval lamprey, the large, identified descending brain neurons (Muller and
      Mauthner cells) are capable of axonal regeneration. However, smaller,
      unidentified descending brain neurons, such as many of the reticulospinal (RS)
      neurons, probably initiate locomotion, and it is not known whether the majority
      of these neurons regenerate their axons after spinal cord transection. In the
      present study, this issue was addressed by using double labeling of descending
      brain neurons. In double-label control animals, in which Fluoro-Gold (FG) was
      applied to the spinal cord at 40% body length (BL; measured from anterior to
      posterior from tip of head) and Texas red dextran amine (TRDA) was applied later
      to the spinal cord at 20% BL, an average of 98% of descending brain neurons were
      double labeled. In double-label experimental animals, FG was applied to the
      spinal cord at 40% BL; two weeks later the spinal cord was transected at 10% BL;
      and, eight weeks or 16 weeks after spinal cord transection, TRDA was applied to
      the spinal cord at 20% BL. At eight weeks and 16 weeks after spinal cord
      transection, an average of 49% and 68%, respectively, of descending brain
      neurons, including many unidentified RS neurons, were double labeled. These
      results in larval lamprey are the first to demonstrate that the majority of
      descending brain neurons, including small, unidentified RS neurons, regenerate
      their axons after spinal cord transection. Therefore, in spinal cord-transected
      lamprey, axonal regeneration of descending brain neurons probably contributes
      significantly to the recovery of locomotor function.

PMID- 10398053
TI  - Metabotropic glutamate receptors in superficial laminae of the rat dorsal horn.
AB  - Light and electron microscopic immunocytochemistry were employed here to show the
      distribution of metabotropic glutamate receptors (mGluRs) mGluR2/3 and mGluR5 in
      laminae I and II of the dorsal horn, to identify their pre- and postsynaptic
      location, and to test colocalization with gamma-aminobutyric acid (GABA).
      mGluR2/3 was mainly in the inner part of lamina II; mGluR5 was mainly in laminae
      I and II. Electron microscopy showed that both mGluR2/3 and mGluR5 were in
      perikarya, dendrites, and vesicle-containing profiles. Two main morphological
      types of primary afferent terminals can be distinguished in the superficial
      laminae: C1, likely to be endings of unmyelinated fibers, and C2, of small
      myelinated fibers. Quantitative data show that only a small fraction of C2s
      stained for either receptor; more common were immunopositive dendrites
      postsynaptic to these terminals, and most common were appositions between C2s and
      mGluR5 immunopositive dendrites. Vesicle-containing profiles were
      characteristically apposed to primary afferent terminals, mainly C2s.
      Immunopositivity for mGluRs, especially mGluR2/3, was present in vesicle
      containing profiles apposed to C2, none to C1, and about half of the profiles
      immunostained for either receptor were also stained for GABA. The presence of
      presynaptic and postsynaptic mGluRs in both inhibitory and excitatory
      interneurons may contribute to complex processing of fast and slow responses to
      peripheral input in superficial laminae. As selective agonists of mGluRs may
      modulate GABA release, the present demonstration of mGluRs in GABAergic terminals
      of presumed interneurons suggests that facilitatory effects may involve a
      mechanism of disinhibition.

PMID- 10398054
TI  - Molecular cloning of the cDNAs and distribution of the mRNAs encoding two
      somatostatin precursors in the African lungfish Protopterus annectens.
AB  - The occurrence of two somatostatin precursors, PSS1 and PSS2, yielding S-14 (SS1)
      and the variant [Pro2, Met13]S-14 (SS2), has been recently reported in the frog
      Rana ridibunda. The evolutionary significance of frog PSS2 is unclear because its
      sequence exhibits very little similarity with other known vertebrate somatostatin
      precursors. In the present study, we report on the characterization of two
      somatostatin precursor cDNAs from the brain of the African lungfish Protopterus
      annectens. One of the cDNAs encodes a 115-amino-acid protein that contains the
      SS1 sequence at its C-terminal extremity and thus is clearly homologous to PSS1.
      Comparison with other vertebrate PSS1 showed that lungfish PSS1 is more closely
      related to PSS1 from tetrapods than to PSS1 from fish. The other cDNA encodes a
      109-amino-acid protein that contains a somatostatin variant [Pro2]S-14 at its C
      terminal extremity. Sequence analysis of this second precursor indicated that it
      is the lungfish counterpart of frog PSS2. Northern blot analysis showed that
      lungfish PSS1 mRNA is widely distributed in the central nervous system and in
      peripheral organs, including the pancreas and gastrointestinal tract. In
      contrast, PSS2 mRNA was primarily found in the central nervous system but not in
      the pancreas or gut. In situ hybridization studies showed that the two genes are
      differentially expressed in various regions of the lungfish brain. The present
      data indicate that the PSS2 gene, initially discovered in frog, appeared early in
      vertebrate evolution, before the emergence of the tetrapod lineage. The recent
      isolation of a [Pro2]S-14 variant in the sturgeon, whose sequence is identical to
      that of lungfish SS2, suggests that the PSS2 gene may actually be present in the
      genome of all Osteichthyii.

PMID- 10398055
TI  - Characteristics of regenerating horizontal semicircular canal afferent and
      efferent fibers in the toadfish, Opsanus tau.
AB  - The horizontal semicircular canal nerve of the toadfish, Opsanus tau, was
      transected and allowed to regenerate. The time course, morphometrics, and
      projection patterns of regenerating afferent and efferent vestibular fibers were
      determined. Nerve transections were performed both pre- and postganglionically,
      and regeneration was assessed in afferent and efferent fibers by bulk labeling
      the peripheral axons of the horizontal semicircular canal nerve with biocytin
      after nerve regrowth. Afferent fibers regrew through the transection site within
      14 days and projected to all vestibular nuclei within 3 weeks. Bouton and branch
      number, axon length, surface area, volume, fiber diameter, and internodal
      distance were quantified for afferent fibers from eight sites within the
      vestibular nuclei, and axon number and soma size was quantified for the efferent
      fibers. Extensive regeneration was seen within 5 weeks of transection in all
      nuclei, and most morphometric parameters approached or exceeded control levels
      within 10 weeks. Regeneration appeared to recapitulate morphogenesis with an
      initial overproduction of boutons and branch points followed by elimination of
      presumably superfluous structures. Internodal distance remained significantly
      shorter in regenerating afferent axons than in control fish throughout the 15
      week observation period. Efferent fibers also were observed to regenerate.
      Efferent axon number, diameter, and soma size were indistinguishable from those
      in controls from 3 weeks posttransection through week 15. Electrophysiological
      recordings from the horizontal canal nerve during mechanical stimuli of the canal
      confirmed that the regenerated axons transmitted normal signals. The return of
      normal equilibrium and behavior coincided with the projection of afferent fibers
      into the central vestibular nuclei, indicating that functional connections had
      been reestablished.

PMID- 10398057
TI  - Molecular and developmental evolution editorial.

PMID- 10398056
TI  - GABAergic and non-GABAergic spiking interneurons of local and intersegmental
      groups in the crayfish terminal abdominal ganglion.
AB  - In the first step toward identifying the neurotransmitter released from spiking
      interneurons of both local and intersegmental groups in the crayfish terminal
      abdominal ganglion, the authors examined whether spiking local interneurons and
      ascending intersegmental interneurons contain the transmitter gamma-aminobutyric
      acid (GABA). In this paper, 17 identified ascending interneurons and three
      spiking local interneurons were stained by intracellular injection of Lucifer
      yellow and subsequently treated for immunocytochemical staining against GABA.
      Double-labeling experiments revealed that six identified ascending interneurons
      are GABAergic, but no spiking local interneurons show GABA-like immunoreactivity.
      Four ascending interneurons with GABA-like immunoreactivity (reciprocal closing
      ascending neuron 5 [RC-5], reciprocal opening ascending neuron 6 [RO-6], variable
      effect ascending interneuron 1 [VE-1], and no-effect ascending interneuron 4[NE
      4]) had cell bodies that formed a cluster on the ventral surface of the rostral
      edge of the ganglion, whereas two GABAergic interneurons (coinhibiting ascending
      interneuron 2 [CI-2] and NE-2) had cell bodies in a caudal region around the cell
      body of the seventh flexor inhibitor (FI) motor neuron. Another four rostral
      interneurons (RC-2, RC-3, RC-4, and NE-3) and seven caudal interneurons (CI-3, RC
      7, RO-1, RO-2, RO-3, RO-4, and NE-1) had no GABA-like immunoreactivity. Because
      VE-1 is known to make direct inhibitory connections with other ascending
      interneurons, whereas RC-3 and RO-1 are known to make direct excitatory
      connections, the immunocytochemical results from this study are consistent with
      previous physiological studies. Although many spiking local interneurons
      (including spiking local interneuron 1 of the anterior group [sp-ant1]) made
      direct inhibitory connections with nonspiking local interneurons, three spiking
      local interneurons (sp-ant1, spiking local interneuron 6 of the medial group [sp
      med6], and spiking interneuron 5 of the posterior group [sp-post]) do not show
      GABA-like immunoreactivity. These results suggest that the inhibitory transmitter
      released from spiking local interneurons is not GABA but that another substance
      mediates the inhibitory action of these interneurons. J. Comp. Neurol. 410:677
      688.

PMID- 10398067
TI  - Drosophila larval neuromuscular junction's responses to reduction of cAMP in the
      nervous system.
AB  - We investigated the effects of chronically lowered cyclic adenosine monophosphate
      (cAMP) on the morphology and physiology of the Drosophila larval neuromuscular
      junction, using two fly lines in which cAMP was significantly lower than normal
      in the nervous system: (a) transgenic flies in which the dunce (dnc) gene product
      was overexpressed in the nervous system, and (b) flies mutant for the rutabaga
      gene (rut1) which have reduced adenylyl cyclase activity. In comparison with
      controls, larvae with reduced cAMP exhibited a smaller number of synaptic
      varicosities. This effect was more pronounced in transgenic larvae, in which the
      reduction of neural cAMP was more pronounced. Synaptic transmission was also
      reduced in both cases, as evidenced by smaller excitatory junctional potentials
      (EJPs). Synaptic currents recorded from individual synaptic varicosities of the
      neuromuscular junction indicated almost normal transmitter release properties in
      transgenic larvae and a modest impairment in rut1 larvae. Thus, reduction in EJP
      amplitude in transgenic larvae is primarily due to reduced innervation, while in
      rut1 larvae it is attributable to the combined effects of reduced innervation and
      a mild impairment of transmitter release. We conclude that the major effect of
      chronically lowered cAMP is reduction of innervation rather than impairment of
      transmitter release properties.

PMID- 10398068
TI  - Basic fibroblast growth factor promotes epidermal growth factor responsiveness
      and survival of mesencephalic neural precursor cells.
AB  - Epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induce
      proliferation of neural precursor cells from several central nervous system
      regions in vitro. We have previously described two neural precursor cell
      populations from 13.5 days postcoitium (dpc) mesencephalon, one forming colonies
      in response to EGF, present in the ventral mesencephalon, and other forming
      colonies in response to EGF + bFGF, mainly present in the dorsal mesencephalon.
      In the present work, we show that 13.5 dpc dorsal mesencephalic cells required
      bFGF only for 1 h to form colonies in response to EGF alone, indicating that
      these two growth factors act in sequence rather than simultaneously. Absence of
      bFGF at the beginning of the culture gave rise to very few colonies, even after
      the addition of EGF + bFGF, suggesting that cells responsive to bFGF were very
      labile in the primary culture condition. This result is in contrast with cells
      pretreated with bFGF, which could survive for up to 5 days in the absence of bFGF
      or EGF, and then were capable of efficiently forming colonies in response to EGF.
      Basic FGF was also able to support survival of EGF-responsive neural precursors
      from both ventral and dorsal mesencephalon. The population requiring bFGF to form
      colonies in response to EGF was identified at different developmental stages
      (11.5-15.5 dpc), with higher contribution to the total number of neural
      precursors cells detected (EGF-responsive plus bFGF-responsive) at early stages
      and in the dorsal region. We show that the differentiation effect of bFGF
      resulted in the appearance of the mRNA coding for the EGF receptor. Our data
      suggest that bFGF-responsive neural precursors are the source of EGF-responsive
      neural precursors.

PMID- 10398069
TI  - Development of the labial pit organ glomerulus in the antennal lobe of the moth
      Manduca sexta: the role of afferent projections in the formation of identifiable
      olfactory glomeruli.
AB  - Iterated neuropil modules called glomeruli are characteristic of primary
      olfactory centers in both vertebrates and invertebrates. To gain insight into the
      developmental mechanisms underlying the formation of such structured, organized
      neuropil, we have examined the development of an identified glomerulus in the
      olfactory (antennal) lobe of the moth Manduca sexta. The labial pit organ
      glomerulus (LPOG) receives bilateral sensory projections from the labial pit
      organs in the labial palps of the mouthparts, while other glomeruli in the
      antennal lobe receive unilateral projections from the antenna. Here, we chronicle
      the development of the LPOG under normal and perturbed conditions. Our findings
      suggest that the sensory axons of the labial pit organ, like those of the
      antenna, induce and shape growth of interneuronal arborizations, but specific
      features of interneuronal arborizations such as the relative position of
      glomerular arborizations within the antennal lobe are independent of both classes
      of afferent innervation. Labial pit organ axons and antennal axons exhibit a high
      degree of specificity for their respective target regions, independent of the
      presence or absence of the other class of afferent axon or the route taken to the
      antennal lobe. Specification of glomerular position is intrinsic to the antennal
      lobe rather than a consequence of competition between afferent axons.

PMID- 10398070
TI  - Aggregates of acetylcholine receptors are not observed under anti-agrin staining
      schwann cell processes at the frog neuromuscular junction.
AB  - The frog neuromuscular junction offers a unique structure in which to observe
      fine details in the relationship between the motor neuron, muscle, and Schwann
      cell, which together comprise the neuromuscular junction. Schwann cell processes
      that extended from the synapse stained positively with anti-agrin antibodies.
      Immunocytochemistry revealed strong anti-agrin staining of the extracellular
      matrix surrounding the entire Schwann cell and the Schwann cell processes come in
      close contact with the muscle fiber. Dual-labeling experiments revealed a lack of
      acetylcholine receptor (AChR) aggregates on the surface of the muscle fiber
      directly under these anti-agrin-staining Schwann cell processes. The cDNA that
      codes for the C-terminal portion of agrin in frog (Rana pipiens) was cloned and
      sequenced. Polymerase chain reaction of frog brain, nerve, and muscle cDNA
      revealed that like other species, agrin transcripts that contain the B8, B11, or
      B19 inserts were observed only in brain tissue. Unlike other species, the exact
      site of the B inserts in frog was slightly altered, with the B insertion site
      occurring within a codon sequence. Our data are consistent with the hypothesis
      that Schwann cells produce agrin which lacks inserts at the B region, and that
      agrin lacking B inserts does not direct the aggregation of AChRs in vivo under
      physiological conditions and concentrations.

PMID- 10398071
TI  - Laminar restriction of retinal macrophagic response to optic nerve axotomy in the
      rat.
AB  - Following optic nerve transection, most of the retinal ganglion cells die. Their
      debris is promptly cleared by phagocytic cells. It is currently not known to what
      extent peripherally derived macrophages contribute to this activity. Using
      antibodies OX42 and ED-1, phagocytic cells were labeled in the retinas of optic
      nerve lesioned adult rats. To distinguish whether the cells were reactive
      microglial or macrophagic in origin, blood-borne monocytes were labeled with
      fluorescent microspheres while in the systemic circulation. Macrophages invaded
      the retina, but only in the nerve fiber layer, sparing the ganglion cell and
      other layers. These macrophages engulfed only the axonal debris from dying
      ganglion cells, not their degenerating cell bodies. These results indicate that
      although peripherally derived monocytic cells are recruited into the retrogradely
      degenerating retina, their role in clearing debris is limited to the optic fiber
      layer.

PMID- 10398073
TI  - Daily rhythmic changes of cell size and shape in the first optic neuropil in
      Drosophila melanogaster.
AB  - Daily rhythms of changes in axon size and shape are seen in two types of
      monopolar cell-L1 and L2-that are unique cells within each of the modules or
      cartridges of the first optic neuropil or lamina in the fly's optic lobe. In the
      fruit fly Drosophila, L1 and L2's axons swell at the beginning of both day and
      night, with larger size increases occurring at the beginning of night. Later,
      they shrink during the day and night, respectively. Simultaneously, they change
      shape from an inverted conical form during the day to a cylindrical one at night.
      This is because the axonal cross section of L1 increases during the night,
      especially at proximal depths of the lamina, closest to the brain, whereas the
      axon of L2 increases in size at distal lamina depths. The cross-sectional areas
      of the L1 cell and of an individual cartridge both change under constant darkness
      (DD), indicating the circadian origin of changes observed under day/night (LD)
      conditions. We sought to see whether such changes impart a net change to the
      entire lamina's volume or shape that is visible by light microscopy, but
      oscillations in the volume or the curvature of the whole lamina neuropil are
      found neither in LD nor in DD. These size changes are discussed in relation to
      previous findings in the housefly Musca, with respect to differences in L1 and L2
      between the two species, and to differences in the time course of their circadian
      changes.

PMID- 10398072
TI  - A single amino acid in the second transmembrane domain of GABA rho subunits is a
      determinant of the response kinetics of GABAC receptors.
AB  - The rho subunits that constitute the gamma-aminobutyric acid (GABA)C receptors of
      retinal neurons form a unique subclass of ligand-gated chloride channels that
      give rise to sustained GABA-evoked currents that exhibit slow offset
      (deactivation) kinetics. We exploited this property to examine the molecular
      mechanisms that govern the disparate response kinetics and pharmacology of perch
      GABA rho1B and rho2A subunits expressed in Xenopus oocytes. Using a combination
      of domain swapping and site-directed mutagenesis, we identified the residues at
      amino acid position 320 in the second transmembrane domain as an important
      determinant of the receptor kinetics of GABAC receptors. When the site contains a
      proline residue, as in wild-type rho1 subunits, the receptor deactivates slowly;
      when serine occupies the site, as in wild-type rho2 subunits, the time course of
      deactivation is more rapid. In addition, we found that the same site also altered
      the pharmacology of GABA rho receptors, e.g., when the serine residue of the
      rho2A receptor was changed to proline, the response of the mutant receptor to
      imidazole-4-acetic acid (I4AA) mimicked that of the rho1B receptor. However,
      despite gross changes in receptor pharmacology, the apparent binding affinity for
      the drug was not significantly altered. These findings provide further evidence
      that the second transmembrane domain is involved in the gating mechanism that
      governs the response properties of the various rho receptor subunits. It is
      noteworthy that the proline residue in native rho1 subunits and the serine
      residue of rho2 subunits are well conserved in all species, a good indication
      that the presence of multiple GABA rho subunits serves to generate GABAC
      receptors that display the wide range of response kinetics observed on various
      types of retinal neurons.

PMID- 10398074
TI  - Topographic regulation of cytoskeletal protein phosphorylation by multimeric
      complexes in the squid giant fiber system.
AB  - In mammalian and squid nervous systems, the phosphorylation of neurofilament
      proteins (NFs) seems to be topographically regulated. Although NFs and relevant
      kinases are synthesized in cell bodies, phosphorylation of NFs, particularly in
      the lys-ser-pro (KSP) repeats in NF-M and NF-H tail domains, seem to be
      restricted to axons. To explore the factors regulating the cellular
      compartmentalization of NF phosphorylation, we separated cell bodies (GFL) from
      axons in the squid stellate ganglion and compared the kinase activity in the
      respective lysates. Although total kinase activity was similar in each lysate,
      the profile of endogenous phosphorylated substrates was strikingly different.
      Neurofilament protein 220 (NF220), high-molecular-weight NF protein (HMW), and
      tubulin were the principal phosphorylated substrates in axoplasm, while tubulin
      was the principal GFL phosphorylated substrate, in addition to highly
      phosphorylated low-molecular-weight proteins. Western blot analysis showed that
      whereas both lysates contained similar kinases and cytoskeletal proteins,
      phosphorylated NF220 and HMW were completely absent from the GFL lysate. These
      differences were highlighted by P13(suc1) affinity chromatography, which revealed
      in axoplasm an active multimeric phosphorylation complex(es), enriched in
      cytoskeletal proteins and kinases; the equivalent P13 GFL complex exhibited six
      to 20 times less endogenous and exogenous phosphorylation activity, respectively,
      contained fewer cytoskeletal proteins and kinases, and expressed a qualitatively
      different cdc2-like kinase epitope, 34 kDa rather than 49 kDa. Cell bodies and
      axons share a similar repertoire of molecular consitutents; however, the data
      suggest that the cytoskeletal/kinase phosphorylation complexes extracted from
      each cellular compartment by P13 are fundamentally different.

PMID- 10398075
TI  - Cellular expression of a leech netrin suggests roles in the formation of
      longitudinal nerve tracts and in regional innervation of peripheral targets.
AB  - Netrins are secreted, diffusible proteins that direct axonal growth. To study the
      functions of netrins in the relatively simple and easily accessible nervous
      system of the leech Hirudo medicinalis, we have cloned a leech netrin and have
      characterized its expression during embryogenesis. By probing a leech cDNA
      library at low stringency with chick netrin probes, we have identified a complete
      cDNA clone that bears significant sequence similarity to netrins of other
      species. In situ hybridization and dye filling of individual neurons show that
      this leech netrin is expressed by several identifiable central neurons in every
      segmental ganglionic primordium during early stages of embryogenesis. Some of
      these neurons, including the bipolar cells which are thought to be involved in
      setting up longitudinal tracts, express this gene only transiently during
      embryogenesis, while others continue to express it in the adult. In addition,
      leech netrin is expressed by ventral but not dorsal longitudinal muscle cells in
      each segment before central neurons project their axons to the periphery. These
      highly specific expression patterns are consistent with the hypothesis that leech
      netrin plays a role in forming the major interganglionic neuronal tracts and in
      defining ventral versus dorsal domains of peripheral innervation.

PMID- 10398076
TI  - N-methyl-D-aspartate receptor-mediated modulation of monoaminergic metabolites
      and amino acids in the chick forebrain: an in vivo microdialysis and
      electrophysiology study.
AB  - The associative avian forebrain region medio-rostral neostriatum/hyperstriatum
      ventrale (MNH) is involved in auditory filial imprinting and may be considered
      the avian analogue of the mammalian prefrontal cortex. In search of the
      neurochemical and physiological mechanisms which play a role in this learning
      process, we introduced microdialysis and a combined
      microdialysis/electrophysiological approach in domestic chicks a few days old.
      With this technique, we were able to follow changes of the extracellular levels
      of glutamate, taurine, 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of
      serotonin, and homovanillic acid (HVA), a metabolite of dopamine, and neuronal
      activity simultaneously in freely moving animals. We obtained first evidence of a
      modulatory interaction between glutamatergic and monoaminergic neurotransmission
      mediated by N-methyl-D-aspartate (NMDA) receptors. During local intracerebral
      infusion of 300 microM NMDA via reverse microdialysis, an increase of taurine and
      a decrease of 5-HIAA and HVA were detected, accompanied by enhanced extracellular
      spike rates. Glutamate was increased only during consecutive infusion of
      increasing NMDA concentrations, when higher (1 mM) NMDA concentrations were
      infused. The effects of NMDA were antagonized by D, L-2-amino-5-phosphonovaleric
      acid (1 mM). Infusion of high potassium induced similar changes in taurine, 5
      HIAA, and HVA, as found during infusion of NMDA, but decreased extracellular
      spike rates, which indicates that different cellular mechanisms may underlie the
      observed neurochemical changes. Neither urethane anesthesia nor different delays
      between probe implantation and experiment influenced the neurochemical and
      electrophysiological results; however, changes of taurine were observed only in
      chronically implanted, awake animals. In summary, microdialysis in combination
      with electrophysiology provides a powerful tool to detect changes of neuronal
      activity and transmitter release in the avian brain, with which the role of
      transmitter interactions can be followed during and after different learning
      events.

PMID- 10398077
TI  - DNA chip technology.
AB  - A mini-revolution is sweeping the world of science and medicine. DNA chip or
      microarray technology will have a more profound impact than other recent major
      advances, including DNA sequencing and the polymerase chain reaction (PCR). This
      mini-review explains the technology, its scope, and impact on science and
      medicine, as well as its cost and possible limitations.

PMID- 10398078
TI  - The transition from hyperplasia to invasive carcinoma of the breast.
AB  - The multistep model of carcinogenesis in the breast suggests a transition from
      normal epithelium to invasive carcinoma via non-atypical and atypical hyperplasia
      and in situ carcinoma. Within the breast, these proliferations are heterogeneous
      in their cytological and architectural characteristics. This review considers the
      evidence supporting a precursor role for these preinvasive lesions.

PMID- 10398079
TI  - Cyclin D1 gene amplification and overexpression are present in ductal carcinoma
      in situ of the breast.
AB  - Cyclin D1 (CCND1) amplification is found in 10-15 per cent of invasive breast
      carcinomas, but it is not well established whether this gene alteration also
      occurs in the precursor of invasive breast carcinoma, ductal carcinoma in situ
      (DCIS). By Southern blot analysis, cyclin D1 gene amplification was detected in
      10 per cent (3/32) of DCIS cases. In addition, 15 cases of DCIS were analysed
      using bright field in situ hybridization (BRISH), of which 11 had already been
      analysed by Southern blotting. One additional case with gene amplification was
      found by BRISH. The use of BRISH for the detection of gene amplification is shown
      to be a novel and reliable in situ method on paraffin-embedded tissue sections.
      By immunohistochemistry, 147 cases of DCIS were analysed for the expression of
      cyclin D1. Cyclin D1 overexpression was found in 9 per cent of well
      differentiated, 29 per cent of intermediately differentiated, and 19 per cent of
      poorly differentiated DCIS. No statistically significant association was found
      between cyclin D1 overexpression and the differentiation grade of DCIS, although
      90 per cent of the cases that show overexpression are classified as
      intermediately and poorly differentiated. An association was found between cyclin
      D1 overexpression and oestrogen receptor positivity. Cyclin D1 overexpression was
      found in all four cases with cyclin D1 gene amplification, but was also found in
      30 per cent (8/27) of cases without detectable gene amplification. It is
      concluded that cyclin D1 gene amplification is an early event in the development
      of breast carcinoma and occurs in poorly differentiated DCIS. Cyclin D1 protein
      overexpression is also present in tumours without cyclin D1 gene amplification
      and is seen predominantly in DCIS of intermediately and poorly differentiated
      histological type and oestrogen receptor positivity.

PMID- 10398080
TI  - Angiogenesis and expression of thymidine phosphorylase by inflammatory and
      carcinoma cells in ductal carcinoma in situ of the breast.
AB  - Angiogenesis is essential for tumour growth and important in metastasis and for
      prognosis in invasive carcinoma of the breast. Two patterns of increased
      vascularity have been shown in mammary ductal carcinoma in situ (DCIS): a cuff of
      vessels close to the involved ducts, and vessels in the interductal stroma.
      Inflammation may potentially promote angiogenesis by release of angiogenic
      factors and digestive enzymes. A correlation has previously been found between
      the intensity of perivascular inflammation and stromal vascularity in DCIS, but
      no strong relationship has been observed between inflammation and angiogenesis in
      invasive carcinoma. Tumour angiogenesis is regulated by a number of angiogenic
      factors, including thymidine phosphorylase (platelet-derived endothelial cell
      growth factor), which is expressed at high levels in macrophages. Using
      immunohistochemical methods, thymidine phosphorylase expression and vascularity
      have been studied in DCIS (n = 34) and invasive carcinoma (n = 32). Stromal
      vascularity in DCIS was associated with thymidine phosphorylase expression in the
      perivascular inflammatory cells and in the cytoplasm of carcinoma cells. In
      invasive carcinoma, no relationship was found between vascularity and thymidine
      phosphorylase expression in either the carcinoma or the inflammatory cells. This
      study suggests that thymidine phosphorylase expression in both inflammatory and
      carcinoma cells may contribute to one of the patterns of vascularity in DCIS, but
      not in invasive disease.

PMID- 10398081
TI  - Urinary tissue factor levels in patients with breast and colorectal cancer.
AB  - Activation of blood coagulation is a common complication of cancer in man and
      experimental animals. The causes of such activation may be multifactorial, but
      increased production of tissue factor (TF) by the host mononuclear cells may be
      involved. TF is not only produced by human monocytes (mTF) and tumour cells, but
      is also found in urine (uTF), where measurements might be clinically important.
      Using a highly reproducible (intra-assay CV 2.3 per cent and inter-assay CV 8.1
      per cent) one-stage kinetic chromogenic assay (KCA) developed by this group, uTF
      levels were measured in controls [healthy volunteers (n = 57), patients with
      renal stones and a normal ESR (n = 30)] and in patients with benign and malignant
      diseases of the breast (n = 94) and large bowel (n = 62). Each benign disease
      group was sub-divided into inflammatory and non-inflammatory categories. There
      were no significant differences between the controls and the benign non
      inflammatory groups, so they were unified for further analysis. Malignant groups,
      irrespective of tumour types, showed significantly higher uTF levels than
      controls (p < 0.001 for breast and p < 0.01 for large bowel). Similarly, breast
      and colorectal benign inflammatory groups showed significant increases over
      controls (p < 0.01 and p < 0.001, respectively). Patients with malignant disease
      showed uTF activity above the upper quartile range of the normal control group
      for breast, 77.3 per cent, and large bowel, 73 per cent. uTF levels were related
      to histological tumour grading and were higher in non-surviving patients. In
      conclusion, uTF levels are raised in malignant and inflammatory disease compared
      with controls and patients with non-inflammatory conditions. uTF levels may
      reflect tumour progression.

PMID- 10398082
TI  - Early expression of cyclo-oxygenase-2 during sporadic colorectal carcinogenesis.
AB  - Regular administration of non-steroidal anti-inflammatory drugs (NSAIDs) may
      reduce the incidence of colorectal cancer by targeting cyclo-oxygenase-2 (Cox-2),
      a key enzyme in arachidonic acid metabolism. To evaluate the role of Cox-2 in
      sporadic colorectal cancer development, Cox-2 expression was investigated by
      immunohistochemistry in 85 adenomas, 53 carcinomas, 34 hyperplastic lesions and
      104 samples of histologically normal mucosa adjacent to adenoma or carcinoma. In
      addition, Cox-2 mRNA expression was assessed by reverse transcription-polymerase
      chain reaction (RT-PCR) in six adenomas and 14 carcinomas with paired grossly
      normal mucosa. Immunohistochemistry for the proliferation-associated antigen Ki
      67 and in situ end labelling for demonstrating apoptotic bodies were also used to
      analyse the associations between Cox-2 expression and proliferation and
      apoptosis. Cox-2 protein expression was increased in 76/85 (89.4 per cent)
      adenomas and 44/53 (83.0 per cent) carcinomas compared with normal mucosa. Cox-2
      protein expression was unrelated either to the degree of dysplasia or to the size
      of the adenomas (p > 0.50, p > 0.10, respectively) or to differentiation, Dukes
      stage or lymph node metastasis of carcinomas (all p > 0.50). Interestingly, 20/34
      (58.8 per cent) hyperplastic lesions adjacent to adenomas or carcinomas displayed
      expression higher than in normal mucosa (18.3 per cent) (p < 0.0001) but lower
      than in adenomas or carcinomas (p < 10(-5), p < 0.001, respectively). There were
      no correlations between Cox-2 protein expression and proliferative or apoptotic
      index in either adenomas or carcinomas (all p > 0.25). Cox-2 mRNA expression was
      significantly increased in adenomas and carcinomas compared with normal mucosa (p
      < 0.005, p < 0.001, respectively). There were no differences between adenomas and
      carcinomas in either protein or mRNA levels (p > 0.25, p > 0.90, respectively).
      These data indicate that enhanced expression of Cox-2 occurs early during
      colorectal carcinogenesis and may contribute to tumour formation.

PMID- 10398083
TI  - p21WAF1/CIP1 expression in colorectal carcinoma correlates with advanced disease
      stage and p53 mutations.
AB  - Defects in the mechanisms controlling the cell cycle are crucial in cell
      transformation and/or tumour progression. p21WAF1/CIP1 is an inhibitor of cyclin
      dependent kinases, induced by p53-dependent and p53-independent pathways, which
      can block progression through the cell cycle. p21WAF1/CIP1 expression has been
      investigated immunohistochemically in a series of 191 patients with colorectal
      cancer of known p53 status. The purpose of the study was two-fold: to assess the
      relationship between p21WAF1/CIP1 immunoreactivity and p53 alterations, and to
      evaluate the prognostic significance of p21WAF1/CIP1 expression. In 96 carcinomas
      (51 per cent), p21WAF1/CIP1 was expressed in over 10 per cent of tumour cells,
      whereas in 26, p21WAF1/CIP1 was detected in under 10 per cent of neoplastic
      cells; 69 tumours lacked p21WAF1/CIP1 expression. Immunoreactivity was more
      frequent in tumours of the right colon (p < 0.003) and was inversely correlated
      with tumour stage (p < 0.03), p53 gene mutations (p < 0.0007), p53 protein
      accumulation (p < 0.019), and Bcl-2 expression (p < 0.0005). In univariate
      analysis, down-regulation of p21WAF1/CIP1 expression was associated with poor
      overall (p = 0.0022) and disease-free survival (p = 0.0009). Multivariate
      analysis, however, did not confirm any independent prognostic significance of
      p21WAF1/CIP1 expression. The results indicate that p21WAF1/CIP1 is associated
      with abnormal accumulation of p53 protein and the occurrence of p53 gene
      mutations in colorectal cancer and that lack of p21WAF1/CIP1 expression is
      correlated with reduced patient survival in univariate analysis. These data
      underline the crucial pathogenetic role of the p53-p21WAF1/CIP1 pathway in
      carcinomas of the large bowel.

PMID- 10398084
TI  - Chromosomal abnormalities in renal cell neoplasms associated with acquired renal
      cystic disease. A series studied by comparative genomic hybridization and
      fluorescence in situ hybridization.
AB  - Sporadic renal cell carcinomas (RCCs) display different chromosomal abnormalities
      according to their morphology; gains of chromosomes 7 and 17 and loss of Y are
      commonly observed in papillary lesions, whereas loss of 3p sequences and multiple
      losses of specific chromosomes are found in non-papillary and chromophobe cell
      carcinomas, respectively. Acquired renal cystic disease (ARCD) is associated with
      an increased incidence of renal cell tumours, especially papillary lesions. The
      aim of this study was to examine a series of ARCD-related tumours for chromosomal
      abnormalities and to compare the findings with those abnormalities commonly
      observed in sporadic RCCs. Nine tumours from four patients with ARCD were
      examined using comparative genomic hybridization (CGH) and interphase
      cytogenetics. Gain of chromosomes 7 and 17 was observed in all four papillary
      lesions and loss of Y in three. In addition, gain of chromosome 16 was observed
      in three papillary tumours. Three chromophobe RCCs originating from the same
      kidney showed different genomic profiles; two had no abnormalities, whereas one
      showed loss of chromosome 17p. Two non-papillary RCCs failed to show chromosome
      3p alterations. In conclusion, renal cell tumours developing in ARCD may show
      chromosomal abnormalities both similar to and different from those seen in
      sporadic tumours.

PMID- 10398085
TI  - Improving the prognostic value of histopathological grading and clinical staging
      in renal cell carcinomas by means of computer-assisted microscopy.
AB  - The present work aims to refine prognosis in cases of renal cell carcinoma (RCC)
      by integrating a variety of parameters with the prognostic information provided
      by histopathological grading and clinical staging, carried out on a series of 97
      RCCs. To this end, Feulgen-stained RCC cell nuclei were characterized by means of
      38 variables describing nuclear DNA ploidy levels and morphology. All of these
      data were subjected to a principal components analysis. On the basis of this
      multivariate analysis, Fuhrman grade II was subdivided into grades II- and II+,
      and Fuhrman grade III into grade III- and III+. The same kind of
      subcategorization was performed in the case of the T2 and T3 clinical stages. The
      results show that the classification into grade II- and III- RCCs correspond to a
      more favourable prognosis than grade II+ and III+, to which shorter survival
      periods were attributable. Similar results were obtained for the
      subcategorization of the T2 and T3 clinical stages. Very simple biological
      characterizations of these grade- or stage-related RCC groups were obtained by
      means of a decision tree approach applied to the cytometry-generated variables.
      The resulting classification rules were validated on a new series of 18 patients
      and enabled very accurate predictions of survival.

PMID- 10398086
TI  - Immunostaining for vasostatin I distinguishes between ileal and lung carcinoids.
AB  - Although chromogranin A (CgA) is a recognized marker of neuroendocrine tumours,
      little is known about the distribution of the CgA-derived peptides, vasostatin
      (VST) I or II, in these tumours. Rabbit polyclonal antiserum was raised to a
      fragment of VST I and used to immunostain sections (5 microns) of wax-embedded
      tumour tissue. Immunoreactivity (IR) was detected using swine anti-rabbit
      fluorescein secondary antibody and sections were viewed by fluorescence
      microscopy. Of 24 tumours from patients with lung carcinoids, one was weakly
      positive, while 23 of 26 ileal carcinoid tumours were immunoreactive. Metastatic
      deposits from patients with ileal carcinoids also tended to be immunoreactive
      (9/10). The difference in IR between lung and ileal carcinoid primary tumours did
      not appear to be related to the metastatic potential, since appendiceal tumours,
      which seldom metastasize, also tended to be immunoreactive (4/6) for VST I. The
      strongest IR was recorded in two patients with flushing as a result of ileal
      carcinoids; five other 'flushers' with ileal carcinoids were also immunopositive
      for VST I-like IR. By contrast, patients with flushing as a result of lung
      carcinoids were immunonegative for VST. In conclusion, VST I-like IR may assist
      in the identification of a secondary deposit from an unknown primary site.

PMID- 10398087
TI  - Frequent expansion of Epstein-Barr virus (EBV) infected cells in germinal centres
      of tonsils from an area with a high incidence of EBV-associated lymphoma.
AB  - Burkitt's lymphoma (BL) and Hodgkin's disease (HD) occurring in developing
      regions are frequently associated with Epstein-Barr virus (EBV) infection and
      have a high incidence in childhood. Recent genotyping studies indicate that the
      tumour cells of both neoplasms represent B cells that contain somatically mutated
      immunoglobulin heavy chain genes. This implies that the precursors of these
      neoplasms have participated in the germinal centre (GC) reaction. We therefore
      presumed that normal lymphoid tissues from children living in developing regions
      would harbour an increased number of EBV-infected cells within the GC, when
      compared with children living in industrialized nations. To test this hypothesis,
      hyperplastic tonsils from 40 children living in Bahia (Brazil) and 40 from German
      children were analysed for the presence of EBV-encoded small nuclear RNA (EBER)
      and EBV-encoded proteins by in situ hybridization and immunohistology,
      respectively. Although the overall EBV infection rate was similar in both groups
      (50 per cent of Bahian vs. 45 per cent of German cases), a significantly higher
      number of EBER-positive lymphoid cells were found in the GCs of 8/20 EBV-positive
      tonsils from Brazil (9-89 cells/GC; mean: 14.5 cells/GC per case), while only
      3/18 tonsils from Germany displayed a few EBER positive cells (1-9 cells/GC;
      mean: 0.5 cell/GC per case) in this compartment (p < 0.007). In addition, the EBV
      infected GC cells in Bahian samples resembled centroblasts, exhibited mitotic
      activity, and in two cases showed expression of EBV-encoded latent membrane
      protein (LMP)-1, findings not present in German samples. These data show that
      latently EBV-infected cells participate more frequently in GC reactions in
      developing regions than in industrialized countries and may abnormally express
      the oncogenic protein LMP-1. This could in part explain the higher incidence in
      this region of EBV association with lymphomas related to GC cells or their
      progeny, such as BL and HD.

PMID- 10398088
TI  - The mucous neck cell in the human gastric corpus: a distinctive, functional cell
      lineage.
AB  - There is considerable debate about whether the mucous neck cell (MNC) in the
      mucosa of the gastric corpus is merely a transit cell population, intermediate
      between gastric stem cells and the differentiated zymogenic (chief or peptic)
      cell lineages, or has distinct functions of its own. To cast light on these
      possibilities, the secretory phenotype of the MNC has been examined. Archival
      gastric body samples from non-ulcer dyspepsia biopsies and gastrectomies
      performed for peptic ulcer disease were stained with antibodies to the trefoil
      peptides TFF1/pS2 and TFF2/SP, pancreatic secretory trypsin inhibitor (PSTI),
      epidermal growth factor (EGF) and its receptor (EGFR), and to the MUC1 gene
      product--HMFG2. Human MNCs express PSTI, TFF1/pS2, TFF2/SP, and EGF proteins,
      while rat MNCs express TFF2/SP; the mucin contained in the MNCs is
      diastase/periodic acid Schiff (D/PAS)-positive and stains with human milk fat
      globulin (HMFG2). The canaliculi but not the cytoplasm of adjacent parietal cells
      were also decorated focally by D/PAS, by HMFG2, and by antibodies to TFF2/SP and
      TFF1/pS2. These findings favour the hypothesis that MNCs have a defined phenotype
      and are thus a separate and distinct cell lineage, secreting a number of
      luminally-active peptides which protect the gastric mucosa, and in particular the
      adjacent parietal cells, from the effects of secreted gastric acid. Moreover, a
      considerable degree of similarity in secretory profile is noted between MNCs and
      the so-called 'reparative lineages' in the gut--the ulcer-associated cell lineage
      (UACL) and hyperplastic polyp epithelium. If, on the other hand, the MNCs are
      indeed a transit population differentiating into zymogenic or peptic cells, then
      it is clear that having differentiated into one secretory phenotype producing a
      range of peptides, the MNC then proceeds to differentiate into a cell with a
      totally different secretory phenotype, a phenomenon unique in gastrointestinal
      cell lineage relationships.

PMID- 10398089
TI  - Localization of syndecan-1 in human gastric mucosa associated with ulceration.
AB  - Syndecans, cell surface heparan sulphate proteoglycans, are known to function as
      cell adhesion molecules and as a co-receptor for heparin-binding growth factors
      that have important roles in tissue homeostasis and repair, but the localization
      of syndecans in gastric mucosa and their role in gastric ulcer healing are not
      known. The licalization of syndecan-1, a subfamily protein of syndecans expressed
      on epithelial cells, was studied in 12 surgically resected human stomachs
      containing an ulcer or early scar tissue. Localization of syndecan-1 was detected
      both by immunohistochemistry and by in situ hybridization In non-ulcer sites of
      gastric mucosa, syndecan-1 protein was expressed at the basolateral surface of
      foveolar epithelial cells and the cells of intestinal metaplasia, and at the cell
      surface of stromal plasma cells. In addition, positive dots of syndecan-1 were
      found in the cytoplasmic area of parietal cells. Foveolar epithelial cells at
      active stage ulcer margins showed nearly the same intensity of staining as those
      at non-ulcer site mucosa. By contrast, enhanced staining was obtained in
      elongated regenerative foveolar cells at the healing ulcer margins and the early
      scar tissues. The migrating cells on ulcer floors also expressed syndecan-1
      protein. The expression sites of syndecan-1 mRNA mostly coincided with those of
      syndecan-1 protein. These results suggest that syndecan-1 participates in cell
      adhesion mainly at the foveolar epithelium and plays a role in the healing of
      gastric ulcers by interacting with heparin-binding growth factors.

PMID- 10398090
TI  - Inducible nitric oxide synthase expression in vascular and glomerular structures
      of human chronic allograft nephropathy.
AB  - Nitric oxide (NO) plays an important role in the cytotoxic mechanisms responsible
      for acute renal allograft rejection, where macrophages produce high levels of
      inducible nitric oxide synthase (iNOS). By contrast, both the source and the role
      of NO in chronic allograft nephropathy (CAN) are still unclear. In this study,
      the expression of iNOS mRNA and protein was assessed in the kidneys of patients
      with graft failure due to chronic rejection. As controls, kidney specimens were
      obtained from patients undergoing nephrectomies for primary renal tumours, and
      from patients suffering from IgA nephropathy or mesangial-proliferative
      glomerulonephritis. In normal kidneys, iNOS production was absent or limited to a
      low signal, while it was found only in the inflammatory infiltrate of kidneys
      affected by glomerulonephritis, as assessed by immunohistochemistry and in situ
      hybridization. In contrast, in CAN, iNOS protein was localized not only in
      inflammatory cells, but also in vascular, glomerular, and, more rarely, tubular
      structures. Accordingly, in situ hybridization localized iNOS mRNA in both
      macrophages and lymphocytes, as well as in vascular structures and glomeruli.
      Double immunostaining for iNOS and a-smooth muscle actin (a-SMA) or von
      Willebrand factor (vWf) revealed that smooth muscle cells were the main vascular
      source of iNOS, while both mesangial and inflammatory cells were immunostained at
      the glomerular level. These data demonstrate that macrophages and lymphocytes are
      not the only source of iNOS mRNA and protein in human CAN. Vascular smooth muscle
      and mesangial cells also synthesize iNOS, raising the question of heterogeneous
      regulation and function of iNOS in this disease.

PMID- 10398091
TI  - Interferon-gamma-induced ICAM-1 and CD40 expression, complete lack of HLA-DR and
      CD80 (B7.1), and inconsistent HLA-ABC expression in basal cell carcinoma: a
      possible role for interleukin-10?
AB  - Basal cell carcinomas (BCCs) of the skin show varying degrees of peritumoural
      inflammatory infiltrate consisting mainly of T cells, but lack an effective T
      cell-mediated immune response. This may be caused by the absence of the major
      histocompatibility complex (MHC) class I and II antigens, intercellular adhesion
      molecule-1 (ICAM-1), CD40 and CD80 (B7.1). Interferon-gamma (IFN-gamma) is known
      to induce or up-regulate their expression on epithelial cells, whereas
      interleukin-10 (IL-10) down-regulates their expression. The induction and up
      regulation of HLA-ABC, HLA-DR, ICAM-1, CD40, and CD80 in BCC and normal skin from
      BCC patients were investigated in a culture system using recombinant human IFN
      gamma (rHuIFN-gamma). The levels of IL-10 were determined in the supernatants
      after culture. The results showed that only ICAM-1 expression was significantly
      up-regulated on BCC cells. However, in the normal epidermis of BCC patients and
      in the epidermis overlying the tumour nests, significant up-regulation of ICAM-1,
      and CD40, and CD80 and slight up-regulation of HLA-DR were observed. No changes
      in HLA-ABC expression were observed in either normal skin or BCC. High levels of
      IL-10 were present in the supernatants of BCC biopsies after culture. It may be
      concluded that it is highly likely that the presence of IL-10 in BCC is directly
      or indirectly responsible for the complete lack of expression of HLA-DR, ICAM-1,
      CD40 and CD80 and the inconsistent expression of HLA-ABC on BCC cells in situ and
      may be a way of escaping immune survillance.

PMID- 10398092
TI  - IL-1 beta and IFN-gamma induce the regenerative epidermal phenotype of psoriasis
      in the transwell skin organ culture system. IFN-gamma up-regulates the expression
      of keratin 17 and keratinocyte transglutaminase via endogenous IL-1 production.
AB  - Skin biopsies from healthy human skin and non-lesional skin from patients with
      psoriasis were cultured for 24 h and stimulated with interleukin-1 beta (IL-1
      beta) and interferon-gamma (IFN-gamma) in a skin organ culture model and the
      induction of the psoriasiform regenerative epidermal phenotype was analysed using
      immunostaining. In the presence of IL-1 beta, the psoriasiform regenerative
      epidermal phenotype was clearly induced. This involved strong up-regulation of
      the expression of keratin 16, keratin 17, and keratinocyte transglutaminase (TGk)
      in the suprabasal layers, strong up-regulation and a shift of the expression of
      keratin 5 and integrin beta 1 from the basal to suprabasal keratinocytes, and
      induction of the expression of ICAM-1 and HLA-DR on basal keratinocytes. The
      effects of IL-1 beta in the organ cultures of normal skin could be completely
      neutralized by anti-IL-1 polyclonal antibodies. The effects of IFN-gamma in
      healthy and non-lesional psoriatic skin were qualitatively similar to those of IL
      1 beta. The IFN-gamma-induced epidermal expression of keratin 17 and TGk could be
      completely blocked by culturing the biopsies in the presence of IL-1ra or anti-IL
      1 antibodies, while the induction of HLA-DR and ICAM-1 was not inhibited. The
      induction of the psoriasiform regenerative epidermal phenotype by IFN-gamma is
      partially mediated via endogenous epidermal IL-1.

PMID- 10398093
TI  - Differentiation-specific regulation of transgene expression in a diploid
      epithelial cell line derived from the normal F344 rat liver.
AB  - To establish the differentiation potential of progenitor cells, non-parenchymal
      epithelial cells from the F344 rat liver (FNRL cells) were studied. These cells
      reacted with the OV-6 antibody marker of oval cells, but were negative for
      hepatocyte markers (albumin, transferrin, glycogen, glucose-6-phosphatase, H4
      antigen), biliary markers (gamma glutamyl transpeptidase, cytokeratin-19), and
      alpha-fetoprotein, although exposure to sodium butyrate induced nascent albumin
      and alpha-fetoprotein mRNA transcription. When stably transduced, FNRL cells
      expressed a retroviral promotor-driven lacZ reporter in vitro, similar to
      transgene expression in hepatocyte-derived HepG2 cells. However, lacZ expression
      in FNRL cells was rapidly extinguished in intact animals, whereas the reporter
      remained active in HepG2 cells. Transplanted FNRL cells showed copious glucose-6
      phosphatase expression; however, the cell differentiation programme remained
      incomplete, despite two-thirds partial hepatectomy, D-galactosamine treatment or
      bile duct ligation. Interestingly, lacZ expression resumed in cultures of FNRL
      cells explanted from recipients. Moreover, lacZ expression was down-regulated by
      gamma-interferon in FNRL cells, without affecting lacZ activity in HepG2 cells.
      The data indicate that although subpopulations of oval cells may not fully
      differentiate into mature hepatocytes, these cells might serve critical
      functions, such as glucose utilization, and help survival after liver injury.
      Also, introduced genes may be regulated in progenitor cells at multiple levels,
      including by interactions between regulatory sequences, differentiation-specific
      cellular factors, and extracellular signals; in vivo studies are thus especially
      important for analysing gene regulation in progenitor cells.

PMID- 10398094
TI  - Osteoblastic differentiation and mRNA analysis of STRO-1-positive human bone
      marrow stromal cells using primary in vitro culture and poly (A) PCR.
AB  - Investigation of osteoblast dysfunction in osteoporosis has been hampered by a
      poor understanding of normal early osteoblast differentiation, due to a relative
      lack of markers for the earliest cells in the lineage. Attempts to identify such
      markers have used cultures of animal or immortalized human cells, of uncertain
      relevance to human biology, or heterogeneous cultures in which genetic
      variability precludes the isolation of stage-specific genotypic markers. Primary
      in vitro generation of clonal populations of human bone marrow stromal cells was
      used in order to overcome these problems. Fibroblast-like stromal cells were
      isolated from human sternal bone marrow. They showed differentiation to an
      osteoblastic phenotype when stimulated with dexamethasone (10(-7) M) and
      fluorescence activated cell analysis demonstrated immunopositivity for STRO-1 (an
      antibody that recognizes osteoprogenitor stem cells of the colony-forming unit
      fibroblastic) in from 8 to 40 per cent of the cells, dependent on time post
      harvest. Cells positive for STRO-1 were immunoselected using magnetic activated
      cell sorting and seeded at low density (10 cells/cm2) to produce clones. Each
      clone was subpassaged, osteoblastic differentiation stimulated with
      dexamethasone, and mRMA-extracted at time points post-stimulation (0 h and 1-14
      days). A novel poly (A) reverse transcriptase-polymerase chain reaction (RT-PCR)
      was used to amplify cDNA representative of all transcripts expressed at each time
      point. Differential gene expression within the amplified cDNA was assessed using
      3' end cDNA probes to osteocalcin, osteopontin, and collagen type I (positive),
      demonstrating the acquisition of an osteoblastic phenotype. Time-specific gene
      products for early osteoblast differentiation have been generated from primary
      human cultures, utilizing very low density seeding and poly (A) RT-PCR. These
      products overcome the problems associated with animal, immortalized or
      heterogeneous culture and can be used to study normal and altered early
      osteoblast differentiation, indicating the possibility of using the same system
      to study other disease states.

PMID- 10398095
TI  - Ductal carcinoma in situ in breast carcinogenesis.
AB  - Evidence is mounting that ductal carcinoma in situ (DCIS) is a direct precursor
      of invasive breast cancer. Recent molecular biological and cytogenetic studies
      have revealed chromosomal gains and losses involved in breast carcinogenesis.
      This editorial discusses how the gains and losses on the different chromosomes
      fit into previously defined morphological routes of progression from normal cells
      through DCIS to invasive carcinoma, and the possible uses of these gains and
      losses in the classification of DCIS and the risk assessment of DCIS patients.

PMID- 10398096
TI  - Comparative genomic hybridization as a tool in tumour cytogenetics.
AB  - The quality of cytogenetic analysis of solid tumours has greatly improved in the
      past decade, but a number of technical difficulties remain which limit the
      characterization of solid tumour chromosomes by conventional cytogenetics alone.
      The identification of regions of chromosomal abnormality has been aided by the
      introduction of molecular cytogenetic techniques such as fluorescence in situ
      hybridization (FISH). Of these, a recently developed approach, comparative
      genomic hybridization (CGH), has had a particular impact on the cytogenetic
      analysis of solid tumours. It incorporates the sensitivity of in situ techniques
      and overcomes many of the drawbacks of conventional cytogenetic analysis. This
      review first outlines the CGH method, giving details for the preparation of DNA
      probes and target human metaphase chromosomes together with information on the in
      situ technique and data handling criteria used in our laboratory. It then
      presents an overview of some of the current applications of CGH, together with a
      discussion of future directions in the field.

PMID- 10398099
TI  - In vivo patterns of Bcl-2 family protein expression in breast carcinomas in
      relation to apoptosis.
AB  - The expression of the pro-apoptotic proteins (Bax, Bak) and anti-apoptotic
      proteins (Bcl-2, Bcl-X, Mcl-1) was studied by immunohistochemistry in 110
      invasive ductal breast carcinomas. The results were correlated with tumour grade,
      expression of oestrogen receptor (ER) and p53 protein, and the apoptotic index by
      combined morphology, immunohistochemistry, and a terminal UTP nick end labelling
      (TUNEL) procedure. Overall, Bcl-2, Bcl-X, Mcl-1, Bax, Bak, ER, and p53 were
      detected in 62, 75, 68, 75, 60, 68 and 26 per cent of the cases respectively, but
      at different levels in each case. A high apoptotic index was correlated with high
      tumour grade (p<0.001), overexpression of p53 (p<0.001), Bak expression
      (p<0.001), and low expression of Bcl-2 (p<0.001) and ER (p<0.001). No correlation
      was found between the apoptotic index and Bax, Bcl-X, and Mcl-1 immunostaining
      results. The expression of Bcl-2 and Bcl-X was correlated to that of ER. Overall,
      the results of this study strongly suggest that Bcl-2 and Bak expression is
      critical in regulating apoptosis in breast carcinomas.

PMID- 10398098
TI  - Widespread chromosomal abnormalities in high-grade ductal carcinoma in situ of
      the breast. Comparative genomic hybridization study of pure high-grade DCIS.
AB  - For a variety of technical reasons it is rarely possible to study cytogenetic
      abnormalities in ductal carcinoma in situ (DCIS) using traditional techniques.
      However, by combining molecular biology and computerized image analysis it is
      possible to carry out cytogenetic analyses on formalin-fixed, paraffin-embedded
      tissue, using comparative genomic hybridization (CGH). The purpose of this study
      was to identify the prevalence of chromosomal amplifications and deletions in
      high-grade DCIS and to look specifically for unique or consistent abnormalities
      in this pre-invasive cancer. Twenty-three cases of asymptomatic, non-palpable,
      screen-detected, high-grade DCIS were examined using CGH on tumour cells obtained
      from histology slides. All cases showed chromosomal abnormalities. A wide variety
      of amplifications and deletions were spread across the genome. The most frequent
      changes were gains of chromosomes 17 (13 of 23), 16p (13 of 23), and 20q (9 of
      23) and amplifications of 11q13 (22 of 23), 12q 24.1-24.2 (12 of 23), 6p21.3 (11
      of 23), and 1q31-qter (6 of 23). The most frequent deletions were on 13q 21.3-q33
      (7 of 23), 9p21 (4 of 23), and 6q16.1 (4 of 23). These findings indicate that
      high-grade DCIS is, from a cytogenetic viewpoint, an advanced lesion. There was
      no absolutely consistent finding in every case, but amplification of 11q13 was
      found in 22 of the 23 cases. The precise significance of this is unknown at
      present. This region of chromosome 11q harbours a number of known oncogenes,
      including cyclin D1 andINT2. It is likely that many of these findings are the
      result of accumulated chromosomal abnormalities, reflecting an unstable genome in
      established malignancy.

PMID- 10398097
TI  - Comparative genomic hybridization of ductal carcinoma in situ of the breast
      evidence of multiple genetic pathways.
AB  - There is strong evidence that ductal carcinoma in situ (DCIS) represents a
      precursor lesion of invasive breast cancer. In order to analyse specific
      chromosomal alterations of DCIS, 38 paraffin-embedded specimens of DCIS and six
      associated invasive carcinomas were examined by means of comparative genomic
      hybridization (CGH). Losses of 16q material were seen almost exclusively in well-
      and intermediately-differentiated DCIS. These two subgroups differed in the
      average number of genetic imbalances, 2.5 and 5.5 respectively. Additionally, a
      higher frequency of gains of 1q and losses of 11q material was seen in
      intermediately-differentiated in contrast to well-differentiated DCIS. Poorly
      differentiated DCIS displayed a higher frequency of amplifications (17q12, 11q13)
      and a higher average rate of genetic imbalances (7.1). Analysis of adjacent
      invasive breast carcinoma revealed a genetic pattern almost identical to the one
      seen in the DCIS counterpart. These data characterize DCIS as a genetically far
      advanced, heterogeneous lesion and as a direct precursor of invasive breast
      cancer.

PMID- 10398100
TI  - Immunolocalization of the fodrin, E-cadherin, and beta-catenin adhesion complex
      in infiltrating ductal carcinoma of the breast-comparison with an in vitro model.
AB  - Fodrin, E-cadherin, and beta-catenin immunolocalization was studied in 54 cases
      of infiltrating ductal carcinoma of the breast and compared with an in vitro
      model in order to study the dynamic relationship between these components of an
      adhesion complex. In low-grade tumours, the staining patterns were similar for
      both fodrin and E-cadherin, with localization of these proteins to the cell
      membranes. beta-Catenin showed reduced membrane staining compared with non
      neoplastic epithelium. High-grade tumours displayed strong membranous as well as
      cytoplasmic immunolocalization of fodrin, while E-cadherin staining was
      fragmented or lost from the membranes, with only occasional weak intracellular
      staining. beta-Catenin showed fragmented membrane staining and cytoplasmic
      accumulation. In addition, nuclear staining of beta-catenin was occasionally
      observed. In a v-src-transformed MDCK cell line, following 15min of src
      activation, beta-catenin began to detach from the cell membrane and localize to
      the cytoplasm, while fodrin and E-cadherin remained unchanged. After 30-45min of
      src activation, the cells lost their cuboidal shape and began to lose cell-to
      cell contact. Fodrin staining remained mostly membranous while that of E-cadherin
      and beta-catenin was fragmented and spiky. After 60min of src activation, fodrin
      localized completely in the cell cytoplasm, while E-cadherin and beta-catenin
      were partly cytoplasmic with fragmented and spiky membranous staining.
      Occasionally, beta-catenin was seen in the nucleus. Both in vivo and in vitro
      findings clearly demonstrated a disruption of the E-cadherin/beta
      catenin/fodrin/cytoskeleton linkage concomitant with the loss of cell-to-cell
      adhesion and change in cell shape, from epithelioid to a fibroblastoid phenotype.
      Membranous localization of E-cadherin showed a positive correlation with
      oestrogen and progesterone expression, whereas loss of membranous E-cadherin and
      cytoplasmic accumulation of fodrin was more often observed in high-grade
      carcinomas and showed a positive correlation with p53 expression.

PMID- 10398101
TI  - Absence of microsatellite instability in breast carcinomas with both p53 and c
      erbB-2 alterations.
AB  - Based on a previous finding that amplification of the c-erbB-2 oncogene and
      alteration of p53 are strongly associated in most aggressive breast tumours, the
      present study investigated whether microsatellite instability (MI) might also be
      associated with this tumour phenotype. Nine polymorphic microsatellite markers,
      including six dinucleotide, one trinucleotide, and two tetranucleotide repeats,
      were amplified from paired normal and tumour DNA samples of 15 breast tumours
      that overexpressed both c-erbB-2 and p53 and of 15 control breast tumours that
      overexpressed neither protein. All 30 breast tumours analysed exhibited a
      replication error-negative phenotype, with only one sample showing MI in one of
      the nine loci. This suggests that the genetic events underlying MI, which are
      critical in colorectal and gastric tumours, are not involved in the pathogenesis
      of c-erbB-2/p53 double-altered breast tumours and do not play a central role in
      breast tumour formation.

PMID- 10398102
TI  - Gastric carcinomas with microsatellite instability: clinical features and
      mutations to the TGF-beta type II receptor, IGFII receptor, and BAX genes.
AB  - The replication error phenotype (RER+) represents an important new form of
      genetic alteration characterized by widespread instability in repetitive
      nucleotide sequences. The aim of this study was to compare the features of RER+
      gastric tumours with those of RER+ colonic tumours. RER status was determined by
      analysis of size alterations in the BAT-26 mononucleotide repeat microsatellite.
      Twelve of 121 (10 per cent) gastric carcinomas from a low-incidence region were
      found to be RER+. BAT-26 instability was associated with tumours showing an
      absence of nodal invasion ( p=0.009) and with a trend for improved prognosis.
      These tumours were more frequent in older, female patients. Frameshift mutations
      in mononucleotide repeat sequences within the transforming growth factor-beta
      receptor II (RII), insulin-like growth factor II receptor (IGFIIR), and BAX genes
      were observed in 83, 33, and 25 per cent, respectively, of RER+ tumours. Only
      1/12 (8 per cent) RER+ tumours contained a p53 gene mutation compared with 29/109
      (27 per cent) RER- tumours. RER+ gastric carcinomas therefore share several
      important features with RER+ colonic tumours, including less frequent nodal
      invasion, improved prognosis, a similar frequency of mutation in growth control
      genes containing repetitive nucleotide sequences, and a low frequency of mutation
      of the p53 tumour suppressor gene.

PMID- 10398104
TI  - Apoptosis and proliferation in relation to histopathological variables and
      prognosis in hepatocellular carcinoma.
AB  - The prognosis of patients with resectable hepatocellular carcinoma depends mainly
      on the anatomical extent of the tumour and on the general condition of the
      patient. Given the growing evidence that proliferation indices may be of
      prognostic significance in hepatocellular carcinomas and that parameters of cell
      loss (usually, but not exclusively, due to programmed cell death) are
      biologically relevant, the identification and quantitation of proliferative
      capacity and apoptosis may be of prognostic importance. In this study four
      different methods have been used to assess proliferation in a series of 193
      curatively (R0) resected hepatocellular carcinomas: mitotic count,
      immunohistochemical assessment of MIB-1 (Ki-67), proliferating cell nuclear
      antigen (PCNA), and silver-stained nucleolar organizer regions (AgNORs).
      Apoptosis was assessed using the in situ-end labelling (ISEL) technique in
      combination with morphological criteria. Patients who received liver
      transplantation were excluded. The results obtained were compared with
      histopathological stage (according to UICC), Edmondson grade, several other
      histopathological factors, and survival rate. Significant statistical
      correlations were seen between the mitotic index, the rate of nuclear positivity
      for MIB-1 and PCNA, and the number of AgNOR dots. In univariate survival
      analysis, tumour stage and Edmondson grade, mitotic index, MIB-1 and PCNA index,
      and mean AgNOR number were significant factors influencing patients' survival. On
      multivariate Cox survival analysis, mitotix index, concomitant cirrhosis,
      Edmondson grade, and patient age were the only significant independent prognostic
      factors. Apoptosis was not related to prognosis or to other parameters examined.
      These results indicated that mitotic index is an additional prognostic parameter
      which could provide auxiliary information for patients' outcome. MIB-1 and PCNA
      immunostaining and AgNORs showed a good correlation among themselves. Apoptosis
      did not predict prognosis in hepatocellular carcinoma.

PMID- 10398103
TI  - Structural differences between valine-12 and aspartate-12 Ras proteins may modify
      carcinoma aggression.
AB  - Recent evidence associates the codon 12 valine-for-glycine (G12V) mutant Ki-Ras
      protein with higher stage and increased lethality of colorectal carcinomas, while
      the codon 12 aspartate-for-glycine (G12D) Ras mutation shows no such association.
      Several observations may be relevant to this phenomenon. First, GTPase activity
      of G12V Ras is one-quarter that of G12D Ras and one-tenth that of wild-type (WT)
      Ras. Second, binding of the GTP analogue GppNp to G12D Ras is 8-fold weaker than
      its binding to G12V or WT Ras and crystal structures indicate that electrostatic
      repulsion between the carboxylate group of the G12D Asp-12 side-chain and the
      gamma phosphate of the bound nucleotide may make GTP binding to G12D Ras weaker
      even than that of GppNp. It is proposed that this lowering of affinity for GTP
      allows G12D Ras an escape from the oncogenic GTP-bound state, whereas GTP tightly
      bound to G12V mutant Ras generates a more persistent, potentially oncogenic,
      signal. Structural comparisons also suggest that differences between the Switch I
      (effector) region of G12D and G12V Ras could modify interactions with downstream
      signalling molecules such as Raf-1, neurofibromin, and phosphatidylinositol 3
      hydroxy-kinase. Other differences between the G12D and G12V mutant Ras proteins
      include a lower affinity of the GTPase activating protein GAP for G12V than for
      G12D or WT Ras; but, as both G12D and G12V Ras are refractory to GTPase
      activation by GAP binding, this may be less significant. These studies complement
      experimental data showing that such Ras mutations differ in their effects in
      vitro and in vivo and, with recent data indicating heterogeneity of ras mutation
      in colorectal carcinomas and other tumours, make it plausible that codon 12 Ras
      mutations differ in carcinogenic potential and prognostic significance.

PMID- 10398105
TI  - In situ expression patterns of melanoma-inhibiting activity (MIA) in melanomas
      and breast cancers.
AB  - Elevated levels of melanoma-inhibiting activity (MIA) were measured previously in
      the serum of patients with metastasized melanomas and in a subgroup of patients
      with advanced-stage breast cancers. This study aimed therefore to visualize in
      situ expression patterns of MIA protein and mRNA in melanomas and breast cancers
      by means of immunohistochemistry, reverse transcription-polymerase chain reaction
      (RT-PCR), and in situ hybridization. Analysis of a panel of seven common
      melanocytic naevi, ten cutaneous melanomas, and 12 melanoma metastases detected
      high levels of both mRNA and protein in all melanomas and metastases, but only
      very low mRNA levels in three of seven naevi. Compared with the expression of
      pMel (HMB-45), tyrosine, and S-100 in these tumours, these results show that MIA
      provides a novel and sensitive marker for neoplastic melanocytes. Expression was
      not detected in other skin tumours including basal cell cancers and squamous cell
      cancers, nor in normal melanocytes and keratinocytes. MIA expression in
      adenocarcinomas was further studied in a panel of 20 specimens obtained from 16
      advanced-stage breast cancers and four metastases. Significant levels of mRNA
      were detected in 17 of the 20 specimens and low levels in the other three
      tumours. Immunostaining visualized specific protein expression in the tumour
      cells of all 20 cancer specimens. These investigations define for the first time
      in situ expression patterns of MIA in melanomas and breast cancers and suggest a
      much broader expression in malignant epithelial neoplasms than previously
      determined by serum studies.

PMID- 10398106
TI  - Renal cell carcinomas and pancreatic adenocarcinomas produce nidogen in vitro and
      in vivo.
AB  - The production of nidogen by four renal cell carcinoma (RCC) and three pancreatic
      adenocarcinoma (PAc) cell lines has been studied in cell culture and in
      xenografted tumours in nude mice. In RCC cells, immunoreactivity for nidogen was
      seen only after exposure to monensin to induce cytoplasmic accumulation of
      secretory proteins. In PAc cells, immunoreaction was also detectable in control
      cells. Immunoblotting of control and monensin-exposed cells and
      immunoprecipitation of culture media of radioactively labelled cells demonstrated
      the production of nidogen polypeptide of Mr ca. 150000 by six of the seven cell
      lines. Basement membranes (BMs) and stroma of the xenografted tumours derived
      from these six cell lines demonstrated immunoreactivity for both human and mouse
      nidogen, as revealed with species-specific antibodies. The ability of the cells
      to produce nidogen in vitro and deposit in vivo was positively correlated with
      high histological grade of the xenografted tumours, although the small number of
      cell lines studied calls for further studies to confirm this. The distribution of
      nidogen in human RCC and PAc specimens was also studied by immunohistochemistry.
      There was strong immunoreactivity for nidogen in tumour stroma, BM of carcinoma
      cell nests, and endothelial basal lamina, but no conclusions could be drawn
      regarding histological grade and immunostaining patterns, because stromal
      production could not be ruled out. The results show that nidogen is produced by
      human carcinoma cells both in vitro and in vivo.

PMID- 10398107
TI  - Inference network-based analyses of the histopathological effects of androgen
      deprivation on prostate cancer.
AB  - The evaluation of prostate cancer histology following hormonal therapy often
      represents a diagnostic problem for the pathologist. Previous studies have shown
      that an inference or Bayesian belief network (BBN) offers a descriptive
      classifier useful for the accurate analysis of morphological changes in
      individual cases of prostate neoplasia. Three different BBNs were evaluated in 94
      cancer foci present in 20 radical prostatectomy (RP) specimens and in the
      matching biopsies in which the initial diagnosis of prostatic adenocarcinoma was
      made. Ten RP specimens were from patients treated with total androgen ablation or
      combination endocrine therapy (CET) before surgery. The first and second BBN
      allowed the identification with high certainty of the cancer foci present in the
      biopsies and RP specimens, as well as their Gleason grade, the belief value often
      being close to 1.0. The results of the second BBN showed a good correspondence
      between the Gleason grade given in the biopsies and that in the RP specimens,
      except in the surgical material of the treated patients, in which upgrading was
      always present. The third BBN showed the existence of three subgroups in treated
      RP specimens, one with morphological effect, another with poor effect, and the
      third with the histology of untreated (i.e. unaffected) cancer. In conclusion, an
      inference network-based analysis allows the characterization of treated prostate
      cancers according to the degree of histopathological change.

PMID- 10398108
TI  - p53 overexpression in oral mucosa in relation to smoking.
AB  - The tumour-suppressor protein p53 is mutated in many head and neck squamous cell
      carcinomas (HNSCCs). In this immunohistochemical study, similar numbers of p53
      overexpressing cells were uniformly distributed throughout normal oral
      epithelium, irrespective of different smoking habits or the presence of an
      adjacent HNSCC. In a previous study, an increased number of proliferating cells
      were observed in normal oral mucosa from (ex)-smoking individuals and the present
      observations indicate that overexpression of p53 does not play a role in this
      increase. In contrast, focally overexpressed p53 occurred more frequently
      (p<0.05) in the tumour-adjacent normal mucosa (TAM) from smoking HNSCC patients
      (50 per cent) than in that from non-smoking HNSCC patients (20 per cent). This
      increase in focal p53 overexpression might represent an early alteration in the
      development of HNSCC, but it could not be detected in mucosa from healthy
      smokers. This indicates that besides the abuse of tobacco, other environmental
      and/or genetic factors must contribute to the presence of p53-positive clusters
      in TAM. Abuse of alcohol, an additional factor in these HNSCC patients, together
      with the abuse of tobacco, might play a role in the development of the p53
      positive clusters.

PMID- 10398109
TI  - Immunoreactive interleukin 4 and interferon-gamma expression by type II alveolar
      epithelial cells in interstitial lung disease.
AB  - Cryptogenic fibrosing alveolitis (CFA), extrinsic allergic alveolitis (EAA), and
      sarcoid are all immunologically mediated forms of interstitial lung disease. In
      contrast to most patients with EAA and sarcoid, patients with CFA show relentless
      pulmonary fibrosis which is unresponsive to immunosuppressive therapy. Previous
      studies have indicated a possible role for epithelial-derived cytokines in the
      regulation of immunological and fibrotic responses in the lung. This study has
      examined lung biopsy specimens from patients with CFA, EAA, and sarcoid for
      immunoreactive interleukin 4 (IL4) and interferon-gamma (INFgamma) expression by
      type II alveolar epithelial cells, as these cytokines have been suggested to have
      in vitro stimulatory and inhibitory effects on fibroblast function. In addition,
      mRNA in situ hybridization was performed on the CFA lung biopsies to confirm
      transcription of these cytokine genes within the cells. The results show that
      type II epithelial cells in EAA and sarcoid show up-regulation of
      immunoreactivity for both IL4 and INF-gamma, but that in CFA only IL4 is
      detectable. The mRNA in situ hybridization results indicate that this may
      represent post-transcriptional regulation of INFgamma expression in CFA. These
      results are consistent with previous observations of a paucity of INFgamma and a
      predominantly type II (Th2-like) pattern of immune response in patients with CFA
      and suggest a possible imbalance of pro-fibrogenic cytokines in the distal lung
      of patients with this condition, compared with those with EAA or sarcoid.

PMID- 10398110
TI  - Galectin-3 modulates rat mesangial cell proliferation and matrix synthesis during
      experimental glomerulonephritis induced by anti-Thy1.1 antibodies.
AB  - Galectin-3 is a beta-galactoside-binding protein synthesized by macrophages and
      other inflammatory cells and expressed in various branching epithelia, including
      the developing kidney. The expression of galectin-3 has been studied in a rat
      model of acute mesangial proliferative glomerulonephritis in which a single
      injection of anti-Thy1.1 antibodies leads to destruction of mesangial cells
      expressing a Thy1.1 epitope on their surface. The glomerular lesion is
      characterized by expansion of the mesangial matrix, especially laminin and
      collagen type IV, and mesangial hypercellularity. Galectin-3 expression, which is
      sparse in mature rat kidney and confined to the apical face of some distal
      tubules, is increased within 1-3 days following antibody administration, with the
      recruitment of glomerular macrophages and pronounced neo-expression in the
      cytoplasm and at the basal face of distal tubules. At later times, galectin-3 is
      detected immunohistochemically in the repopulating mesangial cell mass, preceding
      the extensive mesangial deposition of laminin and collagen type IV. Mesangial
      cells in culture do not produce appreciable amounts of galectin-3 but do bind and
      endocytose exogenously added lectin. Addition of galectin-3 to primary cultures
      of mesangial cells prepared from normal rats induces a 1.5-fold increase in the
      synthesis of collagen type IV and it also acts in synergy with a quantitatively
      similar stimulatory effect of transforming growth factor beta (TGF-beta) on
      matrix synthesis. Exogenous galectin-3 prolongs the survival of mesangial cells
      in serum-free cultures and also protects these cells against cytotoxic effects of
      TGF-beta. The data support the notion that the increased expression and secretion
      of galectin-3 in infiltrating macrophages and in distal tubular epithelia,
      together with up-regulation of IL-1beta and TGF-beta genes, play a role in
      mesangial hypercellularity in the progression of one model of inflammatory renal
      disease.

PMID- 10398111
TI  - Dual colour fluorescence in situ hybridization to paraffin-embedded samples to
      deduce the presence of the der(X)t(X;18)(p11.2;q11.2) and involvement of either
      the SSX1 or SSX2 gene: a diagnostic and prognostic aid for synovial sarcoma.
AB  - Identification of the t(X;18)(p11.2;q11.2) and the fusion gene products, SYT-SSX1
      and SYT-SSX2, associated with a high proportion of synovial sarcomas, has been
      shown to be a useful diagnostic aid. This study demonstrates the application of
      dual colour fluorescence in situ hybridization to paraffin-embedded samples to
      deduce the presence of the derivative X chromosome and also the position of the
      breakpoint on chromosome X at either the SSX1 or the SSX2 gene. This used region
      specific markers from chromosomes X and 18 and an optimized protocol involving
      microwave exposure. Novel and rapid scoring criteria were validated which
      circumvented potential problems of nuclear truncation and defining cell
      boundaries. This involved blind analysis of two negative sarcoma samples and
      three synovial sarcomas in which corresponding frozen material had been
      previously shown to have the translocation involving different SSX genes. Six new
      cases diagnosed as synovial sarcoma were also analysed; two monophasic and two
      biphasic case were deduced to have a breakpoint in the SSX1 gene, one monophasic
      case an SSX2 breakpoint, and one case did not show rearrangement of the region.
      The ability to analyse formalin-fixed, paraffin-embedded samples in this way has
      practical implications for aiding the diagnosis of difficult cases, recently
      ascribed prognostic relevance, and allows further retrospective studies to be
      carried out. The methodology is also applicable to the identification of other
      tumour specific translocations in paraffin-embedded material.

PMID- 10398112
TI  - Serrated adenoma and colorectal cancer.
AB  - Hyperplastic polyps and serrated adenomas of the colorectum show mixed
      gastrointestinal differentiation, expressing both gastric (M1 or MUC5AC) and
      intestinal (MUC2) mucins. They also share the phenotype of mild DNA
      microsatellite instability (MSI-L). Recent findings of clonal genetic changes
      within hyperplastic polyps fit with a pathway of serrated neoplasia, perhaps
      culminating in the subset of colorectal cancer characterized by the mild mutator
      phenotype.

PMID- 10398113
TI  - The clinical manipulation of angiogenesis: pathology, side-effects, surprises,
      and opportunities with novel human therapies.
AB  - The first phase of angiogenesis research has provided knowledge of the basic
      pathobiology of angiogenesis and its manipulation in models, mouse, and man. The
      first line of therapeutic substances has been devised and is now in clinical
      trials. New lessons are being learned from clinical observations. Unexpected side
      effects are being noted, particularly affecting the nervous system. Other side
      effects may be anticipated from a sound knowledge of clinical pathology and
      recognition of the commonality of angiogenesis to multiple disease mechanisms,
      but these may be tolerable or avoidable. Angiogenesis researchers await further
      feedback and ideas from the clinic to stimulate the next phase of basic and
      applied research.

PMID- 10398115
TI  - Analysis of IGF2 gene imprinting in breast and colorectal cancer by allele
      specific-PCR.
AB  - The insulin-like growth factor II (IGF2) gene is imprinted with the paternal
      allele expressed and the maternal one silent. Loss of imprinting (LOI) of IGF2
      has been suggested to play a role in the development of tumours, but the reported
      incidence of IGF2 LOI in tumours shows considerable variation, which may stem
      from different methodologies employed. In particular, partial digestion of
      reverse transcriptase-polymerase chain reaction (RT-PCR) products by restriction
      enzymes can lead to inaccurate measurements. To overcome the problem of partial
      enzymatic digestion, a novel method termed allele specific-polymerase chain
      reaction (AS-PCR) has recently been reported, which provides a significant
      advance over enzymatic digestion. A second problem with measurements of biallelic
      IGF2 transcription is that the co-amplification of contaminating genomic DNA
      during the RT-PCR step can lead to an overestimation of the frequency of
      biallelic IGF2 expression. To investigate the extent of this problem, total RNA
      from breast and colorectal cancer was analysed using two methods. The first
      method involved a first-round PCR using cDNA generated with primers spanning
      exons 8 and 9 (exon connection), followed by a second round of AS-PCR using
      primers from within exon 9. The second method used only AS-PCR with primers from
      within exon 9. The result was that the exon-connection approach was more
      accurate, thereby highlighting a significant problem in imprinting analyses where
      genomic DNA contamination cannot be completely ruled out.

PMID- 10398114
TI  - 'Serrated' adenoma of the colorectum, with reference to its gastric
      differentiation and its malignant potential.
AB  - Serrated adenoma of the colorectum was a newly proposed entity in 1990,
      characterized by epithelial neoplasia combining the architectural features of a
      hyperplastic (metaplastic) polyp with the cytological features of an adenoma. Its
      histogenesis and natural history still remain unclear. Forty-six serrated
      adenomas were obtained from 46 patients. The clinicopathological features were
      summarized. Paraffin-embedded blocks from 34 serrated adenomas were available for
      immunohistochemical studies using pS2, human gastric mucin, and p53 protein.
      Eighteen hyperplastic (metaplastic) polyps, 16 tubular adenomas, and 12 early
      stage adenocarcinomas were randomly selected as control groups for
      immunohistochemical analysis. The patients' ages ranged from 32 to 86 (average
      61.4) years. Males were more frequently affected than females. Serrated adenomas
      were predominantly present in the left-side of the colon and in the rectum (72
      per cent). Their sizes ranged from 3 to 26 mm (average 9. 2mm). Six lesions (13
      per cent) contained foci of high-grade dysplasia. These adenomas were
      significantly larger (12.7 mm) than those containing no high-grade dysplasia
      (8.6mm). pS2 and human gastric mucin were expressed significantly more frequently
      in both hyperplastic (metaplastic) polyps and serrated adenomas than in tubular
      adenomas or adenocarcinomas. p53-positive cells were present in 18 of the 29 pure
      serrated adenomas (62 per cent) and in one of the five areas of low-grade
      dysplasia in serrated adenomas with high-grade dysplasia (20 per cent), most of
      which revealed a sporadic distribution. Only five of the 29 serated adenomas with
      no high-grade dysplasia (17 per cent) were regarded as demonstrating p53
      overexpression. On the other hand, three of the five areas of high-grade
      dysplasia in serrated adenomas (60 per cent) revealed diffuse positivity (3+) for
      p53 protein. The serrated adenoma, which possibly shows gastric differentiation,
      is considered to be an independent histological entity among the various
      phenotypes of colorectal adenomas. Serrated adenoma would seem to be a precursor
      of carcinoma, its potential for malignant transformation being similar to that of
      the traditional tubular adenoma. It would also seem that p53 is involved in the
      serrated adenoma-carcinoma sequence.

PMID- 10398116
TI  - An immunohistochemical examination of the expression of E-cadherin, alpha- and
      beta/gamma-catenins, and alpha2- and beta1-integrins in invasive breast cancer.
AB  - This study examines the expression of the cell-cell adhesion molecules E-cadherin
      and its associated proteins, the catenins and the matrix-cell adhesion molecules
      beta1- and alpha2-integrins, in primary invasive breast carcinoma. Expression was
      assessed immunohistochemically on frozen sections by semi-quantitative scoring of
      the intensity and proportion of immunoreactivity in 55 cases. Associations with
      each other and with other histological and prognostic features and survival were
      sought. There was a significant association between loss of E-cadherin expression
      and loss of alpha- and beta/gamma-catenin immunostaining. In 20 per cent of
      cases, membranous immunoreactivity with E-cadherin antibody was absent. Absent
      cytoplasmic expression of alpha- and beta/gamma-catenins was seen in 24 and 22
      per cent of breast cancers, respectively. The intensity of reactivity with E
      cadherin showed a significant association with histological grade (p=0.002) and
      tumour type (p<0.001). Lobular carcinomas frequently showed loss of expression of
      E-cadherin, as reported elsewhere; loss of catenin expression was also found in
      these tumours. alpha-catenin intensity also showed a relationship with grade
      (p=0.008) and with oestrogen receptor (ER) status (p=0.006). beta/gamma-catenin
      expression was not associated with other known prognostic factors. Forty-nine per
      cent and 42 per cent of cases showed no membrane immunostaining with beta1- and
      alpha2-integrin, respectively, and co-ordinated loss of beta1- and alpha2
      integrin expression was found. Both beta1- and alpha2-integrin expression were
      associated with histological grade (p=0.003 and p=0.031, respectively) and beta1
      immunoreactivity with tumour type (p=0.010). None of the variables examined
      showed a statistically significant association with tumour size or lymph node
      stage, or with overall survival, although a trend was seen (p=0.087) towards
      poorer survival of patients with tumours with absent or weak expression of beta1
      integrin. The expression of these markers is of biological interest, but appears
      to be of little additional use in predicting clinical behaviour.

PMID- 10398117
TI  - Functional loss of E-cadherin and cadherin-11 alleles on chromosome 16q22 in
      colonic cancer.
AB  - Proteins of the cadherin family regulate cellular adhesion and motility and are
      believed to act as tumour suppressors. Previous studies have identified frequent
      mutation and allelic inactivation of the E-cadherin (cadherin-1) locus in diffuse
      gastric cancer. At least two other cadherin genes, P-cadherin (cadherin-3) and OB
      cadherin (cadherin-11), have been mapped close to the E-cadherin gene on
      chromosome 16q22. As this region of the genome is frequently deleted in
      malignancy, multiple cadherin loci may be affected by losses of chromosome 16q22.
      The expression of mRNA transcripts from polymorphic alleles of the E-cadherin and
      cadherin-11 genes was examined in 30 cases of colonic, gastric, and renal
      carcinoma. In gastric cancer, loss of expression of one allele was restricted to
      the E-cadherin locus, whilst in renal carcinoma neither locus was affected. In
      colonic cancers, loss of expression of one E-cadherin allele was detected in 5 of
      22 cases, whilst loss of a cadherin-11 allele was seen in 5 of 23 cases. This
      functional loss of cadherin gene expression may be due to gene deletion,
      inactivation or recombination. As no evidence of cadherin gene mutation was
      observed in the remaining transcripts, we can conclude that these two genes are
      only indirectly involved in the pathogenesis of colorectal cancer.

PMID- 10398118
TI  - Apoptotic and proliferative activity in the neoplastic progression of Barrett's
      oesophagus: a comparative study.
AB  - The balance between proliferation and apoptosis within a tissue is important in
      controlling its overall growth. When either or both are altered, uncontrolled
      cell proliferation can contribute to cancer. The aim of this study was to
      investigate apoptosis and proliferation in the progression from Barrett's
      oesophagus to adenocarcinoma. Fifty-one paraffin sections of Barrett's mucosa
      with both intestinal and gastric-type Barrett's mucosa, dysplasia, and
      adenocarcinoma, from 28 patients, were examined for apoptosis using haematoxylin
      and eosin (H&E)-stained sections counterstained immunohistochemically with CD45
      to distinguish leucocytes from apoptotic bodies. Proliferation was detected by
      immunohistochemistry using the MIB-1 (Ki-67) antibody. There was an increase in
      proliferation in dysplastic and carcinomatous tissue compared with metaplastic
      tissue (p=0.0001). In dysplasia, proliferation was distributed throughout the
      basal-luminal axis, whereas in metaplasia, cell division was compartmentalized to
      the lower crypt (p<0.001). Conversely, there was a decrease in apoptosis in the
      upper crypt and luminal surface in dysplasia and adenocarcinoma compared with
      metaplasia (p<0.0008). There was a significant increase in apoptotic activity in
      intestinal-type Barrett's mucosa compared with gastric-type. There was a highly
      significant increase in the glandular proliferation to apoptosis ratio (GPAR) in
      the progression of metaplasia to dysplasia to adenocarcinoma (p=0.001). The shift
      in the GPAR in the progression of neoplastic change suggests that it may be a
      useful and sensitive marker of neoplastic change in Barrett's oesophagus,
      especially if the assessment of both apoptotic and proliferative activity in the
      mucosa can be made easier by more sophisticated technical methods.

PMID- 10398119
TI  - Patterns of expression of trefoil peptides and mucins in gastric polyps with and
      without malignant transformation.
AB  - The expression of two trefoil peptides (TFF1 and TFF2) and four mucins (MUC1,
      MUC2, MUC5AC, and MUC6) was evaluated by immunohistochemistry and reverse
      transcription-polymerase chain reaction (RT-PCR) in 29 gastric polyps, 10
      hyperplastic and 19 adenomatous, eight of which displayed malignant
      transformation. The aims of this study were to characterize the expression
      profile of these molecules in each type of polyp and to investigate possible
      modifications of the profile during the process of malignant transformation. All
      hyperplastic polyps displayed immunoreactivity for TFF1, MUC5AC, and MUC1 in more
      than 75 per cent of the cells. In adenomatous polyps, three main phenotypes could
      be identified: complete gastric phenotype (co-expression of TFF1 and MUC5AC)-nine
      cases (47.4 per cent); incomplete gastric phenotype (TFF1-positive and MUC5AC
      negative)-seven cases (36.8 per cent); non-gastric (intestinal) phenotype (no
      expression of TFF1 or MUC5AC)-three cases (15.8 per cent). Data yielded by
      immunohistochemistry and RT-PCR showed a good correlation for both TFF1 and TFF2.
      One hyperplastic and seven adenomatous polyps with villous architecture displayed
      foci of diffuse and intestinal-type carcinoma, respectively; in all of these
      cases, MUC1 expression and signs of gastric differentiation were observed in both
      the non-malignant and the carcinomatous component. It is concluded that gastric
      differentiation is a feature of hyperplastic polyps and of a subset of
      adenomatous polyps which is shared by early carcinomas arising in some of these
      polyps, regardless of the histological type of polyp and of carcinoma.

PMID- 10398120
TI  - A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma
      and poorly differentiated head and neck squamous cell carcinoma.
AB  - A20 is an anti-apoptotic gene that can be induced in human epithelial cell lines
      in response to expression of the Epstein-Barr virus (EBV) gene product latent
      membrane protein 1 (LMP1). EBV is a ubiquitous, persistent human herpesvirus that
      is consistently associated with undifferentiated nasopharyngeal carcinoma (NPC),
      in which antigen expression includes LMP1. Consistent with a potential role in
      the development of NPC, LMP1 has profound effects on epithelial cell growth. A20
      may be a key downstream effector of LMP1 in NPC, as LMP1-induced A20 blocks p53
      mediated apoptosis in H1299 epithelial cells and most NPCs have wild-type p53.
      Moreover, the potential role of A20 in the development of epithelial malignancies
      may extend to tumours not associated with EBV. The purpose of this study was to
      develop an in situ hybridization assay to assess expression of A20 RNA in
      undifferentiated NPC and in non-EBV-associated poorly differentiated head and
      neck squamous cell carcinomas (SCCs) and well-differentiated SCCs of the skin.
      A20 RNA expression was also examined in normal samples of oral mucosa and skin.
      Expression of A20 was demonstrated in 76 per cent of undifferentiated NPCs and in
      80 per cent of poorly differentiated head and neck SCCs, suggesting a role for
      A20 in the pathogenesis of these epithelial malignancies. By contrast, A20 RNA
      was not detected in well-differentiated SCCs of the skin, or in any normal
      samples of squamous epithelial tissue. The pathway leading to A20 expression in
      non-EBV-associated poorly differentiated head and neck SCCs is clearly LMP1
      independent. LMP1 expression was demonstrated in 29 per cent of NPC biopsies,
      suggesting an LMP1-independent pathway to A20 induction in undifferentiated NPC.

PMID- 10398121
TI  - TP53 alterations in relation to the cell cycle-associated proteins p21, cyclin
      D1, CDK4, RB, MDM2, and EGFR in cancers of the uterine corpus.
AB  - In the present study, TP53 alterations have been analysed and compared with the
      expression of the proteins p21, cyclin D1, cdk4, RB, EGFR, and MDM2 in 53 cancers
      of the uterine corpus. TP53 gene mutations analysed by CDGE/DGGE and direct
      sequencing showed a TP53 gene mutation in 18 per cent of the cases. TP53 gene
      mutations were not significantly related to overexpression or down-regulation of
      any of the proteins. Immunohistochemically, there was an increased protein level
      of TP53 in 77 per cent, p21 in 36 per cent, cyclin D1 in 45 per cent, cdk4 in 77
      per cent, EGFR in 8 per cent, and MDM2 in 32 per cent of the cases. Expression of
      RB protein was normal in all cancers. Significant association of protein
      expression was seen between TP53 and MDM2 (p=0.005) and p21 and MDM2 (p=0.001).
      Furthermore, there may be an association between TP53 and p21 (p=0. 038) and
      cyclin D1 and cdk4 (p=0.045). The results revealed increased levels of TP53
      protein in all MDM2-positive cases that did not show TP53 mutations, indicating
      TP53 protein stabilization and inactivation by complex formation with MDM2. In
      summary, the high number of cases showing an increased level of TP53 and cdk4
      proteins suggests that these proteins play an important role in the neoplastic
      process in cancers of the uterine corpus.

PMID- 10398122
TI  - Expression of p27/Kip1 is down-regulated in human prostate carcinoma progression.
AB  - p27(Kip1) is a cyclin-dependent kinase inhibitor whose down-regulation has been
      observed in several tumour models, including breast, colorectal, and gastric
      carcinomas. The purpose of this study was to assess p27(Kip1) protein expression
      in normal and benign prostatic epithelia as well as the possible existence of
      abnormalities in prostate carcinoma progression. p27(Kip1) expression was
      immunohistochemically analysed in 51 normal tissue samples, 11 nodular
      hyperplasias (NH), 22 high-grade prostatic intraepithelial neoplasias (PIN), 56
      localized prostate adenocarcinomas, and 19 metastases. Immunoblotting was
      performed in ten cases. Normal prostate epithelium and NH showed diffuse and
      intense p27(Kip1) nuclear expression in most cases. A significant p27(Kip1) down
      regulation was observed in many carcinomas when compared with benign epithelium.
      Forty-seven cases (84 per cent) were low p27(Kip1) expressors (<50 per cent
      positive cells) and nine cases (16 per cent) were high p27(Kip1) expressors.
      p27(Kip1) down-regulation was also consistently seen in PIN. Fourteen out of 19
      metastases (74 per cent) were low p27(Kip1) expressors. Six metastatic samples
      had their corresponding primary tumour analysed and three cases showed decreased
      expression in the metastasis. It is concluded that p27(Kip1) is constitutively
      expressed in normal and benign prostatic tissue. This expression is clearly down
      regulated in neoplastic progression from the preinvasive lesions through invasive
      carcinoma and metastases and this therefore occurs in early stages of neoplastic
      transformation.

PMID- 10398123
TI  - Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed
      during early apoptosis.
AB  - A neo-epitope in cytokeratin 18 (CK18) that becomes available at an early caspase
      cleavage event during apoptosis and is not detectable in vital epithelial cells
      is characterized. The monoclonal antibody M30, specific for this site, can be
      utilized specifically to recognize apoptotic cells, which show cytoplasmic
      cytokeratin filaments and aggregates after immunohistochemistry with M30, while
      viable and necrotic cells are negative. The number of cells recognized by the
      antibody increases after induction of apoptosis in exponentially growing
      epithelial cell lines and immunoreactivity is independent of the phosphorylation
      state of the cytokeratins. The generation of the M30 neo-epitope occurs early in
      the apoptotic cascade, before annexin V reactivity or positive DNA nick end
      labelling. In a flow cytometric assay, the majority of the M30-positive cells
      appear in the 'apoptotic' subG1 peak. Tests with synthetic peptides define
      positions 387-396 of CK18, with a liberated C-terminus at the caspase cleavage
      site DALD-S, as the ten-residue epitope of M30. This epitope starts at the end of
      coil 2 of the predicted CK18 structure, at a probable hinge region, compatible
      with the sensitivity to proteolytic cleavage. The definition of a specific
      caspase cleavage site in CK18 as a neo-epitope can be used for quantification of
      apoptotic epithelial cells with immunocytochemical techniques and is applicable
      to both fresh and formalin-fixed material.

PMID- 10398124
TI  - D-type cyclins in adult human testis and testicular cancer: relation to cell
      type, proliferation, differentiation, and malignancy.
AB  - D-type cyclins are proto-oncogenic components of the 'RB pathway', a G1/S
      regulatory mechanism centred around the retinoblastoma tumour suppressor (pRB)
      implicated in key cellular decisions that control cell proliferation, cell-cycle
      arrest, quiescence, and differentiation. This study focused on
      immunohistochemical and immunochemical analysis of human adult testis and 32
      testicular tumours to examine the differential expression and abundance of
      cyclins D1, D2, and D3 in relation to cell type, proliferation, differentiation,
      and malignancy. In normal testis, the cell type-restricted expression patterns
      were dominated by high levels of cyclin D3 in quiescent Leydig cells and the lack
      of any D-type cyclin in the germ cells, the latter possibly representing the only
      example of normal mammalian cells proliferating in the absence of these cyclins.
      Most carcinoma-in-situ lesions appeared to gain expression of cyclin D2 but not
      D1 or D3, while the invasive testicular tumours showed variable positivity for
      cyclins D2 and D3, but rarely D1. An unexpected correlation with differentiation
      rather than proliferation was found particularly for cyclin D3 in teratomas, a
      conceptually significant observation confirmed by massive up-regulation of cyclin
      D3 in the human teratocarcinoma cell line NTera2/D1 induced to differentiate
      along the neuronal lineage. These results suggest a possible involvement of
      cyclin D2 in the early stages of testicular oncogenesis and the striking examples
      of proliferation-independent expression point to potential dual or multiple roles
      of the D-type cyclins, particularly of cyclin D3. These findings extend current
      concepts of the biology of the cyclin D subfamily, as well as of the biology and
      oncopathology of the human adult testis. Apart from practical implications for
      the assessment of proliferation and oncogenic aberrations in human tissues and
      tumours, this study may inspire further research into the emerging role of the
      cyclin D proteins in the establishment and/or maintenance of the differentiated
      phenotypes.

PMID- 10398125
TI  - Dominant human herpesvirus type 8 RNA transcripts in classical and AIDS-related
      Kaposi's sarcoma.
AB  - Skin biopsy sections of Kaposi's sarcoma (KS) from 25 patients (5 AIDS-related,
      20 classical cases) were histologically staged and hybridized in situ with
      oligonucleotide probes for constitutively transcribed human herpesvirus 8 (HHV-8)
      mRNA T0.7 and T1.1 using a colourimetric technique. T1.1 increases during
      experimental induction of the viral lytic phase in the HHV-8-infected lymphocytes
      of primary effusion lymphoma and its colourimetric detection in KS cells
      presumably corresponds to virion production. Immunostaining with anti-CD20,
      CD45RO, MAC 387, and alpha-smooth muscle actin was performed following T1.1 in
      situ hybridization (ISH). When the amount of T0.7 was above the detection
      threshold, the signal was made up of multiple coarse intranuclear dots in most
      spindle cells. Of the six early-stage lesions, none produced a T1.1 hybridization
      signal. Two of four AIDS-related and two of eight classical lesions with
      incipient spindle cell growth produced rare but distinct dense intranuclear T1.1
      signals in endothelial cells lining narrow tubes. In contrast, eight of ten (all
      classical KS) mature spindle cell lesions displayed a signal, scattered in up to
      2 per cent of spindled endothelial cells. Cell types other than endothelium
      produced no T1.1 hybridization signal in double stains. The results are
      consistent with other published data indicating latent HHV-8 infection in
      endothelium and its tumour cell progeny, with simultaneous virion production in a
      small subset of cells. Immunodeficiency may not influence the number of cells
      lytically infected with HHV-8 in early KS, in contradistinction to other
      herpesviruses with latent-lytic cycles.

PMID- 10398126
TI  - Immunohistochemical screening for oncogenic tyrosine kinase activation.
AB  - Tyrosine kinases causing the abnormal phosphorylation of intracellular proteins
      have been shown to contribute to oncogenic transformation in a number of human
      neoplasms. Immunohistological staining of routine biopsy sections for increased
      levels of phosphotyrosine may therefore provide a simple means of screening for
      tumours containing activated tyrosine kinases. In this study, monoclonal
      antibodies to phosphotyrosine were used to immunostain a cell line and tumour
      biopsies from lymphomas known to contain the activated anaplastic-lymphoma-kinase
      (ALK) tyrosine kinase. A range of normal and other neoplastic tissues were also
      immunostained for comparison. An anaplastic large cell lymphoma (ALCL) cell line
      carrying the (2;5) translocation, which creates the activated nucleophosmin
      anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase, was strongly labelled.
      Routine tissue biopsies from five cases of ALK-positive ALCL were also strongly
      positive for phosphotyrosine. The characteristic granular cytoplasmic labelling
      pattern for phosphotyrosine observed in a B-cell lymphoma (expressing full length
      ALK kinase) was identical to that obtained using an ALK-specific antibody, thus
      confirming that labelling for phosphotyrosine in lymphoma cells reflects the
      presence of an activated kinase. When normal lymphoid tissues were stained, there
      was little or no labelling for phosphotyrosine, but stronger labelling was seen
      in other cells and tissues; for example, endothelial cells and some carcinoma
      samples. Whilst the strong labelling for phosphotyrosine observed in the lymphoma
      cells is due to the presence of activated ALK, the strong staining of some normal
      cells presumably represents physiologically active kinases and this should be
      taken into account when interpreting the immunostaining of non-lymphoid tumours.
      The simplicity of this method, however, means that it offers a new rapid approach
      to the screening of large numbers of tumours for the presence of aberrant
      tyrosine kinase activation, particularly if they arise from tissues which
      normally contain only background levels of phosphotyrosine.

PMID- 10398127
TI  - Further characterization of the human clear cell sarcoma cell line HS-MM
      demonstrating a specific t(12;22)(q13;q12) translocation and hybrid EWS/ATF-1
      transcript.
AB  - Only a small number of clear cell sarcoma (CCS) cell lines have been reported,
      including the cell line HS-MM. In the present study, this cell line, maintained
      for more than 4 years since establishment, was further characterized by
      cytogenetic studies, fluorescence in situ hybridization (FISH) analysis, and
      reverse transcriptase-polymerase chain reaction (RT-PCR). HS-MM cells both in
      vitro and in vivo exhibited pseudodiploid karyotypes with the specific
      t(12;22)(q13;q12) translocation. The translocation between chromosomes 12 and 22
      was confirmed by FISH analysis and the hybrid EWS/ATF-1 transcript induced by
      this translocation was detected by RT-PCR. The HS-MM cell line will be useful for
      further studies of CCS.

PMID- 10398129
TI  - Author's reply

PMID- 10398128
TI  - Re: Expression of transforming growth factor beta isoforms in osteosarcoma
      variants.

PMID- 10398130
TI  - The potential diagnostic use of K-ras codon 12 and p53 alterations in brush
      cytology from the pancreatic head region.

PMID- 10398131
TI  - The hamartoma-adenoma-carcinoma sequence.
AB  - Carcinomas develop, although at low frequency, in hamartomatous polyps in the
      Peutz-Jeghers' syndrome. With the identification of at least one of the genes
      involved (LKB1/STK11), attempts can be made to unravel the molecular events
      responsible for this hamartoma-adenoma-carcinoma sequence. Recent data indicate
      that this sequence is real, that the molecular pathways involved are different
      from those in other hereditary colorectal cancer syndromes, and that, possibly in
      contrast to the hamartomatous polyps in the juvenile polyposis syndrome, the
      genetic abnormalities occur in the epithelial compartment of the lesions.

PMID- 10398132
TI  - Urinary tissue factor: a potential marker of disease.
AB  - Tissue factor (TF) is the main physiological initiator of blood coagulation and
      may be important in the biology of a variety of solid malignancies, particularly
      where angiogenesis is a critical factor. TF is frequently encrypted in the plasma
      membrane of cells in contact with blood, and is exposed only after stimulation by
      certain agonists. Cancer cells variably express TF and cancer cell lines which
      exhibit multidrug resistance contain more TF than parental cells. TF is increased
      in both tumour-associated macrophages and blood monocytes and has been implicated
      in abnormal coagulation activation seen in patients with inflammatory conditions
      and cancer. TF is also found in urine (uTF) in a lipid-associated form, probably
      of kidney origin. uTF levels can be assayed in a cost-effective manner and may be
      clinically important, particularly in patients with renal disorders and
      malignancy. uTF levels are not significantly affected by age, gender or cigarette
      smoking.

PMID- 10398133
TI  - Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz
      Jeghers' syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence.
AB  - Patients with Peutz-Jeghers' syndrome (PJS) develop hamartomatous
      gastrointestinal polyps and characteristic pigmentation, as a result of germline
      mutations in the LKB1 gene. The hamartomas in PJS were long considered to be
      without malignant potential. There is, however, accumulating epidemiological
      evidence to suggest that PJS predisposes to cancers at several different sites
      (colon, pancreas, breast, ovary, testis, and cervix), although large enough
      patient samples are rarely available to prove this. Allelic imbalance [allele
      loss, loss of heterozygosity (LOH)] has previously been reported in a small
      number of PJS polyps, suggesting that LKB1 acts as a tumour suppressor in these
      tumours. This study confirms allelic loss at LKB1 in PJS polyps and shows that
      LOH also occurs in cancers of the colon, breast, and cervix in PJS patients.
      Allele loss was additionally found in a colonic adenoma from a PJS patient,
      strongly suggesting the existence of a hamartoma-(adenoma)-carcinoma sequence in
      tumourigenesis. These results provide molecular evidence that PJS patients are
      predisposed to cancers at several sites, as a direct result of selection for loss
      of the 'wild-type' LKB1 allele in tumours. Given the rare involvement of LKB1 in
      sporadic cancers, these data also suggest that the indirect effect on cancer risk
      (or 'bystander effect') proposed for hamartomas in juvenile polyposis does not
      apply to carcinomas in PJS.

PMID- 10398135
TI  - Prognostic significance of p27(Kip1) expression in colorectal cancer: a clinico
      pathological characterization.
AB  - This study has evaluated the expression of the cyclin-dependent kinase inhibitor
      p27(Kip1) in 89 colorectal cancers (CRCs) using immunohistochemistry and has
      related p27 levels to clinico-pathological characteristics, tumour cell
      proliferation, and the expression of other G1-S transition regulatory proteins.
      Low levels of p27 were common in CRCs; 11 per cent of the tumours expressed very
      low levels and 44 per cent had p27 labelling indices (LIs) below 50 per cent.
      Except for depth of tumour invasion, no significant correlation was found between
      p27 expression and Dukes' stage, differentiation, growth pattern, tumour type or
      lymphocytic infiltration. Interestingly, tumours expressing low or very low p27
      LIs were predominantly found in the right colon (p=0.026). Expression of p27 was
      a strong predictor of survival, both in univariate and in multivariate survival
      analyses; patients with tumours of p27 LI less than 50 per cent had an impaired
      prognosis (p=0.0069). p27 expression did not correlate with tumour cell
      proliferation, or with expression of cyclin D1 or the retinoblastoma protein
      (pRb). These findings support the view that p27 not merely controls cell cycle
      progression, but might be associated with other mechanisms responsible for
      aggressive tumour behaviour in colorectal cancer.

PMID- 10398134
TI  - Microsatellite instability in sporadic colorectal carcinoma is not an indicator
      of prognosis.
AB  - Fifty sporadic colorectal carcinomas diagnosed in 1991 were analysed for
      microsatellite instability at four loci. Five of 50 (10 per cent) tumours showed
      replication errors (RERs) at two or more loci and were classed as RER-positive
      (RER+). A further five showed RERs at one locus only. A significant association
      (Fisher exact test) was found between RER+ tumours and location in the proximal
      colon, exophytic shape, size >5 cm, histological margin, lymphoid reaction, and
      near-diploid DNA content. There was no significant difference for age, sex,
      grade, mucin production, p53 protein overexpression or Duke's stage. There was no
      significant difference in survival as measured over a 60-month follow-up period.
      The findings, though limited by the small case numbers involved, show an
      association between RER positivity in sporadic colorectal tumours and certain
      clinico-pathological features. They do not suggest a better clinical outcome for
      sporadic RER+ tumours.

PMID- 10398137
TI  - Expression of MUC1 and MUC2 mucin core proteins and their messenger RNA in gall
      bladder carcinoma: an immunohistochemical and in situ hybridization study.
AB  - Expression of mucin core protein MUC1 and MUC2 was examined at the protein and
      mRNA level in 55 cases of carcinoma and 20 of dysplasia, and in 15 non-dysplastic
      epithelia of the gall bladder. In non-dysplastic epithelium, MUC1 protein was not
      expressed, while in dysplasia, MUC1 was focally expressed in ten cases,
      particularly in those associated with carcinoma. In carcinoma, MUC1 was expressed
      heterogeneously, and the frequency and extent of MUC1 expression increased with
      histological dedifferentiation. MUC1 was found on the apical cell surface and
      also in the cytoplasm in well- and moderately-differentiated carcinoma, and on
      the cell border in poorly-differentiated cases. In infiltrative regions, MUC1
      expression was more predominant and MUC1 frequently leaked outside the foci of
      carcinoma. By contrast, MUC2 was focally expressed in non-dysplastic as well as
      in dysplastic epithelia and more frequently in well-differentiated
      adenocarcinoma. MUC2-positive cells resembled goblet cells, whether in non
      dysplastic epithelium, dysplasia or carcinoma. Cell proliferative activity was
      higher in MUC1-positive than in MUC1-negative carcinoma cells. Distributions of
      MUC1 and MUC2 mRNA signals and of MUC1 and MUC2 proteins were similar in
      carcinoma and dysplasia. These results suggest that MUC1 expression by gall
      bladder carcinoma may reflect histological dedifferentiation, increased
      proliferative activity, and invasiveness, while MUC2 expression is related to
      lower proliferative activity and reflects some differentiation towards goblet
      cells; and that MUC1 expression in gall bladder dysplasia reflects malignant
      transformation.

PMID- 10398136
TI  - Two- to four-year histological follow-up of gastric mucosa after Helicobacter
      pylori eradication.
AB  - In a 2- to 4-year prospective study, the reversibility of gastritis after
      Helicobacter pylori eradication was analysed. Sixty-three H. pylori-positive,
      chronic duodenal ulcer patients were studied after the successful eradication of
      bacteria in the period from 1990 to 1993. H. pylori eradication was obtained by
      triple antimicrobial regimens (colloidal bismuth subcitrate, amoxycillin, and
      metronidazole) applied for at least 14 days. The criteria for eradication were
      the absence of bacteria from two antral and two body of stomach biopsies stained
      with haematoxylin, eosin, and Warthin Starry, and a negative antral biopsy
      culture. The same diagnostic procedures were repeated, at regular follow-up
      endoscopies, each year for up to 4 years. Neutrophil-granulocyte infiltration of
      gastric mucosa disappeared in 2 months after bacterial eradication. Mononuclear
      cellular infiltration was disappearing with statistical significance up to the
      second year and normal mucosa was observed in the majority of patients in the
      fourth year of follow-up. Degeneratively changed lymphoid aggregates were also
      present in the fourth year in the antrum (12.5 per cent of patients) and in the
      body of stomach (14 per cent of patients). There was no significant change in
      antral intestinal metaplasia during the 4 years of follow-up. Antral atrophy
      declined significantly in the period from 1 to 3 years of follow-up. In
      conclusion, 3-4 years are needed for gastric mucosa to become normal after H.
      pylori eradication, although some residual lymphoid aggregates persist even after
      that period.

PMID- 10398138
TI  - CD40 expression in bladder cancer.
AB  - The CD40 receptor is expressed in many immune cell types and is known to play a
      central role in both humoral and T-cell-mediated immunity, being a subject of
      intense research interest in recent years. It is also expressed on a variety of
      carcinomas and may therefore be of biological significance in the development and
      treatment of cancer. The expression of CD40 was examined immunohistochemically in
      a series of 131 bladder transitional cell carcinomas and the correlation with
      known prognostic markers and clinical outcome assessed. Seventy-eight per cent of
      the tumours were CD40-positive, with a highly significant association with both
      lower stage and lower grade (p<0.001). Ta and T1 tumours expressed CD40 in 89 per
      cent of specimens compared with 62 per cent seen in T2-T4 tumours and in contrast
      to normal urothelium, which was mainly CD40-negative. CD40 expression was not
      related to any other clinicopathological variable including Bcl-2 and p53
      expression, nor was it an independent prognostic marker. The lack of the
      relationship with Bcl-2 staining which is normally seen in basal epidermal cells
      may indicate alternative or abnormal CD40-mediated cell differentiation
      mechanisms. The diffuse expression seen in Ta bladder tumours may account for its
      clinically less aggressive behaviour and is likely to be an important factor in
      the excellent clinical response seen to BCG immunotherapy. It also raises the
      possibility of the future development of CD40/CD40 ligand-based immunotherapy for
      bladder cancer.

PMID- 10398139
TI  - Cyclin D1 overexpression lacks prognostic significance in superficial urinary
      bladder cancer.
AB  - The biological behaviour of urinary bladder neoplasms cannot be adequately
      predicted by histological criteria alone. Cyclin D1 is a cell-cycle regulating
      protein known to be overexpressed in a proportion of bladder carcinomas. To
      evaluate the prognostic significance of cyclin D1 expression and its relationship
      with tumour phenotype, 392 bladder carcinomas were analysed by
      immunohistochemistry. Clinical follow-up information was available in 337
      patients with superficial bladder tumours (stages pTa/pT1). Cyclin D1 positivity
      was seen in 176 of 392 carcinomas. Cyclin D1 overexpression was strongly linked
      to papillary tumour growth, low stage, and low histological grade (p<0.005 each).
      Multivariate analysis showed that papillary tumour growth was the only parameter
      which was independently linked to cyclin D1 positivity. There was no significant
      difference in proliferative activity (Ki67 labelling index) between cyclin D1
      negative and -positive tumours. Cyclin D1 positivity was not linked to the risk
      of recurrence or tumour progression, either in pTa or in pT1 carcinomas. It is
      concluded that cyclin D1 positivity distinguishes a large subgroup of papillary
      bladder tumours, but there is no evidence of prognostic significance for
      increased cyclin D1 expression.

PMID- 10398140
TI  - Prognostic value of p53, bcl-2, and c-erbB-2 protein expression in
      phaeochromocytomas.
AB  - Many studies have tried to discriminate malignant from benign phaeochromocytomas,
      but until now no widely accepted histological, immunohistochemical, or molecular
      methods have been available. In this study of 29 malignant and 85 benign
      phaeochromocytomas from 102 patients, immunohistochemistry was performed with
      antibodies to the tumour suppressor gene product p53 and the proto-oncogene
      products bcl-2 and c-erbB-2, using the avidin-biotin complex method. Malignant
      phaeochromocytomas showed a statistically significant higher frequency of p53
      (p=0.042) and bcl-2 (p=0.037) protein expression than their benign counterparts.
      The combination of both markers showed an even higher significance (p=0.004), to
      which both markers contributed equally. Overexpression of c-erbB-2 was associated
      with the occurrence of familial phaeochromocytomas (p=0. 001), but no difference
      was found between benign and malignant cases. In conclusion, p53, bcl-2, and c
      erbB-2 all appear to be involved in the pathogenesis of a proportion of
      phaeochromocytomas. Immunoreactivity to p53 and bcl-2 proteins may help to
      predict the clinical behaviour of phaeochromocytomas.

PMID- 10398141
TI  - Matrix metalloproteinase-2 (MMP-2) immunoreactive protein--a new prognostic
      marker in uveal melanoma?
AB  - Uveal melanoma is the most common primary intraocular tumour. Once haematogenous
      metastasis has occurred, there is no cure for the disease and there is an obvious
      need for new biological prognostic markers to estimate the risk of metastasis. In
      this study, the expression of matrix metalloproteinase-2 (MMP-2) was
      characterized immunohistochemically in 29 human uveal melanomas. Enzyme-linked
      immunoassays and gelatin zymographies were assessed in order to quantify the
      expression of gelatinases A and B, as well as the tissue inhibitor of
      metalloproteinases (TIMPs), in the vitreous body. A total of 49 per cent of the
      uveal melanomas displayed a positive immunoreaction for MMP-2 in melanoma cells,
      the epithelioid cells showing the most frequent staining. There was no
      correlation between the positivity of MMP-2 staining and the size of the primary
      tumour, gender or age. The expression of MMP-2 was associated with a dismal
      prognosis: the 5-year overall survival rate for MMP-2-positive cases was
      significantly inferior to that of the MMP-2 negative cases, 49 per cent vs. 86
      per cent, respectively (p=0.02). A patient group at high risk of metastatic
      disease was identified; only 38 per cent of patients with a MMP-2-positive non
      spindle cell uveal melanoma survived for 5 years. The analyses of MMPs or TIMPs
      in the vitreous body had no prognostic value. Positive immunostaining for MMP-2
      was observed in the retinal pigment epithelium, corneal epithelium, and
      fibroblasts in the ciliary body and choroid. It is concluded that
      immunohistochemical analysis of MMP-2 may help to predict a risk of metastasis in
      uveal melanoma.

PMID- 10398142
TI  - Keratinocyte apoptosis and p53 expression in cutaneous lupus and dermatomyositis.
AB  - Keratinocyte apoptosis may be induced by ultraviolet-B radiation and represents a
      potential source of fragmented autoantigens in autoimmune diseases. This study
      investigates whether excessive keratinocyte apoptosis occurs in the skin lesions
      of cutaneous lupus (CLE) and dermatomyositis (DM) and the potential mechanisms
      responsible for this phenomenon. Skin biopsies have been studied from 19 patients
      with CLE and DM, eight with scleroderma, and five healthy controls. Apoptosis was
      detected by in situ end-labelling of fragmented DNA. The expression of Bcl-2,
      PCNA, p53, and Ki-67 proteins was studied by immunohistochemistry. In DM and CLE
      skin, the number of apoptotic keratinocytes was significantly increased (p=0.008)
      compared with normal skin. In both diseases, a large accumulation of apoptotic
      keratinocytes and apoptotic bodies was present in the disrupted basal zone.
      Unlike normal skin, a large number of keratinocytes, particularly those
      morphologically apoptotic, expressed p53 protein. A significant increase in the
      number of proliferating Ki-67 positive (p=0.0007) and PCNA-positive (p=0.0008)
      nuclei was also observed. In both CLE and DM, exaggerated and inappropriate
      keratinocyte apoptosis occurs. It is associated with increased expression of p53
      and PCNA. This suggests that normal solar radiation alone or in combination with
      additional local factors induces DNA damage and excessive keratinocyte apoptosis
      in these autoimmune diseases of the skin. Apoptosis can mediate the severe
      epidermal lesions observed in both diseases and the release of fragmented
      autoantigens into the dermis.

PMID- 10398143
TI  - Insulin-like growth factor family in malignant haemangiopericytomas: the
      expression and role of insulin-like growth factor I receptor.
AB  - Haemangiopericytoma is a rare soft tissue tumour originating from the contractile
      pericapillary cells. Relatively little is known about its molecular pathogenesis.
      To address this issue, the insulin-like growth factor family (IGFs) was analysed
      in 19 tumours collected from a human tumour bank network. Seven of the tumours
      were associated with severe hypoglycaemia. Of these, six were retroperitoneal and
      one was located in the leg. 3 out of the 19 tumours (15.8 per cent) were positive
      for insulin-like growth factor I (IGF I) mRNA and 11 were positive for IGF II
      mRNA (57.9 per cent). Almost 90 per cent of haemangiopericytomas expressed IGF I
      receptor (IGF IR) mRNA (17 out of 19), five (26.3 per cent) expressed IGF binding
      protein 1 (IGF BP1), three (15.8 per cent) expressed IGF BP2, and four (21 per
      cent) exhibited IGF BP3 mRNA. All of the 14 haemangiopericytomas examined with
      regard to specific receptor binding were IGF IR positive, ranging from 1.2 to
      16.2 per cent. Binding was much higher in IGF I/IGF IR positive tumours (15.3+/
      0. 7) than in IGF I negative/IGF IR positive tumours (5.1+/-3.3). The potential
      role of IGF IR as a growth promoting factor in malignant haemangiopericytoma was
      studied using antisense oligonucleotides and monoclonal antibody alphaIR3 that
      specifically inhibit IGF IR synthesis or activity. 10 microM IGF IR antisense
      oligonucleotides significantly inhibited the growth of haemangiopericytoma cells
      in culture, by around 50 per cent; monoclonal antibody against IGF IR (alphaIR3)
      also significantly inhibited proliferation. The data suggest that IGF IR may play
      an important role in the genesis and progression of malignant
      haemangiopericytomas.

PMID- 10398144
TI  - Thrombospondin-1 inhibits Kaposi's sarcoma (KS) cell and HIV-1 Tat-induced
      angiogenesis and is poorly expressed in KS lesions.
AB  - Kaposi's sarcoma (KS), a neoplasm often associated with iatrogenic and acquired
      immunosuppression, is characterized by prominent angiogenesis. Angiogenic factors
      released by both KS and host cells, as well as HHV-8 and HIV viral products, have
      been implicated in the pathogenesis of this lesion. Angiogenesis is the result of
      imbalance among angiogenesis promoters and inhibitors, which disrupts
      homeostasis. The aim of this study was to investigate the expression and
      mechanism of KS control of thrombospondin-1 (TSP), a physiological inhibitor of
      angiogenesis. Immunohistochemical analysis of four KS lesions showed only spotty
      reactivity for TSP in the stroma and in less than 10 per cent of lesional blood
      vessels. In addition, the typical KS spindle cells were not stained. In agreement
      with these findings, decreased levels of TSP were measured with an ELISA assay in
      the supernatants of cultured KS cells, compared with endothelial cells. In vitro,
      TSP inhibited the endothelial cell proliferation and motility induced by KS cell
      supernatants. TSP also prevented endothelial cell motility induced by Tat, a
      product of HIV-1 endowed with angiogenic potential and implicated in the
      pathogenesis of AIDS-KS. In vivo, TSP inhibited the angiogenic activity exerted
      by Tat in the Matrigel sponge model. These results suggest that TSP down
      regulation might be permissive for the development of KS-associated angiogenesis.

PMID- 10398145
TI  - Expression of vascular endothelial growth factor in exuberant tracheal
      granulation tissue in children.
AB  - Prolonged tracheotomy and endotracheal intubation often induce symptoms of airway
      obstruction and delay decannulation and extubation. Bronchoscopic examination of
      patients undergoing these treatments usually shows the presence of exuberant
      (pseudopapillary or nodular) granulation tissue occupying the airway lumen. An
      immunohistochemical analysis was undertaken of vascular endothelial growth factor
      (VEGF) expression in exuberant tracheal granulation tissue (n=17) obtained from
      children treated with prolonged tracheotomy or endotracheal intubation. Increased
      levels of VEGF protein and mRNA were expressed mainly by tracheal epithelial
      cells that migrated to cover the granulation tissue and partly by pericapillary
      macrophages in this tissue, whereas normal tracheal epithelium did not express
      VEGF. The VEGF expression level correlated significantly with the severity of the
      exuberant granulation tissue response (p=0.0018). As VEGF induces angiogenesis
      and vascular permeability, characteristics of granulation tissue, and plays a
      pivotal role in granulation tissue development, enhanced VEGF expression may be
      involved in the development of exuberant tracheal granulation tissue.

PMID- 10398146
TI  - TSH receptor status of thyroid neoplasms--TaqMan RT-PCR analysis of archival
      material.
AB  - Regulation of thyroid follicular cell proliferation and function is mediated by
      the interaction of TSH with its receptor (TSHr) on the plasma membrane. While it
      is recognized clinically that responsiveness of thyroid epithelial tumours to TSH
      varies with the histological type and grade of neoplasm, the level of TSHr
      expression in these different tumours has not been quantified hitherto. The aim
      of this study was to provide this information. Total RNA was extracted from 125
      samples of formalin-fixed, paraffin-embedded thyroid tissue comprising 48
      papillary (PTC), 29 follicular (FTC), eight anaplastic (ATC), and five medullary
      thyroid carcinomas (MTC), in addition to 35 samples of either follicular adenoma
      (FA) or normal thyroid tissue. Samples were reverse-transcribed and analysed
      using TaqMan polymerase chain reaction (PCR). TSHr expression was shown to be
      similar to normal in FA and inversely related to the grade of the majority of
      thyroid cancers other than MTC, in which, as expected, there was negligible
      expression. It is concluded that reduced expression of TSHr implies decreased
      responsiveness to TSH manipulation and is therefore a clinically important
      prognostic indicator in thyroid cancers.

PMID- 10398147
TI  - L-selectin and its ligands mediate infiltration of mononuclear cells into kidney
      interstitium after ureteric obstruction.
AB  - It was previously reported that the L-selectin ligands detected by a rat L
      selectin and human IgG chimeric molecule (rLEC-IgG) are expressed in the distal
      tubules of the kidney, where no leukocyte traffic is seen under physiological
      conditions. In the present study, the role of L-selectin ligands in leukocyte
      infiltration into the kidney interstitium was investigated using a rat ureteric
      obstruction model. After ligation of the ureter, ligands for L-selectin rapidly
      disappeared from tubular epithelial cells and were relocated to the interstitium
      and peritubular capillary walls, where infiltration of monocytes and CD8(+) T
      cells subsequently occurred. Mononuclear cell infiltration was significantly
      inhibited by intravenous injection of a neutralizing monoclonal antibody (MAb)
      against L-selectin, indicating the possible involvement of an L-selectin-mediated
      pathway. Interestingly, immunohistochemical studies with a MAb against sulphatide
      showed that the distribution of sulphatide, known to be one of the candidates of
      L-selectin ligand, was almost indistinguishable from the staining pattern of rLEC
      IgG in both normal and ureteric obstructed kidneys, suggesting that sulphatide
      and/or related molecule(s) relocated to the renal interstitium were recognized by
      leukocyte L-selectin, leading to interstitial leukocyte infiltration. In line
      with this notion, intravenous injection of sulphatide markedly inhibited
      leukocyte infiltration, suggesting that L-selectin-sulphatide interaction may
      play a pivotal role in interstitial leukocyte infiltration in the kidney
      following ureteric obstruction.

PMID- 10398148
TI  - Changes in elemental concentrations are associated with early stages of apoptosis
      in human monocyte-macrophages exposed to oxidized low-density lipoprotein: an X
      ray microanalytical study.
AB  - This study examines ion homeostasis in monocyte-macrophages committed to death by
      apoptosis. X-ray microanalysis has been used to demonstrate that intracellular
      concentrations of potassium decreased whilst those of sodium increased following
      3 h of exposure to 100 microg/ml of oxidized low-density lipoprotein (LDL) in
      vitro. In contrast, the maximal incidence of cell death, as determined by the
      inability to exclude trypan blue, was not seen until 24 h of exposure. At 12 h,
      less than 1 per cent of cells were stained using terminal transferase-mediated
      DNA nick-end labelling, which is generally accepted as a marker of late stages in
      the apoptotic pathway. This is the first demonstration of early perturbations of
      ion homeostasis in monocyte-macrophages exposed to concentrations of oxidized LDL
      known to cause apoptosis.

PMID- 10398149
TI  - Effects of in vivo administration of anti-B7-1/B7-2 monoclonal antibodies on the
      survival of mice with chronic ongoing myocarditis caused by Coxsackievirus B3.
AB  - In acute myocarditis and dilated cardiomyopathy, it has previously been reported
      that antigen-specific T-cells infiltrate the heart and play an important role in
      the myocardial damage involved. For antigen-specific T-cell activation to occur,
      it is necessary for the T-cell to receive co-stimulatory signals provided by co
      stimulatory molecules expressed on the antigen-presenting cell (APC), as well as
      the main signal provided by binding of the T-cell receptor (TCR) to the antigen.
      To investigate the roles for the co-stimulatory molecules B7-1 and B7-2 in the
      development of chronic ongoing viral myocarditis, firstly the expression of B7
      1/B7-2 was analysed in the hearts of A/J mice with myocarditis induced by
      Coxsackievirus B3 (CVB3). Secondly the induction of B7-1/B7-2 on cultured cardiac
      myocytes treated with interferon (IFN)-gamma was evaluated. Thirdly the effects
      of the in vivo administration of anti-B7-1/B7-2 monoclonal antibodies (MAbs) on
      the survival of mice with viral myocarditis were examined. CVB3-induced
      myocarditis resulted in enhanced expression of B7-1/B7-2 on cardiac myocytes. The
      expression of B7-1/B7-2 on cardiac myocytes could be induced by IFN-gamma in
      vitro. In vivo anti-B7-1 MAb treatment significantly prolonged the survival of
      mice with myocarditis, whereas anti-B7-2 MAb treatment abrogated the protective
      effect of anti-B7-1. These findings indicate that distinct roles for B7-1 and B7
      2 antigens are involved in the development of viral myocarditis and raise the
      possibility of immunotherapy with anti-B7-1 MAb to prevent T-cell-mediated
      cardiac myocyte injury and to improve the prognosis of viral myocarditis.

PMID- 10398151
TI  - Authors' reply

PMID- 10398150
TI  - Re: Editorial entitled 'The origin of gut and pancreatic neuroendocrine (APUD)
      cells--the last word?'.

PMID- 10398152
TI  - Identifying and quantifying apoptosis: a growth industry in the face of death.
AB  - Apoptosis remains one of the hottest topics in cell biology, and great strides
      are being made in unravelling the complex interplay between the various
      regulatory molecules, particularly between the mammalian homologues of the
      nematode Caenorhabditis elegans death regulatory proteins Ced-3, Ced-4 and Ced-9.
      Curiously, the relative merits of the seemingly simple methodologies to visualize
      and quantify apoptosis still provoke considerable debate. Many are based on the
      ability to detect DNA breaks by enzyme-mediated addition of labelled nucleotides,
      but the capricious nature of many of the available labelling kits, combined with
      a lack of true specificity, continues to fuel the search for more reliable
      apoptosis 'markers'.

PMID- 10398153
TI  - The neoplastic pathogenesis of solitary and multiple osteochondromas.
AB  - Many theories of osteochondroma pathogenesis have been advanced. Genetic research
      into the inherited multiple form, hereditary multiple exostoses, has revealed a
      new family of tumour suppressor genes denoted EXT. Patterns of EXT gene mutation
      in hereditary multiple exostoses, in solitary and multiple osteochondromas, and
      in chondrosarcoma are analogous to those found in other tumour suppressor genes
      responsible for family cancer traits and associated malignancies. With one
      exception, most features of osteochondroma behaviour are comparable to those of
      benign neoplasms. The neoplastic pathogenesis of osteochondromas provides an
      alternative to the traditional 'skeletal dysplasia' theory to explain the growth
      disturbance associated with hereditary multiple exostoses. Recent studies on the
      physiological function of EXT genes are reviewed and implications for
      osteochondroma 'cell-of-origin' theories are discussed.

PMID- 10398155
TI  - Common and HIV-related diffuse large B-cell lymphomas differ in their
      immunoglobulin gene mutation pattern.
AB  - HIV-infected patients are at high risk of developing diffuse large B-cell
      lymphomas (DLBCL). It is currently unclear whether these lymphomas represent
      Epstein-Barr virus (EBV)-driven lymphoproliferations that develop in the setting
      of immunodeficiency, or whether these tumours are more closely related to the
      DLBCL seen in the general population. To clarify this issue, 12 HIV-related DLBCL
      from 11 patients were analysed for the presence of clonally rearranged and
      somatically mutated immunoglobulin heavy chain (IgH) genes and their association
      with EBV was determined. Eleven of the 12 tumour samples displayed monoclonal
      rearrangements of the IgH genes, with or without a moderate number of somatic
      mutations in the CDRII and in the FWIII regions (average four mutations). One
      patient presented two successive lesions; whereas the initial tumour showed an
      oligoclonal IgH rearrangement, the lymphoma at relapse proved to harbour a
      monoclonal B-cell population. Ten of 12 tumour samples expressed the EBV encoded
      small RNAs (EBERs), and six of these EBV-positive cases displayed, in addition,
      an expression of the EBV encoded nuclear antigen 2 (EBNA-2). The results obtained
      from HIV-related DLBCL are at variance to those described for DLBCL occurring in
      the general population, since the latter contain significantly more somatic IgH
      mutations in the CDRII and in the FWIII regions and are only rarely associated
      with EBV. It is concluded from these findings that HIV-related DLBCL represent a
      distinct group of B-cell lymphomas, a significant fraction of which most likely
      originates from EBV-driven lymphoproliferations, and that half of the cases
      derive from pre-germinal centre B-cells.

PMID- 10398154
TI  - p21(WAF1) expression and endocrine response in breast cancer.
AB  - An immunocytochemical assay for the p53-regulated protein product of the
      WAF1/Cip1 gene, p21(WAF1) (p21), was developed and applied to archival primary
      breast tumour material from 91 patients whose subsequent recurrent disease was
      treated with assessable courses of endocrine therapy. Nuclear localization of p21
      protein was observed in 76 (82.4 per cent) cases. Status cut-offs were
      established and 29 (31.9 per cent) were deemed negative, 39 (42.9 per cent)
      weakly positive, and 23 (25.3 per cent) strongly positive. p21 status was
      inversely correlated with p53 protein (p=0.047) but did not relate to oestrogen
      receptor (ER) status, response to endocrine therapy, or time to further disease
      progression (TTP). Highly p21-positive patients had a significantly improved
      overall survival time (p=0. 020). Co-assessment of p21 and p53 subgroups revealed
      p21+/p53- patients to have good survival characteristics, whilst p21-/p53+
      patients did poorly (p=0.008). The p21-/p53- patients overall did intermediately
      well, but Ki67-defined cellular proliferation analysis of these revealed two
      subclasses: those with high proliferation and poor survival times resembling the
      p21-/p53+ phenotype, and those with less proliferative tumours with good
      survival, similar to the p21+/p53- group. The significance of these results is
      discussed in the light of recent research concerning the role of p21 and p53 in
      breast cancer aetiology.

PMID- 10398156
TI  - Hodgkin and Reed-Sternberg cells of classical Hodgkin's disease overexpress the
      telomerase RNA template (hTR).
AB  - There is accumulating evidence to suggest that Hodgkin and Reed-Sternberg (HRS)
      cells represent the malignant cell population in Hodgkin's disease (HD). A recent
      report that HD tissue is in most instances devoid of telomerase activity was
      therefore unexpected. Since telomerase activity was determined in whole tissue
      extracts and HRS cells comprise only a small minority of the cells in the
      affected tissue, the telomerase activity of the HRS cells might have escaped
      detection. To test this possibility and to clarify whether HRS cells contain the
      enzyme telomerase, 13 cases of classical HD were analysed by three different
      methods. The presence of telomerase was studied at the single cell level by a
      sensitive radioactive in situ hybridization method employing a probe specific for
      the telomerase RNA template (hTR). In addition, tissue extracts were studied for
      telomerase activity by a modified TRAP assay and for hTR by reverse transcription
      polymerase chain reaction (RT-PCR). The extractive methods revealed telomerase
      activity in eight and hTR in all of the 13 HD cases studied. In situ
      hybridization located large amounts of hTR in the HRS cells of all 13 HD cases
      and low to medium amounts in some of the non-malignant lymphoid bystander cells.
      These results indicate that HRS cells constitutively overexpress telomerase and
      thus use this enzyme for stabilizing their telomeres. This substantiates the
      malignant nature of HRS cells. Furthermore, the results confirm that normal
      lymphoid cells can express telomerase. In consequence, methods of measuring
      telomerase in tissue extracts are not suitable for determining the presence of
      this molecule in lymphoma cells, since the vast majority of lymphoid neoplasms
      contain significant amounts of non-neoplastic lymphoid cells.

PMID- 10398157
TI  - Clonal T-cell receptor gamma-chain gene rearrangement by PCR-based GeneScan
      analysis in advanced cutaneous T-cell lymphoma: a critical evaluation.
AB  - Detection of clonal T-cell receptor gamma (TCRgamma)-chain gene rearrangement is
      a promising approach to distinguish between cutaneous T-cell lymphomas (CTCLs)
      and reactive T-cell infiltrates. Despite the improved sensitivity by using the
      polymerase chain reaction (PCR) rather than Southern blot analysis, monoclonality
      could be demonstrated in only 53-90 per cent of CTCL biopsies in recent studies.
      In the present study, formalin-fixed, paraffin-embedded specimens of 21 selected
      patients with clear-cut advanced-stage CTCL were analysed using a semi-nested
      TCRgamma PCR with newly developed consensus primer pairs. Detection of PCR
      products was done by GeneScan analysis (GSA); this technique is advantageous due
      to its sensitivity and accuracy in the detection and size determination of PCR
      products and it is easier to interpret than direct read-outs from TGGE or DGGE
      gels. In serial dilution experiments, TCRgamma-PCR-GSA allowed the detection of
      clonal, rearranged T-cells with a high in vitro sensitivity against a polyclonal
      background (1-6 per cent). Despite the selection of clear-cut, advanced-stage
      CTCL cases, however, dominant clonal TCRgamma-chain gene rearrangement was found
      in only 16 of the 21 patients analysed, indicating an overall clinical
      sensitivity of 76 per cent. Specificity was evaluated using biopsy specimens from
      21 control patients suffering from long-standing psoriasis (n=13) and eczema
      (n=8). Surprisingly, GeneScan profiles showing apparently single dominant peaks
      were detected in 14 per cent of these skin lesions, but these profiles turned out
      to be pseudo-monoclonal by repeated determinations. In conclusion, TCRgamma-PCR
      GSA does not suffice reliably to exclude malignancy, due to its limited clinical
      sensitivity, but with precautions taken to detect pseudo-monoclonality and to
      secure specificity, TCRgamma-PCR-GSA is a valuable instrument in the diagnosis of
      CTCL.

PMID- 10398158
TI  - Characterization of the E-cadherin-catenin complexes in pancreatic carcinoma cell
      lines.
AB  - E-cadherin and its associated cytoplasmic proteins alpha-, beta-, and gamma
      catenins play important roles in cell adhesion and signal transduction, as well
      as in maintenance of the structural and functional organization of polarized
      epithelial cells. In this study, the expression, distribution, and complex
      assembly of catenins with E-cadherin was analysed at the steady state in a panel
      of human pancreatic adenocarcinoma cell lines (BxPc3, HPAF, T3M4, and PaTuII cell
      lines). The expression and subcellular distribution were determined by western
      blotting and immunocytochemistry. Co-immunoprecipitation and cross-linking
      studies were performed to examine the complex assembly in both Triton X-100 (TX
      100)-soluble and -insoluble fractions. In BxPc3 and T3M4 cells, E-cadherin exists
      in two complexes, one with alpha- and gamma-catenin, and the other with beta
      catenin alone. In HPAF cells there are two complexes, one consisting of E
      cadherin with alpha- and beta-catenin, and another of E-cadherin with gamma
      catenin. In PaTuII cells, there is only a single complex of E-cadherin with alpha
      catenin and gamma-catenin. Modification of E-cadherin-catenin complexes in HPAF
      and PaTuII cells was associated with loss of membranous E-cadherin
      immunolocalization. The common denominator is impaired beta-catenin association
      with either E-cadherin (PaTuII) or alpha-catenin (BxPc3 and T3M4). This may
      suggest the presence of distinct mechanisms that modulate the assembly of each
      complex, which could disturb the tumour suppressor function of E-cadherin and the
      catenins.

PMID- 10398159
TI  - Expression of EDA/EDB isoforms of fibronectin in papillary carcinoma of the
      thyroid.
AB  - Cellular fibronectins containing the extracellular domain A or B (EDA and EDB)
      are particularly abundant in fetal and neoplastic tissues. The presence of EDA
      and EDB was investigated in 28 cases of papillary carcinoma of the thyroid using
      IST-9 and BC-1 monoclonal antibodies. Immunostaining for EDA and EDB was detected
      in tumour stroma, in tumour basement membranes, and in tumour blood vessels. EDA
      was present in 27 of the 28 cases, in 20 of which more than 75 per cent of the
      tumour stroma was stained. Immunostaining for EDB was detected in 23 of the 28
      cases and was less pronounced than that for EDA, being present in less than 25
      per cent of the tumour stroma in most cases. Reactivity for EDA/EDB was not
      observed in the adjacent normal thyroid in any of the cases investigated. In a
      group of 20 non-papillary tumours, immunostaining for EDA was present in the
      stroma of three follicular carcinomas (one minimally and two widely invasive),
      one medullary carcinoma, and 5 of 16 follicular adenomas; expression of EDB was
      more restricted, being present in only the two cases of widely invasive
      follicular carcinoma. The presence of EDA and EDB was not correlated with the
      extent of fibrosis or the degree of tumour cell differentiation. Immunoreactivity
      was already present in microcarcinomas. These observations raise the possibility
      that the production of oncofetal fibronectins is an important step in papillary
      carcinoma tumourigenesis, perhaps facilitating adhesion and spreading of tumour
      cells.

PMID- 10398160
TI  - Analysis of the MEN1 gene in sporadic pituitary adenomas.
AB  - The MEN1 gene on chromosome 11q13 is mutated in patients afflicted with multiple
      endocrine neoplasia syndrome type 1 (MEN1). These patients develop endocrine
      tumours of the pancreas, the parathyroid, and the anterior pituitary. In order to
      determine the role of MEN1 in sporadic pituitary adenomas, 61 pituitary adenomas
      were analysed from patients without evidence of a familial tumour syndrome.
      Single strand conformation polymorphism (SSCP) analysis was performed for the
      entire coding sequence of MEN1. Fragments with aberrant migration patterns were
      sequenced bidirectionally. Only a single somatic mutation was detected in this
      series. In addition, several previously reported and three novel polymorphisms
      were observed. Loss of heterozygosity analysis with 12 polymorphic markers,
      however, identified 13 pituitary adenomas with allelic deletions on chromosome
      11. Allelic losses occurred significantly more often in pituitary adenomas with
      hormone secretion than in non-functioning adenomas. These data suggest that MEN1
      mutations are rare events in sporadic pituitary adenomas. However, the
      discrepancy of only 1/61 adenomas with MEN1 mutation but 13/61 (22 per cent) with
      allelic loss on chromosome 11 may suggest the presence of a yet unknown tumour
      suppressor gene, relevant to the pathogenesis of sporadic pituitary adenomas.

PMID- 10398161
TI  - Cytokine secretion profiles of cloned T cells from human aortic atherosclerotic
      plaques.
AB  - T cells take part in the chronic inflammatory reaction in atherosclerotic
      plaques, but their specific role in atherosclerosis has not yet been fully
      elucidated. Nevertheless, one may anticipate that activated T cells may secrete
      cytokines capable of modulating the morphology and hence the stability of plaques
      by regulating cell proliferation, lipid metabolism, and extracellular matrix
      (ECM) synthesis and/or degradation. This study has been designed to investigate
      the functional properties of T cells in atherosclerotic lesions. For this
      purpose, T-cell clones were generated from atherosclerotic plaques isolated from
      human aortas obtained at autopsy from six subjects. Cloned cells were activated
      with PMA and OKT-3 to initiate cytokine production and cytokine profiles of CD4
      positive clones were measured by ELISA. The majority of the T-cell clones
      (125/155, 81 per cent) produced both interferon (IFN)-gamma and interleukin (IL)
      4 (type 0 cytokine profile). Moreover, the production of IFN-gamma was dominant
      in the majority of these clones. A type 1 cytokine profile (high levels of IFN
      gamma and low levels of IL-4) was found in 17 per cent of the clones (27/155).
      Only three clones (2 per cent) showed a type 2 cytokine secretion pattern (high
      levels of IL-4 and low levels of IFN-gamma). No cytolytic activity could be
      established in plaque-derived T cells. Our results show that the T-cell
      population in atherosclerotic lesions is heterogeneous, but the most dominant T
      cell by far is the one with a type 0 cytokine profile. The dominant secretion of
      IFN-gamma by T-cell clones suggest an important role for plaque T cells in
      modulating the growth and differentiation of other cells, such as macrophages and
      smooth muscle cells in atherosclerotic plaques.

PMID- 10398162
TI  - Co-localization of tissue factor and tissue factor pathway inhibitor in coronary
      atherosclerosis.
AB  - Tissue factor (TF) initiates the extrinsic pathway of blood coagulation by acting
      as a cofactor for Factor VII. Inhibition of the Factor VIIa-TF complex is
      mediated by the tissue factor pathway inhibitor (TFPI), which is a serine
      protease inhibitor with three Kunitz-type domains. The localization of TF and
      TFPI protein has been examined immunohistochemically in various atherosclerotic
      lesions of coronary arteries from 22 autopsy cases and their messenger RNA
      expression has been confirmed by reverse transcription-polymerase chain reaction.
      Four types of atherosclerotic lesion (types I, II, III, and IV) were classified
      according to the method described by Stary et al. TF and TFPI were localized in
      endothelial cells, macrophages, macrophage-derived foam cells, and smooth muscle
      cells in the intimal lesions, medial smooth muscle cells, and endothelial cells
      of the microvessels in the adventitia. Immunohistochemical double staining
      revealed the co-localization of TF and TFPI in the endothelial cells and
      macrophages in four types of atherosclerotic lesions. In type III and IV lesions,
      the number of TF- and TFPI-positive cells was increased, accompanied by
      extracellular localization of TF and TFPI in the lipid core of atherosclerotic
      plaques. Fibrin deposition was found around TF- and TFPI-positive macrophages and
      in the lipid core of atherosclerotic plaques. TF and TFPI messenger RNA were
      detected more frequently in coronary arteries with type III and IV lesions than
      in those with type I and II lesions. The co-localization of TF and TFPI was
      demonstrated in various atherosclerotic lesions of coronary arteries and was
      shown to be intimately related to fibrin deposition in advanced atherosclerotic
      plaques. The co-localization of TF and TFPI may thus be closely associated with
      thrombogenicity in atherosclerotic lesions of coronary arteries.

PMID- 10398163
TI  - Local neovascularization and cellular composition within vulnerable regions of
      atherosclerotic plaques of human carotid arteries.
AB  - An improved immunohistochemical method has been used to assess neovascularization
      within the vulnerable 'shoulder' regions of atherosclerotic plaques from carotid
      arteries. A combination of monoclonal antibodies (CD31, CD34, +/- von Willebrand
      factor) was shown to be far more effective than conventional techniques in
      demonstrating extensive vascularizations within the 'shoulder' and cap regions of
      late-stage plaques. Such sites were shown to be microfocal, often appearing as a
      plexus of both large and small vessels which occupied a significant proportion of
      the 'shoulder' area. These regions of marked neovascularization were commonly
      associated with accumulations of macrophages, mast cells, and T-cells, indicative
      of local inflammatory reactions. The matrix components elastin and collagen type
      VI showed variable distributions which suggested extensive tissue remodelling,
      whereas collagen type IV was recognized as a basement membrane protein of most
      blood vessels, as well as being associated with 'stellate' smooth muscle cells.
      Evidence of local microvascular damage within the shoulder regions of some
      specimens was demonstrated by extravascular red blood cells, macrophages
      containing haemosiderin, and perivascular fibrin deposition. These local
      haemorrhages derived from microvessels beneath the lining of the arterial lumen
      are a further indication of how the microfocal vascularization of the plaque
      'shoulder' might contribute to further complications of inflammation and plaque
      destabilization in late-stage disease.

PMID- 10398164
TI  - Expression of CYP2E1 by human monocyte-derived macrophages.
AB  - The expression of the ethanol-metabolizing cytochrome P450 (CYP2E1) in human
      monocyte-derived macrophages was studied at the mRNA and protein levels. The
      presence of mRNA was investigated by reverse transcriptase-polymerase chain
      reaction (RT-PCR) and protein by immunocytochemistry. The data show that CYP2E1
      is expressed in human monocyte-derived macrophages at a level similar to that
      demonstrated in other extrahepatic tissues. Although there is circumstantial
      evidence for the presence of CYP2E1 in human macrophages, it has not previously
      been demonstrated directly. Its presence in macrophages underlines the potential
      importance of these cells in initiating alcohol-induced cytotoxicity.

PMID- 10398165
TI  - Expression of Ep-CAM in normal, regenerating, metaplastic, and neoplastic liver.
AB  - Ep-CAM is a homophilic, Ca2+-independent cell-cell adhesion molecule that is
      expressed in many human epithelial tissues. Its increased expression is closely
      associated with active cell proliferation. Furthermore, in epithelial cell types
      that in adults lack Ep-CAM (i. e. squamous epithelia), up-regulation of Ep-CAM
      coincides with the early stages of neoplastic change. This study has analysed the
      expression of Ep-CAM in liver, in the hepatocytes and cells of the biliary duct
      system, in relation to proliferative diseases and carcinogenesis. Adult
      hepatocytes are Ep-CAM negative, with only bile duct epithelium being positive in
      the liver tissue. However, in the 8-week embryonic liver, the majority of
      hepatocytes express Ep-CAM. During regeneration and repair of liver tissues
      associated with focal nodular hyperplasia and (biliary) cirrhosis, activation of
      Ep-CAM expression was observed, with high expression levels in so-called
      'ductular proliferations'-regenerating stem cells. During precursor cell
      differentiation into mature hepatocytes, several intermediate morphological
      stages could be observed, all Ep-CAM positive, including cells morphologically
      close to mature hepatocytes. Full maturation of the precursor resulted in the
      disappearance of Ep-CAM expression. The results suggest that expression of Ep-CAM
      is a prerequisite of the proliferative phenotype during differentiation of
      hepatocyte precursors. In liver neoplasia, Ep-CAM was expressed in almost all
      cholangiocarcinomas (10/11), whereas the majority of hepatocellular carcinomas
      (8/10) were negative, suggesting that malignant proliferation of hepatocellular
      carcinoma cells is not related to expression of Ep-CAM and that hepatocellular
      carcinoma originates from a highly differentiated precursor. The results indicate
      that Ep-CAM can be used as an additional immunohistochemical marker to
      distinguish cholangiocarcinoma from hepatocellular carcinoma due to the
      differential expression of Ep-CAM in these tumours.

PMID- 10398166
TI  - In vivo expression of soluble Fas and FAP-1: possible mechanisms of Fas
      resistance in human hepatoblastomas.
AB  - Many tumour cells express both Fas and its ligand (FasL) on their surface and it
      has remained a mystery why such cells do not simply kill themselves. It remains
      to be determined whether Fas and FasL are expressed in human hepatoblastomas and
      if so, what is responsible for the possible Fas resistance of these tumours. In
      this study, the expression of Fas and FasL was examined in 23 cases of human
      hepatoblastoma by immunohistochemical staining. To elucidate possible Fas
      resistance in hepatoblastomas, Fas-resistance pathways including the expression
      of bcl-2 and Fas-associated phosphatase-1 (FAP-1), and the expression of soluble
      Fas (sFas) mRNA, were analysed by immunohistochemistry and in situ reverse
      transcription-polymerase chain reaction (in situ RT-PCR). Fas gene mutation in
      the death domain was also examined. Fas and FasL were expressed in all
      hepatoblastomas analysed. Twenty (87 per cent) and 18 (78 per cent) cases of
      hepatoblastoma were positive for sFas mRNA and FAP-1, respectively, but none of
      the hepatoblastomas expressed bcl-2. Mutation in the death domain of the Fas gene
      was not found in hepatoblastomas. Taken together, these findings demonstrated
      that Fas, a death receptor, and its ligand are co-expressed in hepatoblastomas in
      vivo, but some inhibitors of Fas-mediated apoptosis are also expressed in these
      tumours. These results suggest that it is probably due to the action of
      inhibitory molecules of the Fas pathway that the tumour cells of hepatoblastomas
      do not kill themselves in an autocrine-driven cycle and that in this manner
      hepatoblastomas avoid apoptosis.

PMID- 10398168
TI  - Release of Helicobacter pylori vacuolating cytotoxin by both a specific secretion
      pathway and budding of outer membrane vesicles. Uptake of released toxin and
      vesicles by gastric epithelium.
AB  - The mechanisms by which Helicobacter pylori releases its virulence factors are
      poorly known. Active secretion has been proposed for some products, including a
      vacuolating toxin (VacA). Outer membrane vesicles represent another mechanism by
      which some Gram-negative bacteria may release virulence factors. This study
      sought to localize VacA by immunocytochemistry in H. pylori cells, to determine
      whether H. pylori produces outer membrane vesicles, and to investigate whether
      such vesicles might constitute a vehicle for the delivery of bacterial virulence
      factors to the gastric mucosa. Small (50-300 nm) membrane vesicles were found in
      H. pylori culture media from both H. pylori strain 60190 and strain CCUG 17874.
      These vesicles appeared to originate from blebs arising on the bacterial outer
      membrane. VacA was immunolocalized in the periplasm and outer membrane of intact
      bacteria and also in outer membrane blebs and vesicles. Both soluble secreted
      VacA and VacA-containing vesicles bound to, and were internalized by, MKN28 cells
      and were detectable in the gastric mucosa from H. pylori-infected humans. The
      release of outer membrane vesicles by H. pylori may represent a mechanism,
      additional to secretory pathways, for the delivery of bacterial toxins and
      antigens to the gastric mucosa.

PMID- 10398167
TI  - Myocyte loss in chronic heart failure.
AB  - This study examined whether or not there is progressive loss of individual
      myocytes in established heart failure, accounting for the progressive left
      ventricular dysfunction; whether such loss is by necrosis or apoptosis; and
      whether such loss is more pronounced in ischaemic heart disease or idiopathic
      dilated cardiomyopathy. Tissue for patients undergoing cardiac transplantation
      for clinical end-stage heart disease was used. The clinical diagnosis was not
      known to the observer at the time of analysis. Indices of potential myocyte loss
      were: detection of apoptotic nuclei in situ, using the TUNEL method,
      immunohistochemistry for CD120a, CD120b, CD95, perforin and granzyme B; binding
      of C9 complex; and lipofuscin deposition within macrophages. Interstitial
      macrophages and T cells and their relationship to myocyte loss were also
      examined. There is indeed low grade myocyte loss in chronic heart failure, but
      there was no difference between the disease groups; rather, there was marked
      patient-to-patient variation within each category. Thus in chronic heart failure
      myocyte loss does occur, and both necrosis and apoptosis contribute to this loss,
      irrespective of the underlying nature of the disease. Any mechanism which
      accounts for myocyte loss must be common to both conditions, rather than specific
      for a pre-operative diagnosis.

PMID- 10398169
TI  - Re: Alterations in cytokeratin expression by the alveolar lining epithelial cells
      in lung tissues from patients with idiopathic pulmonary fibrosis.

PMID- 10398170
TI  - Assessing historical research in the behavioral and social sciences: A symposium.
      Introduction.

PMID- 10398172
TI  - A quarter century of the history of psychiatry.
AB  - This article reviews the development of the historiography of Anglo-American
      psychiatry over the past quarter century, while passing attention to work on the
      history of psychiatry in Europe. The relationship between earlier and later work
      is stressed, and recent trends in the field assessed.

PMID- 10398171
TI  - Assessing research in the history of sociology and anthropology.
AB  - This paper reviews recent interpretive trends among historians of anthropology
      and sociology, examining both introductory texts and scholarly studies. It
      focuses on works published over the last ten years, and stresses that there has
      been no resolution of the long-standing conflict between "presentist" and
      "historicist" approaches to the history of the human sciences.

PMID- 10398173
TI  - Assessing research in the history of psychology: past, present, and future.
AB  - Since 1970, the "New History" of American psychology has grown into a lively
      specialty, characterized by tightly focused research utilizing archival source
      material. The collective product so far is an accumulation of disparate pieces
      rather than a coherent story. For the future, a debate about critical
      developments in the discipline's history and their causes appears desirable, in
      order to produce a more informative analysis of this history.

PMID- 10398174
TI  - A world from brave to new: Talcott Parsons and the war effort at Harvard
      University.
AB  - This article argues that for Parsons and some of his colleagues at Harvard, the
      Second World War and the post-war period provided a context in which their work
      contributed to the transformation from totalitarianism to democracy in Central
      Europe (especially Germany) and Japan. The various agendas of Parsons' work are
      shown, supplemented by that of three of his colleagues with whom he collaborated
      (Gordon W. Allport, Carl J. Friedrich, Clyde Kluckhohn). The immediate effect of
      this work, for Parsons, however, meant frustration rather than fame, and his
      eventual reputation, I maintain, came unexpectedly with the third of his three
      attempts in the immediate post-war period to sum up what he believed were crucial
      insights that the Second World War had yielded concerning the ways in which
      sociology could contribute to the analytical understanding of democracy. The
      significance of this work is that it was both political and scientific. Because
      of the world situation of the 1940s, when the Holocaust in Germany was the nadir
      of civilization, Parsons believed that social science could contribute to the
      cause of making the world safe for future democracy. In the 1940s, this future
      depended on brave citizens, or such might have been Parsons' worldview. Targets
      envisaged for the 1950s, then, were community and citizenship in the newly
      democratic societies such as (West) Germany, the land that defeated Nazism.

PMID- 10398176
TI  - Briefly noted 

PMID- 10398175
TI  - Psychotechnology and insanity at the wheel.
AB  - The article discusses psychological testing of automobile drivers performed by
      the Psychopathic Clinic affiliated with the Traffic Court of the Detroit
      Recorder's Court. Between 1936 and 1965 more than 15,000 drivers who had either
      run afoul of the traffic codes or been involved in a traffic collision. A
      statistical analysis of these cases reveals that the psychologists and
      psychiatrists working at the clinic were reinforcing existing ethnic, racial, and
      gender stereotypes in their pursuit of traffic safety. Patients who were deemed
      unfit drivers were recommended to the judges for sanctions ranging from license
      revokations to forced committment.

PMID- 10398177
TI  - News and notes 

PMID- 10398178
TI  - Effect of low-dose radiation therapy when combined with surgical resection for
      Ewing sarcoma.
AB  - BACKGROUND: As an alternative to high-dose irradiation, limited surgery and low
      dose irradiation have been investigated as a means to achieve local control. We
      retrospectively examined the clinical characteristics, treatment, and outcome for
      25 patients with Ewing sarcoma treated with limited surgery and low-dose
      irradiation. PROCEDURE: The records of 25 patients (age 4-48 years) were reviewed
      who were treated between 1979 and 1996 at Memorial Sloan-Kettering Cancer Center.
      At the time of diagnosis, 21 of the 25 patients had prognostically unfavorable
      tumors including the presence of metastatic disease (n = 12), an axial primary (n
      = 17), and a tumor measuring greater than 8 cm (n = 18). The primary tumor was
      completely resected (wide local excision) in 13 patients, incompletely resected
      (marginal excision) in 7 patients, and biopsied only in the remaining 5 patients.
      The median dose of irradiation to the primary site was 30 Gy. RESULTS: With a
      median follow-up of 67 months (range 16-189 months) for the surviving patients,
      28% failed distantly, and an additional 28% suffered from the progression of
      previously established metastatic disease. No patient failed locally. The median
      overall survival was 43 months. The actuarial overall survival at 5 years was 39%
      (+/-11%) for all patients and 60% (+/-14%) for patients with localized disease.
      CONCLUSIONS: Limited surgery and postoperative irradiation are one strategy that
      promises to balance the goal of achieving local control with the goal of
      diminishing late effects. Apart from the scenario in which radiation therapy is
      absolutely unnecessary, low-dose irradiation may be appropriate after considering
      the risk for local recurrence and overall prognosis.

PMID- 10398179
TI  - Activity of intraarterial carboplatin as a single agent in the treatment of newly
      diagnosed extremity osteosarcoma.
AB  - BACKGROUND: Chemotherapy has dramatically improved the rates of cure and survival
      of patients with localized and metastatic osteosarcoma. Nonetheless, the number
      of chemotherapeutic agents active against osteosarcoma is limited to doxorubicin,
      cisplatin, high-dose methotrexate, and ifosfamide. Carboplatin, a cisplatin
      analogue, has been tested as a single agent in patients with recurrent
      osteosarcoma or as part of multiagent chemotherapy in newly diagnosed patients.
      PROCEDURE: We tested the activity and toxicity of two cycles of intraarterial
      carboplatin as a "window therapy" (600 mg/m2 per cycle) in 33 consecutive
      patients with extremity osteosarcoma before the start of multiagent chemotherapy.
      Response was based on clinical (tumor diameter, local inflammatory signs, and
      range of motion) and radiological parameters (plain local films and
      arteriographic studies prior to drug administration). RESULTS: Patients' age
      ranged between 8 and 18 years (median age 13 years). Primary tumor originated
      from the femur (15 patients), tibia (10 patients), fibula (4 patients), humerus
      (3 patients), and calcaneus (1 patient). Only 7 patients (21%) had metastatic
      disease at diagnosis (5 in the lung and 2 in other bones). A favorable clinical
      and radiological response was documented in 81% and 73% of the patients,
      respectively. Clinical and radiological progression occurred in 12% and 9% of the
      patients, respectively. Seventeen of the patients remain alive and disease-free.
      Survival and event-free survival at 3 years for nonmetastatic patients are 71%
      (SE = 9%) and 65% (SE = 9%), respectively; for metastatic patients, the figures
      are 17% (SE = 15%) and 14% (SE = 13%), respectively. CONCLUSIONS: We conclude
      that carboplatin is an active agent in the treatment of newly diagnosed extremity
      osteosarcoma.

PMID- 10398180
TI  - Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and
      adolescents: the St. Jude Children's Research Hospital experience.
AB  - BACKGROUND: Because the natural history of pediatric patients with metastatic
      nonrhabdomyosarcomatous soft-tissue sarcomas (NRSTS) had not been well described,
      we retrospectively reviewed our single-institution experience with these tumors.
      PROCEDURE: We identified 26 patients with metastatic NRSTS who were treated at
      St. Jude Children's Research Hospital from December 1971 through July 1995. We
      evaluated the characteristics of each patient, including age, sex, primary site,
      stage, type of therapy received, and outcome. Sites of metastatic disease at
      diagnosis and relapse were noted. RESULTS: The median age of the 26 study
      patients at diagnosis was 14. 8 years; 54% of patients were male and 69% were
      white. The most common histologies were synovial sarcoma, alveolar soft-part
      sarcoma, and malignant fibrous histiocytoma. Most primary tumors (73% of cases)
      occurred in the trunk or extremities. Most patients presented with large (>5 cm),
      high-grade lesions. All 26 patients received chemotherapy, and 8 responded to an
      ifosfamide- or cyclophosphamide-doxorubicin-based regimen. Radiotherapy was
      administered to 15 patients, and 13 had a partial or complete resection of the
      primary tumor. Six patients underwent thoracotomy. The estimated 2-year survival
      for the cohort was 34.6% +/- 8.9%; the 2-year progression-free survival was 15.4%
      +/- 6.3%. The lung was the most common site of failure. CONCLUSIONS: Children
      with metastatic NRSTS have a poor outcome, which is similar to that in adults.
      More effective systemic chemotherapy is needed to facilitate complete surgical
      resection of primary and metastatic sites. Aggressive pulmonary metastatectomy
      can increase disease control.

PMID- 10398181
TI  - Regimen-related toxicity of myeloablative chemotherapy with BCNU, thiotepa, and
      etoposide followed by autologous stem cell rescue for children with newly
      diagnosed glioblastoma multiforme: report from the Children's Cancer Group.
AB  - BACKGROUND: The survival of children with glioblastoma multiforme (GBM) remains
      poor. In an effort to improve the cure rate of children with this disease, high
      dose chemotherapy followed by autologous stem cell rescue (ASCR) has been
      evaluated. We report the regimen-related toxicity (RRT) and survival seen in 11
      children with newly diagnosed GBM treated with high-dose chemotherapy on a
      Children's Cancer Group study (CCG-9922). PROCEDURES: This phase II pilot study,
      intended to treat 30 patients, accrued 11 patients from July, 1993, to April,
      1995. The pre-ASCR preparative regimen included BCNU 100 mg/m2 every 12 hr for a
      total of six doses on days -8, -7, -6; thiotepa 300 mg/m2/day on days -5, -4, -3;
      and etoposide 250 mg/m2/day on days -5, -4, -3. All patients received delayed
      radiotherapy at a dose of 5,400 cGy to the primary site commencing on
      approximately day +42 after ASCR. RESULTS: Five patients (45%) developed
      significant, nonfatal (grade III or IV) pulmonary and/or neurological toxicities.
      Three patients developed signs and/or symptoms of idiopathic interstitial
      pneumonitis. Eight patients (73%) have died, two (18%) of toxicity, and six (55%)
      of disease progression. Three patients (27%) achieved and remain in complete
      radiographic remission 2.9, 3.9, and 5.1 years from ASCR. One of these three,
      developed a lymphoblastic non-Hodgkins lymphoma (NHL) 3. 5 years post-ASCR. The
      survival rates for these 11 children at 1 year and 2 years are 73% +/- 13% and
      46% +/- 14%, respectively. The progression-free survival rates at 1 year and at 2
      years are 64% +/- 14% and 46% +/- 14%, respectively. CONCLUSIONS: We conclude
      that high-dose chemotherapeutic regimens followed by ASCR is a feasible treatment
      of childhood GBM. The BCNU-based preparative regimen utilized in this study was
      associated with prohibitive pulmonary toxicity.

PMID- 10398182
TI  - Improved outcome for acute lymphoblastic leukemia in children of a developing
      country: results of the Chilean National Trial PINDA 87.
AB  - BACKGROUND: The National Chilean Pediatric Oncology Group, PINDA, reports the
      first prospective, nonrandomized trial for acute lymphoblastic leukemia (ALL),
      using a modified version of the Berlin-Frankfurt-Munster protocol (ALL BFM 86).
      The aim of this study was to classify immunophenotypes, to decrease cranial
      irradiation, and to assess whether this protocol would improve the survival rate.
      PROCEDURE: From June, 1987, to June, 1992, 444 unselected children were diagnosed
      with ALL. Of them, 425 were evaluable. Therapy was stratified by risk. Standard
      risk (SR) and high-risk (HR) patients received protocols I, M, II, and
      maintenance therapy. Very-high-risk (VHR) patients received protocol E instead of
      protocol M. All patients received a prephase treatment consisting of prednisone
      and intrathecal methotrexate (MTX). HR and VHR patients received cranial
      irradiation (12-18 Gy). The following changes were made to the ALL BFM 86
      protocol: in protocol M, MTX 1 g/m2 instead of 5 g/m2; in protocol E, citarabine
      1 g/m2 instead of 2 g/m2; mithoxantrone and ifosfamide were substituted by
      teniposide and cyclophosphamide. RESULTS: Immunophenotypes: pro-B-ALL, 14%;
      common ALL, 67.4%; pre-B-ALL, 4.3%; T-ALL, 10%; undifferentiated leukemia (AUL),
      4.3%. The overall 5-year event-free survival (EFS) rate was 60% +/- 2% (SE). The
      5-year EFS rate for each risk group was: SR 75%, HR 62%, VHR 28%, with a median
      follow-up of 6.5 years (range 4.5-9.5 years). The cumulative incidence of central
      nervous system (CNS) relapse was 5.4%. CONCLUSIONS: We have been able
      successfully to perform a nationwide study. Our strategy to adapt the BFM
      protocol to our population of patients trial was effective in improving the EFS.
      The immunophenotype distribution is similar to that in other reported series.

PMID- 10398183
TI  - Role of surgical biopsies in the management of bone marrow transplant patients.
AB  - BACKGROUND: Bone marrow transplantation (BMT) patients frequently develop life
      threatening problems that have similar clinical presentations but differing
      aetiologies. Despite intensive investigation by haematological, biochemical, and
      microbiological means, accurate diagnosis is not always possible. Histological
      and microbiological examination of biopsies from the affected organ may be
      indicated to enable an accurate diagnosis to be made in these patients. Here we
      assess the indications, findings, and outcomes in patients who have required
      surgical biopsy after BMT. PROCEDURE: We retrospectively reviewed all BMT
      patients who had surgical biopsies between February 1994 and January 1997. Twenty
      six patients (1-46 years, median age 10 years) underwent 40 biopsies from the
      upper and lower GI tract, lung, or liver. Indications for BMT were: relapsed
      leukaemia = 18; other types of leukaemia = 3; aplastic anaemia=3; other diseases
      = 2. Type of BMT: matched related donor = 3, unrelated T-cell depleted donor =
      23. RESULTS: Eleven (42%) cases had a change in management; 4 (16%) patients
      avoided further aggressive therapy because of poor prognosis. Unexpected
      diagnoses were found in 7 biopsies: 1 acute colitis, 1 duodenal ulcer, 1 liver
      aspergilloma, 2 transfusion siderosis, 1 radiation fibrosis of the lung, and 1
      cytomegalovirus infection of the lung. Three patients were noted to have
      complications after their procedure. CONCLUSIONS: Surgical biopsies for
      undiagnosed problems can be of benefit in the management of very sick patients
      who have received bone marrow transplantations. Despite the fact that these
      patients are so unwell, there is a low rate of complications related to surgery
      and anaesthesia.

PMID- 10398184
TI  - Open-label comparison of the antiemetic efficacy of single intravenous doses of
      dolasetron mesylate in pediatric cancer patients receiving moderately to highly
      emetogenic chemotherapy.
AB  - BACKGROUND: Nausea and vomiting are among the most unpleasant adverse side
      effects of cancer therapy. PROCEDURE: An open-label dose-escalation study was
      conducted to assess the appropriate intravenous dose of dolasetron for pediatric
      patients undergoing chemotherapy. Patients received dolasetron in single
      intravenous doses of 0.6 (n = 10), 1.2 (n = 12), 1.8 (n = 12), or 2.4 (n = 12)
      mg/kg 30 min before receiving emetogenic chemotherapy. Pharmacokinetic parameters
      were evaluated at each dose level and efficacy was evaluated over the first 24 hr
      following the administration of dolasetron. RESULTS: A complete response was
      achieved in 10% of patients given 0.6 mg/kg, 25% of patients given 1. 2 mg/kg,
      67% of patients given 1.8 mg/kg, and 33% of patients given 2.4 mg/kg. Peak plasma
      concentrations (Cmax) were observed between 0. 33 and 0.75 hr following
      dolasetron infusion. Cmax and area under plasma concentration-time (AUC)
      increased with larger doses of dolasetron, while terminal disposition half-life
      (t1/2) and apparent clearance (Clapp) were not significantly changed with respect
      to dose. For 1.8-mg/kg dolasetron, the t1/2 was 4.98 hr and the maximum plasma
      concentration (tmax) 0.47 hr. Adverse events were mild to moderate. No serious
      events occurred. Conclusions. This study suggests that a single intravenous dose
      of 1.8 mg/kg is the optimum single intravenous dose for controlling chemotherapy
      induced emesis in pediatric patients.

PMID- 10398185
TI  - Childhood cancer etiology: recent reports 

PMID- 10398186
TI  - Topical topics: Brain cancer incidence in children: time to look beyond the
      trends.

PMID- 10398187
TI  - Misleading leads: Bone pain caused by isolated paraspinal extramedullary relapse
      of childhood acute lymphoblastic leukemia.

PMID- 10398188
TI  - Perspectives: Chemotherapy of medulloblastoma.

PMID- 10398189
TI  - Cardiac tamponade complicating hyperleukocytosis in a child with leukemia.

PMID- 10398190
TI  - Brief report: Neuroblastoma in Down syndrome.

PMID- 10398191
TI  - Brief report: Medulloblastoma with widespread skeletal metastases presenting with
      hypercalcemia.

PMID- 10398193
TI  - Brief report: Intraspinal leukemia with cord compression.

PMID- 10398192
TI  - Brief report: Advanced paraganglioma: A role for chemotherapy?

PMID- 10398194
TI  - Brief report: Pediatric Burkitt lymphoma with concurrent chronic Epstein-Barr
      virus hepatitis.

PMID- 10398195
TI  - Brief report: Neural differentiation of a novel cell line, YCUS-5, established
      from proximal-type epithelioid sarcoma of a child.

PMID- 10398196
TI  - Excitability of motor axons in neuromyotonia.

PMID- 10398197
TI  - Autoantibodies associated with peripheral neuropathy.
AB  - High titers of serum antibodies to neural antigens occur in several forms of
      neuropathy. These include neuropathies associated with monoclonal gammopathy,
      inflammatory polyneuropathies, and paraneoplastic neuropathies. The antibodies
      frequently react with glycosylated cell surface molecules, including glycolipids,
      glycoproteins, and glycosaminoglycans, but antibodies to intracellular proteins
      have also been described. There are several correlations between antibody
      specificity and clinical symptoms, such as anti-MAG antibodies with demyelinating
      sensory or sensorimotor neuropathy, anti-GM1 ganglioside antibodies with motor
      nerve disorders, antibodies to gangliosides containing disialosyl moieties with
      sensory ataxic neuropathy and Miller-Fisher syndrome, and antibodies to the
      neuronal nuclear Hu antigens with paraneoplastic sensory neuronopathy. These
      correlations suggest that the neuropathies may be caused by the antibodies, but
      evidence for a causal relationship is stronger in some examples than others. In
      this review, we discuss the origins of the antibodies, evidence for and against
      their involvement in pathogenic mechanisms, and the implications of these
      findings for therapy.

PMID- 10398199
TI  - Knee extensor strength, activation, and size in very elderly people following
      strength training.
AB  - Muscle strength, activation, and size were studied in 11 very elderly subjects (8
      women and 3 men; age range, 85-97 years) who completed 12 weeks of strength
      training of the knee extensor muscles. Training increased the maximum amount of
      weight that could be lifted once (134%; P < 0.05) and maximum voluntary isometric
      strength, measured as both force recorded at the ankle with the knee flexed 90
      degrees (17%, ns) and as torque with the knee flexed 60 degrees (37%; P < 0.05).
      Anatomical lean quadriceps cross-sectional area (LCSA) measured at midthigh using
      magnetic resonance imaging increased from 27.5 +/- 9.6 cm2 to 30.2 +/- 10.0 cm2
      (9.8%; P < 0. 05) after training. Both before and after training, isometric
      strength was closely related to LCSA, but training resulted in no significant
      change in muscle force per unit area of quadriceps muscle. Using the twitch
      interpolation technique, muscle activation during a maximal voluntary isometric
      contraction was shown to be incomplete in all subjects before training (ranging
      from 69% to 93%) and was not significantly increased after training. An increase
      in skeletal muscle mass may have important functional and metabolic benefits for
      very elderly people.

PMID- 10398198
TI  - Strength-duration properties of peripheral nerve in acquired neuromyotonia.
AB  - The strength-duration time constant (SDTC) of a myelinated axon is a property of
      the nodal membrane and is sensitive to changes in membrane potential. Strength
      duration time constants for motor axons and cutaneous afferents of the median
      nerve were measured in 9 patients with acquired neuromyotonia (NMT), a condition
      of peripheral nerve hyperexcitability, and 15 control patients. Mean motor axon
      time constants were significantly prolonged (344 +/- 100 micros) in patients
      compared to healthy controls (264 +/- 34 micros; P = 0.038), but sensory axon
      time constants were not significantly different. Motor axon time constants were
      longer than sensory axon time constants in 4 of the patients with neuromyotonia,
      suggesting that the nodal membrane was depolarized by an ectopic focus at the
      site of nerve stimulation at the wrist, ionic conductances were altered at the
      node, or that the size of the node was increased, possibly as a result of immune
      mediated damage. The anti-voltage-gated potassium channel antibodies thought to
      generate peripheral nerve hyperexcitability in acquired neuromyotonia may be
      indirectly responsible for changes in motor axon nodal membrane properties.

PMID- 10398200
TI  - Axonal involvement at the common entrapment sites in Guillain-Barre syndrome with
      IgG anti-GM1 antibody.
AB  - If anti-GM1 antibody plays a role in the axonal damage in Guillain-Barre
      syndrome, the common entrapment sites may be preferentially involved with
      evidence of axonal dysfunction. To assess this hypothesis, we studied nerve
      conduction across the cubital tunnel in 44 patients. Abnormal amplitude reduction
      of compound muscle action potentials (CMAPs) was found in 45% of 20
      immunoglobulin G (IgG) anti-GM1-positive and in 29% of 24 anti-GM1-negative
      patients. The time course and sequel were distinct between the two groups. In the
      former group, the amplitude reduction was prominent in weeks 1 to 2 and was
      followed by a decrease in distal CMAPs (axonal degeneration) or an increase in
      proximal CMAPs (resolution of conduction block). In contrast, anti-GM1-negative
      patients showed slower resolution with temporal dispersion. In anti-GM1-positive
      cases, amplitude reduction at the common entrapment site is frequent and may
      reflect wallerian degeneration or physiological conduction block at the nodes of
      Ranvier, both suggesting axonal involvement.

PMID- 10398201
TI  - Effects of fetal spinal cord tissue transplants and cycling exercise on the
      soleus muscle in spinalized rats.
AB  - Studies were carried out to determine if an intraspinal transplant (Trpl) of
      fetal spinal cord tissue or hind limb exercise (Ex) affected the changes in
      myosin heavy chain (MyHC) composition or myofiber size that occur following a
      complete transection (Tx) of the lower thoracic spinal cord of the adult rat. In
      one group of animals, transplants were made acutely, whereas in a second group,
      daily cycling exercise was initiated 5 days after injury, with animals in both
      groups being sacrificed 90 days after injury. The soleus muscle is normally
      composed of myofibers expressing either type I (90%) or type IIa (10%) MyHC.
      Following a spinal transection, expression of type I MyHC isoform decreased (18%
      of myofibers), type IIa MyHC expression increased (65% of myofibers), and the
      majority of myofibers (80%) expressed type IIx MyHC. Most myofibers coexpressed
      multiple MyHC isoforms. Compared with Tx only, with Ex or with Trpl, there was a
      decrease in the number of myofibers expressing type I or IIa isoforms but little
      change in expression of IIx MyHC. Myofibers expressing the IIb isoform appeared
      in several transplant recipients but not after exercise. Transection resulted in
      atrophy of type I myofibers to approximately 50% of normal size, whereas
      myofibers were significantly larger after exercise (74% of control) and in Trpl
      recipients (77% of control). Type IIa myofibers also were significantly larger in
      Trpl recipients compared with the Tx only group. Overall, the mean myofiber size
      was significantly greater after exercise and in Trpl recipients compared with
      myofibers in Tx only animals. Thus, although neither strategy shifted the MyHC
      profile towards the control, both interventions influenced the extent of atrophy
      observed after spinalization. These data suggest that palliative strategies can
      be developed to modulate some of the changes in hind limb muscles that occur
      following a spinal cord injury.

PMID- 10398202
TI  - Nonspecific facilitation of responses to transcranial magnetic stimulation.
AB  - We examined the effect of facial muscle contraction and eye movements on motor
      evoked potentials (MEPs) from the abductor pollicis brevis muscle (APB) evoked by
      transcranial magnetic stimulation (TMS). The hypothesis was that activity of
      large cortical regions (face) influences the excitability of spinal motoneurons
      via cortical or subcortical pathways. MEPs were recorded in 12 healthy subjects
      during the following conditions: (1) rest; (2) facial muscle contraction; (3) eye
      movements; (4) 10% precontraction of the target muscle; and (5) simultaneous
      target muscle precontraction and facial muscle contraction. In 9 subjects, spinal
      motoneuron excitability was assessed by measurements of F waves during the same
      facilitation maneuvers. Activation of eye and facial muscles clearly facilitated
      MEPs from the APB. The facilitation of MEP size during nonspecific maneuvers was
      almost similar to that obtained by target muscle precontraction, whereas
      shortening of latencies was significantly smaller. The occurrence and amplitude
      of F waves increased in parallel with MEP size during specific and nonspecific
      facilitation, pointing to spinal motoneuronal threshold changes as a potential
      facilitatory mechanism by facial and eye muscle activation. The different MEP
      latencies during specific and nonspecific facilitation were not explained by
      different spinal motoneuron excitability, but raise the possibility that
      supraspinal mechanisms contributed to nonspecific facilitation.

PMID- 10398204
TI  - Dissociated small hand muscle involvement in amyotrophic lateral sclerosis
      detected by motor unit number estimates.
AB  - In some patients with amyotrophic lateral sclerosis (ALS), the thenar hand is
      more severely affected than the hypothenar hand. To quantify the dissociated
      involvement, we examined the motor unit number estimate (MUNE) of both the
      abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles in 23
      patients with ALS. Whereas ALS patients had significantly smaller MUNEs than
      normal subjects in both muscles, the extent of motor unit loss was significantly
      greater in the APB than ADM. Moreover, a simple comparison of the amplitude of
      compound muscle action potentials (CMAPs) showed that ALS patients had
      significantly smaller APB/ADM ratios than normal subjects and patients with
      cervical spondylotic amyotrophy, bulbospinal muscular atrophy, or peripheral
      neuropathy. The more severe involvement of the APB probably reflects the specific
      pathophysiology in ALS, and possible mechanisms for the dissociated involvement
      are discussed.

PMID- 10398203
TI  - Nuclear changes in a case of X-linked Emery-Dreifuss muscular dystrophy.
AB  - Ultrastructural alterations in the nuclear architecture were found in skeletal
      muscle and skin cultured cells from a patient affected by X-linked Emery-Dreifuss
      muscular dystrophy (EMD) carrying a null mutation. The molecular defect of X
      linked EMD is the absence of emerin, a nuclear envelope-associated protein which
      is considered a component of the nuclear lamina. The nuclear changes were present
      in skeletal muscle and skin cultured cells with a frequency of about 10% and 18%,
      respectively. The main structures of the nuclear periphery were involved: lamina
      and nuclear envelope-associated heterochromatin were affected, whereas the
      cisterna and the pore complexes appeared preserved, and the cytoplasm of the same
      cells appeared normal. Analogous localized defects were detectable by
      immunolabeling with antilamin A/C and B2 antibodies, as well as by selective
      propidium iodide chromatin staining. The lesions we describe could be the result
      of anomalous nuclear lamina organization in the absence of emerin.

PMID- 10398205
TI  - Variable-frequency trains offset low-frequency fatigue in human skeletal muscle.
AB  - Variable-frequency trains that exploit the catchlike property of skeletal muscle
      can augment force production in fatigued skeletal muscle. The present study is
      the first to examine the effect of such trains during recovery. The quadriceps
      femoris muscles of 12 healthy individuals were fatigued using six-pulse, 14.3-Hz
      trains delivered at a rate of 1/s for 3 min. The force-generating ability of the
      muscle was tested with several constant-frequency trains (8.3-100 Hz) and a
      variable-frequency train before and after fatigue and at 2, approximately 13, and
      approximately 38 min of recovery. The variable-frequency train produced
      significant augmentation of force versus the best constant-frequency train (12.5
      Hz) in acute fatigue and during recovery. The fatiguing protocol also induced low
      frequency fatigue (LFF); the time courses of the degree of LFF and the amount of
      variable-frequency train force augmentation were inversely related (r = 0.629; F
      = 38.024; P </= 0.001), suggesting a common mechanism between the two phenomena.
      These results suggest that clinical use of variable-frequency trains (e.g.,
      functional electrical stimulation) will enable the muscle to generate more force
      during acute fatigue and offset, at least partially, the long-term effects of
      LFF.

PMID- 10398206
TI  - Denervation enhances spontaneous inflammatory myopathy in SJL mice.
AB  - We studied the effect of denervation on the spontaneous inflammatory myopathy
      that occurs in SJL mice. Cryosections from innervated and denervated calf muscles
      were assessed for severity of inflammation, relative proportions of mononuclear
      cell subsets, and major histocompatibility complex (MHC) class I expression. A
      significant increase in mononuclear cell infiltrates occurred in the denervated
      muscle. Denervation also changed the composition of mononuclear cell infiltrates
      towards a higher percentage of CD8(+) T cells (19% versus 11%). MHC class I
      expression was enhanced in denervated muscle compared with innervated muscle. Our
      findings indicate that inflammation in muscle may be enhanced by denervation.

PMID- 10398207
TI  - Transforming growth factor-beta2 is elevated in skeletal muscle disorders.
AB  - The transforming growth factor betas (TGF-betas) are multifunctional growth
      factors that act on both fibroblasts and myosatellite cells. In rodent models of
      muscle diseases, high levels of TGF-beta2 are expressed by myogenic cells. We
      have examined whether the expression of TGF-beta2 is also elevated in diseased
      human muscles. The disorders examined were Duchenne muscular dystrophy, myotonic
      dystrophy, myotubular myopathy, spinal muscular atrophy, and amyotrophic lateral
      sclerosis. The levels of TGF-beta2 immunoreactivity were elevated in atrophic,
      necrotic, and regenerating fibers and in fibers with central nuclei or
      cytoplasmic masses, irrespective of whether fibrosis was present. We therefore
      suggest that TGF-beta2 is important for muscle repair and that the presence of a
      TGF-beta within a muscle only leads to fibrosis if certain other factors are
      present.

PMID- 10398208
TI  - Activity-dependent excitability changes in chronic inflammatory demyelinating
      polyneuropathy: A microneurographic study.
AB  - The purpose of this study was to investigate activity-dependent excitability
      changes in polyneuropathy and their correlation with symptomatology. First, we
      recorded sensory nerve action potentials (SNAPs) with an intraneural
      microelectrode during impulse trains in 11 patients with chronic inflammatory
      demyelinating polyneuropathy. When the stimulus frequency was increased to >/=20
      Hz, all patients showed marked decreases in the amplitudes of averaged SNAPs (128
      responses) associated with latency increases. The amplitude decreases were much
      greater than those in patients with axonal neuropathies. In single-unit
      recordings, responses showed latency increases, which were small but sufficient
      to cause decreases in the averaged responses. Clinical sensory impairment was
      correlated with the degree of preexisting conduction block or axonal loss, but
      not with the degree of rate-dependent amplitude decreases. Activity-dependent
      changes occur preferentially in demyelinating neuropathy and are a sensitive
      measure of demyelination. The mechanism responsible for the amplitude decreases
      could be conduction slowing or block caused by activity-dependent
      hyperpolarization.

PMID- 10398209
TI  - Generation of spectrin breakdown products in peripheral nerves by addition of M
      calpain.
AB  - Identification of spectrin breakdown products (SBP) in tissues of the central
      nervous system (CNS) has been used to monitor calpain activity in models of
      neurodegeneration. We investigated the use of this technique in the peripheral
      nervous system (PNS) in order to use it as a marker of calpain-mediated
      proteolysis during axonal degeneration. Using in vitro methods for activation of
      calpains, we compared brains and sciatic nerves from rats for the presence of
      calpain-specific SBP. The 150-kDa SBP identified on western blots was
      demonstrated in brain and nerve homogenates subjected to membrane disruption in
      the presence of calcium. Incubation of tissues with recombinant m-calpain
      generated SBP in a dose-dependent fashion, and calpastatin inhibited the
      generation of SBP by either paradigm. In contrast to brain, sciatic nerves showed
      the presence of SBP even in noninjured tissues, suggesting a basal level of
      calpain activity in peripheral nerves. Time-course experiments showed that the
      generation of SBP in sciatic nerves correlated with the breakdown of axonal
      neurofilaments. SBP peaked within minutes after addition of m-calpain and
      disappeared in the homogenates before 1 h, indicating that identification of SBP
      is a transient phenomenon. These data provide a potential new way for studying
      axonal degeneration in both experimental and human neuropathies.

PMID- 10398210
TI  - Different contribution of joint and cutaneous inputs to early scalp somatosensory
      evoked potentials.
AB  - To elucidate whether the frontal components of scalp somatosensory evoked
      potentials (SEPs) depend on the type of peripheral input, we compared scalp SEPs
      in response to electrical stimuli applied to: (i) the proximal phalanx of the
      thumb, involving both deep and cutaneous afferents; and (ii) the distal phalanx
      of the thumb, involving cutaneous afferents, but excluding joint inputs coming
      from the interphalangeal articulation. We applied the same dipolar model that we
      built to explain the scalp SEP distribution to median nerve stimulation in
      previous investigations. Cortical SEPs after proximal stimulation were generated
      by three dipolar sources, one of which was likely to account for the frontal
      scalp N30. When we analyzed SEPs for distal (purely cutaneous) stimulation, the
      frontal and central recordings showed a clear reduction in amplitude of the
      negative responses having a latency of about 30 ms. Moreover, when applying the
      dipole model derived from analysis of responses to proximal stimulation to SEPs
      to distal stimulation, the source corresponding to the N30 distribution showed no
      activity, suggesting a strong relationship between joint and tendinous inputs and
      the activity of the N30 generator.

PMID- 10398212
TI  - Central motor conduction time in patients with multifocal motor conduction block.
AB  - The finding of conduction block (CB) within short consecutive segments along a
      motor nerve is a key feature of multifocal motor neuropathy (MMN). Despite their
      different pathogenesis, this may be the only clinical difference between some
      cases of MMN and the pure spinal muscular atrophy form of motor neuron disease
      (MND). In 12 patients with distal atrophy and fasciculations and
      electrophysiological evidence of CBs in the upper limbs, we measured the
      peripheral and central motor conduction times (PMCT and CMCT) to hand muscles. We
      reasoned that patients with MMN should show an abnormally prolonged PMCT with
      normal CMCT, whereas an increased CMCT would suggest MND. All patients had
      delayed F-wave latency and increased PMCT. Three patients had increased CMCT.
      Follow-up showed little clinical and electrophysiological change in 7 of the 9
      patients with normal CMCT, and a progressive motor deficit leading ultimately to
      death in 1 of the 3 patients with increased CMCT. This patient's
      electrophysiological follow-up showed a significant decrement of the compound
      motor action potential to both proximal and distal stimulation points, with
      disappearance of earlier CBs. Autopsy revealed loss of anterior horn cells and
      axons of the ventral root, and degeneration of large myelinated fibers. We
      conclude that determining the CMCT may help in differentiating MND from MMN.
      Persistence of a stable clinical picture over a span of at least 1 year and lack
      of electrophysiological signs of involvement of upper motor neurons should both
      be required before establishing the diagnosis of MMN even with
      electrophysiological evidence of CB.

PMID- 10398211
TI  - Altered vasoreactivity to angiotensin II in experimental diabetic neuropathy:
      role of nitric oxide.
AB  - We evaluated the effects of angiotensin II and an angiotensin-converting enzyme
      inhibitor (cilazapril) on nerve blood flow (NBF) and electrophysiology in control
      and diabetic rats. When applied locally to the sciatic nerve, the dose-response
      curve of angiotensin II was more potent in experimental diabetic neuropathy (EDN)
      than control rats. No difference existed in plasma angiotensin II levels between
      EDN and controls. The rats were given typical rat pellets or pellets treated with
      10 mg/kg per day cilazapril for 4 weeks. Diabetes caused a significant reduction
      in NBF, nerve conduction velocity, and compound muscle action potential (CMAP)
      amplitudes. NBF was significantly increased in diabetic rats supplemented with
      cilazapril diet, and nerve conduction velocity and amplitudes of the CMAP were
      also improved after 4 weeks on this diet. Direct application 10(-3) mol/L
      cilazapril on sciatic nerve did not increase NBF in normal and EDN rats. We
      topically applied the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine,
      on sciatic nerve and observed reduced inhibition of NBF in EDN, which was
      correctable with a cilazapril diet. These results suggest that diabetic
      neuropathy may have an increasing vasopressor action with angiotensin II and this
      is likely to be the mechanism of NOS inhibition. Angiotensin II-converting enzyme
      inhibitors may have potential in the treatment of diabetic neuropathy.

PMID- 10398213
TI  - Relationship between hypoxemia and fibrillation potential firing rate in
      denervated muscle.
AB  - The effects of hypoxia and ischemia on the firing rate of fibrillation potentials
      in denervated rat muscle were examined. We recorded electromyograms from the
      denervated left extensor digitorum longus muscle. Hypoxia was induced by low
      oxygen ventilation. Ischemia was established by ligating the abdominal aorta and
      inferior vena cava, with or without extracorporeal hindlimb perfusion. The
      fibrillation potential firing rate correlated with the PaO2 (P < 0.0001) and
      temperature (P = 0.0001). Fibrillation potentials disappeared after the
      initiation of ischemia and reappeared after restitution of blood flow; they
      disappeared during ischemia with extracorporeal perfusion. The attenuation curves
      for the firing rate of fibrillation potentials during ischemia were well
      described by exponential curves, but there was no significant difference in the
      attenuation constants for circulatory arrest and perfusion with a physiologic
      salt solution. We conclude that the fibrillation potential firing rate is
      proportional to oxygen supply, presumably because of the rate of aerobic
      metabolism.

PMID- 10398214
TI  - Amplitude-dependent slowing of conduction in amyotrophic lateral sclerosis and
      polyneuropathy.
AB  - The mechanism of motor nerve conduction slowing in amyotrophic lateral sclerosis
      (ALS) is thought primarily to be loss of large, fast-conducting motor fibers;
      this is less certain in axonal polyneuropathy. We compared motor conduction
      studies in 64 patients with axonal polyneuropathy with 72 patients with ALS.
      Compound motor action potential amplitude, distal motor latency, and conduction
      velocity were converted to a percentage of the upper or lower limit of normal and
      then represented as a square root (SQRT) transformation, plotted with SQRT
      amplitude as the independent variable and SQRT latency or SQRT conduction
      velocity as the dependent variables. Regression analysis of the lower extremity
      nerve data showed that prolongation of latency and slowing of velocity were
      amplitude-dependent and were virtually identical in ALS and polyneuropathy. In
      the upper extremity, amplitude-dependent prolongation of latency was similar in
      both groups, but amplitude-dependent slowing of velocity was seen in ALS and not
      in axonal polyneuropathy. Our data support the hypothesis that the major
      mechanism of slowing is similar in both polyneuropathy and ALS and is the loss of
      large, fast-conducting fibers. However, the presence of distal but not proximal
      slowing in the upper extremity of axonal polyneuropathy suggests that additional
      mechanisms may be contributory.

PMID- 10398215
TI  - Molecular analysis in Spanish patients with muscle carnitine palmitoyltransferase
      deficiency.
AB  - The most common mutation in muscle carnitine palmitoyltransferase II (CPT II)
      deficiency is a missense mutation that replaces a leucine for a serine residue at
      amino acid position 113 of the CPT II protein (S113L). We performed molecular
      analysis in a group of 14 Spanish patients with CPT II deficiency from ten
      unrelated families. The S113L mutation was observed in 8 of the 14 patients
      studied. Seven patients were homozygous for the mutation, 1 patient was
      heterozygous, and 6 patients did not carry the mutation on either allele. Seven
      healthy relatives belonging to three different families carried the mutation on
      one allele. One patient carried the missense mutation that replaces a tyrosine
      for a serine at amino acid position 628 on one allele. Our data indicate that the
      S113L is also the most common mutation in Spanish patients with CPT II deficiency
      in muscle, and that further pathogenic mutations remain to be identified.

PMID- 10398216
TI  - Lateral antebrachial cutaneous neuropathy in a windsurfer.
AB  - Lateral antebrachial cutaneous neuropathy (LACN) was diagnosed in a young woman
      who developed pain and paresthesias in the right forearm after a long day of
      windsurfing (board sailing). The symptoms resolved with conservative treatment,
      including cessation of windsurfing and a brief course of oral corticosteroids.
      There was a permanent residual cutaneous sensory deficit in the distribution of
      the LACN. LACN is important to recognize because the symptomatology may mimic
      pathology of a cervical root, the brachial plexus, and the radial and median
      nerves at the level of the elbow.

PMID- 10398217
TI  - Muscle vibration: different effects on transcranial magnetic and electrical
      stimulation.
AB  - Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation
      (TES) were applied before and 3 s after onset of vibration (0.5 mm, 80 Hz) of the
      right extensor carpi radialis muscle in 5 healthy subjects. Vibration induced
      significant augmentation and latency shortening of motor evoked potentials
      elicited by TMS, but not TES. This provides evidence for an involvement of
      cortical mechanisms by muscle vibration in the augmentation of MEPs following
      TMS.

PMID- 10398218
TI  - Biochemical and molecular correlations in carnitine palmitoyltransferase II
      deficiency.
AB  - Carnitine palmitoyltransferase II (CPT II) deficiency is the most common lipid
      myopathy in adults and is characterized by exercise-induced pain, stiffness, and
      myoglobinuria. Retrospective analysis of patients with CPT II deficiency has made
      it possible to correlate the presence of disease-causing mutations in the CPT2
      gene with residual CPT activity in muscle. We present evidence that the ratio of
      CPT II activity to citrate synthase activity in the skeletal muscle of patients
      presumed to have CPT II deficiency is important for predicting whether the
      patient has one, two, or no mutations in the CPT2 gene. This finding will assist
      in the future correlation of the phenotype with the genotype and in identifying
      manifesting heterozygotes.

PMID- 10398219
TI  - Paraneoplastic painful ulnar neuropathy.
AB  - A 58-year-old woman developed painful, bilateral ulnar neuropathy in conjunction
      with small cell lung carcinoma and high serum titer of anti-Hu antibody. An
      incidental stage I plasma cell dyscrasia, with immunoglobulin G kappa monoclonal
      protein, was also present. Electropysiological assessment excluded a generalized
      neuropathy, and nerve biopsy showed marked loss of myelinated and small
      unmyelinated fibers, without inflammatory changes or amyloid deposition. High
      titers of circulating anti-Hu antibody can be associated with symptoms resembling
      a paraneoplastic mononeuropathy.

PMID- 10398220
TI  - Focal myositis presenting with radial nerve palsy.
AB  - Focal myositis is a rare inflammatory pseudotumor of skeletal muscle which
      usually has a benign course. We report a 56-year-old woman with a painful mass in
      the left arm with a radial nerve palsy. Magnetic resonance imaging (MRI) of the
      left arm showed a mass in the triceps muscle that was suggestive of a soft-tissue
      sarcoma. Electromyography showed a severe radial neuropathy involving both motor
      and sensory axons. An open biopsy showed focal myositis. Treatment with
      corticosteroids resulted in complete disappearance of the mass clinically and by
      MRI, without recurrence for more than 2 years. Radial nerve function also
      recovered completely. As a treatable cause of focal neuropathy, focal myositis
      should be included in the differential diagnosis of a muscle mass.

PMID- 10398222
TI  - Conduction block in vasculitic neuropathy.

PMID- 10398221
TI  - Disputed radial tunnel syndrome.
AB  - True neurogenic radial tunnel syndrome is an uncommon condition caused by
      entrapment of the radial or posterior interosseous nerve in the radial tunnel and
      is usually easily identifiable by focal motor weakness in the distribution of the
      posterior interosseous nerve. Roles and Maudsley, analogizing to carpal tunnel
      syndrome, believed "radial tunnel syndrome" had a different presentation:
      proximal forearm pain and tenderness in the region of the supinator muscle.
      However, their patients lacked weakness or other neurologic deficit. They and
      subsequent surgeons have decompressed the radial nerve to treat forearm pain and
      tenderness, even though it is debatable whether radial nerve entrapment causes
      the forearm discomfort. The term "radial tunnel syndrome" is best reserved for
      the truly neurogenic cases. Surgical approaches to "persistent tennis elbow"
      should be assessed in a controlled fashion, rather than adopted on the basis of a
      flawed analogy to carpal tunnel syndrome.

PMID- 10398223
TI  - Heat sensitivity of sensory fibers in carpal tunnel syndrome.

PMID- 10398224
TI  - Reply 

PMID- 10398225
TI  - AAEM news and comments 

PMID- 10398226
TI  - Fragile X syndrome and an isodicentric X chromosome in a woman with multiple
      anomalies, developmental delay, and normal pubertal development.
AB  - We report on an individual with developmental delays, short stature, skeletal
      abnormalities, normal pubertal development, expansion of the fragile X triplet
      repeat, as well as an isodicentric X chromosome. S is a 19-year-old woman who
      presented for evaluation of developmental delay. Pregnancy was complicated by a
      threatened miscarriage. She was a healthy child with intellectual impairment
      noted in infancy. Although she had global delays, speech was noted to be
      disproportionately delayed with few words until age 3.5 years. Facial appearance
      was consistent with fragile X syndrome. Age of onset of menses was 11 years with
      normal breast development. A maternal male second cousin had been identified with
      fragile X syndrome based on DNA studies. The mother of this child (S's maternal
      first cousin) and the grandfather (S's maternal uncle) were both intellectually
      normal but were identified as carrying triplet expansions in the premutation
      range. S's mother had some school difficulties but was not identified as having
      global delays. Molecular analysis of S's fragile X alleles noted an expansion of
      more than 400 CGG repeats in one allele. Routine cytogenetic studies of
      peripheral blood noted the presence of an isodicentric X in 81of 86 cells scored.
      Five of 86 cells were noted to be 45,X. Cytogenetic fra(X) studies from
      peripheral blood showed that the structurally normal chromosome had the fragile
      site in approximately 16% of the cells. Analysis of maternal fragile X alleles
      identified an allele with an expansion to approximately 110 repeats. FMRP studies
      detected the expression of the protein in 24% of cells studied. To our knowledge,
      this is the first patient reported with an isodicentric X and fragile X syndrome.
      Whereas her clinical phenotype is suggestive of fragile X syndrome, her skeletal
      abnormalities may represent the presence of the isodicentric X. Treatment of S
      with 20 mg/day of Prozac improved her behavior. In the climate of cost con trol,
      this individual reinforces the recommendation of obtaining chromosomes on
      individuals with developmental delay even with a family history of fragile X
      syndrome.

PMID- 10398227
TI  - XLMR database.
AB  - The computer database on X-linked mental retardation (XLMR) disorders developed
      by Arena and Lubs in 1991 has now been updated to include all currently known
      XLMR disorders and nonspecific (MRX) families. Currently, it includes 123
      syndromes, 59 nonspecific XLMR families, and 60 families from the Miami/Greenwood
      study. The older clinical reports have been reviewed and revised. The search
      mechanism has also been revised and now includes 740 individual "keywords." Each
      of these keywords recognizes several of clinical descriptive terms, as used in
      published literature reports. Searches can be made according to any clinical
      finding or combination of findings. For each disorder, the database presents a
      graphic display that contains a revised and more complete set of clinical
      findings, references, keywords, map localization, molecular information, access
      to pictures, and OMIM number.

PMID- 10398228
TI  - The other side of the coin: a hypothesis concerning the importance of genes for
      high intelligence and evolution of the X chromosome.

PMID- 10398229
TI  - CAG repeat contraction in the androgen receptor gene in three brothers with
      mental retardation.
AB  - We report on three brothers with mental retardation and a contracted CAG repeat
      in the androgen receptor (AR) gene. It is known that expansion of the CAG repeat
      in this gene leads to spinal and bulbar muscular atrophy (SBMA or Kennedy
      disease); however, contracted repeats have not yet been implicated in disease. As
      the range of the length of CAG repeats in the AR gene, like those of other genes
      associated with dynamic mutations, follows a normal distribution, the theoretical
      possibility of disease at both ends of the distribution should be considered.

PMID- 10398230
TI  - Coffin-Lowry syndrome: current status.

PMID- 10398231
TI  - X-linked mental retardation associated with cleft lip/palate maps to Xp11.3
      q21.3.
AB  - A family is described in which X-linked mild to borderline mental retardation
      (MR) is associated with cleft lip/palate. Linkage analysis showed a maximum LOD
      score of Z=2.78 at straight theta=0.0 for the DXS441 locus with flanking markers
      DXS337 and DXS990, defining the region Xp11.3-q21.3 with a linkage interval of 25
      cM.

PMID- 10398232
TI  - Refined gene localization for the Miles-Carpenter syndrome (MCS)

PMID- 10398234
TI  - X-linked mental retardation syndrome with characteristic "coarse" facial
      appearance, brachydactyly, and short stature maps to proximal Xq.
AB  - We describe a three-generation family in which X-linked mental retardation (XLMR)
      is associated with minor facial anomalies and brachydactyly. Two brothers and
      four nephews have "coarse" facial appearance, brachydactyly with widening of the
      distal phalanges, short stature, and moderate mental retardation. The three
      obligate carrier women have normal intelligence and normal physical findings. The
      results of linkage analysis carried out in 1988 using restriction fragment length
      polymorphisms (RFLPs) were suggestive of linkage to DXYS1 and DXS101 in proximal
      Xq (Zmax = 1.63 at straight thetamax = 0.0) [Carpenter et al., 1988: Am J Med
      Genet 43:A139]. The family was restudied with 16 microsatellite loci from Xp11.4
      through Xq24. Linkage analysis demonstrated significant linkage to DXS1003,
      ALAS2, AR, DXS986, DXS990, DXS454, DXS1106, DXS1105, and DXS1220 from Xp11.3 to
      Xq23 (Zmax = 2.53 at straight thetamax = 0.0). Recombinations detected between
      MAOB and DXS1055 and between DXS1220 and DXS1001 place the disease locus between
      Xp11.3 and Xq23. Among the genes known to map to this region is the XNP gene for
      the alpha-thalassemia/mental retardation syndrome (ATR-X). This fact, along with
      the phenotypic similarity between our patients and ATR-X males, led us to
      consider XNP as a candidate gene for this family. X-inactivation studies provided
      further evidence for the involvement of XNP by showing completely skewed X
      inactivation patterns in the three obligate carrier females, a pattern
      characteristic of carriers of XNP mutations.

PMID- 10398233
TI  - X-linked mental retardation with variable stature, head circumference, and
      testicular volume linked to Xq12-q21.
AB  - Clinical and molecular studies are reported on a family with X-linked mental
      retardation (XLMR) in which there are eight affected males in three generations.
      Although the males have somatic manifestations, these are variable and in most
      cases do not allow clear distinction of affected and unaffected males. Affected
      males are shorter and have a smaller head circumference. Several also have a
      sloping forehead (5/8), hearing loss (3/8), cupped ears (2/8), and small testes
      (4/6). An LOD score of 4.41 with zero recombination was obtained at locus DXS1166
      in Xq13.2. This family highlights the difficulty in classifying XLMR conditions
      as either nonsyndromic or syndromic because of the variable somatic
      manifestations observed in the affected males.

PMID- 10398235
TI  - X-linked mental retardation syndrome with short stature, small hands and feet,
      seizures, cleft palate, and glaucoma is linked to Xq28.
AB  - Of the gene-rich regions of the human genome, Xq28 is the most densely mapped.
      Mutations of genes in this band are responsible for 10 syndromal forms of mental
      retardation and 5 nonsyndromal forms. Clinical and molecular studies reported
      here add an additional syndromic form of X-linked mental retardation (XLMR) to
      this region. The condition comprises short stature, small hands and feet,
      seizures, cleft palate, and glaucoma. One affected male died at age 19 years in
      status epilepticus, but others have survived to old age. Carrier females do not
      have somatic anomalies or mental impairment. The gene is localized to the
      terminal 8 Mb of Xq28 with markers distal to DXS8011 showing linkage to the
      disorder with a lod score of 2.11 at zero recombination.

PMID- 10398236
TI  - XLMR syndrome characterized by multiple respiratory infections, hypertelorism,
      severe CNS deterioration and early death localizes to distal Xq28.
AB  - We report on a family with severe X-linked mental retardation (XLMR) and
      progressive, severe central nervous system deterioration. Three of the five
      affected males died of secondary complications before the age of 10 years and
      none have survived past the age of 10. These complications included swallowing
      dysfunction and gastroesophageal reflux with secondary recurrent respiratory
      infections. In addition, hypotonia and a mild myopathy were also present. All had
      a characteristic facies, including downslanting palpebral fissures,
      hypertelorism, and a short nose with a low nasal bridge. The two older boys
      showed cerebral atrophy by CT. No metabolic abnormalities were identified. Three
      obligate carriers had an IQ less than 80. The causal gene has been localized
      distal to DXS8103 in Xq28, a region spanning 5cM. No other XLMR disorder with
      these manifestations have been localized to this region and this appears to be a
      new disorder.

PMID- 10398237
TI  - Carpenter-Waziri syndrome results from a mutation in XNP.

PMID- 10398238
TI  - Construction of a highly annotated cosmid contig spanning 550Kb within the X
      linked nonspecific mental retardation candidate region at Xp21.3-22.1.

PMID- 10398239
TI  - X-linked mental retardation syndrome with seizures, hypogammaglobulinemia, and
      progressive gait disturbance is regionally mapped between xq21.33 and Xq23.
AB  - We identified a family with three males in two generations with moderate mental
      retardation. The two oldest were first cousins whose mothers were sisters. The
      third affected was a grandson through a daughter of one of the sisters, strongly
      suggesting X- linked inheritance. The affected males had prominent glabella,
      synophrys, prognathism, generalized hirsutism, and bilateral single palmar
      creases. All developed seizures in childhood. The two oldest have had a slow
      deterioration in neurological status with poor gait and balance and progressive
      weakness. No deterioration in their mental status has been observed. The oldest
      had cerebellar atrophy confirmed on computed tomography and magnetic resonance
      imaging scans of the brain and prolonged nerve conduction velocity. Two of the
      males had hypogammaglobulinemia (IgA deficient). Two-point linkage analysis using
      27 microsatellite markers on the X chromosome resulted in a maximum LOD score of
      2.23 at straight theta = 0 for locus DSX101. Recombination was observed at locus
      DSX1170 in Xq21.33 and locus DXS8067 in Xq23. We conclude that this family
      represents an X-linked disorder associated with a recognizable phenotype,
      progressive neurological deterioration, and variable hypogammaglobulinemia. The
      gene appears to lie between Xq21.33 and Xq23.

PMID- 10398240
TI  - X-linked nonspecific mental retardation (MRX) linkage studies in 25 unrelated
      families: the European XLMR consortium.

PMID- 10398241
TI  - Regional localization of a nonspecific X-linked mental retardation gene (MRX59)
      to Xp21.2-p22.2.
AB  - Linkage analysis was performed on a four-generation family with nonspecific
      mental retardation (MRX59). The five affected males, ranging in age from 2 years
      to 52 years, have a normal facial appearance and mild to severe mental
      impairment. Four obligate carriers are physically normal and not retarded. A
      maximum LOD score of 2.41 at straight theta = 0.00 was observed with the
      microsatellite markers, DMD45 in Xp21.2, DXS989 in Xp22.1, and DXS207 in Xp22.2.
      Recombinations were detected within the dystrophin gene (DMD) in one of the
      affected males and between DXS207 and DXS987 in Xp22.2 in one of the carriers.
      These recombinants define the proximal and distal boundaries of a candidate gene
      region. Genetic localization of this familial condition made prenatal diagnosis
      informative for one of the obligate carriers.

PMID- 10398242
TI  - Gene for apparently nonsyndromic X-linked mental retardation (MRX32) maps to an
      18-Mb region of Xp21.2-p22.
AB  - We studied a family with 11 males having X-linked mental retardation (XLMR) using
      microsatellite markers. Aside from the mental retardation, the affected males do
      not appear to differ from their unaffected brothers or uncles. The gene for this
      XLMR condition has been linked to DXS451 in Xp22.13 with a lod score of 5.18 at
      straight theta = 0. Recombination was detected at DXS992 (Xp21.3) and DXS1053
      (Xp22.2), thereby defining the limits of the localization. This family is
      considered to have nonsyndromic XLMR and has been assigned the designation MRX32.

PMID- 10398244
TI  - Regional localization of a gene for nonspecific XLMR to Xp11.3-p11. 23 (MRX51)
      and tentative localization of an MRX gene to Xq23-q26.1.
AB  - Two families with nonspecific X-linked mental retardation (MRX) are presented. In
      the first family, MRX51, three male patients showed mild to borderline mental
      retardation. Multipoint linkage analysis yielded a maximal LOD score of 2.10
      between markers DXS8012 and DXS1003, localizing the MRX51 gene at Xp11.3-p11.23.
      In the second family, XLMR7, three men showed moderate mental retardation (MR),
      and one possible female carrier had mild MR. Multipoint linkage analysis yielded
      an LOD score of 1.80 between markers DXS8063 and DXS1047, situating the disease
      gene at Xq23-q26.1. When the analysis was performed considering the affected
      female to be an expressing heterozygote carrier of the disease mutation, a
      maximal LOD score of 2.10 was found in the same region.

PMID- 10398243
TI  - Refined 2.7 centimorgan locus in Xp21.3-22.1 for a nonspecific X-linked mental
      retardation gene (MRX54).
AB  - Nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in
      which mental retardation (MR) appears to be the only consistent manifestation. A
      large genetic interval of assignment obtained on individual families by linkage
      analysis, genetic, heterogeneity, and phenotypic variability usually are major
      obstacles to fine-map and identify the related disease genes. Here we report on a
      large Tunisian family (MRX54) with an MRX condition. X-linked recessive
      inheritance is strongly suggested by the segregation of MR through seven
      unaffected carrier females to 14 affected males in two generations. Two-point
      linkage analysis demonstrated significant linkage between the disorder and
      several markers in Xp21.3-22.1 (maximum LOD score Zmax = 3.56, recombination
      fraction 0 = 0 at DXS1202), which was confirmed by multipoint linkage analyses.
      Recombinant events observed with the flanking markers DXS989 and DXS1218
      delineate a refined locus of approximately 2.7 cM in accordance with the physical
      distance between these two markers. The small interval of assignment observed in
      this family overlaps not only with nine large MRX loci previously reported in
      Xp21.3-22.1 but also with two inherited microdeletions in Xp21.3-22.1 involved in
      nonspecific MR. Although the involvement of several genes located in the Xp21.3
      22.1 region cannot be ruled out, data reported in this study could be used as a
      starting point for the search of such gene(s).

PMID- 10398245
TI  - Refined gene localization for MRX7.

PMID- 10398246
TI  - Four families (MRX43, MRX44, MRX45, MRX52) with nonspecific X-linked mental
      retardation: clinical and psychometric data and results of linkage analysis.
AB  - Four families are described in which mental retardation segregates in an X-linked
      fashion. Mental retardation was the only consistent clinical finding in all
      affected males. The degree of retardation varied from mild to profound both
      between and within families. Linkage analysis localized the genetic defect of
      MRX43 to Xp22. 31-p21.2, MRX44 to Xp11.3-p11.21, MRX45 to Xp11.3-p11.21, and
      MRX52 to Xp11.21-q21.33 with LOD scores of >2 at straight theta = 0.0 in all four
      families.

PMID- 10398247
TI  - X-linked mental retardation: evidence for a recent mutation in a five-generation
      family (MRX65) linked to the pericentromeric region.
AB  - We report linkage analysis in a new family with nonspecific X-linked mental
      retardation, using 27 polymorphic markers covering the entire X-chromosome. We
      could assign the underlying disease gene, denoted MRX65, to the pericentromeric
      region, with flanking markers DXS573 in Xp11.3 and DXS990 in Xq21.33. A maximum
      LOD score of 3.64 was found at markers ALAS2 (Xp11.22) and DXS453 (Xq12) at
      straight theta = 0. Twenty-five of the 58 reported MRX families are linked to a
      region that is partially overlapping with the region reported here. Extension of
      the pedigree showed a number of unaffected distant relatives with haplotypes
      corresponding to the disease locus. Apparently, a new mutation in a female is
      causative for the disease in the family reported here. Furthermore, we show the
      importance of combining clinical, cytogenetic, and molecular studies since one of
      the family members, expected to be affected by the same genetic defect, has a
      48,XXXY karyotype.

PMID- 10398248
TI  - Refined gene localization for MRX8.

PMID- 10398250
TI  - Workshop on fragile X: future research directions.

PMID- 10398249
TI  - Mosaicism for the full mutation and a microdeletion involving the CGG repeat and
      flanking sequences in the FMR1 gene in eight fragile X patients.
AB  - The molecular mechanism of the fragile X syndrome is based on the expansion of an
      unstable CGG repeat in the 5' untranslated region of the FMR1 gene in most
      patients. This expansion is associated with an abnormal DNA methylation leading
      to the absence of production of FMR1 protein (FMRP). Such expansion apparently
      predisposes the repeat and flanking regions to further instability that may lead
      to mosaic conditions with a full mutation and a premutation or, rarely, with
      normal or reduced alleles that can sometimes be transcriptionally active. In this
      study we describe eight unrelated fragile X patients who are mosaic for both a
      full mutation and an allele of normal (four cases) or reduced size (four cases).
      Sequencing analysis of the deletion breakpoints in 6 patients demonstrated an
      internal deletion confined to the CGG repeat in four of them, which represents
      the most likely explanation for the regression of the full mutation to a normal
      sized allele. In two patients with a reduced allele, the deletion encompassed the
      entire CGG repeat and part of the flanking regions. Analysis of FMRP by Western
      blot was performed in one of the mosaics with a normal sized allele and in three
      of those with a reduced allele. In the first patient's lymphocytes FMRP was
      detected, whereas in the three other patients the deletion is likely to impair
      transcription as no FMRP was present in their lymphocytes.

PMID- 10398251
TI  - Mosaicism in human skin

PMID- 10398253
TI  - Cytogenetic and molecular evidence for cutaneous mosaicism: the ectodermal origin
      of Blaschko lines.
AB  - The idea that skin disorders following Blaschko lines represent genetic mosaicism
      is widely accepted. It seems likely that the two skin types represent the two
      different genotypes, but this has been remarkably difficult to prove, most
      studies showing a mixture of cell types in biopsies from both types of skin. Only
      for linear epidermolytic hyperkeratosis has it been possible to show mutant cells
      confined to the abnormal streaks. The hypothesis proposed here to explain this
      paradox is that disorders following Blaschko lines are due to mutations in genes
      expressed in epidermal cells (keratinocytes and melanocytes) rather than in
      dermal fibroblasts. The work on epidermolytic hyperkeratosis used keratinocytes,
      whereas most studies have used skin fibroblasts. Almost all disorders following
      Blaschko lines are epidermal: inflammatory, dysplastic, dyskeratotic, appendage
      related, or pigmentary, and the remainder can be explained on the basis of
      epidermal influences on the dermis. If this hypothesis is correct, it points to a
      useful model system for elucidating the genetic component of common dermatoses
      sometimes found in Blaschko lines namely eczema, psoriasis, lichen planus, and
      vitiligo.

PMID- 10398252
TI  - Functional X-chromosomal mosaicism of the skin: Rudolf Happle and the lines of
      Alfred Blaschko.
AB  - In this article, the contribution of Rudolf Happle to the understanding of X
      linked skin diseases is reviewed. In 1977 he proposed functional X-chromosomal
      mosaicism as the genetic mechanism underlying cutaneous anomalies that were seen
      in a number of X-linked skin diseases such as incontinentia pigmenti or focal
      dermal hypoplasia. Moreover, he recognized that these cutaneous anomalies
      followed the lines of Blaschko and thus he could tie in the development of the
      lines of Blaschko with a datable embryonic event. Convincing proof for the
      concept of functional X-chromosomal mosaicism was later provided by his group
      from functional sweat studies in female carriers of the X-linked gene defect
      hypohidrotic ectodermal dysplasia showing again on the back of the patient a
      gross, fountain-like mosaic typical of the lines of Blaschko. Moreover, in the
      years 1977 to 1981 he recognized the mosaic pattern in a syndrome of
      chondrodysplasia punctata, linear ichthyosis, patchy cicatricial alopecia,
      unilateral cataracts, and short stature again as a functional X-chromosomal
      mosaic becoming manifest exclusively in women and proposed that this syndrome,
      which is today named after him, is because of an X-linked dominant gene defect.
      Finally, the puzzling molecular genetics of the Happle syndrome are reviewed.
      Most likely, the Happle syndrome gene is not lethal for hemizygously affected
      males but rather similar to the example of epilepsy with mental retardation
      limited to females, the gene actually spares male gene carriers.

PMID- 10398254
TI  - Acquired blaschkolinear dermatoses.
AB  - Congenital and/or nevoid skin disorders following the lines of Blaschko may have
      a delayed onset after birth. They have to be differentiated from acquired
      dermatoses exhibiting the same linear pattern. In common dermatoses, such as
      psoriasis or lichen planus, lesions in a blaschkolinear distribution most often
      occur together with scattered lesions, but occasionally they may be isolated.
      Less common self-limited dermatoses such as lichen striatus and adult blaschkitis
      always present in a blaschkolinear fashion. In these diseases, or some other
      conditions occasionally distributed along these lines (chronic graft versus host
      reaction, fixed drug eruption, lupus erythematosus, atopic dermatitis, etc.), the
      cause of the disease may lead to the unmasking of tolerance to an abnormal
      keratinocyte clone that remained hidden in these lines. In addition to epithelial
      cells, other cells may be involved in the occurrence of acquired blaschkolinear
      dermatoses. In linear atrophoderma and linear fibromatosis, the histogenesis
      seems to involve hypothetic dermal clones. The extension of an acquired
      dermatosis on a preexisting linear nevoid disorder is an argument in favor of an
      early embryonic somatic mutation of a skin cell line.

PMID- 10398255
TI  - Extracutaneous analogies of Blaschko lines.
AB  - In females, early random X-chromosome inactivation in the late blastocyst and
      subsequent embryonic development cause a random distribution of cells with an
      active paternal or maternal X-chromosome. Carriers of X-linked disorders are
      mostly healthy but, when thoroughly examined, may display a characteristic
      pattern of partial involvement, which for the skin, is known to follow the lines
      of Blaschko. Comparable patterns of involvement have been seen in various other
      organs. The evaluation of carriers who are heterozygous for X-linked disorders,
      therefore, is an efficient method for the study of functional genetic mosaicism
      in humans. The same patterns can also be seen in case of early embryonic somatic
      mutations.

PMID- 10398256
TI  - Cutaneous mosaicism of lethal mutations.
AB  - The concept of autosomal lethal genes surviving only in a mosaic state was
      proposed by Happle to explain the genetic basis of several syndromes
      characterized by (almost always) sporadic occurrence, distribution of lesions in
      a scattered or asymmetrical pattern, variable extent of involvement, lack of
      diffuse involvement of entire organs, and equal sex ratio. The mosaic may either
      arise from a gametic half-chromatid mutation or from an early postzygotic
      mutation. The purpose of this article is to review current knowledge of the
      genetics and cutaneous manifestations of some of the birth defects to which the
      lethal gene concept is thought to apply: the Schimmelpenning (Feuerstein-Mims)
      syndrome, Proteus syndrome, encephalocraniocutaneous lipomatosis, Sturge-Weber
      and Klippel-Trenaunay syndrome, cutis marmorata teleangiectatica congenita (van
      Lohuizen syndrome), and neurocutaneous melanosis.

PMID- 10398257
TI  - Hypomelanosis of Ito: no entity, but a cutaneous sign of mosaicism.
AB  - Hypomelanosis of Ito is a neurocutaneous phenotype comprising pigmentary
      anomalies, neurological defects, structural malformations, and chromosomal
      abnormalities. It has been described as a distinct multisystem birth defect or,
      more specifically, as a neurocutaneous syndrome. The main purpose of this study
      is to provide evidence that this disorder does not exist as a syndrome. Rather,
      it is a causally nonspecific pigmentary disorder caused by genetic mosaicism.

PMID- 10398258
TI  - Segmental forms of autosomal dominant skin disorders: the puzzle of mosaicism.
AB  - Autosomal dominant inherited disorders of the skin sometimes present as a
      segmental phenotype. In recent years molecular studies have demonstrated that
      genetic mosaicism leads to such a clinical manifestation. In general the skin
      outside the segmental disorder is normal. This rather common variant of segmental
      manifestation has been termed type 1. Recently, Happle delineated a second type
      of segmental manifestation of autosomal dominant genodermatosis. This variant is
      characterized by a more diffuse clinical presentation of the disease, and a very
      marked linear pattern can be recognized. An explanation of this phenotype is a
      germline mutation of the gene manifests after a postzygotic mutation leading to
      double inactivation of the gene. The severe linear manifestation then reflects a
      doubling of the genetic burden. We present a number of clinical cases to
      demonstrate this phenomenon, and we present a case of the segmental Naegeli
      Franceschetti-Jadassohn syndrome born to a mother with the diffuse manifestation
      of the disorder.

PMID- 10398259
TI  - Concept of twin spotting.
AB  - This article describes the formation of apparent twin spots presumed to be caused
      by a specific form of somatic recombination. Twin spots consist of two
      genetically different clones of neighboring cells in a background of normal
      cells. The phenomenon is well known in plants and animals and is used as a marker
      to evaluate the recombinogenic activity of chemicals. The equivalent of the twin
      spot phenomenon in humans has only been described recently. We now give a review
      on a number of paired skin disorders possibly caused by the mechanism of twin
      spotting. They include vascular twin nevi, phacomatosis pigmentovascularis,
      phacomatosis pigmentokeratotica, Proteus syndrome, and cutis tricolor. Clinicians
      will probably spot other nevoid skin lesions occurring in close proximity to each
      other, which might be explained by the twin spot phenomenon.

PMID- 10398260
TI  - Paradominant inheritance, a hypothesis explaining occasional familial occurrence
      of sporadic syndromes.
AB  - Heterozygous individuals carrying a "paradominant" mutation, as a rule, are
      phenotypically normal. Therefore, the mutation can be transmitted unperceived
      through many generations. The trait becomes manifest when a somatic mutation
      occurs during embryogenesis giving rise to loss of heterozygosity and forming a
      mutant cell population, being either homozygous or hemizygous for the mutation.
      This concept explains the occasional familial occurrence of usually sporadic
      traits like the Klippel-Trenaunay syndrome and others.

PMID- 10398261
TI  - Revertant mosaicism in human genetic disorders.
AB  - Somatic reversion of inherited mutations is known for many years in plant
      breeding, however it was recognized only recently in humans. The concept of
      revertant mosaicism is important in medical genetics.

PMID- 10398262
TI  - Linear lesions reflecting lyonization in women heterozygous for IFAP syndrome
      (ichthyosis follicularis with atrichia and photophobia).
AB  - A diagnosis of IFAP (ichthyosis follicularis with atrichia and photophobia)
      syndrome was established in a 1-year-old boy with congenital hairlessness,
      generalized ichthyotic skin changes with follicular hyperkeratoses, and
      photophobia. IFAP syndrome is considered to be an X-linked recessive trait. The
      phenotype present in female carriers has so far not been delineated. A 2-year-old
      sister had atrophoderma and ichthyotic skin lesions arranged in a linear pattern
      and a large noncicatrical bald patch on her scalp. Similarly, the mother had
      linear lesions of scaling and atrophy as well as circumscribed hairless areas
      involving the scalp, the axillary region, and the lower legs. Sweat testing by
      means of iodine starch-reaction visualized hypohidrotic linear lesions
      corresponding to the areas of hyperkeratosis and atrophy. In both mother and
      daughter the lesions followed the lines of Blaschko, whereas the boy was
      diffusely affected. Family history showed that the boy's maternal uncle who had
      died at age 1 year was likewise affected with the same disorder. Moreover, the
      maternal grandmother had reportedly bald patches on her scalp and very dry skin.
      This is the first report to document linear skin lesions visualizing lyonization
      in women heterozygous for IFAP syndrome.

PMID- 10398263
TI  - Risk of abnormal pregnancy outcome in carriers of balanced reciprocal
      translocations involving the Miller-Dieker syndrome (MDS) critical region in
      chromosome 17p13.3.
AB  - We studied the pedigrees of 14 families segregating a reciprocal translocation
      with one breakpoint in chromosome 17p13 and the other in the distal region of
      another autosome. All 14 were ascertained on the basis of an affected index case:
      13 had Miller-Dieker syndrome (MDS) and one had dup(17p). In these 14 families,
      38 balanced translocation carriers had 127 pregnancies, corrected for
      ascertainment bias by the exclusion of all index cases and carriers in the line
      of descent to the index cases. An abnormal phentotype, unbalanced chromosome
      constitution, or both, were found in 33 of 127 (26%) pregnancies: 15 of 127 (12%)
      had MDS and an unbalanced karyotype with del (17p); 9 of 127 (7%) had a less
      severe phenotype with dup(17p); and 9 were unstudied, although MDS with der(17)
      was usually suspected based on early death and multiple congenital anomalies.
      When unexplained pregnancy losses, including miscarriages and stillbirths, were
      excluded from the total, 33 of 99 (33%) pregnancies were phenotypically or
      genotypically abnormal. The overall risk of abnormal pregnancy outcome of 26% is
      in the upper range of the reported risk for unbalanced offspring of carrier
      parents assessed through liveborn aneuploid offspring [Gardner and Sutherland
      (1996), Oxford Univ. Press]. The risk increases to 33% when unexplained pregnancy
      losses are excluded from the total. These results are consistent with Daniel's
      model of risk based on the size of the unbalanced fragments [Daniel (1985) Clin
      Genet 28:216-224, Daniel et al. (1989) Am J Med Genet 31:14-53]. Pregnancy losses
      included 26 miscarriages (20%) and two stillbirths (2%) among the 127
      pregnancies, similar to the respective population frequencies of 10-20% and 1%.

PMID- 10398264
TI  - Down syndrome in a population of elderly mentally retarded patients: genetic
      diagnostic survey and implications for medical care.
AB  - Ninety-six adults with Down syndrome (DS) from an institutional setting of 591
      mentally retarded were investigated systematically with respect to cytogenetic
      diagnosis, mental functioning and dementia, ophthalmological and audiological
      abnormalities, and thyroid function. Seventy of the 96 DS patients (73%) were
      older than 40 years. Only 4.2% were females. Trisomy 21 was found in 86% and
      mosaic trisomy 21 in 13%. Eighty-two percent of the patients were moderately or
      severely mentally retarded, 15% were profoundly retarded, and only 3% mildly
      retarded. Nineteen percent of the patients had dementia. This number increased to
      42% of the patients above the age of 50 years. Epileptic seizures were present in
      16.7% of all patients, and in 50% of the patients with dementia. Only 17% of the
      patients in the present study had normal visual acuity, one-third had at least
      moderately reduced vision. This number increased significantly with age: in the
      age group 50-59 years almost half of the patients had moderate to severe vision
      loss. Seventy percent of the patients had moderate, severe, or very severe
      hearing loss, which was undiagnosed before systematic hearing testing was
      performed. Increased (48%) or decreased (1%) TSH level was found in 49% of the
      patients examined for thyroid functions. We suggest a regular screening of all
      adults with DS to diagnose early dementia, epilepsy, hypothyroidism, and early
      loss of visual acuity and hearing, with special attention to the group of
      patients who are severely to profoundly mentally retarded and those with advanced
      age. Cytogenetic studies are necessary to confirm the clinical diagnosis and are
      essential for genetic counseling purposes.

PMID- 10398266
TI  - "Essentially pure" partial trisomy (6)(p23-->pter) in two brothers due to
      maternal t(6;17)(p23;p13.3).
AB  - We report on two brothers with low birth weight, growth retardation,
      microcephaly, minor facial anomalies, mental retardation, and trisomy (6)(p23-
      >pter) due to a maternal t(6;17)(p23;p13.3). As demonstrated by fluorescent in
      situ hybridisation (FISH) with the Miller-Dieker cosmid probe (D17S379) and with
      a subtelomeric probe (D17S34) the additional deletion on 17p13 is very small, and
      therefore, the phenotype of these two boys is most likely the result of
      essentially pure partial trisomy 6p. Comparison of the clinical findings with
      those of ten cases from the literature of dup(6p) with a breakpoint in or more
      distal to 6p23 allows delineation of a specific phenotype of dup(6)(p23-->pter)
      characterized by low birth weight, growth retardation, microcephaly, and
      blepharophimosis, blepharoptosis, microstomia, and abnormal ears.

PMID- 10398265
TI  - Neocentromere at 13q32 in one of two stable markers derived from a 13q21 break.
AB  - A 10-month-old girl with psychomotor retardation, microcephaly, bilateral
      microphthalmia, and postaxial polydactyly of the feet was karyotyped using
      banding techniques and (single or dual color) fluorescent in situ hybridization
      (FISH) with four probes: D13Z1/D21Z1, pancentromeric, pantelomeric, and a mix of
      13q subtelomeric and 13/21 alphoid repeats. She was found to have a 47-chromosome
      karyotype in which a normal 13 was replaced by two stable markers derived from a
      breakpoint at 13q21.1, namely a del(13)(q21.1) and an isofragment(13) (qter-
      >q21.1::q21.1-->qter). The latter had a single C-negative but Cd-positive primary
      constriction at 13q32 which, however, was not obvious in about 12% of the cells.
      FISH studies showed that the small 13q- had the 13-centromere and a 13q telomere
      (as shown for a specific 13q subtelomeric signal) onto the broken end whereas the
      isofragment lacked alphoid signals but had 13q subtelomeric sequences on both
      ends. Parental karyotypes were normal. The patient's rearrangement represents the
      eighth chromosome-13-derived marker with a nonalphoid neocentromere located at
      13q. All in all, such neocentromeres have been described in 29 markers derived
      from chromosomes 2, 3, 8-11, 13-15, 20, and Y, and plausibly result from the
      epigenetic activation of a latent centromere, which may even be a telomere with
      neocentric activity. The 13q telomere found in the del(13q) was probably captured
      from the homologous chromosome.

PMID- 10398267
TI  - Congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly: Cantu
      syndrome.
AB  - Cantu syndrome (hypertrichosis, osteochondrodysplasia, cardiomegaly) is a rare
      condition, previously reported in 13 patients. We report on two additional
      patients with this disorder. One of the patients had pulmonary hypertension of
      unknown cause which was responsive to steroid therapy. She also had unusual, deep
      plantar creases, not reported previously in Cantu syndrome. Autosomal recessive
      inheritance has been suggested previously on the basis of sib recurrence in one
      family and consanguinity in another. We have performed a segregation analysis
      based on all reported families to date; the data indicate autosomal recessive
      inheritance is unlikely. A new dominant mutation or microdeletion syndrome are
      more likely possibilities, sib recurrence possibly representing gonadal
      mosaicism.

PMID- 10398268
TI  - Trisomy 20p resulting from inverted duplication and neocentromere formation.
AB  - Normal human centromeres contain large tandem arrays of alpha-satellite DNA of
      varying composition and complexity. However, a new class of mitotically stable
      marker chromosomes which contain neocentromeres formed from genomic regions
      previously devoid of centromere activity was described recently. These
      neocentromeres are fully functional yet lack the repeat sequences traditionally
      associated with normal centromere function. We report here a supernumerary marker
      chromosome derived from the short arm of chromosome 20 in a patient with
      manifestations of dup(20p) syndrome. Detailed cytogenetic, FISH, and polymorphic
      microsatellite analyses indicate the de novo formation of the marker chromosome
      during meiosis or early postzygotically, involving an initial chromosome breakage
      at 20p11.2, followed by an inverted duplication of the distal 20p segment due to
      rejoining of sister chromatids and the activation of a neocentromere within
      20p12. This inv dup(20p) marker chromosome lacks detectable centromeric alpha
      satellite and pericentric satellite III sequences, or centromere protein CENP-B.
      Functional activity of the neocentromere is evidenced by its association with 5
      different, functionally critical centromere proteins: CENP-A, CENP-C, CENP-E,
      CENP-F, and INCENP. Formation of a neocentromere on human chromosome 20 has not
      been reported previously and in this context represents a new mechanism for the
      origin of dup(20p) syndrome.

PMID- 10398269
TI  - Tibial hemimelia in Langer-Giedion syndrome-possible gene location for tibial
      hemimelia at 8q.
AB  - We report on a girl with Langer-Giedion syndrome or tricho-rhino-phalangeal
      syndrome, type II (TRPS II) with deletion on 8q, and the unusual findings of
      bilateral tibial hemimelia and unilateral absence of the ulna. An 8-year-old boy
      with TRPS II with bilateral tibial hemimelia was reported by Turleau et al.
      [1982: Hum. Genet. 62:183-187]. The critical region for TRPS II is 8q24.1.
      Although no genes involving limb development in the human have been identified in
      this region, two mouse syndromes are localized to the homologous chromosome
      region of 9A1-A4 which involve limb abnormalities. We propose that a gene
      involved in limb development is contiguous with the TRPS II gene which, when
      deleted, may cause tibial hemimelia.

PMID- 10398270
TI  - Clinical and molecular studies of brachydactyly type D.
AB  - We report on the clinical manifestations in six affected individuals from a four
      generation family that segregates brachydactyly type D (BDD). All affected
      individuals have either bilateral and symmetric or unilateral first distal
      phalangeal hypoplasia. Metacarpal-phalangeal profiles show that some affected
      individuals also have a more generalized involvement of the apical skeleton.
      However, other than first distal phalangeal hypoplasia, there is no consistent
      pattern of associated skeletal involvement. Linkage analyses were preformed
      between the BDD phenotype in this family and six loci known to contain genes
      involved in apical skeletal patterning. No statistically significant linkage was
      detected.

PMID- 10398271
TI  - Ventricular noncompaction and distal chromosome 5q deletion.
AB  - We describe a 7 1/2-year-old girl with mildly unusual phenotype and complex heart
      disease including ventricular myocardial noncompaction. She was found to have a
      distal 5q deletion, del(5)(q35.1q35.3). Fluorescent in situ hybridization showed
      that this deletion included the locus for the cardiac specific homeobox gene,
      CSX. This suggests that some instances of ventricular myocardial noncompaction
      may be caused by haploinsufficiency of CSX.

PMID- 10398273
TI  - Clarification of a diagnosis of IP.

PMID- 10398272
TI  - Mosaicism in Prader-Willi syndrome: detection using fluorescent in situ
      hybridization.

PMID- 10398275
TI  - Novel 20-epi-vitamin D3 analog combined with 9-cis-retinoic acid markedly
      inhibits colony growth of prostate cancer cells.
AB  - BACKGROUND: 1,25 dihydroxyvitamin D3 (1,25D) and retinoids may play an important
      role in preventing progression of prostate cancer. METHODS: We examined the
      ability of four novel 20-epi-vitamin D3 analogs (CB1093, KH1060, KH1266, and
      CB1267), either alone or in combination with 9-cis retinoic acid (RA) to inhibit
      colony growth of a human prostate cancer cell line, LNCaP, using soft agar as
      well as bone marrow stroma. Also, the effect of these analogs on the cell cycle
      and expression of Ki-67, p21(waf-1), and p27(kip1) in LNCaP cells was examined.
      RESULTS: The analog CB1267 was the most potent, with 8 x 10(-10) M of the analog
      inhibiting 50% colony growth (ED50) of LNCaP. 9-cis-RA also inhibited colony
      growth of LNCaP (ED50, 5 x 10(-7) M). Combined, CB1267 and 9-cis-RA
      synergistically inhibited colony growth and significantly increased the number of
      LNCaP cells in G0/G1 phase. Cell cycle arrest was associated with increased
      levels of p21(waf-1) and p27(kip1) and decreased expression of Ki-67 protein.
      Pulse-exposure to this combination (5 x 10(-8) M) irreversibly inhibited colony
      growth, both in soft agar and on normal human bone marrow stroma. CONCLUSIONS:
      Combination of a new vitamin D3 analog (CB1267) and a retinoid (9-cis-RA)
      potently inhibited colony formation of LNCaP prostate cancer cells in vitro,
      suggesting further studies in animal models. This combination may afford an
      interesting therapeutic approach to low-burden prostate cancer.

PMID- 10398276
TI  - Immortalization of human prostate epithelial cells by HPV 16 E6/E7 open reading
      frames.
AB  - BACKGROUND: The exact pathogenesis for prostate cancer is not known. Progress
      made in prostate cancer research has been slow, largely due to the lack of
      suitable in vitro models. Here, we report our work on the immortalization of a
      human prostate epithelial cell line and show that it can be used as a model to
      study prostate tumorigenesis. METHODS: Replication-defective retrovirus harboring
      the human papillomavirus (HPV) type 16 E6 and E7 open reading frames was used to
      infect primary human prostate epithelial cells. Polymerase chain reaction,
      followed by Southern hybridization for the HPV 16 E6/E7, Western blot for
      prostatic acid phosphatase, telomeric repeat amplification protocol assay for
      telomerase activity, two-dimensional gels for cytokeratins, and cytogenetic
      analysis were undertaken to characterized the infected cells. RESULTS: The
      retrovirus-infected cell line, HPr-1, continued to grow in culture for more than
      80 successive passages. Normal primary cells failed to proliferate after passage
      6. HPr-1 cells bore close resemblance to normal primary prostate epithelial
      cells, both morphologically and biochemically. However, they possessed telomerase
      activity and proliferated indefinitely. Cytogenetic analysis of HPr-1 cells
      revealed a human male karyotype with clonal abnormalities and the appearance of
      multiple double minutes. CONCLUSIONS: The HPr-1 cells expressed prostatic acid
      phosphatase and cytokeratins K8 and K18, proving that they were prostate
      epithelial cells. They were benign in nude mice tumor formation and soft agar
      colony formation assay. The HPr-1 cell line is an in vitro representation of
      early prostate neoplastic progression.

PMID- 10398277
TI  - EGF induces the expression of matrilysin in the human prostate adenocarcinoma
      cell line, LNCaP.
AB  - BACKGROUND: Matrix metalloproteinases (MMPs) are regulated both positively and
      negatively at the transcriptional level by a variety of growth factors,
      oncogenes, and tumor promoters. Induction of the MMP, matrilysin, by epidermal
      growth factor (EGF) was investigated in a human prostate cancer cell line.
      METHODS: Secreted protein and messenger RNA were detected using Western and
      Northern methods, respectively. EGF receptor antibodies were used for
      neutralization of the EGF receptor to determine the role of the EGF growth factor
      family (EGF, transforming growth factor alpha (TGFalpha), or amphiregulin) in the
      basal induction of matrilysin. RESULTS: EGF increased mRNA and secreted protein
      levels for the MMP matrilysin in LNCaP cells, in a concentration- and time
      dependent manner. Transforming growth factor beta1 (TGFbeta1) had no inhibitory
      effect on the levels of mRNA or secreted protein induced by EGF in LNCaP cells.
      Decay of matrilysin mRNA after the addition of actinomycin D indicated that the
      half-life of matrilysin mRNA was not altered by EGF. Blocking with a neutralizing
      antibody to the EGF receptor did not alter the basal level of secreted
      matrilysin. CONCLUSIONS: Exogenously added EGF increased matrilysin mRNA, perhaps
      at a transcriptional level. Growth factors, other than the members of the EGF
      family which act through the EGF receptor, may be involved in the regulation of
      the basal level of secreted matrilysin in LNCaP cells. Our data with LNCaP cells
      suggest that paracrine regulation of matrilysin expression in human prostate
      carcinoma cells could be via the EGF receptor.

PMID- 10398278
TI  - Presence of ganglia within the prostatic capsule: ganglion involvement in
      prostatic cancer.
AB  - BACKGROUND: The presence of ganglia within the prostatic capsule (capsular
      ganglia) is a poorly understood phenomenon. If cancer invasion into or around
      ganglia is identified in a needle biopsy specimen, such a finding may be
      diagnosed as an extraprostatic extension. In this study, the presence of capsular
      ganglia was clarified. Furthermore, we discuss the significance of these ganglia
      in prostatic cancer patients. METHODS: The study group comprised a total of 42
      patients, who had all undergone a radical prostatectomy for prostate
      adenocarcinoma with a relatively small volume. After surgery, the step-sectioned
      radical prostatectomy specimens were histologically evaluated. RESULTS: In 22 of
      42 cases, capsular ganglia were recognized. With respect to the distribution of
      the capsular ganglia, the ganglia were most frequently observed at the
      posteriolateral aspect of the prostatic base. Morphologically there were no
      obvious differences between the capsular and periprostatic ganglia. Moreover, in
      3 of 5 cases with cancer involvement into the capsular ganglia, such involvement
      was not predictive of extraprostatic extension. CONCLUSIONS: The presence of
      capsular ganglia needs to be clarified in prostatic cancer patients. Our findings
      therefore suggest that cancer involvement either in or around the ganglia should
      not be immediately interpreted as indicating an extraprostatic extension, if such
      a finding is recognized in a needle biopsy specimen.

PMID- 10398280
TI  - Targeting human prostatic carcinoma through basic fibroblast growth factor
      receptors in an animal model: characterizing and circumventing mechanisms of
      tumor resistance.
AB  - BACKGROUND: Basic fibroblast growth factor receptors on DU145 human prostatic
      carcinoma xenografts serve as targets for the delivery of a growth factor-toxin
      chimera, basic fibroblast growth factor-saporin (bFGF-SAP), which produces
      significant antitumor activity in a nude mouse model. However, DU145 tumors often
      become resistant to prolonged treatment. METHODS: Nude mice bearing DU145
      xenografts were intravenously administered bFGF-SAP (0.05 microg/kg weekly for 4
      weeks), and a panel of eight tumors was isolated from the treated animals and
      established in monolayer culture. RESULTS: In cell-survival assays, sensitivity
      of the treated tumor-derived cell lines to bFGF-SAP (IC50 = 12-100 nM) varied
      widely from cells derived from a vehicle-treated control tumor (IC50 = 10 nM). A
      significant inverse correlation was observed between increased IC50 values in
      vitro and increased tumor growth delay in vivo. Pretreatment of tumor cells with
      suramin or neutralizing antibodies to bFGF or keratinocyte growth factor (KGF)
      circumvented resistance in one of the tumor lines, confirming autocrine-mediated
      resistance. In another tumor subline, a 3-fold decrease in bFGF high-affinity
      receptor sites, which concurred with a 4-fold decrease in ability to internalize
      the bFGF ligand, was consistent with a decrease in total cellular expression of
      the FGF2 receptor (Bek). Resistance was circumvented by alternatively targeting
      FGF1 receptor (Flg) on these cells with a saporin immunotoxin. CONCLUSIONS: These
      studies identify alterations in the ligand-targeted receptor as a frequent
      contributor to resistance arising in DU145 tumors to in vivo treatment with a
      bFGF receptor-directed-toxin chimera, and provide the basis for designing methods
      to circumvent resistance for the purpose of enhancing efficacy of receptor
      directed therapies in the treatment of prostate cancer.

PMID- 10398279
TI  - Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in
      Jewish men.
AB  - BACKGROUND: Families with a high incidence of hereditary breast cancer, and
      subsequently shown to have terminating mutations in BRCA1 or BRCA2, appear to
      have a higher incidence of prostate cancer among male relatives. We aimed to
      determine whether the common germline mutations of BRCA1 or BRCA2 in Ashkenazi
      Jewish men predisposed them to prostate cancer. METHODS: We examined genomic DNA
      from 83 (for BRCA1 185delAG) or 82 (for BRCA2 6174delT) Ashkenazi Jewish prostate
      cancer patients, most of whom were treated at a relatively young age, for the
      most common germline mutation in each gene seen in the Ashkenazi population.
      RESULTS: Our study should have been able to detect a 4-5-fold increase in the
      risk of prostate cancer due to mutation of BRCA1 or BRCA2. However, only one
      (1.15%; 95% confidence interval, 0-3.6%) of the patients was heterozygous for the
      BRCA1 mutant allele, and only two were heterozygous for the BRCA2 mutation (2.4%;
      95% confidence interval, 0-6.2%). CONCLUSIONS: The incidence of each of the
      germline mutations in these prostate cancer patients closely matched their
      incidence (about 1%) in the general Ashkenazi Jewish population. This suggests
      that unlike cases of breast and ovarian cancers, mutations in BRCA1 or BRCA2 do
      not significantly predispose men to prostate cancer.

PMID- 10398281
TI  - Analysis and sorting of prostate cancer cell types by flow cytometry.
AB  - BACKGROUND: Prostate tumor heterogeneity as manifested by differential expression
      of markers can be attributed to multiple types of cancer cells populating a
      tumor. Does the composition differ between primary tumor and metastasis? How can
      one isolate the different cancer cell types to study? What is the relationship
      among cancer cell types? METHODS: Flow cytometry keying on the prostate
      epithelial cell surface markers CD57 and CD44 was applied to analyze and sort
      single cells prepared from tumor tissue samples by collagenase digestion. In
      normal tissue, CD57 is found on luminal cells and CD44 on basal cells. RESULTS:
      CD57(+) and CD44(+) cells were sorted from various prostate tumor tissue
      specimens. The CD57(+) cancer cell type was found to predominate in primary
      tumors, while the CD44(+) cancer cell type was found to predominate in two
      visceral metastases. All tumors could be characterized by a ratio of CD57(+) and
      CD44(+) cancer cells. CONCLUSIONS: Two types of prostate cancer cells, CD57(+)
      and CD44(+), were identified. The finding that most primary tumors contain a
      predominantly CD57(+) cancer cell population agrees with the argument that cancer
      cells arise from the transformation of CD57(+) luminal cells. However, CD44(+)
      cancer cells are also present in some primary tumors; and in some metastases,
      they, and not CD57(+) cells, constitute a predominant population.

PMID- 10398283
TI  - Conditional inference for predictive agreement.
AB  - We introduce the concept, and a measure of predictive agreement, tau, for two
      raters classifying items into q categories. The measure is based on the linear
      combination of log odds ratios from 2 x 2 subtables of a q x q cross
      classification table. We show that analysis procedures for this measure, and
      transforms of it, can be based on conditional likelihood procedures. These
      procedures are exact, which is particularly helpful because of the small tabular
      cell frequencies which can typically arise with agreement data. To illustrate the
      advantages of the methodology, examples of typical agreement data arising from
      medical studies are considered. We demonstrate that the conditional likelihood
      function portrays the available sample information about tau, often more
      appropriately than the maximum likelihood estimate and an associated standard
      error. We highlight the value of combining information via likelihoods in an
      example involving 24 2 x 2 tables. An example involving three categories is used
      to illustrate that the methodology for the overall agreement measure can be
      adapted to examine relative agreement between pairs of categories.

PMID- 10398282
TI  - Inhibitory effect of zinc on human prostatic carcinoma cell growth.
AB  - BACKGROUND: Normal human prostate accumulates the highest levels of zinc of any
      soft tissue in the body. In contrast, the zinc level in prostate cancer is
      markedly decreased from the level detected in nonprostate tissues. Despite these
      relationships, the possible role of zinc in the growth of normal and malignant
      prostate has not been determined. METHODS: Growth inhibition and various
      regulatory responses were investigated in two human prostate carcinoma cell lines
      (LNCaP and PC-3), treated with or without zinc. RESULTS: Incubation of the
      prostate carcinoma cell lines with physiological levels of zinc resulted in the
      marked inhibition of cell growth. A lower 50% inhibition of cell growth (IC50)
      value for zinc (about 100 ng/ml) was detected in LNCaP cells, which are androgen
      responsive, whereas androgen-independent PC-3 cells exhibited a higher IC50 for
      zinc (about 700 ng/ml). Incubation with 1 microg/ml zinc resulted in maximum
      inhibition of growth in both cell lines. These inhibitory effects of zinc
      correlated well with the accumulation of zinc in the cells. Simultaneously, cell
      flow cytometric analyses revealed a dramatic increase of the cell population in
      G2/M phase, in both LNCaP (2.3-fold vs. control) and PC-3 (1.9-fold vs. control),
      and a decreased proportion of cells in S phase (LNCaP, -51.4%; PC-3, -23%),
      indicating a G2/M phase arrest. The cell growth inhibition and G2/M arrest in
      these cells were accompanied by an increase in apoptosis, as demonstrated by the
      characteristic cell morphology and further confirmed by cellular DNA
      fragmentation. The specificity of zinc-induced apoptosis was identified by
      ethylenediamine-tetraacetic acid (EDTA)-chelation, which abolished the zinc
      effect on cellular DNA fragmentation. The zinc-induced G2/M phase arrest and
      apoptosis were accompanied by increased mRNA levels of p21(Waf1/Cip1/Sdi1) in
      both LNCaP (p53+/+) and PC-3 (p53-/-) cells. CONCLUSIONS: These results suggest
      that zinc inhibits human prostatic carcinoma cell growth, possibly due to
      induction of cell cycle arrest and apoptosis. There now exists strong evidence
      that the loss of a unique capability to retain high levels of zinc is an
      important factor in the development and progression of malignant prostate cells.

PMID- 10398284
TI  - Comparisons of measures of interclass correlations: the general case of unequal
      group size.
AB  - A problem often encountered in epidemiology is the evaluation of the validity of
      a short questionnaire for diet or physical activity administered to large numbers
      of subjects, where the gold standard is a diet record or physical activity diary.
      It is well known that random measurement error can attenuate the interclass
      correlation coefficient (validity coefficient) between these two variables.
      Several authors have proposed a de-attenuated (or corrected) correlation
      coefficient which is an estimate of the true correlation between the two
      variables after removing the effect of random measurement error. By true
      correlation we mean the correlation between the questionnaire and the mean of a
      large or 'infinite' number of diaries (representing the truth). In this paper the
      authors propose three methods (two ad hoc methods, the pairwise and weighted sib
      mean estimators, and the maximum likelihood with confidence limits computed using
      the Wald statistic and profile likelihood approaches) to estimate the true
      correlation between a single questionnaire and the mean of an infinite number of
      follow-up diaries, in the general case where an unequal number of diaries are
      available for each individual. A simulation study is done under the assumption
      that the measured variables are normally distributed. Under the null hypothesis
      of no correlation between the questionnaires and the diaries, all methods had
      negligible biases. In cases closer to what is usually seen in practice (true
      correlation between 0.4 and 0.6), the degree of bias and coverage probability
      depends heavily on the reliability (intraclass correlation) of the diaries. The
      maximum likelihood estimator with confidence intervals computed by the profile
      likelihood approach, while not systematically outperforming the other methods, is
      shown to be the best of the three proposed approaches.

PMID- 10398285
TI  - Selection bias and treatment heterogeneity in clinical trials.
AB  - A common perception about many commercially available medical treatments is that
      they are effective for every patient having the relevant indication and that
      developers have provided the regulatory authorities with evidence of such a
      property. We show that the standard of evidence is much lower and that the
      standard is appropriate only when the treatment effects are almost constant. We
      discuss the implications on the design and analysis of clinical trials if the
      standards were made to correspond with the common perception. We conclude that
      the evidence of positive mean treatment effect should be accompanied by evidence
      of limited dispersion of the effects and by a sensitivity analysis that explores
      the impact of the selection bias in recruitment.

PMID- 10398286
TI  - Sample size determination for multiple comparison studies treating confidence
      interval width as random.
AB  - Methods for optimal sample size determination are developed using four popular
      multiple comparison procedures (Scheffe's, Bonferroni's, Tukey's and Dunnett's
      procedures), where random samples of the same size n are to be selected from k
      (>/=2) normal populations with common variance sigma2, and where primary interest
      concerns inferences about a family of L linear contrasts among the k population
      means. For a simultaneous coverage probability of (1-alpha), the optimal sample
      size is defined to be the smallest integer value n*m such that, simultaneously
      for all L confidence intervals, the width of the lth confidence interval will be
      no greater than tolerance 2deltal (l=1,2,...,L) with tolerance probability at
      least (1-gamma), treating the pooled sample variance S2p as a random variable.
      Using Scheffe's procedure as an illustration, comparisons are made to usual
      sample size methods that incorrectly ignore the stochastic nature of S2p. The
      latter approach can lead to serious underestimation of required sample sizes and
      hence to unacceptably low values of the actually tolerance probability (1
      gamma'). Our approach guarantees a lower bound of [1-(alpha+gamma)] for the
      probability that the L confidence intervals will both cover the parametric
      functions of interest and also be sufficiently narrow. Recommendations are
      provided regarding the choices among the four multiple comparison procedures for
      sample size determination and inference-making.

PMID- 10398287
TI  - Testing for centre effects in multi-centre survival studies: a Monte Carlo
      comparison of fixed and random effects tests.
AB  - The problem of testing for a centre effect in multi-centre studies following a
      proportional hazards regression analysis is considered. Two approaches to the
      problem can be used. One fits a proportional hazards model with a fixed covariate
      included for each centre (except one). The need for a centre specific adjustment
      is evaluated using either a score, Wald or likelihood ratio test of the
      hypothesis that all the centre specific effects are equal to zero. An alternative
      approach is to introduce a random effect or frailty for each centre into the
      model. Recently, Commenges and Andersen have proposed a score test for this
      random effects model. By a Monte Carlo study we compare the performance of these
      two approaches when either the fixed or random effects model holds true. The
      study shows that for moderate samples the fixed effects tests have nominal levels
      much higher than specified, but the random effect test performs as expected under
      the null hypothesis. Under the alternative hypothesis the random effect test has
      good power to detect relatively small fixed or random centre effects. Also, if
      the centre effect is ignored the estimator of the main treatment effect may be
      quite biased and is inconsistent. The tests are illustrated on a retrospective
      multi-centre study of recovery from bone marrow transplantation.

PMID- 10398288
TI  - A comparison of some simple methods to identify geographical areas with excess
      incidence of a rare disease such as childhood leukaemia.
AB  - Six statistics are compared in a simulation study for their ability to identify
      geographical areas with a known excess incidence of a rare disease. The
      statistics are the standardized incidence ratio, the empirical Bayes method of
      Clayton and Kaldor, Poisson probability, a statistic based on the 'Breslow T'
      test (BT) and two statistics based on the 'Potthoff-Whittinghill' test (PW) for
      extra-Poisson variance. Two alternative processes of clustering are simulated in
      which high-risk locations could be caused by environmental sources or could be
      sites of microepidemics of an infectious agent contributing to a rare disease
      such as childhood leukaemia. The simulation processes use two parameters
      (proportion of cases found in clusters and mean cluster size) which are varied to
      embrace a variety of situations. Real and artificial data sets of small area
      populations are considered. The most extreme of the artificial sets has all areas
      of equal population size. The other data sets use the small census areas
      (municipalities) in Finland since these have extremely heterogeneous population
      size distribution. Subset selection allows examination of this variability.
      Receiver operator curve methodology is used to compare the efficacy of the
      statistics in identifying the cluster areas; statistics are compared for the
      proportion of true high-risk areas identified in the top 1 per cent and 10 per
      cent of ranked areas. One of the PW statistics performed consistently well under
      all circumstances, although the results for the BT statistic were marginally
      better when only the top 1 per cent of ranked areas was considered. The
      standardized incidence ratio performed consistently worst.

PMID- 10398289
TI  - A frailty approach for modelling diseases with variable age of onset in families:
      the NHLBI Family Heart Study.
AB  - We use frailty models to analyse the effect of latent genetic and environmental
      risk factors on hazard functions in nuclear families. The approach expresses
      latent risk factors (frailties) as functions of the effects of a single major
      gene and shared familial risk. The latter may result from shared polygenes and/or
      a common environment. Genetic frailties are modelled using a two-point
      distribution, and residual frailties (shared environment, polygenes) using a
      gamma distribution. The two-point distribution follows the laws of Mendelian
      transmission, under either dominant or recessive gene action. We describe a
      robust EM approach for the joint estimation of the magnitude of genetic,
      covariate, gene by covariate interaction effects while allowing residual familial
      correlation. We illustrate the method on coronary heart disease data from the
      National Heart, Lung, and Blood Institute Family Heart Study. In addition, a
      simulation study shows that ignoring possible residual correlation in disease
      status due to a shared familial environment leads to an overestimate of the
      relative risk associated with a latent genotype.

PMID- 10398290
TI  - Modelling covariate adjusted mortality relative to a standard population.
AB  - A study of long term survival of 1487 patients given an allogeneic bone marrow
      transplant for acute myelogenous leukaemia and 729 patients given a transplant
      for severe aplastic anaemia was conducted by the International Bone Marrow
      Transplant Registry. One aim of this study is to determine if the mortality rates
      of these patients return after some period of time to the same mortality rate as
      in the general population. To examine this question a model for the relative
      mortality of a bone marrow transplant patient relative to a matched individual in
      the general population is presented. This model allows for different relative
      mortality rates depending on the risk factors the patient may have. We discuss an
      estimation procedure for this model and construct a test that the mortality rate
      in the transplanted population is the same as in the reference population over a
      given time interval.

PMID- 10398291
TI  - Estimation of mean quality adjusted survival time.
AB  - In clinical studies, we often consider not only patients' survival time, but also
      their quality of life. Quality adjusted life years (QALY) is an integrated
      measure of medical outcome that combines a patient's quantity and quality of
      life. Estimation of mean QALY for a group of patients is complicated by the fact
      that some patients are censored. The conventional approach is to obtain the
      Kaplan-Meier estimate of the survival function associated with individual QALYs
      and then use the area under the Kaplan-Meier curve as an estimate of mean QALY.
      Glasziou, Simes and Gelber showed that this method is biased because censoring at
      the nominal time scale is informative for predicting unobserved QALYs. In this
      paper, we propose a methodology for consistent estimation of mean QALY.
      Simulation studies are conducted to investigate the relative performance of the
      new method and the conventional method.

PMID- 10398292
TI  - On Bayesian calculations for mixture likelihoods and priors.
AB  - We present methodology for calculating Bayes factors between models as well as
      posterior probabilities of the models when the indicator variables of the models
      are integrated out of the posterior before Markov chain Monte Carlo (MCMC)
      computations. Standard methodology would include the indicator functions as part
      of the MCMC computations. We demonstrate that our methodology can give
      substantially greater accuracy than the traditional approach. We illustrate the
      methodology using the model selection prior of George and McCulloch applied to
      logistic regression and to a mixture model for observations in a hierarchical
      random effects model.

PMID- 10398293
TI  - Upregulation of GFRalpha-1 and c-ret in primary sensory neurons and spinal
      motoneurons of aged rats.
AB  - Aging is associated with a decline in neuromuscular and somatosensory functions.
      Senile muscle atrophy, considered to be of neurogenic origin, is prevalent, and
      sensory thresholds increase with age. However, the loss of motoneurons and
      primary sensory neurons is small, while sensory and motor innervation appears
      disturbed due to aging-related axon lesions. One mechanism which may play a role
      in this process is altered trophin signaling. We here report that the glial cell
      line-derived neurotrophic factor (GDNF) receptor GFRalpha-1 mRNA and GFRalpha-1
      protein-like immunoreactivity are upregulated in spinal motoneurons, and in
      dorsal root ganglion neurons of 30-month-old rats. The established signaling
      mechanism for the GDNF/GFRalpha-1 complex is through binding to the tyrosine
      kinase receptor encoded by the c-ret proto-oncogene, and we also show here that c
      ret mRNA is upregulated in both motoneurons and primary sensory neurons of aged
      rats. The findings reported here, combined with evidence presented in other
      studies of changes in p75(NTR) and trk receptor expressions in aging primary
      sensory neurons and motoneurons, point at marked alterations in trophin signaling
      in senescence.

PMID- 10398294
TI  - Multiple connexin expression in peripheral nerve, Schwann cells, and Schwannoma
      cells.
AB  - Myelinating Schwann cells express the gap junction protein, connexin (Cx)32,
      which is present at the nodes of Ranvier and Schmidt-Lantermann incisures
      (Bergoffen et al. [1993] Science (Wash. ) 262:2039-2042). Following peripheral
      nerve injury, other members of the connexin gene family are also expressed
      (Chandross et al. [1996a] Mol. Cell. Neurosci. 7:501-518). This study surveys the
      connexin(s) expressed by rat sciatic nerve, cultured Schwann cells, and a mouse
      Schwannoma (TR6 Bc1) cell line. Reverse transcriptase-polymerase chain reaction
      (RT-PCR) amplification revealed a constitutive expression of mRNA encoding Cx32
      and 43 but not Cx26, 37, 40, 45, and 46 in sciatic nerve. Mitogenic stimulation
      of cultured Schwann cells expressing Cx32 also resulted in the appearance of Cx43
      mRNA. Schwannoma cells expressed exclusively Cx43 mRNA. These results were
      confirmed by Northern blot analysis. Functional gap junctions in cultured Schwann
      and Schwannoma cells were shown by analysis of the intercellular transfer of
      Lucifer yellow, although the coupling between primary Schwann cells was weak or
      undetectable. Treatment of primary Schwann cells with mitogens resulted in
      extensive dye coupling. An immunohistochemical study of adult sciatic nerve
      sections demonstrated Cx32 immunoreactivity at the nodes of Ranvier and in
      Schwann cell bodies. Lower intensity staining of Cx43 along the myelin sheath and
      Schwann cell bodies was also observed. Indirect immunofluorescent studies of
      Schwann cells treated with mitogens showed characteristic punctate cell surface
      staining of Cx43; Cx32 staining was detected mainly intracellularly. These
      results lead to the conclusion that in addition to the expression of Cx32 by
      normal adult sciatic nerve, low amounts of Cx43 protein are also present. The
      implications of the expression of two connexins by Schwann cells in Charcot-Marie
      Tooth X-linked disease, a demyelinating peripheral neuropathy, are discussed.

PMID- 10398295
TI  - Platelet-activating factor (PAF) acetylhydrolase activity, LIS1 expression, and
      seizures.
AB  - Lissencephaly patients are born with severe brain malformations and suffer from
      recurrent seizures. LIS1, the gene mutated in isolated lissencephaly patients, is
      a subunit of the heterotrimeric cytosolic enzyme platelet-activating factor
      acetylhydrolase (PAF-AH), interacts with tubulin, and affects microtubule
      dynamics. In order to gain molecular insights into the possible involvement of
      LIS1 in seizures in lissencephaly patients, we induced seizures in rats by
      injection of kainate. PAF-AH activity was markedly reduced as early as 30 min
      following initiation of seizures, making this parameter a sensitive indicator of
      seizure events. PAF-AH activity returned to and surpassed control values 1 week
      following initiation of seizures. Expression of LIS1 in the dentate gyrus changed
      significantly in a manner similar to that of PAF-AH enzymatic activity. This is
      the first correlation found between LIS1 expression and PAF-AH activity.
      Furthermore, the expression of the alpha2 catalytic subunit, which is the major
      PAF-AH catalytic subunit in rat adult brain, changed in a dramatic fashion. An
      additional higher-mobility LIS1 cross-reactive band was detected in samples
      isolated a week following seizure occurrence. This LIS1 isoform was enriched in
      the microtubule-associated fraction. We propose that LIS1 expression is an
      important factor in regulation of PAF-AH activity. We postulate that reductions
      in LIS1 protein levels found in lissencephaly patients may render them more
      susceptible to seizures.

PMID- 10398296
TI  - Postnatal development of GABAA receptor beta1, beta2/3, and gamma2
      immunoreactivity in the rat retina.
AB  - GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter in the
      mammalian central nervous system and plays an important role in neuronal
      physiology during ontogenesis. The distribution of the beta1-, beta2/3-, and
      gamma2-subunit of the GABAA receptor in the rat retina was studied during
      postnatal development using immunohistochemical methods. All subunits were found
      at birth. However, each subunit showed a unique staining pattern with a different
      local distribution. The immunoreactivity pattern changed during the time course
      of postnatal development for each of the proteins investigated. A clustered
      distribution at presumptive synaptic sites as indicated by a punctate staining
      pattern of the inner plexiform layer was detected as early as the second day of
      postnatal development. However, diffuse staining of presumptive extrasynaptic
      sites was found throughout development. The typical adult layering of
      immunoreactivity into distinctive bands appeared later in development,
      characteristically in the second postnatal week. The results of the present study
      suggest that GABAA receptor expression precedes the formation of functional
      synapses and changes along with cellular differentiation of the rat retina.
      Developmentally regulated changes in GABAA receptor composition and distribution
      indicate possible functions for this receptor during retinal ontogeny.

PMID- 10398297
TI  - Dietary restriction and 2-deoxyglucose administration improve behavioral outcome
      and reduce degeneration of dopaminergic neurons in models of Parkinson's disease.
AB  - Parkinson's disease (PD) is an age-related disorder characterized by progressive
      degeneration of dopaminergic neurons in the substantia nigra (SN) and
      corresponding motor deficits. Oxidative stress and mitochondrial dysfunction are
      implicated in the neurodegenerative process in PD. Although dietary restriction
      (DR) extends lifespan and reduces levels of cellular oxidative stress in several
      different organ systems, the impact of DR on age-related neurodegenerative
      disorders is unknown. We report that DR in adult mice results in resistance of
      dopaminergic neurons in the SN to the toxicity of 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP). MPTP-induced loss of dopaminergic neurons and deficits
      in motor function were ameliorated in DR rats. To mimic the beneficial effect of
      DR on dopaminergic neurons, we administered 2-deoxy-D-glucose (2-DG; a
      nonmetabolizable analogue of glucose) to mice fed ad libitum. Mice receiving 2-DG
      exhibited reduced damage to dopaminergic neurons in the SN and improved
      behavioral outcome following MPTP treatment. The 2-DG treatment suppressed
      oxidative stress, preserved mitochondrial function, and attenuated cell death in
      cultured dopaminergic cells exposed to the complex I inhibitor rotenone or Fe2+.
      2-DG and DR induced expression of the stress proteins heat-shock protein 70 and
      glucose-regulated protein 78 in dopaminergic cells, suggesting involvement of
      these cytoprotective proteins in the neuroprotective actions of 2-DG and DR. The
      striking beneficial effects of DR and 2-DG in models of PD, when considered in
      light of recent epidemiological data, suggest that DR may prove beneficial in
      reducing the incidence of PD in humans.

PMID- 10398298
TI  - Extracellular adenosine triphosphate affects neural cell adhesion molecule (NCAM)
      mediated cell adhesion and neurite outgrowth.
AB  - The neural cell adhesion molecule (NCAM) plays an important role in synaptic
      plasticity in embryonic and adult brain. Recently, it has been demonstrated that
      NCAM is capable of binding and hydrolyzing extracellular ATP. The purpose of the
      present study was to evaluate the role of extracellular ATP in NCAM-mediated
      cellular adhesion and neurite outgrowth. We here show that extracellularly added
      adenosine triphosphate (ATP) and its structural analogues, adenosine-5'-O-(3
      thiothiophosphate), beta, gamma-methylenadenosine-5'-triphosphate, beta, gamma
      imidoadenosine-5-triphosphate, and UTP, in varying degrees inhibited aggregation
      of hippocampal neurons. Rat glial BT4Cn cells are unable to aggregate when grown
      on agar but acquire this capacity when transfected with NCAM. However, addition
      of extracellular ATP to NCAM-transfected BT4Cn cells inhibited aggregation.
      Furthermore, neurite outgrowth from hippocampal neurons in cultures allowing NCAM
      homophilic interactions was inhibited by addition of extracellular nucleotides.
      These findings indicate that NCAM-mediated adhesion may be modulated by
      extracellular ATP. Moreover, extracellularly added ATP stimulated neurite
      outgrowth from hippocampal neurons under conditions non-permissive for NCAM
      homophilic interactions, and neurite outgrowth stimulated by extracellular ATP
      could be inhibited by a synthetic peptide corresponding to the so-called cell
      adhesion molecule homology domain (CHD) of the fibroblast growth factor receptor
      (FGFR) and by FGFR antibodies binding to this domain. Antibodies against the
      fibronectin type-III homology modules of NCAM, in which a putative site for ATP
      binding and hydrolysis is located, also abolished the neurite outgrowth-promoting
      effect of ATP. The non-hydrolyzable analogues of ATP all strongly inhibited
      neurite outgrowth. Our results indicate that extracellular ATP may be involved in
      synaptic plasticity through a modulation of NCAM-mediated adhesion and neurite
      outgrowth.

PMID- 10398299
TI  - NGF-resistant PC12 cell death induced by arachidonic acid is accompanied by a
      decrease of active PKC zeta and nuclear factor kappa B.
AB  - Inflammation and the associated release of inflammatory cytokines such as tumor
      necrosis factor alpha (TNFalpha) may be a component of neurodegenerative diseases
      associated with aging or chronic HIV-1 infection. Most of the neurons that are
      affected under these conditions require a constant supply of trophic factors such
      as nerve growth factor (NGF) for survival. NGF acts via binding to a specific
      tyrosine kinase receptor (TrkA). NGF also binds to the common neurotrophin
      receptor (p75(NTR)), a member of the TNFalpha receptor (TNFR-I) superfamily,
      whose function may be to modulate apoptosis via the release of ceramide and the
      activation of the transcription factor nuclear factor kappa B (NFkappaB). The
      similarity between p75(NTR) and TNFR-I signal transduction pathways suggests that
      one of the mechanisms by which TNFalpha affects neuronal survival is by impacting
      upon these pathways that normally promote NGF support of neurons. Here we show
      that arachidonic acid (AA), a signaling lipid potentially associated with TNFR-I
      signal cascade, induces apoptosis in PC12 cells through inhibition of both
      protein kinase C zeta (PKCzeta) and NFkappaB activity. We also show that
      apoptosis induced by AA cannot be prevented by NGF. These data support the idea
      that PKCzeta and NFkappaB are both essential signaling elements for mediating NGF
      promoted rescue from apoptosis. Our results also suggest that AA, an inflammatory
      signal lipid induced by TNFalpha via binding to TNFR-I, may reduce neuronal
      survival by inhibiting elements of the signal cascade induced by NGF.

PMID- 10398300
TI  - Brain-derived neurotrophic factor prevents neuronal cell death induced by
      corticosterone.
AB  - Corticosterone (CORT), one of the glucocorticoids, causes neuronal damage in the
      hippocampus, but the mechanism(s) of action underlying its effects remains
      unknown. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that
      belongs to the neurotrophin family, affects the survival and/or differentiation
      of various types of neurons in vitro, and is able to antagonize neuronal death
      induced by various brain insults or neurotoxins in vivo. In this study, the
      effects of CORT on BDNF protein contents and mRNA expression were investigated in
      relation to neuronal survival/death of cultured rat hippocampal neurons, because
      the colocalization of BDNF with its receptor, TrkB, suggests that BDNF may exert
      its putative protective and trophic effects through an autocrine mechanism in the
      hippocampus. Administration of CORT accelerated the neuronal death that proceeds
      after serum deprivation, and simultaneously reduced the levels of BDNF mRNA and
      intracellular BDNF content. Exogenously added BDNF actually attenuated CORT
      induced neuronal death, but not in the presence of K252a, an inhibitor of the
      tyrosine kinase activity of Trk family receptors. These observations suggest that
      CORT induces damage to hippocampal neurons, at least partly, via reducing their
      BDNF synthesis.

PMID- 10398301
TI  - Human oligodendroglial cell line, MO3.13, can be protected from apoptosis using
      the general caspase inhibitor zVAD-FMK.
AB  - Recent evidence suggests that the oligodendrocyte cell loss observed in multiple
      sclerosis sufferers is in part mediated by apoptosis. Here we use a human cell
      line, MO3.13, as a model system to investigate the biochemical processes involved
      in oligodendroglial cell death. Treatment with staurosporine kills both naive and
      differentiated cells in a dose-dependent manner; however, much higher
      concentrations of staurosporine are required to kill differentiated cells
      compared to their naive progenitors. Dying cells displayed the typical
      morphological characteristics of apoptosis, including cell shrinkage and
      chromatin condensation. Biochemical analysis showed that caspases, a group of
      enzymes intimately involved in the execution of apoptosis, are activated in both
      naive and differentiated cells. Western blotting analysis revealed that similar
      subsets of caspase enzymes were operating and that the substrate cleavage
      patterns were identical in both naive and differentiated cells. Treatment of
      MO3.13 cells with the general caspase inhibitor zVAD-FMK protected them from
      toxin-induced cell death. These results indicate that when an oligodendroglial
      human cell line is exposed to toxin it dies in an apoptotic manner. In addition,
      we show that cells can be protected from toxin-induced death using an appropriate
      inhibitor.

PMID- 10398302
TI  - Marsupial retinocollicular system shows differential expression of messenger RNA
      encoding EphA receptors and their ligands during development.
AB  - The protracted development of the wallaby (Macropus eugenii) has allowed study of
      messenger RNAs encoding Eph receptors EphA3 and EphA7 and ligands ephrin-A2 and 
      A5 in the retina and superior colliculus at intervals throughout the development
      of the retinocollicular projection: from birth, before retinal innervation, to
      postnatal day 95, when the projection is mature. Reverse transcription-polymerase
      chain reaction showed messenger RNAs for both receptors and ligands were
      expressed at all ages. EphA7 was expressed more highly in the rostral superior
      colliculus. Ephrin-A2 and -A5 were expressed more highly in the caudal
      colliculus. EphA3 was expressed in a complementary manner, more highly in
      temporal than in nasal retina. There are higher levels of expression of the
      ligands when the projection is only coarsely topographically organised. This
      suggests a role for them and their receptor EphA3 in this stage, by repulsive
      interactions which restrict temporal axons to rostral superior colliculus. This
      is the first account in a marsupial mammal of the appearance of this molecular
      family, substantiating its ubiquitous role in topographically organised neuronal
      connections. Nevertheless, expression is not the same as in the mouse, suggesting
      differences in the details of topographic coding between species.

PMID- 10398303
TI  - Astrocytes respond to hypoxia by increasing glycolytic capacity.
AB  - Astrocytes cope more readily with hypoxic insults than do neurons. We
      hypothesized that astrocytes can upregulate their glycolytic capacity, allowing
      anaerobic glycolysis to provide sufficient ATP for cell survival as well as for
      carrying out critical functions such as taking up glutamate. To test this
      hypothesis, astrocytes were subjected to hypoxia for 5 hr. Lactate dehydrogenase
      (LDH) and pyruvate kinase activities increased 3- to 4-fold. Examination of LDH
      isoenzyme patterns determined that it was the anaerobic isoenzymes that were
      upregulated. To determine whether increase in enzyme activity translates into
      increased glycolytic capacity, astrocytes were subjected to varying time periods
      of hypoxia, and glucose uptake was measured under conditions where astrocytes
      were forced to consume more ATP. This demonstrated that 8 hr of hypoxia resulted
      in a doubling of glycolytic capacity. We suggest that how quickly astrocytes
      upregulate glycolytic capacity may determine whether or not neurons within the
      stroke penumbra survive.

PMID- 10398304
TI  - Lithium induces morphological differentiation of mouse neuroblastoma cells.
AB  - Neuroblastoma cells are used as a model system to study neuronal differentiation.
      Here we describe the induction of morphological differentiation of mouse
      neuroblastoma Neuro 2a (N2a) cells by treatments with either chemical inhibitors
      of cyclin-dependent kinases or lithium, which inhibits glycogen synthase kinase
      3. Cyclin-dependent kinase inhibitors cause a rapid cell cycle block as well as
      the extension of multiple neurites per cell. These multipolar differentiated
      cells then undergo a massive death. However, lithium promotes a delayed mitotic
      arrest and the extension of one or two long neurites per cell. This
      differentiation is maximal after 48 hours of lithium treatment and the
      differentiated cells remain viable for long periods of time. Neuronal
      differentiation in lithium-treated cells is preceded by the accumulation of beta
      catenin, a protein which is efficiently proteolyzed when it is phosphorylated by
      glycogen synthase kinase-3. Both neuronal differentiation and beta-catenin
      accumulation are observed in lithium-treated cells either in the absence or in
      the presence of supraphysiological concentrations of inositol. The results are
      consistent with the hypothesis that inhibition of glycogen synthase kinase-3 by
      lithium triggers the differentiation of neuroblastoma N2a cells.

PMID- 10398306
TI  - Neurotoxicity of methylglyoxal and 3-deoxyglucosone on cultured cortical neurons:
      synergism between glycation and oxidative stress, possibly involved in
      neurodegenerative diseases.
AB  - In this study, we investigate the neurotoxicity of glycation, particularly early
      stage glycation, and its mechanisms, which are possibly synergized with oxidative
      stress. Methylglyoxal (MG) and 3-deoxyglucosone (3DG), intermediate products of
      glycation, are known to further accelerate glycation and advanced glycation
      endproducts (AGEs) formation. Both compounds showed neurotoxicity on cultured
      cortical neurons and these effects were associated with reactive oxygen species
      production followed by neuronal apoptosis. Pretreatment with N-acetylcysteine
      induced neuroprotection against MG and 3DG. Cotreatment, but not pretreatment,
      with aminoguanidine protected neurons against the neurotoxicities of both
      compounds. The present study provides the first evidence that MG and 3DG are
      neurotoxic to cortical neurons in culture. Interference with the process by which
      glycation and AGEs formation occur may provide new therapeutic opportunities to
      reduce the pathophysiological changes associated with neurodegeneration, if, as
      indicated here, the participation of glycoxidation in the pathogenesis of
      neurodegenerative diseases is essential.

PMID- 10398305
TI  - Concurrent loss and proliferation of astrocytes following lateral fluid
      percussion brain injury in the adult rat.
AB  - Astrocyte populations were analyzed over a period of 1 month in the hippocampus
      following lateral fluid percussion (FP) brain injury. Rats (n = 23) were
      subjected either to a brain injury of moderate severity, or to anesthesia and
      surgery without injury (n = 7). At 3 days, 1, 2, or 4 weeks postinjury, subgroups
      of animals were sacrificed and the brains removed and sectioned for histochemical
      analysis. The density of astrocytes, identified with gold sublimate staining,
      decreased significantly in the ipsilateral hippocampus of injured rats 3 days
      following injury, eventually falling to 64% of the total astrocyte population
      present in uninjured animals by 1 week postinjury. One month postinjury, the
      density of hippocampal astrocytes had returned to 85% of the total number of
      astrocytes observed in the hippocampus of uninjured animals. In order to
      characterize the post-traumatic formation of new astrocytes, immunohistochemistry
      was performed using antibodies to proliferating cell nuclear antigen (PCNA) and
      to glial fibriallary acidic protein (GFAP). Positive immunolabeling for both PCNA
      and GFAP was most abundant at 3 days following FP brain injury in regions where
      the blood brain barrier was compromised, and was not detectable by 1 month
      postinjury. These results indicate that astrocyte proliferation after injury may
      be evoked by mitogens released from vascular sources, and may be an attempt to
      compensate for some of the astrocytic cell loss observed after injury.

PMID- 10398308
TI  - Regional patterns in the incidence of aplastic anemia in Thailand. The Aplastic
      Anemia Study Group.
AB  - The annual incidence of aplastic anemia has been determined in a rigorous and
      standardized epidemiologic study conducted in Thailand. A total of 374 cases were
      identified over a period of 3-6 years in three geographically defined and
      distinct regions of the country; Bangkok, Khonkaen in the northeast, and Songkla
      in the south. The incidence was 3.9 cases per million persons in Bangkok, 3.0 per
      million in Songkla, and 5.0 per million in Khonkaen. These rates are as high or
      higher than in any region of Europe or Israel as reported in the International
      Agranulocytosis and Aplastic Anemia Study, in which the methods and case
      definition were the same. Rates were stable over the course of the study. There
      were marked differences in incidence between northern and southern rural regions
      of Thailand, and among Bangkok suburbs. These differences, together with an
      unusual peak in the incidence among young people in Bangkok, suggest the
      possibility of occupational and environmental factors in the etiology of aplastic
      anemia.

PMID- 10398307
TI  - Advanced stage and unfavorable Hodgkin's disease in the Chinese-a 20-year
      experience.
AB  - We retrospectively analyzed 57 patients with advanced stage (stage III/IV) or
      unfavorable (presence of B symptoms or bulky disease) Hodgkin's disease from
      January 1977 to December 1997. There were 29 male and 28 female patients. The
      median age was 27 years old (range, 13-59). Lactate dehydrogenase levels ranged
      from 104 units/l to 2320 units/l (median, 433). Eighteen (31.6%), 13 (22.8%), and
      26 (45.6%) patients had stage II bulky, stage III, and stage IV disease,
      respectively. Twenty-five (44%) patients had B symptoms. One (1.8%), 3 (5.3%), 36
      (63.2%), and 17 (29.8%) had lymphocyte predominant, lymphocyte depleted, nodular
      sclerosis, and mixed cellularity histology, respectively. Chemotherapy regimens
      included mechlorethamine, vincristine, procarbazine, prednisone (MOPP) (n = 9),
      adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) (n = 23), MOPP alternating
      with ABVD (n = 13), and COPP-ABV hybrid (n = 12). Complete remission was achieved
      in 47 (82.4%) patients. Eleven patients (23%) relapsed after the first complete
      remission and four (36%) attained a second complete remission with salvage
      chemotherapy. Projected overall survival was 69.0% at 10 years and 20 years.
      Disease-free survival rates were 71% at 10 years and 20 years. Of the potential
      prognostic factors analyzed (age, sex, stage, lactate dehydrogenase, serum
      albumin level, regimen, B symptoms and bulky disease) by using the Cox regression
      model, only a low albumin level was found to adversely affect overall survival (P
      = 0.003). In conclusion, despite the relative low incidence of Hodgkin's disease
      in Hong Kong Chinese, the treatment outcomes in patients with advanced stage or
      unfavorable Hodgkin's disease is comparable to Caucasian patients.

PMID- 10398310
TI  - CD7 expression on CD34+ cells from chronic myeloid leukaemia in chronic phase.
AB  - Thirty-seven patients with chronic phase chronic myeloid leukaemia and fourteen
      healthy controls have been evaluated for lineage differentiation with
      immunological markers on purified bone marrow CD34 positive cells by
      multiparameter flow cytometry. The myeloid-associated antigen CD33 and the stem
      cell factor receptor (CD117, c-kit) was expressed by 82.3% and 73.5% on CP-CML
      patients and by 57% and 57.5% on healthy donors, respectively (P < 0.005).
      CD34+/CD19+ or CD34+/CD10+ B-lymphoid cell population represented 9. 1% and 10.7%
      of the CD34+ cells in CML whereas in normal controls this subpopulation was
      expressed by 27.9% and 30.4% of the CD34+ cells, respectively (P< 0.005). The T
      lineage associated markers (CD7 and CD2) were detected on a minor population of
      CD34+ BM cells of healthy controls (mean, 3.6% and 4.6%, respectively). The CD2
      positive cells represented 1.5% of the CD34+ cells in CML patients. CP-CML
      patients co-expressed the CD7 antigen on a mean of 32.6% of the CD34+ BM cells.
      Moreover, 93% of this CD34/CD7 double positive subpopulation co-expressed CD33
      antigen in CML patients. Co-expression of CD7 on CD34+ cells was induced to
      decrease significantly after short-term in vitro culture with the differentiation
      inducing agent phorbol ester (PMA) and with a combination of cytokines (stem-cell
      factor, interleukin-3 and granulocyte colony-stimulating factor). In conclusion,
      a high co-expression of CD7 antigen is demonstrated on CD34+ cells of chronic
      phase-chronic myeloid leukaemia patients. The loss of CD7 marker following
      incubation with PMA and cytokines suggests that this antigen is expressed
      transiently in early myeloid leukaemic CML haemopoiesis.

PMID- 10398309
TI  - Hematopoietic differentiation activity of a recombinant human interleukin-6 (IL
      6) isoform resulting from alternatively spliced deletion of the second exon.
AB  - We have previously identified and cloned an alternatively spliced form of human
      interleukin-6 mRNA lacking exon II, which encodes amino acid residues known to be
      important in gp130-mediated signal transduction pathways. We expressed and
      purified the recombinant protein (rIL6-alt) resulting from this alternatively
      spliced mRNA and now report the initial characterization of its biologic
      activities with comparison to full length IL6 (rIL6-full). rIL6-alt was found to
      have 10(4) to 10(5) fold less activity in proliferation assays with 7TD1 murine
      plasmacytoma cells and did not competitively inhibit the stimulatory activity of
      rIL6-full. In addition, like rIL6-full, rIL6-alt had antiproliferative activity
      toward M1 murine myeloblast cells and was 10-200-fold less active than rIL6-full.
      In contrast, in assays with human HL60 promyelocytic leukemia cells, rIL6-alt had
      greater antiproliferative activity than rIL6-full and more strongly upregulated
      phagocytosis as well as surface expression of the differentiation antigen CD11b.
      rIL6-full and rIL6-alt upregulated the level of lysozyme mRNA in HL60 cells
      approximately equally. These findings suggest that IL6-alt, which lacks amino
      acid residues encoded by the second exon of the gene, is not a natural inhibitor
      of IL6-full but may be relatively tissue specific and may play a role in
      modulation of hematopoietic cell growth and differentiation.

PMID- 10398311
TI  - Hb Iraq-Halabja beta10 (A7) Ala-->Val (GCC-->GTC): a new beta-chain silent
      variant in a family with multiple Hb disorders.
AB  - A patient originating from Iraq was referred to our laboratory upon suspicion of
      a hemoglobinopathy. Routine hematological tests revealed a microcytic and
      slightly anemic phenotype with an elevated HbA2 suggestive of beta-thalassemia.
      Samples were obtained for several members of the family which upon examination
      revealed highly heterogeneous phenotypes that prompted us to investigate the case
      further. Sequencing of the beta-globin gene and alpha cluster mapping in the
      propositus and his brother showed a previously undescribed beta-globin variant:Hb
      Iraq-Halabja, beta10(A7) Ala-->Val (GCC-->GTC), associated with beta0-thalassemia
      IVS-2 nt1 G-->A and either alpha-thal-2-3.7 kb deletion (brother), or alpha
      globin gene triplication anti-3.7 kb type (propositus). Detailed functional
      studies of the variant gave a normal oxygenation curve, a normal heterotopic
      action of 2,3 DPG, and normal heat stability and isopropanol precipitation tests.
      The variant shows a clear difference in migration properties compared to normal
      beta-chain only when run on PAGE urea Triton. As expected, alpha/beta-globin mRNA
      ratios were influenced by the concomitant presence of an alpha-globin gene
      pathology and the beta0 thalassemia and not by the presence of the beta-globin
      variant which apparently is clinically silent.

PMID- 10398312
TI  - Effect of zinc supplementation on incidence of infections and hospital admissions
      in sickle cell disease (SCD).
AB  - Zinc deficiency is a common nutritional problem in adult sickle-cell disease
      (SCD) patients. Hyperzincuria and increased requirement of zinc due to continued
      hemolysis in SCD are probable bases for zinc deficiency in these patients. Zinc
      deficiency affects adversely T-helper1 (TH1) functions and cell mediated immunity
      and interleukin (IL)-2 production is decreased in zinc deficient subjects. We
      hypothesized that zinc supplementation will improve T-helper1 function and
      decrease incidence of infections in patients with SCD. We tested this hypothesis
      in 32 SCD subjects who were divided in three groups (Grs A, B, and C). Grs A (n =
      11) and B (n = 10) were zinc deficient based on cellular zinc criteria and Gr C
      (n = 11) were zinc sufficient. Gr A subjects were observed for 1 year (baseline),
      following which they received zinc acetate (50 to 75 mg of elemental zinc orally
      daily) for 3 years. Gr B subjects were observed for 1 year (baseline), following
      which they received placebo for 1 year and then switched to zinc supplementation
      (50 to 75 mg of elemental zinc orally daily) for 2 years. Gr C subjects did not
      receive any intervention inasmuch as they were zinc sufficient. Prolonged zinc
      supplementation resulted in an increase in lymphocyte and granulocyte zinc (P =
      0.0001), and an increase in interleukin-2 production (P = 0.0001), decreased
      incidence of documented bacteriologically positive infections (P = 0.0026),
      decreased number of hospitalizations and decreased number of vaso-occlusive pain
      crisis (P = 0.0001). The predominant pathogens isolated were staphylococci and
      streptococci involving the respiratory tract and aerobic gram-negative bacteria,
      particularly Escherichia coli, involving the urinary tract. Further confirmation
      of our observations will require prospective studies of zinc supplementation in a
      larger number of SCD patients.

PMID- 10398313
TI  - Multiple myeloma in the breast.

PMID- 10398314
TI  - Acute profound thrombocytopenia following C7E3 Fab (Abciximab) therapy: case
      reports, review of the literature and implications for therapy.
AB  - Platelets play a crucial role in the ischemic complications of percutaneous
      coronary procedures. The recent availability of C7E3 Fab (Abxiximab or
      ReoProtrade mark), a chimeric monoclonal antibody Fab fragment directed against
      the platelet glycoprotein IIb/IIIa receptor, has reduced abrupt closure and other
      adverse events and lessened the need for revascularization procedures. As the use
      for this drug has increased, rare cases of severe thrombocytopenia have been
      revealed. From August 1995 to June 1997, 452 patients at Charleston Area Medical
      Center who underwent percutaneous coronary revascularization procedures and were
      treated with abciximab were evaluated for the development of severe
      thrombocytopenia (i.e., platelet count less than 20,000 within 48 hr of
      treatment). A review of published reports of severe thrombocytopenia was also
      reviewed. A review of published reports of abciximab-induced severe
      thrombocytopenia, as well as our three cases, reveals that: 1) the incidence is
      less than 0.7%; 2) the nadir platelet count (range 1, 000-16,000) was noted
      within 2-31 hr after abciximab infusion; 3) the platelet count increases to
      greater than 100,000 within 12 days in all patients; 4) bleeding episodes were
      treated with platelet transfusion with an improvement in platelet count within 24
      hr in all patients in whom they were given; and 5) in the one patient treated
      with gamma globulin alone, no significant rise in platelet count was noted. Acute
      severe thrombocytopenia can occur after ReoProtrade mark administration. Its
      development is not predictable and may occur within 2 hr of administration.
      Thrombocytopenia, therefore, requires consideration in every patient treated with
      this drug. It appears prudent to obtain a platelet count 2 hr after initiating
      ReoProtrade mark. If thrombocytopenia develops, then the drug can be stopped in a
      timely manner and platelet transfusion can be given.

PMID- 10398315
TI  - Acute pure red cell aplasia associated with allopurinol therapy.
AB  - Several investigators have reported patients with acute pure red cell aplasia
      (PRCA) caused by anticonvulsants, antibiotics, or antithyroid agents. Allopurinol
      is known to be a causative agent of aplastic anemia, but there have been few
      reports of acute PRCA induced by allopurinol. We describe here a 15-year-old boy
      who suffered from anemia 6 weeks after initiation of allopurinol therapy; his
      anemia immediately improved after cessation of the drug. His bone marrow showed
      severe erythroid hypoplasia with a myeloid/erythroid ratio of 18.6 and low
      expression of glycophorin A detected on cell-surface antigen analysis. No
      morphological abnormalities were observed in myeloid series and megakaryocytes.
      The prolonged plasma iron disappearance rate and the decreased plasma iron
      turnover rate also indicated erythroid hypoplasia. He had been free from any
      infections, including parvovirus B19, before manifestation of PRCA. Taken
      together, these results suggest a diagnosis of acute PRCA. This side effect of
      allopurinol should be taken into consideration.

PMID- 10398316
TI  - Portal, mesenteric, and splenic vein thromboses after splenectomy in a patient
      with chronic myeloid leukemia variant with thrombocythemic onset.
AB  - Portal, mesenteric, or splenic vein thrombosis is a very uncommon complication
      with significant mortality in the patients undergoing splenectomy for hematologic
      disorders. We report a 49-year-old woman who developed portal, superior
      mesenteric, and splenic vein thromboses after splenectomy. Four years before the
      event, she presented with a marked thrombocytosis and was diagnosed to have
      chronic myeloid leukemia variant with thrombocythemic onset as evidence by
      Philadelphia (Ph1) chromosome and a b3a2 BCR/ABL transcript. Six weeks after
      splenectomy, she developed severe epigastric pain. The diagnosis of thromboses of
      portal, mesenteric, and splenic veins was made by computed tomography scan and
      Doppler sonogram. She was successfully treated with antegrade intraarterial
      urokinase therapy via superior mesenteric artery and long-term anticoagulant
      therapies. To our knowledge, our patient is the first case of portal, mesenteric,
      and splenic vein thromboses after splenectomy in a patient with CML variant with
      thrombocythemic onset successfully treated with antegrade intraarterial
      thrombolytic therapy followed by anticoagulant therapies.

PMID- 10398317
TI  - Undetectable plasma L-arginine level before visible hemolysis in thrombotic
      thrombocytopenic purpura.

PMID- 10398318
TI  - Multiple myeloma presenting as Sjogren's syndrome.

PMID- 10398319
TI  - Lack of compliance and late-onset warfarin-induced skin necrosis.

PMID- 10398321
TI  - Ultrastructure of the reproductive system of the black swamp snake (Seminatrix
      pygaea): Part I. Evidence for oviducal sperm storage.
AB  - Oviducal sperm storage in the viviparous (lecithotrophic) colubrid snake
      Seminatrix pygaea was studied by light and electron microscopy. Out of 17 adult
      snakes examined from May-October, sperm were found in the oviducts of only two
      specimens. In a preovulatory female sacrificed 14 May, sperm were found in the
      oviducal lumen and sperm storage tubules (SSTs) of the posterior infundibulum. In
      a nonvitellogenic female sacrificed 9 June, sperm were found in the lumen and
      glands of the posterior uterus and anterior vagina, indicating a recent mating.
      The glands in the posterior infundibulum and vagina were simple or compound
      tubular, whereas glands in the uterus always were simple tubular. The epithelium
      of the sperm storage glands was not modified from that lining the rest of the
      oviduct. The cuboidal or columnar epithelium consisted of alternating ciliated
      and secretory areas. The secretory product released into the lumen by a merocrine
      process contained mucoprotein. Lipid droplets also were numerous in the
      epithelium. Portions of sperm sometimes were embedded in the apical cytoplasm or
      in secretory material. A carrier matrix containing a mucoid substance,
      desquamated epithelium, lipids, membranous structures, and possibly phagocytes
      was found around sperm in the posterior uterus. Copyright 1999 Wiley-Liss, Inc.

PMID- 10398320
TI  - Evan's syndrome precipitated by fludarabine therapy in a case of CLL.

PMID- 10398322
TI  - Histology and lectin-binding patterns in the digestive tract of the carnivorous
      larvae of the anuran, Ceratophrys ornata.
AB  - Larvae of Ceratophrys ornata are carnivorous, have relatively short digestive
      tracts and continue to feed during metamorphic climax, in contrast to those of
      more typical herbivorous anuran larvae. The present study describes both
      histological and histochemical changes in the stomach, small intestine, and large
      intestine of C. ornata prior to and during metamorphic climax. Modifications in
      these organs were found to be similar to but less dramatic than those in
      herbivorous larvae. Luminal epithelial cells in the three regions develop
      vacuoles, suggesting degeneration, but sloughing of this epithelium, as occurs in
      herbivorous larvae, was not observed in C. ornata. Multicellular tubular glands
      develop gradually in the gastric area during the larval stages, gastric pits
      appear during metamorphic climax, and mucous neck cells are first visible in the
      juvenile. Goblet cells in the small and large intestine increase in number during
      larval life, as do the number of folds in the intestinal wall. Increase in
      diameter and thickness of the wall occurs in the stomach as well as in the small
      and large intestine. Such changes result in an adult-type digestive tract
      characteristic of frogs in general. Staining with two horseradish peroxidase
      conjugated lectins, soybean agglutinin (SBA) and Ulex europaeus agglutinin I (UEA
      I), demonstrated specific sites along the digestive tract of glycoconjugates with
      terminal sugars N-acetylgalactosamine and alpha-fucose, respectively. As
      metamorphic climax approaches, staining intensities decrease--thus providing
      evidence for metamorphic changes in the sugar moieties of glycoconjugates present
      in the digestive tract of carnivorous larvae.

PMID- 10398323
TI  - Anatomy of the feeding apparatus of the nurse shark, Ginglymostoma cirratum.
AB  - The anatomy of the feeding apparatus of the nurse shark, Ginglymostoma cirratum,
      was investigated by gross dissection and computer axial tomography. The labial
      cartilages, jaws, jaw suspension, muscles, and ligaments of the head are
      described. Palatoquadrate cartilages articulate with the chondrocranium caudally
      by short, laterally projecting hyomandibulae and rostrally by ethmoorbital
      articulations. Short orbital processes of the palatoquadrates are joined to the
      ethmoid region of the chondrocranium by short, thin ethmopalatine ligaments. In
      addition, various ligaments, muscles, and the integument contribute to the
      suspension of the jaws. When the mouth is closed and the palatoquadrate
      retracted, the palatine process of the palatoquadrate is braced against the
      ventral surface of the nasal capsule and the ascending process of the
      palatoquadrate is in contact with the rostrodorsal end of the suborbital shelf.
      When the mandible is depressed and the palatoquadrate protrudes slightly
      rostroventrally, the palatoquadrate moves away from the chondrocranium. A dual
      articulation of the quadratomandibular joint restricts lateral movement between
      the mandible and the palatoquadrate. The vertically oriented preorbitalis muscle
      spans the gape and is hypothesized to contribute to the generation of powerful
      crushing forces for its hard prey. The attachment of the preorbitalis to the
      prominent labial cartilages is also hypothesized to assist in the retraction of
      the labial cartilages during jaw closure. Separate levator palatoquadrati and
      spiracularis muscles, which are longitudinally oriented and attach the
      chondrocranium to the palatoquadrate, are hypothesized to assist in the
      retraction of the palatoquadrate during the recovery phase of feeding kinematics.
      Morphological specializations for suction feeding that contribute to large
      subambient suction pressures include hypertrophied coracohyoideus and
      coracobranchiales muscles to depress the hyoid and branchial arches, a small oral
      aperture with well-developed labial cartilages that occlude the gape laterally,
      and small teeth. Copyright 1999 Wiley-Liss, Inc.

PMID- 10398324
TI  - Development of dermal denticles in skates (Chondrichthyes, Batoidea): patterning
      and cellular differentiation.
AB  - Patterning, cellular differentiation, and developmental sequences of dermal
      denticles (denticles) are described for the skate Leucoraja erinacea. Development
      of denticles proceeds caudo-rostrally in the tail and trunk. Once three rows of
      denticles form in the tail and trunk, denticles begin to appear in the region of
      the pelvic girdle, medio-caudal to the eyes and on the pectoral fins. Although
      timing of cellular differentiation of denticles differs among different locations
      of the body, cellular development of a denticle is identical in all locations.
      Thickening of the epidermis as a denticle lamina marks initiation of development.
      A single lamina for each denticle forms, and a small group of mesenchymal cells
      aggregates underneath it. The lamina then invaginates caudo-rostrally to form the
      inner- and outer-denticle epithelia (IDE and ODE, respectively). Before nuclei of
      IDE cells are polarized, enameloid matrix appears between the basement membrane
      of the IDE and the apical surface of the pre-odontoblasts. Pre-dentin is then
      laid down along with collagenous materials. Von Kossa stain visualizes initial
      mineralization of dentin, but not enameloid. During the growth of a denticle,
      dense fibrous connective tissue of the dermis forms the deep dermal tissue over
      the dorsal musculature. Attachment fibers and tendons anchor denticles and dorsal
      musculature, respectively, on deep dermal tissue. Basal tissue of the denticles
      develops as the denticle crown grows. If the basal tissue is bone of attachment,
      then the cells along the basal tissue would be osteoblasts. However, these cells
      could not be distinguished from odontoblasts using immunolocalization of type I
      pro-collagen (Col I), alkaline phosphatase (APase), and neural cell adhesion
      molecule (N-CAM). Well-developed dentin, (not pre-dentin), the enameloid matrix
      (probably when it begins to mineralize), and deep dermal tissue are Verhoeff
      stain-positive, suggesting that these tissues contain elastin and/or elastin-like
      molecules. Our study demonstrates that the cellular development of denticles
      resembles tooth development in elasmobranchs, but that dermal denticles differ
      from teeth in forming from a single denticle lamina. Whether the basal tissue of
      denticles is bone of attachment remains undetermined. Confirmation and function
      of Verhoeff-positive proteins in enameloid, dentin, and deep dermal tissue remain
      to be determined. We discuss these issues along with an analysis of recent
      findings of enamel and enameloid matrices.

PMID- 10398325
TI  - Development and evolution of melanophore patterns in fishes of the genus Danio
      (Teleostei: Cyprinidae).
AB  - Pigmentation patterns in vertebrates have become an important model for those
      interested in mechanisms of pattern determination. I present detailed information
      on the development of melanophore patterns in the zebrafish, Danio rerio, five
      close relatives of that species, and an outgroup. The comparison of the ontogeny
      of melanophore patterns in this group is an important first step towards
      understanding the developmental basis of the interspecific variation. Pigment
      patterns in this group range from no distinct patterning at all to stripes of
      differing numbers and widths to reticulated stripes. Species examined form
      identical larval patterns and follow a common sequence of events from which
      different elements are eliminated or altered to produce the variety of patterns
      seen in the group. As flexion is completed, melanophores move from larval
      positions onto the flanks of the fish. In D. rerio, D. rerio 'leo,' D. kerri, and
      D. malabaricus, xanthophores become established on the body of the fish as the
      melanophores move; erythrophores become established on the flanks of D.
      albolineatus and D. sp. cf. aequipinnatus. An increase in melanophore number,
      begun at this time, continues at a higher rate in D. rerio, D. kerri, D. sp. cf.
      aequipinnatus and Tanichthys albonubes than in the other three species. This
      results in a greater number of melanophores on adults in those species with a
      higher rate of melanophore increase. No distinct pattern forms, except on the
      caudal peduncle, in D. albolineatus. In all other Danio species, melanophore
      stripes form first below then above the horizontal myoseptum. Additional stripes
      are added first below then above these initial two stripes. D. kerri develops
      fewer, wider melanophore stripes than D. rerio. After initial stripe formation,
      D. malabaricus and D. sp. cf. aequipinnatus both developed vertical pattern
      elements and reticulations in the melanophore pattern. Differences in patterns
      between species are similar in several cases to described mutants of the
      zebrafish, suggesting that some aspects of interspecific pigmentation pattern
      variation may be under relatively simple genetic control. Copyright 1999 Wiley
      Liss, Inc.

PMID- 10398326
TI  - Introduction to mental illness and criminal responsibility.

PMID- 10398327
TI  - Craziness and criminal responsibility.
AB  - This article addresses why mental disorder is relevant to criminal
      responsibility. It begins by considering the meaning of criminal responsibility
      because it is impossible to understand the relevance of mental disorder unless
      one understands responsibility clearly. The next section provides a theoretical
      account of responsibility and excuse in general and addresses common
      misconceptions about these topics. The third section examines in detail why
      mental disorder can sometimes produce either a complete or partial excusing
      condition, such as legal insanity or "partial responsibility," and whether the
      U.S. Constitution requires the provision of an excuse based on mental disorder.
      The section proposes that mental disorder should produce an excusing condition in
      appropriate cases. The next section considers the relation of mental disorder to
      mens rea, the mental state "element" that is a definitional criterion of most
      crimes, and whether the U.S. Constitution requires that defendants be permitted
      to use evidence of mental disorder to negate mental state elements of the crime
      charged. This section argues that mental disorder rarely negates mens rea, but in
      those cases in which a plausible claim for negation could be made, defendants
      should be allowed to make this claim.

PMID- 10398328
TI  - The mental disability requirement in the insanity defense.
AB  - This paper offers a discussion of some of the nuances of mental disease or defect
      as required for the insanity defense in criminal law. It also compares and
      contrasts the mental disease or defect definitions of criminal law with those
      definitions used in clinical practice. It points out a general pattern of
      vagueness and dispute regarding the proper interpretation of the mental
      disability requirement in the insanity defense and in other legal provisions. It
      reports a variety of interpretations by courts and commentators regarding the
      meaning of these phrases, and it reports attempts by state legislatures to narrow
      the range of applicable conditions by excluding various mental or emotional
      states.

PMID- 10398329
TI  - The R-CRAS and insanity evaluations: a re-examination of construct validity.
      Rogers Criminal Responsibility Assessment Scales.
AB  - Insanity evaluations are characterized by continued professional debate and the
      paucity of empirical research. To address the latter, the construct validity of
      the Rogers Criminal Responsibility Assessment Scales (R-CRAS; Rogers, 1984) was
      examined via an extensive re-analysis of 413 insanity cases. A series of six
      separate discriminant analyses was examined to address major components of
      insanity evaluations. These analyses yielded highly discriminating patterns (M
      hit rates of 94.3%) and accounted for substantial proportion of the variance
      (M=63.7%). In general, predicted relationships between individual variables and
      the discriminant functions were supported. We also addressed the usefulness of
      the R-CRAS additional variables for the assessment of insanity. We found that
      these variables contributed substantially to the determination of criminal
      responsibility. Finally, we pose important and polemical issues for forensic
      experts conducting evaluations of criminal responsibility.

PMID- 10398330
TI  - Voluntary intoxication and criminal responsibility.
AB  - This paper reviews the law related to voluntary intoxication and criminal
      responsibility in the 50 United States, the District of Columbia, the US Virgin
      islands, and Puerto Rico. Statutory and case law citations are provided which
      govern the use of intoxication evidence in each jurisdiction to negate mens rea
      (i.e., to establish diminished capacity), to support an insanity defense, and to
      mitigate criminal sentencing. Factors that courts typically focus on when
      deciding whether to admit this evidence in a particular case are discussed, and
      these factors are related to clinically relevant criteria.

PMID- 10398331
TI  - The medico-legal status of young sex offenders: forensic psychiatric evaluations
      in Sweden 1988-1995.
AB  - Young sex offenders (YSOs) attract significant public and professional concern.
      YSOs might be perceived as more psychologically deviant or dangerous than other
      offenders. This study focused on how often YSOs subjected to forensic psychiatric
      investigation (FPI) were declared medico-legally insane as compared to young non
      sex offenders and adult sex offenders. Logistic regression models were applied to
      data from all major FPIs performed in Sweden between 1988 and 1995 (N=4354) to
      explore factors affecting the likelihood of receiving a medico-legal insanity
      declaration. When we adjusted for the statistical effects of age, sex offender
      status, and psychopathology, YSOs (n=47) were three to four times more likely to
      be declared insane in the medico-legal sense. The results indicate that YSOs in
      Sweden constitute a medico-legally distinct subgroup of forensic psychiatric
      examinees.

PMID- 10398332
TI  - An administrative model for close monitoring and managing high risk individuals.
AB  - The public expects central government to have immediate knowledge of the
      condition and circumstances of certain vulnerable or dangerous individuals such
      as insanity acquittees, and to take action in individual cases to protect the
      individual and the public. Therefore, such persons conditionally released to
      community settings require an unusual degree of close monitoring and management.
      Being immediately aware of the condition and circumstances of its assignees,
      together with other duties of a board or commission responsible for that
      monitoring and management, is largely an information management function. The
      Psychiatric Security Review Board in Oregon is used to illustrate this unique
      mission, operations, and information management. In this paper, the Psychiatric
      Security Review Board is described in terms of its core and secondary businesses,
      together with a model information system that is based on information and
      information management processes actually employed by the Board.

PMID- 10398333
TI  - The potential conflict between clinical and judicial decision making heuristics.
AB  - The Gudjonsson Suggestibility Scale (GSS; Gudjonsson, 1984) was introduced as a
      tool for identifying suspects who are at risk of making false confessions. High
      GSS-scores indicate a greater risk of making false confessions. Recently, some
      authors have claimed that low GSS-scores can be used to support the credibility
      of recovered memories. This new application broadens the use of the GSS in two
      ways. First, low GSS-scores are considered to possess diagnostic value. Second,
      the GSS is advocated as a practical tool in clinical settings. This article
      critically evaluates such a clinical application of the GSS. Our main argument
      has to do with the incompatibility of basic clinical and judicial decision making
      heuristics. Psychotherapists, and other medical professionals, should base their
      decisions on different parameters than judicial professionals. Compared to
      judicial heuristics, clinical heuristics can be characterized as more empathetic,
      less critical, and less conservative. Given these differences, clinical
      conclusions (including those about the accuracy of recovered memories) cannot be
      easily translated into judicial decisions. If they do enter the judicial domain,
      these conclusions may lead to dubious forensic decisions.

PMID- 10398334
TI  - Daily rhythm of responsiveness to prothoracicotropic hormone in prothoracic
      glands of rhodnius prolixus 
AB  - The synthesis of ecdysteroids by the prothoracic glands (PGs) of Rhodnius
      prolixus occurs with a circadian rhythm throughout most of larval-adult
      development. This rhythm is generated by a circadian oscillator within the PGs.
      The principle regulator of the PGs is the cerebral neuropeptide
      prothoracicotropic hormone (PTTH), which is also known to be released with a
      circadian rhythm, but it has not been shown that these daily releases of PTTH are
      detected by the PGs. The present report examines the ability of PTTH to augment
      ecdysteroid synthesis in rhythmic PGs at various times of day. There is a daily
      rhythm in the responsiveness of PGs to PTTH; high responsiveness occurs around
      dusk and PGs are largely unresponsive to PTTH during the daytime. This rhythm
      phase-leads the rhythms of PTTH release and of ecdysteroid synthesis by several
      hours. The data are suggestive of a daily rhythm of up- and down-regulation of
      PTTH receptor availability in the PGs. It is concluded that the daily releases of
      PTTH are detected by the PGs and participate in the regulation of daily
      ecdysteroid synthesis. Therefore, PTTH plays a continuing role in the regulation
      of PGs throughout development. Arch. Copyright 1999 Wiley-Liss, Inc.

PMID- 10398335
TI  - DNA-binding properties of the ecdysteroid receptor-complex (EcR/USP) of the
      epithelial cell line from Chironomus tentans.
AB  - DNA-binding features of EcR and USP were investigated using a 0.4 M NaCl extract
      of the epithelial cell line of Chironomus tentans by means of electrophoretic
      mobility shift assays (EMSAs). It is shown that the DNA-binding is enhanced by
      hormone administration and that in the hormone dependent shift, both EcR and USP,
      are present. Furthermore, we demonstrate that under these conditions, EcR/USP
      form a unique complex on inverted repeat elements (PAL1 and hsp27-EcRE), while on
      direct repeat elements (DR1-5), a second complex with higher mobility is formed.
      In this second complex, neither EcR nor USP are present. Thus, an additional
      difference between PAL1 and DR-elements is the competition of other factors for
      DR-elements, modulating its function as an EcRE. A competition EMSA, using PAL1
      as radiolabeled probe, reveals the following order of binding strength:
      PAL1>DR4/5>DR1>DR2/3/hsp27. Surprisingly, using DR1 as radiolabeled probe, shows
      a different order of binding strength: DR1>DR2>DR3/4/5/PAL1>hsp27. This indicates
      that the complexes formed on PAL1 are not identical to the ones formed on DR1 and
      that both are not easily convertible. Furthermore, the affinity of the EcR/USP
      complex may be altered under various conditions or by interaction with cofactors.
      Upon hormone administration, DNA binding of the receptor complex is enhanced, but
      the difference to hormone-free binding reactions decreases in course of time,
      indicating an additional hormone independent activation. Arch.

PMID- 10398336
TI  - Ecdysteroids during ovarian development and embryogenesis in solitary and
      gregarious schistocerca gregaria 
AB  - Maternal ecdysteroids identified in the vitellogenic oocytes of Schistocerca
      gregaria included more than 80% polar conjugates, up to 5% free ecdysteroids, and
      up to 15% non-hydrolyzable polar metabolites. The representations of ecdysone
      (E), 20-hydroxyecdysone (20E), and 2-deoxyecdysone (2dE) in the conjugates was
      about 16:3:1, and in the free ecdysteroids about 3:1:1. The quantity of
      ecdysteroids in the ovaries before egg-laying reached 2.3 ng 20E equiv. per mg
      tissue in the solitary, and 8.9 ng/mg in the gregarious females. Newly laid eggs
      contained 14 ng and 89 ng, respectively, of 20E equiv. per egg. Nearly all egg
      ecdysteroids were in form of conjugates and their content declined during the
      first half of embryonic development. The amount of ecdysteroids sharply increased
      to over 70 ng 20E equiv./egg in the solitary, and to nearly 400 ng/egg in the
      gregarious phase. In the second half of embryonic development, the representation
      of conjugates in total ecdysteroids was reduced to 45-55%, whereas that of free E
      + 20E rose to 30-40%. Free 2dE remained low but, in the gregarious embryos, free
      26E increased to 10% of all ecdysteroids. The conjugates of solitary embryos
      contained nearly exclusively E and 20E (in ratio 2:1), whereas those of the
      gregarious embryos included E, 20E, 2dE, and 26E (in ratio 12:7:4:1). Towards the
      end of embryonic development, the amounts of conjugates and of free ecdysteroids
      decreased, while that of polar metabolites rose. A sharp drop in ecdysteroid
      content was associated with hatching but the more than five times higher
      ecdysteroid level in the gregarious than in the solitary phase was maintained in
      the newly hatched larvae. Arch. Copyright 1999 Wiley-Liss, Inc.

PMID- 10398337
TI  - Lung local defense in experimental diabetes mellitus and the effect of 11,20
      dihydroxyecdysone in combination with maninil.
AB  - Disorders of lung local defensive mechanisms were noted in rats with alloxane
      induced diabetes mellitus, which showed itself as neutrophilic infiltration and
      decrease of macrophagal bactericidal action in the lungs. All this contributed to
      the development and chronization of bronchopulmonary inflammatory diseases. Use
      of maninil caused further inhibition of cellular and humoral lung immunity
      indices. Addition of 11,20-dihydroxyecdysone (turkesterone) to the therapy
      resulted in positive changes in the lung defense mechanisms. Arch.

PMID- 10398338
TI  - Ecdysteroid biosynthesis in crayfish Y-organs: feedback regulation by circulating
      ecdysteroids 
AB  - In crustaceans, ecdysteroid synthesis in the Y-organs is negatively regulated by
      the molt-inhibiting hormone (MIH). Reduction or cessation of MIH release from the
      sinus gland in the eyestalk, probably due to environmental cues, is one of
      possibly several signals for an increase of edysteroid production and
      subsequently enhancement of 20-hydroxyecdysone (20E) levels in the hemolymph. The
      present study asks the question whether the 20E peak in premoult stages D2/D3 is
      explained solely bythe cessation of MIH release or whether positive feedback
      mechanisms are also involved. Ecdysteroid production by the Y-organ of the
      crayfish Orconectes limosus was found to be under negative feedback control by
      circulating ecdysteroids. Exogenous 20-hydroxyecdysone (20E) as well as RH-5849,
      a non-steroidal ecdysteroid agonist, reduced ecdysteroid synthesis significantly
      when injected into intermoult animals. A direct, short loop inhibitory feedback
      effect was demonstrated by in vitro incubations of Y-organs with RH-5849. Thus,
      the results presented here do not point to a stimulatory effect of 20E on Y-organ
      activity but suggest that during intermolt a negative feedback by ecdysteroids
      plays a role in addition to MIH. Arch. Copyright 1999 Wiley-Liss, Inc.

PMID- 10398339
TI  - 20-hydroxyecdysone as a human lymphocyte and neutrophil modulator: In vitro
      evaluation.
AB  - 20-hydroxyecdysone (1 microM) was found to activate in vitro T-cell CD2
      presentation, which is suppressed both in secondary immunodeficient persons and
      pharmacologically by increasing intracellular cAMP levels. The compound was found
      to act like a synthetic psycho-immunomodulator 1-oxy-4-oxoadamantane (1 microM)
      and to exceed the effects of the thymomimetic agent levamisol (1 microM). In
      addition, 20-hydroxyecdysone (1 microM) was also revealed to modulate the
      fluoride-stimulated respiratory burst of human neutrophils in the same manner as
      water soluble antioxidants. Arch.

PMID- 10398340
TI  - HPLC method for the analysis of acetonides of ecdysteroids providing structural
      information on different vicinal diols 
AB  - The polyhydroxy structure of ecdysteroids provides a basis for the formation of
      various derivatives including the acetonides that have been frequently prepared
      mainly in preparative work. Acetonides can be formed between vicinal diols in cis
      position such as positions C-2/C-3 and C-20/C-22 in 20-hydroxyecdysone, for
      example. We have modified an established procedure for the preparation of
      acetonides, employing a higher concentration of phosphomolybdic acid as a
      catalyst, and developed a reverse-phase HPLC method to analyze the products on a
      micro scale. The derivatization method is fast, taking minutes or less, and does
      not produce artifacts. Thirteen structurally diverse ecdysteroids were studied in
      detail concerning speed of acetonide formation, and the number and type of
      intermediate and end products. Mass spectrometry coupled to HPLC was employed to
      confirm and/or identify ecdysteroids and their acetonide derivatives. Analysis of
      the chromatographic profiles revealed that detailed information on vicinal diols
      of ecdysteroids can be derived from the differences in retention times
      (Deltar.t.)1 of products relative to the parent steroids on reverse-phase HPLC
      using a linear water/methanol gradient for elution. The specific Deltar.t. values
      characterize a product as a monoacetonide, a diacetonide, or a triacetonide.
      Furthermore, this chromatographic shift upon acetonide formation is significantly
      different among the various monoacetonides and, thus, specific for the site on
      the ecdysteroid molecule. The same seems to hold for diacetonides. As variation
      of the Deltar.t. values for a specific type of acetonide was rather small among
      the tested ecdysteroids, the results should provide reliable structural
      information. Muristerone A did not completely fit this common pattern. However,
      this may specify its uncommon ecdysteroid structure. The method has recently been
      successfully employed to solve the structures of new ecdysteroid metabolites.
      Arch. Copyright 1999 Wiley-Liss, Inc.

PMID- 10398341
TI  - XIIIth ecdysone workshop 

PMID- 10398342
TI  - Specific negative effects resulting from elevated levels of the recombinational
      repair protein Rad54p in Saccharomyces cerevisiae.
AB  - RAD54 is an important gene in the RAD52 group that controls recombinational
      repair of DNA damage in Saccharomyces cerevisiae. Rad54p is a DNA-dependent
      ATPase and shares seven conserved sequence motifs with proteins of the
      Swi2p/Snf2p family. Genetic analysis of mutations in motif IA, the putative ATP
      binding fold of Rad54p, demonstrated the functional importance of this motif.
      Overexpression of these mutant proteins resulted in strong, dominant-negative
      effects on cell survival. High levels of full-length wild-type Rad54p or specific
      parts of Rad54p also resulted in negative effects, dependent on the ploidy of the
      host cell. This differential effect was not under a/alpha mating-type control.
      Deletion of the RAD54 gene led to a small but significant increase in the
      mutation rate. However, the negative overexpression effects in haploid cells
      could not be explained by an accumulation of (recessive) lethal mutations. All
      negative overexpression effects were found to be enhanced under genotoxic stress.
      We suggest that the negative overexpression effects are the result of unbalanced
      protein-protein interactions, indicating that Rad54p is involved in multiple
      interactions, dependent on the physiological situation. Diploid wild-type cells
      contained an estimated 7000 Rad54p molecules/cell, whereas haploid cells about
      3500/cell. Rad54p levels were highest in actively growing cells compared to
      stationary phase cells. Rad54 protein levels were found to be elevated after DNA
      damage.

PMID- 10398343
TI  - The Hansenula polymorpha PDD1 gene product, essential for the selective
      degradation of peroxisomes, is a homologue of Saccharomyces cerevisiae Vps34p.
AB  - Via functional complementation we have isolated the Hansenula polymorpha PDD1
      gene essential for selective, macroautophagic peroxisome degradation. HpPDD1
      encodes a 116 kDa protein with high similarity (42% identity) to Saccharomyces
      cerevisiae Vps34p, which has been implicated in vacuolar protein sorting and
      endocytosis. Western blotting experiments revealed that HpPDD1 is expressed
      constitutively. In a H. polymorpha pdd1 disruption strain peroxisome degradation
      is fully impaired. Sequestered peroxisomes, typical for the first stage of
      peroxisome degradation in H. polymorpha, were never observed, suggesting that
      HpPdd1p plays a role in the tagging of redundant peroxisomes and/or sequestration
      of these organelles from the cytosol. Possibly, HpPdd1p is the functional
      homologue of ScVps34p, because-like S. cerevisiae vps34 mutants-H. polymorpha
      pdd1 mutants are temperature-sensitive for growth and are impaired in the sorting
      of vacuolar carboxypeptidase Y. Moreover, HpPdd1p is associated to membranes, as
      was also observed for ScVps34p.

PMID- 10398344
TI  - Characteristics of the heterologously expressed human lanosterol 14alpha
      demethylase (other names: P45014DM, CYP51, P45051) and inhibition of the purified
      human and Candida albicans CYP51 with azole antifungal agents.
AB  - Human and Candida albicans CYP51 were purified to homogeneity after GAL10-based
      heterologous expression in yeast in order to resolve the basis for the selective
      inhibition of the fungal enzyme over the human orthologue by the azole drugs
      ketoconazole and itraconazole, used in the treatment of systemic fungal
      infection. The purified proteins have similar spectral characteristics, both
      giving a maximum at 448 nm in reduced carbon monoxide difference spectra.
      Substrate affinity constants of 20.8 and 29.4 microM and Vmax of 0. 15 and 0.47
      nmol/min/nmol were observed for C. albicans and human enzymes, respectively, in
      reconstituted enzymatic assays, using an intermediate of the demethylation
      reaction [32-3H]-3beta-hydroxylanost-7-en-32-ol as the substrate. Both enzymes
      gave similar type II spectra on titration with drugs, but a reduced affinity was
      observed for human CYP51 using the ability of carbon monoxide to displace the
      drug as a ligand and by calculation of IC50. However, although the results
      indicate higher affinity of the drugs for their target CYP51 in the major fungal
      pathogen C. albicans, when compared directly to CYP51 from humans, the difference
      was less than 10-fold. This difference is an order of magnitude lower than
      previously reported data based on measurements using unpurified human CYP51
      enzyme preparations. Consequently, increased azole doses to combat resistant
      candidaemia may well inhibit endogenous human CYP51 and the potential
      consequences are discussed.

PMID- 10398345
TI  - Combining mutations in the incoming and outgoing pheromone signal pathways causes
      a synergistic mating defect in Saccharomyces cerevisiae.
AB  - Mating pheromones stimulate Saccharomyces cerevisiae yeast cells to form a
      pointed projection that becomes the site of cell fusion during conjugation. To
      investigate the role of mating projections, we screened for mutations that
      enhanced the weak mating defect of MATa ste2-T326 cells that are defective in
      forming pointed projections. These cells are also 10-fold more sensitive to alpha
      factor pheromone because ste2-T326 encodes truncated alpha-factor receptors that
      are not regulated properly. Mutations in AXL1, STE6 and FUS3 were identified in
      the screen. AXL1 was studied further because it is required for efficient a
      factor pheromone production and for selecting the site for bud morphogenesis.
      Mutation of AXL1 did not enhance the morphogenesis or pheromone sensitivity
      defects of ste2-T326. Instead, the synergistic mating defect was apparently due
      to decreased a-factor production because the axl1Delta ste2-T326 cells mated well
      with a sst2 alpha mating partner that is supersensitive to a-factor. When
      combined with a wild-type mating partner, the ste2-T326 axl1Delta cells failed to
      mate because they did not lock cell walls, one of the earliest steps in
      conjugation. Analysis of axl1Delta in combination with other mutations that cause
      defects in morphogenesis or pheromone sensitivity (e.g. bar1, sst2, afr1)
      indicated that both phenotypes of ste2-T326 cells, supersensitivity to alpha
      factor and the defect in forming pointed projections, contributed to the
      synergistic mating defect. We suggest a model that the synergistic mating defect
      is caused by the combined effects of ste2-T326 and axl1Delta on the presentation
      of a-factor to partner cells. Altogether, these results demonstrate an important
      linkage between the incoming and outgoing pheromone signals during the
      intercellular communication that promotes yeast mating.

PMID- 10398346
TI  - Linear DNA plasmid pPK2 of Pichia kluyveri: distinction between cytoplasmic and
      mitochondrial linear plasmids in yeasts.
AB  - The linear plasmids frequently found in plants and filamentous fungi are
      associated with mitochondria or chloroplasts. In contrast, all the linear
      plasmids known in yeasts are cytoplasmic elements. From a strain of the yeast
      Pichia kluyveri, we have isolated a new linear plasmid, pPK2, which was found to
      be associated with mitochondria. This 7.1 kilobase pairs-long DNA contained only
      two genes, which code for DNA and RNA polymerases, as judged from their
      nucleotide sequences translated by a mitochondrial genetic code. When we examined
      several recently isolated yeast plasmids for their subcellular localization, we
      found that two linear plasmids, pPH1 from Pichia heedii, as well as pPK1 from
      another strain of P. kluyveri, were also localized in mitochondria. These
      plasmids are the first examples of mitochondria-associated linear plasmids in
      yeast. All other linear plasmids we examined were of cytoplasmic origin. Whilst
      the cytoplasmic type linear plasmids were efficiently eliminated by ultraviolet
      irradiation of host cells, the mitochondria-associated plasmids were highly
      resistant. The mitochondrial pPK2 plasmid was rapidly lost by treatment of the
      host cells with ethidum bromide.

PMID- 10398347
TI  - Cloning of a centromere binding factor 3d (CBF3D) gene from Candida glabrata.
AB  - The gene encoding centromere binding factor 3d (CBF3D) of the human pathogenic
      yeast Candida glabrata has been isolated by hybridization of Saccharomyces
      cerevisiae CBF3D (ScCBF3D) DNA to a C. glabrata partial genomic library. Sequence
      analysis revealed a 540 bp open reading frame encoding a protein of 179 amino
      acids with a calculated molecular mass of 20.9 kDa. The amino acid sequence is
      highly homologous (78.6% identity) to ScCbf3d and 48.3% identical to the human
      homologue p19 (SKP1). Southern blot analysis indicates that CgCbf3d is encoded by
      an unique nuclear gene. The cloned CgCBF3D gene can functionally substitute the
      S. cerevisiae homologue in a S. cerevisiae CBF3D-deletion mutant. The GenBank
      Accession No. for this gene is AF 072472.

PMID- 10398348
TI  - Isolation of a Histoplasma capsulatum cDNA that complements a mitochondrial
      NAD(+)-isocitrate dehydrogenase subunit I-deficient mutant of Saccharomyces
      cerevisiae.
AB  - A cDNA library was prepared from Histoplasma capsulatum strain G-217B yeast cells
      and an apparently full-length cDNA for a subunit of the citric acid cycle enzyme
      NAD(+)-isocitrate dehydrogenase was identified by sequence analysis. Its
      predicted amino acid sequence is more similar to the IDH1 regulatory subunit of
      S. cerevisiae NAD(+)-isocitrate dehydrogenase than to the IDH2 catalytic subunit.
      After expression in S. cerevisiae from an S. cerevisiae promoter, it was shown to
      functionally complement an S. cerevisiae idh1 mutant, but not an idh2 mutant, for
      growth on acetate as a carbon source and for production of NAD(+)-isocitrate
      dehydrogenase enzyme activity. These results confirm that the H. capsulatum cDNA
      encodes a homologue of subunit I of the S. cerevisiae mitochondrial isocitrate
      dehydrogenase isozyme that functions in the citric acid cycle.

PMID- 10398349
TI  - Prevalence and correlates of Capgras syndrome in Alzheimer's disease.
AB  - OBJECTIVES: This study examined the prevalence and clinical correlates of Capgras
      syndrome (CS) in Alzheimer's disease. DESIGN: Cross-sectional study of elderly
      patients evaluated at an outpatient memory disorders clinic classified according
      to the presence or absence of CS. SUBJECTS: One hundred and fifty-one consecutive
      patients diagnosed with probable (N=110) or possible (N=48) Alzheimer's disease
      (AD) utilizing NINCDS-ADRDA diagnostic criteria. MATERIALS: The Behavioral
      Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), Mini-Mental State
      Examination (MMSE) and Blessed Dementia Scale (BDS). RESULTS: CS was observed in
      10% of the sample (N=16). Associated factors included other delusions, lower MMSE
      scores and higher BDS scores. The relation between CS and both cognitive and
      functional status remained significant after controlling for other delusions.
      CONCLUSION: CS was prevalent in approximately 10% of our community-dwelling AD
      sample. This syndrome was more common at the later stages of the illness and
      showed relations with increased functional impairment and other psychotic
      symptomatology.

PMID- 10398350
TI  - Assessing the pain of people with cognitive impairment.
AB  - This review presents evidence of the undertreatment of pain for people with
      cognitive impairment and explores reasons for this, emphasizing inadequate
      detection due to lack of suitable pain assessment protocols. Implications for
      practice and suggestions for further research are made.

PMID- 10398351
TI  - An overview of behaviour difficulties found in long-term elderly care settings.
AB  - STUDY OBJECTIVE: To provide an understanding of the nature and prevalence of
      behaviour difficulties in long-term care facilities, to compare care settings and
      comment on the appropriateness of the need for specialist care. DESIGN: Nurses or
      carers implemented two rating scales in randomly selected settings. SETTING:
      Nursing homes, residential homes and NHS elderly long-stay wards. SUBJECTS:
      Elderly long-stay patients. MAIN RESULTS: NHS and nursing home long-term care
      facilities show similar behaviour difficulties, with nursing homes experiencing
      more behaviour manifestations in most cases. Residential facilities have
      behaviour difficulties to a lesser extent. CONCLUSIONS: Nursing homes have
      limited formal psychiatric intervention compared to NHS settings. Behaviour
      difficulties result in increased work for general practitioners and increased
      hospital referrals. More prospective research is required into the antecedents,
      effects and treatments of patients with behaviour difficulties in nursing homes.
      For example, it may be appropriate that specialist input is provided for nursing
      homes in order to implement behaviour intentions and contribute to the reduction
      of GP callouts and pharmacological interventions.

PMID- 10398352
TI  - Using an annual over-75 health check to screen for depression: validation of the
      short Geriatric Depression Scale (GDS15) within general practice.
AB  - OBJECTIVE: To validate the short Geriatric Depression Scale (GDS15) as a
      screening instrument and determine the optimal cutpoint for detecting depression
      among older people living in the community. DESIGN: Two stage study with the
      first stage consisting of a health check of people aged 75 years and over by a
      practice nurse which included the GDS15. A second-stage diagnostic interview
      including the criterion standard was carried out blind to GDS15 score. SETTING: A
      large general practice in Melton Mowbray, Leicestershire, UK. PATIENTS: A random
      sample (stratified according to first-stage GDS15 score) of 257 older people
      living in the community, without significant cognitive impairment, were selected
      for the second-stage diagnostic interview. MEASURES: The first-stage GDS15 score
      was compared with diagnostic status for depression and anxiety disorders
      (according to ICD-10 criteria) and presence of depressive symptoms at the second
      stage clinical interview. RESULTS: Ninety-three per cent of those eligible for
      the study were successfully screened with the GDS15. A cutpoint of <3/3+ had a
      sensitivity of 100% and specificity of 72% in detecting cases of depression but
      fewer than one in five of those testing positive reached a diagnostic threshold.
      Only 25% of those with a diagnosis of depression had any mention of mental health
      problems in their medical notes in the year prior to the clinical interview. For
      detecting depressive symptoms the same cutpoint was 79% sensitive and 78%
      specific with a positive predictive value of 46%. CONCLUSIONS: Used as part of an
      annual over-75 health check in primary care, the GDS15 would detect a significant
      amount of hidden morbidity which would serve the original purpose of the annual
      elderly health checks in the UK.

PMID- 10398353
TI  - Dysthymia among the community-dwelling elderly.
AB  - There are few data on the clinical features of dysthymia among the community
      dwelling elderly. Forty elderly individuals with dysthymic disorder were
      identified following screening in the community with GMS-AGECAT. A detailed
      clinical history was obtained and DSM-IV checklists and standardized scales were
      used, at a second interview. Comparisons were made with a group of 630 non
      depressed elderly from the same community. Dysthymia was predominately of late
      onset (93%) and associated with a major stressor in 65% of cases. Comorbid axis 1
      disorders were present in 15% of dysthymics and an axis 2 disorder in 10%. The
      dysthymic group had significantly higher degrees of physical impairment than the
      non-depressed elderly. The symptom profile demonstrated prominent anxiety and
      functional features. Eighty-three per cent of the elderly with dysthymia had
      presented to their GP with anxiety/depressive symptoms at some stage during the
      dysthymic disorder. The presentation of dysthymia in older people differs from
      that in earlier life. Late life dysthymia is less associated with axes 1 and 2
      comorbidity but is associated with significant degrees of physical impairment.
      Dysthymia in older people presents to primary care, rather than specialist
      services, and interventions must be delivered at this level.

PMID- 10398354
TI  - The characteristics of Indian subcontinent origin elders newly referred to a
      psychogeriatric service.
AB  - BACKGROUND: The ethnic elderly population in the United Kingdom is increasing.
      Clinical, social and demographic characteristics of ethnic elders referred to and
      utilizing psychogeriatric services are unknown. Thus, this study was designed to
      compare these characteristics between Indian subcontinent origin ethnic elders
      and indigenous elders newly referred to a psychogeriatric service. METHOD: All
      new referrals to a psychogeriatric service over a 2-year period were examined.
      Clinical, social and demographic characteristics of Indian subcontinent origin
      ethnic elders were compared with those of indigenous elders. RESULTS: Ethnic
      elders were younger, had more children, had more people living in their
      household, were more likely to be married, were less likely to live alone, were
      more likely to have schizophrenia and less likely to have dementia. There were no
      differences between the two groups with regard to use of almost all health and
      social services resources at the time of the referral and after the initial
      assessment. CONCLUSIONS: These findings do not support the traditional view that
      ethnic elders do not adequately access psychogeriatric and social services and
      that they are primarily cared for by extended families.

PMID- 10398355
TI  - Ten-point clock test sensitivity for Alzheimer's disease in patients with MMSE
      scores greater than 23.
AB  - The ten-point clock test is administered by tracing an 11.4 cm (4 1/2 inch)
      diameter circle on a piece of paper and asking the patient to 'Write the numbers
      in the face of a clock'. The patient is then asked to 'Make the clock say 10
      minutes after 11'. The spacing of the numbers and the positions of the hands are
      used to score the test. A score of less than eight points identified 71% of
      patients with Alzheimer's disease who had a Mini-Mental State Examination score
      of greater than 23. The specificity measured in elderly controls was 82%. The
      test may prove useful in screening for early stage Alzheimer's disease.

PMID- 10398356
TI  - Olanzapine in dementia with Lewy bodies: a clinical study.
AB  - OBJECTIVES: Dementia with Lewy bodies (DLB) is now a well-recognized form of
      dementia in which psychosis and behavioural disturbance are common. Treatment
      with conventional neuroleptics is often very poorly tolerated. Olanzapine, a
      newly introduced atypical neuroleptic which binds to multiple receptor types with
      relatively low affinity for D2 receptors, may be a useful treatment option in
      DLB. MAIN OUTCOME MEASURES: The Behavioural Pathology in Alzheimer's Disease
      Rating Scale, The Neuropsychiatric Inventory, Unified Parkinson's Disease Rating
      Scale and The Webster Disability Scale. DESIGN: We present the results of eight
      DLB patients with associated psychotic and behavioural difficulties. All patients
      were given olanzapine 2.5-7.5 mg. Their psychotic phenomena and behavioural and
      extrapyramidal symptoms were monitored at 2-weekly intervals. RESULTS: Three out
      of the eight patients could not tolerate olanzapine even at the lowest available
      dose. Two patients had clear improvement in psychotic and behavioural symptoms.
      Three patients were able to tolerate olanzapine but gained only minimal benefit.
      CONCLUSIONS: Olanzapine at the doses used conferred little advantage over
      conventional neuroleptics and should only be given with great caution to patients
      with DLB. The utility of smaller doses deserves further evaluation.

PMID- 10398357
TI  - Drug treatment of older people with affective disorders in the community: lessons
      from an attempted clinical trial.
AB  - BACKGROUND: Depression and phobic anxiety disorders are the most common
      psychiatric disorders in people aged 65 and over. SSRI antidepressants are
      effective in treating both conditions in younger people, and in treating
      depression in hospital samples of older subjects. No studies have investigated
      the efficacy of SSRIs in older people with these conditions living in the
      community. OBJECTIVES: To evaluate the efficacy and feasibility of treating older
      people suffering from depression and/or phobic anxiety in the community with
      fluoxetine alone. DESIGN: Subjects identified as depressed and/or anxious at
      screening were offered open-label fluoxetine and were reassessed for affective
      illness at 3 and 6 months. MEASURES: Outcome was assessed using the depression
      subscale of the Short Comprehensive Assessment and Referral Evaluation (Short
      CARE) Scale and the Anxiety Disorder Scale. RESULTS: Of 67 subjects with
      depression and/or phobic anxiety, 55 (81%) were eligible to take fluoxetine.
      Fifty-four (98%) of these agreed to follow-up but only six (11%) agreed to take
      medication. No subject was still taking medication by the end of the study. Among
      those subjects on whom follow-up data were available, 70% of subjects depressed
      at screening and 97% of those with phobic anxiety retained their diagnoses at 3
      months; at 6 months, the figures were 65% and 92% respectively. CONCLUSIONS: Drug
      treatment alone is not acceptable to older patients in the community with
      depression and phobic anxiety disorders. Discussion of symptoms with an
      appropriate professional is insufficient therapy on its own. Further work is
      needed to evaluate the effectiveness of a key worker such as a mental health
      nurse in coordinating treatment of patients with these disorders.

PMID- 10398358
TI  - The Even Briefer Assessment Scale for Depression (EBAS DEP): its suitability for
      the elderly in geriatric care in English- and German-speaking countries.
AB  - OBJECTIVES: To determine the psychometric properties of the Even Briefer
      Assessment Scale for Depression (EBAS DEP) developed by Allen et al. (1994) among
      samples of the German elderly and compare the results with those from English
      speaking countries. DESIGN: Depression scale scores from elderly persons in
      residential and gerontopsychiatric care were assessed for internal consistency
      using Cronbach's alpha and validity (Feighner Criteria of Depression and Center
      for Epidemiologic Studies Depression Scale). SUBJECTS: Eight hundred and fifty
      two elderly persons aged 65 years and over, in residential and gerontopsychiatric
      care. MATERIALS: The eight-item Even Briefer Assessment Scale for Depression
      (EBAS DEP) derived from the 21-item Brief Assessment Scale (BAS DEP). RESULTS:
      The analysis of the reliability of the German EBAS DEP yielded, as did that of
      the English version, a satisfactorily high internal consistency (0. 73 and
      higher). Based on a subset of 71 subjects, the validity of the scale was tested
      by independent psychiatric experts using the Feighner Criteria of Depression. The
      EBAS DEP (cutoff 3/4) had a sensitivity and specificity for a diagnosis of
      depression of 93.3% and 85.3%, respectively. Similar results were reported by
      Allen et al., but at a lower cutoff (2/3). In agreement with the English
      findings, the receiver operating curve (ROC) statistics revealed that the EBAS
      DEP is a screening instrument which is as efficient as the longer BAS DEP.
      CONCLUSION: The EBAS DEP is an instrument well suited for use in screening the
      depressed elderly in different care settings in English- and German-speaking
      countries.

PMID- 10398360
TI  - Divalproex for the treatment of geriatric bipolar disorder.
AB  - Divalproex is now commonly used to treat bipolar disorder in older patients.
      However, it has yet to be systematically studied in this population. This report
      describes six older bipolar patients treated with divalproex. Of the six, five
      showed some improvement with divalproex alone or in combination with other
      agents. Clearly, a double-blind, placebo-controlled study is an important next
      step to assess this promising medication.

PMID- 10398359
TI  - Rates of dementia in three ethnoracial groups.
AB  - BACKGROUND: Rates of dementia may vary among ethnoracial groups. Any real and
      substantial such difference would merit serious attention by health planners,
      clinicians and those seeking to advance our understanding of the etiology of this
      group of disorders. METHODS: Randomly selected elderly persons from each of three
      ethnoracial groups (Latinos, African-Americans, non-Latino Whites) residing in a
      geographic area of northern Manhattan in New York City were screened for dementia
      and assessed with respect to functioning in daily tasks and other qualities of
      life. Systematic samples of each group were clinically evaluated for presence and
      subtype of dementia. Subjects were reassessed at an average of 18 months
      following the baseline interview. RESULTS: Age-specific prevalence of dementia
      was found to be higher in Latinos and African-Americans than in non-Latino
      Whites; incidence rates were consistent with this finding. Ethnoracial groups did
      not vary in the proportion of dementias diagnosed as Alzheimer's disease.
      Prevalence differences between ethnoracial groups remained consistent as
      diagnostic criteria were varied in breadth and when the possible mislabelling of
      depression was taken into account. However, level of education was strongly
      associated with rates of dementia and, when age and education were simultaneously
      controlled, the ethnoracial differences in rates were not consistently found.
      CONCLUSIONS: Planning for the wide range of services necessary for care of those
      suffering from dementia should take into account ethnoracial differences in
      rates. The higher rates found in Latino and African-American groups, relative to
      non-Latino Whites, are associated with clear and substantial functional
      dependencies and hence have important implications for qualities of life and
      service needs.

PMID- 10398361
TI  - Impact of chronic systemic and neurological disorders on disability, depression
      and life satisfaction 

PMID- 10398362
TI  - Oleg borisovich ptitsyn: july 18, 1929-march 22, 1999 

PMID- 10398363
TI  - The effect of inhibitor binding on the structural stability and cooperativity of
      the HIV-1 protease.
AB  - The effects of the peptide inhibitor acetyl pepstatin on the structural stability
      of the HIV-1 protease have been measured by high sensitivity calorimetric
      techniques. At 25 degrees C and pH 3.6, acetyl pepstatin binds to HIV-1 protease
      with an affinity of 1.6 x 10(7 )M-1 and an enthalpy of 7.3 +/- 0.5 kcal/mol,
      indicating that binding is not favored enthalpically and that the favorable Gibbs
      energy originates from a large positive entropy. Since the binding of acetyl
      pepstatin is associated with a negative change in heat capacity (-450 cal/K*mol)
      the association reaction becomes enthalpically favored at temperatures higher
      than 40 degrees C. The presence of the inhibitor stabilizes the dimeric structure
      of the protease in a fashion that can be quantitatively described by a set of
      thermodynamic linkage equations. The combination of titration and differential
      scanning calorimetry provides an accurate way of determining binding constants
      for high affinity inhibitors that cannot be determined by titration calorimetry
      alone. A structure-based thermodynamic analysis of the binding process indicates
      that the stabilization effect is not distributed uniformly throughout the
      protease molecule. The binding of the inhibitor selectively stabilizes those
      conformational states in which the binding site is formed, triggering a
      redistribution of the state probabilities in the ensemble of conformations
      populated under native conditions. As a result, the stability constants for
      individual residues do not exhibit the same change in magnitude upon inhibitor
      binding. Residues in certain areas of the protein are affected significantly
      whereas residues in other areas are not affected at all. In particular, inhibitor
      binding has a significant effect on those regions that define the binding site,
      especially the flap region which becomes structurally stable as a result of the
      additional binding free energy. The induced stabilization propagates to regions
      not in direct contact with the inhibitor, particularly to the strand between
      residues Pro9 and Ala22 and the helix between Arg87 and Gly94. On the other hand,
      the stability of the strand between Asp60 and Leu76 is not significantly affected
      by inhibitor binding. The structural distribution of binding effects define
      cooperative pathways within the protease molecule. Proteins 1999;36:147-156.

PMID- 10398365
TI  - Conformational dynamics of cytochrome c: correlation to hydrogen exchange.
AB  - We study the dynamical fluctuations of horse heart cytochrome c by molecular
      dynamics (MD) simulations in aqueous solution, at four temperatures: 300 K, 360
      K, 430 K, and 550 K. Each simulation covers a production time of at least 1.5
      nanoseconds (ns). The conformational dynamics of the system is analyzed in terms
      of collective motions that involve the whole protein, and local motions that
      involve the formation and breaking of intramolecular hydrogen bonds. The
      character of the MD trajectories can be described within the framework of rugged
      energy landscape dynamics. The MD trajectories sample multiple conformational
      minima, with basins in protein conformational space being sampled for a few
      hundred picoseconds. The trajectories of the system in configurational space can
      be described in terms of diffusion of a particle in real space with a waiting
      time distribution due to partial trapping in shallow minima. As a consequence of
      the hierarchical nature of the dynamics, the mean square displacement
      autocorrelation function, <|x(t) - x(0)|2>, exhibits a power law dependence on
      time, with an exponent of around 0.5 for times shorter than 100 ps, and an
      exponent of 1.75 for longer times. This power law behavior indicates that the
      system exhibits suppressed diffusion (sub-diffusion) in sampling of
      configurational space at time scales shorter than 100 ps, and enhanced (super
      diffusion) at longer time scales. The multi-basin feature of the trajectories is
      present at all temperatures simulated. Structural changes associated with inter
      basin displacements correspond to collective motions of the Omega loops and
      coiled regions and relative motions of the alpha-helices as rigid bodies. Similar
      motions may be involved in experimentally observed amide hydrogen exchange.
      However, some groups showing large correlated motions do not expose the amino
      hydrogens to the solvent. We show that large fluctuations are not necessarily
      correlated to hydrogen exchange. For example, regions of the proteins forming
      alpha helices and turns show significant fluctuations, but as rigid bodies, and
      the hydrogen bonds involved in the formation of these structures do not break in
      proportion to these fluctuations. Proteins 1999;36:175-191. Published 1999 Wiley
      Liss, Inc.

PMID- 10398364
TI  - Protein strain in blue copper proteins studied by free energy perturbations.
AB  - Free energy perturbations have been performed on two blue copper proteins,
      plastocyanin and nitrite reductase. By changing the copper coordination geometry,
      force constants, and charges, we have estimated the maximum energy with which the
      proteins may distort the copper coordination sphere. By comparing this energy
      with the quantum chemical energy cost for the same perturbation on the isolated
      copper complex, various hypotheses about protein strain have been tested. The
      calculations show that the protein can only modify the copper-methionine bond
      length by a modest amount of energy-<5 kJ/mol-and they lend no support to the
      suggestion that the quite appreciable difference in the copper coordination
      geometry encountered in the two proteins is a result of the proteins enforcing
      different Cu-methionine bond lengths. On the contrary, this bond is very
      flexible, and neither the geometry nor the electronic structure change
      appreciably when the bond length is changed. Moreover, the proteins are rather
      indifferent to the length of this bond. Instead, the Cu(II) coordination
      geometries in the two proteins represent two distinct minima on the potential
      surface of the copper ligand sphere, characterized by different electronic
      structures, a tetragonal, mainly sigma-bonded, structure in nitrite reductase and
      a trigonal, pi-bonded, structure in plastocyanin. In vacuum, the structures have
      almost the same energy, and they are stabilized in the proteins by a combination
      of geometric and electrostatic interactions. Plastocyanin favors the bond lengths
      and electrostatics of the trigonal structure, whereas in nitrite reductase, the
      angles are the main discriminating factor. Proteins 1999;36:157-174.

PMID- 10398366
TI  - Probing the modelled structure of wheatwin1 by controlled proteolysis and
      sequence analysis of unfractionated digestion mixtures.
AB  - We set up a method to get rapid information on the three-dimensional structure of
      peptide and proteins of known sequence. Both native and alkylated polypeptide is
      hydrolyzed with a number of proteases at different digestion times and the
      resulting mixtures are compared by HPLC analysis to establish the differences in
      the hydrolysis pathways of the folded and unfolded molecule. Then, the
      unfractionated digestion mixtures of the native polypeptide are submitted to
      automatic sequence analysis to identify the hydrolysis sites. The sequence of
      each fragment present in the mixtures is reconstructed and its amount determined
      by quantitative data of the sequence analyses. We used this approach to determine
      the amino acid surface accessibility of wheatwin1, a pathogenesis-related protein
      from wheat, and constructed a predictive three-dimensional model based on the
      knowledge of the tertiary structure of barwin, a highly homologous protein from
      barley. The procedure allowed us to quickly identify and quantify the hydrolysis
      at the susceptible bonds which could be classified as exposed, partially hidden,
      or inaccessible. The results were useful to evidentiate and discuss concordances
      and differences between experimental and model predicted accessibilities of amino
      acid residues. Proteins 1999;36:192-204.

PMID- 10398367
TI  - Differences in the effects of TFE on the folding pathways of human stefins A and
      B.
AB  - Trifluoroethanol (TFE) has been used to probe differences in the stability of the
      native state and in the folding pathways of the homologous cysteine protein
      inhibitors, human stefin A and B. After complete unfolding in 4.5 mol/L GuHCl,
      stefin A refolded in 11% (vol/vol) TFE, 0.75 mol/L GuHCl, at pH 6.0 and 20
      degrees C, with almost identical first-order rate constants of 4.1 s-1 and 5.5 s
      1 for acquisition of the CD signal at 230 and 280 nm, respectively, rates that
      were markedly greater than the value of 0.11 s-1 observed by the same two probes
      when TFE was absent. The acceleration of the rates of refolding, monitored by
      tyrosine fluorescence, was maximal at 10% (vol/vol) TFE. Similar rates of
      refolding (6.2s-1 and 7.2 s-1 for ellipticity at 230 and 280 nm, respectively)
      were observed for stefin A denatured in 66% (vol/vol) TFE, pH 3.3, when refolding
      to the same final conditions. After complete unfolding in 3.45 mol/L GuHCl,
      stefin B refolded in 7% (vol/vol) TFE, 0.57 mol/L GuHCl, at pH 6.0 and 20 degrees
      C, with a rate constant for the change in ellipticity at 280 nm of 32.8 s-1; this
      rate was only twice that observed when TFE was absent. As a major point of
      distinction from stefin A, the refolding of stefin B in the presence of TFE
      showed an overshoot in the ellipticity at 230 nm to a value 10% greater than that
      in the native protein; this signal relaxed slowly (0.01 s-1) to the final native
      value, with little concomitant change in the near-ultraviolet CD signal; the
      majority of this changes in two faster phases. After denaturation in 42%
      (vol/vol) TFE, pH 3.3, the kinetics of refolding to the same final conditions
      exhibited the same rate-limiting step (0.01 s-1) but were faster initially. The
      results show that similarly to stefin A, stefin B forms its hydrophobic core and
      predominant part of the tertiary structure faster in the presence of TFE. The
      results imply that the alpha-helical intermediate of stefin B is highly
      structured. Proteins 1999;36:205-216.

PMID- 10398368
TI  - Design and expression of soluble CTLA-4 variable domain as a scaffold for the
      display of functional polypeptides.
AB  - We have designed and engineered the human cytotoxic T-lymphocyte associated
      protein-4 (CTLA-4) variable (V-like) domain to produce a human-based protein
      scaffold for peptide display. First, to test whether the CTLA-4 CDR-like loops
      were permissive to loop replacement/insertion we substituted either the CDR1 or
      CDR3 loop with somatostatin, a 14-residue intra-disulfide-linked neuropeptide.
      Upon expression as periplasmic-targeted proteins in Escherichia coli, molecules
      with superior solubility characteristics to the wild-type V-domain were produced.
      These mutations in CTLA-4 ablated binding to its natural ligands CD80 and CD86,
      whereas binding to a conformation-dependent anti-CTLA-4 monoclonal antibody
      showed that the V-domain framework remained correctly folded. Secondly, to
      develop a system for library selection, we displayed both wild-type and mutated
      CTLA-4 proteins on the surface of fd-bacteriophage as fusions with the geneIII
      protein. CTLA-4 displayed on phage bound specifically to immobilized CD80-Ig and
      CD86-Ig and in one-step panning enriched 5,000 to 2,600-fold respectively over
      wild-type phage. Bacteriophage displaying CTLA-4 with somatostatin in CDR3 (CTLA
      4R-Som3) specifically bound somatostatin receptors on transfected CHO-K1 cells
      pre-incubated with 1 microg/ml tunicamycin to remove receptor glycosylation.
      Binding was specific, as 1 microM somatostatin successfully competed with CTLA-4R
      Som3. CTLA-4R-Som3 also activated as well as binding preferentially to non
      glycosylated receptor subtype Sst4. The ability to substitute CDR-like loops
      within CTLA-4 will enable design and construction of more complex libraries of
      single V-like domain binding molecules. Proteins 1999;36:217-227.

PMID- 10398369
TI  - Theoretical study of the conformation of the H-protein lipoamide arm as a
      function of its terminal group.
AB  - The glycine decarboxylase complex consists of four different proteins (the L-, P
      , H-, and T-proteins). The H-protein plays a central role in communication among
      the other enzymes, as its lipoamide arm interacts successively with each of the
      components of the complex. The crystal structures of two states of the H-protein
      have been resolved: the oxidized form, Hox at 2 A and the methylamine-loaded
      form, Hmet at 2.2 A. However, the position of the arm for the reduced form, Hred,
      is still unknown. We have performed numerical free-energy calculations in order
      to better understand the differences in the structures and to elucidate the
      conformation of the arm in Hred. The results of the simulations are in agreement
      with the crystallographic results, as the minima of the free energy surface for
      Hox and Hmet correspond to the crystal structures. For Hred, we observe a single
      minimum in which the arm is on the surface of the H-protein, close to its
      position in the Hox structure. In all of our simulations, the lower, lysine
      portion of the arm remains bound to the protein, which substantially reduces the
      number of accessible arm configurations. An analysis of the stability of Hmet in
      the cavity shows that electrostatic interactions are crucial for locking the arm
      in the bottom of the cavity, especially near Glu14. In addition, the analysis
      shows that there is a water molecule, also observed in the crystallographic
      structure, that binds to the arm's terminal NH3+ group and helps to fix it in the
      cavity. In conclusion, because of the close agreement of the results of our
      calculations with the available experimental evidence, we are able to suggest a
      structural basis for the observed behavior. Proteins 1999;36: 228-237.

PMID- 10398370
TI  - A new subfamily of short bacterial adenylate kinases with the Mycobacterium
      tuberculosis enzyme as a model: A predictive and experimental study.
AB  - The adk gene from Mycobacterium tuberculosis codes for an enzyme of 181 amino
      acids. A sequence comparison with 52 different forms of adenylate kinases (AK)
      suggests that the enzyme from M. tuberculosis belongs to a new subfamily of
      "short" bacterial AKs. The recombinant protein, overexpressed in Escherichia
      coli, exhibits a low catalytic activity and an unexpectedly high thermal
      stability (Tm = 64.8 degrees C). Based on various spectroscopic data, on the
      known three-dimensional structure of the AK from E. coli and on secondary
      structure predictions for various sequenced AKs, we propose a structural model
      for AK from M. tuberculosis (AKmt). Proteins 1999;36:238-248.

PMID- 10398371
TI  - Direct computation of long time processes in peptides and proteins: reaction path
      study of the coil-to-helix transition in polyalanine.
AB  - The MaxFlux reaction path algorithm was used to isolate optimal transition
      pathways for the coil-to-helix transition in polyalanine. Eighteen transition
      pathways, each connecting one random coil configuration with an ideal alpha
      helical configuration, were computed and analyzed. The transition pathway
      energetics and mechanism were analyzed in terms of the progression of the peptide
      nonbonded contact formation, helicity, end-to-end distance and energetics. It was
      found that (1) localized turns characterized by i, i + 3 hydrogen bonds form in
      the early stages of the coil-to-helix transition, (2) the peptide first collapses
      and then becomes somewhat more extended in the final stage of helix formation,
      and (3) 310-helix formation does not appear to be a necessary step in the
      transition from coil to helix. These conclusions are in agreement with the
      results of more computationally intensive direct molecular dynamics simulations.
      Proteins 1999;36:249-261.

PMID- 10398372
TI  - In memoriam: robert hall haynes 

PMID- 10398373
TI  - A unified approach to the study of mutation, from bacteria to humans: some
      potentialities of the new DNA technologies.

PMID- 10398374
TI  - Hydrogen peroxide induces oxidative DNA damage in rat type II pulmonary
      epithelial cells.
AB  - Type II epithelial cells, which line the alveolar surface of the lung, are
      exposed to a variety of potentially mutagenic and carcinogenic insults. The
      purpose of this study was to determine if type II cells are susceptible to
      oxidative DNA damage in vitro. Treatment of cultured rat type II lung epithelial
      cells with hydrogen peroxide led to increased concentrations (nmol/mg DNA) of 12
      of 14 monitored DNA base modifications, suggesting oxidative damage by the
      hydroxyl radical. These base modifications are typically associated with
      oxidative stress, and elevated levels have been correlated with mutagenesis and
      carcinogenesis. These data demonstrate that type II cells are indeed vulnerable
      to oxidative DNA damage.

PMID- 10398376
TI  - Genotoxicity biomarkers in the assessment of heavy metal effects in mussels:
      experimental studies.
AB  - Heavy metals are stable and persistent environmental contaminants. The range of
      metal concentrations is generally below acute thresholds in coastal areas, where
      recognition of chronic sublethal effects is more relevant. Evidence of long-term
      adverse effects, such as cancer, due to heavy metals in marine animals comes from
      a number of field and experimental studies. The mechanism of metal
      carcinogenicity remains largely unknown, although several lines of experimental
      evidence suggest that a genotoxic effect may be involved. The aim of our study
      was to evaluate the sensitivity of genotoxicity tests, alkaline elution and
      micronucleus test, as biomarkers for the detection of heavy metals in mussels as
      the sentinel species. Experimental studies were carried out on Mytilus
      galloprovincialis exposed in aquarium (5 days) to different concentrations of
      three selected metal salts, CuCl2 (5, 10, 20, 40, 80 micrograms/l/a), CdCl2
      (1.84, 18.4, 184 micrograms/l/a), and HgCl2 (32 micrograms/l/a), and to a mixture
      of equimolar doses of the three metals to study the results of their joint
      action. Metallothionein quantitation was used as a marker of metal exposure.
      Lysosomal membrane stability was applied to evaluate the influence of
      physiological status on genotoxic damage. The ranking of genotoxic potential was
      in decreasing order: Hg > Cu > Cd. Cu and Hg caused an increase of DNA single
      strand breaks and micronuclei frequency. Cd induced a statistical increase of DNA
      damage, but gave negative results with the micronucleus test. A relationship
      between genotoxic effects and metallothionein content was observed. Reduction in
      lysosomal membrane stability with the increasing concentration of heavy metals
      was also evident.

PMID- 10398375
TI  - Comparison of DNA damage in plants as measured by single cell gel electrophoresis
      and somatic leaf mutations induced by monofunctional alkylating agents.
AB  - The use of single cell gel electrophoresis (SCGE) has recently been applied to
      plant systems. We optimized the experimental conditions for SCGE analysis using
      nuclei isolated from different tissues of intact plants. Concentration-response
      curves of genomic DNA migration were analyzed in intact plants treated with the
      monofunctional alkylating agents ethyl methanesulfonate (EMS), methyl
      methanesulfonate (MMS), N-ethyl-N-nitrosourea (ENU), and N-methyl-N-nitrosourea
      (MNU). These data were used to calibrate SCGE tail moment values to induced
      somatic mutation in plant leaves. We used a genotoxicity index to compare genomic
      DNA damage and the induction of somatic mutation in the leaf tissues. The rank
      order of the genotoxic potency of these alkylating agents assayed by SCGE was MNU
      >> MMS > ENU > EMS. The rank order for the mutagenic potency of these agents was
      MNU >> ENU congruent with MMS > EMS. The data demonstrate the utility of SCGE
      analysis in plant systems. The use of SCGE will permit a larger range of plants
      for use as in situ environmental monitors. Also, this approach may be used to
      search for crop plant germplasm accessions with enhanced genomic stability. We
      investigated whether the intragenomic distributions of DNA damage induced by
      these alkylating agents were uniform and random. When a plot of the ratio of the
      %tail DNA and tail length versus the concentration of the test mutagen was
      generated, the induced SCGE data deviated from a random distribution of genomic
      DNA damage.

PMID- 10398377
TI  - Temporal patterns of DNA adduct formation and glutathione S-transferase activity
      in the testes of rats fed aflatoxin B1: a comparison with patterns in the liver.
AB  - Fisher-344 male rats were fed 1.6 ppm of aflatoxin B1 (AFB1) continuously and
      intermittently for several weeks. At various time periods, DNA was isolated from
      the testes and livers and analyzed for AFB1-DNA adducts. The ability of the
      testis to detoxify AFB1 was also investigated by the glutathione S-transferase
      (GST) activity assay and compared with that of the liver. The levels of
      testicular AFB1-DNA adducts were 2.4 to 8.1 times lower than those of the liver
      after 4 to 16 weeks of continuous treatment and 2.2 to 46.2 times lower after 8
      to 20 weeks of intermittent treatment. The testicular DNA adducts markedly
      decreased over time. By 16 weeks of continuous and 20 weeks of intermittent
      exposure, they had decreased 37 and 91%, respectively. In contrast, hepatic AFB1
      DNA adducts increased four-fold from 4 to 16 weeks of continuous treatment but
      increased at a much slower rate after intermittent exposure. In both the liver
      and testis, significant levels of AFB1-DNA adducts persisted for at least 1 month
      after ending the treatment, suggesting that this type of lesion was poorly
      repaired. In control rats, the testis showed significantly higher GST activity
      than the liver. In treated rats, these differences were significant during the
      first 12 weeks of continuous treatment but not at later times. Tissue-specific
      differences such as germ-cell depletion and increased testicular detoxification
      may play an important role in the observed differential pattern of DNA adduct
      formation between the testis and liver.

PMID- 10398378
TI  - Genotoxicity of complex PAH mixtures recovered from contaminated lake sediments
      as assessed by three different methods.
AB  - Although human exposure generally occurs to mixtures of chemicals, limited
      toxicological information is available to characterize the potential interactions
      of the components of environmental mixtures. This study was conducted to compare
      the genotoxicity of chemically characterized polycyclic aromatic hydrocarbon
      (PAH) mixtures using in vitro and in vivo techniques. A total of three extracts
      (E1-E3) were selected from sediment samples collected from a lake adjacent to an
      abandoned coal gasification site. Sediments were collected on a grid moving
      downstream and away from the most likely source of PAH contamination, with E1
      collected closest to the shore, E2 at an intermediate distance, and E3 furthest
      from the shore. The sediment samples were extracted in methylene chloride and
      methanol, dried, and redissolved in an appropriate solvent for evaluation in a
      battery of genotoxicity assays. Samples were evaluated for their ability to
      produce point mutations in bacteria and DNA adducts in vitro without metabolic
      activation or in vivo. Samples were also analyzed using GC/MS. Sample E1 had both
      the highest concentration of benzo(a)pyrene (BP) (46.5 ppm) and carcinogenic PAHs
      and, using 32P-postlabeling, induced the highest adduct levels overall in vitro
      and in vivo. Sample E2, which had a BP concentration of 14 ppm, induced the
      greatest number of revertants in the bacterial mutagenicity assay. Sample E3,
      which had the lowest level of carcinogenic PAHs and BP, induced the lowest adduct
      levels. However, E3 was capable of inducing a positive genotoxic response in
      bacteria (with S9), although the slope of the response at lower doses was less
      than that of E2. The in vivo data showed that the major adduct formed by E1 and
      E2 was a BP adduct. This information could not have been obtained with the
      Salmonella or in vitro postlabeling tests. Among internal organs, the extracts of
      all three samples induced the greatest adduct levels in the lung, similarly to
      previous complex PAH mixtures studied. These data demonstrate the limitations of
      predicting genotoxic or carcinogenic potential based on chemical analysis or a
      single biological test. The results suggest that mixture interactions,
      cytotoxicity and metabolism are likely to have an influence on the potential of a
      complex mixture of chemicals to produce a carcinogenic effect. In addition, the
      concentration of genotoxic PAHs and both in vitro and in vivo DNA adduct
      formations were decreased with increasing distance from the shoreline.

PMID- 10398379
TI  - Mutational specificity in a shuttle vector replicating in chromium(VI)-treated
      mammalian cells.
AB  - An SV40-based shuttle vector, pZ189, was used to characterize the mutation
      specificity and to explore the mechanism of chromium mutagenesis in mammalian
      cells. We showed previously that mutagenic DNA damage is induced by the treatment
      of plasmid with chromium(VI) plus glutathione in vitro. The induced mutation
      pattern suggested that chromium mutagenesis can be induced by the generation of
      reactive oxygen intermediates. To further investigate the mechanism of chromium
      mutagenesis, we treated cultured mammalian cells containing normal pZ189 vector
      with chromium(VI). Mutations were induced by Cr(VI) in a dose-dependent manner.
      The majority of base substitution mutations were widely distributed across the
      supF mutation target gene and occurred mainly at GC basepairs. Overall, the
      mutation spectra were not significantly different from each other except for a
      mutation hot spot at position 43, observed only in plasmids from Cr(VI)-treated
      cells. The characteristics of Cr(VI)-induced mutations were similar to those
      observed in the mutation spectra induced by H2O2 treatment of the pZ189 plasmid
      or plasmid-containing cells. These results are consistent with the hypothesis
      that induction of mutations by chromium in cultured cells occurs through the
      generation of oxidative DNA damage.

PMID- 10398380
TI  - Tandem-base mutations occur in mouse liver and adipose tissue preferentially as
      G:C to T:A transversions and accumulate with age.
AB  - Tandem-base mutations (TBM) are associated with ultraviolet light and other
      mutagens. Herein, we report an age- and tissue-specific difference in the
      frequency of spontaneous TBM in Big Blue transgenic mice. A total of 390 mutants
      from liver and adipose tissue contained 17 and 4 TBM, respectively, while no TBM
      were detected in 683 mutants from six other tissues. There was a proportional
      increase in the frequency of TBM in liver with age (29 days postconception to 25
      months of age). Nine TBM (43%) were GG to TT transversions that preferentially
      occurred at specific sites. The remaining 12 mutants contained at least one
      transversion mutation each. We speculate that the increase of TBM in liver and
      adipose tissue with age is due to chronic mutagen exposure, perhaps derived from
      fat in the diet.

PMID- 10398381
TI  - Mutagenic and antimutagenic evaluation of the juice of the leaves of Bryophyllum
      calycinum (Kalanchoe pinnata), a plant with antihistamine activity.

PMID- 10398382
TI  - Identification of segments VI and VII of the liver based on the ramification
      patterns of the intrahepatic portal and hepatic veins.
AB  - We describe the pattern of intrahepatic vessel ramification in the right
      posterior hepatic sector in a population of 197 adults. Each specimen was
      dissected from its visceral (inferior) surface in order to demonstrate variations
      in the distribution of the portal vein branches to the hepatic segments of the
      right lobe, especially to segments VI (S6) and VII (S7) as described by Couinaud.
      We also examine whether three hepatic veins, i.e., the right hepatic vein (RHV),
      middle hepatic vein (MHV), and the short hepatic vein (SHV), aid the
      identification of segmental portal branches in the lower posterior sector. Four
      major patterns of branching of the posterior sectorial trunk of the portal vein
      system are described. In group A (32.0%) a single posterior trunk formed an arch
      like pattern sending multiple branches to S6 and S7 (P6 and P7). We named the
      multiple branches to the apparent S6 the inferoposterior portal branches. It was
      difficult to identify which of these branches were equivalent to P6. In group B
      (27.9%), the posterior sectorial trunk bifurcated to form P6 and P7. In most of
      the specimens in this group, therefore, we were able clearly to identify both S6
      and S7 based on the portal vein system. In group C (6.6%), the trunk trifurcated
      to form P6, P7, and an intermediate branch, which supplied both segments or a
      gray zone between them. Group D (33.5%) included variations of the anterior
      segmental branches, and in specimens of this group, the anteromedial border of
      the sector was difficult to identify. Notably, the three-dimensional
      interdigitating topographical relationship of the hepatic veins and the portal
      branches was not evident in the lower posterior sector, since tributaries of the
      RHV and the portal branches followed similar courses and paralleled each other in
      the region and since the territory of the SHV was usually restricted to the
      superficial parenchyma near the inferior surface. In group A, tributaries of the
      RHV/SHV (>3 mm in diameter) passed between the inferoposterior portal branches in
      only 22.2%/14.3% of the specimens. Thus the hepatic veins often did not reveal
      which of the multiple inferoposterior branches was P6. Moreover, in the subset of
      Group B in which the segments were identified based on the portal vein
      ramification, tributaries of the RHV/SHV (>3 mm in diameter) showed the
      intersegmental interdigitating arrangement in only 32.0%/6.0% of the specimens.
      In addition, a thick tributary of the MHV, sometimes arising from S6, did not run
      along, but penetrated the S5/S6 border plane from the lateral to the medial side.
      Therefore, the three hepatic veins (RHV, SHV, MHV) often did not aid the
      identification of the liver segments in the region. Consequently, the less than
      ideal combinations of irregular configurations of the portal and hepatic venous
      systems suggest that the right posterior segments cannot be conclusively
      identified anatomically in 30-40% of cases. Other means of identification, such
      as the conventional proportional manner (the upper and lower halves of the
      posterior sector roughly correspond to S6 and S7) may be required.

PMID- 10398383
TI  - Analysis of the arterial supply of the extrahepatic bile ducts and its clinical
      significance.
AB  - The purpose of this study is to describe the arterial supply of the entire
      extrahepatic bile duct system. The cross-sectional area of all arteries that
      supply the ducts is measured under an operating microscope in 50 adult cadavers
      injected with red latex through the aorta. The extrahepatic bile duct system is
      divided into four topographic portions: cystic duct and gallbladder, right and
      left hepatic ducts, bile (common) duct and including its supra-retroduodenal
      parts, and the pancreatic and intraduodenal portions. The arterial supply to each
      portion is carefully detailed. The ducts are supplied by more than seven
      arteries, of which the major arteries are the cystic artery, posterior superior
      pancreaticoduodenal artery, right hepatic artery, and retroportal artery.
      Collectively they provide 94.5% of the blood supply to the ducts. Arteries form
      three types of anastomotic patterns on the walls of the ducts, suggesting that
      ductal incisions can be made in ways that least disturb the blood supply. The
      patterns are: a network, a longitudinal anastomotic chain, and an arterial
      circle. These data emphasize the importance of the arterial supply in biliary
      surgery and especially the treatment of hemobilia.

PMID- 10398384
TI  - Effect of long-term vasectomy on seminiferous tubules in the guinea pig.
AB  - The little previous work on the influence of vasectomy on the guinea pig testis
      has given controversial results. One group reports that the guinea pig suffers
      autoimmune orchitis while others claim damage may be mechanical. To clarify the
      issue, this study compares the morphology of seminiferous tubules 3 years after
      left unilateral vasectomy (8 guinea pigs) and control sham operation (6 animals).
      Grossly, left and right testes following left-sided vasectomy were similar to
      controls and not significantly different in weight. On histology, left and right
      experimental testes and the control material showed various degrees of
      seminiferous tubular degeneration, including intraepithelial vesicle formation,
      loss of germ cells and intraluminal macrophages. Although vesicle formation was
      striking in most testes, quantitative analysis indicated that it was more
      frequent in the ipsilateral testis following unilateral vasectomy. It seems that
      vasectomy had exacerbated an age-related phenomenon. Lymphocytic infiltration was
      seen in five of the left testes following vasectomy, in two of the corresponding
      right testes, but in none of the controls. Two vasectomized left testes, however,
      showed atrophic changes but no lymphocytic invasion. The results suggest that
      autoimmune orchitis follows vasectomy but that it may not be the primary cause of
      degeneration. Attempts to gain positive evidence for mechanical damage, however,
      were inconclusive.

PMID- 10398386
TI  - Morphology and histochemistry of myogelosis.
AB  - Myogelosis is a common diagnosis in the case of chronic pain conditions,
      especially in the region of the pectoral girdle musculature, the glutei muscles,
      and the erector spinae muscle. Although such indurative areas continue to be
      palpable even on the cadaver, few studies concerning the morphological substrate
      of these areas have been undertaken. Selected biopsies as well as larger tissue
      samples were taken from 11 corpses and prepared for histological study. Following
      staining, the frozen sections were examined morphometrically. A histologically
      constant, significant morphological alteration was found in the areas of concern.
      The spaces between the individual muscle fibers of healthy muscle tissue appear
      relatively wide, the endomysium of the myogelotic area are clearly narrowed.
      Split fibers, ragged red fibers, Type II fiber atrophy, and fibers with a moth
      eaten appearance have been detected. The morphometry shows considerable increase
      in thickness of the affected muscle fibers, suggestive of a pathological, local
      hypertrophy. The changes described may well represent a fixed condition, so that
      it should not be surprising that myogelosis therapy is difficult and protracted.

PMID- 10398385
TI  - Psoas major and its controversial rotational action.
AB  - The action of psoas major muscle as a primary flexor of the hip joint is
      undisputed. However it is also variably reported as being a medial and a lateral
      rotator of the femur at the hip joint. The psoas and iliacus muscles, along with
      their common insertion, were isolated by dissection in six adult cadaveric
      specimens. The action of psoas muscle was assessed by pulling the muscle along
      its long axis and then observing the effects on rotation of the femur, with a
      visual estimation of the rotation in degrees. The experiment was repeated with
      the hip joint capsule removed. In the anatomical position, applied traction along
      the long axis of the muscle produced hip flexion with no rotational component.
      With the hip in the abducted position, traction produced flexion, adduction, and
      lateral rotation of the femur at the hip joint. In adduction of the hip, traction
      on psoas produced only flexion at the hip joint, with no rotation. In maximal
      flexion, traction also produced adduction. The results were unaffected by the
      removal of the joint capsule.

PMID- 10398387
TI  - Profiles of applicants for junior faculty posts to teach anatomy in the UK:
      changing populations of candidates.
AB  - This study was undertaken to document the popularity of appointments as temporary
      lecturer in anatomy (TLA) at the University of Manchester during the period 1991
      1998, and to profile the applicants for the posts. Data concerning 465 applicants
      were collated from departmental records and application forms. Prior to 1996,
      there were about seven applicants per post and most were men who intended to
      pursue surgical careers. The mean age of the applicants was 26 years, range 22-61
      years. Graduates of Manchester University formed 28% of applicants, non-UK
      graduates 11%, and 52% possessed qualifications additional to their medical
      degrees. After 1996, there were fewer applicants, about three per post, who were
      somewhat older, mean age 30 years, range 21-52 years, and from more diverse
      backgrounds; 40% were non-UK graduates. The probable reasons for the decline in
      popularity of the appointments are explored.

PMID- 10398388
TI  - Significance of the role of self-study and group discussion.
AB  - The study of anatomy is experiencing a reduction in course duration and content,
      lecture and dissection hours, and number of lectures and examinations. This
      necessitates that medical students develop skills for self-study. Toward that
      end, a self-study module in basic anatomy was tested. Fifty-seven new entrants
      were given a pretest (Pretest A) containing a questionnaire on basic anatomy.
      Then, in three groups each of 11 and two groups each of 12, they learned basic
      anatomy from recommended books in the library by self-study for 2 hours. They
      discussed what they had learned among their group members during a practical
      exercise, followed by a posttest (Posttest A). A control group of 57 new entrants
      during another year was given the same pretest (Pretest B) and a lecture on basic
      anatomy. Then, without opportunity for self-study, they were given a posttest
      (Posttest B). The answers were scored out of 40. The students' mean mark in
      Pretest A was poor. All the groups performed well in the practical exercise. In
      Posttest A, the mean mark increased significantly (P < 0.001), by 9.4. It shows
      that self-study and group discussions significantly helped the students in
      construction of core anatomical knowledge as well as the acquisition,
      assimilation, and application of anatomical concepts and content. The mean mark
      in Pretest B was also poor. In Posttest B, the mean mark increased significantly
      (P < 0.001), by 14.2. This indicates that the traditional teaching session is
      also useful and serves to advance student knowledge. Thus our innovative study
      module can create a positive learning environment and can become an alternative
      to traditional instruction in teaching anatomical terminology and basic anatomy.

PMID- 10398389
TI  - Anomalous origin of both vertebral arteries.
AB  - The authors describe a case of an unusual origin of both vertebral arteries in a
      singular cadaver. On the left, the artery arises directly from the common trunk
      of vertebral and subclavian artery at the aortic arch and enters the transverse
      cervical foramina at C VI. On the right, the artery originates from the right
      common carotid artery and enters the transverse foramina at C III. Additional
      anomalies were observed on the aortic arch: the common trunk of both common
      carotid arteries, the common trunk of the left vertebral and subclavian artery,
      and as a last branch, the retroesophageal right subclavian artery. The
      morphometric measurements of the vertebral arteries were performed. The
      literature on the variations of the vertebral arteries is reviewed and their
      clinical importance for diagnostical procedures and head and neck surgery
      stressed.

PMID- 10398390
TI  - Anatomy atlases.
AB  - Anatomy atlases are unlike other knowledge sources in the health sciences in that
      they communicate knowledge through annotated images without the support of
      narrative text. An analysis of the knowledge component represented by images and
      the history of anatomy atlases suggest some distinctions that should be made
      between atlas and textbook illustrations. Textbook and atlas should
      synergistically promote the generation of a mental model of anatomy. The
      objective of such a model is to support anatomical reasoning and thereby replace
      memorization of anatomical facts. Criteria are suggested for selecting anatomy
      texts and atlases that complement one another, and the advantages and
      disadvantages of hard copy and computer-based anatomy atlases are considered.

PMID- 10398391
TI  - Molecular recognition in the post-reductionist era.

PMID- 10398392
TI  - Isothermal titration calorimetry and differential scanning calorimetry as
      complementary tools to investigate the energetics of biomolecular recognition.
AB  - The principles of isothermal titration calorimetry (ITC) and differential
      scanning calorimetry (DSC) are reviewed together with the basic thermodynamic
      formalism on which the two techniques are based. Although ITC is particularly
      suitable to follow the energetics of an association reaction between
      biomolecules, the combination of ITC and DSC provides a more comprehensive
      description of the thermodynamics of an associating system. The reason is that
      the parameters DeltaG, DeltaH, DeltaS, and DeltaCp obtained from ITC are global
      properties of the system under study. They may be composed to varying degrees of
      contributions from the binding reaction proper, from conformational changes of
      the component molecules during association, and from changes in molecule/solvent
      interactions and in the state of protonation.

PMID- 10398394
TI  - Epitope mapping of a monoclonal antibody directed against the alpha-subunit of
      phosphofructokinase-1 from Saccharomyces cerevisiae by screening phage display
      libraries.
AB  - Phosphofructokinase-1 from Saccharomyces cerevisiae is composed of two types of
      subunits, alpha and beta. Subunit-specific monoclonal antibodies were raised to
      elucidate structural and functional properties of both subunits. One monoclonal
      antibody, alpha-F3, binds to an epitope either at the C-terminal or at the N
      terminal part of the alpha-polypeptide chain. By screening a heptapeptide library
      with this monoclonal antibody, a set of heptapeptides was selected, which
      contained the consensus sequences D-A-F and D-S-F. Two heptapeptides with these
      motifs were synthesized in order assess their capacity to inhibit the binding of
      antibody alpha-F3 to native phosphofructokinase-1. The peptide G-I-K-D-A-F-L
      inhibited the binding more strongly (IC50 = 1.5 microM) than the peptide A-P-W-H
      D-S-F (IC50 = 33.3 microM). Sequence matching revealed the presence of the D-A-F
      motif in the polypeptide chain of phosphofructokinase-1 at amino acid position
      172-174. As a control, the nonapeptide A-P-T-S-K-D-A-F-L which corresponds to the
      sequence of the putative epitope was tested in the inhibition assay. In view of
      the high inhibitory capacity (IC50 = 0.3 microM) it was concluded that this
      nonapeptide represents the continuous epitope of phosphofructokinase-1 that is
      recognized by antibody alpha-F3.

PMID- 10398393
TI  - Comparison of the three-dimensional structures of a humanized and a chimeric Fab
      of an anti-gamma-interferon antibody.
AB  - The objective of this work is to compare the three-dimensional structures of
      "humanized" and mouse-human chimeric forms of a murine monoclonal antibody
      elicited against human gamma-interferon. It is also to provide structural
      explanations for the small differences in the affinities and biological
      interactions of the two molecules for this antigen. Antigen-binding fragments
      (Fabs) were produced by papain hydrolysis of the antibodies and crystallized with
      polyethylene glycol (PEG) 8,000 by nearly identical microseeding procedures.
      Their structures were solved by X-ray analyses at 2.9 A resolution, using
      molecular replacement methods and crystallographic refinement. Comparison of
      these structures revealed marked similarities in the light (L) chains and near
      identities of the constant (C) domains of the heavy (H) chains. However, the
      variable (V) domains of the heavy chains exhibited substantial differences in the
      conformations of all three complementarity-determining regions (CDRs), and in
      their first framework segments (FR1). In FR1 of the humanized VH, the
      substitution of serine for proline in position 7 allowed the N-terminal segment
      (designated strand 4-1) to be closely juxtaposed to an adjacent strand (4-2) and
      form hydrogen bonds typical of an antiparallel beta-pleated sheet. The tightening
      of the humanized structure was relayed in such a way as to decrease the space
      available for the last portion of HFR1 and the first part of HCDR1. This
      compression led to the formation of an alpha-helix involving residues 25-32. With
      fewer steric constraints, the corresponding segment in the chimeric Fab
      lengthened by at least 1 A to a random coil which terminated in a single turn of
      310 helix. In the humanized Fab, HCDR1, which is sandwiched between HCDR2 and
      HCDR3, significantly influenced the structures of both regions. HCDR2 was forced
      into a bent and twisted orientation different from that in the chimeric Fab, both
      at the crown of the loop (around proline H52a) and at its base. As in HCDR1, the
      last few residues of HCDR2 in the humanized Fab were compressed into a space
      saving alpha-helix, contrasting with a more extended 310 helix in the chimeric
      form. HCDR3 in the humanized Fab was also adjusted in shape and topography. The
      observed similarities in the functional binding activities of the two molecules
      can be rationalized by limited induced fit adjustments in their structures on
      antigen binding. While not perfect replicas, the two structures are testimonials
      to the progress in making high affinity monoclonal antibodies safe for human use.

PMID- 10398395
TI  - Receptins: a novel term for an expanding spectrum of natural and engineered
      microbial proteins with binding properties for mammalian proteins.
AB  - A new term 'receptin', derived from recipere (lat.), is proposed to denote
      microbial binding proteins that interact with mammalian target proteins. An
      example of such a 'receptin' is staphyloccocal protein A which binds to the Fc
      part of many mammalian immunoglobulins. Several other types of 'receptins' are
      listed. This term may easily be distinguished from the similar term 'receptor',
      describing a binding site on a cell surface, mostly eukaryotic, where a secondary
      effect is induced inside the cell upon binding to a ligand. A receptin, however,
      does not necessarily have to induce a secondary event. Receptins include so
      called MSCRAMMs, adhesins, and also engineered receptins, affibodies, and
      engineered ligands. It denotes any protein of microbial origin, cell-bound or
      soluble, which can bind to a mammalian protein. It fulfills the need for an
      umbrella terminology for a large group of binding structures. In contrast, the
      term 'lectin' represents a group of proteins with affinity for carbohydrate
      structures. The new term 'receptin' includes a number of key microbial proteins
      involved in host-parasite interactions and in virulence. Some receptins are
      promising vaccine candidates.

PMID- 10398396
TI  - Synthesis and properties of new coenzyme mimics based on the artificial coenzyme
      CL4.
AB  - We have previously shown that a range of nicotinamide containing 'biomimetic
      coenzymes' function as active analogues of NAD+ in the oxidation of alcohols by
      horse liver alcohol dehydrogenase (HLADH), despite their apparently astonishing
      lack of structural similarity to the natural coenzyme. The simplest structure as
      yet shown to exhibit activity is the biomimetic coenzyme CL4. To investigate the
      effect of the structure of this truncated artificial coenzyme on its activity, a
      range of close structural analogues of CL4 were designed, synthesized and
      characterized. The electrochemical reduction potentials of the analogues were
      strongly influenced by the nature of the groups attached to the pyridine ring.
      All of the analogues could be chemically reduced using sodium borohydride, to
      give compounds with altered UV-visible absorption and fluorescence properties. An
      HPLC-based assay suggested that two of the new analogues were coenzymically
      active in the oxidation of butan-1-ol by HLADH, with one displaying a
      significantly higher activity than CL4. The results demonstrate which features of
      the structures of the coenzymes lead to desirable electrochemical and
      spectroscopic properties, but suggest that the structural requirements for a
      functional coenzyme are quite stringent. These observations may be used to design
      an artificial coenzyme which combines the best features of those studied so far.

PMID- 10398398
TI  - A strategy for the generation of biomimetic ligands for affinity chromatography.
      Combinatorial synthesis and biological evaluation of an IgG binding ligand.
AB  - An IgG-binding ligand library comprising 88 adsorbents based on a known lead
      compound (Li et al., 1998) was generated on an agarose solid phase. Individual
      members of the library were synthesized in two chemical steps using cyanuric
      chloride as the scaffold immobilized on the beaded support. The library was
      screened for binding of pure human IgG, whence selected ligands from the library
      were further assessed for specificity by the purification of IgG from human
      plasma. The potential of this strategy for the rapid identification and
      evaluation of chemical leads was demonstrated by the discovery of ligands with
      IgG binding capabilities. It was found that ligands comprising 3-aminophenol and
      an aminonaphthol moiety substituted on a triazine nucleus generally performed
      better than other ligands in the library. An immobilized ligand 22/8 adsorbent
      was able to purify IgG with high yield and a purity >99% from diluted human
      plasma.

PMID- 10398397
TI  - Design, synthesis and characterisation of affinity ligands for glycoproteins.
AB  - The concepts of rational design and solid phase combinatorial chemistry were used
      to develop affinity adsorbents for glycoproteins. A detailed assessment of
      protein-carbohydrate interactions was used to identify key residues that
      determine monosaccharide specificity, which were subsequently exploited as the
      basis for the synthesis of a library of glycoprotein binding ligands. The ligands
      were synthesised using solid phase combinatorial chemistry and were assessed for
      their sugar-binding ability with the glycoenzymes, glucose oxidase and RNase B.
      Partial and completely deglycosylated enzymes were used as controls. The triazine
      based ligand, histamine/tryptamine (8/10) was identified as a putative
      glycoprotein binding ligand, since it displayed particular affinity for glucose
      oxidase and other mannosylated glycoproteins. Experiments with deglycosylated
      control proteins, specific eluants and retardation in the presence of competing
      sugars strongly suggest that the ligand binds the carbohydrate moiety of glucose
      oxidase rather than the protein itself.

PMID- 10398399
TI  - Advances in surface plasmon resonance biomolecular interaction analysis mass
      spectrometry (BIA/MS).
AB  - Ongoing, worldwide efforts in genomic and protein sequencing, and the ability to
      readily access corresponding sequence databases, have emphatically driven the
      development of high-performance bioanalytical instrumentation capable of
      characterizing proteins and protein-ligand interactions with great accuracy,
      speed and sensitivity. Two such analytical techniques have arisen over the past
      decade to play key roles in the characterization of proteins: surface plasmon
      resonance biomolecular interaction analysis (SPR-BIA) and matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry (MALDI-TOF). SPR-BIA is
      used in the real-time investigation of biomolecular recognition events, and is
      thereby capable of providing details on the association and dissociation kinetics
      involved in the interaction, information ultimately leading to the determination
      of dissociation constants involved in the event. MALDI-TOF is used in the
      structural characterization, identification and sensitive detection of
      biomolecules. Although the two techniques have found many independent uses in
      bioanalytical chemistry, the combination of the two, to form biomolecular
      interaction analysis mass spectrometry (BIA/MS), enables a technique of
      analytical capabilities greater than those of the component parts. Reviewed here
      are issues of concern critical to maintaining high-levels of performance
      throughout the multiplexed analysis, as well as examples illustrating the
      potential analytical capabilities of BIA/MS.

PMID- 10398400
TI  - Biochemical purification and partial characterization of a murine macrophage
      surface receptor possessing specificity for small aromatic moieties including
      fluorescein.
AB  - Binding properties and requirements for internalization of hapten-protein
      antigens, such as fluorescein-polyderivatized bovine serum albumin (FITC-BSA) and
      poly-D-lysine (FITC-PDL), by murine macrophage was consistent with surface
      receptor recognition of fluorescyl moieties (Cherukuri et al., Mol. Immunol. 34,
      21-32, 1997; Cherukuri et al., Cytometry 31, 110-124, 1998). Ligand binding
      properties of the putative macrophage receptor pointed toward specificity for
      various aromatic moieties including phenylalanine, phenyloxazolone and
      fluorescein (Cherukuri and Voss, Mol. Immunol. 35, 115-125, 1998). Purification
      of the hapten-recognizing receptor from J774 macrophage cells involved
      subcellular fractionation of plasma membrane fractions, and affinity
      chromatography of solubilized membranes employing a phenyl-Sepharose adsorbent
      with subsequent specific elution of receptor using fluorescein ligand. The final
      product was a protein with a molecular mass of approximately 180 kDa.
      Characterization of the purified receptor involved absorption and fluorescence
      spectroscopy, circular dichroism, fluorescence quenching analyses, various ligand
      binding assays and an immunological analysis. Spectroscopic analyses revealed
      that the receptor possessed aromatic amino acids while circular dichroism
      suggested significant alpha-helical secondary structure. Binding specificity of
      the purified receptor was confirmed in a spectrofluorometric assay where the
      fluorescence of fluorescein ligand was quenched approximately 97%. Finally,
      specific binding activity of the receptor with FITC-BSA was demonstrated in
      Western blot analysis under native conditions. Receptor purity was confirmed in
      amino acid sequencing analysis when the amino-terminal residue was found to be
      totally blocked. Results are discussed in terms of the possible identity of the
      isolated macrophage receptor and its biological-immunological role.

PMID- 10398401
TI  - Fine mapping of the antigen-antibody interaction of scFv215, a recombinant
      antibody inhibiting RNA polymerase II from Drosophila melanogaster.
AB  - A bacterially expressed single chain antibody (scFv215) directed against the
      largest subunit of drosophila RNA polymerase II was analysed. Structure and
      function of the antigen binding site in scFv215 were probed by chain shuffling
      and by site-specific mutagenesis. The entire variable region of either the heavy
      or light chain was replaced by an unrelated heavy or light chain. Both
      replacements resulted in a total loss of binding activity suggesting that the
      antigen binding site is contributed by both chains. The functional contributions
      of each complementarity determining region (CDR) were investigated by site
      specific mutagenesis of each CDR separately. Mutations in two of the CDRs, CDR1
      of light chain and CDR2 of heavy chain, reduced the binding activity
      significantly. Each of the amino acids in these two CDRs was replaced
      individually by alanine (alanine walking). Seven amino acid substitutions in the
      two CDRs were found to reduce the binding activity by more than 50%. The data
      support a computer model of scFv215 which fits an epitope model based on a
      mutational analysis of the epitope suggesting an alpha-helical structure for the
      main contact area.

PMID- 10398402
TI  - Processing of PDGF gene products determines interactions with glycosaminoglycans.
AB  - The platelet derived growth factor (PDGF), a mitogen for mesenchymal cells, may
      be bound to and inhibited by heparin and other glycosaminoglycans. PDGF is a homo
      or heterodimer of A- and B-chains. They occur as short (A109 and B110) and long
      (A125 and B160) isoforms. The latter contain basic carboxyl-terminal extensions.
      Dimeric A125 binds to heparin through its basic extension in a two-step reaction.
      The mechanism involves a conformational change and is consistent with a Monod
      Wyman-Changeux allosteric model. Previous indirect experiments suggested that
      three critical amino acids (basic R111, K116 and polar T125) might be involved.
      Here, direct binding experiments using dimeric full-length mutants in surface
      plasmon resonanse analysis showed that all three critical amino acids in an
      R(X)4K(X)8T-motif contributed in a concerted manner to the high affinity binding.
      Mutations of these amino acids to alanine resulted in large thermodynamic
      changes, loss of the allosteric mechanism and order(s) of magnitude lower binding
      affinity. The binding mechanism and affinity of long dimeric rB were similar to
      the mutants. Short dimeric rA109 and rB110 showed 100 times lower binding
      affinity than rA125. Consequently, interactions with glycosaminoglycans in
      tissues varies between PDGF isoforms and may influence their local accumulation
      and activity.

PMID- 10398403
TI  - Sequence-specific interactions of minor groove binders with restriction fragments
      of cDNAs for H tau 40 protein and MAP kinase 2. A qualitative and quantitative
      footprinting study.
AB  - A series of DNA minor groove binders comprising netropsin, distamycin, the
      bisquaternary ammonium heterocycles SN 6999 and SN 6570, cis-diammine
      platinum(II)-bridged bis-netropsin, cis-diammine platinum(II)-bridged bis
      distamycin and bis-glycine-linked bis-distamycin were investigated for sequence
      specific interactions. The oligonucleotides used were the 154 base pair HindIII
      RsaI restriction fragment of cDNA of h tau 40 protein and the 113 base pair NcoI
      PvuII restriction fragment of cDNA of MAP kinase 2. Both proteins are believed to
      be involved in the pathology of Alzheimer's disease. For all these ligands,
      binding sites were localised at positions 1134-1139 (5'AATCTT3'), 1152-1156
      (5'ATATT3') and 1178-1194 (5'TTTCAATCTTTTTATTT3') for the former and 720-726
      (5'TATTCTT3'), 751-771 (5'AATTGTATAATAAATTTAAAA3') and 781-785 (5'TATTT3') for
      the latter. The AT-preference of ligand binding was obvious and footprint
      titration experiments were applied to estimate binding constants (Ka) for each
      individual binding site mentioned above. The binding strength decreases in the
      order netropsin > distamycin > SN 6999 approximately SN 6570>platinum-bridged
      netropsin or distamycin approximately bis-glycine-bridged distamycin and was
      found independently of the binding sites examined. GC-base pairs interspersed in
      short AT-tracts reduced the Ka-values by as much as two orders of magnitudes. The
      dependence of extended bidentate as well as of monodentate binding of netropsin
      and distamycin derivatives on the length of AT-stretches has been discussed.

PMID- 10398404
TI  - Unique single-domain antigen binding fragments derived from naturally occurring
      camel heavy-chain antibodies.
AB  - The humoral immune response of camels, dromedaries and llamas includes functional
      antibodies formed by two heavy chains and no light chains. The amino acid
      sequence of the variable domain of the naturally occurring heavy-chain antibodies
      reveals the necessary adaptations to compensate for the absence of the light
      chain. In contrast to the conventional antibodies, a large proportion of the
      heavy-chain antibodies acts as competitive enzyme inhibitors. Studies on the
      dromedary immunoglobulin genes start to shed light on the ontogeny of these heavy
      chain antibodies. The presence of the heavy-chain antibodies and the possibility
      of immunizing a dromedary allows for the production of antigen binders consisting
      of a single domain only. These minimal antigen-binding fragments are well
      expressed in bacteria, bind the antigen with affinity in the nM range and are
      very stable. We expect that such camelid single domain antibodies will find their
      way into a number of biotechnological or medical applications. The structure of
      the camelid single domain is homologous to the human VH, however, the antigen
      binding loop structures deviate fundamentally from the canonical structures
      described for human or mouse VHs. This has two additional advantages: (1) the
      camel or llama derived single domain antibodies might be an ideal scaffold for
      anti-idiotypic vaccinations; and (2) the development of smaller peptides or
      peptide mimetic drugs derived from of the antigen binding loops might be
      facilitated due to their less complex antigen binding site.

PMID- 10398405
TI  - Targetting of the N-terminal domain of the human papillomavirus type 16 E6
      oncoprotein with monomeric ScFvs blocks the E6-mediated degradation of cellular
      p53.
AB  - The E6 protein of cancer-associated human papillomavirus type 16 (HPV16) binds to
      cellular p53 and promotes its degradation through the ubiquitin pathway. In an
      attempt to identify the regions of E6 that could be targetted for functional
      inhibition, we generated monoclonal antibodies to the HPV16 E6 oncoprotein (16E6)
      and analysed their effect on E6-mediated p53 in vitro degradation. The isolated
      antibodies recognize the 16E6 oncoprotein expressed in the CaSki carcinoma cell
      line and strongly inhibit the proteolysis of p53 in vitro by binding specifically
      to a region of 10 residues located at the N-terminal end of 16E6. The variable
      regions of these antibodies were cloned and expressed in E. coli as single chain
      Fvs (scFvs). Purified scFvs were present in monomeric form and totally abolished
      16E6-mediated p53 degradation by preventing the formation of E6/p53 protein
      complexes. Our results demonstrate that monovalent binding of scFvs to the N
      terminal end of 16E6 abrogates the biological mechanisms leading to the
      degradation of p53, and they suggest that this region of 16E6 may be a useful in
      vivo target for blocking the oncogenic activity of HPV16 E6 protein.

PMID- 10398407
TI  - Recognition of defined epitopes by affinity-purified anti-immunoglobulin fab
      autoantibodies isolated from HIV-infected humans.
AB  - Infection of humans with HIV-1 has previously been independently shown to result
      in the generation of autoantibodies (AAbs) reactive with immunoglobulin Fab
      fragments (Heidelberg), and with autoantibodies to T-cell receptors (TCRs)
      (Tucson). Here, we carry out epitope mapping studies of affinity-purified AAbs to
      Fab fragments prepared from individual HIV-positive patients for their capacity
      to bind recombinant constructs and peptide-defined epitopes modeling TCR and Ig
      light chains. Some affinity-purified autoantibodies reacted strongly with TCRs
      expressed by intact T-cells, and recombinant Valpha/Vbeta constructs as well as
      with certain synthetic peptide epitopes. The binding reactions of affinity
      purified AAbs of individual patients were distinct, and the AAb preparations
      consisted of populations of polyclonal lgs as reflected in specificity and
      isotype. AAb pools from individual patients all bound particular regions of TCR
      and Ig chains defined by comprehensive peptide synthesis including the CDR1 and
      Fr3 segments of the variable domains and the joining segment/switch peptide. In
      addition, other reactivities to restricted regions of alpha, beta and lambda
      light chains were documented. These results substantiate the cross-reactivity of
      TCR and Ig-Fab determinants, and are consistent with the hypothesis that
      autoantibodies arising as a consequence of HIV infection can have an
      immunomodulatory role.

PMID- 10398408
TI  - Prediction of the binding energy for small molecules, peptides and proteins.
AB  - A fast and reliable evaluation of the binding energy from a single conformation
      of a molecular complex is an important practical task. Knowledge-based scoring
      schemes may not be sufficiently general and transferable, while molecular
      dynamics or Monte Carlo calculations with explicit solvent are too
      computationally expensive for many applications. Recently, several empirical
      schemes using finite difference Poisson-Boltzmann electrostatics to predict
      energies for particular types of complexes were proposed. Here, an improved
      empirical binding energy function has been derived and validated on three
      different types of complexes: protein-small ligand, protein-peptide and protein
      protein. The function uses the boundary element algorithm to evaluate the
      electrostatic solvation energy. We show that a single set of parameters can
      predict the relative binding energies of the heterogeneous validation set of
      complexes with 2.5 kcal/mol accuracy. We also demonstrate that global
      optimization of the ligand and of the flexible side-chains of the receptor
      improves the accuracy of the evaluation.

PMID- 10398406
TI  - Characterization of protein-glycolipid recognition at the membrane bilayer.
AB  - A growing number of important molecular recognition events are being shown to
      involve the interactions between proteins and glycolipids. Glycolipids are
      molecules in which one or more monosaccharides are glycosidically linked to a
      lipid moiety. The lipid moiety is generally buried in the cell membrane or other
      bilayer, leaving the oligosaccharide moiety exposed but in close proximity to the
      bilayer surface. This presents a unique environment for protein-carbohydrate
      interactions, and studies to determine the influence of the bilayer on these
      phenomena are in their infancy. One important property of the bilayer is the
      ability to orient and cluster glycolipid species, as strong interactions in
      biological systems are often achieved through multivalency arising from the
      simultaneous association of two or more proteins and receptors. This is
      especially true of protein-carbohydrate binding because of the unusually low
      affinities that characterize the monovalent interactions. More recent studies
      have also shown that the composition of the lipid bilayer is a critical parameter
      in protein-glycolipid recognition. The fluidity of the bilayer allows for correct
      geometric positioning of the oligosaccharide head group relative to the binding
      sites on the protein. In addition, there are activity-based and structural data
      demonstrating the impact of the bilayer microenvironment on the modulation of
      oligosaccharide presentation. The use of model membranes in biosensor-based
      methods has supplied decisive evidence of the importance of the membrane in
      receptor presentation. These data can be correlated with three-dimensional
      structural information from X-ray crystallography, NMR, and molecular mechanics
      to provide insight into specific protein-carbohydrate inter--actions at the
      bilayer.

PMID- 10398409
TI  - Identification of peptide mimotopes for the fluorescein hapten binding of
      monoclonal antibody B13-DE1.
AB  - Using 6mer and 12mer phage peptide libraries three unique phage clones were
      identified which specifically bind to a monoclonal anti-FITC antibody, B13-DE1.
      The two 6mer and one 12mer peptide insert sequences are clearly related to each
      other and contain a high proportion of hydrophobic amino acids. The peptides are
      bound by the antibody combining site of B13-DE1 probably in a similar manner to
      FITC and represent therefore true peptidic mimics of the fluorescein hapten. No
      reactivity of the peptides could be demonstrated with another monoclonal anti
      fluorescein antibody or with polyclonal anti-fluorescein antibodies. Immunization
      of mice with the peptides resulted in the production of antibodies cross-reacting
      with all peptides but not with fluorescein. The results show that phage peptide
      libraries can be used to isolate mimotope peptides which can mimic low molecular
      weight structures seen by a specific antibody and probably other recognition
      molecules.

PMID- 10398410
TI  - The use of biosensor technology for the engineering of antibodies and enzymes.
AB  - Recently developed scientific instrumentation featuring surface plasmon resonance
      detection allows the detection of biomolecular interactions in real time and
      without chemical modification of the binding partners. These biosensors are
      proving invaluable tools in protein engineering, particularly in research aimed
      at the isolation and improvement of protein binders and catalysts from
      macromolecular repertoires containing billions of individual members. This
      article reviews the use of biosensor technology for the isolation and
      characterization of engineered antibodies and enzymes.

PMID- 10398411
TI  - Cloning and expression of the zebrafish germ cell nuclear factor.
AB  - Nuclear orphan receptors are DNA-binding proteins that share the domain structure
      of the nuclear hormone receptor superfamily, although their ligands are unknown.
      Members of the nuclear receptor family are involved in the regulation of various
      developmental and reproductive processes. We have identified such a nuclear
      orphan receptor in the zebrafish and named it zebrafish germ cell nuclear factor
      (zfGCNF) based on its high sequence homology to previously described mouse,
      human, and Xenopus laevis GCNF. Detailed sequence comparison of zfGCNF with
      mouse, human, and frog GCNF revealed high homologies in the domains conserved in
      the nuclear receptor family. Homology in the DNA-binding domain is 97% for frog
      and even 98.5% for mouse and human when compared to the zebrafish sequence.
      Homology in the E III subdomain of the transactivation/ligand-binding E domain is
      100% when compared to the mouse and human sequences. Transcripts of different
      size were detected by Northern blot analysis in the zebrafish ovary, whereas, in
      the testis only one transcript was present. In situ hybridization revealed that
      zfGCNF was predominantly expressed in previtellogenic oocytes in the ovary and in
      spermatocytes in the testis.

PMID- 10398412
TI  - Expression of vascular endothelial growth factor (VEGF) and its corresponding
      receptors (flt-1 and flk-1) in the bovine oviduct.
AB  - Vascular endothelial growth factor (VEGF) functions as a potent angiogenic
      protein as well as in regulating permeability. Reverse transcription-polymerase
      chain reaction (RT-PCR) and ribonuclease protection assay (RPA) were used to show
      that the bovine oviduct expresses VEGF and its two receptors flk-1 and flt-1.
      Expression of VEGF was relatively stable during the estrous cycle. In contrast,
      both receptor transcripts showed cycle-dependent variations with significantly
      increased flt-1 mRNA amounts before ovulation. Immunohistochemical studies
      localized VEGF mainly on the epithelial surface of oviducts. Protein
      concentrations of VEGF in oviductal flushings were significantly higher (mean +/-
      SEM: 2.8 +/- 0.8 ng/ml) during the pre-ovulatory phase when compared with the
      other estrous cycle stages (1.0 +/- 0.25 ng/ml). In conclusion, all components of
      a functional VEGF-system in the bovine oviduct were found to undergo specific
      modulations during the cycle. We suggest that VEGF may be involved in creating an
      optimal local environment for fertilization or the developing embryo by
      modulating permeability within the bovine oviduct.

PMID- 10398413
TI  - Antisteroidal compounds and steroid withdrawal down-regulate cadherin-11 mRNA and
      protein expression levels in human endometrial stromal cells undergoing
      decidualisation in vitro.
AB  - The cellular mechanisms by which steroids and antisteroidal compounds modulate
      the function and/or integrity of the human endometrium remain poorly understood.
      We recently determined that the expression of the novel cadherin subtype, known
      as cadherin-11, is tightly regulated in endometrial stromal cells undergoing
      decidualisation in vivo and in vitro. To determine whether the actions of
      antisteroids on the endometrium are mediated, at least in part, by their ability
      to regulate the expression of this cell adhesion molecule, we examined the
      effects of the antiprogestin RU486 and the antiestrogen ICI 182,780 on cadherin
      11 mRNA and protein expression levels in human endometrial stromal cells
      undergoing decidualisation in vitro. RU486 decreased the levels of the cadherin
      11 mRNA transcript and protein species present in these cell cultures in a dose-
      and time-dependent manner. Similarly, ICI 182,780 was capable of reducing stromal
      cadherin-11 mRNA and protein expression levels in a dose-dependent manner,
      suggesting that the progesterone-mediated increase in cadherin-11 expression
      levels in human endometrial cells undergoing decidualisation in vitro is
      dependent on the presence of estrogens. Cadherin-11 expression levels also were
      reduced in endometrial stromal cell cultures subjected to progesterone
      withdrawal, an in vitro model for menstrual breakdown. These studies not only
      give us useful insight into the mechanism(s) by which progesterone regulates
      stromal cadherin-11 expression, but they strengthen our hypothesis that this cell
      adhesion molecule plays a central role in the remodeling processes that occur in
      the human endometrium in response to fluctuations in the levels of gonadal
      steroids.

PMID- 10398414
TI  - Irradiation of fish embryos prior to blastomere transfer boosts the colonisation
      of their gonads by donor-derived gametes.
AB  - Blastomere transplantation into fish blastula embryos results in somatic
      chimeras, which generally provide null or a small proportion of gametes derived
      from the donor. This may partly explain why none of the ES-like cell lines
      established from fish embryos has contributed to the germline of chimeras when
      transplanted at the blastula stage. Here, we report that a moderate gamma
      irradiation of recipient embryos, followed by transplantation of dispersed
      blastomeres, considerably enhances the proportion of donor-derived gametes (53%
      versus 5% in average). In fish, the resulting protocol should maximise the
      pluripotency level measured in vivo for embryonic cell lines and for cultured
      germ cells.

PMID- 10398415
TI  - Messenger RNA expression and protein localization of growth hormone in bovine
      ovarian tissue and in cumulus oocyte complexes (COCs) during in vitro maturation.
AB  - The aim of this study was to investigate whether bovine cumulus oocyte complexes
      (COCs) obtained from 2 to 8 mm follicles synthesize growth hormone (GH) during in
      vitro maturation. In addition the expression of growth hormone releasing hormone
      receptor (GHRH-r) in the COCs before and after in vitro maturation was
      investigated. Therefore, COCs obtained from small and medium sized follicles were
      cultured in M199 supplemented with 10% FCS and gonadotropins for 24 hr. At 0, 6,
      12, and 24 hr after the onset of culture, COCs were removed and were prepared for
      immunohistochemical staining to detect the presence of GH. In addition, sections
      of ovary were stained to study the differential localization of GH in the ovary.
      At 0 and 24 hr COCs were removed and together with samples from granulosa cells
      and theca cells were prepared for reverse transcriptase polymerase chain reaction
      (RT-PCR) to assess the expression of mRNA of GH and GHRH-r. Within COCs, cumulus
      cells and oocytes showed GH immunoreactivity, while expression of GH mRNA was
      only found in the oocyte. At the onset of culture, oocytes and cumulus cells in
      the majority of COCs generally showed moderate and strong staining intensity for
      GH, respectively. While GH staining in the cumulus cells did hardly change during
      24 hr of culture, GH staining in the oocyte was absent after 24 hr of culture in
      70% of COCs. Within the ovary, GH was localized in antral follicles larger than 2
      mm and no staining was found in primordial, primary and secondary follicles or in
      the stroma. The intensity of the staining increased with the size of the
      follicles. Within the follicular wall the GH was persistently observed in
      granulosa cells, while theca cells were occasionally negative. GH mRNA in
      follicular compartments was only found in the oocyte and mural granulosa cells.
      No GHRH-r mRNA was found in the COCs nor in the granulosa or the stroma. In
      conclusion, the gradual increase of GH staining during follicular development and
      the consistent synthesis of GH in oocytes and granulosa cells, suggest a
      paracrine and/or autocrine action for GH in bovine follicular growth and oocyte
      maturation. The absence of mRNA for GHRH receptor in the COCs indicates that
      ovarian production of GH is not regulated by GHRH.

PMID- 10398416
TI  - Simultaneous detection of X- and Y-bearing bull spermatozoa by double colour
      fluorescence in situ hybridization.
AB  - Double colour fluorescence in situ hybridization with sex chromosome probes was
      applied on sperm cells of five Swedish Holstein-Friesian bulls. It was
      demonstrated that cosmids with strong fluorescence signals and scraped
      chromosomes can successfully be used as markers in this type of study. X and Y
      segregated as expected according to a 1:1 ratio, and there were no
      interindividual variations. There was a tendency for there to be more Y- than X
      bearing spermatozoa, but this bias was assumed to be due to the markers used.
      Disomic spermatozoa occurred with a frequency of more than 0.1 % (0.067% XX,
      0.029% YY, and 0.029% XY), which is considerably lower than the frequency in
      humans. Diploid sperm cells occurred with a frequency of 0.05 %.

PMID- 10398417
TI  - The monomeric GTP binding protein, rab3a, is associated with the acrosome in
      mouse sperm.
AB  - Exocytosis of the sperm acrosome is an obligate precursor to successful egg
      penetration and subsequent fertilization. In most mammals, acrosomal exocytosis
      occurs at a precise time, after sperm binding to the zona pellucida of the egg,
      and is induced by a specific component of the zona pellucida. It may be
      considered an example of regulated secretion with the acrosome of the sperm
      analogous to a single secretory vesicle. Monomeric G proteins of the rab3
      subfamily, specifically rab3a, have been shown to be important regulators of
      exocytosis in secretory cells, and we hypothesized that these proteins may
      regulate acrosomal exocytosis. Using alpha[32P] GTP binding to Immobilon blotted
      mouse sperm proteins, the presence of three or more monomeric GTP binding
      proteins was identified with Mr = 22, 24, and 26 x 10(3). Alpha[32P] GTP binding
      could be competed by GTP and GDP, but not GMP, ATP, or ADP. Anti-peptide
      antibodies specific for rab3a were used to identify the 24 kDa G protein as
      rab3a. Using immunocytochemistry, rab3a was localized to the head of acrosome
      intact sperm and was lost during acrosomal exocytosis. It was identified in
      membrane and cytosolic fractions of sperm with the predominant form being
      membrane-bound, and its membrane association did not change upon capacitation.
      Immunogold labeling and electron microscopy demonstrated a subcellular
      localization in clusters to the periacrosomal membranes and cytoplasm. These data
      identify the presence of rab3a in acrosomal membranes of mouse sperm and suggest
      that rab3a plays a role in the regulation of zona pellucida -induced acrosomal
      exocytosis.

PMID- 10398418
TI  - Spermatogonia of rainbow trout: I. Morphological characterization, mitotic
      activity, and survival in primary cultures of testicular cells.
AB  - Prerequisites of developing in vitro studies for a better understanding of the
      control mechanisms underlying the proliferation and differentiation of
      spermatogonia (Go) in the teleost testis are: (1) to be able to identify the
      different types of Go; (2) to maintain in culture the structural relationships
      occurring in situ between the various testicular cell types, as intact as
      possible; and (3) to know how the Go survive and proliferate in culture for
      several days. After very gentle homogenization of trout testes treated with
      collagenase, a cell suspension containing mainly spermatocysts (one or several
      Sertoli cells enclosing one Go or a clone of germ cells) and clusters of myoid
      cells and Leydig cells was seeded in culture onto a laminin plus fibronectin
      coating. After 4.5-6 days in culture, then staining with May-Grunwald and Giemsa
      reagents, the determination of the nuclear and cellular size of the various Go
      and of the number of Go present in clones has enabled the identification of two
      types of large Go, in pairs or alone (Go A) and six successive types of smaller
      Go (Go B). Cell viability determination by staining with Rhodamine 123/propidium
      iodide (PI)/Hoechst 33342 and with FITC-Annexin V/PI indicated that after 5-7
      days in culture, all the somatic cells and most of the Go were viable. Only some
      of the Go, mainly among the most differentiated ones, underwent apoptosis, as it
      was the case for a number of spermatocytes and spermatids increasing with the
      time in culture. Brdu labelling and 3H-Thymidine (3H-Tdr) incorporation indicated
      that the proliferative activity of Go was at a maximum after 4.5 days in culture
      and that the response to at least two molecules (QAYL-IGF-I and GTH-I) remained
      unchanged between 3 and 6 days. As only very scarce somatic cells from
      immature/spermatogenetic testes synthesized DNA up to 6 days in culture, the
      measurement of 3H-Tdr incorporation by cells from such testes reliably reflected
      synthesis of DNA by only the Go (and eventually also by primary spermatocytes
      when they are present). In conclusion, this study provides information allowing a
      detailed analysis of the events related with the mitotic phase of spermatogenesis
      in the trout and it establishes that primary cultures of testicular cells carried
      out in the reported conditions represent a useful tool to develop an analysis of
      the mechanisms participating in the control of this phase.

PMID- 10398419
TI  - Spermatogonia of rainbow trout: II. in vitro study of the influence of pituitary
      hormones, growth factors and steroids on mitotic activity.
AB  - At the present time, in spite of recent advances, knowledge about the factors
      regulating germ cell proliferation in the teleost testis is limited. This study
      was designed to investigate, in vitro, the ability of various hormones, growth
      factors, and steroids to influence the proliferation of trout spermatogonia (Go)
      present in mixed cultures of somatic and germ cells prepared from testes, either
      prespermatogenetic or spermatogenetic. The tested molecules were usually present
      for the duration of culture (4.5 days) and 3H-thymidine (3H-Tdr) for the last day
      in culture. In our cell culture conditions, homologous gonadotropin I (tGTH-I)
      and growth hormone (tGH) moderately stimulated 3H-Tdr incorporation by Go, with
      ED50 equal to 5.5 +/- 3.0 and 1.8 +/- 0.4 ng/ml respectively. Insulin growth
      factor I (rhIGF-I) and fibroblast growth factor (rhFGF-2) stimulated 3H-Tdr
      incorporation by Go from spermatogenetic testes only, with ED50 equal to 16.2 +/-
      9.3 and 2.4 +/- 0.3 ng/ml respectively. The effects of the most efficient
      concentrations of rhIGF-I combined with those of either tGTH-I or tGH were
      additive. Seventy to one hundred microM suramin stimulated 3H-Tdr incorporation
      by Go from testes at all maturation stages and this effect was additive with that
      of tGTH-I. We assume that this effect of suramin could result from the inhibition
      of an unidentified antimitogenic factor. No effect was observed with homologous
      prolactin, human epidermal growth factor, activin A and B, transforming growth
      factor-beta1, testosterone, 11-ketotestosterone, 17beta-estradiol, pregnenolone,
      11beta-hydroxyprogesterone, and 22-hydroxycholesterol. In conclusion, our in
      vitro results suggest that GTH-I, GH, IGF-I, and FGF-2, are potent in situ
      modulators of the proliferative activity of trout Go at the time of induction,
      speeding up, then slowing down spermatogenesis, through direct or indirect
      additive and/or antagonistic influences.

PMID- 10398420
TI  - Spermatogonia of rainbow trout: III. In vitro study of the proliferative response
      to extracellular ATP and adenosine.
AB  - Unlike in higher vertebrates, in fish it is not known whether the nerve supply of
      the testis can influence testicular functions or not. In addition to
      neurotransmitters, nerve terminals may release ATP and adenosine in the
      extracellular medium. On the assumption that these molecules might be released by
      fibers innervating the teleost testis, it is possible that they participate in
      the control of testicular function and, maybe, in the control of spermatogonia
      (Go) proliferation. This study addresses this issue. We have investigated the
      ability for extracellular ATP and adenosine to influence the in vitro
      incorporation, either basal or GTH-, IGF-I- and suramin-stimulated, of 3H
      thymidine (3H-Tdr) by trout Go. Mixed suspensions of somatic and germ cells
      prepared from testes, which were immature or spermatogenetic, were cultured
      usually for 4.5 days in the presence or not of the tested molecules; 3H-Tdr was
      added during the last day in culture. In our cell culture conditions, 25 to 250
      microM adenosine, ATP, ADP, and AMP stimulated the 3H-Tdr incorporation by Go
      from prespermatogenetic testes and from testes starting spermatogenesis, in a
      dose-dependent way. The effect of these molecules decreased when the testes were
      more advanced in spermatogenesis and it became inhibiting when the testes were in
      mid-spermatogenesis. Five'-N-ethylcarboxamidoadenosine (NECA) was as potent as
      adenosine in stimulating or inhibiting 3H-Tdr incorporation, while R-N6-(2
      phenylisopropyl)adenosine (R-PIA) always had a marked inhibiting effect.
      Adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS; 25-200 microM), a non
      hydrolysable analogue of ATP, which had no effect on Go from prespermatogenetic
      testes (collected October-February) and from testes in advanced spermatogenesis,
      stimulated 3H-Tdr incorporation by Go from testes at the beginning of
      spermatogenesis very efficiently. The order of potency of the different ATP
      analogues was as follows: ATPgammaS > ATP congruent with alpha,beta-methylene-ATP
      > UTP > 2-methylthio-ATP. These data suggest that A2 adenosine receptors and P2
      receptors would be present on unidentified testicular cells. The stimulating
      effect of adenosine/ATP was additive with that of either GTH-I or IGF-I or
      suramin when the cells were from testes at the beginning of spermatogenesis, but
      adenosine suppressed their effect when the cells were from testes in mid
      spermatogenesis. In conclusion, our results suggest that in the trout
      extracellular adenosine and ATP are able to influence the in vitro proliferation
      of Go, and are potential candidates for mediating the possible influence of the
      nervous system on the induction, speeding up, then slowing down of
      spermatogenesis.

PMID- 10398421
TI  - Development during single IVP of bovine oocytes from dissected follicles:
      interactive effects of estrous cycle stage, follicle size and atresia.
AB  - Previous work suggests that a number of factors such as follicle size, day of
      estrous cycle, and level of atresia influence the developmental potential of
      bovine oocytes in vitro. To understand better the interactions of these factors,
      1299 follicles > or =3 mm in diameter were dissected from ovaries of synchronized
      dairy cows on four days (d2, d7, d10, or d15) during the estrous cycle. The
      oocyte from each follicle was collected and matured, fertilized, and cultured
      singly to d8 (d0 of culture = IVF). Control follicles (302) were similarly
      dissected and processed from an ovary pair randomly collected from the abattoir
      on each slaughter day. Results showed that development to blastocyst was greater
      in oocytes collected during phases of follicular growth (d2 and d10) than those
      collected during phases of follicular dominance (d7 and d15; 44.8% vs. 36.0%,
      respectively: P < 0.001) over all follicle size categories (3-5 mm, 6-8 mm, 9-12
      mm and > or =13 mm). Oocyte competence tended to increase with increasing
      follicle size (P < 0.1). Follicular cells from follicles containing an oocyte
      that developed to morula or greater by d8 (484 samples) were analyzed by flow
      cytometry to measure the level of apoptosis. Results showed an increase in mean
      percent apoptotic cells in subordinate follicles (18.65 +/- 0.86 over all size
      categories), particularly those of medium size (25.55 +/- 2.2 for 6-8 mm size
      follicles; P < 0.001), during the dominance phase compared to growth phase (9.25
      +/- 0.95 over all sizes; P < 0.05). These results show a significant affect of
      the stage of estrous cycle on both oocyte competence and levels of follicular
      atresia.

PMID- 10398423
TI  - Analysis of ovarian borderline tumors using comparative genomic hybridization and
      fluorescence in situ hybridization.
AB  - It is unclear whether ovarian borderline tumors (tumors of low malignant
      potential) are independent entities or whether they are part of a continuum of
      tumor progression that culminates in ovarian carcinoma. Little is known about
      genetic abnormalities in borderline tumors because of the difficulty of growing
      them in culture for chromosome studies, and because the low ratio of tumor to
      nontumor cells can interfere with molecular genetic examination. To circumvent
      these problems, we performed comparative genomic hybridization (CGH) on 10 serous
      borderline tumors from nine patients, using microdissection to enrich the samples
      for tumor DNA and reduce contamination from stromal and inflammatory cells. CGH
      analysis revealed that three of the tumors had detectable chromosomal imbalances,
      whereas seven were in a balanced state. In those tumors with imbalances, the
      number of abnormalities ranged from 3-6 per tumor. Additional studies by
      fluorescence in situ hybridization (FISH) on disaggregated nuclei confirmed the
      imbalances detected by CGH, revealed one tumor to be hypertriploid, and indicated
      that the remaining tumors were diploid and in a balanced state. All abnormalities
      observed in the aneuploid cases are consistent with chromosomal aberrations
      previously reported for ovarian carinomas, providing further evidence that some
      borderline tumors are part of a continuum of tumor progression. These results
      also suggest that there may be different mechanisms leading to borderline tumor
      formation, including one associated with multiple chromosomal imbalances, and
      others that do not involve imbalances detectable by CGH. Genes Chromosomes Cancer
      25:307-315, 1999.

PMID- 10398422
TI  - Modulation of adenylyl cyclase by FPP and adenosine involves stimulatory and
      inhibitory adenosine receptors and g proteins.
AB  - FPP and adenosine modulate the adenylyl cyclase (AC)/cAMP signal transduction
      pathway in mammalian spermatozoa to elicit a biphasic response, initially
      stimulating capacitation and then inhibiting spontaneous acrosome loss. This
      study addressed the hypothesis that responses to FPP involve interactions between
      receptors for FPP and adenosine, the biphasic responses involving stimulatory and
      inhibitory adenosine receptors. Gln-FPP, a competitive inhibitor of FPP,
      significantly inhibited binding of an adenosine analogue and responses to
      adenosine, especially in capacitated suspensions, consistent with interaction
      between FPP and adenosine receptors. CGS-21680 (1 microM), a stimulatory A2a
      adenosine receptor agonist, significantly stimulated capacitation and cAMP in
      uncapacitated cells, while cyclopentyl adenosine (1 microM), an inhibitory A1
      adenosine receptor agonist only affected capacitated cells, inhibiting
      spontaneous acrosome loss. Responses to FPP and adenosine were inhibited in
      uncapacitated cells by a selective A2a antagonist and in capacitated cells by a
      selective A1 antagonist; subsequent investigations indicated possible involvement
      of G proteins. Like FPP, cholera toxin stimulated capacitation and cAMP
      production in uncapacitated cells, suggesting involvement of a G protein with a
      Galphas subunit. In contrast, pertussis toxin prevented FPP's inhibition of both
      spontaneous acrosome loss and cAMP production, suggesting involvement of a
      Galphai/o subunit. Immunoblotting evidence revealed the presence of proteins of
      the appropriate molecular weights for Galphas, Galphai2, Galpha i3, and Galphao
      subunits. This study provides the first direct evidence suggesting the
      involvement of two different types of adenosine receptors and both Galphas and
      Galphai/o subunits in the regulation of capacitation, resulting in modulation of
      AC activity and availability of cAMP.

PMID- 10398425
TI  - Comparison of genetic changes in primary sarcomas and their pulmonary metastases.
AB  - The aims of the present study were to compare genetic aberrations in primary
      sarcomas and their pulmonary metastases and to explore the pathways associated
      with disease spreading. The primary tumor and its subsequent pulmonary metastasis
      of 22 patients were analyzed by comparative genomic hybridization. All samples
      were obtained before the initiation of chemo- or radiotherapy. The mean total
      number of aberrations per tumor was 7.6 (range, 0-17) in primary tumors and 7. 5
      (range, 0-19) in metastases. The mean numbers of high-level amplifications per
      tumor were similar (0.32 in primary tumors and 0. 36 in metastases). The
      frequencies of the most common aberrations were relatively similar in primary
      tumors and metastases: the most frequent gain affected 1q (minimal common regions
      1q21-q23 in 36% of primary tumors and 1q21 in 45% of metastases). The most
      frequent losses were detected at 9p (9p22-pter in 32% of primary tumors and 9p21
      pter in 32% of metastases), 10p (10p11.2-p12 in 41% of primary tumors and 10p11.2
      pter in 32% of metastases), 11q (11q23-qter in 36% of primary tumors and 32% of
      metastases), and 13q (13q14-q21 in 45% of primary tumors and 50% of metastases).
      No aberrations specific to metastases were detected. An increase in the total
      number of changes during progression was a predominant feature in a majority of
      these paired samples. Also, the number of differences in the genetic profile
      outnumbered common changes in a majority of the samples. However, despite the
      heterogeneous and numerous changes, all pairs with aberrations in both specimens
      had some shared alterations in both samples. Genes Chromosomes Cancer 25:323-331,
      1999.

PMID- 10398424
TI  - HMGIC expression in human adult and fetal tissues and in uterine leiomyomata.
AB  - The high-mobility-group (HMG) protein gene, HMGIC, is localized to chromosome 12,
      band q15, a region often rearranged in benign mesenchymal tumors, including
      uterine leiomyomata. Although some evidence suggests a role in regulation of cell
      proliferation, the precise function of HMGIC in the development or progression of
      these tumors remains unclear. We investigated HMGIC expression in 17 fetal
      tissues (adrenal, aorta, bone, brain, heart, intestine, kidney, liver, lung,
      muscle, ovary, placenta, skin, spleen, stomach, testis, and uterus) and 10 adult
      tissues (aorta, brain, cerebellum, fat, kidney, liver, lung, lymph node,
      myometrium, and spinal cord) by Northern blot and reverse transcriptase
      polymerase chain reaction (RT-PCR) assays. Comparisons between HMGIC gene
      expression in tumor samples from 11 uterine leiomyomata and 7 normal matched
      myometrium or in vitro cell cultures (chorionic villi, placenta, myometrium,
      leiomyoma, and skin) were also performed. The gene was expressed in all fetal
      tissues tested but only in adult lung and kidney. HMGIC was also expressed in
      leiomyoma tumor samples containing t(12;14) and in all in vitro cell cultures.
      The pattern of HMGIC expression suggests that this gene is important in rapidly
      proliferating human fetal tissues. Restoration of expression in leiomyomata
      required dysregulation of HMGIC. Transcripts of HMGIC can also be detected after
      in vitro cell culture, suggesting that HMGIC expression may be affected by
      factors present in culture media and serum. Genes Chromosomes Cancer 25:316-322,
      1999.

PMID- 10398426
TI  - Cytogenetic clonality analysis of megakaryocytes in myelodysplastic syndrome by
      dual-color fluorescence in situ hybridization and confocal laser scanning
      microscopy.
AB  - In the myelodysplastic syndrome (MDS), cytogenetic abnormalities are often
      present and can be used as markers in studies for cell lineage involvement.
      Little is known of the involvement of the megakaryocytic lineage due to the
      variable ploidy of these cells. We applied dual-color fluorescence in situ
      hybridization (FISH) to routinely prepared bone marrow (BM) smears of
      cytogenetically normal patients and seven patients with MDS and monosomy 7 or
      trisomy 8. Probes specific for the centromeric regions of chromosomes 7 and 8
      were detected with fluorescein isothiocyanate (FITC) and Texas Red, respectively.
      This enabled us to assess the ratio between the numbers of chromosomes 7 and 8 in
      the polyploid cells. We utilized confocal laser scanning microscopy to count the
      FITC and Texas Red FISH signals in the different focal layers of the
      megakaryocytes. Fifty-six megakaryocytes in six normal BM smears were analyzed,
      giving a mean ratio of 1.0, a standard deviation (SD) of 0.12, and a range of 0.8
      1.33. This ratio was applied to evaluation of clonal involvement of individual
      megakaryocytes in the patients with MDS. In two patients with monosomy 7, the
      majority of the megakaryocytes were monosomic. In the five patients with trisomy
      8, all or a majority of the analyzed megakaryocytes were trisomic. These results
      add direct evidence that in MDS megakaryocytes are involved in the malignant
      clone. Genes Chromosomes Cancer 25:332-338, 1999.

PMID- 10398427
TI  - CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma
      probands: effect of family history and multiple primary melanomas.
AB  - Mutation analysis of two genes involved in melanoma susceptibility
      (CDKN2A/p16(INK4a) and CDK4) was undertaken in 131 probands with a family history
      of melanoma. Screening of all three exons of CDKN2A and exon 2 of CDK4 by single
      strand conformation polymorphism (SSCP) analysis and/or direct sequencing
      identified a total of 10 different CDKN2A germline mutations, including 6 not
      previously described in the germline. All but one has been previously proven to,
      or is likely to, affect the structure and function of p16(INK4a). The incidence
      of CDKN2A mutation was 8.4% (11/131), but was significantly higher in families
      with three or more cases of melanoma (10/66, 15.1%) than in those in which only
      two relatives were affected (1/65, 1.5%). The incidence of CDKN2A mutation was
      also higher in families with three or more cases of melanoma and at least one
      member with multiple primary melanomas (6/19, 31.6%) than in similar families
      without multiple primary melanomas (4/47, 8.5%). One novel CDK4 variant of
      uncertain significance was found in a kindred that also carries a CDKN2A
      mutation. Genes Chromosomes Cancer 25:339-348, 1999.

PMID- 10398428
TI  - Low frequency of numerical chromosomal aberrations in follicular thyroid tumors
      detected by comparative genomic hybridization.
AB  - Follicular thyroid tumors vary from adenomas to widely invasive carcinomas, and a
      stepwise progression from normal thyrocyte to malignant tumor has been suggested
      to be due to an accumulation of genetic alterations. We have used comparative
      genomic hybridization to screen 21 follicular thyroid tumors (8 adenomas and 13
      carcinomas) for gains and losses of DNA sequence copy numbers. In general, the
      tumors showed few alterations involving several different chromosomal regions.
      The frequency of alterations was similar in the benign (mean, 1.9) and malignant
      (mean, 1.5) tumors, as well as in minimally (mean, 1.5) and widely invasive
      carcinomas (mean, 1.6). However, specific loss of 9q13-q21.3 was detected in
      three tumors, which were all carcinomas showing oxyphilic changes (Hurthle cell
      carcinomas; P = 0.003). The fact that DNA copy number alterations were found with
      a similarly low frequency in both benign and malignant follicular thyroid tumors
      does not support the hypothesis of a multistep tumor progression in these tumors.
      Genes Chromosomes Cancer 25:349-353, 1999.

PMID- 10398429
TI  - Linkage analysis and loss of heterozygosity for chromosome arm 1p in familial
      breast cancer.
AB  - We conducted linkage analysis of 64 multiple-case families with early-onset
      bilateral breast cancer using DNA markers on chromosome band 1p36. Evidence
      against tight linkage was obtained using a dominant model for transmission
      (summary LOD scores at recombination fraction theta = 0.000001 were -4.71 for
      D1S160 and -2.70 for D1S170). Similar results were obtained after excluding 20
      families that were potentially attributable to BRCA1 or BRCA2. We also
      investigated loss of heterozygosity for a panel of markers on chromosome arm 1p
      using breast tumors from affected family members. The most common regions of
      allele loss were 1p36 (32% for D1S160, 35% for D1S243) and 1p32 (51% for MYCL).
      The frequency and location of 1p allele loss did not differ substantially from
      previous studies of sporadic breast cancer. We conclude that 1p36 probably does
      not contain a locus of susceptibility for a large proportion of breast cancer
      families, but a variety of loci on 1p may contribute to progression of familial
      and sporadic disease. Genes Chromosomes Cancer 25:354-361, 1999.

PMID- 10398430
TI  - Analysis of chromosomal imbalances in sporadic and NF1-associated peripheral
      nerve sheath tumors by comparative genomic hybridization.
AB  - Peripheral nerve sheath tumors arise either sporadically or in association with
      neurofibromatosis type 1 (von Recklinghausen's neurofibromatosis, NF1) or type 2.
      In this study, comprehensive screening for relative chromosome copy number
      changes was performed on 10 benign and 19 malignant peripheral nerve sheath
      tumors (MPNSTs) by applying comparative genomic hybridization (CGH). In benign
      tumors, no chromosomal imbalances were found by CGH, whereas in MPNSTs
      chromosomal gains and losses were frequently detected. No differences regarding
      the frequency and distribution of chromosomal imbalances were observed between
      the 13 sporadic and 6 NF1-associated MPNSTs analyzed. In both, the number of
      gains was significantly higher than the number of losses, suggesting a
      predominant role of proto-oncogene activation during MPNST progression. Candidate
      regions with potentially relevant proto-oncogenes included chromosomal bands
      17q24-q25, 7p11-p13, 5p15, 8q22-q24, and 12q21-q24; those with putative tumor
      suppressor genes were 9p21-p24, 13q14-q22, and 1p. High-level amplifications were
      restricted to sporadic tumors and affected eight different chromosomal
      subregions. In three of these MPNSTs, identical subregions on chromosomal arms 5p
      and 12q were coamplified. This study revealed a number of new characteristic
      chromosomal imbalances and provides a basis for molecular identification of
      oncogenes and tumor suppressor genes of pathogenetic relevance in both sporadic
      and NF1-associated MPNSTs. Genes Chromosomes Cancer 25:362-369, 1999.

PMID- 10398432
TI  - Arylamine N-acetyltransferase type 2 (NAT2), chromosome 8 aneuploidy, and
      identification of a novel NAT1 cosmid clone: an investigation in bladder cancer
      by interphase FISH.
AB  - Two genes (arylamine N-acetyltransferase types 1 and 2, NAT1 and NAT2), which are
      known to metabolize bladder carcinogens, are located on chromosome band 8p22.
      Alterations in chromosome 8, including deletions of 8p, occur frequently in many
      epithelium-derived tumors. In this study, fluorescence in situ hybridization
      (FISH) was used for study of the relationship between chromosome 8 deletions in
      the region of NAT1 and NAT2 and grade and stage of tumor in bladder cancer. Cells
      from 52 bladder tumors were examined by dual-labeling FISH with a centromere 8
      specific probe and a cosmid probe for NAT2. A more limited number were examined
      for loss with both the NAT2 probe and a newly constructed NAT1-specific cosmid.
      Loss of NAT2 was found in 6/52 patients in more than 30% of cells, and in 10/52
      in 10%-30% of cells examined. Six samples also showed loss of NAT1, indicating
      that the region of deletion spans at least the distance of the two genes. No
      obvious correlation between loss of NAT genes with grade and stage of tumor was
      evident. Interestingly, 17/52 (32%) tumors showed an increased copy number of
      chromosome 8, with tumors of low stage showing relatively smaller increases of
      chromosome 8. Loss of 8p22 and genetic instability involving chromosome 8
      indicate that this chromosome is important in bladder cancer and that NAT genes
      will act as important genetic landmarks in defining deletions in this disease.
      Genes Chromosomes Cancer 25:376-383, 1999.

PMID- 10398431
TI  - Novel homozygous deletions of chromosomal band 18q22 in pancreatic adenocarcinoma
      identified by STS marker scanning.
AB  - The identification of homozygous deletions in sporadic neoplasms has been pivotal
      in the positional cloning of several tumor suppressor genes. Chromosomal arm 18q
      harbors the DPC4, SMAD2, and DCC genes and is suspected on the basis of high
      frequencies of allelic loss to harbor additional tumor suppressor genes. We
      applied high-resolution sequence-tagged site (STS) marker scanning to a panel of
      106 pancreatic adenocarcinomas to identify novel regions of homozygous deletions
      on 18q. Three homozygous deletions were identified. Physical mapping of these
      deletions showed them to be nonoverlapping, but clustered in an approximately 7-
      to 10-Mb region of chromosome band 18q22. Each deletion spanned physical
      distances of nearly 1.3 to 3 Mb. A number of transcribed genes map within these
      deletions. The identification of these homozygous deletions might aid in the
      identification of novel tumor suppressor genes on chromosomal arm 18q. Genes
      Chromosomes Cancer 25:370-375, 1999.

PMID- 10398433
TI  - Delineation of multiple deleted regions in 7q in myeloid disorders.
AB  - Loss of chromosome material due to deletions of the long arm of chromosome 7,
      del(7q), is a consistent finding in all types of myeloid disorders, invariably
      associated with a poor prognosis. Two different segments, 7q22 and 7q32-q33, have
      been implicated as critical regions of gene loss associated with these disorders.
      In the present study, we used fluorescence in situ hybridization (FISH) to
      characterize the 7q22 breakpoint of an apparently balanced t(7;7)(p13;q22) in an
      acute myeloid leukemia patient. FISH analysis on bone marrow metaphases from this
      patient revealed that the sequence corresponding to a series of three ordered
      cosmids from 7q22 was deleted from one of the der(7) chromosomes. These cosmids
      contain the human homologue of the Drosophila homeobox gene cut (CUTL1) and span
      a region of approximately 150 kb. Although the proximal boundary of the deleted
      segment could not be exactly defined, we estimate the size of this deletion to be
      approximately 500 kb. Subsequently, we carried out FISH studies using the CUTL1
      cosmids on a further 16 patients with deletions of 7q and myeloid disorders. The
      sequence corresponding to at least two of the cosmids was deleted from the
      del(7q) in 11 out of 14 cases with a proximal breakpoint within 7q22. Further
      detailed FISH mapping in this series of 17 patients has identified two other
      nonoverlapping commonly deleted segments at 7q31-q32 and 7q33, respectively.
      These data confirm and refine other studies, implying that several different
      genes on 7q may be involved in the pathogenesis of myeloid diseases. Genes
      Chromosomes Cancer 25:384-392, 1999.

PMID- 10398434
TI  - Determination of the frequency of the common 657Del5 Nijmegen breakage syndrome
      mutation in the German population: no association with risk of breast cancer.
AB  - Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal
      instability syndrome characterized by microcephaly, growth retardation,
      immunodeficiency, and cancer predisposition. It shares a number of features with
      the Ataxia telangiectasia (AT) syndrome: the most notable are high sensitivity to
      ionizing radiation and predisposition to cancer. Recently, the gene responsible
      for NBS has been identified on chromosome band 8q21. It encodes a DNA double
      strand break repair protein, named Nibrin. A truncating 5-bp deletion (657Del5)
      has been identified in 90% of NBS patients and this is presumed to be of Slavic
      origin. There is evidence that heterozygous AT mutation carriers are predisposed
      to breast cancer. Since the NBS phenotype at the cellular level is very similar
      to AT, we have screened 477 German breast cancer patients, aged under 51 years,
      and 866 matched controls for the common NBS mutation. We have identified one
      carrier among the cases and one among the controls, indicating that the
      population frequency of this NBS mutation is 1 in 866 people (95% CI = 1 in
      34,376 to 1 in 156) and the estimated prevalence of NBS is thus 1 in 3 million
      people. The proportion of breast cancer attributable to this mutation is less
      than 1%. Genes Chromosomes Cancer 25:393-395, 1999.

PMID- 10398435
TI  - Germline mutations are frequent in the APC gene but absent in the beta-catenin
      gene in familial adenomatous polyposis patients.
AB  - Inactivation of the adenomatous polyposis coli (APC) gene has been shown to
      initiate the majority of colorectal cancer (CRC), including a familial form
      called familial adenomatous polyposis (FAP). One consequence of the APC mutation
      is the activation of the beta-catenin (CTNNB1)/T-cell transcription factor (Tcf)
      pathway. A recent study has shown that about half of the sporadic CRC lacking APC
      mutation has CTNNB1 mutation, suggesting that CTNNB1 mutation can substitute for
      APC mutation in the initiation of colorectal tumorigenesis. However, the
      frequency of CTNNB1 germline mutation in FAP has not been reported. In the
      present study, we investigated the frequencies of APC and CTNNB1 germline
      mutations in 26 unrelated FAP families. We used the Protein Truncation Test (PTT)
      to screen the entire coding region of APC and found germline mutations in twenty
      families. We then screened for CTNNB1 germline mutations in the rest of the
      families lacking detectable APC mutations. No missense mutations at GSK-3beta
      phosphorylation sites or interstitial deletion of exon 3 of CTNNB1 was found. Our
      results indicate that APC germline mutations are frequent but CTNNB1 germline
      mutations are rare in FAP patients, suggesting that CTNNB1 mutation cannot
      substitute for APC mutation in the initiation of FAP. Genes Chromosomes Cancer
      25:396-398, 1999.

PMID- 10398436
TI  - Beta-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma.
AB  - Hepatoblastoma is a rare malignant tumor of the liver that occurs in children at
      an average age of 2 to 3 years. Epidemiologic studies have shown an increased
      frequency of this tumor type in families affected by adenomatous polyposis coli.
      In addition to the epidemiologic data, molecular genetic studies suggest that
      inactivation of the APC tumor suppressor may be involved in hepatoblastoma
      tumorigenesis. A major function of APC is the downregulation of beta-catenin, a
      transcription-activating protein with oncogenic potential. In an ongoing
      immunohistochemical study of beta-catenin expression in sporadic cases of tumor
      types that are associated with adenomatous polyposis coli, we observed increased
      beta-catenin levels in the cytoplasm and in the nuclei of three investigated
      hepatoblastomas. Sequencing of exon 3 of the beta-catenin gene (CTNNB1) revealed
      an activating mutation in one of the tumor samples. Our data indicate for the
      first time that beta-catenin accumulation may play a role in the development of
      hepatoblastoma and that activating mutations of the beta-catenin gene may
      substitute biallelic APC inactivation in this tumor type. Genes Chromosomes
      Cancer 25:399-402, 1999.

PMID- 10398437
TI  - Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile
      polyposis patients.
AB  - Familial juvenile polyposis (FJP) is a hamartomatous polyposis syndrome
      characterized by the appearance of juvenile polyps in the gastrointestinal tract.
      Patients with this syndrome are at an increased risk for cancer of the colon,
      stomach, and pancreas. Recently, germline mutations in the SMAD4/DPC4 gene
      (official symbol MADH4) have been found in the majority of patients suffering
      from FJP. We have examined 11 unrelated patients with FJP for MADH4 germline
      mutations by direct sequencing of genomic DNA encompassing all 11 exons of the
      gene. Besides a novel mutation (959-960delAC at codon 277, exon 6) in one
      patient, we observed a 4-bp deletion (1372-1375delACAG) in exon 9 in two
      unrelated patients. Examination with microsatellite markers flanking MADH4
      supports an independent origin of the mutation in these two families. The same 4
      bp deletion in exon 9 has previously been described in three out of nine patients
      examined for MADH4 mutations. Our results combined with these previous data
      demonstrate that a unique 4-bp deletion in exon 9 of MADH4 accounts for about 25%
      of all FJP cases and that other MADH4 mutations occur in an additional 15% of
      patients. Genes Chromosomes Cancer 25:403-406, 1999.

PMID- 10398438
TI  - The BRCA2 transactivation domain does not interact with JNK.
AB  - The N-terminal region of BRCA2 has the capacity to activate transcription when
      fused to a heterologous DNA binding domain and includes a segment with amino acid
      similarity to the JNK-docking site in the cellular JUN protein. However, unlike
      JUN, we have determined that this region of BRCA2 neither interacts with nor
      serves as a substrate for JNK, or any other kinase that can be detected in
      extracts from either fibroblasts or epithelial cells. While this clearly does not
      rule out a transcriptional role for BRCA2, our findings indicate that BRCA2 is
      not regulated by the JNK pathway in a manner analogous to JUN. Genes Chromosomes
      Cancer 25:407-409, 1999.

PMID- 10398439
TI  - Deletions below 10 megabasepairs are detected in comparative genomic
      hybridization by standard reference intervals.
AB  - Comparative genomic hybridization (CGH) is a widely used technique for studying
      chromosomal imbalances. The sensitivity of the technique is, however, relatively
      low. Deletions down to a size of 10-12 Mbp have been detected by the use of fixed
      diagnostic thresholds. In this study, we applied standard reference intervals as
      detection criteria on a number of deletions in the range of 3 Mbp to 14-18 Mbp.
      All deletions were detected. Thus, detection by standard reference intervals
      confers a considerably higher sensitivity to CGH analysis compared to fixed
      diagnostic thresholds. Genes Chromosomes Cancer 25:410-413, 1999.

PMID- 10398442
TI  - The CD4 Loss in AIDS Patients is not Immunopathologically Mediated.

PMID- 10398440
TI  - The Pathogenesis of the Acute ExanthemsReproduced from The Lancet 11 December
      1948, 915-920, with kind permission from (c) The Lancet Ltd.

PMID- 10398441
TI  - The CD4 Loss in AIDS Patients is Immunopathologically Mediated.

PMID- 10398443
TI  - Pathophysiology of Pain with Reference to Herpes Zoster.

PMID- 10398444
TI  - Virus Safety of Plasma Products.

PMID- 10398445
TI  - Transforming Proteins of Human Papillomaviruses.

PMID- 10398446
TI  - Production of Plaques in Monolayer Tissue Cultures by Single Particles of an
      Animal VirusReproduced from Proc. Natl Acad. Sci 38, 747-752 (1952) with kind
      permission of Proceedings of the National Academy of Sciences, USA.

PMID- 10398447
TI  - All Patients with Recurrent Genital Herpes Should be Offered Suppressive Therapy
      with Acyclovir.

PMID- 10398448
TI  - All Patients with Recurrent Genital Herpes Should not be Offered Suppressive
      Therapy with Acyclovir.

PMID- 10398450
TI  - Transmission of Epstein - Barr Virus During Transplantation.

PMID- 10398449
TI  - New Agents of Viral Hepatitis.

PMID- 10398451
TI  - Vaccine Therapy for Herpes Simplex Virus Infections: An Historical Perspective.

PMID- 10398452
TI  - What can be Expected from Non-nucleoside Reverse Transcriptase Inhibitors
      (NNRTIs) in the Treatment of Human Immunodeficiency Virus Type 1 (HIV-1)
      Infections?

PMID- 10398453
TI  - HIV/AIDS Vaccine Development: Challenges, Progress and Future Directions.

PMID- 10398454
TI  - Neuropathology and Virology of HIV Associated Dementia.

PMID- 10398455
TI  - Predicting the effect of varicella vaccine on subsequent cases of zoster and
      varicella.

PMID- 10398456
TI  - Interaction of Herpes Viruses with HIV: Can Antiherpes Drugs Prolong Survival
      Among AIDS Patients?

PMID- 10398457
TI  - Human Herpesvirus, Type 8. Early Days.

PMID- 10398458
TI  - Editorial.

PMID- 10398459
TI  - Virus-encoded Zinc Fingers as Targets for Antiviral Chemotherapy.

PMID- 10398460
TI  - Genomic Function and Variation of Human Polyomavirus BK (BKV).

PMID- 10398462
TI  - Bovine Spongiform Encephalopathy.

PMID- 10398461
TI  - Treatment of Chronic Hepatitis B and Chronic Hepatitis C.

PMID- 10398463
TI  - Keeping up with progress.

PMID- 10398464
TI  - Infectious Hepatitis: Evidence for Two Distinctive Clinical, Epidemiological, and
      Immunological Types of Infection.

PMID- 10398465
TI  - Britain Should Immediately Alter its Quarantine Rules for the Control of Rabies.

PMID- 10398466
TI  - Britain Should Not Immediately Alter its Quarantine Rules for the Control of
      Rabies.

PMID- 10398467
TI  - Vitamin A Regulation of Viral Growth.

PMID- 10398469
TI  - Reverse Genetics Meets the Nonsegmented Negative-Strand RNA Viruses.

PMID- 10398468
TI  - Orthopoxviruses and Their Immune Escape.

PMID- 10398470
TI  - How to cross the species-barrier.

PMID- 10398471
TI  - The diagnosis of the invasion of measles from a study of the exanthema as it
      appears on the buccal mucous membraneBy Henry Koplik, M.D. Reproduced from Arch.
      Paed. 13, 918-922 (1886).

PMID- 10398472
TI  - Developed countries should use inactivated polio vaccine for the prevention of
      poliomyelitis.
AB  - As the public health situation regarding polio changes, we should not be afraid
      to change our thinking about vaccination policy. OPV is still the vaccine of
      choice to eradicate wild poliomyelitis from the developing world. However, in
      developed countries free of poliomyelitis there is no longer a necessity to
      tolerate VAPP as the consequence of vaccination. IPV as part of combination
      vaccines or in mixed schedules with OPV is preferable and is in process of
      becoming the norm for those countries. Copyright 1997 John Wiley & Sons, Ltd.

PMID- 10398473
TI  - Developed countries should not use inactivated polio vaccine for the prevention
      of poliomyelitis.
AB  - Taking into account the global status of polio, it seems evident that the
      continuing use of oral poliovaccine in all countries is the most obvious and
      prudent public health policy for the foreseeable future. Possible exceptions
      might include those countries which are not troubled by the added cost of the
      inactivated vaccine; whose health services are able to guarantee high levels of
      vaccine coverage; and which can expect to experience comparatively few
      importations of wild poliovirus. An important question is whether it is warranted
      at this time to recommend a combined schedule of inactivated vaccine followed by
      live vaccine. This implies the addition of at least two inoculations of
      inactivated vaccine to an already complex vaccination schedule. In most
      countries, this now includes the administration of three inoculations each of DTP
      and Haemophilus influenzae as well as one of measles-mumps-rubella vaccine by
      approximately 12 months of age. Some countries also routinely vaccinate young
      children against hepatitis B (three additional inoculations). Because most
      physicians and clinics, as a policy, do not give more than two inoculations at
      one visit, it implies the need for scheduling additional well-child visits. In
      the United States, this is a principal factor in the greatly increased estimated
      costs of such a programme. Experience also shows that as the number of routine
      visits which are required for vaccination increases, overall vaccination coverage
      diminishes. The schedule recommended in the United States possesses yet a further
      problem. Children there would not receive the second dose of oral vaccine until
      five years of age, thus permitting the accumulation of a large number of
      preschool children with limited intestinal immunity-a potentially explosive
      problem were wild virus to be introduced. The inactivated polio vaccine is useful
      and certainly indicated for the small numbers of persons for whom the live, oral
      vaccine is contraindicated. However, to use it routinely implies accepting the
      potential of substantial penalties while reducing but not eliminating, an already
      extremely small risk of vaccine-associated paralytic illness. From the public
      health perspective, I therefore argue against the proposition. Copyright 1997
      John Wiley & Sons, Ltd.

PMID- 10398474
TI  - RNA virus fitness.
AB  - RNA viruses constitute the most abundant group of pathogens of man, animals and
      plants. They share high mutation rates which are in the range 10(-3) to 10(-5)
      misincorporations per nucleotide site and round of copying. This is due to the
      absence or low efficiency of proofreading-repair or postreplicative repair
      activities associated with replicating RNA. Populations of RNA viruses are
      extremely heterogeneous and form dynamic mutant swarms termed viral quasispecies.
      This genetic organisation implies that any individual mutant has only a fleeting
      existence; that is, RNA viral genomes are statistically defined but individually
      indeterminate. RNA viruses are able to accommodate their average nucleotide
      sequences to changes in environment. A parameter used to quantitate adaptation is
      fitness, or the relative ability of a virus to produce infectious progeny.
      Repeated transfers of one or a few particles (bottleneck events) generally lead
      to fitness losses. In contrast, large population passages allow competitive
      optimisation of mutant genomes and fitness gains. Of relevance to medical
      practice is the ability of viral quasispecies to overcome selective pressures
      imposed by vaccines and antiviral agents. Particularly dramatic have been the
      systematic isolations of HIV-1 mutants resistant to antiretroviral inhibitors in
      treated individuals. In addition to the ability of HIV-1 quasispecies to generate
      many mutant genomes in short times, calculations of mutation frequencies in the
      pol gene of HIV-1 populations have documented that mutations related to
      resistance to antiretroviral inhibitors preexist in the mutant swarms of HIV-1
      quasispecies. It is not possible at present to anticipate whether a suitable drug
      cocktail may be capable of sustained inhibition of HIV-1 replication without
      selection of mutants resistant to the combination of antiviral agents. Copyright
      1997 John Wiley & Sons, Ltd.

PMID- 10398475
TI  - Epstein-Barr virus latent infection in vivo.
AB  - Epstein-Barr virus (EBV) is an exclusively human herpes virus which is recognised
      as the causative agent of infectious mononucleosis and which is implicated in the
      aetiology of several cancers. However, it is particularly remarkable that this
      virus is harboured without causing symptoms for the lifetime of most
      immunocompetent adults. Virus and host have co-evolved over millions of years,
      achieving a balance between viral persistence and immune control. It is this
      dynamic equilibrium which is the focus of this review. The main site of viral
      persistence is within latently infected lymphocytes, although infectious virus is
      also released into saliva from productively infected cells in the oropharynx. In
      vitro, EBV efficiently transforms resting B cells to activated, perpetually
      dividing lymphoblasts. These express a repertoire of eight viral antigens,
      several of which have been found to be targets for cytotoxic T cell (CTL)
      responses in healthy carriers. Transformed lymphoblasts are susceptible to immune
      control in vivo, and are abundant only during primary infection or in individuals
      with impaired cell mediated immunity. Other types of viral latent infection have
      been identified in malignant cell lines, in which EBV expresses a more restricted
      range of antigens. These also may have their in vivo equivalents during natural
      infection in healthy carriers. It is likely that the virus evades elimination by
      the immune system by establishing infection in non-activated, relatively non
      immunogenic B cells, in which the main CTL target antigens are not expressed.
      Copyright 1997 John Wiley & Sons, Ltd.

PMID- 10398476
TI  - Capsid assembly and DNA packaging in herpes simplex virus.
AB  - The genome of HSV-1 contains 80-85 open reading frames. Genetic and biochemical
      evidence suggests that at least 39 of these genes encode proteins that are
      components of the HSV-1 virion. The architecture of the HSV-1 virion consists of
      a trilaminar lipid envelope, an amorphous layer known as the tegument, a capsid
      shell, and a DNA-containing core. The capsid is an icosahedral shell whose major
      morphological features are 162 capsomers. It is composed of a major capsid
      protein called VP5 and three less abundant proteins, VP19C, VP23 and VP26. VP5 is
      the structural subunit of all 162 capsomers while VP19C and VP23 are located in
      the space between the capsomers. In addition to the structural proteins, capsid
      assembly involves participation of the HSV-1-encoded protease and the scaffolding
      protein, preVP22a. DNA packaging involves participation of DNA, empty capsids,
      and at least seven additional HSV-1-encoded proteins. Considerable advances have
      been made in understanding the structure of the capsid shell, largely as the
      result of applying cryoelectron microscopy techniques. Use of recombinant
      baculoviruses has allowed for a detailed analysis of the proteins required for
      capsid assembly. More recently, an in vitro system has been developed which has
      aided in defining the assembly pathway by identifying intermediates in the
      assembly of intact capsids. The in vitro system has identified a fragile roundish
      procapsid which matures into the polyhedral capsid in a transition similar to
      that undergone by bacteriophage proheads. This review is a summary of our present
      knowledge with respect to the structure and assembly of the HSV-1 capsid and what
      is known about the seven genes involved in DNA packaging. Copyright 1997 John
      Wiley & Sons Ltd.

PMID- 10398477
TI  - What virology has taught us.

PMID- 10398478
TI  - The pathology of Herpes Zoster and its bearing on sensory localisation.

PMID- 10398479
TI  - Clinical uses of cidofovir.
AB  - Cidofovir is a cytidine nucleotide analogue recently licensed as an intravenous
      treatment for CMV retinitis in AIDS patients. Three controlled clinical trials
      have demonstrated efficacy of cidofovir for this indication, and have generated
      data useful as a guideline to prevent potential toxicity. Although de novo
      emergence of resistance to cidofovir has not been observed clinically in patients
      receiving cidofovir, cross-resistance to cidofovir in ganciclovir-resistant
      clinical DNA polymerase mutants has been identified. Cross-resistance of
      cidofovir and foscarnet has not been identified to date. A broad spectrum agent
      with in vitro activity against human herpesviruses, adenovirus, HPV,
      polyomaviruses and human poxviruses, cidofovir is under clinical investigation
      for a variety of potential applications. Examples include intravenous
      administration of cidofovir for treatment of progressive multifocal
      leukoencephalopathy and Kaposi's sarcoma, intraocular injection for treatment of
      CMV retinitis, intralesional injection for treatment of respiratory
      papillomatosis, topical application for treatment of molluscum contagiosum,
      anogenital condyloma acuminata, and recurrent genital herpes, and ophthalmic
      instillation for treatment of viral keratoconjunctivitis. Copyright 1997 John
      Wiley & Sons, Ltd.

PMID- 10398481
TI  - Cellular proteins in HIV virions.
AB  - Human immunodeficiency virus type-1 (HIV-1) virions contain both virus-encoded
      and cellular proteins. Recent advances in the detection, isolation, and
      functional characterisation of host proteins incorporated in the virion have
      begun to provide for new perspectives on the interactions between virus and cell.
      The acquisition of host proteins by HIV-1 may also influence viral pathology in
      vivo. This article reviews detection and analysis of host proteins found in HIV-1
      particles and presents some potential roles that these proteins might play in the
      biology of this important virus. Copyright 1997 John Wiley & Sons, Ltd.

PMID- 10398482
TI  - T cell therapy of human CMV and EBV infection in immunocompromised hosts.
AB  - Acute virus infections in normal hosts are typically controlled by the
      development of a host immune response that includes MHC-restricted virus-specific
      T cells. Many viruses have developed methods to evade T cell recognition to
      facilitate initial infection and the establishment of a persistent infection in
      the host. Human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are ubiquitous
      human pathogens that utilise novel strategies to evade immune elimination.
      Despite these evasion methods, CD4(+) and CD8(+) T cells expressing alphabeta T
      cell receptors have been shown to play a pivotal role in controlling initial
      infection and in maintaining CMV and EBV in a latent state. However, in settings
      of iatrogenic or acquired T cell deficiency, primary infection or reactivation of
      CMV and EBV frequently progresses to cause life threatening disease. In this
      article the role of MHC-restricted CD8(+) and CD4(+) T cell responses in
      controlling CMV and EBV infections in healthy individuals and the development of
      novel strategies to restore protective T cell immunity to deficient hosts by the
      adoptive transfer of virus-specific T cells is reviewed. Copyright 1997 John
      Wiley & Sons, Ltd.

PMID- 10398480
TI  - HIV-1 pathogenesis and therapeutic intervention in the SCID-hu Thy/Liv mouse: a
      model for primary HIV-1 infection in the human thymus.
AB  - The SCID-hu Thy/Liv mouse is a model for the analysis of human thymopoiesis. It
      has been constructed by engrafting fragments of human fetal liver and thymus into
      the immunodeficient C.B-17 scid/scid (SCID) mouse. The resulting 'Thy/Liv' organ
      promotes long-term differentiation of human T cells. Given the apparently normal
      physiology of the SCID-hu Thy/Liv organ, it has been used to explore the
      pathophysiologic mechanisms of HIV-1 infection in vivo, and to test therapeutic
      modalities such as anti-HIV-1 drugs and haematopoietic stem cell (HSC)-based gene
      therapy. In this review, I will summarise what we have learned from the SCID-hu
      Thy/Liv model, with a focus on recent findings in HIV-1 replication and therapy.
      Unique HIV-1 determinants have been identified which are required for replication
      in the Thy/Liv organ but not for replication in PBMC or in T cell lines in vitro.
      The mechanism of HIV-1 induced thymus depletion is not clear. It is correlated
      with high levels of HIV-1 replication. Both direct and indirect mechanisms may be
      involved. In addition to preclinical evaluation of anti- HIV-1 drugs, the SCID-hu
      Thy/Liv mouse has also been successfully used to test the feasibility of HSC
      based gene therapy. A number of improved SCID-hu models have been constructed to
      meet different requirements. Using these SCID-hu Thy/Liv models, current/future
      efforts will provide insightful information for understanding pathogenesis and
      designing therapeutic interventions against HIV-1 infection in humans, especially
      in paediatric patients. Copyright 1997 John Wiley & Sons, Ltd.

PMID- 10398483
TI  - Neonatal HSV and Evidence-based medicine.

PMID- 10398484
TI  - An Update on Non-clathrin-coated Endocytosis.
AB  - Recent evidence has proved that in addition to the well-documented clathrin
      mediated endocytic route (vesicles of 100-150 nm), at least three distinct non
      clathrin-coated endocytic pathways function at the surface of mammalian cells.
      Endocytosis via these pathways is initiated by caveolae (50-80 nm),
      macropinosomes (500-2000 nm) and micropinosomes (95-100 nm). The current state of
      knowledge about these non-clathrin coated endocytic routes is presented and
      evidence that endocytic routes other than via clathrin-coated vesicles are
      utilised by viruses is discussed. The recent advances in these areas have
      provided us with tools to investigate the entry of those viruses which appear to
      enter cells via endocytosis into non-clathrin-coated vesicles. Data indicate that
      these four endocytic pathways differ in the absence, presence and/or type of coat
      on the vesicles, the size of the vesicles, their sensitivity to a variety of
      inhibitors, and in the ligands endocytosed. A historical perspective of the
      discovery of these non-clathrin-coated endocytic pathways is provided and recent
      information is summarised and discussed. The entry of viruses via non-clathrin
      coated pits is destined to be an exciting new area of viral-cell entry, as has
      been indicated recently by the finding that entry of simian virus type 40 into
      cells occurs via caveolae. Copyright 1997 by John Wiley & Sons, Ltd.

PMID- 10398485
TI  - The Simian Parvoviruses.
AB  - Autonomous parvoviruses with tropism for erythroid cells have recently been
      reclassified in a new genus, erythrovirus. Although B19 is the type member, and
      presently the only internationally accepted member of the erythrovirus genus, we
      have identified three new simian viruses, all of which have the molecular
      features of parvoviruses, and are highly tropic for erythroid progenitor cells.
      This review describes the identification of these new animal parvoviruses and
      summarises current knowledge of their molecular, clinical and epidemiological
      features. Most studies have been performed with the first virus discovered,
      simian parvovirus (SPV), which was isolated from anaemic cynomolgus monkeys. SPV
      is currently under investigation as an animal model for B19 parvovirus infection.
      Clinical similarities and molecular homology to parvovirus B19 justify the
      inclusion of these novel viruses as new members of the erythrovirus genus.
      Copyright 1997 by John Wiley & Sons, Ltd.

PMID- 10398486
TI  - The Structure of the Human Placenta: Implications for Initiating and Defending
      Against Virus Infections.
AB  - The architecture of the human placenta permits an extensive and intimate
      association between the maternal and fetal circulations. The fetal component
      consists of the elaborately branched villous tree, and this is bathed directly by
      maternal blood circulating within the intervillous space. Whilst this arrangement
      may favour metabolic exchange, it poses considerable risks for the vertical
      transmission of pathogens. Some features of placental structure can be considered
      potential impediments to transmission, such as the syncytial nature of the outer
      villous covering, the syncytiotrophoblast, and the ability of this tissue to
      secrete both nitric oxide and interferons. Other features may facilitate vertical
      transmission, including the lack of expression of MHC Class 1 antigens by the
      syncytiotrophoblast, and its vesicular and immunoglobulin transport pathways.
      More importantly, it is known that physical defects occur in the trophoblast
      layers at all stages in gestation. Whilst repair processes have been identified
      it must be assumed that pathogens or infected maternal white cells have access to
      the trophoblastic basement membrane, albeit transiently. The universal nature of
      these defects suggests that the trophoblast cannot be of paramount importance in
      the prevention of transmission. Rather, the defence mechanisms must lie either at
      the level of the basement membrane or within the villous core. There they may be
      represented by the resident macrophage population or the capillary endothelial
      cells and their junctional complexes. Consequently, the placenta should be viewed
      as an active rather than a passive barrier. Copyright 1997 by John Wiley & Sons,
      Ltd.

PMID- 10398487
TI  - Functional Domains within the Nucleus of a Cell Infected with HSV-1.
AB  - HSV-1 is a nuclear replicating DNA virus capable of establishing both lytic and
      latent infections in mammalian cells. Expression of the more than 80 HSV genes
      (the majority of which do not contain introns) requires complex coordination of
      viral and cellular factors both temporally, at appropriate points during the
      infectious cycle, and spatially as the virus transcription, replication and DNA
      packaging factories develop in the cell nucleus. Whilst the HSV genome encodes
      sufficient proteins to sustain viral DNA replication, it is reliant upon its host
      cell for RNA polymerase II and RNA processing machinery, in addition to an
      increasing number of cellular cofactors, for gene expression. As HSV establishes
      a lytic infection, cellular gene expression and splicing are inhibited as
      cellular chromatin is displaced and a dramatic reorganisation of the host cell
      nucleus occurs. The formation of large protein-rich factories synthesising viral
      RNA and replicating and packaging the viral genomes is the most striking
      alteration. In addition to the synthetic factories, large clumps of cellular and
      viral intron-containing RNAs accumulate in the nucleus as a result of the
      inhibition of splicing, at locations which colocalise with splicing factors, but
      are separate from transcription sites. An essential HSV protein IE63, discussed
      here, has been identified with a role in the organisation of the nucleus at many
      levels including replication and transcription site formation, splicing factor
      organisation and the transport of RNA. This review is a summary of our present
      understanding of the organisation of the HSV infected cell nucleus, relating
      viral genomes, RNA, DNA and proteins in the context of the nucleus. However this
      is a rapidly evolving field and new factors (both viral and cellular) involved in
      the regulation of these functional domains are constantly being identified.
      Copyright 1997 by John Wiley & Sons, Ltd.

PMID- 10398488
TI  - Threat to Humans from Virus Infections of Non-human Primates.
AB  - Several hundred distinct non human primate species are recognised, and they are
      likely to harbour a similar range of viruses to humans. Simians such as
      cynomolgus and rhesus macaques, African green monkeys, and marmosets are widely
      used for biomedical research, but despite this extensive close contact very few
      simian viruses have been shown to pose a threat of infection or illness to
      humans. Herpesvirus Simiae is the best recognised zoonotic hazard of simians. It
      is an alphaherpes virus of Asiatic macaques, which causes a mild or subclinical
      primary infection followed by latency in its natural host. It can be acquired by
      humans following a bite and causes an ascending meningoencephalitis. Less than 40
      human cases have been described and the mortality rate in untreated human
      infections is 70%. The infection is treatable with acyclovir and extensive
      guidelines for managing simians and potential exposures have been developed.
      Ebola virus and Marburg virus have caused epizootics in cynomolgus macaques and
      vervet monkeys respectively, which have resulted in human infection and
      fatalities. However, non human primates are unlikely to be their natural host.
      More recently simian immunodeficiency virus and simian foamy virus have infected
      researchers, but infection has not been linked to illness. Simian viruses also
      pose a direct threat to humans through the use of primary monkey tissue cultures
      in laboratory work and vaccine manufacture, indeed a significant exposure of the
      human population occurred when cells contaminated with SV40 a polyomavirus of
      rhesus monkeys were used for polio vaccine production. New medical interventions
      such as xenotransplantation using primate organs pose a potential risk which
      requires careful assessment. Copyright 1997 by John Wiley & Sons Ltd.

PMID- 10398489
TI  - Editorial: HIV: Genetic diversity versus phenotypic selection.

PMID- 10398490
TI  - Viral RNA-dependent DNA polymerase RNA-dependent DNA polymerase in virions of
      Rous sarcoma virus.

PMID- 10398491
TI  - Hepatitis D virus.
AB  - The hepatitis D virus (HDV) relies on the helper hepatitis B virus (HBV) for the
      provision of its envelope, which consists of hepatitis B surface antigen (HBsAg).
      The RNA genome of HDV is a circular rod-like structure due to its extensive
      intramolecular base-pairing. HDV-RNA has ribozyme activity which includes
      autocatalytic cleavage and self-ligation properties, essential in virus
      replication via the rolling circle mechanism. Replication of the RNA is thought
      to be effected by cellular RNA polymerase II. Hepatitis D antigen (HDAg) is the
      only protein encoded by HDV-RNA and its long and short forms have a regulatory
      role in the replication and morphogenesis of the virus. Superinfected HBV
      carriers who become chronically infected with HDV are at increased risk of
      developing cirrhosis. Attempts to treat such carriers with interferon have not
      been particularly successful. In recent years the epidemiology of HDV has changed
      primarily due to the impact of HBV vaccination in preventing an increase in the
      pool of susceptible individuals. Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398492
TI  - Scope for using plant viruses to present epitopes from animal pathogens.
AB  - Epitope presentation to the immune system for vaccination purposes can be
      achieved either via an inactivated or attenuated form of a pathogen or via its
      isolated antigenic sequences. When free, these peptides can adopt a variety of
      conformations, most of which will not exist in their native environment.
      Conjugation to carrier proteins restricts mobility of the peptides and increases
      their immunogenicity. A high local concentration of epitopes boosts the immune
      response further and can be generated by the use of self-aggregating carriers,
      such as the capsid proteins of viruses. In this regard plant viruses have in
      recent years started to make an impact as safer alternatives to the use of
      bacterial and attenuated animal viruses: the latter both require propagation in
      costly cell-culture systems where they can undergo reversion towards a virulent
      form and/or become contaminated by other pathogens. Plant virus-based vectors can
      be multiplied cheaply and to high yields (exceeding 1 mg/g plant tissue) in host
      plants. Both helical (tobacco mosaic virus, potato virus X, alfalfa mosaic virus)
      and icosahedral (cowpea mosaic virus, tomato bushy stunt virus) particles have
      been used to express a number of animal B-cell epitopes, whose immunogenic
      properties have been explored to varying degrees. Copyright 1998 John Wiley &
      Sons, Ltd.

PMID- 10398493
TI  - Prospects for vaccines against rotaviruses.
AB  - Candidate vaccines against rotavirus-caused diarrhoea have been under development
      for more than ten years. Recent research has helped to identify virological and
      immunological parameters which are most likely to be correlates of protection
      from rotavirus infection and disease. Large double-blind, placebo-controlled
      trials in the United States and Venezuela have resulted in successful protection
      from severe disease and dehydration after immunisation with live-attenuated
      rhesus rotavirus-based monovalent and tetravalent vaccine candidates. The
      tetravalent vaccine is now submitted for regulatory approval in the United
      States. The anticipated widespread use of such a vaccine will need careful safety
      and effectiveness surveillance as the enormous diversity of rotavirus
      antigenicity may affect efficacy in different geographical regions. To proceed
      from licensure to reduction of disease a series of goals must be achieved: the
      vaccine must be recommended by major immunisation advisory committees, be
      financed in both the public and private sectors, be integrated into existing
      vaccination schedules, be promoted, find parental acceptance and achieve a high
      level of coverage. Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398494
TI  - Vaccination policies and accountants.

PMID- 10398495
TI  - Relation of Burkitt's tumor-associated herpes-type virus to infectious
      mononucleosis.

PMID- 10398496
TI  - Pathogenesis of puumala and other hantavirus infections.
AB  - Hantaviruses are rodent/insectivore-borne negative-stranded RNA viruses which
      belong to the Bunyaviridae family. They do not cause any symptomatic disease in
      their adult carrier rodents, but in humans they are aetiologic agents of
      haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome
      (HPS), both associated with a significant mortality. In cell culture hantaviruses
      do not cause cytopathic effects and the mechanisms of disease in man are not well
      understood. Increased capillary permeability is a central phenomenon in the
      pathogenesis of hantavirus infections. Although the viruses have in vivo a
      predilection for endothelial cells, it is presumed that inflammatory mediators of
      the host immune response play a significant role in the capillary leak that may
      produce abrupt hypotension and shock in severely ill patients. Mediators released
      by activated macrophages including NO and TNF-alpha are considered important. The
      pathogenesis of renal failure in HFRS also awaits to be resolved. This review
      summarises what is known about these phenomena and discusses also the molecular
      basis of the putative virulence factors of hantaviruses. Finally, the genetic
      predisposition and HLA association with severe Puumala virus infection will be
      discussed. Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398497
TI  - The molecular basis of HIV capsid assembly.
AB  - In common with many aspects of the HIV life cycle, the assembly of the virus
      particle has been the subject of intense investigation over recent years. Study
      of the subject is facilitated by the fact that only a single gene product, the
      Pr55 Gag protein, is required for virus assembly. A combination of site directed
      mutagenesis, biochemical characterisation and structural studies have led to a
      picture of the overall architecture of the particle, the partial structure of
      Pr55, and the subdomains involved in oligomerisation. Copyright 1998 John Wiley &
      Sons, Ltd.

PMID- 10398498
TI  - Intradermal administration of viral vaccines.
AB  - Intradermal administration maybe useful in lowering the cost of vaccination
      against hepatitis B significantly, and may also be helpful for the rapid
      induction of antibodies, reversing non-responsiveness, improving postexposure
      prophylaxis and immunising immunocompromised people. In addition, delayed type
      hypersensitivity skin reaction to the vaccine could serve as a useful marker for
      the acquisition of T helper type 1 immunoreactivity in vivo. However, there are
      some disadvantages when using intradermal vaccinations, including the requirement
      for skilful administration, the absence of approval from licensing authorities,
      the development of local skin reactions and a lower antibody response when 1/10
      of the standard vaccine dose is used. This requires that appropriate vaccination
      regimens, including the correct vaccine dosage, and vaccination schedule are
      followed. In the future, a similar vaccination strategy might also be applied for
      the prevention and control of other infectious diseases. Copyright 1998 John
      Wiley & Sons, Ltd.

PMID- 10398499
TI  - Herpes/HIV/hepatitis viruses: biological similarities despite taxonomic
      differences.

PMID- 10398500
TI  - Poxvirus DNA-dependent RNA polymerase.

PMID- 10398501
TI  - Genetic studies on a mumps vaccine strain associated with meningitis.
AB  - Vaccination with mumps measles and rubella (MMR) vaccine containing the live
      attenuated mumps strain, Urabe AM9, is associated with an increased incidence of
      meningitis. The isolation of mumps virus from CSF and subsequent identification
      as Urabe AM9-like by sequence analysis confirmed the causative role of Urabe AM9
      vaccine in meningitis. To assess the role of genetic reversion in vaccine
      failure, sequence comparisons were made between several genes of Urabe AM9
      vaccine and post-vaccination meningitis mumps isolates. An amino acid
      substitution in the Urabe AM9 HN gene Lys335Glu was not detected in the post
      vaccination meningitis isolates suggesting that reversion to wild type sequence
      was associated with vaccine failure. However, further analysis showed that the
      vaccine was a mixture of viruses that differed at aa 335 of HN, possessing either
      the wild type Lys335 or the mutant Glu335, whereas the clinical isolates were
      homogeneous and possessed the wild type Lys335. Passage of the Urabe AM9 vaccine
      preparations in Vero cells resulted in the amplification of the Glu335 virus,
      however the post-vaccination meningitis isolates (Lys335) grew better in Vero
      cells than Urabe AM9 vaccine. A virus isolate, similar to the post-vaccination
      isolates was obtained from the vaccine suggesting that the strain responsible for
      vaccine failure was a pre-existing component of the vaccine and was not
      necessarily the result of reversion. The Urabe AM9 vaccine is a heterogeneous
      mixture of genotypes that differ in virulence with the HN Glu335 viruses being
      attenuated and at least a subset of the HN Lys335 viruses that are associated
      with disease. The Glu335 mutation may be among a class of attenuating mutations
      identified in several neurotropic viruses that involve charged amino acids in
      neutralising epitopes of receptor binding proteins. Copyright 1998 John Wiley &
      Sons, Ltd.

PMID- 10398502
TI  - Buckminsterfullerene and photodynamic inactivation of viruses.
AB  - The development of new virus inactivation procedures has become an area of
      growing interest mainly due to increased demands concerning the safety of
      biological products. Photochemical processes represent the most promising methods
      for the future to inactivate viruses. In these methods, dyes are the most widely
      used photosensitising reagents. The current article covers a new interesting
      alternative, namely the use of buckminsterfullerene (C60). The unique properties
      of this molecule make it a valid candidate for future applications in the
      inactivation of viruses in biological fluids. Copyright 1998 John Wiley & Sons,
      Ltd.

PMID- 10398503
TI  - Lamivudine treatment of chronic hepatitis B.
AB  - Several new nucleoside analogues have been developed which can inhibit hepatitis
      B replication by at least two logs. Lamivudine is the most widely studied of
      these new agents. Extensive phase II and III studies in patients with chronic
      hepatitis B have been completed. The sustained HBeAg seroconversion rate in
      patients who have received 100 mg lamivudine increases from 17% after a year of
      treatment to 27% after 2 years of treatment. Histological improvement has been
      noted in 38%-52% of lamivudine-treated patients, exceeding the improvement seen
      in placebo recipients. Similar histological improvement has been noted in anti
      HBe-positive, DNA- positive patients. Lamivudine can prevent recurrence of
      hepatitis B after liver transplantation. It is likely that in the absence of
      immune clearance to accelerate elimination of infected hepatocytes, inhibitors of
      virus replication such as lamivudine will need to be administered for a long
      period to reduce the burden of infected hepatocytes in the liver, and to prevent
      relapse. The drug is generally well tolerated with few direct adverse events.
      Genotypic mutations have been observed in 23% (range 13-32%). In a study in Asian
      patients treated for two years the incidence of these mutants increased to 38%
      (as detected by PCR). Loss of susceptibility to lamivudine has been found to be
      due to reverse transcriptase amino acid substitutions. Lamivudine is likely to be
      reserved for patients with replicative hepatitis B infection with active chronic
      hepatitis, and/or active cirrhosis. Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398504
TI  - International issues in transplantation biotechnology, including the use of non
      human cells, tissues and organs.
AB  - A personal overview of the major points discussed at this international meeting
      in March 1998 is presented. Overall, it was a timely and very interesting meeting
      in which most of the issues relating to xenotransplantation were comprehensively
      reviewed and thoroughly discussed with an emphasis on trying to work out common
      procedures and policies and to gain public confidence in this novel field. There
      are still enormous hurdles to be passed with regard to assessing the risks of
      infection, the immunology of xenotransplantation, public acceptance as well as
      numerous ethical, regulatory and economic issues. However, there was also the
      clear message that enormous progress has been and is being made fast in all these
      areas and that therefore xenotransplantation is likely to come of age also
      clinically in the not too distant future. Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398505
TI  - Puns aid understanding of immune evasion strategies.

PMID- 10398506
TI  - Testing for HIV antibodies should be offered on a same-day basis.
AB  - We review our experience of testing over 22 000 patients who requested HIV
      antibody results on a same-day basis. We find that such a service can be provided
      without compromising the quality of laboratory work or increasing the cost per
      test. This service is popular with patients, who appear to contain high risk
      individuals because 2.8 were shown to be HIV-positive. By reducing bureaucratic
      hurdles, same-day testing clinics may encourage people to come forward for HIV
      testing and provide a means of offering chemotherapy (directed either at HIV
      itself or at opportunistic infections) without delay. We thus argue for the
      proposition.Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398507
TI  - Testing for HIV antibodies should not be offered on a same-day basis.
AB  - Same-day testing for HIV is now offered in 16 of Genitourinary Medicine clinics
      in the UK and in 31 of those in London, and supposedly offers a reduction in
      client waiting time and anxiety levels. 'Same-day' is, however, misleading as the
      majority of same-day testing services provide same-day negative results only,
      with confirmed positive results being available no earlier than from a routine
      drop-in clinic. In addition, as most same-day testing services are appointment
      based, patients would generally receive their results much sooner if they were to
      attend a drop-in clinic. The provision of a same-day service causes considerable
      problems for the virology laboratory. Dedicated staff may be required and
      different assays and reporting protocols will need to be implemented. In addition
      to the considerable pressure, and therefore stress, which is placed on staff
      providing a same-day service, it is likely that same-day testing will result in
      significant additional cost. Current assay systems and laboratory protocols
      permit random access of samples which allows urgent samples to be tested
      immediately they are received by the laboratory. The judicious use of this
      facility would offer the equivalent of a same-day testing service for those
      patients whose anxiety health advisors felt warranted an urgent result; would
      provide others with a result within 2 days at the most; would be cheaper, thus
      releasing scarce resources; and would reduce staff stress. In conclusion, we
      argue against the proposition. Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398509
TI  - Viral interference in HIV-1 infected cells.
AB  - The study of viral interference in HIV-1 infected cells has revealed several
      different means whereby infected cells resist superinfection. The most familiar
      of these, down-modulation of cellular receptors for virus, can be accomplished
      through the independent action of at least three HIV-1 proteins. Both the
      principal viral receptor CD4 and the chemokine receptors which serve as co
      receptors are subject to down-modulation as a consequence of infection.
      Elucidation of the specificity of co-receptor utilisation by HIV-1 strains is an
      exciting, ongoing task which has opened new avenues to the understanding of viral
      replication and pathogenesis. Novel routes to resistance to superinfection have
      been discovered during HIV-1 infection and their investigation may reveal new
      pathways to control HIV-1 and the loss of immunological function with AIDS.
      Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398510
TI  - Virus assembly and disassembly: the adenovirus cysteine protease as a trigger
      factor.
AB  - Viruses are efficient carriers of genetic material between cells. They
      specifically recognise a target cell and utilise host functions for genome
      delivery to the replication site. A mature viral capsid emerging from an infected
      cell serves at least three distinct functions. It enables virus egress from the
      infected cell, protects the extracellular genome against chemical and physical
      stress and mediates virus entry into a non-infected cell. How can a virus
      particle be stably assembled in an infected cell and moments later-after passing
      through the extracellular milieu-be disintegrated by a non-infected cell? In this
      review I discuss how adenovirus, a DNA virus, recruits cellular and viral factors
      and makes use of its own cysteine protease to regulate capsid assembly and
      disassembly. Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398508
TI  - Virus infections of the eye.
AB  - In reviewing the clinical features, diagnostic evaluations and therapies of the
      most common ocular viral infections we attempt to whet your appetite for
      attacking the numerous challenges in diagnosis and treatment of viral eye
      disease. The herpes viruses, HSV, VZV and CMV are the cause of significant ocular
      morbidity. HSV most commonly affects the cornea producing keratitis that can be
      recurrent and may lead to corneal clouding and neovascularisation. Manifestations
      can be purely infectious or immunological and treatment options must be tailored
      to the underlying pathophysiology. Herpes zoster ophthalmicus, caused by VZV
      infection of the first branch of the trigeminal nerve, produces a characteristic
      rash and can progress to keratitis and uveitis. HSV and VZV can cause retinitis
      in both immunocompetent and immunocompromised individuals. There has been a
      significant increase in the incidence of CMV retinitis since the beginning of the
      AIDS epidemic. We review the numerous new treatments, diagnostic tests and
      treatment strategies which have been developed in response to this potentially
      blinding retinal infection. Adenovirus produces an epidemic conjunctivitis and
      epidemic keratoconjunctivitis which are severe and extremely contagious
      conjunctival infections. HIV, molluscum contagiosum, EBV and rubeola also cause
      ocular diseases which are described.Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398511
TI  - Advances in the treatment of chronic hepatitis B virus infection.
AB  - Recent advances in our understanding of the replicative mechanism of HBV, and the
      development of potent nucleoside analogues as clinically effective inhibitors of
      the HIV reverse transcriptase or herpesvirus polymerases has opened a new era in
      the treatment of chronic HBV infection. Single agent therapies, such as
      famciclovir, lamivudine or lobucavir, have had some success. There is now a
      logical basis for combination therapy, because of the clear need for prolonged
      treatment and the associated possibility that drug resistant strains will emerge
      with monotherapy, but the choice of agents to combine and the regimens in which
      they should be employed remain uncertain.Copyright 1998 John Wiley & Sons, Ltd.

PMID- 10398512
TI  - Infectious pulmonary disease in patients receiving immunosuppressive therapy for
      organ transplantation.

PMID- 10398513
TI  - Differences in neurotoxic effects of ochratoxin A, ochracin and ochratoxin-alpha
      in vitro.
AB  - The mycotoxin ochratoxin A (OTA) is a chlorinated dihydroisocoumarin derivative
      connected through an amide-bond to L-phenylalanine. In a previous study we could
      show that competition with L-phenylalanine-dependent processes does not play a
      role in OTA neurotoxicity. To test whether the isocoumarin part is responsible
      for the neurotoxic effects, we determined in the present study the effects of the
      hydrolysis product of OTA, ochratoxin-alpha (OTalpha), and of ochracin on
      embryonic chick brain cell cultures. In addition, we investigated the interaction
      between OTA and ochracin regarding the neurotoxic effects. We report here that
      OTalpha did not affect brain cell cultures at concentrations up to 15 microM.
      With the exception of a small (20%) but significant reduction in cell culture,
      cellular protein at concentrations above 0.3 microM, in our cell cultures' cell
      function, as defined by neutral red uptake and MTT-dehydrogenase activity, was
      only reduced by high OTalpha concentrations (1 mM). Addition of 0.1 microM OTA
      increased ochracin cytotoxicity as defined by latter parameters. No effects on
      cell culture NF68kD content could be detected. The results are discussed with
      regard to the existence of an OTA target interaction binding site.

PMID- 10398514
TI  - Occurrence of hemolytic activity in the skin secretion of the caecilian siphonops
      paulensis.
AB  - The skin secretion of the caecilian Siphonops paulensis (SpSS) induces a time-and
      dose-dependent hemolytic response on red blood cells (RBC). When RBC from various
      animals species were subjected to the action of SpSS, a range of sensitivities
      was evident, sheep erythrocytes being the most susceptible, human, mouse and
      rabbit having moderate susceptibility, cow, snake and toad erythrocytes being
      more resistant, while S. paulensis RBC were entirely resistant. The hemolytic
      activity of SpSS was inhibited at temperatures higher than 60 degrees C. Both
      trypsin- and chymotrypsin-treated SpSS were ineffective in inducing RBC lysis.
      The treatment of SpSS with sheep RBC ghosts reduced its activity. There is no
      phospholipase activity in the SpSS.

PMID- 10398515
TI  - Structure-activity relationship studies of putaminoxins and pinolidoxins:
      phytotoxic nonenolides produced by phytopathogenic Phoma and Ascochyta species.
AB  - Putaminoxin and pinolidoxin, two structurally related nonenolides, isolated
      respectively from organic extracts of Phoma putaminum and Aschochyta pinodes
      cultures, together with some of their natural analogs and synthetic derivatives,
      were used in a structure-activity relationship study. Their phytotoxic,
      antifungal and zootoxic activities were assayed with the aim to find compounds
      with potential herbicidal properties. The strongest phytotoxic compounds proved
      to be putaminoxin and pinolidoxin, whose activity appeared to be correlated to
      the integrity of the nonenolide ring and to the presence of both the hydroxy
      groups and the unmodified propyl side chain. None of the assayed nonenolides
      showed antifungal activity, whereas pinolidoxin analogs and derivatives showed
      high to weak zootoxicity.

PMID- 10398516
TI  - In vivo metabolism of beta-N-oxalyl-L-alpha,beta-diaminopropionic acid: the
      Lathyrus sativus neurotoxin in experimental animals.
AB  - A comparative study of the metabolism of 1,2,3 (14)C-ODAP and 4,5 (14)C-ODAP in
      mice, rats and chicks has been carried out. Following oral administration of
      1,2,3 (14)C-ODAP to either black or white mice, nearly 16% of the radioactivity
      appeared in the expired CO2 within 8 h, while in the rat only 3% of it appeared
      and in chicks it was less than 2%. No 14CO2 appeared in the expired air in mice
      given 4,5 (14)C-ODAP. Electrophoregrams of the spot urine samples from the
      animals given 1,2,3 (14)C-ODAP showed the presence of one radioactive metabolite
      (metabolite-1) in addition to ODAP. While the urine from rats and mice given 4,5
      (14)C-ODAP indicated the presence of metabolite-1 as well as 14C-oxalate, in
      chicks, however, no 14C-oxalate was present and only metabolite-1 could be
      detected. The results indicate that ODAP can to some extent undergo oxidation in
      vivo in mice (and to a lesser extent in rats) leading to the formation of CO2 and
      oxalate and a similar pathway might be more prominent in humans leading to a near
      complete oxidation of ODAP.

PMID- 10398517
TI  - Evaluation of the use of two human cell lines for okadaic acid and DTX-1
      determination by cytotoxicity assays and damage characterization.
AB  - Two human cell lines have been used, HEp-2 and (de)differentiated Caco-2, derived
      from a larynx and a colon carcinoma, respectively, with the aim of evaluating and
      characterizing the cytotoxicity of okadaic acid (OA) and related toxins. Effects
      of OA and dinophysistoxin-1 (DTX-1) on cell viability (neutral red uptake) and on
      cell morphology/cytoskeleton structure have been observed in both cell lines,
      though at different time exposures and with different concentrations. The
      morphological alteration was detected earlier than the viability inhibition in
      HEp-2 cells with both toxins and in Caco-2 cells with DTX-1. HEp-2 cells have
      shown to be more sensitive than the intestinal cell line and thus possibly
      suitable for screening of contaminated samples, while Caco-2 cells could be used
      for further investigating the possible mechanisms involved in diarrhoeic
      shellfish poisoning (DSP) toxins.

PMID- 10398518
TI  - Potential protective effect of HSCAS and bentonite against dietary aflatoxicosis
      in rat: with special reference to chromosomal aberrations.
AB  - Bentonite and hydrated sodium calcium aluminsilicate (HSCAS) were added at a
      level of 0.5% (w/w) to the diets containing 2.5 mg aflatoxins (AF) per kg diet
      and fed to male mature rats for 15 successive days. Aflatoxin alone significantly
      decreased feed intake and altered serum biochemical parameters of liver and
      kidney functions. Aflatoxin caused chromosomal aberrations in bone marrow cells.
      Bentonite or HSCAS did not alter any of the parameters measured. The addition of
      bentonite or HSCAS to the AF-contaminated diet diminished most of the deleterious
      effects of the aflatoxin. Pathological examinations of liver and kidney proved
      that both bentonite and HSCAS were hepatonephroprotective agents against
      aflatoxicosis. The cytogenetic findings demonstrated that the addition of
      bentonite or HSCAS to AF-contaminated diet suppressed chromosomal aberrations.
      These findings indicated that bentonite and HSCAS could diminished many of the
      adverse effect of dietary AF in rats.

PMID- 10398519
TI  - Inequalities in health: an introduction.

PMID- 10398520
TI  - Income inequality in the UK.

PMID- 10398521
TI  - 'Our healthier nation'?

PMID- 10398522
TI  - Commentary on the Acheson report.

PMID- 10398523
TI  - The 39 steps: the mystery of health inequalities in the UK.

PMID- 10398524
TI  - The effects of economic reform on health insurance and the financial burden for
      urban workers in China.
AB  - Since 1980, Chinese enterprises have been undergoing reforms in employment
      practice, taxation, and workers' health/welfare benefits coverage. In particular,
      Chinese businesses have been facing a major challenge with respect to the
      financial burden of providing medical benefits to their workers. The purpose of
      this paper is to analyse the impact of enterprise reform on workers' health care
      benefits and their financial burden due to medical expenses. This study is based
      on a 1992 survey conducted in 22 cities, and included 406 enterprises and 5920
      workers. It was found that there were wide variations of coverage for health care
      benefits among urban Chinese workers. It was also found that workers with partial
      coverage were as likely to incur out-of-pocket medical expenditures as workers
      without coverage. These out-of-pocket medical expenditures could reach as high as
      25% of a worker's annual income. Policy recommendations are discussed at the end
      of the paper.

PMID- 10398525
TI  - Estimating uncertainty ranges for costs by the bootstrap procedure combined with
      probabilistic sensitivity analysis.
AB  - When an economic evaluation incorporates patient-level data, there are two types
      of uncertainty over the results: uncertainty due to variation in the sampled
      data, and uncertainty over the choice of modelling parameters and assumptions.
      Previously statistical methods have been used to estimate the extent of the
      former, and sensitivity analysis to estimate the extent of the latter. Ideally
      interval estimates for economic variables should reflect both types of
      uncertainty. This paper describes a method for combining bootstrapping with
      probabilistic sensitivity analysis to estimate a total 'uncertainty range' for
      incremental costs. The approach is illustrated using cost data from a randomized
      controlled trial of endoscopy for Helicobactor pylori negative young dyspeptic
      patients. The trial failed to demonstrate any clinical benefit from endoscopy,
      which was on average pound 395 more costly. The combined 95% uncertainty range
      for incremental costs (-pound 236 to pound 931) was wider than 95% intervals
      estimated by either probabilistic sensitivity analysis (pound 43 to pound 592) or
      the non-parametric bootstrap method (-pound 95 to pound 667) alone. The method
      can easily be extended to the calculation of uncertainty ranges for incremental
      cost-effectiveness ratios.

PMID- 10398526
TI  - Addressing the inequity of capitation by variable soft contracts.
AB  - In the search for greater efficiency and cost-containment, many health systems
      have introduced the practice of medical care providers operating under a fixed
      budget, often referred to as the capitation or fundholding contract. Although the
      capitation contract seems equitable at first glance, the sequential decision
      making practice of providers-shaped by their rate of present-preference and their
      attitude toward the risk of running out of budget-may result in serious
      violations of basic equity principles. We propose a variable soft (or mixed)
      payment contract (VSC), where the share of the retrospective payment increases
      over time, as a way to make the contracts more equitable. We also discuss how the
      parameters of the capitation contract (length of the budget period, soft or hard
      contracts, solo vs. consortium practice etc.), which are usually set by
      efficiency criteria, may have serious implications with regard to the equity of
      the system.

PMID- 10398527
TI  - The appropriate uses of qualitative methods in health economics.
AB  - Ontology, epistemology and methodology are not subjects frequently discussed in
      health economics, yet they are of great relevance to the question of how, or
      whether, to use qualitative methods as a means of examining certain issues. The
      paper discusses the nature of enquiry in health economics and then details the
      nature of qualitative methods and the constructivist philosophy with which they
      are most commonly associated. The paper continues by examining different areas in
      the study of economics: neo-classical positive economics, alternative approaches
      to explanatory economics and normative welfare economics. For each area the
      philosophical approach is outlined as are the areas of research interest.
      Appropriate roles for qualitative methods within these philosophical approaches
      are then suggested. The paper concludes by warning that health economists should
      not use qualitative methods naively. They must be aware of the potential
      difficulties: both of inadvertently ending up outside the intended research
      philosophy and of conducting research which is accepted by neither economists nor
      qualitative researchers. If, however, health economists are aware of ontological,
      epistemological and methodological issues, they can make an informed decision
      about the appropriateness of qualitative methods in their research and thereby
      potentially enhance their ability to answer the questions in which they are
      interested.

PMID- 10398528
TI  - Do you sincerely want to be rich?

PMID- 10398530
TI  - Active gelatinase B is identified by histozymography in the cartilage resorption
      sites of developing long bones.
AB  - In order to determine which proteinases mediate the resorption of endochondral
      cartilage in the course of long bone development, a novel assay called
      "histozymography" has been developed. In this assay, frozen sections of tibial
      head from 21-day-old rats are placed for 4 hr at room temperature on light
      exposed photographic emulsion (composed of silver grains embedded in gelatin). We
      report a localized but complete digestion of emulsion gelatin facing two tissue
      sites which are, therefore, presumed to contain an active proteinase. One of the
      sites is localized at the growth plate surface forming the epiphysis/metaphysis
      interface. The other consists of small patches located within the epiphysis at
      the edge of the marrow space. Both sites are engaged in the resorption of
      endochondral cartilage. In both sites, inhibitor tests have established that the
      involved proteinase is a gelatinase. Furthermore, the use of neutralizing
      antibodies against gelatinase A or B have demonstrated that only those that are
      specific for the latter block the reaction. That gelatinase B is present in the
      two sites has been confirmed by light microscopic immunohistochemistry. Finally,
      when immunoelectron microscopy is used for fine localization of the cartilage
      structures that form the epiphysis/metaphysis interface, the enzyme is detected
      within the 0.5-microm thick edge of the cartilage, and outside the cartilage, it
      is present in debris composed of type II collagen-rich fibrils in various states
      of digestion. It is concluded that gelatinase B attacks the edge of an
      endochondral cartilage and helps to solubilize the type II-collagen-rich
      fibrillar framework, which is then released as debris for further digestion. This
      final step opens the way to invasion by capillaries, thereby making possible the
      replacement of cartilage by bone. Dev Dyn 1999;215:190-205.

PMID- 10398529
TI  - Role of actin stress fibres in the development of the intervertebral disc:
      cytoskeletal control of extracellular matrix assembly.
AB  - Orientation of collagen fibrils is a key event in the development of many
      tissues. In the intervertebral disc, the outer annulus fibrosus comprises
      lamellae of parallel collagen fibres, the direction of orientation of the long
      axis of which alternates in angle between lamellae. In development, this
      organisation is preceded by the formation of sheets of oriented fibroblasts,
      which then deposit the oriented lamellae. Here, using fluorescent labelling,
      confocal and electron microscopic techniques on developmental series, we show
      that the orientation of cells in lamellae is associated with the formation of
      adherens junctions intercellularly, involving cadherins and vinculin, and
      longitudinal stress fibres (label for filamentous actin and tropomyosin)
      intracellularly. The stress fibres direct the initial elongation of cells and
      control the deposition of oriented extracellular matrix via junctional complexes
      with the matrix involving vinculin and alpha 5 beta 1 integrins, which in turn
      promote the formation of oriented fibronectin at the cell surface; oriented
      collagen is deposited between cells at the same stages. Shortly after birth, the
      stress fibres disappear, probably because cells now gain orientational cues from
      the matrix, and are undergoing differentiation-related changes to form
      fibrocartilage cells. Dev Dyn 1999;215:179-189.

PMID- 10398531
TI  - Expression of a novel type of classic cadherin, PB-cadherin in developing brain
      and limb buds.
AB  - PB-cadherin is a novel classic type of cadherin predominantly expressed in brain
      of adult rats (Sugimoto et al. [1996] J. Biol. Chem. 271:11548-11556). To examine
      the spatial and temporal expression of PB-cadherin during development, we
      isolated full-length cDNA of mouse PB-cadherin and studied its expression pattern
      in mouse embryos. In Northern blots, PB-cadherin mRNA was detected at 9.5 days
      postcoitum (dpc) onwards. Whole-mount in situ hybridization showed that PB
      cadherin signals mainly occurred in developing neural tissues, including brain
      and spinal cord, and limb buds in the 10.5 dpc embryo. In the brain, PB-cadherin
      mRNA were strongly expressed in the forebrain and midbrain-hindbrain boundary
      region (isthmus). In isthmus, PB-cadherin expression delineated the expression
      area of Wnt-1, a secreted signaling molecule essential for proper cerebellum
      development. In the developing limb, PB-cadherin mRNA was first localized in
      posterior part of buds at 10.5 dpc, and was thereafter distributed in a domain
      around the digit rudiments. This expression pattern is similar to that of BMP-2,
      a secreted signalling molecule involving limb patterning and morphogenesis. These
      findings suggested the possibility that PB-cadherin-mediated cell-cell adhesion
      has a functional role in pattern formation and morphogenesis of mouse embryonic
      brain and limb. Dev Dyn 1999;215:206-214.

PMID- 10398532
TI  - Analysis of chicken Wnt-13 expression demonstrates coincidence with cell division
      in the developing eye and is consistent with a role in induction.
AB  - We used a degenerate polymerase chain reaction (PCR) strategy to search for Wnt
      RNA in developing ocular tissues. We isolated a Macaca monkey Wnt-13 PCR
      fragment, orthologous to the human and murine Wnt-13 and Xenopus Wnt-2b, and a
      chick Wnt13 cDNA. Wnt-13 is a member of the Wnt-1 class of transforming Wnt
      molecules. In situ RNA hybridization revealed a dynamic Wnt-13 expression pattern
      in numerous developing tissues. Within the eye, Wnt-13 is expressed in the
      proliferative epithelium of the lens and both pigmented and non-pigmented layers
      of the ciliary margin. In vitro BrdU incorporation studies coupled with in situ
      hybridization showed that cWnt-13 expression domains in the lens were coincident
      with cell division. In addition to the eye, cWnt-13 was expressed in head
      ectoderm, prospective forelimb mesenchyme, lung bud, pharyngeal arches, the
      brain, as well as the otic vesicle. Our data are consistent with previous
      observations linking transforming Wnts with cell division and implicate a cascade
      of events involving cWnt-13 first in dorsoventral patterning and later in cell
      proliferation regulation associated with lens development. Dev Dyn 1999;215:215
      224.

PMID- 10398533
TI  - Structure and developmental expression of the ascidian TRP gene: insights into
      the evolution of pigment cell-specific gene expression.
AB  - The tyrosinase family in vertebrates consists of three related melanogenic
      enzymes: tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2. These
      proteins control melanin production in pigment cells and play a crucial role in
      determining vertebrate coloration. We have isolated a gene from the ascidian
      Halocynthia roretzi which encodes a tyrosinase-related protein (HrTRP) with 45
      49% identity with vertebrate TRP-1 and TRP-2. The expression of the HrTRP gene in
      pigment lineage a8.25 cells starts at the early-mid gastrula stage, which
      coincides with the stage when these cells are determined as pigment precursor
      cells; therefore, it provides the earliest pigment lineage-specific marker, which
      enables us to trace the complete cell lineage leading to two pigment cells in the
      larval brain. In addition, the expression pattern of the HrTRP gene appears to
      share similar characteristics with the mouse TRP-2 gene although structurally the
      HrTRP gene is more closely related to mammalian TRP-1 genes. Based on these
      observations and on results from molecular phylogenetic and hybridization
      analyses, we suggest that triplication of the tyrosinase family occurred during
      the early radiation of chordates. Initially, duplication of an ancestral
      tyrosinase gene produced a single TRP gene before the urochordate and
      cephalochordate-vertebrate divergence, and a subsequent duplication of the
      ancestral TRP gene in the vertebrate lineage gave rise to two TRP genes before
      the emergence of teleost fishes. Evolution of the melanin synthetic pathway and
      possible phylogenetic relationships among chordate pigment cells that accommodate
      the metabolic process are discussed. Dev Dyn 1999;215:225-237.

PMID- 10398534
TI  - Misexpression of a bHLH gene, cNSCL1, results in abnormal brain development.
AB  - NSCL1 is a basic helix-loop-helix transcription factor involved in the
      development of the nervous system. To elucidate its role in neurogenesis, we
      cloned chick NSCL1 (cNSCL1) and examined its expression pattern and the effect of
      its misexpression on brain development. cNSCL1 was predominantly expressed during
      active neurogenesis. Double-labeling experiments showed that proliferating
      neuroblasts in the ventricular zone lacked cNSCL1 expression and cells expressing
      cNSCL1 were located just outside the ventricular zone. Retroviral misexpression
      of cNSCL1 in chick embryos produced a brain with abnormal structure. While the
      forebrain of the embryonic day-12 (E12) brain appeared normal, the tectum was
      enlarged. The enlargement was likely due to an increase in cell proliferation,
      since more radioactivity was detected in this region of the brain after
      [3H]thymidine labeling at E9. The cerebellum, on the other hand, was reduced in
      size. Fewer cells were labeled with BrdU in the external granule layer (a
      secondary germinal layer required for cerebellum development) in experimental
      embryos than in the controls, suggesting that misexpression of cNSCL1 might
      interfere with cell proliferation in the external granular layer. Our data
      indicate that regulated expression of cNSCL1 is required for normal brain
      development. They also imply that cNSCL1 might be involved in preventing some
      postmitotic cells from reentering the cell cycle during neurogenesis. Dev Dyn
      1999;215:238-247.

PMID- 10398535
TI  - Endogenous galectins and effect of galectin hapten inhibitors on the
      differentiation of the chick mesonephros.
AB  - Galectins are galactoside-binding lectins. In the mesonephros of the chick
      embryo, the 16-kDa galectin is abundant in the glomerular and tubular basement
      membranes where it colocalizes with fibronectin and laminin. To test whether
      galectin-glycoprotein interactions could play a role in mesonephric development,
      the effects of the galectin hapten inhibitors thiodigalactoside (TDG) and lactose
      on the differentiation of the cultured mesonephros were investigated. When
      compared to control saccharide-free or maltose-treated cultures, mesonephroi
      cultured in the presence of TDG and lactose exhibited defects in tissue
      organization. These included a distorted tubule shape, pseudo-stratification of
      the tubular epithelium, and detachment of glomerular podocytes from the basement
      membrane. The presence of molecular differentiation markers in the developing
      mesonephros was investigated. In vivo, expression of the epithelial-specific cell
      adhesion molecule E-cadherin is restricted to differentiated tubular epithelial
      cells, whereas the intermediate filament protein vimentin is present in
      mesonephrogenic mesenchyme and is undetectable in tubular epithelial cells. In
      mesonephroi cultured in the absence of sugars or in the presence of maltose, the
      expression pattern of these two marker molecules resembles that found in the
      mesonephros in vivo. In contrast, in the mesonephroi cultured in the presence of
      TDG and lactose, the epithelial tubular cells expressing E-cadherin also express
      vimentin. Re-expression of vimentin in the tubular epithelial cells could
      indicate a partial reversal to a mesenchymal phenotype. Results suggest that
      galectin-glycoprotein interactions in the basement membrane are important in the
      maintenance of the renal epithelial phenotype. Dev Dyn 1999;215:248-263.

PMID- 10398536
TI  - Retinoic acid biosynthetic enzyme ALDH1 localizes in a subset of retinoid
      dependent tissues during xenopus development.
AB  - Control of retinoic acid synthesis in vertebrate organisms is undoubtedly
      important for regulating the numerous retinoid signaling events which occur
      during development. The mechanisms which accomplish this task involve enzymes
      such as class I aldehyde dehydrogenase (ALDH1), which has recently been found to
      be conserved from amphibians to mammals and which functions as a retinoic acid
      biosynthetic enzyme in vivo. Here we have found that Xenopus ALDH1 mRNA and
      protein is expressed in a subset of retinoid-dependent tissues which develop
      shortly after neurulation during the tail bud stages. ALDH1 mRNA was first
      clearly detectable by in situ hybridization in stage 28 tail bud embryos
      localized in the olfactory placode and pronephros, and at stage 35 mRNA was also
      detected in the pronephric duct. Antibodies were generated against Xenopus ALDH1,
      and immunohistochemistry was used to demonstrate that ALDH1 protein accumulates
      in the olfactory placode, pronephros, and dorsal retina at stage 28, and
      additionally in the lens placode and pronephric duct at stage 35. Neither ALDH1
      mRNA nor protein was detected in the posterior region of Xenopus embryos during
      the tail bud stages. In contrast to neurula stage embryos in which retinoic acid
      is distributed in an anteroposterior gradient with the high end posteriorly, we
      found that tail bud stage embryos have retinoic acid present in significant
      levels in both the head and trunk regions, but with no detection in the posterior
      region. These findings are consistent with ALDH1 contributing to retinoic acid
      synthesis needed for development of certain head structures (olfactory placodes,
      dorsal retina, lens placode) and certain trunk structures (pronephros and
      pronephric duct). Dev Dyn 1999;215:264-272.

PMID- 10398539
TI  - Diabetes/Metabolism reviews becomes Diabetes/Metabolism research and reviews

PMID- 10398538
TI  - In this issue

PMID- 10398537
TI  - Bending of the neural plate during mouse spinal neurulation is independent of
      actin microfilaments.
AB  - To examine the role of actin microfilaments in mouse spinal neurulation, we
      stained cryosections of E8.5-10.5 CBA/Ca embryos with FITC-phalloidin.
      Microfilaments are present in the apical region of all cells throughout the
      neuroepithelium, irrespective of whether they are involved in bending of the
      neural plate. Disruption of the microfilaments with cytochalasin D inhibited
      closure of the cranial neural folds in cultured embryos, even at the lowest
      concentrations tested, and prevented the initiation of spinal neurulation
      (Closure 1) at higher concentrations. In contrast, closure of the posterior
      neuropore was resistant to cytochalasin D at the highest concentrations tested.
      Phalloidin staining and transmission electron microscopy confirmed that
      cytochalasin D is effective in disassembling microfilaments in spinal
      neuroepithelial cells. We conclude that spinal neural tube closure does not
      require microfilament function, in contrast to cranial neurulation which is
      strongly microfilament-dependent. Histological examination of cytochalasin D
      treated embryos revealed that bending at hinge points, both in the midline (MHP)
      and dorsolaterally (DLHPs), continues in the absence of microfilaments, whereas
      the rigidity of non-bending regions of the neural plate is lost. This suggests
      that spinal neurulation can continue in the presence of cytochalasin D largely as
      a result of intrinsic bending of the neural plate at hinge points. Cytochalasin D
      treatment is a useful tool for revealing the localisation of hinge points in the
      neural plate. Analysis of treated embryos demonstrates a transition, along the
      spinal axis, from closure solely involving midline bending, at high levels of the
      spinal axis, to closure solely involving dorsolateral bending, low in the spinal
      region. These findings support the idea of mechanistic heterogeneity in mouse
      neurulation, along the body axis, and demonstrate that contraction of actin
      microfilaments is not obligatory for epithelial bending during embryonic
      morphogenesis. Dev Dyn 1999;215:273-283.

PMID- 10398540
TI  - You shall know the truth and the truth shall set you free.

PMID- 10398541
TI  - Evaluation of serum markers of neuronal damage following severe hypoglycaemia in
      adults with insulin-treated diabetes mellitus.
AB  - BACKGROUND: Neurone-specific enolase (NSE) and protein S-100 (S-100) may be used
      as markers of acute neuronal damage in humans with neurological disorders.
      METHOD: To evaluate their use following a single episode of severe hypoglycaemia
      (defined as an episode requiring external assistance to aid recovery), serum
      concentrations of NSE and S-100 were measured following hypoglycaemia which had
      not caused persistent neurological impairment in 16 patients with insulin-treated
      diabetes (the 'hypo' subjects), and in three diabetic patients who died following
      severe hypoglycaemia. The serum proteins were also measured in 10 subjects with
      insulin-treated diabetes who had not experienced an episode of severe
      hypoglycaemia within the preceding year (the 'control' subjects). RESULTS: No
      differences in serum concentrations of NSE and S-100 were observed between the
      'control' and the 'hypo' subjects at either 36 hours or seven days after the
      episode of severe hypoglycaemia (p>0.05). However, in two of the three subjects
      who died following hypoglycaemia, serum concentrations of the markers were
      markedly elevated. CONCLUSIONS: Any neuronal injury occurring during severe
      hypoglycaemia that is not associated with persistent neurological deficit is
      insufficient to provoke elevation of these serum markers. However, the
      measurement of serum concentrations of NSE and S-100 may have a prognostic role
      in evaluating clinical outcome following severe hypoglycaemia which is associated
      with neurological damage.

PMID- 10398542
TI  - High glucose modifies heparansulphate synthesis by mouse glomerular epithelial
      cells.
AB  - BACKGROUND: Alterations in proteoglycan metabolism are involved in the
      pathogenesis of diabetic nephropathy. The aim of this study is to evaluate the
      effects of high glucose on proteoglycan production and to find a reliable in
      vitro model for the study of diabetic nephropathy. METHODS: A clone of mouse
      glomerular epithelial cells was cultured in media containing elevated (30 mmol)
      and physiological (5 mmol) glucose, or iso-osmolar (30 mmol) mannitol
      concentrations. We evaluated the synthesis of 35SO4-labeled molecules and the
      amount of proteoglycans by Sepharose CL6B and DEAE-Sephacel chromatographies.
      RESULTS: A clear decrease (56%) in total cell-layer proteoglycan synthesis was
      induced by 30 mmol glucose, in comparison with normal glucose. A reduction of 25%
      in medium associated proteoglycan synthesis was observed in high glucose cultured
      cells. After Sepharose CL6B, in cells cultured in high glucose, cell layer
      heparansulphate proteoglycan-I (Kav 6B 0. 04) synthesis was reduced by about 81%,
      heparansulphate proteoglycan-II (Kav 6B 0.21) by about 87% and heparansulphate
      glycosaminoglycan (Kav 0.4-0.8) by about 91%, respectively. In mannitol-incubated
      cells the reductions observed were less evident and not significantly different
      from those in normal glucose. CONCLUSIONS: These results indicate that (1)
      glomerular epithelial cells play a central role in proteoglycan synthesis, (2)
      high glucose modifies the amount and influences the different species production
      of these macromolecules, while osmotic forces seem to be only partially involved
      in these effects, and (3) this cellular clone of glomerular epithelial cells can
      represent a reliable in vitro model for the study of the mechanisms involved in
      diabetic nephropathy.

PMID- 10398543
TI  - Diet can influence the ability of nicotinamide to prevent diabetes in the non
      obese diabetic mouse: a preliminary study.
AB  - BACKGROUND: The non-obese diabetic (NOD) mouse is a widely used model of Type 1
      diabetes mellitus (Type 1 DM), which displays many of the characteristics of the
      disease found in humans. Nicotinamide (NA) is currently being tested in large
      scale, multi-centre human trials for the prevention of Type 1 DM in subjects
      considered 'at risk' of developing the disease. Human trial populations will
      certainly differ in their dietary patterns and alterations were made to the diet
      given to NOD mice to determine if this could alter the effect of NA
      administration on Type 1 DM incidence. METHODS: The effect of NA in the diet was
      examined, both with and without carbohydrate in the form of a sucrose supplement,
      on diabetes incidence and insulitis levels in the NOD mouse. The effects of NA
      and sucrose were each tested alone as well as in combination. RESULTS: Diabetes
      was unaltered using a low dose NA-supplemented diet (625 mg/kg diet). Diabetes
      incidence was also unaltered using unmodified diet together with drinking water
      supplemented with either 5% or 10% w/v sucrose or plain water for controls.
      However, with mice given NA-supplemented diet (625 mg/kg diet) together with
      sucrose-supplemented or plain water as previously, diabetes was reduced in the
      NA+10% sucrose group (p<0.001). Finally, a higher dose of NA was given in
      supplemented diet (1000 mg/kg). Again, neither sucrose nor NA alone altered the
      incidence of diabetes, but NA treatment combined with a 10% w/v sucrose
      supplemented drinking water reduced diabetes incidence (p<0.001). No mice showed
      alterations in insulitis, blood-glucose or insulin levels with respect to
      controls. CONCLUSION: Altering dietary patterns using sucrose can affect the
      ability of NA to prevent diabetes in the NOD mouse. This finding may be relevant
      for human studies with NA aimed at preventing Type 1 DM and suggests that diet
      may need to be monitored or even controlled in these studies.

PMID- 10398544
TI  - Type 1 diabetes: the facts fit a deficient inhibitory signal given by MHC class
      II.
AB  - This paper presents a hypothesis regarding the aetiology of Type 1 (autoimmune)
      diabetes, which suggests that autoimmunity is normally prevented by an inhibitory
      or negative signal delivered by MHC molecules, and that in Type 1 diabetes it is
      the inability of beta cells to deliver sufficient negative signal from MHC Class
      II that drives the underlying autoimmune process. Based on a broad survey of the
      diabetes literature, a list of clinical, pathological, experimental and
      epidemiological 'facts' about Type 1 diabetes is presented which are considered
      to be widely accepted as proven. The new theory is then compared to other recent
      theories on the aetiology of diabetes with regard to its ability to explain these
      accepted 'facts'.

PMID- 10398545
TI  - Hypoglycemia is the limiting factor in the management of diabetes.
AB  - Hypoglycemia is the limiting factor, both conceptually and in practice, in the
      management of diabetes mellitus. While the long-term goal of diabetes research
      must remain the cure and the prevention of the disease and reasonable near-term
      goals might include perfect insulin replacement or prevention of complications
      despite ongoing hyperglycemia, the most pressing short-term goal for people with
      diabetes would seem to be insight leading to strategies that effectively minimize
      the risk of hypoglycemia and thus permit low-risk glycemic control. Having
      reviewed the field in detail recently, the author offers his personal views of
      the key questions - concerning the physiology of glucose counterregulation, its
      pathophysiology in diabetes, and hypoglycemia in diabetes - that, if answered,
      might lead to a reduced risk of iatrogenic hypoglycemia in people with diabetes.
      The overriding question is: How can we learn to replace insulin more perfectly,
      prevent, correct or compensate for compromised glucose counterregulation, or
      both?

PMID- 10398546
TI  - A role for the endocrine and pro-inflammatory mediator MIF in the control of
      insulin secretion during stress.
AB  - The systemic response to injury or infection is often accompanied by significant
      alterations in host metabolism and glucose homeostasis. Within the liver, these
      changes include a decrease in glycogenesis and an increase in gluconeogenesis,
      and in peripheral tissues, the development of insulin resistance and the
      increased utilization of glucose by non-insulin-dependent pathways. Depending on
      the severity and the duration of the response, both hyper- and hypoglycemia can
      ensue and each can become a clinically important manifestation of the systemic
      inflammatory response. The protein known as macrophage migration inhibitory
      factor (MIF) has been identified recently to play a central role in host immunity
      and to regulate glucocorticoid effects on the immune and inflammatory systems.
      MIF is released in vivo from activated immune cells as well as by the anterior
      pituitary gland upon stimulation of the hypothalamic-pituitary-adrenal axis. MIF
      also has been found to be secreted together with insulin from the pancreatic beta
      cells and to act as an autocrine factor to stimulate insulin release. Since
      circulating MIF levels are elevated during stress or systemic inflammatory
      processes, this protein may play a central role in the control of insulin
      secretion during various disease states.

PMID- 10398547
TI  - AT1 receptor antagonists: a challenge for ACE inhibitors in diabetic nephropathy.
AB  - Due to its hemodynamic, metabolic and growth promoting effects, angiotensin II
      (AII) may play an important role in the pathogenesis of diabetic kidney disease.
      Consequently, decreasing the production or cellular action of AII is a rational
      target for therapeutic attempts aimed at slowing the progression of diabetic
      nephropathy. Based on their superior renoprotective performance in recent
      landmark studies, currently ACE inhibitors are the drugs of choice in diabetic
      patients with microalbuminuria or overt proteinuria. A new class of
      antihypertensive medications, the AT1 receptor antagonists may represent an
      alternative to ACE inhibitors in the treatment of diabetic nephropathy. They
      provide a more complete blockade of the renal renin-angiotensin system and are
      generally better tolerated than ACE inhibitors. On the other hand, AT1 receptor
      antagonists do not increase bradykinin levels, an effect that may contribute to
      the high level of renoprotection achieved by ACE inhibitors. Although human data
      are not available at this point, ACE inhibitors and AT1 receptor antagonists have
      similar beneficial effects on proteinuria, renal hypertrophy and
      glomerulosclerosis in animal models of diabetic kidney disease. Currently several
      prospective studies are being conducted to compare the efficacy of ACE inhibitors
      and AT1 receptor antagonists in the treatment of human diabetic nephropathy.

PMID- 10398548
TI  - The management of neurogenic arthropathy: a tale of two charcots.
AB  - The pathogenesis and natural history of Charcot neuroarthropathy is often poorly
      understood. The diagnosis and treatment of Charcot feet can also prove difficult.
      Two case histories are used to illustrate the key points in the management of
      this potentially devastating condition.

PMID- 10398551
TI  - American diabetes association - http://www.diabetes.org

PMID- 10398549
TI  - United Kingdom prospective diabetes study (UKPDS): what now or so what?
AB  - The UKPDS was a 20-year study involving 23 centres in the United Kingdom. More
      than 5000 patients with Type 2 diabetes were recruited. The aim of the study was
      to determine the impact of intensive blood glucose control on 21 predetermined
      clinical endpoints using, in the care of blood glucose control, sulphonylureas or
      insulin therapy or, in the overweight patient, treatment with metformin. In
      addition, the study investigated the impact of intensive blood pressure control
      on macro- and microvascular complications of diabetes and compared captopril
      treatment with atenolol. UKPDS found that improved control of blood glucose or
      blood pressure reduced the risk of major diabetic eye disease by one quarter,
      serious deterioration of vision by nearly one half, early kidney damage by one
      third, strokes by one third, and death from diabetes-related causes by one third.
      Blood glucose control had little or no effect on macrovascular events. There was
      no evidence of a major detrimental effect of the drugs or insulin on survival or
      outcome other than the expected risk of hypoglycaemia. Metformin appeared to be
      the drug of choice in obese diabetic patients. The targets of glucose and blood
      pressure control were often achieved by using several drugs. Many patients at the
      end of the studies were on four or five drugs for blood glucose and blood
      pressure treatment. The results and implications of the study are discussed. It
      is proposed that the results of UKPDS herald a new era of more focused therapy of
      Type 2 diabetes.

PMID- 10398550
TI  - The development of a World Health Organisation international standard for islet
      cell antibodies: the aims and design of an international collaborative study.
AB  - Islet cell antibodies (ICA) are a specific marker for Type 1 (insulin-dependent)
      diabetes mellitus. ICA are found in the serum of over 80% of newly diagnosed
      patients and the levels of ICA are directly of prognostic value. Standardisation
      of ICA and the uniform reporting of ICA levels in international units is critical
      to preclinical/clinical research and the development of assays for ICA as
      diagnostics, in particular for the differential diagnosis of late onset Type 1
      and Type 2 diabetes. Proficiency studies carried out by the Immunology of
      Diabetes Workshops on Standardization have clearly shown that a single reference
      material, serum sample 673, obtained by Dr J. Ludvigsson, has significantly
      reduced inter- and intra-assay variability in the reporting of ICA levels.
      Nevertheless, this material is a frozen serum of limited shelf-life and is
      difficult to distribute on a worldwide and routine basis. Therefore, the
      Immunology of Diabetes Workshop Standardization Committee and the Juvenile
      Diabetes Foundation International requested that the National Institute for
      Biological Standards and Control (NIBSC) organise an international collaborative
      study to compare the activities of lyophilised, stable ICA preparations. In
      addition, the purpose was to investigate if sample 673 could also serve as a
      standard for GAD65 and IA-2 antibodies. Twenty participants in eight countries
      have been recruited to the study.

PMID- 10398552
TI  - Industry news

PMID- 10398553
TI  - Editorial

PMID- 10398554
TI  - Autoinduction of light emission in different species of bioluminescent bacteria.
AB  - The production of light in most luminescent bacteria lags behind cellular growth
      with induction of luminescence only occurring at high cell density. The maximum
      intensity and the cell density reached before induction of luminescence is highly
      dependent on the bacterial species and the growth conditions including
      temperature, salt and nutrient composition as well as other experimental
      conditions. Although common N-acylhomoserine lactone autoinducers have been
      identified in Vibrio (Photobacterium) fischeri and Vibrio harveyi, most
      regulatory components are quite different. Recognition of the common as well as
      the different elements controlling luminescence in the diverse bacterial species
      is essential to understand the basis for high levels of light emission at the
      later stages of cellular growth.

PMID- 10398555
TI  - Optimal use of photomultipliers for chemiluminescence and bioluminescence
      applications.
AB  - Photomultipliers are the preferred detectors for quantifying weak or short-lived
      light emissions. The quality of signal recovery has an upper limit imposed by the
      statistical nature of light detection. It is shown that the photon counting
      method can provide performance close to ideal, whereas performance in the current
      measuring method is degraded by noise in the multiplier gain process and by the
      nature of the dark current. Performance variations because of changes in
      temperature, shock, vibration and magnetic field effects are significantly
      reduced when using the photon counting method. The effects of dead-time can be
      corrected making photon counting superior to current measuring with regard to
      dynamic range. The benefits of using photon counting packages are presented.

PMID- 10398556
TI  - Application of a new high sensitivity luminometer for industrial microbiology and
      molecular biology.
AB  - A compact new luminometer (FB12) has been developed based on a 370-630 nm photon
      counter and measuring chamber that can accommodate a range of sample formats. The
      FB12 permits measurements as low as 1000 molecules of luciferase in reporter gene
      assays. Its sensitivity for ATP is limited by reagent background. If ATP assay
      reagents had no chemical background, 2 fg of ATP could be detected using 3 SD of
      instrument background as the detection limit. The FB12 has a dynamic range of six
      decades and operates under its own microprocessor programme or protocol-based PC
      software that is integrated with Microsoft(R) Excel(R). An injector port above
      the sample measuring position allows connection of external reagent injectors.
      Applications are performed using protocols provided with the FB12 or user defined
      protocols. Examples are presented that illustrate use of the instrument for
      research and industrial applications.

PMID- 10398559
TI  - Bioluminescent fusion conjugates and bioluminescent immunoassays: 1988-1998
AB  - The first part of this survey focuses on immunoassays and related ligand:binder
      assays (receptor:ligand, DNA probe) that use either a luciferase or a
      photoprotein as a label. In addition, references to assays that use a
      conventional label detected using a bioluminescent assay are included. The second
      part of the survey collects together references to publications on recombinant
      fusion proteins in which one of the fused proteins is bioluminescent (e.g., a
      luciferase or a photoprotein). References are cited by year and then
      alphabetically by first author. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10398557
TI  - In vitro development of Staphylococcus aureus biofilms using slime-producing
      variants and ATP-bioluminescence for automated bacterial quantification.
AB  - In this work, a method was developed to establish Staphylococcus aureus biofilms
      on 96-well plates and automatically quantify viable cells within these biofilms
      by ATP-bioluminescence. Different strains were compared for biofilm formation.
      Cells from slime producing (SP) strain variants were more adherent (p < 0.001)
      and therefore more suitable for biofilm formation than non-slime producing
      original isolates. To compare biofilm support surfaces, SP biofilms were formed
      for 6, 24 and 48 h on 96-well polystyrene plates, containing wells coated with
      gelatin, poly-L-lysine or pre-treated for tissue culture and uncoated wells.
      Tissue culture-treated wells enhanced biofilm formation, allowing the highest
      growth (p < 0.001) in well-established biofilms (24 or 48 h old). For ATP
      quantification, the efficacy of different ATP extractants was compared: dimethyl
      sulphoxide (DMSO), trichloroacetic acid (TCA), a commercially available releasing
      reagent(R) (RR) and lysostaphin. A greater inhibitory effect on the ATP detection
      (p < 0.01), a more variable light emission (variation coefficient >/=50% vs.
      <19%, respectively) and a lower extraction efficiency (p < 0.05) were found in
      the case of TCA or lysostaphin in relation to RR or DMSO. DMSO was found
      preferable in relation to RR (upper detection limits 2.3 x 10(9) and 2 x 10(8)
      CFU/mL respectively) for bacterial ATP extraction from biofilms with high
      bacterial density. DMSO extracted ATP within seconds, light emission being stable
      for 6 h. The method developed allows automated viability determination of biofilm
      cells using bioluminescence and simultaneous study of factors affecting this
      viability (culture media, antibiotic types, antimicrobial concentrations, support
      surfaces and biofilm ages). It may be of use in bacteriological and antimicrobial
      research.

PMID- 10398560
TI  - Time-resolved fluorescence: 1996-1998
AB  - Luminescence continues to provide comprehensive literature surveys which will be
      published in most issues. These are a continuation of the literature surveys
      begun in 1986 in the Journal of Bioluminescence and Chemiluminescence which, up
      until 1998, encompassed more than 6000 references cited by year or specialized
      topic. With this newly named journal these searches are expanding to reflect the
      journal's wider scope. In future we will cover all fundamental and applied
      aspects of biological and chemical luminescence and include not only
      bioluminescence and chemiluminescence but also fluorescence, time resolved
      fluorescence, electrochemiluminescence, phosphorescence, sonoluminescence,
      lyoluminescence and triboluminescence. The compilers would be pleased to receive
      any comments from the readership. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10398558
TI  - Evaluation of two methods for monitoring surface cleanliness-ATP bioluminescence
      and traditional hygiene swabbing.
AB  - The minimum bacterial detection limits and operator reproducibility of the
      Biotrace Clean-Tracetrade mark Rapid Cleanliness Test and traditional hygiene
      swabbing were determined. Areas (100 cm2) of food grade stainless steel were
      separately inoculated with known levels of Staphylococcus aureus (NCTC 6571) and
      Escherichia coli (ATCC 25922). Surfaces were sampled either immediately after
      inoculation while still wet, or after 60 min when completely dry. For both
      organisms the minimum detection limit of the ATP Clean-Tracetrade mark Rapid
      Cleanliness Test was 10(4) cfu/100 cm2 (p < 0.05) and was the same for wet and
      dry surfaces. Both organism type and surface status (i.e. wet or dry) influenced
      the minimum detection limits of hygiene swabbing, which ranged from 10(2) cfu/100
      cm2 to >10(7) cfu/100 cm2. Hygiene swabbing percentage recovery rates for both
      organisms were less than 0.1% for dried surfaces but ranged from 0.33% to 8.8%
      for wet surfaces. When assessed by six technically qualified operators, the
      Biotrace Clean-Tracetrade mark Rapid Cleanliness Test gave superior
      reproducibility for both clean and inoculated surfaces, giving mean coefficients
      of variation of 24% and 32%, respectively. Hygiene swabbing of inoculated
      surfaces gave a mean CV of 130%. The results are discussed in the context of
      hygiene monitoring within the food industry.

PMID- 10398561
TI  - Luminescence on the internet
AB  - This is the first in an occasional survey of Internet sites relating to
      luminescence. This is just a small selection of available sites and readers are
      reminded that web pages are sometimes very temporary in nature. The authors
      welcome details of additional sites of interest to the readers of this journal.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10398562
TI  - Editorial

PMID- 10398563
TI  - Construction of a recombinant herpesvirus expressing the jellyfish green
      fluorescent protein.
AB  - Here we report the insertion of a synthetic version of the cDNA encoding the
      jellyfish (Aequorea victoria) green fluorescent protein (gfph ) into the genome
      of pseudorabies (Aujeszky's disease) virus (PrV). A putative latency promoter
      (PLAT) located at the inverted repeat region of the PrV genome was chosen as the
      target site for the insertion. Recombinant viral DNA designated as vLAT-gfp was
      generated as a result of homologous recombination between the transfected viral
      DNA and a plasmid containing the GFP-expression cassette flanked by viral
      sequences homologous to the target region. Plaques containing recombinant virus
      were selected visually using a fluorescent microscope. We demonstrated a GFP
      expression in infected neurons of rat brain which showed normal morphology at
      early stage of viral infection by monitoring fluorescent light emission.

PMID- 10398564
TI  - Enhancement of aminophthalhydrazides chemiluminescence by N-beta-alanyl-L
      histidine (L-carnosine).
AB  - L-Carnosine was found to be a potent enhancer of chemiluminescence from luminol,
      isoluminol, or N-aminobutyl-N-ethyl-isoluminol oxidized by H5IO6 (2 mmol/L in 11
      mmol/L NaOH) or 20 mmol/L K3Fe(CN)6 + 10 mmol/L H2O2 in 100 mmol/L NaOH.
      Reproducible chemiluminescence enhancement was obtained with luminol and L
      carnosine, each from six different vendors, isoluminol from two different
      vendors, and two different oxidizers. The magnitude of enhancement depended upon
      the source and concentration of L-carnosine, type and concentration of
      aminophthalhydrazide and choice and concentration of oxidizer. Excellent
      signal/noise and fold-enhancement were obtained for all three
      aminophthalhydrazides by including 10 mmol/L L-carnosine during K3Fe(CN)6 + H2O2
      oxidation. L-Carnosine increased the sensitivity of detection of the three
      aminophthalhydrazides by 25-100-fold. A new combination of K3Fe(CN)6 + H2O2
      concentration resulted in 20-30-fold more light emission from N-aminobutyl-N
      ethyl-isoluminol in the presence of 10 mmol/L L-carnosine compared to
      chemiluminescence generated by two previously published concentrations of this
      oxidizer. L-Carnosine could further improve the sensitivity of chemiluminescent
      assays for factor XIIIa and transglutaminase.

PMID- 10398565
TI  - Effect of antioxidants on induction time of luminol luminescence elicited by 3
      morpholinosydnonimine (SIN-1).
AB  - The reaction between luminol as a chemiluminescence probe and 3
      morpholinosydnonimine (SIN-1) as a peroxynitrite donor was evaluated in order to
      determine the action of several antioxidants. Several well-known antioxidants
      found in biological fluids or cells modify the light profile of the reaction
      between SIN-1 and luminol. One main modification was characterized by a transient
      suppression of the light signal, thus permitting evaluation of an induction time
      (sigma) which is linearly related to the concentration of the additive. From
      induction time measurements and using Trolox as a reference antioxidant, the
      trapping ability of a compound against oxidants and radicals produced in the
      luminol-SIN-1 reaction at pH 7. 4 was determined. Uric acid showed higher
      antioxidant capacity than Trolox, while bilirubin and ascorbic acid, in
      decreasing order, were slightly less efficient. On the other hand the main
      modification of the light signal produced by superoxide dismutase,
      desferrioxamine and myoglobin was characterized by a decrease of the luminescence
      during the course of the reaction. The reaction luminol-SIN-1 was compared with
      the known luminol-ABAP (2,2'-azo-bis-2-amidinopropane) method for evaluation of
      antioxidant capacity in human plasma, since this biological fluid modifies the
      luminol-SIN-1 reaction with well-defined induction times. Samples were obtained
      from patients with sepsis, a condition where it has been postulated that excess
      oxygen radicals including peroxynitrite are produced. Using Trolox as reference,
      the results (mean +/- standard error of mean) of both assays showed that the
      patients (SIN-1, 263 +/- 16; ABAP, 218 +/- 13; n = 19) have significantly (SIN-1,
      p < 0.02; ABAP, p < 0.001) lower values in comparison to non-septic controls (SIN
      1, 330 +/- 16; ABAP, 398 +/- 16; n = 20). SIN-1 could be useful as a source of
      oxidant for the characterization of antioxidant behaviour in a system where
      superoxide and nitric oxide are simultaneously generated.

PMID- 10398568
TI  - Sonoluminescence: 1996-1998
AB  - The journal continues to provide comprehensive literature surveys which will be
      published in most issues. These are a continuation of the literature surveys
      begun in 1986 in the Journal of Bioluminescence and Chemiluminescence, and which
      have, up to 1998, encompassed more than 6000 references cited by year or
      specialized topic. With this newly named Journal these searches are expanded to
      reflect the Journal's wider scope. In future we will cover all fundamental and
      applied aspects of biological and chemical luminescence and include not only
      bioluminescence and chemi--luminescence but also fluorescence, time-resolved
      fluorescence, electrochemiluminescence, phosphorescence, sonoluminescence,
      lyoluminescence and triboluminescence, etc. The compilers would be pleased to
      receive any comments from the readership. Contact by E-mail: L. J. Kricka
      (larry_kricka@pathla.med. upenn.edu), and P. E. Stanley (stanley@lumiweb.com).
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10398566
TI  - Optimization of phagocyte chemiluminescence measurements using microplates and
      vials.
AB  - In order to cope with large amounts of samples for chemiluminescence (CL), vials
      were replaced with microplates. Although various types of plates have been
      commercially available for quite some time and the free-plate mode is advocated
      by the producer of the counter, little is known about their impact on the outcome
      of CL measurements. We tested two different 24-well microplates and six different
      96-well microplates in two different luminometers, and results were compared with
      those achieved with vials. Before these comparative tests, we attempted to
      optimize measurement conditions. CL sensitivity was highest with luminol
      concentrations of 0.8-3.3 micromol/L, PMA concentrations of 0.06-80 micromol/L, a
      pH value of 10 and a temperature of 20 degrees C. An indirect correlation was
      found between fluid volume and yield in counts: the lower the volume, the higher
      the counts. With regard to sensitivity and cross-talk, the 96-well Isoplatetrade
      mark was superior to all other plates tested. While all white plates tested gave
      acceptable results, usage of the black 96-well plates resulted in an extremely
      low sensitivity. Plates designed for cell culturing gave even lower counts and a
      cross-talk of up to 31%. All attempts to reduce cross-talk and improve
      sensitivity, such as aluminium foil or grids, irrespective of the position of the
      photomultiplier, did not give results comparable to the original 96-well
      isoplate. Our results suggest that, with the exception of black 96-well
      microplates and cell culture plates, all other plates tested have a sufficient
      sensitivity when compared to vials and acceptable cross-talk, the 96-well
      Isoplatetrade mark being the best. Both types of luminometers used gave
      reproducible results, Wallac having a somewhat higher sensitivity, Canberra
      Packard somewhat less cross-talk.

PMID- 10398569
TI  - Electrochemiluminescence: 1996-1998
AB  - The journal continues to provide comprehensive literature surveys which will be
      published in most issues. These are a continuation of the literature surveys
      begun in 1986 in the Journal of Bioluminescence and Chemiluminescence, and which
      have up to 1998, encompassed more than 6000 references cited by year or
      specialized topic. With this newly named Journal these searches are expanded to
      reflect the Journal's wider scope. In future we will cover all fundamental and
      applied aspects of biological and chemical luminescence and include not only
      bioluminescence and chemi--luminescence but also fluorescence, time-resolved
      fluorescence, electrochemiluminescence, phosphorescence, sonoluminescence,
      lyoluminescence and triboluminescence, etc. The compilers would be pleased to
      receive any comments from the readership. Contact by e-mail: L. J. Kricka
      (larry_kricka@path1a.med. upenn.edu), and P. E. Stanley (stanley@LUMIWEB.COM).
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10398567
TI  - Weak light emission patterns from lactic acid bacteria.
AB  - Distinct low level chemiluminescence patterns during aerobic growth of a
      selection of bacterial strains of the lactic acid group were recorded in on-line
      measurements. These patterns may be specific for the strain and the medium
      employed for cultivation. The patterns are oxygen-dependent and consist in the
      case of Enterococcus faecalis of three basic patterns, which reflect different
      mechanisms leading to both the generation and depletion of initiators of the
      chemiluminescence, particularly hydrogen peroxide and superoxide radical. The
      influence of catalase and superoxide dismutase on the patterns was examined. We
      could demonstrate the sensitivity of chemiluminescence measurements for the
      detection of both exogenous oxidative stress, which is imposed to the cells by
      reactive species formed in the medium, as well as endogenous oxidative stress,
      which is due to products of the cellular oxygen metabolism, the latter being
      often the reason for growth restriction.

PMID- 10398571
TI  - Reply

PMID- 10398570
TI  - Luminescence news

PMID- 10398572
TI  - Reply.

PMID- 10398573
TI  - Author's reply

PMID- 10398574
TI  - Reply 

PMID- 10398575
TI  - Parkinson's syndrome preceding clinical manifestation of Gaucher's disease.

PMID- 10398576
TI  - Isolated retroperitoneal intradiaphragmatic bronchogenic cyst. A case report.
AB  - Isolated retroperitoneal bronchogenic cysts are extremely rare. We report a case
      which was intradiaphragmatic intimately associated with the musculature of the
      left crus diaphragmatic and unconnected with any other structures. Ultrasound and
      computed tomography findings were consistent with a pancreatic or an adrenal
      mass. Pathology confirmed a bronchogenic cyst. The outcome is favourable and the
      overall prognosis is good.

PMID- 10398577
TI  - Brain stem infiltration by mixed Langerhans cell histiocytosis and Chester
      Erdheim disease: more than just an isolated case?
AB  - Langerhans cell histiocytosis is classically considered as totally different from
      Chester-Erdheim's disease which consists in the infiltration of various
      parenchymas by macrophagic CD68-positive histiocytes. We report the case of a 46
      year-old woman with a long history of diabetes insipidus who presented typical
      lesions of Langerhans cell histiocytosis on vulvar and skin biopsies as well as
      bony cellular infiltrates characteristic of Chester-Erdheim's disease. A few
      months later she presented cerebellar disorders and died after an 18-month
      course. At autopsy the pons was enlarged, due to numerous cellular infiltrates
      which were also scattered in the middle cerebellar pedoncles, dentate nuclei,
      midbrain and hypothalamus. There were S100-protein positive Langerhans cells
      intermingled with numerous ovoid CD68-positive histiocytes. There are a few
      reported cases of Chester-Erdheim's disease presenting foci of Langerhans cells
      histiocytosis in other parenchymas. In addition, there are 10 reported cases with
      diabetes insipidus and bilateral infiltration of the brain stem and cerebellum,
      considered as presenting either one type of histiocytosis or the other. Our case
      demonstrates that both histiocytoses may coexist in the brain and thus correspond
      in fact to the same pathology in certain particular cases.

PMID- 10398578
TI  - [Intra-thymic localization of a cystic multi-tissue mature teratoma].
AB  - The authors report a case of mediastinal tumour in a child, corresponding to a
      teratoma arising in the thymus, an original site for this lesion classically
      observed in children.

PMID- 10398579
TI  - [Why we prefer the thin layer technique to conventional Pap smears. A double
      blind study of 473 specimens].
AB  - The study evaluated the feasibility of a thinlayer technique on a routine basis
      for cervical smears and compared 473 ThinPrep preparations to the matched
      conventional Papsmears. The interpretation was double-blind and performed
      according to the Bethesda system. A consensus was established in discordant
      cases. The technique was easily mastered by gynecologists and technicians. Main
      advantages of the thinlayer technique were: a low number (1%) of unsatisfactory
      samples; a constant quality; homogeneity of cell distribution; the disappearance
      of problems of interpretation due to fixation or smear artifacts, red cells,
      polymorphs; a more precise interpretation, a firmer diagnosis; less visual
      fatigue; a shorter time of interpretation; the possibility of preparing more
      slides and performing special techniques on the same specimen. Main disadvantages
      were a higher cost and a necessary period of learning for cytologists.

PMID- 10398580
TI  - [Secretory carcinoma of the breast. Report of a case in a 9-year-old boy].
AB  - The authors report a child male case of secretory carcinoma of the breast,
      associated with a abnormal tumoral karyotype (monosomy 22). The diagnosis was
      made by histopathological examination. This breast carcinoma is characterized by
      an abundant intra and extracellulary secretory material, which present a
      reactivity with antimilk proteins antibodies and includes spherical dense bodies,
      identified by ultrastructural study. The prognosis is not bad, whatever the age
      of the patient, particularly for the children and young women, displaying an
      locoregional aggressivity. The signification of a monosomy 22 in secretory
      carcinoma is unknown.

PMID- 10398581
TI  - [Malignant melanoma in the Ivory Coast. Epidemiologic and histo-prognostic
      aspects. Report of 195 cases].
AB  - Malignant melanomas (MM) are rare tumors of very bad prognosis. Few studies have
      precised the anatomopathological aspects and prognosis of these tumors in Africa
      and especially in Cote d'Ivoire. This has prompted us to review 195 cases of MM
      diagnosed in our laboratories in order to precise their epidemiological and
      anatomical features. Biopsies and/or surgical specimens fixed in 10% buffered
      formalin have been studied using the paraffin embedding methods and staining with
      hematoxylin and eosin, Masson's trichrome and Fontana. 117 men (60%) and 78 women
      (40%) with a medium age of 57 years were studied. Cutaneous MM were predominant
      (174 cases, 93%) with 57.8% located on the foot. Non classified (38.2%) and
      nodular (33.6%) forms were more frequent with only 19% of acral lentiginous
      melanomas. The prognosis of our cases was poor with 71% of levels IV or V
      according to Clark and Mihm, Breslow's thickness superior to 3 mm in 93% of cases
      and ulceration in 91.3%. Our study emphasizes the poor prognosis of MM in Cote
      d'Ivoire. These tumors are frequent in the elderly and located predominantly on
      the foot.

PMID- 10398582
TI  - Chronic pneumonitis of infancy. An autopsy study of 12 cases.
AB  - The authors report 12 cases of chronic pneumonitis of infancy (CPI) studied
      retrospectively, on autopsy specimens. CPI is a new form of interstitial
      pneumonia, occurring exclusively is young infants and first described in 1995.
      Histologically, CPI is characterized by diffuse thickening with hypercellularity
      of the alveolar septa, associated with hyperplasia of type 2 pneumocytes and
      accumulation of intra-alveolar macrophages. In all children, initially in good
      health, the respiratory symptoms initially appeared at the age of 1 to 9 months,
      with a fatal course despite treatment. Many deaths of young infants, previously
      attributed to other types of interstitial pneumonia or unknown aetiology, could
      possibly be due to CPI.

PMID- 10398583
TI  - [Detection of Epstein-Barr virus in Malt type gastric malignant lymphoma using in
      situ hybridization].
AB  - The aim of our study was to look for Epstein Barr virus (EBV) genome by in situ
      hybridization in 23 MALT gastric lymphomas. 15 cases were of low grade, and 8
      were of high grade malignancy. We obtained a positive result in 3 cases (13%) of
      low grade lymphomas. EBV was present in few centrocyte-like and centroblastic
      cells. Literature review shows an EBV infection rate varying between 8 and 12%
      with variables results which don't allow strong and reliable conclusion. An
      etiopathogenic role for EBV in Malt gastric lymphoma remain yet hypothetic.

PMID- 10398584
TI  - Discrimination by Escherichia coli initiation factor IF3 against initiation on
      non-canonical codons relies on complementarity rules.
AB  - Translation initiation factor IF3, one of three factors specifically required for
      translation initiation in Escherichia coli, inhibits initiation on any codon
      other than the three canonical initiation codons, AUG, GUG, or UUG. This
      discrimination against initiation on non-canonical codons could be due to either
      direct recognition of the two last bases of the codon and their cognate bases on
      the anticodon or to some ability to "feel" codon-anticodon complementarity. To
      investigate the importance of codon-anticodon complementarity in the
      discriminatory role of IF3, we constructed a derivative of tRNALeuthat has all
      the known characteristics of an initiator tRNA except the CAU anticodon. This
      tRNA is efficiently formylated by methionyl-tRNAfMettransformylase and charged by
      leucyl-tRNA synthetase irrespective of the sequence of its anticodon. These
      initiator tRNALeuderivatives (called tRNALI) allow initiation at all the non
      canonical codons tested, provided that the complementarity between the codon and
      the anticodon of the initiator tRNALeuis respected. More remarkably, the
      discrimination by IF3, normally observed with non-canonical codons, is
      neutralised if a tRNALIcarrying a complementary anticodon is used for initiation.
      This suggests that IF3 somehow recognises codon-anticodon complementarity, at
      least at the second and third position of the codon, rather than some specific
      bases in either the codon or the anticodon.

PMID- 10398585
TI  - Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein
      kinase CKII in vitro.
AB  - IkappaBalpha is an inherently unstable protein which binds to and retains the
      ubiquitous transcription factor NFkappaB in the cytoplasm of resting cells. A
      continuous low level translocation of NFkappaB to the nucleus, secondary to the
      basal turnover of IkappaBalpha, is hypothesized to be necessary for cellular
      maturation, survival and, potentially, transformation. In response to cellular
      stimulation by inflammatory cytokines or mitogens, IkappaBalpha is rapidly
      degraded allowing larger pools of NFkappaB to translocate to the nucleus.
      Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is
      necessary for this stimuli-induced degradation. IKKalpha/beta kinases and
      p90(rsk1)are involved in stimuli-induced targeting of one or both of these
      IkappaBalpha sites. Whether other kinases phosphorylate S32 and S36 directly, and
      if so, what function they serve in NFkappaB activation remains unknown. Here we
      present evidence of a direct phosphorylation of IkappaBalpha at both S32 and S36
      by purified or immunoprecipitated protein kinase CKII (PK-CKII) and a specific in
      vivo association between IkappaBalpha and PK-CKII. This PK-CKII-specific kinase
      activity is not found within the IKKalpha/beta-containing signalsome complex and
      is biochemically distinct from that of the IKKalpha/beta kinases. The
      identification of an additional N-terminal IkappaBalpha kinase which is
      constitutively active and not significantly inducible raises numerous
      possibilities as to its role in cellular function.

PMID- 10398586
TI  - The reaction center complex from the green sulfur bacterium Chlorobium tepidum: a
      structural analysis by scanning transmission electron microscopy.
AB  - The three-dimensional (3D) structure of the reaction center (RC) complex isolated
      from the green sulfur bacterium Chlorobium tepidum was determined from
      projections of negatively stained preparations by angular reconstitution. The
      purified complex contained the PscA, PscC, PscB, PscD subunits and the Fenna
      Matthews-Olson (FMO) protein. Its mass was found to be 454 kDa by scanning
      transmission electron microscopy (STEM), indicating the presence of two copies of
      the PscA subunit, one copy of the PscB and PscD subunits, three FMO proteins and
      at least one copy of the PscC subunit. An additional mass peak at 183 kDa
      suggested that FMO trimers copurify with the RC complexes. Images of negatively
      stained RC complexes were recorded by STEM and aligned and classified by
      multivariate statistical analysis. Averages of the major classes indicated that
      different morphologies of the elongated particles (length=19 nm, width=8 nm)
      resulted from a rotation around the long axis. The 3D map reconstructed from
      these projections allowed visualization of the RC complex associated with one FMO
      trimer. A second FMO trimer could be correspondingly accommodated to yield a
      symmetric complex, a structure observed in a small number of side views and
      proposed to be the intact form of the RC complex.

PMID- 10398587
TI  - Structural basis and mechanism of enoyl reductase inhibition by triclosan.
AB  - The enoyl-acyl carrier protein reductase (ENR) is involved in bacterial fatty
      acid biosynthesis and is the target of the antibacterial diazaborine compounds
      and the front-line antituberculosis drug isoniazid. Recent studies suggest that
      ENR is also the target for the broad-spectrum biocide triclosan. The 1.75 A
      crystal structure of EnvM, the ENR from Escherichia coli, in complex with
      triclosan and NADH reveals that triclosan binds specifically to EnvM. These data
      provide a molecular mechanism for the antibacterial activity of triclosan and
      substantiate the hypothesis that its activity results from inhibition of a
      specific cellular target rather than non-specific disruption of the bacterial
      cell membrane. This has important implications for the emergence of drug
      resistant bacteria, since triclosan is an additive in many personal care products
      such as toothpastes, mouthwashes and soaps. Based on this structure, rational
      design of triclosan derivatives is possible which might be effective against
      recently identified triclosan-resistant bacterial strains.

PMID- 10398588
TI  - The structure of a tunicate C-type lectin from Polyandrocarpa misakiensis
      complexed with D -galactose.
AB  - C-type lectins are calcium-dependent carbohydrate-recognising proteins.
      Isothermal titration calorimetry of the C-type Polyandrocarpa lectin (TC14) from
      the tunicate Polyandrocarpa misakiensis revealed the presence of a single calcium
      atom per monomer with a dissociation constant of 2.6 microM, and confirmed the
      specificity of TC14 for D -galactose and related monosaccharides. We have
      determined the 2.2 A X-ray crystal structure of Polyandrocarpa lectin complexed
      with D -galactose. Analytical ultracentrifugation revealed that TC14 behaves as a
      dimer in solution. This is reflected by the presence of two molecules in the
      asymmetric unit with the dimeric interface formed by antiparallel pairing of the
      two N-terminal beta-strands and hydrophobic interactions. TC14 adopts a typical C
      type lectin fold with differences in structure from other C-type lectins mainly
      in the diverse loop regions and in the second alpha-helix, which is involved in
      the formation of the dimeric interface. The D -galactose is bound through
      coordination of the 3 and 4-hydroxyl oxygen atoms with a bound calcium atom.
      Additional hydrogen bonds are formed directly between serine, aspartate and
      glutamate side-chains of the protein and the sugar 3 and 4-hydroxyl groups.
      Comparison of the galactose binding by TC14 with the mannose binding by rat
      mannose-binding protein reveals how monosaccharide specificity is achieved in
      this lectin. A tryptophan side-chain close to the binding site and the
      distribution of hydrogen-bond acceptors and donors around the 3 and 4-hydroxyl
      groups of the sugar are essential determinants of specificity. These elements
      are, however, arranged in a very different way than in an engineered galactose
      specific mutant of MBPA. Possible biological functions can more easily be
      understood from the fact that TC14 is a dimer under physiological conditions.

PMID- 10398589
TI  - Crystal structure of the oxidised and reduced acidic cytochrome c3from
      Desulfovibrio africanus.
AB  - Unique among sulphate-reducing bacteria, Desulfovibrio africanus has two
      periplasmic tetraheme cytochromes c3, one with an acidic isoelectric point which
      exhibits an unusually low reactivity towards hydrogenase, and another with a
      basic isoelectric point which shows the usual cytochrome c3reactivity. The
      crystal structure of the oxidised acidic cytochrome c3of Desulfovibrio africanus
      (Dva.a) was solved by the multiple anomalous diffraction (MAD) method and refined
      to 1.6 A resolution. Its structure clearly belongs to the same family as the
      other known cytochromes c3, but with weak parentage with those of the
      Desulfovibrio genus and slightly closer to the cytochromes c3of Desulfomicrobium
      norvegicum. In Dva.a, one edge of heme I is completely exposed to the solvent and
      surrounded by a negatively charged protein surface. Heme I thus seems to play an
      important role in electron exchange, in addition to heme III or heme IV which are
      the electron exchange ports in the other cytochromes c3. The function of Dva.a
      and the nature of its redox partners in the cell are thus very likely different.
      By alignment of the seven known 3D structures including Dva.a, it is shown that
      the structure which is most conserved in all cytochromes c3is the four-heme
      cluster itself. There is no conserved continuous protein structure which could
      explain the remarkable invariance of the four-heme cluster. On the contrary, the
      proximity of the heme edges is such that they interact directly by hydrophobic
      and van der Waals contacts. This direct interaction, which always involves a
      pyrrole CA-CB side-chain and its bound protein cysteine Sgammaatom, is probably
      the main origin of the four-heme cluster stability. The same kind of interaction
      is found in the chaining of the hemes in other multihemic redox proteins.The
      crystal structure of reduced Dva. a was solved at 1.9 A resolution. The
      comparison of the oxidised and reduced structures reveals changes in the
      positions of water molecules and polar residues which probably result from
      changes in the protonation state of amino acids and heme propionates. Water
      molecules are found closer to the hemes and to the iron atoms in the reduced than
      in the oxidised state. A global movement of a chain fragment in the vicinity of
      hemes III and IV is observed which result very likely from the electrostatic
      reorganization of the polypeptide chain induced by reduction.

PMID- 10398590
TI  - Risk screening for exposure to groundwater pollution in a wastewater irrigation
      district of the Mexico City region.
AB  - Untreated wastewater from the Mexico City basin has been used for decades to
      irrigate cropland in the Mezquital Valley, State of Hidalgo, Mexico. Excess
      irrigation water recharges the near-surface aquifer that is used as a domestic
      water supply source. We assessed the groundwater quality of three key groundwater
      sources of domestic water by analyzing for 24 trace metals, 67 target
      base/neutral/acid (BNA) organic compounds, nontarget BNA organics, 23 chlorinated
      pesticides, 20 polychlorinated biphenyls, and nitrate, as well as microbiological
      contaminants--coliforms, Vibrio cholerae, and Salmonella. Study participants
      answered a questionnaire that estimated ingestion and dermal exposure to
      groundwater; 10% of the sample reported frequent diarrhea and 9% reported
      persistent skin irritations. Detection of V. cholerae non-01 in surface waters at
      all sites suggested a potential risk (surrogate indicator present) of diarrheal
      disease for canal and river bathers by accidental ingestion, as well as potential
      Vibrio contamination of near-surface groundwater and potential cholera risk,
      magnified by lapses in disinfection. High total coliform levels in surface water
      and lower levels in groundwater at all sites indicated fecal contamination and a
      potential risk of gastrointestinal disease in populations exposed to inadequately
      disinfected groundwater. Using chemical criteria, no significant risk from
      ingestion or dermal contact was identified at the method detection limits at any
      site, except from nitrate exposure: infants and young children are at risk from
      methemoglobinemia at all sites. Results suggest that pathogen risk interventions
      are a priority, whereas nitrate risk needs further characterization to determine
      if formal treatment is needed. The risks exist inside and outside the irrigation
      district. The method was highly cost-effective.

PMID- 10398591
TI  - The structural era of endocytosis.
AB  - Endocytosis is crucial for an array of cellular functions and can occur through
      several distinct mechanisms with the capacity to internalize anything from small
      molecules to entire cells. The clathrin-mediated endocytic pathway has recently
      received considerable attention because of (i) the identification of an array of
      molecules that orchestrate the assembly of clathrin-coated vesicles and the
      selection of the vesicle cargo and (ii) the resolution of structures for a number
      of these proteins. Together, these data provide an initial three-dimensional
      framework for understanding the clathrin endocytic machinery.

PMID- 10398593
TI  - Variations in atmospheric N2O concentration during abrupt climatic changes 
AB  - Nitrous oxide (N2O) is an important greenhouse gas that is presently increasing
      at a rate of 0.25 percent per year. Records measured along two ice cores from
      Summit in Central Greenland provide information about variations in atmospheric
      N2O concentration in the past. The record covering the past millennium reduces
      the uncertainty regarding the preindustrial concentration. Records covering the
      last glacial-interglacial transition and a fast climatic change during the last
      ice age show that the N2O concentration changed in parallel with fast temperature
      variations in the Northern Hemisphere. This provides important information about
      the response of the environment to global climatic changes.

PMID- 10398592
TI  - The immunological synapse: a molecular machine controlling T cell activation.
AB  - The specialized junction between a T lymphocyte and an antigen-presenting cell,
      the immunological synapse, consists of a central cluster of T cell receptors
      surrounded by a ring of adhesion molecules. Immunological synapse formation is
      now shown to be an active and dynamic mechanism that allows T cells to
      distinguish potential antigenic ligands. Initially, T cell receptor ligands were
      engaged in an outermost ring of the nascent synapse. Transport of these complexes
      into the central cluster was dependent on T cell receptor-ligand interaction
      kinetics. Finally, formation of a stable central cluster at the heart of the
      synapse was a determinative event for T cell proliferation.

PMID- 10398594
TI  - Optical vortices crystals: spontaneous generation in nonlinear semiconductor
      microcavities 
AB  - Broad-area, vertical-cavity surface-emitting lasers were shown to switch their
      emission mode from the regular single or multilobed light fields to exhibit
      complex arrays of "dark beams." Examination of these dark spot arrays revealed
      that they consist of multiple, closely packed optical vortices: optical fields
      that have phase singularities and show increased complexity as the injection
      current level is raised. Contrary to their complex appearance, most of these
      light distributions are not the result of a multimode (multiple-frequency)
      operation but exhibit single-frequency characteristics. The dark beam patterns
      can be described as emanating from a spontaneous process of transverse mode
      locking of nearly degenerate modes, assisted by the laser nonlinearity.
      Surprisingly, these patterns show high resemblance to patterns generated in other
      nonlinear scenarios that are completely different both in scale and in mechanism.

PMID- 10398595
TI  - All-polymer optoelectronic devices 
AB  - Composites of nanoparticles and conjugated polymers that exhibit composition
      tunable optical constants have been developed for use in semiconducting photonic
      structures. For example, the 550-nanometer wavelength in-plane refractive index
      of poly(p-phenylenevinylene)-silica composites can be tailored over the range of
      1.6 to 2.7, allowing efficient distributed Bragg reflectors and waveguides to be
      fabricated. Low levels of chemical doping improve electrical conductivity through
      these structures without detriment to their photonic properties. Exemplifying
      these concepts, all-polymer microcavities and microcavity light-emitting diodes
      were demonstrated. Appropriate confinement of photons and electron-hole pairs in
      these organic semiconductor-based structures can be achieved.

PMID- 10398596
TI  - Role of fluids in faulting inferred from stress field signatures 
AB  - The stress orientation signature of weak faults containing high-pressure fluids
      has been observed for segments of the San Andreas fault system in southern
      California. The inferred lithostatic fluid pressures extend into the surrounding
      relatively intact rock in a zone scaling with the width of the interseismic
      strain accumulation. Repeated strain-related fracturing and crack sealing may
      have created low-permeability barriers that seal fluids into the network of
      currently active fractures.

PMID- 10398597
TI  - Estimation of particulate organic carbon in the ocean from satellite remote
      sensing 
AB  - Measurements from the Southern Ocean show that particulate organic carbon (POC)
      concentration is well correlated with the optical backscattering by particles
      suspended in seawater. This relation, in conjunction with retrieval of the
      backscattering coefficient from remote-sensing reflectance, provides an algorithm
      for estimating surface POC from satellite data of ocean color. Satellite imagery
      from SeaWiFS reveals the seasonal progression of POC, with a zonal band of
      elevated POC concentrations in December coinciding with the Antarctic Polar Front
      Zone. At that time, the POC pool within the top 100 meters of the entire Southern
      Ocean south of 40 degrees S exceeded 0.8 gigatons.

PMID- 10398598
TI  - A nucleoside transporter from Trypanosoma brucei involved in drug resistance.
AB  - Drug resistance of pathogens is an increasing problem whose underlying mechanisms
      are not fully understood. Cellular uptake of the major drugs against Trypanosoma
      brucei spp., the causative agents of sleeping sickness, is thought to occur
      through an unusual, so far unidentified adenosine transporter. Saccharomyces
      cerevisiae was used in a functional screen to clone a gene (TbAT1) from
      Trypanosoma brucei brucei that encodes a nucleoside transporter. When expressed
      in yeast, TbAT1 enabled adenosine uptake and conferred susceptibility to
      melaminophenyl arsenicals. Drug-resistant trypanosomes harbor a defective TbAT1
      variant. The molecular identification of the entry route of trypanocides opens
      the way to approaches for diagnosis and treatment of drug-resistant sleeping
      sickness.

PMID- 10398599
TI  - Pigment epithelium-derived factor: a potent inhibitor of angiogenesis.
AB  - In the absence of disease, the vasculature of the mammalian eye is quiescent, in
      part because of the action of angiogenic inhibitors that prevent vessels from
      invading the cornea and vitreous. Here, an inhibitor responsible for the
      avascularity of these ocular compartments is identified as pigment epithelium
      derived factor (PEDF), a protein previously shown to have neurotrophic activity.
      The amount of inhibitory PEDF produced by retinal cells was positively correlated
      with oxygen concentrations, suggesting that its loss plays a permissive role in
      ischemia-driven retinal neovascularization. These results suggest that PEDF may
      be of therapeutic use, especially in retinopathies where pathological
      neovascularization compromises vision and leads to blindness.

PMID- 10398600
TI  - HMG-1 as a late mediator of endotoxin lethality in mice.
AB  - Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to
      release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1),
      which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists
      of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because
      these cytokines are early mediators in pathogenesis. Here a potential late
      mediator of lethality is identified and characterized in a mouse model. High
      mobility group-1 (HMG-1) protein was found to be released by cultured macrophages
      more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed
      increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure.
      Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in
      mice, and administration of HMG-1 itself was lethal. Septic patients who
      succumbed to infection had increased serum HMG-1 levels, suggesting that this
      protein warrants investigation as a therapeutic target.

PMID- 10398601
TI  - Ploidy regulation of gene expression.
AB  - Microarray-based gene expression analysis identified genes showing ploidy
      dependent expression in isogenic Saccharomyces cerevisiae strains that varied in
      ploidy from haploid to tetraploid. These genes were induced or repressed in
      proportion to the number of chromosome sets, regardless of the mating type.
      Ploidy-dependent repression of some G1 cyclins can explain the greater cell size
      associated with higher ploidies, and suggests ploidy-dependent modifications of
      cell cycle progression. Moreover, ploidy regulation of the FLO11 gene had direct
      consequences for yeast development.

PMID- 10398602
TI  - A functional assay for centromere-associated sister chromatid cohesion.
AB  - Cohesion of sister chromatids occurs along the entire length of chromosomes,
      including the centromere where it plays essential roles in chromosome
      segregation. Here, minichromosomes in the budding yeast Saccharomyces cerevisiae
      are exploited to generate a functional assay for DNA sequences involved in
      cohesion. The centromeric DNA element CDEIII was found to be necessary but not
      sufficient for cohesion. This element was shown previously to be required for
      assembly of the kinetochore, the centromere-associated protein complex that
      attaches chromosomes to the spindle. These observations establish a link between
      centromere-proximal cohesion and kinetochore assembly.

PMID- 10398603
TI  - Reach plans in eye-centered coordinates.
AB  - The neural events associated with visually guided reaching begin with an image on
      the retina and end with impulses to the muscles. In between, a reaching plan is
      formed. This plan could be in the coordinates of the arm, specifying the
      direction and amplitude of the movement, or it could be in the coordinates of the
      eye because visual information is initially gathered in this reference frame. In
      a reach-planning area of the posterior parietal cortex, neural activity was found
      to be more consistent with an eye-centered than an arm-centered coding of reach
      targets. Coding of arm movements in an eye-centered reference frame is
      advantageous because obstacles that affect planning as well as errors in reaching
      are registered in this reference frame. Also, eye movements are planned in eye
      coordinates, and the use of similar coordinates for reaching may facilitate hand
      eye coordination.

PMID- 10398604
TI  - BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator.
AB  - The tumor necrosis factor (TNF) superfamily of cytokines includes both soluble
      and membrane-bound proteins that regulate immune responses. A member of the human
      TNF family, BLyS (B lymphocyte stimulator), was identified that induced B cell
      proliferation and immunoglobulin secretion. BLyS expression on human monocytes
      could be up-regulated by interferon-gamma. Soluble BLyS functioned as a potent B
      cell growth factor in costimulation assays. Administration of soluble recombinant
      BLyS to mice disrupted splenic B and T cell zones and resulted in elevated serum
      immunoglobulin concentrations. The B cell tropism of BLyS is consistent with its
      receptor expression on B-lineage cells. The biological profile of BLyS suggests
      it is involved in monocyte-driven B cell activation.

PMID- 10398605
TI  - hRAD30 mutations in the variant form of xeroderma pigmentosum.
AB  - Xeroderma pigmentosum (XP) is an autosomal recessive disease characterized by a
      high incidence of skin cancers. Yeast RAD30 encodes a DNA polymerase involved in
      the error-free bypass of ultraviolet (UV) damage. Here it is shown that XP
      variant (XP-V) cell lines harbor nonsense or frameshift mutations in hRAD30, the
      human counterpart of yeast RAD30. Of the eight mutations identified, seven would
      result in a severely truncated hRad30 protein. These results indicate that
      defects in hRAD30 cause XP-V, and they suggest that error-free replication of UV
      lesions by hRad30 plays an important role in minimizing the incidence of sunlight
      induced skin cancers.

PMID- 10398606
TI  - What do hospital admission rates say about primary care?

PMID- 10398607
TI  - Radioiodine and thyroid eye disease.

PMID- 10398608
TI  - Reasons for not seeing drug representatives.

PMID- 10398609
TI  - Prescribing medicines for children.

PMID- 10398610
TI  - Skin and nail fungi-almost beaten.

PMID- 10398611
TI  - UK public health plan aims to save 300 000 lives in next decade.

PMID- 10398612
TI  - US National Institutes of Health clarifies E-biomed database.

PMID- 10398613
TI  - BMA backs junior doctors' fight against government 

PMID- 10398614
TI  - Newly identified gene linked to dementia 

PMID- 10398615
TI  - BMA calls for independent commissioner on child health 

PMID- 10398616
TI  - US government debates Medicare coverage of prescription costs.

PMID- 10398617
TI  - Euthanasia endorsed in dutch patient with dementia 

PMID- 10398618
TI  - Philippine plan to cut diarrhoea deaths.

PMID- 10398619
TI  - UK guidelines aim to improve pain management in children.

PMID- 10398620
TI  - First national paediatric formulary is launched in the UK.

PMID- 10398621
TI  - Report calls for GP research in Scotland.

PMID- 10398622
TI  - Ovarian cancer should be treated by specialist teams.

PMID- 10398623
TI  - Suboptimal care implicated in many infant deaths in UK.

PMID- 10398624
TI  - US reconsiders use of seclusion and restraints in psychiatric patients.

PMID- 10398625
TI  - Scientist, superwoman, and sock drawer sorter 

PMID- 10398626
TI  - Systematic review of topical treatments for fungal infections of the skin and
      nails of the feet.
AB  - OBJECTIVE: To identify and synthesise the evidence for efficacy and cost
      effectiveness of topical treatments for superficial fungal infections of the skin
      and nails of the feet. DESIGN: Systematic review. INTERVENTIONS: Topical
      treatments for superficial fungal infections. MAIN OUTCOME MEASURES: Cure
      confirmed by culture and microscopy for skin and by culture for nails in patients
      with clinically diagnosed fungal infections. RESULTS: Of 126 trials identified in
      121 papers, 72 (57.1%) met the inclusion criteria. Placebo controlled trials
      yielded pooled relative risks of failure to cure skin infections: allylamines
      (0.30, 95% confidence interval 0.24 to 0.38); azoles (0.54, 0.42 to 0.68);
      undecenoic acid (0.28, 0. 11 to 0.74); and tolnaftate (0.46, 0.17 to 1.22).
      Although meta-analysis of 11 trials comparing allylamines and azoles showed a
      relative risk of failure to cure of 0.88 (0.78 to 0.99) in favour of allylamines,
      there was evidence of language bias. Seven reports in English favoured
      allylamines (0.79, 0.69 to 0.91), but four reports in foreign languages showed no
      difference between the two drugs (1. 01, 0.90 to 1.13). Neither trial of nail
      infections showed significant differences between alternative topical treatments.
      CONCLUSIONS: Allylamines, azoles, and undecenoic acid were efficacious in placebo
      controlled trials. There are sufficient comparative trials to judge relative
      efficacy only between allylamines and azoles. Allylamines cure slightly more
      infections than azoles but are much more expensive than azoles. The most cost
      effective strategy is first to treat with azoles or undecenoic acid and to use
      allylamines only if that fails.

PMID- 10398627
TI  - Frequency of blood glucose monitoring in relation to glycaemic control:
      observational study with diabetes database.
AB  - OBJECTIVES: To investigate patterns of self monitoring of blood glucose
      concentration in diabetic patients who use insulin and to determine whether
      frequency of self monitoring is related to glycaemic control. SETTING: Diabetes
      database, Tayside, Scotland. SUBJECTS: Patients resident in Tayside in 1993-5 who
      were using insulin and were registered on the database and diagnosed with insulin
      dependent (type 1) or non-insulin dependent (type 2) diabetes before 1993. MAIN
      OUTCOME MEASURES: Number of glucose monitoring reagent strips dispensed (reagent
      strip uptake) derived from records of prescriptions. First recorded haemoglobin
      A1c concentration in the study period, and reagent strips dispensed in the
      previous 6 months. RESULTS: Among 807 patients with type 1 diabetes, 128 (16%)
      did not redeem any prescriptions for glucose monitoring reagent strips in the 3
      year study period. Only 161 (20%) redeemed prescriptions for enough reagent
      strips to test glucose daily. The corresponding figures for the 790 patients with
      type 2 diabetes who used insulin were 162 (21%; no strips) and 131 (17%; daily
      tests). Reagent strip uptake was influenced both by age and by deprivation
      category. There was a direct relation between uptake and glycaemic control for
      258 patients (with recorded haemoglobin A1c concentrations) with type 1 diabetes.
      In a linear regression model the decrease in haemoglobin A1c concentration for
      every extra 180 reagent strips dispensed was 0.7%. For the 290 patients with type
      2 diabetes who used insulin there was no such relation. CONCLUSIONS: Self
      monitoring of blood glucose concentration is associated with improved glycaemic
      control in patients with type 1 diabetes. Regular self monitoring in patients
      with type 1 and type 2 diabetes is uncommon.

PMID- 10398628
TI  - "Thank you for ending 40 years of misery" 

PMID- 10398630
TI  - What are leukotrienes and how do they work in asthma? 

PMID- 10398629
TI  - Randomised, placebo controlled trial of effect of a leukotriene receptor
      antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic
      patients.
AB  - OBJECTIVE: To determine the ability of montelukast, a leukotriene receptor
      antagonist, to allow tapering of inhaled corticosteroids in clinically stable
      asthmatic patients. DESIGN: Double blind, randomised, placebo controlled,
      parallel group study. After a single blind placebo run in period, during which
      (at most) two inhaled corticosteroids dose decreases occurred, qualifying,
      clinically stable patients were allocated randomly to receive montelukast (10 mg
      tablet) or matching placebo once daily at bedtime for up to 12 weeks. SETTING: 23
      academic asthma centres in United States, Canada, and Europe. PARTICIPANTS: 226
      clinically stable patients with chronic asthma receiving high doses of inhaled
      corticosteroids (113 randomised to montelukast and 113 to placebo).
      INTERVENTIONS: Every 2 weeks, the inhaled corticosteroids dose was tapered,
      maintained, or increased (rescue) based on a standardised clinical score. MAIN
      OUTCOME MEASURES: Last tolerated dose of inhaled corticosteroids. RESULTS:
      Compared with placebo, montelukast allowed significant (P=0. 046) reduction in
      the inhaled corticosteroid dose (montelukast 47% v placebo 30%; least square mean
      difference 17.6%, 95% confidence interval 0.3 to 34.8). Fewer patients on
      montelukast (18 (16%) v 34 (30%) placebo, P=0.01) required discontinuation
      because of failed rescue. CONCLUSIONS: Montelukast reduces the need for inhaled
      corticosteroids among patients requiring moderate to high doses of corticosteroid
      to maintain asthma control.

PMID- 10398631
TI  - Questionnaire study of use of emergency contraception among teenagers.

PMID- 10398632
TI  - Neural tube defects and periconceptional folic acid in England and Wales:
      retrospective study.

PMID- 10398633
TI  - Do texts in english encourage quacks? 

PMID- 10398634
TI  - Commentary: food should be fortified with folic acid.

PMID- 10398635
TI  - Measuring quality of care with routine data: avoiding confusion between
      performance indicators and health outcomes.
AB  - OBJECTIVE: To investigate the impact of factors outside the control of primary
      care on performance indicators proposed as measures of the quality of primary
      care. DESIGN: Multiple regression analysis relating admission rates standardised
      for age and sex for asthma, diabetes, and epilepsy to socioeconomic population
      characteristics and to the supply of secondary care resources. SETTING: 90 family
      health services authorities in England, 1989-90 to 1994-5. RESULTS: At health
      authority level socioeconomic characteristics, health status, and secondary care
      supply factors explained 45% of the variation in admission rates for asthma, 33%
      for diabetes, and 55% for epilepsy. When health authorities were ranked, only
      four of the 10 with the highest age-sex standardised admission rates for asthma
      in 1994-5 remained in the top 10 when allowance was made for socioeconomic
      characteristics, health status, and secondary care supply factors. There was also
      substantial year to year variation in the rates. CONCLUSION: Health outcomes
      should relate to crude rates of adverse events in the population. These give the
      best indication of the size of a health problem. Performance indicators, however,
      should relate to those aspects of care which can be altered by the staff whose
      performance is being measured.

PMID- 10398636
TI  - Explaining variation in hospital admission rates between general practices: cross
      sectional study.
AB  - OBJECTIVES: To quantify the extent of the variation in hospital admission rates
      between general practices, and to investigate whether this variation can be
      explained by factors relating to the patient, the hospital, and the general
      practice. DESIGN: Cross sectional analysis of routine data. SETTING: Merton,
      Sutton, and Wandsworth Health Authority, which includes areas of inner and outer
      London. SUBJECTS: 209 136 hospital admissions in 1995-6 in patients registered
      with 120 general practices in the study area. MAIN OUTCOME MEASURES: Hospital
      admission rates for general practices for overall, emergency, and elective
      admissions. RESULTS: Crude admission rates for general practices displayed a
      twofold difference between the 10th and the 90th centile for all, emergency, and
      elective admissions. This difference was only minimally reduced by standardising
      for age and sex. Sociodemographic patient factors derived from census data
      accounted for 42% of the variation in overall admission rates; 45% in emergency
      admission rates; and 25% in elective admission rates. There was a strong positive
      correlation between factors related to deprivation and emergency, but not
      elective, admission rates, raising questions about equity of provision of health
      care. The percentage of each practice's admissions to different local hospitals
      added significantly to the explanation of variation, while the general practice
      characteristics considered added very little. CONCLUSIONS: Hospital admission
      rates varied greatly between general practices; this was largely explained by
      differences in patient populations. The lack of significant factors related to
      general practice is of little help for the direct management of admission rates,
      although the effect of sociological rather than organisational practice variables
      should be explored further. Admission rates should routinely be standardised for
      differences in patient populations and hospitals used.

PMID- 10398637
TI  - No silent areas 

PMID- 10398638
TI  - Clinical evidence: glycaemic control in diabetes.

PMID- 10398639
TI  - Lesson of the week: managing patients with deliberate self harm who refuse
      treatment in the accident and emergency department.

PMID- 10398640
TI  - ABC of intensive care: neurological support.

PMID- 10398641
TI  - Are we really dying for a tan?

PMID- 10398643
TI  - Economics notes: handling uncertainty in economic evaluation.

PMID- 10398642
TI  - The private finance initiative: PFI in the NHS--is there an economic case?

PMID- 10398644
TI  - Routine screening of children returning home from the tropics. Authors'
      definition of asymptomatic children is not the one usually accepted.

PMID- 10398645
TI  - In screening for congenital cataract, many false positive referrals will occur.

PMID- 10398646
TI  - Body mass index standards for children. 1990 data will remain available.

PMID- 10398647
TI  - Closure of Royal Hospital Haslar is necessary.

PMID- 10398649
TI  - Drug and alcohol policies are rare at medical schools in UK.

PMID- 10398648
TI  - Treatment of myocardial infarction should be audited before heart failure clinics
      are set up.

PMID- 10398650
TI  - Bible is disapproving of homosexual activity but not homosexual orientation.

PMID- 10398651
TI  - Reducing antibiotic use in children with acute otitis media. Acute otitis media
      in children is important.

PMID- 10398653
TI  - George sydney anderson 

PMID- 10398652
TI  - Comparison of inhaled beclomethasone and budesonide. Patients do not take
      prescribed doses.

PMID- 10398654
TI  - BMA chairman warns of fight ahead 

PMID- 10398655
TI  - Small wars: the cultural politics of childhood 

PMID- 10398656
TI  - Tropical medicine in the twentieth century 

PMID- 10398657
TI  - Opium and the people: opiate use and drug control policy in nineteenth century
      england 

PMID- 10398658
TI  - Evidence-based family medicine 

PMID- 10398659
TI  - Raging hormones miss the target 

PMID- 10398660
TI  - Pros and cons of suntans 

PMID- 10398661
TI  - Concern, cooperation, and coexistence in healing 

PMID- 10398663
TI  - Ignoring doctors: often advisable 

PMID- 10398662
TI  - St Mark's guideline 

PMID- 10398664
TI  - Treatment for athlete's foot should begin with over the counter drugs 

PMID- 10398665
TI  - Many diabetic patients do not monitor their blood glucose regularly 

PMID- 10398666
TI  - Easy access to emergency contraception does not make it the contraceptive of
      choice 

PMID- 10398667
TI  - Leukotriene receptor antagonist reduces need for inhaled corticosteroids 

PMID- 10398668
TI  - Folate supplements have not reduced neural tube defects 

PMID- 10398669
TI  - Patient factors largely explain variation in GP admission rates 

PMID- 10398671
TI  - Intranasal antibody prophylaxis for protection against viral disease.
AB  - For more than a century, antibody has been used for passive parenteral
      immunization against viral and bacterial pathogens. This approach has been
      successful for prevention of viral respiratory infection and has led to testing
      of intranasal or aerosol delivery of antibody to passively immunize the
      respiratory tract mucosal surface. Mucosal delivery may be advantageous because
      it allows the antibody to neutralize the virus particles before they initiate
      infection and because it concentrates the antibody where viral replication takes
      place. Animal studies have shown the feasibility of passive intranasal
      immunization against a number of respiratory tract viruses. Development of nasal
      antibody treatments for humans is under way, and early clinical studies have
      confirmed that this approach is safe and can be used to prevent respiratory tract
      disease. Polyclonal human immunoglobulin from pooled plasma preparations can be
      used to provide broad protection against a number of different pathogens, while
      monoclonal antibodies or their fragments can be used to target specific viruses.

PMID- 10398672
TI  - Acquisition, transport, and storage of iron by pathogenic fungi.
AB  - Iron is required by most living systems. A great variety of means of acquisition,
      avenues of uptake, and methods of storage are used by pathogenic fungi to ensure
      a supply of the essential metal. Solubilization of insoluble iron polymers is the
      first step in iron assimilation. The two methods most commonly used by
      microorganisms for solubilization of iron are reduction and chelation. Reduction
      of ferric iron to ferrous iron by enzymatic or nonenzymatic means is a common
      mechanism among pathogenic yeasts. Under conditions of iron starvation, many
      fungi synthesize iron chelators known as siderophores. Two classes of compounds
      that function in iron gathering are commonly observed: hydroxamates and
      polycarboxylates. Two major responses to iron stress in fungi are a high-affinity
      ferric iron reductase and siderophore synthesis. Regulation of these two
      mechanisms at the molecular level has received attention. Uptake of siderophores
      is a diverse process, which varies among the different classes of compounds.
      Since free iron is toxic, it must be stored for further metabolic use.
      Polyphosphates, ferritins, and siderophores themselves have been described as
      storage molecules. The iron-gathering mechanisms used by a pathogen in an
      infected host are largely unknown and can only be posited on the basis of in
      vitro studies at present.

PMID- 10398670
TI  - Human cytomegalovirus and human herpesvirus 6 genes that transform and
      transactivate.
AB  - This review is an update on the transforming genes of human cytomegalovirus
      (HCMV) and human herpesvirus 6 (HHV-6). Both viruses have been implicated in the
      etiology of several human cancers. In particular, HCMV has been associated with
      cervical carcinoma and adenocarcinomas of the prostate and colon. In vitro
      transformation studies have established three HCMV morphologic transforming
      regions (mtr), i.e., mtrI, mtrII, and mtrIII. Of these, only mtrII (UL111A) is
      retained and expressed in both transformed and tumor-derived cells. The
      transforming and tumorigenic activities of the mtrII oncogene were localized to
      an open reading frame (ORF) encoding a 79-amino-acid (aa) protein. Furthermore,
      mtrII protein bound to the tumor suppressor protein p53 and inhibited its ability
      to transactivate a p53-responsive promoter. In additional studies, the HCMV
      immediate-early protein IE86 (IE2; UL122) was found to interact with cell cycle
      regulatory proteins such as p53 and Rb. However, IE86 exhibited transforming
      activity in vitro only in cooperation with adenovirus E1A. HHV-6 is a T-cell
      tropic virus associated with AIDS-related and other lymphoid malignancies. In
      vitro studies identified three transforming fragments, i.e., SalI-L, ZVB70, and
      ZVH14. Of these, only SalI-L (DR7) was retained in transformed and tumor-derived
      cells. The transforming and tumorigenic activities of SalI-L have been localized
      to a 357-aa ORF-1 protein. The ORF-1 protein was expressed in transformed cells
      and, like HCMV mtrII, bound to p53 and inhibited its ability to transactivate a
      p53-responsive promoter. HHV-6 has also been proposed to be a cofactor in AIDS
      because both HHV-6 and human immunodeficiency virus type 1 (HIV-1) have been
      demonstrated to coinfect human CD4(+) T cells, causing accelerated cytopathic
      effects. Interestingly, like the transforming proteins of DNA tumor viruses such
      as simian virus 40 and adenovirus, ORF-1 was also a transactivator and
      specifically up-regulated the HIV-1 long terminal repeat when cotransfected into
      CD4(+) T cells. Finally, based on the interactions of HCMV and HHV-6 transforming
      proteins with tumor suppressor proteins, a scheme is proposed for their role in
      oncogenesis.

PMID- 10398673
TI  - Molecular basis of the interaction of Salmonella with the intestinal mucosa.
AB  - Salmonella is one of the most extensively characterized bacterial pathogens and
      is a leading cause of bacterial gastroenteritis. Despite this, we are only just
      beginning to understand at a molecular level how Salmonella interacts with its
      mammalian hosts to cause disease. Studies during the past decade on the genetic
      basis of virulence of Salmonella have significantly advanced our understanding of
      the molecular basis of the host-pathogen interaction, yet many questions remain.
      In this review, we focus on the interaction of enterocolitis-causing salmonellae
      with the intestinal mucosa, since this is the initiating step for most infections
      caused by Salmonella. Animal and in vitro cell culture models for the interaction
      of these bacteria with the intestinal epithelium are reviewed, along with the
      bacterial genes that are thought to affect this interaction. Lastly, recent
      studies on the response of epithelial cells to Salmonella infection and how this
      might promote diarrhea are discussed.

PMID- 10398675
TI  - Pathogenesis of onchocercal keratitis (River blindness).
AB  - Onchocerciasis is a major cause of blindness. Although the World Health
      Organization has been successful in reducing onchocerciasis as a public health
      problem in parts of West Africa, there remain an estimated 17 million people
      infected with Onchocerca volvulus, the parasite that causes this disease. Ocular
      pathology can be manifested in any part of the eye, although disease
      manifestations are frequently characterized as either posterior or anterior eye
      disease. This review focuses on onchocerca-mediated keratitis that results from
      an inflammatory response in the anterior portion of the eye and summarizes what
      is currently known about human disease. This review also describes studies with
      experimental models that have been established to determine the immunological
      mechanisms underlying interstitial keratitis. The pathogenesis of keratitis is
      thought to be due to the host inflammatory response to degenerating parasites in
      the eye; therefore, the primary clinical symptoms of onchocercal keratitis
      (corneal opacification and neovascularization) are induced after injection of
      soluble O. volvulus antigens into the corneal stroma. Experimental approaches
      have demonstrated an essential role for sensitized T helper cells and shown that
      cytokines can regulate the severity of keratitis by controlling recruitment of
      inflammatory cells into the cornea. Chemokines are also important in inflammatory
      cell recruitment to the cornea, and their role in onchocerciasis is being
      examined. Further understanding of the molecular basis of the development of
      onchocercal keratitis may lead to novel approaches to immunologically based
      intervention.

PMID- 10398674
TI  - Cellular biology of prion diseases.
AB  - Prion diseases are fatal neurodegenerative disorders of humans and animals that
      are important because of their impact on public health and because they exemplify
      a novel mechanism of infectivity and biological information transfer. These
      diseases are caused by conformational conversion of a normal host glycoprotein
      (PrPC) into an infectious isoform (PrPSc) that is devoid of nucleic acid. This
      review focuses on the current understanding of prion diseases at the cell
      biological level. The characteristics of the diseases are introduced, and a brief
      history and description of the prion hypothesis are given. Information is then
      presented about the structure, expression, biosynthesis, and possible function of
      PrPC, as well as its posttranslational processing, cellular localization, and
      trafficking. The latest findings concerning PrPSc are then discussed, including
      cell culture systems used to generate this pathogenic isoform, the subcellular
      distribution of the protein, its membrane attachment, proteolytic processing, and
      its kinetics and sites of synthesis. Information is also provided on molecular
      models of the PrPC-->PrPSc conversion reaction and the possible role of cellular
      chaperones. The review concludes with suggestions of several important avenues
      for future investigation.

PMID- 10398677
TI  - Switching on the notochord.

PMID- 10398678
TI  - NeuroD is required for differentiation of the granule cells in the cerebellum and
      hippocampus.
AB  - NeuroD, a bHLH transcription factor, is implicated in differentiation of neurons
      and pancreatic beta cells. NeuroD-null mice die shortly after birth due to severe
      neonatal diabetes. To examine if there is postnatal neuronal phenotype in these
      mice, we rescued them from neonatal lethality by introducing a transgene encoding
      the mouse neuroD gene under the insulin promoter. These mice survive to adulthood
      but display severe neurological phenotype due to neuronal deficit in the granule
      layers of the cerebellum and hippocampus. We show here that NeuroD is required
      for these postnatally generated microneurons to undergo proper differentiation,
      the absence of which results in cell death.

PMID- 10398679
TI  - Heat-shock-induced activation of stress MAP kinase is regulated by threonine- and
      tyrosine-specific phosphatases.
AB  - In eukaryotic species from yeast to human, stress-activated protein kinases
      (SAPKs), members of a MAP kinase (MAPK) subfamily, regulate the transcriptional
      response to various environmental stress. It is poorly understood how diverse
      forms of stress are sensed and transmitted to SAPKs. Here, we report the heat
      shock regulation of the fission yeast Spc1 SAPK, a homolog of human p38 and
      budding yeast Hog1p. Although osmostress and oxidative stress induce strong
      activation of the Wis1 MAPK kinase (MEK), which activates Spc1 through Thr
      171/Tyr-173 phosphorylation, activation of Wis1 upon heat shock is relatively
      weak and transient. However, in heat-shocked cells, Pyp1, the major tyrosine
      phosphatase that dephosphorylates and inactivates Spc1, is inhibited for its
      interaction with Spc1, which leads to strong activation of Spc1. Subsequently,
      Spc1 activity is rapidly attenuated by Thr-171 dephosphorylation, whereas Tyr-173
      remains phosphorylated. Thr-171 dephosphorylation is compromised in a strain
      lacking functional type 2C serine/threonine phosphatases (PP2C), Ptc1 and Ptc3.
      Moreover, Ptc1 and Ptc3 can dephosphorylate Thr-171 of Spc1 both in vivo and in
      vitro. These observations strongly suggest that PP2C enzymes play an important
      role in the attenuation of Spc1 activity in heat-shocked cells. Thus, transient
      activation of Spc1 upon heat shock is ensured by differential regulation of
      threonine and tyrosine phosphorylation.

PMID- 10398676
TI  - Developments in fungal taxonomy.
AB  - Fungal infections, especially those caused by opportunistic species, have become
      substantially more common in recent decades. Numerous species cause human
      infections, and several new human pathogens are discovered yearly. This situation
      has created an increasing interest in fungal taxonomy and has led to the
      development of new methods and approaches to fungal biosystematics which have
      promoted important practical advances in identification procedures. However, the
      significance of some data provided by the new approaches is still unclear, and
      results drawn from such studies may even increase nomenclatural confusion.
      Analyses of rRNA and rDNA sequences constitute an important complement of the
      morphological criteria needed to allow clinical fungi to be more easily
      identified and placed on a single phylogenetic tree. Most of the pathogenic fungi
      so far described belong to the kingdom Fungi; two belong to the kingdom
      Chromista. Within the Fungi, they are distributed in three phyla and in 15 orders
      (Pneumocystidales, Saccharomycetales, Dothideales, Sordariales, Onygenales,
      Eurotiales, Hypocreales, Ophiostomatales, Microascales, Tremellales, Poriales,
      Stereales, Agaricales, Schizophyllales, and Ustilaginales).

PMID- 10398680
TI  - Proper metaphase spindle length is determined by centromere proteins Mis12 and
      Mis6 required for faithful chromosome segregation.
AB  - High-fidelity chromosome transmission is fundamental in controlling the quality
      of the cell division cycle. The spindle pole-to-pole distance remains constant
      from metaphase to anaphase A. We show that fission yeast sister centromere
      connecting proteins, Mis6 and Mis12, are required for correct spindle
      morphogenesis, determining metaphase spindle length. Thirty-five to sixty percent
      extension of metaphase spindle length takes place in mis6 and mis12 mutants. This
      may be due to incorrect spindle morphogenesis containing impaired sister
      centromeres or force unbalance between pulling by the linked sister kinetochores
      and kinetochore-independent pushing. The mutant spindle fully extends in
      anaphase, although it is accompanied by drastic missegregation by aberrant sister
      centromere separation. Hence, metaphase spindle length may be crucial for
      segregation fidelity. Suppressors of mis12 partly restore normal metaphase
      spindle length. In mis4 that is defective in sister chromatid cohesion, metaphase
      spindle length is also long, but anaphase spindle extension is blocked, probably
      due to the activated spindle checkpoint. Extensive missegregation is caused in
      mis12 only when Mis12 is inactivated from the previous M through to the following
      M, an effective way to avoid missegregation in the cell cycle. Mis12 has
      conserved homologs in budding yeast and filamentous fungi.

PMID- 10398681
TI  - Identification of an SCF ubiquitin-ligase complex required for auxin response in
      Arabidopsis thaliana.
AB  - The plant hormone auxin regulates diverse aspects of plant growth and
      development. We report that in Arabidopsis, auxin response is dependent on a
      ubiquitin-ligase (E3) complex called SCFTIR1. The complex consists of proteins
      related to yeast Skp1p and Cdc53p called ASK and AtCUL1, respectively, as well as
      the F-box protein TIR1. Mutations in either ASK1 or TIR1 result in decreased
      auxin response. Further, overexpression of TIR1 promotes auxin response
      suggesting that SCFTIR1 is limiting for the response. These results provide new
      support for a model in which auxin action depends on the regulated proteolysis of
      repressor proteins.

PMID- 10398682
TI  - Crystal structure of the conserved core of the herpes simplex virus
      transcriptional regulatory protein VP16.
AB  - On infection, the herpes simplex virus (HSV) virion protein VP16 (Vmw65;
      alphaTIF) forms a transcriptional regulatory complex-the VP16-induced complex
      with two cellular proteins, HCF and Oct-1, on VP16-responsive cis-regulatory
      elements in HSV immediate-early promoters called TAATGARAT. Comparison of
      different HSV VP16 sequences reveals a conserved core region that is sufficient
      for VP16-induced complex formation. The crystal structure of the VP16 core has
      been determined at 2.1 A resolution. The results reveal a novel, seat-like
      protein structure. Together with the activity of mutant VP16 proteins, the
      structure of free VP16 suggests that it contains (1) a disordered carboxy
      terminal region that associates with HCF, Oct-1, and DNA in the VP16-induced
      complex, and (2) a structured region involved in virion assembly and possessing a
      novel DNA-binding surface that differentiates among TAATGARAT VP16-response
      elements.

PMID- 10398683
TI  - The control of trunk Hox specificity and activity by Extradenticle.
AB  - We characterize a 37-bp element (fkh[250]) derived from the fork head (fkh) gene,
      a natural target of the Hox gene Sex combs reduced (Scr). In vitro, Scr
      cooperatively binds to this DNA with the Hox cofactor Extradenticle (Exd), and
      the activation of this enhancer in vivo requires Scr and exd. Other Hox/Exd
      heterodimers do not activate this element in vivo and do not bind this element
      with high affinity in vitro. The amino-terminal arm of the Scr homeodomain is
      crucial for the specific activation of this element in vivo. By mutating two base
      pairs within this element, we can convert the Scr/Exd-binding site to a Hox/Exd
      consensus site that binds several different Hox/Exd heterodimers. This element,
      fkh[250(con)], is activated by Scr, Antennapedia (Antp), and Ultrabithorax (Ubx)
      but repressed by abdominal-A (abd-A). We also show that Scr and Exd are only able
      to activate the fkh[250] element during the early stages of embryogenesis
      because, by stage 11, Scr negatively regulates the gene homothorax (hth), which
      is required for the nuclear localization of Exd. These results suggest that Exd
      is a specificity cofactor for the trunk Hox genes, and that the control of Exd
      subcellular localization is a mechanism to regulate Hox activity during
      development.

PMID- 10398684
TI  - Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in
      developing dorsal root ganglia.
AB  - Different classes of sensory neurons in dorsal root ganglia (DRG) are generated
      in two waves: large-diameter trkC+ and trkB+ neurons are born first, followed by
      small-diameter trkA+ neurons. All such neurons require either neurogenin (ngn) 1
      or 2, two neuronal determination genes encoding basic helix-loop-helix (bHLH)
      transcription factors. ngn2 is required primarily if not exclusively for the
      generation of trkC+ and trkB+ neurons, whereas the generation of most or all
      trkA+ neurons requires ngn1. Comparison with previous lineage tracing data in the
      chick suggests that this dichotomy reflects a requirement for the two ngns in
      distinct sensory precursor populations. The neurogenesis defect in ngn2(-/-)
      embryos is transient and later compensated by ngn1-dependent precursors,
      suggesting that feedback or competitive interactions between these precursors may
      control the proportion of different neuronal subtypes they normally produce.
      These data reveal remarkable parallels in the roles of bHLH factors during
      neurogenesis in the DRG, and myogenesis in the neighboring myotome.

PMID- 10398685
TI  - Metal ion catalysis during group II intron self-splicing: parallels with the
      spliceosome.
AB  - The identical reaction pathway executed by the spliceosome and self-splicing
      group II intron ribozymes has prompted the idea that both may be derived from a
      common molecular ancestor. The minimal sequence and structural similarities
      between group II introns and the spliceosomal small nuclear RNAs, however, have
      left this proposal in question. Mechanistic comparisons between group II self
      splicing introns and the spliceosome are therefore important in determining
      whether these two splicing machineries may be related. Here we show that 3'
      sulfur substitution at the 5' splice site of a group II intron causes a metal
      specificity switch during the first step of splicing. In contrast, 3'-sulfur
      substitution has no significant effect on the metal specificity of the second
      step of cis-splicing. Isolation of the second step uncovers a metal specificity
      switch that is masked during the cis-splicing reaction. These results demonstrate
      that group II intron ribozymes are metalloenzymes that use a catalytic metal ion
      for leaving group stabilization during both steps of self-splicing. Furthermore,
      because 3'-sulfur substitution of a spliceosomal intron has precisely the same
      effects as were observed during cis-splicing of the group II intron, these
      results provide striking parallels between the catalytic mechanisms employed by
      these two systems.

PMID- 10398686
TI  - p27(Kip1) induction and inhibition of proliferation by the intracellular Ah
      receptor in developing thymus and hepatoma cells.
AB  - The Ah receptor (AhR), a bHLH/PAS transcription factor, mediates dioxin toxicity
      in the immune system, skin, testis and liver. Toxic phenomena are associated with
      altered cell proliferation or differentiation, but signaling pathways of AhR in
      cell cycle regulation are poorly understood. Here we show that AhR induces the
      p27(Kip1) cyclin/cdk inhibitor by altering Kip1 transcription in a direct mode
      without the need for ongoing protein synthesis or cell proliferation. This is the
      first example of Kip1 being a direct transcriptional target of a toxic agent that
      affects cell proliferation. Kip1 causes dioxin-induced suppression of 5L hepatoma
      cell proliferation because Kip1 antisense-expressing cells are resistant to
      dioxins. Kip1 is also induced by dioxins in cultures of fetal thymus glands
      concomitant with inhibition of proliferation and severe reduction of thymocyte
      recovery. Kip1 expression is likely to mediate these effects as thymic glands of
      Kip1-deficient mice (Kip1(Delta51)) are largely, though not completely,
      resistant.

PMID- 10398688
TI  - Elimination of the slow gating of ClC-0 chloride channel by a point mutation.
AB  - The inactivation of the ClC-0 chloride channel is very temperature sensitive and
      is greatly facilitated by the binding of a zinc ion (Zn2+) from the extracellular
      side, leading to a Zn2+-induced current inhibition. To further explore the
      relation of Zn2+ inhibition and the ClC-0 inactivation, we mutated all 12
      cysteine amino acids in the channel and assayed the effect of Zn2+ on these
      mutants. With this approach, we found that C212 appears to be important for the
      sensitivity of the Zn2+ inhibition. Upon mutating C212 to serine or alanine, the
      inactivation of the channel in macroscopic current recordings disappears and the
      channel does not show detectable inactivation events at the single-channel level.
      At the same time, the channel's sensitivity to Zn2+ inhibition is also greatly
      reduced. The other two cysteine mutants, C213G and C480S, as well as a previously
      identified mutant, S123T, also affect the inactivation of the channel to some
      degree, but the temperature-dependent inactivation process is still present,
      likewise the high sensitivity of the Zn2+ inhibition. These results further
      support the assertion that the inhibition of Zn2+ on ClC-0 is indeed due to an
      effect on the inactivation of the channel. The absence of inactivation in C212S
      mutants may provide a better defined system to study the fast gating and the ion
      permeation of ClC-0.

PMID- 10398687
TI  - The Iroquois homeodomain proteins are required to specify body wall identity in
      Drosophila.
AB  - The Iroquois complex (Iro-C) homeodomain proteins allow cells at the proximal
      part of the Drosophila imaginal wing disc to form mesothoracic body wall (notum).
      Cells lacking these proteins form wing hinge structures instead (tegula and
      axillary sclerites). Moreover, the mutant cells impose on neighboring wild-type
      cells more distal developmental fates, like lateral notum or wing hinge. These
      findings support a tergal phylogenetic origin for the most proximal part of the
      wing and provide evidence for a novel pattern organizing center at the border
      between the apposed notum (Iro-C-expressing) and hinge (Iro-C-nonexpressing)
      cells. This border is not a cell lineage restriction boundary.

PMID- 10398689
TI  - On the molecular basis of ion permeation in the epithelial Na+ channel.
AB  - The epithelial Na+ channel (ENaC) is highly selective for Na+ and Li+ over K+ and
      is blocked by the diuretic amiloride. ENaC is a heterotetramer made of two alpha,
      one beta, and one gamma homologous subunits, each subunit comprising two
      transmembrane segments. Amino acid residues involved in binding of the pore
      blocker amiloride are located in the pre-M2 segment of beta and gamma subunits,
      which precedes the second putative transmembrane alpha helix (M2). A residue in
      the alpha subunit (alphaS589) at the NH2 terminus of M2 is critical for the
      molecular sieving properties of ENaC. ENaC is more permeable to Li+ than Na+
      ions. The concentration of half-maximal unitary conductance is 38 mM for Na+ and
      118 mM for Li+, a kinetic property that can account for the differences in Li+
      and Na+ permeability. We show here that mutation of amino acid residues at
      homologous positions in the pre-M2 segment of alpha, beta, and gamma subunits
      (alphaG587, betaG529, gammaS541) decreases the Li+/Na+ selectivity by changing
      the apparent channel affinity for Li+ and Na+. Fitting single-channel data of the
      Li+ permeation to a discrete-state model including three barriers and two binding
      sites revealed that these mutations increased the energy needed for the
      translocation of Li+ from an outer ion binding site through the selectivity
      filter. Mutation of betaG529 to Ser, Cys, or Asp made ENaC partially permeable to
      K+ and larger ions, similar to the previously reported alphaS589 mutations. We
      conclude that the residues alphaG587 to alphaS589 and homologous residues in the
      beta and gamma subunits form the selectivity filter, which tightly accommodates
      Na+ and Li+ ions and excludes larger ions like K+.

PMID- 10398690
TI  - Calcium release flux underlying Ca2+ sparks of frog skeletal muscle.
AB  - An algorithm for the calculation of Ca2+ release flux underlying Ca2+ sparks
      (Blatter, L.A., J. Huser, and E. Rios. 1997. Proc. Natl. Acad. Sci. USA. 94:4176
      4181) was modified and applied to sparks obtained by confocal microscopy in
      single frog skeletal muscle fibers, which were voltage clamped in a two-Vaseline
      gap chamber or permeabilized and immersed in fluo-3-containing internal solution.
      The performance of the algorithm was characterized on sparks obtained by
      simulation of fluorescence due to release of Ca2+ from a spherical source, in a
      homogeneous three-dimensional space that contained components representing
      cytoplasmic molecules and Ca2+ removal processes. Total release current, as well
      as source diameter and noise level, was varied in the simulations. Derived
      release flux or current, calculated by volume integration of the derived flux
      density, estimated quite closely the current used in the simulation, while full
      width at half magnitude of the derived release flux was a good monitor of source
      size only at diameters >0. 7 micrometers. On an average of 157 sparks of
      amplitude >2 U resting fluorescence, located automatically in a representative
      voltage clamp experiment, the algorithm reported a release current of 16.9 pA,
      coming from a source of 0.5 micrometer, with an open time of 6.3 ms. Fewer sparks
      were obtained in permeabilized fibers, so that the algorithm had to be applied to
      individual sparks or averages of few events, which degraded its performance in
      comparable tests. The average current reported for 19 large sparks obtained in
      permeabilized fibers was 14.4 pA. A minimum estimate, derived from the rate of
      change of dye-bound Ca2+ concentration, was 8 pA. Such a current would require
      simultaneous opening of between 8 and 60 release channels with unitary Ca2+
      currents of the level recorded in bilayer experiments. Real sparks differ from
      simulated ones mainly in having greater width. Correspondingly, the algorithm
      reported greater spatial extent of the source for real sparks. This may again
      indicate a multichannel origin of sparks, or could reflect limitations in spatial
      resolution.

PMID- 10398691
TI  - CFTR channel gating: incremental progress in irreversible steps.

PMID- 10398692
TI  - Dual effects of ADP and adenylylimidodiphosphate on CFTR channel kinetics show
      binding to two different nucleotide binding sites.
AB  - The CFTR chloride channel is regulated by phosphorylation by protein kinases,
      especially PKA, and by nucleotides interacting with the two nucleotide binding
      domains, NBD-A and NBD-B. Giant excised inside-out membrane patches from Xenopus
      oocytes expressing human epithelial cystic fibrosis transmembrane conductance
      regulator (CFTR) were tested for their chloride conductance in response to the
      application of PKA and nucleotides. Rapid changes in the concentration of ATP,
      its nonhydrolyzable analogue adenylylimidodiphosphate (AMP-PNP), its photolabile
      derivative ATP-P3-[1-(2-nitrophenyl)ethyl]ester, or ADP led to changes in
      chloride conductance with characteristic time constants, which reflected
      interaction of CFTR with these nucleotides. The conductance changes of strongly
      phosphorylated channels were slower than those of partially phosphorylated CFTR.
      AMP-PNP decelerated relaxations of conductance increase and decay, whereas ATP-P3
      [1-(2-nitrophenyl)ethyl]ester only decelerated the conductance increase upon ATP
      addition. ADP decelerated the conductance increase upon ATP addition and
      accelerated the conductance decay upon ATP withdrawal. The results present the
      first direct evidence that AMP-PNP binds to two sites on the CFTR. The effects of
      ADP also suggest two different binding sites because of the two different modes
      of inhibition observed: it competes with ATP for binding (to NBD-A) on the closed
      channel, but it also binds to channels opened by ATP, which might either reflect
      binding to NBD-A (i.e., product inhibition in the hydrolysis cycle) or allosteric
      binding to NBD-B, which accelerates the hydrolysis cycle at NBD-A.

PMID- 10398693
TI  - Isolation of a single carboxyl-carboxylate proton binding site in the pore of a
      cyclic nucleotide-gated channel.
AB  - The pore of the catfish olfactory cyclic nucleotide-gated (CNG) channel contains
      four conserved glutamate residues, one from each subunit, that form a high
      affinity binding site for extracellular divalent cations. Previous work showed
      that these residues form two independent and equivalent high-pKa (approximately
      7.6) proton binding sites, giving rise to three pH-dependent conductance states,
      and it was suggested that the sites were formed by pairing of the glutamates into
      two independent carboxyl-carboxylates. To test further this physical picture,
      wild-type CNG subunits were coexpressed in Xenopus oocytes with subunits lacking
      the critical glutamate residue, and single channel currents through hybrid CNG
      channels containing one to three wild-type (WT) subunits were recorded. One of
      these hybrid channels had two pH-dependent conductance states whose occupancy was
      controlled by a single high-pKa protonation site. Expression of dimers of
      concatenated CNG channel subunits confirmed that this hybrid contained two WT and
      two mutant subunits, supporting the idea that a single protonation site is made
      from two glutamates (dimer expression also implied the subunit makeup of the
      other hybrid channels). Thus, the proton binding sites in the WT channel occur as
      a result of the pairing of two glutamate residues. This conclusion places these
      residues in close proximity to one another in the pore and implies that at any
      instant in time detailed fourfold symmetry is disrupted.

PMID- 10398694
TI  - Responses of Xenopus laevis water nose to water-soluble and volatile odorants.
AB  - Using the whole-cell mode of the patch-clamp technique, we recorded action
      potentials, voltage-activated cationic currents, and inward currents in response
      to water-soluble and volatile odorants from receptor neurons in the lateral
      diverticulum (water nose) of the olfactory sensory epithelium of Xenopus laevis.
      The resting membrane potential was -46.5 +/- 1.2 mV (mean +/- SEM, n = 68), and a
      current injection of 1-3 pA induced overshooting action potentials. Under voltage
      clamp conditions, a voltage-dependent Na+ inward current, a sustained outward K+
      current, and a Ca2+-activated K+ current were identified. Application of an amino
      acid cocktail induced inward currents in 32 of 238 olfactory neurons in the
      lateral diverticulum under voltage-clamp conditions. Application of volatile
      odorant cocktails also induced current responses in 23 of 238 olfactory neurons.
      These results suggest that the olfactory neurons respond to both water-soluble
      and volatile odorants. The application of alanine or arginine induced inward
      currents in a dose-dependent manner. More than 50% of the single olfactory
      neurons responded to multiple types of amino acids, including acidic, neutral,
      and basic amino acids applied at 100 microM or 1 mM. These results suggest that
      olfactory neurons in the lateral diverticulum have receptors for amino acids and
      volatile odorants.

PMID- 10398696
TI  - The block of Shaker K+ channels by kappa-conotoxin PVIIA is state dependent.
AB  - kappa-conotoxin PVIIA is the first conotoxin known to interact with voltage-gated
      potassium channels by inhibiting Shaker-mediated currents. We studied the
      mechanism of inhibition and concluded that PVIIA blocks the ion pore with a 1:1
      stoichiometry and that binding to open or closed channels is very different. Open
      channel properties are revealed by relaxations of partial block during step
      depolarizations, whereas double-pulse protocols characterize the slower
      reequilibration of closed-channel binding. In 2.5 mM-[K+]o, the IC50 rises from a
      tonic value of approximately 50 to approximately 200 nM during openings at 0 mV,
      and it increases e-fold for about every 40-mV increase in voltage. The change
      involves mainly the voltage dependence and a 20-fold increase at 0 mV of the rate
      of PVIIA dissociation, but also a fivefold increase of the association rate.
      PVIIA binding to Shaker Delta6-46 channels lacking N-type inactivation or to wild
      phenotypes appears similar, but inactivation partially protects the latter from
      open-channel unblock. Raising [K+]o to 115 mM has little effect on open-channel
      binding, but increases almost 10-fold the tonic IC50 of PVIIA due to a decrease
      by the same factor of the toxin rate of association to closed channels. In
      analogy with charybdotoxin block, we attribute the acceleration of PVIIA
      dissociation from open channels to the voltage-dependent occupancy by K+ ions of
      a site at the outer end of the conducting pore. We also argue that the occupancy
      of this site by external cations antagonizes on binding to closed channels,
      whereas the apparent competition disappears in open channels if the competing
      cation can move along the pore. It is concluded that PVIIA can also be a valuable
      tool for probing the state of ion permeation inside the pore.

PMID- 10398695
TI  - Gating kinetics of single large-conductance Ca2+-activated K+ channels in high
      Ca2+ suggest a two-tiered allosteric gating mechanism.
AB  - The Ca2+-dependent gating mechanism of large-conductance calcium-activated K+
      (BK) channels from cultured rat skeletal muscle was examined from low (4 microM)
      to high (1,024 microM) intracellular concentrations of calcium (Ca2+i) using
      single-channel recording. Open probability (Po) increased with increasing Ca2+i
      (K0. 5 11.2 +/- 0.3 microM at +30 mV, Hill coefficient of 3.5 +/- 0.3), reaching
      a maximum of approximately 0.97 for Ca2+i approximately 100 microM. Increasing
      Ca2+i further to 1,024 microM had little additional effect on either Po or the
      single-channel kinetics. The channels gated among at least three to four open and
      four to five closed states at high levels of Ca2+i (>100 microM), compared with
      three to four open and five to seven closed states at lower Ca2+i. The ability of
      kinetic schemes to account for the single-channel kinetics was examined with
      simultaneous maximum likelihood fitting of two-dimensional (2-D) dwell-time
      distributions obtained from low to high Ca2+i. Kinetic schemes drawn from the 10
      state Monod-Wyman-Changeux model could not describe the dwell-time distributions
      from low to high Ca2+i. Kinetic schemes drawn from Eigen's general model for a
      ligand-activated tetrameric protein could approximate the dwell-time
      distributions but not the dependency (correlations) between adjacent intervals at
      high Ca2+i. However, models drawn from a general 50 state two-tiered scheme, in
      which there were 25 closed states on the upper tier and 25 open states on the
      lower tier, could approximate both the dwell-time distributions and the
      dependency from low to high Ca2+i. In the two-tiered model, the BK channel can
      open directly from each closed state, and a minimum of five open and five closed
      states are available for gating at any given Ca2+i. A model that assumed that the
      apparent Ca2+-binding steps can reach a maximum rate at high Ca2+i could also
      approximate the gating from low to high Ca2+i. The considered models can serve as
      working hypotheses for the gating of BK channels.

PMID- 10398698
TI  - Sulfate transport and assimilation in plants 

PMID- 10398699
TI  - The role of phospholipase D in signaling cascades 

PMID- 10398697
TI  - A marine snail neurotoxin shares with scorpion toxins a convergent mechanism of
      blockade on the pore of voltage-gated K channels.
AB  - kappa-Conotoxin-PVIIA (kappa-PVIIA) belongs to a family of peptides derived from
      a hunting marine snail that targets to a wide variety of ion channels and
      receptors. kappa-PVIIA is a small, structurally constrained, 27-residue peptide
      that inhibits voltage-gated K channels. Three disulfide bonds shape a
      characteristic four-loop folding. The spatial localization of positively charged
      residues in kappa-PVIIA exhibits strong structural mimicry to that of
      charybdotoxin, a scorpion toxin that occludes the pore of K channels. We studied
      the mechanism by which this peptide inhibits Shaker K channels expressed in
      Xenopus oocytes with the N-type inactivation removed. Chronically applied to
      whole oocytes or outside-out patches, kappa-PVIIA inhibition appears as a voltage
      dependent relaxation in response to the depolarizing pulse used to activate the
      channels. At any applied voltage, the relaxation rate depended linearly on the
      toxin concentration, indicating a bimolecular stoichiometry. Time constants and
      voltage dependence of the current relaxation produced by chronic applications
      agreed with that of rapid applications to open channels. Effective valence of the
      voltage dependence, zdelta, is approximately 0.55 and resides primarily in the
      rate of dissociation from the channel, while the association rate is voltage
      independent with a magnitude of 10(7)-10(8) M-1 s-1, consistent with diffusion
      limited binding. Compatible with a purely competitive interaction for a site in
      the external vestibule, tetraethylammonium, a well-known K-pore blocker, reduced
      kappa-PVIIA's association rate only. Removal of internal K+ reduced, but did not
      eliminate, the effective valence of the toxin dissociation rate to a value <0.3.
      This trans-pore effect suggests that: (a) as in the alpha-KTx, a positively
      charged side chain, possibly a Lys, interacts electrostatically with ions
      residing inside the Shaker pore, and (b) a part of the toxin occupies an
      externally accessible K+ binding site, decreasing the degree of pore occupancy by
      permeant ions. We conclude that, although evolutionarily distant to scorpion
      toxins, kappa-PVIIA shares with them a remarkably similar mechanism of inhibition
      of K channels.

PMID- 10398700
TI  - Decreased cell wall digestibility in canola transformed with chimeric tyrosine
      decarboxylase genes from opium poppy 
AB  - Tyrosine decarboxylase (TYDC) is a common plant enzyme involved in the
      biosynthesis of numerous secondary metabolites, including hydroxycinnamic acid
      amides. Although a definite function has not yet been determined, amides have
      been proposed to form a physical barrier against pathogens because they are
      usually found as integral cell wall components. Canola (Brassica napus) was
      independently transformed with chimeric genes (35S::TYDC1 and 35S::TYDC2) under
      the transcriptional control of the cauliflower mosaic virus 35S promoter, and
      encoding two TYDC isoforms from opium poppy (Papaver somniferum). All T0 plants
      displayed a suppressed level of wild-type TYDC activity, and transgene mRNAs were
      not detected. Silencing of 35S::TYDC1 was overcome in the T1 progeny of self
      pollinated T0 plants, since high levels of TYDC1 mRNAs were detected, and TYDC
      activity increased up to 4-fold compared with wild-type levels. However, TYDC1
      mRNA levels decreased in T2 plants and were not detected in the T3 progeny. TYDC
      activity also gradually declined in T2 and T3 plants to nearly wild-type levels.
      In contrast, silencing of 35S::TYDC2 was maintained through four consecutive
      generations. T1 plants with a 3- to 4-fold increase in wild-type TYDC activity
      showed a 30% decrease in cellular tyrosine pools and a 2-fold increase in cell
      wall-bound tyramine compared with wild-type plants. An increase in cell wall
      bound aromatic compounds was also detected in these T1 plants by ultraviolet
      autofluorescence microscopy. The relative digestibility of cell walls measured by
      protoplast release efficiency was inversely related to the level of TYDC
      activity.

PMID- 10398701
TI  - A maize glycine-rich protein is synthesized in the lateral root cap and
      accumulates in the mucilage.
AB  - The root cap functions in the perception of gravity, the protection of the root
      apical meristem, and facilitation of the passage of roots through the soil, but
      the genes involved in these functions are poorly understood. Here we report the
      isolation of a root-specific gene from the cap of maize (Zea mays L.) primary
      root by cDNA subtraction and differential screening. The gene zmGRP4 (Z. mays
      glycine rich protein 4) encodes a member of the glycine-rich proteins with a
      putative signal peptide at the amino terminus. The deduced molecular mass of
      mature zmGRP4 is 14.4 kD. In situ-hybridization analysis has shown zmGRP4 to be
      strongly expressed in the lateral root cap and weakly expressed in the root
      epidermis. A polyclonal antibody raised against recombinant zmGRP4 detected a
      protein of 36 kD in the insoluble protein fraction extracted from the root tip
      and the root proper, indicating posttranslational modification(s) of zmGRP4.
      Immunohistochemical analysis showed the accumulation of zmGRP4 in the mucilage
      that covers the root tip. These results indicate that lateral root-cap cells
      secrete modified zmGRP4 into the mucilage to which the protein may contribute to
      its characteristic physical properties.

PMID- 10398702
TI  - EAF1 regulates vegetative-phase change and flowering time in Arabidopsis.
AB  - We have identified a new locus that regulates vegetative phase change and
      flowering time in Arabidopsis. An early-flowering mutant, eaf1 (early flowering
      1) was isolated and characterized. eaf1 plants flowered earlier than the wild
      type under either short-day or long-day conditions, and showed a reduction in the
      juvenile and adult vegetative phases. When grown under short-day conditions, eaf1
      plants were slightly pale green and had elongated petioles, phenotypes that are
      observed in mutants altered in either phytochrome or the gibberellin (GA)
      response. eaf1 seed showed increased resistance to the GA biosynthesis inhibitor
      paclobutrazol, suggesting that GA metabolism and/or response had been altered.
      Comparison of eaf1 to other early-flowering mutants revealed that eaf1 shifts to
      the adult phase early and flowers early, similarly to the phyB (phytochrome B)
      and spy (spindly) mutants. eaf1 maps to chromosome 2, but defines a locus
      distinct from phyB, clf (curly leaf), and elf3 (early-flowering 3). These results
      demonstrate that eaf1 defines a new locus involved in an autonomous pathway and
      may affect GA regulation of flowering.

PMID- 10398704
TI  - Reduced activity of geranylgeranyl reductase leads to loss of chlorophyll and
      tocopherol and to partially geranylgeranylated chlorophyll in transgenic tobacco
      plants expressing antisense RNA for geranylgeranyl reductase 
AB  - The enzyme geranylgeranyl reductase (CHL P) catalyzes the reduction of
      geranylgeranyl diphosphate to phytyl diphosphate. We identified a tobacco
      (Nicotiana tabacum) cDNA sequence encoding a 52-kD precursor protein homologous
      to the Arabidopsis and bacterial CHL P. The effects of deficient CHL P activity
      on chlorophyll (Chl) and tocopherol contents were studied in transgenic plants
      expressing antisense CHL P RNA. Transformants with gradually reduced Chl P
      expression showed a delayed growth rate and a pale or variegated phenotype.
      Transformants grown in high (500 &mgr;mol m-2 s-1; HL) and low (70 &mgr;mol
      photon m-2 s-1; LL) light displayed a similar degree of reduced tocopherol
      content during leaf development, although growth of wild-type plants in HL
      conditions led to up to a 2-fold increase in tocopherol content. The total Chl
      content was more rapidly reduced during HL than LL conditions. Up to 58% of the
      Chl content was esterified with geranylgeraniol instead of phytol under LL
      conditions. Our results indicate that CHL P provides phytol for both tocopherol
      and Chl synthesis. The transformants are a valuable model with which to
      investigate the adaptation of plants with modified tocopherol levels against
      deleterious environmental conditions.

PMID- 10398703
TI  - Chlamydomonas reinhardtii mutants abnormal in their responses to phosphorus
      deprivation.
AB  - P-starved plants scavenge inorganic phosphate (Pi) by developing elevated rates
      of Pi uptake, synthesizing extracellular phosphatases, and secreting organic
      acids. To elucidate mechanisms controlling these acclimation responses in
      photosynthetic organisms, we characterized the responses of the green alga
      Chlamydomonas reinhardtii to P starvation and developed screens for isolating
      mutants (designated psr [phosphorus-stress response]) abnormal in their responses
      to environmental levels of Pi. The psr1-1 mutant was identified in a selection
      for cells that survived exposure to high concentrations of radioactive Pi. psr1-2
      and psr2 were isolated as strains with aberrant levels of extracellular
      phosphatase activity during P-deficient or nutrient-replete growth. The psr1-1
      and psr1-2 mutants were phenotypically similar, and the lesions in these strains
      were recessive and allelic. They exhibited no increase in extracellular
      phosphatase activity or Pi uptake upon starvation. Furthermore, when placed in
      medium devoid of P, the psr1 strains lost photosynthetic O2 evolution and stopped
      growing more rapidly than wild-type cells; they may not be as efficient as wild
      type cells at scavenging/accessing P stores. In contrast, psr2 showed elevated
      extracellular phosphatase activity during growth in nutrient-replete medium, and
      the mutation was dominant. The mutant phenotypes and the roles of Psr1 and Psr2
      in P-limitation responses are discussed.

PMID- 10398705
TI  - Linking development and determinacy with organic acid efflux from proteoid roots
      of white lupin grown with low phosphorus and ambient or elevated atmospheric CO2
      concentration 
AB  - White lupin (Lupinus albus L.) was grown in hydroponic culture with 1 &mgr;M
      phosphorus to enable the development of proteoid roots to be observed in
      conjunction with organic acid exudation. Discrete regions of closely spaced,
      determinate secondary laterals (proteoid rootlets) emerged in near synchrony on
      the same plant. One day after reaching their final length (4 mm), citrate
      exudation occurred over a 3-d pulse. The rate of exudation varied diurnally, with
      maximal rates during the photoperiod. At the onset of citrate efflux, rootlets
      had exhausted their apical meristems and had differentiated root hairs and
      vascular tissues along their lengths. Neither in vitro phosphoenolpyruvate
      carboxylase nor citrate synthase activity was correlated with the rate of citrate
      exudation. We suggest that an unidentified transport process, presumably at the
      plasma membrane, regulates citrate efflux. Growth with elevated (700 &mgr;L L-1)
      atmospheric [CO2] promoted earlier onset of rootlet determinacy by 1 d, resulting
      in shorter rootlets and citrate export beginning 1 d earlier as a 2-d diurnal
      pulse. Citrate was the dominant organic acid exported, and neither the rate of
      exudation per unit length of root nor the composition of exudate was altered by
      atmospheric [CO2].

PMID- 10398706
TI  - Simultaneous expression of NAD-dependent isocitrate dehydrogenase and other krebs
      cycle genes after nitrate resupply to short-term nitrogen-starved tobacco 
AB  - Mitochondrial NAD-dependent (IDH) and cytosolic NADP-dependent isocitrate
      dehydrogenases have been considered as candidates for the production of 2
      oxoglutarate required by the glutamine synthetase/glutamate synthase cycle. The
      increase in IDH transcripts in leaf and root tissues, induced by nitrate or NH4+
      resupply to short-term N-starved tobacco (Nicotiana tabacum) plants, suggested
      that this enzyme could play such a role. The leaf and root steady-state mRNA
      levels of citrate synthase, acotinase, IDH, and glutamine synthetase were found
      to respond similarly to nitrate, whereas those for cytosolic NADP-dependent
      isocitrate dehydrogenase and fumarase responded differently. This apparent
      coordination occurred only at the mRNA level, since activity and protein levels
      of certain corresponding enzymes were not altered. Roots and leaves were not
      affected to the same extent either by N starvation or nitrate addition, the roots
      showing smaller changes in N metabolite levels. After nitrate resupply, these
      organs showed different response kinetics with respect to mRNA and N metabolite
      levels, suggesting that under such conditions nitrate assimilation was
      preferentially carried out in the roots. The differential effects appeared to
      reflect the C/N status after N starvation, the response kinetics being associated
      with the nitrate assimilatory capacity of each organ, signaled either by nitrate
      status or by metabolite(s) associated with its metabolism.

PMID- 10398707
TI  - Xanthophyll cycle pigment localization and dynamics during exposure to low
      temperatures and light stress in vinca major 
AB  - The distribution of xanthophyll cycle pigments (violaxanthin plus antheraxanthin
      plus zeaxanthin [VAZ]) among photosynthetic pigment-protein complexes was
      examined in Vinca major before, during, and subsequent to a photoinhibitory
      treatment at low temperature. Four pigment-protein complexes were isolated: the
      core of photosystem (PS) II, the major light-harvesting complex (LHC) protein of
      PSII (LHCII), the minor light-harvesting proteins (CPs) of PSII (CP29, CP26, and
      CP24), and PSI with its LHC proteins (PSI-LHCI). In isolated thylakoids 80% of
      VAZ was bound to protein independently of the de-epoxidation state and was found
      in all complexes. Plants grown outside in natural sunlight had higher levels of
      VAZ (expressed per chlorophyll), compared with plants grown in low light in the
      laboratory, and the additional VAZ was mainly bound to the major LHCII complex,
      apparently in an acid-labile site. The extent of de-epoxidation of VAZ in high
      light and the rate of reconversion of Z plus A to V following 2.5 h of recovery
      were greatest in the free-pigment fraction and varied among the pigment-protein
      complexes. Photoinhibition caused increases in VAZ, particularly in low-light
      acclimated leaves. The data suggest that the photoinhibitory treatment caused an
      enrichment in VAZ bound to the minor CPs caused by de novo synthesis of the
      pigments and/or a redistribution of VAZ from the major LHCII complex.

PMID- 10398708
TI  - Lysophosphatidic acid acyltransferase from coconut endosperm mediates the
      insertion of laurate at the sn-2 position of triacylglycerols in lauric rapeseed
      oil and can increase total laurate levels 
AB  - Expression of a California bay laurel (Umbellularia californica) 12:0-acyl
      carrier protein thioesterase, bay thioesterase (BTE), in developing seeds of
      oilseed rape (Brassica napus) led to the production of oils containing up to 50%
      laurate. In these BTE oils, laurate is found almost exclusively at the sn-1 and
      sn-3 positions of the triacylglycerols (T.A. Voelker, T.R. Hayes, A.C. Cranmer,
      H.M. Davies [1996] Plant J 9: 229-241). Coexpression of a coconut (Cocos
      nucifera) 12:0-coenzyme A-preferring lysophosphatitic acid acyltransferase (D.S.
      Knutzon, K.D. Lardizabal, J.S. Nelsen, J.L. Bleibaum, H.M. Davies, J.G. Metz
      [1995] Plant Physiol 109: 999-1006) in BTE oilseed rape seeds facilitates
      efficient laurate deposition at the sn-2 position, resulting in the acccumulation
      of trilaurin. The introduction of the coconut protein into BTE oilseed rape lines
      with laurate above 50 mol % further increases total laurate levels.

PMID- 10398710
TI  - Periplasmic carbonic anhydrase structural gene (Cah1) mutant in chlamydomonas
      reinhardtii 
AB  - To survive in various conditions of CO2 availability, Chlamydomonas reinhardtii
      shows adaptive changes, such as induction of a CO2-concentrating mechanism,
      changes in cell organization, and induction of several genes, including a
      periplasmic carbonic anhydrase (pCA1) encoded by Cah1. Among a collection of
      insertionally generated mutants, a mutant has been isolated that showed no pCA1
      protein and no Cah1 mRNA. This mutant strain, designated cah1-1, has been
      confirmed to have a disruption in the Cah1 gene caused by a single Arg7 insert.
      The most interesting feature of cah1-1 is its lack of any significant growth
      phenotype. There is no major difference in growth or photosynthesis between the
      wild type and cah1-1 over a pH range from 5.0 to 9.0 even though this mutant
      apparently lacks Cah1 expression in air. Although the presence of pCA1 apparently
      gives some minor benefit at very low CO2 concentrations, the characteristics of
      this Cah1 null mutant demonstrate that pCA1 is not essential for function of the
      CO2-concentrating mechanism or for growth of C. reinhardtii at limiting CO2
      concentrations.

PMID- 10398709
TI  - Regions of the pea Lhcb1*4 promoter necessary for blue-light regulation in
      transgenic Arabidopsis.
AB  - Pea (Pisum sativum) and Arabidopsis contain similar, if not identical, blue-light
      (BL)-responsive systems that alter expression of specific members of the Lhcb
      (light-harvesting chlorophyll-binding) gene family. In both plants a single,
      short pulse of low-fluence BL (threshold = 10(-1) micromol m-2) causes an
      increase in the rate of transcription from specific members of the Lhcb gene
      family in etiolated seedlings. Constructs of the BL-regulated pea Lhcb1*4
      promoter (PsLhcb1*4) were created, which altered sequences previously implicated
      in light responses, deleted the 5'-promoter sequence, or removed the 5'
      untranslated region. These constructs were tested for BL induction in transgenic
      Arabidopsis. The PsLhcb1*4 promoter deletions to -150 bp maintained normal
      fluence response, time course, and reciprocity characteristics. The 5'-
      untranslated region contained enhancer elements, but was not necessary for BL
      induction. The -95 to +2 promoter was capable of responding to BL, whereas
      sequences from -50 were not. Promoters that lack conserved light-regulatory
      elements or sequences directly implicated in phytochrome and circadian responses
      retained BL activity, suggesting that the low-fluence BL response utilizes
      regions of the promoter independent of those that modulate the phytochrome and
      circadian responses.

PMID- 10398711
TI  - The effect of growth and measurement temperature on the activity of the
      alternative respiratory pathway 
AB  - A postulated role of the CN-resistant alternative respiratory pathway in plants
      is the maintenance of mitochondrial electron transport at low temperatures that
      would otherwise inhibit the main phosphorylating pathway and prevent the
      formation of toxic reactive oxygen species. This role is supported by the
      observation that alternative oxidase protein levels often increase when plants
      are subjected to growth at low temperatures. We used oxygen isotope fractionation
      to measure the distribution of electrons between the main and alternative
      pathways in mung bean (Vigna radiata) and soybean (Glycine max) following growth
      at low temperature. The amount of alternative oxidase protein in mung bean grown
      at 19 degrees C increased over 2-fold in both hypocotyls and leaves compared with
      plants grown at 28 degrees C but was unchanged in soybean cotyledons grown at 14
      degrees C compared with plants grown at 28 degrees C. When the short-term
      response of tissue respiration was measured over the temperature range of 35
      degrees C to 9 degrees C, decreases in the activities of both main and
      alternative pathway respiration were observed regardless of the growth
      temperature, and the relative partitioning of electrons to the alternative
      pathway generally decreased as the temperature was lowered. However, cold-grown
      mung bean plants that up-regulated the level of alternative oxidase protein
      maintained a greater electron partitioning to the alternative oxidase when
      measured at temperatures below 19 degrees C supporting a role for the alternative
      pathway in response to low temperatures in mung bean. This response was not
      observed in soybean cotyledons, in which high levels of alternative pathway
      activity were seen at both high and low temperatures.

PMID- 10398712
TI  - Heavy-metal regulation of thioredoxin gene expression in chlamydomonas
      reinhardtii 
AB  - Heavy metals are highly toxic compounds for cells. In this report we demonstrate
      that the expression of Chlamydomonas reinhardtii thioredoxins (TRX) m and h is
      induced by heavy metals. Upon exposure of the cells to Cd and Hg, a strong
      accumulation of both messengers was observed. Western-blot experiments revealed
      that among these two TRXs, only TRX h polypeptides accumulated in response to the
      toxic cations. A biochemical analysis indicated that heavy metals inhibit TRX
      activity, presumably by binding at the level of their active site. Sequence
      analysis of the C. reinhardtii TRX h promoter revealed the presence of cis-acting
      elements related to cadmium induction. The origins and purposes of this
      regulation are discussed. Our data suggest, for the first time to our knowledge,
      a possible implication of TRXs in defense mechanisms against heavy metals.

PMID- 10398713
TI  - Properties of enhanced tonoplast zinc transport in naturally selected zinc
      tolerant silene vulgaris 
AB  - It was demonstrated recently that isolated tonoplast vesicles derived from plants
      of a Zn-tolerant ecotype of Silene vulgaris accumulate more Zn than vesicles
      derived from a Zn-sensitive ecotype. We have now characterized the tonoplast
      transport system that causes this uptake difference and demonstrated its genetic
      correlation to Zn tolerance using plant crosses. We conclude that the tonoplast
      Zn uptake system of the tolerant ecotype differs greatly in its characteristics
      from that of the sensitive one, with the most prominent differences being its
      insensitivity to protonophores and ortho-vanadate and its stimulation by Mg-GTP.
      These differences in characteristics are most likely due to the fact that Zn can
      be taken up by two or more parallel pathways, which are not present in the same
      proportions in both ecotypes. In both ecotypes, Zn is actively transported across
      the tonoplast (temperature coefficient > 1.6), most likely as a free ion, since
      citrate does not accumulate in vesicles. Most importantly, the uptake difference
      found using the ecotypes was also found between homozygous Zn-tolerant and Zn
      sensitive F3 plants, proving the genetic correlation between increased tonoplast
      Zn transport and naturally selected Zn tolerance in S. vulgaris.

PMID- 10398714
TI  - Characterization and immunolocalization of a cytosolic calcium-binding protein
      from Brassica napus and Arabidopsis pollen.
AB  - Two low-molecular-weight proteins have been purified from Brassica napus pollen
      and a gene corresponding to one of them has been isolated. The gene encodes an
      8.6-kD protein with two EF-hand calcium-binding motifs and is a member of a small
      gene family in B. napus. The protein is part of a family of pollen allergens
      recently identified in several evolutionarily distant dicot and monocot plants.
      Homologs have been detected in Arabidopsis, from which one gene has been cloned
      in this study, and in snapdragon (Antirrhinum majus), but not in tobacco
      (Nicotiana tabacum). Expression of the gene in B. napus was limited to male
      tissues and occurred during the pollen-maturation phase of anther development.
      Both the B. napus and Arabidopsis proteins interact with calcium, and the
      potential for a calcium-dependent conformational change was demonstrated. Given
      this affinity for calcium, the cloned genes were termed BPC1 and APC1 (B. napus
      and Arabidopsis pollen calcium-binding protein 1, respectively).
      Immunolocalization studies demonstrated that BPC1 is found in the cytosol of
      mature pollen. However, upon pollen hydration and germination, there is some
      apparent leakage of the protein to the pollen wall. BPC1 is also concentrated on
      or near the surface of the elongating pollen tube. The essential nature of
      calcium in pollen physiology, combined with the properties of BPC1 and its high
      evolutionary conservation suggests that this protein plays an important role in
      pollination by functioning as a calcium-sensitive signal molecule.

PMID- 10398716
TI  - Abscisic acid induction of vacuolar H+-ATPase activity in mesembryanthemum
      crystallinum is developmentally regulated 
AB  - Abscisic acid (ABA) has been implicated as a key component in water-deficit
      induced responses, including those triggered by drought, NaCl, and low-
      temperature stress. In this study a role for ABA in mediating the NaCl-stress
      induced increases in tonoplast H+-translocating ATPase (V-ATPase) and Na+/H+
      antiport activity in Mesembryanthemum crystallinum, leading to vacuolar Na+
      sequestration, were investigated. NaCl or ABA treatment of adult M. crystallinum
      plants induced V-ATPase H+ transport activity, and when applied in combination,
      an additive effect on V-ATPase stimulation was observed. In contrast, treatment
      of juvenile plants with ABA did not induce V-ATPase activity, whereas NaCl
      treatment resulted in a similar response to that observed in adult plants. Na+/H+
      antiport activity was induced in both juvenile and adult plants by NaCl, but ABA
      had no effect at either developmental stage. Results indicate that ABA-induced
      changes in V-ATPase activity are dependent on the plant reaching its adult phase,
      whereas NaCl-induced increases in V-ATPase and Na+/H+ antiport activity are
      independent of plant age. This suggests that ABA-induced V-ATPase activity may be
      linked to the stress-induced, developmentally programmed switch from C3
      metabolism to Crassulacean acid metabolism in adult plants, whereas, vacuolar Na+
      sequestration, mediated by the V-ATPase and Na+/H+ antiport, is regulated through
      ABA-independent pathways.

PMID- 10398715
TI  - Molecular cloning and tissue-specific expression of an anionic peroxidase in
      zucchini.
AB  - A calcium-pectate-binding anionic isoperoxidase (APRX) from zucchini (Cucurbita
      pepo) was purified and subjected to N-terminal amino acid microsequencing. The
      cDNA encoding this enzyme was obtained by reverse transcriptase polymerase chain
      reaction from a cDNA library. It encoded a mature protein of 309 amino acids
      exhibiting all of the sequence characteristics of a plant peroxidase. Despite the
      presence of a C-terminal propeptide, APRX was found in the apoplast. APRX protein
      and mRNA were found in the root, hypocotyls, and cotyledons. In situ
      hybridization showed that the APRX-encoding gene was expressed in many different
      tissues. The strongest expression was observed in root epidermis and in some
      cells of the stele, in differentiating tracheary elements of hypocotyl, in the
      lower and upper epidermis, in the palisade parenchyma of cotyledons, and in
      lateral and adventitious root primordia. In the hypocotyl hook there was an
      asymmetric expression, with the inner part containing more transcripts than the
      outer part. Treatment with 2,3,5-triiodobenzoic acid reduced the expression of
      the APRX-encoding gene in the lower part of the hypocotyl. Our observations
      suggest that APRX could be involved in lignin formation and that the
      transcription of its gene was related to auxin level.

PMID- 10398717
TI  - Thermotolerance of leaf discs from four isoprene-emitting species is not enhanced
      by exposure to exogenous isoprene 
AB  - The effects of exogenously supplied isoprene on chlorophyll fluorescence
      characteristics were examined in leaf discs of four isoprene-emitting plant
      species, kudzu (Pueraria lobata [Willd.] Ohwi.), velvet bean (Mucuna sp.),
      quaking aspen (Populus tremuloides Michx.), and pussy willow (Salix discolor
      Muhl). Isoprene, supplied to the leaves at either 18 &mgr;L L-1 in compressed air
      or 21 &mgr;L L-1 in N2, had no effect on the temperature at which minimal
      fluorescence exhibited an upward inflection during controlled increases in leaf
      disc temperature. During exposure to 1008 &mgr;mol photons m-2 s-1 in an N2
      atmosphere, 21 &mgr;L L-1 isoprene had no effect on the thermally induced
      inflection of steady-state fluorescence. The maximum quantum efficiency of
      photosystem II photochemistry decreased sharply as leaf-disc temperature was
      increased; however, this decrease was unaffected by exposure of leaf discs to 21
      &mgr;L L-1 isoprene. Therefore, there were no discernible effects of isoprene on
      the occurrence of symptoms of high-temperature damage to thylakoid membranes. Our
      data do not support the hypothesis that isoprene enhances leaf thermotolerance.

PMID- 10398718
TI  - Expansins are conserved in conifers and expressed in hypocotyls in response to
      exogenous auxin.
AB  - Differential display reverse transcription-polymerase chain reaction was used to
      detect the induction of gene expression during adventitious root formation in
      loblolly pine (Pinus taeda) after treatment with the exogenous auxin indole-3
      butyric acid. A BLAST search of the GenBank database using one of the clones
      obtained revealed very strong similarity to the alpha-expansin gene family in
      angiosperms. A near-full-length loblolly pine alpha-expansin sequence was
      obtained using 5'- and 3'-rapid amplification of cDNA end cloning, and the
      deduced amino acid sequence was highly conserved relative to those of angiosperm
      expansins. Northern analysis indicates that alpha-expansin mRNA expression
      increases 50- to 100-fold in the base of hypocotyl stem cuttings from loblolly
      pine seedlings in response to indole-3-butyric acid, with peak expression
      occurring 24 to 48 h after induction.

PMID- 10398719
TI  - Arabidopsis det2 is defective in the conversion of (24R)-24-methylcholest-4-En-3
      one to (24R)-24-methyl-5alpha-cholestan-3-one in brassinosteroid biosynthesis.
AB  - Previously, we have shown that the Arabidopsis det2 (deetiolated2) mutant is
      defective in the biosynthesis of brassinosteroids (BR) and that DET2 (a steroid
      5alpha-reductase) acts early in the proposed BR biosynthetic pathway. In this
      paper we present further biochemical characterization of det2. We have undertaken
      metabolic experiments with 2H-labeled substrates of intermediates involved in the
      formation of campestanol from campesterol, and quantitative analysis of
      intermediates in Arabidopsis wild type and det2. The results of these studies
      indicate the early operating steps of BR biosynthesis as: campesterol --> 4-en
      3beta-ol --> 4-en-3-one --> 3-one --> campestanol in Arabidopsis, with det2
      deficient in the conversion of 4-en-3-one to 3-one. We have also detected these
      intermediates in the formation of campestanol from campesterol and their
      metabolic conversions using cultured cells of Catharanthus roseus. These studies
      confirmed the biosynthetic sequence of events from campesterol to campestanol as
      was found in Arabidopsis. As such, the originally proposed biosynthetic pathway
      should be modified.

PMID- 10398720
TI  - Purification and characterization of the reconstitutively active citrate carrier
      from maize mitochondria.
AB  - The citrate carrier from maize (Zea mays) shoot mitochondria was solubilized with
      Triton X-100 and purified by sequential chromatography on hydroxyapatite and
      hydroxyapatite/celite in the presence of cardiolipin. SDS-gel electrophoresis of
      the purified fraction showed a single polypeptide band with an apparent molecular
      mass of 31 kD. When reconstituted into liposomes, the citrate carrier catalyzed a
      pyridoxal 5'-P-sensitive citrate/citrate exchange. It was purified 224-fold with
      a recovery of 50% and a protein yield of 0.22% with respect to the mitochondrial
      extract. In the reconstituted system the purified citrate carrier catalyzed a
      first-order reaction of citrate/citrate (0.065 min-1) or citrate/malate exchange
      (0.075 min-1). Among the various substrates and inhibitors tested, the
      reconstituted protein transported citrate, cis-aconitate, isocitrate, L-malate,
      succinate, malonate, glutarate, alpha-ketoglutarate, oxaloacetate, and alpha
      ketoadipate and was inhibited by pyridoxal 5'-P, phenylisothiocyanate, mersalyl,
      and p-hydroxymercuribenzoate (but not N-ethylmaleimide), 1,2, 3
      benzentricarboxylate, benzylmalonate, and butylmalonate. The activation energy of
      the citrate/citrate exchange was 66.5 kJ/mol between 10 degrees C and 35 degrees
      C; the half-saturation constant (Km) for citrate was 0.65 +/- 0.05 mM and the
      maximal rate (Vmax) of the citrate/citrate exchange was 13.0 +/- 1.0 micromol min
      1 mg-1 protein at 25 degrees C.

PMID- 10398721
TI  - Inhibition of water channels by HgCl2 in intact wheat root cells 
AB  - To assess the extent of water flow through channels in the membranes of intact
      higher plant cells, the effects of HgCl2 on hydraulic conductivity (LP) of wheat
      (Triticum aestivum L.) root cells were investigated using a pressure probe. The
      LP of root cells was reduced by 75% in the presence of 100 &mgr;M HgCl2. The K+
      channel blocker tetraethylammonium had no effect on the LP at concentrations that
      normally block K+ channels. HgCl2 rapidly depolarized the membrane potential (Vm)
      of the root cells. The dose-response relationship of inhibition of LP and
      depolarization of Vm were not significantly different, with half-maximal
      inhibition occurring at 4. 6 and 7.8 &mgr;M, respectively. The inhibition of LP
      and the depolarization of Vm caused by HgCl2 were partially reversed by beta
      mercaptoethanol. The inhibition of LP by HgCl2 was similar in magnitude to that
      caused by hypoxia, and the addition of HgCl2 to hypoxia-treated cells did not
      result in further inhibition. We compared the LP of intact cells with that
      predicted from a model of cortical cells incorporating water flow across both the
      plasma membrane and the tonoplast using measured values of water permeability
      from isolated membranes, and found that HgCl2 has other effects in addition to
      the direct inhibition of water channels.

PMID- 10398722
TI  - Autophosphorylation-dependent activation of a calcium-dependent protein kinase
      from groundnut 
AB  - Ca2+-dependent protein kinases (CDPKs) containing a calmodulin-like domain
      integrated in their primary sequence are present primarily in plants. A member of
      this family was characterized from the groundnut (Arachis hypogea) plant and
      called GnCDPK (M. DasGupta [1994] Plant Physiol 104: 961-969). GnCDPK
      specifically uses the myosin light chain synthetic peptide (MLCpep), which is the
      phosphate-accepting domain of smooth muscle myosin light chains (KKRPQRATSNVFS),
      as an exogenous substrate under in vitro experimental conditions. In this report
      we show that GnCDPK undergoes intramolecular autophosphorylation. This self
      phosphorylation occurs in threonine residues in a Ca2+-dependent (K0.5 = 0.5
      &mgr;M) and calmodulin-independent manner. The kinase activity toward MLCpep and
      its sensitivity to Ca2+ were unaffected by prior autophosphorylation when
      measured under saturating ATP concentrations. The role of autophosphorylation in
      the exogenous substrate MLCpep phosphorylation reaction was reinvestigated at low
      ATP concentrations. A pronounced lag time of 1 to 2 min, followed by a linear
      increase of activity for 7.5 min, was seen in the initial rate of MLCpep
      phosphorylation under such suboptimal conditions. Prior autophosphorylation
      completely abolished this lag phase, and a sharp rise of exogenous substrate
      phosphorylation was seen from the 1st min. Our results suggest that
      autophosphorylation is a prerequisite for the activation of GnCDPK.

PMID- 10398723
TI  - Sucrose synthase in legume nodules is essential for nitrogen fixation 
AB  - The role of sucrose synthase (SS) in the fixation of N was examined in the rug4
      mutant of pea (Pisum sativum L.) plants in which SS activity was severely
      reduced. When dependent on nodules for their N supply, the mutant plants were not
      viable and appeared to be incapable of effective N fixation, although nodule
      formation was essentially normal. In fact, N and C resources invested in nodules
      were much greater in mutant plants than in the wild-type (WT) plants. Low SS
      activity in nodules (present at only 10% of WT levels) resulted in lower amounts
      of total soluble protein and leghemoglobin and lower activities of several
      enzymes compared with WT nodules. Alkaline invertase activity was not increased
      to compensate for reduced SS activity. Leghemoglobin was present at less than 20%
      of WT values, so O2 flux may have been compromised. The two components of
      nitrogenase were present at normal levels in mutant nodules. However, only a
      trace of nitrogenase activity was detected in intact plants and none was found in
      isolated bacteroids. The results are discussed in relation to the role of SS in
      the provision of C substrates for N fixation and in the development of functional
      nodules.

PMID- 10398724
TI  - Limonene synthase, the enzyme responsible for monoterpene biosynthesis in
      peppermint, is localized to leucoplasts of oil gland secretory cells 
AB  - Circumstantial evidence based on ultrastructural correlation, specific labeling,
      and subcellular fractionation studies indicates that at least the early steps of
      monoterpene biosynthesis occur in plastids. (4S)-Limonene synthase, which is
      responsible for the first dedicated step of monoterpene biosynthesis in mint
      species, appears to be translated as a preprotein bearing a long plastidial
      transit peptide. Immunogold labeling using polyclonal antibodies raised to the
      native enzyme demonstrated the specific localization of limonene synthase to the
      leucoplasts of peppermint (Mentha x piperita) oil gland secretory cells during
      the period of essential oil production. Labeling was shown to be absent from all
      other plastid types examined, including the basal and stalk cell plastids of the
      secretory phase glandular trichomes. Furthermore, in vitro translation of the
      preprotein and import experiments with isolated pea chloroplasts were consistent
      in demonstrating import of the nascent protein to the plastid stroma and
      proteolytic processing to the mature enzyme at this site. These experiments
      confirm that the leucoplastidome of the oil gland secretory cells is the
      exclusive location of limonene synthase, and almost certainly the preceding steps
      of monoterpene biosynthesis, in peppermint leaves. However, succeeding steps of
      monoterpene metabolism in mint appear to occur outside the leucoplasts of oil
      gland cells.

PMID- 10398725
TI  - Photosynthesis and carbon partitioning in transgenic tobacco plants deficient in
      leaf cytosolic pyruvate kinase 
AB  - Whole-plant diurnal C exchange analysis provided a noninvasive estimation of
      daily net C gain in transgenic tobacco (Nicotiana tabacum L.) plants deficient in
      leaf cytosolic pyruvate kinase (PKc-). PKc- plants cultivated under a low light
      intensity (100 &mgr;mol m-2 s-1) were previously shown to exhibit markedly
      reduced root growth, as well as delayed shoot and flower development when
      compared with plants having wild-type levels of PKc (PKc+). PKc- and PKc+ source
      leaves showed a similar net C gain, photosynthesis over a range of light
      intensities, and a capacity to export newly fixed 14CO2 during photosynthesis.
      However, during growth under low light the nighttime, export of previously fixed
      14CO2 by fully expanded PKc- leaves was 40% lower, whereas concurrent respiratory
      14CO2 evolution was 40% higher than that of PKc+ leaves. This provides a
      rationale for the reduced root growth of the PKc- plants grown at low irradiance.
      Leaf photosynthetic and export characteristics in PKc- and PKc+ plants raised in
      a greenhouse during winter months resembled those of plants grown in chambers at
      low irradiance. The data suggest that PKc in source leaves has a critical role in
      regulating nighttime respiration particularly when the available pool of
      photoassimilates for export and leaf respiratory processes are low.

PMID- 10398727
TI  - Biosynthesis of ascorbic acid in kidney bean. L-galactono-gamma-lactone
      dehydrogenase is an intrinsic protein located at the mitochondrial inner membrane
AB  - Hypocotyls of kidney beans (Phaseolus vulgaris L.) accumulated ascorbate after
      preincubation with a number of possible precursors, mainly L-galactono-gamma
      lactone (L-GL) and L-gulono-gamma-lactone. The increase in the intracellular
      ascorbate concentration was parallel to the high stimulation of the L-GL
      dehydrogenase (L-GLD) activity measured in vitro using L-GL as a substrate and
      cytochrome c as an electron acceptor. Cell fractionation using a continuous
      linear Percoll gradient demonstrated that L-GLD is associated with mitochondria;
      therefore, pure mitochondria were isolated and subjected to detergent treatment
      to separate soluble from membrane-linked proteins. L-GLD activity was mainly
      associated with the detergent phase, suggesting that a membrane-intrinsic protein
      is responsible for the ascorbic acid biosynthetic activity. Subfractionation of
      mitochondria demonstrated that L-GLD is located at the inner membrane.

PMID- 10398726
TI  - Ethylene plays multiple nonprimary roles in modulating the gravitropic response
      in tomato.
AB  - Ethylene is known to interact with auxin in regulating stem growth, and yet
      evidence for the role of ethylene in tropic responses is contradictory. Our
      analysis of four mutants of tomato (Lycopersicon esculentum) altered in their
      response to gravity, auxin, and/or ethylene revealed concentration-dependent
      modulation of shoot gravitropism by ethylene. Ethylene inhibitors reduce wild
      type gravicurvature, and extremely low (0.0005-0.001 microliter L-1) ethylene
      concentrations can restore the reduced gravitropic response of the auxin
      resistant dgt (diageotropica) mutant to wild-type levels. Slightly higher
      concentrations of ethylene inhibit the gravitropic response of all but the
      ethylene-insensitive nr (never-ripe) mutant. The gravitropic responses of nr and
      the constitutive-response mutant epi (epinastic) are slightly and significantly
      delayed, respectively, but otherwise normal. The reversal of shoot gravicurvature
      by red light in the lz-2 (lazy-2) mutant is not affected by ethylene. Taken
      together, these data indicate that, although ethylene does not play a primary
      role in the gravitropic response of tomato, low levels of ethylene are necessary
      for a full gravitropic response, and moderate levels of the hormone specifically
      inhibit gravicurvature in a manner different from ethylene inhibition of overall
      growth.

PMID- 10398728
TI  - A plastidial lysophosphatidic acid acyltransferase from oilseed rape.
AB  - The biosynthesis of phosphatidic acid, a key intermediate in the biosynthesis of
      lipids, is controlled by lysophosphatidic acid (LPA, or 1-acyl-glycerol-3-P)
      acyltransferase (LPAAT, EC 2.3.1.51). We have isolated a cDNA encoding a novel
      LPAAT by functional complementation of the Escherichia coli mutant plsC with an
      immature embryo cDNA library of oilseed rape (Brassica napus). Transformation of
      the acyltransferase-deficient E. coli strain JC201 with the cDNA sequence BAT2
      alleviated the temperature-sensitive phenotype of the plsC mutant and conferred a
      palmitoyl-coenzyme A-preferring acyltransferase activity to membrane fractions.
      The BAT2 cDNA encoded a protein of 351 amino acids with a predicted molecular
      mass of 38 kD and an isoelectric point of 9.7. Chloroplast-import experiments
      showed processing of a BAT2 precursor protein to a mature protein of
      approximately 32 kD, which was localized in the membrane fraction. BAT2 is
      encoded by a minimum of two genes that may be expressed ubiquitously. These data
      are consistent with the identity of BAT2 as the plastidial enzyme of the
      prokaryotic glycerol-3-P pathway that uses a palmitoyl-ACP to produce
      phosphatidic acid with a prokaryotic-type acyl composition. The homologies
      between the deduced protein sequence of BAT2 with prokaryotic and eukaryotic
      microsomal LAP acytransferases suggest that seed microsomal forms may have
      evolved from the plastidial enzyme.

PMID- 10398729
TI  - Proline accumulation in developing grapevine fruit occurs independently of
      changes in the levels of delta1-pyrroline-5-carboxylate synthetase mRNA or
      protein.
AB  - Mature fruit of grapevine (Vitis vinifera) contains unusually high levels of free
      proline (Pro; up to 24 micromol or 2.8 mg/g fresh weight). Pro accumulation does
      not occur uniformly throughout berry development but only during the last 4 to 6
      weeks of ripening when both berry growth and net protein accumulation have
      ceased. In contrast, the steady-state levels of both the mRNA encoding V.
      vinifera Delta1-pyrroline-5-carboxylate synthetase (VVP5CS), a key regulatory
      enzyme in Pro biosynthesis, and its protein product remain relatively uniform
      throughout fruit development. In addition, the steady-state protein levels of Pro
      dehydrogenase, the first enzyme in Pro degradation, increased throughout early
      fruit development but thereafter remained relatively constant. The developmental
      accumulation of free Pro late in grape berry ripening is thus clearly distinct
      from the osmotic stress-induced accumulation of Pro in plants. It is not
      associated with either sustained increases in steady-state levels of P5CS mRNA or
      protein or a decrease in steady-state levels of Pro dehydrogenase protein,
      suggesting that other physiological factors are important for its regulation.

PMID- 10398731
TI  - Development of endoscopic dissection of perforating veins and fasciotomy for
      treatment of chronic venous insufficiency.
AB  - As the subfascial endoscopic perforator vein surgery (SEPS) has become
      increasingly popular, it becomes important to trace the development of this
      procedure first initiated in 1985. (Improvements in the technique and
      modifications of initial instrumentation have occurred. These changes are based
      on experience with greater than 1000 patients treated since 1980 at Krankenhaus
      der Barmherzigen Bruder in Munich, Klinikum Merheim in Cologne, and the Weilheim
      Hospital. Results obtained in 96 patients (140 legs) were examined
      retrospectively and are presented as well as the prospective evaluation of 39
      patients with 56 operated legs. (Hauer G, Vasa 1985, 14:59-61; Hauer G, Barkun J,
      Wisser I, Deiler S, Surg Endosc 1988, 2:5-12; Schneidemann B, Inaug Diss, 1985).
      This report details the fact that in using our own instruments, including a
      specially designed videoscope, it has been possible to approach perforating veins
      of the medial anterior and posterior compartments. This can be done through a 2
      cm incision in the proximal calf. Using these instruments, it has been possible
      to perform a fasciotomy under direct vision. This summary emphasizes that it is
      not necessary to locate perforating veins preoperatively, and that wound
      infection and recurrent ulcerations do not occur. This allows application of the
      method to patients with open ulcers. Further, this report emphasizes that
      patients with combined arterial and venous ulceration require arterial
      reconstruction rather than perforator vein interruption. The SEPS operation is
      relatively contraindicated if there is widespread necrosis and infection of the
      fascia, especially in combination with ankle ankylosis. In addition, this is the
      method of choice in patients with multiple incompetent perforating veins with or
      without open venous ulceration.

PMID- 10398730
TI  - Four polymorphic variations in the PEDF gene identified during the mutation
      screening of patients with Leber congenital amaurosis.
AB  - PURPOSE: Leber congenital amaurosis (LCA) has been mapped to chromosome 17p13.1.
      From the candidate genes mapped to this region, thus far, only Retinal Guanylate
      Cyclase (RetGC), has been found to have pathogenic LCA mutations, in families
      from North African origin. However, early reports, demonstrated eight LCA
      families linked to 17p13.1, but only four of them showed mutations in RetGC.
      Mapped in proximity to this locus is the candidate gene Pigment Epithelium
      Derived actor (PEDF), a factor implicated in photoreceptor differentiation and
      neuronal survival. Our purpose in this study was to identify mutations and
      polymorphisms in the PEDF gene in LCA patients of diverse ethnic origin. METHODS:
      Automated genotyping with four 17p13.1 markers flanking the PEDF gene was
      performed to assess homozygosity and PCR-SSCP combined with direct sequencing was
      used to detect mutations in the PEDF gene in 17 LCA patients. RESULTS:
      Homozygosity of markers D17S796 and D17S804 was found and four new intragenic
      basepair alterations were discovered: a Met72Thr polymorphism in exon 3 (T331C),
      a Thr130Thr polymorphism in exon 4 (T506C), a G to A transition in intron 5 (nine
      base pairs upstream from splice acceptor site), and a Tyr321Tyr polymorphism in
      exon 7 (C1079T) were detected. CONCLUSIONS: We report the discovery of four new
      polymorphic alterations in the PEDF gene in LCA patients and exclude by RFLP
      analysis the PEDF gene as a common cause of Leber congenital amaurosis. These
      single nucleotide polymorphisms will aid in future linkage analysis of complex
      multifactorial diseases involving retinal and RPE dysfunctions.

PMID- 10398732
TI  - Duplex directed caval filter insertion in multi-trauma and critically ill
      patients.
AB  - This study was undertaken to determine the safety and feasibility of inferior
      vena cava (IVC) filter insertion at the bedside using duplex imaging in multi
      trauma and/or critically ill patients. From February 1996 to August 1997, 53
      multi-trauma and/or critically ill patients, who were in the intensive care unit
      and referred for an IVC filter, were prospectively evaluated for possible duplex
      directed caval filter (DDCF) insertion. Screening IVC duplex scans were performed
      in all patients. Satisfactory ultrasound visualization in 46 patients (87%)
      allowed attempted DDCF insertion. All procedures were percutaneously performed at
      the bedside using Vena Tech IVC filters. The results from this series showed that
      DDCF insertion can be safely and rapidly performed at the bedside in multi-trauma
      or critically ill patients. The procedure is dependent on satisfactory
      visualization of the IVC by duplex ultrasonography, which was possible in 45 out
      of 53 (85%) patients. Insertion at the bedside substantially reduces the
      procedural cost and avoids the need for transport, radiation exposure, and
      intravenous contrast.

PMID- 10398733
TI  - Development of open-scope subfascial perforating vein surgery: lessons learned
      from the first 67 cases.
AB  - Although perforating vein surgery in treatment and prevention of venous ulcers
      remains controversial, minimization of the procedure has allowed its
      reevaluation. We have chosen to develop the technique using a single port and an
      open scope using a variety of mostly nondisposable instrumentation. Since our
      first subfascial endoscopic perforator vein surgical (SEPS) procedure in July
      1993, we have operated on 67 limbs in 62 patients (27 women, 35 men) ranging in
      age from 24 to 85 years. Using CEAP criteria, there were 16 limbs in class 4, 13
      in class 5, and 38 in class 6. Preoperative investigations included duplex
      ultrasound in 35 cases, ascending phlebography in 29 cases, and selective use of
      physiologic testing with air plethysmography (APG) in 12 patients. A variety of
      initial explorations using different-diameter scopes has given way to single-port
      methodology for medial leg exploration. A mean of 3.08 perforators per patient
      was interrupted using electrocoagulation or metal clips and scissor division.
      This technique, as developed, allows same-day or short-stay (<24 hr) surgery. A
      vigorous program of thromboembolism prophylaxis was used in selected cases. From
      these 67 csaes we conclude that endoscopic perforating vein interruption provides
      a useful tool for the surgeon interested in treating severe chronic venous
      insufficiency. The open-scope, single-port technique accomplishes intervention
      objectives in a simplified manner. Although recurrent chronic venous
      insufficiency (CVI) is not eliminated, its postoperative treatment is markedly
      eased.

PMID- 10398735
TI  - Patency and limb salvage for polytetrafluoroethylene bypasses with vein
      interposition cuffs.
AB  - Polytetrafluoroethelene (PTFE) is often utilized in patients with limb
      threatening ischemia requiring infrainguinal revascularization in the absence of
      autologous saphenous vein. To increase long-term patency of PTFE grafts, vein
      interposition cuffs have been recommended as adjunctive procedures. The purpose
      of this study was to assess the efficacy of vein interposition cuffs on the long
      term patency and limb salvage of patients requiring prosthetic bypass grafts for
      limb-threatening ischemia. Prosthetic bypass grafts with vein interposition cuffs
      (PTFE/VC) were performed on 56 limbs in 55 patients (32 men, 23 women; mean age
      of 67 years) from October 1993 to January 1998. Grafts were prospectively
      evaluated every 3 months for the first 12 months and biannually thereafter with
      duplex ultrasonography. PTFE/VC and PTFE bypasses at the popliteal level appear
      to have comparable patencies. However, PTFE/VC appear to offer an improved
      patency and limb salvage for infrapopliteal bypasses in patients with critical
      limb ischemia. When infrapopliteal revascularization is required in the absence
      of autologous saphenous vein, we recommend the use of PTFE with vein
      interposition cuffs.

PMID- 10398734
TI  - Early morphology of accelerated vein graft atheroma in experimental vein grafts.
AB  - Vein grafts fail because of the development of intimal hyperplasia and atheroma.
      Recent experimental evidence suggests that the presence of hypercholesterolemia
      induces a three-fold increase in intimal hyperplasia with early atheroma
      development within 4 weeks of implantation. We have previously demonstrated
      endothelial cell preservation and a short-lived (3-day) polymorphonuclear
      leukocyte infiltrate in vein grafts. The aim of this study is to define the early
      morphology and ultrastructure of vein grafts implanted into a hyperlipidemic
      environment to provide a pathological foundation on which to examine the cellular
      and molecular events that determine this accelerated response. Twenty-one male
      New Zealand White rabbits underwent a right carotid interposition bypass graft
      using the ipsilateral external jugular vein; all animals received a 1%
      cholesterol diet for 4 weeks prior to surgery and continuing postoperatively
      until harvest. Animals (n = 3 per time point) were sacrificed at 60 min, 1 day, 3
      days, 5 days, 7 days, 14 days, and 28 days postoperatively for scanning and
      transmission electron microscopy of the vein grafts. No concurrent controls were
      employed. The results of this study suggest that in the presence of
      hypercholesterolemia, the pathophysiological processes involved in the vein graft
      are similar to those reported for noncholesterol-fed animals. There is a
      sustained subendothelial response with the prolonged presence of macrophages and
      cellular debris and the accumulation of foam cells.

PMID- 10398736
TI  - Nonfractionated heparin fails to inhibit arterial thrombosis in a human ex vivo
      thrombosis model.
AB  - The effect of nonfractionated heparin on the formation and composition of
      arterial thrombus is unclear. The purpose of this study in a human ex vivo model
      was to analyze fibrinoplatelet thrombi and test the inhibitory effect of
      nonfractionated heparin on arterial thrombus formation. Experiments were carried
      out in Sakariassen perfusion chambers. Strips coated with either tissue factor
      (TF) or collagen were exposed to human blood collected from healthy volunteers at
      an arterial shear stress rate of 2600 s-1 for 1 to 4 min. Platelet deposition was
      determined using immunoenzymatic techniques to quantify P-selectine, a platelet
      membrane receptor, in thrombi. Fibrin deposition was determined by quantifying
      fibrin degradation products released after application of plasmin (D-dimers).
      Heparin was injected into the blood flow through a blender port system located
      between the venous puncture site and perfusion chamber. The results of the study
      showed that in a human ex vivo model, formation of arterial thrombus on two
      thrombogenic surfaces (tissue factor and collagen) is not inhibited by
      nonfractionated heparin.

PMID- 10398737
TI  - Accelerated healing of Dacron grafts seeded by preclotting with autologous bone
      marrow blood.
AB  - > Studies have suggested that bone marrow-derived cells in the circulation may
      have the capacity and potential to endothelialize and heal vascular graft
      surfaces. We have investigated whether accelerated endothelialization could be
      achieved for Dacron grafts seeded by preclotting with bone marrow blood (BMB).
      Five 8 mm x 6 cm Dacron grafts seeded and preclotted with BMB and four controls
      preclotted with peripheral blood were implanted in the descending thoracic aorta
      (DTA) of mongrel dogs for 2 and 4 weeks. Two additional BMB DTA grafts were
      studied for 3 months. Five pairs of BMB and control grafts (4 mm x 6 cm) were
      bilaterally implanted into the carotids of dogs for 1 week and five pairs for 4
      weeks. All grafts remained patent. BMB seeding/preclotting was a simple,
      effective method to accelerate early graft endothelialization without increasing
      thrombogenicity. Further studies are needed before clinical application can be
      recommended.

PMID- 10398738
TI  - Influence of patient characteristics and treatment options on outcome of patients
      with prosthetic aortic graft infection.
AB  - This study was undertaken to determine the influence of patient characteristics
      and treatment options on survival and limb loss after treatment of prosthetic
      aortic graft infection. Fifty-three patients treated for prosthetic aortic graft
      infection were reviewed. Twenty-three presented with groin infection, 12 with
      sepsis, 10 with aortoenteric fistula, 4 with limb ischemia, and 4 with
      pseudoaneurysm. Treatment included staged extraanatomic bypass (EAB) plus graft
      excision in 23 patients, simultaneous EAB and graft excision in 18, in situ graft
      replacement in 5, and local therapy only in 7. Axillofemoral bypass was done for
      revascularization in 53 limbs and axillopopliteal bypass in 16 limbs. The results
      of this study showed that morbidity and mortality of prosthetic aortic graft
      infection is influenced by the presentation and type of treatment of the infected
      graft. Staged axillofemoral bypass (when possible) plus graft excision appears to
      be associated with acceptable outcome (survival with limb salvage in 74%).

PMID- 10398739
TI  - Demonstration of viable Chlamydia pneumoniae in atherosclerotic plaques of
      carotid arteries by reverse transcriptase polymerase chain reaction.
AB  - The presence of Chlamydia pneumoniae in atheromas has been demonstrated in
      several studies. Culture of the organism from arterial tissue has been difficult.
      We report the use of a reverse transcriptase polymerase chain reaction to detect
      viable Chlamydia pneumoniae in carotid atheromas. We analyzed 30 patients (14
      females, mean age 69.6 +/- 8.8 years) who underwent surgery for the removal of
      atherosclerotic plaques from carotid arteries. During surgery, samples of lingual
      vein and superior thyroideal artery were also taken. We applied two molecular
      biology techniques to the carotid plaques on lingual vein or thyroideal artery
      samples: 1) polymerase chain reaction (PCR) and 2) reverse transcriptase-PCR (RT
      PCR) for the detection of bacterial mRNA, employing PCR primers designed to
      detect a fragment of the 16S rRNA gene. Blood samples were obtained from the
      patients for determination of Chlamydia pneumoniae IgG, IgA, and IgM antibody
      titers by a microimmunofluorescence technique. The results of the present study
      confirmed the presence of viable Chlamydia pneumoniae in atheromas and support
      the hypothesis that the organism may be an active factor in the pathogenesis of
      atherosclerosis.

PMID- 10398740
TI  - Shredding embolectomy thrombectomy catheter for treatment of acute lower-limb
      ischemia.
AB  - We undertook a prospective evaluation to prove a new mechanical thrombectomy
      device, the shredding embolectomy thrombectomy catheter (S.E.T. catheter), for
      the treatment of patients with acute lower-limb ischemia. The study evaluated the
      success, patency, mortality, limb salvage, and complication rates for 51 patients
      treated from January 1994 through June 1996, with this device, which was an 8-F
      three-lumen catheter. The onset of symptoms was 8.6 +/- 9 days. Thrombus length
      was 18 +/- 9 cm situated in 44 native vessels and in 7 bypasses, 42 limbs were
      graded as threatened. Hydromechanical thrombectomy with the S.E.T. catheter
      proved to be a quick and safe adjunct for therapy of acute femoropopliteal
      thromboembolic occlusions with a high initial success rate and an acceptable mid
      term patency rate.

PMID- 10398741
TI  - Thrombolytic therapy: the treatment of choice for iliac vein thrombosis in the
      presence of kidney transplant.
AB  - A 49-year-old kidney transplant recipient was admitted with the diagnosis of
      acute iliofemoral deep venous thrombosis (DVT) extending into the external iliac
      vein in close proximity to the renal vein anastomosis. Thrombolytic therapy with
      urokinase was used and complete lysis of the thrombus was achieved within 36 hr.
      We feel that this method of therapy, rather than standard anticoagulation,
      represents the treatment of choice for acute DVT in the presence of a renal
      graft. Using this method we were able to salvage the kidney and avoid the
      complications of postphlebitic syndrome and pulmonary embolus.

PMID- 10398743
TI  - Spontaneous retroperitoneal hematoma from rupture of an aneurysm of the ovarian
      artery following delivery.
AB  - We describe a case involving spontaneous retroperitoneal hematoma caused by
      rupture of an aneurysm of the right ovarian artery 4 days after delivery in a
      multiparous woman. Diagnosis was achieved by arteriography. Bleeding was stopped
      by embolization via selective arteriography. Hematoma was drained by lomboscopy.
      The pathophysiological mechanisms underlying development and treatment of these
      aneurysms are discussed.

PMID- 10398742
TI  - Tuberculous infection of the descending thoracic and abdominal aorta: case report
      and literature review.
AB  - We report here a case of infrarenal aortic disruption and aortoduodenal fistula
      secondary to tuberculous aortitis in a 77-year-old man. From a review of
      experience with operative management of tuberculous infection of the descending
      thoracic and abdominal aorta reported in the English-language literature,
      including the current report, we found that operative repair was attempted in 26
      patients with tuberculous aortitis of the abdominal (n = 16), thoracic (n = 8),
      and thoracoabdominal (n = 2) aorta. Six patients had emergent operations for
      massive hemoptysis (n = 2), aortoduodenal fistula (n = 2), or abdominal rupture
      (n = 2), with an associated 30-day mortality of 50%. Elective or semi-elective
      repair was undertaken in 20 patients, of whom 19 (95%) survived for at least 30
      days. On the basis of limited experience with this rare entity, in situ graft
      replacement is an appropriate treatment of tuberculous aneurysms and
      pseudoaneurysms of the descending thoracic and abdominal aorta.

PMID- 10398744
TI  - Prosthetic replacement of the inferior vena cava.

PMID- 10398745
TI  - Identification of Tn10 insertions in the rfaG, rfaP, and galU genes involved in
      lipopolysaccharide core biosynthesis that affect Escherichia coli adhesion.
AB  - Escherichia coli was used as a model to study initial adhesion and early biofilm
      development to abiotic surface. Tn10 insertion mutants of Escherichia coli K-12
      W3110 were selected for altered abilities to adhere to a polystyrene surface.
      Seven insertion mutants that showed a decrease in adhesion harbored insertions in
      genes involved in lipopolysaccharide (LPS) core biosynthesis. Two insertions were
      located in the rfaG gene, two in the rfaP gene, and three in the galU gene. These
      adhesion mutants were found to exhibit a deep-rough phenotype and to be reduced,
      at different levels, in type 1 fimbriae production and motility. The loss of
      adhesion exhibited by these mutants was associated with either the affected type
      1 fimbriae production and/or the dysfunctional motility. Apart from the
      pleiotropic effect of the mutations affecting LPS on type 1 fimbriae and flagella
      biosynthesis, no evidence for an involvement of the LPS itself in adhesion to
      polystyrene surface could be observed.

PMID- 10398746
TI  - Stimulation of the multiplication of Micrococcus luteus by an autocrine growth
      factor.
AB  - Viable cells of Micrococcus luteus secrete a proteineous growth factor (Rpf)
      which promotes the resuscitation of dormant, nongrowing cells to yield normal,
      colony-forming bacteria. When washed M. luteus cells were used as an inoculum,
      there was a pronounced influence of Rpf on the true lag phase and cell growth on
      lactate minimal medium. In the absence of Rpf, there was no increase in colony
      forming units for up to 10 days. When the inoculum contained less than 10(5)
      cells ml-1, macroscopically observable M. luteus growth was not obtained in
      succinate minimal medium unless Rpf was added. Incubation of M. luteus in the
      stationary phase for 100 h resulted in a failure of the cells to grow in lactate
      minimal medium from inocula of small size although the viability of these cells
      was close to 100% as estimated using agar plates made from lactate minimal medium
      or rich medium. The underestimation of viable cells by the most-probable-number
      (MPN) method in comparison with colony-forming units was equivalent to the
      requirement that at least 10(5) cells grown on succinate medium, 10(3) cells from
      old stationary phase, or approximately 10-500 washed cells are required per
      millilitre of inoculum for growth to lead to visible turbidity. The addition of
      Rpf in the MPN dilutions led to an increase of the viable cell numbers estimated
      to approximately the same levels as those determined by colony-forming units.
      Thus, a basic principle of microbiology - "one cell-one culture" - may not be
      applicable in some circumstances in which the metabolic activity of "starter"
      cells is not sufficient to produce enough autocrine growth factor to support cell
      multiplication.

PMID- 10398747
TI  - Characterization of IS1389, a new member of the IS3 family of insertion sequences
      isolated from Xanthomonas campestris pv. amaranthicola.
AB  - IS1389, a new insertion sequence belonging to the IS3 family, has been identified
      in Xanthomonas campestris pv. amaranthicola. The genome of this bacterium
      contains at least 11 copies of the element, whereas no hybridizing sequences were
      detected in other Xanthomonas species [X. axonopodis, X. fragaridae, X. phaseoli,
      and X. (Stenotrophomonas) maltophila]. Two nearly identical copies of the element
      (IS1389-A and IS1389-B) were characterized. According to analysis of sequence
      alignments and similar structural features, IS1389 belongs to the IS407 subgroup
      of the IS3 family, which duplicates 4 bp of target DNA upon insertion. IS1389-A
      was found in the proximity of the modification gene of the XamI restriction
      modification system.

PMID- 10398749
TI  - Functional assembly of the lambda S holin requires periplasmic localization of
      its N-terminus.
AB  - Bacteriophage-lambda-induced host-cell lysis requires two phage-encoded proteins,
      the S holin and the R transglycosylase. At a specific time during infection, the
      holin forms a lesion in the cytoplasmic membrane that permits access of the R
      protein to its substrate, the peptidoglycan. The lambda S gene represents the
      prototype of holin genes with a dual-start motif; they encode two proteins, a
      lysis effector and a lysis inhibitor. Although the two S proteins differ only by
      two amino acids (Met-1 and Lys-2) at the N-terminus, the longer product (S107)
      acts as an inhibitor of the lysis effector (S105). The functional difference
      between the proteins has been previously ascribed to the Lys-2 residue in S107.
      It was therefore of interest to determine the subcellular localization of the N
      terminus of either S protein. To study the membrane topology of the S proteins,
      we used the topology probe TEM beta-lactamase and an N-terminal tag derived from
      the Pseudomonas aeruginosa phage Pf3 coat protein. We show that both S proteins
      have a type III (Nout/Cin) topology. The results provide insight into the
      regulatory mechanism imposed by the dual-start motif and will be discussed in
      terms of a model for temporal regulation of the S-dependent "hole" in the
      membrane.http://link.springer-ny.
      com/link/service/journals/00203/bibs/172n1p31.html

PMID- 10398748
TI  - Genetic basis of enterobacterial repetitive intergenic consensus (ERIC)-PCR
      fingerprint pattern in Sinorhizobium meliloti and identification of S. meliloti
      employing PCR primers derived from an ERIC-PCR fragment.
AB  - The enterobacterial repetitive intergenic consensus (ERIC)-PCR method was
      employed to generate genomic amplification products of Sinorhizobium meliloti
      strain 2011. Eleven distinctive PCR fragments obtained in PCR reactions by using
      the ERIC2 primer were cloned and their partial or complete nucleotide sequences
      established. DNA sequences that extended past the ERIC2 primer region were not
      conserved among the 11 PCR fragments and showed no sequence similarity to the
      enterobacterial ERIC consensus sequence. Thus, repetitive ERIC or ERIC-like
      sequences seem not to be an integral part of the S. meliloti genome. An
      amplification product of S. meliloti 2011 was identified which was present in S.
      meliloti strains but absent in other rhizobial species. Based on the nucleotide
      sequence information, a pair of PCR primers was designed and used for PCR
      amplification of sequences of S. meliloti laboratory strains 2011, L5-30, AK631
      and 102F34. Nucleotide sequence analysis of the amplification products revealed a
      100% DNA sequence conservation. Database searches showed that the DNA fragment
      putatively encodes the C-terminal part of a protein displaying similarity to 2
      hydroxyacid dehydrogenases of various organisms. The newly designed PCR primers
      should be useful for the rapid identification of S. meliloti isolates.

PMID- 10398750
TI  - Pheophytinization of bacteriochlorophyll c and energy transfer in cells of
      Chlorobium tepidum.
AB  - Bacteriochlorophyll (BChl) c in whole cells of Chlorobium tepidum grown at 46
      degrees C changed into bacteriopheophytin (BPhe) c within 10 days after reaching
      full growth. When a small amount of C. tepidum cells in which BChl c had been
      completely pheophytinized were transferred to a new culture medium, normal growth
      was observed after a short lag phase, and the absorption spectrum of the growing
      cells showed the presence of a normal amount of BChl c. During the growth of C.
      tepidum in the new culture, the BChl c concentration was nearly proportional to
      the cell density measured by turbidity (OD640). These results indicate that C.
      tepidum can survive even when BChl c has been completely pheophytinized and that
      BChl c is newly synthesized in such cells when transferred to a new culture
      medium. In partly pheophytinized cells, upon excitation of BPhe c at 550 nm the
      fluorescence emission spectrum showed maxima at 775 and 810 nm, which correspond
      to emissions from BChl c and BChl a, respectively. This indicates energy transfer
      from BPhe c to BChl c and BChl a. In cells in which BChl c was completely
      pheophytinized, fluorescence measurements were indicative of direct energy
      transfer from BPhe c to baseplate BChl a. These findings suggest that when BChl c
      in C. tepidum cells is pheophytinized, the product (BPhe c) remains in the
      chlorosomes and continues to work as a light-harvesting pigment.

PMID- 10398751
TI  - Construction of a highly bioluminescent Nitrosomonas as a probe for nitrification
      conditions.
AB  - Cloned luciferase-encoding operons were transferred by conjugation to a natural
      isolate of the ammonia-oxidizing bacterial strain Nitrosomonas sp. RST41-3,
      thereby establishing conjugation as a tool for gene transfer into Nitrosomonas
      strains. Luminescence was dependent on the pH of the medium and the concentration
      of the substrate ammonium chloride. Moreover, the luminescence of the
      transconjugants was reduced immediately by micromolar concentrations of
      nitrapyrin and allylthiourea, which are specific inhibitors of nitrification. Our
      results indicate that luminescent Nitrosomonas strains may be useful as a probe
      to detect nitrification conditions in the natural environment as well as in
      sewage plants.

PMID- 10398752
TI  - Characterization of the interaction of dinitrogenase reductase-activating
      glycohydrolase from Rhodospirillum rubrum with bacterial membranes.
AB  - The interaction of dinitrogenase reductase-activating glycohydrolase (DRAG) with
      bacterial membranes and the solubilization of DRAG in response to nucleotides
      were characterized. Purified DRAG from Rhodospirillum rubrum reversibly bound
      bacterial pellet fractions from Rsp. rubrum and other nitrogen-fixing bacteria.
      DRAG saturated the membrane fraction of Rsp. rubrum at a concentration of 0.2 mol
      DRAG/mol bacteriochlorophyll, suggesting that the DRAG-binding species is
      prevalent in the membrane. DRAG bound poorly to phospholipid vesicles, suggesting
      a protein requirement for DRAG interaction with the membrane. Guanosine and
      uridine tri- and di-nucleotides specifically dissociated DRAG from the pellet
      fractions of Rsp. rubrum and Azotobacter vinelandii, while adenosine nucleotides
      had no dissociative effect. Guanosine 5'-triphosphate dissociated DRAG from the
      membrane at a concentration causing 50% dissociation (EC50) of 5.0 +/- 0.5 mM;
      guanosine disphosphate had an EC50 of 15.0 +/- 2.0 mM. We propose that GTP is a
      potential participant in the regulation of DRAG, possibly controlling the extent
      of DRAG association with the membrane. Keywords Rhodospirillum rubrum. Membrane.
      association. Nitrogenase regulation. Nucleotide bindinghttp://link.springer-ny.
      com/link/service/journals/00203/bibs/172n1p51.html

PMID- 10398753
TI  - Discontinuous expansion linked to sector formation in Pseudomonas aeruginosa
      colonies.
AB  - Colonies of Pseudomonas aeruginosa exhibit sectors that were shown to be located
      at specific intervals within the colony. Maxima in the distribution of sectors
      were observed every 5 mm as measured from the center of the colony. These maxima
      correlated with changes in the expansion rates of colonies. The absolute average
      number of sectors per colony was higher for colonies grown at higher
      temperatures. These results increase our understanding of colony pattern
      formation.

PMID- 10398754
TI  - Restoration of culturability of starvation-stressed and low-temperature-stressed
      Escherichia coli O157 cells by using H2O2-degrading compounds.
AB  - Late-exponential-phase cells of Escherichia coli O157:H- strain E32511/HSC became
      nonculturable in sterilized distilled water microcosms at 4 degrees C. Plate
      counts declined from 3 x 10(6) to less than 0.1 CFU/ml in about 21 days. However,
      when samples of microcosms at 21 days were inoculated onto an agar medium amended
      with catalase or nonenzyme peroxide-degrading compounds such as sodium pyruvate
      or alpha-ketoglutaric acid, plate counts increased to 10(4)-10(5) CFU/ml within
      48 h. The proposed mode of action of the catalase or pyruvate is via the
      degradation of the metabolic by-product H2O2, rather than through supplementation
      of a required nutrient in the recovery of nonculturable cells. Our studies were
      based on the assumption that E32511/HSC strain responds to starvation and a low
      temperature by entering a nonculturable state and that the correction of
      oxidative stress upon the inoculation of bacteria on agar plates promotes
      recovery of nonculturable cells.

PMID- 10398755
TI  - Endogenous ion channels in oocytes of xenopus laevis: recent developments.

PMID- 10398756
TI  - Characterization of a P-type copper-stimulated ATPase from mouse liver.
AB  - Mouse liver microsomes treated with octylthioglucoside (OTG-microsomes) were
      examined for copper-stimulated ATPase activity. The activity was about 1 micromol
      Pi/mg protein/hr under optimal conditions [300 mM KCl, 3 mm MgSO4, 10 mM GSH, 0.5
      micron CuSO4, 3 mM ATP and 50 mM acetate buffer at pH5.0]. A reducing agent such
      as GSH or dithiothreitol was required for the activity, and removal of Cu+ from
      the reaction mixture by bathocuporinedisulfonate resulted in a complete loss of
      copper-stimulated ATPase activity. Vanadate inhibited the copper-stimulated
      ATPase activity. The OTG-microsomes were phosphorylated in a hydroxylamine
      sensitive and copper-stimulated way. Iron used instead of copper also stimulated
      both ATPase and phosphorylation. These results suggest that microsomes from mouse
      liver contain copper/iron-stimulated P-type ATPase.

PMID- 10398758
TI  - Directly observed membrane fusion between oppositely charged phospholipid
      bilayers.
AB  - A novel method was developed for the direct examination of pairwise encounters
      between positively and negatively charged phospholipid bilayer vesicles. Giant
      bilayer vesicles (unilamellar, 4-20 micron in diameter) prepared from 1,2
      dioleoyl-sn-glycero-3-ethylphosphocholine, a new cationic phospholipid
      derivative, were electrophoretically maneuvered into contact with individual
      anionic phospholipid vesicles. Fluorescence video microscopy revealed that such
      vesicles commonly underwent fusion within milliseconds (1 video field) after
      contact, without leakage. Fusion occurred at constant volume and, since flaccid
      vesicles were rare, the excess membrane was not available after fusion.
      Hemifusion (the outer monolayers of each vesicle fused while the inner monolayers
      remained intact) was inferred from membrane-bound dye transfer and a change in
      the contact area. Hemifusion was observed as a final stable state and as an
      intermediate to fusion of vesicles composed of charged phospholipids plus
      zwitterionic phospholipids. Hemifusion occurred in one of three ways following
      adhesion: either delayed with an abrupt increase in area of contact, immediately
      with a gradual increase in area of contact, or with retraction during which
      adherent vesicles dissociated from a flat contact to a point contact.
      Phosphatidylethanolamine strongly promoted immediate hemifusion; the resultant
      hemifused state was stable and seldom underwent complete fusion. Although
      sometimes single contacts between vesicles led to rupture of both, in other
      cases, a single vesicle underwent multiple fusion events. Direct observation has
      unequivocally demonstrated the fusion of two, isolated bilayer-bounded bodies to
      yield a stable, non-leaky product, as occurs in cells, in the absence of
      proteins.

PMID- 10398757
TI  - Rapid effects of aldosterone on sodium-hydrogen exchange in isolated colonic
      crypts.
AB  - Aldosterone plays a central role in the homeostatic regulation of extracellular
      fluid volume by stimulating transepithelial electrolyte transport. These effects
      involve binding to an intracellular receptor, modification of genomic events and
      protein synthesis. Rapid cellular responses to steroid hormones have been
      observed in a variety of nonepithelial tissues. The term "nongenomic" has been
      proposed for these fast steroid responses since they are unaffected by inhibitors
      of protein synthesis. We hypothesized that colonic crypts, recently demonstrated
      to absorb fluid, would respond rapidly to aldosterone. Cytoplasmic pH changes in
      crypts loaded with a pH-sensitive, fluorescent dye (BCECF) were recorded with
      confocal laser imaging. An intracellular alkalization of colonic crypts was
      observed within one minute of aldosterone application that was inhibited by
      ethylisopropylamiloride or the absence of extracellular sodium, yet unaffected by
      inhibitors of protein synthesis. The genesis of this rapid and distinct steroid
      action involves a signal transduction pathway that involves G proteins, protein
      kinase C, and prostaglandins. We have identified, by real-time imaging, a
      nongenomic upregulation of sodium-hydrogen exchange in colonic crypts by
      aldosterone that occurs independent of the traditional receptor. This distinct,
      rapid onset effect of aldosterone on epithelial ion transport has major
      implications for our understanding of fluid and electrolyte homeostasis in health
      and disease.

PMID- 10398759
TI  - Cardiac sarcalumenin: phosphorylation, comparison with the skeletal muscle
      sarcalumenin and modulation of ryanodine receptor.
AB  - Cardiac sarcoplasmic reticulum (SR) contains an endogenous phosphorylation system
      that under specific conditions phosphorylates two proteins with apparent
      molecular masses of 150 and 130 kDa. The conditions for their phosphorylation are
      as for the skeletal muscle sarcalumenin and the histidine-rich Ca2+ binding
      protein (HCP) with respect to: (i) Ca2+ and high concentrations of NaF are
      required; (ii) phosphorylation is obtained with no added Mg2+ and shows a similar
      time course and ATP concentration dependence; (iii) inhibition by similar
      concentrations of La3+; (iv) phosphorylation is obtained with [gamma-32P]GTP; (v)
      ryanodine binding is inhibited parallel to the phosphorylation of the two
      proteins. The endogenous kinase is identified as casein kinase II (CK II) based
      on its ability to use GTP as effectively as ATP, and its inhibition by La3+. The
      association of CK II with the cardiac SR, even after EGTA extraction at alkaline
      pH, is demonstrated using antibodies against CK II. The cardiac 130 kDa protein
      is identified as sarcalumenin based on its partial amino acid sequence and its
      blue staining with Stains-All. Cardiac sarcalumenin is different from the
      skeletal muscle protein based on electrophoretic mobilities, immunological
      analysis, peptide and phosphopeptide maps, as well as amino acid sequencing.
      Preincubation of SR with NaF and ATP, but not with NaF and AMP-PNP caused strong
      inhibition of ryanodine binding. This is due to decrease in Ca2+- and ryanodine
      binding affinities of the ryanodine receptor (RyR) by about 6.6 and 18-fold,
      respectively. These results suggest that cardiac sarcalumenin is an isoform of
      the skeletal muscle protein. An endogenous CK II can phosphorylate sarcalumenin,
      and in parallel to its phosphorylation the properties of the ryanodine receptor
      are modified.

PMID- 10398760
TI  - Rescue of dysfunctional deltaF508-CFTR chloride channel activity by IBMX.
AB  - Nucleotide-dependent gating of DeltaF508-CFTR was evaluated in membrane patches
      excised from HEK 293 and mouse L-cells and compared to observations on wt-CFTR
      channels recorded in the same expression systems. DeltaF508-CFTR exhibited PKA
      activated, ATP-dependent channel gating. When compared to wt-CFTR, the Km for ATP
      was increased by ninefold (260 micron vs. 28 micron) and maximal open probability
      (Po) was reduced by 49% (0.21 +/- 0.06 vs. 0.41 +/- 0. 02). Additionally, in the
      absence of PKA, DeltaF508-CFTR inactivated over a 1 to 5 min period whereas wt
      CFTR remained active. Time-dependent inactivation could be mimicked in wt-CFTR by
      the intermittent absence of ATP in the cytosolic solution. The effects of 3
      isobutyl-1-methyl xanthine (IBMX), a compound reported to stimulate DeltaF508
      CFTR, were evaluated on wt- and DeltaF508-CFTR channels. At concentrations up to
      5 mm, IBMX caused a concentration dependent reduction in the observed single
      channel amplitude (i) of wt-CFTR (maximal observed reduction 35 +/- 3%). However,
      IBMX failed to significantly alter total patch current because of a concomitant
      30% increase in Po. The effects of IBMX on DeltaF508-CFTR were similar to effects
      on wt-CFTR in that i was reduced and Po was increased by similar magnitudes.
      Additionally, DeltaF508-CFTR channel inactivation was dramatically slowed by
      IBMX. These results suggest that IBMX interacts with the ATP-bound open state of
      CFTR to introduce a short-lived nonconducting state which prolongs burst duration
      and reduces apparent single channel amplitude. A secondary effect observed in
      DeltaF508-CFTR, which may result from this interaction, is a prolongation of the
      activated state. In light of previously proposed linear kinetic models of CFTR
      gating, these results suggest that IBMX traps CFTR in an ATP-bound state which
      may preclude inactivation of DeltaF508-CFTR.

PMID- 10398762
TI  - Transitional changes in membrane potential and intracellular [Ca2+] in rat
      basophilic leukemia cells.
AB  - Using whole-cell current-clamp measurements we have found that thapsigargin
      mediated activation of store-regulated Ca2+ entry in rat basophilic leukemia
      cells is accompanied by complex changes in membrane potential. These changes
      consisted of: (i) an initial slow, small depolarization, (ii) a transitional
      change in potential to a depolarized value and (iii) transitional changes between
      a hyperpolarized and a depolarized potential. These complex changes in potential
      can be explained by the interaction between the endogenous inwardly rectifying K+
      conductance and the generation of a small inward current. To investigate the
      possible influence of these changes of potential on [Ca2+]i, single cell
      measurements of fura2 fluorescence were undertaken alone or in combination with
      current-clamp measurements. Thapsigargin-mediated activation of the store
      regulated Ca2+ entry pathway was accompanied by a marked increase of [Ca2+]i.
      During this increase, transient, abrupt declines in [Ca2+]i were detected in
      approximately 60% of the cells investigated. These changes of [Ca2+]i are
      consistent with the observed changes of membrane potential recorded under current
      clamp.

PMID- 10398761
TI  - Beta1-adrenergic receptors but not beta2-adrenergic or vasopressin receptors
      regulate K+ secretion in vestibular dark cells of the inner ear.
AB  - Receptors were identified pharmacologically in functional studies where K+
      secretion was monitored as transepithelial current (Isc). Further, receptors were
      identified as transcripts by cloning and sequencing of reverse-transcriptase
      polymerase chain reaction (RT-PCR) products. Isc under control conditions was 796
      +/- 15 microA/cm2 (n = 329) in gerbilline VDC and 900 +/- 75 microA/cm2 (n = 6)
      in murine VDC. Forskolin (10(-5) m) but not 1, 9-dideoxy-forskolin increased Isc
      by a factor of 1.42 +/- 0.05 (n = 7). 10(-9) m Arg8-vasopressin and 10(-9) m
      desmopressin had no significant effect in gerbilline and murine VDC.
      Isoproterenol, norepinephrine, epinephrine and prenalterol stimulated Isc
      maximally by a factor of 1.38 +/- 0.04 (n = 7), 1.59 +/- 0.06 (n = 6), 1.64 +/-
      0.03 (n = 8) and 1.37 +/- 0.03 (n = 6), respectively. The EC50 values were (1.4
      +/- 0.7) x 10(-8) m (n = 36), (2.5 +/- 1.0) x 10(-8) m (n = 31), (1.7 +/- 0.7) x
      10(-7) m (n = 36) and (5 +/- 4) x 10(-7) m (n = 32), respectively. Propanolol
      inhibited isoproterenol-induced stimulation of Isc. Atenolol, ICI118551 and
      CGP20712A inhibited isoproterenol-induced stimulation of Isc with a pKDB of 5.0 x
      10(-8) m (pKDB = 7.30 +/- 0.07, n = 38), 4.4 x 10(-8) m (pKDB = 7.36 +/- 0.14, n
      = 37) and 6.8 x 10(-12) m (pKDB = 11.17 +/- 0.12, n = 37), respectively. RT-PCR
      of total RNA isolated from microdissected vestibular labyrinth tissue using
      specific primers revealed products of the predicted sizes for beta1- and beta2
      adrenergic receptors but not for beta3-adrenergic receptors. Sequence analysis of
      the amplified cDNA fragments from gerbilline tissues revealed a 96.4%, 91.5% and
      89.6% identity compared to rat beta1-, beta2- and beta3-adrenergic receptors,
      respectively. These results demonstrate that K+ secretion in VDC is under the
      control of beta1- but not beta2- or beta3-adrenergic receptors or vasopressin
      receptors.

PMID- 10398763
TI  - Assessment of PCBs and hydroxylated PCBs as potential xenoestrogens: In vitro
      studies based on MCF-7 cell proliferation and induction of vitellogenin in
      primary culture of rainbow trout hepatocytes.
AB  - In the present study, four structurally diverse polychlorinated biphenyls (PCBs)
      were chosen from a set of 20 PCBs selected to represent the 154 tetra- through
      hepta-chlorinated biphenyls. The purpose was to determine estrogenic activities
      of the chosen PCBs and five of their hydroxylated derivatives (OH-PCBs). A human
      breast cancer cell line (MCF-7) and primary cultures of rainbow trout
      (Oncorhyncus mykiss) hepatocytes were used to determine estrogenic effects. The
      PCBs 2,2',4,6,6'-pentachlorobiphenyl (104) and 2,2',3, 4', 5,6,6'
      heptachlorobiphenyl (188), and the hydroxylated PCBs 2,2', 4',6'-tetrachloro-4
      biphenylol (4'-50), 2',4', 6'-trichloro-4-biphenylol (4'-30), 2',3,5, 5'
      tetrachloro-4-biphenylol (4'-72), 2',3,3',5', 6'-pentachloro-4-biphenylol (4'
      112), and 2',3,4',5, 6'-pentachloro-4-biphenylol (4'-121) significantly increased
      MCF-7 cell proliferation. The coaddition of hydroxytamoxifen, an estrogen
      antagonist, inhibited increased cell proliferation. The activity of the
      hydroxylated PCBs 4'-50 and 4'-30 was significantly higher at all nominal
      concentrations tested as compared to the corresponding PCB, viz., PCB 104. The
      hydroxylated PCBs 4'-50, 4'-30, 4'-72 and 4'-112 induced vitellogenin synthesis
      in rainbow trout hepatocytes. Significant differences were found in the MCF-7
      system between the parent PCB and its hydroxylated derivative, viz., for 4'-50/4'
      30 and 104, and in the rainbow trout hepatocyte assay between 4'-112 and 112,
      respectively. No activity was observed for PCB 58 in any of the two assays in the
      present study. Even though cells from two different species (human and fish) are
      used in the present study, the results obtained by the two methods agree fairly
      well. In both studies the hydroxylated PCBs were more active than the PCBs, and
      4'-30 was the most active compound second only to 17beta-estradiol.
      http://link.springer-ny. com/link/service/journals/00244/bibs/37n2p145.html

PMID- 10398764
TI  - Characterization of alpha-pinene-degrading microorganisms and application to a
      bench-scale biofiltration system for VOC degradation 
AB  - A study was conducted to isolate and characterize monoterpene-degrading
      microorganisms and apply them to a biofiltration unit for use in degrading high
      levels of alpha-pinene. Soil from a monoterpene-contaminated site was used with
      enrichment culture techniques to recover a consortium of bacteria able to utilize
      alpha-pinene as the sole source of carbon and energy. The Biolog system was
      utilized to identify the bacteria as Pseudomonas fluorescens and Alcaligenes
      xylosoxidans. Aerobic growth and biodegradation studies confirmed that rapid
      growth and biodegradation were being achieved with alpha-pinene. Complete
      degradation of alpha-pinene was achieved in 36 h with a maximum rate of
      degradation of 3.9 mg/L/h. The microorganisms were placed in a biofiltration
      column and demonstrated good removal of alpha-pinene from an air stream at
      concentrations averaging 295 ppmv. A nitrogen test was performed and confirmed
      that the removal of alpha-pinene was due to biological activity. Given the
      ability of these microorganisms to utilize high levels of alpha-pinene, they will
      be used in a coupled treatment system using a physical/chemical
      adsorption/desorption unit coupled to a biofiltration column. Often,
      biofiltration studies are performed using much lower levels of analyte in the
      influent air stream. However, the ability of these microorganisms to utilize
      higher levels of compounds expands the capabilities for future coupled
      biofiltration systems. During future studies, high flow rates with low levels of
      analyte will be concentrated so that a higher analyte concentration and lower
      flow rate can be utilized with the biofilter.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p151.html

PMID- 10398765
TI  - Biodegradability of cefotiam, ciprofloxacin, meropenem, penicillin G, and
      sulfamethoxazole and inhibition of waste water bacteria 
AB  - Most antibiotics are metabolized only incompletely by patients after
      administration and enter the municipal sewage with the patients' excretions.
      Little is known about their biodegradability in aquatic environments and their
      role with respect to growing bacterial resistance. Therefore, the
      biodegradability of some clinically important antibiotic drugs as a very first
      step of an environmental risk assessment was investigated with the OECD closed
      bottle test (CBT). To assess toxicity of the test compounds against aquatic
      bacteria (1) a growth inhibition test (GIT) with Pseudomonas putida was
      conducted; (2) a toxicity control was used in the CBT; and (3) the colony-forming
      units (CFUs) were monitored in the test vessels. Theoretical concentrations of
      the test substances in hospital effluents were calculated and compared with
      minimum inhibitory concentrations for susceptible pathogenic bacteria. None of
      the test compounds met the criteria for ready biodegradability. Only penicillin G
      was biodegradable to some degree (27%), even when the test was prolonged from 28
      to 40 days (35%). The inhibition concentrations measured in the GIT were in the
      same range or lower than the 50% minimum inhibitory concentrations (MIC50) known
      for susceptible pathogenic bacteria. CFU monitoring revealed high toxicity for
      sulfamethoxazole, whereas ciprofloxacin had a weak but significant effect; only
      for meropenem a weak but significant effect was measured in the toxicity control
      of the CBT. MIC50 published for susceptible pathogenic bacteria were for all
      compounds in the same range as the concentrations expected for hospital
      effluents. Therefore, antibiotic drugs emitted into municipal sewage may affect
      the biological process in sewage treatment plants (STPs), and they may persist in
      the aquatic environment and contribute to the increasing resistance of pathogenic
      bacteria.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p158.html

PMID- 10398766
TI  - Bioassay-directed identification of organic toxicants in river sediment in the
      industrial region of bitterfeld (Germany)-A contribution to hazard assessment 
AB  - Bioassay-directed identification of toxicants in an acetonic extract of a
      sediment of the riverine Spittelwasser in the industrial region of Bitterfeld
      (Germany) was conducted. For this purpose, a combination of chromatographical
      fractionation, chemical analysis, and a biotest battery including Vibrio fischeri
      (inhibition of bioluminescence), Daphnia magna (immobilization), and Scenedesmus
      vacuolatus (inhibition of cell multiplication) was applied. Major toxicants
      identified and confirmed were methyl parathion (D. magna), prometryn, N-phenyl
      beta-naphthalene amine, PAHs (S. vacuolatus), and tributyltin (all biotests).
      Toxicity to V. fischeri was dominated by elemental sulfur. Results indicate high
      toxicant loads in the sediment about 7 years after closedown of a majority of
      chemical production sites at Bitterfeld. Comparison of potential exposure and
      toxicity data indicate a severe hazard potential to aquatic organisms due to
      organic toxicants. The results illustrate the potency of a biotest battery for
      identification of toxicants in contaminated sediment within the frame of toxicity
      identification procedures.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p164.html

PMID- 10398767
TI  - Fluctuating life-history parameters indicating temporal variability in metal
      adaptation in riverine chironomids 
AB  - Adaptation to toxicants in animal populations is influenced primarily by two
      counteracting forces. First, the intensity and duration of peak concentrations of
      toxicants is responsible for the actual level of selection pressure on the
      population. Second, the process of adaptation can be disrupted by gene flow as a
      result of crossings with nontolerant individuals. These counteracting forces were
      analyzed in riverine insects in which we expected that the level of metal
      adaptation is subject of considerable fluctuations, due to variable dilution of
      metals and a variable transport of nontolerant individuals in river water. To
      this purpose, the stability of metal adaptation in different Chironomus riparius
      populations was analyzed during a 5-month period in a heavily polluted lowland
      river. This was examined by measuring mortality, larval dry weight, and
      accumulation of zinc under laboratory conditions. The results showed that in
      midge populations originating from metal-contaminated field sites several life
      history parameters (like control mortality and growth response under cadmium
      exposure) of the laboratory reared F1 generations showed considerable temporal
      variation. In addition, the presence of metal-adapted midge populations was
      indicated on several occasions on the metal-exposed field sites. Reference
      populations on the other hand, showed stable life history patterns throughout the
      sampling period, and no signs of metal adaptation were found. These observations
      showed that the actual level of metal adaptation varies considerably, both in
      time and space. Adaptation to metals in riverine chironomids, therefore, should
      be looked on as a highly dynamic process.http://link. springer
      ny.com/link/service/journals/00244/bibs/37n2p175.html

PMID- 10398768
TI  - Triad assessment of the impact of chromium contamination on benthic
      macroinvertebrates in the chusovaya river (Urals, russia) 
AB  - The impact of chromium (Cr) contamination on the benthic macroinvertebrate
      community of the Chusovaya River in the Ural Mountains of Russia was assessed
      using a triad approach. The triad consisted of chemical analysis of the
      contamination in various environmental compartments, examination of the benthic
      macroinvertebrate community structure, and analysis of ecotoxicological effects
      on the caddisfly Hydropsyche pellucidula (Trichoptera). Chemical analyses of
      water, sediments, and detritus indicated that the main contaminant present was
      indeed Cr and that the level of the Cr contamination near the point source, a
      severely polluted dead tributary, was extremely high: Downstream Cr
      concentrations were about 450 times higher in water and 25 times higher in
      sediments compared with a clean reference site upstream. The contamination at the
      mouth of the tributary was even more severe: 800 times more Cr in water and 50
      times more Cr in sediments. Benthic macroinvertebrate community structure was
      studied using artificial substrates colonized in situ. Lower species richness was
      observed at the downstream site compared with the upstream site. Larvae of H.
      pellucidula collected from the contaminated site on the river bioaccumulated
      large amounts of Cr and exhibited physical abnormalities. The incidence of
      tracheal gill damage was significantly higher than at a reference site on the
      nearby Reshotka River, as was the incidence of discoloration of the anal papillae
      of these animals. The application of a triad demonstrated that the observed
      extreme Cr contamination had an adverse effect on aquatic life in the Chusovaya
      River, both at the community level (reduced diversity) and at the level of
      individuals (sublethal effects on surviving individuals).http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p182.html

PMID- 10398769
TI  - Experimental studies on lead accumulation in the eel-specific endoparasites
      Anguillicola crassus (Nematoda) and Paratenuisentis ambiguus (Acanthocephala) as
      compared with their host, Anguilla anguilla.
AB  - The effect of salinity and the mode of application (oral versus aqueous) on the
      lead accumulation in different tissues of the fish host eel (Anguilla anguilla)
      and its parasites Anguillicola crassus (Nematoda) and Paratenuisentis ambiguus
      (Acanthocephala) was investigated. Waterborne as well as dietary lead exposure
      caused an increase in the metal levels of different eel tissues and the
      parasites. The mode of lead application had a significant influence on the
      distribution of lead in the fish tissues. No significant difference on the lead
      concentration due to water salinity was found for the fish tissues. Among the
      analyzed tissues and helminths, the intestinal acanthocephalan P. ambiguus
      contained the significantly highest amounts of lead, which were affected by
      neither the mode of application nor the water salinity. In contrast, the lead
      level of the nematode A. crassus dwelling in the swim bladder of eels was even
      below the levels detected for host liver, intestine, and bile. Thus, depending on
      the mode of lead application, the resulting metal concentrations were
      approximately 20 to 2,000 times higher in P. ambiguus than in A. crassus. These
      differences may be due to the different microhabitats and nutrient uptake
      mechanisms of both parasite species. This study presents important new facts for
      the use of intestinal fish parasites as biological indicators for water quality,
      not only in freshwater, but also in marine and estuarine ecosystems. The
      combination of the results obtained from the host and the parasites could reveal
      a more detailed tool to ascertain the source of an environmental contamination
      than a study based on a single species.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p190.html

PMID- 10398771
TI  - Analyses of tissues of eight marine species from Atlantic and Pacific coasts for
      dioxin-like chlorobiphenyls (CBs) and total CBs.
AB  - Eight commercially and recreationally important marine species were collected in
      1993 and 1994 from several Atlantic and Pacific coastal regions of the contiguous
      United States. Approximately 700 edible tissue samples (e.g., whole body of
      mussel, crustacean muscle and hepatopancreas, and fish muscle) were analyzed for
      dioxin-like chlorobiphenyls (CBs) and other selected CB congeners using a rapid
      high-performance liquid chromatography photodiode array detection method
      (HPLC/PDA). Total CBs and toxic equivalents (TEQs) of dioxin-like CBs were also
      determined. The most abundant congeners measured in these tissues were the
      moderately chlorinated CBs (e.g., CB 138, 153), with mean concentrations ranging
      from below the limits of detection (approximately 0.2 ng/g) to 1,500 ng/g, wet
      weight. Certain dioxin-like CBs (e.g., CBs 77, 105, 118, 126) were also found in
      several of these samples (mean concentrations ranging from below the limits of
      detection [approximately 0.4 ng/g] to 680 ng/g). Similar to previous studies, the
      majority of seafood tissues contained total CB concentrations that were below the
      U.S. Food and Drug Administration's (FDA) tolerance limit for CBs of 2,000 ng/g,
      wet weight (2.0 ppm). Furthermore, the majority of samples that contained CB
      levels below the FDA CB tolerance limit also had CB TEQs that were lower than the
      FDA's advisory level for TCDD (25 ppt or 25 pg/g, wet weight) in fish from the
      Great Lakes, which is used in evaluating CB TEQs. Several crustacean
      hepatopancreas samples collected from certain Atlantic and Pacific urban sites
      (e.g., Dungeness crab from Elliott Bay in Puget Sound, WA, American lobster from
      Deer Island in Boston Harbor, MA), however, did contain total CB and CB TEQs that
      exceeded the FDA CB tolerance and TCDD advisory limits. Mono-ortho- (e.g., CBs
      118, 105) and non-ortho-substituted congeners (e.g., CBs 77 and 126) were the
      largest contributors to the CB TEQs of the hepatopancreas samples that exceeded
      the action limit.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p205.html

PMID- 10398770
TI  - Bioaccumulation and subchronic physiological effects of waterborne iron overload
      on whitefish exposed in humic and nonhumic water.
AB  - One-year-old whitefish, Coregonus lavaretus, were exposed to three types of iron
      rich water, two dilutions for each, in a subchronic (30-day) experiment. In
      natural iron-rich humic water, both the bioaccumulation and physiological effects
      of iron exposure were negligible. In humic-free water with high amount of
      additional inorganic iron (nominally 8 mg Fe/L), Fe accumulated in gills, liver,
      and gut. This accumulation was accompanied by decreased glycogen phosphorylase
      activities and microsomal EROD activity in the liver as well as decreased plasma
      sodium and potassium concentrations. The third group of whitefish were exposed by
      adding inorganic iron (nominally 2 and 8 mg Fe/L) to natural iron-rich humic
      water. Fish exposed to the higher concentration of waterborne iron exhibited a
      physiological stress response as indicated by increased blood lactate and plasma
      cortisol concentrations. Additionally, plasma 17beta-estradiol concentration was
      increased in fish kept in both water conditions with high amounts of additional
      iron. The observed dissimilarities in bioaccumulation and in physiological
      responses were not connected with the measured amounts of total or dissolved iron
      in water, but to the amount of additional iron in tanks and to the different
      water conditions with or without organic matter. The dissimilarity of
      physiological responses, which was also shown by statistical classification
      through multivariate discriminant analysis, points to the necessity of variable
      and complementary physiological endpoints in describing the effects of similar
      kind of exposures.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p196.html

PMID- 10398772
TI  - Development and application of a high-performance liquid chromatography screening
      method for aromatic compounds in invertebrate tissues 
AB  - Contamination of marine invertebrates by aromatic compounds (ACs) can occur from
      a variety of environmental sources, both natural and anthropogenic. Invertebrate
      species bioaccumulate ACs because they metabolize and eliminate them at a much
      slower rate than do vertebrates, such as fish. We have developed a high
      performance liquid chromatography (HPLC) UV fluorescence screening method that
      measures ACs in invertebrate tissues. Screening methods have proven to be useful
      in response to environmental emergencies (e.g., oil spills) and in environmental
      monitoring because they are more rapid and less expensive than detailed analyses.
      This method was validated using three species of bivalves and lobster
      hepatopancreas and tail muscle as test samples. The AC screening method at
      naphthalene, phenanthrene, and benzo[a]pyrene wavelength pairs showed good
      correlation to GC/MS results. The method was also used successfully in response
      to the North Cape oil spill, off Narragansett, Rhode Island.http://link.springer
      ny. com/link/service/journals/00244/bibs/37n2p220.html

PMID- 10398773
TI  - Developmental effects of urban storm water in Medaka (Oryzias latipes) and inland
      silverside (Menidia beryllina).
AB  - Stormwater runoff in a coastal urban area (San Diego County, CA) produced
      significant toxicity to early life stages of medaka (Oryzias latipes) and Menidia
      (M. beryllina). Exposure of embryos to lower concentrations (5 to 25%) increased
      the incidence of abnormal swim bladder inflation and other teratogenic responses,
      whereas higher concentrations resulted in mortality or failure to hatch.
      Comparisons of EC50s for mortality and failure to hatch with concentrations of
      individual chemical pollutants (including Cd, Cr, Cu, Pb, Ni, and Zn) revealed
      low correlations; however, the correlation with total metals was high (-0.84) and
      corresponded with sample exceedences of Water Quality Criteria (WQC) for Cd, Cu,
      Pb, and Zn. This strong association between developmental toxicity and toxic
      metal content of storm water compared favorably with developmental anomalies
      reported in other studies. Analytical chemistry data for pesticides that may have
      been in these samples were limited to selected pesticides found usually below
      detection limits. Greater toxicity of the watershed effluents sampled was
      generally associated with more developed land surface and less open space. Both
      medaka and Menidia were found to be useful for studying effects of stormwater on
      embryonic and early larval development. http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p227.html

PMID- 10398774
TI  - Biomarkers of oxidative stress and genotoxicity in livers of field-collected
      brown bullhead, Ameiurus nebulosus.
AB  - The objective of this investigation was to determine whether differences in a
      suite of biomarker assays in brown bullhead liver tissues could be detected and
      related to the pollution histories of two Ohio locations, one a reach of the
      Black River that had historically been severely impacted by the effluents of a
      coking plant, the other at Old Woman Creek, a freshwater estuarine research
      preserve. There were no gross differences in pathologies detectable in fish from
      either site, and the major difference found in bullheads at the two sites was in
      the relative liver weight (RLW). Differential responses of glutathione reductase,
      glutathione-S-transferase, Se-dependent glutathione peroxidase, Se-independent
      glutathione peroxidase, and oxidized glutathione have been reported between fish
      from contaminated and uncontaminated sites in other studies, but no such
      differences were observed in the present study. Of the oxidative stress
      biomarkers included in this investigation, only the responses of superoxide
      dismutase, catalase, and total glutathione appeared to correlate with
      environmental exposure of brown bullhead to polycyclic aromatic hydrocarbons.
      Results with single-strand DNA and ethoxyresorufin-O-deethylase were the reverse
      of what has been reported in most other studies, and may reflect adaptation of
      the fish at the previously highly contaminated site. The fish at the Black River
      site appear to have responded to the xenobiotics present in their environment by
      increasing their overall liver size, thereby increasing the overall amount of
      enzymes rather than altering the specific activity of a select set of protective
      enzymes.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p236.html

PMID- 10398776
TI  - Interaction between phenanthrene and zinc in their toxicity to the sheepshead
      minnow (Cyprinodon variegatus).
AB  - Many contaminated sites contain a variety of toxicants. Risk assessment and the
      development of water quality criteria therefore require information on the
      interactive effects among toxicants in such mixtures. Interactions between metals
      are relatively well studied, but little is known about interactions between
      metals and hydrocarbons. This study investigated the interaction between
      phenanthrene and zinc in the sheepshead minnow Cyprinodon variegatus. Interaction
      studies were performed with 7-day-old minnows in 96-h bioassays with zinc and
      phenanthrene at a fixed ratio and with varying proportions of zinc and
      phenanthrene. Mixture toxicity was quantified with the toxic unit, additive
      index, and excess function methods. All three methods generally indicated an
      antagonistic interaction between phenanthrene and zinc, though the results also
      provide some evidence for a synergistic interaction at low toxicant levels or at
      specific phenanthrene-to-zinc ratios. Short-term uptake experiments were
      conducted to determine if the strong antagonistic interaction observed when zinc
      and phenanthrene were present at 50% of their LC50 values was due to effects of
      zinc and phenanthrene on each other's uptake. Significantly less 65Zn uptake
      occurred in the presence of phenanthrene than in its absence. In contrast, zinc
      did not appear to affect the uptake of 14C-phenanthrene.http://link. springer
      ny.com/link/service/journals/00244/bibs/37n2p251.++ +html

PMID- 10398775
TI  - PCB and PAH impacts on cytochrome P-450-dependent oxidases in roach (Rutilus
      rutilus) from the Seine River (France).
AB  - Roach were sampled in the Seine River along a gradient of polyaromatic
      hydrocarbon (PAH) concentrations at three stations: Marnay upstream of Paris and
      Epinay and Poses downstream of Paris. Two hepatic monooxygenase activities: EROD
      (ethoxyresorufine-O-deethylase) and AE (aldrin epoxydase) and muscle residues of
      PCBs and PAHs were investigated during three periods of the year (before
      spawning, during spawning, and postspawning). Before spawning, EROD and AE
      activities were significantly correlated with muscle PCB levels (p </= 0.05 for
      both activities) and with muscle PAH levels (p </= 0.05 for both activities) at
      the three stations. Cd was not inversely related to monooxygenase activities.
      During spawning, enzymatic activities remained low and were not correlated to
      pollutant levels. Postspawning EROD and AE activities were again significantly
      related to muscle PCBs (p </= 0. 05 for both activities). Thus, investigations of
      EROD and AE activities may be considered as a reliable tool for biomonitoring of
      PCB or PAH exposure, as far as appropriate conditions are observed.
      http://link.springer-ny. com/link/service/journals/00244/bibs/37n2p242.html

PMID- 10398777
TI  - Life-cycle toxicity of bis(tributyltin) oxide to the sheepshead minnow
      (Cyprinodon variegatus).
AB  - The effects of tributyltin (TBT) to the life cycle of the estuarine fish
      Cyprinodon variegatus were examined in a 180-day flow-through exposure. The study
      was initiated with embryos less than 24 h postfertilization and monitored through
      hatch, maturation, growth, and reproduction under continuous exposure to mean
      measured TBT concentrations of 5.4, 3.2, 1.3, 0.66, and 0.41 microg TBT/L.
      Progeny isolated at the onset of reproduction by the parental generation (F0)
      were monitored for survival as embryos, survival as fry/juveniles, and growth 30
      days postisolation. TBT, at a concentration of 5.4 microg/L, significantly
      reduced embryo survival of the F0 generation sheepshead minnows. By day 145 of
      the exposure, significant effects to the survival of this generation increased
      and included all test concentrations >/=0.66 microg/L. Survival of 0.66 microg/L
      was reduced 59% relative to control survival by termination of the F0 generation.
      Growth of F0 generation organisms as measured by standard length was
      significantly reduced only on day 90 at 3.2 microg/L, however no significant
      reductions of wet or dry weight related to treatment concentration were detected.
      Due to complete mortality of organisms exposed to 5.4 microg/L by study day 7,
      effects to fecundity and progeny were monitored at measured concentrations of
      3.2, 1.3, 0.66, and 0.41 microg TBT/L. Fecundity, as measured by the production
      of viable eggs produced per female per day, was unaffected by any of the test
      treatments. All F1 generation embryos isolated from treatment chambers into 3.2
      microg/L died. Survival, standard length, wet and dry weight of the F1 generation
      at the remaining treatment concentrations were unaffected. The results of this
      study indicate that exposure to TBT reduced survival of the F0 generation
      sheepshead minnow and establishes the lowest observed effect concentration (LOEC)
      as 0.66 microg TBT/L, and the no observed effect concentration (NOEC) as 0.41
      microg TBT/L for this species.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p258.html

PMID- 10398778
TI  - Concentrations of lead in liver, kidney, and bone of bald and golden eagles.
AB  - The diagnosis of lead poisoning in eagles relies on autopsy information and
      residue analysis of lead in certain tissues, usually liver or blood. Similarly,
      the assessment of elevated lead exposure in eagles depends on the determination
      of lead concentrations in these tissues. Renal and bone lead concentrations have
      rarely been examined in eagles. We examined relationships among hepatic, renal,
      and bone lead concentrations in bald and golden eagles from the Canadian prairie
      provinces. Hepatic and renal lead concentrations were strongly related (R2 =
      0.87) while those in liver and bone were significantly but poorly related (R2 =
      0.22). Renal lead concentrations of 5 and 18 microg x g-1 (dry weight)
      corresponded to hepatic lead concentrations of 6 and 30 microg x g-1, the hepatic
      concentrations that we used as criterion levels associated with elevated lead
      exposure and death from lead poisoning, respectively. Lead was elevated in 19 of
      119 and 21 of 109 liver and kidney samples, respectively. Of these 19 and 21
      liver and kidney samples, 14 and 11, respectively, had lead concentrations
      compatible with death from lead poisoning. Taken together, lead concentrations
      were elevated in liver or kidney samples from 25 eagles and were compatible with
      death from lead poisoning in 15. Mean bone lead was higher in eagles with
      elevated hepatic lead than in those exhibiting background hepatic lead
      concentrations. However, even in the former group, bone lead concentrations were
      lower than those in lead-exposed individuals of other species of birds. Bone is
      probably not a useful tissue for identifying elevated lead exposure in eagles.
      Three of eleven birds that had been shot had anomalous renal lead concentrations,
      suggestive of contamination by residue from lead ammunition. It is important to
      exclude such birds when assessing lead exposure.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p267.html

PMID- 10398779
TI  - Pesticide deposition on coveralls during vineyard applications.
AB  - Deposition of pesticide on the clothing of the applicator was studied in a
      commercial vineyard using two different application technologies. A typical air
      assisted sprayer with centrifugal fans delivered a concentrated spray. A tunnel
      or hooded sprayer was used at two carrier rates-high volume, low concentration
      versus low volume, high concentration-to apply Dithane M-45, an agricultural
      fungicide, at 3,375 g/ha on a light to medium density canopy. Deposition of
      pesticide was on the coveralls worn by the operator for all applications with a
      deposition range of 0.43 to 0.63 ng/cm2. The deposition on the clothing was
      higher for the air-assist sprayer than for the hooded sprayer. However, reducing
      the volume of water in the non-air assist hooded sprayer offered no advantage in
      terms of decreasing operator exposure. While the deposition of pesticide on the
      coveralls of the applicator was fairly uniformly distributed on the garment
      surface, the neck, shoulder, and upper right arm of our right-handed operator had
      the highest amount of pesticide deposit and the lower left quadrant of the
      garment had the lowest deposition. Results of this study indicate that vineyard
      applicator exposure can be reduced by use of the hooded non-air assisted sprayer
      and that extra protection is needed in the region of the neck, shoulder, and arm,
      and attention to the habits of the tractor driver is
      required.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n2p273.html

PMID- 10398780
TI  - MRI: complacency or ascendancy in the evaluation of congenital heart disease.

PMID- 10398782
TI  - Neuroblastoma arising from the organ of Zuckerkandl: an unusual site with a
      favorable biologic outcome.
AB  - BACKGROUND: Prognosis in neuroblastoma has been shown to correlate with age and
      stage at diagnosis and site of origin. Extra-abdominal tumors (chest, neck,
      pelvis) do better in terms of survival than tumors arising from the upper
      abdomen. OBJECTIVE: We evaluated a subgroup of abdominal neuroblastomas arising
      near to the aortic bifurcation (commonly called organ of Zuckerkandl, O. Z.) to
      assess their biologic outcome and problems in diagnosis and therapy. MATERIALS
      AND METHODS: Sixteen O. Z. primary tumors were seen at three children's
      hospitals. Their clinical records and imaging studies were reviewed, including
      the sonographic, CT, and MRI findings. When available, MYCN amplification was
      noted (MYCN is the current term previously called N-MYC). RESULTS: Despite more
      than half of the tumors being very large, survival was the rule, with only one
      fatality (following multiple local recurrences). Only one patient (who survived)
      had bone metastases. The larger masses were usually palpated in otherwise well
      children, while the smaller ones were found in the course of evaluation for
      unrelated problems such as urinary tract infection. Intraspinal extension was
      common, though usually asymptomatic. MYCN amplification was absent in the four
      patients studied. CONCLUSIONS: Lower abdominal (O. Z.) neuroblastomas present
      technical problems of surgical removal, but form a group with a favorable outcome
      similar to cervical and thoracic primary sites. MRI was useful in delineating
      intraspinal extension.

PMID- 10398783
TI  - Separation of renal fragments by a urinoma after renal trauma: percutaneous
      drainage accelerates healing.
AB  - BACKGROUND: Two boys suffered blunt abdominal trauma resulting in renal injury.
      In both cases the damaged kidney was fractured through its mid-portion, and the
      upper and lower fragments of the kidney became widely separated by a urinoma.
      MATERIALS AND METHODS: US-guided drainage of the urinoma resulted in immediate
      apposition of the renal fragments. The drains were left on free drainage by
      gravity for 1 week before removal. RESULTS: The urinomas did not reaccumulate and
      follow-up DMSA scans showed good residual function. CONCLUSION: We suggest that
      drainage of urinomas that separate renal fragments should be considered since
      this may accelerate healing and help preserve renal function.

PMID- 10398784
TI  - Fetal polycystic kidney disease in oro-facio-digital syndrome type I.
AB  - We report a girl with oro-facio-digital syndrome type I (OFD I) associated with
      polycystic kidney disease (PKD), which was identified on fetal US and fetal MRI.
      After birth, the diagnosis of this X-linked dominant disorder, which is lethal in
      males, was achieved by recognition of facial dysmorphism, lingual hamartomas,
      postaxial polydactyly, brain malformations, and the existence of her deceased
      male sibling with similar malformations. Adult PKD is a common feature in
      heterozygous females with OFD I. However, fetal PKD has been reported only in a
      lethal homozygous male. Our observation expands our knowledge about the
      phenotypic variations of PKD in OFD I.

PMID- 10398786
TI  - CT-guided 14-G cutting needle lung biopsy in children: safe and effective.
AB  - CT-guided percutaneous lung biopsy was performed in children with chronic
      respiratory disease to obtain samples for histological examination. An automatic
      cutting device with a 14-G needle was used with one or two cores obtained in each
      procedure. Seven procedures were performed in six children, mostly with local
      anaesthesia. Adequate tissue was obtained in all cases. Although a small
      pneumothorax and/or haemothorax occurred in most procedures, these were usually
      visible only on CT and did not require active management. A larger pneumothorax
      in one child also resolved with conservative management. Percutaneous CT-guided
      14-G automatic cutting-needle biopsy of lung parenchyma in children is a
      minimally invasive alternative to open-lung biopsy with no complications in our
      series.

PMID- 10398785
TI  - Atelectasis on pediatric chest CT: comparison of sedation techniques.
AB  - BACKGROUND: A change in practice at our institution resulted in increased use of
      anesthesia for CT scan of the chest in children who required sedation. OBJECTIVE:
      To determine whether there is a difference in the frequency or severity of
      pulmonary atelectasis on CT scan in children sedated by anesthesiologists
      compared with children sedated by radiologists using intravenous pentobarbital.
      MATERIALS AND METHODS: Retrospective blinded review of 60 CT scans of the chest
      performed in 41 children. Forty-one studies in children sedated by radiologists
      (median age 29 months) were compared with 19 studies in children sedated by
      anesthesiologists (median age 25 months). RESULTS: Atelectasis sufficient to
      obscure pulmonary metastases was shown in 5 of 41 (12 %) radiology sedations and
      13 of 19 (68 %) anesthesiology sedations (P < 0.01). Higher grades of atelectasis
      were recorded in children under anesthesia (P < 0.01). CONCLUSION: Atelectasis is
      more frequent and more severe in children undergoing general anesthesia compared
      with intravenous pentobarbital sedation. Consideration should be given to the use
      of forced inspiration in children anesthetized for CT scan of the chest.

PMID- 10398787
TI  - Posterior mediastinal capillary hemangioma with extradural extension resembling
      neuroblastoma.
AB  - We present two patients with posterior mediastinal capillary hemangiomas that
      were paraspinal and had intraspinal extension. Computed tomography demonstrated
      the strikingly hypervascular nature of these tumors, distinguishing them from
      neuroblastoma.

PMID- 10398788
TI  - Hyperechoic foci in the thalamic region imaged via the posterior fontanelle: a
      potential mimic of thalamic pathology.
AB  - BACKGROUND: We have incidentally noted foci of increased thalamic echogenicity
      (FITE) on cranial sonographic images obtained via the posterior fontanelle (PF)
      that were not confirmed on images obtained while scanning through the anterior
      fontanelle (AF). Therefore, we postulated that this is a normal variant of PF
      imaging rather than true thalamic pathology. OBJECTIVE: The purpose of this study
      was to determine the incidence of FITE detected on posterior and anterior
      fontanelle images. MATERIALS AND METHODS: Parasagittal images were obtained
      bilaterally through the trigone of the lateral ventricles (including the thalami)
      via both the anterior and posterior fontanelles in 15 consecutive neonates (30
      thalami) and evaluated independently by two pediatric radiologists for the
      presence or absence of FITE. Thalami were graded as grade 0 (no FITE), grade 1
      (possible FITE), or grade 2 (definite FITE). Follow-up CT (n = 3) and MR (n = 1)
      were reviewed. RESULTS: FITE were absent in 87 % of thalami imaged via the AF,
      and possible FITE were present in 13 % of these cases. No cases of definite FITE
      were identified via the AF. However, possible FITE were identified in 33-40 % of
      thalami and definite FITE were seen in 33 % of thalami imaged via the PF.
      CONCLUSIONS: FITE seen only on images obtained through the PF on cranial
      sonography are a normal finding and should not be attributed to thalamic
      hemorrhage or ischemia.

PMID- 10398789
TI  - Abnormal diffusion-weighted MRI in medulloblastoma: does it reflect small cell
      histology?
AB  - A 12-year-old boy presented with the classic CT and MRI findings of
      medulloblastoma and the unusual finding of increased signal on diffusion MRI. The
      small-cell histology of medulloblastoma may account for the increased signal seen
      on diffusion MRI. Diffusion MRI with echoplanar technique may be useful in
      evaluation of these tumors and metastatic disease.

PMID- 10398790
TI  - Accelerated phase of Chediak-Higashi syndrome diffuse white-matter-enhancing
      lesions.
AB  - We present the CT and MRI findings of a patient with Chediak-Higashi syndrome in
      the accelerated phase with marked white-matter abnormalities. Pathologic and
      clinical features allow diagnosis of this condition, which in this case had
      dramatic neuroradiographic manifestations not well described in previous reports.

PMID- 10398791
TI  - The "circle sign": a new sonographic sign of pneumatosis intestinalis - clinical,
      pathologic and experimental findings.
AB  - BACKGROUND: Pneumatosis intestinalis (PI) represents gas in the bowel wall. The
      appearance of PI using high-resolution ultrasound (HRUS) has not been well
      described. OBJECTIVE: The purpose of this report is to describe a new ultrasound
      sign of pneumatosis seen in three patients. This sign, called the "circle sign",
      is indicative of bubbles of gas within the circumference of the bowel, producing
      an appearance of a continuous echogenic ring on ultrasound. Further studies of
      the sonographic characteristics of pneumatosis were performed with an in vitro
      model. MATERIALS AND METHODS: HRUS was performed prospectively in three patients
      demonstrating extensive PI radiographically. The appearance of the gas was
      characterized and the behavior of the intramural bubbles was studied when the
      bowel was compressed with the ultrasound transducer. Either CT scan or pathologic
      correlation was obtained in all patients. Experimental models of PI using air
      injected into the wall of sausage casing were developed. RESULTS: The presence of
      echogenic gas bubbles within the circumference of the wall of the bowel seen with
      HRUS was shown to represent pneumatosis intestinalis at histologic examination or
      by CT scanning in the three study patients. In vitro studies confirmed the
      clinical impression that the use of compression is helpful in distinguishing
      intramural from intraluminal air. CONCLUSION: The presence of echogenic gas
      bubbles in the wall of the bowel, often seen as a circle within the circumference
      of the bowel, may be helpful in diagnosing PI on ultrasound using HRUS.

PMID- 10398792
TI  - Tuberculous abdominal aortic aneurysm in a 14-year-old child.
AB  - Abdominal aortic aneurysms are rare in childhood. We present a case of aneurysm
      of the abdominal aorta in a child with tuberculous para-aortic lymphadenitis.

PMID- 10398793
TI  - Coexistent neurenteric cyst and enterogenous cyst. Further support for a common
      embryologic error.
AB  - The authors describe common embryological pathways responsible for coexistent
      neurenteric and enterogenous cysts in a patient with spinal dysraphism.

PMID- 10398794
TI  - Lipoblastoma: MRI appearances of a rare paediatric soft tissue tumour.
AB  - Lipoblastoma is a rare, benign soft-tissue tumour derived from embryonic fat.
      Four patients with tumours located in the upper limb are reported, with special
      reference to imaging techniques and histology. Radical surgical excision is
      essential to prevent local recurrence and exact imaging techniques are thus
      crucial. MRI appears to be a reliable preoperative investigation and is the
      recommended radiological examination. In a child under 3 months of age, images
      showing a predominantly fatty but inhomogeneous soft-tissue mass are suggestive
      of lipoblastoma.

PMID- 10398795
TI  - Abdominal-wall myositis secondary to intra-arterial chemotherapy for femoral
      osteosarcoma.
AB  - With the increasing application of intra-arterial chemotherapy (IAC), new side
      effects are encountered. We describe two children with proximal femoral
      osteosarcoma who developed focal myositis of the abdominal wall musculature after
      IAC. In both cases, myositis presented as abdominal pain and mimicked acute
      abdomen. US demonstrated asymmetrical thickening of abdominal-wall musculature in
      the right lower abdomen. This diagnosis should be considered when evaluating the
      patient with unexplained abdominal pain and a history of IAC.

PMID- 10398796
TI  - CT appearance of congenital defect resembling the Hangman's fracture.
AB  - PURPOSE: Congenital defects of C2 are rare and can be confused with Hangman's
      fractures. CT has been advocated as aiding in differentiation between an acute
      fracture and congenital defects. METHODS: We present a case of a 2-year-old
      recent accident victim, who was erroneously diagnosed by plain film and CT as
      having a Hangman's fracture. RESULTS: The CT demonstrated an atypical appearance
      of a congenital defect. CONCLUSION: This case shows that the radiographic
      differentiation between a Hangman's fracture and a congenital defect is more
      difficult than previously described.

PMID- 10398797
TI  - Variability in kyphomelic dysplasia.
AB  - Four infants with kyphomelic dysplasia ascertained from three families
      demonstrate variability within the syndrome. In the first family, sibling
      recurrence in female sibs was noted with atypical kyphomelic dysplasias,
      suggesting autosomal recessive inheritance. In the second family, with a male
      affected with the 'typical findings' of lethal kyphomelic dysplasia, diagnosis of
      a skeletal dysplasia was suspected at 29-30 weeks' gestation following US
      detection of short, bent femurs. In the third family, with a female affected,
      severe radiographic changes were documented at birth. The clinical course of the
      disease was mild with almost complete regression of the radiographic findings at
      the age of 7 years.

PMID- 10398798
TI  - Renal manifestations of AIDS in children.
AB  - Renal abnormalities in pediatric AIDS patients are common. The most common renal
      abnormality is HIV nephropathy, which usually progresses to end-stage renal
      disease. Other disorders discussed are related to infection, malignancy, and
      medications. This review illustrates several of the imaging findings seen in the
      kidneys of these patients.

PMID- 10398799
TI  - Focal segmental glomerulosclerosis complicating unilateral nephrectomy for Wilms'
      tumor.

PMID- 10398800
TI  - Fractures of the cuboid bone in toddlers.

PMID- 10398801
TI  - Genomic organization and chromosomal mapping of mouse nuclear factor kappa B 2
      (NFKB2).
AB  - NFKB2 is a member of the NFKB/Rel gene family, which is known to be a pivotal
      regulator of the acute phase and immune responses. NF-kappaB2 is initially
      synthesized as a approximately 100 000 Mr protein which needs to be processed in
      order to bind DNA, either as homodimer or as heterodimer with other members of
      the NF-kappaB/Rel family. The unprocessed form of NF-kappaB2 acts as an IkappaB
      like protein. Therefore, NF-kappaB2 has a dual function. In this report we
      describe the genomic structure, expression pattern, and chromosomal localization
      of mouse NFKB2. Genomic clones were isolated, which span the entire gene of
      approximately 8.5 kilobases (kb) including 1.5 kb of the promoter region.
      Comparison to its human and avian homologues revealed a strong evolutionary
      conservation of the gene structure including the exon/intron borders, sequence,
      and position of the nuclear localization signal, the glycine-hinge region, and
      the ankyrin repeats. By fluorescence in situ hybridization, mouse NFKB2 was
      mapped to Chromosome (Chr) MMU 19C3-D2, which is homologous to human Chr 10q24,
      at which position the human NFKB2 was previously located. NFKB2 is ubiquitously
      expressed, highest in lymph nodes and thymus, underlining its role in the immune
      function.

PMID- 10398802
TI  - Cloning and expression of new receptors belonging to the immunoglobulin
      superfamily from the marine sponge Geodia cydonium.
AB  - A cDNA encoding a receptor tyrosine kinase (RTK) was previously cloned and
      expressed from the marine sponge (Porifera) Geodia cydonium. In addition to the
      two intracellular regions characteristic for RTKs, two immunoglobulin (Ig)-like
      domains are found in the extracellular part of the sponge RTK. In the present
      study it is shown that no further Ig-like domain is present in the upstream
      region of the cDNA as well as of the gene hitherto known from the sponge RTK. Two
      different full-length cDNAs have been isolated and characterized in the present
      study, which possess two Ig-like domains, one transmembrane segment, and only a
      short intracellular part, without a TK domain. The two deduced polypeptides were
      preliminarily termed sponge adhesion molecules (SAM). The longer form of the SAM,
      GCSAML, encodes a deduced aa sequence, GCSAML, which comprises in the open
      reading frame 505 amino acids (aa) and has a calculated Mr of 53911. The short
      form, GCSAMS, has 313 aa residues and an Mr of 33987. The two Ig-like domains in
      GCSAML and GCSAMS are highly similar to the corresponding Ig-like domains in the
      RTKs from G. cydonium; the substitutions on both the aa and nt level are
      restricted to a few sites. Phylogenetic analyses revealed that the Ig-like domain
      1 is similar to the human Ig lambda chain variable region, while the Ig-like
      domain 2 is related more closely to the human Ig heavy chain variable region.
      Transplantation experiments (autografting) were performed to demonstrate that the
      level of expression of the two new genes, GCSAML and GCSAMS, is upregulated
      during the self/self fusion process. Immunohistochemical analyses using
      antibodies raised against the two Ig-like domains demonstrate a strong expression
      in the fusion zone between graft and host. This finding has been supported by
      northern blotting experiments that revealed that especially GCSAML is strongly
      upregulated after autografting (up to 12-fold); the expression of GCSAMS reaches
      a value of 5-fold if compared with the controls. The results presented here
      demonstrate that the expression of the new molecules described, comprising two Ig
      like domains, is upregulated during the process of autograft fusion.

PMID- 10398803
TI  - T-cell receptor vbeta deletion and valpha polymorphism are responsible for the
      resistance of SWR mouse to arthritis induction.
AB  - Collagen type II-induced arthritis (CIA) develops in susceptible mouse strains
      after intradermal injections of type II collagen (CII) in complete Freund's
      adjuvant (CFA). Susceptibility to CIA in mice is linked to genes of the major
      histocompatibility complex (MHC). Although the SWR mouse has a susceptible MHC
      haplotype (H2q), it is resistant to CIA. SWR exhibits at least two known
      immunological defects: (1) it contains a germline deletion of about 50% of T-cell
      receptor (TCR) Vbeta-chain gene segments, and (2) SWR is deficient in complement
      component C5. It has been shown that T cells that express TCRValpha11.1 and
      TCRVbeta8.2 play a substantial role in the pathogenesis of arthritis in the DBA/1
      mouse (H2q). We generated SWR transgenic (tg) mice to determine whether the
      expression of pathogenic Valpha11.1 and/or Vbeta8.2 transgenes would confer
      arthritis susceptibility. Arthritis was induced in the SWR TCRalphabeta tg mice,
      but not in SWR TCRbeta tg mice. To address the role of Valpha11.1 in arthritis
      susceptibility, we examined the allelic polymorphisms of the Tcra-V11-gene
      subfamily members between the arthritis susceptible DBA/1 mouse and the arthritis
      resistant SWR mouse strain. The amino acid sequences of the Valpha11.1 alleles
      differ at two positions (codons 18 and 68). Accordingly, these two amino acid
      changes are sufficient to allow the production of pathogenic T cells in SWR mice.
      This is the first demonstration of the association of a particular Tcra-V allele
      and arthritis susceptibility in mice.

PMID- 10398805
TI  - Identification of a new quantitative trait locus on chromosome 7 controlling
      disease severity of collagen-induced arthritis in rats.
AB  - Autoimmune diseases, such as rheumatoid arthritis, Crohn's disease, and multiple
      sclerosis, are regulated by multiple genes. Major histocompatibility complex
      (MHC) genes have the strongest effects, but non-MHC genes also contribute to
      disease susceptibility/severity. In this paper, we describe a new non-MHC
      quantitative trait locus, Cia8, on rat Chromosome (Chr) 7 that controls collagen
      induced arthritis severity in F2 progeny of DA and F344 inbred rats, and present
      an updated localization of Cia4 on the same chromosome. We also describe the
      location of mouse and human genes, orthologous to the genes in the genomic
      intervals containing Cia4 and Cia8, and provide evidence that the segment of rat
      Chr 7 containing Cia4 and Cia8 is homologous to segments of mouse Chr 10 and 15
      and human Chr 8, 12, and 19.

PMID- 10398804
TI  - Origins of immunity: transcription factors and homologues of effector genes of
      the vertebrate immune system expressed in sea urchin coelomocytes.
AB  - Echinoderms share common ancestry with the chordates within the deuterostome
      clade. Molecular features that are shared between their immune systems and that
      of mammals thus illuminate the basal genetic framework on which these immune
      systems have been constructed during evolution. The immune effector cells of sea
      urchins are the coelomocytes, whose primary function is protection against
      invasive marine pathogens; here we identify six genes expressed in coelomocytes,
      homologues of which are also expressed in cells of the mammalian immune system.
      Three coelomocyte genes reported here encode transcription factors. These are an
      NFKB homologue (SpNFKB); a GATA-2/3 homologue (SpGATAc); and a runt domain factor
      (SpRunt-1). All three of these coelomocyte genes respond sharply to bacterial
      challenge: SpNFKB and SpRunt-1 genes are rapidly up-regulated, while transcripts
      of SpGATAc factor disappear within hours of injection of bacteria. Sham injection
      also activates SpNFKB and SpRunt, though with slower kinetics, but does not
      affect SpGATAc levels. Another gene, SpHS, encodes a protein related to the
      signal transduction intermediate HS1 of lymphoid cells. Two other newly
      discovered genes, SpSRCR1 and SpSRCR5, encode proteins featuring SRCR repeats.
      These genes are members of a complex family of SRCR genes all expressed
      specifically in coelomocytes. The SRCR repeats most closely resemble those of
      mammalian macrophage scavenger receptors. Remarkably, each individual sea urchin
      expresses a specific pattern of SRCR genes. Our results imply some shared immune
      functions and more generally, a shared regulatory architecture which underlies
      immune system gene expression in all deuterostomes. We conclude that the
      vertebrate immune system has evolved by inserting new genes into old gene
      regulatory networks dedicated to immunity.

PMID- 10398806
TI  - Sequence and diversity of T-cell receptor beta-chain V and J genes of the owl
      monkey Aotus nancymaae.
AB  - The New World primate Aotus nancymaae is susceptible to infection with the human
      malaria parasite Plasmodium falciparum and has therefore been recommended by the
      World Health Organization as a model for the evaluation of malaria vaccine
      candidates. Recently, we have shown that Aotus TCRVA genes and TCRJA segments
      exhibit a high degree of similarity to human counterparts. In the present report
      we used reverse transcription polymerase chain reaction to analyze the sequences
      of A. nancymaae TCR beta-chain gene rearrangements. Alignment with human
      sequences and phylogenetic comparison identified 18 distinct Aotus TCRBV genes
      homologous to the human TCRBV gene families 2, 4, 5, 6, 7, 9, 12, 15, 24, and 28.
      Multiple Aotus genes were found in the TCRBV4, 5, 6, and 7 families. Some of
      these TCRBV genes aligned best to the same human gene and thus do not seem to
      have separate human homologues. Amino acid sequences of the Aotus TCRBV genes
      were 77 to 90% identical to their closest human counterparts. Ten distinct Aotus
      TCRBJ segments homologous to the human segments J1-1, J1-2, J1-4, J1-5, J1-6, J2
      1, J2-2, J2-3, J2-4, J2-5 were found. In some cases the amino acid sequences of
      Aotus and human TCRBJ segments were completely identical. A comparison of the
      proportion of synonymous and non-synonymous substitutions in Aotus vs human beta
      chain-encoding genes revealed a dominance of synonymous substitutions in TCRBJ
      segments and of nonsynonymous substitutions in TCRBV segments. Dominance of
      nonsynonymous substitutions was more pronounced in TCRBV CDR1 and CDR2 regions
      than in the framework regions. No evidence for the emergence of new TCRBJ
      segments or TCRBV families was found. These results confirm that the TCR
      repertoire in primates is remarkably stable and support the concept of using
      Aotus monkeys as an infection model for the evaluation of future subunit vaccine
      candidates.

PMID- 10398807
TI  - HLA-DR53 molecules are associated with susceptibility to celiac disease and
      selectively bind gliadin-derived peptides.
AB  - Celiac disease (CD) patients usually express a DQ2 heterodimer, whose chains
      DQalpha1*0501/DQbeta1*0201, are encoded by the genes HLA-DQA1*0501 and DQB1*0201,
      respectively. Among the DQ2 carriers, the risk of developing disease was shown to
      correlate with the number of DQbeta1*0201 chains encoded. Studying two separate
      cohorts of Italian and Tunisian patients, we now show a significant association
      of celiac disease with expression of either the DQ2 or DR53 heterodimers. The
      risk is maximal for individuals that carry both DQ2 and DR53 heterodimers. When
      twenty synthetic peptides overlapping most of A-gliadin sequence were tested for
      the binding to various purified DR molecules, it was found that DR53 molecules
      bind selectively and with high affinity (IC50<1 microM) to A-gliadin-derived
      peptides. These data suggest that both HLA DQ2 and DR53 molecules are associated
      with increased genetic risk for CD, and provide a possible biochemical basis for
      this complex association.

PMID- 10398808
TI  - Re-examination of HLA-G polymorphism in African Americans.

PMID- 10398809
TI  - Molecular cloning of cattle CD63 and evidence for high level expression on
      subpopulations of dendritic cells.

PMID- 10398810
TI  - A rat gene homologous to human granule membrane protein 17 is expressed by
      natural killer cells, CD8(+) T cells, and a mast cell line.

PMID- 10398811
TI  - The role of the amino acids associated with the HLA-Bw4/Bw6 epitope in peptide
      binding to HLA-B5, B35 CREG molecules.

PMID- 10398812
TI  - A new polymorphism in the human HFE gene.

PMID- 10398813
TI  - Thirteen Mhc-DQA1 alleles from two populations of baboons.

PMID- 10398814
TI  - Radioiodine (131I) treatment of hyperthyroidism: radiation protection and quality
      assurance.

PMID- 10398815
TI  - Radiation exposure of the families of outpatients treated with radioiodine
      (iodine-131) for hyperthyroidism.
AB  - Patients who receive radioiodine (iodine-131) treatment for hyperthyroidism (195
      800 MBq) emit radiation and represent a potential hazard to other individuals.
      Critical groups amongst the public are fellow travellers on the patient's journey
      home from hospital and members of the patient's family, particularly young
      children. The dose which members of the public are allowed to receive as a result
      of a patient's treatment has been reduced in Europe following recently revised
      recommendations from ICRP. The annual public dose limit is 1 mSv, though adult
      members of the patient's family are allowed to receive higher doses, with the
      proviso that a limit of 5 mSv should not be exceeded over 5 years. Unless the
      doses received during out-patient administration of radioiodine can be
      demonstrated to comply with these new limits, hospitalisation of patients will be
      necessary. The radiation doses received by family members (35 adults and 87
      children) of patients treated with radioiodine at five UK hospitals were measured
      using thermoluminescent dosimeters mounted in wrist bands. Families were given
      advice (according to current practice) from their treatment centre about limiting
      close contact with the patient for a period of time after treatment. Doses
      measured over 3-6 weeks were adjusted to give an estimate of values which might
      have been expected if the dosimeters had been worn indefinitely. Thirty-five
      passengers accompanying patients home after treatment also recorded the dose
      received during the journey using electronic (digital) personal dosimeters. For
      the "adjusted" doses to infinity, 97% of adults complied with a 5-mSv dose limit
      (range:0.2-5.8 mSv) and 89% of children with a 1-mSv limit (range: 0.2-7.2 mSv).
      However 6 of 17 children aged 3 years or less had an adjusted dose which exceeded
      this 1 mSv limit. The dose received by adults during travel was small in
      comparison with the total dose received. The median travel dose was 0.03 mSv for
      1 h travel (range: 2 microSv-0.52 mSv for 1 h of travel time). These data suggest
      that hyperthyroid patients can continue to be treated with radioiodine on an out
      patient basis, if given appropriate radiation protection advice. However,
      particular consideration needs to be given to children aged 3 years or younger.
      Admission to hospital is not warranted on radiation protection grounds.

PMID- 10398816
TI  - Tumour uptake of the radiolabelled somatostatin analogue [DOTA0, TYR3]octreotide
      is dependent on the peptide amount.
AB  - Radiolabelled tumour receptor-binding peptides can be used for in vivo
      scintigraphic imaging. Recently, the somatostatin analogue [Tyr3]octreotide (D
      Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelator DOTA
      (tetra-azacyclododecane-tetra-acetic acid), enabling stable radiolabelling with
      both the high-energy beta particle-emitter yttrium-90 and the Auger electron
      emitter indium-111. The thus produced radiolabelled compounds are promising for
      peptide receptor radionuclide therapy. Our previous in vitro and in vivo (rat)
      experiments with these radiolabelled compounds showed favourable binding and
      biodistribution characteristics with high uptake and retention in the target
      organs. We also demonstrated receptor-specific, time- and temperature-dependent
      internalization of radiolabelled [DOTA0,Tyr3]octreotide in somatostatin receptor
      subtype 2 (sst2)-positive rat pancreatic tumour cell lines. In this study we have
      investigated the effects of differences in the amount of injected peptide on
      tissue distribution of 111In-labelled [DOTA0, Tyr3]octreotide in normal, i.e. non
      tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find
      the amount of peptide at which the highest uptake in target tissues is achieved,
      and thereby to increase the potential of radionuclide therapy while
      simultaneously ensuring the lowest possible radiotoxicity in normal organs.
      Uptake of radiolabelled [DOTA0,Tyr3]octreotide in sst2-positive organs showed
      different bell-shaped functions of the amount of injected peptide, being highest
      at 0.05 (adrenals), 0.05-0. 1 (pituitary and stomach) and 0.25 (pancreas) microg.
      Uptake in the tumour was highest at 0.5 microg injected peptide. The highest
      uptake was found at peptide amounts that were lower than those reported for
      [111In-DTPA0]octreotide ((D-Phe-c(Cys-Phe-D-Trp-Lys-Thr-Cys)-Thr(ol), DTPA =
      diethylene-triamine-penta-acetic acid), consistent with the higher receptor
      affinity of the first compound. Our observations of mass-dependent differences in
      uptake of radiolabelled [DOTA0, Tyr3]octreotide, being the resultant of a
      positive effect of increasing amounts of peptide on, for example, receptor
      clustering and a negative effect of receptor saturation, are of consequence for
      rat radionuclide therapy studies with radiolabelled peptides and may also be of
      consequence for human radionuclide therapy studies with this compound.

PMID- 10398817
TI  - Holmium-166 poly lactic acid microspheres applicable for intra-arterial
      radionuclide therapy of hepatic malignancies: effects of preparation and neutron
      activation techniques.
AB  - Since one of the most frequent sites of human metastatic cancer is the liver,
      particularly in colon and rectum carcinoma, there is a special need for the
      development of an effective therapy. This study describes the parameters for
      reproducible production of poly lactic acid (PLA) microspheres with an average
      diameter of 37 microm and labelled with neutron-activated holmium-166 (Emax=1.84
      MeV, t1/2=26. 8 h), suitable for use in internal radionuclide therapy of liver
      metastases. It is demonstrated that holmium-loaded PLA microspheres can be
      prepared by a relatively simple method, with incorporation of 17.0%+/-0.6%
      holmium (n=5), and that 20 GBq can be obtained from 400 mg neutron activatable
      microspheres. In order to produce this high amount of activity, the microspheres
      must be free of water and irradiation must be performed in a polyethylene vial,
      with a relatively low neutron flux (5x10(13) cm-2 s-1) within 1 h. Under these
      well-defined conditions minor surface changes were seen which barely affected
      total volume and consequently total radioactivity of the microspheres with a
      diameter of 20-50 microm. Overall structural integrity was maintained in terms of
      form and size. In vitro analyses showed that >99.3% of 166Ho activity was
      retained in the microspheres after 192 h incubation in PBS, plasma and
      leucocytes, while in liver homogenate retention was still 98.4%.

PMID- 10398818
TI  - Use of technetium-99m sestamibi ECG-gated single-photon emission tomography for
      the evaluation of left ventricular function following coronary artery bypass
      graft: comparison with three-dimensional magnetic resonance imaging.
AB  - In patients who had undergone cardiac surgery (coronary artery bypass graft) and
      whose hearts showed abnormal movement during the cardiac cycle, we studied the
      accuracy of functional assessment using ECG-gated single-photon emission
      tomography (SPET) and the automated software developed by Germano et al. by
      comparing the findings with magnetic resonance (MR) images acquired three
      dimensionally. Sixteen patients who had undergone cardiac surgery underwent 99mTc
      sestamibi gated SPET (MIBI-g-SPET) and MRI on the same day. Left ventricular end
      diastolic and end-systolic volumes (EDV, ESV) and ejection fraction (LVEF) were
      measured using MIBI-g-SPET and the aforementioned algorithm. Regional wall
      thickening was assessed using a four-point scale on MIBI-g-SPET and cine MRI.
      There was a good correlation between MIBI-g-SPET and MRI in respect of EDV
      (r=0.89), ESV (r=0.93) and LVEF (r=0.89). A high degree of agreement was found
      between the wall thickening scores obtained by MIBI-g-SPET and MRI in total
      segments (kappa=0.62) and in septal segments (kappa=0.67). It is concluded that
      ECG-gated perfusion SPET can provide regional and global functional information,
      including absolute volumes, in patients following cardiac surgery.

PMID- 10398819
TI  - Technetium-99m sestamibi single-photon emission tomography detects subclinical
      myocardial perfusion abnormalities in patients with systemic lupus erythematosus.
AB  - In patients with systemic lupus erythematosus, involvement of the cardiovascular
      system is the third leading cause of death. However, although autopsy studies
      have demonstrated a high incidence of abnormalities in both the myocardium and
      coronary vessels, clinical manifestations have been reported in only a small
      percentage of cases. The aim of this study was to evaluate myocardial perfusion
      in asymptomatic lupus patients using technetium-99m sestamibi single-photon
      emission tomography (SPET). Twenty-eight patients without overt cardiac
      involvement and risk factors were studied with 99mTc-sestamibi SPET at rest and
      after dipyridamole infusion. Perfusion abnormalities were detected in 18 cases:
      six had persistent defects, three had reversible defects, seven had both
      persistent and reversible defects, and two showed rest defects which normalized
      on dipyridamole images ("reverse redistribution pattern"). Coronary angiography
      was performed in eight patients with positive 99mTc-sestamibi SPET, and showed
      normal epicardial vessels in all the cases. These results indicate that 99mTc
      sestamibi SPET reveals a high prevalence (18 out of 28 patients in this study,
      i.e. 64%) of myocardial perfusion abnormalities in asymptomatic lupus patients,
      probably due to the primary immunological damage of this autoimmune disease. In
      conclusion, rest/dipyridamole 99mTc-sestamibi SPET can be a useful non-invasive
      method to identify subclinical myocardial involvement in systemic lupus
      erythematosus, and patients potentially at risk of later cardiac events.

PMID- 10398820
TI  - A multivariate approach to registration of dissimilar tomographic images.
AB  - We devised a method to allow for retrospective registration of tomographic images
      with very different information content, the main emphasis being on sets of
      positron emission tomography images obtained with different tracers. A
      multivariate cost-function based on information theory was used as an index of
      "goodness-of-alignment". The cost-function makes no assumptions regarding the
      form of the relationship between the two image sets, and is hence very general.
      Image volumes, with known relative spatial orientation, were simulated for
      tracers with different uptake patterns and the method was validated by assessing
      its ability to recover these known orientations. The method was able to recover
      the known transformations with an accuracy of about 1 mm and 1 degrees along and
      around all axes, even for tracer combinations with radically different uptake
      patterns and with large initial misalignment. With the suggested method it is
      feasible to retrospectively align examinations obtained with different tracers
      and/or modalities.

PMID- 10398821
TI  - Semi-quantitative ventilation/perfusion scintigraphy and single-photon emission
      tomography for evaluation of lung volume reduction surgery candidates:
      description and prediction of clinical outcome.
AB  - Ventilation/perfusion scans with single-photon emission tomography (SPET) were
      reviewed to determine their usefulness in the evaluation of lung volume reduction
      surgery (LVRS) candidates, and as a predictor of outcome after surgery. Fifty
      consecutive planar ventilation (99mTc-DTPA aerosol) and perfusion (99mTc-MAA)
      scans with perfusion SPET of patients evaluated for LVRS were retrospectively
      reviewed. Technical quality and the severity and extent of radiotracer defects in
      the upper and lower halves of the lungs were scored from visual inspection of
      planar scans and SPET data separately. An emphysema index (EI) (extent x
      severity) for the upper and lower halves of the lung, and an EI ratio for upper
      to lower lung were calculated for both planar and SPET scans. The ratios were
      compared with post-LVRS outcomes, 3, 6 and 12 months after surgery. All perfusion
      and SPET images were technically adequate. Forty-six percent of ventilation scans
      were not technically adequate due to central airway tracer deposition. Severity,
      extent, EI scores and EI ratios between perfusion and SPET were in good agreement
      (r = 0.52-0.68). The mean perfusion EI ratio was significantly different between
      the 30 patients undergoing biapical LVRS and the 17 patients excluded from LVRS
      (3.3+/-1.8 versus 1.2+/-0.7; P<0.0001), in keeping with the anatomic distribution
      of emphysema by which patients were selected for surgery by computed tomography
      (CT). The perfusion EI ratio correlated moderately with the change in FEV1 at 3
      months (r = 0.37, P = 0.04), 6 months (r = 0.36, P = 0.05), and 12 months (r =
      0.42, P = 0.03), and the transition dyspnea index at 6 months (r = 0.48, P =
      0.014) after LVRS. It is concluded that patients selected to undergo LVRS have
      more severe and extensive apical perfusion deficits than patients not selected
      for LVRS, based on CT determination. SPET after aerosol V/Q imaging does not add
      significantly to planar perfusion scans. Aerosol DTPA ventilation scans are not
      consistently useful. Perfusion lung scanning may be useful in selecting patients
      with successful outcomes after LVRS.

PMID- 10398822
TI  - A study of myocardial muscarinic receptors in streptozotocin-induced diabetic
      rats using iodine-123 N-methyl-4-iododexetimide.
AB  - In previous studies we have shown that iodine-123 N-methyl-4-iododexetimide
      ([123I]MIDEX) is a suitable single-photon emission tomography radiotracer for the
      characterisation of myocardial muscarinic acetylcholine receptors (m-AChR) in the
      normal state. It has been demonstrated that m-AChR are altered as a consequence
      of diabetes. The aim of the present study was to examine myocardial m-AChR
      density using [123I]MIDEX in streptozotocin (STZ)-induced diabetic rats. In vitro
      binding experiments were conducted on left and right ventricle and atrium
      homogenate membranes of 1-week, 5-week and 10-week STZ-induced diabetic and aged
      matched normal rats. The m-AChR densities (Bmax values), as determined by
      saturation experiments with [123I]MIDEX, revealed no difference in left and right
      ventricles or atrium in 1-week and 5-week STZ-diabetic rats when compared with
      normal rats. However, the 10-week STZ-diabetic group revealed a 39% (P<0.001)
      decrease in m-AChR density in atrium with no change in left and right ventricles.
      The equilibrium dissociation constant (Kd values) was similar in all groups. In
      vitro binding autoradiography revealed a 40% decrease in m-AChR density in atrium
      in the same 10-week diabetic rats. No statistically significant difference was
      found in 1-week and 5-week diabetic rats compared with normals. Ex vivo
      autoradiography showed a 50% decrease in [123I]MIDEX uptake in atrium in 5-week
      diabetic rats and a 60% decrease in 10-week diabetic rats. These results
      demonstrate the ability of the single-photon agent [123I]MIDEX to measure in
      vitro and ex vivo alterations in myocardial m-AChR density observed in STZ
      induced diabetic rats.

PMID- 10398823
TI  - Comparison of the distribution of fluorine-18 fluoromisonidazole, deoxyglucose
      and methionine in tumour tissue.
AB  - To evaluate the tumour imaging potential of fluorine-18 fluoromisonidazole
      (FMISO), we studied FMISO uptake in an experimental tumour model and examined the
      correlation between intratumoral distributions of FMISO, 14C-2-deoxyglucose (2DG)
      and 14C-methionine (Met). The study was performed using control rats with the
      AH109A tumour and rats with the same tumour under local hypoxia. Tumour uptake of
      FMISO was constant between 30 min and 2 h after injection, and the tumour to
      muscle ratio was 2 from 2 to 4 h. A tumour study with FMISO was scheduled at 2 h.
      Double-tracer autoradiography of the tumour demonstrated that in the areas of
      high FMISO uptake, there was low uptake of Met, while areas of low FMISO uptake
      showed high Met uptake. FMISO showed high grain density in the rim of the tumour
      surrounding the necrotic area. 2DG showed a more uniform distribution over the
      entire section of viable cells. The mean uptake of FMISO by hypoxic,
      radioresistant tumours was significantly higher than that by the control tumours
      (P<0.05), while both 2DG and Met uptake by the control tumours was higher than
      uptake by hypoxic tumours. When individual tumours were examined, the uptake of
      FMISO was inversely correlated with that of Met (r = -0.507, P<0.02), while 2DG
      showed almost uniform uptake with no significant correlation to FMISO. In
      conclusion, hypoxic and radioresistant tumours could be identified by increased
      FMISO uptake in our model, consistent with findings reported by others. We found
      a large overlap in the distribution of FMISO and 2DG within the tumour, but only
      a small overlap in the distribution of FMISO and Met. A combination of FMISO and
      other tracers in positron emission tomography or single-photon emission
      tomography studies might be more helpful than single-tracer studies in predicting
      the response of tumour tissues to radiotherapy.

PMID- 10398824
TI  - Comparison of fluorine-18 and bromine-76 imaging in positron emission tomography.
AB  - State of the art positron emission tomography (PET) systems allow for scatter and
      attenuation correction. However, the size of the structure being studied and the
      region of interest (ROI) chosen also influence the accuracy of measurements of
      radioactive concentration. Furthermore, the limited spatial resolution of PET
      tomographs, which depends, among other factors, on the range of positrons in
      matter, can also contribute to a loss in quantitation accuracy. In this paper we
      address the influence of positron range, structure size and ROI size on the
      quantitation of radioactive concentration using PET. ECAT EXACT HR+ (HR+) and
      ECAT 953B/31 (ECAT 953B) PET systems were used in phantom acquisitions performed
      with two radioisotopes with different positron ranges. The 3D Hoffman phantom was
      scanned on both scanners with both radioisotopes, to visually analyse the image
      quality. A resolution phantom having six spheres of different diameters in a
      Plexiglas cylinder was used to calculate the values of the contrast recovery
      coefficient or hot spot recovery coefficient and of the spill-over or cold spot
      recovery coefficient under different imaging conditions used in clinical routine
      at our institution. Activity ratios were varied between 2 and 30 or between 0.4
      and 200 by filling the spheres with fluorine-18 or bromine-76 respectively and
      the cylinder with 11C. Dynamic scans were performed on each scanner. Data were
      reconstructed using the same parameters as are used in clinical protocols. The
      variations in sphere and cylinder activities with time were fitted using the
      function M(t)=k1. A(t)+k2.B(t), where M(t) is the radioactivity concentration
      measured in an ROI placed on each sphere and A(t) and B(t) represent the true
      radioactivity concentrations present at time t in the spheres and in the cylinder
      respectively. k1 and k2 are factors representing the contrast recovery
      coefficient and the spill-over from surrounding activity on measurements
      respectively. The visual analysis of images obtained using a 3D Hoffman phantom
      showed that image resolution and image contrast between different regions are
      radioisotope dependent and clearly better when using 18F. Linear profiles taken
      on these images confirmed the visual assessment. For a given scanner, the k1
      values obtained with 18F were systematically higher than those measured using
      76Br in the same machine (especially for the smaller spheres) when using the same
      ROI. For a sphere of a particular diameter, the use of a wider ROI resulted in
      lower quantitative accuracy when using the same isotope and the same camera.
      Lower quantitative accuracy was found for smaller spheres for all ROI sizes used
      in image analysis. For the same scanner and for a similar imaging situation (same
      sphere and same ROI), it was found that k1 and k2 values depend on the
      radioisotope used. For the same isotope and tomograph, the k1 values obtained
      decreased with the size of the structures imaged, as well as with the increase in
      ROI size. The use of a tomograph with better spatial resolution (HR+, rather than
      ECAT 953B) greatly increased the k1 values for 18F while only a mild improvement
      in these values was observed for 76Br. The use of 76Br led to k2 values that were
      slightly higher than those measured using 18F. These differences may have been
      due to the difference in the range of the positrons emitted by the radioisotopes
      used in this study. The measurements performed in this study show that the
      comparison of studies obtained on the same camera depends on the radioisotope
      used and may require the adaptation of ROI size between examinations. Marked
      differences are visible if the positron ranges of such radioisotopes are very
      different. Therefore, when employing commercially available tomographs and
      imaging protocols used in clinical routine, the effects of differences in
      positron range on image quality and quantitation are noticeable and correction
      for these effects may be of importance. (ABSTRACT TRUNCATED)

PMID- 10398825
TI  - The detection of local recurrent head and neck cancer with fluorine-18
      fluorodeoxyglucose dual-head positron emission tomography.
AB  - Primary tumors of the larynx and hypopharynx are preferably treated with high
      dose radiation therapy. In these patients, it may be difficult to distinguish
      recurrent disease from post-treatment reactions. The aim of the present study was
      to assess the value of fluorine-18 fluorodeoxyglucose positron emission
      tomography (FDG-PET) in the detection of local relapses of laryngeal or
      hypopharyngeal carcinoma after radiotherapy using a dual-head PET camera. Forty
      eight patients (43 male, 5 female; mean age +/-SD, 61+/-9.5 years) with suspected
      recurrent laryngeal or hypopharyngeal cancer were prospectively studied. The mean
      interval between initial treatment and suspicion of recurrent disease was 14.6
      months (range: 3-100 months). FDG dual-head PET was followed by endoscopy with or
      without biopsy under general anaesthesia within a period of 2 months in all
      patients. The mean period of follow-up after FDG dual-head PET was 13.7 months.
      In 19 out of 31 patients with focally increased uptake, tumour recurrence (mean
      diameter: 2.4 cm; range 0.4-6.5 cm) was found at initial endoscopy. In five
      patients recurrence was found during follow-up with a mean interval of 6.6
      months. Seven patients had a false-positive study due to benign lesions or
      swallowing artefacts. In none of the patients with a normal PET study was tumour
      recurrence found during follow-up. The sensitivity and specificity of FDG dual
      head PET were 100% and 71%, respectively. It is concluded that FDG dual-head PET
      is highly sensitive for the detection of local recurrence of laryngeal and
      hypopharyngeal carcinoma after radiotherapy. Some lesions were detected with a
      mean interval of 6.6 months before histological confirmation. In patients
      suspected of having recurrent laryngeal or hypopharyngeal cancer in whom FDG-PET
      is negative, endoscopy may be omitted for at least 6 months and possibly for up
      to 1 year.

PMID- 10398826
TI  - Radionuclides and radiopharmaceuticals for single-photon emission tomography,
      positron emission tomography and radiotherapy in Russia.
AB  - The current status of the manufacture of radiopharmaceuticals for diagnostic and
      therapeutic application in Russia is discussed, consideration being given to
      various aspects of the production and distribution of radionuclides, radioisotope
      generators and kits as well as individual radiopharmaceuticals in different
      regions of the country. The major focus is on the recent developments in
      production technologies for therapeutic and single-photon emission tomography
      radionuclides, technetium chemistry and synthetic approaches for the labelling of
      compounds with short-lived positron emitters. The status of positron emission
      tomography and its application are considered. The major factors restricting the
      expansion of nuclear imaging techniques and radiotherapy in Russia are also
      discussed.

PMID- 10398827
TI  - Characterization of proteinases in Herpetomonas anglusteri and Herpetomonas
      roitmani.
AB  - We have analyzed the proteinase profile of two Herpetomonas species, H.
      anglusteri and H. roitmani (a symbiont-bearing trypanosomatid), by in situ
      detection of enzyme activities on SDS-PAGE gels containing copolymerized gelatin
      as substrate. Two major cell-associated proteolytic activities, a 60 kDa zinc
      metalloproteinase and a 45 kDa cysteine proteinase could be detected based on the
      inhibition of their activities by 1, 10-phenathroline and E-64, respectively. The
      trypanosomatids released into the growth medium distinct proteinases. H.
      anglusteri expressed three digestion haloes in the gels of approximately 60, 50,
      and 40 kDa, whereas H. roitmani secreted only a 60 kDa enzyme. However, these
      activities were inhibited by 1,10-phenanthroline, suggesting that all of them are
      zinc-metalloproteinase.

PMID- 10398828
TI  - Influence of environmental conditions on hyphal morphology in pellets of
      Aspergillus niger: role of beta-N-acetyl-D-glucosaminidase.
AB  - The influence of modifications of the environmental conditions of growth on beta
      N-acetyl-D-glucosaminidase (EC 3.2.1.30) activity and on hyphal morphological
      patterns in pellets of Aspergillus niger was studied. It was found that changes
      in the degree of branching and, to a lesser extent, in the number of bulbous
      cells were directly related to the activity of the enzyme. Nevertheless, since
      beta-N-acetyl-D-glucosaminidase is not the only enzyme involved in the lytic
      potential of the fungus, these findings do not exclude the possibility that other
      enzymes may be involved.

PMID- 10398830
TI  - Identification and initial characterization of elastase activity associated with
      Vibrio cholerae.
AB  - Strains of Vibrio cholerae O1 (Ogawa, Inaba) and non-O1 serogroups have been
      found to produce an elastolytic protease that can be detected on 0.3% elastin
      agar plates or in broth cultures. The elastase enzyme appears to be maximally
      expressed in late log phase (14-18 h postinoculation) and has optimum activity at
      a pH range between 7 and 8. Comparative studies indicate that more than 60% of V.
      cholerae strains analyzed quantitatively produce more elastase in broth (two- to
      fourfold higher) than other elastase-positive Vibrio species such as Vibrio
      vulnificus. The V. cholerae elastase enzyme was not inhibited by trypsin, serine
      protease, or thiol-protease inhibitors, but was inhibited by phosphoramidon.
      Ultrafiltration studies indicate the V. cholerae elastase enzyme has a molecular
      weight >30,000, and a 34K protein with possible elastase activity has been
      detected by SDS-PAGE for one non-O1 isolate (strain 2396). Cumulative results
      suggest that the V. cholerae elastase is probably a member of the N-type
      metalloprotease family and shares similar properties with other elastase enzymes
      described for pathogenic and nonpathogenic species in this genus.

PMID- 10398829
TI  - Bile salt activation of stress response promoters in Escherichia coli.
AB  - Bile salts are prevalent in the mammalian intestine, a natural habitat of
      Escherichia coli. The bile salts deoxycholate, chenodeoxycholate,
      ursodeoxycholate, and glycocholate were tested for their effect on induction of
      13 specific stress response genes. The most consistently activated E. coli
      promoters were those for genes micF, osmY, and dinD. MicF and osmY gene products
      are associated with membrane functions and are responsive to oxidative stress.
      DinD is induced by DNA damage as part of the SOS response. These results indicate
      that bile acids, to which E. coli are naturally exposed, induce expression of
      specific stress response genes, possibly in response to membrane perturbation,
      oxidative stress, and DNA damage. Altered expression of stress-response genes may
      also promote interaction of E. coli with cells of the colonic epithelium.

PMID- 10398831
TI  - Characterization of Methanosarcina mazei N2M9705 isolated from an aquaculture
      fishpond.
AB  - A new methanogenic isolate, designated as strain N2M9705 (=OCM 668), was isolated
      from an aquaculture fishpond near Wang-gong, Taiwan. This strain grew on
      trimethylamine and methanol, but it did not catabolize H2-CO2, acetate, or
      formate. The cells were stained Gram-negative, nonmotile, irregular coccus 0.6
      0.8 micrometer in diameter. Gas vacuoles were observed and cell aggregated to
      form various sizes of granules. Cells grew optimally at 32 degrees -37 degrees C
      with 1% NaCl. The pH range of growth was 6.2-7.4, and higher pH inhibited the
      cell growth. The cells grew well in minimal medium, but growth was greatly
      stimulated by yeast extract and peptone. A comparison of 16S rDNA sequences of
      this organism phylogenetically related to Methanosarcina mazei. This is the first
      report of methyltrophic methanogenic isolated from an aquaculture fishpond.

PMID- 10398833
TI  - Occurrence of salt, pH, and temperature-tolerant, phosphate-solubilizing bacteria
      in alkaline soils 
AB  - An ecological survey was conducted to characterize 4800 bacterial strains
      isolated from the root-free soil, rhizosphere, and rhizoplane of Prosopis
      juliflora growing in alkaline soils. Of the 4800 bacteria, 857 strains were able
      to solubilize phosphate on plates. The incidence of phosphate-solubilizing
      bacteria (PSB) in the rhizoplane was highest, followed by rhizosphere and root
      free soil. Eighteen bacterial strains out of 857 PSB were able to produce halo at
      30 degrees C in a plate assay in the presence of 5% salt (NaCl) and solubilize
      tricalcium phosphate in National Botanical Research Institute's phosphate growth
      medium (NBRIP) broth, in the presence of various salts, pHs, and temperatures.
      Among the various bacteria tested, NBRI4 and NBRI7 did not produced halo in a
      plate assay at 30 degrees C in the absence of salt. Contrary to indirect
      measurement of phosphate solubilization by plate assay, the direct measurement of
      phosphate solubilization in NBRIP broth assay always resulted in reliable
      results. The phosphate solubilization ability of NBRI4 was higher than in the
      control in the presence of salts (NaCl, CaCl2, and KCl) at 30 degrees C.
      Phosphate solubilization further increased in the presence of salts at 37 degrees
      C as compared with 30 degrees C. At 37 degrees C, CaCl2 reduced phosphate
      solubilization ability of NBRI4 compared with the control. The results indicated
      the role of calcium salt in the phosphate solubilization ability of
      NBRI4.http://link.springer-ny. com/link/service/journals/00284/bibs/39n2p89.html

PMID- 10398832
TI  - Specific detection of Xylella fastidiosa Pierce's disease strains.
AB  - Pierce's disease (PD, Xylella fastidiosa) of grapevine is the primary pathogen
      limiting vinifera grape production in Florida and other regions of the
      southeastern United States. Quick and accurate detection of PD strains is
      essential for PD studies and control. A unique random amplified polymorphic DNA
      (PD1-1-2) was isolated from a PD strain from Florida. Fragment PD1-1-2 was
      cloned, sequenced, and found to be 1005 bp in length. PCR primers were designed
      to utilize these sequence data for PD strain detection. One primer set (XF176f
      XF954r) amplified a 779-bp DNA fragment from 34 PD strains including seven
      pathotypes of X. fastidiosa, but not from strains of Xanthomonas campestris pv.
      campestris, Xan. vesicatoria or Escherichia coli. A second primer set (XF176f and
      XF686r) amplified a 511-bp fragment specific to 98 PD strains, but not from
      strains of citrus variegated chlorosis, mulberry leaf scorch, oak leaf scorch,
      periwinkle wilt, phony peach, or plum leaf scald. Sequence analysis indicated
      that RAPD fragment PD1-1-2 contains a Ser-tRNA gene. The PD-specific region
      includes a TaqI restriction site (TCGA) and is 150 bp downstream of the Ser-tRNA
      gene.

PMID- 10398835
TI  - Dissimilatory reduction of Fe(III) by thermophilic bacteria and archaea in deep
      subsurface petroleum reservoirs of western siberia 
AB  - Twenty-five samples of stratal fluids obtained from a high-temperature (60-84
      degrees C) deep subsurface (1700-2500 m) petroleum reservoir of Western Siberia
      were investigated for the presence of dissimilatory Fe(III)-reducing
      microorganisms. Of the samples, 44% and 76% were positive for Fe(III) reduction
      with peptone and H2 respectively as electron donors. In most of these samples,
      the numbers of culturable thermophilic H2-utilizing iron reducers were in the
      order of 10-100 cells/ml. Nine strains of thermophilic anaerobic bacteria and
      archaea isolated from petroleum reservoirs were tested for their ability to
      reduce Fe(III). Eight strains belonging to the genera Thermoanaerobacter,
      Thermotoga, and Thermococcus were found capable of dissimilatory Fe(III)
      reduction, with peptone or H2 as electron donor and amorphous Fe(III) oxide as
      electron acceptor. These results demonstrated that Fe(III) reduction may be a
      common feature shared by a wide range of anaerobic thermophiles and
      hyperthermophiles in deep subsurface petroleum reservoirs.http://link.springer
      ny. com/link/service/journals/00284/bibs/39n2p99.html

PMID- 10398834
TI  - Mutations of loop 2 and loop 3 residues in domain II of Bacillus thuringiensis
      Cry1C delta-endotoxin affect insecticidal specificity and initial binding to
      Spodoptera littoralis and Aedes aegypti midgut membranes.
AB  - Site-directed mutagenesis was used to examine the role of predicted loops 2
      (374QPWP377) and 3 (436QRSGTPF442) in domain II of the Bacillus thuringiensis
      Cry1C delta endotoxin for insecticidal specificity and receptor binding. Q374E,
      S438F, and G439A substitutions resulted in near or complete loss of toxicity
      toward both Spodoptera littoralis and Aedes aegypti. R437K, R437I, and G439V
      mutants exhibited significantly reduced toxicity to S. littoralis and A. aegypti,
      while mutations of T440, P441, and F442 showed only slight reductions in toxicity
      to both insects. Loop 2 mutations Q374N, P375A, W376Y, and P377A did not
      significantly affect S. littoralis toxicity but exhibited reduced activity to A.
      aegypti. In contrast, the loop 3 mutations Q436K, Q436E, and S438Y had no effect
      on A. aegypti toxicity, but showed significantly decreased S. littoralis
      activity. Heterologous competition binding assays with brush border membrane
      vesicles (BBMV) from both insects correlated well with the toxicity data with the
      exception of the R437 mutants, where steps other than initial receptor binding
      appear to be involved. Overall we conclude that, while loops 2 and 3 play an
      important role in binding and toxicity to both insects, loop 2 appears to play
      the greater role in A. aegypti activity, while loop 3 is more important for S.
      littoralis toxicity.

PMID- 10398836
TI  - Cloning and sequence analysis of the hemB gene of Rhodothermus marinus.
AB  - A Rhodothermus marinus gene, hemB, coding for 5-aminolevulinic acid (ALA)
      dehydratase (ALAD) has been cloned and sequenced. The reading frame of the hemB
      gene is 1020 base pairs encoding a protein of 340 amino acids with a calculated
      molecular mass of 37.4 kDa. The amino acid sequence shows homology with
      eubacterial and eukaryotic ALA dehydratases. A putative metal-binding site of the
      protein shows strongest homology with corresponding sites from plant ALA
      dehydratases that require Mg2+ for activity. It differs with respect to only one
      amino acid out of 20 from a corresponding site in pea ALAD.

PMID- 10398837
TI  - A triply cloned strain of xylella fastidiosa multiplies and induces symptoms of
      citrus variegated chlorosis in sweet orange 
AB  - Xylella fastidiosa isolate 8.1.b obtained from a sweet orange tree affected by
      citrus variegated chlorosis in the state of Sao Paulo, Brazil, and shown in 1993
      to be the causal agent of the disease, was cloned by repeated culture in liquid
      and on solid PW medium, yielding triply cloned strain 9a5c. The eighth and the
      16th passages of strain 9a5c were mechanically inoculated into sweet orange
      plants. Presence of X. fastidiosa in sweet orange leaves of shoots having grown
      after inoculation (first-flush shoots) was detected by DAS-ELISA and PCR. Thirty
      eight days after inoculation, 70% of the 20 inoculated plants tested positive,
      and all plants gave strong positive reactions 90 days after inoculation. Symptoms
      first appeared after 3 months and were conspicuous after 5 months. X. fastidiosa
      was reisolated from sweet orange leaves, 44 days after inoculation. These results
      indicate that X. fastidiosa strain 9a5c, derived from pathogenic isolate 8.1.b by
      triply cloning, is also pathogenic. Strain 9a5c is now used for the X. fastidiosa
      genome sequencing project undertaken on a large scale in Brazil.http://link.
      springer-ny.com/link/service/journals/00284/bibs/39n2p106.html

PMID- 10398838
TI  - Fermenting Escherichia coli is able to grow in media of high osmolarity, but is
      sensitive to the presence of sodium ion.
AB  - Escherichia coli is able to grow at increased NaCl concentrations that provides
      an increase in medium osmolarity and cellular Na+ content. The addition of 0.5 M
      NaCl to the growth medium led to a substantial decrease in growth rate during
      anaerobic fermentation on glucose at pH of 7.3 or 9.0. This inhibitory effect of
      0.5 M NaCl was at least threefold stronger than that seen under aerobic
      conditions, and stronger than equivalent concentrations of sucrose, KCl, or
      potassium glutamate under anaerobic conditions. Further, proline was found to
      stimulate the growth rate at high NaCl concentration under anaerobic and to a
      lesser extent, under aerobic conditions. Wild-type cells and mutants having a
      functional NhaA or ChaA alone grown under anaerobic conditions at pH 9.0 and
      subsequently loaded with Na+ were shown to extrude Na+ at a rate that were lower
      than the extrusion rate reported for appropriate aerobically grown bacteria
      (Sakuma et al. [1998] Biochim Biophys Acta 1363:231-237). The growth rate and Na+
      extrusion activity of a mutant having a functional NhaA were similar to that of
      the wild type and higher than that of a mutant with an active ChaA. A mutant
      defective for both NhaA and ChaA was unable to grow under anaerobic conditions at
      pH 9.0 in the presence of 0.15 M Na+. It is suggested that the observed strong
      inhibition in the growth of E. coli during fermentation under anaerobic
      conditions in the presence of increased NaCl concentration could be due to a
      decrease in Na+ extrusion activity.

PMID- 10398841
TI  - 4th european meiosis meeting obertraun 1999 

PMID- 10398839
TI  - Characterization of Mycobacterium paratuberculosis p36 antigen and its
      seroreactivities in Crohn's disease.
AB  - Recent data using improved cultural, molecular, and serological techniques have
      strengthened the association of Mycobacterium paratuberculosis with Crohn's
      disease, an inflammatory bowel disease (IBD) with unknown etiology. To provide
      more evidence of an etiological association, antibody reactivities of Crohn's
      disease patients were tested by immunoblotting against M. paratuberculosis
      recombinant antigens. A clone containing a 1,402-bp insert and expressing a 36K
      antigen (p36) was analyzed. No homology was found between the deduced amino acid
      sequence of p36 and any protein sequences compiled in the GenBank indicating that
      p36 is a novel mycobacterial protein. The reactivity of 199 serum samples was
      tested against the p36 by immunoblotting technique. Sera from 77 of 89 (86.5%)
      Crohn's disease patients and 16 of 18 (89%) sera from patients with tuberculosis
      and leprosy reacted with p36 compared to 5 of 42 (12%) ulcerative colitis and non
      IBD control sera (p < 0.0001). In addition, p36 reacted to all sera from 10
      normal controls that were Bacillus Calmette-Guerin (BCG)-immunized and only to
      10% of 40 normal controls that were not BCG-immunized. The fact that sera from
      Crohn's disease patients reacted to p36 with the same high frequency as the sera
      from patients that were exposed to mycobacterial antigens further supports the
      hypothesis of the mycobacterial etiology in Crohn's disease.

PMID- 10398842
TI  - Chromosoma prize 1999 to B.F. McEwen 

PMID- 10398843
TI  - Chromosoma prize 1999 to R.G. nagele 

PMID- 10398844
TI  - The ZDS1 and ZDS2 proteins require the Sir3p component of yeast silent chromatin
      to enhance the stability of short linear centromeric plasmids.
AB  - Yeast artificial chromosome (YAC) clones of Saccharomyces cerevisiae containing a
      centromere, origin of replication, two telomeres and a >50 kb insert of DNA are
      maintained as normal yeast chromosomes. However, short linear centromeric
      plasmids of 10-15 kb in size (short YACs) are missegregated at a much higher
      frequency than long YACs or 10-15 kb circular centromeric plasmids. A search for
      genes that stabilized short linear centromeric plasmids when present in multiple
      copies per cell uncovered ZDS1, which reduced the rate at which cells lost the
      short YAC, increased the fraction of cells that maintained the short YAC and
      decreased the number of short YACs per cell. Multiple copies of ZDS2, a homolog
      of ZDS1, had similar effects. Genes near yeast telomeres are transcriptionally
      silenced by the recruitment of proteins encoded by the SIR2, SIR3 and SIR4 genes
      (Sir2p, Sir3p and Sir4p). Multiple copies of ZDS1 and ZDS2 caused an increase in
      telomeric silencing. In addition, ZDS1 and ZDS2 both required the open reading
      frame encoding the N-terminal 174 amino acids of Sir3p to stabilize short YACs.
      Thus, the short YAC stability assay revealed a silencing-independent function for
      the Sir3p N-terminus. Two-hybrid analysis indicated that Zds1p and Zds2p interact
      with Sir2p, Sir3p, Sir4p or the yeast telomere binding protein Rap1p. Deletion of
      both ZDS1 and ZDS2 made short YACs, but not a 100 kb YAC, extremely unstable and
      also caused a 70 bp increase in the length of the telomeric TG1-3 repeats. These
      data indicate that short YACs can be stabilized by trans-acting factors and
      suggest that the proteins encoded by ZDS1 and ZDS2 alter short YAC stability by
      interacting with proteins that function at the telomere.

PMID- 10398845
TI  - The puff-specific RRM protein NonA is a single-stranded nucleic acid binding
      protein.
AB  - The chromatin protein NonA from Drosophila, present in many puffs on polytene
      chromosomes, belongs to the growing class of RRM proteins. Exchange of amino
      acids within the RNP1 and RNP2 consensus sequences, known from other RRM proteins
      to be essential for RNA binding, has been shown drastically to reduce NonA
      function in vivo. Here we compare NonA binding to RNA from the Sgs-4 gene, an in
      situ target for NonA, with binding to Sgs-3 RNA, which is not a target of NonA.
      Using an immunoprecipitation assay in vitro we show that NonA binds to single
      stranded (ss)DNA and RNA with moderate affinity (KD=8x10(-8) M). However, we did
      not observe sequence-specific binding to the Sgs-4 transcript nor to Sgs-4 DNA
      containing upstream regulatory sequences. Point mutations within the RNP1 and
      RNP2 consensus sequences that interfere with NonA function in vivo do not
      significantly change chromosomal binding nor the general affinity for RNA. The
      expression of Sgs-4 RNA relative to the expression of Sgs-3 RNA remains the same
      in the presence or absence of NonA protein.
      com/link/service/journals/00412/bibs/108n3p162.html

PMID- 10398846
TI  - Molecular differentiation of sex chromosomes probed by comparative genomic
      hybridization.
AB  - Comparative genomic hybridization (CGH) was used to identify and probe sex
      chromosomes in several XY and WZ systems. Chromosomes were hybridized
      simultaneously with FluorX-labelled DNA of females and Cy3-labelled DNA of males
      in the presence of an excess of Cot-1 DNA or unlabelled DNA of the homogametic
      sex. CGH visualized the molecular differentiation of the X and Y in the house
      mouse, Mus musculus, and in Drosophila melanogaster: while autosomes were stained
      equally by both probes, the X and Y chromosomes were stained preferentially by
      the female-derived or the male-derived probe, respectively. There was no
      differential staining of the X and Y chromosomes in the fly Megaselia scalaris,
      indicating an early stage of sex chromosome differentiation in this species. In
      the human and the house mouse, labelled DNA of males in the presence of
      unlabelled DNA of females was sufficient to highlight Y chromosomes in mitosis
      and interphase. In WZ sex chromosome systems, the silkworm Bombyx mori, the flour
      moth Ephestia kuehniella, and the wax moth Galleria mellonella, the W chromosomes
      were identified by CGH in mitosis and meiosis. They were conspicuously stained by
      both female- and male-derived probes, unlike the Z chromosomes, which were
      preferentially stained by the male-derived probe in E. kuehniella only but were
      otherwise inconspicuous. The ratio of female:male staining and the pattern of
      staining along the W chromosomes was species specific. CGH shows that W
      chromosomes in these species are molecularly well differentiated from the Z
      chromosomes. The conspicuous binding of the male-derived probe to the W
      chromosomes is presumably due to an accumulation of common interspersed
      repetitive sequences.

PMID- 10398847
TI  - Third-strand in situ hybridization (TISH) to non-denatured metaphase spreads and
      interphase nuclei.
AB  - A methodology has been developed for binding oligodeoxyribonucleotide 'third
      strands' to duplex DNA targets in fixed but not additionally denatured metaphase
      spreads and interphase nuclei under conditions found to be optimal in solution.
      Third-strand in situ hybridization (TISH) at pH 6.0 of a psoralen- and biotin
      modified 16-nucleotide homopyrimidine third strand to a unique multicopy target
      sequence in human chromosome 17 alpha-satellite (D17Z1 locus) is described. UVA
      photofixed third strands, rendered fluorescent by fluorescein isothiocyanate
      labeled avidin, are reproducibly centromere-specific for chromosome 17, and
      visible without amplification of the signal in lymphocyte and somatic cell hybrid
      spreads and interphase nuclei. Two third-strand-specific D17Z1 haplotypes were
      identified. TISH has potential diagnostic, biochemical, and flow cytometric
      applicability to native metaphase and interphase chromatin.

PMID- 10398848
TI  - A novel histone variant localized in nucleoli of higher plant cells.
AB  - Immunofluorescence staining with antisera raised against p35, a basic nuclear
      protein that accumulates in the pollen nuclei of Lilium longiflorum, specifically
      stained the nucleoli in interphase nuclei of somatic tissues, including root and
      leaf, and in pachytene nuclei during meiotic division, whereas antisera raised
      against histone H1 uniformly stained the entire chromatin domain with the
      exception of the nucleoli in these nuclei. Further, p35-specific antisera stained
      the nucleoli in root and leaf nuclei of the monocotyledonous plants Tulipa
      gesneriana, Allium cepa and Triticum aestivum and of the dicotyledonous plants
      Vicia faba and Nicotiana tabacum. Thus, these novel antisera stained the nucleoli
      in cells of all higher plants examined, although the staining patterns within
      nucleoli were somewhat different among plant species and tissues. The full-length
      cDNA of p35 was cloned on the basis of the partial amino acid sequence. The
      deduced amino acid composition and amino acid sequence of p35 indicate that this
      nucleolar protein is a novel variant of histone Hl. Further, p35 was strongly
      bound to ribosomal DNA in vitro. The results of immunoblotting of histones
      extracted from each tissue of the various plant species with the nucleolus
      specific antibodies also suggested the conservation of similar epitope(s) in both
      mono- and dicotyledonous plants. From these results, it is suggested that similar
      variants of histone Hl are specifically distributed in the nucleoli of all plant
      species and help to organize the nucleolar chromatin.

PMID- 10398849
TI  - New ribosomal RNA gene locations in Gossypium hirsutum mapped by meiotic FISH.
AB  - In this study we have mapped newly identified rDNA loci in Gossypium hirsutum.
      Four new minor 18S-26S rDNA loci, in addition to the sites previously identified,
      were mapped using fluorescence in situ hybridization (FISH) to heterozygous
      translocation (NT) quadrivalents (IVs). The newly detected 18S-26S rDNA loci were
      mapped to the right arms of chromosomes 8, 9, 15, 17, 19, 20, and 23 and the left
      arms of chromosomes 5, 11, 12, and 14. Using the rDNA loci as common reference
      points, we detected several erroneous arm assignments in the previously published
      map of NT breakpoints. The data are summarized in the form of an integrated map
      for all 17 known rDNA loci, relative to centromeres, telomeres, and NT
      breakpoints. This information will facilitate future locus-specific research on
      rRNA gene evolution and function.

PMID- 10398851
TI  - TGF-beta1 mediates 70-kDa heat shock protein induction due to ultraviolet
      irradiation in human skin fibroblasts.
AB  - Ultraviolet B (UVB) alters the expression of heat shock protein 70 (HSP70) in
      cultured fibroblast cells derived from human skin. However, the nature of the
      signal transduction pathway remains to be determined. Transforming growth factor
      beta (TGF-beta) has a large variety of biological functions, including cell
      growth control, modulation of inflammation and immunoregulation. In this study,
      we examined whether TGF-beta is associated with the process of HSP70 expression
      induced by UVB irradiation. The constitutive expression of TGF-beta1 mRNA and
      HSP70 expression in human skin fibroblast cells were detected using reverse
      transcription polymerase chain reaction (RT-PCR) and Western blot analysis. The
      results indicate that: (1) UVB irradiation stimulates HSP70 expression in a dose-
      and time-dependent manner, (2) constitutive expression of TGF-beta1 mRNA is
      detected after UVB irradiation, the level of which peaks at 4 h after 10 mJ cm-2
      of UVB irradiation, (3) HSP70 expression is induced by TGF-beta1 without UVB
      irradiation, and (4) HSP70 expression induction with UVB irradiation is inhibited
      by preincubation of the cells with the anti-TGF-beta type II receptor antibody.
      Our results suggest that HSP70 expression induced by UVB involves the autocrine
      signalling of TGF-beta production.

PMID- 10398852
TI  - Rescue of the mineralocorticoid receptor knock-out mouse.
AB  - The mineralocorticoid receptor knock-out mouse (MR-/-), resembling inborn
      pseudohypoaldosteronism, dies 8-12 days after birth in circulatory failure with
      all the signs of terminal volume contraction. The present study aimed to examine
      the functional defects in the kidney and colon in detail and to attempt to rescue
      these mice. In neonatal (nn) MR-/- the amiloride-sensitive short-circuit current
      in the colon was reduced to approximately one-third compared to controls (MR+/+
      and MR+/-). In isolated in vitro perfused collecting ducts the amiloride-induced
      hyperpolarization of the basolateral membrane (Vbl) of nn MR-/- was similar to
      that of controls, but urinary Na+ excretion was markedly increased to 4.3
      micromol/day.g (BW). Based on this measured urinary Na+ loss we tried to rescue
      nn MR-/- mice by injecting NaCl twice daily (3.85 micromol/g BW), corresponding
      to 22 microliter of isotonic saline/g BW subcutaneously. This regimen was
      continued until the animals had reached a body mass of 8.5 g. Thereafter, in
      addition to normal chow and tap water, NaCl drinking water (333 mmol/l) and
      pellets soaked in 333 mmol/l NaCl were offered. Unlike the untreated nn MR-/-
      most of these mice survived. The adult animals were examined between days 27 and
      41, some were used for breeding. When compared to age-matched controls the growth
      of MR-/- was delayed until day 20. Then their growth curve increased in slope and
      reached that of controls. MR-/- retained their Na+-losing defect. Amiloride's
      effect on urinary Na+ excretion was not significant in MR-/- mice and the effect
      on Vbl in isolated cortical collecting ducts was attenuated. The renin-producing
      cells were hypertrophic and hyperplastic. Plasma renin and aldosterone
      concentrations were significantly elevated in MR-/- mice. These data indicate
      that MR-/- can be rescued by timely and matched NaCl substitutions. This enables
      the animals to develop through a critical phase of life, after which they adapt
      their oral salt and water intake to match the elevated excretion rate; however,
      the renal salt-losing defect persists.

PMID- 10398853
TI  - Selective inhibition of the Na+/H+ exchanger type 3 activates CO2/H+-sensitive
      medullary neurones.
AB  - Hypercapnia as well as lowered intracellular pH (pHi) increase the bioelectric
      activity of CO2/H+-sensitive neurones (VLNcs) of the ventrolateral medulla
      oblongata. Here we describe that immunoreactive Na+/H+ exchanger (NHE3) is
      present in ventrolateral neurones from medullary organotypic cultures (obex
      level). To test whether VLNcs can be acidified and thereby activated by
      inhibition of NHE3, we used the novel high-affinity NHE3-inhibitors S1611 and
      S3226. Both drugs raised the firing rates of VLNcs to at least 150% of the
      control values, and depolarized membrane potential by up to 15 mV at
      concentrations (0.5-1 micromol/l) suitable for selective inhibition of NHE3. The
      changes in bioelectric activity strongly resembled the responses to hypercapnia
      (PCO2: 60-100 mmHg). In BCECF-AM-loaded cultures a subfraction of ventrolateral
      VLNcs was found to be intracellularly acidified by 0.05-0.1 pH units following
      treatment with S1611; the time course of this acidification was similar to that
      evoked by hypercapnia. All drug effects were sustained and readily reversible
      upon washing. Non-CO2/H+-responsive medullary neurones as well as hippocampal CA3
      neurones were unaffected by up to 20 micromol/l S1611. It is concluded that the
      selective inhibition of NHE3 acidifies and activates CO2/H+-sensitive neurones
      within the ventrolateral medulla oblongata.

PMID- 10398854
TI  - Leukotriene D4 (LTD4) activates charybdotoxin-sensitive and -insensitive K+
      channels in ehrlich ascites tumor cells.
AB  - The putative role for ATP, UTP, bradykinin and leukotriene D4 (LTD4) in the
      activation of the charybdotoxin-insensitive, volume-activated K+ leak pathway has
      been assessed in Ehrlich cells. K+ channel activity is evaluated from bumetanide
      insensitive 86Rb+ efflux using Rb+ as a tracer for K+. Addition of the Ca2+
      mobilizing agonists bradykinin, ATP, UTP or LTD4 accelerates the regulatory
      volume decrease (RVD) response and activates a fast bumetanide-insensitive,
      charybdotoxin-sensitive efflux of K+. In addition LTD4 activates a charybdotoxin
      insensitive K+ efflux, whereas bradykinin, ATP and UTP do not. The charybdotoxin
      insensitive K+ efflux dominates after addition of LTD4 at concentrations too low
      to elicit an increase in [Ca2+]i but still high enough to be effective in
      accelerating the RVD response. The EC50 values for LTD4-induced K+ effluxes are
      estimated at 2 nM and 15 nM for the charybdotoxin-insensitive and charybdotoxin
      sensitive components, respectively. The LTD4 (cysLT1) receptor antagonist
      L660,711(MK-571) blocks the activation of the charybdotoxin-sensitive but not the
      charybdotoxin-insensitive K+ efflux. Thus, LTD4 activates two different K+ leak
      pathways in Ehrlich cells, one pathway activated by an increase in [Ca2+]i and
      the other via an alternative signalling pathway. LTD4 is thus a potential
      candidate for an autocrine messenger activating the Ca2+-independent,
      charybdotoxin-insensitive K+ channel during the RVD response in Ehrlich cells.

PMID- 10398855
TI  - On the mechanism of genistein-induced activation of protein kinase A-dependent Cl
      conductance in cardiac myocytes.
AB  - Genistein, an inhibitor of protein tyrosine kinase (PTK), enhanced the activation
      of the cardiac isoform of the protein kinase A (PKA)-regulated cystic fibrosis
      transmembrane conductance regulator (CFTR) Cl- conductance in guinea-pig
      ventricular cells. We examined the mechanism(s) underlying this excitatory action
      of genistein by using patch-clamp techniques. The CFTR Cl- conductance, activated
      by isoproterenol (ISO, 10 nM; [Cl-] 153 mM extracellular, 21 mM intracellular; 36
      degrees C), was enhanced by 20 microM genistein. Daidzein, a structural analogue
      of genistein with little inhibitory action on PTK, also enhanced CFTR Cl-
      currents. After maximal activation of the Cl- conductance by a cocktail of
      adenosine 3', 5'-cyclic monophosphate, 3-isobutyl-1-methylxanthine and okadaic
      acid or vanadate plus forskolin in the pipette, genistein was no longer
      stimulatory but was rather slightly inhibitory at 100 microM. Direct exposure of
      myocytes to higher concentrations of genistein (50-100 microM) elicited outwardly
      rectifying currents with a reversal potential of -47 mV in the absence of ISO. In
      the presence of 50 microM H-89, a PKA inhibitor, genistein had no effect.
      Vanadate in the pipette at a concentration (100 microM) inhibiting
      phosphotyrosine phosphatases alone did not prevent the action of genistein. In
      contrast, no conductance was activated by tyrphostins B42 or 51 or lavendustin A,
      other PTK inhibitors. Genistein's stimulation of cardiac CFTR Cl- conductance
      appears to be independent of the PTK pathway and to be due to its direct
      interaction with CFTR Cl- channels.

PMID- 10398856
TI  - Phosphocreatine as a marker of contractile activity in single muscle fibres.
AB  - ATP and phosphocreatine (PCr) were measured in randomly selected single fibres
      from control, 1- and 8-day low-frequency-stimulated rabbit tibialis anterior
      muscles. The fibres were classified according to their myosin heavy chain (MHC)
      complement as type I, IIA or IID. In 1-day stimulated muscle, which has
      previously been shown to exhibit a steep decline in force output, two fibre
      populations could be distinguished according to either normal or markedly
      depressed PCr levels. The fibre population exhibiting normal PCr levels
      encompassed a major fraction (65%) of type IID fibres and a minor fraction (35%)
      of IIA fibres. The population with reduced PCr levels comprised type I fibres
      (@50% reduced), the majority of type IIA fibres (@80% reduced), and a minor
      fraction of type IID fibres (@70% reduced). Levels of ATP were unaltered in type
      I and IIA fibres, but were @ 20% reduced in those IID fibres that exhibited low
      PCr levels. Assuming that those fibres that displayed reduced PCr levels were
      contracting, the IID and IIA fibres with normal PCr levels were regarded as
      metabolically recovering, non-contracting fibres. As previously shown, these
      fibres are transiently refractory during the early phase of low-frequency
      stimulation. After 8 days of chronic low-frequency stimulation, when force was
      shown to rise again, most fibres appeared more uniform with regard to reduced PCr
      and ATP levels. Our results suggest that PCr can be used as a sensitive measure
      of the degree of activity in single-fibre studies.

PMID- 10398857
TI  - Modal gating transitions in cardiac ryanodine receptors during increases of Ca2+
      concentration produced by photolysis of caged Ca2+.
AB  - Channel adaptation is a basic property of the sarcoplasmic reticulum Ca2+-release
      channels/ryanodine receptors (RyRs). It allows channel activity to decay during
      sustained increases in the concentration of activating Ca2+. Despite the
      potential physiological importance of this self-confining process, its molecular
      mechanism is not well understood. To define the mechanism of adaptation we
      studied the dynamics of cardiac Ca2+-release channel (RyR) gating using the
      planar lipid bilayer technique in combination with photolysis of caged Ca2+ (DM
      nitrophen). Channels activated by rapid and sustained increases in Ca2+
      concentration (from 0.1 to 0.5 micromol/l) displayed three distinct gating modes,
      manifested as current records with frequent and long openings (H-mode), with rare
      and short openings (L-mode), and with no openings (I-mode). H-mode channel
      activity occurred primarily at early times while L- and I-modes predominated at
      late times after the rapid Ca2+ concentration increase. The decrease in
      probability of H-mode, mirrored by an increase in the probability of the I-mode,
      proceeded with a time constant similar to that observed for spontaneous decay in
      channel activity (i.e., adaptation) in ensemble average records. These results
      indicate that RyR adaptation transpires by a shift of channel gating from a high
      open probability mode to low open probability and inactivated modes of the
      channel.

PMID- 10398858
TI  - Effects of reactive oxygen species on myofilament function in a rabbit coronary
      artery ligation model of heart failure.
AB  - This study aimed to determine structural alterations occurring in cardiac
      myofilaments after exogenous application of oxidants and the effects of oxidants
      on contractile protein function in a rabbit coronary artery ligation model of
      heart failure. Myocardial "stiffness" was higher in the ligated animals (Lig)
      than sham-operated controls (Sh, 4.9+/-1.5 versus 1.6+/-0.8 mN.mm-1). Superoxide
      anion (O2-) exposure decreased active stiffness in both groups, whereas
      hypochlorous acid (HOCl) had no effect in Lig but increased stiffness in Sh.
      Resting stiffness was higher in Lig than Sh (0.6+/-0.2 versus 0.2+/-0.1 mN.mm-1),
      remaining unchanged after O2- exposure but increasing after HOCl in both groups.
      The frequency at minimum stiffness was lower in Lig than Sh (0.9+/-0.2 versus 1.
      7+/-0.6 Hz) and was reduced in both groups after oxidant exposure. Myofilament
      calcium sensitivity (pCa50) was not altered by O2- in Sh but increased in Lig
      (pCa50 increased from 5.41+/-0.05 to 5.56+/-0. 06). Protease contamination in the
      xanthine oxidase used to generate O2- did not affect myofilament ultrastructure
      at the concentrations used here. These data demonstrate that contractile proteins
      from "failed" myocardium have a similar response to exogenously applied oxidants
      as controls and that application of protease-contaminated xanthine oxidase system
      does not degrade the contractile protein structure.

PMID- 10398859
TI  - Comparison of the postprandial release of peptide YY and proglucagon-derived
      peptides in the rat.
AB  - Endocrine L-cells of the distal intestine synthesize both peptide YY (PYY) and
      proglucagon-derived peptides (PGDPs), whose release has been reported to be
      either parallel or selective. Here we compare the release mechanisms of PYY,
      glucagon-like peptide-1 (GLP-1), and oxyntomodulin-like immunoreactivity (OLI) in
      vivo. Anaesthetized rats were intraduodenally (ID) given either a mixed semi
      liquid meal or oleic acid, or they received oleic acid or short chain fatty acids
      (SCFA) intracolonically (IC). The ID meal released the three peptides with a
      similar time-course (peak at 30 min); ID oleic acid produced a progressive
      release of PYY and OLI, while GLP-1 release was less. IC oleic acid or SCFA
      released smaller (but significant) amounts of PYY but no OLI or GLP-1.
      Hexamethonium inhibited most of the response to the ID meal and ID oleic acid,
      but did not change the PYY response to IC oleic acid. NG-nitro-l-arginine methyl
      ester (l-NAME, a nitric oxide synthase inhibitor) inhibited meal-induced PYY
      release and left OLI and GLP-1 unaffected. BW10 (a gastrin-releasing peptide
      antagonist) had no effect on the meal-induced release of either peptide. These
      results suggest a parallel initial release of PYY, OLI and GLP-1 after the ID
      meal, or oleic acid, by an indirect mechanism triggered in the proximal bowel,
      using nicotinic synapses, and involving nitric oxide release for PYY and an
      unknown mediator for PGDPs. For PYY there is a later phase of peptide release,
      probably induced by direct contact between nutrients and colonic L-cells.

PMID- 10398860
TI  - Excessive microtubules are not responsible for depressed force per cross-bridge
      in cardiac neural-crest-ablated embryonic chick hearts.
AB  - Ablation of the cardiac neural crest (CNCA) in embryonic chicks results in a high
      incidence of persistent truncus arteriosus, a congenital heart defect associated
      with decreased myocardial contractility. Using left ventricular trabeculae from
      chicks at embryonic day (ED) 15, we have previously shown that the twitch force
      of intact preparations is significantly reduced whereas the maximal calcium
      activated force of skinned preparations is not significantly different in CNCA
      and sham-operated animals. We also previously found that the ventricular content
      of myosin, as well as of actin and tropomyosin, was nearly doubled in ED 15
      hearts after CNCA. Since the number of cross-bridges is proportional to the
      myosin concentration, these data suggest that the force exerted per cross-bridge
      is decreased in CNCA hearts. We investigated the possibility that the decrease in
      force per cross-bridge is caused by inhibition of the contractile apparatus by
      excessive microtubules. To the contrary, we found that the total beta-tubulin
      content and the fraction of beta-tubulin polymerized in microtubules measured by
      Western blotting was the same in ventricular muscle strips from CNCA and sham
      operated embryos. Furthermore, exposure to microtubule-destabilizing agents did
      not improve the force-producing capability of the contractile apparatus in CNCA
      embryos. We conclude that depression of force per cross-bridge in hearts from
      CNCA embryos is not due to an excess of microtubules.

PMID- 10398861
TI  - Bicuculline block of small-conductance calcium-activated potassium channels.
AB  - Small-conductance calcium-activated potassium channels (SK channels) are gated
      solely by intracellular calcium ions and their activity is responsible for the
      slow afterhyperpolarization (AHP) that follows an action potential in many
      excitable cells. Brain slice studies commonly employ a methyl derivative of
      bicuculline (bicuculline-m), a GABAA (gamma-aminobutyric acid) receptor
      antagonist, to diminish the tonic inhibitory influences of GABAergic synapses, or
      to investigate the role of these synapses in specialized neural networks.
      However, recent evidence suggests that bicuculline-m may not be specific for
      GABAA receptors and may also block the slow AHP. Therefore, the effects of
      bicuculline-m on cloned apamin-sensitive SK2 and apamin-insensitive SK1 channels
      were examined following expression in Xenopus oocytes. The results show that at
      concentrations employed for slice recordings, bicuculline-m potently blocks both
      apamin-sensitive SK2 currents and apamin-insensitive SK1 currents when applied to
      outside-out patches. Apamin-insensitive SK1 currents run down in excised patches.
      The potency of bicuculline-m block also decreases with time after patch excision.
      Site-directed mutagenesis that changes two residues in the outer vestibule of the
      SK1 pore that confers apamin sensitivity also reduces run down of the current in
      patches, and endows stable sensitivity to bicuculline-m indistinguishable from
      SK2. Therefore, the use of bicuculline-m in slice recordings may mask apamin
      sensitive slow AHPs that are important determinants of neuronal excitability. In
      addition, bicuculline-m-insensitive slow AHPs may indicate that the underlying
      channels have run down.

PMID- 10398862
TI  - Stoichiometry of the rat kidney Na+-HCO3- cotransporter expressed in Xenopus
      laevis oocytes.
AB  - The rat kidney Na+-HCO3- cotransporter (rkNBC) was expressed in Xenopus laevis
      oocytes and transport via rkNBC was studied with the patch-clamp technique in
      giant inside/out (i/o) or outside/out (o/o) membrane patches. The current/voltage
      (I/V) relation(s) of individual patches was(were) determined in solutions
      containing only Na+ and HCO3- as permeable ions. The current carried by rkNBC
      (INBC) was identified by its response to changing bath Na+ concentration(s) and
      quantified as the current blocked by 4, 4'-diisothiocyanatostilbene disulfonate
      (DIDS). The stoichiometric ratio (q) of HCO3- to Na+ transport was determined
      from zero-current (reversal) potentials. The results and conclusions are as
      follows. First, DIDS (250 micromol/l) blocks INBC irreversibly from both the
      extracellular and the intracellular surface. Second, in the presence of Na+ and
      HCO3- concentration gradients similar to those which rkNBC usually encounters in
      tubular cells, q was close to 2. The same value was also observed when the HCO3-
      concentration was 25 mmol/l throughout, but the Na+ concentration was either high
      (100 mmol/l) or low (10 mmol/l) on the extracellular or intracellular surface of
      the patch. These data demonstrate that in the oocyte cell membrane rkNBC works
      with q=2 as previously observed in a study of isolated microperfused tubules
      (Seki et al., Pflugers Arch 425:409, 1993), however, they do not exclude the
      possibility that in a different membrane and cytoplasmic environment rkNBC may
      operate with a different stoichiometry. Third, in most experiments bath
      application of up to 2 mmol/l ATP increased the DIDS-inhibitable conductance of
      i/o patches by up to twofold with a half saturation constant near 0.5 mmol/l.
      This increase was not associated with a change in q, nor with a shift in the I/V
      relationship which would suggest induction of active transport (pump current).
      Since the effect persisted after ATP removal and was not observed with the non
      hydrolysable ATP analogue AMP-PNP, it is possible that rkNBC is activated by
      phosphorylation via protein kinases that might adhere to the cytoplasmic surface
      of the membrane patch.

PMID- 10398863
TI  - Migration of transformed renal epithelial cells is regulated by K+ channel
      modulation of actin cytoskeleton and cell volume.
AB  - Migration of transformed renal epithelial (MDCK-F) cells depends on the polarized
      activity of a Ca2+-sensitive K+ channel (IK channel; Pflugers Arch 432:R87-R93,
      1996). This study was aimed at elucidating the functional link between the IK
      channel and the actin cytoskeleton which is required for cell locomotion. We
      monitored migration of MDCK-F cells with video microscopy, quantified filamentous
      actin with phalloidin binding, and measured the intracellular Ca2+ concentration
      ([Ca2+]i) with the fluorescent dye fura-2/AM. We compared the effects of IK
      channel activation or inhibition with those of hypotonic swelling or hypertonic
      shrinkage. IK channel inhibition with charybdotoxin (CTX) or cell swelling
      (omission of up to 50 mmol/l NaCl) as well as IK channel activation with 1-ethyl
      2-benzimidazolinone (1-EBIO) or cell shrinkage (addition of up to 100 mmol/l
      mannitol) reduce the rate of migration dose-dependently by up to 80%, i.e., to
      the same extent as cytochalasin D. Inhibition of migration is accompanied either
      by actin depolymerization (CTX and cell swelling) or by actin polymerization (1
      EBIO and cell shrinkage). Changes of migration and phalloidin binding induced by
      CTX and cell swelling or by 1-EBIO and cell shrinkage, respectively, are linearly
      correlated with each other. CTX and cell swelling elicit a rise of [Ca2+]i
      whereas 1-EBIO and cell shrinkage induce a slight decrease of [Ca2+]i in most
      MDCK-F cells. Taken together IK-channel-dependent perturbations of cell volume
      and anisotonicity elicit virtually identical effects on migration, actin
      filaments and [Ca2+]i. We therefore suggest that cell volume - possibly via
      [Ca2+]i - is the link between IK channel activity, actin filaments and migration.
      We propose a model for how temporal and local changes of cell volume can support
      the migration of MDCK-F cells.

PMID- 10398865
TI  - Secretory apical Cl- channels in A6 cells: possible control by cell Ca2+ and
      cAMP.
AB  - Distal kidney cells (A6) from Xenopus laevis were cultured to confluency on
      porous supports. Tissues were mounted in Ussing-type chambers to measure short
      circuit current (Isc), transepithelial conductance and capacitance, and to
      analyse the fluctuation in Isc. In the absence of apical NaCl, but with normal
      basolateral NaCl Ringer's solution, extracellular addition of ATP, oxytocin, a
      membrane-permeant cAMP derivative, and forskolin produced a transient increase of
      the electrical parameters. Noise analysis revealed a spontaneous Lorentzian
      component. All responses depend strictly on the presence of basolateral Cl- and
      are caused by the activation of an apical (CFTR type) Cl- permeability.
      Repetitive treatment with ATP (or oxytocin) resulted in refractoriness. ATP and
      oxytocin acted antagonistically, whereas cAMP and ATP had additive effects.
      Incubation with the vesicular Ca2+ pump inhibitor thapsigargin or application of
      the Ca2+ channel blocker nifedipine elicited finite but variable Cl- channel
      activity. After treatment with nifedipine or thapsigargin, the response to
      oxytocin was severely impaired. We speculate that not only cAMP but also cell
      Ca2+ plays a crucial role in the activation of CFTR in A6. Ca2+ may be
      multifunctional but the rise in capacitance (apical area) observed with all
      stimulants strongly suggests its involvement in, and contribution to, exocytosis
      in the process of the CFTR-mediated transcellular Cl- movements.

PMID- 10398864
TI  - Does adrenaline modulate the Na+-Ca2+ exchanger in isolated toad pacemaker cells?
AB  - beta-Adrenergic stimulation of pacemaker cells from the sinus venosus of the cane
      toad (Bufo marinus) increases intracellular calcium ([Ca2+]i) and firing rate.
      The increase in [Ca2+]i could contribute to the increased firing rate by
      increasing the inward Na+-Ca2+ exchange current (INa-Ca) during diastole. In this
      study we measured [Ca2+]i and membrane currents in single, isolated, voltage
      clamped pacemaker cells. We show that INa-Ca increases during beta-adrenergic
      stimulation. To test whether this increase in INa-Ca is caused by elevated
      [Ca2+]i or by changes in the properties of the Na+-Ca2+ exchanger, we made rapid
      applications of caffeine and plotted the INa-Ca against [Ca2+]i. This
      relationship was linear during the declining phase of the [Ca2+]i signal caused
      by caffeine and was not significantly different in the presence or absence of
      beta stimulation. These results show that INa-Ca is increased during beta
      adrenergic stimulation and will contribute to the increased firing rate. However
      the increase in INa-Ca appears to be a consequence of the increase in [Ca2+]i and
      is not caused by changes in the intrinsic properties of the Na+-Ca2+ exchanger.

PMID- 10398866
TI  - Time-dependent regulation by aldosterone of the amiloride-sensitive Na+ channel
      in rabbit kidney.
AB  - The epithelial Na+ channel (ENaC) functions as the rate-limiting factor in
      aldosterone-regulated transcellular Na+ transport. In the study described here,
      the effect of aldosterone on ENaC mRNA levels, protein synthesis and benzamil
      sensitive Na+ transport was investigated using primary cultures of
      immunodissected rabbit kidney connecting tubule and cortical collecting duct
      cells (CNT and CCD, respectively). After a lag time of 3 h, aldosterone caused
      transepithelial Na+ transport to increase, reaching maximal level of 260+/-44%
      after 16 h of incubation. The alpha, beta and gamma rabbit ENaC (rbENaC) mRNA
      levels, measured by semi-quantitative reverse transcriptase-polymerase chain
      reaction, were not changed by aldosterone during the first 3 h, but a twofold
      increase was apparent after 6 h; levels remained elevated for up to 16 h of
      incubation. Immunoprecipitation of [35S]methionine-labeled rbENaC revealed a rise
      in protein levels of the alpha and beta subunits, but the protein level of the
      gamma subunit remained constant. In conclusion, our data suggest that in rabbit
      CNT and CCD the early increase in Na+ transport caused by aldosterone is due to
      the activation or insertion of existing Na+ channels into the apical membrane,
      and that the late response is mediated by increased synthesis of the alpha and
      beta rbENaC subunits.

PMID- 10398867
TI  - Glutathione (GSH) reduces the open probability of mechanosensitive channels in
      Escherichia coli protoplasts.
AB  - The effects of glutathione (reduced GSH, and oxidized GSSG) on mechanosensitive
      (MS) ion channels from Escherichia coli protoplasts were investigated using
      excised, inside-out membrane patches. Our studies demonstrate here that 5 mM GSH
      irreversibly reduces the activities of the 560-pS MS channel by approximately 70
      75% whereas 5 mM GSSG did not alter the MS channel currents. In addition,
      millimolar concentrations of dithiothreitol had similar although weaker effects
      to GSH. The physiological concentration of GSH in E. coli cytoplasm ranges from
      3.5 mM to 6.6 mM, which may indicate that under normal conditions these MS
      channels open less due to membrane stretch.

PMID- 10398868
TI  - Protection of reoxygenated cardiomyocytes against sarcolemmal fragility: the role
      of glutathione.
AB  - This study addressed the question of whether the sarcolemmal fragility of
      cardiomyocytes after anoxia and subsequent reoxygenation can be altered by
      modulation of the cellular glutathione state. Isolated ventricular cardiomyocytes
      (from adult rats) were exposed to 120 min anoxia and subsequently to 30 min
      reoxygenation. Osmotic stress was generated by reduction of medium osmolarity
      from 270 to 80 mosmol/l and sarcolemmal fragility assessed by the leakage of
      lactate dehydrogenase (LDH). Under normoxic conditions 6.7+/-1.0 % of total LDH
      activity was found extracellularly. Hyposmolar reoxygenation, but not hypoosmolar
      anoxia, increased LDH release (17.9+/-2.7% of total, P<0.05). Increasing cellular
      glutathione content by pretreatment with N-acetylcysteine (1 mM) reduced LDH
      release following hyposmolar reoxygenation (12.3+/-1.9% vs. 18.2+/-2.9% of LDH in
      medium, P<0.05). Depletion of glutathione content by pretreatment with buthionine
      sulphoximine (BSO, 200 microM), increased LDH release following osmotic stress
      already in normoxia (10.5+/-1.8% of LDH in medium; P<0.05 vs. no BSO), and even
      further after reoxygenation (21.8+/-3. 2%, P<0.05 vs. normoxia). We conclude that
      the increased sarcolemmal fragility in reoxygenated cardiomyocytes is due to
      reoxygenation in the presence of reduced antioxidant defence.

PMID- 10398869
TI  - Inwardly rectifying K+ currents in fetal alveolar type II cells: regulation by
      protein kinase A and protein phosphatases.
AB  - Fetal guinea-pig lung alveolar type II (ATII) cells have inwardly rectifying (IR)
      K+ currents that display Mg2+- and G-protein-dependent run-down. We have used the
      whole-cell patch-clamp technique to investigate further the regulation of these
      currents. Under control conditions [KCl-rich pipette solution (1 mM free Mg2+, 10
      nM free Ca2+) and KCl-rich bath solution], we found that IR K+ currents
      diminished with a t1/2 of 7.6 min and were absent by 30 min. Experimental
      manoeuvres designed to inhibit phosphorylation increased the rate of current run
      down. Thus, intracellular addition of 100 microM H-7, a general kinase inhibitor,
      reduced the t1/2 to 4.7 min and the currents were absent by 16 min. Similarly,
      protein kinase A (PKA) inhibitor peptide (50 nM) also accelerated run-down.
      Agents known to increase phosphorylation, such as db-cAMP (0.5 mM) and forskolin
      (10 microM), resulted in a significant slowing of run-down (t1/2>16 min) as did
      intracellular addition of the catalytic subunit of PKA (100 nM). Similarly,
      inhibition of dephosphorylation by either 1 microM okadaic acid [protein
      phosphatase 1/2A (PP-1/2A) inhibitor] or anti-human protein phosphatase 2Calpha
      (PP2C) antiserum decreased the rate of run-down. These results indicate that the
      phosphorylation-dependent activation state of the fetal ATII cell IR K+ channel
      is regulated by a complex interplay of kinases and phosphatases involving PKA
      (activation), and PP2C and PP-1/2A (inactivation).

PMID- 10398870
TI  - Voltage-dependent gating of veratridine-modified RIIA Na+ channel alpha subunit
      expressed heterologously in CHO cells.
AB  - The voltage-dependent kinetics of veratridine-modified RIIA Na+ channel alpha
      subunit expressed heterologously in CHO cells were studied using the whole-cell
      patch-clamp technique. The activation and deactivation kinetics are well
      described by double exponential functions but poorly by a monoexponential
      function. Unlike the slow component, the fast time constant and associated
      amplitude factor depended steeply on the potential. The steady-state activation
      of veratridine-modified channels is described by a Boltzmann function with a V1/2
      of -131.9 mV and a slope of 9.41 mV. A two-state model is proposed for the fast
      component that explains the kinetics of veratridine's mechanism of action.

PMID- 10398871
TI  - Acute effects of taurine on intracellular calcium in normal and diabetic cardiac
      myocytes.
AB  - The present study investigated the acute effects of taurine on intracellular Ca2+
      ([Ca2+]i) in normal and diabetic cardiac myocytes. [Ca2+]i was monitored using
      fura-2 in single myocytes isolated from control or streptozotocin-treated rats
      and paced at frequencies between 0.33 Hz and 2.0 Hz in the absence or presence of
      20 mM taurine. Increasing stimulus frequency resulted in significant increases in
      resting and peak [Ca2+]i, and amplitude of the Ca2+ transient in both control and
      diabetic myocytes. The amplitude of the Ca2+ transient and the extent of its
      increase with increasing frequency was, however, significantly lower in the
      diabetic myocytes. Taurine significantly increased resting [Ca2+]i, peak [Ca2+]i,
      and the amplitude of the Ca2+ transient in both control and diabetic myocytes at
      all stimulus frequencies examined. The degree of potentiation of the Ca2+
      transient decreased with increasing stimulus frequency in control cells but not
      in diabetic cells. In the absence of taurine the decay of the Ca2+ transient was
      significantly slower in diabetic than control myocytes. Taurine was without
      significant effect on the time course of the Ca2+ transient decay in control
      cells, however, in diabetic cells it significantly accelerated the rate of decay.
      The data demonstrate directly that taurine is able to increase [Ca2+]i and the
      amplitude of the Ca2+ transient in both normal and diabetic cardiac myocytes. In
      addition several of the effects of taurine appeared to be more pronounced in
      diabetic than control cells.

PMID- 10398872
TI  - Inhibition of phosphatidylinositide 3-kinase in OK-cells reduces Na/Pi
      cotransport but does not interfere with its regulation by parathyroid hormone.
AB  - The importance of phosphatidylinositide 3- kinase(s) [PI 3-kinase(s)] in membrane
      trafficking processes led us to examine its/their possible role in parathyroid
      hormone- (PTH-) induced endocytosis and lysosomal degradation of the type IIa
      Na/Pi-cotransporter in opossum kidney cells (OK-cells). We used wortmannin, a
      potent inhibitor of several mammalian PI 3-kinase isoforms, and measured Na/Pi
      cotransporter activity and type IIa Na/Pi-cotransporter protein expression; also
      the induction of a negative dominant subunit (Deltap85) was used to reduce PI 3
      kinase activity. Wortmannin and Deltap85 led to a reduction of Na/Pi-cotransport
      activity but were unable to prevent its inhibition by PTH. Wortmannin led in a
      dose- and time-dependent manner to a reduction of Na/Pi-cotransport activity and
      transporter protein expression, and retarded their recovery from PTH-induced
      inhibition/degradation. The data suggest that a PI 3-kinase "controlled"
      mechanism is involved in the synthesis (and/or routing) of the apical type IIa
      Na/Pi-cotransporter in OK-cells.

PMID- 10398873
TI  - The activity of the H+-monocarboxylate cotransporter during pre-implantation
      development in the mouse.
AB  - We have reported previously that cytosolic pH (pHi) in the mouse 2-cell conceptus
      is controlled by a H+-monocarboxylate cotransporter (MCT) that is sensitive to
      cinnamates and p-chloromercuriphenylsulfonate. In the present study we have used
      measurement of pHi with BCECF to characterize the changes in MCT activity during
      pre-implantation development. We found that the resting pHi in bicarbonate-free
      conditions increased significantly from the unfertilized oocyte to the 2-cell
      stage, but thereafter remained constant. There was no evidence for changes in MCT
      activity during the cell cycle, but MCT activity was found to increase during
      development. Using RT-PCR we demonstrated that mRNA encoding MCT isoforms 1, 2
      and 3 is present throughout pre-implantation development. The inhibitor of MCT1,
      p-chloromercuribenzoic acid, completely abolished the effect of extracellular l
      lactate on pHi suggesting that MCT1, and not MCT2, plays a functional role in pHi
      regulation in mouse conceptuses, while the role of MCT3 remains unclear. We
      further found that removal of glucose from the culture medium, which has
      previously been shown to stimulate pyruvate uptake by blastocysts, had no effect
      on the activity of the MCT. These findings suggest that the changes in pyruvate
      uptake that have been observed following compaction are not due to changes in the
      activity of the MCT. These findings indicate the presence of MCTs during early
      embryonic development.

PMID- 10398874
TI  - A convenient electrode holder for glass pipettes to stabilize electrode
      potentials.
AB  - Electrophysiological techniques require stable, reversible electrodes for
      accurate recording. Ag/AgCl electrodes are commonly used in patch-clamp and
      intracellular recording pipettes, but when these electrodes are exposed to Cl-
      free media they are no longer reversible and may develop large, unstable offset
      potentials. We present here a simple electrode holder design that provides a
      liquid junction between the electrode solution and a KCl-filled reservoir
      containing the AgCl pellet. This allows an electrode solution of any composition
      to be used without affecting the reversibility of the electrode, and the liquid
      junction potentials that develop are small and well defined. Mechanical isolation
      of the AgCl pellet from the pipette improves long-term stability of the electrode
      because the AgCl coating is not scraped while changing pipettes. The response
      time of the holder and its wide-band noise levels are comparable to those of
      standard holders. For practical experiment durations, the diffusion for KCl from
      the reservoir down the pipette produces negligible contamination at the tip.
      Similarly, back diffusion of the pipette contents into the reservoir is also
      negligible.

PMID- 10398875
TI  - Inverted double-gap isolation chamber for high-resolution calcium fluorimetry in
      skeletal muscle fibers.
AB  - Here we describe an improved inverted double-grease-gap isolation chamber that
      allows the formation of grease seals of high mechanical stability and high
      electrical resistance. We also provide a detailed description of the procedure
      used to mount the muscle fibers onto the apparatus. The new chamber permits the
      electrophysiological study of muscle fibers using an inverted microscope and high
      resolution objectives, thus complying with the requirements of modern
      fluorescence confocal detection methods. The simplicity and reliability of the
      mounting procedure make this chamber preferable over other gap isolation chambers
      currently used for simultaneous electrophysiological and optical studies of
      calcium release. Experimental results obtained from amphibian muscle fibers are
      presented to illustrate the performance of the chamber when using global
      fluorescence detection, confocal spot detection, and laser confocal scanning
      imaging.

PMID- 10398876
TI  - Modulation of HERG potassium channel properties by external pH.
AB  - We expressed the human eag-related gene (HERG), known to encode for the cardiac
      potassium channel IKr, in Chinese hamster ovary (CHO) cells. This study
      investigated effects of external pH (pHo) on HERG current properties using the
      whole-cell patch-clamp technique. We observed that current amplitude was
      decreased and kinetics of activation and deactivation were faster when pHo was
      lowered from 7. 4 to 6.0, while activation was accelerated and V1/2 negatively
      shifted when pHo was changed from 7.4 to 8.0. These effects can be explained by
      surface charge screening, amino acid group titration and/or changes in ionic
      atmosphere. We conclude that alterations of HERG channel by pHo could have
      consequences for the onset of arrhythmias during cardiac ischemia.

PMID- 10398877
TI  - Opioid potentiation of N-type Ca2+ channel currents via pertussis-toxin-sensitive
      G proteins in NG108-15 cells.
AB  - Opioids have both inhibitory and stimulatory effects on neurotransmitter release.
      While the inhibitory effect has been ascribed to presynaptic inhibition of Ca2+
      channels, the cellular mechanism underlying the stimulatory effect is not clear.
      In order to address this issue, we analyzed the effects of [d-Ala2, d-Leu5]
      enkephalin (DADLE) on whole-cell Ba2+ currents (IBa) through voltage-gated Ca2+
      channels in NG108-15 neuroblastoma x glioma hybrid cells. Application of DADLE
      inhibited and washout of DADLE transiently potentiated IBa. Furthermore,
      potentiation of IBa was elicited even in the presence of DADLE, when inhibition
      was relieved by a large depolarizing prepulse. DADLE-induced potentiation, as
      well as inhibition, had both voltage-sensitive and -insensitive components and
      was abolished by treatment with ICI174864, a delta-opioid antagonist, pertussis
      toxin (PTX) and omega-conotoxin GVIA. Potentiation developed over @3 min and took
      5-20 min to recover, whereas inhibition was complete within 30 s and recovered
      within 1 min. Although this potentiation should contribute to DADLE-induced
      desensitization of Ca2+ channel inhibition, it was not the sole mechanism for
      desensitization. We conclude that the delta-opioid receptor exerts a dual action
      on N-type Ca2+ channels via PTX-sensitive G proteins, i.e., rapid inhibition
      followed by slowly developing potentiation.

PMID- 10398879
TI  - Immunfluorescence study of neuropeptides in identified neurons of the rat
      auditory superior olivary complex.
AB  - The present study was conducted to investigate the distribution and
      immunohistochemical characteristics of ascending and descending projection
      neurons of the rat superior olivary complex (SOC), a group of interrelated
      brainstem nuclei. Ascending neurons were identified by injection of cholera toxin
      B subunit (CTB) into the central nucleus of the inferior colliculus (IC),
      descending neurons were labeled by application of Fluoro-Gold (FG) into the scala
      tympani of the cochlea, ipsilaterally to the IC injection. In accordance with the
      literature, we observed neurons innervating the IC located in the lateral
      superior olivary nucleus (LSO) and dorsal periolivary groups (DPO) on both sides,
      in the superior paraolivary nucleus (SPO) predominantly ipsilateral, as well as
      in the ipsilateral medial superior olivary nucleus (MSO) and the medial nucleus
      of the trapezoid body (MNTB). Cochlear projection neurons were found
      predominantly in the ipsilateral LSO as well as in the bilateral SPO, DPO, MSO
      and MNTB. In addition, a considerable population of neurons in the ipsilateral
      LSO and SPO were identified as being both ascending and descending. To further
      characterize these double-projecting neurons, brainstem sections were incubated
      in antisera directed against different neuroactive substances. The majority of
      ascending/descending cells in the LSO contained calcitonin gene-related peptide,
      but not substance P (SP), met-enkephalin (ENK) or tyrosine hydroxylase (TH). Some
      of these neurons apparently were contacted by ENK- or SP-immunoreactive fibers
      and terminals. In addition, we found TH-immunoreactive neurons in the lateral
      MNTB region. These neurons, which were labeled upon tracer injection into the
      cochlea (but not upon IC injection), probably belong to the C1 catecholaminergic
      cell group and may represent a division of the uncrossed olivocochlear bundle.
      The present results reveal the existence of a previously unknown subpopulation of
      SOC neurons that project to both the cochlea and the inferior colliculus. Their
      CGRP immunoreactivity and their uncrossed projection pattern provide evidence
      that they may belong to the cholinergic, putatively excitatory cell group.

PMID- 10398878
TI  - Embryonic lymphangiogenesis.
AB  - About 8-9 decades ago the development of embryonic lymphatics was studied
      intensively. Since then our knowledge has not considerably increased in this
      field, and it is still unknown whether lymphatics are derived by sprouting from
      veins, de novo from lymphangioblasts, or by both mechanisms. However, very recent
      studies have shown that the vascular endothelial growth factor-C (VEGF-C) is a
      highly specific lymphangiogenic growth factor. This raises new questions and
      perspectives. Here we will review the literature on embryonic lymphangiogenesis
      and lymphangiogenic growth factors. We also present a description of the pattern
      of the lymphatics of avian embryos with emphasis on lymph hearts. The avian
      embryo is highly suited for studies on lymphatics, because these can be
      demonstrated by injection methods, serial sectioning and in situ hybridization
      with VEGF-receptor-2 and -3 probes. The greatest advantage resides in the fact
      that the lymphatics of the chorioallantoic membrane are easily accessible for
      experimental studies.

PMID- 10398880
TI  - Survival of rat MCH (melanin-concentrating hormone) neurons in hypothalamus slice
      culture: histological, pharmacological and molecular studies.
AB  - Hypothalamic slices containing the lateral hypothalamic area (LHA) were prepared
      from 6- to 8-day-old rats and maintained in stationary culture for up to 35 days
      in order to analyse how well the melanin-concentrating hormone (MCH) neurons
      survived. As previously reported for other brain areas, this method yielded a
      long-term well-preserved organotypic organization. Light- and electron
      microscopic investigations showed that differentiation continued and that
      synaptic contacts developed in vitro. After a period of elimination of damaged
      cells and fibres, most of the remaining neurons and glial cells retained a normal
      morphology throughout the culture period. MCH neurons, in particular, survived
      well as attested by the strong immunocytochemical and in situ hybridization
      signals still observed after several weeks. In a comparison with the day of
      explantation, competitive reverse transcription/polymerase chain reaction
      demonstrated the remarkable stability of the level of MCH mRNA at least until the
      20th day in culture; after 30 days, the clear decrease in this level seemed to be
      correlated with a loss of MCH neurons, rather than with a decrease in MCH
      expression. After 10 days of culture, the incubation of slices in the presence of
      the hormone leptin (50 ng/ml) resulted in a strong decrease of MCH gene
      expression, suggesting that MCH neurons retained their physiological properties.
      Thus, the LHA slice stationary culture, especially between one and three weeks
      (i.e. after tissue stabilization and before extensive cell loss), appears to be a
      suitable method for physiological and pharmacological studies of these neurons.

PMID- 10398881
TI  - Functional anatomy of the photoreceptor and second-order cell mosaics in the
      retina of Xenopus laevis.
AB  - Mosaics of photoreceptors, and horizontal and bipolar cells of the Xenopus laevis
      retina were studied in whole-mount preparations applying lectin-cytochemical,
      immunocytochemical and intracellular labeling techniques. The combined density of
      all photoreceptor types was about 13700/mm2, of which rods represented 53%. Of
      the cones, the large long-wavelength-sensitive (86% of all cones) and the
      miniature ultraviolet-wavelength-sensitive (4%) ones could be labeled with peanut
      agglutinin, whereas the large short-wavelength-sensitive (10%) cones remained
      unlabeled. There were no significant regional differences in photoreceptor
      distribution. Bipolar cells were selectively labeled with antibodies against
      calretinin. Their density was between 4000 and 6000 cells/cm2, with slightly
      elevated numbers in the superior nasal quadrant. Two types of horizontal cell
      were injected intracellularly. The luminosity-type cells were more frequent
      (approximately 1000 cells/mm2) than the chromaticity cells (approximately 450
      cells/mm2). The dendritic field size of the latter cell type was threefold bigger
      than that of the luminosity cells. The coverage factors were estimated to be 3.3
      for the luminosity cells and 5.2 for the chromaticity cells. The luminosity cells
      contacted all photoreceptor types, whereas chromatic horizontal cells received
      their inputs from the short-wavelength-sensitive cones and from some, but not
      all, rods. Luminosity cells encounter about 50-60 potential synaptic partners
      within their dendritic fields, whereas chromatic horizontal cells only about 20.
      Chromatic horizontal cells form multiple synaptic contacts with the short
      wavelength-sensitive cones. The results indicate that the overall photoreceptor
      to bipolar and bipolar to ganglion cell convergence in Xenopus retina is similar
      to that in the central retinal specialized regions of mammals, predicting
      comparable spatial resolutions.

PMID- 10398882
TI  - Relationship between arginine vasotocin-like and natriuretic peptide-like
      immunoreactive structures in the brain of the toad Bufo marinus.
AB  - The distribution of natriuretic peptide-like immunoreactivity was investigated in
      the brain of Bufo marinus and compared with arginine vasotocin-like
      immunoreactivity using fluorescence immunohistochemistry. The antisera used were
      rabbit anti-porcine brain natriuretic peptide, which recognises the three main
      structural forms of natriuretic peptides, and guinea-pig antivasopressin, which
      recognises arginine vasotocin. Natriuretic peptide-like immunoreactive fibres
      were observed in many regions of the brain, being densest in the
      preoptic/hypothalamic region of the diencephalon and the interpeduncular nucleus
      of the mesencephalon. Natriuretic peptide-like immunoreactive cell bodies were
      observed in the dorsal and medial pallium, the medial amygdala, the preoptic
      nucleus, the ventral hypothalamus, the nucleus posterodorsalis tegmenti
      mesencephali, and the interpeduncular nucleus. No natriuretic peptide-like
      immunoreactivity was seen in the pituitary gland. The distribution of arginine
      vasotocin-like immunoreactivity was similar to that described previously for
      other amphibian species. Numerous immunoreactive cell bodies were present in the
      preoptic nucleus whilst immunoreactive fibres were observed in the
      preoptic/hypothalamic region as well as in extrahypothalamic regions such as the
      medial amygdala and the medial pallium. Double-labelling immunohistochemistry
      revealed no colocalisation of arginine vasotocin-like and natriuretic peptide
      like immunoreactivities in the same neural elements. The results suggest that
      natriuretic peptides and arginine vasotocin have distinct distributions in the
      brain but that natriuretic peptide-like immunoreactive fibres in the hypothalamus
      could influence the activity of arginine vasotocin-like immunoreactive cell
      bodies.

PMID- 10398883
TI  - Changing patterns of spatial buffering of glutamate in developing rat retinae are
      mediated by the Muller cell glutamate transporter GLAST.
AB  - The patterns of expression of the glutamate transporter GLAST were compared with
      the patterns of uptake of exogenous D-aspartate, which is a substrate for all
      glutamate transporters. At postnatal day 0, fine radial processes and end feet of
      presumptive Muller cells were weakly immunoreactive for GLAST. At postnatal day
      3, intense labelling was associated with astrocytes enveloping newly formed blood
      vessels on the vitread surface of the retina. Between postnatal days 7 and 10,
      there was a rapid increase in the intensity of labelling in the Muller cells but
      clear stratification of GLAST-immunoreactive processes in the inner plexiform
      layer was not observed until postnatal day 14. By comparison, D-aspartate uptake
      was initially associated with a wide variety of cellular elements including most
      neuroblasts, presumptive Muller cells, and astrocytes associated with blood
      vessels but was absent from the somata of many neurons in the ganglion cell layer
      and amacrine cell layer. There was a gradual contraction in the numbers of cells
      that were able to take up D-aspartate, such that, by adulthood, uptake was
      restricted mainly to Muller cells and astrocytes. We conclude that, during early
      retinal development, the low levels of GLAST expression by Muller cells permit D
      aspartate, and by inference, glutamate, to permeate the retina freely, thus
      allowing uptake by other glutamate transporters on other cell types. As the
      retina matures, increased expression of GLAST by Muller cells restricts the
      access of D-aspartate to other cellular compartments in the retina. This changing
      pattern of spatial buffering of glutamate by GLAST probably has significant
      implications regarding our understanding of the role of glutamate during
      processes such as retinal synaptogenesis.

PMID- 10398884
TI  - Anatomical distribution of glycoprotein 93 (gp93) on nerve fibers during rat
      brain development.
AB  - Recent studies have implicated glycoconjugates on the membrane of growth cones as
      the necessary markers and intermediaries for axonal recognition, axonal motility,
      and pathway development. One such glycoconjugate, glycoprotein 93 (gp93), has
      been characterized, but the relative distribution of gp93 has yet to be described
      for the embryonic brain. In this study, the anatomical distribution of gp93 has
      been analyzed at embryonic day 15 (E15) and E18, and on postnatal day 3 in the
      rat by using a polyclonal gp93 antibody. Furthermore, fetal brain tissue
      transplanted into the adult rat eye has been tested for gp93 immunoreactivity,
      since central noradrenergic neurons in brainstem transplants are known to provide
      a continuous source of growing axons, even in adult tissue. In general, a greater
      abundance of gp93 immunoreactivity is apparent in the earlier embryonic stages
      (E15 and E18), whereas less is seen in the postnatal brain. The regions showing
      unique dispersal patterns of gp93 are the neuroepithelium, cerebral cortex, septo
      hippocampal pathways, brainstem, and midbrain. This study has therefore focused
      on these areas and found implications for gp93 distribution appearing in the
      early development of specific neuronal pathways. Moreover, axons stain densely
      for gp93 within brain tissue transplants. The presence of gp93 in areas of
      extensive axonal outgrowth in the normal brain and in transplants suggests that
      this antibody is used as an early marker for axonal growth. Furthermore, gp93
      might be used to map normal development in order to improve our understanding of
      diseases arising from developmental abnormalities.

PMID- 10398885
TI  - Neurochemical coding of myenteric neurons in the guinea-pig antrum.
AB  - Electrophysiological studies of myenteric neurons in the guinea-pig antrum
      suggest that different neuroactive compounds are involved in synaptic
      transmission. It is not known what neurotransmitters and neuropeptides are
      present and to what extent they colocalize. Immunohistochemical stainings were
      performed on whole-mount preparations of the guinea-pig antrum. Immunoreactivity
      for neuron-specific enolase was used as a general marker and was set at 100%.
      There was no overlap between cholinergic and nitrergic neurons, resulting in two
      separate subpopulations. The presence of choline acetyltransferase
      immunoreactivity was used to identify the cholinergic subset, which accounted for
      56% of the cells. Immunoreactivity for nitric oxide synthase, on the other hand,
      was displayed in 40.7% of the neurons. Substance-P immunoreactivity was present
      in 37.4% of the cells and vasoactive intestinal peptide and neuropeptide Y in
      21.7% and 28.6%, respectively. Small subsets of neurons had immunoreactivity for
      serotonin (3.9%), calretinin (6.8%) and calbindin (0.5%). Colocalization studies
      revealed several subgroups of neurons, containing one or more of the screened
      markers. Though some similarity is found in the chemical coding of the antrum
      compared to that of the small intestine and the corpus, remarkable differences
      can be seen in the occurrence of some subpopulations. Cholinergic neurons are not
      as predominant as in other parts of the gut, serotonin presence is doubled and
      some vasointestinal-peptide-positive neurons express substance P. These
      differences might reflect the highly specialized function of the antrum; however,
      the exact role of these classes remains to be established.

PMID- 10398886
TI  - Neurohormonal peptides, serotonin, and nitric oxide synthase in the enteric
      nervous system and endocrine cells of the gastrointestinal tract of neotenic and
      thyroid hormone-treated axolotls (Ambystoma mexicanum).
AB  - Immunoreactivity against vasoactive intestinal polypeptide (VIP), neurotensin
      (NT), substance P (SP), calcitonin gene-related peptide (CGRP),
      gastrin/cholecystokinin (GAS/CCK), somatostatin (SOM), serotonin (SER), and
      nitric oxide synthase (NOS) was investigated in the gastrointestinal tract of the
      urodele Ambystoma mexicanum, the axolotl, by the use of immunohistochemical
      techniques. The study also compares the distribution patterns and frequencies of
      the neurohormones, and NOS in neotenic and thyroxine-treated (metamorphosed)
      individuals. GAS/CCK, SP, NT, SOM, and SER immunoreactivities occurred in
      endocrine mucosal cells and VIP, SP, CGRP, NTSER, SER, and NOS immunoreactivities
      in the enteric nervous system. The GAS/CCK-immunoreactive (-IR) cells were
      restricted to the upper small intestine. NT-IR and SP-IR endocrine cells were
      found in the entire gastrointestinal tract and were most prominent in the distal
      large intestine. The density of the SOM-IR cells decreased from the stomach
      toward the large intestine. SER-IR endocrine cells were found throughout the
      gastrointestinal tract, with particularly high densities in the stomach and
      distal large intestine. The VIP-IR enteric nerve fibers were the most prominent
      ones, present in all layers of the entire gastrointestinal tract, and supplied
      the smooth muscle and the vasculature. The SER-IR fibers exhibited similar
      distribution patterns but were less numerous. Very few NT-IR but many SP-IR
      fibers were found in the muscle and submucosal layers. The NT-IR fibers mainly
      supplied blood vessels, while the SP-IR fibers were also in contact with the
      smooth muscle. In the muscle and submucosal layers, CGRP-IR fibers were
      associated to the vasculature; CGRP immunoreactivity occurred also in a minority
      of SP-IR fibers. NOS-IR nerve fibers were in contact with submucosal arteries but
      were the least frequent. After metamorphosis provoked by exogenous thyroxine, the
      number of SOM-IR endocrine cells in the stomach mucosa was increased as well as
      the density of VIP-IR, SER-IR, and SP-IR nerve fibers in the gastrointestinal
      tract. It is proposed that the observed increases may reflect refinements of the
      neurohormonal system after metamorphosis.

PMID- 10398888
TI  - P2X receptors in the rat duodenal villus.
AB  - Immunohistochemical techniques were performed on freshly frozen sections of the
      duodenum of the rat using specific polyclonal antibodies to unique peptide
      sequences of P2X1-7 receptors. Of the antibodies to the seven known P2X receptor
      subtypes that mediate extracellular signalling by nucleotides, three reacted with
      discrete structures in the duodenal villus of the rat. Anti-P2X1 reacted with the
      capillary plexus in the intestinal villus, which did not extend to the crypt
      region, suggesting that nucleotides may be involved in the uptake and transport
      of metabolites. Anti-P2X5 immunostained the membranes of the narrow "stem" of
      villus goblet cells, where the nucleus and cell organelles reside, possibly
      influencing synthesis and release of mucins. P2X7 receptor immunoreactivity was
      only seen in the membranes of enterocytes and goblet cells at the tip of the
      villus, where cells are exfoliated into the lumen, consistent with earlier
      findings that P2X7 is involved in apoptotic events. Thus, in complex structures
      such as the intestinal villus, purinoceptors appear to participate in several and
      diverse signalling functions.

PMID- 10398887
TI  - Expression of a novel member of the TGF-beta superfamily, growth/differentiation
      factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues.
AB  - We have cloned a novel member of the transforming growth factor-beta (TGF-beta)
      superfamily from a human placental cDNA library. The sequence is identical to
      five very recently published sequences, of which only one (macrophage inhibitory
      cytokine-1, MIC-1) has been characterized in terms of function. In light of the
      present data demonstrating the wide distribution of the mRNA and putative
      multifunctionality, we propose to name this molecule growth/differentiation
      factor-15/MIC-1 (GDF-15/MIC-1). The deduced amino acid sequence reveals typical
      features of a secreted molecule. The epithelium of the choroid plexus is the only
      site in the adult brain expressing detectable levels of GDF-15/MIC-1 mRNA. Many
      epithelia of non-neural tissues including those of the prostate and intestinal
      mucosa, bronchi and bronchioli, secretory tubuli of the submandibular gland, and
      lactating mammary gland are prominent sites of GDF-15/MIC-1 synthesis. GDF-15/MIC
      1 is also strongly expressed by macrophages in the adrenal gland. Thus, GDF
      15/MIC-1, like many other members of the TGF-beta superfamily, is widely
      distributed in adult tissues, being most strongly expressed in epithelial cells
      and macrophages.

PMID- 10398889
TI  - Ultrastructure and distribution dynamics of chloride cells in tilapia larvae in
      fresh water and sea water.
AB  - Integumental and branchial chloride cells of tilapia larvae (Oreochromis
      mossambicus) were studied at the light-microscopical and ultrastructural level.
      Total numbers and distribution of chloride cells were quantified after
      immunostaining of cross sections of the entire larvae with an antibody against
      the alpha-subunit of Na+/K+-ATPase. The majority (66%) of Na+/K+-ATPase
      immunoreactive (ir) cells, i.e. chloride cells, of freshwater tilapia larvae were
      located extrabranchially up to 48 h after hatching. Five days after hatching, the
      majority (80%) of chloride cells were found in the buccal cavity. Transfer of 24
      h-old larvae to 20% sea water speeded up this process; 24 h after transfer (i.e.
      48 h after hatching), the majority (59%) of chloride cells were located in the
      buccal cavity. The branchial chloride cell population of 24-h- and 120-h-old
      larvae consisted of immature, mature, apoptotic and necrotic chloride cells.
      However, relatively more immature chloride cells were observed in freshwater
      larvae (42-63%) than in (previously studied) freshwater adults (21%),
      illustrating the developmental state of the gills. After transfer to sea water,
      the incidence of degenerative chloride cells did not change. Furthermore, the
      incidence of immature cells had decreased and a new subtype of chloride cells,
      the "mitochondria-poor" cells, appeared more frequently. These mitochondria-poor
      chloride cells were characterised by an abundant tubular system and relatively
      few mitochondria, which were aligned at the border or concentrated in one part of
      the cytoplasm. Most of these cells did not contact the water. The function of
      their enhanced appearance after seawater transfer is unknown.

PMID- 10398890
TI  - Cell-cell contacts in the human cell line ECV304 exhibit both endothelial and
      epithelial characteristics.
AB  - Endothelial cells separate the intra- and extravascular space and regulate
      transport processes between these compartments. Since intercellular junctions are
      required for these specific cell functions, the cell-cell contacts in the
      permanent cell line ECV304 were systematically analyzed and compared with human
      umbilical vein endothelial cells (HUVECs) in primary culture and with the
      epithelial Madin Darby Canine Kidney (MDCK) cell line. Filter-grown ECV304 cells
      generate a distinct electrical resistance and a permeability barrier between cell
      culture compartments. Electron microscopy of ECV304 cells revealed lateral
      membrane interdigitations, typically found in endothelial cells in vivo, with
      direct membrane contact sites, which prevented the diffusion of lanthanum. By
      immunoblot and immunofluorescence analysis, the expression and cellular
      localization of the tight junction and adherens-type junction proteins occludin,
      ZO-1, symplekin, beta-catenin, and plakoglobin were analyzed. ECV304 cells
      display further characteristics of endothelial cells, including the expresssion
      of thrombomodulin and of the vitronectin receptor CD51, as well as the secretion
      of plasminogen activator inhibitor 1 (PAI-1) and endothelin. However, ECV304
      cells also express proteins characteristically found in epithelial cells,
      including E-cadherin and the desmosomal proteins desmoplakin, desmocollin, and
      desmoglein; occasionally desmosomal structures can be identified by electron
      microscopy. In conclusion, ECV304 cells express many endothelial markers and form
      specialized intercellular junctions that display some epithelial features. Thus
      this reportedly endothelial-derived permanent human cell line may be
      dedifferentiated toward an epithelial phenotype.

PMID- 10398891
TI  - Influence of fulvic acid on the collagen secretion of bovine chondrocytes in
      vitro.
AB  - High concentrations of fulvic acid and selenium deficiency in drinking water are
      the main causative factors of Kashin-Beck disease, an endemic degenerative
      chronic osteoarticular disorder found in China. The influence of fulvic acid on
      collagen secretion was investigated in articular chondrocyte cultures from bovine
      interphalangeal joints. Collagen secretion in 7-day-old chondrocyte monolayers
      was determined by measuring [3H]-proline incorporation into collagen
      macromolecules after a 24-h application in cultured supernatants. Additionally,
      collagen secretion was measured with a collagen assay based on a dye-binding
      method of soluble collagens. Both methods showed a dose-dependent increase of
      collagen secretion after treatment with fulvic acid. The collagen was identified
      by immunoblotting and immunocytochemistry as type II collagen. Fulvic acid also
      induced H2O2 production in cartilage cells. After co-incubation with catalase and
      fulvic acid, the cells secreted the same amount of H2O2 or collagen as the non
      treated controls, indicating an influence of H2O2 on collagen secretion.
      Chondrocytes were then treated directly with H2O2. This led to increased collagen
      secretion showing a positive correlation with the concentration of H2O2 up to 1
      pM H2O2. Larger amounts of H2O2 decreased collagen secretion. Effects of reactive
      oxygen species, such as lipid peroxidation or lactate dehydrogenase (LDH) release
      from damaged cells, were not inducable by fulvic acid (<10 ppm). Our results
      demonstrate a fulvic-acid-induced stimulation of collagen secretion into the
      supernatant by articular chondrocytes via physiological amounts of H2O2.

PMID- 10398892
TI  - Immunohistochemical demonstration of inter-alpha-trypsin inhibitor light chain
      (bikunin) in human mast cells.
AB  - We recently reported that the rat mast cell proteinase inhibitor trypstatin is
      genetically identical with the second half of inter-alpha-trypsin inhibitor light
      chain (ITI-LC), also known as bikunin or urinary trypsin inhibitor (UTI). In this
      study, therefore, immunoreactivities of mast cells of various human tissues were
      examined with three antibodies, anti-human ITI-LC, anti-ITI, which recognizes
      mainly heavy chains or the sugar moiety of ITI, and anti-alpha 1-microglobulin
      (alpha1mG). ITI-LC immunoreactivity was strongly found in mast cells in the
      connective tissues of various organs except for those of the propria mucosae of
      small intestine. Neither anti-ITI antibody nor anti-alpha1mG antibody reacted
      with mast cells in various tissues. By reverse transcription-polymerase chain
      reaction (RT-PCR) analysis, alpha1mG/ITI-LC mRNA was not detected in the skin and
      tongue, and only weakly in small intestine, although ITI-LC immunoreactivity was
      strongly detected in these tissues. Furthermore, the mRNA was not expressed in
      cultured human mast cells. These results suggest that ITI-LC protein is stored in
      the granules of human connective tissue mast cells, though is not produced by
      them.

PMID- 10398893
TI  - Localization of leech excitatory peptide, a member of the GGNG peptides, in the
      central nervous system of a leech (Whitmania pigra) by immunohistochemistry and
      in situ hybridization.
AB  - We have recently isolated a myoactive peptide, called leech excitatory peptide,
      belonging to the GGNG peptide family from two species of leeches, Hirudo nipponia
      and Whitmania pigra. Immunohistochemistry and in situ hybridization were employed
      to localize leech excitatory peptide-like peptide(s) and its gene expression in
      the central nervous system of W. pigra. A pair of neuronal somata were stained by
      both immunohistochemistry and in situ hybridization in the supraesophageal,
      subesophageal, and segmental ganglia. In addition, several other neurons showed
      positive signals by either immunohistochemistry or in situ hybridization in these
      ganglia. An immunoreactive fiber was observed to run in the anterior root of
      segmental ganglion 6, which is known to send axons to the sexual organs, though
      we failed to detect immunoreactivity in possible target tissues. Antiserum
      specificity was established by enzyme-linked immunosorbent assay using different
      leech excitatory peptide-related peptides. Leech excitatory peptide elicited
      muscular contraction of isolated preparations of penis and intestine at
      concentrations of 10(-8 )M. These results suggest that leech excitatory peptide
      is a neuropeptide modulating neuromuscular transmission in multiple systems,
      including regulation of reproductive behavior.

PMID- 10398894
TI  - Differential distribution of somatostatin sst2 receptor splice variants in rat
      gastric mucosa.
AB  - The tetradecapeptide somatostatin (SRIF) has an inhibitory action on acid
      secretion in the stomach. It has been suggested that somatostatin may act
      directly on parietal cells as well as indirectly via histamine-producing cells. A
      family of high affinity membrane-bound receptors, which are termed sst1-sst5
      receptors, mediates the physiological effects of somatostatin. On the basis of
      functional studies it has been suggested that somatostatin may mediate its
      actions in the stomach by activation of a somatostatin sst2 receptor type. Two
      splice variants of the rat sst2 receptor exist, sst2(a) and sst2(b), which differ
      in length and composition of their intracellular carboxy termini. To date, little
      information is available on the distribution of the somatostatin sst2(b) receptor
      in any peripheral tissue. Here we show for the first time the localisation of
      this receptor isoform in the rat oxyntic mucosa, where the receptor protein was
      found to be present in parietal cells. This is in contrast to sst2(a) receptor,
      which was localised to enterochromaffin-like cells and nerve fibres. The
      differential localisation of the receptor isoforms to two key cell types,
      parietal cells and enterochromaffin-like cells, may explain how somatostatin
      inhibits acid secretion by more than one mechanism.

PMID- 10398895
TI  - Macroscopic classification and preoperative diagnosis of intrahepatic
      cholangiocarcinoma in Japan.
AB  - We reviewed the records of 64 patients with resected intrahepatic
      cholangiocarcinoma (ICC) according to the macroscopic classification proposed by
      the Liver Cancer Study Group of Japan, in which ICC is classified into three
      types based on the macroscopic appearance of the cut sur-face of the tumor: mass
      forming, periductal-infiltrating, and intraductal growth types. There were 24
      patients with the periductal-infiltrating type, 28 with the mass-forming type,
      and 12 with the intraductal growth type. The mass-forming type essentially showed
      expansive growth irrespective of hilar invasion. The periductal-infiltrating type
      of tumor exhibited diffuse infiltration along the portal pedicle, and
      preoperative planning of the resection procedure was similar to that for primary
      bile duct carcinoma of the hepatic confluence. Vascular resection and
      reconstruction was required in some patients with advanced disease. In the
      intraductal growth type of tumor, precise determination of tumor extent was
      difficult because of the ambiguity caused by abundant mucin secreted by the tumor
      and/or by the superficial mucosal spread of the tumor along the bile duct.
      Percutaneous transhepatic cholangioscopy provided the most reliable information
      for designing the operative procedure. The macroscopic classification is useful
      for preoperative diagnosis of tumor extent and for planning the surgical
      procedure.

PMID- 10398896
TI  - Clinicopathological features and outcome of hepatic resection for intrahepatic
      cholangiocarcinoma in Japan.
AB  - As a result of an increasing number of studies on the surgical treatment of
      intrahepatic cholangiocarcinoma (ICC), knowledge of its biological
      characteristics has been accumulating. We analyzed the clinicopathological
      features and outcome of 36 of 48 surgical patients with histologically proven ICC
      (75.0%) who underwent hepatic resection between March 1979 and July 1998.
      According to tumor location, 12 patients had the central type and 24, the
      peripheral type. The incidence of portal vein tumor thrombus and lymph node
      metastasis was higher in the central type than in the peripheral type. All 12
      patients with the central type had stage IV disease, and none of them underwent
      complete resection, whereas 12 of the 24 patients with peripheral type tumors had
      stage IV disease; complete resection was achieved in 12 of the 24 patients with
      peripheral type tumors (50%). Outcome after resection was significantly poorer in
      the patients with the central type. The macroscopic type of lesion in the
      resected specimens was the mass-forming type in 15 patients (41.7%), the mass
      forming + periductal-infiltrating type in 15 patients (41.7%), the periductal
      infiltrating type in 3 patients (8.3%) and the intraductal growth type in 3
      patients (8.3%). The macroscopic tumor type was associated with mode of tumor
      spread and outcome. All 3 patients with the intraductal growth type are alive
      without tumor recurrence 26-138 months after surgery. The survival rate was much
      higher in the patients with the mass-forming type than in those with the mass
      forming + periductal-infiltrating type. Importantly, the outcome in the 17
      patients who underwent resection for stage IV-B disease and who accounted for
      47.2% of patients with resection in the present series was very poor, almost the
      same as that in the 12 patients who did not undergo resection. By selecting
      patients based on the biological characteristics of the tumor and taking into
      account patients' quality of life, complete surgical resection can be performed
      safely and is associated with long-term survival.

PMID- 10398897
TI  - Extended resection for intrahepatic cholangiocarcinoma in Japan.
AB  - To elucidate surgical outcome after extended surgery for intrahepatic
      cholangiocarcinoma (ICC), we retrospectively allocated 83 patients who had
      undergone resection to a standard surgery group (n = 56), in which the patients
      had undergone hepatectomy alone or hepatectomy with bile duct resection, and an
      extended surgery group (n = 27), in which the patients had undergone the standard
      operation combined with vessel resection and/or pancreatectomy. The incidence of
      mass-forming plus periductal-infiltrating type lesions (P = 0. 0129), lymph node
      metastasis (P = 0.0005), noncurative resection (P < 0.0001), mortality within 30
      days and within 1 year after surgery (P = 0.0392, P = 0.0010), local recurrence
      (P = 0.0439), and peritoneal disseminated recurrence (P = 0.0241) was
      significantly higher in the extended surgery group than in the standard surgery
      group. The 5-year survival rate was significantly higher in the standard surgery
      group (30%) than in the extended surgery group (10%; P = 0.0061). The mortality
      rate within 1 year after extended surgery was significantly higher in the
      patients with infiltrating-spread type tumors than in the patients with non
      infiltrating spread type tumors (P = 0.0032), and long-term (5-year) survival in
      the extended surgery group was significantly lower in the patients with
      infiltrating-spread type tumors than in the patients with non-infiltrating spread
      type tumors (P = 0.0253). We conclude that extended surgery does not improve the
      curative resection rate or the surgical outcome of ICC, and that extended surgery
      is not indicated for patients with infiltrating-spread type tumors.

PMID- 10398898
TI  - Resection of intrahepatic cholangiocarcinoma: a Western experience.
AB  - We analyzed the results of an aggressive surgical approach to intrahepatic
      cholangiocarcinoma. Between 1990 and 1997, 30 of 42 patients with intrahepatic
      cholangiocarcinoma underwent resection with curative intent. Mean tumor size was
      10 +/- 5 cm, and the tumors were classified as TNM type III, IVa, and IVb in 63%,
      34%, and 3% of the patients, respectively. All patients underwent
      hepaticoduodenal lymphadenectomy. Fifteen patients received adjuvant radio- and
      chemotherapy. The overall survival rates at 1, 2, and 3 years were 86%, 63%, and
      22%, respectively, and the median survival time was 28 months. Tumor recurrence
      was the main cause of death. Three patients survived for more than 5 years,
      including 2 patients with no evidence of recurrence. Factors influencing survival
      were: presence of satellite nodules (P = 0.007) and lymph node invasion (P =
      0.05). The width of the resection margin and the use of an adjuvant therapy had
      no impact on survival. Complete surgical resection may offer a chance for long
      term survival in selected patients and may improve the quality of life of
      patients with more advanced disease.

PMID- 10398899
TI  - Intrahepatic cholangiocarcinoma in Thailand.
AB  - Intrahepatic cholangiocarcinoma is defined as adenocarcinoma originating from
      bile ductules and segmental and lobar intrahepatic ducts. Four types of surgical
      pathology have been identified in the Khon Kaen endemic area in Thailand:
      peripheral, type I; intermediate, type II; central, type III; and diffuse, type
      IV. We report our experience with intrahepatic cholangiocarcinoma with emphasis
      on the surgical pathology, operative procedure, and associated survival time. We
      reviewed the records of patients treated for cholangiocarcinoma at Srinagarind
      Hospital from January 1, 1992 to February 28, 1997. There was a total of 411
      patients, and 138 were intrahepatic and non-jaundiced. Tumors in the proximity of
      the gray zone i.e., portal, periportal with jaundice, were excluded. Patient
      profiles, surgical pathology, operative procedure, postoperative morbidity, and
      mortality were recorded. The data were analyzed using Kaplan-Meier survival
      curves. Of the 138 patients with intrahepatic disease who were non-jaundiced, 116
      had type I, 10 had type II-III, and 12 had type IV. The wear ages of the patients
      were: 53.0, SE 9.2 years in type I; 57.1, SE 4.6 years in type II-III, and 50.2,
      SE 9.2 years in type IV. The male-to-female ratios in the three groups were 1.4 :
      1, 1.5 : 1, and 5 : 1, respectively. The mean survival times in the three groups
      were 556, SE 63 days 374, SE 149 days and 97, SE 35 days. Most of the surgical
      procedures were tumor excisions (108/138). Right hepatectomy was performed in 63
      patients, extended right hepatectomy in 8, left hepatectomy in 18, and extended
      left hepatectomy in 1. Palliative procedures were performed in the other patients
      because tumors were in both lobes. The mean survival time was 582 days (SE, 75),
      for right lobe surgery; 458 days (SE, 89) for left lobe surgery; and 127 days
      (SE, 58) for the other procedures. Mean survival time was 1039 days (SE, 201) in
      tumor stage III, 773 days (SE, 123) in stage IVa, and 382 days (SE, 60) in stage
      IVb. There were no significant differences in survival time according to age or
      sex. The results of surgery in type I and type II-III were better than the
      results in type IV. Survival time after right hepatectomy was better than that
      after left hepatectomy, although without statistical significance, but survival
      time was significantly better after both operations than after palliative
      procedures. The results of surgery according to pathological staging showed that
      survival time in stage III was better than that in either stage IVa or IVb, but
      only the difference from stage IVb was significant.

PMID- 10398900
TI  - Intrahepatic cholangiocarcinoma in Taiwan.
AB  - We report our experience of the surgical treatment of intrahepatic
      cholangiocarcinoma (ICC) in Taiwanese patients. A total of 162 patients with
      histologically proven ICC were treated of whom 106 (65. 4%) had associated
      hepatolithiasis. Patients with hepatolithiasis were in earlier stages than those
      without hepatolithiasis. Two-thirds of the patients with hepatolithiasis
      presented with acute cholangitis, and two-thirds of those without hepatolithiasis
      presented with hepatomegaly. The rate of hepatic resection was 29.6% (48 of 162),
      and these rates were 31.1% and 26.8% for the patients with and without
      hepatolithiasis, respectively. Ninety-three percent of the patients with
      hepatolithiasis underwent common bile duct exploration, compared with 18% of
      those without hepatolithiasis. The surgical mortality rates were 3.7% (6/162),
      for all patients, and 3. 8% and 3.6% for patients with and without
      hepatolithiasis, respectively. The morbidity rate was much higher in the patients
      with hepatolithiasis (37.7% vs 16.1%). The 1-, 3-, and 5-year survival rates were
      35.5%, 20.5%, and 16.5% in the patients with hepatolithiasis and 27.2%, 8.8%, and
      7.8% in those without hepatolithiasis. Concomitant hepatolithiasis prevented
      precise diagnosis preoperatively and precipitated biliary sepsis, which affected
      resectability and increased postoperative morbidity. Hepatolithiasis per se did
      not influence long-term survival.

PMID- 10398901
TI  - Intrahepatic cholangiocarcinoma in Korea.
AB  - We reviewed surgically treated patients with intrahepatic cholangiocarcinoma to
      evaluate the clinical and pathologic features of intrahepatic cholangiocarcinoma
      that may affect long-term survival in Korean patients with the disease. Between
      1990 and 1997, 28 patients with intrahepatic cholangiocarcinoma underwent
      laparotomy. Resection was performed in 25 patients, and wedge resection alone in
      3 patients. The liver resections consisted of right lobectomy in 5 patients,
      right trisegmentectomy in 1, left lobectomy in 7, extended left lobectomy in 3,
      hepatopancreatoduodenectomy in 2, and segmentectomy in 7. Curative resection was
      performed in 15 patients. Histological sections of all resected specimens were
      immunohistochemically stained with p53 and Ki-67 monoclonal antibodies to assess
      the biological behavior of the tumor cells. Cumulative survival rate and
      clinicopathological factors that may influence the prognosis, including
      biological markers (p53, Ki-67), were analyzed statistically. Patients who
      underwent curative resection survived significantly longer than patients who
      underwent noncurative resection. The median survival time of the patients who
      underwent curative resection was 24 months (mean, 34 +/- 8 months), with 1-, 2-,
      and 3-year survival rates of 66.6%, 44.4%, and 35.6%, respectively. The median
      survival time of the patients who underwent noncurative resection was 3 months
      (mean, 8 +/- 3 months), with 1- and 2-year survival rates of 26.7% and 13. 4%,
      respectively. Univariate analysis showed that positive regional lymph nodes
      correlated significantly with poor outcome (P = 0.004) and that curative
      resection significantly correlated with better prognosis (P = 0.001). Age, sex,
      tumor size, degree of cell differentiation, gross type of tumor, and p53 and Ki
      67 labeling index were not significantly correlated with outcome. Our findings
      support the concept that aggressive liver resection, along with regional lymph
      node dissection, be recommended for long-term survival. The validity of molecular
      biologic tumor markers (p53, Ki-67) as prognostic factors has not yet been
      clearly demonstrated.

PMID- 10398902
TI  - Intrahepatic cholangiocarcinoma in Hong Kong.
AB  - We retrospectively analyzed the results of hepatic resection for patients with
      intrahepatic cholangiocarcinoma managed between December 1966 and January 1998 at
      the University of Hong Kong Medical Center, Queen Mary Hospital. There were 61
      men and 40 women (mean age, 61.8 years). The clinical records of these patients
      were reviewed. A survival analysis was performed on the group of patients who had
      undergone hepatic resection. Twenty-one patients were treated conservatively. Non
      resective (palliative) operations were performed in 32 patients. The median
      survivals after conservative management and palliative operation were 2.5 and 3.3
      months, respectively. The remaining 48 patients underwent hepatic resection. The
      overall operative morbidity and mortality rates after hepatic resection were
      41.7% and 16.7%, respectively. The median survival after hepatic resection was
      16.4 months. The overall 1-, 3-, and 5-year survival rates after hepatic
      resection were 60.3%, 29.4% and 22.0%, respectively. Lymphatic permeation (P =
      0.007) and hilar nodal metastases (P = 0.009) were found to be significantly
      associated with poor survival after hepatic resection. Hepatic resection is the
      treatment of choice for intrahepatic cholangiocarcinoma when it is resectable.

PMID- 10398904
TI  - Historical survey of carcinoma of the pancreas.
AB  - The ancient Egyptians probably recognized cancerous lesions on the surface of the
      body. Hippocrates described cancers of the skin, larynx, breast, inguinal region,
      uterus, and vagina. For centuries, the treatments were excision, cauterization,
      ointment application, and fomentation. The development of anesthesia, antisepsis,
      and disinfection, and the discoveries of X-rays and radium in the nineteenth
      century, have greatly promoted advances in surgery in the twentieth century. At
      the beginning of this century, it became possible for surgeons to extirpate
      tumors from previously inaccessible body interiors, and today surgeons are able
      to remove affected organ systems and even entire regions of the body with safety
      because of advances in physiology, anesthesia, transfusion, and anti-infective
      agents. The surgical results for most gastrointestinal cancers have improved
      markedly in recent years, only with pancreatic cancer showing no improvement in
      results. Drastic extensive surgery has not led to better results. A small
      carcinoma less than 1 cm in diameter may not always be an early carcinoma. Early
      cancer in duct cell carcinoma may be one localized in the mucous membrane of the
      pancreatic duct. There is now an expectation that early diagnosis will be
      possible by using magnetic resonance cholangiopancreatography and cytological
      diagnosis of the pancreatic juice.

PMID- 10398903
TI  - Current status of laparoscopic surgery of the pancreas.
AB  - Laparoscopic surgery of the pancreas remains, other than for certain clear
      indications, primarily investigational. However, in the past few years,
      laparoscopic therapy for pancreatic diseases has made significant strides and
      will undoubtedly contribute increasingly to the care of the surgical patient with
      pancreatic disease. This review discusses the current status of minimally
      invasive surgical therapy of pancreatic diseases and reviews the current
      literature. There are four major areas of clinical and laboratory investigation,
      including diagnostic laparoscopy for staging of pancreatic cancer, laparoscopic
      palliation of unresectable pancreatic cancer, laparoscopic management of
      pancreatic pseudocyst, and laparoscopic partial pancreatectomy
      (pancreaticoduodenectomy, distal pancreatectomy, and enucleation for islet cell
      tumors). The increased sensitivity of staging laparoscopy with laparoscopic
      ultrasound as a staging modality in the diagnosis of previously unrecognized
      metastatic disease from pancreatic cancer is clearly the most utilitarian
      application of laparoscopic technology in this patient population. Additionally,
      a natural extension of staging laparoscopy with laparoscopic ultrasound is the
      ability to improve the quality of life for the patient with unresectable
      pancreatic cancer by palliating the biliary and gastrointestinal obstruction and
      the debilitating pain, without the need for and morbidity of open laparotomy.
      Laparoscopic internal drainage of pancreatic pseudocysts remains early in its
      development but appears to have potential benefit from application of minimal
      access techniques. And laparoscopic partial pancreatectomy, both
      pancreaticoduodenectomy, and, to a lesser degree, distal pancreatectomy, remain
      primarily investigational without clearly established benefits from the use of
      minimal access techniques.

PMID- 10398905
TI  - A comparative study of the anatomy of rat and human livers.
AB  - To compare the fundamental structure of the human liver, in relation to that of
      the rat a comparative study was performed, in which 20 rat livers and 78 human
      cadaver livers were examined. The rat livers had four lobes (left, middle, right,
      and caudate). The left and middle lobes formed a single lobe but the middle lobe
      had a deep notch to which the round ligament attached. The right lobe was split
      into two sub-lobes and the caudate lobe was divided into the paracaval portion
      and the Spiegel lobe, which was split into two sub-lobes. The left, right, and
      caudate lobes had one primary portal branch, whereas the middle lobe had two
      portal branches. The left and the right sub- and caudate lobes had one large
      hepatic vein each, whereas three large hepatic veins were observed in the middle
      lobe. Based on the ramifying patterns of the portal and hepatic veins, the rat
      middle lobe possessed left and right hepatic components and a main portal
      fissure. The following rat hepatic lobes were equivalent to the following human
      liver segments: the left lobe to segment II; the middle lobe to segments III, IV,
      V, and VIII; and the right lobe to segments VI and VII. The fundamental
      structures of rat and human livers were similar, and the findings demonstrated a
      new interpretation of the anatomy of the human liver.

PMID- 10398906
TI  - Three-dimensional reconstruction of the ventral and dorsal pancreas: a new
      insight into anatomy and embryonic development.
AB  - The recent introduction of limited resections of the ventral pancreas for benign
      disease and for low-grade malignancies calls for a thorough understanding of its
      anatomy. The two embryonic anlagen were characterized and distinguished through a
      comprehensive study of their macroscopic, histologic, and immunohistochemical
      characteristics in 20 autopsy specimens before reconstruction. Sections were
      histologically stained with hematoxylin-eosin and Grimelius and
      immunohistochemically stained with antibodies to insulin, glucagon, somatostatin,
      and pancreatic polypeptide by the avidin biotin complex method. The ventral and
      dorsal anlagen of the pancreas were reconstructed from eight autopsy specimens,
      using the "macroserial" method, after serial sectioning and immunohistochemical
      staining with anti-pancreatic polypeptide antibodies. Compared with the dorsal
      pancreas, the ventral pancreas was characterized by the presence of smaller and
      more closely packed lobuli, irregular rather than uniform islets of Langerhans,
      and rich immunostaining with anti-pancreatic polypeptide. Construction of the two
      anlagen showed that the dorsal pancreas consisted of the anterior part of the
      head of the pancreas, and the body and tail of the pancreas, while the ventral
      pancreas consisted of the posterior part of the head of the gland and the upper
      two-thirds (62.5%) or all (37.5%) of the uncinate process. The ventral pancreas
      was related to the right lateral surface of the superior mesenteric vein
      extending to the back. However, it did not extend across the front surface of the
      superior mesenteric vein to the left as previously described. The uncinate
      process was also located posterior to but not anterior to the superior mesenteric
      vein. The contributions of the ventral and dorsal anlagen to the anatomy of the
      pancreas gland as demonstrated in this study differ, in some relevant features,
      from the classical descriptions in the medical literature. The current anatomical
      findings add essential knowledge for the pancreatic surgeon who contemplates
      tissue-preserving resections.

PMID- 10398907
TI  - Measurement of serum circulating intercellular adhesion molecule-1 and its
      clinical significance in hepatocellular carcinoma: preliminary report.
AB  - Serum circulating intercellular adhesion molecule-1 (cICAM-1) was measured in 50
      patients with hepatocellular carcinoma (HCC). The mean cICAM-1 level in the 50
      patients was 2220 ng/ml and 43 patients (86%) had a high level of cICAM-1 - more
      than 1000 ng/ml. Comparative analysis of cICAM-1 and alpha-fetoprotein (AFP)
      levels in the HCC patients showed that serum AFP level was negative (<20 ng/ml)
      in five patients or "questionable positive" (20-90 ng/ml) in ten patients, while
      the levels of cICAM-1 in these patients were 1810 and 1710 ng/ml, respectively.
      Seven patients who underwent hepatectomy had tumor recurrences during a follow-up
      period of 6-18 months. Their serum AFP levels were lower than 200 ng/ml (mean
      value, 27 ng/ml), but their mean cICAM-1 level was 1956 ng/ml at the time tumor
      recurrence was diagnosed. We suggest that the measurement of serum cICAM-1 is not
      only useful for prediction of the progression and prognosis of HCC, but that it
      may also be an important marker for the early diagnosis of the disease, and for
      monitoring postoperative recurrence, particularly in patients with low levels of
      serum AFP.

PMID- 10398908
TI  - Adenoma arising from the cystic duct and extending to the confluence of the
      extrahepatic biliary tract.
AB  - We describe a rare case of adenoma with a few foci of severe atypia arising from
      the cystic duct in a 68-year-old woman, initially diagnosed by the presence of
      intracholecystic tumefactive sludge on abdominal ultrasonography. Endoscopic
      retrograde cholangiography (ERC) disclosed a tuberous filling defect at the
      orifice of the cystic duct. Pathology examination of the biopsied specimen
      obtained from ERC disclosed not a cancerous but an adenomatous lesion.
      Macroscopically, the resected specimen showed a superficially spreading and
      shallowly elevated lesion extending from the cystic duct to the common bile duct.
      Although a few sporadic foci of severe atypia were observed, microscopy did not
      reveal any cancer findings, but confirmed the tumorous lesion as benign adenoma,
      showing mild-to-moderate atypia. Postoperative immunohistochemistry revealed no
      expression of p53 protein. We briefly refer to the rarity of adenoma in the
      biliary tract and discuss the difficulty of differential diagnosis of neoplastic
      lesions in the extrahepatic biliary tract.

PMID- 10398909
TI  - Recurrent hepatocellular carcinoma successfully treated with radiofrequency
      thermal ablation.
AB  - We report a patient with hepatocellular carcinoma (HCC) who was successfully
      treated with radiofrequency thermal ablation (RFA). A 71-year-old man was
      admitted to our hospital in August 1996 with recurrence of HCC. Partial hepatic
      resection had been performed in January 1993 for HCC that had measured 1.3 cm in
      segment VIII, and subsequently he had received six sessions of percutaneous
      ethanol injection (PEI) for treatment of recurrence. Dynamic computed tomography
      (CT) performed in August 1996 showed two recurrent tumors, one measuring 3.8 cm
      in segment VIII adjacent to the right hepatic vein, and one measuring 2.0 cm in
      segment V. Three sessions of percutaneous RFA were performed. After this
      treatment, most of the tumor in segment VIII and all the tumor in segment V
      showed low density on dynamic CT, and the right hepatic vein was preserved.
      However, a remnant of the mass appeared near the right hepatic vein 2 months
      after the treatment. An additional two sessions of RFA were performed. After the
      end of treatment, serum alpha-fetoprotein level dropped to the normal range, and
      no sign of recurrence has been observed until September 1998.

PMID- 10398910
TI  - Isolated hepatic tuberculosis: report of five cases and review of the literature.
AB  - Tuberculosis is one of the most common and well-described infectious diseases,
      with a worldwide distribution and a vast spectrum of clinical manifestations.
      Involvement of the liver alone by tuberculosis is, however, uncommon. It usually
      presents as a protracted illness frequently associated with jaundice and
      hepatomegaly. It can, therefore, mimic primary or metastatic liver malignancies.
      We report five cases of isolated hepatic tuberculosis, emphasizing the importance
      of obtaining a tissue diagnosis in all subjects with suspicious liver lesions to
      avoid missing the uncommon but curable hepatic tuberculosis.

PMID- 10398911
TI  - Pancreatic bladder or double gallbladder draining into pancreatic duct?
AB  - We report a case of pancreatic bladder which could also be interpreted as double
      gallbladder draining into the pancreatic duct. A 6-year-old Japanese boy
      underwent a cholecystectomy of the smaller bladder under the diagnosis of
      duplication of the gallbladder, leaving the normal gallbladder and an
      unremarkable biliary ductal system. The smaller bladder was histologically
      similar to the gallbladder tissue. At age 25, relaparotomy was performed. It was
      confirmed that the residual aberrant duct from the smaller bladder joined
      directly with the duct of Wirsung and that the patient had fusiform dilatation of
      the extrahepatic bile duct. The extrahepatic portion of the bile duct was excised
      along with the "normal" gallbladder and the residual aberrant duct. The present
      anomaly seems to validate the designation of pancreatic bladder whose cystic duct
      joined directly with the pancreatic duct, but may also be explained from the view
      point of double gallbladder.

PMID- 10398912
TI  - Real-time 3-dimensional volumetric ultrasound imaging of the vena contracta for
      stenotic valves with the use of echocardiographic contrast imaging: in vitro
      pulsatile flow studies.
AB  - The purpose of our study was to investigate the utility of real-time 3
      dimensional volumetric ultrasound coupled with echo contrast imaging to visualize
      and quantify effective flow areas for stenotic valves in vitro. Real-time 3
      dimensional ultrasound imaging has recently emerged as a promising method for
      increasing the quantitative accuracy of echocardiography. Since the technique
      currently does not process Doppler information, its use for quantifying flow has
      not been studied. However, the use of contrast agents to visualize cardiac flows
      with the use of echocardiography should allow determination of mass-dependent
      flow parameters such as effective flow area (vena contracta area) for stenotic
      lesions. We used real-time 3-dimensional imaging in an in vitro stenotic valve
      model (areas 0.785 to 1.767 cm2) under pulsatile flow conditions (60 bpm; 40 to
      80 mL/beat). An echo contrast agent was used to visualize the distal jet. Real
      time 3-dimensional imaging provides simultaneous views of long-axis and short
      axis (C-scan) image planes of the jet. The vena contracta was identified and
      measured by placing the C-scan line immediately distal to the orifice and
      measuring the cross-sectional flow area. System gain and postprocessing curve
      shape affected 3-dimensional areas; minimal gain and a custom curve produced best
      agreement to actual vena contracta areas measured with a previously validated
      laser method (y = 0.939x + 0.089; r = 0.98; standard error of estimate = 0.158
      cm2). We conclude that real-time 3-dimensional ultrasound imaging coupled with a
      contrast agent can be used as an accurate yet simple clinical means of measuring
      effective flow areas for stenotic valves.

PMID- 10398913
TI  - Impact of on-line endocardial border detection on determination of left
      ventricular volume and ejection fraction by transthoracic 3-dimensional
      echocardiography.
AB  - This study was performed to determine whether use of on-line automated border
      detection (ABD) could reduce data analysis time for 3-dimensional
      echocardiography (3DE) while maintaining accuracy of 3DE in measures of left
      ventricular (LV) volumes and ejection fraction (EF). The study proceeded in 2
      phases. In the validation phase, 20 subjects were examined with the use of 3DE
      and of monoplane 2-dimensional (2D) ABD. Results were compared with the reference
      standard of magnetic resonance imaging (MRI). In the test phase, 20 subjects
      underwent two 3DE studies (once with images optimized for visual border
      definition and once with images optimized for ABD border tracking) and a
      conventionally used 2D ABD study. For 3DE, volumes and EF were determined with
      the use of manually traced borders and ABD. Analysis times were recorded with a
      digital stopwatch. In the validation phase, 3DE and MRI results correlated very
      well (r = 0.99) without systematic differences. Comparison of 2D ABD with MRI
      showed good correlation for LV volumes (r >/= 0.90) and EF (r = 0.85) despite
      significant underestimation. For the test phase, Acoustic Quantification
      optimized 3-dimensional datasets underestimated end-diastolic volume and EF
      relative to visually optimized 3-dimensional datasets regardless of whether
      borders were hand-traced or ABD was used. However, correlations ranged from r =
      0.96 to r = 0.98 for LV volumes and 0.88 to 0.91 for LV EF and were superior to
      those for 2D ABD. Data analysis times decreased moderately with the use of ABD,
      but scan times increased; total study times were unchanged. Use of on-line ABD
      with 3DE reduces data analysis time and is more accurate than conventional
      monoplane 2D ABD but results in underestimation of LV volumes and EF. Additional
      automated postprocessing techniques may be required to obtain accurate measures,
      consistently using 3DE in conjunction with on-line ABD.

PMID- 10398914
TI  - Enhanced endocardial visualization with noncontrast harmonic imaging during
      stress echocardiography.
AB  - The diagnostic value of echocardiography hinges on the reader's ability to
      adequately visualize the endocardium of the left ventricle. This study was
      designed to evaluate the potential benefit of noncontrast harmonic imaging to
      enhance endocardial visualization. Eighty consecutive outpatients who underwent
      treadmill stress echocardiography were randomly assigned to either fundamental or
      harmonic imaging. The echoes were interpreted by 2 experienced readers. Compared
      with fundamental imaging, harmonic imaging of tissue improved the overall
      endocardial visualization score by 35% and 21% for readers 1 and 2, respectively
      (P <.001). Harmonic imaging also reduced the percentage of nondiagnostic segments
      by one half (P <.01). In patients undergoing treadmill stress echo, harmonic
      imaging offers a clinically significant improvement in endocardial visualization.

PMID- 10398915
TI  - Effects of tissue anisotropy and contrast acoustic properties on myocardial
      scattering in contrast echocardiography.
AB  - In this study we explored the potential effects that tissue anisotropy, in
      conjunction with the acoustic properties of contrast, may have on quantitative
      measurements of myocardial perfusion with the use of ultrasonic contrast agents.
      We used a computer simulation of the parasternal short-axis view, based on
      previously measured values for the anisotropy of backscatter and attenuation of
      myocardium, to predict the backscattered energy from 18 specific regions within
      the heart before and after myocardial contrast perfusion. Results demonstrated a
      regional variation of contrast enhancement in the short-axis view and variations
      caused by incremental increases in contrast level for specific myocardial
      regions. Thus quantitative assessment of myocardial perfusion with contrast
      echocardiography is influenced by the anisotropic properties of the myocardium,
      and the resulting postcontrast image will depend on the interaction between
      tissue properties and contrast acoustic properties. The degree of myocardial
      enhancement caused by the presence of contrast may depend on the spatial position
      of the specific region investigated with respect to the transducer and the amount
      of contrast in the myocardium.

PMID- 10398916
TI  - Effect of aging on diastolic left ventricular myocardial velocities measured by
      pulsed tissue Doppler imaging in healthy subjects.
AB  - We evaluated the effect of aging on diastolic left ventricular (LV) wall motion
      velocity in 80 healthy persons with the use of pulsed tissue Doppler imaging. The
      wall motion velocity patterns were recorded at the middle regions of the LV
      posterior wall and ventricular septum in the parasternal (along the short axis)
      and apical (along the long axis) LV long-axis views. In the posterior wall, the
      peak early diastolic wall motion velocities (Ews) along both axes correlated
      inversely with age (long axis: r = -0.61, P <. 0001; short axis: r = -0.55, P
      <.0001), and the peak atrial systolic wall motion velocities(Aws) along both axes
      correlated directly with age (long axis: r = 0.59, P <.0001; short axis: r =
      0.65, P <.0001). In the ventricular septum, the Ew along the long axis correlated
      inversely with age (r = -0.51, P <.0001), and the Aws along both axes correlated
      directly with age (long axis: r = 0.57, P <.0001; short axis: r = 0.53, P
      <.0001). The Ews along both axes at the posterior wall correlated directly with
      the peak early diastolic transmitral flow velocity. The Aws along both axes at
      the ventricular septum and posterior wall correlated directly with the peak
      atrial systolic transmitral flow velocity. The times from the second heart sound
      to the peak of the early diastolic waves of the ventricular septum and posterior
      wall along both axes significantly increased with age. The times from the aortic
      component of the second heart sound to the peak of the early diastolic motion
      velocities along both axes were significantly longer at the ventricular septum
      than at the posterior wall. Pulsed tissue Doppler imaging may be useful for
      evaluating the effect of aging on diastolic LV function in healthy persons.

PMID- 10398917
TI  - Two-dimensional guided M-mode color tissue Doppler echocardiography in artificial
      preexcitation models.
AB  - The purpose of this study was to analyze the left ventricular contraction
      patterns in artificial preexcitation models by using 2-dimensional guided M-mode
      color tissue Doppler echocardiography. Three types of preexcitation models were
      produced in 12 patients by right atrio-mitral annular sequential pacing, carried
      out at the left ventricular lateral, posterior, and posteroseptal walls. Tissue
      Doppler M-mode was recorded at anteroseptal, posterior, lateral, and
      posteroseptal sites in the parasternal short-axis view. The time interval from
      the onset of the QRS complex during sinus rhythm or from the annular pacing spike
      during fusion beats to the beginning of systolic motion was measured. During
      sinus rhythm, the time interval at the anteroseptal wall was shortest. During
      fusion beats, the time intervals at the mitral annular pacing sites were
      shortest. In preexcitation models, tissue Doppler M-mode could clearly
      distinguish the difference of left ventricular contraction patterns and detect
      the earliest contraction site of the left ventricle.

PMID- 10398918
TI  - Potential use of transthoracic echocardiography in the assessment of coronary
      flow reserve.
AB  - Coronary flow reserve provides a gold standard assessment of the epicardial and
      microvascular coronary circulation. However, measurement of coronary flow reserve
      is limited by the invasiveness or complexity of the methods hitherto available.
      We investigated whether transthoracic echocardiography could be used to assess
      coronary flow reserve. We imaged distal left anterior descending coronary artery
      diameter and flow in 14 healthy volunteers, both at rest and during intravenous
      infusion of adenosine (140 microg/kg per minute). Volunteers were men, with an
      average (+/-SD) age of 28.4 +/- 6.3 years. Complete data were acquired in 11
      cases. Average distal left anterior descending coronary artery diameter was 0.213
      +/- 0.03 cm. Velocity time integral rose from 8.6 +/- 2.1 cm to 27.7 +/- 5.6 cm
      with adenosine infusion. Heart rate rose from 64.7 +/- 9. 8 to 75.3 +/- 11.7 bpm.
      The Doppler angle of incidence to flow was 42.4 +/- 8.7 degrees. Resting distal
      left anterior descending coronary artery flow was therefore calculated as 13.4 +/
      3.2 mL/min and hyperemic flow as 51.2 +/- 16.2 mL/min, yielding a coronary flow
      reserve of 3.81 +/- 0.6. We conclude that coronary flow reserve can be assessed
      in a selected population with the use of transthoracic echocardiography and an
      intravenous infusion of adenosine. The simplicity of this noninvasive technique
      suggests that it could become a useful tool for measurement of coronary flow
      reserve if imaging success rates can be optimized.

PMID- 10398919
TI  - Feasibility study: transesophageal echocardiography with a 10F (3.2-mm),
      multifrequency (5.5- to 10-MHz) ultrasound catheter in a small rabbit model.
AB  - Transesophageal echocardiography (TEE) is useful in children with congenital
      heart defects. However, because of available probe size (>/=7 mm diameter), its
      use is limited to patients weighing more than 3 kg. The aim of this study was to
      determine the feasibility of TEE in a small animal model by using a 10F (3.2-mm)
      intravascular ultrasound tipped catheter with a monoplane (longitudinal) 5.5- to
      10-MHz phased vector array transducer. Ten New Zealand White rabbits (400 to 3400
      g; mean 1580 g) underwent TEE. With animals under general sedation, the probe was
      blindly introduced into the esophagus. All intracardiac and extracardiac
      structures were examined, and the images were stored and independently reviewed.
      All pertinent intracardiac and extracardiac structures were identified except in
      the 3 smallest rabbits (400 to 600 g). Doppler hemodynamics and color Doppler
      were possible in each animal. Frequency agility (5.5 to 10 MHz) facilitated
      optimization of image resolution and penetration. Certain transgastric, 4
      chamber, and short-axis views were limited because of the monoplane array. No
      overt adverse effects were associated with the procedure. Diagnostic TEE can be
      performed in a small animal model with a 10F, 5.5- to 10-MHz phased vector array
      ultrasound catheter. Our study suggests that this system has potential in
      performing diagnostic TEE safely in small, even premature, neonates.

PMID- 10398920
TI  - Chiari network entanglement and herniation into the left atrium by an atrial
      septal defect occluder device.
AB  - The Chiari network is a fenestrated membrane consisting of threads and strands in
      the right atrium. First described in 1897 by anatomist Hans Chiari, it is a
      congenital remnant of embryonic development resulting from incomplete resorption
      of the right valve of the sinus venosus. Found in 2% to 3% of the population, it
      is generally not of clinical importance. Rarely, however, the network may be
      associated with serious complications such as thrombus formation, embolus
      entrapment, arrhythmia, tumor development, and catheter entrapment. We report the
      entanglement of an Amplatzer septal occluder device catheter in a prominent
      Chiari network that was herniated into the left atrium. Transesophageal
      echocardiographic recognition of this before deployment and guidance during
      disentanglement is described below.

PMID- 10398921
TI  - Pseudoaneurysm of the left ventricular free wall caused by tumor infiltration.
AB  - Ventricular pseudoaneurysms occur as complications of myocardial infarction,
      heart surgery, trauma, and infective endocarditis. The process involves rupture
      of the ventricular wall where a structural weakness exists and containment of the
      blood by the pericardium. Although various malignancies may invade the heart, a
      pseudoaneurysm of the left ventricle caused by tumor has not been reported.

PMID- 10398923
TI  - Reply: 

PMID- 10398922
TI  - Re: "Echocardiography in emergency medicine: A policy statement by the American
      Society of Echocardiology and the American College of Cardiology".

PMID- 10398925
TI  - SH2 domains: from structure to energetics, a dual approach to the study of
      structure-function relationships.

PMID- 10398926
TI  - NMR structure of phospho-tyrosine signaling complexes.
AB  - A structural basis for activation and substrate specificity of src tyrosine
      kinases, and regulation of protein-protein association by tyrosine
      phosphorylation is described. Lyn, a src-family tyrosine kinase, recognizes and
      phosphorylates the immunoreceptor tyrosine-based activation motif, ITAM, a
      critical component in transmembrane signal transduction in hemopoietic cells. The
      structure of an ITAM peptide substrate bound to an active form of Lyn tyrosine
      kinase was determined by high-resolution NMR, and a model of the complex was
      generated using the crystallographic structure of Lck, a closely related Src
      family kinase. The results provide a rationale for the conserved ITAM residues
      and specificity of Lyn, and suggest that substrate plays a role in stabilizing
      the kinase conformation optimal for catalysis. It is our hope that the Lck-ITAM
      peptide model complex will be useful in aiding structure-based drug design
      efforts that target substrate binding determinants in the design. Concerning the
      regulation of protein-protein association, we report on a complex between
      erythrocyte band 3 and two glycolytic enzymes, aldolase and glyceraldehyde-3
      phosphate dehydrogenase. The formation of this complex is negatively regulated by
      tyrosine phosphorylation of band 3 by p72syk tyrosine kinase. In red blood cells,
      this association results in a decrease in glycolysis due to competitive
      inhibition of the glycolytic enzymes. The structure of band 3 recognized by the
      glycolytic enzymes was determined by solution NMR, and found to be a loop
      structure with tyrosine centrally positioned and excluded from intermolecular
      contact. This phosphorylation sensitive interaction, or PSI, loop may be the
      basis of a general mechanism for negative regulation through tyrosine
      phosphorylation.

PMID- 10398927
TI  - Application of mass spectrometry for target identification and characterization.
AB  - Mass spectrometry-based methodologies span the vast expanse of drug discovery.
      Both electrospray ionization (ESI) and matrix-assisted laser
      desorption/ionization (MALDI) support proteomics-based research projects by
      identifying proteins separated and isolated by polyacrylamide gel
      electrophoresis. MALDI-MS-based surface scanning of one-dimensional isoelectric
      focusing gels, "virtual 2-D gel electrophoresis," represents a potentially high
      throughput means to map proteins and to determine protein profiles. Mass
      spectrometry can also be used to directly study the covalent and noncovalent
      interactions of drug molecules and biomolecule targets. Drug binding examples
      discussed include the binding of covalent and noncovalent inhibitors to src SH2
      domain protein, and the interaction of aminoglycoside antibiotic neomycin and HIV
      Tat peptide-TAR RNA.

PMID- 10398928
TI  - Analysis of the binding surfaces of proteins.
AB  - We have developed an experimental approach to map the complete binding surface of
      any crystalline macromolecule that is fast and flexible. Crystals of the target
      protein are transferred into organic solvents and the crystal structures are
      determined at high (about 2A) resolution. The sites where the solvent molecules
      bind to the protein are thus identified directly. Different solvents serve as
      probes for different organic functional groups; thus, benzene is a probe for
      where aromatic groups like to bind, dimethyl formamide is a probe for peptide
      binding sites, and so forth. A series of about six such experiments suffices to
      locate the major binding regions on the protein surface unambiguously. These
      different sites can then be targeted with "Hydra-headed" inhibitors that interact
      simultaneously with more that one site, thereby providing specificity for the
      desired target. We have used this method to map the complete binding surface of
      elastase, and find that three regions, including the active site cleft, are
      generally "sticky" and can make interactions with almost any functional group.
      Analyses of these binding sites on elastase and other proteins suggests that what
      makes a binding site is amphipathicity and the ease with which water can be
      displaced.

PMID- 10398929
TI  - Predicting binding energetics from structure: looking beyond DeltaG degrees.
AB  - Structure-based design of pharmaceuticals requires the ability to predict ligand
      affinity based on knowledge of structure. The primary term of interest is the
      binding affinity constant, K, or the free energy of binding, DeltaG degrees. It
      is common to attempt to predict DeltaG degrees based on empirically derived terms
      which represent common contributions such as the hydrophobic effect, hydrogen
      bonding, and conformational entropy. Although these approaches have met with some
      success, when they fail it is difficult to know which parameter(s) need
      refinement. Confidence in these approaches is also limited by the fact that
      DeltaG degrees typically is made up of compensating enthalpic and entropic terms,
      DeltaH degrees and DeltaS degrees, so that accurate prediction of a DeltaG
      degrees value may be fortuitous and may not indicate a reasonable understanding
      of the underlying relationship between structure and affinity. This is further
      complicated by the fact that both DeltaH degrees and DeltaS degrees are strongly
      temperature dependent through the heat capacity change, DeltaCp. In order to
      avoid these difficulties, we attempt to use structural data to predict DeltaH
      degrees, DeltaS degrees, and DeltaCp from which DeltaG degrees can be calculated
      as a function of temperature. The predictions are then compared to experimentally
      determined values. These calculations have been applied to several systems by
      ourselves and others. Systems include the binding of angiotensin II to an
      antibody, the dimerization of interleukin-8, and the binding of inhibitors to
      aspartic and serine proteases. Overall the calculations are very successful, and
      suggest that our understanding of the contributions of the hydrophobic effect,
      hydrogen bonding, and conformational entropy are quite good. Several of these
      systems show a strong dependence of the binding energetics on pH, indicative of
      changes in proton affinity of ionizable groups upon binding. It is critical to
      account for these protonation contributions to the binding energetics in order to
      assess the reliability of any computational prediction of energetics from
      structure. Methods have been developed for determining the energetics of proton
      binding using isothermal titration calorimetry. The availability of these methods
      provides a means of understanding how protein structure can modify the pKa's of
      ionizable groups. This information will further add to our understanding of
      structural energetic relationships and our ability accurately to predict binding
      affinities.

PMID- 10398930
TI  - Call for an international ban on asbestos. Collegium Ramazzini.
AB  - The Editorial Board of the American Journal of Industrial Medicine strongly
      supports the "Call for an International Ban on Asbestos". We concur with the
      Collegium Ramazzini that a ban is necessary, overdue and essential for public
      health. To eliminate the burden of disease and death that is caused worldwide by
      exposure to asbestos, the Collegium Ramazzini calls for an immediate ban on all
      mining and use of asbestos. To be effective, the ban must be international in
      scope and must be enforced in every country in the world.

PMID- 10398931
TI  - Sperm aneuploidy among Chinese pesticide factory workers: scoring by the FISH
      method.
AB  - BACKGROUND: A study of the prevalence of sperm aneuploidy among pesticide factory
      workers was conducted in Anhui, China. METHODS: We recruited 75 men: 32 subjects
      from a large pesticide-manufacturing plant and 43 subjects from a nearby textile
      factory free of pesticide exposure. Each subject met the following criteria: age
      of 20-40 years; continuous work in the plant for 3 months prior to the study, no
      congenital anomalies or acquired disease of the external genitalia and no history
      of recent febrile illness or mumps. Within one hour after collection from each
      subject, semen was evaluated in terms of several parameters and smear slides were
      prepared. RESULTS: Exposure assessment revealed that workers in the pesticide
      plant were exposed to ethyl parathion or methamidophos, each of which is a potent
      organophosphate pesticide, at a median level of 0.02 mg/m3 (8-hour time weighted
      average as measured by personal pump) while workers in the control plant had no
      such occupational exposure. Twenty-nine semen slides (13 from the exposed group
      and 16 from the unexposed group) were randomly chosen for aneuploidy scoring by
      the three-color fluorescence in situ hybridization (FISH) method with scorers
      being unaware of exposure status. Median semen parameters were as follows for
      exposed (and unexposed) men: abstinence period, 3 days (4 days); sperm
      concentration, 52.8x10(6)/ml (53.1x10(6)/ml); proportion of sperm with normal
      motility, 50.5% (61.3%); and proportion of sperm with normal morphology, 59%
      (61.5%). The specific chromosome abnormalities of interest were disomy for
      chromosome 18 and the three different types of sex chromosome disomy (i.e. XX,
      XY, YY disomy). The crude proportion of all aneuploidy combined was 0.30% and
      0.19% for sperm from exposed and unexposed men, respectively. Poisson regression
      with overdispersion adjustment yielded significantly different crude risks of
      aneuploidy - 3.03 and 1.94 per 1,000 sperm from exposed and unexposed men,
      respectively - giving a rate ratio of 1.56 (95% CI, 1.06-2.31). The regression
      coefficients remained statistically significant after adjustment for inter
      technician variability giving a rate ratio of 1.51 (95% CI, 1. 04-2.20).
      CONCLUSIONS: We conclude that occupational exposure to organophosphate pesticides
      moderately increases the prevalence of sperm aneuploidy.

PMID- 10398932
TI  - Mortality among aerial pesticide applicators and flight instructors: follow-up
      from 1965-1988.
AB  - BACKGROUND: Vital status followup for a retrospective cohort mortality study of
      9,961 male aerial pesticide applicators was extended beyond a previous study
      (1965-1979) (Cantor et al. 1991), through December 31, 1988. METHODS: Rate ratios
      (RR) were used to compare directly adjusted mortality rates between applicators
      and a comparison cohort of 9,969 flight instructors. Standardized mortality
      ratios (SMR) were calculated for comparisons with the U.S. white male population.
      RESULTS: Among applicator pilots, there were 1,441 deaths, and among instructors,
      1,045. In both groups, aircraft accidents were the major cause of death (446
      applicators; 234 instructors). Compared with flight instructors, aerial
      applicator pilots were at significantly elevated risk for all causes of death
      (risk ratio = 1.34) and for malignant neoplasms (1.18), non-motor vehicle
      accidents (1.71), motor vehicle accidents (1.69), and stroke (1.91). Pancreatic
      cancer (2.71) and leukemia (3.35) were significantly elevated. Applicators were
      at lower risk of colon cancer (0.51) and multiple myeloma (0.23) mortality. Based
      on U.S. rates, the SMR for all causes of death among applicators was 111 (95%
      confidence interval (CI) = 105-117) and among instructors, 81 (CI = 76-85).
      CONCLUSIONS: Aircraft accidents were a major cause of mortality in both
      applicator and flight instructor cohorts. Several other causes of death, some
      possibly related to pesticide exposure, were also elevated among pesticide
      applicator pilots. Published 1999 Wiley-Liss, Inc.

PMID- 10398933
TI  - Cross-sectional study of the relationship between repetitive work and the
      prevalence of upper limb musculoskeletal disorders.
AB  - BACKGROUND: This study examined the relationship of repetitive work and other
      physical stressors to prevalence of upper limb discomfort, tendinitis, and carpal
      tunnel syndrome. METHODS: Three hundred fifty-two workers from three companies
      participated. Job exposure levels for repetition and other physical stressors
      were quantified using an observational rating technique. Ergonomic exposures were
      rated on a 10-point scale, where 0 corresponded to no stress and 10 corresponded
      to maximum stress. Job selection was based on repetition (three categories: high,
      medium, and low) to ensure a wide range of exposures. Physical evaluations on all
      participating workers were performed by medical professionals and included a self
      administered questionnaire, physical exam, and limited electrodiagnostic testing.
      RESULTS: Repetitiveness of work was found to be significantly associated with
      prevalence of reported discomfort in the wrist, hand, or fingers (odds ratio (OR)
      = 1.17 per unit of repetition; OR = 2.45 for high vs. low repetition), tendinitis
      in the distal upper extremity (OR = 1.23 per unit of repetition; OR = 3.23 for
      high vs. low repetition), and symptoms consistent with carpal tunnel syndrome (OR
      = 1.16 per unit of repetition; OR = 2.32 for high vs. low repetition). An
      association was also found between repetitiveness of work and carpal tunnel
      syndrome, indicated by the combination of positive electrodiagnostic results and
      symptoms consistent with carpal tunnel syndrome (OR = 1. 22 per unit of
      repetition; OR = 3.11 for high vs. low repetition). CONCLUSIONS: These findings
      indicate that repetitive work is related to upper limb discomfort, tendinitis,
      and carpal tunnel syndrome in workers. Further research with a wider range of
      exposures is needed to evaluate the effects of other physical stresses alone and
      in combination.

PMID- 10398934
TI  - Occupational risk factors for pancreatic cancer: a case-control study based on
      death certificates from 24 U.S. states.
AB  - BACKGROUND: The relation between occupational exposure and pancreatic cancer is
      not well established. A population-based case-control study based on death
      certificates from 24 U.S. states was conducted to determine if
      occupations/industries or work-related exposures to solvents were associated with
      pancreatic cancer death. METHODS: The cases were 63,097 persons who died from
      pancreatic cancer occurring in the period 1984-1993. The controls were 252,386
      persons who died from causes other than cancer in the same time period. RESULTS:
      Industries associated with significantly increased risk of pancreatic cancer
      included printing and paper manufacturing; chemical, petroleum, and related
      processing; transport, communication, and public service; wholesale and retail
      trades; and medical and other health-related services. Occupations associated
      with significantly increased risk included managerial, administrative, and other
      professional occupations; technical occupations; and sales, clerical, and other
      administrative support occupations. Potential exposures to formaldehyde and other
      solvents were assessed by using a job exposure matrix developed for this study.
      Occupational exposure to formaldehyde was associated with a moderately increased
      risk of pancreatic cancer, with ORs of 1.2, 1.2, 1.4 for subjects with low,
      medium, and high probabilities of exposure and 1.2, 1.2, and 1.1 for subjects
      with low, medium, and high intensity of exposure, respectively. CONCLUSIONS: The
      findings of this study did not suggest that industrial or occupational exposure
      is a major contributor to the etiology of pancreatic cancer. Further study may be
      needed to confirm the positive association between formaldehyde exposure and
      pancreatic cancer. Published 1999 Wiley-Liss, Inc.

PMID- 10398936
TI  - Occupational physical activity and breast cancer risk in the upper Cape Cod
      cancer incidence study.
AB  - BACKGROUND: In several epidemiological studies, breast cancer risk has been
      reduced among women who reported high levels of occupational or leisure-time
      physical activity. We used data from a population-based case control study to
      evaluate the effect of occupational physical activity on breast cancer risk.
      METHODS: Two hundred-thirty three incident cases of breast cancer and 670
      controls or their next of kin were interviewed for information on breast cancer
      risk factors and a complete job history. Physical activity level of jobs were
      classified using a Department of Labor rating scheme. We calculated adjusted odds
      ratios for light and medium/heavy activity jobs compared to sedentary jobs.
      RESULTS: Odds ratios for women who held medium/heavy jobs for less than 10 years
      and more than ten years were, respectively, 0.7 (95% CI = 0.4,1.3) and 1.7 (95%
      CI = 0.9,3.3). CONCLUSIONS: In these data there was no evidence that holding a
      job of medium/heavy activity reduced breast cancer risk. The study was limited by
      misclassification inherent in the occupational exposure scheme and by the lack of
      information on leisure time physical activity. The modest risk increase for
      subjects holding a medium/heavy job for at least 10 years probably represents
      either confounding or random variation.

PMID- 10398935
TI  - Cancer in California school employees, 1988-1992.
AB  - BACKGROUND: Periodic concerns about excesses of cancer among teachers in
      California schools prompted our examination of cancer incidence in California
      school employees. METHODS: Records of school employees between 1987-1992 were
      linked to the California Cancer Registry of incident cases diagnosed 1988-1992.
      Sex-, race-, and age-adjusted standardized incidence ratios were calculated for
      specific cancer sites. Analyses stratified by sex, race/ethnicity, and job
      assignment were also performed. RESULTS: Melanoma of the skin, thyroid cancer,
      prostate cancer, and female cancers of the breast, uterus, and ovary all occurred
      more frequently than expected in these school employees. In contrast, cancers of
      the respiratory system, oral cavity, digestive system, urinary system, and
      uterine cervix occurred less frequently. CONCLUSIONS: The incidence of cancers
      thought to be related to hormones and/or higher socioeconomic status appeared
      elevated while cancers often linked to smoking and/or alcohol intake occurred
      less frequently in this large cohort of professional school employees.

PMID- 10398937
TI  - Potential significance of airborne fiber dimensions measured in the U.S.
      refractory ceramic fiber manufacturing industry.
AB  - BACKGROUND: To determine dimensions of airborne fibers in the U.S. refractory
      ceramic fiber (RCF) manufacturing industry, fibers collected through personal air
      sampling for employees at RCF manufacturing and processing operations have been
      measured. METHODS: Data were derived from transmission electron microscopy
      analyses of 118 air samples collected over a 20-year period. RESULTS:
      Characteristics of sized fibers include: diameter measurements of <60; 0.19 to
      1.0 micron, m of which 75% are less than 0.6 micron and length ranging from < 0.6
      to > 20 micron, with 68% of fibers between 2.4 and 20 micron. CONCLUSIONS:
      Exposures in RCF manufacturing include airborne fibers with dimensions (diameter
      < 0.1-0.4 micron, length < 10 micron) historically associated with biological
      effects in pleural tissues. Air sampling data and a review of studies relating
      fiber size to pleural effects in animals and humans support the belief that
      information on fiber dimensions is essential for studies with synthetic vitreous
      fibers.

PMID- 10398938
TI  - Pulmonary dysfunction in silica-exposed workers: a relationship to radiographic
      signs of silicosis and emphysema.
AB  - BACKGROUND: It has been established that occupational exposure to silica dust may
      cause significant impairment of pulmonary function. To compare the contribution
      of silicosis and emphysema to pulmonary dysfunction, radiographic signs of
      silicosis and emphysema in silica exposed workers were analyzed. METHODS: Two
      hundred and twenty workers exposed to silica working in a Chinese refractory
      plant were selected as study subjects. Their findings of silicosis and
      emphysematous changes on radiograph were classified and evaluated. A
      questionnaire on respiratory symptoms, smoking, and occupational history was
      administered. All the workers performed measurements of spirometry and CO single
      breath diffusing capacity. RESULTS: Radiographic hyperinflation was detected in
      9% of the workers without silicosis and in 33% of the workers with silicosis.
      Silicosis was significantly associated with hyperinflation after adjusting for
      exposure duration, age, and smoking. Respiratory symptoms were more frequent in
      the more severe cases of silicosis. Regression analysis showed that silicosis was
      significantly associated with decreases in the parameters of pulmonary function,
      but the significance disappeared when the hyperinflation term was added to the
      models. Radiographic hyperinflation was strongly associated with decreases in
      FEV1 and FEV1/FVC while relevant factors were controlled. Comparison between
      workers with and without hyperinflation showed that the former had significantly
      lower pulmonary function values. CONCLUSIONS: The results suggest that emphysema
      associated with silicosis is likely to be responsible for pulmonary obstruction
      and decreased diffusing capacity occurring in silica-exposed workers.

PMID- 10398939
TI  - Prevalence of elevated blood leads and exposure to lead in construction trades in
      Iowa and Illinois.
AB  - BACKGROUND: Despite lowering of the permissible exposure level for lead in
      construction from 200 to 50 microg/m3 in 1993, excessive lead exposure continues
      to be a problem. Relatively little data are available from the Midwestern U.S. on
      the environmental lead concentrations generated during various construction
      activities and the potential for worker exposure. This study characterized the
      prevalence of blood lead concentrations in high-risk construction trades in
      Iowa/Illinois, and identified risk factors for occupational exposure to lead in
      these construction workers. METHODS: A sample of 459 workers was selected from
      the total population of all union members from trade groups of painters,
      plumbers/pipefitters, ironworkers, laborers, and electricians. Participants
      completed an interviewer-administered questionnaire obtaining information on
      demographics, symptoms, occupational history, work practices, personal protective
      equipment, and training. Venous blood samples were collected from each
      participant and analyzed for blood lead (using atomic absorption spectroscopy)
      and free erythrocyte protoporphyrin levels. RESULTS: Blood lead levels (BLLs) of
      construction workers ranged from 0.1 to 50 microg/dL. Geometric mean blood lead
      concentrations by trade group were: laborers (7.6 microg/dL, n = 80); painters
      (5.9 microg/dL, n = 83); ironworkers (5.2 microg/dL, n = 87); plumbers (4.4
      microg/dL, n = 82); electricians (2.4 microg/dL, n = 91). Blood lead levels for
      painters and laborers were significantly higher than other trade groups, and
      levels for electricians were significantly lower (p < 0. 01). Participants
      reported working primarily on commercial and industrial projects including new
      construction, renovation, and demolition. There were significant differences
      between the types of projects performed by different trade groups with laborers
      performing more highway/bridge renovation (p < 0.01), and plumbers reporting more
      residential remodeling (p = 0.05), repair of water lines containing lead (p =
      0.04), or work on lead joints (p < 0.01). In addition to trade, elevated blood
      lead levels were associated with the type of construction project (especially
      bridge renovation and residential remodeling) and activities that include
      welding, cutting, rivet busting. The age of the home in which the worker lived,
      and hobbies such as casting/smelting lead for bullets or sinkers, were also
      important risk factors. Compliance with OSHA's Construction Lead Standard, and
      implementation of good occupational health and safety practices in general, was
      poor. CONCLUSIONS: Blood lead levels of 459 construction workers differed by the
      type of trade, type of project and specific job activity owing to differences in
      the inherent exposure potential of each task. Although the numbers of workers
      performing lead abatement projects were small, the trend for lower BLL in this
      group provides evidence that training, implementation of engineering controls,
      and proper use of personal protective equipment such as respirators is effective
      in controlling lead poisoning.

PMID- 10398940
TI  - Comparison of fatal and severe nonfatal traumatic work-related injuries in
      Washington state.
AB  - OBJECTIVE: To compare fatal and hospitalized nonfatal work-related traumatic
      injuries by occupation and cause. METHODS: Fatal and hospitalized nonfatal
      injuries occurring from 1991-1995 were identified from Washington State workers'
      compensation claims data. Nonfatal injuries were classified as severe if they had
      at least one of the following criteria: a brain or spinal cord injury, an Injury
      Severity Score of >/=16, or were hospitalized for more than 7 days. The frequency
      and rate of fatal and severe nonfatal injuries were then described by industrial
      risk class and cause. RESULTS: The study identified 335 fatal injuries and 4,405
      hospitalized nonfatal injuries, of which 1,105 were classified as severe. Tree
      topping and pruning, carnival work, roofing, and metal siding and gutters risk
      classes had several severe nonfatal injuries, but few, if any, fatalities. Causes
      of fatal and severe nonfatal injuries were notably different for the roofing,
      restaurant, and orchard workers risk classes. CONCLUSIONS: The inclusion of
      severe hospitalized injuries in occupational injury surveillance systems will
      provide a broader view of high-risk occupations and profile of injury causation
      with which to direct occupational injury prevention efforts.

PMID- 10398941
TI  - Maintenance work and asbestos-related cancers in the refinery and petrochemical
      sector.

PMID- 10398942
TI  - In vitro and in vivo studies of 1H NMR visibility to detect deoxyhemoglobin and
      deoxymyoglobin signals in myocardium.
AB  - 1H nuclear magnetic resonance (NMR) spectroscopy can be used noninvasively to
      detect the proximal histidyl N delta proton signals of deoxymyoglobin in the
      myocardium. However, the quantification of deoxymyoglobin is based on the
      assumption that the deoxymyoglobin signal detected is not contaminated by the
      deoxyhemoglobin signals contributed from the blood. The purpose of this study was
      to conduct in vitro and in vivo 1H NMR studies to examine the in vivo NMR
      visibility of deoxyhemoglobin in the myocardium. The results demonstrate that the
      NMR visibility of alpha and beta subunits of deoxyhemoglobin is sensitive to the
      pulse width for spin excitation because of short T2 relaxation times, and they
      are not NMR visible in the canine myocardium in vivo at 4.7 T when a 0.5-1.0 msec
      long Gaussian excitation pulse is used. Therefore, the resonance peak detected at
      approximately 72 ppm (relative to the water resonance) in the ischemic canine
      myocardium in vivo is dominated by deoxymyoglobin.

PMID- 10398943
TI  - "Silent" MRI with soft gradient pulses.
AB  - A method to reduce the acoustic noise generated by gradient systems in magnetic
      resonance imaging (MRI) is proposed based on the linear response theory. Since
      the acoustic frequency response function of typical gradient coils is low in the
      range below 200 Hz, the noise level can be significantly reduced by using
      gradient pulse sequences whose spectra are limited to this frequency range. Such
      "soft," i.e., band-limited, pulse shapes can be designed using sinusoidal ramps
      individually adjusted to available delays. "Silent" versions of three basic MRI
      sequences [gradient-echo (GE), spin-echo (SE), and rapid acquisition with
      relaxation enhancement (RARE)] were programmed on 2 and 3 T whole-body scanners.
      High-quality images could be acquired at noise levels as low as 40 dBA (GE and
      SE) and 60 dBA (RARE).

PMID- 10398944
TI  - High-resolution diffusion imaging with DIFRAD-FSE (diffusion-weighted radial
      acquisition of data with fast spin-echo) MRI.
AB  - A novel MRI method, DIFRAD-FSE (diffusion-weighted radial acquisition of data
      with fast spin-echo), is demonstrated that enables rapid, high-resolution multi
      shot diffusion-weighted MRI without significant artifacts due to motion.
      Following a diffusion-weighting spin-echo preparation period, multiple radial
      lines of Fourier data are acquired using spin-echo refocusing. Images can be
      reconstructed from the radial data set using a magnitude-only filtered back
      projection reconstruction algorithm that removes phase errors due to motion.
      Results from human brain imaging demonstrate the ability of DIFRAD-FSE to acquire
      multiple radial lines of Fourier data each TR period without significant
      artifacts due to relaxation and to produce high-resolution diffusion-weighted MRI
      images without significant artifacts from motion.

PMID- 10398945
TI  - Multiple-voxel double-quantum lactate-edited spectroscopy using two-dimensional
      longitudinal Hadamard encoding.
AB  - A conventional gradient-selected double-quantum lactate editing sequence was
      combined with fourth order two-dimensional longitudinal Hadamard encoding and
      slice-selective refocusing to acquire lactate-edited spectra in a 3 x 3 matrix of
      voxels. The performance of the sequence was verified in phantoms at 9.4 T and in
      focally ischemic rat brain at 7.0 T. Efficient suppression of water, lipid, and
      the singlet resonances of creatine, choline, and N-acetylaspartate was achieved,
      giving multi-voxel localized lactate-edited spectra with good signal-to-noise
      ratio.

PMID- 10398946
TI  - 1H chemical shift imaging of the human brain at age 60-90 years reveals metabolic
      differences between women and men.
AB  - 1H magnetic resonance spectroscopy was used to compare brain metabolism in 540
      elderly persons, stratified by sex and age (60-90 years old). An 8 x 8 x 2 cm3
      supraventricular brain volume, a transverse plane parallel to the canthomeatal
      line, was examined by automated 1H chemical shift imaging [point-resolved
      spectroscopy (PRESS), TE of 35 msec]. Regional choline (Cho), creatine (Cr), and
      N-acetyl aspartate (NAA) peak areas in the 518 successful examinations (96%) were
      studied by division through the total area of the particular metabolite in each
      spectral map. This procedure eliminated intersubject variance, maximized
      intervoxel variance (26 < or = F < or = 149, P < 0.0001) and reduced the standard
      deviations in the voxel metabolite signals threefold. Normalized signals in women
      (n = 257) and men (n = 261) differed in 9 (Cho/sigma Cho), 8 (Cr/sigma Cr), and
      10 (NAA/sigma NAA) of 36 voxels examined (P < or = 0.001). In the cingulate gyrus
      Cho/sigma Cho, Cr/sigma Cr, and NAA/sigma NAA were reduced in men compared with
      women. These findings are consistent with a sex-related reduction of glucose
      metabolism in the same brain lobe revealed by positron emission tomography.

PMID- 10398947
TI  - Relaxation properties of a dual-labeled probe for MRI and neutron capture
      therapy.
AB  - Pharmaceutical agents labeled with both boron and gadolinium have potential
      applications in both boron neutron capture therapy (NCT) and magnetic resonance
      imaging. Pre- and post-injection T1 maps provide a method for the indirect
      measurement of the gadolinium and boron concentrations that can then be used in
      NCT treatment planning. This requires an understanding of the relaxation
      properties of the agent. In this paper we present an analysis of the relaxation
      properties of a dual boron and gadolinium agent, Gd (III)
      diethylenetriaminepentaacetate-carborane [Gd (III)-DTPA-carborane], in vitro in
      the presence and absence of serum albumin. The nuclear magnetic relaxation
      dispersion profile of solutions containing albumin obtained with a field cycling
      relaxometer exhibit a peak in the frequency range from 8 to 50 MHz. This
      indicates a long rotational correlation time relative to the solution without
      serum albumin. Results from other experiments indicate that this peak results
      from the binding of Gd (III)-DTPA-carborane derivative to serum albumin.
      Temperature studies indicate that the water proton relaxation efficiency of bound
      agent is limited by the water residence time as the relaxivity increases from 19
      +/- 1 to 32.6 +/-; 0.8 (sec.mM)-1 when the temperature is increased from 5 to 35
      degrees C.

PMID- 10398948
TI  - Non-invasive assessment of axonal fiber connectivity in the human brain via
      diffusion tensor MRI.
AB  - A technique for assessing in vivo fiber connectivity in the human brain is
      presented. The method utilizes a novel connectivity algorithm that operates in
      three spatial dimensions and uses estimates of fiber tract orientation and tissue
      anisotropy, obtained from diffusion tensor magnetic resonance imaging, to
      establish the pathways of fiber tracts. Sample in vivo connectivity images from
      healthy human brain are presented that demonstrate connections in the white
      matter tracts. White matter connectivity information is potentially of interest
      in the study of a range of neurological, psychiatric, and developmental disorders
      and shows promise for following the natural history of disease.

PMID- 10398949
TI  - Deuterium NMR tissue perfusion measurements using the tracer uptake approach: I.
      Optimization of methods.
AB  - This paper considers potential problems encountered when using the Kety approach
      to measure perfusion in small laboratory animals with nuclear magnetic resonance
      (NMR) tracer uptake methods: a) the need to measure the arterial input function
      (AIF) in each animal; b) sensitivity to perfusion heterogeneity; c) sensitivity
      to low signal-to-noise ratio (SNR); and d) influence of changes in the AIF. A
      method to estimate the AIF in rats is presented that derives an AIF from the time
      course of a tracer passing through a carotid chamber. The results of computer
      simulations indicate that a common AIF obtained in one set of animals can be used
      for perfusion estimations in another set of animals if the tracer is delivered as
      a dose and that optimal data analysis (fitting data vs. integration approach) is
      dictated by SNR and perfusion heterogeneity. Experimental strategies are
      suggested to minimize the effects of changes in the individual AIF that could
      distort perfusion estimates.

PMID- 10398951
TI  - Assessment of myocardial viability using MRI during a constant infusion of Gd
      DTPA: further studies at early and late periods of reperfusion.
AB  - It was previously shown in a canine model of ischemia/reperfusion injury that the
      partition coefficient of gadolinium-diethylene triamine pentaacetic acid (Gd
      DTPA) (lambda) increases in infarcted tissue. That previous study used a non
      magnetic resonance imaging (MRI) method to measure lambda and only investigated
      reperfusion times from 2 hr to 3 weeks. This study presents evidence suggesting
      that lambda starts to increase as early as 1 min after reperfusion of a 2 hr
      occlusion and continues to rise for up to 2 hr or more; lambda stays increased as
      late as 8 weeks, reaching peak values at 1-11 days and subsequently decreasing.
      It was also demonstrated that lambda can be accurately measured in vivo using a
      saturation recovery turbo fast low-angle shot (FLASH) sequence. The results of
      this study show that MRI during a constant infusion of Gd-DTPA has great
      potential for the non-invasive determination of myocardial viability as early as
      1 min to as late as 8 weeks following reperfusion of acute myocardial infarction.

PMID- 10398950
TI  - Fast lipid-suppressed MR temperature mapping with echo-shifted gradient-echo
      imaging and spectral-spatial excitation.
AB  - The water proton resonance frequency (PRF) is temperature dependent and can thus
      be used for magnetic resonance (MR) thermometry. Since lipid proton resonance
      frequencies do not depend on temperature, fat suppression is essential for PRF
      based temperature mapping. The efficacy of echo-shifted (TE > TR) gradient-echo
      imaging with spectral-spatial excitation is demonstrated, resulting in accurate
      and rapid, lipid-suppressed, MR thermometry. The method was validated on
      phantoms, fatty duck liver, and rat thigh, demonstrating improvements in both the
      speed and precision of temperature mapping. Heating of a rat thigh with focused
      ultrasound was monitored in vivo with an accuracy of 0.37 degree C and a time
      resolution of 438 msec.

PMID- 10398952
TI  - A flexible view ordering technique for high-quality real-time 2DFT MR
      fluoroscopy.
AB  - A method to tailor the view order to the reconstruction cycle is introduced for
      real-time MRI. It is well known that view sharing and oversampling central k
      space views can improve the temporal resolution of gradient-echo pulse sequences.
      By ordering phase-encodes to synchronize k-space acquisition with the
      reconstruction cycle, apparent temporal resolution can match the frame rate with
      as few as one-fourth of the phase-encodes sampled per reconstruction. Spatial
      resolution is maintained by periodically updating high spatial frequencies. In
      addition to apparent temporal resolution, three other criteria for real-time
      imaging are identified and evaluated: display latency, dispersion, and frame-to
      frame consistency. Latency is minimized by ordering views in a reverse-centric
      manner within each reconstruction interval, sampling high-energy views
      immediately prior to beginning reconstruction. Dispersion is kept low and
      consistent by synchronizing acquisition and reconstruction, thus avoiding poorly
      timed reconstruction instances. Real-time implementation demonstrates pulsatile
      time-of-flight blood signal enhancement in humans.

PMID- 10398953
TI  - Prospective MR signal-based cardiac triggering.
AB  - A cardiac motion compensation method using magnetic resonance signal-based
      triggering is presented. The method interlaces a triggering pulse sequence with
      an imaging sequence. The triggering sequence is designed to measure aortic blood
      velocity, from which cardiac phase can be inferred. The triggering sequence is
      executed repeatedly and the acquired data processed after each sequence
      iteration. When the desired phase of the cardiac cycle is detected, data are
      acquired using the imaging sequence. A signal-processing unit of a conventional
      scanner is used to process the triggering data in real time and issue triggering
      commands. Alternatively, a workstation, with a bus adaptor, can access data as
      they are acquired, process and display the data, and issue triggering commands.
      With a graphical user interface, the triggering pulse sequence and data
      processing techniques can be modified instantaneously to optimize triggering. The
      technique is demonstrated with coronary artery imaging using both conventional
      two-dimensional Fourier transform scans and spiral trajectories.

PMID- 10398954
TI  - Enhancement of BOLD-contrast sensitivity by single-shot multi-echo functional MR
      imaging.
AB  - Improved data acquisition and processing strategies for blood oxygenation level
      dependent (BOLD)-contrast functional magnetic resonance imaging (fMRI), which
      enhance the functional contrast-to-noise ratio (CNR) by sampling multiple echo
      times in a single shot, are described. The dependence of the CNR on T2*, the
      image encoding time, and the number of sampled echo times are investigated for
      exponential fitting, echo summation, weighted echo summation, and averaging of
      correlation maps obtained at different echo times. The method is validated in
      vivo using visual stimulation and turbo proton echoplanar spectroscopic imaging
      (turbo-PEPSI), a new single-shot multi-slice MR spectroscopic imaging technique,
      which acquires up to 12 consecutive echoplanar images with echo times ranging
      from 12 to 213 msec. Quantitative T2*-mapping significantly increases the
      measured extent of activation and the mean correlation coefficient compared with
      conventional echoplanar imaging. The sensitivity gain with echo summation, which
      is computationally efficient provides similar sensitivity as fitting. For all
      data processing methods sensitivity is optimum when echo times up to 3.2 T2* are
      sampled. This methodology has implications for comparing functional sensitivity
      at different magnetic field strengths and between brain regions with different
      magnetic field inhomogeneities.

PMID- 10398955
TI  - Myocardial velocity gradient imaging by phase contrast MRI with application to
      regional function in myocardial ischemia.
AB  - Velocity-encoded phase contrast magnetic resonance imaging (MRI) has the
      potential to quantify regional myocardial contractile function with a sensitivity
      to motion comparable to implanted ultrasonic crystals. An MRI sequence and post
      processing algorithm were developed to measure myocardial velocity gradients on a
      1.5 T MRI scanner. These methods were validated on a rotating phantom and applied
      to dogs before (n = 11) and during prolonged coronary occlusion (n = 5). In
      phantom validation studies, the average absolute error corresponded to motion
      equivalent to 0.03 +/- 0.04 mm (mean +/- SD) during the repetition time of the
      experiment. Rigid body corrections during post-processing significantly
      simplified the interpretation of myocardial velocity vectors. In vivo, rigid body
      motion contributes substantially to the recorded myocardial velocities in systole
      and diastole and can give the false impression of regional wall motion
      abnormalities. After rigid body correction, normal systolic and diastolic
      velocity vectors in short-axis views of the left ventricle were primarily
      directed toward the center of the left ventricle. Transmural radial strain rate
      was 2.0 +/- 0.6 sec-1 during systole and -3.6 +/- 1.1 sec-1 during early diastole
      in normal canine hearts. Ischemic myocardium was easily discriminated from normal
      left ventricle by velocity-encoded phase contrast MRI both qualitatively and
      quantitatively (P < 0.01 in systole and P < 0.05 in early diastole). Although the
      myocardial velocity images have a spatial resolution on the order of a
      millimeter, the velocity encoding describes the mechanical consequences of focal
      myocardial ischemia with sensitivity to submillimeter displacement of the pixels.
      The three-dimensional nature of velocity-encoded MRI is particularly well suited
      to the study of the complex motion of the heart in vivo.

PMID- 10398956
TI  - Composite image formation in z-shimmed functional MR imaging.
AB  - A challenge in functional magnetic resonance imaging (fMRI) is to develop imaging
      methods that are highly sensitive to microscopic field inhomogeneities [the blood
      oxygenation level-dependent (BOLD) effect] and minimally sensitivity to
      macroscopic fields. z-Shimming compensates for the through-plane dephasing that
      arises in gradient-echo images due to magnetic field inhomogeneities. To date, an
      analysis of the formation of composite images from multiple z-shim acquisitions
      has not been presented. This work compares three strategies for forming composite
      images, one of which is introduced for the first time, against the nominal image
      acquisition. True-versus false-positive rates of activation detection are
      considered, in addition to the time efficiency of the methods. It is shown that z
      shimming can provide uniform spatial sensitivity, resulting in increased
      activation detectability, in many cases outperforming the nominal imaging
      approach. Time efficiency is shown to be dependent on field uniformity. Theory,
      computer simulations, and results from fMRI studies are used to demonstrate the
      performance of these methods.

PMID- 10398957
TI  - Gradient echo time dependence and quantitative parameter maps for somatosensory
      activation in rats at 7 T.
AB  - The dependence of functional magnetic resonance imaging (MRI) contrast on the
      gradient echo time TE in T2*-weighted blood oxygenation level-dependent (BOLD)
      fast low-angle shot (FLASH) imaging has been studied at 7 T for electrical
      forepaw stimulation in alpha-chloralose anesthetized rats. The observed variation
      of both the activation signal intensity and spatial pattern with echo time TE,
      resulting from the regional heterogeneity of T2*, was assessed by the calculation
      of quantitative T2* and quantitative STE = 0 maps, the latter representing the
      back-extrapolated signal intensity for TE = 0. The subsequently determined T2*
      and STE = 0 activation maps allowed a pixelwise separation of true BOLD from
      inflow contributions to forepaw stimulation-induced signal change in the
      somatosensory cortex of rat brain. For functional activation experiments
      performed with one single echo time the prior measurement of a quantitative T2*
      map is recommended as minimum further information to judge the intensity and the
      regional pattern of the resulting activation maps.

PMID- 10398958
TI  - Fast, accurate, and reproducible automatic segmentation of the brain in T1
      weighted volume MRI data.
AB  - A new fast automated algorithm has been developed to segment the brain from T1
      weighted volume MR images. The algorithm uses automated thresholding and
      morphological operations. It is fully three-dimensional and therefore independent
      of scan orientation. The validity and the performance of the algorithm were
      evaluated by comparing the automatically calculated brain volume with semi
      automated measurements in 10 subjects, by calculating the brain volume from
      repeated scans in another 10 subjects, and by visual inspection. The mean and
      standard deviation of the difference between semi-automated and automated
      measurements were 0.56% and 2.8% of the mean brain volume, respectively, which is
      within inter-observer variability of the semi-automated method. The mean and
      standard deviation of the difference between the total volumes calculated from
      repeated scans were 0.40% and 1.2% of the mean brain volume, respectively. Good
      results were also obtained from a scan of abnormal brains.

PMID- 10398959
TI  - Radiofrequency current density imaging of kainate-evoked depolarization.
AB  - The purpose of this study was to examine whether radiofrequency current density
      imaging (RF-CDI) can quantitatively monitor depolarizations evoked by excitatory
      amino acids in a rat's brain. To evoke depolarization, a glutamate receptor
      agonist, kainate, was administered into the right lateral ventricle. First,
      electroencephalographic activity was recorded in a basal condition and after the
      application of kainate. Complex behavioral patterns were observed. Second,
      impedance measurements were performed to assess the change in conductivity of the
      brain due to kainate at the Larmor frequency of the imager. Calculated changes
      were about 17%. Third, a set of current density images was obtained with RF-CDI
      before and after the administration of kainate. Kainate-induced excitatory
      changes were observed on current density images as brighter regions, mainly in
      the hippocampal area compared with the same area in the basal condition.

PMID- 10398961
TI  - Multicomponent T2 relaxation of in vivo skeletal muscle.
AB  - In vivo spin-spin (T2) relaxation measurements were acquired from the flexor
      digitorum profundus (FDP) of 13 subjects. A standard imaging T2 measurement
      technique [number of points (N) = 6, TE = 18 msec, signal-to-noise ratio (SNR)
      approximately equal to 300] yielded a single T2 value of 31 msec. A novel
      technique, projection presaturation combined with a CPMG sequence, was used to
      acquire data (N = 1000, TE = 1.2 msec, SNR 3500) from a cylindrical voxel (2 cm
      diameter, 5 cm length) within the FDP. All 13 subjects had at least four T2
      components, at < 5, 21 +/- 4, 39 +/- 6, and 114 +/- 31 msec, with fractional
      areas of 11 +/- 2, 28 +/- 15, 46 +/- 12, and 11 +/- 5% respectively. The shortest
      and longest components have been observed in ex vivo muscle studies, probably
      corresponding to water associated with macromolecules and extracellular water,
      respectively. The middle T2 components are suggestive of an organization of in
      vivo intracellular water.

PMID- 10398960
TI  - MRI-guided radiofrequency thermal ablation of implanted VX2 liver tumors in a
      rabbit model: demonstration of feasibility at 0.2 T.
AB  - Successful radiofrequency (RF) thermal ablation was performed on VX2 tumors
      implanted in 23 rabbit livers under magnetic resonance (MR) guidance using a C
      arm-shaped low-field 0.2 T system. RF application and immediate postprocedure MRI
      of all animals was performed [T2-weighted, turbo short tau inversion recovery
      (STIR), T1-weighted before and after gadopentetate dimeglumine administration).
      Follow-up MRI with a superparamagnetic iron oxide (SPIO) contrast medium was
      performed in nine rabbits at 2 weeks and in four rabbits at 1 month post RF
      ablation. All livers were harvested for pathologic examination. T2-weighted and
      turbo-STIR images demonstrated the highest tumor-to-RF-thermal lesion contrast-to
      noise ratios (CNRs; means 4.5 and 3.8, respectively) on postprocedure images;
      this was redemonstrated at 2- and 4-week follow-up imaging. T2-weighted imaging
      never overestimated pathologic lesion size by more than 2 mm, and the radiologic
      pathologic correlation coefficient was not less than 0.90. In conclusion, MRI
      guided RF thermal ablation in implanted liver tumor is feasible using a C-arm
      shaped low-field 0.2 T system. The thermal lesion size can be most accurately
      monitored with T2-weighted and turbo-STIR images.

PMID- 10398962
TI  - An MRI calorimetry technique to measure tissue ultrasound absorption.
AB  - High-intensity focused ultrasound (US) surgery guided by magnetic resonance
      imaging (MRI) is a very promising form of minimally invasive thermal therapy. To
      apply this technique optimally, the interaction mechanisms of high-intensity US
      with tissue need to be better understood, in particular, the variation of
      ultrasound absorption with frequency and temperature. However, agreement on the
      value of measured tissue US absorption is poor, largely because of intrinsic
      experimental complications of prior investigations. A new approach toward
      measuring tissue US absorption, based on a form of MRI calorimetry, is proposed
      here, which allows non-invasive energy measurement through spatial temperature
      mapping with MRI. A modified two-dimensional spoiled gradient-echo sequence has
      been implemented to map temperature based on proton resonance frequency (PRF)
      shift. Validation experiments show excellent agreement of MRI measured energy
      with that delivered by a calibrated source. MRI calorimetry of US heating of
      tissue-mimicking polyethylene glycerol material has been performed. Using a
      hydrophone measurement of the incident US field, its US absorption coefficient
      was measured as 0.032 cm-1. As this approach can be applied over a range of
      frequencies, tissues, and temperatures, it should provide a much improved means
      of measuring absolute tissue US absorption coefficients to improve US therapy
      planning, future transducer design, and US dosimetry models.

PMID- 10398964
TI  - A practical double-tuned 1H/31P quadrature birdcage headcoil optimized for 31P
      operation.
AB  - A double-tuned 1H/31P birdcage head coil for use with humans at 1.5 T is
      described. The coil was designed for proton-decoupled 31P excitation and
      reception and incorporated a number of practical features including optimized
      sensitivity for 31P, quadrature operation at 1H and 31P frequencies, and a
      radiofrequency (RF) mirror for improved B1 homogeneity. The design achieved
      similar B1 homogeneity at both 31P and 1H frequencies. Inductive matching was
      used to accommodate samples with large loading differences. A facile method for
      tuning and matching over a variety of sample loadings is presented, along with
      capacitively shortened bazookas for suppression of cable braid currents. The
      proton sensitivity, although down by approximately a factor of two compared with
      an optimized 1H birdcage head coil, was still ample for shimming and generation
      of scout images. Advantages of the design are discussed and proton-decoupled 31P
      spectra of human brain are presented.

PMID- 10398963
TI  - Cerebral blood flow measurement by dynamic contrast MRI using singular value
      decomposition with an adaptive threshold.
AB  - Singular value decomposition (SVD) is a promising deconvolution technique for use
      in dynamic contrast agent magnetic resonance perfusion imaging. Computer
      simulations, however, show that the selection of the threshold for SVD affects
      the accuracy of the cerebral blood flow measurements and may distort the shape of
      the vascular residue function. In this report, a pixel-by-pixel thresholding
      method is proposed based on the signal-to-noise ratio of the concentration time
      curve at maximum concentration (SNRC). Monte Carlo simulations were used to
      determine the optimal threshold for different SNRC. This technique was used to
      analyze data from six healthy volunteers, resulting in a mean gray to white
      matter cerebral blood flow ratio of 2.67 +/- 0.07. This value is in excellent
      agreement with values published in the literature.

PMID- 10398965
TI  - Electromagnetic and thermal modeling of SAR and temperature fields in tissue due
      to an RF decoupling coil.
AB  - The finite difference time domain method is used to calculate the specific
      absorption rate (SAR) due to a butterfly surface coil in a realistic tissue model
      of the leg. The resulting temperature distribution and temperature changes are
      found using a finite difference solution to the bioheat transfer equation.
      Reasonable agreement is found between predicted temperature changes and those
      measured in vivo provided that the resulting hyperthermia does not induce
      noticeable changes in perfusion. The method is applicable to radiofrequency
      dosimetry problems associated with high Bo field magnetic resonance systems and
      where knowledge of spatial variation in SAR is important in assessing the safety
      of new magnetic resonance procedures.

PMID- 10398966
TI  - Microencapsulation of paramagnetic particles by pyrroxylin to preserve their
      responsiveness to oxygen when used as sensors for in vivo EPR oximetry.
AB  - Using the broadening of the electron paramagentic resonance (EPR) linewidth of
      paramagnetic particles by oxygen, it is possible to make measurements of the
      partial pressure of oxygen in vivo. While the results obtained so far with EPR
      oximetry are very encouraging, several paramagnetic materials may lose their
      responsiveness to oxygen in tissues. This aim of this study was to provide
      evidence that an appropriate coating can preserve the oxygen sensitivity of
      paramagnetic materials in vivo. Two charcoals that have the oxygen-sensing
      properties required for EPR oximetry (combined with a tendency to lose
      responsiveness to oxygen when placed in tissues) were coated using pyroxylin.
      Sensitivity to variations in pO2 was checked by inducing hypoxia in the muscles
      of mice injected with charcoal. While the uncoated material lost responsiveness
      to oxygen within few days, the particles coated with 20-30% of pyroxylin did not
      lose their responsiveness for more than 2 months.

PMID- 10398967
TI  - Multiple bond 13C-13C spin-spin coupling provides complementary information in a
      13C NMR isotopomer analysis of glutamate.
AB  - Most 13C nuclear magnetic resonance (NMR) isotopomer analyses relate a metabolic
      index of interest to populations of 13C isotopomers as reported by one-bond 13C
      13C spin-spin couplings. Metabolic conditions that produce highly enriched citric
      acid cycle intermediates often lead to 13C NMR spectra of metabolites such as
      glutamate that show extra multiplets due to long-range couplings. It can be
      demonstrated from 13C NMR spectra of hearts perfused with mixtures of acetate
      plus propionate that multiplets in glutamate C2 arising from 3J25 coupling
      provide a direct readout of acetyl-CoA fractional enrichment (FC1 and FC3), while
      multiplets in glutamate C5 arising from 2J35 and 3J25 couplings quantitatively
      reflect enrichment of the anaplerotic substrate.

PMID- 10398969
TI  - Fast T1 mapping on a whole-body scanner.
AB  - A method for the fast acquisition of quantitative T1 maps is presented. It is
      based on the acquisition of a series of snapshot fast low-angle shot (FLASH)
      images after inversion of the magnetization. A drawback of this method is the
      necessity for a sufficiently long relaxation delay before each inversion pulse,
      leading to long experimental times if averaging or segmentation is required. Thus
      implementation of this method on a whole-body scanner is problematic, as the
      longer gradient rise times provide prolonged repetition times, which makes
      segmentation indispensable to provide a sufficient temporal resolution. We
      present a modification of the method that allows for reduction in the
      intermediate relaxation delays and thus for considerably reduced experimental
      durations.

PMID- 10398968
TI  - Simultaneous correction for interscan patient motion and geometric distortions in
      echoplanar imaging.
AB  - A method is presented for simultaneous correction of linear geometric distortions
      and interscan patient motion in echoplanar imaging (EPI). The technique does not
      require the acquisition of specialized scans other than high-resolution magnetic
      resonance images. The method is based on a generalized surface-based
      coregistration algorithm, which accounts for a complete 3-dimensional affine
      transformation, i.e., rotations, translations, scaling, and shearing, between two
      volumetric image data sets. Any minimally distorted high-resolution scan may
      serve as a reference data set, to which the EPI data set is matched. The
      algorithmic accuracy was assessed using simulated data sets with known affine
      distortions. The deviation of the parameters determined by the coregistration
      program from the true values typically was 1% or less. Precise alignment of
      functional and anatomic information will be important for many future clinical
      applications.

PMID- 10398970
TI  - In vivo time course studies of the tissue responses to resorbable polylactic acid
      implants by means of MRI.
AB  - Magnetic resonance (MR) imaging and relaxation time measurements of bioresorbable
      implants made of polylactic acid (PLA), as well as the surrounding tissues, were
      carried out over a period of 6 months to monitor the implant state and the body's
      responses, and to determine how these processes are reflected in MR data. Twelve
      rabbits each received two subcutaneous PLA implants (45 x 10 x 2 mm). Changes in
      tissue relaxation rates demonstrated inflammation and tissue healing time courses
      but were not simply linear functions of the tissue water content and so provide
      new insight into MR characterization of inflammatory processes.

PMID- 10398971
TI  - Applications of high-resolution echoplanar spectroscopic imaging for structural
      imaging.
AB  - Echoplanar spectroscopic imaging (EPSI) was introduced as a fast alternative for
      spectroscopic imaging and has been recently implemented on clinical scanners.
      With further advances in gradient hardware and processing strategies, EPSI can be
      used to obtain spectroscopic images whose spatial resolution parallels that of
      conventional anatomic images within clinically acceptable acquisition time. The
      present work demonstrates that high-resolution EPSI can be used to derive
      structural images for applications in which spectroscopic information is
      beneficial. These applications are chemical shift (fat-water) imaging, narrow
      bandwidth imaging, and T2* mapping. In this paper, the EPSI sequence design and
      processing strategies are detailed and experimental results in normal volunteers
      are presented to illustrate the potential of using EPSI in imaging anatomic
      structures.

PMID- 10398972
TI  - Joint motion in an open MR unit using MR tracking.
AB  - A system for active scan plane guidance during kinematic magnetic resonance (MR)
      examination of joint motion was developed utilizing an external tracking coil and
      MR tracking software. In a phantom study and during upright, weight-bearing,
      physiologic knee flexion, the external tracking coil maintained the scan plane
      through desired structures. Thus, MR tracking provides a robust method to guide
      the scan plane during MR imaging of active joint motion.

PMID- 10398973
TI  - A multisite phase III study of the safety and efficacy of a new manganese
      chloride-based gastrointestinal contrast agent for MRI of the abdomen and pelvis.
AB  - The purpose of this study was to evaluate the safety and efficacy of a manganese
      chloride-based oral magnetic resonance (MR) contrast agent during a Phase III
      multisite clinical trial. Two hundred seventeen patients were enrolled who were
      already scheduled for MRI of the abdomen and/or pelvis. In this group of
      patients, it was postulated that the use of an oral agent would better allow
      discrimination of pathology from bowel. Patients with known gastrointestinal
      pathology including peptic ulcer disease, inflammatory bowel disease,
      obstruction, or perforation were excluded to minimize confounding variables that
      could affect the safety assessment. Of these 217 patients, 18 received up to 900
      mL of placebo, and 199 patients were given up to 900 mL of a manganese chloride
      based oral contrast agent, LumenHance (Bracco Diagnostics, Inc.). Safety was
      determined by comparing pre- and post-dose physical examinations, vital signs,
      and laboratory examinations and by documenting adverse events. Efficacy was
      assessed by unblinded site investigators and two blinded reviewers who compared
      pre- and post-dose T1- and T2-weighted MRI scans of the abdomen and/or pelvis. In
      111 (57%) of the 195 cases evaluated for efficacy by site investigators
      (unblinded readers), MRI after LumenHance provided additional diagnostic
      information. Increased information was found by two blinded readers in 52% and
      51% of patients, respectively. In 44/195 cases (23%) unblinded readers felt the
      additional information would have changed patient diagnosis and in 50 patients
      (26%), it would have changed management and/or therapy. Potential changes in
      patient diagnosis or management/therapy were seen by the two blinded readers in 8
      20% of patients. No clinically significant post-dose laboratory changes were
      seen. Forty-eight patients (24%) receiving LumenHance and four patients (22%)
      receiving placebo experienced one or more adverse events. Gastrointestinal tract
      side effects were most common, seen in 29 (15%) of LumenHance patients and in 3
      (17%) of the placebo patients. LumenHance is a safe and efficacious oral
      gastrointestinal contrast agent for MRI of the abdomen and pelvis.

PMID- 10398974
TI  - Fat-suppressed T2-weighted MR imaging of hepatocellular carcinoma and metastases:
      comparison of conventional spin-echo, fast spin-echo, and echoplanar pulse
      sequences.
AB  - The purpose of our study was to compare the diagnostic accuracy of fat-suppressed
      T2-weighted magnetic resonance (MR) images obtained with conventional spin-echo
      (SE), respiratory-triggered fast SE, and breath-hold multishot SE echoplanar (EP)
      sequences for the detection of hepatocellular carcinoma and metastases. Images
      obtained with the three sequences in 17 patients (15 with cirrhosis) with 31
      hepatocellular carcinomas and 14 patients with 45 metastases were retrospectively
      analyzed. Image review was conducted on a segment-by-segment basis; in all, 248
      liver segments were reviewed separately and independently for detection of solid,
      malignant lesions. Diagnostic accuracy was evaluated with receiver-operating
      characteristic (ROC) curve analysis. Diagnostic accuracy for hepatocellular
      carcinoma as determined by ROC curve analysis was better by a statistically
      significant amount for conventional SE (Az = 0.95) images when compared with
      respiratory-triggered fast SE (Az = 0.83, P < 0.05) and breath-hold multishot SE
      EP (Az = 0.80, P < 0.05) images. Conventional SE MR sequences should not be
      replaced with respiratory-triggered fast SE or breath-hold multishot SE EP
      sequences for T2-weighted MR imaging of patients with hepatocellular carcinoma in
      cirrhosis, unless sufficient contrast-enhanced dynamic MR imaging is subsequently
      performed.

PMID- 10398975
TI  - Stability, repeatability, and the expression of signal magnitude in functional
      magnetic resonance imaging.
AB  - In 23 fMRI studies on six subjects, we examined activation in visual and motor
      tasks. We modeled the expected activation time course by convolving a temporal
      description of the behavioral task with an empirically determined impulse
      response function. We evaluated the signal activation intensity as both the
      number of activated voxels over arbitrary correlation thresholds and as the slope
      of the regression line between our modeled time course and the actual data.
      Whereas the voxel counting was strikingly unstable (standard deviation 74% in
      visual trials at a correlation of 0.5), the slope was relatively constant across
      trials and subjects (standard deviation <14%). Using Monte Carlo methods, we
      determined that the measured slope was largely independent of the contrast-to
      noise ratio. Voxel counting is a poor proxy for activation intensity, with
      greatly increased scatter, much reduced statistical power, and increased type II
      error. The data support an alternative approach to functional magnetic resonance
      imaging (fMRI) that allows for quantitative comparisons of fMRI response
      magnitudes across trials and laboratories.

PMID- 10398976
TI  - Automatic vessel segmentation using active contours in cine phase contrast flow
      measurements.
AB  - The segmentation of images obtained by cine magnetic resonance (MR) phase
      contrast velocity mapping using manual or semi-automated methods is a time
      consuming and observer-dependent process that still hampers the use of flow
      quantification in a clinical setting. A fully automatic segmentation method based
      on active contour model algorithms for defining vessel boundaries has been
      developed. For segmentation, the phase image, in addition to the magnitude image,
      is used to address image distortions frequently seen in the magnitude image of
      disturbed flow fields. A modified definition for the active contour model is
      introduced to reduce the influence of missing or spurious edge information of the
      vessel wall. The method was evaluated on flow phantom data and on in vivo images
      acquired in the ascending aorta of humans. Phantom experiments resulted in an
      error of 0.8% in assessing the luminal area of a flow phantom equipped with an
      artificial heart valve. Blinded evaluation of the volume flow rates from
      automatic vs. manual segmentation of gradient echo (FFE) phase contrast images
      obtained in vivo resulted in a mean difference of -0.9 +/- 3%. The mean
      difference from automatic vs. manual segmentation of images acquired with a
      hybrid phase contrast sequence (TFEPI) within a single breath-hold was -0.9 +/-
      6%.

PMID- 10398977
TI  - Contrast-enhanced MR imaging of two superparamagnetic RES-contrast agents:
      functional assessment of experimental radiation-induced liver injury.
AB  - The purpose of this study was to compare liver contrast-enhancing characteristics
      of two superparamagnetic reticuloendothelial system (RES)-directed agents with
      different particle sizes, polycrystalline iron oxide nanocompounds (PION) and
      carboxydextran-coated maghemite (DDM128N/389, later referred to as DDM128), in an
      experimental model of focal radiation-induced hepatitis. PION, for the small
      particle size (31 nm), and DDM128, for the large particle size (59 nm), RES
      directed agents were compared for liver enhancement after radiation-induced liver
      injury. A single x-irradiation exposure varying from 10 to 60 Gy was delivered to
      one side of the liver. T2-weighted spinecho magnetic resonance imaging was
      performed 3 days after x-irradiation at 30 minutes post-contrast. Using the RES
      directed PION, the normal, non-irradiated portion of the liver decreased in
      signal intensity with a maximum negative enhancement of -66%, while the
      irradiated portion of the liver decreased in signal intensity by -24% (60 Gy).
      The signal intensity decline of irradiated liver tissue using PION was dose
      dependent, but was found at all radiation dose levels (10-60 Gy). The difference
      in signal intensity between irradiated (-63%) and non-irradiated (-82%) portions
      was also statistically different using DDM128 at 60 Gy. However, lower
      irradiation doses (10 and 30 Gy) failed to produce a statistically significantly
      different enhancement in the irradiated and non-irradiated portion of the liver.
      Sensitivity of liver enhancement with RES-directed agents is size dependent. The
      smaller particle (PION) is more sensitive for detection of radiation-induced
      hepatitis than the larger particle (DDM128). The relative insensitivity of DDM128
      enhancement for diffuse liver injury will be clinically advantageous for
      detecting focal lesions in the presence of diffuse hepatic injury.

PMID- 10398978
TI  - Correlation of laminated MR appearance of articular cartilage with histology,
      ascertained by artificial landmarks on the cartilage.
AB  - The object of this study was to correlate the laminae of articular cartilage on
      magnetic resonance (MR) imaging with histologic layers. T1- and fast spin-echo T2
      weighted images of articular cartilage with artificial landmarks were obtained
      under high gradient echo strength (25 mT/m) conditions and a voxel size of 78 x
      156 x 2000 microm. Images were also obtained with a) changed frequency-encoding
      directions; b) changed readout gradient strength; and c) a varied number of phase
      encoding steps. T2 mapping was performed with angular variations. Artificial
      landmarks allowed accurate comparison between the laminae on MR images and the
      histologic zones. No alterations of the laminae were noted by changing the
      frequency gradient direction. Altering readout gradient strengths did not show a
      difference in the thickness of the laminae, and increasing the phase-encoding
      steps resulted in a more distinct laminated appearance, ruling out chemical
      shift, susceptibility, and truncation artifacts. The T2 mapping profile showed an
      anisotropic angular dependency from the magic angle effect. In conclusion, the
      laminated appearance of articular cartilage on spin-echo and fast spin-echo MR
      images correlated with the histologic zones rather than MR artifacts.

PMID- 10398979
TI  - Contrast-enhanced 3D-MRA of the upper abdomen with a bolus-injectable SPIO (SH U
      555 A).
AB  - The purpose of this study was to study temporal changes in signal intensity of
      liver, spleen, abdominal vessels, and focal liver lesions following iv bolus
      injection of a superparamagnetic iron oxide (SPIO) using a breath-held three
      dimensional magnetic resonance angiography (3D-MRA) sequence. Dynamic SH U 555 A
      enhanced 3D-MRA studies were performed in 20 patients with focal liver lesions.
      Sequential coronal 3D-MRA-FISP scans were acquired (TR 5.0 msec, TE 2.0 msec,
      flip angle 25 degrees, 140 x 256 matrix, and 80 mm slab) within 15 seconds.
      Scanning was started immediately after bolus injection of 10 micromol Fe/kg
      bodyweight and was repeated at multiple time points (baseline and 30, 60, 90,
      120, 180, 240, 300, 360, and 420 seconds). Signal intensity values of liver,
      focal liver lesions, spleen, the portal venous system, the abdominal aorta, and
      the inferior vena cava were obtained to calculate relative enhancement (ENH = [SI
      post - SI pre]/SI pre x 100). Visibility of vessels was assessed by consensus of
      two readers. Signal enhancement within abdominal vessels peaked during the first
      pass; however, significant signal enhancement was still present 420 seconds
      following injection. The liver and the spleen also demonstrated a biphasic
      enhancement pattern with prolonged parenchymal enhancement. Dynamic MRA with
      bolus injectable SH U 555 A is clinically feasible, and significant vessel
      enhancement can be achieved even at the dose of 10 micromol Fe/kg bodyweight.
      However, further refinements are required to improve contrast effects.

PMID- 10398980
TI  - How accurate are measurements on MRI? A study on multiple sclerosis using
      reliable 3D stereological methods.
AB  - Unbiased stereological principles for quantifying plaque volume and number in
      multiple sclerosis (MS) are described, and practical problems with their
      implementation are discussed. Plaque volume was estimated using stereological
      methods on 3 mm brain magnetic resonance imaging (MRI). Volume estimates made
      from thick sections are biased. For convex particles as plaques, bias can be
      corrected by excluding the slice of maximal area from the estimate. Comparing the
      corrected with the uncorrected results, bias varied between 15 and 200%,
      depending on object size. By analogy, for the estimates of plaque, bias varied
      between 15 and 90%. The use of 1 mm slices reduces bias to a value close to zero
      and should be preferred when precise plaque measurements are required. An
      unbiased three-dimensional counting rule-the disector-was used to estimate plaque
      number. The coefficient of error of the estimates was calculated. Stereological
      methods applied to MRI provide efficient and reliable estimates of MS plaque
      load.

PMID- 10398981
TI  - MR imaging of the liver with Gd-BOPTA: quantitative analysis of T1-weighted
      images at two different doses.
AB  - This study evaluates the efficacy of gadobentate-dimeglumine (Gd-BOPTA) for
      enhancement of liver signal-to-noise ratio (SNR) and lesion-liver contrast-to
      noise ratio (CNR) on T1-weighted spin-echo (SE) and gradient-recalled-echo (GRE)
      images at two different doses. Fifty patients with known or suspected liver
      lesions were examined at 1.5 T. T1-weighted SE (TR/TE 300/12 msec) and GRE images
      (TR/TE80/4.2 msec/flip angle 80 degrees) were obtained before and at 40-80
      minutes and 90-120 minutes after administration of 0.05 or 0.1 mmol/kg Gd-BOPTA.
      Quantitative measurements of tissue signal intensity were performed at each dose.
      Liver showed significant enhancement after Gd-BOPTA on T1-weighted SE and GRE
      images (0.05 mmol: P < 0.05; 0.1 mmol: P < 0.001). The dose of 0.1 mmol/kg
      provided higher liver SNR than 0.05 mmol/kg. Mean liver SNR was higher on GRE
      than SE images (P < 0.0001). Lesion-liver CNR significantly increased on GRE
      images after 0.1 mmol (P < 0.05). There was a trend toward superiority of 0.1
      mmol over 0.05 mmol/kg. GRE images were superior to SE images for pre- and post
      Gd-BOPTA lesion-liver CNR (P < 0.05). Our study suggests that Gd-BOPTA provides
      prolonged enhancement of liver SNR and CNR, that a dose of 0.1 mmol/Kg appears to
      be superior than 0.05 mmol/Kg, and that GRE techniques should be used in
      preference over SE techniques.

PMID- 10398982
TI  - Spiral reconstruction by regridding to a large rectilinear matrix: a practical
      solution for routine systems.
AB  - Spiral trajectories offer a number of attractive features for fast imaging. A
      practical problem for the implementation on routine magnetic resonance scanners
      is the lack of appropriate and efficient reconstruction algorithms in the
      available scanner software. In this paper, a simple way to implement a spiral
      reconstruction algorithm is described that avoids the data interpolation required
      by gridding approaches commonly used. Using the optimized fast Fourier transform
      built into each scanner, it offers image reconstruction times of less than 1
      second and thus allows the introduction of spiral imaging to routine scanners.

PMID- 10398983
TI  - Early childhood MRI findings in complex partial seizures and hippocampal
      sclerosis.
AB  - Magnetic resonance imaging (MRI) was performed on an infant with typical complex
      partial seizures. Visual analysis revealed MRI signs of left hippocampal
      sclerosis (HS) at an age of 9 months. Morphometric data including volumetry and
      relaxometry confirming the diagnosis are shown. This is the first report of an
      infant younger than 2 years with typical MRI findings including morphometric data
      on HS.

PMID- 10398984
TI  - Chemical shift imaging at 4.7 tesla of thymus in young and old mice.
AB  - We propose an experimental protocol, based on chemical shift magnetic resonance
      imaging (CSI) that improves the methods presently available for the in vivo study
      of the thymus in small animals. Male Balb/c mice were examined in an imager
      spectrometer equipped with a 4.7 T magnet. Three groups of animals with different
      ages were used: the first group consisted of 3-month-old mice (n = 5), the second
      group of 19-month-old mice (n = 5), and the third group of 26-month-old mice (n =
      4). The identification of thymic parenchyma was obtained by two (T1-weighted spin
      echo and CSI water-selective) images. The T1-weighted spin-echo image provided a
      detailed anatomical description of the organs located in the thorax. The CSI
      water-selective image provided a detailed description of thymic location, shape,
      and dimensions. The cross-sectional area of the thymus, measured from CSI images,
      showed a decreasing trend with increasing age. The values of the thymus-muscle
      contrast-to-noise ratio were measured in both spin echo and CSI images. While the
      contrast between thymus and muscle was greatly improved in the young and
      presenescent group, the difference was not statistically significant in the
      senescent group. In conclusion, the proposed method allows the study of thymic
      modification during the passage from young to pre-senescent age and from
      presenescent to old age. This method could be useful in studies in which
      experimental manipulation or drug treatments produce changes in the dimension and
      fat content of this organ. The proposed protocol, based on CSI, appears to be an
      improved methodology for study of the thymus.

PMID- 10398985
TI  - Application and validation of three-dimensional data sets from a phase contrast
      MR angiography for preoperative computer simulation of brain tumors.
AB  - We applied a three-dimensional (3D) phase contrast magnetic resonance angiography
      as the source for generating integrated 3D images for surgical planning of brain
      tumors. In the 3D model, we defined the Cingulomarginal sulcus and subsequently
      the central sulcus in the interhemispheric plane. This method solved the
      misregistration problem caused by the combination of multi-sequence data sets and
      can be feasible for surgical planning.

PMID- 10398986
TI  - MR imaging in patients with intraspinal bullets.

PMID- 10398987
TI  - Temperature Measurement Using Echo-Shifted FLASH at Low Field for Interventional
      MRI.
AB  - Temperature Measurement Using Echo-Shifted FLASH at Low Field for Interventional
      MRI. Yiu-Cho Chung, Jeffrey L. Duerk, Ajit Shankaranarayanan, Monika Hampke,
      Elmar M. Merkle, and Jonathan S. Lewin. (Article was originally published in the
      Journal of Magnetic Resonance Imaging, Volume 9, No. 1, 1999). In this article,
      some of the references were printed with the incorrect journal name. Here is the
      corrected list of references for this article.

PMID- 10398988
TI  - Long-term outcome of patients who underwent percutaneous nucleotomy for lumbar
      disc herniation: results after a mean follow-up of 5 years.
AB  - A total of 41 patients who had undergone percutaneous nucleotomy for a single
      level lumbar disc herniation were clinically examined after a mean postoperative
      follow-up of 5 years (range 4 to 7 years). There were 14 (34%) male and 27 (66%)
      female patients with a mean age of 49 years. By intra-operative discography, the
      herniation had been graded as a protrusion in 21 (51%) patients and as a prolapse
      in 20 (49%) patients. At the time of the investigation, sciatica had completely
      recovered or markedly diminished in 32 (78%) patients, and 29 (71%) patients had
      returned to work. Evaluated by a 100 mm visual analog pain scale (VAS), the
      postoperative pain relief was statistically significant (p < 0.0001). Clinical
      signs and symptoms of segmental instability of the lumbar spine were detected in
      10 (24%) patients. Instability was significantly associated with an
      unsatisfactory long-term outcome in the patients with the occurrence of sciatica
      (p = 0.003) and low back pain (p = 0.001) as well as the VAS score (p = 0.005)
      and Oswestry index (p < 0.0001). Clinical investigation revealed sensory deficits
      in the leg in 12 (29%) patients, weakness of the extensor hallucis longus muscle
      in 5 (12%) patients and a total peroneal paresis in one (2%). The patellar and
      achilles tendon reflexes were depressed in 2 (5%) and 5 (12%) patients,
      respectively. During the follow-up period, recurrent disc herniation was detected
      in 3 (7%) patients who were all re-operated on. In addition, 3 (7%) patients were
      re-operated on for other back problems. Corroborating earlier findings, the
      results of this study indicate that percutaneous nucleotomy is an effective and
      safe alternative to open surgery in the treatment of patients with a small
      prolapse or a protrusion.

PMID- 10398989
TI  - Laminar and arch fractures with dural tear and nerve root entrapment in patients
      operated upon for thoracic and lumbar spine injuries.
AB  - OBJECTIVE: To determine the neurological outcome in patients with laminar
      fractures associated with dural tears and nerve root entrapment, operated upon
      for thoracic and lumbar spine injuries. PATIENT POPULATION: Out of 103 patients
      operated upon consecutively for thoracic and lumbar spine injuries during the
      period 1990 to 1994 inclusive, 24 (23.3%) patients had laminar fractures out of
      whom 3 (2.9%) had an associated dural tear and an other 17 (16.5% or 70.8% of the
      total patients with laminar fractures) had an associated dural tear and nerve
      root entrapment. RESULTS: Twelve (70.5%) patients had injury at the thoraculumbar
      junction, 13 (76.5%) had Magerl's type A3 or above, 10 (58.8%) had a kyphotic
      angle deformity greater than 5 degrees. Seven (41.1%) had their spinal canal's
      sagittal diameter reduced by at least 50% and two had dislocations. Nine (52.9%)
      had initial neurological deficits. Four (50%) out of 8 patients with no initial
      neurological deficits (Frankel E) worsened to Frankel D. However, one patient
      among the 3 with initial Frankel A improved to Frankel C while both patients with
      initial Frankel C usefully improved to final Frankel grades D and E respectively.
      Two of the four patients with initial Frankel D improved to Frankel E, the other
      2 remaining unchanged. All in all five patients neurological status improved, 4
      worsened and 8 remained unchanged after neurosurgical treatment. CONCLUSIONS:
      Vertical laminar fractures with dural tears and nerve root entrapment represent a
      special group of thoracic and lumbar spine injuries that carry a poor prognosis.
      However, special operative precautions lead to significant improvement in some of
      them although a majority remain unchanged or even worsened.

PMID- 10398990
TI  - Long-term outcome of patients suffering from clinical instability after
      microsurgical treatment of lumbar disc herniation.
AB  - A total of 39 patients suffering from clinical instability of the lumbar spine
      after microdiscectomy were evaluated for their long-term outcome. Included there
      were 21 (54%) male and 18 (46%) female patients with a mean age of 55 years. All
      had been operated on for a virgin single-level lumbar disc herniation between the
      years 1985-1989 and they were evaluated for the presence of lumbar instability in
      1991. Clinical signs and symptoms of segmental instability were then detected in
      all patients, with the symptom of "apprehension" positive in 30. During the
      follow-up, 2 (5%) patients had been treated by lumbar spondylodesis. At the time
      of the present investigation, both of them gave the information that their low
      back pain and sciatica had diminished as compared to the prediscectomy situation;
      both were retired. The symptom of "apprehension" was negative in both. Of the
      remaining 37 patients, low back pain had completely recovered in 4 (11%) and
      diminished in 23 (62%) patients, while in 9 (24%) patients, back pain had
      remained unchanged and become worse in 1 (3%). Further, sciatica had completely
      recovered in 4 (11%) and diminished in 23 (62%) patients, while in 7 (19%)
      patients, sciatica had remained unchanged and become worse in 3 (8%). Only 14
      (38%) of these patients were able to work. However, evaluated by the Oswestry
      Index, the overall outcome in daily activities had significantly improved in all
      37 patients since 1991 (p = 0.01). The symptom of "apprehension" was now positive
      in 26 patients. A significant correlation was observed between the positivity of
      this test and the persistence of low back pain (p = 0.02) and a poor outcome in
      daily activities (p < 0.0001). Comfirming earlier observations, the findings of
      this study support the concept that patients with postoperative lumbar
      instability have a poor prognosis. Further studies are needed to define the
      optimal treatment for this problematic patient group.

PMID- 10398991
TI  - Results of the biocompatible osteoconductive polymer (BOP) as an intersomatic
      graft in anterior cervical surgery.
AB  - Eighty-two patients operated on in our Department between 1989 and 1995 with an
      anterior cervical approach for soft and hard cervical disc herniations and
      cervical stenosis were included in this study. In 41 cases a heterologous
      intersomatic bovine graft (Surgibone) was used. Another 41 patients underwent
      surgery with a biocompatible osteoconductive polymer (BOP) as intervertebral
      graft. Both groups were retrospectively reviewed and compared with the objectives
      of evaluating the biodynamic behaviour of the grafts in the intersomatic space,
      the complications which appeared (specially those related to the grafts), the
      bone fusion rate achieved and the clinical outcome of the patients. The results
      of our study show that the BOP group presented a higher tendency to intersomatic
      space collapse 6 months after discectomy. There were no differences in the
      general surgical complications between both groups, but those related directly to
      the graft were significantly higher in the BOP group. The vast majority of the
      graft complications recorded had no clinical correlation. Without a strict
      radiological follow-up such complications would never have been discovered. Bone
      fusion in the BOP group was significantly slower and worse. Finally, the clinical
      outcome in both groups did not show any significant difference.

PMID- 10398992
TI  - Transverse microincisions of the outer layer of the dura mater combined with
      foramen magnum decompression as treatment for syringomyelia with Chiari I
      malformation.
AB  - Numerous surgical procedures have been proposed for treatment of syringomyelia
      associated with Chiari I malformation, but the optimal treatment has not yet been
      uniformly standardised. The main aim of the surgical treatment of
      syringomyelia/Chiari I complex is directed toward restoration of physiological
      cerebrospinal fluid dynamic at the craniovertebral junction. We report the
      surgical results of eight patients, affected by syringomyelia and Chiari I
      malformation, age range from 18 to 62 years, treated by bony foramen magnum
      decompression combined with transverse microincisions of the outer layer of the
      dura mater. In an average postoperative follow-up period of two years
      neurological symptoms and signs improved in seven patients. Postoperative
      Magnetic Resonance showed a decrease in size of the syrinx in seven patients.
      These results suggest that foramen magnum decompression combined with transverse
      microincisions of the outer layer of the dura 1) is an effective and safe
      treatment option for syringomyelia and Chiari I malformation, 2) corrects the
      circulatory disturbances of cerebrospinal fluid dynamic, 3) leads to a decrease
      in size of the syrinx and to a significant improvement in neurological signs and
      symptoms, 4) avoids complications of intradural approaches and
      syringosubarachnoid shunting.

PMID- 10398993
TI  - Prognostic relevance of cell proliferation markers and DNA-ploidy in gliomas.
AB  - The prognostic significance of clinically, histologically and flow cytometrically
      derived parameters was assessed in 49 glioma patients. With flow cytometry, DNA
      index, S-phase fraction (SPF), 5-bromo-2'-deoxyuridine (BrdUrd)-labelling index
      (LI), and potential doubling time (Tpot) were determined. After univariate
      analysis of clinical variables such as, age, seizures as initial symptom, and
      duration of first symptom were found to be significantly associated both with
      proliferation rate and with local progression free survival (LPFS).
      Cytomorphological features such as, the presence or absence of mitosis, necrosis,
      and endothelial proliferation, were separately analysed and appeared to be
      significantly associated with LPFS. With respect to the cell proliferation
      markers, we observed a longer LPFS to be associated with a low SPF, a low LI, and
      a short Tpot. We did not observe a significant association between DNA-ploidy and
      LPFS. After multivariate analysis both of high and of low grade tumours, we found
      that neither LI, SPF, nor age had additional prognostic significance for cells in
      mitoses. We also demonstrated, that necrosis and endothelial proliferation had no
      additional prognostic significance to that for cells in mitoses. In the subgroup
      of low grade gliomas, in contrast to high grade gliomas, we noted prognostic
      significance for LI. We concluded, that i) the presence or absence of cells in
      mitoses was the strongest single prognosticator in gliomas, ii) in low grade
      gliomas LI holds prognostic significance.

PMID- 10398994
TI  - The association of tranexamic acid and nimodipine in the pre-operative treatment
      of ruptured intracranial aneurysms.
AB  - In the scope of a late intervention policy on ruptured intracranial aneurysms, on
      D.+12 on an average, we first used tranexamic acid, at moderate doses: 3 g orally
      or 1.5 g intravenously per day. We, subsequently, added nimodipine, usually 240
      mg orally per day or 2 mg intravenously per hour. The medical treatment consisted
      of amply sufficient hydration, and in systematic and regular administration of
      analgesics and sedatives. Hypotension was absolutely avoided; if necessary, an
      antihypertensive treatment was prescribed very cautiously. Phenytoin was
      regularly given. In the present study, we try to answer the following questions:
      (1) Can we confirm that the preventive action of tranexamic acid remains as
      effective, when doses, markedly lower than usually recommended, are used? (2)
      Does nimodipine prevent the increase of pre-operative ischaemic complications,
      which should be expected when tranexamic acid is administered? Amongst 101
      patients with SAH of proven aneurysmal origin, 84 were treated with tranexamic
      acid and nimodipine. In 25 patients, an aneurysm was not visualised; 21 received
      this treatment. For several reasons, only a retrospective study was possible, to
      evaluate the results of our antifibrinolytic and calcium-blocking therapies, on
      rebleeding and pre-operative delayed ischaemia. We compared, therefore, similar
      cases from the literature, with our own cases, taking into consideration the
      clinical grades, the days of admission and of intervention, the moment of
      rebleeding and of delayed pre-operative ischaemia, etc. The following impressions
      emerge: (1) same effectiveness of moderate doses of tranexamic acid; (2) no
      increase of pre-operative delayed ischaemic complications, in comparison with
      patients not receiving antifibrinolytics but nimodipine; (3) important role of a
      devastating initial bleed and of operative complications; (4) difficulty of
      avoiding rebleeding at D.0, whatever the therapeutic measures, medical and/or
      surgical.

PMID- 10398995
TI  - Serum protein exudation in chronic subdural haematomas: a mechanism for haematoma
      enlargement?
AB  - A study was conducted to investigate the role of serum protein exudation in the
      aetiology of chronic subdural haematoma (SDH). Scintigraphy after intravenous
      injection of 99mTc-labelled human serum albumin (HSA) was performed in three
      patients with chronic SDH and a patient with subdural effusion. In another 60
      haematomas, the amounts of total protein and albumin as indices of serum
      exudation were measured, and then compared among low-density, iso-density and
      high-density haematomas. Accumulation of 99mTc-HSA in the haematoma cavity was
      seen 6 h after isotope injection and became more evident at 24 h. However, the
      protein concentrations and albumin ratios in the haematomas exhibited a
      reciprocal relationship, suggesting that not all the protein in the haematomas
      was derived from serum exudation. The higher the total protein concentration in
      the haematoma became, the higher the haematoma density which was observed on CT.
      The albumin concentration in low-density haematomas was lower than that in iso
      density and high-density haematomas, whereas no significant difference was seen
      between the latter two haematoma types. These results provide morphological
      evidence for serum protein exudation into the haematoma cavity, and therefore it
      is possible that serum protein exudation plays a role in the progression of
      chronic SDH and is related to changes in haematoma density on CT.

PMID- 10398996
TI  - Migration of abdominal catheter of ventriculoperitoneal shunt into the scrotum.
AB  - Four cases of migration of the ventriculoperitoneal (V-P) shunt tip through
      patent processus vaginalis resulting in scrotal hydrocele are presented. These
      cases are considered a rare complication of V-P shunts and causal mechanisms are
      discussed with a review of the literature.

PMID- 10398997
TI  - Mature teratoma of the lateral ventricle: report of two cases.
AB  - In this paper, two cases with mature teratoma of the lateral ventricle are
      presented. Teratomas are rare intracranial tumours and the most common location
      is in the midline pineal region. Lateral ventricle as the site of location is
      very rare. Between the years 1975 and 1996, 120 cases were operated on for
      lateral ventricle tumours at the University of Ankara, Department of
      Neurosurgery, and only two cases (% 1.6) were histologically identified as mature
      teratomas. It is generally accepted that benign teratomas are radioresistant and
      total removal of these tumours results in cure. If mature teratoma of the lateral
      ventricle is totally removed, as done in our cases, the prognosis is usually
      good.

PMID- 10398998
TI  - Fosphenytoin reduces hippocampal neuronal damage in rat following transient
      global ischemia.
AB  - Fosphenytoin, a water-soluble disodium phosphate ester of phenytoin, is a
      phenytoin prodrug with similar anticonvulsant properties. In this study, we
      evaluated its neuroprotective properties in a cardiac arrest-induced global
      ischemia model. After 12 minute ischemia, Long-Evans hooded rats were
      resuscitated, given fosphenytoin (30 mg/kg, i.m.) or saline 5 minutes after the
      ischemic episode, and killed on day 7. Brains were removed, fixed, and vibratome
      sectioned to assess the numbers of normal appearing CAI pyramidal neurons and for
      immunohistological staining of glial fibrillary acidic protein (GFAP). After
      global ischemia, the number of hippocampal CA1 pyramidal neurons decreased
      significantly (from 14.33 +/- 1.73 to 2.19 +/- 0.16 per 100 micron 2). Most
      hippocampal CA1 pyramidal neurons showed signs of injury and GFAP
      immunoreactivity of the region increased. With fosphenytoin treatment 5 min after
      ischemia, hippocampal CA1 pyramidal neurons remained at near control level (13.90
      +/- 0.92), however, GFAP staining was not significantly changed. Our data,
      although indicating different neuronal and glial responses following fosphenytoin
      treatment, nevertheless, suggest that fosphenytoin is an effective
      neuroprotectant against ischemia-induced damage.

PMID- 10398999
TI  - Moyamoya disease of adult onset brain stem haemorrhage associated with bilateral
      occlusion of the vertebral arteries--case report.
AB  - An unusual and first case of moyamoya disease of adult onset brain stem
      haemorrhage associated with occlusion of both vertebral arteries is reported. A
      30-year-old man suddenly suffered from dyspnea, dysphagia, and left-sided
      hemisensory disturbance. Computed tomography and magnetic resonance imaging
      revealed a fresh haematoma in the left medulla oblongata and various-sized old
      infarcts in both parietal lobes. Cerebral angiograms disclosed occlusion of the
      bilateral internal carotid arteries on both sides at their intracranial portion,
      accompanied with the developed basal moyamoya vessels. The right vertebral artery
      occluded at its V2-V3 segment, in which the posterior inferior cerebellar artery
      was opacified via the posterior spinal artery, and the basilar artery was filled
      from the anterior spinal artery. The left vertebral artery was also occluded at
      the craniovertebral junction (V4) with collateral flow. Only one case of moyamoya
      disease associated with bilateral occlusion of the vertebral artery has been
      reported previously, and a haemorrhage into the medulla oblongata in moyamoya
      disease has never been described.

PMID- 10399000
TI  - Ruptured distal anterior choroidal artery aneurysm presenting with casting
      intraventricular haemorrhage.
AB  - This report describes a rare case of a distal anterior choroidal artery aneurysm
      which developed intraventricular haemorrhage without subarachnoid haemorrhage as
      shown on computerized tomographic (CT) scan. A 69-year-old hypertensive man
      suddenly became unconscious. An emergency CT scan showed a severe
      intraventricular haemorrhage and a small round low-dense lesion within the
      haematoma at the right trigone. The haematoma with obstructive hydrocephalus made
      the lateral ventricles larger on the right than on the left. CT scan could not
      detect any subarachnoid haemorrhage. Right interal carotid angiography revealed a
      saccular aneurysm at the plexal point of the right anterior choroidal artery. We
      approached the aneurysm and the small round lesion through the trigone via a
      right temporo-occipital corticotomy. We could clip the aneurysmal neck and remove
      the intraventricular haematoma and the papillary cystic mass (corresponding to
      the small round lesion on CT scan) totally in one sitting. Histological
      examination revealed the aneurysm to be a true one and the papillary cystic mass
      to be a choroid plexus cyst.

PMID- 10399001
TI  - Triple pituitary adenoma in Cushing's disease: case report.
AB  - A case of a triple pituitary adenoma identified in a surgically removed pituitary
      gland from a 52-year-old woman operated on for Cushing's disease is presented.
      The histology revealed 3 distinctly separate microadenomas, 1 corticotroph and 2
      immunoreactive for prolactin (PRL). The latter were apparently silent, since the
      serum PRL levels were within normal range. The problems associated with the
      inability to identify multiple adenomas pre-operatively and the possible failure
      of selective transsphenoidal adenomectomy in case of multiple adenomas are
      emphasised.

PMID- 10399002
TI  - Late complication of radiosurgery of AVMs with the gamma knife: a case report.

PMID- 10399003
TI  - Superior sagittal sinus thrombosis with homocystinuria and deficiency of
      antithrombin III and factor VII: case report.

PMID- 10399004
TI  - Suprasellar ectopic adenoma.

PMID- 10399005
TI  - Mechanisms of exogenous antigen presentation by MHC class I molecules in vitro
      and in vivo: implications for generating CD8+ T cell responses to infectious
      agents, tumors, transplants, and vaccines.

PMID- 10399006
TI  - Signal transduction pathways that regulate the fate of B lymphocytes.

PMID- 10399007
TI  - Oral tolerance: mechanisms and therapeutic applications.

PMID- 10399008
TI  - Caspases and cytokines: roles in inflammation and autoimmunity.

PMID- 10399009
TI  - T cell dynamics in HIV-1 infection.

PMID- 10399010
TI  - Bacterial CpG DNA activates immune cells to signal infectious danger.

PMID- 10399011
TI  - Neutrophil-derived proteins: selling cytokines by the pound.

PMID- 10399012
TI  - Murine models of thymic lymphomas: premalignant scenarios amenable to
      prophylactic therapy.

PMID- 10399013
TI  - Enzymatic resolution of amino acids via ester hydrolysis.
AB  - The present review outlines recent examples of enzyme-based resolution procedures
      for amino acids via the hydrolysis of their esters. The resolutions have been
      achieved by using proteases (alpha-chymotrypsin, subtilisin and other microbial
      proteases, and sulfhydryl proteases of plant origin) and lipases. Relevant work
      utilizing yeast and other microbial cells is also included.

PMID- 10399014
TI  - How to build optically active alpha-amino acids.
AB  - Various methodologies published in the literature dealing with alpha-amino
      carboxylic acid asymmetric synthesis are presented in a digest form. In each
      case, only some recent or most typical works are mentioned.

PMID- 10399015
TI  - Syntheses of optically active 2-amino-4-oxobutyric acid and N,O-protected
      derivatives.
AB  - Strategies for the synthesis of optically active aspartaldehyde derivatives are
      reviewed. Most of them are using the chiral pool: allylglycine or naturally
      occurring homoserine, aspartic acid or methionine and side chain modifications.
      This will be developed in the first part. Some other original routes are also
      displayed in the second part. Different aspects of each strategy are discussed:
      the nature and number of steps, the problem of protecting groups, the price and
      availability of starting materials. Some synthetic applications of such
      interesting chiral synthons are shown in the last part.

PMID- 10399016
TI  - Synthesis of optically active lipidic alpha-amino acids and lipidic 2-amino
      alcohols.
AB  - Lipidic alpha-amino acids (LAAs) are a class of compounds combining structural
      features of amino acids with those of fatty acids. They are non-natural alpha
      amino acids with saturated or unsaturated long aliphatic side chains. Synthetic
      approaches to optically active LAAs and lipidic 2-amino alcohols (LAALs) are
      summarized in this review. A general approach to enantioselective synthesis of
      saturated LAAs is based on the oxidative cleavage of 3-amino-1,2-diols obtained
      by the regioselective opening of enantiomerically enriched long chain 2,3-epoxy
      alcohols. Unsaturated LAAs are prepared in their enantiomeric forms by Wittig
      reaction via methyl (S)-2-di-tert-butoxycarbonylamino-5-oxo-pentanoate. This key
      intermediate aldehyde is obtained by selective reduction of dimethyl N,N-di-Boc
      glutamate with DIBAL. (R) or (S) LAALs may be prepared starting from D-mannitol
      or L-serine. LAAs are converted into LAALs by chemoselective reduction of their
      fluorides using sodium borohydride with retention of optical purity. Replacement
      of the hydroxyl group of LAALs by the azido group, followed by selective
      reduction leads to unsaturated optically active lipidic 1,2-diamines.

PMID- 10399017
TI  - A new protection/activation strategy for the synthesis of naturally occurring and
      non-natural alpha-N-alkylamino acids.
AB  - A new method for the preparation of N-methylamino acids and some of their
      derivatives starting from hexafluoroacetone protected amino acids is described.
      The new concept results in saving of steps compared to conventional
      protection/activation techniques. Protection and deprotection proceed without
      recemization.

PMID- 10399018
TI  - Asymmetric syntheses of pipecolic acid and derivatives.
AB  - Results in the field of asymmetric synthesis of pipecolic acid derivatives are
      reviewed. Three sections describe the asymmetric syntheses of the title compounds
      (i) from the chiral pool (alpha-amino acids or carbohydrates) (ii) using a chiral
      auxiliary either derived from terpenes, alpha-amino acids, tartaric acid, an
      amine or beta-amino alcohols (iii) by means of asymmetric catalysis.

PMID- 10399019
TI  - From beta-lactams to alpha- and beta-amino acid derived peptides.
AB  - The potential of beta-lactams as intermediates for the access to alpha- and beta
      amino acid-derived peptides is shortly reviewed, with major focus on the
      technologies developed in our group. The two general strategies lie, on one side,
      in the oxidative ring expansion of 3-hydroxy beta-lactams to N-carboxy alpha
      amino acid anhydrides or Leuch's anhydrides and subsequent coupling with alpha
      amino acid esters and, on the other side, in the nucleophilic ring opening of N
      Boc-beta-lactams. Both approaches have been successfully applied to the synthesis
      of alpha,beta-diamino acid, alpha-amino-beta-hydroxy acid, polyhydroxylated alpha
      amino acid, alpha,alpha-disubstituted alpha-amino acid, beta-amino acid, beta
      amino-alpha-hydroxy acid and beta,beta-disubstituted beta-amino acid derived
      peptides. Because of the mild reaction conditions needed for the above
      transformations and the highly stereoselective procedures employed for the
      construction of the starting beta-lactam ring, the whole process allows the
      production of optically pure final products.

PMID- 10399020
TI  - Some of the amino acid chemistry going on in the Laboratory of Amino Acids,
      Peptides and Proteins.
AB  - Some of the chemistry of amino acids going on in our laboratory (Laboratoire des
      Amino acides Peptides et Proteines) is described as well as some mass
      spectrometry methodology for their characterization particularly on solid
      supports. Several aspects are presented including: (i) the stereoselective
      synthesis of natural and unnatural amino acids using 2-hydroxypinan-3-one as
      chiral auxiliary; (ii) the stereoselective synthesis of natural and unnatural
      amino acids by deracemization of alpha-amino acids via their ketene derivatives;
      (iii) the synthesis of alpha-aryl-alpha-amino acids via reaction of
      organometallics with a glycine cation; (iv) the diastereoselective synthesis of
      glycosyl-alpha-amino acids; (v) the synthesis of beta-amino acids using alpha
      aminopyrrolidinopiperazinediones as chiral templates; (vi) the reactivity of
      urethane-N-protected N-carboxyanhydrides. To characterize natural and non natural
      amino acids through their immonium ions by mass spectrometry, some methodology is
      also described.

PMID- 10399021
TI  - Synthesis of perfluoroalkylated beta-alanine and some peptide derivatives: an
      access to original surfactants.
AB  - The reaction of amines of sodium azide with 3-perfluoroalkyl-3-fluoroprop-2
      enoate, followed by hydrogenation, affords perfluoroalkylated beta-alanine
      analogues in very good yields. These compounds can be linked via an amide bond to
      produce peptide analogues such as carnosine or carcinine derivatives, which could
      have surfactive and complexing properties.

PMID- 10399022
TI  - Asymmetric hydrogenation of dehydrodipeptide esters bearing different protective
      groups.
AB  - N-[(Z)-N-Benzoyl- or N-Boc-(2-fluorophenyl)dehydroalanyl]-(R)- or (S)
      phenylalanine esters were synthesized and hydrogenated to give the corresponding
      dipeptide derivatives with optical yields in the range of 53-87% de using the
      cationic rhodium complexes of PROPRAPHOS and BPPM. The efficiency of chiral
      diphosphine ligands as well the effect of the chiral center in the substrate on
      the catalytic asymmetric induction was studied.

PMID- 10399023
TI  - Spectral analysis of a series of partially protected and deprotected
      tetrapeptides, analogues of AS-I phytotoxin.
AB  - A series of six tetrapeptides, analogues of AS-I phytotoxin, pathogenic to
      sunflower, have been synthesized either in solution and/or by solid phase methods
      and have been tested for phytotoxic activity in various plants and cytotoxic
      activity in three cancer cell lines. These peptides were identified as model
      compounds by fast atom bombardment (FAB), plasma desorption (PD), electrospray
      ionization (ESI) mass spectrometry and by 1H, 1H-1H, 13C and 1H-13C NMR. The data
      presented show that in protected tetrapeptides the molecular ion was easily
      identified whereas some difficulties appeared with the fully deprotected
      peptides. NMR spectra are given.

PMID- 10399024
TI  - Cu(III)-polypeptide complexes exhibiting SOD-like activity.
AB  - The SOD-like activity of Cu(III)-complexes with polypeptides poly-L-lysine and
      poly-L-glutamic acid respectively was investigated. The Cu(II)-polypeptide
      complexes were first oxidized by K2IrCl6 to give the corresponding Cu(III)
      compounds. The oxidation of Cu(II) and the corresponding Cu(II)/Cu(III) potential
      was evaluated by cyclic voltammetry (c.v.), UV-Vis and EPR spectroscopic (r.t.)
      experiments. Spin trapping EPR spectra were also conducted to confirm the
      formation of the superoxide radical. The SOD-like activity of each Cu(III)
      complex was proved using the nitro blue tetrazolium (NBT) method slightly
      modified.

PMID- 10399025
TI  - Synthesis and anti-phlogistic potency of some new non-proteinogenic amino acid
      conjugates of "Diclofenac".
AB  - In search for more potent, particularly less ulcerogenic gastritis that hopefully
      replace the universal NSAID "Diclofenac", (2-[(2,6-dichlorophenyl)amino]
      phenylacetic acid, C.A.S. 15307-86-5), twelve new non-proteinogenic amino acid
      conjugates of the drug, namely that of sarcosine, beta-alanine, D-leucine and D
      phenylalanine, were synthesized and biologically screened for their anti
      inflammatory, analgesic and ulcerogenic activity in rats. "Diclofenac" amino acid
      esters (IIa-d), were synthesized via the corresponding HOSu or HOBt active
      esters. Alkaline hydrolysis (NaOH) followed by acidification (KHSO4) or thioamide
      formation (Lawsson's Reagent, C.A.S. 19172-47-5), afforded the corresponding free
      acids IIIa-d or the thioamides IVa-d respectively. Interestingly, in contrary to
      the parent "Diclofenac", the synthesized candidates (except IIId), were entirely
      nonulcerogenic in rats. Further, they considerably retained a generalized anti
      phlogistic activity. The major "Diclofenac" irritating gastric side effect was
      thus eliminated. Particularly, the sarcosine conjugate IIa and its thiomimic IVa
      exhibit promising therapeutic perspectives.

PMID- 10399026
TI  - Neuroendocrine gastrointestinal tumors--a condensed overview of diagnosis and
      treatment.
AB  - Neuroendocrine gut and pancreatic tumors are rather rare malignant diseases which
      has gained increased attraction through the last decennium, possibly through
      development of new diagnostic and therapeutic methods. Histopathology
      demonstrating the common neuroendocrine features of these tumors has been the
      diagnostic corner stone for long, but today it should be supplemented with
      information about the tumor biology. An excellent biochemical marker which is
      easy to analyze in serum or plasma is chromogranin A, which is a glycoprotein
      that is stored and released from neuroendocrine cells. This marker can be used
      for diagnosis and follow-up of the patients. Somatostatin receptor scintigraphy
      has been one of the most important diagnostic tools for staging of the disease
      and also indicating sensitivity to treatment with somatostatin analogues. It is a
      general agreement that almost every patient should be subjected to this procedure
      before or during the treatment course. From the therapeutic point of view,
      surgery is nowadays more extensive aiming at reducing the tumor mass in patients
      who could not be cured by surgery alone. Other means of tumor reduction is liver
      dearterialization by embolization with starch spheres. The medical treatment of
      neuroendocrine tumors has made a real break through with the introduction of
      somatostatin analogues, particularly octreotide, and today most of the hormonally
      related symptoms can be controlled by this kind of treatment. Somatostatin
      analogues have also shown to be inhibitors of tumor growth and the latest
      development is tumor targeted radioactive treatment with Ytrium or Indium
      labelled octreotide. Long-acting formulation of somatostatin analogues have come
      into clinical use and significantly improved quality of life for patients with
      neuroendocrine tumors. Other means of medical treatment are alpha interferons,
      which have shown particular effect in patients with midgut carcinoid tumors
      giving both biochemical and tumor responses. Chemotherapy such as streptozotocin
      plus 5-fluorouracil (5-FU) or doxorubicin is still considered as first-line
      treatment in malignant endocrine pancreatic tumors but is combined with
      concomitant somatostatin analogue treatment. In the future a multimodal treatment
      will further develop combining different agents and also somatostatin receptor
      subtype specific analogues will come into clinical use.

PMID- 10399027
TI  - Clinicopathological profile as a basis for classification of the endocrine
      tumours of the gastroenteropancreatic tract.
AB  - Recent developments in the field of endocrine cell biology and pathology, at both
      morphologic and molecular levels, are briefly outlined and discussed as a basis
      for endocrine tumour characterization. The main clinicopathological tools
      available for the identification and characterization of endocrine tumours are
      discussed. Based on this, classifications of endocrine tumours of the pancreas
      and gastrointestinal tract are developed covering most clinical (hyperfunctional
      syndromes included), pathologic and biological patterns and with special emphasis
      on tumour prognosis.

PMID- 10399028
TI  - Somatostatin receptors present knowledge and future directions.
AB  - Genes for five somatostatin receptor subtypes, designated sst1-5, have been
      cloned and shown to belong to the seven transmembrane domain receptor family. The
      sst2 mRNA transcript is alternatively spliced to generate two related receptor
      products (sst2A and sst2B) which differ in their carboxylterminal sequence
      whereas each of the other genes is transcribed to give a single unique receptor
      protein. The six sst receptor subtypes all bind SRIF14, SRIF28 and the
      cortistatins with high affinity but vary in their affinity for analogs, such as
      octreotide. Although the tissue distribution of sst mRNAs has been extensively
      examined, much less is known about the cellular distribution of the individual
      receptor proteins. Recent studies with sst subtype specific antibodies have
      localized individual sst receptors to specific cell types within the rat
      gastrointestinal tract, pancreas, pituitary and brain. Furthermore, sst receptors
      have recently been identified in human tumors by immunocytochemistry, providing a
      significantly improved method for sst receptor detection. All six sst receptor
      subtypes are linked to guanine nucleotide binding proteins (G proteins) and lead
      to inhibition of adenylyl cyclase following hormone binding. The sst receptors
      also regulate a variety of different effectors via G proteins, including calcium
      and potassium channels and serine and tyrosine phosphatases. In addition to
      signalling, two other processes are activated by hormone binding: receptor
      desensitization and receptor internalization. The extent to which these occur
      seems to vary for the different receptor subtypes. Recent studies have shown that
      the sst2A receptor is rapidly phosphorylated upon hormone binding, suggesting
      that this phosphorylation may be responsible for the desensitization and/or
      internalization of this receptor. The importance of receptor regulation in
      cellular responsiveness to somatostatin and for receptor detection as well as the
      molecular mechanisms by which these processes occur provide important areas for
      future investigations.

PMID- 10399029
TI  - Radiolabelled somatostatin analogue(s) for peptide receptor scintigraphy and
      radionuclide therapy.
AB  - BACKGROUND: Peptide receptor scintigraphy with the radioactive somatostatin
      analogue, [111In-DTPA0]octreotide, is a sensitive and specific technique to show
      in vivo the presence and abundance of somatostatin receptors on various tumours.
      AIM: With this technique primary tumours and metastases of neuroendocrine cancers
      as well as of many other cancer-types can be localised. This technique is
      currently used to assess the possibility of peptide receptor radionuclide therapy
      (PRRT) with repeated administrations of high doses of [111In-DTPA0)octreotide.
      111In emits Auger and conversion electrons having a tissue penetration of 0.02-10
      microns and 200 to 500 microns, respectively. PATIENTS AND METHODS: Thirty end
      stage patients with mostly neuroendocrine progressing tumours were treated with
      [111In-DTPA0]octreotide, up to a maximal cumulative patient dose of about 74 GBq,
      in a phase I trial. RESULTS: There were no major clinical side effects after up
      to two years treatment, except that in a few patients a transient decline in
      platelets counts and lymphocyte subsets occurred. Promising beneficial effects on
      clinical symptoms, hormone production and tumour proliferation were found. Of the
      21 patients who received a cumulative dose of more than 20 GBq, eight patients
      showed stabilisation of disease and six other patients a reduction in size of
      tumours. There is a tendency towards better results in patients whose tumours
      have a higher accumulation of the radioligand. CONCLUSIONS: PRRT is feasible,
      also with 111In as radionuclide. Depending on the homogeneity of distribution of
      tumour cells expressing peptide receptors and the size of the tumour, beta
      emitting radionuclides, e.g., 90Y, labelled to DOTA-chelated peptides, are also
      attractive candidates for PRRT. The first PRRT trials with [90Y
      DOTA0,Tyr3]octreotide started recently.

PMID- 10399031
TI  - The implementation of a new parallel child health record.
AB  - After a decade of research, the parent-held Personal Child Health Record was
      introduced in some parts of the United Kingdom in 1991, coinciding with the
      enforcement of the Children Act 1989. It was designed as the main record of a
      child's health and development, to be used until adulthood and to be held by
      parents. Several Health Care Trusts have since discovered a need to maintain
      parallel records in the best interests of children. Barnet introduced the 'Joint
      Professional Record' in 1995 for selected children, such as children on the Child
      Protection Register. The Joint Professional Record (JPR) is a single, clinic
      held, parallel record for multidisciplinary use. We undertook a programme of
      audit and staff seminars to develop and evaluate use of the JPR. We discuss,
      below, the impact of this record on professional working relationships and
      consider the implications of its use as a confidential record and within our
      policy of working in partnership with parents. In our experience, the JPR has
      proved a useful adjunct to clinical supervision in the arena of Child Protection
      and is appropriately used for children in need of protection and those with
      'special needs'.

PMID- 10399030
TI  - Summing up 15 years of somatostatin analog therapy in neuroendocrine tumors:
      future outlook.
AB  - Neuroendocrine gastrointestinal tumors express somatostatin receptors (ssts) in
      80%-90% of cases and somatostatin analogs have become increasingly important in
      the management of these patients. Most of the presently available somatostatin
      analogs (octreotide, RC-160, and lanreotide) bind to the sst2 and sst5, and in
      higher doses to sst3 of the ssts 1-5 described. Clinical improvement during
      somatostatin analog therapy is mainly mediated via a direct inhibitory effect on
      hormone production from the tumors, seen in 30%-70% of the patients. Also
      indirect non-tumor mediated effects on peripheral target organs contribute to the
      subjective improvement, achieved in 30%-70% of patients. Recently, significant
      improvement of quality of life has been demonstrated with long-acting depot
      formulations. There is little or no effect on tumor growth during octreotide
      therapy; tumor shrinkage has been reported in 10%-20% of patients, but
      stabilization of tumor growth can be achieved in about half of the patients with
      a duration of 8-16 months. Recently, induction of apoptosis has been described
      with high doses of lanreotide (12 mg/d). Eventually, however, all patients escape
      from somatostatin analog therapy with regard both to hormonal production and
      tumor growth, and the mechanism behind the tachyphylaxis is not yet known.
      Studies of optimal dosage and modes of administration, development of new slow
      release formulations, the potential value of high-dose somatostatin analog
      therapy and novel somatostatin receptor subtype specific analogs are important
      directions for the use of somatostatin analogs in the future. In addition,
      assessment of somatostatin receptor status for each patient and studies of tumor
      biology, e.g., inhibition of exocytosis, antiproliferative effects and induction
      of apoptosis during treatment will help to optimize treatment and provide new
      insights into mechanisms of action of somatostatin analogs.

PMID- 10399032
TI  - Supporting pupils in mainstream school with an illness or disability: young
      people's views.
AB  - To date, little research has focused directly on health-related support in school
      for children with a chronic illness or physical disability, yet these children
      are known to be at increased risk for psychosocial and academic problems. In
      addition, few studies have sought the views of pupils directly: those which have
      report a wide range of problems with school life. The increasing numbers of
      children surviving and managing their health conditions, together with UK policy
      for inclusive education, means that a growing proportion of pupils in mainstream
      schools require understanding of their special health needs and may need service
      support from education and health professionals. This paper presents findings
      from semistructured interviews with 33 mainstream secondary school pupils with a
      variety of illnesses and disabilities on the impact of their health condition on
      school life. Results show that young people valued school and were actively
      managing the effects of their condition, but needed support from others. Informal
      support was most frequently cited, including parents--particularly mothers-
      teachers and close friends. The main difficulties were implications of school
      absence, exclusion from school life, teachers' reactions to the illness or
      disability, and peer relationships. The discussion focuses on ways in which
      health professionals can play a part in supporting pupils both directly and
      indirectly, through helping others in school understand the condition and its
      impact on school life.

PMID- 10399034
TI  - Coping with a child with disabilities from the parents' perspective: the function
      of information.
AB  - Fifteen semistructured interviews were conducted with 20 parents (n = 5 with both
      parents; n = 10 with mother only) of disabled children who had a range of
      physical and learning difficulties, to explore what information they had received
      about their child's disabilities, from whom and whether they had found it useful.
      Information needs were also explored. The interviews were audiotaped and
      transcribed, then analysed for content. The reasons for needing the information
      was examined for themes. Personal communication was the most frequently cited
      medium of information. Parents most frequently reported professionals as their
      source of information, but parents and voluntary organizations were also
      mentioned. Information was found to assist the process of adjusting emotionally
      to their child's disabilities, to enable parents to access services and benefits,
      and to improve their management of their child's behaviour. Parents' comments
      indicated that information was usually useful, but occasionally of mixed benefit.

PMID- 10399033
TI  - Characteristics of maternal directiveness and responsiveness with young children
      with visual impairments.
AB  - The purpose of this study was to investigate the relation between maternal
      responsive and directive behaviours and the development of young children with
      visual impairments. The participants were 17 mother-child dyads, and the
      children's ages ranged from 20 to 36 months of age. The amount, quality, and
      appropriateness of four maternal behaviours were rated during a free play session
      between mother and child and compared with a developmental outcome measure
      designed for young children with visual impairments. In general, the results
      showed that the quality of maternal control and appropriateness of directiveness
      were positively related to children's language development; whereas, the amount
      of these same behaviours was negatively related to language development. The
      findings also indicated that both the quality and amount of maternal goal-setting
      behaviours, and the quality of responsiveness were positively related to
      children's language skills, exploration of the environment and sensorimotor
      development. The findings are discussed in terms of maternal influence on child
      development.

PMID- 10399035
TI  - Psychological adjustment of children awaiting limb reconstruction treatment.
AB  - The psychological profiles of 53 children aged 6-17 years, with congenital and
      acquired limb abnormalities attending a limb reconstruction centre, were examined
      to determine the level of need for pretreatment psychological intervention. The
      profiles of two groups presenting for treatment--patients of short stature and
      those with other limb abnormalities--were compared with each other and with
      general population norms. Standardized questionnaires were administered to
      patients and their parents during pretreatment assessment visits to the clinic.
      There were few differences between the families taking part in this study and the
      general population norms, or between the scores of children with short stature
      and those with other limb abnormalities. These results may indicate that most
      children awaiting limb reconstructive surgery are not in need of psychological
      intervention other than the support routinely offered. The findings are discussed
      in terms of the biases which may be reflected in the referral process, possible
      protective effects of family environment factors and clinical support systems,
      and the impact of the timing of the assessments. Implications for future research
      are discussed.

PMID- 10399036
TI  - Drugs on trial: experimental pharmacology and therapeutic innovation in the
      eighteenth century.

PMID- 10399037
TI  - Transmission of viral encephalopathy and retinopathy (VER) to yolk-sac larvae of
      the Atlantic halibut Hippoglossus hippoglossus: occurrence of nodavirus in
      various organs and a possible route of infection.
AB  - The susceptibility of the Atlantic halibut Hippoglossus hippoglossus yolk-sac
      larvae to viral encephalopathy and retinopathy (VER) was investigated by
      waterborne challenge experiments with nodavirus. Transfer of VER was indicated by
      several lines of evidence. A significantly higher cumulative mortality was
      observed after challenge with virus compared to mock challenge, and increasing
      doses of virus resulted in shorter incubation periods. When the challenge was
      performed on the day after hatching, the time from inoculation to the time when
      50% of the larvae were dead (LT50) ranged from 26 to 32 d. Postponement of
      challenge for 13 d reduced the LT50 to 14 d, indicating that the susceptibility
      of the larvae to the present nodavirus strain was low during the first 2 wk after
      hatching. The progression of the infection was monitored by sequential
      immunohistochemistry and electron microscopy. On Day 18 after hatching the
      initial signs of infection were observed as a prominent focus of immunolabelling
      in the caudal part of the brain stem. In the same larvae immunolabelled single
      cell lesions were observed in the stratified epithelium of the cranial part of
      the intestine. The portal of entry into the larvae may thus have been the
      intestinal epithelium, while the route of infection to the CNS may have been
      axonal transport to the brain stem through cranial nerves such as the vagus
      nerves. Later in the infection, lesions became more severe and widespread and
      were also found throughout the brain and spinal cord and in the retina, cranial
      ganglia, intestine, liver, olfactory epithelium, yolk-sac epithelium, gills and
      pectoral fins. The mortality in all virus-challenged groups was 100%. This study
      thus demonstrates that the present nodavirus strain is able to replicate and
      cause VER in Atlantic halibut yolk-sac larvae at temperatures as low as 6 degrees
      C.

PMID- 10399039
TI  - Aspects of the epizootiology of pancreas disease in farmed Atlantic salmon Salmo
      salar in Ireland.
AB  - A computerised database containing information on over 17.8 million salmon
      contained within 49 separate marine populations was used to study the
      epidemiology of pancreas disease (PD) in Ireland. Of the 43 recorded PD
      outbreaks, 57% occurred in the 3 mo period August to October inclusive (17 to 32
      wk post-transfer). Analysis of variance of mortality rates during PD outbreaks
      occurring on 6 marine sites over a 5 yr period showed that mortality rates vary
      significantly between sites (p < 0.001) but not between years over this time
      period. The mortality rate during PD outbreaks ranged from 0.1 to 63%. Mortality
      rates were significantly higher when PD outbreaks occurred earlier in the year (y
      = -1.28x + 59, SE of b 0.33). The mean length of a PD outbreak was 112 d (SE =
      7.7, n = 37). There was no correlation between PD mortality rate and smolt input
      weight, initial stocking density and transfer mortality.

PMID- 10399038
TI  - Time course tissue distribution of infectious salmon anaemia virus in
      experimentally infected Atlantic salmon Salmo salar.
AB  - Atlantic salmon Salmo salar L. were injected intraperitoneally with infectious
      salmon anaemia virus (ISAV)-infective tissue homogenate to clarify the tissue
      distribution of ISAV in a time course study. Fish were sampled at 11 different
      intervals between 1 and 40 d post-infection (p.i.) and mid-kidney, head kidney,
      liver, spleen, intestine, gills, muscle and heart were tested for the presence of
      ISAV by reverse transcriptase polymerase chain reaction (RT-PCR). The results
      showed that during a disease outbreak, ISAV is present in most organs. It was
      possible to detect ISAV at all sampling times in at least 1 of the fish examined.
      However, for the first 8 d p.i. positive RT-PCR results were predominantly found
      in samples from the head kidney and mid-kidney. Fish giving positive samples
      after Day 13 p.i. were RT-PCR positive in most organs. These results indicated
      that between Days 8 to 13 p.i. considerable replication of the virus occurred,
      combined with wide tissue dissemination.

PMID- 10399040
TI  - Red drum Sciaenops ocellatus mortalities associated with Streptococcus iniae
      infection.
AB  - We isolated for the first time Streptococcus iniae strains associated with
      diseased marine fish. Diseased red drum Sciaenops ocellatus were lethargic, and
      presented external signs (exophthalmia and loss of orientation) resembling those
      of freshwater fish infected by S. iniae. Skin lesions, extending to a necrotizing
      myositis, were typical of S. iniae infection of red drum. Histopathological
      findings indicate that S. iniae infection in red drum produces a chronic disease
      with systemic involvement characterized by multiple necrotic foci. Molecular
      epidemiology (RFLP [restriction fragment length polymorphism] ribotyping)
      revealed that 2 different ribotypes were involved in a single outbreak. The first
      is the EcoRI 'Israeli' trout and tilapine ribotype (Hind III type a strains),
      while the second is the EcoRI 'American' ribotype (Hind III type b strains),
      typical of tilapines farmed in Texas and Idaho.

PMID- 10399042
TI  - Yellow head virus from Thailand and gill-associated virus from Australia are
      closely related but distinct prawn viruses.
AB  - Corresponding genomic regions of isolates of yellow head virus (YHV) from
      Thailand and gill-associated virus (GAV) from Australia were compared by RT-PCR
      and sequence analysis. PCR primers designed from sequences in the GAV ORF1b
      polyprotein gene amplified the corresponding 577 nucleotide region of the YHV
      genome. Comparison of the amplified region indicated 85.1% nucleotide and 95.8%
      amino acid sequence identity. YHV PCR primers designed to amplify a 135
      nucleotide product previously described as a YHV diagnostic probe failed to
      amplify the corresponding product from GAV RNA. However, the cognate GAV sequence
      for this and another recently reported YHV sequence were located in an upstream
      region of the ORF1b gene. A comparison of these sequences indicated identities of
      83.0 and 80.9% at the nucleotide level and 86.7 and 86.5% at the amino acid
      level, respectively. The data indicate that GAV and YHV are closely related but
      distinct viruses for which differential diagnostic probes can be applied.

PMID- 10399043
TI  - [Perception and insight of illness in schizophrenic patients].
AB  - A review of prevalence and causes of low insight in schizophrenic patient as well
      as of possible interventions. Low insight was found in 20-80% of cases. The
      complex phenomenon 'lack of insight' is caused by a common pathway of different
      psychopathological and adaptive processes: psychotic reality distortion,
      psychotic resistance ('denial') and the expression of neurobiological deficits
      ('anosognosia'), respectively. Step by step, the subjective awareness and the
      individual causal model of the patient have to be adopted to the medical disorder
      model ('vulnerability-stress-coping concept') to achieve a functional
      understanding of the disorder that is optional for good cooperation between
      patient, relatives and professional carers. Thereby, a strengthening of the
      negative self-image and of the weakened autonomy should be given special
      attention to prevent hopeless-suicidal developments.

PMID- 10399041
TI  - A Saprolegnia parasitica challenge system for rainbow trout: assessment of Pyceze
      as an anti-fungal agent for both fish and ova.
AB  - A reproducible Saprolegnia parasitica spore delivery system was developed and
      demonstrated to be effective in providing a sustained spore challenge for up to
      10 d. Treatment of rainbow trout with slow-release intraperitoneal implants
      containing cortisol resulted in chronically elevated blood cortisol levels and
      rendered the fish susceptible to infection by S. parasitica when exposed to the
      spore challenge. Sham-implanted fish were not susceptible to infection. Bronopol
      (2-bromo-2-nitro-propane-1,3-diol), formulated as Pyceze, was effective in
      protecting predisposed fish from infection by S. parasitica when administered as
      a daily bath/flush treatment at concentrations of 15 mg l-1 and greater. Pyceze
      was also demonstrated to protect fertilised rainbow trout ova from S. parasitica
      challenge when administered as a daily bath/flush treatment at concentrations of
      between 30 and 100 mg l-1. Pyceze appears to qualify as a safe and effective
      replacement for malachite green and formalin in the prevention of fungal
      infections in the aquaculture environment.

PMID- 10399044
TI  - [Communicated insanity, folie a deux and shared psychotic disorder. Different
      concepts and a case from Mallorca].
AB  - Following an earlier description of the psychopathological conceptions of
      "communicated insanity" we focus on a remarkable difference concerning the
      development of the historical terminology. The current operationalized definition
      is oriented at the originally French conception of the "folie a deux" which
      includes an adoption of certain delusional ideas by an intimate other. Compared
      with that, in the German psychopathological tradition those cases were also
      included in the conception of the "induziertes Irresein", in which the shocking
      experience of another's psychosis may cause a psychotic illness of somebody else.
      In modern psychiatric terminology this kind of "induction" is rather disregarded.
      We report a case of an induced psychosis in two women and give particular
      attention to the German psychopathological tradition because of still existing
      clinical relevance.

PMID- 10399045
TI  - [Gabapentin in the treatment of mania].
AB  - We present the case of a 60-year old bipolar-I-patient showing a rapid antimanic
      response to gabapentin after having been non-responsive to lithium and perazine.
      This case encouraged us to further evaluate the antimanic potency of gabapentin
      in an open label trial. 20 patients with acute mania were treated for up to 21
      days with gabapentin in a dose range from 1200 to 4800 mg/day. Ten patients were
      treated with gabapentin as add-on medication and ten patients were treated with a
      high dose of gabapentin alone. The BRMAS score declined significantly in patients
      with moderate mania, whereas gabapentin alone was not efficacious in patients
      with very severe mania. Keeping in mind the limitations of an open study, it can
      still be said that gabapentin as add-on medication with other effective mood
      stabilizers appears to be safe and efficacious in the treatment of moderate
      mania.

PMID- 10399046
TI  - [Pharmacologic and cognitive therapy treatment strategies in in persistent
      negative schizophrenic symptoms].
AB  - Negative symptoms are a cofeature of schizophrenia which constitute a severe
      burden on relatives as well as on the patient himself. Novel (atypical)
      antipsychotic drugs unlike conventional antipsychotics cause substantial progress
      in the treatment of negative symptoms. Methodological flaws in recent studies
      which evaluate the effectiveness of neuroleptics in negative symptoms are being
      discussed critically. Especially the needs for differentiation of primary and
      secondary negative symptoms are underlined. Cognitive behavioural rehabilitation
      strategies are also reviewed. A newly developed cognitive behavioural approach in
      the treatment of negative symptoms developed by the "Research Group for
      Rehabilitation in Schizophrenia" of the Department of Psychiatry at the Freiburg
      University is proposed. A framework is discussed in which neuroleptic treatment
      optimalization and enhancement of coping strategies by psychosocial approaches
      are integrated. The need for integrating the patient in rehabilitation and
      treatment planning is underlined. Despite the limitations of methodology of most
      studies the findings of research reviewed here could be able to stimulate the
      optimalization of rehabilitation with these patients. It is necessary to ensure
      that all patients--especially those with high risk for deteriorating outcome-
      receive optimal treatment at the earliest possible stage in the course of their
      schizophrenic disorder. Progress in early intervention strategies [42] are
      therefore of outstanding interest. Main barriers to effective treatment have to
      be considered: noncompliance (and side-effects) of medication, repeated relapse,
      "treatment resistance", negative symptoms, and neurocognitive deficits. These
      factors indicate the need to favour integrated treatment approaches in which
      drugs and psychosocial strategies can be combined in a manner that maximizes the
      potential synergism.

PMID- 10399047
TI  - [Behavioral therapeutic methods in ambulatory treatment of alcoholism. Early
      results of an experimental study].
AB  - Outpatient alcoholism treatment programs are widespread especially in the United
      States and in Great Britain. However, there still exist only a few experimental
      studies investigating the numerous questions arising from this field. In this
      still ongoing project 120 patients were randomly assigned to 3 different
      outpatient group therapy programs: unspecific supportive therapy and 2 forms of
      behavioural therapy--coping skills training [17] and cognitive therapy according
      to Beck [2]. The main hypotheses to be tested are that both forms of behavioural
      therapy will prove superior to supportive treatment and that patients with a
      comorbidity of personality disorders will profit in a different way from these
      differentiated intervention strategies. Treatment lasted 6 months; first results
      obtained after the termination of this period demonstrate the feasibility of the
      study design; patients undergoing behavioural therapy showed good compliance with
      few drop-outs and significantly higher rates of abstinence compared with
      supportive therapy. 60% of the patients suffer from a concomitant personality
      disorder (mostly of the dependent, insecure, and masochistic type). Nevertheless,
      statistically significant differences between the 2 behavioural therapy
      techniques could not be established; a positive correlation between personality
      disorders and relapse or attrition could be confirmed only for relapses occurring
      within the first 3 months of treatment.

PMID- 10399048
TI  - [Frequency of injection of oral methadone solutions at treatment center for
      opiate dependence].
AB  - A sample of 134 patients (mean age 29.35 years, SD = 5.84, 72.4% of all patients
      in treatment at this point of time) were interviewed on the injection of peroral
      methadone. 43% of patients indicated having injected peroral methadone, 21% in
      the preceding month with a mean frequency of 10.3 injections. All of the patients
      concerned were in maintenance either with peroral or with injectable methadone.
      There were no significant differences between males and females and between the
      maintenance program with peroral and the one with injectable methadone regarding
      number of persons concerned and frequency of injection. 75% of patients were
      aware of associated health risks, their knowledge about these risks being modest.
      Asked about the reason for the injection patients most often mentioned a faster
      and more intense effect of the injected methadone as well as dependence on the
      injection per se or the syringe.

PMID- 10399049
TI  - [V. Gerontopsychiatric specialists discussion, Dusseldorf, November, 27-8, 1998].

PMID- 10399050
TI  - Administration of gonadotropins stimulates proliferation of normal mouse ovarian
      surface epithelium.
AB  - Little is known concerning the proliferation of the ovarian surface epithelium or
      the factors which control this process. To define when and under what
      circumstances this epithelium proliferates, we have studied the proliferation of
      mouse ovarian surface epithelium (OSE) during embryogenesis, early postnatal
      life, various physiological circumstances in the adult and in response to
      gonadotropic hormones, using the bromodeoxyuridine technique. Proliferation of
      the OSE is greatest during embryonic development, and falls gradually after birth
      until sexual maturity is reached. Very little proliferation of the OSE is
      detectable in adult life in non-pregnant, pregnant or lactating mice. The basal
      proliferation of the OSE can be increased significantly by inducing follicular
      development with pregnant mare serum gonadotropin (PMSG) or by administration of
      the pure recombinant gonadotropins follicle-stimulating hormone (FSH) or
      luteinizing hormone (LH). These results show that administration of gonadotropins
      to sexually mature mice induces proliferation of ovarian surface epithelium
      concurrently with the process of folliculogenesis.

PMID- 10399052
TI  - Unexpected pregnancy during hormone-replacement therapy in a woman with elevated
      follicle-stimulating hormone levels and amenorrhea.
AB  - Pregnancy in patients with hypergonadotropic amenorrhea, although previously
      reported, remains quite rare. Women may conceive spontaneously or following
      different regimens of ovulation induction, thus indicating that ovarian failure
      is not always permanent. The case of an 18-year-old woman with premature ovarian
      failure, who conceived during hormone-replacement therapy, is reported. During
      hormone-replacement therapy, elevated gonadotropin levels returned to the
      physiologically normal range. It is suggested that this restored the receptors to
      luteinizing hormone and to follicle-stimulating hormone, which might have been
      downregulated. This hypothesis is supported by previous results from clinical
      trials and experimental work on a rat model.

PMID- 10399051
TI  - Levels of sex hormone-binding globulin and corticosteroid-binding globulin mRNAs
      in corpus luteum of human subjects: correlation with serum steroid hormone
      levels.
AB  - To understand regulation of the function of human ovarian corpus luteum by sex
      steroid-binding proteins, the levels of luteal intracellular sex hormone-binding
      globulin (SHBG) and corticosteroid-binding globulin (CBG) mRNAs and serum steroid
      hormones were simultaneously determined. The expression of SHBG and CBG mRNAs was
      detected in all samples analyzed. SHBG mRNA level was positively correlated with
      serum estradiol-17 beta level (p < 0.05), but not with serum progesterone level.
      There was a positive correlation between SHBG mRNA level and serum estradiol-17
      beta/progesterone ratio (p < 0.01). On the other hand, CBG mRNA level was
      positively correlated with serum estradiol-17 beta and progesterone level (p <
      0.01 and p < 0.01, respectively). There was no correlation between CBG mRNA level
      and serum estradiol-17 beta/progesterone ratio. SHBG and CBG mRNA levels were not
      correlated with the levels of serum testosterone, free testosterone or cortisol.
      These findings suggest that the synthesis of luteal SHBG and CBG is complexly
      regulated by estrogen and progesterone, and that SHBG and CBG interact with
      estrogen and progesterone, respectively, for luteal steroidal activity.

PMID- 10399053
TI  - Standard in vitro fertilization or intracytoplasmic sperm injection in advanced
      female age--what may be expected?
AB  - This study was conducted to evaluate the current results of standard in vitro
      fertilization (IVF) and intracytoplasmic sperm injection (ICSI) in the elderly (>
      or = 40 years of age) female population. Oocyte recovery, fertilization, embryo
      transfer, pregnancy and cumulative pregnancy rates were assessed. The results
      were analyzed for: the entire elderly population; the standard IVF group (group
      1); all those in the ICSI group (group 2); and ICSI for severe male-factor
      category (group 3). A total of 330 IVF and 158 ICSI treatment cycles were carried
      out in 249 women. Forty-five (9.2%) clinical pregnancies were achieved. This rate
      was not statistically different from those achieved for groups 1, 2 and 3 (9.1%,
      9.5% and 6.8%, respectively). The cumulative pregnancy rate for a total of five
      cycles was 19.2% and 26.4% for groups 1 and 2, respectively. For those who
      started their treatments at > or = 40 years, the cumulative pregnancy rate for
      three cycles was 26.5% and 36.5% in groups 1 and 2, respectively. These results
      clearly demonstrate that female age is a major success determinant, with similar
      influence on both standard IVF and ICSI therapy modalities.

PMID- 10399054
TI  - Recombinant luteinizing hormone in ovarian hyperstimulation after stimulation
      failure in normogonadotropic women.
AB  - The aim of this study was to examine the effect of an additional administration
      of recombinant luteinizing hormone (r-LH) to a gonadotropin-releasing hormone
      agonist (GnRHa) long protocol using recombinant follicle-stimulating hormone (r
      FSH). In particular we determined whether such a stimulation protocol would be
      more effective in women (1) who respond poorly to stimulation with GnRHa long
      protocol using r-FSH only, and (2) whose LH concentrations after down-regulation
      in the cancelled cycle were low but above the values reported in the literature
      to be sufficient for folliculogenesis. After GnRHa desensitization 150 IU r-FSH
      and 75 IU r-LH were administered subcutaneously daily to six normogonadotropic
      women with low response to ovarian hyperstimulation using a GnRHa long protocol
      with r-FSH and low LH concentrations after down-regulation in the cancelled
      cycle. All six women had an oocyte retrieval and an embryo transfer after
      follicular stimulation. One women conceived but had a miscarriage in the eleventh
      week of gestation. Our results suggest that women with low response to a GnRHa
      long protocol with r-FSH, and whose LH concentration after down-regulation in the
      cancelled cycles were low, benefit from the additional administration of r-LH in
      a GnRHa long protocol using r-FSH. It seems that due to the additional
      administration of r-LH the LH concentration in the follicular phase is sufficient
      to support folliculogenesis.

PMID- 10399055
TI  - Effect of estrogen replacement therapy on cardiac function in postmenopausal
      women with and without flushes.
AB  - Left ventricular heart function and its response to long-term estrogen
      replacement therapy was assessed in 30 postmenopausal women, 20 of whom had
      modest to severe hot flushes and 10 of whom had never had them. Continuous
      transdermal estradiol was given to women who had surgically induced menopause,
      and a combination of transdermal estradiol and sequential medroxyprogesterone
      acetate was given to those who had spontaneous menopause. Left ventricular
      systolic and diastolic function was evaluated by complete two-dimensional M-mode
      and pulsed Doppler echocardiography before and after 6 and 12 months of therapy.
      The parameters assessed were: systolic and diastolic blood pressure, heart rate,
      cardiac septal and posterior wall dimensions, left ventricular end-systolic and
      end-diastolic dimensions and volumes, ejection fraction (EF), ejection time, peak
      left ventricular outflow velocity (PFV), flow velocity integral (FVI),
      acceleration time (AT), mean acceleration of systolic flow (MA), duration of
      early and late filling phase, peak velocity of the early (E) and late (A) mitral
      flow, and A/E velocity ratio. Although no difference in chamber and wall
      dimensions between flushers and non-flushers was found, women with hot flushes
      had lower (not significantly) EF, PFV, FVI, MA, blood pressure and heart rate
      before therapy. Twelve-month estrogen replacement therapy significantly reduced
      cardiac wall dimensions and improved systolic function in both flushers and non
      flushers. However, stroke volume, EF and MA were increased whereas systolic blood
      pressure and heart rate were decreased more in flushers. Also, the increase in E
      mitral flow and decrease in A/E were more pronounced in flushers. Thus, although
      estrogen replacement therapy significantly improves heart function in healthy
      postmenopausal women, there appears to be some minor differences in response
      between flushers and non-flushers.

PMID- 10399056
TI  - Urogenital symptoms in women aged 50-59 years. Women's Health in Lund Area
      (WHILSA) Study Group.
AB  - Problems related to the urogenital tract are common in elderly women. Control of
      micturition is often impeded and questionnaire-based studies have reported a
      prevalence of poor control of micturition in about 30% of postmenopausal women.
      In an ongoing cohort comprising women born between 1935 and 1945, an interim
      analysis was performed in 1800 women based on an interview and questionnaire. The
      prevalence of urinary incontinence was found to be 33%, which is in accordance
      with previous reports. The main difference between the interview and the
      questionnaire was that the interview could take into account intensity as well as
      intermittence of symptoms. There were no differences between premenopausal women
      and postmenopausal women using or not using hormone replacement therapy. In
      agreement with earlier studies, we found poorer control of micturition in parous
      women. A higher percentage of incontinence was also found in women who had lost
      more than 5 kg in body weight during the preceding 5 years. In addition, women
      with a family history of diabetes were more prone to complaints of incontinence.
      Of the 155 women who had a family history of diabetes, 66 were incontinent (p <
      0.01). It was also found that women who were incontinent were more often on
      regular surveillance for various diseases, using more medications regularly and
      had been hospitalized during the last 5 years more often than women who were
      continent. There were no differences in smoking habits. The present results imply
      that urinary incontinence in women is of a complicated origin and that the
      hormonal situation plays a minor role for this socially handicapping symptom.

PMID- 10399057
TI  - Comparison of the effects of conjugated estrogen treatment on blood lipid and
      lipoprotein levels when initiated in the first or fifth postmenopausal year.
AB  - Although estrogen replacement therapy (ERT) is known to be protective against the
      development of cardiovascular disease in patients with surgical menopause, the
      effects of ERT on blood lipids when started late after the operation is not yet
      clear. In this prospective study, blood lipid and lipoprotein levels were
      measured within a 2 year period, in Group I (n = 28 patients) and in Group II (n
      = 21 patients), who had total abdominal hysterectomy and bilateral salphingo
      oophorectomy 10-16 or 55-65 months ago, respectively. Each patient received 0.625
      mg conjugated equine estrogen once daily. Blood levels of total cholesterol (TC),
      triglycerides (TG), low density lipoprotein (LDL), high density lipoprotein (HDL)
      and very low density lipoprotein (VLDL) were measured at the beginning of the
      study as well as 12 and 24 months after ERT, was commenced. When the levels
      obtained after 12 and 24 months of ERT were compared to the baseline levels, LDL
      levels were decreased, whereas HDL levels were increased in Group I (p < 0.05);
      however, only the TC levels were significantly lower in Group II (p < 0.05). In
      conclusion, our results show that ERT is more effective on blood lipid changes
      when initiated within one year of oophorectomy compared with ERT initiated 5
      years after the menopause.

PMID- 10399059
TI  - Postmenopausal hormone replacement, risk estimators for coronary artery disease
      and cardiovascular protection.
AB  - Menopause, regardless of age at onset, is associated with a marked increase in
      coronary artery disease (CAD) risk. A large body of observational clinical
      studies repeatedly demonstrated favorable associations between postmenopausal
      hormone replacement therapy (HRT) and cardiovascular morbidity, mortality, and
      risk factors. Estrogens may act in a gender-specific way on vascular endothelial
      cells and other components of the vessel wall, enhancing the synthesis and
      release of nitric oxide (NO) and other vasodilators, and by inhibiting the
      synthesis and release of vasoconstricting agents, thus favoring vasodilation.
      Menopause-related changes in metabolic cardiovascular risk factors are
      identifiable, as are HRT-related changes in these factors. The metabolic effects
      include changes in lipoprotein (a), coagulation and fibrinolysis as well as
      homocysteine metabolism. The various actions of estrogen alone and combined with
      progestogen on the vascular system are reviewed. Furthermore, the outcome of the
      recently published Heart and estrogen/progestin replacement study (HERS) data are
      put in perspective. In addition, we outline the present data on the effects of
      raloxifene, a new second generation selective estrogen receptor modulator (SERM),
      which has been shown to favorably alter several markers of cardiovascular risk in
      postmenopausal women.

PMID- 10399058
TI  - Doppler, ultrasonographic and endocrinological environment with regard to the
      number of small subcapsular follicles in polycystic ovary syndrome.
AB  - The aim of this study was to evaluate how, in patients with polycystic ovary
      syndrome, the number of small subcapsular follicles correlates with uterine and
      ovarian blood flow and with specific hormonal parameters. At an ultrasonographic
      evaluation, 30 patients with polycystic ovary syndrome showed 5-10 (group I; n =
      14) or > 10 (group II; n = 16) small follicles. These patients underwent
      ultrasonographic (ovarian volume and stroma echodensity; number, diameter and
      distribution of follicles) and color Doppler (uterine and intraovarian vessels)
      analyses, and hormonal assay. In group II, significantly lower pulsatility index
      values than in group I were observed in the ovarian stromal arteries. The
      Ferriman-Gallwey score, plasma androstenedione level and luteinizing
      hormone/follicle stimulating hormone (LH/FSH) ratio results were significantly
      higher in group II than in group I. Androstenedione plasma levels correlated with
      the number of small follicles. Furthermore, the LH/FSH ratio correlated with both
      the number of small follicles and the stromal artery pulsatility index. The
      combined assessment of ovarian morphology by transvaginal ultrasound and color
      Doppler may provide insight into the pathological state of polycystic ovary
      syndrome.

PMID- 10399060
TI  - Stealth, sabotage and exploitation.

PMID- 10399061
TI  - Simian virus 40 infection via MHC class I molecules and caveolae.
AB  - MHC class I molecules are a necessary component of the cell surface receptor for
      simian virus 40 (SV40). After binding to class I molecules, SV40 enters cells via
      a unique endocytic pathway that involves caveolae, rather than clathrin-coated
      pits. This pathway is dependent on a transmembrane signal that SV40 transmits
      from the cell surface. Furthermore, it delivers SV40 to the endoplasmic
      reticulum, rather than to the endosomal/lysosomal compartment, which is the usual
      target for endocytic traffic. The glycosphingolipid and cholesterol-enriched
      plasma membrane domains that contain caveolae are also enriched for class I
      molecules, relative to whole plasma membrane. Nevertheless, although class I
      molecules bind SV40, they do not enter with SV40, nor do they enter spontaneously
      into uninfected SV40 host cells. Instead, they are shed from the cell surface by
      the activity of a metalloprotease. These results imply the existence of a
      putative secondary receptor for SV40 that might mediate SV40 entry. It is not yet
      clear whether class I molecules are active in transmitting the SV40 signal.
      Monoclonal antibodies against class I molecules also induce a signal in the SV40
      host cells. However, the antibody-induced signal is mediated by mitogen-activated
      protein kinase (MAP kinase), whereas the SV40 signal is independent of MAP
      kinase.

PMID- 10399062
TI  - Exploitation of major histocompatibility complex class I molecules and caveolae
      by simian virus 40.
AB  - Simian virus 40 (SV40), a non-enveloped DNA virus, is transported from the cell
      surface to the nucleus where virus replication occurs. This pathway of virus
      uptake involves binding to surface MHC class I molecules, entry via non-coated
      pits, and subsequent transport to the endoplasmic reticulum (ER). At some stage
      in this pathway the virus must cross a membrane to reach the cytosol. In the
      present review, the cellular machinery which the virus has utilized to enter the
      cell will be examined. In particular, we will consider recent evidence for the
      involvement of caveolae in the infectious entry step and propose a model
      involving recruitment of caveolar proteins around the membrane-bound virus. We
      also speculate that a similar mechanism may have been exploited by bacterial
      pathogens. The subsequent steps by which SV40 reaches the ER remain unclear but
      recent evidence suggests that this pathway may be shared with several other
      proteins that are transported from surface caveolae to the ER.

PMID- 10399063
TI  - Chemokine receptor trafficking and viral replication.
AB  - Chemokines and chemokine receptors have emerged as crucial factors controlling
      the development and function of leukocytes. Recent studies have indicated that,
      in addition to these essential roles, both chemokines and chemokine receptors
      play critical roles in viral infection and replication. Not only are chemokine
      receptors key components of the receptor/fusion complexes of primate
      immunodeficiency viruses, but chemokines can also influence virus entry and
      infection. Many viruses, in particular herpesviruses, encode chemokines and
      chemokine receptors that influence the replication of both the parent virus and
      other unrelated viruses. The cell surface expression of the chemokine receptors
      is regulated through their interaction with membrane trafficking pathways.
      Ligands induce receptor internalization and downmodulation through endocytosis,
      and recycling is regulated within endosomes. Part of the mechanism through which
      chemokines protect cells from HIV infection is through ligand-induced
      internalization of the specific chemokine receptor co-receptors. In addition,
      mechanisms may exist to regulate the trafficking of newly synthesized receptors
      to the cell surface. Here we discuss aspects of the mechanisms through which
      chemokine receptors interact with membrane-trafficking pathways and the influence
      of these interactions on viral replication.

PMID- 10399064
TI  - The downregulation of CD4 and MHC-I by primate lentiviruses: a paradigm for the
      modulation of cell surface receptors.
AB  - The human and simian immunodeficiency viruses (HIV and SIV) downregulate the cell
      surface expression of CD4, their primary receptor, and of class I
      histocompatibility complex (MHC-I), a critical mediator of immune recognition.
      While the first of these effects seems important to preserve viral infectivity,
      the second likely promotes immune evasion. Three HIV-1 proteins, Nef, Env and
      Vpu, contribute to downregulate CD4, Env forms a complex with CD4 in the
      endoplasmic reticulum, thereby retaining the receptor in this compartment. Nef
      and Vpu, on the other hand, act as connectors between CD4 and specific
      intracellular trafficking pathways, targeting the receptor for degradation in the
      lysosome and the proteasome, respectively. Some of the downstream partners of the
      viral proteins in these events have been identified, and include the adaptor
      complex of clathrin-coated pits, the beta subunit of COP-I coatomer, and the
      ubiquitin pathway-related h-beta TrCP protein. HIV-induced MHC-I downregulation,
      mostly the effect of Nef, also reflects a redistribution of this receptor, with
      its accumulation in the Golgi. The modalities of this process, however, are as
      yet imperfectly understood. New evidence indicates that the mechanisms employed
      by primate lentiviruses to downmodulate CD4 and MHC-I are also exploited by a
      number of cellular regulatory processes.

PMID- 10399065
TI  - HIV's evasion of the cellular immune response.
AB  - Despite a strong cytotoxic T-lymphocyte (CTL) response directed against viral
      antigens, untreated individuals infected with the human immunodeficiency virus
      (HIV-1) develop AIDS. We have found that primary T cells infected with HIV-1
      downregulate surface MHC class I antigens and are resistant to lysis by HLA-A2
      restricted CTL clones. In contrast, cells infected with an HIV-1 in which the nef
      gene is disrupted are sensitive to CTLs in an MHC and peptide-specific manner. In
      primary T cells HLA-A2 antigens are downmodulated more dramatically than total
      MHC class I antigens, suggesting that nef selectively downmodulates certain MHC
      class I antigens. In support of this, studies on cells expressing individual MHC
      class I alleles have revealed that nef does not downmodulate HLA-C and HLA-E
      antigens. This selective downmodulation allows infected cells to maintain
      resistance to certain natural killer cells that lyse infected cells expressing
      low levels of MHC class I antigens. Downmodulation of MHC class I HLA-A2 antigens
      occurs not only in primary T cells, but also in B and astrocytoma cell lines. No
      effect of other HIV-1 accessory proteins such as vpu and vpr was observed. Thus
      Nef is a protein that may promote escape of HIV-1 from immune surveillance.

PMID- 10399066
TI  - Evolutionary dynamics of HIV-induced subversion of the immune response.
AB  - Human immunodeficiency virus (HIV) disease progression is characterized by a slow
      but steady decline in the number of CD4+ T cells. It results in the development
      of AIDS when the immune response collapses and the virus grows uncontrolled.
      Pathogenicity of HIV may be due to viral escape from cellular immune responses as
      well as virus-induced immune impairment. Here we discuss how the dynamic
      interactions between the virus population and the immune response may lead to the
      development of AIDS. In particular we argue that in vivo evolution of HIV may be
      the driving force successively weakening the immune system. This may lead to
      increased levels of viraemia as well as to the evolution of more virulent
      phenotypes which indicate progression to AIDS. These insights are important for
      understanding the disease process itself and for designing effective treatment
      regimes.

PMID- 10399067
TI  - Measles: immunosuppression, interleukin-12, and complement receptors.
AB  - Measles virus, the first pathogen recognized to cause immunosuppression, induces
      profound and prolonged abnormalities in cellular immune responses in infected
      hosts. The ability of measles virus to specifically ablate monocyte/macrophage
      and dendritic cell production of interleukin (IL)-12 provides a potentially
      unifying mechanism for many of these in vivo and in vitro abnormalities. Cross
      linking of the cellular receptor for measles virus, the complement regulatory
      protein CD46, is sufficient to inhibit IL-12 production. CD46-mediated
      downregulation of IL-12 has turned out to be a specific instance of a more
      general pattern of tight inhibitory control over IL-12 production effected by
      complement and phagocytic receptors on antigen-presenting cells. Exploitation of
      these pathways by other intracellular pathogens is likely.

PMID- 10399068
TI  - Immunomodulation by viruses: the myxoma virus story.
AB  - Myxoma virus is a poxvirus pathogen of rabbits that has evolved to replicate
      successfully in the presence of an active immune response by an infected host. To
      accomplish this, the virus has developed a variety of strategies to avoid
      detection by or obstruct specific aspects of the antiviral response whose
      consolidated action is antagonistic to virus survival. We describe two distinct
      viral strategies carried out by viral proteins with which myxoma virus subverts
      the host immune response. The first strategy is the production of virus-encoded
      proteins known as viroceptors or virokines that mimic host receptors or
      cytokines. These seek to actively block extracellular immune signals required for
      effective virus clearance and produce a local environment in the infected tissue
      that is "virus friendly". The second strategy, carried out by intracellular viral
      proteins, seeks to retard the innate antiviral responses such as apoptosis, and
      hinder attempts by the infected cell to communicate with the cellular arm of the
      immune system. By studying these viral strategies of immune evasion, the myxoma
      system can provide insights into virus-host interactions and also provide new
      insights into the complex immune system.

PMID- 10399069
TI  - Immune evasion by adenoviruses.
AB  - Adenovirus is a human pathogen that infects mainly respiratory and
      gastrointestinal epithelia. While the pathology caused by this virus is generally
      not life threatening in immunocompetent individuals, there is a large literature
      describing its ability to establish a persistent infection. These persistent
      infections typically occur in apparently healthy individuals with no outward
      signs of disease. Such a long term and benign interaction between virus and
      immune system requires adenoviruses to dampen host antiviral effector mechanisms
      that would otherwise eliminate the virus and cause immune-mediated pathology to
      the host. Adenovirus devotes a significant portion of its genome to gene products
      whose sole function seems to be the modulation of host immune responses. This
      review focuses on what is currently understood about how these immunomodulatory
      mechanisms work and how they might play a role in maintaining the virus in a
      persistent state.

PMID- 10399070
TI  - Potential strategies utilised by papillomavirus to evade host immunity.
AB  - The co-evolution of papillomaviruses (PV) and their mammalian hosts has produced
      mechanisms by which PV might avoid specific and non-specific host immune
      responses. Low level expression of PV proteins in infected basal epithelial
      cells, together with an absence of inflammation and of virus-induced cell lysis,
      restricts the opportunity for effective PV protein presentation to immunocytes by
      dendritic cells. Additionally, PV early proteins, by a range of mechanisms, may
      restrict the efficacy of antigen presentation by these cells. Should an immune
      response be induced to PV antigens, resting keratinocytes (KC) appear resistant
      to interferon-gamma-enhanced mechanisms of cytotoxic T-lymphocyte (CTL)-mediated
      lysis, and expression of PV antigens by resting KC can tolerise PV-specific CTL.
      Thus, KC, in the absence of inflammation, may represent an immunologically
      privileged site for PV infection. Together, these mechanisms play a part in
      allowing persistence of PV-induced proliferative skin lesions for months to
      years, even in immunocompetent hosts.

PMID- 10399071
TI  - Varicella-zoster virus immune evasion.
AB  - CD4+ and CD8+ T cells play dual roles in varicella-zoster virus (VZV)
      pathogenesis. The first role is to deliver the virus to cutaneous sites during
      primary VZV infection, permitting replication at these sites and the successful
      transmission of the virus to other susceptible individuals. The second
      contribution of T cells is to provide the critical antigen-specific adaptive
      immunity needed to stop viral replication and maintain VZV latency in sensory
      ganglia. The equilibrium between VZV and the host can be predicted to be served
      by immune evasion mechanisms in at least two important ways, including the
      facilitation of cell-associated viremia during primary VZV infection and silent
      persistence in dorsal root ganglia. Interference with antigen presentation by MHC
      class I downregulation may be expected to play a role in both circumstances.
      Transient interference with MHC class II expression in varicella skin lesions
      should facilitate local replication and transmission. In addition, when VZV
      reactivates, the capacity of viral gene products to block the upregulation of MHC
      class II expression triggered by interferon-gamma should permit a sufficient
      period of viral replication to cause the lesions of herpes zoster, despite the
      presence of VZV-specific T cells, and to allow transmission of the virus to
      susceptible individuals. Although the effort is at an early stage compared to
      studies of other viral pathogens, identifying the VZV gene products that exert
      these effects and their mechanisms of interference has the potential to reveal
      novel aspects of MHC class I and class II antigen processing and presentation.

PMID- 10399072
TI  - A comparison of viral immune escape strategies targeting the MHC class I assembly
      pathway.
AB  - Peptide fragments from proteins of intracellular pathogens such as viruses are
      displayed at the cell surface by MHC class I molecules thus enabling surveillance
      by cytotoxic T cells. Peptides are produced in the cytosol by proteasomal
      degradation and translocated into the endoplasmic reticulum by the peptide
      transporter TAP. Empty MHC class I molecules associate with TAP prior to their
      acquisition of peptides, a process which is assisted and controlled by a series
      of chaperones. The first part of this review summarizes our current knowledge of
      this assembly pathway and describes recent observations that tapasin functions as
      an endoplasmic reticulum retention molecule for empty MHC class I molecules. To
      defeat the presentation of virus-derived peptides, several DNA viruses have
      devised strategies to interfere with MHC class I assembly. Although these evasion
      strategies have evolved independently and differ mechanistically they often
      target the same step in this pathway. We compare escape mechanisms of different
      viruses with particular emphasis on the retention of newly synthesized MHC class
      I molecules in the endoplasmic reticulum and the inhibition of peptide transport
      by viral proteins.

PMID- 10399073
TI  - Cytomegaloviral control of MHC class I function in the mouse.
AB  - Cytomegaloviruses (CMVs) represent prototypic viruses of the beta-subgroup of
      herpesviruses. Murine cytomegalovirus (MCMV) infects mice as its natural host.
      Among viruses, CMVs have evolved the most extensive genetic repertoire to subvert
      MHC class I functions. To date three MCMV proteins have been identified which
      affect MHC I complexes. They are encoded by members of large virus-specific gene
      families located at either flanking region of the 235 kb MCMV genome. The MHC I
      subversive genes belong to the early class of genes and code for type I
      transmembrane glycoproteins. The m152-encoded 37/40 kDa glycoprotein interacts
      with MHC I transiently and retains class I complexes in the endoplasmic reticulum
      (ER) Golgi intermediate compartment on its journey to the endolysosome. In
      contrast, the m06-encoded glycoprotein of 48 kDa complexes tightly with ternary
      MHC class I molecules in the FR. Due to sorting signals in its cytoplasmic tail,
      gp48 redirects MHC I to endolysosomal compartments for proteolytic destruction.
      Likewise, the 34 kDa glycoprotein encoded by m04 binds tightly to MHC class I
      complexes in the ER but the gp34/MHC I complex reaches the plasma membrane. The
      CD8+ T-cell-dependent attenuation of a m152 deletion mutant virus proves for the
      first time that inhibition of antigen presentation is indeed essential for the
      biological fitness of CMVs in vivo.

PMID- 10399074
TI  - Human cytomegalovirus, MHC class I and inhibitory signalling receptors: more
      questions than answers.
AB  - The human cytomegalovirus UL18 protein, an MHC class I homologue, has been shown
      to bind to leucocyte immunoglobulin-like receptor (LIR)-1, a member of a family
      of nine closely related immunoglobulin superfamily receptors expressed on
      leucocytes. The LIRs are related to the natural killer (NK)-cell immunoglobulin
      like receptors and to several other immunoreceptors. Three groups of LIR
      molecules have been defined: those containing cytoplasmic domain inhibitory
      signalling motifs, those with short cytoplasmic domains and a charged residue
      within the transmembrane domain, and a secreted molecule. LIR-1 and LIR-2 bind to
      a broad spectrum of cellular MHC class I antigens, including HLA-A, -B and -C
      alleles. LIR-2 is expressed by all monocytes and dendritic cells, whereas LIR-1
      is additionally expressed by B cells and subsets of T and NK cells. Upon tyrosine
      phosphorylation, LIR-1 and LIR-2 associate with the tyrosine phosphatase, SHP-1,
      and have been shown to inhibit Fc gamma RI signalling when co-crosslinked in
      monocytes. Evidence for and against a role of UL18 as an inhibitor of NK-cell
      function is discussed, as are possible functional outcomes of UL18-LIR-1
      interactions in monocytic cells.

PMID- 10399075
TI  - Cytomegalovirus evasion of natural killer cell responses.
AB  - Natural killer (NK) cells are an important component of the innate cellular
      immune system. They are particularly important during the early immune responses
      following virus infection, prior to the induction of cytotoxic T cells (CTL).
      Unlike CTL, which recognize specific peptides displayed on the surface of cells
      by class I MHC, NK cells respond to aberrant expression of cell surface
      molecules, in particular class I MHC, in a non-specific manner. Thus, cells
      expressing low levels of surface class I MHC are susceptible to recognition by NK
      cells, with concomitant triggering of cytolytic and cytokine-mediated responses.
      Many viruses, including the cytomegaloviruses, downregulate cell surface MHC
      class I: this is likely to provide protection against CTL-mediated clearance of
      infected cells, but may also render infected cells sensitive to NK-cell attack.
      This review focuses upon cytomegalovirus-encoded proteins that are believed to
      promote evasion of NK-cell-mediated immunity. The class I MHC homologues, encoded
      by all cytomegaloviruses characterised to date, have been implicated as molecular
      'decoys', which may mimic the ability of cellular MHC class I to inhibit NK-cell
      functions. Results from studies in vitro are not uniform, but in general they
      support the proposal that the class I homologues engage inhibitory receptors from
      NK cells and other cell types that normally interact with cellular class I.
      Consistent with this, in vivo studies of murine cytomegalovirus indicate that the
      class I homologue is required for efficient evasion of NK-cell-mediated
      clearance. Recently a second murine cytomegalovirus protein, a C-C chemokine
      homologue, has been implicated as promoting evasion of NK and T-cell-mediated
      clearance in vivo.

PMID- 10399076
TI  - Human pathogen subversion of antigen presentation.
AB  - Many pathogens have co-evolved with their human hosts to develop strategies for
      immune evasion that involve disruption of the intracellular pathways by which
      antigens are bound by class I and class II molecules of the major
      histocompatibility complex (MHC) for presentation to T cells. Here the molecular
      events in these pathways are reviewed and pathogen interference is documented for
      viruses, extracellular and intracellular bacteria and intracellular parasites. In
      addition to a general review, data from our studies of adenovirus, Chlamydia
      trachomatis and Coxiella burnetii are summarized. Adenovirus E19 is the first
      viral gene product described that affects class I MHC molecule expression by two
      separate mechanisms, intracellular retention of the class I heavy chain by direct
      binding and by binding to the TAP transporter involved in class I peptide
      loading. Coxiella and Chlamydia both affect peptide presentation by class II MHC
      molecules as a result of their residence in endocytic compartments, although the
      properties of the parasitophorous vacuoles they form are quite different. These
      examples of active interference with antigen presentation by viral gene products
      and passive interference by rickettsiae and bacteria are typical of the
      strategies used by these different classes of pathogens, which need to evade
      different types of immune responses. Pathogen-host co-evolution is evident in
      these subversion tactics for which the pathogen crime seems tailored to fit the
      immune system punishment.

PMID- 10399077
TI  - Phagocytic antigen processing and effects of microbial products on antigen
      processing and T-cell responses.
AB  - Processing of exogenous antigens and microbes involves contributions by multiple
      different endocytic and phagocytic compartments. During the processing of soluble
      antigens, different endocytic compartments have been demonstrated to use distinct
      antigen-processing mechanisms and to process distinct sets of antigenic epitopes.
      Processing of particulate and microbial antigens involves phagocytosis and
      functions contributed by phagocytic compartments. Recent data from our laboratory
      demonstrate that phagosomes containing antigen-conjugated latex beads are fully
      competent class II MHC (MHC-II) antigen-processing organelles, which generate
      peptide:MHC-II complexes. In addition, phagocytosed antigen enters an alternate
      class I MHC (MHC-I) processing pathway that results in loading of peptides
      derived from exogenous antigens onto MHC-I molecules, in contrast to the
      cytosolic antigen source utilized by the conventional MHC-I antigen-processing
      pathway. Antigen processing and other immune response mechanisms may be activated
      or inhibited by microbial components to the benefit of either the host or the
      pathogen. For example, antigen processing and T-cell responses (e.g. Th1 vs Th2
      differentiation) are modulated by multiple distinct microbial components,
      including lipopolysaccharide, cholera toxin, heat labile enterotoxin of
      Escherichia coli, DNA containing CpG motifs (found in prokaryotic and
      invertebrate DNA but not mammalian DNA) and components of Mycobacterium
      tuberculosis.

PMID- 10399078
TI  - Type III secretion machines and the pathogenesis of enteric infections caused by
      Yersinia and Salmonella spp.
AB  - Salmonella and Yersinia spp. infect the intestinal tract of humans. Although
      these organisms cause fundamentally different diseases, each pathogen relies on
      type III secretion machines to either inject virulence factors into the cytosol
      of eukaryotic cells or release toxins into the extracellular milieu. Type III
      secretion machines are composed of many different subunits and export several
      polypeptides with unique substrate requirements. During Salmonella pathogenesis,
      the type III machine encoded by the Salmonella pathogenicity island (SPI)-1
      genetic element functions to cause invasion of the intestinal epithelium, whereas
      another type III machine (SPI-2) is required for survival in macrophages.
      Yersinia enterocolitica and Yersinia pseudotuberculosis employ type III machines
      to resist macrophage phagocytosis and to manipulate the host's immune response,
      thereby colonizing intestinal lymphoid tissues. We describe what is known about
      the pathogenic functions of virulence factors secreted by type III machines.
      Furthermore, type III secretion machines may be exploited for the injection of
      recombinant proteins, a strategy that has already been successfully employed to
      elicit a cell-mediated immune response.

PMID- 10399079
TI  - Understanding the mechanism of action of bacterial superantigens from a decade of
      research.
AB  - In the face of the unique diversity and plasticity of the immune system
      pathogenic organisms have developed multiple mechanisms in adaptation to their
      hosts, including the expression of a particular class of molecules called
      superantigens. Bacterial superantigens are the most potent stimulators of T
      cells. The functional consequences of the expression of superantigens by bacteria
      can be extended not only to T lymphocytes, but also to B lymphocytes and to cells
      of the myeloid compartment, including antigen-presenting cells and phagocytes.
      The biological effects of bacterial superantigens as well as their molecular
      aspects have now been studied for a decade. Although there is still a long way to
      go to clearly understand the role these molecules play in the establishment of
      disease, recently acquired knowledge of their biochemistry now offers unique
      experimental opportunities in defining the molecular rules of T-cell activation.
      Here, we present some of the most recent functional and molecular aspects of the
      interaction of bacterial superantigens with MHC class II molecules and the T-cell
      receptor.

PMID- 10399080
TI  - Cytotoxic T lymphocytes to endogenous mouse retroviruses and mechanisms of
      retroviral escape.
AB  - Mouse retrovirus-induced lymphoma/leukemia and immunodeficiency are useful models
      for analogous human diseases. Both ecotropic (mouse tropic) and recombinant
      retroviruses, including the polytropic mink cytopathic focus-inducing type, have
      been studied for disease pathogenesis and as targets for humoral and cellular
      immunity, particularly cytotoxic T-lymphocyte (CTL) responses. For AKR/Gross
      murine leukemia viruses (MuLV) we have defined an immunodominant CTL epitope in
      the p 15E transmembrane anchor envelope protein and three minor/subdominant
      epitopes. Evidence is presented for retroviral escape from CTL by selection
      following genetic recombination and point mutation both within and outside CTL
      epitope sequences, and via endogenous retrovirus-infected cell downregulation of
      the generation of anti-AKR/Gross MuLV CTL. As demonstrated in vivo in naturally
      occurring non-responder strains by adoptive transfer, and in vitro by cell-mixing
      experiments, a central non-responsiveness mechanism appears to be peripheral
      inhibition mediated by infected cells expressing MHC-presented viral peptides.
      Such inhibition requires Fas expression by antiviral T cells; occurs upon TCR
      mediated recognition of virus-infected, Fas ligand-expressing "veto" cells; and
      apparently leads to an antigen-specific form of activation-induced cell death of
      T cells. In the LP-BM5 MuLV isolate that causes murine AIDS (MAIDS) retroviral
      variation also leads to CTL escape--the BM5-helper virus has altered forms of the
      immunodominant and two minor/subdominant epitopes. In contrast, a novel
      immunodominant CTL epitope is recognized by MAIDS resistant, but not MAIDS
      susceptible, strains. This epitope is uniquely encoded in an alternative
      translational reading frame of the viral gag gene. It also appears that the LP
      BM5 MuLV have co-opted the cells of the immune system for retroviral pathogenesis
      -CD40/CD40L (CD154) interactions are required both for the initiation and
      progression of MAIDS.

PMID- 10399081
TI  - Interplays between mouse mammary tumor virus and the cellular and humoral immune
      response.
AB  - Mouse mammary tumor virus has developed strategies to exploit the immune
      response. It requires vigorous immune stimulation to achieve efficient infection.
      The infected antigen-presenting cells present a viral superantigen on the cell
      surface which stimulates strong CD4-mediated T-cell help but CD8 T-cell responses
      are undetectable. Despite the high frequency of superantigen-reactive T cells,
      the superantigen-induced immune response is comparable to classical antigen
      responses in terms of T-cell priming, T-cell-B-cell collaboration as well as
      follicular and extra-follicular B-cell differentiation. Induction of systemic
      anergy is observed, similar to classical antigen responses where antigen is
      administered systemically but does not influence the role of the superantigen
      reactive T cells in the maintenance of the chronic germinal center reaction. So
      far we have been unable to detect a cytotoxic T-cell response to mouse mammary
      tumor virus peptide antigens or to the superantigen. This might yet represent
      another step in the viral infection strategy.

PMID- 10399082
TI  - General and specific immunosuppression caused by antiviral T-cell responses.
AB  - Immunosuppression caused by the non-cytopathic lymphocytic choriomeningitis virus
      (LCMV) (an RNA virus) is mediated by antiviral cytotoxic T cells that destroy
      LCMV-infected cells, also of the immune system. While this immunopathological
      destruction of antigen-presenting cells, macrophages and follicular dendritic
      cells and of some CD4+ T cells causes general immunosuppression and impairs
      immune response to third party antigens, it also enhances exhaustion/deletion of
      LCMV-specific CD8+ T-cell responses. LCMV seems in addition to infect
      neutralizing antibody-producing B cells via the specific receptor;
      immunopathological LCMV specific CD8+ T-cell-mediated elimination of these
      infected B cells (but not of uninfected internal virus antigen-specific B cells)
      causes a highly specific immunosuppression that delays neutralizing antibody
      responses and thereby enhances virus persistence. Both generalized and specific
      immunosuppression by CD8+ T-cell-mediated immunopathology may be involved in
      human infections with HIV, hepatitis B virus or hepatitis C virus.

PMID- 10399083
TI  - ICN and WMA stop tobacco use.

PMID- 10399084
TI  - ICN on tobacco use: nurses can utilize their unique knowledge and experience to
      promote smoking cessation and prevent the spread of a public health crisis.

PMID- 10399085
TI  - ICN on women's health: making strides: from the Universal Declaration of Human
      Rights to the recognition of women's health rights.

PMID- 10399086
TI  - Discrimination in nursing.

PMID- 10399087
TI  - The evolution of nursing administration in China.

PMID- 10399088
TI  - [Paclitaxel and new concepts. Advances in the management of bronchial carcinoma].

PMID- 10399089
TI  - Liver transplantation for citrullinaemia improves intellectual function.
AB  - BACKGROUND: Arginosuccinic acid synthetase (ASA) (EC 6.3.4.5) deficiency
      (citrullinaemia) (McKusick 215700) is a well-recognized cause of neonatal
      hyperammonaemic coma with poor long-term intellectual function, despite good
      medical management. METHODS: Cadaveric hepatic transplantation was performed in a
      12-year-old boy with citrullinaemia under poor biochemical control. Subsequent
      development of fulminant hepatic failure necessitated a second cadaveric
      transplant. Psychometric assessments before and after transplantation were
      performed using a variety of age-appropriate tests. RESULTS: Normalization of
      plasma ammonium in our patient post transplantation has resulted in dramatic
      improvement in mental functioning and well-being and he now enjoys a normal diet.
      Psychometric assessment confirmed decline in his abilities prior to
      transplantation with particular post-transplantation improvement in perceptual
      organization and visuospatial abilities; these did not, however, return to
      normal. His family report considerable reduction in stress associated with the
      unpredictable nature of previous hyperammonaemic crises and recurrent
      hospitalization. CONCLUSIONS: Liver transplantation should be considered as an
      early therapeutic option in children with citrullinaemia to prevent ongoing
      cerebral insult associated with hyperammonaemia.

PMID- 10399090
TI  - Fasting, postprandial, and post-methionine-load homocysteinaemia and
      methylenetetrahydrofolate reductase polymorphism in vascular disease.
AB  - Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease.
      The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) is a common
      genetic cause of increased homocysteine (HCY) levels. Post-methionine-load HCY
      concentrations allow identification of certain cases of hyperhomocysteinaemia not
      demonstrated by fasting levels. This study investigated the relationship between
      MTHFR polymorphism and (1) fasting HCY levels (77 patients); (2) post-methionine
      HCY levels (54 patients); and (3) postprandial HCY concentrations (36 patients)
      in cardiovascular disease. As expected, mean fasting HCY value was higher in the
      +/+ patients. Moreover, patients who were homozygous for the mutation exhibited
      significantly increased mean post-methionine-load HCY; in contrast, literature
      results are conflicting. Mean postprandial HCY, which is not known to be
      increased in controls, was also increased in the (+/+) patients, although the
      difference did not reach statistical significance, probably owing to the small
      size of the sample. MTFHR polymorphism is known to be aggravated by a drop in
      circulating folate. Additional risk factors may be more prevalent in patients
      with cardiovascular disease.

PMID- 10399091
TI  - 3-Methylglutaconic aciduria and hypermethioninaemia in a child with clinical and
      neuroradiological findings of Leigh disease.
AB  - We report on a child with a clinical and neuroradiological picture consistent
      with Leigh disease and an unusual association of isolated hypermethioninaemia and
      3-methylglutaconic aciduria. A low-methionine diet normalized both plasma
      methionine and urine 3-methylglutaconic acid; a methionine-loading test led to
      significant increase of both metabolites. In the skin fibroblasts the activity of
      3-methylglutaconyl-CoA hydratase was essentially normal. No explanation of this
      uncommon association of hypermethioninaemia and glutaconic aciduria is available.
      The possibility of a common transporter for 3-methylglutaconic acid and
      methionine is an attractive hypothesis.

PMID- 10399093
TI  - Single-cell analysis of mitochondrial DNA in patients and a carrier of the
      tRNA(Leu)(UUR) gene mutation.
AB  - We examined heteroplasmy of mutated mitochondrial DNA in single peripheral
      lymphocytes derived from 4 individuals carrying the nt 3243 A-to-G mutation,
      including two patients with MELAS, a patient with cardiomyopathy, deafness and
      diabetes mellitus, and the asymptomatic mother of one of the MELAS patients. In
      these subjects, all lymphocytes examined were heteroplasmic to different degrees,
      with a wider range of heteroplasmy evident in the symptomatic patients than in
      the healthy carrier.

PMID- 10399092
TI  - Progressive neurological deterioration and MRI changes in cblC methylmalonic
      acidaemia treated with hydroxocobalamin.
AB  - Cobalamin C (cblC) defects result in decreased activity of both methylmalonyl-CoA
      mutase and N5-methyltetrahydrofolate:homocysteine methyltransferase (methionine
      synthase), with subsequent methylmalonic acid-uria and homocystinuria. Patients
      typically show failure to thrive, developmental delay and megaloblastic anaemia.
      Vitamin B12 therapy has been beneficial in some cases. We report a now 4-year-old
      Hispanic girl with cblC disease documented by complementation analysis, with
      progressive neurological deterioration and worsening head MRI changes while on
      intramuscular hydroxocobalamin begun at age 3 weeks. Oral carnitine and folic
      acid were added at age 1 year. Blood levels of methylmalonic acid were reduced to
      treatment ranges. In the absence of acute metabolic crises, she developed
      microcephaly, progressive hypotonia and decreased interactiveness. Funduscopic
      examination was normal at age 13 months. At age 19 months, she developed
      nystagmus, and darkly pigmented fundi and sclerotic retinal vessels were observed
      on examination. Her neonatal head MRI was normal. By age 1 year, the MRI showed
      diffuse white-matter loss with secondary third and lateral ventricle enlargement,
      a thin corpus callosum, and normal basal ganglia. At age 15 months, progression
      of the white-matter loss, as well as hyperintense globi pallidi, were present.
      Interval progression of both grey- and white-matter loss was seen at age 27
      months. We therefore caution that progressive neurological deterioration and head
      MRI abnormalities may still occur in cblC disease, despite early initiation of
      hydroxocobalamin therapy and improvement in toxic metabolite concentrations in
      physiological fluids.

PMID- 10399094
TI  - Personality profiles of mothers of children with mitochondrial disorders.
AB  - Mothers of children with mitochondrial disorders, inherited neurodegenerative
      diseases, are faced with a frightening diagnosis and numerous demands associated
      with caring for these children. The psychological profile of mothers whose
      children carry a mitochondrial disorder is unknown. Forty-two mothers of children
      with mitochondrial disorders were interviewed and administered the Minnesota
      Multiphasic Personality Inventory--Second Edition (MMPI-2). Fifty-six per cent of
      the mothers had scores in the pathological range on three or more scales, most
      notably on Hypochondriasis, Hysteria and Paranoia scales. The MMPI-2 profile is
      associated with situational anxiety and stress or may be associated with carrier
      status characteristics. Whatever the cause, future studies need to determine
      whether supportive services can reduce the level of anxiety and stress in mothers
      of children with these disorders.

PMID- 10399095
TI  - Intracellular degradation of fluorescent glycolipids by lysosomal enzymes and
      their activators.
AB  - Fluorescent glycolipids were utilized for detection of the intracellular,
      activator-dependent, activities of beta-glucocerebrosidase and arylsulphatase A.
      Activities were measured in primary skin fibroblasts from normal individuals,
      from patients with Gaucher disease who had mutations within the beta
      glucocerebrosidase gene, and from a prosaposin-deficient patient. Fluorescent
      microscopy demonstrated that glucosylceramide or sulphatide labelled with a
      fluorescent probe (lissamine-rhodamine) were endocytosed and reached the
      lysosomes. There, in the presence of active enzyme and the corresponding saposin,
      they were hydrolysed to fluorescent ceramide, which changed its intracellular
      localization. When these substrates were labelled with pH-sensitive lissamine
      rhodamine, which loses its fluorescence at neutral or alkaline pH, the transport
      of the product, i.e. fluorescent ceramide, from the lysosomes resulted in
      disappearance of the cellular fluorescence. In cells of patients having mutations
      within the genes encoding the glucocerebrosidase or the prosaposin, there was a
      considerable reduction in the intracellular rate of substrate hydrolysis that
      could be followed by fluorescence microscopy or measured quantitatively in cell
      extracts.

PMID- 10399096
TI  - Long-term follow-up following bone marrow transplantation for Hunter disease.
AB  - Bone marrow transplantation (BMT) was performed in 10 patients with Hunter
      disease (mucopolysaccharidosis type II, iduronate-2-sulphatase deficiency). The
      donor was an HLA-identical sibling in 2 cases, an HLA-nonidentical relative in 6
      cases, a volunteer unrelated donor in 1 case, and details were not available in 1
      case. Only three patients have survived for more than 7 years post BMT; however,
      this high mortality probably resulted from poor donor selection. In two, there
      has been a steady progression of physical disability and mental handicap. One
      patient has maintained normal intellectual development, with only mild physical
      disability. It is possible that BMT may be useful in selected patients with MPS
      II.

PMID- 10399098
TI  - Recurrent rhabdomyolysis in a child with glutaric aciduria type I.

PMID- 10399097
TI  - Ceramide accumulation is associated with increased apoptotic cell death in
      cultured fibroblasts of sphingolipid activator protein-deficient mouse but not in
      fibroblasts of patients with Farber disease.
AB  - Ceramide is recognized as an intracellular mediator of cell growth,
      differentiation and apoptosis. Tumour necrosis factor, anti-fas antibody,
      radiation and anticancer drugs such as actinomycin D are known to induce
      apoptosis in several cell types through generation of ceramide by activation of
      the sphingomyelinase pathway or ceramide synthetase. In this study, we examined
      the occurrence of apoptosis in fibroblasts from patients with Farber disease and
      from sphingolipid activator protein-deficient (sap -/-) mouse. These cells
      accumulate ceramide as the result of genetic deficiency of acid ceramidase and
      the ceramidase activator (sap-D), respectively. Amounts of ceramide in
      fibroblasts from Farber patients and in fibroblasts from sap -/- mouse were
      increased 2.9-fold and 2.8-fold, respectively, over the level of controls.
      Despite the similar degree of ceramide accumulation, cells exhibiting apoptotic
      features were increased only in fibroblasts from the sap -/- mouse but not those
      from the Farber patients. Thymidine uptake of Farber fibroblasts was normal while
      that of sap -/- mouse fibroblasts was twice normal, consistent with the
      apparently normal growth and the different rates of apoptotic cell death in these
      two cell lines. These data suggest that intralysosomal accumulation of ceramide
      due to defective acid ceramidase or its activator may not play an important role
      as a mediator of apoptosis. The increased apoptosis in the cultured fibroblasts
      from the sap -/- mouse may be caused by mechanisms other than the ceramide
      accumulation. Although more frequent than normal, significant apoptotic cell
      death was not observed in sap -/- mouse brain in vivo.

PMID- 10399099
TI  - NTBC as palliative treatment in chronic tyrosinaemia type I.

PMID- 10399101
TI  - A case with early infantile form of galactosialidosis with unusual haematological
      findings.

PMID- 10399100
TI  - Early-infantile type of galactosialidosis as a cause of heart failure and
      neonatal ascites.

PMID- 10399102
TI  - Absence of apolipoprotein B3500 mutation in type 2a hyperlipoproteinemia patients
      and in the general population from southern Italy.

PMID- 10399103
TI  - Ornithine carbamoyltransferase deficiency: unusual clinical findings and novel
      mutation.

PMID- 10399104
TI  - Is the common 844ins68 polymorphism in the cystathionine beta-synthase gene
      associated with atherosclerosis?

PMID- 10399105
TI  - An 84 bp insertion found in a propionic acidaemia patient is not a disease
      causing mutation but a product of cryptic mRNA.

PMID- 10399106
TI  - Enantiomeric analysis of D- and L-pipecolic acid in plasma using a chiral
      capillary gas chromatography column and mass fragmentography.

PMID- 10399108
TI  - A novel exonic mutation in the aspartylglucosaminidase gene causes exon skipping.

PMID- 10399107
TI  - Molecular characterization of Polish patients with classical galactosaemia.

PMID- 10399109
TI  - Changes in granulocyte-macrophage colony formation in relation to chemotherapy
      and clinical progress in acute myeloblastic leukaemia patients.
AB  - To investigate the correlation between granulocyte-macrophage colony formation
      and the prognosis of acute myelocytic leukaemia, an in vitro colony formation
      assay using a practical method was performed at diagnosis in 50 patients newly
      diagnosed with acute myelocytic leukaemia. Granulocyte-macrophage colony counts
      were significantly lower in acute myelocytic leukaemia patients than in the
      control group (n = 5). The diminished colony formation was restored to within the
      normal range in 15 patients after complete remission was achieved. In eight
      patients, serial evaluation of granulocyte-macrophage colony formation was
      performed, and suppression of colony formation was observed at relapse. The
      comparison of granulocyte-macrophage colony counts at diagnosis between a group
      of patients with complete remission (n = 26) and a group of treatment failure
      cases (n = 24) revealed a significant difference suggesting that high counts of
      granulocyte-macrophage colony formation are predictive of a favourable prognosis
      for acute myelocytic leukaemia.

PMID- 10399110
TI  - Efficacy and safety of oral levofloxacin compared with clarithromycin in the
      treatment of acute sinusitis in adults: a multicentre, double-blind, randomized
      study. The Canadian Sinusitis Study Group.
AB  - Adult patients with acute sinusitis (n = 236) were randomized in a double-blind
      study to levofloxacin 500 mg orally once daily (n = 119) or clarithromycin 500 mg
      orally twice daily (n = 117) for 10-14 days. Between 2 and 5 days after therapy
      participants were evaluated as cured (no symptoms), improved (symptoms improved,
      no further therapy required), or failed (further therapy required). Clinical
      response rates (cured plus improved) for clinically evaluable patients were 93.9%
      for levofloxacin (n = 98) and 93.5% for clarithromycin (n = 93). The proportion
      of patients evaluated as cured was higher in the levofloxacin (40.8%) than in the
      clarithromycin arm (29.0%) and individual symptoms showed higher rates of
      resolution. Of patients receiving levofloxacin and clarithromycin, 22.5% and
      39.3%, respectively, experienced adverse events related or possibly related to
      the study therapy. This study showed that, in the treatment of acute sinusitis,
      daily levofloxacin therapy is as effective as twice-daily clarithromycin therapy
      with more complete clearing of symptoms and a more tolerable side-effect profile.

PMID- 10399111
TI  - Rapid and sustained efficacy of mizolastine 10 mg once daily in seasonal allergic
      rhinitis.
AB  - This 28-day, double-blind, randomized study in 256 patients compared the efficacy
      and safety of mizolastine 10 mg daily with placebo in patients with seasonal
      allergic rhinoconjunctivitis. All four nasal symptoms (itch, rhinorrhoea,
      sneezing, obstruction) and three ocular symptoms (itch, tears, redness) were
      rated by investigators using both a 0-3 and a 0-9 rating scale. Compared with the
      placebo group total, nasal and ocular scores were all significantly lower in the
      mizolastine-treated patients at day 14 of the study (P = 0.0002-0.0009, using the
      0-9 scale) and relief was maintained throughout the 4-week study duration.
      Patient diary total scores showed that mizolastine was effective from the first
      day of treatment. The 0-9 scale appears to be more sensitive than the 0-3 scale
      for rating symptoms of seasonal allergic rhinitis.

PMID- 10399112
TI  - Oral ciprofloxacin in the treatment of pseudomonas exacerbations of paediatric
      cystic fibrosis: clinical efficacy and safety evaluation using magnetic resonance
      image scanning.
AB  - Ciprofloxacin is effective for treating pulmonary infection in adult cystic
      fibrosis patients, and demonstrates excellent efficacy against Pseudomonas
      aeruginosa, but its use in paediatric cystic fibrosis patients has been limited
      because quinolone-induced cartilage toxicity has been observed in juvenile
      animals and has been considered a potential risk for children. Children with
      cystic fibrosis (n = 26; aged 6-16 years), with proven P. aeruginosa colonization
      of their sputum, were enrolled into a 14-day, open, non-comparative study.
      Patients were assigned to twice-daily treatment with oral ciprofloxacin 250 mg,
      500 mg or 750 mg, depending on their body weight. None of the patients exhibited
      any signs or symptoms of arthropathy, as assessed by magnetic resonance imaging
      of the right knee, during or immediately after treatment, or at the 3-month post
      therapy assessment. Cough, sputum production and sputum purulence were improved
      in more than 70% of patients. Patients showed a mean weight increase of 0.4 kg
      (95% confidence interval 0.1 to 0.7 kg) over the study period. Only one patient
      required a repeat chest radiograph, which showed no resolution of the abnormal
      radiographic appearances. Three patients reported adverse events during the
      trial, none of which were considered to be related to the study treatment.

PMID- 10399113
TI  - Serum levels of soluble intercellular adhesion molecule-1 and soluble vascular
      cell adhesion molecule-1 in asymptomatic carriers of hepatitis C virus.
AB  - High levels of serum-soluble intercellular adhesion molecule-1 (sICAM-1) and
      soluble vascular cell adhesion molecule-1 (sVCAM-1) have been noted in patients
      with chronic hepatitis C. This study aimed to measure serum levels of sICAM-1 and
      sVCAM-1 in asymptomatic hepatitis C virus carriers and clarify the clinical
      significance of measuring soluble forms. Serum levels of sICAM-1 were
      significantly higher than in healthy controls but serum sVCAM-1 levels did not
      differ statistically from those in healthy controls. Liver biopsy obtained from
      12 asymptomatic hepatitis C virus carriers showed evidence of hepatitis.
      Estimating sICAM-1 and sVCAM-1 in asymptomatic carriers may be helpful,
      especially in cases in which liver biopsy is not possible.

PMID- 10399114
TI  - Significance of synovitis in Legg-Calve-Perthes disease.
AB  - Synovitis is an important feature in Legg-Calve-Perthes disease (LCPD) with a
      significant prognostically negative impact on clinical symptoms, cartilage
      biochemistry, mechanical properties of the cartilage, joint biomechanics, and
      prognosis toward healing with a congruent, spherical head of femur. Synovitis
      causes cartilage edema, deterioration of the cartilage's mechanical properties,
      cartilage hypermetabolism, and, subsequently, cartilage hypertrophy. This
      sequence of events could explain the clinical course, which consists of cartilage
      hypertrophy, lateral subluxation, anterolateral deformation of the head, and,
      subsequently, joint incongruence in prognostically poor cases of LCPD. A factor
      in the deformation of the hypertrophic cartilage of the epiphysis is decreased
      range of motion of the hip, because of pain caused by the increase in
      intracapsular pressure and the subsequent decrease in the "molding" ability of
      the acetabulum. Synovitis in LCPD causes an increased intracapsular pressure, the
      magnitude of which may, in some patients, intermittently compromise the blood
      supply to the proximal femoral epiphysis. Whether synovitis is the consequence
      of, or precedes, the loss of blood supply and epiphyseal necrosis is not yet
      established. Significant and persistent synovitis during the entire course of the
      disease emphasizes the importance of magnetic resonance imaging as the method of
      choice for the diagnosis and the prognosis, as well as the monitoring of therapy.
      The prognostically negative effects of synovitis suggest that more therapeutic
      efforts should be focused on the treatment of synovitis, from a palliative and
      prognostic point of view.

PMID- 10399115
TI  - Preliminary report on usefulness of magnetic resonance imaging for outcome
      prediction in early-stage Legg-Calve-Perthes disease.
AB  - The usefulness of magnetic resonance imaging (MRI) for predicting prognosis was
      evaluated in 11 patients with unilateral early-stage Legg-Calve-Perthes disease
      who were treated with a non-weight-bearing abduction brace. Six to 10 months
      after disease onset, severity of cartilage hypertrophy and physeal curvature of
      the femoral head were scored on MRI. Femoral head deformity was radiographically
      evaluated. Among five patients whose MRI score was 8 or greater, radiographic
      evaluation after the treatment was "poor" or "fair," whereas evaluation for the
      other six patients whose MRI score was 7 or less was "good." The MRI scores
      indicated possible occurrence of femoral head deformation. Treatment method
      should be considered carefully when the MRI score is high.

PMID- 10399116
TI  - Bilateral Legg-Calve-Perthes disease: different from unilateral disease?
AB  - Twenty-five patients or 50 hips with bilateral Legg-Calve-Perthes disease were
      reviewed at skeletal maturity in the orthopaedic departments of Leuven, Belgium,
      and Montpellier, France. The two groups were very similar as to age at onset of
      the disease, severity of involvement, and classification at skeletal maturity.
      The results seem to indicate that bilateral disease runs a more severe course as
      compared with unilateral Legg-Calve-Perthes disease. Eighty percent presented
      with a Catterall group III and IV and Herring classification B and C. Forty-eight
      percent rated as Stulberg 4 and 5 at skeletal maturity.

PMID- 10399117
TI  - Long-term prognosis of Legg-Calve-Perthes disease: a meta-analysis.
AB  - In the literature, long-term prognosis of Legg-Calve-Perthes disease (LCPD) means
      prognosis for secondary osteoarthritis of the hip joint or leg-length inequality
      and its consequences. Most studies show results after conservative treatment. The
      long-term natural history of LCPD is not known. In spite of deformity, most
      patients do well in early adulthood. Radiographic and clinical osteoarthritis is
      increased in 20-year to 40-year follow-ups and degenerative joint disease
      develops in the majority of patients by the sixth or seventh decade of life. The
      reported average shortening of the affected leg has usually been 1 to 1.5 cm.
      There are no thorough long-term reports on low back pain after LCPD. The only
      evidence-based factors that are of prognostic importance in the long-term are age
      of the patient at the onset of the disease and shape of the femoral head at
      skeletal maturity.

PMID- 10399118
TI  - Can an enlarged acetabulum cover the femoral head well in Legg-Calve-Perthes
      disease?
AB  - Changes in the acetabulum play an important role in the final results of Legg
      Calve-Perthes disease (LCPD). To determine the relationship between the
      acetabulum and the final results, the acetabulum was measured in 108 children
      with unilateral LCPD. The acetabular radius, depth, width; iliac width and
      height; and medial joint distance were measured on the radiographs initially and
      on follow-up. The parameters between the affected and the unaffected sides were
      compared by using t test. Herring's classification was employed to evaluate the
      extent of involved femoral head. The results showed that the radius of the
      acetabulum was the most sensitive measurement representing the pathologic changes
      in the acetabulum. The acetabular hypertrophy occurred very early in the
      avascular necrosis stage. It resulted in the lateral subluxation of the femoral
      head and in loss of containment. During the later stage of the disease, the
      femoral head overgrew and broke the growth limit of the acetabulum. Coxa magna
      made it difficult for a hypertrophic acetabulum to contain it.

PMID- 10399119
TI  - Ultrasonography in the diagnosis of transient synovitis of the hip and Legg-Calve
      Perthes disease.
AB  - Ultrasonography was used to establish the diagnosis of transient hip synovitis
      and the onset of Legg-Calve-Perthes disease. A total of 115 patients presenting
      with 119 painful hips and the preliminary diagnosis of transient hip synovitis
      were reviewed. Hip effusion, resulting in capsular distension, was documented
      accurately with ultrasound. In nine patients, capsular distension persisted
      longer than 6 weeks and was associated with the onset of Legg-Calve-Perthes
      disease.

PMID- 10399120
TI  - Results of complete soft tissue clubfoot release combined with calcaneocuboid
      fusion in the 4-year to 8-year age group following failed clubfoot release.
AB  - A subset of postoperative recurrent clubfeet was isolated in a group of patients
      4 to 8 years old. Twenty-seven consecutive patients who underwent redo surgery
      consisting of complete soft tissue clubfoot release combined with a
      calcaneocuboid fusion were reviewed for this study. Twenty-six feet of 27 feet in
      20 patients had a long-term good result, suggesting that this procedure is the
      one of choice for this age group.

PMID- 10399121
TI  - Confirmation of arterial deficiencies in a limb with necrosis following clubfoot
      surgery.
AB  - This study describes postoperative necrosis of the hallux and first ray in a
      child with clubfoot. Arteriography performed on this child's lower limbs
      demonstrated, in the operated leg, hypoplasia of both the anterior and posterior
      tibial arteries and failure of the dorsalis pedis artery to traverse the tarsus
      and complete the deep plantar arch. Previously, congenital vascular deficiency
      was suggested to predispose such operated limbs to necrosis. These findings
      confirm the association between vascular deficiency and necrosis. In this present
      study, the metabolic demands of wound healing were sufficient in a limb with
      vascular deficiency to cause localized distal hypoperfusion leading to cyanosis
      and necrosis of the hallux and medial foot.

PMID- 10399122
TI  - Results of surgical treatment of Sprengel deformity by a modified Green's
      procedure.
AB  - The results of treatment of seven children with Sprengel deformity are reviewed.
      The patients were subjected to a modified Green procedure without dissection of
      the serratus anterior muscle and immediate postoperative mobilization. The
      results seem to indicate that the postoperative abduction gain (77 degrees)
      compares favorably in regard to the current literature and that this modification
      of the classic technique offers a substantial advantage concerning functional
      outcome in these patients.

PMID- 10399123
TI  - Radiographic evaluation of Baumann angle in Chinese children and its clinical
      relevance.
AB  - Normal Baumann angles in 98 children aged 2 to 13 years and abnormal Baumann
      angles in 71 children with supracondylar humeral fractures were evaluated. In
      healthy children, Baumann angles ranged from 64 degrees to 80 degrees (72.4
      degrees +/- 4.6 degrees) in boys and from 65 degrees to 81 degrees (72.9 degrees
      +/- 5.9 degrees) in girls. A significant negative relation (P < 0.01) between
      Baumann angle and carrying angle was noted, but there were no significant
      differences in Baumann angles between boys and girls (P > 0.05) and no
      significant correlation of Baumann angle with increasing age (P > 0.05). In
      patients with fractures, the Baumann angle measured after immediate reduction
      correlated well with the carrying angle measured after union or at final follow
      up (P < 0.01). This angle measured after reduction may be used to predict the
      final carrying angle so that cubitus varus deformity can be effectively
      prevented.

PMID- 10399124
TI  - A new modification of rotationplasty in a patient with proximal femoral focal
      deficiency Pappas type II.
AB  - The application of rotationplasty type B III (Winkelmann) for a patient with
      proximal femoral focal deficiency (PFFD) Pappas type II in a 5-year-old patient
      is described. The advantages for prosthetic management are discussed in
      comparison with other surgical options.

PMID- 10399125
TI  - Complications of the Bailey-Dubow elongating nail in osteogenesis imperfecta: 34
      children with 110 nails.
AB  - The Bailey-Dubow nail, inserted in the femur or tibia of 34 children with
      osteogenesis imperfecta (OI), was studied retrospectively. Comparing the various
      groups of OI, no significant difference was found. Location of the nail (tibia or
      femur) did not influence the complication rate significantly. The reoperation
      rate was 29%, a rate comparable to that reported in earlier studies. The part of
      the nail located around the knee had a significantly higher migration rate (P =
      0.005 at obturator ends and P = 0.007 at sleeve ends). Migration of the nail was
      the reason to reoperate in 50% of the patients. Better anchoring of the T-piece
      will substantially decrease the complication rate. In consideration of the
      different functional capacities of the OI population, the complications are
      likely related more to the hardware than to the patient.

PMID- 10399126
TI  - Transverse stress fracture of the patella in a child.
AB  - Transverse stress fracture of the patella in a child is an exceptional injury in
      childhood. Only one case has been previously reported. The present study reports
      a new case of a 12-year-old boy with anterior knee pain misdiagnosed for 5 months
      as Sinding-Larsen-Johansson disease who developed sudden anterior right knee pain
      and pop while running in a soccer match. Surgery was performed. The evolution was
      favorable without any immobilization required and the patient achieved full
      recovery.

PMID- 10399128
TI  - Chronic slipped capital femoral epiphysis: treatment by pinning in situ.
AB  - Chronic or stable slipped capital femoral epiphysis (SCFE) is a lesion of the
      hip, affecting the adolescent patient through adulthood. The change in the shape
      of the femoral head and to the biomechanics of the hip joint leads to early
      osteoarthritis. Treatment of SCFE is designed to stop slip progression to reduce
      the degree of osteoarthritis. Complications, such as avascular necrosis and
      chondrolysis, may also cause osteoarthritis. In situ pinning of SCFE is
      considered the best treatment modality currently available. In situ pinning of
      SCFE has the advantages of effectiveness, low morbidity, and a low complication
      rate. These advantages outweigh the disadvantage of fusing the slip in the
      uncorrected position. The authors review the indications, the techniques of in
      situ pinning, the results, and the complications of the procedure. The technique
      of in situ pinning necessitates experience and understanding of the anatomy of
      the adolescent hip, as well as adequate imaging equipment.

PMID- 10399127
TI  - Blood loss in Duchenne muscular dystrophy: vascular smooth muscle dysfunction?
AB  - Patients with Duchenne muscular dystrophy (DMD) tend to bleed more during surgery
      than do patients with other conditions. A retrospective analysis of blood loss
      after spinal surgery for scoliosis was therefore undertaken in 102 patients
      undergoing surgery in the senior author's unit. These included 48 patients with
      DMD, 26 patients with spinal muscular atrophy, and a miscellaneous group of 28
      other patients most of whom had idiopathic scoliosis. For each patient the age at
      surgery, estimated blood volume, duration of operation, Cobb angle, and number of
      vertebrae fused were recorded and compared. Expression of dystrophin in skeletal
      muscle and the underlying gene mutation were also determined. The estimated blood
      loss in patients with DMD was significantly higher than that in patients with
      spinal muscular atrophy undergoing the same or similar procedure (P < 0.005) and
      was also significantly greater than that of the third group, which consisted
      mostly of patients with idiopathic scoliosis (P < 0.0005). Blood loss in the
      patient group with DMD showed a significant relationship with duration of surgery
      (P < 0.05). As most patients expressed no dystrophin, this did not correlate with
      the estimated blood loss. There was also no correlation between the estimated
      blood loss and the type of gene mutation found causing DMD. The authors' previous
      observations confirm the increased blood loss in patients with DMD who undergo
      scoliosis surgery. Because children with DMD lack dystrophin in all muscle types,
      including smooth muscle, the excessive blood loss may be because of a poor
      vascular smooth muscle vaso-constrictive response due to a lack of dystrophin.

PMID- 10399129
TI  - Intertrochanteric corrective osteotomy for moderate and severe chronic slipped
      capital femoral epiphysis.
AB  - A total of 299 acute, acute on chronic, and chronic slips were treated from 1975
      to 1997. The patients were reviewed in three cohorts: 75 patients with slipped
      capital femoral epiphysis (SCFE) were treated between 1975 and 1982, 101 patients
      with 107 slips were treated from 1983 to 1991, and 110 patients with 117 slips
      were treated from 1992 to 1997. The authors have corrected 130 hips with chronic
      slips by intertrochanteric osteotomy. Of these 130 hips, 111 were moderate slips
      between 20 and 50 degrees, 19 hips with a slipping angle of more than 50 degrees
      were classified as severe chronic slips. During the same period, 92 chronic slips
      less than 20 degrees were treated by fixation in situ, and 77 acute or acute on
      chronic slips had an open and exceptionally a closed reduction followed by
      fixation. Eight postoperative fractures caused by inadequate plate fixation were
      observed after these 130 intertrochanteric osteotomies. They all necessitated
      plate replacement followed by uneventful healing. Three patients with major
      displacement developed chondrolysis after the corrective osteotomy, two were
      transient, and one patient developed avascular necrosis (AVN). The midterm
      clinical results showed a satisfactory outcome in all three cohorts. In 47
      patients in the series from 1975 to 1982, the clinical outcome was measured using
      Imhauser's score: 43 patients had good and very good results, 4 patients had a
      moderate or bad result. In the second and third series, the IOWA hip score was
      used to measure the clinical outcome. The 49 patients with osteotomies for
      chronic slips treated from 1983 to 1991 had an average score of 90.3 points, and
      1 patient had AVN. In the latest series from 1992 to 1997 with 34 corrective
      osteomies, there was no chondrolysis or AVN and the average IOWA score was 93.9
      points.

PMID- 10399130
TI  - Mechanisms of bradykinin-induced relaxation in pig coronary arteries.
AB  - Bradykinin (BK) induced endothelium- and concentration-dependent relaxations in
      segments of porcine posterior descending coronary arteries submaximally
      precontracted with the thromboxane A2 mimetic, U-46619. The effects of BK were
      reduced by L-NG-monomethylarginine (L-NMMA) and 6-anilinoquinoline-5,8-quinone
      (LY-83583), respective inhibitors of nitric oxide (NO) synthase and guanylate
      cyclase, but were unaffected by the cytochrome P450 monoxygenase blocker,
      thiopentone sodium; however, BK effects were slightly reduced by dimethyl
      sulfoxide (DMSO), an hydroxyl radical scavenger. Relaxant responses were reduced
      markedly by ouabain, a sodium pump inhibitor but only slightly by
      tetraethylammonium (TEA) and charybdotoxin, respective blockers of Ca-activated
      (KCa) and large-conductance (BKCa) K+ channels. However, BK responses were
      practically abolished by TEA + L-NMMA + ouabain while unaffected by apamin, 4
      aminopyridine and glibenclamide, blockers of small-conductance KCa voltage
      sensitive and ATP-sensitive K+ channels, respectively. In segments submaximally
      precontracted with K+, BK-induced relaxation was lower than that of those
      precontracted with U-46619, and was further reduced by L-NMMA, LY-83583 and
      especially, ouabain; L-NMMA + ouabain + TEA abolished the effect. Precontraction
      of segments with higher K+ concentrations almost abolished the relaxation. These
      results suggest that the relaxation to BK is mediated: 1) by endothelial NO
      release which activates guanylate cyclase of smooth muscle cells; 2) by hydroxyl
      radicals; and 3) by an endothelial hyperpolarizing factor, that does not seem to
      be a metabolite derived from cytochrome P450 monoxygenases and that relaxes
      activating K+ channels (mainly BKCa), and especially, the sodium pump.

PMID- 10399131
TI  - Proliferation of human peripheral blood mononuclear cells during calcium entry
      blockade. Role of protein kinase C.
AB  - To evaluate the role of protein kinase C (PKC) and intracellular calcium and
      particularly Ca(2+)-uptake in the initiation of lymphocyte mitogenesis, the
      proliferation of human peripheral blood mononuclear cells (PBMC) was investigated
      during calcium entry blockade with nifedipine (an L-type calcium channel blocker)
      and mibefradil (an L- and T-type calcium channel blocker with a higher
      selectivity for T-type channels). The rate of [3H]-thymidine, [3H]-uridine and
      [3H]-leucine incorporation into control and concanavalin A-stimulated PBMC
      cultured for 3 days in the presence or absence of the calcium channel blockers
      nifedipine or mibefradil (1, 10 or 50 microM) is assayed. Nifedipine and
      mibefradil concentration-dependently reduced cell number and [3H]-thymidine
      incorporation or de novo DNA synthesis in control and concanavalin A-stimulated
      PBMC, as well as de novo RNA and protein synthesis. The proliferative response of
      nifedipine- or mibefradil-treated cells was restored by addition of phorbol-12
      myristate-13-acetate (PMA), an exogenous PKC activator. Our data show that PBMC
      treated with the Ca2+ channel blockers nifedipine or mibefradil are still capable
      of proliferating in response to PMA. However, in PKC-depleted cells, the
      proliferative response of PBMC was suppressed.

PMID- 10399132
TI  - Effects of sairei-to and tokishakuyaku-san on cytokine release from peripheral
      blood mononuclear cells upon recognition of HLA-G protein in the treatment of
      recurrent abortion.
AB  - Human leukocyte antigen (HLA)-G has been shown to play a role in establishing
      pregnancy through the mechanism of modulating cytokine secretion from maternal
      lymphocytes. To elucidate the mechanisms of actions of the herbal medicines,
      Sairei-to and Tokishakuyaku-san, in the treatment of recurrent abortion, we
      investigated whether these medicines modulate cytokine secretion from peripheral
      blood mononuclear cells (PBMCs) upon recognition of HLA-G protein on
      trophoblasts. Sairei-to and Tokishakuyaku-san increased the interleukin (IL)-1
      beta and tumor necrosis factor (TNF)-alpha secretion and decreased the IL-3
      secretion from PBMCs regardless of whether these cells recognized HLA-G protein
      or not. Accordingly, Sairei-to nullified the effects of HLA-G to reduce the
      secretion of IL-1 beta and TNF-alpha and to enhance the secretion of IL-3.
      Tokishakuyaku-san also abolished the effect of HLA-G to reduce IL-1 beta and TNF
      alpha secretion but did not affect the increase in IL-3 secretion. Thus, it is
      conceivable that Sairei-to may normalize Th1/Th2 balance by enhancing Th1
      polarization in autoimmunity-related recurrent abortion in which Th1/Th2 balance
      might be shifted towards Th2 polarization. However, the mechanisms of action of
      Tokishakuyaku-san when used in treating unexplained recurrent abortion, cannot be
      explained only by the Th1/Th2.

PMID- 10399133
TI  - A study of the effect of benzylpenicillin on isolated human gallbladder.
AB  - The contractile effect of benzylpenicillin on isolated rings of human gallbladder
      was studied using preparations taken from surgical specimens after
      gallbladderectomy. The gallbladder was cut into two pieces and one ring was cut
      from each piece; one ring was mounted in a 100 ml organ bath containing Krebs
      solution and the isotonic changes of the preparation were recorded for each
      experiment. Benzylpenicillin (1 x 10(4) to 1 x 10(8) IU/l) was shown to exert a
      dose-dependent contractile effect on isolated human gallbladder rings which was
      blocked by atropine (1 x 10(-8) M). The benzylpenicillin-induced contractile
      effect was analogous to contraction observed with acetylcholine (1 x 10(-7) to 1
      x 10(-2) M). The effect of benzylpenicillin on isolated human gallbladder may
      reflect a possible decrease in gallbladder emptying time in vivo, suggesting a
      beneficial effect of benzylpenicillin in antimicrobial treatment of gallbladder
      infections.

PMID- 10399134
TI  - Possible role of cardiac mast cells in norepinephrine-induced myocardial
      preconditioning.
AB  - The present study was designed to investigate the role of cardiac mast cells in
      the cardioprotective effect of norepinephrine-induced preconditioning. Isolated
      rat heart was subjected to 30 min of global ischemia followed by 30 min of
      reperfusion. Both ischemic and norepinephrine (100 microM) preconditioning
      markedly reduced ischemia-reperfusion-induced release of lactate dehydrogenose
      (LDH) in the coronary effluent and the incidence of ventricular premature beats
      (VPBs) and ventricular tachycardia/fibrillation (VT/VF) during the reperfusion
      phase. Ischemic and norepinephrine preconditioning also significantly reduced
      ischemia-reperfusion-induced release of mast cell peroxidase (MPO), a marker of
      mast cell degranulation. However, MPO release increased immediately after
      ischemic or norepinephrine preconditioning. Histological study with ruthenium red
      (0.005%) staining confirmed cardiac mast cell degranulation in ischemic and
      norepinephrine preconditioned isolated rat hearts. These findings tentatively
      suggest that pharmacological preconditioning with norepinephrine produces a
      cardioprotective and antiarrhythmic effect similar to ischemic preconditioning
      through degranulation of resident cardiac mast cells.

PMID- 10399135
TI  - Dose-dependent effect of dietary fish-oil (n-3) polyunsaturated fatty acids on in
      vivo insulin sensitivity in rat.
AB  - The objective of this study was to assess the effect of dietary fish oil (n-3)
      polyunsaturated fatty acids (PUFA) on in vivo glucose metabolism and insulin
      sensitivity of rats. The experiments were carried out on 18 Wistar male rats
      divided into three groups: control rats given a normal diet containing corn oil,
      and two experimental groups given 1% or 5% fish oil supplemented diets. Glucose
      metabolism and insulin sensitivity were assessed by euglycemic clamp technique on
      anesthetized animals. The results showed: 1) despite the normotensive state of
      the animals, a significant decrease in blood pressure, especially systolic, and
      decreased heart rate in both experimental groups; 2) significantly decreased
      plasma total and LDL cholesterol and nonsignificantly decreased plasma
      triglycerides; 3) significantly increased bleeding time; 4) normoglycemia and
      dose-dependent hypoinsulinemia; and 5) significantly increased and dose-dependent
      in vivo glucose utilization and glucose clearance, significantly increased
      insulin sensitivity. The above results suggesting that insulin production is
      suppressed, provide another possible explanation for the beneficial effects of
      fish oil via modulation of the well-known damaging cardiovascular effects of
      insulin.

PMID- 10399136
TI  - Effects of certain cerebral circulation activating drugs on regional cerebral
      blood flow in rats.
AB  - The effects of certain cerebral circulation activating drugs on regional cerebral
      blood flow (rCBF) in the frontal cortex (FCOR), hippocampus (HPC) and nucleus
      caudatus (CAD) were investigated using the hydrogen clearance method in rats. All
      the drugs used in the present study, i.e., ozagrel, ifenprodil, pentoxifylline,
      cinnarizine and dilazep, caused an increase in rCBF in the FCOR, HPC and CAD.
      Ozagrel was the most potent in increasing rCBF at the FCOR. Ozagrel, ifenprodil,
      cinnarizine and dilazep were more effective than pentoxifylline in increasing
      rCBF at the HPC. On the other hand, all the drugs showed almost the same potency
      in increasing rCBF at the CAD. These results suggested that measurement of rCBF
      is useful for estimating the efficacy of cerebral circulation activating drugs.

PMID- 10399137
TI  - Pharmacological evaluation of an in vivo model of vestibular dysfunction in the
      rat.
AB  - A unilateral microinjection of either histamine or kainic acid was made into the
      medial vestibular nucleus of rats, eliciting robust barrel rotations that were
      evaluated by an elevated body-rotation test. Systemic pretreatment with
      betahistine or GT-2016 significantly attenuated the kainic acid-induced barrel
      rotations. These data indicate that the animal model described herein may
      represent a new model to identify novel drugs with potential antivertigo
      properties.

PMID- 10399138
TI  - Action of antidepressant drugs on maternal stress-induced hypoactivity in female
      rats.
AB  - It has been reported that rats forced to swim in a restricted space assume, after
      initial frenzied attempts to escape, an immobile posture. Porsolt et al. referred
      to this phenomenon as "behavioral despair", an animal model of depression.
      Prenatal stress induces an increase of behavioral depression in adult female
      offspring. This study presents new evidence supporting the hypothesis that
      maternal stress during gestation increases the risk of depression in the
      offspring since immobility time was modified by antidepressant drugs (tricyclics
      and an atypical antidepressant). In rats, amitriptyline (5 mg/kg), imipramine (5
      mg/kg) and nomifensine (1 mg/kg) decreased the immobility time in Porsolt test in
      offspring of mothers stressed during gestation. Moreover, increasing doses of
      amitriptyline (1, 5, 25 and 40 mg/kg) reduced depression in the forced swimming
      test in dose-dependent manner.

PMID- 10399139
TI  - Effect of the acetylcholinesterase inhibitor galanthamine on learning and memory
      in prolonged alcohol intake rat model of acetylcholine deficit.
AB  - Different cholinomimetics are used in conditions of CNS acetylcholine (ACh)
      deficit. In this study, we examined the effect of the acetylcholinesterase
      inhibitor galanthamine in a prolonged alcohol intake model of ACh deficit in male
      Wistar rats. After 16 weeks of alcohol intake and a 2-week pause, rats
      administered galanthamine (2.5 mg/kg/day i.p.) showed an improved speed of
      learning and short-term memory in the shuttle box test as compared to the saline
      injected alcoholic group (p < 0.05). Four weeks later, significant improvement in
      the passive avoidance memory of alcoholic galanthamine-treated rats was noted in
      the eight-arm radial maze (14 day test duration) as compared to the saline
      injected alcoholic group (p < 0.05). During the first week in the shuttle box
      test, the nonalcoholic galanthamine-treated animals exhibited significantly
      impaired performance as compared to the untreated nonalcoholic control, while
      four weeks later, in the eight-arm radial maze, both groups did not differ. Our
      results show that galanthamine improves the speed of learning, short-term memory
      and spatial orientation of rats in conditions of prolonged alcohol intake.

PMID- 10399141
TI  - In vitro analysis of GPI biosynthesis in mammalian cells.

PMID- 10399140
TI  - Effects of Sho-seiryu-to on experimental allergic rhinitis in guinea pigs.
AB  - The effects of Sho-seiryu-to, an antiallergic Kampo medicine, on experimental
      allergic rhinitis were investigated in actively sensitized guinea pigs. The
      number of sneezes and scratches by the animals after a topical antigen challenge
      was significantly inhibited by pretreatment with Sho-seiryu-to (1000 mg/kg per os
      p.o.). The antigen-induced eosinophil infiltration in the nasal mucosa was
      significantly inhibited by Sho-seiryu-to (1000 mg/kg p.o.). Sho-seiryu-to (100
      mg/kg p.o.) also reduced the increase in dye leakage to the nasal cavity induced
      by the antigen challenge and the antigen-induced decrease in volume of the nasal
      cavity was inhibited. Moreover, Sho-seiryu-to (1000 mg/kg p.o.) suppressed the
      volume change in the nasal cavity induced by leukotriene D4. These results
      demonstrate that Sho-seiryu-to inhibits experimental allergic rhinitis in guinea
      pigs, confirming that the agent may be beneficial for the treatment of allergic
      rhinitis.

PMID- 10399142
TI  - Selection of mammalian cell mutants in GPI biosynthesis.

PMID- 10399143
TI  - Analysis of the cell-surface distribution of GPI-anchored proteins.

PMID- 10399144
TI  - Imaging fluorescence resonance energy transfer as probe of membrane organization
      and molecular associations of GPI-anchored proteins.

PMID- 10399145
TI  - Purification of caveolae-derived membrane microdomains containing lipid-anchored
      signaling molecules, such as GPI-anchored proteins, H-Ras, Src-family tyrosine
      kinases, eNOS, and G-protein alpha-, beta-, and gamma-subunits.

PMID- 10399146
TI  - Analysis of lipids in caveolae.

PMID- 10399147
TI  - Analysis of the carbohydrate components of glycosylphosphatidylinositol
      structures using fluorescent labeling.

PMID- 10399148
TI  - Analysis of the lipid moiety of GPI anchor in the yeast Saccharomyces cerevisiae.

PMID- 10399149
TI  - Rapid identification of cysteine-linked isoprenyl groups by metabolic labeling
      with [3H]farnesol and [3H]geranylgeraniol.

PMID- 10399150
TI  - Incorporation of radiolabeled prenyl alcohols and their analogs into mammalian
      cell proteins. A useful tool for studying protein prenylation.

PMID- 10399151
TI  - Reconstitution of yeast farnesyltransferase from individually purified subunits.

PMID- 10399152
TI  - Probing the role of H-Ras lipidation for signaling functions in Xenopus laevis
      oocytes.

PMID- 10399153
TI  - Fluorescence measurement of lipid-binding affinity and interbilayer transfer of
      bimane-labeled lipidated peptides.

PMID- 10399154
TI  - Determination of the kinetics of intervesicle transfer and transbilayer diffusion
      of bimane-labeled lipidated peptides.

PMID- 10399155
TI  - Preparation and assay of myristoyl-CoA:protein N-myristoyltransferase.

PMID- 10399156
TI  - Metabolic labeling of protein-derived lipid thioesters in palmitoyl-protein
      thioesterase-deficient cells.

PMID- 10399157
TI  - Fatty acid analysis of protein-derived lipid thioesters isolated from palmitoyl
      protein thioesterase-deficient cells.

PMID- 10399158
TI  - [Peripheral COMT-inhibition with Entacapon. Optimal therapy of Parkinson
      disease].

PMID- 10399159
TI  - Arsenic: a new place?

PMID- 10399160
TI  - Childhood cancer in New Zealand 1990 to 1993.
AB  - An epidemiological study of childhood cancer in New Zealand identified 409
      children aged 0 to 14 years with malignant neoplasms newly diagnosed between 1990
      and 1993 inclusive. The original microscopic material on which the diagnoses were
      based was reviewed in 398 cases and the neoplasms were allocated into the 12
      major groupings and 48 further subcategories of the International Classification
      of Childhood Cancer (ICCC). The pathology reviewers agreed with group and
      subcategory classification of the confirmed cancers in all but one case of acute
      leukemia and three cancers of the central nervous system. Changes were also made
      in the FAB classification of three cases of acute non-lymphocytic leukemia and in
      the further subcategorisation of three Hodgkin's lymphomas and ten astrocytomas.
      The results show a high level of diagnostic accuracy for confirmed childhood
      neoplasms in that time period. Nine of 15 cases of malignant melanoma notified to
      the study were not confirmed for various reasons, which included a change in the
      pathological diagnosis in four cases. Compared with Victoria (Australia), New
      Zealand has a high incidence rate of lymphomas in boys and an unusual female
      preponderance of Wilms' tumor cases.

PMID- 10399162
TI  - Heterotopic pancreas, periampullary somatostatinoma and type I neurofibromatosis:
      a pathogenetic proposal.
AB  - This case documents the association of ectopic pancreatic tissue with a duodenal
      somatostatinoma in a patient with type I neurofibromatosis. Pancreatic ducts have
      been noted within the centres of somatostatinomas, but little significance has
      been attached to this finding. Here we describe a patient in whom a separate
      proliferation of somatostatin cells occurred in association with the ectopic
      pancreatic ductular epithelium. This lesion bore a striking resemblance to the
      ductulo-insular or ductulo-endocrine complexes that are seen in nesidioblastosis
      in the pancreas. We therefore postulate that the ducts, which are sequestered
      within somatostatinomas, are of pathogenetic significance. The somatostatin
      producing cells arise from these ducts, very much in the fashion of ductulo
      endocrine complexes in nesidioblastosis.

PMID- 10399161
TI  - The value of S-phase and DNA ploidy analysis as prognostic markers for node
      negative breast cancer in the Australian setting.
AB  - This study aimed to determine the prognostic significance of DNA ploidy and S
      phase fraction (SPF) measurements in our laboratory for patients with node
      negative breast cancer. Frozen tumors from axillary node-negative breast cancer
      patients (n = 50) treated at Westmead Hospital, NSW, between 1988 and 1991 were
      analysed by flow cytometry. The median duration of follow-up for all patients was
      8.4 years. Forty-six specimens provided evaluable DNA histograms with 43% (n =
      20) diploid and 56% (n = 26) aneuploid tumors identified. Comparisons of DNA
      ploidy status and SPF were made with traditional prognostic variables, which
      included age, menopausal status, tumor size, histologic grade and hormone
      receptor status. Our results showed that there was no significant difference in
      disease-free or overall survival between patients with diploid and aneuploid
      tumors. Histologic grade 3 tumors were more likely to be aneuploid and had higher
      SPF than grade 1 or 2 tumors. Patients with grade 3 tumors and a high SPF were
      four times more likely to relapse than the rest of the population. These results
      indicate that DNA flow cytometric analysis in our laboratory provides additional
      prognostic data that could be utilised alongside traditional clinical and
      histopathologic indicators for predicting outcome for patients.

PMID- 10399163
TI  - Anitschkow myocytes or cardiac histiocytes in human hearts.
AB  - The caterpillar chromatin pattern of the nucleus in longitudinal section and owl
      eye appearance in transverse section characterize the Anitschkow cell of Aschoff
      bodies in rheumatic heart disease. Determining whether it is of muscle origin or
      cardiac histiocyte has been a source of controversy for many years. In a study of
      fetal and neonatal hearts from humans, vesicular nuclei often displaying the
      Anitschkow chromatin pattern were the predominant cell type in the myocardium.
      Because a similar pattern was also observed in two cell types related to
      laryngeal cartilage and the neighbouring fibrous tissue in a six week old
      neonate, it was concluded that the Anitschkow chromatin pattern probably
      indicates cellular immaturity rather than any specific cell type.

PMID- 10399165
TI  - Broadsheet. Number 50: Diagnosis of human cytomegalovirus infection and disease.
AB  - Human cytomegalovirus (CMV) remains an important cause of illness in
      immunocompromised individuals and the most common viral cause of congenital
      malformation. The tests available for diagnosis of CMV include serology, antigen
      detection, virus culture, tissue histopathology and nucleic acid detection. The
      diagnosis of CMV remains difficult because of the issues of virus latency, virus
      infection versus clinical disease and virus reactivation. The tests available and
      the use of these tests are undergoing significant changes. This Broadsheet
      presents a review of these tests, particularly in the diagnosis of congenital
      infection and infection in pregnant women and immunocompromised individuals.

PMID- 10399164
TI  - Broadsheet. Number 49: Laboratory investigation of hepatitis C: a review.

PMID- 10399166
TI  - Tumor metastasis biopsy as a surrogate marker of response to melanoma
      immunotherapy.
AB  - In patients undergoing immunotherapy for metastatic melanoma, the clinical
      response in immunotherapeutic trials may be partial or difficult to detect. Tumor
      metastasis biopsy allows direct characterisation of an anti-tumor immunological
      response. During a phase I/II trial of granulocyte macrophage colony stimulating
      factor (GM-CSF) transduced autologous melanoma immunotherapy, the cellular
      response was examined by immunohistochemical analysis in a limited number of
      tumor biopsies taken from patients who either responded or progressed. Clinical
      response was associated with tumor infiltration by CD4+ and CD8+ T-cells,
      macrophages and differentiated dendritic cells (DC), and expression of HLA-DR by
      the tumor cells. This tumor infiltration was associated with increased melanoma
      specific peripheral blood precursor cytotoxic T-lymphocyte (pCTL) and the ability
      to obtain tumor-infiltrating lymphocytes in vitro. In contrast, progression or a
      lack of clinical response was associated with a lack of T-cell and DC
      infiltration into the tumor tissue in all such biopsies. Macrophages and
      eosinophils infiltrated these tumors, while T-cells and DC were present at some
      distance from the tumor. These preliminary data strongly suggest that the
      location and extent of T-cell and DC infiltration, as well as the expression of
      HLA-DR by tumor cells are associated with a clinical response in this form of
      melanoma immunotherapy.

PMID- 10399167
TI  - nm23 protein expression and p53 immunoreactivity in cutaneous fibrohistiocytic
      tumors.
AB  - Recent data indicate that reduced expression of the 17-kD protein encoded by the
      nm23 gene may be important in the pathogenesis of several types of human tumors.
      Immunohistochemistry was performed using a murine monoclonal antibody, NCL-nm23
      (Novocastra, 1:150 dilution) to investigate nm23 protein immunoreactivity in a
      group of locally aggressive cutaneous fibrohistiocytic tumors;
      dermatofibrosarcoma protuberans (DFSP) (n = 14) and atypical fibroxanthoma (AFX)
      (n = 7). Cases of dermatofibroma (DF) (n = 17) formed the benign control group.
      Comparison with p53 protein immunoreactivity in the same cases studied previously
      was made. Strong immunohistological expression of the nm23 protein was seen in
      most of the cases of DF (n = 15; 88%) in the form of strong cytoplasmic
      immunolabelling without nuclear staining. However, strong nm23 immunoreactivity
      was observed in only a minority of the cases of DFSP (n = 5; 36%) and AFX (n = 2;
      29%). Statistically significant differences in nm23 immunoreactivity were found
      between DFSP and DF (p = 0.008, chi 2 test with continuity correction) and
      between AFX and DF (p = 0.015; chi 2 test with continuity correction). No
      significant difference was seen between DFSP and AFX (p = 0.87, chi 2 test with
      continuity correction). There was inverse correlation between nm23 and p53
      immunoreactivity (r = 0.331; r2 = 0.109; p = 0.046; simple regression analysis).
      In summary, nm23 protein immunoreactivity is reduced in DFSP and AFX but not in
      dermatofibroma suggesting that reduced expression of the protein may be important
      in influencing the behavior of fibrohistiocytic tumors, although this is not well
      characterised. nm23 protein expression is also found to be inversely related to
      p53 immunohistological expression in these tumors.

PMID- 10399168
TI  - A comparison of polymerase chain reaction and phenotyping for rapid speciation of
      enterococci and detection of vancomycin resistance.
AB  - This study aimed to ascertain the ability of the microbiology laboratory to
      detect and identify catalase-negative Gram-positive cocci with particular
      reference to vancomycin-resistant enterococci (VRE). Twenty-seven reference
      strains and 42 prospectively collected catalase-negative Gram-positive cocci were
      screened by agar dilution breakpoint susceptibility and linked biochemical
      methods in routine use. Ability to speciate organisms was then compared using:
      (i) a multiplex polymerase chain reaction, designed to detect gene sequences
      specific to Enterococcus faecalis and E. faecium, and vancomycin resistance (van)
      genes; (ii) a commercial "API 20 strep" (iii) an algorithm using individual tests
      from a commercial API 20 strep strip; and (iv) the same algorithm utilising
      traditional phenotyping methods. All vancomycin resistant catalase-negative Gram
      positive cocci were detected by an agar dilution screening plate containing 4
      micrograms/ml of vancomycin. Polymerase chain reaction (PCR) detected all
      enterococci with van genes, speciated all vancomycin-sensitive E. faecalis and E.
      faecium isolates and excluded non-enterococcal vancomycin-resistant catalase
      negative Gram-positive cocci. Algorithm-based methods speciated 41 of the 42
      study isolates (98%). The API 20 strep correctly identified only 25 (60%) of
      these organisms, 38 of which were vancomycin-sensitive E. faecalis. VRE are
      detected by current screening methods for vancomycin-resistant catalase-negative
      Gram-positive cocci in this laboratory. API 20 strep, currently used to speciate
      catalase-negative Gram-positive cocci, is less reliable and should be replaced.
      Algorithm-based phenotyping by either method tested is more reliable for
      speciation than API 20 strep in its recommended form. Compared to the other
      methods tested, PCR is a rapid, accurate and inexpensive method of detecting and
      speciating vancomycin-resistant enterococci and it provides important extra
      information impacting on clinical therapy and infection control.

PMID- 10399169
TI  - Benchmarking pathology services: implementing a longitudinal study.
AB  - This paper details the benchmarking process and its application to the activities
      of pathology laboratories participating in a benchmark pilot study [the Royal
      College of Pathologists of Australasian (RCPA) Benchmarking Project]. The
      discussion highlights the primary issues confronted in collecting, processing,
      analysing and comparing benchmark data. The paper outlines the benefits of
      engaging in a benchmarking exercise and provides a framework which can be applied
      across a range of public health settings. This information is then applied to a
      review of the development of the RCPA Benchmarking Project. Consideration is also
      given to the nature of the preliminary results of the project and the
      implications of these results to the on-going conduct of the study.

PMID- 10399170
TI  - Clinical utility of anticardiolipin antibody assays: high inter-laboratory
      variation and limited consensus by participants of external quality assurance
      programs signals a cautious approach.
AB  - Antibodies that bind phospholipid (anti-phospholipid antibodies [APA]) are a
      focus of major interest to both clinical and laboratory personnel across a
      variety of disciplines because of the assortment of disorders with which they are
      reportedly associated. A solid phase assay using cardiolipin as the test
      phospholipid (anti-cardiolipin antibody assay [ACA]) has now become a laboratory
      standard for the detection of APA. In the current report, data from two separate
      external quality assurance programs (QAP) and collected over the past four years,
      have been evaluated to assess the utility of the ACA. Despite attempted
      standardizations, exceedingly high inter-laboratory variation and a general lack
      of test result consensus would signal the adoption of a cautious clinical
      approach towards laboratory findings. For example, for a total of 21 cross
      laboratory tested serum samples (tested for both IgG and IgM for 41 quantitative
      estimations), inter-laboratory variation for both ACA-IgG and ACA-IgM was higher
      than 50% in 20 of 41 testing cases (48.8%). The situation with regard to testing
      consensus was equally concerning. Total consensus (i.e., 100% of participating
      laboratories agreed that a given serum sample gave an ACA result of either
      negative or positive) occurred in less than 20% of cases for ACA-IgG. More
      importantly, in about 50% of serum testing occasions there was no general
      consensus in returned laboratory data (i.e., more than 80% of labs could not
      agree on whether a serum sample tested was either ACA-positive or ACA-negative).
      Thus, despite attempted international standardizations, exceedingly high inter
      laboratory variation and a general lack of test result consensus would argue that
      the assay has limited utility. We conclude that single point laboratory results
      must be used with considerable caution before accepting that ACA activity is
      present in patient serum or not. We agree with recommendations indicating that
      laboratory tests should be repeated at least once prior to making a clinical
      diagnosis of any APS-like disorder.

PMID- 10399171
TI  - Epithelial-myoepithelial carcinoma arising in the nasal cavity: a case report and
      review of literature.
AB  - Epithelial-myoepithelial carcinoma is an uncommon, low-grade, malignant
      epithelial neoplasm composed of variable proportions of ductular cells and large,
      clear staining, myoepithelial cells arranged around the periphery of the ducts.
      About 120 cases have been reported in the world literature, most of which were
      located in salivary glands, except for a few cases occurring in unusual locations
      such as breast, lacrimal gland, nose, paranasal sinus, trachea, bronchus, and
      lung. We here reported the second case of epithelial-myoepithelial carcinoma of
      the nasal cavity with extension to the nasopharynx. The patient was a 61 year old
      Chinese female with two month's history of progressive nasal obstruction.
      Histopathologically, the tumor showed typical myoepithelial and ductal cells
      biphasic differentiation, duct-like structure and infiltrating growth pattern.
      Some ductal cells showed the characteristics of oxyphilic cell, which had never
      been reported before. Recurrence and metastasis rates of epithelial-myoepithelial
      carcinoma varied from 35% to 50% and 8.1% to 25% respectively in different
      reports. The present case had neither recurrence nor metastasis twenty months
      after operation. When epithelial-myoepithelial carcinoma is mainly composed of
      spindle myoepithelial cells, the differential diagnosis should include
      myoepithelioma, neurofibroma, leiomyoma and hemangiopericytoma.

PMID- 10399172
TI  - Ultrastructural changes in a case of mucoid degeneration of the brachial artery.
AB  - An electron microscopic (EM) description of mucoid degeneration of the brachial
      artery in a 67 year old man is presented. In this case, the affected artery
      showed mucoid degeneration of the intima and media circumferentially, dissecting
      and destroying the muscle fibres. Ultrastructurally, mucoid degenerating muscle
      cells showed numerous large mucin-containing vesicles in the cytoplasm. Cells
      were widely separated by large accumulation of mucoid material, which appeared to
      penetrate the extracellular collagen fibre bundles. Most of the nuclei of the
      smooth muscle cells displayed typical necrotic changes undergoing dissolution or
      having already broken up into discrete fragments. This case of intimo-medial
      degeneration (IMMD) suggests that the condition could arise spontaneously
      anywhere in the inner coats of the arterial system away from the vessels that are
      close to synovial joints. This is a rare presentation of IMMD of arteries, which
      has been described mainly in the aorta and its major branches.

PMID- 10399173
TI  - Large cell neuroendocrine carcinoma of the uterine cervix: a report of a case
      with coexisting cervical intraepithelial neoplasia and human papillomavirus 16.
AB  - Large cell neuroendocrine carcinomas (LCNECs), one of the four newly categorised
      endocrine tumors of the uterine cervix, are unusual and aggressive tumors. The
      present report describes a case of LCNEC diagnosed at an early stage and
      associated with cervical intraepithelial neoplasia (CIN). The LCNEC showed
      organoid and trabecular growth patterns and was positive for chromogranin and
      synaptophysin. The CIN lesion was of a high grade and was negative for these
      neuroendocrine markers. Polymerase chain reaction (PCR) using genomic DNA
      extracted from archival tissue demonstrated human papillomavirus (HPV) type 16
      DNA in both the LCNEC and CIN lesions. These histological, immunohistochemical
      and PCR findings suggested that the LCNEC lesion was distinct from the CIN lesion
      and that both resulted from the carcinogenic field effect of HPV 16.

PMID- 10399174
TI  - Malignant melanoma metastatic to a meningioma.
AB  - The case presented is that of a 63 year old man with a metastasis to an
      intracranial meningioma from a malignant melanoma. Although the phenomenon of
      tumor to tumor metastasis to a meningioma has been previously reported, this is
      the first case in the literature to date, in which the primary tumor is a
      malignant melanoma. The criteria for the diagnosis of tumor-to-tumor metastasis
      and possible reasons for the frequency of metastasis to meningiomas are briefly
      reviewed.

PMID- 10399175
TI  - Secretory carcinoma of the breast in a nine year old boy.
AB  - Carcinoma of the breast is very rare in childhood and is exceedingly rare in
      boys. Secretory carcinoma, a distinctive and rare variant of breast carcinoma is
      for some unknown reason the commonest type seen in children. To our knowledge
      there have been only four previous reports in boys under ten years old. We report
      the first case in Australia of this unusual tumor in a nine year old boy. The
      child presented with a subareolar nodule 12 mm in its greatest dimension. High
      resolution sonography showed a well defined hypoechoic nodule. Histology revealed
      classical features of secretory carcinoma with circumscribed, pushing margins,
      except for one site of invasion. The tumor displayed the typical cribriform and
      microcystic pattern with PAS positive, diastase resistant secretions, and lack of
      pleomorphism and mitotic activity. Tumor cells showed positive staining with S100
      and polyclonal CEA and negative staining for estrogen and progesterone receptors.
      Although, because of its rarity, the natural history of this tumor is not well
      documented and optimal management is uncertain, prognosis happens to be excellent
      as these tumors behave in an indolent manner, both in children and in adults.

PMID- 10399176
TI  - The year 2000 problem: hiccough or approaching Armageddon.
AB  - The complexity of information technology systems has increased to approximate
      that of biological organisms, with a similar unpredictability of behaviour. With
      several million lines of code, a modern computer operating system, still can only
      be compared in complexity to a bacterial genome. However, just as unpredictable
      mutations continuously arise in the 3000 million haploid base pairs of human code
      and cause much misery and disease, undiscovered errors lie buried in the
      accumulated machine code which make up our world. As in human genetics, the
      difficulty is often distinguishing the harmless polymorphisms from the dangerous
      or lethal mutations. Similarly there is uncertainty about the impact of errors in
      data-handling code, which make up the "Year 2000 Problem". Over the remaining
      months it is vital that critical systems are checked for year 2000 compliance so
      as to avoid potentially serious disruption.

PMID- 10399177
TI  - Value of the Australian antibiotic guidelines nomogram in monitoring
      aminoglycoside concentrations.

PMID- 10399178
TI  - Pathological relevance of epithelial and mesenchymal phenotype plasticity.
AB  - Epithelium and mesenchyme, two tissue types virtually found in every organ, are
      endowed with fundamentally different functional properties. Active motility, a
      capability that is limited to the mesenchymal repertoire, is the principal
      characteristic that distinguishes them. During embryonic development, conversions
      from epithelium to mesenchyme and from mesenchyme to epithelium normally occur,
      allowing morphogenetic processes and tissue remodelling to take place. However,
      there is now increasing evidence that the modulation between the epithelial and
      the mesenchymal phenotypes is not limited to embryonic life. Indeed, the
      pathogenesis of some adult diseases seems to implicate an inappropriate
      activation of this change. On the other hand, failure of normally occurring
      embryonic epithelial-mesenchymal interconversions could result in the development
      of some pathologies. It is now possible to study some molecular events underlying
      these phenotype transitions, since several biological agents implicated in the
      epithelial-mesenchymal interconversion, such as growth factors, extracellular
      matrix components and their receptors, transcription factors and oncogenes have
      been identified. The malignant potential of some oncogenes seems to express
      itself through the disruption of the mechanisms involved in the maintenance of
      the epithelial phenotype while, on the other hand, some observations suggest the
      existence of regulatory genes able to counteract the action of oncogenes by
      restoring epithelial characteristics. Therefore, the manipulation of the tissue
      phenotype could represent a novel strategy for the prevention and treatment of
      diseases in the future.

PMID- 10399179
TI  - Immunohistochemical and histochemical characterization of the mucosubstances of
      odontogenic myxoma: histogenesis and differential diagnosis.
AB  - To discuss the dental origin of odontogenic myxoma and to provide further
      information for the differential diagnosis between this tumor and myxoid
      malignant fibrous histiocytoma (MFH) which occasionally occurs in jaw bones, the
      contents of glycosaminoglycans (GAGs) and proteoglycans (PGs) in the
      mucosubstances of 15 odontogenic myxomas, 5 myxoid MFH and 3 human fetal tooth
      germs in the bell stage of development were characterized using histochemical and
      immunohistochemical methods. Histochemical staining of hyaluronic acid (HA) was
      undertaken using biotinylated HA binding protein (B-HABP), and
      immunohistochemical detection was done using a panel of antibodies against
      chondroitin 6-sulfate (CS-6), chondroitin 4-sulfate (CS-4), dermatan sulfate
      (DS), keratan sulfate (KS), heparan sulfate (HS), aggrecan, PG-M/versican,
      decorin and biglycan. In odontogenic myxoma, CS-6, HA and PG-M/versican were
      observed in the myxomatous matrix of all cases, while KS and HS were seen in
      none. As for CS-4, DS, aggrecan, decorin and biglycan, only irregular and mild
      stainings were shown. Consistent and strong positive straining for CS-6, HA and
      PG-M/versican were seen in dental papilla and provided evidence supporting the
      origin of this tumor from dental papilla. Except for the constant staining for
      HA, the myxoid matrix was rarely stained for most GAGs and PGs in myxoid MFH.
      Immunodetection of CS-6 and PG-M/version with the use of monoclonal antibodies 3
      B-3 and 2-B-1 is therefore recommended as a useful tool in differentiating
      odontogenic myoma from myxoid MFH.

PMID- 10399180
TI  - Malignancy-simulating change in parotid gland oncocytoma following fine needle
      aspiration. Report of 3 cases.
AB  - We report here there cases of benign parotid gland oncocytoma with
      pseudomalignant change that mimic acinic cell carcinoma. All patients underwent
      fine-needle aspiration biopsy of the tumor 62, 725 and 33 days before surgical
      excision. In histologic sections, there were clusters of pigmented cells with PAS
      positive foamy to finely granular cytoplasm similar to those seen in salivary
      gland acinic cell carcinomas. This report provides another, previously
      undescribed, example of a diagnostic pitfall that may be observed in histologic
      tissue specimens removed after FNA of oncocytic tumors.

PMID- 10399181
TI  - The detection of Epstein-Barr virus in the lesions of salivary glands.
AB  - Epstein-Barr virus (EBV) is known in association with lymphoid and epithelial
      lesion. Because the salivary gland is an organ close to the oropharynx, it has a
      higher incidence of EBV infection and is a possible route of EBV infection.
      Formalin-fixed, paraffin embedded tissue sections of 87 cases of salivary gland
      diseases were used for the study of EBV with PCR, in situ PCR for EBNA-1 (EBV
      nuclear antigen-1), and immunohistochemistry for LMP-1 (latent membrane protein
      1). EBV was detected in 12 cases (13.8%): 7 of nonspecific chronic sialadenitis
      (21.2%), 4 of Warthin's tumors (30.8%), and one lymphoepithelial carcinoma. EBNA
      1 was negative in all the other lesions. EBV DNA was detected in the nucleus of
      epithelial cells and the surrounding lymphocytes. LMP-1 positivity was found in
      the cytoplasm of epithelial cells. The results of the present study showed that
      EBV is implicated in some of the inflammatory and neoplastic lesions of the
      salivary gland in which the lymphocytes are abundant. However, the pathogenesis
      and mechanism of immortalization and tumorigenesis of the epithelial cells in the
      salivary glands remain to be determined.

PMID- 10399182
TI  - Giant cell fibroblastoma: an entity or a reactive phenomenon?
AB  - The histological and immunohistochemical features of four tumors displaying the
      characteristic pattern of Giant Cell Fibroblastoma (GCF) are presented. Three of
      them were found in association with classical and/or myxoid dermatofibrosarcoma
      protuberans, while the fourth tumor was a retroperitoneal malignant
      hemangiopericytoma where foci with features of GCF were found. Typical sinusoidal
      spaces and the bizarre mononuclear and multinucleated cells in close association
      to blood vessels presenting a wide spectrum of lesions of their walls are also
      described. These last changes led us to believe that GCF-like lesions might not
      always characterize an entity but could often represent a host reaction of the
      connective tissue to locally aggressive or malignant tumors.

PMID- 10399183
TI  - Assessment of nucleolar organizer regions (NORs) in proliferative conditions of
      the liver.
AB  - To overcome the diagnostic dilemma in proliferative conditions of the liver which
      sometimes pose a problem to the working pathologist especially when the material
      is inadequate, a special staining technique (AgNOR) has been applied. By using
      this technique, nucleolar organizer regions were counted which determine the
      proliferative status of the cells. This prospective study included 65 cases of
      randomly selected liver core and fine needle aspiration biopsies. AgNOR staining
      was performed on formalin-fixed, paraffin-embedded tissue sections NOR dots were
      counted in 100 randomly selected hepatocytes at x100 oil immersion objective, and
      the mean count per cell was calculated for each case. Statistical analysis was
      done by using the Mann Whitney U test. AgNOR count results were later compared
      with the histologic diagnosis. The study revealed a gradual increase in mean
      AgNOR counts from normal liver through cirrhosis to hepatocellular carcinoma. The
      difference in NOR counts was significant in these three groups. The
      hepatocellular carcinomas were graded according to the Edmondson-Steiner
      histological grading system. The Grade I hepatocellular carcinomas show AgNOR
      counts ranging between 5-6/cell, a score which is much higher than in the normal
      liver, where it ranges between 1.2-2.0/cell. This technique can be used to assess
      the lesions where the distinction between normal liver and Grade I hepatocellular
      carcinoma is difficult with the use of routine methods. AgNOR counts in normal
      liver and chronic hepatitis cases were insignificant, but there was an
      appreciable difference between cases of chronic hepatitis, cirrhosis and
      hepatocellular carcinoma. In view of the results of this study, the AgNOR
      staining method is found to be a useful diagnostic tool to differentiate between
      normal liver, cirrhosis and hepatocellular carcinoma and also to precisely
      discriminate between cases of normal liver and Grade I hepatocellular carcinoma.

PMID- 10399184
TI  - Overexpression of c-Met protein in human thyroid tumors correlated with lymph
      node metastasis and clinicopathologic stage.
AB  - To examine the expression of c-Met protein in thyroid tumors and the correlation
      of c-MET protein expression with lymph node metastasis (LNM) and pathological
      stage, 111 papillary thyroid carcinomas (PTC), including 44 with synchronous LNM,
      and 117 follicular adenomas (FA) were immunohistochemically examined using
      dewaxed sections of formalin-fixed, paraffin-embedded tissues.
      Immunohistochemical results were confirmed by Western blot analysis. For PTC,
      positive immunostaining was observed in 107 of 111 (96.4%) cases and was
      diffusely present in either cytoplasm and nucleus, or only cytoplasm or only
      nucleus of cancer cells at varying intensities. Staining tended to be stronger in
      the periphery of cancer cell nests. Positive reaction was also found in 44 of 117
      (37.6%) cases of FA. However, the extent and intensity of c-Met immunostaining in
      FA were far less than those in PTC (p < 0.0001). Forty-four PTC cases (39.6%)
      exhibited LNM, and the extent and intensity of c-Met expression were
      significantly correlated with both LNM (p < 0.0001) and pathological stage (p <
      0.0001). No significant correlation of c-Met expression with age, sex or tumor
      size was found. Our findings suggest that PTC expresses c-Met protein much more
      strongly and intensively than does FA, and that strong and intense overexpression
      of c-Met protein may be an indicator of the presence of lymph node metastasis and
      advanced pathological stage of papillary thyroid carcinoma.

PMID- 10399186
TI  - Epithelioid sarcoma of the penis. Clinicopathologic study of a tumor with
      myogenic features and review of the literature concerning this unusual location.
AB  - Soft tissue tumors of the penis are uncommon. We report here the
      clinicopathologic features of a penile epithelioid sarcoma (ES), review the
      literature concerning this unusual location and focalize our attention on its
      differentiation. The 34-year-old patient was admitted for abrupt urinary
      retention due to the growth of a firm and painful plaque on the left side of the
      shaft, three years previously clinically diagnosed as Peyronie's disease.
      Magnetic nuclear resonance revealed an infiltrating lesion of both corpora
      cavernosa. Histology of bioptic fragments showed a nodular malignant spindle and
      epithelioid cell tumor with focal necrosis and relatively high mitotic rate.
      Based on the immunohistochemical data (cytokeratin+, vimentin+, EMA+, CD34+, and
      S100-), the diagnosis of ES was strongly considered. Penectomy was undertaken and
      the diagnosis confirmed by both light and ultrastructural microscopy. The 22
      month follow-up was free of recurrences and metastases. Although not dissimilar
      from the 10 previously described ES of the penis in terms of natural history and
      histology, the tumor reported here showed myogenic features as revealed by both
      immunohistochemistry (immunoreactivity for muscle specific actin) and
      ultrastructure (intercellular junctions, discontinuous basal lamina, pinocytotic
      vesicles and thin filaments with intercalated dense bodies). Although previously
      observed in ES of other sites, this feature has never been established in ES of
      the penis.

PMID- 10399185
TI  - Cotyledonoid dissecting leiomyoma (Sternberg tumor): an unusual form of
      leiomyoma.
AB  - Smooth muscle tumors are the most common neoplasms of the female genital tract.
      While most are usually easy to diagnose, several variants pose considerable
      diagnostic difficulties. Recently, a new form of uterine smooth muscle tumor was
      described that has an infiltrative character, which was named "cotyledonoid
      dissecting leiomyoma" or "Sternberg tumor" due to its macroscopic similarity to
      the gross architecture of the placental cotyledon. This report, the second such
      of this tumor, describes the macroscopic, microscopic, immunohistochemical and
      ultrastructural features of one of these unusual cases.

PMID- 10399187
TI  - Therapeutic and clinical regimens against Helicobacter pylori infections in
      humans: an overview.

PMID- 10399188
TI  - Synthesis, toxicological and pharmacological assessment of morpholinooximes.
AB  - The synthesis, pharmacology and toxicology of four morpholine derivatives from 1
      (2-arylmorpholino)-3-phenyl-3-propanonoxime and the synthesis of two anilides are
      described. The structures of the synthesized derivatives were proved by IR, 1H
      NMR and occasionally with 13C NMR. The acute toxicity of the compounds in mice
      was determined. A comparative pharmacological study of the in vivo effect on the
      central nervous system was realised by the following screening tests:
      pentobarbital induced sleeping time, locomotor activity and behaviour despair
      test for antidepressive activity. The most active compound was 1-(2
      phenylmorpholino)-3-phenyl-3-propanonoxime (2b) which showed low toxicity and
      antidepressive activity at a dose of 1/10 LD50.

PMID- 10399189
TI  - Magnetic marker monitoring of esophageal, gastric and duodenal transit of non
      disintegrating capsules.
AB  - The purpose of the study was to investigate in detail the esophageal, gastric and
      duodenal passage of non-disintegrating capsules in a fasted, healthy volunteer
      using Magnetic Marker Monitoring (MMM). Five independent experiments were
      performed. In each case the same healthy male volunteer ingested one magnetically
      marked capsule after fasting for at least 8 h. The magnetic dipole fields of the
      capsules were recorded by biomagnetic multichannel measuring equipment. The
      positions of the capsules were calculated from the recorded data by methods
      established in magnetic source imaging. The esophageal, gastric and duodenal
      passages of the capsules were successfully reconstructed from all recorded data
      sets. The spatial resolution of the capsules' three-dimensional positions in the
      organs of the gastrointestinal tract was within a range of several millimeters,
      with a chosen temporal resolution of up to four milliseconds. The esophageal
      transit times were between 3-13 s, the gastric residence times were between 14
      133 min and the duodenal transit times were between 7-245 s. The data demonstrate
      that Magnetic Marker Monitoring permits the detailed investigation of the
      gastrointestinal transit of solids.

PMID- 10399190
TI  - A topical dosage form of liposomal clofazimine: research and clinical
      implications.
AB  - A novel topical clofazimine (CLO) gel formulation containing liposomally
      encapsulated CLO, was prepared and investigated in vitro followed by a clinical
      evaluation. CLO liposomes were prepared by the lipid film hydration technique.
      Comparative in vitro diffusion studies were conducted with plain and liposomal
      CLO in HPMC K4M gel base (2% and 5%) using human cadaver skin (HCS). A double
      blind clinical study was conducted on eight leprosy patients. The results of
      these studies show that the new liposomal topical gel formulation not only
      prolongs the drug release but also promotes drug retention by the skin. Studies
      further support formation of a reservoir of drug on the skin modifying
      therapeutic efficacy of the formulation. The new liposomal gel formulation of CLO
      considerably reduces the healing time of external lesions due to a significantly
      prolonged skin residence time compared to plain CLO gel and hence is expected to
      reduce the time needed for leprosy treatment.

PMID- 10399191
TI  - Aspects of the antimicrobial efficacy of grapefruit seed extract and its relation
      to preservative substances contained.
AB  - The antimicrobial efficacy as well as the content of preservative agents of six
      commercially available grapefruit seed extracts were examined. Five of the six
      extracts showed a high growth inhibiting activity against the test germs Bacillus
      subtilis SBUG 14, Micrococcus flavus SBUG 16, Staphylococcus aureus SBUG 11,
      Serratia marcescens SBUG 9, Escherichia coli SBUG 17, Proteus mirabilis SBUG 47,
      and Candida maltosa SBUG 700. In all of the antimicrobial active grapefruit seed
      extracts, the preservative benzethonium chloride was detected by thin layer
      chromatography. Additionally, three extracts contained the preserving substances
      triclosan and methyl parabene. In only one of the grapefruit seed extracts tested
      no preservative agent was found. However, with this extract as well as with
      several self-made extracts from seed and juiceless pulp of grapefruits (Citrus
      paradisi) no antimicrobial activity could be detected (standard serial broth
      dilution assay, agar diffusion test). Thus, it is concluded that the potent as
      well as nearly universal antimicrobial activity being attributed to grapefruit
      seed extract is merely due to the synthetic preservative agents contained within.
      Natural products with antimicrobial activity do not appear to be present.

PMID- 10399192
TI  - In vitro effects of selected flavonoids on the 5'-nucleotidase activity.
AB  - A series of structurally related flavonoids and related compounds were evaluated
      whether they have inhibitory properties on the 5'-nucleotidase (5'-ribonucleotide
      phosphohydrolase; EC 3.1.3.5, 5'-NT) activity. Some of the flavonoids tested
      inhibit the enzyme such as quercetin, morin, apigenin, chrysin, myricetin,
      luteolin, diosmetin, (+/-)naringenin and diosmin. Rutin, naringin, hyperosid, (+/
      )catechin, caffeic acid and rosmarinic acid had no inhibitory effect on the 5'-NT
      activity. Myricetin and quercetin were the most potent inhibitors for 5'-NT with
      IC50 values of 1.1 and 1.4 microM, respectively. Kinetic analysis showed a mixed
      type of inhibitor for both myricetin (Ki = 1.5 microM at pH 7.45), and quercetin
      (Ki = 0.6 microM at pH 7.45). The K(m) value for 5'-adenosine monophosphate (5
      AMP) was determined with 77 microM at pH 7.45. The differential inhibitory
      potencies of flavonoids seem to be structurally related (hydroxylation pattern).
      The results demonstrate that some flavonoids are strong inhibitors of 5'-NT
      activity which can be correlated to their pharmacological effects.

PMID- 10399193
TI  - Comparative study on the in vitro antibacterial activity of Australian tea tree
      oil, cajuput oil, niaouli oil, manuka oil, kanuka oil, and eucalyptus oil.
AB  - To compare the antibacterial activity of the Australian tea tree oil (TTO) with
      various other medicinally and commercially important essential myrtaceous oils
      (cajuput oil, niaouli oil, kanuka oil, manuka oil, and eucalyptus oil) the
      essential oils were first analysed by GC-MS and then tested against various
      bacteria using a broth microdilution method. The highest activity was obtained by
      TTO, with MIC values of 0.25% for Enterobacter aerogenes, Escherichia coli,
      Klebsiella pneumoniae, Proteus mirabilis, Salmonella choleraesuis, Shigella
      flexneri, Bacillus subtilis, Listeria monocytogenes, Staphylococcus aureus, S.
      saprophyticus, and S. xylosus. It is noteworthy that manuka oil exhibited a
      higher activity than TTO against gram-positive bacteria, with MIC values of
      0.12%. Both TTO and manuka oil also demonstrated a very good antimicrobial
      efficacy against various antibiotic-resistant Staphylococcus species. Pseudomonas
      aeruginosa was resistant to all essential oils tested, even at the highest
      concentration of 4%.

PMID- 10399194
TI  - Isolation and identification of compounds with antinociceptive action from
      Ipomoea pes-caprae (L.) R. Br.
AB  - This study describes the isolation and identification of several constituents
      from Ipomoea pes-caprae (L.) R. Br., a medicinal plant frequently employed in
      folk medicine of many countries as a remedy against several diseases, including
      inflammation and pain. Our results demonstrate that some of these compounds, such
      as glochidone, betulinic acid, alpha- and beta-amyrin acetate, isoquercitrin,
      etc. showed pronounced antinociceptive properties in the writhing test and
      formalin test in mice. These data confirm our previous work concerning the
      antinociceptive action of the hydroalcoholic extract of I. pes-caprae and
      justify, at least in part, the popular use of this plant for the treatment of
      dolorous processes.

PMID- 10399195
TI  - [Enzyme immunoassay determination of the antidepressive fluoxetine].

PMID- 10399196
TI  - Influence of nutrition factors forming stable mixed micelles on permeation of
      quinine in vitro studied by the everted sac technique.

PMID- 10399197
TI  - Interim analyses with delayed observations in clinical trials.
AB  - The interim analyses based on group sequential procedures are not convenient if
      the response time relative to the patient accrual rate is long. Since in most
      trials patients are accrued and randomized continuously, the response data from
      those already randomized will continue to accumulate when a trial terminates at
      an interim test. One should analyse all observations received after the trial
      terminates along with the data that led to the decision to terminate the trial.
      Although the most likely case is that the combined results are significant, it
      could happen that the combined results are not significant. We examined the
      likelihood of such an event. Our study indicated that the O'Brien-Fleming type of
      group sequential tests with conservative boundaries in the early stages protects
      from such an unsettling event.

PMID- 10399198
TI  - Adaptive design improvements in the continual reassessment method for phase I
      studies.
AB  - The continual reassessment method (CRM) enables full and efficient use of all
      data and prior information available in a phase I study. However, despite a
      number of recent enhancements to the method, its acceptance in actual clinical
      practice has been hampered by several practical difficulties. In this paper, we
      consider several further refinements in the context of phase I oncology trials.
      In particular, we allow the trial to stop when the width of the posterior 95 per
      cent probability interval for the maximum tolerated dose (MTD) becomes
      sufficiently narrow (that is, when the information accumulating from the trial
      data reaches a prespecified level). We employ a simulation study to evaluate five
      such stopping rules under three alternative states of prior knowledge regarding
      the MTD (accurate, too low and too high). Our results suggest our adaptive
      designs preserve the CRM's estimation ability while offering the possibility of
      earlier stopping of the trial.

PMID- 10399199
TI  - Optimal multi-stage designs for a phase II trial that permits one dose
      escalation.
AB  - Simon's optimal two-stage design is widely used to conduct single-dose phase II
      clinical trials. We extend this basic methodology to the situation where the
      researcher desires to test an experimental drug for activity at a low dose level,
      but is willing to increase the dose part-way through the trial if the early
      results suggest that the low dose is ineffective. Interest is confined to at most
      one dose escalation, and no consideration is given to escalating the dose within
      a patient. Optimal multi-stage designs are presented that are more efficient than
      the naive approach of merely conducting two consecutive Simon optimal trials, one
      at the low dose and the second (if deemed necessary) at the high dose. As in
      Simon's original design, toxicity is not considered here as a primary endpoint.
      Hence, the designs presented in this paper are appropriate only when the toxicity
      of the drug is well understood at both dose levels.

PMID- 10399200
TI  - Combining mortality and longitudinal measures in clinical trials.
AB  - Clinical trials often assess therapeutic benefit on the basis of an event such as
      death or the diagnosis of disease. Usually, there are several additional
      longitudinal measures of clinical status which are collected to be used in the
      treatment comparison. This paper proposes a simple non-parametric test which
      combines a time to event measure and a longitudinal measure so that a substantial
      treatment difference on either of the measures will reject the null hypothesis.
      The test is applied on AIDS prophylaxis and paediatric trials.

PMID- 10399201
TI  - A Bayesian approach to modelling the natural history of a chronic condition from
      observations with intervention.
AB  - To assess the costs and benefits of screening and treatment strategies, it is
      important to know what would have happened had there been no intervention. In
      today's ethical climate, however, it is almost impossible to observe this
      directly and therefore must be inferred from observations with intervention. In
      this paper, we illustrate a Bayesian approach to this situation when the
      observations are at separated and unequally spaced time points and the time of
      intervention is interval censored. We develop a discrete-time Markov model which
      combines a non-homogeneous Markov chain, used to model the natural progression,
      with mechanisms that describe the possibility of both treatment intervention and
      death. We apply this approach to a subpopulation of the Wisconsin Epidemiologic
      Study of Diabetic Retinopathy, a population-based cohort study to investigate
      prevalence, incidence, and progression of diabetic retinopathy. In addition,
      posterior predictive distributions are discussed as a prognostic tool to assist
      researchers in evaluating costs and benefits of treatment protocols. While we
      focus this approach on diabetic retinopathy cohort data, we believe this
      methodology can have wide application.

PMID- 10399202
TI  - A simple method for analysing overdispersion in clustered Poisson data.
AB  - A simple method is proposed for analysing grouped count data exhibiting
      overdispersion relative to a Poisson model. The method is similar to the approach
      suggested for the analysis of clustered binary data in Rao and Scott (1992). It
      requires no specific model for the overdispersion and it can be implemented
      easily using standard programs designed to handle independent Poisson counts,
      after a small amount of preprocessing.

PMID- 10399203
TI  - Use of the Mann-Whitney U-test for clustered data.
AB  - The Mann-Whitney U-test is ubiquitous in statistical practice for the comparison
      of measures of location for two samples where the assumption of normality is
      questionable. Frequently, one has replicate data for each individual in a group
      and would like to compare measures of central tendency between groups without
      assuming normality. For this purpose, we present a generalization of the Mann
      Whitney U-test for clustered data. The test is performed by computing zc = (Wc -
      mu c)/sigma c, approximately N(0, 1) under H0, where Wc, mu c are the observed
      and expected Mann-Whitney U-statistic based on a comparison of all pairs of
      replicates in the two groups and sigma c is the standard deviation of Wc that is
      modified to account for clustering effects within a cluster. We obtain an
      explicit variance formula that is a function of four clustering parameters. We
      validate the properties of the test procedure in a simulation study. We
      illustrate the methods with an example comparing the baseline Humphrey visual
      field between two treatment groups in a randomized clinical trial of patients
      with retinitis pigmentosa (RP).

PMID- 10399204
TI  - The minimum sum of absolute errors regression: a robust alternative to the least
      squares regression.
AB  - This paper concerns the minimum sum of absolute errors regression. It is a more
      robust alternative to the popular least squares regression whenever there are
      outliers in the values of the response variable, or the errors follow a long
      tailed distribution, or the loss function is proportional to the absolute errors
      rather than their squared values. We use data from a study of interstitial lung
      disease to illustrate the method, interpret the findings, and contrast with least
      squares regression. We point out some of the problems with the least squares
      analysis and show how to avoid these with the minimum sum of absolute errors
      analysis.

PMID- 10399205
TI  - Testing proportionality in the proportional odds model fitted with GEE.
AB  - Generalized estimating equations (GEE) methodology as proposed by Liang and Zeger
      has received widespread use in the analysis of correlated binary data. Miller et
      al. and Lipsitz et al. extended GEE to correlated nominal and ordinal categorical
      data; in particular, they used GEE for fitting McCullagh's proportional odds
      model. In this paper, we consider robust (that is, empirically corrected) and
      model-based versions of both a score test and a Wald test for assessing the
      assumption of proportional odds in the proportional odds model fitted with GEE.
      The Wald test is based on fitting separate multiple logistic regression models
      for each dichotomization of the response variable, whereas the score test
      requires fitting just the proportional odds model. We evaluate the proposed tests
      in small to moderate samples by simulating data from a series of simple models.
      We illustrate the use of the tests on three data sets from medical studies.

PMID- 10399206
TI  - Anatomic guidelines for the prevention of abdominal wall hematoma induced by
      trocar placement.
AB  - A knowledge of the parietal structures of the abdominal wall is necessary to
      minimize risks of operative procedures like laparoscopy. For means to prevent
      intraoperative bleeding and the occurrence of abdominal wall hematoma, we studied
      the course of the inferior epigastric arteries and the ascending branch of the
      deep circumflex iliac artery in 21 human cadavers. The abdominal wall structures
      were dissected and the distances of the arteries in relation to anatomic
      structures such as the umbilicus, pubic symphysis, superior ischial spine and
      lower edge of the rib-cage were measured. Comparison of the morphometric results
      obtained with the location of 36 trocar incision sites recommended in the common
      literature yields the information that about half of these incision sites incur
      the risk of injuring the arteries.

PMID- 10399207
TI  - Anatomic basis of vascularized nerve graft using the long thoracic nerve.
AB  - Vascularized nerve transplants can lead to satisfactory functional reconstruction
      for nerve defects. These include defects following traumatic nerve severance,
      iatrogenic severance during tumour resection and extensive defects in poorly
      vascularized transplant sites. No previous description of the long thoracic nerve
      as a vascularized nerve graft is available. The aim of this study was to
      demonstrate the anatomic and initial clinical application of such a graft. The
      long thoracic nerve was dissected in 84 cases to examine its length, diameter,
      ramification and type of perfusion. On removal of the nerve, adequate perfusion
      through the thoracodorsal artery and a constant anatomic course with minimal loss
      of function were found. The long thoracic nerve is accessible anatomically,
      easily dissected and removed. This may be carried out together with the
      thoracodorsal vein and artery and even with a pedicled myocutaneous latissimus
      dorsi transplant, an osseo-myocutaneous scapulo-latissimus dorsi transplant or an
      osseous scapular transplant. The long thoracic nerve transplant can be employed
      for extensive facial defects together with simultaneous osseous and myocutaneous
      transplants of the shoulder region.

PMID- 10399208
TI  - Anatomic basis of vascularised nerve grafts: the blood supply of peripheral
      nerves.
AB  - The present study was carried out on 30 cadavers (5 fresh, 20 preserved adult and
      5 fresh stillborn) following injection of red latex through the subclavian and
      common iliac arteries. The blood supply to the peripheral nerves was studied in
      general, together with the vascular pedicles to the ulnar, saphenous, sural, deep
      and superficial peroneal nerves, and the superficial branch of the radial nerve.
      The nutrient arteries supplying the peripheral nerves came from either the
      adjacent axial artery or the fasciocutaneous or muscular arteries. They formed
      anastomotic channels in the epineurium and penetrated it to form a continuous
      longitudinal artery. Based on the presence of absence of dominant arterial
      pedicles, five patterns of blood-supply to the nerves could be identified. I: no
      dominant arterial pedicle; II: only one dominant artery (e.g. artery with a
      diameter more than 0.8 mm and accompanying the nerve for most of its length);
      III: only one dominant vessel that divided into ascending and descending branches
      to supply the nerve; IV: multiple dominant pedicles; V: multiple dominant
      arterial pedicles forming a continuous artery that accompanied the nerve. The
      arterial pedicles to the ulnar, saphenous and deep peroneal nerves and the
      superficial branch of the radial n. had mean diameters of over 0.8 mm, thus being
      suitable for microvascular anastomosis. Those to the sural nerve were not present
      in two thirds of the dissected cadavers. In 10% of the cadavers the superficial
      peroneal nerve had an arterial pedicle that accompanied the nerve for less than
      two cm with a mean diameter less than 0.8 mm. The ulnar nerve could be very
      suitable as a donor vascularized nerve graft as it had a dominant vascular
      pedicle in all the cases studied; however, its use should be restricted to C8 and
      T1 root damage of the brachial plexus. The superficial branch of the radial n.
      might be suitable for vascularized nerve grafting, but this is difficult in
      practice since the radial artery is a major limb artery. The saphenous nerve had
      a dominant arterial pedicles in all the cadavers dissected and could be the most
      suitable as a donor vascularized nerve graft, unlike the sural nerve which did
      not have a dominant arterial pedicle in two-thirds of the specimens. The deep and
      superficial peroneal nerves may also be unsuitable since the former is
      accompanied by a major limb vessel while the latter had a dominant vascular
      pedicle that accompanied the nerve for only a short distance in 10% of the
      dissected cadavers.

PMID- 10399209
TI  - Anatomic basis of iliac crest flap pedicled on the iliolumbar artery.
AB  - This paper presents the anatomy and clinical applications of an iliac crest flap
      pedicled on the iliolumbar artery. 54 iliolumbar arteries were filled with pink
      plastic in 27 adult cadavers. Their origin, course and branches, and the
      surroundings were investigated, and the external diameter, length of segments and
      terminal distribution were measured. The iliolumbar artery was constant, but with
      a few variations. Its length was 7.0 +/- 3.9 cm, and the outer diameter 2.0 +/-
      0.4 mm at the lateral edge of the psoas major muscle. Based on the anatomic
      findings, the surgical technique for a bone flap based on the iliolumbar artery
      was designed. Its clinical applications included both free bone grafting (in 2
      patients) and pedicled bone transfer (in another 2 patients). The clinical
      results were satisfactory. The iliac crest flap pedicled on the iliolumbar artery
      is a reliable bone flap for clinical usage.

PMID- 10399210
TI  - Changes of contour of the spine caused by load carrying.
AB  - The development of new leisure activities such as walking has spread the use of
      the backpack as a means of carrying loads. The aim of this work was to present a
      way of defining the movements imposed on the trunk by this type of load carrying.
      A 20 kg load situated at the thoracic level (T9) of the trunk, was placed in a
      backpack (2.5 kg). The 12 subjects were average mountain guides of Auvergne
      region, intermediate level and complete beginners. External markers were glued to
      the projecting contours of the spinous processes of the C7, T7, T12, L3 and S1
      vertebrae, the shin and the external occipital tuberosity (EOT). Using a Vicon
      140 3-D system we measured the effective mobility of the different spinal
      segments in the sagittal plane during one step. For every subject, we noticed a
      significant decrease of the effective inter-segmental mobility (EISM) between S1
      L3-T12 (p < .01) while backpacking a 22.5 kg load. A decrease of EISM also
      appeared at the next level between L3-T12-T7 (p < .05). An increase of the EISM
      between T7-C7-EOT was noted (p < .05). We supposed that strength loss of the back
      muscles and/or angular oscillations of the trunk could be a common cause of
      symptoms during backpacking. The subjects using this type of load carrying have
      to adopt an adequate position of the lumbar, dorsal and cervical vertebrae.

PMID- 10399211
TI  - Martin-Gruber communicating branch: anatomical and histological study.
AB  - We dissected 72 upper limbs of fresh cadavers and found 17 cases with a Martin
      Gruber communicating branch (23.6%). These were classified into 4 types: type I
      (n = 5, 29.4%): communicating branch between the anterior interosseous and ulnar
      nn, type II (n = 3, 17.6%): Communicating branch between the median and ulnar
      nn., type III (n = 3, 17.6%): Communicating branch between the muscular branches
      to the flexor digitorum profundus m., type IV (n = 6, 35.3%): combination of type
      I or II and type III. At histologic examination the number and size of the nerve
      bundles each communicating branch contained proved to be very different. In one
      case of type II only a single nerve bundle was found. We suggest that the
      different numbers of nerve bundles innervate different amounts of the intrinsic
      hand musculature. The communicating branch with a single nerve bundle probably
      innervated only the first dorsal interosseous muscle.

PMID- 10399212
TI  - Frequency of septum pellucidum anomalies in non-psychotic population: a magnetic
      resonance imaging study.
AB  - This prospective MRI investigation was performed to investigate septum pellucidum
      (SP) anomalies in 505 (242 male, 263 female) non-psychotic persons. The mean age
      of the population was 39.179 +/- 0.904 (40.461 +/- 1.395 male, 38 +/- 1.166
      female). There was no significant difference between the means of age in the male
      and female groups (t-test, DF = 479, p > 0.05). The SP anomalies were classified
      as cavitation anomalies (Type I) and absence of the SP (Type II). Type I
      anomalies were subdivided into four groups as isolated cavum septi pellucidi
      (Ia), cavum septi pellucidi et cavum vergae (Ib), anterior small triangular
      cavities (Ic), and cysts of the SP (Id). The incidences of the anomalies (Type I
      + Type II) were 17.31%, 1.89%, 7.55%, 3.53%, 7%, 4.55%, 4.76% and 6.06% for the
      age groups of 0-9, 10-19, 20-29, 30-39, 40-49, 50-59, 60-69 and 70-79 years
      respectively. The anomalies were very significantly more frequent in the 0-9
      years age group than in the other age groups (chi 2 = 9.7858, DF = 1, p < 0.05).
      The incidences of the anomalies (Type I + Type II) were 6.34%, 5.37%, 7.22% for
      the whole, male, and female populations, respectively. These values were 1.39%,
      1.65% and 1.14% for Type Ia, 2.77%, 2.89% and 2.66% for Type Ib, and 1.78%, 0.83%
      and 2.66% for Type Ic. Both Type Id and II anomalies were determined in only one
      case for each group in females (0.2%). There was no significant difference
      between the incidences of the anomalies in both sexes (chi 2 = 0.45, DF = 1, p >
      0.05).

PMID- 10399213
TI  - Three-dimensional motion patterns of the carpal bones: an in vivo study using
      three-dimensional computed tomography and clinical applications.
AB  - A three-dimensional (3D) CT technique was developed to analyze in vivo segmental
      carpal kinematics. Transverse CT data of the distal forearm, carpals and proximal
      metacarpals was acquired and 3D reconstructed in various wrist positions. Carpal
      kinematics were analyzed in two groups of 20 asymptomatic volunteers, one group
      in neutral position, flexion and extension (45 degrees), and the other group in
      neutral position, radial (15 degrees) and ulnar deviation (30 degrees).
      Qualitative analysis included the 3D study of carpal anatomy, and comparison of
      carpal bone position between the different sets of data obtained. Carpal bone
      motion was quantified using rigid body and finite helical axis concepts. The
      results, although agreeing in principle with previous findings, showed important
      individual variations in carpal bone motion. Clinical applications were conducted
      in a series of 25 patients with various wrist disorders. There was no significant
      difference between the injured wrist and the heterolateral, asymptomatic wrist,
      but there was a significant difference between asymptomatic volunteers and both
      the injured wrist and heterolateral wrist of patients. In particular, scaphoid
      motion was altered bilaterally in our patient group, suggesting the existence of
      anatomic and/or kinematic factors predisposing to certain carpal pathologies.
      This hypothesis needs to be confirmed and refined.

PMID- 10399214
TI  - Dynamic magnetic resonance imaging of the female pelvis: radio-anatomy and
      pathologic applications. Preliminary results.
AB  - Dynamic MRI of the pelvis was performed in 16 young nulliparous, normally
      continent women. The examinations were performed in the dorsal decubitus
      position. Using Turbo-Flash scans (acquisition time: 2.1 sec), sagittal images
      were obtained at rest and with maximal pelvic straining. The sacral promontory
      subpubic (PSP) and the subpubic-subsacral axes (SPSS) measured respectively 80.5
      degrees and 30 degrees in relation to the horizontal plane, without a
      statistically significant difference between rest and straining. A marked
      deformation of the posterior wall of the bladder was observed in 13 cases and the
      bladder neck was frontally deformed in 10 cases. With straining, the base of the
      bladder did not descend beyond 15 mm below the SPSS, and the cervix stayed at
      least 14 mm above the SPSS. These were established as the normal criteria for
      pelvic assessment. 20 multiparous patients (mean age 65 years), referred for
      urinary stress incontinence and/or prolapse, were investigated using the criteria
      previously established. The PSP, SPSS, and vaginal angle measured 80.95 degrees,
      30.57 degrees, and 69.69 degrees respectively in relation to the horizontal. No
      statistically significant difference was detected between straining and rest
      conditions. The angle of the uterus in relation to the horizontal was 57.36
      degrees at rest and 65.90 degrees in straining with a difference that was
      statistically significant. In six patients, the base of the bladder descended
      more than 1.5 cm while straining and in seven patients the cervix descended at
      least 1.4 cm below the SPSS while straining, both statistically significant
      differences. Overall, between our control and study populations, there were no
      significant differences between PSP and SPSS measured on straining and at rest.
      However, differences were detected in the vaginal angle, bladder-base position,
      and cervical position. These results suggest the potential substitution of MRI
      for colpocystography.

PMID- 10399215
TI  - French mirror site of the NPAC visible human viewer: first year evaluation.
AB  - The NPAC visible human viewer (NPAC VHV), graphical interface written in JAVA,
      freely accessible by the Web, allows the display of anatomic cross-sections of
      the Visible Human Project developed by the National Library of Medicine. In April
      1997, the Medical Media Library of Lyons undertook the construction of a French
      language mirror site of the NPAC VHV. The aim of this work is to evaluate first
      year utilisation of this site. From May 1st, 1997 to April 30th, 1998, the mirror
      site was consulted 34,752 times. In 45.14% of cases, the request came from
      France, in 4.42% of cases from Belgium, in 3.98% from Canada and in 2.12% from
      Switzerland. Other connections came either from a country responsible for fewer
      than 1% of connections or from unidentified computers. Data analysis showed a
      peak of connections between 15:00 and 17:00, and an increased number of
      connections from September to March 1998. The NPAC VHV is housed in 5 sites in
      the world. It is a software very simple to use. As the figures have no legends,
      it is more appropriate for group teaching than for self-teaching.

PMID- 10399216
TI  - A case of malrotation and situs ambiguus.
AB  - Isolated levocardia is a rare condition in which intestinal malrotation may be
      encountered. The case herein reported is particularly uncommon and raises a
      number of questions about the development of abdominal symmetry.

PMID- 10399217
TI  - Retrocaval ureter and preaortic iliac venous confluence in a patient with an
      abdominal aortic aneurysm.
AB  - Anomalous anatomic location of a large venous system poses a potential hazard in
      aortic operations. We encountered a patient with an infrarenal abdominal aortic
      aneurysm who was also found at preoperative contrast-enhanced computed tomography
      to have a retrocaval right ureter and a preaortic iliac vein confluence. This
      combined anomaly has not previously been reported except for one postmortem case.
      As abdominal aortic surgery is currently performed routinely, care must be taken
      to avoid injury to surrounding organs due to rare anatomic anomalies.

PMID- 10399218
TI  - Persistent sciatic artery: report of an original aneurysm-associated case.
AB  - Persistent sciatic artery (PSA) is a rare embryologic abnormality and can
      sometimes be bilateral. It may be discovered because of a gluteal aneurysm or
      ischemic or embolic complications in the lower limb. The case we report was a
      unilateral type III aneurysm-associated PSA. Since the abnormal artery may be the
      only source of blood supply to the lower limb, a thorough knowledge of the artery
      and its embryologic origins is essential.

PMID- 10399219
TI  - An unusual variation of the superficial ulnar artery.
AB  - Anomalous superficial ulnar arteries were found bilaterally during routine
      dissection of the upper limbs of a 60-year-old male cadaver. In the left arm, the
      superficial ulnar artery originated from the axillary artery. It crossed the
      median nerve anteriorly and ran anteromedial to this nerve and the brachial
      artery. The superficial ulnar artery was also rudimentary and gave rise to only a
      narrow muscular branch to the biceps brachii. In the hand, it anastomosed with
      the radial artery, completing the superficial palmar arch. The radial artery was
      larger than usual and the deep palmar arch was formed only by the radial artery.
      In the right arm, the superficial ulnar artery originated from the brachial
      artery at the level of the inter-epicondylar line. Additionally there were
      "inverse palmaris longus muscles" bilaterally. This was a rare case in which the
      superficially ulnar artery originated from a different source on each side
      accompanied by anomalies of the palmar arches on one side.

PMID- 10399220
TI  - [Glucocorticoids: 50 years of their use in rheumatology].

PMID- 10399221
TI  - [The prevalence of rheumatoid arthritis and the rheumatoid factor in the native
      inhabitants of northeastern Siberia].
AB  - AIM: The study of rheumatoid arthritis (RA) and rheumatoid factor (RF) prevalence
      among residents of eastern Chukotka--Eskimos and Chukchi. MATERIALS AND METHODS:
      Simultaneous total survey covered 974 of 1176(83.3%) residents of 4 villages in
      the eastern Chukotka. RESULTS: RA was diagnosed in 7(0.7%) examines. Clinical
      picture of the disease was characterized by for the most part symmetric affection
      of hand and feet joints, absence of systemic manifestations, favourable course
      and frequent absence of RF. RF positive titers (1:160 and higher) occurred in 23
      of 804 examinees (2.9%), among Eskimos--6%. This was significantly higher than in
      Chukchi (2.0%) and in subjects of mixed nationality (1.3%). CONCLUSION:
      Prevalence and clinical picture of RA in residents of northeast Siberia were
      comparable with such observed in other epidemiological surveys in Russia and
      Alaska.

PMID- 10399222
TI  - [The characteristics of the distribution of painfulness and erosive lesions of
      the small joints in rheumatoid arthritis].
AB  - AIM: Identification of all small joints the affection of which is interrelated
      and the study of such joints grouping in polyarthritis clinical picture variants.
      MATERIALS AND METHODS: Upon examination of 102 patients with rheumatoid arthritis
      (RA) we assessed articular pain, erosion of bones in small joints by x-ray
      picture of the feet and hands, estimated correlations between the pain and
      erosion in each joint and compared distribution of small joint erosions with
      distribution of pain in these joints. RESULTS: The groups of small joints of the
      bones and feet have been compiled in which RA pain or erosions were independent
      of the condition of the joints from the other groups. CONCLUSION: RA patients'
      distribution by joint lesions reflects latent mechanisms of RA development
      operating separately within various groups of small joints.

PMID- 10399224
TI  - [Changes in the acid-base status of the synovial fluid in rheumatoid arthritis
      patients].
AB  - AIM: The study of changes in joint fluid (JF) acid-base balance in RA patients to
      evaluate severity of joint lesions, efficacy of on-going therapy and to predict
      appearance and persistence of RA remission. MATERIALS AND METHODS: A routine
      examination and measurements of JF pH of the affected joints and venous blood
      before and during the treatment were performed in 65 RA patients with articular
      or articular-visceral forms (46 and 19 patients, respectively). 19 patients were
      seropositive and 20 seronegative by rheumatoid factor. A group of 17 patients
      suffering from osteoarthritis deformans with synovitis served control. RESULTS:
      Inflammation in RA is running with lowering of JF pH in the affected joints and
      with acidic shift in the acid-base balance manifesting as compensated metabolic
      acidosis in blood. JF pH of the affected joints inversely correlated with
      activity of the inflammation. Its changes were more pronounced in RA systemic
      lesions and in the seropositive variant. CONCLUSION: JF pH may be used for
      assessment of inflammation activity in RA.

PMID- 10399223
TI  - [Soluble adhesion molecules (P-selectin, ICAM-1 and ICAM-3) in rheumatoid
      arthritis].
AB  - AIM: Investigation of serum levels and clinical role of soluble intercellular
      molecules of adhesion (pICAM-1, PICAM-3 and pP-selectin) in rheumatoid arthritis
      (RA). MATERIALS AND METHODS: Enzyme immunoassay with Bender MedSystem kits
      (Austria) was employed to measure serum concentration of soluble intercellular
      molecules of adhesion in 36 RA patients. RESULTS: Elevated levels of serum pICAM
      1, pICAM-3 and pP-selectin were registered in 74.2, 28.6 and 25.7% of RA
      patients, respectively. Content of pP-selectin more strongly correlated with
      activity and severity indices than that of pICAM-3 (p < 0.001). Content of pICAM
      1 and clinical picture of RA were unrelated. CONCLUSION: Levels of pP-selectine
      can characterize RA activity.

PMID- 10399225
TI  - [The joint use of hemosorption and plasmapheresis in the combined treatment of
      rheumatoid arthritis patients].
AB  - AIM: Assessment of hemopheresis effects on calcium-regulating and immune systems,
      clinical and laboratory activity of rheumatoid arthritis (RA). MATERIALS AND
      METHODS: Hemosorption and plasmapheresis were included in combined treatment of
      86 RA patients. Plasmapheresis was performed 3-5 days after hemosorption (a total
      of 4-6 procedures per course). The activity of RA, immune and calcium-regulating
      system were assessed clinically, with laboratory tests, enzyme immunoassay.
      RESULTS: Hemosorption plus plasmapheresis produced positive effects on the
      disease course, activity. Laboratory indices improved. Percentage of T-helpers
      and T-suppressors, calcitonin loading rate, levels of parathormone, calcidiol
      normalized. CONCLUSION: Combined hemopheresis therapy promotes correction of
      disorders in immune and calcium-regulating systems.

PMID- 10399226
TI  - [Sandimmun-Neoral--a new quality of life for patients with severe systemic
      juvenile rheumatoid arthritis].
AB  - AIM: To develop an effective and safe therapeutic policy for Sandimmun-Neoral in
      order to prevent joint destruction, invalidation, achieve higher life quality in
      patients with systemic juvenile rheumatoid arthritis (SJRA). MATERIALS AND
      METHODS: The trial included 26 patients with SJRA aged 4-15 years. 12 of them had
      early SJRA, 14--late SJRA. 13 patients received Neoral for one year and the other
      13 for 2-3.5 years. Markers of aggressive SJRA course in the debut were
      registered in all the patients. Previous treatment incorporated nonsteroid
      antiinflammatory drugs, intraarticular corticosteroids (all the patients),
      prednisolone (19 patients), methotrexate (3 patients). Before Neoral treatment
      80% of the patients had structural alterations in the joints, signs of
      invalidation, low quality of life. SJRA activity was defined as the 3d degree.
      All the patients suffered from obesity, hypertrichosis, steroid spondylopathy,
      nanism. RESULTS: Neoral recovered joint motility in 30% of patients, 60% were
      capable for self-service. Quality of life was assess as high in 80%, moderately
      reduced--in 20%. 35% of the patients achieved clinico-laboratory remission. The
      disease activity dropped to degree I-II in 65% of patients. Structural changes in
      the joints stopped progressing in 77%, regress of the anatomic stage was seen in
      20% of patients. Prednisolone was discontinued in 7 and dose-reduced in 6
      patients. Exogenic hypercorticism relieved and growth resumed in all the
      patients. Neoral proved effective both in early and late SJRA, inhibited
      destruction both in patients in remission and in active disease. Side effects
      were: hypertrichosis in 13 patients, moderate blood hypertension in 1 case.
      CONCLUSION: Neoral can control the disease. It is indicated both in early and
      late SJRA in the presence of aggressive course markers, acute coxitis with
      aseptic necrosis of the head of the femur or free of it. Neoral treatment should
      be started as early as on the first year of the disease, before the structural
      changes in the joints. For safe long-term therapy it is valid to give cyclosporin
      A in monotherapy or in combination with voltaren in minimal doses.
      Corticosteroids are used on demand. The preference should be given to
      intraarticular or intravenous prolonged drugs but not oral prednisolone which may
      course such severe complications as obesity, hypertension, nanism.

PMID- 10399227
TI  - [The classical and alternative pathways of T-lymphocyte activation in patients
      with systemic lupus erythematosus].
AB  - AIM: To study activation of T-lymphocytes by the CD3 (antigen-dependent) and CD2
      (non-antigen-dependent) routes in patients with systemic lupus erythematosus
      (SLE). MATERIALS AND METHODS: Peripheral blood mononuclears were studied in 66
      patients with SLE and 27 donors. Proliferative response to activation by anti
      CD3, anti-CD3+ phorbol-12-myristate-13-acetate (PMA), phytohemagglutinin (PHA),
      and autologous erythrocytes in combinations with PMA and recombinant interleukin
      2 (rIL-2) was assessed. RESULTS: T-cell proliferation was at least two times
      increased under the effect of CD3 in 40.9% patients and in 100% normal subjects.
      Stimulation with CD3 antibodies in combination with PMA leveled the differences
      due to boosting of T-cell response in SLE patients. PMA alone caused mononuclear
      proliferation in 25% patients with SLE but not in normal subjects. Decreased
      response of T-cells to adhesive stimulus (autologous erythrocytes + PMA) in SLE
      patients was leveled by rIL-2. CONCLUSION: The proliferative response of T
      lymphocytes is decreased upon stimulation with CD3 and CD2 and in some patients
      increased by PMA in submitogenic doses, added alone or in combination with anti
      CD3.

PMID- 10399228
TI  - [The lipid-protein indices of the blood cholesterol transport system in systemic
      lupus erythematosus].
AB  - AIM: To assess parameters of blood cholesterol lipid-protein spectrum and
      characteristics of blood cholesterol (C) transport system in patients with
      systemic lupus erythematosus (SLE). MATERIALS AND METHODS: Lipid-protein blood
      spectrum was studied in 60 patients (45 females and 15 males) with verified SLE
      aged 15-44 years (mean age 28.9 +/- 8.1 years). The duration of the disease
      varied from 2 months to 28 years (mean 8.6 +/- 6.6 years). SLE course and
      activity were defined according to V. A. Nasonova's classification. The control
      patients (35 healthy subjects) were matched by age (30.0 +/- 6.1 years) and
      gender (27 females and 8 males). RESULTS: Elevated levels of C and C of low
      density lipoproteins (LDLP), triglycerides (TG) were found in 35% and 30% of
      patients, respectively. C of high-density lipoproteins (HDLP) was low in 32% of
      patients. HDLP phospholipids were also subnormal, their proportion changed:
      concentrations of phosphatidylcholine were low, those of lisophosphatidylcholine,
      sphingomyelin, diethanolamine, cardiolipin were higher than in the controls. TG
      and proportion apo/B/AI were higher, content of HDLP components low in patients
      with the disease duration up to 5 years. Patients with highly and moderately
      active SLE had high levels of TG, apo/B, apo/B/apo/AI, low levels of HDLP C,
      apo/AI and HDLP phospholipids. CONCLUSION: Marked dyslipidemias were detected in
      1/3 of SLE patients. Cholesterol transport changes arise at early SLE stages.
      Alterations in the blood lipid-protein spectrum appeared more pronounced and
      atherogenic in maximal SLE activity. Quantitative and qualitative shifts in HDLP
      composition induce changes in antiatherogenic properties of relevant lipoproteins
      in SLE patients.

PMID- 10399229
TI  - [The evaluation of hemostatic disorders in patients with systemic lupus
      erythematosus].
AB  - AIM: Assessment of hemostasis in SLE patients. MATERIALS AND METHODS: We studied
      different coagulation parameters such as activated partial thromboplastin time
      (APTT), thrombin time (TT), prothrombin time (PT), activated clotting time (ACT);
      platelet aggregation (spontaneous and induced), fibrinolytic activity,
      concentration of fibrinogen, fibrinogen degradation products (FDP) and serotonin.
      RESULTS: Coagulation abnormalities were found with prevalence of hypercoagulation
      in APTT and TT tests. Fibrinolysis was inhibited. Levels of serotonin, FDP and
      spontaneous aggregation activity significantly increased. CONCLUSION: The above
      changes were typical for lingering DIC syndrome.

PMID- 10399230
TI  - [The use of Vasaprostan in patients with systemic lupus erythematosus and the
      antiphospholipid syndrome].

PMID- 10399231
TI  - [The relation between the level of antibodies to the glycosaminoglycans of the
      cartilage in patients with osteoarthritis and the efficacy of treatment with
      chondroprotectors].
AB  - AIM: To improve the efficacy of osteoarthrosis (AO) treatment by
      chondroprotectors by defining individual indications for their use, based on the
      initial level of antibodies to cartilaginous glycosaminoglycans (GAG) in the
      blood serum. MATERIALS AND METHODS: Anti-GAG were detected by indirect solid
      phase enzyme immunoassay. The antigen was a sulfated GAG preparation GAG
      polysulfate (arteparon) manufactured by Luitpold-Werk (Germany). Sera of 110 OA
      patients were tested. Fifty of them were treated by rumalon, 20 with arteparon,
      and protocols of 40 patients included no chondroprotectors. RESULTS: The highest
      levels of anti-GAG were found in OA patients with multiple involvement of the
      joints, rapidly progressing disease, and secondary synovitis. The titer of
      antibodies increases with disease duration and in patients with the
      roentgenological stage of OA, reaching the maximum by 10-15 years of disease or
      by stage III. Efficacy of chondroprotectors was lower at lower levels of
      antibodies to cartilaginous GAG. CONCLUSION: Chondroprotector therapy of patients
      with initially high levels of antibodies to GAG is unadvisable, for it can lead
      to exacerbations, specifically, to secondary synovitis.

PMID- 10399232
TI  - [Structum (chondroitin sulfate)--a new agent for the treatment of
      osteoarthrosis].
AB  - AIM: To study efficiency and tolerance of Structum in gonarthrosis patients as
      well as duration of its effect after discontinuation. MATERIALS AND METHODS: 100
      patients with femorotibial gonarthrosis aged 45 years and older entered an open
      randomised trial. They had knee joint arthrosis satisfying diagnostic criteria OA
      ACR at stage II-III according to Kellgren-Lawrence with pain syndrome. Walking
      pain intensity was > or = 30 mm by the visual analogue scale (VAS), Leken total
      functional index > or = 4 and < or = 11. Antiinflammatory drugs (AI) were
      regularly taken for 30 days for the 3 pretreatment months. 50 patients of the
      study group received Structum and ibuprofen (1200 mg/day) for 6 months. 50
      patients of the control group received ibuprofen only. The two groups were
      followed up for 3 months. Clinical examination was made monthly. RESULTS: There
      were significant differences between the groups by the Leken's index (p < 0.005),
      VAS, pain, daily AI drug requirement. Structum proved more effective. Tolerance
      was good. Side effects were observed only in two patients (diarrhea and nausea).
      In the control group, side effects made 15 patients to discontinue the treatment.
      CONCLUSION: Structum is a new effective drug against gonarthrosis which reduces
      pain, improves joint function. It is well tolerated and allows to diminish the
      dose of AI drugs. The response to Structum persisted for 3 months after the
      treatment.

PMID- 10399233
TI  - [The role of an imbalance of sex and calcium-regulating hormones in
      osteoarthrosis deformans in women].
AB  - AIM: Determination of essential changes in hormonal background in evaluation of
      sex and calcium-regulating hormones levels in women of different age with
      osteoarthrosis deformans (OAD). MATERIALS AND METHODS: 30-34-year-old and 45-60
      year-old females (60 premenopausal and 51 menopausal) with x-ray confirmed OAD
      and 34 control healthy women (23 premenopausal and 11 in menopause) were examined
      with radioimmunoassay for the baseline serum levels of calcitonin, parathyrine,
      osteocalcin, estradiol, testosterone, progesterone, dehydroepiandrosterone
      sulfate (DHAS). RESULTS: Both age-groups patients had abnormal levels of
      testosterone and its metabolite DHAS. Significant deviations were found in
      menopausal women. With age, both patients and healthy women exhibited increasing
      levels of parathyrine and calcitonine. Compared to controls, OAD women had lower
      parathyrine, osteocalcine and higher calcitonine levels. With OAD progression,
      serum osteocalcin tended to lowering while testosterone was on the increase.
      CONCLUSION: Changes in blood levels of calcium-regulating hormones observed in
      osteoarthrosis may result in stimulation of cartilage degeneration. Calcitonine
      was low in premenopausal and menopausal OAD patients indicating impairment of
      bone metabolism in osteoarthrosis.

PMID- 10399234
TI  - [The significance of determining antibodies to viruses of the Herpesviridae
      family in rheumatic diseases].
AB  - AIM: Assay of antibodies to cytomegalovirus (CMV), herpes simplex virus type 1
      and 2 (HSV-1 and HSV-2) and Epstein-Barr virus (EBV) in rheumatic patients.
      Specification of their correlations with clinical symptoms. MATERIALS AND
      METHODS: 66 rheumatic patients were examined for the above antibodies. The
      admission diagnosis of rheumatic disease (RD) was confirmed in 42 of them. 24
      were diagnosed to have active or chronic viral infection (A/CVI) simulating
      systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and other RD.
      RESULTS: IgG-antibodies to CMV and VCA-IgG to EBV were detected in 79 and 70.3%
      of the examinees, respectively. In SLE more frequent were IgM-antibodies to CMV
      (78.9%), in RA-IgM-antibodies to CMV (85.7%) and IgG-antibodies to EBV (85.7%)
      while in A/CVI--to CMV (IgM--86.4%), EBV (IgG--80%; IgM--73.7%), HSV-1 (IgM-
      57.1%). Analysis of clinical correlations indicated that high titers to CMV and
      to EBV are related in RD patients. CONCLUSION: It is necessary to examine
      rheumatic patients for antibodies to Herpesviridae viruses and prescribe
      antiviral drugs.

PMID- 10399235
TI  - [Comparative sonographic, x-ray and morphological studies of the salivary glands
      in Sjogren's syndrome].
AB  - AIM: To define diagnostic value of parotid gland (PG) sonography in Sjogren's
      syndrome (SS) as compared to sialography and morphological changes of labial
      salivary glands (LSG). MATERIALS AND METHODS: Examination of 50 females with
      primary (20 patients) and secondary (30 patients) SS consisted of clinical,
      ultrasonic, x-ray and morphological investigations. RESULTS: Sonographically, PG
      in SS is characterized by nonhomogeneity of parenchymal picture detected in 75%
      of patients with primary and 50% of patients with secondary SS. Moderate and
      severe nonhomogeneity of PG parenchyma was seen in the stage of marked
      manifestations of chronic parenchymatous parotitis. CONCLUSION: Relationship
      between PG sonographic image in SS and morphological changes in LSG need further
      study. PG sonography may help in combined examination of SS patients.

PMID- 10399236
TI  - [An analysis of the linkage of hypertrophic cardiomyopathy and the delta locus of
      the T-cell receptor (TCRD) chain in the family of P].
AB  - AIM: To estimate probability of location of the gene determining family
      hypertrophic cardiomyopathy (HCMP) in family P. on the 14th chromosome in segment
      14q11 using parametric method "lod score". MATERIALS AND METHODS: The family of
      proband P. had multiple cases of HCMP. Dinucleotide GT repeat and NT 256 point
      variation located in the cluster of genes coding synthesis of TCRD (14q11
      chromosome segment) were used as markers of HCMP gene (FHC-1 gene 14q1 chromosome
      segment). Allele polymorphism of the two markers was defined at polymerase chain
      reaction, restriction of the amplificate by restrictase BamHI (for NT 256 point
      variation) and vertical electrophoresis in polyacrylamide and agar gels. RESULTS:
      Basing on the distribution of the above markers in P. family, lod score estimates
      in all the standard values of recombination frequency were determined (0-0,45,
      step 0.05). The maximal estimate corresponded to zero recombination frequency and
      was equal to 1.17 (this was below the critical value 3). However, the obtained
      lod score value satisfied the chance ratio 15:1 in favor of the link presence.
      CONCLUSION: The data obtained evidence for the presence of the link of HCMP gene
      with marker locus TCRD which is nearby the identified locus of the disease (FHC-1
      14q11.2 segment). This suggests that HCMP in family P may be due to mutant allele
      of the gene coding synthesis of beta-polypeptide chains of cardial myosin.

PMID- 10399237
TI  - [N. S. Molchanov--clinician, pedagogue, scientist (on the centenary of his
      birth)].

PMID- 10399238
TI  - [A life dedicated to rheumatology (on the centenary of the birth of M. A.
      Iasinovskii)].

PMID- 10399240
TI  - [An integrated quality policy for and by (cattle) veterinarians: 2. A comparison
      with the quality policy of family physicians].
AB  - The core of the integrated quality control policy of Dutch general practitioners
      is the development of treatment guidelines. These guidelines are the basis for
      assessing interventions and for improving quality. General practitioners took the
      initiative to prepare these guidelines without there being external pressure on
      them to do so. The quality control policy strengthens the position of this
      professional group by diminishing differences in therapeutic approach. The
      procedures followed for establishing guidelines, such as those for human
      medicine, are described and may be of use to veterinarians.

PMID- 10399241
TI  - [Permission to use recombinant bovine somatotropin: considered once more].

PMID- 10399239
TI  - [An integrated quality policy for and by veterinarians: 1. Status of business].
AB  - Several initiatives are being developed by the livestock industry and
      veterinarians to improve quality. This article describes the term quality
      control. Although action has been taken to improve quality, at the moment there
      is no integrated policy of quality control for veterinarians. To date,
      initiatives have been limited to defining the preconditions for such policies and
      little has been done to establish the content of veterinary interventions.

PMID- 10399242
TI  - [Acute blindness as the consequence of trauma in a Welsh pony foal].

PMID- 10399243
TI  - Foot lesions in finishing pigs and their associations with the type of floor.
AB  - The associations between individual foot lesions and different types of floor
      were investigated in 4038 finishing pigs on 21 units. The overall prevalence of
      foot lesions was 93.8 per cent and the prevalence ranged from 79.4 per cent to
      100 per cent on different units. Analysis showed that pigs kept on bedded floors,
      with either sparse or deep straw, had a lower prevalence of sole erosions, heel
      erosions and heel flaps and a higher prevalence of white line lesions, false sand
      cracks, wall separations and toe erosions than pigs kept on bare solid concrete
      floors. Partially slatted floors were associated with an increased prevalence of
      heel erosions, heel flaps, white line lesions, wall separations and false sand
      cracks, and totally slatted floors were associated with an increased prevalence
      of sole erosions and heel flaps.

PMID- 10399244
TI  - Prevalence of haematozoa in birds of prey in Catalonia, north-east Spain.
AB  - Blood samples from birds of prey, 95 Strigiformes and 190 Falconiformes, were
      examined for the presence of haematozoan parasites. The birds had been admitted
      to a raptor recovery centre in Catalonia, north-east Spain. Parasites were
      counted in positive smears. A second blood sample was obtained from 99 birds at
      least seven days after their arrival at the centre. Haematozoa were detected in
      all seven species of Strigiformes and in nine of 19 species of Falconiformes. The
      overall prevalences in the two groups were significantly different, 30.5 per cent
      and 46.3 per cent in the nocturnal and diurnal raptors, respectively. Eleven
      species of haematozoan parasites were identified. The genus most commonly
      detected in members of the nocturnal Strigiformes was Leucocytozoon, followed by
      Haemoproteus, Plasmodium and Trypanosoma. In the diurnal Falconiformes only
      Leucocytozoon and Haemoproteus were detected. The highest infection rates were
      found in Accipiter nisus (sparrow hawks), Accipiter gentilis (goshawks) and
      Athene noctua (little owls). Relapses were detected in 9 per cent of the birds
      sampled twice. The highest intensity of infection (6.2 per cent) was observed in
      a Buteo buteo (buzzard) infected with Haemoproteus.

PMID- 10399245
TI  - Characterisation of a potentially abortigenic strain of feline calicivirus
      isolated from a domestic cat.
AB  - Feline calicivirus (FCV) was isolated from one of four dead fetuses delivered by
      ovariohysterectomy from a queen with an acute FCV infection. The most prominent
      lesions in the fetuses were petechial haemorrhages in the skin. The virus
      isolated was characterised as FCV by antigenic analysis and cDNA sequence
      analysis. This is the second report of abortion associated with acute FCV
      infection.

PMID- 10399247
TI  - Persistence of foot blocks used in the treatment of lame cows.

PMID- 10399246
TI  - Abdominal distension in collapsed diarrhoeic calves: biochemical findings and
      treatment.
AB  - Thirty-seven of 53 diarrhoeic calves hospitalised for intravenous fluid therapy
      were classified as very severely acidotic (total carbon dioxide less than 8
      mmol/litre) by using a Harleco apparatus. All the calves were given intravenously
      10 to 20 litres of electrolyte solution which contained 144 mmol/litre sodium, 4
      mmol/litre potassium, 113 mmol/litre chloride and 35 mmol/litre bicarbonate, and
      in addition the 37 very severely acidotic calves received 400 ml of 1M sodium
      bicarbonate in the first 5 litres of fluid administered. Sixteen of the 37 very
      severely acidotic calves had a distended right flank, suggesting the presence of
      a dilated fluid-filled viscus. Neither their history nor other clinical signs
      were useful predictors of the distension. The distended calves had significantly
      higher plasma concentrations of sodium and chloride, and significantly lower
      plasma creatinine concentrations than the calves which were not distended.
      Treatment was successful in all the 21 non-distended calves but four of the
      distended calves died despite treatment. The resolution of the distension in the
      successfully treated calves, coincided with a significant increase in plasma
      bicarbonate concentration and the passage of large amounts of malodorous mucoid
      faeces.

PMID- 10399248
TI  - Pituitary function and morphology in two German shepherd dogs with congenital
      dwarfism.

PMID- 10399249
TI  - Analysis of faecal samples from wild animals for verocytotoxin producing
      Escherichia coli and E coli O157.

PMID- 10399250
TI  - Duration of activity of oral moxidectin against Haemonchus contortus,
      Teladorsagia circumcincta and Trichostrongylus colubriformis in goats.

PMID- 10399252
TI  - [The CLASSICS Study: Clopidogrel plus ASA vs. Ticlopidin plus ASA in stent
      patients].

PMID- 10399251
TI  - Silage clamp hazards.

PMID- 10399253
TI  - [In Process Citation]
AB  - OBJECTIVE: We examined the placental transfer of the calcium antagonists
      Flunarizine and Verapamil and their effects on the placental metabolism using the
      dual in vitro perfusion of the human placental lobulus. MATERIAL AND METHODS:
      Eight placental lobuli were perfused with either 10 micrograms/ml Flunarizine or
      Verapamil over 6 hours. Two perfusions without any substrate were used as
      control. RESULTS: The transfer of the control substances antipyrin and kreatinin
      was not affected by the perfusion with the calcium antagonists. Flunarizine and
      Verapamil crossed quickly the placental wall, but most of them were accumulated
      in the perfused placental tissue. Verapamil had a greater placental transfer than
      Flunarizine. The placental glucose consumption as well as the lactate production
      were not changed by both of the calcium antagonists. Flunarizine and Verapamil
      stimulated the placental beta HCG synthesis into the maternal circulation.

PMID- 10399254
TI  - [In Process Citation]
AB  - OBJECTIVE: The objective of the study was to analyse the prognostic impact of
      several criteria for median survival and recurrence free interval in patients
      with uterine sarcomas. Factors included to our analysis were the staging
      according to FIGO, DNA content (ploidy), mitotic index, histology, the kind of
      primary therapy, grading and menopausal status. MATERIAL AND METHODS:
      Retrospectively, clinical data of 78 patients (41 leimyosarcomas, 23
      carcinosarcomas = homologous malignant mixed Mullerian tumors, 14 endometrial
      stromal sarcomas--10 low grade, 4 high grade) were analysed. Additionally, in 36
      of the cases mitoses were counted. Furthermore, DNA ploidy was determined using
      image cytometry on paraffine sections stained according to the Feulgen method.
      Receptor status was determined using immunohistochemical staining. Two and five
      year survival rates were 22% and 15%. There were 21 cases with local relapse and
      27 cases with metastasis. RESULTS: The staging according to FIGO was the main
      prognostic factor, significantly influencing median survival time (p = 0.001) as
      well as the recurrence free interval (p = 0.03). There was a significant
      difference between median survival time compared to mitotic index (p = 0.014) and
      DNA ploidy (p = 0.02). A mitotic index < 10/10 HPF and diploidy were related with
      a better prognosis. Receptor status did not have an impact on median survival
      time. CONCLUSIONS: As our results suggest, DNA ploidy and mitotic index are
      likely to provide additional information for prognosis in patients with uterine
      sarcomas and could be used as criteria for selecting patients for adjuvant
      therapy.

PMID- 10399255
TI  - [In Process Citation]
AB  - OBJECTIVE: The purpose of this study was to evaluate the effects of opioid
      addiction on pregnancy, perinatal period, and the long-term development of mother
      and child. MATERIAL AND METHODS: Records of 44 opioid-dependent women and their
      children were analyzed. Thirty-three patients were enrolled in methadone
      maintenance treatment (MMT) programs or received codeine. RESULTS: Problems
      during pregnancy were premature rupture of membranes (n = 8), premature labor (n
      = 21), premature delivery (n = 9), abruption placentae (n = 2), cesarean section
      (n = 10), and fetal growth retardation (n = 15). Whereas MMT improved fetal
      growth, no influence was seen on other problems during pregnancy. Thirty newborns
      had significant withdrawal symptoms. One child became HIV-positive and two
      children required treatment for suspected congenital syphilis. One child died of
      sudden infant death syndrome. CONCLUSIONS: The major goal has to be the avoidance
      of an unwanted pregnancy. Does it still happen, the patient needs special
      support. If an opioid-dependent woman presents herself the first time, an
      anamnesis concerning drugs in addition to a general anamnesis should be arisen.

PMID- 10399256
TI  - [In Process Citation]
AB  - This paper was intended to settle the question whether the so-called gentle
      sectio caesarea with a high skin incision as described by Cohen in 1972 [2] could
      be applied in combination with a sectio on the level of the classic
      Pfannenstiel's incision which would be more satisfying cosmetically. Furthermore
      a comparison was to be drawn between the postoperative condition of those
      patients on whom this surgical method had been performed and the condition
      following a classic Pfannenstiel's incision. Between January 1997 and July 1997
      we compared the classic method of Pfannenstiel's incision with the variant of
      Cohen's method as described above in a prospective randomised study. On applying
      this surgical technique, the abdomen was opened according to Cohen's method using
      a surgical knife but for the skin, and the tissue layers underneath were opened
      blunt with two fingers. Following the extraction of the child only three sutures
      were made: Uterus, fascia and skin. Redon drainages were not inserted. We were
      able to show that this method of applying mainly blunt "incision" to sectio
      caesarea the tissue is at least equal to the sharp opening of the abdominal
      cavity. In some respects, such as the early postoperative mobilisation, it is, in
      fact, superior, because the blunt opening causes less bleeding and the reduction
      to three sutures only, deliberately leaving the two peritoneal membranes open, as
      well as leaving away the redon drainages, considerably increases the patients'
      postoperative well-being. It is for these reasons that we call for this method to
      become part of the routine procedures in caesarean sectio.

PMID- 10399257
TI  - [In Process Citation]
AB  - OBJECTIVE: The objective of this retrospective analysis was to compare the
      obstetrical procedures at premature birth and delivery at term. The aim was to
      show the influence of gestational time on mode of delivery and neonatal state.
      MATERIAL AND METHODS: 339 births from breech presentation between 1988-1990 were
      compared with premature births and deliveries at term. RESULTS: Frequency of
      breech presentation totalled 4.1%. 173 deliveries (51.7%) resulted vaginally, 26
      cases (7.8%) with freeing of arms and 4 cases (1.2%) as extraction. Frequency of
      cesarean sections totalled 48.3%. The number of premature births reached in the
      group of breech presentation 23.1%. Births at term resulted with 58%
      predominantly vaginally (abdominally in 42%). Between the 31st and 36th
      gestational week the number of cesarean sections rose to 67.3%, in the 31st week
      it even reached 78.9%. The neonatal state was described with the help of Apgar
      scores and umbilical cord-pH-values. The share of newborns with optimal Apgar
      values after 1 minute (8-10) was in premature births with 36.5% only about half
      as large as in deliveries at term (77.6%). Only 9.6% of the children showed pH
      values below 7.20. Number of newborns with these pH-values totalled in premature
      births in the 31st week 35.3%, for terms between the 31st and 36th week 15.6%,
      and declined in mature births to only 6.2%. CONCLUSIONS: Estimating the neonatal
      state of the group of breech presentations the vaginal birth should keep an equal
      rank in the delivery plan of a clinic. At the appraisal of the childlike early
      morbidity of a delivery group the number of premature newborns is decisive.

PMID- 10399258
TI  - [In Process Citation]
AB  - Few cases of surgical scar endometriosis have been reported yet, which may occur
      following episiotomies and caesarean sections. The classic presentation is that
      of a tender mass becoming symptomatic with menstruation. Patients are complaining
      of cyclic pain and pre-menstrual swelling. In our case, a 34-year-old gravida
      III/-para II with osteogenesis imperfecta presented herself with a non
      symptomatic scar endometrioma following a caesarean section 4 years previously.
      The diagnosis based on an incidental finding after scar removal during the
      subsequent caesarean section. As known so far, surgical intervention is the
      method of choice if singular endometriosis lesions occur.

PMID- 10399260
TI  - [In Process Citation]

PMID- 10399259
TI  - Giant mucinous malignant ovarian tumor
AB  - A case of a 76-year-old woman with a giant malignant mucinous tumor of the right
      ovary, weighting 35 kg (FIGO III C), is presented. Surgical procedure was
      successfully performed, but the patient died on day 10 postoperatively with a
      picture of cardiorespiratory insufficiency.

PMID- 10399261
TI  - [In Process Citation]
AB  - OBJECTIVE: Endometriosis is one of the most common benign gynaecological
      diseases. Its aetiology is uncertain and there are many unanswered questions
      about its pathogenesis and treatment. MATERIAL AND METHODS: Medline search of
      relevant publications. RESULTS: Particularly the early stages of endometriosis,
      usually located in the peritoneum, are metabolically highly active and, even from
      the start, set in motion a vicious circle of progressive organ destruction,
      adhesions and inflammatory processes. This can lead to chronic cyclic or acyclic
      pains and/or sterility. Invasiveness and potential for progression are based on
      the secretion of prostaglandin derivatives and numerous cytokines which, together
      with the gradual failure of immune resistance and the local hormonal environment,
      usually dominated by oestrogen, are responsible for the progressive nature of
      around 50% of endometriosis cases. The estimated incidence of active, progressive
      endometriosis is 21,000 new cases per year in Germany, placing it on a par with
      prostate cancer. Subtle microscopic and morphological grading of the activity of
      the lesions is crucial to the choice of treatment. Early results of clinical
      trials indicate that the highest pregnancy rates and the lowest recurrence rates
      at follow-up can be achieved with individualised hormonal and surgical treatment
      of active endometriosis, even for mild or minimal endometriosis, in comparison
      with the laparoscopic removal of lesions alone. CONCLUSIONS: The combined use of
      hormonal and surgical treatment could become the new gold standard for treating
      active endometriosis.

PMID- 10399262
TI  - [In Process Citation]
AB  - Since February 1997 the Departments of Dentistry and Oral & Maxillofacial Surgery
      of the University of Munster, Germany, can be visited on the Internet on more
      than 1400 HTML pages. These Web pages have been organized using an especially
      designed database which ensures standardized layout of the presented information
      and systematic navigation. A various amount of the Web pages are created fully
      automatically from a database (e.g. lectures, list of resources (URLs)); manually
      created pages are automatically adjusted concerning layout, integrated in the
      overall structure and given uniform navigation elements. Among other things, the
      database generates an interactive Web-site index (like a tree view), which
      facilitates search.

PMID- 10399263
TI  - Clinical utility of magnetic resonance angiography in the evaluation of aneurysms
      from a neurosurgical point of view.
AB  - The possibilities and limitations of MRA in the evaluation of intracranial
      aneurysms were investigated in this study. 54 patients, 30 with acute SAH were
      diagnosed using the three dimensional time-of-flight MRA in comparison with a
      conventional four vessel digital subtraction angiography prior to surgery.
      Furthermore, postoperative MRA was performed to assess clip placement and vessel
      patency and to search for innocent additional aneurysms in patients with
      emergency surgery due to intracerebral hemorrhage causing mass effect in whom
      preoperatively only the side of the lesion was investigated in DSA. 64 aneurysms
      in all vessel territories were detected. Three aneurysms were missed in MRA and
      there were three false positive results. Four baby-aneurysms were missed by both
      imaging modalities and were found during surgery. In all patients with CT scans
      suspicious of aneurysms MRA was able to detect or rule out the aneurysm.
      Postoperative MRA to demonstrate clip placement and vessel patency was not
      possible due to susceptibility artefacts. MRA should be the diagnostic procedure
      of first choice in CT findings suspicious of aneurysms. The follow-up of
      confirmed aneurysms is safely possible. MRA is very well applicable in the acute
      setting after SAH. The axial acquisition films and the rotatable maximum
      intensity projection reconstructions provide useful insights into the location of
      the aneurysm and its neighboring structures thus influencing the preoperative
      planning of surgical strategies. Keeping the limitations in mind it is a safe
      tool in the evaluation of aneurysms, especially with the rapidly improving
      postoprocessing possibilities.

PMID- 10399264
TI  - Suboccipital decompressive surgery in cerebellar infarction.
AB  - In a retrospective study 100 consecutive patients with cerebellar apoplexy were
      evaluated with regard to presenting symptoms, diagnostic and therapeutic
      strategies according to changes in the clinical condition of the patients. The
      results of decompressive suboccipital craniectomy in patients with a cerebellar
      infarction is also evaluated in this retrospective study as the valency from use
      the Glasgow-Coma-Score as prognostical factor and monitoring instrument in
      patients with a cerebellar stroke. Different therapeutic modalities were
      critically analyzed. Outcome was sgnificantly influenced by age (p = 0.003),
      localisation and size of the lesion (p = 0.004), space-occupying character on
      computed tomography (p < 0.001), the progressive appearance of brainstem
      dysfunction and reduction of the level of consciousness as measured with the
      Glasgow Coma Scale (p < 0.001). We were able to show that the GCS is a valid
      instrument for the evaluation of the clinical course of patients with cerebellar
      stroke since a statistically significant relationship exists between the GCS
      prior to surgical intervention and outcome. In patient with a GCS < 12 a
      reduction of mortality by 15% was obtained by surgical intervention and the
      outcome as measured by the GOS was significantly improved.

PMID- 10399265
TI  - [Motor evoked potentials during embolization of arteriovenous malformations for
      the detection of ischemic complications].
AB  - Motor evoked potentials (MEP) recorded from the distal extremity muscles in
      response to transcranial magnetoelectrical stimulation were analyzed in a total
      of 10 patients during embolization of arteriovenous malformations (AVM) localized
      in frontal and parietal lobe (N = 5), in the temporal lobe (N = 2), in the the
      brain stem (N = 1), in the medulla oblongata (N = 1), and in the cerebellum (N =
      1). The objective of this study was to clarify whether MEP allow reliable
      detection of ischemic complications during these procedures. Stable potentials as
      observed in 8 of 10 patients coincided in every case with an uneventful
      neurological outcome. Temporary significant prolongation of the central motor
      conduction time (CMCT) was observed in 2 patients. Both patients demonstrated a
      transient hemiparesis after the procedure, probably caused by ischemia. Our
      results clearly indicate that MEP are able to detect ischemic events during
      embolization of AVMs. Therefore, the use of MEP as a monitor of pyramidal
      function during endovascular therapeutic procedures seems to be promising.

PMID- 10399266
TI  - [De novo formation of a cavernoma in association with a preformed venous
      malformation during immunosuppressive treatment].
AB  - We report the clinical course of a 48 year old woman, who underwent a cranial MRI
      examination in 1995, which confirmed the diagnosis of encephalomyelitis
      disseminata, but also showed a left temporal venous malformation without evidence
      of prior hemorrhage. Three month after immunosuppressive treatment with
      Methotrexate in 1997 begun, first hemorrhage in the left temporal lobe occurred
      with de novo formation of a cavernoma in association to the known venous
      malformation. The lesion was totally removed after stereotactic guided craniotomy
      without any complication. The pathogenetic relationship of de novo cavernomas and
      associated venous malformations and the remarkable association with
      immunosuppressive treatment will be discussed.

PMID- 10399267
TI  - Extradural spinal hemangioblastomas: report of two cases.
AB  - Two cases of predominantly extraspinally extra- and intradural spinal cord
      hemangioblastomas in two patients each with and without von Hippel-Lindau-disease
      are reported. Preoperative MRI and angiographic findings are presented and the
      differential diagnosis is discussed. The surgical procedure is described and the
      literature of hemangioblastomas in this rare localization is reviewed.
      Improvements in both radiologic diagnosis and microsurgical techniques, and
      consequent screening programs will enhance life expectancy in patients afflicted
      with von Hippel-Lindau disease.

PMID- 10399268
TI  - [Acute symptom transverse laminectomy for a benign osteoclastoma of thethoracic
      spine--case report and review of the literature].
AB  - Benign osteoclastomas of the spine above the sacrum are uncommon lesions. Acute
      paraparesis as the presenting sign of disease is unusual and rarely described in
      the literature. We report on the case of a 41 yrs old male who underwent acute T3
      5 laminectomy for spinal cord decompression from a T4 expansive mass lesion with
      locally destructive growth. Although a malignant lesion was suspected, definitive
      histologic examination disclosed a benign osteoclastoma. Therefore, elective
      trans-thoracic total vertebrectomy T4 with ventral stabilization was performed to
      allow for marginal total resection of the tumor and reconstruction of the spine.
      Twenty-four months after the procedure the patient has made a good neurologic
      recovery with no evidence of tumor recurrence.

PMID- 10399269
TI  - Environmentally friendly lubricating oil candidate.
AB  - Synthetic lubricating oils based on renewable sources, excluding petroleum, have
      a great importance among all of the lubricating oil alternatives that are
      included in the research field about clean and environmentally friendly
      lubricating oil technologies. One of the environmentally friendly lubricating
      oils is a vegetable oil-based product. In this study, the esterification product
      of oleic acid with a fraction of molasses fusel oil as a lubricating oil
      candidate was determined according to the American Society for Testing and
      Materials (ASTM) standard tests. The results indicate that the ester product can
      be used as an environmental friendly lubricating oil or lubricating oil additive.

PMID- 10399272
TI  - Site-directed mutagenesis study on the thermal stability of a chimeric PQQ
      glucose dehydrogenase and its structural interpretation.
AB  - We have previously reported that a chimeric pyrroloquinoline quinone (PQQ)
      glucose dehydrogenase (GDH), E97A3, which was made up of 97% of Escherichia coli
      PQQGDH sequence and 3% of Acinetobacter calcoaceticus PQQGDH, showed increased
      thermal stability compared with both parental enzymes. Site-directed mutagenesis
      studies were carried out in order to investigate the role of amino-acid
      substitution at the C-terminal region, Ser771, of a chimeric PQQGDHs on their
      thermal stability. A series of Ser771 substitutions of a chimeric PQQGDH, E99A1,
      confirmed that hydrophobic interaction governs the thermal stability of the
      chimeric enzymes. Comparison of the thermal denaturation of E. coli PQQGDH and
      E97A3 followed by far-ultraviolet (UV) circular dichroism (CD) spectroscopy
      revealed that E97A3 acquired stability at the first step of denaturation, which
      is reversible, and where no significant secondary structure change was observed.
      These results suggested that the interaction between C-terminal and N-terminal
      regions may play a crucial role in maintaining the overall structure of beta
      propeller proteins.

PMID- 10399274
TI  - A high-copy-number plasmid capable of replication in thermophilic cyanobacteria.
AB  - A 2.5 kb high-copy-number plasmid, pMA4 in thermophilic cyanobacterium
      Synechococcus sp. MA4 was isolated and characterized to develop a genetic
      engineering system for thermophilic cyanobacteria. The copy number of pMA4 was
      determined to be by densitometry about 350/cell. The pMA4 may be a type of
      rolling-circle plasmid, because a possible rep gene encoding 34 kD-protein and a
      consensus sequence of a double-stranded origin nick site of rolling circle
      plasmids were found in the pMA4 sequence. The pMA4 was electro-introduced into
      another thermophile, Synechococcus sp. MA19, which is the strongest poly-beta
      hydroxybutyrate (PHB) accumulator in photoautotrophic organisms. The pMA4 was
      incorporated and retained in MA19. These results indicate that pMA4 could be
      developed as a useful vector for thermophilic cyanobacteria.

PMID- 10399275
TI  - L-asparaginase II of saccharomyces cerevisiae. Activity profile during growth
      using an ure2 mutant P40-3C and a P40-3C + URE2p strain.
AB  - The activity profile of the periplasmic asparaginase of Saccharomyces cerevisiae
      was determined during cell growth in an ure2 mutant; in an ure2 transformed with
      a plasmid containing the gene URE2 and, for comparison, in the strain D273-10B.
      Cells were cultivated in media presenting variable quantitative and qualitative
      nitrogen availability and the enzyme activity was evaluated in fresh and in
      nitrogen-starved cells. Nitrogen affected the asparaginase II level in fresh and
      starved cells of all strains. In the best condition, enzyme was produced by the
      wild-type cells at the late log-phase in the glucose/ammonium medium with a
      carbon to nitrogen ratio 4.3:1. Upon starvation, the activity doubled. The
      overall profile of the transformed strain was similar to that of the wild-type
      strain. In the ure2 mutant, high-enzyme levels were observed during growth, as
      expected. However the activity level, upon starvation, in proline grown cells,
      increased sixfold, suggesting that in addition to the Ure2p-Gln3p system, another
      system regulates asparaginase II biosynthesis.

PMID- 10399279
TI  - Bioconversion of secondary fiber fines to ethanol using counter-current enzymatic
      saccharification and co-fermentation.
AB  - This research examined several enzymatic and microbial process for the conversion
      of waste cellulosic fibers into ethanol. The first was a one-stage process in
      which pulp fines were contacted with commercial enzyme solutions. The second
      process used sequential, multistage saccharification. The third used sequential
      enzyme addition in a countercurrent mode. Experiments compared the results with
      various feedstocks, different commercial enzymes, supplementation with beta
      glucosidase, and saccharification combined with fermentation. The highest
      saccharification (65%) from a 4% consistency pulp and the highest sugar
      concentration (5.4%) from an 8% consistency pulp were attained when 5 FPU/g plus
      10 IU/g of beta-glucosidase were used. Sequential addition of enzyme to the pulp
      in small aliquots produced a higher overall sugar yield/U enzyme than the
      addition of the same total amount of enzyme in a single dose. In the
      saccharification and fermentation experiments, we produced 2.12% ethanol from a
      5.4% sugar solution. This represents 78% of the theoretical maximum. This yield
      could probably be increased through optimization of the fermentation step. Even
      when little saccharification occurred, the enzyme facilitated separation of
      water, fiber, and ash, so cellulase treatment could be an effective means for
      dewatering pulp sludges.

PMID- 10399281
TI  - Bioconversion of mixed solids waste to ethanol.
AB  - A mixed solids waste (MSW) feedstock, comprising construction lumber waste (35%
      oven-dry basis), almond tree prunings (20%), wheat straw (20%), office waste
      paper (12.5%), and newsprint (12.5%), was converted to ethanol via dilute-acid
      pretreatment followed by enzymatic hydrolysis and yeast fermentation. The MSW was
      pretreated with dilute sulfuric acid (0.4% w/w) at 210 degrees C for 3 min in a 4
      L steam explosion reactor, then washed with water to recover the solubilized
      hemicellulose. The digestibility of water-washed, pretreated MSW was 90% in batch
      enzymatic hydrolysis at 66 FPU/g cellulose. Using an enzyme-recycle bioreactor
      system, greater than 90% cellulose hydrolysis was achieved at a net enzyme
      loading of about 10 FPU/g cellulose. Enzyme recycling using membrane filtration
      and a fed-batch fermentation technique is a promising option for significantly
      reducing the cost of enzyme in cellulose hydrolysis. The hexose sugars were
      readily fermentable using a Saccharomyces cerevisiae yeast strain that was
      adapted to the hydrolysate. Solid residue after enzyme digestion was subjected to
      various furnace experiments designed to assess the fouling and slagging
      characteristics. Results of these analyses suggest the residue to be of a low to
      moderate slagging and fouling type if burned by itself.

PMID- 10399284
TI  - Bioconversion of fumarate to succinate using glycerol as a carbon source.
AB  - In this study, a facultative bacterium that converts fumarate to succinate at a
      high yield was isolated. The yield of bioconversion was enhanced about 1.2 times
      by addition of glucose into culture medium at an initial concentration of 6 g/L.
      When the initial cell density was high (2 g/L), the succinate produced at pH 7.0
      for initial fumarate concentrations of 30, 50, 80, and 100 g/L were 29.3, 40.9,
      63.6, and 82.5 g/L, respectively, showing an increase with the initial fumarate
      concentration. The high yield of 96.8%/mole of fumarate in just 4 h was obtained
      at the initial fumarate concentration of 30 g/L. Comparing these values to those
      obtained with low cell culture (0.2 g/L), we found that the amount of succinate
      produced was similar, but the production rate in the high cell culture was about
      three times higher than was the case in the low cell culture. This strain
      converted fumarate to succinate at a rate of 3.5 g/L.h under the sparge of CO2.

PMID- 10399285
TI  - Biosorption of actinides from dilute waste actinide solution by egg-shell
      membrane.
AB  - Removal of radioactive elements from the effluent and waste aqueous solutions is
      an important problem. In previous laboratory batch experiments, hen egg-shell
      membrane (ESM) was stable as an insoluble protein and was very capable of binding
      heavy metal ions from aqueous solution. Batch laboratory pH profile, time
      dependency, and capacity experiments were performed to determine the binding of
      uranium (U) and thorium (Th) to ESM. Batch pH profile experiments indicated that
      the optimum pH for binding these actinides was approx 6.0 (U) or 3.0 (Th). The
      adsorption isotherms were developed at pH 5.0 (U) or 3.0 (Th) at 25 degrees C,
      and the adsorption equilibrium data fitted both Langmuir and Freundlich models.
      The maximum uptakes by the Langmuir model were about 240 mg U/g and 60 mg Th/g
      dry weight ESM. In addition, their adsorption capacities increased as salt
      concentration increased. ESM could also accumulate uranium from dilute aqueous
      solution by adjusting to the optimum pH. These results showed that ESM was
      effective for removing actinides from solution and would be useful in filtration
      technology to remove actinides from aqueous solution.

PMID- 10399295
TI  - Nuclear magnetic resonance spectroscopy of peracetylated oligosaccharides having
      13C-labeled carbonyl groups in lieu of permethylation analysis for establishing
      linkage substitutions of sugars.
AB  - Peracetylation of free hydroxyl groups in model saccharides with [13C
      carbonyl]acetic anhydride resulted in additional splittings of sugar ring proton
      signals in NMR spectra, due to 3-bond J couplings between each acetyl carbonyl
      carbon and a sugar ring proton at that position. Quantification of 144 of these 3
      bond coupling constants in different saccharide structures showed a range between
      2.5 and 4.7 Hz, whereas all possible 4-bond couplings between sugar ring protons
      and acetyl carbonyl carbons were within linewidth (< 0.5 Hz). Therefore, further
      splitting of sugar ring proton signals in the range of 2.5-4.7 Hz upon
      acetylation with a [13C-carbonyl]acetyl group identifies that position as
      (formerly) having a free hydroxyl group. This performs the same basic function as
      permethylation analysis, but does not require hydrolysis of glycosidic linkages.
      Additionally, proton-detected 2D heteronuclear multiple bond correlation (HMBC)
      experiments or proton-detected heteronuclear correlation spectroscopy (hetCOSY)
      enabled ring proton-carbonyl-13C 3-bond J connectivities to be correlated with
      high sensitivity. Modified NMR pulse sequences are reported that include
      frequency selective decoupling schemes to enable coupling constants to be
      determined from 2D data. The tailored pulse sequences resulted in higher spectral
      resolution and sensitivity for [13C-carbonyl]-ring proton correlations.

PMID- 10399289
TI  - Two-phase methanization of food wastes in pilot scale.
AB  - A 5 ton/d pilot scale two-phase anaerobic digester was constructed and tested to
      treat Korean food wastes in Anyang city near Seoul. The easily degradable
      presorted food waste was efficiently treated in the two-phase anaerobic digestion
      process. The waste contained in plastic bags was shredded and then screened for
      the removal of inert materials such as fabrics and plastics, and subsequently put
      into the two-stage reactors. Heavy and light inerts such as bones, shells,
      spoons, and plastic pieces were again removed by gravity differences. The
      residual organic component was effectively hydrolyzed and acidified in the first
      reactor with 5 d space time at pH of about 6.5. The second, methanization reactor
      converted the acids into methane with pH between 7.4 and 7.8. The space time for
      the second reactor was 15 d. The effluent from the second reactor was recycled to
      the first reactor to provide alkalinities. The process showed stable steady-state
      operation with the maximum organic loading rate of 7.9 kg volatile solid
      (VS)/m3/d and the volatile solid reduction efficiency of about 70%. The total of
      3.6 tons presorted MSW containing 2.9 tons of food organic was treated to produce
      about 230 m3 of biogas with 70% (v/v) of methane and 80 kg of humus. This process
      is extended to full-scale treating 15 tons of food waste a day in Euiwang city
      and the produced biogas is utilized for the heating/cooling of adjacent
      buildings.

PMID- 10399296
TI  - Synthesis of sulfated oligosaccharide glycosides having high anti-HIV activity
      and the relationship between activity and chemical structure.
AB  - Sulfated laminara-oligosaccharide glycosides having high anti-human
      immunodeficiency virus (HIV) activities were synthesized from laminara-tetraose, 
      pentaose and -hexaose. The oligosaccharide glycosides were synthesized by
      treating peracetylated beta-oligosaccharides with various alcohols and Lewis acid
      catalysts. The effects of the number of glucose residues and the alkyl chain
      length on anti-HIV activity were examined. The anti-HIV activity of sulfated
      dodecyl laminara-pentaosides and -hexaosides increased with increasing degree of
      sulfation (DS) and the pentaoside having an almost fully-sulfated saccharide
      portion had the highest activity, whereas for the hexaoside a somewhat lower DS
      manifested the highest activity. Sulfated laminara-oligosaccharide glycosides
      having fluoroalkyl-containing aglycons of high hydrophobicity showed potent
      inhibitory effects against HIV infection. In contrast, hydrophilic substituents
      containing oligo(ethyleneoxy) groups as aglycons in the sulfated oligosaccharides
      did not show high anti-HIV activity.

PMID- 10399297
TI  - Synthesis of a Neu2en5Ac analog hapten and isolation of monoclonal antibody to
      Neu2en5Ac.
AB  - Neu2en5Ac is a minor component of body fluids and is abundant in sialuria, but no
      antibody to detect it has been reported. 5-Acetamido-2,6-anhydro-9-glutaramido
      3,5,9-trideoxy-D-glycero-D- galacto-non-2-enonic acid has been synthesized and
      conjugated with keyhole limpet hemocyanin (KLH) for immunization. A hybridoma
      named SIC172 was obtained that produces a monoclonal antibody (MAb) to Neu2en5Ac.
      SIC172 MAb in culture supernatant bound strongly to the hapten conjugated to BSA
      in ELISA, but slightly to fetuin, a glycoprotein which is rich in Neu5Ac. SIC172
      MAb (IgG3(kappa)), purified with a protein A/G affinity column, bound strongly to
      fetuin. Neu2en5Ac competed with the MAb in binding in amounts as low as 3 microM,
      while the competition of Neu5Ac appeared at amounts of more than 300 microM.
      SIC172 MAb is a unique MAb specific to Neu2en5Ac and might be useful for
      detecting Neu2en5Ac, which occurs naturally and in sialuria.

PMID- 10399298
TI  - Synthesis and NMR assignments of galactosylgloboside and its beta-D-GalNAc-(1-
      >4)-alpha-D-Gal-linked positional isomer in a conjugatable form.
AB  - Two pentasaccharides suitable for conjugation, namely 3-aminopropyl
      glactosylgloboside and its beta-D-GalNAc-(1-->4)-alpha-D-Gal-linked positional
      isomer, were synthesized from 3III,4III-di-O-unprotected globotrioside and the
      trichloroacetimidate of beta-D-Gal-(1-->3)-beta-D-GalNPhth derivative.
      Glycosylation at both positions led to the formation of beta-D-GalNPhth-(1-->4)
      alpha-D-Gal and beta-D-GalNPhth-(1-->3)-alpha-D-Gal-linked products in a ratio of
      1:1 without selectivity. Complete NMR spectral assignments are also described.

PMID- 10399299
TI  - Synthesis of glucosylated 1,2,3-triazole derivatives.
AB  - A series of potential bioactive compounds, 1-glucosyl-4-heterocyclyl-5-(p
      substituted-phenyl)-1,2,3-triazoles , were synthesized. Highly stereoselective
      products were obtained in good yield. Primary activity screening showed that this
      type of N-glucosylic compound possessed antitumour and antiviral activities.

PMID- 10399301
TI  - Structural determination of the exopolysaccharide of Pseudoalteromonas strain HYD
      721 isolated from a deep-sea hydrothermal vent.
AB  - The structure of the exopolysaccharide produced by Pseudoalteromonas reference
      strain HYD 721 recovered from a deep-sea hydrothermal vent has been investigated.
      By means of methylation and beta-elimination analysis, selective degradation of
      the uronic acids, partial depolymerization and NMR studies, the repeating unit of
      the polymer was deduced to be a branched octasaccharide with the structure shown.
      [formula: see text]

PMID- 10399302
TI  - Structure of dicarboxyl malto-oligomers isolated from hypochlorite-oxidised
      potato starch studied by 1H and 13C NMR spectroscopy.
AB  - The main oxidised component in hypochlorite-oxidised potato starch was isolated
      by anion-exchange chromatography after enzymatic hydrolysis. The primary
      structure of the isolated oligosaccharides was determined by 1H and 13C NMR
      spectroscopy, using homonuclear and heteronuclear two-dimensional techniques. The
      isolated pentamer and hexamer contained one glucose unit oxidised to a dicarboxyl
      residue. As the hypochlorite oxidation has occurred at positions C-2 and C-3 of a
      glucose unit, the introduced carboxyl groups caused ring cleavage between the
      carbons C-2 and C-3. The ring-cleaved dicarboxyl residue had glycosidic linkages
      on both sides, implying that this oxidation pathway does not result in
      depolymerisation. The vicinal coupling constant between H-4 and H-5 in the ring
      cleaved dicarboxyl residue was 3.2 Hz, showing that the gauche orientations are
      preferred. As a result, a different bending of the starch chain is observed and
      is probably, therefore, one of the reasons why hypochlorite oxidation reduces the
      tendency to retrogradation. The pKa values (3.0) were determined from the pH
      dependent chemical shifts of H-1, H-4 and H-5 of the dicarboxylic residue.

PMID- 10399303
TI  - Structural studies of a heteroxylan from Plantago major L. seeds by partial
      hydrolysis, HPAEC-PAD, methylation and GC-MS, ESMS and ESMS/MS.
AB  - The seed mucilage from Plantago major L. contains acidic heteroxylan
      polysaccharides. For further structural analysis, oligosaccharides were generated
      by partial acid hydrolysis and then isolated by high-pH anion-exchange
      chromatography (HPAEC). Each HPAEC fraction was shown by ESMS to contain one
      major oligosaccharide and several minor components. Partial structures of the
      oligosaccharides were determined using GC-MS, ESMS and ES tandem mass
      spectrometry (ESMS/MS). A (1-->4)-linked xylan trisaccharide and (1-->3)-linked
      xylan oligosaccharides with DP 6-11 suggested that the backbone of the
      heteroxylan polysaccharide consisted of blocks of (1-->4)-linked and (1-->3)
      linked Xylp residues. A (1-->2)-linked Xylp disaccharide and a branched
      tetrasaccharide were also found, revealing that single Xylp residues are linked
      to the O-2 of some of the (1-->4)-linked Xylp residues in the backbone. In
      addition, our results confirm the presence of side chains consisting of the
      disaccharide GlcpA-(1-->3)-Araf.

PMID- 10399305
TI  - Stability studies of chondroitin sulfate.
AB  - The stability of chondroitin sulfate (CS) was studied under acidic, neutral and
      basic conditions at 30 and 60 degrees C. CS is remarkably stable under neutral
      conditions at low temperature, while it degrades at 60 degrees C producing low
      molecular-mass fragments and desulfated products. This decomposition process
      begins at ca. 500-600 h and is consistent with an acid-catalyzed hydrolysis of
      glycosidic linkages caused by a drop in pH resulting from acidic products. Under
      basic conditions, a breakdown of glycosidic linkages causes a decrease in
      molecular mass due to the beta-elimination reaction, confirmed by a strong
      increase of absorbance at 232 nm and 1H NMR. Virtually no loss of O-sulfate
      groups can be detected in the base-treated CS. Under acidic conditions, the
      molecular mass decreases probably through hydrolysis of polysaccharidic linkages
      resulting in an increased number of reducing end groups. Little or no beta
      elimination occurs. A loss of O-sulfate groups was detected, producing desulfated
      derivatives.

PMID- 10399304
TI  - An easy stereospecific synthesis of 1-amino-2,5-anhydro-1-deoxy-D-mannitol and
      arylamino derivatives.
AB  - 1-Amino-2,5-anhydro-1-deoxy-D-mannitol and a series of arylamino derivatives were
      prepared by nitrous acid deamination of 2-amino-2-deoxy-D-glucose and subsequent
      reductive amination of the resulting 2,5-anhydro-D-mannose. Some of these
      compounds showed an enhanced affinity for the hexose transporter of Trypanosoma
      brucei as compared to D-fructose.

PMID- 10399306
TI  - Use of a phenyl 1-selenogalactofuranoside as a glycosyl donor for the synthesis
      of galactofuranosyl-containing disaccharides.
AB  - The use of acetylated phenyl 1-seleno-beta-D-galactofuranoside as a glycosyl
      donor for the synthesis of protected D-Galf-beta-(1-->3)-alpha-D-Manp as its
      methyl or ethylthio glycoside has been demonstrated. Activation of the
      selenoglycoside over a thioglycoside acceptor by NIS/TfOH is extremely selective
      and gives the ethylthio disaccharide in 91% yield. The parent disaccharide is
      found as a terminal and branched unit in the lipopeptidophosphoglycan
      oligosaccharides of the protozoan Trypanosoma cruzi, the causative agent of
      Chagas' disease.

PMID- 10399307
TI  - Genetic differentiation of mites of the genus Chorioptes (Acari: Psoroptidae).
AB  - In an effort to clarify the species status of mites of the genus Chorioptes the
      second internal transcribed spacer of the rRNA gene was characterized in 14
      isolates from cattle, horse, sheep and llama of different geographic origins. The
      genotypes segregated into two clearly separated groups of DNA sequences. In
      addition, two phenotypes could be distinguished by the lengths of the outer
      opisthosomal setae of male adults which had previously been designated as
      Chorioptes bovis and Chorioptes texanus. The bipartite division of genotypes and
      phenotypes correlated completely in all isolates. Nine out of ten cattle isolates
      from three continents were determined to be C. texanus including the first
      description in Europe and Northern America. Chorioptes texanus appears to have a
      wider geographic distribution than previously known. Chorioptes bovis was found
      in four different host species. The apparent lack of host specificity of both
      species implicates a potential that mites are dispersed freely in a wide range of
      hosts and this might have contributed to the wide geographic distribution of
      these species.

PMID- 10399308
TI  - Mosaic pattern of Borrelia infection in a continuous population of the tick
      Ixodes ricinus (Acari: Ixodidae).
AB  - An array of 12 20 x 20 m quadrats in a mixed forest near Poteply, Central
      Bohemia, Czech Republic, was investigated for the abundance and spatial
      distribution of host-questing Ixodes ricinus nymphs and their infection with
      borreliae. Tick densities were estimated by flagging and their borrelia infection
      status was determined by direct immunofluorescence. While the tick population
      appeared to be continuous and homogeneous based on quadrat counts, their
      infection with borreliae evinced a mosaic pattern. The nymphal infection rates
      ranged between 1.6 and 10.5% (mean = 6.0%) with significant differences between
      adjacent quadrats. Home ranging of small rodents (Apodemus flavicollis and
      Clethrionomys glareolus) inhabiting the forest seems to be responsible for the
      spatial pattern of borrelial infection.

PMID- 10399309
TI  - Hopf bifurcation in epidemic models with a time delay in vaccination.
AB  - Two SIR models for the spread of infectious diseases which were originally
      suggested by Greenhalgh & Das (1995, Theor. Popul. Biol. 47, 129-179; 1995,
      Mathematical Population Dynamics: Analysis of Heterogeneity, pp. 79-101,
      Winnipeg: Wuerz Publishing) are considered but with a time delay in the
      vaccination term. This reflects the fact that real vaccines do not immediately
      confer permanent immunity. The population is divided into susceptible,
      infectious, and immune classes. The contact rate is constant in model I but it
      depends on the population size in model II. The death rate depends on the
      population size in both models. There is an additional mortality due to the
      disease, and susceptibles are vaccinated and may become permanently immune after
      a lapse of some time. Using the time delay as a bifurcation parameter, necessary
      and sufficient conditions for Hopf bifurcation to occur are derived. Numerical
      results indicate that that for diseases in human populations Hopf bifurcation is
      unlikely to occur at realistic parameter values if the death rate is a concave
      function of the population size.

PMID- 10399310
TI  - A two-type model for the Cuban national programme on HIV/AIDS.
AB  - We study deterministic and stochastic versions of a birth and death process for a
      two-type population with immigration for both types. For the stochastic model we
      consider the case where the rates are time dependent, and also when they are
      constant, as is the case in our AIDS application. We derive the probability
      generating function of the bivariate process and the expectations of the marginal
      processes. We also study the marginal behaviour of the bivariate process in a
      particular case where we suppose that the first event is an immigration, and
      examine the behaviour of the marginal processes divided by their expectations.
      Finally, we apply some of these results to a sexual-partner notification system,
      as in the Cuban national programme on HIV/AIDS.

PMID- 10399311
TI  - The use of dummy data points when fitting bacterial growth curves.
AB  - We consider the problem of fitting mathematical models for bacterial growth and
      decline to experimental data. Using models which represent the phases of the
      growth and decline cycle in a piecewise manner, we describe how least-squares
      fitting can lead to potentially misleading parameter estimates. We show how these
      difficulties can be overcome by extending a data set to include hypothetical
      observations (dummy data points) which reflect biological beliefs, and the
      resulting stabilization of parameter estimates is analysed mathematically. The
      techniques are illustrated using real and simulated data sets.

PMID- 10399312
TI  - Mathematical modelling of avascular-tumour growth. II: Modelling growth
      saturation.
AB  - We build on our earlier mathematical model (Ward & King, 1997, IMA J. Appl. Math
      Appl. Med. Biol., 14, 39-69) by incorporating two necrotic depletion mechanisms,
      which results in a model that can predict all the main phases of avascular-tumour
      growth and heterogeneity. The model assumes a continuum of live cells which,
      depending on the concentration of a generic nutrient, may reproduce or die,
      generating local volume changes and thus producing movement described by a
      velocity field. The necrotic material is viewed as basic cellular material (i.e.
      as a generic mix of proteins, DNA, etc.) which is able to diffuse and is utilized
      by living cells as raw material to construct new cells during mitosis. Numerical
      solution of the resulting system of partial differential equations shows that
      growth ultimately tends either to a steady-state (growth saturation) or becomes
      linear. Both the travelling-wave and steady-state limits of the model are
      therefore derived and studied. The analysis demonstrates that, except in a very
      special case, passage of cellular material across the tumour surface is necessary
      for growth saturation to occur. Using numerical techniques, the domains of
      existence of the large-time solutions are explored in parameter space. For a
      particular limit, asymptotic analysis makes explicit the main phases of growth
      and gives the location of the bifurcation between the long-time outcomes.

PMID- 10399314
TI  - Vitronectin.
AB  - Vitronectin is a multifunctional glycoprotein present in blood and in the
      extracellular matrix. It binds glycosaminoglycans, collagen, plasminogen and the
      urokinase-receptor, and also stabilizes the inhibitory conformation of
      plasminogen activation inhibitor-1. By its localization in the extracellular
      matrix and its binding to plasminogen activation inhibitor-1, vitronectin can
      potentially regulate the proteolytic degradation of this matrix. In addition,
      vitronectin binds to complement, to heparin and to thrombin-antithrombin III
      complexes, implicating its participation in the immune response and in the
      regulation of clot formation. The biological functions of vitronectin can be
      modulated by proteolytic enzymes, and by exo- and ecto-protein kinases present in
      blood. Vitronectin contains an RGD sequence, through which it binds to the
      integrin receptor alpha v beta 3, and is involved in the cell attachment,
      spreading and migration. Antibodies against alpha v beta 3 or synthetic peptides
      containing an RGD sequence are now being tested as therapeutic agents in the
      treatment of human cancers, bone diseases (e.g. osteoporosis) and in pathological
      disorders which involve angiogenesis.

PMID- 10399313
TI  - FADD/MORT1, a signal transducer that can promote cell death or cell growth.
AB  - FADD/MORT1 is a cytosolic adaptor protein which is critical for signalling from
      CD95 (Fas/APO-1) and certain other members of the tumour necrosis factor receptor
      (TNF-R) family (called 'death receptors'). Two protein interaction domains have
      been identified in FADD/MORT1. The C-terminal 'death domain' is needed for
      recruitment of FADD/MORT1 to ligated 'death receptors' and the N-terminal 'death
      effector domain' mediates oligomerisation and activation of caspase-8 zymogens.
      Caspase-8 activates other cysteine proteases by cleavage and this starts a
      proteolytic cascade which constitutes the 'point of no return' in apoptosis
      signalling. Experiments in mice lacking FADD/MORT1 function proved that this
      adaptor is required for CD95- and TNF-RI-transduced cell death but is dispensable
      for other pathways to apoptosis. Surprisingly, FADD/MORT1 is also essential for
      mitogen-induced proliferation of T-lymphocytes. Therapeutic activation of
      FADD/MORT1 function may be used to kill unwanted cells in cancer or autoimmunity
      and its suppression may help prevent cell death in certain degenerative
      disorders.

PMID- 10399315
TI  - CD14.
AB  - The GPI-anchored 55 kDa glycoprotein CD14 is expressed on monocytes/macrophages
      and to a lesser extent on granulocytes. Engagement of CD14 by ligands like
      lipopolysaccharide, intact bacteria or apoptotic cells can result in either pro-
      or anti-inflammatory responses. Since the CD14 molecule does not have a membrane
      spanning domain it cannot transmit a signal into the cell. Some as yet
      unidentified accessory protein is thought to be involved. It will be important to
      clarify the signalling systems involved since they may provide a therapeutic
      target for sepsis intervention strategies.

PMID- 10399316
TI  - Cyclooxygenase-1 and -2 isoenzymes.
AB  - The cyclooxygenase isoenzymes (COX-1 and -2) catalyze the rate-limiting steps in
      prostanoid biosynthesis. COX-1 and -2 genes encode two isoenzymes with
      overlapping yet distinct expression patterns and functions. Physiologically,
      various extracellular stimuli such as growth factors, cytokines and tumor
      promoters regulate the expression of COX-1 and -2 genes at both transcriptional
      and post-transcriptional levels. COX-2 is overexpressed in rheumatoid arthritis,
      colorectal and breast cancer. Prostanoids produced by the COX pathway signal via
      plasma membrane-localized, G-protein-coupled receptors as well as via nuclear
      receptors. Currently, several COX-2-selective inhibitors are developed to control
      the anti-inflammatory and anti-neoplastic activities of the COX-2 isoenzyme.
      Inhibition of the COX isoenzyme activity and/or expression may be the basis of
      future generation of anti-inflammatory and anti-neoplastic drugs.

PMID- 10399317
TI  - Heat stress proteins and myocardial protection: experimental model or potential
      clinical tool?
AB  - Heat stress proteins (hsp) are induced by a variety of stimuli including elevated
      temperature, ischaemia, hypoxia, pressure overload and some chemicals. They help
      to maintain the metabolic and structural integrity of the cell, as a protective
      response to external stresses. They are known to protect the myocardium from the
      damaging effects of ischaemia and reperfusion. The heat stress response results
      in accumulation of heat stress proteins. The beneficial effects associated with
      their expression include improved endothelial and mechanical recovery of the
      ischaemic heart. In addition, preservation of high energy phosphates and
      reduction in infarct size. It has also been shown that critical amounts of hsp70
      are necessary to ensure protection of the myocardium. However, questions remain
      regarding the biochemical mechanisms underlying this protective effect.
      Alterations in the cell metabolism and chaperone function of cells expressing
      heat shock proteins, are thought to be responsible. Despite the obvious clinical
      benefits related to the heat stress response in a clinical setting, the
      application of this phenomena remains limited. Heat, both quantitatively and
      qualitatively is one of the best inducers of heat stress proteins. However, the
      effects of heat stress are nonspecific and intracellular damage is a common
      occurrence. The search for alternative stimuli, particularly within the fields of
      pharmacotherapy or genetic manipulation may offer more viable options, if the
      heat stress response is take its place as an established strategy for myocardial
      protection.

PMID- 10399318
TI  - Factors and processes involved in membrane potential build-up in yeast: diS-C3(3)
      assay.
AB  - No methods are currently available for fully reliable monitoring of membrane
      potential changes in suspensions of walled cells such as yeast. Our method using
      the Nernstian cyanine probe diS-C3(3) monitors even relatively fast changes in
      membrane potential delta psi by recording the shifts of probe fluorescence
      maximum lambda max consequent on delta psi-dependent probe uptake into, or exit
      from, the cells. Both increased [K+]out and decreased pHout, but not external
      NaCl or choline chloride depolarise the membrane. The major ion species
      contributing to the diS-C3(3)-reported membrane potential in S. cerevisiae are
      thus K+ and H+, whereas Na+ and Cl- do not perceptibly contribute to measured
      delta psi. The strongly pHout-dependent depolarisation caused by the
      protonophores CCCP and FCCP, lack of effect of the respiratory chain inhibitors
      rotenone and HQNO on the delta psi, as well as results obtained with a
      respiration-deficient rho- mutant show that the major component of the diS-C3(3)
      reported membrane potential is the delta psi formed on the plasma membrane while
      mitochondrial potential forms a minor part of the delta psi. Its role may be
      reflected in the slight depolarisation caused by the F1F0-ATPase inhibitor azide
      in both rho- mutant and wildtype cells. Blocking the plasma membrane H(+)-ATPase
      with the DMM-11 inhibitor showed that the enzyme participates in delta psi build
      up both in the absence and in the presence of added glucose. Pore-forming agents
      such as nystatin cause a fast probe entry into the cells signifying membrane
      damage and extensive binding of the probe to cell constituents reflecting
      obviously disruption of ionic balance in permeabilised cells. In damaged cells
      the probe therefore no longer reports on membrane potential but on loss of
      membrane integrity. The delta psi-independent probe entry signalling membrane
      damage can be distinguished from the potential-dependent diS-C3(3) uptake into
      intact cells by being insensitive to the depolarising action of CCCP.

PMID- 10399319
TI  - Lipopolysaccharide-induced priming of the human neutrophil is not associated with
      a change in phosphotyrosine phosphatase activity.
AB  - The activation of the neutrophil respiratory burst is a two-step process
      involving an initial 'priming' phase followed by a 'triggering' event. The
      biochemical mechanisms which underlie these events are yet to be fully
      elucidated, but the evidence suggests a crucial role for stimulus-induced
      tyrosine phosphorylation. The enhanced tyrosine phosphorylation observed upon
      triggering primed cells may reflect an increase in tyrosine kinase activity or a
      reduction in the levels of the opposing phosphotyrosine phosphatases (PTPases).
      We have investigated the latter by examining the possibility that
      lipopolysaccharide (LPS)-induced priming of the neutrophil respiratory burst
      involves the suppression of cellular PTPase activity. Purified human neutrophils
      were incubated for 60 min with and without LPS. Priming of the respiratory burst
      was confirmed by fMet-Leu-Phe-induced cytochrome c reduction. The level of PTPase
      activity was assessed by dephosphorylation of [32P]RR-src peptide as substrate.
      Pretreatment of human neutrophils with 200 ng/ml LPS induced a 2.9 +/- 0.3 (mean
      +/- SEM, n = 3, P = 0.022) fold increase in the fMet-Leu-Phe-triggered
      respiratory burst. In the same cells, LPS did not induce a significant change in
      the total cellular PTPase activity (1.02 +/- 0.02-fold, mean +/- SEM, n = 3, P =
      0.63). Similarly, stimulation of neutrophils with fMet-Leu-Phe or phorbol
      myristate acetate did not significantly affect the cellular PTPase activity (P =
      0.94 and 0.68, respectively). Our results suggest that suppression of PTPase
      activity is not the mechanism underlying the priming and/or triggering of the
      neutrophil respiratory burst.

PMID- 10399320
TI  - Effects of mono-ADP-ribosylation on cytoskeletal actin in chromaffin cells and
      their release of catecholamine.
AB  - To better understand the physiological role of mono-ADP-ribosylation in animals,
      we examined its role in chromaffin cells. Monoclonal antibodies against rat brain
      ADP-ribosylhydrolase were prepared, one of which (9E7) completely inhibited the
      enzyme's activity with ADP-ribosylated actin as the substrate. After actin
      monomers were polymerized by the addition of Mg2+, mono-ADP-ribosylation induced
      actin depolymerization. After mono-ADP-ribosylation, the actin monomers did not
      polymerize by the addition of Mg2+. Polymerized actin cosedimented with
      chromaffin granules but mono-ADP-ribosylated actin did not. After ADP
      ribosylhydrolase on the membrane of chromaffin granules was incubated with 9E7,
      mono-ADP-ribosylated actin did not cosediment with chromaffin granules. When
      chromaffin cells permeabilized with saponin were incubated with NAD and 9E7,
      actin and rho protein was mono-ADP-ribosylated and stimulated catecholamine
      release from the cells. In histochemical experiments, catecholamine and actin
      filaments disappeared when the permeabilized chromaffin cells were treated with
      NAD and 9E7. These findings indicate that mono-ADP-ribosylation breaks the actin
      barrier in order to move granules during exocytosis, and ADP-ribosylactin
      hydrolase may keep the granules within the actin barrier.

PMID- 10399321
TI  - Molecular cloning of a novel human PAPS synthetase which is differentially
      expressed in metastatic and non-metastatic colon carcinoma cells.
AB  - Subtractive hybridisation was used to select for genes which are differentially
      expressed between a highly metastatic human colon carcinoma cell line, KM12SM,
      and the isogenetic non-metastatic cell line, KM12C. This led to the isolation of
      cDNA clones for a novel human adenosine 5'-phosphosulphate kinase/ATP
      sulphurylase (PAPS synthetase). Northern hybridisation revealed a single 4.2 kb
      mRNA species which showed an approximately 20-fold higher level of expression in
      the non-metastatic cell line than in the metastatic cell line. The overlapping
      cDNA clones together covered 3,774 bp including the entire coding region of 1,842
      bp encoding a protein of 614 amino acids (calculated molecular mass of 69,496
      Da). The protein contains consensus sequences for APS kinase and ATP
      sulphurylase, in its amino- and carboxy-terminal regions, respectively, as well
      as other sequences that are highly conserved amongst ATP sulphurylases and APS
      kinases. Interestingly, consensus sequences for GTPase activity were also
      identified, indicating that enzyme activity may be regulated by an intrinsic
      GTPase mechanism. Overall the new protein is 78% homologous with a previously
      described human PAPS synthetase (PAPSS1) indicating that we have identified the
      second member of a gene family which we have provisionally named PAPSS2. The gene
      locus for PAPSS2 was identified on chromosome 10 at 10q23.1-q23.2. This locus has
      synteny with the mouse brachymorphic gene recently identified as a PAPS
      synthetase (SK2). PAPSS2 appears to be the human homologue of this gene and thus
      PAPSS2 is likely to be important in human skeletogenesis.

PMID- 10399322
TI  - Artifacts in trimethylsilyl derivatization reactions and ways to avoid them.
AB  - Trimethylsilyl derivatives are routinely employed in gas chromatography to
      increase the volatility and stability of organic compounds containing active
      hydrogens. Normally only the desired derivative is formed when organic compounds
      are derivatized with common silylation reagents. However, some compounds form
      additional unexpected derivatives or by-products (artifacts). Artifact formation
      leads to multiple peaks for the same compound or unexpected components in the gas
      chromatographic analysis of mixtures. This review includes silylation artifacts
      identified in our laboratory by mass spectrometry during the last 20 years and
      references to those found in the literature. Also, means of avoiding artifact
      formation are discussed in detail.

PMID- 10399323
TI  - Liquid chromatographic methods for the isolation and identification of new
      pectenotoxin-2 analogues from marine phytoplankton and shellfish.
AB  - Two acidic analogues of the polyether marine toxin, pectenotoxin-2 (PTX-2),
      responsible for diarrhetic shellfish poisoning (DSP), have been isolated from the
      toxic marine phytoplankton (Dinophysis acuta), collected in Irish waters. Liquid
      chromatography with fluorimetric detection (LC-FLD) analyses of the extracts of
      bulk phytoplankton samples, following derivatisation with 9-anthryldiazomethane
      (ADAM) or 1-bromoacetylpyrene (BAP), showed a complex toxin profile with peaks
      corresponding to okadaic acid (OA) and its isomers, dinophysistoxin-2 (DTX-2) and
      DTX-2C, as well as other unidentified lipophilic acids. LC-UV analysis showed the
      presence of a diene moiety in these new compounds and two acids have been
      isolated. LC coupled with mass spectrometry (MS) and tandem mass spectrometry (LC
      MS-MS) were used to gain structural information. Through flow injection analysis
      (FIA)-MS, both in positive and negative ion modes, the molecular weight of 876
      for both compounds was determined. Collision Induced Dissociation (CID) from each
      parent ion, as performed both in positive and negative ion mode, produced mass
      spectra which were very similar to those obtained for authentic PTX-2 (mw 858).
      These new compounds have been confirmed to be pectenotoxin-2 seco acids (PTX
      2SAs) and they are closely related to PTX-2 except that they contain an open
      chain carboxylic acid rather than a lactone ring. Toxic mussels also contained
      these pectenotoxin-2 analogues.

PMID- 10399324
TI  - Effort to improve the quantitative determination of oxidation and hydrolysis
      compound classes in edible vegetable oils.
AB  - This paper proposes an analytical method to evaluate the classes of products of
      polymerization, oxidation and hydrolysis as well as the polar compounds present
      in refined edible oils in a more reliable fashion. The polar compounds of a
      marketed refined peanut oil were analyzed by preparative gel permeation
      chromatography and the classes of substances corresponding to single chromatogram
      peaks were collected by means of a fraction collector, purified and used as
      standards for high-performance size-exclusion chromatographic analysis. The
      linearity of detector response, the precision and accuracy of the method for each
      class of compounds and for polar compounds were assessed. Another aim was to
      verify whether this method may be applied to other refined peanut oils and to
      edible vegetable oils in general, even of different botanical origin, using the
      standards that had already been prepared for that particular peanut oil. The
      results obtained showed that this was possible and the analytical method
      developed can be extended to the most common edible vegetable oils.

PMID- 10399325
TI  - Sensitive determination of RDX, nitroso-RDX metabolites, and other munitions in
      ground water by solid-phase extraction and isotope dilution liquid chromatography
      atmospheric pressure electro-spray [correction of chemical] ionization mass
      spectrometry.
AB  - Recent improvements in the LC-MS interface have increased the sensitivity and
      selectivity of this instrument in the analysis of polar and thermally-labile
      aqueous constituents. Determination of RDX, nitroso-RDX metabolites, and other
      munitions was enhanced using LC-MS with solid-phase extraction, 15N3-RDX internal
      standard, and electrospray ionization (ESI) in negative ion mode. ESI produced a
      five-fold increase in detector response over atmospheric pressure chemical
      ionization (APCI) for the nitramine compounds, while the more energetic APCI
      produced more than twenty times the ESI response for nitroaromatics. Method
      detection limits in ESI for nitramines varied from 0.03 microgram l-1 for MNX to
      0.05 microgram l-1 for RDX.

PMID- 10399326
TI  - Determination of explosives in soil and ground water by liquid chromatography
      amperometric detection.
AB  - Electrochemical reduction of trinitrotoluene (TNT) and several nitroaromatics has
      been exploited toward the development of an amperometric detector for liquid
      chromatography (LC). Up to a ten-fold increase in sensitivity was accomplished
      for the explosives using amperometric detection instead of conventional UV
      measurement. A working glassy carbon electrode (poised at -0.80 V vs. Ag/AgCl)
      offered a detection limit of 9, 44 and 550 nM for trinitrobenzene, TNT and 1,4
      dinitrobenzene, respectively. Separation of eleven TNT-related compounds in a
      mixture was achieved within 15 min using a C18 column and a mobile phase
      consisting of acetonitrile-50 mM phosphate buffer pH 5 (1:2, v/v) and 18 mM
      sodium dodecylsulfate. The LC-amperometric detection system was applicable for
      analyzing soil extracts and ground water and the results obtained agreed well
      with that of the US Environmental Protection Agency recommended procedure.
      Extension to analysis of HMX (octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine)
      and RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) was accomplished with a silver
      working electrode instead of a glassy carbon electrode installed in a thin
      channel cell.

PMID- 10399327
TI  - Condensation nucleation light scattering detection for biogenic amines separated
      by ion-exchange chromatography.
AB  - A sensitive method of analysis for biogenic amines, putrescine, cadaverine,
      histamine and an amino acid precursor, histidine is described herein using ion
      exchange chromatography and condensation nucleation light scattering detection.
      The method was successfully used for the analysis of biogenic amines in fish
      samples. The method offers a number of advantages: fast elution of analytes with
      no need for mobile phase conductivity suppression, no derivatization and no
      electrochemical activity for the analyte's detection. The 3 sigma detection
      limits for these compounds were found to range from 8 to 20 ng/ml.

PMID- 10399328
TI  - Production of highly purified clotting factor IX by a combination of different
      chromatographic methods.
AB  - A highly enriched preparation of human clotting factor IX was produced by a
      combination of adsorption chromatography, hydrophobic interaction chromatography
      and heparin affinity chromatography. The introduction of adsorption
      chromatography with a hydroxyaminopropyl support allows the capture step to be
      carried out directly from the cryoprecipitate-depleted plasma with a
      chromatographic column in flow-through mode. This replaces the batch procedure
      used until now. The other two chromatographic steps are designed in such a way
      that the eluate from the preceding step can be directly applied, without any
      intermediate treatment of the sample. This cuts the period of time required for
      the process by almost 50%, and increases the yield considerably. The isolated
      factor IX contains practically no contaminants and has a specific activity over
      200 IU/mg of protein.

PMID- 10399329
TI  - Direct visualisation of plasmid DNA in individual chromatography adsorbent
      particles by confocal scanning laser microscopy.
AB  - Confocal microscopy was used for the measurement of plasmid DNA adsorbed to
      individual adsorbent particles intended for anion-exchange and triple helix
      affinity chromatography. Plasmid DNA was visualized with the fluorescent dye YOYO
      1, that forms a highly fluorescent complex with double stranded DNA. Confocal
      images were translated into fluorescence intensity profiles and the distribution
      of plasmid DNA in the particles was measured. The results that adsorption of
      plasmid DNA mainly takes place in an outer layer of the particles. The described
      procedure can also be advantageously used to demonstrate triple helix formation
      between plasmid DNA and immobilized oligonucleotides.

PMID- 10399330
TI  - Optimization and validation of chiral high-performance liquid chromatographic
      method for analysis of a fibrinogen (gpIIb/IIIa) receptor antagonist.
AB  - A chiral HPLC separation on an alpha 1-acid glycoprotein (AGP) column was
      developed for the separation of roxifiban, a fibrinogen receptor antagonist, from
      its related chiral impurities. The proposed method was optimized for mobile phase
      buffer concentration, organic modifier, and temperature using experimental
      design. The method was then validated for use in release testing of the roxifiban
      drug substance.

PMID- 10399331
TI  - Qualitative and quantitative evaluation of mono- and disaccharides in D-fructose,
      D-glucose and sucrose caramels by gas-liquid chromatography-mass spectrometry. Di
      D-fructose dianhydrides as tracers of caramel authenticity.
AB  - The monosaccharide (D-fructose, D-glucose, anhydrosugars), disaccharide
      (glucobioses) and pseudodisaccharide (di-D-fructose dianhydrides) content of D
      fructose, D-glucose and sucrose caramels has been determined by gas-liquid
      chromatography-mass spectrometry (GLC-MS) of their trimethylsilyl (TMS) or TMS
      oxime derivatives. The chromatographic profiles revealed significant differences
      in the disaccharide/pseudodisaccharide distribution depending on the caramel
      source: a D-fructose caramel contains prominent proportions of di-D-fructose
      dianhydrides, a D-glucose caramel mainly D-glucobioses, and a sucrose caramel
      similar proportions of both disaccharide/pseudodisaccharide series. It is
      noteworthy that di-D-fructose dianhydrides are found in all three types of
      caramels and might then be used as specific tracers of the authenticity of
      caramel, i.e., a product resulting from the controlled heat treatment of food
      grade carbohydrates for use as food additives.

PMID- 10399332
TI  - Trace-level determination of polar flavour compounds in butter by solid-phase
      extraction and gas chromatography-mass spectrometry.
AB  - Volatile compounds are responsible for the aromas of butter. A simple technique
      for the determination of these components is described which is based on solid
      phase extraction (SPE) after melting of the butter and separation of the aqueous
      phase from the fat. Volatile flavours present in the water fraction are collected
      by off-line SPE on cartidges packed with a copolymer sorbent. After desorption
      with 500 microliters of methyl acetate, 1-microliter aliquots are quantified
      and/or identified by gas chromatography-mass spectrometry. The procedure was
      tested with respect to recovery, linearity and limit of detection in real-life
      samples using five polar model analytes. It allows the characterisation of polar
      flavour compounds in butter prior to and after heat treatment at 170 degrees C.
      From the five model compounds, vanillin, traces of diacetyl and maltol were found
      to be present in the butter samples. After heat treatment 500-1000-fold increased
      concentration of maltol, and substantial amounts of furaneol were detected.

PMID- 10399333
TI  - Reassessment of the calibration constant for the IAsys biosensor.
AB  - A magnitude of 50 are s ng-1 mm2 has been determined for the calibration constant
      relating biosensor response to the amount of protein bound to the sensor surface
      of an IAsys cuvette. These studies entailed enzymatic assessment of the extent of
      lactate dehydrogenase depletion in the liquid phase arising from enzyme binding
      to a carboxymethyldextran-coated sensor surface, and also estimation of a maximum
      biosensor response for the electrostatic interaction of ovalbumin with an
      aminosilane-coated sensor surface. The latter results required correction for
      contributions to biosensor response resulting from changes in the refractive
      index of the liquid phase effected by high protein concentrations.

PMID- 10399334
TI  - Trace analysis of carbonyl compounds by liquid chromatography-mass spectrometry
      after collection as 2,4-dinitrophenylhydrazine derivatives.
AB  - This study describes the utilization of carbonyl- 2,4-dinitrophenylhydrazine
      (DNPH) derivatives for the determination of a micro amount of carbonyl compounds
      in air by liquid chromatography-mass spectrometry (LC-MS). After the carbonyl
      compounds are collected using a Waters Sep-Pak C18 cartridge column with
      impregnated DNPH on octadecylsilica, they are eluted by acetonitrile as carbonyl
      DNPH derivatives. A 20-mm3 aliquot of eluent is injected into the LC-MS system.
      The four derivatives (formaldehyde-, acetaldehyde-, acrolein- and acetone-DNPH)
      were eluted within 7 min with acetonitrile-water (60:40, v/v) as the mobile
      phase. The proposed method offers sub-ppb sensitivity and good reproducibility
      and was applied to the determination of these carbonyl compounds in actual air
      samples from store rooms, laboratories and offices. The relative standard
      deviations for these samples (n = 6) were 1 to 3%.

PMID- 10399335
TI  - Optimization of solid-phase microextraction conditions using a response surface
      methodology to determine organochlorine pesticides in water by gas chromatography
      and electron-capture detection.
AB  - A response surface methodology was applied to optimise the solid-phase
      microextraction (SPME) conditions using a polyacrylate-coated fiber to determine
      thirteen organochlorine pesticides from water. Analyses were performed using gas
      chromatography-electron-capture detection. Variables affecting absorption in both
      the headspace and immersion extraction were optimised by using a response surface
      generated with a Doehlert design, and the results were compared. The immersion
      SPME method was selected since higher recoveries were obtained for most of the
      compounds studied. The method developed was applied to the analysis of tap and
      Ebro river water samples. The linear range of most pesticides for real samples
      was found to be between 0.001 and 2.5 micrograms l-1 and the limits of detection
      were between 0.15 and 0.35 ng l-1. The repeatability and the reproducibility
      between days of the method (n = 6), expressed as relative standard deviation, for
      tap water spiked at a level of 1 ng l-1 were between 5.7 and 25.6% and between
      7.6 and 26.5%, respectively.

PMID- 10399336
TI  - Physico-chemical characterization of recombinant hepatitis B surface antigen by a
      multidimensional approach.
AB  - Initially, our work was directed to respond to the question: why hepatitis B
      surface antigen (HBsAg) produces a very broad peak in preparative size-exclusion
      chromatography (SEC). For this purpose, we used a multidimensional approach based
      on SEC fractionation of purified HBsAg followed by the individual analysis of SEC
      fractions by a battery of assays, such as SEC, sodium dodecyl sulfate
      polyacrylamide gel electrophoresis, enzyme-linked immunosorbent assay and
      transmission electron microscopy. As a result, HBsAg particles were shown to be
      heterogeneous in terms of particle assembly. In order to elucidate the origin of
      HBsAg heterogeneity, we included here the denaturing SEC into a multidimensional
      approach. The data from denaturing SEC evidenced the fragmentation of protein
      monomers within the HBsAg particle that, probably, occurs during fermentation
      broth, rather than during in vitro HBsAg processing. The fractions isolated from
      widely separated regions of HBsAg peak differed in the extent of protein
      fragmentation, suggesting that the variable extent of protein degradation within
      HBsAg particles may be one of the factors responsible for broadening of the HBsAg
      peak in SEC.

PMID- 10399337
TI  - Solute-solvent interactions in micellar electrokinetic chromatography.
      Characterization of sodium dodecyl sulfate-Brij 35 micellar systems for
      quantitative structure-activity relationship modelling.
AB  - The solvation parameter model has been applied to the characterization of
      micellar electrokinetic chromatographic (MEKC) systems with mixtures of sodium
      dodecyl sulfate and Brij 35 as surfactant. The variation in MEKC surfactant
      composition results in changes in the coefficients of the correlation equation,
      which in turns leads to information on solute-solvent and solute-micelle
      interactions. Since the same solvation model can be used to describe many
      biological processes, particular MEKC surfactant compositions can be selected
      that model the solute-solvent interactions of some of these processes. Two
      different MEKC systems have been selected to model the solute-solvent
      interactions of two processes of biological interest (octanol-water partition and
      tadpole narcosis).

PMID- 10399338
TI  - Open tubular capillary electrochromatography in etched, chemically modified 20
      microns I.D. capillaries.
AB  - Fused silica capillaries with an I.D. of 20 microns are etched and then
      chemically modified by the silanization/hydrosilation method to attach an
      octadecyl moiety for use in electrokinetic chromatography. The etched capillaries
      after chemical modification are shown to have an anodic electroosmotic flow below
      pH 4.5. In comparison to bare 20 microns capillaries and unetched but chemically
      modified 20 microns capillaries, the etched C18 fused silica tubes show better
      separation of mixtures of lysozymes and cytochrome c's under identical conditions
      of buffer, pH and applied voltage. It was also demonstrated that this open
      tubular approach to capillary electrochromatography was amenable to a number of
      different types of basic compounds ranging in size from typical small amines to
      biomolecules. As expected, pH is an important variable that must be controlled in
      order to obtain an optimized separation. Reproducibility studies verify the
      stability of the silicon-carbon linkage produced in this modification method so
      that column lifetimes of at least 300 injections can be expected.

PMID- 10399339
TI  - Semisynthetic chondroitins as chiral buffer additives in capillary
      electrophoresis.
AB  - Chemically oversulfated galactosaminoglycans with potential as therapeutic agents
      (inhibitors of human leukocyte elastase) were tested as chiral selectors in
      capillary electrophoresis of basic racemates. The high anionic character of these
      compounds provides them with anodic mobility in acidic buffer; using uncoated
      capillaries, the enantioresolution of racemic basic drugs was obtained at pH 2.5.
      Dimethindene, chloroquine and chlorpheniramine were enantioresolved applying
      negative voltage (-15 kV) while the other analytes (propranolol, pindolol,
      tetrahydrozoline and cloperastine) exhibited catodic migration. The addition of
      organic solvents to the running buffer was evaluated in order to increase the
      resolution; methanol provides the best results and in general, baseline
      separation of the analytes was reached. The studied oversulfated
      mucopolysaccharide, shows the same ionic character of heparin but presents
      different stereochemistry and sites of sulfation. A comparison with heparin, used
      in the same acidic conditions, may underline the role of ionic, spatial and
      steric features of glycosaminoglycans in the enantiorecognition.

PMID- 10399340
TI  - Chromatographic models for the sorption of neutral organic compounds by soil from
      water and air.
AB  - The solvation parameter model is used to construct models for the estimation of
      the soil-water and soil-air distribution constants and to characterize the
      contribution of fundamental intermolecular interactions to the underlying
      sorption processes. Wet soil is shown to be quite cohesive and polar but
      relatively non-selective for dipole-type, lone-pair electron and hydrogen-bond
      interactions. Using a comparison of system constant ratios chromatographic
      systems employing reversed-phase liquid chromatography on polar bonded phases are
      shown to provide suitable models for estimating soil-water distribution
      constants. No suitable gas chromatographic models were found for the soil-air
      distribution constant but the requirements for such a system are indicated.
      Models are also provided for adsorption at the air-water interface. Estimation
      methods based on either the solvation parameter model or chromatographic model
      reproduce experimental distribution constants for a wide variety of compounds
      with a similar error (0.2-0.3 log units) to that expected in the experimental
      data.

PMID- 10399341
TI  - Interaction of some steroid drugs with beta-cyclodextrin polymer.
AB  - The interaction of 15 steroidal drugs with a water-soluble beta-cyclodextrin
      polymer was studied by reversed-phase thin-layer chromatography in the absence
      and in the presence of 0.1 M sodium chloride. The relative strength of
      interaction was calculated and the relationship between the hydrophobicity
      parameters of the drugs and the strength of the drug-beta-cyclodextrin polymer
      was elucidated by principal component analysis. Drugs readily formed inclusion
      complexes with the cyclodextrin derivatives; the strength of the interaction was
      higher in the presence of sodium chloride. It was assumed that the formation of
      inclusion complexes may influence the behaviour of the drugs resulting in
      modified biological efficacy.

PMID- 10399342
TI  - Properties of adenosine monophosphate deaminase of Candida albicans.
AB  - Adenosine monophosphate deaminase (AMPD; EC 3.5.4.6) catalyses the hydrolysis of
      adenosine monophosphate (AMP) to commensurate amounts of inosine monophosphate
      (IMP) and ammonia. The production of AMP deaminase in Candida albicans was
      measured in Lee's medium grown cultures. The highest AMPD activity was observed
      at 24 h of growth. The enzyme had an optimum pH and temperature at 6-7 and 28
      degrees C, respectively. This enzyme was inhibited under iron-limited growth
      conditions as well as by protease inhibitors. The AMPD of C. albicans showed a
      moderate increase in activity when cultures were grown in the presence of the
      divalent cations Mg2+, Ca2+, and Zn2+. Moreover, ADP, ATP, adenine, adenosine,
      deoxyribose and hypoxanthine increased the enzyme activity. Cultures grown in
      trypticase soy broth exhibited maximum AMPD activity compared with those grown in
      Sabouraud dextrose broth or Lee's medium.

PMID- 10399343
TI  - Heavy metal uptake by polyphosphate bodies in living and killed cells of
      Plectonema boryanum (cyanophycae).
AB  - The study was conducted to determine whether living or killed cell polyphosphate
      bodies (PPB) would sequester more of several heavy metals. Living and heat- or
      glutaraldehyde-killed cells were exposed to 20 ppm of Zn, Pb, Mn and Al. Air
      dried cells on Formvar-coated grids were first observed in the transmission
      electron microscope. The unit was then switched to the scanning transmission mode
      of operation with the spot setting. X-rays were collected on an energy dispersive
      X-ray spectrometer and mass fractions of the metals were determined. In all cases
      live cells sequestered a larger amount of the metal than cells killed by boiling
      or with glutaraldehyde. In all cases the cells killed by glutaraldehyde
      sequestered more of the heavy metals than cells killed by boiling. The results of
      the investigation show that PPB in living cells with active uptake systems take
      up and sequester more of the metals Zn, Pb, Mn and Al than killed cells.

PMID- 10399344
TI  - The antibacterial activity of plaunotol against Staphylococcus aureus isolated
      from the skin of patients with atopic dermatitis.
AB  - Plaunotol was tested for possible antibacterial activity against twenty strains
      of methicillin-resistant Staphylococcus aureus (MRSA) and fourteen strains of
      methicillin-sensitive S. aureus (MSSA) which had been isolated from the skin of
      patients with atopic dermatitis under growth-promoting conditions. Plaunotol was
      effective against all strains tested. The dose of plaunotol for 50% inhibition of
      growth (ID50) ranged from 2.5 to 16 micrograms/ml for strains of MRSA and from
      2.5 to 7.0 micrograms/ml for those of MSSA. These results suggest that plaunotol
      may be useful in the prevention of infection by MRSA and in skin care for
      patients with atopic dermatitis.

PMID- 10399345
TI  - Biosynthesis of endochitinase of Serratia marcescens.
AB  - The growth of a mutant strain of Serratia marcescens with high chitinase activity
      and the biosynthesis of endochitinase by this strain were investigated. The study
      was carried out using semisynthetic culture medium without inducers and culture
      medium containing colloidal chitin as a sole nitrogen and carbon source, with and
      without mitomycin C. The mutant strain, unlike the native one, was shown to
      produce endochitinase and to secrete the enzyme into the medium during the growth
      on culture medium without the inducers, chitin and mitomycin C. During growth on
      the medium with chitin the mutant strain differed from the native one with a
      short lag-phase of growth, the early appearance of endochitinase in the culture
      liquid and a high level of endochitinase activity. The difference between the
      strains disappeared after the addition of mitomycin C, an inducer of the cell SOS
      response, to the culture medium containing chitin. Specific endochitinase
      activity of S. marcescens mutant strain grown on various culture media had two
      maxima, namely at the beginning and at the end of the stationary phase. Mitomycin
      C increased the specific activity in a second peak of endochitinase activity
      during the growth of the mutant strain.

PMID- 10399346
TI  - Probiotics in the new millennium.
AB  - Beneficial effects on human health by specific probiotic microorganisms such as
      prevention of gastrointestinal tract infections immune stimulation, and balancing
      of the intestinal microflora have been established in numerous clinical trials.
      The successful probiotic strains which are mainly members of Lactobacillus and
      more recently Bifidobacterium naturally found in the human intestinal tract, have
      been traditionally incorporated into fermented milk products but have excellent
      potential for further inclusion in functional foods and health-related products.
      While the health claims are generally accepted by both scientists and consumers,
      often the molecular mechanisms underlying the probiotic properties remains
      controversial. Further progress concerning the molecular basis of probiotic
      traits will give vital reinforcement to the probiotic concept and is a
      prerequisite for rational development into further applications. In this review,
      current research on the genetics of properties of the intestinal lactobacilli
      that may contribute to the activity and effectiveness of probiotics is described.
      The potential of molecular biology for future probiotic applications is addressed
      and a probiotic strains developed by modern biotechnology with advantages for
      specific consumers is presented.

PMID- 10399347
TI  - Modulation of intestinal functions by food substances.
AB  - The small intestinal epithelium plays a crucial role in the
      digestion/modification of food components, absorption of nutrients and
      recognition of food-derived signals. It also acts as a barrier against
      unfavourable materials in food. These intestinal functions may be influenced by
      food substances. In this paper, the effects of various food substances on the
      intestinal functions, particularly the absorption functions, are discussed. A new
      assay method, using a monolayer culture system of human intestinal epithelial
      cells, is applied to examine food-derived substances which could modulate the
      tight junction (TJ). Capsianoside, a diterpene glycoside from sweet pepper, was
      isolated and identified as one of the TJ-modulating substances. Those substances
      can be expected to facilitate the paracellular absorption of small molecular
      functional substances such as bioactive oligopeptides. The use of a human
      intestinal cell culture system also enabled us to make a simple screen test for
      food substances which affect the intestinal transporter functions. Substances
      which could suppress the activity of intestinal glucose transporters, for
      example, can be expected to reduce the dietary glucose uptake in the intestinal
      epithelium and control the blood glucose level. Polyphenolic compounds from
      plants, including green tea, were found to have such activity. Modulation of the
      brush border enzymes by food substances is also discussed.

PMID- 10399348
TI  - Antihypertensive peptides derived from milk proteins.
AB  - This paper reviews the angiotensin I-converting enzyme inhibitory peptides
      originated from milk proteins. Focus was put on the peptides derived from milk
      casein by the action of some proteolytic enzymes and fermented products by lactic
      acid bacteria. Some of the angiotensin I-converting enzyme inhibitory peptides
      exhibit significant antihypertensive effects in spontaneously hypertensive rats.
      However, there were some antihypertensive peptides with low inhibitory activity
      of this enzyme. Key factors needed for the peptide to demonstrate the
      antihypertensive effects are discussed. Fermented milk, which has inhibitory
      activity of the enzyme, showed the reduction of blood pressure of hypertensive
      subjects. The possibility of the bioactive peptides for functional foods are also
      discussed.

PMID- 10399349
TI  - Lactokinins: whey protein-derived ACE inhibitory peptides.
AB  - Angiotensin-I-converting enzyme (ACE) has been classically associated with the
      renin-angiotensin system which regulates peripheral blood pressure. Peptides
      derived from the major whey proteins, i.e. alpha-lactalbumin (alpha-la) and beta
      lactoglobulin (beta-lg) in addition to bovine serum albumin (BSA), inhibit ACE.
      Some of these inhibitory peptides, i.e. alpha-lactorphin (alpha-la f(50-53)),
      beta-lactorphin (beta-lg f(102-105)), beta-lactotensin (beta-lg f(146-149) and
      albutensin A (BSA f(208-216)), have other bioactivities. The most potent
      lactokinin reported to date, (beta-lg f(142-148)), has an ACE IC50 of 42.6
      mumol/l. While they do not have the inhibitory potency of synthetic drugs
      commonly used in the treatment of hypertension, these naturally occurring
      peptides may represent nutraceutical/functional food ingredients for the
      prevention/treatment of high blood pressure. Studies with gastric and pancreatic
      proteinase digests of whey proteins indicate that enzyme specificity rather than
      extent of hydrolysis dictates the ACE inhibitory potency of whey hydrolysates.

PMID- 10399350
TI  - Assessment of allergic potential of (novel) foods.
AB  - In safety assessment of Novel Foods such as functional foods, allergy is a
      special issue on which particular emphasis has been placed. The reason for such
      concern is that incidence of food allergies is constantly and rapidly increasing.
      The severity of the reported incidents and the number of foods incriminated are
      also on the rise. The outstanding challenge is to understand what makes a common
      innocuous protein or peptide behave as an allergen for some groups of people, or
      why it may suddenly or progressively become a much more potent allergen than
      usual. It is therefore necessary to consider the risks of creating or unmasking
      new immunoreactive structures, or of overexposure to already reactive substances,
      as a result of new food-production and processing technologies. No test such as
      the use of animal models, the analysis of structure, function and physico
      chemical properties is as yet available to evaluate or predict the allergenicity
      of a "novel" protein in a wholly reliable and objective manner. No indication has
      yet suggested that novel foods, and particularly recombinant proteins or
      genetically modified foods, would be more (or less) allergenic than the
      corresponding conventional foods. No particular structure can be described as
      being solely and intrinsically allergenic. The predictive approaches to
      determining the allergenic potential of NFs should therefore be subject to case
      by-case critical appraisal allied to mandatory implementation of monitoring of
      the potential postmarketing impact of these new foodstuffs on public health.

PMID- 10399351
TI  - Bioactive antinutritional peptides derived from cereal prolamins: a review.
AB  - Alcohol-soluble endosperm proteins (prolamins) from some cereals (e.g. wheat,
      barley, and rye) give origin upon proteolytic digestion to biologically-active
      antinutritional peptides able to adversely affect in vivo the intestinal mucosa
      of coeliac patients, whereas prolamins from other cereals (e.g. maize and rice)
      do not. These antinutritional peptides are also able to: (a) prevent in vitro
      recovery of atrophic coeliac mucosa; (b) to inhibit differentiation of isolated
      rat fetal and chick fetal intestines; and (c) to interact with undifferentiated
      cells either agglutinating them or affecting their proliferation and metabolism.
      Studies performed with A-gliadin, a highly purified bread wheat prolamin
      fraction, and its fragments obtained either by chemical cleavage of A-gliadin or
      by synthesis from aminoacids, clearly pointed out to a few small sequences very
      rich in glutamine and proline residues as the biologically-active agents. Several
      protective substances, including mannan and N,N',N"-triacetylchitotriose, have
      been identified as being able to prevent the effects of these peptides in vitro,
      but the evidence of their in vivo activity is still missing. The present paper
      provides a synthetic overview of the available data concerning this highly
      complex matter and offers a critical appraisal of present hypotheses on the
      action mechanism of biologically-active peptides derived from cereal prolamins.

PMID- 10399352
TI  - Bioactive lipids naturally occurring in bovine milk.
AB  - Bioactive properties of food components increasingly gain in importance in the
      modern diet. Bovine milk fat (BMF) exhibits bioactive substances mainly in the
      class of fatty acids. Currently, most interest is addressed to trans fatty acids
      (TFA) and particularly conjugated linoleic acids (CLA) with BMF being the main
      source of CLA in food. Whereas saturated fatty acids (C12-C16) and TFA are
      reported to be positively correlated (negatively for oleic acid) with
      atherosclerosis and coronary heart disease, CLA are regarded as potent
      anticarcinogens. Also butyric acid (C4) as well as some phospholipids and either
      lipids present in BMF are thought to have anticarcinogenic properties.
      Furthermore, BMF contains the essential fatty acids C18:2 n-6 and C18:3 n-3 that
      have many and diverse functions in human metabolism and, thus, control a variety
      of biochemical and physiological processes. Altogether, BMF contains
      approximately 75 wt% of bioactive substances. However, the overall impact on
      human health can hardly be assessed.

PMID- 10399353
TI  - Database of biologically active peptide sequences.
AB  - Proteins are sources of many peptides with diverse biological activity. Such
      peptides are considered as valuable components of foods with desired and designed
      biological activity. Two strategies are currently recommended for research in the
      area of biological activity of food protein fragments. The first strategy covers
      investigations on products of enzymic hydrolysis of proteins. The second one is
      synthesis of peptides identical with protein fragments and investigations using
      these peptides. It is possible to predict biological activity of protein
      fragments using sequence alignments between proteins and biologically active
      peptides from database. Our database contains currently 527 sequences of
      bioactive peptides with antihypertensive, opioid, immunomodulating and other
      activities. The sequence alignments can give information about localization of
      biologically active fragments in protein chain, but not about possibilities of
      enzymic release of such fragments. The information is thus equivalent with this
      obtained using synthetic peptides identical with protein fragments. Possibilities
      offered by the database are discussed using wheat alpha/beta-gliadin, bovine beta
      lactoglobulin and bovine beta-casein (including influence of genetic polymorphism
      and genetic engineering on amino acid sequences) as examples.

PMID- 10399354
TI  - Intraluminal immunoreactive caseinomacropeptide after milk protein ingestion in
      humans.
AB  - Caseinomacropeptide (CMP)is a 64 amino acids peptide which is the first product
      released after kappa-casein hydrolysis. The present work investigates the
      kinetics delivery of CMP in human jejunal lumen during the digestion of
      intrinsically [15N]-labelled casein, whey protein, yoghurt and pea flour meal.
      Effluents were collected through a nasointestinal tube and analysed for the
      enrichment in [15N] to evaluate the dietary nitrogen fraction. Detection and
      quantification of CMP was performed by an inhibition Elisa procedure. No trace of
      CMP was detected in the ileum of volunteers after the ingestion of the casein
      meal. The results showed that CMP appears in the jejunal effluents within the
      first 20 min after meal ingestion at a level varying from meal to meal. During
      digestion of whey protein, CMP appeared rapidly as a single peak and in high
      amounts, whereas it is discharged slowly in moderate proportions with the casein
      meal. These results demonstrate that CMP is emptied from the stomach in
      significant amounts during milk products digestion and support the hypothesis
      that food-born peptides could exert a physiological function. Moreover, in the
      present study a relation could be assumed between the amount of CMP in the meal
      and the stimulation of luminal endogenous nitrogen secretion. However, the
      specific physiological activity of CMP in humans, particularly on the digestion
      process, requires further studies.

PMID- 10399355
TI  - Flavonols and flavones of parsley cell suspension culture change the
      antioxidative capacity of plasma in rats.
AB  - The flavonoid aglycones from an illuminated parsley (Petroselinum crispum (Mill.)
      Nym.) cell suspension culture were identified and quantified as the flavones
      apigenin, luteolin and chrysoeriol and the flavonols kaempferol, quercetin and
      isorhamnetin. Flavonoid extracts from these cultures were purified by solid phase
      extraction from RP C-18 phase and given by gavage to rats. Only extract from
      illuminated culture increased the antioxidative capacity (AOC) of blood plasma
      temporarily with maximum values after 1 h. It is concluded that the course of AOC
      reflects changes in the plasma content of flavonoids.

PMID- 10399356
TI  - Distribution pattern of a flavonoid extract in the gastrointestinal lumen and
      wall of rats.
AB  - Purified flavonoid extract from illuminated parsley (Petroselinum crispum (Mill.)
      Nym.) cell culture was administered by gavage to Wistar rats. The dose
      corresponded to 6.9 mg flavonoids on aglycone base/kg body mass. Segments of the
      gastrointestinal wall from stomach to colon, their luminal contents, and liver
      and kidneys were collected at time intervals between 1 and 12 h and investigated
      by HPLC of the respective extracts for flavonoids. The spreading of the
      flavonoids was accompanied by partial deglycosylation that began already in the
      stomach where at first quercetin and later apigenin, chrysoeriol and isorhamnetin
      aglycones were detected. We got evidence of flavonoid absorption by the stomach
      that does not require the liberation of aglycones. Due to obvious differences in
      metabolization and absorption rates the composition and the content of flavonoids
      changes in the gastrointestinal segments and their contents with time. Flavonoids
      could be detected neither within the gastrointestinal lumen after 12 h nor in the
      kidneys at any time. But traces of flavonoids were found in the livers at 1.5 and
      12 h.

PMID- 10399357
TI  - Cow's milk proteins and insulin-dependent diabetes mellitus. Something to worry
      about?

PMID- 10399358
TI  - Peptide synthesis during in vitro proteolysis--transpeptidation or condensation?

PMID- 10399359
TI  - Modulating effects of adenosine and modified adenine ribonucleosides on human
      cells (HL-60).

PMID- 10399360
TI  - Antioxidative activity of an ethanolic extract of evening primrose.

PMID- 10399361
TI  - Pyranonaphthoquinone antibiotics--isolation, structure and biological activity.

PMID- 10399362
TI  - Genes and enzymes involved in deoxysugar biosynthesis in bacteria.

PMID- 10399363
TI  - Stable long-term germ-line transmission of transgene integration sites in mice.
AB  - Transgenic mice provide a valuable tool in all fields of basic and applied
      biological and medical research. In this study, we describe the fate of
      integrated transgenes in the mammalian host genome over a large number of
      generations. The stability of the germ-line transmission of integrated tyrosinase
      transgene copies was monitored up to generation F20 in a large number of
      individuals from seven transgenic mouse lines. Phenotypic and molecular genetic
      analysis of the offspring both within the different lines and in cross-breeding
      experiments revealed the high stability of the transgene integration sites in
      mice. Only very few individuals were affected by a transgene copy loss. These
      results indicate that, once homozygous transgenic lines are established, breeding
      programs can be continued to a high number of generations without further
      stringent molecular genetic analysis.

PMID- 10399364
TI  - Transgenic over-expression of a motor protein at high levels results in severe
      cardiac pathology.
AB  - Transgenesis has become a useful tool in effecting a complete or partial
      remodeling of the cardiac contractile apparatus. Although gene dosage effects
      were initially a concern, recent data showed that the heart is able to
      accommodate varying levels of transgenic over-expression without detectable ill
      effects. The present study was designed to test the limits of the transgenic
      paradigm in terms of the production of a cardiac phenotype due simply to the over
      expression of a contractile protein. To this end, eight lines of mice which
      express an isoform of the essential myosin light chain 1 that is normally found
      in the adult ventricle (ELC1v) were generated. Overt phenotype was correlated
      both with the level of expression/protein replacement and copy number of the
      transgene. Two of the lines showed essentially complete replacement of the atrial
      isoform (ELC1a) with ELC1v. However, the phenotypes of the two lines differed
      dramatically. The line with the lower copy number (37 copies), and moderate over
      expression (16 fold) showed no overt pathology while a line with very high copy
      number (94 copies) and extremely high levels of over-expression (27-50 fold)
      developed a significant atrial hypertrophy, dilation and cardiomyopathy. These
      data indicate that very high expression levels of a contractile protein can cause
      a cardiac pathology that is unrelated to its degree of replacement in the
      sarcomere and the unique role(s) it may assume in motor protein function.

PMID- 10399365
TI  - Introduction of a proximal Stat5 site in the murine alpha-lactalbumin promoter
      induces prolactin dependency in vitro and improves expression frequency in vivo.
AB  - In order to establish a possible correlation between in vitro prolactin induction
      and the transcriptional activity of mammary gene promoters in transgenic mice, a
      functional Stat5-binding site was created by means of site-directed mutagenesis
      at position -70 on a 560 bp murine alpha-lactalbumin promotor linked to a CAT
      reporter gene. Surprisingly, the wild-type promoter was constitutively active in
      vitro and could not be induced by prolactin. Introducing the proximal Stat5 site
      abolished this constitutive activity and resulted in prolactin dependence in both
      CHO-K1- and HC11-transfected cells. In transgenic mice, both the frequency of
      lines expressing the transgene and the prevalence of mid to late pregnancy
      expression were increased.

PMID- 10399366
TI  - Increased gene dosage augments antifreeze protein levels in transgenic Drosophila
      melanogaster.
AB  - One of the principal environmental adaptations of certain fishes inhabiting polar
      and northern coastal waters is the synthesis of antifreeze proteins (AFPs). AFPs
      bind to and prevent the growth of nascent ice crystals, thus depressing the serum
      freezing point. The transgenic expression of AFP holds great promise for
      conferring freeze resistance to commercially important plant and animal species.
      Since fish at the greatest risk of freezing have multiple AFP gene copies in
      order to synthesize higher levels of this protein, we have evaluated this
      evolutionary strategy as a way to maximize AFP expression in a model transgenic
      host, the fruit fly Drosophila melanogaster. A construct in which AFP genes of
      the Atlantic wolffish are fused to the Drosophila yolk protein 1,2
      promoter/enhancer region was transferred to flies through P-element mediated
      transformation. Several independent transgenic fly lines were used in genetic
      crosses to obtain multi-insert lines. Haemolymph freezing point depression
      (thermal hysteresis) was greater in homozygotes relative to heterozygotes for a
      given insert. Similarly, multi-insert lines consistently displayed greater
      haemolymph AFP activity than the single insert lines from which they were
      derived. The thermal hysteresis value obtained with a fly line harboring 8 AFP
      gene copies, 0.43 degree C, represents the highest such value to date recorded in
      a transgenic host, and is even higher than the levels found in some AFP-producing
      fish.

PMID- 10399367
TI  - [Factor V: Dr. Jekyll or Mr. Hyde?].

PMID- 10399369
TI  - Clinical evaluation of systemic sclerosis: a comprehensive panel of diagnostic
      tests to assess skin, microvascular and visceral involvement. The Genoese Group
      for the Study of Systemic Sclerosis.
AB  - The work proposes a set of diagnostic tests and relative clinical scores for the
      staging and follow-up of patients with systemic sclerosis. Thirty-one consecutive
      patients (30 females, 1 male, age range 17-65 years) affected by systemic
      sclerosis, according to the American College of Rheumatology criteria for
      classification of this disease, were enrolled in the study at the time of their
      first admission to the Department of Internal Medicine in Genoa. The following
      battery of tests was utilized: nailfold capillary videomicroscopy, esophageal
      manometry and pH-metry, lung vital capacity and diffusing capacity for carbon
      monoxide, intrarenal duplex Doppler sonography, echocardiography and skin
      plicometry. Good compliance by the patients was obtained for the tests we used.
      We found that nailfold capillary videomicroscopy and plicometry scores were
      statistically associated each other as well as with the scores measuring
      esophagus and/or lung function. The use of wide range of diagnostic procedures,
      such as those proposed in this paper, allows appropriate definition of the stage
      of patients with systemic sclerosis. The use of nailfold capillaroscopy and skin
      plicometry as the simplest tests for monitoring patients is suggested: the scores
      derived from these procedures are statistically associated with some internal
      organ status and could be useful in the evaluation of therapeutical results.

PMID- 10399368
TI  - Clinical experiences with emergency ultrasound guided diagnostic and therapeutic
      procedures in a department of internal medicine.
AB  - In some particular clinical emergencies, it is mandatory to obtain a pathological
      diagnosis as soon as possible and to start therapy quickly. This can be often
      done by means of ultrasound guided fine needle biopsy. The cases of emergency
      ultrasound guided fine needle biopsies and drainages performed in our Ultrasound
      Laboratory over the past 5 years represent 1.6% of all procedures performed on
      deeply located lesions. Diagnostic accuracy of emergency ultrasound guided fine
      needle biopsies was comparable to that obtained in routine situations. In 11/12
      patients, this diagnostic procedure allowed the immediate start of proper
      therapy. Emergency ultrasound guided percutaneous drainage was performed in 6
      patients and all of them had a successful outcome. We conclude that emergency
      ultrasound guided diagnostic and therapeutic procedures, although rarely
      necessary, can be very useful in some clinical situations. The high efficacy of
      these techniques is not impaired in an emergency.

PMID- 10399370
TI  - Histamine releasability after adenosine challenge in subjects with allergic and
      non-allergic rhinitis: possible implications for mast cell priming.
AB  - Nasal provocation with adenosine 5'-monophosphate elicits nasal symptoms in
      subjects with rhinitis. Histamine released from airway mast cells may play a role
      in adenosine-induced nasal responses. To investigate the possible role of
      histamine in mediating adenosine-induced nasal responses, we measured its release
      in the fluid obtained by nasal lavage after adenosine 5'-monophosphate, guanosine
      5'-monophosphate, and placebo instillations. Nasal lavages were performed before
      and 3, 5, 10, 15, 30 and 45 min after challenge with adenosine 5'-monophosphate,
      guanosine 5'-monophosphate, and normal saline in 11 patients with rhinitis and 7
      normal subjects in a double-blind randomized placebo-controlled cross-over study
      to evaluate symptoms and to monitor changes in histamine levels. No symptoms or
      significant increases in histamine were observed after guanosine 5'-monophosphate
      and placebo challenge. Symptom scores increased in response to adenosine 5'
      monophosphate challenge in the rhinitic subjects but not in the normal controls.
      Nasal provocation with adenosine elicited a significant release of histamine in
      the nasal lavage fluids with an immediate peak response: its median (range)
      concentration increased from the baseline value of 1.33 (0.16-14.54) ng/mL to
      2.68 (0.31-61.11) ng/mL at 3 min. However, increased histamine levels were not
      associated with nasal symptom scores. When compared to non-atopic subjects,
      significantly higher levels of histamine were seen in the nasal lavage fluids of
      the atopic subjects following adenosine challenge. In the atopic subjects, the
      median (range) histamine concentration increased from the baseline value of 1.54
      (0.16-14.54) ng/mL to that of 4.21 (0.70-61.11) ng/mL at 3 min, whereas no
      increment was seen in the non-atopic subjects, their histamine concentration
      being 0.81 (0.29-5.56) ng/mL and 0.74 (0.31-14.25) ng/mL at baseline and 3 min
      after adenosine challenge respectively. These findings indicate that adenosine
      elicits nasal responses in patients with rhinitis but not in normal controls.
      Moreover, adenosine elicits an immediate rise in histamine levels in the nasal
      lavage fluid, with the highest rise in atopic compared to non-atopic volunteers,
      suggesting that the nasal responses to adenosine may be an index of mast cell
      priming.

PMID- 10399371
TI  - [The molecular mechanisms of cerebral ischemia: the possible therapeutic
      interventions].
AB  - Therapeutic interventions for acute ischemic stroke have not yet been established
      in clinical practice. The recognition of an area of reduced blood flow in which
      neuronal death may be prevented has focused attention on treatments aiming at
      minimizing ischemic brain damage, if they are initiated within short time after
      occlusion. The combination of restoring blood flow and providing neuroprotection
      may be the most productive approach in human acute ischemic stroke, but this
      combined therapy requires testing through clinical trials. To gain insight into
      the molecular mechanisms of cerebral ischemia, this review examines the excito
      toxic cascade, synthesis and role of nitric oxide and oxidants, gene regulation
      and possible neuroprotective therapeutic targets. As neuroprotectants, glutamate
      antagonists, calcium-antagonists and free radical scavengers have been
      investigated. The role of nitric oxide is very complex, as it can be cytotoxic or
      cytoprotective in relation to sources, time of synthesis, and medium redox state.
      Animal gene studies suggest that nitric oxide produced by endothelial nitric
      oxide synthase may be advantageous, while nitric oxide produced by neuronal and
      inducible nitric oxide synthase disadvantageous. A treatment strategy could
      involve the use of selective inhibitors of different types of nitric oxide
      synthase. Cell death after cerebral ischemia occurs through the dual pathway of
      ischemic necrosis and apoptosis. Novel therapies may be directed at genes
      mediating either recovery or apoptosis. There are, as yet, no conclusive data
      concerning the safety and efficacy of neuroprotectants in humans. Differences
      between animal models and clinical conditions may justify the discrepancy between
      experimental data and clinical practice.

PMID- 10399372
TI  - [Endothelial function and the microcirculation in diabetes mellitus].
AB  - The role of endothelial dysfunction in the pathogenesis of diabetic
      microangiopathy is reviewed. Reversible alterations in microcirculation,
      consisting of increased capillary pressure, blood flow and endothelial
      permeability, can be detected at an early stage in diabetes mellitus.
      Irreversible structural modifications of the vascular wall, such as thickening of
      the basal membrane due to the extracellular accumulation of proteins, take place
      at later stages. Atherosclerosis further affects microcirculation in diabetes
      mellitus by decreasing autoregulatory capacity and blood flow reserve.
      Endothelial dysfunction has been observed to precede the onset of microvascular
      lesions, as demonstrated by reduction in the vasodilatory response to vasoactive
      agents and by alterations in the antithrombotic properties of the endothelium.
      Experimental data available so far suggest that endothelial dysfunction may be
      directly related to hyperglycemia. Abnormalities in lipoprotein metabolism,
      generation of glycation end products, and increased oxidative stress may also be
      responsible for the endothelial dysfunction in diabetes mellitus. Insulin
      resistance appears to be related to endothelial dysfunction in non-insulin
      dependent diabetes mellitus through a reduction in the biological activity of
      endothelial-derived nitric oxide.

PMID- 10399374
TI  - [Lymphomas presenting as Tietze's syndrome: a report of 4 clinical cases].
AB  - We describe 4 cases of malignant lymphoma (3 women, 1 man, age range 20-49 years)
      presenting with a tender and fusiform swelling at the level of the upper
      costosternal joints, with the clinical characteristics of classic Tietze's
      syndrome. Physical examination, laboratory findings and chest X-rays all were
      negative, while telethermography examination evidenced an area of hyperthermia at
      the level of the swelling in the chondrosternal region. Tietze's syndrome was
      diagnosed and the patients were treated with non-steroidal anti-inflammatory
      drugs and a local injection of corticosteroid. The clinical picture did not
      change, and in 2 cases a cervical lymphadenopathy developed. A biopsy of the
      lymph nodes and articular tumefaction disclosed Hodgkin's disease in 3 cases and
      non-Hodgkin's lymphoma in 1 case. Computerized tomography, lymphography and bone
      marrow biopsy permitted the complete staging of the lymphoma. After beginning a
      therapeutic program with chemotherapy and irradiation therapy, all 4 patients
      underwent complete remission.

PMID- 10399373
TI  - Two cases of autoimmune thrombocytopenic purpura associated with antiphospholipid
      antibodies.
AB  - We report 2 cases of autoimmune thrombocytopenic purpura associated with
      antiphospholipid antibodies. In the first case the titer of antiphospholipid
      antibodies was neither related to disease activity nor influenced by
      immunosuppressive therapy. In the second, cerebral infarction occurred in spite
      of severe thrombocytopenia. Our results provide additional evidence that
      antiphospholipid antibodies are not involved in the pathogenesis of autoimmune
      thrombocytopenic purpura. Nevertheless, the frequency and clinical significance
      of this association would suggest that patients with autoimmune thrombocytopenic
      purpura should be tested for antiphospholipid antibodies, particularly before
      pregnancy or surgical procedures.

PMID- 10399375
TI  - [Hyperthyroidism due to the improper use of povidone-iodine].
AB  - A 48-year-old female was referred to Perugia Hospital because of cardiac
      palpitations and insomnia. The clinical history, the physical examination and
      laboratory tests were supportive of hyperthyroidism. Since July 1994 the patient
      had been combating constipation by improper use of an iodine-containing
      antiseptic cream for external use only. She had inserted povidone-iodine into the
      rectum by means of a cannula. The iodine-containing cream was suspended, and a
      beta-blocker prescribed. Cardiac palpitations disappeared within 2 weeks, and
      plasma thyroid hormone levels returned to normal within 1 month. Hyperthyroidism
      in this patient was probably triggered by improper long-term use of an over-the
      counter cream. When investigating the etiology of hyperthyroidism, a history of
      long-term use of iodine-containing medication should always be considered. These
      medications should be used with caution for only short periods of time and, if
      usage is prolonged, medical supervision should be recommended; above all, they
      should be applied only as directed.

PMID- 10399376
TI  - [The concomitant presence of prohemorrhagic and thrombophilic changes in
      coagulation factor V: a severe defect of coagulant activity and homozygote
      resistance to activated protein C].
AB  - We describe the peculiar and concomitant presence of a severe coagulation defect
      predisposing to bleeding and a mutation associated with inherited thrombophilia.
      A 6-year-old boy had a severe deficiency in factor V procoagulant activity and
      antigen and yet remained asymptomatic. This paradox might be explained by the
      hypothesis of the simultaneous presence of a thrombophilic disorder that might
      have restored hemostatic balance. The boy was a homozygous carrier of the
      Arg506Gln mutation of coagulation factor V, that renders this factor resistant to
      inactivation by its naturally occurring inhibitor, activated protein C. The
      family members, none of whom had bleeding or thrombotic symptoms, were
      heterozygotes for either the bleeding or the thrombophilic defect. Despite the
      severity of the bleeding defect, the absence of bleeding symptoms in the boy can
      be explained by the hypothesis that any residual amount of factor V present in
      his plasma is resistant to inactivation by activated protein C.

PMID- 10399377
TI  - [The impact factor: a factor of impact or the impact of a (sole) factor? The
      limits of a bibliometric indicator as a candidate for an instrument to evaluate
      scientific production].
AB  - The Impact Factor is a bibliometric quantitative parameter introduced in 1971 and
      used to evaluate, classify and compare scientific journals. It is essentially the
      ratio between the number of citations they receive, computed on the basis of
      those included in the Science Citation Index, and the number of published
      articles. It is thus a dynamic parameter and an indicator of the editorial
      quality of a journal. It has also been considered a putative index of the
      scientific production of a single author. The Impact Factor was first proposed as
      a useful instrument for planning library choices, programming personal journal
      buying and reading, and directing scientific journal editors in their editorial
      strategies. However, since among the numerous variables which may influence the
      Impact Factor there are such parameters as: the average number of bibliographical
      references in a single article, self-citations, "salami publications", the Impact
      Factor, though adequate to judge entities such as journals, institutions and
      whole scientific communities, seems on the contrary inadequate to evaluate
      accurately the quality of the single investigator, paper, and research group.
      Furthermore, a limited number of papers, all focused on the so-called "hot
      topics", may contribute to increase the Impact Factor of a single journal. There
      is therefore still much research to be done to find truly "objective" methods to
      evaluate critically the "quality" (and not only the "quantity") of the work of a
      single author, a scientific group, and an entire institution, so that not only
      quantitative, but also qualitative evidence may be acquired!

PMID- 10399379
TI  - Feminisation of the medical workforce. Is it just a gender issue?

PMID- 10399380
TI  - Does it matter that your research is qualitative?

PMID- 10399381
TI  - New warning about cefaclor and serum sickness in children.

PMID- 10399382
TI  - Whooping cough infection.

PMID- 10399383
TI  - Whooping cough infection.

PMID- 10399384
TI  - Help seeking among a sample entering treatment for cannabis dependence.

PMID- 10399385
TI  - The young athlete.
AB  - BACKGROUND: It is very much part of the Australian lifestyle to encourage
      children and adolescents to participate in sport and exercise. As a result the
      general practitioner is often presented with injuries in younger patients.
      OBJECTIVE: This article presents an overview of the growth and development of the
      musculoskeletal system, and discusses relevant aspects of conditioning and
      training and the nature of injuries seen in the younger athlete. DISCUSSION: The
      range of common musculoskeletal problems seen in young children and adolescents
      is outlined with some recommendations made for an approach to management of the
      commoner conditions.

PMID- 10399386
TI  - Is it legal? Prescribing for the athlete.
AB  - BACKGROUND: The taking of performance enhancing drugs is an issue in many sports.
      To counteract this health endangering problem most sports have adopted the
      International Olympic Committee Medical Commission's classes of banned drugs.
      OBJECTIVE: Practitioners may inadvertently prescribe banned drugs, resulting in a
      positive drug test and a penalty for the athlete. This paper reviews the current
      recommendations when prescribing for an athlete. DISCUSSION: Medical
      practitioners will avert potentially disastrous situations for athletes by being
      aware of the drugs that are prohibited for sportspersons or by knowing how to
      rapidly access such information when prescribing for athletes.

PMID- 10399387
TI  - After an injury. What next?
AB  - BACKGROUND: The goal of treatment of sports injuries must be restoration of
      function to the greatest possible degree in the shortest possible time. Initially
      this will require first aid treatment to decrease swelling, congestion and muscle
      spasm but it is equally important to minimise deconditioning of the rest of the
      body. OBJECTIVE: This article summarises the approach to minimising the effects
      of an acute injury in an athlete and maximising the chances for a full return to
      sport without incurring further injuries. DISCUSSION: A good knowledge of anatomy
      is needed to make a specific diagnosis so a comprehensive treatment plan can be
      implemented. Treatment involves several options: immobilisation, NSAIDs,
      physiotherapy, surgery and rehabilitation. Rehabilitation, which should not wait
      until after the injury has healed, encompasses strength, flexibility,
      proprioception, endurance, motor relearning, aerobic fitness and sometimes
      counselling.

PMID- 10399388
TI  - Nutrition for sport. Getting the most out of training.
AB  - BACKGROUND: Sports nutrition involves the application of eating strategies to
      promote good health and adaptation to the training program, to recovery quickly
      after each exercise session and to perform optimally during competition.
      OBJECTIVE: This article explores the many myths about sports nutrition principles
      and provides answers to the most common questions that arise in sports nutrition.
      DISCUSSION: Good nutrition practices will enhance the performance and enjoyment
      of sport and exercise activities at all levels.

PMID- 10399389
TI  - Exercise-related chronic lower leg pain.
AB  - BACKGROUND: Musculoskeletal injuries result from physical activity and seem to
      have a dose-response relationship to the amount of that activity. The more
      exposure to training or sport the greater the risk of injury. OBJECTIVE: This
      article examines the common causes of chronic exertional leg pain in the
      community. DISCUSSION: The common presentations include muscle injury, medial
      tibial stress syndrome, stress fractures of the lower limb, chronic exertional
      compartment syndromes as well as nerve entrapments. A description of these and an
      algorithm to assist in the diagnostic dilemma are presented.

PMID- 10399390
TI  - Doctors badmouthing each other. Does it affect medical students' career choices?
AB  - OBJECTIVES: To study the frequency of negative comments (badmouthing) made by
      teaching hospital specialists about metropolitan and rural general practitioners
      (GPs) and by GPs about hospital specialists and the impact of these comments on
      medical students' intended career choice. In this study badmouthing is defined as
      unwarranted, negative, denigrating, even sarcastic comments made by doctors about
      other doctors. METHODS: A retrospective questionnaire survey of 170 5th and 6th
      year medical students from The University of Western Australia conducted in 1997.
      The questionnaire was a modified version of one developed by medical educators at
      the University of Washington School of Medicine, using both ranked and open
      questions. RESULTS: Overall students reported either no comments or hearing
      balanced comment from both teaching hospital specialists and GPs. Seventy-eight
      percent of all students reported at least one negative comment per year about
      urban GPs, 50% reported a negative comment on rural GPs and 59% a negative
      comment by GPs about specialists in teaching hospitals. The reported impact on
      students, intentions to pursue any of these three disciplines was inversely
      proportional to the frequency of negative comments heard. Twelve percent of
      students reported being influenced against pursuing a future career in urban
      general practice, 7% against becoming a rural GP and 8% against becoming a
      specialist. Widespread badmouthing of rural GPs, reported in 1987, has apparently
      diminished with students reporting balanced and positive comment on rural GPs to
      be five times more common than negative comment. CONCLUSION: A low level of
      badmouthing by all medical disciplines is an unattractive part of the learning
      milieu of medical students. In this study it had an influence on the current
      career choices of 21% of participating students.

PMID- 10399391
TI  - Badmouthing between disciplines.

PMID- 10399392
TI  - Incontinence in women. Don't suffer it.
AB  - BACKGROUND: Urinary incontinence is a distressing and embarrassing condition
      suffered by at least 1 in 10 women. Incontinence is not just a disease of the
      elderly: 40% of women aged 30 to 50 suffer from incontinence and a surprising 11%
      of young women who have never borne children may also experience it. OBJECTIVE:
      Incontinence unlike other chronic diseases can be cured in up to 70% of patients.
      DISCUSSION: The cost of incontinence is immense. Studies based on health care
      costs of urine incontinence in the USA indicate expenses as high as 2% of the
      national health care budget. Australia spends nearly 1 billion dollars per year
      on incontinence aids and this represents only a fraction of the total cost of
      incontinence.

PMID- 10399394
TI  - Compliance and the adverse event profile.

PMID- 10399393
TI  - Clinical audit activity. Prescribing for common conditions--hypertension.

PMID- 10399396
TI  - A painless penile ulcer.

PMID- 10399395
TI  - A man with hemiparesis.

PMID- 10399397
TI  - Practice tip. Apgar system for newborns.

PMID- 10399398
TI  - Patient information. Urinary incontinence.

PMID- 10399399
TI  - The body is the shadow of the soul.

PMID- 10399400
TI  - A duty of compassion.

PMID- 10399401
TI  - [Reproductive performance and milk production of Israeli-Holstein cows with
      different supplementation during the dry period].
AB  - In three field trials comprising 602 Israeli-Holstein dairy cows, the effect of
      the dry period ration on reproductive performance, culling rate and milk
      production was investigated. The cows were fed in groups. The basic dry period
      rations consisted for two herds of medium quality cereal hay and for one herd of
      corn straw, which were fed ad libitum. In each herd dry cows were assigned to an
      experimental and control group. Cows of the experimental group were supplemented
      with 1.5 to 3 kg of lactating cows mixed ration (LMR), whereas in the control
      group the amount of supplement was increased by the factor two or 3.3. In the
      experimental group the amount of the supplement was calculated to achieve levels
      of net energy and of crude protein close to NRC requirements; in the control
      group the level of net energy and protein was 12 to 18% higher as compared to the
      experimental group. The amount of LMR supplement in the experimental group of
      herds A, B, C were 1.5 kg, 1.9 kg, and 3 kg, respectively. In the control groups
      these amounts were 5 kg, 3.8 kg, and 6 kg, respectively. The groups fed moderate
      amounts of LMR supplement had a higher conception rate at first insemination, a
      higher percentage of cows conceiving and fewer cows culled in the consecutive
      lactation than cows fed increased amounts of LMR supplement. The lactational
      incidence of reproductive disorders and the milk production were not affected by
      the differences in feeding during the dry period. Reproductive performance and
      culling rate appeared to be more favorable for cows fed moderate amounts of
      supplement during the entire dry period or during the last 3 to 4 weeks of the
      dry period.

PMID- 10399402
TI  - [Acid-base status in newborn calves during the first days of life considering
      different states of vitality].
AB  - The aim of this study is to describe the differentiations of the acid-base status
      in bovine neonates during the first 96 hours of life. Due to the short intervals
      in the taking of blood samples, noticeable fluctuations in the acid-base status
      during the first minutes and hours of life of newborn calves were documented.
      Altogether, 25 matures and eutrophe calves of the DSB, DRB and DFV breeds were
      provided by the clinic for this study. Apart from an immediate post natum
      clinical interpretation of the vital signs in the neonates-using the APGAR-score
      the pH value, current Base Excess and the CO2 pressure were simultaneously
      ascertained. Further continuous evaluation of the acid-base status was
      subsequently followed in the first phase of adaptation. For that alone, twelve
      blood samples were taken from the vena jugularis within the first 60 minutes
      after parturition. Until the end of the examination period on the fourth day of
      life, the tests amounted to 26 measurements altogether per experimentee. Due to
      the concrete results ascertained from the initial clinical and laboratory
      observations, the experimentees could be divided into distinct classes of
      vitality. The acid-base status of all the calves deteriorated during the first
      minutes of life, indicating that the pH value and Base Excess fall clearly under
      the initial level in all aspects of vitality directly post natum. On average the
      minimum pH values are reached between the third and 15th minute of life and
      remain between 0.019 and 0.096 below the initial values during this period. A
      varying rapid increase of the pH value follows, together with a balancing out of
      the Base difference. Despite isolated individual variations as the acid-base
      status develops, the lowering of the pH values in the first minutes of life is
      assessed as being a normal biological phenomenon. Deviations from this occur
      rarely (8%) and do not conform to the norm. The pH value stabilization in
      connection with this crucial early postnatal phase occurs to such a high degree
      that, without stagnation, on average all experimentees show pH values between
      7,270 and 7,300 after 180 minutes of life-regardless of which vitality group they
      belong to. After reaching this common value at the end of the third hour of life,
      the further development of the ph values and the consequential resulting
      parameters in all three vitality groups are similar. A stagnation of the rising
      pH value between the 4th and 12th hour of life was established during the
      examination. Moderate stabilization then set in after this phase. Between the
      24th and 36th hour of life all experimentees reached an average highest pH value
      of 7,400. Until the end of the examination period, however, this then dropped
      slightly to values between 7,380 and 7,395.

PMID- 10399403
TI  - Case report: idiopathic toxic epidermal necrolysis in a one-week old calf.
AB  - A sporadic case of apparent toxic epidermal necrolysis in a one-week-old calf is
      presented. The clinical picture was characterized by full-thickness epidermal
      exfoliation. No underlying disease or drug administration could be detected in
      the affected animal, therefore, the case was classified as idiopathic. The
      clinical and histological findings are discussed in the light of the pertinent
      literature. Recovery was noted within three months.

PMID- 10399404
TI  - [Elephant herpes virus--a problem for breeding and housing of elephants].
AB  - Herpesvirus infections which take a fatal turn on African elephants as well as on
      Asian elephants seem to occur increasingly not only in the USA but also in
      European stocks. The endotheliotropic herpesvirus causes a rapidly progressing
      and severe disease which makes any therapeutical effort unsuccessful and finally
      results in death of the animal, especially in young Asian elephants. As all
      attempts to culture the virus failed up to now, molecular biological procedures
      have to be used more often for diagnostical purpose together with the common
      methods of pathology, virology, and electronmicroscopical evaluation. This is a
      report on the case of 'KIBA', an eleven year old male elephant at the Zoological
      Garden Berlin, infected with the endotheliotropic elephants herpesvirus. 'KIBA'
      was born at the Zoo in Houston, Texas, and raised within his herd. Upon arriving
      in Berlin in November 1997 he adapted to the new premises and climate and new
      social circumstances without any problems. In June 1998 he already serviced three
      females of his new herd several times. In August 1998 he died after passing a
      peracute progression of the disease after residenting in Berlin for only 9
      months. The dissection of the animal revealed some evidence on an agent damaging
      the endothelium. Major signs indicating this agent were bleedings in several
      serous membranes, mucosa and on the the right atrium, as well as other parts of
      the myocardium. Furthermore there have been ulcerations at various localisations
      of the whole digestive tract. Slightly basophilic intranuclear inclusion bodies
      have been found histologically in endothelial cells of different organ samples.
      An examination of altered organ-material by electronmicroscopy made some
      herpesvirus-like particles visible. A virological investigation first revealed
      evidence of giant cell formations with solitary basophilic intranuclear inclusion
      bodies in different cell cultures, however, without any distinct cytopathogenic
      effect. Supported by molecular biological procedures the infection of 'KIBA'
      could be verified as the elephants herpesvirus. By means of PCR and subsequent
      sequence analysis a DNA-sequence typical for the elephants herpesvirus could be
      obtained which showed an identity of 97% with the terminase sequence of the
      elephant herpesvirus described by American authors. The deduced amino acid
      sequences were 100% identical. To the terminase of the human cytomegalovirus, the
      elephant sequence had an identity of 53% (similarity: 74%). Based on the
      cooperation of ILAT, Institute of Veterinary-Pathology/Free University Berlin,
      Robert-Koch-Institut Berlin, and Zoological Garden Berlin, the cause of 'KIBA's'
      death could be discovered immediately. Possible implications of this case
      especially on breeding and keeping elephants are discussed briefly.

PMID- 10399405
TI  - [Determination of beta-adrenergic binding sites in the myocardium of young female
      chickens of various strains--a study for the clarification of frequent occurrence
      of sudden death and ascites in male broilers].
AB  - The present investigations should contribute to clarify the importance of beta
      adrenergic system in myocard for the triggering of sudden death syndrome and
      ascites in male broiler chickens. Therefore it should be verified if differences
      in density of beta-adrenergic receptors in myocard exist in several strains and
      sexes of chickens. We showed in both male and female broilers that the receptor
      density was significantly higher as in chickens of the laying strain. There were
      no significant differences in receptor density between sexes in both investigated
      strains as well as in KD-values between all groups. The latter finding is
      referred to the absence of differences in receptor affinity for 3H
      dihydroalprenolol between the groups. Clarification of the question if chronic
      heart failure is in contrast to myocard hypertrophy accompanied with reduction of
      beta-adrenergic receptor density or receptor affinity in broilers too, as could
      be shown in other species, has to carried out in further investigations.

PMID- 10399406
TI  - [Molecular biology of neurosecretion and its inhibition bu tetanus and botulinum
      toxins (review)].
AB  - Signal transfer between neurons and between neurons and muscle cells is mediated
      by the secretion of neurotransmitters. The axon of the presynaptic cell contains
      synaptic vesicles, the storage organelles for neurotransmitters. Arrival of an
      action potential causes calcium-influx into the axon and leads to fusion of
      synaptic vesicles with the presynaptic plasma membrane. Recently, the events
      between calcium-influx and membrane fusion were elucidated on a molecular level.
      The family of SNARE-proteins was identified as the key players in neurosecretion.
      They are located on synaptic vesicles (VAMP) or on the presynaptic plasma
      membrane (syntaxin, SNAP-25). Intimate protein-protein interactions between the
      SNARE-proteins are responsible for the attachment and merger of vesicle and the
      plasma membrane. Fusion is triggered by calcium-binding to synaptotagmin, another
      protein recently identified on synaptic vesicles. The molecular mechanism of the
      action of clostridial neurotoxins was also elucidated. Botulinum-as well as
      Tetanus toxins are proteases which cleave neuronal SNARE-proteins. This explains
      the long known inhibition of neurosecretion caused by these toxins. The
      proteolytic action of Tetanus- and Botulinum toxin occurs in different types of
      neurons, resulting in a stimulatory or inhibitory effect on muscle cells. This
      selective degradation of SNAREs explains the opposing clinical signs of tetanus
      (cramps) and botulismus (paralysis).

PMID- 10399407
TI  - Vector of Lyme borreliosis, Ixodes scapularis, identified in Saskatchewan.

PMID- 10399408
TI  - False-positive laboratory tests for Cryptosporidium involving an enzyme-linked
      immunosorbent assay--United States, November 1997-March 1998.

PMID- 10399409
TI  - Dental materials: 1997 literature review.
AB  - This review of the published literature on dental materials for the year 1997 has
      been compiled by the Dental Materials Panel of UK. It continues a series of
      annual reviews started in 1973. Emphasis has been placed upon publications, which
      report upon the materials science or clinical performance of the materials. The
      review has been divided by accepted materials classifications (fissure sealants,
      glass polyalkenoate cements, dentine bonding, dental amalgam, endodontic
      materials, casting alloys, ceramometallic restorations and resin-bonded bridges,
      ceramics, denture base resins and soft lining materials, impression materials,
      dental implant materials, orthodontic materials, biomechanics and image
      processing, resin composites, and casting investment materials and waxes). Three
      hundred and thirty three articles have been reviewed.

PMID- 10399410
TI  - Clinical behaviour of glass ionomer restorations in primary teeth.
AB  - OBJECTIVE: To compare a silver-reinforced glass ionomer material (cermet) with a
      resin-modified glass ionomer in minimal Class II preparations in primary teeth.
      METHODS: Matched pairs of primary molars with approximal caries that required
      operative treatment were used. Each cavity was filled with either Vitremer or
      Ketac-Silver. The restorations were followed for at least 36 months and examined
      annually using bitewing radiographs and clinical inspections. Impressions were
      taken at each recall and models were examined microscopically. RESULTS: After 36
      months, one of the resin-modified glass ionomer (RMGI) restorations and 13
      (26.5%) of the silver cermet restorations had failed. The RMGI failed because of
      secondary caries, while most of the failures of the silver cermet fillings were
      marginal defects alone or in combination with secondary caries. The median
      survival time (MST) for the silver cermet restorations was 37 months. The RMGI
      restorations had a MST exceeding 42 months, but MST could not be calculated
      exactly because of the low failure rate during the study period. CONCLUSIONS: The
      resin-modified glass ionomer had the overall best performance of the two
      materials under comparison. The silver cermet material cannot be recommended for
      Class II restorations in primary teeth.

PMID- 10399411
TI  - Oral status and nutrition in the institutionalized elderly.
AB  - OBJECTIVES: To evaluate, in an elderly population, whether poor oral status might
      be a contributing factor to the development of undernutrition and might be
      associated with less eating pleasure, more subjective eating difficulty and
      increased mashed food consumption. METHODS: An oral examination and an evaluation
      of masticatory capacity were performed on 120 institutionalized elderly subjects.
      The nutritional assessment included serum albumin concentration, the Mini
      Nutritional Assessment and a questionnaire on eating habits. RESULTS: Edentulous
      subjects without dentures or with only one complete denture had significantly
      lower MNA scores than edentulous subjects with two complete dentures (p < 0.05).
      Edentulous subjects with two complete dentures more frequently reported taking
      pleasure from eating (p = 0.05), and had less frequent difficulties with hard
      foods (p = 0.01) than edentulous subjects without dentures or with only one
      complete denture. Mashed food consumption (p < 0.01) was also reported more
      frequently in edentulous subjects without dentures or with only one complete
      denture. Subjects with two complete dentures had similar or better MNA scores as
      dentate subjects with relatively few remaining teeth (10.4 +/- 7.8 teeth). About
      half of the subjects (53%) could not perform the masticatory test. These subjects
      had lower MNA scores (p = 0.001) and a larger proportion ate mashed food (p <
      0.001) compared to those who were able to perform the test. CONCLUSIONS: Poor
      oral status (edentulous without dentures or with only one complete denture)
      increased difficulty in eating hard foods, increased mashed food consumption and
      decreased eating pleasure. It seemed also to put institutionalized subjects at
      higher risk of undernutrition.

PMID- 10399412
TI  - Ion release from orthodontic appliances.
AB  - OBJECTIVE: The microbiological and enzymatic characteristics of the oral cavity
      would seem to provide a suitable environment for the corrosion of metals. We
      assayed the release of metal ions from one orthodontic appliance which included
      two 304 and 316 steel molar bands, ten 316 steel brackets, one nickel-titanium
      archwire and a brazing alloy to connect the elements of molar bands and brackets.
      METHODS: The orthodontic appliance was dipped in both inorganic (pH 3.5-6.5) and
      organic acid solutions (w/v 1% each of tartaric, citric and ascorbic acid at pH
      2.2 or 1.5% each of lactic and acetic acid at pH 2.5). The release of nickel
      (Ni), chromium (Cr), copper (Cu), silver (Ag) and palladium (Pd) was determined
      using an atomic absorption spectrophotometer Varian AA 10. RESULTS: The release
      of Ni, Cr and Cu was markedly less at pH 6.5 than at pH 3.5 at all time points in
      acid solution. Daily release/single appliance after the first day decreased.
      Contrary to expectations, appliances immersed in organic acid solutions at pH 2.2
      or 2.5 after 28 days generally released an amount of ions similar to that
      observed in inorganic acid solution at pH 3.5, with the exception of Cu. Release
      of silver and palladium, two metals present in the brazing alloy, proved to be
      very low (approximately 0.2 microgram after 28 days). CONCLUSIONS: The daily
      release of Ni, Cu and Cr by an orthodontic appliance in acid pH, particularly
      favourable to corrosion, was well below that ingested with a normal daily diet.
      It is therefore concluded that the quantities of metal ions released in our
      experimental conditions should not be cause for concern in utilising the
      appliance.

PMID- 10399413
TI  - Fluoride release, microbial inhibition and microleakage pattern of two
      orthodontic band cements.
AB  - OBJECTIVES: To compare, in vitro, the fluoride release, microbial inhibition and
      microleakage pattern of a conventional glass ionomer cement (Ketac-Cem) and an
      acid-modified composite (Ultra Band-Lok) for band cementation. METHODS: Fluoride
      release was measured from cement discs (3.0 mm diameter and 1.5 mm thick) at
      regular intervals over 40 days using a potentiometric method. Microbial
      inhibition was determined for each cement using an agar diffusion test against
      one of four different strains of Streptococcus mutans. Thirty pairs of banded
      third molars (15 banded pairs for each cement) were thermocycled and microleakage
      determined by a dye penetration method. The depth of microleakage was assessed by
      an index applied by two examiners independently to photographic records taken of
      the mid-buccal aspect of each tooth. RESULTS: The cumulative and daily fluoride
      release for days 5, 15 and 40 were significantly greater for Ketac-Cem than for
      Ultra Band-Lok (all p < 0.05). After the initial set, the anti-microbial activity
      was significantly greater for Ketac-Cem than for Ultra Band-Lok over the
      following 24 h period for all four strains of S. mutans (all p < 0.05). There was
      no significant difference between the two cement groups for microleakage at the
      cement/enamel interface (p = 0.66) but a borderline significance was detected for
      microleakage at the cement/band interface (p = 0.051). CONCLUSIONS: The fluoride
      release and anti-microbial activity of Ketac-Cem were greater than that of Ultra
      Band-Lok. There was no significant difference in microleakage between the cements
      at the cement/enamel interface but a borderline difference existed between the
      cements at the cement/band interface.

PMID- 10399414
TI  - Hemoglobin near-infrared spectroscopy and surface EMG study in muscle ischaemia
      and fatiguing isometric contraction.
AB  - BACKGROUND: To assess how muscle ischaemia and isometric fatiguing contraction
      influence oxygen content in striated muscle. METHODS: We simultaneously measured
      changes in hemoglobin near-infrared (NIR) spectroscopy and in surface EMG before,
      during, and after muscle ischaemia and ischaemia plus muscle isometric fatiguing
      contraction. Seventeen healthy male subjects (age range: 19-40 yrs) were examined
      in our Clinical Neurophysiology Unit. Test I (9 subjects): hemoglobin NIR
      spectroscopy and stimulated surface EMG were measured for 2 minutes at rest, for
      4 minutes during complete ischaemia of tibialis anterior muscle, and for twelve
      minutes during recovery. Test II (all subjects): hemoglobin NIR spectroscopy and
      surface EMG were measured for 2 minutes with the subjects performing brief non
      fatiguing contractions, for 4 minutes with the subject performing maximal
      isometric contraction in complete ischaemia, and for twelve minutes during
      recovery. EMG parameters measured: median density frequency (MDF); muscle fiber
      conduction velocity (MFCV). NIR spectroscopy parameters measured: percentage of
      amplitude decrement (% AD) and nadir time (NT) during ischaemia and ischaemic
      effort; half-recovery time (1/2 RT) from ischaemia effort. RESULTS: At EMG, we
      observed a significant shift towards lower values of both MFCV and MDF during
      fatiguing isometric contraction. MDF recovery was faster then MFCV recovery. At
      NIR spectroscopy, the 1/2 RT slowed a fast pattern in twelve subjects and a slow
      pattern in five. A significant relationship was found between AD% and 1/2 RT
      values of test I and AD% and 1/2 values of test II. We found a positive
      relationship between NT and 1/2 RT in test II. CONCLUSIONS: Surface EMG and
      hemoglobin NIR spectroscopy can be applied simultaneously to evaluate both
      fatigue intensity and blood flow changes in striated muscle.

PMID- 10399415
TI  - Transcutaneous carbon dioxide threshold during exercise.
AB  - BACKGROUND: To study the possible use of transcutaneous carbon dioxide pressure
      measurements to estimate ventilatory threshold during exercise. METHODS: 
      EXPERIMENTAL DESIGN: comparative study. SETTINGS: Institutional practice,
      ambulatory care. Patients and measures: seventy-nine subjects. INTERVENTION:
      incremental exercise tests with simultaneous recordings of breath by breath gas
      exchange and transcutaneous carbon dioxide pressure. MEASURES: Six reviewers
      determined the ventilatory threshold using both the graphs for the carbon dioxide
      excretion to oxygen consumption relationship: V slope technique (VTa), and the
      ventilatory equivalent for oxygen uptake changes over time: (VTb), the
      respiratory compensation point (RCP) on ventilatory equivalent for carbon
      dioxide, and the transcutaneous threshold (Ttc) on the transcutaneous carbon
      dioxide pressure changes over time respectively. RESULTS: A Ttc could be defined
      by all observers in 85% of the subjects. Correlation between Ttc and VT expressed
      as oxygen consumption absolute values ranged from 0.971 to 0.975 on the mean
      values of six observers. Using the Bland-Altmann approach, differences (mean +/-
      SD) were 13 +/- 215, -40 +/- 204, 231 +/- 221 ml.min-1 between Ttc and VTa, RCP
      respectively. A difference of 38 +/- 173 ml.min-1 was found between VTa and VTb.
      This suggests that Ttc shows little difference with VT but not with RCP.
      CONCLUSIONS: We suggest that a carbon dioxide transcutaneous threshold can be
      found close to the ventilatory threshold. Potential clinical use of
      transcutaneous device are vast.

PMID- 10399416
TI  - Characteristic feature of oxygen cost at simulated laboratory triathlon test in
      trained triathletes.
AB  - BACKGROUND: The present study was carried out in order to investigate the
      respiratory and circulatory features during a simulated laboratory triathlon test
      in trained triathletes. METHODS:  EXPERIMENTAL DESIGN: Sixteen male triathletes
      were divided into superior (n = 8) and slower triathletes (n = 8) according to
      their race time. These subjects performed both maximal exercise tests and a
      simulated laboratory triathlon test (ST). The latter test consisted of flume-pool
      swimming for 30 min, ergometer cycling for 75 min and treadmill running for 45
      min as a continuous task. The exercise intensity was 60% of VO2 max during
      swimming, cycling and running, respectively. RESULTS: In slower triathletes, VO2,
      minute ventilation (VE), heart rate (HR) and temperature of external auditory
      canal were increased from an earlier stage compared with those in superior
      athletes. The percent increase (delta) of VO2, VE and HR between the 10th and
      last min of cycling and running stages in superior triathletes were significantly
      smaller than those in slower athletes. The oxygen cost (oxygen uptake/running
      velocity) of running stage was significantly lower in superior triathletes (0.220
      +/- 0.020 ml.kg-1.m-1) compared with slower athletes (0.264 +/- 0.014 ml.kg-1.m
      1). CONCLUSIONS: These results suggest that superior triathletes performed ST
      more economically than slower athletes and had excellent thermoregulatory
      adaptation.

PMID- 10399417
TI  - Validity of the Universite de Montreal Track Test to assess the velocity
      associated with peak oxygen uptake for adolescents.
AB  - BACKGROUND: The purpose of the study was to test the ability to determine the
      velocity associated with peak oxygen uptake for adolescents by means of a simple
      field test, the Universite de Montreal Track Test (UMTT). METHODS: Fifteen
      adolescents, 13.4 +/- 1.0 years, performed two maximal field tests where oxygen
      uptake and heart rate were continuously monitored. The first test (graded field
      test, first stage 8 km.h-1, increment 1.5 km.h-1, duration 3 min) allowed the
      subjects to reach a steady-state oxygen uptake. Then, the velocity associated
      with peak oxygen uptake was calculated from the ratio between peak oxygen uptake
      above resting level to energy cost of running. The calculated velocity was kept
      as the criterion velocity. For the second test (UMTT, first stage 8 km.h-1;
      increment 1 km.h-1; duration 2 min), the velocity measured at the last completed
      stage was retained. RESULTS: The measured peak oxygen uptake for the graded field
      test (51.8 +/- 6.5 ml.kg-1.min-1) and for the UMTT (51.0 +/- 7.9 ml.kg-1.min-1)
      were not significantly different. The calculated velocity (12.9 +/- 1.0 km.h-1)
      and the measured velocity (12.7 +/- 0.9 km.h-1) were not significantly different
      and were significantly correlated (r = 0.80, p < 0.001). CONCLUSIONS: It was
      concluded that, for adolescents, the velocity measured at the last completed
      stage of the UMTT allows a valid estimation of the velocity associated with peak
      oxygen uptake.

PMID- 10399418
TI  - Reliability and validity of a new device to measure isometric strength in
      polyarticular exercises.
AB  - BACKGROUND: The purpose of this study was to assess the validity of a new device
      to evaluate isometric strength during multi-joint exercise such as the squat or
      bench press. METHODS: The device used an electric motor-driven bar to
      simultaneously generate and measure forces during weight lifting exercises. This
      new device and a force platform measured the forces generated by either the motor
      on a fixed telescopic steel girder (passive condition) or a subject pushing
      vertically against the bar from three squat positions (active condition). In the
      passive condition, 252 measurements were made, with 3 trials for 6 bar heights
      and 14 bar loads. In the active condition, 8 young physically active students
      (age, height and body mass were 25.1 +/- 2.6 years, 179.3 +/- 7.2 cm and 82.0 +/-
      9.9 kg, respectively) performed 3 maximal isometric strength (MIS) trials in each
      of the 3 squat exercise positions (parallel, half and quarter squat), and 3
      additional MIS trials in one position randomly assigned two weeks later to test
      inter-day reliability. RESULTS: In the passive condition, no differences were
      observed between the forces measured by the force platform and the new device.
      The coefficient of linear regression (r) and the coefficient of variation (CV)
      were 1 and below 0.23%, respectively. In the active condition, the peak MIS
      measured was 2828 N and the values of r and CV were above 0.982 and below 5.96%,
      respectively. The assessment of inter-day reliability showed an r value of 0.984
      and a CV of 3.98%. CONCLUSIONS: This study demonstrated that the new electric
      motor-driven exerciser provides valid and reliable data when used to generate
      forces and measure isometric strength throughout the load and motion ranges
      commonly used in squat exercise.

PMID- 10399419
TI  - Anthropometric, strength, and power predictors of sprinting performance.
AB  - BACKGROUND: The purpose of this study was to examine relations between sprinting
      performance (i.e. average velocity within both the initial acceleration and
      maximum speed phases of sprint running) and some standard anthropometric,
      strength, and power tests. METHODS: Twenty-four male students of physical
      education were timed over the distances of 0.5-15 m and 15-30 m from the sprint
      start. Several measures of muscle isometric strength (knee extensors, hip
      extensors and flexors) and power (height of the counter movement jump and the
      average power of leg extensors during continuous jumping) were also collected, in
      addition to the lean body mass and the percentage of both muscle and fat tissue.
      RESULTS: The results obtained demonstrated that, except for the height of the
      counter movement jump, all correlation coefficients between the selected
      variables and sprinting performance were low and, therefore, insignificant. As a
      consequence, multiple correlation coefficients were also low (0.43 and 0.56 for
      the initial acceleration and maximal speed phase, respectively). CONCLUSIONS:
      Most of the standard anthropometric, strength and power tests could be poor
      predictors of sprinting performance. A better assessment of sprinting performance
      could be based on more specific tests that, unfortunately, require more complex
      measurements.

PMID- 10399420
TI  - Can oxypurines plasma levels classify the type of physical exercise?
AB  - BACKGROUND: A laboratory-based model able to describe muscle energy status during
      physical exercise and changes in myofibrillar composition in response to training
      would be desirable. Lactate and ammonia concentrations are not sufficient for a
      comprehensive knowledge of these systems. All muscle fibres, irrespective of the
      type, show ATP depletion and IMP accumulation following exhausting muscular
      exercise with quantitative differences due to the different concentrations of
      deaminase. We studied the plasma concentration of metabolites of oxypurine
      cascade to test their reliability to classify different exercises. METHODS: We
      studied 52 athletes, measuring plasma metabolites at the beginning and at the end
      of their specific field exercise (cycle pursuers, 8 cases; soccer players, 19;
      marathon runners, 25). K3EDTA-blood samples were assayed for plasma hypoxanthine,
      xanthine, and inosine, using an HPLC technique, as well as ammonia and lactate by
      means of enzymatic methods. RESULTS AND CONCLUSIONS: Basal oxypurines levels were
      not different in relation to any specific physical exercise. Post-exercise
      oxypurines, namely hypoxanthine, were more precise predictors of muscle energy
      exhaustion than strain intensity or duration. Plasma levels of hypoxanthine may
      be elevated also in the presence of normal xanthine and uric acid concentrations,
      due to an exhaustion of the enzymatic pathway, to a reduced activity of xanthine
      oxidase or finally to a substrate-dependent inhibition of the process.

PMID- 10399421
TI  - Plasma ammonia response to sprint swimming.
AB  - BACKGROUND: To study the plasma ammonia response after sprint crawl swimming.
      METHODS: Nine sprinters (S) and ten non-sprinters (NS) completed a 15-, a 25- and
      a 50-m crawl at maximal intensity with a 10-min and a 15-min resting period in
      between. Capillary blood samples were collected before and at regular intervals
      after each effort for plasma ammonia determination. RESULTS: Ammonia kinetics
      differed among distances, but not between groups, with peak values (observed 2-8
      min postexercise) being higher after 50 m as compared to shorter distances.
      Significant differences between S and NS were found in peak ammonia after 50 m
      (124.5 +/- 58.2 vs 98.7 +/- 6.3 mumoL-1) and in the change of ammonia relative to
      swim time (delta NH3/delta t) after 25 m (2.66 +/- 1.87 vs 1.49 +/- 0.84 mumol L
      1 s-1) and 50 m (1.87 +/- 1.33 vs 1.01 +/- 0.49 mumol L-1 s-1). delta NH3/delta t
      was highest after 15 m (3.33 +/- 2.53 in S, 3.92 +/- 1.67 mumol L-1 s-1 in NS).
      CONCLUSIONS: These differences in the plasma ammonia response to sprint swimming
      according to duration and athlete seem to be connected to distinctions in muscle
      fiber profile and energy providing processes.

PMID- 10399422
TI  - Muscle enzyme release does not predict muscle function impairment after
      triathlon.
AB  - BACKGROUND: We sought to determine the effects of a long distance triathlon (4 km
      swim, 120 km bike-ride, and 30 km run) on the four-day kinetics of the
      biochemical markers of muscle damage, and whether they were quantitatively linked
      with muscle function impairment and soreness. METHODS:  EXPERIMENTAL DESIGN: Data
      were collected from 2 days before until 4 days after the completion of the race.
      PARTICIPANTS: Twelve triathletes performed the triathlon and five did not.
      MEASURES: Maximal voluntary contraction (MVC), muscle soreness (DOMS) and total
      serum CK, CK-MB, LDH, AST and ALT activities were assessed. RESULTS: Significant
      changes after triathlon completion were found for all muscle damage indirect
      markers over time (p < 0.0001). MVC of the knee extensor and flexor muscles
      decreased over time (p < 0.05). There is disparity in the time point at which
      peak values where reached for DOMS, MVC and enzyme leakage. There is no
      correlation between serum enzyme leakage, DOMS and MVC impairment which occur
      after triathlon. CONCLUSIONS: Long distance triathlon race caused muscle damage,
      but extent, as well as muscle recovery cannot be evaluated by the magnitude of
      changes in serum enzyme activities. Muscle enzyme release cannot be used to
      predict the magnitude of the muscle function impairment caused by muscle damage.

PMID- 10399424
TI  - Head and neck injuries in young taekwondo athletes.
AB  - BACKGROUND: To investigate the location, type, situation and mechanism of head
      and neck injuries in young taekwondo athletes. METHODS:  EXPERIMENTAL DESIGN:
      Prospective. SETTING: National and international taekwondo tournaments.
      PARTICIPANTS: 3,341 boys and 917 girls, aged 6 to 16 years. MEASURES: Injury
      rates per 1,000 athlete-exposures (A-E) for total number of head and neck
      injuries, location, type, situation, and mechanism of injury. RESULTS: There was
      a significant difference between young male and female taekwondo athletes in
      total head and neck injury rate (p < 0.001) with the boys (21.42/1,000 A-E)
      recording a higher rate than the girls (16.91/1,000 A-E). The head was the most
      often injured body part (6.10/1,000 A-E and 4.55/1,000 A-E for boys and girls,
      respectively). The contusion was the most often occurring injury type for both
      boys (8.41/1,000 A-E) and girls (7.80/1,000 A-E). The cerebral concussion ranked
      second in both boys (5.11/1,000 A-E) and girls (4.55/1,000 A-E). The unblocked
      attack was the major injury situation for both boys (19.78/1,000 A-E) and girls
      (14.96/1,000 A-E). As a consequence, the major injury mechanism was receiving a
      blow (20.93/1,000 A-E and 16.25/1,000 A-E for boys and girls, respectively). Only
      the boys (0.66/1,000 A-E) incurred the most serious head and neck injuries that
      resulted in > or = 21 days away from participation. CONCLUSIONS: The national and
      international taekwondo governing bodies should review their current injury
      prevention measures. Given the potentially debilitating nature of these injuries,
      implications for any diagnostic capabilities on site should be carefully
      reviewed.

PMID- 10399423
TI  - Can reticulocyte parameters be of use in detecting iron deficient erythropoiesis
      in female athletes?
AB  - BACKGROUND: The purpose of this study was to investigate whether monitoring
      reticulocyte profiles, which are known to respond to iron store depletion in
      sedentary populations, could also be utilised with intensely training athletes.
      METHODS: A retrospective study of blood samples from 134 national level athletes
      (61 males, 73 females) at the Australian Institute of Sport were analysed, from
      which reference ranges were calculated. To ascertain the stability of
      reticulocyte profiles during periods of intense physical training, the intra
      individual variation of these parameters in 12 iron-replete female athletes over
      a four month period of training was documented. The precision with which the
      analyzer measured these parameters was also determined using duplicate samples
      from 37 female athletes. To establish whether reticulocyte parameters were
      sensitive to iron deficient erythropoiesis in athletes, reticulocyte profiles of
      five female athletes diagnosed by medical personnel as having depleted iron
      stores were compared before and after iron therapy to seven controls. RESULTS:
      Corpuscular hemoglobin concentration mean (CHCMr) and mean corpuscular volume
      (MCVr) showed little variation over time in iron-replete females, with 95% of all
      fluctuations being within 5.8% and 4.3% of original values, respectively. Iron
      supplementation in athletes with depleted iron stores elicited an increase in
      CHCMr (p = 0.01), and a decrease in the distributions of reticulocyte volume
      (RDWr, p = 0.01) and cell hemoglobin concentration (HDWr, p < 0.01). The ratios
      of reticulocyte to mature cell MCV (p < 0.01) and CHCM (p < 0.01) also changed
      following iron therapy. No such changes occurred in non-supplemented controls
      with normal iron stores. CONCLUSIONS: These data lend support to the thesis that
      monitoring of reticulocyte parameters can be of use in detecting iron deficient
      erythropoiesis in female athletes.

PMID- 10399425
TI  - Regional and total body bone mineral density in elite collegiate male swimmers.
AB  - BACKGROUND: To examine the role of long-term swimming exercise on regional and
      total body bone mineral density (BMD) in men. METHODS:  EXPERIMENTAL DESIGN:
      Cross-sectional. SETTING: Musculoskeletal research laboratory at a medical
      center. PARTICIPANTS: We compared elite collegiate swimmers (n = 11) to age-,
      weight-, and height-matched non-athletic controls (n = 11). MEASURES: BMD (g/cm2)
      of the lumbar spine (L2-4), proximal femur (femoral neck, trochanter, Ward's
      triangle), total body and various subregions of the total body, as well as
      regional and total body fat and bone mineral-free lean mass (LM) was assessed by
      dual-energy X-ray absorptiometry (DXA, Hologic QDR 1000/W). RESULTS: Swimmers,
      who commenced training at 10.7 +/- 3.7 yrs (mean +/- SD) and trained for 24.7 +/-
      4.2 hrs per week, had a greater amount of LM (p < 0.05), lower fat mass (p <
      0.001) and percent body fat (9.5 vs 16.2%, p < 0.001) than controls. There was no
      significant difference between groups for regional or total body BMD. In stepwise
      multiple regression analysis, body weight was a consistent independent predictor
      of regional and total body BMD. CONCLUSIONS: These results suggest that long-term
      swimming is not an osteogenic mode of training in college-aged males. This
      supports our previous findings in young female swimmers who displayed no bone
      mass benefits despite long-standing athletic training.

PMID- 10399426
TI  - Investigation of anthropometric and work-rate profiles of Rugby Sevens players.
AB  - BACKGROUND: To describe anthropometric and match performance profiles of
      international Rugby Sevens players and explore correlations between
      anthropometric characteristics and work-rates in matches. METHODS: Profiles were
      compared by means of multivariate analysis and correlation techniques. SETTINGS:
      measurements were made on players participating in the 1996 International Rugby
      Sevens tournament in Uruguay. SUBJECTS: Thirty male players. MEASURES: work-rate
      analysis during matches (n = 30) and a comprehensive anthropometry profile of 27
      of the 30 players. RESULTS: Forwards had more mass (whole-body, adipose tissue,
      muscle) than backs, jogged more frequently and paused more often. High intensity
      activity was negatively correlated with muscle mass and with mesomorphy.
      CONCLUSIONS: Anthropometric features are related to components of match play in
      Rugby Sevens but do not necessarily determine whether a game is won or lost.

PMID- 10399427
TI  - The effects of long-term aerobic dance on agility and flexibility.
AB  - BACKGROUND: The benefits of aerobic dance toward the contribution to overall
      wellness have been studied in a skewed manner. Numerous studies in the past have
      examined the cardiorespiratory benefits of aerobic dance. Fewer studies have
      reported the effects on agility, flexibility and coordination. Moreover even
      fewer studies have used aerobic dance instructors as subjects. METHODS: To
      examine the effects of long-term aerobic dance on agility and selected measures
      of flexibility, fifty-four experienced and non-experienced aerobic dance teachers
      were tested on these parameters. RESULTS: No significant differences were
      identified in any parameter. CONCLUSIONS: On the basis of the present data we
      conclude that extended participation in aerobic dance does not contribute to
      better sit and reach flexibility, trunk flexibility, dynamic rotational
      flexibility or agility and that aerobic dance teachers should participate in
      general flexibility stretching activities and secondary activities to improve
      and/or maintain agility and general coordination.

PMID- 10399429
TI  - [The cholesterol ester-carrying protein in the transport of saturated fatty acids
      (a review of the literature)].

PMID- 10399428
TI  - Emotions, heart rate and performance in archery. A case study.
AB  - BACKGROUND: A case study of an elite female archer was conducted to gain insight
      into individual psychophysical reactions accompanying an athletic event, and to
      test predictions of pre-performance emotions effects upon performance. Good
      performance was expected when the actual pre-performance emotions resembled the
      recalled optimal emotion pattern. Conversely, poor performance was expected when
      the actual pre-performance emotions paralleled the recalled ineffective emotion
      pattern. METHODS:  EXPERIMENTAL DESIGN: the investigation comprised individual
      emotion profiling, emotions and heart rate monitoring, final interview and
      performance evaluation. SETTING: The research was accomplished during the 1996
      European Archery Championships, one of the most important international archery
      competitions. PARTICIPANT: An 18-year-old female athlete of the Italian archery
      national team. INTERVENTIONS: Because of the exploratory nature of the study, no
      intervention was implemented. MEASURES: Emotion profiling was carried out using
      an idiographic approach based on recalled optimal and poor performances,
      according to the Individual Zones of Optimal Functioning (IZOF) model. Emotions,
      heart rate, and performance were monitored across the five days of practice and
      competition. RESULTS: Individual pre-performance optimal emotion pattern, heart
      rate deceleration during shooting, consistent shooting scores were revealed
      throughout practice and competition. CONCLUSIONS: The good performance predicted
      on the basis of pre-performance emotion assessments was met and was confirmed by
      the archer's interpretation.

PMID- 10399430
TI  - [Drug monitoring during the treatment with theophylline preparations of children
      with bronchial asthma].

PMID- 10399431
TI  - [A programmed system of nonlinear calibration of the devices in an express
      laboratory].
AB  - In accordance with the concept of a laboratory clinical diagnostic program
      proposed by I. S. Balakhovskii (1997), a programmed system is developed, which
      realizes the method of nonlinear calibration of devices in a clinical diagnostic
      laboratory.

PMID- 10399432
TI  - [The optimization of a method for determining RNAse activity by using high
      polymer RNA].
AB  - Different methods for precipitation of free nucleotides are compared with the aim
      of improving the method for estimating RNAse activity. The precipitators were
      0.75% uranyl acetate in 0.25% HClO4, 96% ethanol with MgCl2 in different
      concentrations, pure ethanol, and chlorine acid. Measurements of RNAse activity
      by means of 0.02M MgCl2 in 96% ethanol whose volume is equal to the reaction
      mixture were the optimal.

PMID- 10399433
TI  - [The albumin-binding capacity of the blood serum in diphtheria patients].
AB  - Total and effective concentrations of blood serum albumins were measured in 45
      patients with various clinical forms of diphtheria. Both parameters were
      decreased in patients with toxic forms of the disease in comparison with the norm
      and with those in patients during the period when specific complications develop
      and in patients with all clinical forms of diphtheria at the beginning of the
      illness.

PMID- 10399435
TI  - [The metabolic monitoring of drug therapy in patients in a critical state (a
      lecture)].

PMID- 10399434
TI  - [Hemoglobinopathies in students at the Russian University of the Friendship of
      Peoples].
AB  - Screening of the university students for hemoglobinopathies detected 153 patients
      with various hemoglobin abnormalities; 69 with Hb AS, 3 with Hb S-beta
      thalassemia, 4 with Hb S-alpha-thalassemia, 3 with hb SC, 1 with Hb SK, 1 with Hb
      CC, 38 with Hb AC, 1 with Hb A O Arab, 4 with Hb EE, 25 with Hb AE, 1 with Hb AD,
      1 with Hb AI, 1 with beta-thalassemia major, and 1 with beta-thalassemia minor.
      The most grave disease was observed in a child with Hb S-beta-thalassemia and in
      a youth with beta-thalassemia major. The patterns of Hb SC disease varied. The
      majority of heterozygote carriers of Hb S, Hb C, Hb E, etc. were healthy. A total
      of 7000 students were screened by express electrophoresis on cellulose acetate
      films. more than 400 subjects with abnormal hemoglobins were detected, the most
      numerous of which were heterozygote carriers of Hb S (Hb AS).

PMID- 10399436
TI  - [Clinico-laboratory algorithms for assessing the functional activity of the
      thyroid gland].
AB  - Three diagnostic algorithms making use of automated chemiluminescent analyzers
      are proposed for evaluation of the thyroid function, depending on the clinical
      situation. Laboratory criteria of hypothyrosis and thyrotoxicosis therapy
      monitoring are discussed. Main variants of disagreement between clinical data and
      values of thyrotropic hormone and free T4 are presented.

PMID- 10399437
TI  - [Integral hematological indices in assessing body immunological reactivity in
      patients with ophthalmic pathology].

PMID- 10399438
TI  - [The nuclear morphotypes of epithelial cells in breast diseases].
AB  - Staining of the nucleolar ribosome organizer with AgNO3 followed by computer
      analysis of images by discriminant analysis helped distinguish 6 morphological
      types in the cells of cytological preparations of mammary glands. Comparison of
      the morphometrical data and results of visual examination of cells showed that
      the first type included nonproliferating fibroadenoma and mastopathy, type 2
      fibroadenoma and mastopathy with moderate proliferation of epithelium, type 3
      fibroadenoma and mastopathy with precancer epithelial proliferation, and types 4
      6 included malignant proliferating cells which are compatible with well,
      moderately, and poorly differentiated cancer.

PMID- 10399440
TI  - [The determination of class-M immunoglobulins in the latex agglutination
      reaction].
AB  - Results of measuring the concentrations of IgM in human serum using a specific
      latex diagnostic agent in the latex agglutination test (LAT) are presented. The
      authors demonstrate a higher efficacy of LAT in comparison with Mancini's method.

PMID- 10399439
TI  - [The puncture cytological diagnosis of neoplasms of the mediastinum (11 years of
      experience)].
AB  - Routinely stained cytological preparations of puncture biopsy specimens of
      mediastinal tumors from 870 patients are examined. Diagnostically informative
      material is investigated in 759 (87.3%) cases; malignant tumors are diagnosed in
      538 (62%) cases, benign in 221 (25.2%). In 59 (6.8%) cases the cytological
      answers were descriptive, and in 52 (6%) puncture biopsy material was not
      informative for cytological verification. Diagnostic sensitivity of the
      cytological method is 94%, diagnostic specificity 71%, and diagnostic efficacy
      91%.

PMID- 10399441
TI  - [The rapid diagnosis of tropical malaria using the ParaSight-F test].

PMID- 10399443
TI  - Treatment of hypopituitarism in infancy. Effect on head circumference growth.
AB  - BACKGROUND: Head circumference of children with multiple pituitary-hormone
      deficiency (MPHD) may be subnormal for age. Moreover it is known that linear
      growth in infancy is growth-hormone (GH) dependent. Therefore, aim of the study
      has been to compare head circumference measurements in children with
      hypopituitarism after L-thyroxine (L-T4) therapy alone, before therapy with GH,
      and after GH was added to the therapy. METHODS: Five infants (2 girls, 3 boys)
      with MPHD, diagnosed and treated before the age of 2 years and whose auxological
      parameters records during L-T4 therapy alone were available, were retrospectively
      studied. Head circumference and length measurements were expressed as standard
      deviation score (SDS). Weight measurements were expressed as weight for length
      ratio percentage. RESULTS: Initially treated with L-T4 alone for a mean period of
      4, 5 months, there were neither positive effects on head circumference nor on
      linear growth. A significant catch-up growth was observed only employing GH
      therapy in addition to L-T4: mean head circumference SDS and length SDS increased
      respectively from -2.20 to -0.89 SDS and from -4.16 to -0.87 SDS after a mean
      period of 18 months of combined GH and L-T4 therapy. CONCLUSIONS: Therefore, head
      circumference growth, in infancy, is growth hormone dependent as well as linear
      growth, and during GH treatment, monitoring head circumference growth is
      important as much as monitoring linear growth.

PMID- 10399444
TI  - [A survey regarding the problem of cigarette smoke pollution in a hospital
      environment].
AB  - AIMS: The study aimed to survey smoking habits in a specific environment, namely
      hospitals, paying special attention to the pediatric sector. METHODS: The survey
      was carried out using data from questionnaires distributed to all hospital
      personnel. RESULTS: Of a total of 2425 forms distributed, only 20% were compiled
      and returned. The most interesting findings to emerge were that in 86% of cases
      smokers admit to smoking in the presence of others and 10% admit to smoking in
      the presence of patients. 83% affirm that non-smokers should be protected. The
      most popular proposal was to create "smoking" rooms inside hospitals.
      CONCLUSIONS: Almost all smokers say that they are aware of the damage caused by
      tobacco, but they justify the habit by the fact that "they cannot do without it".
      Non-smokers feel that health education courses or personal conviction are of
      little use, and that punitive measures should be introduced for those smoking in
      hospitals.

PMID- 10399442
TI  - ["Labquality"--an organizer of external quality control plans].

PMID- 10399445
TI  - [Tic disorders in children and adolescents. Clinical and genetic features,
      comorbidity].
AB  - Tic disorders in children and adolescents. Clinical and genetic features,
      comorbidity. BACKGROUND: Aim of the study is to evaluate the clinical and genetic
      characteristics of tic disorders, in view of individuating similarities or
      differences relevant to the prognosis among different nosological groups.
      METHODS: A retrospective study of 79 children and adolescents (average age 9.3
      yrs) was performed. The cases were diagnosed according to DSM-IV as: transitory
      tics (TT) 13 cases; chronic tics (CT) 50 cases; Tourette disease (TD) 16 cases.
      They were compared to a control group of 18 school age children without any
      neurological or psychiatric disturbance. The study included: semi-structured
      interviews focused on natural history of the disturbances, familiarity, presence
      of perinatal pathology, comorbidity; neurological examination, EEG,
      psychodiagnostic tests and investigation. RESULTS: Mean age of onset and type of
      first symptoms are the same in the three groups. Compared to the control group
      there is a significant increase in: familiarity for tics disturbances in TD;
      presence of perinatal pathological factors in the three groups of patients;
      comorbidity for obsessive-compulsive disorder (OCD) in CT and TD, comorbidity
      with ADHD in CT group. Three clinical cases are reported to exemplify the mixed
      features in the families and the different responsivity to the pharmacological
      treatment.

PMID- 10399446
TI  - [Urinary tract ultrasonography in newborns with late oligohydramnios].
AB  - BACKGROUND AND AIM: The aim of this study was to evaluate the value of neonatal
      renal ultrasonography in the diagnosis of urinary tract malformation pathologies
      in newborns from pregnancies complicated by late oligohydramnios. METHODS: During
      the period January 1994-October 1997, 119 newborns from pregnancies complicated
      by oligohydramnios occurring in the third trimester of pregnancy underwent
      ultrasonography of the urinary tract at our Centre. All newborns had previously
      undergone prenatal ultrasonography. RESULTS: Ultrasonography revealed
      calicopyelic dilatation < 10 mm in 7 newborns (5.8%), 5 of whom had already been
      reported at the prenatal ultrasonography. One new-born (0.8%) also showed the
      presence of an ectopic kidney that had not been diagnosed at the prenatal scan.
      By the next follow-up all the calico-pyelic dilatations had become normal.
      CONCLUSIONS: Neonatal ultrasonography did not show any alterations to the urinary
      tract that might be responsible for the reduction of amniotic liquid. We
      therefore feel that is useful to perform neonatal ultrasonography in those
      situations in which the onset of oligohydramnios occurred in the second trimester
      of pregnancy and in cases in which no scan was performed during the prenatal
      period.

PMID- 10399447
TI  - [Pediatrics and child care in the Renaissance].

PMID- 10399448
TI  - Preoperative optimisation of oxygen delivery. Intensive care moves into
      preventive medicine.

PMID- 10399449
TI  - Prevention of hypotension after induction of anesthesia after preoperative tune
      up. A preliminary report of the Groningen Tune-up Study.
AB  - OBJECTIVE: To investigate whether the frequently occurring hypotension after
      induction of anesthesia can be prevented by preoperative treatment at the ICU
      guided by hemodynamic data obtained from a pulmonary artery (PA) catheter.
      DESIGN: Prospective controlled open randomized single center study. SETTING:
      University tertiary referral hospital. PATIENTS: Thirty-one patients undergoing
      major vascular- or abdominal surgery. INTERVENTIONS: Patients were randomized to
      either the control group or the ICU group. Patients allocated for the ICU group
      were admitted to the ICU the day before the operation and treatment was started
      aimed at a CI > or = 4.0 l/min/m2. No special treatment was given to the control
      group the day before the operation. Anesthesia was induced with etomidate,
      rocuronium and sufentanil. MEASUREMENTS AND MAIN RESULTS: Seventeen patients were
      allocated for the control group and 14 for the ICU-group. Mean ages were 65 +/-
      2.5 and 66 +/- 2.5 years, respectively. Both groups were comparable regarding
      age, sex, blood pressure and type of operation. Filling pressures at admission on
      the ICU were: central venous pressure 3 +/- 2 mm Hg and pulmonary capillary wedge
      pressure 8 +/- 3 mm Hg while CI was 3.2 +/- 0.8 l/min/m2. The hemodynamic goal
      was achieved in all 14 patients of the ICU-group preoperatively with a background
      infusion of three l/24 h crystalloids, after a mean infusion of 1623 +/- 552 ml
      colloids, and in seven patients a median dose of 3 micrograms/kg/min (range 2-6)
      dopamine. Blood pressure before induction was comparable in both groups. The fall
      in systolic BP 10 min after induction of anesthesia was 22 +/- 18 in the ICU
      group versus 41 +/- 17 mm Hg in the control group (p = 0.004). The fall in
      diastolic BP was 11 +/- 6 mm Hg in the ICU group versus 25 +/- 11 mm Hg in the
      control group (p = 0.0003). No differences between the groups in changes of heart
      rate were observed: a decrease of 13 +/- 7 bpm (95% confidence intervals 8.5 to
      17.0) in the ICU group versus 15 +/- 14 (95% confidence intervals 7.6 to 21.9)
      bpm in the control group (p = 0.6). CONCLUSIONS: Hypotension after induction of
      anesthesia is significantly attenuated by preoperative treatment aiming at a CI >
      or = 4.0 l/min/m2 in high risk patients planned for major vascular- or abdominal
      surgery.

PMID- 10399450
TI  - Human parvovirus B19: relevance in internal medicine.
AB  - Infection by the human parvovirus B19 can lead to several clinical manifestations
      which are relevant in internal medicine. These include aplastic crisis in chronic
      haemolytic anaemias, exanthemathous disease and arthropathy, mainly in women, and
      chronic anaemia in the immunocompromised host. After initial replication,
      probably in the respiratory tract, the virus enters its target cells in the bone
      marrow, erythroid precursor cells, through its receptor, the blood group P
      antigen. Viral replication in these cells leads to an arrest in erythropoiesis,
      normally lasting approximately 1 week. In this stage, an aplastic crisis can be
      produced in all patients under 'erythropoietic stress'. The viraemia disappears
      as specific antibodies to the virus become detectable in serum, which may give
      rise to a rash or arthralgia, symptoms that are probably immune-mediated. In
      immunologically normal individuals the infection is cleared by the humoral immune
      system within several weeks, whereafter detectable specific IgG confers lifelong
      immunity to reinfection. In patients with absent or dysfunctional humoral
      immunity to this virus, however, persistent infection can occur, which results in
      chronic suppression of erythropoiesis with chronic anaemia. Passive immunization,
      by means of normal immunoglobulin preparations has been reported to be effective
      in treating this condition. Diagnosis of parvovirus infection is usually possible
      by the detection of specific antibodies of IgM class in cases of recent
      infection. In patients with aplastic crisis and patients with chronic anaemia
      diagnosis rests upon the detection of parvovirus B19 DNA in serum by polymerase
      chain reaction. Parvovirus B19 is a ubiquitous virus. By the age of 15, about 50%
      of individuals have serologic evidence of a past infection, which may present as
      the common childhood disease erythema infectiosum. At the age of 70,
      seroprevalence reaches 80 to 100%. A vaccine against this virus is currently
      being developed.

PMID- 10399451
TI  - Late recurrence of liposarcoma simulating adenoma of the duodenum.
AB  - A large pedunculated, polypoid mass in the duodenum of a patient with
      asymptomatic anaemia, with mucosal biopsies indicating a villous adenoma, turned
      out to be a liposarcoma during laparotomy. The patient had had a completely
      resected retroperitoneal liposarcoma 8 years before. Liposarcoma recurrence
      should be highly suspected even in case of atypical presentation and long disease
      free interval.

PMID- 10399452
TI  - High grade MALT-lymphoma of the breast.
AB  - A 65-year-old woman presented with a rapidly growing breast tumor, initially
      diagnosed as a carcinoma. Histology showed a breast lymphoma of high grade MALT
      type. A lymphoma should always be considered in the differential diagnosis of a
      breast tumor, because it needs a different work-up and treatment. The subgroup of
      NHL of Mucosa-Associated-Lymphoid-Tissue origin has different clinical behaviour,
      as illustrated in this report.

PMID- 10399453
TI  - Hodgkin's disease presenting as a parasternal chest wall mass.
AB  - A 53 year-old Moroccan woman presented with a tender parasternal mass.
      Computerized tomography showed a mediastinal mass protruding through the sternum.
      Cytologic examination of fluid collected from the mass repeatedly showed acute
      inflammation. Tuberculostatics were started. Since patient did not improve on
      tuberculostatics, a small supraclavicular lymph node was removed. Histologic
      examination showed Morbus Hodgkin of the nodular sclerosing type. Ultimately,
      cytologic examination of fluid from the parasternal mass showed atypical cells.
      Response on chemotherapy was excellent with complete disappearance of the
      parasternal mass. This is a very unusual extranodal presentation of Hodgkin's
      disease.

PMID- 10399454
TI  - Acute myopericarditis in a streptococcal carrier.

PMID- 10399455
TI  - Acute nonrheumatic streptococcal tonsillitis-myopericarditis.

PMID- 10399456
TI  - [Glaucoma therapy with a prostaglandin analogue. Latanoprost--sure indications,
      safe monotherapy].

PMID- 10399457
TI  - A journey into wholistic medicine.

PMID- 10399458
TI  - Health care cost crisis in Pennsylvania: where are the physicians?

PMID- 10399459
TI  - The practical side of politics ... ignore the facts.

PMID- 10399460
TI  - Residency and volunteerism: not mutually exclusive.

PMID- 10399462
TI  - Doctor to doctor: landmark diabetes studies make a difference. Interview by Linda
      Walburn.

PMID- 10399461
TI  - Acetaminophen hepatotoxicity without intentional overdose.

PMID- 10399463
TI  - [DNA as a drug].

PMID- 10399464
TI  - [Spin trapping in the determination of nitric oxide (NO)].

PMID- 10399466
TI  - [The number of people in Germany living with HIV infection has reached a new
      high].

PMID- 10399465
TI  - [HMG-CoA reductase antagonists in review].

PMID- 10399467
TI  - [The functioning of the Internet for the control of pain].

PMID- 10399468
TI  - [Pain: recent progress and prospects].

PMID- 10399469
TI  - [The prospects in the treatment of hemicrania].

PMID- 10399470
TI  - [Towards a pain-free hospital. A project and a campaign for the improvement of
      health care].
AB  - This article outlines the project entitled "Towards a Pain Free Hospital" which
      aims to make both citizens and health sector workers more aware of the problem of
      pain in hospitalised patients. The project is already under way in some countries
      and is being implemented in others. It has been introduced into the local Health
      Authority Hospital of Vicenza for the first time in Italy and will later be
      introduced into other Italian hospitals. The article deals with the various
      initiatives which make up the project and the methods used to involve those
      assisting the patient in pain.

PMID- 10399472
TI  - [Pleural mesothelioma. A case report].
AB  - Malignant mesothelioma can be considered a rare neoplasm, very aggressive, chemo-
      and radio-resistant, characterized by high percentage of mortality and precarious
      quality of life. Surgery, radio- and chemo-therapy must be administered with
      articulate strategy and with realistic objective of palliation. Our experience
      can represent a model in this direction: we treated a patient with palliative
      surgery and following loco-regional and "maintenance" systemic chemotherapy with
      taxol at minimal efficacious dosage (135 mg/m2 every 3 weeks). After 27 months
      the patient is alive and with a good quality of life.

PMID- 10399471
TI  - [The efficacy of cetirizine in the treatment of perennial allergic rhinitis].
AB  - We have evaluated the effectiveness of cetirizine in 40 patients (25 males and 15
      females, mean age 32.8 yrs) suffering from perennial allergic rhinitis due to
      Dermatophagoides pteronyssinus. Patients were treated for 30 days with oral
      cetirizine (10 mg once a day) and had to report the severity of the symptoms
      considered (sneezing, runny nose, itching and congestion) on daily card. During
      the study no other medication was allowed. After 4 weeks symptoms were
      statistically improved and this beneficial effect increased at the end of the
      treatment. No side effects were reported. Oral cetirizine is therefore a useful
      treatment in perennial allergic rhinitis due to Dermatophagoides pteronyssinus.

PMID- 10399473
TI  - [Chronic pleuropathy due to asbestos and malignant mesothelioma of the pleura: a
      differential diagnosis not always easy. A case report].
AB  - A case of long-lasting chronic asbestos pleuritis is described. Radiological
      picture was initially that of an exudative pleuritis and subsequently that of
      pleural thickening associated to chronic pleural effusion. Cytological findings
      were suggestive for malignant pleural mesothelioma. Diagnosis was made only at
      autopsy. In absence of a sure histological diagnosis, the differential diagnosis
      of the two diseases (chronic asbestos pleuritis and malignant pleural
      mesothelioma) is not easy, so that necropsy retains a fundamental role in
      patients without a certain diagnosis in vita.

PMID- 10399474
TI  - [Suffering. The old-fashioned considerations of a psychopathologist].

PMID- 10399475
TI  - [Advanced cancer of the ovary. The paclitaxel-cisplatin combination as the first
      line standard of treatment].

PMID- 10399477
TI  - [Peptic ulcer, functional dyspepsia, Helicobacter pylori: a 1998 stock-taking on
      the topic of their correlation and therapeutic strategies].
AB  - While the correlation between Helicobacter pylori and peptic ulcer is accepted
      worldwide, the role of Hp in functional dyspepsia is still a debatable issue.
      Therefore, Hp eradication in all dyspeptic patients has both supporters and
      opponents. In contrast, anti-Hp regimens are increasingly well defined, most
      convincing treatments being triple therapies consisting of one proton pump
      inhibitor (PPI) or ranitidine bismuth citrate (RBC) plus two antimicrobials.
      Duration of anti-Hp regimens varies from 2 weeks (more usually adopted in USA)
      and 1 week (more usually adopted in Europe). Due to the short and simple anti-Hp
      triple therapies, side effects prove to be few and negligible and patient
      compliance is significantly better. By contrast, Hp resistance to extensively
      used antimicrobials, such as metronidazole and clarithromycin, is more than an
      emerging problem causing significantly lower eradication rates. Very recent data
      indicate that RBC-based triple therapy is much less affected by the
      helicobacterial resistance, and is also effective in non-responders to a PPI
      based triple therapy.

PMID- 10399476
TI  - [Biochemical markers of gastric functioning].
AB  - The serum determination of pepsinogen A (PGA) and pepsinogen C (PGC) might
      indicate gastric mucosal inflammation and atrophy. Body gastric mucosa produces
      both PGA and PGC, while antral mucosa produces only PGC. Therefore, diseases
      involving mainly the antrum, such as H. pylori infection, are mainly indicated by
      the variations in serum PGC than in serum PGA. In agreement, when the antral
      mucosa is infected by the more virulent cagA positive H. pylori strains, which
      cause severe inflammation, serum PGC significantly increases. Another indirect
      indicator of gastric inflammation is polymorphonuclear (PMN) oxidative burst
      after the stimulation with water extracts from H. pylori culture: this parameter
      is significantly increased in infected if compared to non-infected subjects. The
      higher oxidative burst response of peripheral PMN in infected patients, possibly
      consequent to the release of specific cytokines able to prime PMN towards H.
      pylori products, is unable to eliminate the infection, but it might concur in
      damaging the gastric mucosa.

PMID- 10399478
TI  - Alterations of brain monoamine levels in pigs exposed to acute immobilization
      stress.
AB  - Concentrations of noradrenaline (NA), adrenaline (A), dopamine (DA) and 5
      hydroxytryptamine (5-HT), as well as DA metabolites 3,4-dihydroxyphenylacetic
      acid (DOPAC), homovanillic acid (HVA) and the main 5HT metabolite, 5
      hydroxyindole-3-acetic acid (5-HIAA), were measured using the HPLC technique in
      15 brain areas of control and immobilized Duroc pigs. The animals were
      immobilized for 5, 15, 30 and 60 min in a prone position. Control pigs displayed
      patterns of regional distribution of brain monoamines similar to those described
      in other species, especially rats and dogs. However, absolute values of
      noradrenaline and adrenaline in the hypothalamus were much higher than in other
      species. Also, in most structures, the DOPAC/DA ratio was relatively high, in
      comparison to a relatively low HVA/DA ratio, which suggests a species-related
      difference in the turnover of dopamine. The most conspicuous changes produced by
      immobilization stress consisted of a substantial decrease in the hypothalamic
      levels of noradrenaline and adrenaline. Dopamine and 5-HT turnover was affected
      in the hippocampus (cornu Ammonis), and in the raphe nuclei. These structures are
      proposed to play a major role in the responsiveness of pigs to acute stress
      conditions.

PMID- 10399479
TI  - A comparison of the ultrastructure and metabolic response of the skeletal muscle
      of horses performing intense treadmill exercise at 20 and 35 degrees C.
AB  - The aim of this study was to determine whether the metabolic response and
      ultrastructure of muscle differed when horses performed intense exercise at
      different ambient temperatures. Four Standardbred geldings performed treadmill
      exercise, including an intensive trot of 2600 m on two different occasions,
      either at a high ambient temperature of 35 degrees C or at a temperature of 20
      degrees C. The horses had a warm-up period of 23.5 min of submaximal exercise,
      followed by 2 h of box rest before the intensive exercise. Muscle biopsy data of
      adenine nucleotides, creatine phosphate, lactate and glycogen concentrations
      measured before the warm-up period were similar to those measured before the
      period of intensive exercise. Muscle lactate concentrations did not differ
      between the two temperatures, but increased significantly after intense exercise
      to levels of 34.7 +/- 8.3 mmol/kg d.w. at 20 degrees C, and to 41.7 +/- 12.5
      mmol/kg d.w. at 35 degrees C. Muscle glycogen and creatine phosphate
      concentrations did not differ between the two ambient temperatures, but decreased
      significantly by 122 +/- 82 mmol/kg d.w. and 25.2 +/- 17.4 mmol/kg d.w.,
      respectively, after the intensive exercise. No changes were seen in adenosine
      triphosphate, adenosine diphosphate and adenosine monophosphate concentrations.
      The muscle biopsies were investigated by electron microscopy, and showed no
      marked changes in the ultrastructure of the muscle due to exercise at the two
      different ambient temperatures. In conclusion, no marked changes were seen in the
      muscle metabolic response or in the ultrastructure of the muscle when the horses
      performed intense exercise at 35 degrees C compared to 20 degrees C.

PMID- 10399480
TI  - A study of lipid peroxidation and vitamin E in dairy cows with hepatic
      insufficiency.
AB  - Sixteen dairy cows were studied to assess the status of the natural antioxidant
      vitamin E and lipid peroxidation in their livers. Cows with liver failure (n = 7)
      showed clinical signs of a hepatic encephalopathy and had the following values of
      selected blood indices: AST > 80 U/l and GLDH > 15 U/l in serum, and venous
      plasma ammonia > 35 mmol/l. The control group (n = 9) consisted of dairy cows
      which were recovering from surgery (omentopexy) and were free of any health
      complications. Blood was analysed for alpha-tocopherol, aspartate
      aminotransferase, glutamate dehydrogenase, gamma-glutamyl transferase, total
      bilirubin, ammonia, cholesterol, albumin, free fatty acids, glucose, and beta
      hydroxybutyrate. Alpha-tocopherol, triglyceride and malondialdehyde were measured
      in wet liver tissue. The cows with hepatic failure were clearly low in alpha
      tocopherol and had significantly lower (P < 0.01) plasma alpha-tocopherol than
      the controls. Both liver triglycerides and MDA were higher (P < 0.05) in the cows
      with fatty livers. It is concluded that the cows with liver failure had an
      increase in the intensity of hepatic lipoperoxidative processes and a low
      antioxidative status, which should be taken into consideration in cases where
      treatment of the disease is proposed.

PMID- 10399481
TI  - Morphology and amplitude values of the P and T waves in the electrocardiograms of
      Spanish-bred horses of different ages.
AB  - This investigation was undertaken to determine values of electrocardiographic
      parameters in Spanish-bred horses at different stages of growth. The study was
      carried out on 179 healthy Spanish-bred (Andalusian) horses (98 females and 81
      males), which were aged between 1 month and 17 years. The ECGs showed P waves of
      different configurations. The bifid shape deflection of the P wave was generally
      more frequent than the simple one in animals from 6 months of age. The first
      component of bifid P waves (P1) did not vary in a statistically significant way
      with increasing age, showing a mean value of 0.105 mV. The amplitudes of the P2
      (the second component of the bifid P waves) and simple P waves showed
      statistically significant differences between the age groups. The highest values
      were found in animals up to 3 months and over 2 years of age. Several
      configurations of the T wave were observed in the different age groups: a
      negative shape was generally present for the youngest animals (foals up to 2
      years old); the biphasic (/+) pattern became more frequent in animals 3 and 4
      years old. In adult horses the positive configuration was the most frequent. No
      statistically significant differences according to age were found for the
      amplitude values of the different T-wave configurations.

PMID- 10399482
TI  - Correlation between alpha 1-acid glycoprotein and total sialic acid in serum from
      dogs with tumours.
AB  - The influence of the acute phase protein alpha 1-acid glycoprotein (AGP) on the
      concentration of total sialic acid (TSA) in serum was investigated by assessing
      their degree of correlation in 115 clinically healthy dogs, 29 dogs with
      malignant mammary tumours, 12 dogs with various other malignant tumours, 12 dogs
      with benign mammary tumours and 10 dogs with various other benign tumours. Serum
      from dogs with malignant mammary tumours and other malignant tumours had a
      statistically significant correlation between AGP and TSA concentrations
      (Spearman correlation coefficient (rS) = 0.52, P = 0.0005, n = 41). The
      correlation was also statistically significant in dogs with benign mammary
      tumours and other benign tumours (rS = 0.48, P = 0.02, n = 22). The Spearman
      correlation coefficient was 0.51 (P = 0.0001, n = 63) in all dogs with tumours.
      This was also the case if only those dogs with levels of AGP comparable to
      healthy dogs (< 750 mg/l) were included in the analysis (rS = 0.42, P = 0.01, n =
      56). In clinically healthy dogs, the correlation was not statistically
      significant (rS = 0.17, P = 0.07, n = 115). None of the four groups of dogs with
      tumours had changed serum AGP concentrations compared to clinically healthy dogs
      (all t-tests gave P values above 0.05). The serum concentrations of AGP did not
      correlate with the clinical stage of dogs with mammary tumours. In conclusion,
      AGP and TSA concentrations in serum are positively correlated in dogs with
      tumours, partially explaining the increase in serum TSA in these dogs. Increased
      sialylation of the AGP molecule in dogs with tumours might contribute to the
      increased serum TSA levels.

PMID- 10399483
TI  - Pharmacokinetics of amikacin in lactating goats.
AB  - The pharmacokinetics of amikacin was studied in five lactating goats after single
      intravenous and intramuscular administrations of 7.5 mg kg-1 body weight. After
      intravenous injection, the plasma concentration-time curve of amikacin was
      characteristic of a two-compartment open model with a distribution half-life of
      11.03 min and an elimination half-life of 114.81 min. The mean residence time was
      142.96 min and the volume of the central compartment was 0.061 kg-1. Following
      intramuscular injection, amikacin was rapidly absorbed with an absorption half
      life of 20.39 min. The peak plasma concentration was 34.48 micrograms ml-1 and
      was attained at 62.15 min. The elimination half-life of amikacin after
      intramuscular administration was 122.86 min and the corresponding mean residence
      time was 205.51 min. The systemic bioavailability of amikacin after intramuscular
      administration was 98.27%. Amikacin was not bound to plasma and milk proteins in
      vitro. Amikacin was detected only at low concentrations in the goat's milk 2-6 h
      after intravenous and intramuscular injections. Amikacin urine concentrations
      were much higher than those of plasma. Thus, amikacin is likely to be efficacious
      in the eradication of many Gram-negative urinary tract pathogens.

PMID- 10399484
TI  - Plasma levels of catecholamines and lipolysis during starvation in growing pigs.
AB  - The aim of this study was to clarify the triggering mechanism of lipolysis in
      adipose tissue during feed withdrawal in pigs. Evaluation of blood samples drawn
      via an intravenous catheter from 10 growing pigs fasted for 60 h demonstrated, in
      addition to a haemodilution, a significant rise in plasma levels of non
      esterified fatty acids (250 +/- 37 to 1427 +/- 144 mumol/l) and free glycerol (98
      +/- 27 to 232 +/- 41 mumol/l) within 48 h of feed restriction, and thereafter the
      concentrations levelled off. The pigs also showed a significant decrease in
      plasma levels of glucose (6.01 +/- 0.20 to 4.62 +/- 0.12 mmol/l) within 48 h of
      fasting, followed by repeated increase until the end of the experimental period.
      A significant decrease in plasma insulin-like growth factor I (84 +/- 13 to 65 +/
      7 ng/ml) was observed after 16 h, which continued during the whole period of
      feed withdrawal. However, no significant changes in plasma levels of adrenaline
      and noradrenaline during the period of increased lipolysis were detected.
      Therefore, the observed stimulation of lipolysis in growing swine during fasting
      is not the result of an increase in plasma concentration of catecholamines.

PMID- 10399485
TI  - Comparison of blood ionized calcium and acid-base variables in samples obtained
      from different sampling sites in dairy cows.
AB  - Ionized calcium (Ca2+) concentrations, pH, blood gas tensions (pCO2 and pO2),
      base excess (BE), and bicarbonate (HCO3-) concentrations were determined and
      standard ionized calcium (stCa2+) concentrations were calculated (Ca2+ corrected
      to pH 7.4) for the blood withdrawn from the jugular vein, the coccygeal vein or
      coccygeal artery and the milk vein in 29 clinically healthy post-partum dairy
      cows. The blood withdrawal site had no significant effect on the blood ionized
      calcium and standard ionized calcium (mean differences among the blood samples
      varied between 0.01 and 0.05 mmol/l), or on bicarbonate concentrations or base
      excess. pH, pCO2 and pO2 were significantly lower or higher in samples taken from
      the coccygeal vein compared to other venous blood samples.

PMID- 10399486
TI  - Synthesis and biological activities of C-2, N-9 substituted 6-benzylaminopurine
      derivatives as cyclin-dependent kinase inhibitor.
AB  - In this study, C-2, N-9 substituted 6-benzylaminopurine derivatives were
      synthesized and their inhibitory effects on cyclin-dependent kinase (CDK2) were
      evaluated. The effect of substituents at the C-2 and N-9 positions of substituted
      purine was investigated. Among the compounds tested, compound 7b-iii (6
      benzylamino-2-thiomorpholinyl-9-isopropylpurine) was the most active inhibitor
      (IC50 = 0.9 microM). Compound 7b-iii showed 10-fold higher activity compared to
      olomoucine and almost the same activity as roscovitine. Results from structure
      activity relationship studies should allow the design of more potent and
      selective CDK inhibitors, which may provide an effective therapy for cancer or
      other CDK dependent diseases.

PMID- 10399487
TI  - Synthesis and potential muscarinic receptor binding and antioxidant properties of
      3-(thiadiazolyl)pyridine 1-oxide compounds.
AB  - The synthesis of two different series of 3-(thiadiazolyl)pyridine 1-oxide
      containing 1,2,5- and 1,2,4-thiadiazole moiety respectively is described. The
      potential muscarinic receptor binding together with the antioxidant properties of
      the new compounds were evaluated.

PMID- 10399489
TI  - Synthesis, glycine/NMDA and AMPA binding activity of some new 2,5,6
      trioxopyrazino[1,2,3-de]quinoxalines and of their restricted analogs 2,5-dioxo-
      and 4,5-dioxoimidazo[1,5,4-de]quinoxalines.
AB  - The synthesis of some new 1,2,3,5,6, 7-hexahydro-2,5,6-trioxopyrazino[1,2,3
      de]quinoxalines 1c-g and of their restricted analogs 2,4,5,6-tetrahydro-2,5-dioxo
      1H- 2a-g and 5,6-dihydro-4,5-dioxo-4H-imidazo[1,5,4-de]quinoxalines 3a-d is
      reported. Compounds 1c-g, 2a-g, and 3a-d were tested for their binding activity
      at the glycine/NMDA and AMPA receptors. The results show that only the 6,6,6
      tricyclic derivatives 1c-g are able to bind to the glycine/NMDA and AMPA
      receptors, although with lower affinity than the previously reported lead
      compounds 1a-b. In contrast, the 5,6,6-tricyclic derivatives 2a-g are inactive at
      both receptors and only one 4,5-dioxoimidazoquinoxaline (3b) displays a weak
      glycine/NMDA receptor affinity.

PMID- 10399488
TI  - [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine] sulfatoplatinum(II)-
      pharmacokinetic studies.
AB  - The maximally attainable level of the non-plasma protein bound fraction of a
      single 10.0 mumol/kg i.p. dose of [meso-1,2-bis(2,6-dichloro-4
      hydroxyphenyl)ethylenediamine] sulfatoplatinum(II), a drug active on the murine,
      hormone-sensitive MXT-M-3.2 breast cancer, lies markedly below the concentration
      causing a significant cytotoxic effect on a cell line derived from this tumor.
      This result confirms our opinion that the strong in vivo activity of this drug on
      hormone-sensitive breast cancers is mediated by its estrogenic potency by analogy
      with high dosed steroidal and non-steroidal estrogens. A specific cytotoxic
      effect utilizing the estrogen receptor as carrier, as formerly postulated, is
      unlikely.

PMID- 10399490
TI  - Synthesis and analgesic activity of some condensed analogs of anpirtoline.
AB  - New condensed derivatives of anpirtoline, in which the pyridine ring is replaced
      with quinoline, isoquinoline, quinazoline, and phthalazine nuclei, have been
      synthesized. Their receptor binding profiles (5-HT1A, 5-HT1B) and analgesic
      activity (hot plate, acetic acid induced writhing) have been studied. The
      analgesic activity of compounds 7d, 8b, 8c, and 8e are at least comparable to
      that of the clinically used drugs flupirtine and tramadol under the same
      conditions.

PMID- 10399491
TI  - Synthesis and analgesic activity of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4
      dihydropyridyl)]acetic acid methyl esters, acetic acids, and acetamides.
AB  - A group of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4-dihydropyridyl)]acetic acid
      methyl esters (7), weak acetic acids (8), and acetamides (9) were designed for
      evaluation as less acidic non-ulcerogenic non-steroidal antiinflammatory drugs
      (NSAIDs). In this respect, the model compound 2-methyl-2-[1-(3-benzoyl-4-phenyl
      1,4-dihydropyridyl)]acetic acid (8a), unlike traditional arylacetic acid NSAIDs,
      was shown to be a weak acid with a pKa of 9.17. In contrast to arylacetic acid
      NSAIDs, the alpha-methylacetic acid sodium salt of 8a, or the methyl alpha
      methylacetate ester (7a) did not inhibit cyclooxygenase-1 (COX-1) or -2 (COX-2).
      In vitro stability studies showed that the methyl alpha-methylacetate ester (7a)
      acts as a prodrug to the alpha-methylacetic acid derivative (8a), undergoing
      rapid (< 10 minutes) and quantitative conversion upon incubation with rat plasma,
      or incubation with rat liver homogenate (t1/2 = 25 min). In contrast, the alpha
      methylacetamide (9a) underwent negligible (< 2%) conversion to the alpha
      methylacetic acid derivative (8a) upon incubation with either rat plasma, or rat
      liver homogenate, for incubation times up to 24 h. The effect of a C-3 para
      substituted-benzoyl substituent (R1 = H, Cl, Me), a C-4 substituent (R2 = aryl,
      benzyl, cyclohexyl, alkyl), and the nature of the N1-acetic acid moiety [methyl
      ester (R3 = OMe), acetic acid (R3 = OH), acetamide (R3 = NH2)] on analgesic
      activity was determined using the 4% NaCl-induced abdominal constriction
      (writhing) assay. Compounds 7-9 inhibited writhing 27-95% relative to the
      reference drug aspirin (58% inhibition). The analgesic potency with respect to
      the para-benzoyl substituent was H > Cl or Me. Although the effect of the C-4 R2
      substituent on analgesic activity was variable within the ester, acid and amide
      sub-groups of compounds, compounds having a R2-cyclohexyl substituent generally
      provided superior analgesic activity relative to those having a lipophilic alkyl
      substituent. The nature of the R3-substituent (OMe, OH, NH2) was a determinant of
      analgesic activity where the potency order was acetic acid methyl ester > acetic
      acid or acetamide, except when the C-4 R2-substituent was cyclohexyl or benzyl
      where the potency order was acetamide > acetic acid methyl ester or acetic acid.
      Reduction of the 5,6-olefinic bond of the 1,4-dihydropyridyl compound (9a, 94%
      inhibition) to the corresponding 1,2,3,4-tetrahydropyidyl derivative (10, 69%
      inhibition) reduced analgesic activity.

PMID- 10399492
TI  - 3-Amino- and 5-aminopyrazoles with anticonvulsant activity.
AB  - New 3-amino- and 5-aminopyrazoles were synthesised. 3-Aminopyrazoles exert a
      strong anticonvulsant effect, 4-Chlorophenyl-3-(morpholin-4-yl)-1 H-pyrazole 2
      distinctively blocks sodium channels and is strongly effective in the Maximal
      Electroshock Seizure (MES) test.

PMID- 10399493
TI  - Measuring post-traumatic stress: a psychometric evaluation of symptom--and coping
      questionnaires based on a Norwegian sample.
AB  - The purpose of this study was to evaluate the psychometric characteristics of the
      Norweigian versions of the Impact of Event Scale, the Post Traumatic Stress Scale
      10 item version and General Coping Questionnaire-30 item version. A group of 40
      male and 56 female medical students was tested one week and four months after
      having started dissection of cadavers for the first time. The results showed that
      all scales had good internal consistency and test-retest reliability. The student
      sample scored lower on the IES and PTSS-10 than comparable groups of traumatized
      subjects. A gender difference emerged, with female subjects scoring higher than
      male subjects. The factor analysis of the instruments indicated good construct
      validity for the symptom scales. The analysis of content validity related to DSM
      IV criteria indicated that the IES and PTSS-10 may have some limitations in their
      predictive validity of PTSD. Taken together, the three scales have shown good
      psychometric properties and could be used in future research and clinical work.

PMID- 10399494
TI  - The Yale Children's Inventory--a screening tool for attention deficits and
      related disorders. Normative data for boys.
AB  - Norwegian populated-based normative data on the Yale Children's Inventory (YCI)
      were provided for boys. All parents of boys aged 8 through 11 years in the county
      of Hammerfest received the YCI, and 77% responded. Mean scores on the YCI scales
      attention, activity, tractability, and fine motor were significantly lower in the
      Norwegian sample compared to the US normative data. Factor analysis of the 40
      scale items yielded factors that corresponded generally well to the YCI scale
      constructs derived from US samples. We conclude that the scale constructs of the
      YCI seem to be transferable across these two cultures, but that restandardization
      is warranted. Further research is needed to establish cut-off values for clinical
      screening purposes. The Yale Children's Inventory has the potential to become a
      valuable screening tool for behavioral problems at school-age.

PMID- 10399495
TI  - Intelligence and dyslexia: implications for diagnosis and intervention.
AB  - In this paper we critically examine theoretical issues and practical consequences
      of including IQ in the definition of dyslexia. According to the discrepancy
      criterion individuals are classified as dyslexic if their reading skills are
      below what would be expected from their IQ scores. However, we argue that
      intelligence is a fuzzy concept and that there is no clear causal relationship
      between intelligence level and word decoding skills. Also, high and low IQ poor
      readers show the same reading performance patterns, indicating that both groups
      might benefit from the same remedial activities. Evidence for the critical role
      of phonological skills in dyslexia is presented and a more recent definition of
      dyslexia is discussed in relation to these findings. Finally, two alternative,
      more outcome-based classifications of poor readers are suggested and some
      critical consequences for individual interventions are outlined.

PMID- 10399496
TI  - Comorbidity in schizophrenia: a prognostic study of personality disorders in
      recovered and non-recovered schizophrenia patients.
AB  - Symptoms and outcome in schizophrenia are heterogeneous. Part of the variation in
      outcome might be due to the coexistence of other forms of psychopathology. In the
      present study the prevalence of personality disorders in a group of recovered and
      non-recovered schizophrenia patients was focused to examine the prognostic
      implications of comorbidity for the outcome of the disorder. The results showed
      no significant differences in prevalence of personality disorders in the two
      groups at first admission to the hospital, but the difference at the time of
      interview was close to significance. Emotional and conduct difficulties in
      adolescence were significantly more prevalent in the non-recovered group.
      Schizoid features and emotional and conduct disorders in childhood were also more
      often reported among the non-recovered subjects. The results confirm that
      comorbidity contributes to the variation in outcome for schizophrenia patients,
      but does not confirm its prognostic significance.

PMID- 10399497
TI  - [Prospective comparative study of HCV serologic status in and AIDS population].
AB  - OBJECTIVE: Study the influence of hepatitis C virus (HCV) serology on the course
      of HIV disease in AIDS patients. PATIENTS AND METHODS: A prospective study of
      survival prognosis in HIV infected patients who had reached the AIDS stage was
      conducted in the Saint-Etienne, Clermond-Ferrand and Lyons infectious disease
      centers to compare patients with positive and negative HCV serology. Data were
      collected using the clinico-epidemiological software DMI II. The effect of HCV
      ico-infectioni defined by RIBA II or III confirmed seropositivity, was studied
      using Kaplan-Meier survival plots. RESULTS: Among the 1,005 HIV-infected subjects
      included in the study, 219 had AIDS and 43 of them (19.6%) were HCV positive.
      Survival curves in HIV/HCV positive patients with AIDS were not significantly
      different from those of HCV-negative AIDS patients (median 17.8 versus 18.6
      months respectively, p = 0.93). This result was confirmed by univariate Kaplan
      Meier analysis. Only 2 patients were treated with interferon and no deaths were
      attributed to liver disease. CONCLUSION: HCV positivity in AIDS patients does not
      appear to influence survival. The longer survival obtained with the new anti
      retroviral treatments may have an effect on the HIV-HCV interaction.

PMID- 10399498
TI  - [Early signs of systemic disease in patients taking minocycline chlorhydrate].
AB  - BACKGROUND: Search for etiology in young subjects with joint disease must take
      into consideration causes other than reactional arthropathy or systemic disease.
      CASE REPORTS: Two young subjects consulted for joint pain involving various
      joints. Physical examination did not reveal any other abnormality. Serum tests
      were positive for antinuclear antibodies and/or showed moderately and
      persistently elevated transaminases. History taking revealed that these subjects
      had been taking minocyclin chlorhydrate for several months, or even years, for
      acne. Joint pain subsided with drug withdrawal and serum tests returned to
      normal. DISCUSSION: Long-term treatment with minocylin chlorhydrate should always
      be included in the search for an etiology in patients presenting joint pain.

PMID- 10399499
TI  - [A paraneoplastic acrosyndrome].
AB  - BACKGROUND: Paraneoplastic digital ischemia is an uncommon complication of
      metastatic adenocarcinomas. CASE REPORT: Two years after remission of an uterine
      adenocarcinoma, the patient developed an acrosyndrome involving all four limbs
      with digital ischemia. Recurrent carcinoma was evidenced by a very high
      antinuclear antibody titer. Chemotherapy improved the acrosyndrome. DISCUSSION:
      Vasomotor disorders which developed in older subjects with no other signs of
      autoimmune disorders should suggest a neoplastic origin. Icshemia of the fingers
      would be caused by vasculitis. An elevated antinuclear antibody titer may be a
      supplementary argument suggesting a neoplastic etiology.

PMID- 10399500
TI  - [Central pontine myelinolysis following correction of hypernatremia in an aged
      patient].

PMID- 10399501
TI  - [An unexpected consequence of using "joints"?].

PMID- 10399502
TI  - [Mesenteric panniculitis. Report of a case].

PMID- 10399503
TI  - [Statistical comparison of activities of general practitioners and their impact
      on prescription habits].

PMID- 10399504
TI  - [Place and mode of teaching therapeutics in the curriculum of medical education].
AB  - The current medical school curriculum in France includes a comprehensive
      examination on therapeutic management which medical students must pass before
      admission into residency. The proposed reform in the medical school curriculum
      considerably modifies the training program. The main objective is for students to
      acquire the minimal degree of responsibility necessary from the very beginning of
      residency, particularly in terms of therapeutic decision making. A survey
      currently being analyzed was conductec by the national association for training
      in therapeutics (APNET) and the national association of French medical students
      (ANEMF). It showed that at the end of pre-residence training, student demand for
      practical training in therapeutics and decision making is very strong. This round
      table revealed a consensus concerning the proposed reform. Faculty members,
      medical school deans, and students agree on the need for an improvement in
      training in therapeutics. The following points were discussed: what is the
      objective of training in therapeutics? When should it be taught? When should
      training be validated? And by whom?

PMID- 10399505
TI  - [How do physicians evaluate their medical school training. Retrospective survey
      of 4 groups of medical students 8-11 years after graduation].
AB  - A survey was conducted among 250 graduates of the Bobigny School of Medicine
      (University Paris-Nord) who had completed medical school from 1986 to 1989 in
      order to ascertain their opinion concerning the training received. Ninety former
      students (36%) responded. The mean age of the sample was 34 years; 46 women and
      44 men. Most (88.9%) were practicing medicine, principally as general
      practitioners (61.8%). 81.6% felt they had been well prepared to practice
      medicine. The rate of satisfaction was higher in the area of fundamental science
      than in clinical science. The responders generally felt that teaching and
      validation methods should emphasize real situations. The main criticism
      concerning the curriculum was an insufficient degree of professionalism,
      particularly in fields currently of particular importance: epide miology, health
      economics, education, prevention, office management. Training was also considered
      to be insufficient in medical techniques, communication, priority decision
      making, team work, emergency care, organization of time and handling stress. The
      responders suggested that the future curriculum should focus more on information
      search, research methodology and computer science. The results of this survey
      collaborate findings of recent retrospective long-term analyses conducted in
      other European countries.

PMID- 10399506
TI  - [Low molecular weight heparin in unstable angina and myocardial infarction
      without Q wave].
AB  - SEARCH FOR MORE EFFECTIVE ANTICOAGULATION: The limitations of conventional
      treatment with non-fractionated heparin (NFH) in patients with unstable angina
      and myocardial infarction without Q wave are demonstrated by the 7 to 9% rate of
      serious complications (infarction and/or death) at 30 days and has motivated
      search on the use of low-molecular-weight heparins (LMWH). PROVEN CLINICAL
      EFFICACY: As early as 1995, a pilot study reported the superiority of the aspirin
      LMWH (nadroparin) combination compared with aspirin alone or the aspirin-NFH
      combination. In 1996, the FRIC study compared for the first time a LMWH with
      conventional NFH and reported rather disappointing results with LMWH
      (dalteparin). However, the ESSENCE study showed the success of LMWH (enoxaparin)
      versus NFH in unstable angina and infarction without Q wave. A MORE COMFORTABLE
      PRESCRIPTION: The subcutaneous administration, the lack of a need for laboratory
      tests, better predictability of the anticoagulant effect and better tolerance are
      powerful arguments favoring LMWH for use in unstable angina and infarction
      without Q wave. ROLE IN THE MANAGEMENT OF ACUTE CORONARY PATIENTS: LMWH have come
      to play an important role in the management of uncontrolled coronary artery
      disease where treatment protocols are evolving rapidly with the development of
      new antiplatelet compounds. The requirement for prolonged oral antiplatelet or
      LMWH treatment in ambulatory patients after an acute coronary event remains to be
      evaluated.

PMID- 10399507
TI  - [Non-transfusional and non-intravenous drug addiction related transmission of
      hepatitis C virus].
AB  - PARENTERAL TRANSMISSION: Among subjects infected by the hepatitis C virus (HCV),
      about 40% have no history of blood transfusion or intravenous drug abuse. The
      highly variable presence of HCV in biological fluids other than blood would
      suggest that HVC transmission basically follows the parenteral route.
      Transmission of HCV via medical material contaminated by blood of an infected
      subject is a clinical reality: accidental needle prick, medical material
      (endoscope, physician-patient), tattooing, acupuncture, ear piercing, certain
      traditional practices, sharing toilet instruments (tooth brush, razor, fingernail
      shears). RARE SEXUAL TRANSMISSION: The prevalence of HCV infection is higher in
      people living with infected subjects, particularly spouses, than in the general
      population. However, transmission of HCV in this population probably follows a
      parenteral route (common risk factors, sharing toilet instruments) rather than by
      sexual transmission which plays a minor role except in sexually transmitted
      diseases with genital lesions. MOTHER-INFANT TRANSMISSION: Per- or post-partum
      transmission is possible though the risk is low, less than 5% of all infants are
      infected at the age of 1 year. The data are contradictory, but breast feeding
      would appear to play a role. Co-infection by the HIV virus, via high HCV viremia,
      clearly increases the risk of mother-infant transmission and perhaps also sexual
      transmission. NOSOCOMIAL TRANSMISSION: Nosocomial transmission is probably the
      most important factor in HCV transmission, but the risk remains to be quantified.

PMID- 10399508
TI  - [Mini-Mental State Examination:a useful method for the evaluation of the
      cognitive status of patients by the clinician. Consensual French version].
AB  - A PRACTICAL TOOL: Screening for cognitive deficiency has been considerably
      improved by the use of a standardized tool, the Mini-Mental State Examination
      (MMSE). The MMSE only takes a few minutes and furnishes quantitative data for
      comparison between patients and to follow the evolution of a given patient. AN
      IMPORTANT ROLE: The MMSE is particularly useful for screening for dementia and
      states of mental confusion. It should be used systematically for elderly
      subjects, not only in the neurology setting, but also in geriatrics, psychiatrics
      and internal medicine. INTERPRETATION: The global score gives an assessment of
      the subject's performance level, taking into account for age, affective status
      and cultural situation. The MMSE cannot alone provide the diagnosis of dementia
      which requires a complete neurological examination. THE CONSENSUAL FRENCH
      VERSION: Diverse French versions have been developed with considerable
      differences in scoring schemes. For this reason, the Working Group on Cognitive
      Evaluations (GREC) has established a consensual version of the MMSE in French.

PMID- 10399510
TI  - [The use of Cantonese pain descriptors among healthy young adults in Hong Kong].
AB  - BACKGROUND: The interpretation and expression of pain are closely related to an
      individual's social and cultural background. To convey messages on pain, language
      and words (pain descriptors) is particularly significant in assessment and
      evaluation of pain severity and its management. Therefore, the study of pain
      descriptors is crucial in clinical practice. METHODS: It was of exploratory
      descriptive design. Samples were recruited by convenience. Data were collected by
      structured self-administered questionnaire. Data obtained included demographic
      information and pain descriptors used by the subjects in various pain conditions.
      Data were analyzed by descriptive statistics. Pain descriptors were categorized
      according to nature, process, intensity, aggravating factors, accompanying
      symptoms and behavioral manifestation. RESULTS: Total number of pain descriptors
      (in Cantonese) based on real pain experience was 3017, mean was 3 (n = 986). The
      commonest used descriptors was the nature of pain (41%). The intensity of pain
      constituted 20%. There was no significant difference in the number of pain
      descriptors between male and female. However, there was a significant difference
      between the type of pain descriptors used (Mfemale = 526, Mmale = 453, Z = 
      2.9729, p = 0.0029). There were also significant differences in the use of pain
      descriptors among the various age groups (X2 = 15.0157, df = 4, P = 0.0047) and
      educational levels (X2 = 11.2443, df = 4, P = 0.0240). The types of descriptors
      used increased with an increase in age and education levels. CONCLUSIONS: This
      exploratory-descriptive study explores the use of pain descriptors among Chinese
      young adults in Hong Kong. The result shows that female use more pain descriptors
      than male. The pain descriptors that female used are mostly of nature type. The
      similarities and differences in findings with those of the Ho's (1991) are
      compared.

PMID- 10399509
TI  - [Images in medicine. Giant gastric ulcer revealed by anemia].

PMID- 10399511
TI  - Preemptive neural blockade--attenuation of stress response and central
      sensitization.

PMID- 10399512
TI  - Preoperative evaluation and postoperative prediction of hemostatic function with
      thromboelastography in patients undergoing redo cardiac surgery.
AB  - BACKGROUND: Patients who receive cardiac procedures, in particular "redo" ones,
      often suffer complications from massive bleeding, largely due to bypass-induced
      coagulopathies. Cardiopulmonary bypass (CPB) may cause damage of the blood
      components, both in terms of quality and quantity. In order to investigate the
      qualitative changes of blood constituents with special regard to coagulation
      resulting from the complex insult of previous cardiac surgery,
      thromboelastography (TEG) was used to analyze the whole clotting process.
      METHODS: Seventy-four patients who underwent cardiac surgery with CPB were
      prospectively studied. Of them, 32 patients received "redo" cardiac surgery.
      Blood samples for routine laboratory coagulation tests (RCT) and TEG examination
      were drawn before and after cardiopulmonary bypass. Clinically significant
      bleeding was defined if the chest tube drainage was greater than 100 ml/h for 3
      consecutive h or greater than 300 ml in 1 h during the first 8 h after surgery.
      Prebypass and postbypass coagulation parameters were compared and the percentage
      of accuracy, false positive and false negative rate were deduced from
      calculation. RESULTS: In the TEG tracings, preoperative alpha angle and maximum
      amplitude were significantly decreased in the "redo" group when compared with
      primary group, indicating less competent platelet function and platelet-fibrin
      interaction. Lower platelet count was also found by conventional coagulation
      tests in "redo" patients. Postoperatively, higher percentage of excessive
      hemorrhage was also noted in the "redo" group (42.8% vs. 27.5% in primary group).
      However, a much lower predictive accuracy was found in "redo" patients in
      comparison with primary cardiac patients (53.5% vs. 90%). CONCLUSIONS: We
      concluded that thromboelastography failed to predict postoperative hemorrhage in
      "redo" cardiac patients and the graphic recordings derived could not be treated
      as a guide of transfusion therapy. We thought that inferior preoperative
      hemostatic status and severer coagulopathy might be responsible for the
      differences between "redo" and primary cardiac patients.

PMID- 10399513
TI  - Comparison of the cuffed oropharyngeal airway and laryngeal mask airway in
      spontaneous breathing anesthesia.
AB  - BACKGROUND: The cuffed oropharyngeal airway (COPA) is a modified Guedel airway
      with a cuff at its distal end and a standard 15 mm connector at its proximal end.
      This study was performed to determine if the COPA would offer any advantage over
      the laryngeal mask airway (LMA). METHODS: Eighty ASA class I to II adult patients
      scheduled for short elective procedures (less than 1 h) were randomly allocated
      into two groups. All patients were given atropine 0.01 mg/kg, fentanyl 2
      micrograms/kg and propofol 2 mg/kg intravenously for induction of anesthesia. The
      COPA or LMA was inserted following the loss of eyelash reflex. If the jaw was not
      relaxed enough for insertion of a COPA or LMA, succinylcholine 1 mg/kg was given
      to facilitate the insertion. When correctly positioned, the cuff was immediately
      inflated with an appropriate volume. Gentle positive pressure ventilation was
      applied before spontaneous breathing resumed. Capnography was used to assess the
      patency of the airway. Anesthesia was maintained with isoflurane-N2O-O2 until the
      end of surgery. The success rate, vital signs, and adverse events were evaluated
      and compared. RESULTS: The success rate in the LMA group (95%) was higher than
      the COPA group (85%). The increase in circulatory response after the LMA
      insertion was greater than that after the COPA insertion (P < 0.05). Nine
      patients (22.5%) in the LMA group needed succinylcholine to facilitate insertion
      compared with only two patients (5%) in the COPA group. Additional manipulation
      was frequently (57.5%) needed after inserting the COPA to maintain the patency of
      the airways, but none needed so in the LMA group. Two patients had laryngospasms
      upon removal of the LMA, but none had laryngospasm in the COPA group. The
      incidence of sore throat in the LMA group was higher than in the COPA group (18%
      vs. 10%). CONCLUSIONS: We demonstrated that the COPA could be easily inserted
      without the need of muscle relaxants in most patients. But the COPA needed airway
      intervention to provide an effective airway in most patients. Compared with the
      LMA, the COPA caused less stimulation than the LMA.

PMID- 10399514
TI  - Softened endothracheal tube reduces the incidence and severity of epistaxis
      following nasotracheal intubation.
AB  - BACKGROUND: Many complications were reported to be related with nasotracheal
      intubation. Various chemical or mechanical techniques have been proposed to
      decrease hemorrhage and trauma associated with nasotracheal intubation but the
      results remain controversial. We conducted a prospective, randomized, single
      blind study to elucidate the effect of an endotracheal tube softened with warm
      water before use on the incidence and severity of epistaxis following
      nasotracheal intubation. METHODS: Sixty-two healthy, (ASA class I or II) patients
      scheduled for elective surgery were randomly assigned into two groups. Patients
      in the treatment group were intubated with a softened endotracheal tube made
      possible by heating it in warm water while those in the control group were
      intubated with unsoftened (intact) tube. Epistaxis was evaluated immediately
      after intubation and its severity was graded as none, mild, moderate and severe.
      The use of Magill forceps and postoperative nasal morbidity were also recorded.
      RESULTS: The total incidence of epistaxis in the "unsoftened" group was
      significantly higher than that of "softened" group (76.7% vs. 43.8%, P = 0.0002).
      The severity of nasal hemorrhage was also significantly lightened in the
      "softened" group. No technical difficulty was encountered in intubation with a
      softened endotracheal tube by prewarming. The morbidity referable to nasal
      intubation, however, did not differ in both groups. CONCLUSIONS: In conclusion,
      our study shows that using an endotracheal tube softened by warm water could
      reduce the incidence and severity of epistaxis during the act of nasotracheal
      intubation. It is an effective way and worth a try.

PMID- 10399515
TI  - Modified transcranial electromagnetic motor evoked potential obtained with train
      of-four monitor for scoliosis surgery.
AB  - BACKGROUND: To monitor the spinal cord with somatosensory evoked potential (SSEP)
      is an accepted adjunct in the surgical correction of spinal deformities, but it
      does not directly assess the motor function. The use of motor evoked potential
      (MEP) has thus been introduced in an effort to meet this important need. METHODS:
      This preliminary report concerned 30 cases of scoliosis who underwent surgical
      correction under the surveillance of modified transcranial electromagnetic motor
      evoked potential (tcMMEP). Train-of four (TOF) stimulator output was connected to
      an electromagnetic stimulator. The rate of repetition and interval of stimulation
      were controlled by TOF stimulator. Electromyographic (EMG) signals were obtained
      from the abductor hallucis muscle of both feet and interpreted as MEP activity.
      Anesthesia was made possible by propofol as a basic agent and isoflurane as
      supplement. Analgesia was obtained with sufentanil and fentanyl and amnesia
      enhanced by midazolam. Atracurium mixed with vecuronium in a ratio of 4:1 by
      weight in possible lowest dose was given to provide adequate muscle relaxation
      yet without the molestation of rapid reversal upon the request of wake-up test by
      the surgeon. Deliberate hypothermia and controlled hypotension were also applied
      since they did not interfere with the tcMMEP signals. RESULTS: Although no
      attempt was made to control the level of muscle relaxation at T1 more than 30%,
      tcMMEP signals could be obtainable during induction, at the time of surgical
      correction and at the end of the operation. TcMMEP onset latency was 27.32 +/-
      0.45 msec on the left side and 27.27 +/- 0.54 msec on the right side. The
      amplitude was 3.52 +/- 1.97 mV on the left side and 4.05 +/- 1.22 mV on the right
      side. CONCLUSIONS: The modified tcMMEP is so stable and convincing that research
      for similar modification is now undergoing with the other brand of TOF monitor by
      our team.

PMID- 10399517
TI  - Combination of bupivacaine scalp circuit infiltration with general anesthesia to
      control the hemodynamic response in craniotomy patients.
AB  - BACKGROUND: Sudden and overwhelming increases in blood pressure (BP) and heart
      rate (HR) during incision of the scalp may give rise to morbidity or mortality in
      patients with intracranial pathology undergoing neurosurgery. A modification of
      the method proposed by Labat to abate this circumstantiality was applied in a
      group of patients receiving craniotomy. The modified method was to combine scalp
      circuit infiltration of local anesthetic with general anesthesia to control the
      hemodynamic response to craniotomy. METHODS: Twenty-six patients scheduled to
      undergo craniotomy were randomly divided into two groups. Patients whose
      conditions or their current medication that might affect the stability of
      hemodynamics were excluded. In group A patients (N = 16) 25-30 ml of 0.25%
      bupivacaine was used for scalp circuit infiltration on the operation side, while
      in those of group B (N = 10) the same volume of 0.9% normal saline was used.
      After induction, anesthesia was maintained with 0.6% to 1.2% end-tidal isoflurane
      (ET-Iso) and 50% N2O in oxygen (N2O:O2 = 2 l/min:2 l/min). The end-tidal CO2 was
      kept within the range of 25-30 mmHg. BP and HR were recorded every five min
      before incision and then every two min after incision until one hour after
      induction. ET-Iso was also recorded every two min throughout a period of sixty
      min. If the BP and HR increased above 20% of the baseline (10 min before
      incision), thiopental 2.5 mg/kg and fentanyl 2 micrograms/kg were administered.
      If hypertension became sustained, the isoflurane concentration was adjusted until
      an acceptable level was obtained. RESULTS: The mean BP during the surgery was 92
      +/- 1 mmHg in group A and 92 +/- 7 mmHg in group B. The difference in BP between
      incision to 6 min after incision was statistically significant (P < 0.05). The
      mean HR during surgery was 101 +/- 5 beats/min in group B and 91 +/- 2 beats/min
      in group A, the difference of which was not statistically significant. All of the
      patients in group B required a deepened anesthesia to keep the BP and HR within
      the normal range, but no patient in group A had such need. The average
      concentration of ET-Iso during the 60 min period was 0.95 +/- 0.12% in group B
      and 0.41 +/- 0.01% in group A, respectively. The difference was statistically
      significant (P < 0.05). CONCLUSIONS: Our results showed that scalp circuit
      infiltration with 0.25% bupivacaine significantly improved the cardiovascular
      stability and reduced the requirement of isoflurane during craniotomy. The
      routine use of bupivacaine scalp circuit infiltration in patients undergoing
      craniotomy should be considered.

PMID- 10399516
TI  - Subarachnoid fentanyl with diluted small-dose bupivacaine for cesarean section
      delivery.
AB  - BACKGROUND: The use of neuraxial opioid was very popular in recent years, and
      they may augment the analgesia produced by local anesthetic through direct
      binding with the spinal opioid receptors. Hemodynamic stability is very important
      during Cesarean section. Theoretically, the reduction of local anesthetic by
      addition of fentanyl would provide better hemodynamic stability and good
      anesthetic status. METHODS: Thirty healthy parturients undergoing Cesarean
      section were assessed in a randomized fashion. They were divided into two groups.
      Each subject received 5 mg hyperbaric bupivacaine plus 25 micrograms fentanyl
      (0.5 ml) and cerebrospinal fluid (CSF) 0.6 ml (Group M + F) or 8 mg hyperbaric
      bupivacaine plus 0.5 ml of CSF (Group M). The effects of hemodynamic stability,
      side effects, and complete analgesic duration were observed. RESULTS: It was
      disclosed that the hemodynamic status was more stable in group M + F. The
      incidence of nausea and vomiting appeared to be not statistically significant
      between groups. The incidence of pruritus was apparently higher in group M + F
      (93.5% vs. 0) but the incidence of shivering was much lower in group M + F (0 vs.
      33.3%). The complete analgesic duration was longer in group M + F (146 +/- 47 min
      vs. 104 +/- 44 min). There were no significant differences in the anesthetic and
      surgical status, 1-min and 5-min Apgar scores, and the time of regression of
      sensory level to T10. CONCLUSIONS: The combination of small-dose bupivacaine with
      fentanyl could provide more stable hemodynamic status, longer postoperative
      analgesia, and lower incidence of shivering. The incidence of pruritus in group M
      + F was high, but it was usually mild.

PMID- 10399518
TI  - An alternative continuous caudal block with caudad catheterization via lower
      lumbar interspace in adult patients.
AB  - BACKGROUND: Continuous caudal block with caudad catheterization has not yet been
      mentioned in literatures. We designed a preliminary study to investigate the
      feasibleness of this technique, spread of contrast medium under fluoroscopy, and
      its clinical effectiveness. METHODS: Ten patients were subjected to epidural
      block (caudal) for elective anal or vaginal procedures. The entry of the epidural
      needle was made at the L4-5 interspace either with midline or paramedian
      approach. Through an 18 G Touhy needle with its bevel facing caudally an epidural
      catheter was threaded until a length of 10 cm was beyond the point of entry. The
      presence or absence of paresthesia during the passage of catheter and the ease
      with which the catheter was inserted were recorded. After the procedure, the
      course on which the catheter traversed and the spread of the medicinal substance
      in the epidural space were visualized and studied fluoroscopically using 1 and 3
      ml iohexol (omnipaque 300 mg/ml) as contrast medium respectively. Then the
      patients were brought to operating rooms for anesthesia and surgery. Sensory
      anesthetic level and motor blockade were evaluated fifteen min after 11-15 ml of
      2% lidocaine had been injected through the epidural catheter. During anesthesia
      vital signs were closely monitored, and adverse reaction if any was evaluated and
      managed. RESULTS: The insertion of the epidural catheter was considered easy and
      caused no paresthesia in nine patients. Catheter insertion encountered moderate
      resistance and induced paresthesia in one patient. Yet, the catheter was advanced
      successfully to the expected length. In radiological study with contrast medium,
      the course of the epidural catheter was not always traceable, while the spread of
      the contrast medium was clearly identified. Epidural spread occurred in eight
      patients, left paravertebral spread in one patient, and right retrorectal spread
      in another one patient. As to clinical assessment, adequate sensory blockade with
      local anesthetic was gained in 8 patients with well-preserved motor function of
      the lower limbs. In one patient the caudal block worked well after the withdrawal
      of the catheter 5 cm in length. Spinal anesthesia was supplemented in one patient
      due to failure of the caudal block. CONCLUSIONS: Continuous caudal block with
      caudawise catheterization via lower lumbar interspaces is feasible (eight of 10
      patients in this study) with respect to technique and clinical effect.
      Paravertebral and retrorectal migrations of the catheter may occur in spite of
      smooth catheterization. Either migration might lead to a failure of caudal block.

PMID- 10399519
TI  - Alternation of one-lung and two-lung ventilations with the same single-lumen
      endobronchial tube during thoracoscopic surgery--a case report.
AB  - One-lung ventilation is sometimes necessary for procedures performed through
      thoracotomy. Single lumen endobronchial tube has been used purposefully for one
      lung ventilation since 1931. However, there are no reports on intra-operative
      alternation of one-lung and two-lung ventilations through the same single lumen
      endobronchial tube as it can only provide unilateral lung ventilation. We present
      a case in whom a tube exchanger was used to readjust tube position so as to
      provide alternation of one-lung and two-lung ventilations in a thoracoscopic
      procedure.

PMID- 10399520
TI  - Patient-controlled epidural analgesia for postherpetic neuralgia in an HIV
      infected patient as a therapeutic ambulatory modality.
AB  - A 43-year-old HIV-positive male was referred to our pain clinic one month after
      his fourth attack of herpes zoster infection. He complained of intermittent
      intolerable sharp and lancinating pain accompanied by numbness over the inner
      aspect of the left upper extremity, left anterior chest wall and the back.
      Physical examination revealed allodynia over the left T1 and T2 dermatomes
      without any obvious skin lesion. The pain was treated with epidural block made
      possible by a retention epidural catheter placed via the T2-3 interspace. After
      the administration of 8 ml of 1% lidocaine in divided doses, the pain was
      completely relieved for 4 h without significant change of blood pressure or heart
      rate. A pump (Baxter API) for patient-controlled analgesia (PCA) filled with
      0.08% bupivacaine was connected to the epidural catheter on the next day and
      programmed at a basal rate of 2 ml/h, PCA dose 2 ml, lockout interval 15 min,
      with an one-hour dose limit of 8 ml. He was instructed to report his condition by
      telephone every weekday. The pump was refilled with drug and the wound of
      catheter entry was checked and managed every 3 or 4 days. The epidural catheter
      was replaced every week. During treatment, the pain intensity was controlled in
      the range from 10 to 0-2 on the visual analogue scale. He was very satisfied with
      the treatment and reported only slight hypoesthesia over the left upper extremity
      in the early treatment period. Epidural PCA was discontinued after 28 days. He
      did not complain of pain thereafter but reported a slight numb sensation still
      over the lesion site for a period of time. In conclusion, postherpetic neuralgia
      in an HIV-infected man was successfully treated with ambulatory therapeutic
      modality of epidural PCA for 28 days.

PMID- 10399521
TI  - Influence of nasal provocation on FEV1/PEF of asthmatic patients with or without
      rhinitis.
AB  - BACKGROUND/AIMS: Rhinitis is a potential aggravating factor for asthma. Our
      objective was to evaluate if HDM nasal challenges would induce lung function
      changes, assessing any differences between asthmatics with and without rhinitis.
      MATERIAL AND METHODS:  POPULATION: 40 stable moderate persistent HDM allergic
      asthmatics, on inhaled steroids; 20 also had mild-moderate perennial HDM allergic
      rhinitis, treated only with oral cetirizine when needed. 10 non-allergic, non
      asthmatic patients served as controls. Nasal provocation: standardised HDM
      extract, in powder-form, in sequentially increasing concentrations. Lung
      function: FEV1 before, 30 and 60' after the last nasal challenge. Peak-Expiratory
      Flow (PEF) measurements were performed in the morning and evening, during the
      prior week and the 2 days following nasal provocation. MEDICATIONS ALLOWED: All
      patients maintained their inhaled steroids. Anti-histamines or b2-agonists in the
      preceding week constituted exclusion criteria. RESULTS: Nine asthmatic, rhinitis
      patients showed statistically significant lung function decreases versus only two
      of the asthmatic non-rhinitic and none of the controls. No patient had any
      clinically significant asthma exacerbation. CONCLUSIONS: Although not sufficient
      to induce asthma symptoms, nasal HDM provocation can induce slight lung function
      decrease, more frequently in patients who have both asthma and rhinitis than in
      patients with asthma without rhinitis.

PMID- 10399522
TI  - Anaphylaxis in schools and other child-care settings--the situation in France.
AB  - The American Academy of Allergology and Clinical Immunology joined to the
      Canadian Society published in August 1998 guidelines for the management of
      anaphylaxis in schools. The authors assess the situation in France. An emergency
      health care form entitled "Projet d'Accueil Individualise", is carried out by
      allergologists, and countersigned by the physician in charge of the School Health
      Department. The clinical symptoms that may occur, are described, as well as the
      incriminated foods to be avoided, the treatment to be used, the content of the
      mergency kit. Epinephrine is the first drug to be used. Beta adrenergic drugs are
      advised on the account of severe attacks of asthma. School lunches being not safe
      are not allowed. Civil society's liability is a question that has not yet been
      solved.

PMID- 10399523
TI  - [Prevention of allergic diseases].
AB  - Within the purview of a formation day in Allergy for General Practitioners, this
      presentation on prevention recalls recent data obtained by the expedient of
      epidemiological studies, the aim of which was to aquaint the treating physicians
      with the growth in prevalence of the diseases of allergy and to alert them to the
      need of present advice on the elementary preventative measures for their patients
      at risk. These elementary measures are a healthy interior environment that is low
      in pneumoallergens, with especially a fight against passive tobacco smoking, and
      a differential and progressive introduction of solid foods to infants.

PMID- 10399524
TI  - [Generalized acute exanthematous pustulosis caused by carbamazepine].
AB  - Generalised acute exanthematic pustuloses are severe skin reactions that are
      induced by drugs. These toxidermies are characterised by sudden appearance of a
      diffuse area of erythema, covered with a scattering of superficial pustules,
      starting most often on the face and in the folds. Most often, the inducing drugs
      are the antibiotics, more rarely carbamapezine.

PMID- 10399525
TI  - [Crossed spinach-latex allergy revealed by exercise-induced anaphylaxis].
AB  - Diagnosis of exercise-induced anaphylaxis is based on conjunction between a
      specific factor: a specific or nonspecific food allergy and exercise. The authors
      report observation of a patient who presented with exercise-induced anaphylaxis
      associated with food allergy to spinach, but also with a cross reaction with
      latex.

PMID- 10399526
TI  - [Evolution of the medical writing of the scientific reports published by the
      Annales d'Otolaryngologie et de Chirurgie Cervico- Faciale].
AB  - OBJECTIVES: To evaluate the quality and evolution of the medical writing of the
      scientific reports published by the Annales d'Otolaryngologie et de Chirurgie
      Cervico-faciale. MATERIAL AND METHODS: A comparative study of quantitative and
      qualitative data regarding the medical writting of 98 scientific reports
      published in 1977, 1987, and 1997 in the Annales d'Otolaryngologie et de
      Chirurgie Cervico-faciale. RESULTS: Various significant statistical results
      documented an increase within the quality of the medical writing of the
      scientific reports published. However, various probllems regarding the medical
      writing of the chapters "Title", "Summary", or "Discussion", the type of study
      performed, the use of biostatistics, the references, and the style still exist.
      CONCLUSION: Based upon the data collected, the author supports the actual policy
      of the editorial board regarding the increased severity concerning the medical
      writing of the scientific reports submitted to the Annales d'Otolaryngologie et
      de Chirurgie Cervico-faciale. Various propositions are also performed to increase
      the quality of the medical writting and the diffusion of the scientific reports
      published by the Annales d'Otolaryngologie et de Chirurgie Cervico-faciale.

PMID- 10399527
TI  - [A clinical study of chronic perennial and permanent rhino-sinusal dysfunction.
      II. Clinical pattern of different pathologies].
AB  - Following a univariate analysis of the clinical features of chronic perannual and
      permanent rhinosinus dysfunction, the aim of this work was to complete the study
      by a multivariate analysis. The analysis was based on the three main pathologies
      retained (chronic sinusitis, bilateral symmetrical pansinusitis, anterior facial
      sinusitis). Each pathological situation was divided into subgroups, Phadiatop
      positive or negative chronic rhinitis, bilateral symmetrical chronic
      panethmoiditis or stage I, II or III naso-sinus polyposis, maxillary sinusitis or
      anterior facial pansinusitis. The clinical features of these different entities
      were detailed (number, quality and laterality of the symptoms, results of the
      physical examination). This clinical description was compared with paraclinical
      findings, particularly computed tomography of the face.

PMID- 10399529
TI  - [Surgical management of laryngeal stenosis in children].
AB  - Surgical management of children with laryngotracheal stenosis changed recently
      because of the procedure of single-stage approach. Between January 1992 and April
      1997, 101 children underwent surgery for laryngotracheal stenosis in our
      department: 47 of them had a single stage procedure, and 54 a classic
      laryngotracheoplasty with stenting with an Aboulker's tube or silastic sheets.
      The majority of the cases were acquired stenosis (64%) and the others congenital.
      The degree of stenosis was graded into four categories according to Cotton's
      classification. Thirty six cases were grade 2, 44 cases were grade 3, 21 cases
      were grade 4. Subglottic localization of the stenosis was found in 64% of the
      cases and the mobility of the vocal folds was normal in 60% of the cases. The
      surgery was considered successful after one procedure when there was a permanent
      and permeable laryngotracheal lumen (no more than grade 1) not requiring a
      tracheotomy. Of the 47 single-stage procedures, 38 were successful (81%); of the
      54 cases managed with classic methods, 30 were successful (55%). These results
      and the indications of the different surgical procedures are discussed.

PMID- 10399528
TI  - [Severe Frey syndrome after parotidectomy: treatment with botulinum neurotoxin
      type A].
AB  - Based upon an inception cohort of 30 patients with severe Frey's syndrome, after
      conservative parotidectomy, the technique and the results of intracutaneous
      injection of botulinum toxin type A are presented. The skin surface involved with
      Frey's syndrome was managed with intracutaneous injection of 2.5 international
      units of botulinum toxin type A per square centimeter. A minimum follow-up of 16
      months was achieved. The only adverse side effect encountered was a temporary
      paresis of the upper lid noted in 2 patients. Frey's syndrome vanished within 2-5
      days from the intracutaneous injection of botulinum toxin type A. Frey's syndrome
      was controlled in 53.2% of cases (17/30) after the initial injection of botulinum
      toxin type A. Five of the 13 patients with recurrence of Frey's syndrome elicited
      to undergo a watch and wait policy due to the lack of discomfort induced by the
      recurrence. The remaining eight patients with recurrence of Frey's syndrome were
      successfully managed with a secondary intracutaneous injection of botulinum toxin
      type A. Such preliminary data, together with the review of the literature
      suggests, that the intracutaneous injection of botulinum toxin type A should now
      be the first line treatment option in patients with severe Frey syndrome.

PMID- 10399530
TI  - [Squamous cell carcinoma of the ENT organs in the course of the HIV infection].
AB  - The link between the occurrence of a SCC in the head and neck and human
      immunodeficiency virus infection is controversial. METHODS: A survey of
      specialists in France was carried out in 1995 to investigate it's incidence since
      the start of the epidemic. RESULTS: Twenty one patients (sex ratio 20/1) with
      concomitant HIV infection and SCC of the head and neck were evaluated. The age
      distribution ranged from 30 to 63 with a mean of 44 years-old. Twelve patients
      were under 45 years-old. There was no obvious relationship between any peculiar
      risk group for HIV infection and occurrence of a SCC. At the time of diagnosis of
      their carcinoma 10 patients had clinical and/or biological features for AIDS.
      Alcohol and tobacco consumption were present in twelve patients, moderate in four
      and absent in five patients. Oropharyngeal carcinoma was frequent in patients
      without risk factors and immunodepression. CONCLUSION: The high rate of young
      adults and patients with no or moderate risk factors for SCC suggests that SCC
      could be related to HIV infection.

PMID- 10399531
TI  - [Postoperative pain assessment in head and neck cancer surgery: benefit of
      patient controlled analgesia (PCA)].
AB  - Acute postoperative pain has seldom been assessed in head and neck cancer
      surgery. The estimation of actual pain is more difficult when communication is
      impaired by tracheotomy or tracheostomia. The aim of the present prospective
      study was the assessment of analgesia level during the first 48 postoperative
      hours after head and neck cancer surgery. The analgesic procedure involved intra
      venous morphine injected by means of a PCA pump (Patient controlled analgesia).
      Thirty patients were thus treated after cancer surgery of the larynx or the
      oropharynx. The protocol included during 48 hours the assessment of pain, using a
      visual analogic scale (VAS) every fourth hour, while recording the total injected
      dose of morphine, the localisation of pains, as well as the occurrence of side
      effects. The control of postoperative pain was shown to be satisfactory, with a
      VAS grade smaller than 3 at time zero and kept below this value during 48 hours.
      At the end of this period, the mean total dose of morphine injected was 38 mg. No
      case of respiratory depression was even seen. It can be concluded that PCA seems
      to be an efficient procedure for controlling postoperative pain in head and neck
      cancer surgery. This technique proved to be better than delivering analgesia on
      requirement.

PMID- 10399532
TI  - [Chronic sinusitis in patients infected by HIV: therapeutic strategies].
AB  - Chronic sinus pathology is a frequently encountered disease in HIV infected
      patients. The responsible bacterial agents and management are yet to be settled.
      The authors report the results of a retrospective study led in the unit of Head
      and Neck Surgery of the University Hospital of Nice. 25 patients where HIV
      holders and had a sinus pathology which had lasted more than 6 weeks, despite one
      or several antimicrobial drug administrations. Clinical and CT scan data are
      detailed as well as pathology results of the samples harvested during sinus
      surgery (bacteria free 32%, Pseudomonas aeruginosa 32%, Streptococcus pneumoniae
      16%, Staphylococcus aureus 16%, Hemophilus influenzae 16%, anaerobic agents 16%
      and Toxoplasma gondii 4%). All patients underwent surgery (antral puncture with
      maxillary sinus drainage 17, functional endoscopic sinus surgery 8). Results
      where gathered at 4 months with 76% of relapse (100% in patients with less than
      200/mm3 CD4 cells). In conclusion empiric antimicrobial drug therapy will be
      expected to be also effective on Pseudomonas aeruginosa, the surgical management
      being most often deceiving and leading to relapse especially when considering the
      frequency of bilateral morbidity and the level of CD4 cell below 200/mm3.

PMID- 10399533
TI  - [The role of areolar tissue on otologic surgery].
AB  - Areolar tissue is a loose conjunctive tissue, located between the fascia
      temporalis superficialis and the temporal aponeurosis. It can be used in several
      circumstances during otologic surgery. First, in stapes surgery, it can be used
      as an interposition between the piston and the platinotomy. Its thickness has no
      equivalent in comparison with other temporal tissues, explaining in part its
      usefulness in this indication. In perilymphatic fistula surgery, the areolar
      tissue is especially recommended for round window and oval window grafting
      because of its spontaneous adhesive capacity. It can be useful in myringoplasty,
      to reenforce an atrophic tympanic membrane or to close a small perforation. Also
      areolar tissue can be used as a flap or as a free graft to reconstruction of the
      external acoustic meatus. It's a good conjunctive support, which can be covered
      by skin graft. Finally areolar tissue is an interesting and useful material for
      otologic surgery. Its qualities are complementary to those of the temporal
      aponeurosis.

PMID- 10399534
TI  - [Prescription and consumption of antibiotics in the outpatient setting. National
      Control of Prescriptions and Use of Medications in the outpatient and inpatient
      setting. Medication Agency, Directory of Studies and Information].

PMID- 10399535
TI  - The olfactory origin of luteinizing hormone-releasing hormone (LHRH) neurons. A
      new era in reproduction physiology.
AB  - This paper reviews those studies which conceived the concept that the brain LHRH
      synthesizing neurons originate in the nasal placode. LHRH isolated from mammalian
      hypothalamus in 1971 was first shown immunohistochemically two years later in the
      hypothalamic neurons which project processes to the median eminence, to release
      it into the portal capillaries in the guinea pig. At an early stage of
      development, the LHRH cells were found in the nasal placode but not in the
      hypothalamus as shown in in vivo and in vitro developmental studies. The cells
      arising in the brain were delayed. This discrepancy was solved in 1989-1990 by
      findings that the cells derived in the placode at an early stage left the site
      and migrated to the forebrain vesicles along the placode-derived terminal and
      vomeronasal nerve fibers, both of which were found to express immunoreactive cell
      adhesion molecules. The neurons, after reaching the surface of the forebrain
      vesicles, entered into the brain by the guidance of the cell adhesion molecule
      positive fibers, and came to be distributed not only in the hypothalamus but also
      in the telencephalon cortex, midbrain, limbic brain, and main and accessory
      olfactory bulbs. The attention to these heterogeneties led to discussion of the
      possible neurobiological significance of this peculiar peripheral neurogenesis
      from an evolutionary viewpoint.

PMID- 10399536
TI  - Multi-label image analysis of secretory cell juxtaposition in the sheep pituitary
      gland.
AB  - An image analysis system, assigned different pseudocolors to different types of
      immunolabeled cells, allowed us to make a montage from two images of the
      respective types of cells. This system was therefore used for simultaneous
      identification of two or more types of immunolabeled cells in the sheep anterior
      pituitary. Morphometry--including a neighboring proportion defined as the
      probability of a cell type adjoining other cell types--was performed. We also
      conducted a simulation of an artificial cell mass with an image analyzer to
      evaluate the effects of cell populations on the neighboring proportion.
      Simulation analysis showed that the predominant cell type tended to have a higher
      neighboring proportion, while rarer cell types had lower proportions according to
      their small population density. In the sheep pituitary gland, the neighboring
      proportions against PRL-, GH-immunolabeled cells were high (about 65% and 55%,
      respectively), according to their large populations. The neighboring proportion
      of LH beta-immunolabeled cells to the same type of cells was lower (11%) than
      that against other types of cells. It was thus suggested that LH cells were
      scattered throughout the anterior lobe. The neighboring proportion of ACTH
      immunolabeled cells to the same type of cells was somewhat higher, but that of
      ACTH cells to PRL cells was low (52%). Accordingly, this cell type was often
      distributed in clusters. These quantitative results confirmed the topographical
      characteristics of secretory cells deduced from visual observation. In addition,
      a low topographical affinity between PRL and ACTH cells was indicated.

PMID- 10399537
TI  - Effects of ATP and its analogues on [Ca2+]i dynamics in the rabbit corneal
      epithelium.
AB  - Adenosine-5'-triphosphate (ATP) plays a pivotal role in various tissues as an
      extracellular transmitter. ATP released from nerve endings and/or damaged cells
      may elicit reactions in adjacent cells. To identify such reactions, we
      investigated the dynamics of the intracellular calcium ion concentrations
      ([Ca2+]i) in the rabbit corneal epithelium during ATP-stimulation. Intact
      epithelial sheets isolated from corneal tissue were loaded with Fura-2, and
      [Ca2+]i dynamics in each cell layer were analyzed using a digital imaging system
      (Argus 50/CA). Normal architecture was preserved, suggesting that functional
      integrity remained intact. Perfusion with HEPES-buffered Ringer's solution
      containing ATP (10 microM) and uridine-5'-triphosphate (UTP; 10 microM) caused a
      biphasic [Ca2+]i increase in the superficial layer that manifested itself as a
      rapid initial spike followed by a long-lasting plateau phase. Adenosine-5'
      diphate (10 microM) elevated the [Ca2+]i level, but induced only the initial
      spike, which was smaller than those induced by ATP and UTP. Adenosine (10 microM)
      did not elicit any [Ca2+]i changes in the epithelial cells. Suramin (10 microM; a
      P2 receptor antagonist) blocked the ATP-induced [Ca2+]i increase, whereas the P2X
      receptor agonists, alpha, beta-methylene ATP (10 microM), 2-methyl-thio ATP (10
      microM) and Benzoylbenzoyl ATP (10 microM), did not elicit any increases in
      [Ca2+]i. In the basal cell layer, ATP-induced [Ca2+]i dynamics were biphasic,
      while oscillatory fluctuations of [Ca2+]i were induced in the wing cells of the
      mid layer of the corneal epithelium by ATP stimulation. Ca2+ oscillations were
      sometimes synchronized among adjacent wing cells, but these waves did not
      propagate to other cell layers. These results suggest that extracellular ATP
      elicits a [Ca2+]i increase mainly via P2Y receptors. In addition, synchronized
      Ca2+ oscillation in the wing cell layer indicates that intracellular events may
      spread to neighboring cells within the layer.

PMID- 10399538
TI  - Alteration in the expression level of calbindin D28k in the periodontal ligament
      of the rat molar during experimental tooth movement.
AB  - The present immunohistochemical study was designed to investigate changes in the
      distribution and expression level of calbindin D28k in the periodontal ligament
      during experimental tooth movement in the rat molar to clarify the physiological
      role of this protein in the ligament. In normal animals, calbindin D28k-like
      immunoreactivity appeared sparsely in spindle-shaped cells in the alveolar half
      of the periodontal ligament. Electron microscopic observations showed that these
      immunoreactive cells were characterized by well-developed rough-surfaced
      endoplasmic reticulum and phagosomes--which often contained collagen fibers-
      suggesting that these cells could be categorized as periodontal fibroblasts.
      Twelve hours following the onset of the experimental tooth movement, cells
      positive for calbindin D28k increased in number in the periodontal ligament,
      especially in the alveolar half of the pressured side. Immunoelectron microscopy
      showed that the calbindin D28k-immunopositive cells had morphological features
      similar to those of fibroblasts in the normal ligament, and that these cells
      occasionally made contact with immunonegative macrophage-like cells.
      Immunopositive cells gradually decreased in number, and the distribution of the
      cells and intensity of the immunoreactivity returned to normal levels by 14 days
      following the induction of the experimental tooth movement. The present results
      suggest that calbindin D28k plays an important role in the homeostasis and cyto
      protection of fibroblasts in the periodontal ligament at the initial phase of
      experimental tooth movement.

PMID- 10399539
TI  - Composition of the extracellular matrix in human cricoarytenoid joint articular
      cartilage.
AB  - The extracellular matrix of the human cricoarytenoid joint articular cartilage is
      involved in different pathological changes. Interestingly, in contrast to the
      limb joints, the extracellular matrix composition of the healthy cricoarytenoid
      joint articular cartilage has not yet been elucidated except by some light
      microscopical investigations. The present study investigates the extracellular
      matrix components of the cricoarytenoid joint articular cartilage by means of
      light microscopy, immunohistochemistry, transmission electron microscopy and
      scanning electron microscopy and compares them with the limb joints for a better
      understanding of their involvement in joint disease. Chondrocytes near the joint
      surface of the cricoid and arytenoid cartilage differ from chondrocytes of deeper
      cartilage layers. The extracellular matrix of the articular cartilage contains
      chondroitin-4-sulfate, chondroitin-6-sulfate and keratansulfate as well as
      collagen types II, III, VI, IX and XI. Type-III-collagen shows a special
      distribution throughout the joint cartilage. In deeper cartilage layers, type-III
      collagen occurs only pericellularly; in higher cartilage layers type-III-collagen
      is also located territorially and interterritorialy in small amounts. Scanning
      and transmission electron microscopy have revealed the articular surface of the
      cricoid and arytenoid cartilage to consist of a network of irregularly organized
      collagen fibrils, which are lined by a layer of electron dense material. The
      network coats subjacent collagen bundles which descend obliquely downward and
      intermingle at right angles in the middle part of the articular cartilage with
      collagen bundles of the deeper cartilage zones. The articular cartilage surface
      shows structural characteristics which differ from the underlying cartilage. The
      superficial electron dense layer possibly plays a role in the lubrication of the
      articular cartilage surface. The alignment of the fibrillar structures in the
      articular cartilage of the cricoarytenoid joint varies from those of the limb
      joints based on the different strain occurring during arytenoid movement.
      Nevertheless, the human cricoarytenoid joint articular cartilage can be compared
      with the joints of the limbs despite its extracellular matrix composition and its
      involvement in joint pathology. Evidence of type III collagen in the outermost
      layer of the articular cartilage of the cricoarytenoid joint presents a
      peculiarity, which has yet not be demonstrated in the articular cartilage of limb
      joints.

PMID- 10399540
TI  - Changes in c-Fos expression induced by noxious stimulation in the trigeminal
      spinal nucleus caudalis and C1 spinal neurons of rats after hyperbaric exposure.
AB  - The present study aims to test the hypothesis that hyperbaric exposure inhibits
      nociceptive processing in the trigeminal spinal nucleus caudalis and C1 spinal
      neurons. We investigated the c-Fos-like immunoreactivity of the brainstem and
      upper cervical spinal cord (C1 region) following an injection of mustard oil (15
      microliters of 20%) into the nasal mucosa of pentobarbital anesthetized rats
      after exposure to hyperbaric (2-atmospheres, 1 h) and normobaric pressures. After
      the hyperbaric exposure, the mean number of Fos-immunoreactive neurons in the
      ipsilateral laminae I-II and III-IV of the trigeminal spinal nucleus caudalis
      were significantly lower than those in the normobaric condition. Similarly, the
      mean number of c-Fos positive neurons in the superficial layer (I-II) of the
      ipsilateral C1 segment were significantly reduced as compared with that in the
      normobaric condition. When treated with the vehicle alone, no significant
      difference was detected in the numbers of c-Fos positive neurons in the
      trigeminal spinal nucleus caudalis and C1 regions between hyperbaric and
      normobaric conditions. These results suggest that hyperbaric exposure may
      attenuate nociceptive signals from the area innervated by the trigeminal nerves
      at the level of both the trigeminal spinal nucleus caudalis and C1 dorsal horn.

PMID- 10399541
TI  - Intermittent inhibition of dentin mineralization of rat incisors under continual
      infusion of 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) using a subcutaneous
      mini osmotic pump.
AB  - The inhibitory effect of the continual administration of 1-hydroxyethylidene-1, 1
      bisphosphonate (HEBP) (8 mgP/kg/day) through a mini osmotic pump on dentin
      mineralization was examined in relation to the diurnal rhythm of the rat and
      compared with that of daily injections of same amounts of HEBP known to inhibit
      dentin mineralization. After daily injections of HEBP, a series of alternating
      rows of mineralized and non-mineralized dentin islands appeared in the newly
      formed portion of the crown-analogue of rat incisors. A similar phenomenon
      occurred under the continual administration of HEBP in rats raised either under
      regular environmental photofraction or constant lighting conditions. The average
      distance between the adjacent mineralized dentin islands was 521.0 +/- 51.3
      microns in the injected rats. After continual HEBP administration, this was 426.0
      +/- 13.2 microns and 416.5 +/- 19.4 microns under ordinary photofraction and
      constant light, respectively. Although the pattern of individual mineralized
      dentin islands tended to become irregular in nocturnal rats, no statistical
      difference was noted between the two values. Rows of mineralized and non
      mineralized dentin islands also appeared in the root analogue dentin. No sign of
      the intermittent inhibition of mineralization was recognized in mesodermal hard
      tissues other than dentin in the HEBP-affected animals. These data implicate the
      presence of intrinsic cycles in dentin mineralization at the growing end of rat
      incisors independent of environmental photofraction as well as the ameloblast
      function.

PMID- 10399542
TI  - Scanning electron microscopic observation of apical sites of open-type
      paraneurons in the stomach, intestine and urethra.
AB  - The apical region of open-type paraneurons in tubular organs functions as a
      receptor site for chemical information in the lumen. Electron microscopic studies
      have demonstrated a tuft of microvilli on the luminal surface of cells, but
      failed to visualize it three-dimensionally. The present scanning electron
      microscope (SEM) observation succeeded in viewing, from the luminal side, open
      type paraneurons distributed in epithelia of the stomach, intestine, and urethra.
      The pyloric antrum of avian species and the duodenum of human fetuses, the latter
      forming an endocrine cell colony at every villus tip, were chosen for SEM
      observation in order to eliminate visual obstruction by adjacent epithelial cells
      with developed microvilli. The luminal surface of gut endocrine cells was
      consistently covered with a tuft of 80-200 microvilli. Pyloric paraneurons
      possessed thick and stiff microvilli as compared with those of exocrine cells.
      The microvilli on intestinal paraneurons were more irregular in length and more
      loosely grouped than those composing the striated border of enterocytes. Urethral
      paraneurons containing serotonin were surrounded by three or four polygonal
      epithelial cells. Their narrow apical surface was provided with 30-100 microvilli
      which varied in length from cell to cell, and which were conspicuously projected
      above the luminal surface of the urethra. The microvillous crown of the gut and
      urethral paraneurons was so prominent and constant a structure on the apical
      surface as to allow easy identification of open-type paraneurons under the SEM.

PMID- 10399543
TI  - An immunocytochemical study of amelogenin proteins in the developing tooth enamel
      of the gar-pike, Lepisosteus oculatus (Holostei, Actinopterygii).
AB  - Previous studies have demonstrated the morphological similarity of the enamel
      like layer found in the teeth of the coelacanth, lungfish and gar-pike to the
      enamel of tetrapods. In order to clarify the phylogenetic continuity between both
      structures, tooth germs of the gar-pike were immunocytochemically studied using
      an anti-bovine amelogenin polyclonal antibody. Intense immunoreaction was shown
      over the enamel-like matrix layer. Certain cell organelles associated with the
      secretory pathway of the ameloblasts were recognized as immunoreactive. These
      results indicate that the enamel-like layer of the gar-pike is a tissue
      homologous with the mammalian enamel because both possess a common, amelogenin
      like substance.

PMID- 10399544
TI  - Perineuronal nets of proteoglycans in the adult mouse brain are digested by
      collagenase.
AB  - As our previous study has indicated, perineuronal proteoglycans in the adult
      mouse brain are associated with some collagenous molecules which can be stained
      with Gomori's ammoniacal silver and are resistant to hyaluronidase digestion. The
      present study demonstrated that these molecules are thoroughly digested with
      collagenase, and suggests that they represent a hyaluronic acid-binding domain of
      the ligand proteoglycans connecting the perineuronal proteoglycans and nerve cell
      surface glycoproteins.

PMID- 10399545
TI  - [Errors in targeted movements of the hand under the conditions of orbital space
      flight].
AB  - Three crew members of the Russian-French MIR mission were tested to determine
      errors in pointing to memorized visual targets. In the laboratory, all test
      subjects consistently used to point to the spot below the actual target
      presentation. The mean Y-error (the vertical error) made up -31.6 +/- 21.8 mm. In
      microgravity, the Y-error moved "upward" so that the mean Y-error was -16.8 +/-
      37.0 mm. The data demonstrate adaptation of the central program of aiming arm
      movement to the microgravity conditions.

PMID- 10399546
TI  - [The influence of hypokinesia on the mother-fetus system].
AB  - In experiments with rats effects of hypokinesia on the course of pregnancy and
      the mother-fetus system were investigated. Immobilization in penal-type cages of
      female rats on days 8 through to 19 of pregnancy gave rise to significant shifts
      in mother's organism, i.e. retarded body mass gain, mass reductions in thymus,
      spleen, liver, some other organs, and adipose tissue. Rates of prenatal fatality
      in the experimental group were not changed; yet, fetuses were behind the control
      by the values of body mass, ossification ranges, development of analyzers and
      other parameters. Quantities of liquid, sodium, magnesium and calcium per one
      gram of dry tissue were equal in the experimental and control fetuses. Comparison
      of the data with results of the embryological experiment with rats aboard the
      space "shuttle" suggests that immobilization is more baneful for the mother-fetus
      system than microgravity of the same length.

PMID- 10399547
TI  - [Specific aspects of the nervous system and brain blood supply in women during
      prolonged anti-orthostatic hypokinesia].
AB  - The nervous system and cerebral hemodynamics studies of eight essentially healthy
      female test-subjects during the 120-d head-down bed rest included analysis of
      life history and monthly clinical/neurophysiological examinations (neurological
      testing, REG, Doppler ultrasound investigation of main arteries of the head).
      Altered positioning of the head and prolonged bed rest were shown to incur the
      risk of insufficient cerebral circulation. Most often hemodynamic deviations were
      observed in the vertebrobasilar basin consequent to the experimental conditions
      and specifics of the anatomical site of the vertebral arteries in the bony
      vertebral canal; clinically they were manifested by involvement of truncal
      structures of the brain. The second month of bed rest should be considered
      critical because of the evidence of the unstable neurological microsymptomatology
      implying hemodynamic shifts in the main cerebral arteries by the time. Physical
      exercises during bed rest slacken the pace of cerebral hemodynamics deviations.

PMID- 10399548
TI  - [The use of microfluorimetric analysis for the studies of the influence of
      changed gravity on isolated lymphocytes in the spleen of the mouse].
AB  - Effects of simulated changed gravity on isolated splenetic lymphocytes of mouse
      were evaluated with the microfluorimetic technique enabling observation of probe
      fluorescence in individual cells. It was stated that 5 and 60 min of
      clinostatting stimulated fluorochrome accumulation in cells whereas
      centrifugation, particularly for 60-minutes, decreased the ability of cells to
      accumulate fluorescein. Also, alteration of the gravity force had the opposite
      effect on the ability of cells to retain fluorescein. The most significant drain
      of the dye immediately after short hypogravity may be indicative of the
      functional lability of cells during clinostatting. However, as judged by slight
      changes in intracellular pH, metabolic and regulatory functions were not
      affected. Hypergravity for 15 min decreased intracellular pH. The increased
      period of centrifugation stabilized the parameter. Absence of changes in the
      proliferative activity in all the test exposures also backs up the conclusion
      that short-term changes in gravity do not produce any substantial shifts in the
      morphofunctional state of cells in vitro.

PMID- 10399550
TI  - [Sensitivity of the respiratory center to carbon dioxide during prolonged
      exposure of humans to gas environment with unchanging level of hypercapnia].
AB  - Effects of moderate CO2 concentrations (2.2-3.2%) on external respiration were
      studied in a series of extended (30-d) continuous tests with volunteered human
      subjects. In one test, PCO2 in the gas mixture was maintained at 15-19 mm Hg (2.0
      2.5%), in the other, at 20-23 mm Hg (2.7-3.0%). Partial pressure of oxygen was
      controlled at 144-152 mm Hg (19-20%) with the barometric pressure, temperature
      and humidity at the norm. As compared with the onset, at the end of the first
      test parameters of the external respiration were changed neither at rest nor
      during exercises. At the end of the second test, the minute pulmonary ventilation
      showed a steady rise in synch with the duration of exposure growing in 2.5 times
      at rest and in 1.7-2 times during physical exercises suggesting an increase in
      the respiratory center sensitivity to the CO2 level under study. Hence, breathing
      CO2 at 2.7-3.0% for many days did not sensitize the respiratory center of the
      human subjects.

PMID- 10399549
TI  - [The neurons of the medial vestibular nucleus initiating the relaxation of the
      rat's stomach wall].
AB  - In acute rat experiments the technique of retrograde axonal transport of
      horseradish peroxidase in the medial vestibular nucleus allowed to identify a
      group of neurones sending axons to the "stomach" region of a single tract
      nucleus. These neurones and, accordingly, the descending vestibular/solitary
      links can be viewed as the morphologic basis for vestibular influences on the
      gastric motor activity. As was shown, local irritation of the neurones initiates
      relaxation of the stomach wall. Activation of the anterior limbic cortex
      modulates the vestibular/autonomous responses of the intragastric pressure
      reduction. Irritation of the infralimbic cortex of the rat's brain may have a
      preventive effect on the stomach wall relaxation stimulated by the vestibular
      neurones projecting on the "stomach" region of single tract nucleus.

PMID- 10399551
TI  - [The mechanism of breathing under the conditions of prolonged voluntary
      hyperventilation].
AB  - Effects of voluntary hyperventilation (2 h, 70-80% of maximal lung ventilation)
      on external breathing, gas exchange and blood circulation were studied in 12
      healthy male volunteers. Hyperventilation was shown to change structure of the
      respiratory cycle as variation and expiration time were decreased. Indices of the
      external breathing did not reduce but, on the contrary, there was a significant
      increase in the alveolar ventilation and a reduction in the dead space
      ventilation. Considerable losses of carbon dioxide with the expired air were
      noted only during initial 10-15 min of intensive breathing. The angular
      coefficient for the most steep section of the CO2 loss curve ranged from 150 to
      200 ml/min as a result of which the total CO2 deficit in this period (i.e. the
      CO2 release exceeds the O2 consumption) was about 2 l. Hereafter, the CO2 deficit
      did not virtually increase despite intensive functioning of the external
      breathing system. This became apparent from the regain of the respiratory
      coefficient, a significant and gradually growing CO2 ventilation coefficient.
      Values of PETO2 and PETCO2 remained stable throughout the experiment with quite
      substantial hypocapnia: up to 15-20 mm Hg. Thus, the cardiorespiratory system has
      a powerful defence mechanism to prevent exacerbation of hypocapnia despite
      intensive ventilation of the alveolar space. This mechanism comes into action at
      the very first minutes of hyperventilation, reaches maximal efficiency within 10
      15 min and maintains this level during the whole period of investigation (about 2
      h).

PMID- 10399552
TI  - [The individual and integral effects of brief simulated descents and anesthetic
      pharmacological preparations on human metabolism].
AB  - In short-term chamber (GVK-250) "descents" by three healthy male volunteers
      mechanisms of hyperbaric narcosis against high partial pressures of indifferent
      nitrogen and argon were compared with anesthetic ketamine and sibason. Clinical
      biochemistry was engaged to determine any possible changes in metabolism due to
      the "descents" up to 0.4-0.6 MPa. Cubital vein blood was sampled prior to and
      following decompression. Plasma spectrophotometry was performed using biochemical
      analyzer EPAC-6140 (Eppendorf, Germany) and standard sets of reagents by Raichem
      (USA) and Biocon (Germany). On the whole, shifts in albumin, total protein, uric
      acid, lactate, and the creatine kinase activity were found to be within the
      physiological norm. However, several cases of excursion outside the boundaries of
      the clinical norm (A/T, AT, lactate dehydrogenase, triglycerides, lipase) could
      be associated with changes in the functional state of the liver caused by
      administration of the anesthetics during the hyperbaric exposure.

PMID- 10399554
TI  - [The influence of space flight factors on the growth and development of super
      dwarf wheat cultivated in greenhouse Svet].
AB  - In 1996-1997 an experiment with super dwarf wheat (Greenhouse-2) was made aboard
      the orbital complex MIR as a part of the MIR-NASA space science program. The
      article deals with the main production and morphometric characteristics of plants
      that completed their vegetation cycle in the space flight. Lengths of the whole
      cycle of vegetation and its individual stages were essentially same as in ground
      control experiments. Dry mass of one plants equal, the number of headed shoots
      was in 2.7 times less in the flight harvest as compared with the control. The
      height of shoots was reduced by one half. No seeds were found in the heads formed
      in space. The architecture of heads was substantially different from what had
      been observed in the preceeding ground control experiments: mass of the heads was
      halved and lengths of inflorescence and palea awn shortened. The number of
      spikelets in a head reduced up to 8-10 vs. 13-14 in the controls, whereas the
      number of florets per a spikelet averaged 5 vs. 3 in the controls. The
      experiments showed that mainly the most profound changes in the productive and
      morphometric parameters of the super dwarf wheat plants were largely caused by
      the phytotoxic effects of ethylene rather than spaceflight specific factors as
      its concentrations in the MIR air amount to 0.3-1.8 mg/m3.

PMID- 10399553
TI  - [Cyto-embryologic investigation of super dwarf wheat grown on board of the Mir
      orbital complex].
AB  - The cytoembryologic analysis of wet and dry samples of super dwarf wheat
      cultivated in greenhouse SVET aboard the MIR station over the whole cycle of
      vegetation was made with the use of light microscopy. Characteristic features of
      wheat development in space flight are plentiful early tillering, and formation
      and rapid growth of side shoots. Elementary spikelets in the composite head were
      more numerous but the top spikelets were rudimentary and, therefore, the ripe
      head contained less of these spikelets as compared with the ground controls (9-13
      and 14, respectively). The number of florets in a spike was also higher reaching
      14-16 vs. 7-8 in the control. Typically, no more than 4 to 5 florets vs. 3 in the
      control were fully differentiated while the others died off earlier in
      development. The fact that there were no caryopses found in the flight crop is
      explained by absolute male sterility appearing at different stages of staminal
      development: before archesporium formation, on the stage of differentiated
      archesporium, during meiosis, on the stage of microspores or uninucleate
      "pollen". The female generative system developed mainly without abnormalities. An
      assumption was made that elevated ethylene concentrations in the MIR atmosphere
      at the time of the wheat experiment were the cause for abnormal development of
      the male generative system which led to barrenness of the super dwarf wheat crop.

PMID- 10399555
TI  - [Chromosome aberrations as a bio-dosimetric test of space radiation (experimental
      data from the seeds of higher plants)].
AB  - The authors analyzed the data about seeds of higher plants obtained in space
      experiments from several days to a year and a half in duration, and ground-based
      simulation studies on beams of accelerated heavy ions by the universal biological
      criterion of the chromosome aberrations. The criterion was also used to compare
      these data with those about lymphocytes in human peripheric blood in vitro. The
      number of aberrant cells, including cells with multiple aberrations, grew with
      mission duration, absorbed dose, and fluence of heavy charged particles as well
      as the topography of particles traverse of cells. Methodical dimensions of the
      test-object as a detector to evaluate the biological effects of and risk from
      space radiation in long-term space missions are considered.

PMID- 10399556
TI  - [The influence of the water potential in the root-habitable area on the
      efficiency of the higher-order plants].
AB  - In a set of 8 experiments, in leaf mustard Brassica junceae L. (cult. Volnushka)
      and in soft wheat Triticum aestivum L. (cult. Super Dwarf) there has been studied
      dynamics of accumulating biomass in the ontogenesis in accordance with the value
      of water potential in the root-habitable medium. Besides, in wheat there has been
      investigated the process of forming the grain crop capacity in a period between V
      and XII stages of the organogenesis from Kuperman's classification. The plants
      have been grown in the root modules with the perlite used as a substitute for
      soil and with water supply through the porous hydrophilic membranes. The levels
      of water potential in the root-habitable medium, namely in the perlite, were kept
      unchanged in the range from -0.5 to -13 kPa (or from -5 to -130 cm water column)
      which corresponded to volumetric humidity ranged from 63 to 25%. Tests exposition
      was in the range of 13 to 78 and 25 to 46 days for wheat and mustard,
      respectively. The value of upper limit of an allowable water potential was
      determined from the magnitude of critical pressure of the puncture at which the
      most large through pores in the perlite layer break free of water, the value of
      lower limit was determined after criterion of a significant decrease in the
      plants harvest. In accordance with the paper results an allowable range of water
      potential in a perlite-based root-habitable medium ranged from -1.0 to -2.0 kPa
      which was in agreement with the range of volume humidity from 61% to 51%. In
      decreasing the water potential beyond the lower limit of mentioned range to -3.0
      kPa, the mass of mustard shoots has reduced by 30% and the wheat crop was not
      good. The elaborated procedure and equipment can be used for determining the
      thresholds of permissible water potentials (humidity) for any soil substitutes
      irrespective of the construction of root module and the species of cultivated
      plants.

PMID- 10399557
TI  - [Arterial hypertension as a problem of medical certification of the flying
      personnel in civil aviation].
AB  - Subjects of the longitudinal study (1974-1996) were about 300 pilots who
      participated in international transmeridian flights. Arterial hypertension (AH)
      diagnosed in 29 pilots was the main cause for their disqualification. They made
      up 16.8% of the total number of medically disqualified persons. The flight
      surgeon of the corps consulted 26 pilots with elevated arterial pressure (AP) or
      8.8% of the corps roll. Clinical examination revealed the "white coat"
      hypertension in five pilots (1.7% of the corps roll). Percentage of pilots
      disbarred in the course of preflight physical check for the reason of high AP
      amounted to 32.7; hence, elevated AP was the most frequent cause for disbarring.
      The circannual distribution of elevated AP measured during the preflight medical
      check correlates with the challenges of either making the transmeridian flights
      in cold seasons due to the contrast of the climatogeographical zones or more
      tense flight schedule in summer. The greatest concern arise pilots whose AP was
      found normal during the preflight check but who were later on disqualified with
      the diagnosis of the 2nd degree hypertension as representatives of this cohort
      were documented to suffer myocardial infarction and acute disturbance of the
      cerebral circulation in the rest periods.

PMID- 10399558
TI  - [The methodology of establishing the radiation hazard to cosmonauts on long-term
      mission based on the generalized dosimetric functional].
AB  - The paper describes an original methodology for evaluation of the radiation
      hazard to cosmonauts on mission based on generalized dose from ionizing
      radiations. This is a new dosimetric functional that allows convert the complex
      radiation of space to standard radiation. The conversion is achieved by
      calculation of mean tissue equivalent doses from each source of radiation hazard
      in space flight and scaling factors which take into account the radiobiological
      effect of intricate macrospatial and temporal dose distributions along the human
      body. Besides, consideration is given for the impact of non-radiation factors
      inherent to space flight. The generalized dose which is the dose from standard
      radiation inducing radiation damage similar to the multicomponent space radiation
      can be used to ascertain the character and degree of performance degradation, and
      radiation risk for cosmonauts both in and long after mission.

PMID- 10399559
TI  - [Diagnosis of healthy and depressed patients based on their speech patterns].
AB  - Analysis of the speech signal allowed to propose methods for quantitative
      diagnosis of patients with psychogenic depression with overwhelming melancholy
      and anxiety, and the functional state of essentially healthy professional
      operators. The methods are based on evaluation of intonation, motor and
      ideational speech parameters. They were successfully demonstrated in a
      psychiatric clinic and during fulfillment of jobs by operators.

PMID- 10399560
TI  - [The study of vertical vestibulo-ocular reflexes].
AB  - Methodical approaches for studying the vertical vestibuloocular reflexes (VVOR)
      have been proposed. Eye movements were recorded by the electronystagmography:
      vertical movements of each ball of the eye was separately recorded and horizontal
      movements--in combination. Stimulation of the semicircular canals was performed
      by active movements of the head in the saggital plane with a frequency of 0.04 Hz
      (stimulus 1), 0.12 Hz (stimulus 2) and 0.24 Hz (stimulus 3). The VVORs have been
      recorded with the eyes closed (Program I) and with fixing the visual object on
      the eyes (Program II). Then, there has been recorded a vertical component of the
      horizontal vestibulovertical reflexes which evoked by active turn of the head
      around vertical axis of the body with the eyes closed (Program III) and fixation
      with the eyes of visual object (Program IV). The elaborated methods enable one to
      record steadily the VVOR in the all categories of test-subjects. As the VVOR
      indices there accepted the coefficient of reactivity, phase displacement;
      coefficients of asymmetry allowing one to compare the intensity of eye movements
      directed upwards and downwards; to reveal intraocular asymmetry.

PMID- 10399561
TI  - [Specific aspects of binding of lipids and their metabolites with albumin during
      physical testing].

PMID- 10399562
TI  - [Dynamic theory of hematopoiesis].

PMID- 10399563
TI  - [Effect of the tonic activity and physiologic tremor on evoked auxotonic human
      muscle contractions].

PMID- 10399564
TI  - [Effect of Polyosm preparation on the viscoelastic properties of the craniospinal
      system in the model of acute hypertensive encephalopathy].

PMID- 10399565
TI  - [Effect of acidic fibroblast growth factor on experimental parkinsonism and
      levels of dopamine and its metabolites in the striatum of mice of various ages].

PMID- 10399566
TI  - [Myocardial hypertrophy in rabbits with vasorenal arterial hypertension during
      pharmacological blockade of formation of angiotensin II and its interaction with
      specific receptors].

PMID- 10399568
TI  - [Intercentral interactions during typical and atypical neuroleptics
      administration].

PMID- 10399567
TI  - [Effect of NO-synthetase inhibitor L-NAME on occlusive and reperfusion
      arrhythmias in cats].

PMID- 10399569
TI  - [Biological effects of the microwave radiation].

PMID- 10399570
TI  - [Dynamics of changes in the rat skin lipids during stress: effects of exogenous
      melatonin].

PMID- 10399571
TI  - [Antioxidant effects of lactoferrin from woman's milk].

PMID- 10399572
TI  - [Effects of thyroliberin on nonapeptidergic cells in the rat hypothalamus
      slides].

PMID- 10399573
TI  - [Various parameters of the proteinase-inhibitors system during adaptive responses
      of the body after intensive physical loading].

PMID- 10399575
TI  - [Effect of chorionic gonadotropin on the radiation exposed animals].

PMID- 10399574
TI  - [Effects of the water and ethanol extracts from the root bark of the peony
      Paeonia lutea on the hemostatic blood parameters].

PMID- 10399576
TI  - [Mechanisms of tacrine modulation of the GABA-activated currents in the isolated
      cerebellar neurons].

PMID- 10399577
TI  - [Stimulation of the nonspecific resistance by beta-heptylglycoside
      muramyldipeptide in mice].

PMID- 10399578
TI  - [Ability of staphylococcus to inactivate carnosine].

PMID- 10399579
TI  - [Effects of the potentiated forms of antibodies to the brain-specific S-100
      protein on the integrative brain activity].

PMID- 10399580
TI  - [Age-related changes in the stromal clonogenic cell number in the hematopoietic
      and lymphoid organs].

PMID- 10399581
TI  - [Production and characteristics of monospecific antibodies to beta2
      microglobulin].

PMID- 10399582
TI  - [Effects of interleukin-1beta and indomethacin on interleukin-1beta gene
      expression in the brain hemispheres].

PMID- 10399584
TI  - [Adrenergic gum innervation during experimental periodontitis].

PMID- 10399583
TI  - [Identification of DNA of cytomegalovirus, its antibodies and viral antigens in
      patients after organ transplantation].

PMID- 10399585
TI  - [Catabolic effect of the anabolic steroid in the skeletal muscle when the
      neurotrophic control is disturbed].

PMID- 10399586
TI  - [The role of prolactin in the functional regulation of liver cells after the
      common bile duct ligation].

PMID- 10399587
TI  - [Morphologic characteristics of the juxtaglomerular apparatus of the kidney in
      rats with hereditary stress induced arterial hypertension (HSIAH)].

PMID- 10399588
TI  - [Nuclear prolactin receptor manifestation in the rat hepatocytes and effect of
      prolactin].

PMID- 10399589
TI  - [Alteration and intracellular regeneration of hepatocytes during RNA-genomic
      hepatitis C virus exposure].

PMID- 10399590
TI  - [Ultrastructural reorganization of the adrenal cortex during hypoxia and its
      correction by nerobolil in rats].

PMID- 10399591
TI  - [A modified thermodilution method of the cardiac output determination in small
      laboratory animals].

PMID- 10399592
TI  - [One-stage solid phase immunoenzyme sandwich technique for the determination of
      myoglobin in serum using three types of monoclonal antibodies to various
      epitopes].

PMID- 10399593
TI  - [Chikungunya virus outbreak in Senegal in 1996 and 1997].
AB  - Chikungunya disease is generally recognized in Africa by serosurveys conducted in
      rural areas. Epidemics are rarely documented. We report two outbreaks in Senegal:
      one having occurred near Kaffrine in 1996 during an epidemic of yellow fever
      (YF), the second in Niakhar in 1997. Both diagnoses were conducted by IgM
      antibodies captures and confirmed by virus isolations. In Kaffrine, a randomised
      study was carried out on 447 blood donors whose serum was systematically tested
      for the most frequently encountered arboviruses in Senegal. The incidence rate
      was higher for the unrecognized Chikungunya infection (35.3%) than for the
      notified YF infection (21%). In Niakhar, Chikungunya infection was initially
      detected through three cases having occurred in health workers. A serosurvey was
      then conducted to define the area of prevalence. We report the clinical forms of
      Chikungunya virus infections, the interest in detecting IgM for recent arbovirus
      infections and the duration of these IgM. The difficulties of diagnosis of
      Chikungunya infection in malaria endemic areas are stressed. The occurrence of
      arbovirus infections, Yellow fever and Chikungunya viruses, transmitted by the
      same vectors (Aedes aegypti) in Kaffrine are also discussed.

PMID- 10399594
TI  - [Prevalence of serum markers of hepatitis B and C virus in blood donors of
      Nouakchott, Mauritania].
AB  - This preliminary survey was intended to collect transversal data to ensure a
      better understanding of the hepatitis B and C epidemiology in Mauritania. The
      authors have studied the seroprevalence rate of HBs antigen and HCV antibodies
      among 349 blood donors. Data of this study showed that anti-HCV antibody was
      detected in 1.1% and HBs antigen in 20.3% blood donors.

PMID- 10399595
TI  - [Variations under genetic control of onchocerca infection as a function of
      clinical profile in the endemic center of Cameroon].
AB  - Onchocerciasis, also known as "river blindness", presents a plenum of clinical
      manifestations which vary from one individual to another, and from one area to
      another. This large spectrum of clinical manifestations of the disease is an
      indication of the complexity of the pathogenesis of onchocerciasis and suggests
      that many interacting factors might influence the clinical features of the
      disease. The present study has focused on the heterogenicity of the host immune
      response as a plausible explanation for differences in clinical manifestations of
      the infection. Host genetic factors, namely HLA genes, might play an important
      role in determining the nature of the immune response mounted against the
      parasite Onchocerca volvulus, and thus the development of different
      manifestations of the infection. Genetic diversity of onchocerciasis was assessed
      in different endemic foci in Cameroon. In order to investigate the possibility
      that the Major Histocompatibility Complex (MHC) genes might be associated with
      the different clinical types of onchocerciasis, 146 subjects living in three
      endemic areas of Cameroon were studied. They were classified in four groups: A
      (asymptomatic subjects), P (putatively immune subjects) L (patients with
      localised disease) and G (patients with generalised disease). The four groups
      differed in the distribution of HLA class II alleles as determined by Direct
      Heteroduplex Analysis. On the one hand, allele HLA-DQA1*0501 appeared to be
      associated with protection against severe onchocerciasis; on the other, allele
      HLA-DQB1*0201 might play an important role in the severe form of the disease.

PMID- 10399597
TI  - [Intrathecal synthesis of anti-Toxoplasma gondii antibodies during cerebral
      toxoplasmosis associated with African AIDS].
AB  - Thirty-four HIV-1-infected in-patients of the Hopital Central des Forces Armees
      Congolaises, Brazzaville, Congo, hospitalized for suspected cerebral
      toxoplasmosis, have been evaluated for integrity of the blood-brain barrier,
      intrathecal synthesis of total IgG, toxoplasmic serology in blood and
      cerebrospinal fluid, and for intrathecal synthesis of IgG to Toxoplasma gondii.
      An empiric scale to gauge the possibility of clinical cerebral toxoplasmosis was
      used to classify the patients (+, +2, +3). Only an intrathecal synthesis of IgG
      to Toxoplasma gondii was found to be associated with suspected cerebral
      toxoplamosis: it was found in about 80% of patients, and more frequently in
      patients with a higher probability of disease. In contrast, alteration of the
      blood-brain barrier, intrathecal synthesis of total IgG and toxoplasmic serology
      in blood as well as in cerebrospinal fluid were not associated with suspected
      cerebral toxoplamosis. Taken together, these findings confirm that intrathecal
      synthesis of antitoxoplasmic antibodies of IgG isotype occurs in cerebral
      toxoplasmosis. Demonstration of intrathecal synthesis of antitoxoplasmic IgG
      antibodies could be used to confirm clinical diagnosis of cerebral toxoplamosis,
      especially in an African context, where sophisticated laboratory facilities are
      often lacking.

PMID- 10399596
TI  - [In vitro sensitivity of Plasmodium falciparum isolates from Gabon to chloroquine
      and cycloguanil].
AB  - The in vitro susceptibility of 91 Plasmodium falciparum isolates obtained from
      malaria-infected children living near Libreville (Gabon) was evaluated against
      chloroquine and cycloguanil (biologically active metabolite of proguanil), using
      an isotopic micro-drug susceptibility test. In vitro resistance to chloroquine
      and cycloguanil was observed in 83% (35/42) and in 38% (30/78) of the patients,
      respectively. Our data showed that 41% (16/39) of Gabonese field isolates were
      resistant both to chloroquine and cycloguanil. These findings are of great
      importance because they might indicate imminent chloroquine-proguanil failure,
      and there are not many affordable antimalarial drugs to replace chloroquine
      proguanil combination.

PMID- 10399598
TI  - [Intestinal schistosomiasis from Schistosoma mansoni in Madagascar: extent and
      center of the endemic].
AB  - Schistosoma mansoni and S. haematobium affect respectively 2 million and 500,000
      persons in Madagascar. Over the past decade, S. mansoni has spread in the central
      Highlands of Madagascar, essentially throughout the mid-west and Antananarivo
      plain. To understand this recent change in the epidemiology of S. mansoni, we
      examined the relationship between its spatial distribution and several host
      factors, including labour migration, urbanization and water development projects.
      In the Highlands, the disease in distribution could be superimposed on the
      potential expansion areas of snail distribution defined in 1958. However, the
      distribution is not homogeneous, as for example the road between Betafo and
      Mandoto (South West of Antananarivo). This focal pattern described in other
      African countries is unique to the central Highlands of Madagascar. Rice
      cultivation is the main economic activity and is associated with intense water
      contact. The focal distribution may be related to an environmental adaptation of
      host-parasite interaction depending on behavioural patterns, water and soil
      chemistry and incompatibility between Biomphalaria pfeifferi and S. mansoni. It
      is also possible that these focal patterns precede homogeneous endemicity, as
      along the road Itasy-Tsiroanomandidy (west Antananarivo). Major water development
      carried out in this migration area led to a rapid endemization of the disease. In
      Befato-Mandoto, where soil management is more restricted, schistosomiasis due to
      S. mansoni seems to have been established in some foci where epidemiologic
      conditions are favourable (for example, traditional irrigation canals). In
      contrast, the spread of S. mansoni in the Antananarivo plain closely follows the
      settlement of an infected rural population. Epidemiologic surveys conducted on
      school children in the Antananarivo suburbs, where sanitary conditions are poor,
      showed a prevalence of 25%. Human migration linked to development projects and
      urbanization seems to be the principal factor associated with the spread of
      schistosomiasis in the mid-west area and Antananarivo plain. In the Highlands,
      the preferential exposure of adult labour migrants has contributed to the
      widening of the endemic area.

PMID- 10399599
TI  - [Subconjunctival localization of a Wuchereria bancrofti adult female].
AB  - The authors describe a case of conjunctival localization of a living adult
      Wuchereria bancrofti female observed in a 6 year old native Haitian girl, two
      years after her arrival in France. The adult was surgically removed from the
      conjunctiva. Microfilariae were evidenced in blood samples obtained at midnight.
      This is the first case of sub-conjunctival localization of W. bancrofti. This
      case stresses the necessity to identify the filaria by studying the microfilariae
      in blood samples obtained at different times of the nycthemere and/or by
      observing the adult after surgical extraction. The presence of a Loa, a
      Dirofilaria, a Mansonella, or a Wuchereria calls for different medical therapies.

PMID- 10399601
TI  - [Diagnosis and monitoring of hemorrhage due to viper envenomation in the African
      savanna].
AB  - A study on blood incoagulability due to snake bites was carried out in the
      Soudanian savanna of North Cameroon, in a provincial hospital receiving patients
      with severe envenoming coming from areas within 250 km of the hospital. Clinical
      and biological examinations were conducted on 57 voluntary patients to determine
      the aetiology of blood incoagulability. The aetiology of this syndrome is complex
      and seems to depend on the variability of venom components and/or the time
      between bite and hospital admission inducing a diversity of biological signs.
      Furthermore, the presence of bleeding and the 30 minute whole blood clotting test
      performed in dry tube were tested in view to propose simple diagnosis and
      monitoring indicators. It appeared that the combination of the two indicators
      allowed an early diagnosis of blood incoagulability and a valid monitoring test
      particularly well adapted to peripheral African health centres. The recommended
      treatment is intravenous immunotherapy using F(ab')2, renewed in case of
      persistence of bleedings or a whole blood clotting test higher than 30 minutes.
      However, the interval between immunotherapy administration renewals remains to be
      defined.

PMID- 10399600
TI  - [Lipoprotein profile of patients infected with HIV in Cote d'Ivoire].
AB  - Aids is a cachexysing disease which is striking Africa. Cote d'Ivoire with its
      12% seroprevalence is paying a heavy tribute to this pandemia. The course of the
      disease is characterized by the occurrence of immunological and biochemical
      disorders. The aim of this study is to offer African practitioners, clinicians
      and biologists some biochimical parameters that would help them to follow up
      people infected with HIV. The authors determined the lipoprotein profile in 204
      people (112 Aids patients, 61 HIV infected asymptomatics and 31 controls
      seronegative to HIV), of both sexes aged 17 to 70 years old. The results show a
      relatively high level of triglyceridemia, a decreased level of total cholesterol,
      apoproteins A1 and B and a hypergammaglobulinemia with concomitant and
      significant increase in the level of orosomucoide as a stigmate of inflammation.
      These data could help practitioners who lack CD4/CD8 count and viral load
      monitoring in the follow up of their AIDS patients.

PMID- 10399602
TI  - [Acute poisoning in pediatrics at the CHU of Yopougon, Cote d'Ivoire].
AB  - From 1st January 1995 to 31st December 1996, 92 children from 1 month to 15 years
      old admitted for poisoning were studied. The purpose of this work was to describe
      the characteristics of child intoxication in our area; 64% were under 5 five
      years. Petroleum was the main poison (25/92). Certain traditional measures
      carried out by parents were identified as dangerous because leading to a high
      mortality rate. Two deaths were due to petroleum poisoning. In 96% of the cases,
      it was due to an inappropriate conservation of the hydrocarbure. The
      intoxications by amino-4-quinolines were also mainly due to bad self-medication.
      For these reasons, parents must be educated.

PMID- 10399604
TI  - [Resistance of malaria vectors to pyrethrins used for impregnating mosquito nets
      in Benin, West Africa].
AB  - Impregnated bednets can be considered a major tool for reducing Anopheles bites,
      malaria morbidity and overall mortality. The resistance of Anopheles gambiae to
      pyrethroids used to impregnate bednets and curtains has already been noted in the
      urban area of Cotonou in Benin (18, 21). In this study, we wished to find out if
      the resistance observed in Cotonou is localized only in this town or is already
      extensive throughout Benin. In this case, such resistance would be a handicap to
      the promotion of impregnated bednets in Benin. The study was carried out in 15
      localities throughout the different ecological zones of Benin. The study has also
      taken into account environmental factors favouring the emergence of resistance.
      We did susceptibility tests with WHO test kits for adult mosquitoes using
      impregnated papers. The papers were impregnated with permethrin 0.25%,
      deltamethrin 0.025% and lambdacyhalothrin 0.1%. We also tested DDT 4% to find out
      if there was a cross resistance between DDT and the pyrethroids. Two mosquito
      species were tested: An. gambiae and An melas. In northern Benin, where farmers
      use insecticides against cotton pests, vectors are susceptible to deltamethrin
      and lambdacyhalothrin and resistant to permethrin. In the south, An. gambiae is
      resistant to deltamethrin and permethrin. This resistance is high in the urban
      zone of Cotonou, in the coastal and lagoon areas and at Krake, a frontier viliage
      with Nigeria. The resistance observed in southern Benin is confirmed by the
      lengthening of the knock-down time of mosquitoes which were exposed for 1 hour to
      insecticide in impregnated WHO test tubes, and by a reduction of permethrin and
      deltamethrin remanence effect.

PMID- 10399603
TI  - [Epidemiology and control of bacterial meningitis in children less than 1 year in
      Niamey (Niger)].
AB  - A bacteriological and epidemiological study of bacterial meningitis occurring in
      infants under one year of age was performed from September 1981 to June 1997 in
      Niamey, a city of 575,000 residents, located within the African meningitis belt.
      Cases of meningitis were defined either by culture of the cerebrospinal fluid
      (CSF), specific antigen agglutination, staining or cell counts of the CSF. Over
      the 16 years involving both epidemic and non epidemic periods, 1,481 infant's CSF
      were analysed, representing 20% out of the total CSF samples. The average of
      annual incidence rates was 511.4 cases per 100,000 infants under one year.
      Haemophilus influenzae b represented 35.1% of the cases, Streptococcus pneumoniae
      26.3% and Neisseria meningitidis 17.6%. The other bacteria represented 5.5% and,
      for 15.5% out of the analysed CSF, the causative agent was not identified. The
      average annual mortality rate was 146.9 deaths for 100,000 infants under one
      year. The specific case fatality rates were 43% for H. influenzae b, 58.9% for S.
      pneumoniae and 17.8% for N. meningitidis. This study showed that in Niamey, as in
      the rest of the meningitis belt, S. pneumoniae and H. influenzae b were the main
      causes of bacterial meningitis occurring in infants under one year. However, the
      specific incidence of N1 meningitidis was identical for every age group between 0
      and 20 years, and varied from 45 per 100,000 during non epidemic year to 550 per
      100,000 during epidemic year. Immunisation with conjugate vaccines, particularly
      anti-Haemophilus vaccine appears to be the best preventive measure. The
      systematic use of ceftriaxone in infants, during meningococcal meningitis either
      epidemics or not, is highly recommended.

PMID- 10399605
TI  - [Phlebotomus of Senegal: survey of the fauna in the region of Kedougou. Isolation
      of arbovirus].
AB  - Phlebotomine sand-flies were captured on a bimonthly basis from April 1995 to
      March 1996 in the Kedougou district of south-east Senegal. In all, 6,642
      specimens were identified belonging to 25 species. Eleven species were captured
      in tree holes, 17 in termites hills, 19 in rodent burrows and 23 on grass.
      Sergentomyia buxtoni, S. clydei, S. dubia, S. squamipleuris et S. schwetzi were
      the most abundant. Species from the genus Sergentomyia accounted for 99.3% versus
      0.7% for the genus Phlebotomus, Phlebotomus duboscqi, the leishmaniasis vector in
      Senegal, was very rare. The male of S. edentula and S. herollandi were recorded
      for the first time. The sand-fly population was observed to peak in April. The
      most populated resting sites were, in decreasing order, termite-hills, burrows
      and tree-holes. Thirty virus strains from 5 different viruses (Saboya,
      Chandipura, Tete, ArD 95737, ArD 111740) were isolated from 30,482 specimens
      tested.

PMID- 10399606
TI  - [Anopheles mascarensis (De Meillon, 1947): main vector of malaria in the region
      of Fort-Dauphin (south-east of Madagascar)].
AB  - Anopheles funestus and Anopheles gambiae s.l. have been considered until now the
      major vectors of malaria everywhere in Madagascar. Anopheles mascarensis, a
      mosquito native to Madagascar, has been identified in Sainte-Marie island as a
      secondary vector only. In 1997, an entomological study was carried out to
      identify the malaria vectors in the area of Fort-Dauphin, South-East of
      Madagascar. Every month, mosquitoes were collected from landing catches on human
      volunteers (from 7:00 am to 5:00 pm inside dwellings and from 7:00 am to 0:00 pm
      outside) and from knockdown spray-collections indoors. An mascarensis was the
      most abundant mosquito, the average number of An. mascarensis bites per man/night
      was 7.6. The sporozoite index was 0.89%. Despite the presence of An. funestus and
      An. gambiae s.l., An. mascarensis was found to be responsible for 2/3 of the
      infectious bites (25 infectious bites per man/year). An. mascarensis is widely
      distributed ih Madagascar but only specimens from the east coast have been found
      to carry sporozoites of human malaria. Further arguments are thus advanced for
      the hypothesis according to which a sibling species of An. mascarensis is present
      in Madagascar.

PMID- 10399607
TI  - Fast magnetic resonance imaging of liver.
AB  - Recent magnetic resonance (MR) units with a stronger gradient system have allowed
      various fast MR imaging techniques to develop. These fast scan techniques have
      easily realized breath-holding acquisition in the liver and the image quality has
      been greatly improved without sacrificing spatial resolution. The majority of the
      fast imaging techniques have been devoted to T2-weighted imaging to obtain useful
      T2-weighted images in the shortest possible time. Among the fast sequences, fast
      spin-echo (FSE) sequence is the most promising technique and allows high-quality
      T2-weighted images with reduced motion artifacts. However, FSE sequences using
      multiple refocused pulses may essentially realize only poor soft-tissue contrast
      due to magnetization transfer and T2-filtering effects, and therefore, echo
      planar (EP) imaging is expected to provide high image contrast. In addition,
      single-shot EP imaging allows even diffusion-weighted (DW) and perfusion-weighted
      (PW) imaging in the liver due to its short scanning time. Recent development of
      fast gadolinium-enhanced 3D MR angiography has also impacted liver imaging.
      Combined with such gadolinium-enhanced 3D-MRA sequences and zerofilling image
      interpolation technique, biphasic gadolinium-enhanced 3D-MRA (whole-liver dynamic
      MR imaging in the arterial phase and MR portography in the portal phase) can be
      obtained.

PMID- 10399608
TI  - Fast MR imaging for evaluating the pancreaticobiliary system.
AB  - Due to physiological movement clinical MR applications for abdominal organs got
      off to a very slow start compared to MR imaging of other organs. However, with
      recent cutting-edge hardware technologies such as high performance gradient
      systems and phased-array capability, as well as software innovations including
      short TR fast spoiled gradient recalled acquisition in the steady state (GRASS),
      snapshot imaging such as single shot fast spin echo sequence (SSFSE) and echo
      planar imaging (EPI), scan times have been further reduced to make breath-hold
      imaging clinically viable and to enable semi-fluoroscopic, kinematic imaging
      recognition. The elimination of physiological motion has contributed to the
      significant improvement in image quality, or more specifically, the physiological
      motion that had long been problematic has been turned into a source of
      physiological information about pancreaticobiliary pathologies. In this article,
      the author reviewed the current status of fast MR technologies for examining
      pancreaticobiliary pathologies, stressing the functional and physiological
      aspects of the corresponding anatomy. The technologies included secretin MRCP,
      which became a powerful tool when combined with kinematic imaging.

PMID- 10399609
TI  - Ultrafast MR imaging of the pelvis.
AB  - MR gradient systems with higher slew rates and gradient amplitude enable certain
      forms of imaging that are not practical with older gradient systems. These newer
      pulse sequences include single shot half-Fourier T2-weighted images and echo
      planar imaging. More important in MR imaging of the pelvis, these gradient
      systems benefit more conventional imaging methods such as gadolinium-enhanced 3D
      MR angiography, dynamic gradient echo contrast-enhanced images, and T2-weighted
      fast spin echo images, by shortening echo times. For most MR imaging of the
      pelvis, spatial resolution is paramount, and therefore sequences such as half
      Fourier acquisition Turbo spin echo (HASTE) and 3D gadolinium-enhanced dynamic
      imaging play a less important role than in the upper abdomen. The potential of
      these techniques for diffusion or perfusion studies in the pelvis has not been
      explored.

PMID- 10399610
TI  - T2* and proton density measurement of normal human lung parenchyma using
      submillisecond echo time gradient echo magnetic resonance imaging.
AB  - OBJECTIVE: To obtain T2* and proton density measurements of normal human lung
      parenchyma in vivo using submillisecond echo time (TE) gradient echo (GRE)
      magnetic resonance (MR) imaging. MATERIALS AND METHODS: Six normal volunteers
      were scanned using a 1.5-T system equipped with a prototype enhanced gradient (GE
      Signa, Waukausha, WI). Images were obtained during breath-holding with
      acquisition times of 7-16 s. Multiple TEs ranging from 0.7 to 2.5 ms were tested.
      Linear regression was performed on the logarithmic plots of signal intensity
      versus TE, yielding measurements of T2* and proton density relative to chest wall
      muscle. Measurements in supine and prone position were compared, and effects of
      the level of lung inflation on lung signal were also evaluated. RESULTS: The
      signal from the lung parenchyma diminished exponentially with prolongation of TE.
      The measured T2* in six normal volunteers ranged from 0.89 to 2.18 ms (1.43 +/-
      0.41 ms, mean +/- S.D.). The measured relative proton density values ranged
      between 0.21 and 0.45 (0.29 +/- 0.08, mean +/- S.D.). Calculated T2* values of
      1.46 +/- 0.50, 1.01 +/- 0.29 and 1.52 +/- 0.18 ms, and calculated relative proton
      densities of 0.20 +/- 0.03, 0.32 +/- 0.13 and 0.35 +/- 0.10 were obtained from
      the anterior, middle and posterior portions of the supine right lung,
      respectively. The anterior-posterior proton density gradient was reversed in the
      prone position. There was a pronounced increase in signal from lung parenchyma at
      maximum expiration compared with maximum inspiration. The ultrashort TE GRE
      technique yielded images demonstrating signal from lung parenchyma with minimal
      motion-induced noise. CONCLUSION: Quantitative in vivo measurements of lung T2*
      and relative proton density in conjunction with high-signal parenchymal images
      can be obtained using a set of very rapid breath-hold images with a recently
      developed ultrashort TE GRE sequence.

PMID- 10399611
TI  - Application of a spectral-spatial water excitation for MR angiography.

PMID- 10399612
TI  - Quiz case 5. Pneumococcal sepsis in a patient with hereditary hypoplasia of the
      spleen.

PMID- 10399613
TI  - 3D spiral CT imaging of bone anomalies in a case of diastematomyelia.
AB  - The case of a 48-year-old woman, suffering from a diastematomyelia, is presented.
      This case and the diagnostic findings are used to demonstrate the demands on
      imaging methods with respect to a new classification of split cord malformations
      (SCMs) recently published. Although MRI is the method of choice for imaging of
      the spinal cord generally, only X-ray methods and especially conventional
      computer tomography provide the information necessary for correct classification
      of SCMs. Additional 3D-reconstructions from suitable CT-data are helpful in
      visualizing complex anomalies of bony structures found in most cases of SCM.

PMID- 10399614
TI  - Evaluation of hepatic venous pulsatility and portal venous velocity with Doppler
      ultrasonography during the puerperium.
AB  - OBJECTIVE: The aim of this study is to evaluate pregnancy-induced changes of
      hepatic venous pulsatility and portal venous velocity in the puerperium and to
      determine if these changes disappeared by the end of the puerperium. METHODS AND
      MATERIAL: Healthy normal volunteers (90) were examined on the 2nd and 7th days of
      puerperium and between the 6th and 8th weeks postpartum. Doppler waveform
      patterns were obtained in the middle hepatic vein and main portal vein. The
      hepatic venous pulsatility was named as normal, damped or flat. RESULTS: On the
      2nd day postpartum, the hepatic vein pulsatility was shown as normal in 8 (26%),
      damped in 11 (37%) and flat in 11 (37%) cases. On the 7th day postpartum, 15
      (50%) cases had normal, 9 (30%) cases had dampened, and 6 (20%) cases had still
      flat pattern. The majority of the cases (60%) displayed normal hepatic venous
      pulsatility in the 6th and 8th weeks of puerperium, whereas 23% had still
      dampened and 17% had flat patterns. There was a trend toward normal pulsatility
      with increasing puerperal age. The mean portal venous velocity was still higher
      than the non-pregnant levels and did not showed significant alterations during
      puerperium. CONCLUSION: This study emphasised that, since pregnancy-induced
      alterations in hepatic venous pulsatility and portal venous velocity had not
      completely returned to normal in most cases until the end of the puerperium,
      these physiological changes should be considered whenever hepatic and portal
      systems are interpreted with Doppler sonography during the puerperal period.

PMID- 10399615
TI  - Evanescent exostosis. A new case.
AB  - Much has been written about the natural history of osteochondromas, but there are
      only a few reports in the literature reflecting the spontaneous disappearance of
      this lesion. For that reason, we report an additional case which makes the total
      number of reported cases eleven, and also includes a review of the literature.

PMID- 10399616
TI  - A surgical gauze appearing as a retrocardiac mass in a patient after coronary
      artery bypass surgery.
AB  - Five years after open chest surgery because of three vessel coronary artery
      disease a patient was referred for progressing dyspnea and recent onset of atrial
      fibrillation. A retrocardiac mass was detected on chest X-ray and
      echocardiography. On CT-scan, the inhomogenous tumor made the diagnosis of a
      retained surgical gauze likely. Through a left incision the sponge was removed
      uneventfully and the dyspnea resolved.

PMID- 10399618
TI  - "Ottorino Rossi" Award 1999. Unilateral headache: a worthwhile line of research?

PMID- 10399617
TI  - Stenting in the femoral superficial artery: an overview.
AB  - Stenting in the superficial femoral artery is still a controversial treatment in
      case of occlusive disease. Although the results of percutaneous treatment
      especially in the Hunter canal region are moderate, balloon angioplasty is
      nowadays an established technique. Many investigators tried to improve their
      results with additional stenting of the superficial femoral arteries after
      inappropriate results of balloon angioplasty and/or stenting. Although the
      figures of results after stenting are not consistent in literature even when
      using stent graft material I still feel that especially in the superficial
      femoral artery stenting procedures should not be performed on a routine basis.
      The main issue in stent failure is the extensive intima hyperplasia. Many
      investigators are working on this problem but as long as no real solution is
      available I feel that we have to act reluctantly in treating superficial femoral
      arteries with stents.

PMID- 10399619
TI  - How the brain anticipates an attack: a study of neurophysiological periodicity in
      migraine.
AB  - We investigated cortical excitability and the pattern of arousal in migraine
      patients using contingent negative variation (CNV) and EEG power spectrum
      analysis performed before and after a migraine attack. Twenty females suffering
      from migraine without aura and 12 healthy controls were enrolled in the study. In
      the group of patients, the CNV, EEG power spectrum and hemispheric asymmetry
      analyses were performed 1-4 days before the first day of an attack and 4 days
      following the last day with migraine. The recordings in healthy subjects were
      carried out on a day chosen by the participants. The comparisons were made using
      non-parametric procedures. After an attack no difference was found between
      patients and controls in EEG power spectrum, hemispheric asymmetry or CNV
      components (with the exception of the beta 1 power, which was more pronounced in
      patients). Before an attack, however, a significant increase in the power of
      delta and theta frequency bands, in the alpha asymmetry, and in early CNV
      amplitude were observed. The patients differed from controls both in the extent
      of cortical excitability and in the arousal pattern found. In such a way migraine
      is characterized by periodic CNV and EEG power spectrum changes during the pain
      free interval. The abnormalities in cortical excitability and arousal were only
      observed before an attack, and could be used to predict the next migraine
      episode. We assume that these changes reflect the increased susceptibility of the
      migrainous brain to precipitating factors and the neurophysiological readiness to
      generate an attack. The time duration since the last attack must be taken into
      account when performing studies in the field of migraine research.

PMID- 10399620
TI  - Quantitative analysis of the pendulum test: application to multiple sclerosis
      patients treated with botulinum toxin.
AB  - The aim of this study was to develop quantitative analytical methods in the
      application of the pendulum test to both normal and spastic subjects. The lower
      leg was released by a torque motor from different starting positions. The
      resulting changes in the knee angle were fitted by means of a time-varying model.
      Stiffness and viscosity coefficients were derived for each half-cycle oscillation
      in both flexion and extension, and for all knee starting positions. This method
      was applied to the assessment of the effects of Botulinum toxin A (BTX) in
      progressive multiple sclerosis patients in a follow-up study. About half of the
      patients showed a significant decrement in stiffness and viscosity coefficients.

PMID- 10399621
TI  - Hemicrania continua: ocular discomfort heralding painful attacks.
AB  - It is known that in a minority of patients attacks of hemicrania continua may be
      accompanied by ipsilateral ocular discomfort. This symptom mostly occurs during
      exacerbations and is regularly concurrent with the pain. The observations
      reported here suggest that in hemicrania continua, ocular discomfort may, in rare
      cases, precede by a considerable length of time the onset of pain. It is
      postulated that the asynchronous appearance of these clinical features may
      reflect either an extreme fluctuation of the intensity of the pain or a
      dissociation of the pain from the ocular discomfort.

PMID- 10399622
TI  - The functional anatomy of noradrenergic neurons in Parkinson's disease.

PMID- 10399623
TI  - c-erbB-2 in serum of patients receiving fractionated paclitaxel chemotherapy.
AB  - Humanized anti-c-erbB-2 antibodies (Herceptin) in a weekly schedule are a new
      therapeutic option for the treatment of c-erbB-2-positive, advanced breast cancer
      (ABC). Addition of Herceptin to first-line chemotherapy for c-erbB-2
      overexpressing ABC increased anticancer activity in a randomized phase III trial.
      However, except from standard UICC response criteria, there are hitherto no
      recommendations as to how to monitor Herceptin therapy. In a therapy optimizing
      study with weekly dose-intensified paclitaxel monotherapy (schedule: 90 mg/m2
      weekly x 6, q9w), we correlated the clinical course of stage IV breast cancer in
      UICC criteria with the course of the shed c-erbB-2 protein fragment and the CA
      27.29 serum level. Serum samples were taken weekly from 35 patients to measure
      the serum c-erbB-2 and CA 27.29 protein levels over time. Up to now, 10 patients
      (28.5%) are c-erbB-2 positive (> 15 U/mL), with a median baseline protein
      expression of 65 U/mL. While the overall response rate in the study is 36%, the
      response rate among c-erbB-2-positive patients is 62%, indicating a high
      sensitivity of c-erbB-2 positive patients to dose-intense paclitaxel treatment.
      In all responders the c-erbB-2 serum level decreased below the detection limit
      either before the clinical diagnosis of response or by the end of the next cycle.
      However, the normalization of the c-erbB-2 serum level was not specific for
      responders as patients with stable or progressive disease presented normalized
      levels or a > 50% decrease of the baseline level, too. The courses of the c-erbB
      2 protein levels correlated closely with the courses of CA 27.29. The decrease in
      the serum c-erbB-2 oncoprotein level might indicate a regression of c-erbB-2
      positive tumor load. This may even happen in progressive disease according to
      UICC criteria when the c-erbB-2-negative tumor fraction progresses while the c
      erbB-2-positive fraction is controlled. Another explanation would be that the
      mechanisms of c-erbB-2 shedding change under chemotherapy, with less of the c
      erbB-2 protein fragment being released to the serum, which would make the c-erbB
      2 positive tumor cells a better target for anti-c-erbB-2 antibody treatment.

PMID- 10399624
TI  - Relationship between steroid receptors (as continuous variables) and response to
      adjuvant treatments in postmenopausal women with node-positive breast cancer.
AB  - In current clinical practice for breast cancer patients, estrogen (ER) and
      progesterone receptor (PgR) concentrations, quantified by the dextran-coated
      charcoal assay, are categorized by an arbitrary cutoff into a negative or
      positive status. However, although the results obtained with this approach are
      easy to interpret, such a representation could oversimplify the relationship
      between ER and PgR content and patient outcome and imply an assumption of
      monotonicity, which is generally expected but rarely proven. We evaluated the
      relationship between ER and PgR content (considered on a continuous scale) and
      clinical outcome, using a flexible statistical model, in a group of
      postmenopausal patients with N-positive operable tumors who were submitted to
      surgery and different adjuvant treatments (tamoxifen or CMF). Univariate analysis
      indicated that in the tamoxifen-treated group, ER level, number of metastatic
      nodes (pN) and age, but not PgR, were significant indicators of clinical outcome
      (p = 0.032, p = 0.021 and p = 0.029, respectively). Multivariate analysis
      indicated that in this group of patients there was no interaction between
      variables, and in the final model for disease-free survival (DFS) only ER and pN
      were retained with an overall predictive ability of the regression model of
      0.723, as evaluated by Harrell's c. However, pN markedly contributed to the
      predictive ability of the model with respect to ER, since a marked decrease in
      Harrell's c statistic (c = 0.582) was observed when pN was removed from the
      model. In the CMF-treated group, only pN affected clinical outcome. When the
      estimated DFS curves obtained from the final Cox regression models were plotted
      according to four values of ER (in the tamoxifen-treated group) or three values
      of pN (in the CMF-treated group) we observed that in the tamoxifen-treated group
      patients with an ER concentration equal to 0 fmol/mg cytosol protein had the
      worst prognosis, whereas a marked improvement of the expected DFS was observed
      for patients with a low but detectable ER level (generally classified as ER
      negative because falling below the conventional cutoff value of 10 fmol/mg
      cytosol protein). Our results seem to suggest that the use of steroid receptor
      concentrations on a continuous scale, instead of dichotomous "status", is to be
      preferred in the choice of adequate therapeutic strategies.

PMID- 10399625
TI  - Production of a monoclonal antibody directed against the high-affinity nerve
      growth factor receptor.
AB  - The high-affinity nerve growth factor receptor corresponds to the tyrosine
      protein kinase encoded by the proto-oncogene trkA. Different findings suggest
      that nerve growth factor (NGF) can be operative in the growth modulation of tumor
      cell lines possessing high-affinity binding sites for this molecule. Using as
      immunizing material the SKNBE neuroblastoma cell line transfected with proto-trkA
      we produced a monoclonal antibody (MAb) able to recognize the high-affinity nerve
      growth factor receptor. The selected MAb, designated MGR12, is directed against
      an epitope present on the extracellular domain of the receptor since it showed
      reactivity on living trkA-expressing cells and was able to immunoprecipitate the
      proto-trkA molecule. The MGR12 MAb is directed against a non-functional epitope
      since it neither inhibited NGF binding nor induced receptor internalization. This
      new reagent appears to be an appropriate tool for analyzing the expression of
      high-affinity nerve growth factor receptor in tumors of different origin and for
      elucidating its involvement in tumor progression.

PMID- 10399626
TI  - Multicenter evaluation of the performance and clinical utility in longitudinal
      monitoring of the Bayer Immuno 1 complexed PSA assay.
AB  - We conducted a multicenter evaluation of the analytical and clinical performance
      of the automated Bayer Immuno 1 complexed PSA (cPSA) assay, and compared assay
      performance to the Bayer Immuno 1 PSA assay. We sought to determine whether
      measurements of cPSA could be of clinical utility in the management of patients
      with prostate cancer. Results of the 10-day imprecision across three evaluation
      sites produced total CV < 2.50% and an analytical sensitivity of 0.02
      microgram/L. There was an increased trend in clinical sensitivity for prostate
      cancer with increasing stage of disease (71-86%). Clinical specificity for
      patients with benign urogenital disease was 74.8%, and for other nonprostate
      diseases ranged from 91.1-100%. Retrospective serial monitoring of 155 patients
      with prostate cancer demonstrated concordance of cPSA measurements to clinical
      status for 97% of the patients analyzed. Results from the clinical studies using
      the Bayer Immuno 1 cPSA assay were comparable to results obtained with the Bayer
      Immuno 1 PSA assay. The Bayer Immuno 1 cPSA assay demonstrates analytical
      performance and clinical effectiveness in the management of prostate cancer
      patients during the course of disease and therapy.

PMID- 10399627
TI  - Apoptosis and Bcl-2 expression in relation to age, tumor characteristics and
      prognosis in breast cancer. South-East Sweden Breast Cancer Group.
AB  - The extent of apoptosis and the expression of Bcl-2 was investigated in tumor
      samples from 165 women who underwent surgery for primary breast carcinoma between
      1989 and 1990 in South-East Sweden. Apoptosis was assessed by a DNA fragmentation
      assay for flow cytometry. Bcl-2 protein expression was analyzed with
      immunocytochemistry. Bcl-2 immunoreactivity correlated with estrogen receptor
      (ER) and progesterone receptor (PgR) positivity and was inversely correlated with
      p53 accumulation. Apoptosis increased with patient age and a high degree of
      apoptosis was negatively associated with Bcl-2 immunostaining. Apoptosis showed
      no significant correlation with any of the other variables studied, including
      prognosis. The group with Bcl-2-positive tumors tended to have a lower risk of
      distant recurrence than others, but the association of Bcl-2 with recurrence was
      different in groups divided by ER and PgR status. Whereas Bcl-2 positivity
      indicated a low recurrence rate among PgR-negative patients, in the PgR-positive
      group, those with Bcl-2-positive tumors showed a non significantly higher
      recurrence rate than Bcl-2-negative cases. In the PgR-positive group, Bcl-2
      positive tumors also appeared more frequently to be lymph node positive and DNA
      aneuploid. The results suggest that hormone receptor status is of importance for
      the prognostic role of Bcl-2. Likewise, patient age merits consideration when
      apoptosis is studied in human cancer.

PMID- 10399628
TI  - Preoperative CEA, NSE, SCC, TPA and CYFRA 21.1 serum levels as prognostic
      indicators in resected non-small cell lung cancer.
AB  - In 62 patients affected by resectable non-small cell lung cancer (NSCLC)
      submitted to radical surgery we evaluated the prognostic significance of CEA,
      NSE, SCC, TPA, and CYFRA 21.1 serum levels at diagnosis, as well as the
      predictive ability of these tumor markers with respect to histological type and
      pathological stage. The group was composed of 56 male and 6 female patients; the
      median age was 62 years (range 29-73 years). Thirty-four patients had a
      histological diagnosis of adenocarcinoma and 28 of squamous cell carcinoma; with
      regard to pathological stage, 32 patients had stage 1, 4 patients stage II and 23
      patients stage IIIA disease. A good predictive ability with respect to
      histological type was obtained with SCC serum levels; as for pathological stage,
      TPA and CYFRA 21.1 were found to have moderate predictive ability. In this series
      of patients, at a median follow-up of 55 months after surgery, we found that both
      TPA and CYFRA 21.1 serum levels at diagnosis were reliable predictors of overall
      survival, high values of these markers being associated with a worse prognosis.

PMID- 10399629
TI  - Disappearance curves for tumor markers after resection of intrathoracic
      malignancies.
AB  - Determination of the standard elimination kinetics of tumor markers will be
      helpful in the diagnosis of malignancies. We analyzed the disappearance curves
      for serum tumor marker levels after resection of intrathoracic malignancies.
      Serum levels of CEA, SLX, AFP, CA 19-9, SCC, TPA and CYFRA were measured several
      times after surgery in a total of 40 patients. To obtain precise biological half
      lives, we applied non-linear least square analysis, taking into consideration the
      possibility of residual tumor cells. Disappearance curves were monophasic for
      CEA, SCC, TPA, CYFRA and SLX and biphasic for CA 19-9 and AFP. Temporary
      elevation of serum levels after surgery was observed for SCC, TPA and CYFRA. The
      average half-lives of CEA, SLX, SCC, TPA and CYFRA were 1.5 days, 2.7 days, 2.2
      hours, 2.5 hours and 1.5 hours, respectively. The average half-life of CA 19-9
      was 0.5 days in the first compartment and 4.3 days in the second compartment,
      while that of AFP was 1.0 days and 6.3 days, respectively. These values will be
      helpful in the interpretation of serum tumor marker levels after surgery.

PMID- 10399630
TI  - Tissue quantification of CA 125 in epithelial ovarian cancer.
AB  - The objectives of this study were the determination of CA 125 in the cytosol of
      healthy and carcinomatous ovarian tissue by immunoanalysis, analysis of its
      correlation with the biological characteristics of ovarian carcinoma,
      determination of serum CA 125 levels, and study of the prognostic value of the
      marker in cytosol. The levels of the marker depend not only on the tumor's
      production rate, so its determination in tissue can indicate more accurately if
      the tumor is a producer of the marker and establish its value for the prognosis
      of the disease. Determination of CA 125 in tissue was performed by immunoanalysis
      in 50 ovarian epithelial cancer samples, 13 benign pathology samples and 32
      healthy ovary samples. The presurgical serum level of the marker was also
      obtained. The correlation between the CA 125 level in the cytosol and the
      different biological characteristics of the ovarian carcinoma, the serum levels
      of the marker and survival were analyzed. The CA 125 level proved to be higher in
      malignant tissue (p < 0.0001). There was a significant association between the
      tissue marker and histological type (high CA 125 was associated with serous and
      endometrioid tumors) and between the marker and survival. No relation with stage
      was found. There was a correlation between the CA 125 level in the cytosol and
      serum both variables being dependent, with a correlation coefficient of 0.44.
      This good correlation speaks in favor of the usefulness of CA 125 determination
      in serum in the follow-up of ovarian cancer. Tumors having high tissue expression
      of CA 125 were found to have a double relative risk of death, independently of
      tumor stage.

PMID- 10399631
TI  - Changes in lymphocyte number during cancer chemotherapy and their relation to
      clinical response.
AB  - Since hematologic examination during cancer chemotherapy is generally limited to
      the evaluation of neutrophil and platelet numbers, at present there are no clear
      data about the possible prognostic significance of changes in lymphocyte number
      in relation to the clinical efficacy of chemotherapy itself. To obtain some
      preliminary data about this issue, we have evaluated changes in lymphocyte number
      and percentage in a group of 50 advanced non-small cell lung cancer patients
      treated with three cycles of cisplatin (20 mg/m2/day) plus etoposide (100
      mg/m2/day) i.v. for three days every 21 days. The clinical response consisted of
      partial response (PR) in nine (18%), stable disease (SD) in 18 (36%) and
      progressive disease (PD) in the remaining 23 (46%) patients. The lymphocyte
      percentage increased during chemotherapy, without, however, a significant
      difference with respect to the pretreatment values. In contrast, the mean number
      of lymphocytes observed after the first chemotherapeutic cycle significantly
      decreased in patients with PD, whereas it increased in patients with PR or SD,
      even though the difference did not reach statistical significance. These
      preliminary data, which have to be confirmed in a large number of patients and in
      patients treated with other chemotherapeutic schedules for different tumor types,
      seem to suggest that a chemotherapy-induced decline in lymphocyte number may be
      associated with a lack of efficacy of chemotherapy itself.

PMID- 10399632
TI  - Utility of tumor marker CA 72.4 in patients with chronic renal failure.
AB  - The tumor marker CA 72.4 is composed of two monoclonal antibodies, B 72.3 and
      cc49, which detect the glycoprotein TAG 72 present in tumor cells. The levels of
      CA 72.4 may be modified depending on the route of excretion of the antigen TAG
      72. The objective of this study was to evaluate the behavior of CA 72.4 in
      healthy subjects and to assess the influence of chronic renal failure (CRF) on
      the levels of this tumor marker. Random serum samples were collected in 181
      individuals (148 healthy volunteers and 33 patients with CRF) and 214
      determinations of CA 72.4 were performed. We also performed 66 determinations of
      plasma creatinine. In healthy subjects the cutoff value of CA 72.4 was
      established at 3 U/mL, with a sensitivity of 53% and a specificity of 85.8%. In
      the CRF patients we found no statistically significant differences when we
      compared the values of CA 72.4 predialysis and postdialysis (p = 0.197). However,
      a statistically significant difference was found in the plasma creatinine levels
      (p < 0.001). Chronic renal failure does not affect the result of CA 72.4
      determinations; this tumor marker may therefore be useful in the monitoring of
      patients with cancer, independent of their renal function.

PMID- 10399633
TI  - Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with
      renal impairment.
AB  - RATIONALE AND OBJECTIVES: To determine the safety and pharmacokinetics of
      gadobenate dimeglumine in a group of subjects with moderate or severe renal
      impairment. METHODS: The safety and pharmacokinetic profile of gadobenate
      dimeglumine, a gadolinium (Gd3+) chelate complex in development as a contrast
      agent for MRI, were evaluated in a placebo-controlled, double-blind, multicenter
      trial. Subjects with moderate or severe renal impairment (creatinine clearances
      of 31 to 60 or 10 to 30 mL/min, respectively) received a 0.2-mmol/kg intravenous
      bolus of Gd3+ or saline placebo. Blood samples (up to 72 hours) and urine and
      fecal samples (up to 216 hours) were assayed for total Gd3+ content by
      inductively coupled plasma atomic emission spectroscopy. Gd3+ blood
      concentration/time data were analyzed nonparametrically and parametrically using
      the software program WinNonlin VI.1. RESULTS: Mean (SD) values for Gd3+ area
      under the curve, blood clearance, steady-state volume of distribution, renal
      clearance, and creatinine clearance for the moderate group were 862 (392)
      micrograms.h/mL, 56 (25) mL/min, 21 (5) L, 47 (23) mL/min, and 46 (16) mL/min.
      Values for the severe group were 1347 (366) micrograms.h/mL, 31 (7) mL/min, 19
      (6) L, 22 (7) mL/min, and 21 (8) mL/min. No Gd(3+)-related adverse events
      occurred. Mean values for Gd3+ recovery in urine and feces for moderate and
      severe groups were 74% and 6%, and 69% and 8% of the dose, respectively. Linear
      regression analysis demonstrated a significant relation between the level of
      renal function and blood clearance of Gd3+. CONCLUSIONS: Although mean blood
      clearance and renal clearance values progressively declined with increasing
      degree of renal impairment, based on the safety profile and the fact that the
      administered dose was double the standard dose used for MRI purposes, there
      appears to be no need for dose reduction in this population.

PMID- 10399634
TI  - Embryo depth during the first trimester. Data required for embryo dosimetry.
AB  - RATIONALE AND OBJECTIVES: To provide data regarding embryo depth during the
      extremely radiosensitive gestational stages of organogenesis and early fetal
      period for use in embryo dosimetry. METHODS: Ultrasound examination was performed
      in 73 pregnant women at gestational age 5 to 13 weeks and in a control group of
      75 nonpregnant women. Embryo skull and abdominal depth from the maternal skin
      surface were determined in the anteroposterior direction. Uterus depth was
      measured in the control group. Measurements were taken before and after voiding.
      Gestational age and maternal age, height, and weight were noted. Body mass index
      (BMI) was estimated for every woman from the formula BMI = W/H2. RESULTS: The
      mean embryo pre- and postvoid skull depth was 8.3 and 5.7 cm and the mean
      abdominal depth was 8.4 and 5.8 cm, respectively. The mean pre- and postvoid
      uterus depth was 9.5 and 4.7 cm. Mean abdominal depth and mean skull depth values
      were significantly different than mean uterus depth for full as well as for empty
      bladder. Embryo skull depth and abdominal depth were found to be significantly
      correlated with maternal BMI. Skull and abdominal dimensions were found to be
      significantly correlated with gestational age. CONCLUSIONS: During the first
      trimester, embryo depth ranges from 4 to 10 cm, depending on the individual, the
      status of the bladder, and the maternal BMI. For an accurate determination of
      embryo depth, ultrasound measurement should be performed.

PMID- 10399635
TI  - Effects of radiocontrast, mannitol, and endothelin on blood pressure and renal
      damage in the aging male spontaneously hypertensive rat.
AB  - RATIONALE AND OBJECTIVES: The purpose of this research was to study the effects
      of the radiocontrast medium (CM) Hypaque-76 (diatrizoate meglumine sodium),
      equiosmolar mannitol, and endothelin on blood pressure and renal damage in a
      aging male spontaneously hypertensive rat, a small animal model for CM-induced
      renal damage. The importance of the pressor effect and the high osmolality of CM
      in producing renal damage was investigated by first reducing the blood pressure
      with pentobarbital anesthesia, which suppresses sympathetic nervous system
      activity, then testing the effects of CM, saline, mannitol, and the potent
      vasoconstrictor endothelin alone and in combination with CM. METHODS: Systolic
      blood pressure was measured in 14-month-old male rats (1) when awake, (2) after
      pentobarbital anesthesia, (3) after the administration of saline, CM, mannitol,
      endothelin, or CM plus endothelin, (4) after awakening the same day, and (5) the
      following day while awake. Renal damage was quantified by evaluating
      histopathologically the left kidney removed the day after administration of test
      substances. RESULTS: The pentobarbital-lowered blood pressure remained depressed
      after saline and mannitol but rose dramatically after CM, endothelin, and CM plus
      endothelin. Renal damage, compared with the saline controls, occurred with CM,
      mannitol, endothelin, and endothelin plus CM. The order of increasing severity
      was mannitol = CM < endothelin < endothelin plus CM. CONCLUSIONS: The effect of
      CM on systolic blood pressure is not related to its osmolality. High osmolality,
      however, appears to be a factor in CM-induced renal damage. Ischemia and direct
      nephrotoxicity are factors contributing to the renal-damaging effects of CM,
      mannitol, and endothelin.

PMID- 10399636
TI  - Lesions of the reflection pulley of the long biceps tendon. MR arthrographic
      findings.
AB  - RATIONALE AND OBJECTIVES: The purpose of this study was to assess the diagnostic
      value of MR arthrography in detecting a lesion of the common insertion of the
      coracohumeral and the superior glenohumeral ligaments and the superior border of
      the subscapularis tendon (pulley lesion), which predisposes to biceps tendon
      subluxation and subsequent degeneration. METHODS: Parasagittal T1-weighted turbo
      spin-echo and axial gradient-echo (three-dimensional fast imaging with steady
      state-precession [FISP]) MR arthrographic images were obtained in 14 patients
      with surgically confirmed pulley lesions and in 10 patients with an intact
      pulley. Various MR arthrographic signs potentially associated with a pulley
      lesion were evaluated separately and independently in a blinded fashion by two
      radiologists. RESULTS: Abnormalities of the superior border of the subscapularis
      tendon on axial and parasagittal images, extra-articular contrast collection, and
      biceps tendon subluxation were the MR findings of a pulley lesion. The
      coracohumeral and superior glenohumeral ligaments were not readily visible in all
      patients and were not helpful in diagnosing pulley lesions in this study. The
      overall sensitivity for detecting a pulley lesion by MR arthrography was 86% and
      93% for readers 1 and 2, with a specificity of 100% and 80% and an accuracy of
      92% and 87% (kappa = 0.75). CONCLUSIONS: Based on the authors' experience, MR
      arthrography is valuable in detecting lesions of the reflection pulley of the
      long biceps tendon, although differentiation from an isolated lesion of the
      superior border of the subscapularis tendon may not be possible.

PMID- 10399638
TI  - In vitro effectiveness study for hydrodynamic thrombectomy devices of the second
      generation.
AB  - RATIONALE AND OBJECTIVES: To determine the efficacy of clot removal and the
      amount of applied saline and aspirated fluid and to compare procedure-related
      particle embolization for the hydrodynamic thrombectomy devices the LF 140
      Angiojet (LF 140), the double-lumen Hydrolyser (double HL), and the triple-lumen
      Hydrolyser (triple HL) in an in vitro flow model. METHODS: Thrombectomy of clots
      (n = 42) from 7-day-old porcine blood (9.8 g) was performed with the LF 140, the
      double HL, and the triple HL in a flow model (flow 1 L/min) made of silicone
      tubes (7 mm inner tube diameter). All catheters were used according to the
      manufacturer's recommendations. RESULTS: Mean time of thrombectomy ranged from 20
      seconds (triple HL) to 58 seconds (LF 140, P < 0.05). Only for the triple HL was
      remaining thrombus found within the tubes (41 mg). None of the tested devices
      worked isovolumetrically: the mean ratio of applied saline and aspirated fluid
      for the devices ranged from 0.79 (triple HL) to 0.89 (double HL, P < 0.05). Mean
      embolus weight and percentage of embolism from original thrombus were 675 mg/6.7%
      (LF 140, P < 0.05), 38 mg/0.4% (double HL), and 26 mg/0.3% (triple HL).
      CONCLUSIONS: Thrombectomy time and embolus weight depend on the device chosen.
      The ratio of applied to aspirated fluid, indicating the capability to work nearly
      isovolumetrically, is acceptable for all tested devices. In vitro, the triple HL
      seems to be the most appropriate device for rapid mechanical, hydrodynamic
      thrombectomy. Because of the high in vitro particle embolization rate, the LF 140
      seems to be strictly limited to small-caliber vessels.

PMID- 10399637
TI  - Cardiac metal contents after infusions of manganese. An experimental evaluation
      in the isolated rat heart.
AB  - RATIONALE AND OBJECTIVES: Manganese dipyridoxyl diphosphate (MnDPDP), a contrast
      agent for liver MRI, releases free Mn2+ in a graded manner. The aim of the study
      was to compare the effects of brief versus prolonged infusions of MnDPDP and
      manganese chloride (MnCl2) on cardiac function, metabolism, Mn accumulation, and
      tissue metal content. METHODS: Isolated perfused rat hearts received 1-minute or
      10-minute infusions of MnDPDP (100 microM, 1000 microM) or of MnCl2 (10 microM,
      100 microM). Physiologic indices were measured intermittently, and tissue high
      energy phosphate compounds and Ca/Fe/Mg/Mn/Zn contents were measured after a
      standardized Mn washout. RESULTS: One-minute and 10-minute infusions induced,
      respectively, minor and marked depressions of contractile function and
      corresponding elevations in myocardial Mn content. MnCl2 was markedly more potent
      than MnDPDP. Ten-minute infusions of the highest concentration of MnDPDP and
      MnCl2 lowered tissue Mg and elevated tissue Ca (MnCl2), whereas high-energy
      phosphates were unaffected. CONCLUSIONS: Mn uptake after Mn infusion is strongly
      related to the duration, concentration, and dose of free Mn ions. Differences in
      Mn accumulation between MnDPDP and MnCl2 were more pronounced after the 10-minute
      infusion.

PMID- 10399639
TI  - Double-helical CT as a new tool for tracking of allograft atherosclerosis in
      heart transplant recipients.
AB  - RATIONALE AND OBJECTIVES: Tracking the progression of allograft atherosclerosis
      in heart transplant recipients is currently accomplished using invasive
      techniques. If its monitoring feasibility is demonstrated, spiral CT could be a
      non-invasive alternative for this objective. METHODS: Twenty-four consecutive
      heart transplant patients (21 men, 3 women, mean age 55 +/- 11 years) were
      scanned using double-helical CT. The first scan was performed 1.9 +/- 1.3 years
      after transplantation. After 2 years of follow-up, 4 patients died and the
      remaining 20 underwent a second scan. All scans were performed according to a
      previously reported double-helical CT protocol. RESULTS: The incidence of
      coronary calcification at the first scan was 4.2% (1/24); it increased to 40%
      (8/20) at the second scan (P < 0.001). Spiral CT identified new but very mild
      calcific deposits in seven patients with a mean total calcium score of 6.7 +/-
      4.0. CONCLUSIONS: Double-helical CT is a viable tool to diagnose and track newly
      developed allograft atherosclerosis.

PMID- 10399640
TI  - Mechanical thrombectomy in hemodialysis access shunts using a 5F pigtail rotation
      catheter. In vitro and in vivo investigations.
AB  - RATIONALE AND OBJECTIVES: To evaluate the feasibility of mechanical thrombectomy
      in occluded hemodialysis access shunts by using a newly developed 5F pigtail
      rotation catheter. METHODS: Thrombosed hemodialysis access shunts were simulated
      by clotted bovine blood in silicone tubing (diameter 6 mm). After retrograde and
      antegrade sheath placement (6F), mechanical fragmentation was performed using a
      5F rotatable pigtail device. Average tube length was 27 to 47 cm; average
      thrombus weight was 5 to 11.9 g (8.2 +/- 1.59). Clinical application involved six
      patients with fresh shunt occlusions (three Brescia-Cimino shunts, three Gore-Tex
      shunts). RESULTS: Using the in vitro setup, the device was able to restore a
      continuous lumen within 10 minutes with no remaining wall-adherent thrombi. The
      average amount of particles in the effluent was 3.0 g (2.0 to 3.9) for particles
      < or = 1.0 mm and 0.67 g (0.44 to 0.96) for particles > or = 0.2 mm wet weight;
      (compared with initial thrombus weight, 30.7% and 1.1%, respectively).
      Clinically, all six hemodialysis access shunts were successfully recanalized.
      Technical problems did not occur. There were no clinical symptoms indicating
      pulmonary embolism in any of the treated patients. CONCLUSIONS: In our
      experimental setup as well as under clinical conditions, effective treatment of
      occluded hemodialysis access sites was achieved. The pigtail rotation device is
      an easy-to-handle, inexpensive alternative to mechanical thrombus fragmentation
      in occluded hemodialysis access shunts. The rate of emboli in the effluent vein
      of approximately one third of the initial thrombus weight must be taken into
      consideration in frequent intraindividual use of this technique.

PMID- 10399641
TI  - The endothelium in the pathogenesis of systemic sclerosis: is it primary or
      secondary?

PMID- 10399642
TI  - [Hemorheology and vascular endothelial cells].
AB  - The vascular endothelium is a biologically active monolayer of cells providing an
      interface between the blood flow and tissues. Vascular Endothelial Cells (VEC)
      have two functional states. The endothelium is normally anti-thrombotic and anti
      adhesive to ensure blood fluidity. During aggressions, such as atherosclerosis,
      inflammation states, metabolic diseases (through chemical or mechanical stimuli),
      VEC can reverse its functions by expressing stored material or by slower
      involvement of previously are repressed genes. Endothelial cells have three types
      of anti-thrombotic properties: vaso regulating properties: VEC release vasomotor
      components, such as endothelin (vasoconstriction), prostacyclin and nitric oxide,
      (vasodilatation). Endothelial cells also have antithrombotic and hemostatic
      properties. They express proteoglycans on their surface, including some negative
      charge, plasminogen, sulfate glycosaminoglycans (heparan-sulfate), and secrete
      plasminogen tissular activator (t-PA) and tissular factor inhibitor. One
      fundamental action of the endothelium in that area is the production and
      expression of thrombomodulin, a thrombin receptor. This function has a major
      anticoagulation effect, controlling continual thrombin generation at the sub
      endothelium and blood cell interface. Moreover, endothelial cells show anti
      adhesion properties. During cardio-vascular diseases, all of these properties may
      be reversed. Thus the VEC have a determinant role in hemodynamic control through
      these various metabolic activities, such as control of homeostasis, vascular
      tone, blood fluidity, coagulating properties, cellular adhesion. Otherwise, many
      studies have demonstrated that local blood flow conditions have a crucial role on
      the VEC properties (mechanoactivation and mechanotransduction concept). In
      conclusion, knowledge of all the properties of the endothelial cells and control
      of the phenomena which define their functions is a key element in understanding
      cardiovascular diseases.

PMID- 10399643
TI  - Haemorheological disturbances and possibility of their correction in
      cerebrovascular diseases.
AB  - The presence of a hemorheological disturbance must be considered in the
      pathophysiological and therapeutical approach to vascular diseases, including
      cerebral diseases. A reduction of blood fluidity, due either to increase of
      hematocrit (polycythemic hyperviscosity) or of fibrinogen concentration
      (plasmatic hyperviscosity) or of red cell rigidity (sclerocythemic
      hyperviscosity) is commonly considered a condition of high risk for acute or
      chronic brain ischemia. So many attempts have been made for improving blood
      fluidity with the purpose to prevent stroke and to delay cerebral deterioration
      in chronic condition. This paper will present a review of the literature on this
      subject and the personal experience of our research group with the use of
      hemodilution, plasmapheresis and pharmacological agents. In our opinion the
      possible correction of hyperviscosity is very helpful in the prevention of acute
      ischemic attacks and in the reduction of their incidence in chronic cerebral
      ischemia. During the acute phase of stroke, hemorheological disturbance is only a
      part of the complex hemodynamic situation: a primary blood hyperviscosity can
      favor the onset of the disease but, because of its secondary increase after
      stroke, a vicious circle might be set in motion resulting in a further reduction
      of blood supply to the brain. Considering this, attempts in improving blood
      fluidity during stroke could be made, but with the caution that is required in
      this complicated "circulatory storm".

PMID- 10399644
TI  - [Biomechanical study of the vasomotor system of the arterial smooth muscle after
      long-term cryopreservation of a human arterial graft at two different
      temperatures -80 and -150C].
AB  - We conducted two parallel studies on cryopreserved arterial homografts: a
      biomechanical study based on traction tests and a functional study coupled with a
      histology examination. Twenty-four arterial segments from 6 donors (2 iliac and 2
      superficial femoral segments per donor) were cryopreserved at -150 degrees C and 
      80 degrees C. Cryopreservation lasted at least 6 months. Lengthening at rupture,
      the Young elasticity module, and rupture stress were calculated from the traction
      test. Results were significantly different depending on the preservation
      temperature. The functional properties of the cryopreserved arterial grafts were
      evaluated by studying the vasomotricity capacity of the vascular smooth muscle
      (VSM) and the endothelium. The expected results (direct contracture of VSM
      induced by PHE and endothelial dependent relaxation of VSM induced by ACH) were
      measured on fresh arteries. Cryopreserved arteries showed no response to
      physiological doses of PHE and ACH, whatever the preservation temperature. In one
      third of the cases, a lower amplitude vasoconstriction was obtained using
      nonphysiological doses of PHE; there was no relaxation with ACH.

PMID- 10399645
TI  - [Fate of the competence of the valvular apparatus of the femoral veins after
      cryopreservation. Preliminary study].
AB  - PURPOSE: The aim of this study was to determine the impact of cryopreservation on
      the competency of human femoral vein valve. MATERIALS AND METHODS: Nine
      superficial femoral veins bearing 24 valves were harvested in brain death
      patients (5 men, mean age 32 years, range 16 to 63 years). Veins were divided in
      24 segments bearing only one valve. Each segments was tested for reflux by using
      a pressure column filled with heparinized saline. After harvest, vein segments
      were kept in Belzer solution with antibiotics (gentamycin, colistin, lincomycin
      and amphotericin B). Histological study was undertaken in a fresh valve segment
      (n = 9). The remaining segments (n = 15) were stored in 15% dimethyl sulfoxide
      (DMSO) and cryopreserved in liquid nitrogen vapor for 120 days. Afterwards the 15
      cryopreserved vein segments were thawed in 37 degrees C water bath and were
      studied for mechanical and histological changes. RESULTS: All the 24 valve
      segments initially tested were competent. Off the 15 cryopreserved segments only
      4 (26%) were found to be non refluxive after cryopreservation. Histological study
      performed before cryopreservation showed a normal appearance of the vein wall (n
      = 9). On the contrary after cryopreservation, microscopic examination showed that
      in the incompetent veins, the endothelium surface was either absent or poor with
      a marked decrease in elastic fibres. CONCLUSION: This preliminary study indicates
      that DMSO cryopreservation must be improved in order to preserve vein valve
      competency: 26% of the cryopreserved valves remained competent. Histological
      findings also suggest that elastic fibres play a major role in the failure of the
      vein competency.

PMID- 10399646
TI  - [Calf muscle venous thrombosis and pulmonary embolism].
AB  - INTRODUCTION: The clinical significance of calf muscle venous thrombosis (CMVT)
      still remains a matter of debate. Detected by ultrasonography, they are
      overlooked by venography. This prompted us to evaluate the frequency of such
      localizations and their association to pulmonary embolism (PE). METHODS:
      Retrospective review of our database over a three-year period. All patients with
      an isolated CMVT were included. RESULTS: Isolated CMVT were detected in 106
      patients (mean age 68.6 years; 65% women), that is 12.5% of all venous thromboses
      diagnosed in the vascular sonography unit over the study period Sixteen
      associated PE were detected (15%). CONCLUSIONS: Association of CMVT and PE is not
      infrequent. Whether or not such thromboses have the potential to extend into deep
      veins and/or to migrate into pulmonary circulation requires further studies.

PMID- 10399647
TI  - [Infection and angiomatous cutaneous lesions].
AB  - The occurrence of angiomatous cutaneous lesions in the presence of an infective
      process is not a frequent phenomenon. Most infectious diseases are associated
      with an exanthematous reaction. The combination of an infective illness and
      angiomatous lesions is seen essentially in the bartonelloses and in Kaposi's
      disease. Bartonelloses: group of infections due to alpha-proteobacteria such as
      Bartonella. Bartonella bacilliformis (BB), is the causal agent of Carrion's
      disease, the chronic cutaneous form of which (verruga peruana), in which the
      vector is an arthropod of the Lutzomyia species found in South America, presents
      superficial and deep angiomatous cutaneous nodules. Spontaneous regression occurs
      in a few months or years. Bartonella henselae (BH) and Bartonella quintana (BQ),
      are the causal agents of bacillary angiomatosis (BA), described in 1983, in which
      angiomatous papules or nodules with an appearance like botryomycomas, are
      associated with visceral lesions. The characteristic histological features (with
      the demonstration or the bacilli by Warthin-Starry stain) together with culture
      of the bacterium in various tissues (including the blood) are diagnostic. BA
      occurs most commonly, but not exclusively, in patients with HIV infection.
      Furthermore, BH is responsible for cat scratch disease while BQ causes trench
      fever. The reservoir of BH is the cat. The bartonella produce angiogenic factors
      responsible for the neovascularisation seen in angiomatous lesions. The
      differential diagnosis is between botryomycomas and Kaposi's disease. Numerous
      antibiotics are effective against botryomycomas, particularly chloramphenicol and
      penicillin for BB and macrolides, cyclins and fluoroquinolones for BH and BQ.
      Kaposi's disease (KD): whether classical, endemic or epidemic (due to HIV
      infection) is characterised by cutaneous and visceral angiomatous lesions: these
      are associated with multifocal tumorous proliferations (of endothelial and
      fusiform cells) affected by angiogenic growth factors (PDGF, FGF, IL6, alphaTGF,
      HIVtat, androgens) and strongly linked to the lymphocytic and endothelial tropism
      of a gamma herpes virus (HHV8, Chang and Moore 1994). HHV8 infection, probably
      sexually transmitted, is also the cause of lymphomas occurring in cavities and of
      Castleman's disease. The course of KD is very variable: from the indolent form in
      elderly HIV-ve patients, to the explosive forms in the immunodepressed
      (particularly in HIV+ve patients.

PMID- 10399648
TI  - [Osteo-neuro-meningeal-lumbosacral involvement in Marfan syndrome. Report of a
      case].
AB  - Marfan syndrome is an hereditary condition which primarily affects conjunctive
      tissue with predominant vascular lesions, aortic insufficiency and aortic
      dissection which condition vital prognosis. Until further progress is made in the
      genetic determination of the disease, the diagnosis is currently based on the
      association of clinical criteria, which enables multidisciplinary management.
      This approach should lead to specific medical and surgical treatment--which may
      reduce Marfan morbidity and mortality. We report the case of a 45 year-old
      patient with suspected Marfan syndrome during adolescence. The presence of a
      cardiovascular lesion and a recently reported abnormality i.e. a sacral erosion
      by a dural ectasia, enabled us to confirm the diagnosis. We reviewed the current
      criteria in Marfan diagnosis and their specific management.

PMID- 10399649
TI  - [Vascular exploration of erectile dysfunction].
AB  - INTRODUCTION: Since its development echo-Doppler investigation has become the
      mainstay in the diagnosis of vascular impotence. This paper reviews its present
      use. METHOD: Personal experience and a review of the literature form the basis of
      a critical analysis of this investigation. RESULTS: The standardised technique
      proposed by the AA for the echo-Doppler investigation of impotence includes:
      Doppler examination of the dorsal and deep arteries of the penis; a
      pharmacological test with volume measurements and direct examination of the
      penile arteries by pulsed echo-Doppler. Future developments will allow venous
      exploration (of the deep vein of the penis); power Doppler examination of the 2nd
      and 3rd degree arteries of the penis. CONCLUSIONS: There is no present consensus.
      The arterial inflow, caverno-venous retention and overall size of the erection,
      can be quantified.

PMID- 10399651
TI  - Assessing community attitude towards home-based care for people with AIDS (PWAs)
      in Kenya.
AB  - This paper presents data on an assessment of community attitudes toward HIV/AIDS
      and home based care. The findings indicate that due to inadequate information
      about the disease and care expectations, people were ambivalent toward the sick
      and in some instances out-right rejection prevailed. This formed the basis for
      their preference for institutional based care as opposed to home based care. This
      was further compounded by the economic status of the household/family. Sheer
      poverty militates against providing adequate home care in as much as families may
      be willing to do so. It also confirms that one may perhaps be too taken in by the
      romanticized idea of unswerving community support. This may further relegate the
      burden to the primary unit, the family and especially the women who ultimately
      carry the load with limited resources. This emphasizes the need to initially
      share the issue with the community in order to work out the mechanisms that will
      lessen the burden of, and facilitate home care. Training in the care of AIDS
      patients is crucial yet lacking at the family and community level. Whereas care,
      counseling and social support are particularly important prerequisites for home
      based care, these were conspicuously lacking. Very few caregivers had appropriate
      training and were worried about their lack of knowledge and yet they had to care
      for patients. It was evident that they lacked a framework that would provide the
      capacity to facilitate home care. Such a framework would bridge the gap between
      the noble concept of home-based care and the realities of home based care.

PMID- 10399650
TI  - Understanding the use of a community-based drive-home service after alcohol
      consumption among young adults.
AB  - To know and understand the intention of young adults to use, during the Christmas
      and New Year's period, the community drive-home service after drinking alcohol,
      that is, to phone for oneself when they are the driver or when they are the
      passenger to suggest to a friend who is the driver to phone for the service. This
      study was conducted in the Province of Quebec, Canada, among a representative
      sample of 544 young adults aged 18 to 24 years. Self-administered questionnaires
      were completed by mail. Young adults showed a very good knowledge of the drive
      home service and had a very positive attitude toward its use. Among those who
      reported having experienced drinking too much alcohol during the Christmas and
      New Year's period, 17 percent had phoned when they were the driver and 36 percent
      had, when they were a passenger, suggested to a friend who was the driver to
      phone the community drive-home service. Nonetheless, more than half of them
      intended to use or to recommend its use to a friend in the future. Several
      factors identified in this study might be useful for increasing this drive-home
      service and therefore, contribute to lowering the risk of injury related to
      alcohol-impaired driving among young adults.

PMID- 10399652
TI  - Linking clients from HIV antibody counseling and testing to prevention services.
AB  - The effectiveness of HIV antibody counseling and testing as a prevention
      intervention is limited: persons testing seronegative do not usually change their
      risk behaviors, some actually increase their risk behaviors, and decreases in
      risk behaviors are usually short-lived. Referrals to additional prevention and
      other needed services are therefore recommended, although the extent and
      determinants of referral provision for persons testing seronegative are unknown.
      We assessed the prevalence of referrals and the association between risk
      behaviors and prevention referrals among seronegatives. We reviewed HIV testing
      and referral data on all persons receiving confidential seronegative test results
      in San Francisco (SF) in the first 10 months of 1995 (n = 5,595), and gathered
      more detailed referral information at the municipal STD clinic from November 1995
      through May 1996 (n = 747). The overall prevalence of referrals was low: a
      referral was given to 19.1% of the SF sample and 10.6% of the STD clinic sample;
      15.4% of the SF sample and 5.9% of the STD clinic sample received a prevention
      referral. Injection drug users (IDUs) were the most likely to receive a
      prevention referral (48.5% of SF IDUs, 36.4% of STD clinic IDUs); men having sex
      with men and women with high-risk partners were also more likely to get a
      prevention referral than others. For SF IDUs, unsafe sex and needle sharing were
      not associated with an increased likelihood of receiving a prevention referral.
      Opportunities to link high-risk clients from counseling and testing to HIV
      prevention services are being missed. The referral component of HIV counseling
      and testing should be improved.

PMID- 10399654
TI  - Barriers and facilitators to providing common preventive screening services in
      managed care settings.
AB  - Despite increasing emphasis on disease prevention and health promotion, and ample
      evidence demonstrating the effectiveness of preventive services, such services
      are underutilized in the United States. The current trend of health care toward
      health maintenance organizations and other managed care systems opens the door,
      perhaps to more effective control of heart disease, cancers and other chronic
      diseases through preventive care. This warrants attention to the
      barriers/facilitators to the provision/utilization of preventive screening
      services in such settings. Overall goal of this study was to assess
      barriers/facilitators to the provision/utilization of preventive services in
      managed care organizations (MCOs). This was accomplished by a) identifying
      barriers/facilitators to the provision/utilization of three common preventive
      screening services (cholesterol screenings, mammograms, and Pap smears); and b)
      profiling typical MCO recipients of these three preventive screening services. A
      self-administered, mail questionnaire was used to obtain information from a
      national sample of 1,200 Directors of MCOs associated with preventive care. A
      total of 175 usable responses were received resulting in a 17.3 percent net
      response rate. The strongest barrier to the provision of all three screening
      services is the inability of them to generate short term savings for the MCO.
      Other barriers include high disenrollment rates, conflicting recommendations
      about effectiveness (for mammograms and cholesterol screenings), and patients'
      fears of getting a positive result (for mammograms and Pap smears). The improved
      health status as a result of early intervention, high consumer awareness (for
      mammograms and Pap smears), and long term savings are important facilitators to
      the provision/utilization of these screening services. Comparing barriers and
      facilitators across the three services shows the stronger barriers affecting the
      provision/utilization of mammograms. For all three screening services, typical
      managed care recipients are those in the high income groups with greater
      education levels. However, with the increasing enrollment of Medicaid
      beneficiaries into managed care, MCOs may find themselves selectively targeting
      these high risk low income and less educated individuals to receive the
      preventive screening services. Study findings should be useful to health
      planners, policymakers and researchers at all levels in their efforts to
      encourage and promote healthier lifestyle choices among U.S. residents. Future
      studies should address receipt of preventive services by Medicaid and Medicare
      beneficiaries in managed care settings.

PMID- 10399653
TI  - Reasons for testing and exposure sources among women of childbearing age with
      moderate blood lead levels.
AB  - The purpose of this study was to examine the circumstances under which women
      receive blood lead tests in New York State and to characterize the sources of
      lead exposure among women of childbearing age with moderate blood lead levels.
      Telephone interviews were conducted with 135 women between the ages of 18 and 45,
      with blood lead levels from 10 through 25 micrograms/dl, were used to collect
      information on the reason for their blood lead test and possible sources of lead
      exposure. It was found that the two most common reasons to be tested for blood
      lead were workplace screening (47%) and pregnancy (27%). Occupational exposure
      was the primary source of lead exposure in this population (46%). Another common
      source of lead exposure was home renovation (24%). A significant proportion (31%)
      of women with blood lead levels from 10 through 25 micrograms/dl had no known
      current source of lead exposure. Based on New York's sample, there are a
      significant number of women of reproductive age with potentially fetotoxic blood
      lead levels.

PMID- 10399655
TI  - Acute aortic endocarditis with annular destruction: assessment of surgical
      treatment with cryopreserved valvular homografts.
AB  - BACKGROUND AND AIM OF THE STUDY: Valve ring abscesses in acute infective aortic
      endocarditis have a low, though not insignificant, prevalence. Surgical treatment
      with implantation of prosthetic valves may lead to major life-threatening
      complications, such as recurrent endocarditis and partial or complete prosthetic
      dislocation. Valvular homografts may offer a higher resistance to recurrent
      infection and have thus become recognized as an excellent and safe substitute for
      orthotopic left ventricular outflow reconstruction. METHODS: Between May 1991 and
      July 1996, 25 patients underwent surgical treatment for aortic endocarditis with
      annular destruction. Staphylococcus spp. were present in 32% of patients and
      Streptococcus spp. in 48%. Seven aortic valve replacements (AVR) and 18 aortic
      root replacements (ARR) were performed using cryopreserved valvular homografts.
      All grafts were implanted in the subannular position. RESULTS: The overall
      outcome was good in 23 patients, two died in the early postoperative period. Mean
      follow up was 38 +/- 18 months (range: 14 to 76 months). No recurrence of
      endocarditis was detected and no significant alterations of the implants were
      described. Transvalvular gradients were significantly lower in ARR patients than
      in AVR patients. CONCLUSIONS: Despite the severity of the tissue damage,
      cryopreserved homografts, when implanted in the subannular position, constitute a
      safe and reproducible surgical treatment of aortic endocarditis with annular
      involvement.

PMID- 10399656
TI  - The influence of sizing on the dynamic function of the free-hand implanted
      porcine aortic homograft: an in vitro study.
AB  - BACKGROUND AND AIMS OF THE STUDY: The influence of sizing on the function of a
      porcine aortic valve after its implantation using the free-hand technique in the
      subcoronary position was investigated. METHODS: Dynamic function and leaflet
      configuration of the valve (n = 16) were first analyzed in its natural aortic
      root in a left heart simulator at 120/80 mmHg pressure and 4 l/min cardiac
      output. The valve was then implanted in the recipient porcine aortic root and re
      studied. Three groups were investigated: group I (n = 4) comprised of 1-2 mm
      smaller donor aortic valve than the recipient; group II (n = 8) 3-4 mm smaller;
      and group III (n = 4) 5-7 mm smaller. Orifice area (OA), systolic and diastolic
      configurations of the leaflets, pattern and timing of leaflet opening and
      closure, commissural movement, pressure gradient and valvular regurgitation were
      analyzed. RESULTS: In the intact donor aortic root, average expansion of the
      aorta at the commissures, for a pressure change from 0 to 80 mmHg, was about 42%.
      This was reduced significantly in all assemblies. Group I showed a 34% reduction
      in OA, and excessive leaflet bending; there was no aortic insufficiency (AI) or
      pressure gradient across the valve. In group III there was a lesser reduction in
      OA and reduced leaflet bending, but two of four valves had AI. In group II, the
      reduction in OA was only 13%, there was less leaflet bending, and no AI.
      CONCLUSIONS: The donor valve 3-4 mm smaller than the recipient seems an optimal
      match. The current practice of using the same size donor as recipient may be
      responsible for excessive leaflet bending and may be implicated in early
      deterioration of the homograft.

PMID- 10399657
TI  - Identification and characterization of calcifying valve cells from human and
      canine aortic valves.
AB  - BACKGROUND AND AIM OF THE STUDY: Cardiac valve calcification is the predominant
      pathology in patients needing valve replacement. The aim of this study was to
      determine if aortic valve cells calcify spontaneously and, if so, to characterize
      the nodular complex and response to growth factors. METHODS: Aortic valves were
      obtained from humans undergoing surgical valve replacement, and from female dogs.
      The valvular endothelium was removed and explants cultured in medium. RESULTS: A
      population of valvular interstitial cells spontaneously formed distinct calcified
      nodules containing hydroxyapatite within two to three weeks in canine and within
      six weeks in human aortic valves. The nodules contained an inner ring of dead
      cells surrounded by an outer ring of living cells. Cells associated with nodules
      had osteoblast-like characteristics and stained positively for extracellular bone
      matrix proteins. Incubating canine cells with potential calcifying stimuli tested
      the stimulus for calcification. The rate of nodule formation was increased with
      transforming growth factor beta-1 (+25 nodules), 25-hydroxycholesterol (+9
      nodules) and bone morphogenetic protein 2 (+4 nodules) as compared with vehicle
      control (+3 nodules) over 25 days. CONCLUSIONS: We identified a population of
      valvular interstitial cells with osteoblast-like characteristics that
      spontaneously form calcific nodules in cell culture. In addition, the rate of
      calcific nodule formation was increased with transforming growth factor beta-1
      and 25-hydroxycholesterol. Further study of these 'calcifying valve cells' may
      yield a new in vitro model for testing therapy aimed at preventing calcific valve
      stenosis.

PMID- 10399658
TI  - Doppler echocardiographic evaluation of right ventricular diastolic function in
      isolated valvular aortic stenosis.
AB  - BACKGROUND AND AIM OF THE STUDY: Left ventricular diastolic function (LVDF) in
      patients with aortic stenosis (AS) has been adequately studied, in contrast to
      right ventricular diastolic function (RVDF). In this study, RVDF in patients with
      AS was evaluated using pulsed-wave Doppler echocardiography. METHODS: The study
      population comprised 20 patients with isolated AS (mean age 53.7 +/- 6.5 years)
      and 20 healthy volunteers (control group, mean age 52.6 +/- 8.8 years). The
      diastolic indices of right ventricular (RV) function were calculated using
      transtricuspid and transpulmonary Doppler flow velocities. Statistical analysis
      was performed using Student's t-test. There was no statistically significant
      difference between patients and controls with regard to age, height, bodyweight,
      heart rate, systolic and diastolic blood pressures, end-diastolic and end
      systolic left ventricular (LV) diameter, LV fractional shortening and RV end
      diastolic diameter. RESULTS: RV diastolic indices in patients (versus controls)
      were as follows: E/A ratio of transtricuspid flow waves was significantly lower
      (0.88 +/- 0.20 versus 1.25 +/- 0.33, p < 0.001); deceleration time of E wave was
      significantly longer (184 +/- 3 versus 127 +/- 3 ms, p < 0.001); atrial filling
      fraction was significantly augmented (43.1 +/- 7.7 versus 33.6 +/- 7.6%, p <
      0.001); and isovolumic relaxation time was significantly prolonged (116 +/- 73
      versus 31 +/- 15 ms, p < 0.001). There was no statistically significant
      correlation between diastolic indices and interventricular septum thickness and
      LV mass index. CONCLUSIONS: RVDF in AS patients is impaired, reflecting abnormal
      relaxation.

PMID- 10399659
TI  - The quality of life after aortic valve replacement with homografts or prosthetic
      valves.
AB  - BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the quality of
      life in patients after homograft or prosthetic aortic valve implantation.
      Evaluation was based on clinical and echocardiographic examinations, and on
      analysis of data from patient questionnaires. METHODS: Patients undergoing either
      homograft (HV, n = 220) or prosthetic (PV, n = 220) aortic valve replacement were
      investigated. The patients groups were similar in age, sex, follow up period,
      risk factors and type of heart defect, and did not demonstrate any dysfunction of
      the replacement valve. RESULTS: During both pre- and postoperative periods, no
      significant inter-group differences were identified with regard to the occurrence
      of retrosternal pain, dyspnea, palpitation, fear reaction and circulatory
      efficiency based on NYHA classification, and self-evaluation of physical activity
      assessed by patient questionnaires. The majority of patients in both groups
      noticed on increase in their quality of life and physical activity. The reduced
      sexual activity (50%) and fear reaction (30%) in both groups did not correlate
      with their improved sense of well-being. Up to 14.6% of PV patients did not
      accept the implanted valve, and 65 (29.5%) would have preferred an HV, despite
      the need for reoperation. Following surgery, 21% of HV patients resumed work,
      compared with only 7.7% of PV patients. The frequency of claims for disability
      pension after surgery did not correlate with the considerate clinical and
      subjective improvement. CONCLUSIONS: In patients receiving either homograft or
      prosthetic valves, the subjective evaluation of life quality is comparable with
      the clinical evaluation, though the homograft valve was better accepted than its
      prosthetic counterpart.

PMID- 10399660
TI  - Can high blood pressure mask severe aortic stenosis?

PMID- 10399661
TI  - Transaortic gradient is pressure-dependent in a pulsatile model of the
      circulation.
AB  - BACKGROUND AND AIM OF THE STUDY: Although the transvalvular gradient is described
      as flow-dependent, pressure-dependence of the gradient, irrespective of flow, has
      not been demonstrated. METHODS: The Sheffield pulse duplicator equipped with a X
      Cell 21 porcine valve mounted in the aortic position was used. Transaortic
      gradient was measured at a constant rate of 80 beats/min, while flow was kept at
      2, 5 or 8 l/min, and systemic pressure was increased up to 200 mmHg by adjusting
      peripheral resistance manually. Valve area was computed with the Gorlin formula.
      A total of 87 measurements was carried out. RESULTS: For each flow, transvalvular
      gradient increased linearly with pressure, and computed area decreased. The slope
      of the pressure-gradient relationship was independent of flow. CONCLUSION:
      Transaortic gradient depends not only on flow, but also shows pressure-dependency
      that should be taken into account when evaluating aortic stenosis, especially in
      hypertensive and hypotensive states.

PMID- 10399662
TI  - Congenital aortic insufficiency due to aortic cusp stretching: 'kite anomaly'.
AB  - Aortic insufficiency may be either acquired or congenital. A 46-year-old male had
      a congenital pathology which resulted in aortic insufficiency due to the presence
      of a fibrous band that stretched from the non-coronary cusp to the aortic wall.
      The patient underwent successful aortic valve replacement. At surgery, the
      fibrous band was stretching the non-coronary cusp so that it prevented coaptation
      of the aortic valve. The situation was termed by us as the 'kite anomaly'.

PMID- 10399663
TI  - Intraoperative transesophageal echocardiography for evaluation of mitral valve
      repair.
AB  - BACKGROUND AND AIM OF THE STUDY: Although mitral valve repair is a well
      established procedure, incorrect assessment of the repaired valve may
      occasionally lead to the need for reoperation. This study was performed to
      evaluate the accuracy of color Doppler in assessing the competence of the
      repaired mitral valve. METHODS: Transesophageal echocardiography (TEE) and left
      ventriculography were each performed in 72 patients to compare the two techniques
      and a semi-quantitative index derived. Using this relationship, post bypass
      intraoperative TEE was then performed in 34 patients who underwent mitral valve
      repair, in order to assess the competence of the repaired valve. RESULTS:
      Significant differences were apparent in maximal regurgitant mosaic area between
      angiographic grade 0, and grades 1+ (p = 0.0006), 1+ and 2+ (p < 0.0001) and 2+
      and 3+ (p = 0.0010). A maximal regurgitant area < 2 cm2 predicted angiographic
      grade as 0 (sensitivity 100%, specificity 95%), an area of 2-4 cm2 as 1+
      (sensitivity 82%, specificity 100%), an area of 4-7 cm2 as 2+ (sensitivity 78%,
      specificity 90%), and an area > 7 cm2 as grade 3+ or 4+ (sensitivity 79%,
      specificity 93%). All 34 patients completed valve repair with the maximal
      regurgitant mosaic area < 2.5 cm2. Postoperative left ventriculography showed
      grade +1 in only five patients; four of these completed mitral valve repair with
      a maximal mosaic area > 2.0 cm2 as assessed by post bypass intraoperative TEE.
      During follow up, transthoracic echocardiography (TTE) detected recurrent mitral
      regurgitation which required mitral valve replacement in one patient, and rapid
      progression of mitral regurgitation in three patients. CONCLUSIONS: It is
      important that mitral valve repair should be completed with a maximal mosaic area
      < 2.0 cm2 as assessed by intraoperative TEE, in order to reduce the need for
      reoperation.

PMID- 10399664
TI  - Mitral valve compensation for annular dilatation: in vitro study into the
      mechanisms of functional mitral regurgitation with an adjustable annulus model.
AB  - BACKGROUND AND AIM OF THE STUDY: Mitral annulus dilatation has been identified as
      an important factor in functional mitral regurgitation (FMR). However, the
      pathophysiologic interaction of annular dilatation and papillary muscle (PM)
      displacement in FMR, which occurs clinically in left ventricular (LV) dilatation,
      is still not well understood. It is difficult to separate these competing factors
      in vivo, leading to confusion in identifying the real role of the annular
      dilatation in FMR and its interaction with PM displacement. METHODS: To better
      understand the competing factors, an in vitro model was developed with a D-shaped
      adjustable mitral annulus that could be changed from 5.5 cm2 to 13.0 cm2 during
      experiments, independent of varying PM positions. Six excised normal porcine
      mitral valves were mounted in a left ventricular model with the adjustable
      annulus device and tested in a physiologic pulsatile flow system under normal
      cardiac output and left ventricular pressure (5.0 l/min, 120 mmHg). Papillary
      muscles were placed in normal and then displaced to an apical posterolateral
      position, to simulate pathological conditions seen clinically. Regurgitation was
      measured directly by a flow probe and the mitral valve geometry and leaflet
      coaptation were recorded by video camera through the model's atrium window. In
      addition, 2D echocardiography was used to evaluate leaflet coaptation and color
      Doppler flow mapping to detect the regurgitant flow field. RESULTS: The results
      showed that in normal PM position, the mitral regurgitant was consistently at low
      level until the annulus was enlarged to 1.75 times the normal size, at which time
      it increased sharply. Papillary muscle apical posterolateral displacement, which
      simulates a dilated LV, caused regurgitation to occur earlier (1.5 times the
      normal annulus size), and had an increased regurgitant volume (p < 0.05). The
      leaflet gaps were first observed at the commissural areas of the valves,
      consistent with the location of regurgitant jets detected by color Doppler flow
      mapping. Asymmetric PM displacement created more regurgitation than both the
      symmetric PM tethering (p = 0.063) and normal PM position (p < 0.01). The
      regurgitant jets were observed at the same commissural side as the PM
      displacement, even without significant enlargement of the annulus. CONCLUSIONS:
      This in vitro study provides insight into the interaction between annular
      dilatation and PM displacement on FMR. The resulting effects and their overall
      similarity to clinical observation could help further understand the mechanism of
      FMR and provide additional information to improve future therapeutic strategies.

PMID- 10399665
TI  - Collapse and massive pulmonary edema secondary to thrombosis of a mitral
      mechanical heart valve prosthesis during low-molecular weight heparin therapy.
AB  - Mechanical heart valves (MHV) are particularly exposed to thrombosis if
      anticoagulation becomes ineffective. Thromboembolic complications may be avoided
      by oral anticoagulation with vitamin K antagonists or derivatives of
      unfractionated heparin. A few cases of low-molecular weight heparin (LMWH) as
      sole anticoagulant in patients with MHV have been published, though with
      contradictory results. We report a case of a massive thrombosis of a St. Jude
      Medical mitral valve after the patient had been treated for one month with
      calcium nadroparin (Fraxiparine).

PMID- 10399666
TI  - The left ventricle and the low stroke volume: the biter bit?

PMID- 10399667
TI  - Pulmonary stenosis and severe biventricular dysfunction: improvement following
      percutaneous valvuloplasty.
AB  - A 15-year-old boy with severe pulmonary stenosis associated with severe right and
      left ventricular systolic dysfunction is reported. After successful percutaneous
      pulmonary valvuloplasty, there was an initial and early improvement in right
      ventricular (RV) function, followed by a delayed and more gradual improvement in
      left ventricular (LV) function. At long-term follow up, both RV and LV systolic
      functions were nearly normalized. Several mechanisms may be implicated, including
      ventricular interdependence, geometric factors, altered compliance and intrinsic
      alteration in the LV muscle. A delayed, but sustained, improvement in LV systolic
      function following relief of RV pressure overload suggests that the latter
      mechanism must have played an important role in the genesis of the LV
      dysfunction. Pulmonary stenosis associated with severe biventricular dysfunction
      may be treated primarily by percutaneous pulmonary balloon valvuloplasty with
      near-total recovery of the ventricular function.

PMID- 10399668
TI  - Leakage flow at mechanical heart valve prostheses: improved washout or increased
      blood damage?
AB  - BACKGROUND AND AIMS OF THE STUDY: An essential problem of mechanical heart valve
      (MHV) prostheses is the risk of thromboembolic events and consequent need of
      lifetime anticoagulation due to unnatural hemodynamics that results in
      traumatization of red blood cells and platelets. The precise spatial and tidal
      localization of blood-damaging events within the flow is poorly understood. The
      present study addresses the question whether leakage flow at MHV, which is
      claimed to improve washout in the hinge areas of microthrombi and platelet
      activating agents, is responsible for significant blood damage. METHODS: This
      study investigated leakage flow in vitro, primarily within turbulent leakage jets
      of currently used mechanical valves. St. Jude Medical, Sorin Bicarbon, Duromedics
      Edwards and CarboMedics valves were analyzed in the mitral position of a
      circulatory mock loop. Jet configuration was determined by echocardiography;
      velocity and shear stress distributions within jets were measured using laser
      Doppler anemometry (LDA). A blood damage index (BDI) was developed in terms of
      lactate dehydrogenase release by platelets and hemoglobin release by red blood
      cells (RBC), as a function of exposure time and shear stresses within the flow
      field. BDIs were validated by direct measurement of hemolysis caused by leakage
      flow, using porcine blood. RESULTS: All valves showed characteristic and
      reproducible jet patterns, mainly emerging from the hinge areas. Maximum
      velocities up to 1.7 m/s were measured. Maximum turbulent shear stresses > 80 Pa
      were found. The investigated MHV revealed significant differences in calculated
      BDIs. The Sorin Bicarbon had a significantly lower BDI for RBC damage, as well as
      for platelet damage; this was validated by direct hemolysis measurements.
      CONCLUSIONS: The relevance of the leakage-induced blood damage was demonstrated
      from a literature investigation of hemolysis as a function of valve type and
      implant position.

PMID- 10399669
TI  - Thrombogenicity of polyethylene oxide-bonded Dacron sewing ring in a mechanical
      heart valve.
AB  - BACKGROUND AND AIM OF THE STUDY: The aim of the study was to evaluate the effect
      of binding hydrophilic polyethylene oxide (PEO) onto Dacron fibers in the sewing
      ring of a mechanical heart valve (MHV), in terms of thrombogenicity of the
      prosthesis. METHODS: The study was performed in blinded fashion. Six Yorkshire
      cross pigs (bodyweight 35-45 kg) were implanted with MHVs, in the mitral annulus,
      with the PEO-treated sewing ring. An additional five pigs implanted with
      identical MHVs, but with untreated sewing rings, served as controls. PEO of chain
      length 10,000 Da was grafted to Dacron fibers using gamma irradiation. PEO-bonded
      Dacron fibers (diameter 100 microns) were used to weave the sewing ring, which
      was then assembled on a titanium stent (OD 25 mm). Autologous platelets were
      labeled with 111In-tropolone and injected intravenously (850-1250 microCi per
      injection) into the pigs on removal from cardiopulmonary bypass (CPB). At 20-24 h
      after surgery, platelet thrombi adherent to MHV components, and shed emboli
      trapped in the brain, lung, heart, kidneys and other organs/connective tissues
      were imaged using a gamma camera. The animals were killed and the amounts of
      thrombi adherent to MHV components and organ-trapped emboli quantified using an
      ionization chamber and gamma counter. RESULTS: There was no statistically
      significant difference in the adhesion of 111In-labeled platelets to either
      control sewing rings (0.08 +/- 0.06% dose) or PEO-treated rings (0.19 +/- 0.21%
      dose). The thrombogenicity of MHV components in both animal groups was in the
      ascending order: Dacron ring > Teflon pledgets > polypropylene sutures > titanium
      housing > pyrolytic carbon. The number of platelet-emboli trapped in the organs
      was not significantly different between the two groups. CONCLUSIONS: Simple
      modifications may not reduce platelet thrombosis or wound-healing of the sewing
      ring in the acute phase, at which time several complex processes are activating
      and inactivating platelets and coagulant factors during CPB and implantation of
      MHVs.

PMID- 10399670
TI  - Polymer heart valves.
AB  - Since the introduction of valve replacement surgery, research has aimed at
      creating a prosthesis that is safe, durable and effective. Neither of the two
      broad groups of valve currently available is ideal. A prosthetic valve is needed
      that does not suffer from the known disadvantages of calcification and premature
      failure (bioprostheses), and thrombogenicity (mechanical valves). Much progress
      has been made, both in design and materials, and an extensive range of polymer
      valves has been produced and tested both in vitro and in vivo. Unfortunately,
      each stage of development has encountered problems preventing successful clinical
      application. Many design difficulties have been addressed and potentially reduced
      to acceptable levels, but calcification remains a problem, although much less so
      than with bioprostheses. New developments in surface modification may hold the
      key to the elimination of thrombus and calcification, and early in vivo results
      are promising. It is likely that an effective and safe polymer valve will soon
      become a third clinical option. The historic aspects behind the development of
      polymer valves and the current state of research and evaluation are discussed.

PMID- 10399671
TI  - Technique of mitral valve replacement with the Monostrut prosthesis preserving
      the posterior leaflet.
AB  - BACKGROUND AND AIM OF THE STUDY: Techniques of mitral valve replacement with
      leaflet and chordal preservation normally involve the use of a bioprosthesis or
      bileaflet valve to reduce the risk of obstruction of the prosthesis by the
      retained subvalvular apparatus. METHODS: The technique of mitral valve
      replacement with the Monostrut prosthesis and with preservation of the posterior
      leaflet is described. The stitches are placed in such a manner that the posterior
      leaflet is folded under the posterior aspect of the prosthetic ring. RESULTS AND
      CONCLUSIONS: The technique allows safe implantation of the Monostrut valve. The
      excellent performance of this prosthesis can be therefore combined with the
      beneficial effects of chordal preservation on left ventricular function.

PMID- 10399672
TI  - Reconstruction of the mitral and aortic annuli for advanced management of the
      Shone complex.
AB  - Shone's complex is a congenital cardiac abnormality which consists of
      surpravalvular mitral ring, parachute mitral valve, subaortic stenosis and aortic
      coarctation. Initial operative management has traditionally proven difficult,
      with multiple procedures often necessary to control symptoms. Advanced management
      had required a careful, individual approach based on both clinical and anatomic
      patient presentation. We present the first patient in whom mitral and aortic
      annular reconstruction with bovine pericardial gussets was successful in managing
      the late sequelae of Shone complex.

PMID- 10399673
TI  - In response to: In vivo efficacy of silver-coated (Sil-zone) infection-resistant
      polyester fabric against a biofilm-producing bacteria, Staphylococcus
      epidermidis. J Heart Valve Disease; 1998;7:524-530.

PMID- 10399674
TI  - Adenosine-angiotensin II interactions in pentylenetetrazol seizure threshold in
      mice.
AB  - The effects of adenosinergic and angiotensin IIergic agents and of their
      combinations on the seizure threshold in mice were determined by measuring the
      dose of timed-intravenous (tail vein) infused pentylenetetrazol (PTZ) required to
      elicit clonic seizures. All drugs were administered intracerebroventricularly
      (i.c.v.). Angiotensin II (ANG II), its peptide analogue sarmesin, the selective
      adenosine A1 receptor agonists N6-cyclopentyladenosine (CPA) and 2
      chloroadenosine (2-ClAdo) significantly increased the PTZ seizure threshold. The
      selective AT1 receptor antagonist losartan blocked the anticonvulsant effect of
      ANG II, sarmesin and CPA. The selective AT2 receptor antagonist PD 123319 failed
      to block the effect of ANG II and sarmesin on the PTZ seizure threshold but
      reversed the threshold-increasing effect of CPA. The selective adenosine A1
      receptor antagonist 8-(p-sulfophenyl)-theophylline (8-p-SPT) alleviated the
      threshold-increasing effect of CPA and ANG II. Concurrent injection of 2-ClAdo
      and ANG II as well as of 2-ClAdo and sarmesin, at doses which had no significant
      effect on the PTZ seizure threshold when given alone, acted synergistically,
      producing greater effect on the threshold. Taken together, the findings support
      the possibility of specific ANG II-adenosine A1 receptor interactions in the
      regulation of the PTZ seizure threshold.

PMID- 10399675
TI  - Fictive hindlimb motor patterns evoked by AMPA and NMDA in turtle spinal cord
      hindlimb nerve preparations.
AB  - Application of the glutamate agonists alpha-amino-3-hydroxy-5-methyl-4
      isoxazoleproprionate (AMPA, 5-10 microM), or N-methyl-D-aspartate (NMDA, 50-100
      microM) to the turtle spinal cord produced fictive hindlimb motor patterns in low
      spinal immobilized animals (in vivo) and in isolated spinal cord-hindlimb nerve
      preparations (in vitro). For in vivo experiments, drugs were applied onto the
      dorsal surface of 2-4 adjacent spinal cord segments in and near the anterior
      hindlimb enlargement. Motor output was recorded unilaterally or bilaterally from
      hindlimb muscle nerves. AMPA elicited vigorous motor patterns in vivo that
      included strict hip flexor-extensor and right-left alternation. In most turtles,
      the monoarticular knee extensor nerve FT-KE was active during the HE phase of
      AMPA evoked burst cycles, similar to the timing of pocket scratch motor patterns.
      NMDA was less effective in vivo, typically producing only weak and irregular
      bursting from hip nerves and little or no knee extensor (KE) discharge. Sensory
      stimulation of a rostral scratch reflex in vivo could reset an ongoing AMPA
      evoked motor rhythm, indicating that cutaneous reflex pathways interact centrally
      with the chemically activated rhythm generator. Most in vitro preparations
      consisted of six segments of spinal cord, including the entire 5-segment hindlimb
      enlargement (D8-S2) and the segment immediately anterior to the enlargement (D7),
      with attached hindlimb nerves. In contrast to in vivo experiments, in vitro
      preparations exhibited highly regular, long-lasting motor rhythms when NMDA was
      superfused over the spinal cord. AMPA also produced rhythmic motor patterns in
      vitro, but these lasted only a few minutes before they were replaced with tonic
      discharge. FT-KE timing during in vitro chemically elicited activity was similar
      to that of sensory-evoked pocket scratch motor patterns. Some NMDA-evoked
      rhythmicity persisted even in 3-segment (D6-D8) and 1-segment (D8) in vitro
      preparations, demonstrating that neural mechanisms for chemically activated
      rhythmogenesis reside even in a single segment of the hindlimb enlargement.

PMID- 10399676
TI  - Protective effect of histidine on iron (II)-induced hydroxyl radical generation
      in rat hearts.
AB  - We investigated the efficacy of histidine on iron (II)-induced hydroxyl radical
      (.OH) generation in extracellular fluid of the rat myocardium using a flexibly
      mounted microdialysis technique (O system). Rats were anesthetized and a
      microdialysis probe was implanted in the left ventricular, followed by infusion
      of sodium salicylate in Ringer's solution (0.5 nmol/microL/min) to detect the
      generation .OH as reflected by the non-enzymatic formation of 2,3
      dihydroxybenzoic acid (DHBA). Iron (II) clearly produced a concentration
      dependent increase in .OH formation. A positive linear correlation between iron
      (II) and the formation of 2,3-DHBA (R2 = 0.987) was observed. However, histidine
      (25 mM) was infused through a microdialysis probe; iron (II) failed to increase
      the 2,3-DHBA formation obtained. To examine the effect of histidine on ischemia
      reperfusion of the myocardium, the heart was subjected to myocardial ischemia for
      15 min by occlusion of the left anterior descending coronary artery (LAD). When
      the heart was reperfused, a marked elevation of the levels of 2,3-DHBA was
      observed in the heart dialysate. When corresponding experiments were performed
      with histidine (25 mM)-pretreated animals, histidine prevented the ischemia
      reperfusion induced .OH generation trapped as 2,3-DHBA. These results indicate
      that histidine protects the myocardium against ischemia-reperfusion damage by .OH
      generation.

PMID- 10399677
TI  - Effects of peptide and non-peptide antagonists of angiotensin II receptors on
      drinking behavior in rats.
AB  - The effects of the non-peptide selective angiotensin II AT1 receptor antagonist
      DuP 753 and its metabolite EXP 3174, of the peptide ANGII analogues saralasin and
      sarmesin and of the newly synthesized imidazole compound (1-methyl-4,5
      diphenylimidazole) on ANGII-induced drinking in rats were investigated. The
      effect of the AT2 selective antagonist PD 123319 on ANGII-induced drinking in
      rats was also studied. DuP 753, EXP 3174, saralasin and sarmesin (peptides and
      non-peptides) dose-dependently inhibited ANGII-induced water intake. The ID50
      values of these drugs showed the following order of potency: EXP 3174 > saralasin
      > sarmesin > DuP 753 indicating their ability to block central AT1 receptors. The
      imidazole compound increased ANGII-induced water intake suggesting its AT1
      receptor agonistic properties. PD 123319 inhibited ANGII-induced water intake at
      a higher dose (64 nmol), allowing to assume AT1 receptor agonistic properties.

PMID- 10399678
TI  - Olfactory memory in rats, cholinergic agents and benzodiazepine receptor ligands.
AB  - Drugs and their effects on olfactory learning processes in rats were tested using
      a modified version of the runway apparatus developed by Ades. Rats were first
      exposed to a conspecific urine sample and 24 h later were exposed to the same
      stimulus in the runway. Observations recorded the time spent investigating the
      urine and the number of sniffs at the site, these being considered to be indices
      of memory. Diazepam-treated rats (4 or 6 mg/kg) and scopolamine-treated rats (0.5
      or 1 mg/kg) showed increases for both parameters. When both drugs were
      administered simultaneously, the impairing effect was potentiated. However, no
      changes in learning responses were observed in rats treated with physostigmine
      (0.125, 0.25, 0.5 mg/kg) or methyl beta-carboline-3-carboxylate (0.3, 0.5, 1
      mg/kg), although the administration of physostigmine or methyl beta-carboline-3
      carboxylate was shown to antagonize the impairing effect of diazepam or
      scopolamine respectively. These observations support the hypothesis of
      interactions existing between cholinergic agents and benzodiazepine receptor
      ligands and of such interactions affecting olfactory acquisition processes. The
      runway apparatus appears to be a valid candidate model to be used for the
      assessment of pharmacological influences on olfactory learning in rats.

PMID- 10399679
TI  - The contribution of vision in dynamic spontaneous sways of male classical dancers
      according to student or professional level.
AB  - We investigated the involvement of vision in the regulation of dynamic
      equilibrium in male children and young adults performing a physical activity
      requiring a high level of spatial skill: self-induced body sways of ballet
      dancers on a free unstable platform, 45 professional male dancers (Paris Opera)
      participated in the study. They included two student groups (beginners and
      confirmed) and two performer groups (adolescent and adult). They maintained their
      equilibrium on the platform under different visual and position conditions. The
      displacement of the seesaw platform were calculated from accelerometer measures.
      Fast Fourier transform processing of stabilograms allowed spectral frequency
      analysis. The total spectrum energy and the energies of the three frequency bands
      (0-0.5 Hz, 0.5-2 Hz, 2-20 Hz) were determined. For all groups, ANOVA indicated
      that values were higher for eyes-closed than for eyes-open conditions. The visual
      dependence differed according to age: for 14-year-old students the postural
      control for dynamic equilibrium was less visually dependent than for 11-year-old
      students. The 18-year-old dancers, although professional, were more dependent on
      vision than 14-year-old student dancers. These 18-year-old dancers were still
      adolescent because they had recently undergone growth acceleration which could
      disturb their proprioceptive references and internal body representations. Thus,
      visual input may dominate over the other sensory inputs in the regulation of
      postural control.

PMID- 10399680
TI  - Histamine excites rat cerebellar granule cells in vitro through H1 and H2
      receptors.
AB  - The effects of histamine on the firing of cerebellar granule cells were
      investigated in vitro. Histamine predominantly produced excitatory (117/123,
      95.1%) and in a few cases inhibitory (6/123, 4.9%) responses in granule cells.
      The histamine-induced excitation was not blocked by perfusing the slice with low
      Ca2+/high Mg2+ medium, supporting a direct postsynaptic action of histamine. The
      H1 receptor antagonists triprolidine and chlorpheniramine significantly
      diminished the histamine-induced excitation, but the H2 receptor antagonist
      ranitidine did not significantly reduce the excitation. On the other hand, the H2
      receptor agonist dimaprit could elicit a weak excitation of granule cells. This
      dimaprit-induced excitation was blocked by ranitidine but not triprolidine. These
      results reveal that the excitatory effect of histamine on cerebellar granule
      cells is mediated by both H1 and H2 receptors with a predominant contribution of
      H1 receptors. The relevance of these findings to the possible function of the
      hypothalamocerebellar histaminergic fibers in cerebellum is discussed.

PMID- 10399681
TI  - Distributions of sensory spots in the hand and two-point discrimination
      thresholds in the hand, face and mouth in dental students.
AB  - Densities of pressure, pain and temperature spots in the back of the hand in 551
      students and two-point discrimination thresholds in the hand, the face and the
      mouth in 684 students were measured. The mean numbers of pressure, pain, warm and
      cold spots in the back of the hand were 24.7/cm2, 130.5/cm2, 3.4/cm2 and 9.1/cm2,
      respectively. The mean thresholds of two-point discrimination were 1.7 mm in the
      tip of the tongue, 2.4 mm in the upper lip, 5.5 mm in the lower jaw, 7.5 mm in
      the palm, 8.8 mm in the forehead, and 11.8 mm in the back of the hand. There were
      mostly no differences between males and females in the values of sensory spots
      and two-point discrimination thresholds.

PMID- 10399682
TI  - Projection to the lateral reticular nucleus from neurons located in C6-C7
      segments of the spinal cord. An electrophysiological study in the cat.
AB  - Spinoreticular neurons projecting to the lateral reticular nucleus (LRN) were
      investigated electrophysiologically in the cervical enlargement of the cat spinal
      cord. Experiments were performed on alpha-chloralose anaesthetized animals.
      Antidromic action potentials were recorded extracellularly from cells located in
      C6 and C7 segments following stimulation of the ipsilateral LRN. The total sample
      included 50 neurons. Their cell bodies were found to be distributed in Rexed's
      laminae VI-VIII of the gray matter. Axonal conduction velocities ranged from 14.7
      to 89.7 ms-1. Considerable differences between particular cases enabled two
      separate groups of slower and faster conduction to be distinguished. Values for
      these two groups were 14.7-44.3 ms-1 and 52.2-89.7 ms-1, respectively. Discrete
      differences with regard to the location of these groups were also pointed out.
      Such differentiation suggests that a proportion of axons from the slower
      conducting pool may be in fact collaterals of neurons that project to other
      brainstem centers or to lower levels of the spinal cord.

PMID- 10399683
TI  - [The medicosurgical field hospital: first African unit in a humanitarian
      situation].

PMID- 10399684
TI  - [The Dakin solution].

PMID- 10399685
TI  - [Biosynthesis of nitric oxide in infection: should it be induced or avoided?].

PMID- 10399686
TI  - [Norwegian scabies].

PMID- 10399687
TI  - [Mali: a health care system in full transformation].

PMID- 10399688
TI  - [Function and significance of travel (collective evidence of peculiar
      resonance)].

PMID- 10399690
TI  - [The face of bioterrorism].

PMID- 10399689
TI  - [Travel medicine and epidemiologic monitoring: the example of schistosomiasis].

PMID- 10399691
TI  - [Impact of resistance of Anopheles gambiae s.s. to permethrin and deltamethrin on
      the efficacy of impregnated mosquito nets].
AB  - Trials to assess the impact of resistance of Anopheles gambiae s.s. to permethrin
      and deltamethrin on the efficacy of insecticide-treated bednets were carried out
      from October 1997 to April 1998 in six experimental huts at the Yaokoffikro
      testing station in Cote d'Ivoire. Six polyester bednets were used. Two bednets
      were treated with permethrin at a dose of 500 mg/m2 and two with deltamethrin at
      25 mg/m2. The remaining two untreated bednets served as controls. The number of
      Anopheles gambiae s.s. entering the hut was reduced 18% with permethrin-treated
      bednets and 43% with deltamethrin-treated bednets. Threefold fewer female
      mosquitoes were found under insecticide-treated bednets than under untreated nets
      (controls). The number of mosquitoes passing through the treated net was
      threefold lower. The number of mosquitoes exiting from the treated bednets
      increased twofold. The blood-feeding rate dropped by 55%. Forty percent of
      mosquitoes entering the permethrin-treated bednets and 56% entering the
      deltamethrin-treated bednets died. Immediate mortality was always greater (> 85%)
      than delayed mortality (< 15%). Bioassays confirmed the results from hut
      experiments. A lower knockdown effect was recorded with permethrin in the
      resistant strain. Conversely deltamethrin showed the same knockdown effects in
      the susceptible (Kisumu) and resistant (Yaokoffikro) strain. Mortality rates were
      low with both permethrin and deltamethrin. This study shows that, even in areas
      where Anopheles gambiae s.s. is resistant to permethrin and deltamethrin, bednets
      treated with these insecticides remain effective and can still be considered as
      an excellent method of personal protection.

PMID- 10399692
TI  - [Impact of the use of permethrin pre-impregnated mosquito nets on malaria
      transmission in a hyperendemic village of Senegal].
AB  - The efficacy of permethrin-treated bednets was evaluated in Wassadou, a
      hyperendemic village located in the Sudanese grasslands of southeast Senegal.
      Pretreatment data were collected between 1992 and 1993. Bednets were distributed
      to the whole population in June 1995 and impact of their use on vector
      populations and malaria transmission was evaluated until November 1995. This
      period corresponds to the rainy season during which malaria transmission is
      highest. Data were compared with a control village in which bednets were not
      distributed. Findings showed that use of bednets led to a sharp decrease in the
      density of the vector population and malaria transmission. The number of bites by
      Anopheles gambiae s.1. decreased 69%. The density of blood-laden and pregnant
      females inside dwellings decreased 91% and 96% respectively. The sporozoite index
      of females captured on the skin decreased 76% and the daily rate of entomological
      inoculation decreased 88%. This impact was not great enough to eliminate the risk
      of infection. Prolonged study over a period of 4 to 5 years is needed to evaluate
      the impact of long-term use of insecticide-treated bednets on vector population
      and malaria transmission.

PMID- 10399693
TI  - [Malaria lethality in Dakar pediatric environment: study of risk factors].
AB  - To determine risk factors for fatal malaria in Senegalese children, a 3-year case
      control study was carried out between October 1992 and November 1995 at the
      Albert Royer Hospital in Dakar. The case group included 52 children who died from
      documented malaria in the hospital. The matched control group consisted of
      children who responded favorably to hospital treatment. Exposure to risk was
      measured with regard to age, nutritional status, educational level of parents,
      self-medication prior to hospitalization, socioeconomic level, degree of fever,
      and blood parasite levels. Cases and controls were compared using statistical
      tests for matched groups. Age lower than 5 years, poor educational level of
      parents, delay of treatment more than 24 hours, nutritional status, and blood
      parasite levels greater than 5% were associated with a significantly higher risk
      of fatal outcome. Conversely, low socio-economic level, recent self-medication,
      and fever over 41 degrees C were not associated with higher fatality. These
      findings emphasize the need for more information campaigns to encourage people to
      seek institutionalized care when fever appears. Our results also suggest that
      prophylactic treatment may be advisable in children under 5 years of age and in
      some high risk groups.

PMID- 10399694
TI  - [Sociocultural approach to epilepsy in Mauritania].
AB  - In Black Africa, treatment of epilepsy is affected by sociocultural attitudes.
      The purpose of this report is to describe attitudes towards epilepsy in
      Mauritania and assess repercussions in 150 patients. Most patients were deprived
      of educational and occupational opportunities. Seventy-seven percent of patients
      were treated by traditional remedies. Regardless of ethnic origin, a widely held
      notion was that epilepsy was caused by djinns (evil spirits). An additional cause
      almost consistently cited by the Moorish population was diet. In these ethnic
      groups, the term iguindi refers to all clinical manifestations including seizures
      attributed to excessive eating. Traditional treatment involves ingestion of foods
      considered as antidotes for iguindi. These findings underline the need for
      information campaigns to enhance public awareness and understanding of epilepsy.

PMID- 10399696
TI  - [Monthly variations in the level of infestation and the potential for
      transmission of Biomphalaria pfeifferi in 2 aquatic systems in Lwiro, Democratic
      Republic of Congo].
AB  - This study of variations in the rate of infestation by Biomphalaria pfeifferi and
      risk of schistosomiasis transmission was carried out to determine optimal timing
      for control measures. The study was conducted in two aquatic ecosystems, i.e.
      creek and fish pond, in the Lwiro region located in the eastern part (sud-Kivu)
      of the Democratic Republic of Congo. Biomphalaria pfeifferi infestation rates
      were high in the creek from November to January and consistently low in the fish
      pond. The risk of schistosomiasis transmission to man was highest in the creek
      especially during the months of January, February, May, and September. The risk
      of transmission was always less than 16% in the fish pond. Based on these
      findings, the optimal timing for control measures is the dry season for creeks
      and the rainy season for fish ponds.

PMID- 10399695
TI  - [Validity of a test for diagnosis and monitoring of hemorrhagic syndrome after
      viper envenomation in sub-saharan Africa].
AB  - The purpose of this study was to validate a test for diagnosis and monitoring of
      hemorrhagic syndrome following viper envenomation in sub-Saharian Africa. A total
      of 276 patients treated at 7 health centers or hospitals in North Cameroon were
      included. Hemorrhage was observed in 144 patients (52.2%). Coagulation time was
      longer than 30 minutes in 196 patients (71%). Overall hemorrhage and/or prolonged
      coagulation time was noted in 223 patients (80.8%). Combination of these two
      findings was a reliable indicator for diagnosis and monitoring. Observation of
      one of these factors, i.e. hemorrhage or prolonged coagulation time, indicates
      immunotherapy using F(ab')2. This treatment should be continued until the
      indicator disappears and renewed in case of relapse.

PMID- 10399697
TI  - [First case of cutaneous leishmaniasis from Leishmania infantum in Corsica].
AB  - Canine leishmaniasis is endemic in Corsica. Sporadic cases of visceral
      leishmaniasis due to Leishmania infantum have been reported in humans, but no
      case of cutaneous leishmaniasis has been reported to date. In August 1994, a 42
      year-old woman living in Orleans (France) presented with two nodular lesions on
      the face. These lesions appeared two months after a stay near the Gulf of Ajaccio
      in Corsica. Histopathological examination revealed intracellular amastigotes. The
      culture isolate was identified as Leishmania infantum zymodeme MON-29.
      Epidemiological data and climatic conditions prevailing during the patient's stay
      suggest that contamination took place in Corsica.

PMID- 10399699
TI  - [Ultrasonographic fetal biometry charts in Niger].
AB  - Ultrasound scanning to confirm fetal growth is an essential part of prenatal
      screening and depends on comparison with biometric reference charts. Charts for
      ultrasound scanning in Niger were established at the Poudriere Hospital in Niamey
      between 1994 and 1997. A total of 5,197 measurements were made on 736 fetuses to
      obtain 50 values for biparietal diameter, transverse abdominal diameter, and
      femoral length between the 14th and 41st weeks from the last menses. Each
      parameter was presented with dispersion and compared with similar findings from
      other series to establish reference charts for the population of Niger.
      Transverse abdominal fetal diameter in Niger appeared to be below normal. These
      charts establish a local reference at a given time but will require revision in
      the future.

PMID- 10399698
TI  - [Giant anovulvar condyloma acuminata revealing hiv-1 seropositivity in a
      Centrafrican patient].
AB  - As a general rule, genital condylomas present as localized lesions and large
      masses of warts are observed only during pregnancy. In this report we describe a
      giant anogenital condyloma in a non-pregnant 18-year-old Centrafrican woman. Soft
      papillomas completely covered the anterior and posterior perineum and obstructed
      the vagina. Clinical findings were suggestive of vulvar Buschke and Loewenstein
      tumor. The extent of the lesions and a history of unprotected relations with
      several sex partners raised suspicion of HIV infection which was subsequently
      confirmed. The CD4+ lymphocyte count was 540/min3. Surgical removal led to
      complete cure after healing of the surgical wound. Histological findings showed
      that the lesions were benign and ruled out malignant vulvar tumor. This case
      documents the link between florid genital condylomas and HIV infection with no
      change in immune status.

PMID- 10399700
TI  - [Tubal sterilization by minilaparotomy under local anesthesia].
AB  - Minilaparotomy under local anesthesia (ML/LA) is the most widely used technique
      of tubal sterilization in the world. Since 1993, the University Hospital Center
      of Dakar, Senegal has been the reference center performing 20 ML/LA a month. Most
      procedures (72%) are carried out for non-medical personal reasons. The remaining
      cases (28%) involve physical conditions incompatible with completion of normal
      pregnancy. In all cases, voluntary, informed consent is obtained from the couple
      and is documented in writing. Preoperative evaluation is performed to detect
      contraindications. The procedure consists of five steps: the vaginal phase, local
      anesthesia, abdomen incision, tubal ligation, and closure. Morbidity is less than
      1%. The most common complications involve damage to visceral organs (intestine,
      bladder). These injuries are accessible to immediate repair and thus have a good
      prognosis. Failure rate due to technical error is low (average: 5.8/10,000).
      Current experience shows that ML/AL is a safe, effective, low-cost technique well
      suited to use in developing countries.

PMID- 10399701
TI  - [American human trypanosomiasis 90 years after its discovery by Carlos Chagas. I.
      Epidemiology and control].
AB  - It was in 1909 that Carlos Chagas described the disease which now bears his name.
      During the ensuing 90 years, our knowledge of this apparently whimsical,
      protozoan disease has grown enormously but many points remain unclear.
      Epidemiologically speaking, current knowledge is poor about the mechanisms and
      markers of variability of Trypanosoma cruzi, mechanisms allowing the organism to
      survive in the host, and susceptibility of infected individuals to disabling or
      fatal late complications. With regard to vector control, it is increasingly
      obvious that success will be more difficult than previously thought due to the
      likelihood that, as domestic species are exterminated, they will be replaced by
      semi-domesticated or wild species. Two other factors that have significantly
      changed the conventional epidemiological profile of Chagas'disease on the
      subcontinent over the past 50 years are human intervention in the environment and
      population migration from rural to urban zones. Despite the breakthroughs
      achieved in the last decade. Chagas'disease, with its multiple modes of
      transmission (vector-borne, congenital, and transfusional to name but the most
      important), diverse reservoir involving over 175 species, and potential for
      course of the disease in man, will remain a major health problem in Latin America
      countries for many years to come.

PMID- 10399703
TI  - [Management of motor disability in rural Sahelian environment. Experience of the
      center for rehabilitation and devices in Bogande, Burkina Faso].
AB  - The center for rehabilitation and fitting of the disabled in Bogande, Burkina
      Faso has been in operation since 1992. It was created by a non-governmental
      organization named Actions de Solidarite Internationale (ASI). The primary goal
      of the center is to provide support devices to restore upright position and
      mobility and allow social reinsertion especially for disabled persons between the
      ages of 0 and 20 years. Approximately one hundred people are treated annually.
      Treatment is delivered either directly in villages or in dispensaries if the
      disabled person can be brought in with the assistance of family members or health
      care workers. This policy has enhanced the quality of information, training, and
      prevention. Patients with severe disabilities beyond the scope of treatment at
      the center are contraindicated. The activities of the center have been organized
      with a view to covering costs. A welding shop has been set up to produce aid
      devices and provide revenues to pay for some services. The major lessons of this
      experience involve the need for active recruitment in villages, for
      contraindicating patients with severe untreatable disability, for developing
      economically sustainable programs, for training management staff, and for good
      financial planning. In 4 years of operation, the rehabilitation and fitting
      center has demonstrated its ability to meet the needs of the disabled in Bogande.

PMID- 10399702
TI  - [Pleuropulmonary manifestations of salmonellosis].
AB  - Salmonella infections are widespread particularly in tropical zones. Each year,
      12.5 million cases of typhoid fever are reported with an incidence of 540 cases
      for every 100,000 inhabitants in developing countries versus 0.2 cases in
      industrialized countries. Pleuropulmonary manifestations constitute the most
      common extra-intestinal manifestation of salmonella infection. Counts are usually
      carried out in the digestive tract. Respiratory tract manifestations result from
      blood-borne diffusion from mesenteric lymph nodes, but gastroenteritis goes
      unnoticed in 2 of 3 cases. Predisposing factors are frequent including cancer,
      previous graft placement and immunosuppressant therapy, sickle cell disease,
      alcohol abuse, and pre-existing pulmonary disease. Clinical manifestations are
      usually acute but subacute forms cannot be ruled out. Cough is a common symptom
      observed in 25% of patients with typhoid fever. Pneumonia is uncommon overall
      (1%) but occurs in 50% of patients with pleural effusion, empyema, lung abscess,
      or bronchopleural fistula. A few cases of adult respiratory distress syndrome
      have been described in the literature. Recognition is important since these
      manifestations may signal previously unsuspected underlying pulmonary disease.
      Treatment requires appropriate antimicrobial therapy and close surveillance to
      prevent recurrence or complications.

PMID- 10399705
TI  - [A case of intestinal schistosomiasis imported from Djibouti].

PMID- 10399704
TI  - [Cryptococcal meningitis and AIDS in Dakar, Senegal: apropos of 5 cases collected
      from 1995 to 1997 at the Principal Hospital].

PMID- 10399706
TI  - [Family infected bathing in Malawi lake].

PMID- 10399707
TI  - [Schistosomiasis risk in the region of the dam of Bagre, Burkina Faso].

PMID- 10399708
TI  - Childhood leukaemia relapse risk factors. A rough sets approach.
AB  - A rough sets approach was applied to a data set consisting of clinical and
      laboratory examinations (condition attributes) of children with acute
      lymphoblastic leukaemia to generate a set of rules for the prediction of disease
      relapse (conclusion attributes). The information system is presented as a table
      composed of 69 rows corresponding to the patients and 16 columns corresponding to
      the attributes. Using manipulation based on rough set theory the information
      system is reduced to get a subset of a minimum number of attributes ensuring an
      acceptable quality of classification. Then the conclusion algorithm derived from
      the reduced system is presented as a conclusion table. The relationship between
      condition and conclusion attributes is being shown. The research leads to the
      conclusion that intensive, high dose central nervous system prophylactic
      irradiation seems to be a better prevention against CNS relapse. Rough set theory
      is a useful and still complementary tool of medical (biological) data analysis.

PMID- 10399709
TI  - Quality assurance guidelines for a biomedical information web system: the working
      experience of the BreakIT project.
AB  - The paper outlines the quality control issues that arise in the implementation of
      a Web site which delivers biomedical information. At the heart of this study is
      the need for a methodology to guarantee that the information contained in the
      site is viable and accurate from both an informatic and a content point of view.
      This methodology is currently adopted in the Web development of the BreakIT
      project sponsored by the EU INFO2000 Programme.

PMID- 10399711
TI  - Practical evaluation of standard-based low-cost video conferencing in
      telemedicine and epidemiological applications.
AB  - The results of the evaluation of use of low-cost video conferencing systems
      (VCSs) in telemedicine is presented. Applications sharing, a new feature of these
      systems, recently has allowed high-quality computer-supported collaborative work
      (CSCW). The video conferencing (VCing) equipment used was Intel ProShare 200
      v2.0a. It is representative of other low-cost VCSs. The areas of application are
      epidemiology and telemedicine (orthopaedics and radiology). Potential end users
      filled out 58 evaluation questionnaires concerning user profiles, contents and
      benefits of the sessions, organizational aspects, user friendliness, user
      acceptance, cost effectiveness, technical and multipoint related aspects.
      Although the end users had a lot of computer experience, their knowledge in VCSs
      was rather limited. The users assessed the system capable of being integrated
      into routine work, despite a high organizational impact. The VCS is user
      friendly, application sharing being used in almost every session. Audio quality
      was not always sufficient. The remote video was sufficient, as was the quality of
      medical images such as CT, MRI or X-ray. The user acceptance of the system was
      high. Multipoint sessions require a structured protocol to be effective. Some
      technical problems with MCUs (Multipoint Control Units) occurred. The use of low
      cost standard VCSs in telemedicine is advisable and is a good substitute for real
      meetings.

PMID- 10399710
TI  - Influence of the teleradiology technology (N-ISDN and ATM) on the inter-hospital
      management of neurosurgical patients.
AB  - We set out to assess the influence of a teleradiology network on the relations
      between a general hospital and a 100 km distant university hospital in the
      context of neurosurgical emergencies, and compared a commercially available
      technology, N-ISDN (Narrowband Integrated Service/Digital Network), to an
      emerging technology, ATM (Asynchronous Transfer Mode). The evaluation was
      conducted using records of advice request calls and patient transfers. Three
      phases were considered: without teleradiology, with transfer of digitized images
      over N-ISDN at 64 kbps, and with an experimental ATM network at 10.5 Mbps with
      DICOM image transfers and videoconferencing. Additionally, staff meetings over
      ATM videoconferencing were set up. To assess the ATM service, we used log files
      and questionnaires, 108 advice requests were studied over a 18 month period. The
      average transmission time for one examination was 38 s with full DICOM image
      resolution over ATM, versus 150 s with 10:1 JPEG (Joint Photographic Expert
      Group) compression over N-ISDN. Up to 50% unnecessary patient transfers were
      avoided. Advice requests increased fourfold, and non-urgent advice requests
      increased from 0 to 21%. Despite the experimental configuration of the ATM
      network, the service gave satisfaction to all the physicians. Videoconferencing
      was unanimously regarded as a prominent tool to improve the quality of
      interaction. It was particularly useful for non-urgent cases and distant staff
      meetings. Teleradiology can improve the relations between hospitals through an
      increase of urgent and non-urgent advice requests. Asynchronous transfer mode is
      an efficient way for fast transfer of radiological examinations in DICOM format
      and for discussing them through high-quality videoconferencing.

PMID- 10399712
TI  - [The causes of increased risk for lung cancer in the pulp and paper industry
      workers. The effect of smoking and exposure to chemicals].
AB  - An analysis of mortality in a cohort of workers employed in the pulp and paper
      industry, carried out by the authors of this presentation several years ago,
      indicated an increase of 22% in the risk of mortality from lung cancer. This risk
      decreased by only 4% after taking account of smoking. The results obtained then
      were considered as sufficient to undertake further studies aimed at identifying
      specific occupational factors responsible for an increased risk for mortality
      from lung cancer in the population under study. The nested case-control study, in
      which cases (of lung cancer) and controls were selected from the same cohort
      observed earlier, was approved as the most suitable method for achieving the
      aforesaid aim. The study covered 79 cases of deaths from lung cancer confirmed by
      histological and cytological or radiological examinations, and 237 'healthy'
      controls matched in the ratio of one to three, taking into account gender, date
      of birth and date of employment. A group of experts carried out in-depth analysis
      of exposure to harmful factors in each case of death and in each control. Using a
      questionnaire, specially developed for this purpose, detailed data on smoking
      habits among persons under study were collected. Odds ratio was used as a measure
      of a relative risk for death from lung cancer. A crude relative risk and risk
      adjusted by eliminating the effect of smoking, applying the model of conditional
      logistic regression, were calculated for individual exposure factors. Smoking
      proved to be a significant causal factor responsible for the development of lung
      cancer in the cohort studied. That was evidenced by relative risk accounting for
      12.9 for smokers in relation to non-smokers and an enhanced risk with the
      increasing number of cigarettes smoked daily, the number of smoking years and an
      accumulated dose. The study does not confirm a hypothesis that chemical factors
      specific of the pulp and paper industry exert a significant effect on the risk of
      death from lung cancer. Odds ratios, crude and adjusted for smoking, were lower
      than one in all distinguished categories of exposure.

PMID- 10399713
TI  - [Quality assessment of radiological diagnostic examinations from the perspective
      of radiological protection].
AB  - The paper presents current recommendations on radiological protection concerning
      medical exposure, especially during X-ray diagnostic examinations. Major factors
      responsible for the level of radiological risk for patients undergoing X-ray
      examinations are also discussed. (In Poland about 28 million X-ray examinations
      are performed annually.) A thorough evaluation of 18 X-ray units used in
      diagnostic laboratories in the Lodz district is presented. It was found that only
      6 of 18 X-ray units controlled, satisfy best the evaluation criteria laid down
      according to the recommendations of the International Atomic Energy Agency
      (IAEA). The significance of satisfying individual criteria for the achievement of
      high quality radiological examinations was highlighted.

PMID- 10399714
TI  - [Lacrimation disorders in workers chronically exposed to petroleum derivatives].
AB  - Lacrimal fluid plays a very significant role in maintaining proper functions of
      conjuctivas, cornea and eyelids. The fluid is secreted by the main lacrimal gland
      and additional glands. It produces the so called preocular lacrimal film. A
      number of clinical tests, such as Chirmer's tests I and II, break-up-time (BUT),
      lysozyme, and flow tests are used in quantitative and qualitative analyses, as
      well as in the determination of the lacrimal film stability. The aim of work was
      to utilize these in assessing the lacrimal secretion and the lacrimal film
      stability in workers chronically exposed to petroleum derivatives. Fifty three
      workers from departments of acetobenzene, benzene and butadiene, phenol and
      acetone, sewage waters, asphalt oxidas, polyethylene and polypropylene, were
      eligible for the study (group I). During previous examinations, acquired
      disorders in colour perception were diagnosed in all the subjects by means of the
      Mansuella-Fansworth 100-Hue test. The age range was 25 to 56 years, with a
      mediane of 44.1 years +/- 6.5. Mean duration of employment was 22 years (SD +/-
      8.25). The control group (group II) was composed of 28 men aged between 24 and 60
      years with a median of 42.7 years +/- 6.3, never employed under conditions of
      exposure to toxic chemicals. On the right eye of each subject Schirmer's test was
      performed after instilling into the conjunctival sac 1-2 drops of Alcain solution
      according to Whitcher. Five min following anesthesia of the conjunctival sac, a
      standardised belt of blotting-paper with colour dampness markers Vidisic (Dr Mann
      Pharma GMBH, Germany) was placed in the vicinity of the external angle of the
      eye. After 5 min the degree of the belt dampness was measured in millimetres.
      After 30 min the break-up-time test was performed on the left eye. Fluorescein
      was released to conjunctival sac from a sterile belt of blotting-paper (Haag
      Strait Co.). A slit lamp with cobalt filter was used to calculate time (in sec)
      that elapsed between opening of the lid slit and the first symptom of breaking-up
      the lacrimal film. The results obtained were presented in the form of arithmetic
      means and standard deviation values +/- SD. Schirmer's test was 13.40 +/- 7.43 mm
      in group 1, and 22.54 +/- 8.25 mm in the control group, mean values differed
      significantly, p < 0.01. Lacrimal film break-up-time was 16.30 +/- 6.19 sec in
      group 1, and 31.48 +/- 7.96 sec in the control group, mean values differed
      significantly, p < 0.01. In persons chronically exposed to petroleum derivatives,
      statistically significant decrease in lacrimal secretion, as well as shortening
      of lacrimal film break-up-time were found when compared with the control group.

PMID- 10399715
TI  - [Occupational N-hexane neuropathy: clinical and neurophysiological
      investigation].
AB  - A group of 37 patients (26 men and 11 women), aged 18-49 (mean: 29.7) with
      subacute toxic polyneuropathy was investigated clinically and
      electrophysiologically. In all cases the disease was induced by occupational
      exposure to n-hexane in a small enterprise of purse makers. Toxicological
      investigations revealed a highly increased concentration of n-hexane in glue used
      in the manufacture process. The clinical course, including delayed worsening of
      symptoms after cessation of exposure, was typical when compared with previously
      reported cases of n-hexan-induced neuropathy after glue sniffing and industrial
      exposure. Electroneurographic (ENeG) studies showed a predominately decreased
      motor nerve conduction velocity (MNCV) with focal conduction block followed by
      dramatically diminished CMAPs. Recovery of EneG abnormalities paralled the
      clinical improvement.

PMID- 10399716
TI  - [Types of hearing disorders in drug addicts and individuals drinking non
      consumable alcohols].
AB  - All over the world an increase in the number of subjects addicted to various
      chemical substances has been observed. The studies of their toxic effect on the
      hearing have been so far most frequently limited to acute intoxication or direct
      effect: there are no data concerning distant and persistent effects. The aim of
      the study was to determine the type of hearing loss in drug addicts and
      individuals drinking non-consumable alcohols, examined during the period of
      abstinence. A group of 210 subjects addicted to various substances was examined
      using acumetry test and tuning forks, as well as threshold, suprathreshold and
      speech audiometry. Taking into consideration the threshold results for particular
      subjects, the percentage of hearing loss for both ears was calculated using CPT
      index. Most frequent complaints connected with the organ of hearing, such as
      tinnitus and hearing impairment were reported by alcoholics and opioid addicts.
      In the age adjusted threshold audiometry, perceptive hearing loss was diagnosed
      in nearly 50% of the subjects. The percentage of hearing loss calculated for both
      ears, using CPT index, demonstrated the highest values in the group of subjects
      drinking non-consumable alcohols and addicted to volatile organic substances.

PMID- 10399717
TI  - [Some occupational determinants of work disability].
AB  - Occupational determinants play a significant role in the studies of the causes of
      work disability. The duration of employment is that particular variable,
      frequently analysed, which reflects indirectly the effect of work conditions on
      the worker's health state and also on his her disease-related work disability.
      Therefore, the aim of this work was to show the difference in sick absenteeism
      between various occupational groups, depending on the duration of employment. The
      empirical material embraced data on work disability, among workers employed in
      the automative industry plant during the years 1989-94. Out of 8,599 persons
      covered with the study, 77% left the job, including 7% of those who left the job
      because of health problems. An analysis of the impact of occupational
      determinants on the sick absenteeism was carried out on the basis of the
      absenteeism rate adjusted by age, sex and occupational activity in groups of the
      production, auxilliary and administrative workers, as well as in occupational
      groups exposed to possibly similar harmful factors. The duration of worker's
      employment in the plant showed a positive influence on sick absenteeism, since
      together with extended period of employment the decrease in the rate of general
      sick absenteeism was observed. However, in a number of disease categories an
      increase in absenteeism together with extended duration of employment, and a high
      level of absenteeism among workers involved directly in the production, were
      noted. This proves an adverse effect of work conditions on work disability among
      workers. The effect of harmful factors present at workposts is also confirmed by
      the increasing sick absenteeism together with the prolonged duration of
      employment in various occupational groups. In the group of welders the highest
      level of sick absenteeism was observed among persons with duration of employment
      ranging from 11 to 20 years (rate: 10.52), and it was related to diseases of the
      respiratory (3.10) and circulatory (2.09) systems. In this group the increase in
      absenteeism together with prolonged duration of employment was related to
      diseases of the genitourinary system (about fourfold), musculoskeletal system
      (about threefold) and nervous system and sense organs (about 20%). It may be
      concluded that in selected high risk occupational groups, the duration of
      employment may reflect the effect of work conditions on workers' sick
      absenteeism, and the analysis of work disability caused by individual diseases
      provides an image of health effects due to hazards to which those groups are
      exposed.

PMID- 10399719
TI  - [Cytostatic drugs: occupational hazard to health care workers].
AB  - Cytostatic anticancer drugs are known as carcinogenic, mutagenic, and teratogenic
      risk factors for health care workers who are occupationally exposed during
      preparation and management of such drugs. Risk assessment for occupational
      exposure to antiblastic chemotherapeutic drugs is carried out by means of
      environmental and biological monitoring. During last twenty years, several
      researchers have developed and validated methods for monitoring occupational
      exposure to such agents. The author reviews the literature on possible effects of
      occupationally exposed hospital workers and occupational exposure.

PMID- 10399718
TI  - [Natural radioactivity of underground waters: surveying of alpha and beta global
      activity].
AB  - Two sets of measurements used in surveying of the alpha and beta global activity
      of drinking water drawn from 44 abyssal wells located in the Lodz cretaceous
      basin are discussed. The measurement method used involved the comparison between
      the activities of a model source and a prepared sample of water. Radioactive
      isotopes Am-241 were employed in alpha and K-40 in beta measurements. In order to
      detect radiation, a semiconducting radiation detector Si of high purity for
      registration of alpha molecules and a set of two G-M counters operating in the
      anticoincidence circuit for registration of beta radiation were used.

PMID- 10399720
TI  - [The relation between ischemic cerebral stroke and heart diseases].
AB  - The aim of the study was to evaluate the relation between heart diseases and
      ischemic cerebral stroke. In addition to routine tests, echocardiographic
      examinations were performed in 70 patients with ischemic cerebral stroke and in
      30 persons constituting the control group. It was found that heart diseases
      occurred in 70% of the patients in the group studied i.e. three times more
      frequently than in the control group. Heart disease confirmed by echocardiography
      and electrocardiography occurred more frequently in patients with cerebral
      infarct than in those with RIND. In the majority of cases cardiac valve diseases
      and/or atrial fibrillation were noted. It was found that in 14.3% of the patients
      studied, the results of the echocardiography indicated the need for modification
      of the treatment applied.

PMID- 10399721
TI  - [Autonomic nervous system disturbances in Parkinson's disease].
AB  - On the basis of neurophysiological tests we conclude that subclinical signs of
      dysautonomia appear in Parkinsonians. Various autonomic functions are not
      disturbed in the same degree. Examinations of cardiovascular system showed that
      functions connected with parasympathetic system were affected, while those
      connected with sympathetic part were not. Examinations of skin sympathetic
      reflexes displayed rather patchy, disseminated type of damage: only latencies of
      responses recorded from hands (but not from feet) were prolonged when compared to
      the control group.

PMID- 10399722
TI  - [Electrophysiological abnormalities in acute and chronic inflammatory
      demyelinating polyneuropathies].
AB  - Electrophysiologic changes in G-B and CIDP polyneuropathy. Retrospective
      comparative study of the electrophysiologic changes in 7 cases of GBS and 12
      cases of CIDP polyneuropathy were performed. In all cases nerve stimulation data
      fulfilled the diagnostic electrophysiologic criteria of demyelinated inflammatory
      polyneuropathy. Our material confirms that electrophysiological investigations
      are a very important diagnostic tool in inflammatory demyelinating
      polyneuropathy. However, different electrophysiologic features in individual
      cases and in the course of the disease cause that nerve stimulation data have no
      diagnostic value in differentiation between the GBS and CIDP cases.

PMID- 10399723
TI  - [Auditory evoked potentials from brain stem determined in acoustic nerve
      neurinomas].
AB  - An analysis of the studies of Brain Stem Electric Response Audiometry of patients
      operated on Bachaumont Clinic or in Cochin hospital in Paris, because of acoustic
      neurinoma, was carried out. The studies comprised 88 patients divided into groups
      according to the size of tumour. A group of small intrameatal tumours, a group of
      up to 2 cm tumours, a group of between 2 and 3 cm tumours and a group of above 3
      cm tumours. A control group of examined patients consisted of 20 persons with one
      side acoustic impairment or two-side impairment but predominant on one side and
      patients with one-side tinnitus or two-side tinnitus but predominant on one side.
      Examinations of these patients made with CT and NMR did not show presence of
      acoustic neurinoma. BERA's tests did not show a response in case of 22 patients
      with acoustic neurinoma. In 71% of cases BERA's tests showed an extrahelix type,
      for which in 50% of cases a prolonged latency on the side of the tumour was
      found. In 4% of cases Brain Stem Electric Response Audiometry gave results within
      normal range both with respect to morphology and latency time of each wave. A
      slight correlation between the size of tumour and type of BERA change was found.

PMID- 10399724
TI  - [Electrophysiological analysis of changes in peripheral nervous system in
      multiple sclerosis].
AB  - In order to analyse the peripheral disturbances repetitive stimulation test (RNS
      Test) and nerve conduction studies were done in 33 patients, 19 women and 14 men
      (mean age 38.2 years), with at least probable diagnosis of multiple sclerosis. In
      RNS Test the mean CMAP amplitude was significantly lower in comparison to the
      control group without any difference after 30 seconds of effort. Significant
      decrementing response was revealed at low rate of stimulation (2Hz) and
      incrementing response during tetanic stimulation. Significant lower mean
      amplitude of M wave in all investigated nerves was found in motor nerve
      conduction velocity test. Abnormal mean distal latency and motor conduction
      velocity were less common. The mean results of sensory conduction velocity test
      were similar to the control group.

PMID- 10399725
TI  - [Treatment of vertigo with betahistine and its clinical and electrophysiological
      evaluation].
AB  - Betahistine was administered during 4 weeks to 31 patients with vertigo, divided
      into 3 groups depending on changes in neurological examination. 1 group--13
      patients without abnormalities, 2 group--11 with ischemia vertebrobasilaris, 3
      group--7 with lesion of VIII nerves. Significant improvement was obtained in 20
      patients (65%), most evident in group 1 (in 11). BAEP examination revealed
      abnormalities in 12 cases before the treatment and recovery in 4 (33.3%) after 4
      weeks of treatment. They were: longer latency of the 1 component (39%), and III
      and V components mainly in the group with baso-vertebral ischemia. It confirms
      the supposition that disturbances of microcirculation are responsible for the
      mechanism of vertigo in these cases.

PMID- 10399726
TI  - [Clinical course and epidemiological analysis of amyotrophic lateral sclerosis in
      Szczecin in 1986-1995].
AB  - 49 patients diagnosed as amyotrophic lateral sclerosis (ALS), hospitalized
      between 1986-1995, inhabitants of Szczecin-City were included in this study. ALS
      was diagnosed according to WFN criteria. The control group consisted of 60
      people. Men:women ratio was 1.57:1. The mean age at ALS onset was 53.2 years. The
      disease was most often present between 51 and 60 years. Only one ALS patient was
      observed in the group of patients aged 21-30 and in the group of individuals
      older than 70 years. ALS incidence was 0.9 per 100,000 inhabitants and its
      prevalence in 1995 was 2.7 per 100,000 inhabitants. The mean duration was 30.8
      months and was slightly higher in women. The shortest duration was observed in
      the bulbar form of ALS--21 months. Patients with ALS had been exposed to head
      trauma and contact with animals more often than the average population. There is
      no difference between Szczecin and previously analysed Polish cities in the
      considered epidemiological parameters. No discrepancies of clinical picture and
      course of the disease were found in comparison with other reported by other
      authors.

PMID- 10399727
TI  - [The evaluation of humoral immunity response in subacute sclerosing
      panencephalitis (SSPE)].
AB  - The purpose of the study was the assessment of humoral response markers in 20
      patients with SSPE in phase I, II and III of the disease during immunomodulating
      treatment. In the CSF IgG levels were determined by nephalometric method, with
      its share in the total protein level, and with determination of the local IgG
      synthesis in CNS by Reiber method, 24-hour IgG synthesis by Tourtellotte-Boce
      method, IgG index by Link-Tibbling method and albumin index. Oligoclonal IgG was
      determined by isoelectrofocusing. All mathematical tests indicating IgG synthesis
      in CSF were abnormal in all cases, and also in all cases oligoclonal IgG was
      found (type 3 of electrophoresis separation pattern). The results point to far
      reaching changes of the humoral immune response in SSPE persisting also during
      immunomodulating treatment independently of disease phase and duration. In only
      10% of cases abnormal values of the albumin index suggested damage to the blood
      brain barrier.

PMID- 10399728
TI  - [Proliferative activity of glial neoplasms of the brain].
AB  - The aim of the study including 89 brain gliomas was to determine their
      proliferative activity assayed with immunohistochemical methods (PCNA and Ki-67)
      and with the method of AgNORs, as well as to evaluate the correlation between the
      proliferative activity and features of histological malignancy. The study reveals
      that the estimation of PCNA, Ki-67 and AgNORs are effective methods for the
      determination of the proliferative activity of brain gliomas. Statistically
      significant differences were noted in the proliferative PCNA, Ki-67 and AgNORs
      between groups of gliomas with lower and higher malignancy, which indicated a
      distinct correlation between histological malignancy of the tumours and their
      proliferative activity. High values of PCNA and Ki-67 (> 40%) and AgNORs (> 15)
      were found to considerably deteriorate prognosis in brain gliomas.

PMID- 10399729
TI  - [Clinical course and results of surgical treatment of epidermoid and dermoid
      tumors].
AB  - Seventeen cases (7 males and 10 females) of intracranial epidermoid tumours and
      one case (a male) of intracranial dermoid tumours were described. The patients
      with epidermoids represented 1.7% and the patients with dermoids represented 0.1%
      of all patients operated from January 1989 to July 1998 because of intracranial
      tumours. The average age of the patients with epidermoid tumours was 44.5 and
      ranged from 17 to 69 years whereas in patient with dermoid it was 19 years.
      Twelve epidermoid tumours (70.6%) and one dermoid tumour (100%) were located at
      the basal cisterns of the brain, i.e. 4 epidermoid tumours were located at the
      cerebello-pontine angle, 4--in the suprasellar region, 3 (2 epidermoid and 1
      dermoid tumours)--in the parasellar region, and 2 in the retrosellar region. Four
      epidermoid tumours (23.5%) were found intraventricularly while only one (5.9%)
      located in the cerebral hemisphere. Mainly symptoms of cranial nerves (II, V,
      VII, VIII) dysfunction were observed among the patients. The average duration of
      the symptomatic period was 3 years. All operations were performed in a single
      stage using microneurosurgical techniques. Radical removal was possible in nine
      cases (50%) while in other nine cases the removal was subtotal. Two patients
      (11.1%) died in the postoperative period. Mean follow-up for the patients was 3.3
      years. Among the patient three (16.7%) had a recurrence of the tumor and were
      operated on again. In 14 patients (72.2%) the results were very good and good.
      There was no difference of statistical significance of the results between
      patients with total and subtotal removal of tumours.

PMID- 10399730
TI  - [Assessment of regional blood flow in patients after mild head trauma].
AB  - Single photon emission computerized tomography (SPECT) using radioisotope markers
      was applied for analysis of regional blood flow in the brain. The method makes
      possible demonstration of the presence and extent of damage to the nervous tissue
      caused by trauma. The degree of blood flow impairment is of prognostic
      significance in cases of cerebral concussion. In the present study the regional
      brain blood flow was assessed shortly after trauma and one year in cases of mild
      cerebral concussion. In the studied group immediately after trauma blood flow
      impairment was found mostly in the left temporal area and in frontal areas.
      Changes of rCBI were present also late after trauma. In 7 out of 16 cases SPECT
      image failed to change one year after trauma. In 8 cases the rCB improved up to
      normalization. In 1 case the changes progressed, in another case hyperperfusion
      focus changed to hypoperfusion. In 2 cases the pattern was normal early and lata
      after trauma. In the studied group in cases with changed rCBF no changes were
      found in CT and MRI examinations. This evidence a greater sensitivity and
      usefulness of SPECT in the assessment of early and late consequences of head
      trauma.

PMID- 10399731
TI  - [Shoulder-hand syndrome in patients after stroke].
AB  - Basing on the literature, the information on the shoulder-hand syndrome in stroke
      patients is presented. The syndrome is believed to be a clinical form of
      algodystrophy of the upper extremity. The main signs and symptoms include pain
      and considerable reduction of movement in shoulder joint, wrist and hand. The
      condition usually develops 1-6 months after stroke with pain and loss of range of
      motion in the shoulder at the beginning; then the distal part of the extremity is
      involved. The syndrome is considered to develop in three consecutive phases: I-
      acute, II--dystrophic and III--atrophic. Besides classical clinical form,
      affecting distal and proximal part of extremity, the incomplete forms confined
      only to one of this parts may exist. The prevalence of the condition is rated at
      12.5-27% in stroke patients. It is believed that the development of the syndrome
      is related to altered biomechanics of the hemiplegic shoulder. Stability of the
      joint is considerably affected due to paresis or palsy of shoulder girdle muscles
      what results in partial subluxation of humeral head. Repeated microtraumas of
      shoulder joint may cause chronic pain and may initiate development of abnormal,
      regional sensory-sympathetic reflex arch, or--according to the other concept--it
      results in "sensitization" of neurons in the dorsal horn; this state may alter
      dorsal horn central mechanisms processing sensory and painful stimuli. The
      diagnosis of the syndrome is based on clinical ground. Three-phase bone
      scintigraphy is believed to be the most useful additional diagnostic test. The
      diagnostic and predictive value of this technique is presented. For all
      advantages of scintigraphic examination, it does not need to be performed in the
      majority of stroke patients since the presence of typical signs and symptoms is
      usually sufficient to make a diagnosis. The treatment of shoulder-hand syndrome
      included administration of steroids with satisfactory response. The role of
      proper physical therapy in improving of the results of treatment as well as in
      prophylactics of the syndrome is emphasised. Considering the fact that many of
      stroke patients may have contraindications to steroid therapy, other methods of
      effective treatment are proposed.

PMID- 10399732
TI  - [Elastase imbalance: alpha-1 antitrypsin in aneurysms].
AB  - The balance between proteinases and their inhibitors is important in maintaining
      structural integrity of connective tissues, including the arterial wall. Elevated
      serum elastase level is a possible serum marker of patients with high risk of
      aneurysm formation. Possibly, the heterozygous and the homozygous AAT deficiency
      states are genetic risk factors that could predispose a aneurysm formation.

PMID- 10399733
TI  - [The application of transcranial doppler sonography in the evaluation of cerebral
      flow disturbances after head trauma].
AB  - Several types of cerebral blood flow disturbances, resulting from head trauma are
      discussed. Application of Transcranial Doppler Sonography in diagnosing of
      posttraumatic cerebral vasospasm and cerebral hyperaemia, increased intracranial
      pressure, autoregulation disturbances, and brain death is described. Clinical
      examples of isolated cerebral blood flow disturbances, and several types of their
      co-existence are given. Special attention was paid to the noninvasiveness,
      repetitiveness, and relative ease of use of the technique. Transcranial Doppler
      examination can be especially useful in diagnosis and monitoring of different
      cerebral blood flow disturbances, which is especially important in therapy of
      brain trauma patients.

PMID- 10399734
TI  - [Neurological aspects of two patients with non-mosaic and mosaic polysomy of the
      X and Y chromosomes].
AB  - Clinical features were compared of a patient with the 48,XXYY karyotype and a
      case of 47,XXY/48,XXYY mosaicism. In the former patient tremor of the upper
      extremities of unclear aetiology was present. In both cases epilepsy was
      suspected. Similarly as in other cases of 48,XXYY karyotype the first patient had
      skeletal anomalies, abnormalities of dermatoglyphics and personality changes.
      These features are rarely found in Klinefelter syndrome. The differences in
      relation to the syndrome were less evident in the case of mosaicism
      47,XXY/48,XXYY.

PMID- 10399735
TI  - [Hereditary neuropathy with liability to pressure palsies caused by 17p11.2
      chromosome deletion].
AB  - Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal
      dominant disorder characterised by recurrent mononeuropathies.
      Electrophysiological studies reveal slowed conduction velocity in peripheral
      nerves. The main histopathological findings are focal thickenings of myelin
      tomaculae. In most cases HNPP is associated with a deletion within PMP-22
      (peripheral myelin protein; PMP) gene on chromosome 17p11.2. The gene penetration
      is almost complete but the expression may be variable. DNA analysis is of
      practical importance in diagnosing HNPP especially in sporadic cases and also in
      individuals without clinical and electrophysiological signs of neuropathy. We
      present the first Polish family with HNPP, in which the genetic defect has been
      confirmed by DNA analysis.

PMID- 10399736
TI  - [Shoulder-hand syndrome after stroke: a case report].
AB  - A case of shoulder-hand syndrome (algodystrophy, reflex sympathetic dystrophy) in
      a stroke patient is presented. Six weeks after stroke the condition started with
      pain, swelling and considerable reduction of movements of the hand and wrist
      followed by involvement of shoulder joint a few days later. Initially, the
      complaints were attributed to excessive rehabilitation, however, when cessation
      of exercises and anti-inflammatory treatment failed to improve, the diagnosis of
      shoulder-hand syndrome was suspected. Three phase bone scintigraphy performed 2
      weeks after the onset of symptoms revealed features of possible algodystrophy. X
      ray revealed no significant changes. The patient satisfactory responded to nasal
      salmon calcitonin treatment 300 units daily during 4 weeks. The reassessment
      performed 3 months after the onset of disease showed regression of most signs and
      symptoms as well as satisfactory range of motion of the hand and shoulder. Bone
      scintigraphy revealed typical algodystrophy pattern (diffusely increased
      periarticular uptake). The cause of such evolution of scintigraphic changes as
      well as some implications of nasal calcitonin administration were discussed.

PMID- 10399737
TI  - [Lipoma of the corpus callosum].
AB  - The authors present a case of lipoma of corpus callosum in a 25-years old
      patient. The results of psychological testing, plain skull X-ray. EEG
      investigation, images of CT, MRI of the brain and right carotid angiography are
      presented. The patient refused surgical treatment. His neurological state after
      discharge from hospital was good.

PMID- 10399738
TI  - [Diagnostic difficulties in a polytrauma case].
AB  - Even with the advent of the present diagnostic possibilities, polytraumas are
      still a serious problem with a large mortality. Owing to the complexity of the
      clinical picture, severe craniocerebral injury masks other extracerebral signs
      and creates a risk of unnoticeable injury of another organ. We describe a case of
      a 63 year-old patient, who suffered a polytrauma in road accident. A typical
      treatment of traumatic subarachnoid haemorrhage was administered and patient's
      state of consciousness improved. On 5-th day after the trauma the patient's state
      deteriorated. The neurological examination didn't reveal intracranial
      hypertension signs. Increasing anaemia was detected and an extracerebral reason
      of deterioration was sought. The following x-ray picture of chest was taken
      revealing elevation of the diaphragm without any other posttraumatic lesions. The
      patient was selected for thoracosurgical operation because pericordial sac
      disruption and diaphragm contusion were found. The pericardial sac was sutured.
      During further treatment the patient's state improved. He was discharged walking
      and independent.

PMID- 10399739
TI  - [Neural endoscopy in hydrocephalus treatment in a case of tuberous sclerosis].
AB  - Tuberous sclerosis is a rare, autosomal dominant neurocutaneous disease. The
      disease can also result from spontaneous mutations. Manifestations of this
      disease are typically characterized by involvement of the CNS (early childhood
      seizures, multiple brain tumours), skin (facial angiofibromas, Pringle's
      birthmarks), kidneys and liver (angiomyolipomas), heart and others. We present a
      case of 26 years old patient with brain tumour, with clinical and radiological
      signs of hydrocephalus due to a cystic lesion in the III ventricle. The patient
      was operated upon using neuroendoscopy, with clinical and radiological
      improvement.

PMID- 10399740
TI  - [The use of doppler color ultrasonography in the evaluation of superior sagittal
      sinus patency in operations for parasagittal meningiomas].
AB  - The authors present the possibility of replacement of invasive angiography by non
      invasive, safer, more accurate USG-colour Doppler performed during the operation
      to estimate the permeability of superior sagittali sinus in falx meningioma
      cases. Based on the presented case they discuss the advantages of this method in
      relation to angiography routinely performed so far.

PMID- 10399741
TI  - [Surgical treatment of hydrocephalus: comments on the use of valves inserted into
      the burr hole].

PMID- 10399742
TI  - [Report on the 71st Congress of the German Neurological Society, Munich,
      September 2-6, 1998].

PMID- 10399743
TI  - [Report on the Forum on Multiple Sclerosis: practical treatment, September 9,
      1998, Stokholm (Sweden)].

PMID- 10399744
TI  - [Report on the 7th European Conference on Cerebral Stroke, Edinburgh, Great
      Britain, May 267-29, 1998].

PMID- 10399745
TI  - Muscle ultrasound in the assessment of suspected neuromuscular disease in
      childhood.
AB  - One hundred paediatric, muscle ultrasound examinations performed in the
      evaluation of suspected neuromuscular disease were reviewed. The results were
      related to the presence or absence of neuromuscular disease in each child
      assessed. The group comprised 66 males and 34 females, age range 2 months to 16
      years (mean 5.3 years). Scans were graded I-IV, according to muscle echogenicity,
      using Heckmatt's criteria. Thirty-two children had a final diagnosis of
      neuromuscular disease. The sensitivity of ultrasound in detecting neuromuscular
      disease was 78% with 91% specificity. The test was more reliable in the sub-group
      of > 3 years with a sensitivity of 81% and specificity of 96%. There was a
      significant difference in disease status, (with and without neuromuscular
      disease), between children with a normal, grade I, scan and those with an
      abnormal, grade II, III, IV, image (chi-square, P < 0.001, 95% confidence limits
      0.54-0.86). Muscle ultrasound is a specific and sensitive investigation for
      suspected neuromuscular disease in children.

PMID- 10399746
TI  - Myopathy with trabecular muscle fibers.
AB  - A systematic review of muscle biopsies over a 15 year period in a large
      neurological hospital revealed 21 cases (7% of the total of non-inflammatory
      myopathies) with a distinctive pattern of myopathology and a limb-girdle clinical
      phenotype. The muscle pathology was dominated by a large prevalence (20-90%) of
      trabecular or lobulated fibers in which maldistribution of intermyofibrillar
      mitochondria produced a lobulated pattern of oxidative enzyme activity on
      transverse sections. The clinical picture was characterized by adult onset,
      slowly progressive muscle weakness affecting mainly proximal limb musculature,
      although mild distal weakness was also present in 60% of the cases. The
      trabecular pattern of oxidative enzyme reaction reflects maldistribution of the
      intermyofibrillar mitochondria; this may be caused by malfunction of a putative
      anchoring mechanism. While trabecular fibers can occur as a nonspecific
      alteration of muscle fibers in many diverse myopathies, the high prevalence of
      trabecular fibers as the dominant pathology in trabecular fiber myopathy makes it
      a distinctive (though not necessarily etiologically homogeneous) clinico
      pathological entity.

PMID- 10399747
TI  - Reduction of the DM-associated homeo domain protein (DMAHP) mRNA in different
      brain areas of myotonic dystrophy patients.
AB  - Myotonic dystrophy (DM) is a multisystemic disease caused by expansion of a CTG
      trinucleotide repeat in the 3' untranslated region of the DMPK protein kinase
      gene on chromosome 19q13.3. The mechanism by which this expansion causes disease
      remains unknown. It has been suggested that CTG expansion not only affects the
      expression of the DMPK gene, but also alters the nuclear RNA metabolism and
      expression of neighboring genes. DMAHP, which is expressed in various human
      tissues, including skeletal muscle, heart and brain, is immediately distal to the
      3' end of DMPK gene, in a CpG island which contains the CTG repeat. Here we
      report a 4- to 5-fold reduction of the expression of the DMAHP gene in different
      brain areas of DM patients. Our results demonstrate that [CTG]n expansion alters
      the brain DMAHP mRNA expression supporting a dominant-negative effect at the
      cellular level of DM [CTG]n mutation. The reduced brain expression of DMAHP could
      explain cerebral impairment in DM patients.

PMID- 10399748
TI  - Undetectable dystrophin can still result in a relatively benign phenotype of
      dystrophinopathy.
AB  - We present here a 28-year-old male patient with Becker muscular dystrophy whose
      skeletal muscle showed an absence of dystrophin. He has had progressive and
      predominantly proximal muscular wasting since 5 years of age, but was able to
      walk until 26 years of age. He showed hypertrophic calves, cardiomyopathy, and an
      elevated serum creatine kinase level (934 U/1). A skeletal muscle biopsy revealed
      advanced chronic myopathic changes. Immunohistochemical examination using anti
      dystrophin antibodies against C-terminus showed deficiency of the protein. Rod
      domain and N-terminus were also absent in almost all muscle fibers, but only in a
      small part of the sample, they were faintly stained. beta-Dystroglycan and
      utrophin were present only in a small number of muscle fibers. DNA and RT-PCR
      analysis showed a frame-shift deletion of exons 3-7 in the dystrophin gene. In
      such an exceptional case as this one, it is important to investigate the factors
      which determine the severity of dystrophinopathy.

PMID- 10399749
TI  - Dysfunction of sensory nerves during attacks of hypokalemic periodic paralysis.
AB  - Reversible electrophysiologic abnormalities of sensory nerve function were found
      by chance in three patients with hypokalemic periodic paralysis, a disorder
      previously considered to affect the function of muscle membranes only. A formal,
      prospective study was therefore conducted. Serial nerve conduction studies were
      done in ten additional patients. Amplitude of sensory action potentials was
      significantly smaller during paralytic attacks, but did not differ from controls
      after normalization of serum potassium concentration. These apparently novel
      findings might be explained by previous electrodiagnostic studies either not
      involving the testing of sensory nerves at all, or not being repeated after
      recovery from an attack. Involvement of sensory nerves in hypokalemic periodic
      paralysis is suggested to arise through dorsal root ganglia having an incomplete
      blood-nerve barrier and sensory neurons being particularly vulnerable to
      derangements affecting nerve cell metabolism. Neuronal inexcitability is
      postulated to occur consequent upon possible inactivation of the sodium-potassium
      pump by the low concentration of extracellular potassium. In patients with acute
      areflexic limb weakness, the diagnosis of hypokalemic periodic paralysis should
      not be excluded by abnormal results of sensory nerve conduction studies.

PMID- 10399750
TI  - Germline mosaicism of MPZ gene in Dejerine-Sottas syndrome (HMSN III) associated
      with hereditary stomatocytosis.
AB  - We report on two sisters with Dejerine-Sottas syndrome (DSS) who had a
      heterozygous Gly 167 Arg mutation in the myelin protein zero (MPZ) gene and
      hereditary stomatocytosis (HSt). Genetic haplotype analysis suggested that the
      allele with the MPZ gene mutation originated from maternal lineage. However, the
      parents, who were normal clinically and electrophysiologically, had no mutation
      in the MPZ gene. Therefore, the MPZ gene mutation in these sisters was due to
      germline mosaicism of the MPZ gene in their mother. Stomatocytosis was detected
      in their mother and a sister who had no neurological symptoms, and therefore
      autosomal dominant HSt was suspected in this family. As stomatocytosis is very
      severe in our patients with DDS, we speculate that the association of DSS with
      stomatocytosis is coincidental but may have additively affected erythrocyte
      morphology. To our knowledge, these are the first familial cases of DSS with a
      mutation due to germline mosaicism of the MPZ gene to be reported.

PMID- 10399752
TI  - A protein truncation test for Emery-Dreifuss muscular dystrophy (EMD): detection
      of N-terminal truncating mutations.
AB  - X-linked Emery-Dreifuss muscular dystrophy (EMD) is caused by mutations in the
      emerin gene. Since the emerin gene is ubiquitously expressed and since all EMD
      mutations published so far should be detectable by an RNA-based mutation assay,
      we have designed a protein truncation test for emerin. To facilitate the
      detection of mutations in the translation initiation site, reported for several
      EMD-cases, the standard tailed forward PTT-primer had to be modified. The
      effectiveness of the assay was established by a mutation scan in four EMD
      patients. Two patients could be shown to carry emerin mutations, one affecting
      the ATG translation initiation codon. The PTT-assay did not detect a mutation in
      the two other patients. Since an immunohistochemical analysis of patient-derived
      cells revealed normal emerin levels, these patients are thus affected by another
      muscular dystrophy, most likely autosomal dominant EMD.

PMID- 10399751
TI  - Immunolocalization of tumor necrosis factor-alpha and its receptors in
      inflammatory myopathies.
AB  - Adhesion molecule upregulation occurs in inflammatory myopathies, and is one of
      the myriad functions of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha acts
      via two different receptors of 55 (TNF-R55) and 75 kD (TNF-R75). We
      immunolocalized TNF-alpha and its receptors in polymyositis, inclusion body
      myositis and dermatomyositis. In each myopathy, TNF-alpha was detected in
      macrophages, in myonuclei in regenerating muscle fibers, and freely dispersed in
      endomysial or perimysial connective tissue. Many endothelial cells in
      dermatomyositis expressed TNF-alpha. TNF-R55 was strongly expressed on myonuclei
      of regenerating muscle fibers. TNF-R75 was increased on endothelial cells in the
      midst of inflammatory infiltrates in each myopathy, and on perifascicular and
      perimysial endothelia, remote from inflammatory foci in dermatomyositis. Possible
      TNF-alpha-mediated effects include: increased transendothelial cell trafficking,
      activation of T/B cells and macrophages, induction of MHC-I gene products, and
      focal muscle fiber atrophy. In dermatomyositis, the upregulated TNF-R75, via its
      consensus elements for transcription factors, may be involved in endothelial cell
      degeneration. Strong TNF-R55 expression on regenerating myonuclei is consistent
      with a role of TNF-alpha and TNF-R55 in muscle regeneration.

PMID- 10399753
TI  - Congenital muscular dystrophy with central and peripheral nervous system
      involvement in a Belgian patient.
AB  - We report a patient with congenital muscular dystrophy (CMD), developmental brain
      defects, and peripheral neuropathy. Marked hypotonia and plagiocephaly were noted
      at birth. Failure to thrive, generalized muscle weakness and wasting, absent deep
      tendon reflexes, partial seizures, and secondary microcephaly developed. Brain
      MRI showed a large area of cortical dysplasia, a thin but complete corpus
      callosum, and diffuse ventriculomegaly. Nerve conduction velocities were slow and
      creatine kinase levels only mildly elevated. Muscle biopsy showed dystrophic
      features with normal merosin, sarcoglycan, and dystrophin immunostaining. The
      Japanese Fukuyama CMD founder mutation was not detected. This is the first report
      of a patient with merosin-positive CMD, cobblestone lissencephaly, and
      demyelinating peripheral neuropathy.

PMID- 10399754
TI  - Congenital hypomyelination neuropathy with Ser72Leu substitution in PMP22.
AB  - We describe a patient with congenital hypomyelination neuropathy. The
      pathological and morphometrical findings in the sural nerve biopsy were
      consistent with a defect of myelin formation and maintenance. Direct sequence
      analysis of the genomic regions coding the peripheral myelin proteins P0 and
      PMP22 disclosed a heterozygous missense point mutation that leads to a Ser72Leu
      substitution in the second transmembrane of PMP22. Codon 72 mutations of PMP22
      are associated with different phenotypes encompassing the Dejerine-Sottas
      syndrome and including congenital hypomyelination neuropathy.

PMID- 10399755
TI  - Myasthenia gravis and peripheral neuropathy in an Amazon indigenous female.
AB  - A 15 year-old female presented with anti-acetylcholine receptor antibody-positive
      myasthenia gravis and electrophysiological signs of sensory peripheral
      neuropathy. The repetitive stimulation test showed decremental response of 31% in
      the median nerve. The clinical picture improved with prostigmine,
      corticosteroids, plasmapheresis and thymectomy. This is the first case report of
      an Amazon indigenous patient with myasthenia gravis.

PMID- 10399757
TI  - 59th ENMC International Workshop: Spinal Muscular Atrophies: recent progress and
      revised diagnostic criteria 17-19 April 1998, Soestduinen, The Netherlands.

PMID- 10399758
TI  - 4th Workshop of the European CMT-Consortium--62nd ENMC International Workshop:
      rare forms of Charcot-Marie-Tooth disease and related disorders 16-18 October
      1998, Soestduinen, The Netherlands.

PMID- 10399756
TI  - A novel de novo mutation in the triple helix of the COL6A3 gene in a two
      generation Italian family affected by Bethlem myopathy. A diagnostic approach in
      the mutations' screening of type VI collagen.
AB  - Bethlem myopathy is an autosomal dominant inherited disease producing a mild
      neuromuscular disorder, characterized mainly by muscular weakness and multiple
      joint contractures. Bethlem myopathy is caused by mutations in one of the three
      chains of collagen type VI. Here we report the clinical description and the
      molecular characterization of the defect in a two-generation Italian family in
      which a Gly-->Arg substitution disrupts the triple helix structure of the alpha 3
      chain of collagen type VI, an ubiquitous glycoprotein of the extracellular
      matrix. In this family the identification of the mutation also allowed one to
      exclude the disease in the grandfather. It is noteworthy that the father of the
      proband carries a de novo mutation, the first described for Bethlem myopathy.

PMID- 10399759
TI  - Cervical ripening.
AB  - Induction of labor is indicated when the benefits to either the mother or the
      fetus outweigh the benefits of continuing the pregnancy. The state of the cervix
      is clearly related to the success of labor induction and the duration of labor.
      In cases of unfavorable cervices, physicians usually use a ripening agent before
      inducing labor. Unfortunately, as reviewed in this article, the ideal ripening
      agent is not found yet. No method of cervical ripening has shown a consistent and
      significant reduction in CS rate. In fact, women with the most unfavorable
      cervices (Bishop score, < or = 2) still face high rates of induction failure and
      CS.

PMID- 10399760
TI  - Management of fetal distress.
AB  - Since its introduction more than 20 years ago, continuous electronic FHR
      monitoring has become the standard in most modern obstetric units. Practitioners
      well versed in FHR pattern interpretation do not question the value of fetal
      monitoring. Not only does this modality detect hypoxia early in its evolution,
      but also it allows the opportunity to understand the physiology of the hypoxia
      and to intervene if necessary. Although nonrandomized studies demonstrate an
      improvement in the perinatal death rate with continuous monitoring, most
      randomized studies have failed to confirm this observation. Continuous fetal
      monitoring has been associated in several studies with an increase in the CS
      rate; however, concomitant changes in obstetric practice have also raised the
      incidence of CS, making the interpretation of to what degree fetal monitoring is
      responsible for this increase difficult. Other than this association with an
      increased CS rate, fetal monitoring seems to present few risks. A thorough
      understanding of basic fetal heart abnormalities is crucial to prevent
      unnecessary intervention; however, although quite sensitive, FHR monitoring
      remains nonspecific in predicting fetal metabolic acidosis. Fetal pulse oximetry
      is a recent development still undergoing investigation. The ability to measure
      fetal oxygen saturation during labor adds critical information about fetal status
      and refines the interpretation of abnormal FHR patterns. If approved by the US
      Food and Drug Administration, it has the potential to affect dramatically the
      practice of obstetrics.

PMID- 10399761
TI  - Cesarean delivery rates in the United States. The 1990s.
AB  - The increase in CS rates in the United States in the 1970s and 1980s and the
      gradual decrease in the 1990s have been the focus of considerable attention
      because of the increased maternal morbidity and cost associated with the
      procedure without apparent impact on infant mortality. Focused efforts to reduce
      CS have resulted in a modest decrease the rate of primary CS and a marked
      increase in VBAC. Considerable variation in CS rates exists among regions in the
      United States and among states within those regions. The states with the higher
      CS rates are clustered in the South and Northeast regions of the United States,
      whereas rates tend to be lower in the West and Midwest. This variation cannot be
      explained by standard demographic risk factors and is likely related to local
      culture and mode of practice. Patient case mix should also be taken into account
      when comparing CS rates. Accounting for differences risk may help highlight
      differences in mode of practice and thus identify opportunities for improvement.
      Several reports from hospitals and communities of education and peer review
      programs have resulted in a significant reduction in their CS rates without
      increasing perinatal or maternal morbidity and mortality. A common theme in these
      reports of successful strategies to decrease the CS rate safely is the importance
      of physician motivation to make a change.

PMID- 10399762
TI  - Active management of labor.
AB  - The active management of labor may be one approach to achieving lower rates of
      intervention. Numerous institutions have reported lower CS rates since initiating
      this labor management scheme, and concurrent decreases in the length of labor and
      infectious morbidity have been demonstrated. Sufficient data now exist to
      conclude that such programs can be instituted without deleterious effects on
      neonatal outcomes. Nevertheless, success in decreasing CS rates has not been
      uniform and may be confined to certain settings. Other approaches to labor
      management may be as good or better at achieving low rates of intervention with
      minimum morbidity. Any approach that emphasizes advocacy for vaginal birth is
      likely to produce some success and should receive support.

PMID- 10399763
TI  - Vaginal birth after cesarean delivery.
AB  - VBAC is considered safe and is often successful in carefully selected populations
      of women. Women with prior CDs are given the option of elective repeat CD or a
      trial of labor; neither option is risk free. Less morbidity is encountered in
      women with successful VBACs versus those with elective repeat CD. Patients who
      undergo successful trials of labor experience fewer blood transfusions, fewer
      postpartum infections, and shorter hospital stays and generally have no increased
      perinatal mortality. The high CD rate begins with the high frequency of the first
      CD. Therefore, a concerted effort should be made to decrease primary CDs. Paul
      and Miller remind us of the importance of the decision to proceed with the
      initial CD in their statement, "once a cesarean, always a scar (p 1907)." Many
      patients present for prenatal care with one or more prior uterine scars. Careful
      and thoughtful counseling of patients with a previous CD regarding the risks and
      benefits of a labor trial based on the current available literature is prudent.
      Pitkin's editorial in Obstetrics and Gynecology in 1991 stated, "Without
      question, the most remarkable change in obstetric practice over the last decade
      involves management of the woman with a prior cesarean delivery (p 939)."
      Controversies regarding the management of women with scarred uteri remain. In his
      review of the CD controversy, Flamm leaves us with an important thought: "A woman
      with a prior cesarean is at increased risk regardless of her mode of birth, and
      eliminating VBAC will not eliminate the risks. Vigilance with respect to primary
      cesarean delivery is the only way to avoid this dilemma (p 315)."

PMID- 10399764
TI  - Routine use of episiotomy in modern obstetrics. Should it be performed?
AB  - Episiotomy continues to be a frequently used procedure in obstetrics despite
      little scientific support for its routine use. Although episiotomy does decrease
      the occurrence of anterior lacerations, it fails to accomplish the majority of
      goals stated as reasons for its use. Episiotomy does not decrease damage to the
      perineum but rather increases it. The midline episiotomy increases the risk for
      third-degree and fourth-degree lacerations. Episiotomy fails to prevent the
      development of pelvic relaxation and its attendant complications. Rather than
      decreasing maternal morbidity, episiotomy increases blood loss and is related to
      greater initial postpartum pain and dyspareunia. It has been associated with a
      more difficult and lengthy repair as measured by the need for suture material and
      operating room time. The claims of a protective effect on the fetus in shortening
      the second stage of labor, improving Apgar scores, and preventing perinatal
      asphyxia have not been borne out. The value of episiotomy use on a routine basis
      bears scientific examination in prospective, randomized, controlled trials. These
      types of trials are certainly achievable, ethically correct, and much needed.
      Until these trials are completed and published, obstetricians should not
      routinely perform the procedure but rather determine the need for episiotomy on a
      case-by-case basis.

PMID- 10399765
TI  - Controversies in the intrapartum management of twin gestations.
AB  - Advances in reproductive endocrine technology have helped to make twin gestations
      commonplace; however, as this article suggests, many unanswered questions and
      areas of controversy about the intrapartum management of twin gestations remain.
      Continued research in this area and the performance of prospective studies will
      shed further light on many of these topics.

PMID- 10399766
TI  - Forceps-assisted vaginal delivery.
AB  - Operative vaginal delivery using forceps has been an important part of obstetric
      practice for nearly 400 years. Countless women and their children have benefited
      from timely and expertly performed procedures. Physicians must, therefore, make
      every effort to retain these skills, to modify and improve them in every possible
      way, and to pass them on. In this way, women and children of future generations
      will benefit from the many years of experience that have gone before them.

PMID- 10399767
TI  - Shoulder dystocia.
AB  - Shoulder dystocia is an infrequent and unexpected emergency requiring rapid and
      deft solution. Identifiable risk factors include maternal diabetes, fetal
      macrosomia (especially in the presence of diabetes), and maternal history of
      previous delivery of a large infant. Other reported risk factors include arrest
      and protraction disorders of labor and midpelvic operative delivery; however,
      more than 50% of shoulder dystocia occurs in instances without identifiable risk
      factors, and permanent neonatal injury is thus unpredictable. Therefore, all
      personnel in the delivery suite must be well versed in the timely and appropriate
      application of corrective measures. Although most instances of shoulder dystocia
      cannot be predicted, the judicious use of CS delivery in diabetic patients with
      expected birth weights of more than 4250 g should reduce the risk of shoulder
      dystocia in this subgroup of patients. A trial of labor for nondiabetic patients
      with suspected fetal macrosomia is recommended because predicting actual birth
      weights in this population remains difficult.

PMID- 10399768
TI  - Peripartum hemorrhage.
AB  - This article has reviewed the causes and potential therapies for PPH. These
      include both predictable and unpreventable causes and methods of differential
      diagnosis. Triage of therapeutic interventions and prompt diagnosis are critical
      in reducing morbidity and mortality caused by PPH.

PMID- 10399769
TI  - Considerations for delivery of infants with congenital abnormalities.
AB  - The antepartum evaluation of fetuses with congenital anomalies includes
      consideration of peripartum variables, such as route of delivery, gestational
      age, and location of each, which may impact eventual outcomes. In this article,
      the controversies, risks, and benefits surrounding peripartum interventions for
      various fetal congenital anomalies are discussed.

PMID- 10399771
TI  - Emotional stability, anxiety, and natural killer activity under examination
      stress.
AB  - This study was performed to evaluate the relation between a stable personality
      trait, a mood state and immune response to an examination stress. A self-reported
      measure of emotional stability (BFQ-ES scale) was obtained in a sample (n = 39)
      randomly selected from 277 cadets; this personality trait was also investigated
      by completing a neuroticism scale (Eysenck personality inventory) and a trait
      anxiety scale (STAI). Natural killer (NK) cell activity was measured at baseline,
      long before the examination time and the examination day. The state-anxiety scale
      evaluated the response to the stressful stimulus. Taking subjects all together,
      the academic task did not result in significant modification over baseline in NK
      cell activity. Subjects were then divided into three groups based on emotional
      stability and state-anxiety scores: high emotional stability/low anxiety, medium,
      and low emotional stability/high anxiety. Examination stress induced significant
      increases in NK cell activity in the high emotional stability/low anxiety group,
      no effect in the medium group, and significant decreases in the low emotional
      stability/high anxiety group. The repeated-measure ANOVA revealed a significant
      interaction of group x period (baseline vs. examination) for both lytic units and
      percent cytolysis. The results did not change after introducing coffee and
      smoking habits as covariates. Our findings suggest that the state-anxiety acts in
      concert with a stable personality trait to modulate NK response in healthy
      subjects exposed to a psychological naturalistic stress. The relation between
      anxiety and poor immune control has been already described, whereas the ability
      of emotional stability to associate with an immunoenhancement has not yet
      reported. The peculiarity of our population, a very homogeneous and healthy group
      for life style and habits, can have highlighted the role of emotional stability,
      and may account for the difference with other studies.

PMID- 10399770
TI  - Chronic intermittent stress does not differentially alter brain corticosteroid
      receptor densities in rats prenatally exposed to ethanol.
AB  - Prenatal ethanol exposure produces hypothalamic-pituitary-adrenal (HPA)
      hyperresponsiveness to stressors. The present study tested the hypothesis that
      decreased corticosteroid receptor densities at HPA feedback sites may play a role
      in deficient feedback inhibition and the resultant HPA hyperresponsiveness that
      is observed following prenatal ethanol exposure. Brains of adult Sprague-Dawley
      rats from prenatal ethanol (E), pair-fed (PF) and ad libitum-fed control (C)
      treatment groups were examined for both mineralocorticoid receptor (MR; Type I)
      and glucocorticoid receptor (GR; Type II) densities using a cytosolic binding
      assay. Experiment 1 compared the effects of chronic intermittent stress (Stress
      Regimen I) and corticosterone (CORT) pellet implants on hippocampal
      corticosteroid receptor densities in control rats. Experiment 2 determined
      whether exposure to Stress Regimen I would differentially downregulate and
      whether adrenalectomy (ADX) would differentially upregulate hippocampal
      corticosteroid receptors in E compared with PF and C animals. Experiment 3
      examined the effects of a modified chronic intermittent stress regimen (Stress
      Regimen II) on corticosteroid receptor densities at several HPA feedback sites
      (hippocampus, prefrontal cortex, hypothalamus, and anterior pituitary) in E
      compared with PF and C animals. CORT pellet implants significantly downregulated
      hippocampal GR and MR densities in control males and females. Exposure to Stress
      Regimen I produced downregulation of hippocampal GRs and MRs in males comparable
      with that produced with CORT pellet implants, and significant downregulation of
      hippocampal GRs in females across all prenatal treatment groups. This stress
      regimen also elevated basal plasma CORT levels without concurrent changes in
      plasma CBG levels, and increased relative adrenal weights in both males and
      females. In addition, upregulation of hippocampal GRs occurred at 7 days compared
      with 24 h following ADX in females that had previously been exposed to this
      stress regimen. Following exposure to Stress Regimen II, both the downregulation
      of hippocampal corticosteroid receptors and the increase in basal CORT levels in
      males and females appear to have been abolished by the changes in housing
      condition during the period of chronic stress. Importantly, prenatal ethanol
      exposure did not differentially alter GR or MR densities at any feedback site
      under non-stressed conditions. Exposure to Stress Regimen II, revealed subtle
      effects of prenatal treatments on hippocampal GRs however it is unlikely that
      these changes in corticosteroid receptor densities mediated the feedback
      inhibition deficits observed in E animals. Together, these data demonstrate that:
      (1) a relatively mild intermittent stress regimen can increase basal CORT levels
      and downregulate hippocampal corticosteroid receptor densities (2) a seemingly
      small change in housing conditions during stress appears to eliminate both
      receptor downregulation and increase in basal CORT levels and (3) decreased
      corticosteroid receptor densities at HPA feedback sites in the brain do not
      appear to underlie the HPA hyperresponsiveness observed in E animals.

PMID- 10399772
TI  - mu-opioid receptor variants and dopaminergic sensitivity in alcohol withdrawal.
AB  - OBJECT: The endogenous opioid system plays an important role in the reinforcing
      properties of alcohol by an interconnected activation of the mesolimbic dopamine
      system. The Asn40Asp substitution polymorphism of the human mu-opioid-receptor
      (OPRM) influences binding of opioids and signal transduction and may, thereby,
      contribute to the development of alcoholism. The present study tested whether the
      Asn40Asp substitution polymorphism of the OPRM gene is associated with a
      variation in central dopaminergic sensitivity during alcohol withdrawal in
      alcoholics. METHOD: Sensitivity of central dopamine receptors was assessed by
      apomorphine-induced growth hormone (GH) secretion in 97 alcohol-dependent
      patients before and 1 week after alcohol cessation, and in a subgroup of 19
      alcoholics after 3 months of abstinence. GH response was defined as area under
      the hormone/time curve. Comparisons of the GH response were conducted between
      alcoholics carrying the Asn40Asp genotype versus those with the Asn40Asn genotype
      using U-test statistics. RESULTS: Marginal differences in apomorphine-induced GH
      response were found between both genotype groups before detoxification (P = 0.799
      (n = 97)/P = 0.459 (n = 19)) and after 3 months of abstinence (P = 0.331 (n =
      19)). In contrast, the GH response measured seven days after alcohol withdrawal
      was significantly increased in alcoholics with the Asn40Asp genotype compared
      with those carrying the Asn40Asn genotype (P = 0.013 (n = 97)/P = 0.026 (n =
      19)). CONCLUSION: Our results suggest that genetic variation of the mu-opioid
      receptor modulates the central dopaminergic sensitivity during acute alcohol
      withdrawal.

PMID- 10399773
TI  - Behavioral and hormonal effects of partner familiarity in periadolescent rat
      pairs upon novelty exposure.
AB  - In periadolescent rats, social interactions are typically characterized by
      elevated levels of playful and affiliative behavior. Aim of the present study was
      to assess the behavioral and hormonal effects of partner familiarity upon the
      separation and reunion in a novel environment of established pairs of
      periadolescent subjects. At weaning (post-natal day, PND 21), Sprague-Dawley rats
      were pair housed with a non-sibling subject of the same age and sex. On PND 35,
      the members of each pair were separated for a 24-h period, and randomly assigned
      to different experimental groups: (1) sacrificed before separation; (2)
      sacrificed immediately after the isolation period; (3-4) placed individually in a
      novel cage for 30 min either in low-light or in high-light conditions; (5-6)
      reunited for 30 min in a novel cage either with their previous cagemate
      (familiar, FAM); or (7-8) with an unfamiliar rat (UNF) of the same age and sex,
      in either light conditions. During reunion, the occurrence of social and non
      social behaviors was scored. Blood samples were collected at the end of the
      session from all groups and assayed for corticosterone (CORT). The separation of
      the two members of an established pair did not affect baseline CORT levels. Upon
      reunion, the presence of a conspecific exerted a significant buffering effect on
      the novelty-induced increase in CORT levels. Such an effect of the social
      companion appeared more marked in males than in females, and in FAM compared to
      UNF pairs. Interestingly, FAM rats also expressed a significantly higher amount
      of social investigation and play-soliciting behavior compared to UNF animals.
      Behavioral results, together with previous data, suggest that periadolescent rats
      housed in established pairs develop a sort of amicable relationship. The overall
      CORT output measured at the end of the session is also in line with this
      interpretation. As a whole, these findings indicate that periadolescence is a
      time period during rat development, during which social variables play a very
      important role in modulating both behavioral and physiological responses to
      novelty in a fashion that does not completely overlap with data on adult
      subjects.

PMID- 10399774
TI  - Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal
      women with Alzheimer's disease: results of a placebo-controlled, double-blind,
      pilot study.
AB  - Preliminary evidence from clinical studies indicates that treatment with estrogen
      augments cognitive function for women with Alzheimer's disease (AD). The
      neurobiology of estrogen, particularly its neuromodulatory and neuroprotective
      actions, provide a viable basis to support such cognition-enhancing effects. We
      conducted a placebo-controlled, double-blind, parallel-group design pilot
      clinical study to evaluate the cognitive and neuroendocrine response to estrogen
      administration for postmenopausal women with AD. Twelve women with probably AD of
      mild-moderate severity completed the study. During an eight week treatment
      period, six women received 0.05 mg/day dosage of 17 beta-estradiol via a skin
      patch and the remaining six wore a placebo skin patch. Subjects were randomized
      to equal distribution, and evaluated at baseline, at weeks 1, 3, 5, and 8 on
      treatment, and at weeks 9, 10, 11, and 13 off treatment. On each day of
      evaluation, cognition was assessed using a battery of neuropsychological tests,
      and blood samples were collected to measure plasma concentrations of estradiol
      and estrone. In addition, several neuroendocrine markers were measured in plasma
      to evaluate the relationship between estrogen-induced cognitive effects and
      fluctuations in the catecholaminergic and insulin-like growth factor systems.
      Significant effects of estrogen treatment were observed on attention (i.e.
      Stroop: number of self-corrections in the Interference condition, F[1,8] = 8.22,
      P < 0.03) and verbal memory (i.e., Buschke: delayed cued recall, F[3,30] = 4.31,
      P < 0.02). The salutary effects of estrogen on cognition were observed after the
      first week of treatment, and started to diminish when treatment was terminated.
      For women treated with estrogen, enhancement in verbal memory was positively
      correlated with plasma levels of estradiol (r = 0.96, P < 0.02) and negatively
      correlated with concentrations of insulin-like growth factor binding protein-3
      (IGFBP-3) in plasma (r = -0.92, P < 0.03). Furthermore, a trend in the data was
      evident to suggest a negative relationship between plasma levels of insulin-like
      growth factor-1 (IGF-1) and verbal memory (r = -0.86, P = 0.06). Estrogen
      administration suppressed peripheral markers of the IGF system, as evidenced by a
      negative correlation between plasma concentration of estradiol and IGF-1 (r = 
      0.93, P < 0.03), and a trend for a similar relationship between plasma levels of
      estradiol and IGFBP-3 (r = -0.86, P = 0.06). With respect to the catecholamines
      assayed, norepinephrine was positively correlated with verbal memory (r = 0.95, P
      < 0.02) for women who were treated with estrogen. Furthermore, there was a trend
      to suggest a negative relationship between plasma epinephrine levels and the
      number of errors committed on a test of attention (r = -0.84, P = 0.07). In the
      placebo group, no significant effects of estrogen replacement were evident either
      on measures of cognition or on any of the neuroendocrine markers. The results of
      this study suggest that estrogen replacement may enhance cognition for
      postmenopausal women with AD. Furthermore, several markers of neuroendocrine
      activity may serve to index the magnitude of estrogen-induced facilitation on
      cognition. In addition, research findings from the present study will provide
      important information for the design of larger prospective clinical studies that
      are essential to definitively establish the therapeutic role of estrogen
      replacement for postmenopausal women with AD.

PMID- 10399775
TI  - Transient hepatic attenuation difference (THAD) in patients without neoplasm:
      frequency, shape, distribution, and causes.
AB  - Transient hepatic attenuation difference (THAD) is a valuable finding in
      detecting hypervascular lesions. However, similar findings are also observed in
      patients even without known hepatic diseases. We elucidate the characteristic
      findings and the causes of THAD in patients without hepatic neoplasm in this
      article. Dual-phased contrast-enhanced CT studies performed in 450 patients were
      reviewed, and THAD was observed in 42 (9.3%). THAD was linear or wedge-shaped and
      was seen contiguous to the liver surface with a relatively obscure margin in 40
      of the 42 cases. The most common cause of THAD was chronic cholecystitis followed
      by previous biliary surgery. THAD was also seen in 30 patients with no hepatic
      diseases in whom it had a tendency to locate around the gallbladder fossa or in
      the periphery of the liver particularly in the left lobe. The knowledge of the
      prevalence, shape, distribution and causes of THAD is essential for the
      evaluation of contrast-enhanced CT images obtained during the arterial phase.

PMID- 10399776
TI  - Attenuation changes in periportal region during triple-phasic contrast-enhanced
      CT.
AB  - OBJECTIVE: To evaluate attenuation changes in the periportal regions of the liver
      during triphasic contrast CT. MATERIALS AND METHODS: The study group consisted of
      93 patients, all of whom underwent triphasic contrast-enhanced CT with a helical
      scanner for survey of liver disease. The three phases included the arterial
      phase, portal venous phase, and equilibrium phase. Attenuation changes in the
      periportal area in each phase were evaluated in every patient. Factors surmised
      to be related with periportal low attenuation, including elevation of venous
      pressure, presence of ascites, cardiac enlargement, and lymphadenopathy of the
      porta hepatis and lesser omental region, were also evaluated. RESULTS: Periportal
      low attenuation was seen in 65 patients (69.8%) in the portal venous phase where
      the liver parenchyma showed the largest attenuation value. Among them, periportal
      low attenuation was continuously observed in every phase in 13 patients (13.9%),
      while it was confirmed only in the portal venous phase in 28 patients (30.1%),
      and in 24 patients (32.2%) in the portal venous phase plus either the arterial or
      equilibrium phase. None of the factors that were investigated could be related to
      the appearance of periportal low attenuation. CONCLUSION: Periportal low
      attenuation was a relatively common finding in the portal venous phase of
      triphasic contrast CT, whereas it was less usual in the arterial or equilibrium
      phase.

PMID- 10399777
TI  - MR imaging of the posterior fossa structures of human embryos and fetuses.
AB  - There have been few reports on MR imaging of the developing human fetal brain.
      The aim of this article is to establish a standard atlas of developing fetal
      brain, focusing in particular on posterior fossa structures. Eighty-eight
      formalin-fixed embryos and fetuses were examined using 1.5 Tesla MR units.
      Specimens ranged from Carnegie stage 17 to 28 gestational weeks. The morphologic
      changes in developing cerebellum, cerebellar fissures, pontine flexure, fourth
      ventricle, and cerebral aqueduct were observed in each developmental period. The
      height of the fourth ventricle and cerebral aqueduct and the thickness of the
      tectum and the tegmentum of the midbrain were measured. We obtained detailed MR
      images of the developmental changes in posterior fossa structures and produced an
      atlas of these images. Our study showed that the period of visualization of
      cerebellar structures and fissures was later on MR imaging than described in past
      anatomical and embryological studies. In addition, the sudden decrease in height
      of the fourth ventricle and the cerebral aqueduct found in our study might
      reflect the presence of communication between the fourth ventricle and
      subarachnoid space.

PMID- 10399778
TI  - Reproducibility of short echo time proton magnetic resonance spectroscopy using
      point-resolved spatially localized spectroscopy sequence in normal human brains.
AB  - The reproducibility of short echo time proton MR spectroscopy (1H-MRS) in normal
      human brains was examined. Thirteen healthy volunteers were studied, and each
      underwent three MRS examinations. Second and third measurements were done on the
      same day, about two months after the first measurement, and interday and intraday
      reproducibility were evaluated. MRS was performed with proton brain
      examination/single voxel (PROBE/SV) and point-resolved spatially localized
      spectroscopy (PRESS) (repetition time = 2000 ms, echo time = 30 ms). Five
      metabolite ratios were computed; N-acetyl-aspartate (NAA)/creatine (Cr), choline
      (Cho)/Cr, myo-inositol (mI)/Cr, NAA/(NAA + Cr + Cho), and NAA/Cho. Their normal
      range and reproducibility were measured. For each metabolite ratio, there was no
      significant difference between interday difference and intraday difference,
      suggesting that the interval of two months has minimal effect on MRS
      measurements. MRS may be utilized for the observation of central nervous system
      diseases.

PMID- 10399779
TI  - Intussusception: the role of general anesthesia during hydrostatic barium
      reduction.
AB  - MATERIALS AND METHODS: A total of 74 patients with intussusception were divided
      into two groups: 43 cases in 39 patients between April 1974 and June 1988 were
      treated under general anesthesia, and 39 cases in 35 patients between July 1988
      and January 1994 were treated without it. We compared the success rates of barium
      reduction of intussusception in the two groups and used Fisher's exact
      probability test to assess whether they differed significantly. RESULTS: The
      overall success rates with general anesthesia and without general anesthesia were
      91% (39/43) and 95% (37/39), respectively. The use of general anesthesia did not
      significantly affect the success rate of barium reduction (p > 0.3). CONCLUSION:
      The use of general anesthesia for hydrostatic barium reduction of intussusception
      did not improve the success rate of this procedure. Therefore we recommend that,
      in view of its associated disadvantages, general anesthesia should not be used
      during this procedure.

PMID- 10399780
TI  - Correlation of 99mTc-GSA hepatic scintigraphy with liver biopsies in patients
      with chronic active hepatitis type C.
AB  - 99mTc-DTPA-galactosyl human serum albumin (99mTc-GSA) liver scintigraphy was
      performed in 230 patients with chronic active hepatitis type C, and its
      quantitative indices were compared with histological findings. 99mTc-GSA findings
      correlated well with four indices of the histology activity index (HAI),
      especially with the fibrosis score. Ninety patients were given interferon
      treatments, and 99mTc-GSA findings were compared with the results of the
      treatments. We classified the effects of interferon treatment into three groups
      according to clinical outcome: group 1: good effect (HCV-RNA negative, n = 34),
      group 2: moderate effect (HCV-RNA positive, but the value of GPT was normal for
      six months after the end of treatment, n = 19) and group 3: no effect (n = 37).
      Quantitative indices of 99mTc-GSA showed significant differences between groups.
      Follow-up study with 99mTc-GSA scintigrams was obtained in eight patients. The
      results of 99mTc-GSA improved in three patients in group 1 and deteriorated in
      five patients in group 3. There is a possibility that 99mTc-GSA scintigraphy can
      be used to predict the clinical outcome of chronic active hepatitis type C after
      interferon treatment.

PMID- 10399781
TI  - Quantitative evaluation of pulmonary ventilation dynamics using MR imaging:
      comparison of smokers and non-smokers.
AB  - PURPOSE: This quantitative study was conducted to evaluate lobar ventilation
      dynamics in non-smokers and smokers using MR imaging. METHODS: Ten non-smoker
      males and ten smoker males underwent MR imaging in the supine position without
      breath-holding. The volume rates and fluctuation rates were calculated for each
      lobe from MR images. TVRCs were constructed and analyzed. RESULTS: In non
      smokers, the mean volume rates for each lung and lobe arranged in order of
      diminishing values were RL (54.8%), LL (45.2%), RLL (25.9%), LUL (24.2%), LLL
      (21.0%), RUL (18.5%), and RML (10.3%). In smokers, the mean volume rates for each
      lung and lobe arranged in order of diminishing values were RL (55.7%), LL
      (44.3%), RLL (25.1%), LUL (24.0%), RUL (21.0%), LLL (19.9%), and RML (9.5%). In
      both groups, there was a tendency for the fluctuation rates of the lower lobes to
      be higher than those of the upper and middle lobes. Although TVRCs for the right
      and left lung were nearly parallel, with no time lag, the peaks of TVRCs for the
      upper and middle lobes appeared slightly earlier than those for the lower lobes.
      CONCLUSION: The evaluation of pulmonary ventilation dynamics using MR may be a
      useful non-invasive technique by which to assess lung lobar ventilation.

PMID- 10399782
TI  - Markedly high signal intensity lesions in the uterine cervix on T2-weighted
      imaging: differentiation between mucin-producing carcinomas and nabothian cysts.
AB  - PURPOSE: Both mucin-producing carcinomas and nabothian cysts in the cervix show
      very high signal intensity on T2-weighted images (WI). The purpose of this study
      was to evaluate the potential of MR imaging in differentiating mucin-producing
      carcinomas from nabothian cysts. MATERIALS AND METHODS: Forty-six patients who
      underwent hysterectomy and had very high signal intensity lesions in the uterine
      cervix on T2-WI were included in this study. The pathological diagnoses were
      mucin-producing carcinoma in 13 patients, non-mucin-producing carcinoma
      accompanied with nabothian cyst in four patients, and nabothian cyst in 29
      patients. T1-WI, T2-WI, and Gd-T1-WI were obtained in all patients. Malignancies
      were diagnosed on Gd-T1-WI as follows: (1) an enhanced lesion, (2) an irregular
      margin, (3) iso-intensity on T1-WI. In contrast, high signal intensity on T1-WI
      was considered benign. RESULTS: Thirteen of 17 malignant lesions and three of 29
      benign lesions were enhanced. Irregular margins were observed in 12 of 17
      malignant lesions and four of 29 benign lesions. Nineteen benign lesions and
      seven malignant lesions demonstrated high signal intensity on supplemental T1-WI.
      Combining the lesion criteria of enhancement, irregular lesion margin, and iso
      intensity on T1-WI, the overall accuracy, sensitivity, and specificity rates of
      diagnosing malignancy were 89%, 88%, and 90%, respectively (p < 0.01).
      CONCLUSION: MR imaging accurately differentiated mucin-producing carcinomas from
      nabothian cysts that showed high signal intensity on T2-WI in the cervical
      stroma. For diagnosing mucin-producing carcinomas and nabothian cysts when signal
      intensity was remarkably high on T2-WI, Gd-T1-WI findings provided key
      information for differentiation, and T1-WI was useful for improving specificity.

PMID- 10399783
TI  - Functional magnetic resonance imaging of auditory cortex: with special reference
      to the side of aural stimulation.
AB  - PURPOSE: To determine whether left- or right-side uniaural stimulation produces
      different fMRI activation patterns. METHODS: Subjects were 12 volunteers (8 right
      handed, 4 left-handed) with normal hearing. Functional imaging using FE-type
      multishot echo planar imaging was obtained in the axial plane during pure-tone
      and pseudoword tasks. Auditory stimuli were presented to each ear individually.
      In pure-tone tasks, subjects heard clustered sequences at 2000 Hz. In pseudoword
      tasks, subjects heard spoken Japanese syllables. The numbers of activated pixels
      in the auditory cortex were counted and compared for pure-tone and pseudoword
      tasks, as was activation according to the side of aural stimulation. RESULTS: In
      right-handed subjects, prominent activation in pure-tone tasks was noted in the
      dominant hemisphere in 100% of cases and was unrelated to the side of the
      stimulation. In pseudoword tasks, prominent activation was noted on the side
      contralateral to the stimulus in 62.5-100% of cases. In left-handed subjects,
      prominent activation was noted on the side contralateral to the stimulus in both
      pure-tone and pseudoword tasks. CONCLUSION: Left- and right-side stimulation
      produced differences in fMRI responses, especially between pure-tone and
      pseudoword tasks. Moreover, right-handedness and left-handedness affected
      results. This type of auditory fMRI may be a noninvasive indicator of language
      lateralization.

PMID- 10399784
TI  - Three-dimensional computed tomographic angiography of pulmonary vessels.
AB  - OBJECTIVE: To assess the image quality of multiple threshold display (MTD) as a
      new technique for generating three-dimensional (3D) pulmonary computed
      tomographic (CT) angiographic images. METHODS: We used MTD, a type of shaded
      surface display (SSD) offering the selection of multiple thresholds and
      transparencies, to reconstruct 3D-CT angiograms from enhanced helical CT data
      sets in 33 patients with lung disease. In MTD, eight thresholds of CT values are
      selected, and transparency is assigned to each. The selected voxels, ranging from
      -600 to 1,000 Hounsfield Units, were divided into eight classes, and transparency
      ranging from 0 to 100% was assigned to each. The CT scanner employed was a
      Toshiba Xvigor. MTD and SSD images were generated by using an Xtension with a Sun
      SPARC station 20, and they were compared by two radiologists. RESULTS: The image
      quality of MTD images was superior to that of SSD images (p < 0.01), because the
      MTD images demonstrated clearly both the major and small vessels. CONCLUSION: MTD
      is a useful technique for 3D pulmonary CT angiography.

PMID- 10399785
TI  - Interactive fusion of three-dimensional images of upper abdominal CT and FDG PET
      with no body surface markers.
AB  - The aim of this study was to propose and validate a new method of making fused
      images from CT and FDG PET images for the upper abdominal area with no body
      surface marker. PET and CT were carried out in patients with pancreatic cancer (N
      = 5) and mass-forming pancreatitis (N = 2). First, we determined the midsagittal
      plane from PET and CT data. From the difference in location of the midsagittal
      planes, rotations of Y (from back to front) and Z axes (from foot to head) and X
      translation (from right to left) were calculated. An upper pole of the kidney was
      determined from PET and CT data. It showed Y and Z translations. The images of
      the three-dimensional data sets were fused on a workstation. Reproducibility was
      assessed with randomly misaligned PET and CT data sets. Pancreatic cancer and its
      lymph node metastases were identified easily on fused images. In reproducibility
      assessment, the average error of rotation was 0.77 degree. The average errors of
      translation were 3.43, 4.70, and 9.23 mm on the X, Y, and Z axes, respectively.
      In conclusion, this PET/CT image registration technique is feasible and
      practical. It allows precise anatomical assessment of normal and abnormal FDG
      accumulation.

PMID- 10399786
TI  - A quantitative analysis of rat osteoporosis model with a microfocus X-ray tube
      and digital radiography system.
AB  - We have developed an X-ray magnification radiographic system incorporating a
      microfocus X-ray tube and an imaging plate in order to analyze the trabecular
      structure and mineral content of rat bone. Femoral bones of control, ovariectomy,
      and leuprorelin acetate depot rat groups were extracted and tested after the
      animals were sacrificed. Eleven water-equivalent phantoms, which contained
      hydroxyapatite at a density of 0 to 400 mg/cm3, were set around each femur and
      radiographed at the same time. The mean read-out signal intensity of the region
      of interest in the femur was converted to bone mineral density expressed in
      hydroxyapatite density through the use of a calibration curve relating the signal
      intensity to the hydroxyapatite density of the phantoms. The bone mineral density
      of the ovariectomy group was significantly lower than that of the control group,
      and no differences were found between the control and the leuprorelin acetate
      depot group. The present system is thought to be useful for quantitative
      evaluation of the mineral density of the rat femur.

PMID- 10399787
TI  - Treatment of age-related subfoveal neovascular membranes by teletherapy: results
      of a non-randomized study.
AB  - This investigation was designed to determine whether low-dose radiation to the
      macular region could influence the natural course of age-related subfoveal
      neovascularization. Thirty-one patients with subfoveal membranes due to age
      related macular degeneration (ARMD) were treated with 12 Gy of 6MV X-rays, and 72
      patients who were untreated served as a control group. Both groups were followed
      up. At six months of follow-up visual acuity was maintained in 54.8% and improved
      25.8% of patients treated by radiotherapy. In the control group, visual acuity
      showed deterioration in 55.5%. There was a significant difference between the
      treated and untreated groups (p < 0.01). Significant neovascular membrane
      regression or stabilization was recorded in 61.3% of treated patients at six
      months post-radiation, whereas the membranes in all. 72 control patients showed
      progressive enlargement. This non-randomized study suggested that low doses of
      radiation may be an alternative treatment for ARMD without an immediate drop in
      visual acuity or significant radiation morbidity.

PMID- 10399788
TI  - Oxygenation status and tumor response during fractionated irradiation in two
      murine tumor cell lines of same origin but different intrinsic
      radiosensitivities.
AB  - Two murine tumor cell lines derived from the same origin and having different
      intrinsic radiosensitivities, one radiosensitive, SHA3K4-Ic (Ic), and the other
      relatively radioresistant, SHA3K4-III19 (III19), were compared in vivo regarding
      oxygenation, proliferation, and tumor response during fractionated irradiation.
      Tumors transplanted into nude mice were irradiated five times a week with a
      fraction size of 3 Gy up to a total dose of 30 Gy. Oxygenation status was
      analyzed using a non-invasive system with near infrared reflection spectroscopy.
      Proliferation status was quantified as the percentage of bromodeoxyuridine
      labelled tumor cells and the percentage of necrotic area. All parameters were
      compared between untreated and irradiated tumors of the two lines. The
      oxygenation status in the untreated tumors did not correlate with tumor response.
      However, for the radioresponsive line, Ic, O2 saturation was significantly higher
      in irradiated than in untreated tumors, suggesting the existence of reoxygenation
      following fractionated irradiation. On the other hand, oxygenation status
      remained almost unchanged for the non-radioresponsive line, III19. Proliferation
      status did not correlate with tumor response. The results indicate that
      comprehensive investigations, including oxygen measurements, are necessary to
      understand the various intrinsic and extrinsic factors determining in vivo tumor
      radioresponse.

PMID- 10399790
TI  - Echocardiographic findings and 24-h electrocardiographic Holter monitoring in
      patients with nodular and non-nodular rheumatoid arthritis.
AB  - Echocardiographic examination and 24-h electrocardiographic Holter monitoring
      were carried out on 35 patients with nodular rheumatoid arthritis (RA) and 35
      with non-nodular RA, who were matched with the nodular RA group regarding age,
      sex and BSA. A further 35 patients with osteoarthrosis and spondyloarthrosis
      matched, with both RA groups, constituted a control group. Patients with a
      history of myocardial infarction, hypertension, rheumatic fever and diabetes were
      excluded from the study. Cardiac involvement, evaluated using echo-Doppler
      cardiography, 24-h electrocardiographic Holter monitoring and ECG at rest,
      occurred in 25 (71.9%) patients with nodular RA and in 15 (42.9%) with non
      nodular RA in comparison to 8 (22.9%) control group patients (P < 0.0002). Holter
      electrocardiographic monitoring over 24 h did not present any essential
      differences in frequency of rhythm disorders between the examined groups and the
      control group. However, it revealed more patients with 1-mm ST depression in the
      nodular RA group than in the non-nodular and control groups. Echocardiographic
      examination revealed more cases of valvular heart abnormalities, especially those
      of mitral insufficiency, in nodular RA patients than in non-nodular and control
      patients. Both a mitral valve prolapse and a pericardial effusion were noted in
      8.6% of nodular RA patients. Patients with nodular RA were noted to have a bigger
      aortic root diameter, but smaller ejection fraction, mean velocity of
      circumferential fibre shortening and fractional shortening in comparison to non
      nodular and to control group patients.

PMID- 10399789
TI  - Colonic anastomotic healing after preoperative chemo-radiotherapy in rat.
AB  - PURPOSE: To prevent micrometastasis at an earlier stage and to increase the
      lateral or circumferential tumor free margins, there is a rationale for neo
      adjuvant chemo-radiotherapy in patients with colorectal cancer. In order to
      investigate the effects of such a protocol on colonic anastomotic healing, an
      experimental study resembling the clinical use of neo-adjuvant concomitant 5-FU+
      irradiation treatment of colorectal cancer was conducted. MATERIALS AND METHODS:
      Seventy-one male Wistar rats were divided into three groups: a control group (I)
      underwent left colon resection and primary anastomosis (n = 20); a sham-treated
      group (II, n = 20); and a study group (III) which received fractionated
      irradiation to the whole pelvis to a total dose of 22 Gy, 5.5 Gy per fraction, in
      four consecutive days with linear accelerator and concomitant intra-peritoneal 5
      FU (20 mg/kg/day) for five consecutive days. The last fraction of irradiation and
      the last injection were given four and three days before colonic resection and
      anastomosis, respectively. Within each group one-half of the animals were
      anesthetized on the third postoperative day and one-half on the seventh
      postoperative day. Abdominal wound healing, intraperitoneal adhesions,
      anastomotic complications, and anastomotic bursting pressure measurements were
      recorded. Following these measurements the anastomotic segment was resected for
      hydroxyproline content, myeloperoxidase activity, and histopathological
      evaluation. RESULTS: There were no differences in the abdominal wound healing,
      intraperitoneal adhesions, and anastomotic complications between groups. At three
      and seven days, the mean bursting pressures of the anastomoses were 36.5 mm Hg
      and 208 mm Hg in group I, 34.5 and 228 in group II, and 27 and 167 in group III,
      respectively (p < 0.01, group III vs both groups I and II on day seven). The
      burst occurred at the anastomosis in all animals tested on the third
      postoperative day, and one in group I (10%), none in group II, and four in group
      III (40%) on the seventh postoperative day. CONCLUSION: Preoperative pelvic
      fractionated irradiation and concomitant 5-FU delays anastomotic healing.

PMID- 10399791
TI  - Agalactosyl IgG is elevated in patients with active spondyloarthropathy.
AB  - Patients with rheumatoid arthritis or with Crohn's disease have deficient
      galactosylation of serum IgG [Gal(0)]. To study whether such deviation occurs in
      patients with spondyloarthropathy (SPA), we studied the percentage incidence of
      Gal(0) corrected for age [Gal(0)corr] in 47 SPA patients undergoing
      ileocolonoscopy and correlated the findings with clinical variables and prognosis
      of the patients. Gal(0)corr was elevated in 36% of the patients. Such patients
      had a higher number of inflamed joints (P < 0.02), higher ESR (P < 0.001) and CRP
      (P < 0.001). Elevated Gal(0)corr was also of prognostic significance: at 6-month
      follow-up those with elevated levels had a higher number of inflamed joints (P <
      0.02) and ESR (P < 0.05). The presence of high Gal(0)corr did not associate with
      gut inflammation. In conclusion, a proportion of SPA patients has elevated levels
      of Gal(0), the amount of which correlates with severity of the disease and is a
      prognostic marker for chronicity of the disease.

PMID- 10399792
TI  - Sicca syndrome in patients with sarcoidosis.
AB  - Out of 134, 12 sarcoidosis patients with symptoms of mucosal dryness as the first
      clinical manifestation were identified and compared with 30 consecutive
      unselected Sjogren's syndrome (SS) patients. Sicca manifestations were similar
      among the two groups, while parotid gland enlargement (PGE) was more frequently
      found in sarcoidosis patients (P < 0.05). Patients with sarcoidosis had mainly
      pulmonary (P < 0.001) and skin involvement (P < 0.05), while SS patients
      presented more frequently with Raynaud's phenomenon (P < 0.05). Autoantibody
      profile was more often found in SS patients compared to sarcoidosis (P < 0.0025).
      The histopathological findings of minor salivary gland biopsy (MSGB) revealed
      noncaseating granulomas (NCG) in 58% of patients with sarcoidosis, while in SS,
      MSGB showed focal sialadenitis in the majority of the patients. Transbronchial
      lung biopsy (TBLB), which was performed in 10 sarcoidosis patients, revealed the
      presence of NCG in all patients. In patients with sarcoidosis and sicca symptoms
      as the presenting syndrome, PGE is a useful clinical finding. Searching for
      pulmonary involvement is a determining factor to differentiate sarcoidosis from
      SS. The absence of autoantibodies is another useful tool for the diagnosis of
      sarcoidosis. Finally, MSGB is very helpful to discriminate between sarcoidosis
      and SS and when MSGB is not specific, then TBLB is valuable to confirm the
      diagnosis.

PMID- 10399793
TI  - Is routine synovial fluid analysis necessary? Lessons and recommendations from an
      audit.
AB  - This audit of 408 synovial fluid samples, analysed for cell counts and crystals,
      revealed that crystals were present in only 25 samples (6.1%). Of these, in only
      three patients was the diagnosis uncertain and therefore the analysis helpful.
      Cell counts and types generally reflected known underlying diagnoses of
      inflammatory arthritis or osteoarthritis. Routine synovial fluid analysis does
      not contribute to diagnosis or management in established rheumatic disorders and
      should be performed only when the underlying cause is uncertain or in newly
      presenting patients. Major savings can be made by abandoning routine synovial
      fluid analysis.

PMID- 10399794
TI  - Expression of the tissue inhibitor of metalloproteinases (TIMP) gene family in
      normal and osteoarthritic joints.
AB  - The pathophysiological and biological significance of tissue inhibitor of the
      metalloproteinases-3 (TIMP-3) gene compared to other TIMPs was investigated in
      osteoarthritic (OA) human and normal bovine joint tissues. Human OA synovial
      fibroblasts in culture constitutively expressed TIMP mRNAs. TIMP-3, TIMP-1 and
      gelatinase A mRNAs were elevated in most human OA synovia over controls, while
      TIMP-2 expression was similar. TIMP-3 and TIMP-1 mRNAs present in bovine
      cartilage were inducible by serum factors. Transforming growth factor beta (TGF
      beta 1) induced TIMP-3 RNA and protein in human OA and normal bovine
      chondrocytes. TIMP mRNAs were low (TIMP-1) or undetectable in human fetal
      chondrocytes but were expressed at all other ages. Thus, the two main joint
      tissues, synovial membranes and cartilage, express TIMP genes. Due to their
      matrix protecting activities, the presence of multiple TIMPs may be beneficial
      for normal joints, while increased TIMP-3 and TIMP-1 expression in arthritic
      joints may be associated with pathological remodeling.

PMID- 10399795
TI  - Structural mechanisms of bone loss in iliac biopsies: comparison between
      rheumatoid arthritis and postmenopausal osteoporosis.
AB  - To assess the mechanisms that cause generalized osteoporosis in rheumatoid
      arthritis (RA), 40 postmenopausal women with RA (46-74 years) and 40 age-matched
      controls with osteopenia underwent iliac bone biopsies. A structural analysis of
      histomorphometry and two-dimensional strut analysis were performed. As compared
      to those with primary osteoporosis, there were a few unique characteristics in
      those with RA. Trabecular thickness and wall thickness declined with age, and
      this decline was especially accelerated by glucocorticoids. Decreased
      connectivity of the trabecular (Nd.Nd) was more prominent than the disappearance
      of the nodes. The connectivity of cortical bone to the nodes (Ct.Nd) and cortical
      thickness significantly decreased with age. With glucocorticoid therapy, the
      disappearance of the nodes was accelerated. In the case of vertebral compression
      fractures, the parameters of Nd.Nd and Ct.Nd significantly decreased. Although a
      bone biopsy is needed to analyze strut, this method is useful to evaluate the
      quality or intensity of the bone.

PMID- 10399796
TI  - Recombinant human erythropoietin improves health-related quality of life in
      patients with rheumatoid arthritis and anaemia of chronic disease; utility
      measures correlate strongly with disease activity measures.
AB  - Treatment with recombinant human erythropoietin (r-hu-Epo) in patients with
      rheumatoid arthritis (RA) and anaemia of chronic disease (ACD) resulted in
      improvement of both anaemia and disease activity. Utilities represent a generic
      and comprehensive quality of life measure, capable of integrating domain-specific
      information into one overall value which a patient assigns to his state of
      health. Therefore, the effect of r-hu-Epo on quality of life was studied by
      measuring utilities, derived from the rating scale and standard gamble, in a 52
      week placebo-controlled randomised double-blind study with r-hu-Epo in 70
      patients with active RA and ACD. Furthermore, the relation between anaemia as
      assessed by haemoglobin levels (Hb), disease activity as assessed with the
      Disease Activity Score (DAS), and utilities was investigated. Compared to the
      placebo group, significant improvement of Hb (P < 0.001), DAS (P = 0.01) and
      rating scale utilities (P = 0.002), but not of standard gamble utilities, was
      observed in the Epo group. Rating scale utilities correlated strongly with DAS (r
      = -0.47, P < 0.01), Hb (r = 0.37, P < 0.01) and changes in both DAS (r = -0.74, P
      < 0.01) and Hb (r = 0.44, P < 0.01). Both DAS and Hb contributed significantly to
      the variance in rating scale utilities (21% and 3% respectively) and to changes
      in rating scale utilities (43% and 3% respectively). Standard gamble utilities
      correlated less well with clinical disease variables than rating scale utilities
      did. These results indicate, that r-hu-Epo improves utility-derived health
      related quality of life, most probably by improving both disease activity and
      anaemia. Utilities, particularly rating scale utilities, correlated well with
      conventional disease activity variables and proved sensitive to change. Utilities
      may be a useful tool for investigating quality of life in RA-patients.

PMID- 10399797
TI  - Analysis of functional elements in the human Egr-1 gene promoter.
AB  - The early growth response (Egr)-1 gene encoding a zinc-finger transcription
      factor is transiently induced in many different cell types upon various
      differentiation signals. However, in synovial fibroblasts of rheumatoid arthritis
      patients, Egr-1 is constitutively expressed at high levels, and several genes
      with Egr-1 binding sites in their promoter regions have been associated with
      disease progression of RA. We analyzed the control of Egr-1 transcription by
      characterizing those regulatory elements in the Egr-1 promoter that induce Egr-1
      expression in fibroblasts. Using reporter gene assays and deletion mutants of the
      Egr-1 promoter we could demonstrate that Egr-1 transcription is mainly activated
      by a single serum response element, whereas other transcription factor binding
      sites, including binding sites for AP-1 or Egr-1, were found to play a minor
      role. Furthermore, we identified a novel regulatory element in the human Egr-1
      promoter similar to a NF kappa-B binding site. Deletion of this element enhanced
      Egr-1 promoter activity in 3T3 but not in L929 fibroblasts. Stimulation by
      phorbolester induced only transient Egr-1 expression in 3T3 fibroblasts but a
      extended expression of Egr-1 in L929 cells. These data suggest that in
      fibroblasts the most proximal serum response element in the Egr-1 promoter
      represents the major activation site, whereas binding of the NFkB-like factor may
      serve as negative regulatory signal for Egr-1 transcription in fibroblasts.

PMID- 10399798
TI  - Microscopic polyangiitis presenting as schizophrenia.
AB  - Primary vasculitides can affect the central nervous system but the psychiatric
      manifestations are not well described. The hallmark of the disorder is an acute
      necrotizing inflammation of the vessel media with fibrinoid necrosis. We report a
      case of a 31-year-old man who had been treated for schizophrenia but was found to
      have vasculitides of the microscopic polyangiitis type and who improved on
      therapy with corticosteroids and immunosuppressive drugs. We would like to draw
      attention to this rare but important manifestation of vasculitis, and to the
      importance of its recognition.

PMID- 10399799
TI  - Pulmonary function in chronic heart failure. Changes after heart transplantation.
AB  - To investigate the impact of chronic heart failure on pulmonary function in heart
      transplant recipients, pulmonary function was evaluated in 41 consecutive
      patients (mean age 43 years, range 15-57 years) before and 6 months after
      successful heart transplantation. The pulmonary function tests included
      measurements of forced vital capacity [FVC], forced expiratory volume in 1.s
      [FEV1], FEV1/FVC ratio, total lung capacity [TLC], and diffusion capacity for
      carbon monoxide [TLCO] and KCO [TLCO per l alveolar volume]. Compared to
      pretransplant values, spirometry after transplantation revealed modest
      improvements in FVC (from 77 +/- 16 to 88 +/- 21% of predicted [%pred]; p <
      0.001) and FEV1 (from 75 +/- 16 to 85 +/- 22%pred; p < 0.001), whereas the
      FEV1/FVC ratio was unchanged (81% +/- 11 and 80% +/- 10; p = NS). A slight but
      statistically significant increase in TLC (from 78 +/- 15 to 86 +/- 18%pred, p <
      0.001) was also observed. Prior to transplantation the mean TLCO was 76 +/-
      17%pred; 7 of the patients had a TLCO below 60%pred (mean 51% pred). In 33 of the
      41 patients a reduction in TLCO was observed after transplantation; for all 41
      patients the mean fall in TLCO was 14% of the predicted value (SD 12%pred) (p <
      0.0001). Likewise, a significant reduction in KCO was noted (p < 0.0001).
      Multiple regression analysis revealed that high pretransplant TLCO %pred (p =
      0.02) and FVC %pred (p = 0.04) were associated with a less favorable outcome
      concerning posttransplant TLCO %pred. Although normalization of FEV1, FVC and TLC
      can be anticipated after correction of severe chronic left ventricular failure by
      heart transplantation, the pronounced concomitant decline in diffusion capacity
      observed in this study may be explained by underlying pulmonary disease caused by
      factors other than long-standing heart failure. Our findings support the notion
      that pulmonary function abnormalities attributable to chronic heart failure
      should not preclude consideration for heart transplantation.

PMID- 10399800
TI  - Clinical assessment of indication for ACE-inhibitor treatment early after acute
      myocardial infarction.
AB  - An investigation was conducted to assess whether an algorithm based on simple
      clinical information would suffice to classify patients with acute myocardial
      infarction, with respect to indication for angiotensin-converting-enzyme
      inhibitor treatment. One hundred consecutive patients with myocardial infarction
      were prospectively studied. Based on clinical, radiological, electrocardiographic
      and biochemical information, the patients were classified as having (a)
      significantly depressed left ventricular function (ejection fraction < or = 40%)
      justifying treatment with angiotensin-converting-enzyme inhibitors (ACEI), (b)
      preserved ventricular function (ejection fraction > 40%) making ACEI unnecessary,
      or (c) indeterminate ventricular function, requiring further examination. Using a
      blinded design, ejection fraction was determined by echocardiography and
      radionuclide ventriculography. A clinical assumption of reduced left ventricular
      function had a predictive value of an echocardiographically determined ejection
      fraction < or = 40% of 83% (n = 23). Clinical criteria of good ventricular
      function had a predictive value of ejection fraction > 40% of 96% (n = 24). In
      these two groups clinical misclassification occurred in five patients with
      ejection fraction within the range of 39-45%. Left ventricular function was found
      to be clinically indeterminate in 53 of the 100 patients. Ejection fraction
      values assessed by radionuclide ventriculography (n = 44) were on average 9.3%
      points lower than echocardiographic values. The indication for ACEI can
      apparently be determined on the basis of readily available clinical information
      in approximately 50% of patients with acute myocardial infarction.

PMID- 10399801
TI  - Endothelial injury and trapping of blood cells in human myocardium following
      coronary bypass surgery.
AB  - To investigate the focal myocytic and microvascular injury that develops during
      the first hour of reperfusion after hypothermic cardioplegic cardiac arrest, and
      to compare the influence of gentle versus more abrupt reperfusion, serial atrial
      biopsies were obtained from 14 patients undergoing uneventful coronary bypass
      surgery. The biopsies were taken before cardioplegia, at the start of
      reperfusion, and after 20 and 60 min of reperfusion. Transmission electron
      micrographs of biopsies examined by stereological techniques revealed endothelial
      injury. Following 20 min reperfusion there was accumulation of both red blood
      cells (p = 0.03) and polymorphonuclear leucocytes (p = 0.0004) were found. There
      was also intravascular accumulation of platelets (p = 0.008) and extravasation of
      red blood cells (p = 0.02), which increased throughout the observation period. If
      reperfusion was started with a gradual rise in temperature and pressure, the
      numbers of platelets in the microvessels were lower than following ordinary,
      abrupt reperfusion (p = 0.06). It is concluded that reperfusion injury is
      associated with microcirculatory disturbances with trapping of blood cells,
      changes which may be favourably modified by a gentle reperfusion technique.

PMID- 10399802
TI  - ET-1 infusion increases systemic vascular resistance and depresses cardiac output
      in patients with chronic hypoxaemia and pulmonary hypertension.
AB  - The pulmonary vascular effects of the endothelium-derived peptide endothelin (ET)
      vary depending on the existing vascular tone, modes of administration and species
      studied; ET can cause both pulmonary vasodilatation and vasoconstriction.
      Increased plasma levels of ET have been reported in hypoxic pulmonary
      hypertension, although it is unclear whether ET is a mediator or a marker of
      hypoxia-induced increase in pulmonary vascular resistance (PVR). In our study,
      the plasma levels of ET-1 and the functional effects of ET-1 infusion in patients
      (n = 4) with chronic hypoxaemia and elevated PVR were evaluated. At rest, the
      arterial and venous ET-1-levels (13 +/- 2 and 12 +/- 1 fmol/ml, respectively)
      were significantly higher than those detected in venous plasma of an age-matched
      healthy control group (7 +/- 1 fmol/ml). Consecutive 10 min infusions of ET-1 at
      1, 5, 10 and 15 ng/kg/min into the pulmonary artery decreased cardiac output (by
      32%) and stroke volume (by 33%) and increased the systemic vascular resistance
      (by 62%) and arteriovenous oxygen difference (by 83%) at the highest dose. No
      deleterious effect was observed in the pulmonary circulation. The present study
      therefore suggests that intra-pulmonarily administered ET does not attenuate the
      increased PVR associated with chronic hypoxaemia.

PMID- 10399803
TI  - Severe impairment of graft flow without electrocardiographic changes during
      coronary artery bypass grafting.
AB  - Early graft occlusion after coronary artery bypass grafting may have deleterious
      consequences. We routinely use transit-time flowmetry after termination of
      cardiopulmonary bypass, and we report five cases of early graft failure detected
      by the flowmeter. Electrocardiographic (ECG) changes were seen in only one of
      these five cases, and none of the patients had low cardiac output or other signs
      of graft failure at the end of the operation. The cause of graft failure was
      tagging in one case, rotation of internal mammary artery grafts in two and
      kinking of vein grafts in two cases. All errors were corrected, and control
      flowmetry showed normal flow rates after correction. Flowmetry takes less than 10
      min, even with multiple bypass grafts. Based on our results, we advocate routine
      quality control with flowmetry after termination of cardiopulmonary bypass, since
      ECG changes are insufficient as checks of flow in bypass grafts.

PMID- 10399804
TI  - Differences in quality of life in men and women with ischemic heart disease. A
      prospective controlled study.
AB  - A study was conducted in Sweden in 1989-1992 to evaluate differences in quality
      of life (QL) in consecutive male and female patients after acute myocardial
      infarction (AMI), coronary artery by-pass grafting (CABG) and percutaneous
      transluminal coronary angioplasty (PTCA). Somatic and psychological dimensions of
      QL were assessed by self-administered questionnaire in patients one month (n =
      376) and one year (n = 349) after the cardiac event. Normal controls (n = 88)
      were used for comparison. Differences between gender groups, as well as between
      study patients and controls in somatic and psychological dimensions of QL were
      studied. Patients were shown to experience poorer QL when compared with
      demographically similar controls, especially at the one-month assessment. Female
      patients had poorer QL after one month (in general health, feeling of arrythmia,
      anxiety, depression, self-esteem, experience of sex life) and after one year
      (general health, anxiety, depression) compared with male patients. In all
      dimensions of QL a proportion of patients (19-45%) experienced a decrease in QL
      from the one-month to the one-year assessment occasion. Healthcare workers
      concerned with secondary prevention must be aware that QL differs between male
      and female patients in several dimensions after a cardiac event. These findings
      should be taken into account in the clinical management of patients, particularly
      for female patients who may need special attention.

PMID- 10399805
TI  - In-hospital outcome for diabetic patients with acute myocardial infarction in the
      thrombolytic era.
AB  - A 3-year retrospective study was carried out at the Department of Cardiology,
      Aalborg Hospital, Denmark. The aim of the study was to investigate the in
      hospital mortality and complications resulting from acute myocardial infarction
      in diabetic patients compared with non-diabetic patients in the thrombolytic era
      and to investigate the correlation between mortality and blood glucose levels in
      diabetic patients. All patients admitted to the study suffered acute myocardial
      infarctions. One hundred and twenty-three patients with diabetes and 856 patients
      without diabetes were included. Mortality was 13% (110 patients) in non-diabetic
      patients compared with 28% (34 patients) in diabetic patients (p = 0.00002).
      Eighty-nine patients with diabetes (72%) experienced heart failure or a worsening
      of heart failure compared with 424 patients without diabetes (50%), p = 0.00001.
      Twenty-eight diabetic patients (23%) had high-degree atrioventricular block,
      compared with only 99 non-diabetic patients (12%), p = 0.001. Atrial fibrillation
      developed in 35 patients with diabetes (28%) and in only 141 patients without
      diabetes (16%), p = 0.002. No difference was seen in occurrence of ventricular
      tachyarrhythmias. Diabetic patients with a fatal outcome had significantly higher
      blood glucose values at admission compared with diabetic patients who survived
      (17.1 +/- 8.3 vs 13.5 +/- 6.3 mmol/l; p = 0.034), and during hospitalization
      (85.7 +/- 26.0% of blood glucose values exceeding 10 mmol/l vs 64.5 +/- 33.1; p =
      0.00065). In the thrombolytic era diabetic patients with acute myocardial
      infarction had a higher mortality and experienced more complications during
      hospitalization compared with non-diabetic patients, and diabetic patients with a
      fatal outcome had higher blood glucose levels compared with surviving diabetic
      patients.

PMID- 10399806
TI  - Incidence, risk factors and management of bronchopleural fistulae after
      pneumonectomy.
AB  - Postpneumonectomy bronchopleural fistula (BPF) remains a serious and often life
      threatening complication. Over a seven-year period, seven cases of BPF occurred
      in a series of 100 consecutive pneumonectomies performed for lung carcinoma by
      the same surgical team. The incidence increased from 3% (1/33) prior to 1993 to
      9% (6/67) thereafter. The presence of tumour within the main stem bronchus and
      the need for postoperative mechanical ventilation correlated significantly with
      the occurrence of BPF. However, it is likely that other risk factors, such as the
      introduction of systematic mediastinal lymph nodes dissection since 1992 and
      bronchial stapling since 1993, were involved. In four patients, closure of BPF
      was achieved by transposition of pedicled latissimus dorsi (LD) muscle flap and
      closed-chest irrigaiton of the pleural cavity. Patients were discharged after a
      median stay of 19 d; fistula recurred in one case and was successfully treated
      with an omental flap. No complications related to the LD division were observed.
      In conclusion, mediastinal lymph node dissection may increase the risk of post
      pneumonectomy BPF. Systematic bronchial stapling should be used cautiously,
      especially if the tumour is present within the main stem bronchus. Treatment with
      predicted LD muscle flap or omental flap associated with closed-chest irrigation
      proved to be simple, time-saving and efficient.

PMID- 10399807
TI  - Spontaneous coronary artery dissection. Case report and literature review.
AB  - Primary coronary artery dissection occurring 2 months post partum in a 33-year
      old woman is described. Owing to suspected acute myocardial infarction, the
      patient was treated with thrombolytic therapy but her condition deteriorated.
      Coronary angiography showed dissection of the left anterior descending artery
      (LAD). Her condition stabilized during treatment with intravenous heparin,
      aspirin, nitrates, beta-blockers, digoxin, ACE inhibitor and anticoagulants. At
      discharge she had no symptoms of heart failure. One hundred and forty one cases
      from the literature are reviewed with special reference to patient
      characteristics, patient treatment, and prognosis. Primary spontaneous coronary
      artery dissection is a rare condition but one that must be considered when young
      people, especially post partum women, present an acute ischaemic syndrome.
      Thrombolytic therapy may be a two-edged sword and therefore early angiography
      should be considered in making the diagnosis and choosing the therapy.

PMID- 10399808
TI  - Metastatic lung choriocarcinoma resected nine years after hydatidiform mole.
AB  - A 38-year-old woman with metastatic choriocarcinoma of the lung had been treated
      for a hydatidiform mole nine years previously. During the interval she had
      conceived and given birth to a child. Following lobectomy she has been metastasis
      free for five years.

PMID- 10399809
TI  - Profound ECG abnormalities during emergency cesarean section in a patient with
      pre-eclampsia.
AB  - A case of severe ECG abnormalities occurring during pre-eclampsia is presented.
      Although these electrocardiographic changes were indicative of severe alterations
      of coronary flow, neither structural nor functional abnormalities could be
      documented during subsequent diagnostic workup. The pathogenetic pathways
      potentially involved in this case including coronary spasms are briefly
      discussed.

PMID- 10399810
TI  - Fatal pulmonary embolism after atrial septal defect closure in a paediatric
      patient.
AB  - A four-year-old girl died of massive acute bilateral pulmonary embolism 11 days
      after direct closure of a secundum atrial septal defect (ASD II), despite
      postoperative anticoagulation until the patient was ambulatory. An autopsy showed
      thrombotic deposits on the suture line of the ASD closure, bilateral 90%
      occlusion of the pulmonary arteries, and haemorrhagic ulcerative ischaemic
      colitis of the descending colon and the sigmoid.

PMID- 10399811
TI  - An outbreak of suspected poisoning of cattle by Dichapetalum sp. in Tanzania.
AB  - Between September and December 1995, 72 out of 476 cattle on 15 dairy farms in
      the Dar es Salaam region of Tanzania, died of suspected Dichapetalum poisoning.
      Following a drought and a resultant forage shortage, 12 of the farms had
      purchased hay from commercial farms in the Coast region, particularly from one
      seed and hay farm located about 60 km west of Dar es Salaam city. Following
      ingestion of the purchased hay, affected animals were acutely ill and their
      clinical signs included inappetence, dullness, high stepping gait, disinclination
      to move, jugular vein distension and gastrointestinal malfunctions. Fatal cases
      died suddenly after a short course of illness. Toxic plants identified as
      Dichapetalum mossambicense Engl. and D. stuhlmannii Engl. were found mixed in the
      hay. A diagnosis of Dichapetalum poisoning was made on the basis of history,
      clinical signs and post-mortem findings in fatal cases. On withdrawal of the
      contaminated hay, the outbreak subsided and deaths ceased. The findings of the
      investigation are discussed.

PMID- 10399812
TI  - Rinderpest antibody detected in sheep and goats before an outbreak of rinderpest
      reported in cattle in northern Tanzania.
AB  - In January 1997, serum samples from 1346 adult sheep and goats were tested by a
      competitive ELISA to determine the prevalence of rinderpest in the northern zone
      of Tanzania. Seroconversion rates of 20%, 13%, 9%, 7% and 3% in sheep and goats
      were recorded in Ngorongoro, Monduli, Hai, Arumeru and Simanjiro districts,
      respectively. The low profile and insidious nature of the rinderpest virus
      involved caused very mild disease in cattle in some of these area. The mild signs
      associated with this outbreak of rinderpest resulted in difficulty in its
      diagnosis. In these circumstances, the presence of rinderpest antibody in sheep
      and goats served as a valuable and effective indicator of the rinderpest outbreak
      in cattle.

PMID- 10399813
TI  - Coenurus cerebralis infection in Ethiopian highland sheep: incidence and
      observations on pathogenesis and clinical signs.
AB  - An investigation was carried out at Debre Berhan, Ethiopia, between 1996 and
      1997, into the epidemiology of coenurosis in Menz and Horro breeds of sheep. A
      total of 37 heads from clinically sick and 183 heads from apparently healthy
      sheep were examined post mortem for the presence of the cystic larvae of Taenia
      multiceps, of which 37 and 5 heads, respectively, contained 1 to 8 coenurus cysts
      (diameter 0.8 to 6.5 cm). The bladder worms were located in the cerebral
      hemisphere in 96% of the cases (43% and 57% for left and right, respectively), 4%
      being in the cerebellum. Prediction of cyst locations based on the direction of
      circling and head deviation had a 62% success rate. A retrospective study
      generated from the health record book at the ILRI Debre Berhan Station in 1992
      1996 (199 Horro and 174 Menz) revealed that the incidence of coenurosis ranged
      from 2.3% to 4.5%. There was no significant breed difference in the incidence.
      The age of the affected sheep ranged from 4 to 96 months, with a mean of 19.3
      months, and 72% of the cases were within the range of 6 to 24 months. In a
      complementary survey on necropsied stray dogs, 8 out of 17 were positive for
      Taenia spp. Both studies confirm the endemicity of coenurosis at the ILRI Debre
      Berhan Research Station. Appropriate strategies for the control of coenurosis are
      suggested.

PMID- 10399815
TI  - Financing the delivery of animal health services in developing countries: a case
      study of Ghana.
AB  - Inadequate financing for the delivery of animal health services in many
      developing countries has been blamed for lack of efficiency and effectiveness of
      veterinary services. There are no reports of how the delivery of veterinary
      services in Ghana is financed. The aim of this paper is to provide information on
      the funding of veterinary services in Ghana to help in decision making on
      resource allocation. Various indicators and measures were used in assessing the
      adequacy of financing and resource allocation from 1990 to 1995. These measures
      were the veterinary budget as proportions of the national budget, GDP and AGDP;
      the proportions of the veterinary budget allocated to salaries; the ratios of
      salaries to non-staff expenditure and of non-staff expenditure to veterinary
      livestock units and technical staff; coefficient of efficacy; and R-ratio. These
      generally declined or worsened over the period, deviating from recommended norms
      where such norms exist. This confirmed the paucity of financing and resource
      allocation for the delivery of veterinary services. Revenue generation from cost
      recovery over the 1993-95 period was a potential source of funding, exceeding
      100% of non-staff expenditure for 1993 and 1994. However, the revenue generated
      was not channelled back to veterinary services but went to the national coffers.
      This served as a disincentive. There is an urgent need to review how veterinary
      services are financed in Ghana, if the delivery of services is to improve in
      efficiency and effectiveness.

PMID- 10399814
TI  - Epidemiology of Trypanosoma evansi infection in crossbred dairy cattle in
      Malaysia.
AB  - An investigation into the epidemiology of Trypansoma evansi infection in
      crossbred dairy cattle was conducted for a period of 12 months on a dairy cattle
      farm in Penninsular Malaysia. The prevalence of parasitaemia was highest in
      lactating animals (13.4%), followed by those in the dry herd (8.8%), late
      pregnant animals (8.1%), early pregnant animals (4.7%), calves (0.3%) and heifers
      (0.2%). The prevalence of antigenaemia was highest in the lactating animals
      (54.7%), followed by that in dry animals (53.7%), heifers (51.1%), late pregnant
      animals (47.7%), early pregnant animals (46.5%) and calves (24.2%).

PMID- 10399816
TI  - Performance of pigs on diets containing detoxified sheanut cake.
AB  - Ninety Large White grower pigs were used to determine the most efficient way to
      hydrothermally detoxify sheanut cake (SNC) and to measure the influence of the
      detoxified SNC on the performance of grower and finisher pigs. In the first
      experiment, SNC was boiled in water for 30, 60, or 90 min, dried and included in
      the pigs' diets at a single level of 20%. There was also another treatment in
      which the SNC was only steeped in cold water overnight and a control in which the
      diet did not contain any SNC. In the second experiment, SNC which had been boiled
      for 90 min was included in the diets at 0%, 20%, 30% and 40%. In both studies,
      the pigs were fed from an average initial live weight of 20 kg until they
      attained an average final live weight of 90 kg. In the first experiment the
      average daily gains (ADG) of the pigs during the grower period were,
      respectively, 0.46, 0.32, 0.31 and 0.39 kg/day on the control, cold-treated SNC,
      30, 60 and 90 min boiled SNC diets (p < 0.01). The corresponding ADGs of pigs
      during the finisher period were 0.41, 0.36, 0.33, 0.46 and 0.55 kg/day (p <
      0.01). The feed conversion efficiencies (FCEs) were, respectively, 6.4, 7.2, 7.5,
      7.1 and 6.5 kg feed/kg live weight gain. In experiment 2, the ADGs of pigs during
      the grower period were 0.44, 0.35, 0.20 and 0.09 kg/day on 0%, 20%, 30% and 40%,
      respectively, of 90 min boiled SNC diets. The corresponding ADGs of pigs during
      the finisher period were 0.66, 0.44, 0.27 and 0.13 kg/day (p < 0.01). The FCEs
      were 4.67, 5.10, 5.90 and 7.10, respectively. The study indicated that the
      theobromine in SNC is removed by boiling in water and that the level may be
      reduced to a greater extent by boiling for 90 min rather than for 30 min. It also
      indicated that a 20% level of inclusion of 90-min heat-treated SNC should not be
      exceeded for either grower or finisher pigs.

PMID- 10399817
TI  - Reduced ovulatory and oestrous activity in zebu heifers following Trypanosoma
      vivax infection.
AB  - This paper describes a study on the oestrous and ovarian activity and responses
      to prostaglandin F2 alpha (PGF2 alpha) administration and artificial insemination
      in zebu heifers. Four cycling heifers were artificially infected with 5 x 10(6)
      Trypanosoma vivax organisms. Two heifers served as controls. Two injections of
      PGF2 alpha were given 11 days apart, commencing at the peak of parasitaemia in
      the infected animals, followed by artificial insemination 72 and 96 h after the
      second administration of PGF2 alpha. Sera were analysed for progesterone by
      radioimmunoassay, while ovarian activity and oestrus were determined by rectal
      palpation and visual observation, respectively. All the infected heifers
      developed the clinical disease. All control and infected heifers had progesterone
      profiles consistent with luteolysis and the occurrence of oestrus following the
      second administration of PGF2 alpha. Progesterone levels did not return to normal
      luteal values in infected animals, however, whilst they did so in control
      animals. No control or infected heifers became pregnant. The findings suggest
      that PGF2 alpha will induce a non-fertile oestrus in zebu heifers acutely
      infected with T. vivax. Re-ovulation is also inhibited within 22 days in a
      majority of infected animals.

PMID- 10399818
TI  - [Current concepts on structure and catalytic properties of cholinesterase from
      vertebrates and invertebrates].

PMID- 10399819
TI  - [Effect of stress and acetylcholinesterase inhibition in vivo on the erythrocyte
      Na, K-ATPase properties in rats].

PMID- 10399820
TI  - [Comparative analysis of the serum albumin level by immunochemical,
      radioisotopic, and dye-sorption protein identification in rat tissues during
      hyperoxia].

PMID- 10399821
TI  - [Phosphorus atom availability and mechanism enzyme inhibiting effect of
      organophosphorous inhibitors of cholinesterases of various origin. Results of
      conformational and correlational analysis].

PMID- 10399822
TI  - [Oxygen deficiency tolerance in rodents nonadapted and adapted to water
      environment].

PMID- 10399823
TI  - [Participation of monoaminergic hypothalamus cells in the regulation of the
      stressor body reaction in process of aging].

PMID- 10399825
TI  - Drosophila centrosomes are unable to trigger parthenogenetic development of
      Xenopus eggs.
AB  - Centrosomes are powerful and exclusive parthenogenetic agents in the Xenopus egg.
      We have previously shown that heterologous centrosomes from various vertebrate
      species were able to promote egg cleavage in Xenopus and that human centrosome
      activity was associated with an insoluble proteinacious structure that is not
      significantly simpler than the native centrosome. In this work, we have
      investigated the parthenogenetic capacity of more evolutionary distant
      centrosomes. We show that centrosomes devoid of centrioles, such as SPBs isolated
      from Saccharomyces cerevisiae, do not form asters of microtubules in cytoplasmic
      extracts from Xenopus eggs, and are inactive in the parthenogenetic test. We
      further show that Drosophila centrosomes which possess a typical centriole
      architecture, and are quite active to nucleate microtubules in Xenopus
      cytoplasmic extracts, are unable to trigger egg cleavage. This was observed both
      with centrosomes isolated from Drosophila syncytial embryos and nucleus
      centrosome complexes from the Drosophila Kc23 cell line. We demonstrate that this
      inability could not be restored after pre-incubation of Drosophila centrosomes in
      the egg cytoplasm before injection. We conclude that the parthenogenetic activity
      of a centrosome is not directly linked to its capacity to nucleate microtubules
      from the egg tubulin, and that the evolutionary conserved nine-fold symmetrical
      structure of the centriole cannot be considered as sufficient for triggering
      procentriole assembly.

PMID- 10399824
TI  - Na,K-ATPase and V-ATPase in ovarian follicles of Drosophila melanogaster.
AB  - Uncovering the cause and meaning of bioelectric phenomena in developing systems
      requires investigations of the distribution and activity of ion-transport
      mechanisms. In order to identify and localize ion pumps in ovarian follicles of
      Drosophila, we used immunofluorescence microscopy, immunoelectron microscopy,
      subcellular fractionation, immunoblots, and acridine-orange staining. We applied
      various antibodies directed against the Na,K-pump (Na,K-ATPase) and against
      vacuolar-type proton pumps (V-ATPase). During all phases of oogenesis, Na,K
      ATPase were found in apical and lateral follicle-cell membranes and, during rapid
      follicle growth (beginning with stage 10), also in nurse-cell membranes and in
      the oolemma. V-ATPase were detected in various cytoplasmic vesicles and in yolk
      spheres and, beginning with stage 10, also in apical follicle-cell membranes and
      in the oolemma. Given these and earlier results, we propose that: 1) V-ATPase
      coupled to secondary active antiporters represent the ouabain-intensitive
      potassium pumps described previously; 2) both Na,K-ATPase and V-ATPase are
      involved in bioelectric phenomena as well as in osmoregulation and follicle
      growth, especially during stages 10-12; 3) organelle-associated V-ATPase play a
      role in vesicle acidification and in yolk processing; and 4) the channel-forming
      protein ductin is a component of both V-ATPase and gap junctions in ovarian
      follicles of Drosophila.

PMID- 10399826
TI  - Correlation of the changes of the frequency of perichromatin granules with the
      RNA content of the interchromatin region of uterine cells in normal and
      ovariectomized rats. A high resolution in situ hybridization and stereological
      study.
AB  - The changes in the number of perichromatin granules (PCG) and the alterations in
      the RNA content of the interchromatin and perichromatin regions caused by
      ovariectomy and estradiol injection were studied in rat endometrial fibroblast
      and myometrial muscle cells. Twelve rats were divided in four groups. A group of
      rats was fixed without any treatment, the other three groups were ovariectomized
      and processed 21 days after the operation. One of them was studied without
      further treatment, and two groups were injected intraperitoneally with 20
      micrograms of 17 beta-estradiol hemisuccinate and fixed 0.5 and 2 h after the
      injection. The frequency of PCG was evaluated in preparations stained with EDTA
      procedure preferential for RNP. The alterations of RNA content were estimated by
      post-embedding high resolution in situ hybridization using a total DNA probe
      labeled with biotinilated nucleotides revealed by streptavidin coupled with 10 nm
      gold grains. Most of the non-nucleolar labeling is associated to RNP containing
      fibrils. Perichromatin and interchromatin granules are labeled to a lesser
      extent. Castration brings about a reduction of the number of PCG and of the
      numerical density of labeling in endometrial fibroblasts. The injection of
      estradiol causes a rapid increase in both parameters. On the contrary, the
      frequency of PCG and intensity of labeling of epithelial endometrial cells and in
      muscle cells increase after ovariectomy and are reduced by estradiol
      administration. These results suggest that estradiol may affect differentially
      various types of target cells in the same organ, and also that PCG are not the
      only nuclear compartment of pre-mRNA or mRNA altered by the changes in estradiol,
      the RNP containing fibrils located in the perichromatin and in the interchromatin
      regions are also involved.

PMID- 10399827
TI  - Drug-induced alterations in rat peritubular cell cytoskeleton result in
      proteoglycan synthesis modifications. Comparison with some intracellular
      signaling pathways.
AB  - The influence of phorbol myristate acetate (PMA), dibutyryl cAMP and insulin-like
      growth factor (IGF-1) as well as cytoskeletal disrupting drugs on morphological
      changes has been studied in peritubular cells isolated from immature rat testis.
      Morphological studies were combined with immunofluorescence investigations of
      cytoskeletal elements and their rearrangements by various agents. The results
      were correlated with modulation of proteoglycan synthesis. Peritubular cells
      exposed to dibutyryl cAMP or cytochalasin D were transformed from flattened,
      fibroblast-like into neuronal-like morphology. In such cells, destruction of
      actin filaments was accompanied with a 50% decrease in cell-associated
      proteoglycan synthesis as well as with oversulfation of total proteoglycans. On
      the contrary, peritubular cell shape has been slightly altered after addition of
      PMA, IGF-1, vinblastine or colchicine. After these treatments, destruction or
      rearrangement of cytoskeletal elements was observed; cell-layer proteoglycan
      synthesis remained either unchanged or increased while total proteoglycans were
      always undersulfated. IGF-1, PMA and dibutyryl cAMP modified the peritubular cell
      morphology, cytoskeletal organization and proteoglycan production; the
      cytoskeleton disrupting drugs such as vinblastine, colchicine and cytochalasin D
      mimicked some of these effects. These observations suggest that alterations in
      proteoglycan biosynthesis, after activation of tyrosine kinase, protein kinase C
      and protein kinase A pathways might be mediated, at least in part, by the
      disorganization of the cytoskeleton structure.

PMID- 10399830
TI  - The antimalarial agent halofantrine perturbs phosphatidylcholine and
      phosphatidylethanolamine bilayers: a differential scanning calorimetric study.
AB  - The interaction of halofantrine with phosphatidylcholine and
      phosphatidylethanolamine bilayers has been investigated by differential scanning
      calorimetry. Halofantrine caused a broadening of the gel to liquid crystalline
      phase transition endotherm of the phosphatidylcholines. A decrease in the
      transition temperature Tm and enthalpy (delta H) of transition was also observed.
      This varied with the chain length of the phospholipid and was more pronounced
      with short chain members. Halofantrine-induced changes to the thermotropic
      characteristics of dipalmitoylphosphatidylcholine (DPPC)/cholesterol bilayers
      suggested that the penetration of halofantrine into the bilayer was diminished in
      the presence of cholesterol. A more complex calorimetric profile was observed in
      the interaction of halofantrine with phosphatidylethanolamines and the results
      suggested that halofantrine did not disrupt the cooperativity of the
      phosphatidylethanolamine bilayers to the same extent as that observed with the
      phosphatidylcholines. Halofantrine caused significant perturbation of
      phospholipids and this property might have an important bearing on its
      pharmacodynamic effects.

PMID- 10399829
TI  - Follicle-like structures formed by intestinal cell lines derived from the HT29-D4
      adenocarcinoma cell line: morphological and functional characterization.
AB  - When cultured in high glucose containing medium, the human colon carcinoma cell
      line HT29-D4 and a clone derived by transfection with the MDR1 cDNA (MDR31) form
      multilayers of unorganized cells which are not polarized and are linked by
      desmosomes. Within these multilayers appear spontaneously large multicellular
      follicle-like-structures (FLS) where polarized cells linked by tight junctional
      complexes surround a lumen. Electron microscopy showed that some FLS display well
      developed brush borders with densely packed microvilli. Others have irregularly
      oriented microvilli of various lengths or are even completely devoid of apical
      differentiation. The lumen contains a variable amount of amorphous osmiophilic
      material. The apical surface of FLS forming cells express dipeptidylpeptidase IV,
      carcinoembryonic antigen, the mucin MUC1 and for the transfected cells the gp-170
      protein. The organic anion fluorescein is transported from the cell to the lumen
      of FLS. Rhodamine 123, a substrate of the gp-170 ABC transporter is also
      concentrated in the lumen formed by MDR31 cells. Verapamil and cyclosporine A
      inhibited this last transport. Cyclic AMP stimulates the formation of these
      structures since treatment of post-confluent multilayers dramatically increased
      the number of FLS in HT29-D4 and MDR31 cell cultures within 24 h. The spontaneous
      formation of these morphologically and functionally polarized structures appeared
      at random and might respond to the coincidence of fluctuating parameters of the
      regulatory pathways (cAMP, Ca2+).

PMID- 10399828
TI  - Mechanism of BMP-2 stimulated adhesion of osteoblastic cells to titanium alloy.
AB  - Cell adhesion is dependent on many factors, including the repertoire of
      extracellular matrix (ECM) proteins and their receptors, e.g. integrins,
      synthesized by the cell, the composition of the ECM adsorbed to the surface, and
      the intrinsic chemistry of the surface. Factors that govern bone cell, i.e.
      osteoblast, adhesion and ECM elaboration significantly influence its re-modeling
      into mature bone, and ultimately its ability to integrate with biomaterials used
      for orthopedic prostheses. In this study, we have investigated how treatment with
      bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor
      beta (TGF-beta) superfamily that promotes ectopic bone formation, modulates the
      organization and expression of osteoblastic cell proteins. Specifically, we
      analyzed how BMP-2 treatment affects cytoskeletal components, ECM, and alpha 5
      and beta 1 integrin receptor subunits in osteoblastic cells plated on Ti6A14V, a
      titanium alloy widely used for orthopedic implants that interacts with bone cells
      in vitro and in vivo. Osteoblastic cells were pre-treated with BMP-2 for 12 h
      prior to plating; BMP-2 treatment stimulated adhesion and proliferation of
      osteoblastic cells and this adhesive advantage was reflected in enhanced long
      term matrix mineralization in the BMP-2 pretreated cultures. Confocal laser
      scanning microscopic analysis of BMP-2 treated cells showed that enhanced
      cytoskeletal organization and focal contact formation occurred. These changes
      were accompanied by a concomitant increase in the spatial organization of
      fibronectin, whereas vitronectin, collagen type I, osteopontin, and osteocalcin
      showed little change. The changes in ECM organization correlated with increased
      fibronectin, alpha 5 and beta 1 integrin subunit, and focal adhesion kinase
      (p125FAK) expression, as well as increased p125FAK phosphorylation. By confocal
      microscopy, the alpha 5 integrin subunit was more concentrated in lamellipodia
      after BMP-2 treatment. These results demonstrate that BMP-2 significantly altered
      osteoblastic cytoskeletal and ECM organization and enhanced expression of
      fibronectin and of specific integrin receptor subunits, with concomitant changes
      in the levels and phosphorylation of p125FAK. These effects may contribute to
      downstream cellular responses important for bone cell function, and growth.

PMID- 10399832
TI  - Mixed base of hydrophilic ointment and purified lanolin to improve the drug
      release rate and absorption of water of minocycline hydrochloride ointment for
      treatment of bedsores.
AB  - A desired ointment bases for better treatment of bedsores was developed to
      improve the release rate of minocycline hydrochloride (MH) and the water
      absorption capacity using various types of hydrophobic to hydrophilic ointment
      base. The influence of purified lanolin (PL) on the release behavior of MH from
      hydrophilic ointment (HO) base was primarily focused on. It was found that the
      release rate of drug increased with increase in the hydrophilicity of the base. A
      linear correlation between the apparent release rate constant of drug from the HO
      and PL mixed ointment base at various combination ratios and the elution of
      ointment base was noted. The HO ointment base containing 30% PL had the highest
      apparent release rate constant of MH. The mixed ointment base with the lowest
      viscosity showed the highest absorption of water and elution of ointment base. In
      conclusion, it was found that HO (70%) and PL (30%) mixed ointment base was a
      promising candidate for better treatment of bedsores.

PMID- 10399831
TI  - Steroidal saponins from the bulbs of Allium karataviense.
AB  - Chemical examination of the bulbs of Allium karataviense led to the isolation of
      five new spirostanol saponins (7-11) and a new furostanol saponin (12), together
      with a known steroidal sapogenin (1) and five known saponins (2-6). The
      structures of the new saponins were determined by detailed analysis of their
      spectral data, including two-dimensional NMR spectroscopy. The steroidal saponins
      produced by A. karataviense, except for 5 and 6, were found to be based upon
      (25R)-5 alpha-spirostane-2 alpha,3 beta,5,6 beta-tetrol (alliogenin) and contain
      a beta-D-glucopyranosyl moiety with the formation of an O-glycoside linkage to C
      2 of the polyhydroxylated steroidal skeleton as the common structural feature.
      The isolated compounds were evaluated for cytostatic activity against human
      promyelocytic leukemia HL-60 cells.

PMID- 10399833
TI  - Skin disposition of drugs after topical application in hairless rats.
AB  - Drug fraction transported from a topical formulation on skin to subcutaneous
      tissues or muscles is dependent on the physicochemical properties of the
      entrapped drug. Cutaneous disposition of model drugs, antipyrine (ANP), lidocaine
      (LC) and piroxicam (PXC) as well as flurbiprofen (FP) was thus evaluated in
      hairless rats in which an agar gel disc was subcutaneously inserted into the
      abdominal region as a drug receptor and a drug donor cell was placed above it.
      Time courses of plasma level and agar gel amount were measured after topical
      application of 50% ANP, 3% LC, 1% PXC and 1% FP in hydroxypropylcellulose gel.
      Percutaneous absorption clearance of unionized form, CLab* was proportional to
      true octanol/water distribution coefficient and the order of FP > PXC > LC > ANP,
      suggesting that skin permeation of the drug was determined mainly by its
      distribution from the formulation to the skin barrier. PXC, however, had a
      relatively low flux compared to the other three drugs, probably due to its high
      molecular weight and melting point. Migration clearance of unionized form from
      systemic circulation to the subcutaneous agar gel, CLg* was also influenced by
      the lipophilicity of drugs. On the other hand, fraction from the formulation to
      the systemic circulation was in the order of PXC > FP > ANP > LC. This fraction
      was much higher than the direct migration fraction from the formulation to the
      subcutaneous agar gel. Factors determining for these fractions are still unclear.
      A drug having a low lipophilicity and a low protein binding, however, had a
      tendency to have a great targeting ability to the subcutaneous agar gel. In
      addition, most of the drug in the agar gel was contributed by the direct flow
      from formulation, not from the systemic circulation. The present in situ
      experimental method is a useful tool to evaluate skin disposition of drugs.
      Detailed understanding of the skin disposition of drugs from several formulations
      will enable the findings of a good drug and formulation candidates.

PMID- 10399834
TI  - Synthesis of phenoxyacetic acid derivatives as highly potent antagonists of
      gastrin/cholecystokinin-B receptors. III.
AB  - In order to improve the biological characteristics of DA-3934 (5), a novel
      gastrin/cholecystokinin (CCK)-B receptor antagonist, phenoxyacetic acid
      derivatives replacing the N-methyl-N-phenylcarbamoylmethyl moiety of 5 with
      various alkyl chains have been synthesized and their biological activity
      evaluated. The relationship between the structure of these compounds and their
      human gastrin receptor binding affinity showed that there should be the optimal
      size among the various N-alkyl chains. Also a significant increase in the
      receptor binding affinity was achieved by several compounds. Among those
      compounds, 2-[3-[3- [N-cyclohexylmethyl-N-[2-(N-methyl- N
      phenylcarbamoylmethoxy)phenyl]carbamoylmethyl]ureido]pheny l]acetic acid (22c)
      and (+/-)-2-[3-[3-[N-[2-(N-methyl-N- phenylcarbamoylmethoxy)phenyl]-N-(3
      methylpentyl)carbamoy lmethyl]ureido] phenyl]acetic acid (22h) exhibited high
      affinity for human gastrin receptors and were also more potent inhibitors in a
      pentagastrin-induced gastric acid secretion model than the parent compound, 5.
      The ED50 values of these compounds when administered intraduodenally to rats were
      0.12 and 0.63 mg/kg, respectively.

PMID- 10399835
TI  - Inhibition effects of 5-S-glutathionyl-N-beta-alanyl-L-dopa analogues against Src
      protein tyrosine kinase.
AB  - Twelve analogues of the antibacterial phenolic peptide 5-S-glutathionyl-N-beta
      alanyl-L-dopa (5-S-GA-L-D, 1) were synthesized via orthoquinone using tyrosinase.
      Several synthesized compounds inhibited the v-Src autophosphorylation tyrosine
      kinase reaction with an IC50 value comparable to that of herbimycin A. The
      inhibition of c-Src substrate phosphorylation was much less active than v-Src
      autophosphorylation inhibition. 5-S-GA-L-D (1) and its analogous competed with
      peptide substrate and non-compared with ATP. The analogues showed no effects on
      substrate phosphorylation by epidermal growth factor receptor (EGFR), and this
      selectivity is the most characteristic feature of the 5-S-GA-L-D and its
      analogues (1-12).

PMID- 10399836
TI  - Topology effect for DNA structure of cisplatin: topological transformation of
      cisplatin-closed circular DNA adducts by DNA topoisomerase I.
AB  - The reaction of cis-Pt(NH3)2Cl2(cis-DDP)-closed circular DNA adducts with DNA
      topoisomerse I(topo I) were studied by electron microscopy. We identified unique
      topoisomers such as a singly-linked catenane (2(1)2), trefoil (3(1), and dimetric
      catenane (2(1)2), etc., by analysis with electron micrographs. These unique
      recombination products resulted from cis-DDP-intra-twisting looped DNA adducts by
      DNA topo I, and the products could be explained a new mechanism based on an odd
      even number rule. Our results suggest a new model on the working mechanisms for
      DNA topology of cis-DDP which enhances the recombination of DNA. Based on our
      results, we propose the topological idea that the yields of a mini closed
      circular DNA and pseudo trefoil DNA, etc., can be expected by reaction of cis-DDP
      DNA-histone complexes with DNA topo I in the body.

PMID- 10399837
TI  - Pregnane glycosides, gymnepregosides G-Q from the roots of Gymnema alternifolium.
AB  - The structural elucidation of eleven new related polyoxypregnane glycosides,
      gymnepregosides G (1), H (2), I (3), J (4), K (5), L (6), M (7), N (8), O (9), P
      (10) and Q (11), from the roots of Gymnema alternifolium (Asclepiadaceae) was
      achieved by a detailed study of 1H- and 13C-NMR spectral data and chemical means.
      The results obtained for new compounds, 1-11, show that they are (20S)-pregn-6
      ene-3 beta,5 alpha,8 beta,12 beta,14 beta,17 beta,20-heptaol 3-O-glycosides, and
      all the sugars at C-3 are beta(i-->4)-linked. Some of them possess benzoyl, (E)-
      and (Z)-cin-namoyl, and tigloyl residues as the ester linkages located at C-12
      and/or C-20 of the aglycone.

PMID- 10399838
TI  - Preparation of gadopentetic acid-loaded chitosan microparticles for gadolinium
      neutron-capture therapy of cancer by a novel emulsion-droplet coalescence
      technique.
AB  - Biodegradable gadopentetic acid (Gd-DTPA)-loaded chitosan microparticles (Gd
      microCPs) were prepared as a device for gadolinium neutron-capture therapy (Gd
      NCT) by a novel emulsion-droplet coalescence technique: a water-in-oil (w/o)
      emulsion A containing chitosan and Gd-DTPA in droplets and a w/o emulsion B
      containing NaOH in droplets were mixed and stirred to solidify chitosan as a
      result of collision and coalescence between droplets of each emulsion. Gd
      microCPs prepared by using 100% deacetylated chitosan in 25% Gd-DTPA solution
      were 4.1 microns (non-lyophilized) and 3.3 microns (lyophilized) in mass median
      diameter, and were 3.4% in gadolinium content, corresponding to 11.7% as Gd-DTPA.
      The particle size and gadolinium content of Gd-microCPs were not affected by Gd
      DTPA concentration in the chitosan medium. However, the deacetylation degree of
      chitosan influenced the particle size; as the deacetylation degree of chitosan
      decreased, the particle size increased. The incorporated Gd-DTPA was not released
      entirely from Gd-microCPs in an isotonic phosphate buffered saline solution
      despite the high water-solubility of Gd-DTPA (less than 0.8% with every type of
      Gd-microCPs). These results indicated that ion-complex formation might be
      contributable to incorporation of Gd-DTPA. As a preliminary study, it was
      confirmed that the loss of gamma-ray emission by gadolinium-loading in
      microparticle was negligible in the thermal neutron irradiation test in vitro.
      These results suggested that Gd-microCPs could be a useful device for
      intratumoral injection into solid tumor on Gd-NCT.

PMID- 10399839
TI  - Synthesis of (1-azabicyclo[3.3.0]octanyl)methyl-substituted aromatic heterocycles
      and their muscarinic activity.
AB  - In our development of drugs effective against Alzheimer's disease, we have
      researched a series of aromatic compounds having a characteristic cyclic amine, 1
      azabicyclo[3.3.0]octane ring. In this report, we describe synthesis of a series
      of aromatic heterocycles with the 1-azabicyclo[3.3.0]octane ring and their
      pharmacological evaluation. 3-Amino-5-(1-azabicyclo[3.3.0]octan-5-yl)methyl-1,2,4
      oxadiazole (2b) showed the highest M1 selectivity.

PMID- 10399840
TI  - Synthesis and biological activity of the metabolites of N-[2-(1
      azabicyclo[3.3.0]octan-5-yl)ethyl]-2-nitroaniline fumarate (SK-946).
AB  - Three metabolites of N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-2-nitroaniline
      fumarate (SK-946), a novel central muscarinic cholinergic receptor agonist, were
      prepared to confirm their proposed structures, and tested for muscarinic receptor
      affinity in vitro.

PMID- 10399841
TI  - A novel synthesis of benzo[c]phenanthridine skeleton and biological evaluation of
      isoquinoline derivatives.
AB  - Benzo[c]phenanthridine skeleton was synthesized from easily available starting N
      methyl-o-toluamide 2 and o-methylbenzonitrile 5 in 7 steps. Radical cyclization
      of styrene 10 afforded 6,11-dimethyl-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5
      one 13. Most 3-arylisoquinolines have displayed strong activities against human
      tumor cell lines. Especially, indenoisoquinolinone 13 exhibited excellent
      cytotoxicity (IC50 = 0.002 microgram/ml; HCT 15).

PMID- 10399842
TI  - Two new triterpenoid saponins from Platycodon grandiflorum.
AB  - Two new triterpenoid saponins, platycoside D [3-O-beta-D-glucopyranosyl-(1-->6)
      beta-D-glucopyranosyl-(1-->6)-beta-D- glucopyranosyl-2 beta, 3 beta, 16 alpha, 23
      tetrahydroxyolean-12-ene-28-oic acid 28-O-beta-D- apiofuranosyl-(1-->3)-beta-D
      xylopyranosyl-(1-->4)-alpha-L-rhamnop yranosyl- (1-->2)-alpha-L
      arabinopyranoside] and platycoside E [3-O-beta-D-glucopyranosyl-(1-->6)-beta-D
      glucopyranosyl- (1-->6)-beta-D-glucopyranosyl-2 beta,3 beta,16 alpha,23,24
      pentahydroxyolean-12-ene-28-oic acid 28-O-beta-D-apiofuranosyl-(1-->3)-beta-D
      xylopyranosyl-(1-->4)-alp ha-L- rhamnopyranosyl-(1-->2)-alpha-L
      arabinopyranoside] were isolated from the roots of Platycodon grandiflorum.
      Structural determination is based on spectral and chemical evidence.

PMID- 10399843
TI  - Protective role of zeolite on short- and long-term lead toxicity in the teleost
      fish Heteropneustes fossilis.
AB  - The high ion-exchange capacity of zeolite (sodium aluminium silicate) enhances
      the removal of lead from water, thus decreasing its availability to fish.
      Zeolites are very important in the field of environmental preservation due to the
      low cost and ecological compatibility. Zeolites can adsorb metallic ions by
      cation exchange reactions. Continuous exposure of the teleost fish Heteropneustes
      fossilis to sublethal concentrations of lead nitrate in water solution for short
      (35 days) and long (120 days) periods decreased both the soluble protein, RNA and
      glycogen contents in the liver and the body weight, but increased the cholesterol
      content. The presence of zeolite in the exposure solution decreased all of the
      adverse effects. In fish exposed to zeolite as feed additive, all the parameters
      improved in comparison to control fish, indicating that zeolites can be used
      safely in biological systems.

PMID- 10399844
TI  - Cesium-137 and mercury contamination in lake sediments.
AB  - The contribution of fluvial discharge and global fallout of 137Cs and mercury to
      sedimentation fluxes in Lake Shinji and Lake Nakaumi, Japan, was studied. The
      fluvial flux through soil erosion accounted for 11 to 27% of accumulated 137Cs in
      the sediments in the 1950's and 1960's, which were the periods of the most
      extensive atmospheric input, and for 90 to 100% in the 1990's. The vertical
      profiles of mercury concentrations in the lake sediments studied showed a maximum
      between 1959 and 1963, which was originated mostly from the extensive use of
      mercury-agrochemicals in paddyfields of the watershed in the past. These findings
      are representative examples of long-term contamination of lake sediments caused
      by the contaminated ground soil erosion.

PMID- 10399845
TI  - Bioavailability of 2,4-D sorbed to a chlorite-like complex.
AB  - An Al(OH)x-montmorillonite (chlorite) complex (AM18) was prepared and 2,4
      dichlorophenoxyacetic acid (2,4-D) sorbed to saturation. After several washing
      cycles the 'strongly sorbed' 2,4-D was 507 micrograms g-1 AM18. The
      bioavailability of sorbed 2,4-D was assessed in a minimal salts medium with the
      AM18-2,4-D as the sole C and energy source. Over a 28-day period a Pseudomonas
      sp. degraded 23% more of the sorbed 2,4-D than could be accounted for by
      desorption from AM18 in the non-inoculated controls. Possible explanations for
      the increase in bioavailability are presented.

PMID- 10399846
TI  - Speciation of heavy metals in marine sediments vs their bioaccumulation by
      mussels.
AB  - Total contents and speciation of selected heavy metals, including Al, Fe, Co, Ni,
      Pb, Zn, Cu, Cr, were measured in sediment samples and mussels Mya arenaria and
      Astarte borealis collected in the Horsund Fjord off Spitsbergen (Norwegian Sea)
      and the Bay of Gdansk (Baltic Sea). The investigation aimed at revealing
      differences in the accumulation pattern of heavy metals in mussels inhabiting
      sediments characterized by varying metal bioavailability. The contents of metals
      adsorbed to sediments and associated with iron and manganese hydroxides, which
      were obtained by sequential extraction, were utilized as a measure of metal
      bioavailability. The contents of Cd, Pb, Zn, Cu and Cr in mussels collected off
      Spitsbergen were generally lower than those in mussels from the Baltic Sea. In
      sediments collected off Spitsbergen the bioavailable fraction represented a small
      proportion (0-3.7% adsorbed metals and 0-11% associated with metals hydroxides)
      of total heavy metal contents. In sediments from the Baltic Sea the percentages
      of metals adsorbed and bound to hydroxides were 1-46% and 1-13%, respectively.
      The differences in bioavailable metal contents measured in sediments were
      utilized to explain the different contents of metals in mussels collected in the
      corresponding sites.

PMID- 10399847
TI  - Trace element inputs into soils by anthropogenic activities and implications for
      human health.
AB  - Trace element definition and functions, and inputs into soils from the most
      important anthropogenic sources, related and not related to agricultural
      practices, of general and local or incidental concern, are discussed in the first
      part of this review. Trace element inputs include those from commercial
      fertilizers, liming materials and agrochemicals, sewage sludges and other wastes
      used as soil amendments, irrigation waters, and atmospheric depositions from
      urban, industrial, and other sources. In the second part of the review, the most
      important ascertained effects of soil trace elements on human health are
      presented. The possible relations found between some specific soil trace
      elements, such as Cd, Se, As and others, and cancer incidence and mortality, and
      diffusion of other important human diseases are reviewed. Brief conclusions and
      recommendations conclude this review.

PMID- 10399848
TI  - Development of an optimal bacterial medium based on the growth inhibition assay
      with Vibrio fischeri.
AB  - Chronic toxicity level of chemicals to bacteria can depend on composition and
      concentration of medium ingredients. This was demonstrated by means of a growth
      rate inhibition test with the marine bacterium V. fischeri. In a minimal medium
      (following the validity criterion of achieving a least cell multiplication rate)
      containing only yeast extract as organic nutrient component, V. fischeri was to
      Cu2+ 11.9 times, to Hg2+ 3 times and to Zn2+ 2.8 times more sensitive than in the
      complete defined medium. Obviously yeast extract did not interfere greatly in the
      complexation mechanisms. The detection limits of the toxicity of Cd2+, 3,5
      dichorophenol and nitrobenzene were not influenced by the substrate.

PMID- 10399849
TI  - Toxaphene and other chlorinated compounds in human milk from northern and
      southern Canada: a comparison.
AB  - Human milk from residents of northern Canada (Keewatin) was compared to that in
      national surveys of southern Canada with respect to residues of toxaphene, PCBs,
      PCDD/PCDFs, chlordane, and several other persistent organic compounds.
      Concentrations of toxaphene were approximately ten-fold higher in specimens from
      Keewatin than from the south. Toxaphene concentrations in samples from the Great
      Lakes Basin collected in 1992 were not significantly (p < 0.05) different from
      those of the rest of Canada; however they were significantly (p < 0.05) lower
      than concentrations reported in a 1986 survey. Hexachlorobenzene, trans nonachlor
      and oxychlordane were three to five times higher in concentration in the Keewtin
      samples than in samples reported in the 1992 national survey. Total PCB
      congeners, DDTs, PCDD/PCDFs, and other chlorinated compounds were not
      significantly higher in northern samples.

PMID- 10399850
TI  - Saturation units for use in aquatic bioassays.
AB  - Methods were developed for preparing liquid/liquid and glass wool column
      saturators for generating chemical stock solutions for conducting aquatic
      bioassays. Exposures have been conducted using several species of fish,
      invertebrate, and mollusks in static and flow-through conditions using these
      methods. Stock solutions for 82 organic chemicals were prepared using these
      saturation units. The primary purpose of stock generation was to provide a
      continuous and consistent amount of toxicant laden solution at a measured
      analytical level which would be available to test organisms for the test
      duration. In the present study, the glass wool column and liquid/liquid
      saturators were used to provide consistent stock concentrations, at times
      approaching saturation, for fathead minnow (Pimephales promelas) acute exposures.
      Attempts were made to achieve the maximum solubility of these compounds for
      comparison purposes to water solubility values available in the literature.
      Literature solubility values from a database by Yalkowsky et al. [1] provided
      information on temperatures and data quality which allowed comparison to values
      obtained from the present study. Twenty four compounds were identified and
      analyzed for the comparison of maximum obtainable solubility levels. Maximum
      saturator stock water concentrations were generally lower (R = 0.98) but were in
      close agreement with published water solubility values.

PMID- 10399851
TI  - Solid-phase analytical derivatization: enhancement of sensitivity and selectivity
      of analysis.
AB  - Analytical derivatizations enhance the sensitivity and selectivity of
      determinations for organic compounds. Classical techniques are often based on
      solution chemistry. Most modern sample preparation techniques, however, are based
      on solid-phase extractions. Solid-phase analytical derivatization bridges this
      gap and facilitates sample preparation by combining the isolation step with the
      derivatization. The solid-phase retains both reagents and derivatized analytes
      and often permits facile separation of excess reagent or selective elution of the
      desired products. The most recent solid-phase extraction techniques have been
      used in conjunction with analytical derivatization to automate the analysis. In
      this review, analytical derivatizations are presented as functional group
      analysis.

PMID- 10399852
TI  - Cyclodextrin derivatives as chiral selectors for direct gas chromatographic
      separation of enantiomers in the essential oil, aroma and flavour fields.
AB  - This article reviews papers published over the period 1995-1998 dealing with the
      application of cyclodextrin derivatives (CDs) as chiral selector for direct
      enantiomer GC separation of volatile optically active components in the essential
      oil, extract, flavour and aroma fields. For each application, the racemate
      analysed, the CD employed as chiral selector and the matrix investigated are
      reported. The applications are grouped by analytical technique employed:
      capillary gas chromatography and capillary gas chromatography-mass spectrometry
      (GC and GC-MS); two-dimensional gas chromatography (GC x GC); capillary gas
      chromatography-isotope ratio-mass spectrometry (GC-IRMS); liquid chromatography
      capillary gas chromatography (LC-GC).

PMID- 10399853
TI  - Gas chromatography in space.
AB  - Gas chromatography has proven to be a very useful analytical technique for in
      situ analysis of extraterrestrial environments as demonstrated by its successful
      operation on spacecraft missions to Mars and Venus. The technique is also one of
      the six scientific instruments aboard the Huygens probe to explore Titan's
      atmosphere and surface. A review of gas chromatography in previous space missions
      and some recent developments in the current environment of fiscal constraints and
      payload size limitations are presented.

PMID- 10399854
TI  - Profiling of organic acids by capillary gas chromatography-mass spectrometry
      after direct methylation in urine using trimethyloxonium tetrafluoroborate.
AB  - Trimethyloxonium tetrafluoroborate (TMO) is applied as derivatising reagent to
      transform urinary organic acids into their methyl esters. The method is suggested
      as an alternative to the use of diazomethane which is carcinogenic and explosive.
      In contrast to other methods avoiding diazomethane, such as derivatizations with
      acetyl chloride-methanol and boron trifluoride-methanol, which require an organic
      reaction medium and therefore an extraction of the organic acids from the urine,
      TMO efficiently reacts with the acids in an aqueous solution and can therefore be
      directly applied to native urine. The use of TMO simplifies and improves the
      sample preparation in the profile analysis of urinary organic acids by capillary
      GC-MS and hereby increases the speed of analysis. The method gives reproducible
      results which are comparable with the data obtained using conventional solid
      phase extraction with strong anion-exchange cartridges prior to derivatisation.

PMID- 10399855
TI  - Clinical applications of gas chromatography and gas chromatography-mass
      spectrometry of steroids.
AB  - This review article underlines the importance of gas chromatography-mass
      spectrometry (GC-MS) for determination of steroids in man. The use of steroids
      labelled with stable isotopes as internal standard and subsequent analysis by GC
      MS yields up to now the only reliable measurement of steroids in serum. Isotope
      dilution GC-MS is the reference method for evaluation of routine analysis of
      serum steroid hormones. GC-MS is an important tool for detection of steroid
      hormone doping and combined with a combustion furnace and an isotope ratio mass
      spectrometer the misuse of testosterone by athletes can be discovered. Finally
      the so called urinary steroid profile by GC and GC-MS is the method of choice for
      detection of steroid metabolites in health and disease.

PMID- 10399856
TI  - Introduction to the application of capillary gas chromatography of performance
      enhancing drugs in doping control.
AB  - Performance-enhancing drugs banned by antidoping rules are detected in doping
      control preferably by hyphenated chromatographic techniques, capillary gas
      chromatography in particular. Based on the prohibited classes of substances and
      on the general aspects of sample collection and preparation, a survey is given
      about the usual procedures of screening, identification and confirmation of the
      most important doping agents: stimulants, narcotics, anabolics, diuretics, beta
      blockers. In addition to gas chromatography itself, the application of various MS
      techniques doping is outlined.

PMID- 10399857
TI  - Carbohydrate profiling of bacteria by gas chromatography-mass spectrometry and
      their trace detection in complex matrices by gas chromatography-tandem mass
      spectrometry.
AB  - Bacterial cellular polysaccharides are composed of a variety of sugar monomers.
      These sugars serve as chemical markers to identify specific species or genera or
      to determine their physiological status. Some of these markers can also be used
      for trace detection of bacteria or their constituents in complex clinical or
      environmental matrices. Analyses are performed, in our hands, employing
      hydrolysis followed by the alditol acetate derivatization procedure. Substantial
      improvements have been made to sample preparation including simplification and
      computer-controlled automation. For characterization of whole cell bacterial
      hydrolysates, sugars are analyzed by gas chromatography-mass spectrometry (GC
      MS). Simple chromatograms are generated using selected ion monitoring (SIM).
      Using total ion GC-MS, sugars can be readily identified. In more complex clinical
      and environmental samples, markers for bacteria are present at sufficiently low
      concentrations that more advanced instrumentation, gas chromatography-tandem mass
      spectrometry (GC-MS-MS), is preferred for optimal analysis. Using multiple
      reaction monitoring, MS-MS is used (replacing more conventional SIM) to ignore
      extraneous chromatographic peaks. Triple quadrupole and ion trap GC-MS-MS
      instruments have both been used successfully. Absolute chemical identification of
      sugar markers at trace levels is achieved, using MS-MS, by the product spectrum.

PMID- 10399858
TI  - Trace analysis of pesticides by gas chromatography.
AB  - The analysis of pesticides is relevant to both food quality and the environment.
      Many laboratories are occupied with the analysis of pesticides in food, water or
      soil. Capillary gas chromatography is the technique most widely used in pesticide
      analysis. In present laboratory practice it serves as a screening method for over
      300 pesticides. In this review we describe the role of gas chromatography as an
      analytical tool in combination with currently used or recently developed sample
      preparation techniques.

PMID- 10399859
TI  - Recent developments in the high-resolution gas chromatography of polychlorinated
      biphenyls.
AB  - The capillary gas chromatography of polychlorinated biphenyls (PCBs) is reviewed.
      Focus is on the most recent developments in the separation and detection of PCBs
      rather than sample preparation methods. Included are a comprehensive look at
      stationary phases that have been used to separate PCBs and the relatively new
      work on chiral separations of PCBs. Mass spectrometry and atomic emission are
      presented as selective detection techniques. Suggestions for additional research
      are proposed where appropriate.

PMID- 10399861
TI  - Classification and clinical features of motor neurone diseases and motor
      neuropathies in adults.
AB  - The term motor neurone disease encompasses combined upper and lower motor neurone
      disorders (amyotrophic lateral sclerosis), pure lower motor neurone disorders
      (spinal muscular atrophies, multifocal motor neuropathies, post irradiation
      lumbosacral radiculopathy, post-polio syndrome, hereditary bulbar palsy) and pure
      upper motor neurone disorders (primary lateral sclerosis, hereditary spastic
      paraplegia, neurolathyrism, Konzo). The chief clinical and electrophysiological
      criteria for these different disorders are discussed, with particular attention
      to diagnostically distinctive characteristics of each. Age of onset, and
      inheritance are considered as additional diagnostic features.

PMID- 10399862
TI  - Myotonic dystrophy and proximal myotonic myophathy.
AB  - Myotonic dystrophy (DM) is a well-known multisystem disorder with dominant
      inheritance. Proximal myotonic myopathy (PROMM) has been defined only recently,
      it is rather similar to but distinct from DM. Molecular genetic testing of the
      CTG trinucleotide repeat expansion is a reliable diagnostic method in DM. In
      PROMM these CTG repeats are normal, and no genetic test is so far available.
      Comparing the phenotypes of DM and PROMM, an important point seems to be that
      PROMM is a more benign disorder. There are almost no obvious mental changes in
      PROMM patients; premature death is extremely rare; anticipation appears to be
      present but to a milder degree; a severe congenital type of PROMM apparently is
      very rare if it occurs at all. On the other hand, at least in the German
      population, the frequency of PROMM may be almost equal to that of DM.

PMID- 10399863
TI  - Cyclosporine neurotoxicity: a review.
AB  - Cyclosporin A (CsA) induces neurological side effects in up to 40% of patients. A
      reversible posterior leukoencephalopathy syndrome is the most serious
      complication. Symptoms include headache, altered mental functioning, seizures,
      cortical blindness, and other visual disturbances, with hypertension.
      Neuroimaging studies show white matter changes in the posterior regions of the
      brain. Other neurological side effects of CsA include tremor, diffuse
      encephalopathy, cerebellar syndrome, extrapyramidal syndrome, pyramidal weakness,
      and peripheral neuropathy. Hypertension, hypomagnesemia, hypocholesteremia, and
      the vasoactive agent endothelin may all play a role in the pathogenesis of CsA
      neurotoxicty. Neurotoxicity is more frequent with high CsA blood levels, but
      levels may be within the therapeutic range. Dose reduction or withdrawal of CsA
      usually results in resolution of clinical symptoms and of neuroimaging
      abnormalities.

PMID- 10399864
TI  - Abolished laser-evoked potentials and normal blink reflex in midlateral medullary
      infarction.
AB  - We investigated two patients presenting with the rare finding of almost isolated
      hemianalgesia with a sensory level on the contralateral side sparing the face.
      Clinical findings, electrophysiological studies (absent laser-evoked pain-related
      somatosensory potentials, normal electrically evoked somatosensory potentials,
      magnetically evoked potentials, and blink reflexes), and magnetic resonance
      imaging showed the ventrolateral medullar tegmentum containing the spinothalamic
      tract to be affected by lacunar infarction. The blink reflex R2 component was
      unimpaired in both patients.

PMID- 10399865
TI  - Why do some Friedreich's ataxia patients retain tendon reflexes? A clinical,
      neurophysiological and molecular study.
AB  - Among 101 patients homozygous for GAA expansion within the X25 gene, 11 from 8
      families had Friedreich's ataxia with retained reflexes in the lower limbs
      (FARR). These patients had a lower occurrence of decreased vibration sense, pes
      cavus, and echocardiographic signs of left ventricular hypertrophy than the 90 FA
      patients with areflexia. The mean age at onset was significantly later (26.6+/
      11.4 vs. 14.2+/-6.9 years), and the mean size of the smaller allele was
      significantly less (408+/-252 vs. 719+/-184 GAA triplets) in FARR patients. The
      neurophysiological findings were consistent with milder peripheral neuropathy and
      milder impairment of the somatosensory pathways in FARR patients.

PMID- 10399867
TI  - Medication-induced hallucination and cerebral blood flow in Parkinson's disease.
AB  - Although hallucinations in Parkinson's disease (PD) are not unusual in the long
      term treatment with anti-parkinsonian agents, their mechanism is not fully
      understood. We compared both the neuropsychiatric state and the results of 99mTc
      labeled hexamethyl propyleneamine oxime single-photon emission computed
      tomography in 12 PD patients with medication-induced hallucinations and 21 PD
      patients without hallucinations. Hallucinatory patients showed significantly
      lower cerebral blood flow in left temporal regions than nonhallucinatory
      patients. The cerebral blood flow reduction in these regions may be related to
      the mechanism of medication-induced hallucinations in PD.

PMID- 10399866
TI  - Activation of macrophages/microglia with the calcium-binding proteins MRP14 and
      MRP8 is related to the lesional activities in the spinal cord of HTLV-I
      associated myelopathy.
AB  - Macrophages and microglia may play an important role in the pathogenesis of
      chronic inflammatory process in HTLV-I associated myelopathy (HAM) and tropical
      spastic paraparesis (TSP). However, the etiology and cellular mechanism of
      chronic inflammation are poorly understood in HAM/TSP. To help to define the
      roles of macrophages and microglia we analyzed the various patterns of macrophage
      and microglia activation in the central nervous system (CNS) of HAM/TSP using
      several monoclonal antibodies recognizing the different states of activation. The
      results indicate that a large number of macrophages and microglia express both
      MRP14 and MRP8 in active-chronic inflammatory lesions of the patients with a
      short duration of illness (2.5 years). In the patient whose duration of illness
      was 4.5 years, perivascular and parenchymal macrophages and microglia were
      reactive for MRP8 but not for MRP14. In contrast, MRP14 and MRP8 were negative on
      the perivascular and parenchymal macrophages and microglia in inactive-chronic
      lesions and in controls. This study suggests that (a) activated macrophages and
      microglia as well as CD4+ T lymphocytes and CD8+ cytotoxic T lymphocytes are main
      components of the inflammatory process in the CNS in HAM/TSP, (b) activation of
      macrophages and microglia is related to the amount of HTLV-I proviral DNA in
      situ.

PMID- 10399868
TI  - Butyrycholinesterase K variant and Alzheimer's disease.
AB  - This study attempted to corroborate findings on the association between
      butyrylcholinesterase K variant and Alzheimer's disease. This was performed on an
      autopsy-confirmed series of patients with Alzheimer's disease and controls. The
      butyrylcholinesterase K variant was found to be of increased allele frequency in
      patients with sporadic Alzheimer's disease. When related to APOE epsilon4 typing
      the association was specific but not sensitive for the diagnosis of Alzheimer's
      disease.

PMID- 10399869
TI  - The criteria of the International Headache Society for Tolosa-Hunt syndrome need
      to be revised.
AB  - In 1988 the International Headache Society defined the diagnostic criteria of
      Tolosa-Hunt syndrome (THS) to include episode(s) of unilateral orbital pain for
      an average of 8 weeks if untreated, with associated paresis of one or more of the
      third, fourth, and sixth cranial nerves. Cranial nerve paresis may coincide with
      the onset of pain or follow it within a period of up to 2 weeks, and the pain
      must be relieved within 72 h after the initiation of corticosteroid therapy.
      Other causative lesions must be excluded by neuroimaging. On the basis of the
      history and neuroradiological findings of six patients we show the pitfalls in
      diagnosing THS with these criteria. We propose a revision of the criteria: Other
      causative lesions must be excluded by neuroimaging, especially of the region of
      the cavernous sinus and the orbita, and by blood and CSF examinations. Since
      imaging techniques have dramatically improved, it is now possible to visualize
      the inflammatory tissue in THS. Positive magnetic resonance imaging or computed
      tomography findings compatible with inflammatory tissue neither exclude nor
      confirm THS and remain suspect until a malignant tumor or inflammation other than
      THS is excluded. Clinical and radiological follow-up examinations must be
      performed for at least 2 years, even in patients with negative findings on
      magnetic resonance imaging at onset.

PMID- 10399870
TI  - L-2-hydroxyglutaric aciduria: two Japanese adult cases in one family.
AB  - We report two adult Japanese sisters with L-2-hydroxy-glutaric aciduria
      (acidemia), both of whom were much older (aged 57, 47 years old) than previously
      reported patients (from neonate to 44 years old), and who presented with
      differing severity. Magnetic resonance imaging revealed typical subcortical white
      matter lesions in both cases and showed brainstem atrophy and thickness of the
      calvarium in the elder sister. L-2-Hydroxyglutaric acid levels were increased in
      urine, plasma, and cerebrospinal fluid. These cases suggest that organic acid
      analysis is necessary even in elderly patients who seem to have neurodegenerative
      disorders.

PMID- 10399871
TI  - Supratentorial atrophy in spinocerebellar ataxia type 2: MRI study of 20
      patients.
AB  - There have been only few studies of brain magnetic resonance imaging (MRI) in
      spinocerebellar ataxia (SCA) type 2. We investigated 20 SCA2 patients, from 11
      Sicilian families, and 20 age-matched control subjects using MRI. Our data
      confirm that olivopontocerebellar atrophy (OPCA) is the typical pattern in SCA2.
      We found no significant correlation between infratentorial atrophy, disease
      duration, or the number of CAG repeats in our SCA2 patients, but there was
      supratentorial atrophy in 12 patients, with a significant correlation between
      supratentorial atrophy and disease duration. OPCA appears to represent the "core"
      of the SCA2: however, central nervous system involvement is not limited to
      pontocerebellar structures. We therefore consider central nervous system
      degeneration in SCA2 as a widespread atrophy. MRI is helpful in diagnosing SCA,
      but it is not diagnostic in the absence of clinical and molecular studies. We
      suggest that serial MRI may play a role in evaluating "in vivo" the progressive
      steps of neurodegeneration in SCA2, for a better comprehension of the
      pathophysiology of this disorder.

PMID- 10399872
TI  - Clinical and molecular studies of 73 Italian families with autosomal dominant
      cerebellar ataxia type I: SCA1 and SCA2 are the most common genotypes.
AB  - We clinically and genetically evaluated 73 Italian families with autosomal
      dominant cerebellar ataxia (ADCA) type I. Spinocerebellar ataxia (SCA) type 1 was
      the most common genotype (SCA1), accounting for 41% of cases (30 families), SCA2
      was slightly less frequent (29%, 21 families), and the remaining families were
      negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped
      families, SCA1 was found most frequently in families from northern Italy (50%),
      while SCA2 was the most common mutation in families from the southern part of the
      country (56%). Slow saccades and decreased deep tendon reflexes were observed
      significantly more frequently in SCA2 patients, while increased deep tendon
      reflexes and nystagmus were more common in SCA1. In SCA1 and SCA2 families there
      was a significant inverse correlation between expansion size and age at onset.
      Analysis of triplet repeat numbers in parent-offspring pairs showed greater
      meiotic instability, which was associated with an earlier onset of the disease in
      SCA2 families than in SCA1 families.

PMID- 10399873
TI  - Quantitative sensory testing and risk factors of diabetic sensory neuropathy.
AB  - The goal of this study was to identify risk factors for diabetic peripheral
      sensory neuropathy in type 2 diabetes mellitus in a Chinese population.
      Peripheral sensory neuropathy was detected by quantitative sensory testing
      (5.07/10 g monofilament, neurometer and 128-Hz Riedel Seiffert graduated tuning
      fork). Those who had two or more abnormal quantitative sensory testings were
      defined as having diabetic sensory neuropathy. Of the 558 non-insulin dependent
      diabetes mellitits subjects, 62 (11.1%) had peripheral neuropathy. In 59 (10.6%)
      detection was by monofilament testing, 45 (8.1%) by graduated tuning fork, and
      189 (33.9%) by neurometer. In a multivariate logistic regression model, age and
      insulin therapy were significantly associated with peripheral neuropathy. Age,
      serum triglyceride, height, and fasting plasma glucose were independently
      associated with large fiber neuropathy. Our results confirm the previously
      identified multiple risk factors of diabetic neuropathy. Different quantitative
      sensory testings detect different nerve fiber defects. The weak correlation
      between these tests indicates the need to use more than one test in screening for
      diabetic neuropathy.

PMID- 10399875
TI  - Blood transfusion in motor neurone disease (amyotrophic lateral sclerosis)

PMID- 10399874
TI  - Distal neuralgic amyotrophy.
AB  - Neuralgic amyotrophy consists of severe pain around the shoulder and arm followed
      by weakness in one or several muscles of the same area. We describe four patients
      with distal neuralgic amyotrophy in whom acute, severe, and transient pain around
      the shoulder or arm was followed by weakness of the forearm and hand muscles
      only. Minor sensory symptoms were present in only one patient. The presence of
      structural lesions causing the extent of the forearm and hand motor deficit was
      excluded by ancillary examinations. Electrophysiological studies showed a motor
      axonopathy and minimal sensory axonopathy. A follow-up of 2 years or longer
      showed either spontaneous improvement or residual motor deficit. Unfamiliarity
      with a clinically distal localization of neuralgic amyotrophy may result in
      misdiagnosis of lower cervical (poly)radiculopathy in view of the distal
      localization of the motor deficit and the high prevalence of coincidental
      abnormalities of the lower cervical spine on plain radiography, computed
      tomography, or magnetic resonance imaging.

PMID- 10399876
TI  - Cluster of Machado-Joseph disease in a small rural town near Nagasaki City,
      Japan: clinical and genetic studies of two families.

PMID- 10399877
TI  - Phenotypic variability in two brothers with sarcotubular myopathy.

PMID- 10399878
TI  - So-called posterior internuclear ophthalmoplegia due to a pontine glioma: a
      clinicopathological study.

PMID- 10399880
TI  - Study on steroidal oximinoethers: synthesis and stereostructure by NMR
      spectroscopy.
AB  - The condensation of O-substituted hydroxylamines with conjugated 3-oxo-4-en
      steroids results in a mixture of syn-anti configurations. Syn-anti ratios are
      influenced by sterical hindrance between the oximino substituents (e.g. O-benzyl)
      and the steroidal skeleton. Stereostructures and isomeric ratios were proved by
      detailed 1H and 13C NMR studies and also by using 2D-COSY, 2D-HSC, DEPT, 2D-COLOC
      and DNOE measurements.

PMID- 10399881
TI  - Effect of metal ions on the stable adduct formation of 16alpha-hydroxyestrone
      with a primary amine via the Heyns rearrangement.
AB  - 16alpha-Hydroxyestrone (16alpha-OHE1), one of the major estrogen metabolites in
      humans that may plays a role in cell transformation, has been found to form
      stable adducts with nuclear proteins. The mechanism for the formation of a stable
      covalent adduct of 16alpha-OHE1 with protein has been postulated via the Heyns
      rearrangement after Schiff base formation. The Heyns rearrangement on the
      steroidal D-ring alpha-hydroxyimine was investigated using 17-(2
      methoxyethylimino)estra-1,3,5(10)-triene-3,16alpha-dio l as a model intermediate.
      Rates of the Heyns rearrangement and hydrolysis of the steroidal a-hydroxyimine
      were determined by a high-performance liquid chromatography (HPLC)
      simultaneously. The Heyns rearrangement was demonstrated to be optimum at pH 6.2
      and the reaction rate at physiological pH, 7.3-7.5, was more than 90% of that at
      the optimum pH. On the other hand, modulator(s) to the reactions were also
      examined. According to our previous finding of the proton-mediated mechanism of
      the Heyns rearrangement, the effects of cationic metal ions on the reactions were
      examined with 29 metal chlorides. Five metal ions, Pt4+, Cu2+, Ni2+, Co2+, and
      Mn2+, suppressed the formation of Heyns product significantly while Fe2+, Y3+,
      Gd3+, and Er3+ slightly increased it. The suppression rate was synergistically
      enhanced by the combination of Pt4+ with Co2+, Cu2+, or Ni2+. These results
      suggest the five metal ions, Pt4+, Cu2+, Ni2+, Co2+, and Mn2+, reduce the
      formation of the Heyns product in vivo and, therefore, would be useful tools to
      clarify the implication of the stable adduct formation of 16alpha-OHE1 with
      protein.

PMID- 10399882
TI  - Monoclonal antibodies to human sex hormone-binding globulin (SHBG):
      characterization and use in a simple enzyme-linked immunosorbent assay (ELISA) of
      SHBG in plasma.
AB  - Four monoclonal antibodies to human sex hormone-binding globulin were raised and
      characterized. Three of the four antibodies recognised different antigenic
      determinants on SHBG. Two of the distinct antibodies were useful for Western
      blotting and recognized a major 48 kDa band in human plasma as well as a 46 kDa
      minor component. Carbohydrate residues do not form part of the antigenic
      determinants of these two antibodies, although one of these showed increased
      signal following removal of N-linked oligosaccharides. Some of the antibodies
      were selected to form a basis of a same-day, non-competitive, enzyme-linked
      immunosorbent assay (ELISA) for SHBG in plasma. The assay employs a purified
      IgG2a SHBG monoclonal antibody adsorbed to the wells of a microtitre plate. After
      blocking any further adsorption to the plate, standards or diluted patient
      samples were added for a 5-h incubation at room temperature, after which the
      plate was washed and antibody-bound SHBG was detected with an anti-SHBG IgG1
      monoclonal antibody followed by peroxidase-labeled antimouse-IgG1 and o
      phenylenediamine substrate. The assay correlated well with an existing 2-day
      ELISA for SHBG in plasma using polyclonal antibodies and also correlated with a
      dihydrosterone (DHT) ligand-binding assay. The monoclonal antibody-based ELISA
      shows excellent performance characteristics and is unaffected by added
      testosterone or estradiol.

PMID- 10399883
TI  - In vitro evaluation of aromatase enzyme in granulosa cells using a [11C]vorozole
      binding assay.
AB  - An in vitro method for measuring aromatase cytochrome P450 enzyme (P450AROM) in
      human granulosa cells (GC) has been developed, based on binding of the 11C
      labeled aromatase inhibitor vorozole. GC were obtained following superstimulation
      during in vitro fertilisation. The method revealed a binding affinity (Kd) of 0.4
      nM and a maximum binding (Bmax) at 11 fmol/4000 cells which is equal to 1.6
      million binding sites per cell. Linear Scatchard plots indicated a single type of
      binding site. P450AROM concentrations measured by [11C]vorozole binding
      correlated positively with aromatisation of [1beta-3H]androst-4-ene-3,17-dione
      measured as [3H]water release, and a positive association was also found with the
      ovarian in vivo response to follicle-stimulating hormone (FSH) stimulation
      expressed as 1000 times the ratio of the number of oocytes recovered from a
      patient and the total dose of recombinant FSH administered. Frozen cells could be
      used for P450AROM quantitation, provided the correct freezing procedure was used.
      Quantitation of P450AROM, based on binding of [11C]vorozole is an accurate and
      sensitive in vitro method, which might be extended to the measurement of
      aromatase expression by a noninvasive technique in the intact ovary in vivo using
      positron emission tomography.

PMID- 10399884
TI  - C-6 functionalized analogs of 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin
      D3: synthesis and binding analysis with vitamin D-binding protein and vitamin D
      receptor.
AB  - In this article, we describe the development of a general synthetic strategy to
      functionalize the C-6 position of vitamin D3 and its biologically important
      metabolites, i.e. 25-hydroxyvitamin D3 (25-OH-D3) and 1alpha,25-dihydroxyvitamin
      D3 [1,25(OH)2D3]. We employed Mazur's cyclovitamin D method to synthesize vitamin
      D3 analogs with several functionalities at the C-6 position. In addition, we
      synthesized 6-(3-hydroxypropyl) and 6-[(2-bromoacetoxy)propyl] derivatives of 25
      OH-D3 15 and 16, respectively, and 6-(3-hydroxypropyl) derivative of 1,25(OH)2D3
      17. Competitive binding assays of 15-17 with human serum vitamin D-binding
      protein showed that all these analogs specifically bound to this protein,
      although with significantly lower affinity than the 25-OH-D3, the strongest
      natural binder, but with comparable affinity with 1,25(OH)2D3, the hormone. On
      the other hand, 6-[3-hydroxypropyl], 1alpha,25-dihydroxyvitamin D3 17 did not
      show any specific binding for recombinant nuclear vitamin D receptor. These
      results indicated that the region containing the C-6 position of the parent seco
      steroid [1,25(OH)2D3] may be an important recognition marker towards vitamin D
      receptor binding. Information, delineated in this article, will be important for
      evaluating structure-activity relationship in synthetic analogs of vitamin D and
      its metabolites.

PMID- 10399885
TI  - O-(fluoresceinylmethyl)hydroxylamine (OFMHA): a reagent for the preparation of
      fluorescent O-(fluoresceinylmethyl)oxime (FMO)-steroid conjugates.
AB  - The 5 and 6-isomers of O-(fluoresceinylmethyl)hydroxylamine reacted with a
      representative sample of oxo-steroids (6-oxoestradiol, estrone, norethindrone,
      cortisol, progesterone, and digitoxin-dialdehyde) to produce O
      (fluoresceinylmethyl)oxime conjugates in a single step in 24-84% yield after
      preparative high performance liquid chromotography.

PMID- 10399886
TI  - Effects of cholic acid on blood pressure and production of vascular aldosterone
      and corticosterone.
AB  - The aims of this study were to search for the role of cholic acid in the
      regulation blood pressure of humans and rats and to investigate the effects of
      cholic acid on the production of vascular aldosterone and corticosterone in rats.
      Levels of serum total bile acids were measured by an enzymic spectrophotometeric
      method in normal controls, patients with essential hypertension, and in Wistar
      and spontaneously hypertensive rats. Levels in essential hypertension (7.3+/-3.4
      micromol/l, n = 88) were higher than those of normal subjects (4.9+/-3.3
      micromol/l, n = 86), and levels in SHR (13.9+/-3.8 micromol/l, n = 11) were
      slightly increased, but not significantly different from Wistar rats (10.4+/-5.1
      micromol/l, n = 12). Male Wistar rats received cholic acid 80 mg/kg/day, orally,
      for 30 days, and blood pressure was monitored by a pressure transducer. Systolic
      blood pressure increased in Wistar rats treated with cholic acid compared to
      control rats. Mesenteric artery perfusion ex vivo was performed, and pressor
      responses to norepinephrine were determined in Wistar rats. The pressor responses
      to norepinephrine in mesenteric arteries treated with cholic acid were
      significantly increased. The perfusate from the mesenteric arteries was collected
      and applied to a Sep-Pak C 18 cartridge column for reverse phase high performance
      liquid chromatography, and levels of both aldosterone and corticosterone were
      determined by radioimmunoassay. Levels of aldosterone were decreased but those of
      corticosterone increased in the perfusate from arteries treated with cholic acid.
      Reverse transcriptase polymerase chain reaction showed that cholic acid inhibited
      the expression of 11beta-HSD2 and CYP11B2 mRNA in mesenteric arteries. These
      results reveal that cholic acid is able to induce hypertension and provide
      evidence that cholic acid inhibits the transcription of both 11beta-HSD2 and
      CYP11B2 in vasculature, leading to lower aldosterone and higher corticosterone
      production in vessels and increased vasoconstrictor responses to norepinephrine.

PMID- 10399887
TI  - An easy diagnostic approach to primary aldosteronism.
AB  - The infusion of 40 mEq potassium (aspartate) in 250 ml isotonic 1-fructose at a
      rate of 20 mEq/h into 5 patients (34-56 years old) with aldosteronoma and 2
      patients with bilateral primary aldosteronism consistently raised their mean
      arterial pressure by 15-20 mmHg. Their pressure values returned to the baseline
      levels 4-5 h after the infusion. In contrast, in controls (10 patients with
      idiopathic arterial hypertension, matched for age, sex, and magnitude of the
      untreated hypertension, and 7 patients with inactive adrenal nodules as
      incidental findings on upper abdomen ultrasound or computerized tomography) the
      same procedure caused negligible arterial pressure changes. The cause of the rise
      in blood pressure observed uniquely in patients with primary aldosteronism after
      infusion of potassium (aspartate) cannot be accounted for by an increase in
      plasma aldosterone, blood volume, or plasma angiotensin II. The cause of this
      response thus remains obscure; nonetheless, this simple procedure may prove
      useful in differentiating primary aldosteronism from idiopathic hypertension, in
      excluding the adrenal disorder, and in revealing even its mildest forms.

PMID- 10399888
TI  - Enzyme immunoassay for the measurement of 17alpha-estradiol 17-N
      acetylglucosaminide in rabbit urine.
AB  - 17alpha-estradiol 17-N-acetylglucosaminide (17alphaE2 17NAG) is an estrogen
      metabolite hitherto obtained only in rabbits. To gain insight into this unique
      conjugate, an enzyme immunoassay (EIA) was established by using antiserum
      elicited against 3-[3-(1-carboxypropyl)] ether of 17alphaE2 17NAG-bovine serum
      albumin conjugate; horseradish peroxidase, as a label; and 3,3',5,5'
      tetramethylbenzidine, as a chromogen. The method proved to be specific, and the
      detection range of the assay was 0.20-10.00 ng/ml. A proposed double conjugate, 3
      glucuronide of 17alphaE2 17NAG, was synthesized to validate the EIA. The EIA was
      applied to the determination of the urinary level of 17alphaE2 17NAG in male and
      female (pregnant and non-pregnant) rabbits with and without beta-glucuronidase
      sulfatase preparation from Helix pomatia. The results showed that 17alphaE2 17NAG
      was mainly excreted as a double conjugate (17alphaE2 17NAG 3-glucuronide and/or 3
      sulfate) and that its level varies during pregnancy.

PMID- 10399889
TI  - Corticosteroid pharmacokinetics in the inner ear fluids: an animal study followed
      by clinical application.
AB  - OBJECTIVE: Autoimmune disease (e.g., Cogan syndrome) and other inflammatory inner
      ear diseases may ravage the labyrinth if not treated aggressively with
      antiinflammatory medication. Corticosteroids are the mainstay of treatment, yet,
      partly because of the existence of the blood-labyrinthine barrier, the ideal
      drug, dose, and route of administration are currently unknown. STUDY DESIGN: In
      the present study, we established cochlear fluid pharmacokinetic profiles of
      hydrocortisone, methylprednisolone, and dexamethasone in the guinea pig following
      oral, intravenous, and topical (intratympanic) administration. High-performance
      liquid chromatography was used to determine the drug concentrations, and
      comparisons were made with simultaneous pharmacokinetic profiles from blood and
      cerebrospinal fluid. RESULTS: Our findings demonstrated a much higher penetration
      of all three drugs into the cochlear fluids following topical application as
      compared with systemic administration, with methylprednisolone showing the best
      profile. DISCUSSION: The results suggested that intratympanic administration of
      corticosteroids might be more efficacious while avoiding high blood levels and
      therefore the deleterious side effects of systemic use. CLINICAL APPLICATION:
      Thirty-seven patients with various inner ear disorders causing sensorineural
      hearing loss were subsequently treated using intratympanic corticosteroids, 20
      with dexamethasone, and 17 with methlyprednisolone. Patients with immune-mediated
      hearing losses showed the best results, with notable improvement also seen in
      several cases of a "sudden deafness." No benefit was seen in patients with
      cochlear hydrops or those with sudden deterioration of a preexisting hearing
      loss. Three patients developed a transient otitis media related to the
      treatments, easily controlled with antibiotics. There were no cases of treatment
      induced hearing loss and no permanent tympanic membrane perforations.
      CONCLUSIONS: Overall injection of intratympanic corticosteroids for the treatment
      of hearing loss in inner ear disorders appears to be both safe and highly
      effective for certain disorders. The concept of this technique is supported by
      animal experimental data. The findings from the present study warrant further
      clinical application and experimental investigation.

PMID- 10399890
TI  - Outcome analysis and quality assessment. Autopsy Committee of the College of
      American Pathologists.

PMID- 10399892
TI  - Barrett's esophagus: update on screening, surveillance, and treatment.
AB  - The last 2 decades have seen dramatic advances in Barrett's esophagus. The
      definition has evolved; the rising incidence of adenocarcinoma has been
      recognized; and effective therapy to control gastroesophageal reflux disease has
      been developed. Both proton pump inhibitor therapy and laparoscopic
      fundoplication represent major developments. Studies of patients with dysplasia
      have helped to clarify appropriate surveillance intervals and treatment
      strategies for these patients, although controversy still exists. The possibility
      of reversing Barrett's esophagus in selected high-risk patients offers major hope
      for the future prevention of adenocarcinoma of the esophagus.

PMID- 10399891
TI  - National recommendations for the pharmacological treatment of hypertension:
      should they be revised?

PMID- 10399893
TI  - Career satisfaction of US women physicians: results from the Women Physicians'
      Health Study. Society of General Internal Medicine Career Satisfaction Study
      Group.
AB  - BACKGROUND: Despite major changes in health care, the prevalence and predictors
      of career satisfaction have not recently been comprehensively studied in either
      women or men physicians. METHODS: The Women Physicians' Health Study surveyed a
      nationally representative random sample (n = 4501 respondents; response rate,
      59%) of US women physicians. Using univariate and logistic regression analyses,
      we examined personal and professional characteristics that were correlated with 3
      major outcomes: career satisfaction, desire to become a physician again, and
      desire to change one's specialty. RESULTS: Women physicians were generally
      satisfied with their careers (84% usually, almost always, or always satisfied).
      However, 31% would maybe, probably, or definitely not choose to be a physician
      again, and 38% would maybe, probably, or definitely prefer to change their
      specialty. Physician's age, control of the work environment, work stress, and a
      history of harassment were independent predictors of all 3 outcomes, with younger
      physicians and those having least work control, most work stress, or having
      experienced severe harassment reporting the most dissatisfaction. The strongest
      association (odds ratio, 11.3; 95% confidence interval, 7.3-17.5; P<.001) was
      between work control and career satisfaction. Other significant predictors
      (P<.01) of outcomes included birthplace, ethnicity, sexual orientation, having
      children, stress at home, religious fervor, mental health, specialty, practice
      type, and workload. CONCLUSIONS: Women physicians generally report career
      satisfaction, but many, if given the choice, would not become a physician again
      or would choose a different specialty. Correctable factors such as work stress,
      harassment, and poor control over work environment should be addressed to improve
      the recruitment and retention of women physicians.

PMID- 10399894
TI  - Outcome following acute myocardial infarction: are differences among physician
      specialties the result of quality of care or case mix?
AB  - BACKGROUND: Studies to determine whether care by cardiologists improves the
      survival of patients with acute myocardial infarction (MI) have produced
      conflicting results, and it is not known what accounts for differences in patient
      outcome by physician specialty. OBJECTIVES: To evaluate whether cardiologists
      provide more recommended therapies to elderly patients with acute MI and, if so,
      to determine whether variations in processes of care account for differences in
      patient outcome. DESIGN: Retrospective cohort study using medical chart data and
      administrative data files. SETTING: All nonfederal acute care hospitals in
      California. PATIENTS: A cohort of 7663 Medicare beneficiaries 65 years and older
      directly admitted to the hospital with a confirmed acute MI from April 1994 to
      July 1995 with complete data regarding potential contraindications to recommended
      therapies. MAIN OUTCOME MEASURES: Percentage of "good" and "ideal" candidates for
      a given acute MI therapy who actually received that therapy, percentage who
      received exercise stress testing or coronary angiography, percentage who
      underwent revascularization, and 1-year mortality, stratified by specialty of the
      attending physician. RESULTS: During hospitalization, good candidates for aspirin
      were more likely to receive aspirin if they were treated by cardiologists (87%)
      than by medical subspecialists (73%; P<.001), general internists (84%; P = .003),
      or family practitioners (81%; P<.001). Cardiologists were also more likely to
      treat good candidates with thrombolytic therapy (51%) than were medical
      subspecialists (29%; P<.001), general internists (40%; P<.001), or family
      practitioners (27%; P<.001). Patients of cardiologists were 2- to 4-fold more
      likely to undergo a revascularization procedure. Despite these differences in
      utilization, we found similar 30-day mortality rates across physician
      specialties. However, 1-year mortality rates were greater for patients treated by
      medical subspecialists (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6
      2.3), general internists (OR, 1.4; 95% CI, 1.3-1.6), and family practitioners
      (OR, 1.7; 95% CI, 1.4-1.9) than for those treated by cardiologists. Adjusting for
      differences in patient and hospital characteristics markedly reduced the ORs for
      those treated by medical subspecialists (OR, 1.2; 95% CI, 0.9-1.4), general
      internists (OR, 1.1; 95% CI, 1.0-1.3), and family practitioners (OR, 1.3; 95% CI,
      1.1-1.6), whereas further adjustment for medication use and revascularization
      procedures had little effect. CONCLUSIONS: Differences in the use of recommended
      therapies by physician specialty are generally small and do not explain
      differences in patient outcome. In comparison, differences among patients treated
      by physicians of various specialties (case mix) have a large impact on patient
      outcome and may account for the residual survival advantage of patients treated
      by cardiologists. With the exception of the in-hospital use of aspirin,
      recommended MI therapies are markedly underused, regardless of the specialty of
      the physician.

PMID- 10399895
TI  - Risk factors for hospital-acquired Staphylococcus aureus bacteremia.
AB  - BACKGROUND: Staphylococcus aureus bacteremia (SAB) acquired in hospitals
      continues to be a frequent and serious complication to hospitalization, and no
      previous case-control studies dealing with risk factors of this severe disease
      are available. METHODS: Based on a 1-year prospective analysis, the data from all
      patients with hospital-acquired SAB admitted to 4 hospitals in Copenhagen County,
      Denmark, from May 1, 1994, through April 30, 1995, were evaluated. Eighty-five
      patients with hospital-acquired SAB were matched to 85 control patients with a
      similar primary diagnosis at admission (matched controls). Of these, 62 patients
      with hospital-acquired SAB were compared with 118 other patients with a similar
      time of admission, who were randomly selected with no clinical evidence of SAB
      (unmatched controls). RESULTS: The incidence of hospital-acquired SAB was 0.71
      per 1000 hospital admissions. The presence of a central venous catheter (odds
      ratio, 6.9; 95% confidence interval [CI], 2.8-17.0), anemia (odds ratio, 3.3; 95%
      CI, 1.4-7.6), and hyponatremia (odds ratio, 3.3; 95% CI, 1.5-7.0) was
      significantly associated with hospital-acquired SAB in a conditional and a usual
      logistic regression analysis. Nasal carriage was not an independent risk factor,
      but nasal carriers among patients in surgery (odds ratio, 4.0; 95% CI, 1.3-13.0)
      had a significantly higher risk for hospital-acquired SAB compared with matched
      and unmatched controls. The presence of hospital-acquired SAB increased the
      mortality rate 2.4-fold (95% CI, 1.1-5.2). CONCLUSIONS: The presence of a central
      venous catheter is an important risk factor, and hyponatremia and anemia are
      associated with the development of hospital-acquired SAB. Furthermore, hospital
      acquired SAB in itself increases mortality.

PMID- 10399896
TI  - Rapid rise in the incidence of type 2 diabetes from 1987 to 1996: results from
      the San Antonio Heart Study.
AB  - BACKGROUND: The prevalence of type 2 diabetes has increased in the early part of
      the 20th century, particularly in developing countries. There is now evidence
      that the prevalence also continues to increase in developed countries, including
      the United States. However, it is unknown whether this increase is due to a rise
      in the incidence of diabetes or to decreasing diabetic mortality or both.
      METHODS: Participants in the San Antonio Heart Study, who were nondiabetic at
      baseline and who returned for a 7- to 8-year follow-up examination, were examined
      for secular trends in the incidence of type 2 diabetes. Risk factors for
      diabetes, such as obesity, were also examined. Patients were enrolled in the San
      Antonio Heart Study from 1979 to 1988 and 7- to 8-year incidence of diabetes was
      determined from 1987 to 1996. RESULTS: A significant secular trend in the 7- to 8
      year incidence of type 2 diabetes was observed in Mexican Americans (5.7% for
      participants enrolled in 1979 to 15.7% for participants enrolled in 1988). In non
      Hispanic whites, the incidence increased from 2.6% for participants enrolled in
      1980 to 9.4% for participants enrolled in 1988 (P = .07) . After adjusting for
      age and sex, the secular trend remained significant in Mexican Americans and
      borderline significant in non-Hispanic whites. This indicates that between 1987
      and 1996 the 7- to 8-year incidence of type 2 diabetes approximately tripled in
      both ethnic groups. The overall secular trend also remained significant after
      adjusting for additional risk factors for diabetes, such as obesity. A rising
      secular trend in obesity was also observed. CONCLUSIONS: There has been a
      significant increasing secular trend in the incidence of type 2 diabetes in
      Mexican Americans and a borderline significant trend in non-Hispanic whites
      participating in the San Antonio Heart Study. Unlike other cardiovascular risk
      factors such as lipid levels, cigarette smoking, and blood pressure, which are
      either declining or under progressively better medical management and control,
      and unlike cardiovascular mortality, which is also declining, obesity and type 2
      diabetes are exhibiting increasing trends. Thus, obesity and diabetes could
      easily become the preeminent US public health problem.

PMID- 10399897
TI  - Individualizing therapy to prevent long-term consequences of estrogen deficiency
      in postmenopausal women.
AB  - BACKGROUND: Alendronate sodium and raloxifene hydrochloride were recently
      approved for the prevention of postmenopausal osteoporosis, but data on their
      clinical efficacy are limited. We compared these drugs with hormone replacement
      therapy (HRT) to help women and physicians guide postmenopausal treatment
      decisions. OBJECTIVE: To help physicians understand how they can best help women
      choose the most beneficial therapy after menopause based on their individual risk
      profile. METHODS: We developed a decision analytic Markov model to compare the
      effects of alendronate therapy, raloxifene therapy, and HRT on risks of hip
      fracture, coronary heart disease (CHD), breast cancer, and life expectancy.
      Regression models linked individual risk factors to future disease risks and were
      modified by drug effects on bone density, lipid levels, and associated breast
      cancer effects. RESULTS: Hormone replacement therapy, alendronate therapy, and
      raloxifene therapy have similar predicted efficacies in preventing hip fractures
      (estimated relative risk, 0.57, 0.54, and 0.58, respectively). Hormone
      replacement therapy should be more than 10 times more effective than raloxifene
      therapy in preventing CHD, but raloxifene therapy may not induce breast cancer.
      Women at low risk for hip fracture, CHD, and breast cancer do not benefit
      significantly from any treatment. Among women at average risk, HRT was preferred
      unless raloxifene therapy could reduce the risk of breast cancer by at least 66%,
      compared with a 47% increase for HRT. Women at high risk for CHD benefit most
      from HRT; women at high risk for breast cancer but low risk for CHD benefit most
      from raloxifene therapy, but only if it lowers the risk of breast cancer.
      CONCLUSION: Because of significant differences in the impact of these drugs,
      treatment choice depends on an individual woman's risk for hip fracture, CHD, and
      breast cancer.

PMID- 10399898
TI  - Vancomycin-resistant enterococci in intensive care units: high frequency of stool
      carriage during a non-outbreak period.
AB  - BACKGROUND: We aimed to define the epidemiological associations of vancomycin
      resistant enterococci (VRE) in intensive care units (ICUs) during a non-outbreak
      period by examining prevalence, risk factors for colonization, frequency of
      acquisition, and molecular strain types. DESIGN: A prospective cohort design was
      followed. Consecutive patient admissions to 2 surgical ICUs at a tertiary care
      hospital were enrolled. The main outcome measures were results of serial
      surveillance cultures screened for VRE. RESULTS: Of 290 patients enrolled, 35
      (12%) had colonization with VRE on admission. The VRE colonization or infection
      had been previously detected by clinical cultures in only 4 of these patients.
      Using logistic regression, VRE colonization at the time of ICU admission was
      associated with second- and third-generation cephalosporins (odds ratio [OR] =
      6.0, P<.0001), length of stay prior to surgical ICU admission (OR = 1.06, P =
      .001) greater than 1 prior ICU stay (OR = 9.6, P = .002), and a history of solid
      organ transplantation (OR = 3.8, P = .021). Eleven (12.8%) of 78 patients with
      follow-up cultures acquired VRE. By pulsed-field gel electrophoresis, 2 strains
      predominated, one of which was associated with an overt outbreak on a non-ICU
      ward near the end of the study period. CONCLUSIONS: Colonization was common and
      usually not recognized by clinical culture. Most patients who had colonization
      with VRE and were on the surgical ICU acquired VRE prior to surgical ICU entry.
      Exposure to second- and third-generation cephalosporins, but not vancomycin, was
      an independent risk factor for colonization. Prospective surveillance of
      hospitalized patients may yield useful insights about the dissemination of
      nosocomial VRE beyond what is appreciated by clinical cultures alone.

PMID- 10399899
TI  - Enteric infections and diarrhea in human immunodeficiency virus-infected persons:
      prospective community-based cohort study. Swiss HIV Cohort Study.
AB  - BACKGROUND: Persons infected with human immunodeficiency virus (HIV) are at
      increased risk for diarrhea and enteric infections. We studied (1) the
      epidemiology of enteric pathogens associated with diarrhea, (2) the diagnostic
      yield of stool examination and endoscopic evaluation, (3) risks to develop
      diarrhea, and (4) the impact of diarrhea on patients' survival. METHODS: A total
      of 1933 participants in the Swiss HIV Cohort Study were prospectively followed up
      for a median of 25.5 months. A total of 560 diarrheal episodes were evaluated by
      standardized stool examination. Endoscopic evaluation was performed in 25% of
      patients with chronic diarrhea. RESULTS: The incidence of diarrhea was 14.2 per
      100 person-years (95% confidence interval, 13.0-15.4). Among patients with CD4
      cell counts below 0.05 x 10(9)/L, the probability to develop diarrhea within 1,
      2, and 3 years was 48.5%, 74.3%, and 95.6%, respectively. The risk to develop
      diarrhea was increased among patients with severe immunodeficiency, homosexual
      men, and patients taking antiretroviral therapy. Pneumocystis carinii
      chemoprophylaxis did not reduce the risk of diarrhea. Diarrhea was an independent
      negative predictor of survival. Enteric pathogens were detected in 16.5% of 212
      acute diarrheal episodes and in 46% of 348 chronic diarrheal episodes. The
      sensitivity of histological and stool examination was similar except for the
      diagnosis of intestinal cytomegalovirus infection and leishmaniasis, which
      required invasive evaluation. CONCLUSIONS: Intestinal infections were diagnosed
      in less than 50% of chronic diarrheal episodes. The prevalence of enteric
      pathogens tended to decrease during the observation period, possibly because of
      improved antiretroviral therapy. Endoscopic evaluation did not improve the
      diagnostic yield compared with stool examination except for the diagnosis of
      cytomegalovirus enteritis and leishmaniasis.

PMID- 10399900
TI  - Serologic hepatitis B immunity in vaccinated health care workers.
AB  - BACKGROUND: Hepatitis B vaccination is recommended for health care workers but
      has a nonresponse rate of 5% to 32% and an unknown duration of immunity. There is
      no standardized postvaccination protocol to confirm, monitor, and maintain
      immunity. OBJECTIVE: To assess the hepatitis B serologic immune status in health
      care workers who were previously vaccinated. METHODS: A convenience survey and an
      objective laboratory study, which included testing for hepatitis B surface
      antigen, core antibody, and qualitative and quantitative surface antibody (anti
      HBs), were performed. The data collected included vaccination date, number of
      doses of vaccine, whether and when titers had previously been checked, titer
      results, sex of patient, job description, and age at the time of our study and at
      vaccination. RESULTS: Group A (n = 109, 71%) had detectable anti-HBs titers, and
      group B (n = 45, 29%) had no detectable anti-HBs titers. Group A was vaccinated
      4.80 +/- 0.30 (mean +/- SEM) years prior to our testing, received 2.91 +/- 0.04
      (mean +/- SEM) vaccinations, and had a mean +/- SEM titer of 112.91 +/- 5.18
      mIU/mL. There was no statistical significance in time since vaccination, number
      of doses of vaccine, sex, job description, age at the time of our serologic
      testing, or age at the time of vaccination between groups A and B. Six of 6
      subjects given booster doses of vaccine in group B developed anti-HBs. Only 62
      subjects (40%) in the entire study population had anti-HBs status previously
      determined, with 48 (77%) reporting immunity to hepatitis B virus. CONCLUSIONS:
      Twenty-nine percent of the health care workers who were vaccinated against
      hepatitis B showed no serologic evidence of hepatitis B immunity. It is unclear
      whether these subjects are nonresponders, lost immunity, or retained anamnestic
      potential. Booster vaccination response in 6 of 6 subjects suggests immunity. We
      recommend (1) postvaccination testing within 1 to 2 months to document immunity,
      (2) periodic anti-HBs monitoring, and (3) booster vaccination to maintain
      protective titer levels.

PMID- 10399901
TI  - Increased incidence of infectious diseases during prospective follow-up of human
      T-lymphotropic virus type II- and I-infected blood donors. Retrovirus
      Epidemiology Donor Study.
AB  - BACKGROUND: To determine whether human T-lymphotropic virus type II (HTLV-II)
      infection is associated with an increased incidence of bacterial infections, we
      prospectively observed cohorts of HTLV-I- and HTLV-II-infected and seronegative
      subjects in 5 US cities. METHODS: Of 1340 present and former blood donors
      examined at enrollment, 1213 (90.5%) were re-examined after approximately 2
      years, including 136 HTLV-I- and 337 HTLV-II-seropositive subjects and 740
      demographically stratified HTLV-seronegative subjects. All subjects were
      seronegative for human immunodeficiency virus. Odds ratios (ORs) for incident
      disease outcomes were adjusted for covariates, including age, sex, race or
      ethnicity, education, and, if significantly associated with the outcome, blood
      center, donation type, income, smoking, alcohol intake, and injected drug use.
      RESULTS: Compared with seronegative status, HTLV-II infection was associated with
      an increased incidence of bronchitis (OR, 1.81; 95% confidence interval [CI],
      1.20-2.75), bladder and/or kidney infection (OR, 1.94; 95% CI, 1.26-2.98), oral
      herpes infection (OR, 9.54; 95% CI, 3.33-27.32), and a borderline increased
      incidence of pneumonia (OR, 2.09; 95% CI, 0.92-4.76); HTLV-I infection was
      associated with an increased incidence of bladder and/or kidney infection (OR,
      2.79; 95% CI, 1.63-4.79). One incident case of HTLV-I-positive adult T-cell
      leukemia was observed (incidence, 348 per 100,000 HTLV-I person-years), and 1
      case of HTLV-II-positive tropical spastic paraparesis-HTLV-associated myelopathy
      was diagnosed (incidence, 140 per 100,000 HTLV-II person-years). CONCLUSIONS:
      These data support an increased incidence of infectious diseases among otherwise
      healthy HTLV-II- and HTLV-I-infected subjects. They are also consistent with the
      lymphoproliferative effects of HTLV-I, and with neuropathic effects of HTLV-I and
      HTLV-II.

PMID- 10399902
TI  - Rapid improvement of osteoporosis following parathyroidectomy in a premenopausal
      woman with acute primary hyperparathyroidism.
AB  - We describe a premenopausal white woman with symptomatic acute primary
      hyperparathyroidism and marked osteoporosis. After undergoing a
      parathyroidectomy, the patient experienced not only rapid symptomatic relief, but
      also marked improvement in bone mineral density, which increased by 25% in the
      hip and by 22% in the lumbar spine 1 year after the surgery. Acute primary
      hyperparathyroidism should be considered in any patient with severe symptomatic
      hypercalcemia. Appropriate treatment with early parathyroidectomy can result in
      significant and rapid improvement in bone mineral density.

PMID- 10399903
TI  - Hypernatremia with edema.

PMID- 10399904
TI  - Is the prevalence of gallstones in cirrhosis not higher?

PMID- 10399905
TI  - Plunging clinical standards under managed care.

PMID- 10399906
TI  - Use of the combination product ipratropium and albuterol in chronic obstructive
      pulmonary disease.

PMID- 10399907
TI  - Should we fear "health foods"?

PMID- 10399908
TI  - Phosphoinositide binding domains: embracing 3-phosphate.

PMID- 10399909
TI  - Attraction versus repulsion: modular receptors make the difference in axon
      guidance.

PMID- 10399910
TI  - Net results of nucleolar dynamics.

PMID- 10399911
TI  - Sir-Ku-itous routes to make ends meet.

PMID- 10399912
TI  - ATP-dependent histone octamer sliding mediated by the chromatin remodeling
      complex NURF.
AB  - Drosophila NURF is an ATP-dependent chromatin remodeling complex that contains
      ISWI, a member of the SWI2/SNF2 family of ATPases. We demonstrate that NURF
      catalyzes the bidirectional redistribution of mononucleosomes reconstituted on
      hsp70 promoter DNA. In the presence of NURF, nucleosomes adopt one predominant
      position from an ensemble of possible locations within minutes. Movements occur
      in cis, with no transfer to competing DNA. Migrating intermediates trapped by Exo
      III digestion reveal progressive nucleosome motion in increments of several base
      pairs. All four core histones are retained quantitatively during this process,
      indicating that the general integrity of the histone octamer is maintained. We
      suggest that NURF remodels nucleosomes by transiently decreasing the activation
      energy for short-range sliding of the histone octamer.

PMID- 10399913
TI  - Nucleosome movement by CHRAC and ISWI without disruption or trans-displacement of
      the histone octamer.
AB  - The chromatin accessibility complex (CHRAC) belongs to the class of nucleosome
      remodeling factors that increase the accessibility of nucleosomal DNA in an ATP
      dependent manner. We found that CHRAC induces movements of intact histone
      octamers to neighboring DNA segments without facilitating their displacement to
      competing DNA or histone chaperones in trans. CHRAC-induced energy-dependent
      nucleosome sliding may, in principle, explain nucleosome remodeling, nucleosome
      positioning, and nucleosome spacing reactions known to be catalyzed by CHRAC. The
      catalytic core of CHRAC, the ATPase ISWI, also mobilized nucleosomes at the
      expense of energy. However, the directionality of the CHRAC- and ISWI-induced
      nucleosome movements differed drastically, indicating that the geometry of the
      native complex modulates the activity of its catalytic core.

PMID- 10399914
TI  - Pak functions downstream of Dock to regulate photoreceptor axon guidance in
      Drosophila.
AB  - The SH2/SH3 adaptor protein Dock has been proposed to transduce signals from
      guidance receptors to the actin cytoskeleton in Drosophila photoreceptor (R cell)
      growth cones. Here, we demonstrate that Drosophila p21-activated kinase (Pak) is
      required in a Dock pathway regulating R cell axon guidance and targeting. Dock
      and Pak colocalize to R cell axons and growth cones, physically interact, and
      their loss-of-function phenotypes are indistinguishable. Normal patterns of R
      cell connectivity require Pak's kinase activity and binding sites for both Dock
      and Cdc42/Rac. A membrane-tethered form of Pak (Pak(myr) acts as a dominant gain
      of-function protein. Retinal expression of Pak(myr) rescues the R cell
      connectivity phenotype in dock mutants. These data establish Pak as a critical
      regulator of axon guidance and a downstream effector of Dock in vivo.

PMID- 10399915
TI  - Autonomous control of cell and organ size by CHICO, a Drosophila homolog of
      vertebrate IRS1-4.
AB  - The control of growth is fundamental to the developing metazoan. Here, we show
      that CHICO, a Drosophila homolog of vertebrate IRS1-4, plays an essential role in
      the control of cell size and growth. Animals mutant for chico are less than half
      the size of wild-type flies, owing to fewer and smaller cells. In mosaic animals,
      chico homozygous cells grow slower than their heterozygous siblings, show an
      autonomous reduction in cell size, and form organs of reduced size. Although
      chico flies are smaller, they show an almost 2-fold increase in lipid levels. The
      similarities of the growth defects caused by mutations in chico and the insulin
      receptor gene in Drosophila and by perturbations of the insulin/IGF1 signaling
      pathway in vertebrates suggest that this pathway plays a conserved role in the
      regulation of overall growth by controling cell size, cell number, and
      metabolism.

PMID- 10399916
TI  - Rhodopsin's carboxy-terminal cytoplasmic tail acts as a membrane receptor for
      cytoplasmic dynein by binding to the dynein light chain Tctex-1.
AB  - The interaction of cytoplasmic dynein with its cargoes is thought to be
      indirectly mediated by dynactin, a complex that binds to the dynein intermediate
      chain. However, the roles of other dynein subunits in cargo binding have been
      unknown. Here we demonstrate that dynein translocates rhodopsin-bearing vesicles
      along microtubules. This interaction occurs directly between the C-terminal
      cytoplasmic tail of rhodopsin and Tctex-1, a dynein light chain. C-terminal
      rhodopsin mutations responsible for retinitis pigmentosa inhibit this
      interaction. Our results point to an alternative docking mechanism for
      cytoplasmic dynein, provide novel insights into the role of motor proteins in the
      polarized transport of post-Golgi vesicles, and shed light on the molecular basis
      of retinitis pigmentosa.

PMID- 10399917
TI  - RAGE mediates a novel proinflammatory axis: a central cell surface receptor for
      S100/calgranulin polypeptides.
AB  - S100/calgranulin polypeptides are present at sites of inflammation, likely
      released by inflammatory cells targeted to such loci by a range of environmental
      cues. We report here that receptor for AGE (RAGE) is a central cell surface
      receptor for EN-RAGE (extracellular newly identified RAGE-binding protein) and
      related members of the S100/calgranulin superfamily. Interaction of EN-RAGEs with
      cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers
      cellular activation, with generation of key proinflammatory mediators. Blockade
      of EN-RAGE/RAGE quenches delayed-type hypersensitivity and inflammatory colitis
      in murine models by arresting activation of central signaling pathways and
      expression of inflammatory gene mediators. These data highlight a novel paradigm
      in inflammation and identify roles for EN-RAGEs and RAGE in chronic cellular
      activation and tissue injury.

PMID- 10399918
TI  - A sonic hedgehog-independent, retinoid-activated pathway of neurogenesis in the
      ventral spinal cord.
AB  - Sonic hedgehog (Shh) is thought to control the generation of motor neurons and
      interneurons in the ventral CNS. We show here that a Shh-independent pathway of
      interneuron generation also operates in the ventral spinal cord. Evidence for
      this parallel pathway emerged from an analysis of the induction of ventral
      progenitors that express the Dbx homeodomain proteins and of Evx1/2 (V0) and En1
      (V1) neurons. Shh signaling is sufficient to induce Dbx cells and V0 and V1
      neurons but is not required for their generation in vitro or in vivo. Retinoids
      appear to mediate this parallel pathway. These findings reveal an unanticipated
      Shh-independent signaling pathway that controls progenitor cell identity and
      interneuron diversity in the ventral spinal cord.

PMID- 10399919
TI  - Chimeric axon guidance receptors: the cytoplasmic domains of slit and netrin
      receptors specify attraction versus repulsion.
AB  - Frazzled (Fra) is the DCC-like Netrin receptor in Drosophila that mediates
      attraction; Roundabout (Robo) is a Slit receptor that mediates repulsion. Both
      ligands are expressed at the midline; both receptors have related structures and
      are often expressed by the same neurons. To determine if attraction versus
      repulsion is a modular function encoded in the cytoplasmic domain of these
      receptors, we created chimeras carrying the ectodomain of one receptor and the
      cytoplasmic domain of the other and tested their function in transgenic
      Drosophila. Fra-Robo (Fra's ectodomain and Robo's cytoplasmic domain) functions
      as a repulsive Netrin receptor; neurons expressing Fra-Robo avoid the Netrin
      expressing midline and muscles. Robo-Fra (Robo's ectodomain and Fra's cytoplasmic
      domain) is an attractive Slit receptor; neurons and muscle precursors expressing
      Robo-Fra are attracted to the Slit-expressing midline.

PMID- 10399920
TI  - A ligand-gated association between cytoplasmic domains of UNC5 and DCC family
      receptors converts netrin-induced growth cone attraction to repulsion.
AB  - Netrins are bifunctional: they attract some axons and repel others. Netrin
      receptors of the Deleted in Colorectal Cancer (DCC) family are implicated in
      attraction and those of the UNC5 family in repulsion, but genetic evidence also
      suggests involvement of the DCC protein UNC-40 in some cases of repulsion. To
      test whether these proteins form a receptor complex for repulsion, we studied the
      attractive responses of Xenopus spinal axons to netrin-1, which are mediated by
      DCC. We show that attraction is converted to repulsion by expression of UNC5
      proteins in these cells, that this repulsion requires DCC function, that the UNC5
      cytoplasmic domain is sufficient to effect the conversion, and that repulsion can
      be initiated by netrin-1 binding to either UNC5 or DCC. The isolated cytoplasmic
      domains of DCC and UNC5 proteins interact directly, but this interaction is
      repressed in the context of the full-length proteins. We provide evidence that
      netrin-1 triggers the formation of a receptor complex of DCC and UNC5 proteins
      and simultaneously derepresses the interaction between their cytoplasmic domains,
      thereby converting DCC-mediated attraction to UNC5/DCC-mediated repulsion.

PMID- 10399921
TI  - Structure of a voltage-dependent K+ channel beta subunit.
AB  - The integral membrane subunits of many voltage-dependent potassium channels are
      associated with an additional protein known as the beta subunit. One function of
      beta subunits is to modify K+ channel gating. We have determined the structure of
      the conserved core of mammalian beta subunits by X-ray crystallography at 2.8 A
      resolution. Like the integral membrane component of K+ channels, beta subunits
      form a four-fold symmetric structure. Each subunit is an oxidoreductase enzyme
      complete with a nicotinamide co-factor in its active site. Several structural
      features of the enzyme active site, including its location with respect to the
      four-fold axis, imply that it may interact directly or indirectly with the K+
      channel's voltage sensor. This structure suggests a mechanism for coupling
      membrane electrical excitability directly to chemistry of the cell.

PMID- 10399922
TI  - Attracted or repelled? Look within.

PMID- 10399923
TI  - The Narp hypothesis?

PMID- 10399924
TI  - Leaky synapses.

PMID- 10399925
TI  - Thalamocortical synapses: sparse but stentorian.

PMID- 10399926
TI  - Presenilins, processing of beta-amyloid precursor protein, and notch signaling.

PMID- 10399927
TI  - Variability in single photon responses: a cut in the Gordian knot of rod
      phototransduction?

PMID- 10399928
TI  - The hippocampus, memory, and place cells: is it spatial memory or a memory space?

PMID- 10399929
TI  - Is the amygdala a locus of "conditioned fear"? Some questions and caveats.

PMID- 10399930
TI  - Why we think plasticity underlying Pavlovian fear conditioning occurs in the
      basolateral amygdala.

PMID- 10399931
TI  - F-Spondin is required for accurate pathfinding of commissural axons at the floor
      plate.
AB  - The commissural axons project toward and across the floor plate. They then turn
      into the longitudinal axis, extending along the contralateral side of the floor
      plate. F-spondin, a protein produced and secreted by the floor plate, promotes
      adhesion and neurite extension of commissural neurons in vitro. Injection of
      purified F-spondin protein into the lumen of the spinal cord of chicken embryos
      in ovo resulted in longitudinal turning of commissural axons before reaching the
      floor plate, whereas neutralizing antibody (Ab) injections caused lateral turning
      at the contralateral floor plate boundary. These combined in vitro and in vivo
      results suggest that F-spondin is required to prevent the lateral drifting of the
      commissural axons after having crossed the floor plate.

PMID- 10399932
TI  - Doublecortin is a developmentally regulated, microtubule-associated protein
      expressed in migrating and differentiating neurons.
AB  - Recently, we and others reported that the doublecortin gene is responsible for X
      linked lissencephaly and subcortical laminar heterotopia. Here, we show that
      Doublecortin is expressed in the brain throughout the period of corticogenesis in
      migrating and differentiating neurons. Immunohistochemical studies show its
      localization in the soma and leading processes of tangentially migrating neurons,
      and a strong axonal labeling is observed in differentiating neurons. In cultured
      neurons, Doublecortin expression is highest in the distal parts of developing
      processes. We demonstrate by sedimentation and microscopy studies that
      Doublecortin is associated with microtubules (MTs) and postulate that it is a
      novel MAP. Our data suggest that the cortical dysgeneses associated with the loss
      of Doublecortin function might result from abnormal cytoskeletal dynamics in
      neuronal cell development.

PMID- 10399933
TI  - Doublecortin is a microtubule-associated protein and is expressed widely by
      migrating neurons.
AB  - Doublecortin (DCX) is required for normal migration of neurons into the cerebral
      cortex, since mutations in the human gene cause a disruption of cortical neuronal
      migration. To date, little is known about the distribution of DCX protein or its
      function. Here, we demonstrate that DCX is expressed in migrating neurons
      throughout the central and peripheral nervous system during embryonic and
      postnatal development. DCX protein localization overlaps with microtubules in
      cultured primary cortical neurons, and this overlapping expression is disrupted
      by microtubule depolymerization. DCX coassembles with brain microtubules, and
      recombinant DCX stimulates the polymerization of purified tubulin. Finally,
      overexpression of DCX in heterologous cells leads to a dramatic microtubule
      phenotype that is resistant to depolymerization. Therefore, DCX likely directs
      neuronal migration by regulating the organization and stability of microtubules.

PMID- 10399934
TI  - Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of
      ErbB2 in peripheral nervous system development.
AB  - ErbB2 receptor tyrosine kinase plays a role in neuregulin signaling and is
      expressed in the developing nervous system. We genetically rescued the cardiac
      defect of erbB2 null mutant embryos, which otherwise died at E11. These rescued
      erbB2 mutant mice die at birth and display a severe loss of both motor and
      sensory neurons. Motor and sensory axons are severely defasciculated and
      aberrantly projected within their final target tissues. Schwann cells are
      completely absent in the peripheral nerves. Schwann cell precursors are present
      within the DRG and proliferate normally, but their ability to migrate is
      decreased. Acetylcholine receptors cluster within the central band of the mutant
      diaphragm muscle. However, these clusters are dispersed and morphologically
      different from those in control muscle. Our results reveal an important role for
      erbB2 during normal peripheral nervous system development.

PMID- 10399935
TI  - Retinal ganglion cells lose trophic responsiveness after axotomy.
AB  - Whereas PNS neurons in culture are intrinsically responsive to peptide trophic
      factors, retinal ganglion cells (RGCs) are not unless they are depolarized, or
      their intracellular levels of cyclic AMP (cAMP) are elevated. We show here that
      depolarization increases cAMP in cultured RGCs sufficiently to enhance their
      responsiveness and that the trophic responsiveness of developing RGCs in intact
      retinas depends on physiological levels of activity and cAMP elevation.
      Responsiveness is lost after axotomy but is restored by cAMP elevation. The death
      of axotomized RGCs can be prevented if they are simultaneously stimulated by
      several trophic factors together with cAMP elevation. Thus, the death of RGCs
      after axotomy is not caused solely by the loss of retrograde trophic stimuli but
      also by a profound loss of trophic responsiveness.

PMID- 10399936
TI  - Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after
      ablation of scar-forming, reactive astrocytes in adult transgenic mice.
AB  - Reactive astrocytes adjacent to a forebrain stab injury were selectively ablated
      in adult mice expressing HSV-TK from the Gfap promoter by treatment with
      ganciclovir. Injured tissue that was depleted of GFAP-positive astrocytes
      exhibited (1) a prolonged 25-fold increase in infiltration of CD45-positive
      leukocytes, including ultrastructurally identified monocytes, macrophages,
      neutrophils, and lymphocytes, (2) failure of blood-brain barrier (BBB) repair,
      (3) substantial neuronal degeneration that could be attenuated by chronic
      glutamate receptor blockade, and (4) a pronounced increase in local neurite
      outgrowth. These findings show that genetic targeting can be used to ablate scar
      forming astrocytes and demonstrate roles for astrocytes in regulating leukocyte
      trafficking, repairing the BBB, protecting neurons, and restricting nerve fiber
      growth after injury in the adult central nervous system.

PMID- 10399937
TI  - Synaptic clustering of AMPA receptors by the extracellular immediate-early gene
      product Narp.
AB  - Narp (neuronal activity-regulated pentraxin) is a secreted immediate-early gene
      (IEG) regulated by synaptic activity in brain. In this study, we demonstrate that
      Narp possesses several properties that make it likely to play a key role in
      excitatory synaptogenesis. Narp is shown to be selectively enriched at excitatory
      synapses on neurons from both the hippocampus and spinal cord. Overexpression of
      recombinant Narp increases the number of excitatory but not inhibitory synapses
      in cultured spinal neurons. In transfected HEK 293T cells, Narp interacts with
      itself, forming large surface clusters that coaggregate AMPA receptor subunits.
      Moreover, Narp-expressing HEK 293T cells can induce the aggregation of neuronal
      AMPA receptors. These studies support a model in which Narp functions as an
      extracellular aggregating factor for AMPA receptors.

PMID- 10399938
TI  - Laser ablations reveal functional relationships of segmental hindbrain neurons in
      zebrafish.
AB  - Segmentation of the vertebrate brain is most obvious in the hindbrain, where
      successive segments contain repeated neuronal types. One such set of three
      repeated reticulospinal neurons--the Mauthner cell, MiD2cm, and MiD3cm--is
      thought to produce different forms of the escape response that fish use to avoid
      predators. We used laser ablations in larval zebrafish to test the hypothesis
      that these segmental hindbrain cells form a functional group. Killing all three
      cells eliminated short-latency, high-performance escape responses to both head-
      and tail-directed stimuli. Killing just the Mauthner cell affected escapes from
      tail-directed but not from head-directed stimuli. These results reveal the
      contributions of one set of reticulospinal neurons to behavior and support the
      idea that serially repeated hindbrain neurons form functional groups.

PMID- 10399939
TI  - Variability in the time course of single photon responses from toad rods:
      termination of rhodopsin's activity.
AB  - We examined the responses of toad rod photoreceptors to single photons of light.
      To minimize the effects of variability in the early rising phase, we selected
      sets of responses that closely matched the rise of the mean single photon
      response. Responses selected in this way showed substantial variations in
      kinetics, appearing to peel off from a common time course after different delays.
      Following incorporation of the calcium buffer BAPTA, the time to peeling off was
      retarded. Our analysis indicates that it is not necessary to invoke a long series
      of reaction steps to explain the shutoff of rhodopsin activity. Instead, our
      results suggest that the observed behavior is explicable by the presently known
      shutoff reactions of activated rhodopsin, modulated by feedback.

PMID- 10399940
TI  - Destabilization of cortical dendrites and spines by BDNF.
AB  - Particle-mediated gene transfer and two-photon microscopy were used to monitor
      the behavior of dendrites of individual cortical pyramidal neurons coexpressing
      green fluorescent protein (GFP) and brain-derived neurotrophic factor (BDNF).
      While the dendrites and spines of neurons expressing GFP alone grew modestly over
      24-48 hr, coexpressing BDNF elicited dramatic sprouting of basal dendrites,
      accompanied by a regression of dendritic spines. Compared to GFP-transfected
      controls, the newly formed dendrites and spines were highly unstable. Experiments
      utilizing Trk receptor bodies, K252a, and overexpression of nerve growth factor
      (NGF) demonstrated that these effects were mediated by secreted BDNF interacting
      with extracellular TrkB receptors. Thus, BDNF induces structural instability in
      dendrites and spines, which, when restricted to particular portions of a
      dendritic arbor, may help translate activity patterns into specific morphological
      changes.

PMID- 10399941
TI  - Surface expression of AMPA receptors in hippocampal neurons is regulated by an
      NSF-dependent mechanism.
AB  - Here, we show that disruption of N-ethylmaleimide-sensitive fusion protein- (NSF
      ) GluR2 interaction by infusion into cultured hippocampal neurons of a blocking
      peptide (pep2m) caused a rapid decrease in the frequency but no change in the
      amplitude of AMPA receptor-mediated miniature excitatory postsynaptic currents
      (mEPSCs). N-methyl-D-aspartate (NMDA) receptor-mediated mEPSCs were not changed.
      Viral expression of pep2m reduced the surface expression of alpha-amino-3-hydroxy
      5-methyl-isoxazolepropionate (AMPA) receptors, whereas NMDA receptor surface
      expression in the same living cells was unchanged. In permeabilized neurons, the
      total amount of GluR2 immunoreactivity was unchanged, and a punctate distribution
      of GluR2 was observed throughout the dendritic tree. These data suggest that the
      NSF-GluR2 interaction is required for the surface expression of GluR2-containing
      AMPA receptors and that disruption of the interaction leads to the functional
      elimination of AMPA receptors at synapses.

PMID- 10399942
TI  - Glutamate spillover mediates excitatory transmission in the rat olfactory bulb.
AB  - In the CNS, glutamate typically mediates excitatory transmission via local
      actions at synaptic contacts. In the olfactory bulb, mitral cell dendrites
      release glutamate at synapses formed only onto the dendrites of inhibitory
      granule cells. Here, I show excitatory transmission mediated solely by
      transmitter spillover between mitral cells in olfactory bulb slices. Dendritic
      glutamate release from individual mitral cells causes self-excitation via local
      activation of N-methyl-D-aspartate (NMDA) receptors. Paired recordings reveal
      that glutamate release from one cell generates NMDA receptor-mediated responses
      in neighboring mitral cells that are enhanced by blockade of glutamate uptake.
      Furthermore, spillover generates spontaneous NMDA receptor-mediated population
      responses. This simultaneous activation of neighboring mitral cells by a diffuse
      action of glutamate provides a mechanism for synchronizing olfactory principal
      cells.

PMID- 10399943
TI  - Efficacy of thalamocortical and intracortical synaptic connections: quanta,
      innervation, and reliability.
AB  - Thalamocortical (TC) synapses carry information into the neocortex, but they are
      far outnumbered by excitatory intracortical (IC) synapses. We measured the
      synaptic properties that determine the efficacy of TC and IC axons converging
      onto spiny neurons of layer 4 in the mouse somatosensory cortex. Quantal events
      from TC and IC synapses were indistinguishable. However, TC axons had, on
      average, about 3 times more release sites than IC axons, and the mean release
      probability at TC synapses was about 1.5 times higher than that at IC synapses.
      Differences of innervation ratio and release probability make the average TC
      connection several times more effective than the average IC connection, and may
      allow small numbers of TC axons to dominate the activity of cortical layer 4
      cells during sensory inflow.

PMID- 10399944
TI  - Released fraction and total size of a pool of immediately available transmitter
      quanta at a calyx synapse.
AB  - The size of a pool of readily releasable vesicles at a giant brainstem synapse,
      the calyx of Held, was probed with three independent approaches. Using
      simultaneous pre- and postsynaptic whole-cell recordings, two forms of
      presynaptic Ca2+ stimuli were applied in rapid succession: uncaging of Ca2+ by
      flash photolysis and the opening of voltage-gated Ca2+ channels. The ensuing
      transmitter release showed a nearly complete cross-inhibition between the two
      stimuli, indicating the depletion of a limited pool of about 700 transmitter
      quanta. The pool size was confirmed in experiments using enhanced extracellular
      Ca2+ concentrations, as well as short, high-frequency stimulus trains. The
      results reveal a surprisingly large pool of functionally available vesicles, of
      which a fraction of about 0.2 is released by a single presynaptic action
      potential under physiological conditions.

PMID- 10399945
TI  - Intake of food groups and associated micronutrients in relation to risk of early
      stage breast cancer.
AB  - Epidemiologic studies have evaluated the risk of breast cancer related to dietary
      fat intake, but only recently have other dietary factors received attention.
      Frequent intakes of fruit, vegetables and fiber have been associated with low
      risk of the disease in some studies but results are inconsistent. In a large case
      control study of early-onset breast cancer, we evaluated risk related to a
      variety of food groups, associated micronutrients and non-nutritive constituents.
      Cases treated with chemotherapy appeared to have altered reporting of food intake
      and were excluded. Analyses were restricted to 568 cases with in situ and
      localized disease and 1,451 population-based controls. Reduced risks were
      observed for high intake of cereals and grains [odds ratio (OR) = 0.84, 95%
      confidence interval (CI) = 0.6-1.1 for highest compared with lowest quartile],
      vegetables (OR = 0.86, 95% CI = 0.6-1.1), beans (OR = 0.87, 95% CI = 0.7-1.2) and
      fiber from beans (OR = 0.88, 95% CI = 0.7-1.2). However, no trends of decreasing
      risk across quartiles of increasing intake were observed. Risk was not associated
      with dietary constituents related to these food groups including dietary fiber,
      carotenoids, vitamins A, C and E and folate. Incorporation of information from
      vitamin supplements did not alter the results for micronutrients. Our data
      suggest that intakes of cereals and grains, vegetables and beans are associated
      with minimal, if any, reduction in risk of early-stage breast cancer among young
      women.

PMID- 10399946
TI  - Genetic deletion and human papillomavirus infection in cervical cancer: loss of
      heterozygosity sites at 3p and 5p are important genetic events.
AB  - "High-risk" human papillomavirus (HPV) types 16/18 are recognized as being
      associated with cervical cancer. We have already reported frequent loss of
      heterozygosity (LOH) at 3p, 3q, 4q, 5p and 5q in primary cervical cancer, the
      frequency at these sites ranging from 31.0 to 56.3%. The present analysis deals
      with these frequent-deletion sites in relation to HPV infection. HPV frequency,
      as determined by PCR and by Southern-blot, was 87.0%. Out of 45 HPV-positive
      tumours, 26 (57.8%) were "high-risk" HPV-16/18-positive, with HPV type 16
      predominant (24 of 26). Among these 24, 14 (58.3%) tumours had HPV-16 DNA
      integrated with the host genome. LOH on 3p revealed significant association with
      HPV-16/18 infection; 64.0% of LOH at 3p was in HPV16/18-positive tumours, vs.
      23.3% in the tumours that did not reveal the presence of HPV16/18. On the other
      hand, 78.6% of LOH at 5p, which was the most frequent (56.3%), was in tumours
      without HPV16/18 infection, vs. 43.7% in tumours that had HPV 16/18 infection,
      suggesting independence of HPV 16/18 infection. At other sites, LOH did not
      differ, irrespective of the presence or absence of "high-risk" HPV infection.

PMID- 10399947
TI  - Germline brca2 sequence variants in patients with ocular melanoma.
AB  - On the basis, chiefly, of anecdotal reports of cases of ocular melanoma (OM)
      occurring in families with inherited susceptibility to breast cancer due to brca2
      germline mutations, we examined the frequency of brca2 alterations in a series of
      62 ocular melanoma cases. These cases were preferentially selected on the basis
      of reported family history of breast or ovarian cancer, or OM, although the
      series also included a randomly selected set of cases without family history of
      cancer. A total of 7 germline alterations were found, of which 3 were likely to
      be associated with disease. While all 3 deleterious mutations were found in
      patients who also had a personal history of breast cancer, only 1 of the 3
      families had a family history of breast/ovarian cancer or OM. Although germline
      brca2 mutations may account for a small proportion of all OM cases, there may be
      additional loci that contribute to familial aggregation of OM and to the familial
      association between OM and breast cancer.

PMID- 10399948
TI  - Characterization of the 17p amplicon in human sarcomas: microsatellite marker
      analysis.
AB  - The structure of the 17p amplicon from 9 human sarcoma specimens evaluated by
      comparative genomic hybridization (CGH) has been studied by analyzing 28
      microsatellite markers by PCR. Eleven sarcoma specimens showing no DNA copy
      number increases at 17p by CGH were analyzed as control samples. Five specimens
      were analyzed by Southern blotting using probes that have previously shown
      amplification at the 17p12 region in astrocytoma and high-grade osteosarcoma
      samples. Microsatellite marker analyses revealed that all samples but 1 showing
      copy number increases at 17p by CGH displayed allelic imbalance that confirmed
      the CGH findings. Seven of these 9 cases displayed gain in copy number by
      microsatellite marker analysis. Four cases displaying gain in copy number were
      associated with loss of heterozygosity at other loci. Southern blot analysis
      showed amplification in 3 cases, all of them had shown copy number increases by
      CGH and microsatellite marker analysis, except one case, which was not included
      in the microsatellite marker analysis. Our results reveal the complexity of the
      17p amplicon in sarcomas, suggesting that multiple target genes are involved in
      tumorigenesis.

PMID- 10399949
TI  - Risk of invasive cervical cancer among women with, or at risk for, HIV infection.
AB  - Although invasive cervical cancer (ICC) has been included among the AIDS-defining
      conditions since 1993, it remains controversial whether HIV infection increases
      the risk of developing such neoplasm. In this study, ICC risk was longitudinally
      investigated among 1,340 HIV-positive intravenous drug user (IDU), 811 HIV
      negative IDU, and 801 HIV-positive heterosexual women. These women, aged 15-49
      years, were followed up at the Italian HIV Seroconverter Study, at the San
      Patrignano Community (Rimini, North Italy), and in South-eastern France (the DMI
      2 study). The number of observed cases of ICC was compared with the expected one,
      based on ICC incidence rates among women of the same age in the general
      population of Italy or France, and standardized incidence ratios (SIR) were
      computed; 9,070 person-years of observation were accumulated among HIV-positive
      women and 2,310 among HIV-negative ones. Ten cases of ICC were diagnosed among
      HIV-positive women (SIR = 12.8): ICC risk was apparently higher among HIV
      positive IDU (SIR = 16.7) than among heterosexual women (SIR = 6.7). No cases of
      ICC were diagnosed among HIV-negative IDU women admitted to the San Patrignano
      Community (0.15 cases were expected). Our findings confirm previous suggestions
      showing an increased risk of ICC among HIV-infected women and have important
      implications at the individual and public health levels.

PMID- 10399950
TI  - Growth-factor-dependent migration of human lung-cancer cells.
AB  - Human lung tumors express different types of growth-factor receptors and
      corresponding ligands that might modulate several biological functions such as
      proliferation, differentiation, adhesion, and chemotaxis. In the present study,
      we have investigated the expression of different growth-factor receptors and
      their ligands in 5 established human lung-cancer cell lines. Using RT-PCR, we
      found that IGF-II/mannose-6-phosphate (M6P), c-met, EGF and c-kit receptors are
      expressed in 5/5 human lung-cancer cell lines. In order to investigate the
      biological function of these receptors, we performed Boyden-chamber assays using
      various growth factors as chemo-attractants. Human non-small-cell-lung-cancer
      cells (non-SCLC) migrated to recombinant human (rh)IGF I and IGF II at
      concentrations ranging from 1 to 1000 ng/ml, to HGF at 10 to 100 ng/ml, to EGF at
      1 to 100 ng/ml and SCF at 1 to 50 ng/ml. In addition, we performed Boyden-chamber
      assays using U-1810-, U-1752- and Wart-derived serum-free conditioned medium as
      chemo-attractants. Serum-free conditioned medium stimulated migration of producer
      cells in a dose-dependent manner. The autocrine motility stimulating effect of U
      1810-derived serum-free conditioned medium could be inhibited by 50% in the
      presence of neutralizing ahIGF-II antibodies in the assay, suggesting a possible
      autocrine motility loop in vitro.

PMID- 10399951
TI  - Tumor-specific expression of anti-mdr1 ribozyme selectively restores
      chemosensitivity in multidrug-resistant colon-adenocarcinoma cells.
AB  - P-glycoprotein (Pgp)-conferred multidrug resistance (MDR) is expressed in cancer
      and in normal colon tissues and has important physiological functions. In order
      to selectively reverse MDR in malignant tissue without disrupting the function of
      normal colonocytes, a retroviral vector (pCEAMR) containing anti-mdr1 ribozyme
      coupled to the carcino-embryonic-antigen (CEA) promoter was constructed and
      introduced into resistant colon-cancer cells (SW1116R) that produce CEA and into
      control resistant cells (HeLaK) that do not produce CEA. Anti-mdr1 ribozyme was
      expressed in SW1116R cells but not in HeLaK cells. Subsequently, the expression
      of mdr1 mRNA and Pgp decreased significantly in the transfected SW1116R cells,
      and was even lower than in parent non-resistant SW1116 cells. The functional
      ability of Pgp to facilitate rhodamine 123 (Rh123) efflux showed that the
      transfected SW1116R cells with low Pgp expression retained Rh123, whereas non
      transfected SW1116R cells with high Pgp expression released the dye quickly.
      There was no difference in mdr1 mRNA or in Pgp between non-transfected and
      transfected HeLaK cells. Drug resistance to doxorubicin (DOX) decreased 93.1% in
      the transfected SW1116R cells, while no change in drug resistance occurred in the
      infected HeLaK cells. DOX could clearly inhibit the growth of transfected SW1116R
      tumors but had no effect on untransfected and on transfected HeLaK cells in vivo.
      These results indicate that our anti-mdr1 ribozyme is expressed only in CEA
      producing colon-cancer cells and reverses their drug resistance selectively.

PMID- 10399952
TI  - Changes in the levels of integrin and focal adhesion kinase (FAK) in human
      melanoma cells following 532 nm laser treatment.
AB  - Despite the increase in laser therapy, concern remains that sublethal treatment
      of pre-malignant lesions may adversely affect the biological behaviour of
      surviving cells. Integrin receptors mediate interaction of cells with the
      extracellular matrix and their occupation leads to focal adhesion kinase (FAK)
      activation. Using our previously established model we have now investigated
      subcellular changes and compared integrin and FAK concentrations, the degree of
      FAK phosphorylation and its association with the beta1 integrin in laser vs. non
      laser treated cells. We treated cells with laser generated from a frequency
      doubled Q-switched (Nd:YAG) laser system (532 nm) at 0.4 J/cm2 twice per week for
      4 weeks. Using cell lysates we performed Western immunoblotting 24 hr later to
      detect integrin subunits and FAK proteins and immunoprecipitation to investigate
      FAK phosphorylation and its association with beta1. Cell morphology was examined
      using electron microscopy. SK23 and G361 cells exhibited an 3.4- and 11.2-fold
      increase, respectively, in FAK protein following laser treatment. FAK
      phosphorylation in SK23 cells was increased by 82%, whereas FAK phosphorylation
      in G361 cells was reduced slightly (2%). Furthermore, both alpha3 and 4 integrins
      were up-regulated, by approximately 4-fold and 7- to 9-fold, respectively. In
      addition, the beta1 integrin was proteolysed in both cell lines and the levels of
      FAK associated with beta1 was increased (2.1- and 2.7-fold, respectively).
      Finally, laser treatment of SK23 cells caused an increased number of cell
      processes. Sublethal 532 nm laser light thus induces changes in integrin and FAK
      concentrations and subsequently influences cellular attachment and morphology.

PMID- 10399953
TI  - FAS(CD95) ligand expression by tumor cell variants can be unrelated to their
      capacity to induce tolerance or immune rejection.
AB  - According to the results of in vitro experiments, Fas(CD95) ligand expression by
      cancer cells might induce apoptosis of activated T cells and contribute to immune
      tolerance. However, Fas ligand expression had never been explored in vivo in
      tumor cell models yielding either immune response or tolerance. In the present
      study, we analyzed the expression and function of Fas ligand in 2 clones of tumor
      cells originating from the same rat colon carcinoma. REGb cells were immunogenic
      and yielded tumors that regressed in immunecompetent syngeneic hosts, whereas
      PROb cells induced active tolerance and yielded progressive tumors. Fas ligand
      was expressed on the plasma membrane of both REGb and PROb cells, and its cDNA
      sequencing showed no mutation. However, neither REGb nor PROb cells induced
      apoptosis of co-cultured Fas-sensitive target cells. Our results show that
      surface expression of Fas ligand by tumor cells does not always induce killing of
      adjoining Fas-sensitive cells and that tumor cells may induce a protective immune
      response or an active tolerance independently of Fas ligand expression.

PMID- 10399954
TI  - Altered expression of mRNAs for apoptosis-modulating proteins in a low level
      multidrug resistant variant of a human lung carcinoma cell line that also
      expresses mdr1 mRNA.
AB  - An in vitro model that might be relevant to cancer cell chemoresistance in vivo
      was generated by exposing the human lung carcinoma clonal cell line DLKP-SQ to 10
      sequential pulses of pharmacologically attainable doses of doxorubicin. The
      resistant variant, DLKP-SQ/10p, was found to be cross-resistant to doxorubicin
      (10x), vincristine (43x), etoposide (3x), sodium arsenate (3x), paclitaxel (38x)
      [which could imply overexpression of P-glycoprotein (P-gp) and possibly increased
      multidrug resistance-associated protein activity] and 5-fluorouracil (4x), but
      slightly sensitized to carboplatin. Analysis of mRNA levels in the resistant
      variant revealed overexpression of mdr1 mRNA without significant alteration in
      mrp, Topo. IIalpha, GSTpi, dhfr or thymidylate synthase mRNA levels.
      Overexpression of the anti-apoptotic bcl-xL transcript and the pro-apoptotic bax
      mRNA was also detected but no alterations in bcl-2 or bag-1 mRNA levels were
      observed. Resistance to a P-gp-associated drug, doxorubicin, could be reversed
      with P-gp circumventing agents such as cyclosporin A and verapamil, but these
      substances had no effect on resistance to 5-fluorouracil. Overexpression of the
      pro-apoptotic bcl-xS gene in the DLKP-SQ/10p line partially reversed resistance
      not only to P-gp-associated drugs but also to 5-fluorouracil, indicating that the
      ratio of bcl family members may be important in determining sensitivity to
      chemotherapeutic drug-induced apoptosis.

PMID- 10399955
TI  - Decreased expression of CD80 is a marker for increased tumorigenicity in a new
      murine model of oral squamous-cell carcinoma.
AB  - We established a new syngeneic murine model of oral squamous-cell carcinoma (SCC)
      to analyze the potential role of immune recognition determinants in the early
      development of oral cancer. In this study, we examined whether SCC that undergo
      transformation and development in the absence of specific immunity exhibit
      differences in tumorigenicity that relate to differences in expression of CD80,
      CD86 or MHC class I. Mucosal keratinocytes from BALB/c mice were transformed in
      vitro with 4-nitroquinolone-1-oxide (4-NQO) and inoculated into SCID mice to
      obtain tumorigenic cell lines. Five SCC cell lines were re-isolated from tumors,
      and 4 retained cytokeratin and beta4-integrin markers of epithelial origin. Their
      growth was compared in BALB/c and in congenic SCID mice to establish whether the
      cell lines exhibit differences in immunogenicity. Three lines that showed slower
      growth or completely regressed when implanted in immune competent hosts retained
      or developed increased expression of CD80 during development in SCID mice.
      Conversely, 2 SCC lines that lost expression of CD80 after passage in vivo grew
      progressively in immune-competent hosts. MHC-class-I and CD86 expression did not
      correlate with tumorigenicity. These observations provide evidence that decreased
      expression of CD80 may serve as a marker for increased tumorigenicity during
      early development of oral SCC. The development of this new murine oral SCC model
      should prove useful in determining the potential effects of CD80 expression on
      the immune pathogenesis and therapy of SCC.

PMID- 10399956
TI  - Radiation-induced normal tissue injury: role of adhesion molecules in leukocyte
      endothelial cell interactions.
AB  - The late onset of necrosis and fibrosis in normal tissues can be a serious
      consequence of radiotherapy in cancer patients. Because radiation-induced
      vascular injury precedes the tissue damage, vascular injury is regarded as
      crucial in the pathogenesis of tissue damage. An understanding of the processes
      responsible is essential to develop strategies for the amelioration of radiation
      induced normal tissue damage. Leukocyte infiltration is commonly observed at
      sites of irradiation and is likely to lead to the acceleration and/or induction
      of parenchymal atrophy, fibrosis and necrosis in normal tissues following
      radiotherapy. The molecular mechanisms mediating leukocyte infiltration of
      tissues during inflammation have been studied extensively. It is now well
      established that cell adhesion molecules (CAMs) expressed on leukocytes and
      endothelial cells control the trafficking of leukocytes from the blood vessel
      lumen in these conditions. CAMs including E (endothelial), P (platelet) and L
      (leukocyte)-selectins, intercellular adhesion molecule 1 (ICAM-1), vascular cell
      adhesion molecule 1 (VCAM-1), beta1 and beta2 integrins and CD31 are involved in
      the cascade of events resulting in rolling, arrest and transmigration of
      leukocytes through the inflamed endothelium. Whether a similar sequence of
      molecular events induces leukocyte sequestration in irradiated normal tissues is
      not known. This review is focussed on the role of CAMs in radiation-induced
      leukocyte infiltration of normal tissues and the therapeutic implications of
      these findings.

PMID- 10399957
TI  - Apoptotic response to camptothecin and 7-hydroxystaurosporine (UCN-01) in the 8
      human breast cancer cell lines of the NCI Anticancer Drug Screen: multifactorial
      relationships with topoisomerase I, protein kinase C, Bcl-2, p53, MDM-2 and
      caspase pathways.
AB  - Derivatives of camptothecins, topoisomerase I inhibitors and 7
      hydroxystaurosporine (UCN-01), a protein kinase C (PKC) inhibitor and cell cycle
      checkpoint abrogator, are promising anticancer drugs. We characterized the
      apoptotic response to camptothecin and UCN-01 for the 8 human breast carcinoma
      cell lines (MCF-7, MCF-7/ADR, T47D, HS578T, BT549, MDA-N, MDA MB231, MDA435) from
      the National Cancer Institute (NCI) Anticancer Drug Screen. MCF-7 and T47D cells
      exhibited marked resistance to apoptosis, whereas MCF-7/ADR (NCI/ADR-RES) and
      HS578T cells exhibited the most pronounced apoptotic response. Apoptotic response
      was not correlated with growth inhibition measured by sulforhodamine B (SRB)
      assay, indicating that apoptosis is not the only mechanism of drug-induced cell
      death. Measurements of topoisomerase I levels and cleavage complexes and of PKC
      isoforms demonstrated that primary target inhibition was not correlated with
      apoptotic response. Several key apoptotic pathways were evaluated. Only MCF-7
      cells had wild-type p53, indicating that p53 is not required for drug-induced
      apoptosis. MCF-7 cells also showed the highest MDM-2 expression (along with T47D
      cells, which were also resistant to apoptosis). Bcl-2, Mcl-1 and caspases 2 and 3
      protein levels varied widely, whereas Bax expression was comparable among cell
      lines. Interestingly, Bcl-2, Mcl-1 and Bcl-X(L) cumulative expressions were
      inversely correlated with apoptotic response. Our results provide a comparative
      molecular characterization for the breast cancer cell lines of the NCI Anticancer
      Drug Screen and demonstrate the diversity of cellular responses to drugs
      (apoptosis vs. cell cycle arrest) and the importance of multifactorial analyses
      for modulating/predicting the apoptotic response to chemotherapy.

PMID- 10399958
TI  - Co-expression of gamma-glutamylcysteine synthetase sub-units in response to
      cisplatin and doxorubicin in human cancer cells.
AB  - Glutathione (gamma-glutamylcysteinyl glycine, GSH) is believed to be important in
      the acquisition of resistance to anti-cancer drugs such as cisplatin (CDDP) and
      doxorubicin (DOX). gamma-Glutamylcysteine synthetase (gamma-GCS) is a key enzyme
      for maintaining intracellular GSH levels; it is composed of a catalytic heavy
      (gamma-GCSh) and a regulatory light (gamma-GCSl) sub-unit. In the present study,
      the expression of gamma-GCS sub-units was examined in human cancer cell lines.
      The levels of GSH, the expression of gamma-GCSh and gamma-GCSl mRNAs and proteins
      in human cancer cells were higher in CDDP-resistant cells and DOX-resistant cells
      than in the drug-sensitive cells. Treatment of CDDP/DOX-resistant human colonic
      cancer cells (HCT8DDP) with CDDP and DOX caused simultaneous induction of the
      expression of gamma-GCSh and gamma-GCSl mRNAs. The transcriptional regulation of
      gamma-GCS was studied and it was observed that the DNA-binding activity of
      activator protein 1 (AP-1) is induced by CDDP and DOX using an electrophoretic
      mobility shift assay. We constructed chimeric genes containing various regions of
      the gamma-GCSh-promoter gene and the coding region for luciferase. The HCT8DDP
      cells transiently transfected with a plasmid containing an AP-1 site of the gamma
      GCSh-promoter-luciferase construct showed increased luciferase activity when
      treated with CDDP and DOX. These results suggest that stimulation of the
      expression of gamma-GCSh by CDDP and DOX is mediated by AP-1, which relates to
      the resistance of cancer cells to the drug.

PMID- 10399959
TI  - Physiological concentrations of gangliosides GM1, GM2 and GM3 differentially
      modify basic-fibroblast-growth-factor-induced mitogenesis and the associated
      signalling pathway in endothelial cells.
AB  - It has been suggested that gangliosides can influence the growth of cells by
      modulation of growth-factor-receptor signalling. The activation of endothelial
      cells (EC) during angiogenesis is crucial for tumour growth and for metastasis,
      also for numerous other physiological and pathological situations. Pre-treatment
      of bovine aortic endothelial cells (BAEC) with GM1 or GM2 (5-20 microM) inhibited
      basic-fibroblast-growth-factor (bFGF)-induced mitogenesis, but GM3 (0.1-20
      microM) acted synergistically, increasing proliferation above that of bFGF alone
      (p < 0.05). The mitogenic effect of all 3 gangliosides was markedly reduced if
      the cells were washed to remove excess gangliosides from the medium before
      addition of bFGF. We further show that GM1 and to a lesser extent GM2 modify bFGF
      binding to its receptor and inhibit the associated mitogenic signal-transduction
      pathway of protein-tyrosine phosphorylation of 40 to 120 kDa, PLCgamma1, MAP
      kinase and protein-kinase-C activation. In contrast, GM3 increased tyrosine
      phosphorylation and MAP kinase activity, as compared with bFGF alone. The
      observed differential modulation of bFGF-induced mitogenesis by GM1, GM2 and GM3
      was at concentrations routinely occurring in the serum of cancer patients. The
      results suggest that circulating gangliosides may have a role in regulating solid
      tumour growth by modulating angiogenesis.

PMID- 10399960
TI  - Androgenic regulation of growth factor and growth factor receptor expression in
      the CWR22 model of prostatic adenocarcinoma.
AB  - The effects of androgen manipulation on epidermal growth factor (EGF) receptor,
      p185erbB-2 and transforming growth factor-alpha (TGF-alpha) levels were examined
      in prostatic adenocarcinoma. Male nude mice were inoculated with the CWR22
      androgen-dependent human prostatic tumor or an androgen-independent (CWR22R)
      derivative. Mice with CWR22 tumors were castrated and subsequently killed at 3,
      7, 21, 28 or 42 days post-castration. Other CWR22-bearing mice received s.c.
      testosterone pellets at 21 days post-castration and were killed 7 days later. EGF
      receptor, p185erbB-2 and TGF-alpha levels were examined by immuno-histochemistry.
      Strong EGF receptor and p185erbB-2 immunostaining was detected in CWR22 tumors
      from intact controls. EGF receptor immunostaining decreased by 65% to 70% at 21
      to 42 days post-castration. Testosterone treatment at 21 to 28 days post
      castration resulted in a 2-fold increase in EGF receptor immunostaining. p185erbB
      2 immunostaining within CWR22 tumors did not decrease following castration and,
      in fact, was slightly increased at 7 days post-castration. The effects of
      castration on EGF receptor and p185erbB-2 levels were confirmed by Western blot
      analysis. Fewer than 10% of CWR22 tumor cells demonstrated strong TGF-alpha
      immunostaining, and androgen manipulation did not effect TGF-alpha
      immunostaining. In contrast, 30% of androgen-independent CWR22R tumor cells were
      strongly immunostained for TGF-alpha. Our findings indicate that EGF receptor
      levels, but not p185erbB-2 levels, are strongly dependent on testosterone in
      CWR22 tumors. The co-localization of TGF-alpha and the EGF receptor in CWR22R
      tumors suggests that these factors may constitute an autocrine pathway that
      regulates androgen-independent growth.

PMID- 10399962
TI  - Betulinic acid: a new cytotoxic agent against malignant brain-tumor cells.
AB  - Malignant brain tumors are the most common solid tumors in children. The overall
      prognosis for this group of patients is still poor, emphasizing the importance of
      more effective therapies. Betulinic acid (Bet A) has been described as a novel
      cytotoxic compound active against melanoma and neuroblastoma cells. Here we
      report that Bet A was active against medulloblastoma and glioblastoma cell lines.
      In addition, Bet A exerted cytotoxic activity against primary tumor cells
      cultured from patients in 4 of 4 medulloblastoma-tumor samples tested and in 20
      of 24 glioblastoma-tumor samples. Since a small percentage of primary
      glioblastoma-tumor cells (4/24) did not respond to Bet-A treatment, resistance to
      Bet A might occur. Induction of apoptosis by Bet A involved mitochondrial
      perturbations, since inhibition of the mitochondrial permeability transition by
      the mitochondrion-specific inhibitor bongkrekic acid (BA) reduced Bet-A-induced
      apoptosis. In addition, mitochondria undergoing Bet-A-induced permeability
      transition triggered DNA fragmentation in isolated nuclei. Cytochrome c was
      released from mitochondria of Bet-A-treated cells, and might be involved in
      activation of caspases. Following treatment with Bet A, caspase-8, caspase-3 and
      PARP were proteolytically processed. Inhibition of caspase cleavage by the broad
      range caspase inhibitor zVAD.fmk strongly reduced Bet-A-induced apoptosis,
      indicating that apoptosis was mediated by activation of caspases. Since Bet A did
      not exhibit cytotoxicity against murine neuronal cells in vitro, these findings
      suggest that Bet A may be a promising new agent for the treatment of
      medulloblastoma and glioblastoma cells that clearly warrants further pre-clinical
      and clinical evaluation.

PMID- 10399961
TI  - Apoptosis of medulloblastoma cells in vitro follows inhibition of farnesylation
      using manumycin A.
AB  - Medulloblastoma is a malignant cerebellar tumor usually manifesting in childhood.
      We have previously shown that blocking the mevalonate pathway with lovastatin, a
      competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
      reductase, inhibits medulloblastoma proliferation and induces apoptosis in vitro.
      The underlying mechanism may involve blocking post-translational modification of
      important mitogenic signal-transduction proteins. We show that p21 ras processing
      is blocked by lovastatin, suggesting that inhibition of isoprenylation may be
      important in lovastatin-induced apoptosis. To test this hypothesis, manumycin A,
      an antibiotic which inhibits farnesyl protein transferase and thus farnesylation,
      was administered to 4 medulloblastoma cell lines in vitro. We found that blocking
      protein farnesylation with manumycin A was followed by apoptosis in a time- and
      dose-dependent manner. However, cell death induced by manumycin A was uniformly
      more rapid and efficient, requiring only 12 to 24 hr of treatment, than
      lovastatin-induced apoptosis, which required 36 to 96 hr (depending on the cell
      line tested). In addition, unlike lovastatin, which caused cell-cycle arrest in
      G1 phase and HMG-CoA reductase gene up-regulation, manumycin A had no effect on
      the cell cycle and resulted in down-regulation of HMG-CoA reductase gene
      expression. In both lovastatin- and manumycin A-treated cells, cellular cysteine
      protease precursor (CPP32) was activated, confirming the occurrence of apoptosis.

PMID- 10399963
TI  - Interleukin-2-induced, melanoma-specific T cells recognize CAMEL, an unexpected
      translation product of LAGE-1.
AB  - Melanoma-specific cytotoxic T lymphocytes (CTLs) were induced by in vitro
      stimulation of peripheral blood mononuclear cells of a melanoma patient with
      autologous IL-2-producing melanoma 518/IL2.14 cells. CTL clone 1/29 recognized,
      in addition to autologous melanoma cell lines, a panel of HLA-A*0201-expressing
      allogeneic melanoma cell lines but was not reactive with normal melanocytes.
      Here, we report the full molecular characterization of the target structure for
      CTL 1/29, which was identified by cDNA expression cloning. The recognized antigen
      was named CAMEL (CTL-recognized antigen on melanoma). The CAMEL cDNA turned out
      to be derived from the LAGE-1 gene, a recently described tumor antigen that is
      strongly homologous to NY-ESO-1. CAMEL, however, is not encoded by the putative
      open reading frame (ORF) of LAGE-1 but by an alternative frame starting from the
      second ATG of the mRNA. The first 11 amino acids of the CAMEL protein,
      MLMAQEALAFL, constitute the epitope of CTL 1/29. This epitope is also encoded by
      a similar alternative ORF in NY-ESO-1. In summary, CTL induction with IL-2
      transfected melanoma cells has revealed a new tumor antigen that may serve as a
      target for immunotherapy.

PMID- 10399964
TI  - Role of fibroblasts in HGF/SF-induced cohort migration of human colorectal
      carcinoma cells: fibroblasts stimulate migration associated with increased
      fibronectin production via upregulated TGF-beta1.
AB  - Carcinoma cells frequently invade the surrounding tissue as coherent clusters or
      nests of cells. We have called this type of movement "cohort migration." We have
      previously presented an in vitro two-dimensional cohort migration model, in which
      highly metastatic variant L-10 cells of human rectal adenocarcinoma cell line RCM
      1 moved as coherent cell sheets when stimulated with 12-O-tetradecanoylphorbol-13
      acetate (TPA) or hepatocyte growth factor/scatter factor (HGF/SF). Pericellular
      deposition of EDA-containing fibronectin (EDA+FN) was essential for TPA-induced
      cohort migration. In this study, we investigated how colon-derived fibroblasts
      could affect the induction of cohort migration of colorectal carcinoma cells by
      HGF/SF, since carcinoma cell-fibroblast interactions frequently regulate
      biological events during cancer cell invasion. Fibroblasts co-cultured with L-10
      carcinoma cells stimulated HGF/SF-induced cohort migration of L-10 cells up to 2
      to 3-fold. Conditioned medium (CM) from fibroblasts that were cultured alone was
      not effective but CM from fibroblasts cocultured with carcinoma cells enhanced
      HGF/SF-induced cohort migration, and this effect in CM was found to be mediated
      by TGF-beta1 upregulated in co-cultured conditions. Among the motogenic growth
      factors examined, only TGF-beta1 synergistically stimulated HGF/SF-induced L-10
      cell cohort migration, although TGF-beta1 alone did not induce cohort migration.
      TGF-beta1 also exhibited synergistic effect in several other human colorectal
      carcinoma cell lines. The synergistic stimulation of L-10 cell cohort migration
      by HGF/SF and TGF-beta1 was associated with increased production of motility
      enhancing EDA+FN by L-10 cells, and blocking FN with a specific antibody
      effectively inhibited the synergistic effect.

PMID- 10399966
TI  - The patient, burnout, and the practice of surgery.

PMID- 10399965
TI  - A new human synovial sarcoma cell line, HS-SY-3, with a truncated form of hybrid
      SYT/SSX1 gene.
AB  - Recent cytogenetical and molecular studies have indicated that synovial sarcoma
      harbors a t(X;18)(p11.2;q11.2) translocation, resulting in the formation of a
      hybrid SYT/SSX (SSX1 or SSX2) gene. We newly established a human cell line, HS-SY
      3, from a synovial sarcoma. HS-SY-3 cells were shown to harbor the pathognomonic
      t(X;18)(p11.2;q11.2) translocation by chromosome analysis but not to exhibit the
      classical hybrid SYT/SSX transcripts induced by this translocation, using RT-PCR.
      To determine the reason for this discrepancy, we analyzed cDNA from HS-SY-3
      cells, as well as the original sarcoma tissue by the rapid amplification of cDNA
      3' end assay, and found that the chimaeric cDNA was 240 bp shorter than the
      previously established SYT/SSX1 cDNA due to truncation of the 3' side of SSX1.
      The HS-SY-3 cells should be useful for future functional studies of the SYT/SSX
      chimeric gene.

PMID- 10399967
TI  - Laparoscopic transcystic management of choledocholithiasis.
AB  - Our objective was to review our community hospital experience with laparoscopic
      management of choledocholithiasis from 1991 to 1997. We performed a retrospective
      review of all case records of patients with choledocholithiasis managed
      surgically at St. Francis Hospital during the study period. Data regarding the
      history, presentation, investigations, operative details, and follow-up were
      recorded. Procedures were performed by multiple attending surgeons supervising
      surgical residents. All common bile duct explorations (CBDEs) were performed by a
      transcystic approach and followed routine cholangiography. In most cases, cystic
      duct dilatation over a guide wire was followed by transcystic CBDE with
      choledochoscopy. Stone extraction was accomplished through a combination of
      flushing, basket manipulation, fragmentation, retrieval, or advancement of stones
      through the ampulla. Data were analyzed using SPSS computer software, and P <
      0.05 was considered statistically significant. During the period of study there
      were 1053 laparoscopic cholecystectomies with and without cholangiography and 100
      total CBDE performed. Of these, 54/100 had an attempt at laparoscopic CBDE. There
      were 39 females and 15 males, with a median age of 52 years (range 14-88).
      Presentation included acute cholecystitis or biliary colic (63%), gallstone
      pancreatitis (20%), and jaundice or cholangitis (17%). Successful laparoscopic
      stone removal was achieved in 36 of 54 (67%) cases. Eighteen of the remainder
      (33%) were converted to an open procedure. Size, number, position of stones,
      technical difficulties in accessing the common bile duct, and patient factors
      contributed to open conversion. The rate of successful laparoscopic CBDE improved
      for each individual surgeon from an average of 22 per cent in the first half of
      the study period (1991-1994) to 87 per cent in the second half (1995-1997). There
      was no operative mortality. Significant morbidity in the laparoscopic group
      included one retained stone and two cases of postoperative pancreatitis. There
      were three false negative preoperative endoscopic retrograde
      cholangiopancreatography examinations. Multivariate analysis showed that
      experience of the individual surgeon was the only significant factor predicting
      successful laparoscopic CBDE. Low initial success rate in the early phase of the
      study period improved dramatically to reach an overall success rate of 87 per
      cent in the second half. Laparoscopic management of common bile duct stones is
      possible in a community setting with a high success rate and minimal morbidity.
      It precludes excessive use of endoscopic retrograde cholangiopancreatography with
      its own set of complications but is associated with a significant learning curve.
      It is currently our preferred therapeutic approach for choledocholithiasis
      discovered pre- or intraoperatively.

PMID- 10399968
TI  - The effect of lexipafant on bacterial translocation in acute necrotizing
      pancreatitis in rats.
AB  - Bacterial translocation (BT) from the gastrointestinal tract to mesenteric lymph
      nodes (MLNs) and other extra intestinal organs is an important source of
      infection in acute pancreatitis (AP). Lexipafant (BB-882) is a potent platelet
      activating factor receptor antagonist that has an anti-inflammatory effect. To
      examine whether BB-882 could affect BT in acute necrotizing pancreatitis, 48 male
      Sprague Dawley rats (250-350 g) were studied. AP was induced in Group I and Group
      II by pressure injection of 3% taurocholate and trypsin into the common
      biliopancreatic duct (1 mL/kg of body weight). Group I rats received BB-882 (10
      mg/kg, i.p. qd) and Group II rats received a similar volume of normal saline as a
      placebo postoperatively for 2 days. Group III and Group IV received BB-882 and
      placebo, respectively, after an exploratory laparotomy. At 48 hours
      postoperatively, blood was drawn for culture, serum amylase, and tumor necrosis
      factor (TNF)-alpha determinations. Specimens from MLNs, spleen, liver, pancreas,
      and cecum were harvested for culture of gram-positive, gram-negative, and
      anaerobic bacteria. Quantitative cecal cultures of gram-positive, gram-negative,
      and anaerobic bacteria were obtained. A point scoring system for five
      histological features that include interstitial edema, inflammatory cellular
      infiltration, fat necrosis, parenchymal necrosis, and hemorrhage was used to
      evaluate the severity of pancreatitis. There was no difference in serum amylase
      levels (2415 +/- 127 IU/L versus 2476 +/- 170 IU/L), serum TNF-alpha levels (7820
      +/- 1396 pg/mL versus 7318 +/- 681 pg/mL), and the mean pancreatic histology
      score (5.9 +/- 1.2 versus 6.5 +/- 1.1) between Group I and Group II, respectively
      (P > 0.05). Seven of 12 Group I rats had BT to MLNs, compared with 11 of 12 rats
      in Group II (P > 0.05). Five of 12 Group I rats had BT to distant sites such as
      pancreas, spleen, liver, and/or blood, compared with 11 of 12 rats in Group II (P
      < 0.05). BB-882 treatment decreases bacterial spread to distant sites, but does
      not reduce serum amylase levels and serum TNF-alpha levels or ameliorate
      pancreatic damage in rats with AP.

PMID- 10399969
TI  - Prognostic factors associated with resectable adenocarcinoma of the head of the
      pancreas.
AB  - A retrospective study of patients with surgically resectable adenocarcinoma of
      the pancreatic head was undertaken to determine which prognostic factors are
      independently associated with improved survival. Thirty-four men and 41 women
      (mean age, 61.9 years) had resection for adenocarcinoma of the pancreatic head
      between 1980 and 1997 at Rush-Presbyterian-St. Luke's Medical Center. Surgical
      resections included 15 total pancreatectomies, 43 pyloric-preserving procedures,
      and 17 standard Whipple procedures. Thirty-six patients received adjuvant
      radiation and/or chemotherapy. Overall median survival was 13 months, with a 5
      year survival of 17 per cent. Thirty-day surgical mortality was 1.3 per cent.
      Significant factors that negatively influenced survival using univariate Kaplan
      Meier analysis were: positive resection margin (P = 0.01), intraoperative blood
      transfusion (P = 0.01), and lymph node metastases (P = 0.01). Presenting signs
      and symptoms, patient demographics, operative procedure, tumor size, histologic
      differentiation, and adjuvant therapy did not have a significant impact on
      survival. Using multivariate Cox regression analysis, the only significant
      independent factors improving survival were the absence of intraoperative blood
      transfusion (P = 0.02) and a negative resection margin (P = 0.04). Performing
      pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas with
      negative microscopic margins of resection and without intraoperative transfusion
      significantly improves survival.

PMID- 10399970
TI  - Local excision and chemoradiation for low rectal T1 and T2 cancers is an
      effective treatment.
AB  - Lesions located in the distal third of the rectum are usually treated with
      abdominoperineal resection or a low anterior resection with a coloanal
      anastomosis. However, in a select group of patients with favorable histology and
      a low probability of lymphatic spread, sphincter-sparing procedures will afford
      long-term disease-free survival and cure without the need for extensive,
      complicated surgery. We performed a 10-year retrospective review, including
      pathologic examination of specimens by a single pathologist, in an attempt to
      identify factors associated with a decreased disease-free survival. Thirty-five
      patients (median age, 71 years; range, 48-88) with low rectal carcinomas were
      treated with full-thickness disc excision (with or without chemoradiation), with
      curative intent. Median follow-up was 46 months (range, 8-120). There were 15 T1,
      16 T2, and 4 T3 lesions. Tumors with poor histologic factors or greater than T1
      received adjuvant radiation (with or without 5-fluorouracil). Four patients
      developed a local failure at a median of 21.5 months (range, 9-30) and were
      salvaged with abdominoperineal resection. The 5-year cancer-specific survival was
      91 per cent. Negative margins approached statistical significance (P < 0.07) in
      influencing local control. We conclude that, when combined with chemoradiation
      for lesions deeper than submucosa or with adverse histologic factors, local
      resection of rectal cancer is an effective treatment in selected patients.

PMID- 10399971
TI  - Same hospitalization resection for acute diverticulitis.
AB  - We reviewed our experience with same hospitalization resection in the treatment
      of acute diverticulitis (AD) and compared outcomes with patients admitted for
      elective resection. From January 1987 through December 1996, 20 patients (Group
      1) were admitted with AD and were operated on during the same hospital admission.
      During that same time period, 22 patients (Group 2) were admitted for elective
      resection and found to have an abscess intraoperatively. Thirty patients had
      elective resection with no abscess found (Group 3), and 10 patients were found to
      have a fistula to adjacent structures during elective resection (Group 4).
      Demographics and type of procedure done were similar in all groups. Fifteen
      patients (75%) in Group 1 had an abscess; eight were pericolic, and seven were
      pelvic. In contrast, all Group 2 abscesses were pericolic (P < 0.001). There was
      no mortality or major morbidity in any group. Patients in Groups 1 and 4 had
      higher fluid requirements (not significant), estimated blood loss (P < 0.01), and
      longer operative times (P < 0.05) when compared with the other groups.
      Postoperative and total hospital stay was significantly longer in Group 1. We
      conclude that hospitalized patients with AD who meet indications for surgery can
      be operated on during the same hospitalization without an increase in morbidity,
      compared with those patients discharged and later readmitted for elective
      resection.

PMID- 10399972
TI  - Hemorrhagic shock impairs mucosal immunity to gut-derived antigens.
AB  - Secretory immunoglobulin A (sIgA) is the principal antibody protecting against
      pathogens in the respiratory tract and other mucosal surfaces. Nosocomial
      pneumonias are frequent after injury and critical illness and are often due to
      enteric pathogens. The aim of this study was to assess the relative effect of
      hemorrhagic shock (HS) on mucosal immunity at intestinal and respiratory mucosal
      sites. Fisher rats were immunized intragastrically with dinitrophenylated (DNP)
      Pneumococcus (Pn). Three weeks later, animals were subjected to sham treatment or
      HS. The animals were then rechallenged with DNP-Pn 1 or 3 days later. Animals
      were sacrificed 7 days later, and bronchoalveolar and gastric lavage was
      performed. Total and anti-DNP-specific sIgA were quantitated from these
      secretions by enzyme-linked immunosorbent assay. There was a significant decrease
      in DNP-Pn-specific sIgA at 72 hours after HS, which was not present in animals at
      24 hours after HS. This was most profound in bronchoalveolar lavage specimens. We
      conclude that impaired mucosal defense against gut-derived antigens after HS may
      be important mechanistically for the development of posttraumatic pneumonia and
      other mucosally related infectious complications.

PMID- 10399973
TI  - Is resuscitation after traumatic suicide attempt a futile effort? A five-year
      review at a level I trauma center.
AB  - A retrospective analysis of all traumatic suicide attempts at a Level I regional
      trauma center between 1990 and 1994 was performed. Data were obtained from the
      trauma registry, charts, computer data, and telephone interviews. Age, gender,
      mechanism of injury, and prior mental status were noted. Repeat suicide
      attempts/ideation, postinjury employment status, and subsequent deaths were
      recorded. Nontraumatic attempts and successful suicides not transported to the
      hospital were excluded. Ninety-one patients (71 males and 20 females) with
      attempted suicide were identified. Average patient age was 33.6 years. Method of
      attempted suicide and deaths by that method were: firearms (n = 55 attempts/36
      deaths), sharp instrumentation (n = 22 attempts/0 deaths), and others. Mortality
      by firearms and all other mechanisms were 65.0 per cent and 8.3 per cent,
      respectively. Fifty-two patients survived to be discharged from the hospital.
      Follow-up data were available for 38 patients with a mean follow-up interval of
      53.6 months. Three subsequent deaths were confirmed. The mortality from the index
      attempt was 42.9 per cent. Mortality by firearms was significantly higher than by
      all other mechanisms. Patients with chronic mental illness had a significantly
      higher incidence of subsequent suicide attempts/ideation and unemployment.
      Confirmed mortality at follow-up was only eight per cent (mean, 53.6 months), and
      all were patients with chronic mental illness.

PMID- 10399975
TI  - Follow-up evaluation and clinical course of patients with benign nodular thyroid
      disease.
AB  - Reliance on fine-needle aspiration biopsy (FNAB) in determining which patients
      with a thyroid nodule can be observed depends on a low false-negative rate. The
      purpose of this study was to determine the false-negative rate of FNAB, the
      utility of routine repeat FNAB, and the clinical course of patients with benign
      nodular thyroid disease. The records of all patients with nodular thyroid disease
      evaluated between June 1990 and May 1998 were reviewed. Patients with a benign
      FNAB were identified, and nodule size, substernal extension, the results of
      repeat FNAB, clinical course, histologic diagnosis, and length of follow-up were
      determined. Of the 341 patients referred with nodular thyroid disease, 121 had a
      benign FNAB. In 80 patients with a mean nodule size of 3.5 +/- 1.6 cm, clinical
      follow-up was recommended. The mean duration of follow-up was 20.5 months for 74
      patients, and 6 patients were lost to follow-up. Nodule resolution was observed
      in 7 patients. Repeat FNAB was performed in 45 patients and was benign in 39
      (87%), nondiagnostic in 2 (4%), cellular in 3 (7%), and malignant in 1 (2%).
      Thyroidectomy was performed in the patients with the cellular and malignant
      aspirates, and the pathology was adenomatous hyperplasia (2), follicular adenoma
      (1), and papillary carcinoma (1). Thyroidectomy was performed for increasing
      nodule size and/or compressive symptoms in 41 patients with a mean nodule size of
      5.7 +/- 1.9 cm, 19 of whom had substernal extension (P < 0.05). Pathology
      included benign disease in 39, papillary cancer in 1, and lymphoma arising in
      Hashimoto's thyroiditis in 1 patient. Given that repeat FNAB was of value in only
      1 patient and the false-negative rate for FNAB was only 2.5 per cent, the routine
      use of repeat FNAB in patients with benign nodular thyroid disease may not be
      justified. Development of compressive symptoms and diagnosis of unsuspected
      malignancy in patients with nodule enlargement, including lymphoma in patients
      with Hashimoto's thyroiditis, underscores the importance of long-term follow-up.

PMID- 10399974
TI  - The hemodynamic effects of local anesthetic injection into the carotid body
      during carotid endarterectomy.
AB  - Hemodynamic changes consisting of hypertension, hypotension, or bradycardia are
      commonly seen in patients undergoing carotid endarterectomy. It is a potentially
      serious clinical problem that may increase mortality rates or incidence of
      neurologic deficits. The frequency of hemodynamic alterations has been believed
      to be related to the proximity of the carotid sinus baroreceptor to the
      endarterectomized region. Consequently, intraoperative or postoperative injection
      of local anesthetics into the carotid body have been recommended to help offset
      this compensatory mechanism. However, its effectiveness has not been thoroughly
      studied. We examined this situation with a prospective, randomized, double-blind
      clinical study consisting of 99 patients. Xylocaine (short-acting anesthetic),
      bupivacaine (long-acting anesthetic), or saline (control) was injected into the
      carotid body intraoperatively. Intraoperative and postoperative hemodynamic
      changes were then closely monitored and evaluated. We were unable to detect a
      significant difference in hypotension, hypertension, or bradycardia either during
      or after surgery. Therefore, on the basis of this study, routine use of local
      anesthetic injection into the carotid body cannot be recommended.

PMID- 10399976
TI  - Endoscopic ultrasound for diagnosis and staging of pancreatic tumors.
AB  - Endoscopic ultrasound (EUS) is proving to be a useful tool for evaluation of
      clinically suspected pancreatic masses unsatisfactorily evaluated by other means
      of imaging. We reviewed the records of 19 patients who had CT and EUS performed
      for clinically suspected pancreatic masses. Each patient had subsequent surgical
      exploration. Nineteen patients (11 females and 8 males) presenting with symptoms
      (11 with obstructive jaundice, 6 with abdominal pain and weight loss) or
      incidental CT findings suspicious for pancreatic carcinoma underwent EUS for
      further pancreatic evaluation. All of these patients had exploratory
      laparotomies, with 13 pancreaticoduodenectomies, 3 distal pancreatectomies and
      splenectomies, 1 bypass procedure, 1 open pancreatic and hepatic biopsy showing
      metastatic disease, and 1 open exploration with negative fine-needle aspiration
      biopsy. EUS correctly identified pancreatic neoplasms in 17 of 19 cases, with two
      false positives. The tumors included 15 adenocarcinomas, 1 microcystic adenoma,
      and 1 lymphoma. Node status was correctly predicted in 9 of 12 specimens. Nine of
      12 tumors had accurate tumor staging by EUS. Absence of vascular invasion was
      accurately predicted in 13 of 14 cases. Two patients had metastatic disease
      discovered at laparotomy. All 19 patients had preoperative abdominal CT scans,
      with six of these negative for pancreatic masses. EUS is more sensitive than CT
      in detecting pancreatic masses and is more accurate than CT in locally staging
      pancreatic tumors. This higher sensitivity is important because those patients
      with earlier stage tumors are the most likely to benefit from resection.

PMID- 10399977
TI  - Alteration of the Roux Stasis syndrome by an isolated Roux limb: correlation of
      slow waves and clinical course.
AB  - The Roux-Y stasis syndrome after antrectomy and vagotomy has been well described.
      Delayed gastric emptying after vagotomy and antrectomy with Roux-Y anastomosis
      has been attributed to loss of the duodenal pacemaker and to the effects of
      retrograde slow-wave activity arising from distal small bowel pacemakers. Small
      bowel contractions are closely coupled with slow-wave activity. Transection and
      anastomosis of the small bowel distal to the jejuno-jejunostomy has been shown to
      electrically isolate the Roux limb from distal small bowel pacemakers. Using a
      canine model, a vagotomy and hemigastrectomy with Roux-Y were performed in five
      dogs using the standard operation (control); in four dogs (experimental), an
      additional transection and reanastomosis of the jejunum 25 cm distal to the Y
      anastomosis of the Roux limb was performed. All specimens had six electrodes
      implanted along the Roux limb at 5-cm intervals, used for weekly analysis of the
      jejunal slow-wave activity. The isolated loop cohort had reduced incidence of
      retrograde slow waves, reduced emesis, improved gastric emptying by upper
      gastrointestinal series, and reduced gastric pouch size at autopsy. Adding a
      distal transection and anastomosis, thus creating an isolated Roux-Y segment, may
      improve the course of the Roux stasis syndrome.

PMID- 10399978
TI  - The effect of peritoneal contamination on wound strength of small bowel and
      colonic anastomoses.
AB  - Primary bowel repair in the face of peritoneal soilage is still a controversial
      area. Previous studies using the rat model have demonstrated a difference in new
      collagen synthesis after 24 hours of peritoneal contamination. Currently, the
      effect of short-term fecal contamination of the peritoneal cavity on anastomotic
      healing and strength is not known. This study was designed to evaluate
      anastomotic wound strength in the face of fecal contamination during this time
      period. Twenty Sprague Dawley rats were randomized into two groups: twelve-hour
      control (n = 10) and 12-hour cecal ligation and puncture (CLP; n = 10). Both
      groups underwent laparotomy with either CLP (12-hour) or cecal manipulation (12
      hour control). Animals were allowed to recover for 12 hours, according to their
      assigned groups. A second laparotomy was subsequently performed in which the CLP
      groups had partial cecectomy to remove the source of contamination, followed by
      mid-jejunal and colonic division with associated primary anastomosis. Control
      groups had a similar procedure without partial cecectomy. All abdomens were
      irrigated, and all animals received immediate postoperative antibiotics and an
      initial fluid bolus. Animals were recovered and received 3 days of postoperative
      antibiotics. On postoperative day 4, animals were sacrificed and anastomotic
      sites were resected. Specimens were then placed in a tensiometer and disrupted
      under dynamic stress. Peak load was recorded for each, and maximum standard load
      was calculated. Hydroxyproline content of each segment was also determined after
      disruption. CLP values were compared with control values using unpaired Student's
      t test. Statistical significance threshold was P < 0.5. There was no significant
      difference in maximum anastomotic wound strength or hydroxyproline content
      between 12-hour CLP and 12-hour control group for both small bowel and colon
      anastomoses. Short-term peritoneal soilage (12-hour) does not significantly
      effect the maximum tensile strength or hydroxyproline content of primary small
      bowel or colonic anastomoses in this model. This study suggests that short-term
      fecal contamination of the peritoneal cavity may not be a contraindication to
      primary bowel anastomosis.

PMID- 10399979
TI  - Cryosurgical effects on growing vessels.
AB  - Cryosurgical treatment of unresectable hepatic malignancies has proven beneficial
      in adults. Concerns regarding its use in children include the effect on growth
      and the risk of injury to adjacent structures. To test the effect of cryoablation
      on adjacent vascular structures in a growing animal, liquid nitrogen cryoablation
      was performed on a juvenile murine model. Sprague Dawley rats underwent double
      freeze-thaw cryoablation of the abdominal aorta with interposed liver tissue.
      Serial sacrifices were performed over 120 days. Comparisons were made with sham
      operated controls. Overall, animal growth paralleled that of sham controls
      through all time points. Gross examination of aortic diameter also showed similar
      growth in vessel size between the groups. Histologic analysis demonstrated injury
      after cryoablation with smooth muscle cell vacuolization, followed by cell death.
      Aortic media layer collapse resulted from cellular loss, however, elastin fiber
      composition was maintained. Aortic patency was preserved despite evidence of
      cellular injury and aortic wall remodeling. An associated thermal sink effect on
      the opposing wall was identified. After cryoablation adjacent to the abdominal
      aorta in adolescent rats, vascular patency is maintained and animal growth and
      structural function is preserved, despite cellular injury and wall compression.
      These observations suggest that cryoablation may be a useful treatment adjunct in
      young subjects.

PMID- 10399980
TI  - Stab wounds to the back/flank in hemodynamically stable patients: evaluation
      using triple-contrast computed tomography.
AB  - Triple-contrast computerized tomography (3CT) has been proposed as a method to
      detect high-risk injuries in hemodynamically stable patients with stab wounds
      (SWs) to the back/flank and to successfully triage patients with low-risk scans
      into a potentially cost-effective treatment algorithm. The purpose of this study
      was to retrospectively review our experience with the use of 3CT for diagnostic
      accuracy of SWs to the back/flank and to evaluate potential decreased length of
      stay (LOS) in the hospital for patients with low-risk scans and no associated
      injuries. Seventy-nine hemodynamically stable patients met criteria for inclusion
      in this review. Fifty-eight 3CTs were performed for initial evaluation, 44 low
      risk and 14 high risk, and 21 patients underwent mandatory laparotomy. The
      accuracy of 3CT was found to be 97.9 per cent. The LOS was significantly less in
      patients who had no associated injuries and a low-risk 3CT (16.5 hours), as
      compared with all other treatment groups. Hemodynamically stable patients with
      SWs to the back/flank may be safely triaged using 3CT. Patients with low-risk
      scans and no associated injuries may be discharged immediately, and those with
      potential delayed associated injuries should be observed for 6 to 24 hours. This
      strategy significantly decreases LOS in patients with low incidence of
      significant injury.

PMID- 10399981
TI  - Traditional criteria for observation of splenic trauma should be challenged.
AB  - Age less than 55 years, normal Glasgow Coma Score (GCS), and absence of
      hypotension are traditional criteria for the selection of adult patients with
      blunt splenic trauma for observation. The objective of this study is to challenge
      these criteria. Two hundred twelve patients who presented with blunt splenic
      injury between 1992 and 1997 were identified from the Trauma Registry at our
      Level I trauma center. The patients were divided into three groups: 100 patients
      (47%) were observed, 108 (51%) underwent immediate splenorrhaphy or splenectomy,
      and 4 (2%) failed observation. The three groups were compared by participants'
      ages, GCSs, and histories of hypotension. No statistical differences were noted
      between the successfully observed patients and those requiring immediate surgery
      with respect to these criteria. Of the 4 patients who failed observation, all
      were younger than 55 years, all had a GCS >12, and all were normotensive. Our
      findings suggest that traditional criteria used to select patients for splenic
      trauma observation are not absolute indicators and should be liberalized:
      patients can be successfully observed despite having criteria that, in the past,
      would have led to immediate operative intervention.

PMID- 10399982
TI  - Childhood farm injuries.
AB  - During a recent 6-year period (1991-1997), 143 children and adolescents less than
      18 years of age were admitted to a Level I trauma center for agriculture-related
      trauma. Mechanized pieces of equipment were responsible for half of the injuries.
      The pattern of injury was clearly seasonal and a daytime occurrence. Half of the
      patients came from the scene and half from rural hospital emergency rooms, with
      only 25 per cent being transported via advanced life support. Rural geography led
      to both long distance (mean, 55 miles) and long transport time to definitive care
      (mean, 2 hours, 15 minutes). There was a predilection for fractures, amputations,
      head injuries, and soft-tissue infections. Operative intervention was required
      immediately in two-thirds, and one-third were admitted to an intensive care unit.
      Whereas hospital mortality was low at 1.4 per cent, most childhood farm deaths
      during the study period occurred in the field. Severe permanent disability was
      present in one-third of children, and 7 per cent incurred a second injury during
      the study period. Using this review, prevention programs have been developed to
      minimize death and disability in children sustaining farm injuries.

PMID- 10399984
TI  - 50th anniversary historical article. Perfusion imaging.

PMID- 10399983
TI  - Results from late-breaking clinical trials sessions at ACCIS '99 and ACC '99.
      American College of Cardiology.

PMID- 10399985
TI  - A comparison of U.S. and Canadian cardiac catheterization practices in detecting
      severe coronary artery disease after myocardial infarction: efficiency, yield and
      long-term implications.
AB  - OBJECTIVES: We sought to compare U.S. and Canada's post-myocardial infarction
      (MI) cardiac catheterization practices in the detection of severe coronary artery
      disease (CAD). BACKGROUND: Little is known about the efficiency with which the
      aggressive post-MI catheterization strategy observed in the U.S. detects severe
      CAD compared with the more conservative strategy observed in Canada. METHODS:
      From the U.S. and Canadian patients who had participated in the Global
      Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded
      Arteries trial (n = 22,280, 11.5% Canadian), we examined the frequency of in
      hospital cardiac catheterization, the prevalence of severe CAD observed at
      catheterization (diagnostic efficiency) and the total number of MI patients with
      severe CAD identified (diagnostic yield). RESULTS: The rate of catheterization in
      the U.S. was more than 2.5 times that in Canada (71% vs. 27%, respectively, p <
      0.001). With identical prevalences of severe CAD at catheterization (17%) in the
      two countries, the higher frequency of catheterization in the U.S. resulted in
      the identification of more than two and a half times as many cases of severe CAD
      compared with Canada (12 severe CAD cases identified per 100 post-MI patients in
      the U.S., vs. 4.6 per 100 in Canada). If considered in isolation, we estimated
      that these differences in severe disease detection might effect a small long-term
      survival advantage in favor of the U.S. strategy (estimated 5.0 lives saved per
      1,000 MI patients). CONCLUSIONS: Canada's more restrictive post-MI cardiac
      catheterization strategy is no more efficient in identifying severe CAD than the
      aggressive U.S. strategy, and may fail to identify a substantial number of post
      MI patients with high risk coronary anatomy. The long-term impact of these
      differences in practice patterns requires further evaluation.

PMID- 10399986
TI  - Comparing the U.S. and Canadian approaches to coronary angiography: what have we
      learned?

PMID- 10399987
TI  - Catheterization after myocardial infarction and the mismeasure of un-American
      inactivity.

PMID- 10399988
TI  - Laser angioplasty of restenosed coronary stents: results of a multicenter
      surveillance trial. The Laser Angioplasty of Restenosed Stents (LARS)
      Investigators.
AB  - OBJECTIVES: This study evaluated safety and efficacy of excimer laser angioplasty
      for treatment of restenosed or occluded coronary stents. BACKGROUND: Balloon
      angioplasty of in-stent restenosis is limited by a high recurrence rate.
      Debulking by laser angioplasty is a novel concept to treat in-stent restenosis.
      METHODS: A total of 440 patients with restenoses or occlusions in 527 stents were
      enrolled for treatment with concentric or eccentric laser catheters and
      adjunctive balloon angioplasty. RESULTS: Laser angioplasty success (< or =50%
      diameter stenosis after laser treatment or successful passage with a 2.0-mm or
      1.7-mm eccentric laser catheter) was achieved in 92% of patients. Adjunctive
      balloon angioplasty was performed in 99%. Procedural success (laser angioplasty
      success followed by < or =30% stenosis with or without balloon angioplasty) was
      91%. There was neither a significant difference in success with respect to lesion
      length, nor were there differences between small and large vessels or native
      vessels and vein grafts. Success was higher and residual stenosis lower using
      large or eccentric catheters. Serious adverse events included death (1.6%, not
      directly laser catheter related), Q-wave myocardial infarction (0.5%), non-Q-wave
      infarction (2.7%), cardiac tamponade (0.5%) and stent damage (0.5%). Perforations
      after laser treatment occurred in 0.9% of patients and after balloon angioplasty
      in 0.2%. Dissections were visible in 4.8% of patients after laser treatment and
      in 9.3% after balloon angioplasty. Reinterventions during hospitalization were
      necessary in 0.9% of patients; bypass surgery was performed in 0.2%. CONCLUSIONS:
      Excimer laser angioplasty with adjunctive balloon angioplasty is a safe and
      efficient technology to treat in-stent restenoses. These data justify a
      randomized comparison with balloon angioplasty.

PMID- 10399989
TI  - Mechanisms of acute lumen gain and recurrent restenosis after rotational
      atherectomy of diffuse in-stent restenosis: a quantitative angiographic and
      intravascular ultrasound study.
AB  - OBJECTIVES: This quantitative angiographic and intravascular ultrasound study
      determined the mechanisms of acute lumen enlargement and recurrent restenosis
      after rotational atherectomy (RA) with adjunct percutaneous transluminal coronary
      angioplasty in the treatment of diffuse in-stent restenosis (ISR). BACKGROUND: In
      stent restenosis remains a significant clinical problem for which optimal
      treatment is under debate. Rotational atherectomy has become an alternative
      therapeutic approach for the treatment of diffuse ISR based on the concept of
      "tissue-debulking." METHODS: Rotational atherectomy with adjunct angioplasty of
      ISR was used in 45 patients with diffuse lesions. Quantitative coronary
      angiographic (QCA) analysis and sequential intravascular ultrasound (IVUS)
      measurements were performed in all patients. Forty patients (89%) underwent
      angiographic six-month follow-up. RESULTS: Rotational atherectomy lead to a
      decrease in maximal area of stenosis from 80+/-32% before intervention to 54+/
      21% after RA (p < 0.0001) as a result of a significant decrease in intimal
      hyperplasia cross-sectional area (CSA). The minimal lumen diameter after RA
      remained 15+/-4% smaller than the burr diameter used, indicating acute neointimal
      recoil. Additional angioplasty led to a further decrease in area of stenosis to
      38+/-12% due to a significant increase in stent CSA. At six-month angiographic
      follow-up, recurrent restenosis rate was 45%. Lesion and stent length,
      preinterventional diameter stenosis and amount of acute neointimal recoil were
      associated with a higher rate of recurrent restenosis. CONCLUSIONS: Rotational
      atherectomy of ISR leads to acute lumen gain by effective plaque removal. Adjunct
      angioplasty results in additional lumen gain by further stent expansion and
      tissue extrusion. Stent and lesion length, severity of ISR and acute neointimal
      recoil are predictors of recurrent restenosis.

PMID- 10399990
TI  - Implications of small reference vessel diameter in patients undergoing
      percutaneous coronary revascularization.
AB  - OBJECTIVES: The purpose of this study was to determine whether small reference
      diameter of the culprit coronary artery influences the outcome of an attempted
      percutaneous revascularization procedure in the current era of interventional
      cardiology. BACKGROUND: Although the interventional strategy is largely
      determined by the size of the culprit coronary artery, earlier quantitative
      studies have not shown a worse acute outcome for small reference vessel diameter
      (< or =2.5 mm). METHODS: A total of 2,306 patients undergoing percutaneous
      coronary revascularization was divided in groups with reference diameters < or
      =2.5 mm (n = 813) or >2.5 mm (n = 1,493). Success and in-hospital major adverse
      cardiac event (death, Q-wave myocardial infarction and emergency coronary artery
      bypass graft) rates between both groups were compared. RESULTS: Patients with
      lesions in small vessels were older and presented more frequently with female
      gender, diabetes mellitus, heart failure, peripheral vascular, multivessel
      coronary disease and American Heart Association/American College of Cardiology
      (AHA/ACC) lesion type C (p < or = 0.01, each). Further, utilization of
      interventional devices differed markedly. In contrast to stents (18.5% vs. 41.9%)
      and directional atherectomy (3.7% vs. 13.5%), conventional balloon angioplasty
      (73% vs. 50%) and rotational atherectomy (16.1% vs. 8.3%) were used more often in
      smaller vessels (p < or = 0.0001, each). Success rate was lower in the small
      vessel group (92% vs. 95%; p = 0.006). Major adverse cardiac events occurred more
      frequently in small than large vessels (univariate 3.4% vs. 2.0%, p = 0.03;
      multivariate odds ratio 2.1, p = 0.02), particularly when proximal coronary
      segments were compared. CONCLUSIONS: Lesions in vessels with small reference
      diameter represent a distinct group with respect to clinical and morphologic
      characteristics as well as device utilization. These lesions have lower chances
      of successful percutaneous intervention and carry relatively higher risks,
      specifically when located in proximal coronary segments.

PMID- 10399991
TI  - Is redo percutaneous mitral balloon valvuloplasty (PMV) indicated in patients
      with post-PMV mitral restenosis?
AB  - OBJECTIVES: The purpose of this study was to assess the immediate and long-term
      outcome of repeat percutaneous mitral balloon valvuloplasty (PMV) for post-PMV
      mitral restenosis. BACKGROUND: Symptomatic mitral restenosis develop in 7% to 21%
      of patients after PMV. Currently, most of these patients are referred for mitral
      valve replacement. However, it is unknown if these patients may benefit from
      repeat PMV. METHODS: We report the immediate outcome and long-term clinical
      follow-up results of 36 patients (mean age 58+/-13 years, 75% women) with
      symptomatic mitral restenosis after prior PMV, who were treated with a repeat PMV
      at 34.6+/-28 months after the initial PMV. The mean follow-up period was 30+/-33
      months with a maximal follow-up of 10 years. RESULTS: An immediate procedural
      success was obtained in 75% patients. The overall survival rate was 74%, 72% and
      71% at one, two, and three years respectively. The event-free survival rate was
      61%, 54% and 47% at one, two, and three years respectively. In the presence of
      comorbid diseases (cardiac and noncardiac) the two-year event-free survival was
      reduced to 29% as compared with 86% in patients without comorbid diseases. Cox
      regression analysis identified the echocardiographic score (p = 0.03), post-PMV
      mitral valve area (p = 0.003), post-PMV mitral regurgitation grade (p = 0.02) and
      post-PMV pulmonary artery pressure (p = 0.0001) as independent predictors of
      event-free survival after repeat PMV. CONCLUSIONS: Repeat PMV for post-PMV mitral
      restenosis results in good immediate and long-term outcome in patients with low
      echocardiographic scores and absence of comorbid diseases. Although the results
      are less favorable in patients with suboptimal characteristics, repeat PMV has a
      palliative role if the patients are not surgical candidates.

PMID- 10399992
TI  - Factors correlating with risk of mortality after transmyocardial
      revascularization.
AB  - OBJECTIVES: The purpose of this study was to determine factors correlating with
      the risk of postoperative mortality after transmyocardial laser revascularization
      (TMR). BACKGROUND: Clinical studies have indicated that TMR reduces angina by an
      average of two classes in patients with medically refractory symptoms not
      treatable by coronary artery bypass graft (CABG) or percutaneous transluminal
      coronary angioplasty. Factors which correlate with mortality after TMR, however,
      have not been extensively investigated. METHODS: One hundred thirty-two patients
      with severe angina underwent TMR as sole therapy with a CO2 laser. Age, gender,
      ejection fraction, prior CABG, unstable angina and the severity of coronary
      artery disease (graded on the basis of a newly proposed Anatomic Myocardial
      Perfusion index, AMP) were each determined. Each vascular territory (left
      anterior descending artery [LAD] left circumflex artery and posterior descending
      artery [PDA]) was graded as either having (AMP = 1) or not having (AMP = 0) blood
      flow through an unobstructed major vessel in the territory. Univariate and
      multivariate analysis determined which factors correlated with mortality.
      RESULTS: Patients with at least one AMP = 1 vascular territory (overall AMP = 1)
      had a 5% (4/82) postoperative mortality rate (POM), compared with 25% (12/49)
      with overall AMP 0 (p = 0.002). Left anterior descending artery AMP (p = 0.03)
      and previous CABG (p = 0.04) each correlated with the risk of POM. However,
      multivariate analysis indicated that no factor improved the correlation obtained
      with overall AMP by itself. With regard to overall mortality (Kaplan-Meier
      curves), univariate analysis also revealed correlations with overall AMP (p <
      0.001), LAD AMP (p = 0.005), previous CABG (p = 0.003) and PDA AMP (p = 0.05)
      each individually correlated with mortality. Multivariate analysis indicated that
      overall AMP = 1, female gender and previous CABG together correlated best with
      lower postoperative mortality. CONCLUSIONS: Patients with good blood flow to at
      least one region of the heart through a native artery or a patent vascular graft
      have a markedly reduced risk of perioperative and longer term mortality.

PMID- 10399993
TI  - Survival 12 years after randomization to streptokinase: the influence of
      thrombolysis in myocardial infarction flow at three to four weeks.
AB  - OBJECTIVES: The purpose of this study was to determine whether the mortality
      benefit of intravenous streptokinase administered within 4 h of the onset of
      acute myocardial infarction is maintained at 12 years, and whether Thrombolysis
      in Myocardial Infarction (TIMI) flow grades independently influence late
      survival. BACKGROUND: Treatment with reperfusion therapies and achievement of
      TIMI 3 flow are associated with increased short- and medium-term survival after
      infarction. Whether infarct artery flow independently influences survival more
      than five years after infarction is unknown. METHODS: The late survival of
      patients randomized to receive either streptokinase (1,500,000 IU over 30 to 60
      min) or a matching placebo within 4 h of symptom onset in 1984-1986 was
      determined. Angiography was performed in surviving patients at three to four
      weeks, and TIMI flow grades were assessed blind to randomization and outcomes.
      The late vital status was determined in 99% of patients. RESULTS: Patients
      randomized to receive streptokinase (n = 107) had improved survival compared with
      those randomized to placebo (n = 112) at five years (84% vs. 70%; p = 0.023) and
      12 years (66% vs. 51%; p = 0.022). At five years 94% of patients with TIMI grade
      3 flow, 81% of those with TIMI grade 2 flow and 72% of those with TIMI grade 0-1
      flow survived (p = 0.005). At 12 years 72% of patients with TIMI 3, 67% of those
      with TIMI 2 and 54% of those with TIMI 0-1 flow survived (p = 0.023).
      Multivariate analysis identified the ejection fraction (p = 0.014), exercise
      duration (p = 0.013) and TIMI 3 flow (p = 0.04 compared with TIMI 0-2 flow) as
      important factors for five-year survival. At 12 years multivariate predictors of
      late survival were the ejection fraction (p = 0.006), exercise duration (p =
      0.003) and myocardial score (p = 0.013). The end-systolic volume index was
      similar to the ejection fraction as a predictor of survival at five and 12 years.
      CONCLUSIONS: The survival benefits of streptokinase persist for 12 years after
      infarction. TIMI flow at three to four weeks is an independent predictor of five
      year survival.

PMID- 10399995
TI  - Effect of the angiotensin-converting enzyme inhibitor trandolapril on mortality
      and morbidity in diabetic patients with left ventricular dysfunction after acute
      myocardial infarction. Trace Study Group.
AB  - OBJECTIVES: This study evaluated the efficacy of long-term treatment with the
      angiotensin-converting enzyme (ACE) inhibitor trandolapril in diabetic patients
      with left ventricular dysfunction after acute myocardial infarction (AMI).
      BACKGROUND: Patients with diabetes mellitus have a high mortality following AMI,
      probably due to a high risk of congestive heart failure and reinfarction. Because
      ACE inhibition effectively reduces progression of heart failure, it could be
      particularly beneficial in diabetic patients after AMI. METHODS: The study is a
      retrospective analysis using data from the Trandolapril Cardiac Evaluation
      (TRACE) study, which was a randomized, double-blind, placebo-controlled trial of
      trandolapril in 1,749 patients with AMI and ejection fraction < or =35%. The mean
      follow-up time was 26 months. RESULTS: A history of diabetes was found in 237
      (14%) of the 1,749 patients. Treatment with trandolapril resulted in a relative
      risk (RR) of death from any cause for the diabetic group of 0.64 (95% confidence
      interval 0.45 to 0.91) versus 0.82 (0.69 to 0.97) for the nondiabetic group. In
      the diabetic group, trandolapril reduced the risk of progression to severe heart
      failure markedly (RR, 0.38 [0.21 to 0.67]), and no significant reduction of this
      end point was found in the nondiabetic group. CONCLUSIONS: The ACE inhibition
      after myocardial infarction complicated by left ventricular dysfunction appears
      to be of considerable importance in patients with diabetes mellitus by saving
      lives and substantially reducing the risk of progression to severe heart failure.

PMID- 10399994
TI  - Long-term (three-year) prognosis of patients treated with reperfusion or
      conservatively after acute myocardial infarction. Israeli Thrombolytic Survey
      Group.
AB  - OBJECTIVES: This survey sought to assess the frequency of the use of thrombolytic
      therapy, invasive coronary procedures (ICP) (angiography, percutaneous
      transluminal coronary angioplasty and coronary artery bypass grafting [CABG]),
      variables associated with their use, and their impact on early (30-day) and long
      term (3-year) mortality after acute myocardial infarction (AMI). BACKGROUND: Few
      data are available regarding the implementation in daily practice of the results
      of clinical trials of treatments for AMI and their impact on early and long-term
      prognosis in unselected patients after AMI. METHODS: A prospective community
      based national survey was conducted during January-February 1994 in all 25
      coronary care units operating in Israel. RESULTS: Among 999 consecutive patients
      with an AMI (72% men; mean age 63+/-12 years) acute reperfusion therapy (ART) was
      used in 455 patients (46%; thrombolysis in 435 patients [44%] and primary
      angioplasty in 20 [2%]). Its use was independently associated with anterior AMI
      location and hospitals with on-site angioplasty facilities, whereas advancing
      age, prior myocardial infarction (MI) and prior angioplasty or CABG were
      independently associated with its lower use. The three-year mortality of patients
      treated with ART was lower than in counterpart patients (22.0% vs. 31.4%, p =
      0.0008), mainly as the result of 30-day to 3-year outcome (12.4% vs. 21.1%;
      hazard ratio = 0.73, 95% confidence interval [CI] 0.52 to 1.03). Independent
      predictors of long-term mortality were: age, heart failure on admission or during
      the hospitalization, ventricular tachycardia or fibrillation and diabetes. The
      outcome of patients not treated with ART differed according to the reason for the
      exclusion, where patients with contraindications experienced the highest three
      year (50%) mortality rate. After ART, coronary angiography, angioplasty and CABG
      were performed in-hospital in 28%, 12% and 5% of patients, respectively. Their
      use was independently associated with recurrent infarction or ischemia, on-site
      catheterization or CABG facilities, non-Q-wave AMI and anterior infarct location.
      In the entire study population, and in patients with a non-Q-wave AMI,
      performance of ICP was associated with lower 30-day mortality (odds ratio [OR] =
      0.53, 95% CI 0.25 to 0.98, and OR = 0.21, 0.03 to 0.84, respectively), but not
      thereafter. CONCLUSIONS: This survey demonstrates the extent of implementation in
      daily practice of ART and ICP and their impact on early and long-term prognosis
      in an unselected population after AMI.

PMID- 10399996
TI  - Noninvasive evaluation of pulmonary capillary wedge pressure in patients with
      acute myocardial infarction by deceleration time of pulmonary venous flow
      velocity in diastole.
AB  - OBJECTIVES: This study investigates the correlation between deceleration time of
      diastolic pulmonary venous flow (PV-DT) and of early filling mitral flow (LV-DT),
      and pulmonary capillary wedge pressure (PCWP) in patients with acute myocardial
      infarction (AMI). BACKGROUND: An earlier study suggests that Doppler-derived LV
      DT provides an accurate means of estimating PCWP in postinfarction patients with
      left ventricular systolic dysfunction. Furthermore, recent studies have suggested
      that PCWP correlates better with PV-DT than with LV-DT. However, the value of PV
      DT and LV-DT for assessment of PCWP in patients with AMI has not been evaluated.
      METHODS: In 141 consecutive patients with AMI, we measured PV-DT and LV-DT by
      Doppler echocardiography, and compared these variables with PCWP measured using a
      Swan-Ganz catheter. RESULTS: There was a weak negative correlation between the LV
      DT and PCWP (r = -0.54). Although the sensitivity of < or =130 ms in LV-DT in
      predicting > or =18 mm Hg in PCWP was high (86%), its specificity was low (59%).
      On the other hand, a very close negative correlation was found between PV-DT and
      PCWP (r = -0.89). The sensitivity and specificity of < or =160 ms in PV-DT in
      predicting > or =18 mm Hg in PCWP were 97% and 96%, respectively. CONCLUSIONS: In
      patients with AMI, Doppler-derived PV-DT showed a stronger correlation with PCWP
      than LV-DT.

PMID- 10399997
TI  - Risk stratification of emergency department patients with acute coronary
      syndromes using P-selectin.
AB  - OBJECTIVES: We compared the predictive properties of P-selectin to creatine
      kinase, MB fraction (CK-MB) for detecting acute myocardial infarction (AMI),
      acute coronary syndromes (ACS) and serious cardiac events upon emergency
      department (ED) arrival. BACKGROUND: Practioners detecting early diagnosis of ACS
      have focused on cardiac markers of myocardial injury. Plaque rupture/platelet
      aggregation precedes myocardial ischemia. Therefore, markers of platelet
      aggregation may detect ACS earlier than cardiac markers. METHODS: Consecutive
      patients with potential ACS presenting to an urban university ED were identified
      by research assistants who screened all ED patients between November 12, 1997 and
      January 31, 1998. Whole blood was drawn at presentation and 1 h later and rapidly
      stained and fixed for membrane P-selectin assay and plasma was separated for
      soluble P-selectin assay. Creatine kinase, MB fraction values were determined
      using standard immunoassay techniques. Clinical history and hospital course were
      followed daily. Outcomes were AMI, ACS (AMI and unstable angina) and serious
      cardiac events. Receiver operator characteristic curves were derived for CK-MB,
      and soluble and membrane-bound P-selectin to determine the optimal cutoff values.
      Predictive properties were calculated with 95% confidence intervals. RESULTS: A
      total of 263 patients were enrolled. They had a mean age of 56.5+/-14 years; 52%
      were male. There were 22 patients with AMI; 87 patients with ACS and 54 patients
      with serious cardiac events. Creatine kinase, MB fraction had a higher
      specificity for detection of AMI, ACS and serious cardiac events than both
      soluble and membrane-bound P-selectin. At the time of ED presentation, the
      specificity of CK-MB, and soluble and membrane-bound P-selectin for AMI was 91%
      versus 76% versus 71%; for ACS, 95% versus 79% versus 71%, and for serious
      cardiac events, 91% versus 76% versus 72% (p < 0.05). The sensitivities for AMI
      were 50% versus 45% versus 32%; for ACS, 26% versus 35% versus 30%, and for
      serious cardiac events, 29% versus 35% versus 36%. CONCLUSIONS: Although
      theoretically attractive, the use of soluble and membrane-bound P-selectin for
      risk stratification of chest pain patients at the time of ED presentation does
      not appear to have any advantages over the use of CK-MB.

PMID- 10399998
TI  - Pravastatin prevents clinical events in revascularized patients with average
      cholesterol concentrations. Cholesterol and Recurrent Events CARE Investigators.
AB  - OBJECTIVES: This analysis was carried out to determine if revascularized patients
      derive benefit from the 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase
      inhibitor pravastatin. BACKGROUND: The HMG-CoA reductase inhibitors result in
      substantial reductions in serum cholesterol and stabilization of atherosclerotic
      plaques in patients with coronary artery disease. METHODS: Pravastatin was found
      to reduce clinical cardiovascular events in the Cholesterol and Recurrent Events
      (CARE) trial consisting of 4,159 patients with a documented myocardial infarction
      and an average cholesterol level (mean 209 mg/dl and all <240 mg/dl). A total of
      2,245 patients underwent coronary revascularization before randomization
      including 1,154 patients with percutaneous transluminal coronary angioplasty
      (PTCA) alone, 876 patients with coronary artery bypass graft (CABG) alone, and
      215 patients with both procedures. Clinical events in revascularized patients
      were compared between patients on placebo and on pravastatin. RESULTS: In the
      2,245 patients who had undergone revascularization, the primary endpoint of
      coronary heart disease death or nonfatal myocardial infarction (MI) was reduced
      by 4.1% with pravastatin (relative risk [RR] reduction 36%, 95% confidence
      interval [CI] 17 to 51, p = 0.001). Fatal or nonfatal MI was reduced by 3.3% (RR
      reduction 39%, 95% CI 16 to 55, p = 0.002), postrandomization repeat
      revascularization was reduced by 2.6% (RR reduction 18%, 95% CI 1 to 33, p =
      0.068) and stroke was reduced by 1.5% (RR reduction 39%, 95% CI 3 to 62, p =
      0.037) with pravastatin. Pravastatin was beneficial in both the 1,154 PTCA
      patients and in the 1,091 CABG patients who had undergone revascularization
      before randomization. CONCLUSIONS: Pravastatin reduced clinical events in
      revascularized postinfarction patients with average cholesterol levels. This
      therapy was well tolerated and its use should be considered in most patients
      following coronary revascularization.

PMID- 10399999
TI  - Effects of medical therapy on outcome assessment using exercise thallium-201
      single photon emission computed tomography imaging: evidence of a protective
      effect of beta-blocking antianginal medications.
AB  - OBJECTIVES: The purpose of this study was to determine whether antianginal
      medications modify the prognostic significance of exercise single photon emission
      computed tomography (SPECT) ischemia. BACKGROUND: Antianginal medications
      (especially beta-adrenergic blocking agents) limit exercise SPECT ischemia, but
      it is not known whether such medications also modify the prognostic effect of
      exercise SPECT ischemia. METHODS: We included 352 patients with coronary heart
      disease, who had exercise Tl-201 SPECT and coronary angiography, and who were
      initially treated medically. Survival Cox models were applied in patients for
      whom classes of antianginal medications taken at exercise SPECT were the same as
      those prescribed for follow-up (GI; n = 136), and in patients for whom new
      classes of antianginal medications, including beta-blockers (GII; n = 79) or not
      including beta-blockers (GIII; n = 113), were added for follow-up. RESULTS:
      During a mean 5.3+/-1.6 years of follow-up, 45 patients had cardiac death or
      myocardial infarction. Variables reflecting necrosis (irreversible defect extent,
      left ventricular ejection fraction) and those from coronary angiography provided
      equivalent prognostic information in the three groups. In contrast, the SPECT
      variable reflecting ischemia (reversible defect extent), which provided
      comparable prognostic information in GI (p = 0.005) and GIII (p = 0.004), lost
      its prognostic significance (p = 0.54) in GII, and was associated with a lower
      relative risk in GII than in GI or GIII (both p < 0.05). CONCLUSIONS: In patients
      with coronary heart disease, the introduction of antianginal medications, when
      including beta-blockers, appears to have a favorable effect on the deleterious
      prognostic effect of exercise ischemia.

PMID- 10400000
TI  - Contrast-enhanced transthoracic second harmonic echo Doppler with adenosine: a
      noninvasive, rapid and effective method for coronary flow reserve assessment.
AB  - OBJECTIVES: The purpose of this study is to evaluate the feasibility in detecting
      blood flow in the left anterior descending coronary artery (LAD) using
      transthoracic color Doppler (CD) imaging (in both second harmonic and fundamental
      mode) along with contrast enhancement and to verify if this new noninvasive
      method along with adenosine is safe, rapid and effective in assessing coronary
      flow reserve (CFR). BACKGROUND: Feasibility of contrast-enhanced transthoracic
      Doppler recording (in both second harmonic and fundamental mode) of blood flow
      velocity in the LAD has not been assessed. Adenosine has a greater vasodilator
      potency and more favorable kinetics than dipyridamole and thus it can be more
      suitable for assessing CFR in conjunction with this method. METHODS: Sixty-one
      patients with angiographically patent LAD underwent CD (both in fundamental and
      harmonic mode) as well as color-guided pulsed wave (PW) Doppler recording of
      blood flow velocity in the distal LAD before and after intravenous contrast
      injection. A second group of patients (n = 77), undergoing coronary angiography,
      was submitted to transthoracic contrast-enhanced PW Doppler recording of blood
      flow velocity in the LAD using harmonic CD as a guide, at rest and during
      adenosine-induced hyperemia. RESULTS: Harmonic CD along with echo contrast
      consistently improved blood flow detection in the LAD; the success rate in
      detecting flow of optimal quality was 88% with this approach, whereas it was 11%
      and 16% with CD in fundamental mode, respectively, before and after contrast.
      Pulsed wave Doppler results paralleled those of harmonic CD (p < 0.001 contrast
      harmonic vs. fundamental). In the second group of patients coronary angiography
      revealed 0% to <40% stenosis in 24 patients (group I), > or =40% to < or =75% in
      17 patients (group II) and >75% stenosis in 34 patients (group III). There was a
      significant difference in CFR among the three groups of patients; CFR for peak
      diastolic velocity was (mean +/- SD): 2.88+/-0.7 (group I), 2.09+/-0.5 (group II)
      and 1.51+/-0.5 cm/s (group II) (p < 0.05 group I vs. both group II and group III;
      p < 0.05 group II vs. group III). The whole examination took less than 10 min.
      CONCLUSIONS: Contrast-enhanced second harmonic Doppler recording of blood
      velocity in the LAD is highly feasible and in combination with adenosine it is a
      rapid, safe and effective method for assessing CFR ratio.

PMID- 10400002
TI  - Postmenopausal hormone therapy--good for smokers?

PMID- 10400001
TI  - Hormone replacement therapy in postmenopausal women protects against smoking
      induced changes in vascular structure and function.
AB  - OBJECTIVES: The purpose of this study was to investigate the role of hormone
      replacement therapy (HRT) in postmenopausal women who smoke. BACKGROUND: Hormone
      replacement therapy appears to afford cardiovascular protection in postmenopausal
      women; however, in high risk individuals, specifically smokers, this has not been
      adequately studied. This question was addressed in a cross-sectional study of
      arterial structure, function and plasma lipids in postmenopausal smokers and
      nonsmokers. METHODS: Vascular ultrasound was performed in two age-matched groups
      of postmenopausal women, 70 on HRT (35 smokers) and 70 control subjects not on
      HRT (35 smokers). Indexes of arterial structure (carotid intima-media thickness
      [IMT]) and vascular function (systemic arterial compliance [SAC]) and lipid
      profiles were measured. RESULTS: Participant characteristics were similar in the
      two groups. Smokers on HRT, compared with smoking control subjects, had lower
      cholesterol (6.0+/-0.2 vs. 6.8+/-0.3 mmol/liter, p = 0.03) and more favorable
      mean values for IMT (0.64+/-0.02 vs. 0.74+/-0.03 mm, p = 0.007) and SAC (0.41+/
      0.03 vs. 0.32+/-0.03 U/mm Hg, p = 0.03). Nonsmokers on HRT compared with
      nonsmoking control subjects had lower total cholesterol (5.7+/-0.2 vs. 6.5+/-0.2
      mmol/liter, p = 0.02) and low density lipoprotein cholesterol (3.4+/-0.2 vs.
      4.4+/-0.3 mmol/liter, p = 0.01). Mean IMT and SAC values in nonsmokers on HRT and
      control subjects were not significantly different. Multiple regression
      demonstrated significant correlation between HRT status and both IMT and SAC, in
      smokers and in those with increased cholesterol. In nonsmokers and those with
      lower cholesterol, HRT status was not significantly correlated with vascular
      parameters. CONCLUSIONS: In postmenopausal women who smoke there may be a
      beneficial effect of long-term estrogen therapy on indexes of arterial structure
      and function as surrogate markers of cardiovascular disease. Long-term controlled
      studies are needed to confirm these findings.

PMID- 10400003
TI  - Effect of angiotensin-converting enzyme inhibition and angiotensin II type 1
      receptor antagonism on postprandial endothelial function.
AB  - OBJECTIVES: The purpose of this study was to determine whether endothelial
      dysfunction as a consequence of direct postprandial lipid response might be
      favorably influenced by angiotensin-converting enzyme inhibitors or angiotensin
      AT1 receptor antagonists. BACKGROUND: Postprandial triglyceride-rich lipoproteins
      cause endothelial dysfunction. Angiotensin-converting enzyme inhibitors have been
      shown to improve vascular reactivity. For angiotensin II type 1 receptor
      antagonists this effect is as yet uncertain. METHODS: A randomized, double-blind,
      placebo-controlled crossover study in 30 healthy volunteers, aged 18 to 33 years,
      evaluated the effect of quinapril (40 mg daily for two weeks) and losartan (50 mg
      daily for two weeks) on basal as well as postprandial endothelial function
      measured noninvasively as percentage diameter change in the brachial artery after
      reactive hyperemia. Endothelium-independent dilation was measured after
      nitroglycerine spray sublingual. RESULTS: An acute oral fat load impaired
      endothelial function. Flow-mediated vasodilation (FMD) decreased from a median of
      6.2% to 4.2% (p < 0.05). There was no significant difference in preprandial
      endothelial function after two weeks of treatment with either quinapril or
      losartan compared with placebo in these healthy volunteers. Both quinapril (FMD
      6.4% to 6.3%) and losartan (7.1% to 5.4%) prevented endothelial dysfunction
      induced by an oral fat load, although the protective effect of quinapril appeared
      to be more profound. The response to the endothelium-independent vasodilator
      nitroglycerine was unaltered throughout the study. CONCLUSIONS: Both losartan and
      quinapril prevent endothelial dysfunction induced by triglyceride-rich
      lipoproteins in healthy volunteers. However, the protective effect of quinapril
      is more pronounced.

PMID- 10400004
TI  - Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation
      of brachial artery.
AB  - OBJECTIVES: We examined whether endothelial dysfunction occurs when acute
      hyperglycemia is induced by oral glucose loading. BACKGROUND: Endothelial
      dysfunction has been shown to occur in patients with diabetes mellitus (DM), and
      chronic hyperglycemia is implicated as a cause of endothelial dysfunction.
      However, in many patients with Type 2 DM and in those with impaired glucose
      tolerance (IGT), fasting blood glucose may be within normal limits, and
      hyperglycemia occurred only post-prandially. METHODS: With ultrasound technique,
      we measured flow-mediated endothelium-dependent vasodilation during oral glucose
      tolerance test in 58 subjects: (17 patients with normal glucose tolerance [NGT],
      24 with IGT, and 17 with type 2 DM). In addition, we measured the levels of
      thiobarbituric acid reactive substances (TBARS) and nitrite/nitrate. RESULTS:
      Flow-mediated vasodilation decreased after glucose loading (NGT: 7.53+/-0.40,
      4.24+/-0.28 and 6.35+/-0.40, in fasting, at 1- and 2-h, respectively, IGT: 6.50+/
      0.48, 1.40+/-0.41** and 4.00+/-0.47*, respectively; DM: 4.77+/-0.37, 1.35+/
      0.38** and 1.29+/-0.29%**, respectively; *p < 0.01 vs. fasting, **p < 0.005 vs.
      fasting). The TBARS concentration increased in parallel with plasma glucose level
      in each group (NGT: 1.43+/-0.07, 2.03+/-0.12 and 1.80+/-0.12, respectively; IGT:
      1.65+/-0.11, 2.46+/-0.12** and 1.94+/-0.08*, respectively; DM: 1.73+/-0.07,
      2.34+/-0.08** and 2.47+/-0.09** nmol/ml, respectively; *p < 0.05 vs. fasting, **p
      < 0.01 vs. fasting). Glucose loading did not change nitrite/nitrate concentration
      in any of the groups. CONCLUSIONS: Hyperglycemia in response to oral glucose
      loading rapidly suppresses endothelium-dependent vasodilation, probably through
      increased production of oxygen-derived free radicals. These findings strongly
      suggest that prolonged and repeated post-prandial hyperglycemia may play an
      important role in the development and progression of atherosclerosis.

PMID- 10400005
TI  - Sustained hemodynamic effects of an infusion of nesiritide (human b-type
      natriuretic peptide) in heart failure: a randomized, double-blind, placebo
      controlled clinical trial. Natrecor Study Group.
AB  - OBJECTIVES: The goal of this study was to further define the role of nesiritide
      (human b-type natriuretic peptide) in the therapy of decompensated heart failure
      (HF) by assessing the hemodynamic effects of three doses (0.015, 0.03 and 0.06
      microg/kg/min) administered by continuous intravenous (IV) infusion over 24 h as
      compared with placebo. BACKGROUND: Previous studies have shown beneficial
      hemodynamic, neurohormonal and renal effects of bolus dose and 6-h infusion
      administration of nesiritide in HF patients. Longer term safety and efficacy have
      not been studied. METHODS: This randomized, double-blind, placebo-controlled
      multicenter trial enrolled subjects with symptomatic HF and systolic dysfunction
      (left ventricular ejection fraction < or =35%). Central hemodynamics were
      assessed at baseline, during a 24-h IV infusion and for 4 h postinfusion.
      RESULTS: One hundred three subjects with New York Heart Association class II
      (6%), III (61%) or IV (33%) HF were enrolled. Nesiritide produced significant
      reductions in pulmonary wedge pressure (27% to 39% decrease by 6 h), mean right
      atrial pressure and systemic vascular resistance, along with significant
      increases in cardiac index and stroke volume index, with no significant effect on
      heart rate. Beneficial effects were evident at 1 h and were sustained throughout
      the 24-h infusion. CONCLUSIONS: The rapid and sustained beneficial hemodynamic
      effects of nesiritide observed in this study support its use as a first-line IV
      therapy for patients with symptomatic decompensated HF.

PMID- 10400006
TI  - Improvement of left ventricular ejection fraction, heart failure symptoms and
      prognosis after revascularization in patients with chronic coronary artery
      disease and viable myocardium detected by dobutamine stress echocardiography.
AB  - OBJECTIVES: This study was designed to address, in patients with severe ischemic
      left ventricular dysfunction, whether dobutamine stress echocardiography (DSE)
      can predict improvement of left ventricular ejection fraction (LVEF), functional
      status and long-term prognosis after revascularization. BACKGROUND: Dobutamine
      stress echocardiography can predict improvement of wall motion after
      revascularization. The relation between viability, improvement of function,
      improvement of heart failure symptoms and long-term prognosis has not been
      studied. METHODS: We studied 68 patients with DSE before revascularization; 62
      patients underwent resting echocardiography/radionuclide ventriculography before
      and three months after revascularization. Long-term follow-up data (New York
      Heart Association [NYHA] functional class, Canadian Cardiovascular Society [CCS]
      classification and events) were acquired up to two years. RESULTS: Patients with
      > or =4 viable segments on DSE (group A, n = 22) improved in LVEF at three months
      (from 27+/-6% to 33+/-7%, p < 0.01), in NYHA functional class (from 3.2+/-0.7 to
      1.6+/-0.5, p < 0.01) and in CCS classification (from 2.9+/-0.3 to 1.2+/-0.4, p <
      0.01); in patients with <4 viable segments (group B, n = 40) LVEF and NYHA
      functional class did not improve, whereas CCS classification improved
      significantly (from 3.0+/-0.8 to 1.3+/-0.5, p < 0.01). A higher event rate was
      observed at long-term follow-up in group B versus group A (47% vs. 17%, p <
      0.05). CONCLUSIONS: Patients with substantial viability on DSE demonstrated
      improvement in LVEF and NYHA functional class after revascularization; viability
      was also associated with a favorable prognosis after revascularization.

PMID- 10400007
TI  - Effect of aspirin and ifetroban on skeletal muscle blood flow in patients with
      congestive heart failure treated with Enalapril. Ifetroban Study Group.
AB  - OBJECTIVES: The purpose of this study was to determine the acute and chronic
      effects of cyclooxygenase inhibition with aspirin and thromboxane A2 receptor
      blockade with ifetroban on the chronic vasodilating effects of enalapril in the
      skeletal muscle circulation of patients with heart failure. BACKGROUND:
      Angiotensin-converting enzyme inhibition and antiplatelet therapy with aspirin
      independently reduce the risk for subsequent nonfatal coronary events in
      survivors of myocardial infarction. The safety of the combined administration of
      angiotensin-converting enzyme inhibitors and aspirin has been questioned due to
      their divergent effects on the vascular synthesis of vasodilating prostaglandins.
      METHODS: Forearm blood flow (ml/min/100 ml) at rest and during rhythmic handgrip
      exercise and after transient arterial occlusion was determined by strain gauge
      plethysmography before and 4 h and six weeks after combined administration of
      enalapril with either aspirin, ifetroban or placebo in a multicenter, double
      blind, randomized trial of 62 patients with mild to moderate heart failure.
      RESULTS: Before randomization, forearm hemodynamics were similar in the three
      treatment groups except for increased resting forearm blood flow and decreased
      resting forearm vascular resistance in the aspirin group when compared with the
      placebo group. After combined administration of enalapril and study drug for 4 h
      and six weeks, changes from prerandomization values of mean arterial pressure,
      forearm blood flow and forearm vascular resistance at rest, during handgrip
      exercise and after transient arterial occlusion did not differ among the three
      treatment groups. CONCLUSIONS: These findings demonstrate that the vasodilating
      effects of enalapril in the skeletal muscle circulation of patients with heart
      failure are not critically dependent on prostaglandin pathways.

PMID- 10400008
TI  - Intravenous immune globulin in the therapy of peripartum cardiomyopathy.
AB  - OBJECTIVES: We sought to evaluate the effect of therapy with intravenous immune
      globulin on recovery of left ventricular function in women presenting with
      peripartum cardiomyopathy. BACKGROUND: Peripartum cardiomyopathy is a rare
      complication of pregnancy that results in significant morbidity and mortality in
      women of childbearing age. Intravenous immune globulin has been reported to
      improve left ventricular systolic function in patients with acute dilated
      cardiomyopathy and myocarditis, but its effectiveness in peripartum
      cardiomyopathy is unknown. METHODS: In this retrospective study, we compared the
      clinical outcomes of six women with peripartum cardiomyopathy treated with
      intravenous immune globulin (2 g/kg) with those of 11 recent historical control
      subjects. All women in the study were referred between 1991 and 1998 with class
      II to IV heart failure and a left ventricular ejection fraction of <0.40. Left
      ventricular ejection was reassessed during early follow-up (6.1+/-2.9 months).
      RESULTS: The two groups did not differ in terms of baseline left ventricular
      ejection fraction, left ventricular end-diastolic diameter, months to
      presentation, age or multiparity. The improvement in left ventricular ejection
      fraction in patients treated with immune globulin was significantly greater than
      in the conventionally treated group (increase of 26+/-8 ejection fraction units
      vs. 13+/-13, p = 0.042). CONCLUSIONS: In this small retrospective study of women
      with peripartum cardiomyopathy, patients treated with immune globulin had a
      greater improvement in ejection fraction during early follow-up than patients
      treated conventionally. Given the poor prognosis of women with peripartum
      cardiomyopathy who do not improve, this therapy merits further study.

PMID- 10400009
TI  - Familial dilated cardiomyopathy: evidence for genetic and phenotypic
      heterogeneity. Heart Muscle Disease Study Group.
AB  - OBJECTIVES: This study was performed to evaluate the characteristics, mode of
      inheritance and etiology of familial dilated cardiomyopathy (FDC). BACKGROUND: A
      genetic form of disease transmission has been identified in a relevant proportion
      of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics
      and patterns of inheritance, and an increased frequency of cardiac antibodies
      have been reported. An analysis of FDC may improve the understanding of the
      disease and the management of patients. METHODS: Of 350 consecutive patients with
      idiopathic DCM, 281 relatives from 60 families were examined. Family studies
      included clinical examination, electrocardiography, echocardiography and blood
      sampling. Of the 60 DCM index patients examined, 39 were attributable to FDC and
      21 were due to sporadic DCM. Clinical features, histology, mode of inheritance
      and autoimmune serology were examined, molecular genetic studies were undertaken
      and the difference between familial and sporadic forms was analyzed. RESULTS:
      Only a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could
      clinically distinguish FDC patients from those with sporadic DCM. However, a
      number of distinct subtypes of FDC were identified: 1) autosomal dominant, the
      most frequent form (56%); 2) autosomal recessive (16%), characterized by worse
      prognosis; 3) X-linked FDC (10%), with different mutations of the dystrophin
      gene; 4) a novel form of autosomal dominant DCM with subclinical skeletal muscle
      disease (7.7%); 5) FDC with conduction defects (2.6%), and 6) rare unclassifiable
      forms (7.7%). The forms with skeletal muscle involvement were characterized by a
      restrictive filling pattern; the forms with isolated cardiomyopathy had an
      increased frequency of organ-specific cardiac autoantibodies. Histologic signs of
      myocarditis were frequent and nonspecific. CONCLUSIONS: Familial dilated
      cardiomyopathy is frequent, cannot be predicted on a clinical or morphologic
      basis and requires family screening for identification. The phenotypic
      heterogeneity, different patterns of transmission, different frequencies of
      cardiac autoantibodies and the initial molecular genetic data indicate that
      multiple genes and pathogenetic mechanisms can lead to FDC.

PMID- 10400010
TI  - Comparison of dual-chamber pacing versus septal myectomy for the treatment of
      patients with hypertrophic obstructive cardiomyopathy: a comparison of objective
      hemodynamic and exercise end points.
AB  - OBJECTIVES: The purpose of this study was to compare the treatment effects of
      septal myectomy with dual-chamber pacing in patients with hypertrophic
      obstructive cardiomyopathy (HOCM). BACKGROUND: The optimal treatment for
      symptomatic patients with drug-refractory HOCM is unknown. Both dual-chamber
      pacing and surgical myectomy may result in subjective symptom improvement.
      However, no direct comparisons with objective end points have been reported.
      METHODS: Thirty-nine patients with symptomatic HOCM were analyzed in this
      concurrent cohort study. Twenty patients underwent surgical myectomy, and 19
      received dual-chamber pacemakers based on patient preference. These patients had
      prospective baseline and follow-up evaluations including physician assessment,
      echocardiography and standardized metabolic treadmill exercise testing. RESULTS:
      Baseline symptom status, left ventricular outflow tract gradients, exercise times
      and maximal oxygen consumption peak were similar between the two groups. Left
      ventricular outflow gradient was reduced from 76+/-57 to 9+/-17 mm Hg (p =
      0.0001) after myectomy, and from 77+/-61 to 55+/-39 mm Hg (p = 0.07) after pacing
      (p = 0.02 for comparison with myectomy). Ninety percent of myectomy patients
      experienced symptomatic improvement as compared with 47% in the pacing group.
      Exercise duration increased significantly from 6.6+/-2.8 to 8.7+/-3.0 min (p =
      0.0003) after myectomy compared with a change from 6.4+/-2.1 to 7.0+/-2.2 min (p
      = NS) in the pacing group. Maximal oxygen consumption increased from 19.4+/-6.4
      to 22.2+/-6.5 ml/kg/min after myectomy (p = 0.004), whereas the pacing group did
      not experience any significant change (19.6+/-6.5 vs. 20.1+/-6.5 ml/kg/min, p =
      NS). CONCLUSIONS: Surgical myectomy and dual-chamber pacing improve subjective
      measures of functional status in patients with symptomatic HOCM. In this
      nonrandomized study, myectomy offered greater reduction in left ventricular
      outflow tract gradients and larger improvements in objective measures of patient
      symptoms and functional status when compared with dual-chamber pacing.

PMID- 10400011
TI  - Volumetric remodeling of the proximal left coronary artery: early versus late
      after heart transplantation.
AB  - OBJECTIVES: The aim of this study was to characterize progression of cardiac
      allograft vasculopathy (CAV) with special respect to coronary artery geometry.
      BACKGROUND: As previously shown by intravascular ultrasound (IVUS), CAV is
      characterized by a multifocal intimal hyperplasia. Little is known, however,
      about vascular remodeling processes influencing vessel geometry and luminal
      narrowing. METHODS: In 30 heart transplant recipients serial IVUS studies were
      performed at baseline (BL) and after a mean follow-up period of 12.5+/-2.5
      months. Changes in plaque, lumen and vessel volume were assessed in the proximal
      left anterior descending artery. Pattern of remodeling was analyzed in patients
      "early" (n = 15, BL study 1.4+/-0.7 months after heart transplantation [HTX])
      compared with "late" after HTX (n = 15, BL 46.1+/-29.1 months). RESULTS: Plaque
      volume was found to increase by a mean of 23.8+/-25.9 mm3, not significantly
      different within and beyond the 1st year after HTX. Significant differences,
      however, were observed in changes in vessel volume with a mean decrease of 
      52.8+/-70.9 mm3 in the early group, whereas late follow-up group presented with
      an enlargement of 32.3+/-46.0 mm3. Based on these changes, lumen volume decreased
      by -73.2+/-69.8 mm3 early, in contrast to a slight increase of 5.2+/-32.6 mm3 in
      the late group. CONCLUSIONS: Progression of CAV is a complex process, modified by
      changes in the vascular geometry. Especially within the 1st year after HTX,
      luminal loss is influenced not only by an increase in plaque area but by a
      decrease in total vessel volume as well.

PMID- 10400012
TI  - Shocks as predictors of survival in patients with implantable cardioverter
      defibrillators.
AB  - OBJECTIVES: The objective of the study was to determine whether the occurrence of
      shocks for ventricular tachyarrhythmias during therapy with implantable
      cardioverter-defibrillators (ICD) is predictive of shortened survival.
      BACKGROUND: Ventricular tachyarrhythmias eliciting shocks are often associated
      with depressed ventricular function, making assessment of shocks as an
      independent risk factor difficult. METHODS: Consecutive patients (n = 421) with a
      mean follow-up of 756+/-523 days were classified into those who had received no
      shock (n = 262) or either one of two shock types, defined as single (n = 111) or
      multiple shocks (n = 48) per arrhythmia episode. Endpoints were all-cause and
      cardiac deaths. A survival analysis using a stepwise proportional hazards model
      evaluated the influence of two primary variables, shock type and left ventricular
      ejection fraction (LVEF <35% or >35%). Covariates analyzed were age, gender, NYHA
      Class, coronary artery disease, myocardial infarction, coronary
      revascularization, defibrillation threshold and tachyarrhythmia inducibility.
      RESULTS: The most complete model retained LVEF (p = 0.005) and age (p = 0.023)
      for the comparison of any shock versus no shock (p = 0.031). The occurrence of
      any versus no shock, or of multiple versus single shocks significantly decreased
      survival at four years, and these differences persisted after adjustment for
      LVEF. In the LVEF subgroups <35% and <25%, occurrence of multiple versus no shock
      more than doubled the risk of death. Compared with the most favorable group LVEF
      > or =35% and no shock, risk in the group multiple shocks and LVEF <35% was
      increased 16-fold. CONCLUSIONS: In defibrillator recipients, shocks act as potent
      predictors of survival independent of several other risk factors, particularly
      ejection fraction.

PMID- 10400013
TI  - Noninvasive assessment of the cardiac baroreflex: response to downward tilting
      and comparison with the phenylephrine method.
AB  - OBJECTIVES: We studied the relation between changes in systolic blood pressure
      and RR interval during downward tilting in comparison with assessment of
      baroreflex sensitivity (BRS) measured by the phenylephrine method (Phe-BRS) and
      with measures of heart rate variability (HRV). BACKGROUND: The method most
      extensively used for assessing BRS involves bolus injections of phenylephrine.
      Several noninvasive methods proposed to assess BRS have not been widely applied
      in the clinical setting. METHODS: Sixteen healthy male volunteers were studied
      (mean age +/- SD 27.5+/-4.6 years). Arterial blood pressure using tonometry and
      electrocardiogram was simultaneously recorded. After 20 min of 70 degrees upright
      tilting, the table was returned to supine position at a speed of 3.2 degrees/s.
      Subsequently, BRS was assessed using an intravenous bolus injection of
      phenylephrine (2 to 3 microg/kg). Heart rate variability under resting conditions
      also was analyzed. RESULTS: In all subjects, a beat to beat systolic blood
      pressure increase associated with corresponding RR interval lengthening was
      observed during downward tilting as well as during phenylephrine administration.
      During both testing procedures, these two variables showed linear correlation,
      and the slope of regression line during downward tilting (DT-BRS) correlated
      significantly with Phe-BRS (r = 0.79, p = 0.0003). The DT- and Phe-BRS also
      correlated significantly with the high frequency component of resting HRV (r =
      0.70, p = 0.0023 for DT-BRS; r = 0.58, p = 0.0185 for Phe-BRS). CONCLUSIONS: We
      conclude that in a small homogeneous group DT-BRS provided an assessment of
      reflex cardiac vagal function comparable to that obtained by the phenylephrine
      method.

PMID- 10400015
TI  - Eisenmenger syndrome in adults: ventricular septal defect, truncus arteriosus,
      univentricular heart.
AB  - OBJECTIVES: Morbidity and mortality patterns were characterized in adults with
      the Eisenmenger syndrome when two ventricles with a ventricular septal defect
      (VSD) joined two great arteries or one great artery, or when one ventricle joined
      two great arteries. BACKGROUND: Although afterload in these disorders differs,
      clinical differences have not been defined. METHODS: Seventy-seven patients were
      studied. Group A comprised 47 patients with VSD, aged 23 to 69 years (mean 39.5+/
      10.2), follow-up 5 to 18 years (mean 7.2+/-4.9); group B, 14 patients with
      truncus arteriosus, aged 27 to 50 years (mean 33.7+/-7.3), follow-up 6 to 18
      years (mean 7.7+/-5.1), and group C, 16 patients with univentricular heart, aged
      18 to 44 years (mean 30.6+/-8.4), follow-up 5 to 15 years (mean 4.4+/-4.2).
      Echocardiography established the diagnoses and anatomic and hemodynamic features.
      Data were compiled on tachyarrhythmias, pregnancy, infective endocarditis,
      noncardiac surgery and the multisystem disorders of cyanotic adults. RESULTS:
      Thirty-five percent of the patients died. Sixty-three percent of deaths were
      sudden, and resulted from intrapulmonary hemorrhage, rupture of either the
      pulmonary trunk, ascending aorta or a bronchial artery, or vasospastic cerebral
      infarction, or the cause was unestablished. There were no documented
      tachyarrhythmic sudden deaths. CONCLUSIONS: Medical management of coexisting
      cardiac disease, multisystem systemic disorders, noncardiac surgery and pregnancy
      has reduced morbidity. Increased longevity exposed patients to proximal pulmonary
      arterial aneurysms, thromboses and calcification; to truncal valve stenosis and
      regurgitation; to semilunar and atrioventricular valve regurgitation, and to
      major risks of nontachyarrhythmic sudden death.

PMID- 10400014
TI  - Effect of acetylsalicylate on cardiac and muscular pain induced by intracoronary
      and intra-arterial infusion of bradykinin in humans.
AB  - OBJECTIVES: This study assessed the algesic activity of bradykinin (BK) in humans
      and the effects of acetylsalicylate on muscular and cardiac BK-induced pain.
      BACKGROUND: Bradykinin is released by the ischemic myocardium and may be involved
      in the genesis of ischemic pain. METHODS: Increasing doses of BK (from 30 to 960
      ng/min) were randomly infused, for periods of 2 min each, into the iliac artery
      of 10 patients. The same protocol was repeated 30 min after the IV administration
      of 1 g of acetylsalicylate. In eight other patients with coronary artery disease,
      the same increasing doses of BK, for periods of 2 min each, were infused into the
      left coronary artery. The same protocol was repeated 30 min after the IV
      administration of 1 g of acetylsalicylate. Time to pain onset and maximal pain
      severity were obtained. RESULTS: Before acetylsalicylate administration, all
      patients experienced pain during intra-iliac infusion of BK. After
      acetylsalicylate, eight patients did not experience any pain during BK infusion
      (p = 0.0014), and in the two remaining patients, time to pain onset and maximal
      pain severity were similar to those recorded before acetylsalicylate. Before
      acetylsalicylate administration, all patients experienced pain similar to their
      habitual angina during intracoronary BK infusion. After acetylsalicylate, six
      patients did not experience any pain during BK infusion (p = 0.0098), whereas in
      the two remaining patients time to pain onset and maximal pain severity were
      similar to those recorded before acetylsalicylate. CONCLUSIONS: Intra-iliac
      infusion of BK causes muscular pain, and its intracoronary infusion in patients
      with coronary artery disease causes cardiac pain, which is similar to their
      habitual angina. The BK-induced pain is abolished or reduced by acetylsalicylate,
      thus suggesting that acetylsalicylate-sensitive mediators, such as
      prostaglandins, are involved in its pathogenesis.

PMID- 10400016
TI  - Clinical features of isolated noncompaction of the ventricular myocardium: long
      term clinical course, hemodynamic properties, and genetic background.
AB  - OBJECTIVES: A nationwide survey was conducted to clarify the clinical features of
      isolated noncompaction of the ventricular myocardium (INVM) in Japanese children
      in comparison with features previously described in patients with INVM.
      BACKGROUND: Isolated noncompaction of the ventricular myocardium is a rare
      disorder characterized by an excessively prominent trabecular meshwork. It is
      accompanied by depressed ventricular function, systemic embolism and ventricular
      arrhythmia. METHODS: A questionnaire specifically designed for this study was
      sent to 150 hospitals in Japan where a pediatric cardiology division exists.
      RESULTS: Twenty-seven patients were diagnosed by two-dimensional
      echocardiography, their ages ranging from one week to 15 years at presentation,
      with follow-up lasting as long as 17 years. The gross anatomical appearance and
      the extension of noncompacted myocardium predominantly at the apex observed on
      two-dimensional echocardiograms were similar to observations reported previously.
      Dissimilarities included a greater number of asymptomatic patients at initial
      presentation, a longer clinical course with gradually depressed left ventricular
      function, no systemic embolism, and rare ventricular tachycardia in the Japanese
      children. Cardiac catheterization disclosed normal left ventricular end-diastolic
      volume and increased left ventricular end-diastolic pressure in most cases,
      consistent with restrictive hemodynamics. A higher incidence of Wolff-Parkinson
      White syndrome was found in the children, whereas left bundle branch block was
      rarer than reported in adults. Familial recurrence was high (44%) and included
      many women. CONCLUSIONS: In Japanese children, INVM can be found by screening
      examinations at asymptomatic stage, and it might have a longer dinical course
      with gradually depressed left ventricular function and restrictive hemodynamics.
      The pattern of familial recurrence we observed implies that INVM is a distinctive
      clinical entity with a heterogeneous genetic background.

PMID- 10400017
TI  - Remote telemedical interpretation of neonatal echocardiograms: impact on clinical
      management in a primary care setting.
AB  - OBJECTIVE: The purpose of this study was to evaluate the utility of telemedical
      echocardiographically assisted neonatal cardiovascular evaluation in a primary
      care setting. BACKGROUND: Neonates with congenital heart disease are frequently
      born far from pediatric subspecialty centers and can be clinically unstable at
      presentation. Recent advances in telecommunication technology have made it
      possible to transmit echocardiographic images over long distances. This
      technology may be beneficial to newborns with heart defects who are born in
      primary care centers. METHODS: A retrospective review of all telemedical
      echocardiograms obtained from neonates (aged 1 day to 30 days) was performed. A
      telemedical link was created using a T-1 transmission line and a standard voice
      telephone line between the Mayo Clinic, Rochester, Minnesota (pediatric
      cardiology site), and the Altru Clinic, Grand Forks, North Dakota (primary care
      site), which is a general pediatric practice 400 miles from Rochester. Neonates
      with possible cardiac disorders were identified by the general pediatricians, who
      then requested telemedical echocardiography. RESULTS: The 133 neonates had 161 T
      1 echocardiograms. Median patient age was two days (range, one day to 29 days).
      One hundred thirty-two of 133 initial echocardiograms (99%) were obtained because
      of urgent indications. Transmitted images provided adequate diagnostic
      information in all patients. Seventy-nine neonates (59%) had a change in medical
      management or required cardiology follow-up. An immediate change in management
      occurred in 32 patients (24%), including seven in whom emergency transfer was
      either arranged or avoided. CONCLUSIONS: Telemedical echocardiography provides
      accurate diagnostic data in neonates. Rapid telediagnosis facilitates appropriate
      care of sick neonates with possible congenital heart disease in the primary care
      setting. Unnecessary long-distance transfers can be avoided with this technology.

PMID- 10400018
TI  - Catheter-based myocardial gene transfer utilizing nonfluoroscopic
      electromechanical left ventricular mapping.
AB  - OBJECTIVES: This study investigated the feasibility and safety of percutaneous,
      catheter-based myocardial gene transfer. BACKGROUND: Direct myocardial gene
      transfer has, to date, required direct injection via an open thoracotomy.
      METHODS: Electroanatomical mapping was performed to establish the site of left
      ventricular (LV) gene transfer. A steerable, deformable 7F catheter with a 27G
      needle, which can be advanced 3 to 5 mm beyond its distal tip, was then directed
      to previously acquired map sites, the needle was advanced, and injections were
      made into the LV myocardium. RESULTS: In two pigs in which methylene blue dye was
      injected, discretely stained LV sites were observed at necropsy in each pig,
      corresponding to the injection sites indicated prospectively by the endocardial
      map. In six pigs in which the injection catheter was used to deliver plasmid
      using cytomegalovirus promoter/enhancer, encoding nuclear-specific LacZ gene
      (pCMV-nlsLacZ) (50 microg/ml) to a single LV myocardial region, peak beta
      galactosidase activity after five days (relative light units [RLU], mean
      135,333+/-28,239, range = 31,508 to 192,748) was documented in the target area of
      myocardial injection in each pig. Percutaneous gene transfer of pCMV-nlsLacZ (50
      microg/ml) was also performed in two pigs with an ameroid constrictor applied to
      the left circumflex coronary artery, in each pig, peak beta-galactosidase
      activity after five days (214,851 and 23,140 RLU) was documented at the injection
      site. All pigs survived until sacrifice, and no complications were observed with
      either the mapping or the injection procedures. CONCLUSIONS: Percutaneous
      myocardial gene transfer can be successfully achieved in normal and ischemic
      myocardium without significant morbidity or mortality. These findings establish
      the potential for minimally invasive cardiovascular gene transfer.

PMID- 10400019
TI  - Alterations in cardiac sarcoplasmic reticulum Ca2+ regulatory proteins in the
      atrial tissue of patients with chronic atrial fibrillation.
AB  - OBJECTIVES: Our purpose was to determine whether atrial fibrillation (AF)
      patients have alterations in sarcoplasmic reticulum (SR) Ca2+ regulatory proteins
      in the atrial myocardium. BACKGROUND: Clinically, AF is the most frequently
      encountered arrhythmia. Recent studies indicate that an inability to maintain
      intracellular Ca2+ homeostasis with a consequent increase in membrane-triggered
      activity could be the primary initiating factor in some circumstances, and that
      cytosolic Ca2+ abnormalities are an important mediator of sustained AF. METHODS:
      We measured the maximum number of [3H]ryanodine binding sites (Bmax) and the
      expression levels of ryanodine receptor (RyR) mRNA and calcium-adenosine
      triphosphatase (Ca2+-ATPase) mRNA in atrial myocardial tissue from 13 patients
      with AF due to mitral valvular disease (MVD) and 9 patients with normal sinus
      rhythm (NSR). RESULTS: In AF patients, 1) Bmax was significantly lower in each
      atrium (0.21+/-0.03 pmol/mg [right], 0.16+/-0.04 pmol/mg [left]) than in the
      right atrium (0.26+/-0.08 pmol/mg) of NSR patients; 2) Bmax was significantly
      lower in the left atrium than in the right atrium; 3) Bmax in the left atrium was
      significantly lower at higher levels of pulmonary capillary wedge pressure; 4)
      the expression level of RyR mRNA was significantly lower in both the left (1.24 x
      10(-2)+/-1.28 x 10(-2)) and right (1.70 x 10(-2)+/-1.78 x 10(-2)) atrium than in
      the right atrium of NSR patients (6.11 x 10(-2)+/-2.79 x 10(-2)); and 5) the
      expression level of Ca2+-ATPase mRNA was significantly lower in both the left
      (5.67 x 10(-2)+/-4.01 x 10(-2)) and right (7.71 x 10(-2)+/-3.56 x 10(-2)) atrium
      than in the right atrium (12.60 x 10(-2)+/-3.92 x 10(-2)) of NSR patients.
      CONCLUSIONS: These results provide the first direct evidence of abnormalities in
      the Ca2+ regulatory proteins of the atrial myocardium in chronic AF patients.
      Conceivably, such abnormalities may be involved in the initiation and/or
      perpetuation of AF.

PMID- 10400020
TI  - Gender differences in molecular remodeling in pressure overload hypertrophy.
AB  - OBJECTIVES: The objective of this study was to examine gender differences in left
      ventricular (LV) function and expression of cardiac genes in response to LV
      pressure overload due to ascending aortic stenosis in rats. BACKGROUND: Clinical
      studies have documented gender differences in the pattern of adaptive LV
      hypertrophy. Whether these differences result from intrinsic differences in
      molecular adaptation to pressure overload between men and women, or are related
      to other factors is not known. METHODS: Male (n = 8) and female (n = 8) Wistar
      rats underwent ascending aortic stenosis and were studied 6 weeks after banding
      with gender-matched control rats (male n = 7; female n = 7). The LV contractile
      reserve was examined in isolated hearts from each group. We compared LV messenger
      ribonucleic acid (mRNA) levels of atrial natriuretic factor (ANF), beta-myosin
      heavy chain, sarcoplasmic reticulum Ca2+-adenosine triphosphatase (ATPase) and
      Na+-Ca2+ exchanger. Reverse transcriptase polymerase chain reaction was used to
      identify estrogen receptor transcript in cardiac myocytes and LV tissue. RESULTS:
      The magnitude of LV hypertrophy (LVH) and systolic wall stress were similar in
      male and female animals with LVH. Male LVH hearts demonstrated a depressed
      contractile reserve; in contrast, contractile reserve was preserved in female LVH
      hearts. The expression of beta-myosin heavy chain and ANF mRNA was greater in
      male versus female LVH hearts. Sarcoplasmic reticulum Ca2+-ATPase mRNA levels
      were depressed in male LVH but not in female LVH compared with control rats, and
      Na+-Ca2+ exchanger mRNA levels were increased similarly in both male and female
      LVH hearts. Estrogen receptor transcript was detected in both adult male and
      female cardiac myocytes and LV tissue. CONCLUSIONS: There are significant gender
      differences in the LV adaptation to pressure overload despite a similar degree of
      LVH and systolic wall stress in male and female rats. There is the potential for
      estrogen signaling through the adult myocyte estrogen receptor in both male and
      female rats to contribute to gender differences in gene expression in pathologic
      hypertrophy.

PMID- 10400021
TI  - Effects of folate supplementation in hyperhomocysteinemic pigs.
AB  - OBJECTIVES: The aim of this study was to evaluate the therapeutic effects of
      folic acid in the pig model of hyperhomocysteinemia. BACKGROUND: We have
      previously shown that pigs fed a methionine-rich diet develop
      hyperhomocysteinemia, arterial lesions and thrombotic events. Elevated
      homocysteine level is an independent risk factor for atherosclerosis that can be
      markedly lowered with daily folic acid administration. However, it is not known
      whether this treatment can prevent arterial lesions. METHODS: Three groups of
      pigs were studied: 8 control subjects received a standard diet; 8 received a
      methionine-rich diet for four months; 8 received a methionine-rich diet for 1
      month and then the methionine-rich diet + 5 mg/day folic acid for 3 months. At
      month 4 after hemodynamic investigation, all the pigs were sacrificed. RESULTS:
      Control animals developed few usual vascular streaks. All the pigs fed a
      methionine-rich diet without folic acid treatment developed hyperhomocysteinemia
      (10.3+/-1.3 micromol/liter at basal state, 18.2+/-2.5 micromol/liter at one month
      and 14.6+/-3.8 micromol/liter at four months), hemodynamic abnormalities and
      diffuse arterial lesions with smooth muscle cell hyperplasia, endothelial
      alterations and elastic lamina dislocation. In this group, one pig died of venous
      thromboembolism and one of myocardial infarction. The pigs fed a methionine-rich
      diet + folic acid displayed similar arterial lesions and two had thrombotic
      events (one myocardial infarction and one pulmonary embolism), despite
      normalization of homocysteine levels (10.9+/-1.3 micromol/liter at basal state,
      19.5+/-2.5 micromol/liter at one month and 11.4+/-3.8 micromol/liter at four
      months). CONCLUSIONS: In the pig model of hyperhomocysteinemia, 5 mg/day folic
      acid did not prevent arterial lesions or thrombotic events.

PMID- 10400022
TI  - P-selectin inhibition prevents early neutrophil activation but provides only
      modest protection against myocardial injury in dogs with ischemia and forty-eight
      hours reperfusion.
AB  - OBJECTIVES: This study was designed to determine whether antibody neutralization
      of the adhesion protein P-selectin would prevent neutrophil activation and reduce
      myocardial reperfusion injury. BACKGROUND: Although inhibition of P-selectin
      markedly reduces short-term myocardial injury after ischemia and reperfusion, it
      is unknown whether it can provide meaningful long-term protection and preserve
      left ventricular function. METHODS: Closed-chest dogs underwent 90 min left
      anterior descending coronary artery occlusion and 48 h reperfusion, and were
      randomized to 1) a treatment group (n = 11) receiving 1 mg/kg of the blocking
      anti-P-selectin antibody PB1.3, or 2) a control group receiving 1 mg/kg PNB1.6
      (nonblocking antibody against P-selectin, n = 7) or an equivalent volume of
      saline (n = 2) 10 min before reperfusion. Infarct size was assessed postmortem by
      triphenyl tetrazolium chloride staining. Contrast left ventriculography was used
      to measure left ventricular function. Activation of circulating polymorphonuclear
      neutrophils (PMNs) was assessed by an increase in surface CD18 expression.
      RESULTS: Neutrophil activation was observed at 30 min after reperfusion in the
      control group, but was abolished in the treatment group. Infarct size was reduced
      about 25% in the treatment group after controlling for variations in ischemic
      blood flow (p = 0.003, by analysis of covariance). However, this protective
      effect was not associated with preservation of blood flow to the ischemic
      reperfused myocardium, nor with any improvement in global or regional left
      ventricular function. CONCLUSIONS: The anti-P-selectin antibody PB1.3 prevented
      early PMN activation, but had only a modest long-term infarct-limiting effect
      over 48 h reperfusion. Adhesion molecules other than P-selectin may mediate
      delayed PMN activation and accumulation in reperfused myocardium.

PMID- 10400024
TI  - President's page: The Great Circle: a target for better patient care.

PMID- 10400023
TI  - How much to lower serum cholesterol: is it the wrong question?

PMID- 10400025
TI  - Myocardial salvage, AT1-receptor blockade, AT2-receptor activation and coronary
      collaterals.

PMID- 10400026
TI  - Additive effects of simvastatin and hormone replacement therapy in
      hypercholesterolemic postmenopausal women.

PMID- 10400027
TI  - Aortic debris and coronary guiding catheters.

PMID- 10400028
TI  - ST elevation secondary to microvascular dysfunction.

PMID- 10400029
TI  - Radiofrequency ablation of unresectable primary and metastatic hepatic
      malignancies: results in 123 patients.
AB  - OBJECTIVE: To describe the safety and efficacy of radiofrequency ablation (RFA)
      to treat unresectable malignant hepatic tumors in 123 patients. BACKGROUND: The
      majority of patients with primary or metastatic malignancies confined to the
      liver are not candidates for resection because of tumor size, location, or
      multifocality or inadequate functional hepatic reserve. Local application of heat
      is tumoricidal; therefore, the authors investigated a novel RFA system to treat
      patients with unresectable hepatic cancer. PATIENTS AND METHODS: Patients with
      hepatic malignancies were entered into a prospective, nonrandomized trial. The
      liver tumors were treated percutaneously or during surgery under ultrasound
      guidance using a novel LeVeen monopolar array needle electrode and an RF 2000
      generator. All patients were followed to assess complications, treatment
      response, and recurrence of malignant disease. RESULTS: RFA was used to treat 169
      tumors (median diameter 3.4 cm, range 0.5 to 12 cm) in 123 patients. Primary
      liver cancer was treated in 48 patients (39.1%), and metastatic liver tumors were
      treated in 75 patients (60.9%). Percutaneous and intraoperative RFA was performed
      in 31 patients (35.2%) and 92 patients (74.8%), respectively. There were no
      treatment-related deaths, and the complication rate after RFA was 2.4%. All
      treated tumors were completely necrotic on imaging studies after completion of
      RFA treatments. With a median follow-up of 15 months, tumor has recurred in 3 of
      169 treated lesions (1.8%), but metastatic disease has developed at other sites
      in 34 patients (27.6%). CONCLUSIONS: RFA is a safe, well-tolerated, and effective
      treatment to achieve tumor destruction in patients with unresectable hepatic
      malignancies. Because patients are at risk for the development of new metastatic
      disease after RFA, multimodality treatment approaches that include RFA should be
      investigated.

PMID- 10400030
TI  - Radiofrequency ablation of hepatic malignancies: is heat better than cold?

PMID- 10400032
TI  - Hepatic vascular exclusion with preservation of the caval flow for liver
      resections.
AB  - OBJECTIVE: To report the technique and results of an alternative method of
      vascular clamping during liver resections. BACKGROUND: Most liver resections
      require vascular clamping to avoid excessive blood loss. Portal triad clamping is
      often sufficient, but it does not suppress backflow bleeding, which can be
      prevented only by hepatic vascular exclusion. The latter method adds clamping of
      the inferior vena cava, which results in hypotension, requiring invasive
      anesthetic management. There is growing evidence that intermittent clamping is
      better tolerated than continuous clamping, especially in the presence of
      underlying liver disease. METHODS: Hepatic vascular exclusion with preservation
      of the caval flow (HVEPC) involved conventional inflow clamping associated with
      outflow control by clamping the major hepatic veins, thus avoiding caval
      occlusion. HVEPC was used in 40 patients undergoing major or complex liver
      resection, including 16 with underlying liver disease. HVEPC was total (clamping
      of the porta hepatis and all major hepatic veins) in 20 cases and partial
      (clamping of the porta hepatis and the hepatic veins of the resected territory)
      in 20. Clamping was continuous in 22 cases and intermittent in 18. Resections
      included 12 hemihepatectomies, 12 extended hepatectomies, 3 central
      hepatectomies, and 13 uni- or bisegmentectomies. RESULTS: Hemodynamic tolerance
      of clamping was excellent in all cases, without the need for therapeutic
      adjustment. Median red cell transfusion requirements were 0 units, and 28
      patients (70%) did not receive any transfusions during the hospital stay. There
      were no deaths, and the morbidity rate was 17.5%. Median hospital stay was 10
      days. CONCLUSION: HVEPC is a safe and effective procedure applicable to liver
      tumors without invasion to the inferior vena cava. It offers the advantages of
      conventional hepatic vascular exclusion without its hemodynamic drawbacks, and it
      can be applied intermittently or partially.

PMID- 10400031
TI  - Current concepts in gastrointestinal photodynamic therapy.
AB  - OBJECTIVE: To review current concepts of photodynamic therapy (PDT) applied to
      the treatment of tumors of the gastrointestinal tract. SUMMARY BACKGROUND DATA:
      PDT initially involves the uptake or production of a photosensitive compound by
      tumor cells. Subsequent activation of the photoreactive compound by a specific
      wavelength of light results in cell death, either directly or as a result of
      vascular compromise and/or apoptosis. METHODS: The authors selectively review
      current concepts relating to photosensitization, photoactivation, time of PDT
      application, tissue selectivity, sites of photodynamic action, PDT effects on
      normal tissue, limitations of PDT, toxicity of photosensitizers, application of
      principles of PDT to tumor detection, and current applications of PDT to tumors
      of the gastrointestinal tract. RESULTS: PDT is clearly effective for small
      cancers, but it is not yet clear in which cases such treatment is more effective
      than other currently acceptable approaches. The major side effect of PDT is
      cutaneous photosensitization. The major limitation of PDT is depth of tumor kill.
      As data from current and future clinical trials become available, a clearer
      perspective of where PDT fits in the treatment of cancers will be gained. Many
      issues regarding pharmacokinetic data of photosensitizers, newer technology
      involved in light sources, optimal treatment regimens that take advantage of the
      pharmacophysiology of photoablation, and light dosimetry still require solution.
      One can foresee application of differing sensitizers and light sources depending
      on the specific clinical situation. As technologic advances occur, interstitial
      PDT may have significant application. CONCLUSIONS: PDT has a potentially
      important role either as a primary or adjuvant mode of treatment of tumors of the
      gastrointestinal tract.

PMID- 10400034
TI  - Reduced adrenomedullin expression in gastric mucosa of portal hypertensive rats
      after ethanol-induced injury.
AB  - OBJECTIVE: To determine the expression and localization of adrenomedullin (AM)
      and its receptor (AM-R) in portal hypertensive (PHT) gastric mucosa after
      intragastric ethanol administration. SUMMARY BACKGROUND DATA: The repair of
      gastric mucosal injury requires reestablishment of the microvascular network. The
      authors previously demonstrated impaired angiogenesis of PHT gastric mucosa after
      ethanol-induced injury. Because AM, a potent vasodilatory peptide, is also a
      novel growth and angiogenic factor, the authors hypothesized that AM is involved
      in the impaired repair of PHT gastric mucosa and its microvasculature after
      damage. METHODS: Either PHT or sham-operated rats received intragastrically 100%
      ethanol, and the stomachs were excised at 1, 6, and 24 hours later. Expression
      and localization of AM and AM-R mRNA were examined by competitive reverse
      transcription-polymerase chain reaction and in situ hybridization. AM protein
      expression was examined by Western blot analysis. RESULTS: One hour after ethanol
      administration, AM mRNA expression in PHT gastric mucosa was significantly
      decreased by 81%, especially in the superficial mucosa, compared with the gastric
      mucosa in sham-operated rats. The significant decrease lasted for 24 hours. AM
      protein expression was significantly decreased by 43% compared with the sham
      operated gastric mucosa. Although AM-R mRNA expression in both groups was
      significantly increased 1 hour after ethanol administration and lasted for 24
      hours compared with baseline, there were no differences between the two groups.
      CONCLUSIONS: The expression of AM in PHT gastric mucosa after ethanol-induced
      injury is significantly decreased compared with controls. This finding could
      explain one mechanism for the impaired angiogenesis after injury of PHT gastric
      mucosa.

PMID- 10400033
TI  - Selection of patients for resection of colorectal metastases to the liver using
      diagnostic laparoscopy and laparoscopic ultrasonography.
AB  - OBJECTIVE: To assess the value of diagnostic laparoscopy (DL) and laparoscopic
      ultrasonography (LUS) in the staging and selection of patients with colorectal
      liver metastasis. SUMMARY BACKGROUND DATA: Preoperative imaging modalities such
      as ultrasound, computed tomography, and magnetic resonance imaging are limited in
      the assessment of the number and exact location of hepatic metastases and in the
      detection of extrahepatic metastatic disease. Consequently, the surgeon is often
      faced with a discrepancy between preoperative imaging results and perioperative
      findings, resulting in either a different resection than planned or no resection
      at all. METHODS: Fifty consecutive patients were planned for DL and LUS in a
      separate surgical sitting to assess the resectability of their liver metastases.
      All patients were considered to be candidates for resection on the basis of
      preoperative imaging studies. RESULTS: Laparoscopy could not be performed in 3 of
      the 50 patients because of dense adhesions. The remaining 47 patients underwent
      DL. On the basis of DL and LUS, 18 (38%) patients were ruled out as candidates
      for resection. Of the 29 patients who subsequently underwent open exploration and
      intraoperative ultrasonography, another 6 (13%) were deemed to have unresectable
      disease. CONCLUSIONS: The combination of DL and LUS significantly improves the
      selection of candidates for resection of colorectal liver metastases and
      effectively reduces the number of unnecessary laparotomies.

PMID- 10400035
TI  - Long-term results of artificial anal sphincter implantation for severe anal
      incontinence.
AB  - OBJECTIVE: To evaluate the long-term results of implantation of an artificial
      anal sphincter (AAS) for severe anal incontinence. SUMMARY BACKGROUND DATA:
      Implantation of an AAS is one of the options for treatment of anal incontinence
      when standard operations have failed. It is the only surgical option for
      treatment of anal incontinence in patients with neurologic disease that affects
      the pelvic floor and the muscles of the lower limb. METHODS: Seventeen patients
      underwent implantation of an AAS before 1993. These patients have been followed
      and their continence status evaluated. RESULTS: Two patients died of unrelated
      causes within the first 3 years after surgery, and in three patients the AAS was
      explanted because of infection. During the follow-up period, four patients had
      the AAS removed because of malfunction, and eight patients had a functioning AAS
      > or =5 years after the primary implantation. Five of these patients had
      revisional procedures, mainly because of technical problems in the early part of
      the study, when a urinary sphincter or slightly modified urinary sphincter was
      used. Continence at follow-up was good in four patients and acceptable in three,
      whereas one patient still had occasional leakage of solid stool. One patient had
      rectal emptying problems, which she managed by enema. CONCLUSIONS: An AAS based
      on the same principles as the artificial urinary sphincter seems to be a valid
      alternative in selected patients when standard surgical procedures have failed or
      are unsuitable. Approximately half of the patients have an adequate long-term
      result. Infectious complications still present a problem, whereas mechanical
      problems are less frequent with the modification of the device now available.

PMID- 10400036
TI  - Long-term follow-up of patients with rectal cancer managed by local excision with
      and without adjuvant irradiation.
AB  - OBJECTIVE: The long-term outcomes of patients undergoing local excision with or
      without pelvic irradiation were examined to define the role of adjuvant
      irradiation after local excision of T1 and T2 rectal cancers. METHODS: Ninety
      nine patients with T1 or T2 rectal cancers underwent local excision with or
      without adjuvant irradiation at Massachusetts General Hospital and Emory
      University Hospital between January 1966 and January 1997. Of these, 52 patients
      were treated by local excision alone and 47 patients by local excision plus
      adjuvant irradiation. Twenty-six of these 47 patients were treated by irradiation
      in combination with 5-fluorouracil chemotherapy. The outcomes of these groups
      were compared. RESULTS: The 5-year actuarial local control and recurrence-free
      survival rates were 72% and 66%, respectively, for the local excision alone group
      and 90% and 74%, respectively, for the adjuvant irradiation group. This
      improvement in outcome was evident despite the presence of a higher-risk patient
      population in the adjuvant irradiation group. Adverse pathologic features such as
      poorly differentiated histology and lymphatic or blood vessel invasion decreased
      local control and recurrence-free survival rates in the local excision only
      group. Adjuvant irradiation significantly improved 5-year outcomes in patients
      with high-risk pathologic features. Four cases of late local recurrence were seen
      at 64, 72, 86, and 91 months in the adjuvant irradiation group. CONCLUSIONS: The
      authors recommend adjuvant chemoradiation for all patients undergoing local
      excision for T2 tumors, and for T1 tumors with high-risk pathologic features. The
      four cases of late local failures beyond 5 years in the adjuvant irradiation
      group underscores the need for careful long-term follow-up in these patients.

PMID- 10400037
TI  - Laser-induced thermotherapy combined with hepatic arterial embolization in the
      treatment of liver tumors in a rat tumor model.
AB  - OBJECTIVE: To assess the effect of combined laser-induced thermotherapy (LITT)
      and hepatic arterial embolization with degradable starch microspheres (DSM) on
      tumor response and intrahepatic temperature distribution in rats with liver
      tumors. SUMMARY BACKGROUND DATA: Laser-induced thermotherapy is a promising in
      situ ablation technique for malignant liver tumors. However, clinical use is
      still limited, mainly because of the small size of the inducible coagulation
      necroses. This results in insufficient tumor destruction. METHODS: Colon
      carcinoma CC531 was implanted in 60 WAG rat livers. Fourteen days later, a
      silicon catheter was implanted in the hepatic artery for DSM administration.
      Tumors were exposed to 1064 nm Nd:YAG laser light at 2 watts for 10 minutes from
      a diffuser tip applicator placed in the tumor. The animals were randomized into a
      sham-operated control (group I) and three test groups. Group II received DSM
      alone, group III received LITT alone, and group IV received DSM + LITT. Tumor
      control was examined 1, 7, and 14 days after treatment. RESULTS: A complete tumor
      remission was achieved in all rats treated with LITT + DSM (group IV). In
      contrast, tumor progression was seen in animals treated with LITT alone (group
      III) or DSM alone (group II), as well as in the sham-operated controls (group I).
      CONCLUSIONS: The authors' results suggest that the combination of LITT and DSM
      considerably increases the efficacy of LITT in the treatment of liver metastases
      in the rat.

PMID- 10400038
TI  - Connective tissue growth factor is a regulator for fibrosis in human chronic
      pancreatitis.
AB  - OBJECTIVE: To evaluate the parameters that mediate fibrogenesis in chronic
      pancreatitis (CP). BACKGROUND: Connective tissue growth factor (CTGF), which is
      regulated by transforming growth factor beta (TGF-beta), has recently been
      implicated in skin fibrosis and atherosclerosis. In the present study, the
      authors analyzed the concomitant presence of TGF-beta1 and its signaling
      receptors-TGF-beta receptor I, subtype ALK5 (TbetaR-I(ALK5)), and TGF-beta
      receptor II (TbetaR-II)-as well as CTGF and collagen type I in the pancreatic
      tissue of patients undergoing surgery for chronic pancreatitis. PATIENTS AND
      METHODS: CP tissue samples were obtained from 40 patients (8 women, 32 men)
      undergoing pancreatic resection. Tissue samples of 25 previously healthy organ
      donors (12 women, 13 men) served as controls. The expression of TGF-beta1, TbetaR
      I(ALK5), TbetaR-II, CTGF, and collagen type I was studied by Northern blot
      analysis. By in situ hybridization and immunohistochemistry, the respective mRNA
      moieties and proteins were localized in the tissue samples. RESULTS: Northern
      blot analysis showed that CP tissue samples exhibited concomitant enhanced mRNA
      expression of TGF-beta1 (38-fold), TbetaR-II (5-fold), CTGF (25-fold), and
      collagen type I (24-fold) compared with normal controls. In addition, TbetaR
      I(ALK5) mRNA was increased in 50% of CP tissue samples (1.8-fold). By in situ
      hybridization, TGF-beta1, TbetaR-I(ALK5), and TbetaR-II mRNA were often seen to
      be colocalized, especially in the ductal cells and in metaplastic areas where
      atrophic acinar cells appeared to dedifferentiate into ductal structures. In
      contrast, CTGF was located in degenerating acinar cells and principally in
      fibroblasts surrounding these areas. Moreover, CTGF mRNA expression levels
      correlated positively with the degree of fibrosis in CP tissues. CONCLUSION: The
      concomitant overexpression of CTGF, collagen type I, TGF-beta1, and its signaling
      receptors in CP suggests that these proteins contribute to enhanced extracellular
      matrix synthesis and accumulation, resulting finally in the fibrogenesis observed
      in CP.

PMID- 10400039
TI  - Incidence and impact of documented eradication of breast cancer axillary lymph
      node metastases before surgery in patients treated with neoadjuvant chemotherapy.
AB  - OBJECTIVE: To determine the incidence and prognostic significance of documented
      eradication of breast cancer axillary lymph node (ALN) metastases after
      neoadjuvant chemotherapy. SUMMARY BACKGROUND DATA: Neoadjuvant chemotherapy is
      the standard of care for patients with locally advanced breast cancer and is
      being evaluated in patients with earlier-stage operable disease. METHODS: One
      hundred ninety-one patients with locally advanced breast cancer and cytologically
      documented ALN metastases were treated in two prospective trials of doxorubicin
      based neoadjuvant chemotherapy. Patients had breast surgery with level I and II
      axillary dissection followed by additional chemotherapy and radiation treatment.
      Nodal sections from 43 patients who were originally identified as having negative
      ALNs at surgery were reevaluated and histologically confirmed to be without
      metastases. An additional 1112 sections from these lymph node blocks were
      obtained; half were stained with an anticytokeratin antibody cocktail and
      analyzed. Survival was calculated using the Kaplan-Meier method. RESULTS: Of 191
      patients with positive ALNs at diagnosis, 23% (43 patients) were converted to a
      negative axillary nodal status on histologic examination (median number of nodes
      removed = 16). Of the 43 patients with complete axillary conversion, 26% (n = 11)
      had N1 disease and 74% (n = 32) had N2 disease. On univariate analysis, patients
      with complete versus incomplete histologic axillary conversion were more likely
      to have initial estrogen-receptor-negative tumors, smaller primary tumors, and a
      complete pathologic response in the primary tumor. The 5-year disease-free
      survival rates were 87% in patients with preoperative eradication of axillary
      metastases and 51% for patients with residual nodal disease after neoadjuvant
      chemotherapy. Of the 39 patients with complete histologic conversion for whom
      nodal blocks were available, occult nodal metastases were found in additional
      nodal sections in 4 patients (10%). At a median follow-up of 61 months, the 5
      year disease-free survival rates were 87% in patients without occult nodal
      metastases and 75% in patients with occult nodal metastases. CONCLUSIONS:
      Neoadjuvant chemotherapy can completely clear the axilla of microscopic disease
      before surgery, and occult metastases are found in only 10% of patients with a
      histologically negative axilla. The results of this study have implications for
      the potential use of sentinel lymph node biopsy as an alternative to axillary
      dissection in patients treated with neoadjuvant chemotherapy.

PMID- 10400040
TI  - Adults with Ewing's sarcoma/primitive neuroectodermal tumor: adverse effect of
      older age and primary extraosseous disease on outcome.
AB  - OBJECTIVE: To assess outcome and prognostic factors for survival of adults with
      Ewing's sarcoma/primitive neuroectodermal tumor (PNET). BACKGROUND: Ewing's
      sarcoma/PNET is a disease of childhood rarely seen in adults. Accordingly, there
      is a relative paucity of published literature pertaining to outcome for adults
      with this disease. METHODS: Between 1979 and 1996, 37 patients with newly
      diagnosed Ewing's sarcoma/PNET were evaluated and treated at the Adult Sarcoma
      Program at Dana-Farber Cancer Institute and Brigham & Women's Hospital. Twenty
      six patients had localized disease at presentation and 11 had metastatic disease.
      All but two patients received multiagent chemotherapy. Local treatment consisted
      of surgery (7 patients), surgery and radiation therapy (19), radiation therapy
      (6), or no local treatment (5). Median follow-up for living patients was 100
      months (range 8 to 199). RESULTS: The 5-year survival rate for the group overall
      was 37%+/-9%. The 5-year local control rate was 85%+/-7%. Significant favorable
      predictors for survival on univariate analysis included localized disease at
      presentation, primary origin in bone, primary size <8 cm, and a favorable
      objective response to chemotherapy. Patients with localized disease had a 5-year
      survival rate of 49%+/-11% compared with 0% for those with metastatic disease at
      presentation. Multivariate analysis showed three significant independent
      predictors for death: metastatic disease at presentation, primary origin in
      extraosseous tissue versus bone, and age 26 years or older. CONCLUSION: Adult
      patients with Ewing's sarcoma/PNET at highest risk for death are those who are
      older than 26 years and have metastatic disease or an extraosseous primary tumor.
      The development of novel therapies should target these high-risk groups.

PMID- 10400041
TI  - Trauma center maturation: quantification of process and outcome.
AB  - BACKGROUND AND OBJECTIVE: The regional trauma system with the trauma center as
      its center is a model for health care networks. However, trauma center maturation
      has not been defined in the literature. The authors' hypothesis was that
      maturation of the trauma center would affect quantitatively both process and
      patient outcome. MATERIALS AND METHODS: A total of 15,303 trauma patients were
      admitted from 1987 to 1995. Annual admissions increased from 813 to 2669.
      Resources were generated as patient volume increased. Time to the operating room,
      length of stay, and complications were determined. TRISS methodology was used to
      calculate z scores and w values to compare actual with predicted mortality rates.
      RESULTS: Time to the operating room for laparotomy decreased from 62+/-73 to 35+/
      47 minutes, from 32+/-32 to 20+/-17 minutes in hypotensive patients, and for
      craniotomy decreased from 88+/-54 to 67+/-49 minutes. The incidence of
      infectious, airway, neurologic, orthopedic, respiratory, gastrointestinal, and
      procedure-related complications declined significantly. Z scores and w values
      increased for penetrating and blunt injuries. Deaths for patients with ISS >15
      declined significantly. Hospital length of stay decreased for all ranges of
      injury severity. CONCLUSIONS: As the trauma center matured, the process of
      delivering patient care became more efficient. The result was improved survival,
      fewer complications, and a shorter length of stay.

PMID- 10400042
TI  - Early activation of hepatic NFkappaB and NF-IL6 in polymicrobial sepsis
      correlates with bacteremia, cytokine expression, and mortality.
AB  - BACKGROUND: The role of transcription factor activation in the pathophysiology of
      sepsis syndrome has not been established. This study investigated the relation
      between tissue nuclear factor kappaB (NFkappaB) and nuclear factor interleukin 6
      (NF-IL6 or C/EBP) activation and bacteremia, inflammatory cytokine expression,
      and mortality in a murine model of cecal ligation and puncture (CLP). METHODS:
      Transcription factor activation was assessed by the electrophoretic mobility
      shift assay. Cytokine mRNA levels were established by reverse transcription
      polymerase chain reaction and quantified by scanning densitometry. Bacteremia was
      evaluated by standard aerobic and anaerobic microbiologic methods. RESULTS: CLP
      stimulated hepatic NFkappaB activation at 2, 3, 4, 5, 6, and 8 hours compared
      with control and sham-operated mice. Hepatic NFkappaB activation during CLP
      peaked at 4 hours (1114% vs. no surgery, 609% vs. sham). Hepatic NF-IL6
      activation was observed at 3, 4, and 6 hours after CLP. Hepatic and splenic
      levels of tumor necrosis factor-alpha and IL-6 mRNA were also elevated after CLP.
      Bacteremia in CLP mice consisted of Bacteroides species and to a lesser extent
      facultative gram-negative bacilli and group D Enterococcus. CONCLUSIONS: Early
      activation of hepatic and splenic NFkappaB and NF-IL6 positively correlates with
      tissue cytokine mRNA expression and mortality in a surgical model of
      polymicrobial sepsis. The data suggest that transcription factor activation is an
      early event in the pathophysiology of sepsis.

PMID- 10400043
TI  - Organ preservation solutions increase endothelial permeability and promote loss
      of junctional proteins.
AB  - OBJECTIVE: To investigate the effects of the organ preservation solutions UW and
      Plegisol on endothelial permeability; occludin and vascular endothelial (VE)
      cadherin content in human umbilical vein endothelial cells (HUVEC); and
      junctional localization of these proteins after exposure to these solutions.
      SUMMARY BACKGROUND DATA: Organ preservation for transplantation is limited by
      several challenges, including loss of tissue function, tissue injury, and tissue
      edema. Occludin and VE-cadherin are responsible for maintaining and regulating
      the endothelial solute barrier. Several studies have noted organ edema and
      dysfunction with preservation, as well as gaps between endothelial cells
      suggesting that disorganization of junctional proteins (e.g., occludin and VE
      cadherin) is responsible for interstitial edema. METHODS: HUVEC monolayers were
      treated with 4 degrees C UW and Plegisol for 3 and 6 hours and then reperfused
      with normal buffer. Permeability was examined using FITC-dextran tracer during
      the reperfusion phase. Occludin and VE-cadherin content at different time points
      was measured by Western blotting. Treated groups were also examined by
      immunofluorescence for occludin, VE-cadherin, and F-actin. RESULTS: Compared with
      untreated controls, cold preservation for 3 and 6 hours increased endothelial
      permeability after rewarming, which appears to depend on the duration of cold
      exposure. Monolayers exposed to 3 hours of cold preservation did not have
      increased permeability in the first hour after rewarming but had significantly
      increased permeability after the first hour and all subsequent time points.
      Monolayers exposed to 6 hours of cold preservation had increased permeability
      after the first hour and at all later time points. Western blotting demonstrated
      that occludin content was decreased to a similar extent with all solutions after
      3 hours of cold preservation. Six hours of cold preservation in Plegisol reduced
      the occludin content significantly compared with UW and control. VE-cadherin
      content was unchanged after 3 hours of cold preservation but was dramatically
      reduced in all groups at 6 hours. Immunofluorescent staining demonstrated
      junctional gap formation and discontinuous staining of occludin and VE-cadherin
      with all cold preservation protocols; changes in F-actin organization were
      observed at 3 and 6 hours after cold preservation. CONCLUSION: The changes in
      occludin, VE-cadherin, and F-actin content and organization and increased
      permeability associated with cold storage demonstrate that alterations of the
      tight and adherens junctions may underlie organ edema associated with cold organ
      preservation. These data also suggest that novel strategies to maintain the
      content and integrity of endothelial junctional proteins may provide an important
      therapeutic avenue for organ preservation.

PMID- 10400044
TI  - Acceptance of skin allografts in pigs by portal venous injection of donor bone
      marrow cells.
AB  - OBJECTIVE: To confirm in pigs whether a new method for organ allografts,
      originally established in mice by the authors, might be applicable to humans.
      SUMMARY BACKGROUND DATA: The authors recently established a new method for organ
      allografts in mice that includes the injection of donor bone marrow cells (BMCs)
      using the portal vein (PV), followed by the administration of cyclosporin A (CsA)
      on days 2 and 5, and the intravenous injection of BMCs on day 5. In the present
      study, they modify this method (a single-day protocol) and apply it to pigs.
      METHODS: Allogeneic BMCs of donor pigs were injected using the PV (a superior
      mesenteric vein). The skin grafting was carried out on the day of the PV
      injection. The recipient pigs received donor grafts, autologous grafts, and third
      party grafts at the same time. In addition, an open wound was made as the
      epithelized control. Full-thickness skin grafts were harvested from the dorsal
      wall of the donors. CsA (10 mg/kg) was injected intramuscularly into recipient
      pigs on days 2 and 5 after the PV injection. RESULTS: One hundred percent of skin
      grafts survived for >300 days when donor BMCs were injected using the PV (n = 6).
      However, the skin grafts of the three pigs that had received BMCs using the
      intravenous route were rejected within 3 to 4 weeks after transplantation. The
      third-party skin grafts showed necrotic changes on day 21 after transplantation.
      CONCLUSIONS: One hundred percent of skin allografts can be obtained, even in
      pigs, by injecting donor BMCs using the PV, carrying out skin allografts, and
      administering CsA on days 2 and 5. This single-day protocol would be of great
      advantage for human organ transplantation.

PMID- 10400046
TI  - Echo-enhanced Doppler sonography of focal nodular hyperplasia of the liver.
AB  - Lesions of focal nodular hyperplasia are hypervascular, benign focal liver
      lesions whose differentiation from other focal liver lesions is of significant
      clinical relevance. The purpose of this study was to investigate the echo
      enhancing agent SHU 508A (Levovist) in the evaluation of focal nodular
      hyperplasia with Doppler sonography. We examined 49 patients with 71 lesions of
      focal nodular hyperplasia in the liver with gray scale and power Doppler
      sonography. In all patients Levovist was administered intravenously in a
      concentration of 300 to 400 mg galactose per milliliter. Visualization of the
      feeding vessels and the vascularity of the lesions were evaluated, and the
      resistive indices in the feeders and the hepatic arteries were assessed. In
      comparison with unenhanced power Doppler sonography, echo-enhanced power Doppler
      sonography yields a higher sensitivity in the detection of the feeding artery
      (97% versus 82%) in focal nodular hyperplasia and in the depiction of the radial
      vascular architecture in such lesions, especially those located in the left lobe
      of the liver. Lesions less than 3 cm in diameter do not consistently show a
      characteristic vascular architecture with echo-enhanced Doppler sonography. The
      resistive index of the tumor-feeding artery (mean, 0.51 +/- 0.09) is
      significantly (P < 0.0001) lower than that of the hepatic artery (mean, 0.65 +/-
      0.06) and decreases as the size of the focal nodular hyperplasia increases. The
      administration of Levovist may improve the signal-to-noise ratio and thus
      visualization of the vascular architecture in focal nodular hyperplasia. Lesions
      located in the left lobe of the liver, which commonly are subject to disturbing
      motion artifacts in color Doppler sonography, will significantly benefit from the
      administration of Levovist. Echo-enhanced power Doppler sonography, however, is
      not capable of depicting a characteristic vascular pattern in small (< or = 3 cm)
      lesions of focal nodular hyperplasia that would guarantee a specific diagnosis.

PMID- 10400047
TI  - Endoscopic ultrasonography: changes of chronic pancreatitis in asymptomatic and
      symptomatic alcoholic patients.
AB  - Changes suggestive of chronic pancreatic damage by endoscopic ultrasonography
      were studied in 31 asymptomatic and symptomatic alcohol abusers. Fifteen
      additional patients who did not drink alcohol served as controls. Eighty-nine
      percent (17 of 19) of the alcohol abusers with chronic abdominal pain had chronic
      pancreatitis by endoscopic ultrasonography. Similarly, 58%, (7 of 12)
      asymptomatic alcoholic patients also had changes of chronic pancreatitis on
      endosonography. Endoscopic ultrasonography has thus detected changes suggestive
      of alcohol-induced chronic pancreatic damage in up to 58% of asymptomatic
      alcoholic persons and in 89% of alcoholic persons with pancreatic type pain.

PMID- 10400045
TI  - Equipment standards: history, litigation, and advice.
AB  - The authors present a concise history of the development of national and
      international standards for surgical equipment. Standards-writing organizations,
      surgical and other specialty societies, universities, test houses, and the U.S.
      government have influenced this process, which is now manifested in complex
      interactions between national and international standards-writing organizations,
      and in CE (Conformite Europeene) marks being placed on surgical equipment in the
      United States and elsewhere. The history of litigation in standards development
      is also reviewed. Recommendations to maximize patient safety and to help ensure
      successful, cost-effective defense in litigation for surgeons who use equipment
      and may suffer its malfunctions are given. Overall, the complicated oversight of
      surgical equipment standards and the approval process appears to be contributing
      to the improving and outstanding results of U.S. surgery reported by the U.S.
      government.

PMID- 10400048
TI  - Accuracy of prenatal ultrasonographic diagnosis of duplex renal system.
AB  - Duplex renal system is a rare congenital anomaly of the urinary tract that can be
      diagnosed in utero. The purpose of this study was to establish the optimal
      diagnostic criteria for fetal renal duplication in a population undergoing
      prenatal sonographic screening. Between January 1989 and June 1997 we found 11
      cases of duplex renal system, 10 of which were correctly identified in utero at a
      median gestational age of 28 weeks (range, 20 to 38 weeks), and one of which was
      a false-negative diagnosis. Prenatal diagnosis of duplex renal system can be made
      in utero during the second half of pregnancy in the presence of two or more of
      the following signs: hydronephrosis limited to one pole in a kidney with two
      separate, noncommunicating renal pelves; ipsilateral megaureter; and ureterocele.

PMID- 10400050
TI  - Hepatic involvement in hypereosinophilia: sonographic findings.
AB  - Hypereosinophilic syndrome may cause eosinophil-related tissue damage to various
      organs. The purpose of this paper is to describe sonographic findings in 13
      patients with hypereosinophilia in whom the liver was involved. The diagnosis in
      these 13 patients was based on liver biopsy in seven patients with bone marrow
      biopsy in six patients. Eight patients had hypereosinophilic syndrome and five
      patients had clonorchiasis. All 13 patients had mild to marked hepatomegaly.
      Seven of 13 patients showed multiple round or oval hypoechoic (n = 6) or variably
      echogenic (n = 1) lesions measuring 1 to 2 cm with poorly defined margins in both
      lobes of the liver. Four patients had one or two hypoechoic lesions 3 to 4 cm in
      size, with geographic pattern and poorly defined margins. Two patients showed
      diffuse hepatomegaly with increased parenchymal echogenicity. The number of
      lesions and the extent of diffuse lesions seem to be proportional to the degree
      of eosinophilia. Hypereosinophilia may produce multiple small focal hepatic
      lesions or diffuse segmental or lobar echogenic lesions simulating primary or
      metastatic tumor of the liver.

PMID- 10400049
TI  - Best second trimester sonographic markers for the detection of trisomy 21.
AB  - We analyzed all genetic sonograms obtained during a 6 year period to establish
      the independent ability of the following sonographic markers of aneuploidy in the
      diagnosis of trisomy 21: structural anomalies, cardiac abnormalities, nuchal fold
      thickness of 6 mm or greater, bowel echogenicity, choroid plexus cysts, and renal
      pyelectasis. With the exception of bowel echogenicity and choroid plexus cysts,
      the sonographic markers were more common in trisomy 21 than euploid fetuses (all
      P < 0.001). Logistic regression analysis demonstrated that cardiac anomalies
      (odds ratio = 255; 95% confidence interval, 25, 2592), other structural anomalies
      (odds ratio = 25; 95% confidence interval, 6, 97), and nuchal fold thickness of 6
      mm or greater (odds ratio = 13; 95% confidence interval, 3, 50) were the only
      independent predictors of trisomy 21. The false-positive rate and sensitivity
      were 5.3% (48 of 898) and 59.2% (13 of 22), respectively, when any of the
      sonographic markers significant at univariate analysis was considered, and 3.1%
      (28 of 898) and 54.5% (12 of 22), respectively, when any of the predictors at
      multivariate analysis was present. Because a considerable overlap of sonographic
      markers exists among trisomy 21 fetuses, use of those that are not independent
      predictors leads to an increase in false-positive rate without a gain in
      sensitivity.

PMID- 10400051
TI  - Effect of angiotensin converting enzyme inhibition on the Doppler waveform in
      dogs with renal artery stenosis.
AB  - Our objective was to investigate whether the angiotensin converting enzyme
      inhibitor enalaprilat improves detection of hemodynamically significant renal
      artery stenoses in dogs. Renal artery stenoses of 50 to 99% were surgically
      created unilaterally in five dogs. Doppler ultrasonographic evaluation was
      performed at baseline (no stenosis), after creation of the stenosis, and after
      the administration of enalaprilat. The resistive index increased in the
      nonstenotic kidney (P < 0.01) but not in the stenotic kidney after administration
      of enalaprilat. The difference in resistive indices between nonstenotic and
      stenotic kidneys increased significantly (P < 0.05) after administration of
      enalaprilat. Measurement of the resistive index after administration of an
      angiotensin converting enzyme inhibitor in humans may improve the performance of
      Doppler ultrasonography in detecting hemodynamically significant renal artery
      stenoses.

PMID- 10400052
TI  - Feasibility of three-dimensional intravascular ultrasonography: preliminary
      clinical studies.
AB  - The aim of this study was to demonstrate the clinical utility of reconstructed
      three-dimensional intravascular ultrasonography using a voxel-based volume
      rendering technique. Three-dimensional reconstruction of intravascular
      ultrasonographic data was performed in 12 patients with various vascular
      abnormalities during interventional radiology procedures. A stepping motor device
      was used to pull either a 12.5 or a 20 MHz catheter-based transducer through the
      lumen of a variety of vessels at a rate of 1.5 mm/s. Images were downloaded to a
      Life Imaging System for three-dimensional reconstruction. The value of three
      dimensional ultrasonographic imaging was evaluated in comparison to conventional
      intravascular ultrasonography. A variety of abnormalities were demonstrated in
      reconstructed three-dimensional ultrasound imaging, including arterial atheroma
      and plaque, aneurysm and pseudoaneurysm, aortic dissection and stenosis (May
      Thurner syndrome). The vascular branches and accessory vessels, as well as their
      relationships to each other, were easily demonstrated on three-dimensional
      imaging by selecting an appropriate angle, plane, and section of the image. The
      dimensions and shapes of the vascular lumen were determined in the longitudinal
      view. Three-dimensional information proved useful for determining the
      distribution and type of plaque in vessels. Reconstructed three-dimensional
      imaging allows for global evaluation of the dissection entry site, extent of the
      flap, and the false lumen of a pseudoaneurysm. Intravascular three-dimensional
      ultrasonography provides information complementary to that obtained with two
      dimensional imaging. It supplies information about spatial relationships of
      anatomic structures that cannot be evaluated using conventional imaging methods.

PMID- 10400053
TI  - Doppler ultrasonographic evaluation of the early changes in renal resistive index
      in cirrhotic patients undergoing liver transplantation.
AB  - Renal vasoconstriction commonly occurs in decompensated liver cirrhosis and is
      entirely reversible after hepatic transplantation. In this study we evaluated by
      Doppler ultrasonography the changes of renal vascular resistance occurring during
      the first month after transplantation. In 16 cirrhotic patients the intrarenal
      resistive index at the level of interlobar arteries and the blood urea nitrogen
      and serum creatinine levels were measured before (range, 1 to 34 days) and after
      transplantation (days 1, 3, 7, 14, 30). Before transplantation the median
      resistive index value was 0.69 (95% CI, 0.65 to 0.71) and eight of 16 patients
      showed abnormal values (0.70 or more). After transplantation, the median
      resistive index was significantly decreased on all the evaluation days, and no
      patient had abnormal values on posttransplantation day 7. No significant
      correlation was found between resistive index and serum creatinine or blood urea
      nitrogen levels. Doppler ultrasonography is a simple tool to evaluate the
      recovery of normal intrarenal arterial resistance levels after liver
      transplantation. One week appears to be the optimal timing to evaluate the renal
      resistive index in the posttransplantation period.

PMID- 10400054
TI  - Sonographic assessment of the endometrium in osteopenic postmenopausal women
      treated with idoxifene.
AB  - Idoxifene is a novel selective estrogen receptor modulator that has shown
      beneficial effects on bone turnover and lipid metabolism in clinical studies.
      Preclinical studies have demonstrated that idoxifene has estrogen antagonist
      activities on the endometrium. This paper describes the results of a double
      blind, placebo-controlled, and dose ranging study involving 331 osteopenic
      postmenopausal women who were treated with either placebo or idoxifene (2.5, 5,
      or 10 mg/day) for 12 weeks. In these women, endometrial assessment was carried
      out by transvaginal sonography and endometrial biopsy on selected patients at
      baseline and on all women at the end of treatment. Women with an endometrial
      thickness greater than 10 mm were excluded from the study. Aspiration endometrial
      biopsy was performed on women with an endometrial thickness between 6 and 10 mm
      at baseline and on all women after treatment. Of the 298 biopsies performed in
      the subjects at the end of treatment, 99% of the women were reported to have
      either a benign or atrophic endometrium (85%) or insufficient tissue for
      diagnosis (14%). Proliferative histologic features were reported in two cases
      (1%) (2.5 mg idoxifene) and atypical hyperplasia in one placebo patient. Even
      though idoxifene use was associated with a dose related increase in endometrial
      thickness as evaluated by transvaginal sonography, no relationship was
      established between endometrial histologic features and change in endometrial
      thickness. On histologic analysis, the increase in endometrial thickness seen on
      transvaginal sonography was not associated with proliferative or hyperplastic
      change in the epithelial (glandular) endometrial tissue. In 48 patients (16% of
      total) transvaginal sonography showed endometrial thickening of 5 mm or more over
      the study period. The endometrial histologic features were benign in all these
      patients. Nineteen percent of women developed intraluminal fluid, even though
      endometrial thickness was normal and unchanged and histologic features were
      normal. Our data show that after 3 months of treatment, no significant pathologic
      changes of the endometrium were observed. Our data indicate that measurements of
      endometrial thickness by transvaginal sonography may falsely suggest the presence
      of endometrial pathologic changes in some postmenopausal women treated with
      idoxifene. Additional testing using saline infusion sonohysterography is an
      important part of the transvaginal sonography protocol in equivocal or abnormal
      cases to exclude focal lesions such as polyps. In addition, our data indicate
      that pathologic changes of the endometrium are extremely rare in the treated
      group, indicative of its short term safety. Continued investigation such as this
      will be needed to establish long term safety.

PMID- 10400055
TI  - Sonographic target sign in neurofibromas.

PMID- 10400056
TI  - Granulomatous angiopanniculitis of the breast: mammographic and sonographic
      findings.

PMID- 10400057
TI  - Using genetic analyses to clarify the distinction between depressive and anxious
      symptoms in children.
AB  - Self-report measures of depression and anxiety in children are highly correlated
      and distinguishing between shared and independent factors in their etiologies is
      therefore problematic. The aim of this article was to test whether less
      correlated measures of depression and anxiety could be produced and, if so, what
      genetic and environmental factors would account for the variance in these
      symptoms. Second-order factor analysis of the items from two standardized self
      report questionnaires of depression and anxiety collected from 395 pairs of same
      sex twins aged 8 to 16 years resulted in purer dimensions of depression and
      anxiety. Behavioral genetic analyses confirmed the distinction between these two
      dimensions, and bivariate analyses revealed that the association between the two
      was primarily accounted for by shared genetic factors.

PMID- 10400058
TI  - A multimethod exploration of the friendships of children considered socially
      withdrawn by their school peers.
AB  - Friendships of children considered socially withdrawn by their school peers were
      investigated within a population of elementary school children. Reciprocal
      friends were identified by a friendship nomination procedure; social withdrawal
      was assessed by peer nominations. Trained graduate students rated videotapes of
      dyads of friends (n = 58 dyads, of which 29 contained at least one withdrawn
      child) for selected features of friendship quality. In addition, each friend
      within a dyad provided ratings of the quality of the relationship. The videotaped
      data showed the withdrawn children to be somewhat restricted in their verbal
      communication with their friends, and less competitive with their friends, than
      were friends in a comparison group. In dyads consisting of one withdrawn and one
      nonwithdrawn child, the withdrawn child perceived the relationship as
      characterized by greater closeness and helpfulness than did the nonwithdrawn
      friend. Despite some signs of inhibited behavior within the friendship context,
      withdrawn children seem to have access to close friendships of high quality.

PMID- 10400059
TI  - The phenomenology of homesickness in boys.
AB  - Homesickness is the distress or impairment caused by an actual or anticipated
      separation from home. It is characterized by acute longing and preoccupying
      thoughts of home and attachment objects. This study extended previous research on
      the phenomenology of childhood homesickness by assessing a sample of 316 boys,
      ages 8-16, who were spending 2 weeks at a single-sex residential summer camp.
      Some 18% of the children reported moderate or high levels of homesickness; 7%
      reported concomitant severe depressive and anxious symptoms. Homesickness
      intensity was negatively correlated with separation experience and age. It was
      most commonly associated with depressive symptoms and internalizing behavior
      problems. For severely homesick boys, intensity increased over time, decreasing
      just prior to their return home. Preseparation assessment suggested that severely
      homesick boys had elevated levels of homesickness and negative emotions months
      before arriving at camp. One-year follow-up data suggested that the intensity of
      severe homesickness decreased with age and experience. However, severely homesick
      boys were less likely than other boys to return to camp. The results demonstrate
      how brief separations can affect children's well-being and attitudes about
      separations. Severe homesickness is distinct from separation anxiety disorder,
      but has elements of this and other psychopathologies. Theories of negative
      emotion, attachment, and coping complement emerging theories of homesickness.

PMID- 10400061
TI  - Measurement of impulsivity: construct coherence, longitudinal stability, and
      relationship with externalizing problems in middle childhood and adolescence.
AB  - This study focused on the assessment of impulsivity in nonreferred school-aged
      children. Children had been participants since infancy in the Bloomington
      Longitudinal Study. Individual differences in impulsivity were assessed in the
      laboratory when children were 6 (44 boys, 36 girls) and 8 (50 boys, 39 girls)
      years of age. Impulsivity constructs derived from these assessments were related
      to parent and teacher ratings of externalizing problems across the school-age
      period (ages 7-10) and to parent and self-ratings of these outcomes across
      adolescence (ages 14-17). Consistent with prior research, individual measures of
      impulsivity factor-analyzed into subdimensions reflecting children's executive
      control capabilities, delay of gratification, and ability or willingness to
      sustain attention and compliance during work tasks. Children's performance on the
      main interactive task index, inhibitory control, showed a signficant level of
      stability between ages 6 and 8. During the school-age years, children who
      performed impulsively on the laboratory measures were perceived by mothers and by
      teachers as more impulsive, inattentive, and overactive than others, affirming
      the external validity of the impulsivity constructs. Finally, impulsive behavior
      in the laboratory at ages 6 and 8 predicted maternal and self-ratings of
      externalizing problem behavior across adolescence, supporting the long-term
      predictive value of the laboratory-derived impulsivity measures.

PMID- 10400060
TI  - Development of adolescent problem behavior.
AB  - The developmental model of adolescent antisocial behavior advanced by Patterson
      and colleagues (e.g., Patterson, Reid, & Dishion, 1992) appears to generalize the
      development of a diverse set of problem behaviors. Structural equation modeling
      methods were applied to 18-month longitudinal data from 523 adolescents. The
      problem behavior construct included substance use, antisocial behavior, academic
      failure, and risky sexual behavior. Families with high levels of conflict were
      less likely to have high levels of parent-child involvement. Such family
      conditions resulted in less adequate parental monitoring of adolescent behavior,
      making associations with deviant peers more likely. Poor parental monitoring and
      associations with deviant peers were strong predictors of engagement in problem
      behavior. These constructs accounted for 46% of the variance in problem behavior.
      Although association with deviant peers was the most proximal social influence on
      problem behavior, parental monitoring and family factors (conflict and
      involvement) were key parenting practices that influenced this developmental
      process.

PMID- 10400063
TI  - Insulin effects on extracellular signal regulated kinase cascade in fetal rat
      astrocyte cell cultures.
AB  - Insulin within the nervous system promotes cell differentiation and survival. In
      addition extracellular signal regulated kinase (ERK) promotes cell
      differentiation and survival. We studied the effects of insulin on astrocyte ERK
      1 and 2, in fetal enriched astrocyte cell cultures incubated in an insulin free
      defined medium (G3 medium). After 2 days in G3 medium the astrocytes were
      stimulated with 5 ng/ml of insulin for 2 min, and insulin effects on insulin
      receptor, insulin receptor substrate-1 (IRS-1) and ERK-1 and 2 were studied using
      Western blots. Insulin inhibited the phosphorylation of the insulin receptor and
      IRS-1 and decreased the activity of the ERK-1, and inhibited the activation of
      the ERK-2. Thus, insulin is involved in ERK regulation in fetal astrocytes.

PMID- 10400062
TI  - Identification of AD/HD subtypes using laboratory-based measures: a cluster
      analysis.
AB  - The current investigation used laboratory-based measures of inattention,
      impulsivity, and activity level to identify subgroups of children with attention
      deficit/hyperactivity disorder (AD/HD). Data derived from solid state actigraphs
      and a continuous performance test (CPT) were obtained from a clinically referred
      sample and submitted to a cluster analysis. These empirically derived groups were
      then evaluated for clinical relevance and subsequently validated by parent and
      teacher ratings and tests of intellectual functioning and academic achievement.
      Four distinct subgroups emerged: Hyperactive-inattentive (HYP-IN), impulsive
      inattentive (IMP-IN), inattentive only, and hyperactive only. The HYP-IN group
      was impaired on measures of intellectual functioning and academic achievement
      relative to the other three groups. In contrast, the IMP-IN group was generally
      rated as more aggressive, although this difference was not statistically
      significant for all measures. The data suggest that the augmentation of clinical
      descriptors with laboratory-based data may be an effective strategy by which to
      categorize diagnostic subgroups of AD/HD.

PMID- 10400064
TI  - Clustering of cerebral cortical lesions in patients with corticobasal
      degeneration.
AB  - Clustering of ballooned neurons (BN) and tau positive neurons with inclusion
      bodies (tau+ neurons) was studied in the upper and lower laminae of the frontal,
      parietal and temporal cortex in 12 patients with corticobasal degeneration (CBD).
      In a significant proportion of brain areas examined, BN and tau+ neurons
      exhibited clustering with a regular distribution of clusters parallel to the pia
      mater. A regular pattern of clustering of BN and tau+ neurons was observed
      equally frequently in all cortical areas examined and in the upper and lower
      laminae. No significant correlations were observed between the cluster sizes of
      BN or tau+ neurons in the upper compared with the lower cortex or between the
      cluster sizes of BN and tau+ neurons. The results suggest that BN and tau+
      neurons in CBD exhibit the same type of spatial pattern as lesions in Alzheimer's
      disease, Lewy body dementia and Pick's disease. The regular periodicity of the
      cerebral cortical lesions is consistent with the degeneration of the cortico
      cortical projections in CBD.

PMID- 10400065
TI  - Cyclothiazide and GYKI 52466 modulate AMPA receptor-mediated apoptosis in
      cortical neuronal cultures.
AB  - In neocortical neuronal cultures, (S)-AMPA caused neurotoxicity which was
      concentration-dependent, receptor-mediated, slow and apoptotic in nature. (S)
      AMPA (3-600 microM) failed to produce rapid neuronal swelling, but morphological
      observations and monitoring of viability at 24-72 h revealed 50% cell death
      consistent with apoptosis. (S)-AMPA induced cell shrinkage, neurite blebbing and
      nuclear condensation. Cyclothiazide (50 and 100 microM), which blocks AMPA
      receptor desensitization potentiated excitotoxicity with 75% of neurones
      undergoing slow death. The AMPA-selective antagonist GYKI 52466 (10-50 microM),
      attenuated (S)-AMPA-mediated neurotoxicity. DNA condensation, a hallmark of
      apoptosis, was found by labelling neurones with the DNA binding dye 4,6-diamidino
      2-phenylindole HCl (DAPI). Gel electrophoresis revealed DNA fragmentation, which
      was increased by cyclothiazide and reduced by GYKI 52466 and cycloheximide.
      Overstimulation of the AMPA receptor produces a novel form of neuronal death,
      which is apoptotic, very slow in nature, and which could contribute to various
      neuropathologies.

PMID- 10400066
TI  - Chronology of upper limb anticipatory postural adjustments associated with
      voluntary wrist flexions and extensions in humans.
AB  - Six sitting healthy subjects were instructed to keep a constant upper limb
      posture while performing wrist flexions and extensions. Acceleration of the
      wrist, elbow and shoulder joints, and surface electromyograms (EMGs) of the upper
      limb's main flexors and extensors were studied. Results indicated the existence
      of anticipatory (APA) and corrective postural adjustments. The APAs were based on
      a reproducible directional chronology of postural muscle activations. As shown by
      a simple mechanical model, this chronology was in accordance with the muscular
      torque which should be applied to the joints to keep the upper limb posture
      constant. All these data indicate that APA are involved in segmental posture,
      where their general organization is similar to those of APA associated with whole
      body movements. The use of constant directional postural synergies well agrees
      with a simplification of the motor control according to Bernstein's theory.

PMID- 10400067
TI  - Intravascular beta-amyloid infusion increases blood pressure: implications for a
      vasoactive role of beta-amyloid in the pathogenesis of Alzheimer's disease.
AB  - Hypertension has been recognized as a risk factor for Alzheimer's disease (AD).
      Moreover, serum beta-amyloid (A beta) levels are elevated in several mutations
      linked to familial AD, as well as in some sporadic AD individuals. To determine
      the in vivo effects of A beta on blood pressure, A beta(1-40) was infused intra
      arterially into anesthetized rats. For all animals, strong correlations exist
      between pre-infusion mean arterial blood pressure (MA beta) and post-arterial
      infusion increases in blood pressure. In spontaneously hypotensive animals, A
      beta infusion resulted in substantial increases in MA beta compared to vehicle
      distilled water infusion. A beta(1-40) was also able to accelerate MA beta return
      from induced hypotension, but infusion of A beta(1-42), or rat amylin had no such
      effect. These results provide evidence that circulating A beta(1-40) can exert
      vasopressor actions in vivo. Moreover, they suggest a pathophysiologic role for
      vascular A beta in AD that precedes A beta deposition and dementia onset.

PMID- 10400068
TI  - Music effects on event-related potentials of humans on the basis of cultural
      environment.
AB  - Auditory oddball responses were recorded from Turkish subjects in a silent
      environment or superimposed on white noise, or music played with violoncello or a
      similar music played with ney, a reed flute frequently listened by the Turkish
      population. P3 amplitudes with ney music in the background were significantly
      larger than both the white noise and violoncello backgrounds. The topography of
      the P3 response changed significantly between the ney and silent background
      conditions, indicating a relatively higher participation of frontal areas during
      hearing ney. Our results showed that hearing music of a familiar style increases
      the allocation of attentional resources during memory updating processes which is
      supposed to determine the P3 amplitude, and therefore showed the effects of
      cultural environment on the cognitive processes.

PMID- 10400069
TI  - Taurine antagonizes calcium overload induced by glutamate or chemical hypoxia in
      cultured rat hippocampal neurons.
AB  - Taurine has been proposed to have antiexcitotoxic and antihypoxic activity. To
      explore the effect of taurine on neuronal calcium overload evoked by glutamate or
      hypoxia, we employed fluo-3 imaging of intracellular calcium ([Ca2+]i) in
      confocal laser scanning microscope to measure real-time changes of [Ca2+]i arose
      from glutamate/2,4-dinitrophenol (DNP, mimic hypoxia) and taurine in cultured rat
      hippocampal neurons. We found that 3 mM taurine could inhibit [Ca2+]i elevation
      ascribed to 0.5 mM glutamate or 0.2 mM DNP. Low (0.5 mM) or high (12 mM) level of
      taurine displayed no significantly depressant effect. However, sole application
      of taurine could increase [Ca2+]i transiently. The results indicate that taurine
      in moderate concentration may exert antiexcitotoxic and antihypoxic effect
      partially via its antagonism to [Ca2+]i overload.

PMID- 10400070
TI  - Ultrastructural change of synapses of Betz cells in patients with amyotrophic
      lateral sclerosis.
AB  - This report concerns an ultrastructural study of the synapses present on the
      surface of somata of normal-looking Betz cells in the fifth layer of motor cortex
      of seven patients with amyotrophic lateral sclerosis (ALS). Specimens from 12 age
      matched, neurologically normal control individuals were included for comparison.
      Presynaptic terminals on the somata of normal-appearing Betz cells showed a wide
      range of changes including increased mitochondria, and the dark type of
      degenerative change of synapses such as dense conglomerates of dark mitochondria
      with dense cristae and densely aggregated presynaptic vesicles. These alterations
      were significantly more common in ALS patients than in controls, suggesting that
      a substantial synaptic change occurs in Betz cells even in the early stage of
      ALS.

PMID- 10400072
TI  - Biphasic effects of melatonin on the propagation of excitation waves in the
      chicken retina.
AB  - The retinal spreading depression (SD) is a propagating wave in an excitable
      medium, the neuronal tissue of the retina. Its velocity is about 3 mm/min and it
      is accompanied by a variety of changes in the tissue, including electrical and
      optical events. The pronounced intrinsic optical signal (IOS) of the retinal SD
      makes it an extremely versatile tool for the investigation of the action of drugs
      on neuronal tissue and more specific on propagating excitation waves in neuronal
      tissue. Furthermore, in the last decade increasing evidence has been collected,
      which shows that SD waves are the basic mechanism of the aura in classical
      migraine. We have investigated the influence of melatonin on the propagation of
      retinal SD waves as it has been postulated to have protective effects on neuronal
      tissue. The results demonstrate that melatonin indeed slows down the retinal SD,
      however, only in a defined concentration range. Additionally, it changes the IOS
      of the wave.

PMID- 10400071
TI  - The course of putrescine immunocytochemical appearance in neurons, astroglia and
      microglia in rat brain cultures.
AB  - Putrescine, the diamine precursor for polyamine biosynthesis, is a ubiquitous
      molecule normally present at low concentration in quiescent cells. During
      development, or after traumatic stress, putrescine concentrations are greatly
      increased. Here we describe the localization of putrescine by fluorescence
      immunocytochemistry in primary cultures of embryonic rat brain using specific
      antibodies. Antibodies against putrescine conjugated to keyhole limpet hemocyanin
      (KLH) were produced in rabbits. The antisera were adsorbed on KLH affinity
      columns and the specificity of the antibodies was assessed by inhibition enzyme
      linked immunoassays (ELISA). The cellular localization paralleled the temporal
      sequence of appearance and disappearance of the different cell types in these
      mixed cultures. During the first 3 days after plating the antibodies were
      localized mainly in neurons. As the neurons disappeared the localization was
      mainly in the growing astroglia, and then, as astroglia reached confluence
      between 10 and 14 days in vitro, labeled astroglia were diminished in numbers
      while the number of labeled microglia was greatly increased. The subcellular
      localization was prominent in the perinuclear region of the cytoplasm. The
      results indicate that antibodies to KLH-conjugated putrescine can be used for
      immunocytochemical studies of changes in putrescine concentrations during
      development and after traumatic injuries.

PMID- 10400073
TI  - Corticosterone modifies muscarinic receptor immunoreactivity in rat hippocampus.
AB  - In the present study we report the effect of corticosterone in the regulation of
      hippocampal muscarinic acetylcholine receptor immunoreactivity (mAChR-ir)
      expression in rats. Adrenalectomy (ADX) or a single injection of a
      mineralocorticoid antagonist RU-28318 (1.0 mg/100 g body weight (b.w.)) in
      adrenally intact rats 24 h prior to sacrifice revealed an increased mAChR-ir in
      hippocampal CA1 and CA3 areas. Corticosterone replacement (100 microg/100 g b.w.)
      prevented the increase in mAChR-ir of ADX animals. However, glucocorticoid
      receptor antagonist (RU38486) treatment in adrenally intact rats failed to affect
      the mAChR immunolabeling. These results point to a modulation of muscarinic
      receptors by corticosterone that is predominantly mediated by the
      mineralocorticoid receptor.

PMID- 10400074
TI  - Ionizing radiation-induced alterations in the electrophysiological properties of
      Aplysia sensory neurons.
AB  - It is clear that ionizing radiation can alter neuronal function. Recently it has
      been suggested that radiation can directly influence neurons and/or the neuronal
      microenvironment. We have developed a simple in vitro model system utilizing the
      marine mollusc Aplysia californica to test this hypothesis. We show that ionizing
      radiation at doses of 5, 10 or 15 Gy produces complex effects on the
      electrophysiological properties of a population of Aplysia nociceptive sensory
      neurons at 24 and 48 h post irradiation. These results add support to the notion
      that ionizing radiation can directly influence neurons and/or the neuronal
      microenvironment. Furthermore, they demonstrate that Aplysia may be used as a
      useful model system to study radiation-induced neuronal plasticity.

PMID- 10400075
TI  - Substance P immunoreactive nerves and interstitial cells of Cajal in the rat and
      guinea-pig ileum. A histochemical and quantitative study.
AB  - The substance P (SP)-containing nerves at the deep (DMP) and myenteric (MP)
      plexuses and the related interstitial cells of Cajal (ICC-DMP and ICC-MP) were
      immunohistochemically studied in rat and guinea-pig ileum. All the ICC expressed
      SP-preferred receptor NK1r: the ICC-DMP showed an intense and the ICC-MP a faint
      NK1r-immunoreactivity(IR). c-kit-labeling confirmed that they were ICC. The SP-IR
      nerves at the DMP were significantly more numerous in the guinea-pig than in the
      rat, and more numerous than those at the MP in both animal species. All the ICC
      DMP in the guinea-pig and half of them in the rat were close to SP-IR nerves. The
      ICC-MP were rarely near to SP-IR nerves in either species. The SP-innervation
      shows interspecies differences at the DMP that imply a different tachykinergic
      control of the local ICC.

PMID- 10400077
TI  - Post-withdrawal changes in middle-latency auditory evoked potentials in abstinent
      human alcoholics.
AB  - We investigated the effects of chronic alcoholism on middle-latency auditory
      evoked potentials (MAEP) in 14 male alcoholics with 1-6 weeks of abstinence
      (without other severe disorders) and 13 age-matched male social-drinker controls.
      The peak amplitude of a positive deflection (Pa) of the MAEP, peaking at about 30
      ms post-stimulus, was significantly larger in the alcoholics than in the controls
      (P < 0.01), and notably, a significant negative correlation (r = -0.65) was
      observed between the Pa amplitude and duration of abstinence in the alcoholics.
      The present results suggest that the post-withdrawal brain hyperexcitability in
      the alcoholic brain, gradually recovering with abstinence, could be objectively
      and non-invasively studied with the MAEP.

PMID- 10400078
TI  - Subjective time estimation by humans is increased by counterclockwise but not
      clockwise circumcerebral rotations of phase-shifting magnetic pulses in the
      horizontal plane.
AB  - Volunteers were required to estimate 10-s intervals after 2.5 min exposures to
      each of six different patterns of complex magnetic fields. The approximately 10
      microT fields were applied sequentially through eight solenoids that were
      arranged circumcerebrally (every 45 deg) at the level of the temporoorbital
      plane. There were three rates of change for the circumcerebral rotations whose
      durations ranged between about 200 and 2000 ms. Successive additions of 20 ms of
      the complex fields during the counterclockwise circumcerebral rotation at each
      solenoid distended subjective time most effectively. Subjective time of the group
      who received these counterclockwise rotations was about 3 s longer than the group
      who received the clockwise rotations (explaining approximately 50% of the
      variance). The results are consistent with the model that the temporal binding
      for experience, most likely a feature of the rostrocaudal waves recreated every
      approximately 20 ms over the cerebral cortices, can be modified by weak magnetic
      fields whose spatial direction and temporal complexity are designed to interact
      with this process.

PMID- 10400079
TI  - Representations in human visual short-term memory: an event-related brain
      potential study.
AB  - Behavioral measures and event-related potentials (ERPs) were recorded from 12
      subjects while performing three delayed matching-to-sample tasks. The task
      instructions indicated whether stimulus locations, shapes or conjunctions of
      locations and shapes had to be memorized and matched against a probe. Memory load
      was varied trial-by-trial by cueing one or two of three stimuli for memorization,
      followed by one probe. ERPs during memorization and probe response times varied
      as a function of memory load (posterior negative and anterior positive ERP wave),
      but not between single-feature and conjunction of features, nor was an
      interaction found between them. The results support and extend hypotheses by Luck
      and Vogel (Luck, S.J. and Vogel, E.K., The capacity of visual working memory for
      features and conjunctions. Nature, 390 (1997) 279-281.) that visual short-term
      memory stores conjunctions of features rather than single features.

PMID- 10400080
TI  - Blocking of the axon spikes by pentylenetetrazol in an identified neuron of the
      snail Helix lucorum, with consequent induction of epileptic activity in the cell
      body of the same neuron.
AB  - In an isolated preparation which consists of the buccal ganglia and the salivary
      nerve of Helix lucorum, neuron B2 can be identified by simultaneously recording
      the soma spike intracellularly and the axon spike extracellularly from the
      peripheral salivary nerve. The convulsant drug pentylenetetrazol (PTZ) eliminates
      the axon spike of the neuron within 1-5 min after its application while epileptic
      activity is induced in the soma of the same neuron for hours. It is interesting
      that almost all nerve activity in the peripheral nerve is blocked by PTZ.

PMID- 10400076
TI  - Adenosine 5' triphosphate evoked mobilization of intracellular calcium in central
      nervous system white matter of adult mouse optic nerve.
AB  - Although it has been established that immature glial cells express functional
      purinergic receptors, the responsiveness of mature glial cells in vivo had not
      been elucidated. This question was addressed using fura-2 ratiometric
      measurements of [Ca2+]i in the adult mouse optic nerve, a central nervous system
      (CNS) white matter tract, taking advantage of the facts that (i), the optic nerve
      contains glial cells but not neurons and (ii), that fura-2 loads primarily
      astrocytes in isolated intact optic nerves. We show that adenosine 5'
      triphosphate (ATP) evoked an increase in [Ca2+]i in a concentration-dependent
      manner with a half-maximal effect at 3 microm ATP, and with a rank order of
      agonist potency of ATP > ADP > alpha,beta-methyline-ATP > UDP > adenosine. The
      results indicate mainly P2Y and P2X components, consistent with the in vitro
      astroglial purinergic receptor profile. The in vivo response of mature glia to
      ATP may be important in their response to CNS damage.

PMID- 10400081
TI  - Cell-specific expression of heat shock transcription factors 1 and 2 in
      unstressed rat spinal cord.
AB  - We investigated the intracellular distribution of heat shock factors 1 and 2
      (HSF1, HSF2) in rat spinal cord by immunoblotting and immunohistochemistry using
      selective policlonal antibodies. Our results showed that both HSF1 and HSF2 were
      expressed in spinal cord cells (both neurons and glia) but at different intensity
      and cell localization. HSF1 was unusually distributed in the perinuclear
      compartment of selected neurons of the gray matter while astrocytes,
      oligodendrocytes and ependymal cells were predominantly stained in the nucleus.
      HSF2 was expressed at lower levels than HSF1 and was scattered in both nucleus
      and cytoplasm of the motoneurons of the ventral horns while glial cells again
      showed a nuclear positivity. This study suggested that the different ability of
      neurons vs. glial cells to react against adverse conditions might well be
      correlated with the different constitutive localization of HSFs.

PMID- 10400083
TI  - Expression of long-term potentiation of the striatum in methamphetamine
      sensitized rats.
AB  - We examined the change of corticostriatal glutamatergic neuronal transmission in
      striatal slices of methamphetamine (MAP)-sensitized rats in vitro. Tetanic
      stimulation induced long-term depression (LTD) of the field potential in the
      striatum of saline-treated rats. However, it induced long-term potentiation (LTP)
      in the striatum of MAP-sensitized rats. This LTP was significantly suppressed by
      a N-methyl-D-aspartate (NMDA) receptor antagonist, aminophosphonovaleric acid
      (APV). These results suggest that LTP is expressed in the striatum of MAP
      sensitized rats, and that NMDA receptors are indispensable for the LTP formation.

PMID- 10400082
TI  - Distribution of neurons expressing alpha 1G subunit mRNA of T-type voltage
      dependent calcium channel in adult rat central nervous system.
AB  - T-type voltage-dependent calcium channel has central roles in neuronal burst
      firing. The alpha1G subunit of T-type channel has been recently cloned and we
      here reported a cellular distribution of the alpha1G by in situ hybridization in
      adult rat brain and spinal cord. The cells expressing alpha1G were widely
      distributed in the central nervous system. The distribution seemed to be
      restricted to neurons, and exhibited a specific pattern in the cerebellum,
      thalamus, hippocampus and cerebral cortex.

PMID- 10400084
TI  - Selective coupling of mouse brain metabotropic sigma receptor with recombinant
      Gi1.
AB  - Various sigma (sigma) ligands including (+)-pentazocine stimulated [35S]GTPgammaS
      binding in synaptic membranes from the mouse cerebellum. The (+)-pentazocine
      stimulated [35S]GTPgammaS binding was blocked by the treatment of membranes with
      pertussis toxin (PTX), but completely recovered by the reconstitution of PTX
      treated membranes with recombinant Gi1, but not with GoA. These findings suggest
      that metabotropic sigma receptors are selectively coupled to Gi1 protein.

PMID- 10400085
TI  - Fast excitatory post synaptic potentials and their response to catecholaminergic
      antagonists in rat sympathetic preganglionic neurones in vitro.
AB  - In an in vitro slice preparation from neonatal rats intracellular recordings were
      made from electrophysiologically identified sympathetic preganglionic neurones.
      Electrical stimulation in the lateral funiculus (>500 microm) from the recording
      site elicited a mono- or polysynaptic excitatory post synaptic potential. The
      latter potential was blocked with the dopamine D2 antagonist haloperidol but not
      with the dopamine D1 antagonist SCH 23390. We therefore report the first showing
      of a functional descending pathway in an in vitro slice preparation describing
      both the transmitter and the receptor subtype involved and physiologically show
      that dopamine may exert an indirect excitatory influence on sympathetic
      preganglionic neurones possibly via interneurones present in the spinal cord.

PMID- 10400086
TI  - Galanin-containing-neurons, in the gastrointestinal tract of the lizard Podarcis
      s. sicula, as components of anally projecting nerve pathway.
AB  - The distribution of galanin immunoreactive (Gal/IR) neurons was investigated in
      the gastrointestinal (GI) tract of the lizard Podarcis s. sicula. The indirect
      immunofluorescence method, image analysis and confocal analysis were applied to
      cryostat sections and whole mount preparations. Gal/IR nerve fibers and cell
      bodies were found throughout the lizard GI tract in the myenteric plexus,
      circular muscle layer and mucosa. These nerve structures decreased caudally. The
      stomach revealed a denser reactive nerve population than elsewhere. The
      projections of Gal/IR neurons were detected in the myenteric plexus of lizard gut
      using a confocal microscope which analyzed the immunoreactive material on the
      proximal and distal sides of muscle myotomies. An accumulation of Gal/IR material
      on the oral side of the myotomies demonstrated the oral-to-anal projection of Gal
      containing nerve structures. Based on our results, it can be hypothesized that
      Gal/IR neurons of the lizard digestive tract belong to the inhibitory descending
      pathway, which in most vertebrates is responsible for gut peristalsis regulation.

PMID- 10400087
TI  - Projections from the medial column of the inferior olive to different classes of
      rotation-sensitive Purkinje cells in the flocculus of pigeons.
AB  - In the flocculus of pigeons, as in other species, there are two major types of
      Purkinje cell responses to rotational optokinetic stimuli. One type prefers
      rotation about the vertical axis (VA neurons) whereas the other prefers rotation
      about an horizontal axis oriented at 135 degrees ipsilateral azimuth (H-135
      neurons). In this study, we injected the retrograde tracer cholera toxin subunit
      B into the VA and H-135 zones in attempt to determine the origin of inferior
      olive inputs. We found that VA and H-135 zones received input from the caudal and
      rostral margins of the medial column of the inferior olive, respectively. There
      is a similar pattern of connectivity in mammalian species.

PMID- 10400088
TI  - Increase in level of tumor necrosis factor (TNF)-alpha in 6-hydroxydopamine
      lesioned striatum in rats without influence of systemic L-DOPA on the TNF-alpha
      induction.
AB  - We previously reported that the levels of proinflammatory cytokines such as tumor
      necrosis factor (TNF)-alpha are increased in the striatum and cerebrospinal fluid
      from patients with Parkinson's disease (PD) and in the striatum from 1-methyl-4
      phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, a murine model of PD.
      Presently we examined the changes in cytokine levels in the nigrostriatal
      dopaminergic regions in rats treated with an intrastriatal injection of 6
      hydroxydopamine (6-OHDA) as a model of slowly progressive neurodegeneration
      similar to that seen in PD. We compared the content of TNF-alpha in the
      nigrostriatal dopaminergic regions of the control side with that of the 6-OHDA
      injected experimental side, and also explored the effects of 6-OHDA injection
      combined with the L-DOPA treatment on the TNF-alpha level in the dopaminergic
      regions of rats. TNF-alpha was measured by a highly sensitive sandwich enzyme
      linked immunosorbent assay (ELISA). The concentrations of TNF-alpha in the
      dopaminergic regions (striatum and substantia nigra) on the 6-OHDA injection side
      (right side: R) were significantly higher than those in the regions on the
      control side (left side: L) (Wilcoxon's test, P < 0.05). The ratio of the
      concentration of TNF-alpha on the injection side to that on the control side (TNF
      alpha (R/L)) of each rat was not significantly different in the striatum and
      substantia nigra between the control group and the group treated with 25 or 50
      mg/kg L-DOPA (Mann-Whitney Utests). These results show that TNF-alpha is
      increased in the striatum and substantia nigra in 6-OHDA-injected dopaminergic
      regions in rats, which finding is similar to the increase in the striatal
      dopaminergic regions in patients with PD. The results also indicate that L-DOPA
      alone or together with 6-OHDA does not increase the level of TNF-alpha in the
      brain in vivo.

PMID- 10400089
TI  - Benzodiazepine temazepam suppresses the transient auditory 40-Hz response
      amplitude in humans.
AB  - To discern the role of the GABA(A) receptors in the generation and attentive
      modulation of the transient auditory 40-Hz response, the effects of the
      benzodiazepine temazepam (10 mg) were studied in 10 healthy social drinkers,
      using a double-blind placebo-controlled design. Three hundred Hertz standard and
      330 Hz rare deviant tones were presented to the left, and 1000 Hz standards and
      1100 Hz deviants to the right ear of the subjects. Subjects attended to a
      designated ear and were to detect deviants therein while ignoring tones to the
      other. Temazepam significantly suppressed the amplitude of the 40-Hz response,
      the effect being equal for attended and non-attended tone responses. This
      suggests involvement of GABA(A) receptors in transient auditory 40-Hz response
      generation, however, not in the attentive modulation of the 40-Hz response.

PMID- 10400090
TI  - Isolated axons of Wlds mice regrow centralward.
AB  - We have conjectured that axons embody a post transcriptional sprouting programme
      repressed by mature Schwann cells. Injured nerves of Wld(s) mice neither
      degenerate nor regenerate for several weeks but axons do regrow if the resident
      cells of the distal stump are destroyed. To test our hypothesis we made an
      extended crush in Wld(s) nerves to destroy resident cells, transected the nerve
      at the proximal end of the lesion, and searched for sprouts in the injured
      domain. These isolated axons regrew centralward as supported by ultrastructure,
      labelling with horseradish peroxidase, and staining with DiI. This result
      indicates that: (i) axons embody a post transcriptional sprouting programme; (ii)
      resident cells of the nerve, probably Schwann cells, repress this programme, and
      (iii) navigation of regrowing axons is determined by the environment.

PMID- 10400091
TI  - 7-Nitroindazole attenuates nitrotyrosine formation in the early phase of cerebral
      ischemia-reperfusion in mice.
AB  - The purpose of this study was to evaluate the role of neuronal nitric oxide
      synthase (nNOS) in nitrotyrosine (NO2-Tyr) formation in the early phase of
      ischemia-reperfusion in mouse brain. Using a hydrolysis/high pressure liquid
      chromatography (HPLC) procedure (0.6 microM detection limit), we measured %NO2
      Tyr (ratio of NO2-Tyr to total tyrosine) in 23 male C57Black/6J mice subjected to
      2-h middle cerebral artery occlusion followed by 0.5-h reperfusion, in the
      presence (25 or 50 mg/kg) and absence of 7-nitroindazole (7-NI), a relatively
      specific nNOS inhibitor. At 25 mg/kg, 7-NI reduced NO2-Tyr formation to about a
      half of that in the vehicle-treated group (0.10 +/- 0.07 vs. 0.18 +/- 0.05%),
      while 50 mg/kg suppressed NO2-Tyr formation to below the limit of detection,
      indicating that nNOS is responsible for most of the NO2-Tyr formation in the
      early phase after reperfusion.

PMID- 10400092
TI  - The Shwachman Award of the North American Society for Pediatric Gastroenterology
      and Nutrition presentation.

PMID- 10400093
TI  - Cisapride for the treatment of gastroesophageal reflux disease in children.

PMID- 10400094
TI  - Alternate funding arrangements to compensate physicians at academic health
      science centers.

PMID- 10400095
TI  - Meeting report: the Banff Inflammation Workshop.

PMID- 10400096
TI  - Propranolol and portal hypertension: should kids be on the block?

PMID- 10400097
TI  - Propranolol in prevention of portal hypertensive hemorrhage in children: a pilot
      study.
AB  - BACKGROUND: Data regarding the use of propranolol in the prevention of portal
      hypertensive hemorrhage in pediatric patients are limited despite its widespread
      use in adults with cirrhosis. The purpose of this study was to evaluate safety
      and efficacy of propranolol in the management of portal hypertension in the
      pediatric population. METHODS: Medical information was retrieved from the records
      of 21 children with portal hypertension who received propranolol either before or
      after an episode of gastrointestinal bleeding. Data collected included diagnosis,
      type of portal hypertension, age at initiation of therapy, bleeding episodes
      before and during propranolol therapy, degree of reduction of heart rate,
      adherence, and adverse effects. RESULTS: Fourteen of 21 patients did not
      experience portal hypertensive bleeding while receiving propranolol. Of the seven
      patients who had bleeding episodes, two had failed to adhere to the medication
      regimen, and four were receiving doses of less than 1 mg/kg per day. Only one of
      the four patients who experienced bleeding before initiation of therapy also bled
      while receiving propranolol, and two of the three patients who had a heart rate
      reduction of less than 25% each experienced a bleeding episode. Side effects were
      minimal and did not necessitate discontinuation of therapy in any patient.
      CONCLUSIONS: Propranolol was well tolerated with minimal side effects in our
      patients with portal hypertension. Adherence and adequacy of dosage (>1 mg/kg per
      day, more than twice daily dose frequency) are important determinants of
      efficacy. A reduction in heart rate of less than 25% may be associated with
      suboptimal efficacy.

PMID- 10400098
TI  - Diet fat and oral insulin-like growth factor influence the membrane fatty acid
      composition of suckling rat small intestine.
AB  - BACKGROUND: Insulin-like growth factor- plays an important role in small
      intestine development. The presence of insulin-like growth factor-1 and the
      complexity of the fatty acid composition in breast milk suggests that intestinal
      development may be influenced by manipulating the levels of these components.
      METHODS: To determine whether a physiological dose of insulin-like growth factor
      1 would influence sucrase and lactase activity levels, 10-day-old suckling rat
      pups were treated with an oral gavage of insulin-like growth factor-1. Four diets
      differing in fat composition were fed to lactating dams. Brush border membranes
      were isolated from jejunal and ileal segments of suckling rat small intestine.
      Fatty acid analysis of choline and ethanolamine phospholipids was performed.
      RESULTS: Insulin-like growth factor-1 was found to have no effect on the sucrase
      and lactase activities of suckling rats. Changes in the diet fat composition of
      the mother's diet indirectly influenced the fatty acid composition of suckling
      rat small intestine. Insulin-like growth factor-1 decreased ileal C20:4n-6
      levels. A correlation was observed between lactase activity and C20:4n-6 and
      C22:6n-3 levels. As C20:4n-6 levels increased, lactase activity appeared to
      decline. Increased lactase activity was observed when C22:6n-3 levels increased.
      CONCLUSIONS: The changes observed in C20:4n-6 levels in response to oral insulin
      like growth factor-1, combined with the apparent trend of increased lactase
      activity with declining levels of C20:4n-6, may be of significance in the
      development of the small intestine in early life.

PMID- 10400099
TI  - Reproducibility of the 13C-octanoic acid breath test for assessment of gastric
      emptying in healthy preterm infants.
AB  - BACKGROUND: The 13C-octanoic acid breath test has been used to measure gastric
      emptying in preterm infants, but the reproducibility of the test has not been
      evaluated in this population. METHODS: Fifty-six paired breath test analyses were
      performed on 28 healthy preterm infants 1 to 5 days apart using the same food
      type, volume, and energy content for each paired sample. Breath samples were
      taken before the feeding, at 5-minute intervals after feeding for 30 minutes,
      then each 15 minutes for 4 hours. Samples were analyzed using an isotope-ratio
      mass spectrometer, and 3C recovery was used to calculate values for gastric
      emptying coefficient and gastric half-emptying time. RESULTS: There was no
      significant difference between test results on different days in the paired
      samples studied. gastric-emptying coefficients for the first and subsequent
      samples were 2.6+/-0.1 (mean+/-SEM) and 2.7+/-0.1, respectively, and half
      emptying times were 44.5+/-3.7 minutes and 41.4+/-3.2 minutes. CONCLUSION: The
      13C-octanoic acid breath test is a reliable, noninvasive, and reproducible
      measure of gastric emptying in preterm infants that should have wide application
      for use in this population.

PMID- 10400100
TI  - Oropharyngeal dysfunction and gastroesophageal dysmotility are present in girls
      and women with Rett syndrome.
AB  - BACKGROUND: Feeding impairment frequently complicates the course of children with
      neurologic disorders and places them at risk for malnutrition and growth failure.
      Although feeding abnormalities have been reported in female patients with Rett
      syndrome, the mechanisms that account for these findings have not been elucidated
      fully. This study was designed to characterize the clinical features of
      oropharyngeal and gastroesophageal dysfunction and their impact on the dietary
      intake and nutritional status of female subjects with Rett syndrome. METHODS: The
      clinical features of oropharyngeal and gastroesophageal dysfunction in 13 female
      patients with Rett syndrome, (age range, 3.7 to 25.7 years) were characterized by
      an oral feeding assessment, swallowing function study, and upper gastrointestinal
      series. Growth, nutritional status, and body composition were determined by
      stadiometry and anthropometry. Dietary intakes were determined from 3-day food
      records. RESULTS: Oropharyngeal dysfunction and gastroesophageal dysmotility were
      present in 100% and 69%, respectively, of the study patients with Rett syndrome.
      The scope and severity of these abnormalities were apparent only by
      videofluoroscopy. Abnormalities of oropharyngeal function included poor tongue
      mobility, reduced oropharyngeal clearance, and laryngeal penetration of liquids
      and solid food during swallowing. Esophageal dysmotility included absent primary
      or secondary waves, delayed emptying, atony, the presence of tertiary waves,
      spasm, and gastroesophageal reflux. Gastric dysmotility included diminished
      peristalsis or atony. Lower dietary energy intakes were associated with
      persistence of residue in the valleculae and pyriform sinuses and less body fat.
      CONCLUSION: The prevalence of oropharyngeal dysfunction and gastroesophageal
      dysmotility warrants early diagnostic evaluation and intervention strategies to
      improve the nutritional status of girls and women with RS.

PMID- 10400101
TI  - Serum type III procollagen in children with type I hereditary tyrosinemia.
AB  - BACKGROUND: Type I hereditary tyrosinemia leads to hepatic dysfunction and
      fibrosis and is associated with a high risk of hepatic malignancy. Serum N
      terminal propeptide of type III procollagen is a sensitive marker of organ
      fibrosis of diverse origins. The current study was conducted to determine whether
      analysis of serum levels of type III procollagen in hereditary tyrosinemia would
      be useful in the follow-up of the progressive liver disease and eventually in
      detecting hepatic malignancy. METHODS: Serum N-terminal propeptide of type III
      procollagen was sequentially studied in 10 children with type I hereditary
      tyrosinemia. RESULTS: At diagnosis of type I hereditary tyrosinemia, serum N
      terminal propeptide of type III procollagen ranged from 0.6 to 2.9 multiples of
      age-related median. During follow-up, serum N-terminal propeptide of type III
      procollagen decreased, yet remained elevated 0.2 to 2.6 years after diagnosis.
      Children with the acute type of the disease tended to have higher serum N
      terminal propeptide of type III procollagen than did those with the chronic type.
      Porphyria crises were associated with elevated serum type III procollagen. The
      one patient receiving 2-(2-nitro-4-trifluoromethyl-benzoyl)-1,3-cyclohexanedione
      (NTBC) did not differ from the other ones in serum type III procollagen levels.
      Serum N-terminal propeptide of type III procollagen did not increase with
      developing hepatocellular carcinoma. CONCLUSIONS: Serum N-terminal propeptide of
      type III procollagen may be useful in monitoring the hepatopathy in type I
      hereditary tyrosinemia but is not useful in detecting malignant transformation in
      the liver.

PMID- 10400102
TI  - Percutaneous endoscopic gastrostomy for continuous feeding in children with
      chronic cholestasis.
AB  - BACKGROUND: Malnutrition associated with chronic cholestasis in children often
      requires continuous enteral feeding through a nasogastric tube, which may be
      poorly tolerated. METHOD: Percutaneous endoscopic gastrostomy was performed in
      five children (age range, 20 months to 13 years) with severe cholestasis
      (Alagille syndrome in four; biliary atresia in one) and severe malnutrition (mean
      weight, -2.6 standard deviations; mean height, -2.7 standard deviations) who were
      awaiting liver transplantation. The pull-through technique was used in patients
      under general anesthesia, and the button was set within 2 months. RESULTS: Minor
      wound infection required antibiotic therapy in one patient. In the four children
      with Alagille syndrome, enteral feeding by means of percutaneous endoscopic
      gastrostomy was used until liver transplantation for a mean period of 14 months
      with a mean weight gain of 350 g/mo and a mean height gain of 0.53 cm/mo.
      Seventeen months to 3 years, 3 months after liver transplantation, all four
      children were alive and in good clinical condition with normal readings in liver
      function tests. The technique had to be discontinued in the child with biliary
      atresia because of secondary occurrence of ascites, gastric intolerance, and
      refractory wound infection. CONCLUSION: Percutaneous endoscopic gastrostomy may
      be a valuable alternative to nasogastric tube for nutritional support in children
      with cholestasis and mild portal hypertension.

PMID- 10400103
TI  - Gastric emptying in formula-fed and breast-fed infants measured with the 13C
      octanoic acid breath test.
AB  - BACKGROUND: The 13C-octanoic acid breath test, a noninvasive method for measuring
      gastric emptying, was used to compare the gastric-emptying rate of formula-fed
      and breast-fed infants. Octanoic acid, a medium-chain fatty acid marked with the
      stable isotope 13C is immediately absorbed in the duodenum. Because gastric
      emptying is the rate-limiting step for the absorption of medium-chain fatty
      acids, the fraction of 13C expired in the breath indicates the rate of gastric
      emptying. METHODS: Twenty-nine newborn infants (16 boys, 13 girls) were
      investigated, with parental consent. The infants had a mean gestational age at
      birth of 34.5 weeks (range, 27-41 weeks) and a birth weight of 2148 g (range, 960
      4100 g). Their mean weight on the day of the test was 2496 g (range, 1998-4140
      g), and their mean age was 23 days (range, 7-74 days). Each infant received a
      test meal after a maximum fasting period of 3 hours. Fourteen infants were fed
      formula milk (Nutrilon Premium, NV Nutricia, Zoetermeer, The Netherlands) with
      13C-octanoic acid and 15 infants received expressed mother's milk mixed with 13C
      octanoic acid. After obtaining two basal breath samples and the feeding, breath
      samples were collected using a nasal prong, every 5 minutes during the first half
      hour and every 15 minutes during the next 3.5 hours. Analysis of the expired 13C
      fraction in the breath samples was performed using isotope-ratio mass
      spectrometry, and the gastric emptying curve and gastric emptying parameters were
      determined. RESULTS: The mean half-emptying time determined by the 13C-octanoic
      acid breath test was 65 minutes (range, 27-98 minutes) for the formula fed
      infants and 47 minutes (range, 16-86 minutes) for the breast-fed infants. The
      difference between the half-emptying times is significant (t-test, p < 0.05).
      CONCLUSIONS: The results of the 13C-octanoic acid breath test indicated faster
      gastric emptying of human milk than formula. Our findings are in accordance with
      those in earlier studies, using the invasive-dilution technique; noninvasive and
      detailed ultrasonography, which is not easily used because it is operator
      dependent and the observation time is short; or cineesophago-gastroscintigraphy,
      which is less suitable for infants (because of the radiation involved). The 13C
      octanoic acid breath test is a safe and noninvasive method for measuring gastric
      emptying in small infants and allows comparison of various feeding methods.

PMID- 10400104
TI  - Systemic Bartonella henselae infection with hepatosplenic involvement.
AB  - BACKGROUND: Systemic manifestations of Bartonella henselae infection are rare in
      the immunocompetent host. The infection generally has initial symptoms of
      prolonged fever and multiple granulomatous lesions in liver and spleen. METHODS:
      Retrospective analysis of the records of all patients with hypoechogenic lesions
      in the liver and/or spleen diagnosed from 1990 through 1996 in three pediatric
      clinics in northern Italy. RESULTS: Among the 13 patients reviewed, 9 had
      evidence of B. henselae infection and hepatosplenic involvement: five had
      prolonged and unexplained fever lasting from 3 to 16 weeks, and four had typical
      cat-scratch disease and peripheral lymphadenitis. All patients had increased
      sedimentation rate and normal aminotransferase serum activity. Five children had
      a liver biopsy, by laparotomy in three and by needle in two. In all, the
      predominant liver lesion was a necrotizing granuloma. All patients were treated
      with broad-spectrum antibiotics. Fever lasted from 3 to 16 weeks, and hepatic and
      splenic lesions resolved in all with residual splenic calcification in one.
      CONCLUSIONS: Systemic B. henselae infection represents an important cause of
      inflammatory hypoechogenic hepatosplenic lesions in children. Serology provides
      rapid diagnosis, avoiding multiple and invasive investigations. Hepatosplenic
      involvement can be found even in children with typical cat-scratch disease
      without apparent systemic manifestations. The frequency of liver and/or splenic
      involvement in cat-scratch disease is probably underestimated.

PMID- 10400105
TI  - Lymphonodular hyperplasia as a sign of food allergy in children.
AB  - BACKGROUND: Lymphonodular hyperplasia of the gastrointestinal tract in children
      is a rare endoscopic finding of uncertain clinical significance. In this study,
      12 children with lymphonodular hyperplasia of the duodenum from a series of 63
      children were studied for recurrent abdominal pain. Four additional children with
      lymphonodular hyperplasia of the colon are described. All the patients with
      lymphonodular hyperplasia were also evaluated for food allergy. METHODS: A
      gastroduodenoscopy was performed in the patients with recurrent abdominal pain
      and in the four in whom lymphonodular hyperplasia of the colon had been diagnosed
      by colonoscopy. An open oral elimination and challenge test to diagnose food
      allergies was scheduled for all subjects with lymphonodular hyperplasia or any
      suspicion of food allergy. The study design also included skin prick tests with
      common allergens and determination of serum immunoglobulin A and immunoglobulin E
      concentrations. RESULTS: Lymphonodular hyperplasia of the duodenal bulb was the
      main finding in 12 (19%) of the 63 children. The condition was found to be
      associated with food allergy in nine subjects (75%), which was significantly more
      often than among the remaining 51, 12 (24%) of whom had food allergy by the same
      criteria. In an oral challenge, food allergy first manifested gastrointestinal
      symptoms in the subjects of both groups and, in all except one, on days 2 through
      5 after the foodstuffs were administered in minimal doses. In a histologic study,
      the duodenal specimens revealed significantly more eosinophilic cells in the
      children with food allergy and lymphonodular hyperplasia than in the children
      with food allergy but no lymphonodular hyperplasia. The major symptoms in the
      four patients with lymphonodular hyperplasia of the colon had been anemia and
      blood in stool in two and abdominal pains with mucous loose stools in the
      remaining two. Colonoscopic examination showed one to have diffuse and the other
      three patchy lymphonodular hyperplasia of the colon. In an oral challenge, three
      reacted to milk and two to cereals. CONCLUSIONS: Preliminary observations showed
      that lymphonodular hyperplasia of the duodenum or the colon is related to the
      gastrointestinal type of food allergy to basic foodstuffs. Further research is
      needed to define this finding as a separate entity.

PMID- 10400106
TI  - Severe and protracted diarrhea: results of the 3-year SIGEP multicenter survey.
      Working Group of the Italian Society of Pediatric Gastroenterology and Hepatology
      (SIGEP).
AB  - BACKGROUND: The spectrum of severe and protracted diarrhea (SPD), previously
      defined as intractable diarrhea, has changed during the past several decades.
      Despite recent advances in determining the cause of SPD and in treatment, this
      syndrome still represents a challenge and is becoming a major problem affecting
      health care resources. This study was conducted to characterize the epidemiology,
      spectrum of causes, and the outcome of SPD in Italy in recent years. METHODS: All
      the SPD cases seen at the major centers of pediatric gastroenterology in Italy
      during a 3-year period (1993-1996) were recruited in this multicenter,
      prospective survey. RESULTS: Thirty-two children (26 boys and 6 girls; median age
      at the onset of SPD, 40 days) were enrolled in this study by 9 of 26
      participating centers. Twelve were newly diagnosed cases, with an estimated SPD
      incidence rate in Italy of 0.64 to 0.92 x 10(-5) infants per year. The most
      common causes were autoimmune enteropathy (n = 8) and ultrastructural
      abnormalities of the enterocyte (n = 7), whereas food intolerance and
      postenteritis syndrome were less frequent (3 and 2 cases, respectively). Two
      children with autoimmune enteropathy fulfilled the criteria for the X-linked
      variant of this condition. At the end of the study period, 9 of 31 patients had
      recovered, 15 still had diarrhea, and 7 had died. CONCLUSIONS: Severe and
      protracted diarrhea is a rare but challenging problem in Italy. Because
      parenteral nutrition or intestinal transplantation are the only options in a
      subset of cases (e.g., ultrastructural abnormalities of the enterocyte), infants
      with SPD should be referred to specialized centers where advanced diagnostic and
      therapeutic facilities are available.

PMID- 10400107
TI  - Amelioration of ischemia-reperfusion injury in rat intestine by pentoxifylline
      mediated inhibition of xanthine oxidase.
AB  - BACKGROUND: Intestinal ischemia-reperfusion (IR) injury results in cell
      destruction, which may be mediated by the generation of reactive oxygen species,
      potentially toxic metabolites of xanthine oxidase. Pentoxifylline (PTX) possesses
      a variety of biochemical and antioxidant properties that can improve capillary
      flow and tissue oxygenation. Because of these combined effects, it has been
      hypothesized that pentoxifylline would protect against intestinal IR. METHODS:
      Young adult rats were randomly assigned to one of four experimental groups:
      IR/Placebo (n = 12) in which superior and inferior mesenteric arteries were
      clamped for 45 minutes and then reopened; IR/PTX (n = 11) in which IR was induced
      as in the Placebo group, but with 25 mg/kg PTX at 0, 30, and 60 minutes; No
      IR/Placebo (n = 12); and No IR/PTX (n = 6) in which placebo and PTX were applied
      with no IR. Blood and intestinal samples were taken for serial thiobarbituric
      acid-reducing substances (TBARS; index of lipid peroxidation), for xanthine
      oxidase-xanthine dehydrogenase ratios, glutathione, myeloperoxidase, and
      histopathology. RESULTS: Animals in the IR/PTX group had lower TBARS and the
      least severe histopathologic injury. Xanthine oxidasexanthine dehydrogenase
      ratios were elevated only in IR/ Placebo (0.67+/-0.22 vs. 0.45+/-0.14 in IR/PTX;
      0.42+/-0.22 in No IR/Placebo; and 0.40+/-0.11 in No IR/PTX; p = 0.0009). Reduced
      glutathione was diminished in IR/PTX animals (38.9 +/-1.35 vs. 46.1+/-7.0 in
      IR/Placebo; 41.1+/-2.5 in No IR/ Placebo; 43.6+/-1.0 in No IR/PTX; p = 0.048). No
      differences were recorded in myeloperoxidase levels among groups. CONCLUSIONS:
      Pentoxifylline ameliorates histopathologic signs of injury and decreases lipid
      peroxidation (TBARS). Normal xanthine oxidase-xanthine dehydrogenase ratios in
      the treated compared with IR-only animals imply that the protective effect of PTX
      is at least partially mediated through inhibition of xanthine oxidase.

PMID- 10400108
TI  - Immunological and nutritional composition of human milk in relation to
      prematurity and mother's parity during the first 2 weeks of lactation.
AB  - BACKGROUND: To investigate the effect of prematurity and parity on the dynamics
      of the major immunologic and nutritional proteins of human milk over the first 2
      weeks of lactation. METHODS: Microparticle-enhanced nephelometric immunoassays
      were developed for the quantification of alpha-lactalbumin, beta-casein, serum
      albumin, lactoferrin, and lysozyme in human milk. These components,
      immunoglobulin A, and total proteins were assayed in 368 individual samples
      collected from 74 mothers. RESULTS: The dynamics of the major immunologic and
      nutritional proteins in early lactation presented similar patterns in preterm and
      term human milks. In comparison with term milk, preterm milk was globally
      characterized by higher concentrations of immune proteins and lower
      concentrations of nutritive proteins. These differences were increased by the
      degree of prematurity, which, however, influenced the absolute and relative
      protein concentrations differently, depending on the stage of lactation. The
      protein composition of term milk was similar, whatever the mother's parity.
      Conversely, the influence of prematurity on the levels of milk proteins during
      the first days of lactation was even greater in primiparous mothers. CONCLUSIONS:
      This precise description of the composition of preterm and term milk, regarding
      the main nutritional and immunologic proteins, confirms the influence of both
      prematurity and parity on milk components and demonstrates the combined effect of
      these two conditions.

PMID- 10400109
TI  - Influence of jejunal morphology changes on exocrine pancreatic function in celiac
      disease.
AB  - BACKGROUND: Concurrent exocrine pancreatic dysfunction may be one of the factors
      implicated in malabsorption in untreated celiac disease, as shown by studies on
      bicarbonate and pancreatic enzyme secretion. The purpose of this study was to
      evaluate exocrine pancreatic function in relation to jejunal morphology in celiac
      disease. METHODS: Thirty-six patients fulfilling the ESPGHAN criteria for celiac
      disease, aged 3 to 18 years and 36 control subjects matched for age and sex were
      investigated. The design of the study included measurement of serum pancreatic
      isoamylase by a chromogenic method after selective inhibition of sialic
      isoamylase in the untreated phase in patients consuming a gluten-containing diet
      and after gluten elimination for a period of 1 year; fecal human elastase
      activity determined by enzyme-linked immunosorbent assay in patients consuming a
      gluten-free diet and again after gluten challenge for 6 months; correlation of
      serum pancreatic isoamylase and fecal elastase to the jejunal morphology,
      classified by criteria described by Marsch; the enzymes in the control group; and
      ultrasonography of the pancreas in both groups. RESULTS: Enzyme values obtained
      from celiac disease patients with normal mucosa were significantly higher than
      those obtained from patients with villous atrophy (p < 0.001) and comparable to
      those obtained from the control group. Serum pancreatic isoamylase activity
      increased to normal after gluten elimination, and human elastase activity
      decreased to values below 200 microg/g of stool after gluten challenge. Enzyme
      activity was related inversely to the degree of intestinal damage. The
      echogenicity of the pancreas was normal, regardless of enzyme activity or gut
      morphology. CONCLUSIONS: Exocrine pancreatic function is abnormal in celiac
      disease when mucosal atrophy is present. Exocrine pancreatic function parameters
      are associated with the changes of intestinal mucosal morphology in three
      consecutive phases of the disease.

PMID- 10400110
TI  - Clinical quiz. Hydatid disease.

PMID- 10400111
TI  - Cytomegalovirus enterocolitis in an immunocompetent infant host: another cause of
      treatable intractable diarrhea in infancy.

PMID- 10400112
TI  - Chronic inflammatory demyelinating polyradiculoneurophathy and Graves' disease in
      an adolescent with Crohn's disease.

PMID- 10400113
TI  - Neonatal pancreatitis associated with familial lipoprotein lipase deficiency.

PMID- 10400114
TI  - Appendicovesical fistula in a child with Crohn's disease: a unique case.

PMID- 10400115
TI  - Lack of transmission of hepatitis C virus in very close family contacts of
      patients undergoing multitransfusions for thalassemia.

PMID- 10400116
TI  - Bone marrow transplantation in Crohn's disease.

PMID- 10400117
TI  - New diagnosis and treatment of congenital hepatic fibrosis.

PMID- 10400118
TI  - Cystic fibrosis is a cause of apple peel syndrome.

PMID- 10400119
TI  - Celiac disease and Turner syndrome.

PMID- 10400120
TI  - Cystic fibrosis and congenital pancreatic insufficiency.

PMID- 10400121
TI  - Being labeled as gifted, self-appraisal, and psychological well-being: a life
      span developmental perspective.
AB  - This study examined the relation of being labeled as intellectually gifted to a
      midlife appraisal of having lived up to one's abilities and to psychological well
      being at age eighty. Participants in the study were 399 individuals in the Terman
      Study of the Gifted who were between the ages of seventy-five and eighty-four in
      1992. A proxy index of Terman Study membership was derived from participants'
      self-report during their mid-twenties of the age at which they first learned that
      they were members of the Terman Study. Learning at a younger age of membership in
      a study of intellectual giftedness was related to less likelihood of believing
      that one had lived up to one's intellectual abilities at midlife and to less
      favorable psychological well-being at age eighty. Results are discussed in terms
      of the possible implications of being labeled as gifted for the formation of
      unrealistic expectations about achievement.

PMID- 10400122
TI  - Continuity in the lives of elder catholic women religious.
AB  - Data from life review interviews with thirty-nine elder Catholic women religious
      (68-98) show these women's lives do not conform to a sequential pattern of late
      life developmental stages. Their lives can best be understood in terms of
      continuous themes throughout individual lives. The majority of the women reach
      ego integrity in young old age and continue to reestablish this by adhering to
      themes in their life stories. Themes serve as a framework of the self. The main
      themes of the participants are: faith, family, education, friends, community,
      caring for others, and prayer. Communal aspects of religious life support the
      women in their continuous development of identity. Generativity is evidenced in
      their lives as an ongoing component of self-identity. These data show the
      continuous process of establishing ego integrity throughout late life. The life
      review data can best be explained using the continuity theory of identity
      development.

PMID- 10400123
TI  - The impact of parental separation/divorce on grandparent-grandchild
      relationships.
AB  - Eighty-six members of the Grandparents' Federation in Britain returned
      questionnaires about changes in contact with their grandchildren following
      parental divorce; ten grandparents were also interviewed to obtain more
      contextual information and measures of health and coping strategies. Three
      questionnaire measures of the grandparent-grandchild relationship, proximity,
      contact frequency, and emotional involvement, were interrelated and a significant
      decrease was reported after parental divorce. There were no significant
      differences on these measures between grandparents all of whose grandchildren
      were affected by parental divorce, and grandparents for whom only some
      grandchildren were so affected; but the latter group did show a greater decline
      in emotional involvement and also had less recourse to legal action to sustain
      contact. With grandchildren affected by parental divorce, proximity to
      grandparents was not significantly less than for grandchildren not so affected,
      but contact and emotional involvement were significantly less. Many grandparents
      reported emotional and physical health problems related to the loss of contact.
      Results are discussed in terms of the extent to which grandparents are victims of
      the divorce situation, or agents involved in cross-generational family
      dysfunction; the victim model appears to get more support from our data.
      Recommendations are made for further research, as well as counseling to help move
      grandparents through the grief process and to a better quality of life.

PMID- 10400124
TI  - The grief experienced by spousal caregivers of dementia patients: the role of
      place of care of patient and gender of caregiver.
AB  - A comparison of the grief responses of spousal caregivers who cared for their
      demented partners at home with those who provided ongoing nursing home care,
      together with an examination of gender differences, is reported here. Four
      psychological states of grief were examined: anxiety, sadness, anger, and guilt.
      Sixty spousal caregivers participated in the study: thirty husbands and thirty
      wives, with equal numbers of home and nursing home caregivers. Content analysis
      scales were scored to assess the four psychological states. A self-rating,
      adjective mood scale was also used as a secondary measure of those states. A
      personal construct model of spousal caregivers' bereavement for their demented
      partners was developed and provided the two hypotheses about differences in
      grieving. As predicted, nursing home caregivers expressed significantly higher
      levels of sadness and guilt than home caregivers. Against prediction, home
      caregivers expressed significantly more anger than nursing home caregivers. Home
      caregiving wives were found to be the most angry cohort. Also, as predicted,
      caregiving wives expressed significantly higher levels of anxiety, sadness, and
      anger than caregiving husbands. The results of the content analysis scales were
      confirmed by the secondary measure, but the former measure proved more powerful
      for detecting statistically significant differences. The inclusion of severity of
      the patients' dementia, and the spiritually and age of the spousal caregivers as
      covariates in the statistical analyses showed place of care and gender of
      caregiver to remain the most powerful predictors of the four psychological states
      of grief.

PMID- 10400125
TI  - Formal and informal network factors as sources of morale in a senior center
      population.
AB  - This study examined the relative effects of senior center factors and social
      network attributes on the morale of a sample of senior center participants in
      Israel (N = 85), controlling for respondents' background characteristics. The
      multivariate model accounted for 56 percent of the variance in morale scores.
      Respondents' health was the primary explanatory factor, followed by selected
      attributes of participants' informal social networks. The formal network factors
      had a minor and partly negative effect. The findings suggest that participants'
      morale was shaped more by the configuration of their interpersonal social
      networks than by factors related to the senior center environment.

PMID- 10400126
TI  - Development of postural adjustments during reaching in preterm infants.
AB  - Preterm infants often show postural abnormalities, such as hyperextension of neck
      and trunk, which can interfere with motor and cognitive development. Little is,
      however, known on the pathophysiology of postural development in preterm infants.
      Therefore, we longitudinally studied the development of postural adjustments
      during reaching movements in 12 preterm infants between the (corrected) ages of 4
      and 18 mo. Five infants showed minor neurological dysfunctions at 18 mo, such as
      a mild diffuse hypotonia, a mild hypertonia of the legs, or a mild asymmetry in
      posture and motility, and seven infants were neurologically normal. Each
      assessment consisted of a simultaneous recording of video-data and surface
      electromyograms of arm, neck, trunk, and leg muscles during reaching in various
      lying and sitting positions. Comparable data on postural development in ten full
      term infants were available. The preterm infants showed an excessive amount of
      postural activity during reaching movements at all ages studied. Moreover, the
      postural adjustments were temporally disorganized and could not be modulated with
      respect to the velocity of the arm movement and the initial sitting position. We
      hypothesized that the preterms' disability to modulate their postural adjustments
      might be due to a reduced capacity to learn from prior experience. In our small
      group the postural dysfunctions were not related to the presence of
      hyperextension at early ages, to the neurological outcome at 18 mo, or to the
      lesions found on the neonatal brain ultrasound scans.

PMID- 10400127
TI  - Nitric oxide synthase inhibition and delayed cerebral injury after severe
      cerebral ischemia in fetal sheep.
AB  - After transient cerebral ischemia in fetal sheep, delayed disruptions in cerebral
      energetics are represented by a delayed increase in cortical impedance, a
      progressive decrease in the concentration of oxidized cytochrome oxidase as
      measured by near-infrared spectroscopy, and cortical seizures. Because the
      production of nitric oxide (NO), a potent mediator of neuronal death, is
      increased during this phase, the present study investigated whether inhibition of
      NO synthesis could ameliorate the delayed disruption in cerebral energetics.
      Eleven late gestation fetal sheep were subjected to 30 min of transient cerebral
      ischemia in utero. Two hours later, the treatment group (n = 5) received a
      continuous infusion of N(G)-nitro-L-arginine, a competitive inhibitor of NO
      synthase, whereas the control group (n = 6) received PBS. Changes in
      concentration of oxidized cytochrome oxidase, cortical impedance, and
      electrocortical activity were observed for 3 d. A delayed increase in cortical
      impedance of similar magnitude and duration commenced at 14+/-4 h in the control
      and at 15+/-3 h in the treatment groups. The progressive decrease in oxidized
      cytochrome oxidase signal, by -2.2+/-0.2 micromol/L in the control and -2.0+/-0.4
      micromol/L in the treatment group at 72 h postischemia, was similar in both
      groups. In both groups, delayed cortical seizures were indicated by intense low
      frequency electrocortical activity. In the treatment group, duration of cortical
      seizures was increased and the intensity of the final electrocortical activity
      was more depressed (-19+/-1 dB versus -10+/-2 dB). The results indicate that
      after cerebral ischemia in fetal sheep, NO synthase inhibition does not
      ameliorate the delayed disruptions in cerebral energetics. However, the effect of
      NO synthase inhibition on delayed cortical seizures may improve our understanding
      of the role of NO during this phase.

PMID- 10400128
TI  - The relationship between differentiation and proliferation in late gestation
      fetal rat hepatocytes.
AB  - Hepatocyte proliferation and differentiation occur simultaneously during late
      mammalian gestation. We hypothesized that regulation of hepatocyte growth and
      differentiation would be coordinated in late gestation fetal hepatocyte cultures
      such that proliferation would be most active in a population of less well
      differentiated cells. Cultured fetal hepatocytes (embryonic d 19 and 21; E19 and
      E21) were studied using double staining immunofluorescent microscopy.
      Differentiation was assessed as staining for alpha-fetoprotein (AFP), three
      markers of enzymic differentiation (glucokinase [GK], phosphoenolpyruvate
      carboxykinase [PEPCK], and carbamoyl phosphate synthase [CPS]), and a hepatocyte
      cell-cell adhesion molecule (C-CAM). Proliferation was assessed using
      immunocytochemical detection of proliferating cell nuclear antigen (PCNA) or 5
      bromo-2'-deoxy-uridine (BrdU) incorporation into DNA. Fetal hepatocyte cultures
      consisted of a heterogeneous population of cells, slightly more than half of
      which were proliferative under defined, growth factor-free conditions. These
      cultures were heterogeneous for AFP expression. There was no correlation between
      the expression of AFP and PCNA or AFP and S-phase entry (BrdU staining) during
      the first 48 h in culture. Similar results were obtained in staining for the
      enzymic differentiation markers and C-CAM. In addition, the differentiation
      status of cultured fetal hepatocytes was unrelated to a presumed indicator of
      mature growth regulation, mitogenic responsiveness to transforming growth factor
      alpha (TGFalpha), and hepatocyte growth factor (HGF). Finally, absence of any
      correlation between proliferation and differentiated phenotype was supported by
      in vivo studies using staining for PCNA, AFP, CPS, and PEPCK in liver sections.
      These results indicate that the developmental program governing differentiation
      of late gestation fetal rat hepatocytes is independent from mechanisms
      controlling proliferation.

PMID- 10400129
TI  - Mutations causing profound biotinidase deficiency in children ascertained by
      newborn screening in the United States occur at different frequencies than in
      symptomatic children.
AB  - Biotinidase deficiency is an autosomal recessive disorder of biotin metabolism
      that can lead to varying degrees of neurologic and cutaneous symptoms when
      untreated. Because this disorder meets the criteria for newborn screening, many
      states and countries perform this testing. Because newborn screening should
      result in complete ascertainment of mutations causing profound biotinidase
      deficiency (less than 10% of mean normal serum activity), we compared the
      mutations in a group of 59 children with profound biotinidase deficiency who were
      identified by newborn screening in the United States with 33 children ascertained
      by exhibiting symptoms. Of the 40 total mutations identified among the two
      populations, four mutations comprise 59% of the disease alleles studied. Two of
      these mutations occur in both populations, but in the symptomatic group at a
      significantly greater frequency. The other two common mutations occur only in the
      newborn screening group. Because two common mutations do not occur in the
      symptomatic population, it is possible that individuals with these mutations
      either develop mild or no symptoms if left untreated. However, inasmuch as biotin
      treatment is inexpensive and innocuous, it is still recommended that all children
      with profound biotinidase deficiency be treated.

PMID- 10400130
TI  - Thrombopoietin has a primary role in the regulation of platelet production in
      preterm babies.
AB  - Thrombocytopenia in the first days of life, in association with evidence of
      reduced megakaryocytopoiesis and platelet production at birth, is common in sick
      preterm babies. Thrombopoietin (Tpo) is the major regulator of platelet
      production in adults. However, these babies have low Tpo levels at birth,
      suggesting that the Tpo response to thrombocytopenia may be impaired. To test
      this hypothesis we 1) measured Tpo levels, 2) measured circulating megakaryocyte
      progenitors serially over the first 12 d of life in 13 preterm babies with early
      onset thrombocytopenia and in 14 control babies with evidence of normal
      megakaryocytopoiesis, and 3) measured Tpo levels in thrombocytopenic children (n
      = 13). In control babies, platelet counts and progenitor numbers remained normal
      and Tpo levels were consistently low-d 1:160+/-23 pg/mL (mean+/-SEM), d 4/5:
      154+/-18 pg/mL and d 12: 150+/-58 pg/mL. In thrombocytopenic babies, platelet
      counts and megakaryocyte progenitor numbers were significantly lower than
      controls at d 1: platelets 130+/-14 x 10(9)/L versus 255+/-20 x 10(9)/L (p <
      0.001) and megakaryocyte progenitors 552 versus 3907 colonies/mL (mean, p <
      0.001), and fell further to nadir on d 4/5: platelets 76+/-6 X 10(9)/L versus
      259+/-21 x 10(9)/L (p < 0.001) and MK progenitors 479 versus 2742 colonies/mL (p
      < 0.05). Tpo levels were only slightly raised on d 1:247+/-52 pg/mL (p = 0.24),
      but then rose sharply by d 4/5: 425+/-75 pg/mL (p < 0.001). By d 12, platelet
      count, megakaryocyte progenitors and Tpo level (145+/-29 pg/mL) had returned to
      control levels. Tpo levels at platelet nadir in thrombocytopenic babies were
      significantly lower than in thrombocytopenic children: mean 425 versus 1383 pg/mL
      (p < 0.001). These data show that Tpo is important in platelet homeostasis in
      preterm babies, with a close reciprocal relationship with platelet count and
      progenitor numbers during thrombocytopenia. However, the increase in Tpo levels
      seen in these babies was modest, despite significantly impaired
      megakaryocytopoiesis, and when compared with that seen in children with
      thrombocytopenia. This offers further evidence that preterm babies have an
      impaired Tpo response to thrombocytopenia and suggests that recombinant human Tpo
      may have a role in the prevention/treatment of preterm thrombocytopenia.

PMID- 10400131
TI  - Decreased autonomic responses to obstructive sleep events in future victims of
      sudden infant death syndrome.
AB  - To evaluate changes in autonomic nervous system controls in response to
      obstructive events in future victims of sudden infant death syndrome (SIDS), we
      studied the polysomnographic sleep recordings of 18 future SIDS infants and those
      of 36 matched control infants. A heart rate autoregressive power spectral
      analysis was performed preceding and after the obstructive apneas. The low
      frequency to high-frequency power ratio was computed to evaluate sympathovagal
      balance. Future SIDS victims had significantly more obstructive apneas (p =
      0.001) and mixed apneas (p = 0.005) than control infants. Obstructive events
      occurred mainly during rapid eye movement sleep in the two populations (84.5% in
      future SIDS victims and 95.8% in control infants; p = NS). Comparing heart rate
      power spectral analysis before and after obstructive apneas in rapid eye movement
      sleep, high-frequency power values were significantly lower and low-frequency to
      high-frequency power ratios higher in future SIDS victims than in control
      infants. Compared with preapnea values, low-frequency to high-frequency power
      ratios significantly decreased after obstructive apneas in control infants (p <
      0.001) but not in the future SIDS victims. When the obstructive apneas were
      divided according to duration, the findings were seen mainly for long apneas. In
      conclusion, future SIDS victims were characterized by different autonomic status
      and responses to obstructive apneas during sleep. These findings could be
      relevant to mechanisms implicated in some cases of SIDS.

PMID- 10400132
TI  - Impact of a single exercise bout on energy expenditure and spontaneous physical
      activity of obese boys.
AB  - The main objective of the present study was to determine whether a structured,
      laboratory-based exercise task would modify the energy expenditure (EE) and the
      pattern of spontaneous physical activity (PA) of obese boys on the day of an
      exercise laboratory visit and on the following day. Fourteen 10- to 15-y-old
      moderately obese (36.6+/-3.3% fat) boys volunteered. They each had three
      laboratory visits, I wk apart. In one visit, they performed a strenuous 50-min
      cycling task; in another, a 30-min medium-intensity cycling task; and in another
      (which served as placebo), they did not exercise. PA was monitored the day before
      (d 1), during (d 2), and after (d 3) each laboratory visit by use of a heart rate
      monitor and a 12-h recall interview. EE was calculated from minute-by-minute
      heart rate and each child's predetermined relationship between oxygen uptake and
      heart rate. EE and PA were analyzed from 1300 to 1900 h each day using 15-min
      intervals. EE tended to decrease (p < 0.087) in the afternoon of all d 2 compared
      with d 1, and it increased on d 3 after the medium-intensity exercise (p <
      0.0005). EE during d 2 and 3 combined, compared with d 1, decreased after the
      high-intensity exercise (534.2 versus 564.3 kJ/h, p < 0.05). It increased after
      the medium-intensity exercise (561.8 versus 526.7 kJ/h, p = 0.052) and was not
      affected after the placebo visit (589.4 versus 574.3 kJ/h). Time spent outdoors
      was consistently reduced on the day of laboratory visit compared with the day
      before and after the visit, regardless of the contents of intervention. In
      conclusion, a single laboratory visit is followed by a reduction in EE and PA on
      the day of intervention. However, its effect on EE the following day may be dose
      dependent: medium-intensity exercise induces an increase in EE, but high
      intensity exercise causes a decrease in EE. One implication is that intervention
      by physical training should employ medium-intensity exercise to enhance the EE of
      obese boys.

PMID- 10400133
TI  - Diagnosis of mitochondrial trifunctional protein deficiency in a blood spot from
      the newborn screening card by tandem mass spectrometry and DNA analysis.
AB  - Trifunctional protein (TFP) plays a significant role in the mitochondrial beta
      oxidation of long-chain fatty acids. Its deficiency impairs the energy generating
      function of this pathway and causes hypoketotic hypoglycemia once hepatic
      glycogen stores are depleted. A Reye-like syndrome, cardiomyopathy, and sudden
      death may follow. The diagnosis is based on demonstration of significantly
      decreased enzyme activity of at least two of the three involved enzymes in
      fibroblasts. The possibility of prospective diagnosis of TFP deficiency by
      newborn screening using tandem mass spectrometry (MS/MS) has not been evaluated.
      We report the postmortem diagnosis of a male newborn, who suffered sudden death
      at 2 wk of age, and his younger sister, who died of cardiomyopathy complicated by
      acute heart failure at the age of 6 mo, after she had acquired a common viral
      infection. Blood spots from the original newborn screening cards were the only
      remaining material from the patients. Analysis by MS/MS revealed acylcarnitine
      profiles consistent with either TFP or long-chain 3-hydroxyacyl coenzyme A
      dehydrogenase (LCHAD) deficiency. To prove the diagnosis, the alpha- and beta
      subunit genes coding for TFP were examined. The patients were compound
      heterozygous for a 4-bp-deletion and an a-->g missense mutation, both in the same
      exon 3 donor consensus splice site. This is the first report of the diagnosis of
      TFP deficiency using blood spots obtained for newborn screening and suggests that
      TFP deficiency may be detectable by prospective newborn screening using MS/MS.

PMID- 10400134
TI  - Cerebral blood volume measured using near-infrared spectroscopy and radiolabels
      in the immature lamb brain.
AB  - Near-infrared spectroscopy (NIRS) is a technique that is increasingly being used
      for the noninvasive measurement of cerebral blood volume (CBV) in newborn
      infants, but it has not been fully validated against established methods. These
      experiments in immature lambs (gestation 92+/-1 d, mean+/-SEM) compared CBV
      measured using NIRS-derived estimates of oxygenated Hb (n = 5) with CBV estimated
      with radiolabeled indicators (125I-labeled serum albumin and 51Cr-labeled red
      blood cells, n = 10). Total brain CBV (mL/100 g tissue) measured using NIRS was
      2.5+/-0.2 compared with 2.5+/-0.2 using radiolabels (NS). Regional tissue plasma,
      red blood cells, and whole blood volumes from radiolabels varied significantly (p
      < or = 0.05) throughout the brain. Whole blood volume (mL/100 g tissue) was
      largest in choroid plexus (16.2+/-2.1) and least in white matter (0.7+/-0.1) with
      a significant hierarchy evident among regions: choroid plexus > cerebellum >
      cortex > brain stem = midbrain > white matter. Regional plasma and red blood cell
      distributions were similar to whole blood, being highest in choroid plexus
      (13.0+/-1.6 and 3.2+/-0.9, respectively), and least in white matter (0.8+/-0.1
      and 0, respectively). These data from the immature lamb brain indicate that total
      CBV measured with NIRS is essentially identical with the volumes obtained using
      intravascular radiolabels. Among cerebral regions, white matter contributes
      little to the global blood volume measured with NIRS because its red blood cell
      content is very low.

PMID- 10400135
TI  - Quantitation of gene expression by real-time PCR disproves a "retroviral
      hypothesis" for childhood-onset diabetes mellitus.
AB  - Children with insulin-dependent diabetes mellitus (IDDM) suffer from a chronic
      autoimmune beta cell destruction of unknown origin, maybe due to superantigens or
      retroviral endogenous genes. Recently, a novel endogenous retrovirus designated
      as IDDMK 22 was proposed to encode for such a candidate autoimmune gene in type 1
      diabetes. We therefore analyzed the expression of IDDMK 22 genes in peripheral
      blood leukocytes and plasma from 55 healthy children and 55 diabetic children
      including 11 patients with acute disease onset. In our study we applied an
      improved quantitative and highly specific real-time PCR assay. In contrast to
      previous data obtained by conventional PCR. IDDMK 22 gene expression did not
      differ between diabetic and nondiabetic individuals. For this reason, we propose
      that IDDMK 22 is an ubiquitous endogenous retroviral element in the human genome
      but not a candidate autoimmune gene for IDDM, especially in childhood-onset
      disease. Real-time PCR proved to be a highly sensitive and specific method for
      detection and quantitation of very low amounts of mRNA and will thereby be useful
      regarding the special demands in pediatric studies dealing with very low amounts
      of specimen.

PMID- 10400136
TI  - Human pulmonary acinar aplasia: reduction of transforming growth factor-beta
      ligands and receptors.
AB  - Pulmonary hypoplasia has been found in the human neonatal autopsy population and
      has been attributed to an alteration in epithelial-mesenchymal interactions
      during development of the lung. Pulmonary acinar aplasia is a very rare and
      severe form of pulmonary hypoplasia. The transforming growth factor-betas (TGF
      beta) are multifunctional regulatory peptides that are secreted by a variety of
      normal and malignant cells and are expressed in developing organs including the
      lung; their tissue distribution patterns have possible significance for signaling
      roles in many epithelial-mesenchymal interactions. Here, we report our
      examination of TGF-beta in the lungs of a term female infant diagnosed with
      pulmonary acinar aplasia whose autopsy revealed extremely hypoplastic lungs with
      complete absence of alveolar ducts and alveoli. Immunohistochemical and in situ
      hybridization analyses were used to localize and measure the proteins and mRNA,
      respectively, for TGF-beta1, TGF-beta2, TGF-beta3, and TGF-beta type I and type
      II receptors (TGF-beta RI and RII) in formalin-fixed and paraffin-embedded
      sections of these hypoplastic lungs and normal lungs. Immunostaining for TGF
      beta1, TGF-beta2, and TGF-beta RI and RII was significantly lower in the
      bronchial epithelium and muscle of the hypoplastic lungs than in normal lungs,
      whereas no difference was detected in staining for other proteins including Clara
      cell 10-kD protein, adrenomedullin, hepatocyte growth factor/scatter factor, and
      hepatocyte growth factor receptor/Met in the hypoplastic and normal lungs or in
      the liver and kidneys of this infant compared with normal liver and kidney. In
      addition, in situ hybridization showed that TGF-beta1 and TGF-beta RI transcripts
      were considerably reduced in the bronchial epithelium of the hypoplastic lung
      compared with normal lung. These results show that there is a selective reduction
      of TGF-beta in pulmonary acinar aplasia and suggest that the signaling action of
      TGF-beta in epithelial-mesenchymal interactions in the lungs of this
      developmental condition may be compromised.

PMID- 10400137
TI  - Serum leptin levels in patients with progressive central precocious puberty.
AB  - Leptin is a metabolic signal that may be involved in signaling adequacy of energy
      metabolism for the onset of reproductive function. The aim of this study was to
      investigate the relationship between leptin serum levels and pubertal development
      in girls with progressive central precocious puberty (CPP). We investigated
      longitudinally 14 girls with CPP before and during treatment with depot
      leuprorelin acetate. Mean (+/-SEM) chronological age and bone age at start of
      therapy were 6.0+/-0.6 y and 9.5+/-0.7 y, respectively. Leptin was determined by
      RIA. Girls with CPP showed no significant difference in leptin levels at
      pretreatment and after 1 and 2 y of treatment compared with healthy girls of the
      same body mass index (BMI). Mean leptin SD score adjusted for BMI was 0.31+/-0.4,
      0.24+/-0.2, and 0.49+/-0.3, respectively (not significant). In a stepwise
      regression analysis model with BMI, bone age, chronological age, basal and
      stimulated LH, estradiol, dehydroepiandrosterone, androstenedione, and clinical
      pubertal signs, BMI was the only parameter that showed a significant correlation
      with leptin (p = 0.006). In conclusion, these data suggest that serum leptin
      levels are not significantly elevated at the onset of CPP compared with normal
      girls. Treatment with depot gonadotropin releasing hormone agonist seems to have
      no influence on leptin concentrations. As in normal girls, serum leptin levels in
      girls with CPP are mainly determined by BMI. Thus, we have no evidence that
      alterations of leptin are related to premature onset of puberty.

PMID- 10400138
TI  - Limited proteolysis of the IGF binding protein-2 (IGFBP-2) by a specific serine
      protease activity in early breast milk.
AB  - IGF in milk possibly promote maturation of the gastrointestinal tract in
      newborns. We studied the composition of milk samples derived from 99 healthy
      women at regular intervals during a period beginning 3 d and ending 6 mo after
      birth. The concentrations measured by RIA on d 3 were 10.7+/-0.4 ng/mL for IGF
      II, 1.9+/-0.1 ng/mL for IGF-I, 100+/-5 ng/mL for IGF binding protein-3 (IGFBP-3),
      and 2163+/-108 ng/mL for IGFBP-2. All factor concentrations decreased by up to
      70% in the course of the 6 mo. The most striking finding was an IGFBP-2-specific
      protease activity. Protease assays performed by incubation of 125I-IGFBP-2 with
      milk yielded fragments of 14, 16, 23, and 25 kD. 125I-IGFBP-3 was not cleaved.
      Proteolysis occurred only in milk from mothers until 4 wk postpartum and could be
      visualized by immunoblots. Since the affinity of the fragments to 125I-IGF-II was
      low, they were not demonstrable by ligand blot. Inhibitor studies and pH
      optimizing classified the IGFBP-2 protease as an Me2(+)-dependent serine protease
      with a pH optimum of 7 to 8. The proteolytic activity of further milk proteins,
      known as IGFBP proteases, was analyzed. Epidermal growth factor receptor peptide
      and prostate-specific antigen did not cleave IGFBP-2, although the protease
      activity correlated (r = 0.84, p < 0.00003) with the prostate-specific antigen
      concentration in milk. The y-nerve growth factor cleaved 125I-IGFBP-2, but in a
      completely different manner than the milk protease. In conclusion, the IGFBP-2
      protease in milk is most probably a kallikrein. The specific proteolysis of
      IGF/IGFBP-2 complexes may increase the biologic availability of IGF in early
      milk. This mechanism may promote growth of the maternal breast epithelium and
      maturation of the gastrointestinal tract of newborns.

PMID- 10400139
TI  - Chemokine receptor CCR2 and CCR5 polymorphisms in children with insulin-dependent
      diabetes mellitus.
AB  - Studies have shown the important roles of several regulatory and proinflammatory
      cytokines in insulin-dependent diabetes mellitus (IDDM). CC-chemokine receptors
      CCR2 and CCR5 bind chemokines that are involved in the trafficking of leukocytes
      in both basal and inflammatory states. A common 32-bp deletion mutation in the
      CCR5 gene (CCR5delta32) and a G-to-A nucleotide substitution in the CCR2 at
      position 190 (CCR2-64I) have recently been described. In the present study, we
      have determined the frequency of the CCR5delta32 and CCR2-64I alleles in children
      with IDDM [n = 115; age 1-14 (9.3+/-4.3) y] and in nondiabetic subjects [n = 280;
      age 1-14 (8.5+/-4.5) y]. The CCR5delta32 allele frequencies were 0.117 in
      children with IDDM and 0.111 in nondiabetic subjects, indicating that the
      deletion allele has no association with IDDM. The CCR2-64I allele frequency in
      children with IDDM was 0.226, which differed significantly from the allele
      frequency in controls (0.114, p = 0.001). The role of this mutation in IDDM
      cannot be explained yet, but, because CCR2 mediates the chemotaxis of CD4+ and
      CD8+ T cells to areas of inflammation and because these cells play important
      roles in insulitis, a mutation in the CCR2 gene may contribute to the
      susceptibility to the disease. Alternatively, the 64I allele could be a marker of
      a linked mutation through linkage disequilibrium. According to these results, the
      CCR2 gene may be a new candidate for the susceptibility locus of IDDM. However,
      because no IDDM locus has been identified near 3p21 until now, further
      investigations are needed to confirm this statement.

PMID- 10400140
TI  - Multiple mechanisms of lung surfactant inhibition.
AB  - We studied the mechanisms by which C16:0 lysophosphatidylcholine (LPC) and
      albumin inhibit the surface activity of calf lung surfactant extract (CLSE) by
      using a pulsating bubble apparatus with a specialized hypophase exchange system,
      plus adsorption and Wilhelmy balance measurements. In the absence of inhibitors,
      CLSE (1 mg phospholipid/mL) reached minimum surface tension (gamma(min)) < 1 mN/m
      within 5 min of bubble pulsation at 20 cycles/min at 37 degrees C. Mixtures of
      CLSE:LPC had impaired surface activity depending on LPC content: gamma(min) was
      raised to 5 mN/m by 14 wt % LPC, to 15 mN/m by 25-30 wt% LPC, and to >20 mN/m (67
      wt % LPC), even at high CLSE concentrations (3 and 6 mg phospholipid/mL). In
      contrast, inhibition of CLSE by albumin was more easily abolished when surfactant
      concentration was raised. Mixtures of albumin (3 mg/mL) and CLSE (1 mg
      phospholipid/mL) had gamma(min) >20 mN/m, but normal values of gamma(min) < 1
      mN/m were reached at higher CLSE concentration (3 mg phospholipid/mL) even when
      albumin concentration was increased 8-fold to 24 mg/mL. In hypophase exchange
      studies, LPC, but not albumin, was able to penetrate preformed CLSE surface films
      and raise gamma(min) CLSE surface films with gamma(min) < 1 mN/m were isolated by
      an initial hypophase exchange with saline, and a second exchange with an LPC
      containing hypophase raised gamma(min) to approximately 10 mN/m. CLSE surface
      films retained the ability to reach gamma(min) < 1 mN/m in analogous hypophase
      exchange studies with albumin. The ability of LPC to penetrate surface films of
      CLSE, although albumin could not, was also demonstrated in adsorption experiments
      in a Teflon dish, where diffusion was minimized by subphase stirring. Wilhelmy
      balance experiments also demonstrated that LPC could mix and interact with CLSE
      or dipalmitoyl phosphatidylcholine in solvent-spread surface films. The ability
      of LPC or other cell membrane lipids to penetrate interfacial films and raise
      gamma(min) even at high surfactant concentration may increase their inhibitory
      actions during acute lung injury.

PMID- 10400141
TI  - Dexamethasone reduces oxygen induced retinopathy in a mouse model.
AB  - Dexamethasone is widely used in the postnatal period. Its impact on retinopathy
      of prematurity (ROP) is extremely controversial; published studies have found a
      detrimental, protective, or no effect on ROP. The goal of this study was to test
      the hypothesis that use of dexamethasone during the injury phase (oxygen
      exposure) reduces the severity of oxygen-induced retinopathy (OIR) in a mouse
      model. C57BL6 mice pups were exposed to either room air or hyperoxia (75% FiO2)
      from postnatal d 7 through 12 (PN7-12) with or without dexamethasone (0.5 mg/kg/d
      s.c.) and killed on PN17-21. Retinopathy was assessed by a scoring system of
      retinal flat mount preparations and periodic acid-Schiff (PAS) staining of
      retinal sections. Pups exposed to dexamethasone and oxygen had a lower median
      retinopathy score of 5 (4, 6) [median (25th, 75th quartile)] compared with
      animals exposed to oxygen alone with median score of 9 (6, 10) with p < 0.001.
      PAS staining for extra retinal neovascularization in the dexamethasone and oxygen
      treated animals showed a significant reduction in number of nuclei extending
      beyond the inner limiting membrane when compared with oxygen exposed alone (p =
      0.04). Animals treated with dexamethasone had decreased weight gain compared with
      control animals. Dexamethasone did not appear to affect the normal development of
      retinal vasculature as assessed by the scoring system when compared with control
      animals. Thus, dexamethasone decreases severity of OIR without having an adverse
      effect on normal retinal vascular development in the mouse model. We speculate
      that dexamethasone decreases the injury response that occurs during the hyperoxic
      phase, thus protecting the developing vasculature and improving the subsequent
      retinopathy.

PMID- 10400142
TI  - IGF-I, IGF-II, IGF binding protein 1, and C-peptide in second trimester amniotic
      fluid are dependent on gestational age but do not predict weight at birth.
AB  - Previous data suggested that small for gestational age newborns have increased
      levels of IGF binding protein 1 (IGFBPI) in amniotic fluid (AF) at 15-16 wk of
      pregnancy. In this study, we developed an RIA for IGFBP1 and measured IGFBP1
      concentrations in 209 AF samples with normal fetal karyotype between 14 and 20
      wk; we measured IGF-I, IGF-II, and C-peptide in the same samples. Concentrations
      of these growth-modulating factors were all positively correlated with
      gestational age at sampling (p < 0.0001). After correcting for gestational age,
      AF IGFBP1 remained strongly correlated with IGF-I and IGF-II (both p < 0.0001);
      their concentrations were many times higher in AF than in cord serum during the
      third trimester. None of the growth-modulating factors in AF correlated with
      birth weight, after correction for gestational age; birth weight percentile
      distribution was comparable in two groups of newborns who had AF values of IGF-I,
      IGF-II, IGFBP1, or C-peptide that were either less than or equal to the 50th
      percentile or more than the 50th percentile at sampling. However, placenta weight
      and the placenta weight to birth weight percentage were negatively correlated
      with AF IGF-I, IGF-II, and IGFBP1; placenta weight to birth weight percentage was
      lower in pregnancies with IGFBP1 values more than the 50th percentile compared
      with those less than or equal to the 50th percentile at sampling. In conclusion,
      AF concentrations of IGFBP 1 increase gradually between 14 and 20 wk gestational
      age and correlate with IGF-I and IGF-II levels; high IGFBP1 levels do not predict
      small for gestational age newborns, but are associated with lower placenta
      weight.

PMID- 10400143
TI  - Energy expenditure and energy intake during dexamethasone therapy for chronic
      lung disease.
AB  - Dexamethasone is commonly administered to ventilator-dependent preterm infants
      with chronic lung disease. Infants receiving dexamethasone therapy frequently
      exhibit decreased rates of weight gain. The purpose of this investigation was to
      determine whether decreased growth in infants receiving dexamethasone therapy is
      caused by increased energy expenditure. Twelve infants were studied: 6 received
      dexamethasone treatment at 2 wk of age and crossed over to receive placebo
      treatment at 4 wk; the treatment order was reversed in the other 6 infants. The
      doubly labeled water method was used to determine energy expenditure for a 1-wk
      period during each treatment phase. The rate of weight gain during dexamethasone
      treatment was 6.5+/-10.6 and 20.0+/-5.7 g/kg/d during placebo treatment. Energy
      expenditure was 93.1+/-34.6 kcal/kg/d during dexamethasone treatment and 88.3+/
      37.1 kcal/kg/d during placebo treatment. Energy intake was 119.2+/-29.0 kcal/kg/d
      during dexamethasone treatment and 113.8+/-23.7 kcal/kg/d during placebo
      treatment. The difference between intake and expenditure, or the energy available
      for growth, was 26.2+/-36.8 kcal/kg/d during dexamethasone treatment and 25.5+/
      37.4 kcal/kg/d during placebo treatment. No significant differences were found in
      energy expenditure or energy intake between the treatment phases. The reduced
      growth seen in infants receiving dexamethasone treatment cannot be explained by
      increased energy expenditure or decreased energy intake, but may be due to
      differences in the composition of newly accreted tissue.

PMID- 10400144
TI  - Steady state maternal-fetal leucine enrichments in normal and intrauterine growth
      restricted pregnancies.
AB  - The aim of this study was to compare the fetal/maternal (F/M) leucine-enrichment
      ratio in normal (AGA) and intrauterine growth-restricted (IUGR) pregnancies at
      the time of fetal blood sampling (FBS). A maternal primed-constant infusion of L
      [1-13C]-leucine was given in six AGA and 14 IUGR pregnancies, divided into three
      groups according to the pulsatility index (PI) of the umbilical artery and to
      fetal heart rate (FHR): group 1 (normal FHR and PI, four cases); group 2 (normal
      FHR and abnormal PI, five cases); and group 3 (abnormal FHR and PI, five cases).
      Maternal arterialized samples were taken at time zero and every 20 min for 125+/
      7 min. Umbilical venous samples were obtained after 114+/-42 min of infusion.
      Under steady state conditions, there was a significant linear relationship
      between maternal leucine disposal rate and maternal leucine concentration. The
      comparison of fetal to maternal leucine enrichment showed a progressive dilution
      of the fetal enrichment relative to the mother between AGA and IUGR of group 1
      (0.89 versus 0.78, p < 0.02), group 2 (0.71, p < 0.001), and group 3 (0.62, p <
      0.001), and also among the three IUGR groups. The F/M leucine molar percent
      enrichment (MPE) ratio showed a positive correlation with the umbilical venous
      oxygen content and an inverse correlation with fetal lactate concentration. We
      conclude that the dilution in the fetal/maternal leucine-enrichment ratio
      correlates with the severity of growth restriction and reflects decreased
      transplacental leucine flux and/or increased protein breakdown within the
      fetoplacental compartments.

PMID- 10400145
TI  - Repeated acute hypoxia temporarily attenuates the ventilatory respiratory
      response to hypoxia in conscious newborn rats.
AB  - We asked whether repeated hypoxic exposures during the early neonatal periods
      could affect the ventilatory control, such as the lung volume-dependent
      ventilatory inhibition (HBR), pulmonary ventilation (VE), and CO2 production
      (VCO2). Within each litter of rats, one group of pups (experimental group H) was
      exposed to 6% O2 (30-min duration twice a day from postnatal d 1 to 4). The other
      group (control group C) was exposed to air. At 5 d after birth, the HBR was
      triggered by lung inflation via negative body surface pressure (10 cm H2O).
      Measurements of VE and VCO2 were done by plethysmography and the inflow-outflow
      CO2 difference, respectively. At 2 wk of age, VE and VCO2 measurements were
      repeated by the barometric technique and the inflow-outflow CO2 difference,
      respectively. Each conscious pup was breathing normoxia (21% O2) and then hypoxia
      (10% O2). Results were as follows: 1) during normoxia, HBR was stronger and both
      VE and VCO2 were higher in H pups than in C pups; 2) during hypoxia, the HBR of C
      was as in normoxia, whereas that of H was increased above the normoxic value; 3)
      during hypoxia, C maintained VE, whereas H decreased it; 4) in hypoxia, VCO2 was
      reduced significantly in both groups; 5) at 2 wk of age, VE and VCO2 did not
      differ between H and C during normoxia or in response to 10% hypoxia. We conclude
      that in rat pups, repeated hypoxic episodes can modify the HBR and, at least
      temporarily, reduce the VE response to hypoxia with a decrease in VCO2. The
      findings are in agreement with the view that repeated hypoxic exposures in the
      neonatal period could interfere with the development of respiratory control and
      could possibly be involved in the mechanisms of neonatal apnea or sudden infant
      death syndrome.

PMID- 10400147
TI  - On controllable dose.

PMID- 10400146
TI  - Quantitative echocardiographic characterization of abdominal aortic pulsatility
      in children with coarctation.
AB  - Obstructed blood flow due to aortic coarctation leads to a pressure drop and loss
      of the pulse wave distal to the stenosis. This can be observed by
      echocardiography as typically decreased pulsatility of the abdominal aorta after
      cardiac systole. Our study intended to quantitatively describe abnormal abdominal
      aortic pulsatility in children with coarctation. A standardized M-mode
      echocardiographic study of the abdominal aorta was prospectively performed with
      measurements of minimum and maximum abdominal aortic diameters and the
      corresponding time intervals during the cardiac cycle. Of these measurements the
      percent increase in aortic diameter was calculated and this increase was indexed
      to a unit of time. A total of 50 children were studied: 27 had angiographically
      proven severe coarctation (19 unoperated and 8 operated children with recurrent
      coarctation) with a mean minimum aortic lumen of 32+/-6% of the prestenotic
      aortic lumen. A total of 23 healthy children were studied as a control group.
      Children with significant coarctation differed from normals in all parameters
      evaluated. Two calculated values, the percent increase in aortic diameter (5-25%
      in patients and 27-50% in normals) and the percent increase per unit of time (18
      108%/s in patients and 154-288%/s in normals) allowed for a clear discrimination
      between patients and normals with no overlap of individual values. Quantitative
      characterization of abnormal pulsatility of the abdominal aorta due to the loss
      of pulse wave pressure clearly discriminated children with angiographically
      proven significant coarctation from normal controls.

PMID- 10400148
TI  - Neutron RBE values and their relationship to judgements in radiological
      protection.
AB  - This review traces the history of radiological protection judgements concerning
      the relative biological effectiveness (RBE) for neutrons and quality factor. The
      basis of the different views coming from the International Commission on
      Radiological Protection (ICRP) and the International Commission on Radiation
      Units and Measurements (ICRU) is explained. A review of present-day information
      on neutron RBE relevant to judgements for radiological protection purposes is
      presented. It is argued that variations in neutron RBE measurements are large so
      that for practical purposes pragmatic judgements need to be made. It is further
      suggested that no inconsistency arises if different judgements are made for
      different purposes. However, this would require some resolution of the
      contrasting views of ICRP and ICRU.

PMID- 10400149
TI  - Control of low-level radiation exposure: time for a change?
AB  - The carcinogenic risks of exposure to low-level ionising radiation used by the
      ICRP have been challenged as being, at the same time, both too high and too low.
      This paper explains that the epidemiological evidence will always be limited at
      low doses, so that understanding the cellular mechanisms of carcinogenesis is
      increasingly important to assess the biological risks. An analysis is then given
      of the reasons why the challenges to the ICRP, especially about the linear non
      threshold response model, have arisen. As a result of considering the issues, the
      Main Commission of the ICRP is now proposing a revised, simpler, approach based
      on the concept of what is being called 'controllable dose'. This is an individual
      based philosophy and represents a shift in emphasis by the Commission from
      societal-oriented criteria using Collective Dose. Finally the paper speculates on
      the consequences for radiological protection of such a change in policy. The
      Commission wishes its ideas to be discussed as part of its reconsideration of its
      recommendations.

PMID- 10400150
TI  - A system for radiological protection of the environment: some initial thoughts
      and ideas.
AB  - Radiological protection has always been based on protection of man. Protection of
      the environment is often assumed to be implicit in the application of
      radiological protection generally, but this assumption is increasingly being
      challenged. It is therefore time to consider the feasibility of developing a
      complementary system for protecting the environment itself from ionising
      radiation, which would be both explicit and applicable to a wide range of
      situations. This paper outlines a possible approach using reference dose models
      and different types of dose effects.

PMID- 10400151
TI  - Dose estimate of exposure to radioisotopes in molecular and cellular biology.
AB  - A method for prospectively evaluating the annual equivalent doses and effective
      dose to biomedical researchers working with unsealed radioisotopes, and their
      classification, is presented here. Simplified formulae relate occupational data
      to a reasonable overestimate of the annual effective dose, and the equivalent
      doses to the hands and to the skin. The procedure, up to the classification of
      personnel and laboratories, can be made fully automatic, using a common
      spreadsheet on a personal computer. The method is based on occupational data,
      accounting for the amounts of each radioisotope used by a researcher, the time of
      exposure and the overall amounts employed in the laboratories where experiments
      are performed. The former data serve to forecast a contribution to the dose
      arising from a researcher's own work, the latter to a forecast of an
      'environmental' contribution deriving simply from the presence in a laboratory
      where other people are working with radioisotopes. The estimates of the doses due
      to one's own radioisotope handling and to 'environment' were corrected for
      accidental exposure, considered as a linear function of the manipulated activity
      or of the time spent in the laboratories respectively, and summed up to give the
      effective dose. The effective dose associated with some common experiments in
      molecular and cellular biology is pre-evaluated by this method.

PMID- 10400152
TI  - A gamma camera for measurements of internal contamination after a radiological
      accident.
AB  - After a radiological accident with the release of large amounts of radionuclides
      into the environment, measurements of the external and internal exposure of the
      public will be urgently required. The aim of this study was to investigate the
      properties of a gamma camera with regard to measurements of internal
      contamination. The gamma camera was used as a detector without any imaging
      function. The lowest minimum detectable activity, 100 Bq 131I in thyroid measured
      over the neck and 400 Bq 137Cs in the whole body measured over the trunk (1 min
      measuring time), was found when using the lowest (50 keV-450 keV) energy interval
      among the three investigated (also 550-750 keV and 450-550 keV), in measurements
      without a collimator. The mechanical difficulties in handling a gamma camera
      without a collimator may also have to be considered. It is essential to pay
      attention to the influence of body size on both background and sensitivity.
      Provided proper calibrations are carried out and routines for measurements are
      established, a gamma camera is useful for fast identification and quantification
      of internal contamination with gamma-emitting radionuclides down to levels so low
      that in most situations they give a low contribution to the effective dose.

PMID- 10400153
TI  - Management of radiological safety--lessons learnt and issues arising from the
      decommissioning of Berkeley power station.
AB  - Berkeley Power Station was a world leader when in June 1962 it became the UK's
      first commercial nuclear power station to produce electricity for the National
      Grid. Berkeley then stood at the leading edge of nuclear technology. After 27
      years of successful operation and the supply of nearly 40 billion units of
      electricity, Berkeley ceased generation in March 1989. Just as it was at start
      up, Berkeley is continuing to lead the way as the UK's first commercial nuclear
      power station to be decommissioned. A three-stage decommissioning process is
      under way to safely dismantle the plant and eventually return the site to its
      original 'green field' state. Stage 1 of this process is well advanced. To set
      the scene, and for general interest, this paper first provides some background to
      the development of the decommissioning strategy and a brief summary of the
      progress to date. Recognising the specific interest of the reader, the paper then
      focuses on the radiological aspects of the work carried out, specifically the
      hazards, the risk assessment process and the ALARP performance. Finally, and in
      some detail, the paper reports on the important lessons learnt and discusses one
      of the issues arising.

PMID- 10400154
TI  - Caffeine protects mice against whole-body lethal dose of gamma-irradiation.
AB  - Administration of caffeine (1,3,7-trimethylxanthine), a major component of
      coffee, to Swiss mice at doses of 80 or 100 mg/kg body weight 60 min prior to
      whole-body lethal dose of gamma-irradiation (7.5 Gy) resulted in the survival of
      70 and 63% of animals, respectively, at the above doses in contrast to absolutely
      no survivors (LD-100/25 days) in the group exposed to radiation alone. Pre
      treatment with a lower concentration of caffeine (50 mg/kg) did not confer any
      radioprotection. The protection exerted by caffeine (80 mg/kg), however, was
      reduced from 70 to 50% if administered 30 min prior to irradiation. The trend
      statistics reveal that a dose of 80 mg/kg administered 60 min before whole-body
      exposure to 7.5 Gy is optimal for maximal radioprotection. However, caffeine (80
      mg/kg) administered within 3 min after irradiation offered no protection. While
      there is documentation in the literature that caffeine is an antioxidant and
      radioprotector against the oxic pathway of radiation damage in a wide range of
      cells and organisms, this is the first report demonstrating unequivocally its
      potent radioprotective action in terms of survival of lethally whole-body
      irradiated mice.

PMID- 10400155
TI  - Transformation of C3H 10T(1/2) cells by low doses of ionising radiation.

PMID- 10400156
TI  - First EC/ISOE Workshop on Occupational Exposure Management at Nuclear Power
      Plants, Malmo, 16-18 September 1998.

PMID- 10400157
TI  - SRP meeting: Radiological effects on the environment--measurable? Important?
      London, 20 January 1999.

PMID- 10400158
TI  - SRP meeting: External radiation dosimetry in practice, London, 25 March 1999.

PMID- 10400159
TI  - Seminar on revision of arrangements under the Radioactive Substances Act, London,
      26 March 1999.

PMID- 10400160
TI  - Carvastatin suppresses intimal thickening of rabbit carotid artery after balloon
      catheter injury probably through the inhibition of vascular smooth muscle cell
      proliferation and migration.
AB  - In order to test whether a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
      reductase inhibitor has an anti-atherogenic activity, the effects of carvastatin,
      a newly developed potent inhibitor, and pravastatin were examined on the intimal
      thickening of the artery after the endothelial denudation induced by balloon
      catheter injury. Rabbits were divided into four groups; control, pravastatin
      treated (20 mg kg(-1) day(-1)) and two of carvastatin-treated groups (10 or 20 mg
      kg(-1) day(-1)). Two weeks after balloon catheter injury, the areas of intima and
      media of the injured carotid arteries were determined, and the ratios of intima
      to media (I/M) were calculated as an index of intimal thickening. Average I/M
      ratios of the injured artery were 0.42+/-0.05 for control, 0.49+/-0.07 for
      pravastatin, 0.19+/-0.03 (10 mg kg(-1) day(-1)) and 0.20+/-0.04 (20 mg kg(-1)
      day(-1)) for carvastatin-treated rabbits, respectively. Thus, carvastatin reduced
      I/M ratio of the injured artery to approximately half versus control, but
      pravastatin failed to suppress the intimal thickening. For in vitro study,
      vascular smooth muscle cells (SMC) from rabbit aorta were explanted, then
      cultured, and the effects of carvastatin on SMC migration and SMC proliferation
      were also examined. Carvastatin inhibited dose-dependently SMC migration and SMC
      proliferation with IC50 values of 0.5 microM and 1 microM, respectively. These
      inhibitory effects of carvastatin were cancelled by the coexistence of
      mevalonate, a metabolite of cholesterol synthesis. Our results suggest that
      carvastatin may be useful in rabbits as an anti-atherogenic drug by means of the
      inhibition of SMC migaration or SMC proliferation.

PMID- 10400161
TI  - Comparison of three methods of microsatellite detection.
AB  - Examination of microsatellites is frequent in the diagnosis of cancer.
      Microsatellites are repeat DNA sequences scattered throughout the human genome.
      These repeat regions are very frequent and highly polymorphic elements. In this
      study we focus on dinucleotide repeats. We compared three different methods for
      the detection of microsatellites: use of the ABI Prism 377 fluorescence
      sequencer, autoradiography and silver-stained gels. DNA was extracted from
      various clinical samples and amplified by different polymerase chain reaction
      (PCR) protocols. DNA from normal and tumor tissues was analysed using each
      method. The fluorescence method was more sensitive than the two other methods;
      however, this technology is very expensive. It seems possible, when examining
      microsatellites on a low budget, to avoid radioactivity by using silver-stained
      gels as an alternative. In conclusion, we observed identical results when
      comparing autoradiography with the fluorescence technique. However, we observed
      variability in the results when interpreting a single locus comparing silver
      staining with autoradiography and the fluorescence technique. Classification of
      the tumors based on several microsatellite loci was always identical.

PMID- 10400162
TI  - Lipoprotein(a), apolipoprotein A-I and B serum levels in young families from
      Tallinn, Estonia. Relationships with other cardiovascular risk factors and
      nationality.
AB  - Serum lipid, lipoprotein(a) (Lp(a)), apolipoprotein (apo) A-I and B
      concentrations were studied in young families of Tallinn: 157 husbands, 81 wives
      and 149 newborns participated in the study; 48% of subjects were Estonians, 39%
      Russians and 13% other nationalities. As previous studies among middle-aged men
      and school children of Estonia revealed clear national differences in serum
      lipoprotein profiles, our special interest was to study lipoprotein parameters in
      relation to ethnic origin. Body mass index (BMI), blood pressure (BP) and smoking
      habits were determined. In newborns, maturity by physical and neurological
      criteria and Apgar score after birth were assessed. At the age of 18-30 years,
      Estonian men had significantly higher serum total cholesterol, LDL cholesterol,
      triglyceride and Lp(a) levels than did Russian men. Estonian newborns had higher
      serum triglyceride concentration than Russian ones. Among women no national
      differences were recorded in the measured parameters. Lp(a) levels were not
      statistically correlated with age, BMI, BP or current smoking. Negative
      associations were revealed between Lp(a) and serum level of apo A-I (in men) or
      triglycerides (in newborns). Lp(a) concentrations correlated positively with LDL
      cholesterol (in women) and apo B (in newborns). Lp(a) levels of newborns were not
      associated with birthweight or health status, but correlated strongly with the
      sum of parental and fathers' Lp(a) concentrations, demonstrating that a genetic
      factor(s) is involved in the values of plasma Lp(a) levels.

PMID- 10400163
TI  - Adsorption of EGF receptor ligands to test tubes--a factor with implications for
      studies on the potency of these peptides.
AB  - Studies on the relative potency of ligands for the epidermal growth factor
      receptor are usually performed with highly purified ligand specimens. However,
      adsorption of ligands to glass and plastic surfaces may affect the results by
      reducing the ligand concentration in an unpredictable way. The aim of this study
      was to examine the adsorption of four epidermal growth factor (EGF) receptor
      ligands, EGF, transforming growth factor alpha (TGF-alpha), heparin binding-EGF
      (HB-EGF) and betacellulin, to commonly used test tubes of polyethylene,
      polystyrene and glass, respectively. The ligands were kept in a sodium phosphate
      buffer, both with and without 0.1% human albumin as carrier protein. Adsorption
      was examined after 20 minutes at room temperature as well as after overnight
      storage at 4 degrees C. The ligands were quantitated by ELISAs. In the buffer not
      containing 0.1% human albumin there was a marked adsorption, which differed both
      among the ligands and among the test tubes. After 20 minutes the ligand
      concentrations were reduced to 33-73% in polyethylene tubes, to 15-46% in
      polystyrene tubes and to 12-29% in glass tubes. The adsorption was even more
      pronounced after storage overnight. The use of 0.1% human albumin in the buffer
      solved the problem in polyethylene and polystyrene tubes, but not in glass tubes.
      The results demonstrate that adsorption to surfaces can be a significant problem
      for EGF receptor ligands and emphasize the need for controlling the growth factor
      concentration in the final experimental setting.

PMID- 10400164
TI  - Impaired endothelium-dependent relaxation in mesenteric arteries of reduced renal
      mass hypertensive rats.
AB  - Endothelium-dependent relaxation is not fully understood in volume-dependent
      models of hypertension. This study investigated the relaxation mediated by
      endothelium-derived nitric oxide (EDNO) and hyperpolarizing factor (EDHF) in
      superior mesenteric arteries from reduced renal mass hypertensive rats, an
      experimental model for volume-dependent hypertension. Hypertension was induced in
      male Wistar rats by subtotal nephrectomy and salt-loading (hypertensive group).
      The control group comprised rats that drank tap water after subtotal nephrectomy.
      Relaxation of isolated superior mesenteric arterial rings was investigated at the
      end of the 2-week study. In high K+-precontracted arterial rings, relaxation
      caused by acetylcholine (ACh) was markedly reduced in the hypertensive group
      compared with the findings for the control group (34+/-4% vs. 54+/-5% decrease in
      tension). In both groups, the relaxation was abolished by N(omega)-nitro-L
      arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase. In
      phenylephrine-precontracted arterial rings, relaxation caused by ACh was also
      small in the hypertensive group, while it was large in the control group (49 +/-
      5% vs. 96 +/- 2%). Superfusion of L-NAME inhibited most of the relaxation caused
      by ACh, but the arteries still exhibited relaxation. Apamin, a blocker of Ca
      dependent K+ channel, together with L-NAME further inhibited the residual
      relaxation. The relaxation inhibited by apamin was also reduced in the
      hypertensive group. We conclude that the relaxation inhibited by L-NAME was
      mediated by EDNO, while that inhibited by apamin was mediated by EDHF.
      Endothelium-independent relaxation caused by nitroprusside and diazoxide was
      normal in the hypertensive group. The relaxation mediated by both EDNO and EDHF
      was depressed in the arteries of reduced renal mass hypertensive rats as the
      result of an arterial endothelial abnormality.

PMID- 10400165
TI  - An optimized method for fatty acid analysis, including quantification of trans
      fatty acids, in human adipose tissue by gas-liquid chromatography.
AB  - Considering the need for a quick direct method for measurement of the fatty acid
      composition including trans isomers of human adipose tissue we have developed a
      procedure using gas-liquid chromatography (GLC) alone, which is thus suitable for
      validation of fatty acid status in epidemiological studies. Fatty acids ranging
      in carbon number from 12 to 22 and with 0-6 double bonds were resolved and
      identified by capillary column GLC with a temperature program starting at 150
      degrees C. Following injection, the oven temperature was increased at a rate of 3
      degrees C/min to 200 degrees C, then held constant for 25 min, and finally raised
      at 25 degrees C/min to 225 degrees C. The trans and cis isomers of 18:1 were well
      separated from each other, as shown by silver-ion thin-layer chromatography.
      Verification by standards showed that the trans 18:1 isomers with a double bond
      in position 12 or lower were separated from the cis 18:1 isomers with a double
      bond in position 6 or higher. As the adipose tissue samples contained only small
      amounts of the 13t-, 14t- and 15t-18:1 isomers and the 4c- and 5c-18:1 isomers
      the overlapping was found to be minimal. The GLC method may also be valuable for
      determining the fatty acid profiles including total trans in other tissues.

PMID- 10400166
TI  - The role of oxidized HDL in monocyte/macrophage functions in the pathogenesis of
      atherosclerosis in Rhesus monkeys.
AB  - The effect of oxidative modification of high-density lipoprotein (HDL) was
      assessed by incubation of normal HDL (obtained from Rhesus monkeys fed a stock
      diet) with 5 microM CuSO4 at 37 degrees C for 12 h/24 h. The physicochemical
      properties of oxidized-HDL (Ox-HDL) were found to be affected in terms of lipid
      peroxidation, as observed by the increased level of thiobarbituric acid reactive
      substances (nmol MDA/mg HDL protein). The biological properties of HDL were
      altered, since a decrease in the efflux of free cholesterol into the medium was
      found in the presence of Ox-HDL24h compared with normal HDL (N-HDL). The binding,
      uptake and degradation of 125I-LDL by macrophages increased in the presence of Ox
      HDL24h. The activity of antioxidant enzymes (superoxide dismutase, catalase and
      glutathione-peroxidase) was reduced in monocytes in the presence of Ox-HDL.
      However, in the presence of N-HDL, the levels of antioxidant enzymes were
      maintained at a higher level than in the control (in the absence of HDL)
      monocytes. Furthermore, the number of monocytes adhered to aortic endothelium
      were found to be increased in the presence of Ox-HDL. These findings suggest that
      HDL is susceptible to oxidative modification. Since the parameters selected in
      the present study are involved in the pathogenesis of atherosclerosis, it can be
      postulated that the in vivo protection of HDL in atherosclerosis can be reversed
      in the circumstances in which HDL undergoes oxidative modification like low
      density lipoprotein (LDL).

PMID- 10400167
TI  - Adipose tissue fatty acids in men from two populations with different
      cardiovascular risk: the LiVicordia study.
AB  - The LiVicordia study was set up to investigate possible causes for coronary heart
      disease mortality in middle-aged Lithuanian men being four times higher than in
      Swedish men. In a previous part of this study we found lower total and low
      density lipoprotein (LDL) cholesterol in the Lithuanian men in spite of them
      having a higher fat intake than in the Swedish men. Their LDL was also more
      susceptible to oxidation in vitro than was that of the Swedish men. Fat quality
      can influence LDL oxidation. In order to obtain data on long-term fat quality
      intake we measured the fatty acid composition of abdominal wall adipose tissue by
      gas chromatography in men aged 50 years from Vilnius, Lithuania (n=50) and
      Linkoping, Sweden (n=50). Men from Vilnius had a significantly higher percentage
      of adipose tissue long chain polyunsaturated fatty acids (PUFA) (20:4n6, 20:5n3,
      22:5n5, 22:6n3) and lower percentage of saturated fatty acids, especially
      myristic acid (14:0), 3.4+/-0.7 versus 4.6+/-0.8, p<0.0001. The percentage
      content of adipose tissue linoleic acid (18:2n6) was 11.5+/-2.1 versus 11.0+/-1.4
      (n.s.) and of linolenic acid (18:3n3) 0.7+/-0.3 versus 0.6+/-0.2 (n.s.) in men
      from Vilnius and Linkoping, respectively. It is concluded that the adipose tissue
      content of essential fatty acids is similar in men from Vilnius and men from
      Linkoping and therefore the intake is also likely to be similar. The higher
      contents of long chain highly unsaturated fatty acids in men from Vilnius may be
      of importance in the oxidation process of LDL.

PMID- 10400168
TI  - Determination of the effect of pH and foetal haemoglobin fraction on haemoglobin
      oxygen saturation readings by the OSM3 hemoximeter.
AB  - The visible absorption spectrum of oxyhaemoglobin depends on its content of
      foetal haemoglobin and on the pH of the blood. These variables are known to
      affect oxygen saturation readings measured by the OSM3 Hemoximeter. As the
      hemoximeter estimates foetal haemoglobin content from the absorption spectrum of
      oxyhaemoglobin, this estimation is affected by pH. We quantified the effect of pH
      on oxyhaemoglobin reading in order to calculate a correction factor to adjust for
      pH. We manipulated a pool of fresh heparinized cord blood samples to produce a
      range of pH values from 6.99-7.53 in fully oxygenated blood with a carbon dioxide
      tension of 5.3 kPa. We measured oxygen saturation and percent foetal haemoglobin
      using an OSM3 Hemoximeter and pH with a linked blood gas analyser. The effect of
      pH on readings of saturation and fractional foetal haemoglobin was confirmed and
      a correction factor was calculated. The value of KHbF, the coefficient used in
      the OSM3 Hemoximeter to estimate the amount of fractional foetal haemoglobin
      present in a sample, was determined to be 18.3, which slightly but significantly
      differed (p = 0.04) from the 18.6 used by the OSM3 Hemoximeter. An equation was
      derived to correct the errors made by pH on the saturation measurement of
      oxygenated blood.

PMID- 10400169
TI  - Gait analysis: past, present, and future.

PMID- 10400170
TI  - Consciousness in congenitally decorticate children: developmental vegetative
      state as self-fulfilling prophecy.
AB  - According to traditional neurophysiological theory, consciousness requires
      neocortical functioning, and children born without cerebral hemispheres
      necessarily remain indefinitely in a developmental vegetative state. Four
      children between 5 and 17 years old are reported with congenital brain
      malformations involving total or near-total absence of cerebral cortex but who,
      nevertheless, possessed discriminative awareness: for example, distinguishing
      familiar from unfamiliar people and environments, social interaction, functional
      vision, orienting, musical preferences, appropriate affective responses, and
      associative learning. These abilities may reflect 'vertical' plasticity of
      brainstem and diencephalic structures. The relative rarity of manifest
      consciousness in congenitally decorticate children could be due largely to an
      inherent tendency of the label 'developmental vegetative state' to become a self
      fulfilling prophecy.

PMID- 10400171
TI  - Head circumference in ELBW babies is associated with learning difficulties and
      cognition but not ADHD in the school-aged child.
AB  - This study examines whether a small head circumference (HC) and low head
      circumference growth velocity (HGV) during the first year of life predict
      consequences at school age in learning, cognition, and concentration. A total of
      124 extremely-low-birthweight (ELBW) infants (birthweight 500 to 999 g) born
      between 1977 and 1986 were eligible for follow-up at the corrected ages of 4, 8,
      and 12 months and 2, 4, and 6 years. Infants were categorized as having a small
      HC (< 3% or 3 to 10%) on the basis of the 1990 British growth data which allowed
      standardized z-scores to be calculated for HC, independent of gestation and
      corrected age. HGV measurements were calculated using differences in the HC z
      scores. In 1995, parents of 87 children agreed to participate in a study of
      learning and attention at school age. Attention-deficit-hyperactivity disorder
      (ADHD) was assessed using the Du Paul Rating Scale. Academic performances were
      based on a teacher questionnaire dealing with aspects of reading, writing,
      mathematics, and spelling. A child was considered to have a learning difficulty
      if academic problems were present in at least one of these four areas.
      Intellectual ability was assessed using the McCarthy Scale at 6 years. HC < 3%
      and 3 to 10% at 8 months' corrected age was strongly associated with school-aged
      learning problems (P=0.004), with a moderate specificity (70%), positive
      predictive value (PPV) (67%), and sensitivity (67%). HGV < or = 10% from birth to
      4 months was also associated with learning problems at school age (P=0.01) with a
      higher specificity (98%) and PPV (88%) but lower sensitivity (20%). A logistic
      regression analysis was performed with the risk for learning difficulties at 8
      months as the dependent variable. Sex, gestation, birthweight, multiple births,
      and a history of intraventricular hemorrhage did not substantially alter the
      unadjusted odds ratio (4.7; 95% CI 1.9 to 13.6). Maternal age and education did
      not confound the relation. No association was found between HC or HGV and ADHD.
      HC < 3% at 4 months (P<0.02), 8 months (P=0.02), and 12 months (P=0.04), and HGV
      between birth and 4 months (P<0.01) were significantly associated with low
      cognitive ability at 6 years.

PMID- 10400172
TI  - Quality of general movements in infancy is related to neurological dysfunction,
      ADHD, and aggressive behaviour.
AB  - The quality of general movements (GMs) was assessed repeatedly during the first
      postnatal months in a mixed group of 52 children at either low or high risk for
      neurodevelopmental disorders. In addition, all children were reexamined at 4 to 9
      years. The follow-up assessment consisted of a neurological examination and an
      evaluation of behaviour by means of parental questionnaires. The quality of GMs
      changed frequently, to stabilize in the final phase. The final GM phase is that
      of the so-called fidgety GMs which occurs between 2 and 4 months postterm. The
      quality of the fidgety GMs predicted outcome very well. Definitely abnormal GMs
      were associated with a high risk for the development of cerebral palsy, whereas
      mildly abnormal GMs were associated with the development of minor neurological
      dysfunction, attention-deficit-hyperactivity disorder, and aggressive behaviour.

PMID- 10400173
TI  - Premature sexual development in individuals with neurodevelopmental disabilities.
AB  - Studies on precocious puberty have primarily focused on children with typical
      patterns of growth and cognitive development. This study reviewed diagnostic data
      from the records of 15,719 patients with neurodevelopmental disabilities for
      diagnoses associated with premature sexual development/precocious puberty. Thirty
      two individuals with premature sexual development were identified, with the
      earliest changes seen in one girl at 1 year 7 months of age. In this group, the
      mean age at onset was 7 years 2 months in boys and 5 years 11 months in girls.
      Central precocious puberty, which was the most common cause of onset of early
      pubertal changes, was present in 15 of the 32 children. The results of this study
      suggest that children with a neurodevelopmental disability are at increased risk
      of premature pubertal changes when compared to children without a
      neurodevelopmental disability. This study indicates the need for health-care
      providers to be vigilant in screening for early pubertal changes in children with
      neurodevelopmental disabilities.

PMID- 10400174
TI  - Refractive errors in children with cerebral palsy, psychomotor retardation, and
      other non-cerebral palsy neuromotor disabilities.
AB  - The aim of this study was to analyse the refractive state of four different
      groups of children: those with spastic cerebral palsy (CP), aged between 7 and 81
      months (N=50); psychomotor retardation, aged between 19 and 70 months (N=16);
      other neuromotor dysfunctions, aged between 12 and 75 months (N=37); and without
      psychomotor retardation, aged between 9 and 73 months (N=181). Refractive errors
      were determined using cycloplegic retinoscopy and non-cycloplegic retinoscopy
      (Mohindra's technique). We found higher percentages of hyperopia, tendency toward
      hyperopia, and other refractive anomalies in all the pathological groups of
      children than in the non-pathological control groups. Children from both the non
      CP pathological control group and the group with psychomotor retardation had
      similar or even higher levels of hyperopia than children from the group with
      spastic CP. Our results in different age groups indicate a less effective normal
      emmetropization course in all the pathological groups of children studied. The
      correction of refractive errors is needed in these children before the end of the
      neural plasticity period.

PMID- 10400175
TI  - Reliability and responsiveness of the Barry-Albright Dystonia Scale.
AB  - The reliability and responsiveness of the Barry-Albright Dystonia (BAD) Scale, a
      5-point ordinal severity scale for secondary dystonia, was assessed. For
      interrater reliability, 13 raters scored 10 videotaped patients; for intrarater
      reliability, two raters rated the videotape again. For test-retest reliability,
      patients were rated on two occasions. Four inexperienced raters scored patients,
      received training, then scored additional patients. To assess responsiveness, we
      compared patient and physician global ratings of change (better, same, and worse)
      with BAD Scale score changes for 18 patients on intrathecal baclofen (ITB)
      trials. We assessed reliability with the intraclass correlation coefficient
      (ICC). The mean ICC for total BAD Scale scores were as follows: interrater
      reliability 0.866, intrarater reliability 0.967 and 0.978, test-retest
      reliability 0.978 (before training) and 0.967 (after training). We found the BAD
      Scale responsive to change, with most improved scores in patients rated by the
      patient, family, and neurosurgeon as 'better'. The total scores were reliable for
      experienced raters. We recommend training for clinicians interested in using the
      scale.

PMID- 10400176
TI  - Behaviour of Finnish 3-year-old children. I: Effects of sociodemographic factors,
      mother's health, and pregnancy outcome.
AB  - The aim of this prospective follow-up study was to assess the effects of pre- and
      perinatal factors on children's behaviour at the age of 3 years. Nulliparous
      women who attended a maternity health care clinic were invited to participate:
      1443 women were included. Data were obtained from the mother, father, and clinic
      nurse. A Finnish translation of Achenbach's Child Behavior Checklist for Ages 2-3
      was completed by 1086 families at the child's 3-year visit to the well-baby
      clinic. The results were analysed using Pearson's chi2, multivariate regression
      analysis, and coefficient of determination (100 x r2). A good basic education
      (i.e. >9 years) of the mother and age over 25 years were associated with low
      syndrome-scale scores, indicating fewer behavioural problems. Poor health of the
      mother, a high number of pregnancy-related symptoms, and low Apgar scores for the
      newborn infant were associated with high syndrome-scale scores. In this
      population sample, the mother's health during pregnancy together with level of
      education, and marital status are more important in explaining the variation in a
      child's behaviour than biological risks during pregnancy.

PMID- 10400177
TI  - Status epilepticus-induced brain damage and opercular syndrome in childhood.
AB  - This study reports on a girl with a permanent cerebral lesion and opercular
      syndrome after status epilepticus (SE). She had previously been healthy and had
      her first focal motor seizure at 5 years of age, which was controlled with
      intravenous phenytoin and rectal diazepam. Twenty-four hours later, she developed
      partial SE consisting of right facial twitching and right-hand clonic movements.
      These uncontrollable seizures lasted for 5 days, after which the partial SE
      changed to generalized SE, and the seizures continued for another 5 days. CT
      performed the day before onset of SE revealed no brain abnormality. Another CT
      performed a year later disclosed bilateral brain lesions, more severe in the left
      hemisphere. Follow up at 16 years of age revealed moderate motor sequelae of the
      right-hand side of the body, anarthria, difficulty chewing, dysphagia, bilateral
      facial weakness, and drooling, all of which clinically characterize opercular
      syndrome. An MRI study performed at 14 years of age showed a cerebral
      parenchymatous lesion which extended between the parietal cortices of both
      hemispheres, more severe on the left side, and which crossed the corpus callosum,
      destroying the posterior-middle zone. Evidence from the CT indicates that the
      lesion was not present before onset of SE. It seems likely that the focal SE
      caused the focal brain damage, but the possibility that the subsequent
      generalized SE played a role cannot be excluded.

PMID- 10400178
TI  - New surgical interventions for cerebral palsy and the place of gait analysis.

PMID- 10400179
TI  - 'Saccadic strategies in children with hemianopia'.

PMID- 10400180
TI  - 'Multidisciplinary appraisal of the British Institute for Brain Injured Children,
      Somerset, UK'.

PMID- 10400181
TI  - Acute myeloid leukemia in the elderly: 'per aspera ad astra'?

PMID- 10400182
TI  - Malignancies of natural killer (NK) cell precursor: myeloid/NK cell precursor
      acute leukemia and blastic NK cell lymphoma/leukemia.
AB  - Malignant hematolymphoid disorders arising from natural killer (NK) cells have
      become widely recognized in the past decade. Recently, we as well as others have
      drawn attention to some neoplasms of conceivable NK cell precursor origin that
      might represent two distinct entities, i.e. myeloid/NK cell precursor acute
      leukemia and blastic NK cell lymphoma/leukemia. Both of these diseases were
      characterized by remarkable extramedullary involvement and lymphoblastoid
      morphology, although the sites of involvement differed. Myeloid/NK cell precursor
      acute leukemia exhibited more frequent involvement of bone marrow (BM) and lymph
      nodes, whereas blastic NK cell lymphoma/leukemia affected extranodal sites,
      mainly the skin/subcutis. Tumor cells of these two diseases shared the CD16-,
      CD56+ and CD57- phenotype, but differed in other phenotypic profiles. Indeed,
      myeloid/NK cell precursor acute leukemia was immunophenotypically characterized
      by the expression of CD34 and blastic NK cell lymphoma/leukemia by that of CD4.
      On the theoretical level in the NK cell differentiation pathway, myeloid/NK cell
      precursor acute leukemia might be derived from a myeloid antigen-positive
      precursor preceding a NK cell committed precursor as a conceivable counterpart of
      blastic NK cell lymphoma/leukemia. Most cases with either disease lacked
      cytotoxic activities or molecules, a finding which seems to support their
      precursor origin. Notably, Epstein Barr virus (EBV) was negative in all cases,
      which contrasted with its high level associated with mature NK cell malignancies.
      Chemotherapy for acute myeloid leukemia was generally effective for myeloid/NK
      cell precursor acute leukemia, while the regimen for lymphoid malignancy was
      effective for blastic NK cell lymphoma/leukemia. These data suggests that each of
      these two diseases constitutes a distinct entity, which is also different from
      mature NK cell malignancies.

PMID- 10400183
TI  - Quantification of human herpesvirus 6 in healthy volunteers and patients with
      lymphoproliferative disorders by PCR-ELISA.
AB  - To determine whether actual numbers of human herpesvirus 6 (HHV-6) genome in
      hematologic neoplasias are associated with disease condition, we developed a
      quantitative PCR-ELISA for detection of HHV-6. The amount of viral DNA was
      determined using externally amplified known amounts of the plasmid DNA containing
      the viral target sequences. First, we determined a viral burden in peripheral
      blood leukocytes obtained from 23 healthy volunteers and four specimens of lymph
      nodes with reactive hyperplasia. Using 1 microg of DNA, the prevalence of HHV-6
      was 43.4% (10/23), ranging from 0 to 100 HHV-6 genomes in blood obtained from
      healthy volunteers. The amounts of HHV-6 genomes were < 10 in four non-neoplastic
      lymph node specimens. We next examined the amount of viral DNA in 21 blood
      specimens and 19 lymph node specimens obtained from patients with
      lymphoproliferative diseases (LPD) at the time of diagnosis. The number of HHV-6
      genomes in most of the B-cell lymphoma was < 5 in both blood and lymph node
      specimens, however, two lymph node specimens obtained from immunoblastic
      lymphadenopathy (IBL) and T-cell lymphoma had very high levels of HHV-6 viral DNA
      (3705 and 810, respectively). We also found that HHV-6 genomes in peripheral
      blood were more than 1000 in two patients with chronic lymphocytic leukemia. For
      all LPD patients combined, there were significantly higher levels of viral DNA
      (200.6 +/- 654.8 HHV-6 genomes per 1 microg purified DNA) compared to those in
      healthy volunteers (10.0 +/- 21.0 HHV-6 genomes per 1 microg purified DNA) (P <
      0.05). This study demonstrates that a high level of HHV-6 viral DNA is
      occasionally associated with LPD patients. Although it is still uncertain whether
      HHV-6 is related to the pathogenesis in LPD or not, our results suggest that
      measurement of HHV-6 genomes using PCR-ELISA may be useful not only to understand
      the mechanism of HHV-6 infection in hemopoietic neoplasia but also to manage the
      care of immnocompromised patients such as bone marrow transplant patients.

PMID- 10400184
TI  - P16 gene deletions and point mutations in patients with agnogenic myeloid
      metaplasia (AMM).
AB  - Studies of p16 alterations with homozygous deletions and mutation analysis were
      done in 32 patients with agnogenic myeloid metaplasia (AMM) including six
      patients in leukemic phase. No homozygous deletions were found and, one patient
      was found to have a shift band in exon 2C fragment by PCR-SSCP analysis. Further
      sequence analysis demonstrated that the mutated band was a point mutation of G to
      A in exon 2 codon 140 (GCG-->ACG) causing an amino acid substitution of alanine
      to threonine demonstrating this patient either carried an mutated gene in one
      allele as a polymorphism (heterozygous carrier of a mutant p16 gene) or carried a
      mutant p16 gene clone. This study demonstrates that p16 alterations with
      homozygous deletions and mutations were very rare in patients with AMM. A single
      patient found to have a shifted band by PCR-SSCP may be represented as a
      coincidence or as a polymorphism with a heterozygous carrier of mutated p16 gene,
      predisposable to AMM or as a mutant p16 gene which can be infrequently observed
      in this disease.

PMID- 10400185
TI  - Metabolism of an artificial emulsion resembling chylomicrons in patients with
      multiple myeloma.
AB  - Multiple myeloma, as other neoplastic diseases, is accompanied by alterations in
      lipid metabolism. The metabolism of chylomicrons is unexplored in this condition,
      despite the importance of these lipoproteins for the energy body supply.
      Chylomicron metabolism in the bloodstream consists of lipolysis by lipoprotein
      lipase and uptake of remnants by the liver. Triglyceride-rich emulsions can mimic
      chylomicron metabolism in man and are a useful tool to evaluate this metabolic
      pathway. A double-labeled chylomicron-resembling emulsion was injected into 20
      patients with multiple myeloma and 30 normolipidemic healthy subjects. The plasma
      kinetic curves of the emulsion 3H-triglyceride and 14C-cholesteryl ester were
      determined in plasma samples collected over 60 minutes. The fractional clearance
      rate (FCR) of triglycerides in multiple myeloma was not changed compared to
      controls. However, FCR of cholesteryl esters was smaller in multiple myeloma
      (0.025 +/- 0.003 and 0.061 +/- 0.010 min(-1), respectively). These results
      indicate that chylomicron lipolysis is not affected in multiple myeloma, whereas
      remnant removal is diminished.

PMID- 10400186
TI  - Expression of the growth arrest-specific gene 6 (GAS6) in leukemia and lymphoma
      cell lines.
AB  - The initial identification of GAS6 as a protein expressed in response to growth
      arrest suggested that it might function as a negative regulator of cell
      proliferation. Since the transforming activity of the GAS6 receptor (AXL/UFO) was
      documented, GAS6 might stimulate rather than inhibit proliferation. In order to
      detect aberrant expression of GAS6 we examined gene expression in 46 cell lines
      of precursor B-, B- and T-cell origin as well as from Hodgkin's disease and cell
      lines established from various myeloproliferative disorders. In our study, the
      expression of GAS6 reveals a constitutive transcriptional activation in 8/46
      cases of proliferating cell lines. The GAS6 mRNA expression could be shown in
      4/22 cell lines of the lymphoid arm and in 4/17 of the myeloid lineages of the
      hematopoietic system. No transcripts could be detected in the CD30+ Hodgkin and
      anaplastic large cell lymphomas (0/7). Interestingly, the steady state mRNA
      levels showed neglectable GAS6 expression in precursor B and B-cell lines (1/9),
      but could be detected in terminally differentiated plasma cell lines (4/4). The
      predominantly GAS6-expressing cell lines of non-lymphoid origin have been
      established from acute myeloid leukemias of the M4 subtype (3/4). In order to
      demonstrate evidence for an autocrine regulation of growth in permanent
      hematopoietic cell lines, we measured the GAS6 expression in cell lines with
      strong positivity for the AXL/UFO receptor mRNA. Constitutive basal levels of
      GAS6 mRNA and protein expression could be only detected in 3/23 AXL/UFO
      expressing cell lines. Although a general mechanism seems most unlikely, further
      studies are necessary to demonstrate the involvement of GAS6 in single cases of
      disordered growth or chemotaxis/adhesion of leukemia and lymphomas.

PMID- 10400187
TI  - A new PCR MIMIC strategy to quantify low mdr1 mRNA levels in drug resistant cell
      lines and AML blast samples.
AB  - Determination of the MDR-phenotype in patients suffering from AML is an important
      hallmark of treatment outcome but is often complicated by technical problems in P
      gp assessment. A PCR-MIMIC strategy was employed to construct PCR-fragments for a
      competitive and quantitative mdr1 reverse transcription-PCR-assay. Using K562
      cells, which had been selected for drug resistance to the epipodophyllotoxin
      VP16, a stepwise increase of mdr1 levels depending on the concentration of VP16
      was shown with the MIMIC technique. Comparison of mdr1 levels in drug selected
      K562 cells with the corresponding levels for P-gp and functional data indicated a
      mRNA threshold that has to be exceeded for the full expression of the MDR
      phenotype. Subsequently mdr1 levels of 34 samples of de novo acute myeloid
      leukemia were determined with the PCR-MIMIC strategy. Ten patient samples could
      be identified with elevated mdr1 levels which were substantially lower than the
      levels observed in the MDR-cell line K 562 0.7 microM VP16. Outcome analysis
      revealed that eight of the ten patients had an unfavourable prognosis and did not
      achieve CR after induction chemotherapy. Coexpression of mdr1 and CD 34 was not
      associated with CR in all examined cases. Moreover all these patients had
      unfavourable cytogenetic aberrations. These data indicate a sensitive technique
      with applicability in patient material.

PMID- 10400188
TI  - Induction of type 1 programmed cell death in U937 cells by the antioxidant,
      butylated hydroxy-toluene or the free radical spin trap, NTBN.
AB  - Oxidative stress can initiate programmed cell death and contributes to the patho
      physiology of a number of diseases. Low micromolar to millimolar concentrations
      of various antioxidants or free radical scavengers promote cell growth and reduce
      cellular suicide induced by several functionally distinct agents, including some
      known to produce oxidative stress. Severe anoxia or inhibitors of oxidative
      phosphorylation also initiate programmed cell death. These results seem
      paradoxical. In order to compare the response of U937 monoblastoid cells to
      higher concentrations of an antioxidant or a free radical-spin trap, cells were
      cultured with 20-80 microM concentrations of butylated hydroxy-toluene or with 5
      to 60 mM concentrations of the free radical spin trap, N-tertiary butyl phenyl
      nitrone. At these concentrations, both agents inhibited cellular proliferation
      and induced oligosomic DNA, detected by its 'laddering' after electrophoresis on
      agarose, confirmed by TUNEL (BHT) or flow cytometric (NTBN) evidence of
      hypodiploid DNA and ultrastructural evidence of a type 1 programmed cell death.
      The ability of hydroxy-toluenes to oxidize DNA and promote carcinogenesis and
      whether free radical spin traps could augment or interfere with the response of
      malignantly transformed cells to chemotherapy or ionizing radiation provide the
      raison d'etre of these studies.

PMID- 10400189
TI  - CD56+ hematologic malignancies.

PMID- 10400190
TI  - Acute myeloid leukemia with t(5;11): two case reports.
AB  - A case of acute monocytic leukemia (AMoL) with t(5;11)(q31;q23) and a case of
      acute myelomonocytic leukemia (AMMoL) with t(5;11)(q35;q13.1) are reported. The
      translocation between the long arm of chromosome 11q and that of chromosome 5q
      with leukemia have been rarely reported. Though breakpoint of both cases were
      subtlety different, they had morphologically monocytic character and showed
      hyperleukocytosis and chemoresistance.

PMID- 10400191
TI  - Designing optimal spatial filters for single-trial EEG classification in a
      movement task.
AB  - We devised spatial filters for multi-channel EEG that lead to signals which
      discriminate optimally between two conditions. We demonstrate the effectiveness
      of this method by classifying single-trial EEGs, recorded during preparation for
      movements of the left or right index finger or the right foot. The classification
      rates for 3 subjects were 94, 90 and 84%, respectively. The filters are estimated
      from a set of multichannel EEG data by the method of Common Spatial Patterns, and
      reflect the selective activation of cortical areas. By construction, we obtain an
      automatic weighting of electrodes according to their importance for the
      classification task. Computationally, this method is parallel by nature, and
      demands only the evaluation of scalar products. Therefore, it is well suited for
      on-line data processing. The recognition rates obtained with this relatively
      simple method are as good as, or higher than those obtained previously with other
      methods. The high recognition rates and the method's procedural and computational
      simplicity make it a particularly promising method for an EEG-based brain
      computer interface.

PMID- 10400192
TI  - Mental representations of movements. Brain potentials associated with imagination
      of eye movements.
AB  - OBJECTIVE: Current research in motor imagery is focused on similarities between
      actual and imagined movements on a central and a peripheral level of the nervous
      system. The present study measured slow cortical potentials (DC-potentials)
      during execution and internal simulation of memorized saccadic eye movements.
      METHODS: In 19 healthy righthanded subjects DC-potentials were recorded from 28
      electrodes during execution and during imagination of a sequence of memorized eye
      movements during a visual imagery condition. RESULTS: Both oculomotor conditions
      showed a similar global level and similar topography of performance related DC
      potentials, both strongly differed from the visual imagery condition and were
      lateralized to the left hemisphere. CONCLUSION: This study therefore supports the
      hypothesis that cortical brain structures responsible for execution and
      imagination of memorized saccadic eye movements are similar. The observed left
      hemispheric lateralization is in contrast to a previous study using bimanual
      movements. This discrepancy is discussed in relation to recent observations in
      apractic patients with parietal lesions.

PMID- 10400193
TI  - Reorganization of cortical motor area in prior polio patients.
AB  - OBJECTIVE: Focal transcranial magnetic stimulation (TMS) was used to study the
      motor maps of upper limb muscles in 7 adult patients with a history of paralytic
      poliomyelitis. The aim of the study was to verify the potential for long-term
      cortical reorganization of a selective peripheral motor neuron lesion suffered
      early in life. METHODS: Patient selection was based on the prevalent involvement
      of proximal muscles in only one of the upper limbs. Motor evoked potentials
      (MEPs) were recorded from deltoid and abductor pollicis brevis (APB) muscles.
      Each muscle map was characterized by area (no. of excitable positions), volume
      (the sum of MEP amplitudes at all scalp positions), maximal amplitude (the
      highest MEP recorded). RESULTS: In the patients, the mean area, volume and
      maximal amplitude were significantly greater in affected vs. contralateral
      deltoid (P<0.05) and vs. controls (P<0.01). No significant differences were found
      in APB map parameters. The APB/deltoid ratio for area was lower in the affected
      compared with the unaffected side and controls (P = 0.06). Cortical
      reorganization was not significantly correlated with motor performance.
      CONCLUSION: These findings are consistent with a rearrangement in human motor
      pathways targeting muscles affected by a lower motor neuron lesion.

PMID- 10400194
TI  - N400 and lexical decisions: automatic or controlled processing?
AB  - OBJECTIVE: To investigate whether the N400 effect is sensitive to automatic or
      controlled processes. METHODS: Two experiments were performed. In one experiment,
      directly related word pairs were used. In the other experiment, mediated-related
      word pairs were used. In order to reduce controlled processes, each experiment
      consisted of 3 tasks: Low- and high-proportion of related pairs, and single
      presentation lexical decision task. RESULTS: In the first experiment, the amount
      of priming was equivalent for the 3 tasks. The N400 effect appeared in the high
      and low proportion of directly related words, but not in the single presentation
      task. In the second experiment, behavioral priming was also found in the 3 tasks.
      However, the N400 effect was observed only in the task with low proportion of
      related pairs. CONCLUSION: These results suggest that the N400 effect may be
      related to controlled processes.

PMID- 10400195
TI  - The diagnostic value of electroencephalography in mild senile Alzheimer's
      disease.
AB  - OBJECTIVE: We investigated the diagnostic value of the visually assessed
      electroencephalogram (EEG) in patients with mild Alzheimer's disease (AD), using
      the grand total of EEG (GTE) score. METHODS: Forty-nine non-demented control
      subjects with and without minimal cognitive impairment from the general
      population and 86 probable AD patients (NINCDS-ADRDA criteria), consecutively
      referred to a memory clinic, participated in this study. RESULTS: Frequency of
      rhythmic background activity (P<0.05), diffuse slow activity (P<0.001), and
      reactivity of the rhythmic background activity (P<0.001) were statistically
      significant related to the diagnosis control subject or AD patient, using
      logistic regression analysis with adjustment for age and sex. When these
      subscores were used to confirm the diagnosis of AD, thus at high specificity of
      89.1% (GTE cut-off point of 3), the sensitivity was 44.6% and positive predictive
      value was 88.1%. Incremental ruling-in and ruling-out curves showed a maximum
      diagnostic gain of 38% for a positive test result at a prior probability ranging
      from 30 to 40%. At high pretest probability levels of 80-90%, the diagnostic gain
      for a positive test result was low, varying from 7 to 14%. CONCLUSION: In
      conclusion, the visually assessed EEG may give a clinically meaningful
      contribution to the diagnostic evaluation of AD when there is diagnostic doubt.

PMID- 10400196
TI  - Age-related changes in the brain electrical correlates of response control.
AB  - OBJECTIVES: Previously, a quantification method was validated which, on a single
      case basis, allows one to assess the NoGo-anteriorisation (NGA) of the positive
      area of long latency event-related potential (ERP) fields elicited by a cued
      continuous performance test (CPT). The NGA was shown to be associated with right
      frontal activity. The present study was conducted to investigate the influence of
      age and gender on this topographical index of cognitive response control.
      METHODS: Thirty-seven healthy controls were investigated with 21-channel
      recordings during the execution of a cued CPT, and ERPs of the Go and NoGo
      condition were obtained. The location of the positive area centroids in a P300
      range and the NGA were calculated and related to age and gender by means of
      correlation analysis and t tests. RESULTS: The centroid locations of the brain
      electrical activity during the NoGo- and the Go-condition of the CPT, were both
      located in more anterior brain regions with increasing age (P<0.01 and P<0.1,
      respectively); the NGA, however, was not correlated with the subject's age.
      Latencies and amplitudes of the Go- and NoGo-centroids were not correlated with
      age. No gender differences were found. CONCLUSIONS: The study showed that age is
      a source of variance for the positive area centroid locations in this Go-NoGo
      paradigm. The NGA, on the other hand, was robust to age and gender effects. The
      result is interpreted as a sign of an increasing contribution of frontal brain
      areas to cognitive response control during lifespan. The finding is consistent
      with the age-related topographical changes described in acoustic oddball
      paradigms and, therefore, appears to be a general topographical ERP effect.

PMID- 10400197
TI  - Modulation of sleep interictal epileptiform discharges in partial epilepsy of
      childhood.
AB  - OBJECTIVE: NREM sleep increases the Interictal Epileptic Discharges (IEDs) in the
      majority of children affected by partial epilepsy (both symptomatic or
      cryptogenetic). Experimental data revealed that the normal sleep oscillations,
      leading to the appearance of spindles and delta waves on the surface EEG during
      NREM sleep, might develop into paroxysmal synchronization. Spectral analysis
      enables the quantitative description of the dynamics of delta (slow wave
      activity, SWA, 0,5-4,5 Hz) and sigma activity (SA, 12.0-16.0 Hz) and can be used
      to assess the relationship between SA, SWA and IEDs during sleep. DESIGN AND
      METHODS: We have performed overnight continuous EEG-polysomnographic studies in 7
      patients (mean age 7.2+/-1.3). The temporal series of SWA and SA were obtained
      from a spike-free derivation lead. The IEDs count was performed on the most
      active lead. Relationships between sigma and SWA and time series of IEDs were
      tested by means of correlation techniques after data normalization. RESULTS: Our
      results revealed a significant higher correlation between IEDs and SA with
      respect to SWA in all the subjects, in total sleep time. The same analysis
      limited to NREM sleep highlights the better correlation between SA and IEDs.
      CONCLUSIONS: Our data suggest that the neural mechanisms involved in the
      generation of sleep spindles facilitate the IEDs production in childhood partial
      epilepsies at least in those strongly activated by sleep.

PMID- 10400198
TI  - Interictal spike localization using a standard realistic head model: simulations
      and analysis of clinical data.
AB  - OBJECTIVES: In this paper realistic and standard realistic head models were
      applied to neural source localization. METHODS: Three different triangulated head
      structures; the brain, the skull and the scalp were constructed from MRI
      information of each patient. For each subject the exact positions of the
      electrodes were digitized. RESULTS: The influence of the number of triangles and
      of the skull conductivity on the accuracy of the method was tested. The use of a
      standard realistic head model instead of spherical models is proposed in cases
      where detailed MRI information is not available, and the accuracy of this
      procedure is tested with dipole simulations. These techniques were applied also
      to EEG signals from 3 patients with focal epilepsy. In all cases the neural
      activity was assumed to be confined to a small portion of cortical tissue, so
      that the neural generator was approximated to a current dipole. The realistic
      head model localization is discussed on the basis of neuroimaging information.
      CONCLUSIONS: We show that the standard realistic head model is two or 3 times
      better than the spherical model for dipole localization and we propose it as a
      good alternative to the spherical model for EEG data processing, in cases where
      full MRI information is not available.

PMID- 10400199
TI  - Deconvolution of 40 Hz steady-state fields reveals two overlapping source
      activities of the human auditory cortex.
AB  - Steady-state auditory evoked fields were recorded from 15 subjects using a whole
      head MEG system. Stimuli were 800 ms trains of binaural clicks with constant
      stimulus onset asynchrony (SOA). Seven different SOA settings (19, 21, 23, 25,
      27, 29 and 31 ms) were used to give click rates near 40 Hz. Transient responses
      to each click were reconstructed using a new algorithm that deconvoluted the
      averaged responses to the different trains. Spatio-temporal multiple dipole
      modelling in relation to 3D MRI scans revealed two overlapping source components
      in both the left and right auditory cortex. The primary sources in the medial
      part of Heschl's gyrus exhibited a N19-P30-N40 m pattern. The secondary, weaker
      sources at more lateral sites on Heschl's gyrus showed a N24-P36-N46 m pattern.
      When applied to transient middle latency auditory evoked fields (MAEFs) recorded
      at SOAs of 95-135 ms, the primary sources imaged activities similar to the
      deconvoluted steady-state responses, but the secondary source activities were
      inconsistent. Linear summation of the deconvoluted source waveforms accounted for
      more than 96% of the steady-state variance. This indicates that the primary
      activity of the auditory cortex remains constant up to high stimulation rates and
      is not specifically enhanced around 40 Hz.

PMID- 10400200
TI  - Regional differences in the dynamics of the cortical EEG in the rat after sleep
      deprivation.
AB  - OBJECTIVE: To investigate regional changes of the cortical sleep EEG in the rat,
      recordings were obtained from a frontal and an occipital derivation, on a
      baseline day (n = 14 male rats, Sprague-Dawley strain) and after 24 h sleep
      deprivation (SD, n = 7). METHODS: Spectral analysis of the vigilance states
      revealed state and frequency specific differences in EEG power by two-way ANOVA
      and post-hoc t tests. RESULTS: In the theta band (6.25-9.0 Hz) occipital power
      was larger than frontal power in waking and REM sleep, whereas frontal power was
      larger in the frequency range between 10.25-16.0 Hz in non-REM sleep and REM
      sleep. After SD frontal power in the 2-4 Hz band in non-REM sleep was increased
      more than occipital power and frontal power in the 10.25-16.0 Hz range was more
      attenuated. In REM sleep frontal power in the theta band and in the 10.25-16.0 Hz
      range was more increased than occipital power. Power in the waking EEG did not
      differ between the two derivations after SD. CONCLUSIONS: The differential
      responses to SD may reflect regional use-dependent aspects of sleep regulation.
      These observations support the notion that sleep is not only a global phenomenon
      but has also local, use-dependent features.

PMID- 10400202
TI  - Multifold features determine linear equation for automatic spike detection
      applying neural nin interictal ECoG.
AB  - OBJECTIVE: A 3-layer detection procedure was designed including preselection
      applying TEMPLAS software, feature extraction and artificial neural networks to
      determine a fast, precise and highly selective spike algorithm. METHODS: Ten
      intraoperative ECoG recordings of patients with temporal lobe epilepsy were
      computer-assisted and evaluated by 3 experts upon preselected events. For each
      event, 19 features were extracted, normalized and fed into a two-layer and 3
      layer feedforward, back-propagate network. The weights of the 5 best individual
      two-layer networks of patients were averaged separately to derive a mean network,
      where weights were pruned, rounded off and the configuration approximated by a
      linear equation. RESULTS: In addition. when investigating latency histograms, a
      method for multi-channel artefact detection and elimination of too close intra
      channel events could be found. Out of several training trails only the mean
      network and the linear equation were able to generalize. In comparison with the
      results of 19 publications, the developed solution and the estimated overall
      detection rates (spikes: 81%; non-spikes: 99.3%) were found to be of high
      quality. The processing time is short, and therefore, the method can be used to
      initiate other measurements. CONCLUSION: The developed solution is a fast,
      precise and highly selective spike detection method.

PMID- 10400201
TI  - Losses of hemifield contrast sensitivity in patients with pituitary adenoma and
      normal visual acuity and visual field.
AB  - OBJECTIVE: To detect early losses of contrast sensitivity (CS) in patients with
      pituitary adenomas, before the occurrence of visual acuity and visual field
      defects. METHODS: CS has been evaluated in both hemifields of 28 patients with
      different kinds of pituitary adenoma (mainly intrasellar) and normal visual
      acuity and visual field, as well as in 15 age-matched controls. Two different
      stimuli were used: a coarse (0.3 c/deg) dynamic (10 Hz) grating and a finer (2
      c/deg) static grating. RESULTS: On average, CS and/or hemifield asymmetry were
      reduced in patients, whereas perimetric sensitivity was normal. CS losses were
      more frequent for 2 c/deg static-, as compared with 0.3 c/deg, 10 Hz stimuli.
      However selective losses for either stimuli were also found. CS losses did not
      correlate with anatomical measurements (size, chiasm involvement) of tumors as
      established by MRI scans. CONCLUSIONS: CS evaluation may provide a simple and
      effective tool for early detection and monitoring of visual dysfunction in
      patients with pituitary adenoma. The lack of correlation between CS losses and
      chiasm involvement suggests causes different from chiasmal compression for visual
      dysfunction.

PMID- 10400203
TI  - Comparison of sphenoidal, foramen ovale and anterior temporal placements for
      detecting interictal epileptiform discharges in presurgical assessment for
      temporal lobe epilepsy.
AB  - OBJECTIVES: Some authors have recently stressed that the position of the tip of
      the sphenoidal electrode plays a crucial role in its efficacy to detect mesio
      basal spikes. We have tested this hypothesis by comparing the sensitivity of a
      contact of a foramen ovale bundle located at the foramen ovale (CFO) with scalp
      electrodes in detecting interictal epileptiform discharges. We have also compared
      deep and superficial foramen ovale contacts in the same bundle in order to
      establish whether deeper contacts can detect epileptiform discharges not seen at
      the foramen ovale or on the scalp. METHODS: The sensitivity for detecting
      epileptiform discharges of simultaneous intracranial and scalp EEG recordings
      from 20 patients under telemetric presurgical assessment for temporal lobe
      epilepsy were compared. RESULTS: Out of 2280 epileptiform discharges evaluated,
      about 70% were seen only at the deep foramen ovale contacts. Out of the 722
      discharges recorded by CFO and/or scalp electrodes, 698 were seen at the CFO and
      690 at the scalp anterior temporal electrode. Only on 29 occasions (4.15%) were
      discharges recorded at the CFO and not at the anterior temporal electrode. On 21
      occasions (3.04%) CFO failed to detect discharges seen at the anterior temporal
      electrode. CONCLUSIONS: Our findings confirm previous results suggesting that
      sphenoidal electrodes, however accurately positioned, offer no significant
      increase in detection sensitivity compared with anterior temporal scalp
      electrodes. In addition, these results confirm that a large proportion of
      discharges seen at the deepest foramen ovale contacts are not seen either on the
      scalp nor at the superficial foramen ovale contacts.

PMID- 10400204
TI  - Somatosensory evoked fields to large-area vibrotactile stimuli.
AB  - We describe a method to apply large-area vibrotactile stimuli, based on a
      vibrating balloon, on the palms of both hands during evoked response studies.
      Magnetoencephalographic (MEG) signals were recorded with a whole-scalp
      neuromagnetometer from six healthy subjects while they held their hands on a
      balloon which was made to vibrate by delivering tones to it through a loudspeaker
      and a tube. The 200 Hz stimuli, presented once every 1 or 2 s in separate
      sessions, elicited prominent and replicable somatosensory evoked fields (SEFs)
      and also auditory evoked fields (AEFs) due to the concomitant sound. Source
      modelling allowed reliable differentiation between bilateral activation of the
      primary somatosensory (SI) cortices (peaks at 46-61 ms after the stimulus onset)
      and of the supratemporal auditory cortices (peaks at 104-126 ms). These simple
      vibrotactile stimuli could be useful for rapid and reliable identification of the
      somatosensory and auditory cortices, for example in presurgical evaluation of
      children.

PMID- 10400205
TI  - ERP evidence of developmental changes in processing of faces.
AB  - OBJECTIVES: There is disagreement in the behavioural literature, as to whether
      face processing undergoes qualitative or quantitative change with age. METHODS:
      We studied event-related potentials (ERPs) associated with facial processing in
      48 children (4-14 years) and 12 adults. Five categories of stimuli were
      presented: faces, cars, scrambled faces, scrambled cars, butterflies. The
      butterflies were targets (P = 12%); the other stimulus categories were equally
      represented and all were non-targets. RESULTS: An N170 was recorded only to the
      faces at posterior temporal sites and in adults it was largest at T6'. This
      component was seen across age groups, but at steadily increasing latencies in
      younger children. Age-related increases in N170 amplitude were found at T6'. In
      children under 12 years of age, the frontal P170 was not reliably seen.
      CONCLUSION: This study suggests that the underlying neural basis associated with
      processing faces matures in a gradual, quantitative manner throughout childhood.

PMID- 10400206
TI  - Somatosensory evoked magnetic fields from the primary somatosensory cortex (SI)
      in acute stroke.
AB  - We recorded somatosensory evoked magnetic fields (SEFs) to median nerve
      stimulation from 15 patients in the acute stage (1-15 days from the onset of the
      symptoms) of their first-ever unilateral stroke involving sensorimotor cortical
      and/or subcortical structures in the territory of the middle cerebral artery
      (MCA). Neuronal activity corresponding to the peaks of the N20m, P35m and P60m
      SEF deflections from the contralateral primary somatosensory cortex (SI) was
      modelled with equivalent current dipoles (ECDs), the locations and strengths of
      which were compared with those of an age-matched normal population. Four patients
      with pure motor stroke had symmetric SEFs. In one of the 4 patients with pure
      sensory stroke, and in 5 of the 7 patients with sensorimotor paresis, the SEFs
      were markedly attenuated or missing. All except one patient with abnormal SEFs
      had deficient two-point discrimination ability; especially the attenuation of
      N20m was more clearly correlated with two-point discrimination than with joint
      position or vibration senses. Of the different SEF deflections, P35m and P60m
      were slightly more sensitive indicators of abnormality than N20m, the former
      being affected in two patients with symmetric N20m. Three patients with pure
      sensory stroke and lesions in the opercular cortex had normal SEFs from SI. We
      conclude that the SEF deflections N20m, P35m and P60m from SI are related to
      cutaneous sensation, in particular discriminative to touch. The results also
      demonstrate that basic somatosensory perception can be affected by lesions in the
      opercular cortex in patients with functionally intact SI.

PMID- 10400207
TI  - Effects of intensity and order of stimuli presentation on AEPs: an analysis of
      the consistency of EP augmenting/reducing in the auditory modality.
AB  - OBJECTIVES: (1) To achieve a better understanding of the intensity dependence
      function of AEPs recorded at fronto-central and temporal electrode sites; (2) To
      assess the possible influence of the order of stimuli presentation on this
      function; and (3) To investigate if a subject's AEPs augmenting or reducing (A/R)
      tendency is consistent throughout two intra-session runs. METHODS: Two sequences
      of 288 stimuli of different intensities (60, 80, 90 and 110 dB SPL) were
      delivered to 29 psychology students. In the first run, stimuli were presented in
      4 consecutive blocks of 72 tones of each intensity, either in an ascendant (from
      lowest to loudest stimuli) or descendent (from loudest to lowest) way. In the
      second run, a pseudo-randomized sequence of stimuli of the 4 intensities was
      presented. RESULTS: (1) AEPs recorded at fronto-central electrodes showed a
      stronger intensity dependence than those recorded at temporal leads; (2) The
      delivery of tones of different intensities in an aleatory sequence provoked
      higher amplitudes at Fz and Cz - especially for the loudest tones - but not at
      temporal leads; (3) The individual's AEP responses to stimuli of increasing
      intensity are highly consistent throughout two intra-session runs. CONCLUSIONS:
      The different findings obtained for the fronto-central N1P2 and the T complex in
      relation to the effect of intensity and order of stimuli presentation may be
      explained in terms of the cortical origin of those components. The higher
      amplitudes found with an aleatory sequence, especially for the highest intensity
      stimuli, may reflect that these stimuli capture the subject's attention and
      provoke an enhancement of the N1 component. The implications of the present
      results for investigation into A/R and the clinical relevance of this phenomenon
      are discussed.

PMID- 10400208
TI  - The influence of temperature on nerve conduction in patients with chronic axonal
      polyneuropathy.
AB  - OBJECTIVES: To determine whether the increase in conduction velocity with
      temperature (deltav/deltaT) is decreased in axonal polyneuropathy and to compare
      methods to account for low limb temperature in electroneurography. METHODS:
      Median nerve motor and sensory conduction and tibial nerve motor conduction were
      measured in 19 patients with chronic idiopathic axonal polyneuropathy at baseline
      temperature, after warming at 37 degrees C, and after cooling at 25 degrees C.
      Deltav/deltaT was determined, using the skin temperature difference and the
      presumed nerve temperature difference of 12 degrees C. The baseline conduction
      velocity was corrected for 37 degrees C, using mean deltav/deltaT values for
      normal subjects taken from the literature. RESULTS: Deltav/deltaT was positively
      correlated with the conduction velocity after warming at 37 degrees C: the lower
      the conduction velocity, the lower the deltav/deltaT. In nerves with a slow
      conduction velocity, deltav/deltaT was often zero. As slower conducting nerve
      fibers have smaller deltav/deltaT values, the decreased deltav/deltaT values in
      our study are probably related to loss of fast conducting fibers. The corrected
      conduction velocity was usually faster and considerably less often abnormal than
      the conduction velocity after warming at 37 degrees C. The latter can be
      considered the gold standard. CONCLUSION: Deltav/deltaT may be reduced in axonal
      polyneuropathy. The correction method is, therefore, not suitable to account for
      low limb temperature, as the conduction velocity is overestimated.

PMID- 10400209
TI  - A model of the effect of MEP amplitude variation on the accuracy of TMS mapping.
AB  - We have modelled the effect of motor evoked potential (MEP) amplitude variation
      on transcranial magnetic stimulation (TMS) maps. The range of variability in TMS
      map parameters was estimated by randomly altering the MEP amplitude associated
      with each stimulus site and re-calculating the map parameters. TMS map position
      and area were remarkably stable, with variations of the order of 1 mm for map
      position and less than 5% for map area. The results indicate that reliable and
      accurate mapping studies can be carried out in the presence of an intrinsic
      variability in MEP amplitude measurements.

PMID- 10400210
TI  - Electromyographic evidence for functional heterogeneity in the inferior head of
      the human lateral pterygoid muscle: a preliminary multi-unit study.
AB  - OBJECTIVE: Functional heterogeneity, i.e. regional or selective activation of
      subpopulations of fibres within a muscle, has been described in some jaw and limb
      muscles. Each head of the lateral pterygoid muscle may also be functionally
      heterogeneous. The aims of this investigation were to develop a technique to test
      this hypothesis, and to use this technique to determine whether there is any
      multi-unit electromyographic (EMG) evidence for functional heterogeneity within
      the inferior head of the lateral pterygoid (IHLP). METHODS: In 3 human subjects
      without craniomandibular disorders, recordings were made of condylar movement and
      multi-unit EMG activity from two sites in the IHLP during repeated trials of a
      contralateral (n = 21) and a protrusive (n = 26) jaw movement. The recording
      sites within IHLP were approached extraorally (labelled IHLP-extra) and were
      verified by computer tomography (CT); the other (IHLP-intra) were from sites in
      IHLP approached intraorally. RESULTS: In each subject, the time of occurrence of
      the peak filtered signal from IHLP-extra was significantly different (P<0.05)
      from IHLP-intra for all protrusion trials but not for contralateral trials.
      CONCLUSIONS: The data suggest a task-dependent change in motor unit recruitment
      order within IHLP and that IHLP is functionally heterogeneous.

PMID- 10400211
TI  - Soleus long-latency stretch reflexes during walking in healthy and spastic
      humans.
AB  - The present study was carried out to investigate the long-latency soleus stretch
      reflexes M2 (peak latency of approximately 85 ms) and M3 (peak latency of
      approximately 115 ms) during walking in healthy and spastic multiple sclerosis
      (MS) patients. An 8 degrees stretch was applied to the ankle extensors of the
      left leg in 8 healthy subjects during normal walking speed and 9 spastic MS
      patients and 10 age-matched healthy subjects during slow walking. When present in
      walking healthy subjects, M2 and M3 were modulated in a similar way and with the
      same amplitudes as previously described for the short latency soleus stretch
      reflex (M1). The spastic patients' soleus M1 was significantly less modulated
      during walking. The patients' M2 long-latency response was modulated in the same
      way as the age-matched healthy subjects. All patients' M3 responses were absent
      or much suppressed during walking. The origin and functional importance of the
      short- and long-latency stretch reflexes in healthy and spastic persons are
      discussed in relation to the above findings and the behaviour of the stretch
      reflexes during matched isometric contractions. M3 is argued to be part of a
      transcortical reflex in healthy subjects.

PMID- 10400212
TI  - Electromechanical coupling and synchronous firing of single wrist extensor motor
      units in sporadic amyotrophic lateral sclerosis.
AB  - Electrical and contractile properties of motor units (MU) were studied in the
      extensor carpi radialis muscles during voluntary contraction. The discharge of
      234 single MUs was recorded in 11 patients with sporadic amyotrophic lateral
      sclerosis (ALS) and compared with that of the 260 MUs recorded in 12 healthy
      control subjects. Characteristics of the MU twitches and of the macro-potentials,
      the electromechanical coupling and the synchronization of the motor neurone
      discharges, were compared. In 5 patients (population ALS1), the twitch
      contraction force and macro-MUP area values were much larger than those of the
      controls. In the 6 other patients (population ALS2), the twitch force was
      considerably depressed, whereas the macro-MUP area was slightly, but
      significantly, increased. In ALS1, as well as in ALS2, the electromechanical
      coupling was much weaker than in the controls, and the fast-contracting MUs were
      more severely affected than the slowly contracting MUs. The motoneuronal
      synchronization was assessed by performing cross-correlation analysis on MUs
      discharges, and was used as an index to the strength of the common motoneuronal
      inputs. The rate of occurrence of synchronous firing was conspicuously lower in
      both populations of patients than in the control group. This might reflect the
      loss of corticospinal projections that occurs in ALS. The data are discussed in
      terms of the time course of motor neurone axonal sprouting, and in terms of the
      neuronal and muscular dysfunction possibly involved in ALS disease.

PMID- 10400213
TI  - Motor neuron disease: usefulness of transcranial magnetic stimulation in
      improving the diagnosis.
AB  - Clinical upper motor neuron (UMN) involvement is sometimes difficult to detect in
      motor neuron disease (MND). For this reason we performed transcranial magnetic
      stimulation (TMS) to find out whether this technique may be useful in revealing
      signs of pyramidal tract impairment. Fifty-five MND patients, clinically divided
      into 22 amyotrophic lateral sclerosis (ALS), 18 ALS with probable UMN signs (ALS
      PUMNS), 10 pure lower motor neuron syndrome (LMNS), and 5 progressive bulbar
      palsy (PBP), underwent standard TMS, recording from abductor digiti minimi and
      flexor allucis muscles. Prolongation of cortical motor evoked potential (MEP)
      latency and central conduction time (CCT) and absent MEP were considered as
      pathologic. ALS-PUMNS and LMNS patients were clinically reclassified after 1
      year. TMS was abnormal in 95.4% of ALS, 72.2% of ALS-PUMNS, 50% of LMNS and 20%
      of PBP. Correlations between TMS parameters and both clinical signs of UMN
      involvement and disease severity were highly significant. TMS showed a high
      sensitivity, but lacked specificity. After 1 year, 11 patients among the ALS
      PUMNS group were clinically reclassified as definite ALS: all of them had shown
      TMS abnormalities at the first examination. In conclusion, TMS provides important
      diagnostic information for an early prediction of ALS in those MND patients
      presenting with clinically equivocal UMN impairment.

PMID- 10400215
TI  - A new way of building a database of EEG findings.
AB  - Whereas computer-based electroencephalography (EEG) is widely applied, the EEG
      interpretations are usually not stored in a way that favours exploitation of
      modern computer technology. This paper reports an EEG description system
      facilitating categorization of EEG data in a computerized database. The system
      interactively communicates with the digital EEG system and also with the general
      patient administrative system. The main new quality of this system is the methods
      for data input and automatic data retrieval from several systems, rather than the
      establishment of a database of EEG data itself. The EEGs are visually analysed
      and categorized. Manually marked EEG events are automatically transferred to the
      database and such events as well as defined electrode positions within these
      epochs are directly linked to their corresponding descriptions. The database is
      updated without demand for filling in the events in the database in a second
      operation. Thereby, the EEG interpreter builds the database while analysing the
      EEG. This system provides an improved accessibility of EEG data for clinical,
      normative, educational and scientific use.

PMID- 10400214
TI  - Separation of contamination caused by coil clicks from responses elicited by
      transcranial magnetic stimulation.
AB  - Transcranial magnetic stimulation (TMS) is accompanied with loud clicks that
      evoke auditory responses in the brain, confounding several types of TMS studies.
      We investigated the effects of these clicks with high-resolution EEG by applying
      TMS pulses at 3 magnitudes, with the coil placed either at 10 or 50 mm over the
      subjects' vertex and recording event-related potentials (ERPs). The clicks were
      found to elicit a positively displaced response at 150-250 ms post-TMS.
      Furthermore, clicks were found to interact with simultaneously presented auditory
      sinewave stimuli, resulting in an amplitude decrease in the auditory N1 response.

PMID- 10400216
TI  - Melanin-concentrating hormone expression in slice cultures of rat hypothalamus is
      not affected by 2-deoxyglucose.
AB  - In rats, melanin-concentrating hormone (MCH) neurons are mainly located within
      the lateral hypothalamic area (LHA). This area is known to be involved in the
      control of feeding and to contain glucose-sensitive cells. As a role for MCH in
      the regulation of food intake has been reported, we investigated the effects of 2
      deoxyglucose (2DG) on MCH expression in cultured LHA slices, to verify if MCH
      neurons are sensitive to local glucoprivation through a modulation of MCH
      synthesis. After a 2-10 h 2DG incubation, competitive reverse transcription
      polymerase chain reaction (RT-PCR) did not show any variation of MCH mRNA; no
      change was also observed in MCH immunocytochemical labeling. A slight decrease of
      MCH mRNA (5-15%) after a 17 h 2DG treatment might be due to a general degradation
      of neurons induced by long-term glucoprivation. In conclusion, we suggest that
      MCH neurons are not the glucose-sensitive cells previously described in the LHA
      and that the signals inducing their previously reported response to glycemia
      variations do not arise from the LHA itself.

PMID- 10400217
TI  - Repeated stress increases catalytic TrkB mRNA in rat hippocampus.
AB  - Northern blot analysis was utilized to distinguish between catalytic and
      truncated TrkB mRNA on the basis of transcript size. Repeated (10 days), but not
      acute, immobilization stress significantly increased levels of catalytic TrkB
      mRNA, but did not influence expression of truncated TrkB transcripts in rat
      hippocampus. Exposure to another paradigm, a combination of different,
      unpredictable stressors, also increased levels of catalytic, but not truncated,
      TrkB mRNA. In situ hybridization analysis demonstrated that chronic stress up
      regulated TrkB mRNA in CA1 and CA3 pyramidal and dentate gyrus granule cells
      layers of hippocampus. As previously reported, both acute and chronic
      immobilization stress decreased expression of BDNF mRNA, suggesting that up
      regulation of catalytic TrkB mRNA may be a compensatory adaptation to repeated
      stress.

PMID- 10400218
TI  - The distribution and gene expression of adrenomedullin in the rat brain:
      peptide/mRNA and precursor/active peptide relationships.
AB  - The highest immunoreactive adrenomedullin (AM) concentrations were found in the
      pituitary gland, hypothalamus and brainstem. Rat preproadrenomedullin mRNA levels
      were highest in the pituitary, followed by the hypothalamus. The peptide to mRNA
      ratios are higher in the neurointermediate lobe, brainstem and hypothalamus.
      Immunocytochemical study showed discrete localization of AM immunostaining in
      various brain regions including the cerebral cortex, hypothalamus and brainstem
      and in the pituitary gland. By gel filtration chromatography, the precursor peaks
      were low in the pituitary, hypothalamus and brainstem but high in other brain
      regions.

PMID- 10400219
TI  - Thalamic asymmetry is related to acoustic signal complexity.
AB  - Hemispheric asymmetries in response to speech sounds are well documented.
      However, it is not known if these asymmetries reflect only cortical hemispheric
      specialization to language or whether they also reflect pre-conscious encoding of
      signals at lower levels of the auditory pathway. This study examined differences
      in neural representations of signals with acoustic properties inherent to speech
      in the left versus right side of the thalamus. Specifically, 2000 Hz tone bursts,
      clicks and synthesized forms of the phoneme /da/ were presented to anesthetized
      guinea pigs. Evoked responses were recorded simultaneously from aggregate cell
      groups in the left and right medial geniculate bodies. Results showed an
      asymmetric response to complex auditory stimuli between the left versus right
      auditory thalamus, but not to the simple tonal signal. Moreover, asymmetries
      differed in male versus female animals.

PMID- 10400220
TI  - Nicergoline facilitates vestibular compensation in aged male rats with unilateral
      labyrinthectomy.
AB  - The ergoline derivatives, nicergoline (NIC) or dihydroergocristine (DHE) were
      administered at various doses (0.1, 0.5 and 1 mg/kg) to aged male rats subjected
      to labyrinth unilateral lesion (LBX). The nystagmus rate appeared to be lower in
      animals treated with DHE or NIC 1mg/kg than in saline-injected rats, when
      observed on day 1 and 2 after operation. The number of falls in the rotorod test
      of LBX animals was decreased by NIC 0.5 or 1 mg/kg at all observation times. This
      parameter was affected by DHE only at the higher dose. These results suggest that
      NIC facilitates vestibular compensation of LBX rats. DHE appeared to be less
      potent in this respect. Since both drugs act on central dopaminergic
      neurotransmission, it is possible that this neurotransmission may be involved in
      their mechanism of action.

PMID- 10400221
TI  - Angiotensin converting enzyme deletion allele in different kinds of dementia
      disorders.
AB  - In order to verify the association of Angiotensin converting enzyme (ACE) gene
      with different kinds of dementia, as well as its association with APO-E
      (genotype), we performed ACE genotyping in subjects with late-onset probable
      Alzheimer's disease (LOAD, n = 64), early-onset probable Alzheimer's disease
      (EOAD, n = 32), possible Alzheimer's disease (pAD, n = 44), vascular dementia
      (VD, n = 12), age-associated memory impairment (AAMI, n = 15) and 40 healthy age
      matched controls, who were previously characterized for APO-E. After the
      principal component analysis ACE D and Apo-Eepsilon4 alleles disclosed the
      highest prevalence in the cognitively impaired groups of subjects, Apo-Eepsilon4
      being more specific for LOAD and pAD. ACE D allele seems to be an unspecific
      susceptibility factor for mental decline.

PMID- 10400222
TI  - Anti-analgesia and reduced antinociception from supraspinally administered beta
      endorphin in stressed rats: dependence on spinal cholecystokinin via
      cholecystokinin B receptors.
AB  - Rats exposed to the stress of repeated exposure to a noxious heat source (52.5
      degrees C, hot plate) exhibit stress-induced analgesia, but reduced
      antinociception (detected using the tail-flick test) to the administration of
      beta-endorphin into the periaqueductal gray region of the brain. This is
      accompanied by an anti-analgesic response (reduction in the stress-induced
      increase of tail flick latency) to doses of beta-endorphin (0.03 nmol) lower than
      those usually associated with antinociception. These alterations are prevented
      and antinociceptive potency is maintained when rats are treated with
      cholecystokinin (CCK) antagonists intrathecally. The potency of L-365,260 and L
      364,718, selective CCK(B) and CCK(A) receptor antagonists, respectively,
      correlated with their apparent affinities for CCK(B) receptors, suggesting that
      the altered sensitivity to beta-endorphin is mediated via CCK(B) receptors.

PMID- 10400223
TI  - Mechanical sensitization of cutaneous C-fiber nociceptors by prostaglandin E2 in
      the rat.
AB  - While it is generally assumed that nociceptor sensitization underlies peripheral
      hyperalgesia, there is disagreement regarding the ability of inflammatory
      mediators to sensitize nociceptors to mechanical stimuli. In this in vivo
      electrophysiological study, mechanical threshold and response to sustained
      threshold and sustained suprathreshold mechanical stimuli were measured before
      and after intradermal administration of prostaglandin E2 (PGE2) into the
      receptive field of cutaneous C-fiber nociceptors in the rat. PGE2 produced a
      decrease in mechanical threshold and an increase in response to sustained
      threshold but not sustained suprathreshold mechanical stimulation. These data
      suggest that while inflammatory mediators produce a decrease in mechanical
      threshold and/or an increase in number of action potentials to sustained
      threshold stimuli, they do not increase the maximal response to mechanical
      stimuli in C-fiber nociceptors.

PMID- 10400224
TI  - The neuroprotective effect of DL-tetrahydropalmatine in rat heatstroke.
AB  - After the onset of heatstroke, rats with saline injection displayed hyperthermia,
      decreased mean arterial pressure, decreased cerebral blood flow, increased brain
      monoamine release, and increased neuronal damage score compared with those of
      normothermia, control rats. The heatstroke-induced hyperthermia, arterial
      hypotension, cerebral ischemia, brain monoamine overload, and cerebral neuronal
      injury were attenuated by pretreatment with dl-tetrahydropalmatine. The data
      indicate that DL-tetrahydropalmatine pretreatment provides neuroprotective effect
      in heatstroke.

PMID- 10400225
TI  - Distribution of prolactin-releasing peptide-immunoreactive neurons in the rat
      hypothalamus.
AB  - A newly identified hypothalamic peptide whose specific receptors are present in
      the anterior pituitary gland is a selective and potent stimulator of prolactin
      secretion and is therefore termed prolactin-releasing peptide (PRP). We
      investigated the distribution of PRP-containing neurons in the hypothalamus of
      female rats by immunocytochemical techniques. Immunocytochemistry using a
      specific antibody raised to PRP revealed that PRP-immunoreactive perikarya were
      located in the posteroventral part of the dorsomedial nucleus of the
      hypothalamus. PRP-immunoreactive nerve terminals were present in high
      concentrations in a region ventral to the bed nucleus of the stria terminalis,
      but scarcely observed in the external layer of the median eminence in which well
      known hypothalamic hormones such as growth hormone-releasing hormone and
      somatostatin were abundantly detected. This specific distribution in the
      hypothalamus suggests a novel route of the hypophysiotropic action of PRP.

PMID- 10400226
TI  - Supersensitization of the adenylyl cyclase system in Chinese hamster ovary cells
      co-expressing cloned opioid receptors and Gz, a PTX-insensitive G protein.
AB  - Chronic and/or sustained stimulation of opioid receptors has been shown to lead
      to an increase in activity of the adenylyl cyclase (AC) system via pertussis
      toxin (PTX)-sensitive Gi/o, family G protein. In the present study, we examined
      whether supersensitization of the AC system is induced via a PTX-insensitive G
      protein, Gz, activation of which leads to the inhibition of AC activity. In
      Chinese hamster ovary (CHO) cells expressing either mu- or kappa-opioid
      receptors, acute treatment with morphine or U69,593, but not naloxone or
      norbinaltorphimine, respectively, suppressed forskolin-induced cyclic AMP (cAMP)
      accumulation, while sustained (4 h) treatment with the opioid agonists induced
      cAMP overshoot above the naive level (supersensitization of the AC system). Both
      effects were completely blocked by pretreatment with PTX. In CHO cells co
      expressing mu- or kappa-opioid receptors and alpha(z), inhibitory effects of cAMP
      accumulation by acute treatment with the opioid agonists and supersensitization
      of the AC system by sustained treatment with them were induced despite
      pretreatment with PTX. These data suggest that supersensitization of the AC
      system is induced by sustained opioid agonist treatment not only via Gi/o but
      also via Gz.

PMID- 10400227
TI  - Presenilin-1 exists in the axoplasm fraction in the brains of aged Down's
      syndrome subjects and non-demented individuals.
AB  - Missense mutations in the presenilin-1 (PS-1) gene are known to be responsible
      for early-onset familial Alzheimer's disease (AD). The normal physiological
      functions of PS-1 are still incompletely understood, although data on the
      intracellular localization of PS-1 are accumulating, indicating that it exists
      mainly in endoplasmic reticulum and Golgi compartments. To investigate the
      localization and functions of PS-1 in the human brain, we separated axoplasm
      fractions from the cerebral white matter of Down's syndrome (DS) subjects with AD
      pathology and non-demented individuals using the axonal flotation method, and
      analyzed them immunocytochemically. All axoplasm fractions contained the 28-34
      kDa amino-terminal fragment and the 18 kDa carboxy-terminal fragment of PS-1,
      although there was no specific abnormality of this protein in the DS brains with
      AD pathology. This finding indicates that there is intracellular trafficking of
      PS-1 through the axons in the human brain, and thus provides new information
      about the physiology of PS-1.

PMID- 10400229
TI  - Tremor-frequency (3-6 Hz) activity in the sensorimotor arm representation of the
      internal segment of the globus pallidus in patients with Parkinson's disease.
AB  - Neurons in the internal segment of the globus pallidus (GPi) oscillate at
      approximately the frequency of parkinsonian tremor. However, the correlation of
      that activity with tremor has not previously been studied. We now describe the
      relationship between single neuron activity in the arm sensorimotor portion of
      GPi and upper extremity tremor in patients with Parkinson's disease. There was a
      significant concentration of power in the tremor-frequency range (3-6 Hz) for
      11/44 GPi neurons. However, pallidal tremor-frequency activity correlated
      significantly with electromyogram (EMG) activity during tremor for only a single
      GPi neuron. These data are most consistent with the hypothesis that the output of
      neurons in GPi is transformed in thalamus by a non-linear mechanism, before
      transmission via the cortex to the spinal motorneurons that drive movement.

PMID- 10400228
TI  - Urocortin mRNA is expressed in the enteric nervous system of the rat.
AB  - The expression of the urocortin gene in the gastrointestinal tract was
      investigated using reverse transcription polymerase chain reaction (RT-PCR) and
      in situ hybridization histochemistry. PCR demonstrated the presence of urocortin
      mRNA in the rat brain, duodenum, small intestine, and colon. By in situ
      hybridization, urocortin-containing cells were exclusively localized to the
      submucosal plexus and myenteric plexus in the duodenum, small intestine and
      colon. These results suggest that urocortin may play an important role in the
      regulation of gastrointestinal motor function throughout the enteric nervous
      system.

PMID- 10400231
TI  - Apolipoprotein E immunoreactivity in human and mouse olfactory bulb.
AB  - We evaluated the distribution of apolipoprotein E (apoE) immunoreactivity in
      mouse and human olfactory bulbs. ApoE immunoreactivity was present in the
      olfactory nerve and around the glomeruli. Immunoreactivity was seen in somata
      that appeared to be glial. No neuronal staining was seen. The apoE
      immunoreactivity was also present in the mouse olfactory bulb subependymal layer.
      The specificity of immunoreactivity was confirmed with apoE-deficient mice (apoE
      gene knock-out mice, apoE KO) which did not display any immunoreactivity. The
      presence of apoE around glomeruli and nerve suggest that apoE is associated with
      the continuous degeneration and regeneration processes that occur in the
      olfactory nerve. Experimental manipulation of the olfactory nerve may be a useful
      technique to determine the functions of apoE in a well-defined neural system.

PMID- 10400230
TI  - Age-related changes in serotonin in the hypoglossal nucleus of rat: implications
      for sleep-disordered breathing.
AB  - We are attempting to determine the neuronal factors that influence upper airway
      patency during sleep in the elderly. Serotonin has a facilitatory effect on
      hypoglossal motoneurons that innervate the tongue, and manipulations of the
      serotonergic system alter airway patency. We hypothesized that age-associated
      changes in serotonergic input to the hypoglossal nucleus might be a factor in the
      increased susceptibility to sleep-disordered breathing in the elderly. We used
      light microscopic immunocytochemistry to study the distribution of serotonin in
      the hypoglossal nucleus in young and old rats. Rats > 18 months had fewer
      serotonin immunoreactive axons and boutons in the hypoglossal nucleus than rats <
      6 months. These data suggest that normal aging may result in a change in the
      availability of serotonin that results in decreased facilitation of hypoglossal
      motoneurons.

PMID- 10400233
TI  - Naturally occurring somatic motoneuron death in a teleost angelfish, Pterophyllum
      scalare.
AB  - Naturally occurring somatic motoneuron death in a teleost angelfish, Pterophyllum
      scalare, was investigated histochemically and electron microscopically. The
      number of motor axons in the ventral root, which corresponds to the motoneuron
      number in spinal hemisegment, was rapidly increased beyond the adult value within
      3 days after hatching, and then decreased to reach the adult value within a few
      weeks. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate
      biotin nick end labeling (TUNEL) histochemistry, which detects fragmented nuclear
      DNA characteristic to apoptotic cells, showed that the apoptotic cells are
      located in the motor column of the cord in the larvae at specific developmental
      stages. Electron microscopic observations of the spinal cells further confirmed
      the motoneuron apoptosis. The present data suggest that the massive death of
      somatic motoneurons at certain ontogenic stages which has been known to occur in
      higher vertebrates also takes place in fish.

PMID- 10400232
TI  - Inhibition of neurite outgrowth by familial Alzheimer's disease-linked presenilin
      1 mutations.
AB  - Two (P117L; M146L) familial Alzheimer's disease (FAD)-causing presenilin-1 (PS1)
      mutations have been tested fortheir effect in stably transfected mouse
      neuroblastoma (N2a) cell lines. The P117L mutation is associated with the
      earliest onset of AD reported so far (24 years), while the M146L is less
      pathogenic with the onset at about 43 years. Overexpression of wild-type (wt) PS1
      gene was associated with the marked increase in the number and the length of
      neuritic outgrowths accompanied by accumulation of PS1 immunoreactivity in
      neurites. The highly pathogenic P117L mutation completely suppressed this effect
      and the pattern of PS1 immunolabeling resembled a cup structure with all
      immunoreactivity gathered at one pole of the cell. The effect of less pathogenic
      M146L mutation was similar, but not as pronounced. These findings suggest that
      one of the normal functions of PS1 may be the control of neurite outgrowth, and
      the inhibitory effect of two FAD-linked mutations stresses its importance in the
      cellular mechanism that leads to the development of Alzheimer's disease (AD).

PMID- 10400235
TI  - EEG patterns in theta and gamma frequency range and their probable relation to
      human voluntary movement organization.
AB  - In experiments with EEG accompanying continuous slow goal-directed voluntary
      movements we found abrupt short-term transients (STs) of the coefficients of EEG
      time-varying autoregressive (TVAR) model. The onset of STs indicated (i) a
      positive EEG wave related to an increase of 3-7 Hz oscillations in time period
      before the movement start, (ii) synchronization of 35-40 Hz prior to movement
      start and during the movement when the target is nearly reached. Both these
      phenomena are expressed predominantly over supplementary motor area, premotor and
      parietal cortices. These patterns were detected after averaging of EEG segments
      synchronized to the abrupt changes of the TVAR coefficients computed in the time
      course of EEG single records. The results are discussed regarding the cognitive
      aspect of organization of goal-directed movements.

PMID- 10400234
TI  - Hypoxia stimulates cerebral blood flow in the estuarine crocodile (Crocodylus
      porosus).
AB  - The effect of N2 respiration on cerebral blood flow (CBF) velocity on the dorsal
      surface of cerebellum was examined in the estuarine crocodile, Crocodylus
      porosus, using epi-illumination microscopy. Twelve minutes of N2 respiration
      resulted in a 126% increase in CBF velocity. N2 respiration had no effect on
      blood pressure, indicating an underlying cerebral vasodilation. In addition,
      heart rate increased significantly. Systemic injections of aminophylline and the
      NO synthase (NOS) inhibitor nitro-L-arginine (L-NA) did not affect the hypoxia
      induced increase in CBF. We conclude that C. porosus responds to hypoxia with
      adenosine and nitric oxide (NO) independent cerebral vasodilation, and that this
      is likely to be a mechanism protecting the brain from energy deficiency during
      prolonged dives.

PMID- 10400236
TI  - Evidence for extensive inter-connections within the zona incerta in rats.
AB  - We have examined whether there is an extensive system of inter-connections
      between the functionally distinct sectors of the zona incerta (ZI) of the
      thalamus. Unilateral injections of biotinylated dextran were made into each of
      the different incertal sectors (rostral, dorsal, ventral and caudal) of Sprague
      Dawley rats by using stereotaxic coordinates. Our results show that after
      separate injections limited to each of the incertal sectors, many labelled
      terminals and cells were seen across the different sectors of the ipsilateral, as
      well as the contralateral side, with the heaviest labelling being on the side
      ipsilateral to the injection. Thus, these results suggest that the ZI is in a
      position to integrate an extensive array of afferents from many functionally
      diverse neural centres of the brain.

PMID- 10400237
TI  - Extracellular superoxide dismutase deficiency worsens outcome from focal cerebral
      ischemia in the mouse.
AB  - The role of endogenous extracellular superoxide dismutase (EC-SOD) was examined
      in a murine model of transient focal cerebral ischemia. Homozygous EC-SOD
      deficient (EC-SOD-/-; n = 18) and wild type (EC-SOD+/+; n = 19) littermates were
      anesthetized with halothane and subjected to 50 min of intraluminal middle
      cerebral artery occlusion with pericranial temperature maintained at 37.0 degrees
      C. After 24 h of reperfusion, resultant hemiparesis and cerebral infarct size
      were measured. Total infarct volume was 81% greater (P = 0.03) and hemiparesis
      was more severe (P = 0.01) in EC-SOD-/- versus EC-SOD+/+ mice. The worsened
      ischemic outcome observed in EC-SOD-/- mice is consistent with prior work which
      found transgenic EC-SOD overexpressing mice to exhibit enhanced tolerance to
      focal ischemia. The results suggest that endogenous antioxidant activity in the
      extracellular compartment plays an important role in the histologic/neurologic
      response to focal cerebral ischemia.

PMID- 10400238
TI  - Estrogen receptor-alpha-immunoreactive neurons in the mesencephalon, pons and
      medulla oblongata of the female golden hamster.
AB  - Recent studies have revealed brainstem-spinal pathways involved in the generation
      of receptive behavior in hamster and cat, and the enormous influence of estrogen
      on these pathways. The present study gives an overview of the location of
      estrogen receptor-alpha-immunoreactive neurons (ER-alpha-IR) in the brainstem of
      the female hamster. In the mesencephalon, ER-alpha-IR cells were found in the
      arcuate and peripeduncular nuclei as well as throughout the rostrocaudal extent
      of the periaqueductal gray (PAG), and the laterally adjoining tegmentum. In the
      caudal brainstem, groups of ER-alpha-IR cells were present in the ventrolateral
      parabrachial nucleus, the solitary nucleus, and in contrast to the cat, in the
      nucleus retroambiguus. No ER-alpha-IR cells were found in any other part of the
      brainstem. The functional implications of these findings are discussed.

PMID- 10400239
TI  - Quantification of neuron survival in monolayer cultures using an enzyme-linked
      immunosorbent assay approach, rather than by cell counting.
AB  - The determination of neurotoxicity in monolayer mixed cultures has traditionally
      necessitated the time consuming and subjective procedure of counting neurons. In
      this paper, we propose a modification of an immunohistochemical staining method
      with a neuron-specific antibody against MAP2, that allows for quantification of
      neuron number to be done using an enzyme-linked immunosorbent assay (ELISA) plate
      reader. This new procedure involves the use of the compound 2,3'-azino
      bis(ethylbenzothiazoline-6-sulphonic acid) (ABTS) at the last stage of the
      staining procedure. We employed two neurotoxicity models (the excitotoxin kainic
      acid and the interactions between gp120, the glycoprotein of HIV, and the stress
      hormone corticosterone) to compare the results obtained with this new method and
      the old method of immunohistochemical staining followed by 3,3'-daminobenzidine
      (DAB) and the counting of neurons. The ABTS/ELISA method was found to be a fast,
      reliable and objective procedure for the quantification of neurotoxicity.

PMID- 10400240
TI  - Potentiation of beta-folding of beta-amyloid peptide 25-35 by aluminum salts.
AB  - The formation of the beta pleated configuration of the amyloid peptide fragment
      25-35 in aqueous solution, has been studied using thioflavin-T fluorescence as an
      indicator of such folding. Both phosphate and adenosine triphosphate (ATP)
      enhance the formation of aggregated beta-sheets. This phosphate-induced
      aggregation is greater in the presence of aluminum sulfate in a dose dependent
      manner. In the absence of ATP or phosphate, aluminum salts do not promote
      aggregation. It is proposed that a particulate aluminum phosphate complex may
      form critical nuclei upon whose surface the amyloid peptide can change its
      configuration. This capacity for seeding may be a relevant factor in the
      formation of insoluble proteinaceous materials such as amyloid plaques and
      neurofibrillary tangles found in Alzheimer's disease.

PMID- 10400242
TI  - Efficacy of delayed or discontinuous FK506 administrations on nerve regeneration
      in the rat sciatic nerve crush model: lack of evidence for a conditioning lesion
      like effect.
AB  - We examined whether the nerve regenerative property of FK506 exhibits a 'window
      of-opportunity' corresponding to the time of injury for maximal efficacy in the
      sciatic nerve crush model. FK506 (5 mg/kg, s.c.) was administered over the 18-day
      period of study according to three dosage regiments: delayed (days 9-17),
      discontinuous (days 0-8) and continuous (days 0-17) administrations. Quantitation
      of axonal calibers and the extend of myelination in the soleus nerve at 18 days
      demonstrated that both delayed and discontinuous administrations were equally
      effective, arguing against a 'window-of-opportunity' for FK506 nerve regenerative
      effect. However, both protocols were less effective than continuous
      administration indicating that the compound needs to be given during the entire
      regenerative period to elicit maximal efficacy.

PMID- 10400243
TI  - D-aspartate is present in human retinoblastoma Y79 cells.
AB  - In mammals, D-aspartate is present in various neuroendocrine cells, being
      especially abundant in pinealocytes. Although D-aspartate is suggested to be
      involved in some neuroendocrine function, little is known about its origins as
      well as its physiological roles. In the present study, we found that an
      appreciable amount of D-aspartate (50.8 pmol/1 x 10(6) cells) is present in
      clonal human retinoblastoma Y79 cells. The amount of D-aspartate corresponds to
      28% of that in rat pinealocytes. The D-aspartate concentration did not change
      with the culture duration or passage, suggesting de novo biosynthesis of it.
      Thus, Y79 cells may constitute a suitable experimental system for studies on the
      biogenesis and signal transduction of D-aspartate in mammalian cells.

PMID- 10400241
TI  - Motivation effects in a dichotic listening task as evident from functional
      magnetic resonance imaging in human subjects.
AB  - The present study addresses the effect of motivation on cerebral activity using
      functional magnetic resonance imaging. Five healthy volunteers performed a
      dichotic listening task in two sets of three trials during which high or low
      levels of achievement motivation were introduced. They were told that the first
      set would be used for calculation of intellectual capacity (high achievement
      motivation) and the second set for scanner calibration (neutral motivation). In
      three volunteers, high compared with neutral motivation produced activation in
      the right prefrontal cortex and the dorsal cingulate. We conclude that
      motivational effects may lead to significant activations and should be controlled
      in future cognitive imaging studies. We present preliminary evidence that right
      prefrontal and dorsal cingulate regions might be involved in motivational
      processes.

PMID- 10400244
TI  - Maternal separation: hypothalamic-preoptic area and hippocampal calbindin-D28K
      and calretinin in male and female infantile rats.
AB  - Calcium-binding proteins (CaPs) potentially play important roles in neurogenesis
      and neuronal survival. Calbindin-D28K (CALB) and calretinin (CALRET) in the
      medial basal hypothalamic (and preoptic area) (MBH) and hippocampus (HIPPO) from
      control and maternally separated male and female infantile rats were examined by
      Western analysis. Significantly greater levels of the CaPs in the MBH vs. the
      HIPPO may suggest enhanced or decreased neuroprotection, respectively, during the
      stress hyporesponsive period (SHRP). Male infantile rats separated from their
      mother's from postnatal day 2-10 displayed significant changes in CALB and CALRET
      for the MBH (decrease) and HIPP (increase) brain sites suggesting possible
      modified (negative feedback) mechanism(s) in HPA dysfunction observed during
      postnatal life.

PMID- 10400245
TI  - Differential loss of spinal sensory but not motor neurons in the p75NTR knockout
      mouse.
AB  - Sensory neurons in the dorsal root ganglia (DRG) and motor neurons in the spinal
      cord express the 75 kDa low-affinity neurotrophin receptor (p75NTR) during
      prenatal development. The p75NTR gene knockout mouse provides a unique
      opportunity to assess the role of p75NTR during this period. Quantitative
      analysis of the p75NTR knockout mouse revealed a significant developmental loss
      of sensory neurons. In the cervico-thoracic ganglia approximately 75% of the
      neurons are lost, while in the lumbar ganglia the loss is approximately 50%. In
      contrast, motor neurons were not lost in either the cervical or lumbar spinal
      cord. These data suggest that p75NTR is essential for the prenatal survival of a
      significant number of sensory, but not motor neurons.

PMID- 10400246
TI  - Expression of integrins by murine MSC80 Schwann cell line: relationship to cell
      adhesion and migration.
AB  - Schwann cells (Sc) are one of the most important factors promoting regeneration
      of both the peripheral and the central nervous system. They provide a permissive
      environment for neurite outgrowth and the making of this environment requires
      interactions between Sc and extracellular matrix proteins that are mediated via
      integrin receptors. This study characterized, by immunoprecipitation, the
      integrins expressed by the mouse MSC80 Sc line. Our results showed that MSC80 Sc
      expressed alpha1beta1, alpha5beta1 and alpha6beta1 integrins as well as the alpha
      v-subunit associated with an unidentified 80-90 kDa beta-subunit. Adhesion and
      migration assays revealed a hierarchy of protein influences that are dependent
      upon the type of cellular behaviour. Integrin expression correlated with MSC80 Sc
      line adhesion and migration on extracellular matrix proteins. The MSC80 Sc line
      expressed a pattern of integrins which allowed adherence on vitronectin and
      collagen IV, and faster migration on merosin and laminin. As the integrin pattern
      and the behaviour of MSC80 on ECM were similar to primary Sc, MSC80 are a
      potential abundant source of Sc for further in vitro and in vivo experiments.

PMID- 10400247
TI  - Leukemia inhibitory factor expression is not induced in activated microglia and
      reactive astrocytes in response to rat basal forebrain cholinergic lesion.
AB  - In adult intact rat brain, leukemia inhibitory factor (LIF) mRNA has been found
      to be constitutively expressed in basal forebrain cholinergic neurons. To reveal
      a functional role of LIF in neurodegenerative events, the cellular expression
      pattern of LIF was determined by combining in situ hybridization and
      immunocytochemistry after specific and selective degeneration of basal forebrain
      cholinergic cells by a single intracerebroventricular application of the
      cholinergic immunotoxin 192IgG-saporin. Although basal forebrain cholinergic
      lesion resulted in a dramatic activation of micro- and astroglial cells at the
      lesion site, LIF mRNA expression was not detected in any of the lesion-induced
      activated glial cell types. As the cholinergic immunotoxin exerts its
      degenerative action by the ribosome-inactivating property of saporin, the lack of
      glial LIF induction might be due to the incapability of the dying cholinergic
      cell to form and release factors which induce LIF expression in activated glial
      cells.

PMID- 10400249
TI  - Pindolol potentiates the effect of fluoxetine on hippocampal seizures in rats.
AB  - Recent studies have shown that behavioral and neurochemical changes induced by
      selective serotonin (5-HT) reuptake inhibitors such as fluoxetine are potentiated
      by coadministration of a 5-HT1A receptor antagonist. The present study assessed
      the effects of concomitant administration of fluoxetine and a 5-HT1A receptor
      antagonist, pindolol, on focal hippocampal (HIP) seizures elicited by electrical
      stimulation in rats. A 10 mg/kg dose of fluoxetine, which was ineffective by
      itself, produced a significant increase in the afterdischarge threshold of HIP
      seizures when combined with pindolol at 10 mg/kg. The inhibitory effect of this
      combination was eliminated by pretreatment with parachlorophenylalanine, a
      depletor of brain 5-HT. These findings suggest that treatments designed to
      increase 5-HT neurotransmission inhibit the generation of HIP seizures. A
      combination of fluoxetine with a 5-HT1A receptor antagonist could thus be
      therapeutically useful for the treatment of depressive symptoms in patients with
      epilepsy.

PMID- 10400248
TI  - Involvement of nitric oxide in aminoglycoside vestibulotoxicity in guinea pigs.
AB  - Involvement of nitric oxide (NO) has been reported in physiological and
      pathological conditions in the inner ear. Recently, the presence of nitric oxide
      synthase (NOS) was demonstrated in the vestibular epithelium. In this study we
      used nicotinamide adenine dinucleotide phosphate-diapholase staining to monitor
      NOS activity during degeneration of guinea pig vestibular epithelia affected by
      streptomycin. Increased NOS activity was observed in affected epithelia in a dose
      and time-dependent manner and a NOS inhibitor could protect hair cells from
      apoptosis. Additionally, cycloheximide significantly reduced NOS activity and the
      occurrence of apoptosis. These findings suggest that NO is involved in the
      degenerative process of vestibular epithelia caused by aminoglycosides.

PMID- 10400250
TI  - Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau
      levels in Alzheimer's disease.
AB  - To examine the effect of apolipoprotein E (ApoE) 4 on the progression of
      Alzheimer's disease (AD), the clinical course of 33 AD patients (17 cases with
      ApoE epsilon4 and 16 cases without ApoE epsilon4) was evaluated with the mini
      mental state examination (MMSE) and cerebrospinal fluid (CSF) biological markers.
      The decline of MMSE scores to zero was shortened in the ApoE4 group. During a
      mean follow-up of 20 months, a significant increase of CSF tau levels was
      observed in the ApoE4 group. A lower level of CSF A beta1-42(43) was found in
      both the ApoE4 and non-ApoE4 groups than in age-matched normal controls. The ApoE
      epsilon4 allele accelerates the progression of dementia and increases the levels
      of CSF tau in AD patients.

PMID- 10400251
TI  - Daily variation and light responsiveness of mammalian clock gene, Clock and
      BMAL1, transcripts in the pineal body and different areas of brain in rats.
AB  - Expression patterns of mammalian clock genes, Clock and BMAL1, were examined by
      in situ hybridization in the pineal body, olfactory bulb, hippocampus and
      cerebellum in rats under constant darkness. In the pineal, the level of Clock
      transcript was significantly higher at ZT18 (subjective night) than at ZT6
      (subjective day), while the level of BMAL1 transcript was significantly higher at
      ZT6 than at ZT18. A 30 min light pulse did not affect the transcript levels of
      Clock nor of BMAL1. The Clock expression in the cerebellum was significantly
      increased at ZT6 than at ZT18, while no difference was detected in the olfactory
      bulb and hippocampus at these two phases. The BMAL1 expressions in these areas
      were similar to the case in the pineal. These findings indicate that the
      mammalian clock gene, Clock and BMAL1, are expressed differently in the different
      areas of the brain and the pineal.

PMID- 10400253
TI  - Integrating response shift into health-related quality of life research: a
      theoretical model.
AB  - Patients confronted with a life-threatening or chronic disease are faced with the
      necessity to accommodate to their illness. An important mediator of this
      adaptation process is 'response shift' which involves changing internal
      standards, values and the conceptualization of quality of life (QOL). Integrating
      response shift into QOL research would allow a better understanding of how QOL is
      affected by changes in health status and would direct the development of reliable
      and valid measures for assessing changes in QOL. A theoretical model is proposed
      to clarify and predict changes in QOL as a result of the interaction of: (a) a
      catalyst, referring to changes in the respondent's health status; (b)
      antecedents, pertaining to stable or dispositional characteristics of the
      individual (e.g. personality); (c) mechanisms, encompassing behavioral,
      cognitive, or affective processes to accommodate the changes in health status
      (e.g. initiating social comparisons, reordering goals); and (d) response shift,
      defined as changes in the meaning of one's self-evaluation of QOL resulting from
      changes in internal standards, values, or conceptualization. A dynamic feedback
      loop aimed at maintaining or improving the perception of QOL is also postulated.
      This model is illustrated and the underlying assumptions are discussed. Future
      research directions are outlined that may further the investigation of response
      shift, by testing specific hypotheses and predictions about the QOL domains and
      the clinical and psychosocial conditions that would potentiate or prevent
      response shift effects.

PMID- 10400252
TI  - Administration of prosaposin ameliorates spatial learning disturbance and reduces
      cavity formation following stab wounds in rat brain.
AB  - The effectiveness of prosaposin as a neurotrophic factor was investigated using
      rats with bilateral stab wounds, injecting 240 ng per day of prosaposin for 3
      days. In Morris water maze task, after 3 weeks postoperation, the stab-wounds
      rats show significant impairment in acquisition compared with the sham-operated
      rats. In the transfer test the mean number of crossings of the platform place in
      stab-wounds was significantly lower than that in sham-operated rats (P < 0.01).
      The stab-wounds rats treated with prosaposin showed significant improvement (P <
      0.05). The cavities following stab wounds in the rats treated with prosaposin
      were significantly smaller than those in the rats treated with (P < 0.05). Our
      data support that prosaposin is likely to be a new agent for brain injury.

PMID- 10400254
TI  - Social comparison as a mediator of response shift.
AB  - Previous research in the domain of social comparison theory has suggested that
      the same factors that have been hypothesized as antecedents to response shift,
      primarily significant life events, also prompt an increase in interest in social
      comparison. Based on this research, it is suggested that social comparison, or
      more specifically, change in social comparison, is a mediator of the relation
      between significant life events and the change in self-perspective--or response
      shift--that they often produce. Evidence supporting this claim is reviewed and
      new data are presented. Finally, the implications of this mediational relation,
      including those relevant to the design of interventions, are discussed.

PMID- 10400255
TI  - Methodological approaches for assessing response shift in longitudinal health
      related quality-of-life research.
AB  - The impact of health state changes on an individual's quality of life (QOL) has
      gained increased attention in social and medical clinical research. An emerging
      construct of relevance to this line of investigation is response shift
      phenomenon. This construct refers to the changes in internal standards, in
      values, or in the conceptualization of QOL which are catalyzed by health state
      changes. In an effort to stimulate research on response shift, we present
      methodological considerations and promising assessment approaches for measuring
      it in observational and interventional clinical research. We describe and
      evaluate individualized methods, preference-based methods, successive comparison
      methods, design approaches, statistical approaches and qualitative approaches.
      The hierarchical structure of the construct is also discussed, with particular
      emphasis on how it might be elucidated by empirical assessment which uses the
      proposed methods and approaches. It is also recommended that criterion measures
      of change be included in future studies of response shift.

PMID- 10400256
TI  - Discrepancies between self-reported and observed physical function in the
      elderly: the influence of response shift and other factors.
AB  - GOAL: To explore the influence of social, psychological, and health factors on
      self-report of function. SUBJECTS: A convenience sample of 289 community-dwelling
      elderly aged 65-97 years. METHODS: We compared a measure of function based on
      observed performance, the Physical Capacity Evaluation (PCE) with a self-reported
      measure of functional limitations (HAQ), in a cross-sectional study. Stepwise
      multiple regression identified variables predicting self-reported disability,
      controlling for observed function. RESULTS: Controlling for PCE, self-reports of
      greater disability (HAQ) were predicted by current joint pain or stiffness, use
      of prescription medications, urban dwelling, depression, female gender, lack of
      memory problems, arthritis and lack of exercise. A final model included recent
      decline in function, dissatisfaction with function, gender, joint pain or
      stiffness, and observed function, explaining 85% of the variance in self-reported
      disability. The hypothesis that aging is associated with declining expectations
      of functional ability was not supported. However, recent health problems affected
      participants' reporting of limitations, consistent with a recalibration-type
      response shift. Perceived decline in function over the past six months, a fall
      within the last month, illness in the last week and pain or stiffness on the day
      of the exam all raised self-reports of disability. As suggested by adaptation
      level theory, subjects with recent problems might have an inflated perception of
      limitations due to shifts in their internal standards. When administered first,
      the observed performance test improved correlations between observed and self
      reported function, primarily among those who did not report a recent decline in
      function. This suggests that this group may have benefited more from salient
      information about their abilities provided by performing the PCE before self
      report. CONCLUSION: Our data confirm the importance of social, psychological, and
      health influences in self-report of disability, and are consistent with the
      hypothesis that people may recalibrate their self assessments based on recent
      health problems.

PMID- 10400257
TI  - Helping others helps oneself: response shift effects in peer support.
AB  - The present work explores the impact of helping others on the physical and
      psychosocial well-being of the provider. Lay people were trained to listen
      actively and to provide compassionate, unconditional positive regard to others
      with the same chronic disease. The recipients of the peer support intervention
      were participants of a psychosocial randomized trial, whereas the peer supporters
      were study personnel and were therefore not randomized. We describe a secondary
      analysis of a randomized trial to explore the impact of being a peer supporter on
      these lay people. Subjects were 132 people with multiple sclerosis, all of whom
      completed quality-of-life questionnaires 3 times over 2 years. A focus group was
      also implemented with the peer telephone supporters 3 years after completion of
      the randomized trial. Effect size was computed for each quality-of-life outcome,
      and the focus group discussion was content analyzed. We found that compared to
      supported patients, the peer telephone supporters: (1) reported more change in
      both positive and negative outcomes as compared to the supported patients and
      that the effect size of these changes tended to be larger (chi2 = 9.6, df = 4, p
      < 0.05) and (2) showed pronounced improvement on confidence, self-awareness, self
      esteem, depression and role functioning. Content analysis revealed that the
      participants articulated a sense of dramatic change in their lives in terms of
      how they thought of themselves and in how they related to others. We conclude
      with a discussion of response shift, a mediator of adaptation to illness which
      involves shifting internal standards, values, and concept definitions of health
      and well-being. We suggest that a response shift may be induced by a therapeutic
      strategy involving the externalization and re-internalization of concern among
      physically ill patients.

PMID- 10400258
TI  - Clinical understanding and clinical implications of response shift.
AB  - The purpose of this paper is to provide clinical understanding and clinical
      context for the concept of response shift. First, the paper describes a variety
      of target constructs or dimensions of health-related quality of life that are
      important in clinical medicine, including biological and physiological measures,
      symptoms, functioning, general health perceptions and overall quality of life. It
      is argued that insight into response shift can be gained by assessing the ways in
      which measures on these different dimensions change relative to each other.
      Second, somatization and hypochondriasis are presented as examples of clinical
      circumstances in which appropriate and adaptive response shifts do not occur.
      Third, placebo effects are defined and it is argued that response shift is one
      subtype of placebo effect. Finally, the role of response shift in routine
      clinical care and its implication for the physician-patient relationship are
      discussed. Although it cannot and should not replace careful attention to and
      appropriate treatment of abnormal biological and physiological processes, there
      are times when explicit attempts to produce response shifts may complement these
      biomedical therapies. Producing response shift probably involves understanding
      the psychological, social and cultural context of the illness; may be mediated by
      the physician-patient relationship and may facilitate coping processes in ways
      that improve health-related quality of life.

PMID- 10400259
TI  - The role of the privatization process on tuberculosis control in HoChiMinh City
      Province, Vietnam.
AB  - In Vietnam, tuberculosis is a major health problem, especially in HoChiMinh City
      Province where living conditions are marginal and HIV infection is increasing. As
      Vietnam has gradually shifted to a market economy, this also has implications for
      the health care system. More and more private practitioners are emerging. At
      present, case-finding and treatment of tuberculosis is under the control of
      Vietnam's National Tuberculosis Program (NTP). The authors argue that the process
      of privatization might have consequences for the implementation of a public
      health program such as the NTP. This argument has been illustrated by using a
      case study on the functioning of the NTP in HoChiMinh City Province.

PMID- 10400260
TI  - Economic and health efficiency of education funding policy.
AB  - Public spending programmes to reduce poverty, expand primary education and
      improve the economic status of women are recommended priorities of aid agencies
      and are now gradually being reflected in third world governments' policies, in
      response to aid conditions imposed by the World Bank and OECD countries. However
      outcomes fall short of aspiration. This paper shows that donors' lending
      policies, especially those restricting public spending on education to the
      primary level, (1) perpetuate poverty, (2) minimise socio-economic impact of
      public health programmes and (3) prevent significant improvement in the economic
      status of women. These effects are the result of fundamental flaws in donors'
      education policy model. Evidence is presented to show that health status in
      developing countries will be significantly enhanced by increasing the proportion
      of the population which has at least post-primary education. Heads of households
      with just primary education have much the same probability of experiencing
      poverty and high mortality of their children as those with no education at all.
      Aid donors' policies, which require governments of developing countries to limit
      public funding of education to the primary level, have their roots in what is
      contended here to be an erroneous interpretation of human capital theory. This
      interpretation focuses only on the declining marginal internal rates of return on
      public investments in successive levels of schooling and ignores the opposite
      message of the increasing marginal net present values of those investments. Cars
      do not travel fastest in their lowest gear despite its fastest acceleration,
      life's long journey is not most comfortable for those with only primary
      schooling.

PMID- 10400261
TI  - The impact of perinatal loss on adjustment to subsequent pregnancy.
AB  - The current study compared the emotional adjustment of pregnant couples with and
      without a history of perinatal loss. Thirty-one pregnant women with a history of
      perinatal loss and 31 pregnant women with an unremarkable reproductive history
      were assessed between their 10th and 24th week of gestation. Partners were also
      recruited. Twenty-eight men were in the loss group and 23 men in the comparison
      group. Couples with a history of loss reported significantly more depressive
      symptomatology and pregnancy-specific anxiety than couples in the comparison
      group. Women reported more depressive symptomatology than men. Regression
      analyses revealed that for the group with a previous loss, depressive
      symptomatology was significantly associated with self-criticism, interpersonal
      dependency and number of previous losses. For the comparison group, depressive
      symptomatology was significantly associated dyadic adjustment. Pregnancy-specific
      anxiety of women with a previous loss was associated with their belief that their
      behavior affects fetal health; for women in the comparison group, pregnancy
      specific anxiety was associated with the belief that health professionals'
      behavior affects fetal health. Implications for practice of health care
      professionals are discussed. The importance of early intervention to reduce
      distress is highlighted by the finding that alterations in mood are apparent in
      the early stages of pregnancy for both women and men who have experienced a
      previous perinatal loss. While carefully reducing personal responsibility for
      fetal health in women with a previous loss may reduce their pregnancy-specific
      anxiety, women with an unremarkable obstetrical history may benefit from an
      approach diminishing their perception of the power that medical staff has on
      fetal health.

PMID- 10400262
TI  - Beyond the biomedical and behavioural: towards an integrated approach to HIV
      prevention in the southern African mining industry.
AB  - While migrant labour is believed to play an important role in the dynamics of HIV
      transmission in many of the countries of southern Africa, little has been written
      about the way in which HIV/AIDS has been dealt with in the industrial settings in
      which many migrant workers are employed. This paper takes the gold mining
      industry in the countries of the Southern African Development Community (SADC) as
      a case study. While many mines made substantial efforts to establish HIV
      prevention programmes relatively early on in the epidemic, these appear to have
      had little impact. The paper analyses the response of key players in the mining
      industry, in the interests of highlighting the limitations of the way in which
      both managements and trade unions have responded to HIV. It will be argued that
      the energy that has been devoted either to biomedical or behavioural prevention
      programmes or to human rights issues has served to obscure the social and
      developmental dimensions of HIV-transmission. This argument is supported by means
      of a case study which seeks to highlight the complexity of the dynamics of
      disease transmission in this context, a complexity which is not reflected in
      individualistic responses. An account is given of a new intervention which seeks
      to develop a more integrated approach to HIV management in an industrial setting.

PMID- 10400263
TI  - Cognitive predictors of adherence to malaria prophylaxis regimens on return from
      a malarious region: a prospective study.
AB  - Cases of 'imported malaria' into countries where malaria is not endemic are
      increasing and evidence suggests that non-use of malaria prophylaxis and lack of
      adherence are contributing to this increase. Non-adherence may be especially
      likely because chemoprophylaxis regimens require travellers to continue to take
      medication for 4 weeks after their return from a malarious region. This study
      investigated the extent to which cognition measures specified by the theory of
      planned behaviour and the health belief model could distinguish between those who
      reported greater or lesser adherence after their return. Cognitions were measured
      using a brief questionnaire on the day of departure from the malarious region and
      reports of adherence were collected between 5 and 7 weeks later. Data from two
      longitudinal samples of UK tourists returning from The Gambia were analysed; 106
      mefloquine users and 61 chloroquine and proguanil users. Results suggested that
      malaria prophylaxis adherence could be improved. 22.5% of mefloquine users and
      31% of chloroquine and proguanil users reported adherence for 3 weeks or less. A
      model based on the theory of planned behaviour explained approximately 50% of the
      variance in reported adherence amongst mefloquine users and 40% amongst
      chloroquine and proguanil users, comparing favorably with other published
      applications of the theory. Findings suggest that targeting key cognitions could
      enhance adherence on return from malarious regions. Enhancing perceived control
      over adherence may be important as well as emphasising susceptibility to malaria
      infection. Reassuring mefloquine users concerning potential side effects of the
      drug may also encourage adherence on return. Implications for future research are
      discussed.

PMID- 10400264
TI  - Harmonising and competing for medicines regulation: how healthy are the European
      Union's systems of drug approval?
AB  - Europeanised procedures of marketing authorisation for medicines are becoming
      increasingly important within EU Member States relative to national licensing
      systems. Since 1 January 1998 parallel national applications for drug approvals
      in EU Member States have disappeared and it is only possible to market a new drug
      in more than one Member State via Europeanised procedures. Yet the implications
      of these Euro-procedures for public health remain little researched or debated.
      This paper discusses the health and safety implications of three key features of
      such Europeanisation, namely, the harmonisation of drug safety standards, the
      competition between the national regulatory agencies of Member States for
      application fees from industry and the industrial capture of regulators within
      the regulatory process. Drawing on 42 interviews in Brussels, Germany, Sweden,
      the Netherlands and the UK, the perspectives of European regulators, industrial
      scientists and regulatory affairs managers on these matters are analysed. While
      most industry sources believe that the new Euro-procedures will not harm public
      health, at least half of the regulators were concerned that European
      harmonisation of safety standards and competition between national agencies to
      accelerate approval times in order to attract industry fees pose a threat to
      public health and safety. National regulatory agencies find themselves in an
      internal EU market competing for regulatory fees from industry. This
      marketisation of regulation puts pressure on regulators to 'sell themselves' as
      the fastest in reviewing and approving drugs. Swedish regulators displayed the
      greatest anxieties about these matters. Unfortunately, we found it impossible to
      verify these regulators' worries or industry's optimism because of the secrecy
      that attends these Euro-procedures. Thus, a situation obtains in which a
      significant number of regulators are warning that the EU medicines licensing
      systems, which are being put in place, might well compromise safety, yet these
      systems are deficient in their capacity to accommodate independent scrutiny, upon
      which informed policy changes could be based.

PMID- 10400265
TI  - Preventive behavior among recent immigrants: Russian-speaking women and cancer
      screening in Israel.
AB  - This study examined the risk profile and preventive practices aimed at female
      reproductive cancer in a national sample of 620 women aged over 35, who
      immigrated to Israel from the former Soviet Union after 1989. The study setting
      typifies a more general problem of the encounter between East European immigrants
      and western-type health cultures and medical systems. It has shown that universal
      access to preventive care may not translate into its optimal utilization among
      marginalized population groups. Specifically, while being at moderate to high
      cancer risk, Russian immigrants avoid screening activities; gynecological check
      ups, breast examination and mammography. This is a reversal of the pre-emigration
      pattern: two thirds of respondents underwent cancer screening in their home
      country and only one third in Israel. The risk groups for late detection of
      cancer are the women least integrated into the mainstream society: those over 60,
      unemployed or having unskilled jobs. Women without regular primary care providers
      showed the lowest cancer awareness and minimal screening activity. Even those who
      knew the key cancer facts, believed in their own susceptibility and in the
      benefit of early detection, in practice did little to avert the danger. Three
      explanations for the discrepancy between cognition and practice are suggested:
      (a) the immigrants' low health motivation, reflecting their downward social
      mobility and preoccupation with resettlement problems; (b) low self-efficacy and
      external locus of control over health, typical of ex-Soviet citizens and (c)
      communicative and other cultural barriers to health care services.

PMID- 10400266
TI  - Stories of illness and trauma survival: liberation or repression?
AB  - This paper aims to expand upon recent research addressing the relationship
      between power and cultural stories of illness. It does this by exploring the
      stories of 'healing' and 'survival' produced by people who have undergone
      traumatic experiences such as childhood sexual abuse and a HIV positive
      diagnosis. The liberating and/or repressive potential of cultural stories of
      illness are defined in accordance with their capacity to produce 'minimal' or
      more 'reflective' selves, as characterised by Lasch [Lasch, C., 1985. The Minimal
      Self. Picador, London.] and Giddens [Giddens, A., 1991. Modernity and Self
      identity: Self and Society in the Later Modern Age. Polity Press, Cambridge.],
      respectively. Two predominant stories of survival are identified in this paper:
      the 'healing' story and the 'normalising' story. Each of these are explored in an
      attempt to address the question: How do we distinguish between 'liberating' and
      'repressing' technologies of the self with regard to the telling of illness
      stories? [Frank, A., 1998. Stories of illness as care of the self: a Foucauldian
      dialogue. Health 2(3), 329-348, forthcoming.]. Through an examination of
      survivors' attempts to overcome their traumatic experiences via the appropriation
      of various illness stories, it is concluded that this question can only be
      answered in the practical and social context of each individual's life.

PMID- 10400267
TI  - Intracellular signalling proteins as smart' agents in parallel distributed
      processes.
AB  - In eucaryotic organisms, responses to external signals are mediated by a
      repertoire of intracellular signalling pathways that ultimately bring about the
      activation/inactivation of protein kinases and/or protein phosphatases. Until
      relatively recently, little thought had been given to the intracellular
      distribution of the components of these signalling pathways. However,
      experimental evidence from a diverse range of organisms indicates that rather
      than being freely distributed, many of the protein components of signalling
      cascades show a significant degree of spatial organisation. Here, we briefly
      review the roles of 'anchor' 'scaffold' and 'adaptor' proteins in the
      organisation and functioning of intracellular signalling pathways. We then
      consider some of the parallel distributed processing capacities of these adaptive
      systems. We focus on signalling proteins-both as individual 'devices' (agents)
      and as 'networks' (ecologies) of parallel processes. Signalling proteins are
      described as 'smart thermodynamic machines' which satisfy 'gluing' (functorial)
      roles in the information economy of the cell. This combines two information
      processing views of signalling proteins. Individually, they show 'cognitive'
      capacities and collectively they integrate (cohere) cellular processes. We
      exploit these views by drawing comparisons between signalling proteins and verbs.
      This text/dialogical metaphor also helps refine our view of signalling proteins
      as context-sensitive information processing agents.

PMID- 10400269
TI  - Biological variation of glucose and insulin includes a deterministic chaotic
      component.
AB  - Serial data of glucose and insulin values of individual patients vary over short
      periods of time; this phenomenon has been called biological variation. The
      classic homeostatic control model assumes that the physiological mechanisms
      maintaining the concentrations of glucose and insulin are linear. The only
      deviations over a short period of time one should observe are in relation to a
      glucose load or major hormonal disturbance. Otherwise, the values of these
      analytes should be constant and any variations seen are due to random
      disturbances. We investigated previously published serial data (three for glucose
      and one for insulin) with nonlinear analytical methods, such as embedding space,
      correlation dimension, Lyapunov exponents, singular value decomposition and phase
      portraits, as well as linear methods, such as power spectra and autocorrelation
      functions. The power spectra failed to show dominant frequencies, but the
      autocorrelation functions showed significant correlation, consistent with a
      deterministic process. The correlation dimension was finite, around 4.0, the
      first Lyapunov exponent was positive, indicative of a deterministic chaotic
      process. Furthermore, the phase portraits showed directional flow. Therefore, the
      short-term biological variation observed for analytes arises from nonlinear,
      deterministic chaotic behavior instead of random variation.

PMID- 10400270
TI  - A quantum mechanical model of adaptive mutation.
AB  - The principle that mutations occur randomly with respect to the direction of
      evolutionary change has been challenged by the phenomenon of adaptive mutations.
      There is currently no entirely satisfactory theory to account for how a cell can
      selectively mutate certain genes in response to environmental signals. However,
      spontaneous mutations are initiated by quantum events such as the shift of a
      single proton (hydrogen atom) from one site to an adjacent one. We consider here
      the wave function describing the quantum state of the genome as being in a
      coherent linear superposition of states describing both the shifted and unshifted
      protons. Quantum coherence will be destroyed by the process of decoherence in
      which the quantum state of the genome becomes correlated (entangled) with its
      surroundings. Using a very simple model we estimate the decoherence times for
      protons within DNA and demonstrate that quantum coherence may be maintained for
      biological time-scales. Interaction of the coherent genome wave function with
      environments containing utilisable substrate will induce rapid decoherence and
      thereby destroy the superposition of mutant and non-mutant states. We show that
      this accelerated rate of decoherence may significantly increase the rate of
      production of the mutated state.

PMID- 10400268
TI  - Memories in context.
AB  - Context-dependent associative memories are models that allow the retrieval of
      different vectorial responses given a same vectorial stimulus, depending on the
      context presented to the memory. The contextualization is obtained by doing the
      Kronecker product between two vectorial entries to the associative memory: the
      key stimulus and the context. These memories are able to display a wide variety
      of behaviors that range from all the basic operations of the logical calculus
      (including fuzzy logics) to the selective extraction of features from complex
      vectorial patterns. In the present contribution, we show that a context-dependent
      memory matrix stores a large amount of possible virtual associative memories,
      that awaken in the presence of a context. We show how the vectorial context
      allows a memory matrix to be representable in terms of its singular-value
      decomposition. We describe a neural interpretation of the model in which the
      Kronecker product is performed on the same neurons that sustain the memory. We
      explored, with numerical experiments, the reliability of chains of contextualized
      associations. In some cases, random disconnection produces the emergence of
      oscillatory behaviors of the system. Our results show that associative chains
      retain their performances for relatively large dimensions. Finally, we analyze
      the properties of some modules of context-dependent autoassociative memories
      inserted in recursive nets: the perceptual autoorganization in the presence of
      ambiguous inputs (e.g. the disambiguation of the Necker's cube figure), the
      construction of intersection filters, and the feature extraction capabilities.

PMID- 10400271
TI  - The effects of meal composition on subsequent craving and binge eating.
AB  - This study investigated the effects of meals differing in macronutrient
      composition on subsequent food craving, bingeing, nutrient intake, and mood. Nine
      women who had prospectively demonstrated episodes of craving received one each of
      a high-protein, high-carbohydrate, and mixed meal on three separate days.
      Appetite and mood ratings were taken before and at four intervals up to 150 min
      after meal consumption. Subsequent ad libitum food intake was recorded in
      diaries. Premeal hunger, appetite and mood ratings were similar across meal type.
      After the protein-rich meal, craving for sweet, carbohydrate-rich foods was
      significantly higher than after the carbohydrate and mixed meals. Elevated
      negative mood state after the protein-rich meal and reduced vigor after the
      carbohydrate meal were not statistically significant. The first ad libitum eating
      episodes after the protein meal contained significantly higher absolute and
      proportional amounts of total carbohydrate and sucrose and were more likely to be
      categorized as a binge than were those after the carbohydrate and mixed meals.
      Those ad libitum eating episodes classified as a craving/binge were characterized
      by a higher energy and absolute carbohydrate, fat, and sucrose content. Evidence
      of macronutrient compensation after a protein-rich meal suggests that
      carbohydrate intake regulation may exist in certain individuals. Possibly via the
      effects of sensory-specific satiety, serotonergic function, or cognitive factors,
      a protein-rich meal may induce craving for sweet-tasting, palatable foods in
      susceptible individuals.

PMID- 10400272
TI  - Therapeutic alliance and the retention of couples in conjoint alcoholism
      treatment.
AB  - Differences were investigated in the degree to which less versus more experienced
      therapists formed a therapeutic alliance with their clients and how these
      differences were related to retaining couples in treatment. Two raters, using the
      Vanderbilt Therapeutic Alliance Scale (VTAS) and the Vanderbilt Negative
      Indicators Scale (VNIS), coded 15-minute audiotaped segments of the first
      treatment session for 66 couples participating in a randomized clinical trial of
      three types of couple therapy for alcoholism. Ten therapists, whose experience
      ranged from 15 years of postdoctoral practice to a 1 year predoctoral practicum,
      administered the treatment. Results indicated that the more experienced
      therapists scored significantly higher on the VTAS and lower on the VNIS than did
      the less experienced therapists. Therapists' scores on these scales were
      significantly related to number of treatment sessions attended and number of
      couples completing treatment, but not to treatment outcomes.

PMID- 10400273
TI  - Smoking attitudes, beliefs, and readiness to change among acute and long term
      care inpatients with psychiatric diagnoses.
AB  - The present study represents an initial assessment of barriers and motives for
      quitting, health risk knowledge, and readiness to change in a hospitalized acute
      and long term care population with psychiatric diagnoses, and dual diagnoses of
      substance abuse and psychiatric disorders. Ninety-two patients residing in
      admissions, long term care, and mentally impaired/chemically addicted (MICA)
      units of a VA Medical Center were interviewed by nursing staff. Among the 78% of
      patients who smoke (smokers), 68% believed smoking was harmful and quitting would
      benefit their health. The majority of smokers were in Precontemplation (53%) or
      Contemplation (24%). Smokers in the MICA unit were more similar to the general
      population in smoking related beliefs and were more likely than other smokers to
      be in Preparation. These results indicate a need for educational and motivational
      enhancement interventions for the majority of smokers hospitalized for
      psychiatric disorders.

PMID- 10400274
TI  - Quality of life and overweight: the obesity related well-being (Orwell 97)
      questionnaire.
AB  - The development and validation of a self-reported measure of obesity-related
      quality of life, the Obesity Related Well-Being (ORWELL 97), were undertaken to
      examine the intensity and the subjective relevance of physical and psychosocial
      distress. The questionnaire was validated in a sample of 147 obese patients (99
      females, 48 males). The Eating Disorder Examination 12.0D interview, a structured
      diagnostic interview for DSM-III-R (DSM-IV criteria for binge eating disorder),
      Beck Depression Inventory, Binge Eating Scale, and the State-Trait Anxiety
      Inventory 1 and 2 scales were also applied. Internal consistency and test-retest
      reliability were satisfactory. Factor analysis allowed the identification of two
      subscales: ORWELL 97-1 related to psychological status and social adjustment, and
      ORWELL 97-2 related to physical symptoms impairment. Obese female patients showed
      a lower quality of life, and the severity of obesity appeared to interfere with
      physical functioning rather than psychological status and social adjustment. The
      ORWELL 97 questionnaire appears to be a simple and reliable measure of obesity
      related quality of life, which can be used in current clinical practice.

PMID- 10400276
TI  - The role of social networks and media receptivity in predicting age of smoking
      initiation: a proportional hazards model of risk and protective factors.
AB  - The increasing prevalence of adolescent smoking demonstrates the need to identify
      factors associated with early smoking initiation. Previous studies have shown
      that smoking by social network members and receptivity to pro-tobacco marketing
      are associated with smoking among adolescents. It is not clear, however, whether
      these variables also are associated with the age of smoking initiation. Using
      data from 10,030 California adolescents, this study identified significant
      correlates of age of smoking initiation using bivariate methods and a
      multivariate proportional hazards model. Age of smoking initiation was earlier
      among those adolescents whose friends, siblings, or parents were smokers, and
      among those adolescents who had a favorite tobacco advertisement, had received
      tobacco promotional items, or would be willing to use tobacco promotional items.
      Results suggest that the smoking behavior of social network members and pro
      tobacco media influences are important determinants of age of smoking initiation.
      Because early smoking initiation is associated with higher levels of addiction in
      adulthood, tobacco control programs should attempt to counter these influences.

PMID- 10400275
TI  - The relationship of positive and negative alcohol expectancies to patterns of
      consumption of alcohol in social drinkers.
AB  - Negative alcohol expectancies have recently come to occupy a more important
      position in the expectancy literature, but recent claims that positive
      expectancies are unimportant in the consumption of alcohol when compared with
      negative expectancies are based on potentially flawed methodology. This study
      investigated the relative contribution of positive and negative expectancies to
      the consumption of alcohol using an instrument designed to measure both positive
      and negative expectancies. One hundred ninety-three men and women from the
      general community participated in the study. Findings showed while negative
      expectancies accounted for the greater proportion of variance of frequency of
      consumption, positive expectancies remained an important predictor of
      consumption, accounting for the greater proportion of variance of quantity
      consumed per session. The interesting but sometimes counterintuitive directions
      of these relationships can be explained in terms of social learning principles.
      The relatively neglected concept of negative expectancies is worthy of further
      use and investigation.

PMID- 10400277
TI  - Psychometric properties of a quitting time for alcohol questionnaire: factor
      structure, reliability, and validity.
AB  - Research into the dynamics of alcohol use has traditionally focused on
      etiological factors, particularly on the reasons an individual engages in
      drinking behaviours. Although reasons for the permanent cessation of drinking
      have also been well documented, little is known about the reasons for the
      episodic cessation of alcohol use that is characteristic of nonproblematic
      drinking patterns. The purpose of the present study was to develop and validate a
      questionnaire designed to monitor the reasons an individual temporarily stops
      drinking at the end of a drinking episode. A 23-item Quitting Time for Alcohol
      Questionnaire (QTAQ) was developed and distributed to a community based sample of
      252 participants. Factor analysis revealed three conceptually distinct factors,
      QTAQ-IS (Internal Status) QTAQ-AA (Avoidance Adherence) and QTAQ-IC (Immediate
      Context), which accounted for 36.3% of the variance. Cross-validation on a large
      sample of undergraduate students (N = 479) confirmed the three-factor solution
      (accounting for 33% of the variance). Cronbach's alpha coefficients for the
      factors ranged from .74 to .81 for the community sample and from .62 to .78 for
      the student sample. The validity of the emergent factors was demonstrated by
      their ability to classify participants according to self-reported alcohol
      consumption and alcohol dependence criteria, and also by their significant
      predictive relationship with these criteria. The present findings suggest that
      the QTAQ is a useful instrument both for research and for use in clinical
      practice.

PMID- 10400278
TI  - Exercise effects on withdrawal and mood among women attempting smoking cessation.
AB  - This study investigated both acute and longer term ("chronic") effects of
      vigorous exercise training on affect, nicotine withdrawal, and cigarette craving
      among women enrolled in a smoking cessation research study. All subjects
      participated in a 12-week cognitive behavioral smoking cessation program and were
      randomly assigned to attend three sessions per week of either a vigorous exercise
      program or contact control. Measures of positive and negative affect, cigarette
      craving, and nicotine withdrawal were administered immediately before, and again
      immediately after the final exercise or contact session each week of the program.
      Study I enrolled 24 women who had been assigned to the exercise condition.
      Significant reductions in negative affect, nicotine withdrawal and cigarette
      craving were observed following exercise most weeks of the program. No
      significant changes in positive affect were observed. In Study II this protocol
      was repeated among 62 women (44 exercise, 18 contact control) in two consecutive
      cohorts of the larger study. Significant reduction were observed in negative
      affect, nicotine withdrawal and cigarette craving during most weeks of the
      program among exercise subjects but not contact condition subjects. No chronic
      (baseline to posttreatment) changes in positive or negative affect, cigarette
      craving or withdrawal symptoms were observed in either study. Vigorous exercise
      appears to produce acute improvements in withdrawal symptoms, cigarette craving,
      and negative affect among sedentary women attempting to quit smoking.

PMID- 10400280
TI  - Associations between the stages of change and the pros and cons of smoking in a
      longitudinal study of Swiss smokers.
AB  - To develop effective smoking prevention interventions, we need to identify
      modifiable variables, such as the "pros and cons" of smoking, that predict self
      initiated smoking cessation. Our objective was to assess associations between the
      pros and cons of smoking and the stages of change, both cross-sectionally and
      longitudinally, in a cohort of smokers. In cross-sectional comparisons, the pros
      of smoking were 0.19-0.31 standard deviation (SD) higher and the cons 0.79-0.87
      SD lower in the precontemplation than in the preparation stage. In follow-up
      data, progressing from precontemplation to contemplation and from contemplation
      to preparation was associated with substantial and significant increases in the
      cons (+0.71 SD and +0.50 SD, respectively). No longitudinal associations were
      found between changes in pros of smoking and progress through stages. Thus this
      study added evidence from longitudinal data to published evidence from cross
      sectional data about the association between the cons of smoking and the stages
      of change. Intervention studies are necessary to establish whether this
      association is causal.

PMID- 10400279
TI  - One-year prospective prediction of marijuana use cessation among youth at
      continuation high schools.
AB  - This article reports a large-scale study of the prediction of marijuana use
      cessation among adolescents who were regular users at baseline. Social, attitude,
      intrapersonal, violence-related, drug-use-related, and demographic baseline
      measures served as predictors of whether or not 566 current marijuana users
      reported having quit use 1 year later. Quitting was defined as having not used
      marijuana in the last 30 days and having no intention to use marijuana in the
      future (31% of the baseline users). Those who were slightly older, who reported
      receiving relatively less approval for using drugs, who held relatively
      unfavorable attitudes about the acceptability of drug use, and who reported
      relatively less victimization in the last year were relatively likely to quit.
      Implications of these results include the need to increase unacceptability of
      marijuana use to help increase efforts at self-initiated quitting.

PMID- 10400281
TI  - Risk factors for anabolic steroid use in college students and the role of
      expectancy.
AB  - Anabolic steroids are now recognized as a widespread addictive and dangerous
      substance, no longer exclusively used as an aid to muscle size and strength in
      world-class athletes. Psychologists have neglected prevention programs for
      steroid abuse, in part because of a lack of knowledge of the precipitants of
      abuse. This study examined demographics, personality factors, and steroid
      expectancies as risk factors for future steroid use. Older subjects,
      extraversion, global-positive expectancies for steroid use, and identification
      with peers who advocated health-risk behaviors predicted higher steroid use,
      whereas specific social-behavioral negative expectancies for steroid use
      significantly predicted lowered risk of steroid use. These findings are discussed
      in the context of past research, and implications for preventive intervention are
      described.

PMID- 10400282
TI  - Smokeless tobacco use in a population of young adults.
AB  - The current study examined characteristics of smokeless tobacco users in a large
      population of Air Force recruits. In addition, smokeless tobacco users were
      compared to non-tobacco users, to cigarette smokers, and to users of both
      smokeless tobacco and cigarettes. Participants were 32,144 individuals who
      entered Basic Military Training from August 1995 to August 1996. A 53-item
      questionnaire assessed demographics, tobacco use history, risk taking, and other
      health-risk factors. Those who both chewed and smoked scored considerably higher
      on a number of risk factors than did those who limited their tobacco consumption
      to either cigarettes or chew. Cigarette smokers in turn tended to score
      consistently higher on self-reported risk factors than did nontobacco users.

PMID- 10400283
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 and ninety-eight high school students (97 males and 101
      females; mean age = 16.45 years) completed questionnaires that 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 1 were found to summarize 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- 10400284
TI  - Effect of counselor and client education in nicotine addiction on smoking in
      substance abusers.
AB  - Smoking cessation has received little attention in substance abuse programs. The
      present study analyzed the effect that counselor and client education in nicotine
      addiction had on clients' treatment readiness for a smoking cessation program.
      Thirty-eight smoking clients and two counselors from a short-term residential
      alcohol treatment facility participated in this study. Counselors served in both
      the treatment and control conditions in this 2x2 mixed factorial design by first
      participating in the control condition (general substance abuse education) and
      then in the treatment condition (smoking education). Counselors proceeded to work
      (for 6 weeks) with clients who had participated in the control education in
      general substance abuse issues and with clients who participated in the treatment
      education series in smoking issues. Clients completed the Fagerstrom Test for
      Nicotine Dependence and Stages of Change Ladders pre- and posttest. Results
      indicated that counselor and client education was effective in significantly
      changing the clients' thoughts toward smoking cessation and their smoking
      behaviors. Implications for instituting a smoking education program involving
      counselors, as well as clients, are discussed.

PMID- 10400285
TI  - The relationship of cognitive functioning to amount of recent and lifetime
      alcohol consumption in outpatient alcoholics.
AB  - Previous investigations of the relationship between drinking patterns and
      cognitive functioning have generally studied severely alcoholic patients, in whom
      the neurocognitive effects of alcohol consumption can be obscured by other
      medical or psychosocial factors. In the present study, cognitive functioning was
      examined after a minimum of 4 days of abstinence in 69 mildly to moderately
      alcohol-dependent outpatients without comorbid psychiatric, neurologic, or
      systemic medical illness. Circumscribed decrements in reaction time and verbal
      memory were associated with higher amounts of alcohol consumption in the 90 days
      prior to enrollment in the study, and amount of recent consumption was correlated
      with scores on numerous cognitive tests. In contrast, longer drinking history was
      not associated with poorer performance on any neuropsychological measures. Thus,
      in this group of high-functioning, mildly to moderately alcohol-dependent
      outpatients, mild cognitive deficits were related to the amount of recent, but
      not lifetime, alcohol consumption.

PMID- 10400286
TI  - Doctor Albert Calmette 1863-1933: founder of antivenomous serotherapy and of
      antituberculous BCG vaccination.
AB  - In 1891 in Saigon (now Ho Chi Minh City), Dr. Albert Calmette established the
      first daughter Pasteur Institute for the protection of the local population
      against rabies and smallpox. Inspired by the discovery of diphtheria antitoxin by
      Behring, Calmette studied ways of raising serum against cobra venom. In 1895, now
      in Lille at the second daughter institute that he established, Calmette produced
      anticobra serum for therapeutic use that was to revolutionize the treatment of
      snakebite worldwide. The incidence of tuberculosis in the working class of the
      industrial north shocked Calmette. In response, firstly he organized an
      antituberculous dispensary to provide assistance to the sick and help limit the
      spread of the disease by improving social hygiene and secondly he devoted
      himself, with the assistance of Camille Guerin, to obtaining an attenuated live
      strain of tubercle bacilli with fixed biological characteristics for use as a
      vaccine. Such a strain developed during repeated passage of a culture of
      Mycobacterium bovis grown on a bile potato medium. In 1919, Dr. Albert Calmette
      took up the appointment of Sub-Director of the Pasteur Institute of Paris.
      Prolonged trials of BCG (Bacille Calmette-Guerin) vaccine showed it to be safe
      and vaccination of very young infants born of tuberculous mothers commenced in
      1921. The use of BCG vaccine as a prophylactic against tuberculosis spread world
      wide and has remained important in combatting this scourge.

PMID- 10400287
TI  - The effects of pretreatment with glycyrrhizin and glycyrrhetinic acid on the
      retrorsine-induced hepatotoxicity in rats.
AB  - A wide variety of medicinal herbs contain hepatotoxic pyrrolizidine alkaloids
      (PAs), and often cause acute and chronic liver damages in man. Liquorice, a known
      antihepatitis, is commonly used with PA-containing herbs concurrently, and
      hepatotoxicity induced by such combined uses was not pronounced. The present
      study is to investigate effects of glycyrrhizin (GL) and 18beta-glycyrrhetinic
      acid (GA), the major biologically active ingredients of liquorice, against PA
      induced hepatotoxicity in rats. Single dose (35 mg/kg, i.p.) of retrorsine (RET),
      a typical potent hepatotoxic PA, was given to rats to induce liver injury. A
      single dose pretreatment with GL or GA prior to retrorsine challenge did not show
      hepatoprotection. However, when rats were pretreated with either GL (200
      mg/kg/day, i.p.) or GA (10 mg/kg/day, i.p.) for three consecutive days prior to
      retrorsine exposure, the elevated serum GOT and GPT levels induced by retrorsine
      were significantly reduced. Serum levels of transaminases almost returned to
      normal (GOT: 56+/-2 (control), 104+/-5 (RET), 64+/-3 (GL + RET) and 59+/-3 (GA +
      RET). GPT: 40+/-2 (control), 90+/-7 (RET), 45+/-2 (GL + RET) and 45+/-4 (GA +
      RET) SF units/ml). Furthermore, no extensive hepatocellular damages were
      observed. The results demonstrated that a three-day pretreatment with either GL
      or GA exhibited protective effect on retrorsine-induced liver damage in rats.

PMID- 10400288
TI  - Protein variation in the venom spat by the red spitting cobra, Naja pallida
      (Reptilia: Serpentes).
AB  - The venom spat by red spitting cobras (Naja pallida) was analyzed to document
      variations in protein composition occurring over short temporal periods (less
      than 5 min). These cobras exhibited distinct control of venom flow with spits
      averaging 1.7% of the volume of the venom gland, thus enabling the cobras to
      rapidly expel over 40 consecutive spits. Variations in the low and high molecular
      weight proteins were observed when comparing the 1st, 20th and 40th spits
      produced by the same specimens. The first few spits were characterized by a
      distinctive 9 kDa protein which was never observed beyond the 7th spit, was
      present in milked venom and was present when the spitting behavior was preceded
      by a 5 min period of induced defensive behaviors.

PMID- 10400289
TI  - Secretory polymorphism and serous cutaneous gland heterogeneity in Bufo
      granulosus (Amphibia, Anura).
AB  - Three types of secretory products (a, b and c) in the poison glands of the
      Argentine toad Bufo granulosus have been detected under light microscope. The
      type a secretory product consists of granules of homogeneous density, type b of
      vesicles with a translucent compartment and type c of granules of varying
      density. Subsequent transmission electron microscope analysis disclosed obvious
      similarities in the secretory pathways of type a and c granules; the differences
      detected under light microscope are due to the functional phases observed. On the
      contrary, production of type b secretory vesicles involves a distinctive pathway.
      Therefore, two classes of glands (I and II) have been identified. Glands of the
      first class are typical of bufonid toads and produce granules provided with
      repeating substructure; glands of the second class, which manufacture a lucent
      product, are unusual in the family Bufonidae. Ultrastructural differences,
      consistent with the two gland classes, have also been described in the
      myoepithelia. The myocytes ensheathing class I secretory units possess striking
      cytoskeletal specializations, whereas those of class II glands are rich in
      sarcoplasmic reticulum. The distinctive ultrastructural traits detected in these
      myoepithelial cells have been compared with the results of previous studies on
      the dimorphic serous glands of Bombina. Findings point to the use of
      pharmacological treatment on the skin of anurans with different classes of serous
      glands to elicit differential secretory discharge.

PMID- 10400290
TI  - Characterization of the local tissue damage induced by LHF-II, a
      metalloproteinase with weak hemorrhagic activity isolated from Lachesis muta muta
      snake venom.
AB  - Local tissue damage induced by LHF-II, a 22-kDa hemorrhagic metalloproteinase
      from Lachesis muta venom was studied. Intravital microscopy experiments evidenced
      hemorrhagic events 2 min after LHF-II application onto cremaster muscle,
      characterized by microhemorrhages in capillary vessels and venules. However,
      histological analysis showed only mild hemorrhage in the gastrocnemius muscle.
      LHF-II degraded laminin, fibronectin and type IV collagen upon incubation in
      vitro, but was not cytotoxic to capillary endothelial cells in culture.
      Intramuscular injection of LHF-II induced a mild myonecrosis, with early small
      increments in plasma creatine kinase activity. It also induced edema in the mouse
      footpad at doses where hemorrhage is absent. Injection of LHF-II induced the
      synthesis of matrix metalloproteinases evidenced in muscle homogenates and in
      exudate samples. It is concluded that LHF-II has weak hemorrhagic and myotoxic
      activities, and that its role in the pathogenesis of L. muta-induced local tissue
      damage is associated with edema formation and degradation of extracellular matrix
      components, either directly or by activation of endogenous matrix
      metalloproteinases.

PMID- 10400291
TI  - Cation channel formed at lipid bilayer by Cinnamomin, a new type II ribosome
      inactivating protein.
AB  - Cinnamomin, a new type II ribosome-inactivating protein, purified from the seeds
      of Cinnamonum camphora is reconstituted into the membranes of planar lipid
      bilayer and giant liposome. The channel-forming activity of the cinnamomin is
      found and cation permeability of the channel is characterized by patch clamp. In
      an asymmetric solution system, bath 150/pipette 100 mM KCl, the unit conductance
      is 140+/-7 pS and the reversal potential is 10.4+/-0.6 mV, very close to the
      theoretical value of the K+ electrode. The results offer an interpretation for
      internalization of the RIP and the cytotoxicity difference between single and two
      chain RIP.

PMID- 10400292
TI  - Development and evaluation of the neutralizing capacity of horse antivenom
      against the Brazilian spider Loxosceles intermedia.
AB  - Spider bites due to Loxosceles intermedia are currently a major public health
      problem in South Brazil. About 3000 cases are reported annually. Specific
      treatment for spider bites is provided by the polyvalent anti-arachnidic
      antiserum produced by Butantan Institute, Sao Paulo, Brazil by immunizing horses
      with mixtures of venoms from Tityus serrulatus and T. bahiensis scorpions, as
      well as Phoneutria nigriventer and L. gaucho spiders. Due to the large amounts of
      the anti-arachnidic antivenom required and since L. intermedia venom has some
      biochemical and pharmacological variations, we have produced a specific anti-L.
      intermedia antivenom. This study shows that horses immunized with crude L.
      intermedia venom produced IgG antibodies that neutralized the dermonecrotic and
      lethal activities of the venom. The neutralizing potency of the anti-loxoscelic
      antivenom was compared with that of the anti-arachnidic antivenom. Our results
      indicate that both antivenoms were effective in terms of neutralization. However,
      the anti-loxoscelic antivenom was more efficient than the anti-arachnidic.

PMID- 10400293
TI  - Bibliography of toxinology.

PMID- 10400294
TI  - Pharmacological effects of the leaf-nosed viper snake (Eristocophis macmahoni)
      venom and its HPLC fractions.
AB  - Crude venom from Eristocophis macmahoni was demonstrated to exert a potent
      inhibition of human blood platelet aggregation mediated by adenosine diphosphate
      (ADP), platelet activating factor (PAF) and arachidonic acid (AA). The venom
      caused lysis of the platelets, however, the red blood cells were not lysed by the
      venom. Substantial oedema was produced upon injection of the venom into the rat
      hind paw. Contrarily, the intraperitoneal injection of the venom to the rats
      caused an inhibition of the carrageenin-induced rat paw oedema. However, an 100%
      lethality within 24 h was observed with a dose of 40 mg/kg body weight. The venom
      was fractionated by reverse phase high pressure liquid chromatography (HPLC) and
      the fractions were analyzed for their effect on ADP-induced platelet aggregation.
      The fraction eluted at 15.5 min (20% acetonitrile concentration) exhibited an
      inhibitory effect of several-fold greater potency than that of the crude venom.
      Fractions eluted at 18.5 min (25.4% acetonitrile concentration) and onward showed
      a proaggregatory but insignificant effect. It is suggested that although the
      venom contains pro aggregatory components, inhibition of platelet aggregation
      seems to be its predominant activity.

PMID- 10400295
TI  - Esters of okadaic acid and dinophysistoxin-2 in Portuguese bivalves related to
      human poisonings.
AB  - Liquid chromatography (HPLC) was used to search for esters of DSP toxins in
      Portuguese bivalves. Hexane-soluble derivatives of okadaic acid (OA) and
      dinophysistoxin-2 (DTX-2) were found. Presumably they are acyl derivatives,
      globally known as 'dinophysistoxin-3' (DTX-3). In certain instances DTX-3 content
      surpassed 50% of the total amount of DSP toxins. A human diarrhetic poisoning
      (DSP) incident with Donax clams (Donax trunculus) harvested at Fuzeta (Algarve
      coast) was confirmed where the apolar (DTX-3 type) and other esters remaining in
      the polar aqueous methanol layer were implicated. The percentage of acyl esters
      of OA was always higher than those of DTX-2. An enzymic mechanism for the
      conversion of OA and DTX-2 seems to be implicated in some kind of detoxification
      process because the percentage of esters increases with the toxin amount ingested
      by the bivalve and there is some degree of selectivity as DTX-2 seems more
      difficult to acylate. These findings pose a problem for the current assay methods
      used to detect DSP because mainly they are able to detect the parent toxins but
      not their esters. The current bioassay method [Le Baut, C., Bardin, B., Bardouil,
      M., Bohec, M., Masselin, P., Truquet, P., 1990. Etude de la decontamination de
      moules toxiques. Rapport IFREMER DERO-90-02 MR. 21 pp.] used in Portugal includes
      a hexane washing step that prevents interference from free fatty acids. However,
      it cannot detect the presence of acyl derivatives because they are highly soluble
      in hexane.

PMID- 10400296
TI  - Synopsis of recent developments in venomous snake systematics, No. 3.
AB  - We present recent findings in the systematics of venomous snakes, with emphasis
      on those which affect the nomenclature and our understanding of species limits in
      these animals. Changes in systematics reviewed here include particularly the
      genera Acanthophis, Elapsoidea, Bitis, Lachesis, Porthidium,
      Trimeresurus/Tropidolaemus and Vipera. Other new publications of more general
      interest to toxinologists are also presented.

PMID- 10400297
TI  - Toxicity and immunogenicity of Crotalus durissus terrificus venom treated with
      different doses of gamma rays.
AB  - Crotalus durissus terrificus venom (CDT venom) was irradiated with four different
      doses of gamma rays (2, 3, 5 and 10 kGy) from a 60Co source and their structural,
      toxic and immunogenic properties were analysed. Venom irradiated with 2 and 3 kGy
      were, respectively, 2.7 and 13.5 times less toxic than the native one, whereas
      the 5 or 10 kGy irradiated venom were at least 100 times less toxic than
      nonirradiated venom. Irradiated venom with all doses were immunogenic and the
      antibodies elicited by them were able to recognise the native venom in ELISA.
      However the toxoid produced with 2 kGy irradiation dose had its immunogenicity
      improved. Antisera raised against this toxoid had a higher neutralising capacity
      than those produced against the native venom. Irradiation of venom with 2 kGy
      dose was the most effective to inactivate the CDT venom toxicity and improve its
      immunogenicity.

PMID- 10400298
TI  - Effects of Bothrops pirajai venom on the mouse extensor digitorum longus (EDL)
      muscle preparation.
AB  - The effects of Bothrops pirajai snake venom on the mouse extensor digitorum
      longus (EDL) preparation were examined using myographic, histopathological and
      biochemical approaches. B. pirajai venom (10, 25 or 50 microg/ml) dose
      dependently and irreversibly blocked the contractile response of indirectly
      stimulated EDL muscle. Histopathological analysis of EDL muscle incubated with
      venom showed dose-dependent damage with a loss of the normal tissue structure and
      the appearance of highly dark, edematous fibers together with myofibrils in
      various stages of condensation. At high doses of venom (50 microg/ml), loss of
      muscle cells was observed. In non-stimulated EDL, B. pirajai venom (10 and 50
      microg/ml) caused a time-dependent release of CK which was maximal after 120 min.
      These results suggest that a component(s) present in the B. pirajai venom has a
      direct myolytic action on the skeletal muscle.

PMID- 10400299
TI  - Serum levels of cytokines in patients envenomed by Tityus serrulatus scorpion
      sting.
AB  - Seventeen patients stung by Tityus serrulatus scorpion were classified as mild
      (pain at the site of the sting, n = 6), moderate (local pain and one of the
      following manifestations: vomiting, psychomotor agitation, prostration, sweating,
      tachypnea, tachycardia and mild arterial hypertension, n = 10) and severe cases
      (equal moderate cases plus cardiac failure, pulmonary edema and shock, n = 1).
      Venous blood was sampled for biochemical and hematological analysis and for IL
      1alpha, IL-6, IL-10, TNF-alpha, IFN-gamma and GM-CSF ELISAs at the time of
      hospital admission, 6 h (moderate and severe cases), and 12, 18, 36 and 72 h
      (severe case) later. Ten age-matched healthy volunteers were used as control.
      Increased serum levels of IL-1alpha was noticed in all patients, high levels of
      IL-6, IFN-gamma and GM-CSF were observed only in a patient with severe
      envenomation. Our data suggest that a systemic inflammatory response-like
      syndrome is triggered during severe envenomation caused by T. serrulatus sting
      and that release of cytokines may be involved in this response.

PMID- 10400300
TI  - Molecular characterization of a new excitatory insect neurotoxin with an
      analgesic effect on mice from the scorpion Buthus martensi Karsch.
AB  - Besides the neurotoxins active on mammals, a new excitatory insect selective
      toxin with a mice analgesic activity was found and purified from the venom of the
      scorpion Buthus martensi Karsch (BmK) (Ji, Y.H., Mansuelle, P., Terakawa, S.,
      Kopeyan, C., Yanaihara, N., Hsu, K., Rochat, H., 1996. Toxicon 34, 987; Luo,
      M.J., Xiong, Y.M., Wang, M., Wang, D.C., Chi, C.W., 1997. Toxicon 35, 723.). This
      peptide (designated as BmK IT-AP) is composed of 72 amino acid residues. Its
      primary structure was determined by automated Edman degradation of the N-terminal
      part of the reduced and S-carboxamidemethylated protein and its
      lysylendopeptidase degraded fragments. Based on the determined sequence, the gene
      specific primers were designed and synthesized for 3' and 5' RACE (rapid
      amplification of cDNA ends). Their partial cDNA fragments obtained by 3' and 5'
      RACEwere cloned and sequenced and the full length cDNA sequence of BmK IT-AP was
      then completed by overlapping their two partial cDNA sequences. It encodes a
      precursor of 90 amino acid residues: a signal peptide of 18 residues and a mature
      peptide of 72 residues which are consistent with the determined protein sequence
      of BmK IT-AP. The genomic DNA of the peptide was also amplified by PCR from the
      scorpion genomic DNA and sequenced, which is a first report on the genomic
      structure of a scorpion toxin specific for insects. Its sequence revealed an
      intron of 590 bp inserted in the end part of the signal peptide. The peptide
      caused a fast excitatory contraction paralysis on house fly larvae. Furthermore,
      the peptide also showed an obvious analgesic effect on mice, as assayed by using
      a twisting test model. This effect of BmK IT-AP well characterized at molecular
      level is first reported among the known scorpion insect neurotoxins.

PMID- 10400301
TI  - Retention of Microcystis aeruginosa and microcystin by salad lettuce (Lactuca
      sativa) after spray irrigation with water containing cyanobacteria.
AB  - Colonies and single cells of Microcystis aeruginosa and the hepatotoxin
      microcystin were retained by salad lettuce after growth with spray irrigation
      water containing the microcystin-producing cyanobacteria. These findings are
      discussed in terms of crop spray irrigation with water containing cyanobacteria
      and potential human exposure to cyanobacterial toxins via plant foods grown in
      such circumstances.

PMID- 10400302
TI  - High levels of yessotoxin in mussels and presence of yessotoxin and
      homoyessotoxin in dinoflagellates of the Adriatic Sea.
AB  - Identification of YTX and homoYTX in natural phytoplankton populations containing
      significant amounts of Gonyaulax polyedra and determination of detailed toxin
      profiles of mussels (Mytilus galloprovincialis) periodically collected from two
      sites of the Northern Adriatic coast from February to October 1997 was performed
      by LC-FLD following derivatization with ADAM or DMEQ-TAD and LC-MS and LC-MS-MS.
      OA and YTX concentrations were recorded in the range 0.11-2.31 and 0.18-9.02
      microg per g of hepatopancreas, respectively. HomoYTX was also detected both in
      phytoplankton and mussel samples.

PMID- 10400303
TI  - Bibliography of Toxinology.

PMID- 10400304
TI  - Assessment of DNA-protein crosslinks in the course of aging in two mouse strains
      by use of a modified alkaline filter elution applied to whole tissue samples.
AB  - Two different mouse strains have been used for determination of age dependence of
      DNA-protein crosslinks by alkaline filter elution: a long lived laboratory
      strain, NMRI and an accelerated senescence-prone, short lived strain, SAMP1. Five
      organs were selected: Brain, kidney, lung, heart and liver. Remarkably in all
      five organs of short lived SAMPI mice crosslinks increased significantly with
      age. In NMRI however only in brain and heart a significant rise in old age has
      been observed, while in the other organs there was no increase in DNA-protein
      crosslinking. Appreciable mitotic activity which is lacking in brain and heart
      could be the reason for this difference. Poor repair in all five organs could be
      an important component for the multiple ailments and shortened life span in SAMP1
      mice.

PMID- 10400305
TI  - Age-related changes of the nucleolar organizer regions without neuron loss in
      medial mamillary bodies (hypothalamus) in old rats.
AB  - Age-related morphological and functional changes were studied in the medial
      mamillary nuclei of the hypothalamus (MMN). The number of nerve cells and the
      volume of MMN were estimated in both groups of Wistar rats, adult and old (3 and
      22 months, respectively) using stereologic methods such as the optical
      fractionator and Cavalieri's method respectively. The number of neurons and glial
      cells remain inalterable with ageing but there was an age-dependent reduction in
      MMN volume. In the second experiment, functional changes in the MMN neurons were
      observed although there was no loss in neuron number. Several functional
      parameters of the Ag-NORs were quantified by a computer analysis system: area and
      number of Ag-NORs per neuron; number of neurons with one or several Ag-NORs and
      also surface of neuronal nucleus. The present study shows how ageing causes
      volumetric and functional changes in the MMN whereas the number of neurons and
      glial cells remain unchanged in the mamillary region. All these results confirm
      the effects of age on proteic synthesis activity in neurons of the MMN, showing a
      decreased neuronal activity in this region.

PMID- 10400306
TI  - Favourable effect of K, Mg aspartate on serum proteins in aging rats.
AB  - The serum concentration of individual proteins in aging rats was studied. We have
      made an attempt to slow down the changes in concentration occurring in rats from
      5 up to 17 months of age by application of aspartate given in drinking water
      containing 500 mg% of monopotassium DL asparagicum and 500 mg% of monomagnesium
      D,L asparagicum. The solution was administered continuously for 14 days a month
      for 1 year. In a part of animals, the aging process was accelerated by ionizing
      radiation with a single dose of 4.0 Gy. We found out that administration of
      aspartate caused slowing of changes in concentration of all proteins observed
      (prealbumin, albumin, A1-globulin, haptoglobin and hemopexin) in non-irradiated
      and prealbumin, albumin, A1-globulin in irradiated rats in comparison with the
      values of proteins in rats drinking water only. The preparation did not influence
      more significantly the changes in the serum concentration of haptoglobin and
      hemopexin in rats whose aging was accelerated by radiation. A favourable effect
      of the preparation used manifested also in the values of survival, because the
      animals protected with K, Mg aspartate survived by 25-30% longer.

PMID- 10400307
TI  - The age-related changes in lipogenic enzymes: the role of dietary factors and
      thyroid hormone responsiveness.
AB  - To determine whether resistance to insulin or to thyroid hormones rather than an
      inherent defect in enzyme activity expression account for the age-related changes
      in lipogenic enzymes, the activities of malic enzymes (ME), fatty acid synthase
      (FAS), glucose-6-phosphate dehydrogenase (G-6PD) and 6-phosphogluconate
      dehydrogenase (6-PGD) were assayed in hepatic, retroperitoneal fat and epididymal
      fat cytosol of male Fischer 344 rats at 3.5, 12 and 25 months of age. The rats
      were maintained on either regular rat chow with 62% of calories as complex
      carbohydrates or were given either high glucose or fructose diet with 65.7% of
      calories provided by glucose or fructose respectively. Additional groups of young
      and aged rats were treated with L-triiodothyronine (T3) (15 microg/100 g body
      weight) for 10 days. Treatment with T3 resulted in higher levels of hepatic ME
      activity regardless of the diet consumed or the age of the rats. T3 had no
      consistent effect on FAS, G-6PD or 6-PGD activities. ME response to T3 in young
      rats was significantly greater than that found in aged rats regardless of diet.
      The age-related decrease in basal hepatic ME activity was not apparent in rats
      maintained on the high glucose or the high fructose diets, yet the T3
      responsiveness of ME in rats maintained on these diets was not normalized. In
      adipose tissue, with the exception of the age-related changes in basal activity
      of the lipogenic enzymes, neither T3 nor the feeding of the test diets had any
      consistent effects. Since insulin resistance induced by high fructose feeding did
      not reduce hepatic lipogenic enzymes, it is unlikely that the age-related
      increase in insulin resistance explains the reduced lipogenic enzyme activity in
      aged rats. However, resistance to thyroid hormone action found in aged rats may
      partly account for the reduced hepatic lipogenic enzyme activity.

PMID- 10400308
TI  - Effect of cellular aging on the induction of cyclooxygenase-2 by mechanical
      stress in human periodontal ligament cells.
AB  - The production of prostaglandin (PGE2) in human periodontal ligament fibroblast
      (hPLF) cells is increased by mechanical stress, however, the age-related changes
      in the susceptibility of hPLF cells in response to mechanical stress remain
      unclear. The purpose of this study was to examine the influence of in vitro
      cellular aging on PGE2 production and the gene expression of cyclooxygenase (COX)
      in mechanically stressed hPLF cells. In vitro cellular aged hPLF cells were
      prepared by sequential subcultivations of hPLF cells from young healthy
      periodontal ligaments. In vitro cellular aged hPLF cells produced a significantly
      higher amount of PGE2, as compared with young hPLF cells, when the cells were
      exposed to cyclic tension force in a time- and magnitude-dependent manner. The
      COX-2 mRNA level in aged cells was higher than that in young cells, whereas COX-1
      mRNA remained unchanged. Since PGE2 from hPLF cells was stimulated by in vitro
      aging as presented here, aging of hPLF cells may affect the severity of
      inflammation and bone resorption in the aged through the production of a large
      amount of PGE2 in response to an excessive force such as a traumatic occlusion.

PMID- 10400309
TI  - Age-related changes of glial fibrillary acidic protein immunoreactive astrocytes
      in the rat cerebellar cortex.
AB  - Age-related changes of glial fibrillary acidic protein (GFAP) immunoreactivity
      were investigated in the cerebellar cortex of young (3 months), adult (12 months)
      and old (24 months) rats using immunohistochemical techniques associated with
      image analysis. In young rats, cell bodies of GFAP-immunoreactive astrocytes were
      found in the white matter and in the granular layer of cerebellar cortex.
      Radially-oriented branches of astrocytes which are sited in the granular layer
      were also observed in the molecular layer. The number of GFAP-immunoreactivity
      astrocytes of white matter was decreased in adult and old rats in comparison with
      young cohorts, whereas their size increased progressively from 3 to 24 months
      old. The number and the size of GFAP-immunoreactive astrocytes of the granular
      layer was similar in young and adult rats. An increased number and size of GFAP
      immunoreactive astrocytes was noticeable in old rats in comparison with younger
      cohorts. The number of radially oriented branches of the molecular layer was the
      same in the three age groups investigated. The above results indicate that GFAP
      immunoreactive astrocytes of rat cerebellar cortex undergo age-related changes.
      The not homogeneous sensitivity to aging of cerebellar astrocytes suggests that
      evaluation of changes of different cell populations of cerebellar cortex should
      represent an important step of research on aging cerebellum.

PMID- 10400310
TI  - Effect of age and carbon tetrachloride on cytokine concentrations in rat liver.
AB  - Interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor
      alpha (TNF-alpha) concentrations were measured in livers of young-adult and old
      rats administered carbon tetrachloride or vehicle. IL-1beta levels were higher
      and IL-6 levels were lower in old rats than in young-adult rats. Carbon
      tetrachloride treatment increased IL-1beta and decreased TNF-alpha and IL-6. The
      elevation in IL-1beta was diminished by aging. These results indicate that the
      increase in carbon tetrachloride hepatotoxicity that occurs in old age could be
      related to a dysregulation of inflammatory cytokines.

PMID- 10400311
TI  - Intracellular signalling pathways induced by chemokines in natural killer cells.
AB  - Chemokines are small peptides involved in the recruitment of various cell types
      into inflammatory sites. They are divided into four sub-families depending on the
      presence of amino acids separating the cysteine residues in their N-terminal
      region. These are the alpha (CXC), beta (CC), gamma (C) and delta (CX)C)
      chemokines. In addition, five CXC chemokine (CXCR1-5), nine CC chemokine (CCR1
      9), one C chemokine (XCR1) and one C-X3C chemokine (CX3CR1) receptors have been
      identified. These receptors belong to the seven transmembrane spanning domain
      family, and are coupled to the heterotrimeric guanine nucleotide binding (G)
      proteins. Chemokines activate various immune cells, and in particular the anti
      viral/anti-tumour effectors, the natural killer (NK) cells by activating members
      of the heterotrimeric G proteins. The importance of the family of chemokines is
      highlighted by the ability of its members to inhibit the replication of HIV-1
      strains in CD4+ cells, where chemokine receptors act as HIV-1 co-receptors. This
      review discusses the intracellular signalling pathways induced by chemokines in
      NK and other cell types, and the relationships to HIV-1 signalling in these
      cells.

PMID- 10400312
TI  - Signal pathway of mitogen-induced Ca2+-activated K+ currents in young and aged T
      cell clones of C57BL/6 mice.
AB  - Signal transduction pathways of mitogenic plant lectin, concanavalin A (Con A)-
      and ionomycin (INM)-induced (Ca2+-dependent K+ currents (I(Con A) and I(INM))
      have been compared in young and aged T-cell clones by using the nystatin
      perforated patch-clamp whole-cell recording technique. In young T-cell clones,
      Con A evoked a long-lasting outward current which is mediated by the activation
      of the Ca2+-dependent K+ channels. The Ca2+ ionophore, INM, evoked a short
      lasting Ca2+-dependent outward K+ current (I(INM)). The protein tyrosine kinase
      (PTK) inhibitor, herbimycin A (3 x 10(-6) M), but not the G protein blocker,
      pertussis toxin (PTX, 500 ng ml(-1)), completely prevented the I(Con A), but did
      not affect the I(INM). In aged T-cell clones, Con A fails to evoke any current
      response, while INM evokes an outward current which is comparable to that in a
      young T-cell clone. It is concluded that PTK, but not PTX-sensitive G proteins,
      plays a critical role in mediation of the signal transduction from Con A
      stimulation to activation of the Ca2+-dependent K+ channels, and that an
      impairment of the early signal pathway, perhaps the PTK, might be involved in the
      mechanism of the age-related decline of the proliferative response of T
      lymphocytes to mitogenic stimulation.

PMID- 10400313
TI  - Resistance of initiation factor 2 (eIF-2alpha) kinases to staurosporine: an
      approach for assaying the kinases in crude extracts.
AB  - We studied the effect of staurosporine on two well characterised mammalian eIF
      2alpha kinases, the heme-regulated translational inhibitor (HRI), and interferon
      inducible double-stranded RNA-activated protein kinase (PKR). Both pure eIF-2 and
      a synthetic peptide used to measure the activity of purified or
      immunoprecipitated enzymes (sequence ILLSELSRRRIRAI) were phosphorylated with
      purified enzymes and crude preparations of tissues or cells in the presence of
      the inhibitor. In the presence of 0.25 microM staurosporine (a concentration
      which completely inhibits a wide range of Ser/Thr protein kinases), the
      phosphorylation of eIF-2alpha by HRI and PKR was not inhibited. The lack of
      response of eIF-2alpha kinases to staurosporine allowed us to measure PKR
      activity in salt washed postmicrosomal supernatants without previous purification
      of the enzyme. In the presence of poly(I):poly(C), the PKR activator, we detected
      both an increased phosphorylation of eIF-2alpha and an increment in the
      autophosphorylation of PKR. We also confirmed an induction of PKR in cultured
      neuronal cells after treatment with interferon. The results obtained following
      phosphorylation of the synthetic peptide with crude extracts are less conclusive.
      Although its phosphorylation is specific because it displaces eIF-2
      phosphorylation, and the presence of staurosporine prevents its phosphorylation
      by other serine/threonine kinases, it is a rather poor substrate for PKR.

PMID- 10400314
TI  - Arachidonic acid release in cell lines transfected with muscarinic receptors: a
      simple functional assay to determine response of agonists.
AB  - Muscarinic agonists stimulated arachidonic acid release from 10- to 32-fold in
      Chinese hamster ovary (CHO) cells transfected with muscarinic M1, M3 and M5
      receptor subtypes. Muscarinic agonists liberated arachidonic acid from the cAMP
      coupled M2 and M4 cells only in the presence of ATP. Partial agonists were less
      efficacious at liberating arachidonic acid than full agonists. The ability of
      muscarinic agonists to liberate arachidonic acid and stimulate phosphoinositide
      hydrolysis in the same CHO M1, M3 and M5 cells was well correlated; however,
      partial agonists were more efficacious at stimulating phosphoinositide hydrolysis
      than arachidonic acid release. The efficacy and potency of 13 muscarinic agonists
      to liberate arachidonic acid was characterised. Influx of external calcium was
      required for arachidonic acid release even after initiation of agonist-induced
      release. It is concluded that arachidonic acid release is a simple assay suitable
      for evaluation of muscarinic agonists, antagonists and the flux of external
      calcium into cells.

PMID- 10400315
TI  - Heterotrimetric Gi/o proteins control cyclic AMP oscillations and cytoskeletal
      structure assembly in primary human granulosa-lutein cells.
AB  - In granulosa cells, the luteinising hormone (LH) and the follicle-stimulating
      hormone (FSH) receptors are coupled to the adenylyl cyclase-cAMP pathway. We
      identified at least eight different G proteins belonging to three families--Gs,
      Gq, and Gi/o--in primary human granulosa-lutein cells. By exploring the function
      of Gi/o by time-lapse and digital-imaging microscopy of live cells, we found that
      the reversible actin stress fibre-dependent cytoplasmic retraction of pre
      luteinised cells in primary culture is a highly sensitive and quite rapid system
      allowing detection of an intracellular cAMP surge. This morphology was
      characterised by maintenance of connexin43-dependent cell-cell contacts and that
      of microtubule-directed cell processes attached to the substrate and to
      neighbouring cells. Inhibitors of cyclic nucleotide phosphodiesterase subfamily
      type 4 (PDE-4), hLH and hFSH provoked this reversible cAMP-dependent phenotype in
      a temporal-, spatial- and dose-dependent manner. Gi/o inhibited adenylyl cyclase
      in membranes, and cell treatment with islet-activating protein (IAP) caused the
      cAMP-dependent retracted phenotype. It is concluded that the basal intracellular
      cAMP level is kept within a narrow range of concentrations, below the threshold
      for disassembly of stress fibres, through Gs, Gi/o, adenylyl cyclases and
      phosphodiesterase-4. This work supports the paradigm that switching of the
      agonist-occupied receptors to Gs and Gi/o would control both the intracellular
      bursts of cAMP (through the gonadotropin-catalysed activation of Gs) and the
      basal cAMP (through a Gi/o-mediated braking effect).

PMID- 10400317
TI  - Investigating the role played by protein-lipid and protein-protein interactions
      in the membrane association of the p120GAP CaLB domain.
AB  - The GTPase activating protein, p120GAP, contains an amino acid sequence motif
      called the Ca2+-dependent lipid binding domain (CaLB) which mediates a protein
      protein interaction between p120GAP and annexin VI and also binds to negatively
      charged phospholipids. Because membrane association of p120GAP is important for
      the regulation of p21 Ras activity, we have studied the roles played by Ca2+,
      phospholipids and annexin VI in the membrane association of p120GAP. Here we
      demonstrate that a truncated CaLB domain GST fusion protein (GSTGAP618-632),
      lacking the ability to bind to phospholipids, is able to bind to rat fibroblast
      membranes in a Ca2+- and concentration-dependent manner. In addition, this fusion
      protein also binds to annexin VI in an amino acid sequence specific but Ca2+
      independent manner. Also, when bound to annexin VI in the presence of Ca2+, this
      fusion protein has the ability to co-bind to phosphatidylserine vesicles. Thus,
      annexin VI may simultaneously mediate an interaction with p120GAP and also an
      interaction with membrane phospholipids. This may in part explain the mechanism
      by which p120GAP associates with membranes in response to Ca2+ elevation and
      suggests the potential importance of annexin VI in the regulation of p21 Ras and
      the role CaLB domains may play in the specific recognition of cellular membranes.

PMID- 10400316
TI  - Effect of ceramide on interleukin-6 synthesis in osteoblast-like cells.
AB  - We previously showed that prostaglandin (PG) E1 stimulates the synthesis of
      interleukin-6 (IL-6) through activation of protein kinase (PK) A in osteoblast
      like MC3T3-E1 cells and that PGF2alpha induces IL-6 synthesis through PKC
      activation. In other studies, we demonstrated that thrombin stimulates IL-6
      synthesis, which depends on intracellular Ca2+ mobilisation in these cells and
      that tumour necrosis factor-alpha (TNF) induces IL-6 synthesis through
      sphingosine 1-phosphate, a product of sphingomyelin turnover. In the present
      study, among sphingomyelin metabolites, we examined the effect of ceramide on the
      IL-6 synthesis induced by various agonists in MC3T3-E1 cells. C2-ceramide, a cell
      permeable ceramide analogue, suppressed the PGE1-induced IL-6 synthesis. C2
      ceramide inhibited the IL-6 synthesis induced by PGF2alpha or 12-O
      tetradecanoylphorbol-13-acetate, an activator of PKC. C2-ceramide reduced the IL
      6 synthesis induced by cholera toxin, forskolin or dibutyryl cAMP. C2-ceramide
      inhibited the IL-6 synthesis induced by thrombin. The IL-6 synthesis stimulated
      by thapsigargin, which is known to stimulate Ca2+ mobilisation from intracellular
      Ca2+ stores, or A23187, a Ca-ionophore, was also inhibited by C2-ceramide. C2
      ceramide did not affect the IL-6 synthesis induced by interleukin-1. On the
      contrary, C2-ceramide enhanced the TNF-induced IL-6 synthesis. D,L-threo
      dihydrosphingosine, an inhibitor of sphingosine kinase, inhibited the enhancement
      by C2-ceramide as well as the TNF-effect. These results strongly suggest that
      ceramide modulates the IL-6 synthesis stimulated by various agonists in
      osteoblasts.

PMID- 10400318
TI  - Potent inhibitory ligands of the GRB2 SH2 domain from recombinant peptide
      libraries.
AB  - We cloned and expressed the SH2 domain of human GRB2 as glutathione S-transferase
      and maltose binding protein fusion proteins. We screened three phagemid-based fd
      pVIII-protein phage display libraries against SH2 domain fusion proteins.
      Sequence analysis of the peptide extensions yielded a variety of related
      peptides. By examining the ability of the phage clones to bind other SH2 domains,
      we demonstrated that the phage were specific for the SH2 domain of GRB2. Based on
      the sequence motif identified in the "random" library screening experiment, we
      also built and screened a phage display library based on a Tyr-X-Asn motif (X5
      Tyr-X-Asn-X8). To examine the affinity of the phage derived peptides for GRB2, we
      set up a radioligand competition binding assay based on immobilized GRB2 and
      radiolabelled autophosphorylated EGFR ICD as the radioligand. Results obtained
      with peptide competitors derived from the phage sequences demonstrated that
      nonphosphotyrosine-containing peptides identified with the phage display
      technology had an affinity for the receptor similar to tyrosine-phosphorylated
      peptides derived from the EGFR natural substrate. Interestingly, when the phage
      display peptides were then phosphorylated on tyrosine, their affinity for GRB2
      increased dramatically. We also demonstrated the ability of the peptides to block
      the binding of the GRB2 SH2 domain to EGFR in a mammalian cell-based binding
      assay.

PMID- 10400319
TI  - Conformational aspects of inhibitor design: enzyme-substrate interactions in the
      transition state.
AB  - The theory of absolute reaction rates suggests that enzymes, like other
      catalysts, can enhance the rate of a reaction only to the extent that they bind
      the altered substrate in the transition state (S++) more tightly than they bind
      the substrate in the ground state (S). ES dissociation constants commonly fall in
      the physiological range, but recent kinetic studies indicate that formal ES++
      dissociation constants of less than 10(-20) M are achieved by enzymes of several
      classes. Studies with stable analogues suggest that these remarkable powers of
      discrimination involve a tendency of the enzyme to close around S++ in such a way
      as to maximize binding contacts; that several parts of the substrate contribute
      to S++ binding; and that their contributions to binding affinity can be strongly
      synergistic.

PMID- 10400320
TI  - Bioorganic chemistry of cyclic ADP-ribose (cADPR).
AB  - The objective of this brief review is to present an overview of the bioorganic
      chemistry of cyclic-ADP-ribose (cADPR) with special emphasis on the methodology
      used for the synthesis of analogues of cADPR. New structural analogues of cADPR
      can be prepared using either the biomimetic method or ADP-ribosyl cyclase from
      Aplysia californica. For the most part, both procedures give similar product
      profiles, but higher yields are generally obtained with the enzymatic method.
      These synthetic methodologies have allowed the transformation of a variety of
      structurally modified analogues of NAD+ into their corresponding cyclic
      nucleotides. Several of these novel analogues are more potent than cADPR in
      inducing calcium release and are also more stable towards degradative enzymes.
      They could serve as valuable affinity probes for the isolation of cADPR-binding
      proteins.

PMID- 10400321
TI  - Total synthesis of epothilone E and related side-chain modified analogues via a
      Stille coupling based strategy.
AB  - A Stille coupling strategy has been utilized to complete a total synthesis of
      epothilone E from vinyl iodide 7 and thiazole-stannane 8h. The central core
      fragment 7 and its trans-isomer 11 were prepared from triene 15 using ring
      closing metathesis (RCM), and were subsequently coupled to a variety of
      alternative stannanes to provide a library of epothilone analogues 18a-o and 19a
      o. The Stille coupling approach was then used to prepare epothilone B analogues
      from the key macrolactone intermediate 24 which was itself synthesized by a
      macrolactonization based strategy.

PMID- 10400322
TI  - Zinc(II) complexes of tripodal peptides mimicking the zinc(II)-coordination
      structure of carbonic anhydrase.
AB  - Two new tripodal peptide ligands with histidine side chains have been synthesized
      and were shown to form stable zinc(II) complexes. Their NMR and mass spectra
      indicate a structure that is analogous to the active center of carbonic
      anhydrase. Both the ligands and the zinc complexes were titrated
      potentiometrically in order to obtain the pKa values for the coordinated water of
      the zinc complexes; due to the low solubility of the complexes only estimates
      could be obtained.

PMID- 10400323
TI  - Reversal of optical induction in transamination by regioisomeric bifunctionalized
      cyclodextrins.
AB  - Two isomeric compounds have been synthesized carrying a pyridoxamine on C-6 of
      beta-cyclodextrin and an imidazole unit on C-6 of the neighboring glucose
      residue. Each one stereoselectively transaminates phenylpyruvic acid to produce
      phenylalanine, and with opposite stereochemical preferences. Structure
      determinations by X-ray crystallography and NMR spectroscopy indicate that the
      imidazole units serve to block proton addition from their side, rather than
      acting to protonate the transamination intermediates. Related cyclodextrin
      pyridoxamine compounds had been reported carrying ethylenediamine units instead
      of imidazoles, and high enantioselectivities in transamination were claimed. Our
      work indicates that these claims are incorrect, and that only poor selectivities
      are seen that are often unrelated to the position of the ethylenediamine units.
      Neither of these transaminating systems yet approaches the enantioselectivity
      seen with a pyridoxamine carrying a chirally mounted internal base group.

PMID- 10400324
TI  - An in vitro investigation into conformational aspects of gabapentin.
AB  - Conformational analysis of constrained cyclohexane systems was pioneered fifty
      years ago by Barton and Hassel. We now report an investigation based on a
      conformational analysis of a number of novel cyclohexane based Gabapentin
      analogues coupled with their in vitro evaluation at the Gabapentin binding site.
      These data are used to propose a possible binding conformation for Gabapentin.

PMID- 10400325
TI  - Enzymatic resolution of (+/-)-gamma-cyclohomogeraniol and conversion of its (S)
      isomer to (S)-gamma-coronal, the ambergris odorant.
AB  - Enzymatic acetylation of (+/-)-gamma-cyclohomogeraniol[2-(2',2'-dimethyl-6'
      methylenecyc lohexyl)ethanol] with vinyl acetate in the presence of lipase AK
      yielded the acetate of its (R)-isomer, leaving its (S)-isomer intact. The (S)
      isomer was chemically converted to (S)-gamma-coronal[2-methylene-4-(2',2'
      dimethyl-6'-methylenecyclohexy l)butanal], the ambergris odorant.

PMID- 10400326
TI  - Design, synthesis, and evaluation of N-aroyloxy-2-thiopyridones as DNA
      photocleaving reagents.
AB  - N-Benzoyloxy-2-thiopyridone (12) was shown to induce single-strand nicks in
      duplex DNA upon irradiation with visible light (lambda&350 nm). This finding led
      to the design of a series of compounds, in which an acridinyl nucleus was
      covalently linked to the N-benzoyloxy-2-thiopyridone unit. These conjugates (15,
      16, 17 and 18) were synthesized and evaluated as novel DNA photocleaving
      reagents. Optimal photocleaving activity was observed for conjugate 16, in which
      a flexible polymethylene spacer of 4 carbons was used to connect the
      aminoacridine entity to the thiopyridone. This compound was shown to cleave DNA
      at low microM concentrations and was approximately two-orders of magnitude more
      efficient than the parent N-benzoyloxy-2-thiopyridone (12). Furthermore, the DNA
      cleavage ladders induced by 16 and 12 were found to be identical and of no
      significant sequence selectivity. These data suggest that the N-aroyloxy-2
      thiopyridones can be used for the design of new DNA photocleaving reagents with
      potential use as 'photofootprinting agents' or as 'site-directed photonucleases'.

PMID- 10400327
TI  - Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and
      8-deoxyhapalosin.
AB  - Hapalosin (2), a 12-membered cyclic depsipeptide possessing MDR-reversing
      activity, and analogues (3) and (4) have been synthesized using
      macrolactamization as an important ring-forming step. Three building blocks:
      (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-methyl-decanoic acid (13), benzyl (S)-2
      hydroxy-3-methylbutanate (14), and (4S,3R)-4-(benzyloxycarbonyl-methylamino)-3
      methoxymethoxy-5-pheny l-pentanoic acid (28) were prepared from Evans's chiral
      imide (9), L-valine, and L-N-Boc phenylalanine (17), respectively, and were
      assembled together by applying twice Yamaguchi's coupling methodology. A new and
      efficient selective N-methylation of gamma-hydroxy-beta-amino ester taking
      advantage of the vicinal amino alcohol function was uncovered in the course of
      this study. Thus, treatment of compound 19 with HCHO in the presence of catalytic
      amount of pTsOH followed by reduction (NaBH3CN, TFA, CH2Cl2) of the so-formed
      oxazolidine 24 gave the N-methylated product 25. Furthermore, a dual role of
      oxazolidine as protecting group of vicinal amino alcohol and latent N-methyl
      function was established which allowed synthesizing both hapalosin (2) and N
      desmethylhapalosin (3) from the same linear precursor 32 in a step-efficient and
      atom economic way. In contrast to hapalosin (2) and N-desmethyl analogue (3), the
      amide bond of 8-deoxy hapalosin (4) exists at room temperature (CDCl3)
      exclusively in s-cis conformation as evidenced by NOE studies. This observation
      has been explained on the basis of computational studies. No significant MDR
      reversing activity of 8-deoxy hapalosin (4) was observed in K562 R and
      S/Adriblastine against human erythroleucemic cell lines indicating thus the
      important contribution of hydroxy group to the bioactivity of hapalosin.

PMID- 10400328
TI  - Synthesis of the palmitoylated and prenylated C-terminal lipopeptides of the
      human R- and N-Ras proteins.
AB  - For the study of biological phenomena influenced by the R- and N-Ras proteins,
      characteristic peptides which embody the correct lipid modifications of their
      parent proteins (palmitoyl thioesters, geranylgeranyl thioethers, and farnesyl
      thioethers), as well as analogues thereof, may serve as efficient tools. For the
      construction of such acid- and base labile peptide conjugates the allyl ester was
      developed as C-terminal protecting group. Allyl esters are cleaved selectively
      and in high yields from lipidated peptides by Pd(0)-mediated allyl transfer to
      accepting N- or C-nucleophiles like morpholine and N,N'-dimethylbarbituric acid.
      This protecting group technique formed the key step in the synthesis of the
      characteristic S-palmitoylated and S-isoprenylated C-terminus of human R-Ras and
      human N-Ras proteins, as well as several analogues thereof. Deprotections are so
      mild that no undesired side reactions of the lipid conjugates are observed.

PMID- 10400329
TI  - The reactivity of well defined diiron(III) peroxo complexes toward substrates:
      addition to electrophiles and hydrocarbon oxidation.
AB  - The reactivity of previously reported peroxo adducts [Fe(mu-O2)(mu-L)(O2CPhCy)2(1
      Bu-Im)2] (1), and [Fe(mu-O2)(mu-L)(O2CPhCy)2(py)2] (2), where L is a dinucleating
      ligand based on the m-xylylenediamine bis(Kemp's triacid imide), toward a variety
      of substrates is described. These studies were performed to probe the electronic
      properties of 1 and 2 and evaluate their potential as selective hydrocarbon
      oxidants. Compound 1 is nucleophilic at -77 degrees C, reacting with phenols and
      carboxylic acids to liberate hydrogen peroxide, whereas the less electron-rich
      pyridine analogue 2 is unreactive toward both reagents. By contrast, neither
      reacts at -77 degrees C with electrophilic reagents such as olefins or
      triphenylphosphine, or with weak hydrogen atom donors such as
      dimethylbenzylamine. When solutions of 1 are warmed to room temperature in
      solvents such as THF, toluene, and cyclopentane, mixtures of alcohol and ketone
      products derived from the solvent are formed. A detailed investigation of
      cyclopentane oxidation strongly points to a radical autoxidation pathway. These
      results are discussed in the context of the selective hydroxylation chemistry
      that occurs at the carboxylate-bridged diiron centers in soluble methane
      monooxygenase.

PMID- 10400330
TI  - Design, synthesis and biological evaluation of aryl-substituted sialyl Lewis X
      mimetics prepared via cross-metathesis of C-fucopeptides.
AB  - Several aryl substituted C-fucopeptides have been developed as sialyl Lewis X
      mimetics. Although the compounds have a much simpler structure compared to
      SLe(x), up to 3-times higher binding affinity toward E-selectin and > 1000 times
      toward P-selectin was observed. Furthermore, a convenient strategy for generating
      a number of analogues from a SLe(x) mimetic template at a very late stage of the
      synthesis was introduced, using a ruthenium catalyzed cross olefin metathesis
      under benchtop conditions.

PMID- 10400331
TI  - Chemoenzymatic synthesis of an unnatural tetramethyl cobalt corphinoid.
AB  - The chemoenzymatic synthesis and structural characterization by 13C NMR of a
      tetramethyl cobalt-corphinoid produced by methylation of cobalt-precorrin-3 using
      CbiF are described.

PMID- 10400332
TI  - Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7
      tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline.
AB  - A series of O- and ring-alkylated derivatives of 4,5,6,7
      tetrahydroisothiazolo[4,5-c]pyridin-3-ol was synthesized via treatment of
      appropriately substituted 4-benzylamino-1,2,5,6-tetrahydropyridine-3-carboxamides
      with hydrogen sulfide and subsequent ring closure by oxidation with bromine. The
      muscarinic receptor affinity as well as estimated relative efficacy and subtype
      selectivity of this series of bicyclic arecoline bioisosteres were determined
      using rat brain membranes and a number of tritiated muscarinic receptor ligands.
      The effects at the five cloned human muscarinic receptor subtypes of a selected
      series of chiral analogues, with established absolute stereochemistry, were
      studied using receptor selection and amplification technology (R-SAT). The
      potency, relative efficacy, and receptor subtype selectivity of these compounds
      were related to the structure of the O-substituents and the position and
      stereochemical orientation of the piperidine ring methyl substituents.

PMID- 10400333
TI  - Spectroscopic studies of PhTX facilitated cation movement across membranes.
AB  - Philanthotoxins, noncompetitive inhibitors of the nicotinic acetylcholine
      receptor and various glutamate receptors, were found to be capable of mediating
      cation transport across lipid bilayers. With respect to the relatively weak
      binding constants of these amphiphilic polyamines to neuronal receptor proteins,
      this finding implies that their interaction with cell membranes might have to be
      considered in addition to that with protein receptors to fully understand the
      molecular mechanism of these neurotoxins.

PMID- 10400334
TI  - Inhibition of thermolysin and human alpha-thrombin by cobalt(III) Schiff base
      complexes.
AB  - Cobalt(III) Schiff base complexes have been shown to inhibit the replication of
      the ocular herpes virus. It is well known that these complexes have a high
      affinity for nitrogenous donors such as histidine residues, and it is possible
      that they bind to (and inhibit) an enzyme that is crucial to viral replication.
      In model studies, we have found that [Co(acacen)(NH3)2]+ is an effective
      irreversible inhibitor of thermolysin at millimolar concentrations; it also
      inhibits human alpha-thrombin. Axial ligand exchange with an active-site
      histidine is the proposed mechanism of inhibition. The activity of thermolysin
      and thrombin can be protected by binding a reversible inhibitor to the active
      site before addition of the cobalt(III) complex.

PMID- 10400335
TI  - Non-thiazolidinedione antihyperglycaemic agents. Part 3: The effects of
      stereochemistry on the potency of alpha-methoxy-beta-phenylpropanoic acids.
AB  - Rhizopus delemar lipase catalysed ester hydrolysis of the alpha-methoxy-beta
      phenylpropanoate 1 affords the (R)-(+) and (S)-(-) isomers in > 84% enantiomeric
      excess. Absolute stereochemistry was determined by a single crystal X-ray
      analysis of a related synthetic analogue. The activity of these two enantiomers
      on glucose transport in vitro and as anti-diabetic agents in vivo is reported and
      their unexpected equivalence attributed to an enzyme-mediated stereospecific
      isomerisation of the (R)-(+) isomer. Binding studies using recombinant human
      PPARgamma (peroxisomal proliferator activated receptor gamma), now established as
      a molecular target for this compound class, indicate a 20-fold higher binding
      affinity for the (S) antipode relative to the (R) antipode.

PMID- 10400336
TI  - The selective enzymatic synthesis of lipophilic esters of swainsonine.
AB  - The potent and specific inhibitor of Golgi alpha-mannosidase II, swainsonine (SW)
      has been isolated in high yield from Swainsona procumbens and derivatised by
      regiospecific enzymatic reactions. In this study the regioselectivity of three
      commercially available enzymes, subtilisin Carlsberg, porcine pancreatic lipase
      (PPL) and Candida cylindracea lipase was determined for the acylation of
      swainsonine in predominantly anhydrous organic medium. The use of subtilisin in
      pyridine facilitated the single step synthesis of 2-O-butyryl-SW in a 23% yield,
      whilst catalysis by PPL in tetrahydrofuran gave 2-O-butyryl-SW (6%) and 1,2-di-O
      butyryl-SW (31%).

PMID- 10400337
TI  - D-glucosamine propanedithioacetal, an efficient chiral auxiliary in beta-lactam
      chemistry.
AB  - The synthesis of some monocyclic beta-lactams (monobactams) by the Staudinger
      reaction using D-glucosamine propanedithioacetal as chiral auxiliary is reported.
      The influence of several radicals at C3, C4, and C1' (sugar moiety) as well as
      other structural aspects are considered in relation to the antielastase activity.

PMID- 10400338
TI  - Estimation of the binding affinities of FKBP12 inhibitors using a linear response
      method.
AB  - A series of non-immunosuppressive inhibitors of FK506 binding protein (FKBP12)
      are investigated using Monte Carlo statistical mechanics simulations. These small
      molecules may serve as scaffolds for chemical inducers of protein dimerization,
      and have recently been found to have FKBP12-dependent neurotrophic activity. A
      linear response model was developed for estimation of absolute binding free
      energies based on changes in electrostatic and van der Waals energies and solvent
      accessible surface areas, which are accumulated during simulations of bound and
      unbound ligands. With average errors of 0.5 kcal/mol, this method provides a
      relatively rapid way to screen the binding of ligands while retaining the
      structural information content of more rigorous free energy calculations.

PMID- 10400339
TI  - Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective
      FPT inhibitors with antitumor activity.
AB  - Introduction of bromine at the 10-position of 3-bromo-8-chloro
      benzocycloheptapyridine analogues of type 3 results in formation of atropisomeric
      compounds of type (+/-)-1 and (+/-)-2 that are easily separable at room
      temperature on a ChiralPak AD column providing pure atropisomers, (+)-1, (-)-1,
      and (+)-2, (-)-2, respectively. Evaluation of the FPT activity of these
      atropisomers revealed that compounds (+)-1 and (+)-2 were more potent in the FPT
      enzyme and cellular assay than their (-)-isomer counterparts. Compounds (+)-1 and
      (+)-2 were found to inhibit FPT processing in COS cells at low micro molar range.
      They were also found to have excellent cellular antitumor activity. Evaluation of
      compound (+)-1 and (+)-2 in DLD-tumor model in nude mice revealed that they were
      efficacious, inhibiting tumor growth by 55 and 63% at 50 mpk, respectively.

PMID- 10400341
TI  - Discovery and development of sesquiterpenoid derived hydroxymethylacylfulvene: a
      new anticancer drug.
AB  - Hydroxymethylacylfulvene (HMAF, MGI 114) is derived from the sesquiterpene
      illudin S by treatment with dilute sulfuric acid and excess paraformaldehyde. It
      is less cytotoxic than illudin S but exhibits much greater selectivity in
      toxicity to malignant cells compared to normal cells. HMAF is believed to undergo
      bioreductive activation in vivo. It is now being tested in human clinical phase
      II trials against solid tumors.

PMID- 10400340
TI  - 1,3-Dimethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines as probes for the
      binding orientation of tetrahydroisoquinoline at the active site of
      phenylethanolamine N-methyltransferase.
AB  - In order to determine the function of epinephrine (Epi) in the central nervous
      system, we have targeted the enzyme that catalyzes the final step in the
      biosynthesis of Epi, phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28).
      1,2,3,4-Tetrahydroisoquinolines (THIQs) are inhibitors of this enzyme, but also
      display affinity for the alpha2-adrenoceptor. To gain further understanding about
      how THIQs bind at the PNMT active site and in an attempt to further increase the
      selectivity of THIQ-type inhibitors versus the alpha2-adrenoceptor, a series of
      cis- and trans-1,3-dimethyl-7-substituted-THIQs were synthesized. Evaluation of
      these compounds suggests that THIQs bind in two different orientations at the
      PNMT active site, based on the lipophilicity of the 7-substituent. However, no
      significant increases in selectivity versus the alpha2-adrenoceptor were observed
      for these compounds.

PMID- 10400342
TI  - The linkage of catalysis and regulation in enzyme action: oxidative diversion in
      the hysteretically regulated yeast pyruvate decarboxylase.
AB  - The reaction catalyzed by the thiamin-diphosphate-dependent yeast pyruvate
      decarboxylase, which is hysteretically regulated by pyruvate, undergoes
      paracatalytic oxidative diversion by 2,6-dichlorophenolindophenol, which traps a
      carbanionic intermediate and diverts the product from acetaldehyde to acetate
      (Christen, P. Meth. Enzymol. 1977, 46, 48). This reaction is now shown to exhibit
      an oxidant on-rate constant somewhat faster than that for pyruvate in the normal
      catalytic cycle and a product off-rate constant about 60-fold smaller than that
      for acetaldehyde. Both on-rates and off-rates exhibit an inverse solvent isotope
      effect of 1.5-2, observed in normal catalysis as a signal of sulfhydryl addition
      to the keto group of pyruvate at the allosteric regulatory site. The findings are
      consistent with a model for regulation in which the sulfhydryl-addition process
      mediates access to a fully catalytically competent active site, the oxidative
      diversion reaction being forced to make use of the normal entry exit machinery.

PMID- 10400344
TI  - Prostaglandin E2-bisphosphonate conjugates: potential agents for treatment of
      osteoporosis.
AB  - Conjugates of bisphosphonates (potential bone resorption inhibitors) and
      prostaglandin E2 (a bone formation enhancer) were prepared and evaluated for
      their ability to bind to bone and to liberate, enzymatically, free PGE2. The
      conjugate 3, an amide at C-1 of PGE2 proved to be too stable in vivo while
      conjugate 6, a thioester, was too labile. Several PGE2, C-15 ester-linked
      conjugates (18, 23, 24 and 31) were prepared and conjugate 23 was found to bind
      effectively to bone in vitro and in vivo and to liberate PGE2 at an acceptable
      rate. A 4-week study in a rat model of osteoporosis showed that 23 was better
      tolerated and more effective as a bone growth stimulant than daily maximum
      tolerated doses of free PGE2.

PMID- 10400343
TI  - Antineoplastic agents. Part 409: Isolation and structure of montanastatin from a
      terrestrial actinomycete.
AB  - A Montana soil actinomycete, Streptomyces anulatus, produced (1 x 10(-2)% yield)
      a new cancer cell growth inhibitory cyclooctadepsipeptide named montanastatin (1)
      accompanied by the potent anticancer antibiotic valinomycin (2) in very high
      (5.1%) yields. Valinomycin but not montanastatin inhibited growth of a number of
      pathogenic bacteria and fungi. Interpretation of high-field (500 MHz) NMR and
      high-resolution FAB mass spectral data allowed assignment of the structure cyclo
      (D-Val-L-Lac-L-Val-D-Hiv) to montanastatin. Valinomycin (2) was also isolated
      from actinomycetes cultured from a tree branch and animal feces collected in
      Malaysia. Streptomyces exfoliatus, isolated from the tree branch, was found to
      contain valinomycin in 1.6% yield, while the fecal isolate, S. anulatus, gave
      valinomycin in 0.9% yield.

PMID- 10400345
TI  - Synthesis and benzodiazepine receptor (omega receptor) affinities of 3
      substituted derivatives of pyrrolo[2,3-c]pyridine-5-carboxylate, a novel class of
      omega1 selective ligands.
AB  - Based on the structure of ZK91296 (4d), a high affinity partial agonist of the
      central benzodiazepine (omega) receptor, a series of pyrrolo[2,3-c]pyridine-5
      carboxylate derivatives having mainly aralkyl and aralkyloxy substituents at C-3
      was synthesized. The in vitro binding affinities of these compounds for three
      subclasses of the omega receptor (omega1, omega2, omega5) were determined using
      rat brain tissue. Practically all of these compounds (except the diethyl ester
      derivative 22c) showed an approximately twofold selectivity for omega1 (IC50's in
      the 200-500 nM range) compared to omega2 receptors and practically no affinity
      for omega5 receptors. Compound 22c showed the highest affinity of all the
      compounds synthesized (IC50 = 70 nM for omega1 receptors) as well as a fivefold
      selectivity for omega1 versus omega2 receptors but also displayed significant
      binding to omega5 receptors (IC50 = 250 nM). The absence of appreciable binding
      of 4-methyl and 4-methoxymethyl derivatives to omega receptors, in contrast to
      beta-carbolines having these similarly located substituents, suggests that the
      pyrrolo[2,3-c]pyridine-5-carboxylates may be considered an entirely novel class
      of selective omega receptor ligands.

PMID- 10400346
TI  - Synthesis of new pyridazinone derivatives and their affinity towards alpha1
      alpha2-adrenoceptors.
AB  - A series of 3(2H)-pyridazinone derivatives was evaluated for their affinity in
      vitro towards alpha1-alpha2-adrenoceptors by radioligand receptor binding assays.
      All target compounds showed good affinities for the alpha1-adrenoceptor (with Ki
      values in the subnanomolar range), and a gradual increase in affinity was
      observed by increasing the polymethylene chain length of this series up to a
      maximum of six and seven carbon atoms, when the fragment 4-[2-(2-methoxyphenoxy)
      ethyl]-1-piperazinyl is linked in 5 position of the 3(2H)-pyridazinone ring,
      while a slight decrease was found for the higher homologues. Increasing the chain
      length when the 4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl group is linked in 6
      position of the 3(2H)-pyridazinone ring, had a different effect: there is the
      highest affinity when the polymethylene chain is of four carbon atoms. The
      alkylic chain, a spacer between the two major constituents of the molecule, can
      influence the affinity and the selectivity.

PMID- 10400347
TI  - Mechanistic studies of the rearrangements of steroidal 16,17-ketols and syntheses
      of 20-->16-cis-gamma-carbolactones.
AB  - Utilization of 17-keto-androstanes as starting materials for the synthesis of
      alpha- or beta-oriented steroidal 20-->16-gamma-carbolactones has been explored
      following two different strategies. A highly efficient, stereospecific protocol
      has been developed for the beta-oriented cis-gamma-lactone. A different approach,
      involving prior attachment of a 3-carbon side chain on C-17 of a 17-oxo-16beta
      acetoxyandrostane led to the epimeric, alpha-oriented lactone. The mechanism of
      the rearrangement of epimeric 16beta- or 16alpha-hydroxy-17-keto-androstanes to
      17beta-hydroxy-16-keto-androstanes was studied by 13C NMR spectroscopy. The
      former occurs through a 1,2-sigmatropic H-shift, while the latter is likely to
      take place by simple enolization-reprotonation.

PMID- 10400348
TI  - Mechanism of 3-methylaspartase probed using deuterium and solvent isotope effects
      and active-site directed reagents: identification of an essential cysteine
      residue.
AB  - The mechanism of the L-threo-3-methylaspartate ammonia-lyase (EC 4.3.1.2)
      reaction has been probed using deuterium and solvent isotope effects with three
      different substrates, (2S,3S)-3-methylaspartic acid, (2S)-aspartic acid and
      (2S,3R)-3-methylaspartic acid. Each substrate appears to form a covalent adduct
      with the enzyme through the amination of a dehydroalanine (DehydAla-173) residue.
      The true substrates are N-protonated and at low pH, the alkylammonium groups are
      deprotonated internally in a closed solvent-excluded pocket after K+ ion, an
      essential cofactor, has become bound to the enzyme. At high pH, the amino groups
      of the substrates are able to react with the dehydroalanine residue prior to K+
      ion binding. This property of the system gives rise to complex kinetics at pH 9.0
      or greater and causes the formation of dead-end complexes which lack Mg2+ ion,
      another essential cofactor. The enzyme-substrate adduct is subsequently
      deaminated in two elimination processes. Hydrazines act as alternative substrates
      in the reverse reaction direction in the presence of fumaric acid derivatives,
      but cause irreversible inhibition in their absence. Borohydride and cyanide are
      not inhibitors. N-Ethylmaleimide also irreversibly inactivates the enzyme and
      labels residue Cys-361. The inactivation process is enhanced in the presence of
      cofactor Mg2+ ions and Cys-361 appears to serve as a base for the removal of the
      C-3 proton from the natural substrate, (2S,3S)-3-methylaspartic acid. The
      dehydroalanine residue appears to be protected in the resting form of the enzyme
      by generation of an internal thioether cross-link. The binding of the substrate
      and K+ ion appear to cause a conformational change which requires hydroxide ion.
      This is linked to reversal of the thioether protection step and generation of the
      base for substrate deprotonation at C-3. The deamination reaction displays high
      reverse reaction commitments and independent evidence from primary deuterium
      isotope effect data indicates that a thiolate acts as the base for deprotonation
      at C-3.

PMID- 10400349
TI  - The 3-methylaspartase reaction probed using 2H- and 15N-isotope effects for three
      substrates: a flip from a concerted to a carbocationic amino-enzyme elimination
      mechanism upon changing the C-3 stereochemistry in the substrate from R to S.
AB  - The mechanisms of the elimination of ammonia from (2S,3S)-3-methylaspartic acid,
      (2S)-aspartic acid and (2S,3R)-3-methylaspartic acid, catalysed by the enzyme L
      threo-3-methylaspartase ammonia-lyase (EC 4.3.1.2) have been probed using 15N
      isotope effects. The 15N-isotope effects for V/K for both (2S,3S)-3
      methylaspartic acid and aspartic acid are 1.0246 +/- 0.0013 and 1.0390 +/-
      0.0031, respectively. The natural substrate, (2S,3S)-3-methylaspartic acid, is
      eliminated in a concerted fashion such that the C(beta)-H and C(alpha)-N bonds
      are cleaved in the same transition state. (2S)-Aspartic acid appears to follow
      the same mechanistic pathway, but deprotonation of the conjugate acid of the base
      for C-3 is kinetically important and influences the extent of 15N-fractionation.
      (2S,3R)-3-Methylaspartic acid is deaminated via a stepwise carbocationic
      mechanism. Here we elaborate on the proposed model for the mechanism of
      methylaspartase and propose that a change in stereochemistry of the substrate
      induces a change in the mechanism of ammonia elimination.

PMID- 10400350
TI  - Characterisation of vortex shedding in vascular anastomosis models using pulsed
      Doppler ultrasound.
AB  - Vortex shedding at vascular anastomoses were investigated in vitro using a 20 MHz
      pulsed-wave Doppler velocimeter. Centreline velocity measurements were made at
      various axial distances in simplified polyurethane models of proximal and distal
      end-to-side anastomoses of angles 15, 30, 45, 60 and 80 degrees using pulsatile
      flow waveforms similar to those in femoropopliteal bypass grafts. The in-phase
      and quadrature Doppler signals were recorded and the maximum frequency waveform,
      averaged over 64 cycles, was obtained using short-time Fourier transform. A
      fourth-order Butterworth low-pass filter was employed to separate the vortex
      velocity signal from the convective velocity. The vortex signal envelope was
      calculated using a Hilbert transform method and the vortex amplitude was taken as
      the maximum of this envelope. The results show that higher vortex amplitude were
      found in the proximal anastomoses and under resting flow conditions. Although the
      vortex amplitudes generally increased with angles of anastomosis, they were found
      to be higher in the 60 degrees than in the 80 degrees proximal anastomosis. The
      vortex structures were investigated using spectrograms and these show prominent
      features at 40-50 Hz indicative of the short-duration oscillatory signals during
      the decelerative phase of systole expected from the passage of vortices. The
      study indicates that flow disturbances due to vortex shedding may be a common
      feature in femoropopliteal bypass grafts.

PMID- 10400352
TI  - Abdominal muscles contribute in a minor way to peak spinal compression in
      lifting.
AB  - In lifting, the abdominal muscles are thought to be activated to stabilize the
      spine. As a detrimental effect, they contribute to spinal compression. The
      existing literature is not conclusive about the biological relevance of this
      effect. From biological, mechanical and anatomical considerations it was
      hypothesised that the relative abdominal contribution to compression would be
      minor in the beginning of the lift, that the relative and absolute abdominal
      contribution to compression would rise throughout the lift, and that the obliques
      would contribute to a larger extent than the rectus abdominis. To investigate
      these hypotheses, 10 subjects lifted 0.5, 10.5 and 22.5 kg. EMG levels obtained
      from the rectus abdominis and the obliques were converted into force using
      normalized EMG, muscle potential and area values, and modulating factors for
      muscle length and contraction velocity. An anatomical model was applied to
      compute the abdominal effects on spinal compression in three consecutive phases
      within a lift. If expressed relative to the total spinal compression, the
      abdominal contribution for the three weight conditions was 7.1% (SD, 1.7), 10.4%
      (4.7) and 12.5% (4.4) in the begin and 21.0% (5.8), 19.0% (5.3) and 22.2% (6.6)
      in the end phase. Thus, the relative abdominal contribution to compression was
      minor in the beginning and increased towards the end. The absolute abdominal
      contribution was constant throughout the lift. The contributions could be
      retraced to the obliques rather than the rectus, while during the lift a shift in
      activation from the obliquus externus to internus was observed.

PMID- 10400351
TI  - Anisotropic mechanical properties of lamellar bone using miniature cantilever
      bending specimens.
AB  - The flexural modulus and work-to-fracture properties of circumferential lamellar
      bone from baboon tibia are presented, based on experiments with miniature
      cantilever bending specimens. Data is provided for specimens in three orthogonal
      directions that show marked anisotropy. The advantages of such miniature
      specimens (about 150 microm in diameter and 2 mm long) include the possibility of
      sampling very small volumes within a heterogeneous structure such as osteonal
      bone, or studying biological materials that are not available in large enough
      volumes for conventional mechanical analysis.

PMID- 10400354
TI  - The role of an effective isotropic tissue modulus in the elastic properties of
      cancellous bone.
AB  - Conceptually, the elastic characteristics of cancellous bone could be predicted
      directly from the trabecular morphology--or architecture--and by the elastic
      properties of the tissue itself. Although hardly any experimental evidence
      exists, it is often implicitly assumed that tissue anisotropy has a negligible
      effect on the apparent elastic properties of cancellous bone. The question
      addressed in this paper is whether this is actually true. If it is, then
      micromechanical finite element analysis (micro-FEA) models, representing
      trabecular architecture, using an 'effective isotropic tissue modulus' should be
      able to predict apparent elastic properties of cancellous bone. To test this,
      accurate multi-axial compressive mechanical tests of 29 whale bone specimens were
      simulated with specimen-specific micro-FEA computer models built from true three
      dimensional reconstructions. By scaling the micro-FEA predictions by a constant
      tissue modulus, 92% of the variation of Young's moduli determined experimentally
      could be explained. The correlation even increased to 95% when the micro-FEA
      moduli were scaled to the isotropic tissue moduli of individual specimens.
      Excellent agreement was also found in the elastic symmetry axes and anisotropy
      ratios. The prediction of Poisson's ratios was somewhat less precise at 85%
      correlation. The results support the hypothesis; for practical purposes, the
      concept of an 'effective isotropic tissue modulus' concept is a viable one. They
      also suggest that the value of such a modulus for individual cases might be
      inferred from the average tissue density, hence the degree of mineralization.
      Future studies must clarify how specific the tissue modulus should be for
      different types of bone if adequate predictions of elastic behavior are to be
      made in this way.

PMID- 10400353
TI  - Fluid pressure relaxation depends upon osteonal microstructure: modeling an
      oscillatory bending experiment.
AB  - When bone is mechanically loaded, bone fluid flow induces shear stresses on bone
      cells that have been proposed to be involved in bone's mechanosensory system. To
      investigate bone fluid flow and strain-generated potentials, several theoretical
      models have been proposed to mimic oscillatory four-point bending experiments
      performed on thin bone specimens. While these previous models assume that the
      bone fluid relaxes across the specimen thickness, we hypothesize that the bone
      fluid relaxes primarily through the vascular porosity (osteonal canals) instead
      and develop a new poroelastic model that integrates the microstructural details
      of the lacunar-canalicular porosity, osteonal canals, and the osteonal cement
      lines. Local fluid pressure profiles are obtained from the model, and we find two
      different fluid relaxation behaviors in the bone specimen, depending on its
      microstructure: one associated with the connected osteonal canal system, through
      which bone fluid relaxes to the nearby osteonal canals; and one associated with
      the thickness of a homogeneous porous bone specimen (approximately 1 mm in our
      model), through which bone fluid relaxes between the external surfaces of the
      bone specimen at relatively lower loading frequencies. Our results suggest that
      in osteonal bone specimens the fluid pressure response to cyclic loading is not
      sensitive to the permeability of the osteonal cement lines, while it is sensitive
      to the applied loading frequency. Our results also reveal that the fluid pressure
      gradients near the osteonal canals (and thus the fluid shear stresses acting on
      the nearby osteocytes) are significantly amplified at higher loading frequencies.

PMID- 10400355
TI  - Total trunk muscle force and spinal compression are lower in asymmetric moments
      as compared to pure extension moments.
AB  - The aim of the present study was to test the assumption that asymmetric trunk
      loading requires a higher total muscle force and consequently entails a higher
      compression forces on the spine as compared to symmetric loading. When the trunk
      musculature is modelled in sufficient detail, optimisation shows that there is no
      mechanical necessity for an increase in total muscle force (or compression force)
      with task asymmetry. A physiologically based optimisation does also not predict
      an increase in total muscle force or spinal loading with asymmetry. EMG data on
      14 trunk muscles collected in eight subjects showed antagonistic coactivity to be
      present in both conditions. However, estimates of total muscle force based on the
      EMG were lower when producing an asymmetric moment. In conclusion, producing an
      asymmetric moment appears to cause slightly lower forces on the lumbosacral joint
      as compared to a symmetric moment. Only lateral shear forces increase with
      asymmetry but these remain well below failure levels.

PMID- 10400356
TI  - About weight factors in the non-linear objective functions used for solving
      indeterminate problems in biomechanics.
AB  - A lot of non-linear objective criteria are applied for solving the indeterminate
      problems formulated for different biomechanical models--most of them can be
      covered by the expression [formula in text]. It might be noted, however, that
      most of the suggested criteria are not applicable if considerable antagonistic co
      contractions exist. This could be an effect of treating the agonistic muscles and
      their respective antagonists in one and the same manner in the objective
      function. Using a completely inverse approach (the muscle forces are supposed to
      be known quantities) and a simple 1DOF model (actuated by three agonistic muscles
      and one corresponding antagonist) it has been shown which values of the weight
      factors c(i) may predict different levels of muscle forces from the two
      antagonistic groups. Three hypothetical border variants for magnitudes of the
      muscle forces are considered (flexor muscles are only active, extensor muscles
      are only active, considerable co-contraction of flexors and extensors exists).
      The main conclusions are: the signs of c(i) at agonistic muscles have to be
      opposite to the c(i) signs at their antagonists; the signs of the weight factors
      depend on the direction of the net external joint moment; the closer c(i) to
      zero, the bigger force will be predicted in the ith muscle.

PMID- 10400357
TI  - Correlation between pre-operative periprosthetic bone density and post-operative
      bone loss in THA can be explained by strain-adaptive remodelling.
AB  - Periprosthetic adaptive bone remodelling after total hip arthroplasty can be
      simulated in computer models, combining bone remodelling theory with finite
      element analysis. Patient specific three-dimensional finite element models of
      retrieved bone specimens from an earlier bone densitometry (DEXA) study were
      constructed and bone remodelling simulations performed. Results of the
      simulations were analysed both qualitatively and quantitatively. Patterns of
      predicted bone loss corresponded very well with the DEXA measurements on the
      retrievals. The amount of predicted bone loss, measured quantitatively by
      simulating DEXA on finite element models, was found to be inversely correlated
      with the initial bone mineral content. It was concluded that the same clinically
      observed correlation can therefore be explained by mechanically induced
      remodelling. This finding extends the applicability of numerical pre-clinical
      testing to the analysis of interaction between implant design and initial state
      of the bone.

PMID- 10400358
TI  - The influence of the non-Newtonian properties of blood on the flow in large
      arteries: unsteady flow in a 90 degrees curved tube.
AB  - A numerical and experimental investigation of unsteady entry flow in a 90 degrees
      curved tube is presented to study the impact of the non-Newtonian properties of
      blood on the velocity distribution. The time-dependent flow rate for the
      Newtonian and the non-Newtonian blood analog fluid were identical. For the
      numerical computation, a Carreau-Yasuda model was employed to accommodate the
      shear thinning behavior of the Xanthan gum solution. The viscoelastic properties
      were not taken into account. The experimental results indicate that significant
      differences between the Newtonian and non-Newtonian fluid are present. The
      numerical results for both the Newtonian and the non-Newtonian fluid agree well
      with the experimental results. Since viscoelasticity was not included in the
      numerical code, shear thinning behavior of the blood analog fluid seems to be the
      dominant non-Newtonian property, even under unsteady flow conditions. Finally, a
      comparison between the non-Newtonian fluid model and a Newtonian fluid at a
      rescaled Reynolds number is presented. The rescaled Reynolds number, based on a
      characteristic rather than the high-shear rate viscosity of the Xanthan gum
      solution, was about three times as low as the original Reynolds number.
      Comparison reveals that the character of flow of the non-Newtonian fluid is
      simulated quite well by using the appropriate Reynolds number.

PMID- 10400359
TI  - Fitting parametrized polynomials with scattered surface data.
AB  - Currently used joint-surface models require the measurements to be structured
      according to a grid. With the currently available tracking devices a large
      quantity of unstructured surface points can be measured in a relatively short
      time. In this paper a method is presented to fit polynomial functions to three
      dimensional unstructured data points. To test the method spherical, cylindrical,
      parabolic, hyperbolic, exponential, logarithmic, and sellar surfaces with
      different undulations were used. The resulting polynomials were compared with the
      original shapes. The results show that even complex joint surfaces can be
      modelled with polynomial functions. In addition, the influence of noise and the
      number of data points was also analyzed. From a surface (diam: 20 mm) which is
      measured with a precision of 0.2 mm a model can be constructed with a precision
      of 0.02 mm.

PMID- 10400360
TI  - A force transducer to measure individual finger loads during activities of daily
      living.
AB  - A new six-degree-of-freedom force transducer has been manufactured, with the
      sensitivity to measure forces in the range +/-100 N and moments of up to +/-5 Nm.
      The transducer incorporates two mechanical components: shear forces and bending
      moments are measured via a strain-gauged tubular section whilst axial forces are
      transmitted to a cantilevered load cell. Both components are instrumented with
      350 ohms strain gauge full bridge circuits and are temperature compensated. After
      calibration, measurement errors are less than +/-0.3 N for direct forces and +/
      0.03 Nm for applied moments. In order to measure sub-maximal finger loads during
      activities of daily living, the transducer has been incorporated into several
      housings representing objects in domestic use: a jar, a tap, a key in a lock and
      a jug kettle.

PMID- 10400361
TI  - Estimation of trunk muscle forces using the finite element method and in vivo
      loads measured by telemeterized internal spinal fixation devices.
AB  - Direct quantitative measurement of muscle forces is not possible. Forces in the
      trunk muscles were estimated for standing and flexion of the upper body using
      three-dimensional, nonlinear finite element models of the lumbar spine with and
      without an internal spinal fixation device. Muscle forces assumed were two pairs
      dorsally and one ventrally, each representing several muscles. Muscle forces in
      the model with internal fixators were varied in discrete steps until the implant
      loads calculated closely corresponded to those measured in a patient with an
      instrumented implant. The calculated angles between adjacent lumbar vertebrae
      were compared with corresponding values measured on X-ray films of a patient as
      well as with literature values and served as a second criterion for predicting
      muscle forces. For the model without an implant, the muscle forces of the first
      model were slightly varied until the lumbar spine shape and the intradiscal
      pressure were physiological. The abdomen was shown to have a considerable
      supporting function for flexion.

PMID- 10400362
TI  - Rectifying postures reconstructed from joint angles to meet constraints.
AB  - Postures are often described and modeled using angles between body segments
      rather than joint coordinates. Models can be used to predict these angles as a
      function of anthropometry and postural requirements. Postural representation,
      however, requires the joint coordinates. The use of conventional forward
      kinematics to derive joint coordinates from predicted angles may violate task
      constraints, such as the placement of a hand on a target or a foot on a pedal.
      Errors arise because the anthropometry or other motion characteristics of a
      subject, for which the prediction is to be made, may differ from the data from
      which the prediction model was derived. We describe how to rectify model
      predicted postures to exactly satisfy such task constraints. We require that the
      model used for predicting the angles also produce estimates of the variation in
      these predictions. We show how to alter the initial angle predictions, with the
      amount of perturbation at each angle dependent on the accuracy of its estimation,
      so as to exactly satisfy the joint coordinate constraints. Finally, we show in an
      empirical example that this correction usually produces better overall
      predictions of posture than those obtained initially.

PMID- 10400363
TI  - Measurement of sarcomere length during fast contraction of muscle fibers by
      digital image analysis.
AB  - A low-cost, high-resolution (spatial and temporal) image analysis system was
      developed to measure sarcomere length (Sl) during fast twitch of isolated
      striated muscle fibers at different temperatures. Fiber images were examined
      during twitch with an imaging rate of 220 Hz. To increase temporal resolution
      beyond 220 Hz, consecutive temporally shifted image sequences (N sequences) were
      acquired. Individual or average Sl was directly measured from a horizontal
      profile without spatial-frequency assessment. Measurement precision (E) was
      determined and expressed as: E(%) = 100xPs/(IsxSl), where Ps is the pixel size
      and Is the involved sarcomere number. At 18 degrees C during isometric twitch,
      Sls were measured with 220 Hz temporal and 0.2% spatial resolutions. Sl shortened
      in the central region (0.21+/-0.12 microm) as tension developed, reaching a
      maximal shortening of 8.09 + 2.05% (at rest, Sl = 2.59+/-0.05 microm, n = 4) in
      32.5+/-1.96 ms. At 30 degrees C, Sl variations were examined with 880 Hz temporal
      resolution, in which case maximal S1 shortening was reached in 15.74+/-1.99 ms,
      and then decreased to 5.19+/-1.97% (at rest, S1 = 2.6+/-0.06 microm). The twitch
      tension developed by the whole fiber was recorded and compared with sarcomere
      length behavior. Sarcomere length variations in the central region were
      representative of overall developed tensions at 18 and 30 degrees C.

PMID- 10400364
TI  - Bone remodeling theory applied to the study of n unit-elements model.
AB  - The aim of this paper is to illustrate the application of mathematical tools for
      the analysis of non-linear dynamical systems to the study of global stability of
      one kind of bone remodeling scheme applied to n unit-elements model. The
      particular aspects analyzed here are the stationary states related to this theory
      and a condition of their stability. The non-linear equations governing the
      remodeling process are solved by finite-difference method and the well-known
      results on the heterogeneous spatial organizations have been retrieved and
      confirm the analytical study. This kind of remodeling theory is useful for
      investigating the effects of physiological parameters on the development,
      maintenance, and adaptation of bone under mechanical loading.

PMID- 10400365
TI  - Neandertal knees and ankles: a comment on Miller and Gross.

PMID- 10400366
TI  - Hematologic malignancies.

PMID- 10400367
TI  - Epidemiology of leukemia and lymphoma.
AB  - The causes of acute leukemia and lymphomas are still largely unknown. These
      malignancies account for approximately 6% of cases of cancer in the US
      population, and active research efforts are now underway to define etiologically
      important genetic or environmental factors for these conditions. Recent
      epidemiologic studies have focused on international variations, secular trends,
      genetic syndromes, familial aggregation, chromosomal abnormalities, environmental
      exposures, and unique subgroups defined either demographically or biologically.

PMID- 10400368
TI  - Hodgkin's disease and non-Hodgkin's lymphoma.
AB  - The development of new classification schemes and prognostic analyses for
      lymphomas has helped to identify patients at high risk for relapse who may
      benefit from intensification of primary therapy. Conventional salvage therapy for
      relapsed follicular or low-grade lymphomas now includes monoclonal antibody
      therapy. The combination of chemotherapy and monoclonal antibody therapy may
      improve outcomes for patients with advanced-stage aggressive non-Hodgkin's
      lymphomas. Confirmatory randomized trials are now in progress. Therapy for
      Hodgkin's disease continues to evolve toward the most efficacious programs, which
      also minimize the long-term probability of toxicity. The combination of high-dose
      chemotherapy and stem cell transplantation is probably the most effective therapy
      for patients with relapsed or refractory Hodgkin's disease.

PMID- 10400369
TI  - Recent advances in the treatment of multiple myeloma.
AB  - Multiple myeloma, a clonal B-cell malignancy, accounts for 10% of all hematologic
      cancers. In patients with multiple myeloma, median survival is approximately 30
      to 36 months with conventional therapy, but high-dose chemotherapy resulted in
      better outcomes in a mature randomized trial. Pamidronate and other
      bisphosponates, used as supportive therapy, effectively reduce the incidence of
      skeletal events and decrease pain. They also have a role in disease control.
      Ongoing trials are now addressing such issues as further intensification with
      tandem transplantations, timing of transplantation, and decrease of malignant
      cell reinfusion by positive selection. Important laboratory observations have
      better defined the malignant clone and its interaction with the microenvironment.
      These observations will be important for the treatment of myeloma in the future.

PMID- 10400370
TI  - Advances in the immunotherapy of hematologic malignancies: cellular and humoral
      approaches.
AB  - Therapy with unconjugated monoclonal antibodies (mAbs) and radiolabeled mAbs has
      shown activity in patients with B-cell non-Hodgkin's lymphoma and leukemia. Drug
      conjugated mAbs are active in relapsed leukemia. Using these new agents with and
      after chemotherapy induces a high rate of remission, but this needs to be
      confirmed in randomized, clinical trials. The antitumor effect of allogeneic stem
      cell transplantation is being explored through the use of donor lymphocyte
      infusions for patients who have relapse after transplantation. Attempts to
      maintain antitumor activity without graft-versus-host disease include CD4
      lymphocyte infusions, suicide gene-transfected cells, and the use of cloned T
      cells more specific for the tumor. Transplantation with nonmyeloablative
      conditioning regimens relying on the graft-versus-tumor effect of allogeneic
      lymphocytes has shown preliminary success in the treatment of many hematologic
      malignancies.

PMID- 10400371
TI  - Molecular diagnostics in the treatment of leukemia.
AB  - The molecular characterization of childhood leukemias directly affects our
      treatment strategies. Acute lymphoblastic leukemia patients with the TEL-AML1
      fusion have a favorable prognosis, whereas those with the E2A-PBX1 fusion require
      more intensive therapy to obtain a good outcome. Acute lymphoblastic leukemia
      patients whose leukemic lymphoblasts contain the MLL-AF4 or the BCR-ABL fusion
      are often candidates for allogeneic hematopoietic stem cell transplantation
      during first remission. Among acute myeloid leukemia patients, AML1-ETO and
      CBFbeta-MYH11 fusions are associated with a favorable response, especially when
      the chemotherapy regimen includes high-dose cytarabine. Patients with acute
      promyelocytic leukemia who carry the PML-RAR alpha fusion respond to all-trans
      retinoic acid and have an excellent outcome after treatment with all-trans
      retinoic acid in combination with anthracyclines. Several novel therapeutic
      agents targeted to molecular lesions of leukemic cells are under investigation.

PMID- 10400372
TI  - Biology and treatment of acute progranulocytic leukemia.
AB  - Acute progranulocytic leukemia (APL) is one of the most curable of all human
      cancers. Combination treatment with retinoic acid (RA) and anthracycline-based
      chemotherapy is safe and effective for the vast majority of patients, and several
      novel treatment approaches are under investigation for high-risk or relapsed
      patients. The APL-specific oncogenes PML-RAR alpha and PLZF-RAR alpha both bind
      nuclear corepressors and recruit histone deacetylase activity to promoters of RA
      target genes. The differential sensitivity of binding of these oncogenes to
      nuclear corepressors in the presence of RA appears to explain the resistance of
      PLZF-RAR alpha-related APL to RA and at the same time explains the effectiveness
      of RA in PML-RAR alpha-positive APL. Transcriptional repression of RA target
      genes, mediated by histone deacetylase activity, may thus be a key pathogenetic
      event in APL. Cure of the minority of resistant patients requires further
      refinement of current treatment approaches and appropriately timed incorporation
      of novel therapies, such as arsenic trioxide or histone deacetylase inhibitors.

PMID- 10400373
TI  - Chronic myelogenous leukemia.
AB  - Over the past year, new information has been reported on the biology and
      treatment of chronic myelogenous leukemia (CML). Chronic myelogenous leukemia is
      characterized by the breakpoint cluster region (BCR-ABL) chimeric gene, the
      product of which is p210BCR-ABL, a tyrosine kinase that gives hematopoietic cells
      the characteristics of excessive proliferation, resistance to physiologic
      apoptotic signals, and resistance to chemotherapy. Recently, investigators have
      attempted to 1) elucidate the mechanisms by which the BCR-ABL gene and its
      product initiate and maintain the malignant phenotype, 2) improve the use of the
      BCR-ABL gene as a diagnostic marker of disease, and 3) inhibit the expression of
      this gene as a therapeutic maneuver. Other investigators have tried to explain
      interferon's mechanism of action in the treatment of CML and to improve the
      safety and applicability of stem cell transplantation (SCT) as a therapy for CML.

PMID- 10400374
TI  - Tailoring the treatment of acute myeloid leukemia.
AB  - For younger patients with acute myeloid leukemia, the current priority is to
      prevent disease relapse. Intensification of induction has been shown to achieve
      this. Several randomized trials have been conducted to evaluate the role of
      autografting in acute myeloid leukemia. All trials reduce the risk of relapse but
      do not necessarily improve the survival, either because the competing effects of
      procedural mortality or salvage after relapse balance the benefits. Patients with
      different risk profiles may have different treatment plans. In older patients,
      progress is difficult to detect. Overcoming inherent drug resistance is of
      current interest, while improving supportive care by the routine use of growth
      factors has been disappointing.

PMID- 10400375
TI  - Chronic lymphocytic leukemia.
AB  - Significant strides have been made in our understanding of the biology and
      treatment of B cell chronic lymphocytic leukemia. Recent studies have defined
      cytogenetic and molecular lesions that may be responsible for leukemogenesis or
      disease progression. Molecular analyses of immunoglobulin genes have delineated
      two or more subgroups of chronic lymphocytic leukemia that may differ in their
      clinical behavior. Research in the biochemistry of chronic lymphocytic leukemia
      has provided insight into the noted resistance of leukemia cells to cytotoxic
      drugs. Investigations into the immunology has revealed mechanisms whereby chronic
      lymphocytic leukemia cells can contribute to the immune deficiency that commonly
      develops in patients with this disease. Clinical studies have delineated factors
      that are helpful in predicting prognosis and have provided data on promising new
      therapies for patients with this disease, including stem cell transplantation,
      monoclonal antibodies, and gene therapy.

PMID- 10400376
TI  - Supportive care in hematological malignancies: hematopoietic growth factors,
      infections, transfusion therapy.
AB  - This article focuses on a selected number of topics among recent developments in
      the supportive care of hematological malignancies. The first section focuses on
      the role of hematopoietic growth factors, such as granulocyte colony-stimulating
      factor, granulocyte-macrophage colony-stimulating factor, thrombopoietin,
      interleukin-11, and keratinocyte growth factor. The following sections discuss
      the management of fungal and viral infections as well as changes in the current
      policies of platelet transfusion. The focus of this review is on the clinical
      utility and economic feasibility of the published findings.

PMID- 10400377
TI  - Bibliography. Current world literature. Hematologic malignancies.

PMID- 10400378
TI  - Recent advances in applied and mechanistic aspects of the enzymatic hydroxylation
      of steroids by whole-cell biocatalysts.
AB  - Recent advances in microbial steroid hydroxylation are covered, including new
      biocatalysts and substrate groups and new methodologies such as the use of low
      water systems, immobilised biocatalysts, genetically constructed biocatalysts and
      enzyme mimics. Mechanistic factors that control the regiochemistry and
      stereochemistry of steroid hydroxylation are also discussed.

PMID- 10400379
TI  - Synthesis and structure-activity relationships of 6-phenylaliphatic-substituted
      C19 steroids having a 1,4-diene, 4,6-diene, or 1,4,6-triene structure as
      aromatase inhibitors.
AB  - A series of 6alpha- and 6beta-phenylaliphatic-substituted androsta-1,4-diene-3,17
      diones [9b-f and 10b-f; (CH2)nPh, n = 1-5] and their 4,6-diene and 1,4,6-triene
      analogs (11b-f and 12b-f) along with their respective phenyl analogs 9a-12a were
      synthesized and tested as aromatase inhibitors. All of the steroids examined were
      very powerful competitive inhibitors of aromatase in human placental microsomes
      with apparent Ki values ranging from 8.5 to 80 nM. The inhibitory activities of
      the benzyl- and phenethyl-4,6-dienes 11b and 11c (Ki, 9.0 and 10 nM) as well as
      the 6-phenethyl-1,4,6-triene 12c (Ki, 8.5 nM) were extremely high among them. All
      of the phenylaliphatic steroids, except for the 6beta-phenethyl compound 10c, and
      the 6-phenyl-4,6-diene 11a had higher affinity for aromatase than the
      corresponding parent 1,4-diene, 4,6-diene, and 1,4,6-triene steroids 9g, 11g, and
      12g. All of the 6alpha-substituted 1,4-dienes (9a-9g) and the 6-substituted 1,4,6
      trienes (12a-12g) caused a time-dependent inactivation of aromatase. On the other
      hand, only the 6beta-substituted 1,4-dienes (10a-10d) having no or less than four
      carbon atoms between the steroid nucleus and the phenyl group also caused a time
      dependent inactivation of aromatase. Their inactivation rates (k(inact) 0.076
      0.156 min(-1)) were higher than the respective parent steroids, 9g and 12g. In
      contrast, in the 4,6-diene series, only the 6-phenpropyl steroids 11d inactivated
      aromatase in a time-dependent manner with 0.155 min(-1) of k(inact) value. The
      inactivation was prevented by the substrate androstenedione, and no significant
      effect of L-cysteine on the inactivation was observed in each case. These results
      indicate that length and/or stereochemistry of the C-6 substituent of steroids 9
      12 as well as a terminal phenyl group incorporated in the C-6 substituent play a
      critical role not only in tight binding to the active site of aromatase but also
      in the cause of a time-dependent inactivation of the enzyme.

PMID- 10400380
TI  - Analysis of the steroid binding domain of rat steroid 5alpha-reductase (isozyme
      1): the steroid D-ring binding domain of 5alpha-reductase.
AB  - We have previously shown that the photoactive 4-azasteroid, [1,2 3H]N
      4(benzylbenzoyl)-3-oxo-4-aza-4-methyl-5alpha-androst an-17beta-carboxamide is an
      effective probe of rat steroid 5alpha-reductase (isozyme-1) (5alphaR-1). In the
      current investigation, PEG-fractionated (6.5%) detergent-solubilized preparations
      containing 5alphaR-1 activity were ultraviolet (UV)-photolyzed with [3H]-4MABP
      and subsequently purified by 8.75% preparative sodium dodecyl sulfate
      polyacrylamide gel electrophoresis. The fractions corresponding to the
      radioactive peak following the dye front were analyzed by 10% sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis and showed the presence of a single,
      labeled, 26 KDa protein band, the apparent molecular weight of 5alphaR-1. TCA
      precipitation of the labeled fractions, followed by long-term digestion of the
      TCA pellet with chymotrypsin and high-performance liquid chromatography analysis,
      indicated that the majority of the radioactivity eluted with a peak retention
      time of 55-56 min. Rechromatography of this fraction using a modified gradient
      (elution 54-55 min), followed by sequence analysis, yielded a single N-terminal
      tetrapeptide with the sequence, -L-E-G-F-, corresponding to residues 15-18 of the
      5alphaR-1 sequence. Site-directed mutagenesis studies indicated that mutant F18L
      showed an approximately 12-fold increase in the Km for testosterone, whereas the
      Km for reduced nicotinomide adenine dinucleotide phosphate remained virtually
      unaltered.

PMID- 10400381
TI  - Synthesis of N-desmethyl derivatives of 17alpha-acetoxy-11beta-(4-N,N
      dimethylaminophenyl)-19-norpregna-4,9-die ne-3,20-dione and mifepristone1:
      substrates for the synthesis of radioligands.
AB  - The syntheses of N-desmethyl derivatives of CDB-2914 and the mono-N-desmethyl
      derivative of Mifepristone are described. We also describe the use of the mono
      desmethyl derivatives as substrates for the synthesis of N-tritomethyl
      derivatives of CDB-2914 and Mifepristone with high specific activity (ca. 80
      Ci/mmol), which serve as radioligands for radioimmunoassay.

PMID- 10400382
TI  - Sex hormone-binding globulin receptor signal transduction proceeds via a G
      protein.
AB  - The plasma protein, sex hormone-binding globulin (SHBG) binds to a receptor
      (R(SHBG)) on cell membranes to form an SHBG-R(SHBG) complex. When an appropriate
      steroid binds to this complex, there is a rapid rise in intracellular cyclic
      adenosine monophosphate (cAMP). Although the system is moderately well
      characterized, the molecular cloning of R(SHBG) has not been accomplished and
      there is a paucity of evidence regarding the mechanism of transmission of the
      R(SHBG) signal. In this communication, we offer two independent lines of evidence
      that a G protein is involved in R(SHBG) signal propagation. Exposure of cell
      membranes containing R(SHBG) to a non-hydrolyzable analog of guanosine
      triphosphate (guanylyl-5'-imidodiphosphate) caused a substantive decrease in the
      binding of SHBG to R(SHBG). This behavior is typical of membrane receptors
      coupled to G proteins and has been used by others as evidence to support that
      relationship. Another set of experiments involved the assumption that, if R(SHBG)
      induced increases in cAMP were diminished when the wild-type alpha subunit of a G
      protein was replaced with mutants that were inefficient/ineffective in signal
      transduction, then the idea that G proteins were involved in that signal would be
      buttressed. Hence, we infected COS-1 cells with a construct containing such
      mutants, along with a cAMP response element reporter, and demonstrated a marked
      decrease in R(SHBG)-engendered reporter activity, e.g. cAMP generation.

PMID- 10400383
TI  - Synthesis and in vitro biological activity of 4alpha-(2-propenyl)-5alpha-cholest
      24-en-3alpha-ol: a 24,25-dehydro analog of the hypocholesterolemic agent 4alpha
      (2-propenyl)-5alpha-cholestan-3alpha-ol.
AB  - 4Alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol (LY295427) was previously
      identified from a Chinese hamster ovary (CHO) cell-based low density lipoprotein
      receptor/luciferase (LDLR/Luc) assay to be a potent transcriptional activator of
      the LDL receptor promoter in the presence of 25-hydroxycholesterol. To
      investigate the effect of the 24,25-unsaturation in the D-ring side chain
      (desmosterol D-ring side chain) on antagonizing the repressing effect of 25
      hydroxycholesterol, 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol (17), a
      24,25-dehydro analog of LY295427, was thus synthesized from lithocholic acid via
      the formation of 3alpha-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4alpha- (2
      propenyl)-5alpha-cholan-24-al (15). Test results showed that 17 had an EC30 value
      of 2.6 microM, comparable to 2.9 microM of LY295427, in the CHO cell-based
      LDLR/Luc assay in the presence of 25-hydroxycholesterol. Apparently, the built-in
      24,25-unsaturation in the D-ring side chain of 17 had added little effect to
      antagonizing the repressing effect of 25-hydroxycholesterol. In the [1-14C
      acetate]cholesterol biosynthesis inhibition assay, 17 at 10 microg/ml (23 microM)
      has been shown to inhibit the cholesterol biosynthesis in CHO cells by 38%
      relative to the vehicle control; whereas LY295427 showed no inhibition in the
      same assay in our previous studies. In contrast to LY295427, the built-in 24,25
      unsaturation in the D-ring side chain of 17 has conferred an inhibitory effect on
      cholesterol biosynthesis in CHO cells. In summary, the observed LDL receptor
      promoter activity of 17 is related to its ability to prevent 25
      hydroxycholesterol from exerting the repressing effect via an undetermined
      mechanism and, in part, to inhibit the cholesterol biosynthesis.

PMID- 10400384
TI  - Antibody binding characteristics of geometrical isomers of testosterone 3-(O
      carboxymethyl)oxime.
AB  - Geometrical isomers of testosterone 3-(O-carboxymethyl)oxime and their histamine
      derivatives were purified on reverse-phase high pressure liquid chromatography,
      and their antibody binding characteristics were studied. Using a competitive
      testosterone enzyme immunoassay, the unfractionated mixture of the oximes showed
      75% cross-reactivity with respect to testosterone, whereas the isolated 3Z- and
      3E-isomers showed 124% and 26% cross-reactivity, respectively. The cross
      reactivity was increased in the histamine derivatives, but the difference in
      cross-reactivity of the two isomers was reduced. Suppression of the ionization of
      the carboxyl group by lowering the pH of the incubation mixture in the antigen
      antibody binding step raised the cross-reactivity of the mixture of free oximes
      to 128%, at pH 4.0. Thus, the geometry and ionization state of the carboxymethyl
      oxime group has a profound effect on the affinity of the isomers for the
      antibody.

PMID- 10400385
TI  - The effect of diurnal and menstrual cyclicity and menopausal status on estrogen
      metabolites: implications for disease-risk assessment.
AB  - It has been proposed that the ratio of two estrogen metabolites, 2-hydroxyestrone
      (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1), may represent a marker to
      predict a woman's risk for developing breast cancer and other estrogen-related
      disease. The present studies evaluated the potential confounders of type of
      sample, diurnal rhythm, menstrual cycle phase, and menopausal status on the ratio
      of 2/16alpha-OHE1 using an urine-based monoclonal antibody enzyme immunoassay.
      Two initial studies to compare a 24-h urine collection with a first-morning void
      and to evaluate diurnal variation were performed. Subsequently, urine samples
      were collected every other day for 2 months from five premenopausal subjects to
      assess the impact of the menstrual cycle. Spot urine samples were then obtained
      from a total of 67 pre, peri-, early post-, and late post-menopausal women to
      assess the effect of menopausal status. No significant difference in the ratio of
      2/16alpha-OHE1 was found between a 24-h and first-morning void or over a 24-h
      period. No significant difference in the mean ratio of 2/16alpha-OHE1 was found
      with the menstrual phase. Intra-individual variability was observed in the ratio
      of 2/16alpha-OHE1, which was attributable to small fluctuations in the small
      denominator, 16alpha-OHE1. No difference in the ratio of 2/16alpha-OHE1 was
      observed in groups of women of different menopausal status. The data suggest that
      a first-morning void is representative of a 24-h collection and that the
      2/16alpha-OHE1 ratio is constant throughout a 24-h period. Moreover, menstrual
      phase and menopausal status do not appear to significantly influence the ratio of
      2/16alpha-OHE1.

PMID- 10400386
TI  - Hbox1 and Hbox7 are involved in pattern formation in sea urchin embryos.
AB  - In spite of their potential importance in evolution, there is little information
      about Hox genes in animal groups that are related to ancestors of deuterostome.
      It has been reported that only two Hox genes (Hbox1 and Hbox7) are expressed
      significantly in sea urchin embryos. Expression of Hbox1 protein is restricted to
      the aboral ectoderm, and Hbox7 expression is restricted to oral ectoderm,
      endoderm and secondary mesenchyme cells in sea urchin embryos after the gastrula
      stage. With the aim of gaining insight into the role of Hbox1 and Hbox7 in sea
      urchin development, Hbox1 and Hbox7 overexpression experiments were performed.
      Overexpression of Hbox1 repressed the development of oral ectoderm, endoderm and
      mesenchyme cells. On the contrary, overexpression of Hbox7 repressed the
      development of aboral ectoderm and primary mesenchyme cells. The data suggest
      that Hbox1 and Hbox7 are expressed in distinct non-overlapping territories, and
      overexpression of either one inhibits territory-specific gene expression in the
      domain of the other. It is proposed that an important function of both Hbox1 and
      Hbox7 genes is to maintain specific territorial gene expression by each one, in
      its domain of expression, while repressing the expression of the other in this
      same domain.

PMID- 10400387
TI  - Brachyury (T) expression in embryonal carcinoma P19 cells resembles its
      expression in primitive streak and tail-bud but not that in notochord.
AB  - Brachyury (T) is involved in mesoderm induction during early mouse development. T
      expression in embryonal carcinoma P19 cells, which differentiate into mesoderm
      derivatives in vitro, was studied. Endogenous T expression in P19 cells was
      transiently induced when the cells were allowed to form aggregates. This
      expression was enhanced by dimethyl sulfoxide. In situ hybridization showed that
      T expressing cells formed clusters on the aggregates. Transfection of plasmids
      encoding reporter genes under the control of the upstream region of T showed that
      the sequence up to -351 bp can resemble the differentiation-dependent expression
      of T in P19 cells. To define the promoter region regulating T expression,
      transgenic mice carrying LacZ under the control of the upstream region were
      prepared. The region up to -351 bp is sufficient to direct the expression in the
      primitive streak and tail-bud. The upstream region up to -2400 bp does not
      support expression in the notochord. The sequence between -987 and -585 bp
      enhances expression in the primitive streak and tail-bud. In the tail-bud where
      new cells for elongation of the anteroposterior axis were continuously supplied,
      the sequence up to -987 bp drove lacZ expression in gut endoderm and prospective
      neuroectoderm as well as in mesoderm derivatives.

PMID- 10400388
TI  - Interactions between cytoskeletal components during myoplasm rearrangement in
      ascidian eggs.
AB  - Ooplasmic segregation in ascidian eggs consists of two phases of cytoplasmic
      movement, the first phase is mediated by the microfilament system and the second
      is mediated by the microtubule system. Recently, two novel proteins, p58 and
      myoplasmin-C1, which are localized to the myoplasm, were suggested to have
      important roles in muscle differentiation. In order to analyze the molecular
      mechanisms underlying ooplasmic segregation, the interactions between actin,
      tubulin, p58 and myoplasmin-C1 were examined. During the first segregation,
      microtubule meshwork in the unfertilized egg disappeared. At the second
      segregation, a novel structure of the microtubules that extended from the sperm
      aster and localized in the cortical region of the myoplasm was found. Moreover,
      uniform distribution of the cortical actin filament was observed at the second
      segregation. During the course of myoplasm rearrangement, p58 and myoplasmin-C1
      are colocalized and can form a molecular complex in vitro. This complex of p58
      and myoplasmin-C1 is a good candidate for a cytoskeletal component of the
      myoplasm, and is likely to be involved in the correct distribution of cytoplasmic
      determinants.

PMID- 10400389
TI  - Lim1 related homeobox gene (HpLim1) expressed in sea urchin embryos.
AB  - A cDNA clone for the LIM class homeobox gene (HpLim1) of the sea urchin,
      Hemicentrotus pulcherrimus, was isolated. HpLim1 contains two LIM domains and a
      LIM-class homeodomain, and amino acid sequences of these three domains are highly
      homologous to corresponding domains of Lim1 of other animals. Accumulation of
      HpLim1 transcripts begins at hatching, and declines after the mesenchyme blastula
      stage. HpLim1 mRNA was localized in the vegetal plates of hatched blastulae, but
      it was not detectable in primary mesenchyme cells (PMC) ingressed into the
      blastocele. HpLim1 mRNA-injected embryos became spherical with markedly reduced
      gut formation, failed to express marker proteins for aboral ectoderm and
      mesoderm, and mainly expressed an oral ectoderm marker. These results imply that
      while short-term expression of HpLim1 in the vegetal plate is needed for
      differentiation of aboral ectoderm, endoderm and PMC, ectopic expression of
      HpLim1 suppresses normal differentiation directing all embryonic cells to
      differentiate into oral ectoderm.

PMID- 10400390
TI  - Changes in the adhesive properties of dissociated and reaggregated Xenopus laevis
      embryo cells.
AB  - Activin A is a member of the transforming growth factor beta superfamily, and the
      strongest candidate mesoderm-inducer. The initial adhesive property changes in
      amphibians are likely to be mediated by mesoderm-inducers like activin A. The
      manner in which these changes actually occur, however, remains poorly understood.
      In the present study, the adhesive property changes mediated by activin A were
      directly demonstrated. Activin A functioned as a morphogen at low concentrations
      (less than 0.5 ng/mL), with no effect on the type A adhesive property. But at
      high concentrations (1 ng/mL), it induced another type of adhesive property, type
      N, and at very high concentrations (more than 10 ng/mL), it induced yet another
      type of adhesive property, type Y. Cells that have types A, N, and Y adhesive
      properties ultimately differentiated into atypical epidermis, notochord, and yolk
      rich cells, respectively. It was also shown that these changes occurred between 5
      and 10 h after induction by activin A. The implications of these results for the
      relationship between the adhesive property acquired during early and later stages
      of differentiation are also discussed.

PMID- 10400391
TI  - Expression of murine early embryonic antigens, SSEA-1 and antigenic determinant
      of EMA-1, in embryos and ovarian follicles of a teleost medaka (Oryzias latipes).
AB  - Stage-specific embryonic antigen-1 (SSEA-1) and the antigenic determinant of
      monoclonal antibody EMA-1 are expressed in a stage-specific manner in mouse early
      embryos. To study whether these antigens generally exist in fish, expression of
      the antigens was examined in embryos, ovarian follicles, and adult tissues of a
      teleost medaka (Oryzias latipes), using immunohistochemical techniques. In 1-cell
      stage embryos, these carbohydrate antigens were found in numerous cytoplasmic
      granules in the blastodisc and the cortical cytoplasm. These granules gradually
      decreased in number as the embryos developed. In 4-cell-stage embryos, the
      antigens appeared on the cleavage planes and were located on the cleavage planes
      within the blastoderm in the following cleavage stages. In blastula-stage
      embryos, the expression was ubiquitously found on the cell surface of
      blastomeres. At the mid-gastrula stage, the antigens were restricted to the
      enveloping layer, yolk syncytial layer, and cortical cytoplasm, but were rarely
      found in deep cells that contribute to formation of the embryonic body. In later
      stage embryos and adult fish, the antigens were located in various tissues. In
      ovarian follicles, the antigens were found in granules of oocytes and granulosa
      cells. These observations were basically consistent with those in mice; however,
      expression in 1-cell-stage embryos and ovarian follicles has not been observed in
      mice. This unexpected finding suggests that the antigens are produced in
      granulosa cells and transferred to 1-cell-stage embryos via oocytes, and that the
      antigens involved in the early developmental process are maternally prepared in
      teleosts.

PMID- 10400392
TI  - SM37, a skeletogenic gene of the sea urchin embryo linked to the SM50 gene.
AB  - The genomic DNA region that contains the SM50 gene also included a second gene
      that appeared to encode another skeletogenic matrix protein. The two genes were
      linked at a distance of about 12 kb. Based on the molecular weight of the implied
      protein the gene was termed SM37. The SM37 protein included a long tandem
      sequence of short glycine-rich repeats that was similar to the glycine-rich
      repeats included in the SM50 protein and several other skeletal matrix proteins,
      although the sequence of SM37 repeat was distinct. The overall structure of the
      SM37 protein was similar to SM50 as well. However, SM37 was only about 30%
      identical in amino acid sequence to SM50, and coding region probes behaved as a
      single copy sequence under standard conditions. The SM37 gene included the same
      cis-regulatory elements as the SM50 gene, although in a different order with
      respect to transcription. This gene was regulated coordinately with SM50 during
      development, and like SM50 was expressed exclusively in skeletogenic mesenchyme
      lineages.

PMID- 10400393
TI  - Fate mapping study of the endoderm in the posterior part of the 1.5-day-old chick
      embryo.
AB  - Various endodermal sites posterior to the caudal-most somite were marked in ovo
      with the vital dye Dil, and the fate of marked endoderm was analyzed after 2 or 3
      days' reincubation. The endoderm in this area became gut epithelium posterior to
      the caudal jejunum and yolk sac. The area occupied by the cells that were to
      contribute to the dorsal part of the digestive tube lay centrally around the area
      overlaid by axial and paraxial mesoderm, with the preventral digestive area lying
      outside with considerable overlapping, which was surrounded by the preyolk sac
      area. During the formation of the posterior digestive tube, the endoderm was
      elongated anteroposteriorly to a considerable degree. Cells that contributed to
      the cloaca and those that produced descendants in the large intestine occupied
      similar areas posterior to the center of the sinus rhomboidalis, which were
      included in the pre-ileal area extending more anteriorly. Prejejunal cells
      generally localized in a more anterior position than pre-ileal cells. Pre
      allantoic cells were located in a rather small area around the posterior
      primitive streak.

PMID- 10400394
TI  - Expression of five novel T-box genes and brachyury during embryogenesis, and in
      developing and regenerating limbs and tails of newts.
AB  - Several T-box genes are considered to play important roles in developing limbs,
      tails and neural retinae. Five novel T-box genes in the Japanese newt were
      isolated and their expression was analyzed, together with another T-box gene of
      brachyury, during embryogenesis and in the developing and regenerating limbs and
      tail. Four are designated CpTbx2, CpTbx3, CpTbx6R and CpEomesodermin based on
      molecular phylogenetic analyses, and the other is named CpUbiqT from its
      ubiquitous expression. While all were expressed during embryogenesis, only four
      of them (CpTbx2, CpTbx3, CpUbiqT and brachyury) were detected in developing limbs
      and/or tails. Except for brachyury, they were continuously expressed in normal
      adult appendages and showed elevated expression levels in regenerating limbs,
      whereas only CpTbx2 showed significant up-regulation in regenerating tails.
      Compared with orthologous genes in other species, CpTbx2, CpTbx3 and
      CpEomesodermin showed several notable differences such as an abundance of
      maternal transcripts of CpEomesodermin, a unique insertion sequence within the T
      box domain of CpTbx2, and a lack of visible expression of CpTbx2and CpTbx3 in the
      apical ectodermal region of developing limbs. In view of the uniqueness of the
      newt, these results are discussed with respect to the possibility of their
      involvement in regeneration.

PMID- 10400395
TI  - Efficient targeting of gene expression in chick embryos by microelectroporation.
AB  - During vertebrate embryonic development, a key to unraveling specific functions
      of gene products is the capability to manipulate expression of the gene of
      interest at the desired time and place. For this, we developed a
      'microelectroporation' technique by which DNA can be locally introduced into a
      targeted site of avian embryos, restricting spatial expression of the protein
      products during development. This technique involved injection of DNA solution in
      ovo around the target tissue and pinpoint application of an electric field by
      tungsten electrodes, allowing efficient and reproducible targeted gene transfer,
      for example, into an optic vesicle, somites, cranial mesoderm and limb
      mesenchyme. Because of the locality of gene introduction and its expression,
      survival rates of the embryos were high: approximately 90% of the embryos
      injected in optic vesicles were alive for at least 1 day after
      microelectroporation. The instantaneous gene transfer into embryonic cells
      allowed rapid expression of protein products such as green fluorescence protein
      within 2.5 h with fluorescence maintained for 3 days of incubation. This improved
      technique provides a convenient and efficient way to express transgenes in a
      spatially and temporally restricted manner in chicken embryos.

PMID- 10400396
TI  - Protein tyrosine kinase-dependent release of intracellular calcium in the sea
      urchin egg.
AB  - The aminoguanide, methylglyoxal bis(guanylhydrazone) (MGBG), was shown to
      stimulate phosphorylation of RR-SRC, a synthetic protein tyrosine kinase (PTK)
      substrate, and different levels of tyrosyl phosphorylation of endogenous proteins
      in a sea urchin egg membrane-cortex preparation. Stimulating protein tyrosine
      kinase activity in the sea urchin egg stimulated intracellular Ca2+ release,
      because microinjection of 1-5 mM of MGBG into unfertilized eggs triggered a
      transient rise in intracellular Ca2+ activity ([Ca2+]i) after a brief latent
      period. Pretreating eggs with PTK-specific inhibitors, genistein or tyrphostin
      B42, significantly inhibited the MGBG-induced rise in [Ca2+]i. Methylglyoxal
      bis(guanylhydrazone) stimulation of PTK activities in the unfertilized sea urchin
      egg appeared to trigger Ca2+ release through phospholipase C (PLC)-dependent
      inositol 1,4,5-trisphosphate (InsP3) production. The MGBG-induced Ca2+ response
      could be suppressed in eggs preloaded with the InsP3 receptor antagonist,
      heparin, and was reduced in eggs pretreated with U73122, a PLC inhibitor.
      However, the response was unchanged in eggs treated with nicotinamide, an
      inhibitor of ADP-ribosyl cyclase, or nifedipine, an inhibitor of nicotinic acid
      adenine dinucleotide phosphate activity. These results suggest that MGBG may be
      useful as a chemical agonist of PTK in sea urchin eggs and allow direct testing
      of the PTK requirement for the transient rise in [Ca2+]i in sea urchin eggs
      during fertilization. Although genistein was observed to significantly delay the
      onset, the sperm-induced Ca2+ response in PTK inhibitor-loaded eggs otherwise
      appeared normal. Therefore, it was concluded that sea urchin eggs contain a PTK
      dependent pathway that can mediate intracellular Ca2+ release, but PTK activity
      does not appear to be required for the fertilization response.

PMID- 10400397
TI  - Sulfated O-linked glycans of the vitelline coat as ligands in gamete interaction
      in the ascidian, Halocynthia roretzi.
AB  - In the ascidian Halocynthia roretzi, sperm-egg binding is probably mediated
      through the interaction between alpha-L-fucosidase present on the sperm surface
      and anionic saccharide chains of the egg vitelline coat. To characterize
      biologically active glycans, total glycans were chemically released from the
      glycopeptide fraction of the vitelline coat. The fraction of uncharged glycans
      and two fractions of negatively charged glycans were separated by
      diethylaminoethyl-anion exchange chromatography. In a competitive inhibition
      assay of fertilization, both anionic fractions showed inhibitory activity, with
      more anionic glycans being most potent, while uncharged glycans were biologically
      inactive. Chemical desulfation combined with a competitive inhibition assay of
      fertilization and ion analysis determined that sulfate groups were responsible
      for anionic character and crucial for biological activity. Monosaccharide
      analysis of anionic fractions showed a high content of N-acetylgalactosamine,
      galactose, xylose and the presence of arabinose, mannose, N-acetylglucosamine,
      glucose and rhamnose. Glycans were O-linked and galactose and xylose residues
      were detected at reducing termini. Linkage analysis suggested that 1,4-linked
      xylose, 1,3-linked galactose and N-acetylgalactosamine residues, substituted to
      different degrees by sulfate groups on the C-3 and C-4 carbons, respectively,
      constituted the core structures of anionic glycans.

PMID- 10400398
TI  - Role of type III iodothyronine 5-deiodinase gene expression in temporal
      regulation of Xenopus metamorphosis.
AB  - To elucidate the role of type III iodothyronine 5-deiodinase (5-D) in the
      temporal regulation of amphibian metamorphosis, the regulation of gene expression
      of 5-D and thyroid hormone receptor beta (TRbeta) in organs of Xenopus laevis was
      investigated. High levels of TRbeta mRNA in the respective organs were observed
      at the times of their major morphological changes. Expression of the 5-D gene was
      highly regulated among the organs during metamorphosis, including up-regulation
      in the tail and down-regulation in the liver. The tail and liver expressed 5-D
      gene before their metamorphic changes. These precocious expressions correlated
      with the lower responsiveness to exogenously added triiodo-L-thyronine (T3) for
      inducing a high level of TRbeta mRNA expression. However, the same organs
      responded to lower doses of T3 to regulate 5-D gene expression as seen in
      spontaneous metamorphosis. The induction of 5-D gene expression was considerably
      delayed in the intestine, even at an excess dose of T3. Thus, the two genes in a
      given organ appeared to respond to T3 either with different dose dependencies or
      with different timetables. The results obtained are also discussed in respect to
      recent findings in Rana catesbeiana.

PMID- 10400399
TI  - Can calcium antagonists provide a neuroprotective effect in Parkinson's disease?
AB  - Although major strides forward have been made in the symptomatic treatment of
      Parkinson's disease (PD), effective neuroprotective therapies have not yet been
      perfected. The role of calcium in neurotoxicity, and specifically in mediating
      the process of apoptosis, raises the possibility that calcium antagonists may
      have a salutary effect on conditions such as PD in which apoptosis may be the
      ultimate mode of cell death. Several lines of evidence support this notion
      including the reported effect of calcium antagonists on other human diseases
      involving apoptosis and animal studies demonstrating the ability of calcium
      antagonists to protect substantia nigra neurons from the toxin MPTP (1-methyl-4
      phenyl-1,2,3,6-tetrahydropyridine). The common calcium antagonists in use for the
      treatment of cardiovascular diseases have the potential to modify calcium
      neurotoxicity in PD since they block L-type calcium channels which are
      predominantly responsible for regulating intracellular calcium in midbrain
      dopaminergic cells. The widespread use of these agents affords the opportunity to
      discern their effect on PD through population studies. Preliminary investigations
      of this type have been performed to date, suggesting that calcium antagonist use
      may be less common in hypertensive PD patients than in non-PD hypertensive
      patients. More extensive investigations of this type, and prospective studies of
      calcium antagonist use in PD will be required to determine if these agents truly
      have a salutary effect on Parkinsonism.

PMID- 10400400
TI  - What is the place of fluoroquinolones in the treatment of community-acquired
      respiratory tract infections?
AB  - The newest (third generation) fluoroquinolones are potentially useful agents in
      the management of community-acquired respiratory tract infections. This is mainly
      due to their increased activity against Streptococcuspneumoniae, a pathogen
      poorly susceptible to the second-generation compounds, and playing a major role
      in upper and lower respiratory tract infections. Also, their spectrum includes
      the other main pathogens involved in those infections, comprising Haemophilus
      influenzae and intracellular agents, against which the newest fluoroquinolones
      exhibit a similar activity to that of the previous compounds. The pharmacokinetic
      and pharmacodynamic properties of the newest quinolones make them suitable for
      effective therapy of lower respiratory tract infections. However, careful
      attention should be paid to the dose and dosing regimen of each compound in
      clinical usage in order to select the most adapted drug. In clinical trials, the
      fluoroquinolones have been shown to be at least as effective as the comparators
      in the treatment of community-acquired pneumonia, acute exacerbations of chronic
      bronchitis (AECB) or sinusitis, including documented pneumococcal infections.
      Their tolerance is generally considered to be good. The main question regarding
      the fluoroquinolones in the treatment of community-acquired respiratory tract
      infections is their role as first-line agents used in single drug therapy. Cost
      effectiveness studies are needed to define this role further. Identification of
      subpopulations of patients at risk of being infected by penicillin-resistant
      pneumococci or Gram-negative bacilli who could benefit from a fluoroquinolone
      could be useful. Also, it must be considered that a large use of fluoroquinolones
      as first-line agents in very common infections such as AECB or sinusitis could
      contribute to the selection of bacteria, including S. pneumoniae, resistant to
      this class of antibiotics. Careful control of fluoroquinolone usage and
      development of bacterial resistance is of great importance.

PMID- 10400401
TI  - Antacids revisited: a review of their clinical pharmacology and recommended
      therapeutic use.
AB  - Antacids are commonly used self-prescribed medications. They consist of calcium
      carbonate and magnesium and aluminum salts in various compounds or combinations.
      The effect of antacids on the stomach is due to partial neutralisation of gastric
      hydrochloric acid and inhibition of the proteolytic enzyme, pepsin. Each cation
      salt has its own pharmacological characteristics that are important for
      determination of which product can be used for certain indications. Antacids have
      been used for duodenal and gastric ulcers, stress gastritis, gastro-oesophageal
      reflux disease, pancreatic insufficiency, non-ulcer dyspepsia, bile acid mediated
      diarrhoea, biliary reflux, constipation, osteoporosis, urinary alkalinisation and
      chronic renal failure as a dietary phosphate binder. The development of histamine
      H2-receptor antagonists and proton pump inhibitors has significantly reduced
      usage for duodenal and gastric ulcers and gastro-oesophageal reflux disease.
      However, antacids can still be useful for stress gastritis and non-ulcer
      dyspepsia. The recent release of proprietary H2 antagonists has likely further
      reduced antacid use for non-ulcer dyspepsia. Other indications are still valid
      but represent minor uses. Antacid drug interactions are well noted, but can be
      avoided by rescheduling medication administration times. This can be inconvenient
      and discourage compliance with other medications. All antacids can produce drug
      interactions by changing gastric pH, thus altering drug dissolution of dosage
      forms, reduction of gastric acid hydrolysis of drugs, or alter drug elimination
      by changing urinary pH. Most antacids, except sodium bicarbonate, may decrease
      drug absorption by adsorption or chelation of other drugs. Most adverse effects
      from antacids are minor with periodic use of small amounts. However, when large
      doses are taken for long periods of time, significant adverse effects may occur
      especially patients with underlying diseases such as chronic renal failure. These
      adverse effects can be reduced by monitoring of electrolyte status and avoiding
      aluminum-containing antacids to bind dietary phosphate in chronic renal failure.
      Antacids, although effective for discussed indications of duodenal and gastric
      ulcer and gastro-oesophageal reflux disease, have been replaced by newer, more
      effective agents that are more palatable to patients. Antacids are likely to
      continue to be used for non-ulcer dyspepsia, minor episodes of heartburn (gastro
      oesophageal reflux disease) and other clear indications. Although their wide
      spread use may decline, these drugs will still be used, and clinicians should be
      aware of their potential drug interactions and adverse effects.

PMID- 10400402
TI  - Antibacterial use in community practice: assessing quantity, indications and
      appropriateness, and relationship to the development of antibacterial resistance.
AB  - Most use of antibacterials occurs in community practice; however, despite the
      widespread belief of inappropriate use and the resultant increase in
      antibacterial resistance, little data exist describing antibacterial use in this
      setting. A MEDLINE search of English-language articles was conducted for
      epidemiological studies assessing quantity, indication and appropriateness of
      antibacterial use in community practice. A 1983 study of international
      antibacterial use described considerable disparities in quantity of use between
      countries. Subsequent longitudinal studies from the US, Canada, Australia and the
      UK described changing patterns of antibacterial use. No increase in the total
      rate of antibacterial use was reported by any of the 4 countries; however, all
      countries reported increased use of newer and/or broad-spectrum agents (e.g.
      fluoroquinolones, amoxicillin-clavulanic acid, cephalosporins and new macrolides]
      coupled with decreased use of older and/or narrow-spectrum agents [e.g.
      phenoxymethylpenicillin (penicillin V), erythromycin, ampicillin and
      tetracycline). Most (approximately three-quarters) use of antibacterials was in
      the treatment of respiratory tract infections. Prescribing rates for respiratory
      tract infections of presumed viral aetiology (e.g. the common cold) ranged from
      17 to 60% in the UK and US, respectively. Among indications for which
      antibacterials were indicated, the appropriateness of antibacterial use received
      little study. Correspondingly, the rates of antibacterial resistance among common
      respiratory pathogens (Streptococcus pneumoniae and Haemophilus influenzae) have
      increased significantly in the past decade, although disparities exist between
      countries. Antibacterial use is considered a major factor in the development of
      antibacterial resistance, although the relationship between community
      antibacterial use and resistance has been poorly described. Further study of
      antibacterial usage patterns and associated resistance patterns is fundamental to
      the development of methods to reduce unnecessary and inappropriate use, thereby
      slowing the development of antibacterial resistance in the community.

PMID- 10400403
TI  - Current concepts in the pharmacological management of obesity.
AB  - The pharmacological management of obesity has gained increasing attention as new
      weight loss treatments are approved and a significant proportion of the public
      strives to lose weight. Obesity is associated with a high mortality rate,
      multiple chronic medical conditions, and carries an enormous financial burden.
      Obesity is a multifactorial condition, most often due to an imbalance in energy
      intake and expenditure. Despite the greater focus on management of obesity,
      weight loss remains a difficult goal to achieve. Obesity is a chronic medical
      condition that may require long term treatment, therefore the risks and benefits
      of all pharmacological agents must be carefully considered. Noradrenergic
      appetite suppressants (ie. phenyl-propanolamine, phentermine) result in weight
      loss but stimulatory effects limit their use. The serotonergic agents
      (fenfluramine, dexfenfluramine) were effective weight loss drugs, but were
      voluntarily withdrawn from the US market last year because of cardiovascular and
      pulmonary complications. The combination noradrenergic/serotonergic agent
      sibutramine is indicated for the management of obesity, particularly in the
      presence of other cardiovascular risk factors. Modest weight loss is achieved
      with sibutramine, although weight gain is significant after discontinuation. In
      addition, long term safety data are not yet available. The thermogenic
      combination of ephedrine plus caffeine is minimally effective, and adverse
      effects are usually transient. Other thermogenic agents, such as beta3-agonists,
      are still under investigation. Agents may alter digestion through lipase
      inhibition (orlistat) or fat substitution (olestra). Orlistat decreases systemic
      absorption of dietary fat, decreasing body weight and cholesterol. Olestra is a
      fat substitute that has been incorporated into snack foods. Olestra substitution
      for dietary fat has not been studied as a weight loss strategy, although olestra
      has no caloric value and may be beneficial. The use of orlistat and olestra may
      be limited by gastrointestinal adverse effects. Finally, the manipulation of
      leptin and neuropeptide Y are under investigation for the treatment of obesity.
      Pharmacological agents should be used as an aid to a structured diet and exercise
      regimen in the treatment of obesity. Weight loss agents may result in initial
      weight loss, but sustained weight loss is not always achieved even with
      continuation of treatment. The effect of weight loss obtained while using
      pharmacotherapeutic agents on morbidity and mortality has not been established.
      Therefore, diet and exercise should be the focus of any weight loss programme.
      There is a continued need for safe and effective pharmacotherapeutic agents for
      the treatment of obesity.

PMID- 10400405
TI  - Rosiglitazone.
AB  - Rosiglitazone, a thiazolidinedione antidiabetic agent, improves insulin
      resistance, a key underlying metabolic abnormality in most patients with type 2
      (non-insulin-dependent) diabetes mellitus. In animal models of insulin
      resistance, rosiglitazone decreased plasma glucose, insulin and triglyceride
      levels and also attenuated or prevented diabetic nephropathy and pancreatic islet
      cell degeneration. In contrast with troglitazone, rosiglitazone does not induce
      cytochrome P4503A4 metabolism. It does not interact significantly with
      nifedipine, oral contraceptives, metformin, digoxin, ranitidine or acarbose. In
      clinical trials in patients with type 2 diabetes mellitus, rosiglitazone 2 to 12
      mg/day (as a single daily dose or 2 divided daily doses) improved glycaemic
      control, as shown by decreases in fasting plasma glucose and glycosylated
      haemoglobin (HbA1c). Addition of rosiglitazone 2 to 8 mg/day to existing
      sulphonylurea, metformin or insulin therapy achieved further reductions in
      fasting plasma glucose and HbA1c. Oral combinations improved insulin sensitivity
      and beta-cell function according to a homeostasis model assessment. Consistent
      with its mechanism of action, rosiglitazone appears to be associated with a low
      risk of hypoglycaemia (<2% of patients receiving monotherapy). There is no
      evidence to date that rosiglitazone shares the hepatotoxicity of troglitazone.

PMID- 10400406
TI  - Salmeterol/fluticasone propionate combination.
AB  - Current evidence suggests that addition of the long-acting beta2-agonist
      salmeterol to an inhaled corticosteroid in patients with persistent asthma
      symptoms provides greater clinical benefit than doubling the dosage of the
      inhaled corticosteroid. Fixed combination salmeterol/fluticasone propionate in 3
      different fluticasone propionate dosage strengths administered via the Diskus
      powder inhaler does not result in any untoward interaction that affects the
      pharmacodynamic or pharmacokinetic profiles of the individual drugs, or their
      adverse effect profiles - including the influence of the corticosteroid on plasma
      cortisol levels. Administration of fixed combination salmeterol/ fluticasone
      propionate to both adults and children with persistent asthma provides greater
      improvements in lung function than either agent alone, and at least equal
      effectiveness to the same dosages of the 2 agents given by separate powder
      inhalers. Preliminary reports indicate that combination therapy has also
      demonstrated superior efficacy to budesonide (fluticasone propionate dosages were
      25% those of budesonide). The most commonly encountered adverse effects in
      clinical trials with combined salmeterol/fluticasone propionate therapy have been
      oropharyngeal candidiasis. hoarseness/dysphonia, throat irritation, headache,
      tachycardia/palpitations, tremor and dizziness (all in < or =5% of patients).

PMID- 10400404
TI  - A practical approach to patients with refractory Helicobacter pylori infection,
      or who are re-infected after standard therapy.
AB  - The vast majority of recurrences of Helicobacter pylori infection after apparent
      eradication are observed during the first year. Almost all of these early
      recurrences are due to recrudescence rather than reinfection by a new strain.
      After the first year, the recurrence rates approximate to the rate of natural
      acquisition of H. pylori infection. By contrast, in developing countries, higher
      rates of recurrence suggest a major role of real reinfection. Important
      predictive factors of H. pylori treatment success are compliance and bacterial
      susceptibility to antibiotics. The new 1-week triple therapies, based on a proton
      pump inhibitor (PPI) and 2 antibiotics, lead to treatment discontinuation but
      rarely. If containing a nitroimidazole, their efficacy is reduced to 60 to 80% by
      pretreatment in vitro resistance. The prevalence of nitroimidazole resistance
      varies dependent on the geographical area, with rates over 50% in tropical
      regions. Resistance against macrolides hinders treatment success in 50 to 80% of
      patients. In the US, south-western Europe and Japan the prevalence of macrolide
      resistance amounts to about 10%, in other countries about 3%. After failed
      treatment, acquired resistance is frequent. Testing for resistance is recommended
      to facilitate the decision for an alternative triple therapy or for quadruple
      therapy comprising bismuth, metronidazole, tetracycline and a PPI. It seems
      reasonable to increase the dose of PPI in a retreatment regimen containing
      amoxicillin. Post-treatment double resistance against nitroimidazoles and
      macrolides reduces the success of most of the currently evaluated retreatment
      regimens. To overcome double resistance, high dose PPI plus amoxicillin is one
      approach, beside other experimental multidrug treatments.

PMID- 10400408
TI  - Sildenafil: a review of its use in erectile dysfunction.
AB  - Sildenafil is an oral therapy for erectile dysfunction of a broad range of
      causes. By selectively inhibiting phosphodiesterase type 5, it allows corpus
      cavernosum smooth muscle to relax, potentiating erections during sexual
      stimulation. Blood pressure is reduced transiently by sildenafil, but more marked
      hypotension may occur during concurrent administration of sildenafil and organic
      nitrates; this combination is contraindicated. Sildenafil is rapidly absorbed,
      with dose-proportional peak plasma concentrations within 1 hour of
      administration. The elimination half-life is 3 to 5 hours. Dosages usually begin
      at 50mg taken when needed =1 hour before sexual activity no more than once daily.
      The maximum dose is 100mg when needed once daily and lower doses (e.g. 25mg) may
      be used in elderly patients and those with hepatic or renal impairment or
      receiving cytochrome P450 enzyme CYP3A4 inhibitors, such as ritonavir,
      saquinavir, ketoconazole, erythromycin or cimetidine. More than 3000 patients
      with erectile dysfunction of organic (e.g. diabetes or spinal cord injury),
      psychogenic or mixed origin received sildenafil 5 to 100mg or placebo in fixed-
      or titrated-dose trials. Sildenafil was associated with dose-related improvements
      in the frequency, hardness and duration of erections and in patients' abilities
      to achieve and maintain erections adequate for successful sexual intercourse. In
      titrated-dose trials, the most commonly effective doses were 50 or 100mg,
      although lower doses were effective in some patients. Sildenafil was
      significantly more effective than placebo in erectile dysfunction of all tested
      causes. The efficacy of sildenafil was not affected by patient age (> or < or =65
      years) or by antihypertensive or antidepressant medications. The drug was
      effective in patients with severe erectile dysfunction. Efficacy was maintained
      in long term (1-year) studies. Sildenafil also appears to improve the quality of
      life of both patients and their sexual partners. Common adverse events associated
      with sildenafil were transient and mild or moderate and included headache,
      flushing, dyspepsia, nasal congestion and abnormal vision. Tolerability was
      maintained in long term (< or =1 year) studies. No serious sildenafil-related
      adverse events occurred in clinical trials; cardiovascular events seen in
      postmarketing surveillance generally occurred in patients with other known risk
      factors. CONCLUSIONS: Sildenafil is an effective oral treatment in men with
      erectile dysfunction. It was significantly superior to placebo in improving
      erections and allowing successful penetrative sexual intercourse. Although its
      place in disease management is still emerging and there are contraindications to
      its use, if preliminary positive reports are confirmed, sildenafil will be the
      pre-eminent first-line therapy for erectile dysfunction.

PMID- 10400407
TI  - Etanercept: a review of its use in rheumatoid arthritis.
AB  - Etanercept, a fusion protein consisting of the extracellular ligand-binding
      domain of the 75kD receptor for tumour necrosis factor-alpha and the constant
      portion of human IgG1, is administered by subcutaneous injection and is the first
      specific anti-cytokine therapy approved for rheumatoid arthritis. In patients
      with active rheumatoid arthritis [American College of Rheumatology (ACR)
      functional class I to III] who had failed to respond to previous treatment with >
      or = 1 disease-modifying antirheumatic drug (DMARD), etanercept, alone or in
      combination with methotrexate, produced improvements in all components included
      in the ACR core set of disease activity measures. A dose-response effect was
      apparent with etanercept 0.25 to 16 mg/m2 twice weekly in a randomised, double
      blind study in 180 patients. The mean number of swollen or tender joints at the
      end of the 12-week study decreased by >50% in patients treated with etanercept 16
      mg/m2 twice weekly and by <25% in patients treated with placebo. In a 24-week
      multicentre, randomised, double-blind study in 234 patients who were not allowed
      to use DMARDs, etanercept 10 or 25mg twice weekly had a rapid onset of effect.
      Significantly more patients treated with etanercept 25mg twice weekly than
      placebo experienced 20 (ACR 20), 50 (ACR 50) or 70% (ACR 70) improvement in ACR
      criteria after 3 and 6 months. Limited evidence suggests that the therapeutic
      effects of etanercept are maintained for up to 2 years. Etanercept 25mg twice
      weekly produced significant improvement in patients receiving oral or
      subcutaneous methotrexate 10 to 25 mg/week in a multicentre, randomised, double
      blind, placebo-controlled study. A significantly greater proportion of patients
      treated with etanercept plus methotrexate (71%) than placebo plus methotrexate
      (27%) achieved the ACR 20 criteria after 6 months. Moreover, 39 and 15% of
      patients treated with etanercept plus methotrexate, but no placebo plus
      methotrexate recipients, had achieved the ACR 50 and ACR 70 criteria at this
      time. Etanercept 0.4 mg/kg twice weekly reduced disease activity in a
      preliminary, noncomparative study in 69 children aged > or =4 years with
      refractory juvenile rheumatoid arthritis. Although the overall frequency of
      infections was similar in patients treated with etanercept or placebo, upper
      respiratory tract infections were more common in patients treated with etanercept
      (29%) than placebo (16%). Injection site reactions occurred more frequently in
      etanercept- than placebo-treated patients, but did not bias the results of any
      study. CONCLUSIONS: When etanercept is administered alone or in combination with
      methotrexate in patients with refractory rheumatoid arthritis, significant
      reductions in disease activity occur within 2 weeks and are sustained for at
      least 6 months. Thus, etanercept appears to be particularly well suited for use
      in patients who fail to respond to treatment with DMARDs.

PMID- 10400409
TI  - Diclofenac-potassium in migraine: a review.
AB  - The NSAID diclofenac is a potent inhibitor of prostaglandin synthesis and an
      established antipyretic and analgesic agent. Diclofenac-potassium was developed
      as an immediate-release tablet with the aim of providing rapid onset of action
      after oral administration. This formulation has been investigated in the acute
      treatment of migraine. Data from available placebo-controlled clinical trials
      indicate that diclofenac-potassium 50 or 100mg as an immediate-release tablet is
      more effective than placebo and as effective as oral sumatriptan 100mg and
      ergotamine plus caffeine at reducing pain intensity in patients with migraine 2
      hours after initial administration. Duration of pain relief is similar for the 3
      drugs but onset appears to be faster with diclofenac-potassium than with oral
      sumatriptan or ergotamine plus caffeine. Diclofenac-potassium appears to have
      favourable effects on some accompanying symptoms such as nausea and vomiting. The
      frequency of these symptoms was significantly lower with diclofenac-potassium
      than with sumatriptan in 1 study, although only a few patients had vomiting at
      baseline. Effects on phonophobia or photophobia did not differ between diclofenac
      potassium, sumatriptan and ergotamine plus caffeine. The need for rescue
      medication is consistently less with diclofenac-potassium than with placebo. Data
      are inconsistent or scarce regarding the effects of diclofenac-potassium versus
      placebo on other measures such as headache recurrence and working ability.
      Diclofenac-potassium was generally well tolerated in clinical trials in patients
      with migraine. Adverse events reported most frequently (abdominal pain, tiredness
      and fatigue and nausea) were typically mild to moderate. CONCLUSION: Diclofenac
      potassium provides rapid pain relief (within 60 to 90 minutes), is well tolerated
      and reduces the frequency of some of the accompanying symptoms in patients with
      migraine. Available trials indicate that diclofenac-potassium provides similar
      pain relief to sumatriptan and is at least as effective as ergotamine plus
      caffeine, but appears to have a greater effect on nausea and vomiting than
      sumatriptan and a faster onset of action than both drugs. Comparisons with other
      NSAIDs are lacking. Diclofenac-potassium is likely to find a role as a useful
      first-line option in the acute treatment of migraine.

PMID- 10400411
TI  - Cardiotoxicity of second-generation antihistamines.

PMID- 10400410
TI  - Tranexamic acid: a review of its use in surgery and other indications.
AB  - Tranexamic acid is a synthetic derivative of the amino acid lysine that exerts
      its antifibrinolytic effect through the reversible blockade of lysine binding
      sites on plasminogen molecules. Intravenously administered tranexamic acid (most
      commonly 10 mg/kg followed by infusion of 1 mg/kg/hour) caused reductions
      relative to placebo of 29 to 54% in postoperative blood losses in patients
      undergoing cardiac surgery with cardiopulmonary bypass (CPB), with statistically
      significant reductions in transfusion requirements in some studies. Tranexamic
      acid had similar efficacy to aprotinin 2 x 10(6) kallikrein inhibitory units
      (KIU) and was superior to dipyridamole in the reduction of postoperative blood
      losses. Transfusion requirements were reduced significantly by 43% with
      tranexamic acid and by 60% with aprotinin in 1 study. Meta-analysis of 60 trials
      showed tranexamic acid and aprotinin, unlike epsilon-aminocaproic acid (EACA) and
      desmopressin, to reduce significantly the number of patients requiring allogeneic
      blood transfusions after cardiac surgery with CPB. Tranexamic acid was associated
      with reductions relative to placebo in mortality of 5 to 54% in patients with
      upper gastrointestinal bleeding. Meta-analysis indicated a reduction of 40%.
      Reductions of 34 to 57.9% versus placebo or control in mean menstrual blood loss
      occurred during tranexamic acid therapy in women with menorrhagia; the drug has
      also been used to good effect in placental bleeding, postpartum haemorrhage and
      conisation of the cervix. Tranexamic acid significantly reduced mean blood losses
      after oral surgery in patients with haemophilia and was effective as a mouthwash
      in dental patients receiving oral anticoagulants. Reductions in blood loss were
      also obtained with the use of the drug in patients undergoing orthotopic liver
      transplantation or transurethral prostatic surgery, and rates of rebleeding were
      reduced in patients with traumatic hyphaema. Clinical benefit has also been
      reported with tranexamic acid in patients with hereditary angioneurotic oedema.
      Tranexamic acid is well tolerated; nausea and diarrhoea are the most common
      adverse events. Increased risk of thrombosis with the drug has not been
      demonstrated in clinical trials. CONCLUSIONS: Tranexamic acid is useful in a wide
      range of haemorrhagic conditions. The drug reduces postoperative blood losses and
      transfusion requirements in a number of types of surgery, with potential cost and
      tolerability advantages over aprotinin, and appears to reduce rates of mortality
      and urgent surgery in patients with upper gastrointestinal haemorrhage.
      Tranexamic acid reduces menstrual blood loss and is a possible alternative to
      surgery in menorrhagia, and has been used successfully to control bleeding in
      pregnancy.

PMID- 10400412
TI  - p73 mutations and expression in adult de novo acute myelogenous leukemia.
AB  - The p73 gene is a candidate tumor suppressor gene that has significant homology
      to p53. Thus far, p73 has not been investigated in hematopoietic malignancies. We
      used single-strand conformation polymorphism analysis to examine 60 de novo acute
      myelogenous leukemia (AML) patients for p73 mutations in exons 4, 6 and 7, which
      are homologous to the most frequently mutated exons in p53. Mutations were not
      found, but we did identify polymorphisms in exons 4 and 7. We also examined p73
      RNA expression in 15 AML samples, eight cell lines, and eight normal bone marrows
      using the reverse transcriptase/polymerase chain reaction assay. All 31 RNA
      samples had p73 expression. Fourteen RNA samples were informative for allelic
      expression, being heterozygous for a polymorphism in codon 173 of exon 4. The two
      normal bone marrows and the K562 cell line had evidence of biallelic expression
      while six of 10 AML patients and the Kasumi (AML) cell line had monoallelic
      expression. These data suggest that functional p73 mutations in exons 4, 6 and 7
      do not occur in most de novo AML patients. In addition, biallelic expression of
      p73 occurs in normal bone marrows, some AML samples, and specific cell lines.
      Lastly, monoallelic p73 expression appears to be common in de novo AML.

PMID- 10400413
TI  - Selection of BCR/ABL-negative stem cells from marrow or blood of patients with
      chronic myeloid leukemia.
AB  - Philadelphia (Ph) or BCR/ABL-negative cells with immature phenotype (CD34
      positive, DR-negative) can be recovered from patients with chronic myeloid
      leukemia (CML) in chronic phase. We used the technique described by Berardi et al
      (Science 1995; 267: 104-108) to select stem cells from marrow or blood of CML
      patients at diagnosis or during treatment with alpha-interferon. Mononuclear
      cells (MNC), and in some experiments CD34+ cells, were maintained for 7 days in
      the presence of 5-fluorouracil (5-FU), stem cell factor and interleukin-3. The
      number of viable cells recovered after culture was between 7.4 and 70.2 for 10(6)
      cells plated. These cells exhibited the following phenotype: CD34+, CD117+, CD38
      , lineage-, and were able to generate cobblestone areas and secondary colonies in
      long-term culture (LTC), with a frequency similar to that of cells selected from
      normal marrow. Study by fluorescence in situ hybridization of LTC cells or
      secondary colonies showed no evidence of BCR/ABL rearrangement. Reverse
      transcriptase polymerase chain reaction studies on pooled LTC cells or secondary
      colonies were also negative. By contrast, LTC cells or secondary colonies
      obtained from CML CD34+ cells without culture in the presence of 5-FU were always
      positive for BCR/ABL rearrangement. Finally, 5-FU selected cells were able to
      engraft NOD/SCID mouse, as human cells were detected in blood and marrow 10 weeks
      post transplantation, which were BCR/ABL negative by RT-PCR. This method of
      culture makes it possible to select constantly BCR/ABL-negative cells with
      capacities of development in LTC assay and of NOD/SCID mouse engraftment.

PMID- 10400415
TI  - Treatment of anemia in low risk myelodysplastic syndromes with granulocyte
      macrophage colony-stimulating factor plus recombinant human erythropoietin.
AB  - The aim of this prospective study was to determine whether treatment with a
      combination of GM-CSF and erythropoietin (rhEpo) can improve the anemia
      associated with low risk myelodysplastic syndrome (MDS), namely refractory anemia
      (RA), RA with ring sideroblasts (RAS), and RA with excess of blasts (RAEB) with
      bone marrow blasts less than 10%. Eligibility criteria included an Hb level of
      less than 10.5 g/dl for newly diagnosed patients, or symptomatic anemia. GM-CSF
      was given at a dose of 3 microg/kg s.c. on days 1-2, rhEpo at a dose of 60 U/kg
      s.c. on days 3-5. No treatment was given on days 6-7. Patients were followed-up
      with full blood count on a weekly basis. The treatment was repeated for a total
      of 6 weeks. At that time, if a rise in Hb above 1.5 g/dl had not been achieved,
      the dose of rhEpo increased to 120 U/kg. Post-treatment evaluation was performed
      at the completion of 12 weeks. Erythroid response was defined as good (GR), if an
      increase in untransfused Hb values above 2 g/dl or a 100% decrease in red blood
      cell transfusion requirements, over the treatment period was observed, while an
      increase in untransfused Hb values 1-2 g/dl or a >50% decrease in transfusion
      requirements, were considered as partial response. Responders continued to
      receive the same treatment until disease progression. Nineteen patients (13 male
      and six female) with a median age of 69 years were enrolled in the study. The FAB
      subtypes were: RA one case, RAS eight cases and RAEB 10 cases. Ten of 19 patients
      (52.6%) responded to the treatment: 7/19 (36.8%) achieved a GR and 3/19 (15.8%) a
      PR. Six of eight (75%) patients with RAS, one case with RA and 3/10 (30%) of
      cases with RAEB responded to treatment. Pretreatment serum epo levels were
      generally low (less than 200 Mu/ml) in responding patients. At the completion of
      the initial 12 weeks, 8/12 responding patients (5 RAS, 2 RAEB and 1 RA) continued
      to receive the same treatment. All responding patients with RAS continued to show
      an erythroid response in a time period from 3 to 24 months, whilst one patient
      with RA and two with RAEB did not have a continuing response at 2, 4 and 12
      months, respectively. The above data suggest that the combination of rhEpo and GM
      CSF should be recommended in all cases with RARS. However, the clear indication
      of this combination for other patients with MDS remains to be determined.

PMID- 10400416
TI  - Chromosome abnormalities and MLL rearrangements in acute myeloid leukemia of
      infants.
AB  - Of 29 infants with acute myeloid leukemia (AML), 14 (48%) had various 11q23
      translocations. MLL rearrangements were examined in 21 of the 29 patients, and 11
      (52%) showed the rearrangements. 11q23 translocations and/or MLL rearrangements
      were found in 17 (58%) of the 29 patients. While all but one of the 17 patients
      with 11q23/MLL rearrangements had M4 or M5 type of the FAB classification, the 12
      patients without such rearrangements had various FAB types, including M2, M4,
      M4EO, M6 and M7. Of the 12 patients with other chromosome abnormalities or normal
      karyotypes, two had inv(16) ort(16;16), one had t(1;22)(p13;q13), and two had a
      novel translocation, t(7;12)(q32;p13). The breakpoint on 12p of the t(7;12) was
      assigned to intron 1 or the region just upstream of exon 1 of the TEL/ETV6 gene
      by fluorescence in situ hybridization. The event-free survival at 5 years for the
      17 patients with 11q23/MLL rearrangements was 42.2%, and that for the 12 patients
      without such rearrangements was 31.3% (P = 0.5544). 11q231MLL rearrangements have
      been frequently reported and a poor prognosis in infant acute lymphoblastic
      leukemia implied. Our study showed that while 11q23/MLL rearrangements were also
      common in infant AML, AML infants with such rearrangements had a clinical outcome
      similar to that of AML infants without such rearrangements.

PMID- 10400414
TI  - Quantitative competitive reverse transcriptase-polymerase chain reaction for BCR
      ABL on Philadelphia-negative leukaphereses allows the selection of low
      contaminated peripheral blood progenitor cells for autografting in chronic
      myelogenous leukemia.
AB  - The Philadelphia (Ph) translocation t(9;22) results in the creation of the BCR
      ABL gene, which is now regarded as central to the mechanism that underlies the
      chronic phase of chronic myelogenous leukemia (CML). From a clinical point of
      view, BCR-ABL mRNA detection has become the basis for the study of minimal
      residual disease in CML, particularly when a complete cytogenetic remission is
      achieved after interferon-alpha (IFN-alpha) therapy or allogeneic stem cell
      transplantation. We have recently demonstrated that it is possible to mobilize
      normal peripheral blood progenitor cells (PBPC) in higher rates if this procedure
      is performed during the early chronic phase. In an attempt to monitor the
      leukemic cell content of PBPC collections, we used quantitative-competitive RT
      PCR (QC-RT-PCR). Thirty consecutive Philadelphia (Ph) chromosome positive
      patients were enrolled in this study. After chemotherapy and G-CSF, 14 patients
      achieved 100% Ph-negative metaphases, nine patients had < or =34% and seven
      patients >34% leukemic metaphases. A total of 116 collection samples were
      studied. For each sample, BCR-ABL transcript numbers and BCR-ABL/ABL ratio were
      evaluated. A highly significant correlation between Ph-positive metaphases and
      BCR-ABL transcript numbers (r = 0.84, P < 0.0001) or BCR-ABL/ABL ratio (r = 0.86,
      P < 0.0001) was found. For patients that underwent the procedure in early chronic
      phase, Ph-negative collections showed different levels of BCR-ABL expression. BCR
      ABL transcript numbers varied from a median of 100/microg RNA in the first and
      second leukaphereses, to 500/microg RNA in the third and fourth leukaphereses,
      and 1500/microg RNA in the fifth leukapheresis (P = 0.002). BCR-ABL/ABL ratio
      values showed similar kinetics. We have also demonstrated that there is a
      correlation between low values in BCR-ABL/ABL ratio (< or =0.01) in the reinfused
      PBPC and the achievement of cytogenetic remission after autografting (chi2 test,
      P = 0.01). In conclusion, this study demonstrates that QC-RT-PCR for BCR-ABL is a
      reliable and helpful method for monitoring residual leukemic load in mobilized
      PBPC, particularly in Ph-negative collections. Moreover, QC-RT-PCR allows
      selection of the best available collections for reinfusion into patients after
      myeloablative therapy.

PMID- 10400417
TI  - Interleukin-11 (IL-11) enhances clonal proliferation of acute myelogenous
      leukemia cells with strong expression of the IL-11 receptor alpha chain and
      signal transducing gp130.
AB  - We examined the effect of recombinant human interleukin (IL)-11 alone or in
      combination with various colony-stimulating factors (CSFs), including IL-3,
      granulocyte/macrophage (GM)-CSF, granulocyte (G)-CSF, stem cell factor (SCF),
      flt3 ligand (FL), and thrombopoietin (TPO), on colony formation by leukemic
      progenitor cells (L-CFU) obtained from 33 patients with acute myelogenous
      leukemia (AML). Leukemic colony formation was found in approximately 70 to 80% of
      the patients in the presence of at least one of the above CSFs. Although IL-11
      alone did not support L-CFU, the growth of these progenitors in the presence of
      other cytokines was enhanced by IL-11 in 16 out of 33 patients and it showed a
      synergistic action with G-CSF in 12 of them. This synergistic action occurred in
      seven out of nine M5 patients (French-American-British (FAB) classification). A
      single cell clone-sorting experiment clearly demonstrated that this synergistic
      effect was operative at the single progenitor cell level. The number of leukemic
      cells proliferating in the presence of G-CSF+IL-11 was significantly higher than
      in the presence of G-CSF alone, suggesting that IL-11 recruited dormant leukemic
      progenitors into the cell cycle. Flow cytometric analysis revealed that all types
      of AML blast cells (M0 approximately M6) ubiquitously expressed gp130, although
      the level of expression was significantly higher in M5 cells. In contrast,
      expression of the IL-11 receptor alpha chain (IL-11Ralpha) varied between FAB
      types. Blast cells obtained from M1, M3 and M5 patients showed higher levels of
      expression, with M5 cells showing the strongest expression. Interestingly, the
      leukemic progenitor cells for which proliferation was synergistically enhanced by
      IL-11 had significantly higher expression of both IL-11Ralpha and gp130. These
      results suggest that administration of IL-11 in vivo may stimulate the
      proliferation of leukemic progenitor cells, particularly M5 cells, in the
      presence of G-CSF, and that the responsiveness of L-CFU to IL-11 may be predicted
      by a simple receptor assay.

PMID- 10400418
TI  - Mitogen-activated protein kinase pathway is dispensable for microtubule-active
      drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells.
AB  - Raf-1 activation and Bcl-2 hyperphosphorylation following treatment with
      paclitaxel (Taxol) or other microtubule-active drugs is associated with mitotic
      arrest. Here we show that microtubule-active drugs do not activate the mitogen
      activated protein kinase (MAPK) pathway in leukemia cells. PD98059, a MEK
      inhibitor, and SB202190, a p38 MAP kinase inhibitor, do not abrogate Bcl-2
      phosphorylation nor apoptosis. Simultaneously with PARP cleavage, paclitaxel
      induces cleavage of Bcl-2 protein yielding a potentially pro-apoptotic 22 kDa
      product. In comparison, the stimulation of Raf-1 by phorbol ester (TPA) activates
      the MAPK pathway, causes MAPK-dependent p21WAF1/CIP1 induction, Rb
      dephosphorylation and growth arrest without Bcl-2 phosphorylation or apoptosis.
      Like TPA, cAMP induces p21WAF1/CIP1 but does not cause Bcl-2 phosphorylation.
      MEKK1 and Ras, upstream activators of JNK and ERK MAPK, also fail to induce Bcl-2
      hyperphosphorylation. Although Lck tyrosine kinase has been recently implicated
      in Raf-1 activation during mitotic arrest, microtubule-active drugs induce Raf
      1/Bcl-2 hyperphosphorylation and apoptosis in a Lck-deficient Jurkat cells.
      Therefore, microtubule-active drugs induce apoptosis which is associated with Raf
      1 and Bcl-2 phosphorylation and Bcl-2 cleavage but is independent of the MAPK
      pathway. In contrast, TPA-activated MAPK pathway causes p21WAF1/CIP1-dependent
      growth arrest without apoptosis.

PMID- 10400419
TI  - A dual function for p38 MAP kinase in hematopoietic cells: involvement in
      apoptosis and cell activation.
AB  - In the present study we examined in more detail the dual role of the c-JUN N
      terminal kinase (JNK) and p38 stress-activated protein kinase pathways in
      mediating apoptosis or cellular activation in hematopoietic cells. Growth factor
      deprivation of the erythroleukemic cell line TF-1 led to apoptosis which was
      associated with an enhanced activity of JNK and p38 and immediate
      dephosphorylation of the extracellular signal-regulated kinases (ERKs). Enhanced
      activity of p38 and JNK was not only observed during apoptosis but also in TF-1
      cells stimulated with IL-1. IL-1 rescued TF-1 cells from apoptosis. In this case,
      the upregulation of p38 and JNK was associated with an enhanced activity of ERK.
      By using SB203580, a specific inhibitor of the p38 signaling pathway, it was
      demonstrated that p38 plays a pivotal role in the apoptotic process. SB203580
      repressed the apoptotic process to a large extent. In contrast, PD98059, a
      specific inhibitor of the ERK pathway, counteracted the suppressive effects of
      SB203580 and IL-1 on the apoptotic process indicating that the protective effect
      of SB203580 and IL-1 might be the result of a shift in the balance between the
      ERK1/2 and p38/JNK route. This was also supported by experiments with TF-1 cells
      overexpressing the Shc protein that demonstrated a significantly lower percentage
      of apoptotic cells, which coincided with higher ERK activity. Finally, the IL-1
      and SB203580-mediated effects were associated with an enhanced nuclear factor
      kappaB (NF-kappaB) and activator protein-1 (AP-1) binding activity, which could
      also be blocked by PD98059. These data demonstrate a dual function of the p38
      pathway whereby other factors, such as ERK kinases, AP-1 and NF-kappaB, might
      determine the final cellular response.

PMID- 10400420
TI  - Induction of apoptosis and differentiation by fludarabine in human leukemia cells
      (U937): interactions with the macrocyclic lactone bryostatin 1.
AB  - We have examined interactions between the purine nucleoside analog fludarabine (9
      beta-arabinofuranosyl-2-fluoroadenine) and the macrocyclic lactone bryostatin 1
      in the human monocytic leukemic cell line U937. Fludarabine exerted dose
      dependent effects on U937 cell viability and growth which were associated with
      both induction of apoptosis, as well as cellular maturation. Incubation of cells
      with bryostatin 1 (10 nM; 24 h) after, but not before a 6-h exposure to 10 microM
      fludarabine resulted in a modest but significant increase in apoptosis, and was
      associated with greater than a 1 log reduction in clonogenicity. Subsequent
      exposure to bryostatin 1 also increased the percentage of fludarabine-treated
      cells displaying differentiation-related features (eg plastic adherence, CD11b
      positivity) compared to cells exposed to fludarabine alone. Bryostatin 1 did not
      increase the retention of the active fludarabine metabolite, F-ara-ATP, nor did
      it increase 3H-F-ara-A incorporation into DNA. Despite its capacity to trigger
      cellular maturation, fludarabine exposure (either with or without bryostatin 1)
      failed to induce the cyclin-dependent kinase inhibitors (CDKls) p21WAF1/CIP1 and
      p27KIP1. Nevertheless, dysregulation of p21 (resulting from stable transfection
      of cells with a p2lWAF1/CIP1 antisense construct) reduced fludarabine-mediated
      differentiation, while inducing a corresponding increase in apoptosis. Enforced
      expression of Bcl-2 partially protected cells from fludarabine-related apoptosis,
      an effect that was overcome, in part, by subsequent exposure of cells to
      bryostatin 1. Interestingly, Bcl-2-overexpressing cells were as or in some cases,
      more susceptible to differentiation induction by fludarabine (+/- bryostatin 1)
      than their empty vector-containing counterparts. Collectively, these results
      indicate that the antiproliferative effects of fludarabine toward U937 leukemic
      cells involve both induction of apoptosis and cellular maturation, and that each
      of these processes may be enhanced by bryostatin 1.

PMID- 10400421
TI  - Caspase-3-like activity is necessary but not sufficient for daunorubicin-induced
      apoptosis in Jurkat human lymphoblastic leukemia cells.
AB  - In the present study we have shown that the cancer therapeutic drug,
      daunorubicin, induces apoptosis in the human lymphoblastic leukemia cell line
      Jurkat E6.1. This effect was both dose-and time-dependent with nuclear
      fragmentation detectable by 8 h. Caspases have been implicated in pro-apoptotic
      events. By utilizing synthetic fluorochrome-linked substrates of the caspases, we
      observed that a caspase-3-like enzyme had dramatically increased activity (3340
      130% with respect to basal levels) in response to daunorubicin treatment.
      Furthermore, by using an inhibitor to caspase-3, Ac-DEVD-CHO, we have shown that
      activation of a caspase-3-like enzyme appears to be necessary for nuclear
      fragmentation and apoptotic body formation, but is not required for chromatin
      condensation. In contrast, a general caspase inhibitor, Z-VAD-fmk, inhibited all
      apoptotic parameters measured. Ceramide has been implicated in daunorubicin
      induced apoptosis in human myeloid leukemia cells. However, in Jurkat cells,
      caspase activation does not appear to be a consequence of ceramide generation
      since, although ceramide levels were elevated through the action of ceramide
      synthase in response to daunorubicin treatment, this occurred with slower
      kinetics than either nuclear fragmentation or caspase activation. In contrast,
      caspase inhibitors abrogated ceramide elevation induced by DNR treatment,
      suggesting that ceramide synthase may be a downstream target for caspase action.
      Therefore, daunorubicin-induced apoptosis does not appear to be mediated by
      ceramide in the lymphoblastic leukemia cell line, Jurkat E6.1. Instead, caspase 3
      activity appears to be necessary, but not sufficient for this process.

PMID- 10400423
TI  - Human acute myeloid leukemia cells with internal tandem duplications in the Flt3
      gene show reduced proliferative ability in stroma supported long-term cultures.
AB  - Recently, in-frame internal tandem duplications have been reported within the
      regions coding for the juxtamembrane through the first tyrosine kinase domain of
      the Flt3 gene. These duplications have been reported to lead to
      autophosphorylation of the receptor. In this study we investigated the effect of
      such mutations in the Flt3 gene on the in vitro proliferation of human acute
      myeloid leukemia cells. The mutations were detected in 10 out of 59 AML bone
      marrow samples analyzed and were not restricted to a specific FAB class or
      cytogenetic aberration. PCR analysis of those samples showed all mutations to be
      present in exon 11 of the gene. Whilst samples without a mutation of the Flt3
      gene showed an increased cell production in response to either IL-3 and G-CSF or
      IL-6, SCF, TPO and Flt3L in long-term stroma supported cultures, mutant samples
      failed to do so. As we could not find a relationship between the absence of a
      response and either FAB class or cytogenetic aberrations, we interpret these
      results as an indication that the internal tandem duplications in the Flt3 gene
      are the prime cause of this unresponsiveness. Although our study does not explain
      the mechanism by which these mutations cause this unresponsiveness it does
      suggest that AML cells need a wild-type Flt3 for optimal in vitro proliferation.

PMID- 10400422
TI  - Tissue factors on acute promyelocytic leukemia and endothelial cells are
      differently regulated by retinoic acid, arsenic trioxide and chemotherapeutic
      agents.
AB  - The aberrant expression of tissue factor (TF) in acute promyelocytic leukemia
      (APL) cells has been implicated in the pathogenesis of the APL coagulopathy. In
      this study, we found that in APL patients receiving ATRA or As2O3 treatment, the
      improvement in hypercoagulobility and hyperfibrinolysis paralleled the correction
      of plasma fibrinogen level and amelioration of bleeding symptoms. Notably,
      clinical improvement was also correlated to ATRA/As2O3-induced rapid decrease of
      membrane procoagulant activity (PCA) and TF contents of APL blasts. Consistent
      with the in vivo findings, the membrane PCA, TF antigen and its mRNA level within
      NB4 cells were rapidly down-regulated by 1 microM ATRA or As2O3, while 0.2
      microg/ml DNR increased these TF parameters prior to its effect upon apoptosis
      induction. The down-regulation of TF mRNA by ATRA was partially de novo protein
      synthesis-dependent and at least partially attributed to a mechanism of
      destabilizing TF mRNA. On the other hand, in addition to its modulation on mRNA,
      As2O3 could also induce an accelerated TF protein turnover. These distinct
      effects were corroborated with the properties of these agents in causing the
      degradation of PML-RARalpha protein. All three therapeutic agents, however,
      enhanced the potential of NB4 cells to stimulate the expression of TF and PCA in
      endothelium. Taken together, our data suggest that the rapid and distinct
      regulation of TF on APL cells by these therapeutic agents might at least
      partially contribute to their effects on APL coagulopathy.

PMID- 10400424
TI  - Factor(s) secreted by AFT024 fetal liver cells following stimulation with human
      cytokines are important for human LTC-IC growth.
AB  - Soluble factors produced by human marrow stroma or the murine marrow derived M2
      10B4 cell line support ex vivo maintenance for 5-8 weeks of 50% of human long
      term culture initiating cells (LTC-IC). As the AFT024 cell line supports LTC-IC
      cultured in contact conditions better than M2-10B4 feeders, we evaluated LTC-IC
      support in non-contact conditions above AFT024 feeders. We show that only 15% of
      LTC-IC were maintained for 5 weeks in AFT024 non-contact cultures (n=6, P<0.05).
      As AFT024-conditioned media added to M2-10B4 non-contact cultures did not inhibit
      LTC-IC maintenance, AFT024 cells do not secrete factors that inhibit LTC-IC
      growth. We next characterized heparan sulfate glycosaminoglycans (HS-GAGs) and
      cytokines produced by AFT024 cells, which are both required for LTC-IC
      maintenance in M2-10B4 non-contact cultures. The size and extent of O-sulfation
      of HS-GAGs in AFT024 and M2-10B4 conditioned medium were similar, indicating that
      absence of hematopoietic specific HS-GAGs is not responsible for the lack of
      hematopoietic in AFT024 non-contact cultures. Levels of 13 different cytokines
      secreted in AFT024- and M2-10B4-conditioned medium were similar. However,
      addition of human SCF, G-CSF, GM-CSF, LIF, MIP-1alpha and IL-6 in concentrations
      found in human marrow stroma-conditioned medium to AFT024 non-contact cultures
      increased LTC-IC-maintenance to 72% at 5 weeks. These cytokines improved LTC-IC
      maintenance in part through interaction with the progenitors and in part, through
      interaction with the AFT024 feeder. Thus, although LTC-IC maintenance is poor in
      AFT024 non-contact cultures, addition of human cytokines enhances LTC-IC
      maintenance in part through indirect effects on the AFT024 feeder.
      Characterization of known or novel growth factors secreted by AFT024 cells before
      and after cytokine stimulation may lead to the identification of cytokines that
      support growth of human hematopoietic stem cells.

PMID- 10400425
TI  - Primary diffuse large B cell lymphoma of the stomach: analysis of somatic
      mutations in the rearranged immunoglobulin heavy chain variable genes indicates
      antigen selection.
AB  - Gastric low grade MALT lymphomas show a pattern of somatic mutations in their
      rearranged immunoglobulin genes, indicative of antigen selection. This provides
      evidence for antigen stimulation in the lymphomagenesis. Gastric diffuse large B
      cell lymphomas develop secondary to low grade MALT lymphoma or de novo. To study
      whether antigen-selection is also a feature of primary diffuse large B cell
      lymphomas, we analysed somatic mutations in the rearranged immunoglobulin heavy
      chain (IgH) variable genes (VH). The rearranged VH genes of six cases of gastric
      primary diffuse large B cell lymphoma were amplified from genomic or
      complementary DNA by a VH gene family-specific polymerase chain reaction method.
      The PCR products were directly sequenced and were compared to published germline
      sequences to analyse somatic mutations. Similarly to low grade MALT lymphomas 5/6
      primary diffuse large B cell lymphomas show a pattern of somatic mutation in
      their rearranged VH genes, indicative of antigen selection and suggesting a role
      for antigens in lymphomagenesis. One case showed bi-allelic VH gene
      rearrangements, which were non-functional due to extensive deletions. Antigen
      selection could not be demonstrated or excluded. Antigen selection is a common
      feature in most analysed primary diffuse large B cell lymphomas, although some
      heterogeneity in the mechanisms involved in the lymphomagenesis of gastric
      primary diffuse large B cell lymphomas has not been excluded entirely (case 4).

PMID- 10400427
TI  - Isolation and characterisation of recombination events involving immunoglobulin
      heavy chain switch regions in multiple myeloma using long distance vectorette PCR
      (LDV-PCR).
AB  - Immunoglobulin class switching occurs as a result of recombination between pairs
      of switch region sequences located 5' to each constant heavy chain gene except
      Cdelta. In the B cell neoplasm multiple myeloma, tumour cells have generally
      undergone class switching and often contain oncogenic sequences translocated into
      switch regions, presumably as a result of aberrant switch recombination. We have
      developed a method (LDV-PCR) which combines long distance PCR with one-sided
      vectorette PCR that is capable of detecting and isolating both normal and
      aberrant switch recombination breakpoints from multiple myeloma cell lines and
      primary multiple myeloma tumour material. Using LDV-PCR we have directly cloned
      the translocation breakpoints present in two multiple myeloma cell lines and
      isolated a normal productive switch recombination event from a primary tumour.
      Furthermore, we have isolated a novel translocation t(14;22)(q32;q12) from a
      primary tumour sample and have demonstrated that internal deletions within switch
      regions can occur in multiple myeloma cells. Compared to a Southern blotting
      approach, LDV-PCR is simpler and more rapid to perform, allows the simultaneous
      detection and isolation of recombination events, and can also be applied to
      amounts of DNA which are too low to permit the conventional cloning of
      recombination breakpoints.

PMID- 10400426
TI  - Immunoglobulin V region gene use and structure suggest antigen selection in AIDS
      related primary effusion lymphomas.
AB  - Primary effusion lymphoma (PEL) is a lymphoproliferation of B cells infected by
      Kaposi's sarcoma-associated herpes-virus/human herpesvirus-8 and reflecting a
      late stage of B cell differentiation close to plasma cell. Apart from viral
      infection, the pathogenesis of PEL is currently unclear. The aim of the present
      study was to investigate the role of antigen stimulation and selection in the
      evolution of PEL. In order to assess the specific variable heavy (VH) and light
      (VL) genes used by PEL and to define the heavy and light chain isotypes expressed
      by these lymphomas, immunoglobulin (Ig) genes from seven AIDS-related PEL were
      sequenced (three cell lines and four primary samples). Most of the samples (five
      out of seven) used lambda light chain genes; the majority of these (n = 4)
      belonged to the V lambda 3 family. Two cases expressed mu chains, whereas gamma
      chains were found in two cases. In all cases, significant deviations from the
      presumed germline counterpart were found in both the expressed VH and VL genes.
      Statistical evidence for antigen selection was evident in four out of seven
      samples studied. Evidence for selection was more frequent in the light chain
      genes than in the heavy chain genes. Collectively, these data indicate that PEL
      originate from mature, antigen-experienced B cells and bear implications for the
      pathogenesis and histogenesis of this lymphoma.

PMID- 10400428
TI  - Are the mentally ill dangerous?
AB  - The author reviews studies that address the question, "Are the mentally ill
      dangerous?" She points out that as psychiatrists, we have the responsibility of
      evaluating the mentally ill and making judgments about their dangerousness that
      may restrict their civil liberties. Therefore, the more practical question for us
      is: "Which mentally ill, under what circumstances, are dangerous?" She discusses
      data from her research group and others that show that short-term predictions of
      violence can be relatively accurate, that we are better at predicting violence
      for some patients than for others, that specific symptom patterns in the acute
      phase of illness are related to violent acts, that the most likely victims of
      violence by decompensating psychiatric patients are caretakers rather than
      strangers, and that a history of violence, co-morbid substance abuse, and
      treatment noncompliance are related to a higher risk of violence in psychiatric
      patients.

PMID- 10400429
TI  - The litigant-patient: mental health consequences of civil litigation.
AB  - Civil litigation often has profound psychological consequences for plaintiffs and
      defendants alike. For those individuals who are involved in ongoing
      psychotherapy, or those who enter psychotherapy during litigation, the stress of
      litigation often adds to whatever issues produced the lawsuit. This article
      reviews the effects of that stress, the mechanisms through which it arises, and
      its manifestations in psychotherapy and offers suggestions to increase
      psychotherapist awareness of the influence of litigation stress on treatment.

PMID- 10400430
TI  - Offender and offense characteristics of a nonrandom sample of mass murderers.
AB  - A nonrandom sample (N = 30) of mass murderers in the United States and Canada
      during the past 50 years was studied. Data suggest that such individuals are
      single or divorced males in their fourth decade of life with various Axis I
      paranoid and/or depressive conditions and Axis II personality traits and
      disorders, usually Clusters A and B. The mass murder is precipitated by a major
      loss related to employment or relationship. A warrior mentality suffuses the
      planning and attack behavior of the subject, and greater deaths and higher
      casualty rates are significantly more likely if the perpetrator is psychotic at
      the time of the offense. Alcohol plays a very minor role. A large proportion of
      subjects will convey their central motivation in a psychological abstract, a
      phrase or sentence yelled with great emotion at the beginning of the mass murder;
      but in our study sample, only 20 percent directly threatened their victims before
      the offense. Death by suicide or at the hands of others is the usual outcome for
      the mass murderer.

PMID- 10400431
TI  - Sexual burglaries and sexual homicide: clinical, forensic, and investigative
      considerations.
AB  - Burglary, the third most common crime after larceny-theft and motor vehicle
      theft, is rarely the focus of forensic psychiatric study. While most burglaries
      are motivated simply by material gain, there is a subgroup of burglaries fueled
      by sexual dynamics. The authors differentiate two types of sexual burglaries: 1)
      fetish burglaries with overt sexual dynamics; and 2) voyeuristic burglaries, in
      which the sexual element is often covert and far more subtle. Many forensic
      practitioners have informally noted the relationship of burglaries to sexual
      homicide, but this relationship has not otherwise been studied in any detail. In
      this article, the incidence of (sexual) burglaries by 52 sexual murderers whom
      the authors evaluated, as well as the incidence in cases reported by others, is
      reported. Implications of these findings for forensic assessments and profiling
      of unidentified offenders are discussed.

PMID- 10400432
TI  - Explaining lifetime criminal arrests among clients of a psychiatric probation and
      parole service.
AB  - This study examines the extent to which sociodemographic characteristics,
      clinical characteristics, substance abuse problems, and the array of lifetime
      criminal behavior may explain lifetime arrests among offenders supervised by the
      psychiatric probation and parole service. Three hundred twenty-five clients with
      new cases at a psychiatric probation and parole service in a large urban center
      were screened for major psychiatric disorders. They were also interviewed for
      socio-demographic characteristics, mental health treatment history, criminal
      behavior, and arrest history. Hierarchical block multiple regression analysis
      tested a model explaining lifetime arrests. After controlling for age and other
      demographic variables, the number of lifetime psychiatric hospitalizations and
      lifetime occurrences of mania diagnosis significantly explained lifetime arrests.
      The total model explained about 10 percent of the variance in lifetime arrests
      after controlling for opportunity variables, which explained 45 percent. The
      explanatory power of lifetime hospitalizations and mania support the contention
      that symptoms, rather than diagnosis, may be the most important clinical factor
      in explaining criminal arrest among persons with mental illness. Implications for
      psychiatric services include the development of effective jail diversion
      programs.

PMID- 10400433
TI  - Relation between command hallucinations and dangerous behavior.
AB  - This article presents an updated review of studies on the relation between
      command hallucinations and dangerous behavior. The author reviewed all studies
      published between 1966 and 1997 according to MEDLINE and between 1974 and 1997
      according to PSYCLIT. Forty-one studies were found, of which 82.9 percent dealt
      with the relation between command hallucinations and dangerous behavior. Of these
      studies, 32.3 percent were controlled, and they were grouped into three partially
      overlapping classes: those concerned with violent behavior, those concerned with
      suicidal behavior, and those concerned with mediating variables. Most of these
      studies agreed on the non-existence of an immediate relation between command
      hallucinations and dangerous (violent or suicidal) behavior. Even though the
      studies were divided about the existence of a relation between
      severity/dangerousness of command content and compliance with the commands, there
      was agreement about the existence of a direct relation between compliance with
      commands and both benevolence and familiarity of commanding voice. It seems that
      the research and knowledge available to date on this subject is both scant and
      methodologically weak. Future study should probably concentrate on mediating
      factors, such as appraisal and coping attitudes and behaviors.

PMID- 10400434
TI  - A typology of patients admitted to a forensic psychiatric hospital from
      correctional settings.
AB  - A typology of inmates and pretrial detainees admitted to a secure forensic
      psychiatric hospital was developed using the referral or adjustment problem at
      the correctional setting as the classifying variable. An eight-group typology was
      derived along with a description of each type's demographic, criminal,
      psychiatric, and institutional characteristics. Although the typology appears to
      be centered primarily on the characteristics of the inmate, closer examination
      reveals that the resulting schema is more accurately a description of the types
      of problems presented by the inmate within the correctional setting. From this
      perspective, the typology is a classification of referral problems that likely
      says as much about the referring institution as it does about the subject of the
      referral. Each group within the typology is based on an interaction representing
      a "poor fit" between the inmate and the institution. Each type of patient problem
      is described, and various solutions aimed toward improving the fit between the
      inmate and the setting are discussed.

PMID- 10400435
TI  - Thirty years and still growing.
AB  - In the 30 years since the founding of the American Academy of Psychiatry and the
      Law in 1969, there has been a tremendous growth in the organization as well as in
      the number of psychiatrists who have a subspecialty of forensic psychiatry. In an
      attempt to explain this exponential growth, the author looks at the many social,
      economic, medical, and legal activities that were active during these years.

PMID- 10400436
TI  - Old duties and new: recovered memories and the question of third-party liability.
AB  - This article addresses how courts have analyzed the question of third-party
      liability in a class of cases that has recently challenged settled law. In these
      cases a patient recovers apparent memories of sexual abuse during the course of a
      therapy. Based on these memories and perhaps with the therapist's aid and
      encouragement, the patient identifies a family member as the perpetrator, often
      in a legal or other public forum. The accused family member then brings a lawsuit
      against the therapist for negligent treatment of the patient. The legal question
      to be determined is whether the therapist owes a duty of care to the third-party
      family member. The article first examines the concept of duty from a historical
      perspective. The article next looks at the method of analysis courts have used to
      approach the question of third-party liability in recovered memory cases. The
      article's third section examines how several state courts have applied this
      analysis to actual cases. Finally, the article evaluates the most compelling
      arguments on both sides of the issue and raises additional arguments suggested by
      the state court analyses.

PMID- 10400437
TI  - Canadian landmark case: Regina v. Swain: translating M'Naughton into twentieth
      century Canadian.
AB  - Since their adoption in 1892, the insanity laws in the Criminal Code of Canada
      have utilized a modified M'Naughton rule. The Department of Justice began work in
      the 1970s to update these laws. In 1983, soon after the Canadian Charter of
      Rights and Freedoms was proclaimed, the case of Regina v. Swain provided the
      impetus for this change. In 1990 the Supreme Court of Canada struck down the old
      law, giving parliament a specific time to pass new legislation. Bill C-30
      modernized the language of the Criminal Code and introduced a number of
      procedural safeguards to protect the rights of the accused.

PMID- 10400438
TI  - Emerich v. Philadelphia Center for Human Development: The new duty to warn in
      Pennsylvania.

PMID- 10400439
TI  - Tardive dyskinesia: tremors in law and medicine.

PMID- 10400440
TI  - Posttraumatic polarization in psychiatry and law.
AB  - Psychological trauma heightens and rigidifies the penchant of humans for
      dichotomizing others into allies and enemies. With today's "adult delayed recall"
      controversy a case in point, traumatized individuals tend to unite into tightly
      knit in-groups that resemble cults and to denigrate others as enemies. This
      process creates new enmities where objective interests otherwise clash only
      minimally. The trauma response is reinforced by the neurobiology of avoidance and
      reenactment. Among all protagonists, polarized beliefs are mutually shaped by
      suggestive interactions that resemble hypnosis. The end result is to reenact and
      perpetuate the trauma response on a large scale. In the contemporary milieu, this
      process presents a formidable obstacle to cooperative problem solving. Discussion
      focuses on strategies by which clinical and forensic psychiatrists can help to
      master this obstacle. These strategies include balancing interests, extending the
      role of informed consent, and overall, striving to mitigate the unwitting
      reinforcement and transmission of the trauma response.

PMID- 10400441
TI  - Videotaping of forensic psychiatric evaluations. AAPL Task Force. American
      Academy of Psychiatry and the Law.

PMID- 10400442
TI  - A kinetic study on benzoic acid pungency and sensory attributes of benzoic acid.
AB  - Aqueous solutions of benzoic acid (BA) were evaluated by two methods: (i) sensory
      profile: a descriptive test of sensory attributes combined with semiquantitative
      analysis; and (ii) pungency intensity measures as a function of time: a
      computerized recording using specific software. Kinetic parameters evaluated were
      maximal intensity (I(MAX)), total time of pungency (Ttot), rates of increase (V1)
      and decrease (V2), half-life (T1/2), area under curve (AUC) and time to maximal
      intensity (T(IMAX)). Results were analyzed by ANOVA, LSD test, iterative
      calculations and adjustment to equations according to mathematical models,
      regression analysis, principal component analysis (PCA) and clusters analysis.
      Pungency was the main sensory attribute of BA (3-36 mM) in the tongue and
      epiglottis. The seven kinetic parameters showed concentration-dependency (P <
      0.001) and were described by different functions: (i) lineal: I(MAX) = 2.24 +/-
      0.14C - 3.06 +/- 2.58, R2 = 0.98; T(IMAX) = 0.19 +/- 0.02C + 6.87 +/- 0.47, R2 =
      0.92; V1 = 0.68 +/- 0.03C + 0.10 +/- 0.69, R2 = 0.99; AUC = 49.10 +/- 3.17C -
      230.78 +/- 59.66, R2 = 0.98; (ii) potency: T1/2 = 6.62 +/- 0.61C(0.39+/-0.03), R2
      = 0.97; V2 = 1.07 +/- 0.11C(0.53+/-0.04), R2 = 0.98; Ttot = 8.08 +/- 1.01C(0.43+/
      0.04), R2 = 0.96. PCA revealed high correlation between (i) T(IMAX) and Ttot;
      (ii) T1/2 and V2; and (iii) I(MAX) and V1. Stimuli grouped across three main
      clusters: (i) 3 and 6 mM; (ii) 9, 12 and 18 mM; and (iii) 24 and 36 mM. Maximal
      pungency intensity best correlated with both concentration and persistence among
      kinetic parameters. Prototypical prickling of BA was observed at 12 and 18 mM.

PMID- 10400443
TI  - Immunohistochemical localization of carbonic anhydrase isozyme II in the
      gustatory epithelium of the adult rat.
AB  - The distribution of carbonic anhydrase isozyme II (CA II)-like immunoreactivity (
      LI) in the gustatory epithelium was examined in the adult rat. In the
      circumvallate and foliate papillae, CA II-LI was observed in the cytoplasm of the
      spindle-shaped taste bud cells, with weak immunoreaction in the surface of the
      gustatory epithelium. No neuronal elements displayed CA II-LI in these papillae.
      There was no apparent difference in the distribution pattern between the anterior
      and posterior portions of the foliate papillae. In immunoelectron microscopy,
      immunoreaction products for CA II were diffusely distributed in the entire
      cytoplasm of the taste bud cells having dense round granules at the periphery of
      the cells. No taste bud cells displaying CA II-LI were detected in the fungiform
      papillae, but a few thick nerve fibers displayed CA II-LI. In the taste buds of
      the palatal epithelium, neither taste bud cells nor neuronal elements exhibited
      CA II-LI. The present results indicate that CA II was localized in the type I
      cells designated as supporting cells in the taste buds located in the posterior
      lingual papillae of the adult animal.

PMID- 10400444
TI  - Olfactory discrimination ability for homologous series of aliphatic alcohols and
      aldehydes.
AB  - We tested the ability of human subjects to distinguish between members of
      homologous series of aliphatic alcohols (ethanol to n-octanol) and aldehydes (n
      butanal to n-decanal). In a forced-choice triangular test procedure 20 subjects
      per series were repeatedly presented with all 21 binary combinations of the seven
      stimuli and asked to identify the bottle containing the odd stimulus. We found
      (i) that as a group, the subjects performed significantly above chance level in
      all tasks but two with the alcohols and all tasks but four with the aldehydes,
      and thus were clearly able to discriminate between most of the odor pairs
      presented; (ii) marked interindividual differences in discrimination performance,
      ranging from subjects who were able to significantly distinguish between all 21
      odor pairs of a series to subjects who failed to do so with the majority of
      tasks; and (iii) a significant negative correlation between discrimination
      performance and structural similarity of odorants in terms of differences in
      carbon chain length for both homologous series. This suggests that carbon chain
      length may be one of presumably several determinants of the interaction between
      stimulus molecule and receptor, and thus may be a molecular property affecting
      odor quality of aliphatic alcohols and aldehydes.

PMID- 10400445
TI  - Some taste molecules and their solution properties.
AB  - The solution properties of a variety of different sapid substances from all four
      basic taste modalities, namely, sweet (n = 24), salty (n = 7), sour (n = 11) and
      bitter (n = 2), have been investigated. Some multisapophoric molecules, i.e.
      molecules exhibiting more than one taste, have also been included in the study in
      an attempt to define their properties in relation to the tastes they exhibit;
      eight sweet-bitter and three salty-bitter molecules were used. The density and
      sound velocity of their solutions in water have been measured and their apparent
      volumes, apparent compressibilities and compressibility hydration numbers
      calculated and compared. Apparent molar volumes (phi(v)) and apparent specific
      volumes (ASV) reflect the state of hydration of the molecules, and thus their
      extent of interaction with water structure. The range of ASVs reported are 0.13
      0.49 cm3/g for salty molecules, 0.55-0.68 cm3/g for sweet molecules, 0.53-0.88
      cm3/g for sweet-bitter molecules and a much wider range (0.16-0.85 cm3/g) for
      sour molecules. Isentropic apparent specific compressibilities range from -2.33 x
      10(-5) to -8.06 x 10(-5) cm3/g x bar for salty molecules, -3.38 x 10(-7) to -2.34
      x 10(-5) cm3/g x bar for sweet molecules, +6.35 x 10(-6) to -2.22 x 10(-5) cm3/g
      x bar for sweet-bitter molecules and +6.131 x 10(-6) to -2.99 x 10(-5) cm3/g x
      bar for sour molecules. Compressibility hydration numbers are also determinable
      from the measurements of isentropic compressibilities and these reflect the
      number of water molecules that are disturbed by the presence of the solutes in
      solution. This study also shows that it is possible to group isentropic apparent
      molar compressibility values by the taste quality exhibited by the molecules in
      the same order as for ASV.

PMID- 10400446
TI  - Perception of sweetness in simple and complex taste stimuli by adults and
      children.
AB  - Currently, there is little information on the ability of children to analyse
      complex chemosensory stimuli in terms of the presence and magnitude of the
      components. The present study investigates this question by comparing the ability
      of 95 adults and 8- to 9-year-olds to estimate the sweetness of several
      concentrations of sucrose in water and in three foods, namely, orange drink,
      custard and shortbread biscuits, using a magnitude estimation procedure. The
      results indicated that similar response functions were produced by adults and
      children for the sweetness of aqueous solutions of sucrose, custard and biscuits,
      but not for orange juice, where the functions produced by both female and male
      children were significantly flatter than those of the adults. Stimulus context
      may have influenced the ratings of children in the no-sucrose and highest sucrose
      concentration conditions with two of the foods. The absence of differences
      between the response functions of the female and male children with all types of
      stimuli indicated that gender had no influence on their responses. It is
      concluded that, at mid-childhood, humans are capable of estimating the sweetness
      of sucrose in foods, but that they have a tendency to limit the range of numbers
      used in their estimates of sweetness at high concentrations of sucrose in some
      foods.

PMID- 10400447
TI  - Induction of estrus in grouped female mice (Mus domesticus) by synthetic
      analogues of preputial gland constituents.
AB  - Two major volatile constituents of the male mouse preputial gland, E,E-alpha
      farnesene and E-beta-farnesene, were examined for their role in inducing estrous
      cycles in grouped female mice. The results indicated that the mixture of the
      farnesenes was as effective as the homogenate of the intact preputial gland,
      while the extract of the castrate preputial tissue did not show a pronounced
      response.

PMID- 10400448
TI  - Protein kinase Cbeta and delta selectively phosphorylate odorant and metabotropic
      glutamate receptors.
AB  - Recombinant protein segments from a metabotropic glutamate receptor and from an
      odorant receptor were used as substrates in protein kinase C phosphorylation
      assays. Protein kinase Cbeta and delta phosphorylated an intracellular consensus
      phosphorylation site in the metabotropic glutamate receptor. Only protein kinase
      Cdelta phosphorylated a novel extracellular consensus phosphorylation site in the
      odorant receptor. These results suggest differential regulation of these
      receptors by protein kinase C isotypes.

PMID- 10400449
TI  - Responses of single taste fibers and whole chorda tympani and glossopharyngeal
      nerve in the domestic pig, Sus scrofa.
AB  - Whole nerve, as well as single fiber, responses in the chorda tympani proper (CT)
      and glossopharyngeal (NG) nerves of 1- to 7-week-old pigs were recorded during
      taste stimulation. In the CT acids and in the NG bitter compounds gave the
      largest responses. Both nerves exhibited large responses to monosodium glutamate
      (MSG), MSG with guanosine 5'-monophosphate (GMP) and MSG with inositine 5'
      monophosphate (IMP) as well as to glycine, xylitol, sucrose, fructose and
      glucose. Alitame, aspartame, betaine, neohesperedin dihydrochalcone (NHDHC),
      super-aspartame, saccharin and thaumatin elicited no or little response.
      Hierarchical cluster analysis of 49 CT fibers separated four major clusters. The
      M cluster, comprising 28.5% of all fibers, is characterized by strong responses
      to MSG, KCl, LiCl and NaCl. The responses to NaCl and LiCl were unaffected by
      amiloride. The H cluster (24.5%) includes units responding principally to acids.
      The Q cluster (18.5%) responds to quinine hydrochloride (QHCl), sucrose
      octaacetate (SOA) and salts with amiloride. The S cluster (28.5%) exhibits strong
      responses to xylitol, glycine and the carbohydrates as well as to MSG alone and
      to MSG with GMP or IMP. In 31 NG fibers, hierarchical cluster analysis revealed
      four clusters: the M cluster (10%), responding to MSG and MSG with GMP or IMP;
      the H cluster (13%), responding to acids; the Q cluster (29%), responding
      strongly to QHCl, SOA and tilmicosinR; and the S cluster (48%), responding best
      to xylitol, carbohydrates and glycine but also to the umami compounds.
      Multidimensional scaling analysis across fiber responses to all stimuli showed
      the best separation between compounds with different taste qualities when
      information from both nerves was utilized.

PMID- 10400450
TI  - Odors: implicit memory and performance effects.
AB  - In order to assess the influence of odors on human performance and implicit
      memory for odors, 108 subjects completed a variety of tests in weakly scented
      (jasmine, lavender or odorless) rooms without having been made aware of the odor.
      After a 30 min interval the subjects were shown slides of different surroundings,
      including the room they had been in, and were requested to rate how well a set of
      12 odors, including a blank, would fit to these surroundings. Half of these
      contexts contained visual cues related to two of the presented odors (leather and
      coffee). After the rating of fit the subjects had to rate the odors for
      pleasantness, were asked to identify the odors with their correct names and to
      tell where and when they had last smelled these odors. One subject remembered
      smelling the odor (jasmine) in the room and was discarded from the analysis of
      the results for the rating of fit. None of the others reported recollection of
      the experimental odors. The results showed that in general jasmine had a negative
      and lavender a positive effect on test performance. If an odor-related visual cue
      was present in the context, the related odor was always rated highest in fit to
      that context. Furthermore, the subjects working in rooms with an odor
      subsequently assigned this odor to the visual context of that room to a
      significantly higher degree than subjects working in rooms with different odors.
      Since none of the subjects reported that they had smelled the odor in the rooms
      where performance testing took place, it was concluded that the memory for these
      odors was implicit. Further analysis showed that such memory was only found in
      subjects who were unable to supply the right name for the odor. The possible
      consequences of this latter finding for understanding the relationship between
      sensory (episodic) and semantic odor memory are discussed.

PMID- 10400451
TI  - Basic emotions evoked by eugenol odor differ according to the dental experience.
      A neurovegetative analysis.
AB  - Subjective individual experiences seem to indicate that odors may form strong
      connections with memories, especially those charged with emotional significance.
      In the dental field, this could be the case with the odorant eugenol, responsible
      for the typical clinging odor impregnating the dental office. The odor of eugenol
      could evoke memories of unpleasant dental experiences and, therefore, negative
      feelings such as anxiety and fear, since eugenates (cements containing eugenol)
      are used in potentially painful restorative dentistry. This hypothesis was tested
      by evaluating the emotional impact of the odor of eugenol through autonomic
      nervous system (ANS) analysis. The simultaneous variations of six ANS parameters
      (two electrodermal, two thermovascular and two cardiorespiratory), induced by the
      inhalation of this odorant, were recorded on volunteer subjects. Vanillin (a
      pleasant odorant) and propionic acid (an unpleasant one) served as controls.
      After the experiment, subjects were asked to rate the pleasantness versus
      unpleasantness of each odorant on an 11-point hedonic scale. The patterns of
      autonomic responses, obtained for each odorant and each subject, were transcribed
      into one of the six basic emotions defined by Ekman et al. (happiness, surprise,
      sadness, fear, anger and disgust). Results were compared between two groups of
      subjects divided according to their dental experience (fearful and non-fearful
      dental care subjects) and showed significant differences only for eugenol. This
      odorant was rated as pleasant by non-fearful dental subjects but unpleasant by
      fearful dental subjects. The evoked autonomic responses were mainly associated
      with positive basic emotions (happiness and surprise) in non-fearful dental
      subjects and with negative basic emotions (fear, anger, disgust) in fearful
      dental subjects. These results suggest that eugenol can be responsible for
      different emotional states depending on the subjects' dental experience, which
      seems to confirm the potential role of odors as elicitors of emotional memories.
      This study also supports the possible influence of the ambient odor impregnating
      the dental office, strengthening a negative conditioning toward dental care in
      some anxious patients.

PMID- 10400452
TI  - Odor identification, consistency of label use, olfactory threshold and their
      relationships to odor memory over the human lifespan.
AB  - The purpose of this study was to investigate olfactory threshold, odor
      identification, consistency of label use and their relationships to odor memory
      in the context of semantic/episodic memory across the human lifespan. A total of
      137 subjects aged 4-90 years were tested with several olfactory test procedures.
      We found that olfactory sensitivity was well developed in children despite the
      finding that their odor naming and odor memory were inferior to that of adults.
      In the elderly population, olfactory functions gradually declined, with odor
      memory and odor identification demonstrating the most significant decline.
      Semantic encoding was differentially related to odor memory over the human age
      span. Whereas consistency of label use was the main predictor for odor memory in
      children and young adults, olfactory identification ability was the main
      predictor in the elderly study group. We also calculated response bias for the
      separate age groups and found no differences between children, young adults and
      elderly. However, with age false alarm rates increased. We conclude that children
      possess equal olfactory sensitivity compared with adults; however, due to
      limitations in linguistic capabilities and familiarity to odorants, odor memory
      and odor identification performance was limited. Additionally, our data indicate
      major alterations of olfactory processing in advanced age with substantial losses
      in odor memory and odor identification performance.

PMID- 10400453
TI  - Implicit testing of odor memory: instances of positive and negative repetition
      priming.
AB  - The study provides a test and evaluation of a new repetition priming procedure
      designed to solve problems in investigating olfactory-specific priming. Although
      the results did not reveal any overall priming effect, a post-hoc analysis showed
      that incorrectly identified odors were more quickly processed than control odors,
      whereas correctly identified odors were processed more slowly These results are
      discussed and interpreted as instances of positive and negative repetition
      priming respectively.

PMID- 10400454
TI  - Antioxidant actions of plant foods: use of oxidative DNA damage as a tool for
      studying antioxidant efficacy.
AB  - Plant-food-derived antioxidants and active principles such as flavonoids,
      hydroxycinnamates (ferulic acid, chlorogenic acids, vanillin etc.), beta-carotene
      and other carotenoids, vitamin E, vitamin C, or rosemary, sage, tea and numerous
      extracts are increasingly proposed as important dietary antioxidant factors. In
      this endeavor, assays involving oxidative DNA damage for characterizing the
      potential antioxidant actions are suggested as in vitro screens of antioxidant
      efficacy. The critical question is the bioavailability of the plant-derived
      antioxidants.

PMID- 10400455
TI  - The influence of alpha-amanitin on the NaCl-induced up-regulation of antioxidant
      enzyme activity in cotton callus tissue.
AB  - Liquid suspensions of cotton callus tissue from a NaCl-sensitive cell line and a
      NaCl-tolerant cell line were subjected to the following treatments: (a) 0 and 150
      mM NaCl, respectively (controls); (b) 75 and 250 mM NaCl, respectively; (c) 100
      ng ml(-1) alpha-amanitin; or (d) pretreatment for 2 h with 100 ng ml(-1) alpha
      amanitin followed by the respective NaCl treatments. The callus tissue was
      harvested at 0, 0.5, 1, 2, 4, and 8h and analyzed for antioxidant enzyme
      activity. In the NaCl-tolerant callus, the 250 mM NaCl treatment resulted in
      transient 2- to 4-fold increases above the control levels in the activities of
      ascorbate peroxidase, catalase, glutathione reductase, and peroxidase within 1 h
      after treatment, while superoxide dismutase activity increased 4-fold within 4 h.
      This rapid increase suggests that the up-regulation of antioxidant capacity is an
      early response to NaCl stress and perhaps provides protection against oxidative
      damage until other acclimating mechanisms can be invoked. In the control callus,
      peroxidase activity remained unchanged, and significant increases in the other
      enzymes were not observed until 8 h after treatment with 75mM NaCl. Pre-treatment
      with alpha-amanitin prior to the NaCl treatment completely inhibited the NaCl
      induced increase in the activities of all five enzymes in both cell lines. This
      data supports the conclusion that the NaCl-induced up-regulation of antioxidant
      enzyme activity in cotton callus tissue is transcriptionally regulated,
      proceeding via a de novo synthesis of poly(A)+RNA and is not due to the
      translation of existing transcripts or the mobilization of existing enzyme pools.
      In addition, the results suggest that it is not only the up-regulation of
      antioxidant activity that bestows a degree of tolerance to environmental stress,
      but also the speed with which this response occurs.

PMID- 10400456
TI  - Chemical reactivity of the carbon-centered free radicals and ferrous iron in
      coals: role of bioavailable Fe2+ in coal workers pneumoconiosis.
AB  - Striking differences in the prevalence of coal workers' pneumoconiosis (CWP)
      exist between different coal mine regions. The major factors responsible for the
      observed regional differences in CWP have not yet been identified. In the present
      study, chemical reactivity of the carbon-centered free radicals in coals and lung
      tissues, as well as ferrous iron in the coals, were studied by ESR techniques.
      The ESR spectra clearly demonstrated the presence of at least two types of carbon
      centered free radical species, which might respectively attribute to the
      macromolecular phase and the molecular phase of coal. Grinding produced free
      radicals in coals. Exposure of freshly ground coal to air for 28 h induced a
      slight increase of free radicals for most of the coals, and a slight decrease
      after 4 months' exposure. The lung tissue samples of coal workers deceased of CWP
      showed similar ESR spectra as coal samples, and these radicals were highly stable
      in the lung. After incubation of coals with glutathione, hydrogen peroxide,
      sodium formate or oxygen, the coal sample from the Gardanne mine which has never
      induced CWP, and thus is the least hazardous coal, showed the most significant
      change in the carbon-centered free radical concentration. No significant changes
      were observed among other coals reported to induce CWP. On the other hand, we
      found that the coals released different amounts of Fe2+ in an acidic medium.
      Interestingly, the prevalence of CWP correlates positively with the released Fe2+
      content in these coals and with the amount of oxygen radicals produced by the
      interaction of Fe2+ with O2 in the acidified coal filtrates. Our studies indicate
      that the carbon-centered free radicals may not be biologically relevant to coal
      dust-induced pneumoconiosis, whereas the acid soluble Fe2+, which may be
      dissolved in the phagolysosomes of macrophages, can then lead to Fe2+-induced
      oxidative stress and eventual CWP development.

PMID- 10400457
TI  - Blood antioxidant status and urinary levels of catecholamine metabolites in beta
      thalassemia.
AB  - It has been reported that iron overload in beta-thalassemia leads to an enhanced
      generation of reactive oxygen species and to oxidative stress. We have studied
      the oxidant/antioxidant imbalance in the blood of 48 transfusion-dependent beta
      thalassemic patients (TLP) (17 males, 31 females, 11-22 year), under chelation
      therapy, and in 40 sex and age matched healthy controls (CTR). Plasma and
      lymphocyte levels of vitamin E (Vit E), ubiquinol (CoQ10H2), ubiquinone (CoQ10),
      plasma concentrations of vitamin A (Vit A), beta-carotene, lycopene, vitamin C
      (Vit C), total thiols, fatty acid patterns of phospholipids (PL-FA), and plasma
      and urinary markers of lipoperoxidation (TBA-RM, conjugated dienes, and azelaic
      acid (AZA), as well as the urinary levels of catecholamine and serotonin
      metabolites, were evaluated by gas chromatography-mass spectrometry (GC-MS), HPLC
      and spectrophotometry. Routine laboratory blood analyses were performed on the
      same samples; 39/48 TLP were HCV positive. Blood samples were collected just
      before transfusion, the 24 h urine samples the day before. Our results clearly
      showed that a severe oxidative stress occurs in the plasma of TLP in comparison
      with CTR. In fact, the levels of lipophilic antioxidants and ascorbate were
      severely depleted: CoQ10H2 (-62.5%), total CoQ10 (-35.1%), Vit E (-43.8%), beta
      carotene (-31.1%), lycopene (-63.7%), Vit A (-35.9%), Vit C (-23.1%). The
      impairment of the antioxidant status was associated with elevated plasma levels
      of by-products of lipoperoxidation and urinary concentrations of catecholamine
      metabolites and of AZA, indicating a high degree of both neurological stress and
      lipoperoxidation. A significant positive correlation was found between vitamin E
      and non-transferrin-bound iron (NTBI) (r = -0.81; p < 0.001), while no
      correlation was found between antioxidant depletion and ferritin serum levels,
      average blood consumption, or the presence of clinical complications. The
      administration of selective antioxidants along with an appropriate diet might
      represent a promising way of counteracting oxidative damage and its deleterious
      effects on the progression of the disease.

PMID- 10400458
TI  - Normothermic liver ischemia and antioxidant treatment during hepatic resections.
AB  - The purpose of our study was to evaluate the clinical impact of reperfusion
      injury after normothermic ischemia during major liver resections and the effect
      of an intraoperative antioxidant infusion. This prospective randomized study
      comprised 50 patients; half of them (treatment group) were given an antioxidant
      infusion containing tocopherol and ascorbate immediately prior to reperfusion
      onset. Venous blood samples for the determination of MDA-TBARS (malondialdehyde
      thiobarbituric acid reactive substances) by a HPLC-based test as a marker of
      lipid peroxidation were taken prior to ischemia, 30 min after reperfusion onset
      and at the end of the operation. In the control group there was a significant
      increase of MDA-TBARS (p = 0.001) at 30 min after reperfusion onset. At the end
      of the operation the values had returned to the initial level. The treatment
      group showed only a marginal increase (p-value for the difference between the two
      groups: 0.007). After exclusion of the patients with histologically proven
      advanced cirrhosis the increase in the control group (p < 0.001) and the
      difference between the increase in the two groups (p = 0.001) became more
      significant. Prothrombin time was also significantly better in the treatment
      group (p = 0.003). Postoperative complications such as prolonged liver failure,
      bleeding disorders and infections were seen more often in the control group. In
      our study MDA-TBARS was increased after liver ischemia, but in patients with
      advanced cirrhosis the effect was smaller or even absent. This increase and
      possible clinical consequences of reperfusion injury could be reduced by
      intraoperative administration of an antioxidant infusion.

PMID- 10400459
TI  - Total antioxidant potential of resinous exudates from Heliotropium species, and a
      comparison of the ABTS and DPPH methods.
AB  - Total reactive antioxidant potential (TRAP) of resinous exudates from
      Heliotropium species was evaluated by measuring the bleaching of stable free
      radicals. The antioxidant capacity of the resinous exudates in Trolox
      equivalents, evaluated from the bleaching of ABTS derived radical cations, ranged
      from 2.0 M (H. huascoense) to 5.2 M (H. stenophyllum), indicating a very high
      concentration of phenolic compounds. Considerably smaller values were obtained by
      measuring the bleaching of DPPH radicals. The ratio between the values obtained
      employing ABTS derived radicals and DPPH, ranged from 37 (H. megalanthum) to 4.5
      (H. chenopodiaceum variety typica). The magnitude of the difference can be
      considered as an indication of the relative reactivity of the antioxidants
      present in the exudates. Similar ratios were observed when stoichiometric
      coefficients were evaluated for representative purified flavonoids obtained from
      the resinous exudates.

PMID- 10400460
TI  - Linoleic acid hydroperoxide favours hypochlorite- and myeloperoxidase-induced
      lipid peroxidation.
AB  - Liposomes composed of soybean phosphatidylcholine were peroxidized using the
      reagent sodium hypochlorite or the myeloperoxidase-hydrogen peroxide-Cl- system.
      Linoleic acid hydroperoxide previously prepared from linoleic acid by means of
      lipoxidase was incorporated into liposomes. The yield of thiobarbituric acid
      reactive substances (TBARS) continuously increased with higher amounts of
      hydroperoxide groups after the initiation of lipid peroxidation by hypochlorous
      acid producing systems. The accumulation of TBARS was inhibited by scavengers of
      free radicals such as butylated hydroxytoluene and by the scavengers of
      hypochlorous acid, taurine and methionine. Lipid peroxidation was also prevented
      by sodium azide or chloride free medium in the myeloperoxidase-hydrogen peroxide
      Cl- system. Here we show for the first time that the reaction of hypochlorous
      acid with a biologically relevant hydroperoxide yields free radicals able to
      cause further oxidation of lipid molecules.

PMID- 10400461
TI  - Influence of copper-(II) on colloidal carbon-induced Kupffer cell-dependent
      oxygen uptake in rat liver: relation to hepatotoxicity.
AB  - Formation of reactive O2 species in biological systems can be accomplished by
      copper-(II) (Cu2+) catalysis, with the consequent cytotoxic response. We have
      evaluated the influence of Cu2+ on the respiratory activity of Kupffer cells in
      the perfused liver after colloidal carbon infusion. Studies were carried out in
      untreated rats and in animals pretreated with the Kupffer cell inactivator
      gadolinium chloride (GdCl3) or with the metallothionein (MT) inducing agent zinc
      sulphate, and results were correlated with changes in liver sinusoidal efflux of
      lactate dehydrogenase (LDH) as an index of hepatotoxicity. In the concentration
      range of 0.1-1 microM, Cu2+ did not modify carbon phagocytosis by Kupffer cells,
      whereas the carbon-induced liver O2 uptake showed a sigmoidal-type kinetics with
      a half-maximal concentration of 0.23 microM. Carbon-induced O2 uptake occurred
      concomitantly with an increased LDH efflux, effects that were significantly
      correlated and abolished by GdCl3 pretreatment or by MT induction. It is
      hypothesized that Cu2+ increases Kupffer cell-dependent O2 utilization by
      promotion of the free radical processes related to the respiratory burst of
      activated liver macrophages, which may contribute to the concomitant development
      of hepatocellular injury.

PMID- 10400463
TI  - Tennet IX: Theoretical and Experimental Neuropsychology. Montreal, Quebec,
      Canada. June 10-12, 1998.

PMID- 10400462
TI  - Alteration of free radical metabolism in the brain of mice infected with scrapie
      agent.
AB  - Alteration of free radical metabolism in the mouse brain by scrapie infection was
      evaluated. The infection of mice with scrapie agent, 87V strain, slightly
      increased the activities of catalase and glutathione-S-transferase, while it had
      no effect on glutathione peroxidase, glutathione reductase, and Cu, Zn-superoxide
      dismutase. Results show that the scrapie infection decreased the activity of
      mitochondrial Mn-superoxide dismutase by 50% but increased that of monoamine
      oxidase (p < 0.05). Scrapie infection also increased the rate of mitochondrial
      superoxide generation (p < 0.05). Following scrapie infection, the level of free
      sulfhydryl compounds in brain homogenates slightly decreased, but the content of
      thiobarbituric-acid-reactive substances and malondialdehyde increased
      significantly. Electron microscopy indicated that the ultrastructure of
      mitochondria was destroyed in the brain of scrapie-infected mice. These results
      suggest that elevated oxygen free radical generation and lowered scavenging
      activity in mitochondria might cause the free radical damage to the brain. Such
      deleterious changes in mitochondria may contribute to the development of prion
      disease.

PMID- 10400465
TI  - Drug reactions to contrimoxazole in HIV infection: possibly not due to the
      hydroxylamine metabolites of sulphamethoxazole.

PMID- 10400464
TI  - Lipoprotein(A) levels and apoprotein(a) phenotypes in a Sicilian population.
AB  - The aim of this study was to evaluate the influence of lipoprotein(a) levels and
      apoprotein(a) isoform size in determining the low cardiovascular risk of a rural,
      inland Sicilian population. Plasma levels of total cholesterol, LDL-cholesterol,
      HDL-cholesterol, triglycerides, lipoprotein(a) and apoprotein B and AI were
      measured in a sample of 278 subjects (141 males, 137 females) representative of a
      population of 1351 subjects (622 males, 729 females). The apoprotein(a) isoforms
      were also identified. Results indicated that the levels of the common lipo
      apoliproprotein parameters were lower than those of other populations, while
      lipoprotein(a) plasmatic levels and apoprotein(a) isoform distribution were
      similar to those of other Caucasian populations. The distribution of
      lipoprotein(a) levels was skewed to the right, with a higher prevalence of low
      levels, the apoprotein(a) isoforms most strongly represented in our sample were
      of intermediate size (25-27 kringles IV). Univariate analysis showed that
      lipoprotein(a) levels were correlated to apoprotein(a) isoform size (R = -0.48, p
      < 0.001) and to the age of the subjects (R = +0.13, p < 0.01). In a multiple
      regression analysis, lipoprotein(a) levels were correlated to the apoprotein(a)
      isoform size of the homozygous isoforms or smaller heterozygous isoforms, while
      larger heterozygous forms were not correlated. In conclusion, our study showed
      that in our population, lipoprotein(a) levels and apoprotein(a) isoforms are
      similar to those of other Caucasian populations. Other factors, such as the
      physical activity of a rural population or the Mediterranean diet, must be
      considered in order to explain the lower cardiovascular risk of this population.

PMID- 10400467
TI  - Proceedings of The British Pharmacological Society Clinical Pharmacology Section
      6-8 January 1999. Stakis Metropole Hotel, Brighton (King's College, London).

PMID- 10400466
TI  - Transplacental distribution of labetalol stereoisomers at delivery.

PMID- 10400468
TI  - [Cover picture: childhood adrenoleukodystrophy].

PMID- 10400470
TI  - Neuromuscular disorders: gene location.

PMID- 10400469
TI  - [The status of diagnostic radiology in Germany (with special reference to MRI)].

PMID- 10400471
TI  - Mitochondrial encephalomyopathies: gene mutation.

PMID- 10400472
TI  - Proceedings of the 3rd International Conference on Advances in Pulmonary
      Rehabilitation and Management of Chronic Respiratory Failure. Florence, Italy,
      March 11-14, 1998.

PMID- 10400473
TI  - Toward understanding centralisation of low back symptoms.

PMID- 10400474
TI  - 1st International Conference on the Mammalian Centromere. Taichung, Taiwan, 2-4
      October 1998. Abstracts.

PMID- 10400475
TI  - RNA-protein complexes.
AB  - RNA-binding proteins are an extremely diverse group of proteins, reflecting the
      diverse functional requirements of cellular RNAs. Whereas the number of
      structures of RNA-binding proteins or modules is increasing at a reasonable rate,
      that of protein-RNA complexes increments by only a few each year. The recently
      determined structure of a complex from the U2 small nuclear ribonucleoprotein
      particle shows the subtleties of RNA stem-loop recognition by ribonucleoprotein
      modules. A second structure provides the first direct information on double
      stranded RNA recognition by the double-stranded RNA-binding module that occurs in
      a variety of functionally distinct proteins. Another two new complexes concern
      proteins interacting with tRNA. The first is methionyl-tRNAf(Met) transformylase,
      which has to compete with elongation factor Tu for charged initiator tRNAMet and
      does so by recognising specific features of the acceptor stem of tRNAf(Met). The
      second is prolyl-tRNA synthetase, complexed with its cognate tRNA, that has to
      specifically recognise the two guanines common to all tRNA anticodons specific
      for proline.

PMID- 10400476
TI  - Physician leadership in the new millennium.

PMID- 10400477
TI  - Antifungals in the treatment of allergic bronchopulmonary aspergillosis.
AB  - OBJECTIVE: The primary objective of this article was to review the therapy of
      allergic bronchopulmonary aspergillosis (ABPA), especially to determine if
      antifungal therapy has a role in treatment of the disease. DATA SOURCES: We
      researched MEDLINE for all published studies on the use of antifungal therapy in
      ABPA. We also surveyed the literature for articles pertinent in the diagnosis and
      treatment of ABPA. We included all publications from MEDLINE written in English
      and non-English publications with English abstracts. STUDY SELECTION: All studies
      were reviewed. Case reports and small studies are presented. No well placebo
      controlled, blinded, parallel studies were located for review. RESULTS: Oral
      corticosteroids are still the therapy of choice for ABPA. Itraconazole may have a
      role in therapy, but controlled studies are needed. At this time itraconazole
      should be limited to cases where oral corticosteroids are contraindicated or
      refused by the patient. In patients requiring large doses of oral steroids,
      itraconazole may allow a reduction in dose, but should not replace the need to
      treat with oral corticosteroids. CONCLUSIONS: Antifungal agents, in particular
      itraconazole may have a role in the treatment of ABPA, but more data are
      necessary to confirm the efficacy of itraconazole in ABPA.

PMID- 10400478
TI  - A six-month, placebo-controlled comparison of the safety and efficacy of
      salmeterol or beclomethasone for persistent asthma.
AB  - BACKGROUND: There is a paucity of data comparing the long-term safety and
      efficacy of long-acting inhaled beta2-agonists versus low-dose inhaled
      corticosteroids in the treatment of asthma. OBJECTIVE: To compare the safety and
      efficacy of salmeterol xinafoate, beclomethasone dipropionate (BDP), and placebo
      over a 6-month treatment period in patients with persistent asthma. METHODS:
      Salmeterol (42 microg twice daily), BDP (84 microg four times daily), or placebo
      was administered via metered-dose inhaler to 386 adolescent and adult inhaled
      corticosteroid-naive patients in a randomized, double-blind, double-dummy,
      parallel-group study. Eligible patients demonstrated a forced expiratory volume
      in 1 second (FEV1) from 65% to 90% of predicted values. Pulmonary function,
      symptom control, frequency of asthma exacerbations, bronchial hyperresponsiveness
      (BHR) to methacholine challenge, and adverse events were assessed. RESULTS: There
      were few statistically significant differences between the two active treatments
      over 6 months of therapy. Asthma symptoms and lung function were significantly
      improved with both salmeterol and BDP compared with placebo (changes from
      baseline in FEV1 of 0.28 L (SE = 0.04) and 0.23 L (SE = 0.04), respectively,
      compared with 0.08 L (SE = 0.04); P < or = .014). There were no significant
      differences among the treatment groups with respect to the distribution of asthma
      exacerbations over time. Both salmeterol and BDP significantly reduced BHR
      compared with placebo (P < or = .033; changes from baseline of 1.29 (SE = 0.26)
      and 1.42 (SE = 0.24) doubling doses at 6 months, respectively, compared with 0.24
      (SE = 0.29) doubling dose for placebo). No rebound effect in BHR was seen upon
      cessation of any of the three treatment regimens. There were no clinically
      important differences in the safety profiles among the three treatments.
      CONCLUSIONS: Both salmeterol and BDP are effective and well-tolerated when
      administered for 6 months to inhaled corticosteroid-naive patients with
      persistent asthma.

PMID- 10400479
TI  - Asthma, mite sensitization, and sleeping in bunks.
AB  - BACKGROUND: Mattresses and bedding are the main reservoirs of house dust mites.
      OBJECTIVE: Subjects sleeping in the bottom bunk may be exposed to house dust
      particles detached from bedding of the top bunk. Our aim was to ascertain whether
      this exposure could influence the development of mite sensitization and/or
      allergic symptoms in these individuals. METHODS: Symptoms of allergic respiratory
      disease were recorded and mite skin tests performed in 94 consecutive bunk
      sleeping subjects (47 pairs of siblings) from an outpatient allergy clinic.
      Levels of Der p I, Der f I, and Der II were determined by enzyme-immunoassay in
      16 randomly selected bedding dust samples (8 pairs of bunks). RESULTS: Mite
      sensitization rate and prevalence of allergic respiratory disease were similar
      for the top-bed and bottom-bed groups, whereas prevalence of asthma was
      significantly higher in the latter. Mite sensitization was significantly
      associated with family atopy background, whereas other factors such as house
      pets, indoor smoke exposure or types of mattress or bunks were not. Der p I
      levels higher than 2 microg/g dust were found in 12 of the 16 mattresses and the
      median of the 8-bed-bottom group was over 10 microg/g. CONCLUSIONS: Sleeping in
      bunks constitutes a greater risk of developing asthma for subjects sleeping in
      the bottom bed. Bunk sleeping should be discouraged in families with an atopic
      background and sensitized subjects should use the top bed.

PMID- 10400480
TI  - Double-blind trials of azelastine nasal spray monotherapy versus combination
      therapy with loratadine tablets and beclomethasone nasal spray in patients with
      seasonal allergic rhinitis. Rhinitis Study Groups.
AB  - BACKGROUND: Azelastine hydrochloride is an H1-receptor antagonist with
      antiinflammatory properties that is available in the US as Astelin Nasal Spray
      for the treatment of seasonal allergic rhinitis. The symptoms of seasonal
      allergic rhinitis can initially be treated with monotherapy using either an
      antihistamine or an intranasal corticosteroid. Patients whose symptoms do not
      respond adequately are often prescribed a combination of both an antihistamine
      and an intranasal corticosteroid. OBJECTIVE: Three multicenter, randomized,
      double-blind studies were conducted to determine whether patients with moderate
      to-severe symptoms of seasonal allergic rhinitis who had responded inadequately
      to monotherapy with either an oral antihistamine or an intranasal corticosteroid,
      and who were candidates for combination therapy with both an oral antihistamine
      and an intranasal corticosteroid, could be effectively treated with azelastine
      nasal spray monotherapy. METHODS: Following a 1- to 2-week washout period,
      patients were randomized to 7 days of double-blind treatment with either
      azelastine nasal spray (2 sprays per nostril bid, 1.1 mg/day) monotherapy or
      combination therapy with oral loratadine (Claritin, one 10-mg tablet/day) plus
      intranasal beclomethasone dipropionate monohydrate (Beconase AQ, 2 sprays per
      nostril bid, 336 microg/day). Efficacy was determined at the end of the study by
      both a physician assessment of the need for additional anti-rhinitis medication
      and a patient global evaluation of therapeutic effectiveness. The three studies
      were conducted at 71 investigational sites during the 1998 spring allergy season.
      Three separate studies were conducted to verify the reproducibility of the new
      study design. RESULTS: In all three studies a total of 1,070 patients were
      randomized to double-blind treatment. There were no statistically significant
      differences in the percentage of patients treated with azelastine nasal spray
      versus patients treated with a combination of loratadine tablets and
      beclomethasone nasal spray who did not require additional anti-rhinitis
      medication (32% to 45% and 39% to 46%, respectively). The patient global
      evaluation indicated that 77% to 84% of the patients treated with azelastine
      nasal spray had symptomatic improvement and 85% to 90% of the patients treated
      with loratadine tablets and beclomethasone nasal spray had symptomatic
      improvement. The most commonly reported adverse experience with azelastine nasal
      spray was a transient aftertaste (8%), while the most commonly reported adverse
      experience with loratadine tablets and beclomethasone nasal spray in combination
      was headache (6%). CONCLUSIONS: Based on the percentage of patients not requiring
      additional antirhinitis medication and the patient assessment of efficacy,
      azelastine nasal spray monotherapy was as effective as the combination of oral
      loratadine plus intranasal beclomethasone in treating moderate-to-severe symptoms
      of seasonal allergic rhinitis.

PMID- 10400481
TI  - A summary of the atmospheric surveys published in the United States allergy
      literature, 1966-1996.
AB  - OBJECTIVE: In this investigation we sought to summarize the atmospheric surveys
      that were published in two United States allergy journals (and subsequent series)
      during a 31-year period beginning in 1966. DATA SOURCES: All original articles
      published in the Annals of Allergy (and its subsequent series) and the Journal of
      Allergy (and its subsequent series) were cataloged in a computer database
      beginning with the first issues of 1966. Publications were classified in a manner
      reflecting their aerobiologic content. STUDY SELECTION: From this database of
      articles (n = 7,403), atmospheric surveys for pollen, spores, and other aeroflora
      were identified and summarized according to standard criteria. For each study we
      documented the sampling instruments used, the height of these instruments off of
      the ground, the study period, and the sampling schedule. RESULTS: Sixty-one
      atmospheric surveys were summarized: 30 from locations in the United States and
      31 from outside of the country. Various volumetric and nonvolumetric samplers
      were used; the height of instruments above the ground and the sampling protocols
      varied widely. CONCLUSIONS: This investigation can serve as a companion to
      earlier compilations. These data should prove more useful than information
      available via electronic and paper indexes.

PMID- 10400482
TI  - Prevention of exercise-induced asthma by a natural isomer mixture of beta
      carotene.
AB  - BACKGROUND: The unicellular alga Dunaliella bardawil was previously shown to
      contain very high concentrations of beta-carotene composed of equal amounts of
      the all-trans and 9-cis stereoisomers which differ in their physicochemical
      features and antioxidative activity. Due to the controversy regarding the
      beneficial effect of antioxidants on asthma, the acute effects of beta-carotene
      of Dunaliella was assessed on airway hyperreactivity in patients with exercise
      induced asthma (EIA). METHODS: Thirty-eight patients with EIA participated in our
      study to verify the antioxidative effect. The test was based on the following
      sequence: baseline pulmonary function, 7 minutes exercise session on a motorized
      treadmill, 8 minutes rest, 1-week oral random, double-blind supplementation of
      placebo or 64 mg/day beta-carotene, pulmonary functions at rest, 7 minutes
      exercise session, 8 minutes rest and again pulmonary functions. RESULTS: All
      patients given placebo showed a significant postexercise reduction of more than
      15% in their forced expiratory volume in one second (FEV1). Of the 38 patients
      who received a daily dose of 64 mg of beta-carotene for 1 week, 20 (53%) were
      protected against EIA. CONCLUSIONS: Our results indicate that a daily dose of
      Dunaliella beta-carotene exerts a protective effect against EIA in some patients
      most probably through in vivo antioxidative effect.

PMID- 10400483
TI  - Risk factors for acetaminophen and nimesulide intolerance in patients with NSAID
      induced skin disorders.
AB  - BACKGROUND: Previous studies show skin reactions after exposure to acetaminophen
      and/or nimesulide to occur in about 10% of patients with a history of urticaria
      induced by aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). This
      fact is surprising since cross-reactivity among different NSAIDs should not occur
      among subjects without a history of chronic urticaria. OBJECTIVE: To detect risk
      factors for intolerance to alternative drugs such as acetaminophen and nimesulide
      in different groups of patients with a history of adverse skin reactions
      (urticaria/angioedema, or anaphylaxis) after the ingestion of aspirin and other
      NSAIDs. METHODS: Two hundred fifty-six patients with a history of recent
      pseudoallergic skin reactions caused by NSAIDs underwent elective oral challenges
      with increasing doses of both acetaminophen and nimesulide. Patients were divided
      into three groups: A = 69 subjects with chronic urticaria, B = 163 otherwise
      normal subjects with a history of urticaria after the ingestion of aspirin, and C
      = 24 otherwise normal subjects with a history of urticaria after the ingestion of
      pyrazolones but aspirin-tolerant. RESULTS: Forty-eight (19%) patients reacted to
      acetaminophen and/or nimesulide. Similar numbers of patients with chronic
      urticaria (23%) and of normal subjects with a history of aspirin-induced
      urticaria (19%) did not tolerate one of the alternative drugs challenged.
      Pyrazolones-intolerant patients showed the lowest number of reactors (4%).
      Aspirin intolerance represented a risk factor for acetaminophen- and/or
      nimesulide-induced urticaria (RR = 5.4). A history of anaphylactoid reactions
      induced by NSAID represented a risk factor for urticaria after the ingestion of
      the alternative study drugs (RR = 5.7). Atopic status was associated with a
      higher risk of reactivity to nimesulide: this drug induced urticaria in 11/47
      (23%) atopics versus 18/209 (9%) non-atopics (P < .005; RR = 3.2). A history of
      intolerance to antibacterial drugs was not associated with a higher prevalence of
      reactivity against acetaminophen and/or nimesulide. CONCLUSIONS: In at least 20%
      of patients with a history of urticaria/angioedema or anaphylaxis induced by
      aspirin or other NSAIDs, but without a history of chronic urticaria, cross
      reactivity with other NSAIDs occurs. Atopy as well as a history of aspirin
      induced anapylactoid reactions seem to represent relevant risk factors for
      intolerance to alternative NSAIDs. In view of these findings, aspirin-intolerant
      patients with such clinical features should be submitted to peroral tolerance
      tests with at least two alternative substances in order to avoid potentially
      severe reactions.

PMID- 10400484
TI  - Relationship between induced sputum cell counts and fluid-phase eosinophil
      cationic protein and clinical or physiologic profiles in mild asthma.
AB  - BACKGROUND: Sputum analysis is the only non-invasive method to examine airway
      inflammatory processes in subjects with asthma. The aim of this study was to
      investigate the relationship between cell counts and fluid phase levels in
      induced sputum in subjects with mild asthma, and the severity of asthma as
      assessed by clinical, physiologic and blood measurements. METHODS: Forty patients
      with mild asthma, aged 17 to 49 years were studied (good sputum sample only from
      31). On the first day, spirometry and methacholine challenges were performed.
      After 2 to 4 days, venous blood for absolute eosinophil count and eosinophil
      cationic protein (ECP) measurement was obtained and sputum was induced by
      inhalation of hypertonic saline. For the next 15 days subjects recorded their
      peak expiratory flow (PEF), symptom scores, and beta2-agonist requirements twice
      daily. Differential counts of leukocytes were done on cytospin preparations of
      homogenized sputum and the supernatant was examined for eosinophil cationic
      protein (ECP). RESULTS: Sputum eosinophil counts and not neutrophil, epithelial
      cells, macrophages, or lymphocytes, were inversely correlated to FEV1/FVC % (r = 
      .57, P = .0008) and to PC20-methacholine (r = -.40, P = .024). No statistical
      relationship was obtained between eosinophil counts and either symptom scores,
      bronchodilator requirements, or daily PEF variability. Sputum ECP values were
      correlated to FEV1/FVC% (r = -.41, P = .026) but not to PC20 (r = -.32, P = .08)
      or clinical scores or PEF variation. A trend to significance was appreciated
      between peripheral blood and sputum eosinophil counts (r = .34, P = .067) and no
      relationship was found between sputum and serum ECP values (r = .10, P = .38).
      CONCLUSIONS: Although sputum markers give some information about disordered lung
      function and physiologic changes in the airways, they are not the only factors
      concerned in the clinical expression of mild asthma.

PMID- 10400485
TI  - Immediate hypersensitivity in adults with IgG deficiency and recurrent
      respiratory infections.
AB  - BACKGROUND: Little is known about the prevalence of atopy in adults with
      recurrent respiratory infections and IgG deficiency. OBJECTIVE AND METHODS: To
      elucidate this aspect, we skin-tested 95 consecutive adults with respiratory
      infections, subnormal levels of IgG subclasses or common variable
      immunodeficiency and usually poor response to vaccination. In 50 subjects we also
      measured total IgE. RESULTS: We found 67 subjects with IgG subclass deficiency,
      21 subjects with mild (partial) and 5 with usual common variable
      immunodeficiency, and 2 subjects with functional IgG deficiency. Atopy was
      encountered in 42/95 subjects, 33/44 (75%) with asthma, 7/19 (38%) with isolated
      rhinosinusitis, 1/27 (4%) with chronic obstructive lung disease, and 1/5 (20%)
      with both the latter disease and asthma, respectively. Atopy was preferentially
      clustered in subjects with asthma (P < .05) who were less than 40 years of age (P
      < .05) and nonsmoking. Atopy was not affected by the type of IgG deficiency,
      unless it was usual common variable immunodeficiency, in which case the skin
      tests tended to be negative (4/5). Total IgE was within normal range but less
      elevated than usually seen in asthma or chronic obstructive lung disease. Total
      IgE was independent of the type of IgG deficiency, except for usual common
      variable immunodeficiency in which it remained < 10 IU/mL. CONCLUSIONS: In adults
      with symptomatic IgG deficiency, the prevalence of immediate hypersensitivity and
      its modulation by age and smoking are similar to the referred, non-IgG deficient
      population; however, total IgE may be lower in the former than in the latter. In
      common variable immunodeficiency, consistent with the literature data, both the
      prevalence of atopy and serum total IgE are decreased.

PMID- 10400486
TI  - Exercise-induced hyperventilation: a pseudoasthma syndrome.
AB  - BACKGROUND: Exercise-induced asthma is common and generally responds well to an
      inhaled beta2 agonist. OBJECTIVE: We examined the physiologic changes in airflow
      and gas exchange that occurred during standardized treadmill exercise in patients
      previously diagnosed with exercise-induced asthma whose histories appeared
      atypical or where conventional treatment, including an inhaled beta2 agonist, was
      ineffective. METHODS: During a 1-year period 32 patients, aged 8 to 18, met these
      criteria. All had been previously diagnosed as having exercise-induced asthma.
      Exercise consisted of treadmill running at a time when the patients had received
      no inhaled beta2 agonist, cromolyn, or nedocromil for at least 4 hours.
      Spirometry was done before and at 2, 5, 10, and 15 minutes after exercise; oxygen
      saturation was monitored by pulse oximetry; and end-tidal CO2 was monitored with
      nasal cannula. RESULTS: Despite their previous diagnoses of exercise-induced
      asthma, 11 patients who described chest tightness during exercise had decreases
      in FEV1 less than 15% with all but one of those less than 10% (mean decrease
      5.6%) but demonstrated decreases in end-tidal CO2 greater than in all of the
      other 21 patients (mean 23.2 versus 9.8%, P < .01). Only 4 patients had
      unequivocal evidence for bronchospasm with cough and wheezing accompanying chest
      tightness in association with decreases in FEV1 from 18 to 22%. Seventeen
      patients had neither their symptoms reproduced nor physiologic abnormalities.
      CONCLUSIONS: These data show that chest discomfort perceived as dyspnea during
      vigorous exercise may be associated with hypocapnia from hyperventilation without
      bronchospasm in children and adolescents previously misdiagnosed and treated as
      having exercise-induced asthma.

PMID- 10400487
TI  - Expression of ICAM-1 on conjunctival epithelium and ECP in tears and serum from
      children with allergic conjunctivitis.
AB  - BACKGROUND: Conjunctival eosinophilia may be considered to be an indicator of
      conjunctival allergic disease. The absence of eosinophils on conjunctival
      scraping, however, cannot rule out the diagnosis of allergic conjunctivitis
      because eosinophil infiltration may be deeper in conjunctival tissue. Eosinophil
      cationic protein (ECP) is a toxic product secreted by activated eosinophil as a
      marker of eosinophil activation. Eosinophil cationic protein concentrations in
      body fluids correlate with the severity of some allergic diseases. ICAM-1
      promotes adhesion of leukocytes to epithelium, endothelium, and upregulates
      inflammation. Expression of adhesion can be modified by many extracellular and
      intracellular variables such as proinflammatory cytokines, extracellular matrix
      proteins, and viral infection. OBJECTIVE: We investigated whether local
      eosinophils are only activated in conjunctival epithelium or circulating
      activated eosinophils are involved in peripheral blood during allergic reaction
      of the eye. We also demonstrated the possible expression of ICAM-1 on epithelial
      cells from conjunctival scraping and compared them with soluble ICAM-1 values of
      serum and tears in children with allergic conjunctivitis and healthy children.
      METHODS: Seventeen subjects were selected on the basis of clinical
      manifestations, history, skin prick test, and total serum IgE. A microcapillary
      tube was used to collect the tears from the inner canthus. Conjunctival epithelia
      were obtained by scraping the upper tarsal conjunctiva. The level of ECP was
      measured by the CAP system, soluble ICAM-1 was measured by ELISA, and ICAM-1 on
      conjunctival epithelial cells were expressed by the avidine-biotin peroxide
      complex procedure. RESULTS: Serum IgE and the eosinophil count were increased in
      10 out of 17 patients, positive skin prick tests were positive in 11 patients
      (Dermatophagoides pternyssinus; 9, Dermatophagoides farinae: 8), and eosinophilia
      in conjunctival epithelium was in 11 patients (4 patients: >3/HPF, 7 patients: 1
      3/HPF). The ECP levels in tears were significantly increased in the patient group
      (12.0+/-8.0 versus 3.9+/-3.8 microg/mL, P = .01), but not in serum (52.5+/-43.1
      versus 28.3+/-25.9 microg/mL). There is significant correlation between the
      eosinophil count in peripheral blood and on conjunctival epithelium (P = .007, r
      = .62; n = 25). The ICAM-1 expression score on conjunctival epithelial cells was
      significantly different between the patient group and controls (patient group:
      1.77+/-1.25 versus control: 0.13+/-0.35 ng/mL, P = .002). There was a significant
      correlation between ICAM-1 expression on conjunctival epithelial cells and the
      ECP levels of tears (P = .01, r = .58; n = 25). Soluble ICAM-1 levels in serum
      and tears showed no significant difference between the patient group and
      controls, and also, there was no correlation between sICAM-1 levels in the serum
      and tears. CONCLUSION: Eosinophil cationic protein in tears and ICAM-1 expression
      scores on conjunctival epithelium showed a significant difference between
      children with allergic conjunctivitis and the healthy controls, but circulating
      ECP and sICAM-1 in serum were not significantly different between the two groups.
      These results may suggest that ICAM-1 is locally upregulated in inflammation,
      mediating eosinophil activation and migration to conjunctival epithelium, but is
      not involved as inflammatory mediators in peripheral blood during allergic
      response in children with allergic conjunctivitis.

PMID- 10400488
TI  - Differences of genetic effects for the development of allergic diseases in two
      cities of Japan.
AB  - BACKGROUND: Differences in the effects of genetic factors on allergic diseases in
      two areas of the same race within the same country have not been studied with
      multiple logistic regression. OBJECTIVE: To determine whether the effects of
      genetic factors on allergic diseases differ between two areas. METHODS: A
      questionnaire provided information about family histories of allergic diseases
      and environmental factors was distributed to children attending kindergarten,
      elementary, or junior high school in two Japanese cities: Gifu, with a temperate
      climate, and Itoman, with a subtropical one. The number of subjects analyzed were
      1,243 in Gifu and 1,953 in Itoman. Multiple logistic regression analysis was
      performed with SAS. RESULTS: Multiple logistic regression analysis showed that in
      both cities children of families with allergic histories have significantly
      higher risk of contracting allergic disease and atopic dermatitis, even after
      being controlled for environmental factors. In Gifu, in families where both
      parents suffered from allergy, there was a higher incidence of allergic diseases
      than when only one of the parents was suffering from it. On the other hand, in
      Itoman there were no differences of relative risk between paternal history and
      maternal history. CONCLUSIONS: We speculated that there are some differences of
      genetic factors between different areas of the same country, and these
      differences of genetic effects may influence on the difference of the prevalence
      of allergic diseases as well as the environmental factors.

PMID- 10400489
TI  - Possible mechanism of paracetamol anaphylaxis.

PMID- 10400490
TI  - The treatment and prophylaxis of nonsteroidal anti-inflammatory drug (NSAID)
      associated ulcers and erosions.

PMID- 10400491
TI  - The bakkenolides from the root of Petasites formosanus and their cytotoxicity.
AB  - Thirty-two new bakkenolides, bakkenolides-Db (1)--Dh(7), -Fa(8), -Fb(9), -I(10)-
      M(14), -Na(15), -Nb(16), -O(17)--T(22), -Ua (23), -Ub(24), -V(25)--X(27), 
      Ya(28), -Yb(29), -Za(30), -Zb(31) and -III(32), from the roots of Petasites
      formosanus together with thirty known compounds were isolated. The structures
      were characterized by spectral analysis. The locations, C-1 and/or C-9 of
      bakkenolide skeleton, of the substituents, such as acetoxy, isobutyroyloxy and
      isovaleroyloxy groups, can be determined by the chemical shifts of their signals
      and the H-1 and/H-9 in the 1H-NMR spectra. The cytotoxicity was also discussed.

PMID- 10400492
TI  - Health status of young Alaska Steller sea lion pups (Eumetopias jubatus) as
      indicated by blood chemistry and hematology.
AB  - Blood chemistry and hematology were examined in 238 Steller sea lion pups
      (Eumetopias jubatus) to assess the health status of pups <1 month of age. Failure
      of juvenile recruitment (possibly due to nutritionally or physiologically
      compromised pups) into breeding populations has been proposed as a cause of
      recent declines of this endangered species in Alaska. To identify potential
      correlations with areas of high population decline, blood chemistry data were
      considered for three areas: eastern Aleutian Islands (low rates of population
      decline to stable populations), Gulf of Alaska (high rates of decline), and
      Southeast Alaska (stable to increasing population). Southeast Alaska pups showed
      elevated ketone body concentrations (beta-hydroxybutyrate,(beta-HBA)) and
      depressed glucose levels than pups in the Gulf of Alaska. Over 40% of the pups
      from Southeast Alaska had elevated beta-HBA concentrations suggesting they
      underwent longer periods of fasting than seen in pups from other areas.
      Hematocrit (Hct), hemoglobin concentration (Hb) and water content of the blood
      exhibited typical mammalian relationships. In summary, blood chemistry and
      hematology data showed no indication that Steller sea lion pups <1 month old from
      areas of population decline were nutritionally compromised.

PMID- 10400493
TI  - Comparison of growth and development of the exocrine pancreas in pigs and rats
      during the immediate postnatal period.
AB  - This study compared pancreatic tissue growth and functional changes during the
      first 3 postnatal days in piglets and rat pups. In piglets the absolute weight
      and the relative weight per unit body weight of the pancreas increased by 97 and
      70%, respectively, while in rat pups the same parameters decreased by 33 and 48%,
      respectively, during this period. The specific activity of pancreatic amylase
      rose by 336% while that of trypsin, chymotrypsin and lipase remained at newborn
      level in piglets. In rat pups the specific activities of all enzymes measured
      declined by 61 to 92% during the first 3 postnatal days. The rate of postnatal
      pancreatic growth in the two species coincide with the levels of epidermal growth
      factor and insulin-like growth factors in maternal milk as reported in the
      literature, suggesting that milk-borne growth factors may stimulate pancreatic
      development in newborn animals.

PMID- 10400494
TI  - The spatial and temporal concentrations of choline in the lumen contents of the
      small intestine of uninfected and Hymenolepis diminuta infected rats.
AB  - The spatial and temporal concentrations of free choline in the lumen of the small
      intestine of the uninfected and Hymenolepis diminuta-infected rat were
      investigated. In the unfed infected or uninfected rat, the choline concentrations
      ranged from approximately 500 microM in the duodenum to approximately 20 microM
      in the posterior ileum, with some segments in infected rats containing
      significantly higher choline levels than in uninfected rats. Following feeding,
      choline levels were significantly elevated to approximately 3 mM by 6 h, although
      these concentrations fell rapidly in transit down the intestine. By 12 h the
      choline levels were similar to those in the unfed rat. An initial small shift in
      the worm biomass toward the duodenum after feeding was followed by a
      redistribution of biomass along the length of the small intestine. The worm
      biomass, however, had little or no effect on the choline levels. The high
      concentrations of free choline observed in the anterior regions of the intestine
      are postulated to be predominantly determined by nutritional intake while the
      concentrations in the posterior region may in part be determined by blood choline
      levels. The high levels of choline indicate that choline is not limiting to
      support the growth of the worms.

PMID- 10400495
TI  - Uncoupling protein mRNA, mitochondrial GTP-binding, and T4 5'-deiodinase activity
      of brown adipose tissue in Daurian ground squirrel during hibernation and
      arousal.
AB  - The mRNA level of uncoupling protein (UCP) specific for brown adipose tissue
      (BAT) in Daurian ground squirrel, was detected by using a [32P]-labeled
      oligonucleotide probe. The UCP concentration in mitochondria was indirectly
      determined by titration with its specific ligand [H3]-labeled GTP. Type II T4 5'
      deiodinase of BAT was assayed concomitantly. We found two species of mRNA for UCP
      with lengths of about 1.9 and 1.5 kb, respectively, both occurring in almost the
      same concentration. UCP mRNA content was elevated significantly during
      hibernation, but the UCP concentration did not change compared with that of
      nonhibernating controls kept at room temperature. When hibernating squirrels were
      aroused, the UCP mRNA remained at the elevated level as during hibernation, but
      the UCP concentration increased in comparison with that of nonhibernating
      controls or during hibernating. Changes in T4 5'-deiodinase activity in BAT were
      similar to the variations of the UCP mRNA level. These results suggest that the
      activation of T4 5'-deiodinase in BAT may be an important factor for the up
      regulation and maintenance of UCP mRNA content needed for the synthesis of
      sufficient UCP to acquire the thermogenic capacity for arousal from hibernation.

PMID- 10400496
TI  - Donald Bruce Scott, M.D., F.R.C.A., F.R.D.P.Ed. 1925-1998.

PMID- 10400497
TI  - Retraction.

PMID- 10400498
TI  - Site specific deoxynucleotide substitutions in yeast U6 snRNA block splicing of
      pre-mRNA in vitro.

PMID- 10400499
TI  - Genetic association studies in coronary disease: the cause of GPIIb-IIIa
      polymorphisms.

PMID- 10400500
TI  - Trial end-point committees: the king-pin of good clinical practice.

PMID- 10400501
TI  - Reuse of devices in cardiology.

PMID- 10400502
TI  - Atrial fibrillation in myocardial infarction complicated by heart failure: cause
      or consequence?

PMID- 10400505
TI  - [More information--less pain. Procedure in pain following amputation of limbs.
      Brachial plexus injury and nerve root avulsion. Interview by Susanne Kammerer].

PMID- 10400503
TI  - Further defining the role for natriuretic peptide levels in clinical practice.

PMID- 10400506
TI  - Transplantation Society of Australia and New Zealand 17th annual scientific
      meeting. Canberra, 14-16 April 1999. Abstracts.

PMID- 10400507
TI  - Research in Medical Imaging Conference. Toulouse, France, February 4-6, 1998.
      Proceedings.

PMID- 10400504
TI  - Bacillus subtilis alpha-amylase: the rate limiting step of secretion is growth
      phase-independent.
AB  - When Bacillus subtilis alpha-amylase was expressed under the control of sacR in a
      degU32(Hy) strain, the production of exoenzyme occurred during both the
      exponential and stationary phases of growth. In each phase, pulse-chase
      experiments showed that the rate-limiting step of the secretion process was the
      release of the processed form of the protein in each physiological context. The
      rate of this event was slightly slower (t(1/2) = 3.2 min) during the stationary
      phase than during the exponential phase (t(1/2) = 2 min). The effectors which
      possibly control the efficiency of the release stage, the level of PrsA or the
      calcium binding properties of the cell wall, remained unchanged throughout growth
      phases.

PMID- 10400508
TI  - How real is the subluxation? A research perspective.

PMID- 10400509
TI  - Complex partial seizures provoked by photic stimulation.

PMID- 10400510
TI  - Creutzfeldt-Jakob-like syndrome induced by lithium, levomepromazine, and
      phenobarbitone.

PMID- 10400511
TI  - Central nervous system involvement in a novel connexin 32 mutation affecting
      identical twins.

PMID- 10400512
TI  - Isolated ischemia of the spinal cord due to bilateral vertebral artery
      dissection.

PMID- 10400513
TI  - Autonomic dysfunction and orthostatic hypotention caused by vitamin B12
      deficiency.

PMID- 10400514
TI  - Sandifer's syndrome and gastro-oesophageal reflux disease.

PMID- 10400515
TI  - Is inherited thrombophilia a risk factor for arterial stroke?

PMID- 10400516
TI  - Lyme borreliosis and intracranial aneurysm.

PMID- 10400518
TI  - Dr William J. Mayo and the patient-physician relationship.

PMID- 10400517
TI  - Does persistent infection with Chlamydia pneumoniae increase the risk of
      atherosclerosis in chronic renal failure?

PMID- 10400519
TI  - Sketches from The Lancet. Royalty.

PMID- 10400520
TI  - [The Vienna Rokitansky celebration].

PMID- 10400522
TI  - Trampoline-related injuries to children.

PMID- 10400521
TI  - Recombinant human granulocyte colony-stimulating factor therapy for sepsis in
      infants with neutropenia.

PMID- 10400523
TI  - Trampoline-related injuries in children.

PMID- 10400524
TI  - Does Group B streptococcal sepsis attenuate endogenous nitric oxide synthesis in
      neonates?

PMID- 10400525
TI  - Toxic beards?

PMID- 10400526
TI  - Reassessment of patients with the diagnosis of fetal alcohol syndrome.

PMID- 10400527
TI  - [Professor Vladimir Syty awarded the medal of the Polish Society of Internal
      Medicine].

PMID- 10400529
TI  - Emerging diseases. Canada dedicates new human, animal labs.

PMID- 10400528
TI  - Mutant fruit flies respond to Lorenzo's oil.

PMID- 10400531
TI  - A high-stakes gamble on genome sequencing.

PMID- 10400530
TI  - Tulane inquiry clears lead researcher.

PMID- 10400532
TI  - Microbes feature as pathogens and pals at gathering.

PMID- 10400533
TI  - Mitigating natural disasters.

PMID- 10400534
TI  - Tulane investigation completed.

PMID- 10400535
TI  - Unsteady aerodynamics.

PMID- 10400536
TI  - Respiration without O2.

PMID- 10400537
TI  - Protein interaction methods--toward an endgame.

PMID- 10400538
TI  - Techsighting. Test tube kidneys.

PMID- 10400539
TI  - Retraction and apology: Is phentermine an inhibitor of monoamine oxidase?

PMID- 10400540
TI  - Resection rates in lung cancer.

PMID- 10400541
TI  - Repeatability of breathlessness measurements in cancer patients.

PMID- 10400542
TI  - Surgical resection rate in lung cancer.

PMID- 10400543
TI  - COPD guidelines.

PMID- 10400544
TI  - [A list of author abstracts of doctoral and candidate dissertations for 1997
      deposited in the Central Research Institute of Stomatology and in the State
      Central Medical Research Library in January-March 1998].

PMID- 10400545
TI  - [On the death of Prof. Dr. med. Franz Josef Wagenhauser].

PMID- 10400546
TI  - Prevalence of people reporting sensitivities to chemicals in a population-based
      survey.
AB  - To describe the prevalence and correlates of reports about sensitivities to
      chemicals, questions about chemical sensitivities were added to the 1995
      California Behavior Risk Factor Survey (BRFS). The survey was administered by
      telephone to 4,046 subjects. Of all respondents, 253 (6.3%) reported doctor
      diagnosed "environmental illness" or "multiple chemical sensitivity" (MCS) and
      643 (15.9%) reported being "allergic or unusually sensitive to everyday
      chemicals." Sensitivity to more than one type of chemical was described by 11.9%
      of the total sample population. Logistic regression models were constructed.
      Hispanic ethnicity was associated with physician-diagnosed MCS (adjusted odds
      ratio (OR) = 1.82, 95% confidence interval (CI) 1.21-2.73). Female gender was
      associated with individual self-reports of sensitivity (adjusted OR = 1.63, 95%
      CI 1.23-2.17). Marital status, employment, education, geographic location, and
      income were not predictive of reported chemical sensitivities or reported doctor
      diagnosis. Surprising numbers of people believed they were sensitive to chemicals
      and made sick by common chemical exposures. The homogeneity of responses across
      race-ethnicity, geography, education, and marital status is compatible with a
      physiologic response or with widespread societal apprehensions in regard to
      chemical exposure.

PMID- 10400548
TI  - Invited commentary: sensitivities to chemicals--context and implications.

PMID- 10400547
TI  - Alcohol intake assessment: the sober facts.
AB  - Recent recommendations in regard to the level of alcohol intake have mainly been
      based on epidemiologic studies which relied on self-reported amounts of alcohol
      consumed. Therefore, it is important to be aware of the quality of self-reported
      measures of alcohol intake. Alcohol intake assessment methods were reviewed with
      respect to their capacity to rank individuals according to alcohol intake and
      their ability to explain the variation in the level of intake in population
      samples. In 33 methodological papers published after 1984, alcohol intake was
      assessed by five main methods: quantity frequency, extended quantity frequency,
      retrospective diary, prospective diary, and 24-hour recalls. The mean level of
      alcohol intake differed by 20% between these methods. It was also found that when
      researchers asked specifically about intake of beer, wine, and liquor, this
      resulted in 20% higher estimates of intake. These percentages were similar among
      populations with low and high mean alcohol consumption (4 vs. 10 drinks per
      week). It was found that ranking of individuals according to intake was
      satisfactory, with weighted correlation coefficients between methods ranging from
      0.63 to 0.73. The authors conclude that, when there is sufficient evidence that
      alcohol intake is underestimated in a population, methods that enquire about both
      the frequency and amount consumed, for beer, wine, and liquor, separately, will
      yield the most realistic levels of intake.

PMID- 10400549
TI  - Adverse work and environmental conditions predict occupational injuries. The
      Israeli Cardiovascular Occupational Risk Factors Determination in Israel (CORDIS)
      Study.
AB  - This study was designed to test whether the total objective adverse work and
      environmental conditions, expressed as the ergonomic stress level (ESL), would
      predict occupational injuries over a 2-year period. The study population
      consisted of 4,096 men from 21 factories in six industrial sectors who were
      studied as part of the Israeli Cardiovascular Occupational Risk Factors
      Determination in Israel (CORDIS) Study, 1985-1987. The ESL (assigned four levels,
      1-4) was based on an ergonomic assessment which covered 17 risk factors
      pertaining to safety hazards, overcrowding, cognitive and physical demands, and
      environmental stressors. The ESL was found to be a highly reliable measure and
      stable over a period of 2-4 years. The incidence of injuries among workers in low
      ESL conditions (level 1) was 10.3%. It increased with higher ESL's: 11.7% in
      level 2 (relative risk (RR) = 1.13, 95% confidence interval (CI) 0.86-1.50);
      21.6% in level 3 (RR = 2.09, 95% CI 1.68-2.62); and 23.8% in level 4 (RR = 2.31,
      95% CI 1.85-2.88). After adjustment for age, job experience, educational level,
      managerial status, and occupational status (white/blue collar), injury occurrence
      was significantly elevated for those at level 3 (adjusted odds ratio (OR) = 1.46,
      95% CI 1.12-1.91) and level 4 (adjusted OR = 1.81, 95% CI 1.39-2.37) but not for
      level 2 (adjusted OR = 0.87, 95% CI 0.65-1.18). The authors conclude that adverse
      work and environmental conditions, objectively assessed, can predict occurrence
      of occupational injuries.

PMID- 10400550
TI  - Reduced excretion of a melatonin metabolite in workers exposed to 60 Hz magnetic
      fields.
AB  - The effects of occupational 60 Hz magnetic field and ambient light exposures on
      the pineal hormone, melatonin, were studied in 142 male electric utility workers
      in Colorado, 1995-1996. Melatonin was assessed by radioimmunoassay of its
      metabolite, 6-hydroxymelatonin sulfate (6-OHMS), in post-work shift urine
      samples. Personal magnetic field and light exposures were measured over 3
      consecutive days using EMDEX C meters adapted with light sensors. Two independent
      components of magnetic field exposure, intensity (geometric time weighted
      average) and temporal stability (standardized rate of change metric or RCMS),
      were analyzed for their effects on creatinine-adjusted 6-OHMS concentrations (6
      OHMS/cr) after adjustment for age, month, and light exposure. Geometric mean
      magnetic field exposures were not associated with 6-OHMS/cr excretion. Men in the
      highest quartile of temporally stable magnetic field exposure had lower 6-OHMS/cr
      concentrations on the second and third days compared with those in the lowest
      quartile. Light exposure modified the magnetic field effect. A progressive
      decrease in mean 6-OHMS/cr concentrations in response to temporally stable
      magnetic fields was observed in subjects with low workplace light exposures
      (predominantly office workers), whereas those with high ambient light exposure
      showed negligible magnetic field effects. Melatonin suppression may be useful for
      understanding human biologic responses to magnetic field exposures.

PMID- 10400551
TI  - Association of antioxidants with memory in a multiethnic elderly sample using the
      Third National Health and Nutrition Examination Survey.
AB  - Oxidative stress has been implicated both in the aging process and in the
      pathological changes associated with Alzheimer's disease. Antioxidants, which
      have been shown to reduce oxidative stress in vitro, may represent a set of
      potentially modifiable protective factors for poor memory, which is a major
      component of the dementing disorders. The authors investigated the association
      between serum antioxidant (vitamins E, C, A, carotenoids, selenium) levels and
      poor memory performance in an elderly, multiethnic sample of the United States.
      The sample consisted of 4,809 non-Hispanic White, non-Hispanic Black, and Mexican
      American elderly who visited the Mobile Examination Center during the Third
      National Health and Nutrition Examination Survey, a national cross-sectional
      survey conducted from 1988 to 1994. Memory is assessed using delayed recall (six
      points from a story and three words) with poor memory being defined as a combined
      score less than 4. Decreasing serum levels of vitamin E per unit of cholesterol
      were consistently associated with increasing levels of poor memory after
      adjustment for age, education, income, vascular risk factors, and other trace
      elements and minerals. Serum levels of vitamins A and C, beta-carotene, and
      selenium were not associated with poor memory performance in this study.

PMID- 10400552
TI  - Incidence of testicular cancer in the United States: has the epidemic begun to
      abate?
AB  - In response to a report that testicular cancer incidence in non-Hispanic White
      males in Los Angeles county had fallen in the 1990s, particularly in young men,
      the authors analyzed data collected by the Surveillance, Epidemiology, and End
      Results (SEER) program from 1973 to 1995. While the incidence rate of testicular
      cancer in US White males ages 15-64 years did stabilize in the first half of the
      1990s, after a number of years of a steady increase, there was no indication of
      an actual decline.

PMID- 10400553
TI  - Wine and good subjective health.
AB  - The association of subjective, self-rated suboptimal (average or poor) health
      with the intake of beer, wine, and liquor and alcohol intoxication was examined
      in a general population sample in Finland in 1992. The odds ratios were adjusted
      for several possible confounders with the use of logistic regression analysis.
      Compared with subjects who drank no wine, suboptimal health was less frequent
      among both men and women who imbibed 1-4 drinks of wine, and more common among
      men who consumed > or = 10 drinks of wine or liquor. Moderate wine drinking seems
      to be related to good self-rated health.

PMID- 10400554
TI  - Prevalence and determinants of prone sleeping position in infants: results from
      two cross-sectional studies on risk factors for SIDS in Germany.
AB  - The authors investigated whether there was a decline in infants sleeping prone
      and other modifiable risk factors for sudden infant death syndrome (SIDS) in
      Germany, where, as in some other countries, no nationwide intervention campaign
      against the prone sleeping position had been initiated. Data were obtained from
      parents by mailed questionnaires in two cross-sectional studies in 1991 (n =
      3,330) and 1995 (n = 3,124). Prevalence of prone sleeping decreased from 37.6% to
      8.7% (p < 0.05) in the German population and from 44.1% to 32.0% (p < 0.05) in
      the Turkish immigrant population. Parents who laid their infants prone in 1995
      were less likely to follow advice from physicians, public media, and other
      parents (relative risks < 0.5, p < 0.05) and were more likely to have a low
      educational level, to be <20 years old, to be single parents, to have two or more
      children, to be raised in West Germany, or to be of Turkish ethnicity. Although
      the information on prone sleeping being a risk factor for SIDS became known among
      the population, these data suggest that subgroup-specific public intervention
      campaigns may be needed to reduce the prevalence of prone sleeping even further
      in those countries where no nationwide campaign has been initiated.

PMID- 10400555
TI  - Hepatitis C prevalence and risk factors in the northern Alberta dialysis
      population.
AB  - Hepatitis C virus (HCV) is an emerging global public health issue with particular
      relevance in multiply transfused renal dialysis patients. This cross-sectional
      study evaluated the prevalence and risk factors for HCV infection among renal
      dialysis patients in northern Alberta, Canada. Ninety-two percent of eligible
      patients (n = 336) provided informed consent to participate. Participants were
      interviewed to gather risk factor information and, using multiple logistic
      regression analysis with exact inference, a predictive model for HCV infection in
      this population was developed. The prevalence of HCV infection in the population
      was 6.5%, and all positive patients had at least one identifiable risk factor.
      The multivariate analysis showed that the risk of HCV infection was greater for
      those in the 18-55 years age category (odds ratio (OR) = 4.9, 95% confidence
      interval (CI) 1.2-27.9), patients who had been on dialysis > 5 years (OR = 3.7,
      95% CI 1.2-12.0), and patients who had > or = 2 high risk life-style behaviors
      (OR = 5.0, 95% CI 1.5-16.7). Transfusion prior to 1990 was marginally associated
      with HCV status (OR = 4.0, 95% CI 0.96-16.3). This study documented previously
      unreported life-style risk factors for HCV infection in patients with renal
      failure, confirmed the expected decline in transfusion-acquired HCV infection in
      this population, and provided evidence against nosocomial transmission of HCV.

PMID- 10400556
TI  - Hyperendemic focus of Q fever related to sheep and wind.
AB  - Q fever is a worldwide zoonosis which is caused by Coxiella burnetii and presents
      as both acute or chronic cases. The disease can be transmitted from animal
      reservoirs to humans by the inhalation of infected aerosols. The authors
      investigated the epidemiology of Q fever in the Bouches-du-Rhone district of
      southern France. The study area was centered around the small town of Martigues
      near the cities of Marseille and Aix-en-Provence, where the incidence of the
      disease seemed higher than in neighboring areas. Epidemiologic data included
      sheep breeding and wind. Between 1990 and 1995, Q fever was diagnosed in 289
      patients, leading to an incidence rate of 35.4 per 100,000 in the study area
      (range: 6-132), compared with 6.6 in the area of Marseille, and 11.4 in the area
      of Aix-en-Provence. There was a graphical and statistical relation between the
      sheep densities, the incidence of the disease, and the strong, local wind known
      as the Mistral, which blows from the northwest. Although Coxiella burnetii
      transmission is multifactorial, we may speculate that the high endemicity in the
      study area is related to a contamination by aerosols because the Mistral blows
      through the local steppe where 70,000 sheep are bred. This public health problem
      requires further studies in order to confirm this hypothesis, and to identify
      more individual and preventable risk factors.

PMID- 10400557
TI  - Evaluation of a food frequency questionnaire with weighed records, fatty acids,
      and alpha-tocopherol in adipose tissue and serum.
AB  - The authors examined the validity of a self-administered 180-item food frequency
      questionnaire in 125 Norwegian men aged 20-55 years who filled in the
      questionnaire and completed 14-day weighed records in fall 1995 to winter 1995/6.
      Spearman correlation coefficients between the two measurements ranged from 0.42
      for percent of energy from fat to 0.66 for sugar intake (median r = 0.51). On
      average, 39% of the men were classified in the same quartile with the two
      methods, and 3% in the opposite quartile. Correlation coefficients between intake
      of fatty acids estimated from the questionnaire and the relative amounts of fatty
      acids in adipose tissue were: linoleic acid (18:2, n-6), r = 0.38; alpha
      linolenic acid (18:3, n-3), r = 0.42; eicosapentaenoic acid (20:5, n-3), r =
      0.52; and docosahexaenoic acid (22:6, n-3), r = 0.49. The correlations for these
      fatty acids between the total serum lipids and the diet were 0.16, 0.28, 0.51 and
      0.52, respectively. The data suggest that very-long-chain n-3 fatty acids in
      adipose tissue and total serum lipids reflect the dietary intake of very-long
      chain n-3 fatty acids to the same degree. No associations were observed between
      intake of alpha-tocopherol and concentration in adipose tissue and serum.

PMID- 10400558
TI  - Mismeasurement and the resonance of strong confounders: correlated errors.
AB  - Confounding in epidemiology, and the limits of standard methods of control for an
      imperfectly measured confounder, have been understood for some time. However,
      most treatments of this problem are based on the assumption that errors of
      measurement in confounding and confounded variables are independent. This paper
      considers the situation in which a strong risk factor (confounder) and an
      inconsequential but suspected risk factor (confounded) are each measured with
      errors that are correlated; the situation appears especially likely to occur in
      the field of nutritional epidemiology. Error correlation appears to add little to
      measurement error as a source of bias in estimating the impact of a strong risk
      factor: it can add to, diminish, or reverse the bias induced by measurement error
      in estimating the impact of the inconsequential risk factor. Correlation of
      measurement errors can add to the difficulty involved in evaluating structures in
      which confounding and measurement error are present. In its presence, observed
      correlations among risk factors can be greater than, less than, or even opposite
      to the true correlations. Interpretation of multivariate epidemiologic structures
      in which confounding is likely requires evaluation of measurement error
      structures, including correlations among measurement errors.

PMID- 10400559
TI  - Transmission disequilibrium test (TDT) when only one parent is available: the 1
      TDT.
AB  - The transmission disequilibrium test (TDT) is a useful method to locate mutations
      linked to disease genes associated with complex diseases. TDT requires genotypes
      of affected individuals and their parents. Recently, Ewens and Spielman (Am J Hum
      Genet 1998;62:450-8) extended the TDT for use in sibships with at least one
      affected and one unaffected individual and devised a new test called the sib
      transmission/disequilibrium test (S-TDT). The S-TDT can be applied to diseases
      with late age at onset such as non-insulin-dependent diabetes mellitus,
      psychiatric disorders, and diseases related to aging. For some disorders, it
      might be relatively easy to obtain the genotype of one parent either because the
      other parent is not available for study or he/she is not cooperative. Curtis and
      Sham (Ann Hum Genet 1995;59:323-36) showed that bias in transmitting certain
      alleles is introduced if only heterozygous parents and homozygous offspring are
      used in the TDT. In this paper, the authors propose a new test, the 1-TDT, to
      detect linkage between a candidate locus and a disease locus using genotypes of
      affected individuals and only one available parent for each affected individual.
      The test is not biased under the null hypothesis of no linkage or association.
      The authors validate their test using both simulated and real data sets. Finally,
      they show how to combine data from different types of families.

PMID- 10400560
TI  - [Radiculoneuritis syndrome with hyperalbuminosis of cerebrospinal fluid without
      cellular reaction. Notes on clinical features and graphs of tendon reflexes.
      1916].

PMID- 10400561
TI  - [A form of subcutaneous calcifications associated with scleroderma. 1910].

PMID- 10400562
TI  - [Kaposi's disease simulating splenolymphatic lymphoma, toxoplasmosis, terminal
      cryptococcosis. 1979].

PMID- 10400563
TI  - Papers presented at the 106th Scientific Session of the Western Surgical
      Association. Indianapolis, Indiana, USA. November 16-18, 1998.

PMID- 10400564
TI  - Attempt to initiate dialogue with the American Society for Artificial Internal
      Organs and sister societies in Japan and Europe.

PMID- 10400565
TI  - Removal of skin lesions.

PMID- 10400566
TI  - Growing pains.

PMID- 10400567
TI  - Medicine and the law.

PMID- 10400568
TI  - Changing views on the nature of the bacterial cell: from biochemistry to
      cytology.

PMID- 10400569
TI  - Overexpression of Methanococcus voltae flagellin subunits in Escherichia coli and
      Pseudomonas aeruginosa: a source of archaeal preflagellin.
AB  - Methanococcus voltae is a flagellated member of the Archaea. Four highly similar
      flagellin genes have previously been cloned and sequenced, and the presence of
      leader peptides has been demonstrated. While the flagellins of M. voltae are
      predicted from their gene sequences to be approximately 22 to 25 kDa, sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of
      purified flagella revealed flagellin subunits with apparent molecular masses of
      31 and 33 kDa. Here we describe the expression of a M. voltae flagellin in the
      bacteria Escherichia coli and Pseudomonas aeruginosa. Both of these systems
      successfully generated a specific expression product with an apparently uncleaved
      leader peptide migrating at approximately 26.5 kDa. This source of preflagellin
      was used to detect the presence of preflagellin peptidase activity in the
      membranes of M. voltae. In addition to the native flagellin, a hybrid flagellin
      gene containing the sequence encoding the M. voltae FlaB2 mature protein fused to
      the P. aeruginosa pilin (PilA) leader peptide was constructed and transformed
      into both wild-type P. aeruginosa and a prepilin peptidase (pilD) mutant of P.
      aeruginosa. Based on migration in SDS-PAGE, the leader peptide appeared to be
      cleaved in the wild-type cells. However, the archaeal flagellin could not be
      detected by immunoblotting when expressed in the pilD mutant, indicating a role
      of the peptidase in the ultimate stability of the fusion product. When the +5
      position of the mature flagellin portion of the pilin-flagellin fusion was
      changed from glycine to glutamic acid (as in the P. aeruginosa pilin) and
      expressed in both wild-type and pilD mutant P. aeruginosa, the product detected
      by immunoblotting migrated slightly more slowly in the pilD mutant, indicating
      that the fusion was likely processed by the prepilin peptidase present in the
      wild type. Potential assembly of the cleaved fusion product by the type IV pilin
      assembly system in a P. aeruginosa PilA-deficient strain was tested, but no
      filaments were noted on the cell surface by electron microscopy.

PMID- 10400570
TI  - Eikenella corrodens phase variation involves a posttranslational event in pilus
      formation.
AB  - The human pathogen Eikenella corrodens synthesizes type IV pili and exhibits a
      phase variation involving the irreversible transition from piliated to
      nonpiliated variants. On solid medium, piliated variants form small (S-phase),
      corroding colonies whereas nonpiliated variants form large (L-phase),
      noncorroding colonies. We are studying the molecular basis of this phase
      variation in the clinical isolate E. corrodens VA1. A genomic fragment encoding
      the major type IV pilin was cloned from the S-phase variant of strain VA1.
      Sequence analysis of the fragment revealed four tandemly arranged potential open
      reading frames (ORFs), designated pilA1, pilA2, pilB, and hagA. Both pilA1 and
      pilA2 predict a type IV pilin. The protein predicted by pilB shares sequence
      identity with the Dichelobacter nodosus FimB fimbrial assembly protein. The
      protein predicted by hagA resembles a hemagglutinin. The region containing these
      four ORFs was designated the pilA locus. DNA hybridization and sequence analysis
      showed that the pilA locus of an L-phase variant of strain VA1 was identical to
      that of the S-phase variant. An abundant pilA1 transcript initiating upstream of
      pilA1 and terminating at a predicted hairpin structure between pilA1 and pilA2
      was detected by several assays, as was a less abundant read-through transcript
      encompassing pilA1, pilA2, and pilB. Transcription from the pilA locus was nearly
      indistinguishable between S- and L-phase variants. Electron microscopy and
      immunochemical analysis showed that S-phase variants synthesize, export, and
      assemble pilin into pili. In contrast, L-phase variants synthesize pilin but do
      not export and assemble it into pili. These data suggest that a posttranslational
      event, possibly involving an alteration in pilin export and assembly, is
      responsible for phase variation in E. corrodens.

PMID- 10400571
TI  - First chromosomal restriction map of Actinobacillus pleuropneumoniae and
      localization of putative virulence-associated genes.
AB  - Combined physical and genetic maps of the genomes of Actinobacillus
      pleuropneumoniae AP76 (serotype 7 clinical isolate) and of A. pleuropneumoniae
      ATCC 27088 (serotype 1 reference strain) were constructed by using the
      restriction endonucleases ApaI, AscI, NotI, and SalI. The chromosome sizes as
      determined by the addition of estimated fragment sizes were 2.4 Mbp, and both
      maps had a resolution of approximately 100 kbp. The linkages between the ApaI,
      AscI, NotI, and SalI fragments and their relative positions were determined by
      (i) fragment excision and redigestion and (ii) partial digests of defined
      fragments and Southern blot using end-standing probes. The single SalI site
      within the chromosome of strain A. pleuropneumoniae AP76 was defined as position
      1 of the map; for the map of A. pleuropneumoniae ATCC 27088, the corresponding
      SalI site was chosen. Putative virulence-associated genes (apx, omlA, sodA,
      tbpBA, ureC, and a repeat element) and housekeeping genes (glyA, metJ, recA, and
      rhoAP) were positioned on the physical maps and located on the ApaI and NotI
      fragments of A. pleuropneumoniae serotype reference strains.

PMID- 10400572
TI  - Increased rrn gene dosage causes intermittent transcription of rRNA in
      Escherichia coli.
AB  - When the number of rRNA (rrn) operons in an Escherichia coli cells is increased
      by adding an rrn operon on a multicopy plasmid, the rate of rRNA expression per
      operon is reduced to maintain a constant concentration of rRNA in the cell. We
      have used electron microscopy to examine rRNA transcription in cells containing a
      multicopy plasmid carrying rrnB. We found that there were fewer RNA polymerase
      molecules transcribing the rrn genes, as predicted from previous gene dosage
      studies. Furthermore, RNA polymerase molecules were arranged in irregularly
      spaced groups along the operon. No apparent pause or transcription termination
      sites that would account for the irregular spacing of the groups of polymerase
      molecules were observed. We also found that the overall transcription elongation
      rate was unchanged when the rrn gene dosage was increased. Our data suggest that
      when rrn gene dosage is increased, initiation events, or promoter-proximal
      elongation events, are interrupted at irregular time intervals.

PMID- 10400574
TI  - Identification of site-specific recombination genes int and xis of the Rhizobium
      temperate phage 16-3.
AB  - Phage 16-3 is a temperate phage of Rhizobium meliloti 41 which integrates its
      genome with high efficiency into the host chromosome by site-specific
      recombination through DNA sequences of attB and attP. Here we report the
      identification of two phage-encoded genes required for recombinations at these
      sites: int (phage integration) and xis (prophage excision). We concluded that Int
      protein of phage 16-3 belongs to the integrase family of tyrosine recombinases.
      Despite similarities to the cognate systems of the lambdoid phages, the 16-3 int
      xis att system is not active in Escherichia coli, probably due to requirements
      for host factors that differ in Rhizobium meliloti and E. coli. The application
      of the 16-3 site-specific recombination system in biotechnology is discussed.

PMID- 10400575
TI  - Visualization of AqpZ-mediated water permeability in Escherichia coli by
      cryoelectron microscopy.
AB  - Transport of water across the plasma membrane is a fundamental process occurring
      in all living organisms. In bacteria, osmotic movement of water across the
      cytoplasmic membrane is needed to maintain cellular turgor; however, the
      molecular mechanisms of this process are poorly defined. Involvement of aquaporin
      water channels in bacterial water permeability was suggested by the recent
      discovery of the aquaporin gene, aqpZ, in Escherichia coli. By employing
      cryoelectron microscopy to compare E. coli cells containing (AqpZ+) and lacking
      (AqpZ-) aquaporin, we show that the AqpZ water channel rapidly mediates large
      water fluxes in response to sudden changes in extracellular osmolarity. These
      findings (i) demonstrate for the first time functional expression of a
      prokaryotic water channel, (ii) evidence the bidirectional water channel feature
      of AqpZ, (iii) document a role for AqpZ in bacterial osmoregulation, and (iv)
      define a suitable model for studying the physiology of prokaryotic water
      transport.

PMID- 10400573
TI  - A novel Sinorhizobium meliloti operon encodes an alpha-glucosidase and a
      periplasmic-binding-protein-dependent transport system for alpha-glucosides.
AB  - The most abundant carbon source transported into legume root nodules is
      photosynthetically produced sucrose, yet the importance of its metabolism by
      rhizobia in planta is not yet known. To identify genes involved in sucrose uptake
      and hydrolysis, we screened a Sinorhizobium meliloti genomic library and
      discovered a segment of S. meliloti DNA which allows Ralstonia eutropha to grow
      on the alpha-glucosides sucrose, maltose, and trehalose. Tn5 mutagenesis
      localized the required genes to a 6.8-kb region containing five open reading
      frames which were named agl, for alpha-glucoside utilization. Four of these
      (aglE, aglF, aglG, and aglK) appear to encode a periplasmic-binding-protein
      dependent sugar transport system, and one (aglA) appears to encode an alpha
      glucosidase with homology to family 13 of glycosyl hydrolases. Cosmid-borne agl
      genes permit uptake of radiolabeled sucrose into R. eutropha cells. Analysis of
      the properties of agl mutants suggests that S. meliloti possesses at least one
      additional alpha-glucosidase as well as a lower-affinity transport system for
      alpha-glucosides. It is possible that the Fix+ phenotype of agl mutants on
      alfalfa is due to these additional functions. Loci found by DNA sequencing to be
      adjacent to aglEFGAK include a probable regulatory gene (aglR), zwf and edd,
      which encode the first two enzymes of the Entner-Doudoroff pathway, pgl, which
      shows homology to a gene encoding a putative phosphogluconolactonase, and a novel
      Rhizobium-specific repeat element.

PMID- 10400576
TI  - The Yersinia enterocolitica pYV virulence plasmid contains multiple intrinsic DNA
      bends which melt at 37 degrees C.
AB  - Temperature has a pleiotropic effect on Yersinia enterocolitica gene expression.
      Temperature-dependent phenotypes include the switching between two type III
      protein secretion systems, flagellum biosynthesis (</=30 degrees C) and virulence
      plasmid-encoded Yop secretion (37 degrees C). The mechanism by which temperature
      exerts this change in genetic programming is unclear; however, altered gene
      expression by temperature-dependent changes in DNA topology has been implicated.
      Here, we present evidence that the Y. enterocolitica virulence plasmid, pYV,
      undergoes a conformational transition between 30 and 37 degrees C. Using a
      simplified two-dimensional, single-gel assay, we show that pYV contains multiple
      regions of intrinsic curvature, including virF, the positive activator of
      virulence genes. These bends are detectable at 30 degrees C but melt at 37
      degrees C, the temperature at which the cells undergo phenotypic switching. We
      also show that pACYC184, a plasmid used as a reporter of temperature-induced
      changes in DNA supercoiling, has a single region of intrinsic bending detected by
      our assay. Topoisomers of pACYC184, with and without this bend, isolated from Y.
      enterocolitica were resolved by using chloroquine gels. The single bend has a
      dramatic influence on temperature-dependent DNA supercoiling. These data suggest
      that the Y. enterocolitica pYV plasmid may undergo a conformational change at the
      host temperature due to melting of DNA bends followed by compensatory adjustments
      in superhelical density. Hence, changes in DNA topology may be the temperature
      sensing mechanism for virulence gene expression in Y. enterocolitica and other
      enteric pathogens.

PMID- 10400577
TI  - Structural and functional analyses of photosynthetic regulatory genes regA and
      regB from Rhodovulum sulfidophilum, Roseobacter denitrificans, and Rhodobacter
      capsulatus.
AB  - Genes coding for putative RegA, RegB, and SenC homologues were identified and
      characterized in the purple nonsulfur photosynthetic bacteria Rhodovulum
      sulfidophilum and Roseobacter denitrificans, species that demonstrate weak or no
      oxygen repression of photosystem synthesis. This additional sequence information
      was then used to perform a comparative analysis with previously sequenced RegA,
      RegB, and SenC homologues obtained from Rhodobacter capsulatus and Rhodobacter
      sphaeroides. These are photosynthetic bacteria that exhibit a high level of
      oxygen repression of photosystem synthesis controlled by the RegA-RegB two
      component regulatory system. The response regulator, RegA, exhibits a remarkable
      78.7 to 84.2% overall sequence identity, with total conservation within a
      putative helix-turn-helix DNA-binding motif. The RegB sensor kinase homologues
      also exhibit a high level of sequence conservation (55.9 to 61.5%) although these
      additional species give significantly different responses to oxygen. A Rhodovulum
      sulfidophilum mutant lacking regA or regB was constructed. These mutants produced
      smaller amounts of photopigments under aerobic and anaerobic conditions,
      indicating that the RegA-RegB regulon controls photosynthetic gene expression in
      this bacterium as it does as in Rhodobacter species. Rhodobacter capsulatus regA-
      or regB-deficient mutants recovered the synthesis of a photosynthetic apparatus
      that still retained regulation by oxygen tension when complemented with reg genes
      from Rhodovulum sulfidophilum and Roseobacter denitrificans. These results
      suggest that differential expression of photosynthetic genes in response to
      aerobic and anaerobic growth conditions is not the result of altered redox
      sensing by the sensor kinase protein, RegB.

PMID- 10400578
TI  - Heterologous expression of correctly assembled methylamine dehydrogenase in
      Rhodobacter sphaeroides.
AB  - The biosynthesis of methylamine dehydrogenase (MADH) from Paracoccus
      denitrificans requires four genes in addition to those that encode the two
      structural protein subunits, mauB and mauA. The accessory gene products appear to
      be required for proper export of the protein to the periplasm, synthesis of the
      tryptophan tryptophylquinone (TTQ) prosthetic group, and formation of several
      structural disulfide bonds. To accomplish the heterologous expression of
      correctly assembled MADH, eight genes from the methylamine utilization gene
      cluster of P. denitrificans, mauFBEDACJG, were placed under the regulatory
      control of the coxII promoter of Rhodobacter sphaeroides and introduced into R.
      sphaeroides by using a broad-host-range vector. The heterologous expression of
      MADH was constitutive with respect to carbon source, whereas the native mau
      promoter allows induction only when cells are grown in the presence of
      methylamine as a sole carbon source and is repressed by other carbon sources. The
      recombinant MADH was localized exclusively in the periplasm, and its physical,
      spectroscopic, kinetic and redox properties were indistinguishable from those of
      the enzyme isolated from P. denitrificans. These results indicate that mauM and
      mauN are not required for MADH or TTQ biosynthesis and that mauFBEDACJG are
      sufficient for TTQ biosynthesis, since R. sphaeroides cannot synthesize TTQ. A
      similar construct introduced into Escherichia coli did not produce detectable
      MADH activity or accumulation of the mauB and mauA gene products but did lead to
      synthesizes of amicyanin, the mauC gene product. This finding suggests that
      active recombinant MADH is not expressed in E. coli because one of the accessory
      gene products is not functionally expressed. This study illustrates the potential
      utility of R. sphaeroides and the coxII promoter for heterologous expression of
      complex enzymes such as MADH which cannot be expressed in E. coli. These results
      also provide the foundation for future studies on the molecular mechanisms of
      MADH and TTQ biosynthesis, as well as a system for performing site-directed
      mutagenesis of the MADH gene and other mau genes.

PMID- 10400579
TI  - The genes encoding formamidopyrimidine and MutY DNA glycosylases in Escherichia
      coli are transcribed as part of complex operons.
AB  - Escherichia coli formamidopyrimidine (Fpg) DNA glycosylase and MutY DNA
      glycosylase are base excision repair proteins that work together to protect cells
      from the mutagenic effects of the commonly oxidized guanine product 7,8-dihydro-8
      oxoguanine. The genes encoding these proteins, fpg and mutY, are both
      cotranscribed as part of complex operons. fpg is the terminal gene in an operon
      with the gene order radC, rpmB, rpmG, and fpg. This operon has transcription
      initiation sites upstream of radC, in the radC coding region, and immediately
      upstream of fpg. There is a strong attenuator in the rpmG-fpg intergenic region
      and three transcription termination sites downstream of fpg. There is an
      additional site, in the radC-rpmB intergenic region, that corresponds either to a
      transcription initiation site or to an RNase E or RNase III cleavage site. mutY
      is the first gene in an operon with the gene order mutY, yggX, mltC, and nupG.
      This operon has transcription initiation sites upstream of mutY, in the mutY
      coding region, and immediately upstream of nupG. There also appear to be
      attenuators in the yggX-mltC and mltC-nupG intergenic regions. The order of genes
      in these operons has been conserved or partially conserved only in other closely
      related gram-negative bacteria, although it is not known whether the genes are
      cotranscribed in these other organisms.

PMID- 10400580
TI  - The unique chaperone operon of Thermotoga maritima: cloning and initial
      characterization of a functional Hsp70 and small heat shock protein.
AB  - The hyperthermophilic eubacterium Thermotoga maritima possesses an operon
      encoding an Hsp70 molecular chaperone protein and a protein with meaningful
      homology to the small heat shock protein family of chaperones. This represents
      the first demonstrated co-operon organization for these two important classes of
      molecular chaperones. We have cloned and initially characterized these proteins
      as functional chaperones in vitro: the Hsp70 is capable of ATP hydrolysis and
      substrate binding, and the small heat shock protein can suppress protein
      aggregation and stably bind a refolding-competent substrate. In addition, the
      primary sequence of the Hsp70 is used to infer the phylogenetic relationships of
      T. maritima, one of the deepest-branching eubacteria known.

PMID- 10400581
TI  - Site-specific recombination of bacteriophage P22 does not require integration
      host factor.
AB  - Site-specific recombination by phages lambda and P22 is carried out by
      multiprotein-DNA complexes. Integration host factor (IHF) facilitates lambda site
      specific recombination by inducing DNA bends necessary to form an active
      recombinogenic complex. Mutants lacking IHF are over 1,000-fold less proficient
      in supporting lambda site-specific recombination than wild-type cells. Although
      the attP region of P22 contains strong IHF binding sites, in vivo measurements of
      integration and excision frequencies showed that infecting P22 phages can perform
      site-specific recombination to its maximum efficiency in the absence of IHF. In
      addition, a plasmid integration assay showed that integrative recombination
      occurs equally well in wild-type and ihfA mutant cells. P22 integrative
      recombination is also efficient in Escherichia coli in the absence of functional
      IHF. These results suggest that nucleoprotein structures proficient for
      recombination can form in the absence of IHF or that another factor(s) can
      substitute for IHF in the formation of complexes.

PMID- 10400582
TI  - A Vibrio cholerae LysR homolog, AphB, cooperates with AphA at the tcpPH promoter
      to activate expression of the ToxR virulence cascade.
AB  - We describe here a new member of the LysR family of transcriptional regulators,
      AphB, which is required for activation of the Vibrio cholerae ToxR virulence
      cascade. AphB activates the transcription of the tcpPH operon in response to
      environmental stimuli, and this process requires cooperation with a second
      protein, AphA. The expression of neither aphA or aphB is strongly regulated by
      environmental stimuli, raising the possibility that the activities of the
      proteins themselves may be influenced under various conditions. Strains of the El
      Tor biotype of V. cholerae typically exhibit lower expression of ToxR-regulated
      virulence genes in vitro than classical strains and require specialized culture
      conditions (AKI medium) to induce high-level expression. We show here that
      expression of aphB from the tac promoter in El Tor biotype strains dramatically
      increases virulence gene expression to levels similar to those observed in
      classical strains under all growth conditions examined. These results suggest
      that AphB plays a role in the differential regulation of virulence genes between
      the two disease-causing biotypes.

PMID- 10400583
TI  - Characterization and submitochondrial localization of the alpha subunit of the
      mitochondrial processing peptidase from the aquatic fungus Blastocladiella
      emersonii.
AB  - In an effort to investigate the molecular mechanisms responsible for the drastic
      morphological changes the mitochondria go through during the life cycle of the
      aquatic fungus Blastocladiella emersonii, the gene encoding the alpha subunit of
      the mitochondrial processing peptidase (alpha-MPP) was isolated. Nucleotide
      sequence analysis revealed that the predicted alpha-MPP polypeptide comprises 474
      amino acids with a calculated molecular mass of 51,900 Da, presenting a
      characteristic mitochondrial signal sequence. Northern blot analysis indicated a
      single 1.4-kb transcript encoding the B. emersonii alpha-MPP, whose levels
      decrease during sporulation, becoming very low in the zoospore, and increase
      again during germination. Despite these variations in mRNA concentration, B.
      emersonii alpha-MPP protein levels do not change significantly during the life
      cycle of the fungus, as observed in Western blots. Experiments to investigate the
      submitochondrial localization of B. emersonii alpha-MPP and beta-MPP were also
      carried out, and the results indicated that both subunits are associated with the
      mitochondrial inner membrane, possibly as part of the bc1 complex, as described
      for plants.

PMID- 10400584
TI  - A mycobacterial extracytoplasmic sigma factor involved in survival following heat
      shock and oxidative stress.
AB  - Extracytoplasmic function (ECF) sigma factors are a heterogeneous group of
      alternative sigma factors that regulate gene expression in response to a variety
      of conditions, including stress. We previously characterized a mycobacterial ECF
      sigma factor, SigE, that contributes to survival following several distinct
      stresses. A gene encoding a closely related sigma factor, sigH, was cloned from
      Mycobacterium tuberculosis and Mycobacterium smegmatis. A single copy of this
      gene is present in these and other fast- and slow-growing mycobacteria, including
      M. fortuitum and M. avium. While the M. tuberculosis and M. smegmatis sigH genes
      encode highly similar proteins, there are multiple differences in adjacent genes.
      The single in vivo transcriptional start site identified in M. smegmatis and one
      of two identified in M. bovis BCG were found to have -35 promoter sequences that
      match the ECF-dependent -35 promoter consensus. Expression from these promoters
      was strongly induced by 50 degrees C heat shock. In comparison to the wild type,
      an M. smegmatis sigH mutant was found to be more susceptible to cumene
      hydroperoxide stress but to be similar in logarithmic growth, stationary-phase
      survival, and survival following several other stresses. Survival of an M.
      smegmatis sigH sigE double mutant was found to be markedly decreased following 53
      degrees C heat shock and following exposure to cumene hydroperoxide. Expression
      of the second gene in the sigH operon is required for complementation of the sigH
      stress phenotypes. SigH is an alternative sigma factor that plays a role in the
      mycobacterial stress response.

PMID- 10400585
TI  - Characterization of the serogroup O11 O-antigen locus of Pseudomonas aeruginosa
      PA103.
AB  - We previously cloned a genomic DNA fragment from the serogroup O11 Pseudomonas
      aeruginosa strain PA103 that contained all genes necessary for O-antigen
      synthesis and directed the expression of serogroup O11 antigen on recombinant
      Escherichia coli and Salmonella. To elucidate the pathway of serogroup O11
      antigen synthesis, the nucleotide sequence of the biosynthetic genes was
      determined. Eleven open reading frames likely to be involved in serogroup O11 O
      antigen biosynthesis were identified and are designated in order as wzzPaO111
      (wzz from P. aeruginosa serogroup O11), wzxPaO11, wbjA, wzyPaO11, wbjB to wbjF,
      wbpLO11 and wbpMO11 (wbpL and wbpM from serogroup O11). Consistent with previous
      descriptions of O-antigen biosynthetic gene loci, the entire region with the
      exception of wbpMO11 has a markedly reduced G+C content relative to the
      chromosomal average. WzyPaO11 shows no significant similarity at the protein or
      DNA sequence level to any database sequence and is very hydrophobic, with 10 to
      12 putative transmembrane domains, both typical characteristics of O-antigen
      polymerases. A nonpolar chromosomal insertion mutation in wzyPaO11 in P.
      aeruginosa PA103 confirmed the identity of this gene. There is striking
      similarity between WbjBCDE and Cap(5/8)EFGL, involved in type 5 and type 8
      capsule biosynthesis in Staphylococcus aureus. There is nearly total identity
      between wbpMO11 and wbpMO5, previously shown by others to be present in all 20 P.
      aeruginosa serogroups. Using similarity searches, we have assigned functions to
      the proteins encoded by the PA103 O-antigen locus and present the potential steps
      in the pathway for the biosynthesis of P. aeruginosa serogroup O11 O antigen.

PMID- 10400586
TI  - Glucose transport in the extremely thermoacidophilic Sulfolobus solfataricus
      involves a high-affinity membrane-integrated binding protein.
AB  - The archaeon Sulfolobus solfataricus grows optimally at 80 degrees C and pH 2.5
      to 3.5 on carbon sources such as yeast extracts, tryptone, and various sugars.
      Cells rapidly accumulate glucose. This transport activity involves a membrane
      bound glucose-binding protein that interacts with its substrate with very high
      affinity (Kd of 0. 43 microM) and retains high glucose affinity at very low pH
      values (as low as pH 0.6). The binding protein was extracted with detergent and
      purified to homogeneity as a 65-kDa glycoprotein. The gene coding for the binding
      protein was identified in the S. solfataricus P2 genome by means of the amino
      terminal amino acid sequence of the purified protein. Sequence analysis suggests
      that the protein is anchored to the membrane via an amino-terminal transmembrane
      segment. Neighboring genes encode two membrane proteins and an ATP-binding
      subunit that are transcribed in the reverse direction, whereas a homologous gene
      cluster in Pyrococcus horikoshii OT3 was found to be organized in an operon.
      These data indicate that S. solfataricus utilizes a binding-protein-dependent ATP
      binding cassette transporter for the uptake of glucose.

PMID- 10400587
TI  - The genes rubA and rubB for alkane degradation in Acinetobacter sp. strain ADP1
      are in an operon with estB, encoding an esterase, and oxyR.
AB  - Alkanes are oxidized in Acinetobacter sp. strain ADP1 by a three-component alkane
      monooxygenase, composed of alkane hydroxylase, rubredoxin, and rubredoxin
      reductase. rubA and rubB encode rubredoxin and a NAD(P)H-dependent rubredoxin
      reductase. We demonstrate here that single base pair substitutions in rubA or
      rubB lead to defects in alkane degradation, showing that both genes are essential
      for alkane utilization. Differences in the degradation capacity for hexadecane
      and dodecane in these mutants are discussed. Two genes, estB and oxyR, are
      located downstream of rubB, but are not necessary for alkane degradation. estB
      encodes a functional esterase. oxyR encodes a LysR-type transcriptional
      regulator, conferring resistance to hydrogen peroxide. rubA, rubB, estB, and oxyR
      constitute an operon, which is constitutively transcribed from a sigma70
      promoter, and an estB-oxyR containing message is also transcribed from an
      internal promoter.

PMID- 10400588
TI  - Interaction of Bacillus subtilis Fur (ferric uptake repressor) with the dhb
      operator in vitro and in vivo.
AB  - Bacillus subtilis contains three metalloregulatory proteins belonging to the
      ferric uptake repressor (Fur) family: Fur, Zur, and PerR. We have overproduced
      and purified Fur protein and analyzed its interaction with the operator region
      controlling the expression of the dihydroxybenzoate siderophore biosynthesis
      (dhb) operon. The purified protein binds with high affinity and selectivity to
      the dhb regulatory region. DNA binding does not require added iron, nor is
      binding reduced by dialysis of Fur against EDTA or treatment with Chelex. Fur
      selectively inhibits transcription from the dhb promoter by sigmaA RNA
      polymerase, even if Fur is added after RNA polymerase holoenzyme. Since neither
      DNA binding nor inhibition of transcription requires the addition of ferrous ion
      in vitro, the mechanism by which iron regulates Fur function in vivo is not
      obvious. Mutagenesis of the fur gene reveals that in vivo repression of the dhb
      operon by iron requires His97, a residue thought to be involved in iron sensing
      in other Fur homologs. Moreover, we identify His96 as a second likely iron
      ligand, since a His96Ala mutant mediates repression at 50 microM but not at 5
      microM iron. Our data lead us to suggest that Fur is able to bind DNA
      independently of bound iron and that the in vivo role of iron is to counteract
      the effect of an inhibitory factor, perhaps another metal ion, that antagonizes
      this DNA-binding activity.

PMID- 10400589
TI  - The chemotactic response of Vibrio anguillarum to fish intestinal mucus is
      mediated by a combination of multiple mucus components.
AB  - Chemotactic motility has previously been shown to be essential for the virulence
      of Vibrio anguillarum in waterborne infections of fish. To investigate the
      mechanisms by which chemotaxis may function during infection, mucus was isolated
      from the intestinal and skin epithelial surfaces of rainbow trout. Chemotaxis
      assays revealed that V. anguillarum swims towards both types of mucus, with a
      higher chemotactic response being observed for intestinal mucus. Work was
      performed to examine the basis, in terms of mucus composition, of this
      chemotactic response. Intestinal mucus was analyzed by using chromatographic and
      mass spectrometric techniques, and the compounds identified were tested in a
      chemotaxis assay to determine the attractants present. A number of mucus
      associated components, in particular, amino acids and carbohydrates, acted as
      chemoattractants for V. anguillarum. Importantly, only upon combination of these
      attractants into a single mixture were levels of chemotactic activity similar to
      those of intestinal mucus generated. A comparative analysis of skin mucus
      revealed its free amino acid and carbohydrate content to be considerably lower
      than that of the more chemotactically active intestinal mucus. To study whether
      host specificity exists in relation to vibrio chemotaxis towards mucus,
      comparisons with a human Vibrio pathogen were made. A cheR mutant of a Vibrio
      cholerae El Tor strain was constructed, and it was found that V. cholerae and V.
      anguillarum exhibit a chemotactic response to mucus from several animal sources
      in addition to that from the human jejunum and fish epithelium, respectively.

PMID- 10400590
TI  - Identification and characterization of a new lipoprotein, NlpI, in Escherichia
      coli K-12.
AB  - We report here the identification of a new lipoprotein, NlpI, in Escherichia coli
      K-12. The NlpI structural gene (nlpI) is located between the genes pnp
      (polynucleotide phosphorylase) and deaD (RNA helicase) at 71 min on the E. coli
      chromosome. The nlpI gene encodes a putative polypeptide of approximately 34 kDa,
      and multiple lines of evidence clearly demonstrate that NlpI is indeed a
      lipoprotein. An nlpI::cm mutation rendered growth of the cells osmotically
      sensitive, and incubation of the insertion mutant at an elevated temperature
      resulted in the formation of filaments. The altered phenotype of the mutant was a
      direct consequence of the mutation in nlpI, since it was complemented by the wild
      type nlpI gene alone. Overexpression of the unaltered nlpI gene in wild-type
      cells resulted in the loss of the rod morphology and the formation of single
      prolate ellipsoids and pairs of prolate ellipsoids joined by partial
      constrictions. NlpI may be important for an as-yet-undefined step in the overall
      process of cell division.

PMID- 10400591
TI  - Mycobacterium tuberculosis rrn promoters: differential usage and growth rate
      dependent control.
AB  - Mycobacterium tuberculosis is a slow-growing pathogen and is characterized by a
      low content of RNA per unit of DNA. rRNAs represent a major proportion of the
      total RNA pool, and the entire requirement for rRNA is met by transcription from
      a single rrn operon that is driven by two promoters, P1 and P3. This study
      attempted to analyze the specific role of the rrn promoter in determining the
      characteristically low levels of RNA in M. tuberculosis. For this purpose, the
      activity of the M. tuberculosis rrn promoter as a function of the growth rate was
      studied by rrn-lacZ promoter fusion, hybridization, and primer extension analysis
      in M. smegmatis. rrn promoter signals were faithfully recognized in M. smegmatis
      cultures harboring the rrn-lacZ promoter construct. In M. smegmatis cultures that
      displayed doubling times varying between 3.06 and 6.5 h, beta-galactosidase
      activity increased approximately sixfold in proportion to the growth rate (mu).
      There was a corresponding increase in the amount of lacZ-specific mRNA, while the
      plasmid copy number remained essentially unchanged. For any given mu, the P3
      promoter was approximately twofold more efficiently utilized than the P1
      promoter. Since both promoters of the M. tuberculosis rrn operon are regulatable
      as a function of growth rate in M. smegmatis cultures, it is implied that the
      inherent structure or sequence of the rrn promoter per se is not primarily
      responsible for the observed lack of modulation of RNA synthesis in M.
      tuberculosis.

PMID- 10400592
TI  - Regulated expression of a highly conserved regulatory gene cluster is necessary
      for controlling photosynthesis gene expression in response to anaerobiosis in
      Rhodobacter capsulatus.
AB  - We utilized primer extension analysis to demonstrate that the divergently
      transcribed regB and senC-regA-hvrA transcripts contain stable 5' ends 43
      nucleotides apart within the regB-senC intergenic region. DNA sequence analysis
      indicates that this region contains two divergent promoters with overlapping
      sigma70 type -35 and -10 promoter recognition sequences. In vivo analysis of
      expression patterns of regB::lacZ and senC-regA-hvrA::lacZ reporter gene fusions
      demonstrates that the regB and senC-regA-hvrA transcripts are both negatively
      regulated by the phosphorylated form of the global response regulator RegA. DNase
      I protection assays with a constitutively active variant of RegA indicate that
      RegA binds between regB and senC overlapping -10 and -35 promoter recognition
      sequences. Two mutations were also isolated in a regB-deficient background that
      increased expression of the senC-regA-hvrA operon 10- and 5-fold, respectively.
      As a consequence of increased RegA expression, these mutants exhibited elevated
      aerobic and anaerobic photosynthesis (puf) gene expression, even in the absence
      of the sensor kinase RegB. These results indicate that autoregulation by RegA is
      a factor contributing to the maintenance of an optimal low level of RegA
      expression that allows responsiveness to activation by phosphorylation.

PMID- 10400593
TI  - Mutagenesis of the Agrobacterium VirE2 single-stranded DNA-binding protein
      identifies regions required for self-association and interaction with VirE1 and a
      permissive site for hybrid protein construction.
AB  - The VirE2 single-stranded DNA-binding protein (SSB) of Agrobacterium tumefaciens
      is required for delivery of T-DNA to the nuclei of susceptible plant cells. By
      yeast two-hybrid and immunoprecipitation analyses, VirE2 was shown to self
      associate and to interact with VirE1. VirE2 mutants with small deletions or
      insertions of a 31-residue oligopeptide (i31) at the N or C terminus or with an
      i31 peptide insertion at Leu236 retained the capacity to form homomultimers. By
      contrast, VirE2 mutants with modifications outside a central region located
      between residues 320 and 390 retained the capacity to interact with VirE1. These
      findings suggest the tertiary structure of VirE2 is important for homomultimer
      formation whereas a central domain mediates formation of a complex with VirE1.
      The capacity of VirE2 mutants to interact with full-length VirE2 in the yeast
      Saccharomyces cerevisiae correlated with the abundance of the mutant proteins in
      A. tumefaciens, suggesting that VirE2 is stabilized by homomultimerization in the
      bacterium. We further characterized the promoter and N- and C-terminal sequence
      requirements for synthesis of functional VirE2. A PvirB::virE2 construct yielded
      functional VirE2 protein as defined by complementation of a virE2 null mutation.
      By contrast, PvirE or Plac promoter constructs yielded functional VirE2 only if
      virE1 was coexpressed with virE2. Deletion of 10 or 9 residues from the N or C
      terminus of VirE2, respectively, or addition of heterologous peptides or proteins
      to either terminus resulted in a loss of protein function. However, an i31
      peptide insertion at Tyr39 had no effect on protein function as defined by the
      capacity of the mutant protein to (i) interact with native VirE2, (ii) interact
      with VirE1, (iii) accumulate at abundant levels in A. tumefaciens, and (iv)
      restore wild-type virulence to a virE2 null mutant. We propose that Tyr39 of
      VirE2 corresponds to a permissive site for insertion of heterologous peptides or
      proteins of interest for delivery across kingdom boundaries.

PMID- 10400594
TI  - An additional regulatory gene for actinorhodin production in Streptomyces
      lividans involves a LysR-type transcriptional regulator.
AB  - The sequence of a 4.8-kbp DNA fragment adjacent to the right-hand end of the
      actinorhodin biosynthetic (act) cluster downstream of actVB-orf6 from
      Streptomyces coelicolor A3(2) reveals six complete open reading frames, named
      orf7 to orf12. The deduced amino acid sequences from orf7, orf10, and orf11 show
      significant similarities with the following products in the databases: a putative
      protein from the S. coelicolor SCP3 plasmid, LysR-type transcriptional
      regulators, and proteins belonging to the family of short-chain
      dehydrogenases/reductases, respectively. The deduced product of orf8 reveals low
      similarities with several methyltransferases from different sources, while orf9
      and orf12 products show no similarities with other known proteins. Disruptions of
      orf10 and orf11 genes in S. coelicolor appear to have no significant effect on
      the production of actinorhodin. Nevertheless, disruption or deletion of orf10 in
      Streptomyces lividans causes actinorhodin overproduction. The introduction of
      extra copies of orf10 and orf11 genes in an S. coelicolor actIII mutant restores
      the ability to produce actinorhodin. Transcriptional analysis and DNA
      footprinting indicate that Orf10 represses its own transcription and regulates
      orf11 transcription, expression of which might require the presence of an unknown
      inducer. No DNA target for Orf10 protein was found within the act cluster.

PMID- 10400596
TI  - Mutational analysis of the cbb operon (CO2 assimilation) promoter of Ralstonia
      eutropha.
AB  - PL promoters direct the transcription of the duplicated cbb operons from the
      facultative chemoautotroph Ralstonia eutropha H16. The operons encode most
      enzymes of the Calvin-Benson-Bassham carbon reduction cycle required for CO2
      assimilation. Their transcription depends on the activator protein CbbR.
      Structure-function relationships in the cloned chromosomal promoter region were
      analyzed by site-directed mutagenesis. PL was altered in its presumed hexameric 
      35 and/or -10 box or in the spacer region between the boxes to achieve a greater
      or lesser resemblance to the structure of the sigma70 consensus promoter of
      Escherichia coli. PL::lacZ transcriptional fusions of various promoter variants
      were assayed in transconjugant strains of R. eutropha as well as in corresponding
      cbbR deletion mutants. Mutations increasing the similarity of the -35 and/or -10
      box to the consensus sequence stimulated PL activity to various extents, whereas
      mutations deviating from the consensus decreased the activity. The length of the
      spacer region also proved to be critical. The conversion of the boxes, either
      individually or simultaneously, into the consensus sequences resulted in a highly
      active PL. All improved PL mutants, however, retained the activation under
      inducing or derepressing growth conditions, although the full-consensus promoter
      was nearly constitutive. They were also activated in the cbbR mutants. The
      activity of the overlapping, divergently oriented cbbR promoter was less affected
      by the mutations. The half- and full-consensus PL mutants were comparably active
      in E. coli. Two major conclusions were drawn from the results: (i) the location
      and function of PL were verified, and (ii) indirect evidence was obtained for the
      involvement of another regulator(s), besides CbbR, in the transcriptional control
      of the R. eutropha cbb operons.

PMID- 10400595
TI  - A region of sigmaK involved in promoter activation by GerE in Bacillus subtilis.
AB  - During endospore formation in Bacillus subtilis, the DNA binding protein GerE
      stimulates transcription from several promoters that are used by RNA polymerase
      containing sigmaK. GerE binds to a site on one of these promoters, cotX, that
      overlaps its -35 region. We tested the model that GerE interacts with sigmaK at
      the cotX promoter by seeking amino acid substitutions in sigmaK that interfered
      with GerE-dependent activation of the cotX promoter but which did not affect
      utilization of the sigmaK-dependent, GerE-independent promoter gerE. We
      identified two amino acid substitutions in sigmaK, E216K and H225Y, that decrease
      cotX promoter utilization but do not affect gerE promoter activity. Alanine
      substitutions at these positions had similar effects. We also examined the
      effects of the E216A and H225Y substitutions in sigmaK on transcription in vitro.
      We found that these substitutions specifically reduced utilization of the cotX
      promoter. These and other results suggest that the amino acid residues at
      positions 216 and 225 are required for GerE-dependent cotX promoter activity,
      that the histidine at position 225 of sigmaK may interact with GerE at the cotX
      promoter, and that this interaction may facilitate the initial binding of sigmaK
      RNA polymerase to the cotX promoter. We also found that the alanine substitutions
      at positions 216 and 225 of sigmaK had no effect on utilization of the GerE
      dependent promoter cotD, which contains GerE binding sites that do not overlap
      with its -35 region.

PMID- 10400597
TI  - Genetic and molecular analysis of cglB, a gene essential for single-cell gliding
      in Myxococcus xanthus.
AB  - Gliding movements of individual isolated Myxococcus xanthus cells depend on the
      genes of the A-motility system (agl and cgl genes). Mutants carrying defects in
      those genes are unable to translocate as isolated cells on solid surfaces. The
      motility defect of cgl mutants can be transiently restored to wild type by
      extracellular complementation upon mixing mutant cells with wild-type or other
      motility mutant cells. To develop a molecular understanding of the function of a
      Cgl protein in gliding motility, we cloned the cglB wild-type allele by genetic
      complementation of the mutant phenotype. The nucleotide sequence of a 2.85-kb
      fragment was determined and shown to encode two complete open reading frames. The
      CglB protein was determined to be a 416-amino-acid putative lipoprotein with an
      unusually high cysteine content. The CglB antigen localized to the membrane
      fraction. The swarming and gliding defects of a constructed DeltacglB mutant were
      fully restored upon complementation with the cglB wild-type allele. Experiments
      with a cglB allele encoding a CglB protein with a polyhistidine tag at the C
      terminus showed that this allele also promoted wild-type levels of swarming and
      single-cell gliding, but was unable to stimulate DeltacglB cells to move.
      Possible functions of CglB as a mechanical component or as a signal protein in
      single cell gliding are discussed.

PMID- 10400599
TI  - Isolation and characterization of mutations in the Escherichia coli regulatory
      protein XapR.
AB  - In this work, the LysR-type protein XapR has been subjected to a mutational
      analysis. XapR regulates the expression of xanthosine phosphorylase (XapA), a
      purine nucleoside phosphorylase in Escherichia coli. In the wild type, full
      expression of XapA requires both a functional XapR protein and the inducer
      xanthosine. Here we show that deoxyinosine can also function as an inducer in the
      wild type, although not to the same extent as xanthosine. We have isolated and
      characterized in detail the mutants that can be induced by other nucleosides as
      well as xanthosine. Sequencing of the mutants has revealed that two regions in
      XapR are important for correct interactions between the inducer and XapR. One
      region is defined by amino acids 104 and 132, and the other region, containing
      most of the isolated mutations, is found between amino acids 203 and 210. These
      regions, when modelled into the three-dimensional structure of CysB from
      Klebsiella aerogenes, are placed close together and are most probably directly
      involved in binding the inducer xanthosine.

PMID- 10400598
TI  - Lysis and lysis inhibition in bacteriophage T4: rV mutations reside in the holin
      t gene.
AB  - Upon infecting populations of susceptible host cells, T-even bacteriophages
      maximize their yield by switching from lysis at about 25 to 35 min at 37 degrees
      C after infection by a single phage particle to long-delayed lysis (lysis
      inhibition) under conditions of sequential infection occurring when free phages
      outnumber host cells. The timing of lysis depends upon gene t and upon one or
      more rapid-lysis (r) genes whose inactivation prevents lysis inhibition. t
      encodes a holin that mediates the movement of the T4 endolysin though the inner
      cell membrane to its target, the cell wall. The rI protein has been proposed to
      sense superinfection. Of the five reasonably well characterized r genes, only
      two, rI and rV, are clearly obligatory for lysis inhibition. We show here that rV
      mutations are alleles of t that probably render the t protein unable to respond
      to the lysis inhibition signal. The tr alleles cluster in the 5' third of t and
      produce a strong r phenotype, whereas conditional-lethal t alleles produce the
      classical t phenotype (inability to lyse) and other t alleles produce additional,
      still poorly understood phenotypes. tr mutations are dominant to t+, a result
      that suggests specific ways to probe T4 holin function.

PMID- 10400600
TI  - Identification and complementation of frameshift mutations associated with loss
      of cytadherence in Mycoplasma pneumoniae.
AB  - Mycoplasma pneumoniae cytadherence is mediated by a specialized, polar attachment
      organelle. Certain spontaneously arising cytadherence mutants (designated class
      I) lack HMW2, fail to localize the adhesin protein P1 to the attachment
      organelle, and exhibit accelerated turnover of proteins HMW1, HMW3, and P65.
      Insertional inactivation of hmw2 by Tn4001 results in a phenotype nearly
      identical to that of the class I mutants, suggesting that the latter may result
      from a defect in hmw2. In this study, the recombinant wild-type hmw2 allele
      successfully complemented a class I mutant when introduced by transposon
      delivery. Synthesis of recombinant HMW2 at wild-type levels resulted in
      reacquisition of hemadsorption and normal levels of HMW1, HMW3, and P65. Low
      level production of HMW2 in some transformants resulted in only an intermediate
      capacity to hemadsorb. Furthermore, full restoration of HMW1 and P65, but not
      that of HMW3, was directly proportional to the amount of recombinant HMW2
      produced, reflecting the importance of proper stoichiometry for certain
      cytadherence-associated proteins. The recombinant class I hmw2 allele did not
      restore cytadherence, consistent with a defect in hmw2 in this mutant. A
      frameshift was discovered in different oligoadenine tracts in hmw2 from two
      independent class I mutants. Finally, protein P28 is thought to be the product of
      internal translation initiation in hmw2. A transposon excision-deletion mutant
      produced a truncated HMW2 but no P28, consistent with this conclusion. However,
      this deletion mutant was hemadsorption positive, indicating that P28 may not be
      required for cytadherence.

PMID- 10400601
TI  - Genetic organization of the citCDEF locus and identification of mae and clyR
      genes from Leuconostoc mesenteroides.
AB  - In this paper, we describe two open reading frames coding for a NAD-dependent
      malic enzyme (mae) and a putative regulatory protein (clyR) found in the upstream
      region of citCDEFG of Leuconostoc mesenteroides subsp. cremoris 195. The
      transcriptional analysis of the citrate lyase locus revealed one polycistronic
      mRNA covering the mae and citCDEF genes. This transcript was detected only on RNA
      prepared from cells grown in the presence of citrate. Primer extension
      experiments suggest that clyR and the citrate lyase operon are expressed from a
      bidirectional A-T-rich promoter region located between mae and clyR.

PMID- 10400602
TI  - Structural characterization of the lactoferrin receptor from Neisseria
      meningitidis.
AB  - The meningococcal lactoferrin receptor is composed of the integral outer membrane
      protein LbpA and the peripheral lipoprotein LbpB. Homooligomeric complexes of
      LbpA and heterooligomers consisting of LbpA and LbpB were identified.
      Furthermore, five cell surface-exposed loops of LbpA were identified, which
      partially confirms a previously proposed topology model.

PMID- 10400603
TI  - Physicochemical evidence that Treponema pallidum TroA is a zinc-containing
      metalloprotein that lacks porin-like structure.
AB  - Although TroA (Tromp1) was initially reported to be a Treponema pallidum outer
      membrane protein with porin-like properties, subsequent studies have suggested
      that it actually is a periplasmic substrate-binding protein involved in the
      transport of metals across the treponemal cytoplasmic membrane. Here we conducted
      additional physicochemical studies to address the divergent viewpoints concerning
      this protein. Triton X-114 phase partitioning of recombinant TroA constructs with
      or without a signal sequence corroborated our prior contention that the native
      protein's amphiphilic behavior is due to its uncleaved leader peptide. Whereas
      typical porins are trimers with extensive beta-barrel structure, size exclusion
      chromatography and circular dichroism spectroscopy revealed that TroA was a
      monomer and predominantly alpha-helical. Neutron activation, atomic absorption
      spectroscopy, and anomalous X-ray scattering all demonstrated that TroA binds
      zinc in a 1:1 molar stoichiometric ratio. TroA does not appear to possess
      structural features consistent with those of bacterial porins.

PMID- 10400604
TI  - Methanobacterium thermoautotrophicum RNA polymerase and transcription in vitro.
AB  - RNA polymerase (RNAP) purified from Methanobacterium thermoautotrophicum DeltaH
      has been shown to initiate transcription accurately in vitro from the hmtB
      archaeal histone promoter with either native or recombinant forms of the M.
      thermoautotrophicum TATA-binding protein and transcription factor TFB. Efforts to
      obtain transcription initiation from hydrogen-regulated methane gene promoters
      were, however, unsuccessful. Two previously unrecognized archaeal RNAP subunits
      have been identified, and complex formation by the M. thermoautotrophicum RNAP
      and TFB has been demonstrated.

PMID- 10400605
TI  - Biochemical and genetic evidence for participation of DevR in a phosphorelay
      signal transduction pathway essential for heterocyst maturation in Nostoc
      punctiforme ATCC 29133.
AB  - In a test of the hypothesis that DevR is a response regulator protein that
      functions in a phosphorelay signal transduction system involved in heterocyst
      development in Nostoc punctiforme ATCC 29133, purified affinity-tagged DevR was
      shown to be phosphorylated in vitro by the noncognate sensor kinase EnvZ. Site
      directed mutagenesis was used to generate N. punctiforme mutants with single
      amino acid substitutions at the putative phosphorylation site of DevR. These
      mutants exhibited a Fox- phenotype like the original devR insertion mutant UCD
      311, consistent with a phosphotransferase role for DevR.

PMID- 10400606
TI  - Growth phase-dependent regulation of Vsr endonuclease may contribute to 5
      methylcytosine mutational hot spots in Escherichia coli.
AB  - Using rabbit polyclonal antibodies, we have shown that the Dcm cytosine methylase
      of Escherichia coli is maintained at a constant level during cell growth, while
      Vsr endonuclease levels are growth phase dependent. Decreased production of Vsr
      relative to Dcm during the log phase may contribute substantially to the
      mutability of 5-methylcytosine.

PMID- 10400607
TI  - Water transport across yeast vacuolar and plasma membrane-targeted secretory
      vesicles occurs by passive diffusion.
AB  - To determine whether solute transport across yeast membranes was facilitated, we
      measured the water and solute permeations of vacuole-derived and late secretory
      vesicles in Saccharomyces cerevisiae; all permeations were consistent with
      passive diffusive flow. We also overexpressed Fps1p, the putative glycerol
      facilitator in S. cerevisiae, in secretory vesicles but observed no effect on
      water, glycerol, formamide, or urea permeations. However, spheroplasts prepared
      from the strain overexpressing Fps1p showed enhanced glycerol uptake, suggesting
      that Fps1p becomes active only upon insertion in the plasma membrane.

PMID- 10400608
TI  - Proteases in cellular regulation minireview series.

PMID- 10400609
TI  - Suicidal tendencies: apoptotic cell death by caspase family proteinases.

PMID- 10400610
TI  - Identification of sequences required for inhibition of oncogene-mediated
      transformation by pp32.
AB  - Oncogenic potential in prostate cancer is modulated in part by alternative use of
      genes of the pp32 family. This family includes the tumor suppressor pp32,
      expressed in normal tissue, and the pro-oncogenic genes pp32r1 and pp32r2 that
      are found principally in neoplastic cells. At the protein level, pp32, pp32r1,
      and pp32r2 are approximately 90% identical, yet they subsume opposite functions.
      In this study, we identify the region of pp32 associated with the ability to
      inhibit oncogene-mediated transformation in a rat embryo fibroblast system, an in
      vitro correlate of tumor-suppressive activity. Deletion and truncation analysis
      define a region spanning pp32 amino acids 150-174 as absolutely required for
      inhibition of transformed foci elicited by RAS and MYC. Comparison of pp32 with
      the pp32r1 sequence by moving averages of sequence identity reveals divergence
      over this region; pp32r2 also differs in this region through truncation after
      pp32 amino acid 131. The deletion experiments and the experiments of nature
      therefore converge to demonstrate that tumor-suppressive functions of pp32 reside
      in amino acids 150-174. Identification of this minimal tumor-suppressive region
      should help elaborate the pathways and mechanisms through which pp32 family
      members exert their functions.

PMID- 10400611
TI  - Activation of the lck tyrosine-protein kinase by the binding of the tip protein
      of herpesvirus saimiri in the absence of regulatory tyrosine phosphorylation.
AB  - The Tip protein of herpesvirus saimiri 484 binds to the Lck tyrosine-protein
      kinase at two sites and activates it dramatically. Lck has been shown previously
      to be activated by either phosphorylation of Tyr394 or dephosphorylation of
      Tyr505. We examined here whether a change in the phosphorylation of either site
      was required for the activation of Lck by Tip. Remarkably, mutation of both
      regulatory sites of tyrosine phosphorylation did not prevent activation of Lck by
      Tip either in vivo or in a cell free in vitro system. Tip therefore appears to be
      able to activate Lck through an induced conformational change that does not
      necessarily involve altered phosphorylation of the kinase. Tip may represent the
      prototype of a novel type of regulator of tyrosine-protein kinases.

PMID- 10400612
TI  - Identification of conserved residues required for the binding of a
      tetratricopeptide repeat domain to heat shock protein 90.
AB  - The sequential binding of heat shock protein 90 (hsp90) to a series of
      tetratricopeptide repeat (TPR) proteins is critical to its function as a
      molecular chaperone. We have used site-directed mutagenesis to clarify the
      structural basis for the binding of hsp90 to the TPR domain of phosphoprotein
      phosphatase 5 (PP5). This TPR domain was chosen for study because its three
      dimensional structure is known. We examined co-immunoprecipitation of hsp90 with
      wild type and mutant TPR constructs from transfected cells. Only mutations
      located on one face of the TPR domain affected hsp90 binding. This allowed the
      identification of a binding groove. Three basic residues that are highly
      conserved in hsp90-binding TPR proteins extend prominently into this groove. Lys
      97 and Arg-101 were absolutely required for hsp90 binding, while mutation of Arg
      74 diminished, but did not abrogate, hsp90 binding. Mutation of Lys-32, another
      conserved basic residue in the binding groove, also blocked hsp90 binding. The
      TPR domain of PP5 bound specifically to a 12-kDa C-terminal fragment of hsp90.
      This binding was reduced by mutation of acidic residues in the hsp90 fragment.
      These data suggest conservation, among hsp90-binding TPR proteins, of a binding
      groove containing basic residues that interact with acidic residues near the C
      terminus of hsp90.

PMID- 10400613
TI  - CD39-L4 is a secreted human apyrase, specific for the hydrolysis of nucleoside
      diphosphates.
AB  - The human ecto-apyrase gene family consists of five reported members (CD39, CD39
      L1, CD39-L2, CD39-L3, and CD39-L4). The family can be subdivided into two groups
      by conservation of proposed structural domains. The CD39, CD39-L1, and CD39-L3
      genes all encode hydrophobic portions in their carboxy and amino termini, serving
      as transmembrane domains for CD39 and potentially for the other two members. CD39
      L2 and CD39-L4 genes encode hydrophobic portions in their amino termini,
      suggesting that they might encode secreted apyrases. We demonstrate that the CD39
      L4 gene encodes the first reported human secreted ecto-apyrase. COS-7 cells
      transfected with a CD39-L4 expression construct utilizing the naturally occurring
      leader peptide express recombinant protein outside of the cells. This expression
      can be blocked by brefeldin A, a chemical that inhibits a step in mammalian
      secretory pathways. We also demonstrate expression of CD39-L4 message in
      macrophages, suggesting that the protein is present in the circulation.
      Furthermore, we show that CD39-L4 is an E-type apyrase, is dependent on calcium
      and magnesium cations, and has high degree of specificity for NDPs over NTPs as
      enzymatic substrates. A potential physiological role in hemostasis and platelet
      aggregation is presented.

PMID- 10400614
TI  - The signal recognition particle-targeting pathway does not necessarily deliver
      proteins to the sec-translocase in Escherichia coli.
AB  - ProW is an Escherichia coli inner membrane protein that consists of a 100-residue
      long periplasmic N-terminal tail (N-tail) followed by seven closely spaced
      transmembrane segments. N-tail translocation presumably proceeds in a C-to-N
      terminal direction and represents a poorly understood aspect of membrane protein
      biogenesis. Here, using an in vivo depletion approach, we show that N-tail
      translocation in a ProW derivative comprising the N-tail and the first
      transmembrane segment fused to the globular P2 domain of leader peptidase depends
      both on the bacterial signal recognition particle (SRP) and the Sec-translocase.
      Surprisingly, however, a deletion construct with only one transmembrane segment
      downstream of the N-tail can assemble properly even under severe depletion of
      SecE, a central component of the Sec-translocase, but not under SRP-depletion
      conditions. To our knowledge, this is the first demonstration that the SRP
      targeting pathway does not necessarily deliver SRP-dependent inner membrane
      proteins to the Sec-translocase. The data further suggest that N-tail
      translocation can proceed in the absence of a functional Sec-translocase.

PMID- 10400615
TI  - Defective secretion of saliva in transgenic mice lacking aquaporin-5 water
      channels.
AB  - Aquaporin-5 (AQP5) is a water-selective transporting protein expressed in
      epithelial cells of serous acini in salivary gland. We generated AQP5 null mice
      by targeted gene disruption. The genotype distribution from intercross of founder
      AQP5 heterozygous mice was 70:69:29 wild-type:heterozygote:knockout, indicating
      impaired prenatal survival of the null mice. The knockout mice had grossly normal
      appearance, but grew approximately 20% slower than litter-matched wild-type mice
      when placed on solid food after weaning. Pilocarpine-stimulated saliva production
      was reduced by more than 60% in AQP5 knockout mice. Compared with the saliva from
      wild-type mice, the saliva from knockout mice was hypertonic (420 mosM) and
      dramatically more viscous. Amylase and protein secretion, functions of salivary
      mucous cells, were not affected by AQP5 deletion. Water channels AQP1 and AQP4
      have also been localized to salivary gland; however, pilocarpine stimulation
      studies showed no defect in the volume or composition of saliva in AQP1 and AQP4
      knockout mice. These results implicate a key role for AQP5 in saliva fluid
      secretion and provide direct evidence that high epithelial cell membrane water
      permeability is required for active, near-isosmolar fluid transport.

PMID- 10400617
TI  - Morphine-like activity of natural human IgG autoantibodies is because of binding
      to the first and third extracellular loops of the mu-opioid receptor.
AB  - We have previously demonstrated that randomly selected healthy individuals
      express anti-human mu-opioid receptor antibodies which behave as agonist in
      vitro. In this study, we show that the activity of these antibodies was not
      affected by the deletion of the amino-terminal region of the receptor. Using
      agarose-bound peptide columns, we affinity-purified IgG specifically directed
      toward each extracellular loop. Whatever its specificity, each anti-human mu
      opioid receptor (hMOR) extracellular loop peptide IgG preparation was unable,
      when examined individually, to reduce adenylate cyclase activity. Activation of
      the hMOR was, however, achieved by the simultaneous binding of IgG to the first
      and third extracellular loops of the receptor. Our results suggest that the
      simultaneous binding of IgG antibodies to these two loops mimics morphine-induced
      receptor activation by triggering a coordinated shift of the third and sixth
      transmembrane helices.

PMID- 10400616
TI  - Sec-dependent pathway and DeltapH-dependent pathway do not share a common
      translocation pore in thylakoidal protein transport.
AB  - Thylakoidal proteins of plant chloroplasts are transported to thylakoids via
      several different pathways, including the DeltapH-dependent and the Sec-dependent
      pathways. In this study, we asked if these two pathways utilize a common
      translocation pore. A fusion protein consisting of a 23-kDa subunit of the oxygen
      evolving complex and Escherichia coli biotin carboxyl carrier protein was
      biotinylated in E. coli cells and purified. When incubated with isolated pea
      thylakoids in the absence of avidin, the purified fusion protein was imported
      into the thylakoids via the DeltapH-dependent pathway. However in the presence of
      avidin, the fusion protein became lodged in the thylakoid membranes, with its N
      terminus reaching the thylakoidal lumen, while its C-terminal segment complexed
      with avidin exposed on the thylakoidal surface. The translocation intermediate of
      the fusion protein inhibited the import of authentic 23-kDa subunit, suggesting
      that it occupies a putative translocation pore for the DeltapH-dependent pathway.
      However the intermediate did not block import of the 33-kDa subunit of the oxygen
      evolving complex, which is a substrate for the Sec-dependent pathway. These
      results provide evidence against the possibility of a common translocation pore
      shared by the Sec-dependent pathway and the DeltapH-dependent pathway.

PMID- 10400618
TI  - 15-Lipoxygenase catalytically consumes nitric oxide and impairs activation of
      guanylate cyclase.
AB  - Analysis of purified soybean and rabbit reticulocyte 15-lipoxygenase (15-LOX) and
      PA317 cells transfected with human 15-LOX revealed a rapid rate of linoleate
      dependent nitric oxide (.NO) uptake that coincided with reversible inhibition of
      product ((13S)-hydroperoxyoctadecadienoic acid, or (13S)-HPODE) formation. No
      reaction of .NO (up to 2 microM) with either native (Ered) or ferric LOXs (0.2
      microM) metal centers to form nitrosyl complexes occurred at these .NO
      concentrations. During HPODE-dependent activation of 15-LOX, there was
      consumption of 2 mol of .NO/mol of 15-LOX. Stopped flow fluorescence spectroscopy
      showed that.NO (2.2 microM) did not alter the rate or extent of (13S)-HPODE
      induced tryptophan fluorescence quenching associated with 15-LOX activation.
      Additionally, .NO does not inhibit the anaerobic peroxidase activity of 15-LOX,
      inferring that the inhibitory actions of .NO are due to reaction with the enzyme
      bound lipid peroxyl radical, rather than impairment of (13S)-HPODE-dependent
      enzyme activation. From this, a mechanism of 15-LOX inhibition by .NO is proposed
      whereby reaction of .NO with EredLOO. generates Ered and LOONO, which hydrolyzes
      to (13S)-HPODE and nitrite (NO2-). Reactivation of Ered, considerably slower than
      dioxygenase activity, is then required to complete the catalytic cycle and leads
      to a net inhibition of rates of (13S)-HPODE formation. This reaction of .NO with
      15-LOX inhibited. NO-dependent activation of soluble guanylate cyclase and
      consequent cGMP production. Since accelerated .NO production, enhanced 15-LOX
      gene expression, and 15-LOX product formation occurs in diverse inflammatory
      conditions, these observations indicate that reactions of .NO with lipoxygenase
      peroxyl radical intermediates will result in modulation of both .NO
      bioavailability and rates of production of lipid signaling mediators.

PMID- 10400620
TI  - Myeloid ELF-1-like factor up-regulates lysozyme transcription in epithelial
      cells.
AB  - Lysozyme is an important component of innate immunity against common pathogens at
      mucosal surfaces. We previously cloned and characterized the bovine lysozyme 5A
      (lys5A) promoter with the purpose of determining cis- and trans-acting elements
      controlling airway epithelial cell-specific expression. We found that such
      expression is controlled by protein binding to an ETS consensus sequence located
      approximately at -46 to -40 bp from the transcription start site. The identity of
      the ETS-related protein responsible for gene transactivation was unknown. In this
      study, we screened six ETS-related proteins by transient transfection into
      epithelial cells and fibroblasts. Results showed that among these factors, the
      myeloid Elf-1-like factor (MEF) was the most potent. Gel shift analysis of
      epithelial cell nuclear extracts using a lys5A probe including the ETS-binding
      site (-50/-31) yielded a single band with retarded mobility. This band was
      supershifted by an antibody directed against MEF. Supporting the possibility that
      MEF is responsible for functional transactivation of lysozyme in epithelial
      cells, we found that antisense MEF mRNA decreased lys5A promoter activity and
      that MEF overexpression in stably transfected cells increased lysozyme mRNA and
      protein expression. We conclude that MEF is required for epithelial cell
      transactivation of lysozyme.

PMID- 10400619
TI  - Antimicrobial activity spectrum, cDNA cloning, and mRNA expression of a newly
      isolated member of the cecropin family from the mosquito vector Aedes aegypti.
AB  - An antimicrobial peptide belonging to the cecropin family was isolated from the
      hemolymph of bacteria-challenged adult Aedes aegypti. This new peptide, named
      cecropin A, was purified to homogeneity and fully characterized after cDNA
      cloning. The 34-residue A. aegypti cecropin A is different from the majority of
      reported insect cecropins in that it is devoid of a tryptophan residue and C
      terminal amidation. The importance of these two structural features on the
      activity spectrum was investigated using a chemically synthesized peptide. A
      comparison of the antimicrobial activity spectrum of A. aegypti and Drosophila
      cecropin A showed a lower activity for the mosquito molecule. A. aegypti cecropin
      mRNA expression was not detected by Northern blot or reverse transcription
      polymerase chain reaction analysis in any immature stage of the mosquito, nor in
      naive adults, but it was observed in challenged adults 6 h after bacteria
      inoculation, and it continued over 7-10 days.

PMID- 10400621
TI  - Recruitment of a heparan sulfate subunit to the interleukin-1 receptor complex.
      Regulation by fibronectin attachment.
AB  - In this study, we identified an adhesion-regulated subunit of the interleukin-1
      (IL-1) receptor complex. Transfection of fibroblasts with an IL-1 receptor-EGFP
      construct showed that the fusion protein was located at focal adhesions in cells
      attaching to fibronectin. Fibronectin attachment caused enhancement in endogenous
      IL-1 type I receptor levels from on average 2500 to 4300 receptors/cell. In
      addition, matrix attachment resulted in a decrease in binding affinity (Ka) from
      1.0 x 10(9) (M-1) to 5.6 x 10(8) (M-1), due to a 2-fold reduction in association
      rate constant. The adhesion-mediated effects were reversed by soluble heparin.
      Cross-linking experiments showed that in cells attached to fibronectin, 50-70% of
      the radiolabeled IL-1 was associated with a heparinase sensitive, high molecular
      mass component of about 300 kDa, with a core protein of 80-90 kDa. Formation of
      the complex was dependent on cell interaction with the heparin binding region in
      fibronectin and required IL-1/type I IL-1 receptor binding. This report
      demonstrates the recruitment of a heparan sulfate to the IL-1 receptor complex,
      following attachment to fibronectin, which correlates with alterations in
      receptor function. The data suggest that the heparan sulfate constitutes an
      attachment regulated component of the IL-1 receptor complex with the role of
      mediating matrix regulation of IL-1 responses.

PMID- 10400622
TI  - Interaction of BiP with the J-domain of the Sec63p component of the endoplasmic
      reticulum protein translocation complex.
AB  - Proteins of the Hsp70 family of ATPases interact with a conserved domain of their
      J-protein partners, the J-domain, to function in numerous cellular processes. We
      have studied the interaction of BiP, an Hsp70 family member in the lumen of the
      endoplasmic reticulum, with the J-domain of Sec63p, a component of the Sec
      complex involved in post-translational protein translocation across the
      endoplasmic reticulum membrane. In a real-time solid phase binding assay, BiP
      binds to the immobilized Sec complex or to a fusion protein of the J-domain and
      glutathione S-transferase in a reaction that requires ATP hydrolysis. In the
      final complex, BiP is bound in the ADP form with its peptide binding pocket
      occupied. An intact peptide binding pocket is required for this interaction. Our
      experiments suggest that the activation of BiP by the J-domain involves a
      transient contact between these components, and that in the absence of
      physiological substrates, J-activated BiP binds even to the J-proteins
      themselves.

PMID- 10400623
TI  - Constitutive phosphorylation of the acidic tails of the high mobility group 1
      proteins by casein kinase II alters their conformation, stability, and DNA
      binding specificity.
AB  - The high mobility group (HMG) 1 and 2 proteins are the most abundant non-histone
      components of chromosomes. Here, we report that essentially the entire pool of
      HMG1 proteins in Drosophila embryos and Chironomus cultured cells is
      phosphorylated at multiple serine residues located within acidic tails of these
      proteins. The phosphorylation sites match the consensus phosphorylation site of
      casein kinase II. Electrospray ionization mass spectroscopic analyses revealed
      that Drosophila HMGD and Chironomus HMG1a and HMG1b are double-phosphorylated and
      that Drosophila HMGZ is triple-phosphorylated. The importance of this post
      translational modification was studied by comparing some properties of the native
      and in vitro dephosphorylated proteins. It was found that dephosphorylation
      affects the conformation of the proteins and decreases their conformational and
      metabolic stability. Moreover, it weakens binding of the proteins to four-way
      junction DNA by 2 orders of magnitude, whereas the strength of binding to linear
      DNA remains unchanged. Based on these observations, we propose that the detected
      phosphorylation is important for the proper function and turnover rates of these
      proteins. As the occurrence of acidic tails containing canonical casein kinase II
      phosphorylation sites is common to diverse HMG and other chromosomal proteins,
      our results are probably of general significance.

PMID- 10400624
TI  - The effects of Shaker beta-subunits on the human lymphocyte K+ channel Kv1.3.
AB  - The activation of T-lymphocytes is dependent upon, and accompanied by, an
      increase in voltage-gated K+ conductance. Kv1.3, a Shaker family K+ channel
      protein, appears to play an essential role in the activation of peripheral human
      T cells. Although Kv1.3-mediated K+ currents increase markedly during the
      activation process in mice, and to a lesser degree in humans, Kv1.3 mRNA levels
      in these organisms do not, indicating post-transcriptional regulation. In other
      tissues Shaker K+ channel proteins physically associate with cytoplasmic beta
      subunits (Kvbeta1-3). Recently it has been shown that Kvbeta1 and Kvbeta2 are
      expressed in mouse T cells and that they are up-regulated during mitogen
      stimulated activation. In this study, we show that the human Kvbeta subunits
      substantially increase K+ current amplitudes when coexpressed with their Kv1.3
      counterpart, and that unlike in mouse, protein levels of human Kvbeta2 remain
      constant upon activation. Differences in Kvbeta2 expression between mice and
      humans may explain the differential K+ conductance increases which accompany T
      cell proliferation in these organisms.

PMID- 10400625
TI  - c-E10 is a caspase-recruiting domain-containing protein that interacts with
      components of death receptors signaling pathway and activates nuclear factor
      kappaB.
AB  - Members of the tumor necrosis factor receptor superfamily induce apoptosis via
      interaction with FADD and regulate cell growth and differentiation through TRADD
      and TRAFs molecules. While screening for molecules involved in the regulation of
      death receptor signaling, we identified a novel protein, c-E10. c-E10 contains an
      amino-terminal caspase-recruiting domain (CARD) and shares a sequence homologous
      with E10, a viral CARD-containing protein that binds to c-E10. In transfection
      experiments c-E10 oligomerizes, binds to the cytoplasmic portion of TRAIL
      receptor 1 (DR4) and coprecipitates with TRADD. Expression of c-E10 under the
      control of a doxycycline-dependent transcriptional transactivator results in NF
      kappaB activation, which is inhibited by dominant negative forms of TRAF2 and NIK
      kinase. Thus, our results suggest that c-E10 is an adapter protein that activates
      NF-kappaB through a molecular pathway involved in death receptor signaling.

PMID- 10400626
TI  - Disturbed communication between actin- and nucleotide-binding sites in a myosin
      II with truncated 50/20-kDa junction.
AB  - The kinetic and functional consequences of deleting nine residues from an actin
      binding surface loop (loop 2) were examined to investigate the role of this
      region in myosin function. The nucleotide binding properties of myosin were not
      altered by the deletion. However, the deletion affected actin binding and the
      communication between the actin- and nucleotide-binding sites. The affinity of
      M765NL for actin (644 nM) was approximately 100-fold lower than that of wild-type
      construct M765 (5.8 nM). Despite this reduction in affinity, actin binding
      weakened the affinity of ADP for the motor to a similar extent for both mutant
      and wild-type constructs. The addition of 0.5 microM actin decreased ADP affinity
      from 0.6 to 34 microM for M765NL and from 1.6 to 39 microM for M765. In contrast,
      communication between the actin- and nucleotide-binding sites appears disturbed
      in regard to phosphate release: thus, basal ATPase activity for M765NL (0.19 s-1)
      was 3-fold larger than for M765 (0.06 s-1), and the stimulation of ATPase
      activity by actin was 5-fold lower for M765NL. These results indicate different
      paths of communication between the actin- and nucleotide-binding sites, in regard
      to ADP and Pi release, and they confirm that loop 2 is involved in high affinity
      actin binding.

PMID- 10400627
TI  - Shc regulates epidermal growth factor-induced activation of the JNK signaling
      pathway.
AB  - Two adaptor molecules, Grb2 and Shc, have been implicated in the extracellular
      signal-regulated kinase (ERK) activation by receptor tyrosine kinases such as the
      epidermal growth factor receptor (EGFR). Here we show that the EGF-mediated ERK
      activation is abolished by loss of Grb2, whereas this response is not affected by
      loss of Shc. Conversely, the EGF-mediated c-Jun N-terminal kinase (JNK)
      activation is dependent on Shc, but not Grb2. These findings strongly support
      distinct roles for Grb2 and Shc in controlling ERK and JNK activation after EGF
      stimulation.

PMID- 10400628
TI  - Shear stress-mediated extracellular signal-regulated kinase activation is
      regulated by sodium in endothelial cells. Potential role for a voltage-dependent
      sodium channel.
AB  - Fluid shear stress is an important regulator of endothelial cell (EC) function.
      To determine whether mechanosensitive ion channels participate in the EC response
      to shear stress, we characterized the role of ion transport in shear stress
      mediated extracellular signal-regulated kinase (ERK1/2) stimulation. Replacement
      of all extracellular Na+ with either N-methyl-D-glucamine or choline chloride
      increased the ERK1/2 stimulation in response to shear stress by 1.89 +/- 0.1
      fold. The Na+ effect was concentration-dependent (maximal effect, </=12.5 mM) and
      was specific for shear stress-mediated ERK1/2 activation as epidermal growth
      factor-stimulated ERK1/2 activation was unaffected by removal of extracellular
      Na+. Shear stress-mediated ERK1/2 activation was potentiated by the voltage-gated
      sodium channel antagonist, tetrodotoxin (100 nM), to a magnitude similar to that
      achieved with extracellular Na+ withdrawal. Transfection of Chinese hamster ovary
      cells with a rat brain type IIa voltage-gated sodium channel completely inhibited
      shear stress-mediated ERK1/2 activation in these cells. Inhibition was reversed
      by performing the experiment in sodium-free buffer or by including tetrodotoxin
      in the buffer. Western blotting of bovine and human EC lysates with SP19 antibody
      detected a 250-kDa protein consistent with the voltage-gated sodium channel.
      Degenerate polymerase chain reaction of cDNA from primary human EC yielded
      transcripts whose sequences were identical to the sodium channel SCN4a and SCN8a
      alpha subunit genes. These results indicate that shear stress-mediated ERK1/2
      activation is regulated by extracellular sodium and demonstrate that ion
      transport via Na+ channels modulates EC responses to shear stress.

PMID- 10400629
TI  - Development of enzymatic activity during protein folding. Detection of a
      spectroscopically silent native-like intermediate of muscle acylphosphatase.
AB  - The recovery of enzymatic activity during the folding of muscle acylphosphatase
      and two single residue mutants (proline 54 to alanine and proline 71 to alanine)
      from 7 M urea has been monitored and compared with the development of intrinsic
      fluorescence emission. Fluorescence measurements reveal the presence in the wild
      type protein of a major rapid refolding phase followed by a second low amplitude
      slow phase. The slow phase is absent in the fluorescence trace acquired with the
      proline 54 to alanine mutant, suggesting the involvement of this proline residue
      in the fluorescence-detected slow phase of the wild-type protein. The major
      kinetic phase is associated with a considerable recovery of enzymatic activity,
      indicating that a large fraction of molecules refolds with effective two-state
      behavior. The use of time-resolved enzymatic activity as a probe to follow the
      folding process reveals, however, the presence of another exponential slow phase
      arising from proline 71. This slow phase is not observable by utilizing optical
      probes, indicating that, unlike proline 54, the cis to trans isomerization of
      proline 71 can take place in an intermediate possessing a native-like fold. We
      suggest that, although spectroscopically silent and structurally insignificant,
      the cis-trans interconversion of proline residues in native-like intermediates
      may be crucial for the generation of enzymatic activity of functional enzymes.

PMID- 10400630
TI  - Human nucleoside diphosphate kinase B (Nm23-H2) from melanoma cells shows altered
      phosphoryl transfer activity due to the S122P mutation.
AB  - The Ser122 --> Pro mutation in human nucleoside diphosphate kinase (NDK)-B/Nm23
      H2 was recently found in melanoma cells. In comparison to the wild-type enzyme,
      steady state activity of NDKS122P with ATP and TDP as substrates was slowed down
      5-fold. We have utilized transient kinetic techniques to analyze phosphoryl
      transfer between the mutant enzyme and various pairs of nucleoside triphosphates
      and nucleoside diphosphates. The two half-reactions of phosphorylation and
      dephosphorylation of the active site histidine residue (His118) were studied
      separately by making use of the intrinsic fluorescence changes which occur during
      these reactions. All apparent second order rate constants are drastically
      reduced, falling 5-fold for phosphorylation and 40-200-fold for
      dephosphorylation. Also, the reactivity of the mutant with pyrimidine nucleotides
      and deoxy nucleotides is more than 100-fold reduced compared with the wild-type.
      Thus, the rate-limiting step of the NDK-BS122P-catalyzed reaction is phosphoryl
      transfer from the phospho-enzyme intermediate to the nucleoside diphosphate and
      not phosphoryl transfer from the nucleoside triphosphate to the enzyme as was
      found for the wild-type protein. This results in a pronounced shift of the
      equilibrium between unphosphorylated and phosphorylated enzyme. Moreover, like
      the Killer-of-prune mutation in Drosophila NDK and the neuroblastoma Ser120 -->
      Gly mutation in human NDK-A/Nm23-H1, the Ser122 --> Pro substitution in NDK-B
      affects the stability of the protein toward heat and urea. These significantly
      altered properties may be relevant to the role of the mutant enzyme in various
      intracellular processes.

PMID- 10400632
TI  - Analysis of GroE-assisted folding under nonpermissive conditions.
AB  - The molecular chaperones GroEL and GroES facilitate protein folding in an ATP
      dependent manner under conditions where no spontaneous folding occurs. It has
      remained unknown whether GroE achieves this by a passive sequestration of protein
      inside the GroE cavity or by changing the folding pathway of a protein. Here we
      used citrate synthase, a well studied model substrate, to discriminate between
      these possibilities. We demonstrate that GroE maintains unfolding intermediates
      in a state that allows productive folding under nonpermissive conditions. During
      encapsulation of non-native protein inside GroEL.GroES complexes, a folding
      reaction takes place, generating association-competent monomeric intermediates
      that are no longer recognized by GroEL. Thus, GroE shifts folding intermediates
      to a productive folding pathway under heat shock conditions where even the native
      protein unfolds in the absence of GroE.

PMID- 10400631
TI  - The inhibition of capacitative calcium entry due to ATP depletion but not due to
      glucosamine is reversed by staurosporine.
AB  - The capacitative Ca2+ entry pathway in J774 macrophages is rapidly inhibited by
      the amino sugar glucosamine. This pathway is also inhibited by treatments such as
      2-deoxy-D-glucose (2dGlc) or glucose deprivation that inhibit glycolysis and lead
      to significant decreases in cellular ATP and other trinucleotides. We sought to
      determine whether glucosamine's effect on capacitative Ca2+ entry was also due to
      ATP depletion, as has been suggested recently for its link to insulin resistance.
      In contrast to brief treatments with 2dGlc, there was no significant decrease in
      ATP following exposure to glucosamine. In addition, the 2dGlc-mediated inhibition
      of capacitative Ca2+ influx was reversed by staurosporine, a microbial alkaloid
      that inhibits a broad range of protein kinases. Staurosporine was also able to
      reverse the inhibition of capacitative Ca2+ entry seen following other treatments
      that decreased cellular ATP levels, including cytochalasin B and iodoacetic acid.
      Other inhibitors of protein kinase C, including bisindolylmaleimide, K252a, H-7,
      and calphostin C, were unable to mimic this effect of staurosporine. However, the
      inhibition of capacitative Ca2+ influx in the presence of glucosamine was not
      reversed by staurosporine. These data indicate that the inhibitory action on
      capacitative Ca2+ entry of glucosamine is distinct from that caused by ATP
      depletion.

PMID- 10400633
TI  - The carboxyl tail of protease-activated receptor-1 is required for chemotaxis.
      Correlation of signal termination and directional migration.
AB  - The G protein-coupled thrombin receptor, protease-activated receptor 1 (PAR1),
      mediates many of the actions of thrombin on cells including chemotaxis. In
      contrast to the reversible agonist binding that regulates signaling by most G
      protein-coupled receptors (GPCRs), PAR1 is activated by an irreversible
      proteolytic mechanism. Although activated PAR1 is phosphorylated, uncoupled, and
      internalized like typical GPCRs, signal termination is additionally dependent on
      lysosomal degradation of cleaved and activated receptors. In the present study we
      exploit two PAR1 mutants to examine the link between chemotaxis and receptor
      shutoff. One, a carboxyl tail deletion mutant (Y397Z), is defective in
      phosphorylation and internalization. The other, a carboxyl tail chimeric receptor
      (P/S), is phosphorylated and internalized upon activation but recycles to the
      plasma membrane like reversibly activated GPCRs. Expression of these receptors in
      a hematopoietic cell line disrupted cell migration along thrombin gradients.
      Thrombin activation of cells expressing P/S or Y397Z resulted in persistent
      signaling independent of the continued presence of thrombin. Signaling in
      response to the soluble agonist peptide SFLLRN was reversible for P/S but
      persisted for Y397Z. Strikingly, cells expressing P/S responded chemokinetically
      to thrombin but chemotactically to SFLLRN. In contrast, Y397Z-mediated migration
      was largely chemokinetic to both agonists. These studies suggest that termination
      of PAR1 signaling at the level of the receptor is necessary for gradient
      detection and directional migration.

PMID- 10400634
TI  - Osmotic response element enhancer activity. Regulation through p38 kinase and
      mitogen-activated extracellular signal-regulated kinase kinase.
AB  - Hypertonicity induces a group of genes that are responsible for the intracellular
      accumulation of protective organic osmolytes such as sorbitol and betaine. Two
      representative genes are the aldose reductase enzyme (AR, EC 1.1.1.21), which is
      responsible for the conversion of glucose to sorbitol, and the betaine
      transporter (BGT1), which mediates Na+-coupled betaine uptake in response to
      osmotic stress. We recently reported that the induction of BGT1 mRNA in the renal
      epithelial Madin-Darby canine kidney cell line is inhibited by SB203580, a
      specific p38 kinase inhibitor. In these studies we report that the hypertonic
      induction of aldose reductase mRNA in HepG2 cells as well as the osmotic response
      element (ORE)-driven reporter gene expression in transfected HepG2 cells are both
      inhibited by SB203580, suggesting that p38 kinase mediates the activation and/or
      binding of the transcription factor(s) to the ORE. Electrophoretic gel mobility
      shift assays with cell extracts prepared from SB203580-treated, hypertonically
      stressed HepG2 cells further show that the binding of trans-acting factors to the
      ORE is prevented and is thus also dependent on the activity of p38 kinase.
      Similarly, treatment of hypertonically stressed cells with PD098059, a mitogen
      activated extracellular regulated kinase kinase (MEK1) inhibitor, results in
      inhibition of the hypertonic induction of aldose reductase mRNA, ORE-driven
      reporter gene expression, and the binding of trans-acting factors to the ORE. ORE
      driven reporter gene expression was not affected by p38 kinase inhibition or MEK1
      inhibition in cells incubated in iso-osmotic media. These data indicate that p38
      kinase and MEK1 are involved in the regulation of the hyperosmotic stress
      response.

PMID- 10400635
TI  - Expression cloning and characterization of a novel sodium-dicarboxylate
      cotransporter from winter flounder kidney.
AB  - A cDNA coding for a Na+-dicarboxylate cotransporter, fNaDC-3, from winter
      flounder (Pseudopleuronectes americanus) kidney was isolated by functional
      expression in Xenopus laevis oocytes. The fNaDC-3 cDNA is 2384 nucleotides long
      and encodes a protein of 601 amino acids with a calculated molecular mass of 66.4
      kDa. Secondary structure analysis predicts at least eight membrane-spanning
      domains. Transport of succinate by fNaDC-3 was sodium-dependent, could be
      inhibited by lithium, and evoked an inward current. The apparent affinity
      constant (Km) of fNaDC-3 for succinate of 30 microM resembles that of Na+
      dicarboxylate transport in the basolateral membrane of mammalian renal proximal
      tubules. The substrates specific for the basolateral transporter, 2,3
      dimethylsuccinate and cis-aconitate, not only inhibited succinate uptake but also
      evoked inward currents, proving that they are transported by fNaDC-3. Succinate
      transport via fNaDC-3 decreased by lowering pH, as did citrate transport,
      although much more moderately. These characteristics suggest that fNaDC-3 is a
      new type of Na+-dicarboxylate transporter that most likely corresponds to the Na+
      dicarboxylate cotransporter in the basolateral membrane of mammalian renal
      proximal tubules.

PMID- 10400636
TI  - Uptake and release of Ca2+ by the endoplasmic reticulum contribute to the
      oscillations of the cytosolic Ca2+ concentration triggered by Ca2+ influx in the
      electrically excitable pancreatic B-cell.
AB  - The role of intracellular Ca2+ pools in oscillations of the cytosolic Ca2+
      concentration ([Ca2+]c) triggered by Ca2+ influx was investigated in mouse
      pancreatic B-cells. [Ca2+]c oscillations occurring spontaneously during glucose
      stimulation or repetitively induced by pulses of high K+ (in the presence of
      diazoxide) were characterized by a descending phase in two components. A rapid
      decrease in [Ca2+]c coincided with closure of voltage-dependent Ca2+ channels and
      was followed by a slower phase independent of Ca2+ influx. Blocking the SERCA
      pump with thapsigargin or cyclopiazonic acid accelerated the rising phase of
      [Ca2+]c oscillations and increased their amplitude, which suggests that the
      endoplasmic reticulum (ER) rapidly takes up Ca2+. It also suppressed the slow
      [Ca2+]c recovery phase, which indicates that this phase corresponds to the slow
      release of Ca2+ that was taken up by the ER during the upstroke of the [Ca2+]c
      transient. Glucose promoted the buffering capacity of the ER and amplified the
      slow [Ca2+]c recovery phase. The slow phase induced by high K+ pulses was not
      affected by modulators of Ca2+- or inositol 1,4,5-trisphosphate-induced Ca2+
      release, did not involve a depolarization-induced Ca2+ release, and was also
      observed at the end of a rapid rise in [Ca2+]c triggered from caged Ca2+. It is
      attributed to passive leakage of Ca2+ from the ER. We suggest that the ER
      displays oscillations of the Ca2+ concentration ([Ca2+]ER) concomitant and
      parallel to [Ca2+]c. The observation that thapsigargin depolarizes the membrane
      of B-cells supports the proposal that the degree of Ca2+ filling of the ER
      modulates the membrane potential. Therefore, [Ca2+]ER oscillations occurring
      during glucose stimulation are likely to influence the bursting behavior of B
      cells and eventually [Ca2+]c oscillations.

PMID- 10400637
TI  - p90(RSK) is a serum-stimulated Na+/H+ exchanger isoform-1 kinase. Regulatory
      phosphorylation of serine 703 of Na+/H+ exchanger isoform-1.
AB  - The Na+/H+ exchanger isoform-1 (NHE-1) is the key member of a family of
      exchangers that regulates intracellular pH and cell volume. Activation of NHE-1
      by growth factors is rapid, correlates with increased NHE-1 phosphorylation and
      cell alkalinization, and plays a role in cell cycle progression. By two
      dimensional tryptic peptide mapping of immunoprecipitated NHE-1, we identify
      serine 703 as the major serum-stimulated amino acid. Mutation of serine 703 to
      alanine had no effect on acid-stimulated Na+/H+ exchange but completely prevented
      the growth factor-mediated increase in NHE-1 affinity for H+. In addition, we
      show that p90 ribosomal S6 kinase (p90(RSK)) is a key NHE-1 kinase since p90(RSK)
      phosphorylates NHE-1 serine 703 stoichiometrically in vitro, and transfection
      with kinase-inactive p90(RSK) inhibits serum-induced phosphorylation of NHE-1
      serine 703 in transfected 293 cells. These findings establish p90(RSK) as a serum
      stimulated NHE-1 kinase and a mediator of increased Na+/H+ exchange in vivo.

PMID- 10400638
TI  - Peptide specificity determinants at P-7 and P-6 enhance the catalytic efficiency
      of Ca2+/calmodulin-dependent protein kinase I in the absence of activation loop
      phosphorylation.
AB  - Phosphorylation of Ca2+/calmodulin-dependent protein kinase I (CaM KI) at Thr-177
      by recombinant rat Ca2+/calmodulin-dependent kinase kinase B (CaM KKB) modulates
      the kinetics of synapsin-(4-13) peptide phosphorylation by reducing the Km 44
      fold and decreasing the KCaM 4-fold. There is also a slight decrease in Km for
      ATP and increase in enzyme Vmax. A synthetic peptide substrate from the yeast
      transcription factor, ADR1-(222-234)G233 is a 15-fold better substrate for the
      Thr-177 dephospho-form of CaM KI than synapsin-(4-13). The Thr-177 dephospho
      enzyme has a Km and Vmax for ADR1-(222-234)G233 similar to the values with
      synapsin-(4-13) using the Thr-177 phosphorylated enzyme. Likewise, with ADR1-(222
      234)G233 as substrate, phosphorylation of Thr-177 or substitution of T177A had
      very little effect on the kinetic values. Using chimeric peptides between
      synapsin-(4-13) and ADR1-(222-234)G233 we found that N-terminal basic residues at
      P-7 and P-6 positions were sufficient to allow efficient phosphorylation by the
      Thr-177 dephospho-form of CaM KI. Phosphorylation of Thr-177 expands the
      substrate specificity of CaM KI and is not merely an "on-off" switch for kinase
      activity.

PMID- 10400639
TI  - The function of HSP72 in suppression of c-Jun N-terminal kinase activation can be
      dissociated from its role in prevention of protein damage.
AB  - Activation of the c-Jun N-terminal kinase (JNK) by a variety of stimuli is
      critical for regulation of many cellular processes including apoptosis. The major
      inducible heat shock protein Hsp72 has previously been demonstrated to inhibit
      activation of JNK in cells exposed to heat shock and other protein-damaging
      agents, thus suppressing apoptosis. Hsp72 can protect proteins from stress
      induced damage. To test if this protective function of Hsp72 is involved in JNK
      suppression, we investigated whether Hsp72 can avert activation of JNK by stimuli
      that do not cause protein damage. We show that Hsp72 suppresses activation of JNK
      induced by non-protein-damaging stimuli, interleukin-1 and UV irradiation, as
      well as by constitutively active components of the JNK signaling cascade Cdc42
      and MEKK1. Furthermore, Hsp72 strongly reduced activation of JNK by phosphatase
      inhibitors. We also demonstrate that an Hsp72 mutant that lacks the ATPase domain
      is still capable of JNK suppression, thus indicating that the protein refolding
      activity of Hsp72 is not critical for inhibition of JNK activation. Taken
      together these data suggest that Hsp72 plays a regulatory role in JNK signaling
      and that the function of Hsp72 in protein protection or refolding is not involved
      in JNK regulation.

PMID- 10400641
TI  - A small region in HMG I(Y) is critical for cooperation with NF-kappaB on DNA.
AB  - The high mobility group HMG I(Y) protein has been reported to promote the
      expression of several NF-kappaB-dependent genes by enhancing the binding of NF
      kappaB to DNA. The molecular origins of cooperativity in the binding of NF-kappaB
      and HMG I(Y) to DNA are not well understood. Here we have examined the
      determinants of specificity in the binding of HMG I(Y), both alone and in
      cooperation with NF-kappaB, to two different DNA elements, PRDII from the
      interferon-beta enhancer and IgkappaB from the immunoglobulin kappa light chain
      enhancer. Of particular interest was the influence of a flanking AT-rich sequence
      on binding by HMG I(Y). Utilizing yeast one-hybrid screening assays together with
      alanine-scanning mutagenesis, we have identified mutations of residues in HMG
      I(Y) that decrease cooperative binding of NF-kappaB to PRDII and IgkappaB sites.
      These same mutations similarly decreased the binding of HMG I(Y) alone to DNA,
      and paradoxically, decreased the strength of protein-protein interactions between
      HMG I(Y) and NF-kappaB. Of the three tandemly repeated basic regions that
      represent putative DNA-binding motifs in HMG I(Y), the residues within the second
      repeat are most important for recognition of core NF-kappaB sites, whereas the
      second and third repeats both appear to be involved in binding to sites that are
      flanked by AT-rich sequences. Overall, the second repeat of HMG I(Y) is primarily
      responsible for the stimulatory effect of this protein on the binding of NF
      kappaB to PRDII and IgkappaB elements.

PMID- 10400640
TI  - The linkage of Kennedy's neuron disease to ARA24, the first identified androgen
      receptor polyglutamine region-associated coactivator.
AB  - Although the linkage of polyglutamine (poly-Q) repeat expansion in the androgen
      receptor (AR) to Kennedy's disease (X-linked spinal and bulbar muscular atrophy)
      was a major step forward, the detailed molecular mechanism of how the change in
      poly-Q length contributes to the disease remains unclear. Here we report the
      identification of a nuclear G-protein, Ras-related nuclear protein/ARA24, as the
      first AR coactivator that can bind differentially with different lengths of poly
      Q within AR. In the yeast and mammalian reciprocal interacting assays, our data
      suggested the interaction of AR N-terminal domain with ARA24 diminishes as the
      poly-Q length increases. The coactivation of ARA24 also diminishes with the poly
      Q expansion within AR. Deletion of the acidic hexapeptide (DEDDDL) at the C
      terminus of ARA24 further enhances its AR coactivation. Together, our data
      suggest that poor interaction and weaker coactivation of ARA24 to the longer poly
      Q AR in the X-linked spinal and bulbar muscular atrophied AR could contribute to
      the weaker transactivation of AR. The consequence of poor interaction and weak
      coactivation may eventually lead to the partial androgen insensitivity during the
      development of Kennedy's disease.

PMID- 10400643
TI  - Suppression of apoptosis by all-trans-retinoic acid. Dual intervention in the c
      Jun n-terminal kinase-AP-1 pathway.
AB  - Retinoic acid induces apoptosis of various cells, whereas little is known about
      its anti-apoptotic potential. In this report, we describe an anti-apoptotic
      property of all-trans-retinoic acid (t-RA) in mammalian cells. Mesangial cells
      exposed to hydrogen peroxide (H2O2) exhibited shrinkage of the cytoplasm,
      membrane blebbing, condensation of nuclei, and DNA fragmentation. Pretreatment
      with t-RA attenuated the morphologic and biochemical hallmarks of apoptosis. t-RA
      also inhibited apoptosis of mesangial cells triggered by pyrrolidine
      dithiocarbamate, whereas it did not prevent tumor necrosis factor-alpha-induced
      apoptosis. The anti-apoptotic effect against H2O2 was similarly observed in
      NRK49F fibroblasts, but not in Madin-Darby canine kidney epithelial cells and
      ECV304 endothelial cells. Mesangial cells exposed to H2O2 undergo apoptosis via
      the activator protein 1 (AP-1)-dependent pathway. We found that t-RA abrogated
      the H2O2-induced expression of c-fos/c-jun and activation of AP-1. Furthermore, t
      RA inhibited H2O2-triggered activation of c-Jun N-terminal kinase (JNK), and
      dominant-negative inhibition of JNK attenuated the H2O2-induced apoptosis. These
      data disclosed the novel potential of retinoic acid as an inhibitor of apoptosis.
      The anti-apoptotic action of t-RA was ascribed, at least in part, to dual
      suppression of the cell death pathway mediated by JNK and AP-1.

PMID- 10400642
TI  - Role of protein kinase C in signal attenuation following T cell receptor
      engagement.
AB  - T lymphocyte activation through stimulation of the T cell receptor complex and co
      stimulatory receptors is associated with acute tyrosine phosphorylation of
      intracellular proteins, which in turn mediate downstream signaling events that
      regulate interleukin-2 expression and cell proliferation. The extent of protein
      tyrosine phosphorylation is rapidly attenuated after only 1-2 min of stimulation
      as a means of tightly controlling the initial signaling response. Here we show
      that this attenuation of tyrosine phosphorylation of Shc, CrkL, and the proto
      oncogene Cbl is mimicked by treatment of mouse T lymphocytes or cultured Jurkat
      cells with phorbol 12-myristate 13-acetate. This effect is blocked by the
      specific protein kinase C inhibitor GF109203X, but not by PD98059, an inhibitor
      of MEK1/2 kinase. Activation of protein kinase C by phorbol ester also causes
      rapid (t(1)/(2) = 2 min) dissociation of both CrkL and p85/phosphoinositide 3
      kinase from Cbl concomitant with Cbl tyrosine dephosphorylation. More important,
      GF109203X treatment of Jurkat cells prior to T cell receptor stimulation by anti
      CD3/CD4 antibodies results in an enhanced (2-fold) peak of Cbl phosphorylation
      compared with that observed in control cells. Furthermore, the rate of
      attenuation of both Cbl tyrosine phosphorylation and its association with CrkL
      following stimulation with anti-CD3/CD4 antibodies is much slower in Jurkat cells
      treated with GF109203X. Taken together, these data provide strong evidence that
      one or more isoforms of phorbol ester-responsive protein kinase C play a key role
      in a feedback mechanism that attenuates tyrosine phosphorylation of proteins and
      reverses formation of signaling complexes in response to T cell receptor
      activation.

PMID- 10400645
TI  - Inhibition of endothelial nitric-oxide synthase by ceruloplasmin.
AB  - The plasma copper protein ceruloplasmin (CP) was found to inhibit endothelial
      nitric-oxide synthase activation in cultured endothelial cells, in line with
      previous evidence showing that the endothelium-dependent vasorelaxation of the
      aorta is impaired by physiological concentrations of ceruloplasmin. The data
      presented here indicate a direct relationship between the extent of inhibition of
      agonist-triggered endothelial nitric oxide synthase activation and CP-induced
      enrichment of the copper content of endothelial cells. Copper discharged by CP
      was mainly localized in the soluble fraction of cells. The subcellular
      distribution of the metal seems to be of relevance to the inhibitory effect of
      CP, because it was mimicked by copper chelates, like copper-histidine, able to
      selectively enrich the cytosolic fraction of cells, but not by copper salts,
      which preferentially located the metal to the particulate fraction.

PMID- 10400644
TI  - Molecular and biochemical analysis of MalK, the ATP-hydrolyzing subunit of the
      trehalose/maltose transport system of the hyperthermophilic archaeon Thermococcus
      litoralis.
AB  - We report the cloning, sequencing, and expression of malK encoding the ATP
      hydrolyzing subunit of the maltose/trehalose transport system of the
      hyperthermophilic archaeon Thermococcus litoralis. According to the deduced amino
      acid sequence, MalK consists of 372 amino acids with a calculated molecular
      weight of 41,787. It shows 47% identity with the MalK protein of Escherichia coli
      and high sequence conservation in important regions. C-terminal His-tagged MalK
      was purified. The soluble protein appeared monomeric by molecular sieve
      chromatography and showed ATPase activity. Enzymatic activity was highest at 80
      degrees C with a Km of 150 microM and a Vmax of 0.55 micromol of ATP
      hydrolyzed/min/mg of protein. ADP was not a substrate but a competitive inhibitor
      (Ki 230 microM). GTP and CTP were also hydrolyzed. ATPase activity was inhibited
      by N-ethylmaleimide but not by vanadate. The strong homology found between the
      components of this archaeal transport system and the bacterial systems is
      evidence for the evolutionary conservation of the ABC transporters in these two
      phylogenetic branches.

PMID- 10400646
TI  - Protein adducts of iso[4]levuglandin E2, a product of the isoprostane pathway, in
      oxidized low density lipoprotein.
AB  - Levuglandin (LG) E2, a cytotoxic seco prostanoic acid co-generated with
      prostaglandins by nonenzymatic rearrangements of the cyclooxygenase-derived
      endoperoxide, prostaglandin H2, avidly binds to proteins. That LGE2-protein
      adducts can also be generated nonenzymatically is demonstrated by their
      production during free radical-induced oxidation of low density lipoprotein
      (LDL). Like oxidized LDL, LGE2-LDL, but not native LDL, undergoes receptor
      mediated uptake and impaired processing by macrophage cells. Since radical
      induced lipid oxidation produces isomers of prostaglandins, isoprostanes (isoPs),
      via endoperoxide intermediates, we postulated previously that a similar family of
      LG isomers, isoLGs, is cogenerated with isoPs. Now iso[4]LGE2-protein epitopes
      produced by radical-induced oxidation of arachidonic acid in the presence of
      protein were detected with an enzyme-linked immunosorbent assay. Iso[4]LGE2
      protein epitopes are also generated during free radical-induced oxidation of LDL.
      All of the LGE2 isomers generated upon oxidation of LDL are efficiently
      sequestered by covalent adduction with LDL-based amino groups. The potent
      electrophilic reactivity of iso-LGs can be anticipated to have biological
      consequences beyond their obvious potential as markers for specific arachidonate
      derived protein modifications that may be of value for the quantitative
      assessment of oxidative injury.

PMID- 10400647
TI  - Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1.
AB  - We used mouse hepatoma (Hepa1c1c7) cells to study the role of the
      serine/threonine kinase Akt in the induction of GLUT1 gene expression. In order
      to selectively turn on the Akt kinase cascade, we expressed a hydroxytamoxifen
      regulatable form of Akt (myristoylated Akt1 estrogen receptor chimera (MER-Akt1))
      in the Hepa1c1c7 cells; we verified that hydroxytamoxifen stimulates MER-Akt1
      activity to a similar extent as the activation of endogenous Akt by insulin. Our
      studies reveal that stimulation of MER-Akt1 by hydroxytamoxifen induces GLUT1
      mRNA and protein accumulation to levels comparable to that induced by insulin;
      therefore, activation of the Akt cascade suffices to induce GLUT1 gene expression
      in this cell system. Furthermore, expression of a kinase-inactive Akt mutant
      partially inhibits the response of the GLUT1 gene to insulin. Additional studies
      reveal that the induction of GLUT1 mRNA by Akt and by insulin reflects increased
      mRNA synthesis and not decreased mRNA degradation. Our findings imply that the
      GLUT1 gene responds to insulin at the transcriptional level and that Akt mediates
      a step in the activation of GLUT1 gene expression in this system.

PMID- 10400648
TI  - Purification and molecular characterization of ortho-chlorophenol reductive
      dehalogenase, a key enzyme of halorespiration in Desulfitobacterium dehalogenans.
AB  - ortho-Chlorophenol reductive dehalogenase of the halorespiring Gram-positive
      Desulfitobacterium dehalogenans was purified 90-fold to apparent homogeneity. The
      purified dehalogenase catalyzed the reductive removal of a halogen atom from the
      ortho position of 3-chloro-4-hydroxyphenylacetate, 2-chlorophenol, 2,3
      dichlorophenol, 2,4-dichlorophenol, 2,6-dichlorophenol, pentachlorophenol, and 2
      bromo-4-chlorophenol with reduced methyl viologen as electron donor. The
      dechlorination of 3-chloro-4-hydroxyphenylacetate was catalyzed by the enzyme at
      a Vmax of 28 units/mg protein and a Km of 20 microM. The pH and temperature
      optimum were 8.2 and 52 degrees C, respectively. EPR analysis indicated one [4Fe
      4S] cluster (midpoint redox potential (Em) = -440 mV), one [3Fe-4S] cluster (Em =
      +70 mV), and one cobalamin per 48-kDa monomer. The Co(I)/Co(II) transition had an
      Em of -370 mV. Via a reversed genetic approach based on the N-terminal sequence,
      the corresponding gene was isolated from a D. dehalogenans genomic library,
      cloned, and sequenced. This revealed the presence of two closely linked genes:
      (i) cprA, encoding the o-chlorophenol reductive dehalogenase, which contains a
      twin-arginine type signal sequence that is processed in the purified enzyme; (ii)
      cprB, coding for an integral membrane protein that could act as a membrane anchor
      of the dehalogenase. This first biochemical and molecular characterization of a
      chlorophenol reductive dehalogenase has revealed structural resemblance with
      haloalkene reductive dehalogenases.

PMID- 10400649
TI  - Rotational echo double resonance detection of cross-links formed in mussel byssus
      under high-flow stress.
AB  - 13C2H rotational echo double resonance NMR has been used to provide the first
      evidence for the formation of quinone-derived cross-links in mussel byssal
      plaques. Labeling of byssus was achieved by allowing mussels to filter feed from
      seawater containing L-[phenol-4-13C]tyrosine and L-[ring-d4]tyrosine for 2 days.
      Plaques and threads were harvested from two groups of mussels over a period of 28
      days. One group was maintained in stationary water while the other was exposed to
      turbulent flow at 20 cm/s. The flow-stressed byssal plaques exhibited
      significantly enhanced levels of 5, 5'-di-dihydroxyphenylalanine cross-links. The
      average concentration of di-dihydroxyphenylalanine cross-links in byssal plaques
      is 1 per 1800 total protein amino acid residues.

PMID- 10400651
TI  - Hydroperoxide dependence and cooperative cyclooxygenase kinetics in prostaglandin
      H synthase-1 and -2.
AB  - Prostaglandin H synthase isoform-1 (PGHS-1) cyclooxygenase activity has a
      cooperative response to arachidonate concentration, whereas the second isoform,
      PGHS-2, exhibits saturable kinetics. The basis for the cooperative PGHS-1
      behavior and for the difference in cooperativity between the isoforms was
      unclear. The two cyclooxygenase activities have different efficiencies of
      feedback activation by hydroperoxide. To determine whether the cooperative
      kinetics were governed by the feedback activation characteristics, we examined
      the cyclooxygenase activities under conditions where feedback activation was
      either assisted (by exogenous peroxide) or impaired (by replacement of heme with
      mangano protoporphyrin IX to form MnPGHS-1 and -2). Heme replacement increased
      PGHS-1 cyclooxygenase cooperativity and changed PGHS-2 cyclooxygenase kinetics
      from saturable to cooperative. Peroxide addition decreased or abolished
      cyclooxygenase cooperativity in PGHS-1, MnPGHS-1, and MnPGHS-2. Kinetic
      simulations predicted that cyclooxygenase cooperativity depends on the
      hydroperoxide activator requirement and initial peroxide concentration,
      consistent with observed behavior. The results indicate that PGHS-1
      cyclooxygenase cooperativity originates in the feedback activation kinetics and
      that the cooperativity difference between the isoforms can be explained by the
      difference in feedback activation loop efficiency. This linkage between
      activation efficiency and cyclooxygenase cooperativity indicates an
      interdependence between fatty acid and hydroperoxide levels in controlling the
      synthesis of potent prostanoid mediators.

PMID- 10400650
TI  - Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial
      PP2A.
AB  - Phosphorylation of Bcl2 at serine 70 is required for its potent anti-apoptotic
      function. We have recently shown that Bcl2 phosphorylation is a dynamic process
      that involves the protein kinase C alpha and protein phosphatase 2A (PP2A)
      (Ruvolo, P. P., Deng, X., Carr, B. K., and May, W. S. (1998) J. Biol. Chem. 273,
      25436-25442; and Deng, X., Ito, T., Carr, B. K., Mumby, M. C., and May, W. S.
      (1998) J. Biol. Chem. 273, 34157-34163). The potent apoptotic agent ceramide can
      activate a PP2A, suggesting that one potential component of the ceramide-induced
      death signal may involve the inactivation of Bcl2. Results indicate that C2
      ceramide but not inactive C2-dihydroceramide, was found to specifically activate
      a mitochondrial PP2A, which rapidly and completely induced Bcl2 dephosphorylation
      and correlated closely with ceramide-induced cell death. Using a genetic
      approach, the gain-of-function S70E Bcl2 mutation, which mimics phosphorylation,
      fails to undergo apoptosis even with the addition of high doses of ceramide (IC50
      > 50 microM). In contrast, cells overexpressing exogenous wild-type Bcl2 were
      sensitive to ceramide at dosages where PP2A is fully active and Bcl2 would be
      expected to be dephosphorylated (IC50 = 14 microM). These findings indicate that
      in cells expressing functional Bcl2, the mechanism of death action for ceramide
      may involve, at least in part, a mitochondrial PP2A that dephosphorylates and
      inactivates Bcl2.

PMID- 10400652
TI  - Vanadate induction of NF-kappaB involves IkappaB kinase beta and SAPK/ERK kinase
      1 in macrophages.
AB  - The present studies investigated the signaling pathways of vanadate, a vanadium
      ion with +5 oxidation state, to activate NF-kappaB transcription factor, a
      pivotal regulator of inflammatory responses. Treatment of macrophages with
      vanadate results in the activation of both NF-kappaB and c-Jun N-terminal kinase
      (JNK). The activity of a recently identified cellular kinase, IkappaB kinase-beta
      (IKKbeta), was significantly elevated concomitant with the increased degradation
      of IkappaBalpha and enhanced NF-kappaB activity in cells exposed to vanadate. To
      determine whether the IKK pathway and JNK pathway are interconnected or bifurcate
      upon vanadate stimulation, cells were transfected with either a kinase inactive
      form of IKKbeta or a kinase inactive form of SAPK/ERK kinase 1 (SEK1). Inactive
      IKKbeta was able to block vanadate-induced degradation of IkappaBalpha, yet it
      was unable to influence the activation of JNK by vanadate. Conversely, blockage
      of JNK activation by transfection of a kinase-inactive form of SEK1 resulted in
      partially inhibition of vanadate-induced IkappaBalpha degradation. Both vanadate
      induced degradation of IkappaBalpha and activation of JNK were potently inhibited
      by pretreatment of cells with N-acetylcysteine or dimercaprol. These results
      demonstrate that early activation of stress kinases or change of cellular redox
      states plays a key role in vanadate-induced activation of NF-kappaB and JNK.

PMID- 10400654
TI  - Identification of P-glycoprotein mutations causing a loss of steroid recognition
      and transport.
AB  - P-glycoproteins transport a wide variety of hydrophobic compounds out of cells.
      While the diversity of transported molecules suggests a mechanism involving broad
      specificity, there is evidence of significant discrimination within given classes
      of molecules. One example of this behavior is transport of corticosteroids by the
      murine mdr1 P-glycoprotein. The presence of hydroxyl groups, associated with
      specific steroid carbon atoms, regulates the ability of corticosteroids to be
      transported. This specificity is demonstrated here by experiments measuring the
      ability of steroids to inhibit drug transport. The results indicate that a keto
      oxygen associated with the 3- and 20-carbon atoms, as well as a 17-carbon
      hydroxyl group, each acts to enhance steroidal P-glycoprotein inhibitory
      activity. Moreover, inhibitory steroids can be used for directed selection of
      variant cells, expressing mutated P-glycoproteins with a severely impaired
      ability to transport dexamethasone. The five mutations, reported here, are
      located within transmembrane domains 4-6, proximal to the cytoplasmic interface.
      The altered P-glycoproteins exhibit reduced capacity to be inhibited by specific
      steroids, suggesting decreased capacity to bind these molecules avidly. Studies
      comparing the relative inhibitory activity of a series of steroids indicate that
      these mutations alter recognition of the 17alpha-hydroxyl group and the 20-keto
      oxygen atom.

PMID- 10400653
TI  - Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A.
      Activation is stereospecific and regulated by phosphatidic acid.
AB  - The search for potential targets for ceramide action led to the identification of
      ceramide-activated protein phosphatases, which include protein phosphatase-2A
      (PP2A) and protein phosphatase-1 (PP1) with roles in regulating apoptosis and
      cell growth. Thus far, in vitro studies on ceramide-activated protein
      phosphatases have been restricted to the use of short chain ceramides, limiting
      the extent of mechanistic insight. In this study, we show that the long chain D
      erythro-C18-ceramide activated PP2A (AB'C trimer), PP2Ac (catalytic subunit of
      PP2A), and PP1gammac and -alphac (catalytic subunits of PP1gamma and -1alpha
      isoforms, respectively) 2-6-fold in the presence of dodecane, a lipid
      solubilizing agent, with 50% maximal activation achieved at approximately 10
      microM D-erythro-C18-ceramide. The diastereoisomers of D-erythroC18-ceramide, D
      threo-, and L-threo-C18-ceramide, as well as the enantiomeric L-erythro-C18
      ceramide, did not activate PP1 or PP2A, but they inhibited PP1 and PP2A activity.
      The addition of phosphatidic acid decreased the basal activity of PP1c but also
      increased the stimulation by D-erythro-C18-ceramide from 1.8- to 2. 8-fold and
      decreased the EC50 of D-erythro-C18-ceramide to 4.45 microM. The addition of 150
      mM KCl decreased the basal activity of PP1 and the dose of D-erythro-C18-ceramide
      necessary to activate PP1c (EC50 = 6.25 microM) and increased the ceramide
      responsiveness up to 10-17-fold. These studies disclose stereospecific activation
      of PP1 and PP2A by long chain natural ceramides under near physiologic ionic
      strengths in vitro. The implications of these studies for mechanisms of ceramide
      action are discussed.

PMID- 10400655
TI  - Phosphorylation-dependent structural changes in the regulatory light chain domain
      of smooth muscle heavy meromyosin.
AB  - Smooth muscle heavy meromyosin, a double-headed proteolytic fragment of myosin
      lacking the COOH-terminal two-thirds of the tail, has been shown previously to be
      regulated by phosphorylation. To examine phosphorylation-dependent structural
      changes near the head-tail junction, we prepared five well regulated heavy
      meromyosins containing single-cysteine mutants of the human smooth muscle
      regulatory light chain labeled with the photocross-linking reagent, benzophenone
      iodoacetamide. For those mutants that generated cross-links, only one type of
      cross-linked species was observed, a regulatory light chain dimer. Irradiated
      mutants fell into two classes. First, for Q15C, A23C, and wild type (Cys-108), a
      regulatory light chain dimer was formed for dephosphorylated but not
      thiophosphorylated heavy meromyosin. These data provide direct chemical evidence
      that in the dephosphorylated state, Gln-15, Ala-23, and Cys-108 on one head are
      positioned near (within 8.9 A) the regulatory light chain of the partner head and
      that thiophosphorylation abolishes proximity. This behavior was also observed for
      the Q15C mutant on a truncated heavy meromyosin lacking both catalytic domains.
      For the actin-heavy meromyosin complex, cross-links were formed in both de- and
      thiophosphorylated states. S59C and T134C mutants were in a second mutant class,
      where regulatory light chain dimers were not detected in dephosphorylated or
      thiophosphorylated heavy meromyosin, suggesting positions outside the region of
      interaction of the regulatory light chains.

PMID- 10400656
TI  - Kinetic analysis of human serine/threonine protein phosphatase 2Calpha.
AB  - The PPM family of Ser/Thr protein phosphatases have recently been shown to down
      regulate the stress response pathways in eukaryotes. Within the stress pathway,
      key signaling kinases, which are activated by protein phosphorylation, have been
      proposed as the in vivo substrates of PP2C, the prototypical member of the PPM
      family. Although it is known that these phosphatases require metal cations for
      activity, the molecular details of these important reactions have not been
      established. Therefore, here we report a detailed biochemical study to elucidate
      the kinetic and chemical mechanism of PP2Calpha. Steady-state kinetic and product
      inhibition studies revealed that PP2Calpha employs an ordered sequential
      mechanism, where the metal cations bind before phosphorylated substrate, and
      phosphate is the last product to be released. The metal-dependent activity of
      PP2C (as reflected in kcat and kcat/Km), indicated that Fe2+ was 1000-fold better
      than Mg2+. The pH rate profiles revealed two ionizations critical for catalytic
      activity. An enzyme ionization with a pKa value of 7 must be unprotonated for
      catalysis, and an enzyme ionization with a pKa of 9 must be protonated for
      substrate binding. Bronsted analysis of substrate leaving group pKa indicated
      that phosphomonoester hydrolysis is rate-limiting at pH 7. 0, but not at pH 8.5
      where a common step independent of the nature of the substrate and alcohol
      product limits turnover (kcat). Rapid reaction kinetics between phosphomonoester
      and PP2C yielded exponential "bursts" of product formation, consistent with
      phosphate release being the slow catalytic step at pH 8.5. Dephosphorylation of
      synthetic phosphopeptides corresponding to several protein kinases revealed that
      PP2C displays a strong preference for diphosphorylated peptides in which the
      phosphorylated residues are in close proximity.

PMID- 10400658
TI  - Chaperone activity of a chimeric GroEL protein that can exist in a single or
      double ring form.
AB  - The molecular chaperone GroEL is a protein complex consisting of two rings each
      of seven identical subunits. It is thought to act by providing a cavity in which
      a protein substrate can fold into a form that has no propensity to aggregate.
      Substrate proteins are sequestered in the cavity while they fold, and prevented
      from diffusion out of the cavity by the action of the GroES complex, that caps
      the open end of the cavity. A key step in the mechanism of action of GroEL is the
      transmission of a conformational change between the two rings, induced by the
      binding of nucleotides to the GroEL ring opposite to the one containing the
      polypeptide substrate. This conformational change then leads to the discharge of
      GroES from GroEL, enabling polypeptide release. Single ring forms of GroEL are
      thus predicted to be unable to chaperone the folding of GroES-dependent
      substrates efficiently, since they are unable to discharge the bound GroES and
      unable to release folded protein. We describe here a detailed functional analysis
      of a chimeric GroEL protein, which we show to exist in solution in equilibrium
      between single and double ring forms. We demonstrate that whereas the double ring
      form of the GroEL chimera functions effectively in refolding of a GroES-dependent
      substrate, the single ring form does not. The single ring form of the chimera,
      however, is able to chaperone the folding of a substrate that does not require
      GroES for its efficient folding. We further demonstrate that the double ring
      structure of GroEL is likely to be required for its activity in vivo.

PMID- 10400657
TI  - Mechanism of scavenger receptor class B type I-mediated selective uptake of
      cholesteryl esters from high density lipoprotein to adrenal cells.
AB  - Despite extensive studies and characterizations of the high density lipoprotein
      cholesteryl ester (HDL-CE)-selective uptake pathway, the mechanisms by which the
      hydrophobic CE molecules are transferred from the HDL particle to the plasma
      membrane have remained elusive, until the discovery that scavenger receptor BI
      (SR-BI) plays an important role. To elucidate the molecular mechanism, we
      examined the quantitative relationships between the binding of HDL and the
      selective uptake of its CE in the murine adrenal Y1-BS1 cell line. A comparison
      of concentration dependences shows that half-maximal high affinity cell
      association of HDL occurs at 8.7 +/- 4.7 micrograms/ml and the Km of HDL-CE
      selective uptake is 4.5 +/- 1.5 micrograms/ml. These values are similar, and
      there is a very high correlation between these two processes (r2 = 0.98),
      suggesting that they are linked. An examination of lipid uptake from
      reconstituted HDL particles of defined composition and size shows that there is a
      non-stoichiometric uptake of HDL lipid components, with CE being preferred over
      the major HDL phospholipids, phosphatidylcholine and sphingomyelin. Comparison of
      the rates of selective uptake of different classes of phospholipid in this system
      gives the ranking: phosphatidylserine > phosphatidylcholine approximately
      phosphatidylinositol > sphingomyelin. The rate of CE-selective uptake from donor
      particles is proportional to the amount of CE initially present in the particles,
      suggesting a mechanism in which CE moves down its concentration gradient from HDL
      particles docked on SR-BI into the cell plasma membrane. The activation energy
      for CE uptake from either HDL3 or reconstituted HDL is about 9 kcal/mol,
      indicating that HDL-CE uptake occurs via a non-aqueous pathway. HDL binding to SR
      BI allows access of CE molecules to a "channel" formed by the receptor from which
      water is excluded and along which HDL-CE molecules move down their concentration
      gradient into the cell plasma membrane.

PMID- 10400659
TI  - Stimulation of expression for the adenosine A2A receptor gene by hypoxia in PC12
      cells. A potential role in cell protection.
AB  - The purpose of this study was to examine the regulation of adenosine A2A receptor
      (A2AR) gene expression during hypoxia in pheochromocytoma (PC12) cells. Northern
      blot analysis revealed that the A2AR mRNA level was substantially increased after
      a 3-h exposure to hypoxia (5% O2), which reached a peak at 12 h. Immunoblot
      analysis showed that the A2AR protein level was also increased during hypoxia.
      Inhibition of de novo protein synthesis blocked A2AR induction by hypoxia. In
      addition, removal of extracellular free Ca2+, chelation of intracellular free
      Ca2+, and pretreatment with protein kinase C inhibitors prevented A2AR induction
      by hypoxia. Moreover, depletion of protein kinase C activity by prolonged
      treatment with phorbol 12-myristate 13-acetate significantly inhibited the
      hypoxic induction of A2AR. A2AR antagonists led to a significant enhancement of
      A2AR mRNA levels during hypoxia, whereas A2AR agonists caused down-regulation of
      A2AR expression during hypoxia. This suggests that A2AR regulates its own
      expression during hypoxia by feedback mechanisms. We further found that
      activation of A2AR enhances cell viability during hypoxia and also inhibits
      vascular endothelial growth factor expression in PC12 cells. Thus, increased
      expression of A2AR during hypoxia might protect cells against hypoxia and may act
      to inhibit hypoxia-induced angiogenic activity mediated by vascular endothelial
      growth factor.

PMID- 10400660
TI  - Purification, characterization, and role of nucleases and serine proteases in
      Streptomyces differentiation. Analogies with the biochemical processes described
      in late steps of eukaryotic apoptosis.
AB  - Two exocellular nucleases with molecular masses of 18 and 34 kDa, which are
      nutritionally regulated and reach their maximum activity during aerial mycelium
      formation and sporulation, have been detected in Streptomyces antibioticus. Their
      function appears to be DNA degradation in the substrate mycelium, and in
      agreement with this proposed role the two nucleases cooperate efficiently with a
      periplasmic nuclease previously described in Streptomyces antibioticus to
      completely hydrolyze DNA. The nucleases cut DNA nonspecifically, leaving 5'
      phosphate mononucleotides as the predominant products. Both proteins require
      Mg2+, and the additional presence of Ca2+ notably stimulates their activities.
      The two nucleases are inhibited by Zn2+ and aurin tricarboxylic acid. The 18-kDa
      nuclease from Streptomyces is reminiscent of NUC-18, a thymocyte nuclease
      proposed to have a key role in glucocorticoid-stimulated apoptosis. The 18-kDa
      nuclease was shown, by amino-terminal protein sequencing, to be a member of the
      cyclophilin family and also to possess peptidylprolyl cis-trans-isomerase
      activity. NUC-18 has also been shown to be a cyclophilin, and "native"
      cyclophilins are capable of DNA degradation. The S. antibioticus 18-kDa nuclease
      is produced by a proteolytic processing from a less active protein precursor. The
      protease responsible has been identified as a serine protease that is inhibited
      by Nalpha-p-tosyl-L-lysine chloromethyl ketone and leupeptin. Inhibition of both
      of the nucleases or the protease impairs aerial mycelium development in S.
      antibioticus. The biochemical features of cellular DNA degradation during
      Streptomyces development show significant analogies with the late steps of
      apoptosis of eukaryotic cells.

PMID- 10400662
TI  - Identification of cis-regulating elements and trans-acting factors regulating the
      expression of the gene encoding the small subunit of ribonucleotide reductase in
      Dictyostelium discoideum.
AB  - We have examined the promoter of rnrB, the gene encoding the small subunit of
      ribonucleotide reductase of Dictyostelium discoideum, using lacZ as a reporter
      gene. Deletion analysis showed that expression of this gene in vegetative cells
      involves an A/T-rich element, whereas its expression in prespore cells during
      development requires a region encompassing two G/C-rich elements, designated box
      A and box B. Removal of boxes A and B results in very low level of activity. When
      either box A or box B is deleted, prestalk cells adjacent to the prespore zone
      also express beta-galactosidase. The behavior of these cis-regulatory elements
      implies that the mechanism regulating the prespore-specific expression of rnrB is
      different from that regulating other known prespore genes. We have used
      electrophoretic mobility shift assays to identify factors that interact with box
      A and box B. Box A interacts with a factor that is found in the nuclear fraction.
      While box B interacts with a factor that is present in the cytosolic fraction
      throughout growth and development, its presence in the nuclear fraction is
      developmentally regulated. Results from competition assays suggest that both box
      A and box B interact with transcriptional activators that have not been
      characterized previously.

PMID- 10400661
TI  - Octamer-dependent in vivo expression of the endothelial cell-specific TIE2 gene.
AB  - The TIE2 gene, also known as TEK, encodes a tyrosine kinase receptor that is
      required for the normal development of the vascular system during embryogenesis.
      TIE2 is specifically expressed in endothelial cells; however, the transcriptional
      mechanisms that regulate this highly restricted pattern of expression remain
      unknown. Here we demonstrate that a consensus octamer element located in the 5'
      flanking region of TIE2 is required for normal expression in embryonic
      endothelial cells. Transgenic embryos carrying a TIE2/LacZ construct spanning 2.1
      kilobases of upstream regulatory sequences exhibit expression of the reporter
      transgene specifically in endothelial cells. Site-directed mutagenesis of a
      consensus octamer element located in this region results in the loss of enhancer
      activity and significantly impairs the endothelial expression of the reporter
      transgene. Consistent with the in vivo data, in vitro DNA-protein binding studies
      show that the consensus octamer element displays an endothelial cell-specific
      pattern of binding, suggesting an interaction with a protein complex consisting
      of Oct1 and an endothelial cell-restricted cofactor. These data identify a novel
      role for the octamer element as an essential regulator of TIE2 expression, define
      the first known transcriptional pathway that mediates the expression of a
      developmental endothelial cell gene, and provide insights into the
      transcriptional mechanisms that regulate development of the vasculature during
      embryogenesis.

PMID- 10400663
TI  - The specificity of TIMP-2 for matrix metalloproteinases can be modified by single
      amino acid mutations.
AB  - Residues 1-127 of human TIMP-2 (N-TIMP-2), comprising three of the disulfide
      bonded loops of the TIMP-2 molecule, is a discrete protein domain that folds
      independently of the C-terminal domain. This domain has been shown to be
      necessary and sufficient for metalloproteinase inhibition and contains the major
      sites of interaction with the catalytic N-terminal domain of active matrix
      metalloproteinases (MMPs). Residues identified as being involved in the
      interaction with MMPs by NMR chemical shift perturbation studies and TIMP/MMP
      crystal structures have been altered by site-directed mutagenesis. We show, by
      measurement of association rates and apparent inhibition constants, that the
      specificity of these N-TIMP-2 mutants for a range of MMPs can be altered by
      single site mutations in either the TIMP "ridge" (Cys1-Cys3 and Ser68-Cys72) or
      the flexible AB loop (Ser31-Ile41). This work demonstrates that it is possible to
      engineer TIMPs with altered specificity and suggests that this form of protein
      engineering may be useful in the treatment of diseases such as arthritis and
      cancer where the selective inhibition of key MMPs is desirable.

PMID- 10400664
TI  - Regulation of peripheral cannabinoid receptor CB2 phosphorylation by the inverse
      agonist SR 144528. Implications for receptor biological responses.
AB  - We recently demonstrated that the selective cannabinoid receptor antagonist SR
      144528 acts as an inverse agonist that blocks constitutive mitogen-activated
      protein kinase activity coupled to the spontaneous autoactivated peripheral
      cannabinoid receptor (CB2) in the Chinese hamster ovary cell line stably
      transfected with human CB2. In the present report, we studied the effect of SR
      144528 on CB2 phosphorylation. The CB2 phosphorylation status was monitored by
      immunodetection using an antibody specific to the COOH-terminal CB2 which can
      discriminate between phosphorylated and non-phosphorylated CB2 isoforms at serine
      352. We first showed that CB2 is constitutively active, phosphorylated, and
      internalized at the basal level. By blocking autoactivated receptors, inverse
      agonist SR 144528 treatment completely inhibited this phosphorylation state,
      leading to an up-regulated CB2 receptor level at the cell surface, and enhanced
      cannabinoid agonist sensitivity for mitogen-activated protein kinase activation
      of Chinese hamster ovary-CB2 cells. After acute agonist treatment, serine 352 was
      extensively phosphorylated and maintained in this phosphorylated state for more
      than 8 h after agonist treatment. The cellular responses to CP-55,940 were
      concomitantly abolished. Surprisingly, CP-55,940-induced CB2 phosphorylation was
      reversed by SR 144528, paradoxically leading to a non-phosphorylated CB2 which
      could then be fully activated by CP-55,940. The process of CP-55,940-induced
      receptor phosphorylation followed by SR 144528-induced receptor dephosphorylation
      kept recurring many times on the same cells, indicating that the agonist switches
      the system off but the inverse agonist switches the system back on. Finally, we
      showed that autophosphorylation and CP-55, 940-induced serine 352 CB2
      phosphorylation involve an acidotropic GRK kinase, which does not use
      Gibetagamma. In contrast, SR 144528-induced CB2 dephosphorylation was found to
      involve an okadaic acid and calyculin A-sensitive type 2A phosphatase.

PMID- 10400665
TI  - Formation of Nepsilon-(hexanonyl)lysine in protein exposed to lipid
      hydroperoxide. A plausible marker for lipid hydroperoxide-derived protein
      modification.
AB  - The objectives of this study were to estimate the structure of the lipid
      hydroperoxide-modified lysine residue and to prove the presence of the adducts in
      vivo. The reaction of lipid hydroperoxide toward the lysine moiety was
      investigated employing N-benzoyl-glycyl-L-lysine (Bz-Gly-Lys) as a model compound
      of Lys residues in protein and 13-hydroperoxyoctadecadienoic acid (13-HPODE) as a
      model of the lipid hydroperoxides. One of the products, compound X, was isolated
      from the reaction mixture of 13-HPODE and Bz-Gly-Lys and was then identified as N
      benzoyl-glycyl-Nepsilon-(hexanonyl)lysine. To prove the formation of Nepsilon
      (hexanonyl)lysine, named HEL, in protein exposed to the lipid hydroperoxide, the
      antibody to the synthetic hexanonyl protein was prepared and then characterized
      in detail. Using the anti-HEL antibody, the presence of HEL in the lipid
      hydroperoxide-modified proteins and oxidized LDL was confirmed. Furthermore, the
      positive staining by anti-HEL antibody was observed in human atherosclerotic
      lesions using an immunohistochemical technique. The amide-type adduct may be a
      useful marker for the lipid hydroperoxide-derived modification of biomolecules.

PMID- 10400666
TI  - NH2-terminal BH4 domain of Bcl-2 is functional for heterodimerization with Bax
      and inhibition of apoptosis.
AB  - The Bcl-2 family proteins comprise pro-apoptotic as well as anti-apoptotic
      members. Heterodimerization between members of the Bcl-2 family proteins is a key
      event in the regulation of apoptosis. We report here that Bcl-2 protein was
      selectively cleaved by active caspase-3-like proteases in CTLL-2 cell apoptosis
      in response to interleukin-2 deprivation. Structural and functional analyses of
      the cleaved fragment revealed that the NH2-terminal region of Bcl-2 (1-34 amid
      acids) was required for its anti-apoptotic activity and heterodimerization with
      pro-apoptotic Bax protein. Site-directed mutagenesis of the NH2-terminal region
      showed that substitutions of hydrophobic residues of BH4 domain resulted in the
      loss of ability to form a heterodimer with Bax. Particularly instructive was that
      the V15E mutant of Bcl-2, which completely lost the ability to form a heterodimer
      with Bax, failed to inhibit Bax- and staurosporine-induced apoptosis. Our results
      suggest that the BH4 domain of Bcl-2 is critical for its heterodimerization with
      Bax and for exhibiting anti-apoptotic activity. Therefore, agents interferring
      with the critical residues of the BH4 domain may provide a new strategy in cancer
      therapy by impairing Bcl-2 function.

PMID- 10400667
TI  - Phospholipase C-gamma1 is required for calcium-induced keratinocyte
      differentiation.
AB  - Phospholipase C-gamma1 is the most abundant member of the phospholipase C family
      in keratinocytes and is induced by calcium. Phospholipase C-gamma1, therefore,
      may be involved in the signal transduction system leading to calcium regulation
      of keratinocyte differentiation. To test this hypothesis, expression of
      phospholipase C-gamma1 in human keratinocytes was blocked by transfecting cells
      with the antisense human phospholipase C-gamma1 cDNA construct. These cells
      demonstrated a dramatic reduction in phospholipase C-gamma1 protein level
      compared with the empty vector-transfected cells and a marked reduction in the
      mRNA and protein levels of the differentiation markers involucrin and
      transglutaminase following administration of calcium. Similarly, cotransfection
      of antisense phospholipase C-gamma1 constructs with a luciferase reporter vector
      containing involucrin or transglutaminase promoters led to a substantial
      reduction in calcium-stimulated involucrin and transglutaminase promoter
      activities. Similar results were seen following treatment with a specific
      phospholipase C inhibitor U73122. To determine whether phospholipase C-gamma1
      regulated differentiation by controlling intracellular calcium, we examined the
      ability of antisense phospholipase C-gamma1 to block the calcium-induced rise in
      intracellular calcium and found that it could. These findings indicate that
      phospholipase C-gamma1 is a critical component of the signaling pathway mediating
      calcium regulation of keratinocyte differentiation via its mobilization of
      intracellular calcium.

PMID- 10400668
TI  - Structure of Ustilago maydis killer toxin KP6 alpha-subunit. A multimeric
      assembly with a central pore.
AB  - Ustilago maydis is a fungal pathogen of maize, some strains of which secrete
      killer toxins. The toxins are encoded by double-stranded RNA viruses in the cell
      cytoplasm. The U. maydis killer toxin KP6 contains two polypeptide chains, alpha
      and beta, having 79 and 81 amino acids, respectively, both of which are necessary
      for its killer activity. The crystal structure of the alpha-subunit of KP6
      (KP6alpha) has been determined at 1.80-A resolution. KP6alpha forms a single
      domain structure that has an overall shape of an ellipsoid with dimensions 40 A x
      26 A x 21 A and belongs to the alpha/beta-sandwich family. The tertiary structure
      consists of a four-stranded antiparallel beta-sheet, a pair of antiparallel alpha
      helices, a short strand along one edge of the sheet, and a short N-terminal
      helix. Although the fold is reminiscent of toxins of similar size, the topology
      of KP6alpha is distinctly different in that the alpha/beta-sandwich motif has two
      right-handed betaalphabeta split crossovers. Monomers of KP6alpha assemble
      through crystallographic symmetries, forming a hexamer with a central pore lined
      by hydrophobic N-terminal helices. The central pore could play an important role
      in the mechanism of the killing action of the toxin.

PMID- 10400669
TI  - DRBP76, a double-stranded RNA-binding nuclear protein, is phosphorylated by the
      interferon-induced protein kinase, PKR.
AB  - The interferon-induced double-stranded RNA-activated protein kinase PKR is the
      prototype of a class of double-stranded (dsRNA)-binding proteins (DRBPs) which
      share a dsRNA-binding motif conserved from Drosophila to humans. Here we report
      the purification of DRBP76, a new human member of this class of proteins.
      Sequence from the amino terminus of DRBP76 matched that of the M phase-specific
      protein, MPP4. DRBP76 was also cloned by the yeast two-hybrid screening of a cDNA
      library using a mutant PKR as bait. Analysis of the cDNA sequence revealed that
      it is the full-length version of MPP4, has a bipartite nuclear localization
      signal, two motifs that can mediate interactions with both dsRNA and PKR, five
      epitopes for potential M phase-specific phosphorylation, two potential sites for
      phosphorylation by cyclin-dependent kinases, a RG2 motif present in many RNA
      binding proteins and predicts a protein of 76 kDa. DsRNA and PKR interactions of
      DRBP76 were confirmed by analysis of in vitro translated and purified native
      proteins. Cellular expression of an epitope-tagged DRBP76 demonstrated its
      nuclear localization, and its co-immunoprecipitation with PKR demonstrated that
      the two proteins interact in vivo. Finally, purified DRBP76 was shown to be a
      substrate of PKR in vitro, indicating that this protein's cellular activities may
      be regulated by PKR-mediated phosphorylation.

PMID- 10400670
TI  - The bacterial magnesium transporter CorA can functionally substitute for its
      putative homologue Mrs2p in the yeast inner mitochondrial membrane.
AB  - The yeast nuclear gene MRS2 encodes a protein of 54 kDa, the presence of which
      has been shown to be essential for the splicing of group II intron RNA in
      mitochondria and, independently, for the maintenance of a functional respiratory
      system. Here we show that the MRS2 gene product (Mrs2p) is an integral protein of
      the inner mitochondrial membrane. It appears to be inserted into this membrane by
      virtue of two neighboring membrane spanning domains in its carboxyl-terminal
      half. A large amino-terminal and a shorter carboxyl-terminal part are likely to
      be exposed to the matrix space. Structural features and a short sequence motif
      indicate that Mrs2p may be related to the bacterial CorA Mg2+ transporter. In
      fact, overexpression of the CorA gene in yeast partially suppresses the pet-
      phenotype of an mrs2 disrupted yeast strain. Disruption of the MRS2 gene leads to
      a significant decrease in total magnesium content of mitochondria which is
      compensated for by the overexpression of the CorA gene. Mutants lacking or
      overproducing Mrs2p exhibit phenotypes consistent with the involvement of Mrs2p
      in mitochondrial Mg2+ homeostasis.

PMID- 10400671
TI  - Fibulin-1 is a ligand for the C-type lectin domains of aggrecan and versican.
AB  - The aggregating proteoglycans (aggrecan, versican, neurocan, and brevican) are
      important components of many extracellular matrices. Their N-terminal globular
      domain binds to hyaluronan, but the function of their C-terminal region
      containing a C-type lectin domain is less clear. We now report that a 90-kDa
      protein copurifies with recombinant lectin domains from aggrecan and versican,
      but not from the brain-specific neurocan and brevican. Amino acid sequencing of
      tryptic peptides from this protein identified it as fibulin-1. This extracellular
      matrix glycoprotein is strongly expressed in tissues where versican is expressed
      (blood vessels, skin, and developing heart), and also expressed in developing
      cartilage and bone. It is thus likely to interact with these proteoglycans in
      vivo. Surface plasmon resonance measurements confirmed that aggrecan and versican
      lectin domains bind fibulin-1, whereas brevican and neurocan do not. As expected
      for a C-type lectin, the interactions with fibulin-1 are Ca2+-dependent, with KD
      values in the low nanomolar range. Using various deletion mutants, the binding
      site for aggrecan and versican lectin domains was mapped to the epidermal growth
      factor-like repeats in domain II of fibulin-1. No difference in affinity was
      found for deglycosylated fibulin-1, indicating that the proteoglycan C-type
      lectin domains bind to the protein part of fibulin-1.

PMID- 10400672
TI  - Neonatal lethality in mice deficient in XCE, a novel member of the endothelin
      converting enzyme and neutral endopeptidase family.
AB  - XCE, a new member of the endothelin-converting enzyme and neutral endopeptidase
      family, is preferentially expressed in specific areas of the central nervous
      system including spinal chord and medulla. To elucidate the importance and
      function of XCE, we disrupted its gene in mouse embryonic stem cells by
      homologous recombination and created mice deficient in XCE. The resulting
      phenotype is characterized by neonatal lethality. All XCE -/- homozygous mice
      died of respiratory failure shortly after birth, and in most cases their lungs
      were never ventilated. Apart from the atelectasis, anatomical and histological
      examinations of embryonic day 18.5 XCE -/- embryos and newborn homozygotes did
      not reveal any obvious abnormalities in organs and tissues. Malformations that
      are related to the knock-out were also not found in the skeletons of XCE -/-
      mice. In addition, XCE knock-out animals showed no deficiency of pulmonary
      surfactant proteins and had normal heart beat frequencies. Taken together, our
      results demonstrate that XCE is an essential gene. The phenotype of the XCE
      deficient mice together with the central nervous system-specific expression
      further suggest that XCE may play a vital role in the control of respiration.

PMID- 10400673
TI  - Arginine 336 and asparagine 333 of the human cholecystokinin-A receptor binding
      site interact with the penultimate aspartic acid and the C-terminal amide of
      cholecystokinin.
AB  - The cholecystokinin-A receptor (CCK-AR) is a G protein-coupled receptor that
      mediates important central and peripheral cholecystokinin actions. Residues of
      the CCK-AR binding site that interact with the C-terminal part of CCK that is
      endowed with biological activity are still unknown. Here we report on the
      identification of Arg-336 and Asn-333 of CCK-AR, which interact with the Asp-8
      carboxylate and the C-terminal amide of CCK-9, respectively. Identification of
      the two amino acids was achieved by dynamics-based docking of CCK in a refined
      three-dimensional model of CCK-AR using, as constraints, previous results that
      demonstrated that Trp-39/Gln-40 and Met-195/Arg-197 interact with the N terminus
      and the sulfated tyrosine of CCK, respectively. Arg-336-Asp-8 and Asn-333-amide
      interactions were pharmacologically assessed by mutational exchange of Arg-336
      and Asn-333 in the receptor or reciprocal elimination of the partner chemical
      functions in CCK. This study also allowed us to demonstrate that (i) the
      identified interactions are crucial for stabilizing the high affinity
      phospholipase C-coupled state of the CCK-AR.CCK complex, (ii) Arg-336 and Asn-333
      are directly involved in interactions with nonpeptide antagonists SR-27,897 and L
      364,718, and (iii) Arg-336 but not Asn-333 is directly involved in the binding of
      the peptide antagonist JMV 179 and the peptide partial agonist JMV 180. These
      data will be used to obtain an integrated dynamic view of the molecular processes
      that link agonist binding to receptor activation.

PMID- 10400674
TI  - Identification of the erythropoietin receptor domain required for calcium channel
      activation.
AB  - Erythropoietin (Epo) activates a voltage-independent Ca2+ channel that is
      dependent on tyrosine phosphorylation. To identify the domain(s) of the Epo
      receptor (Epo-R) required for Epo-induced Ca2+ influx, Chinese hamster ovary
      (CHO) cells were transfected with wild-type or mutant Epo receptors subcloned
      into pTracer-cytomegalovirus vector. This vector contains an SV40 early promoter,
      which drives expression of the green fluorescent protein (GFP) gene, and a
      cytomegalovirus immediate-early promoter driving expression of the Epo-R.
      Successful transfection was verified in single cells by detection of GFP, and
      intracellular Ca2+ ([Ca]i) changes were simultaneously monitored with rhod-2.
      Transfection of CHO cells with pTracer encoding wild-type Epo-R, but not pTracer
      alone, resulted in an Epo-induced [Ca]i increase that was abolished in cells
      transfected with Epo-R F8 (all eight cytoplasmic tyrosines substituted).
      Transfection with carboxyl-terminal deletion mutants indicated that removal of
      the terminal four tyrosine phosphorylation sites, but not the tyrosine at
      position 479, abolished Epo-induced [Ca]i increase, suggesting that tyrosines at
      positions 443, 460, and/or 464 are important. In CHO cells transfected with
      mutant Epo-R in which phenylalanine was substituted for individual tyrosines, a
      significant increase in [Ca]i was observed with mutants Epo-R Y443F and Epo-R
      Y464F. The rise in [Ca]i was abolished in cells transfected with Epo-R Y460F.
      Results were confirmed with CHO cells transfected with plasmids expressing Epo-R
      mutants in which individual tyrosines were added back to Epo-R F8 and in stably
      transfected Ba/F3 cells. These results demonstrate a critical role for the Epo-R
      cytoplasmic tyrosine 460 in Epo-stimulated Ca2+ influx.

PMID- 10400675
TI  - Solution structure of the major alpha-amylase inhibitor of the crop plant
      amaranth.
AB  - alpha-Amylase inhibitor (AAI), a 32-residue miniprotein from the Mexican crop
      plant amaranth (Amaranthus hypochondriacus), is the smallest known alpha-amylase
      inhibitor and is specific for insect alpha-amylases (Chagolla-Lopez, A., Blanco
      Labra, A., Patthy, A., Sanchez, R., and Pongor, S. (1994) J. Biol. Chem. 269,
      23675-23680). Its disulfide topology was confirmed by Edman degradation, and its
      three-dimensional solution structure was determined by two-dimensional 1H NMR
      spectroscopy at 500 MHz. Structural constraints (consisting of 348 nuclear
      Overhauser effect interproton distances, 8 backbone dihedral constraints, and 9
      disulfide distance constraints) were used as an input to the X-PLOR program for
      simulated annealing and energy minimization calculations. The final set of 10
      structures had a mean pairwise root mean square deviation of 0.32 A for the
      backbone atoms and 1.04 A for all heavy atoms. The structure of AAI consists of a
      short triple-stranded beta-sheet stabilized by three disulfide bonds, forming a
      typical knottin or inhibitor cystine knot fold found in miniproteins, which binds
      various macromolecular ligands. When the first intercystine segment of AAI
      (sequence IPKWNR) was inserted into a homologous position of the spider toxin
      Huwentoxin I, the resulting chimera showed a significant inhibitory activity,
      suggesting that this segment takes part in enzyme binding.

PMID- 10400676
TI  - Randomization of the receptor alpha chain recruitment epitope reveals a
      functional interleukin-5 with charge depletion in the CD loop.
AB  - We report the functional phage display of single chain human interleukin-5 (scIL
      5) and its use for receptor-binding epitope randomization. Enzyme-linked
      immunosorbent assays and optical biosensor analyses verified expression of scIL-5
      on the phage surface and binding of scIL-5 phage to interleukin-5 receptor alpha
      chain. Furthermore, an asymmetrically disabled but functional scIL-5 mutant,
      (wt/A5)scIL-5, was displayed on phage. (wt/A5)scIL-5 was constructed from an N
      terminal half containing the original five charged residues (88EERRR92) in the CD
      loop, including the Glu89 and Arg91 believed key in the alpha chain recognition
      site, combined with a C-terminal half containing a disabled CD loop sequence
      (88AAAAA92) missing the key recognition residues. This asymmetric variant was
      used as a starting point to generate an scIL-5 library in which the intact 88-92
      N-terminal CD loop was randomized. From this epitope library, a receptor-binding
      variant of IL-5 was detected, (SLRGG/A5)scIL-5, in which the only charged residue
      in the CD loop is an Arg at position 90. Characterization of this variant
      expressed as a soluble protein in E. coli shows that the IL-5 pharmacophore for
      receptor alpha chain binding can function with a single positive charge in the CD
      loop. Charge-depleted CD loop mimetics of IL-5 suggest the importance of charge
      distribution in functional IL-5 receptor recruitment.

PMID- 10400677
TI  - SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and
      binds to 5'-CACCT sequences in candidate target genes.
AB  - Activation of transforming growth factor beta receptors causes the
      phosphorylation and nuclear translocation of Smad proteins, which then
      participate in the regulation of expression of target genes. We describe a novel
      Smad-interacting protein, SIP1, which was identified using the yeast two-hybrid
      system. Although SIP1 interacts with the MH2 domain of receptor-regulated Smads
      in yeast and in vitro, its interaction with full-length Smads in mammalian cells
      requires receptor-mediated Smad activation. SIP1 is a new member of the
      deltaEF1/Zfh-1 family of two-handed zinc finger/homeodomain proteins. Like
      deltaEF1, SIP1 binds to 5'-CACCT sequences in different promoters, including the
      Xenopus brachyury promoter. Overexpression of either full-length SIP1 or its C
      terminal zinc finger cluster, which bind to the Xbra2 promoter in vitro,
      prevented expression of the endogenous Xbra gene in early Xenopus embryos.
      Therefore, SIP1, like deltaEF1, is likely to be a transcriptional repressor,
      which may be involved in the regulation of at least one immediate response gene
      for activin-dependent signal transduction pathways. The identification of this
      Smad-interacting protein opens new routes to investigate the mechanisms by which
      transforming growth factor beta members exert their effects on expression of
      target genes in responsive cells and in the vertebrate embryo.

PMID- 10400678
TI  - Rank-order of potencies for inhibition of the secretion of abeta40 and abeta42
      suggests that both are generated by a single gamma-secretase.
AB  - The Alzheimer's disease amyloid peptide Abeta has a heterogeneous COOH terminus,
      as variants 40 and 42 residues long are found in neuritic plaques and are
      secreted constitutively by cultured cells. The proteolytic activity that
      liberates the Abeta COOH terminus from the beta-amyloid precursor protein is
      called gamma-secretase. It could be one protease with dual specificity or two
      distinct enzymes. By using enzyme-linked immunosorbent assays selective for
      Abeta40 or Abeta42, we have measured Abeta secretion by a HeLa cell line, and we
      have examined the dose responses for a panel of five structurally diverse gamma
      secretase inhibitors. The inhibitors lowered Abeta and p3 secretion and increased
      levels of the COOH-terminal 99-residue beta-amyloid precursor protein derivative
      that is the precursor for Abeta but did not alter secretion of beta-amyloid
      precursor protein derivatives generated by other secretases, indicating that the
      inhibitors blocked the gamma-secretase processing step. The dose-dependent
      inhibition of Abeta42 was unusual, as the compounds elevated Abeta42 secretion at
      sub-inhibitory doses and then inhibited secretion at higher doses. A compound was
      identified that elevated Abeta42 secretion at a low concentration without
      inhibiting Abeta42 or Abeta40 at high concentrations, demonstrating that these
      phenomena are separable pharmacologically. Using either of two methods, IC50
      values for inhibition of Abeta42 and Abeta40 were found to have the same rank
      order and fall on a trend line with near-unit slope. These results favor the
      hypothesis that Abeta variants ending at residue 40 or 42 are generated by a
      single gamma-secretase.

PMID- 10400679
TI  - p125 is a novel mammalian Sec23p-interacting protein with structural similarity
      to phospholipid-modifying proteins.
AB  - COPII-coated vesicles are involved in protein transport from the endoplasmic
      reticulum to the Golgi apparatus. COPII consists of three parts: Sar1p and the
      two protein complexes, Sec23p-Sec24p and Sec13p-Sec31p. Using a glutathione S
      transferase fusion protein with mouse Sec23p, we identified a novel mammalian
      Sec23p-interacting protein, p125, which is clearly distinct from Sec24p. The N
      terminal region of p125 is rich in proline residues, and the central and C
      terminal regions exhibit significant homology to phospholipid-modifying proteins,
      especially phosphatidic acid preferring-phospholipase A1. We transiently
      expressed p125 and mouse Sec23p in mammalian cells and examined their
      interaction. The results showed that the N-terminal region of p125 is important
      for the interaction with Sec23p. We confirmed the interaction between the two
      proteins by a yeast two-hybrid assay. Overexpression of p125, like that of
      mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi
      intermediate compartment and Golgi apparatus, suggesting its role in the early
      secretory pathway.

PMID- 10400680
TI  - Altered glycosylation sites of the delta subunit of the acetylcholine receptor
      (AChR) reduce alpha delta association and receptor assembly.
AB  - We have used mutagenesis to investigate the potential N-glycosylation sites in
      the delta subunit of the mouse muscle acetylcholine receptor (AChR). Of the three
      sites, Asn76, Asn143, and Asn169, only the first two were glycosylated when the
      delta subunit was expressed in COS cells. Because the heterologously expressed
      delta subunit was similar in its properties to that expressed in C2 muscle cells,
      the sites of glycosylation are likely to be the same in both cases. In COS cells,
      mutations of the delta subunit that prevented glycosylation at either of the
      sites did not change its metabolic stability nor its steady-state level. These
      results are in contrast to those found previously for the alpha subunit, in which
      glycosylation at a single site metabolically stabilized the polypeptide (Blount,
      P., and Merlie, J. P. (1990) J. Cell Biol. 111, 2613-2622). Mutations of the
      delta subunit that prevented glycosylation, however, decreased its ability to
      form an alpha delta heterodimer when the alpha and delta subunit were expressed
      together. When all four subunits of the AChR (alpha, beta, delta, and epsilon)
      were coexpressed, mutation of the delta subunit to prevent glycosylation resulted
      in a reduced amount of fully assembled AChR and reduced surface AChR levels,
      consistent with the role of the heterodimer in the assembly reaction. These
      results suggest that glycosylation of the delta subunit at both Asn76 and Asn143
      is needed for its efficient folding and/or its subsequent interaction with the
      alpha subunit.

PMID- 10400681
TI  - Poly(ADP-ribose) polymerase and Ku autoantigen form a complex and synergistically
      bind to matrix attachment sequences.
AB  - Genomic sequences with a cluster of ATC sequence stretches where one strand
      consists exclusively of well mixed As, Ts, and Cs confer high base unpairing
      propensity under negative superhelical strain. Such base unpairing regions (BURs)
      are typically found in scaffold or matrix attachment regions (SARs/MARs) that are
      thought to contribute to the formation of the loop domain structure of chromatin.
      Several proteins, including cell type-specific proteins, have been identified
      that bind specifically to double-stranded BURs either in vitro or in vivo. By
      using BUR-affinity chromatography to isolate BUR-binding proteins from breast
      cancer SK-BR-3 cells, we almost exclusively obtained a complex of poly(ADP
      ribose) polymerase (PARP) and DNA-dependent protein kinase (DNA-PK). Both PARP
      and DNA-PK are activated by DNA strand breaks and are implicated in DNA repair,
      recombination, DNA replication, and transcription. In contrast to the previous
      notion that PARP and Ku autoantigen, the DNA-binding subunit of DNA-PK, mainly
      bind to free ends of DNA, here we show that both proteins individually bind BURs
      with high affinity and specificity in an end-independent manner using closed
      circular BUR-containing DNA substrates. We further demonstrate that PARP and Ku
      autoantigen form a molecular complex in vivo and in vitro in the absence of DNA,
      and as a functional consequence, their affinity to the BURs are synergistically
      enhanced. ADP-ribosylation of the nuclear extract abrogated the BUR binding
      activity of this complex. These results provide a mechanistic link toward
      understanding the functional overlap of PARP and DNA-PK and suggest a novel role
      for these proteins in the regulation of chromatin structure and function.

PMID- 10400682
TI  - Phosphorylation and cytoskeletal anchoring of the acetylcholine receptor by Src
      class protein-tyrosine kinases. Activation by rapsyn.
AB  - Src class protein-tyrosine kinases bind to and phosphorylate the nicotinic
      acetylcholine receptor of skeletal muscle. This study provided evidence for the
      functional importance of Src kinases in regulating the nicotinic acetylcholine
      receptor at the neuromuscular junction. Three Src class kinases, Fyn, Fyk, and
      Src, each formed a complex with the endplate-specific cytoskeletal protein
      rapsyn. In addition, cellular phosphorylation by each kinase was stimulated by
      rapsyn in heterologous transfected cells. Several lines of evidence supported
      rapsyn as a substrate for Src kinases. Most importantly, rapsyn regulation of
      Fyn, Fyk, and Src resulted in phosphorylation of the nicotinic acetylcholine
      receptor beta and delta subunits and anchoring of the receptor to the
      cytoskeleton. Both nicotinic acetylcholine receptor phosphorylation and
      cytoskeletal anchoring were blocked by the Src kinase-selective inhibitor
      herbimycin A. Rapsyn alone also induced a modest increase in nicotinic
      acetylcholine receptor phosphorylation and cytoskeletal translocation. However,
      inhibition by herbimycin A and a catalytically inactive dominant negative Src
      demonstrated that the effects of rapsyn were mediated by endogenous Src kinases.
      These data support the importance of Src class kinases for stabilization of the
      nicotinic acetylcholine receptor at the endplate during synaptic differentiation
      at the neuromuscular junction.

PMID- 10400683
TI  - Molecular dissection of the intrinsic factor-vitamin B12 receptor, cubilin,
      discloses regions important for membrane association and ligand binding.
AB  - Cubilin, the receptor for intrinsic factor-vitamin B12, is a novel type of high
      molecular weight receptor consisting of a 27 CUB (complement components C1r/C1s,
      Uegf, and bone morphogenic protein-1) domain cluster preceded by 8 epidermal
      growth factor repeats and a short N-terminal sequence. In addition to binding the
      vitamin B12-carrier complex, cubilin also binds receptor-associated protein. To
      delineate the structures for membrane association and ligand binding we
      established a panel of stable transfected Chinese hamster ovary cells expressing
      overlapping segments of rat cubilin. Analysis of conditioned media and cell
      extracts of transfected cells revealed that the N-terminal cubilin region conveys
      membrane association. Helical plotting of this region demonstrated a conserved
      amphipathic helix pattern (Lys74-Glu109) as a candidate site for hydrophobic
      interactions. Ligand affinity chromatography and surface plasmon resonance
      analysis of the secreted cubilin fragments showed ligand binding in the CUB
      domain region. Further dissection of binding-active fragments localized the
      binding site for intrinsic factor-vitamin B12 to CUB domains 5-8 and a receptor
      associated protein-binding site to CUB domains 13-14. In conclusion, the N
      terminal cubilin region seems crucial for membrane association, whereas the CUB
      domain cluster harbors distinct sites for ligand binding.

PMID- 10400684
TI  - The KDEL receptor regulates a GTPase-activating protein for ADP-ribosylation
      factor 1 by interacting with its non-catalytic domain.
AB  - ADP-ribosylation factor 1 (ARF1) is a key regulator of transport in the secretory
      system. Like all small GTPases, deactivation of ARF1 requires a GTPase-activating
      protein (GAP) that promotes hydrolysis of GTP to GDP on ARF1. Structure-function
      analysis of a GAP for ARF1 revealed that its activity in vivo requires not only a
      domain that catalyzes hydrolysis of GTP on ARF1 but also a non-catalytic domain.
      In this study, we show that the non-catalytic domain of GAP is required for its
      recruitment from cytosol to membranes and that this domain mediates the
      interaction of GAP with the transmembrane KDEL receptor. Blocking its interaction
      with the KDEL receptor leaves the GAP cytosolic and prevents the deactivation in
      vivo of Golgi-localized ARF1. Thus, these findings suggest that the KDEL receptor
      plays a critical role in the function of GAP by regulating its recruitment from
      cytosol to membranes, where it can then act on its membrane-restricted target,
      the GTP-bound form of ARF1.

PMID- 10400686
TI  - Molecular and functional identification of a Ca2+ (polyvalent cation)-sensing
      receptor in rat pancreas.
AB  - The balance between the concentrations of free ionized Ca2+ and bicarbonate in
      pancreatic juice is of critical importance in preventing the formation of calcium
      carbonate stones. How the pancreas regulates the ionic composition and the level
      of Ca2+ saturation in an alkaline environment such as the pancreatic juice is not
      known. Because of the tight cause-effect relationship between Ca2+ concentration
      and lithogenicity, and because hypercalcemia is proposed as an etiologic factor
      for several pancreatic diseases, we have investigated whether pancreatic tissues
      express a Ca2+-sensing receptor (CaR) similar to that recently identified in
      parathyroid tissue. Using reverse transcriptase-polymerase chain reaction and
      immunofluorescence microscopy, we demonstrate the presence of a CaR-like molecule
      in rat pancreatic acinar cells, pancreatic ducts, and islets of Langerhans.
      Functional studies, in which intracellular free Ca2+ concentration was measured
      in isolated acinar cells and interlobular ducts, show that both cell types are
      responsive to the CaR agonist gadolinium (Gd3+) and to changes in extracellular
      Ca2+ concentration. We also assessed the effects of CaR stimulation on
      physiological HCO3- secretion from ducts by making measurements of intracellular
      pH. Luminal Gd3+ is a potent stimulus for HCO3- secretion, being equally as
      effective as raising intracellular cAMP with forskolin. These results suggest
      that the CaR in the exocrine pancreas monitors the Ca2+ concentration in the
      pancreatic juice, and might therefore be involved in regulating the level of Ca2+
      in the lumen, both under basal conditions and during hormonal stimulation. The
      failure of this mechanism might lead to pancreatic stone formation and even to
      pancreatitis.

PMID- 10400685
TI  - Intact LIM 3 and LIM 4 domains of paxillin are required for the association to a
      novel polyproline region (Pro 2) of protein-tyrosine phosphatase-PEST.
AB  - The focal adhesion protein p130(Cas) was identified as a substrate for the
      protein-tyrosine phosphatase (PTP)-PEST, and the specificity of this interaction
      is mediated by a dual mechanism involving a Src homology 3 domain-mediated
      binding and PTP domain recognition. Recently, paxillin was also demonstrated to
      interact with PTP-PEST (Shen, Y., Schneider, G., Cloutier, J. F., Veillette, A.,
      and Schaller, M. D. (1998) J. Biol. Chem. 273, 6474-6481). In the present study,
      we show that amino acids 344-397 of PTP-PEST are sufficient for the binding to
      paxillin. We demonstrate that a proline-rich segment of PTP-PEST (Pro 2),
      355PPEPHPVPPILTPSPPSAFP374, is essential for this interaction in vivo.
      Furthermore, mutation of proline residues within the Pro 2 motif reveal that
      proline 362 is critical for the binding of paxillin. Conversely, using deletion
      and point mutants of paxillin, LIM 3 and 4 domains were both found to be
      necessary for binding of PTP-PEST. Finally, using a "substrate trapping"
      approach, we demonstrate that, unlike p130(Cas), paxillin is not a substrate for
      PTP-PEST. In conclusion, we show that a novel proline-rich motif found in PTP
      PEST serves as a ligand for the LIM domains of paxillin. Interestingly, the focal
      adhesion targeting of paxillin is mediated by LIM 3. Thus, we propose that PTP
      PEST, by a competition with the ligand of paxillin in the focal adhesion complex,
      could contribute to the removal of paxillin from the adhesion sites and
      consequently promote focal adhesion turnover.

PMID- 10400687
TI  - Involvement of PITPnm, a mammalian homologue of Drosophila rdgB, in
      phosphoinositide synthesis on Golgi membranes.
AB  - Phosphatidylinositol transfer protein (PITP) is involved in phospholipase C
      mediated signaling and membrane trafficking. We previously reported cloning and
      characterization of a gene encoding for membrane-bound PITP, named PITPnm, that
      is a mammalian homologue of the Drosophila retinal degeneration B (rdgB) gene
      (Aikawa, Y., Hara, H., and Watanabe, T. (1997) Biochem. Biophys. Res. Commun.
      236, 559-564). Here we report the subcellular localization of PITPnm protein and
      provide evidence for its involvement in phosphatidylinositol 4-phosphate (PtdIns
      4-P) synthesis. PITPnm is an integral membrane protein that largely localized in
      close association with membranes of Golgi vacuoles and the endoplasmic reticulum
      (ER). The amino terminus region of PITPnm was exposed to cytoplasmic side.
      Interaction with various phosphoinositides was observed in the amino terminus
      region spanning from 196 amino acids to 257 amino acids of PITPnm. At the amino
      terminus regions of 1-372 amino acids, PITPnm formed a complex with type III
      PtdIns 4-kinase. The transmembrane and carboxyl-terminal portions (residues 418
      1242) functioned to retain the PITPnm in the Golgi vacuole. These results suggest
      that PITPnm plays a role in phosphoinositide synthesis on the Golgi vacuoles and
      possibly in the PtdIns signaling pathway in mammalian cells.

PMID- 10400688
TI  - Broad spectrum thiopeptide recognition specificity of the Streptomyces lividans
      TipAL protein and its role in regulating gene expression.
AB  - Microbial metabolites isolated in screening programs for their ability to
      activate transcription of the tipA promoter (ptipA) in Streptomyces lividans
      define a class of cyclic thiopeptide antibiotics having dehydroalanine side
      chains ("tails"). Here we show that such compounds of heterogeneous primary
      structure (representatives tested: thiostrepton, nosiheptide, berninamycin,
      promothiocin) are all recognized by TipAS and TipAL, two in-frame translation
      products of the tipA gene. The N-terminal helix-turn-helix DNA binding motif of
      TipAL is homologous to the MerR family of transcriptional activators, while the C
      terminus forms a novel ligand-binding domain. ptipA inducers formed irreversible
      complexes in vitro and in vivo (presumably covalent) with TipAS by reacting with
      the second of the two C-terminal cysteine residues. Promothiocin and thiostrepton
      derivatives in which the dehydroalanine side chains were removed lost the ability
      to modify TipAS. They were able to induce expression of ptipA as well as the tipA
      gene, although with reduced activity. Thus, TipA required the thiopeptide ring
      structure for recognition, while the tail served either as a dispensable part of
      the recognition domain and/or locked thiopeptides onto TipA proteins, thus
      leading to an irreversible transcriptional activation. Construction and analysis
      of a disruption mutant showed that tipA was autogenously regulated and conferred
      thiopeptide resistance. Thiostrepton induced the synthesis of other proteins,
      some of which did not require tipA.

PMID- 10400689
TI  - Effect of N-terminal alpha-helix formation on the dimerization and intracellular
      targeting of alanine:glyoxylate aminotransferase.
AB  - The unparalleled peroxisome-to-mitochondrion mistargeting of alanine:glyoxylate
      aminotransferase (AGT) in the hereditary disease primary hyperoxaluria type 1 is
      caused by the combined presence of a common Pro11 --> Leu polymorphism and a
      disease-specific Gly170 --> Arg mutation. The Pro11 --> Leu replacement generates
      a functionally weak N-terminal mitochondrial targeting sequence (MTS), the
      efficiency of which is increased by the additional presence of the Gly170 --> Arg
      replacement. AGT dimerization is inhibited in the combined presence of both
      replacements but not when each is present separately. In this paper we have
      attempted to identify the structural determinants of AGT dimerization and
      mitochondrial mistargeting. Unlike most MTSs, the polymorphic MTS of AGT has
      little tendency to adopt an alpha-helical conformation in vitro. Nevertheless, it
      is able to target efficiently a monomeric green fluorescent (GFP) fusion protein,
      but not dimeric AGT, to mitochondria in transfected COS-1 cells. Increasing the
      propensity of this MTS to fold into an alpha-helix, by making a double Pro11 -->
      Leu + Pro10 --> Leu replacement, enabled it to target both GFP and AGT
      efficiently to mitochondria. The double Pro11 --> Leu + Pro10 --> Leu replacement
      retarded AGT dimerization in vitro as did the disease-causing double Pro11 -->
      Leu + Gly170 --> Arg replacement. These data suggest that N-terminal alpha-helix
      formation is more important for maintaining AGT in a conformation (i. e.
      monomeric) compatible with mitochondrial import than it is for the provision of
      mitochondrial targeting information. The parallel effects of the Pro10 --> Leu
      and Gly170 --> Arg replacements on the dimerization and intracellular targeting
      of polymorphic AGT (containing the Pro11 --> Leu replacement) raise the
      possibility that they might achieve their effects by the same mechanism.

PMID- 10400690
TI  - Regulation of neuronal nitric-oxide synthase by calmodulin kinases.
AB  - Phosphorylation of neuronal nitric-oxide synthase (nNOS) by Ca2+/calmodulin (CaM)
      dependent protein kinases (CaM kinases) including CaM kinase Ialpha (CaM-K
      Ialpha), CaM kinase IIalpha (CaM-K IIalpha), and CaM kinase IV (CaM-K IV), was
      studied. It was found that purified recombinant nNOS was phosphorylated by CaM-K
      Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847
      with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated
      recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate
      incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of
      both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme.
      The activity of mutant S847D was decreased to a level 50-60% as much as the wild
      type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847
      and mutant S847D was partially due to suppression of CaM binding, but not to
      impairment of dimer formation which is thought to be essential for enzyme
      activation. Inactive nNOS lacking CaM-binding ability was generated by mutation
      of Lys732-Lys-Leu to Asp732-Asp-Glu (Watanabe, Y., Hu, Y., and Hidaka, H. (1997)
      FEBS Lett. 403, 75-78). It was phosphorylated by CaM kinases, as was the wild
      type enzyme, indicating that CaM-nNOS binding was not required for the
      phosphorylation reaction. We developed antibody NP847, which specifically
      recognize nNOS in its phosphorylated state at Ser847. Using the antibody NP847,
      we obtained evidence that nNOS is phosphorylated at Ser847 in rat brain. Thus,
      our results suggest that CaM kinase-induced phosphorylation of nNOS at Ser847
      alters the activity control of this enzyme.

PMID- 10400691
TI  - Identification of conserved cis-elements and transcription factors required for
      sterol-regulated transcription of stearoyl-CoA desaturase 1 and 2.
AB  - We previously identified stearoyl-CoA desaturase 2 (SCD2) as a new member of the
      family of genes that are transcriptionally regulated in response to changing
      levels of nuclear sterol regulatory element binding proteins (SREBPs) or
      adipocyte determination and differentiation factor 1 (ADD1). A novel sterol
      regulatory element (SRE) (5'-AGCAGATTGTG-3') identified in the proximal promoter
      of the mouse SCD2 gene is required for induction of SCD2 promoter-reporter genes
      in response to cellular sterol depletion (Tabor, D. E., Kim, J. B., Spiegelman,
      B. M., and Edwards, P. A. (1998) J. Biol. Chem. 273, 22052-22058). In this
      report, we demonstrate that this novel SRE is both present in the promoter of the
      SCD1 gene and is critical for the sterol-dependent transcription of SCD1 promoter
      reporter genes. Two conserved cis elements (5'-CCAAT-3') lie 5 and 48 base pairs
      3' of the novel SREs in the promoters of both the SCD1 and SCD2 murine genes.
      Mutation of either of these putative NF-Y binding sites attenuates the
      transcriptional activation of SCD1 or SCD2 promoter-reporter genes in response to
      cellular sterol deprivation. Induction of both reporter genes is also attenuated
      when cells are cotransfected with dominant-negative forms of either NF-Y or
      SREBP. In addition, we demonstrate that the induction of SCD1 and SCD2 mRNAs that
      occurs during the differentiation of 3T3-L1 preadipocytes to adipocytes is
      paralleled by an increase in the levels of ADD1/SREBP-1c and that the SCD1 and
      SCD2 mRNAs are induced to even higher levels in response to ectopic expression of
      ADD1/SREBP-1c. We conclude that transcription of both SCD1 and SCD2 genes is
      responsive to cellular sterol levels and to the levels of nuclear SREBP/ADD1 and
      that transcriptional induction requires three spatially conserved cis elements,
      that bind SREBP and NF-Y. Additional studies demonstrate that maximal
      transcriptional repression of SCD2 reporter genes in response to an exogenous
      polyunsaturated fatty acid is dependent upon the SRE and the adjacent CCAAT
      motif.

PMID- 10400692
TI  - Requirement for Akt (protein kinase B) in insulin-induced activation of glycogen
      synthase and phosphorylation of 4E-BP1 (PHAS-1).
AB  - The roles of Akt (protein kinase B) and the atypical lambda isoform of protein
      kinase C (PKClambda), both of which act downstream of phosphoinositide 3-kinase,
      in the activation of glycogen synthase and phosphorylation of 4E-BP1 (PHAS-1) in
      response to insulin were investigated. A mutant Akt (Akt-AA) in which the
      phosphorylation sites targeted by growth factors are replaced by alanine was
      shown to inhibit insulin-induced activation of both Akt and glycogen synthase in
      L6 myotubes. Expression of a mutant Akt in which Lys179 in the kinase domain was
      replaced by aspartate also inhibited insulin-induced activation of glycogen
      synthase but had no effect on insulin activation of endogenous Akt. A kinase
      defective mutant of PKClambda (lambdaDeltaNKD), which prevents insulin-induced
      activation of PKClambda, did not affect the activation of glycogen synthase by
      insulin. Insulin-induced phosphorylation of 4E-BP1 was inhibited by Akt-AA in
      Chinese hamster ovary cells. However, lambdaDeltaNKD had no effect on 4E-BP1
      phosphorylation induced by insulin. These data suggest that Akt, but not
      PKClambda, is required for insulin activation of glycogen synthase and for
      insulin-induced phosphorylation of 4E-BP1.

PMID- 10400693
TI  - Functional staging of ADP/ATP carrier translocation across the outer
      mitochondrial membrane.
AB  - The ADP/ATP carrier (AAC) is the major representative of the inner membrane
      carrier proteins of mitochondria that are synthesized without cleavable
      presequences. The characterization of the import pathway of AAC into mitochondria
      has mainly depended on an operational staging system. Here, we introduce two
      approaches for analyzing the import of AAC, blue native electrophoresis and
      folding-induced translocation arrest, that allow a functional staging of AAC
      transport across the outer membrane. (i) Blue native electrophoresis permits a
      direct monitoring of the receptor stage of AAC and its chase into mitochondria.
      Binding to this stage requires the receptor protein Tom70 but not Tom37 or Tom20.
      (ii) A fusion protein between AAC and dihydrofolate reductase can be selectively
      arrested in the general import pore complex of the outer membrane by ligand
      induced folding of the passenger protein. Cross-linking demonstrates that the
      arrested preprotein is in close contact not only with several receptors and Tim10
      but also with the channel protein Tom40, providing the first direct evidence that
      cleavable preproteins and carrier preproteins interact with the same outer
      membrane channel. The staging system presented here permits a molecular
      dissection of AAC transport across the outer mitochondrial membrane, relates it
      to functional units of the translocases, and indicates a coordinated and
      successive cooperation of distinct translocase subcomplexes during transfer of
      the preprotein.

PMID- 10400695
TI  - The CD3-gamma delta epsilon transducing module mediates CD38-induced protein
      tyrosine kinase and mitogen-activated protein kinase activation in Jurkat T
      cells.
AB  - We have examined the ability of the CD3-gamma delta epsilon and CD3-zeta
      signaling modules of the T cell receptor (TCR) to couple CD38 to intracellular
      signaling pathways. The results demonstrated that in TCR+ T cells that express
      the whole set of CD3 subunits CD38 ligation led to complete tyrosine
      phosphorylation of both CD3-zeta and CD3-epsilon polypeptide chains. In contrast,
      in TCR+ cells with a defective CD3-zeta association CD38 engagement caused
      tyrosine phosphorylation of CD3-epsilon but not of CD3-zeta. Despite these
      differences, in both cell types CD38 ligation resulted in protein-tyrosine kinase
      and mitogen-activated protein kinase activation. However, in cells expressing
      chimerical CD25-zeta or CD25-epsilon receptors or in a TCR-beta- Jurkat T cell
      line, CD38 ligation did not result in tyrosine phosphorylation of the chimeric
      receptors, or CD3 subunits, or protein-tyrosine kinase or mitogen-activated
      protein kinase activation. In summary, these results support a model in which
      CD38 transduces activating signals inside the cell by means of CD3-epsilon and
      CD3-zeta tyrosine phosphorylation. Moreover, these data identify the CD3-gamma
      delta epsilon signaling module as a necessary and sufficient component of the
      TCR/CD3 complex involved in T cell activation through CD38.

PMID- 10400694
TI  - The C terminus of SUR1 is required for trafficking of KATP channels.
AB  - In beta cells from the pancreas, ATP-sensitive potassium channels, or KATP
      channels, are composed of two subunits, SUR1 and KIR6.2, assembled in a
      (SUR1/KIR6.2)4 stoichiometry. The correct stoichiometry of channels at the cell
      surface is tightly regulated by the presence of novel endoplasmic reticulum (ER)
      retention signals in SUR1 and KIR6.2; incompletely assembled KATP channels fail
      to exit the ER/cis-Golgi compartments. In addition to these retrograde signals,
      we show that the C terminus of SUR1 has an anterograde signal, composed in part
      of a dileucine motif and downstream phenylalanine, which is required for KATP
      channels to exit the ER/cis-Golgi compartments and transit to the cell surface.
      Deletion of as few as seven amino acids, including the phenylalanine, from SUR1
      markedly reduces surface expression of KATP channels. Mutations leading to
      truncation of the C terminus of SUR1 are one cause of a severe, recessive form of
      persistent hyperinsulinemic hypoglycemia of infancy. We propose that the complete
      loss of beta cell KATP channel activity seen in this form of hyperinsulinism is a
      failure of KATP channels to traffic to the plasma membrane.

PMID- 10400696
TI  - Adenophostin A induces spatially restricted calcium signaling in Xenopus laevis
      oocytes.
AB  - The activation of intracellular calcium release and calcium entry across the
      plasmalemma in response to intracellular application of inositol 2,4,5
      trisphosphate and adenophostin A, two metabolically stable agonists for inositol
      1,4,5-trisphosphate receptors, was investigated using Xenopus laevis oocytes and
      confocal imaging. Intracellular injection of inositol 2,4,5-trisphosphate induced
      a rapidly spreading calcium signal associated with regenerative calcium waves;
      the calcium signal filled the peripheral regions of the cell in 1-5 min.
      Injection of high concentrations of adenophostin A (250 nM) similarly induced
      rapidly spreading calcium signals. Injection of low concentrations of
      adenophostin A resulted in calcium signals that spread slowly (>1 h). With
      extremely low concentrations of adenophostin A (approximately 10 pM), stable
      regions of Ca2+ release were observed that did not expand to peripheral regions.
      When the adenophostin A-induced calcium signal was restricted to central regions,
      compartmentalized calcium oscillations were sometimes observed. Restoration of
      extracellular calcium caused a rise in cytoplasmic calcium restricted to the
      region of adenophostin A-induced calcium mobilization. The limited diffusion of
      adenophostin A provides an opportunity to examine calcium signaling processes
      under spatially restricted conditions and provides insights into mechanisms of
      intracellular calcium oscillations and capacitative calcium entry.

PMID- 10400697
TI  - Intracellular accumulation of insoluble, newly synthesized abetan-42 in amyloid
      precursor protein-transfected cells that have been treated with Abeta1-42.
AB  - Our early study indicates that intracellular Abeta1-42 aggregates are resistant
      to degradation and accumulate as an insoluble residue in lysosomes, where they
      alter the normal catabolism of amyloid precursor protein (APP) to cause the
      accumulation of insoluble APP and amyloidogenic fragments. In this study, we
      examined whether the addition of exogenous Abeta1-42 also leads to the
      accumulation of newly synthesized intracellular Abeta. Here we describe that
      newly synthesized Abeta, especially Abetan-42, is generated from metabolically
      labeled APP and accumulates in the insoluble fraction of cell lysates after
      Abeta1-42 treatment. These results suggest that intracellular Abeta may derive
      from a solid phase, intracellular pathway. In contrast to the pathway that
      primarily produces secreted Abeta1-40, the solid-phase intracellular pathway
      preferentially produces Abetan-42 with ragged amino termini. Biochemical studies
      and amino acid sequencing analyses indicate that these intracellular Abeta also
      share the same types of Abeta structures that accumulate in the brain of
      Alzheimer's disease patients, suggesting that a significant fraction of the
      amyloid deposits in Alzheimer's disease may arise by this solid-phase pathway.

PMID- 10400699
TI  - Apoptosis promotes a caspase-induced amino-terminal truncation of IkappaBalpha
      that functions as a stable inhibitor of NF-kappaB.
AB  - Caspases are cell death cysteine proteases that are activated upon the induction
      of the apoptotic program and cleave target proteins in a sequence-specific manner
      to promote cell death. Recently, Barkett et al. (Barkett, M., Xue, D., Horvitz,
      H. R., and Gilmore, T. D. (1997) J. Biol. Chem. 272, 29419-29422) have shown that
      IkappaBalpha, the inhibitory subunit of the transcription factor NF-kappaB, can
      be cleaved by caspase-3 in vitro at a site that potentially produces a dominant
      inhibitory form of IkappaBalpha. The involvement of NF-kappaB in the inhibition
      of cell death led us to ask whether apoptotic stimuli would induce the caspase
      mediated cleavage of IkappaBalpha in vivo. In this study, we show that apoptosis
      leads to the caspase-mediated amino-terminal truncation of IkappaBalpha (DeltaN
      IkappaBalpha). Our data show that DeltaN-IkappaBalpha can bind NF-kappaB,
      suppress NF-kappaB activation, and sensitize cells to death. Since activated NF
      kappaB plays a role in the inhibition of cell death, these data suggest that
      caspase-mediated cleavage of IkappaBalpha may be a mechanism to suppress NF
      kappaB and its associated antiapoptotic activity.

PMID- 10400698
TI  - Src-family tyrosine kinases in activation of ERK-1 and p85/p110
      phosphatidylinositol 3-kinase by G/CCKB receptors.
AB  - We have analyzed in Chinese hamster ovary cells the upstream mediators by which
      the G protein-coupled receptor, gastrin/CCKB, activates the extracellular
      regulated kinases (ERKs) and p85/p110-phosphatidylinositol 3-kinase (PI 3-kinase)
      pathways. Overexpression of an inhibitory mutant of Shc completely blocked
      gastrin-stimulated Shc.Grb2 complex formation but partially inhibited ERK-1
      activation by this peptide. Expression of Csk, which inactivates Src-family
      kinases, totally inhibited gastrin-induced Src-like activity detected in anti-Src
      and anti-Shc precipitates but diminished by 50% Shc phosphorylation and ERK-1
      activation. We observed a rapid tyrosine phosphorylation of insulin receptor
      substrate-1 (IRS-1) and an increase in Src-like kinase activity in anti-IRS-1
      immunoprecipitates from gastrin-stimulated cells, suggesting that IRS-1 may be a
      direct substrate of Src. This hypothesis was supported by the inhibition of
      gastrin-induced Src. IRS-1 complex formation and IRS-1 phosphorylation in Csk
      transfected cells. In addition, the increase in PI 3-kinase activity measured in
      anti-p85 or anti-IRS-1 precipitates following gastrin stimulation was abolished
      by Csk. Our results demonstrate the existence of two mechanisms in gastrin
      mediated ERKs activation. One requires Shc phosphorylation by Src-family kinases,
      and the other one is independent of these two proteins. They also indicate that
      tyrosine phosphorylation of IRS-1 by Src-family kinases could lead to the
      recruitment and the activation of the p85/p110-PI 3-kinase in response to
      gastrin.

PMID- 10400700
TI  - Phenotypic analysis of seizure-prone mice lacking L-isoaspartate (D-aspartate) O
      methyltransferase.
AB  - Within proteins and peptides, both L-asparaginyl and L-aspartyl residues
      spontaneously degrade, generating isomerized and racemized aspartyl residues. The
      enzyme protein L-isoaspartate (D-aspartate) O-methyltransferase (E.C. 2.1.1.77)
      initiates the conversion of L-isoaspartyl and D-aspartyl residues to normal L
      aspartyl residues. This "repair" reaction helps to maintain proper protein
      conformation by preventing the accumulation of damaged proteins containing
      abnormal amino acid residues. Pcmt1-/- mice manifest two key phenotypes: a fatal
      seizure disorder and retarded growth. In this study, we characterized both
      phenotypes and demonstrated that they are linked. Continuous electroencephalogram
      monitoring of Pcmt1-/- mice revealed that abnormal cortical activity for
      approximately 50% of each 24-h period, even in mice that had no visible evidence
      of convulsions. The fatal seizure disorder in Pcmt1-/- mice can be mitigated but
      not eliminated by antiepileptic drugs. Interestingly, antiepileptic therapy
      normalized the growth of Pcmt1-/- mice, suggesting that the growth retardation is
      due to seizures rather than a global disturbance in growth at the cellular level.
      Consistent with this concept, the growth rate of Pcmt1-/- fibroblasts was
      indistinguishable from that of wild-type fibroblasts.

PMID- 10400701
TI  - ZRP-1, a zyxin-related protein, interacts with the second PDZ domain of the
      cytosolic protein tyrosine phosphatase hPTP1E.
AB  - Protein-protein interactions play an important role in the specificity of
      cellular signaling cascades. By using the yeast two-hybrid system, a specific
      interaction was identified between the second PDZ domain of the cytosolic protein
      tyrosine phosphatase hPTP1E and a novel protein, which was termed ZRP-1 to
      indicate its sequence similarity to the Zyxin protein family. The mRNA encoding
      this protein is distributed widely in human tissues and contains an open reading
      frame of 1428 base pairs, predicting a polypeptide of 476 amino acid residues.
      The deduced protein displays a proline-rich amino-terminal region and three
      double zinc finger LIM domains at its carboxyl terminus. The specific interaction
      of this novel protein with the second PDZ domain of hPTP1E was demonstrated both
      in vitro, using bacterially expressed proteins, and in vivo, by co
      immunoprecipitation studies. Deletion analysis indicated that an intact carboxyl
      terminus is required for its interaction with the second PDZ domain of hPTP1E in
      the yeast two-hybrid system and suggested that other sequences, including the LIM
      domains, also participate in the interaction. The genomic organization of the ZRP
      1 coding sequence is identical to that of the lipoma preferred partner gene,
      another Zyxin-related protein, suggesting that the two genes have evolved from a
      recent gene duplication event.

PMID- 10400702
TI  - Ribonuclease activity of rat liver perchloric acid-soluble protein, a potent
      inhibitor of protein synthesis.
AB  - Rat liver perchloric acid-soluble protein (L-PSP) is a potent inhibitor of cell
      free protein synthesis; however, its mechanism of action is not known. Here we
      show that the protein is a unique ribonuclease and that this activity is
      responsible for the inhibition of translation. The addition of perchloric acid
      soluble protein to a rabbit reticulocyte cell-free system at a concentration of
      6.2 microM led to an almost complete inhibition of protein synthesis. The
      kinetics are unlike those of hemin-controlled inhibitor, a protein that acts at
      the initiation step. The inhibition appears to be due to an endoribonucleolytic
      activity of perchloric acid-soluble protein because L-PSP directly affects mRNA
      template activity and induces disaggregation of the reticulocyte polysomes into
      80 S ribosomes, even in the presence of cycloheximide. These effects were
      observed with authentic as well as recombinant L-PSP. Analysis by thin-layer
      chromatography of [alpha-32P]UTP-labeled mRNA incubated with the protein showed
      production of the ribonucleoside 3'-monophosphates Ap, Gp, Up, and Cp, providing
      direct evidence that the protein is an endoribonuclease. When either 5'- or 3'
      32P-labeled 5 S rRNA was the substrate, L-PSP cleaved phosphodiester bonds only
      in the single-stranded regions of the molecule.

PMID- 10400703
TI  - PTEN interactions with focal adhesion kinase and suppression of the extracellular
      matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway.
AB  - The tumor suppressor PTEN is a phosphatase with sequence homology to tensin. PTEN
      dephosphorylates phosphatidylinositol 3,4, 5-trisphosphate (PIP3) and focal
      adhesion kinase (FAK), and it can inhibit cell growth, invasion, migration, and
      focal adhesions. We investigated molecular interactions of PTEN and FAK in
      glioblastoma and breast cancer cells lacking PTEN. The PTEN trapping mutant D92A
      bound wild-type FAK, requiring FAK autophosphorylation site Tyr397. In PTEN
      mutated cancer cells, FAK phosphorylation was retained even in suspension after
      detachment from extracellular matrix, accompanied by enhanced PI 3-K association
      with FAK and sustained PI 3-K activity, PIP3 levels, and Akt phosphorylation;
      expression of exogenous PTEN suppressed all five properties. PTEN-mutated cells
      were resistant to apoptosis in suspension, but most of the cells entered
      apoptosis after expression of exogenous PTEN or wortmannin treatment. Moreover,
      overexpression of FAK in PTEN-transfected cells reversed the decreased FAK
      phosphorylation and PI 3-K activity, and it partially rescued PIP3 levels, Akt
      phosphorylation, and PTEN-induced apoptosis. Our results show that FAK Tyr397 is
      important in PTEN interactions with FAK, that PTEN regulates FAK phosphorylation
      and molecular associations after detachment from matrix, and that PTEN negatively
      regulates the extracellular matrix-dependent PI 3-K/Akt cell survival pathway in
      a process that can include FAK.

PMID- 10400704
TI  - Priming of human neutrophil respiratory burst by granulocyte/macrophage colony
      stimulating factor (GM-CSF) involves partial phosphorylation of p47(phox).
AB  - Neutrophil superoxide production can be potentiated by prior exposure to
      "priming" agents such as granulocyte/macrophage colony stimulating factor (GM
      CSF). Because the mechanism underlying GM-CSF-dependent priming is not
      understood, we investigated the effects of GM-CSF on the phosphorylation of the
      cytosolic NADPH oxidase components p47(phox) and p67(phox). Preincubation of
      neutrophils with GM-CSF alone increased the phosphorylation of p47(phox) but not
      that of p67(phox). Addition of formyl-methionyl-leucyl-phenylalanine (fMLP) to GM
      CSF-pretreated neutrophils resulted in more intense phosphorylation of p47(phox)
      than with GM-CSF alone and fMLP alone. GM-CSF-induced p47(phox) phosphorylation
      was time- and concentration-dependent and ran parallel to the priming effect of
      GM-CSF on superoxide production. Two-dimensional tryptic peptide mapping of
      p47(phox) showed that GM-CSF induced phosphorylation of one major peptide. fMLP
      alone induced phosphorylation of several peptides, an effect enhanced by GM-CSF
      pretreatment. In contrast to fMLP and phorbol 12-myristate 13-acetate, GM-CSF
      induced phosphorylation of p47(phox) was not inhibited by the protein kinase C
      inhibitor GF109203X. The protein-tyrosine kinase inhibitor genistein and the
      phosphatidylinositol 3-kinase inhibitor wortmannin inhibited the phosphorylation
      of p47(phox) induced by GM-CSF and by fMLP but not that induced by phorbol 12
      myristate 13-acetate. GM-CSF alone did not induce p47(phox) or p67(phox)
      translocation to the membrane, but neutrophils treated consecutively with GM-CSF
      and fMLP showed an increase (compared with fMLP alone) in membrane translocation
      of p47(phox) and p67(phox). Taken together, these results show that the priming
      action of GM-CSF on the neutrophil respiratory burst involves partial
      phosphorylation of p47(phox) on specific serines and suggest the involvement of a
      priming pathway regulated by protein-tyrosine kinase and phosphatidylinositol 3
      kinase.

PMID- 10400705
TI  - Interaction of Smad complexes with tripartite DNA-binding sites.
AB  - The Smad family of transcription factors function as effectors of transforming
      growth factor-beta signaling pathways. Smads form heteromultimers capable of
      contacting DNA through the amino-terminal MH1 domain. The MH1 domains of Smad3
      and Smad4 have been shown to bind to the sequence 5'-GTCT-3'. Here we show that
      Smad3 and Smad4 complexes can contact three abutting GTCT sequences and that
      arrays of such sites elevate reporter expression relative to arrays of binding
      sites containing only two GTCTs. Smad3/4 complexes bound synergistically to
      probes containing two of the four possible arrangements of three GTCT sequences
      and showed a correlated ability to synergistically activate transcription through
      these sites. Purified Smad3 and Smad4 were both able to contact three abutting
      GTCT sequences and reporter experiments indicated that either protein could
      mediate contact with all three GTCTs. In contrast, the Smad4 MH1 domain was
      essential for reporter activation in combination with Smad1. Together, these
      results show that Smad complexes are flexible in their ability to interact with
      abutting GTCT triplets. In contrast, Smads have high affinity for only one
      orientation of abutting GTCT pairs. Functional Smad-binding sites within several
      native response elements contain degenerate GTCT triplets, suggesting that
      trimeric Smad-DNA interaction may be relevant in vivo.

PMID- 10400706
TI  - Regulation of phosphorylation level and distribution of PTP36, a putative protein
      tyrosine phosphatase, by cell-substrate adhesion.
AB  - Recently we have cloned a putative protein tyrosine phosphatase, PTP36/PTPD2/pez,
      which possesses a domain homologous to the N-terminal half of band 4.1 protein.
      In mouse fibroblasts adhered to substrates, PTP36 was phosphorylated on serine
      residues. PTP36 was found to make complexes with serine/threonine kinase(s),
      which phosphorylated PTP36 in vitro. PTP36 was dephosphorylated rapidly when the
      cell-substrate adhesion was disrupted and it was phosphorylated again along with
      the reattachment of the cells to fibronectin. Rephosphorylation of PTP36 seemed
      to depend on actin polymerization since it was inhibited by cytochalasin D. The
      cell detachment also induced the translocation of PTP36 into the membrane
      associated cytoskeletal fraction. Staurosporine and ML-9, which inhibited the
      phosphorylation of PTP36 in vivo, induced the translocation of PTP36 too. On the
      contrary, when the dephosphorylation of PTP36 was inhibited by okadaic acid, no
      translocation of PTP36 was induced by the cell detachment. These results
      demonstrate that the cell-substrate adhesion and cell spreading regulates the
      intracellular localization of PTP36 most likely through its phosphorylation and
      therefore, PTP36 may play important roles in the signal transduction pathway of
      cell-adhesion.

PMID- 10400707
TI  - A convenient oxidation of natural glycosphingolipids to their "ceramide acids"
      for neoglycoconjugation. Bovine serum albumin-glycosylceramide acid conjugates as
      investigative probes for HIV gp120 coat protein-glycosphingolipid interactions.
AB  - A new method to cleave the double bond of sphingolipids has been developed. Using
      limited concentrations of KMnO4 and an excess of NaIO4, in a neutral aqueous tert
      butanol solvent system gave nearly quantitative yields of the oxidized product. A
      variety of natural glycosphingolipids (GSLs): GlcC, GalC, SGC, LC, Gb3C, Gb4C,
      Gg4C, Gb5C, and GM1C, gave the corresponding acids: 2-hydroxy-3-(N-acyl)-4-(O
      glycosyl)-oxybutyric acids, i.e. "glycosyl ceramide acids" (GSL.CCOOH) in
      excellent yields (80-90%). Deacyl GSLs (dGSLs) were oxidized to acids containing
      the oligosaccharides devoid of hydrocarbon chains, i.e. "ceramide
      oligosaccharides" (dGSL. NRR1CCOOH, where R = R1 = H; R = H, R1 = CH3CO; or R =
      R1 = Me). The efficacy of this method was demonstrated by transforming natural
      GSLs: GlcC, GalC, GalS, SGC, LC, Gb3C, and Gb4C into neoglycoproteins via
      coupling glycosyl ceramide acids (except GalS, which was coupled directly) to
      bovine serum albumin (BSA). Mass spectroscopic analysis of GalC-BSA conjugates,
      (GalC.CONH)nBSA and (GalS.NHCO)nBSA gave a value of 9 +/- 1 and 16 +/- 2 for n.
      Neoglycoconjugates derived from GlcC, GalC (type I and II and the behenic
      analog), SGC, LC, and Gb3C were recognized by the recombinant human
      immunodeficiency virus coat protein gp120 (rgp120). The GalS conjugate showed
      significantly reduced binding, and the Gb4C conjugate showed no binding. Thus,
      rgp120/GSL-BSA interaction requires a terminal galactose and/or glucose residue.
      Terminal N-acetylgalactosamine containing GSLs are not bound. The ceramide acid
      conjugates provide a more effective scaffold for presentation of glycone for
      rgp120 binding than those derived from dGSLs. The retention of receptor
      specificity of the glycoconjugates was validated by retention of the expected
      binding specificity of VT1 and VT2e for Gb3C and Gb4C conjugates, respectively.
      These studies open a new vista in the generation of glycoconjugates from GSLs and
      further emphasize the role of aglycone in glycolipid recognition.

PMID- 10400708
TI  - Activation of p53 function in carcinoma cells by the alpha6beta4 integrin.
AB  - The interaction of integrins with extracellular matrix is known to promote cell
      survival by inhibiting apoptotic signaling. In contrast, we demonstrate here that
      the alpha6beta4 integrin induces apoptosis in carcinoma cells by stimulating p53
      function. Specifically, we show that expression of alpha6beta4 in carcinoma cells
      that lack this integrin stimulates an increase in the transactivating function of
      p53 as demonstrated by the ability of this integrin to up-regulate the expression
      of a p53-sensitive reporter gene as well as the endogenous p53 response gene,
      bax. In addition, we report that alpha6beta4 triggers apoptosis in carcinoma
      cells that express wild-type but not mutant p53 and that these alpha6beta4
      functions are inhibited by a dominant negative p53 construct. Importantly, we
      provide a link between integrin signaling and p53 activation by demonstrating
      that the clustering of alpha6beta4 with a beta4 integrin-specific antibody
      promotes p53-dependent apoptosis in cells that express both alpha6beta4 and wild
      type p53. These studies are the first to demonstrate that a specific integrin can
      promote apoptosis by activating p53. Moreover, given the ability of alpha6beta4
      to stimulate invasion (Shaw, L. M., Rabinovitz, I., Wang, H. F., Toker, A., and
      Mercurio, A. M. (1997) Cell 91, 949-960), these studies suggest that the ability
      of alpha6beta4 to promote carcinoma progression will be enhanced in tumor cells
      that express mutant, inactive forms of p53.

PMID- 10400709
TI  - Cloning and characterization of the murine ameloblastin promoter.
AB  - The molecular mechanisms directing the highly restricted expression pattern of
      murine ameloblastin were characterized by cloning and functional analysis of the
      ameloblastin promoter. The transcription start site, mapped by primer extension,
      was located 19 base pairs (bp) 5' of the published cDNA. The promoter was
      analyzed in a mouse ameloblast-like cell line (LS8) and was compared with
      promoter activity in primary gingival fibroblasts and pulp fibroblasts.
      Sequential 5'-deletion mutants encompassing DNA sequences from -1616 to -781 bp
      exhibited high promoter activity in LS8 cells, whereas the promoter activity
      decreased to 50% of the full-length construct in the -781- and -477-bp regions.
      The -217-bp promoter region regained promoter activity that approached the
      activity of the full-length promoter construct, suggesting that both positive and
      negative cis-acting regions may be involved in ameloblastin transcriptional
      regulation. Activity of the ameloblastin promoter in gingival and pulp
      fibroblasts was minimal and ranged from 8 to 30% of the activity in ameloblast
      like cells. Several DNA-protein complexes were formed between functionally
      important promoter fragments and nuclear extracts from LS8 cells. The inactivity
      of promoter constructs in pulp and gingival fibroblasts as well as the absence of
      similar DNA-protein complexes from these cells suggest that regulatory regions of
      the murine ameloblastin promoter may function in a cell-specific manner.

PMID- 10400710
TI  - The human papillomavirus type 16 E6 oncoprotein can down-regulate p53 activity by
      targeting the transcriptional coactivator CBP/p300.
AB  - The transforming proteins of the small DNA tumor viruses, simian virus 40 (SV40),
      adenovirus, and human papillomavirus (HPV) target a number of identical cellular
      regulators whose functional abrogation is required for transformation. However,
      while both adenovirus E1A and SV40 large T transforming properties also depend on
      the targeting of the transcriptional coactivator CBP/p300, no such interaction
      has been described for the HPV oncoprotein E6 or E7. Here, we demonstrate that
      the HPV-16 E6 protein, previously shown to facilitate the degradation of p53 in a
      complex with E6-associated protein (E6AP), also targets CBP/p300 in an
      interaction involving the C-terminal zinc finger of E6 and CBP residues 1808 to
      1826. Furthermore, this interaction is limited to E6 proteins of high-risk HPVs
      associated with cervical cancer that have the capacity to repress p53-dependent
      transcription. An HPV-16 E6 mutant (L50G) that binds CBP/p300, but not E6AP, is
      still capable of down-regulating p53 transcriptional activity. Thus, HPV E6
      proteins possess two distinct mechanisms by which to abrogate p53 function: the
      repression of p53 transcriptional activity by targeting the p53 coactivator
      CBP/p300, and the removal of cellular p53 protein through the proteosome
      degradation pathway.

PMID- 10400711
TI  - Maturation of the hepatitis A virus capsid protein VP1 is not dependent on
      processing by the 3Cpro proteinase.
AB  - Most details of the processing of the hepatitis A virus (HAV) polyprotein are
      known. Unique among members of the family Picornaviridae, the primary cleavage of
      the HAV polyprotein is mediated by 3Cpro, the only proteinase known to be encoded
      by the virus, at the 2A/2B junction. All other cleavages of the polyprotein have
      been considered to be due to 3Cpro, although the precise location and mechanism
      responsible for the VP1/2A cleavage have been controversial. Here we present data
      that argue strongly against the involvement of the HAV 3Cpro proteinase in the
      maturation of VP1 from its VP1-2A precursor. Using a heterologous expression
      system based on recombinant vaccinia viruses directing the expression of full
      length or truncated capsid protein precursors, we show that the C terminus of the
      mature VP1 capsid protein is located near residue 764 of the polyprotein.
      However, a proteolytically active HAV 3Cpro that was capable of directing both
      VP0/VP3 and VP3/VP1 cleavages in vaccinia virus-infected cells failed to process
      the VP1-2A precursor. Using site-directed mutagenesis of an infectious molecular
      clone of HAV, we modified potential VP1/2A cleavage sites that fit known 3Cpro
      recognition criteria and found that a substitution that ablates the presumed
      3Cpro dipeptide recognition sequence at Glu764-Ser765 abolished neither
      infectivity nor normal VP1 maturation. Altered electrophoretic mobility of VP1
      from a viable mutant virus with an Arg764 substitution indicated that this
      residue is present in VP1 and that the VP1/2A cleavage occurs downstream of this
      residue. These data indicate that maturation of the HAV VP1 capsid protein is not
      dependent on 3Cpro processing and may thus be uniquely dependent on a cellular
      proteinase.

PMID- 10400712
TI  - Effect of inserting paramyxovirus simian virus 5 gene junctions at the HN/L gene
      junction: analysis of accumulation of mRNAs transcribed from rescued viable
      viruses.
AB  - Simian parainfluenza virus 5 (SV5) is a prototype of the Paramyxoviridae family
      of nonsegmented negative-sense RNA viruses. The single-stranded RNA genomes of
      these viruses contain a series of tandemly linked genes separated by intergenic
      (IG) sequences flanked by gene-end (GE) and gene-start (GS) sequences. The viral
      RNA polymerase (vRNAP) complex is thought to enter the genome at its 3' end, and
      synthesis of mRNAs is thought to occur by a stop-start mechanism in a sequential
      and polar manner, with transcriptional attenuation occurring primarily at the
      intergenic regions. As a result, multiple nonoverlapping mRNA species are
      generated for each single entry of the vRNAP. To investigate the functions of GE,
      IG, and GS sequences in transcription, we constructed plasmids containing cDNAs
      of the full-length SV5 genome in which the gene junction sequences (GE, IG, and
      GS sequences) located between the hemagglutinin-neuraminidase (HN) and the
      polymerase (L) genes were replaced with the counterpart sequences from other gene
      junctions. By using reverse genetics, we recovered viable viruses from each cDNA
      construct, although their growth characteristics varied. Analysis of the HN and L
      mRNAs by quantitative RNase protection assay indicated that the ratios of HN to L
      mRNAs varied over a fourfold range. The alteration of the gene junction sequences
      also permitted examination of the hypothesized requirement for hexamer nucleotide
      position of the GS sites. The recovery of infectious viruses with transcription
      initiation sites that occurred at nucleotide positions 1, 2, 3, 5, and 6 of the
      hexamer suggest that the requirement is nonstringent.

PMID- 10400713
TI  - Characterization of hepatitis C virus E2 glycoprotein interaction with a putative
      cellular receptor, CD81.
AB  - A truncated soluble form of the hepatitis C virus E2 glycoprotein, E2661, binds
      specifically to the surface of cells expressing human CD81 (hCD81) but not other
      members of the tetraspanin family (CD9, CD63, and CD151). No differences were
      noted between the level of E2661 binding to hCD81 expressed on the surface of rat
      RBL or KM3 cells compared to Daudi and Molt-4 cells, suggesting that additional
      human-cell-specific factors are not required for the primary interaction of E2
      with the cell surface. E2 did not interact with African green monkey (AGM) CD81
      on the surface of COS cells, which differs from the hCD81 sequence at four
      residues within the second extracellular region (EC2) (amino acids [aa] 163, 186,
      188, and 196), suggesting that one or more of these residues defines the site of
      interaction with E2. Various recombinant forms of CD81 EC2 show differences in
      the ability to bind E2, suggesting that CD81 conformation is important for E2
      recognition. Regions of E2 involved in the CD81 interaction were analyzed, and
      our data suggest that the binding site is of a conformational nature involving aa
      480 to 493 and 544 to 551 within the E2 glycoprotein. Finally, we demonstrate
      that ligation of CD81 by E2661 induced aggregation of lymphoid cells and
      inhibited B-cell proliferation, demonstrating that E2 interaction with CD81 can
      modulate cell function.

PMID- 10400714
TI  - Species-independent inhibition of abnormal prion protein (PrP) formation by a
      peptide containing a conserved PrP sequence.
AB  - Conversion of the normal protease-sensitive prion protein (PrP) to its abnormal
      protease-resistant isoform (PrP-res) is a major feature of the pathogenesis
      associated with transmissible spongiform encephalopathy (TSE) diseases. In
      previous experiments, PrP conversion was inhibited by a peptide composed of
      hamster PrP residues 109 to 141, suggesting that this region of the PrP molecule
      plays a crucial role in the conversion process. In this study, we used PrP-res
      derived from animals infected with two different mouse scrapie strains and one
      hamster scrapie strain to investigate the species specificity of these conversion
      reactions. Conversion of PrP was found to be completely species specific;
      however, despite having three amino acid differences, peptides corresponding to
      the hamster and mouse PrP sequences from residues 109 to 141 inhibited both the
      mouse and hamster PrP conversion systems equally. Furthermore, a peptide
      corresponding to hamster PrP residues 119 to 136, which was identical in both
      mouse and hamster PrP, was able to inhibit PrP-res formation in both the mouse
      and hamster cell-free systems as well as in scrapie-infected mouse neuroblastoma
      cell cultures. Because the PrP region from 119 to 136 is very conserved in most
      species, this peptide may have inhibitory effects on PrP conversion in a wide
      variety of TSE diseases.

PMID- 10400715
TI  - Pathogenesis of borna disease virus: granulocyte fractions of psychiatric
      patients harbor infectious virus in the absence of antiviral antibodies.
AB  - Borna disease virus (BDV) causes acute and persistent infections in various
      vertebrates. During recent years, BDV-specific serum antibodies, BDV antigen, and
      BDV-specific nucleic acid were found in humans suffering from psychiatric
      disorders. Furthermore, viral antigen was detected in human autopsy brain tissue
      by immunohistochemical staining. Whether BDV infection can be associated with
      psychiatric disorders is still a matter of debate; no direct evidence has ever
      been presented. In the present study we report on (i) the detection of BDV
      specific nucleic acid in human granulocyte cell fraction from three different
      psychiatric patients and (ii) the isolation of infectious BDV from these cells
      obtained from a patient with multiple psychiatric disorders. In leukocyte
      preparations other than granulocytes, either no BDV RNA was detected or positive
      PCR results were obtained only if there was at least 20% contamination with
      granulocytes. Parts of the antigenome of the isolated virus were sequenced,
      demonstrating the close relationship to the prototype BDV strains (He/80 and
      strain V) as well as to other human virus sequences. Our data provide strong
      evidence that cells in the granulocyte fraction represent the major if not the
      sole cell type harboring BDV-specific nucleic acid in human blood and contain
      infectious virus. In contrast to most other reports of putative human isolates,
      where sequences are virtually identical to those of the established laboratory
      strains, this isolate shows divergence in the region previously defined as
      variable in BDV from naturally infected animals.

PMID- 10400716
TI  - Membrane permeabilization by small hydrophobic nonstructural proteins of Japanese
      encephalitis virus.
AB  - Infection with Japanese encephalitis virus (JEV), a mosquito-borne flavivirus,
      may cause acute encephalitis in humans and induce severe cytopathic effects in
      various types of cultured cells. We observed that JEV replication rendered
      infected baby hamster kidney (BHK-21) cells sensitive to the translational
      inhibitor hygromycin B or alpha-sarcine, to which mock-infected cells were
      insensitive. However, little is known about whether any JEV nonstructural (NS)
      proteins contribute to virus-induced changes in membrane permeability. Using an
      inducible Escherichia coli system, we investigated which parts of JEV NS1 to NS4
      are capable of modifying membrane penetrability. We found that overexpression of
      NS2B-NS3, the JEV protease, permeabilized bacterial cells to hygromycin B whereas
      NS1 expression failed to do so. When expressed separately, NS2B alone, but not
      NS3, was sufficient to alter bacterial membrane permeability. Similarly,
      expression of NS4A or NS4B also rendered bacteria susceptible to hygromycin B
      inhibition. Examination of the effect of NS1 to NS4 expression on bacterial
      growth rate showed that NS2B exhibited the greatest inhibitory capability,
      followed by a modest repression from NS2A and NS4A, whereas NS1, NS3, and NS4B
      had only trivial influence with respect to the vector control. Furthermore, when
      cotransfected with a reporter gene luciferase or beta-galactosidase, transient
      expression of NS2A, NS2B, and NS4B markedly reduced the reporter activity in BHK
      21 cells. Together, our results suggest that upon JEV infection, these four small
      hydrophobic NS proteins have various modification effects on host cell membrane
      permeability, thereby contributing in part to virus-induced cytopathic effects in
      infected cells.

PMID- 10400717
TI  - Numerous length polymorphisms at short tandem repeats in human cytomegalovirus.
AB  - We show the presence of numerous short tandem repeats in the human
      cytomegalovirus (HCMV) genome and assess their usefulness as molecular markers.
      The genome is shown to contain at least 24 microsatellite regions that exhibit
      length polymorphisms. Insertion-deletion polymorphisms at these short tandem
      repeats are common (80% of repeats examined are polymorphic among two laboratory
      strains and 10 clinical isolates). This is the first report of widespread
      microsatellite length polymorphism in a viral genome. Some regions are highly
      polymorphic: one was revealed by DNA sequencing to contain length variants at
      five closely linked sites, which combined resulted in 10 variants for this region
      among the 12 strains and isolates examined. This study not only provides a new
      molecular marker system for this virus but also extends our understanding of
      microsatellite polymorphism in two important ways. First, variable-length repeats
      in HCMV can be considerably shorter than polymorphic repeats previously found in
      other organisms. Second, highly variable microsatellite repeats are not confined
      to prokaryotes and eukaryotes, as previously assumed. This variation provides a
      useful marker system for distinguishing viral isolates, and similar markers are
      also likely to be found in other large-genome DNA viruses.

PMID- 10400720
TI  - Second-site reversion of a human immunodeficiency virus type 1 reverse
      transcriptase mutant that restores enzyme function and replication capacity.
AB  - Nonconservative substitutions for Tyr-115 in the reverse transcriptase (RT) of
      human immunodeficiency virus type 1 (HIV-1) lead to enzymes displaying lower
      affinity for deoxynucleoside triphosphates (dNTPs) (A. M. Martin-Hernandez, E.
      Domingo, and L. Menendez-Arias, EMBO J. 15:4434-4442, 1996). Several mutations at
      this position (Y115W, Y115L, Y115A, and Y115D) were introduced in an infectious
      HIV-1 clone, and the replicative capacity of the mutant viruses was monitored.
      Y115W was the only mutant able to replicate in MT-4 cells, albeit very poorly.
      Nucleotide sequence analysis of the progeny virus recovered from supernatants of
      four independent transfection experiments showed that the Y115W mutation was
      maintained. However, in all cases an additional substitution in the primer grip
      of the RT (M230I) emerged when the virus increased its replication capacity.
      Using recombinant HIV-1 RT, we demonstrate that M230I mitigates the polymerase
      activity defect of the Y115W mutant, by increasing the dNTP binding affinity of
      the enzyme. The second-site suppressor effects observed were mediated by
      mutations in the 66-kDa subunit of the RT, as demonstrated with chimeric
      heterodimers. Examination of available crystal structures of HIV-1 RT suggests a
      possible mechanism for restoration of enzyme activity by the second-site
      revertant.

PMID- 10400719
TI  - The gag domains required for avian retroviral RNA encapsidation determined by
      using two independent assays.
AB  - The Rous sarcoma virus (RSV) Gag precursor polyprotein is the only viral protein
      which is necessary for specific packaging of genomic RNA. To map domains within
      Gag which are important for packaging, we constructed a series of Gag mutations
      in conjunction with a protease (PR) active-site point mutation in a full-length
      viral construct. We found that deletion of either the matrix (MA), the capsid
      (CA), or the protease (PR) domain did not abrogate packaging, although the MA
      domain is likely to be required for proper assembly. A previously characterized
      deletion of both Cys-His motifs in RSV nucleocapsid protein (NC) reduced both the
      efficiency of particle release and specific RNA packaging by 6- to 10-fold,
      consistent with previous observations that the NC Cys-His motifs played a role in
      assembly and RNA packaging. Most strikingly, when amino acid changes at Arg 549
      and 551 immediately downstream of the distal NC Cys-His box were made, RNA
      packaging was reduced by more than 25-fold with no defect in particle release,
      demonstrating the importance of this basic amino acid region in packaging. We
      also used the yeast three-hybrid system to study avian retroviral RNA-Gag
      interactions. Using this assay, we found that the interactions of the minimal
      packaging region (Mpsi) with Gag are of high affinity and specificity. Using a
      number of Mpsi and Gag mutants, we have found a clear correlation between a
      reporter gene activation in a yeast three-hybrid binding system and an in vivo
      packaging assay. Our results showed that the binding assay provides a rapid
      genetic assay of both RNA and protein components for specific encapsidation.

PMID- 10400718
TI  - Characterization of V3 sequence heterogeneity in subtype C human immunodeficiency
      virus type 1 isolates from Malawi: underrepresentation of X4 variants.
AB  - We have examined the nature of V3 sequence variability among subtype C human
      immunodeficiency virus type 1 (HIV-1) sequences from plasma-derived viral RNA
      present in infected men from Malawi. Sequence variability was assessed by direct
      sequence analysis of the V3 reverse transcription-PCR products, examination of
      virus populations by a subtype C V3-specific heteroduplex tracking assay (V3
      HTA), and selected sequence analysis of molecular clones derived from the PCR
      products. Sequence variability in V3 among the subtype C viruses was not
      associated with the presence of basic amino acid substitutions. This observation
      is in contrast to that for subtype B HIV-1, where sequence variability is
      associated with such substitutions, and these substitutions are determinants of
      altered coreceptor usage. Evolutionary variants in subtype C V3 sequences, as
      defined by the V3-HTA, were not correlated with the CD4 level in the infected
      person, while such a correlation was found with subtype B V3 sequences. Viruses
      were isolated from a subset of the subjects; all isolates used CCR5 and not CXCR4
      as a coreceptor, and none was able to grow in MT-2 cells, a hallmark of the
      syncytium-inducing phenotype that is correlated with CXCR4 usage. The overall
      sequence variability of the subtype C V3 region was no greater than that of the
      conserved regions of gp120. This limited sequence variability was also a feature
      of subtype B V3 sequences that do not carry the basic amino acid substitutions
      associated with altered coreceptor usage. Our results indicate that altered
      coreceptor usage is rare in subtype C HIV-1 isolates in sub-Saharan Africa and
      that sequence variability is not a feature of the V3 region of env in the absence
      of altered coreceptor usage.

PMID- 10400721
TI  - The furin protease cleavage recognition sequence of Sindbis virus PE2 can mediate
      virion attachment to cell surface heparan sulfate.
AB  - Cell culture-adapted Sindbis virus strains attach to heparan sulfate (HS)
      receptors during infection of cultured cells (W. B. Klimstra, K. D. Ryman, and R.
      E. Johnston, J. Virol. 72:7357-7366, 1998). At least three E2 glycoprotein
      mutations (E2 Arg 1, E2 Lys 70, and E2 Arg 114) can independently confer HS
      attachment in the background of the consensus sequence Sindbis virus (TR339). In
      the studies reported here, we have investigated the mechanism by which the E2 Arg
      1 mutation confers HS-dependent binding. Substitution of Arg for Ser at E2 1
      resulted in a significant reduction in the efficiency of PE2 cleavage, yielding
      virus particles containing a mixture of PE2 and mature E2. Presence of PE2 was
      associated with an increase in HS-dependent attachment to cells and efficient
      attachment to heparin-agarose beads, presumably because the furin recognition
      site for PE2 cleavage also represents a candidate HS binding sequence. A
      comparison of mutants with partially or completely inhibited PE2 cleavage
      demonstrated that efficiency of cell binding was correlated with the amount of
      PE2 in virus particles. Viruses rendered cleavage defective due to deletions of
      portions or all of the furin cleavage sequence attached very poorly to cells,
      indicating that an intact furin cleavage sequence was specifically required for
      PE2-mediated attachment to cells. In contrast, a virus containing a partial
      deletion was capable of efficient binding to heparin-agarose beads, suggesting
      different requirements for heparin bead and cell surface HS binding. Furthermore,
      virus produced in C6/36 mosquito cells, which cleave PE2 more efficiently than
      BHK cells, exhibited a reduction in cell attachment efficiency correlated with
      reduced content of PE2 in particles. Taken together, these results strongly argue
      that the XBXBBX (B, basic; X, hydrophobic) furin protease recognition sequence of
      PE2 can mediate the binding of PE2-containing Sindbis viruses to HS. This
      sequence is very similar to an XBBXBX heparin-HS interaction consensus sequence.
      The attachment of furin protease cleavage sequences to HS may have relevance to
      other viruses whose attachment proteins are cleaved during maturation at
      positively charged recognition sequences.

PMID- 10400722
TI  - Changes in Rous sarcoma virus RNA secondary structure near the primer binding
      site upon tRNATrp primer annealing.
AB  - Predicted secondary-structure elements encompassing the primer binding site in
      the 5' untranslated region of Rous sarcoma virus (RSV) RNA play an integral role
      in multiple viral replications steps including reverse transcription, DNA
      integration, and RNA packaging (A. Aiyar, D. Cobrinik, Z. Ge, H. J. Kung, and J.
      Leis, J. Virol. 66:2464-2472, 1992; D. Cobrinik, A. Aiyar, Z. Ge, M. Katzman, H.
      Huang, and J. Leis, J. Virol. 65:3864-3872, 1991; J. T. Miller, Z. Ge, S. Morris,
      K. Das, and J. Leis, J. Virol. 71:7648-7656, 1997). These elements include the U5
      Leader stem, U5-IR stem-loop, and U5-TPsiC interaction region. Limited digestion
      of the 5' untranslated region of wild-type and mutant RSV RNAs with structure-
      and/or sequence-specific RNases detects the presence of the U5-Leader stem and
      the U5-IR stem-loop. When a tRNATrp primer is annealed to wild-type RNAs in
      vitro, limited nuclease mapping indicates that the U5-IR stem becomes partially
      unwound. This is not observed when mutant RNAs with altered U5-IR stem-loop
      structures are substituted for wild-type RNAs. The U5-Leader stem also becomes
      destabilized when the tRNA primer is annealed to either wild-type or mutant RNA
      fragments. Nuclease mapping studies of tRNATrp, as well as the viral RNA,
      indicate that the U5-TPsiC helix does form in vitro upon primer annealing.
      Collectively, these data suggest that the various structural elements near the
      RSV primer binding site undergo significant changes during the process of primer
      annealing.

PMID- 10400723
TI  - Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety
      evaluation of intracerebral injection in nonhuman primates.
AB  - This study examined the safety of intracerebral inoculation of G207, an
      attenuated, replication-competent herpes simplex virus type 1 (HSV-1)
      recombinant, in nonhuman primates. Sixteen New World owl monkeys (Aotus nancymae
      [karyotype 1, formerly believed to be A. trivirgatus]), known for their exquisite
      susceptibility to HSV-1 infection, were evaluated. Thirteen underwent
      intracerebral inoculation with G207 at doses of 10(7) or 10(9) PFU, two were
      vehicle inoculated, and one served as an infected wild-type control and received
      10(3) PFU of HSV-1 strain F. HSV-1 strain F caused rapid mortality and symptoms
      consistent with HSV encephalitis, including fever, hemiparesis, meningitis, and
      hemorrhage in the basal ganglia. One year after G207 inoculation, seven of the
      animals were alive and exhibited no evidence of clinical complications. Three
      deaths resulted from nonneurologic causes unrelated to HSV infection, and three
      animals were sacrificed for histopathologic examination. Two animals were
      reinoculated with G207 (10(7) PFU) at the same stereotactic coordinates 1 year
      after the initial G207 inoculation. These animals were alive and healthy 2 years
      after the second inoculation. Cerebral magnetic resonance imaging studies
      performed both before and after G207 inoculation failed to reveal radiographic
      evidence of HSV-related sequelae. Despite the lack of outwardly observable HSV
      pathology, measurable increases in serum anti-HSV titers were detected.
      Histopathological examination of multiple organ tissues found no evidence of HSV
      induced histopathology or dissemination. We conclude that intracerebral
      inoculation of up to 10(9) PFU of G207, well above the efficacious dose in mouse
      tumor studies, is safe and therefore appropriate for human clinical trials.

PMID- 10400724
TI  - Depletion of blood-borne macrophages does not reduce demyelination in mice
      infected with a neurotropic coronavirus.
AB  - Mice infected with the neurotropic coronavirus mouse hepatitis virus strain JHM
      (MHV-JHM) develop a chronic demyelinating disease with symptoms of hindlimb
      paralysis. Histological examination of the brains and spinal cords of these
      animals reveals the presence of large numbers of activated macrophages/microglia.
      In two other experimental models of demyelination, experimental allergic
      encephalomyelitis and Theiler's murine encephalomyelitis virus-induced
      demyelination, depletion of hematogenous macrophages abrogates the demyelinating
      process. In both of these diseases, early events in the demyelinating process are
      inhibited by macrophage depletion. From these studies, it was not possible to
      determine whether infiltrating macrophages were required for late steps in the
      process, such as myelin removal. In this study, we show that when macrophages are
      depleted with either unmodified or mannosylated liposomes encapsulating
      dichloromethylene diphosphate, the amount of demyelination detected in MHV
      infected mice is not affected. At a time when these cells were completely
      depleted from the liver, approximately equivalent numbers of macrophages were
      present in the spinal cords of control and drug-treated animals. These results
      suggest that blood-borne macrophages are not required for MHV-induced
      demyelination and also suggest that other cells, such as perivascular macrophages
      or microglia, perform the function of these cells in the presence of drug.

PMID- 10400725
TI  - Identification of a novel structural protein of arteriviruses.
AB  - Arteriviruses are positive-stranded RNA viruses with an efficiently organized,
      polycistronic genome. A short region between the replicase gene and open reading
      frame (ORF) 2 of the equine arteritis virus (EAV) genome was previously assumed
      to be untranslated. However, here we report that this segment of the EAV genome
      contains the 5' part of a novel gene (ORF 2a) which is conserved in all
      arteriviruses. The 3' part of EAV ORF 2a overlaps with the 5' part of the former
      ORF 2 (now renamed ORF 2b), which encodes the GS glycoprotein. Both ORF 2a and
      ORF 2b appear to be expressed from mRNA 2, which thereby constitutes the first
      proven example of a bicistronic mRNA in arteriviruses. The 67-amino-acid protein
      encoded by EAV ORF 2a, which we have provisionally named the envelope (E)
      protein, is very hydrophobic and has a basic C terminus. An E protein-specific
      antiserum was raised and used to demonstrate the expression of the novel gene in
      EAV-infected cells. The EAV E protein proved to be very stable, did not form
      disulfide-linked oligomers, and was not N-glycosylated. Immunofluorescence and
      immunoelectron microscopy studies showed that the E protein associates with
      intracellular membranes both in EAV-infected cells and upon independent
      expression. An analysis of purified EAV particles revealed that the E protein is
      a structural protein. By using reverse genetics, we demonstrated that both the
      EAV E and GS proteins are essential for the production of infectious progeny
      virus.

PMID- 10400727
TI  - Subcellular localization and rolling circle replication of peach latent mosaic
      viroid: hallmarks of group A viroids.
AB  - We characterized the peach latent mosaic viroid (PLMVd) replication intermediates
      that accumulate in infected peach leaves and determined the tissue and
      subcellular localization of the RNA species. Using in situ hybridization, we
      showed that PLMVd strands of both plus and minus polarities concentrate in the
      cells forming the palisade parenchyma. At the cellular level, PLMVd was found to
      accumulate predominantly in chloroplasts. Northern blot analyses demonstrated
      that PLMVd replicates via a symmetric mode involving the accumulation of both
      circular and linear monomeric strands of both polarities. No multimeric conformer
      was detected, indicating that both strands self-cleave efficiently via their
      hammerhead sequences. Dot blot hybridizations revealed that PLMVd strands of both
      polarities accumulate equally but that the relative concentrations vary by more
      than 50-fold between peach cultivars. Taken together these results establish two
      hallmarks for the classification of viroids. Group A viroids (e.g., PLMVd), which
      possess hammerhead structures, replicate in the chloroplasts via the symmetric
      mode. By contrast, group B viroids, which share a conserved central region,
      replicate in the nucleus via an asymmetric mechanism. This is an important
      difference between self-cleaving and non-self-cleaving viroids, and the
      implications for the evolutionary origin and replication are discussed.

PMID- 10400726
TI  - Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently
      inhibit feline immunodeficiency virus replication.
AB  - Bicyclams are low-molecular-weight anti-human immunodeficiency virus (HIV) agents
      that have been shown to act as potent and selective CXC chemokine receptor 4
      (CXCR4) antagonists. Here, we demonstrate that bicyclams are potent inhibitors of
      feline immunodeficiency virus (FIV) replication when evaluated in Crandell feline
      kidney (CRFK) cells. With a series of bicyclam derivatives, 50% inhibitory
      concentrations (IC50s) against FIV were obtained in this cell system that were
      comparable to those obtained for HIV-1 IIIB replication in the human CD4(+) MT-4
      T-cell line. The bicyclams were also able to block FIV replication in feline
      thymocytes, albeit at higher concentrations than in the CRFK cells. The prototype
      bicyclam AMD3100, 1-1'-[1,4-phenylene-bis(methylene)]-bis(1,4,8, 11
      tetraazacyclotetradecane), was only fourfold less active in feline thymocytes
      (IC50, 62 ng/ml) than in CRFK cells (IC50, 14 ng/ml). AMD2763, 1,1'-propylene
      bis(1,4,8, 11-tetraazacyclotetradecane), which is a less potent CXCR4 antagonist,
      was virtually inactive against FIV in feline thymocytes (IC50, >66.5
      microgram/ml), while it was clearly active in CRFK cells (IC50, 0.9
      microgram/ml). The CXC chemokine stromal-cell-derived factor 1alpha had anti-FIV
      activity in CRFK cells (IC50, 200 ng/ml) but not in feline thymocytes (IC50, >2.5
      microgram/ml). When primary FIV isolates were evaluated for their drug
      susceptibility in feline thymocytes, the bicyclams AMD3100 and its Zn2+ complex,
      AMD3479, inhibited all six primary isolates at equal potency. The marked
      susceptibility of FIV to the bicyclams suggests that FIV predominantly uses
      feline CXCR4 for entering its target cells.

PMID- 10400728
TI  - Reconstitution of human thymic implants is limited by human immunodeficiency
      virus breakthrough during antiretroviral therapy.
AB  - Human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu thymic implants
      depleted of CD4(+) cells can support renewed thymopoiesis derived from both
      endogenous and exogenous T-cell progenitors after combination antiretroviral
      therapy. However, successful production of new thymocytes occurs transiently.
      Possible explanations for the temporary nature of this thymic reconstitution
      include cessation of the thymic stromal support function, exhaustion of T-cell
      progenitors, and viral resurgence. Distinguishing between these processes is
      important for the development of therapeutic strategies aimed at reconstituting
      the CD4(+) T-cell compartment in HIV-1 infection. Using an HIV-1 strain
      engineered to express the murine HSA heat-stable antigen surface marker, we
      explored the relationship between HIV-1 expression and CD4(+) cell resurgence
      kinetics in HIV-1-depleted SCID-hu implants following drug therapy. Antiviral
      therapy significantly suppressed HIV-1 expression in double-positive (DP) CD4/CD8
      thymocytes, and the eventual secondary decline of DP thymocytes following therapy
      was associated with renewed viral expression in this cell subset. Thymocytes
      derived from exogenous T-cell progenitors induced to differentiate in HIV-1
      depleted, drug-treated thymic implants also became infected. These results
      indicate that in this model, suppression of viral replication occurs transiently
      and that, in spite of drug therapy, virus resurgence contributes to the transient
      nature of the renewed thymic function.

PMID- 10400729
TI  - The CC-chemokine RANTES increases the attachment of human immunodeficiency virus
      type 1 to target cells via glycosaminoglycans and also activates a signal
      transduction pathway that enhances viral infectivity.
AB  - We have studied the mechanisms by which the CC-chemokine RANTES can enhance the
      infectivities of human immunodeficiency virus type 1 (HIV-1) and other enveloped
      viruses, when present at concentrations in excess of 500 ng/ml in vitro.
      Understanding the underlying mechanisms might throw light on fundamental
      processes of viral infection, in particular for HIV-1. Our principal findings are
      twofold: firstly, that oligomers of RANTES can cross-link enveloped viruses,
      including HIV-1, to cells via glycosaminoglycans (GAGs) present on the membranes
      of both virions and cells; secondly, that oligomers of RANTES interact with cell
      surface GAGs to transduce a herbimycin A-sensitive signal which, over a period of
      several hours, renders the cells more permissive to infection by several viruses,
      including HIV-1. The enhancement mechanisms require that RANTES oligomerize
      either in solution or following binding to GAGs, since no viral infectivity
      enhancement is observed with a mutant form of the RANTES molecule that contains a
      single-amino-acid change (glutamic acid to serine at position 66) which abrogates
      oligomerization.

PMID- 10400730
TI  - Neutrophils aid in protection of the vaginal mucosae of immune mice against
      challenge with herpes simplex virus type 2.
AB  - Large numbers of polymorphonuclear leukocytes (PMNs) infiltrated the murine
      vaginal mucosa within 24 h after intravaginal inoculation with an attenuated
      strain of herpes simplex virus type 2 (HSV-2). The role of these cells in
      resolution of a primary genital infection and in protection of HSV-immune animals
      against challenge with a fully virulent HSV-2 strain was investigated. Depletion
      of greater than 95% of the PMNs at the vaginal mucosal surface prior to
      intravaginal inoculation with an attenuated HSV-2 strain resulted in
      significantly higher virus titers on days 3 to 7 but only slightly delayed
      resolution of the primary genital infection. These results suggest that
      neutrophils helped control the infection but that other immune mechanisms
      ultimately cleared the virus. Interestingly, depletion of PMNs from HSV-immune
      mice prior to challenge with a fully virulent HSV-2 strain resulted in a rise in
      virus titers to levels comparable to those of nonimmune mice and a more
      pronounced diminution of virus clearance from the vaginal mucosa despite the
      presence of HSV-specific B and T cells. Levels of gamma interferon (IFN-gamma)
      and HSV-specific antibody were comparable in neutrophil-depleted and control
      treated immune mice following HSV-2 challenge, suggesting that RB6-8C5 treatment
      did not impair T- and B-cell function. Therefore, these results suggest that
      neutrophils play a role in limiting and clearing HSV-2 vaginal infections and
      that they are, in association with HSV-specific B and T cells, an important
      component in immune protection of the vaginal mucosa.

PMID- 10400731
TI  - Proteolytic activity, the carboxy terminus of Gag, and the primer binding site
      are not required for Pol incorporation into foamy virus particles.
AB  - Human foamy virus (HFV) is the prototype member of the spumaviruses. While
      similar in genomic organization to other complex retroviruses, foamy viruses
      share several features with their more distant relatives, the hepadnaviruses such
      as human hepatitis B virus (HBV). Both HFV and HBV express their Pol proteins
      independently from the structural proteins. However unlike HBV, Pol is not
      required for assembly of HFV core particles or for packaging of viral RNA. These
      results suggest that the assembly of Pol into HFV particles must occur by a
      mechanism different from those used by retroviruses and hepadnaviruses. We have
      examined possible mechanisms for HFV Pol incorporation, including the role of
      proteolysis in assembly of Pol and the role of initiation of reverse
      transcription. We have found that proteolytic activity is not required for Pol
      incorporation. p4 Gag and the residues immediately upstream of the cleavage site
      in Gag are also not important. Deletion of the primer binding site had no effect
      on assembly, ruling out early steps of reverse transcription in the process of
      Pol incorporation.

PMID- 10400733
TI  - Construction and transposon mutagenesis in Escherichia coli of a full-length
      infectious clone of pseudorabies virus, an alphaherpesvirus.
AB  - A full-length clone of the 142-kb pseudorabies virus (PRV) genome was constructed
      as a stable F plasmid in Escherichia coli. The clone, pBecker1, was colinear with
      PRV-Becker genomic DNA, lacking detectable rearrangements, deletions, or
      inversions. The transfection of pBecker1 into susceptible eukaryotic cells
      resulted in productive viral infection. Virus isolated following transfection was
      indistinguishable from wild-type virus in a rodent model of infection and spread
      to retinorecipient regions of the brain following inoculation in the vitreous
      body of the eye. Mutagenesis of pBecker1 in E. coli with a mini-Tn5-derived
      transposon enabled the rapid isolation of insertion mutants, identification of
      essential viral genes, and simplified construction of viral revertants. The
      serial passage of a viral insertion mutant demonstrated the transposon insertion
      to be stable. However, the F-plasmid insertion present in the viral gG locus was
      found to undergo a spontaneous deletion following transfection into eukaryotic
      cells. The implications of F-plasmid insertion into the viral genome with regard
      to phenotype and genomic stability are discussed.

PMID- 10400734
TI  - Initiation of genomic plus-strand RNA synthesis from DNA and RNA templates by a
      viral RNA-dependent RNA polymerase.
AB  - In contrast to the synthesis of minus-strand genomic and plus-strand subgenomic
      RNAs, the requirements for brome mosaic virus (BMV) genomic plus-strand RNA
      synthesis in vitro have not been previously reported. Therefore, little is known
      about the biochemical requirements for directing genomic plus-strand synthesis.
      Using DNA templates to characterize the requirements for RNA-dependent RNA
      polymerase template recognition, we found that initiation from the 3' end of a
      template requires one nucleotide 3' of the initiation nucleotide. The addition of
      a nontemplated nucleotide at the 3' end of minus-strand BMV RNAs led to
      initiation of genomic plus-strand RNA in vitro. Genomic plus-strand initiation
      was specific since cucumber mosaic virus minus-strand RNA templates were unable
      to direct efficient synthesis under the same conditions. In addition, mutational
      analysis of the minus-strand template revealed that the -1 nontemplated
      nucleotide, along with the +1 cytidylate and +2 adenylate, is important for RNA
      dependent RNA polymerase interaction. Furthermore, genomic plus-strand RNA
      synthesis is affected by sequences 5' of the initiation site.

PMID- 10400732
TI  - Myxoma virus Serp2 is a weak inhibitor of granzyme B and interleukin-1beta
      converting enzyme in vitro and unlike CrmA cannot block apoptosis in cowpox virus
      infected cells.
AB  - The Serp2 protein encoded by the leporipoxvirus myxoma virus is essential for
      full virulence (F. Messud-Petit, J. Gelfi, M. Delverdier, M. F. Amardeilh, R. Py,
      G. Sutter, and S. Bertagnoli, J. Virol. 72:7830-7839, 1998) and, like crmA of
      cowpox virus (CPV), is reported to inhibit the interleukin-1beta-converting
      enzyme (ICE, caspase-1) (F. Petit, S. Bertagnoli, J. Gelfi, F. Fassy, C. Boucraut
      Baralon, and A. Milon, J. Virol. 70:5860-5866, 1996). Serp2 and CrmA both contain
      Asp at the P1 position within the serpin reactive site loop and yet are only 35%
      identical overall. Serp2 protein was cleaved by ICE but, unlike CrmA, did not
      form a stable complex with ICE that was detectable by native gel electrophoresis.
      Attempts to covalently cross-link ICE-serpin inhibitory complexes were successful
      with CrmA, but no complex between ICE and Serp2 was visible after cross-linking.
      Purified His10-tagged Serp2 protein was a relatively poor inhibitor of ICE, with
      a Ki of 80 nM compared to 4 pM for CrmA. Serp2 protein resembled CrmA in that a
      stable complex with the serine proteinase granzyme B was detectable after sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis. However, Serp2 was less
      effective at inhibiting granzyme B activity (Ki = 420 nM) than CrmA (Ki = 100
      nM). Finally, Serp2 was tested for the ability to replace CrmA and inhibit
      apoptosis in LLC-PK1 cells infected with a CPV recombinant deleted for CrmA but
      expressing Serp2. Unlike wild-type-CPV-infected cells, apoptosis was readily
      observed in cells infected with the recombinant virus, as indicated by the
      induction of both nuclear fragmentation and caspase-mediated cleavage of DEVD-AMC
      [acetyl-Asp-Glu-Val-Asp-(amino-4-methyl coumarin)]. These results indicate that
      Serp2 is unable to functionally substitute for CrmA within the context of CPV and
      that the inhibition spectra for Serp2 and CrmA are distinct.

PMID- 10400735
TI  - Use of DNA, RNA, and chimeric templates by a viral RNA-dependent RNA polymerase:
      evolutionary implications for the transition from the RNA to the DNA world.
AB  - All polynucleotide polymerases have a similar structure and mechanism of
      catalysis, consistent with their evolution from one progenitor polymerase. Viral
      RNA-dependent RNA polymerases (RdRp) are expected to have properties comparable
      to those from this progenitor and therefore may offer insight into the
      commonalities of all classes of polymerases. We examined RNA synthesis by the
      brome mosaic virus RdRp on DNA, RNA, and hybrid templates and found that precise
      initiation of RNA synthesis can take place from all of these templates.
      Furthermore, initiation can take place from either internal or penultimate
      initiation sites. Using a template competition assay, we found that the BMV RdRp
      interacts with DNA only three- to fourfold less well than it interacts with RNA.
      Moreover, a DNA molecule with a ribonucleotide at position -11 relative to the
      initiation nucleotide was able to interact with RdRp at levels comparable to that
      observed with RNA. These results suggest that relatively few conditions were
      needed for an ancestral RdRp to replicate DNA genomes.

PMID- 10400736
TI  - Both memory and CD45RA+/CD62L+ naive CD4(+) T cells are infected in human
      immunodeficiency virus type 1-infected individuals.
AB  - Cellular activation is critical for the propagation of human immunodeficiency
      virus type 1 (HIV-1) infection. It has been suggested that truly naive CD4(+) T
      cells are resistant to productive HIV-1 infection because of their constitutive
      resting state. Memory and naive CD4(+) T-cell subsets from 11 HIV-1-infected
      individuals were isolated ex vivo by a combination of magnetic bead depletion and
      fluorescence-activated cell sorting techniques with stringent criteria of
      combined expression of CD45RA and CD62L to identify naive CD4(+) T-cell subsets.
      In all patients HIV-1 provirus could be detected within naive CD45RA+/CD62L+
      CD4(+) T cells; in addition, replication-competent HIV-1 was isolated from these
      cells upon CD4(+) T-cell stimulation in tissue cultures. Memory CD4(+) T cells
      had a median of fourfold more replication-competent virus and a median of sixfold
      more provirus than naive CD4(+) T cells. Overall, there was a median of 16-fold
      more integrated provirus identified in memory CD4(+) T cells than in naive CD4(+)
      T cells within a given patient. Interestingly, there was a trend toward
      equalization of viral loads in memory and naive CD4(+) T-cell subsets in those
      patients who harbored CXCR4-using (syncytium-inducing) viruses. Within any given
      patient, there was no selective usage of a particular coreceptor by virus
      isolated from memory versus naive CD4(+) T cells. Our findings suggest that naive
      CD4(+) T cells may be a significant viral reservoir for HIV, particularly in
      those patients harboring CXCR4-using viruses.

PMID- 10400737
TI  - Establishment of a seronegative human T-cell leukemia virus type 1 (HTLV-1)
      carrier state in rats inoculated with a syngeneic HTLV-1-immortalized T-cell line
      preferentially expressing Tax.
AB  - Human T-cell leukemia virus type 1 (HTLV-1) causes T-cell malignancies in a small
      percentage of the population infected with the virus after a long carrier state.
      In the present study, we established a seronegative HTLV-1 carrier state in rats
      inoculated with a newly established HTLV-1-infected rat T cell line, FPM1. FPM1
      originated from rat thymocytes cocultured with a human HTLV-1 producer, MT-2
      cells, and expressed rat CD4, CD5, CD25, and HTLV-1 Tax. However, FPM1 scarcely
      expressed other major HTLV-1 structural proteins and failed to induce typical
      antibody responses against HTLV-1 in inoculated rats. In contrast, control rats
      inoculated with MT-2 cells generated significant levels of anti-HTLV-1
      antibodies. HTLV-1 proviruses were detected in peripheral blood cells of
      syngeneic rats inoculated with FPM1 for more than 1 year. Analysis of the
      flanking region of HTLV-1 provirus integrated into host cells suggested that FPM1
      cells remained in these animals over a relatively long period of time. However, a
      similar seronegative HTLV-1 carrier state was induced in the rats inoculated with
      mitomycin C-treated FPM1 cells and also in FPM1-inoculated allogeneic rats,
      suggesting that FPM1 could also transmit HTLV-1 into host cells in vivo. Our
      findings indicated that (i) HTLV-1-immortalized T cells which preferentially
      express HTLV-1 Tax persisted in vivo but failed to induce any diseases in
      immunocompetent syngeneic rats and that (ii) suboptimal levels of HTLV-1 for
      antibody responses allowed the establishment of persistent HTLV-1 infection.

PMID- 10400738
TI  - Selective irreversible inactivation of replicating mengovirus by nucleoside
      analogues: a new form of viral interference.
AB  - We describe the selective irreversible inhibition of mengovirus growth in
      cultured cells by a combination of two pyrrolopyrimidine nucleoside analogues, 5
      bromotubercidin (BrTu) and tubercidin (Tu). At a concentration of 5 microgram/ml,
      BrTu reversibly blocked the synthesis of cellular mRNA and rRNA but did not
      inhibit either mengovirus RNA synthesis or multiplication. BrTu is a potent
      inhibitor of adenosine kinase, and low concentrations of BrTu (e.g., 0.5
      microgram/ml), which did not by themselves inhibit cell growth, blocked
      phosphorylation of Tu and thus protected uninfected cells against irreversible
      cytotoxicity resulting from Tu incorporation into nucleic acids. In contrast, in
      mengovirus-infected cells, BrTu did not completely inhibit Tu incorporation into
      mengovirus RNA, allowing the formation of Tu-containing functionally defective
      polynucleotides that aborted the virus development cycle. This increased
      incorporation of Tu coupled to mengovirus infection could be attributed either to
      a reduction in the inhibitory action of BrTu and/or its nucleotide derivatives at
      the level of nucleoside and nucleotide kinases and/or, perhaps, to an effect upon
      the nucleoside transport system. The virus life cycle in nucleoside-treated cells
      progressed to the point of synthesis of negative strands and probably to the
      production of a few defective new positive strands. Irreversible virus growth
      arrest was achieved if the nucleoside mixture of BrTu (0.5 to 10 microgram/ml)
      and Tu (1 to 20 microgram/ml) was added no later than 30 min after virus
      infection and maintained for periods of 2 to 8 h. The cultures thus "cured" of
      mengovirus infection could be maintained and transferred for several weeks,
      during which they neither produced detectable virus nor showed a visible
      cytopathic effect; however, the infected and cured cells themselves, while
      metabolically viable, were permanently impaired in RNA synthesis and unable to
      divide. Although completely resistant to superinfecting picornaviruses, they
      retained the ability to support the growth of several other viruses (vaccinia
      virus, reovirus, and vesicular stomatitis virus), showing that cured cells had,
      in general, retained the metabolic and structural machinery needed for virus
      production. The resistance of cured cells to superinfection with picornaviruses
      seemed attributable neither to interferon action nor to destruction or blockade
      of virus receptors but more likely to the consumption of some host factor(s)
      involved in the expression of early viral functions during the original
      infection.

PMID- 10400739
TI  - Human immunodeficiency virus type 1 strains R5 and X4 induce different pathogenic
      effects in hu-PBL-SCID mice, depending on the state of activation/differentiation
      of human target cells at the time of primary infection.
AB  - In a previous study, we had found that the extent of T-cell dysfunctions induced
      by a T-tropic strain of human immunodeficiency virus type 1 (HIV-1) in SCID mice
      reconstituted with human peripheral blood lymphocytes (hu-PBLs) (hu-PBL-SCID
      mice) was related to the in vivo state of activation of the human lymphocytes. In
      this article, we compared the effect of infection of hu-PBL-SCID mice with either
      T-tropic (X4) or M-tropic (R5) strains of HIV-1 by performing virus inoculation
      at either 2 h or 2 weeks after the hu-PBL transfer, when the human T cells
      exhibited a marked activation state or a predominant memory phenotype,
      respectively. A comparable level of infection was found when hu-PBL-SCID mice
      were challenged with either the SF162 R5 or the IIIB X4 strain of HIV at 2 h
      postreconstitution, while at 2 weeks, the R5 virus infection resulted in a higher
      level of HIV replication than the X4 virus. The R5 strain induced a marked human
      CD4(+) T-cell depletion along with a drop in levels of human immunoglobulin M in
      serum and release of soluble factors at both infection times, while the X4 virus
      induced severe immune dysfunctions only at 2 h. Of interest, injection of hu-PBLs
      into SCID mice resulted in a marked up-regulation of CCR5 on human CD4(+) T
      cells. The percentage of CXCR4(+) cells did not change after transplantation,
      even though a significant decrease in antigen expression was observed.
      Comparative experiments with two molecular clones of HIV-1 (X4 SF2 and R5 SF162)
      and two envelope recombinant viruses generated from these viruses showed that R5
      viruses (SF162 and the chimeric env-SF162-SF2) caused an extensive depletion of
      human CD4(+) T cells in SCID mice at both 2 h and 2 weeks after reconstitution,
      while the X4 viruses (SF2 and the chimeric env-SF2-SF162) induced CD4 T-cell
      depletion only when infection was performed at the 2-h reconstitution time. These
      results emphasize the importance of the state of activation/differentiation of
      human CD4(+) T cells and gp120-coreceptor interactions at the time of primary
      infection in determining HIV-1 pathogenicity in the hu-PBL-SCID mouse model.

PMID- 10400740
TI  - A lysine-to-arginine change found in natural alleles of the human T-cell
      lymphotropic/leukemia virus type 1 p12(I) protein greatly influences its
      stability.
AB  - The HTLV-1 singly spliced open reading frame I protein, p12(I), is highly
      unstable and appears to be necessary for persistent infection in rabbits. Here we
      demonstrate that p12(I) forms dimers through two putative leucine zipper domains
      and that its stability is augmented by specific proteasome inhibitors. p12(I) is
      ubiquitylated, and mutations of its unique carboxy-terminus lysine residue to an
      arginine greatly enhance its stability. Interestingly, analysis of 53 independent
      HTLV-1 strains revealed that the natural p12(I) alleles found in ex vivo samples
      of tropical spastic paraparesis-HTLV-1-associated myelopathy patients contain a
      Lys at position 88 in some cases, whereas arginine is consistently found at
      position 88 in HTLV-1 strains from all adult T-cell leukemia-lymphoma (ATLL)
      cases and healthy carriers studied. This apparent segregation of different
      alleles in tropical spastic paraparesis-HTLV-associated myelopathy and ATLL or
      healthy carriers may be relevant in vivo, since p12(I) binds the interleukin-2
      receptor beta and gammac chains, raising the possibility that the two natural
      alleles might affect differently the regulation of these molecules.

PMID- 10400741
TI  - Lymphocyte deficiencies increase susceptibility to friend virus-induced
      erythroleukemia in Fv-2 genetically resistant mice.
AB  - The study of genetic resistance to retroviral diseases provides insights into the
      mechanisms by which organisms overcome potentially lethal infections. Fv-2
      resistance to Friend virus-induced erythroleukemia acts through nonimmunological
      mechanisms to prevent early virus spread, but it does not completely block
      infection. The current experiments were done to determine whether Fv-2 alone
      could provide resistance or whether immunological mechanisms were also required
      to bring infection under control. Fv-2-resistant mice that were CD4(+) T-cell
      deficient were able to restrict early virus replication and spread as well as
      normal Fv-2-resistant mice, but they could not maintain control and developed
      severe Friend virus-induced splenomegaly and erythroleukemia by 6 to 8 weeks
      postinfection. Mice deficient in CD8(+) T cells and, to a lesser extent, B cells
      were also susceptible to late Friend virus-induced disease. Thus, Fv-2 resistance
      does not independently prevent FV-induced erythroleukemia but works in concert
      with the immune system by limiting early infection long enough to allow virus
      specific immunity time to develop and facilitate recovery.

PMID- 10400742
TI  - Dissection of individual functions of the Sendai virus phosphoprotein in
      transcription.
AB  - The Sendai virus P protein is an essential component of the viral RNA polymerase
      (P-L complex) required for RNA synthesis. To identify amino acids important for P
      L binding, site-directed mutagenesis of the P gene changed 17 charged amino
      acids, singly or in groups, and two serines to alanine within the L binding
      domain from amino acids 408 to 479. Each of the 10 mutants was wild type for P-L
      and P-P protein interactions and for binding of the P-L complex to the
      nucleocapsid template, yet six showed a significant inhibition of in vitro mRNA
      and leader RNA synthesis. To determine if binding was instead hydrophobic in
      nature, five conserved hydrophobic amino acids in this region were also mutated.
      Each of these P mutants also retained the ability to bind to L, to itself, and to
      the template, but two gave a severe decrease in mRNA and leader RNA synthesis.
      Since all of the mutants still bound L, the data suggest that L binding occurs on
      a surface of P with a complex tertiary structure. Wild-type biological activity
      could be restored for defective polymerase complexes containing two P mutants by
      the addition of wild-type P protein alone, while the activity of two others could
      not be rescued. Gradient sedimentation analyses showed that rescue was not due to
      exchange of the wild-type and mutant P proteins within the P-L complex. Mutants
      which gave a defective RNA synthesis phenotype and could not be rescued by P
      establish an as-yet-unknown role for P within the polymerase complex, while the
      mutants which could be rescued define regions required for a P protein function
      independent of polymerase function.

PMID- 10400743
TI  - Cell surface expression of H2 antigens on primary sensory neurons in response to
      acute but not latent herpes simplex virus infection in vivo.
AB  - CD8(+) T lymphocytes and class I major histocompatibility complex (MHC-I)
      molecules profoundly influence the severity of neuronal herpes simplex virus
      (HSV) infection in experimentally infected mice. Paradoxically, neurons are
      classically regarded as MHC-I deficient. However, it is shown here that H2
      encoded heavy chains (alphaCs) and their associated light chain, beta2
      microglobulin, are present on the surfaces of primary sensory neurons recovered
      from sensory ganglia within 1 to 2 weeks of HSV infection. During this time, some
      neurons are found to be tightly associated with T cells in vivo. Prior data
      showed that termination of productive HSV infection in the peripheral nervous
      system is not dependent on cell-mediated lysis of infected neurons. Consistent
      with these data, immunogold electron microscopy showed that the density of cell
      surface H2 on neurons is an order of magnitude lower than on satellite glia,
      which is predicted to favor a noncytolytic CD8 cell response.

PMID- 10400744
TI  - Evolution of the hepatitis C virus second envelope protein hypervariable region
      in chronically infected patients receiving alpha interferon therapy.
AB  - Sustained hepatitis C virus (HCV) RNA clearance is achieved in 8 to 12% of
      patients with chronic HCV infection treated with alpha interferon (IFN-alpha) at
      the approved dose of 3 MU three times a week for 6 months and in about 25% of
      those receiving this treatment for 12 months. We used single-strand conformation
      polymorphism analysis combined with cloning and sequencing strategies to
      characterize the genetic evolution of HCV second envelope gene hypervariable
      region 1 (HVR1) quasispecies during and after IFN therapy in patients who failed
      to clear HCV RNA. Sustained HCV RNA clearance was achieved in 6% of patients.
      Profound changes in HVR1 quasispecies major variants were estimated to occur in
      70% of the patients during and after therapy. These changes were evolutionary and
      were characterized by shifts in the virus population, related to selection and
      subsequent diversification of minor pretreatment variants. The quasispecies
      changes appeared to be induced by changes in the host environment likely
      resulting from the IFN-induced enhancement and post-IFN attenuation of
      neutralizing and possibly cytotoxic responses against HVR1. The remaining
      patients had no apparent changes in HVR1 quasispecies major variants, suggesting
      selection of major pretreatment variants, but some changes were observed in other
      genomic regions. We conclude that IFN-alpha administration and withdrawal
      profoundly alters the nature of circulating HCV quasispecies, owing to profound
      changes in virus-host interactions, in patients in whom sustained HCV RNA
      clearance fails to occur. These changes are associated with profound alterations
      of the natural outcome of HCV-related liver disease, raising the hypothesis of a
      causal relationship.

PMID- 10400745
TI  - A putative cell surface receptor for anemia-inducing feline leukemia virus
      subgroup C is a member of a transporter superfamily.
AB  - Domestic cats infected with the horizontally transmitted feline leukemia virus
      subgroup A (FeLV-A) often produce mutants (termed FeLV-C) that bind to a distinct
      cell surface receptor and cause severe aplastic anemia in vivo and erythroblast
      destruction in bone marrow cultures. The major determinant for FeLV-C-induced
      anemia has been mapped to a small region of the surface envelope glycoprotein
      that is responsible for its receptor binding specificity. Thus, erythroblast
      destruction may directly or indirectly result from FeLV-C binding to its
      receptor. To address these issues, we functionally cloned a putative cell surface
      receptor for FeLV-C (FLVCR) by using a human T-lymphocyte cDNA library in a
      retroviral vector. Expression of the 2.0-kbp FLVCR cDNA in naturally resistant
      Swiss mouse fibroblasts and Chinese hamster ovary cells caused substantial
      susceptibility to FeLV-C but no change in susceptibilities to FeLV-B and other
      retroviruses. The predicted FLVCR protein contains 555 amino acids and 12
      hydrophobic potential membrane-spanning sequences. Database searches indicated
      that FLVCR is a member of the major-facilitator superfamily of transporters and
      implied that it may transport an organic anion. RNA blot analyses showed that
      FLVCR mRNA is expressed in multiple hematopoietic lineages rather than
      specifically in erythroblasts. These results suggest that the targeted
      destruction of erythroblasts by FeLV-C may derive from their greater sensitivity
      to this virus rather than from a preferential susceptibility to infection.

PMID- 10400746
TI  - Antiapoptotic and oncogenic potentials of hepatitis C virus are linked to
      interferon resistance by viral repression of the PKR protein kinase.
AB  - Hepatitis C virus (HCV) is prevalent worldwide and has become a major cause of
      liver dysfunction and hepatocellular carcinoma. The high prevalence of HCV
      reflects the persistent nature of infection and the large frequency of cases that
      resist the current interferon (IFN)-based anti-HCV therapeutic regimens. HCV
      resistance to IFN has been attributed, in part, to the function of the viral
      nonstructural 5A (NS5A) protein. NS5A from IFN-resistant strains of HCV can
      repress the PKR protein kinase, a mediator of the IFN-induced antiviral and
      apoptotic responses of the host cell and a tumor suppressor. Here we examined the
      relationship between HCV persistence and resistance to IFN therapy. When
      expressed in mammalian cells, NS5A from IFN-resistant HCV conferred IFN
      resistance to vesicular stomatitis virus (VSV), which normally is sensitive to
      the antiviral actions of IFN. NS5A blocked viral double-stranded RNA (dsRNA)
      induced PKR activation and phosphorylation of eIF-2alpha in IFN-treated cells,
      resulting in high levels of VSV mRNA translation. Mutations within the PKR
      binding domain of NS5A restored PKR function and the IFN-induced block to viral
      mRNA translation. The effects due to NS5A inhibition of PKR were not limited to
      the rescue of viral mRNA translation but also included a block in PKR-dependent
      host signaling pathways. Cells expressing NS5A exhibited defective PKR signaling
      and were refractory to apoptosis induced by exogenous dsRNA. Resistance to
      apoptosis was attributed to an NS5A-mediated block in eIF-2alpha phosphorylation.
      Moreover, cells expressing NS5A exhibited a transformed phenotype and formed
      solid tumors in vivo. Disruption of apoptosis and tumorogenesis required the PKR
      binding function of NS5A, demonstrating that these properties may be linked to
      the IFN-resistant phenotype of HCV.

PMID- 10400748
TI  - Nonproductive human immunodeficiency virus type 1 infection in nucleoside-treated
      G0 lymphocytes.
AB  - Productive infection by human immunodeficiency virus type 1 (HIV-1) requires the
      activation of target cells. Infection of quiescent peripheral CD4 lymphocytes by
      HIV-1 results in incomplete, labile, reverse transcripts. We have previously
      identified G1b as the cell cycle stage required for the optimal completion of the
      reverse transcription process in T lymphocytes. However, the mechanism(s)
      involved in the blockage of reverse transcription remains undefined. In this
      study we investigated whether nucleotide levels influence viral reverse
      transcription in G0 cells. For this purpose the role of the enzyme ribonucleotide
      reductase was bypassed, by adding exogenous deoxyribonucleosides to highly
      purified T cells in the G0 or the G1a phase of the cell cycle. Our data showed a
      significant increase in the efficiency of the reverse transcription process
      following the addition of the deoxyribonucleosides. To define the stability and
      functionality of these full reverse transcripts, we used an HIV-1 reporter virus
      that expresses the murine heat-stable antigen on the surfaces of infected cells.
      Following activation of infected quiescent cells treated with exogenous
      nucleosides, no increased rescue of productive infection was seen. Thus, in
      addition to failure to complete reverse transcription, there was an additional
      nonreversible blockage of productive infection in quiescent T cells. These
      experiments have important relevance in the gene therapy arena, in terms of
      improving the ability of lentivirus vectors to enter metabolically inactive
      cells, such as hematopoietic stem cells.

PMID- 10400747
TI  - Characterization of CELO virus proteins that modulate the pRb/E2F pathway.
AB  - The avian adenovirus CELO can, like the human adenoviruses, transform several
      mammalian cell types, yet it lacks sequence homology with the transforming, early
      regions of human adenoviruses. In an attempt to identify how CELO virus activates
      the E2F-dependent gene expression important for S phase in the host cell, we have
      identified two CELO virus open reading frames that cooperate in activating an E2F
      inducible reporter system. The encoded proteins, GAM-1 and Orf22, were both found
      to interact with the retinoblastoma protein (pRb), with Orf22 binding to the
      pocket domain of pRb, similar to other DNA tumor virus proteins, and GAM-1
      interacting with pRb regions outside the pocket domain. The motif in Orf22
      responsible for the pRb interaction is essential for Orf22-mediated E2F
      activation, yet it is remarkably unlike the E1A LxCxD and may represent a novel
      form of pRb-binding peptide.

PMID- 10400749
TI  - Characterization of the 5' ends for polyadenylated RNAs synthesized during the
      replication of hepatitis delta virus.
AB  - The genome of hepatitis delta virus (HDV) is a 1,679-nucleotide (nt) single
      stranded circular RNA that is predicted to fold into an unbranched rodlike
      structure. During replication, two complementary RNAs are also detected: an exact
      complement, referred to as the antigenome, and an 800-nt polyadenylated RNA that
      could act as the mRNA for the delta antigen. We used a 5' rapid amplification of
      cDNA ends procedure, followed by cloning and sequencing, to determine the 5' ends
      of the polyadenylated RNAs produced during HDV genome replication following
      initiation under different experimental conditions. The analyzed RNAs were from
      the liver of an infected woodchuck and from a liver cell line at 6 days after
      transfection with either an HDV cDNA or ribonucleoprotein (RNP) complexes
      assembled in vitro with HDV genomic RNA and purified recombinant small delta
      protein. In all three situations the 5' ends mapped specifically to nt 1630. In
      relationship to what is called the top end of the unbranched rodlike structure
      predicted for the genomic RNA template, this site is located 10 nt from the top,
      and in the middle of a 3-nt external bulge. Following transfection with RNP, such
      specific 5' ends could be detected as early as 24 h. We next constructed a series
      of mutants of this predicted bulge region and of an adjacent 6-bp stem and the
      top 5-nt loop. Some of these mutations decreased the ability of the genome to
      undergo antigenomic RNA synthesis and accumulation and/or altered the location of
      the detected 5' ends. The observed end located at nt 1630, and most of the novel
      5' ends, were consistent with transcription initiation events that preferentially
      used a purine. The present studies do not prove that the detected 5' ends
      correspond to initiation sites and do not establish the hypothesis that there is
      a promoter element in the vicinity, but they do show that the location of the
      observed 5' ends could be controlled by nucleotide sequences at and around nt
      1630.

PMID- 10400750
TI  - The Epstein-Barr virus protein BRLF1 activates S phase entry through E2F1
      induction.
AB  - The Epstein-Barr Virus (EBV) immediate-early protein BRLF1 is one of two
      transactivators which mediate the switch from latent to lytic replication in EBV
      infected cells. DNA viruses often modulate the function of critical cell cycle
      proteins to maximize the efficiency of virus replication. Here we have examined
      the effect of BRLF1 on cell cycle progression. A replication-deficient adenovirus
      expressing BRLF1 (AdBRLF1) was used to infect normal human fibroblasts and
      various epithelial cell lines. BRLF1 expression induced S phase entry in contact
      inhibited fibroblasts and in the human osteosarcoma cell line U-2 OS. AdBRLF1
      infection produced a dramatic increase in the level of E2F1 but not E2F4. In
      contrast, the levels of Rb, p107, and p130 were decreased in AdBRLF1-infected
      cells. Electrophoretic mobility shift assays confirmed an increased level of free
      E2F1 in the AdBRLF1-infected human fibroblasts. Consistent with the previously
      described effect of E2F1, AdBRLF1-infected fibroblasts had increased levels of
      p53 and p21 and died by apoptosis. BRLF1-induced activation of E2F1 may be
      required for efficient EBV lytic replication, since at least one critical viral
      replication gene (the viral DNA polymerase) is activated by E2F (C. Liu, N. D.
      Sista, and J. S. Pagano, J. Virol. 70:2545-2555, 1996).

PMID- 10400751
TI  - The Epstein-Barr virus BZLF1 protein interacts physically and functionally with
      the histone acetylase CREB-binding protein.
AB  - The Epstein-Barr virus (EBV) immediate-early protein BZLF1 (Z) is a key regulator
      of the EBV latent-to-lytic switch. Z is a transcriptional activator which induces
      EBV early gene expression. We demonstrate here that Z interacts with CREB-binding
      protein (CBP), a histone acetylase and transcriptional coactivator. This
      interaction requires the amino-terminal region of CBP as well as the
      transactivation and leucine zipper domains of Z. We show that CBP enhances Z
      mediated transactivation of EBV early promoters, in reporter gene assays and in
      the context of the endogenous genome. We also demonstrate that Z decreases CREB
      transactivation function and that this inhibitory effect is reversed by
      overexpression of CBP. We show that Z also interacts directly with CREB. However,
      mutational analysis indicates that Z inhibition of CREB activity requires the
      direct interaction between Z and CBP but not the direct interaction between Z and
      CREB. We propose that Z interacts with CBP to enhance viral early gene
      transcription. In addition, the Z-CBP interaction may control host cellular
      transcription factor activity through competition for limiting amounts of
      cellular CBP.

PMID- 10400752
TI  - Sendai virus C proteins counteract the interferon-mediated induction of an
      antiviral state.
AB  - We have studied the relationship between the Sendai virus (SeV) C proteins (a
      nested set of four proteins initiated at different start codons) and the
      interferon (IFN)-mediated antiviral response in IFN-competent cells in culture.
      SeV strains containing wild-type or various mutant C proteins were examined for
      their ability (i) to induce an antiviral state (i.e., to prevent the growth of
      vesicular stomatitis virus [VSV] following a period of SeV infection), (ii) to
      induce the elevation of Stat1 protein levels, and (iii) to prevent IFN added
      concomitant with the SeV infection from inducing an antiviral state. We find that
      expression of the wild-type C gene and, specifically, the AUG114-initiated C
      protein prevents the establishment of an antiviral state: i.e., cells infected
      with wild-type SeV exhibited little or no increase in Stat1 levels and were
      permissive for VSV replication, even in the presence of exogenous IFN. In
      contrast, in cells infected with SeV lacking the AUG114-initiated C protein or
      containing a single amino acid substitution in the C protein, the level of Stat1
      increased and VSV replication was inhibited. The prevention of the cellular IFN
      mediated antiviral response appears to be a key determinant of SeV pathogenicity.

PMID- 10400753
TI  - Regulation of Epstein-Barr virus promoters in oral epithelial cells and
      lymphocytes.
AB  - Hairy leukoplakia (HL) is a proliferative lesion of the tongue that supports
      abundant Epstein-Barr virus (EBV) replication. Previous work showed high-level
      expression of the EBV BMRF2 gene in HL. To characterize the regulation of BMRF2
      expression in HL, we mapped the 5' ends of the BMRF1 and BMRF2 transcripts and
      showed that BMRF2 is expressed from a novel internal promoter within the BMRF1
      coding region. Mechanisms of BMRF2 regulation were compared in oral epithelial
      cells and B lymphocytes, as were those of BMRF1 and BDLF3, early and late EBV
      transcripts, respectively, that are also known to be expressed in HL. Basal
      activity of the putative BMRF2 promoter was 10-fold higher in HSC-3 epithelial
      cells than in B lymphocytes. The BMRF2 and the BDLF3 promoters were responsive to
      induction by phorbol ester, but unlike the BMRF1 promoter, they were not
      responsive to BZLF1 transactivation. By mutational analysis, the major activity
      of the BMRF2 promoter mapped to a 50-bp region, which includes a TATA-like
      element and a GC box. The BMRF2 promoter may be regulated differentially from the
      BMRF1 promoter and more closely resembles that of BDLF3. This novel BMRF2
      promoter likely belongs to a class of viral promoters that is more responsive to
      mechanisms known to induce epithelial cell differentiation, consistent with its
      high level of expression in HL.

PMID- 10400754
TI  - RNase H requirements for the second strand transfer reaction of human
      immunodeficiency virus type 1 reverse transcription.
AB  - Retroviral reverse transcriptase (RT) enzymes are responsible for transcribing
      viral RNA into double-stranded DNA. An in vitro assay to analyze the second
      strand transfer event during human immunodeficiency virus type 1 (HIV-1) reverse
      transcription has been developed. Model substrates were constructed which mimic
      the viral intermediate found during plus-strand strong-stop synthesis. Utilizing
      wild-type HIV-1 RT and a mutant E478Q RT, the requirement for RNase H activity in
      this strand transfer event was analyzed. In the presence of Mg2+, HIV-1 RT was
      able to fully support the second strand transfer reaction in vitro. However, in
      the presence of Mg2+, the E478Q RT mutant had no detectable RNase H activity and
      was unable to support strand transfer. In the presence of Mn2+, the E478Q RT
      yields the initial endoribonucleolytic cleavage at the penultimate C residue of
      the tRNA primer yet does not support strand transfer. This suggests that
      subsequent degradation of the RNA primer by the RNase H domain was required for
      strand transfer. In reactions in which the E478Q RT was complemented with
      exogenous RNase H enzymes, strand transfer was supported. Additionally, we have
      shown that HIV-1 RT is capable of supporting strand transfer with substrates that
      mimic tRNAHis as well as the authentic tRNA3Lys.

PMID- 10400755
TI  - Escape of human cytomegalovirus from HLA-DR-restricted CD4(+) T-cell response is
      mediated by repression of gamma interferon-induced class II transactivator
      expression.
AB  - Human cytomegalovirus (HCMV), a betaherpesvirus, is a pathogen which escapes
      immune recognition through various mechanisms. In this paper, we show that HCMV
      down regulates gamma interferon (IFN-gamma)-induced HLA-DR expression in U373 MG
      astrocytoma cells due to a defect downstream of STAT1 phosphorylation and nuclear
      translocation. Repression of class II transactivator (CIITA) mRNA expression is
      detected within the first hours of IFN-gamma-HCMV coincubation and results in the
      absence of HLA-DR synthesis. This defect leads to the absence of presentation of
      the major immediate-early protein IE1 to specific CD4(+) T-cell clones when U373
      MG cells, used as antigen-presenting cells, are treated with IFN-gamma plus HCMV.
      However, presentation of endogenously synthesized IE1 can be restored when U373
      MG cells are transfected with CIITA prior to infection with HCMV. Altogether, the
      data indicate that the defect induced by HCMV resides in the activation of the
      IFN-gamma-responsive promoter of CIITA. This is the first demonstration of a
      viral inhibition of CIITA expression.

PMID- 10400756
TI  - Induction of Th-1 and Th-2 responses by respiratory syncytial virus attachment
      glycoprotein is epitope and major histocompatibility complex independent.
AB  - In BALB/c mice, sensitization to respiratory syncytial virus (RSV) attachment (G)
      glycoprotein leads to the development of lung eosinophilia upon challenge
      infection with RSV, a pathology indicative of a strong in vivo induction of a Th
      2-type response. In this study, we found that a strong, RSV G-specific, Th-1-type
      cytokine response occurred simultaneously with a Th-2-type response in G-primed
      mice after RSV challenge. Both Th-1 and Th-2 effector CD4(+) T cells recognized a
      single immunodominant site on this protein, implying that the differentiation of
      memory CD4(+) T cells along the Th-1 or Th-2 effector pathway was independent of
      the epitope specificity of the T cells. A similar observation was made in G
      primed H-2(b) haplotype mice after RSV challenge, further suggesting that this
      process is not dependent on the peptide epitope presented. On the other hand,
      genes mapping to loci outside of the major histocompatibility complex region are
      crucial regulators of the development of a Th-2-type response and lung
      eosinophilia. The implication of these findings for the immune mechanisms
      underlying the pathogenesis of RSV is discussed.

PMID- 10400757
TI  - Mutagenesis of CXCR4 identifies important domains for human immunodeficiency
      virus type 1 X4 isolate envelope-mediated membrane fusion and virus entry and
      reveals cryptic coreceptor activity for R5 isolates.
AB  - CXCR4 is a chemokine receptor and a coreceptor for T-cell-line-tropic (X4) and
      dual-tropic (R5X4) human immunodeficiency virus type 1 (HIV-1) isolates. Cells
      coexpressing CXCR4 and CD4 will fuse with appropriate HIV-1 envelope glycoprotein
      (Env)-expressing cells. The delineation of the critical regions involved in the
      interactions within the Env-CD4-coreceptor complex are presently under intensive
      investigation, and the use of chimeras of coreceptor molecules has provided
      valuable information. To define these regions in greater detail, we have employed
      a strategy involving alanine-scanning mutagenesis of the extracellular domains of
      CXCR4 coupled with a highly sensitive reporter gene assay for HIV-1 Env-mediated
      membrane fusion. Using a panel of 41 different CXCR4 mutants, we have identified
      several charged residues that appear important for coreceptor activity for X4
      Envs; the mutations E15A (in which the glutamic acid residue at position 15 is
      replaced by alanine) and E32A in the N terminus, D97A in extracellular loop 1
      (ecl-1), and R188A in ecl-2 impaired coreceptor activity for X4 and R5X4 Envs. In
      addition, substitution of alanine for any of the four extracellular cysteines
      alone resulted in conformational changes of various degrees, while mutants with
      paired cysteine deletions partially retained their structure. Our data support
      the notion that all four cysteines are involved in disulfide bond formation. We
      have also identified substitutions which greatly enhance or convert CXCR4's
      coreceptor activity to support R5 Env-mediated fusion (N11A, R30A, D187A, and
      D193A), and together our data suggest the presence of conserved extracellular
      elements, common to both CXCR4 and CCR5, involved in their coreceptor activities.
      These data will help us to better detail the CXCR4 structural requirements
      exhibited by different HIV-1 strains and will direct further mutagenesis efforts
      aimed at better defining the domains in CXCR4 involved in the HIV-1 Env-mediated
      fusion process.

PMID- 10400758
TI  - Identification of a linear heparin binding domain for human respiratory syncytial
      virus attachment glycoprotein G.
AB  - Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract
      disease in infants and young children worldwide. Infection is mediated, in part,
      by an initial interaction between attachment protein (G) and a highly sulfated
      heparin-like glycosaminoglycan (Gag) located on the cell surface. Synthetic
      overlapping peptides derived from consensus sequences of the G protein ectodomain
      from both RSV subgroups A and B were tested by heparin-agarose affinity
      chromatography for their abilities to bind heparin. This evaluation identified a
      single linear heparin binding domain (HBD) for RSV subgroup A (184A-->T198) and B
      (183K-->K197). The binding of these peptides to Vero cells was inhibited by
      heparin. Peptide binding to two CHO cell mutants (pgsD-677 and pgsA-745)
      deficient in heparan sulfate or total Gag synthesis was decreased 50% versus the
      parental cell line, CHO-K1, and decreased an average of 87% in the presence of
      heparin. The RSV-G HBD peptides were also able to inhibit homologous and
      heterologous virus infectivity of Vero cells. These results indicate that the
      sequence 184A/183K-->198T/K197 for RSV subgroups A and B, respectively, defines
      an important determinant of RSV-G interactions with heparin.

PMID- 10400759
TI  - Herpes simplex virus latency-associated transcript encodes a protein which
      greatly enhances virus growth, can compensate for deficiencies in immediate-early
      gene expression, and is likely to function during reactivation from virus
      latency.
AB  - Herpes simplex virus types 1 and 2 (HSV1 and HSV2) enter and reactivate from
      latency in sensory neurons, although the events governing these processes are
      little understood. During latency, only the latency-associated transcripts (LATs)
      are produced. However, although the LAT RNAs were described approximately 10
      years ago, their function remains ambiguous. Mutations affecting the LATs have
      minimal effects other than a small reduction in establishment of and reactivation
      from latency in some cases. Mutations in putative LAT-contained open reading
      frames (ORFs) have so far shown no effect. The LATs consist of a large species
      from which smaller (approximately 2 kb), nuclear, nonlinear LATs which are
      abundant during latency are spliced. Thus, translation of ORFs in these smaller
      LATs would not usually be expected to be possible, and if expressed at all, their
      expression might be tightly regulated. Here we show that deregulated expression
      of the largest HSV1 2-kb LAT-contained ORF in various cells of neuronal and
      nonneuronal origin greatly enhances virus growth in a manner specific to HSV1-the
      HSV1 LAT ORF has no effect on the growth of HSV2. Similar results of enhanced
      growth were found when the HSV1 LAT ORF was constitutively expressed from within
      the HSV1 genome. The mechanism of LAT ORF action was strongly suggested to be by
      substituting for deficiencies in immediate-early (IE) gene expression
      (particularly ICP0), because deregulated LAT ORF expression, as well as enhancing
      wild-type virus growth, was also found to allow efficient growth of viruses with
      mutations in ICP0 or VMW65. Such viruses otherwise exhibit considerable growth
      defects. IE gene expression deficiencies are often the block to productive
      infection in nonpermissive cells and are also evident during latency. These
      results, which we show to be protein- rather than RNA-mediated effects, strongly
      suggest a function of the tightly regulated expression of a LAT ORF-encoded
      protein in the reactivation from HSV latency.

PMID- 10400760
TI  - Mapping of the feline calicivirus proteinase responsible for autocatalytic
      processing of the nonstructural polyprotein and identification of a stable
      proteinase-polymerase precursor protein.
AB  - Expression of the region of the feline calicivirus (FCV) ORF1 encoded by
      nucleotides 3233 to 4054 in an in vitro rabbit reticulocyte system resulted in
      synthesis of an active proteinase that specifically processes the viral
      nonstructural polyprotein. Site-directed mutagenesis of the cysteine (Cys1193)
      residue in the putative active site of the proteinase abolished autocatalytic
      cleavage as well as cleavage of the viral capsid precursor, suggesting that this
      "3C-like" proteinase plays an important role in proteolytic processing during
      viral replication. Expression of the region encoding the C-terminal portion of
      the FCV ORF1 (amino acids 942 to 1761) in bacteria allowed direct N-terminal
      sequence analysis of the virus-specific polypeptides produced in this system. The
      results of these analyses indicate that the proteinase cleaves at amino acid
      residues E960-A961, E1071-S1072, E1345-T1346, and E1419-G1420; however, the
      cleavage efficiency is varied. The E1071-S1072 cleavage site defined the N
      terminus of a 692-amino-acid protein that contains sequences with similarity to
      the picornavirus 3C proteinase and 3D polymerase domains. Immunoprecipitation of
      radiolabeled proteins from FCV-infected feline kidney cells with serum raised
      against the FCV ORF1 C-terminal region showed that this "3CD-like" proteinase
      polymerase precursor protein is apparently stable and accumulates in cells during
      infection.

PMID- 10400761
TI  - Expression of mouse mammary tumor virus superantigen mRNA in the thymus
      correlates with kinetics of self-reactive T-cell loss.
AB  - Mouse mammary tumor virus (MMTV) encodes a superantigen (Sag) that is expressed
      at the surface of antigen-presenting cells in conjunction with major
      histocompatibility complex (MHC) type II molecules. The Sag-MHC complex is
      recognized by entire subsets of T cells, leading to cytokine release and
      amplification of infected B and T cells that carry milk-borne MMTV to the mammary
      gland. Expression of Sag proteins from endogenous MMTV proviruses carried in the
      mouse germ line usually results in the deletion of self-reactive T cells during
      negative selection in the thymus and the elimination of T cells required for
      infection by specific milk-borne MMTVs. However, other endogenous MMTVs are
      unable to eliminate Sag-reactive T cells in newborn mice and cause partial loss
      of reactive T cells in adults. To investigate the kinetics of Sag-reactive T-cell
      deletion, backcross mice that contain single or multiple MMTVs were screened by a
      novel PCR assay designed to distinguish among highly related MMTV strains. Mice
      that contained Mtv-17 alone showed slow kinetics of reactive T-cell loss that
      involved the CD4(+), but not the CD8(+), subset. Deletion of CD4(+) or CD8(+) T
      cells reactive with Mtv-17 Sag was not detected in thymocytes. Slow kinetics of
      peripheral T-cell deletion by Mtv-17 Sag also was accompanied by failure to
      detect Mtv-17 sag-specific mRNA in the thymus, despite detectable expression in
      other tissues, such as spleen. Together, these data suggest that Mtv-17 Sag
      causes peripheral, rather than intrathymic, deletion of T cells. Interestingly,
      the Mtv-8 provirus caused partial deletion of CD4(+)Vbeta12(+) cells in the
      thymus, but other T-cell subsets appeared to be deleted only in the periphery.
      Our data have important implications for the level of antigen expression required
      for elimination of self-reactive T cells. Moreover, these experiments suggest
      that mice expressing endogenous MMTVs that lead to slow kinetics of T-cell
      deletion will be susceptible to infection by milk-borne MMTVs with the same Sag
      specificity.

PMID- 10400762
TI  - Comparison of genetic variability at multiple loci across the genomes of the
      major subtypes of Kaposi's sarcoma-associated herpesvirus reveals evidence for
      recombination and for two distinct types of open reading frame K15 alleles at the
      right-hand end.
AB  - Kaposi's sarcoma (KS)-associated herpesvirus or human herpesvirus 8 (HHV8) DNA is
      found consistently in nearly all classical, endemic, transplant, and AIDS
      associated KS lesions, as well as in several AIDS-associated lymphomas. We have
      previously sequenced the genes for the highly variable open reading frame K1 (ORF
      K1) protein from more than 60 different HHV8 samples and demonstrated that they
      display up to 30% amino acid variability and cluster into four very distinct
      evolutionary subgroups (the A, B, C, and D subtypes) that correlate with the
      major migrationary diasporas of modern humans. Here we have extended this type of
      analysis to six other loci across the HHV8 genome to further evaluate overall
      genotype patterns and the potential for chimeric genomes. Comparison of the
      relatively conserved ORF26, T0.7/K12, and ORF75 gene regions at map positions 0.
      35, 0.85, and 0.96 revealed typical ORF-K1-linked subtype patterns, except that
      between 20 and 30% of the genomes analyzed proved to be either intertypic or
      intratypic mosaics. In addition, a 2,500-bp region found at the extreme right
      hand side of the unique segment in 45 HHV8 genomes proved to be highly diverged
      from the 3,500-bp sequence found at this position in the other 18 HHV8 genomes
      examined. Furthermore, these previously uncharacterized "orphan" region sequences
      proved to encompass multiexon latent-state mRNAs encoding two highly diverged
      alleles of the novel ORF-K15 protein. The predominant (P) and minor (M) forms of
      HHV8 ORF-K15 are structurally related integral membrane proteins that have only
      33% overall amino acid identity to one another but retain conserved likely
      tyrosine kinase signaling motifs and may be distant evolutionary relatives of the
      LMP2 latency protein of Epstein-Barr virus. The M allele of ORF-K15 is also
      physically linked to a distinctive M subtype of the adjacent ORF75 gene locus,
      and in some cases, this linkage extends as far back as the T0.7 locus also.
      Overall, the results suggest that an original recombination event with a related
      primate virus from an unknown source introduced exogenous right-hand side ORF
      K15(M) sequences into an ancient M form of HHV8, followed by eventual acquisition
      into the subtype C lineage of the modern P-form of the HHV8 genome and subsequent
      additional, more recent transfers by homologous recombination events into several
      subtype A and B lineages as well.

PMID- 10400763
TI  - Activated memory CD4(+) T helper cells repopulate the intestine early following
      antiretroviral therapy of simian immunodeficiency virus-infected rhesus macaques
      but exhibit a decreased potential to produce interleukin-2.
AB  - Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model, we
      performed a longitudinal study to determine the effect of antiretroviral therapy
      on the phenotype and functional potential of CD4(+) T cells repopulating
      intestinal mucosa in human immunodeficiency virus infection. Severe depletion of
      CD4(+) and CD4(+) CD8(+) T cells occurred in the intestinal mucosa during primary
      SIV infection. The majority of these cells were of activated memory phenotype.
      Phosphonate 9-[2-(phosphomethoxypropyl]adenine (PMPA) treatment led to a moderate
      suppression of intestinal viral loads and repopulation of intestinal mucosa by
      predominantly activated memory CD4(+) T-helper cells. This repopulation was
      independent of the level of viral suppression. Compared to preinfection values,
      the frequency of naive CD4(+) T cells increased following PMPA therapy,
      suggesting that new CD4(+) T cells were repopulating the intestinal mucosa.
      Repopulation by CD4(+) CD8(+) T cells was not observed in either jejunum or colon
      lamina propria. The majority of CD4(+) T cells repopulating the intestinal mucosa
      following PMPA therapy were CD29(hi) and CD11ahi. A subset of repopulating
      intestinal CD4(+) T cells expressed Ki-67 antigen, indicating that local
      proliferation may play a role in the repopulation process. Although the majority
      of repopulating CD4(+) T cells in the intestinal mucosa were functionally capable
      of providing B- and T-cell help, as evidenced by their expression of CD28, these
      CD4(+) T cells were found to have a reduced capacity to produce interleukin-2 (IL
      2) compared to the potential of CD4(+) T cells prior to SIV infection. Persistent
      viral infection may play a role in suppressing the potential of repopulating
      CD4(+) T cells to produce IL-2. Hence, successful antiretroviral therapy should
      aim at complete suppression of viral loads in mucosal lymphoid tissues, such as
      intestinal mucosa.

PMID- 10400764
TI  - Coupled integration of human immunodeficiency virus type 1 cDNA ends by purified
      integrase in vitro: stimulation by the viral nucleocapsid protein.
AB  - Integration of retroviral cDNA involves coupled joining of the two ends of the
      viral genome at precisely spaced positions in the host cell DNA. Correct coupled
      joining is essential for viral replication, as shown, for example, by the finding
      that viral mutants defective in coupled joining are defective in integration and
      replication. To date, reactions with purified human immunodeficiency virus type 1
      (HIV-1) integrase protein in vitro have supported mainly uncoupled joining of
      single cDNA ends. We have analyzed an activity stimulating coupled joining
      present in HIV-1 virions, which led to the finding that the HIV-1 nucleocapsid
      (NC) protein can stimulate coupled joining more than 1,000-fold under some
      conditions. The requirements for stimulating coupled joining were investigated in
      assays with mutant NC proteins, revealing that mutations in the zinc finger
      domains can influence stimulation of integration. These findings (i) provide a
      means for assembling more authentic integrase complexes for mechanistic studies,
      (ii) reveal a new activity of NC protein in vitro, (iii) indicate a possible role
      for NC in vivo, and (iv) provide a possible method for identifying a new class of
      inhibitors that disrupt coupled joining.

PMID- 10400765
TI  - Patterns of chemokine receptor fusion cofactor utilization by human
      immunodeficiency virus type 1 variants from the lungs and blood.
AB  - Human immunodeficiency virus type 1 (HIV-1) infection is highly
      compartmentalized, with distinct viral genotypes being found in the lungs, brain,
      and other organs compared with blood. CCR5 and CXCR4 are the principal HIV-1
      coreceptors, and a number of other molecules support entry in vitro but their
      roles in vivo are uncertain. To address the relationship between tissue
      compartmentalization and the selective use of entry coreceptors, we generated
      functional env clones from primary isolates derived from the lungs and blood of
      three infected individuals and analyzed their use of the principal, secondary,
      orphan, and virus-encoded coreceptors for fusion. All Env proteins from lung
      viruses used CCR5 but not CXCR4, while those from blood viruses used CCR5 or
      CXCR4 or both. The orphan receptor APJ was widely used for fusion by Env proteins
      from both blood and lung viruses, but none used the cytomegalovirus-encoded
      receptor US28. Fusion mediated by the secondary coreceptors CCR2b, CCR3, CCR8,
      and CX3CR1 and orphan receptors GPR1, GPR15, and STRL33 was variable and
      heterogeneous, with relatively broad utilization by env clones from isolates of
      one subject but limited use by env clones from the other two subjects. However,
      there was no clear distinction between blood and lung viruses in secondary or
      orphan coreceptor fusion patterns. In contrast to fusion, none of the secondary
      or orphan receptors enabled efficient productive infection. These results
      confirm, at the level of cofactor utilization, previous observations that HIV-1
      populations in the lungs and blood are biologically distinct and demonstrate
      diversity within lung-derived as well as blood-derived quasispecies. However, the
      heterogeneity in coreceptor utilization among clones from each isolate and the
      lack of clear distinction between lung- and blood-derived Env proteins argue
      against selective coreceptor utilization as a major determinant of
      compartmentalization.

PMID- 10400766
TI  - The baculovirus PE38 protein augments apoptosis induced by transactivator IE1.
AB  - While studying apoptosis induced by baculovirus transactivator IE1 in SF-21
      cells, we found that the levels of IE1-induced apoptosis were increased
      approximately twofold upon cotransfection with the baculovirus early pe38 gene.
      However, no apoptotic activity was observed in cells transfected with pe38 alone,
      even when placed under the control of a constitutive promoter. Thus, pe38 was
      able to augment IE1-induced apoptosis but was unable to induce apoptosis when
      expressed in SF-21 cells alone. PE38, the full-length product of pe38, is a
      nuclear protein with RING finger and leucine zipper motifs. Deletion of the amino
      terminal region, which contains a putative nuclear localization motif, resulted
      in cytoplasmic localization of the PE38 mutants. These N-terminal deletion
      mutants were unable to enhance IE1-induced apoptosis. Mutation of a single
      conserved leucine (L242) of the leucine zipper motif also eliminated the ability
      of PE38 to augment apoptosis induced by IE1. In contrast, PE38 mutants with
      alanine substitutions for conserved cysteine residues (C109 or C138) of the RING
      finger motif were able to increase IE1-induced apoptosis to levels equivalent to
      those of wild-type PE38. We propose that PE38 is one of at least two viral
      factors which collectively evoke a cellular apoptotic response during baculovirus
      infection.

PMID- 10400767
TI  - Reverse transcriptase inhibitors can selectively block the synthesis of
      differently sized viral DNA transcripts in cells acutely infected with human
      immunodeficiency virus type 1.
AB  - We have recently reported that the in vitro inhibition of human immunodeficiency
      virus type 1 (HIV-1) reverse transcription by inhibitors of reverse transcriptase
      (RT) occurred most efficiently when the expected DNA products of RT reactions
      were long (Quan et al. , Nucleic Acids Res. 26:5692-5698, 1998). Here, we have
      used a quantitative PCR to analyze HIV-1 reverse transcription within acutely
      infected cells treated with RT inhibitors. We found that levels of minus-strand
      strong-stop DNA [(-)ssDNA] formed in acutely infected MT2 cells were only
      slightly reduced if cells were infected with viruses that had been generated in
      the presence of either azidothymidine or nevirapine (5 microM) and maintained in
      the presence of this drug throughout the viral adsorption period and thereafter.
      Control experiments in which virus inoculation of cells was performed at 4
      degrees C, followed directly by cell extraction, showed that less than 1% of
      total (-)ssDNA within acutely infected cells was attributable to its presence
      within adsorbed virions. In contrast, synthesis of intermediate-length reverse
      transcribed DNA products decreased gradually as viral DNA strand elongation took
      place in the presence of either of these inhibitors. This establishes that
      nucleoside and nonnucleoside RT inhibitors can exert similar temporal impacts in
      regard to inhibition of viral DNA synthesis. Generation of full-length viral DNA,
      as expected, was almost completely blocked in the presence of these antiviral
      drugs. These results provide insight into the fact that high concentrations of
      drugs are often needed to yield inhibitory effects in cell-free RT assays
      performed with short templates, whereas relatively low drug concentrations are
      often strongly inhibitory in cellular systems.

PMID- 10400768
TI  - The resistance of retroviral vectors produced from human cells to serum
      inactivation in vivo and in vitro is primate species dependent.
AB  - The ability to deliver genes as therapeutics requires an understanding of the
      vector pharmacokinetics similar to that required for conventional drugs. A first
      question is the half-life of the vector in the bloodstream. Retroviral vectors
      produced in certain human cell lines differ from vectors produced in nonhuman
      cell lines in being substantially resistant to inactivation in vitro by human
      serum complement (F. L. Cosset, Y. Takeuchi, J. L. Battini, R. A. Weiss, and M.
      K. Collins, J. Virol. 69:7430-7436, 1995). Thus, use of human packaging cell
      lines (PCL) may produce vectors with longer half-lives, resulting in more
      efficacious in vivo gene therapy. However, survival of human PCL-produced vectors
      in vivo following systemic administration has not been explored. In this
      investigation, the half-lives of retroviral vectors packaged by either canine D17
      or human HT1080 PCL were measured in the bloodstreams of macaques and
      chimpanzees. Human PCL-produced vectors exhibited significantly higher
      concentrations of circulating biologically active vector at the earliest time
      points measured (>1, 000-fold in chimpanzees), as well as substantially extended
      half-lives, compared to canine PCL-produced vectors. In addition, the circulation
      half-life of human PCL-produced vector was longer in chimpanzees than in
      macaques. This was consistent with in vitro findings which demonstrated that
      primate serum inactivation of vector produced from human PCL increased with
      increasing phylogenetic distance from humans. These results establish that in
      vivo retroviral vector half-life correlates with in vitro resistance to
      complement. Furthermore, these findings should influence the choice of animal
      models used to evaluate retroviral-vector-based therapies.

PMID- 10400769
TI  - Association between virus-specific cytotoxic T-lymphocyte and helper responses in
      human immunodeficiency virus type 1 infection.
AB  - Cellular immune responses are thought to be an important antiviral host defense,
      but the relationship between virus-specific T-helper and cytotoxic-T-lymphocyte
      (CTL) responses has not been defined. To investigate a potential link between
      these responses, we examined functional human immunodeficiency virus type 1 (HIV
      1)-specific memory CTL precursor frequencies and p24-specific proliferative
      responses in a cohort of infected untreated persons with a wide range of viral
      loads and CD4 cell counts. Levels of p24-specific proliferative responses
      positively correlated with levels of Gag-specific CTL precursors and negatively
      correlated with levels of plasma HIV-1 RNA. These data linking the levels of HIV
      specific CTL with virus-specific helper cell function during chronic viral
      infection provide cellular immunologic parameters to guide therapeutic and
      prophylactic vaccine development.

PMID- 10400770
TI  - Levels of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte
      effector and memory responses decline after suppression of viremia with highly
      active antiretroviral therapy.
AB  - Therapeutic suppression of human immunodeficiency virus type 1 (HIV-1)
      replication may help elucidate interactions between the host cellular immune
      responses and HIV-1 infection. We performed a detailed longitudinal evaluation of
      two subjects before and after the start of highly active antiretroviral therapy
      (HAART). Both subjects had evidence of in vivo-activated and memory cytotoxic T
      lymphocyte precursor (CTLp) activity against multiple HIV-1 gene products. After
      the start of therapy, both subjects had declines in the levels of in vivo
      activated HIV-1-specific CTLs and had immediate increases in circulating HIV-1
      specific CTL memory cells. With continued therapy, and continued suppression of
      viral load, levels of memory CTLps declined. HLA A*0201 peptide tetramer staining
      demonstrated that declining levels of in vivo-activated CTL activity were
      associated with a decrease in the expression of the CD38(+) activation marker.
      Transient increases in viral load during continued therapy were associated with
      increases in the levels of virus-specific CTLps in both individuals. The results
      were confirmed by measuring CTL responses to discrete optimal epitopes. These
      studies illustrate the dynamic equilibrium between the host immune response and
      levels of viral antigen burden and suggest that efforts to augment HIV-1-specific
      immune responses in subjects on HAART may decrease the incidence of virologic
      relapse.

PMID- 10400773
TI  - Rearrangements in the 5' nontranslated region and phylogenetic analyses of
      cucumber mosaic virus RNA 3 indicate radial evolution of three subgroups.
AB  - Cucumber mosaic virus (CMV) has been divided into two subgroups based on
      serological data, peptide mapping of the coat protein, nucleic acid
      hybridization, and nucleotide sequence similarity. Analyses of a number of
      recently isolated strains suggest a further division of the subgroup I strains.
      Alignment of the 5' nontranslated regions of RNA 3 for 26 strains of CMV suggests
      the division of CMV into subgroups IA, IB, and II and suggests that
      rearrangements, deletions, and insertions in this region may have been the
      precursors of the subsequent radiation of each subgroup. Phylogeny analyses of
      CMV using the coat protein open reading frame of 53 strains strongly support the
      further division of subgroup I into IA and IB. In addition, strains within each
      subgroup radiate from a single point of origin, indicating that they have evolved
      from a single common ancestor for each subgroup.

PMID- 10400772
TI  - Amino acid residues contributing to the substrate specificity of the influenza A
      virus neuraminidase.
AB  - Influenza A viruses possess two glycoprotein spikes on the virion surface:
      hemagglutinin (HA), which binds to oligosaccharides containing terminal sialic
      acid, and neuraminidase (NA), which removes terminal sialic acid from
      oligosaccharides. Hence, the interplay between these receptor-binding and
      receptor-destroying functions assumes major importance in viral replication. In
      contrast to the well-characterized role of HA in host range restriction of
      influenza viruses, there is only limited information on the role of NA substrate
      specificity in viral replication among different animal species. We therefore
      investigated the substrate specificities of NA for linkages between N-acetyl
      sialic acid and galactose (NeuAcalpha2-3Gal and NeuAcalpha2-6Gal) and for
      different molecular species of sialic acids (N-acetyl and N-glycolyl sialic
      acids) in influenza A viruses isolated from human, avian, and pig hosts.
      Substrate specificity assays showed that all viruses had similar specificities
      for NeuAcalpha2-3Gal, while the activities for NeuAcalpha2-6Gal ranged from
      marginal, as represented by avian and early N2 human viruses, to high (although
      only one-third the activity for NeuAcalpha2-3Gal), as represented by swine and
      more recent N2 human viruses. Using site-specific mutagenesis, we identified in
      the earliest human virus with a detectable increase in NeuAcalpha2-6Gal
      specificity a change at position 275 (from isoleucine to valine) that enhanced
      the specificity for this substrate. Valine at position 275 was maintained in all
      later human viruses as well as swine viruses. A similar examination of N
      glycolylneuraminic acid (NeuGc) specificity showed that avian viruses and most
      human viruses had low to moderate activity for this substrate, with the exception
      of most human viruses isolated between 1967 and 1969, whose NeuGc specificity was
      as high as that of swine viruses. The amino acid at position 431 was found to
      determine the level of NeuGc specificity of NA: lysine conferred high NeuGc
      specificity, while proline, glutamine, and glutamic acid were associated with
      lower NeuGc specificity. Both residues 275 and 431 lie close to the enzymatic
      active site but are not directly involved in the reaction mechanism. This finding
      suggests that the adaptation of NA to different substrates occurs by a mechanism
      of amino acid substitutions that subtly alter the conformation of NA in and
      around the active site to facilitate the binding of different species of sialic
      acid.

PMID- 10400771
TI  - Variability of human systemic humoral immune responses to adenovirus gene
      transfer vectors administered to different organs.
AB  - Administration of adenovirus (Ad) vectors to immunologically naive experimental
      animals almost invariably results in the induction of systemic anti-Ad
      neutralizing antibodies. To determine if the human systemic humoral host
      responses to Ad vectors follow a similar pattern, we evaluated the systemic
      (serum) anti-Ad serotype 5 (Ad5) neutralizing antibodies in humans after
      administration of first generation (E1(-) E3(-)) Ad5-based gene transfer vectors
      to different hosts. AdGVCFTR.10 (carrying the normal human cystic fibrosis [CF]
      transmembrane regulator cDNA) was sprayed (8 x 10(7) to 2 x 10(10) particle units
      [PU]) repetitively (every 3 months or every 2 weeks) to the airway epithelium of
      15 individuals with CF. AdGVCD.10 (carrying the Escherichia coli cytosine
      deaminase gene) was administered (8 x 10(8) to 8 x 10(9) PU; once a week, twice)
      directly to liver metastasis of five individuals with colon cancer and by the
      intradermal route (8 x 10(7) to 8 x 10(9) PU, single administration) to six
      healthy individuals. AdGVVEGF121.10 (carrying the human vascular endothelial
      growth factor 121 cDNA) was administered (4 x 10(8) to 4 x 10(9.5) PU, single
      administration) directly to the myocardium of 11 individuals with ischemic heart
      disease. Ad vector administration to the airways of individuals with CF evoked no
      or minimal serum neutralizing antibodies, even with repetitive administration. In
      contrast, intratumor administration of an Ad vector to individuals with
      metastatic colon cancer resulted in a robust antibody response, with anti-Ad
      neutralizing antibody titers of 10(2) to >10(4). Healthy individuals responded to
      single intradermal Ad vector variably, from induction of no neutralizing anti-Ad
      antibodies to titers of 5 x 10(3). Likewise, individuals with ischemic heart
      disease had a variable response to single intramyocardial vector administration,
      ranging from minimal neutralizing antibody levels to titers of 10(4). Evaluation
      of the data from all trials showed no correlation between the peak serum
      neutralizing anti-Ad response and the dose of Ad vector administered (P > 0.1,
      all comparisons). In contrast, there was a striking correlation between the peak
      anti-Ad5 neutralizing antibody levels evoked by vector administration and the
      level of preexisting anti-Ad5 antibodies (P = 0.0001). Thus, unlike the case for
      experimental animals, administration of Ad vectors to humans does not invariably
      evoke a systemic anti-Ad neutralizing antibody response. In humans, the extent of
      the response is dictated by preexisting antibody titers and modified by route of
      administration but is not dose dependent. Since the extent of anti-Ad
      neutralizing antibodies will likely modify the efficacy of administration of Ad
      vectors, these observations are of fundamental importance in designing human gene
      therapy trials and in interpreting the efficacy of Ad vector-mediated gene
      transfer.

PMID- 10400774
TI  - Structure of adenovirus complexed with its internalization receptor, alphavbeta5
      integrin.
AB  - The three-dimensional structure of soluble recombinant integrin alphavbeta5 bound
      to human adenovirus types 2 and 12 (Ad2 and -12) has been determined at
      approximately 21-A resolution by cryoelectron microscopy (cryo-EM). The
      alphavbeta5 integrin is known to promote Ad cell entry. Cryo-EM has shown that
      the integrin-binding RGD (Arg-Gly-Asp) protrusion of the Ad2 penton base protein
      is highly mobile (P. L. Stewart, C. Y. Chiu, S. Huang, T. Muir, Y. Zhao, B.
      Chait, P. Mathias, and G. R. Nemerow, EMBO J. 16:1189-1198, 1997). Sequence
      analysis indicated that the Ad12 RGD surface loop is shorter than that of Ad2 and
      probably less flexible, hence more suitable for structural characterization of
      the Ad-integrin complex. The cryo-EM structures of the two virus-receptor
      complexes revealed a ring of integrin density above the penton base of each virus
      serotype. As expected, the integrin density in the Ad2 complex was diffuse while
      that in the Ad12 complex was better defined. The integrin consists of two
      discrete subdomains, a globular domain with an RGD-binding cleft approximately 20
      A in diameter and a distal domain with extended, flexible tails. Kinetic analysis
      of Ad2 interactions with alphavbeta5 indicated approximately 4.2 integrin
      molecules bound per penton base at close to saturation. These results suggest
      that the precise spatial arrangement of five RGD protrusions on the penton base
      promotes integrin clustering and the signaling events required for virus
      internalization.

PMID- 10400775
TI  - Modified VP22 localizes to the cell nucleus during synchronized herpes simplex
      virus type 1 infection.
AB  - The UL49 gene product (VP22) of herpes simplex virus types 1 and 2 (HSV-1 and HSV
      2) is a virion phosphoprotein which accumulates inside infected cells at late
      stages of infection. We previously (J. A. Blaho, C. Mitchell, and B. Roizman, J.
      Biol. Chem. 269:17401-17410, 1994) discovered that the form of VP22 packaged into
      infectious virions differed from VP22 extracted from infected-cell nuclei in that
      the virion-associated form had a higher electrophoretic mobility in denaturing
      gels. Based on these results, we proposed that VP22 in virions was
      "undermodified" in some way. The goal of this study is to document the biological
      and biochemical properties of VP22 throughout the entire course of a productive
      HSV-1 infection. We now report the following. (i) VP22 found in infected cells is
      distributed in at least three distinct subcellular localizations, which we define
      as cytoplasmic, diffuse, and nuclear, as measured by indirect immunofluorescence.
      (ii) Using a synchronized infection system, we determined that VP22 exists
      predominantly in the cytoplasm early in infection and accumulates in the nucleus
      late in infection. (iii) While cytoplasmic VP22 colocalizes with the HSV-1
      glycoprotein D early in infection, the nuclear form of VP22 is not restricted to
      replication compartments which accumulate ICP4. (iv) VP22 migrates as at least
      three unique electrophoretic species in denaturing sodium dodecyl sulfate-DATD
      polyacrylamide gels. VP22a, VP22b, and VP22c have high, intermediate, and low
      mobility, respectively. (v) The relative distribution of the various forms of
      VP22 derived from infected whole-cell extracts varies during the course of
      infection such that low-mobility species predominate at early times and high
      mobility forms accumulate later. (vi) The highest-mobility forms of VP22
      partition with the cytoplasmic fraction of infected cells, while the lowest
      mobility forms are associated with the nuclear fraction. (vii) Finally, full
      length VP22 which partitions in the nucleus incorporates radiolabel from
      [32P]orthophosphate whereas cytoplasmic VP22 does not. Based on these results, we
      conclude that modification of VP22 coincides with its appearance in the nucleus
      during the course of productive HSV-1 infection.

PMID- 10400776
TI  - Functional analysis of cell surface-expressed hepatitis C virus E2 glycoprotein.
AB  - Hepatitis C virus (HCV) glycoproteins E1 and E2, when expressed in eukaryotic
      cells, are retained in the endoplasmic reticulum (ER). C-terminal truncation of
      E2 at residue 661 or 715 (position on the polyprotein) leads to secretion,
      consistent with deletion of a proposed hydrophobic transmembrane anchor sequence.
      We demonstrate cell surface expression of a chimeric glycoprotein consisting of
      E2 residues 384 to 661 fused to the transmembrane and cytoplasmic domains of
      influenza A virus hemagglutinin (HA), termed E2661-HATMCT. The E2661-HATMCT
      chimeric glycoprotein was able to bind a number of conformation-dependent
      monoclonal antibodies and a recombinant soluble form of CD81, suggesting that it
      was folded in a manner comparable to "native" E2. Furthermore, cell surface
      expressed E2661-HATMCT demonstrated pH-dependent changes in antigen conformation,
      consistent with an acid-mediated fusion mechanism. However, E2661-HATMCT was
      unable to induce cell fusion of CD81-positive HEK cells after neutral- or low-pH
      treatment. We propose that a stretch of conserved, hydrophobic amino acids within
      the E1 glycoprotein, displaying similarities to flavivirus and paramyxovirus
      fusion peptides, may constitute the HCV fusion peptide. We demonstrate that
      influenza virus can incorporate E2661-HATMCT into particles and discuss
      experiments to address the relevance of the E2-CD81 interaction for HCV
      attachment and entry.

PMID- 10400777
TI  - Simian virus 40 large T antigen J domain and Rb-binding motif are sufficient to
      block apoptosis induced by growth factor withdrawal in a neural stem cell line.
AB  - Serum-free mouse embryo (SFME) cells are a neural stem cell line that is
      dependent upon epidermal growth factor (EGF) for survival. Removal of EGF results
      in the G1 arrest and apoptosis of SFME cells. We have shown that the expression
      of simian virus 40 large T antigen in SFME cells blocks apoptosis and allows cell
      survival and division in the absence of EGF. Therefore the presence of T antigen
      abrogates the EGF requirement. The steady-state levels of p53, p21, and mdm-2 do
      not increase as SFME cells undergo apoptosis upon EGF withdrawal. Furthermore,
      the amino-terminal 136 amino acids (N136) of T antigen are sufficient to block
      death and to promote proliferation in the absence of EGF, while the carboxy
      terminal fragment (C251-708), which contains the p53 binding site, is unable to
      block death. Taken together, these data suggest that SFME cells deprived of EGF
      undergo p53-independent apoptosis. Mutations that disrupt either the J domain or
      Rb family binding abolish the ability of T antigen to block SFME cell apoptosis
      and to promote cell growth. We conclude that T antigen must act on one or more
      members of the Rb family to inhibit SFME cell apoptosis.

PMID- 10400778
TI  - The murine cytomegalovirus chemokine homolog, m131/129, is a determinant of viral
      pathogenicity.
AB  - Chemokines are important mediators of the early inflammatory response to
      infection and modify a wide range of host immune responses. Functional homologs
      of cellular chemokines have been identified in a number of herpesviruses,
      suggesting that the subversion of the host chemokine response contributes to the
      pathogenesis of these viruses. Transcriptional and reverse transcription-PCR
      analyses demonstrated that the murine cytomegalovirus (MCMV) chemokine homolog,
      m131, was spliced at the 3' end to the adjacent downstream open reading frame,
      m129, resulting in a predicted product of 31 kDa, which is significantly larger
      than most known chemokines. The in vivo impact of m131/129 was investigated by
      comparing the replication of MCMV mutants having m131/129 deleted (Deltam131/129)
      with that of wild-type (wt) MCMV. Our studies demonstrate that both wt and
      Deltam131/129 viruses replicated to equivalent levels during the first 2 to 3
      days following in vivo infection. However, histological studies demonstrated that
      the early inflammatory response elicited by Deltam131/129 was reduced compared
      with that of wt MCMV. Furthermore, the Deltam131/129 mutants failed to establish
      a high-titer infection in the salivary glands. These results suggest that
      m131/129 possesses proinflammatory properties in vivo and is important for the
      dissemination of MCMV to or infection of the salivary gland. Notably, the
      Deltam131/129 mutants were cleared more rapidly from the spleen and liver during
      acute infection compared with wt MCMV. The accelerated clearance of the mutants
      was dependent on NK cells and cells of the CD4(+) CD8(+) phenotype. These data
      suggest that m131/129 may also contribute to virus mechanisms of immune system
      evasion during early infection, possibly through the interference of NK cells and
      T cells.

PMID- 10400780
TI  - Roles of triplex and scaffolding proteins in herpes simplex virus type 1 capsid
      formation suggested by structures of recombinant particles.
AB  - Typical herpes simplex virus (HSV) capsids contain seven proteins that form a
      T=16 icosahedron of 1,250-A diameter. Infection of cells with recombinant
      baculoviruses expressing two of these proteins, VP5 (which forms the pentons and
      hexons in typical HSV capsids) and VP19C (a component of the triplexes that
      connect adjacent capsomeres), results in the formation of spherical particles of
      880-A diameter. Electron cryomicroscopy and computer reconstruction revealed that
      these particles possess a T=7 icosahedral symmetry, having 12 pentons and 60
      hexons. Among the characteristic structural features of the particle are the
      skewed appearance of the hexons and the presence of intercapsomeric mass
      densities connecting the middle domain of one hexon subunit to the lower domain
      of a subunit in the adjacent hexon. We interpret these connecting masses as being
      formed by VP19C. Comparison of the connecting masses with the triplexes, which
      occupy equivalent positions in the T=16 capsid, reveals the probable locations of
      the single VP19C and two VP23 molecules that make up the triplex. Their
      arrangement suggests that the two triplex proteins have different roles in
      controlling intercapsomeric interactions and capsid stability. The nature of
      these particles and of other aberrant forms made in the absence of scaffold
      demonstrates the conformational adaptability of the capsid proteins and
      illustrates how VP23 and the scaffolding protein modulate the nature of the VP5
      VP19C network to ensure assembly of the functional T=16 capsid.

PMID- 10400779
TI  - Human immunodeficiency virus type 1 intergroup (M/O) recombination in cameroon.
AB  - Here we describe, for the first time, recombinants between two highly divergent
      major groups of human immunodeficiency virus type 1 (HIV-1), M and O, within a
      Cameroonian woman infected with three different HIV-1 strains, a group O virus, a
      subtype D virus, and a recently reported IBNG (A/G)-like recombinant virus. Using
      nested extra-long PCR amplification, we sequenced from the pol region to the env
      region including accessory genes of the viral genome obtained from the patient's
      uncultured peripheral blood mononuclear cells and examined the phylogenetic
      position of each gene. Compared with sequential blood samples obtained in 1995
      and 1996, there were multiple segmental exchanges between three HIV-1 strains (O,
      D, and IBNG) and all the recombinants appeared to be derived from a common M/O
      ancestor. Importantly, recombination between groups M and O occurred, even though
      the homology between these two groups is 69, 76, 68, and 55% in the gag, pol, vif
      vpr, and env regions, respectively. Recombination between strains with such
      distant lineages may contribute substantially to generating new HIV-1 variants.

PMID- 10400781
TI  - Phosphorylation and/or presence of serine 37 in the movement protein of tomato
      mosaic tobamovirus is essential for intracellular localization and stability in
      vivo.
AB  - The P30 movement protein (MP) of tomato mosaic tobamovirus (ToMV) is synthesized
      in the early stages of infection and is phosphorylated in vivo. Here, we
      determined that serine 37 and serine 238 in the ToMV MP are sites of
      phosphorylation. MP mutants in which serine was replaced by alanine at positions
      37 and 238 (LQ37A238A) or at position 37 only (LQ37A) were not phosphorylated,
      and mutant viruses did not infect tobacco or tomato plants. By contrast, mutation
      of serine 238 to alanine did not affect the infectivity of the virus (LQ238A). To
      investigate the subcellular localization of mutant MPs, we constructed viruses
      that expressed each mutant MP fused with the green fluorescent protein (GFP) of
      Aequorea victoria. Wild-type and mutant LQ238A MP fusion proteins showed distinct
      temporally regulated patterns of MP-GFP localization in protoplasts and formation
      of fluorescent ring-shaped infection sites on Nicotiana benthamiana. However
      mutant virus LQ37A MP-GFP did not show a distinct pattern of localization or
      formation of fluorescent rings. Pulse-chase experiments revealed that MP produced
      by mutant virus LQ37A was less stable than wild-type and LQ238A MPs. MP which
      contained threonine at position 37 was phosphorylated, but the stability of the
      MP in vivo was very low. These studies suggest that the presence of serine at
      position 37 or phosphorylation of serine 37 is essential for intracellular
      localization and stability of the MP, which is necessary for the protein to
      function.

PMID- 10400782
TI  - Neural stem cells as engraftable packaging lines can mediate gene delivery to
      microglia: evidence from studying retroviral env-related neurodegeneration.
AB  - The induction of spongiform myeloencephalopathy by murine leukemia viruses is
      mediated primarily by infection of central nervous system (CNS) microglia. In
      this regard, we have previously shown that CasBrE-induced disease requires late,
      rather than early, virus replication events in microglial cells (W. P. Lynch et
      al., J. Virol. 70:8896-8907, 1996). Furthermore, neurodegeneration requires the
      presence of unique sequences within the viral env gene. Thus, the
      neurodegeneration-inducing events could result from microglial expression of
      retroviral envelope protein alone or from the interaction of envelope protein
      with other viral structural proteins in the virus assembly and maturation
      process. To distinguish between these possible mechanisms of disease induction,
      we engineered the engraftable neural stem cell line C17-2 into packaging/producer
      cells in order to deliver the neurovirulent CasBrE env gene to endogenous CNS
      cells. This strategy resulted in significant CasBrE env expression within CNS
      microglia without the appearance of replication competent virus. CasBrE envelope
      expression within microglia was accompanied by increased expression of activation
      markers F4/80 and Mac-1 (CD11b) but failed to induce spongiform neurodegenerative
      changes. These results suggest that envelope expression alone within microglia is
      not sufficient to induce neurodegeneration. Rather, microglia-mediated disease
      appears to require neurovirulent Env protein interaction with other viral
      proteins during assembly or maturation. More broadly, the results presented here
      prove the efficacy of a novel method by which neural stem cell biology may be
      harnessed for genetically manipulating the CNS, not only for studying
      neurodegeneration but also as a paradigm for the disseminated distribution of
      retroviral vector-transduced genes.

PMID- 10400783
TI  - In vivo monocyte tropism of pathogenic feline immunodeficiency viruses.
AB  - Virus-infected monocytes rarely are detected in the bloodstreams of animals or
      people infected with immunodeficiency-inducing lentiviruses, yet tissue
      macrophages are thought to be a major reservoir of virus-infected cells in vivo.
      We have identified feline immunodeficiency virus (FIV) clinical isolates that are
      pathogenic in cats and readily transmitted vertically. We report here that five
      of these FIV isolates are highly monocytotropic in vivo. However, while FIV
      infected monocytes were numerous in the blood of experimentally infected cats,
      viral antigen was not detectable in freshly isolated cells. Only after a short
      term (at least 12-h) in vitro monocyte culture were FIV antigens detectable (by
      immunocytochemical analysis or enzyme-linked immunosorbent assay). In vitro
      experiments suggested that monocyte adherence provided an important trigger for
      virus antigen expression. In the blood of cats infected with a prototype
      monocytotropic isolate (FIV subtype B strain 2542), infected monocytes appeared
      within 2 weeks, correlating with high blood mononuclear-cell-associated viral
      titers and CD4 cell depletion. By contrast, infected monocytes could not be
      detected in the blood of cats infected with a less pathogenic FIV strain (FIV
      subtype A strain Petaluma). We concluded that some strains of FIV are
      monocytotropic in vivo. Moreover, this property may relate to virus virulence,
      vertical transmission, and infection of tissue macrophages.

PMID- 10400784
TI  - The putative helicase of the coronavirus mouse hepatitis virus is processed from
      the replicase gene polyprotein and localizes in complexes that are active in
      viral RNA synthesis.
AB  - The coronavirus mouse hepatitis virus (MHV) translates its replicase gene (gene
      1) into two co-amino-terminal polyproteins, polyprotein 1a and polyprotein 1ab.
      The gene 1 polyproteins are processed by viral proteinases to yield at least 15
      mature products, including a putative RNA helicase from polyprotein 1ab that is
      presumed to be involved in viral RNA synthesis. Antibodies directed against
      polypeptides encoded by open reading frame 1b were used to characterize the
      expression and processing of the MHV helicase and to define the relationship of
      helicase to the viral nucleocapsid protein (N) and to sites of viral RNA
      synthesis in MHV-infected cells. The antihelicase antibodies detected a 67-kDa
      protein in MHV-infected cells that was translated and processed throughout the
      virus life cycle. Processing of the 67-kDa helicase from polyprotein 1ab was
      abolished by E64d, a known inhibitor of the MHV 3C-like proteinase. When infected
      cells were probed for helicase by immunofluorescence laser confocal microscopy,
      the protein was detected in patterns that varied from punctate perinuclear
      complexes to large structures that occupied much of the cell cytoplasm. Dual
      labeling studies of infected cells for helicase and bromo-UTP-labeled RNA
      demonstrated that the vast majority of helicase-containing complexes were active
      in viral RNA synthesis. Dual-labeling studies for helicase and the MHV N protein
      showed that the two proteins almost completely colocalized, indicating that N was
      associated with the helicase-containing complexes. This study demonstrates that
      the putative RNA helicase is closely associated with MHV RNA synthesis and
      suggests that complexes containing helicase, N, and new viral RNA are the viral
      replication complexes.

PMID- 10400785
TI  - Association with the cellular export receptor CRM 1 mediates function and
      intracellular localization of Epstein-Barr virus SM protein, a regulator of gene
      expression.
AB  - Splicing and posttranscriptional processing of eukaryotic gene transcripts are
      linked to their nuclear export and cytoplasmic expression. Unspliced pre-mRNAs
      and intronless transcripts are thus inherently poorly expressed. Nevertheless,
      human and animal viruses encode essential genes as single open reading frames or
      in the intervening sequences of other genes. Many retroviruses have evolved
      mechanisms to facilitate nuclear export of their unspliced mRNAs. For example,
      the human immunodeficiency virus RNA-binding protein Rev associates with the
      soluble cellular export receptor CRM 1 (exportin 1), which mediates
      nucleocytoplasmic translocation of Rev-HIV RNA complexes through the nuclear
      pore. The transforming human herpesvirus Epstein-Barr virus (EBV) expresses a
      nuclear protein, SM, early in its lytic cycle; SM binds RNA and
      posttranscriptionally activates expression of certain intronless lytic EBV genes.
      Here we show that both the trans-activation function and cytoplasmic
      translocation of SM are dependent on association with CRM 1 in vivo. SM is also
      shown to be associated in vivo with other components of the CRM 1 export pathway,
      including the small GTPase Ran and the nucleoporin CAN/Nup214. SM is shown to be
      present in the cytoplasm, nucleoplasm, and nuclear envelope of transfected cells.
      Mutation of a leucine-rich region (LRR) of SM inhibited CRM 1-mediated
      cytoplasmic translocation and SM activity, as did leptomycin B, an inhibitor of
      CRM 1 complex formation. Surprisingly, however, leptomycin B treatment and
      mutation of the LRR both led to SM becoming more tightly attached to intranuclear
      structures. These findings suggest a model in which SM is not merely a soluble
      carrier protein for RNA but rather is bound directly to intranuclear proteins,
      possibly including the nuclear pore complex.

PMID- 10400787
TI  - Long-term infection and transformation of dermal microvascular endothelial cells
      by human herpesvirus 8.
AB  - Human herpesvirus 8 (HHV8) infects Kaposi's sarcoma (KS) spindle cells in situ,
      as well as the lesional endothelial cells considered to be spindle cell
      precursors. The HHV8 genome contains several oncogenes, suggesting that infection
      of endothelial and spindle cells could induce cellular transformation and
      tumorigenesis and promote the formation of KS lesions. To investigate the
      potential of HHV8 infection of endothelial cells to contribute to the development
      of KS, we have developed an in vitro model utilizing dermal microvascular
      endothelial cells that support significant HHV8 infection. In contrast to
      existing in vitro systems used to study HHV8 pathogenesis, the majority of dermal
      endothelial cells are infected with HHV8 and the viral genome is maintained
      indefinitely. Infection is predominantly latent, with a small percentage of cells
      supporting lytic replication, and latency is responsive to lytic induction
      stimuli. Infected endothelial cells develop a spindle shape resembling that of KS
      lesional cells and show characteristics of a transformed phenotype, including
      loss of contact inhibition and acquisition of anchorage-independent growth. These
      results describe a relevant model system in which to study virus-host
      interactions in vitro and demonstrate the ability of HHV8 to induce phenotypic
      changes in infected endothelial cells that resemble characteristics of KS spindle
      cells in vivo. Thus, our results are consistent with a direct role for HHV8 in
      the pathogenesis of KS.

PMID- 10400786
TI  - Three-dimensional structure of Aleutian mink disease parvovirus: implications for
      disease pathogenicity.
AB  - The three-dimensional structure of expressed VP2 capsids of Aleutian mink disease
      parvovirus strain G (ADVG-VP2) has been determined to 22 A resolution by cryo
      electron microscopy and image reconstruction techniques. A structure-based
      sequence alignment of the VP2 capsid protein of canine parvovirus (CPV) provided
      a means to construct an atomic model of the ADVG-VP2 capsid. The ADVG-VP2
      reconstruction reveals a capsid structure with a mean external radius of 128 A
      and several surface features similar to those found in human parvovirus B19
      (B19), CPV, feline panleukopenia virus (FPV), and minute virus of mice (MVM).
      Dimple-like depressions occur at the icosahedral twofold axes, canyon-like
      regions encircle the fivefold axes, and spike-like protrusions decorate the
      threefold axes. These spikes are not present in B19, and they are more prominent
      in ADV compared to the other parvoviruses owing to the presence of loop
      insertions which create mounds near the threefold axes. Cylindrical channels
      along the fivefold axes of CPV, FPV, and MVM, which are surrounded by five
      symmetry-related beta-ribbons, are closed in ADVG-VP2 and B19. Immunoreactive
      peptides made from segments of the ADVG-VP2 capsid protein map to residues in the
      mound structures. In vitro tissue tropism and in vivo pathogenic properties of
      ADV map to residues at the threefold axes and to the wall of the dimples.

PMID- 10400788
TI  - A recombinant measles vaccine virus expressing wild-type glycoproteins:
      consequences for viral spread and cell tropism.
AB  - Wild-type, lymphotropic strains of measles virus (MV) and tissue culture-adapted
      MV vaccine strains possess different cell tropisms. This observation has led to
      attempts to identify the viral receptors and to characterize the functions of the
      MV glycoproteins. We have functionally analyzed the interactions of MV
      hemagglutinin (H) and fusion (F) proteins of vaccine (Edmonston) and wild-type
      (WTF) strains in different combinations in transfected cells. Cell-cell fusion
      occurs when both Edmonston F and H proteins are expressed in HeLa or Vero cells.
      The expression of WTF glycoproteins in HeLa cells did not result in syncytia, yet
      they fused efficiently with cells of lymphocytic origin. To further investigate
      the role of the MV glycoproteins in virus cell entry and also the role of other
      viral proteins in cell tropism, we generated recombinant vaccine MVs containing
      one or both glycoproteins from WTF. These viruses were viable and grew similarly
      in lymphocytic cells. Recombinant viruses expressing the WTFH protein showed a
      restricted spread in HeLa cells but spread efficiently in Vero cells. Parental
      WTF remained restricted in both cell types. Therefore, not only differential
      receptor usage but also other cell-specific factors are important in determining
      MV cell tropism.

PMID- 10400789
TI  - The H gene of rodent brain-adapted measles virus confers neurovirulence to the
      Edmonston vaccine strain.
AB  - Molecular determinants of neuropathogenesis have been shown to be present in the
      hemagglutinin (H) protein of measles virus (MV). An H gene insertion vector has
      been generated from the Edmonston B vaccine full-length infectious clone of MV.
      Using this vector, it is possible to insert complete H open reading frames into
      the parental (Edtag) background. The H gene from a rodent brain-adapted MV strain
      (CAM/RB) was inserted into this vector, and a recombinant virus (EdtagCAMH) was
      rescued by using a modified vaccinia virus which expresses T7 RNA polymerase (MVA
      T7). The recombinant virus grew at an equivalent rate and to similar titers as
      the CAM/RB and Edtag parental viruses. Neurovirulence was assayed in a mouse
      model for MV encephalitis. Viruses were injected intracerebrally into the right
      cortex of C57/BL/6 suckling mice. After infection mice inoculated with the CAM/RB
      strain developed hind limb paralysis and ataxia. Clinical symptoms were never
      observed with an equivalent dose of Edtag virus or in sham infections.
      Immunohistochemistry (IHC) was used to detect viral antigen in formalin-fixed
      brain sections. Measles antigen was observed in neurons and neuronal processes of
      the hippocampus, frontal, temporal, and olfactory cortices and neostriatum on
      both sides of symmetrical structures. Viral antigen was not detected in mice
      infected with Edtag virus. Mice infected with the recombinant virus, EdtagCAMH,
      became clinically ill, and virus was detected by IHC in regions of the brain
      similar to those in which it was detected in animals infected with CAM/RB. The
      EdtagCAMH infection had, however, progressed much less than the CAM/RB virus at 4
      days postinfection. It therefore appears that additional determinants are encoded
      in other regions of the MV genome which are required for full neurovirulence
      equivalent to CAM/RB. Nevertheless, replacement of the H gene alone is sufficient
      to cause neuropathology.

PMID- 10400790
TI  - Retrovirus targeting by tropism restriction to melanoma cells.
AB  - Targeted vectors will be necessary for many gene therapy applications. To target
      retroviruses to melanomas, we fused a single-chain variable fragment antibody
      (scFv) directed against the surface glycoprotein high-molecular-weight melanoma
      associated antigen (HMW-MAA) to the amphotropic murine leukemia virus envelope. A
      proline-rich hinge and matrix metalloprotease (MMP) cleavage site linked the two
      proteins. The modified viruses bound only to HMW-MAA-expressing cells, as
      inclusion of the proline-rich hinge prevented viral binding to the amphotropic
      viral receptor. Following attachment to HMW-MAA, MMP cleavage of the envelope at
      the melanoma cell surface removed the scFv and proline-rich hinge, allowing
      infection. Complexing of targeted retroviruses with 2, 3-dioleoyloxy-N
      [2(spermine-carboxamido)ethyl]N, N-dimethyl-1-propanaminium trifluoroacetate
      dioleoyl phosphatidylethanolamine liposomes greatly increased their efficiency
      without affecting their target cell specificity. In a cell mixture, 40% of HMW
      MAA-positive cells but less than 0.01% of HMW-MAA-negative cells were infected.
      This approach can therefore produce efficient, targeted retroviruses suitable for
      in vivo gene delivery and should allow specific gene delivery to many human cell
      types by inclusion of different scFv and protease combinations.

PMID- 10400791
TI  - Ovine adenovirus vectors overcome preexisting humoral immunity against human
      adenoviruses in vivo.
AB  - Recombinant human adenoviruses (hAd) have become widely used as tools to achieve
      efficient gene transfer. However, successful application of hAd-derived vectors
      in clinical trials is limited due to immunological and potential safety problems
      inherent in their human origin. In this study, we describe a recombinant ovine
      adenovirus (OAV) as an alternative vector for gene transfer in vivo. In contrast
      to an hAd vector, the OAV vector was not neutralized by human sera. An OAV vector
      which contained the cDNA of the human alpha1-antitrypsin (hAAT) gene linked to
      the Rous sarcoma virus promoter was generated and administered systemically to
      mice. The level and duration of hAAT gene expression was similar to that achieved
      with an hAd counterpart in both immunocompetent and immunodeficient mice.
      However, the tissue distribution of the OAV vector differed from that observed
      for hAd vectors in that the liver was not the dominant target. Significantly, we
      demonstrated efficient gene transfer with the OAV vector into mice immunized with
      hAd vectors and vice versa. We also confirm that the immune response to a
      transgene product can prevent its functional expression following sequential
      application of a vector. Our results suggest a possible solution to endemic
      humoral immunity against currently used hAd vectors and should therefore have an
      impact on the design of improved gene therapy protocols utilizing adenovirus
      vectors.

PMID- 10400792
TI  - Replication-competent rhabdoviruses with human immunodeficiency virus type 1
      coats and green fluorescent protein: entry by a pH-independent pathway.
AB  - We describe a replication-competent, recombinant vesicular stomatitis virus (VSV)
      in which the gene encoding the single transmembrane glycoprotein (G) was deleted
      and replaced by an env-G hybrid gene encoding the extracellular and transmembrane
      domains of a human immunodeficiency virus type 1 (HIV-1) envelope protein fused
      to the cytoplasmic domain of VSV G. An additional gene encoding a green
      fluorescent protein was added to permit rapid detection of infection. This novel
      surrogate virus infected and propagated on cells expressing the HIV receptor CD4
      and coreceptor CXCR4. Infection was blocked by SDF-1, the ligand for CXCR4, by
      antibody to CD4 and by HIV-neutralizing antibody. This virus, unlike VSV, entered
      cells by a pH-independent pathway and thus supports a pH-independent pathway of
      HIV entry. Additional recombinants carrying hybrid env-G genes derived from R5 or
      X4R5 HIV strains also showed the coreceptor specificities of the HIV strains from
      which they were derived. These surrogate viruses provide a simple and rapid assay
      for HIV-neutralizing antibodies as well as a rapid screen for molecules that
      would interfere with any stage of HIV binding or entry. The viruses might also be
      useful as HIV vaccines. Our results suggest wide applications of other surrogate
      viruses based on VSV.

PMID- 10400793
TI  - An avian sarcoma/leukosis virus-based gene trap vector for mammalian cells.
AB  - RCASBP-M2C is a retroviral vector derived from an avian sarcoma/leukosis virus
      which has been modified so that it uses the envelope gene from an amphotropic
      murine leukemia virus (E. V. Barsov and S. H. Hughes, J. Virol. 70:3922-3929,
      1996). The vector replicates efficiently in avian cells and infects, but does not
      replicate in, mammalian cells. This makes the vector useful for gene delivery,
      mutagenesis, and other applications in mammalian systems. Here we describe the
      development of a derivative of RCASBP-M2C, pGT-GFP, that can be used in gene trap
      experiments in mammalian cells. The gene trap vector pGT-GFP contains a green
      fluorescent protein (GFP) reporter gene. Appropriate insertion of the vector into
      genes causes GFP expression; this facilitates the rapid enrichment and cloning of
      the trapped cells and provides an opportunity to select subpopulations of trapped
      cells based on the subcellular localization of GFP. With this vector, we have
      generated about 90 gene-trapped lines using D17 and NIH 3T3 cells. Five trapped
      NIH 3T3 lines were selected based on the distribution of GFP in cells. The
      cellular genes disrupted by viral integration have been identified in four of
      these lines by using a 5' rapid amplification of cDNA ends protocol.

PMID- 10400794
TI  - Identification of a spliced gene from Kaposi's sarcoma-associated herpesvirus
      encoding a protein with similarities to latent membrane proteins 1 and 2A of
      Epstein-Barr virus.
AB  - Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) is
      a novel herpesvirus implicated as the causative agent of Kaposi's sarcoma (KS),
      primary effusion lymphoma, and some cases of multicentric Castleman's disease.
      KSHV persists in the majority of KS spindle (endothelial tumor) cells and
      lymphoid cells in a latent form, with only a limited set of viral genes expressed
      in a tissue-specific manner. Here, we report the identification of a family of
      alternatively-spliced transcripts of approximately 7.5 kb expressed in latently
      infected body cavity-based lymphoma (BCBL) cell lines which are predicted to
      encode membrane proteins with similarities to the LMP2A and LMP1 proteins of
      Epstein-Barr virus. In two highly divergent sequence variants of the right end of
      the KSHV genome, alternative splicing of eight exons located between KSHV ORF 75
      and the terminal repeats yields transcripts appropriate for proteins with up to
      12 transmembrane domains, followed by a hydrophilic C-terminal, presumably
      cytoplasmic, domain. This C-terminal domain contains several YxxI/L motifs
      reminiscent of LMP2A and a putative TRAF binding site as in LMP1. In latently
      (persistently) infected BCBL cells the predominant transcript utilizes all eight
      exons, whereas in phorbol-ester-induced cells, a shorter transcript, lacking
      exons 4 and 5, is also abundant. We also found evidence for an alternative use of
      exon 1. Transfection of an epitope-tagged cDNA construct containing all exons
      indicates that the encoded protein is localized on cell surface and intracellular
      membranes, and glutathione S-transferase pull-down experiments indicate that its
      cytoplasmic domain, like that of LMP1, interacts with TRAF1, -2, and -3. Two of
      20 KS patients had antibodies to the hydrophilic C-terminal domain, suggesting
      that the protein is expressed in vivo.

PMID- 10400795
TI  - Jaagsiekte sheep retrovirus is necessary and sufficient to induce a contagious
      lung cancer in sheep.
AB  - Sheep pulmonary adenomatosis (SPA) is a contagious and experimentally
      transmissible lung cancer of sheep resembling human bronchiolo-alveolar
      carcinoma. A type D retrovirus, known as jaagsiekte sheep retrovirus (JSRV), has
      been associated with the etiology of SPA, but its exact role in the induction of
      the tumor has not been clear due to the lack of (i) a tissue culture system for
      the propagation of JSRV and (ii) an infectious JSRV molecular clone. To
      investigate the role of JSRV in the etiology of SPA, we isolated a full-length
      JSRV proviral clone, pJSRV21, from a tumor genomic DNA library derived from a
      natural case of SPA. pJSRV21 was completely sequenced and showed open reading
      frames in agreement with those deduced for the original South African strain of
      JSRV. In vivo transfection of three newborn lambs by intratracheal inoculation
      with pJSRV21 DNA complexed with cationic lipids showed that pJSRV21 is an
      infectious molecular clone. Viral DNA was detected in the peripheral blood
      mononuclear cells (PBMCs) of the transfected animals by a highly sensitive JSRV
      U3 heminested PCR at various time points ranging from 2 weeks to 6 months
      posttransfection. In addition, proviral DNA was detected in the PBMCs, lungs, and
      mediastinal lymph nodes of two lambs sacrificed 9 months posttransfection, but no
      macroscopic or histological SPA lesion was induced. We prepared JSRV particles by
      transient transfection of 293T cells with a JSRV construct (pCMV2JS21) in which
      the upstream U3 was replaced with the cytomegalovirus early promoter. Four
      newborn lambs were inoculated with JSRV21 particles produced in this manner, and
      two of them showed the classical signs of SPA 4 months postinfection. The
      resulting tumors were positive for JSRV DNA and protein. Thus, JSRV21 is an
      infectious and pathogenic molecular clone and is necessary and sufficient to
      induce sheep pulmonary adenomatosis.

PMID- 10400796
TI  - VP1, the putative RNA-dependent RNA polymerase of infectious bursal disease
      virus, forms complexes with the capsid protein VP3, leading to efficient
      encapsidation into virus-like particles.
AB  - A cDNA corresponding to the coding region of VP1, the putative RNA-dependent RNA
      polymerase, of infectious bursal disease virus (IBDV) was cloned and inserted
      into the genome of a vaccinia virus inducible expression vector. The molecular
      mass and antigenic reactivity of VP1 expressed in mammalian cells are identical
      to those of its counterpart expressed in IBDV-infected cells. The results
      presented here demonstrate that VP1 is efficiently incorporated into IBDV virus
      like particles (VLPs) produced in mammalian cells coexpressing the IBDV
      polyprotein and VP1. Incorporation of VP1 into VLPs requires neither the presence
      of IBDV RNAs nor that of the nonstructural polypeptide VP5. Immunofluorescence,
      confocal laser scanning microscopy, and immunoprecipitation analyses conclusively
      showed that VP1 forms complexes with the structural polypeptide VP3. Formation of
      VP1-VP3 complexes is likely to be a key step for the morphogenesis of IBDV
      particles.

PMID- 10400797
TI  - Human MxA protein protects mice lacking a functional alpha/beta interferon system
      against La crosse virus and other lethal viral infections.
AB  - The human MxA protein is part of the antiviral state induced by alpha/beta
      interferon (IFN-alpha/beta). MxA inhibits the multiplication of several RNA
      viruses in cell culture. However, its antiviral potential in vivo has not yet
      been fully explored. We have generated MxA-transgenic mice that lack a functional
      IFN system by crossing MxA-transgenic mice constitutively expressing MxA with
      genetically targeted (knockout) mice lacking the beta subunit of the IFN
      alpha/beta receptor (IFNAR-1(-/-) mice). These mice are an ideal animal model to
      investigate the unique antiviral activity of human MxA in vivo, because they are
      unable to express other IFN-induced proteins. Here, we show that MxA confers
      resistance to Thogoto virus, La Crosse virus, and Semliki Forest virus. No
      Thogoto virus progeny was detectable in MxA-transgenic mice, indicating an
      efficient block of virus replication at the primary site of infection. In the
      case of La Crosse virus, MxA restricted invasion of the central nervous system.
      In contrast, Semliki Forest virus multiplication in the brain was detectable in
      both MxA-expressing and nonexpressing IFNAR-1(-/-) mice. However, viral titers
      were clearly reduced in MxA-transgenic mice. Our results demonstrate that MxA
      does not need the help of other IFN-induced proteins for activity but is a
      powerful antiviral agent on its own. Moreover, the results suggest that MxA may
      protect humans from potential fatal infections by La Crosse virus and other viral
      pathogens.

PMID- 10400798
TI  - Adenovirus-mediated gene expression in vivo is enhanced by the antiapoptotic bcl
      2 gene.
AB  - An adenovirus vector encoding the human Bcl-2 gene (hBcl-2) was derived. In vivo
      expression of hBcl-2 in murine livers enhanced and prolonged adenovirus-mediated
      gene expression. Furthermore, in the hBcl-2-treated group a significant reduction
      in the apoptosis induced by the adenovirus vector was observed. Thus, the
      cytoprotection of the vector-infected cells with antiapoptotic genes appears
      promising for successful in vivo gene therapy.

PMID- 10400799
TI  - Tamplicon-7, a novel T-lymphotropic vector derived from human herpesvirus 7.
AB  - We describe the derivation of a novel T-cell-defective virus vector employing the
      human herpesvirus 7 (HHV-7). The new vector, designated Tamplicon-7, replicates
      in CD4(+) T cells. The system is composed of a helper virus and defective virus
      genomes derived by the replication of the input Tamplicon vector. There are two
      cis-acting functions required for the replication and packaging of the defective
      virus genomes in the presence of the helper virus: the viral DNA replication
      origin and the composite cleavage and packaging signal, which directs the
      cleavage and packaging of defective virus genomes. Viral DNA replication is
      compatible with the rolling circle mechanism, producing large head-to-tail
      concatemers of the Tamplicon vector. Thus, in the presence of the helper virus,
      the replicated vectors are packaged and secreted into the medium. Furthermore, we
      have shown that the vector can be employed to express a foreign gene, encoding
      the green fluorescent protein, in the T cells infected with the HHV-7 helper
      virus. We predict that the Tamplicon-7 vector might be potentially useful for
      gene therapy of diseases affecting the human CD4(+) T cells, including autoimmune
      diseases, T-cell lymphomas, and AIDS.

PMID- 10400800
TI  - Interleukin-16 inhibits human immunodeficiency virus type 1 entry and replication
      in macrophages and in dendritic cells.
AB  - Recombinant interleukin-16 (rIL-16) has been found to inhibit human
      immunodeficiency virus type 1 (HIV-1) replication in acutely or endogenously
      infected CD4(+) T cells. However, the effect of rIL-16 on HIV-1 replication in
      antigen-presenting cells (APCs) is still unknown. We show here a potent HIV
      suppressive activity of rIL-16 in acutely infected monocyte-derived macrophages
      and dendritic cells determined by the levels of viral RNA transcripts or of viral
      reverse transcriptase in culture supernatants. The observed effect was dependent
      on the presence of rIL-16 early after infection and could not be induced by a 24
      h treatment of cells with the cytokine prior to infection. Using macrophage
      tropic and dually tropic primary isolates, we also showed that the addition of
      rIL-16 to cell cultures only during the infection period was effective in
      blocking virus entry and reducing proviral DNA levels in APCs. However, the anti
      HIV activity of rIL-16 could not be linked to the induction of virus-suppressive
      concentrations of beta-chemokines or to the inhibition of HIV-enhancing
      cytokines. These findings establish a critical role for rIL-16 in protecting APCs
      against HIV-1 infection and lend further support to its potential use in the
      treatment of HIV disease.

PMID- 10400801
TI  - Mutations within four distinct gag proteins are required to restore replication
      of human immunodeficiency virus type 1 after deletion mutagenesis within the
      dimerization initiation site.
AB  - Human immunodeficiency virus type 1 (HIV-1) genomic RNA segments at nucleotide
      (nt) positions +240 to +274 are thought to form a stem-loop secondary structure,
      termed SL1, that serves as a dimerization initiation site for viral genomic RNA.
      We have generated two distinct deletion mutations within this region, termed BH10
      LD3 and BH10-LD4, involving nt positions +238 to +253 and +261 to +274,
      respectively, and have shown that each of these resulted in significant
      diminutions in levels of viral infectiousness. However, long-term culture of each
      of these viruses in MT-2 cells resulted in a restoration of infectiousness, due
      to a series of compensatory point mutations within four distinct proteins that
      are normally cleaved from the Gag precursor. In the case of BH10-LD3, these four
      mutations were MA1, CA1, MP2, and MNC, and they involved changes of amino acid
      Val-35 to Ile within the matrix protein (MA), Ile-91 to Thr within the capsid
      (CA), Thr-12 to Ile within p2, and Thr-24 to Ile within the nucleocapsid (NC).
      The order in which these mutations were acquired by the mutated BH10-LD3 was MNC
      > CA1 > MP2 > MA1. The results of site-directed mutagenesis studies confirmed
      that each of these four substitutions contributed to the increased viability of
      the mutated BH10-LD3 viruses and that the MNC substitution, which was acquired
      first, played the most important role in this regard. Three point mutations, MP2,
      MNC, and MA2, were also shown to be sequentially acquired by viruses that had
      emerged in culture from the BH10-LD4 deletion. The first two of these were
      identical to those described above, while the last involved a change of Val-35 to
      Leu. All three of these substitutions were necessary to restore the
      infectiousness of mutated BH10-LD4 viruses to wild-type levels, although the MP2
      mutation alone, but neither of the other two substitutions, was able to confer
      some viability on BH10-LD4 viruses. Studies of viral RNA packaging showed that
      the BH10-LD4 deletion only marginally impaired encapsidation while the BH10-LD3
      deletion caused a severe deficit in this regard.

PMID- 10400802
TI  - Novel endogenous type C retrovirus in baboons: complete sequence, providing
      evidence for baboon endogenous virus gag-pol ancestry.
AB  - A complete endogenous type C viral genome has been isolated from a baboon genomic
      library. The provirus, Papio cynocephalus endogenous retrovirus (PcEV), is 8,572
      nucleotides long, and 38 to 59 proviral copies per baboon genome are found. The
      PcEV provirus possesses the typical simple retroviral gene organization,
      including two long terminal repeats and genes encoding gag, pol, and env
      proteins. The open reading frames for gag-pol and env are complete but have
      premature stop codons or frameshift mutations. The primer binding site of PcEV is
      complementary to tRNAGly. The gag and pol genes of PcEV are closely related to
      those of the baboon endogenous virus (BaEV). The env coding region of PcEV is
      related to the env genes of type C retroviruses. This suggests that PcEV is one
      of the ancestors of BaEV contributing the type C gag-pol genome fragment to the
      type C/D recombinant virus BaEV. Earlier it was shown that another endogenous
      type D virus (simian endogenous retrovirus) provided the env gene for BaEV (A. C.
      van der Kuyl et al., J. Virol. 71:3666-3676, 1997).

PMID- 10400803
TI  - Cytomegalovirus (CMV) DNA load is an independent predictor of CMV disease and
      survival in advanced AIDS.
AB  - The impact of cytomegalovirus (CMV) on human immunodeficiency virus type 1 (HIV
      1) disease progression has been controversial. In this study, we sought to
      determine if CMV viral load is independent of HIV-1 viral load in predicting CMV
      disease and survival. Our findings indicate that in patients with advanced AIDS,
      CMV DNA load is an independent marker of CMV disease and survival and is more
      predictive than HIV-1 RNA load. Moreover, patients who respond to preemptive
      therapy with oral ganciclovir, with resulting undetectable levels of CMV DNA, in
      their plasma, have a significantly lower risk of developing CMV disease and
      higher rates of survival, despite stable or increasing HIV-1 RNA loads. These
      data provide support for CMV as an independent risk factor for mortality in
      persons with advanced AIDS and further suggest that effective preemptive therapy
      for CMV can improve patient survival rates.

PMID- 10400804
TI  - E4ORF3 requirement for achieving long-term transgene expression from the
      cytomegalovirus promoter in adenovirus vectors.
AB  - Analysis of transgene expression under the control of the cytomegalovirus (CMV)
      promoter from adenovirus vectors in which the E4 region was modified indicated
      that E4ORF3 is required for long-term expression in the murine lung. CMV promoter
      truncation led to the persistence of expression in the absence of E4, thus
      eliminating the ORF3 requirement.

PMID- 10400805
TI  - Human parainfluenza virus type 1 matrix and nucleoprotein genes transiently
      expressed in mammalian cells induce the release of virus-like particles
      containing nucleocapsid-like structures.
AB  - The matrix (M) protein plays an essential role in the assembly and budding of
      some enveloped RNA viruses. We expressed the human parainfluenza virus type 1
      (hPIV-1) M and/or NP genes into 293T cells using the mammalian expression vector
      pCAGGS. Biochemical and electron microscopic analyses of transfected cells showed
      that the M protein alone can induce the budding of virus-like particles
      (vesicles) from the plasma membrane and that the NP protein can assemble into
      intracellular nucleocapsid-like (NC-like) structures. Furthermore, the
      coexpression of both the M and NP genes resulted in the production of vesicles
      enclosing NC-like structures, suggesting that the hPIV-1 M protein has the
      intrinsic ability to induce membrane vesiculation and to incorporate NC-like
      structures into these budding vesicles.

PMID- 10400806
TI  - Protection of rabbits from viral challenge by gene gun-based intracutaneous
      vaccination with a combination of cottontail rabbit papillomavirus E1, E2, E6,
      and E7 genes.
AB  - In this study, cottontail rabbit papillomavirus infection of domestic rabbits was
      used as an animal model to develop papillomavirus early gene-based vaccines.
      Groups of rabbits were intracutaneously vaccinated with single papillomavirus
      early genes E1, E2, E6, and E7 or with a combination of these four genes. Only a
      fraction of rabbits were protected from subsequent viral challenge when
      vaccinated with the E1 or E6 gene. Viral tumor growth in those rabbits vaccinated
      with the E1 or E2 gene was suppressed compared to that in controls. In contrast,
      seven of nine rabbits vaccinated with the combination of the E1, E2, E6, and E7
      genes were completely protected against viral challenge. These data indicated
      that intracutaneous genetic vaccination with the combination of the E1, E2, E6,
      and E7 genes can be an effective strategy for immunoprophylaxis of papillomavirus
      infection.

PMID- 10400807
TI  - Specific interaction between the hepatitis C virus NS5B RNA polymerase and the 3'
      end of the viral RNA.
AB  - Hepatitis C virus (HCV) NS5B protein is the viral RNA-dependent RNA polymerase
      capable of directing RNA synthesis. In this study, an electrophoretic mobility
      shift assay demonstrated the interaction between a partially purified recombinant
      NS5B protein and a 3' viral genomic RNA with or without the conserved 98
      nucleotide tail. The NS5B-RNA complexes were specifically competed away by the
      unlabeled homologous RNA but not by the viral 5' noncoding region and very poorly
      by the 3' conserved 98-nucleotide tail. A 3' coding region with conserved stem
      loop structures rather than the 3' noncoding region of the HCV genome is critical
      for the specific binding of NS5B. Nevertheless, no direct interaction between the
      3' coding region and the HCV NS5A protein was detected. Furthermore, two
      independent RNA-binding domains (RBDs) of NS5B were identified, RBD1, from amino
      acid residues 83 to 194, and RBD2, from residues 196 to 298. Interestingly, the
      conserved motifs of RNA-dependent RNA polymerase for putative RNA binding (220
      DxxxxD-225) and template/primer position (282-S/TGxxxTxxxNS/T-292) are present in
      the RBD2. Nevertheless, the RNA-binding activity of RBD2 was abolished when it
      was linked to the carboxy-terminal half of the NS5B. These results provide some
      clues to understanding the initiation of HCV replication.

PMID- 10400809
TI  - Systematic excision of vector sequences from the BAC-cloned herpesvirus genome
      during virus reconstitution.
AB  - Recently the mouse cytomegalovirus (MCMV) genome was cloned as an infectious
      bacterial artificial chromosome (BAC) (M. Messerle, I. Crnkovic, W.
      Hammerschmidt, H. Ziegler, and U. H. Koszinowski, Proc. Natl. Acad. Sci. USA
      94:14759-14763, 1997). The virus obtained from this construct is attenuated in
      vivo due to deletion of viral sequences and insertion of the BAC vector. We
      reconstituted the full-length MCMV genome and flanked the BAC vector with
      identical viral sequences. This new construct represents a versatile basis for
      construction of MCMV mutants since virus generated from the construct loses the
      bacterial sequences and acquires wild-type properties.

PMID- 10400808
TI  - Mass determination of rous sarcoma virus virions by scanning transmission
      electron microscopy.
AB  - The internal structural protein of retroviruses, Gag, comprises most of the mass
      of the virion, and Gag itself can give rise to virus-like particles when
      expressed in appropriate cells. Previously the stoichiometry of Gag in virions
      was inferred from indirect measurements carried out 2 decades ago. We now have
      directly determined the masses of individual particles of the prototypic avian
      retrovirus, Rous sarcoma virus (RSV), by using scanning transmission electron
      microscopy. In this technique, the number of scattered electrons in the dark
      field image integrated over an individual freeze-dried virus particle on a grid
      is directly proportional to its mass. The RSV virions had a mean mass of 2.5 x
      10(8) Da, corresponding to about 1,500 Gag molecules per virion. The population
      of virions was not homogeneous, with about one-third to two-thirds of the virions
      deviating from the mean by more than 10% of the mass in two respective
      preparations. The mean masses for virions carrying genomes of 7.4 or 9.3 kb were
      indistinguishable, suggesting that mass variability is not due to differences in
      RNA incorporation.

PMID- 10400810
TI  - The integration machinery of ZAM, a retroelement from Drosophila melanogaster,
      acts as a sequence-specific endonuclease.
AB  - Retroviruses and retrotransposons insert into the host genome with no obvious
      sequence specificity. We examined the target sites of the retroelement ZAM by
      sequencing each host-ZAM junction in the genome of Drosophila melanogaster. Our
      overall data provide compelling evidence that ZAM integration machinery
      recognizes and leads to ZAM insertion into the sequence 5'-GCGCGCg-3'. This
      unique property of ZAM will facilitate the development of new tools to study the
      integration process of retroelements.

PMID- 10400811
TI  - Virus-specific cytotoxic T lymphocytes in human immunodeficiency virus type 1
      infected chimpanzees.
AB  - Chimpanzees have been important in studies of human immunodeficiency virus type 1
      (HIV-1) pathogenesis and in evaluation of HIV-1 candidate vaccines. However,
      little information is available about HIV-1-specific cytotoxic T lymphocytes
      (CTL) in these animals. In the present study, in vitro stimulation of peripheral
      blood mononuclear cells (PBMC) from infected chimpanzees with HIV-1 Gag peptides
      was shown to be a sensitive, reproducible method of expanding HIV-1-specific
      CD8(+) effector CTL. Of interest, PBMC from two chimpanzees had CTL activity
      against Gag epitopes also recognized by major histocompatibility complex class I
      restricted CTL from HIV-1-infected humans. The use of peptide stimulation will
      help to clarify the role of CTL in vaccine-mediated protection and HIV-1 disease
      progression in this important animal model.

PMID- 10400812
TI  - Resistance of ribosomal protein mRNA translation to protein synthesis shutoff
      induced by poliovirus.
AB  - Poliovirus infection induces an overall inhibition of host protein synthesis,
      although some mRNAs continue to be translated, suggesting different translation
      requirements for cellular mRNAs. It is known that ribosomal protein mRNAs are
      translationally regulated and that the phosphorylation of ribosomal protein S6 is
      involved in the regulation. Here, we report that the translation of ribosomal
      protein mRNAs resists poliovirus infection and correlates with an increase in
      p70(s6k) activity and phosphorylation of ribosomal protein S6.

PMID- 10400813
TI  - Expression of the coxsackievirus and adenovirus receptor in cultured human
      umbilical vein endothelial cells: regulation in response to cell density.
AB  - Primary cultures of human umbilical vein endothelial cells (HUVEC) express the
      human coxsackievirus and adenovirus receptor (HCAR). Whereas HCAR expression in
      HeLa cells was constant with respect to cell density, HCAR expression in HUVEC
      increased with culture confluence. HCAR expression in HUVEC was not
      quantitatively altered by infection with coxsackievirus B.

PMID- 10400814
TI  - Human immunodeficiency virus type 1 tat protein activates transcription factor NF
      kappaB through the cellular interferon-inducible, double-stranded RNA-dependent
      protein kinase, PKR.
AB  - The transactivator protein of human immunodeficiency virus type 1 (HIV-1) (Tat)
      is a powerful activator of nuclear factor-kappaB (NF-kappaB), acting through
      degradation of the inhibitor IkappaB-alpha (F. Demarchi, F. d'Adda di Fagagna, A.
      Falaschi, and M. Giacca, J. Virol. 70:4427-4437, 1996). Here, we show that this
      activity of Tat requires the function of the cellular interferon-inducible
      protein kinase PKR. Tat-mediated NF-kappaB activation and transcriptional
      induction of the HIV-1 long terminal repeat were impaired in murine cells in
      which the PKR gene was knocked out. Both functions were restored by
      cotransfection of Tat with the cDNA for PKR. Expression of a dominant-negative
      mutant of PKR specifically reduced the levels of Tat transactivation in different
      human cell types. Activation of NF-kappaB by Tat required integrity of the basic
      domain of Tat; previous studies have indicated that this domain is necessary for
      specific Tat-PKR interaction.

PMID- 10400815
TI  - Interaction of human immunodeficiency virus-derived vectors with wild-type virus
      in transduced cells.
AB  - The interaction of human immunodeficiency virus (HIV)-derived vectors with wild
      type virus was analyzed in transduced cells. Vector transcripts upregulated by
      infection had no measurable effect on HIV type 1 (HIV-1) expression but competed
      efficiently for encapsidation, inhibiting the infectivity and spread of HIV-1 in
      culture and leading to mobilization and recombination of the vector. These
      effects were abrogated with a self-inactivating vector.

PMID- 10400816
TI  - STAT6-deficient mice exhibit normal induction of murine AIDS and expression of
      immunoglobulin E following infection with LP-BM5 murine leukemia viruses.
AB  - The unique Gag polyprotein of the replication-defective virus responsible for
      murine AIDS (MAIDS) induces B-cell activation, proliferation, and
      differentiation, including immunoglobulin class switch-recombination to
      immunoglobulin E (IgE). Secretion of IgE normally requires the serial induction
      of interleukin 4 (IL-4), engagement of the IL-4 receptor, activation of signal
      transducer and activator of transcription (STAT) 6, and induction of Iepsilon
      germline transcripts as a prelude to switching. Remarkably, expression of IgE is
      equivalent in normal and IL-4-deficient mice with MAIDS (Morawetz et al., J. Exp.
      Med. 184:1651-1661, 1996). To understand this anomaly, we studied mice with a
      null mutation of STAT6. Lymphoproliferation and immunodeficiency, the hallmarks
      of MAIDS, developed with comparable kinetics and degree in normal and mutant
      mice. In addition, serum IgE levels were indistinguishable in mice of either
      genotype. We conclude that B cells from mice with MAIDS activate unique IL-4- and
      STAT6-independent signaling pathways for B-cell activation and differentiation.

PMID- 10400818
TI  - Different cytokine patterns correlate with the extension of disease in pulmonary
      tuberculosis.
AB  - The relative amounts of different pro- and anti-inflammatory cytokines released
      at the site of infection by bronchoalveolar lavage (BAL) cells may influence the
      presentation of tuberculosis. To investigate this hypothesis the in situ release
      by BAL cells of the following cytokines was measured and correlated with the
      chest X-ray findings of 43 patients with pulmonary tuberculosis: interleukin (IL)
      8, macrophage inflammatory protein-1alpha (MIP-1alpha), IL-6, tumor necrosis
      factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interferon
      gamma (IFN-gamma), IL-2, IL-4 and IL-5. The release of IL-8 and IL-6 decreased
      with the progression of the disease, while the release of MIP-1alpha was
      increased in patients with advanced tuberculosis. The release of TNF-alpha and
      TGF-beta did not differ between patients with or without cavitary lesions. The
      Th1 (IFN-gamma and IL-2) and Th2 (IL-4 and IL-5) cytokine release exhibited a
      gradual increment with the advance of tuberculosis. Thus, our data provide
      evidence that a Th0 cytokine pattern is predominant at the site of pulmonary
      tuberculosis. In conclusion, immunoparalysis status could not be observed in our
      patients with severe tuberculosis.

PMID- 10400817
TI  - Cytokines and bullous pemphigoid.
AB  - This report reviews the data presented in the literature concerning the presence
      and levels of different cytokines in sera, lesional tissue or blister fluids of
      patients with bullous pemphigoid. The list of cytokines analysed includes 21
      molecules: interleukins (IL)-1 => 8, IL-10 => 13, IL-15, granulocyte-monocyte
      colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), oncostatin-M
      (OSM), regulated upon activation normal T cell expressed and presumably secreted
      (RANTES), transforming growth factor-beta 1 (TGF-beta 1), tumor necrosis factor
      alpha (TNF-alpha) and vascular endothelial growth factor (VEGF). Basic
      information regarding the functions of these cytokines and their possible
      involvement in the pathogenetic steps of the disease, such as autoantigen
      expression, autoantibody induction, complement activation, local cell recruitment
      and stimulation, resident cell activation, release of various effector molecules
      and tissue damage are also reported. A specific function for each cytokine in
      bullous pemphigoid induction cannot be still defined, however, the literature
      attributes a major role to IL-1, IL-4, IL-5, IL-6, IL-8 and IFN-gamma. On the
      basis of significant (direct or inverse) correlations found between disease
      intensity and the blister fluid/serum levels, the following cytokines IL-7, IL
      15, RANTES, VEGF and TNF-alpha, besides those previously mentioned, may also be
      involved in this disease.

PMID- 10400819
TI  - TNF-alpha and HLA-DR genotyping as potential prognostic markers in pulmonary
      sarcoidosis.
AB  - We have analyzed the HLA-DRB1 alleles and -308 TNF-alpha gene polymorphism in 78
      sarcoidosis patients and 50 controls. The sarcoidosis group as a whole did not
      show any significant correlation with the TNF-A or the HLA-DR alleles compared to
      the control group. However, the patient subgroups of Lofgren and non-Lofgren
      sarcoidosis exhibited significant allele associations. In the Lofgren patient
      group, the TNF-A2 and the HLA-DR3 alleles were represented significantly higher,
      with a highly significant relative risk resulting from the presence of the TNF-A2
      or the HLA-DR3 allele or both. In the non-Lofgren patient group, the phenotype
      expressing HLA-DR2 and lacking TNF-A2 was significantly higher than in the
      Lofgren patient group. Due to these significant genetic differences in the
      subgroups of Lofgren and non-Lofgren sarcoidosis patients, we conclude that the
      genotyping of these two loci (-308 TNF-alpha promoter polymorphism and HLA-DR)
      may be of prognostic value for the course of disease in sarcoidosis.

PMID- 10400820
TI  - Infection of mice with Mycobacterium bovis-BCG induces both Th1 and Th2 immune
      responses in the absence of interferon-gamma signalling.
AB  - A murine pulmonary infection model using Mycobacterium bovis-BCG was used to
      study the development of Th1 and Th2 type responses in mice lacking a functional
      IFN-gamma receptor (IFN-gamma R-/-). Strikingly, the IFN-gamma R-/- mice
      maintained the Th1 response and developed a profound M. bovis-BCG, specific Th2
      type immune response characterized by IL-5-producing CD4+ T cells, eosinophil
      infiltration of granulomas, and significantly elevated serum IgE levels. The
      increase in IL-5 production and eosinophil recruitment into the lung could be
      detected within the first 1-2 weeks of infection, indicating that the Th2
      response was not due to greatly enhanced bacterial numbers observed later in
      infection. These results clearly indicate that IFN-gamma acts during M. bovis-BCG
      infection to suppress the development of Th2 immune responses. Furthermore, they
      demonstrate that IFN-gamma is not a necessary cofactor in the development of Th1
      type cells secreting IFN-gamma. In conclusion, these data demonstrate that IFN
      gamma plays a major role in suppressing a potentially disease-promoting Th2
      immune response during mycobacterial infections.

PMID- 10400821
TI  - Frequency of cytokine-producing CD4-CD8- peripheral blood mononuclear cells in
      patients with Plasmodium falciparum malaria.
AB  - The frequency of cytokine-producing CD4-/CD8- mononuclear cells was assessed in
      patients of different age groups (29 infants, aged 1-5 years; 30 schoolchildren,
      aged 6-14 years, 26 adults, aged > 15 years) with acute Plasmodium falciparum
      malaria, from Gabon. Fifteen patients were followed up before antimalarial
      treatment (day 0), during parasite clearance (day 3) and after resolution of
      parasitemia (day 10). By using flow cytometry for intracellular detection of
      cytokines, a striking expansion of CD4-/CD8- cells producing the type 1 cytokines
      interleukin (IL)-2-/interferon (IFN)-gamma+, IL-2+/IFN-gamma+ and IL-2+/IFN-gamma
      was observed in adults as compared with children. Type 2 cytokine expression (IL
      4+/IFN-gamma-, IL-13+/IFN-gamma-) and type 0 cells (IL-4+/IFN-gamma+, IL-13+/IFN
      gamma+) were not significantly different between the three age groups. Patients
      with severe malaria had a significantly increased frequency of type 2 cytokine
      producing CD4-/CD8- cells. Drug-induced clearance of parasitemia was
      characterized by a decrease of IL-2+/IFN-gamma- and type 2 cytokine expressing
      CD4-/CD8- cells and by a gradual increase of IL-10+/IFN-gamma- expression. The
      type 1/type 2 dichotomy observed within the CD4-/CD8- cell population is likely
      to be of significance in the host response against P. falciparum malaria.

PMID- 10400822
TI  - Systemic delivery of an adenovirus expressing EBV-derived vIL-10 in mice infected
      with Schistosoma mansoni or Leishmania amazonensis: controversial effects on the
      development of pathological parameters.
AB  - Within the context of microorganism/host interactions, those which last over
      weeks are expected to be sensitive to more or less sustained and targeted immuno
      intervention, such as delivery of cytokines known to operate as down-regulators
      of acute inflammatory processes. IL-10 has received growing attention as a
      potential tool in immunotherapy, due to its anti-inflammatory and
      immunosuppressive properties. Therefore, using two experimental models of long
      term interactions between parasites and laboratory mice, we monitored some
      effects of the systemic delivery of an adenovirus (Ad) expressing EBV-derived IL
      10 (vIL-10) designated Ad-vIL-10. We first monitored the vIL-10 serum level
      following intranasal, intraperitoneal, intramuscular and intravenous
      administration. The i. p. and i.v. delivery of Ad-vIL-10 allowed a high serum
      level of vIL-10 (= 100 ng/ml), the i.v. route leading to a more sustained
      expression (up to 3 weeks). As a first model of parasite/mouse interaction,
      Schistosoma mansoni/C57Bl/6 mouse was selected. Ad-vIL-10 delivery was performed
      4 weeks after S. mansoni infection i.e. at the time of egg-laying, and several
      parameters were monitored: (i) number of adult worms in the mesenteric vein, (ii)
      number of eggs trapped in the liver and intestine, (iii) liver fibrosis, (iv)
      serum levels of egg-reactive antibody subclasses, (v) serum content of cytokines,
      and (vi) cytokine production in the supernatant of antigen-stimulated mesenteric
      lymph node cells. No apparent effect was observed, either on the different
      parasitological parameters or on fibrosis development at day 70 of infection.
      Surprisingly, a marked increase in both Th1 and Th2 type cytokines was observed
      in the sera of the Ad-vIL-10 injected animals, as well as in the supernatants of
      their Ag-stimulated mesenteric lymph node cells. Nevertheless, polarization of
      the humoral response towards a Th2 profile was demonstrated by an increase in the
      IgE level in the Ad-vIL-10-injected animals. As far as the second model is
      concerned, namely the Leishmania amazonensis /C57Bl6 mouse interactions, Ad-vIL
      10 was delivered intravenously one day before subcutaneous injection of
      stationary promastigotes and footpad swelling was monitored over 110 days. Under
      these conditions, vIL-10 exhibited a biphasic effect, decreasing the lesion size
      at the early stages of infection, but leading to a more pronounced lesion size
      during the chronic phase. This observation suggests a deactivation of the
      macrophage host cells under the influence of vIL-10. The results are discussed in
      the context of immunotherapy and the paradoxical effects observed in
      immunointervention with vIL-10.

PMID- 10400823
TI  - Role of endogenous interleukin-12 (IL-12) in induced and spontaneous relapses of
      experimental autoimmune encephalomyelitis in mice.
AB  - Actively induced, chronic relapsing experimental autoimmune encephalomyelitis
      (CREAE) was studied in SJL/J and in Biozzi ABH mice. In Biozzi ABH mice, relapses
      occurred spontaneously with high frequency. In SJL/J mice, spontaneous relapses
      occurred infrequently; however they could be induced reproducibly by
      reimmunization. In both models, moderately increased levels of serum IL-12(p40)
      were consistently found shortly before primary attacks, but irregularly at later
      times. Injections of anti-IL-12 antibody inhibited disease development in both
      SJL/J and in Biozzi ABH mice. The time window during which treatment needed to be
      initiated in order to be effective, ranged from before induction until shortly
      before the symptoms of primary attacks emerged. Such treatment inhibited not only
      the first attack but also the spontaneous or induced relapses. Most
      significantly, anti-IL-12 antibody given during remission of primary disease
      inhibited actively re-induced relapses in SJL/J, but not spontaneous relapses in
      Biozzi ABH mice. These results indicate that endogenous IL-12 favours EAE
      development by crucially affecting the active induction process, but that a
      second burst of IL-12 production may not be necessary for triggering spontaneous
      relapses.

PMID- 10400824
TI  - Enhancement by IL-12 of the cytolytic T lymphocyte (CTL) response of mice
      immunized with tumor-specific peptides in an adjuvant containing QS21 and MPL.
AB  - Immunization of cancer patients with tumor-specific antigenic peptides is
      currently being tested in several clinical studies. We have examined the
      induction of CTL responses in mice after various modalities of peptide
      vaccination, to explore protocols that could be applied to humans. Our first
      model antigen was P198, which results from a point mutation in a normal gene.
      While two immunizations with peptide P198 in SBAS-1c adjuvant induced measurable
      CTL responses in less than 10% of DBA/2 mice, the addition of IL-12 to the
      peptide adjuvant mixture resulted in high CTL responses in nearly all mice. This
      strong enhancing effect of IL-12 was observed with 1,000 and 300 units and
      decreased gradually as the doses were reduced to 30 units. When IL-12 was
      replaced by other cytokines acting on T cells or antigen-presenting cells, such
      as IFN-gamma, IL-2, IL-6, IL-7, GM-CSF or MCP-3, no significant enhancing effect
      was observed. The same effect of IL-12 was obtained with peptide P1A, which is a
      major tumor-specific antigen of mastocytoma P815 and is encoded by a gene that is
      specifically activated in tumors.

PMID- 10400826
TI  - Cytokines in Gaucher's disease.
AB  - Gaucher's disease (GD) is characterized by hepatosplenomegaly, bone marrow
      infiltration, osteonecrosis, which may all be associated with the presence of
      pathological macrophages that contain undegraded glycosphingolipids. Levels of
      serum cytokines, which are soluble products of mononuclear phagocytes (MNP), were
      evaluated in 24 GD patients. Levels of interleukin-1beta (IL-1beta), interleukin
      1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), tumor necrosis factor-alpha
      (TNF-alpha), and soluble interleukin-2 receptor (sIL-2R) in GD patients were
      significantly higher than in normal controls. We attempted to correlate cytokine
      levels with disease severity. Type I GD patients with more severe clinical
      manifestations had significantly higher levels of IL-1beta, IL-1Ra and IL-6,
      relative to type I patients with milder disease. Three patients homozygous for
      the 1448C mutation with neuropathic type III disease, had significantly higher
      levels of sIL-2R than type I patients or controls. We speculate that cytokine
      over-expression may relate to the pathophysiology of some of the clinical
      manifestations of GD. Thus, the elevated IL-1beta, TNF-alpha and IL-6 levels may
      induce the bone manifestations, the neutrophil chemotaxis and the increased
      incidence of hyper-gammaglobulinemia present in GD patients.

PMID- 10400825
TI  - Role of interleukin-6 in a non-septic shock model induced by zymosan.
AB  - In the present study, we used IL-6 knock-out mice (IL-6KO) to evaluate a possible
      role of IL-6 in the pathogenesis of non-septic shock induced by peritoneal
      injection of zymosan. A severe inflammatory response characterized by peritoneal
      exudation, high peritoneal levels of nitrate/nitrite, and leukocyte infiltration
      into peritoneal exudate was induced by zymosan administration in wild-type
      control (WT) mice. This inflammatory process coincided with the damage to the
      lung and small intestine, as assessed by histological examination. Lung, small
      intestine and liver myeloperoxidase (MPO) activity, indicative of neutrophil
      infiltration and lipid peroxidation, were significantly increased in zymosan
      treated WT mice. Peritoneal administration of zymosan in the WT mice also induced
      a significant increase in the plasma levels of nitrite/nitrate and in the levels
      of peroxynitrite, 18 hours after zymosan challenge. Immunohistochemical
      examination demonstrated a marked increase in the immunoreactivity to
      nitrotyrosine in the lung of zymosan-treated WT mice. Zymosan-treated IL-6KO
      showed significantly decreased mortality and inhibition of the development of
      peritonitis. In addition, IL-6KO mice showed significant protection from the
      development of organ failure, since tissue injury and MPO was reduced in the
      lung, small intestine and liver. 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 IL-6KO mice subjected to zymosan-induced non-septic shock.
      In vivo treatment with anti-IL-6 (5,000 ng/day per mouse, 24 and 1 hour before
      zymosan administration) significantly reduced the inflammatory process. Taken
      together, the present study clearly demonstrates that IL-6 exerts a role in
      zymosan-induced non-septic shock.

PMID- 10400827
TI  - Differential regulation of tumor necrosing factor-alpha (TNF-alpha) and
      interleukin-10 (IL-10) secretion by protein kinase and phosphatase inhibitors in
      human alveolar macrophages.
AB  - IL-10, a cytokine first identified as a product of cloned Th2 lymphocytes, is
      also produced by monocytes/macrophages. By its ability to inhibit cytokine
      synthesis and the expression of surface antigens, IL-10 is able to temper
      inflammation. In contrast, TNF-alpha plays a key role in acute and chronic
      inflammation and has been implicated in several forms of lung injury. The
      objective of this study was to investigate whether activators or inhibitors of
      LPS-activated signalling pathways might be able to dissociate TNF-alpha from IL
      10 secretion in alveolar macrophages (AM). The results show that PMA activates
      expression of TNF-alpha without inducing IL-10 expression. We further demonstrate
      that LPS-induced TNF-alpha secretion is independent of PKC activation and can be
      increased by inhibitors of the serine/threonine phosphatases PP1 and PP2A. In
      contrast, LPS-mediated IL-10 secretion is down-regulated by PMA and inhibitors of
      PP1 and PP2A. Addition of PKC inhibitors reverses the PMA-mediated down
      regulation of LPS-induced IL-10 secretion, indicating that PKC, once activated in
      vivo, might play a prominent role in controlling the secretion of IL-10 by AM.
      This study provides evidence that the PKC activator PMA and the phosphatase
      inhibitor calyculin A are able to dissociate TNF-alpha from IL-10 secretion by
      AM. Our data further indicate that LPS-mediated activation of certain signalling
      molecules has different consequences on the secretion of TNF-alpha or IL-10 by
      AM, an observation which may be important for the modulation of immune and
      inflammatory processes.

PMID- 10400828
TI  - The frequency of Th2 type cells increases with time on peritoneal dialysis in
      patients with diabetic nephropathy.
AB  - We have analysed the frequency of cytokine-producing T cells in different
      dialysis groups (haemodialysis; HD and peritoneal dialysis; PD) over time.
      Although we saw no difference in type 1 cytokine production (IL-2 and IFN-gamma)
      in either dialysis group, there was a clear increase in the percentage of T cells
      spontaneously producing the type 02 cytokines in the PD group (IL-4, r = 0.558, P
      < 0.05; IL-10, r = 0.527, p < 0.05). Our patient group was carefully selected to
      include patients with an ongoing autoimmune disease, insulin dependent diabetes
      mellitus (IDDM) (DN group) and chronic glomerulonephritis (GN), which are common
      reasons of end stage renal failure. As expected there was no increase in the
      spontaneous production of either IL-4 or IL-10 in either disease group with
      patients undergoing HD treatment. However, there was a clear correlation with the
      frequency of T cells producing IL-4 (r = 0.755, P < 0.05) and IL-10 (r = 0.725, P
      < 0.05) and time on dialysis in the PD patients with DN, but not those with GN.
      Much work has suggested that the pathogenesis of IDDM is associated with a Th1
      dominated response. We show here that this response is skewed towards a Th2
      response after long term treatment with PD. This work demonstrates that the
      immunological effects of different dialysis modalities on patients with different
      diseases vary. This may go some way to explain why certain patient groups have
      more complications with different dialysis modalities.

PMID- 10400829
TI  - Neutrophil F-actin and myosin but not microtubules functionally regulate
      transepithelial migration induced by interleukin 8 across a cultured intestinal
      epithelial monolayer.
AB  - The role of the polymorphonuclear leukocyte (PMN) cytoskeleton during the
      transmigration across colonic epithelial cells is not very well understood. In
      order to study the role of different components of the PMN cytoskeleton during
      transepithelial migration across a colonic epithelial cell monolayer (T84), PMN
      were preincubated with drugs affecting either the actin cytoskeleton
      (cytochalasin B, iota toxin of Clostridium perfringens, and phalloidin) or the
      microtubules (colchicine and taxol). The role of PMN myosin during
      transepithelial migration was investigated using the inhibitor 2,3-butanedione
      monoxime (BDM) and DC3B toxin. PMN intracellular Ca2+, during neutrophil adhesion
      and translocation across the epithelium, was assessed by the Ca2+ chelator 1,
      2bis-(2-aminophenoxy)-ethane-N,N,N', N'-tetra-acetic acid tetrakis
      (acetoxymethyl) ester (BAPTA-AM). Transmigration of PMN was initiated by applying
      either interleukin-8 or formyl-met-leu-phe (fMLP). While colchicine and taxol
      preexposure did not influence PMN transepithelial migration, treatment with
      cytochalasin B, iota toxin, phalloidin, BDM, DC3B toxin and BAPTA-AM greatly
      diminished migration of PMN across T84 monolayers. Similarly, cell-cell contacts
      established between PMN and epithelial cells during the transmigration were
      diminished after treatment of PMN with iota toxin or cytochalasin B. These data
      show that the neutrophil actin cytokeleton and myosin, but not the microtubules,
      evoke a Ca2+ -dependent motility that facilitates migration across the colonic
      epithelial barrier.

PMID- 10400830
TI  - Tyrosine kinase is essential for the constitutive expression of type I
      interleukin-1 receptor in human fibroblast cells.
AB  - The effect of genistein, an inhibitor of tyrosine kinase, on the constitutive
      expression of type I interleukin-1 receptor (IL-1RI) was examined in the human
      lung fibroblast cell line TIG-1, which has been shown to express only type I IL
      1R. Genistein inhibited the 125I-labeled IL-1alpha binding to TIG-1 cells in both
      a time and dose dependent manner. Scatchard plot analysis revealed that the
      number of IL-1RI decreased with no change in binding affinity. Genistein did not
      affect the level of IL-1RI mRNA, and cycloheximide did not inhibit the down
      regulatory effect of genistein. These results indicate that genistein inhibits IL
      1RI expression, not at the transcriptional level, but at the post-translational
      level. IL-1RI expression, IL-1R associated kinase (IRAK) activity and IL-1
      induced-IL-6 production were all down-regulated by pretreatment with genistein.
      These findings indicate that tyrosine kinase activity is essential for the
      constitutive expression of functional IL-1RI.

PMID- 10400831
TI  - Methyltransferase inhibitor S-adenosyl-L-homocysteine sensitizes human breast
      carcinoma MCF7 cells and related TNF-resistant derivatives to TNF-mediated
      cytotoxicity via the ceramide-independent pathway.
AB  - In this study we investigated the signalling requirements for TNF-induced
      cytotoxicity modulated by the methyltransferase inhibitor S-adenosyl-L
      homocysteine (AdoHcy) using the TNF-sensitive human breast carcinoma MCF7 cells
      and its established TNF-resistant clones (R-A1 and clone 1001). Our data indicate
      that inhibition of methylation reactions by adenosine plus homocysteine, which
      are known to condense within cells to AdoHcy, markedly potentiated TNF-induced
      cytotoxicity in MCF7 cells and rendered related TNF-resistant variants, TNF
      sensitive by a mechanism independent from the ceramide pathway. We demonstrated
      that the dominant-negative derivative of FADD (FADD-DN) blocked methylation
      inhibition/TNF-induced cell death. Moreover, TNF-mediated cytotoxicity modulated
      by AdoHcy was blocked by the ICE-inhibiting peptide z-VAD-fmk, suggesting that an
      ICE-like protease is required for the methylation inhibition/TNF-inducible death
      pathway. In conclusion, these results suggest that the methyltransferase
      inhibitor AdoHcy potentiates TNF-induced cytotoxicity in MCF7 cells and renders
      TNF-resistant MCF7 clones, TNF-sensitive via the ceramide independent pathway and
      that FADD and the ICE-like protease are likely necessary components in
      transducing methylation inhibition/TNF signals for cell death.

PMID- 10400832
TI  - Aspirin-induced asthma: advances in pathogenesis and management.
AB  - In some patients with asthma, aspirin (ASA) and all nonsteroidal anti
      inflammatory drugs that inhibit cyclooxygenase enzymes (cyclooxygenase-1 and -2)
      precipitate asthmatic attacks and naso-ocular reactions. This distinct clinical
      syndrome, called aspirin-induced asthma (AIA), is characterized by a typical
      sequence of symptoms, intense eosinophilic inflammation of nasal and bronchial
      tissues, combined with overproduction of cysteinyl-leukotrienes (Cys-LTs). At
      baseline, cys-LT urinary excretion is augmented, and ASA administration leads to
      its further temporary increase. After ASA challenge, cys-LTs are released into
      nasal and bronchial secretions and can be collected in the urine. LTC4 synthase,
      the terminal enzyme for cys-LT production, is markedly overexpressed in
      eosinophils and mast cells from bronchial biopsy specimens of most patients with
      AIA. An allelic variant of LTC4 synthase that enhances enzyme transcription is
      associated with AIA. Avoiding ASA and nonsteroidal anti-inflammatory drugs does
      not prevent progression of the inflammatory disease. Corticosteroids continue to
      be the mainstay of therapy, and anti-LT drugs are also indicated for treatment of
      the underlying disease. After ASA desensitization, daily ingestion of high doses
      of ASA reduces inflammatory mucosal disease symptoms, particularly in the nasal
      passages, in most patients with AIA.

PMID- 10400833
TI  - Apoptosis of eosinophils and lymphocytes in allergic inflammation.
AB  - A characteristic feature of apoptosis is that the cellular contents that are
      biologically active are always surrounded by the cell membrane throughout the
      entire process. Thus the apoptotic cells are eliminated calmly and quickly
      without evoking inflammation. In allergic inflammation activated eosinophils and
      lymphocytes have been known to accumulate at the site of inflammation at least in
      part because of their prolonged survival. Corticosteroids are the most potent
      anti-inflammatory agent used for treating asthma. They inhibit the prolonged
      survival of eosinophils and lymphocytes directly by inducing apoptosis and
      indirectly by suppressing the release of cytokines supporting their survival.
      Theophylline, a classical bronchodilator, has been reported to have anti
      inflammatory effects. Surprisingly, theophylline inhibited the prolonged survival
      of eosinophils in the presence of IL-5 in vitro by means of induction of
      apoptosis. Lymphocytes also undergo apoptosis in the presence of theophylline.
      One of the mechanisms for theophylline to induce apoptosis in eosinophils and
      lymphocytes is to elevate intracellular cyclic adenosine monophosphate because
      phosphodiesterase inhibitors and adenylate cyclase activators, which increase
      intracellular cyclic adenosine monophosphate, can cause apoptosis in those cells.
      Induction of apoptosis is beneficial in allergic inflammation, and the use of
      corticosteroids and theophylline in combination may be appropriate to induce
      apoptosis in eosinophils and lymphocytes.

PMID- 10400834
TI  - Microelectronic adherence monitors for metered-dose inhalers: who monitors the
      monitors?

PMID- 10400835
TI  - Airline snack foods: tension in the peanut gallery.

PMID- 10400836
TI  - Total serum IgE and its association with asthma symptoms and allergic
      sensitization among children.
AB  - BACKGROUND: Asthma and wheezing during childhood are associated with elevated
      total serum IgE and with allergic sensitization to local aeroallergens. However,
      little is known about the longitudinal relationship between total serum IgE and
      the development of wheezing and allergic sensitization during childhood.
      OBJECTIVE: The purpose of our investigation was to determine the relationship
      between total serum IgE and the development of wheezing and allergic
      sensitization in childhood. METHODS: Our study subjects were participants in the
      Tucson Children's Respiratory Study who underwent an IgE measurement in at least
      1 of 3 surveys (at years 1, 6, and 11) and complete allergy skin tests during the
      latter 2 surveys. The children's phenotypes were categorized on the basis of skin
      test response (never, early, and late) and wheezing status (never, early, late,
      and persistent). Repeated-measures analyses were used, allowing subjects to be
      included who had unequal numbers of IgE observations (a total of 263 boys and 277
      girls). RESULTS: We found that total serum IgE levels track with age: subjects
      with high serum IgE levels less than 1 year old continued to have high IgE levels
      at ages 6 and 11 years. Both persistent wheezing and early sensitization were
      associated with high serum IgE levels at all ages. Boys who had late or
      persistent wheezing or who were sensitized early or late had high serum IgE
      levels as early as age 9 months, whereas only girls with persistent wheezing and
      early sensitization had elevated IgE levels at that age. Children who wheezed
      only in the first years of life and not after (ie, those with early wheezing) had
      serum IgE levels that were not different from those of nonwheezing children.
      CONCLUSION: On the basis of these findings we conclude that although total serum
      IgE tracks with age, children who are predisposed to persistent wheezing and
      early sensitization to local aeroallergens already have high levels of IgE at age
      9 months. This suggests that the predisposition to respond to environmental
      stimuli through high levels of IgE precede early allergic sensitization,
      indicating that there may be a common defect in the development of the immune
      system involving IgE production and early allergic sensitization.

PMID- 10400837
TI  - Increased T-cell receptor vbeta8+ T cells in bronchoalveolar lavage fluid of
      subjects with poorly controlled asthma: a potential role for microbial
      superantigens.
AB  - BACKGROUND: T cells are thought to play an important role in the pathogenesis of
      chronic asthma. The immunologic triggers that contribute to poorly controlled
      asthma are unknown but may include infectious agents. Superantigens (SAgs), which
      stimulate T cells expressing selected T-cell receptor (TCR) beta-chain variable
      (Vbeta) regions, are known to be an important mechanism by which microbes can
      contribute to T-cell activation and disease pathogenesis. OBJECTIVE: We sought to
      determine the potential role of SAgs in T-cell activation of patients with poorly
      controlled asthma. METHODS: We studied the TCR-Vbeta repertoire of
      bronchoalveolar lavage (BAL) cells and PBMCs from 9 subjects with poorly
      controlled asthma (FEV1 <75%), 7 subjects with well-controlled asthma (FEV1
      >80%), and 8 normal control subjects with the use of anti-TCR-Vbeta-specific mAbs
      and flow cytometry. RESULTS: Subjects with poorly controlled asthma had a
      significantly higher expression of Vbeta8(+) T cells in BAL fluid than subjects
      with well-controlled asthma and normal control subjects (P <.01) and autologous
      PBMCs (P <.05). Increased Vbeta8(+) BAL T cells were present in CD4(+) (P <.01)
      and CD8(+) (P <.05) subsets, suggesting activation by SAgs. CONCLUSION: These
      results indicate that SAgs are a potential trigger of T-cell activation in poorly
      controlled asthma.

PMID- 10400838
TI  - Administration of budesonide once daily by means of turbuhaler to subjects with
      stable asthma.
AB  - BACKGROUND: Optimal management of chronic, mild-to-moderate asthma with inhaled
      steroids may include use of the lowest possible doses, as recommended in
      guidelines, and a reduction in the frequency of daily administration for greater
      convenience. Lower doses and once daily treatment with inhaled steroids must be
      rigorously evaluated in controlled clinical trials. OBJECTIVES: The objective of
      this study was to assess the efficacy and safety of once daily treatment with
      budesonide in subjects with stable asthma. METHODS: Once daily budesonide was
      assessed in 309 adult subjects, including those who were and were not using an
      inhaled steroid at baseline. The subjects were stratified by inhaled steroid use
      and randomly assigned to one of 3 treatments: 200 microgram budesonide, 400
      microgram budesonide, or placebo administered by means of Turbuhaler once daily
      in the morning for 6 weeks. Beyond this point, treatment was continued unchanged
      for another 12 weeks (maintenance) in those receiving 200 microgram budesonide
      once daily and placebo. In those who received 400 microgram budesonide once
      daily, the dose was reduced to 200 microgram once daily at week 6 and held
      constant for the remaining 12 weeks (400/200 microgram group). Primary efficacy
      endpoints were mean change from baseline in FEV1 and morning peak expiratory
      flow. RESULTS: Once daily budesonide was well tolerated and resulted in
      significant improvements in all efficacy endpoints, even though baselines were
      well stabilized. Baseline lung function was elevated with little room for
      improvement; however, mean increases in FEV1 during the maintenance period were
      0.10 L and 0.11 L in the 200 microgram and 400/200 microgram groups,
      respectively, versus a decrease of -0.09 L in the placebo arm (P <.001). Results
      for peak expiratory flow were similar. Significant improvements in secondary
      endpoints, including symptoms, beta-agonist use, and quality of life, also
      developed with budesonide 200 and 400 microgram once daily. CONCLUSION: Inhaled
      budesonide, in doses as low as 200 microgram, may be an appropriate introductory
      or maintenance dose in subjects with stable, mild-to-moderate asthma.

PMID- 10400839
TI  - Reliability of the model MC-311 MDI chronolog.
AB  - BACKGROUND: The Model MC-311 MDI Chronolog (Medtrac Technologies, Lakewood, Colo)
      is an electronic device for monitoring adherence to metered-dose inhalers (MDIs).
      It is a thermistor-actuated, microprocessor-equipped device that dispenses
      inhaled medication while recording the date and time of each canister activation.
      OBJECTIVE: We evaluated the reliability of the MC-311 MDI Chronolog to determine
      whether the model could accurately record and report the date, time, and number
      of MDI actuations. METHODS: Twenty-four of the MC-311 Chronologs were discharged
      at 8 hourly intervals across 8 days. Battery voltage was assessed before and
      after the experiment. The mouthpieces of 12 Chronologs were washed daily.
      RESULTS: By using generous criteria for acceptable reliability, only 10 of 24
      (42%) were rated as acceptable. None of these 10 Chronologs recorded 320 or
      greater actuations (mean +/- SD, 293.9 +/- 13.3; range, 266 to 308); all reliable
      Chronologs underestimated MDI activation. An additional 6 devices had an initial
      signature of erroneous recordings dating from device initialization. After
      removing this signature, the remaining data showed acceptable reliability. All
      the remaining Chronologs judged to be unacceptable showed time series patterns of
      seizures (ie, bursts of clustered, erroneous records). Seizures were distributed
      across trial days, were associated with washing, and preceded all 4 cases of
      battery failure. Damage to the thermistor is the likely cause of seizure-pattern
      failures. CONCLUSIONS: In summary, because of a combination of a clear
      underreporting bias with frequent initialization and seizure-pattern failures,
      the Model MC-311 MDI Chronolog is not recommended for use in clinical care or
      research

PMID- 10400840
TI  - Association between atopic sensitization and asthma and bronchial
      hyperresponsiveness in swedish adults: pets, and not mites, are the most
      important allergens.
AB  - BACKGROUND: Atopic sensitization is a well-known risk factor for asthma and
      bronchial hyperresponsiveness (BHR). Mites have been regarded as the most
      important allergens, but the prevalence of sensitization to mites is relatively
      low in Sweden. OBJECTIVE: The aim of the study was to investigate possible
      associations between sensitization to various allergens and asthma and BHR in
      adults. METHODS: A random sample of 1859 subjects, aged 20 to 46 years, was
      investigated in a cross-sectional study by using a questionnaire, skin prick
      tests (SPTs), specific and total IgE measurements, and methacholine bronchial
      challenge tests. Possible associations were analyzed univariately and by using
      multivariate logistic regression analysis and proportional hazard regression
      analysis. RESULTS: Positive SPT and specific IgE results were more common in
      subjects with asthma and BHR than in subjects without these conditions for all
      allergens. The independent associations between positive SPT responses and asthma
      and BHR are given as adjusted prevalence ratios (PRRs): pets and asthma, PRR =
      3.6; pets and BHR, PRR = 2.0; grass and asthma, PRR = 2.0; grass and BHR, PRR =
      1.7; mites and asthma, PRR = 1.4; and mites and BHR, PRR = 1.2. The use of
      specific IgE measurements instead of SPTs showed essentially similar results.
      CONCLUSION: Cats and dogs were the sensitizing allergens most closely associated
      with asthma and BHR. The relationships with sensitization to grass and mites were
      less pronounced.

PMID- 10400841
TI  - Repeatability of allergen-induced airway inflammation.
AB  - BACKGROUND: Allergen inhalation challenge is a useful clinical model to
      investigate the effects of asthma therapies on allergen-induced airway responses;
      however, the repeatability of allergen-induced airway inflammation is not known.
      OBJECTIVE: The purpose of this study was to investigate the repeatability of
      allergen-induced increases in sputum eosinophils. This information will allow the
      prediction of the number of subjects required in studies evaluating asthma
      therapies. METHODS: Seventeen subjects completed 2 allergen challenges using the
      same dose of allergen, at least 3 weeks apart. Allergen-induced airway responses
      were measured for 7 hours after challenge. Differential cell counts from induced
      sputum were determined the day before and 7 and 24 hours after challenge;
      methacholine PC20 was measured the day before and 24 hours after challenge.
      RESULTS: The intraclass correlation coefficient for maximum percent late fall in
      FEV1 was 0.32 and for the area of the late response was 0.61. The sample size
      predicted to be necessary to observe 50% attenuation of the maximum percent late
      fall in FEV1 and the late area under the curve with a power of 0.95 was 9
      subjects. The intraclass correlation coefficient for percent of allergen-induced
      sputum eosinophils was 0.60 at 7 hours and 0.53 at 24 hours after challenge. With
      a randomized cross-over study design, the sample size predicted to be necessary
      to observe 50% attenuation of allergen-induced percent of eosinophils with a
      power of 0.95 was 5 subjects. CONCLUSION: Allergen inhalation challenge with
      measurements of sputum eosinophils is a noninvasive and reliable method for
      evaluating the anti-inflammatory effects of asthma therapies.

PMID- 10400842
TI  - Altered respiratory epithelial cell cytokine production in cystic fibrosis.
AB  - BACKGROUND: Reports that lung inflammation in patients with cystic fibrosis (CF)
      might precede infection raise the possibility that the excessive inflammatory
      response in lungs of patients with CF might be directly related to defects in
      epithelial cell cystic fibrosis transmembrane regulator. OBJECTIVE: We sought to
      determine the relationship of epithelial cell cytokine production to CF lung
      disease. METHODS: Immunofluorescence and cultures of freshly obtained bronchial
      epithelial cells and ELISA for IL-10, IL-8, and IL-6 were used to study
      alterations in epithelial cell cytokine production. RESULTS: Fresh bronchial
      epithelial cells from healthy control subjects (HCs) secreted 98 +/- 20 pg/mL of
      the anti-inflammatory cytokine IL-10 when placed in primary culture in vitro but
      little or no IL-8 or IL-6. In contrast, fresh epithelial cells from patients with
      CF did not secrete detectable IL-10 but produced 38 +/- 17 pg/mL IL-8 and 40 +/-
      17 pg/mL IL-6. These data correlated very well with the immunofluorescence data.
      The correlation between the immunofluorescent staining of fresh bronchial
      epithelial cells from both the HCs and patients with CF and the concentrations of
      cytokines in epithelial lining fluid suggests a reciprocal relationship between
      anti-inflammatory (IL-10) and proinflammatory (IL-6 and IL-8) cytokine production
      by the epithelial cells in HCs versus patients with CF. CONCLUSIONS: Alterations
      in epithelial cell cytokine production in the lungs of patients with CF may
      contribute to the excessive local inflammation.

PMID- 10400843
TI  - Quality of life in nasal polyposis.
AB  - BACKGROUND: Nasal polyposis (NP) is a frequent inflammatory chronic disease of
      the upper respiratory tract, which may impair quality of life (QOL). The NP
      impact, which is frequently associated with lower respiratory disorders, has
      never before been studied. OBJECTIVE: We initiated this prospective study to
      establish internal validity and reliability of the generic SF-36 questionnaire in
      NP and to determine to what level daily functioning becomes impaired as a result
      of NP. METHODS: Forty-nine consecutive patients with NP were included. They were
      assessed for the severity of nasal symptoms and underwent pulmonary function
      tests. The QOL profiles in patients with NP were compared with those of patients
      with perennial rhinitis (n = 111) and healthy subjects (n = 116). RESULTS:
      Cronbach's coefficient alpha demonstrated the high reliability and validity of
      the SF-36 questionnaire for patients with NP (alpha =.89). NP impaired QOL more
      than perennial allergic rhinitis (P <.05). The impairment of QOL was greater when
      NP was associated with asthma (P <.05). SF-36 scores appeared highly correlated
      to pulmonary function (FEV1, maximal midexpiratory flow, forced vital capacity),
      suggesting relationships between QOL in NP and associated bronchial obstruction.
      Severity of nasal symptoms were not related to QOL scales. In addition,
      sequential evaluations of QOL, nasal symptoms, and pulmonary function were
      performed 10 months after the first evaluation in 28 patients with NP. These
      evaluations demonstrated that NP treatment either with nasal steroids or
      endonasal ethmoidectomy significantly improved both nasal symptoms and QOL
      without significant change of pulmonary function. CONCLUSION: Our study clearly
      demonstrated that the SF-36 questionnaire presented a high internal validity and
      reliability in patients with NP. NP impaired QOL to a greater degree than
      perennial allergic rhinitis. QOL improvement after NP treatment is related to
      nasal symptoms improvement.

PMID- 10400844
TI  - Eosinophilic airway inflammation in nasal polyposis.
AB  - BACKGROUND: Asthma and asymptomatic bronchial hyperresponsiveness (BHR) are
      frequent findings in patients with nasal polyposis (NP). OBJECTIVE: To elucidate
      mechanisms responsible for the development of BHR, we initiated a prospective
      study of bronchial inflammation as assessed by bronchial lavage (BL) and
      bronchial biopsy specimens in 35 patients with noninfectious NP. METHODS: BHR was
      determined with methacholine provocation testing. Differential cell count, ECP,
      and histamine and tryptase levels were determined in BLs. Pathologic examination
      of bronchial biopsy specimens was performed with May-Grunwald-Giemsa stain to
      assess the number of lymphocytes. Indirect immunoenzymatic methods were used to
      identify eosinophils and mast cells. RESULTS: Fourteen patients did not exhibit
      BHR (group A); 7 patients had asymptomatic BHR (group B); and 14 patients had BHR
      associated with asthma (group C). Patients of group C tended to have a longer
      duration of nasal symptoms than those of groups A and B. FEV1 (L) was
      significantly lower in group C than in groups A and B. The number and percentage
      of eosinophils were significantly higher in BLs in groups B and C than in group A
      (P <. 05). Patients of groups B and C had a significantly higher number of
      eosinophils in bronchial submucosa (14.0 +/- 1.5/mm2 and 19.0 +/- 1. 9/mm2,
      respectively) than patients of group A (0.1 +/- 0.1/mm2). The number of
      lymphocytes was also higher in groups B and C than in group A. FEV1 (percent of
      predicted value) and eosinophil number within bronchial mucosa correlated
      negatively. CONCLUSION: Our results demonstrate that patients with NP and
      asymptomatic BHR had an eosinophilic bronchial inflammation similar to that
      observed in asthmatic patients with NP, whereas patients with NP without BHR do
      not feature eosinophilic lower airways inflammation. The clinical relevance of
      these results requires careful follow-up to determine whether eosinophilic
      inflammation in these patients precedes and is responsible for the development of
      obvious asthma.

PMID- 10400845
TI  - Effect of loratadine on nitrogen dioxide-induced changes in electrical resistance
      and release of inflammatory mediators from cultured human bronchial epithelial
      cells.
AB  - BACKGROUND: Recent studies have demonstrated that some antihistamines can
      attenuate histamine-induced release of inflammatory mediators from bronchial
      epithelial cells. OBJECTIVE: The purpose of study was to test the hypothesis that
      loratadine may influence pollution-induced inflammation of the airways by
      modulating epithelial membrane integrity and the synthesis and/or release of
      inflammatory mediators from airway epithelial cells. METHODS: We have cultured
      human bronchial epithelial cell (HBEC) cultures from surgical explants and
      investigated the effect of loratadine on NO2-induced changes in both electrical
      resistance of HBEC cultures and release of IL-8, RANTES, and soluble
      intercellular adhesion molecule-1 (sICAM-1) from these cells after exposure for 6
      hours to either air or 400 ppb NO2. RESULTS: Exposure for 6 hours to NO2
      significantly decreased the electrical resistance of HBEC cultures by 18.1% from
      baseline (P <.05). Incubation with 0.25 to 25 micromol/L loratadine did not alter
      the NO2-induced decrease in the electrical resistance of HBEC cultures. NO2 also
      significantly increased the release of IL-8 from a control value of 52.5
      pg/microgram cellular protein to 81.9 pg/microgram cellular protein (P <.05),
      RANTES from a control value of 0.023 pg/microgram cellular protein to 0.062
      pg/microgram cellular protein (P <.05), and sICAM-1 from a control value of 7.7
      pg/microgram cellular protein to 16.3 pg/microgram cellular protein (P <.05). The
      NO2-induced release of all 3 mediators was significantly attenuated by incubation
      of HBECs with 25 micromol/L loratadine. Incubation with 2.5 micromol/L loratadine
      also significantly attenuated the NO2-induced release of RANTES and sICAM-1, but
      not IL-8. CONCLUSIONS: These results suggest that loratadine has the potential to
      reduce airway inflammation by modulating the release of inflammatory cytokines
      from airway epithelial cells.

PMID- 10400846
TI  - The efficacy and safety of fexofenadine HCl and pseudoephedrine, alone and in
      combination, in seasonal allergic rhinitis.
AB  - BACKGROUND: Antihistamines effectively treat seasonal allergic rhinitis (SAR),
      although the ability of this drug class to reduce nasal congestion is limited.
      Nasal decongestants effectively treat nasal congestion but not the histamine
      related components of SAR. Therefore antihistamine/nasal decongestant
      combinations are commonly used to maximize the treatment of SAR. Fexofenadine HCl
      is a nonsedating, long-acting H1 receptor antagonist that provides fast and
      effective relief from SAR. It is well tolerated, with no sedative or cardiotoxic
      effects. OBJECTIVE: We sought to compare the efficacy and safety of a
      fexofenadine HCl/pseudoephedrine HCl combination with that of each individual
      component in the treatment of ragweed allergy. METHODS: In this Canadian
      multicenter, double-blind, parallel-group study, 651 patients allergic to ragweed
      were randomized to receive 60 mg of fexofenadine HCl twice daily, 120 mg of
      sustained-release pseudoephedrine HCl twice daily, or a combination of the 2
      drugs (60 mg of fexofenadine HCl/120 mg of sustained-release pseudoephedrine HCl)
      twice daily for 2 weeks. Efficacy analyses were based on symptom severity. In
      addition, a health economic assessment was performed. RESULTS: Combination
      therapy was significantly more effective than pseudoephedrine alone in improving
      primarily histamine-mediated symptoms (sneezing; rhinorrhea; itchy nose, palate,
      and/or throat; and itchy, watery, red eyes) and significantly more effective than
      fexofenadine alone in reducing nasal congestion. Combination therapy also
      produced greater improvements in daily activities and work productivity compared
      with the individual components. No serious adverse events were reported in any of
      the treatment groups. In addition, no clinically significant changes in 12-lead
      electrocardiogram parameters, vital signs, or clinical laboratory values were
      observed. CONCLUSION: Combination therapy is more effective than fexofenadine
      alone or pseudoephedrine alone in relieving the full spectrum of SAR symptoms
      (ie, both the primarily histamine-related symptoms and nasal congestion).

PMID- 10400847
TI  - A dose-ranging study of mometasone furoate aqueous nasal spray in children with
      seasonal allergic rhinitis.
AB  - BACKGROUND: The efficacy and safety of mometasone furoate aqueous nasal spray
      (MFNS; Nasonex) 200 microg once daily for the treatment and prophylaxis of
      seasonal allergic rhinitis (SAR) and treatment of perennial rhinitis have been
      demonstrated in adults. However, the dose response of MFNS in pediatric patients
      has not yet been characterized. OBJECTIVE: This study was conducted to determine
      the dose-response relationship of 3 different doses of MFNS in a pediatric
      population. METHODS: This was a multicenter, double-blind, active- and placebo
      controlled study of 679 children 6 to 11 years of age with histories of SAR and
      documented positive skin test responses. Patients were randomized to one of the
      following treatment groups for 4 weeks: MFNS 25 microgram once daily, MFNS 100
      microgram once daily, MFNS 200 microgram once daily, beclomethasone dipropionate
      84 microgram twice daily (168 microgram/day), or placebo. Physician evaluations
      were performed at days 4, 8, 15, and 29, and patient evaluations were analyzed
      for days 1 to 15 and 16 to 29. RESULTS: The mean reduction from baseline in
      physician-evaluated total nasal symptom scores at day 8 (the primary efficacy
      variable) was significantly greater in the MFNS and beclomethasone dipropionate
      groups than in the placebo group (P </=.02). No significant differences were
      observed among the 3 MFNS groups. However, as treatment continued, symptoms in
      patients treated with MFNS 100 or 200 microgram once daily continued to improve,
      whereas those treated with MFNS 25 microgram once daily demonstrated little
      further improvement. By day 29, MFNS 100 and 200 microgram once daily both were
      significantly more effective than MFNS 25 microgram once daily in relieving
      symptoms of SAR, but MFNS 200 microgram provided no additional benefit over MFNS
      100 microgram. All doses of MFNS were well tolerated, and cosyntropin stimulation
      tests performed before and after treatment found no evidence of hypothalamic
      pituitary-adrenal axis suppression. CONCLUSION: These results indicate that the
      most appropriate therapeutic dosage of MFNS in the treatment of SAR in children 6
      to 11 years of age is 100 microgram once daily. In addition, MFNS at doses up to
      200 microgram once daily for 4 weeks was well tolerated and had no detectable
      effects on hypothalamic-pituitary-adrenal axis function.

PMID- 10400848
TI  - Highly heterogeneous Phl p 5-specific T cells from patients with allergic
      rhinitis differentially recognize recombinant Phl p 5 isoallergens.
AB  - BACKGROUND: The prevalence of atopic allergy to Poaceae grasses poses a serious
      health problem. OBJECTIVE: To evaluate the T cell-activating capacity of
      recombinant grass pollen allergens suggested for immunotherapy, we characterized
      the T-cell response of allergic patients to the Phleum pratense (Phl p) major
      allergen, Phl p 5. METHODS: Thirty-eight Phl p 5-specific CD4(+) T-cell clones
      (TCCs) were isolated from the peripheral blood of 3 patients with allergic
      rhinitis and were characterized with respect to cross-reactivity, HLA
      restriction, cytokine profiles, and isoallergen specificity when tested with
      natural Phl p 5 and 5 rPhl p 5 isoallergens (4 Phl p 5a and 1 Phl p 5b). RESULTS:
      The TCCs were highly cross-reactive with group 5 allergens of related grasses,
      and the different cross-reactivity patterns found indicate that several T-cell
      epitopes are present in Phl p 5. Most TCCs displayed a TH0-like cytokine profile,
      whereas a few TCCs belonged to the TH2 or TH1 subset. The TCCs were restricted by
      HLA-DR (24/38 TCCs), HLA-DQ (11/38 TCCs), or HLA-DP (3/38 TCCs). Interestingly, 4
      of the 34 TCCs tested reacted exclusively with the 4 rPhl p 5a isoforms; 8 of 34
      TCCs were rPhl p 5b specific, and 3 of 34 TCCs reacted with all isoforms; 19 of
      34 TCCs did not react with any of the rPhl p 5 isoallergens. Moreover, the
      overall isoform recognition pattern differed considerably among patients.
      CONCLUSION: These results demonstrate that Phl p 5-specific T cells are highly
      heterogeneous and that individual TCCs, and individual patients, differentially
      recognize isoallergens. The differential isoallergen recognition for Phl p 5
      specific T cells suggests, if confirmed in larger patient groups, that a
      combination of 2 or more rPhl p 5 isoallergens may be needed to replace the
      natural grass allergen for immunotherapy.

PMID- 10400850
TI  - Standardization of Alternaria alternata: extraction and quantification of alt a 1
      by using an mAb-based 2-site binding assay.
AB  - BACKGROUND: Alternaria alternata is recognized as an important cause of allergic
      disease. As with other molds, the extracts of A alternata used for diagnosis and
      therapy are highly heterogeneous, and there is a need for improved
      standardization. The major allergen Alt a 1 is well characterized and has been
      produced as a recombinant protein, but very few data are available on the Alt a 1
      content in extracts. OBJECTIVE: An assay for the quantification of Alt a 1 was
      developed and used for monitoring batch-to-batch consistency of A alternata
      extracts, and the correlation between skin prick test responses and Alt a 1
      concentrations was studied. METHODS: A 2-site binding assay based on an Alt a 1
      specific mAb was developed and used for the quantification of Alt a 1 in allergen
      extracts. Quantitative skin prick tests were performed on 16 A alternata
      sensitive patients and correlated with the Alt a 1 concentration. RESULTS: The
      Alt a 1-specific mAb was found to be suitable for affinity purification, as well
      as for a 2-site binding quantification assay. In allergen extracts the Alt a 1
      content was estimated as 2% to 4.7% of total protein. Quantitative skin prick
      tests showed an Alt a 1 concentration-dependent response. CONCLUSION:
      Quantification of Alt a 1 in A alternata extracts reflects their batch-to-batch
      consistency. Skin prick test responses to a standardized A alternata extract
      correlate with the Alt a 1 contents. An extract containing 3.7 microgram/mL Alt a
      1 caused a response equal to that of a 1% histamine dihydrochloride solution.

PMID- 10400849
TI  - The natural history of exercise-induced anaphylaxis: survey results from a 10
      year follow-up study.
AB  - BACKGROUND: Exercise-induced anaphylaxis (EIA) is a unique physical allergy that
      is triggered by exertion, the clinical spectrum and modifying factors of which
      have been previously studied. At the time of initial description, it was
      postulated that other factors contributed to this disorder. OBJECTIVE: We sought
      to determine the clinical course and potential modifying factors in EIA. METHODS:
      In 1993, we conducted a cross-sectional analysis of 671 individuals with exercise
      associated symptoms for more than a decade using a validated 75-item
      questionnaire. Subjects met criteria for EIA if they had anaphylactic symptoms,
      including hypotension or upper airway obstruction, urticaria, or angioedema with
      physical exertion but without a passive increase in core body temperature.
      RESULTS: Of 365 (54%) questionnaire respondents, 279 (87%) met criteria for EIA
      (199 females and 80 males). At the time of study entry, subjects with EIA (mean
      age, 37.5 years; range, 13 to 77 years) had an average of 10.6 years of symptoms,
      which were most frequently triggered by aerobic activities such as jogging or
      brisk walking (78% and 42%, respectively). On average, subjects reported that the
      frequency of attacks had decreased (47% of subjects) or stabilized (46% of
      subjects) since onset. One hundred (41%) subjects reported being completely free
      of attacks in the past year. Subjects reduced their attacks by avoiding exercise
      during extremely hot or cold weather (44%), avoiding ingestion of certain foods
      before exercise (37%), and restricting exercise during their allergy season (36%)
      or humid weather (33%). The most common pharmacologic agents used to manage
      symptoms were H1 antagonists (56%) and/or epinephrine (31%). However, 28% used no
      treatment at all. CONCLUSION: EIA is an episodic condition in which the frequency
      of attacks tends to stabilize or decrease over time. Improvement appears to
      result from individual modification of exercise and avoidance of known
      environmental and ingestible precipitants.

PMID- 10400851
TI  - Leukemia inhibitory factor is synthesized and released by human eosinophils and
      modulates activation state and chemotaxis.
AB  - BACKGROUND: The cytokine leukemia inhibitory factor (LIF) is known to be produced
      by both inflamed peripheral autonomic nerves and several cell types involved in
      the regulation of the immune response. We have recently demonstrated that several
      structural cell types in human airways produce LIF in response to inflammatory
      stimuli and that LIF augments contractile responses to tachykinins in airway
      explants. Because the eosinophil is a major effector cell in asthma and often
      found adjacent to the nerves, we hypothesized that eosinophils produce LIF and
      that LIF primes and upregulates eosinophil recruitment and function, allowing
      bidirectional neuroimmune interactions and augmentation of eosinophil-mediated
      injury. OBJECTIVE: The purpose of this study was to demonstrate that human
      eosinophils synthesize and release LIF, to determine the effects of LIF on
      eosinophil functions (ie, chemotaxis, granule protein release, expression of the
      activation marker CD69, and apoptosis), and to compare serum LIF levels between
      atopic and nonatopic individuals. METHODS: Reverse-transcription PCR, ELISA,
      immunocytochemistry, chemotaxis assay, and flow cytometry were used. RESULTS:
      Peripheral blood eosinophils express LIF and messenger RNA for LIF and LIF
      receptor. Serum LIF levels were higher in atopic patients with mild asthma than
      in nonatopic normal donors. Eosinophils from nonatopic donors were stimulated by
      calcium ionophore to release small amounts of LIF (from almost none to 5.3 +/-
      1.8 pg/10(6) cells). Eosinophils from atopic donors showed a 10-fold increase
      (from 45.1 +/- 38.7 pg/106 cells to 414.5 +/- 189.9 pg/10(6) cells).
      Preincubation of eosinophils with LIF increased eosinophil peroxidase release 4
      fold. LIF was not chemotactic for eosinophils but augmented chemotaxis mediated
      by substance P by 82% and by platelet-activating factor by 31%. LIF did not
      effect eosinophil apoptosis but increased CD69 expression. CONCLUSION: LIF has
      proinflammatory roles in eosinophil-dependent airway disorders.

PMID- 10400852
TI  - IL-2 enhances allergic airway responses in rats by increased inflammation but not
      through increased synthesis of cysteinyl leukotrienes.
AB  - BACKGROUND: IL-2 has been shown to increase allergic airway responses in rats.
      OBJECTIVE: The purpose of this study was to investigate whether induction of
      inflammation and enhancement of cysteinyl-leukotriene (cys-LT) synthesis were
      involved in the augmentation of airway responses caused by IL-2. METHODS: Brown
      Norway rats received human recombinant IL-2 or saline subcutaneously twice a day
      from day 9 to day 14 after sensitization to ovalbumin (OVA). On day 14, rats
      underwent either lung lavage or were challenged with an aerosol spray of OVA, the
      airway responses and biliary excretion of cys-LTs were measured for a period of 8
      hours after challenge, and the lung leukocyte numbers were determined after
      enzymatic digestion of lung tissues. RESULTS: The early response after OVA
      increased from 184.2% +/- 13.5% in the animals receiving saline (n = 10) to 309%
      +/- 51% (baseline lung resistance) in IL-2-pretreated animals (n = 17; P <.05).
      The late response also increased from 19.6 +/- 4.5 (area under the curve of
      baseline lung resistance vs time) in the animals receiving saline to 37 +/- 5.4
      after administration of IL-2 (P <.05). However, IL-2-treated animals had lower
      levels of biliary cys-LTs during the late response than saline-treated animals
      but similar levels during the early response. This difference could not be
      attributed to an increase in LT metabolism, which we assessed by the recovery of
      3H-LTC4 instilled intratracheally in challenged or unchallenged rats. When
      compared with control animals, pretreatment with IL-2 increased all cell types
      retrieved from lung lavage fluid before OVA challenge (P <.05). After OVA
      challenge, the total cell yield from lung lavage fluid was also increased, mostly
      because of an increase in neutrophils (P <.05). Eosinophils and lymphocytes were
      greater in the lungs of IL-2-treated than vehicle-treated and OVA-challenged rats
      (P <.01), and IL-2-treated rats had a lower CD4(+)/CD8(+) ratio in the blood
      after challenge (P <.001). CONCLUSION: In conclusion, IL-2 increases early and
      late responses in rats, and it induces lung inflammation. Altered airway
      responses are not attributable to an increase in cys-LT production.

PMID- 10400853
TI  - PGE 2 and dibutyryl cyclic adenosine monophosphate prolong eosinophil survival in
      vitro.
AB  - BACKGROUND: Apoptosis represents a mechanism by which the accumulation and
      inflammatory potential of eosinophils in asthma might be limited. Mediators
      derived from the airway epithelium may influence the rate of eosinophil
      apoptosis. OBJECTIVE: We have investigated the effects on eosinophil apoptosis of
      3 mediators that are likely to be produced by the airway epithelium, namely PGE2,
      TNF-alpha, and nitric oxide. METHODS: Peripheral blood eosinophils from healthy
      adult volunteers were purified by density gradient centrifugation and negative
      immunomagnetic selection. Eosinophils were cultured for 16 or 40 hours with PGE2
      (10 nmol/L), dibutyryl cyclic adenosine monophosphate (AMP; 100 micromol/L), TNF
      alpha (500 U/mL), the nitric oxide donors, S-nitroso-N-acetylpenicillamine (100
      micromol/L), and 2,2;-(hydroxynitrosohydrazono)bis-ethanamine (1 mmol/L), or
      dibutyryl cyclic guanosine monophosphate (100 micromol/L). Control cultures
      consisted of untreated, IL5-treated (100 U/mL), and anti-Fas-treated (400 ng/mL)
      cells. Eosinophil apoptosis was assessed by flow cytometric analysis of annexin V
      FITC binding to externalized phosphatidylserine, by electrophoresis of phosphorus
      32 end-labeled DNA fragments, and by flow cytometric assessment of hypodiploid
      DNA with propidium iodide. RESULTS: PGE2 and cyclic AMP inhibited spontaneous
      eosinophil apoptosis at both 16 and 40 hours as did the PGEP2 receptor agonist,
      11-deoxy PGE1, at 40 hours, but these effects were not inhibited by a protein
      kinase A antagonist. TNF-alpha delayed apoptosis in eosinophil cultures at 16
      hours, whereas S-nitroso- N-acetylpenicillamine, 2, 2;
      (hydroxynitrosohydrazono)bis-ethanamine, and cyclic guanosine monophosphate had
      little effect. Anti-Fas had little effect on spontaneous eosinophil apoptosis but
      significantly reduced the inhibitory effects of PGE2, cyclic AMP, and TNF-alpha.
      Assessments of apoptosis by DNA fragmentation gave similar but quantitatively
      less sensitive results. CONCLUSION: Inhibition of spontaneous eosinophil
      apoptosis by PGE2 appears to be mediated by EP2 receptors but is not protein
      kinase A dependent. By enhancing eosinophil survival, PGE2 may increase the
      proinflammatory potential of these cells in chronic asthma.

PMID- 10400854
TI  - Elevated serum L-selectin levels and abnormal regulation of L-selectin expression
      on leukocytes in atopic dermatitis: soluble L-selectin levels indicate disease
      severity.
AB  - BACKGROUND: L-selectin mediates leukocyte rolling on endothelium at sites of
      inflammation, suggesting that L-selectin may be involved in the development of
      cutaneous lesions of atopic dermatitis (AD). After leukocyte activation, L
      selectin is rapidly shed from the cell surface. OBJECTIVE: The purpose of this
      study was to assess leukocyte L-selectin expression and quantitate levels of
      serum soluble L-selectin (sL-selectin) in patients with AD. METHODS: Serum sL
      selectin levels in patients with AD (n = 70), contact dermatitis (n = 18), and
      psoriasis (n = 23), as well as normal control subjects (n = 30), were examined by
      using an ELISA. The L-selectin expression on leukocytes in heparinized blood
      samples from patients with AD (n = 18) and normal control subjects (n = 10) was
      also examined by flow cytometry. RESULTS: Serum levels of sL-selectin in patients
      with AD were significantly higher than those found in normal control subjects.
      Furthermore, sL-selectin levels correlated positively with disease severity and
      total serum IgE levels in AD. The expression of L-selectin on B cells, monocytes,
      and neutrophils was significantly decreased in patients with AD compared with
      normal control subjects, although those on CD4(+) or CD8(+) T cells from patients
      with AD were similar to those from normal control subjects. CONCLUSION: Elevated
      sL-selectin levels and the abnormal expression of L-selectin on some leukocyte
      subsets in patients with AD may correlate with inflammation associated with AD.
      Furthermore, the level of sL-selectin may be a useful immunologic indicator for
      disease activity in AD.

PMID- 10400855
TI  - Complement dependence of histamine release in chronic urticaria.
AB  - BACKGROUND: IgG autoantibodies directed to the alpha-subunit of the IgE receptor
      have been identified in 30% to 45% of patients with chronic urticaria. However,
      the exact mechanism by which histamine secretion is initiated is uncertain.
      OBJECTIVE: Histamine release from cutaneous mast cells may occur by cross-linking
      the IgE receptor or by activation of complement. Our goal is to distinguish these
      2 possibilities. METHODS: We incubated human cutaneous mast cells with patient
      sera, decomplemented sera, or purified patient IgG. The IgG was also added to
      pooled normal serum or to sera deficient in either C2 or C5, and its ability to
      activate mast cells was assessed. Mast cells were incubated with human IgE
      myeloma to saturate alpha-subunits to determine the effect on histamine release.
      RESULTS: Patient sera released histamine (18.26% +/- 4.39%), but purified IgG
      from patients (5.5% +/- 4.3%) did not. Addition of the patient IgG to normal sera
      rendered the sera positive for histamine-releasing activity (18.4% +/- 4.3%),
      whereas control IgG or patient IgG added to C2- or C5-deficient sera did not
      release histamine. Histamine release with decomplemented patient sera was also
      diminished (8.34% +/- 4.3%). Preincubation of mast cells with a C5-blocking
      peptide decreased histamine release but was not statistically significant; there
      was a significant decrease after preincubating mast cells with IgE myeloma.
      CONCLUSION: The degranulation of mast cells by IgG autoantibodies in patients
      with chronic urticaria requires binding to the IgE receptor and activation of the
      classical complement cascade. Saturation of the IgE receptor with IgE inhibits
      such degranulation, presumably by preventing binding of the requisite IgG.

PMID- 10400856
TI  - Effect of stress on atopic dermatitis: investigation in patients after the great
      hanshin earthquake.
AB  - BACKGROUND: Although a variety of factors are responsible for atopic dermatitis
      (AD), very little is known about the effect of stress caused by a natural
      disaster on AD symptoms. OBJECTIVE: This study was conducted to assess the effect
      of stress or trauma on the symptoms of AD. METHODS: One thousand four hundred
      fifty-seven patients with AD (745 males and 712 females), diagnosed by using the
      criteria of the Japanese Dermatology Association, were enrolled in the study. The
      data were obtained from a self-administered questionnaire given to patients with
      AD after experiencing the Great Hanshin Earthquake. The data were analyzed by
      multivariate logistic regression analysis. Patients were divided into 3 groups:
      area A, severe damage to buildings and houses; area B, mild damage; and control
      area, no damage. RESULTS: Exacerbation of skin symptoms was found in 38% and 34%
      of patients in areas A and B, respectively, whereas similar exacerbation was seen
      in 7% of control patients. Nine percent and 5% of the patients in areas A and B,
      respectively, showed improvement in their symptoms compared with 1% in the
      control group. The earthquake caused stress in 63% and 48% of the patients in
      areas A and B, respectively, but fewer patients felt stress in undamaged areas
      (19%). Multiple logistic regression analysis revealed that of the factors
      examined here, subjective distress is the factor that is most responsible for the
      exacerbation of skin symptoms (odds ratio, 2.98; 95% confidence interval, 2.25
      3.96). CONCLUSION: The results presented here strongly suggest that stress caused
      by a natural disaster influences AD symptoms.

PMID- 10400857
TI  - Cow's milk casein, a hidden allergen in natural rubber latex gloves.
AB  - BACKGROUND: We have previously noted that one natural rubber latex (NRL) glove
      brand used for skin prick testing in the diagnosis of NRL allergy contained cow's
      milk casein. OBJECTIVE: We sought to examine whether other commonly marketed NRL
      glove brands contain cow's milk casein. METHODS: The casein content of 30 NRL
      glove extracts (1:5 wt/vol) was measured by RAST inhibition and by rocket
      immunoelectrophoresis and rocket radioimmunoelectrophoresis by using casein
      specific rabbit antiserum, a serum pool from patients with cow's milk allergy,
      and radiolabeled anti-human IgE. The NRL allergen content was measured by ELISA
      inhibition. RESULTS: The casein content of the glove used in NRL allergy
      screening (Triflex, Baxter) was rather high (ie, about 400 microgram/g of glove).
      Its total protein content was 1000 microgram/g of glove. Rocket
      radioimmunoelectrophoresis detected distinct amounts of casein in 8, minimal
      amounts in 7, and no casein in the remaining 15 NRL glove brands. CONCLUSIONS:
      Several brands of NRL gloves were found to contain casein, implying that extracts
      prepared from such gloves can cause false-positive skin prick test reactions when
      diagnosing NRL allergy. The use of casein as a stabilizer in glove manufacture
      without appropriate labeling should be stopped because it can also cause contact
      urticaria syndrome in individuals with cow's milk allergy.

PMID- 10400858
TI  - Occupational allergy caused by carnation (Dianthus caryophyllus).
AB  - BACKGROUND: Occupational respiratory symptoms caused by decorative flowers are
      seldom reported in the literature. In our area a large portion of the population
      works in carnation (Dianthus caryophyllus) winter quarters, and many workers have
      symptoms of rhinitis and asthma related to exposition. OBJECTIVE: The purposes of
      this study were to investigate whether the symptoms induced by carnation were IgE
      mediated and to study the possible allergens involved. METHODS: A total of 16
      subjects employed in indoor carnation cultivation with symptoms during exposition
      time were studied along with 15 patients with allergic asthma who were not
      exposed to carnations and 15 healthy carnation workers used as control subjects.
      Skin prick tests with carnation extract and RASTs were performed. Protein bands
      were isolated by SDS-PAGE, and afterwards immunoblotting was performed to
      characterize the extract. Specific nasal provocation and nonspecific bronchial
      provocation tests were performed for all the asthmatic patients. Diurnal
      variation in peak expiratory flow was also measured. RESULTS: Skin prick test
      responses with carnation extract were positive in 15 of the 16 patients and
      negative in all control subjects. Nasal provocation test responses with carnation
      extract were positive in 13 of 16 patients. A significant correlation was seen
      between RAST and nasal provocation results (P <.01). Immunoblotting of sera from
      13 patients showed 2 major IgE-binding fractions of 34 and 35 kd in most of the
      patients, which could constitute the major allergen. Methacholine PD20 showed a
      variable degree of nonspecific bronchial hyperresponsiveness in all asthmatic
      subjects. CONCLUSION: Data demonstrate the involvement of carnation in
      occupational allergy, mediated by an IgE-dependent mechanism.

PMID- 10400859
TI  - Self-reported allergic reactions to peanut on commercial airliners.
AB  - BACKGROUND: Allergic reactions to food occurring on commercial airlines have not
      been systematically characterized. OBJECTIVE: We sought to describe the clinical
      characteristics of allergic reactions to peanuts on airplanes. METHODS:
      Participants in the National Registry of Peanut and Tree Nut Allergy who
      indicated an allergic reaction while on a commercial airliner were interviewed by
      telephone. RESULTS: Sixty-two of 3704 National Registry of Peanut and Tree Nut
      Allergy participants indicated a reaction on an airplane; 42 of 48 patients or
      parental surrogates contacted confirmed the reaction began on the airplane
      (median age of affected subject, 2 years; range, 6 months to 50 years). Of these,
      35 reacted to peanuts (4 were uncertain of exposure) and 7 to tree nuts, although
      3 of these 7 reacted to substances that may have also contained peanut. Exposures
      occurred by ingestion (20 subjects), skin contact (8 subjects), and inhalation
      (14 subjects). Reactions generally occurred within 10 minutes of exposure (32 of
      42 subjects), and reaction severity correlated with exposure route (ingestion >
      inhalation > skin). The causal food was generally served by the airline (37 of 42
      subjects). Medications were given in flight to 19 patients (epinephrine to 5) and
      to an additional 14 at landing/gate return (including epinephrine to 1 and
      intravenous medication to 2), totaling 79% treated. Flight crews were notified in
      33% of reactions. During inhalation reactions as a result of peanut allergy,
      greater than 25 passengers were estimated to be eating peanuts at the time of the
      reaction. Initial symptoms generally involved the upper airway, with progression
      to the skin or further lower respiratory reactions (no gastrointestinal
      symptoms). CONCLUSIONS: Allergic reactions to peanuts and tree nuts caused by
      accidental ingestion, skin contact, or inhalation occur during commercial
      flights, but airline personnel are usually not notified. Reactions can be severe,
      requiring medications, including epinephrine.

PMID- 10400860
TI  - Anaphylaxis and epinephrine auto-injector training: who will teach the teachers?
AB  - BACKGROUND: Anaphylaxis is the most urgent clinical immunologic event. Effective
      treatment is best achieved by administration of epinephrine. Accidental exposure
      to the responsible allergen is the most common cause of anaphylaxis, and because
      it could be fatal within minutes, epinephrine in preloaded syringes and auto
      injectors has been introduced. In our experience patients and medical personnel
      are not familiar with the use of this device. OBJECTIVE: We sought to assess
      community-based professionals' knowledge of epinephrine auto-injector use and
      their ability to educate patients. METHODS: Study participants consisted of a
      medical convention's delegates and emergency department personnel in metropolitan
      Toronto, as well as pharmacists of the target hospitals and retail pharmacists.
      Research assistants approached eligible professionals to fill out a questionnaire
      and demonstrate their ability to use a standard placebo auto-injector trainer.
      RESULTS: A total of 122 professionals (composed of emergency physicians, family
      practitioners, and pediatricians) consented to participate in this study. The
      majority of participants (81%) did not have a placebo trainer to educate their
      patients; 76% did not know the 2 available dose strengths. To provide
      instructions and reinforcement, physicians clearly must have the necessary skills
      and knowledge, yet only 25% of the study participants were able to demonstrate
      the 3 steps of injection correctly. CONCLUSION: Our study highlights a specific
      and important deficiency in medical professionals' care of patients at risk for
      anaphylaxis. The results challenge the current methods of educating
      professionals, as well as patients, when prescribing or using epinephrine auto
      injectors. Clearly a new approach to educating and maintaining such skills is
      required.

PMID- 10400861
TI  - Increased allergen production in turnip (Brassica rapa) by treatments activating
      defense mechanisms.
AB  - BACKGROUND: Practical applications to enhance the productivity of agriculture by
      using plants with improved resistance to pathogens are expected to increase in
      the near future. Defense proteins play an important role in pathogen resistance,
      and some defense-related proteins are significant cross-reacting allergens. For
      example, cross-allergies are common among patients allergic to natural rubber
      latex (NRL), which contains many defense-related proteins. OBJECTIVE: Using a
      model plant (ie, turnip), we studied whether allergen contents increase after
      treatments activating defense mechanisms of the plants. METHODS: Whole or wounded
      turnips treated with salicylic acid, ethephon, or water were incubated for 2, 4,
      or 8 days. Allergen content was investigated by IgE immunoblotting with sera from
      patients allergic to NRL. An induced protein that bound IgE most intensively was
      purified and further characterized by mass analysis, amino acid sequencing, IgE
      ELISA, and skin prick tests. RESULTS: In immunoblotting, clear IgE-binding bands
      were discernible only in samples from chemically treated plants. IgE was bound
      most intensively to a protein with an apparent molecular weight of 25 kd in SDS
      PAGE and with a determined molecular weight of 18.7 kd. Sequenced peptides of the
      18.7-kd protein showed over 70% homology to prohevein, a major allergen of NRL,
      and to many other prohevein-like defense proteins. In ELISA, sera from 30 of 34
      (88%) adults and 21 of 26 (81%) children previously shown to have IgE against
      prohevein bound to the purified protein. In skin prick testing with the protein,
      4 of 6 patients allergic to NRL had positive reactions. CONCLUSION: These results
      demonstrate that activating defense mechanisms of plants may considerably
      increase their allergen content.

PMID- 10400863
TI  - Adoptively transferred late allergic response is inhibited by IL-4, but not IL-5,
      antisense oligonucleotide.
AB  - BACKGROUND: We have shown previously that the late airways response (LAR) can be
      transferred by ovalbumin-primed CD4(+) T lymphocytes in Brown Norway rats. This
      response is associated with an increase of eosinophils and high expression of TH2
      cytokines (IL-4 and IL-5) in bronchoalveolar lavage (BAL) fluid. OBJECTIVE: In
      this study we hypothesized that the inhibition of IL-4 or IL-5 production in the
      CD4(+) cells transferred to a naive animal could decrease the LAR and prevent
      airway eosinophilia in response to antigen challenge. METHODS: CD4(+) cells,
      purified from the cervical lymph nodes of ovalbumin-sensitized rats, were
      maintained in culture for 6 hours with medium alone or with 10 microgram/mL IL-4
      antisense (AS), IL-5 AS, or control AS oligodeoxynucleotide. Then the cells were
      administrated intraperitoneally to naive rats, which were challenged 2 days later
      by a 5% ovalbumin aerosol. The lung resistance was measured for 8 hours, and then
      BAL was performed. Cytospin preparations from BAL cells were assessed for the
      presence of eosinophils by immunocytochemistry for major basic protein and for IL
      4, IL-5, and IFN-gamma expression. RESULTS: In rats injected with IL-4 AS-treated
      T cells, LAR, eosinophils, and IL-4 and IL-5 expression were significantly
      decreased compared with the other groups. Only IL-5 expression in BAL fluid was
      slightly decreased consequent to the transfer of IL-5 AS-treated T cells.
      CONCLUSION: This study demonstrates that, in the CD4(+) T cell-driven LAR, the
      early production of IL-4, but not IL-5, by the transferred CD4(+) cells is
      essential for the development of the LAR.

PMID- 10400862
TI  - Common allergens in avian meats.
AB  - BACKGROUND: Reports of allergy to bird meats are uncommon, and most have been in
      patients with "bird-egg syndrome." OBJECTIVE: We sought to evaluate 3 patients
      who reported allergic reactions to several avian meats, but who denied allergic
      reactions to eating eggs. The patients required yellow fever vaccine for entry
      into the military. METHODS: Patients were skin tested with commercial extracts of
      chicken, turkey, and egg, as well as with crude extracts made from dove and quail
      meat, and with yellow fever vaccine. Immunoblots for IgE antibody were performed
      by using the same materials used for skin testing plus extracts of duck and goose
      meat. RESULTS: Skin tests were positive in all 3 patients to chicken, turkey,
      dove, quail, and yellow fever vaccine and negative to egg. This included some
      positive skin test responses to bird meats the patients denied ever having eaten.
      The vaccine was administered in graded doses. Immunoblots revealed IgE binding to
      several proteins of similar molecular weights in all of the avian meats but not
      to egg or yellow fever vaccine. Again, this included IgE antibody to some bird
      meats the patients denied ever having eaten. CONCLUSION: Patients allergic to one
      bird meat may be allergic to others, including game birds, probably because of
      cross-reacting allergens. Such patients may have to exercise caution even when
      eating bird meats they have not previously ingested. The relationship of this
      allergy to yellow fever vaccine, if any, remains to be determined.

PMID- 10400864
TI  - Therapeutic efficacy of an anti-IL-5 monoclonal antibody delivered into the
      respiratory tract in a murine model of asthma.
AB  - BACKGROUND: IL-5 is central to the pathogenesis of airway eosinophilic
      inflammation and hyperresponsiveness associated with both atopic and nonatopic
      asthma. The therapeutic potential of IL-5 antagonists in asthma is supported by
      the inhibition of airway eosinophilia and hyperresponsiveness in animal models
      receiving neutralizing anti-IL-5 mAbs intravenously or intraperitoneally.
      OBJECTIVE: The purpose of this study was to test the hypothesis that mAbs against
      IL-5 delivered by way of the respiratory tract are as effective as those
      delivered intraperitoneally in diminishing the pulmonary eosinophilic
      inflammation and airway hyperresponsiveness in a murine model of ovalbumin
      induced asthma. METHODS: Ovalbumin-sensitized Balb/c mice were given an anti-IL-5
      mAb delivered intranasally or an isotype-matched control mAb delivered
      intranasally before respiratory challenge with ovalbumin. Outcome variables
      included respiratory system resistance responses to methacholine, bronchoalveolar
      lavage fluid cellularity, and lung histopathology. RESULTS: Anti-IL-5 mAbs
      administered intranasally to ovalbumin-sensitized and challenged mice
      significantly decreased eosinophil counts in bronchoalveolar lavage fluid and
      lung tissue and significantly reduced airway hyperresponsiveness relative to
      ovalbumin-sensitized and challenged mice that received either no mAb treatment or
      an isotype-matched control mAb. Similar results were obtained when an anti-IL-5
      mAb was given intraperitoneally. CONCLUSION: This is the first study to
      demonstrate that delivery of anti-IL-5 mAbs into the respiratory tract is
      efficacious in attenuating the asthma phenotype in a murine model. These results
      provide impetus for the development of inhaled IL-5 antagonists for the treatment
      of human asthma.

PMID- 10400865
TI  - CD80 (B7-1) and CD86 (B7-2) antigens on house dust mite-specific T cells in
      atopic disease function through T-T cell interactions.
AB  - BACKGROUND: CD80 (B7-1) and CD86 (B7-2) play an important role in antigen
      presentation to effector cells. Recent studies have demonstrated that these
      costimulatory molecules are also expressed on activated T cells. However, the
      functional role of CD80 and CD86 expressed on allergen-specific T cells in atopic
      diseases has not yet been clarified. OBJECTIVE: We sought to determine the
      functional role of CD80 and CD86 expressed on allergen-specific T cells in atopic
      diseases. METHODS: We assayed the expression of CD80 and CD86 on allergen
      specific T-cell lines from patients with perennial allergic rhinitis stimulated
      by Dermatophagoides farinae-crude (Der f-c) antigen, 1 of the major allergens
      causing house dust mite allergy. T-cell proliferation induced by Der f-c-specific
      T-T cell interactions was measured, and the role of CD80 and CD86 in this
      proliferation was examined. In addition, we compared the proportion of
      CD45RO+CD86(+) T cells in primary culture of PBMCs stimulated by Der f-c antigen
      between patients with perennial allergic rhinitis and control subjects. RESULTS:
      On T-cell activation, CD86 antigen was upregulated earlier than CD80. Both CD80
      and CD86 expressed on Der f-c-specific T cells could provide costimulatory
      signals to induce allergen-specific T-cell proliferation that was partially
      inhibitable by both anti-CD80 and anti-CD86 mAbs. The proportion of
      CD45RO+CD86(+) T cells in primary culture from atopic patients was significantly
      higher than that from control subjects. CONCLUSION: These results suggest that
      costimulatory molecules, such as CD80 and CD86, expressed on allergen-specific T
      cells may be involved in the amplification of allergen-specific immune responses
      through T-T cell interactions in atopic diseases.

PMID- 10400866
TI  - Repeated intratracheal inoculation of house dust mite (Dermatophagoides farinae)
      induces pulmonary eosinophilic inflammation and IgE antibody production in mice.
AB  - BACKGROUND: In vitro studies have shown that the biologic activities of dust mite
      allergens probably contribute to their allergenicity. However, little is known
      about their in vivo effect, which may lead to allergic inflammation and
      sensitization. OBJECTIVE: In this study we characterized the pathologic and
      immunologic responses of mice after repetitive challenge with dust mite
      Dermatophagoides farinae. METHODS: Der f crude extract was intratracheally
      instilled into female BALB/c mice either once or a total of 10 times at 1-week
      intervals. The inflammatory responses, morphologic changes, IgE antibody and
      cytokine levels, and costimulatory molecular B7 expression in the airways were
      then monitored. RESULTS: We demonstrated that single Der f challenge provoked an
      acute neutrophilic inflammation in the airways. After repeated Der f challenge,
      there was chronic inflammation characterized by increased numbers of lymphocytes
      and eosinophils in bronchoalveolar lavage (BAL) fluids. Histopathologically, the
      numbers of goblet cells and mast cells were significantly increased in the
      airways of these mice. Repetitive challenge elicited Der f-specific IgE antibody,
      increased IL-5 and IFN-gamma level in BAL fluids, and enhanced costimulatory B7
      molecule expression on BAL cells. CONCLUSIONS: Our findings are in agreement with
      those of other in vitro studies concerning the properties of dust mite allergens.
      Prolonged inhalation of Der f without adjuvant may represent an optimal condition
      to develop experimental animal models of allergic lung diseases.

PMID- 10400867
TI  - Increased postmortem serum mast cell tryptase in a fatal anaphylactoid reaction
      to nonionic radiocontrast medium.

PMID- 10400868
TI  - Allergic bronchopulmonary aspergillosis with multiple Streptococcus pneumoniae
      lung abscesses: an unusual initial case presentation.

PMID- 10400869
TI  - Antigen-specific recall urticaria to a peptide-based vaccine.

PMID- 10400870
TI  - Exposure of submarine personnel to house dust mite allergens.

PMID- 10400871
TI  - Allergen avoidance at high altitude and urinary eosinophil protein X.

PMID- 10400872
TI  - Eosinophil involvement and serum IgE level in HIV-1-infected children.

PMID- 10400873
TI  - A variant in the gene for GM-CSF, I117T, is associated with atopic asthma in a
      Swiss population of asthmatic children.

PMID- 10400874
TI  - Interferon-gamma exacerbates polymethylmethacrylate particle-induced interleukin
      6 release by human monocyte/macrophages in vitro.
AB  - Periprosthetic membranes commonly observed at sites of total joint implant
      loosening exhibit abundant macrophages and particulate debris. Macrophages
      phagocytose orthopedic debris and release the pro-inflammatory mediators
      interleukin-1, interleukin-6, tumor necrosis factor-alpha, and prostaglandin E2.
      In addition, other immunologic agents, such as interferon-gamma, are present in
      tissues harvested from the bone-implant interface of failed orthopedic implants.
      The present study examined the effects of interferon-gamma on
      polymethylmethacrylate (PMMA) particle-challenged monocyte/macrophages in vitro.
      The effects of interferon-gamma were determined by measuring interleukin-6 and
      tumor necrosis factor-alpha release by primary human monocyte/macrophages
      following exposure to PMMA particles. Exposure of the monocyte/macrophages to
      PMMA particles resulted in a dose-dependent release of interleukin-6 and tumor
      necrosis factor-alpha at 48 h. The interleukin-6 release in response to PMMA
      particle challenge was stimulated by 76% and 127% in the presence of 1.0 and 10.0
      ng/mL of interferon-gamma, respectively. Interferon-gamma challenge alone did not
      alter interleukin-6 release relative to controls. In contrast to interleukin-6,
      interferon-gamma challenge stimulated tumor necrosis factor-alpha release in a
      dose-dependent manner. In the presence of particles, addition of 1.0 and 10.0
      ng/mL of interferon-gamma resulted in 17% and 171% increases in the levels of
      tumor necrosis factor-alpha release, respectively, relative to cultures
      challenged solely with particles. Blocking antibody to IFN-gamma inhibited the
      effect of IFN-gamma on particle-induced interleukin-6 and tumor necrosis factor
      alpha release. The data presented in this study demonstrate that the immunologic
      modulator interferon-gamma exacerbates monocyte/macrophage release of the pro
      inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha in response
      to PMMA particle challenge in vitro.

PMID- 10400875
TI  - Porous biodegradable polymeric scaffolds prepared by thermally induced phase
      separation.
AB  - Poly(L-lactic acid) and its copolymers with D-lactic and glycolic acid were used
      to fabricate various porous biodegradable scaffolds suitable for tissue
      engineering and drug delivery based on a thermally induced phase separation
      (TIPS) technique. A variety of parameters involved in TIPS process, such as types
      of polymers, polymer concentration, solvent/nonsolvent ratio, and quenching
      temperature, were examined in detail to produce a wide array of micro- and
      macroporous structures. A mixture of dioxane and water was used for a binary
      composition of solvent and nonsolvent, respectively. In particular, the
      coarsening effect of pore enlargement affected by controlling the quenching
      temperature was used for the generation of a macroporous open cellular structure
      with pore diameters above 100 microm. The use of amorphous polymers with a slow
      cooling rate resulted in a macroporous open cellular structure, whereas that of
      semicrystalline polymers with a fast cooling rate generated a microporous closed
      cellular structure. The fabricated porous devices loaded with recombinant human
      growth hormone (rhGH) were tested for the controlled delivery of rhGH, as a
      potential additional means to cell delivery.

PMID- 10400876
TI  - Biological activities of sustained polymyxin B release from calcium phosphate
      biomaterial prepared by dynamic compaction: an in vitro study.
AB  - Calcium phosphate ceramics (CaP) have recently been proposed as a potential
      matrix for a bioactive drug delivery system (DDS) in which the effect in situ of
      a released therapeutic agent is favored by the biocompatibility,
      osteoconductivity, and bioresorption of the ceramic material. Polymyxin B (PMB)
      is a polypeptidic antibiotic which undergoes thermodamage above 60 degrees C. The
      dynamic compaction method was developed to consolidate the drug load on CaP
      powder without external heating. Two projectile velocities (50 and 25 m/s) were
      used here to achieve powder consolidation. Among the different techniques used to
      associate therapeutic agents with CaP, wet adsorption was performed before the
      dynamic compaction process. The PMB release profile was measured by a capillary
      electrophoresis technique, CaP crystallography was studied by x-ray diffraction,
      and CaP physicochemical analysis was performed by infrared spectroscopy. The
      biological activities of PMB-loaded compacted CaP were determined by the effect
      of the antibiotic and monocyte/macrophage degradation on compact surfaces. PMB
      release began after 2-3 days of incubation for blocks compacted at 25 m/s
      velocity and on day 5 for those compacted at 50 m/s velocity. A discrepancy was
      noted between the amounts of PMB released (0.5-2.1 mg) and the amounts initially
      compacted (2-8 mg) with CaP powder. The biological activities (antibacterial
      activity and inhibited lipopolysaccharide effects on monocyte/macrophage CaP
      degradation) of PMB released from compacted calcium-deficient apatite were
      unaltered. Thus, dynamic compaction allows PMB to be used with CaP ceramics
      without any loss in its integrity and biological effects.

PMID- 10400877
TI  - Kinetic study of bone ingrowth and ceramic resorption associated with the
      implantation of different injectable calcium-phosphate bone substitutes.
AB  - This study investigated the in vivo performance of two composite injectable bone
      substitutes (IBS), each with different calcium-phosphate particles granulometries
      [40-80 (IBS 40-80) and 200-500 microm (IBS 200-500)]. These biomaterials were
      obtained by associating a biphasic calcium-phosphate (BCP) ceramic mineral phase
      with a 3% aqueous solution of a cellulosic polymer (hydroxy-propyl-methyl
      cellulose). Both materials were injected for periods of 2, 3, 8, or 12 weeks into
      bone defects at the distal end of rabbit femurs. Quantitative results on new bone
      formation, BCP resorption, and staining for tartrate-resistant acid phosphatase
      (TRAP) activity were studied for statistical purposes. Measurements with scanning
      electron microscopy and image analysis showed that the final rates of newly
      formed bone were similar for both tested IBS after 12 weeks of implantation. Bone
      colonization occurred more extensively during early implantation times for IBS 40
      80 than for IBS 200-500. For the latter, BCP degradation occurred regularly
      throughout the implantation period, whereas it was very intensive during the
      first 2 weeks for IBS 40-80. Positive TRAP-stained degradation cells were
      significantly more numerous for IBS 40-80 than for IBS 200-500 regardless of
      implantation time. With the granulometry of either mineral phase, both tested IBS
      supported extensive bone colonization, which was greater than that previously
      reported for an equivalent block of macroporous BCP. The resorption-bone
      substitution process seemed to occur earlier and faster for IBS 40-80 than for
      IBS 200-500. Both tested IBS expressed similar biological efficiency, with
      conserved in vivo bioactivity and bone-filling ability.

PMID- 10400878
TI  - A novel high-viscosity, two-solution acrylic bone cement: effect of chemical
      composition on properties.
AB  - Solutions of poly(methyl methacrylate) (PMMA) powder predissolved in methyl
      methacrylate (MMA) have been developed as an alternative to current powder/liquid
      bone cements. They utilize the same addition polymerization chemistry as
      commercial cements, but in mixing and delivering via a closed system, porosity is
      eliminated and the dependence of material properties on the surgical technique is
      decreased. Twelve different sets of compositions were prepared, with two
      solutions of constant polymer-to-monomer ratio (80 g of PMMA/100 mL of MMA) and
      all combinations of four benzoyl peroxide (BPO) initiator levels added to the
      first solution and three N, N-dimethyl-p-toluidine (DMPT) activator levels added
      to the second. These compositions were tested, along with Simplex-P bone cement,
      for effects of BPO and DMPT concentrations on polymerization exotherm, setting
      time, flexural strength, modulus, and maximum strain. The results show that each
      of these dependent variables was affected significantly by the individual
      concentrations of BPO and DMPT and their interactions. The flexural strength,
      modulus, and polymerization exotherm reached their maximums at about a 1:1 molar
      ratio of BPO to DMPT. Most compositions had exotherms, setting times, and maximum
      strains within the range of commercial cements and flexural strengths and moduli
      up to 54 and 43% higher than Simplex-P, respectively.

PMID- 10400879
TI  - Compressive and shear properties of alginate gel: effects of sodium ions and
      alginate concentration.
AB  - The equilibrium and viscoelastic properties of alginate gel crosslinked with Ca2+
      were determined as a function of alginate concentration and duration of exposure
      to physiologic concentrations of NaCl. Compressive and shear stress relaxation
      tests and oscillatory shear tests were performed to measure the material
      properties at two time periods after storage in NaCl compared to no NaCl
      exposure. The effect of concentration was determined by testing 1-3% alginate gel
      in a bath of physiological NaCl and CaCl2. After 15 h of exposure to NaCl, the
      compressive, equilibrium shear, and dynamic shear moduli decreased by 63, 84, and
      90% of control values, respectively. The material properties exhibited no further
      changes after 7 days of exposure to NaCl. The loss angle and amplitude of the
      relaxation function in the shear also decreased, indicating less viscous
      behaviors in both dynamic and transient configurations. All moduli, but not the
      loss angle, significantly increased with increasing alginate concentration. The
      observed decrease in compressive and shear stiffness for alginate gel after
      exposure to Na+ was significant and indicated that physiological conditions will
      soften the gel over a time period of up to 7 days after gelation. The alginate
      gel retains significant solid-like behaviors, however, as measured by a loss
      angle of approximately 3 degrees. This study provides the first available data
      for material properties of alginate gel tested in physiological saline.

PMID- 10400880
TI  - Quantification of bone ingrowth into porous block hydroxyapatite in humans.
AB  - This study sought to quantify bone ingrowth from a single bone-implant surface
      into porous block hydroxyapatite used in maxillofacial applications. Seventeen
      maxillary hydroxyapatite implants (implant time of 4-138 months, 39-month mean)
      were harvested for analysis from 14 patients. The implants had been placed into
      the lateral maxillary wall during orthognathic surgery, juxtapositioned to the
      maxillary sinus. Ingrowth was measured in 100-microm increments from a bone
      implant interface to a depth of 1500 microm. Bone ingrowth averaged over the 14
      patients (0-1100 microm depth) is described by the equation % ingrowth - 20% *
      (depth in millimeters) + 41.25% (R2 = 0.98, n = 10 incremental depths). Beyond
      1100 microm, the average ingrowth remained constant at 15.0 +/- 0.7%. The
      duration of implantation also showed as affect on the percent ingrowth into the
      implants at the incremental depths, and the percent ingrowth asymptotically
      approached a maximum. Overall, the composite average data from all depths is best
      described by the logarithmic function % ingrowth = 15% * ln(implantation time in
      months) - 24.0% (R2 = 0.71, n = 14 patients). Several factors may come into play
      in determining bone ingrowth including the mechanical environment, the
      osteoconductivity of the implant material, and the osteogenic capability of the
      tissues in the pore spaces. Measurements of bone ingrowth are most influenced by
      the depth into the implant and the time the implant was in the body; the age of
      the patient had little affect on bone ingrowth.

PMID- 10400881
TI  - In vitro response of human fibroblasts to commercially pure titanium.
AB  - The generation of metal particles through surface wear of prosthetic joints has
      been associated with biological reactions that may lead to prosthetic component
      loosening. The role of the macrophage in these reactions has been studied
      extensively, but that of the fibroblast has not. The few fibroblast studies that
      there have been have shown that particles of several metals, with sizes over a
      wide range, can promote cytokine release and may cause cell necrosis. The intent
      of this study was to determine if there are metal particle exposure threshold
      levels that result in morphological changes and cell necrosis of fibroblasts in
      peri-articular tissues. Retrieved human fibroblasts (superior medial plica) were
      cultured in standard fashion and then were exposed to various particle dosages of
      commercially pure Titanium (cpTi). Cell morphological changes and necrosis were
      observed to occur when the total mass of the particle dosage exceeded a threshold
      level. These data imply that these cell responses occur at threshold levels of
      wear particle exposure.

PMID- 10400882
TI  - Compliance, elastic modulus, and burst pressure of small-intestine submucosa
      (SIS), small-diameter vascular grafts.
AB  - Small-intestine submucosa (SIS) is cell-free collagen, 100 mu thick, derived from
      the small intestine. It has been used as a vascular graft and has the highly
      desirable property of remodeling itself to become host tissue. To date there has
      been limited reporting on its preimplantation mechanical properties as a vascular
      graft. In this study, compliance, elastic modulus, and burst pressure have been
      measured on 5- and 8-mm SIS grafts. The compliance (percent of diameter increase
      for a pressure rise from 80 to 120 mmHg) was 4.6% av (range 2.9 to 8.6%) for the
      5-mm grafts. For the 8-mm graft, the increase in diameter for the same pressure
      rise was 8.7% av (range 7.2 to 9.5%). The modulus of elasticity (E) increased
      exponentially with increasing pressure according to E = E(o)e(alphaP), where Eo
      is the zero-pressure modulus and alpha is the exponent that describes the rate of
      increase in E with pressure; the units for E, Eo, and P are g/cm2. The mean value
      for Eo was 4106 (g/cm2 range 1348-5601). The mean value for alpha was 0.0059
      (range 0.0028-0.0125). At 100 mmHg, the mean value for E was 8.91 x 10(3) g/cm2
      (range 1.02-8.80 x 10(3)). The mean burst pressure for 5.5-mm grafts was 3517 mm
      Hg (range 2069-4654). In terms of preimplant compliance, the small-diameter SIS
      graft is about (1/2) as compliant as the dog carotid artery, about four times
      more compliant than a typical vein graft, and more than an order of magnitude
      more compliant than synthetic vascular grafts.

PMID- 10400883
TI  - Structure-function relationships for coralline hydroxyapatite bone substitute.
AB  - To improve the understanding of the functional requirements of trabecular bone
      substitutes, the structure-function relationships of coralline hydroxyapatite
      were determined and compared to those of trabecular bone from a variety of
      anatomic sites. Mechanical properties and permeability of cylindrical coralline
      hydroxyapatite specimens were measured and related to various morphological
      parameters that were obtained from analysis of high-resolution (20 microm)
      computer reconstructions of each specimen. Results indicated the average (+/-SD)
      Young's modulus (2900 +/- 1290 MPa, n = 20) and permeability (0.50 +/- 0.19 x 10(
      9) m2, n = 21) of the coralline hydroxyapatite were within the range of values
      exhibited by high density trabecular bone; ultimate stress (5.87 +/- 1.92 MPa, n
      = 13), while in the range of mid-density trabecular bone, was low considering its
      high volume fraction (31.3 +/- 1.9%, n = 49); and ultimate strain (0.22 +/-
      0.03%, n = 13) was much lower than that of trabecular bone from any anatomic
      site. The only correlation found between mechanical and morphological parameters
      was between Young's modulus and "fabric" (a scalar measure of architecture that
      combined the degree of microstructural anisotropy with orientation). These
      results provide insight into the in vivo performance of this implant, as well as
      the biomechanical requirements for successful trabecular bone substitutes in
      general.

PMID- 10400884
TI  - Polypeptide resurfacing method improves fibroblast's adhesion to hyaluronan
      strands.
AB  - Hyaluronic acid (hyaluronan, HyA) is a matrix component that takes part in cell
      adhesion and growth in normal and repaired tissues. Since it is soluble in water,
      HyA has been of limited use in tissue engineering of artificial matrices. Recent
      studies demonstrate that polypeptides have the twin advantages of reducing
      solubility of HyA and improving cellular attachment via cell surface adhesion
      molecule receptors. This paper describes a new approach of using a polypeptide
      resurfacing method to enhance the attachment of cells to HyA strands. HyA strands
      were crosslinked by glutaraldehyde and then resurfaced with poly-D-lysine, poly-L
      lysine, glycine, or glutamine. After inoculation with fibroblasts in vitro,
      modified HyA was evaluated with histological and immunohistochemical staining
      methods for cell adhesion and proliferation. Modified HyA with fibroblast cells
      also were implanted in vivo. The results show that (1) both polylysines enhanced
      fibroblast adhesion to crosslinked HyA strands; (2) HyA strands were able to be
      crosslinked well by 3 days of treatment in glutaraldehyde, and as a biomaterial
      they could resist biodegradation; (3) modified HyA has good biocompatibility,
      both in vitro and in vivo. The results demonstrate that HyA material resurfaced
      by polypeptides has positive advantages for cellular adhesion. Resurfaced HyA has
      much potential as an improved biomaterial for clinical usage.

PMID- 10400885
TI  - A novel approach to AFM characterization of adhesive tooth-biomaterial
      interfaces.
AB  - A novel approach is proposed for studying tooth-biomaterial interactions with
      high resolution. Thus far, polished interfaces examined by AFM have not disclosed
      much detail, mainly due to the destruction of soft surface texture and the
      smearing of polishing debris across the interface that obscures the actual ultra
      structure. Therefore the practical utility of diamond-knife microtomy as a sample
      preparation technique for imaging tooth-biomaterial interfaces by AFM with high
      resolution was tested in this study and compared to that of ultra-fine mechanical
      polishing techniques. The AFM images clearly demonstrated the enhanced potential
      of diamond-knife microtomy for nondestructively producing clean cross-sections
      through interfaces that allow the interfacial ultra-structure to be imaged by AFM
      with a resolution equaling that of TEM. This novel approach opens the field to
      the full range of scanning probe microscopy, including physical and chemical
      surface characterization of interfaces with a mix of soft and hard substrates.

PMID- 10400886
TI  - Bioactive glasses induce chemiluminescence by human polymorphonuclear leukocytes.
AB  - The effect of bioactive glasses on human polymorphonuclear leukocytes (PMNLs)
      were studied in vitro by a chemiluminescence (CL) assay. Eight different glasses
      were chosen. All glasses induced a rapid CL response by human PMNLs, which proved
      to be dose dependent. The CL response also seemed to depend on the durability of
      the glasses. The least durable glass caused the highest CL response, and highly
      durable glasses caused only low CL responses by the cells.

PMID- 10400888
TI  - New synthetic absorbable polymers as BMP carriers: plastic properties of poly-D,L
      lactic acid-polyethylene glycol block copolymers.
AB  - Bone morphogenetic proteins (BMPs) are biologically active molecules capable of
      eliciting new bone formation. In combination with biomaterials, these proteins
      can be used in a clinical setting as bone-graft substitutes to promote bone
      repair. To find new synthetic absorbable polymers with plastic nature that can be
      used as BMP-carrier materials, six types of poly-D,L-lactic acid-polyethylene
      glycol block copolymer (PLA-PEG) with various molecular weights of PLA and PEG
      were synthesized. These were PLA6, 500-PEG3,000 (P-1), PLA11,500-PEG3,000 (P-2),
      PLA17,500-PEG3,000 (P-3), PLA6,500-PEG1,000 (P-4), PLA15,000-PEG8,000 (P-5), and
      PLA8, 500-PEG1,000 (P-6). Fifty milligrams of these polymers was mixed with 0
      microg (control) or 5, 10, or 20 microg of recombinant human BMP-2 (rhBMP-2).
      These pellets were implanted into the dorsal muscle pouches of 144 mice (six
      pellets consisting of the same polymer and dose of rhBMP-2 for a specific group).
      Three weeks after surgery, the pellets were harvested and examined by
      radiographic and histological methods. All P-1 pellets with 10 or 20 microg of
      rhBMP-2 showed bone formation with hematopoietic marrow and bony trabeculae, as
      did one third of those with 5 microg of rhBMP-2. The incidence of new bone
      formation with P-2 pellets or that of P-5 pellets was lower than that of P-1
      pellets. No bone was formed in any other type of pellet. These results indicated
      that the PLA6, 500-PEG3,000 polymer with plastic properties was found to work
      well as a BMP carrier.

PMID- 10400887
TI  - Effect of prosthetic titanium wear debris on mitogen-induced monocyte and
      lymphoid activation.
AB  - Wear debris generated by joint implant components has been reported to activate
      inflammatory and immune cells. Particulate debris derived from prosthetic
      material induces monocytes/macrophages, lymphocytes, synoviocytes, and
      fibroblasts to secrete cellular products, such as cytokines, which mediate
      inflammation. It has been speculated that degradation products impair the ability
      of inflammatory and immune cells to mount a protective response against noxious
      agents and infectious organisms by interfering with cell activation. Recent in
      vitro studies suggest that soluble metal ions inhibit T and B cell activation,
      but it is not known whether insoluble metal particles generated by prosthetic
      wear in tissue have the same effect. The purpose of the present study was to
      determine whether titanium wear debris retrieved from periprosthetic tissues
      surrounding a failed knee prosthesis suppresses activation of human monocytic and
      lymphoid cells. Peripheral blood monocytes and lymphocytes were incubated with
      the nonspecific activator pokeweed mitogen (PWM) in the presence or absence of
      titanium particles. Cell proliferative capacity and production of interleukins IL
      1beta and IL-2 were determined as measures of activation. Titanium wear debris
      induced monocyte secretion of IL-1beta at levels comparable to those induced by
      PWM alone. In combination with PWM, titanium wear debris stimulated monocytes to
      secrete higher concentrations of IL-1beta than is stimulated by titanium itself
      or by PWM alone. Titanium wear debris did not activate lymphocytes, as indicated
      by marginal changes in DNA synthesis and IL-2 secretion, nor did it suppress the
      PWM-induced stimulation of DNA synthesis and IL-2 secretion. Our study suggests
      that nonspecific mitogen activators in spite of exposure to titanium wear debris
      can stimulate monocytic and lymphoid cells.

PMID- 10400889
TI  - Cochlear nerve projections to the small cell shell of the cochlear nucleus: the
      neuroanatomy of extremely thin sensory axons.
AB  - Labeling cochlear nerve fibers in the inner ear of chinchillas with biotinylated
      dextran polyamine was used to trace the thin fibers (Type II), which likely
      innervate outer hair cells. These axons, 0. 1-0.5 microm in diameter, were
      distinguished from the thicker Type I, fibers innervating inner hair cells, and
      traced to small-cell clusters in the cochlear nucleus. This study provided two
      major new insights into the outer hair cell connections in the cochlear nucleus
      and the potential significance of very thin axons and synaptic nests, which are
      widespread in the CNS. 1) EM serial reconstructions of labeled and unlabeled
      material revealed that Type II axons rarely formed synapses with conventional
      features (vesicles gathered at junctions). Rather, their endings contained arrays
      of endoplasmic reticulum and small spherical vesicles without junctions. 2) Type
      II axons projected predominantly to synaptic nests, where they contacted other
      endings and dendrites of local interneurons (small stellate and mitt cells, but
      not granule cells). Synaptic nests lacked intrinsic glia and, presumably, their
      high-affinity amino acid transporters. As functional units, nests and their Type
      II inputs from outer hair cells may contribute to an analog processing mode,
      which is slower, more diffuse, longer-lasting, and potentially more plastic than
      the digital processors addressed by inner hair cells.

PMID- 10400890
TI  - Region-specific induction of deltaFosB by repeated administration of typical
      versus atypical antipsychotic drugs.
AB  - Whereas acute administration of many types of stimuli induces c-Fos and related
      proteins in brain, recent work has shown that chronic perturbations cause the
      region-specific accumulation of novel Fos-like proteins of 35-37 kD. These
      proteins, termed chronic FRAs (Fos-related antigens), have recently been shown to
      be isoforms of DeltaFosB, which accumulate in brain due to their enhanced
      stability. In the present study, we sought to extend earlier findings that
      documented the effects of acute administration of antipsychotic drugs (APDs) on
      induction of Fos-like proteins by investigating the ability of typical and
      aytpical APDs, after chronic administration, to induce these DeltaFosB isoforms
      in several brain regions implicated in the clinical actions of these agents. By
      Western blotting we found that chronic administration of the typical APD,
      haloperidol, dramatically induces DeltaFosB in caudate-putamen (CP), a brain
      region associated with the extrapyramidal side effects of this drug. A smaller
      induction was seen in the nucleus accumbens (NAc) and prefrontal cortex (PFC),
      brain regions associated with the antipsychotic effects of the drug. In contrast,
      chronic administration of the prototype atypical APD clozapine failed to
      significantly increase levels of DeltaFosB in any of the three brain regions, and
      even tended to reduce DeltaFosB levels in the NAc. Two putative atypical APDs,
      risperidone and olanzapine, produced small but still significant increases in the
      levels of DeltaFosB in CP, but not NAc or PFC. Studies with selective receptor
      antagonists suggested that induction of DeltaFosB in CP and NAc is most dependent
      on antagonism of D2-D3 dopamine receptors, with antagonism of D1-like receptors
      most involved in the PFC. Immunohistochemical analysis confirmed the greater
      induction of DeltaFosB in CP by typical versus atypical APDs, with no significant
      induction seen in PFC with either class of APD. Together, these findings
      demonstrate that repeated administration of APDs results in the induction of long
      lasting Fos-like transcription factors that could mediate some of the persistent
      and region-specific changes in brain function associated with chronic drug
      exposure. Synapse 33:118-128, 1999.

PMID- 10400891
TI  - Acute and chronic administration of the selective sigma1 receptor agonist SA4503
      significantly alters the activity of midbrain dopamine neurons in rats: An in
      vivo electrophysiological study.
AB  - In this study, we examined the effect of the acute and repeated administration of
      the selective sigma (sigma)1 receptor agonist 1-(3, 4-dimethoxyphenethyl)-4-(3
      phenylpropyl)piperazine dihydrochloride (SA4503) on the number and firing pattern
      of spontaneously active dopamine (DA) neurons in substantia nigra pars compacta
      (SNC) and ventral tegmental area (VTA) in anesthetized, male Sprague-Dawley rats.
      This was accomplished using the technique of in vivo extracellular single unit
      recording. The intravenous administration of SA4503 (0.01-1.28 mg/kg) did not
      significantly alter the firing rate or pattern of spontaneously active DA neurons
      in either the SNC or VTA. A single injection of either 0.1 or 0.3 mg/kg i.p. of
      SA4503 did not alter the number of spontaneously active SNC and VTA DA neurons.
      In contrast, a single injection of 1 mg/kg i.p. of SA4503 produced a significant
      decrease and increase in the number of spontaneously active SNC and VTA DA
      neurons, respectively. Overall, the firing pattern parameters of spontaneously
      active SNC DA neurons were altered more significantly than those of spontaneously
      active VTA DA neurons following the acute administration of SA4503. The repeated
      administration (one injection per day for 21 days) of 0.3 and 1 mg/kg i.p. of
      SA4503 produced a significant increase in the number of spontaneously active VTA
      DA neurons. In addition, the repeated administration of SA4503 produced a greater
      alteration of the firing pattern of spontaneously active VTA compared to SNC DA
      neurons. Our results suggest that the administration of SA4503 significantly
      alters the activity of spontaneously active midbrain DA neurons, particularly
      those in the VTA following repeated administration.

PMID- 10400892
TI  - Presence of mu-opioid receptors in targets of efferent projections from the
      central nucleus of the amygdala to the nucleus of the solitary tract.
AB  - Opioids acting at mu-opioid receptors (MORs) within the nucleus of the solitary
      tract (NTS) potently modulate autonomic functions that are also known to be
      influenced by inputs from the central nucleus of the amygdala (CEA). In addition,
      many of the physiological effects of MOR agonists have been attributed to
      interactions with neurons that contain gamma-aminobutyric acid (GABA), one of the
      neurotransmitters present in CEA-derived terminals and their targets in the
      medial NTS. Together, these observations suggest that MORs are present at pre- or
      postsynaptic sites within the CEA to NTS circuitry. To test this hypothesis, we
      combined anterograde transport of biotinylated dextran amine (BDA) with
      immunogold-silver localization of an antipeptide antiserum against the MOR in the
      NTS of adult rats. In animals receiving bilateral CEA injections of BDA,
      anterogradely labeled axons were seen throughout the rostrocaudal NTS. Electron
      microscopy of the medial NTS at rostral and intermediate levels showed
      anterograde BDA-labeling in many small unmyelinated axons and axon terminals,
      none of which contained detectable MOR. The BDA-labeled axon terminals formed
      mainly symmetric, inhibitory-type synapses with somata and dendrites. Over half
      of the somatic and approximately 10% of the dendritic targets showed nonsynaptic
      plasmalemmal immunogold labeling for MOR. The BDA-labeled axon terminals were
      also frequently apposed by other small axons that contained MORs. These results
      suggest that within the medial NTS, MOR agonists modulate the postsynaptic
      inhibition produced by CEA afferents and also play a role in the presynaptic
      release of other neurotransmitters.

PMID- 10400894
TI  - Morphine alters the structure of neurons in the nucleus accumbens and neocortex
      of rats.
AB  - Rats were given repeated injections of 10 mg/kg of morphine and were then left
      undisturbed for 24-25 days before their brains were processed for Golgi-Cox
      staining. Prior exposure to morphine decreased the complexity of dendritic
      branching and the number of dendritic spines on medium spiny neurons in the shell
      of the nucleus accumbens and on pyramidal cells in the prefrontal and parietal
      cortex. It is suggested that some of the long-term behavioral consequences of
      repeated exposure to morphine may be due to its ability to reorganize patterns of
      synaptic connectivity in the forebrain.

PMID- 10400893
TI  - Interrupted expression of NAC-1 augments the behavioral responses to cocaine.
AB  - NAC-1 is an mRNA that is increased selectively in the nucleus accumbens after
      acute and repeated cocaine administration. Antisense or control oligonucleotides
      were microinjected into the nucleus accumbens of rats to define the role of NAC-1
      in the behavioral responses to acute systemic cocaine. Antisense oligonucleotides
      decreased NAC-1 mRNA levels by 26% and markedly enhanced the motor stimulant
      response to an acute cocaine injection compared to sense oligonucleotide
      microinjections. The augmentation in cocaine motor behavior produced by NAC-1
      antisense pretreatment in the nucleus accumbens was not associated with increased
      dopamine release as estimated by microdialysis. In contrast, the behavioral
      response to dopamine microinjection into the nucleus accumbens was increased
      after antisense oligonucleotide treatment, while the motor response to mu-opioid
      receptor stimulation was unaltered. These data suggest that the induction of NAC
      1 by cocaine may be a compensatory mechanism that minimizes the behavioral impact
      of cocaine administration by regulating postsynaptic dopamine transmission within
      the nucleus accumbens.

PMID- 10400903
TI  - Inaugural editorial: a new era for Circulation Research.

PMID- 10400904
TI  - Circulation Research Online Only : July 9, 1999.

PMID- 10400905
TI  - Mechanotransduction of rat aortic vascular smooth muscle cells requires RhoA and
      intact actin filaments.
AB  - The growth-promoting effect of mechanical stress on vascular smooth muscle cells
      (VSMCs) has been implicated in the progress of vascular disease in hypertension.
      Extracellular signal-regulated kinases (ERKs) have been implicated in cellular
      responses, such as vascular remodeling, induced by mechanical stretch. However,
      it remains to be determined how mechanical stretch activates ERKs. The
      cytoskeleton seems the most likely candidate for force transmission into the
      interior of the cell. Therefore, we examined (1) whether the cytoskeleton
      involves mechanical stretch-induced signaling, (2) whether Rho is activated by
      stretch, and (3) whether Rho mediates the stretch-induced signaling in rat
      cultured VSMCs. Mechanical stretch activated ERKs, with a peak response observed
      at 20 minutes, followed by a significant increase in DNA synthesis. Treatment
      with the ERK kinase-1 inhibitor, PD98059, inhibited the stretch-induced increase
      in DNA synthesis. Cytochalasin D, which selectively disrupts the network of actin
      filaments, markedly inhibited stretch-induced ERK activation. In the control
      state, RhoA was observed predominantly in the cytosolic fraction, but it was
      translocated in part to the particulate fraction in response to mechanical
      stretch. Botulinum C3 exoenzyme, which inactivates Rho p21 (known to participate
      in the reorganization of the actin cytoskeleton), attenuated stretch-induced ERK
      activation. Inhibition of Rho kinase (p160ROCK) also suppressed stretch-induced
      ERK activation dose dependently. Our results suggest that mechanotransduction in
      VSMCs is dependent on intact actin filaments, that Rho is activated by stretch,
      and that Rho/p160ROCK mediates stretch-induced ERK activation and vascular
      hyperplasia.

PMID- 10400906
TI  - A dual inhibitor of platelet-derived growth factor beta-receptor and Src kinase
      activity potently interferes with motogenic and mitogenic responses to PDGF in
      vascular smooth muscle cells. A novel candidate for prevention of vascular
      remodeling.
AB  - PP1 has previously been described as an inhibitor of the Src-family kinases
      p56(Lck) and FynT. We have therefore decided to use PP1 to determine the
      functional role of Src in platelet-derived growth factor (PDGF)-induced
      proliferation and migration of human coronary artery smooth muscle cells
      (HCASMCs). A synthetic protocol for PP1/AGL1872 has been developed, and the
      inhibitory activity of PP1/AGL1872 against Src was examined. PP1/AGL1872 potently
      inhibited recombinant p60(c-src) in vitro and Src-dependent tyrosine
      phosphorylation in p60(c-srcF572)-transformed NIH3T3 cells. PP1/AGL1872 also
      potently inhibited PDGF-stimulated migration of HCASMCs, as determined in the
      modified Boyden chamber, as well as PDGF-stimulated proliferation of HCASMCs.
      Surprisingly, in addition to inhibition of Src kinase, PP1/AGL1872 was found to
      inhibit PDGF receptor kinase in cell-free assays and in various types of intact
      cells, including HCASMCs. PP1/AGL1872 did not inhibit phosphorylation of the
      vascular endothelial growth factor receptor KDR (VEGF receptor-2; kinase-insert
      domain containing receptor) in cell-free assays as well as in intact human
      coronary artery endothelial cells. In line with the insensitivity of KDR,
      PP1/AGL1872 had only a weak effect on vascular endothelial growth factor
      stimulated migration of human coronary artery endothelial cells. On treatment of
      cells expressing different receptor tyrosine kinases, the activities of the
      epidermal growth factor receptor, fibroblast growth factor receptor-1, and
      insulin-like growth factor-1 receptor were resistant to PP1/AGL1872, whereas PDGF
      alpha-receptor was susceptible, albeit to a lesser extent than PDGF beta
      receptor. These data suggest that the previously described tyrosine kinase
      inhibitor PP1/AGL1872 is not selective for the Src family of tyrosine kinases. It
      is also a potent inhibitor of the PDGF beta-receptor kinase but is not a
      ubiquitous tyrosine kinase inhibitor. PP1/AGL1872 inhibits migration and
      proliferation of HCASMCs probably by interference with 2 distinct tyrosine
      phosphorylation events, creating a novel and potent inhibitory principle with
      possible relevance for the treatment of pathological HCASMC activity, such as
      vascular remodeling and restenosis.

PMID- 10400907
TI  - Modulation of extracellular superoxide dismutase expression by angiotensin II and
      hypertension.
AB  - Angiotensin II and hypertension increase vascular oxidant stress. We examined how
      these might affect expression of the extracellular superoxide dismutase (ecSOD),
      a major form of vascular SOD. In mice, angiotensin II infusion (1.1 mg/kg for 7
      days) increased systolic blood pressure from 107+/-3 to 152+/-9 mm Hg and caused
      a 3-fold increase in ecSOD, but there was no change in the cytosolic Cu/Zn SOD
      protein, as determined by Western blot analysis. This was associated with a
      similar increase in ecSOD mRNA as assessed by RNase protection assay and was
      prevented by losartan. Induction of ecSOD by angiotensin II was not due to
      hypertension alone, because hypertension caused by norepinephrine (5.6 mg. kg-1.
      d-1) had no effect on ecSOD. Similarly, exposure of mouse aortas to angiotensin
      II (100 nmol/L) in organoid culture increased ecSOD by approximately 2-fold. In
      the organoid culture, angiotensin II-induced upregulation of ecSOD was prevented
      by losartan (10 micromol/L) and PD985059 (30 micromol/L), a specific inhibitor of
      p42/44 MAP kinase kinase. Angiotensin II activates the NADH/NADPH oxidase;
      however, diphenyleneiodonium chloride (10 micromol/L), an inhibitor of this
      oxidase, did not prevent p42/44 MAP kinase phosphorylation or ecSOD induction by
      angiotensin II. Finally, in human aortic smooth muscle cells, angiotensin II
      moderately increased transcriptional rate (as assessed by nuclear run-on
      analysis) but markedly increased ecSOD mRNA stability. Thus, angiotensin II
      increases ecSOD expression independent of hypertension, and this increase
      involves both an increase in ecSOD transcription and stabilization of ecSOD mRNA.
      This effect of angiotensin II on ecSOD expression may modulate the oxidative
      state of the vessel wall in pathological processes in which the renin-angiotensin
      system is activated.

PMID- 10400908
TI  - Opposing effects of reactive oxygen species and cholesterol on endothelial nitric
      oxide synthase and endothelial cell caveolae.
AB  - Synthesis of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) is
      critical for normal vascular homeostasis. eNOS function is rapidly regulated by
      agonists and blood flow and chronically by factors that regulate mRNA stability
      and gene transcription. Recently, localization of eNOS to specialized plasma
      membrane invaginations termed caveolae has been proposed to be required for
      maximal eNOS activity. Because caveolae are highly enriched in cholesterol, and
      hypercholesterolemia is associated with increased NO production, we first studied
      the effects of cholesterol loading on eNOS localization and NO production in
      cultured bovine aortic endothelial cells (BAECs). Caveolae-enriched fractions
      were prepared by OptiPrep gradient density centrifugation. Treatment of BAECs
      with 30 microgram/mL cholesterol for 24 hours stimulated significant increases in
      total eNOS protein expression (1.50-fold), eNOS associated with caveolae-enriched
      membranes (2.23-fold), and calcium ionophore-stimulated NO production (1.56
      fold). Because reactive oxygen species (ROS) contribute to endothelial
      dysfunction in hypercholesterolemia, we next studied the effects of ROS on eNOS
      localization and caveolae number. Treatment of BAECs for 24 hours with 1
      micromol/L LY83583, a superoxide-generating napthoquinolinedione, decreased
      caveolae number measured by electron microscopy and prevented the cholesterol
      mediated increases in eNOS expression. In vitro exposure of caveolae-enriched
      membranes to ROS (xanthine plus xanthine oxidase) dissociated caveolin more
      readily than eNOS from the membranes. These results show that cholesterol
      treatment increases eNOS expression, whereas ROS treatment decreases eNOS
      expression and the association of eNOS with caveolin in caveolae-enriched
      membranes. Our data suggest that oxidative stress modulates endothelial function
      by regulating caveolae formation, eNOS expression, and eNOS-caveolin
      interactions.

PMID- 10400909
TI  - Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and
      nonfailing human myocardium.
AB  - Disturbed sarcoplasmic reticulum (SR) Ca2+ content may underlie the altered force
      frequency and postrest contractile behavior in failing human myocardium. We used
      rapid cooling contractures (RCCs) to assess SR Ca2+ content in ventricular muscle
      strips isolated from nonfailing and end-stage failing human hearts. With an
      increase in rest intervals (1 to 240 s; 37 degrees C), nonfailing human
      myocardium (n=7) exhibited a parallel increase in postrest twitch force (at 240 s
      by 121+/-44%; P<0.05) and RCC amplitude (by 69+/-53%; P<0.05). In contrast, in
      failing myocardium (n=30), postrest twitch force decreased at long rest intervals
      and RCC amplitude declined monotonically with rest (by 25+/-9% and 53+/-9%,
      respectively; P<0.05). With an increase in stimulation frequencies (0.25 to 3
      Hz), twitch force increased continuously in nonfailing human myocardium (n=7) by
      71+/-17% (at 3 Hz; P<0.05) and RCC amplitude increased in parallel by 247+/-55%
      (P<0.05). In contrast, in failing myocardium (n=26), twitch force declined by
      29+/-7% (P<0. 05) and RCC amplitude increased only slightly by 36+/-14% (P<0.05).
      Paired RCCs were evoked to investigate the relative contribution of SR Ca2+
      uptake and Na+/Ca2+ exchange to cytosolic Ca2+ removal during relaxation. SR Ca2+
      uptake (relative to the Na+/Ca2+ exchange) increased significantly in nonfailing
      but not in failing human myocardium as stimulation rates increased. We conclude
      that the negative force-frequency relation in failing human myocardium is due to
      an inability of SR Ca2+ content to increase sufficiently at high frequencies and
      thus cannot overcome the frequency-dependent refractoriness of SR Ca2+ release.
      The rest-dependent decay in twitch force in failing myocardium is due to rest
      dependent decline in SR Ca2+ content. These alterations could be secondary to
      depressed SR Ca2+-ATPase combined with enhanced cytosolic Ca2+ extrusion via
      Na+/Ca2+ exchange.

PMID- 10400910
TI  - Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha
      tropomyosin manifests cardiac dysfunction.
AB  - To investigate the functional consequences of a tropomyosin (TM) mutation
      associated with familial hypertrophic cardiomyopathy (FHC), we generated
      transgenic mice that express mutant alpha-TM in the adult heart. The missense
      mutation, which results in the substitution of asparagine for aspartic acid at
      amino acid position 175, occurs in a troponin T binding region of TM. S1 nuclease
      mapping and Western blot analyses demonstrate that increased expression of the
      alpha-TM 175 transgene in different lines causes a concomitant decrease in levels
      of endogenous alpha-TM mRNA and protein expression. In vivo physiological
      analyses show a severe impairment of both contractility and relaxation in hearts
      of the FHC mice, with a significant change in left ventricular fractional
      shortening. Myofilaments that contain alpha-TM 175 demonstrate an increased
      activation of the thin filament through enhanced Ca2+ sensitivity of steady-state
      force. Histological analyses show patchy areas of mild ventricular myocyte
      disorganization and hypertrophy, with occasional thrombi formation in the left
      atria. Thus, the FHC alpha-TM transgenic mouse can serve as a model system for
      the examination of pathological and physiological alterations imparted through
      aberrant TM isoforms.

PMID- 10400911
TI  - Cardiac growth factors in human hypertrophy. Relations with myocardial
      contractility and wall stress.
AB  - The aim of the present study was to investigate whether and which cardiac growth
      factors are involved in human hypertrophy, whether growth factor synthesis is
      influenced by overload type and/or by the adequacy of the hypertrophy, and the
      relationships between cardiac growth factor formation and ventricular function.
      Cardiac growth factor formation was assessed by measuring aorta-coronary sinus
      concentration gradient in patients with isolated aortic stenosis (n=26) or
      regurgitation (n=15) and controls (n=12). Gene expression and cellular
      localization was investigated in ventricular biopsies using reverse transcriptase
      polymerase chain reaction and in situ hybridization. Cardiac hypertrophy with end
      systolic wall stress <90 kdyne/cm2 was associated with a selective increased
      formation of insulin-like growth factor (IGF)-I in aortic regurgitation and of
      IGF-I and endothelin (ET)-1 in aortic stenosis. mRNA levels for IGF-I and
      preproET-1 were elevated and mainly expressed in cardiomyocytes. At stepwise
      analysis, IGF-I formation was correlated to the mean velocity of circumferential
      fiber shortening (r=0.86, P<0.001) and ET-1 formation to relative wall thickness
      (r=0.82, P<0. 001). When end-systolic wall stress was >90 kdyne/cm2, IGF-I and ET
      1 synthesis by cardiomyocytes was no longer detectable, and only angiotensin
      (Ang) II was generated, regardless of the type of overload. The mRNA level for
      angiotensinogen was high, and the mRNA was exclusively expressed in the
      interstitial cells. Ang II formation was positively correlated to end-systolic
      stress (r=0.89, P<0.001) and end-diastolic stress (r=0.84, P<0.001). Multivariate
      stepwise analysis selected end-systolic stress as the most predictive variable
      and left ventricular end-diastolic pressure as the independent variable for Ang
      II formation (r=0.93, P<0.001). In conclusion, the present results indicate that
      the course of human left ventricular hypertrophy is characterized by the
      participation of different cardiac growth factors that are selectively related
      both to the type of hemodynamic overload and to ventricular function.

PMID- 10400912
TI  - Subcellular creatine kinase alterations. Implications in heart failure.
AB  - We have tested the hypothesis that decreased functioning of creatine kinase (CK)
      at sites of energy production and utilization may contribute to alterations in
      energy fluxes and calcium homeostasis in congestive heart failure (CHF). Heart
      failure was induced by aortic banding in 3-week-old rats. Myofilaments,
      sarcoplasmic reticulum (SR), mitochondrial functions, and CK compartmentation
      were studied in situ using selective membrane permeabilization of left
      ventricular fibers with detergents (saponin for mitochondria and SR and Triton X
      100 for myofibrils). Seven months after surgery, animals were in CHF. A decrease
      in total CK activity could be accounted for by a 4-fold decrease in activity and
      content (Western blots) of mitochondrial CK and a 30% decrease in M isoform of CK
      (MM-CK) activity. In myofibrils, maximal force, crossbridge kinetics, and alpha
      myosin heavy-chain expression decreased, whereas calcium sensitivity of tension
      development remained unaltered. Myofibrillar CK efficacy was unchanged. Calcium
      uptake capacities of SR were estimated from the surface of caffeine-induced
      tension transient (SCa) after loading with different substrates. In CHF, SCa
      decreased by 23%, and phosphocreatine was 2 times less efficient in enhancing
      calcium uptake. Oxidative capacities of the failing myocardium measured as oxygen
      consumption per gram of fiber dry weight decreased by 28%. Moreover, the control
      of respiration by creatine, ADP, and AMP was severely impaired. Our observations
      provide evidence that alterations in CK compartmentation may contribute to
      alterations of energy fluxes and calcium homeostasis in CHF.

PMID- 10400913
TI  - Two distinct mechanisms mediate a differential regulation of protein kinase C
      isozymes in acute and prolonged myocardial ischemia.
AB  - An activation of protein kinase C (PKC) in acute myocardial ischemia has been
      shown previously using its translocation to the plasma membrane as an indirect
      parameter. However, whether PKC remains activated or whether other mechanisms
      such as altered gene expression may mediate an isozyme-specific regulation in
      prolonged ischemia have not been investigated. In isolated perfused rat hearts,
      PKC activity and the expression of PKC cardiac isozymes were determined on the
      protein level using enzyme activities and Western blot analyses and on the mRNA
      level using reverse transcriptase-polymerase chain reaction after various periods
      of global ischemia (1 to 60 minutes). As early as 1 minute after the onset of
      ischemia, PKC activity is translocated from the cytosol to the particulate
      fraction without change in total cardiac enzyme activity. This translocation
      involves all major cardiac isozymes of PKC (ie, PKCalpha, PKCdelta, PKCepsilon,
      and PKCzeta). This rapid, nonselective activation of PKCs is only transient. In
      contrast, prolonged ischemia (>/=15 minutes) leads to an increased cardiac PKC
      activity (119+/-7 versus 190+/-8 pmol/min per mg protein) residing in the
      cytosol. This is associated with an augmented, subtype-selective isozyme
      expression of PKCdelta and PKCvarepsilon (163% and 199%, respectively). The
      specific mRNAs for PKCdelta (948+/-83 versus 1501+/-138 ag/ng total RNA, 30
      minutes of ischemia) and PKCepsilon (1597+/-166 versus 2611+/-252 ag/ng total
      RNA) are selectively increased. PKCalpha and PKCzeta remain unaltered. In
      conclusion, two distinct activation and regulation processes of PKC are
      characterized in acute myocardial ischemia. The early, but transient,
      translocation involves all constitutively expressed cardiac isozymes of PKC,
      whereas in prolonged ischemia an increased total PKC activity is associated with
      an isozyme-selective induction of PKCepsilon and PKCdelta. Whether these
      fundamentally different activation processes interact remains to be elucidated.

PMID- 10400914
TI  - Local anesthetic anchoring to cardiac sodium channels. Implications into tissue
      selective drug targeting.
AB  - Local anesthetics inhibit Na+ channels in a variety of tissues, leading to
      potentially serious side effects when used clinically. We have created a series
      of novel local anesthetics by connecting benzocaine (BZ) to the sulfhydryl
      reactive group methanethiosulfonate (MTS) via variable-length polyethylether
      linkers (L) (MTS-LX-BZ [X represents 0, 3, 6, or 9]). The application of MTS-LX
      BZ agents modified native rat cardiac as well as heterologously expressed human
      heart (hH1) and rat skeletal muscle (rSkM1) Na+ channels in a manner resembling
      that of free BZ. Like BZ, the effects of MTS-LX-BZ on rSkM1 channels were
      completely reversible. In contrast, MTS-LX-BZ modification of heart and mutant
      rSkM1 channels, containing a pore cysteine at the equivalent location as cardiac
      Na+ channels (ie, Y401C), persisted after drug washout unless treated with DTT,
      which suggests anchoring to the pore via a disulfide bond. Anchored MTS-LX-BZ
      competitively reduced the affinity of cardiac Na+ channels for lidocaine but had
      minimal effects on mutant channels with disrupted local anesthetic modification
      properties. These results establish that anchored MTS-LX-BZ compounds interact
      with the local anesthetic binding site (LABS). Variation in the linker length
      altered the potency of channel modification by the anchored drugs, thus providing
      information on the spatial relationship between the anchoring site and the LABS.
      Our observations demonstrate that local anesthetics can be anchored to the
      extracellular pore cysteine in cardiac Na+ channels and dynamically interact with
      the intracellular LABS. These results suggest that nonselective agents, such as
      local anesthetics, might be made more selective by linking these agents to target
      specific anchors.

PMID- 10400915
TI  - Cultured porcine coronary artery smooth muscle cells. A new model with advanced
      differentiation.
AB  - Arterial intimal thickening after endothelial injury induced in rodents has
      proven to be a relatively unreliable model of restenosis for testing clinically
      useful compounds. The same has been found for cultured rat or rabbit vascular
      smooth muscle cells (SMCs). To test alternative possibilities, we have studied
      several differentiation features of porcine coronary artery SMCs, cultured up to
      the 5th passage after enzymatic digestion of the media. The effects of heparin,
      transforming growth factor (TGF)-beta1 or TGF-beta2, and all-trans-retinoic acid
      (tRA) on proliferation, migration, and differentiation of these cells also were
      examined. Porcine arterial SMCs in culture not only express high levels of alpha
      smooth muscle (SM) actin but, contrary to rodent SMCs, also maintain an
      appreciable expression of SM myosin heavy chain isoforms 1 and 2, desmin, and
      smoothelin, a recently described late differentiation marker of vascular SMCs. We
      demonstrate for the first time that smoothelin is colocalized with alpha-SM actin
      in these cells. Finally, we show that in the porcine model, heparin is more
      potent than TGF-beta1 or TGF-beta2 and tRA in terms of inhibition of
      proliferation and migration and of increasing the expression of differentiation
      markers. This model should be a useful complement to in vivo studies of SMC
      differentiation and of pathological situations such as restenosis and
      atheromatosis.

PMID- 10400916
TI  - Expression of human scavenger receptor class B type I in cultured human monocyte
      derived macrophages and atherosclerotic lesions.
AB  - The scavenger receptor class B type I (SR-BI) and its human homologue CLA-1 (CD36
      and LIMPII Analogous-1) have recently been identified to bind HDL and mediate the
      selective uptake of HDL lipids. Tissue distribution of both murine and human
      receptors is quite similar, in that they are expressed abundantly in liver and
      steroidogenic tissues. However, expression and function of the human SR-BI (hSR
      BI), in the periphery of reverse cholesterol transport such as macrophages, are
      still unclear. In the present study, we have raised two different kinds of anti
      hSR-BI polypeptide antibodies (Abs): one against the extracellular domain and the
      other against the intracellular domain. We have investigated the expression of
      hSR-BI mRNA and immunoreactive mass in freshly isolated cultured human monocyte
      derived macrophages (hMphi) and in atherosclerotic lesions. Contrary to the
      earlier report, hSR-BI mRNA was expressed in cultured hMphi and markedly
      upregulated with differentiation, determined by Northern blot and reverse
      transcriptase-based polymerase chain reaction analyses. The mRNA expression
      pattern during differentiation of hMphi was very similar to those of SR class A
      and another member of SR class B, CD36. Protein expression was confirmed by
      Western blot analyses with the above Abs to show a major 83-kDa band. Modified
      lipoproteins such as oxidized LDL and acetylated LDL induced a 5-fold increase in
      mRNA and protein expression of hSR-BI. Confocal immunofluorescence microscopy
      demonstrated that hSR-BI immunoreactive mass was detectable as a heterogeneous,
      punctate staining pattern. Furthermore, immunohistochemical analysis showed that
      immunoreactive mass of hSR-BI was detected in foam cells in human aortic
      atherosclerotic lesions and that there was no significant difference of staining
      patterns between the two Abs. This study clearly demonstrates that hSR-BI is
      expressed in the lipid-laden macrophages in human atherosclerotic lesions,
      suggesting that it is very important to know its function and regulation in hMphi
      to understand the biological utility of this molecule.

PMID- 10400920
TI  - Genomic evolution, patterns of global dissemination, and interspecies
      transmission of human and simian T-cell leukemia/lymphotropic viruses.
AB  - Using both env and long terminal repeat (LTR) sequences, with maximal
      representation of genetic diversity within primate strains, we revise and expand
      the unique evolutionary history of human and simian T-cell leukemia/lymphotropic
      viruses (HTLV/STLV). Based on the robust application of three different
      phylogenetic algorithms of minimum evolution-neighbor joining, maximum parsimony,
      and maximum likelihood, we address overall levels of genetic diversity, specific
      rates of mutation within and between different regions of the viral genome,
      relatedness among viral strains from geographically diverse regions, and
      estimation of the pattern of divergence of the virus into extant lineages.
      Despite broad genomic similarities, type I and type II viruses do not share
      concordant evolutionary histories. HTLV-I/STLV-I are united through distinct
      phylogeographic patterns, infection of 20 primate species, multiple episodes of
      interspecies transmission, and exhibition of a range in levels of genetic
      divergence. In contrast, type II viruses are isolated from only two species (Homo
      sapiens and Pan paniscus) and are paradoxically endemic to both Amerindian tribes
      of the New World and human Pygmy villagers in Africa. Furthermore, HTLV-II is
      spreading rapidly through new host populations of intravenous drug users. Despite
      such clearly disparate host populations, the resultant HTLV-II/STLV-II phylogeny
      exhibits little phylogeographic concordance and indicates low levels of
      transcontinental genetic differentiation. Together, these patterns generate a
      model of HTLV/STLV emergence marked by an ancient ancestry, differential rates of
      divergence, and continued global expansion.

PMID- 10400919
TI  - Distribution and prevalence of hyperpolarization-activated cation channel (HCN)
      mRNA expression in cardiac tissues.
AB  - HCN cation channel mRNA expression was determined in the rabbit heart and
      neonatal and adult rat ventricle using RNase protection assays. In the rabbit SA
      node, the dominant HCN transcript is HCN4, representing >81% of the total HCN
      message. HCN1 is also expressed, representing >18% of the total HCN mRNA. Rabbit
      Purkinje fibers contained almost equal amounts of HCN1 and HCN4 transcripts with
      low levels of HCN2, whereas rabbit ventricle contained predominantly HCN2. The SA
      node contained 25 times the total HCN message of Purkinje fibers and 140 times
      the total HCN message of ventricle. No reports of hyperpolarization-activated
      current (If) exist in rabbit Purkinje fibers, and we could not record If in
      rabbit ventricular myocytes. To investigate the possible role of isoform
      switching in determining the voltage dependence of If, we determined the
      prevalence of HCN isoforms in neonatal and adult rat ventricle. We had previously
      determined the threshold for activation of If to be approximately -70 mV in
      neonatal rat ventricle and -113 mV in adult rat ventricle. In both neonatal and
      adult rat ventricle, only HCN2 and HCN4 transcripts are present. The ratio of
      HCN2 to HCN4 is approximately 5:1 in the neonate and 13:1 in the adult. Taken
      together, these results suggest that different cardiac regions express different
      isoforms of the HCN family. The HCN1 and HCN4 isoforms are most closely
      associated with a depolarized threshold for If activation, whereas the HCN2
      isoform is associated with a more negative activation curve.

PMID- 10400921
TI  - Different evolutionary histories in two subgenomic regions of the major
      histocompatibility complex.
AB  - Two subgenomic regions within the major histocompatibility complex, the alpha and
      beta blocks, contain members of the multicopy gene families HLA class I, human
      endogenous retroviral sequence (HERV-16; previously known as P5 and PERB3),
      hemochromatosis candidate genes (HCG) (II, IV, VIII, IX), 3.8-1, and MIC
      (PERB11). In this study we show that the two blocks consist of imperfect
      duplicated segments, which contain linked members of the different gene families.
      The duplication and truncation sites of the segments are associated with
      retroelements. The retroelement sites appear to generate the imperfect
      duplications, insertions/deletions, and rearrangements, most likely via
      homologous recombination. Although the two blocks share several characteristics,
      they differ in the number and orientation of the duplicated segments. On the 62.1
      haplotype, the alpha block consists of at least 10 duplicated segments that
      predominantly contain pseudogenes and gene fragments of the HLA class I and MIC
      (PERB11) gene families. In contrast, the beta block has two major duplications
      containing the genes HLA-B and HLA-C, and MICA (PERB11.1) and MICB (PERB11.2).
      Given the common origin between the blocks, we reconstructed the duplication
      history of the segments to understand the processes involved in producing the
      different organization in the two blocks. We then found that the beta block
      contains four distinct duplications from two separate events, whereas the alpha
      block is characterized by multisegment duplications. We will discuss these
      results in relation to the genetic content of the two blocks.

PMID- 10400922
TI  - The genomic tree as revealed from whole proteome comparisons.
AB  - The availability of a number of complete cellular genome sequences allows the
      development of organisms' classification, taking into account their genome
      content, the loss or acquisition of genes, and overall gene similarities as
      signatures of common ancestry. On the basis of correspondence analysis and
      hierarchical classification methods, a methodological framework is introduced
      here for the classification of the available 20 completely sequenced genomes and
      partial information for Schizosaccharomyces pombe, Homo sapiens, and Mus
      musculus. The outcome of such an analysis leads to a classification of genomes
      that we call a genomic tree. Although these trees are phenograms, they carry with
      them strong phylogenetic signatures and are remarkably similar to 16S-like rRNA
      based phylogenies. Our results suggest that duplication and deletion events that
      took place through evolutionary time were globally similar in related organisms.
      The genomic trees presented here place the Archaea in the proximity of the
      Bacteria when the whole gene content of each organism is considered, and when
      ancestral gene duplications are eliminated. Genomic trees represent an additional
      approach for the understanding of evolution at the genomic level and may
      contribute to the proper assessment of the evolutionary relationships between
      extant species.

PMID- 10400923
TI  - A view of modern human origins from Y chromosome microsatellite variation.
AB  - The idea that all modern humans share a recent (within the last 150, 000 years)
      African origin has been proposed and supported on the basis of three
      observations. Most genetic loci examined to date have (1) shown greater diversity
      in African populations than in others, (2) placed the first branch between
      African and all non-African populations in phylogenetic trees, and (3) indicated
      recent dates for either the molecular coalescence (with the exception of some
      autosomal and X-chromosomal loci) or for the time of separation between African
      and non-African populations. We analyze variation at 10 Y chromosome
      microsatellite loci that were typed in 506 males representing 49 populations and
      every inhabited continent and find significantly greater Y chromosome diversity
      in Africa than elsewhere, find the first branch in phylogenetic trees of the
      continental populations to fall between African and all non-African populations,
      and date this branching with the (deltamu)2 distance measure to 5800-17,400 or
      12,800-36,800 years BP depending on the mutation rate used. The magnitude of the
      excess Y chromosome diversity in African populations appears to result from a
      greater antiquity of African populations rather than a greater long-term
      effective population size. These observations are most consistent with a recent
      African origin for all modern humans.

PMID- 10400924
TI  - The CMT2D locus: refined genetic position and construction of a bacterial clone
      based physical map.
AB  - Charcot-Marie-Tooth (CMT) disease is a progressive neuropathy of the peripheral
      nervous system, typically characterized by muscle weakness of the distal limbs.
      CMT is noted for its genetic heterogeneity, with four distinct loci already
      identified for the axonal form of the disease (CMT2). In 1996, linkage analysis
      of a single large family revealed the presence of a CMT2 locus on chromosome 7p14
      (designated CMT2D). Additional families have been linked subsequently to the same
      genomic region, including one with distal spinal muscular atrophy (dSMA) and one
      with mixed features of dSMA and CMT2; symptoms in both of these latter families
      closely resemble those seen in the original CMT2D family. There is thus a
      distinct possibility that CMT2 and dSMA encountered in these families reflect
      allelic heterogeneity at a single chromosome 7 locus. In the study reported here,
      we have performed more detailed linkage analysis of the original CMT2D family
      based on new knowledge of the physical locations of various genetic markers. The
      region containing the CMT2D gene, as defined by the original family, overlaps
      with those defined by at least two other families with CMT2 and/or dSMA symptoms.
      Both yeast artificial chromosome (YAC) and bacterial clone-based [bacterial
      artificial chromosome (BAC) and P1-derived artificial chromosome (PAC)] contig
      maps spanning approximately 3.4 Mb have been assembled across the combined CMT2D
      critical region, with the latter providing suitable clones for systematic
      sequencing of the interval. Preliminary analyses have already revealed at least
      28 candidate genes and expressed-sequence tags (ESTs). The mapping information
      reported here in conjunction with the evolving sequence data should expedite the
      identification of the CMT2D/dSMA gene or genes.

PMID- 10400925
TI  - A locus linked to p16 modifies melanoma risk in Dutch familial atypical multiple
      mole melanoma (FAMMM) syndrome families.
AB  - The CDKN2A gene that encodes the cell cycle inhibitor p16 shows mutations in many
      but not all 9p21-linked melanoma families. Most Dutch melanoma families segregate
      for a unique founder mutation (p16-Leiden), encoding a truncated nonfunctional
      p16 protein. The highly variable risk for p16-Leiden carriers to develop melanoma
      suggests a role for other genetic and/or environmental factors. We hypothesized
      that a 9p21 gene other than CDKN2A may be relevant in the remaining 9p21-linked
      melanoma families without p16 mutations but may also act as a risk modifier in
      p16-Leiden carriers. Haplotype analysis for 9p21 was performed using
      microsatellite markers in six p16-Leiden families originating from a founder
      population. p16-Leiden carriers in two families shared an unexpectedly large
      founder haplotype ( approximately 20-cM) around CDKN2A, mostly in proximal
      direction. Melanoma-positive p16-Leiden carriers from these families showed this
      extensive proximal haplotype compared with melanoma-negative p16-Leiden carriers
      from the same families. Additional p16-Leiden families less heavily affected with
      melanoma showed shorter haplotypes sharing, excluding the region proximally of
      CDKN2A. The presence of a gene involved in melanoma susceptibility proximal of
      CDKN2A is corroborated by somatic deletions of 9p in tumors, which frequently do
      not include CDKN2A but a more proximal chromosomal area instead. Our results
      provide a candidate region for further gene mapping in p16-negative 9p21-linked
      melanoma families and guide the search for risk modifiers in melanoma
      development.

PMID- 10400926
TI  - Physical and meiotic mapping of the region of human chromosome 4q11-q13
      encompassing the vitamin D binding protein DBP/Gc-globulin and albumin multigene
      cluster.
AB  - The vitamin D binding protein/Gc-globulin (DBP) gene is a member of a multigene
      cluster that includes albumin (ALB), alpha-fetoprotein (AFP), and alpha
      albumin/afamin (AFM). All four genes have structural and functional similarities
      and map to the same chromosomal regions in humans (4q11-q13), mice, and rats. An
      accurate physical map of the region encompassing these genes is a prerequisite
      for study of their respective transcriptional regulation and identification of
      potential shared regulatory elements. By refining the physical and meiotic maps
      of the 4q11-q13 region and creating a local PAC contig, the order and
      transcriptional orientations of these four genes were determined to be centromere
      3'-DBP-5'-5'-ALB-3'-5'-AFP-3'-5'-AFM3'-telomere. The ancestral DBP gene was
      separated from the ALB gene by >1.5 Mb. This organization and spacing establishes
      a foundation for ongoing functional studies in this region.

PMID- 10400927
TI  - Improved DNA sequencing accuracy and detection of heterozygous alleles using
      manganese citrate and different fluorescent dye terminators.
AB  - The use of dideoxynucleotide triphosphates labeled with different fluorescent
      dyes (dye terminators) is the most versatile method for automated DNA sequencing.
      However, variation in peak heights reduces base-calling accuracy and limits
      heterozygous allele detection, favoring use of dye-labeled primers for this
      purpose. We have discovered that the addition of a manganese salt to the PE
      Applied Biosystems dye-terminator sequencing kits overcomes these limitations for
      the older rhodamine dyes as well as the more recent dichloro-rhodamine dyes
      (dRhodamine and BigDyes). Addition of manganese to reactions containing
      dRhodamine-based dye terminators produced the highest base-calling accuracy. This
      combination resulted in the most uniform electropherogram profiles, superior to
      those produced by BigDye terminators and published for dye primers, and
      facilitated detection of heterozygous alleles.

PMID- 10400928
TI  - A high-density integrated genetic linkage and radiation hybrid map of the
      laboratory rat.
AB  - The laboratory rat (Rattus norvegicus) is a key animal model for biomedical
      research. However, the genetic infrastructure required for connecting phenotype
      and genotype in the rat is currently incomplete. Here, we report the construction
      and integration of two genomic maps: a dense genetic linkage map of the rat and
      the first radiation hybrid (RH) map of the rat. The genetic map was constructed
      in two F2 intercrosses (SHRSP x BN and FHH x ACI), containing a total of 4736
      simple sequence length polymorphism (SSLP) markers. Allele sizes for 4328 of the
      genetic markers were characterized in 48 of the most commonly used inbred
      strains. The RH map is a lod >/= 3 framework map, including 983 SSLPs, thereby
      allowing integration with markers on various genetic maps and with markers mapped
      on the RH panel. Together, the maps provide an integrated reference to >3000
      genes and ESTs and >8500 genetic markers (5211 of our SSLPs and >3500 SSLPs
      developed by other groups). [Bihoreau et al. (1997); James and Tanigami, RHdb
      (http:www.ebi.ac.uk/RHdb/index.html); Wilder
      (http://www.nih.gov/niams/scientific/ratgbase); Serikawa et al. (1992); RATMAP
      server (http://ratmap.gen.gu.se)] RH maps (v. 2.0) have been posted on our web
      sites at http://goliath.ifrc.mcw.edu/LGR/index.html or
      http://curatools.curagen.com/ratmap. Both web sites provide an RH mapping server
      where investigators can localize their own RH vectors relative to this map. The
      raw data have been deposited in the RHdb database. Taken together, these maps
      provide the basic tools for rat genomics. The RH map provides the means to
      rapidly localize genetic markers, genes, and ESTs within the rat genome. These
      maps provide the basic tools for rat genomics. They will facilitate studies of
      multifactorial disease and functional genomics, allow construction of physical
      maps, and provide a scaffold for both directed and large-scale sequencing efforts
      and comparative genomics in this important experimental organism.

PMID- 10400930
TI  - Alphaxalone activates a Cl- conductance independent of GABAA receptors in
      cultured embryonic human dorsal root ganglion neurons.
AB  - Whole cell and cell-attached patch-clamp techniques characterized the
      neurosteroid anesthetic alphaxalone's (5alpha-pregnane-3alpha-ol-11,20-dione)
      effects on GABAA receptors and on Cl- currents in cultured embryonic (5- to 8-wk
      old) human dorsal root ganglion neurons. Alphaxalone applied by pressure pulses
      from closely positioned micropipettes failed to potentiate the inward Cl-
      currents produced by application of GABA. In the absence of GABA, alphaxalone
      (0.1-5.0 microM) directly evoked inward currents in all dorsal root ganglion
      neurons voltage-clamped at negative membrane potentials. The amplitude of the
      current was directly proportional to the concentration of alphaxalone (Hill
      coefficient 1.3 +/- 0.15). The alphaxalone-induced whole cell current was carried
      largely by Cl- ions. Its reversal potential was close to the theoretical Cl-
      equilibrium potential, changing with a shift in the external Cl- concentration as
      predicted by the Nernst equation for Cl- ions. And because the alphaxalone
      current was not suppressed by the competitive GABAA receptor antagonist
      bicuculline or by the channel blockers picrotoxin and t
      butylbicyclophosphorothionate (TBPS; all at 100 microM), it did not appear to
      result from activation of GABAA receptors. In contrast to GABA-currents in the
      same neurons, the whole cell current-voltage curves produced in the presence of
      alphaxalone demonstrated strong inward rectification with nearly symmetrical bath
      and pipette Cl- concentrations. Fluctuation analysis of the membrane current
      variance produced by 1.0 microM alphaxalone showed that the power density spectra
      were best fitted to double Lorentzian functions. The elementary conductance for
      alphaxalone-activated Cl- channels determined by the relationship between mean
      amplitude of whole cell current and variance was 30 pS. Single-channel currents
      in cell-attached patches when the pipette solution contained 10 microM
      alphaxalone revealed a single conductance state with a chord conductance of
      approximately 29 pS. No subconductance states were seen. The current-voltage
      determinations for the single-channels activated by alphaxalone demonstrated a
      linear relationship. Mean open and shut times of single alphaxalone-activated
      channels were described by two exponential decay functions. Taken together, the
      results indicate that in embryonic human DRG neurons, micromolar concentrations
      of alphaxalone directly activate Cl- channels whose electrophysiological and
      pharmacological properties are distinct from those of Cl- channels associated
      with GABAA receptors.

PMID- 10400929
TI  - GABA-Induced Cl- current in cultured embryonic human dorsal root ganglion
      neurons.
AB  - gamma-Aminobutyric acid (GABA)-activated channels in embryonic (5-8 wk old) human
      dorsal root ganglion (DRG) neurons in dissociated culture were characterized by
      whole cell and single-channel techniques. All DRG neurons when held at negative
      holding membrane potentials displayed inward current to micromolar concentrations
      of GABA applied by pressure pulses from closely positioned micropipettes. The
      current was directly proportional to the concentration of GABA (EC50, 111 microM;
      Hill coefficient, 1.7). DRG neurons also responded to micromolar concentrations
      of pentobarbital and alphaxalone but not to cis-4-aminocrotonic acid (CACA),
      glycine, or taurine. Baclofen (100 microM) affected neither the holding currents
      nor K+ conductance (when patch pipettes were filled with 130 mM KCl) caused by
      depolarizing pulses. Whole cell GABA-currents were blocked by bicuculline,
      picrotoxin, and t-butylbicyclophosphorothionate (TBPS; all at 100 microM). The
      reversal potential of whole cell GABA-currents was close to the theoretical Cl-
      equilibrium potential, shifting with changes in intracellular Cl- concentration
      in a manner expected for Cl--selective channels. The whole cell I-V curve for
      GABA-induced currents demonstrated slight outward rectification with nearly
      symmetrical outside and inside Cl- concentrations. Spectral analysis of GABA
      induced membrane current fluctuations showed that the kinetic components were
      best fitted by a triple Lorentzian function. The apparent elementary conductance
      for GABA-activated Cl- channels determined from the power spectra was 22.6 pS.
      Single-channel recordings from cell-attached patches with pipettes containing 10
      microM GABA indicated that GABA-activated channels have a main and a
      subconductance level with values of 30 and 19 pS, respectively. Mean open and
      closed times of the channel were characterized by two or three exponential decay
      functions, suggesting two or three open channel states and two closed states.
      Single channels showed a lack of rectification. The actions of GABA on cultured
      human embryonic DRG neurons are mediated through the activation of GABAA
      receptors with properties corresponding to those found in the CNS of human and
      other mammalian species but differing from those of cultured human adult DRG
      neurons.

PMID- 10400931
TI  - Response of anterior parietal cortex to cutaneous flutter versus vibration.
AB  - The response of anesthetized squirrel monkey anterior parietal (SI) cortex to 25
      or 200 Hz sinusoidal vertical skin displacement stimulation was studied using the
      method of optical intrinsic signal (OIS) imaging. Twenty-five-Hertz ("flutter")
      stimulation of a discrete skin site on either the hindlimb or forelimb for 3-30 s
      evoked a prominent increase in absorbance within cytoarchitectonic areas 3b and 1
      in the contralateral hemisphere. This response was confined to those area 3b/1
      regions occupied by neurons with a receptive field (RF) that includes the
      stimulated skin site. In contrast, same-site 200-Hz stimulation ("vibration") for
      3-30 s evoked a decrease in absorbance in a much larger territory (most
      frequently involving areas 3b, 1, and area 3a, but in some subjects area 2 as
      well) than the region that undergoes an increase in absorbance during 25-Hz
      flutter stimulation. The increase in absorbance evoked by 25-Hz flutter developed
      quickly and remained relatively constant for as long as stimulation continued
      (stimulus duration never exceeded 30 s). At 1-3 s after stimulus onset, the
      response to 200-Hz stimulation, like the response to 25-Hz flutter, consisted of
      a localized increase in absorbance limited to the topographically appropriate
      region of area 3b and/or area 1. With continuing 200-Hz stimulation, however, the
      early response declined, and by 4-6 s after stimulus onset, it was replaced by a
      prominent and spatially extensive decrease in absorbance. The spike train
      responses of single quickly adapting (QA) neurons were recorded extracellularly
      during microelectrode penetrations that traverse the optically responding regions
      of areas 3b and 1. Onset of either 25- or 200-Hz stimulation at a site within the
      cutaneous RF of a QA neuron was accompanied by a substantial increase in mean
      spike firing rate. With continued 200-Hz stimulation, however, QA neuron mean
      firing rate declined rapidly (typically within 0.5-1.0 s) to a level below that
      recorded at the same time after onset of same-site 25-Hz stimulation. For some
      neurons, the mean firing rate after the initial 0.5-1 s of an exposure to 200-Hz
      stimulation of the RF decreased to a level below the level of background
      ("spontaneous") activity. The decline in both the stimulus-evoked increases in
      absorbance in areas 3b/1 and spike discharge activity of area 3b/1 neurons within
      only a few seconds of the onset of 200-Hz skin stimulation raised the possibility
      that the predominant effect of continuous 200-Hz stimulation for >3 s is
      inhibition of area 3b/1 QA neurons. This possibility was evaluated at the
      neuronal population level by comparing the intrinsic signal evoked in areas 3b/1
      by 25-Hz skin stimulation to the intrinsic signal evoked by a same-site skin
      stimulus containing both 25- and 200-Hz sinusoidal components (a "complex
      waveform stimulus"). Such experiments revealed that the increase in absorbance
      evoked in areas 3b/1 by a stimulus having both 25- and 200-Hz components was
      substantially smaller (especially at times >3 s after stimulus onset) than the
      increase in absorbance evoked by "pure" 25-Hz stimulation of the same skin site.
      It is concluded that within a brief time (within 1-3 s) after stimulus onset, 200
      Hz skin stimulation elicits a powerful inhibitory action on area 3b/1 QA neurons.
      The findings appear generally consistent with the suggestion that the activity of
      neurons in cortical regions other than areas 3b and 1 play the leading role in
      the processing of high-frequency (>/=200 Hz) vibrotactile stimuli.

PMID- 10400932
TI  - Fastigial nucleus activity during different frequencies and orientations of
      vertical vestibular stimulation in the monkey.
AB  - Neurons in the rostral part of the fastigial nucleus (FN) respond to vestibular
      stimulation but are not related to eye movements. To understand the precise role
      of these vestibular-only neurons in the central processing of vestibular signals,
      unit activity in the FN of alert monkeys (Macaca mulatta) was recorded. To induce
      vestibular stimulation, the monkey was rotated sinusoidally around an earth-fixed
      horizontal axis at stimulus frequencies between 0.06 (+/-15 degrees) and 1.4 Hz
      (+/-7.5 degrees). During stimulation head orientation was changed continuously,
      allowing for roll, pitch, and intermediate planes of orientation. At a frequency
      of 0.6 Hz, 59% of the neurons had an optimal response orientation (ORO) and a
      null response (i.e., no modulation) 90 degrees apart. The phase of neuronal
      response was constant except for a steep shift of 180 degrees around the null
      response. This group I response is compatible with a semicircular canal input,
      canal convergence, or a single otolith input. Several other features indicated
      more complex responses, including spatiotemporal convergence (STC). 1) For 35% of
      the responses at 0.6 Hz, phase changes were gradual with different orientations.
      Fifteen percent of these had a null response (group II), and 20% showed only a
      minimal response but no null response (group III). The remaining responses (6%),
      classified as group IV, were characterized by a constant sensitivity at different
      orientations in most instances. 2) For the vast majority of neurons, the stimulus
      frequency determined the response group, i.e., an individual neuron could show a
      group I response at one frequency and a group II (III or IV) response at another
      frequency. 3) ORO changed with frequency by >45 degrees for 44% of the neurons.
      4) Although phase changes at different frequencies were close to head velocity
      (+/-45 degrees ) or head position (+/-45 degrees ) for most neurons, they
      exceeded 90 degrees for 29% of the neurons between 0.1 and 1.0 Hz. In most cases,
      this was a phase advance. The change in sensitivity with change in frequency
      showed a similar pattern for all neurons; the average sensitivity increased from
      1.24 imp. s-1. deg-1 at 0.1 Hz to 2.97 imp. s-1. deg-1 at 1.0 Hz. These data
      demonstrate that only an analysis based on measurements at different frequencies
      and orientations reveals a number of complex features. They moreover suggest that
      for the vast majority of neurons several sources of canal and otolith information
      interact at this central stage of vestibular information processing.

PMID- 10400933
TI  - Activity-dependent depression of GABAergic IPSCs in cultured hippocampal neurons.
AB  - Short-term depression of monosynaptic GABAergic inhibitory postsynaptic currents
      (IPSCs) evoked between pairs of cultured rat hippocampal neurons was investigated
      using dual whole cell patch-clamp recordings. Paired stimuli applied to the
      GABAergic neuron resulted in paired-pulse depression (PPD) of the second IPSC
      (IPSC2) at interpulse intervals from 25 to 2,000 ms. CGP 55845A, but not CGP
      35348, reduced PPD marginally. Brief paired-pulse applications of exogenous GABA
      indicated that postsynaptic factors made only minimal contribution to PPD of
      IPSCs. IPSC1 and PPD was reduced on lowering [Ca2+]o and enhanced on increasing
      [Ca2+]o. The potassium-channel blocker 4-aminopyridine (4-AP), which increases
      presynaptic Ca2+ influx, enhanced IPSC1 and PPD. Chelation of residual Ca2+ in
      the GABAergic boutons with EGTA-AM enhanced PPD. Stimulation of the presynaptic
      neuron at frequencies (f) ranging from 2.5 to 80 Hz resulted in tetanic
      depression of IPSCs, which declined rapidly and reached a plateau depending on f
      and [Ca2+]o. CGP 55845A decreased tetanic depression in the first part of the
      train, but this could be overcome with continued stimulation. We show that
      GABAergic IPSCs are robustly depressed by paired-pulse stimulation in cultured
      hippocampal neurons. The depression of IPSCs is mainly independent of presynaptic
      GABAB receptors and could be caused by depletion of releasable vesicles. Depleted
      synapses recover with a slow time course, depending on factors that regulate
      [Ca2+]i in the GABAergic boutons.

PMID- 10400934
TI  - Antibodies against cysteine string proteins inhibit evoked neurotransmitter
      release at Xenopus neuromuscular junctions.
AB  - Cysteine string proteins (CSPs) are evolutionarily conserved proteins that are
      associated with synaptic vesicles and other regulated secretory organelles. To
      investigate the role of CSPs in vertebrate neuromuscular transmission, we
      introduced anti-CSP antibodies into the cell bodies of Xenopus spinal motor
      neurons that form synapses with embryonic muscle cells in culture. These
      antibodies produced a rapid (within 3-6 min), and in most cases complete,
      inhibition of stimulus-dependent neurotransmitter secretion. However, spontaneous
      neurotransmitter release was stable (both in frequency and amplitude) throughout
      the period of antibody exposure. Several control experiments validated the
      specificity of the anti-CSP antibody effects. First, the anti-CSP antibody
      actions were not mimicked either by antibodies against another synaptic vesicle
      protein SV2, or by nonspecific immunoglobins. Second, heat treatment of the anti
      CSP antibodies eliminated their effect on evoked secretion. Third, immunoblot
      experiments showed that the anti-CSP and anti-SV2 antibodies were highly
      selective for their respective antigens in these Xenopus cultures. We conclude
      from these results that CSPs are vital constituents of the pathway for regulated
      neurotransmitter release in vertebrates. Moreover, the selective inhibition of
      evoked, but not spontaneous transmitter release by anti-CSP antibodies indicates
      that there is a fundamental difference in the machinery that mediates these
      secretory processes.

PMID- 10400935
TI  - Differential roles of ionotropic glutamate receptors in canine medullary
      inspiratory neurons of the ventral respiratory group.
AB  - The relative roles of ionotropic N-methyl-D-aspartate (NMDA) and non-NMDA
      glutamate receptors in supplying excitatory drive to inspiratory (I) augmenting
      pattern neurons of the ventral respiratory group were studied in anesthetized,
      ventilated, paralyzed, and vagotomized dogs. Multibarrel micropipettes were used
      to record simultaneously single-unit neuronal activity and pressure microeject
      the NMDA antagonist, 2-amino-5-phosphonovalerate (AP5; 2 mM), the non-NMDA
      antagonist 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX; 0.25
      mM), and an artificial cerebrospinal fluid vehicle. Ejected volume-rates were
      measured directly via meniscus level changes. The moving time average of phrenic
      nerve activity was used to determine respiratory phase durations and to
      synchronize cycle-triggered histograms of the discharge patterns. Both AP5 and
      NBQX produced dose-dependent reductions in peak spontaneous I neuronal discharge
      frequency (Fn). The average (+/- SE) maximum reduction in peak Fn produced by AP5
      was 69.1 +/- 4.2% and by NBQX was 47.1 +/- 3.3%. Blockade of both glutamate
      receptor subtypes nearly silenced these neurons, suggesting that their activity
      is highly dependent on excitatory synaptic drive mediated by ionotropic glutamate
      receptors. Differential effects were found for the two glutamatergic antagonists.
      AP5 produced downward, parallel shifts in the augmenting pattern of discharge,
      whereas NBQX reduced the slope of the augmenting discharge pattern. These results
      suggest that time-varying excitatory input patterns to the canine I bulbospinal
      neurons are mediated by non-NMDA glutamate receptors and that constant or tonic
      input patterns to these neurons are mediated by NMDA receptors.

PMID- 10400936
TI  - Serotonergic modulation of neurotransmission in the rat basolateral amygdala.
AB  - Whole cell patch-clamp recordings were obtained from projection neurons and
      interneurons of the rat basolateral amygdala (BLA) to understand local network
      interactions in morphologically identified neurons and their modulation by
      serotonin. Projection neurons and interneurons were characterized morphologically
      and electrophysiologically according to their intrinsic membrane properties and
      synaptic characteristics. Synaptic activity in projection neurons was dominated
      by spontaneous inhibitory postsynaptic currents (IPSCs) that were multiphasic,
      reached 181 +/- 38 pA in amplitude, lasted 296 +/- 27 mS, and were blocked by the
      GABAA receptor antagonist, bicuculline methiodide (30 microM). In interneurons,
      spontaneous synaptic activity was characterized by a burst-firing discharge
      patterns (200 +/- 40 Hz) that correlated with the occurrence of 6-cyano-7
      nitroquinoxaline-2,3-dione-sensitive, high-amplitude (260 +/- 42 pA), long
      duration (139 +/- 19 mS) inward excitatory postsynaptic currents (EPSCs). The
      interevent interval of 831 +/- 344 mS for compound inhibitory postsynaptic
      potentials (IPSPs), and 916 +/- 270 mS for EPSC bursts, suggested that
      spontaneous IPSP/Cs in projection neurons are driven by burst of action
      potentials in interneurons. Hence, BLA interneurons may regulate the excitability
      of projection neurons and thus determine the degree of synchrony within ensembles
      of BLA neurons. In interneurons 5-hydroxytryptamine oxalate (5-HT) evoked a
      direct, dose-dependent, membrane depolarization mediated by a 45 +/- 6.9 pA
      inward current, which had a reversal potential of -90 mV. The effect of 5-HT was
      mimicked by the 5-HT2 receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha
      methyl-5-HT), but not by the 5-HT1A receptor agonist, (+/-) 8
      hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), or the 5-HT1B agonist, CGS
      12066A. In projection neurons, 5-HT evoked an indirect membrane hyperpolarization
      ( approximately 2 mV) that was associated with a 75 +/- 42 pA outward current and
      had a reversal potential of -70 mV. The response was independent of 5-HT
      concentration, blocked by TTX, mimicked by alpha-methyl-5-HT but not by 8-OH
      DPAT. In interneurons, 5-HT reduced the amplitude of the evoked EPSC and in the
      presence of TTX (0.6 microM) reduced the frequency of miniature EPSCs but not
      their quantal content. In projection neurons, 5-HT also caused a dose-dependent
      reduction in the amplitude of stimulus evoked EPSCs and IPSCs. These results
      suggest that acute serotonin release would directly activate GABAergic
      interneurons of the BLA, via an activation of 5-HT2 receptors, and increase the
      frequency of inhibitory synaptic events in projection neurons. Chronic serotonin
      release, or high levels of serotonin, would reduce the excitatory drive onto
      interneurons and may act as a feedback mechanism to prevent excess inhibition
      within the nucleus.

PMID- 10400937
TI  - Effect of the group II metabotropic glutamate agonist, 2R,4R-APDC, varies with
      age, layer, and visual experience in the visual cortex.
AB  - Group II metabotropic glutamate receptors (mGluR 2/3) are distributed
      differentially across the layers of cat visual cortex, and this distribution
      varies with age. At 3-4 wk, mGluR 2/3 receptor immunoreactivity is present in all
      layers. By 6-8 wk of age, it is still present in extragranular layers (2, 3, 5,
      and 6) but has disappeared from layer 4, and dark-rearing postpones the
      disappearance of Group II receptors from layer 4. We examined the physiological
      effects of Group II activation, to see if these effects varied similarly. The
      responses of single neurons in cat primary visual cortex were recorded to visual
      stimulation, then the effect of iontophoresis of 2R,4R-4 aminopyrrolidine-2, 4
      decarboxylate (2R,4R-APDC), a Group II specific agonist, was observed in animals
      between 3 wk and adulthood. The effect of 2R, 4R-APDC was generally suppressive,
      reducing both the visual response and spontaneous activity of single neurons. The
      developmental changes were in agreement with the immunohistochemical results: 2R,
      4R-APDC had effects on cells in all layers in animals of 3-4 wk but not in layer
      4 of animals >6 wk old. Moreover, the effect of 2R, 4R-APDC was reduced in the
      cortex of older animals (>22 wk). Dark-rearing animals to 47-54 days maintained
      the effects of 2R, 4R-APDC in layer 4. The disappearance of Group II mGluRs from
      layer 4 between 3 and 6 wk of age is correlated with the segregation of ocular
      dominance columns in that layer, raising the possibility that mGluRs 2/3 are
      involved in this process.

PMID- 10400939
TI  - Failure of cerebellar patients to time finger opening precisely causes ball high
      low inaccuracy in overarm throws.
AB  - We investigated the idea that the cerebellum is required for precise timing of
      fast skilled arm movements by studying one situation where timing precision is
      required, namely finger opening in overarm throwing. Specifically, we tested the
      hypothesis that in overarm throws made by cerebellar patients, ball high-low
      inaccuracy is due to disordered timing of finger opening. Six cerebellar patients
      and six matched control subjects were instructed to throw tennis balls at three
      different speeds from a seated position while angular positions in three
      dimensions of five arm segments were recorded at 1,000 Hz with the search-coil
      technique. Cerebellar patients threw more slowly than controls, were markedly
      less accurate, had more variable hand trajectories, and showed increased
      variability in the timing, amplitude, and velocity of finger opening. Ball high
      low inaccuracy was not related to variability in the height or direction of the
      hand trajectory or to variability in finger amplitude or velocity. Instead, the
      cause was variable timing of finger opening and thereby ball release occurring on
      a flattened arc hand trajectory. The ranges of finger opening times and ball
      release times (timing windows) for 95% of the throws were on average four to five
      times longer for cerebellar patients; e.g., across subjects mean ball release
      timing windows for throws made under the medium-speed instruction were 11 ms for
      controls and 55 ms for cerebellar patients. This increased timing variability
      could not be explained by disorder in control of force at the fingers. Because
      finger opening in throwing is likely controlled by a central command, the results
      implicate the cerebellum in timing the central command that initiates finger
      opening in this fast skilled multijoint arm movement.

PMID- 10400938
TI  - GABAB receptor-mediated regulation of glutamate-activated calcium transients in
      hypothalamic and cortical neuron development.
AB  - In the mature nervous system excitatory neurotransmission mediated by glutamate
      is balanced by the inhibitory actions of GABA. However, during early development,
      GABA acting at the ligand-gated GABAA Cl- channel also exerts excitatory actions.
      This raises a question as to whether GABA can exert inhibitory activity during
      early development, possibly by a mechanism that involves activation of the G
      protein-coupled GABAB receptor. To address this question we used Ca2+ digital
      imaging to assess the modulatory role of GABAB receptor signaling in relation to
      the excitatory effects of glutamate during hypothalamic and cortical neuron
      development. Ca2+ transients mediated by synaptic glutamate release in neurons
      cultured from embryonic rat were dramatically depressed by the administration of
      the GABAB receptor agonist baclofen in a dose-dependent manner. The inhibitory
      effects of GABAB receptor activation persisted for the duration of baclofen
      administration (>10 min). Preincubation with the Gi protein inhibitor pertussis
      toxin resulted in a substantial decrease in the inhibitory actions of baclofen,
      confirming that a Gi-dependent mechanism mediated the effects of the GABAB
      receptor. Co-administration of the GABAB receptor antagonist 2-hydroxy-saclofen
      eliminated the inhibitory action of baclofen. Alone, GABAB antagonist application
      elicited a marked potentiation of Ca2+ transients mediated by glutamatergic
      neurotransmission, suggesting that tonic synaptic GABA release exerts an
      inhibitory tone on glutamate receptor-mediated Ca2+ transients via GABAB receptor
      activation. In the presence of TTX to block action potential-mediated
      neurotransmitter release, stimulation with exogenously applied glutamate
      triggered a robust postsynaptic Ca2+ rise that was dramatically depressed (>70%
      in cortical neurons, >40% in hypothalamic neurons) by baclofen. Together these
      data suggest both a pre- and postsynaptic component for the modulatory actions of
      the GABAB receptor. These results indicate a potentially important role for the
      GABAB receptor as a modulator of the excitatory actions of glutamate in
      developing neurons.

PMID- 10400940
TI  - Dynamic control of irregular bursting in an identified neuron of an oscillatory
      circuit.
AB  - In the oscillatory circuits known as central pattern generators (CPGs), most
      synaptic connections are inhibitory. We have assessed the effects of inhibitory
      synaptic input on the dynamic behavior of a component neuron of the pyloric CPG
      in the lobster stomatogastric ganglion. Experimental perturbations were applied
      to the single, lateral pyloric neuron (LP), and the resulting voltage time series
      were analyzed using an entropy measure obtained from power spectra. When isolated
      from phasic inhibitory input, LP generates irregular spiking-bursting activity.
      Each burst begins in a relatively stereotyped manner but then evolves with
      exponentially increasing variability. Periodic, depolarizing current pulses are
      poor regulators of this activity, whereas hyperpolarizing pulses exert a strong,
      frequency-dependent regularizing action. Rhythmic inhibitory inputs from
      presynaptic pacemaker neurons also regularize the bursting. These inputs 1) reset
      LP to a similar state at each cycle, 2) extend and further stabilize the initial,
      quasi-stable phase of its bursts, and 3) at sufficiently high frequencies
      terminate ongoing bursts before they become unstable. The dynamic time frame for
      stabilization overlaps the normal frequency range of oscillations of the pyloric
      CPG. Thus, in this oscillatory circuit, the interaction of rhythmic inhibitory
      input with intrinsic burst properties affects not only the phasing, but also the
      dynamic stability of neural activity.

PMID- 10400942
TI  - Shape interactions in macaque inferior temporal neurons.
AB  - Missal et al. observed that the responses of inferior temporal (IT) neurons to a
      shape were reduced markedly when this shape partially overlapped a larger second
      shape, suggesting that shape interactions determine IT responses. In the present
      study, we compared the responses of IT neurons with combinations of two shapes
      which did or did not overlap and studied the effect of the relative and absolute
      positions of the two shapes. In a first test, a preferred shape (figure) was
      presented at the fixation point while a second, nonpreferred, shape was displayed
      either in the background of the figure (overlap) or at one of four peripheral
      positions (nonoverlap). Controls consisted of presentations of either shape in
      isolation at each of the five positions. The stimuli were presented during a
      fixation task. The responses to these combinations of two shapes were, on
      average, reduced compared with those elicited by the preferred shape presented in
      isolation. This suppression occurred whether or not the two shapes overlapped,
      but the degree of suppression in the overlap and nonoverlap conditions did not
      correlate. These interactions were stronger when the interacting stimulus was
      located in the contralateral compared with the ipsilateral hemifield. The
      position of the interacting stimulus within a hemifield significantly affected
      the suppression associated with combined shapes in some neurons. The strength of
      the interactions of the two nonoverlapping shapes depended on the shape of the
      interacting stimulus in half of the neurons. In a second test, the preferred
      shape and interacting stimulus could appear either at the fixation point or at
      one eccentric position. Here we found that the suppression was, on average,
      strongest when the interacting stimulus, rather than the preferred shape, was
      presented at the fixation position. Also, in 40% of the neurons, the response
      reduction was similar in overlap and nonoverlap conditions if effects of stimulus
      position were taken into account. In both tests, we also measured the responses
      to combinations of a nonpreferred shape and the interacting stimulus and showed
      that the response to a combination of two nonpreferred shapes was, in general,
      smaller than the response to a combination of the preferred and nonpreferred
      shape. Overall the results indicate that stimulus interactions in the receptive
      fields of IT neurons can be position and shape selective; this can contribute to
      the coding for the relationships between object parts.

PMID- 10400941
TI  - The Drosophila NSF protein, dNSF1, plays a similar role at neuromuscular and some
      central synapses.
AB  - The N-ethylmaleimide sensitive fusion protein (NSF) was originally identified as
      a cytosolic factor required for constitutive vesicular transport and later
      implicated in synaptic vesicle trafficking as well. Our previous work at
      neuromuscular synapses in the temperature-sensitive NSF mutant, comatose (comt),
      has shown that the comt gene product, dNSF1, functions after synaptic vesicle
      docking in the priming of vesicles for fast calcium-triggered fusion. Here we
      investigate whether dNSF1 performs a similar function at central synapses
      associated with the well-characterized giant fiber neural pathway. These include
      a synapse within the giant fiber pathway, made by the peripherally synapsing
      interneuron (PSI), as well as synapses providing input to the giant fiber
      pathway. The latency (delay) between stimulation and a resulting muscle action
      potential was used to assess the function of each class of synapses. Repetitive
      stimulation of the giant fiber pathway in comt produced wild-type responses at
      both 20 and 36 degrees C, exhibiting a characteristic and constant latency
      between stimulation and the muscle response. In contrast, stimulation of
      presynaptic inputs to the giant fiber (referred to as the "long latency pathway")
      revealed a striking difference between wild type and comt at 36 degrees C.
      Repetitive stimulation of the long latency pathway led to a progressive, activity
      dependent increase in the response latency in comt, but not in wild type. Thus
      the giant fiber pathway, including the PSI synapse, appears to function normally
      in comt, whereas the presynaptic inputs to the giant fiber pathway are disrupted.
      Several aspects of the progressive latency increase observed in the long latency
      pathway can be understood in the context of the activity-dependent reduction in
      neurotransmitter release we observed previously at neuromuscular synapses. These
      results suggest that repetitive stimulation causes a progressive reduction in
      neurotransmitter release by presynaptic inputs to the giant fiber neuron,
      resulting in an increased latency preceding a giant fiber action potential. Thus
      synapses presynaptic to the giant fiber appear to utilize dNSF1 in a manner
      similar to the neuromuscular synapse, whereas the PSI chemical synapse may differ
      with respect to the expression or activity of dNSF1.

PMID- 10400943
TI  - Neurosteroid modulation of synaptic and GABA-evoked currents in neurons from the
      rat medial preoptic nucleus.
AB  - The effects of the neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one
      (allopregnanolone) on synaptic and GABA-evoked currents in acutely dissociated
      neurons from the medial preoptic nucleus of rat were investigated by perforated
      patch recordings under voltage-clamp conditions. The effect of 2.0 microM
      allopregnanolone on GABA-evoked currents depended strongly on the GABA
      concentration: the currents evoked by 100 microM GABA were markedly depressed and
      the desensitization was faster, but the decay after GABA application was
      prolonged. In contrast, the currents evoked by 1.0 microM GABA were markedly
      potentiated, the activation was faster, a prominent desensitization was induced,
      and the decay after GABA application was prolonged. In the absence of externally
      applied GABA, 2.0 microM allopregnanolone induced a slow current that could be
      attributed to Cl-. Allopregnanolone did not significantly affect the amplitude of
      spontaneous tetrodotoxin-insensitive (miniature) synaptic currents (mIPSCs)
      originating from synaptic terminals releasing GABA onto the dissociated neurons.
      However, the mIPSC decay phase was dramatically prolonged, with half-maximal
      effect at approximately 50 nM allopregnanolone. A qualitatively similar effect of
      allopregnanolone was seen when KCl was used to evoke synchronous GABA release.
      The frequency of mIPSCs was also affected, on average increased 3.5-fold, by 2.0
      microM allopregnanolone, suggesting a presynaptic steroid action.

PMID- 10400945
TI  - Single-unit responses in the inferior colliculus of decerebrate cats. II.
      Sensitivity to interaural level differences.
AB  - Single units in the central nucleus of the inferior colliculus (ICC) of
      unanesthetized decerebrate cats can be grouped into three distinct types (V, I,
      and O) according to the patterns of excitation and inhibition revealed in
      contralateral frequency response maps. This study extends the description of
      these response types by assessing their ipsilateral and binaural response map
      properties. Here the nature of ipsilateral inputs is evaluated directly using
      frequency response maps and compared with results obtained from methods that rely
      on sensitivity to interaural level differences (ILDs). In general, there is a one
      to-one correspondence between observed ipsilateral input characteristics and
      those inferred from ILD manipulations. Type V units receive ipsilateral
      excitation and show binaural facilitation (EE properties); type I and type O
      units receive ipsilateral inhibition and show binaural excitatory/inhibitory (EI)
      interactions. Analyses of binaural frequency response maps show that these ILD
      effects extend over the entire receptive field of ICC units. Thus the range of
      frequencies that elicits excitation from type V units is expanded with increasing
      levels of ipsilateral stimulation, whereas the excitatory bandwidth of type I and
      O units decreases under the same binaural conditions. For the majority of ICC
      units, application of bicuculline, an antagonist for GABAA-mediated inhibition,
      does not alter the basic effects of binaural stimulation; rather, it primarily
      increases spontaneous and maximum discharge rates. These results support our
      previous interpretations of the putative dominant inputs to ICC response types
      and have important implications for midbrain processing of competing free-field
      sounds that reach the listener with different directional signatures.

PMID- 10400944
TI  - Single-unit responses in the inferior colliculus of decerebrate cats. I.
      Classification based on frequency response maps.
AB  - This study proposes a classification system for neurons in the central nucleus of
      the inferior colliculus (ICC) that is based on excitation and inhibition patterns
      of single-unit responses in decerebrate cats. The decerebrate preparation allowed
      extensive characterization of physiological response types without the
      confounding effects of anesthesia. The tone-driven discharge rates of individual
      units were measured across a range of frequencies and levels to map excitatory
      and inhibitory response areas for contralateral monaural stimulation. The
      resulting frequency response maps can be grouped into the following three
      populations: type V maps exhibit a wide V-shaped excitatory area and no
      inhibition; type I maps show a more restricted I-shaped region of excitation that
      is flanked by inhibition at lower and higher frequencies; and type O maps display
      an O-shaped island of excitation at low stimulus levels that is bounded by
      inhibition at higher levels. Units that produce a type V map typically have a low
      best frequency (BF: the most sensitive frequency), a low rate of spontaneous
      activity, and monotonic rate-level functions for both BF tones and broadband
      noise. Type I and type O units have BFs that span the cat's range of audible
      frequencies and high rates of spontaneous activity. Like type V units, type I
      units are excited by BF tones and noise at all levels, but their rate-level
      functions may become nonmonotonic at high levels. Type O units are inhibited by
      BF tones and noise at high levels. The existence of distinct response types is
      consistent with a conceptual model in which the unit types receive dominant
      inputs from different sources and shows that these functionally segregated
      pathways are specialized to play complementary roles in the processing of
      auditory information.

PMID- 10400947
TI  - Multimodal medullary neurons and correlational linkages of the respiratory
      network.
AB  - This study addresses the hypothesis that multiple sensory systems, each capable
      of reflexly altering breathing, jointly influence neurons of the brain stem
      respiratory network. Carotid chemoreceptors, baroreceptors, and foot pad
      nociceptors were stimulated sequentially in 33 Dial-urethan-anesthetized or
      decerebrate vagotomized adult cats. Neuronal impulses were monitored with
      microelectrode arrays in the rostral and caudal ventral respiratory group (VRG),
      nucleus tractus solitarius (NTS), and n. raphe obscurus. Efferent phrenic nerve
      activity was recorded. Spike trains of 889 neurons were analyzed with cycle
      triggered histograms and tested for respiratory-modulated firing rates. Responses
      to stimulus protocols were assessed with peristimulus time and cumulative sum
      histograms. Cross-correlation analysis was used to test for nonrandom temporal
      relationships between spike trains. Spike-triggered averages of efferent phrenic
      activity and antidromic stimulation methods provided evidence for functional
      associations of bulbar neurons with phrenic motoneurons. Spike train cross
      correlograms were calculated for 6,471 pairs of neurons. Significant correlogram
      features were detected for 425 pairs, including 189 primary central peaks or
      troughs, 156 offset peaks or troughs, and 80 pairs with multiple peaks and
      troughs. The results provide evidence that correlational medullary assemblies
      include neurons with overlapping memberships in groups responsive to different
      sets of sensory modalities. The data suggest and support several hypotheses
      concerning cooperative relationships that modulate the respiratory motor pattern.
      1) Neurons responsive to a single tested modality promote or limit changes in
      firing rate of multimodal target neurons. 2) Multimodal neurons contribute to
      changes in firing rate of neurons responsive to a single tested modality. 3)
      Multimodal neurons may promote responses during stimulation of one modality and
      "limit" changes in firing rates during stimulation of another sensory modality.
      4) Caudal VRG inspiratory neurons have inhibitory connections that provide
      negative feedback regulation of inspiratory drive and phase duration.

PMID- 10400948
TI  - Nonlinear frequency-dependent synchronization in the developing hippocampus.
AB  - Synchronous population activity is present both in normal and pathological
      conditions such as epilepsy. In the immature hippocampus, synchronous bursting is
      an electrophysiological conspicuous event. These bursts, known as giant
      depolarizing potentials (GDPs), are generated by the synchronized activation of
      interneurons and pyramidal cells via GABAA, N-methyl-D-aspartate, and AMPA
      receptors. Nevertheless the mechanism leading to this synchronization is still
      controversial. We have investigated the conditions under which synchronization
      arises in developing hippocampal networks. By means of simultaneous intracellular
      recordings, we show that GDPs result from local cooperation of active cells
      within an integration period prior to their onset. During this time interval, an
      increase in the number of excitatory postsynaptic potentials (EPSPs) takes place
      building up full synchronization between cells. These EPSPs are correlated with
      individual action potentials simultaneously occurring in neighboring cells. We
      have used EPSP frequency as an indicator of the neuronal activity underlying GDP
      generation. By comparing EPSP frequency with the occurrence of synchronized GDPs
      between CA3 and the fascia dentata (FD), we found that GDPs are fired in an all
      or-none manner, which is characterized by a specific threshold of EPSP frequency
      from which synchronous GDPs emerge. In FD, the EPSP frequency-threshold for GDP
      onset is 17 Hz. GDPs are triggered similarly in CA3 by appropriate periodic
      stimulation of mossy fibers. The frequency threshold for CA3 GDP onset is 12 Hz.
      These findings clarify the local mechanism of synchronization underlying bursting
      in the developing hippocampus, indicating that GDPs are fired when background
      levels of EPSPs or action potentials have built up full synchronization by firing
      at specific frequencies (>12 Hz). Our results also demonstrate that spontaneous
      EPSPs and action potentials are important for the initiation of synchronous
      bursts in the developing hippocampus.

PMID- 10400946
TI  - Responses of simultaneously recorded respiratory-related medullary neurons to
      stimulation of multiple sensory modalities.
AB  - This study addresses the hypothesis that multiple afferent systems share elements
      of a distributed brain stem network that modulates the respiratory motor pattern.
      Data were collected from 18 decerebrate, bilaterally vagotomized, paralyzed,
      artificially ventilated cats. Up to 28 neurons distributed in the rostral and
      caudal ventral respiratory group, nucleus tractus solitarius, and raphe obscurus
      were recorded simultaneously with microelectrode arrays. Phases of the
      respiratory cycle and inspiratory drive were assessed from integrated efferent
      phrenic nerve activity. Carotid chemoreceptors were stimulated by injection of
      CO2-saturated saline solution via the external carotid artery. Baroreceptors were
      stimulated by increased blood pressure secondary to inflation of an embolectomy
      catheter in the descending aorta. Cutaneous nociceptors were stimulated by
      pinching a footpad. Four hundred seventy-four neurons were tested for respiratory
      modulated firing rates and responses; 403 neurons were tested with stimulation of
      all 3 modalities. Chemoreceptor stimulation and pinch, perturbations that tend to
      increase respiratory drive, caused similar responses in 52 neurons; 28 responded
      oppositely. Chemoreceptor and baroreceptor stimulation resulted in similar
      primary responses in 45 neurons; 48 responded oppositely. Similar responses to
      baroreceptor stimulation and pinch were recorded for 38 neurons; opposite effects
      were measured in 26 neurons. Among simultaneously recorded neurons, distinct
      combinations of firing rate changes were evoked in response to stimulation of the
      different modalities. The results show a functional convergence of information
      from carotid chemoreceptors, baroreceptors, and cutaneous nociceptors on
      respiratory-modulated neurons distributed in the medulla. The data are consistent
      with the hypothesis that brain stem neurons have overlapping memberships in
      multifunctional groups that influence the respiratory motor pattern.

PMID- 10400949
TI  - Developmental changes in membrane properties of chemoreceptor afferent neurons of
      the rat petrosal ganglia.
AB  - Carotid body chemoreceptors increase their responsiveness to hypoxia in the
      postnatal period, but the mechanism for this increase is unresolved. The purpose
      of the present study was to examine developmental changes in cellular
      characteristics of chemoreceptor afferent neurons in the petrosal ganglia with
      the underlying hypothesis that developmental changes occur and may account for
      the developmental increase in chemoreceptor responsiveness. Chemoreceptor
      complexes (carotid body, sinus nerve, glossopharyngeal nerve, and petrosal
      ganglia) were harvested from rats, aged 3-40 days, and intracellular recordings
      were obtained from petrosal ganglion neurons using sharp electrode impalement.
      All chemoreceptor neurons across ages were C fibers with conduction velocities <1
      m/s and generated repetitive action potentials with depolarization. Resting
      membrane potential was -61.3 +/- 0.9 (SE) mV (n = 78) and input resistance was
      108 +/- 6 MOmega and did not significantly change with age. Cell capacitance was
      32.4 +/- 1.7 pF and did not change with age. Rheobase averaged 0.21 +/- 0.02 nA
      and slightly increased with age. Action potentials were followed by an
      afterhyperpolarization of 12.4 +/- 0.6 mV and time constant 6.9 +/- 0.5 ms; only
      the time constant decreased with age. These results, obtained in rat, demonstrate
      electrophysiologic characteristics which differ substantially from that
      previously described in cat chemoreceptor neurons. In general developmental
      changes in cell characteristics are small and are unlikely to account for the
      developmental increase in chemoreceptor responsiveness with age.

PMID- 10400950
TI  - Modulatory effects of myomodulin on the excitability and membrane currents in
      Retzius cells of the leech.
AB  - Ion channel modulation by the peptide myomodulin (MM) has been demonstrated in a
      wide variety of organisms including Aplysia, Lymnaea, and Pleurobranchaea. This
      neural and muscular modulation has been shown to be important for shaping and
      modifying behavior. In this paper, we report that MM modulates several distinct
      ionic channels in another species, the medicinal leech Hirudo medicinalis.
      Experiments have focused on the Retzius cell (R) because the R cell is a
      multifunction neuron that has been implicated in a number of behaviors including
      feeding, swimming, secretion, thermal sensing, and the touch elicited shortening
      reflex and its plasticity. Previous work had identified a MM-like peptide in the
      leech and demonstrated that this peptide modulated the excitability of the R
      cell. Using combined current- and voltage-clamp techniques to examine the effects
      of MM on the R cell, we found that in response to a step pulse, MM increased the
      excitability of the R cell such that the cell fires more action potentials with a
      shorter latency to the first action potential. We found that this effect was
      mediated by the activation of a Na+-mediated inward current near the cell resting
      membrane potential. Second, we found that MM differentially modulated the
      potassium currents IA and IK. No effect of MM was found on IA, whereas MM
      significantly reduced both the peak and steady-state amplitudes of IK by 49 +/-
      2.9% and 43 +/- 7.2%, respectively (means +/- SE). Finally we found that MM
      reduced the amplitude of the Ca2+ current by approximately 20%. The ionic
      currents modulated by MM are consistent with the overall effect of MM on the
      cellular activity of the R cell. An understanding of the cellular mechanisms by
      which MM modulates the activity of the R cell should help us to better understand
      the roles of both MM and the R cell in a variety of behaviors in the leech.

PMID- 10400951
TI  - Odorants suppress a voltage-activated K+ conductance in rat olfactory neurons.
AB  - Stimulation of olfactory receptor neurons (ORNs) with odors elicits an increase
      in the concentration of cAMP leading to opening of cyclic nucleotide-gated (CNG)
      channels and subsequent depolarization. Although opening of CNG channels is
      thought to be the main mechanism mediating signal transduction, modulation of
      other ion conductances by odorants has been postulated. To determine whether K+
      conductances are modulated by odorants in mammalian ORNs, we examined the
      response of rat ORNs to odors by recording membrane current under perforated
      patch conditions. We find that rat ORNs display two predominant types of
      responses. Thirty percent of the cells responded to odorants with activation of a
      CNG conductance. In contrast, in 55% of the ORNs, stimulation with odorants
      inhibited a voltage-activated K+ conductance (IKo). In terms of pharmacology, ion
      permeation, outward rectification, and time course for inactivation, IKo
      resembled a delayed rectifier K+ conductance. The effect of odorants on IKo was
      specific (only certain odorants inhibited IKo in each ORN) and concentration
      dependent, and there was a significant latency between arrival of odorants to the
      cell and the onset of suppression. These results indicate that indirect
      suppression of a K+ conductance (IKo) by odorants plays a role in signal
      transduction in mammalian ORNs.

PMID- 10400952
TI  - Recovery of functional response in the nucleus of the solitary tract after
      peripheral gustatory nerve crush and regeneration.
AB  - Single-unit recording and transganglionic tracing techniques were used to assess
      the properties of, and inputs to, neurons within the rostral nucleus of the
      solitary tract (NST) after peripheral gustatory nerve injury and regeneration in
      adult hamsters (Mesocricetus auratus). Tastant-evoked responses were recorded
      from 43 neurons in animals in which the ipsilateral chorda tympani (CT) nerve was
      crushed 8 wk earlier (experimental animals) and from 46 neurons in unlesioned
      control animals. The 89 neurons were separated into three functional clusters
      named according to the best stimulus for neurons in the cluster: S, sucrose; N,
      sodium acetate; and H, HCl or KCl. Stimulus-evoked spike rates across all stimuli
      were 35.4 +/- 4.4% lower in the experimental hamsters. The largest difference in
      evoked spike rates occurred for neurons in the H cluster, in which the response
      to KCl also was delayed relative to normal responses. The response of S-cluster
      units to sucrose and saccharin was also lower in the experimental animals. The
      mean response rate and the time course of response of neurons in the N cluster
      did not differ between the two groups. For each cluster, the spontaneous rates
      and mean response profiles across eight stimuli were very similar in the
      experimental and control animals, and the breadth of tuning hardly differed. In
      both groups, Na+ responses in the N cluster were amiloride sensitive, and
      responses to the water rinse after stimulation with HCl were common in the S
      cluster. At 8-20 wk after nerve crush, biotinylated dextran tracing of the CT
      nerve revealed that the regenerated CT fibers did not sprout outside the normal
      terminal zone in the NST, but the density of the central terminal fibers was 36.9
      +/- 6.35% lower than normal. After CT nerve crush and regeneration, the overall
      reduction in taste-evoked spike rates in NST neurons is likely a consequence of
      this change in terminal fibers; this in turn likely results from the known
      reduction in CT fibers regenerating past the crush site. In the face of this
      reduction, the normal taste-evoked spike rate in N-cluster neurons requires
      explanation. The observed recovery of normal specificity could be mediated by a
      restoration of specific connections by primary afferent fibers peripherally and
      centrally or by central compensatory mechanisms.

PMID- 10400953
TI  - Evidence for chloride ions as intracellular messenger substances in astrocytes.
AB  - Cultured rat hippocampal astrocytes were used to investigate the mechanism
      underlying the suppression of Ba2+-sensitive K+ currents by GABAA receptor
      activation. Muscimol application had two effects on whole cell currents: opening
      of the well-known Cl- channel of the GABAA receptor and a secondary longer
      lasting blockade of outward K+ currents displaying both peak and plateau phases.
      This blockade was independent of both Na+ (inside and outside) and ATP in the
      pipette. It also seemed to be independent of muscimol binding to the receptor
      because picrotoxin application showed no effect on the K+ conductance. The effect
      is blocked when anion efflux is prevented by replacing Cl- with gluconate (both
      inside and out) and is enhanced with more permeant anions such as Br- and I-.
      Moreover, the effect is reproduced in the absence of muscimol by promoting Cl-
      efflux via lowering of extracellular Cl- levels. These results, along with the
      requirement for Cl- efflux in muscimol experiments, show a strong dependency of
      the secondary blockade on Cl- efflux through the Cl- channel of the GABAA
      receptor. We therefore conclude that changes in the intracellular Cl-
      concentration alter the outward K+ conductances of astrocytes. Such a Cl-
      mediated modulation of an astrocytic K+ conductance will have important
      consequences for the progression of spreading depression through brain tissue and
      for astrocytic swelling in pathological situations.

PMID- 10400954
TI  - An unlearned principle for controlling natural movements.
AB  - Recently, Gottlieb and colleagues discovered a linear relation between elbow and
      shoulder dynamic torque in natural pointing movements in the sagittal plane. The
      present study investigates if the process of learning to reach involves
      discovering this linearity principle. We inspected torque data from four infants
      who were learning to reach and grab a toy in front of them. In a longitudinal
      study, we collected data both in the period before and after they performed their
      first successful reaches. Torque profiles at the shoulder and elbow were
      typically multipeaked and became more and more biphasic toward the end of the
      first year of life. Torques at the shoulder and elbow were correlated tightly for
      movements in the prereaching period as well as for reaches later in the year.
      Furthermore, slopes of a regression of shoulder dynamic torque on elbow dynamic
      torque were remarkably constant at a value approximately 2.5-3.0. If linear
      synergy is used by the nervous system to reduce the controlled degrees of
      freedom, it will act as a strong constraint on the complex of possible
      coordination patterns for arm movement early in life. Natural reaching movements
      can capitalize on this constraint because it simplifies the process of learning
      to reach.

PMID- 10400955
TI  - Characterization of chloride currents and their noradrenergic modulation in rat
      taste receptor cells.
AB  - Taste receptor cells contain a heterogeneous array of voltage-dependent ion
      conductances that are essential components for the transduction of gustatory
      stimuli. Although mechanistic roles have been proposed for several cationic
      conductances, the understanding of anionic currents is rudimentary. This study
      characterizes biophysical and pharmacological properties of chloride currents in
      rat posterior taste cells using whole cell patch-clamp recording technique. Taste
      cells express a heterogeneous array of chloride currents that displayed strong
      outward rectification, contained both calcium-dependent and calcium-independent
      components, and achieved a maximal conductance of almost 1 nS. Reversal
      potentials altered predictably with changes in chloride concentration. Currents
      were sensitive to inhibition by the chloride channel pharmacological agents DIDS,
      SITS, and niflumic acid but were insensitive to 9-AC. Adrenergic enhancement of
      chloride currents, present in other cell types, was tested on taste cells with
      the beta-adrenergic agonist isoproterenol (ISP). ISP enhanced the outwardly
      rectifying portion of the chloride current. This enhancement was calcium
      dependent and was blocked by the beta-adrenergic antagonist propranolol.
      Collectively these observations suggest that chloride currents may participate
      not only in usually ascribed functions such as stabilization of the membrane
      potential and volume regulation but additionally play active modulatory roles in
      the transduction of gustatory stimuli.

PMID- 10400956
TI  - Role of metabotropic glutamate receptor subtype mGluR1 in brief nociception and
      central sensitization of primate STT cells.
AB  - G-protein coupled metabotropic glutamate receptors (mGluRs) are important
      modulators of synaptic transmission in the mammalian CNS and have been implicated
      in various forms of neuroplasticity and nervous system disorders. Increasing
      evidence also suggests an involvement of mGluRs in nociception and pain behavior
      although the contribution of individual mGluR subtypes is not yet clear. Subtypes
      mGluR1 and mGluR5 are classified as group I mGluRs and share the ability to
      stimulate phosphoinositide hydrolysis and activate protein kinase C. The present
      study examined the role of group I mGluRs in nociceptive processing and capsaicin
      induced central sensitization of primate spinothalamic tract (STT) cells in vivo.
      In 10 anesthetized male monkeys (Macaca fascicularis) extracellular recordings
      were made from 20 STT cells in the lumbar dorsal horn. Responses to brief (15 s)
      cutaneous stimuli of innocuous (BRUSH) and barely and substantially noxious
      (PRESS and PINCH, respectively) intensity were recorded before, during, and after
      the infusion of group I mGluR agonists and antagonists into the dorsal horn by
      microdialysis. Cumulative concentration-response relationships were obtained by
      applying different concentrations for at least 20 min each (at 5 microl/min). The
      actual concentrations reached in the tissue are 2-3 orders of magnitude lower
      than those in the microdialysis fibers (values in this paper refer to the
      latter). The group I antagonists were also applied at 10-25 min after capsaicin
      injection. S-DHPG, a group I agonist at both mGluR1 and mGluR5, potentiated the
      responses to innocuous and noxious stimuli (BRUSH > PRESS > PINCH) at low
      concentrations (10-100 microM; n = 5) but had inhibitory effects at higher
      concentrations (1-10 mM; n = 5). The mGluR5 agonist CHPG (1 microM-100 mM; n = 5)
      did not potentiate but inhibited all responses (10-100 mM; n = 5). AIDA (1 microM
      100 mM), a mGluR1-selective antagonist, dose-dependently depressed the responses
      to PINCH and PRESS but not to BRUSH (n = 6). The group I (mGluR1 > mGluR5)
      antagonist CPCCOEt (1 microM-100 mM) had similar effects (n = 6). Intradermal
      injections of capsaicin sensitized the STT cells to cutaneous mechanical stimuli.
      The enhancement of the responses by capsaicin resembled the potentiation by the
      group I mGluR agonist S-DHPG (BRUSH > PRESS > PINCH). CPCCOEt (1 mM) reversed the
      capsaicin-induced sensitization when given as posttreatment (n = 5). After
      washout of CPCCOEt, the sensitization resumed. Similarly, AIDA (1 mM; n = 7)
      reversed the capsaicin-induced sensitization and also blocked the potentiation by
      S-DHPG (n = 5). These data suggest that the mGluR1 subtype is activated
      endogenously during brief high-intensity cutaneous stimuli (PRESS, PINCH) and is
      critically involved in capsaicin-induced central sensitization.

PMID- 10400957
TI  - Resistance of retinal extracellular space to Ca2+ level decrease: implications
      for the synaptic effects of divalent cations.
AB  - Ion-sensitive microelectrodes were used to measure the variations of [Ca2+]o
      induced by application of low Ca2+ media in the superfused eyecup preparation of
      the Pseudemys turtle. The aim of the experiments was to evaluate the possibility,
      suggested by previous studies, that in the deep, sclerad, layers of the retina
      [Ca2+]o may remain high enough to sustain chemical synaptic transmission even
      after prolonged application of low-Ca2+ saline. It was found that, at depths of
      100-200 micron from the vitreal surface, [Ca2+ ]o did not fall below 1 mM even
      after application for periods of 30-60 min of nominally Ca2+-free media, and it
      was >0.3 mM after 30-min application of media containing EGTA and with a Ca2+
      concentration of 1 nM. Previous studies in isolated salamander photoreceptors
      have shown that a reduction of [Ca2+ ]o to 0.3-1.0 mM may result in a paradoxical
      increase of Ca2+ influx into synaptic terminals due to the reduced screening of
      negative charge on the external face of the plasma membrane. On the basis of
      these results, the persistence or enhancement of synaptic transmission from
      photoreceptors to horizontal cells observed in various retinas treated with low
      Ca2+ media may be accounted for within the classical Ca2+-dependent theory of
      synaptic transmission without invoking a Ca2+-independent mechanism.

PMID- 10400958
TI  - Stimulation of a restricted region in the midline cerebellar white matter evokes
      coordinated quadrupedal locomotion in the decerebrate cat.
AB  - In the reflexively standing acute decerebrate cat, we have previously shown that
      pulse train microstimulation of the hook bundle of Russel in the midline of the
      cerebellar white matter, through which crossed fastigiofugal fibers decussate,
      augments the postural tone of neck, trunk, fore-, and hindlimb extensor muscles.
      In the present study we examined the possible role of such stimulation in evoking
      locomotion as the animal is supported by a rubber hammock with its feet
      contacting the moving surface of a treadmill. We were able to provoke well
      coordinated, bilaterally symmetrical, fore- and hindlimb movements, whose cycle
      time and pattern were controlled by appropriate changes in stimulus intensity and
      treadmill speed. We carefully and systematically mapped this cerebellar locomotor
      region (CLR) through repeated dorsoventral penetrations with a glass-coated
      tungsten microelectrode in a single animal and between animals. We found that the
      optimal locus for evoking locomotion was centered on the midline, at Horsley
      Clarke coordinates H0 and P7.0, and extended over a rostrocaudal and dorsolateral
      range of approximately 0.5 mm. The lowest effective stimulus intensity at the
      optimal site was in the range of 5-8 microA. Along penetration tracks to left or
      right of the midline, effective stimulus intensity increased and evoked locomotor
      patterns were no longer symmetrical, but rather shifted toward the contralateral
      limbs. In the same animals, controlled locomotion was evoked by stimulating the
      mesencephalic locomotor region (MLR). With concomitant stimulation of the optimal
      sites in the CLR and the MLR, each at subthreshold strength, locomotor movements
      identical to those seen with suprathreshold stimulation of each site alone were
      evoked. With concomitant stimulation at suprathreshold strength for each site,
      locomotion became vigorous, with a shortened cycle time. After making ablative
      lesions at either the CLR or MLR (unilateral or bilateral), controlled locomotion
      was still evoked at the prior stimulus strength by stimulating the remaining
      site. Together, these results demonstrate that selective stimulation of the hook
      bundle of Russel in the midsagittal plane of the cerebellar white matter evokes
      "controlled" locomotion identical to that evoked by stimulating the MLR. We have
      shown that the fastigial nucleus is one of the supraspinal locomotion inducing
      sites and that it can independently and simultaneously trigger brain stem and
      spinal locomotor subprograms formerly believed to be the domain of various brain
      stem regions including the MLR and the subthalamic locomotor region.

PMID- 10400959
TI  - Receptive field properties of single neurons in rat primary visual cortex.
AB  - The rat is used widely to study various aspects of vision including developmental
      events and numerous pathologies, but surprisingly little is known about the
      functional properties of single neurons in the rat primary visual cortex (V1).
      These were investigated in the anesthetized (Hypnorm-Hypnovel), paralyzed animal
      by presenting gratings of different orientations, spatial and temporal
      frequencies, dimensions, and contrasts. Stimulus presentation and data collection
      were automated. Most neurons (190/205) showed sharply tuned (</=30 degrees
      bandwidth at half height) orientation selectivity with a bias for horizontal
      stimuli (31%). Analysis of response modulation of oriented cells showed a bimodal
      distribution consistent with the distinction between simple and complex cell
      types. Orientation specific interactions occurred between the center and the
      periphery of receptive fields, usually resulting in strong inhibition to center
      stimulation when both stimuli had the same orientation. There was no evidence for
      orientation columns nor for orderly change in optimal orientation with tangential
      tracks through V1. Responses were elicited by spatial frequencies ranging from
      zero (no grating) to 1.2 cycle/degree (c/ degrees ), peaking at 0.1 c/ degrees,
      and with a modal cutoff of 0.6 c/ degrees. Half of the neurons responded
      optimally to drifting gratings rather than flashing uniform field stimuli.
      Directional preference was seen for 59% of oriented units at all depths in the
      cortex. Optimal stimuli velocities varied from 10 to 250 degrees /s. Some units,
      mainly confined to layer 4, responded to velocities as high as 700 degrees /s.
      Response versus contrast curves (best fit with Naka-Rushton) varied from nearly
      linear to extremely steep (mean contrast semisaturation 50% and threshold 6%).
      There was a trend for cells from superficial layers to be more selective to
      different stimulus parameters than deeper layers cells. We conclude that neurons
      in rat V1 have complex and diverse visual properties, necessary for precise
      visual form perception with low spatial resolution.

PMID- 10400960
TI  - Glycinergic miniature synaptic currents and receptor cluster sizes differ between
      spinal cord interneurons.
AB  - The structural features of a synaptic connection between central neurons play an
      important role in determining the strength of the connection. In the present
      study, we have examined the relationship between the structural and functional
      properties of glycinergic synapses in the rat spinal cord. We have analyzed the
      structure of glycinergic receptor clusters on rat ventral horn interneurons using
      antibodies against the glycine receptor clustering protein, gephyrin. We have
      examined the properties of quantal glycinergic currents generated at these
      synapses using whole cell patch-clamp recordings of miniature postsynaptic
      inhibitory currents (mIPSCs) in rat spinal cord slices in vitro. Our
      immunolabeling results demonstrate that there is a considerable variability in
      the size of glycine receptor clusters within individual neurons. Furthermore
      there are large differences in the mean cluster size between neurons. These
      observations are paralleled closely by recordings of glycinergic mIPSCs. The
      mIPSC amplitude varies significantly within and between neurons. Results obtained
      using combined immunolabeling and electrophysiological recording on the same
      neurons show that cells with small glycine receptor clusters concurrently exhibit
      small mIPSCs. Our results suggest that the differences in the size of glycinergic
      receptor clusters may constitute an important factor contributing to the observed
      differences in mIPSC amplitude among spinal cord interneurons.

PMID- 10400961
TI  - Rapid and slow swelling during hypoxia in the CA1 region of rat hippocampal
      slices.
AB  - The role of swelling in hypoxic/ischemic neuronal injury is incompletely
      understood. We investigated the extent and time course of cell swelling during
      hypoxia, and recovery of cell volume during reoxygenation, in the CA1 region of
      rat hippocampal slices in vitro. Cell swelling was measured optically and
      compared with simultaneous measurements of the extracellular DC potential,
      extracellular [K+], and synaptic transmission in the presence and absence of
      hypoxic depolarization. Hypoxia-induced swelling consisted of rapid and/or slow
      components. Rapid swelling was observed frequently and always occurred
      simultaneously with hypoxic depolarization. Additionally, rapid swelling was
      followed by a prolonged phase of swelling that was approximately 15 times slower.
      Less frequently, slow swelling occurred independently, without either hypoxic
      depolarization or a preceding rapid swelling. For slices initially swelling
      rapidly, recovery of both cell volume and the slope of field excitatory
      postsynaptic potentials were best correlated with the duration of hypoxia (r =
      0.77 and 0.87, respectively). This was also the case for slices initially
      swelling slowly (r = 0.70 and 0.58, respectively). In contrast, the degree of
      recovery of cell volume was the same at 30 or 60 min of reoxygenation, indicating
      that prolonging the duration of reoxygenation within these limits was ineffective
      in improving recovery. Spectral measurements indicated that the hypoxia-induced
      changes in light transmittance were related to changes in cell volume and not
      changes in the oxidation state of mitochondrial cytochromes. The persistent
      impairment of synaptic transmission in slices swelling slowly (i.e., without
      hypoxic depolarization) indicates that swelling may play a role in this injury
      and that hypoxic depolarization is not required. Additionally, the correlation
      between the degree of recovery of cell volume and the degree of recovery of
      synaptic transmission during reoxygenation supports a role for swelling in
      hypoxic neuronal injury.

PMID- 10400962
TI  - Responses to auditory stimuli in macaque lateral intraparietal area. I. Effects
      of training.
AB  - The lateral intraparietal area (LIP) of macaques has been considered unresponsive
      to auditory stimulation. Recent reports, however, indicate that neurons in this
      area respond to auditory stimuli in the context of an auditory-saccade task. Is
      this difference in auditory responsiveness of LIP due to auditory-saccade
      training? To address this issue, LIP responses in two monkeys were recorded at
      two different times: before and after auditory-saccade training. Before auditory
      saccade training, the animals had never been trained on any auditory task, but
      had been trained on visual tasks. In both sets of experiments, activity of LIP
      neurons was recorded while auditory and visual stimuli were presented and the
      animals were fixating. Before training, 172 LIP neurons were recorded. Among
      these, the number of cells responding to auditory stimuli did not reach
      significance, whereas about one-half of the cells responded to visual stimuli. An
      information theory analysis confirmed that no information about auditory stimulus
      location was available in LIP neurons in the experiments before training. After
      training, activity from 160 cells was recorded. These experiments showed that 12%
      of cells in area LIP responded to auditory stimuli, whereas the proportion of
      cells responding to visual stimuli remained about the same as before training.
      The information theory analysis confirmed that, after training, information about
      auditory stimulus location was available in LIP neurons. Auditory-saccade
      training therefore generated responsiveness to auditory stimuli de novo in LIP
      neurons. Thus some LIP cells become active for auditory stimuli in a passive
      fixation task, once the animals have learned that these stimuli are important for
      oculomotor behavior.

PMID- 10400963
TI  - Responses to auditory stimuli in macaque lateral intraparietal area. II.
      Behavioral modulation.
AB  - The lateral intraparietal area (LIP), a region of posterior parietal cortex, was
      once thought to be unresponsive to auditory stimulation. However, recent reports
      have indicated that neurons in area LIP respond to auditory stimuli during an
      auditory-saccade task. To what extent are auditory responses in area LIP
      dependent on the performance of an auditory-saccade task? To address this
      question, recordings were made from 160 LIP neurons in two monkeys while the
      animals performed auditory and visual memory-saccade and fixation tasks.
      Responses to auditory stimuli were significantly stronger during the memory
      saccade task than during the fixation task, whereas responses to visual stimuli
      were not. Moreover, neurons responsive to auditory stimuli tended also to be
      visually responsive and to exhibit delay or saccade activity in the memory
      saccade task. These results indicate that, in general, auditory responses in area
      LIP are modulated by behavioral context, are associated with visual responses,
      and are predictive of delay or saccade activity. Responses to auditory stimuli in
      area LIP may therefore be best interpreted as supramodal responses, and similar
      in nature to the delay activity, rather than as modality-specific sensory
      responses. The apparent link between auditory activity and oculomotor behavior
      suggests that the behavioral modulation of responses to auditory stimuli in area
      LIP reflects the selection of auditory stimuli as targets for eye movements.

PMID- 10400964
TI  - Hindlimb locomotor and postural training modulates glycinergic inhibition in the
      spinal cord of the adult spinal cat.
AB  - Adult spinal cats were trained initially to perform either bipedal hindlimb
      locomotion on a treadmill or full-weight-bearing hindlimb standing. After 12 wk
      of training, stepping ability was tested before and after the administration
      (intraperitoneal) of the glycinergic receptor antagonist, strychnine. Spinal cats
      that were trained to stand after spinalization had poor locomotor ability as
      reported previously, but strychnine administration induced full-weight-bearing
      stepping in their hindlimbs within 30-45 min. In the cats that were trained to
      step after spinalization, full-weight-bearing stepping occurred and was
      unaffected by strychnine. Each cat then was retrained to perform the other task
      for 12 wk and locomotor ability was retested. The spinal cats that were trained
      initially to stand recovered the ability to step after they received 12 wk of
      treadmill training and strychnine was no longer effective in facilitating their
      locomotion. Locomotor ability declined in the spinal cats that were retrained to
      stand and strychnine restored the ability to step to the levels that were
      acquired after the step-training period. Based on analyses of hindlimb muscle
      electromyographic activity patterns and kinematic characteristics, strychnine
      improved the consistency of the stepping and enhanced the execution of hindlimb
      flexion during full-weight-bearing step cycles in the spinal cats when they were
      trained to stand but not when they were trained to step. The present findings
      provide evidence that 1) the neural circuits that generate full-weight-bearing
      hindlimb stepping are present in the spinal cord of chronic spinal cats that can
      and cannot step; however, the ability of these circuits to interpret sensory
      input to drive stepping is mediated at least in part by glycinergic inhibition;
      and 2) these spinal circuits adapt to the specific motor task imposed, and that
      these adaptations may include modifications in the glycinergic pathways that
      provide inhibition.

PMID- 10400965
TI  - Adaptive changes in motor activity associated with functional recovery following
      muscle denervation in walking cats.
AB  - In this investigation we examined the changes in the pattern of activity in the
      medial gastrocnemius (MG) muscle in walking cats following transection of the
      nerves innervating synergist muscles (lateral gastrocnemius, soleus, and
      plantaris). Immediately following the nerve transections, there was a large
      increase in ankle flexion during early stance (from approximately 10 to
      approximately 30 degrees ) and a marked increase in the magnitude of the MG
      bursts during stance. We attribute this increase in the magnitude of the MG
      bursts to an increase in afferent feedback from the abnormally stretched MG
      muscle. During the week after the nerve transections, there was a progressive
      decrease in ankle yield. This improvement in ankle function was correlated with
      an increase in magnitude of two components of the MG bursts; the initial
      component starting during late swing and ending approximately 40 ms after ground
      contact, and a late component associated with stance. The time courses of the
      increases in the initial and late components of the MG bursts were different.
      Large and significant increases in the late component occurred the day after the
      nerve transections, whereas increases in the initial component occurred more
      gradually. This difference in time course was reflected in the kinematics of
      ankle movement. Over the first few days after the nerve transections, improvement
      in ankle movement occurred primarily late in the stance phase, and there was
      little change in ankle yield during early stance. At 1 wk, however, there was a
      significant reduction in ankle yield during early stance. This decreased yield
      was most likely due to an increase in stiffness of the MG muscle at the time of
      ground contact resulting from the increase in magnitude of the initial component
      of the MG bursts. The increases in the magnitude of the initial and late
      components of the MG bursts, as well as the improvement in ankle function,
      depended on use of the leg. All these changes were delayed by immobilizing the
      leg for 6 days in an extended position. We discuss possible mechanisms underlying
      the increase in the magnitude of the MG bursts and propose that proprioceptive
      signals from the stretched MG muscles provide an error signal for rescaling the
      magnitude of the centrally generated initial component. Our data support the
      concept that proprioceptive feedback functions to scale the magnitude of feed
      forward motor commands to ensure they are appropriate for the biomechanical
      properties of the musculoskeletal system.

PMID- 10400966
TI  - Models of respiratory rhythm generation in the pre-Botzinger complex. I. Bursting
      pacemaker neurons.
AB  - A network of oscillatory bursting neurons with excitatory coupling is
      hypothesized to define the primary kernel for respiratory rhythm generation in
      the pre-Botzinger complex (pre-BotC) in mammals. Two minimal models of these
      neurons are proposed. In model 1, bursting arises via fast activation and slow
      inactivation of a persistent Na+ current INaP-h. In model 2, bursting arises via
      a fast-activating persistent Na+ current INaP and slow activation of a K+ current
      IKS. In both models, action potentials are generated via fast Na+ and K+
      currents. The two models have few differences in parameters to facilitate a
      rigorous comparison of the two different burst-generating mechanisms. Both models
      are consistent with many of the dynamic features of electrophysiological
      recordings from pre-BotC oscillatory bursting neurons in vitro, including voltage
      dependent activity modes (silence, bursting, and beating), a voltage-dependent
      burst frequency that can vary from 0.05 to >1 Hz, and a decaying spike frequency
      during bursting. These results are robust and persist across a wide range of
      parameter values for both models. However, the dynamics of model 1 are more
      consistent with experimental data in that the burst duration decreases as the
      baseline membrane potential is depolarized and the model has a relatively flat
      membrane potential trajectory during the interburst interval. We propose several
      experimental tests to demonstrate the validity of either model and to
      differentiate between the two mechanisms.

PMID- 10400967
TI  - Models of respiratory rhythm generation in the pre-Botzinger complex. II.
      Populations Of coupled pacemaker neurons.
AB  - We have proposed models for the ionic basis of oscillatory bursting of
      respiratory pacemaker neurons in the pre-Botzinger complex. In this paper, we
      investigate the frequency control and synchronization of these model neurons when
      coupled by excitatory amino-acid-mediated synapses and controlled by convergent
      synaptic inputs modeled as tonic excitation. Simulations of pairs of identical
      cells reveal that increasing tonic excitation increases the frequency of
      synchronous bursting, while increasing the strength of excitatory coupling
      between the neurons decreases the frequency of synchronous bursting. Low levels
      of coupling extend the range of values of tonic excitation where synchronous
      bursting is found. Simulations of a heterogeneous population of 50-500 bursting
      neurons reveal coupling effects similar to those found experimentally in vitro:
      coupling increases the mean burst duration and decreases the mean burst
      frequency. Burst synchronization occurred over a wide range of intrinsic
      frequencies (0.1-1 Hz) and even in populations where as few as 10% of the cells
      were intrinsically bursting. Weak coupling, extreme parameter heterogeneity, and
      low levels of depolarizing input could contribute to the desynchronization of the
      population and give rise to quasiperiodic states. The introduction of sparse
      coupling did not affect the burst synchrony, although it did make the interburst
      intervals more irregular from cycle to cycle. At a population level, both
      parameter heterogeneity and excitatory coupling synergistically combine to
      increase the dynamic input range: robust synchronous bursting persisted across a
      much greater range of parameter space (in terms of mean depolarizing input) than
      that of a single model cell. This extended dynamic range for the bursting cell
      population indicates that cellular heterogeneity is functionally advantageous.
      Our modeled system accounts for the range of intrinsic frequencies and spiking
      patterns of inspiratory (I) bursting cells found in the pre-Botzinger complex in
      neonatal rat brain stem slices in vitro. There is a temporal dispersion in the
      spiking onset times of neurons in the population, predicted to be due to
      heterogeneity in intrinsic neuronal properties, with neurons starting to spike
      before (pre-I), with (I), or after (late-I) the onset of the population burst.
      Experimental tests for a number of the model's predictions are proposed.

PMID- 10400968
TI  - Firing behavior of vestibular neurons during active and passive head movements:
      vestibulo-spinal and other non-eye-movement related neurons.
AB  - The firing behavior of 51 non-eye movement related central vestibular neurons
      that were sensitive to passive head rotation in the plane of the horizontal
      semicircular canal was studied in three squirrel monkeys whose heads were free to
      move in the horizontal plane. Unit sensitivity to active head movements during
      spontaneous gaze saccades was compared with sensitivity to passive head rotation.
      Most units (29/35 tested) were activated at monosynaptic latencies following
      electrical stimulation of the ipsilateral vestibular nerve. Nine were vestibulo
      spinal units that were antidromically activated following electrical stimulation
      of the ventromedial funiculi of the spinal cord at C1. All of the units were less
      sensitive to active head movements than to passive whole body rotation. In the
      majority of cells (37/51, 73%), including all nine identified vestibulo-spinal
      units, the vestibular signals related to active head movements were canceled. The
      remaining units (n = 14, 27%) were sensitive to active head movements, but their
      responses were attenuated by 20-75%. Most units were nearly as sensitive to
      passive head-on-trunk rotation as they were to whole body rotation; this suggests
      that vestibular signals related to active head movements were cancelled primarily
      by subtraction of a head movement efference copy signal. The sensitivity of most
      units to passive whole body rotation was unchanged during gaze saccades. A
      fundamental feature of sensory processing is the ability to distinguish between
      self-generated and externally induced sensory events. Our observations suggest
      that the distinction is made at an early stage of processing in the vestibular
      system.

PMID- 10400969
TI  - Spontaneous action potentials initiate rhythmic intercellular calcium waves in
      immortalized hypothalamic (GT1-1) neurons.
AB  - GT1-1 cells exhibit spontaneous action potentials and transient increases in
      intracellular calcium concentration ([Ca2+]i) that occur in individual cells and
      as spatially propagated intercellular Ca2+ waves. In this study, simultaneous
      cell-attached patch-clamp recording of action currents (indicative of action
      potentials) and fluorescence imaging of [Ca2+]i revealed that Ca2+ transients in
      GT1-1 cells were preceded by a single action current or a burst of action
      currents. Action currents preceded Ca2+ transients in a similar pattern
      regardless of whether the Ca2+ transients were limited to the individual cell or
      occurred as part of an intercellular Ca2+ wave. Both the action currents and Ca2+
      transients were abolished by 1 microM tetrodotoxin. Removal of extracellular Ca2+
      abolished all spontaneous Ca2+ transients without inhibiting the firing of action
      currents. Nimodipine, which blocks L-type Ca2+ currents in GT1-1 cells, also
      abolished all spontaneous Ca2+ signaling. Delivery of small voltage steps to the
      patch pipette in the cell-attached configuration elicited action currents the
      latency to firing of which decreased with increasing amplitude of the voltage
      step. These results indicate that spontaneous intercellular Ca2+ waves are
      generated by a propagated depolarization, the firing of action potentials in
      individual cells, and the resulting influx of Ca2+ through L-type Ca2+ channels.
      These patterns of spontaneous activity may be important in driving the pulsatile
      release of GnRH from networks of cells.

PMID- 10400970
TI  - Integration of vestibular and head movement signals in the vestibular nuclei
      during whole-body rotation.
AB  - Single-unit recordings were obtained from 107 horizontal semicircular canal
      related central vestibular neurons in three alert squirrel monkeys during passive
      sinusoidal whole-body rotation (WBR) while the head was free to move in the yaw
      plane (2.3 Hz, 20 degrees /s). Most of the units were identified as secondary
      vestibular neurons by electrical stimulation of the ipsilateral vestibular nerve
      (61/80 tested). Both non-eye-movement (n = 52) and eye-movement-related (n = 55)
      units were studied. Unit responses recorded when the head was free to move were
      compared with responses recorded when the head was restrained from moving. WBR in
      the absence of a visual target evoked a compensatory vestibulocollic reflex (VCR)
      that effectively reduced the head velocity in space by an average of 33 +/- 14%.
      In 73 units, the compensatory head movements were sufficiently large to permit
      the effect of the VCR on vestibular signal processing to be assessed
      quantitatively. The VCR affected the rotational responses of different vestibular
      neurons in different ways. Approximately one-half of the units (34/73, 47%) had
      responses that decreased as head velocity decreased. However, the responses of
      many other units (24/73) showed little change. These cells had signals that were
      better correlated with trunk velocity than with head velocity. The remaining
      units had responses that were significantly larger (15/73, 21%) when the VCR
      produced a decrease in head velocity. Eye-movement-related units tended to have
      rotational responses that were correlated with head velocity. On the other hand,
      non-eye-movement units tended to have rotational responses that were better
      correlated with trunk velocity. We conclude that sensory vestibular signals are
      transformed from head-in-space coordinates to trunk-in-space coordinates on many
      secondary vestibular neurons in the vestibular nuclei by the addition of inputs
      related to head rotation on the trunk. This coordinate transformation is
      presumably important for controlling postural reflexes and constructing a central
      percept of body orientation and movement in space.

PMID- 10400971
TI  - Geometry of dendritic spines affects calcium dynamics in hippocampal neurons:
      theory and experiments.
AB  - The role of dendritic spine morphology in the regulation of the spatiotemporal
      distribution of free intracellular calcium concentration ([Ca2+]i) was examined
      in a unique axial-symmetrical model that focuses on spine-dendrite interactions,
      and the simulations of the model were compared with the behavior of real
      dendritic spines in cultured hippocampal neurons. A set of nonlinear differential
      equations describes the behavior of a spherical dendritic spine head, linked to a
      dendrite via a cylindrical spine neck. Mechanisms for handling of calcium
      (including internal stores, buffers, and efflux pathways) are placed in both the
      dendrites and spines. In response to a calcium surge, the magnitude and time
      course of the response in both the spine and the parent dendrite vary as a
      function of the length of the spine neck such that a short neck increases the
      magnitude of the response in the dendrite and speeds up the recovery in the spine
      head. The generality of the model, originally constructed for a case of release
      of calcium from stores, was tested in simulations of fast calcium influx through
      membrane channels and verified the impact of spine neck on calcium dynamics.
      Spatiotemporal distributions of [Ca2+]i, measured in individual dendritic spines
      of cultured hippocampal neurons injected with Calcium Green-1, were monitored
      with a confocal laser scanning microscope. Line scans of spines and dendrites at
      a <1-ms time resolution reveal simultaneous transient rises in [Ca2+]i in spines
      and their parent dendrites after application of caffeine or during spontaneous
      calcium transients associated with synaptic or action potential discharges. The
      magnitude of responses in the individual compartments, spine-dendrite disparity,
      and the temporal distribution of [Ca2+]i were different for spines with short and
      long necks, with the latter being more independent of the dendrite, in agreement
      with prediction of the model.

PMID- 10400972
TI  - Functional anatomy of pursuit eye movements in humans as revealed by fMRI.
AB  - We have investigated the functional anatomy of pursuit eye movements in humans
      with functional magnetic imaging. The performance of pursuit eye movements
      induced activations in the cortical eye fields also activated during the
      execution of visually guided saccadic eye movements, namely in the precentral
      cortex [frontal eye field (FEF)], the medial superior frontal cortex
      (supplementary eye field), the intraparietal cortex (parietal eye field), and the
      precuneus, and at the junction of occipital and temporal cortex (MT/MST) cortex.
      Pursuit-related areas could be distinguished from saccade-related areas both in
      terms of spatial extent and location. Pursuit-related areas were smaller than
      their saccade-related counterparts, three of eight significantly so. The pursuit
      related FEF was usually inferior to saccade-related FEF. Other pursuit-related
      areas were consistently posterior to their saccade-related counterparts. The
      current findings provide the first functional imaging evidence for a distinction
      between two parallel cortical systems that subserve pursuit and saccadic eye
      movements in humans.

PMID- 10400973
TI  - Cannabinoid WIN 55,212-2 inhibits the activity-dependent facilitation of spinal
      nociceptive responses.
AB  - Cannabinoids suppress nociceptive processing of acute stimuli, but little is
      known about their effects on processes that lead to hyperexcitability of
      nociceptive neurons following prolonged noxious stimulation. Wind-up, the
      increasingly strong response of spinal nociceptive neurons to repetitive noxious
      electrical stimuli, results from a fast-rising cumulative depolarization and
      increase in intracellular calcium concentration. These processes produce central
      sensitization, the increased excitability of spinal nociceptive neurons that
      contributes to the hyperalgesia and allodynia associated with chronic pain.
      Intravenous injection of the potent, synthetic cannabinoid agonist WIN 55, 212-2,
      but not the inactive enantiomer, WIN 55,212-3, dose-dependently decreased the
      wind-up of spinal wide dynamic range and nociceptive-specific neurons independent
      of acute responses to activation of low- and high-threshold primary afferents.
      This is the first direct evidence that cannabinoids inhibit the activity
      dependent facilitation of spinal nociceptive responses.

PMID- 10400974
TI  - NPY inhibits glutamatergic excitation in the epileptic human dentate gyrus.
AB  - Neuropeptide Y (NPY) has been shown to depress hyperexcitable activity that has
      been acutely induced in the normal rat brain. To test the hypothesis that NPY can
      also reduce excitability in the chronically epileptic human brain, we recorded
      intracellularly from dentate granule cells in hippocampal slices from patients
      with hippocampal seizure onset. NPY had a potent and long-lasting inhibitory
      action on perforant path-evoked excitatory responses. In comparison, the group 3
      metabotropic glutamate receptor agonist L-2-amino-4-phosphonobutyric acid (L-AP4)
      evoked a mild and transient decrease. NPY-containing axons were found throughout
      the hippocampus, and in many epileptic patients were reorganized, particularly in
      the dentate molecular layer. NPY may therefore play a beneficial role in reducing
      granule cell excitability in chronically epileptic human tissue, and subsequently
      limit seizure severity.

PMID- 10400975
TI  - Movement-related cerebellar activation in the absence of sensory input.
AB  - Movement-related cerebellar activation may be due to sensory or motor processing.
      Ordinarily, sensory and motor processing are obligatorily linked, but in patients
      who have severe pansensory neuropathies with normal muscle strength, motor
      activity occurs in isolation. In the present study, positron emission tomography
      and functional magnetic resonance imaging in such patients showed no cerebellar
      activation with passive movement, whereas there was prominent movement-related
      cerebellar activation despite absence of proprioceptive or visual input. The
      results indicate that motor processing occurs within the cerebellum and do not
      support the recently advanced view that the cerebellum is primarily a sensory
      organ.

PMID- 10400976
TI  - Dendrodendritic recurrent excitation in mitral cells of the rat olfactory bulb.
AB  - Most neuronal interactions within the olfactory bulb network are mediated by
      dendrodendritic synapses. Dendritic transmitter release potentially could affect
      the parent dendrite as well as local neuronal elements that have receptors for
      the released transmitter. Here we report that under conditions that facilitate N
      methyl-D-aspartate (NMDA) receptor activity (reduced GABAA inhibition and
      extracellular Mg2+), a single action potential evoked by brief intracellular
      current pulses in mitral cells is followed by a prolonged depolarization, which
      is blocked by an NMDA receptor antagonist. This depolarization also is evoked by
      a presumed calcium spike in the presence of tetrodotoxin. A similar NMDA-receptor
      dependent prolonged depolarization is elicited by stimulation of the lateral
      olfactory tract at current intensities subthreshold for antidromic activation of
      the recorded neuron. These observations suggest that glutamate released from the
      dendrites of mitral cells excites the same and neighboring mitral cell dendrites.
      Further evidence suggests that both the apical and lateral dendrites of mitral
      cells participate in this recurrent excitation. These dendrodendritic
      interactions may play a role in the prolonged, NMDA-receptor-dependent
      depolarization of mitral/tufted cells evoked by olfactory nerve stimulation.

PMID- 10400978
TI  - Motor unit substitution in long-duration contractions of the human trapezius
      muscle.
AB  - We examined the activity pattern of low-threshold motor units in the human
      trapezius muscle during contractions of 10 min duration. Three procedures were
      applied in sequence: 1) static contraction controlled by maintaining a constant
      low level of the surface electromyogram (EMG)-detected root-mean-square signal,
      2) a manipulation task with mental concentration, and 3) copying a text on a word
      processor. A quadrifilar fine-wire electrode was used to record single motor unit
      activity. Simultaneously, surface electrodes recorded the surface EMG signal.
      During these contractions, low-threshold motor units showed periods of inactivity
      and were substituted by motor units of higher recruitment threshold. This
      phenomenon was not observed during the first few minutes of the contraction. In
      several cases the substitution process coincided with a short period of
      inactivity in the surface EMG pattern. Substitution was observed in five of eight
      experiments. These observations may be explained by a time-variant recruitment
      threshold of motor units, sensitive to their activation history and temporal
      variation in the activity patterns. We speculate that the substitution phenomenon
      protects motor units in postural muscles from excessive fatigue when there is a
      demand for sustained low-level muscle activity.

PMID- 10400977
TI  - Protein synthesis-dependent and mRNA synthesis-independent intermediate phase of
      memory in Hermissenda.
AB  - The conditioned stimulus pathway in Hermissenda has been used to examine the time
      dependent mechanisms of memory consolidation following one-trial conditioning.
      Here we report an intermediate phase of memory consolidation following one-trial
      conditioning that requires protein synthesis, but not mRNA synthesis. In
      conditioned animals, enhanced excitability normally expressed during an
      intermediate phase of memory was reversed by the protein synthesis inhibitor
      anisomycin, but not by the mRNA synthesis inhibitor 5, 6-dichloro-1-beta-D
      ribobenzimidazole (DRB). Associated with the intermediate phase of memory is an
      increase in the phosphorylation of a 24-kDa protein. Anisomycin present during
      the intermediate phase blocked the increased phosphorylation of the 24-kDa
      phosphoprotein, but did not block the increased phosphorylation of other proteins
      associated with conditioning or significantly change their baseline
      phosphorylation. DRB did not reverse enhanced excitability or decrease protein
      phosphorylation expressed during the intermediate phase of memory formation, but
      it did reverse enhanced excitability 3.5 h after conditioning. Phosphorylation of
      the 24-kDa protein may support enhanced excitability during the intermediate
      phase, in the transition period between short- and long-term memory.

PMID- 10400979
TI  - Muscle spindle afferent input to motoneurons in human masseter.
AB  - The H-reflex response in large and small single motor units in human deep
      anterior masseter was studied to investigate the distribution of muscle spindle
      afferents onto masseter motoneurons. We found that only the larger units
      displayed H-reflex responses. This indicates preferential distribution of muscle
      spindle input onto large motoneurons or a skewed distribution of tonic
      presynaptic inhibitory mechanisms.

PMID- 10400980
TI  - Oxidative downmodulation of the transient K-current IA by intracellular
      arachidonic acid in rat hippocampal neurons.
AB  - Membrane-permeable arachidonic acid (AA) is liberated in a Ca2+-dependent way
      inside cells. By using whole cell patch clamp we show that intracellular AA (1
      pM) selectively reduces IA in rat hippocampal neurons, whereas extracellular
      application requires a 10(6)-fold concentration. The nonmetabolized AA analogue
      ETYA mimics the effect of AA that is blocked by ascorbic acid or intracellular
      glutathione, suggesting an intracellular oxidative mechanism. We conclude that
      intracellular AA is extremely potent in reducing IA by an oxidative mechanism,
      particularly during oxidative stress.

PMID- 10400981
TI  - Multimodal convergence of presynaptic afferent inhibition in insect
      proprioceptors.
AB  - In the leg motor system of insects, several proprioceptive sense organs provide
      the CNS with information about posture and movement. Within one sensory organ,
      presynaptic inhibition shapes the inflow of sensory information to the CNS. We
      show here that also different proprioceptive sense organs can exert a presynaptic
      inhibition on each other. The afferents of one leg proprioceptor in the stick
      insect, either the position-sensitive femoral chordotonal organ or the load
      sensitive campaniform sensilla, receive a primary afferent depolarization (PAD)
      from two other leg proprioceptors, the campaniform sensilla and/or the coxal
      hairplate. The reversal potential of this PAD is about -59 mV, and the PAD is
      associated with a conductance increase. The properties of this presynaptic input
      support the hypothesis that this PAD acts as presynaptic inhibition. The PAD
      reduces the amplitude of afferent action potentials and thus likely also afferent
      transmitter release and synaptic efficacy. These findings imply that PAD
      mechanisms of arthropod proprioceptors might be as complex as in vertebrates.

PMID- 10400982
TI  - Paternal deletion from Snrpn to Ube3a in the mouse causes hypotonia, growth
      retardation and partial lethality and provides evidence for a gene contributing
      to Prader-Willi syndrome.
AB  - Prader-Willi syndrome (PWS) is caused by paternal deficiency of human chromosome
      15q11-q13. There is conflicting evidence from human translocations regarding the
      direct involvement of SNRPN in the pathogenesis of PWS and it is not known if the
      phenotypic features result from the loss of expression of a single imprinted gene
      or multiple genes. In an attempt to dissect genotype/phenotype correlations for
      the homologous region of mouse chromosome 7C, we prepared three mutant genotypes:
      (i) mice with a deletion of Snrpn exon 2, which removes a portion of a small,
      upstream open reading frame (ORF); (ii) mice with double targeting for Snrpn exon
      2 and Ube3a; (iii) mice deleted from Snrpn to Ube3a, removing coding exons for
      both loci and intervening genes. Mice deleted for Snrpn exon 2 have no obvious
      phenotypic abnormalities and switching of the genomic imprint for the region is
      conserved. Mice carrying the Snrpn - Ube3a deletion on the paternal chromosome
      showed severe growth retardation, hypotonia and approximately 80% lethality
      before weaning. The surviving mice were fertile and were not obese up to 14
      months of age. The deletion was transmitted for multiple generations and
      continued to cause partial lethality when inherited paternally, but not when
      inherited maternally. The normal imprinted expression and methylation patterns of
      necdin, a gene outside the deletion region, indicate that the deletion is not an
      imprinting mutation. The data suggest the presence of a paternally expressed
      structural gene between Snrpn and Ipw whose deficiency causes lethality, although
      other possibilities exist, including position effects on expression of imprinted
      genes or that simultaneous deficiency of both ORFs of Snrpn causes lethality.

PMID- 10400984
TI  - The pattern of replication at a human telomeric region (16p13.3): its
      relationship to chromosome structure and gene expression.
AB  - We have studied replication throughout 325 kb of the telomeric region of a human
      chromosome (16p13.3) and related the findings to various aspects of chromosome
      structure and function (DNA sequence organization, nuclease-hypersensitive sites,
      nuclear matrix attachment sites, patterns of methylation and gene expression).
      The GC-rich isochore lying adjacent to the telomere, which contains the alpha
      globin locus and many widely expressed genes, replicates early in the cell cycle
      regardless of the pattern of gene expression. In subtelomeric DNA, replication
      occurs later in the cell cycle and the most telomeric region (20 kb) is late
      replicating. Juxtaposition of early replicating DNA next to the telomere causes
      it to replicate later in S-phase. Analysis of the timing of replication in
      chromosomes with deletions, or in transgenes containing various segments of this
      telomeric region, suggests that there are no critical origins or zones that
      initiate replication, rather the pattern of replication appears to be related to
      the underlying chromatin structure which may restrict or facilitate access to
      multiple, redundant origins. These results contrast with the pattern of
      replication at the human beta-globin locus and this may similarly reflect the
      different chromosomal environments containing these gene clusters.

PMID- 10400983
TI  - Targeted disruption of the lysosomal alpha-mannosidase gene results in mice
      resembling a mild form of human alpha-mannosidosis.
AB  - Alpha-mannosidosis is a lysosomal storage disease with autosomal recessive
      inheritance caused by a deficiency of the lysosomal alpha-mannosidase, which is
      involved in the degradation of asparagine-linked carbohydrate cores of
      glycoproteins. An alpha-mannosidosis mouse model was generated by targeted
      disruption of the gene for lysosomal alpha-mannosidase. Homozygous mutant animals
      exhibit alpha-mannosidase enzyme deficiency and elevated urinary secretion of
      mannose-containing oligosaccharides. Thin-layer chromatography revealed an
      accumulation of oligosaccharides in liver, kidney, spleen, testis and brain. The
      cellular alterations were characterized by multiple membrane-limited cytoplasmic
      vacuoles as seen for instance in liver, exocrine pancreas, kidney, thyroid gland,
      smooth muscle cells, osteocytes and in various neurons of the central and
      peripheral nervous systems. The morphological lesions and their topographical
      distribution, as well as the biochemical alterations, closely resemble those
      reported for human alpha-mannosidosis. This mouse model will be a valuable tool
      for studying the pathogenesis of inherited alpha-mannosidosis and may help to
      evaluate therapeutic approaches for lysosomal storage diseases.

PMID- 10400985
TI  - Functional characterization of the Opitz syndrome gene product (midin): evidence
      for homodimerization and association with microtubules throughout the cell cycle.
AB  - Opitz syndrome (OS) is a multiple congenital anomaly manifested by abnormal
      closure of midline structures. The gene responsible for the X-linked form of this
      disease, MID1, encodes a protein (midin) that contains a RING, two B-boxes, a
      coiled-coil (the so-called tripartite motif) and an RFP-like domain. The
      tripartite motif is characteristic of a family of proteins, named the B-box
      family, involved in cell proliferation and development. Since the subcellular
      compartmentalization and the ability to form multiprotein structures both appear
      to be crucial for the function of this family of proteins, we have studied these
      properties on the wild-type and mutated forms of midin. We found that endogenous
      midin is associated with microtubules throughout the cell cycle, co-localizing
      with cytoplasmic fibres in interphase and with the mitotic spindle and midbodies
      during mitosis and cytokinesis. Immunoprecipitation experiments demonstrated the
      ability of the tripartite motif to mediate midin homodimerization, consistent
      with the evidence, obtained by gel filtration analysis, that midin exists in the
      form of large protein complexes. Functional characterization of altered forms of
      midin, resulting from mutations found in OS patients, revealed that association
      with microtubules is compromised, while the ability to homodimerize and form
      multiprotein complexes is retained. We suggest that midin is involved in the
      formation of multiprotein structures acting as anchor points to microtubules and
      that impaired association with these cytoskeletal structures causes OS
      developmental defects.

PMID- 10400987
TI  - Mild impairment of learning and memory in mice overexpressing the mSim2 gene
      located on chromosome 16: an animal model of Down's syndrome.
AB  - Human Sim2 is a product of one of the genes located on human chromosome 21q22 and
      is a homolog of Drosophila single-minded ( sim ) which is a critical player in
      midline development of the central nervous system of the fly. Since Sim2 mRNA is
      expressed in facial, skull, palate and vertebra primordia in human and rodent
      embryos, features that are associated with phenotypes of Down's syndrome (DS),
      its trisomic state is suspected to contribute to the symptoms of DS. Here we
      describe that mSim2 mRNA is expressed in hippocampus and amygdala of adult mice,
      and that while mice overexpressing mSim2 under the control of the beta-actin
      promoter are viable and fertile and have superficially normal skeletal, brain and
      heart structures, they exhibit a moderate defect in context-dependent fear
      conditioning and a mild defect in the Morris water maze test. Taken together, our
      data show that overdosage of Sim2 may be important for the pathogenesis of Down's
      syndrome, especially mental retardation.

PMID- 10400986
TI  - MID2, a homologue of the Opitz syndrome gene MID1: similarities in subcellular
      localization and differences in expression during development.
AB  - The B-box family is an expanding new family of genes encoding proteins involved
      in diverse cellular functions such as developmental patterning and oncogenesis. A
      member of this protein family, MID1, is the gene responsible for the X-linked
      form of Opitz G/BBB syndrome, a developmental disorder characterized by defects
      of the midline structures. We now report the identification of MID2, a new
      transcript closely related to MID1. MID2 maps to Xq22 in human and to the
      syntenic region on the mouse X chromosome. The two X-linked genes share the same
      domains, the same exon-intron organization, a high degree of similarity at the
      protein level and the same subcellular localization, both being confined to the
      cytoplasm in association to micro-tubular structures. The expression pattern
      studied by RNA in situ hybridization in mouse revealed that Mid2 is expressed
      early in development and the highest level of expression is detected in the
      heart, unlike Mid1 for which no expression was detected in the developing heart.
      Together, these data suggest that midin and MID2 have a similar biochemical
      function but a different physiological role during development.

PMID- 10400988
TI  - Use of a human minichromosome as a cloning and expression vector for mammalian
      cells.
AB  - A natural human minichromosome (MC1) derived from human chromosome 1 was shown to
      be linear and to have a size of 5.5 Mb. Human IL-2 cDNA and the neo gene were co
      transfected into a MC1-containing human-CHO hybrid cell line. Integration of the
      foreign genes was directed to the pericentromeric region of MC1 by co
      transfection of chromosome 1-specific satellite 2 DNA. A number of G418-resistant
      transfectants were obtained and expression of IL-2 was determined. FISH analysis
      demonstrated co-localization in the minichromosome of the IL-2 gene and of the
      satellite 2 DNA. An IL-2-producing clone was used in cell fusion experiments with
      IL-2-dependent murine CTLL cells to generate CTLL-human hybrids containing the
      modified minichromosome (MC1- IL2 ). The hybrids were able to grow in medium
      lacking IL-2 for 17 mean population doublings (MPD), indicating that expression
      of the cytokine was sufficient to relieve the IL-2 dependence of CTLL
      proliferation. Endogenous IL-2 production delayed the onset of apoptosis in the
      IL-2-dependent CTLL cells. Mitotic stability was shown to be 100% in the human
      CHO hybrids and 97% per MPD in CTLL cells. These results demonstrate that a
      natural human minichromosome can be utilized as a cloning and expression vector
      for mammalian cells and that the MC1 minichromosome can be engineered to deliver
      IL-2 to two types of cells, fibroblasts and lymphocytes.

PMID- 10400989
TI  - High prevalence of symptoms of Meniere's disease in three families with a
      mutation in the COCH gene.
AB  - We report the genetic analysis of one large Belgian and two small Dutch families
      with autosomal dominant non-syndromic progressive sensorineural hearing loss
      associated with vestibular dysfunction. Linkage studies in the Belgian family
      mapped the disease to the DFNA9 locus on chromosome 14. Mutation analysis of the
      COCH gene, which is responsible for DFNA9, revealed a missense mutation changing
      a highly conserved residue. One of the patients, who had an earlier age of onset
      in comparison with most of the affected family members, was shown to be
      homozygous for the mutation. After the mutation was found in the Belgian family,
      we discovered that the same missense mutation was also present in two Dutch
      families with similar cochleo-vestibular symptoms. In all three families with
      hearing loss and imbalance problems, >25% of the patients showed additional
      symptoms, including episodes of vertigo, tinnitus, aural fullness and hearing
      loss. Clinically, these symptoms are consistent with the criteria for Meniere's
      disease. The importance of genetic factors in Meniere's disease has been
      suggested on many occasions, but this study is the first report of a mutation in
      a gene leading to the symptoms of Meniere's disease in a significant portion of
      the carriers. The COCH gene may be one of the genetic factors contributing to
      Meniere's disease and the possibility of a COCH mutation should be considered in
      patients with Meniere's disease symptoms.

PMID- 10400990
TI  - An L1 element intronic insertion in the black-eyed white (Mitf[mi-bw]) gene: the
      loss of a single Mitf isoform responsible for the pigmentary defect and inner ear
      deafness.
AB  - Waardenburg syndrome type 2 (WS2) is an autosomal dominant disorder characterized
      by a combination of pigmentary and auditory abnormalities. Approximately 20% of
      WS2 cases are associated with mutations in the gene encoding microphthalmia
      associated transcription factor (MITF). MITF plays a critical role in the
      development of both neural-crest-derived melanocytes and optic cup-derived
      retinal pigmented epithelium (RPE); the loss of a functional Mitf in mice results
      in complete absence of all pigment cells, which in turn induces microphthalmia
      and inner ear deafness. The black-eyed white Mitf mi-bw homozygous mouse normally
      has a pigmented RPE but lacks melanocytes essential for the pigmentation of the
      body and hearing. We show here that Mitf mi-bw is caused by an insertion into
      intron 3 of a 7.2 kb novel L1 element, L1bw, which belongs to an actively
      retrotransposing TF subfamily. The L1bw insertion reduces the amount of mRNAs for
      two Mitf isoforms, Mitf-A and Mitf-H, by affecting their overall expression
      levels and pre-mRNA splicing patterns, while it abolishes mRNA expression of
      another isoform, Mitf-M, which is specifically expressed in neural-crest-derived
      melanocytes. The consequence of the L1 insertion in the black-eyed white Mitf mi
      bw mouse is that the developmental programme for RPE cells proceeds normally,
      most likely because of the presence of residual, full-length Mitf-A and Mitf-H
      proteins, whereas the lack of Mitf-M results in loss of the melanocyte
      population. The results suggest that melanocyte development depends critically on
      a single Mitf isoform, Mitf-M, and raise the possibility that specific mutations
      affecting MITF-M, the human equivalent of Mitf-M, may be responsible for a subset
      of WS2 conditions.

PMID- 10400991
TI  - A common functional polymorphism (C-->A substitution at position -863) in the
      promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated
      with reduced circulating levels of TNF-alpha.
AB  - Tumour necrosis factor-alpha (TNF-alpha) plays a key role in orchestrating the
      complex events involved in inflammation and immunity. Accordingly, TNF-alpha has
      been implicated in a wide range of autoimmune and infectious diseases, but also
      in conditions such as obesity and insulin resistance. The regulation of TNF-alpha
      expression in man is indicated to be partly genetically determined. We therefore
      screened a 1263 bp section of the proximal promoter of the TNF-alpha gene for
      common genetic variants affecting the transcriptional activity of the gene. Here
      we report the characterization of a common functional polymorphism in the
      promoter region of the TNF-alpha gene, a C-->A substitution at position -863.
      Electromobility shift assays provided evidence for a distinct difference in the
      binding of monocytic and hepatic nuclear factors to the -863C and -863A alleles.
      The rare -863A allele was associated with 31% lower transcriptional activity ( P
      < 0.001) in chloramphenicol acetyltransferase (CAT) reporter gene studies in
      human hepatoblastoma (HepG2) cells, indicating that the-863C/A polymorphism
      influences the basal rate of transcription of the TNF-alpha gene in vitro. Allele
      frequencies were 0.83/0.17 amongst 254 apparently healthy men of Swedish origin,
      aged 35-50 years. In 156 men, the -863C/A polymorphism was associated with the
      serum TNF-alpha concentration, carriers of the rare A allele having a
      significantly lower TNF-alpha level ( P < 0.05). It is concluded that the common
      863C/A polymorphism in the promoter region of the TNF-alpha gene is functional in
      vitro in monocytic and hepatic cells and influences the serum TNF-alpha
      concentration in vivo in healthy middle-aged men.

PMID- 10400992
TI  - Variation in the biochemical/biophysical properties of mutant superoxide
      dismutase 1 enzymes and the rate of disease progression in familial amyotrophic
      lateral sclerosis kindreds.
AB  - Mutations in superoxide dismutase 1 (SOD1) polypeptides cause a form of familial
      amyotrophic lateral sclerosis (FALS). In different kindreds, harboring different
      mutations, the duration of illness tends to be similar for a given mutation. For
      example, patients inheriting a substitution of valine for alanine at position
      four (A4V) average a 1.5 year life expectancy after the onset of symptoms,
      whereas patients harboring a substitution of arginine for histidine at position
      46 (H46R) average an 18 year life expectancy after disease onset. Here, we
      examine a number of biochemical and biophysical properties of nine different FALS
      variants of SOD1 polypeptides, including enzymatic activity (which relates
      indirectly to the affinity of the enzyme for copper), polypeptide half-life,
      resistance to proteolytic degradation and solubility, in an effort to determine
      whether a specific property of these enzymes correlates with clinical
      progression. We find that although all the mutants tested appear to be soluble,
      the different mutants show a remarkable degree of variation with respect to
      activity, polypeptide half-life and resistance to proteolysis. However, these
      variables do not stratify in a manner that correlates with clinical progression.
      We conclude that the basis for the different life expectancies of patients in
      different kindreds of sod1-linked FALS may result from an as yet unidentified
      property of these mutant enzymes.

PMID- 10400993
TI  - PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley
      Ruvalcaba syndrome suggest a single entity with Cowden syndrome.
AB  - Germline mutations in the tumour suppressor gene PTEN have been implicated in two
      hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and
      Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual
      specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5
      triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is
      characterized by multiple hamartomas and an increased risk of benign and
      malignant disease of the breast, thyroid and central nervous system, whilst the
      presence of cancer has not been formally documented in BRR. The partial clinical
      overlap in these two syndromes is exemplified by the hallmark features of BRR:
      macrocephaly and multiple lipomas, the latter of which occur in a minority of
      individuals with CS. Additional features observed in BRR, which may also occur in
      a minority of CS patients, include Hashimoto's thyroiditis, vascular
      malformations and mental retardation. Pigmented macules of the glans penis,
      delayed motor development and neonatal or infant onset are noted only in BRR. In
      this study, constitutive DNA samples from 43 BRR individuals comprising 16
      sporadic and 27 familial cases, 11 of which were families with both CS and BRR,
      were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR
      cases. Genotype-phenotype analyses within the BRR group suggested a number of
      correlations, including the association of PTEN mutation and cancer or breast
      fibroadenoma in any given CS, BRR or BRR/CS overlap family ( P = 0.014), and, in
      particular, truncating mutations were associated with the presence of cancer and
      breast fibroadenoma in a given family ( P = 0.024). Additionally, the presence of
      lipomas was correlated with the presence of PTEN mutation in BRR patients ( P =
      0.028). In contrast to a prior report, no significant difference in mutation
      status was found in familial versus sporadic cases of BRR ( P = 0.113).
      Comparisons between BRR and a previously studied group of 37 CS families
      suggested an increased likelihood of identifying a germline PTEN mutation in
      families with either CS alone or both CS and BRR when compared with BRR alone ( P
      = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation
      positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS
      and BRR may be different presentations of a single syndrome and, hence, both
      should receive equal attention with respect to cancer surveillance.

PMID- 10400994
TI  - Characterization of the Menkes protein copper-binding domains and their role in
      copper-induced protein relocalization.
AB  - Menkes disease is a fatal X-linked disorder of copper metabolism. The gene
      defective in Menkes disease (ATP7A) encodes a copper transporting P-type ATPase
      (MNK or ATP7A) with six copper-binding domains at its N-terminus. MNK is normally
      localized to the trans -Golgi network in cultured cells, but relocates to the
      plasma membrane in the presence of elevated extracellular copper. In this study,
      the role of the six copper-binding domains on copper-induced redistribution is
      investigated. In a recombinant clone, when all the wild-type copper-binding
      motifs are mutated from GMXCXXC to GMXSXXS and the cells grown in medium
      containing elevated copper, relocalization of the recombinant protein to the
      plasma membrane was not observed. Using the same assay with any one of the six
      copper-binding domains intact, MNK moves to the plasma membrane in a way
      indistinguishable from the wild-type protein. Therefore, the copper-binding
      domains are vital for MNK trafficking and only a single domain is sufficient for
      this redistribution to occur.

PMID- 10400995
TI  - The mouse Peutz-Jeghers syndrome gene Lkb1 encodes a nuclear protein kinase.
AB  - The protein kinase gene LKB1 has recently been identified as the gene mutated in
      the Peutz-Jeghers cancer predisposition syndrome. This condition is characterized
      by inherited susceptibility to a range of cancers but in particular those of the
      gastrointestinal tract. Here we have characterized the mouse Lkb1 gene. The mouse
      Lkb1 gene consists of 10 exons covering approximately 15 kb in length, maps to
      mouse chromosome 10 and encodes a protein showing strong sequence similarity to
      human LKB1. The 3" end of Lkb1 in the mouse is in very close proximity to the 3"
      end of an apparently unrelated gene R29144/1 and it seems probable that
      overlapping transcripts of the two genes are produced. Using transfection of Lkb1
      cDNAs we have shown that Lkb1 is most likely a nuclear protein and have defined a
      nuclear localization signal within the protein sequence. Thus the defect in Peutz
      Jeghers syndrome may directly result in changes in gene expression in the nucleus
      of target cells.

PMID- 10400996
TI  - Linkage and association of atopic asthma to markers on chromosome 13 in the
      Japanese population.
AB  - Chromosome 13 contains several candidate genes for asthma and atopy, and markers
      on this chromosome have been shown to be linked to phenotypes of atopy or asthma
      in two genome-wide searches. We conducted a linkage study for atopic asthma using
      markers spanning the whole of chromosome 13 in Japanese families ascertained
      through asthmatic children and examined associations of atopic asthma with
      markers where linkage was suggested. Data were analysed using MAPMAKER/SIBS for
      the multipoint lod score (MLS) analysis and SIB-PAIR for the transmission dis
      equilibrium test (TDT). Three peaks which exceeded a lod score of 1.0 were
      observed (MLS 2.4 between D13S175 and D13S217, MLS 2.0 between D13S153 and
      D13S156, and MLS 1.4 between D13S285 and D13S293). The global TDT for atopic
      asthma was significant for the marker D13S153 ( P = 0.0065) and the 96 bp allele
      of D13S153 was preferentially transmitted to atopic asthma-affected children ( P
      = 0.0009, Bonferroni correction 5% = 0. 0037, 1% = 0.00072). These findings
      indicate that genes on chromosome 13 may play an important role in the
      development of atopy or asthma across various populations.

PMID- 10400997
TI  - Myotonic dystrophy is associated with a reduced level of RNA from the DMWD allele
      adjacent to the expanded repeat.
AB  - Myotonic dystrophy is caused by the expansion of a CTG repeat sequence. The
      mechanism by which this expanded repeat produces the pathophysiology of myotonic
      dystrophy is not clear. It has been shown previously that expansion of the repeat
      produces allele-specific effects on transcripts from two genes, DMPK and SIX5. We
      have examined the effect of repeat expansion on the level of RNA from a third
      gene, DMWD. We have identified a polymorphism in this gene and developed a
      quantitative allele-specific assay for DMWD RNA levels, which we have applied to
      nuclear and cytoplasmic fractions of RNA from DM cell lines. We have found that
      the level of the DM-associated allele in the cytoplasm of DM cell lines is
      reduced by 20-50% compared with the wild-type allele, similar to the level of
      reduction found for SIX5 in allele-specific analysis. However, no such reduction
      is observed in RNA from the nuclear fraction of DM cell lines. This may reflect
      the complex nature of processing transcriptional units at the DM locus.

PMID- 10400998
TI  - Cellular dysfunction of LQT5-minK mutants: abnormalities of IKs, IKr and
      trafficking in long QT syndrome.
AB  - Mutations in the minK gene KCNE1 have been linked to the LQT5 variant of human
      long QT syndrome. MinK assembles with KvLQT1 to produce the slow delayed
      rectifier K+ current IKs and may assemble with HERG to modulate the rapid delayed
      rectifier IKr. We used electrophysiological and immunocytochemical methods to
      compare the cellular phenotypes of wild-type minK and four LQT5 mutants co
      expressed with KvLQT1 in Xenopus oocytes and HERG in HEK293 cells. We found that
      three mutants, V47F, W87R and D76N, were expressed at the cell surface, while one
      mutant, L51H, was not. Co-expression of V47F and W87R with KvLQT1 produced IKs
      currents having altered gating and reduced amplitudes compared with WT-minK, co
      expression with L51H produced KvLQT1 current rather than IKs and co-expression
      with D76N suppressed KvLQT1 current. V47F increased HERG current but to a lesser
      extent than WT-minK, while L51H and W87R had no effect and D76N suppressed HERG
      current markedly. Thus, V47F interacts with both KvLQT1 and HERG, W87R interacts
      functionally with KvLQT1 but not with HERG, D76N suppresses both KvLQT1 and HERG,
      and L51H is processed improperly and interacts with neither channel. We conclude
      that minK is a co-factor in the expression of both IKs and IKr and propose that
      clinical manifestations of LQT5 may be complicated by differing effects of minK
      mutations on KvLQT1 and HERG.

PMID- 10400999
TI  - Enoyl-CoA hydratase deficiency: identification of a new type of D-bifunctional
      protein deficiency.
AB  - D-bifunctional protein is involved in the peroxisomal beta-oxidation of very long
      chain fatty acids, branched chain fatty acids and bile acid intermediates. In
      line with the central role of D-bifunctional protein in the beta-oxidation of
      these three types of fatty acids, all patients with D-bifunctional protein
      deficiency so far reported in the literature show elevated levels of very long
      chain fatty acids, branched chain fatty acids and bile acid inter-mediates. In
      contrast, we now report two novel patients with D-bifunctional protein deficiency
      who both have normal levels of bile acid intermediates. Complementation analysis
      and D-bifunctional protein activity measurements revealed that both patients had
      an isolated defect in the enoyl-CoA hydratase domain of D-bifunctional protein.
      Subsequent mutation analysis showed that both patients are homozygous for a
      missense mutation (N457Y), which is located in the enoyl-CoA hydratase coding
      part of the D-bifunctional protein gene. Expression of the mutant protein in the
      yeast Saccharomyces cerevisiae confirmed that the N457Y mutation is the disease
      causing mutation. Immunoblot analysis of patient fibroblast homogenates showed
      that the protein levels of full-length D-bifunctional protein were strongly
      reduced while the enoyl-CoA hydratase component produced after processing within
      the peroxisome was undetectable, which indicates that the mutation leads to an
      unstable protein.

PMID- 10401001
TI  - Identification and characterization of three novel missense mutations in
      mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene
      biosynthesis.
AB  - Mevalonic aciduria is a rare autosomal recessive metabolic disorder,
      characterized by psychomotor retardation, failure to thrive, hepatosplenomegaly,
      anemia and recurrent febrile crises. The disorder is caused by a deficient
      activity of mevalonate kinase due to mutations in the encoding gene. Thus far,
      only two disease-causing mutations have been identified. We now report four
      different missense mutations including three novel ones, which were identified by
      sequence analysis of mevalonate kinase cDNA from three mevalonic aciduria
      patients. All mutations affect conserved amino acids. Heterologous expression of
      the corresponding mutant mevalonate kinases as fusion proteins with glutathione S
      -transferase in Escherichia coli showed a profound effect of each of the
      mutations on enzyme activity. In addition, immunoblot analysis of fibroblast
      lysates from patients using specific antibodies against mevalonate kinase
      identified virtually no protein. These results demonstrate that the mutations
      affect not only the activity but also the stability of the mutant proteins.

PMID- 10401000
TI  - Spectrum of mutations in the HFE gene implicated in haemochromatosis and
      porphyria.
AB  - Mutation analysis was performed on DNA samples of 965 individuals from four
      different ethnic groups in South Africa, in an attempt to determine the spectrum
      of sequence variants in the haemochromatosis ( HFE ) gene. This population
      screening approach, utilizing a combined heteroduplex and single-strand
      conformation polymorphism (HEX-SSCP) method, revealed three previously described
      and four novel missense mutations. Novel variants V53M and V59M were identified
      in exon 2, Q127H in exon 3 and R330M in exon 5. The exon 5 variant was identified
      in one of 13 patients referred for a molecular diagnosis of hereditary
      haemochromatosis (HH), who tested negative for the known C282Y and H63D
      mutations. Mutation Q127H was detected in exon 3 of the HFE gene together with
      mutation H63D in an apparently severely affected patient previously shown to
      carry the protoporphyrinogen oxidase ( PPOX ) gene mutation R59W, which accounts
      for dominantly inherited variegate porphyria (VP) in >80% of affected South
      Africans. The mutant allele frequency of the C282Y mutation was found to be
      significantly lower in 73 apparently unrelated VP patients with the R59W mutation
      than in 102 controls drawn from the same population ( P = 0.005). The population
      screening approach used in this study revealed considerable genotypic variation
      in the HFE gene and supports previous data on the involvement of this gene in the
      porphyria phenotype.

PMID- 10401002
TI  - Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile
      Alzheimer's disease by increased Abeta42 secretion.
AB  - We previously described a splice donor site mutation in intron 4 of presenilin-1
      (PSEN1) in two patients with autopsy-confirmed early-onset Alzheimer's disease
      (AD). Here we provide evidence that the intron 4 mutation is present in four
      additional unrelated early-onset AD cases, that the mutation segregates in an
      autosomal dominant manner and that all cases have one common ancestor. We
      demonstrate that the intron 4 mutation produces three different transcripts, two
      deletion transcripts (Delta4 and Delta4cryptic) and one insertion transcript
      (insTAC), by aberrant splicing. The deletion transcripts result in the formation
      of C-truncated (approximately 7 kDa) PSEN1 proteins while the insertion
      transcript produces a full-length PSEN1 with one extra amino acid (Thr) inserted
      between codons 113 and 114 (PSEN1 T113-114ins). The truncated proteins were not
      detectable in vivo in brain homogenates or lymphoblast lysates of mutation
      carriers. In vitro HEK-293 cells overexpressing Delta4, Delta4cryptic or
      insTACPSEN1 cDNAs showed increased Abeta42 secretion (approximately 3.4 times)
      only for the insertion cDNA construct. Increased Abeta42 production was also
      observed in brain homogenates. Our data indicate that in the case of intron 4
      mutation, the AD pathophysiology results from the presence of the PSEN1 T113
      114ins protein comparable with cases carrying dominant PSEN1 missense mutations.

PMID- 10401004
TI  - Defective copper-induced trafficking and localization of the Menkes protein in
      patients with mild and copper-treated classical Menkes disease.
AB  - Menkes disease is an X-linked disorder of copper metabolism. An overall copper
      deficiency reduces the activity of copper-dependent enzymes accounting for the
      clinical presentation of affected individuals. The Menkes gene product (MNK) is a
      P-type ATPase and is considered to be the main copper efflux protein in most
      cells. The protein is located primarily at the trans -Golgi network (TGN), but
      relocalizes to the plasma membrane in elevated copper conditions to expel the
      excess copper from the cell. Here we report the first missense mutation which
      causes mild Menkes disease, a mutation in a successfully copper-treated classical
      Menkes patient and the effect of each mutation on the localization of MNK within
      the cell. Using western blot analysis, MNK was detectable in cells from both
      patients, but appeared to be mislocalized in the treated case. In the mild Menkes
      patient, the protein appeared to be located in the TGN but failed to redistribute
      towards the cell periphery in response to copper. This is the first description
      of a mutation in a Menkes patient which affects the trafficking of MNK, and the
      loss of this process is consistent with the clinical phenotype.

PMID- 10401003
TI  - A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a
      family linked to the RP1 locus.
AB  - Retinitis pigmentosa (RP) represents a group of inherited human retinal diseases
      which involve degeneration of photoreceptor cells resulting in visual loss and
      often leading to blindness. In order to identify candidate genes for the causes
      of these diseases, we have been studying a pool of photoreceptor-specific cDNAs
      isolated by subtractive hybridization of mRNAs from normal and photoreceptorless
      rd mouse retinas. One of these cDNAs was of interest because it mapped to
      proximal mouse chromosome 1 in a region homo-logous to human 8q11-q13, the locus
      of autosomal dominant RP1. Therefore, using the mouse cDNA as probe, we cloned
      the human cDNA (hG28) and its corresponding gene and mapped it near to D8S509,
      which lies in the RP1 locus. This gene consists of four exons with an open
      reading frame of 6468 nt encoding a protein of 2156 amino acids with a predicted
      mass of 240 kDa. Given its chromosomal localization, we screened this gene for
      mutations in a large family affected with autosomal dominant RP previously linked
      to the RP1 locus. We found an R677X mutation that co-segregated with disease in
      the family and is absent from unaffected members and 100 unrelated controls. This
      mutation is predicted to lead to rapid degradation of hG28 mRNA or to the
      synthesis of a truncated protein lacking approximately 70% of its original
      length. Our results suggest that R677X is responsible for disease in this family
      and that the gene corresponding to hG28 is the RP1 gene.

PMID- 10401005
TI  - Full-length human L1 insertions retain the capacity for high frequency
      retrotransposition in cultured cells.
AB  - Functional L1 elements are autonomous retrotransposons that can insert into human
      genes and cause disease. To date, 10 of 12 known L1 retrotranspositions into
      human genes have been found to be 5"-truncated and incapable of further
      retrotransposition. Here we report the nucleotide sequences of the two full
      length L1 elements, L1beta-thal and L1RP, that have inserted into the beta-globin
      and retinitis pigmentosa-2 (RP2) genes, respectively. L1beta-thal is 99. 4%
      identical to a consensus sequence of active human L1s, while L1RP is 99.9%
      identical. Both elements retain impressive capacity for high frequency
      retrotransposition in cultured HeLa cells. Indeed, L1RP is the most active L1
      isolated to date. Our data indicate that not all L1 insertions into human genes
      are 'dead on arrival'. Our findings also lend further credence to the concept of
      cis preference, that the proteins encoded by a particular L1 preferentially act
      upon their encoding RNA as opposed to other L1 RNAs.

PMID- 10401007
TI  - RPGR transcription studies in mouse and human tissues reveal a retina-specific
      isoform that is disrupted in a patient with X-linked retinitis pigmentosa.
AB  - X-linked retinitis pigmentosa (XLRP) is a genetically heterogeneous group of
      progressive retinal degenerations. The disease process is initiated by premature
      apoptosis of rod photoreceptor cells in the retina, which leads to reduced visual
      acuity and, eventually, complete blindness. Mutations in the retinitis pigmentosa
      GTPase regulator ( RPGR ), a ubiquitously expressed gene at the RP3 locus in
      Xp21.1, account for approximately 20% of all X-linked cases. We have analysed the
      expression of this gene by northern blot hybridization, cDNA library screening
      and RT-PCR in various organs from mouse and man. These studies revealed at least
      12 alternatively spliced isoforms. Some of the transcripts are tissue specific
      and contain novel exons, which elongate or truncate the previously reported open
      reading frame of the mouse and human RPGR gene. One of the newly identified exons
      is expressed exclusively in the human retina and mouse eye and contains a
      premature stop codon. The deduced polypeptide lacks 169 amino acids from the C
      terminus of the ubiquitously expressed variant, including an isoprenylation site.
      Moreover, this exon was found to be deleted in a family with XLRP. Our results
      indicate tissue-dependent regulation of alternative splicing of RPGR in mouse and
      man. The discovery of a retina-specific transcript may explain why phenotypic
      abberations in RP3 are confined to the eye.

PMID- 10401006
TI  - Novel alternatively spliced isoforms of the neurofibromatosis type 2 tumor
      suppressor are targeted to the nucleus and cytoplasmic granules.
AB  - We cloned novel splice variants Mer150, Mer151 and Mer162 of the
      neurofibromatosis 2 (NF2) tumor suppressor, which demonstrate a tissue-specific
      and development-specific expression pattern. Isoform Mer150 is created by cryptic
      splicing from exon 8 to 14 and represents an N-terminal truncation of 259
      residues. Mer151 is characterized by in-frame splicing out of several exons and a
      modified C-terminus due to a frameshift in exons 13+14 and premature termination.
      Mer162 represents a head-to-tail isoform resulting from in-frame skipping of
      exons 5-16. As a common feature, the alpha-helical domain and a variable
      proportion of the ERM homology domain are spliced out in these isoforms. To
      investigate differences in subcellular localization, we expressed epitope-tagged
      cDNA constructs of the wild-type NF2 as well as of the three alternatively
      spliced transcripts in NIH 3T3 cells by nuclear microinjection or lipid-mediated
      transfection. Subcellular localization of Mer151 in filopodia and ruffling
      membranes was similar to the wild-type NF2. Mer151, however, was targeted to the
      nucleus, which was not observed for wild-type NF2, Mer150 or Mer162. A putative
      nuclear localization signal created by alternative splicing was identified in
      Mer151. In contrast to Mer151, Mer150 and Mer162 were not found in regions of the
      plasma membrane, but localized to a granular intracellular compartment. The
      results suggest that the recently described actin-binding domain in exon 10, but
      not the presence or absence of exons 2+3, is relevant for subcellular targeting.
      Although the NF2 protein is known as a cytoskeletal linker, additional functions
      in a cytoplasmic compartment and in the nucleus may exist.

PMID- 10401008
TI  - Mutation of the Na-K-Cl co-transporter gene Slc12a2 results in deafness in mice.
AB  - Hearing impairment is a common human condition, but we know little about the
      molecular basis of cochlear function. Shaker-with-syndactylism (sy) is a classic
      deaf mouse mutant and we show here that a second allele, sy(ns), is associated
      with abnormal production of endolymph, the fluid bathing sensory hair cells.
      Using a positional candidate approach, we demonstrate that mutations in the gene
      encoding the basolateral Na-K-Cl co-transporter Slc12a2 (Nkcc1, mBSC2) cause the
      deafness observed in sy and sy(ns) mice. This finding provides the molecular
      basis of another link in the chain of K+recycling in the cochlea, a process
      essential for normal cochlear function.

PMID- 10401009
TI  - Risk for posttransplant Diabetes mellitus with current immunosuppressive
      medications.
AB  - With improvements in the practice of transplantation and the introduction of new
      immunosuppressive medications, there has been a substantial increase in 1-year
      allograft survival rates. Consequently, the pool of potential candidates for
      organ transplants continues to grow and a greater preponderance of older patients
      with more comorbidities are undergoing transplantation. As a result, there is
      interest in such medical complications as posttransplantation diabetes mellitus
      (PTDM) that develop after the transplantation of a successful allograft. PTDM is
      an undesirable consequence of transplantation because of its associated morbidity
      and impairment of both patient and graft survival. Although some controversy
      exists, it is likely that glucose intolerance after transplantation results in
      both macrovascular and microvascular disease, and there is an increasing risk for
      infectious and cardiovascular diseases, to which transplant recipients are
      already at increased susceptibility. Both experimental and clinical observations
      have shown that immunosuppressive agents currently used in transplantation
      account for a large degree of the increased risk for PTDM. Consequently, improved
      understanding of the effects of currently used immunosuppressive medicines on
      glycemic tolerance is of interest in clinical transplantation.

PMID- 10401010
TI  - Effect of aminoglycoside use on residual renal function in peritoneal dialysis
      patients.
AB  - Residual renal function (RRF) is a major contributor to total solute clearance in
      peritoneal dialysis (PD) patients, and maintenance of RRF has been linked to
      decreased morbidity and mortality in PD. There have been few clinical studies
      examining the impact of factors that potentially affect RRF in PD. This is a
      prospective observational study that examines the effects of parenteral
      aminoglycosides, a common nephrotoxin in the general population, on RRF in a
      cohort of PD patients. Seventy-two patients from two Rhode Island PD units were
      observed over 4 years. Twenty-four-hour renal creatinine clearances and urine
      volumes were measured every 4 to 6 months. The patients were divided into three
      groups, depending on exposure to peritonitis and aminoglycoside use. Group I
      included patients without peritonitis who received no intravenous (IV) or
      intraperitoneal (IP) antibiotics. Group II included patients with peritonitis who
      received IV or IP penicillins, cephalosporins, vancomycin, or quinolones, but no
      aminoglycosides. Group III included patients with peritonitis who received IV or
      IP aminoglycosides for at least 3 days. Patients in group III had a more rapid
      decline in renal creatinine clearance (-0.66 +/- 0.58 mL/min/mon) than groups I
      and II (P < 0.005) and had a more rapid decline in daily urine volume (-74 +/- 62
      mL/d/mon) than groups I and II (P < 0.01). We conclude that IV or IP
      aminoglycosides seem to increase the rapidity of decline in RRF in PD patients.
      In patients with solute clearance dependent on RRF, it seems reasonable to
      withhold aminoglycosides, especially if other antibiotics are available and
      appropriate.

PMID- 10401011
TI  - A study of parenteral iron regimens in hemodialysis patients.
AB  - The administration of parenteral iron dextran to hemodialysis patients is
      typically intermittent. We sought to determine the most appropriate intervals for
      sampling iron parameters during intermittent need-based and continuous
      maintenance regimens and to quantify differences in efficacy between such
      regimens during long-term therapy. After a single course of 10 consecutive 100-mg
      iron doses administered to 14 patients on 16 occasions, transferrin saturation
      (TSAT) and ferritin were unreliable indices of iron status for the next 2 and 6
      weeks, respectively. TSAT and ferritin levels at 1 week were virtually identical
      to those at 2 weeks after the administration of a single 50-mg or 100-mg iron
      dextran dose to 16 other patients. Twelve patients on maintenance iron therapy
      (25 to 100 mg/wk; TSAT, 30% to 50%) had a statistically significant decrease in
      the amount of recombinant human erythropoietin (rHuEPO) needed to maintain
      hemoglobin (Hb) levels between 10 and 11 g/dL compared with 12 patients receiving
      intermittent need-based dosing, an effect that persisted from week 16 to week 72
      of the study. Maintenance iron was feasible even in a third group of eight
      patients targeted to sustain an Hb level of 14 g/dL. In both iron maintenance
      groups, iron indices could be measured at weekly intervals, and ferritin levels
      did not progressively increase over time. Continuous maintenance iron dextran
      used to maintain TSATs of 30% to 50% significantly reduced rHuEPO requirements
      and resulted in no adverse side effects in chronic hemodialysis patients. After
      weekly maintenance 25- to 100-mg iron dextran doses, iron indices can be measured
      after 1 week; a delay of 2 weeks is not necessary.

PMID- 10401012
TI  - Indices of iron status in continuous ambulatory peritoneal dialysis patients.
AB  - Data for iron-status indices in continuous ambulatory peritoneal dialysis
      patients are limited. The reliability of commonly used indices for the diagnosis
      of iron-deficiency anemia in peritoneal dialysis patients is still unknown. To
      study diagnostic values of iron-status indices, including serum ferritin,
      transferrin saturation, reticulocyte hemoglobin content, and bone marrow
      stainable iron, 21 stable anemic peritoneal dialysis patients who have been
      treated with erythropoietin and oral iron supplementation for more than 3 months
      were enrolled in this study. The mean age was 51.4 +/- 2.9 years; dialysis
      duration, 28.7 +/- 5.1 months; initial hemoglobin, 8.4 +/- 0.2 g/dL;
      erythropoietin dosage, 71 +/- 2 micro/kg/wk; serum albumin, 3.5 +/- 0.1 g/dL;
      intact parathyroid hormone (PTH), 233 +/- 44 ng/mL; serum ferritin, 643 +/- 135
      ng/mL; transferrin saturation, 33.93% +/- 3.9%; and reticulocyte hemoglobin
      content, 31.6 +/- 4 pg. Bone marrow aspiration was performed in all patients to
      determine marrow iron content and exclude hematological disorders. All patients
      were treated with 1, 000 mg of intravenous ferric saccharate infusion in two
      divided doses more than 1 week apart. Patients who responded to the iron infusion
      within 3 months by increasing serum hemoglobin of greater than 1 gm/dL more than
      baseline were defined as being functional iron deficient before the intravenous
      iron infusion. Serum ferritin, transferrin saturation, and reticulocyte
      hemoglobin content were followed serially after iron infusion. Fifteen patients
      (71.4%) responded to the iron administration, indicating iron deficiency. Nine of
      13 (69%) patients with the presence of bone marrow-stainable iron still responded
      to intravenous iron supplementation, suggesting functional iron deficiency.
      Absence of bone marrow-stainable iron was not a sensitive marker for the
      diagnosis of iron deficiency, 25% sensitivity. No single value of iron-status
      indices that can definitely exclude iron-deficiency anemia in peritoneal dialysis
      patients was found. Therefore, failure to increase hemoglobin concentration after
      intravenous iron administration should be shown before excluding iron-deficiency
      anemia as a cause of poor erythropoietic response to erythropoietin therapy.

PMID- 10401013
TI  - Low thrombogenicity of polyethylene glycol-grafted cellulose membranes does not
      influence heparin requirements in hemodialysis.
AB  - Heparin is the most commonly used anticoagulant for hemodialysis despite
      potentially serious side effects. Polyethylene glycol-grafted cellulose (PGC)
      membranes produce less activation of the coagulation cascade than cuprophane
      membranes. Anecdotally, we found some patients required a surprisingly low level
      of anticoagulation using these membranes. We compared the anticoagulant
      requirement of the PGC membrane with that of the cuprophane membrane in this
      randomized, prospective, crossover study. Sixty-three patients were randomized to
      treatment using either membrane, and heparin administration was progressively
      reduced to the lowest dose that prevented visible clotting in excess of that
      normally encountered. Patients underwent dialysis at this dose for 1 month, after
      which the heparin requirement and Kt/Vurea (1.162 x ln [urea pre/urea post]) were
      assessed. This process was then repeated for each patient using the other
      membrane, and the results were compared. Heparin administration during dialysis
      was reduced from a mean loading dose of 29.0 +/- 9.4 to 1.5 +/- 3.2 IU/kg for
      both membranes and a mean maintenance infusion of 14.0 +/- 6.7 to 0.77 +/- 1.6
      IU/kg/h for both membranes (both P < 0.0001 v full anticoagulation; no difference
      between membranes). The Kt/Vurea was not significantly altered. Forty-six
      patients with PGC and 45 patients with cuprophane membranes underwent dialysis
      successfully without heparin during dialysis, and the other patients were using
      considerably reduced doses. Aspirin and warfarin had no effect on the heparin
      requirement. These results do not support the theory that PGC membranes have a
      lower anticoagulant requirement than cuprophane membranes; however, they suggest
      that dialysis can be performed successfully with much smaller anticoagulant doses
      than are currently in common use.

PMID- 10401014
TI  - Relationship between serum magnesium and parathyroid hormone levels in
      hemodialysis patients.
AB  - Acute magnesium (Mg) infusion decreases patathyroid hormone (PTH) secretion.
      However, the effect of chronic hypermagnesemia on PTH levels in dialysis patients
      is not well established. We studied 110 hemodialysis patients (mean age, 55 +/-
      14 years; time on dialysis, 35 +/- 28 months) not receiving vitamin D and
      undergoing dialysis with an Mg dialysate concentration of 1.2 mg/dL. The primary
      phosphate binder was calcium carbonate, and 43% of the patients also needed
      aluminum hydroxide. During a 6-month period, calcium (Ca), phosphorus (P), and
      total serum Mg were measured every 2 months; intact PTH and aluminum (Al) were
      measured every 6 months. The mean value of each parameter was computed.
      Hypermagnesemia (serum Mg > 2.47 mg/dL) was observed in 73% of the patients. Mg
      and Ca were inversely correlated with PTH levels (r = -0.48; P < 0.001 and r = 
      0.21; P < 0.05, respectively). After adjusting for Ca and P (partial correlation
      analysis), Mg and PTH were inversely correlated (r = -0.58; P < 0.001). A
      stepwise multiple regression analysis showed that PTH levels were predicted by Mg
      (P < 0.001), alkaline phosphatase (P < 0.01), and P levels (P< 0.05; multiple R =
      0.57; P < 0.001), whereas Ca level, sex (dummy variable), diabetes (dummy
      variable), time on dialysis, and Al level were not predictive. Patients with
      inadequately low PTH levels (relative hypoparathyroidism, PTH < 120 pg/mL; n =
      52) showed greater serum Mg concentrations than the rest (n = 58; 3.01 +/- 0.33 v
      2.63 +/- 0.38 mg/dL; P < 0.001). In conclusion, serum Mg concentrations in
      dialysis patients are independently associated with PTH levels, suggesting that
      chronic hypermagnesemia may decrease PTH secretion and/or synthesis. In addition,
      chronic hypermagnesemia of dialysis patients may have a role in the pathogenesis
      of adynamic bone disease.

PMID- 10401015
TI  - Evaluation and prediction of urea rebound and equilibrated Kt/V in the pediatric
      hemodialysis population.
AB  - The posthemodialysis blood urea nitrogen (BUN) concentration rebounds for 30 to
      60 minutes after hemodialysis in adults. Timing of the posttreatment BUN sample
      has a significant impact on the calculation of Kt/V. Urea rebound and its effect
      on Kt/V have not been extensively studied in children and adolescents. We
      evaluated posthemodialysis urea rebound after 46 treatments in 18 pediatric
      patients with end-stage renal disease. BUN levels were drawn at 30 seconds and 5
      and 15 minutes posttreatment. From these values, a logarithmic regression curve
      was derived that defined percentage of urea rebound (%UR) = -0.254 + 10.9*log(t),
      (r = 0.79). Using this equation, we estimated BUN, %UR, and Kt/V at equilibration
      (50 minutes) for each treatment. Estimated mean %UR was 18.7%. Single-pool Kt/V
      (spKt/V) and estimated double-pool Kt/V (estKt/V) values were significantly
      different (P < 0.0001). %UR and percentage of difference between spKt/V and
      estKt/V did not vary as a function of dry weight, body surface area, or K/V. To
      test the validity of logarithmic extrapolation, additional BUN levels were drawn
      at 30 seconds and every 10 minutes for 1 hour postdialysis in six patients.
      Percentage of difference between estKt/V and measured equilibrated Kt/V was 3.6%
      +/- 1.7%. Our results show %UR has a significant impact on the calculation of
      Kt/V in children, does not vary with patient size, and is similar to that seen in
      adults. We have devised an easy and accurate method to predict equilibrated BUN
      and calculate double-pool Kt/V in children, which requires only an additional 15
      minute posttreatment BUN sample.

PMID- 10401016
TI  - Interferon-alpha in chronic hepatitis C infection in dialysis patients.
AB  - This study assesses the efficacy and adverse effects of interferon-alpha (IFN
      alpha) administered at a dosage of 3 million units three times weekly for 1 year
      in 17 hemodialysis patients with hepatitic C virus (HCV)-associated chronic
      hepatitis (biopsy proven). The patients were prospectively followed up for a
      period of 18 months. Liver biopsy was repeated after 6 months of treatment in 13
      patients. Patients were classified according to the histological activity index.
      Biochemical and virological responses were evaluated at the end (end-of-treatment
      response) and 6 months after completion of therapy (sustained response). HCV RNA
      became negative in 76% of the patients after 12 weeks of treatment, in 88% after
      12 months of treatment, and in 71% of the patients 6 months after completion of
      therapy. HCV genotype 4 was found in 60% of our population. Alanine
      aminotransferase (ALT) levels were initially increased in only 6 patients and
      normalized in 4 of these patients after 12 weeks of therapy, with end-of
      treatment and sustained biochemical responses of 83% and 67%, respectively. Of 13
      patients who underwent liver biopsies after 6 months of therapy, 11 patients
      (85%) showed histological improvement. One patient could not tolerate therapy
      because of marked lethargy and myalgia; the other patients had minor side effects
      that did not require discontinuation of treatment. Two patients received a
      cadaveric renal transplant after 1 year of IFN treatment, and they continued to
      maintain biochemical and virological responses after a follow-up of 17 and 28
      months, respectively.

PMID- 10401018
TI  - Prevalence of cytomegalovirus in the gastrointestinal tract of renal transplant
      recipients with persistent abdominal pain.
AB  - Abdominal pain occurs frequently in renal transplant recipients receiving
      mycophenolate mofetil (MMF) therapy. The cause of this abdominal pain has not
      been fully elucidated, but may involve local irritation, as well as inhibition of
      rapidly dividing cells of the gastrointestinal (GI) tract. This milieu of
      inflammation and added immunosuppression is conducive to activation of
      cytomegalovirus (CMV). We therefore sought to find the prevalence of active CMV
      in patients presenting with abdominal pain on maintenance MMF therapy. All
      patients receiving a renal transplant at our center from March 1, 1997, to
      September 1, 1997, were studied. Any patient presenting with midepigastric pain
      for greater than 3 days underwent esophagogastroduodenoscopy (EGD) with biopsy.
      CMV was diagnosed by the presence of inclusion bodies and immunohistochemical
      studies. Ten patients presented with persistent midepigastric pain; nine of these
      patients had evidence of GI CMV. Patients who were CMV negative and received an
      allograft from CMV-positive donors and those with leukopenia were at
      significantly increased risk for the development of abdominal pain. In our study
      population, the majority of patients on maintenance MMF therapy who presented
      with persistent midepigastric pain had evidence of active CMV infection in the
      upper gastrointestinal tract.

PMID- 10401017
TI  - Are all successful renal transplants really successful?
AB  - We previously described a small group of renal transplant recipients considered
      to have successful allografts statistically, but who did not benefit clinically.
      These were patients in whom the grafts survived greater than 6 months but less
      than 3 years. This expanded study evaluates 179 consecutive renal transplant
      recipients divided into three groups. Group 1 (n = 18), group 2 (n = 41), and
      group 3 (n = 120) have patients with graft survival less than 6 months, between 6
      months and 3 years, and greater than 3 years, respectively. Mean age, cause of
      renal failure, HLA match, and immunosuppressive regimen were not statistically
      different in any group. The number of acute rejection episodes, number of
      hospitalizations, and number and seriousness of complications were significantly
      greater in group 2 patients compared with the other groups. Patients in group 2
      experienced five times the number of acute rejections (P < 0.0001), three times
      the number of hospitalizations (P < 0.0001), and two times the number of
      complications (P < 0.0001) compared with group 3 patients. In conclusion, those
      transplant recipients whose grafts survived longer than 6 months but less than 3
      years were the most unfortunate. They experienced repeated and serious
      complications and spent many days in the hospital at great expense. A study with
      more sensitive methods of detecting presensitization might impact on graft
      performance in the future.

PMID- 10401019
TI  - Smooth muscle-specific actin levels in the urine of renal transplant recipients:
      correlation with cyclosporine or tacrolimus nephrotoxicity.
AB  - Cyclosporine A (CSA) and tacrolimus (FK506) are powerful immunosuppressive agents
      that have proven useful for antirejection therapy in patients with solid organ
      transplants, including kidney. However, both drugs are nephrotoxic, each
      producing similar histological patterns of injury to renal tubules and
      preglomerular arterioles, and this toxicity is a major cause of renal allograft
      dysfunction. A renal transplant biopsy presently represents the most reliable
      means of diagnosing nephrotoxicity caused by CSA or tacrolimus and distinguishing
      it from acute rejection. Because CSA and tacrolimus nephrotoxicity often involve
      arteriolar smooth muscle, whereas vascular smooth muscle is rarely involved in
      acute rejection, we investigated if the appearance of a smooth muscle-specific
      isoform of alpha-actin (SMA) in the urine of renal transplant recipients about to
      undergo a biopsy for graft dysfunction correlated with biopsy evidence of CSA or
      tacrolimus toxicity. Eighty-nine urine samples from 61 patients, plus 6 samples
      from healthy control subjects, were analyzed in a blinded manner by enzyme-linked
      immunosorbent assay using a specific anti-SMA monoclonal antibody. For the
      patient samples, the results of these assays were then correlated with the biopsy
      findings. Those 40 cases in which the biopsy showed evidence of CSA or tacrolimus
      nephrotoxicity had a significantly (P < 0.01) greater SMA level in the
      corresponding urine samples (0.089 +/- 0.126 microgram/mL; mean +/- SD) than the
      49 cases without toxicity (0.018 +/- 0.027 microgram/mL) or 6 control subjects
      (0.003 +/- 0.007 microgram/mL), although there was considerable overlap of SMA
      values among these groups. The greatest SMA levels were seen in patients with CSA
      or tacrolimus nephrotoxicity that was likely to be relatively acute, namely those
      with thrombotic microangiopathy and those without previous biopsy evidence of
      toxicity. SMA levels correlated significantly with the estimated severity of
      arteriolopathy on biopsy. In patients with tubular but not arteriolar lesions of
      CSA or tacrolimus toxicity, the mean SMA level was not significantly greater than
      that in patients without toxicity. Urine SMA levels in patients with a biopsy
      specimen showing acute rejection were not significantly different from those in
      patients without rejection, and there was no correlation between urine SMA level
      and severity of rejection. Whereas the degree of overlap of SMA levels in
      patients with and without nephrotoxicity was far too great to consider this assay
      as a potential alternative to renal transplant biopsy for the diagnosis of
      nephrotoxicity, the assay may have potential as a marker for active arteriolar
      injury in renal transplant recipients and other patients receiving CSA or
      tacrolimus therapy.

PMID- 10401020
TI  - Spatial arrangement of subepithelial deposits in lupus and nonlupus membranous
      nephropathy.
AB  - Subepithelial deposits are a common feature of idiopathic membranous
      glomerulonephritis (MGN) and lupus membranous glomerulopathy (LMGN). We
      investigated the spatial arrangement of immunoglobulin G (IgG) and C3c fraction
      of complement (C3c) in the immune deposits of MGN and LMGN with confocal laser
      scanning microscopy to correlate specific patterns of IgG-C3 interactions with
      different diseases. Ten patients with MGN and 8 patients with LMGN (World Health
      Organization class VB) were selected. A determination of the spatial arrangement
      of the two fluorochromes and the glomerular area occupied by each fluorochrome
      was performed for each case. Our results showed MGN specimens have an orderly
      distribution of IgG and C3c, with each deposit showing an outer ring of sole IgG.
      IgG was always more abundant than C3c (1,619 +/- 271 v 790 +/- 105 micrometer(2),
      P = 0.002). In LMGN, IgG and C3c were haphazardly arranged, with deposits made of
      C3c only and an outer ring of IgG only rarely present. Also, the relative amounts
      of the two antigens were variable, and two groups could be identified (group 1:
      IgG, 5,515 +/- 1,179 micrometer(2) v C3c, 4,810 +/- 1,174 micrometer(2); P =
      0.02; group 2: IgG, 3,358 +/- 658 micrometer(2) v C3c, 4,047 +/- 740
      micrometer(2); P = 0.03). Our data show that diffuse IgG capping of the
      subepithelial immune deposits is diagnostic of MGN. The absence of an orderly
      three-dimensional arrangement in LMGN deposits (ie, outer ring of IgG) is likely
      to render active complement components more readily available to inflammatory
      activities.

PMID- 10401021
TI  - Percutaneous renal biopsy in the 1990s: safety, value, and implications for early
      hospital discharge.
AB  - To determine the parameters associated with significant bleeding and to examine
      the value of performing a renal biopsy, we studied 83 consecutive patients,
      including 24 renal allograft recipients, who had undergone percutaneous renal
      biopsy. The patients were stratified into four groups according to the percentage
      of decline in their hematocrit (Hct) at 24 hours postbiopsy, as follows: 10% or
      greater (n = 21; 25%) and less than 10% decline (n = 62; 75%). The latter group
      was further subgrouped into 5% to 10% (n = 22) and less than 5% decline (n = 40).
      There was a significant decline in Hct postbiopsy, with a linear correlation
      between the decrease in Hct at 6 and 24 hours (R2 = 0.47; P < 0.0001), suggesting
      that the former was a predictor of the latter. There was a linear correlation
      between the number of passes and number of cores obtained for the first four
      passes, but an inverse correlation when five passes or greater were required.
      Interestingly, there was no correlation between bleeding (>10% decline in Hct)
      and the number of passes or cores obtained. Gross hematuria and blood transfusion
      requirement were each encountered in three patients (3.6%). Importantly, the
      prebiopsy clinical diagnosis was altered in 18 of 59 native kidney biopsies (33%)
      and 10 of 24 transplant biopsies (41%). We conclude that percutaneous renal
      biopsy using an automated spring-loaded gun device coupled with ultrasound
      guidance is a safe technique and provides essential clinical information.
      Importantly, patients with a stable Hct at 6 hours were at low risk for bleeding
      at 24 hours while hospitalized. It remains to be determined if these findings
      could be extrapolated to early discharge from hospital.

PMID- 10401022
TI  - Deletions in the mitochondrial DNA and decrease in the oxidative phosphorylation
      activity of children with Fanconi syndrome secondary to antiblastic therapy.
AB  - The aim of this study is to verify whether there are deletions in mitochondrial
      DNA (mtDNA) and disorders in oxidative phosphorylation (Ox-phos) complexes in the
      pathogenesis of secondary Fanconi syndrome (FS). We studied 18 children with
      tumors who were previously treated with chemotherapy and were off therapy for at
      least 1 year. All the children had normal renal function at diagnosis. Only 4
      children received ifosfamide (IFO) and platinum compounds. We evaluated renal
      function, Ox-phos activity measured on platelets, and mtDNA extracted from
      platelets for all patients. Only 2 patients, both treated with IFO and
      carboplatinum (CARBO) for Wilms' tumor and germ-cell tumor, respectively,
      developed FS 1 and 3 years after termination of therapy. They had decreased
      activities of Ox-phos that were statistically significant only for nicotinamide
      adenine dinucleotide (NAD)-reduced cytochrome-c reductase and cytochrome-c
      oxidase and specific and unidentified deletions in mtDNA that were not maternally
      inherited. Our data suggest that treatment with IFO and CARBO might be
      responsible for deletions in mtDNA, decreased activity of Ox-phos, and impaired
      rates of transport of D-glucose, phosphate, and amino acids.

PMID- 10401023
TI  - Effect of potassium magnesium citrate on thiazide-induced hypokalemia and
      magnesium loss.
AB  - The study was performed to ascertain the value of potassium magnesium citrate,
      magnesium citrate, and potassium citrate in overcoming thiazide-induced
      hypokalemia and magnesium loss. Sixty-two healthy subjects were first
      administered hydrochlorothiazide, 50 mg/d. After 3 weeks of thiazide treatment
      (or earlier for potassium level </=3.5 mEq/L), they were randomized to receive
      one of three drugs while continuing to receive thiazide: potassium magnesium
      citrate (49 mEq of potassium, 24.5 mEq of magnesium), magnesium citrate (24.5
      mEq/d of magnesium), or potassium citrate (49 mEq/d of potassium). Outcome
      measures were changes in serum potassium and magnesium levels and urinary
      potassium, magnesium, pH, and citrate values. All three drugs increased serum
      potassium concentration compared with that resulting from thiazide alone.
      Potassium magnesium citrate increased serum potassium levels from 3.3 +/- 0.2 to
      3.8 +/- 0.3 mEq/L (P < 0.001), potassium citrate increased serum potassium levels
      from 3.4 +/- 0.4 to 3.9 +/-0.3 mEq/L (P < 0.001), and magnesium citrate from 3.4
      +/- 0.4 to 3.7 +/- 0.3 mEq/L (P < 0.001). Potassium magnesium citrate led to a
      significant increase in urinary magnesium levels by the third week of
      supplementation (from 120 +/- 34 to 149 +/- 58 mg/d; P < 0.01) and produced a
      small but significant increase in serum magnesium level. Magnesium citrate
      significantly increased 24-hour urinary magnesium after the first week of
      supplementation and maintained this increase throughout the study. Potassium
      magnesium citrate and potassium citrate, but not magnesium citrate, significantly
      increased urinary pH and citrate values. Potassium magnesium citrate not only
      corrects thiazide-induced hypokalemia, but also may avert magnesium loss while
      providing an alkali load.

PMID- 10401024
TI  - Plasma and urine levels of adrenomedullin and proadrenomedullin N-terminal 20
      peptide in chronic glomerulonephritis.
AB  - Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide
      present in the precursor of adrenomedullin (AM), a vasodilative and natriuretic
      peptide. We examined the plasma and urinary levels of these peptides in patients
      with chronic glomerulonephritis (CGN). The mean plasma AM concentration of the
      patients with CGN did not differ from that of control subjects (4.17 +/- 0.17 v
      3.87 +/- 0.21 fmol/mL, respectively), whereas urinary AM excretion was
      significantly less in the patients with CGN (5.96 +/- 0.95 v control, 8.93 +/-
      1.02 fmol/mg of creatinine; P < 0.05). Plasma concentrations and urinary
      excretion of PAMP were significantly less for the patients with CGN compared with
      control subjects (0.91 +/- 0.08 v 1.23 +/- 0.20 fmol/mL; P < 0.05 and 25.0 +/-
      3.0 v 35.0 +/- 3.6 fmol/mg of creatinine, respectively; P < 0. 05). The plasma AM
      concentration was negatively correlated with plasma renin activity (r = -0.58; P
      < 0.01) and aldosterone concentration (r = -0.40; P < 0.05). Urinary excretions
      of AM and PAMP showed significant correlations with urine excretion of sodium (r
      = 0.39; P < 0.05 and r = 0.49; P < 0.01, respectively). These findings suggest
      that AM and PAMP may have roles in the regulation of sodium in patients with CGN.

PMID- 10401025
TI  - Frequency of ovarian cysts in patients with autosomal dominant polycystic kidney
      disease.
AB  - Extrarenal cysts occur in patients with autosomal dominant polycystic kidney
      disease (ADPKD) most frequently in the liver. Ovarian cysts have been reported in
      women with ADPKD, but their frequency has not been determined. Therefore, we
      analyzed the historical data in our database of 337 women with ADPKD and 199 of
      their unaffected female family members (NADPKD). In addition, we prospectively
      studied 25 nonpregnant, premenopausal women with ADPKD and 25 nonpregnant,
      premenopausal, age-matched control women recruited from the general population to
      assess the occurrence of ovarian cysts. No women in either the control or ADPKD
      groups were receiving exogenous estrogen or progesterone. All women underwent
      sonographic examination using a 5- or 7.5-MHz vaginal probe. A normal ovarian
      follicle was defined as a fluid-filled structure less than 2 cm in average
      diameter, and an ovarian cyst as one of 2 cm or greater. From the historical
      data, 28% of the women with ADPKD gave a history of ovarian cysts compared with
      18% of the NADPKD women (P < 0.05). In the prospective study, the mean age of the
      women with ADPKD was not different from that of the control women (40.9 +/- 1.2 v
      39.3 +/- 1.2 years; P = not significant [NS]). There was no difference in
      frequency of normal follicles found in women with ADPKD or controls (80% v 96%; P
      = NS), nor was there a difference in the frequency of ovarian cysts found in
      women with ADPKD or controls (12% v 12%; P = NS). There was no difference in the
      calculated ovarian volumes between the women with ADPKD and controls (9.9 +/- 2.
      5 v 7.2 +/- 1.2 cm3). Among the women with ADPKD, there was no correlation
      between mean ovarian volume and mean renal volume, nor was there a significant
      relationship between the occurrence of hepatic cystic disease and ovarian cysts.
      Therefore, a prospective imaging study suggests that ovarian cysts have no
      increased frequency in women with ADPKD compared with women in the general
      population.

PMID- 10401026
TI  - Left ventricular mass index increase in early renal disease: impact of decline in
      hemoglobin.
AB  - Cardiovascular disease occurs in patients with progressive renal disease both
      before and after the initiation of dialysis. Left ventricular hypertrophy (LVH)
      is an independent predictor of morbidity and mortality in dialysis populations
      and is common in the renal insufficiency population. LVH is associated with
      numerous modifiable risk factors, but little is known about LV growth (LVG) in
      mild-to-moderate renal insufficiency. This prospective multicenter Canadian
      cohort study identifies factors associated with LVG, measured using two
      dimensional-targeted M-mode echocardiography. Eight centers enrolled 446
      patients, 318 of whom had protocol-mandated clinical, laboratory, and
      echocardiographic measurements recorded. We report 246 patients with assessable
      echocardiograms at both baseline and 12 months with an overall prevalence of LVH
      of 36%. LV mass index (LVMI) increased significantly (>20% of baseline or >20
      g/m2) from baseline to 12 months in 25% of the population. Other than baseline
      LVMI, no differences in baseline variables were noted between patients with and
      without LVG. However, there were significant differences in decline of Hgb level
      (-0.854 v -0.108 g/dL; P = 0.0001) and change in systolic blood pressure (+6.50 v
      -1.09 mm Hg; P = 0.03) between the groups with and without LVG. Multivariate
      analysis showed the independent contribution of decrease in Hgb level (odds ratio
      [OR], 1.32 for each 0.5-g/dL decrease; P = 0.004), increase in systolic blood
      pressure (OR, 1.11 for each 5-mm Hg increase; P = 0.01), and lower baseline LVMI
      (OR, 0.85 for each 10-g/m2; P = 0.011) in predicting LVG. Thus, after adjusting
      for baseline LVMI, Hgb level and systolic blood pressure remain independently
      important predictors of LVG. We defined the important modifiable risk factors.
      There remains a critical need to establish optimal therapeutic strategies and
      targets to improve clinical outcomes.

PMID- 10401027
TI  - Role of urine and serum protein electrophoresis in evaluation of nephrotic-range
      proteinuria.
AB  - The usefulness of routine serum protein electrophoresis (SPEP) and urine protein
      electrophoresis (UPEP) screening in the evaluation of proteinuria is not known.
      The data on the clinical utility of these tests in 165 male patients with
      proteinuria greater than 3 g/d of protein who were screened for the presence of
      an M-spike are presented. Two hundred fifty-four studies were performed (SPEP,
      155; UPEP 99) in these 165 patients. Twenty-four studies (9.8%) were positive for
      an M-spike (15 serum; 9 urine samples) in 19 patients (11.5%). Fourteen patients
      (8.5%) had an M-spike in either serum or urine, five patients (3%) in both
      studies. Two of these 19 patients were diagnosed with myeloma and 1 patient was
      diagnosed with primary amyloidosis. The other 16 patients were diagnosed with
      monoclonal gammopathy of unknown significance (MGUS). The group with a positive M
      spike was significantly older (mean +/- SEM, 65 +/- 2 years; range, 39 to 78
      years v 58 +/- 1 years; range, 25 to 84 years; P = 0.03), had a lower incidence
      of coexistent diabetes (21.1% v 61.6%; P = 0. 01), and a lower serum albumin
      level (3.2 v 3.6 g/dL; P = 0.05). Using a multivariable logistic regression
      model, the presence of an M band was positively correlated with age (odds ratio
      [OR], 1.056; 95% confidence interval [CI], 1.006 to 1.108) and negatively
      correlated for serum albumin level (OR, 0.386; 95% CI, 0.184 to 0. 810),
      hematocrit (OR, 0.923; 95% CI, 0.852 to 1.001), and the presence of diabetes
      mellitus (OR, 0.128; 95% CI, 0.038 to 0.434). In summary, routine SPEP and UPEP
      screening in patients with proteinuria greater than 3 g/d of protein detected an
      M-spike in 11. 5% and myeloma in 1.2% of the patients. The cost per case of
      myeloma or MGUS discovered was $1,192.

PMID- 10401028
TI  - Implications of certain genetic polymorphisms in scarring in vesicoureteric
      reflux: importance of ACE polymorphism.
AB  - Polymorphisms of the renin-angiotensin system (RAS) have been shown to affect
      renal prognosis in a number of diseases. We examined the influence of deletion
      (D) and insertion (I) polymorphism in the angiotensin I-converting enzyme (ACE)
      gene and the other polymorphic markers of RAS, and that of plasminogen-activator
      inhibitor-1 (PAI-1) on renal scarring in reflux nephropathy. Ninety-four children
      with third- or fourth-degree reflux were the subject of the study. They were
      stratified into two groups according to the technetium-99m-dimercaptosuccinic
      acid (DMSA) findings: the first group consisted of 41 patients with no scar
      formation. In the second group (n = 53), there was significant scar formation in
      the refluxing units. ACE levels, ACE gene, angiotensin-1 receptor (AT1) A1166C,
      angiotensinogen (ATG) M235T, and PAI-1 4G/5G polymorphisms were studied. In the
      second group with scarred kidneys, 18 patients had decreased renal function. The
      frequency of patients homozygous for the D allele was significantly greater in
      the second group with scar formation in the refluxing units compared with the
      first group of patients (P < 0.005). On multivariate analysis, the DD genotype
      was the only factor that had a significant impact on renal scar formation,
      introducing a 4.9-fold risk (P < 0.05, 95% confidence interval). We were unable
      to find any correlation with the presence ofDD genotype and hypertension,
      decreased renal function, proteinuria, or sex of the patient. DDgenotype
      correlated with the serum ACE levels (P < 0.005). AT1and ATGpolymorphisms and PAI
      1 polymorphism did not correlate with scar formation or any of the parameters.
      This study provides evidence that the DDgenotype of ACE may be a genetic
      susceptibility factor contributing to adverse renal prognosis in reflux
      nephropathy; namely, scar formation. The role of the synergism between the
      aforementioned genetic polymorphisms can be enlightened with larger patient
      groups, possibly through multicenter studies.

PMID- 10401029
TI  - Anti-HIV indeterminate western blot in dialysis patients: a long-term follow-up.
AB  - In a group of 520 patients undergoing chronic hemodialysis, 23 (4. 4%) were
      enzyme immunoassay (EIA) positive for human immunodeficiency virus (HIV) and
      indeterminate by Western blot (IWB) analysis. The antibodies were mostly directed
      against p24 and p55 antigens. A comparison between hemodialysis patients with and
      without IWB showed significant differences between the two groups with respect to
      number of units of blood transfused, history of renal transplant rejection, and
      Rh status. No significant differences were observed with respect to ethnic group,
      nature of renal disease, duration of hemodialysis, associated diseases, and ABO
      blood group. The HIV IWB phenomenon may represent abnormal immune reactivity as a
      result of transplantation antigens and/or autoantibody formation. Five-year
      follow-up of the HIV EIA-positive IWB patients showed that none had seroconverted
      to HIV-positive status.

PMID- 10401030
TI  - Febrile lady with acute renal failure and desquamating erythema.
AB  - A 63-year-old woman developed acute renal failure and streptococcal toxic shock
      syndrome caused by streptococcus group G. Initially, an erythema resembling
      vasculitis was misleading. The subsequent clinical course, however, was typical
      for streptococcal toxic shock syndrome and met the criteria put forward by The
      Working Group on Severe Streptococcal Infections. In patients infected with
      streptococcus group G, toxic shock syndrome is rare. The streptococcus group G
      strains isolated from this patient did not produce pyrogenic exotoxins. Instead
      they produced an M-like protein related to group C and G streptococci that do not
      act as superantigens.

PMID- 10401031
TI  - Bullous dermatoses in end-stage renal failure: porphyria or pseudoporphyria?
AB  - Bullous dermatoses (BD) are well recognized in patients with end-stage renal
      disease (ESRD). It is important to distinguish pseudoporphyria (porphyrin
      accumulation due to decreased clearance) from true porphyrias, particularly those
      in which acute neurological attacks may occur. Investigation of the dialysis
      patient poses practical diagnostic difficulties because urinary porphyrin
      profiles are not available. We describe a patient on continuous ambulatory
      peritoneal dialysis (CAPD) with several recognized causative factors for
      porphyria cutanea tarda (PCT). The patient presented with a blistering
      photosensitive rash. We highlight the importance of investigating anuric patients
      with fractionation of both fecal and plasma porphyrins. Plasma porphyrins were
      grossly elevated (345 nmol/L; reference range, <13), whereas plasma porphyrins in
      a control group of CAPD patients without blistering rashes were only minimally
      elevated (mean, 23.9 nmol/L; SD, 11.0; n = 9). Fractionation of fecal porphyrins
      by high-performance liquid chromatography (HPLC) yielded a pattern typical of
      PCT. In addition to the contributory factors for PCT that were present, it is
      possible that porphyrin accumulation secondary to renal failure played a role in
      the expression of her disease. Patients with ESRD presenting with BD require
      careful evaluation, including fractionation of fecal porphyrins.

PMID- 10401032
TI  - Delayed gallium-67 uptake in renal atheroembolic disease.
AB  - The differentiation between atheroembolic disease (AED) and allergic interstitial
      nephritis (AIN) may pose a clinical challenge. Gallium scans have been proposed
      to identify AIN with good discriminating ability. We report herein a case of
      atheroembolic disease presenting as acute renal failure with persistent delayed
      uptake of gallium-67 by nuclear imaging. The distinction between AED and AIN
      could be made only with a renal biopsy, which confirmed the correct diagnosis.
      This case report and the presented review of the literature suggest that gallium
      scans are nonspecific and should not supplant renal biopsy for definitive
      histological diagnosis.

PMID- 10401033
TI  - Benign monoclonal gammopathy turning to AL amyloidosis after kidney
      transplantation.
AB  - The fate of preexisting benign monoclonal gammopathy after organ transplantation
      is largely unknown. We report the case of a 47-year-old male kidney graft
      recipient with a pretransplantation IgG kappa monoclonal gammopathy who
      developed, 10 years after transplantation, de novo augloid light chain (AL)
      amyloidosis involving skin and kidney graft. The potential role of heavy
      immunosuppressive treatment in the development of this complication is discussed.
      The possible occurrence of AL amyloidosis should be kept in mind when a patient
      with benign monoclonal gammopathy is evaluated for organ transplantation, as well
      as when a transplanted patient with pre-existing monoclonal gammopathy develops
      new onset of proteinuria.

PMID- 10401035
TI  - Iron replacement in rHuEPO-treated dialysis patients: DOQI and beyond.

PMID- 10401034
TI  - Thoracoscopic surgery and pleurodesis for pleuroperitoneal communication in
      patients on continuous ambulatory peritoneal dialysis.
AB  - Two patients on continuous ambulatory peritoneal dialysis (CAPD) developed right
      massive hydrothorax and were diagnosed as having pleuroperitoneal communication.
      Thoracoscopic surgery and pleurodesis were performed. It showed that one was
      caused by multiple flaws in the diaphragm and that the other was attributable to
      multiple blebs in the diaphragmatic dome. After the procedure, both of them had
      no recurrence of hydrothorax and underwent CAPD safely. We recommend
      thoracoscopic surgery and pleurodesis as the first choice of therapeutic methods
      for pleuroperitoneal communication.

PMID- 10401036
TI  - Glomerulosclerosis, tubulointerstitial fibrosis, and obstructive uropathy in
      PEPCK-TGF-beta1 transgenic mice.

PMID- 10401037
TI  - Three-year-old boy with partial Fanconi syndrome.

PMID- 10401038
TI  - Regulation of glucose transport by hypoxia.
AB  - Transport of glucose into most mammalian cells and tissues is rate-controlling
      for its metabolism. Glucose transport is acutely stimulated by hypoxic
      conditions, and the response is mediated by enhanced function of the facilitative
      glucose transporters (Glut), Glut1, Glut3, and Glut4. The expression and activity
      of the Glut-mediated transport is coupled to the energetic status of the cell,
      such that the inhibition of oxidative phosphorylation resulting from exposure to
      hypoxia leads to a stimulation of glucose transport. The premise that the glucose
      transport response to hypoxia is secondary to inhibition of mitochondrial
      function is supported by the finding that exposure of a variety of cells and
      tissues to agents such as azide or cyanide, in the presence of oxygen, also leads
      to stimulation of glucose transport. The mechanisms underlying the acute
      stimulation of transport include translocation of Gluts to the plasma membrane
      (Glut1 and Glut4) and activation of transporters pre-exiting in the plasma
      membrane (Glut1). A more prolonged exposure to hypoxia results in enhanced
      transcription of the Glut1 glucose transporter gene, with little or no effect on
      transcription of other Glut genes. The transcriptional effect of hypoxia is
      mediated by dual mechanisms operating in parallel, namely, (1) enhancement of
      Glut1 gene transcription in response to a reduction in oxygen concentration per
      se, acting through the hypoxia-signaling pathway, and (2) stimulation of Glut1
      transcription secondary to the associated inhibition of oxidative phosphorylation
      during hypoxia. Among the various hypoxia-responsive genes, Glut1 is the first
      gene whose rate of transcription has been shown to be dually regulated by
      hypoxia. In addition, inhibition of oxidative phosphorylation per se, and not the
      reduction in oxygen tension itself, results in a stabilization of Glut1 mRNA. The
      increase in cell Glut1 mRNA content, resulting from its enhanced transcription
      and decreased degradation, leads to increased cell and plasma membrane Glut1
      content, which is manifested by a further stimulation of glucose transport during
      the adaptive response to prolonged exposure to hypoxia.

PMID- 10401039
TI  - Drug substitution in transplantation.

PMID- 10401040
TI  - Telecommunications and the dialysis patient.

PMID- 10401041
TI  - Rapidly developing T-cell posttransplantation lymphoproliferative disorder.
AB  - Posttransplantation lymphoproliferative disorder (PTLD) of T-cell origin has been
      rarely described in chronically immunosuppressed allograft recipients. We report
      a case of renal PTLD of a T lineage that occurred shortly after transplantation
      under a triple-immunosuppressive regimen. Renal graft biopsy performed 58 days
      posttransplantation showed extensive interstitial infiltrates of polymorphic
      lymphoid cells, which expressed the UCHL-1 and CD3 markers for T-cell lineage.
      The clonal nature of the T cells in renal tissue was identified by showing
      rearrangement of the T-cell receptor gamma chain genes using a polymerase chain
      reaction (PCR). DNA extracted from the graft biopsy specimen did not show the
      sequences of human T-cell leukemia virus type 1 (HTLV-1) by PCR. Signals for
      Epstein-Barr virus (EBV) infection in renal tissue were not shown by in situ
      hybridization. After the reduction of immunosuppressive therapy, regression of
      PTLD lesion and development of rejection were shown in the second graft biopsy
      and graftectomy specimen. The extreme rarity of rapidly developing T-cell PTLD in
      a renal allograft prompted us to write this report.

PMID- 10401042
TI  - Preface.

PMID- 10401043
TI  - The Biology and Anatomy of Inguinofemoral Hernia.
AB  - The purpose of this article is to discuss the biology of hernia and covers such
      features as the male predominance of hernia, the causal significance of a patent
      processus vaginalis, the effect of the shape of the skeleton on liability to the
      development of hernia, and the alterations in collagen structure and metabolism
      that may be involved in the genesis of hernia. In addition, the influence of such
      factors as peritoneal dialysis, appendectomy, and pregnancy are reviewed. The
      anatomy of the groin is outlined in detail. The lower abdominal region is a
      layered structure; the defect in musculoaponeurotic continuity that leads to a
      hernia exists only in the transversus abdominis layer. The external oblique and
      internal oblique layers are not primarily involved in the genesis of hernia. The
      major structures within the transversus abdominis layer are described and
      illustrated including the deep inguinal ring, iliopubic tract, transversus
      abdominis arch, femoral sheath, and Cooper's ligament. The structure of the
      inguinal canal and spermatic cord, and the continuities of investing fascia from
      the abdominal wall to the spermatic cord are also described in detail. The
      essential features of anatomic repair of groin hernias are reviewed. Anatomic
      repairs are always conducted within the transversus abdominis lamina. The
      structures that need to be apposed in primary repair are specified.

PMID- 10401044
TI  - Traditional Preperitoneal Approach to Inguinal Hernias.
AB  - The preperitoneal approach desirably and advantageously permits direct exposure
      to transversalis fascia without disturbing the inguinal canal structures and
      allows restoration of the integrity of this layer in a anatomical, tension-free,
      and sutureless manner. The essential feature of prosthetic versus nonprosthetic
      repair of inguinofermoral hernias is the replacement of the transversalis fascia
      by a large mesh that extends far beyond the borders of myopectineal orifice
      unnecessary. Therefore, the indications for preperitoneal prosthetic repair
      include all recurrent and multiply recurrent groin hernias, and bilateral hernias
      in older patients.

PMID- 10401045
TI  - Transabdominal Preperitoneal Procedure.
AB  - The technique of transperitoneal inguinal herniorrhaphy evolved its principles
      for success through the process of continuous quality improvement. Between
      December 21, 1989 and December 20, 1993, 278 patients had repair of 348 inguinal
      and/or femoral hernias using any of four transperitoneal methods. Group I had
      mesh repair of only the visualized defect; Group II had mesh support of the
      entire inguinofemoral area; Group III had staple fixation of mesh as in Group I;
      whereas Group IV had staple fixation of mesh as in Group II. Recurrence rates
      were 23% in Group I at 4 years, Group II had 6% at 3(1/2) years, Group III had
      33% at 3 years, and Group IV had 0% at 3 years. On average, patients returned to
      unrestricted activity in 4.5 days. The most significant complication was that of
      small bowel obstruction secondary to partial or complete peritoneal flap
      dehiscence. These continuously scrutinized data resulted in elucidation of the
      principles of successful repair. They include, complete dissection and mesh
      coverage of the entire inguinofemoral area regardless of where the visualized
      defect presents, staple fixation of mesh to prevent its displacement, and close
      reapproximation of the peritoneal edges. For the past 3 years, adherence to these
      principles has resulted in 0% recurrence rates and prompt resumption of activity.

PMID- 10401046
TI  - Prosthetic Inguinal Hernia Repair Using a Laparoscopic Extraperitoneal Approach.
AB  - The preperitoneal technique offers several advantages over conventional anterior
      approaches in the surgical repair of inguinal hernias: direct access to the
      posterior inguinal anatomy, clear visibility of all possible hernial defects,
      ability to circumvent scar tissue and intra-abdominal adhesions, and ease of
      effecting difficult repairs. A preperitoneal prosthetic procedure has been
      successfully used, performed laparoscopically, to repair 163 indirect, 163
      direct, and one femoral inguinal defects. In the approach used, a piece of
      polypropylene mesh, placed extraperitoneally, is used to reinforce or replace the
      transversalis fascia. In only one of 197 patients (0.5%) was it necessary to
      convert to an open procedure; this patient had a severely incarcerated hernia.
      Almost all patients were discharged on the day of surgery, and all returned to
      normal activities within 7 days. There were few complications, and the recurrence
      rate in the series of 300 repairs was only 0.3%. One patient required a second
      procedure because of a retained indirect hernia. Based upon these results and the
      experience of others using a similar approach, the laparoscopic extraperitoneal
      prosthetic repair is advocated for patients with recurrent, as well as bilateral
      and complicated inguinal defects.

PMID- 10401047
TI  - Technology of Prosthetic Material.
AB  - Prosthetic material to repair a hernia is indicated for large defects, attenuated
      muscle, or tension avoidance on a repair. Biological, absorbable, and permanent
      material can be used to repair a hernia. Absorbable substances such as Dexon
      (Davis & Geck, Wayne, NJ) and Vicryl (Ethicon, Inc, Somerville, NJ) are useful in
      infected areas but have a high recurrence rate. Nonabsorbable material such as
      polyethylene, polypropylene, and polytetrafluoroethylene (PTFE) are the most
      commonly used materials for mesh repair of a hernia. The properties of these
      meshes are determined not only by their composition but also by the size of the
      fibrils and interstices. Marlex (Bard Vascular, Billerica, MA) has a thicker
      fibril diameter and large interstices that allow ingrowth of surrounding material
      but has some stiffness in handling. PTFE has small fibrils and interstices that
      result in less ingrowth of tissue but ease in handling. Prolene (Ethicon,
      Somerville, NJ) has intermediate size fibrils and interstices and moderate
      ingrowth of tissue and ease of handling.

PMID- 10401048
TI  - Inguinal Herniorrhaphy: Complications and Recurrences.
AB  - Because laparoscopic surgical techniques have been applied to inguinal hernia
      repair, the surgeon has been forced to re-evaluate his particular open technique
      and its resultant complications and recurrences to determine what is the best
      procedure for patients. In this article, complication rates for open inguinal
      herniorrhaphy varied from 7% to 12% with some reports as low as 1% using the
      anterior mesh technique. The most frequent complications were wound problems and
      scrotal and testicular swelling. In the laparoscopic series using retroperitoneal
      mesh or the "onlay" technique, the number of complications in 3,288 inguinal
      herniorrhaphies was 522 (16.8%). On the other hand, recurrence rates for open
      inguinal herniorrhaphy ranged from 1% to 10% for primary repair to as high as 35%
      for the repair of recurrent hernias. The laparoscopic series involved 3,178
      repairs using the retroperitoneal and onlay techniques, and 61 recurrences
      (1.92%) were noted in a follow-up greater than 6 months. These data emphasize
      that complication and recurrence rates are similar between open and laparoscopic
      inguinal herniorrhaphy.

PMID- 10401049
TI  - Preface.

PMID- 10401050
TI  - Medical Therapy Versus Laparoscopic Surgical Treatment for Ulcer Disease.
AB  - The development of low morbidity vagotomy and H2 antagonists in the early 1970s
      began the debate as to which was the most appropriate treatment for uncomplicated
      duodenal ulcer. A review of Australian Medicare and Pharmaceutical Benefits
      Scheme data shows that medical treatment in this country was the preferred
      option. In the past 12 years, vagotomies have decreased 15-fold while, in the
      same period, H2 antagonist prescriptions have increased from 0 to 2.5 million per
      year, doubling in the past 3 years, and currently costs $96 million per year or
      6.7% of the country's entire pharmaceutical budget. Similarly, upper
      gastrointestinal tract endoscopies have increased, costing $15 million per year,
      doubling in the past 6 years and representing a cost almost equivalent to all
      other upper gastrointestinal procedures combined. Despite known efficacy and
      recommendations for use, triple therapy for Heliobacter species is not being used
      with prescriptions for surface agents actually decreasing to 40,000 per year. A
      review of the outcome of medical and surgical therapy shows that this expense is
      not justified; surgery would be more costeffective than medicine at 2 years and
      safer than medicine after 4 years as a result of complications from failed
      medical treatment. This margin of benefit is predicted to be greater with
      laparoscopic vagotomy. Failed medical treatment needs to be redefined by limiting
      H2 antagonists to a 6-week course. Recurrences or failures are than evaluated
      endoscopically and those diagnosed with having chronic duoderal ulcers have
      biopsies taken. Heliobacter pylori positive patients are treated with triple
      therapy. Failures, recurrences, and originally H pylori negative patients have
      laparoscopic vagotomy. For such a trial protocol to be evaluated, it requires the
      long-term use of H2 antagonists to be restricted and laparoscopic vagotomists to
      document the efficacy of their surgery, including gastric secretion tests.

PMID- 10401051
TI  - Laparoscopic Highly Selective Vagotomy.
AB  - Various procedures have been described to reduce gastric acidity for a potential
      cure of recurrent duodenal ulcer disease. Long-term follow-up is available in
      open surgery for the highly selective vagotomy (HSV), with a 5% recurrent rate
      for 5 years. With the success of minimal invasive surgery (MIS), it seemed
      feasible to adapt the MIS approach to HSV. The investigators present the
      technique, as well as their first results. From January 1991 to December 1993, 65
      patients underwent a laparoscopic HSV. There was not conversion to open surgery.
      To date, there are two proven recurrences and one ischemic gastric ulcer.

PMID- 10401053
TI  - Posterior Truncal Vagotomy and Anterior Highly Selective Vagotomy.
AB  - Peptic ulcer disease continues to be a major health care problem in the United
      States. Fortunately, the overall majority of patients can be expected to heal
      their ulcers with aggressive medical treatment. Nonetheless, a small but discrete
      group of patients will require surgical treatment for their disease. A minimally
      invasive approach to the treatment of peptic disease offers numerous advantages
      to patients including, early discharge from the hospital, early return to normal
      activity, and minimal postoperative discomfort. Numerous options are available to
      the surgeon for the treatment of patients presenting with peptic ulcer disease.
      One of these, posterior truncal vagotomy combined with anterior highly selective
      vagotomy, seems to provide definitive treatment of chronic duodenal ulcer
      disease.

PMID- 10401052
TI  - Laparoscopic Posterior Truncal Vagotomy and Anterior Seromyotomy.
AB  - For patients with peptic ulcer disease who only require acid reduction,
      laparoscopic procedures such as posterior truncal vagotomy and anterior
      seromyotomy can be offered. Elective surgery after a complete physiological
      workup can improve the results for a certain group of patients. The experiences
      with the Taylor procedure in open surgery promise the interest of
      gastroenterologists to include elective surgery among the therapeutic options. As
      experienced with other procedures, a minimally invasive approach will increase
      patients' acceptance of surgical treatment.

PMID- 10401054
TI  - Laparoscopic Billroth II Gastrectomy.
AB  - The totally intra-abdominal laparoscopic Billroth II gastrectomy offers a
      minimally invasive option for gastric resection that is remarkably less traumatic
      and more "patient friendly." Initial experience in this operation around the
      world has largely concentrated on resection for benign gastric ulcer, but
      recently the indications have been extended to both benign and neoplastic lesions
      of the stomach. Experience with a small experimental series of 16 cases has shown
      that this operation has many advantages over open surgery in terms of
      postoperative pain, quicker mobilization, fewer wound problems, better cosmesis,
      and quicker discharge. The main problem remains the cost of disposable stapling
      devices.

PMID- 10401055
TI  - Laparoscopic Repair of Perforated Peptic Ulcer.
AB  - The recent introduction of laparoscopy into the armamentarium of the general
      surgeon has revolutionized many aspects of surgical practice. The repair of
      perforated peptic ulceration is ideally suited to a laparoscopic approach. An
      accurate diagnosis is obtained, and closure of the perforation with thorough
      peritoneal toilet safely can be undertaken. The main advantages include the
      avoidance of a major incision and the reduction of postoperative pain. This may
      benefit the patient with associated respiratory disease in particular. Although
      mobilization may be improved, early discharge from the hospital is unlikely
      because the patient must recover from the peritonitis and associated ileus. The
      main drawback is a longer operating time caused by technical difficulty with
      laparoscopic suturing. Many innovative techniques have been described to simplify
      the procedure. The reported experience with laparoscopic repair of perforated
      peptic ulcers is encouraging, and randomized trials comparing it with open
      surgery are eagerly awaited.

PMID- 10401056
TI  - Laparoscopic Management of Complicated Ulcer Disease.
AB  - Laparoscopic surgery for complicated ulcer disease has to be tailored to the
      specific needs imposed by the pathology and clinical state of the patient. In the
      elective situation, patients with concomitant reflux esophagitis and duodenal
      ulcer disease are best treated by partial crurally-fixed posterior fundoplication
      and highly selective vagotomy. Patients with resistant prepyloric ulcers and
      those on long-term medication with ulcerogenic drugs require truncal vagotomy and
      antrectomy. Because many patients with benign pyloric stenosis are elderly and
      exhibit hypochlorhydria, a drainage procedure without vagotomy is sufficient. The
      type of drainage performed, gastrojejunostomy or pyloroplasty, depends on the
      extent of scarring of antroduodenal segment. In the emergency situation, patients
      with perforated ulcer disease are best treated by simple closure with adequate
      peritoneal toilet. A definitive procedure should be reserved for fit patients
      with prior symptoms and limited chemical peritonitis of less than 6 to 8 hours
      duration. All perforated gastric ulcers should be biopsied at the time of
      laparoscopic closure. New endogastric techniques are being evaluated for the
      treatment of patients with bleeding gastroesophageal lesions.

PMID- 10401057
TI  - Preface.

PMID- 10401058
TI  - Anesthetic Considerations for Laparoscopic Surgery.
AB  - Laparoscopic surgery presents attendant challenges for the anesthesiologist.
      Cardiovascular and respiratory function may be affected adversely by the presence
      of a pneumoperitoneum; airway management may be difficult because of the
      patient's position; and postoperative pain, although less than that experienced
      after traditional, open surgery, can still result in considerable discomfort.
      These complications, and several choices of anesthetic technique, are discussed.

PMID- 10401059
TI  - Laparoscopic Surgery: A View From the Head of the Table.
AB  - Impressive advances in laparoscopic surgical technique have taken place,
      especially since the late 1980s. These developments have motivated patients as
      well as surgeons, institutions, and payers; accordingly, the variety and
      frequency of these procedures have vastly increased. In the rush to expand the
      frontiers of laparoscopic surgery, we must not lose sight of the potential
      pitfalls resulting either from the physiological effects of the procedure itself
      or from the influence of underlying disease processes.

PMID- 10401060
TI  - Anesthesia and Thoracoscopic Surgery.
AB  - An appreciation of the physiological changes and possible complications of
      thoracoscopic surgery is required by the medical team caring for the patient. The
      alteration of ventilatory and cardiac status under anesthesia can have
      significant impact on the morbidity and mortality of the patient. Considerations
      of the interaction between surgical and anesthetic effects may help to identify
      the problems early and avoid deleterious changes.

PMID- 10401061
TI  - Pain Mechanisms in Laparoscopic Surgery.
AB  - Laparoscopic surgery is minimally invasive surgery designed to reduce tissue
      damage. The pleural and peritoneal anatomy can develop nocioceptive afferent
      impulses. Common pain pathways are described, and therapeutic options based on
      physiology are discussed. The underlying anatomical basis of the pain pathway is
      described.

PMID- 10401062
TI  - Complications of Laparoscopic Surgery: Surgical and Anesthetic Considerations.
AB  - The potential complications of laparoscopic surgery generally result from
      insertion of the needle and trocar, creation of the pneumoperitoneum, positioning
      of the patient, and insertion and manipulation of the instruments. By promptly
      recognizing and treating these complications, the surgical and anesthesia teams
      can minimize morbidity and mortality.

PMID- 10401063
TI  - Monitoring for Laparoscopic Surgery.
AB  - Laparoscopy has come to be used for a large variety of surgical procedures. This
      has necessarily led to its use in patients who have a variety of interrelated
      diseases. While the postoperative course tends to be more benign than in
      traditional "open" procedures, the intraoperative period may be even more
      stressful to the patient from a physiological perspective. Use of sophisticated
      monitoring techniques in selected patients can help yield the optimal
      postoperative outcome.

PMID- 10401064
TI  - Anesthetic and Physiological Changes During Laparoscopy and Thoracoscopy: The
      Surgeon's View.
AB  - Although physiological changes during laparoscopy and thoracoscopy generally are
      similar to those seen during standard open procedures, these minimally invasive
      techniques are accompanied by some unique changes. General, regional, and local
      anesthesia during laparoscopy and thoracoscopy, and potential complications, are
      discussed. The physiological responses that are discussed include hemodynamic
      effects, acid-base and pulmonary effects, and hormonal effects.

PMID- 10401066
TI  - Preface.

PMID- 10401067
TI  - Pathogenesis and Clinical Presentation of Bile Duct Calculi.
AB  - Clearer understanding of the pathogenesis of bile duct calculi and better
      recognition of the clinical presentation of various clinical disorders caused by
      biliary stones are essential for proper diagnosis and treatment. This article
      reviews the pathogenesis of secondary stones (cholesterol and black pigment
      stones) and primary stones (brown pigment stones), as well as the main features
      of biliary calculi (pain, obstruction, and sepsis), followed by discussion of the
      clinical presentations of bile duct stones with gallbladder in situ and after
      cholecystectomy, and description of the manifestations of primary bile duct
      stones, cholangitis, primary sclerosing cholangitis, oriental cholangitis, and
      gallstone pancreatitis.

PMID- 10401065
TI  - Endoscopic Sympathectomy.
AB  - Denervation of the sympathetic nerve can be accomplished with much less operative
      trauma by using the endoscopic surgical approach. Although endoscopic thoracic
      sympathectomy is not new, the techniques and the extent of denervation have not
      been standardized. The anatomic appearances and configurations of the sympathetic
      chain are explained, and various procedures, including ramisections,
      interganglionic sympathectomy, and ganglionectomy, are reviewed. Thoracoscopic
      approaches, operative techniques, and potential complications are discussed.

PMID- 10401068
TI  - Investigations for Bile Duct Calculi.
AB  - Bile duct stones are common, occurring in approximately 15% of patients with
      gallstones. Radiological techniques for preoperative detection of stones are
      determined by the clinical presentation of the stones. In patients who are not
      symptomatic, detection of a dilated bile duct on ultrasound strongly suggests
      bile duct stones. In up to 80% of patients, ultrasound may detect stones, but the
      accuracy of this technique is operator-dependent. Although there has been a
      resurgence of interest in intravenous cholangiography in recent years, its use is
      not supported on grounds of either accuracy or safety. Other techniques, such as
      percutaneous cholangiogram, computed tomography, and magnetic resonance imaging,
      may be used in those particular circumstances when endoscopic retrograde
      cholangiography cannot be used.

PMID- 10401069
TI  - Endoscopic Retrograde Cholangiopancreatography.
AB  - Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for
      radiological visualization of the common bile duct. In addition to its diagnostic
      applications, ERCP, along with sphincterotomy, is a standard therapy for bile
      duct calculi. The advent of laparoscopic cholecystectomy (LC) has focused much
      attention on the role of ERCP in the management of bile duct calculi. The use of
      ERCP before LC should be selective, with ERCP restricted to patients with a high
      risk of bile duct calculi. ERCP should be performed after LC in patients with
      continuing symptoms suggestive of bile duct calculi or when operative
      cholangiography has demonstrated calculi. Intravenous cholangiography (IVC) has
      no role as a screening test for bile duct calculi, and percutaneous transhepatic
      cholangiography (PTC) should be restricted to those patients in whom bile duct
      calculi is highly suspected and in whom ERCP has failed. Elderly and frail
      patients with bile duct calculi may be satisfactorily managed by ERCP alone.
      Although a "minimally invasive" procedure, ERCP is not without risks. Local
      practice will depend to a great extent on the availability of ERCP expertise.

PMID- 10401070
TI  - Acute Presentations of Bile Duct Calculi.
AB  - The majority of bile duct stones in Western patients originate in the
      gallbladder. Many patients with bile duct stones are asymptomatic. However, the
      acute complications of bile duct calculi-jaundice, cholangitis, and pancreatitis
      may present in insolation or in combination with each other. Successful treatment
      of cholangitis and severe biliary pancreatitis requires urgent biliary
      decompression, which is best achieved by endoscopic sphincterotomy. Similarly,
      endoscopic sphincterotomy is the most appropriate method of relieving obstructive
      jaundice caused by biliary stones and, in some patients, may be the sole
      treatment required. Surgical intervention rarely is necessary in the acute stage,
      although definitive surgery may be required later, when the patient's clinical
      condition has improved.

PMID- 10401071
TI  - Operative Cholangiogram at Laparoscopic Cholecystectomy.
AB  - In the open cholecystectomy era, the established principle for treating biliary
      calculi was to perform intraoperative cholangiography to diagnose and treat the
      concomitant common duct stone at the time of cholecystectomy. To reduce
      unnecessary cholangiograms, a selective cholangiogram policy based on
      preoperative and operative criteria was sometimes used. Although both time and
      cost were saved, a 4% to 10% chance of missing unsuspected common duct stones was
      associated with this policy. The introduction of laparoscopic cholecystectomy in
      Australia initially led to an abandonment of the principles of biliary surgery.
      Rates of intraoperative cholangiography declined as stones were either ignored or
      diagnosed preoperatively by endoscopic retrograde cholangiopancreatography and/or
      intravenous cholangiography. When stones were identified, they were treated by
      preoperative endoscopic sphincterotomy. This decline in cholangiography was
      associated with a twofold to fourfold rise in serious bile duct injury as well as
      a delay in its diagnosis. Over the past two years, as laparoscopic
      cholecystectomy has become established in Australia, practice is returning to the
      standards of the open cholecystectomy era. Intraoperative cholangiography rates
      have been increasing along with the proportion of patients having their duct
      stones removed laparoscopically. To succeed, this practice depends on the use of
      fluoroscopic cholangiography, which should be the standard of care in the
      laparoscopic era. With laparoscopic cholecystectomy, intraoperative
      cholangiography is no longer optional, but mandatory. Not only does it reduce the
      incidence and severity of bile duct injury, but it also trains the surgeon to
      develop techniques of laparoscopic duct exploration.

PMID- 10401072
TI  - Laparoscopic Bile Duct Techniques.
AB  - The debate over selective versus routine cholangiography during cholecystectomy
      has been refueled since the advent of laparoscopic cholecystectomy. Regardless of
      whether routine or selective cholangiography is performed, if the need for common
      bile duct (CBD) exploration arises, it can be conducted laparoscopically in more
      than 80% of cases. The techniques of fluoroscopically guided CBD stone removal,
      transcystic choledochoscopy, and choledochotomy are described. Each technique has
      specific indications and advantages. It behooves the surgeon to become familiar
      with the various techniques of laparoscopic CBD exploration. This allows the
      treatment of cholelithiasis and CBD stones to become a single-stage procedure.

PMID- 10401073
TI  - Peroperative Endoscopic Sphincterotomy.
AB  - A major aim in the treatment of bile duct stones detected at the time of
      laparoscopic cholecystectomy should be to remove the stones during the same
      operation. In most instances, and for patients with small stones, this aim can be
      achieved using techniques through the cystic duct. In patients in whom these
      techniques failed, the role of a duodenal approach for removing the stones was
      evaluated by performing perendoscopic sphincterotomy (PES) and clearing the bile
      duct via this route. In an initial series of 13 patients, it was demonstrated
      that perendoscopic sphincterotomy and extraction of stones from the bile duct can
      be effectively performed in patients in the supine position with minimal
      interference to the laparoscopic cholecystectomy operation. The perendoscopic
      approach does not add to the complication rate of the operation, and short-term
      follow-up of patients indicates no significant postoperative sequalae. This
      approach adds to the various techniques being developed for the minimal-access
      approach to the treatment of bile duct stones.

PMID- 10401074
TI  - Open Operations on the Bile Duct for Stones.
AB  - The management of bile duct stones attained an acceptable plateau of development
      in the late 1980s, with the majority of bile duct stones removed by open
      exploration and the difficult stone delegated to the endoscopist. This situation
      was disturbed by the introduction of laparoscopic cholecystectomy; it was no
      longer straightforward policy to explore the bile duct, and alternatives had to
      be considered. Open operation may now be required (1) if an unexpected stone is
      found during laparoscopic cholecystectomy with a small cystic duct, (2) if
      laparoscopic choledochotomy is undertaken and technical problems are encountered,
      (3) when stones in the duct cannot be removed endoscopically, (4) by preference
      of the surgeon on the basis of similar risk factors, (5) in the sick patient with
      cholangitis, and (6) after technical failure of endoscopic sphincterotomy. The
      technique of open operation must be meticulous and should preferably be performed
      with choledochoscopy either peroperatively or postoperatively. The open technique
      for bile duct exploration continues to have a role, and when performed expertly,
      its morbidity and mortality will be similar to the endoscopic and laparoscopic
      techniques.

PMID- 10401076
TI  - Concluding Remarks.

PMID- 10401075
TI  - Endoscopic Sphincterotomy and Stone Extraction.
AB  - Recent development of new cannulation techniques, improvement of lithotripsy
      methods, and the advent of laparoscopic cholecystectomy have extended the
      efficacy and broadened the application of endoscopic sphincterotomy and stone
      extraction. Choledocholithiasis, a condition that once was believed to invariably
      require surgical intervention, now can successfully be treated endoscopically in
      85% to 90% of cases, with a complication rate of 7% to 10% and a mortality rate
      of 0.5% to 1.0%. In patients scheduled for laparoscopic cholecystectomy in whom
      bile duct stones are suspected, the indication and timing of perioperative
      endoscopic retrograde cholangiopancreatography depend on the likelihood of ductal
      stones being present as well as local endoscopic expertise. The increase in the
      number of younger patients referred for endoscopic stone extraction, mainly as a
      consequence of the advent of laparoscopic cholecystectomy, and the unknown long
      term effects of sphincterotomy have led to the development of techniques in which
      stones are extracted from the bile duct without sphincterotomy. This article
      concentrates on the technique of endoscopic sphincterotomy and stone extraction,
      defines its indications (with special reference to laparoscopic cholecystectomy)
      and discusses occurrence and management of complications.

PMID- 10401077
TI  - Preface.

PMID- 10401078
TI  - Principles of Cancer Biology in Relation to Minimal Access Surgical Techniques.
AB  - Recurrence in abdominal incisions, whether created to allow traditional "open"
      operation or laparoscopic approaches, is related in many ways to the principle of
      tumor biology. Tissue trauma enhances the growth of many types of malignant cells
      and is related to the recurrences of being observed after laparoscopic
      approaches. Additional mechanisms such as the effect of pneumoperitoneum may play
      a role in the dispersement of cells at the time of manipulation for diagnosis or
      therapy of cancer. Techniques must be developed to reduce the potential for
      spillage of cancer cells and the dissemination of cells at the time of
      laparoscopy. Once access site recurrence develops, metastasis of tumor to other
      sites may be consequence. Ongoing research regarding the effects of laparoscopic
      techniques on tumor biology must be supported in order to limit the complication
      of access site recurrence once additional techniques for therapeutic manipulation
      become available.

PMID- 10401079
TI  - Mechanism of Abdominal Wall Recurrence After Laparoscopic Resection of Colonic
      Cancers.
AB  - Although abdominal wall recurrence after conventional resection for colon cancer
      remains a rare event, several reports of trocar site recurrence after
      laparoscopic oncological procedures have been reported. Although the mechanism is
      unclear, it appears that local factors are important for trocar recurrence after
      colorectal cancer procedures. Hematogenous dissemination to the trocar site does
      not appear to be a primary mechanism. The full realization of port-site
      recurrence has yet to be uncovered because only a relatively small number of
      colonic resections have performed laparoscopically for cancer. Prospective
      studies must include opportunities for both the discovery of trocar site
      recurrence and documenting this entity carefully.

PMID- 10401080
TI  - Potential for Abdominal Wall Implantation After Laparoscopic Procedures of the
      Hepatobiliary Tract.
AB  - Hepatobiliary malignancies are often unsuspected at routine laparoscopic
      operations. Case reports have recently drawn attention to the potential for
      neoplastic "seeding" of laparoscopic incision sites. Although the exact incidence
      of tumor implantation-as well as if there is any change in incidence or with
      laparoscopic surgery-will remain obscure, surgeons must remain alert to this
      possibility. If cancer is suspected or found after laparoscopy, time-honored
      surgical principles apply to the management of these patients at risk for early
      and aggressive recurrences.

PMID- 10401081
TI  - Port-Site Recurrence of Cancer Associated With Laparoscopic Diagnosis and
      Resection: The European Experience.
AB  - Port-site recurrences of cancer have drawn attention to the potential risks of
      laparoscopy for the diagnosis and treatment of digestive cancers. The first
      observations concerned unsuspected gallbladder cancers shown by laparoscopic
      cholecystectomy for lithiasis. Seventeen cases in patients with advanced or early
      colon cancer followed. It eventually became clear that all cancers could be the
      origin of such recurrences, which present as apparently isolated nodules embedded
      in the wall. These parietal recurrences were well known in open surgery, having
      been reported for most cancers, but they drew little attention because they
      usually occur in the context of carcinosis. It must be remembered that digestive
      cancers in general have a high potential for dissemination and that nearly 30% of
      patients have micrometastases in the bloodstream, the lymph nodes, the
      peritoneum, or even the bone marrow. The mechanism of tumor implantation is
      analogous to development of an inflammatory reaction. Under these conditions,
      laparoscopic surgery is susceptible to cause neoplastic dissemination for a
      number of mechanical reasons: CO2 insufflation, tumor manipulation, failure to
      isolate the tumor, forceful extraction of the surgical specimen, and
      exsufflation. Multiinstitutional trials of well-defined laparoscopic protocols
      based on the same oncologic principles as in open surgery should reduce the
      frequency of tumor cell dissemination and the incidence of port-site recurrences.

PMID- 10401082
TI  - Mechanisms to Reduce Incidence of Tumor Implantaton During Minimal Access
      Procedures for Colon Cancer.
AB  - Implantation of tumor during minimal access procedures such as laparoscopic
      colectomy is a disturbing phenomenon. Although the actual incidence of this
      problem is unknown, its existence is a threat to the further clinical development
      of minimally invasive oncological procedures. We have adopted the hypothesis that
      these recurrences are the result of suboptimal technique or instrumentation and
      therefore that the problem can be avoided by identifying and correcting these
      technical factors. Our purpose is to analyze the possible mechanisms by which
      tumor cells become implanted in the trocar sites and to propose rational
      solutions to the problem.

PMID- 10401083
TI  - Ports, Trocars/Cannulae, and Access Techniques.
AB  - One of the keys to safe laparo-endoscopic surgery is an expeditious, reliable,
      and safe access to the operative field. Aside from appropriate surgical
      technique, the technology of trocars, cannulae, and other endoscopically guided
      insertion techniques plays a decisive role for safe identification of and access
      to the peritoneal cavity. This report takes a close look at critical features of
      trocar and cannula design for blind insertion with the focus on the biomechanical
      principles involved in traversing the abdominal wall. Particular attention has
      been paid to techniques minimizing the risk of accidental injury to major
      vessels, intestine, and other important structures. The principle of controlled
      visualized access led to several developments in the field of trocars, cannulae,
      and puncture techniques. Aside from blind and open access with the Veress needle,
      conventional trocars and cannulae, a selected variety of endoscopically assisted
      ports such as the optical Veress needle, optical trocars and optical scalpel, and
      a vacuum-supported access system are described in detail.

PMID- 10401084
TI  - Abdominal Wall Lifting Devices as Alternatives to Pneumoperitoneum.
AB  - Conventional laparoscopy requires pneumoperitoneum to elevate the abdominal wall
      for exposure. A continuous insufflation of a noncombustible gas in a sealed
      environment is essential. Undesirable physiological side effects have been
      observed with CO2 pneumoperitoneum. Furthermore, it has been necessary to retrain
      surgeons to use specialized instruments in order to operate on video images.
      Japanese and American investigators have recently used mechanical devices without
      pneumoperitoneum to elevate the abdominal wall for laparoscopic surgery. With
      their gasless technique, conventional instruments can be used, direct
      visualization of abdominal viscera is possible, and digital examination of
      abdominal contents can be performed without the fear o losing exposure. Since
      these procedures are being performed in a isobaric abdominal cavity, the risk of
      body fluid contamination to operating team is diminished when compared to open or
      traditional laparoscopic surgery. With this technique, transition from open to
      laparoscopic surgery is minimal; it should be added to the training of future
      surgeons.

PMID- 10401085
TI  - Visual Displays and Visual Perception in Minimal Access Surgery.
AB  - Visual perceptual processing underlies safe execution of endoscopic surgery. This
      review deals with the limitations of the present visual display technology used
      in endoscopic surgery with reference to the normal direct stereoscopic vision and
      pints to the research and development needed in this important technological and
      psychomotor aspect of endoscopic surgery. Eyeball movements (saccadic and smooth
      pursuit), visual cues (stereoscopic and monoscopic), accommodation, individual
      visual attributes, and the display technology itself are all important. Monocular
      depth cues are degraded by the cureent display systems, and technological
      advances in this are will improve perceptual processing and reduce both fatigue
      and human error during endoscopic interventions. Depth perception can be improved
      by alternative techniques to three-dimensional imaging such as the VISTRAL system
      and the Suspended Image System based on projection of image by parabolic mirrors
      and advanced beam spitter technology.

PMID- 10401086
TI  - Preface.

PMID- 10401087
TI  - Laparoscopic Resection for Colorectal Cancer: A USA Perspective.
AB  - Laparoscopic surgery has gained in popularity in the last few years. As the
      technology for minimally invasive surgery improves and surgeons' laparoscopic
      skills progress, more advanced surgical procedures are being attempted with the
      laparoscope. The role of the laparoscope in the field of colon and rectal surgery
      is still being defined. Of particular controversy is the issue of laparoscopic
      colon resection for malignancy. The long-term effect of laparoscopic colectomy on
      either local or distant recurrence is not obvious in the immediate postoperative
      period, and how the use of the laparoscope for resection of colorectal malignancy
      will affect survival is unknown. This chapter reviews the published "USA
      Experience" with laparoscopic resection for colorectal cancer.

PMID- 10401088
TI  - Laparoscopic Resection for Colorectal Cancer: A European Perspective.
AB  - The increasing use of laparoscopic techniques in colorectal surgery is
      controversial. The technical feasibility of such methods is now beyond doubt;
      however, their clinical evaluation is at an early stage. The expectation that the
      laparoscopic approach would confer benefit to patients in terms of reduced
      postoperative pain and other morbidity has been questioned. The safety of these
      methods in neoplasia is unproven. This article presents those laparoscopic
      resectional techniques available to the colorectal surgeon. The authors' personal
      experience with these procedures is review and those issues of controversy are
      discussed, with particular reference to the question of the suitability of these
      techniques for the treatment of malignancy.

PMID- 10401089
TI  - Laparoscopic Resection for Colorectal Cancer: An Australian Perspective.
AB  - Laparoscopic colectomy for both benign and malignant conditions has been
      performed in many institutions worldwide. Because of its recent inception, there
      has been little data available about follow-up in cancer patients. This
      prospective study assesses the operating statistics, postoperative complications,
      and long-term outcomes for 128 patients with colorectal cancer who were treated
      selectively with laparoscopic surgery. Median operating times for right
      hemicolectomy, anterior resection, and abdominoperineal resection were 3 hours,
      3.3 hours, 3.5 hours, respectively. For right hemicolectomy and anterior
      resection patients, the median postoperative stay was 6 days. This stay was 9
      days for abdominoperineal patients. Open conversion occurred in 9 patients (7%).
      30 patients suffered from some postoperative morbidity (23%). Of 102 potentially
      curative procedures, there have been 9 recurrences (8,8%) to date. Fifteen
      patients have died. There is a low incidence of intestinal ileus (3%) and wound
      infection (1.8%).

PMID- 10401090
TI  - Laparoscopic Resection for Colorectal Cancer: Limitations and Concerns.
AB  - Laparoscopic skills and perceptions are an increasing part of the "surgical
      commonsense" of the younger surgeon. The part played by the laparoscope in
      colorectal surgery will thus increase gradually over the coming years, and this
      process is unlikely to be prevented by widespread doubts and scepticism, which
      are quite properly applied at this time to cancer surgery. Nevertheless,
      permanent cure and the absence of a stoma-thus, the avoidance of autonomic nerve
      damage-remain far more important to the patient than any of the advantages so far
      conferred by the laparoscopic approach. However, there is a possibility that
      improved visualization low in the pelvis, particularly with the development of
      newer and better instruments, will actually facilitate better dissection and more
      accurate deep pelvic surgery than has been possible by open surgery in the past.

PMID- 10401091
TI  - Laparoscopic Techniques for Inflammatory Bowel Disease.
AB  - Very little has been written concerning the use of laparoscopic techniques in
      inflammatory bowel disease. Its most useful indications appear to be in Crohn's
      disease, especially for intestinal diversions when severe perineal/perianal
      sepsis occurs. In this instance, avoidance of a laparotomy is a major advantage,
      and the simplicity of a laparoscopic stoma formation makes this a procedure that
      most surgeons may perform, even with minimal laparoscopic experience.
      Laparoscopic techniques may also be used for the limited resections required in
      Crohn's ileal or ileocolonic disease and for diagnostic purposes when indicated.
      The laparoscopic approach to the surgical treatment of ulcerative colitis (total
      abdominal colectomy, possibly with proctectomy and ileoanal pouch formation)
      remains to be evaluated before it can be contemplated as an alternative to
      conventional procedures.

PMID- 10401092
TI  - Laparoscopic Appendicectomy.
AB  - Acute appendicitis is a common condition, accounting for substantial number of
      hospital days in all institutions and giving rise to considerable adverse
      economic and social consequences in the postoperative period. Laparoscopic
      appendicectomy offers several advantages over the open procedure. Diagnostic
      accuracy is improved. Postoperative morbidity, in particular wound infection, is
      reduced, as is postoperative pain, and cosmesis is improved. Discharge from
      hospital is hastened, as is return to normal activity and work. Surgical
      technique is detailed, including the approach to specific clinical scenarios such
      as perforated and retrocaecal appendicitis. The utilization of ultrasonically
      activated dissection for laparoscopic removal of the appendix is explained. The
      implications of laparoscopic appendicectomy for surgical training are discussed.

PMID- 10401093
TI  - Laparoscopic Treatment of Rectal Prolapse.
AB  - Rectal prolapse is a distressing condition often affecting elderly patients. Open
      rectopexy has a proven track record in the treatment of this condition but may be
      complicated by significant morbidity. The benign nature of the disease and
      reduced pain and pulmonary complications of the laparoscopic approach makes this
      an attractive operation in this patient group. Laparoscopic prosthesis fixation
      rectopexy and lateral ligament suspension with and without colectomy have been
      described with low recurrence rates, good patient acceptance, improvement in
      symptoms, and both radiological and physiological assessments, although these
      initial findings require further evaluation with prospective controlled trials.

PMID- 10401094
TI  - Endoscopic Approach.
AB  - The increasing use of the laparoscopic approach in colorectal surgery depends not
      only on the indications but also on technological development. Better
      visualization of the operative field is available using a three-chip camera or
      three-dimensional system. Alternative port positionings together with curved
      instruments increase the degree of freedom during operation. Complex laparoscopic
      procedures need highly specific instruments. We have developed atraumatic bowel
      graspers, different types of retractors, and innovative combination instruments.
      OREST II, a new multipurpose system that assists the organization of laparascopic
      surgery is described.

PMID- 10401095
TI  - Preface.

PMID- 10401096
TI  - Laparoscopic Exposure of the Pancreas and Staging of Pancreatic Cancer.
AB  - Laparoscopy combined with laparoscopic contact ultrasonography was recently
      proposed as a new and effective method for staging and assessment of
      resectability in pancreatic cancer. In order to limit the occurrence of false
      negative findings, the laparoscopic technique should be as close as possible to
      the equivalent laparotomic procedure. That includes opening of the lesser sac,
      which is best achieved through an infragastric route, with resulting wide
      exposure of the pancreatic body and tail. Laparoscopic contact ultrasonography is
      then performed for the purpose to define tumor limits, study relationships with
      major vessels, and assess limphnodal invasion. The results of this procedure in a
      series of 25 patients are discussed in this report. It is concluded that
      laparoscopic staging of pancreatic cancer is safe and effective in achieving the
      goal of avoiding unnecessary laparotomies and selecting candidates for surgical
      resection.

PMID- 10401097
TI  - Laparoscopic Bypass for Inoperable Disease of the Pancreas.
AB  - Based on the literature and the authors' experience, the principal laparoscopic
      techniques of cholecystojejunostomy, choledochoenterostomy, and gastrojejunostomy
      for palliative treatment of pancreatic carcinoma are described.

PMID- 10401098
TI  - Laparoscopic Pancreatic Resections.
AB  - Resection of the pancreas by the laparoscopic approach is still in its infancy
      and the reported experience is very limited. Despite its retroperitoneal
      location, exposure and mobilisation of the pancreas can be achieved in the vast
      majority of patients and does not usually pose major technical problems provided
      the surgeon is experienced in advanced laparoscopic techniques and in pancreatic
      surgery. Based on our experience, laparoscopic enucleation of islet-cell tumours
      constitutes an ideal indication. Both the precise location (by contact
      ultrasonography of the pancreas) and the enucleation (by ultrasonic dissection)
      are facilitated by the laparoscopic approach. Laparoscopic distal 70-80%
      pancreatectomy for chronic pancreatitis and cystic tumors appears to confer
      benefit over the equivalent open operation by accelerating recovery and return to
      full activity of the patient after surgery. By contrast, our experience with
      laparoscopic pancreaticoduodenectomy for periampullary cancer has been
      disappointing and we have not documented any benefit from this approach. In
      addition, there are real concerns that an oncologically adequate operation (with
      extended lymphadenectomy) for cancer of the head of the pancreas is not possible
      by the laparoscopic approach.

PMID- 10401099
TI  - Laparoscopic Treatment of Acute Necrotizing Pancreatitis.
AB  - Laparoscopic debridement and necrosectomy are described for the treatment for
      acute necrotizing pancreatitis. Three techniques are described: (1) retrogastric
      retrocolic debridement; (2) a full retroperitoneoscopic approach; and (3) a
      transgastric drainage. These three techniques were performed for necrotizing
      pancreatitis in a group of patients from 1993 to 1994. These techniques have
      resulted in 75% success of drainage and debridement of necrotizing pancreatitis.
      No mortalities were encountered during this time period, and reintervention was
      necessary in 25% of patients. Apart from a cosmetic advantage, less stress has
      resulted from the procedure, therefore promoting earlier recovery with
      potentially less fistula complications, which are often observed after open
      drainage.

PMID- 10401100
TI  - Thoracoscopic Splanchnicectomy for Chronic, Severe Pancreatic Pain.
AB  - Fourteen patients with pancreatic cancer, 2 with cancer of the papilla of Vater,
      and 14 with chronic pancreatitis were operated on with bilateral thoracoscopic
      splanchnicectomy caused by severe chronic pain. The median follow-up time was 13
      months. Twenty patients were followed up for 3 months and 14 for at least 6
      months. The surgical results were evaluated prospectively, both with visual
      analogue scale (VAS) and with documentation of the consumption of analgesics at
      elective follow-up after 1 week and 1, 3, 6, and 12 months postoperatively. All
      30 patients stated that the characteristics of their pain had changed at recovery
      from anaesthesia, but only 6 of them reported immediate complete pain relief. All
      but 1 of the 14 patients with chronic pancreatitis had clearly reduced pain as
      evaluated by VAS 1 month after the operation, and this beneficial effect remained
      for the whole study period. Furthermore, the need for analgesics decreased. Also,
      in the 16 patients with cancer, there was on average a marked relief of pain from
      1 week and onwards. The 6 cancer patients with survival more than 3 months had
      reduced pain for the remaining period of their lives. It seems that the final
      pain relief is persistent as is the reduced consumption of analgesics. There was
      no correlation between the number of cut nerves and pain relief as evaluated by
      VAS. Three patients were reoperated on for intrathoracic bleeding the evening
      after the operation, and one had transient pain located to one of the port sites.
      Otherwise, there were no postoperative complications. The operation time was
      short and the length of hospital stay in most patients was 24 hours or less. It
      was concluded that thoracoscopic splanchnicectomy appears to be a promising and
      relatively simple treatment for severe chronic pancreatic pain. Further studies
      are needed to establish its role in the management of intractable pancreatic
      pain.

PMID- 10401101
TI  - Elective Laparoscopic Splenectomy: Person Experience and Literature Review.
AB  - Laparoscopic splenectomy has become an attractive treatment for patients with
      selected hematologic disorders. Almost 200 observations have been reported. The
      rate of conversion to laparotomy is 10% to 15%, and the complication rate is
      between 0% and 30%. Adequate selection of patients, preoperative administration
      of intravenous immunoglobulin in patients with idiopathic thrombocytopenic
      purpura, meticulous surgical techniques, and careful preoperative and
      intraoperative search for accessory spleen are critical factors for success in
      these patients. The procedure should be confined to expert laparoscopic surgeons
      with considerable experience in the management of hematologic diseases.

PMID- 10401102
TI  - Laparoscopic Treatment of Splenic Injuries.
AB  - The spleen is the intrabdominal organ that is commonly injured after blunt
      abdominal trauma. The use of laparoscopy to diagnose intrabdominal lesions after
      abdominal trauma has been recommended for many years, but not until the explosive
      diffusion of laparoscopic cholecystectomy did it attract the interest of
      surgeons. Standard diagnostic methods for assessment of splenic rupture are
      peritoneal lavage, computed tomography scan, and ultrasonography. Based on the
      clinical picture and results of these tests, a conservative policy for splenic
      trauma is possible in some cases, but these diagnostic methods have a number of
      shortcomings that may be overcome by laparoscopy. Recents reports confirm that
      laparoscopy for abdominal trauma carries a high diagnostic yield in the
      identification of intra-abdominal injuries, and by exclusion of significant intra
      abdominal trauma, it reduces the negative laparotomy rate. Therapeutic
      laparoscopy can be used to deal with mild splenic lesions in stable patients and
      in the treatment of late consequences of splenic injury, such as post-traumatic
      cysts.

PMID- 10401104
TI  - Preface.

PMID- 10401103
TI  - Laparoscopic Ultrasound: Its Role in Laparoscopic Surgery.
AB  - Laparoscopic surgery has been accepted as the surgery of choice for may
      diagnostic and therapeutic abdominal procedures because of decreased morbidity,
      reduced cost, and improvement in long-term outcomes compared with open
      procedures. However, this approach has inherent limitations in the evaluation of
      diseases concealed within solid organs, hollow viscera, or the retroperitoneum.
      Laparoscopic ultrasound, which evolved from the concepts of intraoperative and
      endoscopic ultrasound, opens a whole new dimension to accurately diagnose and
      treat conditions laparoscopically. This technique shows promise of becoming a
      valuable new adjunct to a variety of laparoscopic procedures for the diagnosis
      and treatment of various abdominal and pelvic abnormalities.

PMID- 10401105
TI  - Laparoscopic Pelvic and Para-Aortic/Retroperitoneal Lymph Node Dissection.
AB  - The application of laparoscopy in genitourinary surgery has broadened with recent
      advances in laparoscopic technique and instrumentation. Specifically, the
      laparoscopic pelvic lymph node dissection has become a viable alternative to open
      lymphadenectomy for the accurate staging of prostatic adenocarcinoma. The
      laparoscopic pelvic lymph node dissection is a less morbid method of determining
      nodal status and can potentially prevent a noncurative procedure in those
      patients with metastatic prostate cancer. Therefore, the laparoscopic pelvic
      lymph node dissection is limited to those patients with prostate cancer who have
      a high likelihood of metastatic disease as predicted by preoperative clinical
      staging, prostate-specific antigen, and Gleason grade. In contrast, the accuracy
      of the laparoscopic paraaortic/retroperitoneal lymph node dissection in the
      staging of nonseminomatous testis cancers has not yet been established. Although
      technically feasible, controversy over the increased morbidity and unproven
      accuracy of the laparoscopic retroperitoneal lymph node dissection exists when
      compared with its potentially curative, open counterpart. Therefore, the
      laparoscopic retroperitoneal lymph node dissection is performed only in those
      patients with nonseminomatous testis cancer who have a low likelihood of
      metastatic disease.

PMID- 10401106
TI  - Laparoscopic Nephrectomy: Retroperitoneal Approach.
AB  - Laparoscopic nephrectomy was originally described using a transperitoneal
      approach. However, detractors have argued that the transperitoneal approach
      provides a less direct approach to retroperitoneal structures, risks injury to
      intraperitoneal viscera, and results in a longer postoperative ileus. With the
      development of a variety of dissecting balloons, retroperitoneal laparoscopic
      nephrectomy has been demonstrated to be safe and efficacious; in particular,
      small, benign kidneys may be best suited to the retroperitoneal approach. A
      variety of centers have reported excellent results using this approach.

PMID- 10401107
TI  - Laparoscopic Adrenalectomy.
AB  - Adrenal pathology requiring surgical intervention is relatively uncommon.
      Nevertheless, there are a number of conditions that warrant such consideration.
      Most surgically correctable diseases of the adrenal glands are associated with
      excess production of adrenal corticosteroids or catecholamines by an adrenal
      tumor. Classic open approaches toward adrenalectomy in the past have included an
      anterior, transabdominal, or posterior route. Laparoscopic adrenalectomy offers
      the advantages of excellent exposure through minimally damaging portals. This
      results in an expected very benign postoperative course. It has now been almost 4
      years since the first reported laparoscopic adrenalectomy. Since then, numerous
      small series have been reported and experienced laparoscopic surgeons have proven
      the merits of a laparoscopic approach to adrenalectomy. This reviews the current
      state of the art and offers descriptions of selected approaches to both the right
      and left adrenal glands.

PMID- 10401108
TI  - Laparoscopic Lumbar Discectomy.
AB  - The developing field of laparoscopic spinal surgery is indebted not only to
      laparoscopy but also to the fields of arthroscopy and percutaneous
      microdiscectomy. These fields all share a common theme: the accomplishment of
      ever more advanced surgical procedures via minimally invasive approaches. The
      recent explosive development and application of these various techniques provides
      ample evidence that physicians and patients alike demand and expect a more
      refined approach to the spine. More than 90% of surgically significant disc
      disease occurs at the L3-L4, L4-L5, and L5-S1 levels. Reviewed here are the
      surgical techniques necessary for the safe laparoscopic exposure of the lumbar
      spine for the purpose of discectomy or fusion.

PMID- 10401109
TI  - Laparoscopic Aortic Surgery.
AB  - With the success of laparoscopic cholecystectomy in decreasing postoperative
      pain, morbidity, hospital stay and costs, there has been much interest in
      applying minimally invasive techniques to other fields. Although endovascular
      stenting first emerged as a minimally invasive approach to vascular surgery,
      laparoscopic aortic surgery for both occlusive and aneurysmal disease has only
      recently been developed. Although technical feasibility has been demonstrated in
      animal and human studies, several issues still need to be resolved. These include
      the optimal surgical approach to the aorta, methods of maintaining a working
      cavity, technical issues specifically related to aortic surgery, and
      documentation of the exact benefits for patients. The purpose of this article is
      to review the current literature on laparoscopic aortic surgery and discuss them
      in the context of the above issues.

PMID- 10401110
TI  - Techniques, Equipment, and Exposure for Endoscopic Retroperitoneal Surgery.
AB  - The videoendoscopic revolution has now reached the field of retroperitoneal
      surgery. However, safe retroperitoneoscopy demands perfect and detailed knowledge
      of the local anatomy. It also involves new dissecting techniques with new tools
      and specific strategies.

PMID- 10401111
TI  - High-Frequency Electrosurgery in Minimal Access Procedures.
AB  - In open surgery preparation, dissection and hemostasis are easy to perform
      compared with endoscopic surgery. In open surgery, the surgeon is able to use a
      variety of instruments and methods, In endoscopic surgery, scalpels cannot be
      used and the freedom of manipulation of instruments such as scissors and forceps
      is limited. Hence, endoscopic surgery depends on the availability of special
      methods, instruments, and equipments for different endoscopic operations. High
      frequency surgery offers different methods and instruments for preparation,
      dissection, and hemostasis for endoscopic interventions.

PMID- 10401112
TI  - Preface.

PMID- 10401113
TI  - Microimaging.
AB  - Recent technological advances in optics, imaging, and illumination have brought
      forth a new generation of miniature laparoscopes suitable for emergency
      laparoscopy. A simple comparative analysis was conducted to determine which optic
      would be most suitable in an emergent environment. Animal experiments were
      designed to emulate a videolaparoscopic procedure. Six telescopes were visually
      assessed as to sharpness, depth of field, brightness and displayed image size on
      the TV monitor. A videotape record was obtained. Two telescopes were perceived as
      clearly superior in the field. When they meet image specification, miniature
      laparoscopes can be useful in the emergency setting.

PMID- 10401114
TI  - Laparoscopy for the Acute Abdomen.
AB  - The application of laparoscopy for therapy is well established in biliary tract
      disease, inguinal herniorrhaphy, and fundoplication. Frequently, the diagnostic
      capability of laparoscopy is overlooked. A review of the literature and an
      institution's experience in laparoscopy for the acute abdomen is presented.
      Therapy was completed laparoscopically in a substantial number of cases.

PMID- 10401115
TI  - Laparoscopy for Acute Diseases of the Lower Abdomen and Pelvis.
AB  - Laparoscopy is an important tool for evaluating acute lower abdominal and pelvic
      pain. Although a complete history and physical examination often provide an
      accurate diagnosis, laparoscopy can serve as an adjunct in many patients with
      unclear symptoms. An acute abdomen can be caused by many pelvic sources.
      Laparoscopy can assist in the diagnosis of abdominal and pelvic pathologies and
      can often be therapeutic, eg, the treatment of adnexal torsion and endometriosis.
      The early use of laparoscopy for the diagnosis of acute lower abdominal and
      pelvic pain of unclear etiology often leads to an earlier diagnosis and allows
      for definitive treatment using minimal access techniques.

PMID- 10401116
TI  - The Role of Laparoscopy in the Intensive Care Unit.
AB  - Evaluation of the abdomen in critically ill intensive care unit patients remains
      problematic. Sedation, neuromuscular blockade, and head injury frequently make
      physical examination unreliable. As intra-abdominal processes frequently
      contribute to the development of multiple organ failure, it is imperative to
      establish a diagnosis and initiate treatment as soon as possible while the organ
      failures remain reversible. A diagnostic algorithm is presented as well as a
      summary of recent literature that places diagnostic laparoscopy in context with
      other diagnostic studies for evaluation of the abdomen in this complex population
      of patients.

PMID- 10401117
TI  - Laparoscopy for Acute Abdominal Conditions in Children.
AB  - Laparoscopy for acute abdominal conditions if one area where laparoscopy is being
      used in children. However, because of the reduced abdominal surface area of small
      children, special concerns, are present and must be appreciated. The most common
      acute abdominal in children for which laparoscopy is used is appendicitis. Other
      indications include cholecystectomy for acute cholecystitis, Meckel's
      diverticulectomy, evaluation for trauma, and correction or excision of adnexal
      torsions. In addition, the future of laparoscopy for acute abdominal conditions
      is speculated.

PMID- 10401118
TI  - The Role of Laparoscopy in the Management of Penetrating Trauma.
AB  - To ascertain the need for operative intervention is the key management issue in
      stable patients with penetrating abdominal trauma. This article addresses the
      role of laparoscopy in refining the indications for celiotomy, especially in
      wounds of the intrathoracic abdomen and those with doubtful peritoneal violation.
      Technical considerations, possible future uses, and cost also are discussed.

PMID- 10401119
TI  - The Role of Laparoscopy in the Acute Abdomen and Trauma.
AB  - The use of laparoscopy for the treatment of various surgical diseases has been
      well described, and its use is widely accepted. Diagnostic laparoscopy (DL) has
      been used by gynecologists for many years, and only recently has its use by the
      general surgeon gained interest. The ease of use and its ability to directly
      visualize the abdominal viscera have lead many surgeons to suggest the use of
      laparoscopy in the evaluation of the acute and traumatized abdomen, The proposed
      benefits include reduced incidence of nontherapeutic laparotomies and shortened
      hospital stay as compared with current diagnostic regimens. Despite these
      proposed benefits, the use of DL in the management of the trauma patients is
      restricted to the hemodynamically stable patient. In the setting of blunt trauma,
      DL has been demonstrated to accurately diagnose solid organ injuries and is
      capable of predicting individuals requiring celiotomy. The role of DL in this
      setting has been shown to accurately determine the absence of peritoneal
      violation and has resulted in shortened hospital stay and reduced hospital costs.
      In summary, the role of DL in the injured patient is evolving. In the setting of
      blunt trauma, further research is required to accurately identify a subset of
      patients that will benefit from the use of DL over current methods.
      Hemodynamically stable victims of penetrating trauma clearly benefit most from
      DL's ability to determine the presence of peritoneal violation and avoid a formal
      laparotomy with its increased morbidity.

PMID- 10401120
TI  - The Role of Laparoscopy in the Evaluation of Abdominal Trauma.
AB  - The evaluation of patients sustaining abdominal trauma remains one of the most
      challenging tasks for the general surgeon. Diagnostic peritoneal lavage and
      computerized tomography are well-established studies, each with its own
      indications, advantages, and disadvantages. Ultrasonography has been widely used
      in Europe and has only recently gained popularity in the United States. With the
      recent explosion of laparoscopic techniques in general surgery, it was only
      natural that its application in the evaluation and perhaps even treatment of the
      injured patient would be forthcoming. The definitive role of both ultrasonography
      and diagnostic laparoscopy in the evaluation of abdominal injury has yet to be
      determined. This review looks at the role of these various diagnostic procedures
      in the evaluation of both penetrating and blunt abdominal trauma.

PMID- 10401121
TI  - Laparoscopy for Acute Appendicitis.
AB  - The "classical" symptoms of appendicitis are rarely found, and this most common
      of surgical emergencies can present a diagnostic conundrum. Laparoscopy was
      originally used as a diagnostic aid in acute appendicitis, but since the early
      1980s, it has been a vehicle for removal of the diseased organ. The literature
      reviewed and a rationale for the role of this endoscopic technique are discussed.

PMID- 10401122
TI  - Three-Dimensional Imaging and Image Displays: Surgical Application of Advanced
      Technologies.
AB  - One of the cornerstones of modern technology that was ushered in by laparoscopic
      surgery is the use of the video image. The importance of this "virtual
      representation" of the patient goes well beyond the application to laparoscopic
      surgery, and lies at the very heart of the revolution of surgery into the
      Information Age. Real objects, organs and patients can be represented as 2 and 3
      dimensional computer generated images and viewed upon displays beyond the simple
      video monitor which permit a level of clinical practice not possible on the
      actual patients. These fundamental concepts that form the foundation of the
      revolution in surgery are placed in a framework for the future of surgery, and
      illustrate how their implementation can dramatically improve patient care.

PMID- 10401123
TI  - Preface.

PMID- 10401124
TI  - Introduction to Thoracoscopic Surgery: Indications, Basic Techniques, and
      Instrumentation.
AB  - Thoracoscopy is a useful tool for diagnosing and managing intrathoracic disease.
      With the new technologies in endoscopic surgery, a whole variety of diagnostic
      and therapeutic procedures is now possible thoracoscopically, which has led to an
      increase in both the therapeutic and diagnostic indications for thoracoscopic
      surgery. Thoracoscopy has therefore become an important part of the armamentarium
      of general thoracic surgery. Safe thoracoscopy includes the use of careful one
      lung ventilation. New instruments are now available to allow thoracoscopy to be
      performed more easily. Thoracoscopy is a safe and effective technique that can be
      performed with minimal morbidity and excellent results.

PMID- 10401125
TI  - The Current Status of Thoracoscopic Surgery.
AB  - Video-assisted thoracic surgery is increasingly being applied to treat a variety
      of intrathoracic disease processes. Numerous pleural, pulmonary, esophageal,
      autonomic nervous system, spinal, and even cardiac procedures are now being
      performed using this minimally invasive approach. An overview of these
      thoracoscopic interventions is the focus of this review. It must be realized that
      although the technical feasibility of these operations has been demonstrated,
      their role in the practice of general thoracic surgery remains to be defined by
      critical scientific comparisons with established standards.

PMID- 10401126
TI  - Thoracoscopy for Management of Lung Disease (Including Emphysema).
AB  - Thoracic applications for thoracoscopy or video-assisted thoracic surgery (VATS)
      remain many. Wedge resection for lung nodules and lung biopsy remains the most
      frequently performed VATS procedure. Thoracoscopy has been very valuable as a
      diagnostic technique for undiagnosed lung nodules and infiltrates. Using VATS for
      therapeutic resection of metastatic nodules remains controversial with potential
      adverse consequences. Recently there has been a great deal of interest and
      enthusiasm for VATS techniques in emphysematous patients. Surgical procedures
      such as resection of apical blebs and bullae have become standard. However, VATS
      volume reduction is aimed at a different segment of the emphysema population. The
      theoretic and potential surgical role in emphysema is discussed. VATS offers
      decreased pain and shortened hospital stays for many disorders and as such
      remains a valuable tool for the surgeon.

PMID- 10401127
TI  - Video-Assisted Thoracic Surgery: Pulmonary Lobectomy.
AB  - Three techniques are currently used to perform video-assisted thoracic surgery
      (VATS) lobectomy:endoscopic hilar dissection, minithoracotomy, and mass stapling
      of the lobar pedicle at the hilum. The reported results demonstrate that VATS
      lobectomy is technically feasible and safe. In comparison with open lobectomy, it
      is associated with less postoperative pain and a reduced incidence of respiratory
      complications. Lymph node harvest is equal to that achieved at open surgery, and
      the available intermediate survival data for stage I or II bronchogenic carcinoma
      indicate that VATS resection is at least equal to open lobectomy. Preliminary
      laboratory data suggest that a VATS approach may result in decreased cytokine
      activation and cell immunity changes.

PMID- 10401128
TI  - Thoracoscopy for the Diseases of the Mediastinum Including Thymectomy for
      Myasthenia Gravis.
AB  - The majority of mediastinal structures and diseases can be approached
      thoracoscopically. Diagnostic procedures for anterior mediastinal masses,
      mediastinal cysts, and staging of lung cancer are well accepted. Small but
      increasing experience has been gained with posterior neurogenic tumors. Complete
      thymectomy for management of myasthenia gravis has been performed, but the
      efficacy of the procedure for this indication awaits longer-term results.

PMID- 10401129
TI  - Thoracoscopic Surgery of the Spine.
AB  - Anterior approach to the thoracic spine has been limited by the morbidity of a
      thoracotomy. By a thoracoscopic approach, a majority of thoracic spine procedures
      can now be performed from the anterior approach including diskectomy for
      herniation, release for correction of spinal deformity and corpectomy for tumor.
      Although experience is limited and results still short term, the thoracoscopic
      approach appears to be a promising one for the treatment of thoracic spine
      disease.

PMID- 10401130
TI  - Minimally Invasive Cardiac Surgery.
AB  - Minimally invasive techniques have recently been introduced into cardiac surgical
      procedures. Opportunities to make coronary artery bypass less invasive include
      elimination or minimization of both incisions and cardiopulmonary bypass. The
      current spectrum of minimally invasive coronary bypass procedures range from the
      minimally invasive direct vision coronary artery bypass procedure, which
      eliminates both the sternotomy incision and cardiopulmonary bypass, to the port
      access approach, which uses femoral-femoral bypass. Current procedures are also
      being used to make mitral and aortic valve surgery as well as saphenous vein
      harvest less invasive.

PMID- 10401131
TI  - Preface.

PMID- 10401132
TI  - The Conventional Management of Common Bile Duct Stones Before Laparoscopic
      Cholecystectomy.
AB  - The management of common bile duct stones traditionally required laparotomy for
      extraction. Recent advances have occurred in radiologic, endoscopic, and surgical
      techniques to broaden our options to treat patients with choledocholithiasis. The
      surgical approaches to the common duct stone have expanded to include open and
      laparoscopic techniques. Despite the increased surgical armamentarium, the
      principles of surgical management have not been altered. This chapter addresses
      the traditional surgical approaches to common bile duct stones.

PMID- 10401133
TI  - Preoperative, Intraoperative, and Postoperative Imaging Techniques for Diagnosis
      Leading to the Treatment of Common Bile Duct Stones.
AB  - All patients undergoing laparoscopic or open cholecystectomy are potentially
      harboring common bile duct (CBD) stones. Because laparoscopic cholecystectomy
      imposes a greater challenge for managing choledocholithiasis, the tests chosen to
      evaluate the CBD must consider the ability of the surgeon to manage these stones.
      Those who are skilled at laparoscopic CBD exploration or intraoperative
      endoscopic retrograde cholangiopancreatography (ERCP) may take the traditional
      approach of intraoperative cholangiography. Those who are not skilled at
      intraoperative management of choledocholithiasis, or for that matter laparoscopic
      intraoperative cholangiography, must carefully plan when and how to determine the
      presence of CBD stones. Preoperative imaging techniques include biochemical
      tests, plain film of the abdomen, oral cholecystography, ultrasonography (US),
      endoscopic US, intravenous cholangiography, ERCP, percutaneous transhepatic
      cholangiography, choledochoscopy, computed tomography, radioisotope imaging, and
      magnetic resonance imaging. Intraoperative imaging techniques include
      intraoperative US, intraoperative cholangiography, choledochoscopy, ERCP, and
      endoluminal US. Postoperative imaging techniques include preoperative techniques
      plus T-tube cholangiography and T-tube choledochoscopy.

PMID- 10401134
TI  - The Role of Endoscopic Retrograde Cholangiopancreatography in the Era of
      Laparoscopic Cholecystectomy.
AB  - The technique of endoscopic retrograde cholangiopancreatography (ERCP) and
      endoscopic sphincterotomy (ES), for removal of bile duct (BD) stones have been
      highly successful (>90%). The preoperative indications include cholangitis,
      worsening gallstone pancreatitis, patients with jaundice, and in those patients
      who have common bile duct stones seen on ultrasonography. Intraoperatively
      ERCP/ES has been used along with the placement of a papillotome through the
      cystic duct and papilla and performing a sphincterotomy in an antegrade fashion.
      The approach with the least complications is with the antegrade passage of the
      papillotome, and both techniques are efficient and safe in removal of proximal
      and distal BD stones. The postoperative indications for ERCP include retained
      common bile duct stones, bile duct injury, bile leak, and in patients who have
      developed a bile duct stricture. A success rate of 90% to 95% for complete
      removal of bile duct stones has been achieved. Overall, ERCP/ES is a highly
      effective procedure for removing bile duct stones, but it should be used only in
      selected patients preoperatively, intraoperatively, and postoperatively.

PMID- 10401135
TI  - Techniques and Cost of Common Bile Duct Exploration.
AB  - The introduction of laparoscopic techniques to treat biliary tract disease in the
      last decade heralded the beginning of a new age of surgery where strong emphasis
      is placed not only on the efficacy of the operation, but at least as importantly
      on the "side effects" of surgical intervention. Thus, the focus has recently
      centered on the application of minimally invasive and minimally damaging
      techniques to perform operations that heretofore had required laparotomy.
      Laparoscopic cholecystectomy (LC) itself is an excellent example of a procedure
      that produces an equivalent disease-related treatment endpoint, without the
      morbidity of previous "open" techniques. Laparoscopic treatment of common bile
      duct stones, while technically much more difficult than cholecystectomy, offers
      the same minimally invasive benefits to the patient without the necessity of
      laparotomy or secondary procedures such as endoscopic retrograde
      choledocholithotomy or sphincterotomy. Numerous techniques for laparoscopic
      common bile duct exploration (LCDE) have been developed. Each of them accesses
      the stones by one of two routes: through the cystic duct or through a
      choledochotomy. Both approaches are associated with equivalent success rates in
      removing stones, but the transcystic approach has the added benefit of being
      truly minimally invasive, as compared with choledochotomy. This report reviews
      the current state of the art of the transcystic approach to the laparoscopic
      treatment of choledocholithiasis.

PMID- 10401136
TI  - Laparoscopic Common Bile Duct Exploration By Choledochotomy.
AB  - Choledocholithiasis uncomplicated by acute ascending cholangitis is being treated
      by a two step approach involving two separate teams of specialized care resulting
      in more expense and potentiating possible complications. Laparoscopic common bile
      duct exploration by choledochotomy is a capable means of managing this problem in
      a one step fashion. The experience with 137 patients has resulted in a 94.1%
      success rate in technically clearing the common bile duct with a 2.2% retained
      stone rate all of which were removed by postoperative endoscopic retrograde
      cholangio pancreatography. Conversion to open procedure was in five patients
      (3.6%). Laparoscopic common bile duct exploration by choledochotomy depends on
      routine intraoperative fluorocholangiography (99.7% successful) and is especially
      useful with proximal stones or multiple, large stones.

PMID- 10401137
TI  - Laparoscopic Antegrade Sphincterotomy.
AB  - The authors describe the technique and results of laparoscopic antegrade
      sphincterotomy. The procedure was performed in 42 selected cases of
      choledocholithiasis. The indications for attempting laparoscopic antegrade
      sphincterotomy included impacted stones in the papilla, multiple common bile duct
      stones, one or more common hepatic or intrahepatic stones, dilated common bile
      duct requiring a drainage procedure, suspicion of papillary stenosis, whenever
      numerous fragments are found after lithotripsy, and as an adjunct procedure when
      the surgeon cannot completely remove all the stones in the bile ducts. No major
      complications or mortality was observed. One patient had a self-limited drop in
      the hematocrit and four patients presented with transitory mild hyperamylasemia
      that returned to normal levels in 72 hours. Laparoscopic antegrade sphincterotomy
      added an average of 17 minutes to the laparoscopic operation. The mean
      postoperative stay was 1.4 days. The results of this study conclude that
      laparoscopic antegrade sphincterotomy is an option of great therapeutic value for
      selected cases when drainage of the biliary tract concomitant to the treatment of
      choledocholithiasis is necessary.

PMID- 10401138
TI  - Future Treatment of Common Bile Duct Stones.
AB  - Management options for patients found to have common bile duct stones have
      expanded as a function of improved instrumentation and radiographic support.
      Technological advances initially lead to increased costs but eventually result in
      improved quality for patients. Controversy exists for patients with either soft
      clinical findings or stones found at the time of laparoscopic cholecystectomy. As
      laparoscopic common duct exploration becomes more widespread the need for
      perioperative ERCP will likely decrease; however, this will depend on the
      experience of the surgeons at a given institution. Common bile duct stones found
      at the time of laparoscopic cholecystectomy can be approached in a variety of
      different ways. The most commonly used methods are laparoscopic transcystic
      common bile duct exploration, laparoscopic choledochotomy with common bile duct
      exploration, open common bile duct exploration, laparoscopic antegrade
      sphincterotomy, and postoperative ERCP. In the future, the treatment goal of
      biliary lithiasis will be to accomplish cholecystectomy and removal of bile duct
      stones in a single stage. Advances in fiberoptic technology will make transcystic
      duct exploration more effective, but it is likely that sphincterotomy (antegrade
      or retrograde) will be used preferentially for the distally impacted stone.

PMID- 10401139
TI  - Laparoscopic Common Bile Duct Bypass Procedures.
AB  - The vast majority of benign obstructive processes of the biliary tract can be
      handled by simple clearance of the common bile duct. Malignant disease and
      complicated biliary tract problems may require a stenting procedure or a bypass
      of the obstructed segment. Most general surgeons have been trained to perform one
      of a number of bypass procedures of the biliary tract but the advent of
      laparoscopy has diminished the frequency with which many surgeons have the
      opportunity to perform this type of surgery. This section discusses several
      laparoscopic bypass procedures that have been highly successful in our hands as
      well as the results of our series.

PMID- 10401140
TI  - Legal and Ethical Considerations in Laparoscopic Surgery.
AB  - Legal and ethical obligations of the laparoscopic surgeon are explored, including
      such issues as the following: What is the standard care and when are we straying
      from it? What is proper informed consent? When is a new procedure "experimental"
      and which procedures need IRB approval before they can be performed on a patient?
      What is your liability when you assist, proctor, or provide access for someone
      else? What are the pitfalls of video documentation?, and How can lawsuits related
      to minimal access surgery best be prevented?

PMID- 10401141
TI  - Preface.

PMID- 10401142
TI  - Computed Tomography- and Magnetic Resonance Imaging: Guided Microtherapy.
AB  - This report describes techniques of computed tomography (CT) and magnetic
      resonance imaging (MRI) image-guided diagnosis and therapy. Fine-needle biopsy,
      interstitial tumor therapy, and chemical sympathectomy, as well as the treatment
      of chronic spinal diseases, including periradicular infiltration at irritated
      spinal nerve roots, percutaneous laser decompression of intervertebral disks, and
      intraspinal microendoscopic scar dissection after failed back surgery are
      described. To overcome specific drawbacks of CT application, we have evaluated
      technological prerequisites and feasibility of MRI guidance of interventional
      procedures, such as biopsy, aspiration of neoplasm, and local interstitial drug
      instillation. New MR-compatible needles, trocars/cannulae, endoscopes, and
      ancillary equipment were developed and evaluated in collaboration with industry.
      Sequences, study protocols, and the strategies of performing the procedure within
      the environment of an interventional MRI suite have been formulated. In 168
      patients, 204 interventions such as aspiration biopsy, peridural corticoid
      injection at spinal nerve roots, intratumoral ethanol instillation, chemical
      sympathectomy, and percutaneous laser decompression of herniated intervertebral
      disks were performed successfully. CT and MRI guidance of percutaneous and
      microendoscopic interventions provides a reproducible and precise means of
      instrument control. Aside from preoperative planning of the access trajectory,
      instruments can be placed under CT or MRI control and the therapeutic process can
      be monitored. Although MRI avoids the need for ionizing radiation and provides
      multiplanar multislice images with excellent soft tissue contrast, the
      representation of instruments and the resolution is currently inferior to that
      achieved by CT imaging.

PMID- 10401143
TI  - Developing Technology for Suspended Imaging for Minimal Access Surgery.
AB  - Some of the problems of performing laparoscopic surgery can be traced to the
      position and intrinsic qualities of the displayed video image. Conversion of the
      normal monitor screen image to a suspended image can reduce image-related
      difficulties. The principles of suspended image production are described and the
      potential for more flexible image positioning and enhanced depth perception is
      explained. A recently initiated research program is investigating design
      possibilities and conducting fundamental research into suspended image appraisal.

PMID- 10401144
TI  - Emerging Techniques for Optical Detection of Early Mucosal Cancer.
AB  - Most methods of optical detection of gastrointestinal cancer are aimed at
      improving the contrast between malignant lesions and normal or metaplastic
      tissue. Although almost any optical property of matter can theoretically be
      exploited in this manner, recent work has focused on the use of exogenous
      fluorescent substances or their metabolic precursors to provide this contrast.

PMID- 10401145
TI  - Needle Implantation Cryoprobes: Biophysical and Thermal Characteristics.
AB  - There has been increased recent interest in hepatic cryosurgery for primary and
      metastatic tumors in the liver. This has been realized through technological
      advances in intraoperative ultrasound monitoring and cryoprobe technology.
      Purpose-designed needle implantable cryoprobes have been developed to freeze deep
      seated tumors in the hepatic parenchyma. However, the biophysical and thermal
      characteristics of these implantable cryoprobes have not been studied. This
      article discusses the biophysical and thermal characteristics of recently
      developed high-efficiency, implantable needle cryoprobes that can be used
      laparoscopically. The cryolesion was formed along the whole length of the
      cryoprobe implanted into hepatic tissue. It was cylindrical in shape and extended
      8 mm beyond the tip of the cryoprobe after 20 minutes of freezing. During this
      period of freezing, the volume of the cryolesion increased in a near constant
      manner, but the diameter increased in a logarithmic fashion. In addition, single
      cycle freezing produced a larger cryolesion than a dual freeze cycle interrupted
      by a 5-minute thaw. Further, increasing the length of cryoprobe implantation
      increased the volume of the cryolesion, although the diameter was smaller. The
      rate of cooling at the tip of the cryoprobe was also faster with partial
      implantation of the cryoprobe than with complete implantation. The cooling rate
      varied vertically along the length of the cryoprobe, as well as horizontally from
      the cryoprobe.

PMID- 10401146
TI  - Technology for Radiofrequency Thermal Ablation of Liver Tumors.
AB  - In this review the usefulness of percutaneous radiofrequency interstitial thermal
      ablation of liver cancer has been evaluated. The technique has been recently
      improved by using modified needle electrodes (eg, expandable needle, cooled
      needle) that allow the ablation of tumors of less than 3.5 cm in diameter in only
      one session. Tumor necrosis has been shown by imaging techniques such as dynamic
      or spiral CT, MRI, selective hepatic angiography, ultrasonography-guided fine
      needle biopsy, and pathologic studies. Both in hepatocellular carcinoma and liver
      metastases, a complete necrosis has been obtained in more than 80% of the cases.
      The complication rate has been low without any mortality. In a series of
      hepatocellular carcinoma followed for a mean time of 23 months, median survival
      time has been 44 months, whereas recurrence rate was similar to that observed
      after surgery or ethanol injection. In two small series of metastases, the
      percentage of disease-free survivors at 1 year ranged from 11 to 66%. In
      conclusion, radiofrequency interstitial thermal ablation is a safe and effective
      technique for ablation of liver tumor; however, its precise role in the treatment
      of liver metastases needs to be defined.

PMID- 10401147
TI  - Laparoscopic-Assisted Surgery.
AB  - Laparoscopy has changed our approach to surgery, instrumentation, and training.
      Remote control surgery with robotics and telematics is a future possibility.
      Laparoscopic surgery still has limitations not least the manual assessment of
      fixity and extraction of tumors with concern for oncological efficacy and port
      site seeding of cancer. We report an Intromit (Medtech Ltd, Dublin, Ireland) hand
      access device, allowing insertion of a hand and instruments while maintaining
      pneumoperitoneum. It has been used for splenectomy, colectomy, adhesiolysis,
      rectopexy, and fundoplication. It is hoped that this will facilitate laparoscopic
      cancer surgery, encourage surgeons to develop and engage in more advanced
      laparoscopic cancer procedures, and maintain many of the advantages of
      laparoscopic surgery including cost benefits.

PMID- 10401148
TI  - Laparoscopic Intraoperative Ultrasonography, Color Doppler, and Power Flow
      Application.
AB  - The applications of color Doppler and power flow imaging for laparoscopic
      intraoperative ultrasonography (LIOU) are discussed. Basic principles concerning
      Doppler, color Doppler imaging (CDI), and power flow (PF) are briefly reviewed,
      and a number of representative examples of imaging are provided. LIOU is
      progressively gaining importance, not only for screening of the biliary tract,
      but in particular, for staging laparoscopy in patients with gastrointestinal
      cancer. The CDI technology that was developed relatively quickly is now in
      widespread use in diagnostic ultrasound, particularly for vascular surgery. CD
      options are no longer restricted to the expensive high-end ultrasound scanners,
      but are available in the majority of modest duplex systems with limited
      additional costs. Ongoing developments in ultrasound technology have resulted in
      the introduction of an alternative option to mean frequency-based CD ultrasound,
      ie, the PF. There are several advantages that emanate from the combination of B
      mode ultrasound with CDI and/or PF. These include (1) rapid identification of
      anatomical structures, ie, vessels, ducts, tissue spaces, and cysts; (2)
      detection of small vessels that are difficult or impossible to recognize by B
      mode scanning alone; (3) more accurate assessment of vascular
      encasement/involvement by tumor and a precise display of major vessels
      anatomically related to the tumor; (4) real-time guidance for safe parenchymal
      dissection of solid organs with identification and preservation of blood supply;
      (5) precise guided needle biopsy or puncture; and (6) visualization of bile flow
      in common bile by PF. This has the potential to enable dynamic flow studies of
      the function of the papilla of Vater in the near future.

PMID- 10401149
TI  - Technology for Psychomotor Skills Testing in Endoscopic Surgery.
AB  - Psychomotor research is essential for aptitude-based selection of surgical
      trainees and sound surgical practice. Two microprocessor-controlled psychomotor
      testers were developed to evaluate psychomotor skills related to endoscopic
      surgery. Dundee Endoscopic Psychomotor Tester (DEPT) measures single-handed
      performance in an endoscopic environment and therefore it can be used to evaluate
      differing abilities between the right and left hand. Advanced Dundee endoscopic
      Psychomotor Tester (ADEPT) measures two-handed performance, and consequently it
      can be used to assess coordinated bimanual endoscopic manipulations. Psychomotor
      testers provide real-time objective scoring systems that have several aspects of
      face validity to real endoscopic environment. Studies on medical students have
      confirmed that objective evaluation of task performance in an endoscopic field is
      feasible and have documented differences in psychomotor abilities between
      subjects.

PMID- 10401150
TI  - Shape Memory Stents for Biliary and Esophageal Strictures.
AB  - Metallic self-expanding stents can now be used to palliate biliary and esophageal
      malignancies. Their ease of insertion and wide diameter, resulting in improved
      long-term patency, make them the palliative method of choice for appropriate
      patients. These stents are now available in covered versions, improving their
      longevity and ultimately possible allowing for removal and reinsertion and wider
      use in benign strictures. This review details appropriate use and results with
      metallic stents and comparison with standard methods.

PMID- 10401151
TI  - [High pressure liquid chromatographic methods for compendium of purity tests].
AB  - The paper is addressed to the institute of Pharmaceutical Chemistry, Budapest, on
      the 50th anniversary of its foundation, paying tribute to Prof. Antal Vegh, the
      first director of the Institute and his first deputy dr. Laszlo Auber and all the
      members of the Staff having merit in developing the research activity at the
      Department. After surveying the early papers published from the fifties through
      the seventies, concerning the profile of drug purity control, the factors
      increasing HPLC selectivity are shortly reviewed. In the concluding part of the
      paper, some recent results, as HPLC purity control methods suitable for
      compendial purposes (methylxanthines, opium alkaloids, tropane-alkaloids,
      enantiomer purity control of different drug compounds on glycoprotein and
      chirelcel columns) are summarized.

PMID- 10401152
TI  - [In vitro interaction of selegiline, riboflavin and light. Sensitized
      photodegradation of drugs. I].
AB  - Selegiline (Deprenyl, Jumex, Movergan etc.) is primarily used in the therapy of
      Parkinson's disease due to its neuroprotective, antidepressive and oxidative
      stress-preventing activities. Its prime effect is based upon the inhibition of
      the monoamine oxidase enzyme (MAO-B). The cofactor of this flavoenzyme is
      riboflavin (vitamin B2). Riboflavin, on the other hand, is an effective
      photosensitizer, with the capacity to promote the photodegradation of molecules
      (drugs, biological systems) which are otherwise stable against daylight. It has
      been studied whether this property of riboflavin is expressed against selegiline
      as well. This experiments proved that in the presence of riboflavin, both
      daylight and the light of daylight-lamps are sufficient to significantly
      decompose selegiline. The major decomposition product is methamphetamine.

PMID- 10401153
TI  - [Microequilibrium of drug molecules].
AB  - Protonation macro-, micro-, and submicro constants are physico-chemical
      parameters of crucial importance, concerning the fate of bio-, drug, and narcotic
      drug molecules in the body and in protic solvents. The most important
      characteristics, relationships, applications and biological significance of these
      parameters are reviewed, using acetylcysteine and cysteine, as examples. The
      mucolytic effect of acetylcysteine, an active principle in numerous drugs, is
      interpreted in terms of protonation state of the molecule and its thiolate site.
      Microscopic protonation constants of acetylcysteine, data that have not
      previously appeared, are also reported.

PMID- 10401154
TI  - [Preparation and characterization of potential antineoplastic agents].
AB  - A parallel combinatorial library of over sixteen hundred compounds has been
      designed and synthesized for the development of new potential peptidomimetic
      protein tyrosine kinase (PTK) inhibitor leads that is aimed for intervening with
      the substrate binding site of the pp60c-src enzyme. The new structures were based
      on known PTK inhibitors having at least two variously substituted aromatic
      moieties attached by spacer groups of different length and flexibility. Eleven
      bis-aryl type inhibitory compounds were found in the range of 18-100 micromolar
      IC50 concentrations from combinations of twelve different substituents. Molecular
      modeling of the active compounds showed a characteristic distance of 13-14 A
      between the farthest sp2 carbon atoms of the two aromatic rings. Conformational
      analysis of several peptide substrates recently found for pp60c-src PTK [5,6,7]
      showed that the energy minimized conformers had the same distance between two
      aromatic moieties. Several compounds in the library not only showed remarkable
      PTK inhibitory activity but also a significant apoptosis inducing effect on HT-29
      human colon tumor cells.

PMID- 10401155
TI  - [Investigation of the physico-chemical properties of deramciclane (EGIS-3886), a
      new anxiolytic compound. Ionization and lipophilicity].
AB  - Ionization and lipophilicity of deramciclane hydrogenfumarate (EGIS-3886), a
      novel anxiolytic compound being under clinical trial were investigated. The
      aqueous pKa value and the octanol/water partition coefficient (logP) have been
      determined using validated analytical approaches. The favourable pharmacokinetic
      properties of deramciclane are interpreted on the bases of its ionization
      capability and extreme high lipophilicity.

PMID- 10401156
TI  - [Novel chiroptical methods in pharmaceutical analysis].
AB  - Chiroptical spectroscopy, and its double and triple hyphenated combinations with
      UV-VIS spectroscopy and/or separation techniques constitute great progress in
      pharmaceutical analysis, of which five recently developed methods are surveyed
      here, as follows: The determination of enantiomeric purity by double, CD/UV
      detection without, and with the latter one provides enhanced sensitivity and
      selectivity. The determination of chromatographic peak homogeneity, by double
      detection, and peak slicing by recording. The separation, identification and four
      stereoisomers of doubly chiral compounds, by HPLC separation on chiral column,
      and optical-chiroptical detection.

PMID- 10401157
TI  - [Synthesis and reactivity of debenzorutaecarpine derivatives].
AB  - A series of 7,12-dihydropyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-ones was
      prepared by Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4H
      pyrido[1,2-a]pyrimidin-4-one s. Quantumchemical calculations (ab initio and AM1)
      indicate that position 3 of 7,12-dihydro-pyrimido[1',2';1,2]pyrido[3,4-b]indol
      4(6H)-one can be involved in electrophilic substitutions, while position 2 is
      sensitive towards nucleophilic attack. Bromination of 6-methyl-7,12
      dihydropyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-o ne (16) with bromine
      afforded 3-bromo derivative (25), which was reacted with cyclic amines to give 2
      amino-7,12-dihydro-pyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-ones (26-30) in an
      addition-elimination reaction. Vielsmeier-Haack formylation of compound (16) give
      12-formyl (31) and 3,12-diformyl (32) derivatives (an N-formyl-1-aza derivative
      of nauclefidine alkaloid (34) at 60 degrees C and 100 degrees C, respectively.
      3,12-dformyl compound (32) was oxidized to 3-carboxyl derivative (33). The
      quaternary salt (35), obtained from compound (16) with dimethyl sulphate,
      suffered a ring opening on the action of aqueous sodium hydroxide. The new
      compounds have been characterized by elemental analyses uv, 1H nmr and in some
      cases by 13C ruler, CD spectra and X-ray investigations.

PMID- 10401158
TI  - [Characterization of the kinetics of ester hydrolysis at the submolecular level].
AB  - Ester-type compounds are important drugs as directly binding active principles,
      but also, as prodrugs that provide the acting agent after hydrolytic
      decomposition. The profound characterisation of the kinetics of ester hydrolysis
      is therefore equally important to interpret and design metabolic processes and
      prodrug-->drug transitions. The extramolecular factors (temperature, ionic
      strength, solvent etc.) influencing the rate constant values have extensively
      been studied. Contrary to that, few data can be found on the effect and magnitude
      of the intramolecular factors (substituent effect, neighbour-group protonation).
      This paper reports the introduction and determination of microscopic rate
      constants of ester hydrolysis, a new physicochemical parameter, which is defined
      in the sense of the protonation state of the basic site(s) adjacent the ester
      group. The microscopic rate constants of phenylalanine-methyl-ester hydrolysis
      are determined and interpreted. Also, the principles to characterise the rate of
      monobasic double esters at the submolecular level, exemplified by cocaine, are
      established.

PMID- 10401159
TI  - [Lipase-catalyzed resolution of 2-dialkylaminomethylcyclanols. Comparative
      studies].
AB  - Extensive lipase screening was performed in relation to the asymmetric
      acetylation of rac-2-dialkylaminomethylcyclanols (1-6). The lipase PS- and
      Novozym 435-catalysed resolutions of 1-6 with various vinyl esters were studied
      in different organic media. High enantioselectivity (E > 200) was observed when
      vinyl acetate was used as acylating agent and diethyl ether as solvent. The
      (1R,2R) enantiomers react preferentially in the case of the cis isomers, whereas
      the (1R,2S) enantiomers do so in the case of the trans counterparts. The
      enantioselective acetylation of the five-membered amino alcohols (1, 3 and 5)
      proceeded much more rapidly than that of the six-membered amino alcohols (2, 4
      and 6). The reaction rates were also affected by the solvent and by the quantity
      of the enzyme.

PMID- 10401160
TI  - [Pre- and postsynaptic action of the ATP-dependent K+-channel-(K+ATP)-opener
      pinacidil in rabbit pulmonary artery].
AB  - Low frequency (2 Hz) of electrical depolarisation induced [3H]noradrenaline
      ([3H]NA) release has been measured from the isolated main pulmonary artery of the
      rabbit in the presence of uptake blockers (cocaine, 3x10(-5)M and corticosterone,
      5x10(-5)M), with parallel measurements of post-junctional contractile responses.
      The K+ATP-channel opener pinacidil (10(-6)-10(-4)M), slightly potentiated the
      nerve-evoked release of [3H]NA which failed to show close concentration
      dependency. Large concentration of pinacidil (10(-4)M) increased the ratio of
      [3H]NA release from 0.99 +/- 0.02 to 1.28 +/- 0.05 (P < 0.0005). On the other
      hand, pinacidil inhibited the nerve-evoked contractions in a concentration
      dependent manner. 10(-4)M caused nearly 70% inhibition of contractile response.
      The pre- and post-junctional effects of pinacidil were studied under the
      following experimental conditions: 1) exogenously applied 1-NA; 2) excess K+; 3)
      'L-type' Ca(2+)-channel activation (BAY K 8644); K(+)-channel inhibition (4-AP);
      and 5) Na(+)-pump inhibition/reactivation. Pinacidil (10(-4)M) retained its
      marginal NA-release stimulatory effect in all cases. However, pinacidil inhibited
      the contraction of smooth muscle, although to a different extent, in all of the
      experimental conditions used in our study.

PMID- 10401161
TI  - Health surveillance: changing needs, constant function.

PMID- 10401162
TI  - A tuberculosis screening and chemoprophylaxis project in children from a high
      risk population in Edmonton, Alberta.
AB  - Current recommendations for tuberculosis control are to screen high risk
      populations and provide chemoprophylaxis for those infected. In Edmonton,
      Alberta, one strategy has been to identify and provide TB skin tests to newly
      arrived immigrant school age children from TB endemic areas. The difficulty has
      been in identifying these children in the school population. This article
      describes a process tried in 1993-94 to find a better approach and to determine
      the outcome of a concentrated effort at screening and follow-up of this
      population. Using this method, 1,146 students were TB skin tested using 5tu PPD:
      15% showed significant reactions (10 mm), 89% were offered chemoprophylaxis, and
      68% of those offered (84% of those accepting) completed 9 months of
      chemoprophylaxis. The success of this process was dependent on the dedicated
      follow-up provided by the specialty public health clinic devoted to the
      prevention and treatment of tuberculosis.

PMID- 10401163
TI  - [Epidemiological study of a tuberculosis case in a large manufacturing enterprise
      in Quebec].
AB  - OBJECTIVES: To determine the prevalence of tuberculosis infection related to a
      case of pulmonary and laryngeal tuberculosis in a workplace and to study PPD
      predictors. METHODS: The Mantoux skin test (PPD) was offered to all potentially
      infected contacts. Participants were asked to answer a questionnaire. RESULTS:
      Among 112 exposed employees, 92 (82.1%) were tested. At the 5 mm level, 65.2% of
      employees had positive tuberculin skin test (PPD). By controlling prior BCG and
      the degree of exposure, it showed a positive association between age and PPD (RC:
      3.5; 95% CI: 1.25-10.03). When age and BCG were controlled, high exposure was
      statistically associated with PPD results (RC: 5.6; 95% CI: 1.25-24.68).
      CONCLUSION: The observed prevalence rate is probably related to the fact that the
      index case was very infectious and had contact in an enclosed area over a long
      period of time before withdrawal from work.

PMID- 10401164
TI  - An outbreak of mumps among young adults in Vancouver, British Columbia,
      associated with 'rave' parties.
AB  - In early 1997 an unexpectedly high number of cases of mumps was reported in
      Vancouver, British Columbia. METHODS: A case control study was conducted to
      address four objectives: 1) Describe the outbreak and the population at risk, 2)
      examine the impact of mumps on this population, 3) identify personal risk factors
      for infection, and 4) test the hypothesis that social gatherings, 'rave' parties
      in particular, were a risk factor in this outbreak. RESULTS: Mumps infection was
      associated with: attending a rave party [OR = 17; 95% CI: 2.7-710], residing in
      Vancouver [OR = 3.7; 95% CI: 1.4-10], and contact with a person with mumps [OR =
      13; 95% CI: 2-552], during the 'exposure' period. Vaccine effectiveness,
      ascertained by self-reported immunization status, was 80% [95% CI: 29%-96%].
      CONCLUSIONS: Attendance at rave parties was associated with mumps infection
      during this outbreak. Many persons aged 17-40 may remain susceptible to mumps; in
      BC these persons are eligible for one dose of MMR and should be encouraged to be
      vaccinated.

PMID- 10401165
TI  - Non-nominal HIV surveillance: preserving privacy while tracking an epidemic.
AB  - OBJECTIVE: To enhance HIV surveillance within a non-nominal provincial testing
      system. METHODS: Confirmatory HIV tests from a provincial laboratory were
      analyzed during 1995 and 1996. Enhancements included elimination of repeat
      positive tests for the same individual using automated matching of non-nominal
      identifiers and nurse call-back of health care providers, completion of missing
      information through call-back and connection of providers with resources for
      patient care. RESULTS: Forty-seven percent of 2,683 reactive HIV tests were
      identified as duplicates for the same individual, meaning that 1,401 people
      tested positive for the first time. From laboratory test data to enhanced
      unduplicated data after call-back, the proportion of tests for which risk and
      ethnic information was unknown dropped from 37% to 11% and from 64% to 18%
      respectively (p < 0.0001). CONCLUSIONS: Enhanced non-nominal surveillance for HIV
      is a practical means of marrying the needs of public health for epidemiological
      information and the rights of patients to privacy.

PMID- 10401166
TI  - Cost effectiveness of Streetworks' needle exchange program of Edmonton.
AB  - OBJECTIVE: To conduct a cost-effectiveness analysis of the Edmonton Streetworks
      needle exchange program, in terms of the additional cost per HIV infection
      averted. The main outcome measures were needle use with and without Streetworks,
      HIV cases averted, and program costs. METHODS: We conducted interviews and HIV
      saliva tests on a sample of street-involved intravenous drug users (IDU) who are
      regular Streetworks' clients. Outcomes were used in a cost-effectiveness model.
      RESULTS: It is projected that the program has a cost-effectiveness of $9,500
      (Canadian) per HIV infection delayed for one year. CONCLUSIONS: The discounted
      cost per case averted is less than the cost of a case of AIDS. Continuing the
      program is a dominant strategy.

PMID- 10401167
TI  - The relationship between E. coli indicator bacteria in well-water and
      gastrointestinal illnesses in rural families.
AB  - OBJECTIVES: To determine the relationship between consumption of E. coli
      contaminated well-water and gastrointestinal illness in rural families. METHODS:
      One hundred and eighty-one families with well-water as a drinking source
      participated in a one-year follow-up study. Water was tested for E. coli bacteria
      and health outcomes were monitored for house-hold members. RESULTS: E. coli in
      well-water was significantly associated with gastrointestinal illness in family
      members, however the relationship was modified by the distance from the septic
      tank to the well. E. coli had an odds ratio of 2.16 [95% CI 1.04, 4.42] if the
      septic tank was greater than 20 metres from the well and 0.46 [95% CI 0.07, 2.95]
      if the septic tank was within 20 metres. CONCLUSIONS: Consumption of contaminated
      well-water is associated with gastrointestinal illness. E. coli can be a useful
      marker for detecting wells that pose a potential public health problem in rural
      areas.

PMID- 10401168
TI  - Birth cohort effects underlying the increasing testicular cancer incidence in
      Canada.
AB  - PURPOSE: To examine the pattern of testicular cancer incidence by age, time
      period and birth cohort since 1969 in Canada. METHODS: In addition to analyses of
      the secular trends by age group and birth cohort separately, an age-period-cohort
      model and the submodels with standard Poisson assumptions were fitted to the
      data. RESULTS: The overall age-adjusted incidence of testicular cancer increased
      in Canada, from 2.8 per 100,000 males in 1969-71 to 4.2 in 1991-93. The younger
      age groups showed much higher absolute incidence rates in the recent period
      compared with those in the early period. Age-period-cohort modelling of data
      restricted to males aged 20-84 years suggested that the observed increase in
      testicular cancer could be largely attributed to a birth cohort effect. A steady
      increase in risk was observed among men born since 1945; those born between 1959
      and 1968 were 2.0 (95% CI, 1.5-2.6) times as likely to develop testicular cancer
      as those born between 1904 and 1913. CONCLUSION: The risk of testicular cancer
      has increased over time and changing exposure to environmental factors early in
      life may be responsible for this.

PMID- 10401169
TI  - Violence exposure and mental health of adolescents in small towns: an exploratory
      study.
AB  - This study explores the impact of violence exposure on the mental health of the
      adolescents in a rural small town. A structured questionnaire was used to survey
      347 adolescents. Violence experienced and witnessed by the adolescents at school,
      in the neighbourhood, and at home was measured. Mental health was represented by
      the psychiatric symptoms, depression level, and self-esteem. The level of
      violence perpetrated by the adolescents was also explored. Results of the
      multiple regression analysis show that adolescents who have been exposed to more
      violence, either as a victim or as a witness, report more psychiatric symptoms,
      higher levels of depression, and more problems of self-esteem. Being a witness of
      violence also contributes significantly to the variance of violence committed by
      the adolescents. The implications of the findings to violence prevention are
      discussed in the conclusion.

PMID- 10401170
TI  - Sexual partnering and risk of HIV/STD among Aboriginals.
AB  - OBJECTIVE: To examine the contribution of patterns of sexual partnering to the
      spread of HIV/STD infection between communities. METHODS: 651 randomly selected
      Aboriginals from 11 reserve communities in Ontario were interviewed. This
      analysis included those who had sex in the previous 12 months. Descriptive
      statistics and multivariate analyses identified associations with patterns of
      sexual partnering. RESULTS: 22% reported having partners from both within and
      outside the community, 51% from within only, and 27% from outside only. Those
      with partners from both within and outside were more likely to be male,
      unmarried, from a remote community, have more sexual partners and perceive that
      their behaviour placed them at higher risk of HIV/STD infection. They were least
      likely to perceive their community to be at risk from their behaviour.
      CONCLUSIONS: Findings suggest that Aboriginal communities are not insulated and
      that HIV could spread rapidly if introduced.

PMID- 10401171
TI  - Incidence of fetal alcohol syndrome in northeastern Manitoba.
AB  - The incidence of fetal alcohol syndrome (FAS) in northeastern Manitoba was
      investigated by examining all 745 live births occurring in Thompson General
      Hospital in 1994. Birth records were screened with criteria designed to capture
      all potential FAS cases. Cases were then eliminated if follow-up records
      indicated the child was not developmentally delayed or no longer had the small
      head or body size identified at birth. Cases still meeting criteria were
      personally examined. Five cases of FAS were identified among the 46% of eligible
      children screened at age 2, roughly an incidence of 7.2/1,000. However, because
      only 46% of the high risk cases were personally examined, incidence could be as
      high as 14.8/1,000. Only 1/5 FAS cases had been identified prior to our
      investigation. The results indicate the incidence of FAS in northeastern Manitoba
      is very high and that much greater effort needs to be made in its prevention and
      early detection.

PMID- 10401172
TI  - Children's feeding programs in Atlantic Canada: reducing or reproducing
      inequities?
AB  - This study analyzed, through case studies of day-to-day observations and
      interviews with recipients and operators, the operations of nine children's
      feeding programs in Nova Scotia, New Brunswick, and Newfoundland. We found that
      children's feeding programs result in the stigmatization of participants and
      families, despite an ideology of equality. Most programs adopt a family
      substitution role in the lives of children they serve and function in a way that
      excludes parental participation. Programs also transmit a hidden curriculum to
      children that teaches them how to behave and how a 'proper' family functions. We
      found that the professionalization of food and nutrition, a desire for an
      expanded client base, and dependency creation through the provision of other
      material goods, permit programs to exert increasing institutional control over
      recipients, a process we, following Illich, call the dragnet. While these
      programs may be meeting some nutritional needs in a few poverty-stricken
      children, they ultimately reproduce, rather than reduce, inequities.

PMID- 10401173
TI  - Validation of self-reported transfusion histories in renal dialysis patients.
AB  - The purpose of this analysis was to assess the validity of self-reported
      transfusion histories in dialysis patients. Using data from a cross-sectional
      study of a dialysis population being investigated for hepatitis C virus (HCV)
      infection, the correspondence between self-reported transfusion history and
      transfusion records was explored. Demographic data and dialysis histories were
      examined in relation to the accuracy of self-reports. Overall, the questionnaire
      data and the blood bank records agreed for 89% of participants. The Kappa
      statistic was 0.72 (95% CI: 0.61, 0.83) indicating an acceptable level of
      agreement. The effect of non-differential exposure misclassification on the risk
      estimates for transfusion history as a determinant of HCV infection is
      demonstrated. Exploring the discrepancies between self-reports and documented
      transfusion histories underlines the need to communicate clearly medical
      interventions in chronically ill patients. Additionally, it suggests that studies
      into transfusion-acquired blood-borne pathogens should use all available
      information sources to establish exposure.

PMID- 10401174
TI  - Cold/flu knowledge, attitudes and health care practices: results of a two-city
      telephone survey.
AB  - The purpose of this paper is to describe knowledge, attitudes and practices of
      cold and flu self-care and health care utilization, and to identify the
      predictors of health care utilization for the cold and flu among residents of
      London and Windsor. Using a random digit dialing survey method, 417 residents
      were interviewed between November-December, 1993 and February-March, 1994. This
      survey revealed good knowledge about colds and flu and understanding of
      appropriate physician visits. Only seven percent reported a doctor visit for
      their last cold. Socio-demographic, health status, attitude and knowledge level
      variables were subjected to a logistic regression analysis to identify which
      variables predicted self-reported physician visits. Only attitudes and health
      status showed statistically significant log odds (3.6 and 1.5, respectively). In
      summary, consistent with other studies, attitude and health status, not
      knowledge, appear to be significant predictors of physician visits for colds/flu.

PMID- 10401175
TI  - Formative evaluation of an Inspection Certificate Program (ICP) pilot in Toronto.
AB  - The inspection certificate program consists of food establishments voluntarily
      posting a certificate to inform patrons that inspection reports can be accessed
      from operators or the public health department. A three-month pilot program was
      evaluated for program improvement purposes. Only 65% of the selected operators
      were willing to participate, which suggests a challenge to fully implementing the
      program. Thirty-nine randomly selected restaurant operators participated. Most
      operators posted the certificate at the front entrance, and patrons indicated
      that reports were clear. Operators were supportive of the program. Some operators
      reported that the program was good for business and offered suggestions to
      improve it. A total of 583 requests for reports were made which suggests that the
      program empowered patrons to request reports, mostly from operators. Most patron
      evaluation forms came from a few operators that had no deficiencies, which limits
      generalizability.

PMID- 10401177
TI  - Assessing the effect of and support for youth involvement in public decision
      making: a report on nine case studies.

PMID- 10401176
TI  - Communication courses in Canadian graduate programs in health promotion.

PMID- 10401178
TI  - [Overdue term of pregnancy: current concepts].

PMID- 10401179
TI  - [Diagnostic and therapeutic management of postpartum hemorrhage].

PMID- 10401180
TI  - [Screening for Chlamydia trachomatis during gynecological consultation by
      endocervical sampling (PCR technique)].

PMID- 10401181
TI  - [Impact of adenomyosis on results of endometrial ablations].
AB  - The authors report the results of a retrospective series concerning 121 patients
      who presented abnormal uterine bleeding resistant to progestogen therapy. These
      patients were adenomyosis carriers and who underwent loop endometrial ablation.
      Over a maximum period of 8 years, the success rate was 56% following one
      endometrial resection and 67% following one or two resections. The study recorded
      a repeat resection level of 11%. Seventeen hysterectomies (19%) were performed
      because of the recurrence of abnormal uterine bleeding. These results are
      comparable to those observed in endometrial ablation performed for menorrhagia,
      all benign etiology included. Adenomyosis does not appear to be a factor in the
      failure of endometrial ablation, except in the case of deep adenomyosis which is
      difficult to diagnose pre-operatively.

PMID- 10401182
TI  - [Hidden factors of breast cancer: recommended follow-up for hyperplasia or
      carcinoma in situ].
AB  - After the diagnosis of breast epithelial hyperplasia or carcinoma in situ, the
      clinical follow-up must take into account several parameters. First, the adequacy
      of the diagnostic and the therapeutic approach is to be evaluated. Second, the
      patient must be informed of her risk of subsequent breast cancer. In such a
      protocol, one can recommend a program of close follow-up in an attempt at early
      detection. An annual clinical examination combined with a mammographic and a
      sonographic exam is considered as the method of choice. In between annual check
      ups, clinical exam is encouraged. The potential benefits of magnetic-resonance
      imaging in these circumstances is currently evaluated. In rare instances, the
      absolute risk of breast cancer is so high that a prophylactic mastectomy can be
      considered.

PMID- 10401183
TI  - [Action of SERM and SAS (tibolone) on breast tissue].
AB  - SERMs are developed in HRT in order to provide the beneficial effects of
      estradiol on bone and the cardiovascular system. SERMs are antiestrogens and
      their properties depend upon the pharmacological class they belong to. Tibolone
      is a progestin with mixed properties. Our studies on breast cells in vitro
      demonstrated that it behaves as a progestin in these cells. The clinical data
      obtained with these various therapies on breast are presented.

PMID- 10401184
TI  - [When daughter becomes mother].
AB  - The mother-daughter link is more complex than at first appears. Its influence is
      in fact so crucial as to be able to determine factors such as access of daughter
      to fertility and the gender of the children she will bear.

PMID- 10401185
TI  - [Complications of laparoscopy in gynecology].
AB  - In a review of the literature the authors describe the complications encountered
      during gynecological laparoscopy, insisting on the preparation phase, the
      conversion to laparotomy and the death cases. Vascular, digestive and urinary
      lesions, as well as anesthetic difficulties are discussed, aiming at a better
      prevention. Early recognition of the problem is an important prognostic factor
      for these patients.

PMID- 10401186
TI  - [Preliminary evaluation of a histocytological association predicted in a single
      sample of uterine exploration via a modified pipette: Mark II pipette].
AB  - The pipelle has become the sampling tool of choice for histological detection of
      endometrial adenocarcinoma. Some practitioners still prefer cytological sampling.
      The distal extremity of the pipelle has been modified to allow removal of both
      types of samples simultaneously. The aim of this preliminary study was to
      evaluate the feasibility of this method. A positive agreement between
      histological and cytological results was found in 10 out of the 12 cases
      examined, among which an adenocarcinoma was positively detected. A prospective
      study on larger size must confirm these first findings. The new modified pipelle
      (Pipelle Mark II) offers a possible approach for reduction of false negatives.

PMID- 10401187
TI  - Onchocerciasis.

PMID- 10401188
TI  - Evaluation of serum levels of IgG subclasses and anti-ribosyl-ribitolphosphate
      IgG and IgG2 in children with Haemophilus influenzae b meningitis.
AB  - In 40 children with Haemophilus influenzae b (Hib) meningitis, we determined
      serum levels (mg/dl) of IgG subclasses using the radial immunodiffusion method;
      67.8 per cent of these children were less than 24 months old. In 14 children of
      the sample we measured serum IgG and IgG2 anti-ribosyl-ribitolphosphate (anti
      PRP) (by enzyme-linked immunosorbent assay, ELISA) in the acute and convalescent
      phases of the disease. Lower IgG2 levels than those of the control group were
      obtained in all age ranges: 3-12 months, 1-2 years (p < 0.01), and 2-5 years (p <
      0.001). IgG4 was also present in lower levels in patients of all age ranges (p <
      0.05, p < 0.001, and p < 0.01 respectively). Serum levels of IgG anti-PRP and
      IgG2 anti-PRP measured were very low in the acute phase of the disease in all age
      ranges and there was no notable increase in levels during the convalescent phase
      of the disease. This result indicates that children less than 24 months old do
      not produce sufficient levels of IgG and IgG2 anti-PRP even after Hib meningitis.

PMID- 10401189
TI  - Human fascioliasis in Egyptian children: successful treatment with
      triclabendazole.
AB  - Human fascioliasis (HF) is an increasingly recognized public health problem in
      Egypt. During the past two years we diagnosed HF in 40 Egyptian children.
      Diagnosis was based on some or all of the following criteria: fever, tender
      hepatomegaly and high eosinophilia (febrile eosinophilic syndrome), presence of
      Fasciola hepatica eggs in stools, and/or serodiagnosis using the indirect
      haemagglutination test (IHAT). Eight of the 40 children had failed to respond to
      previous treatment with praziquantel. All children were treated with
      triclabendazole in a dose of 10 mg/kg as a single oral dose. Within 2 months, 31
      children (78 per cent) were cured as evidenced by clinical well-being,
      normalization of eosinophil counts, Fasciola antibody titres, and absence of
      Fasciola hepatica eggs in stools. The remaining nine cases achieved clinical and
      laboratory cure after a second dose of triclabendazole. No side-effects were
      encountered in any of the cases. We conclude that triclabendazole is an
      effective, well-tolerated, easy to administer drug that should be considered in
      HF.

PMID- 10401190
TI  - Ankle clonus and thiocyanate, linamarin, and inorganic sulphate excretion in
      school children in communities with Konzo, Mozambique.
AB  - We examined 397 school children for ankle clonus in five communities in three
      districts affected by konzo, spastic paraparesis associated with cassava
      consumption. From a subsample of 131 children, we analysed urine specimens for
      urinary thiocyanate, linamarin, and inorganic sulphate. The proportion of
      children with clonus varied between sites, ranging from 4 to 22 per cent.
      Geometric mean thiocyanate, linamarin, and inorganic sulphate concentrations were
      163 and 60 mumol/l and 4.4 mmol/l, respectively. Children with ankle clonus had
      higher urinary thiocyanate concentrations. We recommend prevention to reduce
      cyanide exposure and further monitoring of cyanide exposure and neurological
      damage in these communities.

PMID- 10401191
TI  - Isolation pattern and clinical outcome of genital mycoplasma in neonates from a
      tertiary care neonatal unit.
AB  - The role of genital mycoplasma in perinatal mortality and morbidity has been
      debated. This study was undertaken to determine the frequency of isolation of
      genital mycoplasma and evaluate its association with clinical outcome. Sixty-six
      cerebrospinal fluid (CSF) and 49 tracheal aspirates taken from 100 low
      birthweight infants who had suspected meningitis and/or respiratory distress
      respectively were cultured for genital mycoplasma. Ureaplasma urealyticum was
      isolated from 9 per cent of CSF and 14 per cent of tracheal aspirates. Mycoplasma
      hominis was isolated from CSF in one case and none at the tracheal aspirates.
      Three out of seven mycoplasma-infected CNS cases showed CSF pleocytosis while
      three out of seven patients whose tracheal aspirates grew mycoplasma had
      congenital pneumonia. None of the patients were treated with antimycoplasmal
      therapy and none developed chronic lung disease.

PMID- 10401192
TI  - The bacteriology of neonatal septicaemia in Ile-Ife, Nigeria.
AB  - The incidence of septicaemia among neonates categorized as being at high risk was
      55 per cent in Ile-Ife, Nigeria. Gram-positive organisms, specifically
      Staphylococcus aureus, were predominant (33.8 per cent) among bacteria cultured
      from proven cases of septicaemia. Other coagulase-negative staphylococci also
      contributed 21 per cent, with Staphylococcus epidermidis occurring in 5 per cent
      of the isolates. Listeria monocytogenes was cultured from 8.4 per cent of septic
      neonates. Pseudomonas aeruginosa was cultured from 3 per cent, Klebsiella
      pneumoniae from 14 per cent, and Escherichia coli from 7 per cent. Other Gram
      negative bacilli cultured were Enterobacter aerogenes (5 per cent), Citrobacter
      freundii, Salmonella sp., and Proteus sp. (2 per cent each). The bacterial
      isolates were relatively resistant to antibiotics traditionally employed to treat
      cases of septicaemia. The study shows a high prevalence of neonatal bacterial
      sepsis at the centre and the emerging role of Listeria monocytogenes in the
      aetiology of neonatal sepsis. It highlights the preponderance of multiple
      antibiotic resistant organisms among these neonates early in life which is of
      epidemiological importance in the control of the infectious agents.

PMID- 10401193
TI  - Low birthweight in infants born to African HIV-infected women: relationship with
      maternal body weight during pregnancy: Pregnancy and HIV Study Group (EGE).
AB  - The effect of maternal HIV infection on birthweight was estimated. In the
      prenatal clinic of the Centre Hospitalier de Kigali, HIV screening was proposed
      to women with a gestational age (GA) of less than 28 weeks. HIV-infected (HIV+)
      and uninfected (HIV-) women were recruited, when they consented. At inclusion,
      socioeconomic, obstetrical data, and body weight were collected, a clinical
      examination was performed, and tests for sexually transmitted diseases (STDs) and
      malaria were performed. Two prenatal visits were made, at 28-32 and 32-36 weeks,
      with clinical data and weight measurement. At delivery, birthweight, body length,
      and head circumference of the infant were documented. At inclusion and at the
      second follow-up visit, HIV+ women (N = 177) weighed less than HIV- women (N =
      194) (p = 0.004). Mean birthweight in infants born to HIV+ women was 2947 g (SD =
      429) and 3104 g (SD = 461) in infants born to HIV- women (p = 0.001). Frequencies
      of low birthweight (LBW, weight < 2500 g), prematurity (GA < 37 weeks, according
      to Finnstrom score at birth), and intrauterine growth retardation (defined by LBW
      and GA > or = 37 weeks) were higher in infants born to HIV+ women than to HIV-
      women (p = 0.009, 0.01, and 0.053, respectively). In multivariate logistic
      regression, the association between maternal HIV infection and LBW disappeared (p
      = 0.61), while low GA (p = 0.01) and low last prenatal weight (p = 0.01) were
      independant risk factors of LBW. LBW in infants born to HIV+ women could be
      partly attributable to impaired maternal weight. These results underline the need
      for nutritional surveillance and dietary counselling, hoping to improve the
      prognosis of pregnancy in HIV+ women, regardless of other therapeutic
      interventions.

PMID- 10401194
TI  - Radiological analysis of children with cystic fibrosis who are homozygous for
      cystic fibrosis transmembrane conductance regulator mutation S549R (T-->G).
AB  - Genotype-phenotype analyses in cystic fibrosis (CF) have shown that cystic
      fibrosis transmembrane conductance regulator (CFTR) genotypes can predict
      pancreatic status but that correlations with pulmonary status remain elusive. We
      investigated the extent and severity of lung disease associated with CFTR
      mutation S549R (T-->G). This mutation is localized in intron 11 (nucleotide
      binding fold 1 of the CFTR protein) and had so far been described as a private
      mutation only. It is associated with an extremely severe overall CF phenotypic
      expression. Detailed radiological analyses were performed by a single observer in
      12 children with CF from the United Arab Emirates who were homozygous for CFTR
      mutation S549R (T-->G). A diversity of pulmonary changes included marked
      hyperinflation in early infancy in conjunction with inflammation of the
      interstitium. After 2 years of age, signs of central airway involvement occurred
      in association with early signs of pulmonary hypertension. In conclusion,
      although there is some diversity in the radiological findings of these CF
      patients, R549 is a very severe allele associated with extreme lung disease and
      rapid pulmonary decline.

PMID- 10401195
TI  - Does treatment change the outcome of seizures and computerized tomographic
      lesions in intracranial granulomas?
AB  - In children, intracranial granuloma diagnosed on computerized tomography (CT)
      scan and presenting with seizures as the sole manifestation has traditionally
      been treated with antitubercular (ATB) therapy or albendazole (Alb) in addition
      to antiepileptic drugs (AED). This study was conducted to determine whether AED
      therapy alone or specific treatment (ATB + Alb) influences the outcome of
      seizures and the CT lesion. Sixty-eight children presenting with seizures along
      with intracranial granuloma on CT scan were selected for the study. They were
      randomly divided into two groups. Group A (n = 34) was treated with AED alone and
      group B (n = 34) received antitubercular therapy and albendazole in addition to
      AED. Seizure type was noted and electroencephalogram (EEG) and CT scan were done
      in all. They were followed up for a period of 2 to 9 years, during which a record
      of seizure count and type was maintained. CT scans were repeated at 3 monthly
      intervals and EEGs were repeated whenever indicated. Four patients in each group
      were lost to follow-up. Seizures persisted in four out of 30 in group A and six
      out of 30 in group B. There was no statistically significant difference (p >
      0.05) in the outcome of seizures in the two groups. Taking the whole group
      together (n = 60), of the 13 who had presented with multiple seizures at onset,
      epilepsy was a sequela in five (p < 0.05); and of the 17 in whom the lesion had
      calcified, seizures persisted in seven (p < 0.05), irrespective of treatment
      modality. In conclusion, though specific treatment did not alter the outcome of
      seizures, children with multiple seizures at presentation and calcification of CT
      lesion had epilepsy as a sequela.

PMID- 10401196
TI  - Lack of difference in iron status assessed by soluble transferrin receptor
      between children with cerebral malaria and those with non-cerebral malaria.
AB  - We conducted this study to determine whether children with cerebral malaria are
      less likely to have tissue iron deficiency than those with non-cerebral malaria.
      Iron status was assessed by soluble transferrin receptor (sTfR), serum ferritin,
      and haemoglobin in 44 Zairian children: 15 with cerebral malaria, 14 with non
      cerebral malaria, and 15 without malaria (age range 0.5-16 years). Although there
      was no significant difference in the mean concentrations of sTfR, serum ferritin,
      or haemoglobin between either group of patients, a higher percentage of children
      with cerebral malaria (27 per cent) than those with non-cerebral malaria (14 per
      cent) or controls (7%) had sTfR levels above 7.3 mg/l (suggestive of tissue iron
      deficiency). A higher percentage of children with cerebral malaria (40 per cent)
      than with non-cerebral malaria (29 per cent) or controls (20 per cent) also had
      either serum ferritin < 100 micrograms/l and inflammation or sTfR > 7.3 mg/l or
      both. The data suggest that children with cerebral malaria are as likely to have
      tissue iron deficiency as those with non-cerebral malaria.

PMID- 10401197
TI  - Serum-free carnitine levels in children with heart failure.
AB  - The serum-free carnitine (SFC) levels of 91 children with heart failure (HF) and
      of a control group consisting of 30 healthy children were measured. Twenty-four
      of 91 children with HF were administered oral L-carnitine. The mean SFC level of
      children with HF (20.16 +/- 0.30 nmol/l) was significantly lower than that of the
      control group (38.98 +/- 0.79 nmol/ml) (p < 0.01). Mean SFC levels of 24
      patients, after L-carnitine administration, increased significantly (p < 0.01).
      Patients administered L-carnitine displayed a marked difference in time taken for
      clinical improvement compared with those not given oral L-carnitine.

PMID- 10401198
TI  - HIV-related gender biases among malnourished children in Abidjan, Cote D'Ivoire.
AB  - This study, conducted in a health centre in Abidjan for malnourished children,
      shows that there were more girls than boys among children admitted who were HIV
      seropositive whereas there were more boys than girls among seronegative children.
      Reasons for this gender bias are investigated.

PMID- 10401200
TI  - Isolation of respiratory bacterial pathogens from the throats of healthy infants
      fed by different methods.
AB  - Most bacterial infections are caused by organisms that have already colonized the
      host. Bacterial attachment to pharyngeal cells and proliferation may be necessary
      to infect the lower respiratory tract or middle ear. We investigated the
      incidence of pathogenic bacteria isolated from the throat of healthy infants with
      different feeding methods. The protecting role of breastmilk is also discussed.
      The incidence of respiratory bacterial pathogens isolated from the oropharynx of
      113 normal infants with different feeding methods was investigated. Group A beta
      haemolytic Streptococcus, Streptococcus pneumoniae, Haemophilus influenzae and
      Moraxella catarrhalis were selected as respiratory bacterial pathogens. No
      respiratory bacterial pathogens were detected in breastfed and mixed-fed infants.
      Haemophilus influenzae and Moraxella catarrhalis were isolated from the
      oropharynx of formula-fed infants. The incidence of respiratory bacterial
      pathogens did differ among infants with different feeding methods. These results
      suggest that breastmilk may inhibit the colonization by respiratory bacterial
      pathogens of the throat of infants, by enhancing mucosal immunity against
      respiratory tract infection.

PMID- 10401199
TI  - Placental transfer of IgG antibodies against Haemophilus influenzae type b
      capsular polysaccharide in Brazilian term and preterm newborns.
AB  - Placental transfer of antibodies to polysaccharide antigens is still a
      controversial subject. The incidence of invasive Haemophilus influenzae type b
      (Hib) infections is high in countries where the vaccine has not been included in
      routine immunization schedules. In the present work, we proposed to evaluate the
      natural immune response to Hib capsular polysaccharide in term and preterm
      Brazilian newborns and their respective mothers. Although the means, medians, and
      ranges of antibody titres in paired maternal and cord sera from preterm neonates
      were similar, the maternal levels were slightly higher than the cord levels and a
      poor correlation between these levels was verified. Term neonates showed similar
      antibody levels to those of their respective mothers and a very significant
      correlation between these levels was observed.

PMID- 10401201
TI  - Paediatric patients with Henoch-Schonlein purpura followed up at Cumhuriyet
      University, Sivas, Turkey during 1993-1996: role of parasitosis in the aetiology
      of Henoch-Schonlein purpura.

PMID- 10401202
TI  - Relationship of nucleated erythrocyte count at birth with the severity and
      outcome of persistent pulmonary hypertension in neonates.

PMID- 10401203
TI  - Levels of immunoglobulins and complement C3 in protein-energy malnutrition.

PMID- 10401204
TI  - Booster vaccination at 1 year with a rabies vaccine associated with DTP-IPV in
      infants living in a rabies endemic country.

PMID- 10401205
TI  - Food and asthma symptoms in Malaysian children.

PMID- 10401206
TI  - Polio surveillance in Lao PDR: a two-year experience of active case search, 1994
      96.
AB  - The underdeveloped health infrastructure and limited epidemiological data on
      polio are major obstacles to the establishment of the acute flaccid paralysis
      (AFP) surveillance system in Lao People's Democratic Republic (Lao PDR). We
      initiated a nationwide active case search for case investigations at the
      community level in March 1994 to support the development of the AFP surveillance
      system. We identified 164 polio cases that occurred between 1979 and 1993 in 511
      villages, indicating that wild poliovirus had circulated extensively during that
      period. Of these, only 59 (36 per cent) had visited health facilities, and polio
      was diagnosed in 15 (9 per cent). As national immunization days (NIDs)
      progressed, the number of polio cases decreased to an undetectable level after
      1994. The active case search was useful for educating the local staff about AFP
      and the components of a surveillance system, and as an adjunct to national AFP
      surveillance programme in the country as it approaches the goal of polio
      eradication.

PMID- 10401207
TI  - [The behavior of angiotensin-converting enzyme in patients with uveitis].
AB  - Serum angiotensin-converting enzyme (ACE) is considered as a marker in many
      disorders, especially in sarcoidosis. The aim of this study was to assess ACE
      activity using Haiakari spectrophotometry in patients with non-sarcoidosis
      uveitis before and after treatment. MATERIAL AND METHODS: 36 patients, including
      21 adults and 15 children, were investigated. ACE concentration was increased
      mostly in patients with recurrent toxoplasmic and toxocaral iridocyclitis and
      choroiditis. RESULTS: It was demonstrated that concentration of ACE was increased
      especially in toxocariasis uveitis. After treatment the concentration of ACE was
      significantly decreased in all patients.

PMID- 10401208
TI  - [Diagnostic problems in intraocular melanoma].
AB  - PURPOSE: To evaluate accuracy of the diagnosis, rate of advancement and
      therapeutic possibilities of intraocular malignant melanomas, basing on our one
      year clinical material. MATERIAL AND METHODS: The total of 288 consecutive
      patients with suspicion or diagnosis of intraocular malignant melanoma, referred
      in the year 1997 to the Department of Ophthalmology CM UJ, were analysed. There
      were 121 males and 167 females, aged 22-76, mean 50. The period of time between
      the patient's first ocular symptoms and his visit to the ophthalmologist ranged
      between 7 days and several years. Besides routine ophthalmological examination
      each patient underwent USG and, if necessary AF, ICG, CT and IMR. RESULTS:
      Diagnosis of malignant melanoma was confirmed in 141 cases. Among these patients
      in 69 brachytherapy was applied, in 20 surgical resection of the tumor and in 52
      enucleation. In 111 cases other following diseases were diagnosed: iris cysts,
      deficient iridectomy, iris nevus, choroidal nevus, metastatic tumors, age-related
      macular degeneration, myelinated nerve fibres, Leber-Coats syndrome,
      toxoplasmosis and granulomatous uveitis. In 36 cases the diagnosis was not exact
      and those patients remained under periodic clinical observation. CONCLUSIONS: Our
      study shows that in many patients intraocular malignant melanoma is diagnosed too
      late and in these cases enucleation is the only method of treatment. The most
      diagnostic challenges are connected with differentiation of choroidal melanoma
      from choroidal nevus and exudative form of age-related macular degeneration.

PMID- 10401209
TI  - [Brachytherapy in choroidal melanoma].
AB  - BACKGROUND AND PURPOSE: Brachyterapy in the management of intraocular tumors was
      introduced in the Department of Ophthalmology in Cracow in the late sixties, soon
      after it was applied by Stallard. For many years, similar to other oncological
      centers, we used 60Co and in 1994 we started with 106Ru and at the end of 1997
      with 125J. The aim of this paper is to present our experiences with 106Ru and
      125J brachytheray in posterior uveal melanoma. MATERIAL AND METHODS: Our studies
      comprised 164 patients with choroidal melanoma, treated in the years 1995-1997
      with 106Ru and 19 patients treated between December 1997 nad April 1998 with 125J
      plaque brachytherapy. There were 93 women and 90 men, aged 18-86. Tumor thickness
      was beneath 6 mm in 85 cases, 6-9 mm in 63 and above 9 mm in 35. In 121 eyes
      anterior margin of the tumor was located in equatorial region or posterior to it,
      62 the tumor situated anterior to the equator attached to the ciliary body. The
      usual dosage was 60-100 Gy to the tumor apex; in 33 eyes transpupillary
      thermotherapy (TTT) with diode laser was added. The follow-up ranges from 3
      months to 3 years after 106Ru plaque brachytherapy and 1-3 months after 125J.
      RESULTS: Criteria of the treatment efficacy were decrease of tumor thickness at
      least 10%, increase of its density and vessel obliterations. Among 164 patients
      treated with 106Ru improvement was achieved in 84 (51.2%) of cases, stabilization
      in 50 (30.5%) and negative results in 30 (18.3%). Enucleation was performed in 16
      (9.7%) cases. Among 19 patients treated with 125J preliminary evaluation
      indicates positive reaction for treatment in 14 cases. CONCLUSIONS: Our studies
      confirm the opinion that brachytherapy is a method of choice in the management of
      many cases of posterior uveal melanoma. There are significant relationships
      between the results of treatment and the size of tumor and its location. The
      adequate choice of the kind of radioactive isotope in the plaque is very
      important.

PMID- 10401210
TI  - [Use of diode laser in the treatment of intraocular tumors: preliminary report].
AB  - PURPOSE OF THE STUDY: The purpose of the study was to evaluate the effectiveness
      of diode laser transpupillary thermotherapy and to determine in what extent it
      may act as the only method of therapy of choroidal tumors, and when it should be
      used in combination with other methods. The study has preliminary character.
      PATIENTS: 15 eyes of 14 patients aged 38 to 82 years (mean--57 years) were
      treated because of intraocular tumor with the use of diode laser transpupillar
      thermotherapy in 13 patients primary intraocular tumor was diagnosed, and in 1
      patient there was metastasis; in 13 cases tumors were localized unilaterally,
      whereas in 1 case they appeared in both eyes. The follow-up period (from the
      start of the treatment) ranged from 1 to 3 months. METHODS: All patients were
      treated with transpupillary thermotherapy (TTT) with the use of diode laser
      OcuLight SLx, IRIS Medical instruments, Inc. The power and size of the laser
      spots depended on the tumor size and pigmentation. Mean power used for the
      treatment was 600 mW, while mean exposure time was 1 minute. RESULTS: Altogether,
      within 15 treated eyes in 8 cases regression, in 6--stabilization and in 1-
      progression was stated. As to complications and side effects, visual field
      scotomas in the treated area as well as deterioration of visual acuity were found
      during the treatment. In 2 cases a slight improvement of visual acuity was found.
      CONCLUSIONS: In selected cases transpupillary thermotherapy (TTT) can be
      effective especially in regard to small tumors (height up to 4.5 mm). Probably in
      the future it will be the only method of treatment. Treatment of larger tumors
      (height more than 4.5 mm) should be connected with the use of ruthenium plaque
      (106Ru). All complications and side effects found in the course of treatment were
      not dangerous to the eye (small hemorrhage) and were relatively easily tolerated
      by the patients. With longer follow-up of greater group of patients probably it
      will be possible to establish optimal parameters, advantages and possible other
      complications of such therapy.

PMID- 10401211
TI  - [Evaluation of some clinical parameters in patients with retinitis pigmentosa in
      relationship to the type of inheritance].
AB  - PURPOSE: Analysis of selected clinical parameters in patients with various types
      of retinitis pigmentosa. PATIENTS AND METHODS: We examined 51 patients aged 8-67
      suffering from different genetic forms of RP identified on the ground of pedigree
      analysis. We analyzed onset of nyctalopia, degree of retinal degeneration, degree
      of visual field loss, dark adapted electroretinographic testing flicker (ERG) and
      presence of posterior subcapsular cataract. CONCLUSIONS: XLRP is one of the most
      severe RP forms. In the groups with ADRP and sRP, the patients have varied
      expression of disease.

PMID- 10401212
TI  - [The significance of computer video-keratography in refractory surgery of the
      cornea].
AB  - In this review authors explain the meaning of CVK in refractive surgery; before
      the procedure and in the postoperative period. A special attention is paid to the
      postoperative complications.

PMID- 10401213
TI  - [The function of corneal endothelium after penetrating keratoplasty as measured
      with fluorophotometry].
AB  - The aim of the study was to calculate the corneal endothelial permeability (Pac)
      12 and 18 months after penetrating keratoplasty in patients (aged 42-60 years)
      with very good prognosis for graft clarity (10 eyes with pseudophakic and 4 eyes
      with aphakic bullous keratopathy; 6 eyes with keratoconus; 2 eyes with granular
      dystrophy; 6 eyes with central inactive scars; 1 eye with early central Fuchs'
      dystrophy). The normal eyes (10 eyes) served as control group in persons aged 40
      65 years. Each operated eye was submitted to fluorophotometry of the anterior
      segment with measurement of corneal endothelial permeability (Fluorotron Master,
      Coherent) 12 and 18 months after the surgery. The cornea thickness measurement
      and endothelial cell counting were performed by specular microscopy with
      pachymeter 12 and 18 months after penetrating keratoplasty in cases with very
      good prognosis for graft clarity. The mean values of Pac: 4.48 x 10(-4) +/- 1.24
      cm/min after 12 months were significantly higher (p < 0.05) than in the control
      group (3.61 x 10(-4) + 0.51 cm/min). Neither significant changes in corneal
      thickness nor endothelial cell density were noted as a result of surgery. The
      calculation of Pac in a late period after penetrating keratoplasty revealed a
      stable partial exhaustion of the corneal endothelium function in cases with good
      prognosis for graft clarity.

PMID- 10401214
TI  - [Squamous metaplasia of bulbar conjunctiva in the course of long-term topical
      antiglaucoma therapy].
AB  - PURPOSE: The aim of this study was to determine how long-term topical
      antiglaucoma treatment affects the bulbar conjunctiva. MATERIAL AND METHODS: 59
      glaucoma patients and 30 healthy people were examined by the use of impression
      cytology for changes in bulbar conjunctiva. Patients with glaucoma were on stable
      regimen of one or two antiglaucoma drugs for a minimum 1 year. RESULTS: Squamous
      metaplasia of bulbar conjunctiva was found in 26.6% of patients treated with beta
      blocker alone for 1-2 years and in 42.8% of patients treated with this drug for
      longer than 2 years. Similar changes were found in patients treated with beta
      blocker with miotic--in 60% people who were on stable regimen for 1-2 years and
      in 70% treated longer than 2 years. No conjunctival changes were observed in
      healthy people. CONCLUSIONS: Long-term topical antiglaucoma medication may
      produce squamous metaplasia of bulbar conjunctiva.

PMID- 10401215
TI  - [Goblet cells density of bulbar conjunctiva after long-term topical antiglaucoma
      agents].
AB  - AIM: The purpose of this study was to determine the effect of long-term topical
      antiglaucoma therapy on goblet cells density of the bulbar conjunctiva. MATERIAL
      AND METHODS: Conjunctiva impression cytology specimens from 59 glaucoma patients
      and 30 healthy people were assessed quantitatively by light microscopy. Patients
      with glaucoma were on a stable regimen of one (beta-blocker alone) or two (beta
      blocker with miotic) topically administered medications for a minimum 1-year.
      RESULTS: The results show statistically significant decrease in goblet cells
      associated with number of antiglaucoma drugs and duration of treatment.
      CONCLUSIONS: Long-term topical antiglaucoma treatment decrease goblet cells
      population of bulbar conjunctiva.

PMID- 10401216
TI  - [Schirmer test I and BUT (break-up-time) in patients treated with topical
      antiglaucoma drugs for a long time].
AB  - PURPOSE: The aim of this study was to evaluate Schirmer test I and BUT in
      patients after long-term topical antiglaucoma medication. MATERIAL AND METHODS:
      59 glaucoma patients on stable regimen of one or two antiglaucoma drugs (for a
      minimum 1 year) and 30 healthy people were checked for changes of the precorneal
      tear film. Tear secretion was measured by Schirmer test I and stabilization of
      precorneal film by break-up time. RESULTS: We found no influence of antiglaucoma
      drugs on tear secretion. Statistically significant decrease in break-up time was
      found in glaucoma patients. CONCLUSIONS: Long-term topical antiglaucoma
      medication may alter precorneal film stabilization.

PMID- 10401217
TI  - [Consecutive exotropia as a result of esotropia surgery].
AB  - PURPOSE: To find out the probable reasons of the postoperative consecutive
      exotropy. MATERIAL AND METHODS: We studied 22 patients aged more than 14 years,
      operated due to esotropia during the first 7 years of life. Two categories were
      formed: the first contained the patients in the age between 14 and 18, and the
      second one the patients 19 years old and older. The period between the first and
      the second procedure was not shorter than seven years. The reoperations were
      performed due to exotropia in 15 cases. The following examinations were performed
      before the surgery: visual acuity, squint angle, eye movements, convergention,
      binocularity by Sobanski, Bagolini, TNO, Worth, Titmus tests and with synoptofor.
      RESULTS: We found out the probable reasons of the postoperative exotropia:
      incorrect, unconservative surgery, high hypermetropia, primary vertical
      deviation, amblyopia, absence of binocularity, simultaneous surgery for 3 or 4
      muscles, too extensive surgery and irregular treatment.

PMID- 10401218
TI  - [The significance of ocular signs for early diagnosis of pituitary tumors].
AB  - The aim of the study was to analyze intensified ocular symptoms of patients with
      diagnosed and surgically treated pituitary macroadenoma. Material from
      Neurosurgery Clinic of Medical University in Warsaw covering the period since
      1935 was included in the study. Duration of the period from first ocular symptoms
      to final diagnosis as well as condition of visual organ, especially number of
      patients with irreversibly damaged sight (blindness, marginal vision), were
      evaluated. The results of the study show that still a great number of patients
      undergo surgical treatment too late; in the last period 36% of patients had
      irreversibly damaged sight. The reason was found to be partially carelessness of
      the patients, however in many cases it was wrong initial medical diagnosis and
      not performed full diagnostic examinations. The study points to the necessity of
      performing adequate additional tests in cases of patients with visual field
      narrowing or visual acuity deterioration without clearly determined other
      pathology.

PMID- 10401219
TI  - [Professor Witold J. Orlowski. Obituary for 10th anniversary of his death].
AB  - The article presents an outline of Prof. W.J. Orlowski's (1918-1988) biography.
      He studied at Warsaw University (1936-1939) and Lodz University (1945-1947). He
      became interested in ophthalmology as early as before completing his studies. He
      graduated in medicine in 1950, few years later obtained doctor's degree and in
      1961 received the thid degree (habilitation) and lectureship. From 1st June 1965
      till 30th June 1988 he was Head of Ophthalmologic Clinic at Poznan Medical
      Academy. He wrote a considerable number of ophthalmologic textbooks, 208 research
      papers, and was an editor of textbooks and periodicals. Prof. W.J. Orlowski's
      scientific interest focused on retina diseases which resulted in founding
      Retinological Section in 1970, and thus starting to develop Polish retinology. As
      a humanist he rendered services to journalism where, as early as his high school
      time, he used to publish board bulletins, and edited periodicals including "Glass
      Houses", "The Forge at the Young", "Life of Youth". During his university studies
      he worked as journalist in "The Republic" and in "Lodz Daily". After graduating
      from university he continued his medical and journalist passions as author and
      editor for "Medical News", "Let's Live Longer", "The Eye Clinic". He was an
      outstanding expert in the history of ophthalmology. Prof. W.J. Orlowski was a man
      of a wide range of interests. His hobbies included stamps collecting and
      numismatics. He received wide recognition among both Polish and foreign
      ophthalmologists as well earned deep respect from his colleagues and students.

PMID- 10401220
TI  - [David H. Hubel, Torsten N. Wiesel, Nigel W. Daw: the creators of modern visual
      neurophysiology].
AB  - Curriculum vitae as well as scientifical out-put of the Nobel Price winners-
      David Hunter Hubel and Torsten Nils Wiesel, and the Friedenwald Memorial Award
      laureate--Nigel Warwick Daw are described. D.H. Hubel was born in 1926 in
      Windsor, Canada. In 1951 he received a medical degree from McGill University.
      From 1955-1958 he worked at Walter Reed Army Institute of Research, from 1958
      1959 at Johns Hopkins University, and since 1959 at Harvard University. T.N.
      Wiesel was born in 1924 in Uppsala, Sweden. In 1954 he received a medical degree
      from Karolinska Institute. From 1955-1959 he worked at Johns Hopkins University,
      from 1959-1982 at Harvard University, and since 1983 at the Rockefeller
      University, New York. N.W. Daw was born in 1933 in London, England. In 1961 he
      received a bachelor's degree in mathematics from Trinity College. In 1967 he
      became a doctor of philosophy in biophysics at Johns Hopkins University. From
      1967-1969 he worked at Harvard University, from 1969-1992 at Washington
      University, and since 1992 at Yale University.

PMID- 10401221
TI  - [Associate Professor of Medicine Zofia Falkowska -- a precursor of the Warsaw
      orthooptics, co-founder of the Polish school of squint treatment].

PMID- 10401222
TI  - Results of surgical treatment for thoracoabdominal aneurysm using cardiopulmonary
      bypass under moderate hypothermia and selective visceral artery perfusion.
AB  - From 1994 to 1997, 11 consecutive patients with thoracoabdominal aneurysms
      underwent surgery using cardiopulmonary bypass under moderate hypothermia (33
      degrees C) and selective visceralartery perfusion for spinal cord and visceral
      organ protection. Distal perfusion pressure was maintained above 60 mmHg (mean)
      during cardiopulmonary bypass. In the four patients, one or two pairs of large
      intercostal arteries between Th10 and L2 were reimplanted. In the four patients,
      visceral and renal arteries were reconstructed. Surgical mortality rate within 1
      month was 18.2% (2/11). One patient died of bleeding from old empyema and another
      of multiple organ failure. No patients had paraplegia. In conclusion,
      cardiopulmonary bypass with selective visceral artery perfusion under moderate
      hypothermia may contribute to the prevention of the occurrence of paraplegia and
      acute renal failure.

PMID- 10401223
TI  - Hepatic microcirculation during transient hepatic venous occlusion--intravital
      microscopic observation using hepatic vein clamp model in the mouse.
AB  - The purpose of this experiment was to evaluate the etiology of hepatic
      dysfunction in patients difficult to wean from cardiopulmonary bypass. We
      hypothesized that increased central venous pressure and subsequent hepatic
      congestion during weaning from cardiopulmonary bypass would lead to hepatic
      dysfunction. To induce hepatic congestion in mice, we clamped the hepatic vein
      for fifteen min, and observed the microcirculation of the liver using an
      intravital microscope during clamping and the following 30 min of reperfusion.
      During reperfusion, non-reflow phenomenon, leukocytes adhesion to the wall of
      sinusoids, erythrocytes sludging, acute swelling of hepatic cells and narrowing
      of sinusoids were observed. These phenomena were indicative of warm ischemia
      reperfusion injury of the liver itself. Based on these findings we concluded
      that, after repeated episodes of warm ischemia and reperfusion of the liver,
      hepatic cells would be damaged, and finally hepatic dysfunction was induced. To
      prevent hepatic dysfunction, repeated attempts to wean the patient from
      cardiopulmonary bypass should be avoided and increases central venous pressure
      should be prevented by early use of cardiopulmonary support.

PMID- 10401224
TI  - Alterations in retrograde axonal transport in optic nerve of type I and type II
      diabetic rats.
AB  - Clinical and electrophysiological examinations have yielded visual pathway
      function abnormalities in both humans and animal models with diabetes mellitus
      (DM). However, subclinical involvement of the optic nerve has not yet been fully
      investigated. In this study, we demonstrated the different impairments in
      retrograde axonal transport occurring in selective retinal ganglion cells (RGCs)
      of Type I and II diabetic rats. Rats were injected with streptozotocin (STZ) to
      induce Type I DM. The Otsuka Long-Evans Tokushima Fatty (OLETF) rats represented
      the Type II DM group. The STZ-induced (Type I) diabetic rats had low body weights
      and significant elevations in blood glucose levels compared with the age-matched
      control rats. On the contrary, the OLETF rats (Type II) had high body weights and
      significant elevations in blood glucose concentrations compared with the age
      matched controls. Fluoro-Gold (FG) was injected into the bilateral dorsal lateral
      geniculate nucleus. Accumulation of FG in large and medium type RGCs in STZ
      induced diabetic rats was significantly decreased compared with the controls.
      However, the accumulation of FG in RGCs of OLETF rats did not show a significant
      decrease compared with the controls. Our findings suggest that, within the time
      frame of study, retrograde axonal transport impairment of large and medium type
      RGCs in the STZ-induced (Type I DM) diabetic rats was greater than in the OLETF
      (Type II DM) diabetic rats. Impairment of retrograde axonal transport in Type I
      diabetes may precede or be a consequence of metabolic dysfunctions in the large
      and medium-sized RGCs eventually leading to optic nerve atrophy.

PMID- 10401225
TI  - Establishment of a non-union model using muscle interposition without osteotomy
      in rats.
AB  - Many attempts have described a standard experimental model for fracture non-union
      in laboratory conditions, but the majority of them produced after an experimental
      osteotomy, so it is different from clinical disturbed fracture healing. The
      purpose of this study is to establish a standard method for producing fracture
      non-union with only muscle interposed into the fracture site in rats. Bilateral
      tibial fractures were made in forty-eight male Wister rats by three point bending
      and we surgically interposed the distal end of the tibialis anterior muscle into
      the fracture site. They were sacrificed at 1, 2, 3, 6, 12, 24, 48, and 96 weeks
      after fracture. The rentgenograms were obtained, and the fractured tibias were
      harvested in each time period and investigated histologically and
      immunohistochemically. The rentgenogram at six weeks, in the non-union rats,
      showed abundant callus at each end of the fracture fragments, but no bridging
      callus. The histological finding with hematoxylin and eosin, at this point, shows
      no bridging soft callus, and small isolated regions of cartilage were observed
      only where the bone was not covered by the muscle. The proliferating cell nuclear
      antibody immunostaining which is associated with cell proliferation was abruptly
      lost in chondrocytes at two weeks. This early disappearance of chondrocytes
      without endochondral ossification may be a significant etiological factor in the
      development of a non-union. This non-union model is technically simple and
      reproducible, and dose not require periosteal stripping or surgical osteotomy to
      produce an artificial bone gap.

PMID- 10401226
TI  - Susceptibility of non-HDL fraction to oxidation in experimental nephrotic
      syndrome.
AB  - Hyperlipidemia is a striking feature of nephrotic syndrome (NS) and the lipid
      profile seen in NS is accepted as atherogenic. Both low density lipoprotein (LDL)
      and very low density lipoprotein (VLDL) are apolipoprotein B-containing
      lipoproteins which are accepted as atherogenic. Oxidized-LDL (ox-LDL) has been
      suggested to play a fundamental role in atherogenesis. In this study, male
      Sprague-Dawley rats were made nephrotic by a single intraperitoneal injection of
      puromycin aminonucleoside (100 mg/kg body weight). We found significant elevation
      in serum triglycerides, total cholesterol, malondialdehyde, vitamin E levels and
      total cholesterol/vitamin E ratio and decrease in total protein and albumin
      levels in the NS group (n:8) compared with the control group (n:9). High density
      lipoprotein (HDL)-cholesterol and free fatty acid levels were not significantly
      different between these two groups. Apolipoprotein B-containing lipoproteins (non
      HDL fraction) were separated by precipitation and amount of thiobarbituric acid
      reactive substances (TBARS) of non-HDL fraction were measured after 60, 90, 120,
      180 minutes of incubation with copper sulphate. TBARS levels of non-HDL fraction
      were significantly higher in the NS group compared with the control group at all
      of the time periods above. In nephrotic animals, the increased lipid peroxidation
      was influenced by serum lipids.

PMID- 10401227
TI  - The prognostic factor of the surgically treated metastatic lung cancer.
AB  - Surgical treatment for metastatic lung tumor has also been aggressively performed
      to treat multiple or bilateral lesions recently. However, in some patients,
      metastatic pulmonary foci have recurred after surgery for metastatic lung tumor.
      These foci could not be controlled even after performing thoracotomy several
      times in some patients. In this study, we examined prognostic factors in patients
      undergoing surgery for metastatic lung tumor with respect to early relapse of
      metastatic pulmonary foci after surgery, and discussed strategies for improving
      long-term results. This study included 120 patients who underwent surgery for
      metastatic lung tumor in our department between November 1975 and November 1997.
      Overall, the 5-year survival rate was 37.1%. When results were compared among
      groups, there were no significant differences related to age, gender, primary
      organ, DFI, number of metastatic foci or surgical technique. However, the
      prognosis was significantly poorer in patients with recurrent metastatic
      pulmonary foci after surgery. Especially in patients with early relapse within 6
      months after resection of the lung, the prognosis was markedly poor. Early
      relapse was an important factor involved in unfavorable surgical outcomes. The
      mechanism involved in the early relapse of metastatic pulmonary foci after
      surgery for metastatic lung tumor may be associated with the presence of several
      micrometastases that could not be recognized during surgery for metastatic lung
      tumor, that is, dormancy, in the lung. Surgical outcomes in patients with
      metastatic lung tumor will be improved if a method of controlling this increase
      in dormant metastases is established.

PMID- 10401228
TI  - Extra-anatomical bypass with EPTFE graft for residual pulmonary artery stenosis
      in Tetralogy of Fallot.
AB  - We describe the case of 35-year old woman who had undergone radical surgery to
      correct Tetralogy of Fallot malformation at the age of nine admitted to our
      hospital because of palpitation and exertional dyspnea. Angiography revealed 90%
      re-stenosis of the right pulmonary artery and grade IV tricuspid regurgitation.
      Right lung was perfused only 16.7% as shown by pulmonary perfusion scintigraphy.
      Interposition between the pulmonary trunk and right pulmonary artery using an
      EPTFE graft and tricuspid annuloplasty using a Duran ring was performed. Blood
      flow to the right lung improved markedly from 16.7% to 37.0% and her symptom
      disappeared completely.

PMID- 10401229
TI  - [Cardiomyocyte transplant--a new treatment for congestive heart failure?].

PMID- 10401230
TI  - Breast cancer associated with Recklinghausen's disease: report of a case.
AB  - A 49-year-old woman with Recklinghausen's disease presented to our department for
      investigation of a left breast lump, measuring 60 mm x 50 mm, which she had first
      noticed 6 months earlier, but had disregarded, believing it to be another
      manifestation of her Recklinghausen's disease. The lump was suspected to be
      malignant based on physical examination and ultrasonography. Biopsy and frozen
      sections subsequently confirmed a diagnosis of scirrhous carcinoma. A standard
      radical mastectomy was performed, followed by postoperative chemoendocrine
      therapy. However, lungs, liver, and bone metastasis, as well as a contralateral
      breast tumor, developed and she died 4 months after surgery.

PMID- 10401231
TI  - Percutaneous autologous bone marrow transplantation for nonunion of the femur.
AB  - Percutaneous bone marrow injections were performed on 7 nonunions of the femur.
      There were 6 hypervascular nonunions and one avascular nonunion. Two nonunions
      presented with active infections. One other patient had a history of infection
      which had subsided. One nonunion received the injection twice. After the site of
      nonunion was curetted and the bone surface was scored, 150 ml of bone marrow
      aspirated from the iliac bone was injected. Complete union occurred in 4 patients
      within 9 months; all of them were uninfected hypervascular nonunions following
      intramedullary nail fixation. One nonunion with a bone defect united partially
      leaving a 1 x 1 cm defect. The two infected femoral nonunions failed to unite.
      The results show that percutaneous autologous bone marrow injection for femoral
      nonunions can be considered for uninfected hypervascular nonunions following
      intramedullary nail fixation. In these cases stimulation of healing processes of
      fracture leading to consolidation can be expected from bone marrow injection.
      However, femoral nonunion with an active infection and loss of fixation is
      considered to be a contraindication for this technique.

PMID- 10401232
TI  - [Current tendency in treatment for acute ischemic stroke].

PMID- 10401233
TI  - Ultrastructural changes and immunohistochemical localization of nitric oxide
      synthase, advanced glycation end products and NF-kappa B in aorta of
      streptozotocin treated Mongolian gerbils.
AB  - To evaluate the relationship among the induction of nitric oxide synthase (NOS),
      advanced glycation end products (AGEs) and NF-kappa B for vascular damage in
      hyperglycemia, we injected Mongolian gerbils intravenously with 150 mg/kg
      streptozotocin (STZ) and observed over the next one year the resulting aortic
      changes by immunohistochemical and electron microscopical techniques. After STZ
      treatment, hyperglycemia was confirmed and body weight transiently decreased.
      Morphological observation revealed no remarkable changs in vascular endothelial
      cells or vascular smooth muscle cells in the aorta at one week after STZ
      administration. After 4 weeks increased collagen fibrils were observed in the
      pericellular spaces of media. At one year after STZ administration, increased
      collagen fibrils and thickened elastic fibers were found around the vascular
      smooth muscle cells with vacuolization and increased cytoplasmic organellae
      compared with non-treated animals of the same age. Immunohistochemically
      endothelial constitutive NOS (ecNOS) was localized in the endothelium of the
      aorta of Mongolian gerbils. At one year after STZ administration, the reaction
      products of iNOS, AGEs and NF-kappa B in vascular endothelial cells and smooth
      muscle cells were much more greatly increased than at one week and 4 weeks. After
      STZ administration, the localization of NOS, AGEs and NF-kappa B was observed in
      the aorta, which suggests these factors play important roles in the pathogenesis
      of vasculopathy in diabetes mellitus.

PMID- 10401234
TI  - The influence of hypothyroidism on wound healing. An experimental study.
AB  - An experimental study was performed to investigate the influence of
      hypothyroidism on wound healing. A state of severe hypothyroidism was induced
      initially by performing a total thyroidectomy on rat models; subsequently wounds
      were made by making long midline abdominal incisions and then suturing them. The
      parameters used to evaluate the process of wound healing of these incisions were
      the assay of type-I collagen, type-III collagen (procollagen peptide PIPC and P
      III P, each being the precursor of collagen), type-IV collagen, and
      hydroxyproline. The assays were repeated at specific times and compared to assays
      of similar parameters taken from a control group. In the state of hypothyroidism,
      a decrease was observed in type-IV collagen and hydroxyproline during the
      proliferative phase of wound healing. This indicated that the state of
      hypothyroidism constitutes an important factor in delaying wound healing.

PMID- 10401235
TI  - [The relationship between p53 protein and c-erb B-2 expression and apoptosis in
      colorectal cancer].
AB  - In order to elucidate the relationship between tumor growth and various kinds of
      gene expression and the occurrence of apoptosis in the front portion of
      neoplastic invasion, 57 advanced colorectal cancers were studied by
      immunohistochemical staining of p53, c-erb B-2, the TUNEL method and electron
      microscopy. Light microscopically, the columnar epithelial cells of
      adenocarcinoma frequently showed a decrease in high and a fall off into the lumen
      in tumor invasive forefront. Immunohistochemically the positive rate of p53 and c
      erb B-2 in tumors with high vascular invasion were higher (p < 0.05) than in
      those with low vascular invasion. There was a close correlation between the
      vascular or lymphatic invasion and positive immunoreactivity of p53 and c-erb B
      2. The apoptosis index was demonstrated to be related to vessel invasion, over
      expression of p53 and inflammatory cell infiltration around the front portion of
      the tumor invasion. These results suggested that p53. c-erb B-2 and the apoptosis
      index should be evaluated in conjunction with the prognostic factors in
      colorectal cancer. The infiltrative inflammatory cells may induce apoptosis of
      the tumor cells.

PMID- 10401236
TI  - Prenatal diagnosis of autosomal recessive polycystic kidney disease. A case
      report.
AB  - We present a case of autosomal recessive polycystic kidney disease diagnosed at
      28 weeks' gestation by ultrasonographic examination and magnetic resonance
      imaging (MRI). The fetal kidneys were symmetrically enlarged and highly echogenic
      by ultrasonographic examination and showed high-signal intensity on T2-weighted
      images by MRI. Cystic lesions were recognized by neither examination. In
      addition, the pulsatility index of the fetal renal artery was normal. These
      findings suggest a high water content in the renal parenchyma with tiny cysts and
      normal blood flow in autosomal recessive polycystic kidney disease.

PMID- 10401237
TI  - [Percutaneous endoscopic gastrostomy].

PMID- 10401238
TI  - [Current advances in the treatment of diabetes mellitus].

PMID- 10401240
TI  - [Guarding the health of the border guards].

PMID- 10401239
TI  - [Case records from Nippon Medical School. Emergency endoscopy and endoscopic
      treatment to hemorrhagic peptic ulcer].

PMID- 10401241
TI  - [The organization of transfusion care in the Federal Border Guards Service of the
      Russian Federation].
AB  - A study of special features and trends of medical maintenance in the BGS, troops'
      medical service units' and set-ups' organisation and their transfusion therapy
      tasks. 1990-1995 case records analyses with a view on transfusion therapy needs
      and medical materials' demands and expenditures at the stage of specialist
      medical care. Transfusion aid to patients in the Main Clinical Military Hospital.

PMID- 10401242
TI  - [The comprehensive assessment of the health indices during the training of youth
      drafted for military service].

PMID- 10401243
TI  - [Surgical problems in catastrophic medicine and the prospects for their
      resolution].

PMID- 10401244
TI  - [Current problems of a blood service in the troop unit of a medical service: the
      responsibilities of the posted personnel].

PMID- 10401245
TI  - [The developmental aspects of the standardization of medical services in a
      military medical service].

PMID- 10401246
TI  - [The optimization of the regeneration of a suppurative wound in the maxillofacial
      area by using lymphogenic therapy].

PMID- 10401247
TI  - [The rehabilitative treatment of victims with multiple and combined trauma].
AB  - Traditional methods of rehabilitation period treatment are not always possible
      with poly-trauma patients due to the presence of several fractures in association
      with internal injuries, bed-rest regime, hypokinesia of long duration and other
      factors. The author offers a complex approach to treatment with the provision for
      individual state of the patient. A consistent and gradual application of
      individual rehabilitation programmes together with physiotherapy, physical
      exercises, acupuncture, reflexotherapy and psychotherapy often helped to obtain
      good results.

PMID- 10401248
TI  - [Experience in introducing laparoscopic operations into the practice of the
      gynecology department of a military hospital].

PMID- 10401249
TI  - [Air baths in the treatment of hypertension at the sanatorium stage].

PMID- 10401250
TI  - [An automated system for the integral assessment of the functional reserves of
      servicemen].
AB  - A review of issues of application of IBM-compatible PC and information systems of
      medical appointment for decision-making on professional reliability of military
      specialists with a base of set of objective criteria of various functional
      systems in human organisms, in particular, for standardization of adequate
      loading on servicemen during their combat training. Principles of expert
      evaluations of determination of functional resources of servicemen in situations
      of high intensity and psychophysiological tension of work.

PMID- 10401251
TI  - [Treatment efficacy in acute intestinal infections, chronic diseases of the
      gastrointestinal tract and viral hepatitis B using large doses of Russian
      Bifidumbacterin-forte].
AB  - Until now viral and bacterial acute intestinal infections have a high percent in
      the whole structure of modern intestinal disorders morbidity. Taking into
      consideration inefficacy of antibacterial treatment in a number of cases,
      probiotics with antagonist effect on a wide range of bacteria have found a wide
      usage. This study proves clinic and morphological efficacy of large doses
      Bifidumbacterinum forte for the treatment of the diseases mentioned. The patients
      of the test group demonstrated a relation dyspeptic disturbances, improvement of
      total state in a shorter period than the patients of control group.

PMID- 10401252
TI  - [A trial of the use of an EHF therapy apparatus in preventing immunodeficiency
      states in acute respiratory diseases].

PMID- 10401253
TI  - [The concept of psychophysiological support for the professional activities of
      servicemen].

PMID- 10401254
TI  - [The training of medical service specialists of the Federal Border Guards Service
      of Russia who conduct epidemiological health surveillance].

PMID- 10401255
TI  - [Modern principles of supplying drugs to military medical establishments].

PMID- 10401257
TI  - [Experience in organizing surgical care in a partisan force during World War II].

PMID- 10401256
TI  - [Experience in preparing injection solutions in the pharmacy of a military
      hospital].

PMID- 10401258
TI  - [The 60th anniversary of the Medical Section of the Main Command of the Border
      Guard Forces].

PMID- 10401259
TI  - [The 65th anniversary of Chemitokvadzhe Sanatorium].

PMID- 10401260
TI  - [The 55th anniversary of the graduation of military physicians].

PMID- 10401261
TI  - Conferences--good practice or good fun?

PMID- 10401262
TI  - A qualitative study of the Victorian critical care nurse labour force.
AB  - A perceived shortage of critical care nurses in Victorian public and private
      hospitals, largely attributed to an increase in attrition from critical care
      areas and a failure to attract sufficient replacement for those who leave, served
      as the impetus for this project, which explored registered nurses' (RNs')
      attraction to and attrition from critical care practice areas. Multiple sources
      of data were utilised, including a series of individual interviews and focus
      group discussions with critical care students and past and current critical care
      nurses, telephone interviews with RNs who had completed a critical care re-entry
      course, interviews with key informants and an analysis of applications to study
      in a critical care postgraduate nursing course. Results revealed that the
      challenge of the work, intellectual stimulation, the high level of autonomy, use
      of increased knowledge and career development were primary motivators for RNs to
      engage in critical care practice. Limitations to lifestyle choices, practice
      demands, political changes within critical care arenas, inappropriate
      remuneration and a lack of career structure and opportunity were salient features
      of why employment was discontinued within the critical care practice areas.

PMID- 10401263
TI  - Rural people's experience of critical illness involving inter-hospital
      transportation: a qualitative study.
AB  - In recent years there has been a growing awareness of the problems people living
      in rural areas of Australia face in accessing health-care services. In
      particular, those experiencing a critical illness or major trauma and requiring
      specialist critical care services, often available only in metropolitan areas,
      may require inter-hospital transportation, usually by air ambulance. Management
      of such patients aims at achieving physiological stabilisation, organising the
      transfer and communicating with the transport team. As critical care nurses
      espouse a holistic approach to care, it is imperative that nursing practice aim
      to meet all the needs of these people. Therefore, critical care nurses should be
      aware of what such patients are experiencing. A qualitative research study, using
      Heideggerian hermeneutic phenomenology, was undertaken to explore the experiences
      of a group of people from rural NSW with a critical illness that necessitated
      their transfer by air ambulance to a metropolitan critical care unit for further
      management. Data analysis from interviews with the study participants revealed
      four major themes. This paper discusses the findings from one such theme, the
      impact of interhospital transportation, and highlights the anxiety and confusion
      experienced by rural people transferred to a metropolitan critical care unit.
      Recommendations for nursing care that minimises this anxiety and confusion are
      discussed.

PMID- 10401264
TI  - Artificial ventilation in the prone position.
AB  - Turning a ventilated patient into the prone position can greatly enhance arterial
      blood oxygenation independent of ventilator parameters. This article explores the
      physiology relating to pulmonary ventilation, highlighting an overall improvement
      in ventilation/perfusion matching as a result of the prone position. A series of
      small studies seems to suggest that prone positioning can have a dramatic effect
      on life-threatening hypoxia, including adult respiratory distress syndrome (ARDS)
      but as yet there have been no large, randomised, multi-centre trials to put
      beyond doubt the benefits of prone ventilation. Turning the patient prone
      precipitates many issues in caring for him/her in this position. Many are
      practical problems and the article goes on to explore a variety of these,
      including turning and positioning the patient, emergencies and access and the
      psychological effects of being in the prone position. It is important that nurses
      understand the physiological basis for any actions, including turning the patient
      prone, but it is also important that nurses doctors and other professionals
      appreciate the practical difficulties that this form of management can produce.
      All team members must work together to ensure a safe, cohesive approach to
      turning and caring for the ventilated patient in the prone position.

PMID- 10401266
TI  - Multiple sclerosis: an overview for nurses.

PMID- 10401265
TI  - Elderly trauma: they are different.
AB  - The elderly currently represent 11 per cent of the Australian population. By the
      year 2051 it has been estimated that 24 per cent of the population will be older
      than 65 years. One of the hazards facing the elderly is the risk of trauma. With
      this in mind, this paper has two major aims: one is to review the incidence and
      outcome of elderly trauma and the other is to identify pertinent points when
      assessing and managing the elderly trauma patient. Background information for
      this paper was obtained from the Australia Bureau of Statistics, Roads and
      Traffic Authority and Injury Surveillance Unit. A comprehensive literature review
      was then undertaken using the Medline and CINAHL databases.

PMID- 10401267
TI  - Will I make it through this choppy water? A psychological characteristic as a
      predeterminant factor to coping with multiple sclerosis.
AB  - The ability to cope with major stressors and adversity in our lives is as
      individual as the human experience. An unpredictable disease such as Multiple
      Sclerosis (MS) can demand major adjustments to one's lifestyle, employment, and
      personal relationships. Why is it that some sail smoothly through major upheaval
      in all of these realms despite the acquisition of significant physical disability
      while others are immobilized by seemingly trivial disruptions in their routine.
      How can we, as health professionals, assist those who are coping in a non
      adaptive manner, to identify and implement more effective strategies. Does
      focused counseling early in the disease promote effective coping? Existing
      literature reviews coping with chronic illness, detailing the tools and
      strategies which individuals may use to manage stressors. This paper will build
      on this foundation of knowledge. How well you are determines how well you cope.
      The emphasis will be on "premorbid" personality traits which may be critical to
      coping. The author will critically examine the practicality of utilizing existing
      assessment tools for those at differing stages of MS and offer assessment
      guidelines for nurses working both with newly diagnosed and well-established
      disease. Suggestions for counseling techniques which may promote effective coping
      behaviors will be offered. How an individual copes with a chronic illness such as
      MS has implications for that person's family, social network and society at
      large. Those who become overwhelmed by a disease such as MS will stop working
      earlier, utilize more healthcare resources, and rate themselves as having poor
      quality of life. Nurses and other health professionals who have regular contact
      with those with MS may be able to influence this scenario.

PMID- 10401268
TI  - Continuous intrathecal baclofen infusions. An introduction and overview.
AB  - Continuous intrathecal baclofen infusion (CIBI) is a relatively new treatment
      modality for severe spasticity of spinal cord origin. Literature review suggests
      relief of severe spasms and rigidity is proven with CIBI, in patients with spinal
      cord injury and multiple sclerosis, while ongoing research exists for patients
      with acquired brain injury and cerebral palsy. Criteria for patient selection,
      the screening trial process, an outline of the surgical procedure, and
      generalities of maintenance therapies, will be reviewed broadly as per
      literature, as well as specifically to the Vancouver experience with adults.
      Additionally, reported patient outcomes and implications for nursing will be
      shared.

PMID- 10401270
TI  - An ace up her sleeve

PMID- 10401269
TI  - New treatments for multiple sclerosis.

PMID- 10401271
TI  - Human sexuality in long-term care.
AB  - Sexual expression is a basic human need, a normal part of life that is integral
      to who we are as human beings. As we age, we continue to be challenged to grow in
      every area of our lives, including our sexuality. In institutionalized settings,
      however, human sexuality can be an area in which growth is not fostered, but
      restrained. Challenges leading to restraint include limited privacy, concerns
      about the consent of cognitively impaired sexual partners and conflicts with the
      personal values of institutional staff. Challenges exist in many areas, including
      inappropriate sexual expression toward a staff member or other residents.

PMID- 10401272
TI  - Telephone triage in acute oncology.
AB  - Cancer patients experience a variety of complex problems over the course of their
      illness. Shorter hospital stays and fewer inpatient beds have created additional
      challenges for patients diagnosed with cancer, as they often continue complicated
      treatment protocols as outpatients. As one result, patients and their families
      often telephone their physician or cancer clinic to seek advice.

PMID- 10401273
TI  - Strike contingency planning.
AB  - On Monday, February 26, 1996, the Ontario Public Service Employees Union (OPSEU)
      went on strike. The month-long strike included the 10 provincial psychiatric
      hospitals in Ontario. Within the psychiatric hospitals, the included direct care
      providers--RNs, RPNs, psychologists, social workers, occupational therapists--as
      well as support workers (food service, maintenance, housekeeping, and office
      employees). In anticipation, the mental health program at the London Health
      Science Centre (LHSC) developed a contingency plan that went into action when the
      strike was announced. This paper outlines the plan, describes what happened and
      makes recommendations for nurses who may be faced with similar situations.

PMID- 10401274
TI  - [Health care needs of students and personnel at a university].
AB  - Working with a professor and the head of a clinical laboratory, a group of
      nursing students interested in setting up a health clinic conducted an analysis
      of the health needs of students and staff at a university. The results high-light
      the importance of providing health activities to the entire university community.
      Many of the activities selected focus on prevention, screening and health
      promotion. Several could be conducted by nursing students as part of their career
      training.

PMID- 10401275
TI  - Managing risks in obstetrical nursing.

PMID- 10401276
TI  - Professional practice and parish nurses.

PMID- 10401277
TI  - Queen Tut of the island. Interview by Barbara Sibbald.

PMID- 10401278
TI  - Computers everywhere!

PMID- 10401279
TI  - Origin of the medical model.

PMID- 10401280
TI  - Rethinking nursing.

PMID- 10401281
TI  - The problem of patient vulnerability.
AB  - In a recent study undertaken in Western Australia to explore the quality of
      nursing care from the perspective of adult patients in acute care hospitals, the
      core problem found to be shared by the study participants was that of
      vulnerability. The study used grounded theory method and the main source of data
      was in-depth interviews with 23 patients following discharge from an array of
      hospitals. Vulnerability was related to an inability to retain control of their
      life situation and/or to protect themselves against threats to their integrity
      (physical and emotional wholeness, intactness). Different levels of vulnerability
      were found to indicate different types of nursing intervention in order to
      achieve positive outcomes in terms of patient satisfaction. Specific factors
      causing and contributing to patient vulnerability were identified. This paper
      presents these aspects of the study findings. Measures for reducing vulnerability
      are proposed.

PMID- 10401282
TI  - Patient or customer?
AB  - This paper investigates caring in practice within the context of the global
      imperative of increasing rationalisation of care based on an economic ethic. The
      notion of the global marketplace has spread to the domain of health services, so
      that 'health' has come to be seen as a commodity, with the body as its site, and
      the 'patient' a customer; clinicians work to construct standard pathways through
      the healthcare supermarket. The challenge for nurses is to work within but also
      to challenge and resist the reductionist impetus of economically based and
      commercially driven approaches to health care. They must retain the sense of the
      value of the wholeness of the person, the deeply personal and profoundly
      significant professional-recipient relationship, and find ways of demonstrating
      their capacity to deliver high-quality care in a cost-effective way. Proper and
      appropriate accountability is a key strategy to maintaining quality nursing as a
      significant aspect of care. The expansion of the role of the advanced practice
      nurse is very useful in providing holistic and cost-effective care, though there
      are currently limitations to scope of practice that need to be removed. The
      metaphor of the marketplace, underpinned by powerful global economic forces, can
      draw us into unthinking compliance with its imperatives--but other metaphors are
      available. Metaphor and creativity are linked, and we need to consider how the
      creative use of language can facilitate the emergence of new ways of
      understanding in health care.

PMID- 10401283
TI  - Reflective topical autobiography: an under utilised interpretive research method
      in nursing.
AB  - Reflective topical autobiography (an autobiographical method) belongs to the
      genre of testimonial research and is located within the postpositivist
      interpretive research paradigm. Despite the (reflective) topical autobiographical
      method enjoying a 'rebirth' in recent years and being utilised by a range of
      researchers in the human and literary disciplines, it remains largely unknown and
      under utilised in nursing research domains. In this article it is proposed that
      reflective topical autobiography is an important research method in its own
      right, and one which promises to make a substantive contribution to the overall
      project of advancing nursing inquiry and knowledge. This is particularly so where
      nursing research shares in the affirming projects of interpretive research
      generally and the relatively new sociology of the emotions in particular apropos:
      (i) increasing understanding of subjectivity and making subjective experiences
      more visible and intelligible, (ii) the search for meaning and increasing
      understanding of the commonality of existential human experience, and (iii)
      decentring the detached observer and his/her privileging the objectivist illusion
      in the hierarchy of research discourses, paving the way for the admission of
      multiple realities and interpretations of lived experience. In this article, a
      coherent reflective topical autobiographical research method is advanced for use
      in nursing education and research contexts.

PMID- 10401284
TI  - Beyond the sick role: situating community health nursing practice.
AB  - This grounded theory research into the role of the community health nurse in
      Australia identified that moving from the comfort and structure of an
      institutional setting to the client's turf results in profound changes to the
      purpose of nursing practice. Data were collected from 17 'excellent' community
      health nurses practising in a range of community health settings in three states
      of Australia. Data included transcripts from in-depth interviews, questionnaires,
      group discussions with participants, job descriptions, agency documentation,
      professional organisation documentation and focus groups. Data were analysed
      using constant comparative techniques. In community health nursing practice, the
      client's role changes from a sick role to a well role and there is a shift in
      responsibility for outcomes from the nurse to the client. The central purpose of
      the community health nursing role is to facilitate Situated Health Competence,
      which the client achieves within the context of going about their everyday life,
      including work, recreation, relationships and role responsibilities. Situated
      Health Competence requires families, groups and communities to address their own
      illnesses, health problems, health issues and health behaviours; have enough
      knowledge and power to make their own decisions; question matters that impact on
      their health; and seek out and access appropriate health resources on an ongoing
      basis. The findings of this study make the intangible motivations of the
      community health nurse more explicit. The aim of facilitating Situated Health
      Competence results in an expanded view of the boundaries of nursing practice. The
      traditional foci of nursing practice are still present, but are incorporated
      within a broader 'situated' role.

PMID- 10401286
TI  - TB on the rise.
AB  - In Australia, infection rates have remained stable over the last decade although
      drug resistance has increased from 0.7 percent in 1995 to two percent in 1996.
      Early detection and treatment together with the monitoring of compliance with and
      sensitivity to drug regimens is essential, as is careful management of those
      admitted to hospital. Because of the global distribution of tuberculosis and the
      presence within the population of groups with high rates of disease, tuberculosis
      control and management activities must be maintain and developed within Australia
      (Oliver & Harvey 1997).

PMID- 10401285
TI  - 'Concerning our national honour': Florence Nightingale and the welfare of
      aboriginal Australians.
AB  - Florence Nightingale was a prolific writer on many subjects from nursing to
      religion to hospital design and sanitary statistics. Her writing on the
      indigenous people of Australia is little known but should be of interest
      especially to those involved in the present desperate search for ways to improve
      the health of Australia's first settlers. Nightingale's evidence was second-hand,
      derived largely from missionaries, especially Bishop Salvado of the Benedictine
      foundation of New Norcia in Western Australia. This paper reviews the attitudes
      to Australian Aborigines which emerge from Nightingale's and others' writings and
      argues that their place in modern nursing is to stimulate a reappraisal of
      current attitudes to Aboriginal health.

PMID- 10401287
TI  - Web site review: web search tips.

PMID- 10401288
TI  - New era of reperfusion in acute myocardial infarction.

PMID- 10401289
TI  - Improving the care of cardiothoracic surgery patients through advanced nursing
      skills.
AB  - All the nurses in the cardiothoracic ICU are now certified in these advanced
      skills. The skills are reviewed with current staff members on a yearly basis
      during the annual evaluation. During their orientation to the cardiothoracic ICU,
      new staff nurses are certified by using the original process of attending an in
      service training program and demonstrating the skill 3 times. The quality
      management department reviews medical records daily to detect complications. In
      addition, we (DRZ and MB) conducted a quality assurance review in which we
      monitored 20 patients being extubated and having PA catheters removed by nurses.
      No complications were noted during either review. The institution has seen
      improvements in quality of care and earlier discharge from the hospital. With
      earlier removal of endotracheal tubes and PA catheters, patients are more
      comfortable and their rehabilitation can be advanced sooner. Comparison of the
      mean length of stay for patients undergoing coronary artery bypass graft in March
      1995 with the mean length of stay for such patients in March 1998 showed a 50.6%
      decrease, from 14.94 days to 7.38 days. These advanced skills have provided an
      increased autonomy for the nurses and have benefited the patients undergoing
      cardiac surgery in our institution.

PMID- 10401290
TI  - Cervical cancer: caring for patients undergoing total pelvic exenteration.

PMID- 10401291
TI  - Use of measurements of myoglobin and cardiac troponins in the diagnosis of acute
      myocardial infarction.
AB  - Research indicates that no tests of a single cardiac marker are 100% specific and
      sensitive for diagnosis of AMI in all patients. Each biomarker has advantages and
      disadvantages (see Table). Over-reliance on a single diagnostic test is risky.
      Specific tests should be ordered on the basis of the individual patient's
      assessment and medical history. Nurses are an important link in the collection of
      patients' medical history and in assessment as well as in the interpretation of
      patients' laboratory results. A knowledge of diagnostic tests commonly used in
      the care of patients with ischemic heart disease is imperative if patients are to
      receive appropriate, timely, cost-effective care.

PMID- 10401292
TI  - Nutritional assessment in the critically ill.

PMID- 10401293
TI  - Psychiatric aspects of transplantation, I: Evaluation and selection of
      candidates.

PMID- 10401294
TI  - The Synergy Model: linking patient needs to nurse competencies.

PMID- 10401295
TI  - Nutrition support for the mechanically ventilated patient.
AB  - Nutrition support is a hotly debated topic in most intensive care units. Is
      enteral nutrition or TPN best? Is gastric or small-bowel feeding safer? Are
      specialized formulas needed? These are only some of the issues, and the fact
      remains that there is a paucity of clear, solid data. Folklore has become the
      standard of practice in many areas of medicine; it is richly found in nutrition
      support. We must be careful not to get caught up in the trappings of our beliefs
      about nutrition support. Instead, we must continue to evaluate our own practices
      and fine-tune our skills of clinical assessment and common sense.

PMID- 10401296
TI  - Can a patient who has an endotracheal tube and is on mechanical ventilation be
      given ice chips?

PMID- 10401297
TI  - Healing touch therapy makes a difference in surgery unit.

PMID- 10401298
TI  - From the family perspective: critical care nurses are a critical link in organ
      donation.

PMID- 10401299
TI  - Referral, request, and consent for organ donation: best practice--a blueprint for
      success.

PMID- 10401300
TI  - Determining brain death.

PMID- 10401301
TI  - The role of critical care nurses in organ donation: a case study.

PMID- 10401302
TI  - Needs of families of organ donors: facing death and life.

PMID- 10401303
TI  - Ethical considerations in organ donation for critical care nurses.

PMID- 10401304
TI  - Organs from non-heart-beating donors: an answer to the organ shortage.

PMID- 10401306
TI  - A critical pathway: guiding care for organ donors.

PMID- 10401305
TI  - Xenotransplantation: the potential and the challenges.
AB  - Clinical use of xenotransplants is a potential way to provide care for a
      population of seriously ill patients and alleviate the demand for human organs.
      However, xenotransplantation also presents a spectrum of concerns, not only for
      individual patients but also for the public health, that must be discussed and
      dealt with in a science-based and public manner. Such discussions should take
      place on a national level and should include scientists, physicians, and policy
      makers from all countries in which the clinical use of xenografts is being
      considered.

PMID- 10401307
TI  - The Synergy Model: contemporary practice of the clinical nurse specialist.

PMID- 10401308
TI  - Arterial pressure monitoring.

PMID- 10401310
TI  - Integrated patient records benefit both patients and the healthcare team.

PMID- 10401311
TI  - Nursing in the cyberspace era.

PMID- 10401309
TI  - What is the most current recommendation for analgesic agents and pain management
      in patients with pancreatitis and other obstructive gastrointestinal (GI)
      disorders?

PMID- 10401312
TI  - [Enthusiasm about community health centers].

PMID- 10401313
TI  - [Safe use of the Orthographique II table in the operating room].

PMID- 10401315
TI  - [Info-Sante CLSC: accessibility, quality and efficiency are recognized].

PMID- 10401314
TI  - [Saguenay-Lac-Saint-Jean. The convalescent home Le Versant. Between hospital and
      the home].

PMID- 10401316
TI  - [The McGill model and local community service centers. A fetching combination].
AB  - How can the use of a specific conceptual model help nurses provide care that is
      best suited to their clients' real needs? The McGill model, for example, seems to
      be appropriate to community health applications, for it concentrates on health
      promotion and brings together all the elements underlying a family-development
      view of care. The authors of this article describe the basics of the McGill
      model, in terms of the four concepts of the nursing metaparadigm (health, the
      person, the environment and nursing (and discuss a concrete example of a health
      situation.

PMID- 10401317
TI  - [Collaboration CEGEP-CLSC. Learning one's profession with the clients].

PMID- 10401318
TI  - [Relief of chronic pain. Ethical aspects].

PMID- 10401319
TI  - [Distribution lists, a new source of information].

PMID- 10401320
TI  - [Giving more weight to calcium. Misplaced values] [In Process Citation]

PMID- 10401322
TI  - [Nutrition a la carte. Hypertension: search for a solution. Premenstrual
      syndrome: remember milk products] [In Process Citation]

PMID- 10401321
TI  - Shortage of nurses. Who will care for the baby boomers in 2005?

PMID- 10401323
TI  - [Interventions in a case of retrosternal pain] [In Process Citation]

PMID- 10401324
TI  - [Using one's place for political action].

PMID- 10401325
TI  - [Nurses in the era of cyberspace ... from collective conscience to collective
      intelligence].

PMID- 10401326
TI  - [Joya Balfour: "Join in!"] [In Process Citation]

PMID- 10401327
TI  - [Hend Abdel-Al is inviting the nurses past cyberspace] [In Process Citation]

PMID- 10401328
TI  - [Congress 1998. Helene Salette: a new place to meet the population] [In Process
      Citation]

PMID- 10401329
TI  - [Bibiane Courtois: woman, native and nurse. Interview by Emmanuele Garnier].

PMID- 10401331
TI  - [Systematic follow-up of patients with a cerebral vascular accident. A
      qualitative approach to care].

PMID- 10401330
TI  - [The project Metamorphosis. A new face on mental health].

PMID- 10401332
TI  - [A preoperative clinic at the heart of the ambulatory stage].

PMID- 10401333
TI  - [Women, the forgotten ones in AIDS research].

PMID- 10401334
TI  - [The "Dumas", an innovative tool for the evaluation of teaching experiential
      learning].

PMID- 10401335
TI  - Critical care--shifting boundaries and opening the doors.

PMID- 10401336
TI  - Implementation of associate practitioner roles within critical care.

PMID- 10401337
TI  - Roles of the allocated nurse and shift leader in the intensive care unit:
      findings of an ethnographic study.
AB  - In the UK, recent policy guidelines emphasize the role of nurses in managing the
      minute-by-minute care of critically ill patients (Department of Health 1996).
      This article reports on a study that explored the extent to which the nurse at
      the bedside (the allocated nurse) and the nurse in charge of the shift (the shift
      leader) make decisions about the needs of children who are critically ill. The
      study also identified areas of need using a modified Delphi study and explored
      how nurses perceive and act on the needs of critically ill children. These
      aspects are presented elsewhere.

PMID- 10401338
TI  - Acute confusion and unreal experiences in intensive care patients in relation to
      the ICU syndrome. Part II.
AB  - The intensive care unit syndrome (ICU syndrome) is defined as an altered
      emotional state occurring in a highly stressful environment, which may manifest
      itself in various forms such as delirium, confusion, crazy dreams or unreal
      experiences. The purpose of this part of a study of patients' experiences is to
      describe and illuminate patients' experiences of acute confusion, disorientation,
      wakefulness, dreams and nightmares during and after their stay in the ICU. The
      data were obtained from 19 ventilated patients, who were interviewed twice and
      had stayed at least 36 hours in the ICU, the first interview being about one week
      after discharge from the ICU, and the second 4-8 weeks later. The hermeneutic
      approach used when interpreting and analysing the text from the interviews
      revealed that patients' experiences of unreal experiences were often associated
      with intense fear. Intense or continuous unbearable fear seems to result in
      frightening unreal experiences, which further increase the level of fear. Care
      actions or caring relationships with relatives or nurses can reduce this fear,
      which can help to prevent the occurrence and/or duration and intensity of the
      unreal experiences. Trust and confidence in nurses or significant others and
      feelings of self-control or trust in self-control seemed to reduce the risk of
      unreal experiences so that adverse stimuli might only trigger a mild confusion.

PMID- 10401340
TI  - Measuring the outcome of paediatric intensive care.
AB  - This paper describes the background to the publication of the paediatric
      intensive care framework (NHS Executive 1997a) and sets out the case for outcome
      assessment of paediatric intensive care. Issues relating to mortality and
      morbidity assessment are discussed and several assessment tools are outlined. It
      is proposed that functional and psychological outcome assessments are important
      indicators of the quality of health care provision.

PMID- 10401339
TI  - Nurses' narrations about caring for inpatients with acute myocardial infarction.
AB  - The purpose of this study was to examine the meaning of lived experiences of
      caring for people affected by acute myocardial infarction. Thirty-four registered
      nurses at a Coronary Care Unit in the north of Sweden narrated their experiences
      of this specialized care of inpatients. The interview texts were transcribed and
      then interpreted using a phenomenological-hermeneutic method, inspired by the
      philosophy of Ricoeur. Two groups of texts were identified. One comprised
      'narratives about the patient' within which were the themes: 'distancing oneself
      from what is happening' and 'showing oneself as vulnerable'. The other was
      'narratives about caring', with the themes: 'reading of', 'adapting', 'coming
      close' and 'helping'. Various views on caring were disclosed and interpreted with
      reference to Martin Buber's philosophy. A comprehensive understanding of caring
      as oscillations between the poles distance and relation was formulated.

PMID- 10401341
TI  - Workforce dilemmas: a comparison of staffing in a generalist and a specialist
      intensive care unit.
AB  - Intensive care units are arguably one of the most costly resources a hospital has
      to maintain in terms of nursing staff, skills and technology. Given that the
      Government's agenda on quality remains one of obtaining cost-effective
      healthcare, it is imperative that nursing managers consider the implications of
      the new policy shift for how they currently provide services. The purpose in this
      paper is to compare the different staffing levels adopted by managers in
      generalized and neurosurgical intensive care in an acute hospital trust. The
      dilemmas facing managers making staffing decisions without any definitive
      guidelines for resourcing these specialized units are examined.

PMID- 10401342
TI  - Analgesics in the management of chronic pain. Part five: Step 3 parenteral
      analgesic drug therapy.
AB  - This, the last article in the series, describes the administration of analgesics
      other than via the enteral route in the treatment of chronic severe pain.

PMID- 10401344
TI  - Evidence-based care: issues in biomedical nursing

PMID- 10401343
TI  - Chest X-ray quiz. Pulmonary embolism with infarction.

PMID- 10401345
TI  - Research in peri-operative nursing care.
AB  - This review analyses 97 research reports dealing with peri-operative care which
      included patients. The literature review was done as the basis of a development
      project to measure the quality of intra-operative nursing care from the patient's
      perspective. The pre-operative phase provides information about the teaching,
      anxiety and stress of patients. Few sources dealt with the intra-operative phase;
      there were a small amount of reports concerning concrete nursing activities (e.g.
      surgical position and warming the patient). The most information was available on
      the post-operative phase, such as recovery, adaptation and the treatment of pain.
      Peri-operative research is mainly concerned with the quality of nursing care,
      control of life and ambulatory surgery. The main defects of analysed studies can
      be characterized as follows: small samples and a single hospital, lack of
      definition of terms, theoretical ambiguity, short follow-up times, anaesthetic or
      other drugs used during the care not mentioned in the report (especially in
      studies on pain and quality). Previously developed research tools had usually
      been well tested, but there was great variety in the testing of investigator
      constructed tools. There were also discrepancies in the evaluation of validity
      and reliability. Future research should especially deal with treatment of pain
      and anxiety, information and guidance given to patients, and the costs of
      surgical care; there is also a need for studies dealing with intra-operative care
      from the patient's perspective. Although information is already available on the
      above mentioned topics, more detailed and comprehensive facts are still needed.

PMID- 10401346
TI  - The implications of latex allergy in healthcare settings.
AB  - Latex allergy is on the increase. This paper focuses on how sensitization can
      occur and the use of latex gloves. Implications for the healthcare setting are
      addressed and recommendations made focusing on glove usage.

PMID- 10401347
TI  - Latex allergy: how to identify it and the people at risk.
AB  - Some patients and staff are more at risk to latex allergy than others. This paper
      identifies those people and the ways in which their allergy can be confirmed.
      Recommendations are made for their care and to prevent sensitization occurring.

PMID- 10401348
TI  - Testing an oral assessment guide during chemotherapy treatment in a Swedish care
      setting: a pilot study.
AB  - Oral complications are common in patients with haematological malignancies who
      undergo chemotherapy treatment. A pilot study including 16 haematological
      patients was carried out to evaluate the oral status using an Oral Assessment
      Guide (OAG) and to test the reliability of the OAG. The oral assessments were
      made daily by registered nurses at a Department of Internal Medicine in Sweden.
      Once a week a dental hygienist made the oral assessments independent of the
      registered nurses in order to provide data for calculations of inter-rater
      reliability. All patients had varying degrees of alterations in the oral cavity,
      especially in the mucous membranes, teeth/dentures and gums. The inter-rater
      agreement between the nurses and the dental hygienist was good for saliva and
      swallow, and moderate for voice and gums. Assessments to detect alterations in
      the oral cavity afford the opportunity for early and individualized interventions
      and may decrease the risk of oral infections. It is necessary to train the nurses
      to ensure high levels of reliability in the oral assessments. The OAG seems to be
      a reliable and clinical useful tool for assessing the oral cavity status and
      determining changes.

PMID- 10401349
TI  - Pain in older adults living in sheltered accommodation--agreement between
      assessments by older adults and staff.
AB  - This study aimed to investigate the presence of pain, pain duration,
      localization(s), intensity, type and pharmacological treatment among older adults
      living in sheltered accommodation or receiving rehabilitation, as well as the
      agreement between pain assessments performed by staff and the older adults.
      Twenty-nine randomly selected older adults (65+ years) and the staff who looked
      after them participated in a structured interview based on standardized measures
      for pain assessment and physical, intellectual and communicative functions. Pain
      was found to be common, with a majority of participants experiencing it every day
      or all of the time. Nine out of 22 of the older adults in pain had no pain relief
      drugs at all. Agreement between assessments by the older adults and the staff was
      no higher than moderate and in general pain levels were underestimated. The
      findings indicate that older adults were at risk of undetected and untreated pain
      and the risk was even higher for those with speech difficulties. The provision of
      good nursing care for older adults in sheltered accommodation requires systematic
      routines for frequent pain assessments.

PMID- 10401350
TI  - Pressure sore prevalence: a national survey.
AB  - A cross-sectional nation-wide sample was used to determine the point prevalence
      and grading of pressure sores in patients in all hospitals in Iceland (22
      hospitals). The pressure sore prevalence was 8.9% (n = 57 patients), 7.12% for
      women (n = 26) and 11.2% for men (n = 31); the mean age for both sexes with
      pressure sores was 78.4 years. Grade I sores were most frequently identified and
      Grade IV the least. Eighty-five per cent of pressure sores were located below the
      waist. 'No dressings' and occlusive dressings were the treatment of choice for
      pressure sores. Results from this study are important for international
      comparisons.

PMID- 10401351
TI  - Pain and the administration of analgesia: what nurses say.
AB  - Pain of moderate to severe intensity continues to be an important problem for
      many hospitalized patients. Nurses spend more time with patients than any other
      health professional group and have a key role to play in the management of
      patients' pain. This paper reports the findings from a series of focus group
      interviews which were undertaken to explore nurses' perceptions regarding pain
      and the administration of narcotic analgesia. Themes identified from
      participants' comments related to (1) the pivotal role of nurses in pain
      management; (2) nursing assessment and pain management decisions (3) individual
      factors influencing nurses' pain management decisions and (4) the influence of
      others on nurses' pain management decisions.

PMID- 10401352
TI  - Exercise and nursing therapy for patients with intermittent claudication.
AB  - Intermittent claudication is a common manifestation of arterial disease in the
      second half of life. Invasive treatments may be inappropriate or unsuccessful,
      leaving patients with a significant handicap. Nursing intervention can improve
      the functional ability and the general well-being of many patients. This paper
      provides an account of the development of an out-patient nursing service for
      patients with intermittent claudication. It focuses on the exercise training and
      the psychological support given to patients. A review of the first 102
      claudicants referred to the programme shows the outcome for the patients in terms
      of improved walking ability. The details of the nursing intervention reported in
      the paper should help the growing number of nurses starting similar programmes
      for vascular patients. They may also be of interest to nurses caring for patients
      with other chronic health problems.

PMID- 10401353
TI  - An evaluative study of the basic life support skills of nurses in an independent
      hospital.
AB  - This paper reports on a research study carried out in an independent hospital in
      the south east of England. The aim of the study was to assess the basic life
      support skills of nurses in order to compare the results with those reported for
      nurses in public hospitals. The findings show that the basic life support skills
      of the nurses studied are poor but no worse than those of their public sector
      colleagues.

PMID- 10401354
TI  - The risk of pressure sores: a conceptual scheme.
AB  - Based on a review of the literature related to the prediction and prevention of
      pressure sores, a conceptual scheme on pressure sores in introduced. The article
      highlights the four elements of the scheme: pressure, shearing force, tissue
      tolerance for pressure and tissue tolerance for oxygen. Factors influencing
      pressure and shearing forces, the pressure distribution capacity of tissue, the
      oxygen need of tissue and oxygen supply to tissue are discussed.

PMID- 10401355
TI  - Nutritional care of the patient: nurses' knowledge and attitudes in an acute care
      setting.
AB  - Concern is growing about the occurrence of malnutrition in hospitals throughout
      the developed world. Reduced involvement of nurses in patients' nutritional care
      may be one of the contributing factors. This study explored nurses' attitudes and
      knowledge about nutrition and food service in hospital. Semi-structured
      interviews were conducted with seven nurses from the internal medical service of
      a large Australian acute care hospital. Analysis of the interview transcripts
      revealed that many nurses lacked the in-depth knowledge needed to give proper
      nutritional care to their patients. Although nurses considered nutritional care
      to be important many had difficulty in raising its priority above other nursing
      activities, as a result of time constraints and multitasking issues. Several
      problems relating to food service arrangements were also highlighted. The
      findings suggest a need to raise nurses' awareness of the importance of nutrition
      in patient outcome. This study provides information which will guide in-service
      nurse education programs about nutrition, and suggests strategies for practice
      and organizational change.

PMID- 10401356
TI  - Routine post-natal perineal inspection by midwives.

PMID- 10401357
TI  - Dynamic high performance transplant teams: trust, talent, and collaboration.

PMID- 10401358
TI  - Promoting adherence to transplant medication regimens: a review of behavioral
      analysis.
AB  - Failure to adhere to complex behavioral regimens has been a significant and long
      standing problem in healthcare. Transplant recipients are one patient population
      that needs to learn and incorporate a multidimensional regimen of behaviors into
      their lives. The literature indicates that not all transplant recipients adhere
      to their medication regimens, which can lead to graft loss and possibly death.
      Behavioral analysis is often used to increase adherence to health-related
      regimens and has been effective for a variety of health conditions. The use of
      behavioral analysis as a strategy to promote adherence behaviors has not been
      reported in the transplant literature. Transplant coordinators and clinicians
      should learn the principles of behavioral analysis and apply them to the care of
      transplant recipients to facilitate recipients' lifelong adherence behaviors.

PMID- 10401359
TI  - The use of over-the-counter medications by transplant recipients: a guideline.
AB  - Over-the-counter medications are becoming increasingly available to the general
      public. One of the issues facing clinicians working with transplant recipients is
      how to advise patients regarding management of symptoms associated with common
      ailments. Minimal literature is available to assist the transplant coordinators
      in this process. This article describes the usual immunosuppressants prescribed
      for transplant recipients and the over-the-counter medications used to manage
      these symptoms, and provides recommendations for over-the-counter medications
      with the least side effects.

PMID- 10401360
TI  - Heart transplantation: a review.
AB  - This article explores current developments and continuing dilemmas in heart
      transplantation. Statistical trends such as the increased number of candidates
      and the increased waiting time are described. Recent developments in implantable
      ventricular assist device technology and the perioperative use of nitric oxide
      are also highlighted. In addition, advances in patient management from
      pretransplant care to long-term follow-up are presented, and alternatives to
      heart transplantation in current use and for the future are explored.

PMID- 10401361
TI  - Azathioprine monotherapy in HLA-identical live donor kidney transplant
      recipients.
AB  - The high success rate of HLA-identical sibling transplants and our previous
      experience with steroid-free immunosuppressive regimens and cyclosporine
      withdrawal prompted us to evaluate the safety and efficacy of monotherapy with
      azathioprine in 12 HLA-identical kidney transplant recipients with a serum
      creatinine concentration less than 176.8 mumol/L, a 1-way stimulatory index less
      than 2.0 in a post-transplant mixed lymphocyte culture, and a demonstrated
      tolerance of a minimum azathioprine dose of 1.0 mg/kg per day without leukopenia.
      Eleven of 12 patients were successfully converted to azathioprine monotherapy
      without a significant change in serum creatinine concentration for as long as 76
      months. Benefits of steroid and cyclosporine withdrawal included a significant
      reduction in mean systolic and diastolic blood pressure, number of blood pressure
      medications, total serum cholesterol, and glycohemoglobin in diabetic subjects.
      Our results suggest that azathioprine monotherapy is safe and effective in a
      select group of HLA-identical sibling transplants, but these benefits must be
      carefully balanced against an associated risk of precipitating acute allograft
      rejection.

PMID- 10401362
TI  - Program development and routine notification in a large, independent OPO: a 12
      year review.
AB  - Since its inception 12 years ago, a large, independent OPO experienced a 631%
      growth in the number of organ donors. These increases in organ recovery were
      achieved initially through successful mergers, and later, following the mergers,
      through focused management, OPO organizational development, and hospital
      marketing and system development. The cumulative percentage increases beginning
      in 1987 resulted in the OPO achieving 27.2 donors per million population. In 1996
      a system of routine notification of all hospital deaths was implemented and a 24
      hour communications center was operated. After 3 full years of routine
      notification, 73% of all deaths were called to the OPO, resulting in the
      following increases: total referrals, 691%; organ referrals, 41%; organ donors,
      16%; bone donors, 149%; skin donors, 123%; and heart valve donors, 78%. The 16%
      increase in organ donors was twice the national growth rate and significantly
      more than the 2% growth experienced by the OPO in the year preceding the
      implementation of routine notification. The OPO has demonstrated sustained growth
      over the past decade in a time when erosion of donor recovery levels is always a
      possibility and frequently a reality for many OPOs.

PMID- 10401363
TI  - Discriminant variables between organ donors and nondonors: a post hoc
      investigation.
AB  - CONTEXT: Few studies in organ donation have focused on the attitudes and opinions
      of families who were asked to donate the organs of a deceased relative.
      OBJECTIVE: To determine what variables influenced a family's decision to donate.
      DESIGN: Post hoc investigation using a survey. SETTING: Malaga, Spain.
      PARTICIPANTS: Seventy-one people who had been approached for the donation of
      their deceased relatives' organs at a single hospital. MAIN OUTCOME MEASURE:
      Consent to donate. RESULTS: Based on a stepwise discriminant function analysis,
      the following variables played a determining role in a family member's decision
      to donate: (1) the expressed wish of the deceased, (2) having a clear
      understanding of the definition of "brain death." (3) the manners and approach of
      the doctors, (4) the hospital facilities, (5) concerns regarding the donation
      process, and (6) educational level. CONCLUSION: Prodonation campaigns geared
      toward the public and hospital staff should focus on specific objectives to
      increase the likelihood of consent for organ donation.

PMID- 10401364
TI  - Dealing with the fear of mutilation in the donation discussion.
AB  - Fear of mutilation is a significant barrier to organ and tissue donation. It
      constitutes an example of Mystical Thinking and may be seen as an exemplar of
      animal learning or, more specifically, as a representation of the "blood phobia."
      As such the fear is not amenable to conventional public education efforts.
      Cognitive and behavioral techniques used in treating other types of phobias
      should be studied as a way to remove this barrier to donation.

PMID- 10401366
TI  - [Against tunnel anxiety] [In Process Citation]

PMID- 10401365
TI  - Willingness to donate organs and tissues in Vietnam.
AB  - CONTEXT: Few studies on public attitudes toward organ and tissue donation have
      been carried out in Asia. OBJECTIVE: To determine demographic influences on
      attitudes toward organ and tissue donation in Vietnam. DESIGN: Face-to-face
      interviews. SETTING: Tan Binh District, Ho Chi Minh City, Vietnam. PARTICIPANTS:
      Random sample of adults (N = 785). MAIN OUTCOME MEASURES: Awareness of donation
      and transplantation, acceptance of organ and tissue donation. RESULTS: 75% of
      respondents stated they had heard of organ or tissue donation, but only 55% were
      aware of organ and tissue transplantation taking place in Vietnam. Forty-eight
      percent of Buddhists and 27.5% of Christians had either no knowledge or incorrect
      knowledge about their religion's official position toward donation and
      transplantation. Sixty-four percent stated they would give consent for the
      donation of their decreased relative's tissues and organs, 66% would themselves
      become posthumous donors, and 21% to 22% would donate multiple organs and
      tissues. A significant association was found between respondents' acceptance of
      organ and tissue donation and their educational level, sex, occupation, and
      awareness of transplantation. Most respondents stated that their willingness to
      donate depended on whether other family members agreed. Many noted the importance
      of preventing commerce in organ and tissue transplantation but were in favor of
      providing healthcare for the donor's family or monetary incentives as a reward
      for donating. CONCLUSION: Nearly two thirds of urban Vietnamese surveyed were
      willing to donate organs or tissues after death. Their willingness was related to
      awareness of transplantation, sex, education level, and occupation.

PMID- 10401367
TI  - [Decubitus ulcer: faulty care or risk from illness].

PMID- 10401368
TI  - [Scabies is advancing--nursing personnel is particularly endangered].

PMID- 10401369
TI  - [Innocuous head cold or serious infection? The grippe (influenza)].

PMID- 10401370
TI  - [Nutrition for cancer patients].

PMID- 10401371
TI  - [Klehr's treatment with autologous blood cytokines has now been patented].

PMID- 10401372
TI  - [Importance of nutrition in ambulatory tumor therapy].

PMID- 10401373
TI  - [... and life goes on! The stoma and its care].

PMID- 10401374
TI  - [What is current status? Current status in the primary therapy of advanced
      ovarian cancer].

PMID- 10401375
TI  - [Ovarian cancer: the silent tumor. Facts].

PMID- 10401376
TI  - [Infanticide in India. Genital and anal injuries in little girls].

PMID- 10401377
TI  - [In praise of solitude. Solace in your own company].

PMID- 10401378
TI  - [In the treatment of pain Germany is still underdeveloped].

PMID- 10401379
TI  - [When our very future kills itself].

PMID- 10401380
TI  - [Suicide in children. No child really wants to die].

PMID- 10401381
TI  - [Crisis intervention and prevention in Switzerland. It is not simply going to get
      better].

PMID- 10401382
TI  - [Anthroposophic care. Visions of wholeness].

PMID- 10401383
TI  - [The patient in no man's land].

PMID- 10401385
TI  - [An accident that was not].

PMID- 10401384
TI  - [Short story].

PMID- 10401386
TI  - [The elderly person at home. Multidimensional geriatric evaluation].

PMID- 10401387
TI  - [A new master's degree in the field of health and social work].

PMID- 10401388
TI  - [Answering the needs of families of patients in intensive care. When a smile is
      gold].

PMID- 10401389
TI  - [Noise in intensive care units. Noise and commotion].

PMID- 10401391
TI  - [A patient's words].

PMID- 10401390
TI  - [Balint Prize 1998: Growing together. Sarah's story].

PMID- 10401392
TI  - [The Grinberg method: living, not surviving].

PMID- 10401393
TI  - [A person's rights. 2. Everybody has inalienable rights].

PMID- 10401394
TI  - [Burnout study. Nursing institutions should become active].

PMID- 10401395
TI  - Nursing at the millennium: looking back, looking forward.

PMID- 10401396
TI  - Crystallization of the professional self: a concentrated, senior clinical
      experience.
AB  - Senior baccalaureate nursing students (N = 10) just weeks away from graduation
      volunteered to participate in a concentrated clinical experience being offered at
      a large urban medical center new to them. Students worked with a preceptor for
      five consecutive 8-hour evening shifts on one of four general medical-surgical
      units, a pediatric unit, or an ambulatory surgery unit. Students lived in the
      hospital in available patient rooms for that week. A week after the experience,
      students participated in a focus group designed to elicit feedback about their
      experiences. Content analysis revealed that the two major categories that
      comprised the Crystallization of the Professional Self were (1) validating
      professional identity and (2) viewing the culture of work. This consolidated
      experience resulted in changes in self-image and in role expectations.

PMID- 10401397
TI  - Feminist ethics in women's health.

PMID- 10401398
TI  - Future realities in nursing: partnerships, practice, and economics.
AB  - Health care reform, innovations in technology, and the need to make health care
      cost-effective have affected all aspects of health care practice and education.
      Critical thinking skills, interpersonal and communication skills, leadership and
      motivation skills, computer literacy, and cultural sensitivity are all
      capabilities nursing graduates must now possess if they are to practice
      effectively in the complex and competitive contexts that today define the health
      care marketplace. Partnerships with community agencies are essential if faculty
      are to prepare a new generation of nurses who will be proficient in the skills
      that 21st-century nursing practice will demand. Although academic institutions
      have made some changes to meet marketplace demands, nursing educators,
      practitioners, and researchers must thoroughly reconceptualize their philosophies
      and retool their curricula in response to these changes.

PMID- 10401399
TI  - Role clarity, organizational commitment, and job satisfaction during hospital
      reengineering.
AB  - This study investigated the relationships among role conflict, role ambiguity,
      organizational commitment, and job satisfaction experienced by clinical team
      members in a hospital undergoing reengineering. The sample consisted of 409
      registered nurses (RNs) and 278 non-RNs. Participants who experienced much role
      conflict and ambiguity exhibited less organizational commitment and job
      satisfaction. RNs had more role conflict and ambiguity than non-RNs. No
      significant differences in role conflict and role ambiguity, organizational
      commitment, and job satisfaction were observed between RNs working on medical
      surgical units and those on specialty units. Strategies that reduce role conflict
      and role ambiguity to increase organizational commitment and job satisfaction are
      discussed.

PMID- 10401400
TI  - Baccalaureate nursing education and home health: a collaborative alliance.
AB  - Nursing educators are challenged to prepare practitioners to move out of acute
      care and perform competently in nontraditional settings. Faculty from a
      university college of nursing and registered nurse preceptors from 13 home health
      agencies formed an alliance to serve as co-educators for junior-level
      baccalaureate nursing students in a 35-hour, two-semester home health clinical
      rotation. The outcomes of this alliance were evaluated with a qualitative
      descriptive study that evaluated the effectiveness of the model. Content analysis
      of students' journal reflections revealed that the collaborative alliance in home
      health enabled students to integrate practice with theory and to view the new
      practice environment as a meaningful learning experience. Nurse preceptors
      serving as co-educators in the home setting were viewed as valuable role models
      who provided opportunities for active participation of students. In addition,
      this collaborative alliance enhanced students' assimilation of the principles of
      nontraditional practice and facilitated the personal and professional growth they
      needed to prepare them for nursing practice in the future.

PMID- 10401402
TI  - Looking around at home.

PMID- 10401401
TI  - Job satisfaction in a rural differentiated-practice setting.
AB  - This article reports the findings of a 3-year study that assessed the job
      satisfaction of nursing personnel in a rural nursing center that uses a
      differentiated practice model. Job satisfaction was measured using the Brayfield
      Job Satisfaction Questionnaire, the McCloskey/Mueller Satisfaction Survey, and
      the Job Descriptive Index. A high level of job satisfaction was found across all
      3 years. Factors associated with job satisfaction are also described. The
      findings of this study add to the growing body of literature on the importance of
      differentiated practice in creating satisfying work environments.

PMID- 10401403
TI  - What to do with febrile children.

PMID- 10401404
TI  - What are midwives doing in neonatal intensive care units?

PMID- 10401405
TI  - Caring for babies and children with dry skin.

PMID- 10401406
TI  - Managing diabetes in children and adolescents: 2.

PMID- 10401407
TI  - Preterm babies: effects of early diet on later IQ.

PMID- 10401408
TI  - Scabies: a practical approach.

PMID- 10401409
TI  - "I'd have given anyone a hundred pounds for a fag!".

PMID- 10401410
TI  - Uptake and timing of immunisations in preterm and term infants.
AB  - Preterm infants are more at risk of complications from infectious disease and
      should be immunised as a matter of priority. This retrospective study followed
      the immunisations given to 110 premature infants and 220 control term infants
      admitted to the Neonatal Unit at the Royal United Hospital, Bath over a 12-month
      period. The overall immunisation uptake for infants admitted to the neonatal unit
      was 99.93, better than for the general population of the area. However, in both
      preterm and term infants there were considerable variations in the age at which
      each immunisation was given. Fewer of the preterm infants had their first three
      immunisations on time. The difference in timings between the two groups was
      statistically significant. Earlier immunisations were more often given on time
      than later ones. The greater the gestational age, the more likely that the infant
      would be immunised at the correct times. It is important to stress to parents the
      importance of immunisation for babies who are born prematurely or who have been
      unwell.

PMID- 10401412
TI  - [Letter of a private nurse to the medical service in control] [In Process
      Citation]

PMID- 10401411
TI  - Family therapy: current thinking and practice.

PMID- 10401413
TI  - [The clinic of Medecins du Monde at Lyons: health in spite of exclusion].

PMID- 10401414
TI  - [Answering calls for service by the physicians on duty by nursing students].

PMID- 10401416
TI  - [The skin and scar formation].

PMID- 10401417
TI  - [Prevention of the complications of decubitus ulcers].

PMID- 10401415
TI  - [Results of a year of training nursing students in resuscitation].

PMID- 10401418
TI  - [Decubitus ulcers should not exist...].

PMID- 10401419
TI  - [Treatment, care and nursing supervision of decubitus ulcers].

PMID- 10401420
TI  - [Prevention of decubitus ulcers].

PMID- 10401421
TI  - [Care of patients hospitalized for polysomnography].

PMID- 10401422
TI  - [Taking charge of many burn victims within a humanitarian assistance set-up.
      Adaptation of principles to local conditions: the catastrophe in N'sam (Cameroon)
      in 1998].

PMID- 10401423
TI  - [A small lexicon of molecular genetics].

PMID- 10401424
TI  - [Psychological determinants for the motivation of nurses in their work].

PMID- 10401425
TI  - [Working in psychiatry today].

PMID- 10401426
TI  - [The psychomotor therapist within the patient care team].

PMID- 10401427
TI  - [Why would one want to be a psychiatric nurse?].

PMID- 10401428
TI  - [Psychiatry and social problems].

PMID- 10401429
TI  - [The nursing diploma, between ethics and the recurrence of the problem of
      madness].

PMID- 10401430
TI  - [The 15 socio-psychiatric encounters] [In Process Citation]

PMID- 10401431
TI  - [Talking about the Joly report].

PMID- 10401432
TI  - [Talking about the "club"].

PMID- 10401433
TI  - [A new rubric: "Keeping together"].

PMID- 10401434
TI  - [Surfing in nursing care].

PMID- 10401435
TI  - [School nurses are angry] [In Process Citation]

PMID- 10401437
TI  - [Nursing care in mental health and in psychiatry] [In Process Citation]

PMID- 10401436
TI  - [The 1st President of the French Nursing Association has died] [In Process
      Citation]

PMID- 10401439
TI  - [Hospitals seeking hospitality] [In Process Citation]

PMID- 10401438
TI  - [Education and the needs of psychiatry, a necessary adaptation] [In Process
      Citation]

PMID- 10401441
TI  - Evidence of clozapine's effectiveness in schizophrenia: a systematic review and
      meta-analysis of randomized trials.
AB  - OBJECTIVE: The purpose of this study was to evaluate all available trial-based
      evidence on the effectiveness of clozapine in schizophrenia as compared with
      conventional neuroleptics. METHOD: All randomized, controlled trials comparing
      clozapine with a conventional neuroleptic in which there was satisfactory
      concealment of patients' treatment allocation were located through electronic
      searches in all languages of several databases and through contacting authors of
      recent trials as well as the manufacturer of clozapine. At least two independent
      reviewers assessed trials for inclusion in the study and extracted data for meta
      analysis. RESULTS: The review included 2,530 randomly assigned participants in 30
      trials, most of them short-term. Clozapine-treated patients showed more clinical
      improvement and experienced significantly fewer relapses during treatment,
      although the risk of blood dyscrasias in long-term treatment may be as high as
      7%. Scores on symptom rating scales showed greater improvement among clozapine
      treated patients, who were also more satisfied with their treatment. However,
      there was no evidence that the superior clinical effect of clozapine is reflected
      in levels of functioning; on the other hand, global functional and pragmatic
      outcomes were frequently not reported. Clinical improvement was most pronounced
      in patients with treatment-resistant illness. CONCLUSIONS: This meta-analysis
      confirms that clozapine is more effective than conventional neuroleptics in
      reducing symptoms of patients with both treatment-resistant and nonresistant
      schizophrenia. Future trials should be long-term pragmatic community trials or
      should address the effectiveness of clozapine in special patient populations. An
      international standard set of outcomes, including pragmatic assessments of
      functioning, would greatly enhance the comparison and summation of trials and
      future assessments of effectiveness.

PMID- 10401442
TI  - Recurrence after recovery from major depressive disorder during 15 years of
      observational follow-up.
AB  - OBJECTIVE: The recurrence of an affective disorder in people who initially
      recover from major depressive disorder was characterized by using the unique
      longitudinal prospective follow-up data from the National Institute of Mental
      Health Collaborative Program on the Psychobiology of Depression-Clinical Studies.
      METHOD: Up to 15 years of prospective follow-up data on the course of major
      depressive disorder were available for 380 subjects who recovered from an index
      episode of major depressive disorder and for 105 subjects who subsequently
      remained well for at least 5 years after recovery. Baseline demographic and
      clinical characteristics were examined as predictors of recurrence of an
      affective disorder. The authors also examined naturalistically applied
      antidepressant therapy. RESULTS: A cumulative proportion of 85% (Kaplan-Meier
      estimate) of the 380 recovered subjects experienced a recurrence, as did 58%
      (Kaplan-Meier estimate) of those who remained well for at least 5 years. Female
      sex, a longer depressive episode before intake, more prior episodes, and never
      marrying were significant predictors of a recurrence. None of these or any other
      characteristic persisted as a predictor of recurrence in subjects who recovered
      and were subsequently well for at least 5 years. Subjects reported receiving low
      levels of antidepressant treatment during the index episode, which further
      decreased in amount and extent during the well interval. CONCLUSIONS: Few
      baseline demographic or clinical characteristics predict who will or will not
      experience a recurrence of an affective disorder after recovery from an index
      episode of major depressive disorder, even in persons with lengthy well
      intervals. Naturalistically applied levels of antidepressant treatment are well
      below those shown effective in maintenance pharmacotherapy studies.

PMID- 10401443
TI  - Medications versus cognitive behavior therapy for severely depressed outpatients:
      mega-analysis of four randomized comparisons.
AB  - OBJECTIVE: The purpose of this study was to compare the acute outcomes of
      antidepressant medication and cognitive behavior therapy in the severely
      depressed outpatient subgroups of four major randomized trials. A secondary
      objective was to compare the results obtained in the National Institute of Mental
      Health Treatment of Depression Collaborative Research Program, upon which
      treatment guidelines have been based, with those obtained in the other three
      studies. METHOD: Outcomes of antidepressant medication and cognitive behavior
      therapy were compared within each of the four studies separately and for patients
      aggregated across the four studies. In addition, the outcomes in the
      antidepressant medication and cognitive behavior therapy conditions of the
      Treatment of Depression Collaborative Research Program were compared with those
      obtained in the other three studies. RESULTS: The overall effect sizes comparing
      antidepressant medication to cognitive behavior therapy favored cognitive
      behavior therapy, but tests comparing the two modalities did not reveal a
      significant advantage for either modality overall. CONCLUSIONS: Cognitive
      behavior therapy has fared as well as antidepressant medication with severely
      depressed outpatients in four major comparisons. Until findings emerge from
      current or future comparative trials, antidepressant medication should not be
      considered, on the basis of empirical evidence, to be superior to cognitive
      behavior therapy for the acute treatment of severely depressed outpatients.

PMID- 10401444
TI  - Therapeutic drug monitoring of mood stabilizers in Medicaid patients with bipolar
      disorder.
AB  - OBJECTIVE: The authors' goal was to determine the extent and pattern of blood
      serum monitoring of mood stabilizers in Medicaid patients with bipolar disorder.
      METHOD: Data were drawn from a Medicaid medical claims data set from Pittsburgh
      and the surrounding region. The authors identified bipolar patients using
      lithium, valproate, and carbamazepine (N = 718) and then examined the patient
      demographic, diagnostic, and service use variables associated with therapeutic
      drug monitoring. RESULTS: A substantial proportion of lithium users (36.5%),
      valproate users (42.4%), and carbamazepine users (42.2%) with bipolar disorder
      diagnoses did not receive therapeutic drug level testing during the 12-month
      study period. Carbamazepine users who were male or in the 30-49-year age range
      were significantly less likely to be tested for serum drug level. Lithium users
      who did not receive partial-hospitalization psychiatric services and valproate
      users who received mental health case management were also less likely to be
      tested for serum drug level. Over one-half of the lithium users (54.1%) did not
      receive thyroid function tests, and few (4.2%) received renal function tests.
      Patients who did receive tests for serum drug level were likely to receive the
      other recommended tests. CONCLUSIONS: Many Medicaid patients with bipolar
      disorder received no therapeutic drug monitoring. Patient sociodemographic
      characteristics contributed little to explaining this omission, although some
      types of service utilization were related to rates of serum drug level testing.

PMID- 10401446
TI  - Treatment of major depression with nortriptyline and paroxetine in patients with
      ischemic heart disease.
AB  - OBJECTIVE: This study compared the efficacy, tolerability, and safety of
      paroxetine and nortriptyline in depressed patients with ischemic heart disease.
      METHOD: After a 2-week, single-blind placebo lead-in phase, 81 outpatients with
      DSM-III-R-defined nonpsychotic unipolar major depression and ischemic heart
      disease were randomly assigned to double-blind treatment with paroxetine or
      nortriptyline for 6 weeks. Paroxetine was administered at a fixed-flexible dose
      of 20-30 mg/day. Nortriptyline dose was adjusted with the use of blood-level
      monitoring to reach a plasma concentration of 50-150 ng/ml. RESULTS: Twenty-seven
      of the 41 patients who started treatment with paroxetine and 29 of the 40
      patients who started treatment with nortriptyline had an improvement of at least
      50% in their Hamilton Depression Rating Scale scores. Significantly more patients
      taking nortriptyline discontinued treatment prematurely (35% versus 10%), and
      more patients taking nortriptyline had adverse events resulting in termination
      (25% versus 5%). CONCLUSIONS: Both treatments were efficacious. Sixty-three
      percent of all patients improved at least 50%, and of these, 90% met the criteria
      for remission. Paroxetine was better tolerated than nortriptyline and less likely
      to produce cardiovascular side effects.

PMID- 10401445
TI  - Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder.
AB  - OBJECTIVE: New mood stabilizers are needed that possess efficacy for all phases
      of bipolar disorder. This study was designed to provide preliminary evidence for
      the safety and efficacy of a new anticonvulsant, lamotrigine, in adult patients
      with bipolar disorder who had been inadequately responsive to or intolerant of
      prior pharmacotherapy. METHOD: A 48-week, open-label, prospective trial was
      conducted in 75 patients with bipolar I or bipolar II disorder. Lamotrigine was
      used as adjunctive therapy (N = 60) or monotherapy (N = 15) in patients
      presenting in depressed, hypomanic, manic, or mixed states. RESULTS: Of the 40
      depressed patients included in the efficacy analysis, 48% exhibited a marked
      response and 20% a moderate response as measured by reductions in 17-item
      Hamilton Depression Rating Scale scores. Of the 31 with a hypomanic, manic, or
      mixed state, 81% displayed a marked response and 3% a moderate response on the
      Mania Rating Scale. From baseline to endpoint, the depressed patients exhibited a
      42% decrease in Hamilton depression scale scores, and the patients presenting
      with hypomania, mania, or a mixed state exhibited a 74% decrease in Mania Rating
      Scale scores. The most common drug-related adverse events were dizziness, tremor,
      somnolence, headache, nausea, and rash. Rash was the most common adverse event
      resulting in drug discontinuation (9% of patients); one patient developed a
      serious rash and required hospitalization. CONCLUSIONS: These open-label data
      provide preliminary evidence that lamotrigine may be an effective treatment
      option for patients with refractory bipolar disorder; however, potential benefits
      must be weighed against potential side effects, including rash.

PMID- 10401447
TI  - Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging
      study.
AB  - OBJECTIVE: Widespread disturbances of serotonin (5-HT) are implicated in the
      pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most
      replicated finding is increased 5-HT2 receptor binding in the postmortem
      prefrontal cortex of depressed suicide victims. The extent to which these
      findings exist in depressed persons without recent suicide attempts is uncertain.
      The objective of this study was to evaluate 5-HT2 receptors in depressed patients
      who were medication-free and who had not made recent suicide attempts. METHOD:
      With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2
      receptor binding potential was assessed in 14 depressed and 19 healthy subjects.
      Exclusion criteria for depressed patients included use of antidepressant
      medication within the past 6 months, a history of suicide attempts within the
      past 5 years, other current axis I disorders including bipolar disorder, and the
      presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the
      two groups of subjects was compared by analysis of covariance with age as the
      covariate. RESULTS: Age had a significant effect on 5-HT2 binding potential, but
      depression did not. The interaction of age and depression was not significant.
      CONCLUSIONS: The 5-HT2 binding potential is not increased in untreated depressed
      subjects who have not made recent suicide attempts. This negative finding does
      not rule out the possibility that there is a role for 5-HT2 receptors in
      treatment or that 5-HT2 receptors are increased in highly suicidal states.

PMID- 10401448
TI  - Memory self-appraisal in middle-aged and older adults with the apolipoprotein E-4
      allele.
AB  - OBJECTIVE: Because subjective memory complaints may indicate subtle functional
      brain abnormalities, the authors studied the influence of the major genetic risk
      for Alzheimer's disease, the apolipoprotein E-4 (APOE-4) allele, on self-reports
      of memory performance in middle-aged and older adults. METHOD: Subjective and
      objective assessments of memory performance were compared in relation to the
      presence or absence of the APOE-4 allele in 39 cognitively intact persons with
      mild memory complaints. RESULTS: Subjects with the APOE-4 allele had lower scores
      on objective verbal memory and on the subjective memory measure for retrospective
      functioning. Among the subjects in the age range where APOE-4 has its greatest
      influence on the risk of Alzheimer's disease (55-74 years), the APOE-4 group had
      lower scores on the subjective memory measure for frequency of forgetting.
      Moreover, the standardized difference in retrospective functioning scores between
      the two genetic risk groups increased when the mid-age-range group was examined
      rather than the whole study group. CONCLUSIONS: The APOE-4 allele is associated
      with increased subjective memory impairment in middle-aged and older adults.
      Longitudinal studies of age-related memory loss should include genetic risk and
      subjective memory measures as potential predictors of decline.

PMID- 10401449
TI  - Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical and
      neuropathological comparative study with Alzheimer's disease.
AB  - OBJECTIVE: The literature reports considerable variation in the rates of
      psychiatric morbidity for patients with dementia with Lewy bodies. The authors
      intended to clarify the frequency of psychiatric morbidity in dementia with Lewy
      bodies and how it differs from probable Alzheimer's disease. METHOD: The study
      incorporated two groups--a clinical case register cohort (98 with dementia with
      Lewy bodies; 92 with Alzheimer's disease) and 80 (40 with dementia with Lewy
      bodies: 40 with Alzheimer's disease) prospectively studied, neuropathologically
      confirmed cases. Diagnoses were made by using the McKeith et al. consensus
      criteria for dementia with Lewy bodies and the National Institute of Neurological
      and Communicative Disorders and Stroke and the Alzheimer's Disease and Related
      Disorders Association criteria for Alzheimer's disease. Neuropathological
      diagnoses were made by using the consensus criteria for dementia with Lewy bodies
      and the Mirra et al. protocol for Alzheimer's disease. RESULTS: The occurrence of
      psychiatric symptoms was reported over 1 month. Hallucinations, depression,
      delusions, and delusional misidentification were all significantly higher for
      patients with dementia with Lewy bodies. The differences in frequency between
      dementia with Lewy bodies and Alzheimer's disease for auditory and visual
      hallucinations were especially pronounced for patients with mild cognitive
      impairment. The presence of psychiatric symptoms at presentation was a better
      discriminator between dementia with Lewy bodies and Alzheimer's disease than
      occurrence over the course of dementia. CONCLUSIONS: Delusional misidentification
      and hallucinations in the early stages of dementia may improve differentiation
      between patients with dementia with Lewy bodies and those with Alzheimer's
      disease and have important treatment implications.

PMID- 10401450
TI  - Normalization of information processing deficits in schizophrenia with clozapine.
AB  - OBJECTIVE: The authors tested the hypothesis that the use of an atypical drug,
      clozapine, for patients with schizophrenia is related to less impairment in
      information processing deficits (assessed by prepulse inhibition of the startle
      response) than is the use of typical antipsychotics. METHOD: Two groups of
      schizophrenic patients--receiving either clozapine or a range of typical
      antipsychotics--were tested for prepulse inhibition (a reduction in response to a
      starting stimulus, if preceded briefly by a weak, nonstartling stimulus; measured
      at prepulse-to-pulse intervals of 30 msec, 60 msec, and 120 msec) of the acoustic
      startle response and compared with a group of healthy volunteers. RESULTS:
      Patients receiving typical antipsychotics showed less prepulse inhibition with 30
      msec and 60-msec prepulse trials than did comparison subjects. Clozapine-treated
      patients showed normal levels of prepulse inhibition. CONCLUSIONS: Clozapine is
      superior to typical antipsychotics in normalizing prepulse inhibition, presumably
      because of its pharmacological effects on prefrontal regions of the brain or its
      effects on a broader range of neuroreceptors.

PMID- 10401451
TI  - Electrophysiological correlates of language processing in schizotypal personality
      disorder.
AB  - OBJECTIVE: This study examined whether the electrophysiological correlates of
      language processing found previously to be abnormal in schizophrenia are also
      abnormal in schizotypal individuals. The authors used the N400 component to
      evaluate language dysfunction in schizotypal individuals. METHOD: Event-related
      potentials were recorded in 16 comparison subjects and 17 schizotypal individuals
      (who met full DSM-III-R criteria) to sentences presented both visually and
      aurally; half of the sentences ended with an expected word completion (congruent
      condition), and the other half ended with an unexpected word completion
      (incongruent condition). RESULTS: In the congruent condition, the N400 amplitude
      was more negative in individuals with schizotypal personality disorder than in
      comparison subjects in both the visual and auditory modalities. In addition, in
      the visual modality, the N400 latency was prolonged in the individuals with
      schizotypal personality disorder. CONCLUSIONS: The N400 was found to be abnormal
      in the individuals with schizotypal personality disorder relative to comparison
      subjects. The abnormality was similar to the abnormality the authors' laboratory
      reported earlier in schizophrenic subjects, in which the N400 amplitude was found
      to be more negative in both congruent and incongruent sentence completions. The
      N400 abnormality is consistent with the inefficient use of context.

PMID- 10401452
TI  - Earlier puberty as a predictor of later onset of schizophrenia in women.
AB  - OBJECTIVE: The aim of this study was to determine whether puberty plays a
      mediating role in onset of schizophrenia. The hypothesis was that there is an
      inverse relation between age at puberty (menarche) and age at onset in women.
      METHOD: Competent and consenting individuals with DSM-IV-defined schizophrenia or
      schizoaffective disorder and their mothers underwent a 45-minute interview to
      ascertain age at first odd behavior, age at first psychotic symptoms, age at
      first hospitalization, and ages at various indices of puberty. Information about
      substance use, head injury, perinatal trauma, and first-degree family history of
      schizophrenia was also obtained. RESULTS: In the women (N = 35), the earlier the
      age at menarche, the later the ages at both the first psychotic symptoms and the
      first hospitalization. There was no significant association between puberty and
      onset in the men (N = 45). Other than gender, none of the examined variables
      played a role in the interaction of puberty and onset of illness. CONCLUSIONS: In
      women, early puberty (whether through hormonal or social influence) was
      associated with later onset of schizophrenia. This effect was not found in men;
      in fact, the trend was in the opposite direction.

PMID- 10401454
TI  - Clinical needs assessment of middle and high school students following the 1995
      Oklahoma City bombing.
AB  - OBJECTIVE: This clinical assessment was designed to identify middle and high
      school students in need of formal evaluation for posttraumatic response symptoms
      following the 1995 bombing of the Alfred P. Murrah Federal Building in Oklahoma
      City. METHOD: A clinical needs assessment instrument was developed and
      administered to grade 6 through 12 students 7 weeks after the bombing (N =
      3,218). RESULTS: More than 40% of the students reported knowing someone injured,
      and more than one-third reported knowing someone killed in the blast.
      Posttraumatic stress symptoms at 7 weeks significantly correlated with gender,
      exposure through knowing someone injured or killed, and bomb-related television
      viewing. CONCLUSIONS: This study documents the intensity of community exposure to
      the bombing and the lingering symptoms of stress. The assessment was used in
      planning for clinical service delivery, training professional responders, and
      supporting funding requests.

PMID- 10401453
TI  - Including children and adolescents with schizophrenia in medication-free
      research.
AB  - OBJECTIVE: There has been an increasing focus on the ethical issues raised by
      studies requiring the withdrawal of effective medication in schizophrenic adults.
      This article examines the risks and benefits of a medication-free period for
      pediatric patients with treatment-refractory schizophrenia who are participating
      in an ongoing study. METHOD: Between April 1993 and March 1998, 31 children and
      adolescents were admitted with a diagnosis of treatment-resistant, childhood
      onset schizophrenia. Parental consent was obtained so that patients could
      participate in a medication-free research period. Patients were evaluated at
      screening, at the end of a 4-week washout, at the completion of a 6- to 8-week
      atypical neuroleptic trial, and at a 2- to 4-year follow-up. RESULTS: At the
      completion of a 4-week drug-free period, seven patients (23%) were diagnosed with
      another disorder on the basis of data gained from the drug-free period and their
      lack of schizophrenic symptoms. Their revised diagnoses were posttraumatic stress
      disorder (N = 1), an atypical psychosis labeled "multidimensionally impaired" (N
      = 4), and personality disorder (N = 2). At follow-up, three of these patients
      remained free of neuroleptic therapy. For eight patients (26%), the washout was
      curtailed because of rapid and severe deterioration of their schizophrenic
      symptoms. CONCLUSIONS: For children and adolescents with treatment-refractory
      schizophrenia, a medication-free period can be conducted safely for at least 4
      weeks for inpatients. Such trials are useful on clinical grounds and for
      providing homogeneous patient groups for research. This study also highlights the
      necessity of having access to hospitalization to observe children and adolescents
      with psychotic symptoms while medication free.

PMID- 10401455
TI  - Anniversary reactions in Gulf War veterans: a follow-up inquiry 6 years after the
      war.
AB  - OBJECTIVE: The goal of this study was to assess the occurrence of anniversary
      reactions in Gulf War veterans 6 years after the conclusion of the war. METHOD:
      Subjects were administered questionnaires and asked to identify specific months
      of best and worst functioning and months of least or most symptoms of
      posttraumatic stress disorder (PTSD) for the 12 months before the study. Months
      of negative experiences were compared with previously documented dates of
      exposure to traumatic events during the war. Similar reports were also obtained
      from the veterans' spouses in order to assess corroborative evidence for the
      occurrence of anniversary reactions. RESULTS: Anniversary reactions occurred with
      a frequency greater than chance and most often in individuals exposed to a
      greater number of traumatic events. Overall, spouse reports matched the veterans'
      reports of anniversary reactions. In addition, spouses identified anniversary
      reactions that were not endorsed by their veterans. CONCLUSIONS: These data
      suggest that anniversary reactions occur in numbers greater than those expected
      by chance, are correlated to the occurrence of traumatic events, and may be a
      part of the syndrome of PTSD.

PMID- 10401456
TI  - Psychological defense styles in women who report childhood sexual abuse: a
      controlled community study.
AB  - OBJECTIVE: The psychological defense styles of women who reported childhood
      sexual abuse were assessed and compared to those of women without childhood
      sexual abuse. METHOD: Subjects in a random community sample (N = 354) of New
      Zealand women were interviewed and completed two relevant questionnaires, the
      Defense Style Questionnaire and the Dissociative Experiences Scale. RESULTS:
      Women reporting childhood sexual abuse showed more immature defense styles, and
      those who experienced the most severe childhood sexual abuse showed the most
      immature styles. Dissociation, however, as measured on the Dissociative
      Experiences Scale, was not linked to childhood sexual abuse. CONCLUSIONS:
      Reporting childhood sexual abuse was associated with more immature coping styles,
      although not dissociation, in this community sample of women. Coping styles are
      likely to be a major mechanism through which childhood sexual abuse increases
      rates of later psychological problems.

PMID- 10401457
TI  - A dilemma born of progress: switching from clozapine to a newer antipsychotic.

PMID- 10401459
TI  - Awareness of illness and subjective experience of cognitive complaints in
      patients with bipolar I and bipolar II disorder.
AB  - OBJECTIVE: The authors' goal was to investigate the awareness of illness and
      subjective cognitive complaints of patients with either bipolar I disorder or
      bipolar II disorder during a phase of clinical stabilization. METHOD: They used a
      structured clinical interview, the Frankfurt Complaints Questionnaire, to
      determine subjective cognitive complaints, and the Scale of Unawareness of Mental
      Disorder to assess 57 consecutively enrolled patients with bipolar I or bipolar
      II disorder. RESULTS: Patients with bipolar II disorder had significantly less
      insight and a higher level of subjective complaints of stimulus overload than
      patients with bipolar I disorder. CONCLUSIONS: These results suggest that a
      severe deficit in self-awareness may constitute a distinguishing
      psychopathological characteristic of patients with bipolar II disorder. Further
      studies are required to determine if there are associated neuropsychological
      dysfunctions.

PMID- 10401458
TI  - Subgenual cingulate cortex volume in first-episode psychosis.
AB  - OBJECTIVE: Gray matter volume and glucose utilization have been reported to be
      reduced in the left subgenual cingulate of subjects with familial bipolar or
      unipolar depression. It is unclear whether these findings are secondary to
      recurrent illness or are part of a familial/genetic syndrome. The authors' goal
      was to clarify these findings. METHOD: Volumetric analyses were performed by
      using magnetic resonance imaging in 41 patients experiencing their first episode
      of affective disorder or schizophrenia and in 20 normal comparison subjects.
      RESULTS: The left subgenual cingulate volume of the patients with affective
      disorder who had a family history of affective disorder was smaller than that of
      patients with affective disorder with no family history of the illness and the
      normal comparison subjects. Patients with schizophrenia did not differ from
      comparison subjects in left subgenual cingulate volume. CONCLUSIONS: Left
      subgenual cingulate abnormalities are present at first hospitalization for
      psychotic affective disorder in patients who have a family history of affective
      disorder.

PMID- 10401460
TI  - Relationship of awareness of dyskinesia in schizophrenia to insight into mental
      illness.
AB  - OBJECTIVE: The purpose of this study was to determine whether lack of awareness
      of motor dysfunction and lack of insight into mental dysfunction are related and
      to evaluate the longitudinal stability of lack of awareness of abnormal movements
      in schizophrenia. METHOD: Forty-three patients with schizophrenia and tardive
      dyskinesia participated in the study. The Scale of Unawareness of Mental Disorder
      was used to assess insight. All patients still meeting inclusion criteria after 2
      years (N = 16) were reevaluated at follow-up. RESULTS: Twenty (46.5%) of the 43
      patients had at least moderate unawareness of their tardive dyskinesia. Awareness
      of tardive dyskinesia was only modestly related to two of the five dimensions of
      insight into mental disorder assessed. Patients with the deficit syndrome showed
      significantly less awareness of their tardive dyskinesia than patients without
      the deficit syndrome. Lack of awareness of tardive dyskinesia was stable over
      time. CONCLUSIONS: Lack of awareness of tardive dyskinesia is a common feature in
      schizophrenia and is stable over time. Since patients are often unaware of
      dyskinesia, direct clinical examination is required to identify early tardive
      dyskinesia.

PMID- 10401461
TI  - Association between prenatal exposure to poliovirus infection and adult
      schizophrenia.
AB  - OBJECTIVE: The authors' goal was to determine whether there is an association
      between prenatal exposure to poliovirus infection and later development of
      schizophrenia. METHOD: All Finnish patients born between 1951 and 1969 with
      discharge diagnoses of schizophrenia (N = 13,559) were identified from the
      Finnish Hospital Discharge Register. Information on the monthly number of cases
      of paralytic poliomyelitis was obtained for each province in Finland. The authors
      analyzed the incidence of births of individuals who later developed schizophrenia
      by using a Poisson regression model with year and place of birth, age, sex,
      season of birth, and smoothed incidence of poliomyelitis in different gestational
      periods as explanatory variables. RESULTS: An association between the incidence
      of poliomyelitis and the incidence of births 5 months later of individuals who
      later developed schizophrenia was observed. Without controlling for seasonality,
      the effect was significant throughout the second trimester. CONCLUSIONS: Second
      trimester exposure to poliovirus infection may increase the risk for the later
      development of schizophrenia.

PMID- 10401462
TI  - Antibodies to heat shock proteins in schizophrenic patients: implications for the
      mechanism of the disease.
AB  - OBJECTIVE: The involvement of heat shock proteins has been determined in the
      pathophysiology of several disorders of the central nervous system, including
      multiple sclerosis. To elucidate their role in schizophrenia, the authors
      investigated antibody titers to heat shock proteins in unmedicated and medicated
      patients with schizophrenia. METHOD: Using the enzyme-linked immunosorbent assay
      technique, the authors measured titers of antibodies to 60 kilodaltons (kD) heat
      shock proteins (HSP60) and 70 kD heat shock proteins (HSP70) in 30 patients with
      schizophrenia before and during neuroleptic treatment and compared the titers
      with those of 31 healthy individuals. RESULTS: Ten (33%) of 30 patients with
      schizophrenia but only one (3%) of 31 healthy individuals showed immunoreactivity
      to HSP60 or HSP70. The authors found especially high anti-HSP70 titers in never
      medicated patients. High anti-HSP60 titers were mainly found in patients who were
      being treated with neuroleptics. CONCLUSIONS: Since heat shock proteins are
      involved in diverse neuroprotective mechanisms, antibodies against heat shock
      proteins may inhibit neuroprotection. The authors discuss the implications of
      these findings for schizophrenia.

PMID- 10401464
TI  - Olanzapine-induced mania.

PMID- 10401465
TI  - Quinapril and depression.

PMID- 10401463
TI  - Quantitative volumetric MRI study of the cerebellum and vermis in schizophrenia:
      clinical and cognitive correlates.
AB  - OBJECTIVE: Recent evidence suggests that the cerebellum may play a role in higher
      cognitive functions and, therefore, may play an important role in schizophrenia.
      METHOD: The authors used magnetic resonance imaging to measure cerebellum and
      vermis volume in 15 patients with schizophrenia and 15 normal comparison
      subjects. RESULTS: They found that 1) vermis volume was greater in patients with
      schizophrenia than in normal subjects, 2) greater vermis white matter volume in
      the patients with schizophrenia significantly correlated with severity of
      positive symptoms and thought disorder and with impairment in verbal logical
      memory, and 3) patients with schizophrenia showed a trend for more cerebellar
      hemispheric volume asymmetry (left greater than right). CONCLUSIONS: These data
      suggest that an abnormality in the vermis may contribute to the pathophysiology
      of schizophrenia.

PMID- 10401466
TI  - Risperidone monotherapy for mania and depression.

PMID- 10401467
TI  - Olanzapine-induced neuroleptic malignant syndrome with mental retardation.

PMID- 10401468
TI  - Improvement of sleep and behavior by methylphenidate in Alzheimer's disease.

PMID- 10401469
TI  - Possible nefazodone withdrawal syndrome.

PMID- 10401471
TI  - Olanzapine overdose.

PMID- 10401470
TI  - Treating visual hallucinations with donepezil.

PMID- 10401472
TI  - Amiodarone-induced delirium.

PMID- 10401473
TI  - Clozapine for substance-abusing schizophrenic patients.

PMID- 10401474
TI  - Depression from interferon therapy in patients with hepatitis C.

PMID- 10401475
TI  - Smoking in first-episode patients with schizophrenia.

PMID- 10401476
TI  - Clozapine to olanzapine.

PMID- 10401477
TI  - Psychopharmacologic Calvinism.

PMID- 10401478
TI  - Valproate for alcoholics with bipolar disorder.

PMID- 10401479
TI  - Ketanserin treatment of Tourette's syndrome in children.

PMID- 10401480
TI  - Hallucinogens and obsessive-compulsive disorder.

PMID- 10401481
TI  - Individualized risperidone dosing.

PMID- 10401482
TI  - Personality ratings of depressed outpatients.

PMID- 10401483
TI  - Neuroleptic discontinuation and tardive dyskinesia risk.

PMID- 10401484
TI  - Risperidone and clozapine for treatment-resistant schizophrenia.

PMID- 10401485
TI  - Risperidone and clozapine for treatment-resistant schizophrenia.

PMID- 10401486
TI  - Risperidone and clozapine for treatment-resistant schizophrenia.

PMID- 10401487
TI  - Fetal alcohol exposure and adult psychiatric disorders.

PMID- 10401488
TI  - Treatment of panic disorder.

PMID- 10401489
TI  - Lithium discontinuation.

PMID- 10401490
TI  - Reproductive physiology and treatment-related loss of sex hormone production.

PMID- 10401491
TI  - Factors of importance for implantation and problems after treatment for childhood
      cancer.
AB  - The uterus is of fundamental importance to reproduction; it nourishes the early
      embryo and accommodates growth and differentiation of the developing fetus. It is
      thus possible that the modalities employed to treat childhood cancer, that is;
      chemotherapeutic agents, and particularly irradiation, may result in damage to
      the uterine structure (musculature and local vasculature), with potential
      impairment of normal uterine function and thus increased risk of subsequent
      defective implantation. This may result in an impaired reproductive outcome
      (increased risk of spontaneous abortion, preterm labour, and low-birth-weight
      infants). Thus the reproductive problems foreseen following treatment of
      childhood cancer will be 1) ovarian failure or impaired ovarian activity and 2)
      uterine/endometrial structural and functional damage. The mode of treatment and
      age at its administration will be the major determinants of residual ovarian and
      uterine function. To understand the mechanisms that may be responsible for
      potential problems in reproductive function after treatment, it is essential to
      consider the mechanisms governing normal early pregnancy. Ovarian estradiol (E)
      and progesterone (P) secreted in a cyclical manner orchestrate the spatial and
      temporal morphological and functional changes in the endometrium required for
      implantation. In the absence of sex steroids, the endometrium is inactive.
      Implantation takes place in the midsecretory phase, that is, 5-9 days
      postovulation. E and P act sequentially to regulate cellular concentrations of
      their respective receptors and in turn gene transcription events are initiated to
      prepare the endometrium for implantation. A complex interaction exists between
      the network of uterine cells (epithelial, stroma, vascular, haemopoietic) and the
      endocrine system. Several key factors implicated in the implantation process will
      be addressed. There is published evidence that reports the risk of pubertal
      failure and early menopause after treatment for childhood cancer and, in those
      women who continue with ovarian activity and achieve pregnancy, a risk of poor
      reproductive outcome. It is likely that radiation damage to the uterus will
      adversely effect pregnancy potential. Our own group has reported impaired uterine
      characteristics in women after abdominal irradiation. More recently, we have
      shown that lower doses of radiotherapy (as with total-body irradiation) may be
      associated with a potential for improved uterine characteristics in response to
      physiological sex steroid replacement. The outlook after chemotherapy alone may
      be more optimistic; our early data support a normal uterine morphological
      response. Reproductive outcome in these patients remains unpredictable, so simple
      noninvasive assessment of uterine characteristics may provide data of predictive
      value with respect to future fertility potential.

PMID- 10401492
TI  - Surviving cancer: the importance of sexual self-concept.
AB  - Sexual self-schemas are cognitive generalizations regarding sexual aspects of the
      self; they represent a core component of one's sexuality. We contend that
      individual differences in sexual self-view are an important cognitive diathesis
      for predicting sexual difficulty or dysfunction. We illustrate the role of sexual
      self-schemas in sexual behavior and responsiveness in healthy female and male
      samples. Next, we examine the diathetic properties of sexual self-schemas.
      Finally, we discuss an empirical test of the proposed diathesis-stress
      interaction, reviewing the role of women's sexual self-views on sexual morbidity
      following diagnosis and treatment for gynecologic cancer.

PMID- 10401493
TI  - Infertility and premature menopause in childhood cancer survivors.

PMID- 10401494
TI  - Pregnancy outcome in long-term survivors of childhood cancer.
AB  - BACKGROUND: By the year 2010, 1/250 young adults will be long-term survivors of
      childhood cancer. One of the major concerns is whether they will be able to have
      healthy children. PROCEDURE: The literature was reviewed to determine 1) the
      extent of intrapartum and perinatal complications experienced by survivors or
      their spouses and 2) the risk of congenital malformations or cancer in their
      children. RESULTS AND CONCLUSIONS: Series have reported on pregnancy
      complications among approximately 400 female survivors and 300 partners of male
      survivors. An increased incidence of spontaneous abortions, low-birth-weight
      babies, and neonatal deaths has been described for women with Wilms tumor who had
      received at least 20 Gy abdominal radiation. Hodgkin disease survivors who had
      received both radiation and chemotherapy (but not either alone) also appear to be
      at increased risk of spontaneous abortions. Based on several thousand survivor
      offspring, there is no overall increased risk of either congenital malformations
      or childhood cancer. Further studies will define the outcome of offspring of
      cancer survivors treated in the modern era.

PMID- 10401495
TI  - Reproductive technologies 1998: options available for the cancer patient.
AB  - Recent advances in the field of reproduction have potentially opened
      opportunities for the preservation of the reproductive potential of young cancer
      patients with good long-term prognosis for survival. In the postpubertal male,
      cryopreservation of ejaculated sperm is both feasible and potentially successful.
      Semen parameters at the time of procurement are of minor significance;
      intracytoplasmic sperm injection (ICSI) can bypass sperm concentration and
      motility problems and can lead to successful fertilization. For the prepubertal
      male there are no clinically applicable options insofar as extraction and
      cryopreservation of postmeiotic sperm cells (mature spermatozoa or round
      spermatids) is not feasible. To date, efforts for culture of testicular tissue
      and in vitro maturation of male germ cells have not been successful. In both pre-
      and postpubertal females, cryopreservation of ovarian cortical tissue or
      enzymatically extracted follicles and the in vitro maturation of preantral
      follicles are of potential clinical use, but, to date, these approaches have been
      successful only in laboratory animals. An additional option available to the
      postpubertal female is the stimulation of ovaries with exogenous gonadotropins
      and retrieval of mature oocytes for cryopreservation. The recent application of
      ICSI in previously cryopreserved human mature oocytes has improved fertilization
      rates and has resulted in live births. Unfortunately, a shortcoming of this
      approach is the limited number of oocytes that can be harvested after stimulation
      of the ovaries. Further, all these approaches potentially harbor the risk of the
      cryopreservation of malignant cells with their subsequent reintroduction in the
      patient at a later date. This is a more realistic concern for patients suffering
      from hematologic or gonadal tumors. Finally, even though cryopreservation of
      embryos has been successfully used for many years, this option is not available
      to the pediatric and adolescent patient. It should not be forgotten that, even if
      the patients' own gametes are not available in the future, donor sperm and eggs
      provide the option for offspring and can give the opportunity to the females to
      carry a pregnancy as long as their uterus has not been affected by the cancer
      treatment. Given the rapid progress we are witnessing in the field of
      reproductive medicine, it is probable that in the very near future most of the
      options described and newer ones will be clinically available.

PMID- 10401496
TI  - Pharmacological protection of the gonads.

PMID- 10401497
TI  - Benefits and risks of hormone replacement therapy in young adult cancer survivors
      with gonadal failure.

PMID- 10401498
TI  - Psychosocial aspects of infertility and decisions about reproduction in young
      cancer survivors: a review.
AB  - BACKGROUND: Several types of cancer treatment interfere with male and female
      fertility or can complicate pregnancy. Rates of birth defects and cancer have
      also been studied in the offspring of cancer survivors. Little is known, however,
      about the impact of a history of cancer on survivors' attitudes, anxieties, and
      choices about having children of their own. PROCEDURE: We review the relevant
      literature on cancer survivor's concerns about infertility and childbearing and
      propose areas for future research. RESULTS: We generate several hypotheses,
      including that cancer survivors will be more distressed than infertility patients
      without a major medical disorder, that survivors diagnosed in adolescence will
      have the most anxieties about parenthood, that women will be more distressed over
      infertility and more concerned about their children's health than men, that
      survivors who rate their overall quality of life more negatively will be less
      concerned about infertility and more apt to decide to forego parenthood, that
      survivors of inheritable cancer syndromes will have more distress about
      childbearing issues than other survivors, and that survivors who do have children
      after treatment will perceive them more positively than do parents who have not
      confronted cancer. CONCLUSIONS: Research on the emotional aspects of infertility
      after cancer and on the factors that influence survivors' decisions about having
      children assumes increasing importance with the growth in number of survivors of
      reproductive age.

PMID- 10401499
TI  - Marriage in the survivors of childhood cancer: a preliminary description from the
      Childhood Cancer Survivor Study.
AB  - BACKGROUND: The goal of this paper is to provide a preliminary description of the
      marital status for a large number of childhood cancer survivors participating in
      the Childhood Cancer Survivor Study (CCSS). PROCEDURE: This report includes
      children and adolescents (< 21 years of age) diagnosed with cancer between 1970
      and 1986 at 25 oncology centers in the United States and Canada who survived at
      least 5 years from diagnosis. Self-reported data from 10,425 survivors are used
      in this preliminary descriptive summary. The proportion of survivors ever married
      and divorced/separated is compared to the U.S. population according to age
      specific groups. The median age of the survivor population at diagnosis was 7
      years and 26 years at the time martial status was ascertained. Excluded from this
      assessment are children < 15 years of age at the time of study, those whose
      martial status was unknown, and those married prior to diagnosis. Data for
      marital status of the U.S. population, as tabulated in the Bureau of Census 1995
      Update, is used as a general comparison to the survivor population. RESULTS:
      Overall, 32% of the survivors reported being married or living as married, 6%
      being divorced or separated, 0% being widowed, and 62% having never been married.
      In general, compared to the U.S. population, survivors were less likely to have
      ever married, particularly females and whites, but, once married, were less
      likely to divorce/separate, again particularly females and whites. Black
      survivors were generally found to be more likely to have married, with males and
      blacks more likely to divorce/separate once married. Comparison of childhood
      tumor types suggested that survivors of CNS tumors, particularly males, were less
      likely to have ever married and more likely to divorce/separate compared to those
      with other cancer diagnoses and the general U.S. population. CONCLUSIONS: This
      interim evaluation of the CCSS cohort provided preliminary data describing a
      suggested decreased likelihood of marriage, which may be influenced by gender
      and/or race. These patterns must be confirmed within the entire CCSS cohort and
      comparisons made with an appropriate sibling comparison group before making final
      conclusions.

PMID- 10401500
TI  - Assessment of visual acuity in children aged 1 1/2-6 years, with normal and
      subnormal vision.
AB  - The aim of the study was to assess different visual acuity tests in the age group
      1 1/2-6 years in 105 children with assumed normal vision, visual impairment due
      to ocular disease or strabismus. Acuity tasks for young children can be divided
      into three subtypes according to the kind of stimulus used. For "detection
      acuity", the stimulus should be detected or distinguished from the background, as
      assessed with the Stycar Rolling Balls. For "resolution acuity", the stimulus
      pattern should be resolved, as assessed with the Preferential Looking procedure
      (Teller Acuity Cards). For "recognition acuity", the stimulus must be recognized
      by the subject as assessed with the BUST-D symbol test, Sheridan Gardiner (S-G)
      single letters, LH single symbols and line tests, and also the HVOT test.
      Different acuity values were obtained with regard to detection, resolution and
      recognition acuities. Assessment with the Stycar Rolling Balls only gave a rough
      estimate of the visual function. There was an overestimation of the acuity values
      in all groups of children when using the Preferential Looking technique. Good
      agreement was found between the LH line and HVOT tests. The BUST-D test, S-G
      single letters, and LH single symbols gave slightly better acuity values than
      linear recognition tests. A "crowding ratio" was calculated by dividing the
      single optotype acuity by the linear acuity, and also by dividing the grating
      acuity by the optotype linear and single acuity. The crowding ratio varied in the
      individual children and in the different groups, being highest for strabismic
      amblyopia. The general conclusion is that reliable visual acuity measurements
      were not obtained until the visual acuity could be assessed with a recognition
      test using linear letters or symbols.

PMID- 10401501
TI  - Effects of Duane's retraction syndrome on sensory visual development.
AB  - PURPOSE: To study the effects of Duane's retraction syndrome on sensory visual
      development. METHODS: Monocular and binocular visual function and ocular motility
      have been studied and pattern reversal visual evoked potentials recorded from 22
      patients with Duane's syndrome aged from 4 to 55 years. RESULTS: Sixteen of the
      patients maintained binocular single vision using an abnormal head posture. All
      had normal visual acuities in both eyes. The 12 adults in this group had a mean
      stereoacuity of 78 seconds of arc with the Titmus stereotest and 101 seconds of
      arc with the TNO test. Both these values were significantly worse than for normal
      adults with a similar age range. The binocular VEPs from these patients showed
      enhancement of the binocular P100 VEP amplitude compared to the mean monocular
      P100 amplitude when they used their head posture but, unlike in normal subjects,
      this binocular enhancement was not reduced significantly after the age of 5. Six
      patients had lost binocular function and had a manifest convergent squint. Of
      these, 4 were anisometropic. VEPs in this group showed mildly delayed P100
      latencies in the affected eye with asymmetric amplitudes even though their
      amblyopia had been successfully treated by patching and only one patient had a
      substantially reduced acuity. In neither group was there any relationship between
      the degree of restriction of ocular motility and the sensory changes. CONCLUSION:
      Patients with Duane's syndrome who retain binocular single vision show abnormal
      binocular visual maturation after the age of 5 years. This results in reduced
      stereoacuity in the absence of amblyopia.

PMID- 10401502
TI  - Neuromyotonia of the abducens nerve after hypophysectomy and radiation.
AB  - The clinical signs of the rarely encountered ocular neuromyotonia consist of
      transient involuntary tonic contraction and delayed relaxation of single or
      multiple extraocular muscles, resulting in episodic diplopia. With a mean time
      delay of 3.5 years, this motility disorder frequently follows tumor excision or
      adjuvant radiation near the skull base. Ocular neuromyotonia may reflect
      inappropriate discharge from oculomotor neurons with unstable cell membranes
      because of segmental demyelinization by tumor compression and radiation-induced
      microangiopathy. In the present paper, the authors present the case of a 53-year
      old patient with a history of transsphenoidal hypophysectomy and adjuvant
      radiotherapy, who underwent strabismus surgery for abducens palsy.

PMID- 10401503
TI  - Ocular physiology.

PMID- 10401504
TI  - Childhood maltreatment increases risk for personality disorders during early
      adulthood.
AB  - BACKGROUND: Data from a community-based longitudinal study were used to
      investigate whether childhood abuse and neglect increases risk for personality
      disorders (PDs) during early adulthood. METHODS: Psychosocial and psychiatric
      interviews were administered to a representative community sample of 639 youths
      and their mothers from 2 counties in the state of New York in 1975, 1983, 1985 to
      1986, and 1991 to 1993. Evidence of childhood physical abuse, sexual abuse, and
      neglect was obtained from New York State records and from offspring self-reports
      in 1991 to 1993 when they were young adults. Offspring PDs were assessed in 1991
      to 1993. RESULTS: Persons with documented childhood abuse or neglect were more
      than 4 times as likely as those who were not abused or neglected to be diagnosed
      with PDs during early adulthood after age, parental education, and parental
      psychiatric disorders were controlled statistically. Childhood physical abuse,
      sexual abuse, and neglect were each associated with elevated PD symptom levels
      during early adulthood after other types of childhood maltreatment were
      controlled statistically. Of the 12 categories of DSM-IV PD symptoms, 10 were
      associated with childhood abuse or neglect. Different types of childhood
      maltreatment were associated with symptoms of specific PDs during early
      adulthood. CONCLUSIONS: Persons in the community who have experienced childhood
      abuse or neglect are considerably more likely than those who were not abused or
      neglected to have PDs and elevated PD symptom levels during early adulthood.
      Childhood abuse and neglect may contribute to the onset of some PDs.

PMID- 10401505
TI  - Childhood victimization and the development of personality disorders. Unanswered
      questions remain.

PMID- 10401506
TI  - Costs of health care use by women HMO members with a history of childhood abuse
      and neglect.
AB  - BACKGROUND: Early childhood maltreatment has been associated with adverse adult
      health outcomes, but little is known about the magnitude of adult health care use
      and costs that accompany maltreatment. We examined differences in annual health
      care use and costs in women with and without histories of childhood sexual,
      emotional, or physical abuse or neglect. METHODS: A random sample of 1225 women
      members of a health maintenance organization completed a 22-page questionnaire
      inquiring into childhood maltreatment experiences as measured by the Childhood
      Trauma Questionnaire. Health care costs and use data were obtained from the
      automated cost-accounting system of the health maintenance organization,
      including total costs, outpatient and primary care costs, and emergency
      department visits. RESULTS: Women who reported any abuse or neglect had median
      annual health care costs that were $97 (95% confidence interval, $0.47-$188.26)
      greater than women who did not report maltreatment. Women who reported sexual
      abuse had median annual health care costs that were $245 (95% confidence
      interval, $132.32-$381.93) greater than costs among women who did not report
      abuse. Women with sexual abuse histories had significantly higher primary care
      and outpatient costs and more frequent emergency department visits than women
      without these histories. CONCLUSION: Although the absolute cost differences per
      year per woman were relatively modest, the large number of women in the
      population with these experiences suggests that the total costs to society are
      substantial.

PMID- 10401507
TI  - Prevalence of and risk factors for lifetime suicide attempts in the National
      Comorbidity Survey.
AB  - BACKGROUND: General population survey data are presented on the lifetime
      prevalence of suicide attempts as well as transition probabilities to onset of
      ideation, plans among ideators, and attempts among ideators either with or
      without a plan. Risk factors for these transitions are also studied. METHODS:
      Data are from part II of the National Comorbidity Survey, a nationally
      representative survey carried out from 1990 to 1992 in a sample of 5877
      respondents aged 15 to 54 years to study prevalences and correlates of DSM-III-R
      disorders. Transitions are estimated using life-table analysis. Risk factors are
      examined using survival analysis. RESULTS: Of the respondents, 13.5% reported
      lifetime ideation, 3.9% a plan, and 4.6% an attempt. Cumulative probabilities
      were 34% for the transition from ideation to a plan, 72% from a plan to an
      attempt, and 26% from ideation to an unplanned attempt. About 90% of unplanned
      and 60% of planned first attempts occurred within 1 year of the onset of
      ideation. All significant risk factors (female, previously married, age less than
      25 years, in a recent cohort, poorly educated, and having 1 or more of the DSM
      III-R disorders assessed in the survey) were more strongly related to ideation
      than to progression from ideation to a plan or an attempt. CONCLUSIONS:
      Prevention efforts should focus on planned attempts because of the rapid onset
      and unpredictability of unplanned attempts. More research is needed on the
      determinants of unplanned attempts.

PMID- 10401508
TI  - A randomized clinical trial of supported employment for inner-city patients with
      severe mental disorders.
AB  - BACKGROUND: This experiment evaluated the effectiveness of 2 approaches to
      vocational services for persons with severe mental disorders: (1) individual
      placement and support (IPS), in which employment specialists within the mental
      health center help patients to obtain competitive jobs and provide ongoing
      support, and (2) enhanced vocational rehabilitation (EVR), in which stepwise
      vocational services are delivered by rehabilitation agencies. METHODS: One
      hundred fifty-two unemployed, inner-city patients with severe mental disorders
      who expressed interest in competitive employment were randomly assigned to IPS or
      EVR and followed up for 18 months. Following diagnostic assessment, participants
      were assessed with standardized measures of work, income, self-esteem, quality of
      life, symptoms, and hospitalization at baseline and at 6-, 12-, and 18-month
      follow-up evaluations. Employment was tracked monthly and job satisfaction every
      2 months. RESULTS: During the 18-month study, participants in the IPS program
      were more likely to become competitively employed (60.8% vs 9.2%) and to work at
      least 20 hours per week in a competitive job (45.9% vs 5.3%), whereas EVR
      participants had a higher rate of participation in sheltered employment (71.1% vs
      10.8%). Total earnings, job satisfaction, and nonvocational outcomes were
      similarly improved for both groups. CONCLUSION: The IPS model of supported
      employment is more effective than standard, stepwise EVR approaches for achieving
      competitive employment, even for inner-city patients with poor work histories and
      multiple problems.

PMID- 10401509
TI  - Very preterm birth, birth trauma, and the risk of anorexia nervosa among girls.
AB  - BACKGROUND: Obstetrical complications, based on parental recall, have been
      reported to be associated with development of anorexia nervosa. We used
      prospectively collected data about pregnancy and perinatal factors to examine the
      subsequent development of anorexia nervosa. METHODS: This population-based, case
      control study was nested in cohorts defined by all liveborn girls in Sweden from
      1973 to 1984. From the Swedish Inpatient Register, 781 girls had been discharged
      from any hospital in Sweden with a main diagnosis of anorexia nervosa at the age
      of 10 to 21 years. For each case, 5 controls were randomly selected, individually
      matched by year and hospital of birth (n = 3905). Conditional logistic regression
      was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for
      potential risk factors. RESULTS: Increased risk of anorexia nervosa was found for
      girls with a cephalhematoma (OR, 2.4; 95% CI, 1.4-4.1) and for very preterm birth
      (< or = 32 completed gestational weeks) (OR, 3.2; 95% CI, 1.6-6.2). In very
      preterm births, girls who were small for gestational age faced higher risks (OR,
      5.7; 95% CI, 1.1-28.7) than girls with higher birth weight for gestational age
      (OR, 2.7; 95% CI, 1.2-5.8). CONCLUSIONS: Our results show that perinatal factors,
      possibly reflecting brain damage, had independent associations with anorexia
      nervosa. These risk factors may uncover the mechanisms underlying the development
      of the disorder, even if only a fraction of cases of anorexia nervosa may be
      attributable to perinatal factors.

PMID- 10401510
TI  - Functional mechanisms underlying impaired recognition memory and conscious
      awareness in patients with schizophrenia.
AB  - BACKGROUND: Schizophrenia impairs episodic memory in its critical feature,
      autonoetic awareness, i.e., the type of awareness that is characterized by
      mentally reliving events from one's personal past. It spares noetic awareness,
      another form of awareness based on feelings of familiarity. We investigated the
      hypothesis that the impairment of autonoetic awareness is related to defective
      information that binds together separate aspects of events. METHODS: An
      experiential approach to recognition memory was used. Twenty-five patients with
      schizophrenia and 25 normal subjects performed or watched actions consisting of
      pairing objects. Then, they had to recognize pairs of objects and who paired them
      (source recognition). Subjects were also asked to provide a "remember"
      (autonoetic awareness) or a "know" (noetic awareness) response according to their
      subjective state at the time they recognized each pair of objects and each
      source. RESULTS: Patients exhibited an impaired recognition memory. When actions
      were observed, recognition of pairs of objects, but not of source, was no better
      than chance. There was a reduction in frequency of autonoetic awareness, its
      consistency throughout recognition of objects and source, and its relationship to
      source discrimination accuracy. Recognition was based largely on noetic
      awareness. CONCLUSIONS: Patients with schizophrenia are unable to link the
      separate aspects of events into a cohesive, memorable, and distinctive whole. The
      corollary of this defective relational binding is a quantitative and qualitative
      impairment of autonoetic awareness.

PMID- 10401511
TI  - When conscious recollection disrupts memory.

PMID- 10401512
TI  - Deficits of information management associated with schizophrenia. Awareness and
      associated integrative cognitive functions.

PMID- 10401513
TI  - Progressive cortical change during adolescence in childhood-onset schizophrenia.
      A longitudinal magnetic resonance imaging study.
AB  - BACKGROUND: Adolescence provides a window to examine regional and disease
      specific late abnormal brain development in schizophrenia. Because previous data
      showed progressive brain ventricular enlargement for a group of adolescents with
      childhood-onset schizophrenia at 2-year follow-up, with no significant changes
      for healthy controls, we hypothesized that there would be a progressive decrease
      in volume in other brain tissue in these patients during adolescence. METHODS: To
      examine cortical change, we used anatomical brain magnetic resonance imaging
      scans for 15 patients with childhood-onset schizophrenia (defined as onset of
      psychosis by age 12 years) and 34 temporally yoked, healthy adolescents at a mean
      (SD) age of 13.17 (2.73) years at initial baseline scan and 17.46 (2.96) years at
      follow-up scan. Cortical gray and white matter volumes were obtained with an
      automated analysis system that classifies brain tissue into gray matter, white
      matter, and cerebrospinal fluid and separates the cortex into anatomically
      defined lobar regions. RESULTS: A significant decrease in cortical gray matter
      volume was seen for healthy controls in the frontal (2.6%) and parietal (4.1%)
      regions. For the childhood-onset schizophrenia group, there was a decrease in
      volume in these regions (10.9% and 8.5%, respectively) as well as a 7% decrease
      in volume in the temporal gray matter. Thus, the childhood-onset schizophrenia
      group showed a distinctive disease-specific pattern (multivariate analysis of
      variance for change X region X diagnosis: F, 3.68; P = .004), with the frontal
      and temporal regions showing the greatest between-group differences. Changes in
      white matter volume did not differ significantly between the 2 groups.
      CONCLUSIONS: Patients with very early-onset schizophrenia had both a 4-fold
      greater decrease in cortical gray matter volume during adolescence and a disease
      specific pattern of change. Etiologic models for these patients' illness, which
      seem clinically and neurobiologically continuous with later-onset schizophrenia,
      must take into account both early and late disruptions of brain development.

PMID- 10401514
TI  - Common genetic vulnerability for nicotine and alcohol dependence in men.
AB  - BACKGROUND: Nicotine and alcohol dependence often occur together. We examined
      data from male twin pairs to determine whether there are genetic or environmental
      influences common to nicotine and alcohol dependence, and, if so, to estimate the
      magnitude and correlation of these influences. METHODS: Subjects were 3356 male
      male twin-pair members of the Vietnam Era Twin Registry who participated in a
      1992 telephone administration of the Diagnostic Interview Schedule Version 3
      Revised. Genetic model fitting was performed to estimate the magnitude and
      correlation of genetic and environmental contributions to lifetime nicotine and
      alcohol dependence. RESULTS: The heritability of nicotine dependence was 60.3%
      (95% confidence interval [CI], 55.4%-65.2%); that of alcohol dependence, 55.1%
      (95% CI, 49.7%-60.5%). The best-fitting model for the co-occurrence of lifetime
      nicotine and alcohol dependence included a substantial genetic correlation
      between both disorders (r = 0.68; 95% CI, 0.61-0.74) and a modest unique
      environmental correlation (r = 0.23; 95% CI, 0.14-0.32). CONCLUSIONS: These data
      suggest a common genetic vulnerability to nicotine and alcohol dependence in men.
      This common genetic influence may partially explain the clinical and
      epidemiological observations that alcoholics are often dependent smokers.

PMID- 10401515
TI  - Naloxone challenge in smokers. Preliminary evidence of an opioid component in
      nicotine dependence.
AB  - BACKGROUND: This study used an opioid antagonist challenge procedure to evaluate
      the responsivity of the endogenous opioid system in nicotine-dependent
      individuals, as evidenced by naloxone-induced alterations in both behavioral
      (withdrawal, craving) and neuroendocrine (cortisol levels) parameters. METHODS:
      Twenty subjects (9 smokers and 11 nonsmokers) participated in 4 laboratory
      sessions during which they were challenged with 0, 0.8, 1.6, or 3.2 mg/70 kg of
      naloxone and then monitored for 1 hour for subjective signs and symptoms of
      opiate-like withdrawal, nicotine craving, and alterations in cortisol levels.
      RESULTS: Nicotine-dependent subjects evidenced naloxone dose-dependent increases
      in withdrawal signs and symptoms. Lower doses of naloxone also produced increases
      in urges to smoke (craving) and tiredness in smokers. Smokers, when compared with
      nonsmokers, had lower prenaloxone baseline levels of cortisol and attenuated
      cortisol release in response to challenge with naloxone. CONCLUSIONS: These
      results provide preliminary evidence to suggest that long-term exposure to
      cigarette smoke is associated with alterations in the responsivity of the
      endogenous opioid system and the hypothalamic-pituitary-adrenal axis that may
      contribute to the development of nicotine dependence.

PMID- 10401516
TI  - Factor analysis of mania.

PMID- 10401517
TI  - A new classification for the psychoses?

PMID- 10401518
TI  - Failure to recognize adverse drug reactions despite warnings.

PMID- 10401519
TI  - European Union directives on medicinal products found to be seriously defective.

PMID- 10401520
TI  - Drug-related erectile dysfunction.
AB  - Erectile dysfunction is a highly prevalent medical problem affecting a
      significant proportion of men. It is important for a number of reasons, causing
      impairment of quality of life and, if related to drug therapy, leading to non
      compliance. Drug therapy accounts for erectile dysfunction in approximately 25%
      of cases and is mostly readily reversible when the offending agent is stopped, or
      a suitable alternative is substituted. Many classes of drug may be responsible,
      interfering with the normal physiological processes leading to penile erection in
      a dose-related fashion, and in ways which can usually be predicted from their
      pharmacology. The most commonly implicated classes of drug include
      antihypertensives such as thiazide diuretics and beta-adrenoceptor antagonists
      and psychotherapeutic drugs, especially selective serotonin reuptake inhibitor
      (SSRI) antidepressants. We review the agents which can cause erectile
      dysfunction, the evidence for this adverse effect and the physiological
      mechanisms involved. We present an approach to the management of the patient with
      erectile dysfunction in whom concomitant drug therapy may be responsible. We
      recommend that drug therapy should always be considered as a possible cause of
      erectile dysfunction before specific investigation and therapy is considered.

PMID- 10401521
TI  - Drug interactions with antimalarial agents.

PMID- 10401522
TI  - Endogenous salivary inhibitors of human immunodeficiency virus.
AB  - The human immunodeficiency virus type 1 (HIV-1) is rarely transmitted through
      salivary secretions, due in part to the presence of endogenous inhibitors. Here,
      the protective characteristics of the intraoral environment are summarized and
      inhibitory factors that reduce HIV-1 infectivity in vitro described, focusing on
      secretory leucocyte protease inhibitor (SLPI), a 12-kDa mucosal protein that
      blocks HIV infection in several cell-culture systems. SLPI appears to interact
      with a cellular surface molecule to limit viral entry into target cells. To
      determine whether the inhibitor has a similar role in vivo, the contribution of
      salivary SLPI to anti-HIV-1 activity was assessed. Whole unstimulated filtered
      salivas from infected and uninfected donors contained similar concentrations of
      the inhibitor. Depletion from SLPI filtered saliva produced a corresponding loss
      of inhibitory activity. In general, filtered whole salivas obtained from 10
      donors had antiviral activities that correlated positively with SLPI
      concentrations. However, some samples having SLPI well below the concentration
      required for inhibitory activity in vitro exhibited modest inhibition, suggesting
      the presence of other anti-HIV-1 components in oral fluids. Thus, SLPI is a major
      but not sole inhibitor of this virus in saliva.

PMID- 10401523
TI  - Tachykinin-induced responses via neurokinin-1 and -3 receptors in hamster
      submandibular ganglion neurones.
AB  - Both substance P and neurokinin A are known as neurotransmitters of the
      submandibular ganglion cell. In this study, the effects of neurokinin (NK)
      receptor-subtype agonists on hamster submandibular ganglion cells were
      investigated using the whole-cell patch-clamp technique. Membrane currents evoked
      by a ramp pulse from +50 to -100 mV (-150 mV/1000 msec) were compared in both the
      absence and presence of NK receptor agonist. The NK-1 receptor agonist [Sar9, Met
      (O2)11]-substance P, the NK-2 receptor agonist [Ala5, beta-Ala8]-alpha-neurokinin
      fragment 4-10, and the NK-3 receptor agonist senktide were used. The three
      agonists dose-dependently increased the amplitude of the inward current with a
      reversal potential near 0 mV. Their rank order was NK-1 = NK-3 > NK-2. Even when
      the external solution was replaced with Cs+ or N-methyl-D-glucamine+ instead of
      Na+, the NK receptor agonists also increased the amplitude of the inward current.
      Thus, NK-1 and NK-3 receptors are apparently coupled with non-selective cation
      channels in submandibular ganglion cells.

PMID- 10401524
TI  - Blood volume in human bicuspid periodontal ligament determined by electron
      microscopy.
AB  - The microvascular volume of periodontal ligament is reported to range from 1.63
      to 3.5% in man, whereas that of animals varies from 7.5 to 11.5%. This
      transmission electron-microscopic investigation was undertaken to determine
      stereologically the volume in human periodontal ligament. The hypothesis tested
      was that the ligament blood volume in man is similar to that in animals. Left and
      right segments of mandible containing first and second premolars came from an
      adult burns' victim who underwent jaw reconstruction. The segments were immersion
      fixed in 2.5% glutaraldehyde, demineralized at 4 degrees C in 0.1 M EDTA and
      processed for microscopy. Segments of distal periodontal ligament were sectioned
      at 150-micron intervals from the alveolar crest to the root apex and random
      tissue quadrats recorded for point counting and data analysis using a generalized
      linear-regression statistical model. Mean adjusted microvascular luminal volume
      was 9.52 +/- 2.28% (SEM) and the abluminal volume 12.91 +/- 2.76%; the wall
      volume was 3.39%. Significant differences existed between the luminal and
      abluminal volumes of the different vessel type (p < 0.05) and their distribution
      across the circumferential thirds of the ligament (p < 0.05). Total length
      density of the blood vessels was 149.84 x 10(3) cm/cm3 and the surface density
      330.19 cm2/cm3. Postcapillary-sized venules held 69.1% of the total blood volume
      and provided 49.3% of the luminal surface area. Venous capillaries were the most
      common vessel, comprising 48.5%, and they contributed 71.5% of the overall length
      density. This study confirmed the hypothesis for the blood volume in the
      periodontal ligament in man. Blood volumes do not reflect the configurations of
      microvascular beds.

PMID- 10401525
TI  - Effect of intravenous infusion of a beta-adrenergic blocking agent on the
      haemodynamic changes in human masseter muscle induced by cold-pressor
      stimulation.
AB  - Eight healthy non-smoking males (mean age: 24.1 +/- 1.1 years) without any
      history of chronic muscle pain and migraine participated in this study.
      Haemoglobin (Hb) and oxygen (O2) saturation in the right masseter muscle were
      continuously recorded with a non-invasive near-infrared spectroscopic device.
      Heart rate and blood pressure were also recorded. The experiment had three
      phases: a placebo drug (physiological saline) with cold-pressor trial, a 30-sec
      maximal voluntary clenching (MVC) trial, and a propranolol with cold-pressor
      trial. The saline and drug trials each involved continuous recording for 1 min
      before, 2 min during and 5 min after the cold-pressor stimulation (4 degrees C).
      Physiological saline (20 ml) or propranolol hydrochloride (20 ml) were infused at
      the rate of 2 ml/min. This infusion was begun 20 min before the baseline
      recording and participants did not know which solution (saline or propranolol)
      was being infused. For the MVC trial, each participant was asked to perform a 30
      sec clench of their jaw-closing muscles. There was a rest period of 15 min
      between each trial. The individual Hb and O2 data were normalized so that the
      baseline at the beginning of the experiment was equal to zero, and the Hb and O2
      data were normalized as a percentage of the individual's own highest absolute Hb
      and O2 after and during the MVC, respectively. The results showed that the mean
      baseline Hb 1 min before cold-pressor stimulation was significantly lower in the
      beta-blocker trial than in the placebo trial (p = 0.035). The mean change in Hb
      from baseline during cold-pressor stimulation in the beta-blocker trial was also
      significantly less than in the placebo trial (p = 0.035). The mean Hb rebound
      change after the cold-pressor stimulation in the beta-blocker trial was
      significantly higher than in the placebo trial, and no significant heart-rate
      differences were observed in the period after cold-pressor stimulation. Overall,
      the mean heart rate before and during that stimulation was significantly lower in
      the beta-blocker trial than the placebo trial (p < 0.001). There was no
      significant mean blood-pressure difference between placebo and beta-blocker
      trials at any time. These results suggest that beta-adrenoceptor blocking
      decreases the blood volume in the resting masseter, suppresses the incremental
      blood-volume change during cold-pressor stimulation, and discloses a hidden
      vasoconstrictive effect after that stimulation.

PMID- 10401526
TI  - Effect of smoking one cigarette on antioxidant metabolites in the saliva of
      healthy smokers.
AB  - Concentrations of glutathione, uric acid and total antioxidant activity,
      expressed as Trolox (a water-soluble vitamin E analogue) equivalent, were
      measured in the saliva of healthy non-smokers and smokers before and just after
      smoking a single cigarette. There was no statistically significant difference
      between smokers and non-smokers in uric acid concentrations and total radical
      trapping antioxidant capacity, but glutathione concentrations were significantly
      (p < 0.05) higher in smokers. Smoking of a single cigarette induced a significant
      reduction in glutathione concentration (p < 0.05). Salivary antioxidant power may
      affect individual sensitivity toward tobacco stress.

PMID- 10401527
TI  - Maintenance of regional histodifferentiation patterns and a spatially restricted
      expression of type X collagen in rat Meckel's cartilage explants in vitro.
AB  - The major, central portion of Meckel's cartilage undergoes fibrous transformation
      and contributes to the sphenomandibular ligament, whereas its distal end
      undergoes endochondral ossification ultimately giving rise to inner-ear ossicles.
      This regional histodifferentiation of Meckel's cartilage is known to be
      associated with the spatially restricted expression of type X collagen. The
      objective of this study was to determine if this unique histodifferentiation is
      regulated by local environmental factors or by a preprogrammed genetic mechanism.
      Meckel's cartilage, and condylar cartilage used for comparison, were isolated
      from 17-day-old rat embryos and from newborn rats, respectively. The cartilage
      explants were maintained in vitro for 50 days with or without supplementation
      with 10% fetal bovine serum. When the explants were cultured under serum-free
      conditions, well-regulated cartilage development was observed. Expression of type
      X collagen, a differentiation marker for hypertrophic cartilage, was restricted
      to the distal end of Meckel's cartilage, whereas type II and IX collagens were
      found uniformly along the entire explant. Matrix calcification was examined
      histochemically using alizarin red S staining and found to be restricted to the
      distal end of Meckel's cartilage. Both Meckel's and condylar cartilage cultured
      with 10% fetal bovine serum developed unregulated dysmorphogenesis. These data
      suggest that, although Meckel's cartilage has an intrinsic potential to
      differentiate to its terminal stage, external regulatory factors can
      significantly influence its normal development at the molecular level.

PMID- 10401528
TI  - Distribution of interleukin-2, -4, -10, tumour necrosis factor-alpha and
      transforming growth factor-beta mRNAs in oral lichen planus.
AB  - In the present study, MRNA for the cytokines interleukin-2 (IL-2), IL-4, IL-10
      tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor beta-1
      (TGF-beta-1) were investigated in oral lichen planus (OLP) lesions using in situ
      hybridization with 35S-labelled oligonucleotide probes on frozen tissue sections.
      In addition, the expression of interferon-gamma (IFN-gamma), IL-10 and IL-4 mRNAs
      was analysed in cultured lesional T lymphocytes from oral lichen planus by
      polymerase chain reaction. Cells expressing mRNA for IL-2, IL-4, IL-10, TNF-alpha
      and TGF-beta 1 were found in all the biopsies studied. Approximately 1-2% of the
      total number of infiltrating cells in the lesions were positive for each of the
      different cytokine mRNAs. Most biopsies contained basement membrane-oriented,
      mRNA-positive cells. In the cultured T-cell lines, message for IFN-gamma was
      detected in all the patients, IL-10 in all but one, and IL-4 in just one of the
      seven patients investigated. The results suggest that mRNA for both pro- and anti
      inflammatory cytokines, i.e., mixed T-helper 1 (TH1) and TH2 cytokine profiles,
      are generated simultaneously by a limited number of cells in chronic lesions of
      OLP.

PMID- 10401530
TI  - A technique for the study of endocytosis in human oral epithelial cells.
AB  - Fluorescently labelled latex microspheres (0.01, 0.1 and 1.0 micron dia.) were
      used to establish whether oral epithelial cells could exhibit an endocytic
      function. Oral mucosa biopsies were incubated in organ culture at 37 degrees C
      for 20 h with one of the three sizes of fluorescent microspheres in the medium.
      Tissue pieces were then disaggregated and cell suspensions analysed for cell
      content and viability. Evidence of endocytosis was sought by using fluorescence
      activated cell scanning (FACS) and confocal microscopy to study the epithelial
      cell suspensions for internalization of the microspheres. Confirmation that the
      microspheres had been internalized and were not merely attached to the cell
      exterior was shown by using trypan blue quenching to extinguish extracellular
      fluorescence, allowing analysis of only intracellular fluorescent microspheres.
      Both FACS and confocal microscopy confirmed uptake of 0.01 and 0.1 micron dia.
      microspheres but not 1.0 micron. Endocytosis was quantitated using FACS and a
      dose-dependent relation between the concentration of spheres in the incubation
      medium and uptake was found. Internalization of microspheres of < 1.0 micron dia.
      and the dose-dependent uptake support a fluid-phase constitutive endocytic
      process.

PMID- 10401529
TI  - Comparative data from young men and women on masseter muscle fibres, function and
      facial morphology.
AB  - The primary aim was to relate information about masseter muscle fibres and
      function to aspects of facial morphology in a group of healthy young men. The
      secondary aim was to investigate possible sex differences using data previously
      obtained from a comparable group of age-matched, healthy women. Dental status and
      facial morphology were recorded in 13 male students aged 20-26 years. Functional
      examinations included bite-force measurements and electromyographic recordings of
      masseter activity. A biopsy was removed from the masseter of each participant
      during surgical extraction of a wisdom tooth, and the tissue examined for myosin
      ATPase activity. Further, the cross-sectional areas of the different fibre types
      were measured. In spite of using age-matched healthy men and women with a full
      complement of teeth, statistically significant sex differences were found among
      measures related to muscle function and some measures of facial morphology. Thus
      data from men and women should not be pooled uncritically. The greater bite force
      in men than women corresponded with the greater diameter and cross-sectional area
      of type II fibres. Further, the males had more anteriorly inclined mandibles and
      shorter anterior facial height, suggesting a relation between the greater muscle
      force and the shape of the face. However, linear regression analysis failed to
      demonstrate any significant association between bite force and facial morphology
      among men and women. Thus, craniofacial morphology could be a result of far more
      contributing factors than previously believed.

PMID- 10401531
TI  - Placental glutathione S-transferase isoenzyme expression during promotion of two
      stage hamster cheek-pouch carcinogenesis.
AB  - Glutathione S-transferases (GSTs) are the products of a multigene family. A well
      established function of GSTs is to metabolize carcinogens by catalysing the
      conjugation of electrophilic substrates to glutathione. Whether placental GST
      (GST-P) is expressed during the promotion of two-stage hamster buccal-pouch
      mucosa (HBPM) carcinogenesis was investigated here, using 7,12
      dimethylbenz[a]anthracene (DMBA) as the initiator and 12-O-tetradecanoylphorbol
      13-acetate (TPA) as the promoter. Cytoplasmic and nuclear staining for GST-P was
      seen in pouches treated with DMBA for 4 or 16 weeks, as well as in those treated
      with DMBA for 4 weeks and then TPA for 12 weeks. No GST-P positivity was seen in
      any pouches treated with only TPA or with mineral oil for either 4 or 16 weeks.
      The average number of GST-P-stained foci in the groups treated with DMBA for 16
      weeks (246 +/- 96; mean +/- SD) or DMBA for 4 weeks followed by TPA for 12 weeks
      (186 +/- 67) was significantly higher than in pouches treated with only DMBA for
      4 weeks (97 +/- 24). These results demonstrate that TPA alone is not sufficient
      for GST-P expression in hamster buccal pouch mucosa. However, after being
      initiated with DMBA, then promoted with TPA, GST-P activity is induced in hamster
      buccal pouch mucosa during squamous-cell carcinogenesis. This underpins the
      suggestion that GST-P may play an important part during the promotion stage of
      oral carcinogenesis.

PMID- 10401532
TI  - Immunocytochemical demonstration of laminin in the synovial lining layer of the
      rat temporomandibular joint.
AB  - This immunocytochemical study describes the distribution of laminin in the
      synovial lining of the rat temporomandibular joint. Laminin immunostaining was
      present around some synovial lining cells and blood vessels. Ultrastructurally,
      immunoreactive products for laminin were deposited around cells with a well
      developed rough endoplasmic reticulum and secretory granules, suggesting that
      they were type B synovial lining cells. The localization of laminin
      immunoreactivity was not uniform around the cell membrane, the most intense
      immunoreaction being present on the basal aspect membrane as is seen in the
      basement membrane of epithelia. In contrast, macrophage-like synovial lining type
      A cells did not show laminin immunoreactivity. This different immunostaining
      pattern suggests that laminin acts as an adhesion molecule for the type B cells
      in their epithelial-like arrangement.

PMID- 10401533
TI  - Interleukin 1 beta, interleukin 6, beta 2-microglobulin, and transforming growth
      factor-alpha in gingival crevicular fluid from human periodontal disease.
AB  - Inflammatory mediators are central to the pathogenesis of periodontal diseases
      and may be used as markers in diagnosis. The aim of this study was to identify
      and quantify the various growth factors, apoptosis-related modifiers [soluble
      form of Fas (sFas) and bcl-2] and cytokines in the gingival crevicular fluid
      (GCF) of patients with different severities of periodontitis as compared with
      those of controls. GCF samples were taken from patients with periodontal disease
      and from controls. The concentrations of epidermal growth factor, transforming
      growth factor (TGF)-alpha, interleukin (IL)-1 beta, IL-6, interferon-gamma, beta
      2-microglobulin (beta 2-MG), and apoptosis-related modifiers sFas and bcl-2 in
      the samples were determined by enzyme-linked immunosorbent assay. TGF-alpha was
      significantly lower in patients with periodontal disease than in the controls. In
      contrast, the concentrations of IL-1 beta, IL-6; and beta 2-MG were significantly
      higher in the group with severe periodontal disease than in the controls. The
      amount of total protein in the GCF was considerably higher in the disease group
      than the controls (p < 0.05). TGF-alpha, IL-1 beta, and beta 2-MG concentrations
      were associated (Spearman rank correlation, r < 0.05 for all) with clinical
      measures of disease severity (pocket depth) and inflammation (bleeding when
      probed). Apoptosis-related modifiers (sFas and bcl-2) could not be detected in
      any samples. These results suggest that the growth factor TGF-alpha and certain
      cytokines are associated with the presence of periodontal disease.

PMID- 10401534
TI  - Providers' smoking cessation attitudes and practices for older patients.
AB  - A mail survey of 136 providers in a health maintenance organization in the
      Chicago metropolitan area examined smoking cessation attitudes and performance of
      the 4As protocol (asking, advising, assisting, arranging) for patients aged 50
      years or older. Asking about smoking was most frequent, followed by arranging,
      advising, and assisting. Physicians and nurse practitioners performed each of the
      4As more often than did registered and licensed practical nurses. In multiple
      logistic regression analyses, provider type was the only significant predictor of
      asking about smoking. Advising, assisting, and arranging follow-ups were more
      likely to be performed by providers who perceived a sense of professional
      responsibility about older patients' smoking; advising was more likely for
      providers who perceived that they had enough time to advise older patients about
      smoking; and assisting and arranging were more likely for providers with a
      stronger sense of self-efficacy for helping older patients stop smoking.

PMID- 10401535
TI  - Iron status and depression in premenopausal women: an MMPI study. Minnesota
      Multiphasic Personality Inventory.
AB  - To test the hypothesis that low iron status or other nutritional deficiencies are
      associated with symptoms of depression in premenopausal women, the authors
      related blood indices of iron status to scores on the Minnesota Multiphasic
      Personality Inventory (MMPI) and responses to a mood adjective checklist.
      Participants recruited locally provided fasting blood samples and completed the
      MMPI during the follicular phase of the menstrual cycle. Of 365 apparently
      healthy participants, 4% had hemoglobin < 120 g/L, 6% had transferrin saturation
      < 16%, 20% had ferritin < 12 micrograms/L, and 8% had clinically elevated scores
      (T > or = 70) on the Depression scale of the MMPI. The frequency of elevated MMPI
      Depression scores was unrelated to the frequency of low hemoglobin, transferrin
      saturation, or ferritin. The results do not support the hypothesis that low iron
      status contributes to symptoms of depression in women.

PMID- 10401536
TI  - Is there consensus between breast cancer patients and providers on guidelines for
      breaking bad news?
AB  - Eighty-four breast cancer patients, 64 oncologists, and 140 oncology nurses rated
      the importance of 15 general principles and 12 recommended steps to guide
      clinicians in breaking bad news to patients. At least 70% of the three samples
      rated 7 of the 15 principles and 6 of the 12 steps as essential. All three groups
      agreed that patients have a legal and moral right to accurate and reliable
      information and that patients should be given the diagnosis and prognosis
      honestly and in simple language, though not bluntly. The groups differed on the
      relative importance of other items, with less variation about the steps than
      about the principles. Patients' perceptions of the importance of various
      guideline steps and principles are probably most important, given that patients
      receive the troubling news and that research indicates that how the news is
      delivered is associated with important patient outcomes. Recommendations for
      further research are discussed.

PMID- 10401537
TI  - An evaluation of the impact of social support manipulations on cardiovascular
      reactivity to laboratory stressors.
AB  - Research findings have suggested that social support decreases cardiovascular
      reactivity and reduces the incidence of cardiovascular disease. The authors
      describe 2 studies evaluating the association between social support and
      cardiovascular reactivity to a stressor. In both studies, it was predicted that
      the presence of a supportive person would exert a buffering effect on
      cardiovascular reactivity. In Study 1, 68 participants were randomly assigned to
      1 of 3 conditions: alone, supportive, and nonsupportive. In Study 2, 60
      participants were randomly assigned to 1 of 3 conditions: highly supportive,
      supportive, and nonsupportive. In both studies, a speech was the stressor.
      Results in both studies showed no significant differences in cardiovascular
      reactivity between supportive and nonsupportive conditions. The results failed to
      support the reactivity buffering effects of social support. Findings are
      explained in terms of evaluation apprehension theory, familiarity of support
      provider, and level of social support.

PMID- 10401539
TI  - The 1999 WHO-ISH Guidelines for the Management of Hypertension--new targets, new
      treatment and a comprehensive approach to total cardiovascular risk reduction.

PMID- 10401538
TI  - Maternal depression and risk for postpartum complications: role of prenatal
      corticotropin-releasing hormone and interleukin-1 receptor antagonist.
AB  - The pregnancies of 58 healthy adolescents (ages 13 to 19 years) were followed to
      examine links between symptoms of depression, corticotropin-releasing hormone
      (CRH), interleukin-1 beta, (IL-1 beta), and IL-1 receptor antagonist (IL-1ra) as
      possible predictors of maternal and infant outcomes. Maternal psychological
      adjustment and medical complications during gestation, labor, delivery, and the
      postpartum period were monitored. Plasma samples collected during gestation were
      assayed for CRH, IL-1 beta, and IL-1ra. During gestation, symptoms of maternal
      depression were found to be associated with lower levels of CRH; lower levels of
      CRH were associated with lower levels of IL-1ra. In addition, lower levels of IL
      1ra predicted higher rates of maternal complications after childbirth. IL-1 beta,
      detected in only 4 mothers, was not associated with any predictor or outcome
      measures. During gestation, CRH may induce circulating cytokine inhibitors
      without significantly affecting cytokine production or synthesis. Maternal
      symptoms of depression during gestation may attenuate the association between CRH
      and IL-1ra.

PMID- 10401540
TI  - 1999 World Health Organization--International Society of Hypertension Guidelines
      for the Management of Hypertension. Guidelines Sub-Committee.

PMID- 10401541
TI  - Emotional activation during therapeutic interaction in traumatic brain injury:
      effect of apathy, self-awareness and implications for rehabilitation.
AB  - Apathy and reduced self-awareness are frequent occurring neurobehavioural
      sequelae following traumatic brain injury (TBI). Apathy, in terms of reduced goal
      directed activity and lowered motivation, and reduced self-awareness have a
      negative impact on the rehabilitation process. In this study, 30 patients
      suffering severe TBI were clinically rated for apathy and monitored for
      cardiovascular and electrodermal reactivity during baseline, neutral speech and
      therapeutic interaction. Applying a cut-off score criterion, two thirds of the
      TBI sample were classified as apathetic. The apathetic patients showed less
      psychophysiological reactivity from neutral speech to therapeutic interaction,
      compared to non-apathetic patients. They also reported less perceived emotional
      discomfort in the therapeutic situation measured with a visual analogue scale.
      Moreover, reduced self-awareness was associated with low autonomic reactivity.
      The results suggest that the reduced psychophysiological reactivity in apathetic
      patients may be a correlate to the lack of emotional responsivity, disengagement,
      lack of insight and concern about their own situation. Clinically, these results
      may have implications for psychotherapeutic intervention aimed at improving self
      awareness. Recording psychophysiological responses during therapeutic interaction
      may serve as a method for monitoring emotional involvement during psychotherapy
      with TBI patients.

PMID- 10401542
TI  - A multidisciplinary TBI inpatient rehabilitation programme for active duty
      service members as part of a randomized clinical trial.
AB  - OBJECTIVE: To design and describe an effective rehabilitation programme for use
      in an ongoing trial on the efficacy of multidisciplinary brain injury
      rehabilitation for moderately head injury military service members. DESIGN:
      Treatment arm of a randomized control trial. SETTING: US military tertiary care
      hospital inpatient rehabilitation programme. PATIENTS: Sixty seven active duty
      military with moderate to severe TBI who were randomized to the treatment arm of
      the protocol. INTERVENTION: Eight week rehabilitation programme combining group
      and individual therapies with an inpatient milieu-oriented neuropsychological
      focus. Group therapies included fitness, planning and organization, cognitive
      skills, work skills, medication, and milieu groups, and community re-entry
      outings. Individual therapy included neuropsychology, work therapy, occupational
      therapy, and speech and language pathology. MAIN OUTCOME MEASURES: Successful
      return to work and return to duty. RESULTS: At 1 year follow-up, 64 patients
      returned to work (96%) and 66% (44/67) returned to duty. CONCLUSION: The
      described rehabilitation programme demonstrates one successful effort to
      rehabilitate active duty military service members with TBI who have the potential
      to return to duty.

PMID- 10401543
TI  - Prediction of community integration and vocational outcome 2-5 years after
      traumatic brain injury rehabilitation in Australia.
AB  - OBJECTIVES: To predict community integration and vocational outcomes 2-5 years
      after traumatic brain injury (TBI). DESIGN: Multivariate correlational design
      incorporating retrospective data collection and questionnaire follow-up. METHODS:
      Four hundred and forty six patients admitted to a Head Injury Unit between 1991
      and 1995 were contacted. Data on predictor variables (demographic, injury
      severity and functional) were retrieved from hospital records. Community
      integration and vocational outcome was assessed by self-administered
      questionnaire. Two hundred and nine patients/carers completed and returned the
      questionnaires. Mean follow-up was 3.5 years. Data were analysed by descriptive
      statistics, multiple regression and discriminant analysis using SPSS. RESULTS:
      Community integration was predicted by age, disability level and cognition.
      Length of PTA, cognition, disability levels, GCS, functional status, length of
      acute stay and prior occupation discriminated those who returned to work. A total
      of 46.5% returned to work with 74.5% in the same or similar jobs. CONCLUSION:
      Long term outcomes post-TBI can be predicted by demographic, injury severity and
      functional status variables.

PMID- 10401544
TI  - Community-based empowerment programme for families with a brain injured survivor:
      an outcome study.
AB  - Rehabilitation of brain injured persons has been one of the challenges of the
      modern health care team. Brain injured persons' problems are termed complex and
      multiple, and may persist long after the acute management stage. Families caring
      for their brain-injured members are, however, ill prepared to face this long-term
      rehabilitation process. A previous study of an empowerment framework applicable
      among these Hong Kong Chinese families resulted in the development of a 52-item
      empowerment questionnaire with four interpretable factors (efficacy, knowledge,
      support and aspiration). This can also serve as a valid and reliable outcome
      measure of their empowerment efforts. As a follow-up of this development, an 8
      week community-based empowerment programme was thus designed and implemented for
      a total of 50 family members in six repeated groups. Outcome indicators including
      empowerment questionnaire, psychological well-being, self-efficacy, subjective
      experience of the burdens in care-giving, and support systems were used to
      monitor changes in empowerment status during the periods of pre- and post
      programme, and during the 3 month follow-up. The programmes were found to be
      effective in empowering family members in the four postulated empowering
      dimensions, and improving all other outcome measures. The follow-up studies
      reflect stability in empowerment, though there were no further improvement. From
      regression analysis, it was suggested that, for optimum empowerment to take
      place, important predictors included careers' education levels, age ranges and
      work status.

PMID- 10401545
TI  - Special education services provided to students with and without parental reports
      of traumatic brain injury.
AB  - The purpose of this study was to determine the frequency and type of special
      education services provided to youths who had sustained one or more traumatic
      brain injuries (TBIs) according to parental report but who did not have verified
      TBIs according to school records. A parental questionnaire formulated for a
      related research project served as the basis for data collection. Results
      indicated the most common special education verification categories both for
      students with and without reported TBIs were speech-language impairment and
      specific learning disability. Approximately 29% of children with reported TBIs
      received special education services--a percentage not differing significantly
      from students without TBIs. However, students with TBIs whose parents reported
      long-term consequences were significantly more likely to receive special
      education services than students with TBIs whose parents did not report long-term
      consequence or students without TBIs. A chi-square analysis using the number of
      students whose reported TBIs occurred before versus after special education
      evaluations revealed no significant difference in the types of services received.
      However, those evaluated for special education services after sustaining TBIs
      were more than two times as likely to receive services for behavioural disorders
      than those evaluated prior to sustaining TBIs.

PMID- 10401546
TI  - A non-typical neuropsychological case presentation of Huntington's disease.
AB  - The documentation of Huntington's disease as an autosomal-dominant disorder can
      be traced to the late 19th century, the first recorded cases as far back as the
      early 1600s. However, only recently have the neuropsychological correlates of the
      condition begun to be examined. Contemporary investigators have documented
      general findings of Huntington's Disease on a variety of cognitive and
      neuropsychological instruments with the presentation of the disorder generally
      being consistent from case to case. The purpose of this article is to provide an
      overview of the neuropsychological findings of Huntington's disease. Published
      research documenting functional impairments will be reviewed. A case will then be
      presented illustrating a somewhat non-typical neuropsychological presentation of
      the disorder.

PMID- 10401548
TI  - A single amino acid confers barbiturate sensitivity upon the GABA rho 1 receptor.
AB  - Many structurally diverse general anaesthetics enhance inhibitory
      neurotransmission in the central nervous system by interacting with the GABAA
      receptor. By contrast, GABA receptors composed of the rho 1 subunit are
      anaesthetic-insensitive. Here, we demonstrate that both delta
      hexachlorocyclohexane (delta-HCH; 1-100 microM), a positive allosteric modulator
      of the GABAA receptor, and the anaesthetic pentobarbitone (10-600 microM) have no
      effect on GABA-evoked currents mediated by wild-type rho 1 recombinant receptors
      (expressed in Xenopus laevis oocytes). By contrast, these agents produce up to a
      10 fold enhancement of GABA responses transduced by a rho 1 receptor in which a
      transmembrane located isoleucine residue is replaced by serine. However, not all
      general anaesthetics were similarly influenced by this mutation, because propofol
      and 5 beta-pregnan-3 alpha-ol-20-one (5 beta 3 alpha) remained ineffective. These
      data are discussed in relation to the specificity of general anaesthetic action.

PMID- 10401547
TI  - Augmented acetylcholine-induced, Rho-mediated Ca2+ sensitization of bronchial
      smooth muscle contraction in antigen-induced airway hyperresponsive rats.
AB  - Treatment with acetylcholine (ACh) of a beta-escin-permeabilized intrapulmonary
      bronchial smooth muscle of the rat induced force when the Ca2+ concentration was
      clamped at 1 microM. The ACh-induced Ca2+ sensitization of myofilaments was
      significantly greater in antigen-induced airway hyperresponsive rats than in
      control rats. The ACh-induced Ca2+ sensitization was completely blocked by
      treatment with Clostridium botulinum C3 exoenzyme, an inactivator of Rho family
      of proteins. Moreover, the protein level of RhoA in the intrapulmonary bronchi
      was significantly increased in the airway hyperresponsive rats. Thus, increased
      airway smooth muscle contractility observed in asthmatics may be related to
      augmented agonist-induced, Rho-mediated Ca2+ sensitization of myofilaments.

PMID- 10401549
TI  - Naloxone blocks endomorphin-1 but not endomorphin-2 induced inhibition of
      tachykinergic contractions of guinea-pig isolated bronchus.
AB  - The recently identified endogenous agonists on the mu-opioid-receptor (mu OR),
      endomorphin-1 (EM-1) and endomorphin-2 (EM-2), induce a concentration dependent
      inhibition of electrical field stimulation (EFS)-induced tachykinin-mediated
      contractions of the guinea-pig bronchus (ED50s < 10 nM for both compounds).
      Surprisingly, only endomorphin-1 effects could be blocked by naloxone (10
      microM), whereas endomorphin-2 effects were not affected by specific antagonists
      for the mu-, kappa-, and delta-opioid-receptor.

PMID- 10401550
TI  - Pharmacological evidence for the 5-HT7 receptor mediating smooth muscle
      relaxation in canine cerebral arteries.
AB  - 1. We investigated in the present study whether 5-HT is able to exert direct
      relaxant responses in canine basilar and middle cerebral arteries via the 5-HT7
      receptor. 2. In arterial rings deprived of endothelium and pre-contracted with
      prostaglandin F2 alpha (2 microM), 5-HT, 5-carboxamidotryptamine (5-CT), 5
      methoxytryptamine, sumatriptan or alpha-methyl-5-HT produced further increase in
      tone and/or slight relaxation. Blockade of 5-HT1B 1D and 5-HT2A receptors with
      GR127935 (1 microM) and ketanserin (0.1 microM), respectively, antagonized the
      vasoconstrictor component of the response and unmasked a concentration-dependent
      relaxation to 5-HT, 5-CT and 5-methoxytryptamine; sumatriptan and alpha-methyl-5
      HT remained inactive as relaxant agonists. The rank order of agonist potency in
      both arteries was 5-CT > 5-HT > 5-methoxytryptamine >> sumatriptan > or = alpha
      methyl-5-HT. 3. In dog basilar artery, pre-incubated with GR127935 (1 microM) and
      ketanserin (0.1 microM) and precontracted with prostaglandin F2 alpha (2 microM),
      the 5-HT7 ligands, clozapine (1 microM), mesulergine (0.3 microM), methiothepin
      (3 nM), risperidone (3 nM), spiperone (1 microM) and LY215840 (10-100 nM),
      produced significant rightward shifts of the concentration-response curves for 5
      HT and 5-CT. Only methiothepin and risperidone reduced significantly the maximum
      relaxant response (Emax), whilst the other drugs behaved as competitive
      antagonists with affinity values (pKB) that significantly correlated with their
      binding affinity (pKi) at recombinant 5-HT7 receptors. 4. These data disclosing
      the involvement of the 5-HT7 receptor in cerebrovascular relaxation may be
      strongly relevant in the light of: (1) the involvement of 5-HT in migraine; (2)
      the putative linkage between cephalovascular vasodilatation and migraine
      headache; and (3) the relatively high 5-HT7 receptor affinity of migraine
      prophylactic 5-HT antagonists.

PMID- 10401551
TI  - Protease-activated receptor-2 turnover stimulated independently of receptor
      activation in porcine coronary endothelial cells.
AB  - 1. Protease-activated receptors (PARs) are activated by an irreversible
      proteolytic mechanism which renders cleaved receptors unresponsive to subsequent
      challenges with activating enzymes. Non-specific proteolysis of PARs downstream
      of the activation site also prevents subsequent enzymic activation. Therefore, we
      investigated the effects of non-activating amino-terminal proteolysis with the
      bacterial protease thermolysin on PAR-mediated relaxation of porcine coronary
      artery ring preparations contracted with the thromboxane A2 mimetic U46619 (1-10
      nM). 2. Treatment of contracted artery ring segments with thermolysin (0.01-1 u
      ml-1, 20 min) caused no response, but abolished endothelium-dependent relaxations
      induced by the enzymic activators of PAR-1, and PAR-2, thrombin (0.01-0.3 u ml-1)
      and trypsin (0.003-0.1 u ml-1) respectively. The same treatment, however, did not
      affect similar responses to the proteolysis-independent PAR-1 and PAR-2
      activating peptides, SFLLRN-NH2 and SLIGRL-NH2 respectively (0.1-10 microM). 3.
      The inhibition of responsiveness to trypsin after thermolysin treatment recovered
      in a time-dependent manner, with maximal recovery (77.3 +/- 8.0% of time
      controls) occurring 150 min after thermolysin treatment. No recovery of
      responsiveness to thrombin after thermolysin treatment was observed within this
      time, however, the thrombin response returned to control levels after 20 h. 4.
      The recovery of responsiveness to trypsin was inhibited by the translation
      inhibitor cycloheximide (100 microM; 17.3 +/- 4.7%) and the protein trafficking
      inhibitor brefeldin A (10 microM; 12.1 +/- 4.8%) but was unaffected by the
      transcription inhibitor actinomycin D (2 microM; 65.1 +/- 3.6%), which did,
      however, abolish upregulation of B1-kinin receptors in this preparation. 5. In
      conclusion, our findings indicate that activation-independent amino-terminal
      proteolysis of PARs stimulates selective recovery of endothelial cell PAR-2
      responsiveness, which appears to be regulated by translation. Such a novel
      mechanism for the maintenance of responsiveness to enzymic PAR-2 activators may
      imply that these receptors play important roles in vascular homeostasis.

PMID- 10401554
TI  - Influence of S-adenosyl-L-methionine on chronic mild stress-induced anhedonia in
      castrated rats.
AB  - 1. S-adenosyl-L-methionine (SAMe) is the most important methyl donor in the brain
      and is essential for polyamine synthesis. Methyl group deficiency in the brain
      has been implicated in depression; on the other hand, polyamines enhance
      phosphorylation processes, and phosphorylation of functional proteins in neurons
      in involved in the therapeutic mechanisms of antidepressants. 2. The effect of
      SAMe in an animal model of 'depression', the chronic mild stress-induced
      anhedonia, was studied using long-term castrated male and female Lister hooded
      rats. 3. Chronic daily exposure to an unpredictable sequence of mild stressors
      produced, within 3 weeks, a significant reduction of the consumption of a sucrose
      solution. SAMe (100, 200 or 300 mg kg-1 daily i.m.) while having no influence on
      sucrose intake in non-stressed animals, dose-dependently reinstated sucrose
      consumption within the first week of treatment, both in male and in female
      stressed rats. Imipramine (10 mg kg-1 daily i.p.) produced a similar effect after
      a 3 week treatment. 4. Similarly, a palatable food reward-induced place
      preference conditioning was developed in SAMe (200 or 300 mg kg-1 daily i.m.)-
      and in imipramine (10 mg kg-1 daily i.p.)--treated chronically stressed animals
      (males and females), whilst it could not be obtained in vehicle-treated rats. 5.
      Moreover, the same doses of SAMe (but not of imipramine) restored the exploratory
      activity and curiosity for the environment (rearing), in the open-field test. 6.
      While imipramine caused a blockade of the growth throughout the treatment, SAMe
      produced only a transient growth arrest during the first week of treatment. 7.
      These results show that SAMe reverses an experimental condition of 'depression
      like' behaviour in rats, the effect being more rapid and complete than that of
      imipramine, and without apparent side effects.

PMID- 10401552
TI  - Non-NMDA glutamate receptors modulate capsaicin induced c-fos expression within
      trigeminal nucleus caudalis.
AB  - 1. We examined the effects of the alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid (AMPA)/kainate receptor antagonists 6-cyano-7
      nitroquinoxaline-2,3-dione (CNQX) and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo
      benzol[f]quinoxaline-7-sulpho namide (NBQX), the kainate receptor antagonists
      gamma-(R-)-glutamylaminomethanesulphonic acid (GAMS) and 6,7,8,9-tetrahydro-5
      nitro-1H-benz[g]indole-2,3-dione-3-oxime (NS-102), and the group III metabotropic
      glutamate receptor (mGluR) agonist 2-amino-4-phosphono-S-butanoic acid (L-AP4) on
      c-fos-like immunoreactivity (c-fos LI) in trigeminal caudalis (Sp5C), lateral
      reticular (LRt), medullary reticular (Md) and solitary tract (Sol) nuclei, after
      intracisternal injection of capsaicin in urethane anaesthetized Sprague-Dawley
      rats. 2. Few c-fos labelled cells were observed within Sp5C in capsaicin-vehicle
      treated animals. The number of positive c-fos cells increased by 17 fold after
      intracisternal capsaicin (5 nmol) administration. 3. Pretreatment with CNQX
      (0.02, 0.1, 0.6, 3 and 15 mg kg-1) or NBQX (0.01, 0.1 and 1 mg kg-1),
      administered intraperitoneally 15 min before capsaicin, significantly reduced
      labelled cells within Sp5C by a maximum of 45 and 34%, respectively. The number
      of c-fox LI cells within LRt, Md and Sol was not affected. Pretreatment with L
      AP4 (1, 3 and 10 mg kg-1) decreased the number of Sp5C c-fos LI cells by a
      maximum of 30%, whereas GAMS (1 and 10 mg kg-1) and NS-102 (1 and 5 mg kg-1) did
      not show any significant effect. 4. These results suggest that blockade of AMPA
      receptors, but not kainate receptors, or the activation of group III mGluRs,
      decrease the response of Sp5C neurons to trigeminovascular activation. Thus, in
      addition to NMDA receptors, mGluRs and AMPA receptors may modulate cephalic pain
      and may provide a potential therapeutic target for antimigraine drugs.

PMID- 10401553
TI  - Comparative effects of cyclo-oxygenase and nitric oxide synthase inhibition on
      the development and reversal of spinal opioid tolerance.
AB  - 1. This study examined the effects of the COX inhibitors, ketorolac and
      ibuprofen, and the NOS inhibitor L-NAME for their potential to both inhibit the
      development and reverse tolerance to the antinociceptive action of morphine. 2.
      Repeated administration of intrathecal morphine (15 micrograms), once daily,
      resulted in a progressive decline of antinociceptive effect and an increase in
      the ED50 value in the tailflick and paw pressure tests. Co-administration of
      ketorolac (30 and 45 micrograms) or S(+) ibuprofen (10 micrograms) with morphine
      (15 micrograms) prevented the decline of antinociceptive effect and increase in
      ED50 value. Similar treatment with L-NAME (100 micrograms) exerted weaker
      effects. Administration of S(+) but not R(-) ibuprofen (10 mg kg-1) had similar
      effects on systemic administration of morphine (15 mg kg-1). 3. Intrathecal or
      systemic administration of the COX or NOS inhibitors did not alter the baseline
      responses in either tests. Acute keterolac or S(+) ibuprofen also did not
      potentiate the acute actions of spinal or systemic morphine, but chronic
      intrathecal administration of these agents increased the potency of acute
      morphine. 4. In animals already tolerant to intrathecal morphine, subsequent
      administration of ketorolac (30 micrograms) with morphine (15 micrograms)
      partially restored the antinociceptive effect and ED50 value of acute morphine,
      reflecting the reversal of tolerance. Intrathecal L-NAME (100 micrograms) exerted
      a weaker effect. 5. These data suggest that spinal COX activity, and to a lesser
      extent NOS activity, contributes to the development and expression of opioid
      tolerance. Inhibition of COX may represent a useful approach for the prevention
      as well as reversal of opioid tolerance.

PMID- 10401555
TI  - Nociceptin/orphanin FQ and nocistatin on learning and memory impairment induced
      by scopolamine in mice.
AB  - 1. Nociceptin, also known as orphanin FQ, is an endogenous ligand for the orphan
      opioid receptor-like receptor 1 (ORL1) and involves in various functions in the
      central nervous system (CNS). On the other hand, nocistatin is recently isolated
      from the same precursor as nociceptin and blocks nociceptin-induced allodynia and
      hyperalgesia. 2. Although ORL1 receptors which display a high degree of sequence
      homology with classical opioid receptors are abundant in the hippocampus, little
      is known regarding their role in learning and memory. 3. The present study was
      designed to investigate whether nociceptin/orphanin FQ and nocistatin could
      modulate impairment of learning and memory induced by scopolamine, a muscarinic
      cholinergic receptor antagonist, using spontaneous alternation of Y-maze and step
      down type passive avoidance tasks in mice. 4. While nocistatin (0.5-5.0 nmol
      mouse-1, i.c.v.) administered 30 min before spontaneous alternation performance
      or the training session of the passive avoidance task, had no effect on
      spontaneous alternation or passive avoidance behaviours, a lower per cent
      alternation and shorter median step-down latency in the retention test were
      obtained in nociceptin (1.5 and/or 5.0 nmol mouse-1, i.c.v.)-treated normal mice.
      5. Administration of nocistatin (1.5 and/or 5.0 nmol mouse-1, i.c.v.) 30 min
      before spontaneous alternation performance or the training session of the passive
      avoidance task, attenuated the scopolamine-induced impairment of spontaneous
      alternation and passive avoidance behaviours. 6. These results indicated that
      nocistatin, a new biologically active peptide, ameliorates impairments of
      spontaneous alternation and passive avoidance induced by scopolamine, and
      suggested that these peptides play opposite roles in learning and memory.

PMID- 10401556
TI  - Analysis of alpha 1L-adrenoceptor pharmacology in rat small mesenteric artery.
AB  - 1. To illuminate the controversy on alpha 1A- or alpha 1L-adrenoceptor
      involvement in noradrenaline-mediated contractions of rat small mesenteric artery
      (SMA), we have studied the effects of subtype-selective alpha 1-adrenoceptor
      agonists and antagonists under different experimental conditions. 2. The agonist
      potency order in rat SMA was: A61603 >> SKF89748-A > cirazoline > noradrenaline >
      ST-587 > methoxamine. Prazosin antagonized all agonists with a low potency (pA2:
      8.29-8.80) indicating the involvement of alpha 1L-rather than alpha 1A
      adrenoceptors. 3. The putative alpha 1L-adrenoceptor antagonist JTH-601, but not
      the alpha 1B-adrenoceptor antagonist chloroethylclonidine (10 microM) antagonized
      noradrenaline-induced contractions of SMA. The potency of the selective alpha 1D
      adrenoceptor antagonist BMY 7378 against noradrenaline (pA2 = 6.16 +/- 0.13) and
      of the selective alpha 1A-adrenoceptor antagonist RS-17053 against noradrenaline
      (pKB = 8.35 +/- 0.10) and against the selective alpha 1A-adrenoceptor agonist A
      61603 (pKB = 8.40 +/- 0.09) were too low to account for alpha 1D- and alpha 1A
      adrenoceptor involvement. 4. The potency of RS-17053 (pKB/pA2's = 7.72-8.46) was
      not affected by lowering temperature, changing experimental protocol or inducing
      myogenic tone via KCl or U46619. 5. Selective protection of a putative alpha 1A
      adrenoceptor population against the irreversible action of phenoxybenzamine also
      failed to increase the potency of RS-17053 (pA2 = 8.25 +/- 0.06 against A61603).
      6. Combined concentration-ratio analysis demonstrated that tamsulosin, which does
      not discriminate between alpha 1A- and alpha 1L-adrenoceptors, and RS-17053
      competed for binding at the same site in the SMA. 7. In summary, data obtained in
      our experiments in rat SMA indicate that the alpha 1-adrenoceptor mediating
      noradrenaline-induced contraction displays a distinct alpha 1L-adrenoceptor
      pharmacology. This study does not provide evidence for the hypothesis that alpha
      1L-adrenoceptors represent an affinity state of the alpha 1A-adrenoceptor in
      functional assays. Furthermore, there is no co-existing alpha 1A-adrenoceptor in
      the SMA.

PMID- 10401557
TI  - Pharmacological modulation of secondary mediator systems--cyclic AMP and cyclic
      GMP--on inflammatory hyperalgesia.
AB  - 1. The objective of the present paper was to evaluate the relevance of neuronal
      balance of cyclic AMP and cyclic GMP concentration for functional regulation of
      nociceptor sensitivity during inflammation. 2. Injection of PGE2 (10-100 ng paw
      1) evoked a dose-dependent hyperalgesic effect which was mediated via a cyclic
      AMP-activated protein kinase (PKA) inasmuch as hyperalgesia was blocked by the
      PKA inhibitor H89. 3. The PDE4 inhibitor rolipram and RP73401, but not PDE3 and
      PDE5 inhibitors potentiated the hyperalgesic effects of PGE2. The hyperalgesic
      effect of dopamine was also enhanced by rolipram. Moreover, rolipram
      significantly potentiated hyperalgesia induced by carrageenan, bradykinin, TNF
      alpha, IL-1 beta, IL-6 and IL-8. This suggests that neuronal cyclic AMP mediates
      the prostanoid and sympathetic components of mechanical hyperalgesia. Moreover,
      in the neuron cyclic AMP is mainly metabolized by PDE4. 4. To examine the role of
      the NO/cyclic GMP pathway in modulating mechanical hyperalgesia, we tested the
      effects of the soluble guanylate cyclase inhibitor, ODQ. This substance
      counteracts the inhibitory effects of the NO donor, SNAP, on the hyperalgesia
      induced by PGE2. 5. The ODQ potentiated hyperalgesia induced by carrageenan,
      bradykinin, TNF alpha, IL-1 beta, IL-6 and IL-8. In contrast, ODQ had no
      significant effect on the hyperalgesia induced by PGE2 and dopamine. This
      indicates that the hyperalgesic cytokines may activate soluble guanylate cyclase,
      which down-regulate the ability of these substances to cause hyperalgesia. This
      event appears not to be mediated by prostaglandin or dopamine. 6. In conclusion,
      the results presented in this paper confirm an association between (i)
      hyperalgesia and elevated levels of cyclic AMP as well as (ii) antinociception
      and elevated levels of cyclic GMP. The intracellular levels of cyclic AMP that
      enhance hyperalgesia are controlled by the PDE4 isoform and appear to result in
      activation of protein kinase A whereas the intracellular levels of cyclic GMP
      results from activation of a soluble guanylate cyclase.

PMID- 10401558
TI  - Halothane enhances exocytosis of [3H]-acetylcholine without increasing calcium
      influx in rat brain cortical slices.
AB  - 1. The effect of halothane on the release of [3H]-acetylcholine ([3H]-ACh) in rat
      brain cortical slices was investigated. 2. Halothane (0.018 mM) did not
      significantly affect the basal and the electrical field stimulation induced
      release of [3H]-ACh. However, halothane (0.063 mM) significantly increased the
      basal release of [3H]-ACh and this effect was additive with the electrical field
      stimulation induced release of [3H]-ACh. 3. The release of [3H]-ACh induced by
      0.063 mM halothane was independent of the extracellular sodium and calcium ion
      concentration and was decreased by tetracaine, an inhibitor of Ca(2+)-release
      from intracellular stores or dantrolene, an inhibitor of Ca(2+)-release from
      ryanodine-sensitive stores 4. Using 2-(4-phenylpiperidino)-cyclohexanol
      (vesamicol), a drug that blocks the storage of ACh in synaptic vesicles, we
      investigated whether exocytosis of this neurotransmitter is involved in the
      effect of halothane. Vesamicol significantly decreased the release of [3H]-ACh
      evoked by halothane. 5. It is suggested that halothane may cause a Ca2+ release
      from intracellular stores that increases [3H]-ACh exocytosis in rat brain
      cortical slices.

PMID- 10401559
TI  - Protective effects of a superoxide dismutase mimetic and peroxynitrite
      decomposition catalysts in endotoxin-induced intestinal damage.
AB  - 1. The relative contributions of superoxide anion (O2-) and peroxynitrite (PN)
      were evaluated in the pathogenesis of intestinal microvascular damage caused by
      the intravenous injection of E. coli lipopolysaccharide (LPS) in rats. The
      superoxide dismutase mimetic (SODm) SC-55858 and the active peroxynitrite
      decomposition catalysts 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5
      disulphonatophenyl)-por phyrinato iron (III) and 5,10,15,20-tetrakis(N-methyl-4'
      pyridyl)-porphyrinato iron (III) (FeTMPS, FeTMPyP respectively) were used to
      assess the roles of O2- and PN respectively. 2. The intravenous injection of LPS
      elicited an inflammatory response that was characterized by a time-dependent
      infiltration of neutrophils, lipid peroxidation, microvascular leakage
      (indicative of microvascular damage), and epithelial cell injury in both the
      duodenum and jejunum. 3. Administration of the SODm SC-55858, FeTMPS or FeTMPyP
      at 3 h post LPS reduced the subsequent increase in microvascular leakage, lipid
      peroxidation and epithelial cell injury. Inactive peroxynitrite decomposition
      catalysts exhibited no protective effects. Only, SC-55858 inhibited neutrophil
      infiltration. 4. Our results suggest that O2 and peroxynitrite play a significant
      role in the pathogenesis of duodenal and intestinal injury during endotoxaemia
      and that their remoyal by SODm and peroxynitrite decomposition catalysts offers a
      novel approach to the treatment of septic shock or clinical conditions of
      gastrointestinal inflammation. Furthermore, the remarkable protection of the
      intestinal epithelium by these agents suggests their use during chemo- and
      radiation therapy, cancer treatments characterized by gastrointestinal damage.
      Potential mechanisms through which these radicals evoke damage are discussed.

PMID- 10401560
TI  - Failure of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) to inhibit soluble
      guanylyl cyclase in rat ventricular cardiomyocytes.
AB  - 1. The effects of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor
      of soluble guanylyl cyclase (sGC), were investigated in aortic rings and
      ventricular cardiomyocytes from rats. The production of cyclic GMP was stimulated
      by NO.-donors or carbachol. Additionally, the effects of ODQ were studied in
      cytosolic extracts from both tissues in which the cyclic GMP production was
      stimulated by S-nitroso-N-acetylpenicillamine (SNAP). 2. In endothelium-intact
      aortic rings, SNAP (100 microM), 2,2'-(hydroxynitrosohydrazino)bis-ethana-mine
      (DETA NONOate; 100 microM), or carbachol (10 microM) increased cyclic GMP levels
      about 4 fold. These effects were abolished by ODQ (50 microM). 3. In
      cardiomyocytes, SNAP (100 microM), DETA NONOate (100 microM), or carbachol (10
      microM) increased cyclic GMP levels about 2 fold. These effects were not affected
      by ODQ (50 microM). 4. In cytosolic extracts from aortic rings and
      cardiomyocytes, SNAP (100 microM) induced about 50 fold increases in cyclic GMP
      levels. ODQ (50 microM) reduced these effects by about 50%. 5. In extracts from
      cardiomyocytes, increases by SNAP (100 microM) of cyclic GMP levels were
      attenuated by myoglobin dependent on concentration: at 300 microM myoglobin, SNAP
      (100 microM) increased cyclic GMP levels only 3 fold. Inhibitory effects of ODQ
      (50 microM) were abolished by 300 microM myoglobin. 6. It is suggested that both
      NO. and ODQ can bind to myoglobin which, at high concentrations. can diminish
      their effects on sGC. Such a scavenger function of myoglobin could explain why
      NO. and ODQ exert only minor effects in cardiomyocytes (with high myoglobin
      content) but strong effects in aortic tissue (virtually devoid of myoglobin).

PMID- 10401561
TI  - Intravascular ATP and coronary vasodilation in the isolated working rat heart.
AB  - 1. Adenosine-5'-triphosphate (ATP) is a potent coronary vasodilator. Because of
      the efficient hydrolysis of ATP, adenosine-5'-diphosphate (ADP) and adenosine-5'
      monophosphate (AMP) by ectonucleotidases located in the coronary endothelium ATP
      induced vasodilation may be mediated via both P1 (AMP and adenosine) and P2Y (ATP
      and ADP) receptors. We have used the change in total coronary resistance (TCR)
      induced by intravascular ATP in the isolated working rat heart to determine both
      the component of the vasodilation mediated via P2Y receptors and the identity of
      the subclass of receptor involved. 2. The dose response for ATP revealed a half
      maximal effect at an apparent ATP concentration of 0.08 +/- 0.009 microM. The
      response was saturated at apparent ATP concentrations greater than 0.23 microM.
      Contrary to much of the current literature, the perfusion of a 0.25 microM
      concentration of adenosine resulted in the identical response to an equimolar
      concentration of ATP suggesting a significant role for adenosine in coronary
      vasodilation. 3. The non-selective P1 receptor antagonist 8-(p
      Sulfophenyl)theophylline (8-SPT) was used to show that the response to ATP was
      mediated via both P1 and P2Y receptors. Whilst 8-SPT abolished the effect of
      adenosine it reduced the effect of ATP by only 50%. Thus, at a saturating
      concentration of ATP, P1 and P2Y receptors were shown to contribute equally to
      the observed vasodilation. 4. Uridine-5'-triphosphate (UTP), ADP and adenosine-5'
      O-thiotriphosphate (ATP gamma S) were used to characterize the component of
      coronary vasodilation that was mediated via P2Y receptors. UTP at 0.25 microM was
      ineffective and did not induce vasodilation. Perfusion with 0.25 microM ADP
      resulted in a vasodilation that was identical to 0.25 microM ATP. In the absence
      of 8-SPT the perfusion of 0.25 microM ATP gamma S produced a vasodilation that
      was significantly (P < 0.05) less than ATP. However, the vasodilation due to ATP
      gamma S, like that of adenosine, but unlike that of both ATP and ADP, was
      abolished in the presence of 8-SPT. The ability of ADP to induce vasodilation
      combined with both the lack of response to UTP and the ability of 8-SPT to
      abolish the vasodilation induced by ATP gamma S suggested very strongly that the
      component of ATP-induced coronary vasodilation in the isolated working rat heart
      that was mediated via P2Y receptors was achieved by the action of ADP (and not
      ATP) at P2Y1 receptors. 5. These results suggest that the vasodilatory action of
      intravascular ATP in the coronary circulation should be attributed to the dual
      and equal activities of adenosine and ADP acting at P1 and P2Y1 receptors
      respectively.

PMID- 10401562
TI  - Human P2Y2 receptor polymorphism: identification and pharmacological
      characterization of two allelic variants.
AB  - 1. In the process of cloning the human P2Y2 receptor in order to establish 1321N1
      cell lines expressing this receptor, we detected a gene polymorphism
      characterized by an arginine 334 to cysteine 334 transition. 2. The frequency
      distribution of the polymorphism was studied in a European population. We
      observed that 66% of the tested persons are homozygotes R/R, 29% are
      heterozygotes R/C and 5% are homozygotes C/C. The frequency of the R allele was
      0.8 versus 0.2 for the C allele. 3. We stably expressed each form of the human
      P2Y2 receptor into 1321N1 cells and isolated clones by limiting dilution. The
      effects of nucleotides and antagonists on inositol trisphosphate accumulation and
      cyclic AMP formation were compared between the two cell lines. 4. The time
      courses of inositol trisphosphate accumulation as well as concentration-response
      curves characterizing the effects of UTP, ATP, AP4A and ATP gamma S were mostly
      similar, except for slight kinetic differences (slower time-course with the 334C
      form). 5. The sensitivity to pertussis toxin of inositol trisphosphates
      accumulation was critically dependent on the agonist concentration and
      stimulation duration, suggesting the involvement of a Gi.0 protein during the
      early stimulation by low nucleotide concentrations. No inhibition of cyclic AMP
      accumulation could be detected. These properties were observed with both
      polymorphic receptors.

PMID- 10401564
TI  - Extracellular adenosine concentrations during in vitro ischaemia in rat
      hippocampal slices.
AB  - 1. The application of an ischaemic insult in hippocampal slices results in the
      depression of synaptic transmission, mainly attributed to the activation of A1
      adenosine receptors by adenosine released in the extracellular space. 2. To
      estimate the concentration of endogenous adenosine acting at the receptor level
      during an ischaemic episode, we recorded field e.p.s.ps (fe.p.s.ps) from
      hippocampal slices, and evaluated the ability of the selective A1 receptor
      antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), to reverse the fe.p.s.p.
      depression induced by in vitro ischaemia. A relationship between the IC50 of an
      antagonist and the endogenous concentration of a neurotransmitter has been used
      for pharmacological analysis. 3. The complete and reversible depression of
      fe.p.s.p. in the CA1 region induced by 5 min ischaemia was decreased in the
      presence of DPCPX (50-500 nM). 8-Phenyltheophylline (10 microM) abolished the
      depression of fe.p.s.ps during the ischaemic period, while a small (peak effect
      12 +/- 4%) decrease in fe.p.s.ps was observed during the initial phase of
      reperfusion. 4. In the time-interval of maximal depression of fe.p.s.ps., IC50
      and adenosine concentration changed as function of time with a good degree of
      correlation. The maximal value of adenosine concentration was 30 microM. 5. Our
      data provide an estimation of the adenosine concentration reached at the receptor
      level during an ischaemic episode, with a higher time discrimination (15 s) than
      that achieved with any biochemical approach. This estimation may be useful in
      order to establish appropriate concentrations of purinergic compounds to be
      tested for their pharmacological effects during an ischaemic episode.

PMID- 10401563
TI  - Characterization of central and peripheral effects of septide with the use of
      five tachykinin NK1 receptor antagonists in the rat.
AB  - 1. Effects of two tachykinin NK1 receptor selective agonists (septide and [Sar9,
      Met(O2)11]SP) were compared on the increases in mean arterial pressure (MAP),
      heart rate (HR) and motor behaviour following intracerebroventricular (i.c.v.)
      administration in unanaesthetized rat, and on the vascular permeability increases
      to intradermal (i.d.) injection in the anaesthetized rat. Moreover, five
      tachykinin NK1 receptor selective antagonists (LY303870, LY306740, LY303241,
      SR140333 and RP67580) were tested against the two agonists to compare their
      pharmacological profile. 2. [Sar9, Met(O2)11]SP and septide (10-100 pmol per rat,
      i.c.v.) were equipotent in increasing MAP and HR, yet they had dissimilar time
      course. Both agonists increased dose-dependently face washing and sniffing while
      [Sar9, Met(O2)11]SP was the sole to produce grooming, septide was more potent
      than [Sar9, Met(O2)11]SP (6.5-650 pmol) in increasing vascular permeability. 3.
      For most centrally mediated responses, LY303870 and RP67580 were significantly
      more potent in inhibiting septide than [Sar9, Met(O2)11]SP. In some parameters,
      greater blockade was achieved when antagonists (particularly LY306740) were given
      1 h instead of 10 min prior to i.c.v. septide. 4. All antagonists except LY303241
      blocked dose-dependently the increases in vascular permeability to equipotent
      doses of [Sar9, Met(O2)11]SP and septide. LY303870 and LY306740 were more potent
      against septide. 5. The antagonism afforded by LY303870, LY306740 and LY303241
      was stereoselective and only SR140333 was found to cause central and peripheral
      non specific effects. 6. The data confirm a distinct pharmacological profile for
      septide in vivo. RP67580 and LY306740 are currently the most valuable tachykinin
      NK1 receptor antagonists for in vivo studies in rat.

PMID- 10401565
TI  - Serotonin reuptake inhibitor, fluoxetine, dilates isolated skeletal muscle
      arterioles. Possible role of altered Ca2+ sensitivity.
AB  - 1. Inhibitors of serotonin reuptake in the central nervous system, such as
      fluoxetine, may also affect the function of vascular tissues. Thus, we
      investigated the effect of fluoxetine on the vasomotor responses of isolated,
      pressurized arterioles of rat gracilis muscle (98 +/- 4 microns in diameter at 80
      mmHg perfusion pressure). 2. We have found that increasing concentrations of
      fluoxetine dilated arterioles up to 155 +/- 5 microns with an EC50 of 2.5 +/- 0.5
      x 10(-6) M. 3. Removal of the endothelium, application of 4-aminopyridine (4-AP,
      an inhibitor of aminopyridine sensitive K+ channels), or use of glibenclamide (an
      inhibitor of ATP-sensitive K+ channels) did not affect the vasodilator response
      to fluoxetine. 4. In the presence of 10(-6), 2 x 10(-6) or 10(-5) M fluoxetine
      noradrenaline (NA, 10(-9)-10(-5) M) and 5-hydroxytryptamine (5-HT, 10(-9)-10(
      5)M)-induced constrictions were significantly attenuated resulting in
      concentration-dependent parallel rightward shifts of their dose-response curves
      (pA2 = 6.1 +/- 0.1 and 6.9 +/- 0.1, respectively). 5. Increasing concentrations
      of Ca2+ (10(-4) 3 x 10(-2) M) elicited arteriolar constrictions (up to
      approximately 30%), which were markedly reduced by 2 x 10(-6)M fluoxetine,
      whereas 10(-5)M fluoxetine practically abolished these responses. 6. In
      conclusion, fluoxetine, elicits substantial dilations of isolated skeletal muscle
      arterioles, a response which is not mediated by 4-AP- and ATP-sensitive K+
      channels or endothelium-derived dilator factors. The findings that fluoxetine had
      a greater inhibitory effect on Ca2+ elicited constrictions than on responses to
      NA and 5-HT suggest that fluoxetine may inhibit Ca2+ channel(s) or interfere with
      the signal transduction by Ca2+ in the vascular smooth muscle cells.

PMID- 10401566
TI  - Modulation of haemostatic function and prevention of experimental thrombosis by
      red wine in rats: a role for increased nitric oxide production.
AB  - 1. The effects of ethyl alcohol and wine (red and white) on haemostatic
      parameters and experimental thrombosis were studied in rats; NO was evaluated as
      a possible mediator of these effects. 2. We found that red wine (12% alcohol)
      supplementation (8.4 +/- 0.4 ml d-1 in drinking water, for 10 days) induced a
      marked prolongation of 'template' bleeding time (BT) (258 +/- 13 vs 132 +/- 13 s
      in controls; P < 0.001), a decrease in platelet adhesion to fibrillar collagen
      (11.6 +/- 1.0 vs 32.2 +/- 1.3%; P < 0.01) and a reduction in thrombus weight
      (1.45 +/- 0.33 vs 3.27 +/- 0.39 mg; P < 0.01). 3. Alcohol-free red wine showed an
      effect similar to red wine. In contrast, neither ethyl alcohol (12%) nor white
      wine (12% alcohol) affected these systems. 4. All these effects were also
      observed after red wine i.v. injection (1 ml kg-1 of 1:4 dilution) 15 min before
      the experiments. 5. The effects of red wine were prevented by the NO inhibitor, N
      omega nitro-L-arginine-methyl ester (L-NAME). L-arginine, not D-arginine,
      reversed the effect of L-NAME on red wine infusion. 6. Red wine injection induced
      a 3 fold increase in total radical-trapping antioxidant parameter values of rat
      plasma with respect to controls, while white wine and alcohol did not show any
      effect. 7. Our study provides evidence that red wine modulates primary
      haemostasis and prevents experimental thrombosis in rats, independently of its
      alcohol content, by a NO-mediated mechanism.

PMID- 10401567
TI  - Characterization of alpha 1-adrenoceptors expressed in a novel vascular smooth
      muscle cell line cloned from p53 knockout mice, P53LMAC01 (AC01) cells.
AB  - 1. We pharmacologically studied the alpha 1-adrenoceptor (AR) subtype(s) involved
      in receptor-mediated signalling in a novel vascular smooth muscle cell line
      cloned from p53 knockout mice, P53LMAC01 (AC01) cells. 2. Radioligand binding
      studies with [125I]-HEAT showed the existence of a homogeneous population of
      binding site with an affinity (Kd value) of 0.4 nM and a maximum number of
      binding sites (Bmax) of 100 fmol mg-1 protein. Catecholamines competed for [125I]
      HEAT binding stereospecifically and with the characteristic alpha 1-AR potency
      series. 3. Displacement curves for BMY-7378 and KMD-3213 best fitted a one-site
      model with a pKi value (-log10 (equilibrium inhibition constant)) of 6.06 and
      7.07, respectively. 4. Reverse transcription-polymerase chain reaction (RT-PCR)
      assay detected alpha 1B- and alpha 1D-AR, but not alpha 1A-AR transcript. 5.
      Chlorethylclonidine (CEC) treatment nearly abolished (-)noradrenaline (NA) (10
      microM)-induced inositol[1,4,5]trisphosphate (IP3) production, and BMY-7378
      inhibited the response with a Ki value of 0.3 nM, which value was similar to that
      obtained in the cells expressing alpha 1D-AR. In both AC01 cells and cells
      expressing alpha 1D-AR, BMY-7378 protected alpha 1-ARs from CEC alkylation while
      it had little protective effect on CEC alkylation and NA-induced IP3 production
      in cells expressing alpha 1B-AR. 6. The results indicate that AC01 cells contain
      predominantly alpha 1B-ARs and a small population of alpha 1D-ARs; however,
      phosphoinositide (PI)/Ca2+ signalling is mainly mediated through the minor
      population of alpha 1D-ARs, rather than the alpha 1B-ARs.

PMID- 10401568
TI  - Stimulant action of pituitary adenylate cyclase-activating peptide on normal and
      drug-compromised peristalsis in the guinea-pig intestine.
AB  - 1. Pituitary adenylate cyclase-activating peptide (PACAP) is known to influence
      the activity of intestinal smooth muscle. This study set out to examine the
      action of PACAP on normal and drug-inhibited peristalsis and to shed light on its
      site and mode of action. 2. Peristalsis in isolated segments of the guinea-pig
      small intestine was elicited by distension through a rise of the intraluminal
      pressure. Drug-induced motility changes were quantified by alterations of the
      peristaltic pressure threshold at which aborally moving peristaltic contractions
      were triggered. 3. PACAP (1-30 nM) stimulated normal peristalsis as deduced from
      a concentration-related decrease in the peristaltic pressure threshold (maximum
      decrease by 55%). The peptide's stimulant effect remained intact in segments pre
      exposed to apamin (0.5 microM), N-nitro-L-arginine methyl ester (300 microM),
      naloxone (0.5 microM), atropine (1 microM) plus naloxone (0.5 microM) or
      hexamethonium (100 microM) plus naloxone (0.5 microM). 4. PACAP (10 nM) restored
      peristalsis blocked by morphine (10 microM), noradrenaline (1 microM) or N6
      cyclopentyladenosine (0.3 microM) and partially reinstated peristalsis blocked by
      Rp-adenosine-3',5'-cyclic monophosphothioate triethylamine (100 microM) but
      failed to revive peristalsis blocked by hexamethonium (100 microM) or atropine (1
      microM). The peptide's spectrum of properistaltic activity differed from that of
      naloxone (0.5 microM) and forskolin (0.3 microM). 5. The distension-induced
      ascending reflex contraction of the circular muscle was facilitated by PACAP (1
      30 nM) which itself evoked transient nerve-mediated contractions of intestinal
      segment preparations. 6. These data show that PACAP stimulates normal peristalsis
      and counteracts drug-induced peristaltic arrest by a stimulant action on
      excitatory enteric motor pathways, presumably at the intrinsic sensory neurone
      level. The action of PACAP seems to involve multiple signalling mechanisms
      including stimulation of adenylate cyclase.

PMID- 10401569
TI  - Recovery of impaired K+ channels in mesenteric arteries from spontaneously
      hypertensive rats by prolonged treatment with cholecalciferol.
AB  - 1. The mechanism responsible for blood pressure reduction in spontaneously
      hypertensive rats (SHR) after prolonged cholecalciferol treatment was studied.
      Two-week treatment of SHR with 0.125 mg cholecalciferol kg-1 body weight per day
      orally caused significant reductions of systolic blood pressure and of the
      resting perfusion pressure of the mesenteric vascular bed at constant flow. 2. In
      addition, the treated animals presented a normalization of the maximum
      vasoconstriction response to noradrenaline and a reduction of the maximum effect
      of the adrenaline concentration-response curves. This latter effect probably was
      due to recovery of the impaired Ca(2+)-dependent K+ channels coupled to alpha 2
      adrenoceptors since it was prevented by apamin. 3. The treatment with
      cholecalciferol also normalized the smooth muscle cell membrane potential of de
      endothelialized mesenteric arteries of SHR and their hyperpolarizing responses to
      alpha 2-adrenergic agonists, which were depressed in untreated SHR. 4. In
      mesenteric rings with endothelium, alpha 2-adrenergic agonists caused similar
      hyperpolarizing responses in the SHR and in normotensive Wistar (NWR) and Wistar
      Kyoto (WKY). In non cholecalciferol-treated SHR the hyperpolarizing mediator
      involved in this effect was NO, while in NWR it was the endothelium-derived
      hyperpolarizing factor (EDHF). After cholecalciferol treatment, the
      hyperpolarization induced by alpha 2-adrenergic agonists in SHR smooth muscle
      cells was mediated by EDHF, as in NWR. 5. Our results indicate that the
      hypotensive effect of cholecalciferol in the SHR is probably due to the
      normalization of vascular reactivity, by restoring the functioning of apamin- and
      ATP-sensitive K+ channels located in the vascular smooth muscle cell membrane,
      which are impaired in the SHR.

PMID- 10401571
TI  - Tyrosine nitration in blood vessels occurs with increasing nitric oxide
      concentration.
AB  - 1. Experiments were designed to explore the effects of nitric oxide (NO) donors
      on generation of superoxide (O2.-) and peroxynitrite (ONOO-) in rabbit aortic
      rings. 2. Following inhibition of endogenous superoxide dismutase (SOD),
      significant basal release of O2.- was revealed (0.9 +/- 0.01 x 10(-12) mol min-1
      mg-1 tissue). Generation of O2.- increased in a concentration-dependent manner in
      response to NADH or NADPH (EC50 = 2.34 +/- 1.18 x 10(-4) and 6.21 +/- 1.79 x 10(
      3) M respectively, n = 4). NADH-stimulated O2.- chemiluminescence was reduced by
      approximately 85% in the presence of exogenous SOD (15 x 10(3) U ml-1). 3.
      Incubation of aortic rings with S-nitrosoglutathione (GSNO; 1 x 10(-5)-3 x 10(-3)
      M) or sodium nitroprusside (SNP; 1 x 10(-8)-1 x 10(-3) M), resulted in a
      concentration-dependent quenching of O2.- chemiluminescence which was
      proportional to NO release. 4. ONOO- formation was assessed indirectly by
      determining protein tyrosine nitration in rabbit aorta using a specific antibody
      against nitrotyrosine. Basally and in the presence of NADH, a single band was
      detected. Incubation of aortic rings with either GSNO (1 x 10(-3) M) alone or
      GSNO with NADH resulted in the appearance of additional nitrotyrosine bands.
      Incubation of serum albumin with GSNO alone did not cause nitrotyrosine
      formation. In contrast, incubation with 3-morpholinosydonomine (SIN-1; 1 x 10(-3)
      M, 10 min), resulted in marked nitration of albumin which was reduced by
      oxyhaemoglobin or SOD. Incubation of albumin with GSNO and pyrogallol, a O2.-
      generator, also resulted in protein nitration. 5. Addition of exogenous NO
      results in nitrotyrosine formation in rabbit aortic rings. Nitrotyrosine
      formation is likely to result from the reaction of exogenous NO and basal
      endogenous O2.- resulting in the formation of ONOO-. Formation of ONOO- and
      nitration of tyrosine residues potentially could lead to vascular damage and
      might represent unexpected adverse effects of long-term nitrate therapy.

PMID- 10401570
TI  - Comparative effects of several nitric oxide donors on intracellular cyclic GMP
      levels in bovine chromaffin cells: correlation with nitric oxide production.
AB  - 1. Sodium nitroprusside, S-nitroso-N-acetyl-D,L-penicillamine, Spermine NONOate
      and DEA NONOate raised cyclic GMP levels in bovine chromaffin cells in a time and
      concentration dependent manner with different potencies, the most potent being
      DEA/NO with an EC50 value of 0.38 +/- 0.02 microM. 2. Measurements of NO released
      from these donors revealed that DEA/NO decomposed with a half-life (t1/2) of 3.9
      +/- 0.2 min. The t1/2 for SPER/NO was 37 +/- 3 min. SNAP decomposed more slowly
      (t1/2 = 37 +/- 4 h) and after 60 min the amount of NO produced corresponded to
      less than 2% of the total SNAP present. The rate of NO production from SNAP was
      increased by the presence of glutathione. 3. For DEA/NO and SPER/NO there was a
      clear correlation between nitric oxide production and cyclic GMP increases. Their
      threshold concentrations were 0.05 microM and maximal effective concentration
      between 2.5 and 5 microM. 4. For SNAP, threshold activation was seen at 1 microM,
      whereas full activation required a higher concentration (500-750 microM). The
      dose-response for SNAP increases in cyclic GMP was shifted nearly two orders of
      magnitude lower in the presence of glutathione. At higher concentrations an
      inhibition of cyclic GMP accumulation was found. This effect was not observed
      with either the nitric oxide-deficient SNAP analogue or other NO donors. 5.
      Although NO-donors are likely to be valuable for studying NO functions, their
      effective concentrations and the amount of NO released by them are very different
      and should be assessed in each system to ensure that physiological concentrations
      of NO are used.

PMID- 10401572
TI  - NPY receptor subtype in the rabbit isolated ileum.
AB  - 1. The purpose of this work was to verify the hypothesis that the rabbit ileum is
      a selective preparation for the NPY Y5 receptor by using new selective
      antagonists recently synthesized. Spontaneous contractions of the rabbit isolated
      ileum were recorded and binding experiments were performed in cells expressing
      the human NPY Y1, Y2, Y4 or Y5 receptor subtype. 2. NPY analogues produced a
      concentration-dependent transient inhibition of the spontaneous contractions of
      the rabbit ileum with the following order of potency hPP > rPP > PYY > or =
      [Leu31,-Pro34]-NPY > NPY >> NPY13-36. Pre-exposure to rPP, PYY, [Leu31,Pro34]-NPY
      or NPY (but not NPY13-36) inhibited the effect of subsequent administration of
      hPP suggesting cross-desensitization of the preparation. The apparent affinity of
      the various agonists studied was correlated to the affinity reported for the
      human Y4 receptor subtype (and to a lesser extent for the rat Y4 subtype) but not
      to the affinity for the Y5 receptor subtype. 3. BIBO 3304, a selective NPY Y1
      receptor antagonist, and CGP 71683A, a selective NPY Y5 receptor antagonist, did
      not affect the response to hPP. JCF 109, another NPY Y5 receptor antagonist,
      produced an inhibition of the response to hPP but only at the highest dose tested
      (10 microM) which also, by itself, produced intrinsic inhibitory effects. 4.
      1229U91, a non-selective ligand for Y1, Y2, Y4 and Y5 receptors with high
      affinity toward the Y1 and Y4 receptor subtypes, produced a concentration
      dependent transient inhibition of the spontaneous contractions of the rabbit
      ileum and a dose-dependent inhibition of the response to hPP (apparent pKB: 7.2).
      5. These results suggest that in the rabbit ileum, the NPY receptor involved in
      the inhibition of the spontaneous contractile activity is a NPY Y4 receptor
      subtype.

PMID- 10401573
TI  - Effects of endothelial impairment by saponin on the responses to vasodilators and
      nitrergic nerve stimulation in isolated canine corpus cavernosum.
AB  - 1. Responsiveness to EDRF-releasing substances and inhibitory nerve stimulation
      of canine isolated penile corpus cavernosum with and without saponin treatment
      were investigated. 2. Histological studies demonstrated that saponin did not
      detach endothelial cells from underlying tissues, but induced degenerative
      changes in the endothelial cells selectively. 3. In the cavernous strips
      contracted with phenylephrine, addition of acetylcholine, sodium nitroprusside,
      ATP and Ca2+ ionophore A23187 induced relaxations, but substance P and bradykinin
      did not change the muscle tone. 4. Acetylcholine-induced relaxation was
      significantly attenuated but not abolished by NG-nitro-L-arginine (L-NOARG). L
      arginine restored the response inhibited by L-NOARG. The L-NOARG resistant
      relaxation was not influenced by 1H[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ)
      but was suppressed in the strips contracted with K+. Treatment with saponin
      abolished the relaxation elicited by acetylcholine and A23187 but did not
      influence the response to nitroprusside and ATP. The ATP-induced relaxation was
      attenuated by aminophylline. 5. Transmural electrical stimulation at 2-20 Hz
      produced endothelium-independent relaxations which were abolished by tetrodotoxin
      and L-NOARG but unaffected by treatment with saponin. In saponin-treated
      cavernous strips, the neurogenic relaxation was not affected by acetylcholine,
      physostigmine, atropine and vasoactive intestinal peptide (VIP) but was abolished
      by ODQ. 6. It is concluded that acetylcholine-induced relaxations are endothelium
      dependent and mediated partly by NO and also by other substances from the
      endothelium. The endothelium-independent relaxation to ATP is likely to be
      mediated by P1 purinoceptors. The function of nitrergic nerve does not seem to be
      prejunctionally modulated by acetylcholine and VIP.

PMID- 10401574
TI  - "Dumb" versus "smart" kinetochore models for chromosome congression during
      mitosis in vertebrate somatic cells.

PMID- 10401575
TI  - MEKK1 interacts with alpha-actinin and localizes to stress fibers and focal
      adhesions.
AB  - Mitogen-activated protein (MAP) kinases orchestrate the effects of many
      extracellular stimuli on cells. The serine/threonine protein kinase MEKK1 is an
      upstream activator of the MAP kinases c-Jun N-terminal kinase/stress-activated
      protein kinase (JNK/SAPK), extracellular signal-regulated kinase (ERK), and p38
      as well as NF-kappa B. In a yeast two-hybrid interaction screen to identify
      proteins that bind to an N-terminal fragment of MEKK1 (amino acids 1-719), the
      actin-crosslinking protein alpha-actinin was identified as a MEKK1-binding
      protein. Over-expressed MEKK1 co-immunoprecipitated with alpha-actinin in cell
      lysates. Both endogenous and over-expressed MEKK1 colocalized with alpha-actinin
      along actin stress fibers and at focal adhesions. Residues 221-559 of MEKK1 bound
      to purified alpha-actinin in vitro, indicating that the interaction is direct,
      and this fragment localized to actin filaments in cells. MEKK1 kinase activity
      was not required for association with actin filaments, because a catalytically
      inactive mutant of MEKK1 (MEKK1 D1369A) localized to stress fibers. These results
      provide strong evidence for the interaction between MEKK1 and alpha-actinin.
      Thus, restriction of the kinase to the actin cytoskeleton may serve to regulate
      its specificity towards downstream targets.

PMID- 10401576
TI  - Chromosome movement during meiotic prophase in crane-fly spermatocytes: IV. Actin
      and the effects of cytochalasin D.
AB  - Cytochalasin D (CD) was applied to crane-fly spermatocytes at late diakinesis
      with the aim of perturbing actin structure and actin function, thereby testing
      the hypothesis that intranuclear chromosome movement during late diakinesis is
      actin-based. Isolated tests were incubated in a range of CD concentrations (2-100
      microM) for 1 or 2 h. None of those treatments resulted in cessation of prophase
      movements in living cells. An immediate effect of 10-100 microM CD at late
      diakinesis was the formation of highly refractile, actin-containing cables within
      the nonchromosomal nucleoplasm. No such cables were observed in vehicle-treated
      control cells. CD treatments caused autosomal bivalents in unusually large
      numbers of spermatocytes to become aggregated into densely-packed clusters; for
      example, with 40 microM CD about 80% of late diakinesis spermatocytes had
      clustered autosomes, vs. about 25% clustering in untreated cells. We conclude
      from these data that the mechanism of chromosome positioning at the nuclear
      envelope is CD-sensitive. Rhodamine-conjugates of phalloidin and DNase I were
      used to assess the status of actin in untreated cells as well as the effect of CD
      on actin distribution. Differences in nucleoplasmic staining with phalloidin and
      DNase I conjugates suggest that nucleoplasm at late diakinesis contains actin in
      a nonfilamentous form.

PMID- 10401577
TI  - Organization and possible functions of microtubule cytoskeleton in hymenopteran
      nurse cells.
AB  - The results of systematic cytochemical and EM studies on the distribution of
      actin filaments and microtubules in hymenopteran nurse cells are presented. We
      demonstrate that each nurse cell nucleus is surrounded by a thick three
      dimensional cage of microtubules that is engaged in maintaining the position of
      the nuclei in the cell centers during the flow of the cytoplasm from nurse cells
      into the oocyte. Hence, the cages represent functional counterparts of actin
      bundles described in the Drosophila nurse cells. Furthermore, our data suggest
      that a subset of the microtubules is involved in transferring nuage aggregates
      from the vicinity of the nucleus towards the nurse cell periphery and the nearest
      intercellular bridge. A conclusion is reached that despite similar polytrophic
      organization of the ovaries in both hymenopterans and dipterans, the physiology
      of their nurse cell-oocyte syncytia appears distinctly different.

PMID- 10401578
TI  - Cloning of Chlamydomonas p60 katanin and localization to the site of outer
      doublet severing during deflagellation.
AB  - Katanin, a heterodimeric microtubule-severing protein that localizes to sites of
      microtubule organization, can mediate in vitro the ATP-dependent disassembly of
      both taxol-stabilized microtubules and axonemal doublet microtubules. In the
      unicellular biflagellate alga Chlamydomonas, katanin has been implicated in
      deflagellation, a highly specific process that involves a Ca(2+)-signal
      transduction pathway starting at the plasma membrane and culminating in the
      severing of axonemal outer doublet microtubules and excision of both flagella
      from the cell body. Previously, we showed that the microtubule severing activity
      of deflagellation and katanin's 60 kD catalytic subunit (termed p60) purified
      with the flagellar basal body complex (FBBC). Additional evidence supporting the
      involvement of katanin in deflagellation came from the observation that an
      antibody against human p60 katanin significantly inhibited FBBC-associated
      microtubule-severing activity. Here we report the cloning of p60 katanin from
      Chlamydomonas reinhardtii. Immunogold electron microscopy places Chlamydomonas
      p60 at several locations within the basal body apparatus and associated
      structures. Importantly, we find a dense accumulation of colloidal gold labeling
      the distal end of the flagellar transition zone, the site of outer doublet
      severing during deflagellation. These results suggest that, in addition to a
      potential involvement in the deflagellation pathway, katanin-mediated microtubule
      severing may be associated with multiple processes in Chlamydomonas.

PMID- 10401579
TI  - Tau is required for neurite outgrowth and growth cone motility of chick sensory
      neurons.
AB  - The role of the microtubule-associated protein (MAP) tau in axon growth remains
      controversial. Antisense experiments have suggested that tau is required for axon
      outgrowth, whereas genetic knockout and immunodepletion studies have suggested
      that tau plays no role in this process. To investigate the role of tau in both
      neurite outgrowth and growth cone motility, we have used a different approach,
      the chromophore-assisted laser inactivation (CALI) of tau in chick dorsal root
      ganglion (DRG) neurons in culture. This approach generates an acute loss of tau
      function that is not subject to compensation by other MAPs. Inactivation of tau
      in whole DRG neurons (including cell body and neurites) reduced neurite number
      and length. Inactivation of tau within regions of growth cones using micro-scale
      CALI caused a decrease in neurite extension rate by approximately 2-fold.
      Surprisingly, it also caused a approximately 20% decrease in the lamellipodial
      size within the inactivation region, whereas the filopodial motility was not
      affected. These results suggest that tau is required in neurite outgrowth and
      that tau also functions in lamellipodial motility at the growth cone leading
      edge.

PMID- 10401580
TI  - Regulated expression of p14 (cofactor A) during spermatogenesis.
AB  - The correct folding of tubulins and the generation of functional alpha beta
      tubulin heterodimers require the participation of a series of recently described
      molecular chaperones and CCT (or TRiC), the cytosolic chaperonin containing TCP
      1. p14 (cofactor A) is a highly conserved protein that forms stable complexes
      with beta-tubulin which are not apparently indispensable along the in vitro beta
      tubulin folding route. Consequently, the precise role of p14 is still unknown,
      though findings on Rb12p (its yeast homologue) suggest p14 might play a role in
      meiosis and/or perhaps to serve as an excess beta-tubulin reservoir in the cell.
      This paper investigates the in vivo possible role of p14 in testis where mitosis,
      meiosis, and intense microtubular remodeling processes occur. Our results confirm
      that p14 is more abundantly expressed in testis than in other adult mammalian
      tissues. Northern blot, Western blot, in situ hybridization, and
      immunocytochemical analyses have all demonstrated that p14 is progressively
      upregulated from the onset of meiosis through spermiogenesis, being more abundant
      in differentiating spermatids. The close correlation observed between the mRNA
      expression waves for p14 and testis specific tubulin isotypes beta 3 and alpha
      3/7, together with the above results, suggest that p14 role in testis would
      presumably be associated to beta-tubulin processing rather than meiosis itself.
      Additional in vitro beta 3-tubulin synthesis experiments have shown that p14
      plays a double role in beta-tubulin folding, enhancing the dimerization of newly
      synthesized beta-tubulin isotypes as well as capturing excess beta-tubulin
      monomers. The above evidence suggests that p14 is a chaperone required for the
      actual beta-tubulin folding process in vivo and storage of excess beta-tubulin in
      situations, such as in testis, where excessive microtubule remodeling could lead
      to a disruption of the alpha-beta balance. As seen for other chaperones, p14
      could also serve as a route to lead excess beta-tubulin or replaced isotypes
      towards degradation.

PMID- 10401581
TI  - Regulatory light chain phosphorylation and the assembly of myosin II into the
      cytoskeleton of microcapillary endothelial cells.
AB  - During the crawling movements of non-muscle cells, myosin II-containing
      structures assemble and disassemble with a high degree of spatial and temporal
      heterogeneity. In order to understand how this is controlled, we examined factors
      that influence the association of myosin II with detergent-resistant
      cytoskeletons of cultured endothelial cells. Treatment of cells with 0.05% Triton
      X-100 in an actin-stabilizing buffer released approximately 42% of the myosin II
      from the cytoplasm. Most remaining myosin II was dissociated from the
      cytoskeleton by treatment with ATP or AMPPNP, but not ADP, suggesting that myosin
      II is retained as ATP-sensitive filaments or via rigor-like binding to F-actin.
      Disruption of actin filaments with cytochalasin or latrunculin prior to detergent
      permeabilization sharply decreased the amount of myosin II retained, suggesting
      the latter type of association. Because phosphorylation of myosin II affects
      filament assembly and actin binding in vitro, phosphorylation levels in soluble
      and cytoskeletal myosin II were measured. Phosphorylation of myosin heavy chains
      was not significantly different between the two fractions, but regulatory light
      chains of cytoskeletal myosin II were 5 times more phosphorylated than in soluble
      myosin II. Tryptic-peptide mapping showed that cytoskeletal light chains were
      phosphorylated predominantly at serine 19/threonine 18, which regulates myosin II
      assembly in vitro, whereas soluble light chains were not phosphorylated or were
      phosphorylated at threonine 9. Treating cells with the kinase inhibitor,
      staurosporine, prior to permeabilization decreased light-chain phosphorylation
      with concomitant reduction in myosin retention. These observations suggest that
      assembly of myosin II into cytoskeletal structures, where it can generate and
      resist forces, is regulated in vivo by phosphorylation of myosin light chains at
      serine 19/threonine 18.

PMID- 10401582
TI  - Reproducible methods for experimental infection with Flavobacterium psychrophilum
      in rainbow trout Oncorhynchus mykiss.
AB  - Experiments were done in order to achieve a reproducible method that can be used
      to infect rainbow trout Oncorhynchus mykiss with Flavobacterium psychrophilum,
      the causal agent of coldwater disease and rainbow trout fry syndrome. The main
      method investigated was intraperitoneal injection, and this method was tested
      using isolates with different elastin-degrading profiles and representing
      different serotypes. Injecting trout, average weight 1 g, with 10(4) CFU (colony
      forming units) per fish caused cumulative mortalities around 60 to 70%. The
      virulent strains belonged to certain serotypes and degraded elastin. The
      intraperitoneal injection challenge method could be used on larger fish, but the
      infection dose was 10(7) CFU per fish before mortalities occurred. Bath infection
      and bath infection in combination with formalin treatment (stress) seemed to be
      reproducible methods that could be used as alternatives to the intraperitoneal
      method, although the mortalities among infected trout were lower. The results of
      investigated methods were influenced by parameters such as the challenge isolate,
      number of fish in the tank affecting the infection pressure, origin of fish and
      weight of fish.

PMID- 10401583
TI  - Streptococcus iniae, a bacterial infection in barramundi Lates calcarifer.
AB  - The cause of ongoing mortality in barramundi Lates calcarifer (Bloch) in seawater
      culture was identified as Streptococcus iniae by biochemical and physiological
      tests. This is the first published record of this bacterial species in Australia
      and the first confirmed report of S. iniae causing mortality in barramundi. The
      bacterium was highly pathogenic for barramundi when challenged by bath exposure.
      The pathogen was found to have a LD50 of 2.5 x 10(5) and 3.2 x 10(4) colony
      forming units at 48 h and 10 d respectively. Experimental challenge of barramundi
      resulted in high levels of mortality (> 40%) within a 48 h period. Ten days after
      the challenge, S. iniae could not be isolated from kidney, spleen, liver or eye
      of surviving fish. However, the organism was easily isolated from the brain of
      both moribund and healthy fish, indicating that barramundi can carry the
      bacterium asymptomatically.

PMID- 10401584
TI  - Ultrastructural alterations in the liver and intestine of carp Cyprinus carpio
      induced orally by ultra-low doses of endosulfan.
AB  - In order to elucidate the importance of food-borne chemical contamination in
      fish, cytological and ultrastructural alterations in hepatocytes and enterocytes
      of common carp Cyprinus carpio L. exposed for 5 wk to 0.5 microgram endosulfan
      (6,7,8,9,10,10-hexachloro-1,5,5a,6,9a-hexahydro-6,9-methano-2,4,3-benzo-
      dioxyanthiepin-3-oxide) kg-1 food dry weight, equivalent to an ultra-low dosis of
      15 ng kg-1 fish d-1, were investigated by means of light and electron microscopy.
      Observations on liver alterations were quantified by morphometric analysis.
      Livers show enlargement of the nucleolus, increase in number and size of both
      Golgi fields and rough endoplasmic reticulum (ER) lamellae, as well as
      proliferation of peroxisomes and lysosomes. Taken together, these alterations
      represent the morphological equivalent of a general stimulation of hepatic
      metabolism. Proliferation of the smooth ER is indicative of the onset of
      biotransformation processes under the influence of food-borne endosulfan. Further
      pathological processes in the liver were evident by glycogen and lipid depletion,
      invasion of phagocytic macrophages, and accumulation of myelinated bodies in
      endothelial cells of hepatic sinusoids. In the intestinal tract, exposure to
      endosulfan is associated with a complete lack of chylomicrons in the epithelial
      lining, which indicates disturbance of intestinal absorption. The reaction of the
      gut epithelium also included considerable distension of the intercellular space
      and an elevated number of lysosomal inclusions in enterocytes. An increased rate
      of mucous cell precursors was detectable, and macrophages were numerous. Results
      are consistent with endosulfan resorption by the intestinal epithelium and the
      coexistence of gut and liver ultrastructural changes at extremely low doses.
      Thus, the substantiation of pathological alterations in organs sequentially in
      contact with toxicants appears useful as a biomarker of pollutant exposure and
      effect. With regard to a chemical spill into the Rhine river at Basel,
      Switzerland, in November 1986, endosulfan, as a component of the mixture of toxic
      substances, may well have contributed to the overall toxicity of the chemicals
      released during the accident and the subsequent fish kill, less as a toxicant in
      itself than as a stimulant for the toxicity of other xenobiotics.

PMID- 10401585
TI  - Ichthyophthiriasis in carp Cyprinus carpio: infectivity of trophonts prematurely
      exiting both the immune and non-immune host.
AB  - Ichthyophthirius multifiliis exposed to naturally immunised carp established
      short-term infections, the majority of parasites actively emerging within 2 h of
      entering the epidermis. A small, but significant, number of these expelled
      parasites were shown to retain theront-like properties with the capacity to
      directly re-invade a further fish host. Infectivity fell rapidly with time in the
      host and was comparable to that of trophonts of a similar age artificially
      induced to emerge from non-immune hosts with the aid of MEM (minimal essential
      medium). Trophonts recovered with MEM from immune carp 2 to 8 h post infection
      rarely established infections upon exposure to susceptible new hosts and no
      infections resulted from older trophonts recovered after 8 to 24 h exposure;
      older trophonts, however, represented only a small percentage of the original
      parasite population. A low level of infectivity was recorded in trophonts
      collected with the aid of MEM from non-immune carp after up to 24 h of infection.
      The results are discussed in relation to theront transformation and evasion of
      the host immune response.

PMID- 10401586
TI  - Molecular evidence that the proliferative kidney disease organism unknown (PKX)
      is a myxosporean.
AB  - The proliferative kidney organism unknown (PKX), a serious salmonid fish
      pathogen, is considered to be a myxosporean on the basis of ultrastructural
      studies, but its real taxonomic position has never been confirmed. In order to
      ascertain its position, genomic DNA was extracted from PKX and small subunit
      (SSU) ribosomal DNA was amplified by PCR, cloned and sequenced. A phylogenetical
      analysis on SSU rDNA from 76 or 128 eucaryotic species was carried out. Whatever
      the tree reconstruction methods used, PKX was found to be a sister group of the
      Myxozoa phylum, providing the first molecular evidence for its membership in this
      phylum.

PMID- 10401587
TI  - Environmental factors and chemical agents affecting the growth of the pathogenic
      marine ciliate Uronema nigricans.
AB  - The scuticociliate Uronema nigricans is an opportunistically parasitic marine
      ciliate known to cause disease in some aquacultural environments with epizootics
      documented from marine larval rearing systems, marine aquaria and in southern
      bluefin tuna Thunnus macoyii growout enclosures. This study examined growth
      responses of laboratory cultures of the ciliate and prey bacteria to variations
      in temperature and salinity, and the efficacy of potential chemotherapeutants for
      control of U. nigricans infections. Differences in ciliate growth responses were
      marginal at temperatures of 10 to 25 degrees C and at salinities between 15 and
      35 ppt, though 3.5 ppt or less was lethal. Ciliates were found to be sensitive to
      fluctuations in bacterial densities, which may be a factor in the seasonal
      occurrence of the ciliate-related disease in tuna. Commonly used
      chemotherapeutants such as formalin, malachite green and hydrogen peroxide were
      all effective against the ciliate during in vitro trials.

PMID- 10401588
TI  - Lactococcus garvieae and Streptococcus iniae infections in rainbow trout
      Oncorhynchus mykiss: similar, but different diseases.
AB  - Clinical and macroscopic findings (anorexia, lethargy, loss of orientation and
      exophthalmia) indicate that Streptococcus iniae and Lactococcus garvieae
      infections of trout share some common features, but histopathology reveals
      notable differences between the 2 diseases. Meningitis and panophthalmitis are
      the main lesions among S. iniae infected trout, whereas L. garvieae infection
      results in a hyperacute systemic disease. Differences in the LD50s of the 2
      pathogens and the sudden onset of signs and death correlate with the
      histopathological findings, indicating the severity of L. garvieae infection of
      trout.

PMID- 10401590
TI  - Neuropsychiatric dynamics: the study of mental illness using functional magnetic
      resonance imaging.
AB  - Functional magnetic resonance imaging (fMRI) is poised to make significant
      contributions to the study of neuropsychiatric illnesses. Whatever neural
      pathology attends such illnesses has proven subtle at best. By identifying
      predictable, regionally specific deficits in brain function, fMRI can suggest
      brain regions for detailed cellular analyses, provide valuable in vivo data
      regarding effective connectivity, provide a means to model the effects of various
      drug challenge paradigms, and characterize intermediate phenotypes in the search
      for the genes underlying mental illness. Nonetheless, as promising as fMRI
      appears to be in terms of its relative safety, repeatability, ability to generate
      individual brain maps and widespread availability, it is still subject to a
      number of unresolved conceptual conundrums inherited from earlier neuroimaging
      work. For example, functional neuroimaging has not generated any pathognomic
      findings in mental illness, has not established a clear link between
      neurophysiology and observable behavior, and has not resolved the potential
      confounds of medication. In this article, we will review the relevant historical
      background preceding fMRI, address methodological considerations in fMRI, and
      summarize recent fMRI findings in psychiatry. Finally, fMRI is being used to
      simplify the complex genetics of neuropsychiatric illness by generating
      quantitative and qualitative brain phenotypes.

PMID- 10401589
TI  - Exploring brain function with magnetic resonance imaging.
AB  - Since its invention in the early 1990s, functional magnetic resonance imaging
      (fMRI) has rapidly assumed a leading role among the techniques used to localize
      brain activity. The spatial and temporal resolution provided by state-of-the-art
      MR technology and its non-invasive character, which allows multiple studies of
      the same subject, are some of the main advantages of fMRI over the other
      functional neuroimaging modalities that are based on changes in blood flow and
      cortical metabolism. This paper describes the basic principles and methodology of
      fMRI and some aspects of its application to functional activation studies.
      Attention is focused on the physiology of the blood oxygenation level-dependent
      (BOLD) contrast mechanism and on the acquisition of functional time-series with
      echo planar imaging (EPI). We also provide an introduction to the current
      strategies for the correction of signal artefacts and other image processing
      techniques. In order to convey an idea of the numerous applications of fMRI, we
      will review some of the recent results in the fields of cognitive and
      sensorimotor psychology and physiology.

PMID- 10401591
TI  - Organization of the human motor system as studied by functional magnetic
      resonance imaging.
AB  - Blood oxygenation level dependent functional magnetic resonance imaging (BOLD
      fMRI), because of its superior resolution and unlimited repeatability, can be
      particularly useful in studying functional aspects of the human motor system,
      especially plasticity, and somatotopic and temporal organization. In this survey,
      while describing studies that have reliably used BOLD fMRI to examine these
      aspects of the motor system, we also discuss studies that investigate the neural
      substrates underlying motor skill acquisition, motor imagery, production of motor
      sequences; effect of rate and force of movement on brain activation and
      hemispheric control of motor function. In the clinical realm, in addition to the
      presurgical evaluation of neurosurgical patients, BOLD fMRI has been used to
      explore the mechanisms underlying motor abnormalities in patients with
      neuropsychiatric disorders and the mechanisms underlying reorganization or
      plasticity of the motor system following a cerebral insult.

PMID- 10401592
TI  - Perfusion magnetic resonance imaging with continuous arterial spin labeling:
      methods and clinical applications in the central nervous system.
AB  - Several methods are now available for measuring cerebral perfusion and related
      hemodynamic parameters using magnetic resonance imaging (MRI). One class of
      techniques utilizes electromagnetically labeled arterial blood water as a
      noninvasive diffusible tracer for blood flow measurements. The
      electromagnetically labeled tracer has a decay rate of T1, which is sufficiently
      long to allow perfusion of the tissue and microvasculature to be detected.
      Alternatively, electromagnetic arterial spin labeling (ASL) may be used to obtain
      qualitative perfusion contrast for detecting changes in blood flow, similar to
      the use of susceptibility contrast in blood oxygenation level dependent
      functional MRI (BOLD fMRI) to detect functional activation in the brain. The
      ability to obtain blood flow maps using a non-invasive and widely available
      modality such as MRI should greatly enhance the utility of blood flow measurement
      as a means of gaining further insight into the broad range of hemodynamically
      related physiology and pathophysiology. This article describes the biophysical
      considerations pertaining to the generation of quantitative blood flow maps using
      a particular form of ASL in which arterial blood water is continuously labeled,
      termed continuous arterial spin labeling (CASL). Technical advances permit
      multislice perfusion imaging using CASL with reduced sensitivity to motion and
      transit time effects. Interpretable cerebral perfusion images can now be reliably
      obtained in a variety of clinical settings including acute stroke, chronic
      cerebrovascular disease, degenerative diseases and epilepsy. Over the past
      several years, the technical and theoretical foundations of CASL perfusion MRI
      techniques have evolved from feasibility studies into practical usage. Currently
      existing methodologies are sufficient to make reliable and clinically relevant
      observations which complement structural assessment using MRI. Future technical
      improvements should further reduce the acquisition times for CASL perfusion MRI,
      while increasing the slice coverage, resolution and stability of the images.
      These techniques have a broad range of potential applications in clinical and
      basic research of brain physiology, as well as in other organs.

PMID- 10401593
TI  - Proton MRS in neurological disorders.
AB  - Proton magnetic resonance spectroscopy (1H MRS) permits the acquisition of the
      signal arising from several brain metabolites. At long echo-time (TE) 1H MRS can
      detect N-acetyl-aspartate containing compounds, choline containing compounds,
      creatine + phosphocreatine and lactate. At short TE, lipids, tryglicerides,
      alanine, glutamate, glutamine, GABA, scyllo-inositol, glucose, myo-inositol,
      carnosine and histydine are visible. 1H MRS can be performed with single-voxel,
      multivoxel, single slice and multislice techniques. With single voxel 1H MRS it
      is possible to measure metabolites relaxation time, which allows the measurement
      of metabolite concentrations. This technique can be useful in the study of focal
      lesions in the central nervous system (CNS) such as epilepsy (pre-surgical
      identification of epileptic focus), brain tumors (evaluation of recurrence and
      radiation necrosis), stroke, multiple sclerosis, etc. Single slice and multislice
      1H MRS imaging (1H MRSI) can be performed only at long TE and permits the mapping
      of the brain metabolites distribution which makes them particularly useful in
      studying diffuse diseases and heterogeneous lesions of the CNS. 1H MRS can also
      be useful in the evaluation of 'ischemic penumbra' of stroke; developmental
      (myelin and neuronal dysgenesis); head trauma (evaluation of cerebral damage not
      visible with MRI); degenerative disorders (identification of microscopic
      pathology not visible with MRI); and metabolic diseases (metabolic disturbances
      with specific metabolic patterns).

PMID- 10401594
TI  - Proton magnetic resonance spectroscopy in schizophrenia.
AB  - Proton magnetic resonance spectroscopy (MRS) has become an important tool to
      study in vivo certain biochemical aspects of brain disorders. In the last decade
      this technique has been applied to the in vivo investigation of
      pathophysiological aspects of psychiatric disorders, extending knowledge of the
      related brain alterations. This review will focus on providing some background to
      clarify technical and biochemical issues and it will describe the studies that
      have been performed in schizophrenia. The results will be framed in a more
      general context to highlight what we have learned and what remains to be
      understood from the application of this technique to schizophrenia.

PMID- 10401595
TI  - Proton magnetic resonance spectroscopy of the brain in pediatric patients.
AB  - H1-MRS is a non-invasive technique which provides different levels of information
      on brain tissue: the N-acetyl aspartate (NAA) is an indicator of neuronal
      development, the choline containing compound peak (Cho) provides information on
      myelination and on cell membrane turnover and gliosis, inositol (Ins) is
      considered a marker of neuronal degeneration. Lactate may be detected in presence
      of defective energy metabolism. In the perineonatal period, the brain is apt to
      be insulted by a variety of events including asphyxia, hypoxemia, hemorrhage,
      which may subsequently cause delay in development. It is clinically important to
      assess the degree of brain damage and to obtain the prognostic information in the
      neonatal and early infantile period. MRS has become available for clinical
      examinations of the brain during development and these techniques can be used to
      document improvement or the progression towards irreversible damage.

PMID- 10401596
TI  - Role of short TE 1H-MR spectroscopy in monitoring of post-operation irradiated
      patients.
AB  - Post-surgical radiation therapy is a routine procedure in the treatment of
      primary malignant brain tumors. Along with modest therapeutic effects
      conventional fractionated radiotherapy, in spite of any modifications, produces
      damage to non-malignant brain tissues lying within the treatment volume, the
      extent of which depends on radiation dose. Serial 1H-MRS allows non-invasive
      investigation of tissue metabolic profiles. In the present study the ratios of
      resonance signals assigned to the major 1H-MRS-visible metabolites (N
      acetylaspartate, choline, creatine, inositol, lactate and lipid methylene group)
      were evaluated before, during and after post-surgical fractionated radiotherapy
      in brain regions close to and more distant from the tumor bed, receiving
      different radiation exposures (60 and < 40 Gy, respectively). The study group
      consisted of ten patients (aged 28-51). A MRI/MRS system (Elscint 2T Prestige)
      operating at the field strength of 2 T and the proton resonance frequency of 81.3
      MHz has been used and the 1H-MR spectra were acquired using single voxel double
      spin-echo PRESS sequence with a short TE. The spectra were post-processed with
      automatic fitting in the frequency domain. It was found that although the
      metabolite profiles depend on the dose obtained, but other stress factors (like
      surgery) seem to contribute to the overall picture of the metabolic status of the
      brain as well. In studies of early irradiation injuries, an increase of choline
      related ratios may serve rather as cell proliferation indictors than as cell
      injury ones, whereas the mI/Cr ratio appears as one of the first indicators of
      local irradiation injury. In order to establish the prognostic marker for early
      radiation damage, however, it seems necessary to analyze all visible metabolites
      as well. None of the metabolites separately may serve as such an indicator due to
      the complexity of tissue metabolism. Interestingly, MRI reveals no changes during
      the therapy process, whereas the metabolite ratios are being affected in the
      course of time, thus supporting the presumption that the 1H-MRS is a valuable
      method of radiation therapy monitoring.

PMID- 10401597
TI  - Quiz case 7. Osteogenesis imperfecta tarda with association of the inner ear also
      called Van Hoeve-Klein-syndrome.

PMID- 10401598
TI  - H2O2 mediates O2 toxicity in cultured fetal rat distal lung epithelial cells.
AB  - It is unknown which of the reactive oxygen species is primarily responsible for
      the cytotoxicity of 95% O2 for rat distal fetal lung epithelial cells in vitro.
      Incubation of cells with 25 U/ml polyethylene glycol (PEG)-conjugated SOD and 50
      U/ml PEG-catalase, but not PEG-SOD or SOD mimics alone, significantly reduced 95%
      O2-mediated cytotoxicity. Liposome-entrapped catalase, without SOD, also
      significantly reduced 95% O2-mediated cytotoxicity. Increased formation of lipid
      hydroperoxides, as assessed by the formation of 8-isoprostane and aldehydes, was
      attenuated by both 100 microM Trolox, a vitamin E analogue, and by 5 microM
      U74389G, an amino steroid. Trolox, but not U74389G, prevented an increase in cell
      derived H2O2, hydroxyl radical and 95% O2-mediated cytotoxicity. An increase in
      hydroxyl radical formation, but not cell death, observed in 95% O2, was prevented
      by 0.1 microM phenanthrolene, a cell permeant iron chelator. DNA extracts of rat
      distal fetal lung epithelial cells maintained under serum-free conditions had an
      electrophoretic pattern consistent with some degree of apoptosis. However, no
      increase in laddering was seen with exposure to 95% O2. These data are consistent
      with hydrogen peroxide, but not lipid hydroperoxides or hydroxyl radical, being a
      critical effector of O2-mediated necrotic cell death in distal lung epithelial
      cells.

PMID- 10401599
TI  - Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia
      intoxication.
AB  - Acute ammonia intoxication diminishes the activities of antioxidant enzymes and
      increases superoxide formation in brain. These effects could play a role in the
      mechanism of ammonia toxicity. It has been shown that ammonia toxicity is
      mediated by activation of NMDA receptors. The aim of this work was to assess
      whether ammonia-induced changes in antioxidant enzymes and in superoxide
      formation are mediated by activation of NMDA receptors. It is shown that MK-801,
      an antagonist of NMDA receptors prevents ammonia-induced changes in superoxide
      dismutase, glutathione peroxidase and catalase. Ammonia intoxication also induces
      a depletion of glutathione and an increase in lipid peroxidation. Both effects,
      as well as ammonia-induced increase in superoxide formation are prevented by MK
      801. These results indicate that ammonia-induced oxidative stress in brain is
      mediated by excessive activation of NMDA receptors and support the idea that
      oxidative stress can play a role in the mechanism of ammonia toxicity.

PMID- 10401600
TI  - Effects of coenzyme Q10 and alpha-tocopherol administration on their tissue
      levels in the mouse: elevation of mitochondrial alpha-tocopherol by coenzyme Q10.
AB  - Coenzyme Q (CoQ) was previously demonstrated in vitro to indirectly act as an
      antioxidant in respiring mitochondria by regenerating alpha-tocopherol from its
      phenoxyl radical. The objective of this study was to determine whether CoQ has a
      similar sparing effect on alpha-tocopherol in vivo. Mice were administered CoQ10
      (123 mg/kg/day) alone, or alpha-tocopherol (200 mg/kg/day) alone, or both, for 13
      weeks, after which the amounts of CoQ10, CoQ9 and alpha-tocopherol were
      determined by HPLC in the serum as well as homogenates and mitochondria of liver,
      kidney, heart, upper hindlimb skeletal muscle and brain. Administration of CoQ10
      and alpha-tocopherol, alone or together, increased the corresponding levels of
      CoQ10 and alpha-tocopherol in the serum. Supplementation with CoQ10 also elevated
      the amounts of the predominant homologue CoQ9 in the serum and the mitochondria.
      A notable effect of CoQ10 intake was the enhancement of alpha-tocopherol in
      mitochondria. alpha-Tocopherol administration resulted in an elevation of alpha
      tocopherol content in the homogenates of nearly all tissues and their
      mitochondria. Results of this study thus indicate that relatively long-term
      administration of CoQ10 or alpha-tocopherol can result in an elevation of their
      concentrations in the tissues of the mouse. More importantly, CoQ10 intake has a
      sparing effect on alpha-tocopherol in mitochondria in vivo.

PMID- 10401601
TI  - 4-Hydroxynonenal inhibits glutathione peroxidase: protection by glutathione.
AB  - 4-Hydroxy-2,3-trans-nonenal, a lipid peroxidation product, inhibits glutathione
      peroxidase in a concentration-dependent manner. The concentration providing 50%
      inhibition is 0.12 mM. This inhibition can be almost completely (89%) prevented
      by 1 mM glutathione added to the incubation mixture 30 min before 4-hydroxy-2,3
      trans-nonenal or 2,3-trans-nonenal, but not by other thiol-containing
      antioxidants such as 0.5 mM dithiothreitol or beta-mercaptoethanol. Again the
      addition of 1 mM glutathione, and not of 0.5 mM dithiothreitol or beta
      mercaptoethanol, to the enzyme 30 min after incubation with 4-hydroxy-2,3-trans
      nonenal restores activity to the same extent as does the preincubation with GSH.
      In view of the known reactivity of 4-hydroxy-2,3-trans-nonenal with lysine
      residues and the reversibility of the inhibition, the involvement of a lysine
      residue in GSH binding to glutathione peroxidase is proposed. The potential
      relevance of the inhibition of glutathione peroxidase by 4-hydroxy-nonenal to
      oxidative tissue damage is discussed with particular emphasis on neurological
      disorders.

PMID- 10401603
TI  - Singlet oxygen is part of a hyperoxidant state generated during spore
      germination.
AB  - We show that singlet oxygen is generated in asexual spores (conidia) from
      Neurospora crassa at the onset of germination. Oxidation of N. crassa catalase-1
      (Cat-1) was previously shown to be caused by singlet oxygen (Lledias et al. J.
      Biol. Chem. 273, 1998). In germinating conidia, increased protein oxidation,
      decrease of total protein, Cat-1 oxidation and accumulation of cat-1 mRNA was
      detected. These changes were modulated in vivo by light intensity, an external
      clean source of singlet oxygen, and by carotene amount and content of coordinated
      double bonds. Conditions that stimulated singlet oxygen formation increased Cat-1
      oxidation and accumulation of cat-1 mRNA. Germinating conidia from mutant strains
      altered in carotene synthesis showed increased levels of protein degradation, Cat
      1 oxidation and accumulation of cat-1 mRNA. During germination Cat-1a was
      oxidized, oxidized Cat-1c-Cat-1e conformers disappeared and Cat-1a was
      synthesized de novo. Furthermore, spontaneous oxygen-dependent chemiluminescence
      increased as soon as conidia absorbed dissolved oxygen. Low-level
      chemiluminescence is due to photon emission from excited electrons in carbonyls
      and singlet oxygen as they return to their ground state. H2O2 added to conidia
      under Ar caused a peak of chemiluminescence and germination of 20% of conidia,
      suggesting that a hyperoxidant state suffices to start germination under
      anaerobic conditions. Taken together, these results show that singlet oxygen is
      part of a hyperoxidant state that develops at the start of germination of
      conidia, in consonance with our proposal that morphogenetic transitions occur as
      a response to a hyperoxidant state.

PMID- 10401602
TI  - Potential roles of myoglobin autoxidation in myocardial ischemia-reperfusion
      injury.
AB  - The source(s) of reactive partially reduced oxygen species associated with
      myocardial ischemia/reperfusion injury remain unclear and controversial.
      Myoglobin has not been viewed as a participant but is present in relatively high
      concentrations in heart muscle and, even under normal conditions, undergoes
      reactions that generate met (Fe3+) species and also superoxide, hydrogen
      peroxide, and other oxidants, albeit slowly. The degree to which the decrease in
      pH and the freeing of copper ions, as well as the variations in pO2 associated
      with ischemia and reperfusion increase the rates of such myoglobin reactions has
      been investigated. Solutions of extensively purified myoglobin from bovine heart
      in 50 mM sodium phosphate buffer were examined at 37 degrees C. Sufficiently
      marked rate increases were observed to indicate that reactions of myoglobin can
      indeed contribute substantially to the oxidant stress associated with
      ischemia/reperfusion injury in myocardial tissues. These findings provide
      additional targets for therapeutic interventions.

PMID- 10401604
TI  - Influence of the antioxidants vitamin E and idebenone on retinal cell injury
      mediated by chemical ischemia, hypoglycemia, or oxidative stress.
AB  - A role for the antioxidants vitamin E and idebenone in decreasing retinal cell
      injury, after metabolic inhibition induced by chemical ischemia and hypoglycemia,
      was investigated and compared with oxidative stress conditions. Preincubation of
      the antioxidants, vitamin E (20 microM) and idebenone (10 microM), effectively
      protected from retinal cell injury after oxidative stress or hypoglycemia,
      whereas the protection afforded after postincubation of both antioxidants was
      decreased. Delayed retinal cell damage, mediated by chemical ischemia, was
      attenuated at 10 or 12 h postischemia, only after exposure to the antioxidants
      during all the experimental procedure. An antagonist of the N-methyl-D-aspartate
      (NMDA) receptors, an inhibitor of nitric oxide synthase (NOS) or a blocker of L
      type Ca2+ channels were ineffective in reducing cell injury induced by chemical
      ischemia, hypoglycemia or oxidative stress. Oxidative stress and hypoglycemia
      increased (about 1.2-fold) significantly the fluorescence of the probe DCFH2-DA,
      that is indicative of intracellular ROS formation. Free radical generation
      detected with the probe dihydrorhodamine 123 (DHR 123) was enhanced after
      oxidative stress, chemical ischemia or hypoglycemia (about 2-fold). Nevertheless,
      the antioxidants vitamin E or idebenone were ineffective against intracellular
      ROS generation. Cellular energy charge decreased greatly after chemical ischemia,
      was moderately affected after hypoglycemia, but no significant changes were
      observed after oxidative stress. Preincubation with vitamin E prevented the
      changes in energy charge upon 6 h posthypoglycemia. We can conclude that
      irreversible changes occurring during chemical ischemia mainly reflect the
      alterations taking place at the ischemic core, whereas hypoglycemia situations
      may reflect changes occurring at the penumbra area, whereby vitamin E or
      idebenone may help to increase cell survival, exerting a beneficial
      neuroprotective effect.

PMID- 10401605
TI  - Neuroprotective effects of alpha-lipoic acid and its positively charged amide
      analogue.
AB  - Elevated levels of extracellular glutamate have been linked to reactive oxygen
      species mediated neuronal damage and brain disorders. Lipoic acid is a potent
      antioxidant that has previously been shown to exhibit neuroprotection in clinical
      studies. A new positively charged water soluble lipoic acid amide analog, 2-(N,N
      dimethylamine) ethylamido lipoate HCl (LA-plus), with a better cellular reduction
      and retention of the reduced form was developed. This novel antioxidant was
      tested for protection against glutamate induced cytotoxicity in a HT4 neuronal
      cell line. Glutamate treatment for 12 h resulted in significant release of LDH
      from cells to the medium suggesting cytotoxicity. Measurement of intracellular
      peroxides showed marked (up to 200%) increase after 6 h of glutamate treatment.
      Compared to lipoic acid, LA-plus was more effective in (1) protecting cells
      against glutamate induced cytotoxicity, (2) preventing glutamate induced loss of
      intracellular GSH, and (3) disallowing increase of intracellular peroxide level
      following the glutamate challenge. The protective effect of LA-plus was found to
      be independent of its stereochemistry. The protective function of this
      antioxidant was synergistically enhanced by selenium. These results demonstrate
      that LA-plus is a potent protector of neuronal cells against glutamate-induced
      cytotoxicity and associated oxidative stress.

PMID- 10401606
TI  - Scavenging of hydrogen peroxide and inhibition of ultraviolet light-induced
      oxidative DNA damage by aqueous extracts from green and black teas.
AB  - Aqueous extracts of green and black teas have been shown to inhibit a variety of
      experimentally induced animal tumors, particularly ultraviolet (UV) B light
      induced skin carcinogenesis. In the present study, we compared the effects of
      different extractable fractions of green and black teas on scavenging hydrogen
      peroxide (H2O2), and UV irradiation-induced formation of 8-hydroxy 2'
      deoxyguanosine (8-OHdG) in vitro. Green and black teas have been extracted by
      serial chloroform, ethyl acetate and n-butanol, and divided into four
      subfractions designated as GT1-4 for green tea and BT1-4 for black tea,
      respectively. The total extracts from green and black teas exhibited a potent
      scavenging capacity of exogenous H2O2 in a dose-dependent manner. It appeared
      that the total extracts from black tea scavenged H2O2 more potently than those
      from green tea. When tested individually, the potency of scavenging H2O2 by green
      tea subfractions was: GT2 > GT3 > GT1 > GT4, whereas the order of efficacy for
      black tea was: BT2 > BT3 > BT4 > BT1. In addition, we demonstrated that total
      fractions of green and black teas substantially inhibited the induction of 8-OHdG
      in calf thymus by all three portions of UV spectrum (UVA, B and C). Consistent
      with the capacity of scavenging H2O2, the subfractions from black tea showed a
      greater inhibition of UV-induced 8-OHdG than those from green tea. At low
      concentrations, the order of potency of quenching of 8-OHdG by green tea
      subfractions was: GT2 > GT3 > GT4 > GT1 and the efficacy of all subfractions
      became similar at high concentrations. All subfractions of the black tea except
      BT1 strongly inhibited UV-induced 8-OHdG and the order of potency was: BT2 > BT3
      > BT4 > BT1. Addition of (-)-epigallocatechin gallate (EGCG), an ingredient of
      green tea extract, to low concentration of green and black tea extracts
      substantially enhanced the scavenging of H2O2 and quenching of 8-OHdG, suggesting
      the important role of EGCG in the antioxidant activities of tea extracts. The
      potent scavenging of oxygen species and blocking of UV-induced oxidative DNA
      damage may, at least in part, explain the mechanism(s) by which green/black teas
      inhibit photocarcinogenesis.

PMID- 10401607
TI  - Retinal pigment epithelium pigment granules stimulate the photo-oxidation of
      unsaturated fatty acids.
AB  - The cellular pigments of the retinal pigment epithelium (RPE) have been shown to
      catalyze free radical activity, especially when illuminated with visible or
      ultraviolet light. This activity is sufficient to cause photooxidation of several
      major cellular components. The present investigation determined the relative
      ability of melanin, lipofuscin, and melanolipofuscin granules isolated from human
      and bovine eyes to oxidize polyunsaturated fatty acids, specifically linoleic and
      docosahexaenoic acids. The dark reactivity as well as the light-stimulated
      reactions were determined. The production of hydroperoxide derivatives of the
      linoleic and docosahexaenoic acids were determined by NADPH oxidation coupled to
      the activity of glutathione peroxidase, and also by production of thiobarbituric
      acid reactive substances. All RPE pigment granules stimulated fatty acid
      oxidation when irradiated with short wavelength (< 550 nm) visible light, with
      the melanosomes exhibiting the greatest light-induced activity. Only lipofuscin
      granules, however, caused peroxidation of fatty acids in the dark. These findings
      provide additional support for the role of RPE pigments in "blue light toxicity"
      as well as indicating that accumulation of lipofuscin may contribute to increased
      photooxidation in the aging RPE.

PMID- 10401608
TI  - Iron and dioxygen chemistry is an important route to initiation of biological
      free radical oxidations: an electron paramagnetic resonance spin trapping study.
AB  - Iron can be a detrimental catalyst in biological free radical oxidations. Because
      of the high physiological ratio of [O2]/[H2O2] (> or = 10(3)), we hypothesize
      that the Fenton reaction with pre-existing H2O2 is only a minor initiator of free
      radical oxidations and that the major initiators of biological free radical
      oxidations are the oxidizing species formed by the reaction of Fe2+ with
      dioxygen. We have employed electron paramagnetic resonance spin trapping to
      examine this hypothesis. Free radical oxidation of: 1) chemical (ethanol,
      dimethyl sulfoxide); 2) biochemical (glucose, glyceraldehyde); and 3) cellular
      (L1210 murine leukemia cells) targets were examined when subjected to an aerobic
      Fenton (Fe2+ + H2O2 + O2) or an aerobic (Fe2+ + O2) system. As anticipated, the
      Fenton reaction initiates radical formation in all the above targets. Without pre
      existing H2O2, however, Fe2+ and O2 also induce substantial target radical
      formation. Under various experimental ratios of [O2]/[H2O2] (1-100 with [O2]
      approximately 250 microM), we compared the radical yield from the Fenton reaction
      vs. the radical yield from Fe2+ + O2 reactions. When [O2]/[H2O2] < 10, the Fenton
      reaction dominates target molecule radical formation; however, production of
      target-molecule radicals via the Fenton reaction is minor when [O2]/[H2O2] > or =
      100. Interestingly, when L1210 cells are the oxidation targets, Fe2+ + O2 is
      observed to be responsible for formation of nearly all of the cell-derived
      radicals detected, no matter the ratio of [O2]/[H2O2]. Our data demonstrate that
      when [O2]/[H2O2] > or = 100, Fe2+ + O2 chemistry is an important route to
      initiation of detrimental biological free radical oxidations.

PMID- 10401610
TI  - Dehydroepiandrosterone protects tissues of streptozotocin-treated rats against
      oxidative stress.
AB  - Chronic hyperglycemia in diabetes determines the overproduction of free radicals,
      and evidence is increasing that these contribute to the development of diabetic
      complications. It has recently been reported that dehydroepiandrosterone
      possesses antioxidant properties; this study evaluates whether, administered
      daily for three weeks per os, it may provide antioxidant protection in tissues of
      rats with streptozotocin-induced diabetes. Lipid peroxidation was evaluated on
      liver, brain and kidney homogenates from diabetic animals, measuring both steady
      state concentrations of thiobarbituric acid reactive substances and fluorescent
      chromolipids. Hyperglycemic rats had higher thiobarbituric acid reactive
      substances formation and fluorescent chromolipids levels than controls.
      Dehydroepiandrosterone-treatment (4 mg/day for 3 weeks) protected tissues against
      lipid peroxidation: liver, kidney and brain homogenates from
      dehydroepiandrosterone-treated animals showed a significant decrease of both
      thiobarbituric acid reactive substances and fluorescent chromolipids formation.
      The effect of dehydroepiandrosterone on the cellular antioxidant defenses was
      also investigated, as impaired antioxidant enzyme activities were considered
      proof of oxygen-dependent toxicity. In kidney and liver homogenates,
      dehydroepiandrosterone treatment restored to near-control values the cytosolic
      level of reduced glutathione, as well as the enzymatic activities of superoxide
      dismutase, glutathione-peroxidase, catalase. In the brain, only an increase of
      catalase activity was evident (p < .05), which reverted with
      dehydroepiandrosterone treatment. The results demonstrate that DHEA treatment
      clearly reduces oxidative stress products in the tissues of streptozotocin
      treated rats.

PMID- 10401609
TI  - Repair of iron-induced DNA oxidation by the flavonoid myricetin in primary rat
      hepatocyte cultures.
AB  - Oxidative DNA damage and its repair in primary rat hepatocyte cultures was
      investigated following 4 h of incubation with the toxic iron chelate, ferric
      nitrilotriacetate (Fe-NTA), in the presence or absence of the potent protective
      flavonoid myricetin (25-50-100 microM). Seven DNA base oxidation products were
      quantified in DNA extracts by gas chromatography-mass spectrometry (GC-MS) in
      selected ion monitoring mode. Concomitantly, DNA repair capacity of hepatocytes
      was estimated by the release of oxidized-base products into culture media, using
      the same GC-MS method. A genotoxic effect of Fe-NTA (100 microM) in hepatocytes
      was evidenced by a severe increase in DNA oxidation over basal levels, with
      accumulation in cellular DNA of five oxidation products derived from both purines
      and pyrimidines. This prooxidant effect of iron was also noted by an induction of
      lipid peroxidation, estimated by free malondialdehyde production. Addition of
      increasing concentrations of myricetin (25-50-100 microM) simultaneously with
      iron prevented both lipid peroxidation and accumulation of oxidation products in
      DNA. Moreover, as an activation of DNA repair pathways, myricetin stimulated the
      release of DNA oxidation bases into culture media, especially of purine-derived
      oxidation products. This removal of highly mutagenic oxidation products from DNA
      of hepatocytes might correspond to an activation of DNA excision-repair enzymes
      by myricetin. This was verified by RNA blot analysis of DNA polymerase beta gene
      expression which was induced by myricetin in a dose-dependent manner. This
      represented a novel and original mechanism of cytoprotection by myricetin against
      iron-induced genotoxicity via stimulation of DNA repair processes. Since iron
      induced DNA damage and inefficient repair in hepatocytes could be related to
      genotoxicity and most probably to hepatocarcinogenesis, modulation of these
      processes in vitro by myricetin might be relevant in further prevention of liver
      cancer derived from iron overload pathologies.

PMID- 10401611
TI  - Inhibition of 2,3-dimethyl-1,4-naphthohydroquinone auto-oxidation by copper and
      by superoxide dismutase.
AB  - 2,3-Dimethyl-1,4-naphthohydroquinone undergoes auto-oxidation to the
      corresponding quinone at pH 7.4, with stoichiometric consumption of oxygen and
      formation of hydrogen peroxide. In an unpurified buffer, the rate of oxidation
      was low, but it increased nearly 9-fold when trace metals were removed from the
      buffer by treatment with Chelex resin. A similar increase in rate was achieved by
      addition of DTPA or bathophenanthroline sulfonate to unpurified buffer, whereas
      EDTA and desferal were less effective. Addition of copper to purified buffer led
      to inhibition of oxidation, with a 50% decrease in rate being observed at a metal
      concentration of 7.1 nM, and it is likely that the low auto-oxidation rate
      recorded in unpurified buffer was due to copper contamination of the latter. The
      auto-oxidation of 2,3-dimethyl-1,4-naphthohydroquinone was exceptionally
      sensitive to inhibition by superoxide dismutase, with a concentration of only 4.5
      ng/ml being sufficient for a 50% decrease in rate, and the inhibitory effect of
      copper may be due to the ability of this metal to catalyse the dismutation of
      superoxide. Previous studies have shown that the rates of auto-oxidation of 1,4
      naphthohydroquinone and 2-methyl-1,4-naphthohydroquinone are influenced by copper
      contamination of buffer and the present study shows that this is also true for a
      di-substituted naphthohydroquinone. For accurate assessment of rates of
      naphthohydroquinone auto-oxidation, it is important that purified buffers or
      appropriate chelating agents, are employed.

PMID- 10401612
TI  - Hydrogen peroxide induces endothelial cell atypia and cytoskeleton
      depolymerization.
AB  - Reactive oxygen intermediates induce cell injury in a variety of
      pathophysiological conditions. Human umbilical cord vein endothelial cell (HUVEC)
      cultures were exposed to 1 or 200 microM H2O2 for 15 min, and observed after 15
      min, or 1, 4, 24, or 120 h. Factor VIII and the cytoskeletal proteins vimentin
      and tubulin were visualized immunocytochemically. Release of lactate
      dehydrogenase (indices of cell membrane injury) did not increase after H2O2
      exposure; nor was cellular expression of factor VIII affected. 200 microM H2O2
      induced cell contraction after 15 min which disappeared after 1 and 4 h, but was
      evident again after 24 h. Immediately after exposure, the filamentous structure
      of vimentin and tubulin disappeared, but normalized after 1 h. After 120 h, the
      cytoskeleton filaments were coarsened and disorganized, and an abundance of
      multinucleated giant cells were observed. Catalase (150 U/ml) abolished all
      effects of H2O2. One microM H2O2 did not induce any changes in HUVEC. Thus, the
      present concentrations of H2O2 did not induce cell necrosis or altered expression
      of factor VIII. Early, reversible cell contraction and depolymerization of
      cytoskeletal proteins were observed, followed by a delayed contraction and cell
      atypia after 200 microM H2O2.

PMID- 10401613
TI  - Presence of aldehydic epitopes on a minor low-density lipoprotein fraction.
AB  - A more negatively charged low-density lipoprotein (LDL), named minor LDL (mi
      LDL), was separated by ionic exchange chromatography and further characterized.
      This mi-LDL contained lower amounts of polyunsaturated fatty acids, alpha- or
      gamma- tocopherol, but higher amounts of lipid hydroperoxides than the major LDL
      fraction (ma-LDL). We show here for the first time that apoB of mi-LDL is
      modified by lipid peroxidation products, such as 4-hydroxynonenal (4-HNE) and
      malondialdehyde (MDA). Using polyclonal antibodies, generated against 4-HNE- or
      MDA-LDL and apoB, the ratio of 4-HNE- or MDA-derived epitopes to apoB of mi-LDL
      and ma-LDL was estimated by means of a solid phase fluorescence immunoassay. The
      ratio of 4-HNE-derived epitopes to apoB on mi-LDL was fourfold higher, while the
      ratio of MDA-derived epitopes to apoB was twofold higher, compared with the
      ratios obtained with ma-LDL. In a competition assay with mi- and ma-LDL, only mi
      LDL was an effective competitor to inhibit the immunoreaction of anti-4-HNE-LDL
      with 4-HNE-LDL (by 24%) and of anti-MDA-LDL with MDA-LDL (by 10%).

PMID- 10401614
TI  - alpha-Lipoic acid decreases oxidative stress even in diabetic patients with poor
      glycemic control and albuminuria.
AB  - In the present cross-sectional study, the influence of alpha-lipoic acid on
      markers of oxidative stress, assessed by measurement of plasma lipid
      hydroperoxides (ROOHs), and on the balance between oxidative stress and
      antioxidant defence, determined by the ratio ROOH/(alpha-tocopherol/cholesterol),
      was examined in 107 patients with diabetes mellitus. Patients receiving alpha
      lipoic acid (600 mg/day for > 3 months) had significant lower ROOHs and a lower
      ROOH/(alpha-tocopherol/cholesterol) ratio than those without alpha-lipoic acid
      treatment [ROOH: 4.76 +/- 2.49 vs. 7.16 +/- 3.22 mumol/l; p < .0001] and
      [ROOH/(alpha-tocopherol/cholesterol): 1.37 +/- 0.72 vs. 2.16 +/- 1.17; p <
      0.0001]. In addition, the influence of glycemic control and albuminuria on ROOHs
      and on the ratio of ROOH/(alpha-tocopherol/cholesterol) was examined in the
      presence and absence of alpha-lipoic acid treatment. Patients were subdivided
      into three groups based on (1) their HbA1 levels (< 7.5, 7.5-9.5, and > 9.5%) and
      (2) their urinary albumin concentrations (< 20, 20-200, and > 200 mg/l). Neither
      poor glycemic control, nor the presence of micro- or macroalbuminuria prevented
      the antioxidant effect of alpha-lipoic acid. Using stepwise multiple regression
      analysis, alpha-lipoic acid was found to be the only factor significantly
      predicting low ROOHs and a low ratio of ROOH/(alpha-tocopherol/cholesterol).
      These data provide evidence that treatment with alpha-lipoic acid improves
      significantly the imbalance between increased oxidative stress and depleted
      antioxidant defence even in patients with poor glycemic control and albuminuria.

PMID- 10401615
TI  - Metabolism of vitamin A in the heart increases after a myocardial infarction.
AB  - The supply of vitamin A to the myocardium by storage organs during increased
      oxidative stress subsequent to myocardial infarction (MI) was examined in
      hemodynamically assessed rats using compartment analysis of a radio-labeled
      vitamin A. 3H-Vitamin A was injected into two groups of rats: an MI group and a
      control group. There were no differences in the plasma or myocardial content of
      total vitamin A (unlabeled + labeled) between the two groups. However, the
      proportion of 3H-vitamin A was greater in the myocardium as well as plasma of MI
      rats. Rats with MI also had significantly lower 3H-vitamin A levels in liver and
      kidney than sham controls. The greatest difference in vitamin A content was in
      the concentrations of 3H-labeled storage forms of vitamin A in the liver of MI
      animals. Activity of bile salt-dependent retinyl ester hydrolase, an enzyme
      responsible for hydrolyzing vitamin A storage forms, was significantly increased
      in the liver of MI animals. These data indicate that analysis of plasma
      concentrations of vitamin A to ascertain links to cardiac conditions may be
      inappropriate. Specifically, during MI, increased amounts of vitamin A are
      mobilized from the liver to the heart without changing plasma concentrations.
      This is facilitated by an increase in the activity of an enzyme that hydrolyzes
      vitamin A storage forms.

PMID- 10401616
TI  - Is increased redox-active iron in Alzheimer disease a failure of the copper
      binding protein ceruloplasmin?
AB  - One of the most striking features of Alzheimer disease (AD) is an accumulation of
      iron in neurofibrillary tangles and senile plaques. Intriguingly, this iron is
      found as both iron (II) and iron (III) and is redox-active. To address the issue
      of whether such iron participates in redox cycling, it was essential to
      investigate how iron (II) accumulates, since oxidation of iron (II) can lead to
      the generation of reactive oxygen species. To begin to address this issue, here
      we investigated ceruloplasmin, a key protein involved in the regulation of the
      redox state of iron by converting iron (II) to iron (III). Cases of AD and age
      matched controls, obtained at autopsy with similar postmortem intervals, display
      similar levels of ceruloplasmin immunoreactivity that is mainly confined to
      neurons. However, in marked contrast, cases of AD show a significant increase in
      ceruloplasmin within the neuropil determined by immunoblot analysis of tissue
      homogenates as well as a generalized increased neuropil staining. Together, these
      findings suggest that neuronal induction of ceruloplasmin is feeble in AD, even
      while there is an increase in tissue ceruloplasmin. Therefore, a failure of
      neuronal ceruloplasmin to respond to iron may be an important factor that then
      leads to an accumulation of redox-active iron in neurons in AD.

PMID- 10401617
TI  - Vitamin C recycling and function in human monocytic U-937 cells.
AB  - The uptake, recycling, and function of ascorbic acid was evaluated in cultured U
      937 monocytic cells. Dehydroascorbic acid, the two-electron oxidized form of the
      vitamin, was taken up on the glucose transporter and reduced to ascorbate to a
      much greater extent than ascorbate itself was accumulated by the cells. In
      contrast to dehydroascorbic acid, ascorbate entered the cells on a sodium- and
      energy-dependent transporter. Intracellular ascorbate enhanced the transfer of
      electrons across the cell membrane to extracellular ferricyanide. Rates of
      ascorbate-dependent ferricyanide reduction were saturable, fivefold greater than
      basal rates, and facilitated by intracellular recycling of ascorbate. Whereas
      reduction of dehydroascorbic acid concentrations above 400 microM consumed
      reduced glutathione (GSH), even severe GSH depletion by 1-chloro-2,4
      dinitrobenzene was without effect on the ability of the cells to reduce
      concentrations of dehydroascorbic acid likely to be in the physiologic range (<
      200 microM). Dialyzed cytosolic fractions from U-937 cells reduced
      dehydroascorbic acid to ascorbate in an NADPH-dependent manner that appeared due
      to thioredoxin reductase. However, thioredoxin reductase did not account for the
      bulk of dehydroascorbic acid reduction, since its activity was also decreased by
      treatment of intact cells with 1-chloro-2,4-dinitrobenzene. Thus, U-937 cells
      loaded with dehydroascorbic acid accumulate ascorbate against a concentration
      gradient via a mechanism that is not dependent on GSH or NADPH, and this
      ascorbate can serve as the major source of electrons for transfer across the
      plasma membrane to extracellular ferricyanide.

PMID- 10401618
TI  - The importance of lipid solubility in antioxidants and free radical generating
      systems for determining lipoprotein proxidation.
AB  - The oxidative modification of low-density lipoprotein (LDL) plays an important
      role in atherosclerosis. Protecting LDL from oxidation has been shown to reduce
      the risk of coronary heart disease. In this study, we compared the protective
      effects of two lipophilic antioxidants (vitamin E and lazaroid) with two
      hydrophilic antioxidants (trolox and vitamin C) in the presence of several
      different free radical generating systems. Vitamin E (IC50 = 5.9 microM) and
      lazaroid (IC50 = 5.0 microM) were more effective in inhibiting lipid peroxidation
      caused by a Fe-ADP free radical generating system than vitamin C (IC50 = 5.2 x
      10(3) microM) and trolox (IC5 = 1.2 x 10(3) microM). Preincubation of
      lipoproteins with a lipophilic antioxidant increased the protective effect
      against various free radicals. Preincubation with hydrophilic antioxidants did
      not have an effect. We also tested the efficacy of the antioxidants when the free
      radicals were generated within the lipid or the aqueous environment surrounding
      the LDL. For this purpose, we used the peroxyl generating azo-compounds AMVN
      (2,2'-azobis(2,4-dimethylvaleronitrile)) and AAPH (2,2'azobis(2-amidinopropane)
      dihydrochloride). All of the antioxidants tested were more effective against free
      radicals generated in a water soluble medium than they were against free radicals
      generated in a lipid environment. In conclusion, our data demonstrate that lipid
      solubility is an important factor for both the antioxidant and the free radical
      generating systems in determining the extent of lipid peroxidation in LDL. Our
      data also demonstrate that antioxidant efficacy in one set of experimental
      conditions may not necessarily translate into a similar degree of protection in
      another set of conditions where lipophilicity is a variable.

PMID- 10401619
TI  - Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA
      damage induced by the kidney carcinogen KBrO3.
AB  - Free radical scavengers can protect against the genotoxicity induced by chemical
      carcinogens by decreasing oxidative damage. The protective effect of the
      antioxidants melatonin, resveratrol, vitamin E, butylated hydroxytoluene and 2
      mercaptoethylamine, and the spin-trapping compound alpha-phenyl-N-tert-butyl
      nitrone (PBN) against oxidative DNA damage was studied in the kidney of rats
      treated with the kidney-specific carcinogen potassium bromate (KBrO3). KBrO3 was
      given to rats previously treated with melatonin, resveratrol, PBN, vitamin E,
      butylated hydroxytoluene, or 2-mercaptoethylamine. Oxidative damage to kidney DNA
      was estimated 6 hours afterwards by measuring 8-oxo-7,8-dihydro-2'-deoxyguanosine
      (oxo8dG) referred to deoxyguanosine (dG) by means of high performance liquid
      chromatography with electrochemical-coulometric and ultraviolet detection. Levels
      of oxo8dG in the renal genomic DNA significantly increased by more than 100%
      after the KBrO3 treatment. This increase was completely abolished by the
      treatment with resveratrol and was partially prevented by melatonin, PBN and
      vitamin E. Resveratrol and PBN also prevented the increase in relative kidney
      weight induced by KBrO3. These results show that various different antioxidants
      and a free radical trap, working in either the water-soluble or the lipid-soluble
      compartments, can prevent the oxidative DNA damage induced in the kidney by the
      carcinogen KBrO3.

PMID- 10401620
TI  - Structure-activity relationships in a series of melatonin analogues with the low
      density lipoprotein oxidation model.
AB  - Despite an increasing number of publications concerning the antioxidant activity
      of melatonin, little is known about the structural features responsible for this
      kind of activity. To understand the role played by the different elements of
      melatonin structure in its antioxidant activity, we have designed and tested
      several compounds related to this molecule in the low-density lipoprotein
      peroxidation model. We present here the results of this study in terms of
      structure-activity relationships focusing on the influence of the acetamidoethyl
      side chain, the methoxy group, and the indole heterocycle. In this model, we
      found that changing the acyl residue generally resulted in more active products.
      We obtained particularly good results with the nonanoyl derivative which showed a
      level of activity comparable to that of phenols despite lacking a phenolic
      function. The presence of a methoxy group in position 5 generally had a
      beneficial influence on the activity, but when located in position 6, the effects
      were various. The substitution of a hydroxy for the methoxy group led to phenolic
      compounds endowed with very high antioxidant activity. Replacing the amide with a
      ketone function did not affect the activity while replacement with an amine group
      in some cases resulted in prooxidant compounds. Finally, we compared the efficacy
      of different aromatic rings. The indole heterocycle proved to be better than
      benzofurane and naphthalene rings.

PMID- 10401621
TI  - Nitric oxide and superoxide inhibit platelet-derived growth factor receptor
      phosphotyrosine phosphatases.
AB  - Platelet derived growth factor receptor (PDGFR) became tyrosine
      autophosphorylated in rat mesangial cells shortly after platelet derived growth
      factor (PDGF) ligation in a tyrosine kinase inhibitor (tyrphostin AG 1296)
      sensitive manner. Ligand-independent, massive tyrosine PDGFR phosphorylation was
      achieved by diverse NO releasing compounds. Phosphorylation was slow compared to
      PDGF, revealed a concentration- and time-dependency, and was not mimicked by
      lipophilic cyclic-GMP analogues. Interleukin-1 beta/cAMP activated mesangial
      cells released NO and in turn showed PDGFR phosphorylation. A NO-synthase
      involvement was assured by L-NG-nitroarginine methyl ester inhibition. PDGFR
      phosphorylation was also achieved by the redox cycler 2,3-dimethoxy-1,4
      naphthoquinone. NO- and O2(.-)-evoked PGDFR phosphorylation was N-acetylcysteine
      reversible. Cell free dephosphorylation assays revealed PDGFR dephosphorylation
      by tyrosine phosphatases. Receptor dephosphorylation by cytosolic phosphatases
      was completed within 30 min and was sensitive to the readdition of NO donors or
      orthovanadate. In addition, phosphatase activity determined in a direct
      dephosphorylation assay using the substrate para-nitrophenyl phosphate was
      attenuated by NO or vanadate. We conclude that cytosolic protein tyrosine
      phosphatases are targeted by exogenously supplied or endogenously generated NO in
      mesangial cells. Radical (NO. or O2.-) formation shifts the phosphorylation-
      dephosphorylation equilibrium towards phosphorylation, thus integrating redox
      mediated responses into established signal transducing pathways.

PMID- 10401622
TI  - Two distinct mechanisms for inhibition of cell growth in human prostate carcinoma
      cells with antioxidant enzyme imbalance.
AB  - The purpose of the present study was to determine whether manganese superoxide
      dismutase (MnSOD) overexpression in DU145 human prostate carcinoma cells affected
      cell reduction-oxidation state (cell redox) and to correlate changes in cell
      redox status with cell cycle progression and plating efficiency. One MnSOD
      overexpressing cell line had no change in other antioxidant enzymes (AEs)
      (nonadapted clone), whereas a second MnSOD-overexpressing cell line studied had
      an increase in catalase (CAT) activity (adapted clone). Correlation of
      biochemical studies with cell cycle studies suggested that heteroploidy observed
      in the nonadapted MnSOD-overexpressing cell line may be due to increased
      intracellular peroxides with resultant disruption of the microtubule network,
      while a decreased mitotic rate was associated with decreased ATP levels in
      mitosis. In contrast, the decrease in cell growth in the adapted cell line was
      demonstrated to be due to a decrease in plating efficiency. Our results
      demonstrate complex effects of AE imbalance on cell growth of DU145 prostate
      cancer cells.

PMID- 10401623
TI  - Acetaldehyde (CH3CHO) production in rodent lung after exposure to metal-rich
      particles.
AB  - Epidemiological reports demonstrate an association between increased human
      morbidity and mortality with exposure to air pollution particulate matter (PM).
      Metal-catalyzed oxidative stress has been postulated to contribute to lung injury
      in response to PM exposure. We studied the effects of residual oil fly ash
      (ROFA), a component of ambient air PM, on the formation of lung carbonyls that
      are indicators of lipid peroxidation. Rats were instilled intratracheally with
      ROFA (62.5-1000 micrograms) and underwent lung lavage. Lavage fluid carbonyls
      were derivatized with 2,4-dinitrophenylhydrazine, and measured by high
      performance liquid chromatography with UV detection. Dose-dependent increases in
      a peak that eluted with the same retention time as the acetaldehyde (CH3CHO)
      derivative was observed in rats treated with ROFA 15 min after instillation (up
      to 25-fold greater than saline treated controls). The identification of CH3CHO
      was confirmed using gas chromatography-mass spectroscopy. ROFA-induced increases
      in other lavage fluid carbonyls were not seen. Increased CH3CHO in lavage fluid
      was observed as late as 8 h later. No increase in CH3CHO was observed in plasma
      from ROFA-treated rats. An increased formation of CH3CHO was observed in a human
      airway epithelial cell line incubated with ROFA suggesting a pulmonary source of
      CH3CHO production. Instillation of solutions of metals (iron, vanadium, nickel)
      contained in ROFA, or instillation of another ROFA-type particle containing
      primarily iron, also induced a specific increase in CH3CHO. These data support
      the hypothesis that metals were involved in the increased CH3CHO formation. Thus
      metals on PM may mediate lung responses through induction of lipid peroxidation
      and carbonyl formation.

PMID- 10401625
TI  - Tissue damage in acute myocardial infarction: selective protection by vitamin E.
AB  - A growing amount of scientific evidence supports the participation of oxygen
      radicals in heart disease and, consequently, a protective effect of vitamin E
      (VE), beta-carotene (BC), and other antioxidants. The aim of this study was to
      correlate plasma VE and BC concentration with the clinical course of the acute
      myocardial infarction (AMI). We evaluated 120 patients that were admitted at the
      coronary units within 12 h after the development of AMI symptoms. The AMI was
      diagnosed by clinical and biochemical criteria and by electrocardiography and
      echocardiography. Plasma VE and BC concentration was determined by high
      performance liquid chromatography. The patients were separated according to the
      plasma concentration of VE (group H, VE > 17.5 microM; group L, VE < 17.5
      microM). Clinical history of patients, age, sex, associated cardiovascular risk
      factors, AMI localization, hemodynamic class, and the treatment received were
      similar between different groups. The blood levels of creatine phosphokinase (CK)
      evaluated either 24- or 48-h after admittance, were higher in group L than in
      group H (24 h: H = 436 +/- 31 U/ml vs. L = 642 +/- 84 U/ml; p < .005; 48 h: H =
      242 +/- 21 U/ml; L = 423 +/- 82 U/ml, p < 0.005). The number of deflexions in the
      electrocardiogram at admittance (ECG-D) was significantly higher in group L than
      in group H (4.7 +/- 0.3 vs. 3.7 +/- 0.2; p < .005). The number of new Q waves in
      the ECG of release (ECG-Q) was higher in group L than in group H (2.9 +/- 0.3 vs.
      2.2 +/- 0.2; p < .05). The number of segments affected in the echocardiograms (EC
      S) was: L = 5.3 +/- 0.6 vs. H = 4.4 +/- 0.2; p = 0.11. No significant differences
      in CK levels, ECG-D, ECG-Q, and EC-S were observed when the patients were
      separated according their plasma BC levels. These results indicate that a high
      concentration of plasma VE, but not BC, was associated with a diminution in the
      creatine phosphokinase release and with the AMI extension.

PMID- 10401624
TI  - Inhibition of D1, D2, and A-cyclin expression in HL-60 cells by the lipid
      peroxydation product 4-hydroxynonenal.
AB  - 4-Hydroxynonenal (HNE), a product of lipid peroxidation, is an highly reactive
      aldehyde that, at concentration similar to those found in normal cells, blocks
      proliferation and induces a granulocytic-like differentiation in HL-60 cells.
      These effects are accompained by a marked increase in the proportion G0/G1 cells.
      The mechanisms of HNE action were investigated by analyzing the expression of the
      cyclins and cyclin-dependent protein kinases (CDKs), controlling the cell cycle
      progression. Data obtained by exposing cells to dimethyl sulfoxide (DMSO) were
      used for comparison. 4-Hydroxynonenal downregulated both mRNA and protein
      contents of cyclins D1, D2, and A until 24 h from the treatments, whereas DMSO
      inhibited cyclin D1 and D2 expression until the end of experiment (2 days) and
      induces an increase of cyclin A until 1 day. Cyclins B and E, and protein kinase
      CDK2 and CDK4 expressions were not affected by HNE, whereas DMSO induced an
      increase of cyclin E, B, and CDK2 from 8 h to 1 day. These data are in agreement
      with previous results indicating a different time-course of accumulation in G0/G1
      phases of cells treated with HNE and DMSO and suggest that the HNE inhibitory
      effect on proliferation and cell cycle progression may depend by the
      downregulation of D1, D2, and A cyclin expression.

PMID- 10401626
TI  - Glutathione-dependent ascorbate recycling activity of rat serum albumin.
AB  - An efficient regeneration of vitamin C (ascorbate) from its oxidized byproduct,
      dehydroascorbate (DHAA), is necessary to maintain sufficient tissue levels of the
      reduced form of the vitamin. Additionally, the recycling may be more significant
      in mammals, such as guinea pigs and humans, who have lost the ability to
      synthesize ascorbate de novo, than it is in most other mammals who have retained
      the ability to synthesize the vitamin from glucose. Both a chemical and an
      enzymatic reduction of DHAA to ascorbate have been proposed. Several reports have
      appeared in which proteins, including thioltransferase, protein disulfide
      isomerase, and 3-alpha-hydroxysteroid dehydrogenase, characterized for other
      activities have been identified as having DHAA reductase activity in vitro.
      Whether these previously characterized proteins catalyze the reduction of DHAA in
      vivo is unclear. In the present study, a 66 kD protein was purified strictly on
      the basis of its DHAA-reductase activity and was identified as rat serum albumin.
      The protein was further characterized and results support the suggestion that
      serum albumin acts as an antioxidant and exerts a significant glutathione
      dependent DHAA-reductase activity that may be important in the physiologic
      recycling of ascorbic acid.

PMID- 10401627
TI  - Contribution of O4+ oligodendrocyte precursors and astrocytes to the glial
      ensheathment of vessels in the rabbit myelinated streak.
AB  - The barrier properties and glial ensheathment of blood vessels in the retinal
      myelinated streak of adult New Zealand White rabbits were characterized at the
      ultrastructural level by intravascular injection of horseradish peroxidase (HRP)
      and immuno-electron microscopy with monoclonal antibody O4 and antibodies to
      glial fibrillary acidic protein (GFAP). Vessels within the myelinated streak did
      not leak HRP, and they exhibited tight junctions between adjacent endothelial
      cells. However, unlike their adult counterparts, the retinal blood vessels at
      postnatal day 18 exhibited substantial endocytotic activity. Both GFAP+
      astrocytes and O4+ cells were evident surrounding the preretinal blood vessels of
      the myelinated streak. Furthermore, O4+ cells exhibited features indicative of
      high synthetic activity, including a large proportion of extended chromatin and
      prominent nucleoli within the nucleus, as well as a well-developed Golgi
      apparatus and numerous mitochondria in the cytoplasm. O4+ cells also exhibited
      variable quantities of heterochromatin, indicative of early stages of cellular
      differentiation. These observations are consistent with previous data showing
      that O4+ cells in the myelinated streak include oligodendrocyte precursor cells,
      pre-oligodendrocytes, and immature oligodendrocytes (Morcos Y, Chan-Ling T. Glia
      21:163-182, 1997). The present data indicate that the preretinal vessels of the
      myelinated streak possess barrier properties typical of microvasculature in the
      central nervous system, and that both O4+ cells and astrocytes contribute to the
      glial ensheathment of these vessels. These vessels thus differ markedly from the
      leaky preretinal vessels associated with pathological conditions such as
      retinopathy of prematurity.

PMID- 10401628
TI  - Molecular heterogeneity of oligodendrocytes in chicken white matter.
AB  - The classical studies by Del Rio Hortega (Mem. Real. Soc. Espan. Hist. Nat. 14:40
      122, 1928) suggest that the oligodendrocyte population includes four
      morphological subtypes. Recent data from the cat and the rat show that the
      anatomy of oligodendrocytes related to early myelinating prospective large fibers
      differs from that of oligodendrocytes related to late myelinating prospective
      small fibers. After application of a polyclonal antiserum to cryostat sections
      from the chicken CNS, we noted that glial cells in the spinal cord white matter
      had become labeled. Analysis of the occurrence and cellular localization of this
      immunoreactivity--the T4-O immunoreactivity--in the CNS of the adult chicken
      showed that T4-O immunoreactive cells are enriched in the ventral funiculus and
      superficially in the lateral funiculus of the spinal cord, where they are co
      localized with large fibers. Double staining with T4-O antiserum and anti-GFAP or
      the lectin BSI-B4 revealed that T4-O immunoreactive cells are not astrocytes or
      microglia. Staining with anti-HSP108, a general marker for avian
      oligodendrocytes, showed that T4-O immunoreactivity defines an oligodendroglial
      subpopulation. A search for T4-O immunoreactivity in spinal cord white matter of
      some other vertebrates revealed that T4-O immunoreactive cells are not present in
      sections from fish, frog, turtle, rat, and rabbit spinal cord white matter. These
      results suggest the presence of a fiber size-related molecular heterogeneity
      among chicken white matter oligodendrocytes.

PMID- 10401629
TI  - Enzymatic modulation of cell volume in C6 glioma cells.
AB  - We monitored the volume of C6 glioma cells in suspension using a Coulter Counter
      and exposed the cells to micromolar or nanomolar levels of collagenase or
      clostripain. In 13 experiments, type IV collagenase (310 units ml-1;
      approximately 3 microM L-1) decreased the volume by 8-12%, 8 min after addition.
      In 13 of 21 experiments, the volume decrease was followed by a volume regulatory
      increase (VRI) back to control levels in the continued presence of collagenase.
      The shrinkage evoked by type IV collagenase was eliminated by heat-inactivation
      of the enzyme preparation. A highly purified collagenase (type VII) at the same
      concentration evoked a relatively minor decrease in volume. A well-known
      contaminating protease present in type IV collagenase, clostripain, which
      specifically cleaves arginyl peptide bonds, evoked a 7 +/- 2% shrinkage (100 nM L
      1, 7 experiments). Clostripain did not evoke a volume regulatory increase. The
      initial velocity of shrinkage evoked by clostripain (0.0012 pL min-1, 0.0034 pL
      min-1, 0.0132 pL min-1; 1 pL = 10(-12) liters) scaled with its concentration (1
      nM L-1, 10 nM L-1, 100 nM L-1). The effect of clostripain was inhibited by heat
      inactivation of the enzyme. Leupeptin, an inhibitor of clostripain, prevented the
      decrease in volume evoked by clostripain. The activity of stretch-activated ion
      channels was unaffected by type IV collagenase. Barium, cesium, amiloride, DIDS,
      or bumetanide failed to block the shrinkage evoked by type IV collagenase. These
      results demonstrate that clostripain, present in crude collagenase enzyme
      preparations, causes the shrinkage, and that C6 glioma cells can undergo a volume
      regulatory increase at virtually constant osmotic pressure. In addition, cleavage
      of a cell surface moiety, which contains arginine, and possibly proline, causes
      shrinkage. This moiety may be part of the extracellular or intracellular matrix
      providing mechanical support to the cells. VRI reflect actions of another
      substance in the type IV crude collagenase preparations, on a receptor
      independent of the arg-pro moiety. The enzymatic modulation of glioma cell volume
      by these two receptors may reflect a new mechanism by which such cells, and
      possibly other glia, regulate their contact area and interactions with other
      cells in the central nervous system.

PMID- 10401630
TI  - Glial hyperpolarization upon nerve root stimulation in the leech Hirudo
      medicinalis.
AB  - Hyperpolarizing responses in neuropil glial cells evoked by nerve root
      stimulation were studied in the central nervous system of the leech Hirudo
      medicinalis using intracellular recording and extracellular stimulation
      techniques. From a mean resting potential of -60.5 +/- 1.0, the glial membrane
      was hyperpolarized by -8.6 +/- 0.8 mV, via stimulation of the dorsal posterior
      nerve root in an isolated ganglion. Nerve root stimulation evoked biphasic or
      depolarizing responses in glial cells with resting potentials around -70 mV (Rose
      CR, Deitmer JW. J. Neurophysiol. 73:125-131, 1995). The hyperpolarizing response
      was reduced by the ionotropic glutamate receptor antagonist CNQX (50 microM) to
      58% of its initial amplitude. In 15 mM Ca2+/15 mM Mg(2+)-saline the
      hyperpolarization was reduced by 44%. The hyperpolarization that persisted in
      high-divalent cation saline was not affected by CNQX. Bath-applied glutamate (500
      microM) and kainate (2 microM) elicited glial hyperpolarizations that were
      sensitive to CNQX and 10 mM Mg2+/1 mM Ca(2+)-saline. The 5-HT-antagonist
      methysergide did not affect the hyperpolarizations evoked by nerve root
      stimulation. The results show that in the leech glial membrane responses to
      neuronal activity include not only depolarizations, as shown previously, but also
      hyperpolarizations, which are mediated by direct and indirect neuron-glial
      communication pathways. In the indirect pathway, glutamate is a transmitter
      between neurons.

PMID- 10401631
TI  - Caveolin-1 expression in Schwann cells.
AB  - Caveolae are non-clathrin-coated invaginations of the plasma membrane, which are
      present in most cell types. An integral component of caveolae is the caveolin
      family of related proteins, which not only forms the structural framework of
      caveolae, but also likely subserves its functional roles, including regulation of
      signal transduction and cellular transport, in particular, cholesterol
      trafficking. Although caveolae have been identified ultrastructurally in the
      peripheral nervous system (PNS), caveolin expression has not previously been
      studied. To date, three caveolin genes have been reported. Here, we show for the
      first time that caveolin-1 is expressed by Schwann cells (SC) as well as several
      SC-derived cell lines. Caveolin-1 is enriched in the buoyant, detergent-insoluble
      membranes of rat sciatic nerve (SN) and SC, a hallmark of the caveolar
      compartment. Caveolin-1 exists as both soluble and insoluble forms in rat SN and
      SC, and localizes to SC cytoplasm and abaxonal myelin. SC caveolin-1 decreases
      after axotomy, when SC revert to a premyelinating phenotype. We speculate that
      caveolin-1 may regulate signal transduction and/or cholesterol transport in
      myelinating SC.

PMID- 10401632
TI  - Regulation of gelatinases in microglia and astrocyte cell cultures by plant
      lectins.
AB  - The effects of 25 recently discovered plant lectins on cell proliferation and
      enzyme release were compared to those of previously known lectins on rat
      microglia and astrocyte cell cultures. A dose-dependent proliferation of
      microglial cells, but not of astrocytes, was induced by seven lectins, whereas
      five lectins showed dose-dependent cytotoxicity on both microglia and astrocyte
      cell cultures. The activity of gelatinase B (MMP-9) was strongly increased in
      microglial cells by the aforementioned seven lectins, by concanavalin A, and by
      phytohemagglutinin (PHA-E4), whereas gelatinase A (MMP-2) remained at
      constitutive levels. The five cytotoxic lectins decreased the activity of
      gelatinase B in microglia and of gelatinase A in astrocytes, in a dose-dependent
      manner. The lectin wheat germ agglutinin induced a decrease in gelatinase B
      activity in microglia, but stimulated gelatinase A and B activity in astrocytes.
      These results indicate that lectins possess neuromodulatory effects that may
      motivate the study of their effects on central nervous system (CNS) function in
      vivo. This, in turn, may lead to better insight into whether lectin or lectin
      like molecules can interact with glial cells, and whether they have a role in
      acute toxicity and in multifactorial diseases in which environmental factors may
      play a role.

PMID- 10401633
TI  - FasL (CD95L, Apo1L) is expressed in the normal rat and human brain: evidence for
      the existence of an immunological brain barrier.
AB  - Despite the mechanical blood-brain barrier, activated T-cells can cross brain
      vessels. Thus, the CNS is routinely surveyed by immune competent cells; yet the
      healthy brain is not a target of antigen-specific immune reactions. Therefore,
      mechanisms must exist to prevent brain-antigen-specific T-cells from inducing
      immune responses. Data indicate that activated T-cells entering the CNS may
      undergo apoptosis rather than leaving the brain to induce immune responses.
      Applying RT-PCR, Western-blots, and immunocytochemistry, we have demonstrated
      expression of the apoptosis-inducing protein Fas ligand on astrocytes and neurons
      of apparently normal rat and human brains. FasL-positive astrocytes were often
      situated in close vicinity to cerebral blood vessels in vivo and induced
      apoptosis of Fas expressing Jurkat cells in vitro. We propose that similar to
      other immune privileged organs FasL-induced apoptosis of activated T-cells in the
      brain protects the tissue from self damaging immune attacks by forming an
      immunological brain barrier.

PMID- 10401634
TI  - Differential injury-dependent glial expression of interleukins-1 alpha, beta, and
      interleukin-6 in rat brain.
AB  - Interleukins (IL)-1 alpha, beta and IL-6 may play essential roles in early
      inflammatory processes in response to degenerating cholinergic cells observed in
      the basal forebrain of Alzheimer patients. To address this question in vivo, two
      distinct lesion paradigms were used. A specific and selective basal forebrain
      cholinergic cell loss was achieved by a single intracerebroventricular
      application of the cholinergic immunotoxin, 192IgG-saporin. Intrahippocampal
      injection of lipopolysaccharide and interferon-gamma was used to produce an
      exogenously-induced acute inflammation in the brain. In order to disclose the
      lesion-induced temporal cascade of the expression pattern of IL-1 alpha, IL-1
      beta, and IL-6, and the cell types expressing IL-1 alpha, beta/IL-6 mRNA, Western
      analysis, RT-PCR, and double labeling immunocytochemistry were applied. In the
      intact brain, IL-6, IL-1 alpha and IL-1 beta demonstrated a constitutive
      expression in neurons. Following cholinergic lesion neither IL-1 beta nor IL-6
      expression could be detected in any of the activated glial cell types, whereas IL
      1 alpha was found to be expressed in astroglial cells only. In contrast,
      hippocampal administration of lipopolysaccharides/interferon-gamma resulted in
      expression of IL-1 alpha in microglial but not astroglial cells. These in vivo
      studies clearly demonstrate that the cellular expression of IL-1 alpha, IL-1
      beta, and IL-6 in the brain is differentially regulated depending on the kind of
      injury producing the inflammatory response in the brain. The data suggest that
      each glial cell seems to be equally capable of expressing a number of various
      cytokines, but it depends on the kind of stimulus which temporal and cellular
      cascade of cytokine expression pattern is initiated under a particular
      pathological condition in the brain.

PMID- 10401635
TI  - Seasonal changes in astrocytes parallel neuronal plasticity in the song control
      area HVc of the canary.
AB  - In the song control area HVc of the canary, intercellular dye-coupling among
      astrocytes was studied by intracellular injection of neurobiotin into identified
      single astrocytes. Injection of individual astrocytes into acute slices resulted
      in dye spread to neighboring astrocytes, covering a sphere of up to 1 mm in
      diameter. The astrocytic nature of the dye-coupled cells was verified by double
      labeling of neurobiotin-filled cells with antisera for the astrocytic filament
      proteins GFAP or vimentin. The similarity in the number of dye-coupled cells and
      the total number of astrocytes labeled by immunocytochemical markers indicate
      that dye-coupling is specific for astrocytes and labels almost the entire local
      astrocytic population. Within the major nucleus for vocal control (HVc),
      approximately 25% more astroglial cells were present than in the surrounding
      forebrain tissue. There is no apparent hindrance of dye spread at the border of
      the HVc. The density of dye-coupled astrocytes and the expression of cytoskeletal
      filament proteins differed markedly between the reproductive period in spring and
      the quiescent period in autumn. While vimentin is the major astroglial filament
      in autumn, GFAP is strongly expressed in spring. The density of dye-coupled
      astrocytes reveals a marked increase in the reproductive period, followed by a
      reduction in autumn. The data indicate that the astrocytic population in the
      avian forebrain undergoes significant changes coincident with the known
      functional changes in the vocal control nuclei during periods of song production.

PMID- 10401636
TI  - Hypoxia-induced loss of synaptic transmission is exacerbated in hippocampal
      slices of transgenic mice expressing C-terminal fragments of Alzheimer amyloid
      precursor protein.
AB  - To investigate the possible involvement of beta-amyloid (A beta) in disrupting
      neuronal function during ischemia, we examined whether overexpression of C
      terminal fragments of beta-amyloid precursor protein (beta-APP) in transgenic
      (Tg) mice is capable of altering the capacity of hippocampus slices to recover
      synaptic transmission after transient hypoxic episodes. Recovery of synaptic
      transmission was monitored in area CA1 of perfused hippocampal slices prepared
      from both control and Tg mice. The results obtained indicate that hippocampal
      slices prepared from Tg mice exhibited a much lower level of recovery in synaptic
      transmission following reoxygenation. This reduction in the capacity of Tg slices
      to recover from hypoxia-induced impairment of synaptic transmission in the
      hippocampus does not appear to be related to pre-existing alterations in either
      functional or biochemical properties of glutamate receptors in Tg mice. The
      present results provide the first experimental evidence that overexpression of
      the C-terminal fragment of APP exacerbates functional damage of hippocampal
      neurons after hypoxic episodes.

PMID- 10401637
TI  - Head direction cells in the primate pre-subiculum.
AB  - The function of the primate hippocampus and related structures was analysed by
      making recordings from the hippocampus, subiculum, presubiculum, and
      parahippocampal gyrus in monkeys actively walking in the laboratory. Head
      direction cells were found in the presubiculum. The firing rate of these cells
      was a function of the head direction of the monkey, with a response that was
      typically 10-100 times larger to the best as compared to the opposite direction.
      The mean half-amplitude width of the tuning of the cells was 76 degrees. The
      response of head direction cells in the presubiculum was not influenced by the
      place where the monkey was, there being the same tuning to head direction at
      different places in a room, and even outside the room. The response of these
      cells was also independent of the "spatial view" observed by the monkey, and also
      the position of the eyes in the head. The average information about head
      direction was 0.64 bits, about place was 0.10 bits, about spatial view was 0.27
      bits, and about eye position was 0.04 bits. The cells maintained their tuning for
      periods of at least several minutes when the view details were obscured or the
      room was darkened. This representation of head direction could be useful together
      with the hippocampal spatial view cells and whole body motion cells found in
      primates in such spatial and memory functions as path integration.

PMID- 10401638
TI  - Comparison of medial and lateral septal neuron activity during performance of
      spatial tasks in rats.
AB  - The septal complex, having close and reciprocal connections with the hippocampus,
      is known to play an important role in learning and memory. Anatomically, the
      septal complex is divided into the medial and lateral areas (MS and LS). In the
      present study, in order to elucidate functional differences between the MS and
      LS, we recorded single unit activity in the MS or LS and electroencephalogram
      (EEG) in the hippocampus simultaneously while the rats performed the following 2
      spatial tasks in an open-field chamber. In task 1, the rat received rewarding
      intracranial electrical stimulation (ICES) when it entered in a reward place that
      was set randomly in the open field in each trial. In task 2, the rat received
      rewarding ICES when it alternately visited two fixed reward places in the open
      field. Unit activity was analyzed in relation to the pattern of hippocampal EEG,
      and rat's location, locomotion direction and locomotion speed in the spatial
      tasks. A total of 47 neurons were recorded in the septal complex (MS, 19; LS,
      28). The majority of neurons with activity correlated with hippocampal EEG were
      found in the MS (14/19). All of the neurons with place-related activity (an
      increase in unit activity when the rat was in a specific location in the open
      field) were found in the LS (n = 15). The majority of neurons with direction
      related activity were found in the LS (18/23). Twenty-one neurons displayed speed
      related activity (MS, 9; LS, 12). The present results indicate that (1) the MS is
      directly involved in the formation and control of hippocampal EEG patterns, and
      (2) the LS is important for the processing and integration of spatial information
      in the environment.

PMID- 10401639
TI  - Hippocampal place cells can develop distinct representations of two visually
      identical environments.
AB  - The pattern separation ability of hippocampal place cells was tested in an
      environment in which two visually identical rectangular compartments (Box A and
      Box B) were connected by a hidden door. Small ensembles of neurons were recorded
      with tetrodes while the rat searched for randomly distributed loci for
      reinforcing brain stimulation. The first recording session in Box A was conducted
      after the rat had explored the environment for the first time for 30 min.
      Immediately thereafter, a hidden door between Box A and Box B was opened to let
      the rat into the unexplored compartment, and a 5-min recording session was run
      with the door concealed. A rearrangement of place fields in Box B was observed in
      18/20 neurons and in 5/6 ensembles. Most place fields did not change between two
      successive sessions in Box B. When the rat returned to Box A, the ensembles of
      neurons were as likely to adopt the original Box A firing field pattern as the
      more recent Box B pattern. In order to control for the influence of extra-arena
      cues, the rat was gradually lifted in a closed bucket from Box A into Box B while
      the whole arena was rotated by 90 degrees. All but one neuron and all the
      ensembles followed the intra-arena cues. Both rotated Box B and Box A firing
      field patterns were represented but Box B pattern was stronger among the neuronal
      ensembles. These findings indicate that hippocampal place cells not only can
      develop distinct representations of two visually identical environments but also
      can selectively reactivate either one of these representations depending on the
      rat's recent experience.

PMID- 10401640
TI  - Temporally-specific retrograde amnesia in two cases of discrete bilateral
      hippocampal pathology.
AB  - The role of the hippocampus in retrograde amnesia remains controversial and
      poorly understood. Two cases are reported of discrete bilateral hippocampal
      damage, one of which was a rare case of limbic encephalitis secondary to the
      human herpes virus 6. Detailed memory testing showed marked anterograde memory
      impairment, but only mild, temporally-limited retrograde amnesia that covered a
      period of several years in both autobiographical and factual knowledge domains.
      The absence of extensive retrograde amnesia in these two cases points to a time
      limited role for the hippocampus in the retrieval of retrograde memories, and
      suggests that entorhinal, perirhinal, parahippocampal, or neocortical areas of
      the temporal lobe may be more critical than the hippocampus proper for long-term
      retrograde memory functioning. Our findings offer general support to theories of
      memory consolidation that propose a gradual transfer of memory from hippocampal
      to neocortical dependency.

PMID- 10401641
TI  - Morphometry of a peptidergic transmitter system: dynorphin B-like
      immunoreactivity in the rat hippocampal mossy fiber pathway before and after
      seizures.
AB  - While the morphometry of classical transmitter systems has been extensively
      studied, relatively little quantitative information is available on the
      subcellular distribution of peptidergic dense core vesicles (DCVs) within axonal
      arbors and terminals, and how distribution patterns change in response to neural
      activity. This study used correlated quantitative light and electron microscopic
      immunohistochemistry to examine dynorphin B-like immunoreactivity (dyn B-LI) in
      the rat hippocampal mossy fiber pathway before and after seizures. Forty-eight
      hours after seizures induced by two pentylenetetrazol injections, light
      microscopic dyn B-LI was decreased dorsally and increased ventrally.
      Ultrastructural examination indicated that, in the hilus of the dentate gyrus,
      these alterations resulted from changes that were almost entirely restricted to
      the profiles of the large mossy-like terminals formed by mossy fiber collaterals
      (which primarily contact spines), compared to the profiles of the smaller, less
      convoluted terminals found on the same collaterals (which primarily contact
      aspiny dendritic shafts). Dorsally, mossy terminal profile labeled DCV (/DCV)
      density dropped substantially, while ventrally, both mossy terminal profile
      perimeter and /DCV density increased. In all terminal profile examined, /DCVs
      also were closely associated with the plasma membrane. Following seizures, there
      was a reorientation of /DCVs along the inner surface of mossy terminal profile
      membranes, in relation to the types of profiles adjacent to the membrane: in both
      the dorsal and ventral hilus, significantly fewer /DCVs were observed at sites
      apposed to dendrites, and significantly more were observed at sites apposed to
      spines. Thus, after seizures, changes specific to: (1) the dorsoventral level of
      the hippocampal formation, (2) the type of terminal, and (3) the type of profile
      in apposition to the portion of the terminal membrane examined were all observed.
      An explanation of these complex, interdependent alterations will probably require
      evoking multiple interrelated mechanisms, including selective prodynorphin
      synthesis, transport, and release.

PMID- 10401642
TI  - Field potential recordings in dentate gyrus of anesthetized rats: stability of
      baseline.
AB  - Urethane is a standard anesthetic utilized for in vivo recordings in the
      hippocampus. In studies of long-term potentiation (LTP), the measure of interest
      is the response amplitude minutes to hours following train delivery. In the
      absence of experimental treatment, we have consistently observed upward drift in
      the amplitude of the population spike (PS) and EPSP slope of the dentate gyrus
      (DG) evoked field response in acute surgical preparations performed in the
      urethanized rat. The present study systematically monitored PS amplitude and EPSP
      slope in the DG every 30 minutes for 6 hours following optimal positioning of
      Teflon-coated bipolar stainless steel electrodes under urethane anesthesia. At
      maximal stimulus intensities, large time-dependent increases in PS amplitude (70
      80%) were observed over the first 2-4 hours, an effect that was exaggerated at
      lower stimulus intensities. Increases in the EPSP slope were smaller in magnitude
      (20-30%) and stabilized within a shorter period of time (1-2 hours). Animals were
      warmed on a heating pad and body and brain temperature remained constant over the
      recording session. Reducing stimulating electrode size and recording with glass
      micropipettes did not alleviate the upward drift in response amplitude. Similar
      increases were also seen under pentobarbital anesthesia. To dissociate anesthetic
      from surgical effects, recordings were obtained from animals previously prepared
      with indwelling electrodes and injected with urethane. Although slight declines
      (10-15%) in EPSP slope occurred over time, no significant alterations in PS
      amplitude were seen in the chronic preparation at high stimulus intensities. Low
      stimulus intensities yielded a more variable response pattern and, in direct
      contrast to the acute preparation, time-dependent declines, not increases, were
      noted in both parameters. These data suggest that generalized surgical trauma
      contributes to the upward drift in response amplitude and indicate that long
      stabilization periods are required in acute surgical preparations for accurate
      field potential recordings.

PMID- 10401643
TI  - Distribution and analysis of hippocampal theta-related cells in the pontine
      region of the urethane-anesthetized rat.
AB  - In the present study 99 cells were recorded in the pontine region of urethane
      anesthetized rats during: (1) the spontaneous occurrence of hippocampal formation
      (HPC) theta field activity; (2) sensory-induced (tail pinch) theta field
      activity; and (3) large amplitude irregular field activity (LIA). Using the
      criteria of Colom and Bland (Brain Res 1997;422:277-286) for the classification
      of theta-related cells, 58/99 cells (59%) were involved with changes in activity
      related to the occurrence of HPC theta field activity, 24/99 (24%) were non
      related, and 17/99 (17%) were related to the sensory input (tail pinch). All
      cells recorded discharged in a tonic, non-rhythmic pattern in relation to the HPC
      field activity occurring during the three conditions. Of the 58 theta-related
      cells, 52 (90%) were classified as tonic theta-ON cells and 6 (10%) as tonic
      theta-OFF cells. There were no clear regional differences in the distribution of
      cell types. Statistical analysis of the discharge rates of tonic theta-ON cells
      during spontaneously occurring theta and tail pinch-induced theta (tested on 48
      cells) revealed that 22/48 (46%) of these cells discharged at significantly
      higher rates during the faster theta field frequencies associated with tail
      pinches while 26/48 (54%) tonic theta-ON cells did not change discharge rate
      between the spontaneously occurring theta and the tail pinch-induced theta
      states. In addition, the discharges of 11/52 (21%) tonic theta-ON cells exhibited
      weak to moderate correlations with the negative peak of HPC theta field activity
      recorded from the stratum moleculare of the dentate gyrus. Of the 17 cells
      related to the sensory stimulation (tail pinch), 12 (71%) cells increased
      discharge rate during the tail pinch and were classified as sensory activated,
      while 5 (29%) cells decreased discharge rate during the tail pinch and were
      classified as sensory inactivated. The results supported the following
      conclusions: (1) the main cells in the pontine region involved with changes in
      activity related to the occurrence of HPC theta field activity are tonic theta-ON
      cells and tonic theta-OFF cells; (2) a subpopulation of tonic theta-ON cells
      coded the increasing intensity of activation of the ascending brainstem HPC
      synchronizing pathways by an increase in discharge rate; and (3) a smaller
      population of cells in the rostral pontine region appeared to be related to
      sensory stimulation, independent of theta-related activity.

PMID- 10401644
TI  - Loss of NADPH diaphorase-positive neurons in the hippocampal formation of chronic
      pilocarpine-epileptic rats.
AB  - Recent evidence suggests an important role for NO in cholinergic models of
      epilepsy. Nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd), a
      marker of NO containing neurons, was shown to intensely colocalize with GABA in
      double-labeling studies performed in the hippocampal formation (exception made
      for the pyramidal cell layer) (Valtschanoff et al., J Comp Neurol 1993:331:111
      121). In this sense, it further characterizes an extremely important cell
      category due to the relevant involvement of inhibitory systems in the mechanisms
      of genesis and propagation of seizures. Here, we assessed the histochemistry for
      NADPHd in the hippocampal complex of chronic pilocarpine-epileptic animals.
      NADPHd-positive cells were lost in almost every hippocampal subfield in
      pilocarpine-treated rats. The central portion of the polymorphic layer of the
      dentate gyrus (hilus) presented one of the highest losses of NADPHd-positive
      cells (55-79%) in the hippocampus. A significant loss of NADPHd-positive cells
      was seen in strata oriens, pyramidale, and radiatum CA1, CA2, and CA3 subfields.
      NADPHd staining in the subicular pyramidal cell layer was not different from that
      observed in controls. A significant loss of NADPHd-stained cells was observed in
      entorhinal cortex layers II and III in the epileptic group. For entorhinal cortex
      layers V and VI, however, results varied from an almost complete tissue
      destruction to an overexpression of NADPHd-positive cells, as well as an increase
      in neuropil staining. In summary, loss of NADPHd staining was not uniform
      throughout the hippocampal formation. There has been a growing support for the
      notion that GABAergic neurons in the hippocampal formation are not equally
      sensitive to insults. Our results suggest that, as a marker for a subpopulation
      of GABAergic neurons, NADPHd helps in further refining the characterization of
      the different neuronal populations sensitive to epileptic activity.

PMID- 10401645
TI  - Cholinergic innervation of mossy cells in the rat fascia dentata.
AB  - Hilar mossy cells are the main cells of origin of the commissural/associational
      projection to the inner molecular layer of the rat fascia dentata. In order to
      analyze the cholinergic innervation of hilar mossy cells, a light and electron
      microscopic double-labeling technique was used. Immunolabeling for calcitonin
      gene-related peptide (CGRP) was employed to identify mossy cells and
      immunocytochemistry for choline acetyltransferase (ChAT) was used to label
      cholinergic septohippocampal fibers. Cholinergic boutons were abundant around
      mossy cell somata and on their proximal dendrites. Electron microscopy confirmed
      that many of these boutons formed synapses with the CGRP-positive mossy cells.
      These data demonstrate a direct innervation of hilar mossy cells by cholinergic
      septohippocampal afferents. This connectivity could contribute to the
      electrophysiological behavior of mossy cells during theta oscillations.

PMID- 10401646
TI  - Experience-dependent regulation of adult hippocampal neurogenesis: effects of
      long-term stimulation and stimulus withdrawal.
AB  - Exposure to an enriched environment has been shown to cause an increase in
      neurogenesis in the dentate gyrus of adult mice. In this study we examined how
      this experience-dependent response in adult hippocampal neurogenesis of C57BL/6
      mice is modulated under the conditions of long-term stimulation and of withdrawal
      from the enriched environment. We found that a group which experienced withdrawal
      from the enriched environment 3 months earlier, had more than twice as many
      proliferating cells in the subgranular zone as controls and mice experiencing
      long-term stimulation. We propose that the greater number of proliferating cells
      after withdrawal reflects a survival-promoting effect on the dividing neuronal
      stem and progenitor cells during the earlier period of stimulation. No
      differences between the groups were observed in the number of surviving progeny
      or their phenotypes. Therefore, the existence of more dividing cells in the
      withdrawal group did not translate into a significant net increase in
      neurogenesis in the absence of continued stimulation. Similarly, the finding in
      the group experiencing long-term stimulation showing no clear benefit over
      controls could be interpreted as a diminished efficiency of continued
      environmental stimuli to elicit a neurogenic response. Thus, we propose as a
      working hypothesis that: 1) stimulation early in life may preserve the neurogenic
      potential in the dentate gyrus, and 2) the novelty of complex stimuli rather than
      simply continued exposure to complex stimuli elicits the environmental effects on
      adult hippocampal neurogenesis.

PMID- 10401647
TI  - Instability of dentate gyrus field potentials in awake and anesthetized rats.
AB  - Adult male Long-Evans rats were prepared with stimulating and recording
      electrodes in the perforant path and dentate gyrus, respectively. Urethane
      anesthetized acute (ACU) preparations and chronically-implanted freely-moving
      (CHR) animals received moderate-intensity (50-75% of maximum) stimulation pulses
      every 15-20 s for 4-5 hr in order to assess the stability of evoked field
      potentials. Significant increases in both population spike amplitude (+6.3%/hr)
      and EPSP slope (+2.5%/hr) were seen over the course of testing in the ACU group
      as a whole, while the CHR group showed significant decreases in EPSP slope (
      3.3%/hr) but not spike (-1.2%/hr). Thus, both preparations were unstable, though
      the group mean drift differed in direction. Field potential drift was also
      affected by body temperature and stimulation intensity; drift was significantly
      greater when temperature was not controlled, and responses to moderate-intensity
      stimulation tended to be less stable than responses to high-intensity pulses. Our
      results indicate that a drift of 4-6% per hour in individual subjects is common;
      in unheated acute preparations, drift can equal or exceed 20% per hour (3/7
      cases). These findings show that response instability can pose significant
      problems for electrophysiological investigations of neural plasticity.

PMID- 10401648
TI  - How do we treat first time traumatic shoulder dislocations in young athletes?

PMID- 10401649
TI  - Tunnel widening in anterior cruciate ligament reconstruction: a prospective
      evaluation of hamstring and patella tendon grafts.
AB  - We report a prospective series evaluating the incidence and degree of tunnel
      widening in a well-matched series of patients receiving a hamstring or patella
      tendon graft for anterior cruciate ligament (ACL) deficiency. We correlated
      tunnel widening with clinical factors, knee scores, KT-1000 and isokinetic muscle
      strength to determine the clinical significance of this finding. Seventy-three
      patients at least 12 months post-ACL reconstruction were evaluated. Thirty-eight
      patients had received a doubled semitendinous and gracilis graft and 35 a bone
      patella tendon-bone graft. All patients underwent a similar endoscopic procedure
      and accelerated postoperative rehabilitation. Tunnel widening was determined
      using standardized anteroposterior (AP) and lateral X-rays adjusted for
      magnification. A limited series of MRIs was performed to validate these
      measurements. There was a significant difference in the degree of tunnel widening
      between the two groups. The mean increase in femoral tunnel area in the hamstring
      group was 100.4% compared with a decrease of 25% in the patella tendon group (P =
      < 0.0001). In the tibial tunnel the mean increase in the hamstring group was
      73.9% compared with a decrease of 2.1% in the patella tendon group (P = <
      0.0001). The MRIs validated the plain film measurements. Tunnel widening did not
      correlate with the clinical findings, knee scores, KT-1000 or isokinetic muscle
      strength. Tunnel widening is marked in the hamstring group. Tunnel widening does
      not correlate with instability or a poor clinical outcome in the short term. The
      long-term implications of this finding are still to be determined.

PMID- 10401650
TI  - Subacute versus delayed reconstruction of the anterior cruciate ligament in the
      competitive athlete.
AB  - The objective of this study was to compare the function and activity level in
      patients with anterior cruciate ligament injuries, who participated in
      competitive sports (Tegner activity level > or = 7) and underwent a
      reconstruction of the anterior cruciate ligament, either subacute (2-12 weeks,
      group I) or late (12-24 months, group II) after the injury. The patients in group
      I (n = 97) were comparable with those in group II (n = 103) in terms of gender,
      age, preinjury activity level, and the reconstruction technique. At the final
      follow-up (2-5.5 years after the operation), the Lysholm score, the IKDC
      evaluation system and the one-leg-hop test revealed no differences between the
      groups. There were also no differences between the groups in terms of the
      patients' subjective evaluation or expectations. The Tegner activity level at
      follow-up was 8 (range 2-10) in group I and 6 (range 2-9) in group II (P =
      0.0001). The same thing was found in terms of the desired Tegner activity level,
      which was 9 (range 4-9) in group I and 7 (range 3-10) in group II (P = 0.0002).
      The KT-1000 laxity meter revealed a total side-to-side difference of 1.5 mm (-3.5
      8.5) in group I and 1.5 mm (-3.5-7) in group II (NS). Associated meniscal surgery
      between the index injury and the reconstruction, or during the reconstruction,
      was performed in 37/97 (38%) of the patients in group I and 59/103 (57%) of the
      patients in group II (P < 0.01). This study revealed that competitive athletes
      who underwent reconstruction at a subacute stage after the anterior cruciate
      ligament injury had a higher activity level 2-5.5 years after the index
      operation, as well as a higher desired level of activity compared to athletes who
      had the reconstruction delayed by 12-24 months. Furthermore, meniscal injuries
      were significantly more frequent if the reconstruction was delayed.

PMID- 10401651
TI  - Sensitivity to changes over time for the IKDC form, the Lysholm score, and the
      Cincinnati knee score. A prospective study of 120 ACL reconstructed patients with
      a 2-year follow-up.
AB  - The purpose of this study was to determine: (1) the sensitivity to changes over
      time for the IKDC form, the Lysholm score, and the Cincinnati knee score, (2) the
      relationship between the IKDC form, the Lysholm score and the Cincinnati knee
      score, (3) the criterion validity of each graded variable included in the IKDC
      form, and (4) if a functional knee test should be included as a graded variable
      and part of the final result of the IKDC form. We included in this prospective
      study 120 subjects who underwent ACL reconstruction with follow-up times of 3 and
      6 months, and 1 and 2 years after surgery. Outcome measurements were the graded
      variables of the IKDC form (IKDC1-4 and IKDC-final), the Lysholm score, the
      Cincinnati knee score, a visual analogue scale for patient's satisfaction, knee
      joint laxity measurement (KT-1000 knee arthrometer), and two functional knee
      tests (the triple jump and stairs hopple tests). The IKDC1, IKDC2, IKDC-final,
      and the Lysholm score were not sensitive to changes over time. The Cincinnati
      knee score was highly sensitive to changes over time and showed significantly
      improved outcome between each follow-up. IKDC1-4 showed high criterion validity,
      indicating that the IKDC1-4 is a good means of documenting clinical examination
      at one follow-up, but not of detecting changes over time. The functional knee
      tests were significant outcome measurements after ACL reconstruction, and should
      be reported separately.

PMID- 10401652
TI  - Analysis of subjective, objective and functional examination tests after anterior
      cruciate ligament reconstruction. A follow-up of 527 patients.
AB  - This study included 527 patients (178 female and 349 male) with unilateral
      anterior cruciate ligament (ACL) rupture who underwent arthroscopic ACL
      reconstruction using bone-patellar tendon-bone autograft and interference screw
      fixation. The follow-up examination was performed by independent observers at a
      median of 38 (21-68) months after the index operation. At the follow-up, the
      Lysholm score was 86 (14-100) points, the Lysholm instability subscore was 22 (0
      25) points and the Lysholm pain subscore was 19 (0-25) points. The Tegner
      activity level was 6 (1-10). The one-leg-hop test was 91 (0-167)% of the non
      injured knee. The difference in the anterior side-to-side laxity as measured with
      the KT-1000 arthrometer at 89 Newton (N) was 1.5 (-5-13) mm and the total KT-1000
      side-to-side difference at 89 N was 2 (-7-11) mm. Using the International Knee
      Documentation Committee (IKDC) evaluation system, 177 (33.6%) patients were
      classified as normal (group A), 211 (40%) as nearly normal (group B), 109 (20.7%)
      as abnormal (group C) and 30 (5.7%) as severely abnormal (group D). The highest
      correlation coefficients were recorded between the IKDC evaluation system and the
      Lysholm score (p = 0.66), the patients' subjective evaluation (p = 0.53), the
      Tegner activity level (p = 0.34), all the laxity tests (p > or = 0.34) and the
      one-leg-hop test (p = 0.28). The resumption of sporting activities and work as
      evaluated by the Tegner activity level correlated with the patients' subjective
      evaluation (p = 0.34) but did not correlate with the laxity tests, i.e., the
      manual Lachman test (p = -0.06) and the total and anterior KT-1000 tests (p = 
      0.06). Furthermore, none of the laxity tests correlated with the functional tests
      or the patients' subjective evaluation. We conclude that the IKDC evaluation
      system is a reliable and useful tool for evaluating the post-operative outcome
      after an ACL reconstruction.

PMID- 10401653
TI  - Ultrasound evaluation of gravity induced anterior drawer following anterior
      cruciate ligament lesion.
AB  - Ultrasound is not so far a standard procedure to visualize the anterior drawer
      following anterior cruciate ligament (ACL) lesions. This is because the described
      techniques are either technically difficult or depend on the experience of the
      performer and are not standardized. The purpose of this prospective analysis on
      ACL intact, ACL deficient and ACL reconstructed knees was to compare the
      diagnostic accuracy of prone ultrasonographic Lachman testing with KT-1000
      measurements in the same study population. Our technique is based on a prone
      position of the patient. The thigh lies on the table surface such that the
      patella has no contact. The lower leg is placed on a roll in the ankle area and
      flexed to 30 degrees . The transducer (5 MHz) is positioned over the medial
      aspect of the popliteal fossa to visualize the femoral condyle as well as the
      tibial head. Under ultrasound control the lower leg is manually lifted as far the
      thigh stays in contact with the surface defining the start position. The lower
      leg is then released and drawn by gravity into the anterior drawer position, the
      final position. The distance between the posterior tangent from the medial
      femoral condyle to the medial tibial plateau was registered by three independent
      ultrasound measurements of the injured knee. The uninvolved opposite knee served
      as an internal control. The same procedure was done using a KT-1000 device (89
      and 133 Newton and manual maximum force). The patients were split into two
      groups: acute injury (A), and (B) 6 months following ACL repair with a patellar
      tendon graft. All patients then underwent arthroscopy. In group A with acute ACL
      lesions the anterior drawer resulted in 14.1 mm (+/- 3.5) and was significantly
      (P < 0.001) different from the contralateral knee (7.7 mm +/- 2.9). The KT 1000
      showed a comparable difference with 14.4 mm (+/- 3.9) for the injured knee and
      8.3 mm (+/- 3.4) for the uninjured (P < 0.001). Sonometrically, group B patients
      showed no clear difference between the repaired (9.9 mm +/- 2.7) knee and its
      control (8.1 mm +/- 2.5). This was found for the KT-1000 results as well. The
      results derived from the ultrasound evaluation of the anterior drawer correlated
      well with those from the KT-1000 (r = 0.46). Based on a minimum intra-individual
      difference of 5 mm in the ultrasound measured anterior drawer, the sensitivity of
      the test in group A resulted in 0.96, and the specificity in 0.98. The described
      technique is reproducible, painless and easy to perform in order to evaluate
      acute ACL tears using any commercially available ultrasound device. The
      reproducibility is similar to the KT-1000 device. We recommend this technique for
      use in cases of acute ACL tears as well as in the follow-up of ACL repair.

PMID- 10401654
TI  - Medium-term results of the operative treatment of recurrent patellar dislocation
      by Insall proximal realignment.
AB  - Between 1984 and 1991, 36 patients with the diagnosis of recurrent patellar
      dislocation were treated operatively using the proximal realignment procedure.
      Thirty patients were available for follow-up. The average follow-up period was
      6.3 years (range 2-9.6 years). The average age at injury was 21.3 years with a
      predominance of female patients. At follow-up all knees were physically examined.
      The results were evaluated using the score of Larsen and Lauridsen as well as the
      Tegner score and subjective assessment. Radiographs from 19 patients (63%) were
      available for review. At follow-up one patient suffered from a recurrence of
      patellar dislocation. All patients had stable knee joints and a full range of
      motion. There was no statistically significant difference between pre- and
      postoperative sports activity level. Seven patients (23.3%) had excellent
      results, 12 patients (39.9%) good results and 1 a poor result using the Larsen
      and Lauridsen score. Subjective assessment revealed the operative result as very
      good, good or satisfactory in 90%. Patellofemoral osteoarthritis was seen in 7 of
      19 patients (36.8%). With a proximal realignment procedure good clinical results
      can be achieved for recurrent patellar dislocation. Subjective satisfaction with
      this procedure is rated as good. It is successful in preventing redislocation.

PMID- 10401655
TI  - Distribution of substance-P nerve fibers in the knee joint in patients with
      anterior knee pain syndrome. A preliminary report.
AB  - The etiology of pain in anterior knee pain syndrome is a matter of controversy.
      The normal, articular cartilage is aneural, so defects in the surface are not
      thought to produce pain. Some authors have sought the origin of the pain in soft
      tissue structures around the knee. Knowledge of the distribution of nociceptive
      nerve fibers around the knee would provide insight for treating anterior knee
      pain syndrome. Twenty consecutive patients (28 knees), all women, with anterior
      knee pain syndrome (group I) participated in the study. For comparison we used
      two groups of patients: 20 patients with an osteoarthritic knee (group II) and 20
      patients with anterior cruciate ligament rupture or meniscal lesion with no
      history of pain in the anterior compartment (group III). Immunohistochemical
      techniques using a monoclonal antibody to substance-P (SP) were employed to
      identify nociceptive fibers. For statistical analyses we used the one-way ANOVA
      test, which was corrected with the LSD test, at the level of significance P <
      0.05. Results of the study demonstrate that SP-immunoreactive nerve fibers are
      widespread within the soft tissues around the knee. These tissues include the
      retinaculum, synovium, fat pad and, in some circumstances, bone. In cases of
      anterior knee pain, the presence of neuropeptide-containing fibers was
      statistically significant in the medial retinaculum (P < 0.005) and in the fat
      pad (P < 0.001) compared to group III, and compared to group II (P < 0.05 and P <
      0.007, respectively). For lateral retinaculum this relationship was not so
      statistically strong (P < 0.02) and was equal in comparison between anterior knee
      pain patients (group I) and group II or group III. There were no statistically
      significant differences in the distribution of substance-P nerve fibers in the
      fat pad, lateral and medial retinaculum or synovium between groups II and III.
      The results of this study provide immunohistochemical evidence suggesting that
      pain may originate in the fat pad and medial retinaculum of many patients with
      anterior knee pain syndrome.

PMID- 10401656
TI  - Reduced degenerative articular cartilage changes after meniscal allograft
      transplantation in sheep.
AB  - The objective of this study was to examine the gross changes after meniscal
      allograft transplantation with reference to the development of degenerative
      articular cartilage changes (DACC) and to examine the transplant behavior. The
      medial menisci of both knees in 32 Iceland sheep were operated on with either
      sham operation (C6), medial meniscectomy (M6), primary transplantation (P6), or
      secondary transplantation 3 months after meniscectomy (S6). These sheep were
      observed for 6 months. Another six sheep were observed for 3 months after
      meniscectomy (M3) and contralateral sham operation (C3). The DACC of the knee
      were visualized with an intra-articular toluidine blue injection. The
      dissemination area of DACC on the medial tibial plateau (MTP), the meniscal area,
      and the meniscus-free, exposed central area on the MTP were measured by computer
      image analysis based on digitized photos of the tibial plateau. These area
      measurements were calculated relative to the area of the MTP. The DACC in P6
      knees had a mean of 4.3%, which was less than the 12.6% in M6 (P < 0.001) and the
      16.1% in S6 (P < 0.001), but more pronounced than the 0.5% in C6 (P < 0.005).
      There were no detectable differences in DACC between M6, S6 and M3 (16.9%). The
      measurements of DACC were reproducible with correlation coefficient r = 0.97 on
      intra-tester test-retest measurements. The area of the free exposed MTP was
      larger in P6 and in S6 than in C6 (P < 0.001), demonstrating a displacement of
      the graft. S6 transplants showed shrinkage and were smaller than C6 menisci (P <
      0.01). In conclusion, primary meniscal allograft transplantation reduced DACC
      within 6 months in sheep knees, but DACC were still present in transplanted
      knees. The meniscal transplants demonstrated peripheral displacement.

PMID- 10401657
TI  - Arthroscopic lavage reduced the recurrence rate following primary anterior
      shoulder dislocation. A randomised multicentre study with 1-year follow-up.
AB  - Young individuals have a high recurrence rate following non-operative treatment
      of traumatic primary anterior shoulder dislocation. The present multicentre study
      was undertaken to find out whether the results could be improved by using
      arthroscopic lavage as treatment. Sixty patients aged 16-30 years, with traumatic
      primary anterior shoulder dislocation were randomised into two groups. One group
      was treated with arthroscopic lavage within 10 days, while the other group was
      treated non-operatively. Rehabilitation was otherwise identical. At 1-year follow
      up, 4 of 30 patients (13%) in the lavage group had had redislocation compared
      with 13 of 30 (43%) in the group treated non-operatively (P = 0.01). The
      difference in recurrence rate was more pronounced in younger patients. The
      functional outcome according to the Rowe shoulder score was better in the lavage
      group (P = 0.003), as was the anterior stability according to the apprehension
      test (P = 0.008). We conclude that arthroscopic lavage reduced the recurrence
      rate and produced a better functional outcome at 1-year follow-up than the non
      operative treatment in young individuals.

PMID- 10401658
TI  - A gene therapy approach to accelerating bone healing. Evaluation of gene
      expression in a New Zealand white rabbit model.
AB  - It has been demonstrated that BMPs, IGFs, and TGFbetas improve the process of
      bone healing in vivo. We have suggested the use of gene therapy as a possible way
      to deliver growth factors to fracture sites in order to improve repair. The aim
      of this study was to develop a minimally invasive gene therapy approach to treat
      bone injuries locally without damaging the local blood circulation. A segmental
      defect of 1.3 cm was created in the diaphysis of the femur in mature NZW rabbits.
      Internal fixation with 7-hole DCP plates and 2.7 mm screws was used to stabilize
      the bone. After building a chamber by tightly closing the muscles around the
      segmental defect, 0.5 ml of either saline solution or a collagen gel containing 1
      x 10(10) particles of adenovirus carrying cDNA encoding either the bacterial beta
      galactosidase gene (LacZ), or the firefly luciferase gene were injected into the
      gap. The control side received 0.5 ml of saline solution without virus particles.
      Bone marrow, cortical and trabecular bone and surrounding muscle were harvested
      from the injected femur and were analyzed for local gene expression through X-gal
      staining or measurement of local luciferase activity. To determine whether
      distant sites were transduced, tissue from the spleen, liver, and lung were
      harvested as well as bone, bone marrow and muscle from the contralateral
      diaphysis of the femur. The delivery of the adenoviral vector suspended in saline
      solution led to local transduction of the bone, bone marrow and the muscle
      surrounding the gap. No luciferase activity was found in the contralateral femur,
      lung, or spleen, and only transient luciferase activity was seen in the liver.
      While marker gene expression persisted within the surrounding soft tissues for at
      least 2 weeks, the expression in bone lasted up to 6 weeks. This study has shown
      that it is possible to use adenoviral vectors to transfer and express genes
      locally within a segmental defect. Gene expression persisted for several weeks,
      which may be already sufficient to accelerate repair.

PMID- 10401659
TI  - Response to thyrotropin of normal thyroid follicular cell strain FRTL5 in
      hypergravity.
AB  - Thyroid hormones control every cell in the organisms and, as indicated by many
      hormonal changes in astronauts during and shortly after space missions, its
      complex regulation may be influenced by gravity. To test in vitro the effects of
      gravity environment on thyroid, we selected a unique cultured cell system: the
      FRTL5, a normal follicular thyroid cell strain in continuous culture, originally
      derived from adult rat thyroids. To establish if modifications of the
      gravitational environment may interfere with post-receptorial signal transduction
      mechanisms in normal mammalian cultured cells, following our previous
      microgravity experiments, we exposed thyrotropin-stimulated and unstimulated
      FRTL5 cells to hypergravity (5 g and 9 g) in a special low-speed centrifuge. At
      all thyrotropin doses tested, we found significant increases in terms of cyclic
      AMP production in FRTL5 thyroid cells. The data here reported correlate well with
      our previous microgravity data, showing that the FRTL5 cells functionally respond
      to the variable gravity force in a dose-dependent manner in terms of cAMP
      production following TSH-stimulation.

PMID- 10401660
TI  - Inhibition of farnesylation blocks growth but not differentiation in FRTL-5
      thyroid cells.
AB  - The cholesterol lowering drug lovastatin, a competitive inhibitor of 3-hydroxy-3
      methylglutaryl coenzyme A (HMG-CoA) reductase, blocks DNA synthesis and
      proliferation of thyrotropin (TSH) primed FRTL-5 rat thyroid cells. The blockade
      can be completely prevented and/or reversed by mevalonate and largely prevented
      and/or reversed by farnesol whereas cholesterol and/or other non-sterol
      mevalonate derivatives such as ubiquinone, dolichol or isopentenyladenosine are
      ineffective. TSH-dependent augmentation of cyclic-AMP and cAMP dependent
      differentiated functions, such as iodide uptake, are unaffected by lovastatin. 3H
      Thymidine incorporation into DNA is also decreased by alpha-hydroxyfarnesyl
      phosphonic acid, an inhibitor of protein farnesylation which mimicks the effect
      of lovastatin since it also leaves unaffected TSH stimulated iodide uptake. It is
      suggested that the HMG-CoA reductase inhibitor lovastatin affects cell
      proliferation mainly through inhibition of protein farnesylation which results in
      altered function proteins relevant for proliferation control, notably p21ras
      and/or other small GTPases.

PMID- 10401661
TI  - Effects of thyroid-stimulating hormone on the replicative cycle of vesicular
      stomatitis virus in primary cultured sheep thyroid cells.
AB  - Sheep thyroid cells in primary culture are highly sensitive to thyroid
      stimulating hormone (TSH). We infected thyroid cells with vesicular stomatitis
      virus (VSV) in the course of studies on cell polarity, and we found that TSH
      augmented the speed of the replicative cycle of VSV but did not affect the final
      yield of the virus. Three hours post-infection, at a multiplicity of infection of
      10, the virus was detected in the cell layer of the cultures incubated with TSH
      but not in those without TSH. Five hours post-infection, there was a 100-fold
      increase in the medium in the yield of VSV and a 60-fold increase in the cell
      associated virus in the TSH-treated cells compared with the cells without TSH. We
      found that the early stages of infection were accelerated by TSH. This effect
      appears to be due, at least in part, to increased processing in the lysosomes,
      thus allowing deposition of the transcriptionally-active nucleocapsid into the
      cytoplasm. These studies show that TSH is critically involved in the infectivity
      of VSV and that by manipulating cell culture conditions, an increased rate of
      virus production can be achieved.

PMID- 10401662
TI  - DNA binding affinity of hTRbeta1 mutants as heterodimers with traps from
      different tissues.
AB  - Patients with generalized resistance to thyroid hormone (GRTH) show various organ
      specific features, for example mental retardation, growth abnormalities, liver
      damage, delayed bone age or cardiac disorders. Could this reflect aberrant mutant
      thyroid hormone receptor beta1 (TRbeta1) heterodimerization with specific TR
      auxiliary proteins (TRAPs) from different tissues, altering the mutant's ability
      to transactivate tissue-specific genes? To answer this question, we examined the
      heterodimerization of TRbeta1 mutants and TRAPs of several rat tissues (cerebrum,
      cerebellum, liver, heart, lung, spleen, and kidney), and in vitro translated
      RXRalpha, beta and gamma by electrophoretic gel mobility shift assay (EMSA).
      Mutant TRbeta1 proteins, synthesized in reticulocyte lysate, were incubated with
      32P rat malic enzyme (rME) thyroid hormone response elements (TRE) and nuclear
      extracts of rat tissues. The TRbeta1 mutants used were Mf (G345R), and GH
      (R316H). Both have non-detectable T3 binding affinity. GH has weak dominant
      negative effect and Mf has strong dominant negative effect. Two major bands were
      observed in EMSA. Cerebrum, cerebellum, lung and liver extracts formed a slower
      migrating band than a TR homodimer, while kidney extracts formed a faster
      migrating band, and heart and spleen extracts had both bands. There were no
      qualitative differences in heterodimerization between TRbeta1wt, and TRbeta1
      mutants, when using tissue extracts and DNA in excess ratio to TR. We found that
      RXRalpha, beta, and gamma were differentially expressed in each rat tissue and
      formed heterodimer complexes with wild type (WT) TRbeta1. Scatchard analysis of
      affinity and capacity of the binding of TR-TRAP heterodimers to response elements
      was performed by competing with 2.5-, 5-, 10-, 25-, and 250-fold excess non
      radiolabeled rME-TRE. When using kidney extract, the DNA binding affinity of
      heterodimers was significantly decreased both in wild type and mutant TRs,
      suggesting that the DNA binding affinity of the faster migrating band was lower
      than that of the slower migrating band. Mutant GH, which causes 'pituitary RTH'
      and shows weak dominant negative effect, tended to form heterodimers with lower
      DNA binding affinity than TRbeta1wt with all extracts. Mutant Mf, which has
      strong dominant negative effect, tended to show higher DNA binding affinity than
      TRbeta1WT. When the data were pooled for all tissues, GH and Mf were found to
      form heterodimers with significantly lower, or higher, affinity for TREs than
      TRbeta1wt. These results indicate that: 1) differences of DNA binding affinity of
      mutant TR-TRAP heterodimers to response elements in DNA play a part in its
      reduced or strong dominant negative effect; and 2) differences in formation of
      heterodimers with TRAPs present in tissues do not appear to explain the apparent
      tissue-specific and mutant-specific variations seen in RTH.

PMID- 10401663
TI  - Identification and characterization of mRNAs differentially expressed in thyroid
      cells stimulated by a mitogenic treatment.
AB  - The aim of our work is to identify new genes and proteins involved in the control
      of the proliferation of thyroid cells as putative protooncogenes and
      antioncogenes. Several strategies are discussed. A first study has allowed to
      identify three new genes. Further search will use the differential display and
      gene arrays methodology. The role of the identified proteins coded by the genes
      is studied in vitro by the search of partner proteins by the double hybrid method
      and in vivo by mice gene knockout technology.

PMID- 10401664
TI  - Induction of apoptosis in porcine thyroid follicles by transforming growth factor
      beta1 and epidermal growth factor.
AB  - For thyroid cells in culture DNA fragmentation and morphological changes related
      to apoptosis were first described in dog thyroid cells after deprivation of
      serum, epidermal growth factor or thyrotropin. With intact porcine thyroid
      follicles in three-dimensional culture, the effect of deprivation of growth
      factors and of incubation with transforming growth factor beta1 (TGF-beta1),
      epidermal growth factor (EGF), thyrotropin (TSH) or insulin-like growth factor I
      (IGF-I) on the incidence of apoptosis was studied. Thyroid follicles were
      embedded in growth factor-depleted Matrigel and cultured in serum-free medium
      with or without growth factors for 7 days followed by incubation for 4, 24 and 72
      h with TGF-beta1 (2 or 5 ng/mL). The percentage of apoptotic cells was determined
      by direct counting in electron-microscopy. Approximately 1% of apoptotic bodies
      could be detected in unstimulated follicles. This was unchanged in the presence
      of TSH (1 mU/mL) or IGF (10 ng/mL) but significantly increased up to 3.99 +/-
      1.24% with 2 ng/mL of EGF. After incubation with TGF-beta apoptosis increased
      dose-dependently to 4.05 +/- 0.67% with 2 ng/mL TGF-beta1 and 5.16 +/- 1.75% with
      5 ng/mL TGF-beta1. The incidence of necrotic cells remained constant at about 1
      to 2%. Preincubation of follicles with 2 ng/mL of EGF followed by incubation with
      5 ng/mL TGF-beta1 increased the rate of apoptic bodies up to 13.19 +/- 1.9%. We
      conclude that growth factor depletion in thyroid follicles in three-dimensional
      culture does not lead to apoptosis. TGF-beta1, however, induces apoptosis even in
      quiescent thyroid follicular cells and is significantly more pronounced in
      growing thyroid cells. EGF, which is a dedifferentiating growth factor for
      thyroid cells, also induces apoptosis. As EGF enhances TGF-beta1 mRNA and protein
      in thyroid follicular cells, the induction of apoptosis by EGF might also be due
      to TGF-beta1.

PMID- 10401665
TI  - Thyroid-specific enhancer-binding protein/thyroid transcription factor 1 is not
      required for the initial specification of the thyroid and lung primordia.
AB  - Targeted disruption of the homeobox gene T/ebp (Ttf1) in mice results in ablation
      of the thyroid and pituitary, and severe deformities in development of the lung
      and hypothalamus. T/ebp is expressed in the thyroid, lung, and ventral forebrain
      during normal embryogenesis. Examination of thyroid development in T/ebp
      homozygous null mutant embryos revealed that the thyroid rudiment is initially
      formed but is eliminated through apoptosis. Absence of T/EBP expression in the
      lung primordium does not activate apoptosis since a lung tissue, albeit
      dysmorphic, is nevertheless formed in T/ebp-/- embryos. These results demonstrate
      that T/EBP is not required for the initial specification of thyroid or lung
      primordia, but is absolutely essential for the development and morphogenesis of
      these organs.

PMID- 10401666
TI  - Thyroglobulin regulates follicular function and heterogeneity by suppressing
      thyroid-specific gene expression.
AB  - Thyroglobulin (TG) is the primary synthetic product of the thyroid and the
      macromolecular precursor of thyroid hormones. TG synthesis, iodination, storage
      in follicles, and lysosomal degradation can each modulate thyroid hormone
      formation and secretion into the circulation. Thyrotropin (TSH), via its receptor
      (the TSHR), increases thyroid hormone levels by upregulating expression of the
      sodium iodide symporter (NIS), thyroid peroxidase (TPO), and TG genes. TSH does
      this by modulating the expression and activity of the thyroid-specific
      transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8,
      which coordinately regulate NIS, TPO, TG, and the TSHR. Major histocompatibility
      complex (MHC) class I gene expression, which is also regulated by TTF-1 and Pax-8
      in the thyroid, is simultaneously decreased; this maintains self tolerance in the
      face of TSH-increased gene products necessary for thyroid hormone formation. We
      now show that follicular TG, 27S > 19S > 12S, counter-regulates TSH-increased
      thyroid-specific gene transcription by suppressing the expression of the TTF-1,
      TTF-2, and Pax-8 genes. This decreases expression of the TG, TPO, NIS and TSHR
      genes, but increases class I expression. TG action involves an apical membrane TG
      binding protein; however, it acts transcriptionally, targeting, for example, a
      sequence within 1.15 kb of the start of TTF-1 transcription. TG does not affect
      ubiquitous transcription factors regulating TG, TPO, NIS and/or TSHR gene
      expression. TG activity is not duplicated by thyroid hormones or iodide. We
      hypothesize that TG-initiated, transcriptional regulation of thyroid-restricted
      genes is a normal, feedback, compensatory mechanism which regulates follicular
      function, regulates thyroid hormone secretion, and contributes to follicular
      heterogeneity.

PMID- 10401667
TI  - An adenosine receptor agonist-induced modulation of TSH-dependent cell growth in
      FRTL-5 thyroid cells mediated by inhibitory G protein, Gi.
AB  - Adenosine has been shown to modulate the TSH-induced DNA synthesis in FRTL-5
      thyroid cells. The mechanism of this adenosine action has been somewhat
      controversial because both A1 adenosine receptor-mediated and non-receptor
      mediated mechanisms have been proposed. We have now reexamined our preliminary
      finding of the inhibitory action of a non-metabolizable adenosine derivative, N6
      (L-2-phenylisopropyl)adenosine (PIA), on the TSH-induced DNA synthesis to clarify
      the adenosine-dependent mechanism of cell growth modulation. PIA dose-dependently
      inhibited the TSH-induced DNA synthesis expressed by [3H]thymidine incorporation
      into DNA. This adenosine derivative also prevented the TSH-induced entry of the
      cell cycle to the S phase at 24 h of culture and the increase in cell number at
      48 h. These PIA actions on different aspects of TSH-dependent cell growth were
      abolished by the treatment of the cells with pertussis toxin, suggesting the
      involvement of Gi in the PIA action mechanism. Dibutyryl cAMP-induced DNA
      synthesis was not influenced by PIA. In concert with our previous finding that
      PIA in a similar concentration range inhibited TSH-induced cAMP production
      through the adenosine A1 receptor, the present results strongly support the idea
      that the major pathway of adenosine signaling for the inhibition of the TSH
      induced cell proliferation is through the A1 adenosine receptor-Gi system.

PMID- 10401668
TI  - Mechanisms of apical protein sorting in polarized thyroid epithelial cells.
AB  - The process leading to thyroid hormone synthesis is vectorial and depends upon
      the polarized organization of the thyrocytes into the follicular unit. Thyrocyte
      membrane proteins are delivered to two distinct domains of the plasma membrane
      using apical (AP) and basolateral (BL) sorting signals. A recent hypothesis for
      AP sorting proposes that apically destined proteins cluster with
      glycosphingolipids (GSLs) and cholesterol, into microdomains (or rafts) of the
      Golgi membrane from which AP vesicles originate. In MDCK cells the human
      neurotrophin receptor, p75hNTR, is delivered to the AP surface through a sorting
      signal, rich in O-glycosylated sugars, identified in its ectodomain. We have
      investigated whether this signal is functional in the thyroid-derived FRT cell
      line and whether p75hNTR clusters into lipid rafts to be sorted to the AP
      membrane. We found that p75hNTR is apically delivered via a direct pathway and
      does not associate with rafts during its transport to the surface of FRT cells.
      Therefore, although the same signal could be recognized by different cell types
      thyroid cells may possess a tissue-specific sorting machinery.

PMID- 10401669
TI  - Urokinase-type plasminogen-activator and normal thyroid cell adhesion to the
      extracellular matrix.
AB  - The urokinase-type plasminogen activator receptor (uPA-R) focuses the proteolytic
      activity of its ligand, the urokinase-type plasminogen activator (uPA), on the
      cell surface, and can also act as an adhesion receptor for vitronectin (VTN). uPA
      increases uPA-R affinity for VTN and is also able to cleave its receptor. We have
      previously shown that uPA-R is involved in the adhesion of normal thyroid cells
      to VTN. In the present report, we have investigated the effect of uPA on normal
      thyroid cell adhesion to some extracellular matrix (ECM) components. We show that
      a short-term treatment with uPA does not change normal thyroid cell adhesion to
      fibronectin (FNT), collagen (CGN), laminin (LMN) and VTN. The prolongation of uPA
      treatment increases cell adhesion to VTN, and, less efficiently, to other ECM
      components. Since the short term uPA treatment causes a partial cleavage of uPA
      R, that does not increase with time, the observed increase in cell adhesivity
      cannot be related to the cleavage of uPA-R. We show that the adhesion improvement
      after the long term uPA treatment is instead due to a strong increase of the cell
      surface expression of the integrin beta3 and a moderate increase of the integrin
      alpha(v). Both alpha(v) beta3 and alpha(v) beta1 are integrinic receptors for
      VTN.

PMID- 10401670
TI  - Amphibian metamorphosis as a model for studying the developmental actions of
      thyroid hormone.
AB  - The thyroid hormones L-thyroxine and triiodo-L-thyronine have profound effects on
      postembryonic development of most vertebrates. Analysis of their action in
      mammals is vitiated by the exposure of the developing foetus to a number of
      maternal factors which do not allow one to specifically define the role of
      thyroid hormone (TH) or that of other hormones and factors that modulate its
      action. Amphibian metamorphosis is obligatorily dependent on TH which can
      initiate all the diverse physiological manifestations of this postembryonic
      developmental process (morphogenesis, cell death, re-structuring, etc.) in free
      living embryos and larvae of most anurans. This article will first describe the
      salient features of metamorphosis and its control by TH and other hormones.
      Emphasis will be laid on the key role played by TH receptor (TR), in particular
      the phenomenon of TR gene autoinduction, in initiating the developmental action
      of TH. Finally, it will be argued that the findings on the control of amphibian
      metamorphosis enhance our understanding of the regulation of postembryonic
      development by TH in other vertebrate species.

PMID- 10401672
TI  - Biochemical characterization of a Ca2+/NAD(P)H-dependent H2O2 generator in human
      thyroid tissue.
AB  - An NAD(P)H-dependent H2O2 forming activity has been evidenced in thyroid tissue
      from patients with Grave's disease. Its biochemical properties were compared to
      those of the NADPH oxidase previously described in pig thyroid gland. Both were
      Ca2+-dependent and activated by inorganic phosphate anions in the same range of
      concentrations. Both are flavoproteins using FAD as cofactor, but the human
      enzyme was also able to utilize FMN. The apparent Km for NADPH of the human
      enzyme (100 microM) was 5-10 times higher than that of porcine enzyme. Vm was 3
      to 10 times higher in pig (150 nmol x h(-1) x mg(-1)) than in man (14 to 45).
      Total content in human tissue was 7 to 9% of that in porcine tissue. An
      unidentified inhibitor has been detected in the 3000 g particulate fraction from
      most patients, which could account for this apparently low enzyme content. An
      NADH-dependent H2O2 production has also been observed in porcine and human
      thyroid tissues. This activity was only partly Ca2+-dependent (man, 50-70%; pig,
      80-90%) and presented similar apparent Km values for NADH (man, 100 microM; pig,
      200 microM). In pig thyrocytes, the expression of the Ca2+-dependent part of the
      NADH-oxidase activity was induced by TSH and down-regulated by TGFbeta, as was
      the NADPH oxidase activity. Furthermore, NADPH and NADH-dependent activities were
      not additive. We conclude that a single, inducible, NAD(P)H-oxidase can use NADPH
      or NADH as substrate to catalyse H2O2 formation, and that human and porcine
      NAD(P)H-oxidases are highly similar. Differences observed could be attributed to
      minor differences in enzyme structure and/or in membrane microenvironment. The
      NADH-dependent Ca2+-independent activity observed in human and porcine thyroid
      fractions could be attributed to a distinct and constitutive enzyme.

PMID- 10401671
TI  - Endogenous insulin-like growth factors regulate the proliferation of TSH
      independent mutants derived from FRTL5 cells.
AB  - TSH-independent mutant clones (M cells) derived from FRTL5 cells, proliferate
      vigorously in the absence of TSH. The growth of M cells is stimulated by IGF-I in
      a dose-dependent fashion, but it is not influenced by TSH. Sm1.2, an antibody
      against IGF-I cross-reacting with IGF-II, significantly decreases basal DNA
      synthesis in the M cells. Binding of 125I-IGF-I to M cells is significantly lower
      than that to FRTL5 cells. M cells produce in their culture medium IGF-like
      peptides which appear to influence their basal DNA synthesis and the availability
      of type I receptors to bind exogenous IGF-I.

PMID- 10401673
TI  - Control of galectin gene expression.
AB  - In this review we summarize the available information on the expression of
      mammalian galectins in normal and transformed cells. From all these studies it is
      apparent that each cell might express most of galectins; yet, during development
      or in various differentiation stages or under different physiological or
      pathological conditions, one or more galectins are preferentially expressed in
      each cell type. This implies a fine control of gene expression and suggests that
      such control should be coordinated. Nevertheless, to date very few studies have
      been performed on the mechanisms responsible for the regulation of galectin
      genes. We review the current knowledge on galectin promoter function. We believe
      that this area of galectin research will expand rapidly in the near future.

PMID- 10401674
TI  - Thyroid-specific gene expression in the multi-step process of thyroid
      carcinogenesis.
AB  - Thyroid-specific transcription factors TTF-1 and Pax-8 play a decisive role in
      the determination and maintenance of cellular phenotype activating thyroglobulin
      (Tg), thyroperoxidase (TPO), thyrotropin receptor (TSH-R) and the sodium/iodide
      symporter (NIS) gene transcription. In the present work, we have studied the
      expression of TTF-1 and Pax-8 and their target genes in samples derived from
      thyroid neoplasms of follicular origin, as well as in medullary carcinoma (MTC),
      obtained from surgery or from fine needle aspiration (FNA) biopsies. The results
      show that TTF-1 and Pax-8 are expressed in well differentiated adenomas and that
      their expression decreases in less differentiated papillary and follicular
      carcinomas and is lost in undifferentiated anaplastic carcinomas. Parallel levels
      of Tg, TPO and TSH-R expression were found in the same neoplasm samples.
      Interestingly TSH-R and TTF-1 gene expression was found in MTC samples.
      Furthermore, the expression of the thyroid-specific genes and their transcription
      factors is lost in thyroid cells derived from follicular, papillary and
      anaplastic human carcinomas. In these cells, Tg, TPO and TSH-R promoter
      activities were absent. Cotransfection with expression vectors for TTF-1 and Pax
      8 resulted in the stimulation of transcription to a different extent for each
      promoter. These results may be clinically relevant for the evaluation and
      prognosis of thyroid cancer since the loss of specific markers correlates with
      the degree of tumor differentiation.

PMID- 10401675
TI  - Different mutations of the RET gene cause different human tumoral diseases.
AB  - The RET gene encodes a tyrosine kinase receptor for neurotrophic molecules. RET
      is a conceptually valuable example of how different mutations of a single gene
      may cause different diseases. Gene rearrangements activate the oncogenic
      potential of RET in human thyroid papillary carcinomas. On the other side,
      different point mutations activate RET in familial multiple endocrine neoplasia
      syndromes. Finally, inactivating mutations of RET can be present in
      Hirschsprung's disease patients. The detailed knowledge of the specific RET
      mutations responsible for human tumors provides relevant tools for the clinical
      management of these diseases. Moreover, the recent discovery of the growth
      factors which in vivo stimulate its signaling may shed new light on the role
      played by RET in the development and differentiation of the central and
      peripheral nervous system.

PMID- 10401676
TI  - Insulin/IGF-I hybrid receptors play a major role in IGF-I signaling in thyroid
      cancer.
AB  - The insulin-like growth factor-I (IGF-I) plays an important role in determining
      the biological behavior of a variety of malignancies. We measured IGF-I, its
      receptor and related receptors in thyroid cancer. IGF-I was present both in
      normal thyroid tissue and in thyroid cancer tissue and it was produced by stromal
      cells but not by thyrocytes. Values were significantly higher in malignant than
      in normal tissue. IGF-I receptors (IGF-I-Rs) and the homologous insulin receptors
      (IRs) were found overexpressed in both thyroid cancer cell lines (n = 4) and
      specimens (n = 17) as compared to normal values. In addition, high levels of
      hybrid IGF-I/insulin receptors (IR/IGF-I-Rs) were present in both thyroid cancer
      specimens and cell lines. IR/IGF-I-R hybrids were the most represented type of
      receptor in 14/17 specimens and exceeded the IGF-I-R content in all cases. Hybrid
      content correlated with the IR and IGF-I-R content, suggesting that in thyroid
      tissue hybrid formation occurs by random assembly of IR and IGF-I-R half
      receptors. Hybrid receptor autophosphorylation was stimulated by IGF-I with high
      affinity. In cells with a high IR/IGF-I-Rs content, blocking antibodies specific
      to these receptors substantially inhibited IGF-I induced cell growth. These data
      indicate that the IGF-I system is overactivated in thyroid cancer and that IR/IGF
      I-R hybrid receptors play an important role in IGF-I mitogenic signaling in these
      tumors.

PMID- 10401677
TI  - Summary of observations on transplantable tumors of the rat thyroid gland.
AB  - Transplantable tumors of the thyroid gland have been produced by feeding of
      thiouracil (TU) to inbred Fischer 344 rats followed by the transplantation,
      initially, of pieces of hyperplastic thyroid gland, and in later generations, of
      pieces of transplanted tissue into similar rats or into rats fed a high iodine
      diet. In early generations, transplants grew only in the rats fed the TU diet,
      and this tissue was called dependent, whereas if the tissue grew in rats fed the
      high iodine diet in the absence of TU, it was called independent. Dependent
      tumors were, initially, either papillary or of follicles distended with colloid.
      Later generations of some sublines were cellular or microfollicular in pattern
      and some became progressively more heterogeneous with later generations.
      Independent tumors began to appear by the third transplant generation. They were,
      initially, relatively uniform in pattern, and some tended to remain so, whereas
      other sublines exhibited some heterogeneity. Tumors had patterns that were
      cellular, or microfollicular, or follicular or had open follicles, etc.; there
      was one cellular ascites tumor subline. Other observations were made of vascular
      patterns, connective tissue, necrosis, and metastases.

PMID- 10401678
TI  - Studies on the dermal and systemic bioavailability of polycyclic aromatic
      compounds in high viscosity oil products.
AB  - The assessment of skin penetration by viscous oil products is an important
      element in the risk assessment of these materials where skin contact is likely.
      Systemic bioavailability (body uptake) is viewed as a good indicator of skin
      penetration following cutaneous exposures. The results of this study provide
      quantitative information on the influence of viscosity on the bioavailability of
      a specific polycyclic aromatic compound (benzo(a)pyrene) in base oils, residual
      aromatic extracts and bitumens following skin exposures to mice. The materials
      studied were a base mineral oil (viscosity 32 cSt at 35 degrees C), a 1:1 blend
      of the mineral base oil and a residual aromatic extract (198 cSt), several
      residual aromatic extracts (ca. 5000 cSt, 35 degrees C) and a range of bitumens
      (0.65-69 x 10(6) cSt, 35 degrees C). These were each spiked with 0.1%
      radiolabelled benzo(a)pyrene, as a representative carcinogenic polycyclic
      aromatic compound, then used for cutaneous exposures to mice. The results
      indicate that as viscosity increased in the range ca. 30 to 5000 cSt (base oil to
      residual aromatic extract) the uptake of the radiolabelled benzo(a)pyrene into
      blood was reduced by ca. fivefold. Further increases in viscosity from ca. 5000
      to 69 x 10(6) cSt (i.e. residual aromatic extract to bitumen) resulted in a
      further but smaller (ca. twofold) reduction in uptake. The relationship between
      the amounts of free benzo(a)pyrene measured in blood and viscosity showed the
      same trend. This trend was also mirrored by the degree of binding of
      benzo(a)pyrene metabolites to DNA in skin. The findings in mouse skin in vivo
      indicate that viscosity can significantly affect skin penetration and systemic
      bioavailability of polycyclic aromatic compound components of oil products.
      Results obtained with viable human skin in vitro also showed that the
      bioavailability of benzo(a)pyrene was reduced by the viscosity of the oil product
      matrix. It is thus necessary to take account of physical properties such as
      viscosity in the overall risk assessment of viscous oil products, particularly in
      the case of very viscous materials such as bitumens. The significantly reduced
      bioavailability of hazardous compounds from undiluted materials is thus an
      important factor to consider when assessing the risks from dermal exposures.

PMID- 10401680
TI  - Imipramine- and mianserin-induced acute cell injury in primary cultured rat
      hepatocytes: implication of different cytochrome P450 enzymes.
AB  - The antidepressants, imipramine and mianserin, have been reported to cause liver
      damage. We investigated a role of cytochrome P450 (CYP)-mediated formation of a
      reactive metabolite in antidepressant-induced acute cell injury using hepatocytes
      isolated from male and female Wistar rats, and male Dark Agouti rats, which have
      different relative abundance of CYP enzymes. Culture of the hepatocytes with
      imipramine and mianserin caused a marked decrease in glutathione followed by
      protein thiol, which preceded lactate dehydrogenase leakage. The decreases in
      glutathione and protein thiol contents by imipramine were significantly slower in
      hepatocytes from male Dark Agouti rats than those from male Wistar rats, whereas
      no significant sex difference in Wistar rats was observed. The decrease in thiol
      by mianserin was significantly slower in hepatocytes from female Wistar than
      those from male Wistar rats, whereas no significant differences were found
      between Wistar and Dark Agouti males. Results consistent with alteration of the
      thiols were obtained for lactate dehydrogenase leakage induced by imipramine and
      mianserin. These findings indicated that CYP-mediated metabolic activation was
      involved in acute cell injury induced by the antidepressants; namely a CYP2D
      enzyme(s), which is deficient in Dark Agouti rats, and a male specific CYP
      enzyme(s) were suggested to be responsible for the cytotoxicity of imipramine and
      mianserin, respectively.

PMID- 10401679
TI  - Effects of N-nitrosodimethylamine (NDMA) on the oxidative status of rat liver.
AB  - To investigate oxidative effects of N-nitrosodimethylamine (NDMA) on the liver,
      rats were challenged by the reagent with a dose range of 10 to 40 mg/kg. With
      lower dose levels, protective responses were prominent, such as elevation of the
      hepatic glutathione and metallothionein (MT) levels. Increased activities were
      also evident of gamma-glutamylcysteine synthetase, glucose-6-phosphate
      dehydrogenase (G6PD), and malic enzyme. In the high dose range, however, toxic
      responses, such as increases in lipid peroxide levels in liver and serum, and
      glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), and
      ketone bodies in serum became marked. Some of the protective responses became
      less marked at the highest dose. Catalase and glutathione peroxidase activities
      in the liver were also inhibited by NDMA treatment. On the other hand, when NDMA
      was injected as a series of doses (10 mg/kg on four separate occasions), the
      effects were less marked, and the hepatic levels of MT and lipid peroxide
      remained unchanged even after the 4th injection. Only the increase in G6PD
      activity was more marked after four times repeated injection than after a single
      injection. These results suggest that oxidative and hepatotoxic effects of NDMA
      are more moderate when given in repeated doses than in a single dose. In contrast
      to the liver, elevation of MT levels was the only detectable change in the
      kidney.

PMID- 10401682
TI  - T cell-dependent immune reactions to reactive benzene metabolites in mice.
AB  - Using the popliteal lymph node (PLN) assay in mice, we studied the sensitizing
      potential of benzene and its metabolites. Whereas benzene and phenol failed to
      induce a PLN reaction, catechol and hydroquinone induced a moderate, and p
      benzoquinone a vigorous response. Following a single injection of the reactive
      metabolite p-benzoquinone (100 nmol/mouse), cellularity in the draining PLN was
      increased > 15-fold, and reverted back to normal only after approximately 100
      days. Although the PLN response was T cell-dependent, flow cytometric analysis
      revealed that the increased cellularity in the PLN after a single injection of p
      benzoquinone was mainly due to an increase in B cells. Mice primed to p
      benzoquinone and challenged with a small dose of p-benzoquinone (0.1 nmol/mouse)
      mounted a secondary PLN reaction, indicating hapten specificity of the reaction;
      this was confirmed by results obtained in the adoptive transfer PLN assay. An
      unexpected finding was the secondary PLN response to benzene (1 nmol/mouse)
      observed in mice primed to p-benzoquinone. This finding suggests that some of the
      benzene (at least 10%) was locally converted into p-benzoquinone, which then
      elicited the secondary response observed. In conclusion, the reactive
      intermediate metabolites hydroquinone and p-benzoquinone can act as haptens and
      sensitize; their precursors, benzene and phenol, may be considered as prohaptens.

PMID- 10401683
TI  - Immunotoxicity of the anticancer drug CI-994 in rats: effects on lymphoid tissue.
AB  - CI-994 (acetyldinaline) is an investigative oral anticancer drug currently in
      clinical trials. To characterize the effects of CI-994 on lymphoid tissue, male
      rats were administered single oral doses at 0 (vehicle control), 10, 23, and 45
      mg/kg and killed up to 7 days after dosing for evaluation of white blood cell
      differentials, bone marrow differentials, lymphoid tissue weights, and selected
      histopathology of lymphoid tissue. Statistically significant dose-related
      reductions in blood lymphocytes (CD-3+, CD-4+, CD-8+, CD-20+), monocytes,
      neutrophils, and bone marrow lymphoid cells were observed in all drug-treated
      groups on days 1 and/or 3. Statistically significant reductions in bone marrow
      myeloid cells were also observed on days 1 and 3 at 23 and 45 mg/kg. Complete or
      partial reversal of most parameters was evident on day 7. Spleen and/or thymus
      weights were significantly decreased in the groups administered 23 and 45 mg/kg
      on days 1, 3, and/or 7. Minor reductions in lymphoid organ weights were noted at
      10 mg/kg. Minimal to moderate lymphoid depletion of the spleen and thymus was
      noted on day 3 in animals dosed at 23 mg/kg. In vitro, CI-994 inhibited mitogen
      stimulated blood lymphocyte proliferation with a 50% inhibitory concentration
      (IC50) value of 3 microM. The results demonstrate that CI-994 can effect lymphoid
      tissue in rats within 1 day of a single oral dose, that effects are generally
      reversible within 7 days, and that inhibition of lymphocyte proliferation is a
      sensitive indicator of CI-994 immunotoxicity in vitro.

PMID- 10401681
TI  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated membrane translocation of c
      Src protein kinase in liver WB-F344 cells.
AB  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental
      contaminant and the most potent agonist of the aryl hydrocarbon receptor (AhR).
      Persistent activation of the AhR has been shown to be responsible for most TCDD
      mediated toxic responses, including liver tumour promotion. However, the
      mechanisms responsible for these complex toxic reactions are still unknown. TCDD
      (1 nM) has previously been shown to reduce DNA synthesis of primary hepatocyte
      cultures and cell contact inhibition of confluent WB-F344 cells. The latter model
      was used to study early effects of TCDD on protein tyrosine kinase c-Src in
      confluent WB-F344 cells. It was found that TCDD decreased cytosolic c-Src
      (protein and tyrosine kinase activity) after 20-60 min, and increased c-Src in
      the membrane fraction. Membrane translocation of c-Src occurred in the presence
      of 100 microM cycloheximide and was observed after treatment with 1 nM TCDD or 50
      nM 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin. Under these conditions epidermal
      growth factor (EGF) receptor tyrosine phosphorylation was also studied. As
      expected, its phosphorylation was low in confluent cells but was significantly
      enhanced by TCDD treatment. Pretreatment of WB-F344 cells for 1 h with 1 microM
      geldanamycin, which disrupts cytosolic heat shock protein Hsp90 complexes with
      AhR and Src, abolished TCDD-mediated Src translocation and TCDD-mediated
      reduction of cell contact inhibition. The WB-F344 cell model appears to be very
      useful to study TCDD effects on protein tyrosine kinases and of signaling
      pathways responsible for modulation of the cell cycle by TCDD.

PMID- 10401684
TI  - Suppression of uterine decidualization as a cause of implantation failure induced
      by triphenyltin chloride in rats.
AB  - In our previous study, triphenyltin chloride (TPTC1) was found to induce
      implantation failure, as preimplantation embryonic loss, in rats. In this study,
      the effects of TPTC1 on the uterine function, as a cause of implantation failure,
      were determined using pseudopregnant rats. Female rats were given TPTC1 by
      gastric intubation at 3.1, 4.7, and 6.3 mg/kg on pseudopregnant day (PPD) 0 to
      PPD 3 and the decidual cell response was induced on PPD 4. The uterine weight on
      PPD 9 served as an index of uterine decidualization. A significant decrease in
      the uterine weight, which indicates suppression of the uterine decidualization,
      was detected at 4.7 and 6.3 mg/kg. In our previous study, these doses induced a
      significant increase in implantation failure in female rats given TPTC1 on
      gestational day (GD) 0 to 3. The ovarian weight and number of corpora lutea in
      the TPTC1-treated groups were comparable to that of the controls. A significant
      decrease in serum progesterone levels after administration of TPTC1 was found at
      4.7 and 6.3 mg/kg. These findings suggest that implantation failure due to TPTC1
      may be mediated via the suppression of uterine decidualization and correlated
      with the reduction in serum progesterone levels.

PMID- 10401685
TI  - Development of a carcinogenic potency index for dermal exposure to viscous oil
      products.
AB  - Polycyclic aromatic compounds (PACs) present in oil streams and formulated
      products are important determinants of possible carcinogenicity. Following dermal
      exposures the transport of the PACs from oil (the carrier) into the skin is a
      factor that may affect macromolecular (DNA) adduct formation and thus determine
      carcinogenicity. We have developed a mathematical model, which describes the flux
      into the skin for a representative carcinogenic PAC, benzo(a)pyrene. The model is
      based on measurements of the amount of benzo(a)pyrene bound to skin DNA or blood
      observed in mouse skin painting studies. The degree of adduct formation from a
      particular oil product, which we term the Bioavailability Index (BI), was shown
      to be a function of both the viscosity of the oil product, which affected the
      transport of the PAC through the carrier, and the aromaticity, which affected the
      partition of PAC between the carrier and the skin. Literature data were analysed
      from mouse skin painting studies with mineral oils of known carcinogenicity. A
      linear relationship was shown between the amount of DNA adduct formation,
      expressed as alkylation frequency, and the arithmetic product of the total (3-6)
      ring PAC content and the BI, which we have termed the Carcinogenic Potency Index
      (CPI). Comparison of literature data on DNA alkylation frequencies for oil
      products and their carcinogenicity indicated that oils giving rise to an
      alkylation frequency below a certain threshold (ca. 1 adduct in 10(8)
      nucleotides) are non-carcinogenic to mouse skin. This threshold level can be
      translated into a value for the CPI, below which the genotoxic carcinogenic risk
      arising from skin contact with the oil product is considered to be negligible.
      The CPI for bitumens is well below this value, being both due to the low BI from
      bitumen, but more so, due to their low PAC content. For some bitumens diluted
      with solvents, i.e. cutback-bitumens, the CPI may exceed this value, indicating a
      possible carcinogenic risk for some of the cutback-bitumens. The main determining
      factor is the PAC content which is principally determined by the nature of the
      diluent used.

PMID- 10401686
TI  - The Peter Emil Becker Award lecture 1998. The saga of congenital muscular
      dystrophy.
AB  - The first credible descriptions of congenital muscular dystrophy (CMD) were made
      at the beginning of this century but the individuality of this condition had
      difficulty to be accepted because its distinction from other types of childhood
      neuromuscular disorders was far from clear. The reports of different clinico
      pathological phenotypes of CMD and recently of immunocytochemical and molecular
      genetic studies allowed the precise definition of specific entities within the
      group of CMD. Here we present the historical background of CMD, its vicissitudes
      and the main steps leading to the individualisation of the merosin-deficient CMD
      to which the author has contributed. Mention is also made to major achievements
      in the characterisation of other types of CMD, namely the Fukuyama CMD, the
      muscle-eye-brain disease and a peculiar form of CMD with the rigidity of the
      spine. Animal models of merosin-deficient congenital muscular dystrophy were
      identified and their current study may lead to a better understanding of the
      pathogenesis of the human disease and to therapeutic strategies.

PMID- 10401687
TI  - Dopamine receptor upregulation in Lesch-Nyhan syndrome: a postmortem study.
AB  - The brains of two patients with Lesch-Nyhan syndrome (LNS) were studied. The
      concentration of dopamine was decreased in the caudate nucleus of LNS patients.
      Immunohistochemical methods revealed that the dopamine (DA) D1 and D2 receptor
      and methionine-enkephalin immunoreactivities (IRs) were increased in the putamen,
      and less significantly in the caudate nucleus. The D1 and D2 receptor IRs of the
      cingulate cortex, the tryptophan-hydroxylase IR in the dorsal nucleus of the
      midbrain, as well as the substance P and methionine-enkephalin IRs of the
      nociception-conducting structures, including the periaqueductal gray and spinal
      trigeminal nucleus, were not changed. Tyrosine-hydroxylase IR was not decreased
      in the substantia nigra of the LNS patients. Therefore, the cause of the
      decreased dopaminergic activity in LNS may not be involved in the production of
      tyrosine hydroxylase in the substantia nigra. Developmental abnormalities due to
      the DA defect at an early age might exist in the postsynaptic structure in the
      striatum.

PMID- 10401688
TI  - Clinical and genetic correlate in childhood onset Friedreich ataxia.
AB  - We analyzed the clinical and genetic aspects of 28 FRDA patients from 20
      families. 19 families were consanguineous. The onset was between 4 and 13 1/2
      years of age (mean 15.4 +/- 6.2). Three patients presented with cardiomyopathy,
      one with weakness, and the rest with ataxia. There were two patients with
      preserved lower-limb deep tendon reflexes. Sensory nerve action potentials were
      reduced in 14/14 patients. Cardiac echograms were abnormal in 17/19 cases, and
      this was between 6 and 16 years of age (mean 10.1 +/- 3.5). Four families were
      multiplex. Clinical intra-familial variability was observed. Increased GAA
      repeats of the X25 gene were found in 27/28 patients studied, all in a homozygous
      state. 88.9% of patients had a smaller allele larger than 500 repeats, and 66.7%
      had more than 700 repeats. The patient who did not have increased GAA repeats in
      both alleles had peculiar findings. Significant correlation of expansion was
      obtained for the early onset, and cardiomyopathy as the onset.

PMID- 10401690
TI  - Neonatal neurological examination in infants with hypoxic ischaemic
      encephalopathy: correlation with MRI findings.
AB  - Neurological examination and magnetic resonance imaging were performed in the
      neonatal period in 58 full-term infants who presented with hypoxic-ischaemic
      encephalopathy. The aim of this study was to evaluate the patterns of
      neurological abnormalities and their correlation to brain lesions on MRI. The
      prognostic value of the neurological examination performed at different times in
      the neonatal period was also evaluated. Our results showed that specific clinical
      patterns can be observed in infants with HIE and these can be related to the
      pattern of lesion on brain MRI. In particular, while infants with normal MRI or
      minimal changes tend to show only minor tone abnormalities after the first week
      of life, infants with more severe lesions such as basal ganglia lesions show
      persistent and diffuse neurological abnormalities. Infants with white matter
      changes but intact basal ganglia show a different clinical pattern with improved
      sucking reflex and behaviour and less severe tone abnormalities. Our results also
      suggested that the neurological examination performed after the second week of
      life is a reliable indicator of outcome in these infants.

PMID- 10401689
TI  - Gross and fine motor development is impaired in children with cyanotic congenital
      heart disease.
AB  - Many factors may intervene with the motor development of children with congenital
      heart disease (CHD). Children aged 5 to 14 years with various CHD were examined
      for disturbances of gross and fine motor development using motometric tests and
      compared with 30 healthy controls. The results of the Korperkoordinationstest fur
      Kinder (KTK) (a body coordination test for children) for gross motor development
      were significantly lower in patients with uncorrected cyanotic CHD (motor
      quotient MQ 74.8 +/- 11.7, mean +/- 1 standard deviation, n = 16) and after
      corrective surgery (MQ 81.2 +/- 16.6, n = 25) than in controls (MQ 102.8 +/-
      11.8, n = 30). No relationship between these results and the cardiopulmonary
      exercise capacity was found. In patients with cyanotic CHD, significant deficits
      in fine motor development were present before corrective surgery (e.g.
      Zielpunktiertest [dotting] MQ 87.7 +/- 9.9 vs. 106.5 +/- 10.8), but already two
      years afterwards the results reached nearly normal values (MQ 97.1 +/- 17.0). In
      contrast, children with acyanotic CHD demonstrated normal gross and fine motor
      development. These results indicate that long-standing hypoxemia in infancy must
      be considered as an important cause of the pronounced motor disturbances. Early
      neurological evaluation of these children and a specialized motor physiotherapy
      are recommended.

PMID- 10401691
TI  - A neurodystrophic syndrome resembling carbohydrate-deficient glycoprotein
      syndrome type III.
AB  - A 10-month old girl is described with a serum transferrin isoform abnormality of
      the same kind as in two previously reported girls with carbohydrate-deficient
      glycoprotein syndrome type III. This patient presented with joint abnormalities
      and rapidly developing hypsarrhythmia, hypotonia, psychomotor delay and growth
      retardation. Fingers, toes, nails and local skin were dysmorphic. She had pale
      optic discs, thoracic syringomyelia and frontal lobe atrophy at three months. The
      CDT value in serum was greatly elevated. Several carbohydrate-deficient isoforms
      were found in transferrin (four), alpha1-antitrypsin (three), antithrombin (two)
      and thyroxine-binding globulin (four). Mutations in the CDGS 1-gene were
      excluded. The CDGS III glycoprotein abnormality most probably represents a
      distinct disorder of glycoprotein metabolism, and needs to be considered in
      unclear hypsarrhythmia with developmental delay. Dysmorphic features may be added
      to this syndrome.

PMID- 10401692
TI  - Pontocerebellar hypoplasia associated with respiratory-chain defects.
AB  - Pontocerebellar hypoplasias are congenital disorders of brain morphogenesis which
      include such diverse etiologies as carbohydrate-deficient glycoprotein syndrome
      type 1, cerebromuscular dystrophies (Walker-Warburg syndrome, Fukuyama syndrome,
      muscle-eye-brain disease) and at least two types of autosomal recessive
      neurodegenerations known as pontocerebellar hypoplasia type I and II.
      Pontocerebellar hypoplasia type 1 is a lethal phenotype and clinical features
      include congenital contractures, respiratory insufficiency, central and
      peripheral motor dysfunction and spinal anterior horn degeneration. Type 2 is
      characterized by progressive microcephaly, extrapyramidal dyskinesia and normal
      spinal cord findings. In this paper, we describe a girl, born at 33 weeks of
      gestation, presenting with respiratory insufficiency and multiple contractures.
      MRI scan of the brain demonstrated pontocerebellar hypoplasia and cortical and
      diffuse periventricular white matter abnormalities. Postmortem examination showed
      pontocerebellar hypoplasia with extensive gliosis of the periventricular white
      matter and of the basal ganglia with normal spinal cord findings. Histology of
      skeletal muscle was normal. Biochemical analysis demonstrated multiple
      deficiencies of respiratory chain enzymes in skin fibroblasts. This case
      demonstrates a lethal phenotype of pontocerebellar hypoplasia without spinal cord
      abnormalities associated with a respiratory-chain disorder. The diagnostic workup
      in a patient whose brain image shows pontocerebellar hypoplasia should include a
      search for respiratory-chain impairment.

PMID- 10401693
TI  - Chorea as the presenting clinical feature of primary antiphospholipid syndrome in
      childhood.
AB  - Three patients, aged five to 16 years, developed chorea as the only or main
      clinical manifestation of primary antiphospholipid syndrome. In two cases,
      complaints were self-limited five to eight months after onset. In one patient,
      the clinical course was complicated by valvulitis. Under corticosteroid
      treatment, chorea disappeared and cardiac involvement stabilised. Primary
      antiphospholipid syndrome is a probably under-recognised differential diagnosis
      of choreatic syndromes in childhood. Assessment of anticardiolipin antibodies
      and/or lupus anticoagulant should be an obligatory part of the diagnostic work-up
      of such patients. Early diagnosis of primary antiphospholipid syndrome may
      improve clinical management and prognosis.

PMID- 10401694
TI  - Benign infantile familial convulsions: natural history of a case and clinical
      characteristics of a large Italian family.
AB  - We present a patient (3 months old) with partial and generalized seizures who has
      a family history of seizures with a onset during the first 12 months of life. We
      diagnosed benign infantile familial convulsions (BIFC) and we did not introduce
      any antiepileptic therapy. We present clinical data of her family where 18 out of
      35 members were affected; to our knowledge this is the largest family with BIFC.
      BIFC is transmitted as an autosomal dominant trait; recently it has been reported
      that the gene for BIFC maps to the long arm of chromosome 19. We conducted
      linkage analysis in our family providing significant exclusion of linkage between
      the BIFC locus phenotype and chromosome 19 markers, suggesting that a second
      locus is involved in this family.

PMID- 10401695
TI  - Oligogyric microcephaly.

PMID- 10401696
TI  - Dacrystic seizures reconsidered.

PMID- 10401697
TI  - Treatment with 17beta-oestradiol does not influence age and weight at puberty in
      Bos indicus heifers.
AB  - The working hypothesis was that treatment of heifers with 17beta-oestradiol (E2)
      during specific periods of prepuberty would reduce the response of the
      hypothalamic-pituitary axis to E2 negative feedback and induce an earlier onset
      of puberty. The effects of chronic treatment with exogenous E2 administered at
      specific maturational phases on the age and weight at puberty were studied in 96
      prepubertal Brahman (3/4-7/8 Bos indicus) heifers (187.0 +/- 3.3 days of age,
      mean +/- SEM), weighing 149.9 +/- 2.5 kg. Heifers were randomly assigned to one
      of six groups (n = 16 per group). Groups 2-6 received E2 implants (Compudose 200)
      for 90-day periods starting at 10, 13, 16, 19 and 22 months of age, while animals
      in group 1 remained untreated. Implants were placed subcutaneously at the base of
      the ear. Blood was collected for progesterone (P4) determination by
      radioimmunoassay (RIA) and the animals were weighed at monthly intervals from 6
      to 15 months then weekly from 15 to 28 months of age. Puberty was defined by
      concentrations of P > 1 ng/ml in plasma and identification of a corpus luteum
      (CL) by transrectal ultrasonography (Aloka 210DX:7.5 MHZ probe). Treatment with
      exogenous E2 at any of the ages/treatment intervals evaluated in this study did
      not reduce age or weight at puberty (P > 0.7). The mean age and weight at puberty
      of control heifers was 735.3 +/- 19.7 days (range: 597-861) and 299.2 +/- 10.2 kg
      (range: 233-382), respectively, which is greater than the age and weight at
      puberty of 481 days and 246 kg, that was previously reported for B. indicus
      heifers [Post, T.B., Reich, M.M., 1980. Puberty in tropical breeds of heifers as
      monitored by plasmaprogesterone. Proceedings of the Australian Society of Animal
      Production 13, 61-62.]. The large variation in age and weight at puberty that was
      observed in the present study among heifers might indicate an individual animal
      effect to E2 treatment among some of the treated animals. The lengthy interval
      from birth to puberty observed in this study, as compared to other studies,
      reflects the effects of other factors such as genotype, environmental or
      nutritional influences on puberty.

PMID- 10401698
TI  - Effect of ovarian steroids and oxytocin on the production of prostaglandin E2,
      prostaglandin F2alpha and endothelin-1 from cow oviductal epithelial cell
      monolayers in vitro.
AB  - Cyclic physio-anatomical variation in the oviducts is mediated by the local
      countercurrent transfer of ovarian products. Thus, in this study cow oviductal
      epithelial cells (COEC) culture were utilized to investigate the effects of
      ovarian products such as progesterone (P4), estradiol 17beta (E2) and oxytocin
      (OT) on local oviductal prostaglandin E2 (PGE2), F2alpha (PGF2alpha) and
      endothelin-1 (ET-1) production. COEC were collected from non-pregnant Holstein
      cows (n = 8) during the follicular phase and cultured in M199 under standard
      culture conditions until monolayer formation. Cells in first passage were
      incubated for 24 or 48 h with P4 (500 ng/ml), E2 (1 ng/ml), OT (10(-9) M) or
      combination of E2 + P4. Administration of E2 significantly increased the
      production of PGE2, PGF2alpha and ET-1. However, simultaneous administration of
      P4 blocked the effect of E2. OT did not show any effect on oviductal productions
      of either PGs or ET-1. The results of this study show that E2 stimulates PG and
      ET-1 production by COEC in vitro. Thus, it can be suggested that locally
      transferred E2 from the ovarian follicles may be important for oviductal
      contraction and gamete/zygote transport during the peri-ovulatory period.

PMID- 10401699
TI  - Development and viability of bovine preplacentation embryos treated with
      swainsonine in vitro.
AB  - This study investigated the effects of swainsonine (a locoweed toxin) on bovine
      preplacentation embryo development using in vitro procedures. We examined and
      confirmed the viability and developmental potential of swainsonine-treated
      embryos by transfer to synchronized recipient heifers. Oocytes (n = 6338) were
      aspirated from ovaries collected from the abattoir and subjected to in vitro
      maturation (IVM), in vitro fertilization (IVF) and in vitro culture (IVC).
      Swainsonine was added to IVM, IVF, IVC media spatially and IVM/IVF/IVC
      continuously, at 0 ng/ml (TRTI, control), 200 ng/ml (TRT2), 400 ng/ml (TRT3), and
      800 ng/ml (TRT4). Embryo development was evaluated with respect to oocyte
      cleavage rate and the rates of morula and blastocyst formation. There was no
      difference (P > 0.05) among treatments. The average number of nuclei per
      blastocyst at Day 7.5 of culture (Day 0 = IVF) was 85.9 +/- 4.3 (n = 47) and 89.3
      +/- 4.4 (n = 44) for swainsonine-treated embryos (800 ng/ml) and control embryos,
      respectively. Pregnancy rate as determined by ultrasonography on day 35 to 40
      post embryo transfer was 43.8% and 38.3% for swainsonine-treated (800 ng/ml) and
      control embryos, respectively. Nine (9.4%) healthy calves were delivered from
      heifers receiving swainsonine-exposed and nine (9.6%) from control embryos. No
      difference (P > 0.05) was detected in number of calves developing from TRT and
      control embryos. We conclude that swainsonine does not have an adverse effect on
      the development and viability of preplacentation bovine embryos.

PMID- 10401700
TI  - Changes in follicular populations following treatment of buffaloes with PMSG
      (eCG) and Neutra-PMSG for superovulation.
AB  - Some 19 buffaloes were synchronized by administration of a prostaglandin (PG)
      salt Lutalyse, with a single intramuscular (i.m.) injection of 25 mg at day -13.
      Luteolysis was induced by administration of 50 mg PG, in divided doses of 30 and
      20 mg i.m. 12 h apart on day 0 of experiment. The 30 mg PG injection was
      designated as 0 h of experiment. Group I animals (n = 6) received saline and
      served as controls while animals in Groups II (n = 7) and III (n = 6) received
      2500 I.U. PMSG (eCG) i.m. at day -2. Group III animals were administered 5 ml
      Neutra-eCG intravenously at 60 h. The number of follicles, classified on the
      basis of diameter as small (2-5 mm), medium (6-9 mm) and large (> or = 10 mm) was
      assessed by ultrasonography on days -2, -1, 0, 1, 2, 5 and 7 of experiment. The
      number of corpora lutea (CL) was recorded by palpation per rectum on day 8. The
      number of small follicles which did not differ among the three groups on days 0,
      1 and 2 was significantly lower (P < 0.05) in Group II animals compared to those
      in Groups I and III on days 5 and 7. The number of medium follicles increased
      after eCG treatment and was significantly higher (P < 0.05) in animals of Groups
      II and III on days 0 and 1, compared to control animals of Group I. It was,
      however, not different among the three groups on subsequent days of experiment.
      The number of large follicles which did not differ among the three groups on days
      -2, 0, 1 and 2 was significantly higher in Groups II (P < 0.01) and III (P <
      0.05) animals compared to those of Group I on day 5. On day 7, the number of
      large follicles was in the order (P < 0.05) Group II > Group III > Group I. The
      number of CL in Group II animals was significantly higher (P < 0.05) than that in
      Group I animals but was not different from that of Group III animals. These
      results suggest that treatment of buffaloes with eCG for superovulation reduces
      the number of small follicles and increases the number of large follicles 5-7
      days after PG treatment. Administration of Neutra-eCG 60 h after PG treatment can
      partly reverse this trend but has no effect on ovulation rate. The possibility
      that part of the variability in ovulation rates in this study may have resulted
      from Neutra-eCG been given prior to or at the LH surge, or from the absence or
      presence of a dominant follicle at the time of eCG treatment cannot be ruled out.

PMID- 10401701
TI  - Effect of the interval of serial sections of ovarian tissue in the tissue chopper
      on the number of isolated caprine preantral follicles.
AB  - The present work investigated the effect of the interval of serial sections of
      ovarian tissue on the number of isolated preantral follicles in the goat. Goat
      ovaries were cut in the tissue chopper at eight different intervals. The quality
      of isolated follicles were evaluated by histology and transmission electron
      microscopy. Best results were obtained when the ovaries were cut in the tissue
      chopper at intervals of 75.0 microm (9664 preantral follicles per ovary).
      Histochemical and ultrastructural analysis showed that the follicular morphology
      was preserved after mechanical isolation as demonstrated by the normality of
      oocytes and granulosa cells as well as by preservation of basement membrane. The
      percentages of isolated primordial, primary and secondary follicles were 96.3%,
      2.5%, and 1.2% and their average diameters were 21.5, 34.7 and 65.3 microm,
      respectively. It was concluded that the interval of serial sections of ovarian
      tissue in the tissue chopper affects the number of isolated preantral follicles,
      and that the follicles remained intact after mechanical isolation in goats.

PMID- 10401702
TI  - In vitro interactions of cryopreserved stallion spermatozoa and oviduct (uterine
      tube) epithelial cells or their secretory products.
AB  - Formation of a spermatozoa ('sperm') reservoir in the mare is thought to occur
      through lectin-mediated sperm attachment to the oviductal epithelium. Once
      attached, prefertilization sperm survival is supported by oviductal factors.
      Cryopreservation of stallion sperm decreases the number of sperm attaching to
      oviduct epithelial cells (OEC) and the length of time these sperm survive.
      Quantification of in vitro interactions between sperm and OEC in a co-culture
      system may provide an assay for functional integrity of cryopreserved or fresh
      sperm samples. Additionally, superior additives for in vitro handling of stallion
      sperm may be isolated from OEC secretory products. Experiment 1 compared first
      service conception (FSC) rates resulting from the use of cryopreserved sperm of
      seven stallions, with sperm function in co-culture such as attachment to OEC and
      subsequent survival time. Stallions were grouped by cumulative FSC rates observed
      over three seasons as having average (44 +/- 3%) or high (65 +/- 2%) fertility
      over a total of 217 first services (31 +/- 9 per stallion). Samples from
      stallions in the high fertility group had more (P = 0.04) sperm attached to OEC
      and longer subsequent sperm survival in co-culture (P = 0.05) as compared with
      those from the average fertility group. FSC rates correlated with numbers of
      sperm attaching to OEC and their survival time in co-culture (r > or = 0.71). In
      Experiment 2, the function of cryopreserved stallion sperm was evaluated in
      culture with OEC secretory products from three different sources. After 5 h of
      culture, sperm incubated with medium conditioned by bovine OEC which had been
      'bioactivated' (e.g. previously exposed to sperm in culture) were found to be
      more (P < or = 0.05) motile and capacitated as compared to sperm in basal TALP
      medium alone. Sperm in this conditioned medium also survived longer (P = 0.05; 27
      +/- 5 h vs. 17 +/- 4 h) than did those in control medium.

PMID- 10401703
TI  - Comparison of cyclic AMP production in response to LH by granulosa and theca
      cells from Meishan and Large-White hybrid gilts.
AB  - Previous experiments have demonstrated differences in various follicular
      characteristics between the prolific Chinese Meishan (MS) pig and European Large
      White (LW) hybrids and the present experiment was designed to compare the cAMP
      response to LH by granulosa and theca cells in vitro between the two breeds.
      Ovaries were recovered from MS (n = 7) and LW hybrid (n = 8) gilts on the day
      before predicted oestrus and the 12 largest follicles dissected. Quadruplicate
      aliquots of granulosa cells or minced theca tissue were incubated for 1 h in the
      presence of 0, 0.1, 1.0, 10, 100 or 1000 ng/ml LH and cAMP production measured.
      Follicles from MS gilts were smaller (5.9 vs. 7.7 mm; P < 0.001), contained less
      fluid (81.5 vs. 177.4 microl; P < 0.001), had fewer granulosa cells (3.8 vs. 5.3
      x 10(6); P < 0.01) and less theca tissue (30.3 vs. 50.5 mg; P < 0.05) than those
      from LW hybrid animals. Mean follicular fluid oestradiol concentration was > or =
      149 ng/ml in all animals and tended to be higher in the MS follicles (P = 0.07).
      LH stimulated cAMP production by granulosa and theca cells from both breeds (P <
      0.001). Although there was no overall breed effect for the granulosa cells, there
      was a significant (P < 0.001) interaction between LH dose and breed in the
      granulosa cells, whether cAMP production was expressed per 10(6) cells or per
      follicle. In the theca incubations, cAMP production by MS tissue was higher (P <
      0.01) when results were expressed per mg tissue and again there was an
      interaction (P < 0.001) between LH dose and breed whether cAMP production was
      expressed per mg tissue or per follicle. For both tissue types, MS follicles
      produced more cAMP at the higher LH doses. In conclusion, this study has shown
      that MS granulosa and theca tissue respond differently to increasing doses of LH
      in terms of cAMP production in vitro compared to LW hybrid tissue and this
      supports previous suggestions of enhanced maturity of MS follicles in the late
      follicular phase.

PMID- 10401704
TI  - Enterochromaffin cells in the stomach of the rat after prolonged administration
      of cortisol and both cortisol and salmon calcitonin.
AB  - Young adult male Wistar rats (eight controls and ten experimental animals per
      group) were injected parenterally for 28 days: 1) cortisol or 2) cortisol and
      salmon calcitonin. Morphological changes of the stomach wall and enterochromaffin
      cells, stained immunocytochemically for serotonin, were assessed. In the group
      treated with cortisol superficial desquamation and erosions of the gastral mucosa
      were found. In this group the number of enterochromaffin cells was significantly
      decreased and low intensity of the immunocytochemical reaction of these cells was
      observed. In the cortisol-calcitonin-treated group there were no apparent changes
      of the gastral mucosa and the enterochromaffin cells presented a normal picture
      comparable to that of controls.

PMID- 10401705
TI  - The effects of food restriction on maternal endocrine adaptations in pregnant
      rats.
AB  - The aim of this study was to characterize hemodynamic, electrolytic and endocrine
      alterations produced by food restriction (50%) in pregnant rats for the purpose
      of evaluating the importance of these parameters on the plasma volume expansion
      and fetal growth. One hundred seventy six pregnant rats were divided into two
      groups, a control group (C) with an ad libitum diet and another with a restricted
      diet (U) (50% by weight of the diet of the control group). On days 5, 10, 15 and
      20 of pregnancy, the weight of the mother, water intake, urine output, urine and
      plasma sodium concentration, plasma potassium concentration, blood pressure and
      heart rate, osmolality, plasma renin activity (PRA) and vasopressin were
      recorded. The number and weight of the fetuses were determined on days 15 and 20
      of gestation. Food restriction results in inadequate weight gain in the mother
      and retardation of fetal growth. Water and sodium balance (p< or =0.001) were
      decreased in U group and basal PRA (p< or =0.001) was increased in U group. Food
      restriction did not significantly alter urine sodium excretion, plasma
      osmolality, plasma sodium and potassium values, blood pressure and basal
      vasopressin values. We conclude that the higher values of PRA, described in food
      restriction situations during pregnancy, seem to be caused by the adaptation to
      low sodium intake.

PMID- 10401706
TI  - Effects of two years of growth hormone (GH) replacement therapy on bone
      metabolism and mineral density in childhood and adulthood onset GH deficient
      patients.
AB  - The aim of the current study was to evaluate bone metabolism and mass before and
      after 2 years of GH replacement therapy in adults with childhood or adulthood
      onset GH deficiency. Thirty-six adults with GH deficiency, 18 with childhood
      onset, 18 with adulthood onset GH deficiency and 28 sex-, age-, height- and
      weight-matched healthy subjects entered the study. Biochemical indexes of bone
      turnover such as serum osteocalcin, serum carboxyterminal telopeptide of type-I
      procollagen, urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine,
      of soft tissue formation such as aminoterminal propeptide of type-III and bone
      mineral density were evaluated. Childhood onset GH deficient patients had
      significantly decreased bone (osteocalcin: 2.5+/-1.3 vs 6.6+/-4.8 mcg/l, p<0.001)
      and soft tissue formation (aminoterminal propeptide of type III: 273+/-49 vs
      454+/-23 U/I, p<0.001) indexes and normal bone resorption indexes (serum
      carboxyterminal telopeptide of type-I procollagen: 105+/-48 vs 128+/-28 mcg/l
      p=NS; urinary hydroxyproline/creatinine: 0.19+/-0.16 vs 0.28+/-0.16 mmol/mol,
      p=NS; urinary deoxypyridinoline/creatinine: 21 +/-10 vs 25+/-8 mcmol/mol, p=NS)
      compared to healthy subjects. On the contrary, no significant difference in bone
      turnover indexes between adulthood onset GH deficient patients and healthy
      subjects was found. Moreover, significantly decreased bone mineral density at any
      skeletal site and at whole skeleton was found in GH deficient patients compared
      to healthy subjects (e.g. femoral neck: 0.74+/-0.13 vs 0.97+/-0.11 g/cm2,
      p<0.001). In addition, a significant reduction of bone mineral density was found
      in childhood compared to adulthood onset GH deficient patients at any skeletal
      site, except at femoral neck. After 3-6 months of treatment, both groups of
      patients had a significant increase in bone turnover and in soft tissue
      formation. In particular, in childhood onset GH deficient patients after 3 months
      osteocalcin increased from 2.5+/-1.3 to 7.9+/-2.1 mcg/l, p<0.001 aminoterminal
      propeptide of type-III from 273+/-49 to 359+/-15 U/I p<0.001; serum
      carboxyterminal telopeptide of type-I procollagen from 105+/-48 to 201+/-45
      mcg/l, p<0.001; urinary hydroxyproline/creatinine from 0.19+/-0.16 to 0.81+/-0.17
      mmol/mol, p<0.001; urinary deoxypyridinoline/creatinine from 21 +/-10 to 54+/-20
      mcmol/mol, p<0.001; while in adulthood onset GH deficient patients after 6 months
      osteocalcin increased from 4.2+/-3.6 to 6.5+/-1.9 mcg/l, p<0.05; aminoterminal
      propeptide of type- III from 440+/-41 to 484+/-37 U/I, p<0.05; serum
      carboxyterminal telopeptide of type-I procollagen from 125+/-40 to 152+/-22
      mcg/l, p<0.05; urinary hydroxyproline/creatinine from 0.24+/-0.12 to 0.54+/-0.06
      mmol/mol, p<0.001; urinary deoxypyridinoline/creatinine from 23+/-8 to 42+/-5
      mcmol/mol, p<0.001. No significant difference in bone turnover between pre- and
      post-treatment period was found after 18-24 months of GH therapy. Conversely,
      bone mineral density was slightly reduced after 3-6 months of GH therapy, while
      it was significantly increased after 18-24 months. In fact, femoral neck bone
      mineral density values significantly rose from 0.74+/-0.13 g/cm2 to 0.87+/-0.11
      g/cm2 (pre-treatment vs 2 years of GH treatment values). In conclusion, patients
      with childhood or adulthood onset GH deficiency have osteopenia that can be
      improved by long-term treatment with GH.

PMID- 10401707
TI  - The role of nitric oxide in the control of basal and LHRH-stimulated LH
      secretion.
AB  - The gaseous transmitter nitric oxide (NO) appears to be involved in the control
      of LH secretion and in the modulation of LH responses after stimulation with
      luteinizing hormone releasing hormone (LHRH), excitatory amino acids (EAAs) and
      leptin. The regulatory action of NO in the control of LH secretion includes
      modulation of LHRH release, changes in hypothalamic-pituitary blood flow and
      direct effects at pituitary level. To determine the net balance of these actions
      we evaluated (1) the effects of systemic administration of sodium nitroprusside
      (SNP, a NO donor) and Nw-nitro-L-arginine methyl ester (NAME, a blocker of NO
      synthase) on basal and LHRH-stimulated LH secretion in intact and ovariectomized
      females; and (2) the effects of SNP and NAME on LH secreted by dispersed
      pituitary cells. Finally, since NO is involved in the stimulatory effect of
      excitatory amino acids (EAAs) on LH secretion, we analyzed the effects of
      different inhibitors of NO synthase (NOS) in the LH response to kainic acid (KA),
      an agonist of kainate receptors, in male and female rats, neonatally injected
      with estradiol that show an increased sensitivity to EAAs. We found that NAME (40
      and 60 mg/kg) increases LH secretion in intact and ovariectomized females, while
      SNP had no effect. The effect of NAME was not mediated through a direct action at
      pituitary level, since the basal and LHRH-stimulated LH release remained
      unchanged in presence of NAME. Similarly, basal and LHRH-stimulated LH secretion
      from dispersed pituitary cells were unaffected by NAME. Finally, the stimulatory
      effects of KA on LH release were not abolished by NOS inhibitors. In conclusion,
      our results provide evidence that the global action of NOS inhibitors is an
      increase in basal LH secretion, through a mechanism that remains to be fully
      characterized. In addition, our data demonstrate that the KA-stimulated LH
      secretion is not mediated by an increase in NO generation.

PMID- 10401708
TI  - Symptomatic hypercalcemia in the first months of life: calcium-regulating
      hormones and treatment.
AB  - Neonatal hypercalcemia is a rare condition often of unclear pathogenesis. If
      unrecognized and untreated it may result in central nervous system and renal
      damage. We studied three infants with symptomatic neonatal hypercalcemia pointing
      out pathogenetic and therapeutic aspects. One infant was found to have transient
      hyperparathyroidism with high intact parathyroid hormone (iPTH) levels. One
      infant had an incomplete form of Williams syndrome with hypercalcemia and an
      elfin facies. The pathogenesis is unclear in this case. A reduced secretion of
      calcitonin or an hypersensitivity to vitamin D might be the underlying defect.
      The third case was found to have subcutaneous fat necrosis and hypercalcemia
      associated with high 1,25(OH)2D levels and suppressed iPTH levels. These findings
      suggest an unregulated extrarenal 1,25(OH)2D production. These infants were
      treated with hydratation, furosemide, corticosteroids and low calcium diet.
      Symptomatic neonatal hypercalcemia should be treated promptly. However blood has
      to be taken before starting treatment to study calcium-regulating hormones and
      clarify pathogenesis.

PMID- 10401709
TI  - Cabergoline: a first-choice treatment in patients with previously untreated
      prolactin-secreting pituitary adenoma.
AB  - Cabergoline (CAB) treatment is an effective, safe and well tolerated approach for
      hyperprolactinemia. We investigated the efficacy of 24-month treatment with CAB
      in 37 patients with previously untreated PRL-secreting pituitary adenoma and
      evaluated the hormonal and neuroradiological changes after the discontinuation of
      long-term therapy. Eleven patients with macroprolactinoma (1M/10F) and 26 with
      microprolactinoma (4M/22F) started treatment taking 0.25 mg CAB twice a week for
      4 weeks. The dose was increased stepwise in 0.5 mg increments until reaching
      lowest maximally effective and tolerated dose. CAB was withdrawn before the end
      of the study in 6 women who became pregnant and in one patient who showed a
      slight increase of the macroadenoma at MRI. During treatment, PRL levels
      decreased significantly in macro (11.1+/-1.1 vs 407.8+/-98.3 microg/l, p<0.001)
      and microprolactinomas (11.1+/-1.6 vs 193.8+/-23.4 microg/l, p<0.05) and
      normalized in all macro and in 23/26 microprolactinomas. In 3 cases PRL levels
      decreased but did not normalize because the appearance of side effects, such as
      nausea or hypotension, prevented the increase of the dose of CAB. The effective
      dose of drug correlated significantly with basal serum PRL levels (p<0.05) and
      with the pituitary tumor size (p<0.05). A significant decrease of the mean
      adenoma size was evident for macro (6.9+/-1.8 vs 16.0+/-1.8 mm, p<0.001) and
      microprolactinomas (3.0+/-0.5 vs 6.5+/-0.4 mm, p<0.001) at MRI. The tumor
      disappeared in 4 macroadenomas and in 11 microadenomas after 12 months of
      treatment. CAB withdrawal was followed by serum PRL increase in 13 cases after 3
      months, in 6 after 6 months, in 2 after 9 months, and in one patient at the 12th
      month. Five patients showed normoprolactinemia with negative MRI after one year.
      Regular menses were restored in 7/10 macroprolactinomas and in all oligo
      amenorrhoic patients with microadenoma; serum testosterone levels normalized in
      2/3 hypogonadic men. Five out of 6 women become pregnant and had uneventful
      pregnancies which resulted in deliveries of normal babies. In conclusion, this
      study confirms the effectiveness and safety of CAB for patients with PRL
      secreting pituitary adenoma and suggests that it can be considered a first choice
      treatment.

PMID- 10401710
TI  - Hexarelin-induced growth hormone response in short stature. Comparison with
      growth hormone-releasing hormone plus pyridostigmine and arginine plus estrogen.
AB  - Hexarelin (HEX) is a synthetic hexapeptide with strong GH-stimulating activity.
      We evaluated GH response (expressed as maximum value after stimulus [Cmax] and as
      area under the curve [AUC]) to HEX at the doses of 1 microg/kg i.v. (HEX 1) and 2
      microg/kg i.v. (HEX 2), in comparison with the responses to GHRH (1 microg/kg
      i.v.) + pyridostigmine (PD, 60 mg po) and to arginine (ARG, 0.5 mg/kg i.v.) +
      ethinylestradiol (EE, 1 mg/day po for 3 days before the stimulation), in 5
      subjects with familial short stature (FSS), 11 with constitutional growth delay
      (CGD), 6 with GH neurosecretory dysfunction (NSD), and 5 with isolated growth
      hormone deficiency (GHD). Cmax and AUC after HEX 1 were 26.8+/-10.5 ng/ml and
      1448+/-514 ng/min x ml in FSS, 23.6+/-14.4 ng/ml and 1146+/-750 ng/min x ml in
      CGD, 36.9+/-21.5 ng/ml and 2048+/-1288 ng/min x ml in NSD, 9.4+/-5.8 ng/ml and
      498+/-200 ng/min x ml in GHD (Cmax and AUC in FSS and CGD, p<0.05 vs GHD). Cmax
      and AUC after HEX 2 were 37.7+/-16 ng/ml and 1979+/-888 ng/min x ml in FSS,
      32.5+/-16.2 ng/ml and 1613+/-237 ng/min x ml in CGD, 39.7+/-20.7 ng/ml and 2366+/
      1569 ng/min xml in NSD, 13.4+/-4.2 ng/ml and 645+/-293 ng/min x ml in GHD (Cmax
      in FSS, CGD and NSD p<0.01 vs GHD; AUC in NSD, p<05 vs GHD). Cmax and AUC after
      GHRH+/-PD were 46.6+/-8.8 ng/ml and 3294+/-1031 ng/min x ml in FSS, 25.9+/-11.2
      ng/ml and 1464+/-735 ng/min x ml in CGD, 38.8+/-21.7 ng/ml and 2428+/-1399 ng/min
      x ml in NSD, 8.4+/-6.2 ng/ml and 685+/-572 ng/min x ml in GHD (Cmax and AUC in
      FSS, p<0.001 vs CGD and GHD; Cmax in CGD and NSD, p<0.001 vs GHD). Cmax and AUC
      after ARG+EE were 21.3+/-4.2 ng/ml and 1432+/-514 ng/min x ml in FSS, 14.8+/-10
      ng/ml and 805+/-489 ng/min x ml in CGD, 22.2+/-12.8 ng/ml and 1199+/-309 ng/min x
      ml in NSD, 4.6+/-2.5 ng/ml and 247+/-191 ng/min x ml in GHD (Cmax and AUC in FSS,
      CGD and NSD, p<0.01 vs GHD). Specificity was 62% for HEX 1 and 75% for HEX 2,
      GHRH+PD and ARG+EE. From a diagnostic point of view, HEX 1 + HEX 2 was the
      association with the largest percentage of false positives (20% in FSS, 27% in
      CGD and 33% in NSD), HEX 1 +GHRH+PD resulted in 9% in CGD, while the combined use
      of HEX 1 or HEX 2 with GHRH+PD or ARG+EE and of GHRH+PD with ARG+EE did not show
      false positive responses. IN CONCLUSION: I) the most effective dose of HEX was 2
      microg/kg i.v.; 2) HEX did not show more specificity than GHRH+PD and ARG+EE; 3)
      the association of GHRH+PD with ARG+EE could yield the best results at lower
      costs, confirming these tests as first-line tools in evaluating GH secretion.

PMID- 10401711
TI  - Mineralocorticoid status and endocrine dysfunction in severe hemochromatosis.
AB  - Selective iron deposition in the zona glomerulosa of the adrenal cortex is
      observed in hemochromatosis. Hypoaldosteronism should be excluded before starting
      venesection, to avoid long-term volume depletion. We evaluated the aldosterone
      status in patients with hemochromatosis. As other endocrine organs can be
      affected by the disease as well, we simultaneously evaluated anterior pituitary,
      gonadal, thyroid and pancreatic beta-cell activity. Nine patients with hereditary
      or acquired hemochromatosis and highly increased plasma ferritin levels were
      investigated. In patients, liver cirrhosis had been confirmed histologically.
      Five patients complained of sexual dysfunction, and one had impaired glucose
      tolerance. Plasma aldosterone (PA) and renin activity (PRA) were measured after a
      period of normal (100 mmol/day) and low (10 mmol/day) sodium intake. A combined
      anterior pituitary function test and a glucagon stimulation test were undertaken
      to evaluate other endocrine functions. Both PA and PRA levels were decreased in
      one patient with liver cirrhosis, who also presented attenuated cortisol,
      prolactin and gonadotrophin secretion. No patients had signs of primary
      hypoaldosteronism with hyperreninemia. Hypogonadotropic hypogonadism was observed
      in 3 males and 1 female. Pituitary ACTH reserve was impaired in 2, GH and
      prolactin response in 1, and thyroid function in none of the patients. Glucagon
      stimulated plasma C-peptide was impaired in one patient. In conclusion, primary
      aldosterone deficiency was not observed in patients with severe iron overload.
      Hyporeninemic hypoaldosteronism was found in one patient who also presented other
      endocrinopathies. Hypogonadotropic hypogonadism is the most frequent endocrine
      abnormality in hemochromatosis.

PMID- 10401712
TI  - Body-fat distribution and responsiveness of the pituitary-adrenal axis to
      corticotropin-releasing-hormone stimulation in sedentary and exercising women.
AB  - Excess upper-body (android) fat is considered an health hazard. Exercise training
      is known to have the potential to modify body composition and to induce a
      preferential loss of abdominal fat. We studied and compared the composition of
      whole body and major body regions using dual-energy X-ray absorptiometry (DEXA)
      in 21 exercising (3-4 hours of intense physical activity/day) and 21 sedentary
      eumenorrhoic women of similar ages, body mass index (BMI), waist-to-hip ratio
      (WHR) and age of menarche. In a small number of women in each group (6 out of
      21), the ACTH and cortisol response to CRH test and the 24-h urinary cortisol
      excretion was evaluated. Exercising women had 10% higher total and leg lean mass
      (p<0.05), and 38% lower total fat mass (p<0.01) than sedentary women.
      Furthermore, the proportion of android fat was 22% lower in exercising than
      sedentary women (p<0.01), while the proportion of lower-body (gynoid fat) was
      unchanged. BMI and WHR were not different between the two groups, while the
      android/gynoid fat ratios were 16% lower in exercising than in sedentary women
      (p<0.01). In the exercising women, ACTH and cortisol plasma levels, as well as
      the 24-h urinary cortisol excretion, were significantly (p<0.01) higher than in
      the sedentary women studied. In these subjects, a direct relationship between the
      peak delta percentage increases of ACTH and cortisol after the CRH test and the
      proportion of android fat was found (r=0.60, p<0.05 and r=0.69, p<0.02,
      respectively). These results demonstrate that in women who practise intense
      exercise there are significant differences in body fat distribution in comparison
      to sedentary women, with a marked less amount of android fat, and suggest that
      this difference may be related to a reduced response of the pituitary-adrenal
      axis to CRH.

PMID- 10401713
TI  - A rare case of acromegaly associated with pachydermoperiostosis.
AB  - Pachydermoperiostosis (PDP) is a rare syndrome manifested clinically by finger
      clubbing, extremity enlargement, hypertrophic skin changes, and periosteal bone
      formation. The pathogenesis of the disorder has not been clarified and few
      endocrine abnormalities were apparent. We report here a 58-year-old man with
      acromegaly associated with PDP, the features of clubbed fingers, coarse skin, and
      cutis verticis gyrata. Acromegaly due to GH-producing pituitary adenoma was
      confirmed in endocrinological and pathological studies.

PMID- 10401714
TI  - Unusual association of thyroiditis, Addison's disease, ovarian failure and celiac
      disease in a young woman.
AB  - The coexistence of autoimmune endocrine diseases, particularly autoimmune thyroid
      disease and celiac disease (CD), has recently been reported. We here present a 23
      year-old woman with a diagnosis of hypothyroidism due to Hashimoto's thyroiditis,
      autoimmune Addison's disease, and kariotypically normal spontaneous premature
      ovarian failure. Considering the close association between autoimmune diseases
      and CD, we decided to search for IgA anti-endomysium antibodies (EmA) in the
      serum. The positivity of EmA and the presence of total villous atrophy at jejunal
      biopsy allowed the diagnosis of CD. On a gluten-free diet the patient showed a
      marked clinical improvement accompanied, over a 3-month period, by a progressive
      decrease in the need for thyroid and adrenal replacement therapies. After 6
      months, serum EmA became negative and after 12 months a new jejunal biopsy showed
      complete mucosal recovery. After 18 months on gluten-free diet, the anti-thyroid
      antibodies titre decreased significantly, and we could discontinue thyroid
      substitutive therapy. This case emphasizes the association between autoimmune
      polyglandular disease and CD; the precocious identification of these cases is
      clinically relevant not only for the high risk of complications (e.g. lymphoma)
      inherent to untreated CD, but also because CD is one of the causes for the
      failure of substitute hormonal therapy in patients with autoimmune thyroid
      disease.

PMID- 10401715
TI  - White Addison's disease: what is the possible cause?
AB  - A case of chronic primary adrenal insufficiency without hyperpigmentation in a 64
      year-old woman is reported. Due to the absence of hyperpigmentation the diagnosis
      was delayed and she became critically ill. During endocrine evaluation, in order
      to investigate the mechanism responsible for the absence of hyperpigmentation,
      skin biopsy was done and hormones responsible for the skin pigmentation were
      measured. Absence of hyperpigmentation is explained by high degree of melanosome
      degradation in secondary lysosomes called "compound melanosomes", which
      overwhelmed increased stimulation of the skin pigmentation. Melanocyte
      stimulating hormones were elevated with a strikingly high beta-LPH/ACTH ratio. To
      our knowledge, this is the first study of pathogenic mechanisms responsible for
      the absence of hyperpigmentation in white Addison's disease.

PMID- 10401717
TI  - The use of perchlorate for the prevention of thyrotoxicosis in patients given
      iodine rich contrast agents.

PMID- 10401716
TI  - Clinical usefulness of the low dose ACTH test.

PMID- 10401718
TI  - Antibody response in goats vaccinated with liposome-adjuvanted Clostridium
      perfringens type D epsilon toxoid.
AB  - A trial was performed using 20 goats to evaluate the antibody responses to a
      liposome-adjuvanted Clostridium perfringens epsilon toxoid vaccine (LIPV). The
      antibody response was compared with those produced by epsilon toxoid vaccines
      prepared using aluminium hydroxide (ALV) and incomplete Freud's adjuvant (FAV).
      The animals were allocated to four groups at the beginning of the trial. The
      animals in group 1 were vaccinated with ALV, while the animals in group 2
      received FAV and those in groups 3 and 4 were vaccinated with LIPV. The animals
      in groups 1 to 3 received three doses of the corresponding vaccine at intervals
      of three weeks, while those in group 4 received only 1 dose of vaccine at the
      beginning of the trial. A blood sample was obtained from all the goats at the
      beginning of the trial and then weekly for 8 weeks. The samples were analysed for
      epsilon toxoid antibodies by an indirect ELISA technique. No major clinical
      abnormalities were observed in the animals after vaccination, with the exception
      of those that received the FAV, which experienced transient lameness. The highest
      antibody response was observed in the animals vaccinated with FAV, but they
      presented moderate to severe inflammatory tissue reactions at the injection site.
      Moderately high antibody responses were obtained with the ALV, with which only
      minor local reactions were observed. No significant antibody responses were
      obtained with the LIPV, nor were local reactions observed.

PMID- 10401719
TI  - Three enzymes newly identified from the genus Eimeria and two more newly
      identified from E. maxima, leading to the discovery of some aliphatic acids with
      activity against coccidia of the domesticated fowl.
AB  - Nine enzymes were detected in sporulated oocysts of Eimeria tenella and E.
      maxima, parasites of the domesticated fowl (Gallus gallus). Three enzymes,
      hydroxybutyrate dehydrogenase, alanine aminotransferase and gamma
      glutamyltransferase, all identified for the first time in Eimeria of fowl,
      occurred both in E. tenella and in E. maxima. The remaining enzymes assayed had
      previously been found in various Eimeria species of fowl, although creatine
      kinase and glutamate dehydrogenase were hitherto unknown from E. maxima. The
      three enzymes newly recorded from Eimeria of fowl are of interest as potential
      genetic markers, and also as potential chemotherapeutic targets. The discovery of
      hydroxybutyrate dehydrogenase led to the demonstration of anticoccidial activity
      by some aliphatic acids. The paper also includes a list of the enzymes detected
      in Eimeria of fowl in previous studies.

PMID- 10401721
TI  - Culicoides spp. (Diptera: Ceratopogonidae) associated with farmed ostriches
      (Struthio camelus) in Botswana.

PMID- 10401720
TI  - Purification and characterization of liver ferritins from different animal
      species.
AB  - The ferritins were purified from liver homogenates of buffalo, camel, cattle,
      sheep and shark by thermal denaturation, ammonium sulphate fractionation,
      Sephacryl S-300 gel filtration and DEAE-blue gel affinity chromatography. The
      yield and iron content of affinity-purified liver ferritins ranged from 0.008 to
      0.052 mg/g and 3.17% to 11.4% respectively. As they are glycoproteins, the
      ferritins contained variable amounts of neutral carbohydrates. Except for shark
      ferritin, the ferritins all exhibited immunological cross-reactivity with anti
      buffalo liver ferritin and anti-horse spleen ferritin by immunodiffusion and
      immunoelectrophoresis. Gel electrophoresis, gel filtration and ultracentrifugal
      analysis indicated the presence of a monomeric ferritin in all cases. SDS-gel
      electrophoresis of shark ferritin gave a protein band of 18 kDa. Ovine, buffalo
      and bovine ferritin comprised two protein subunits, the H (20 and 21 kDa) and the
      L types (18 and 19 kDa). Oligomeric ferritin subunits with molecular weights of
      27, 37 and 55 kDa were also found for bovine and buffalo ferritin. SDS-PAGE of
      camel ferritin revealed a complex pattern with four prominent bands of 61, 51, 44
      and 39 kDa. Two fast-migrating components of 15 and 16 kDa were also found in the
      purified liver ferritins, including reference preparations. The PO4(3-)/Fe ratios
      of purified shark (0.10) and bovine ferritin (0.12) were similar to that of
      standard equine spleen ferritin (0.11). However, the ratio was higher in ovine
      (0.17), camel (0.22) and bovine (0.26) ferritins. The amino acid compositions,
      molecular weights and sedimentation coefficients of the different liver ferritins
      were similar.

PMID- 10401722
TI  - Anthelmintic resistance in Pashmina (Cashmere) producing goats in India.

PMID- 10401723
TI  - Dynamics of protein 27 of avian leukosis virus and transforming growth factor
      beta2 in lymphoid leukosis susceptible and resistant broiler chicken breeding
      stock.
AB  - The dynamics of the serum concentration of protein 27 (P27) of avian leukosis
      virus and transforming growth factor beta2 (TGF-beta2) were compared during the
      period between 29 and 59 weeks of age in two flocks of broiler chicken breeding
      stock undergoing outbreaks of severe lymphoid leukosis (LL) associated with
      persistent high mortality (susceptible) and in another two flocks of breeding
      stock with the presence of avian leukosis virus in association with low mortality
      due to LL (resistant). The average mean concentration of serum P27 in the LL
      susceptible flocks was significantly higher (p<0.05) than that in the LL
      resistant flocks in six out of seven samplings performed at 5-week intervals,
      between 29 and 59 weeks of age. The peak in the average rise of serum P27 in the
      LL-resistant flocks (309 pg/ml) was associated with the highest level of TGF
      beta2 (1282 pg/ml) among all flocks and at all sampling times. The significance
      of TGF-beta2 in inhibition of lymphoid tumour development is discussed.

PMID- 10401724
TI  - Role of diltiazem on tacrolimus pharmacokinetics in tacrolimus-induced
      nephrotoxic rats.
AB  - The effects of diltiazem on tacrolimus pharmacokinetics during tacrolimus-induced
      nephrotoxicity were studied. In normal rats, co-administration of diltiazem
      significantly increased AUC(0-infinity) of tacrolimus and reduced total body
      clearance, Cltot, after intravenous and oral administration. In tacrolimus
      induced nephrotoxicity, AUC(0-infinity) of tacrolimus increased 40.7%, while the
      apparent volume of initial distribution space, Vd1, the apparent volume of steady
      state distribution space, Vdss, and Cltot decreased 27.4%, 19.5% and 27.4%,
      respectively, as compared with the control. Co-administration of diltiazem
      lowered the AUC(0-infinity) of tacrolimus 36.2% and increased Vd1i.v. 62.8% in
      Vdss 45.9% and Cltot(i.v) 59.0% in tacrolimus-induced nephrotoxicity, resulting
      in partial improvement in renal function. These pharmacokinetic alterations due
      to diltiazem contrasted with those seen in normal rats. As a result, the
      pharmacokinetic parameters in tacrolimus-induced nephrotoxicity with
      coadministration of diltiazem resembled those in control rats. Mean tacrolimus
      concentrations in kidney cortex and medulla in a tacrolimus nephrotoxic group
      given diltiazem were 33.1% and 44.7% lower than those in a nephrotoxic model due
      to tacrolimus alone. But the tissue/blood concentration ratio of tacrolimus did
      not change regardless of the presence of diltiazem. Our findings suggest that co
      administration of diltiazem has an advantageous effects on tacrolimus
      pharmacokinetics to protect against tacrolimus-induced nephrotoxicity.

PMID- 10401725
TI  - Electrophysiological deficiency in peripheral nerve induced by treatment for 12
      weeks with 2-butenenitrile, 3-butenenitrile, cis-2-pentenenitrile and 3,3
      iminodipropionitrile in rats.
AB  - Motor and sensory conduction velocities and amplitudes of the sensory and motor
      action potentials of the tail nerve were studied in male Sprague-Dawley rats
      during subchronic oral treatment with three unsaturated aliphatic nitriles. The
      rats were given, by gastric intubation, doses of 10, 20 and 40 mg x kg(-1) 3
      butenenitrile (allyl cyanide) and 25, 50 and 100 mg x kg(-1) of either cis/trans
      2-butenenitrile (crotononitrile) or cis-2-pentenenitrile once a day, 5 days per
      week for 12 weeks. Moreover, 3,3'-iminodipropionitrile was administered likewise
      at doses of 25, 50 and 100 mg x kg(-1) as reference neurotoxicant. Oral
      administration of the three unsaturated nitriles produced deafness and absence of
      reaction when the animals were subject to droptest. Moreover, rats exhibited both
      time- and concentration-dependent decreases in motor and sensory conduction
      velocities and amplitudes of the sensory action potentials. Nerve conduction
      velocities were partially reversible after 8 weeks of recovery. Rats receiving
      3,3'-iminodipropionitrile developed deafness, head weaving and significant
      irreversive deficiencies in all the electrophysiological parameters studied.
      Further toxicological studies with related unsaturated nitriles should be carried
      out to determine the potential importance of the cis/trans isomerism in the
      observed neurotoxicity.

PMID- 10401726
TI  - The effect of heavy metal-induced metallothionein on Zn, Cu and Cd accumulation
      in rat kidney.
AB  - To examine the role of metallothionein on heavy metal accumulation in kidneys of
      rats after Zn, Cd or Cu injection, the relative Zn, Cd or Cu-binding capacity of
      heavy metal-induced metallothionein in renal cytosol of rats after Zn, Cd or Cu
      injection was determined. The Zn or Cu increment in renal cytosol after Zn or Cu
      injection was attributable to low and high molecular weight proteins, while most
      of the Cd increment was attributable to a low molecular weight protein. The low
      molecular weight, metal-binding protein was identified as metallothionein using a
      competitive ELISA. There was a close relationship between heavy metal contents in
      the renal cytosol and metallothionein of all heavy metal-injected rats. In dose
      response and time-course studies, approximately 45, 40 and 85% of the Zn, Cu and
      Cd increments in renal cytosol were bound to metallothionein after Zn, Cu and Cd
      injection, respectively. Therefore the order of relative binding capacities of
      Zn, Cu and Cd-induced metallothionein in kidney was determined to be Cd>Zn
      approximately Cu. These results suggest that the role of metallothionein in Zn or
      Cu accumulation in the kidney after Zn or Cu injection is different from that of
      metallothionein in Cd accumulation in the kidney after Cd injection.

PMID- 10401727
TI  - The acute effect in rats of 3,4-methylenedioxyethamphetamine (MDEA, "eve") on
      body temperature and long term degeneration of 5-HT neurones in brain: a
      comparison with MDMA ("ecstasy").
AB  - Administration of a single dose of the recreationally used drug 3,4
      methylenedioxyethamphetamine (MDEA or "eve") to Dark Agouti rats resulted in an
      acute dose-dependent hyperthermic response. The peak effect and duration of
      hyperthermia of a dose of MDEA of 35 mg/kg intraperitoneally was similar to a
      dose of 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") of 15 mg/kg
      intraperitoneally. Seven days later this dose of MDMA produced a marked
      (approximately 50%) loss of 5-HT and its metabolite 5-HIAA in cortex, hippocampus
      and striatum and a similar loss of [3H]-paroxetine binding in cortex: these
      losses reflecting the MDMA-induced neurotoxic degeneration of 5-HT nerve endings.
      In contrast, administration of MDEA (15, 25 or 35 mg/kg), even at the highest
      dose, produced only a 20% loss in cortex and hippocampus and no decrease in
      striatum. The neurotoxic effect of MDEA was only weakly dose-dependent. Neither
      MDEA (35 mg/kg) nor MDMA (15 mg/kg) altered striatal dopamine content 7 days
      later. MDEA appeared to have about half the potency of MDMA in inducing acute
      hyperthermia and 25% of the potency in inducing degeneration of cerebral 5-HT
      neurones. However since higher doses of MDEA (compared to MDMA) are probably
      necessary to induce mood changing effects, these data do not support any
      contention that this compound is a "safer" recreational drug than MDMA in terms
      of either acute toxicity or long term neurodegeneration.

PMID- 10401728
TI  - The influence of humic substances on the absorption and distribution of cadmium
      in mice.
AB  - The complex binding of cadmium ions to humic and fulvic acids in water may
      influence the absorption and distribution of drinking-water Cd in humans. Thus,
      in the present study mice were given a single oral dose of Cd (109CdCl2, 25
      microg/l) in 100 microl Millipore water containing different concentrations of
      humic compounds (0, 1, 10 and 100 mg dissolved organic carbon/l). The complex
      binding of Cd was studied by dialysis. At neutral pH, 1 mg dissolved organic
      carbon/l caused complex binding of more than 50% of the Cd, whereas more than 90%
      of Cd was bound at 10 and 100 mg dissolved organic carbon/l. At pH 3 the complex
      binding of Cd decreased somewhat, but over 90% of the Cd was bound at 100 mg
      dissolved organic carbon/l. Complex binding of Cd increased the lipid solubility
      of Cd, expressed as an octanol/ water partition coefficient, Nevertheless, more
      than 99% of the bound Cd was present as hydrophilic binding forms. Irrespective
      of the bound of Cd, the intestinal uptake and intracellular distribution (gel
      filtration on Sephadex G-75 column) were not affected by the humic substances 6
      hr after dosage. Moreover, complex binding did not influence the intestinal
      absorption of Cd 24 hr after exposure. The median Cd retention in the kidneys of
      the 100 mg dissolved organic carbon/l group was 23% and 46% lower than that of
      the control group 6 and 24 hr after administration, respectively, indicating
      alterations in the distribution of Cd after absorption. Thus humic substances may
      affect the metabolism of toxic heavy metals, such as Cd, in vivo in mice,
      indicating that the presence of humic and fulvic acids in drinking water should
      be considered in future risk assessments of metals in drinking water.

PMID- 10401729
TI  - Nicotinic acid and pyridoxine modulate arachidonic acid metabolism in vitro and
      ex vivo in man.
AB  - The in vitro effects of nicotinic acid (10-1000 microM), pyridoxine (0.1-500
      microM) and pyridoxal-5'-phosphate (0.1-500 microM) and the ex vivo effects of
      nicotinic acid (2500 mg orally during 12 h) and pyridoxine (600 mg orally daily
      for seven days) on arachidonic acid metabolism were investigated in calcium
      ionophore A23187 (calcimycin)-stimulated human whole blood. In vitro nicotinic
      acid stimulated prostaglandin E2, thromboxane B2 and leukotriene E4 synthesis.
      Pyridoxine at all concentrations and pyridoxal-5'-phosphate at the highest
      concentration stimulated prostaglandin E2 and thromboxane B2 production, but had
      no effect on leukotriene E4 synthesis. Nicotinic acid treatment increased ex vivo
      prostaglandin E2, thromboxane B2 and leukotriene E4 synthesis to 185%, 165% and
      175% of the initial values, respectively. In the pyridoxine-treated subjects, ex
      vivo prostaglandin E2, thromboxane B2 and leukotriene E4 synthesis was decreased
      after seven days to 75%, 65% and 45% of the initial values, respectively. In the
      present study the effects of nicotinic acid on the 5-lipoxygenase pathway in
      arachidonic acid metabolism were studied for the first time and the drug was
      found to stimulate this pathway in vitro and ex vivo. In vitro pyridoxine and
      pyridoxal-5'-phosphate had no effect on the 5-lipoxygenase pathway. The
      inhibition of leukotriene synthesis by pyridoxine ex vivo might be of therapeutic
      importance.

PMID- 10401730
TI  - Airway hyperresponsiveness in anaesthetised guinea-pigs 18-24 hours after antigen
      inhalation does not occur with all intravenously administered spasmogens.
AB  - Actively sensitised guinea-pigs were exposed to inhalation challenges with
      ovalbumin aerosol (macro- and microshock) and airway responsiveness to six
      intravenously administered spasmogens was evaluated 18 to 24 hr later in the
      anaesthetised animal. An increase in airway sensitivity was defined as a
      significant leftward shift of the dose-response curve when compared with saline
      challenged control sensitized animals. After ovalbumin-macroshock (1% ovalbumin
      for 2 min. with mepyramine cover against fatal anaphylaxis), airway
      hyperresponsiveness was seen to 5-HT, the thromboxane A2-mimetic, U-46619, and
      bradykinin but not to methacholine, histamine or substance P. A similar pattern
      was seen after ovalbumin-microshock (0.010% ovalbumin for 60 min.), with
      induction of airway hyperreactivity to 5-HT and U-46619 but not methacholine or
      histamine. When the U-46619 dose-response curve was constructed following
      treatment of the animals with atropine (1 mg/kg, intravenously), airway
      hyperresponsiveness was no longer significant. As an index of airway
      inflammation, lung weights were significantly heavier in ovalbumin-challenged
      animals, than in saline-challenged controls. The results of this study with
      intravenously administered spasmogens does not support claims that ovalbumin
      induced airway hyperreactivity in the guinea-pig is a 'non-specific' phenomenon.

PMID- 10401731
TI  - Inhibitory effects of baicalein and wogonin on lipopolysaccharide-induced nitric
      oxide production in macrophages.
AB  - In order to elucidate the mechanism of the antiinflammatory action of baicalein
      and wogonin, flavonoids from the root of Scutellaria baicalensis, the effects of
      these compounds were investigated on lipopolysaccharide-induced nitric oxide
      production in a macrophage-derived cell line, RAW 264.7. Baicalein (5-25 microM)
      and wogonin (5-50 microM) inhibited lipopolysaccharide-induced nitric oxide
      generation in a concentration-dependent manner. The inhibitory effect of these
      compounds was observed only when they were added at the start of cell incubation
      soon after the stimulation with lipopolysaccharide. Baicalein (25 microM) and
      wogonin (25 microM) also inhibited protein expression of inducible nitric oxide
      synthase. This inhibitory effect of wogonin was stronger than that of baicalein,
      which agrees with the result that wogonin showed stronger inhibition of nitric
      oxide production than baicalein. These results suggest that baicalein and wogonin
      attenuate lipopolysaccharide-stimulated nitric oxide synthase induction in
      macrophages and thus may help to explain the antiinflammatory action of these
      flavonoid compounds.

PMID- 10401732
TI  - Effects of repeated low dose administration and withdrawal of haloperidol on
      sexual behaviour of male rats.
AB  - Neuroleptics are known to cause anhedonia and attenuate sexual behaviour at
      therapeutic doses in humans. These effects are assumed to result from the
      dopamine antagonism of the drugs. It has been observed that a mixed dopamine
      D1/D2 antagonist, haloperidol, may cause a reduction in the number of
      intromissions required to achieve ejaculation. On the other hand, dopamine
      antagonists are considered unable to modify sexual behaviour once the copulatory
      sequence is initiated. In this study, male rats received low doses of haloperidol
      (30 or 60 microg/kg) before the investigation of sexual behaviour in five
      consecutive days and the mating test was repeated after withdrawal periods of
      four and five days. Haloperidol dose-dependently reduced intromission frequency,
      and this effect was maintained for four days after withdrawal. Ejaculation
      latency was reduced in all groups, including controls. The results indicate that
      at low doses haloperidol dose-dependently reduces intromission frequency, and the
      effect of a repeated dosage may persist several days after cessation of
      medication.

PMID- 10401733
TI  - Pancreatic cancer: a report of treatment and survival trends for 100,313 patients
      diagnosed from 1985-1995, using the National Cancer Database.
AB  - BACKGROUND: The National Cancer Database is an electronic registry system
      sponsored jointly by the American College of Surgeons Commission on Cancer and
      the American Cancer Society. Patients diagnosed with pancreatic adenocarcinoma
      from 1985 to 1995 were analyzed for trends in stage of disease, treatment
      patterns, and outcomes. STUDY DESIGN: Seven annual requests for data were issued
      by the National Cancer Database from 1989 through 1995. Data on 100,313 patients
      were voluntarily submitted using a standardized reporting format. RESULTS: The
      anatomic site distribution was: head, 78%; body, 11%; and tail, 11%. The ratios
      of limited to advanced disease (Stage I/Stage IV) were 0.70 for tumors in the
      head, 0.24 for body tumors, and 0.10 for tail tumors. Of all patients, 83% did
      not have a surgical procedure and 58% did not have cancer-directed treatment.
      Resection was done for 9,044 (9%) patients, including 22% of those with Stage I
      disease. The overall 5-year survival rate was 23.4% for patients who had
      pancreatectomy, compared with 5.2% for those who had no cancer-directed
      treatment. CONCLUSIONS: Overall survival rates for pancreatic cancer have not
      changed in 2 decades. A small minority of patients presented with limited,
      resectable disease, but the best survival rates per stage were achieved after
      surgical resection. Five-year survival rates after resection reported herein
      corroborated the improved survival rates of more recent large, single institution
      studies.

PMID- 10401734
TI  - Patterns of surgical practice in a small rural hospital.
AB  - BACKGROUND: A significant proportion of the population in the United States lives
      in rural areas, yet these areas are traditionally underserved in terms of
      surgical and other medical specialists. As a result, the operative experience of
      surgeons practicing in rural areas is different than that of surgeons operating
      in urban centers. This study was undertaken with the goal of delineating the
      surgical experience in a small hospital in rural Mississippi and correlating that
      with the training of surgical residents. STUDY DESIGN: The operative experience
      between July 1, 1996, and December 31, 1998, of a single surgeon at Newton
      Regional Hospital in rural Newton, MS, was evaluated. All cases were classified
      as either traditional-general-surgical or nongeneral-surgical; the latter
      category was further divided into endoscopy, gynecology, orthopedic, ENT,
      urology, and vascular. RESULTS: A total of 1,153 operations was performed by the
      one-man surgical department during the study period. Traditional general surgery
      patients accounted for 50.6% of the total, endoscopy totalled 21%, and vascular
      patients totalled 2.6%. The remaining 25.8% were stratified as follows:
      gynecology, 4.3%; orthopedics, 10.3%; ENT, 3.5%; and urology, 7.7%. CONCLUSIONS:
      The operative experience in a small rural hospital is significantly different
      from that at larger urban centers and is also markedly different from the
      experience of residents in major teaching centers. This would suggest the need to
      broaden the experience of graduating residents intending to practice in a rural
      setting.

PMID- 10401735
TI  - Analysis of laparoscopy in trauma.
AB  - BACKGROUND: The optimum roles for laparoscopy in trauma have yet to be
      established. To date, reviews of laparoscopy in trauma have been primarily
      descriptive rather than analytic. This article analyzes the results of
      laparoscopy in trauma. STUDY DESIGN: Outcome analysis was done by reviewing 37
      studies with more than 1,900 trauma patients, and laparoscopy was analyzed as a
      screening, diagnostic, or therapeutic tool. Laparoscopy was regarded as a
      screening tool if it was used to detect or exclude a positive finding (eg,
      hemoperitoneum, organ injury, gastrointestinal spillage, peritoneal penetration)
      that required operative exploration or repair. Laparoscopy was regarded as a
      diagnostic tool when it was used to identify all injuries, rather than as a
      screening tool to identify the first indication for a laparotomy. It was regarded
      as a diagnostic tool only in studies that mandated a laparotomy (gold standard)
      after laparoscopy to confirm the diagnostic accuracy of laparoscopic findings.
      Costs and charges for using laparoscopy in trauma were analyzed when feasible.
      RESULTS: As a screening tool, laparoscopy missed 1% of injuries and helped
      prevent 63% of patients from having a trauma laparotomy. When used as a
      diagnostic tool, laparoscopy had a 41% to 77% missed injury rate per patient.
      Overall, laparoscopy carried a 1% procedure-related complication rate. Cost
      effectiveness has not been uniformly proved in studies comparing laparoscopy and
      laparotomy. CONCLUSIONS: Laparoscopy has been applied safely and effectively as a
      screening tool in stable patients with acute trauma. Because of the large number
      of missed injuries when used as a diagnostic tool, its value in this context is
      limited. Laparoscopy has been reported infrequently as a therapeutic tool in
      selected patients, and its use in this context requires further study.

PMID- 10401736
TI  - Use of N-butyl-2-cyanoacrylate in elective surgical incisions--longterm outcomes.
AB  - BACKGROUND: Histoacryl Blue (N-butyl-2-cyanoacrylate) is a tissue adhesive that
      has been used clinically for more than 20 years. In the last decade, N-butyl-2
      cyanoacrylate has been used for cutaneous closure of low-tension lacerations in
      children and adults and has become a preferred method for closure of pediatric
      facial lacerations in many emergency rooms outside the United States. Many
      pediatric elective surgical procedures are performed in tension-free areas and
      may be suitable for closure with a tissue adhesive. In order to assess this
      approach, a retrospective study was conducted to evaluate the cosmetic outcomes
      and complications of the application of N-butyl-2-cyanoacrylate for the
      approximation of elective surgical incisions in a pediatric population. STUDY
      DESIGN: Records of 1,098 patients, ages 1 month to 16 years, who, between January
      1995 and December 1996, underwent one of the following: orchidopexy, inguinal
      hernia, umbilical hernia, or hydrocele repair were analyzed. In all patients, N
      butyl-2-cyanoacrylate was applied to close the surgical incision. A 12-item
      questionnaire was created to assess the presence of complications and to
      determine shortterm and longterm cosmetic outcomes of the incision. Data were
      collected by conducting telephone interviews of family members. RESULTS: Among
      the 1,033 children who were treated, 66% had inguinal hernias, 15% hydroceles,
      15% undescended testis, and 4% umbilical hernias. Redness or tenderness at the
      incision site (5.5%), discharge from the surgical wound (1.9%), and wound
      dehiscence (1.1%) were the main immediate complications after surgery. Overall
      satisfaction with the cosmetic outcomes of the surgical scar was high, with an
      average score of 4.73 out of 5 (94.6%). CONCLUSIONS: Our results demonstrate that
      administration of N-butyl-2-cyanoacrylate for the closure of small low-tension
      surgical incisions in the pediatric population is safe, has a low complication
      rate, and produces excellent cosmetic outcomes.

PMID- 10401737
TI  - Longterm effects of pulmonary resection on cardiopulmonary function.
AB  - BACKGROUND: Major lung resection decreases ventilatory capacity and reduces
      exercise tolerance, impairing postoperative quality of life. But we have often
      seen respiratory symptoms improve during several years of postoperative followup.
      In the current study, we evaluated postoperative changes in cardiopulmonary
      function on exertion of patients with lung cancer surviving for more than three
      years, and the corresponding changes of their respiratory symptoms. METHODS: The
      effects of pulmonary resection on cardiopulmonary function were evaluated in
      eight patients with lung cancer. Pulmonary function tests and hemodynamic study
      at rest and during exercise were performed before, in the early (4 to 6 months)
      and late (42 to 48 months) postoperative phases after major lung resection.
      RESULTS: None of the eight patients had any remarkable symptoms before lung
      resection. In the early postoperative study, the general condition of five
      patients deteriorated compared with their preoperative status. In the late
      postoperative study, four patients showed an improvement of their daily
      activities from the early postoperative phase. Pulmonary function in the late
      postoperative phase did not show major changes except for airway resistance and
      percentage of carbon monoxide diffusing capacity as compared with the early
      phase, which showed deterioration as compared with the preoperative period.
      Cardiac index and stroke volume index were significantly decreased during
      exercise on maximal effort in the late postoperative phase compared with other
      phases. These results suggest that the peak blood flow per unit of remaining lung
      during exercise becomes lower with time after lung resection, indicating
      deterioration of the condition of the pulmonary vascular bed. The deterioration
      was also revealed from the pressure-flow curve. CONCLUSIONS: The condition of the
      pulmonary vascular bed after major lung resection does not improve, even in the
      late postoperative phase, although clinical symptoms were sometimes improved
      compared with the early postoperative period.

PMID- 10401738
TI  - Positive predictive value of the Breast Imaging Reporting and Data System.
AB  - BACKGROUND: The American College of Radiology has established guidelines for
      outcomes monitoring known as the Breast Imaging Reporting and Data System
      (BIRADS). These recommendations include calculation of positive predictive values
      (PPV) and tracking of both benign and malignant histology. We collected this data
      for 688 radiographically guided biopsies and organized it according to the BIRADS
      assessment categories. The objective was to evaluate the contribution of the
      BIRAD System when used to stratify PPV, histology, and biopsy modality data
      according to the overall assessment rating. STUDY DESIGN: This study included
      data from 688 image-guided biopsies. Mammographic studies were either assigned a
      BIRADS rating at the time of examination or, if the image was taken before our
      use of BIRADS, examined retrospectively and rated. In these retrospective cases,
      the histologic outcomes of the biopsy remained unknown to the radiologist until
      ratings were assigned. Positive predictive value was calculated for each BIRADS
      category. RESULTS: The overall PPV for the sample was 0.23. The PPVs increased
      with increasing level of suspicion as follows: category 1 (0.0), category 2
      (0.04), category 3 (0.03), category 4 (0.23), category 5 (0.92). Category 1
      lesions represented 0.1% of the biopsies; category 2, 3.6%; category 3, 46.8%;
      category 4, 34.0%; and category 5, 15.4%. The most common histologic diagnoses of
      benign lesions biopsied were fibroadenoma and fibrocystic changes-proliferative
      and nonproliferative. The most common histologic diagnoses of malignant lesions
      biopsied were infiltrating ductal carcinoma and ductal carcinoma in situ.
      Utilization rates of the biopsy techniques varied by BIRADS category.
      CONCLUSIONS: Our study revealed that BIRADS does improve the quality of the risk
      assessment information by making the PPV more specific to a patient's mammogram
      rather than simply related to an overall PPV. Our histology analysis showed
      category 3 and category 4 benign biopsies were predominantly because of
      fibrocystic changes. Category 5 lesions were predominantly invasive ductal
      carcinoma. Analysis of biopsy modalities indicated the preferred method for
      management of radiographically detected lesions evolved from stereotactic core
      biopsy to directional, vacuum-assisted biopsy over the course of the study.

PMID- 10401739
TI  - Is race a poor prognostic factor in breast cancer?
AB  - BACKGROUND: African American breast cancer patients have a higher mortality rate
      than their Caucasian counterparts. The purpose of this study was to evaluate
      whether race is a poor prognostic factor in breast cancer survival after multiple
      other prognostic factors are taken into account. STUDY DESIGN: The tumor registry
      data from two institutions between the years 1982 and 1995 were combined for the
      analysis. A total of 1,745 patients, including 1,297 African American and 448
      Caucasian women, were available for analysis. Race, age, income, stage,
      histologic findings, type of operation, and treating institution were evaluated
      as possible key prognostic variables. RESULTS: In a univariate Cox proportional
      hazards regression analysis, African American patients with breast cancer were
      1.27 times more likely to die than Caucasians when death from disease was
      measured (p = 0.01, 95% confidence interval 1.03 to 1.47). When all factors were
      included in a Cox regression analysis, only the stage of disease at diagnosis,
      age, and whether the patient had a therapeutic surgical treatment were
      statistically significant. Race, income, hospital, and histologic findings were
      not significant, although they were significant when used in a univariate
      analysis. CONCLUSIONS: Poor survival of African American breast cancer patients
      seems to be related to their advanced stage at presentation and young age. To
      improve survival in these women, efforts should be concentrated on aggressive
      screening at a young age to detect the disease at an earlier stage.

PMID- 10401740
TI  - Complex gastrointestinal surgery: impact of provider experience on clinical and
      economic outcomes.
AB  - BACKGROUND: Commonly performed elective gastrointestinal surgical procedures are
      carried out with low morbidity and mortality in hospitals throughout the United
      States. Complex operative procedures on the alimentary tract are performed with a
      relatively low frequency and are associated with higher mortality. Volume and
      experience of the surgical provider team have been correlated with better
      clinical and economic outcomes for one complex gastrointestinal surgical
      procedure, pancreaticoduodenectomy. This study evaluated whether provider volume
      and experience were important factors influencing clinical and economic outcomes
      for a variety of complex gastrointestinal surgical procedures in one state. STUDY
      DESIGN: Complex high-risk gastrointestinal surgical procedures were defined as
      those with statewide in-hospital mortality of > or = 5%, frequency of greater
      than 200 per year in the state, and requiring special surgical skill and
      expertise. Six procedures met these criteria. Using publicly available discharge
      data, all patients discharged from Maryland hospitals from July 1989 to June 1997
      with a primary procedure code for one of the six study procedures were selected.
      Hospitals were classified into one of six groups based on the average number of
      study procedures per year: 10 or less; 11 to 20; 21 to 50; 51 to 100; 101 to 200;
      and 201 or more procedures per year. A hospital was included if at least one
      procedure was performed there during the study period. No providers fell within
      the 51 to 100, and 101 to 200 groups, so all analyses were performed for the
      remaining four volume groups that were classified, respectively, as minimal (10
      or fewer procedures), low (11 to 20 procedures), medium (21 to 50 procedures),
      and high-volume groups (201 or more procedures). Poisson regression was used to
      assess the relationship between in-hospital mortality and hospital volume after
      case-mix adjustment. Multiple linear regression models were used to assess
      differences in average length-of-stay and average total hospital charges among
      hospital volume groups. We further analyzed mortality, length-of-stay, and
      charges at the procedural level to understand these subgroups of complex
      gastrointestinal patients. We also examined the relationship between provider
      volume and outcomes for malignant versus benign diagnosis groups. RESULTS:
      Complex gastrointestinal surgical procedures were performed on 4,561 patients in
      Maryland from July 1989 through June 1997. The study population averaged 61.6
      years of age, was 55% male, 71% Caucasian, and had predominantly Medicare as a
      payment source. After case-mix adjustment, patients who underwent complex
      gastrointestinal surgical procedures at the medium-, low-, and minimal-volume
      provider groups had a 2.1, 3.3, and 3.2 times greater risk of in-hospital death,
      respectively, than patients at the high-volume provider (p < 0.001 for all
      comparisons); longer lengths-of-stay, 16.1, 15.7, and 15.5 days at the low-,
      medium-, and minimal-volume groups, respectively, versus 14.0 days for the high
      volume provider (p < 0.001 for all comparisons). Similarly, adjusted charges at
      the high-volume provider were, on average, 14% less than those of the low-volume
      group, which had the next lowest charges. Although mortality rates differed by
      procedure type, for each procedure, mortality increased as provider volume
      decreased, following the pattern found in the aggregate analysis. After case-mix
      adjustment, the risk of in-hospital death for patients with malignant diagnoses
      was significantly higher for the medium-, low-, and minimal-volume groups
      compared with patients at the high-volume provider, relative risk of 3.1, 4.0,
      and 4.2, respectively, (p < 0.001 for all comparisons). CONCLUSIONS: This study
      demonstrates that increased hospital experience is associated with a marked
      decrease in hospital mortality. The decreased mortality at the high-volume
      provider was also associated with shorter lengths-of-stay and lower hospital char

PMID- 10401741
TI  - Carcinoma of the gallbladder associated with anomalous junction of the
      pancreaticobiliary duct in adults.
AB  - BACKGROUND: Anomalous junction of the pancreaticobiliary duct (AJPBD) is a
      congenital anomaly in which the junction is located outside the sphincter of
      Oddi. A high incidence of gallbladder carcinoma (GBC) has been reported in adult
      patients with AJPBD. STUDY DESIGN: Fourteen adult patients with AJPBD and 50 with
      GBC not associated with AJPBD were reviewed retrospectively to identify the
      clinical characteristics of AJPBD accompanied by GBC and to clarify the
      differences in clinicopathologic features between GBC associated with AJPBD and
      GBC without AJPBD. RESULTS: Among the 14 patients with AJPBD, there were five
      fusiform, four cystic, and two cylindric dilatations of the biliary tract and
      three nondilated bile ducts. Nine (64%) of 14 patients had GBC, five with
      fusiform dilatations, two with cylindric dilatations, and two with nondilated
      bile ducts. No patient with cystic dilatation had GBC. There were two stage I
      cancers, four stage II, two stage III, and one stage IVB. One patient with stage
      IVB GBC died of recurrence 8 months after operation. The remaining 8 patients
      were well without signs of recurrence from 8 to 72 months after operation. The
      frequency of grossly polypoid or histologically papillary adenocarcinoma was
      higher in GBC patients with AJPBD than in those without AJPBD (p < 0.01). The
      proportion of disease-free survivors was greater among GBC patients with AJPBD
      than among those without AJPBD (p < 0.05). CONCLUSIONS: AJPBD with noncystic
      dilatation or without dilatation appears to be an important risk factor for GBC.
      In this limited series, patients with GBC accompanied by AJPBD have had
      relatively favorable outcomes.

PMID- 10401742
TI  - Utility of magnetic resonance cholangiography in the evaluation of biliary
      obstruction.
AB  - BACKGROUND: Evaluation of suspected biliary obstruction has traditionally
      involved a variety of imaging modalities including ultrasound, CT, and invasive
      cholangiography. These techniques have limitations because of poor visualization
      of intraductal stones (ultrasound and CT) and the need for an invasive procedure
      (ERCP and percutaneous transhepatic cholangiography). Magnetic resonance
      cholangiography (MRC) is a noninvasive imaging modality that provides good
      visualization of the hepatobiliary system. The aim of the present study was to
      determine the utility of MRC in evaluating patients with suspected biliary
      obstruction. STUDY DESIGN: One hundred forty-three patients were identified with
      suspected acute biliary obstruction and underwent MRC. Patient selection was
      based on clinical criteria including an elevation in serum liver chemistries or
      evidence of biliary ductal dilatation on conventional imaging. MRC was performed
      using a half-Fourier acquisition single-shot turbo spin-echo sequence involving
      single breath-hold rapid image acquisition. A final diagnosis was determined in
      each patient based on invasive cholangiography, findings at surgery, and clinical
      course. RESULTS: Of the 143 patients, 73 had an obstructing biliary lesion. A
      malignant process was identified in 25 patients with final diagnoses of
      pancreatic cancer (n = 15), ampullary cancer (n = 4), cholangiocarcinoma (n = 3),
      and hepatic or nodal metastases (n = 3). MRC correctly identified biliary
      obstruction in all these patients and accurately identified the level of biliary
      obstruction in 24 of 25 patients. Based on the MRC images alone, a malignant
      process was suspected in 21 of the 25 patients. Forty patients were found to have
      common bile duct stones and eight patients had a benign distal bile duct
      stricture. MRC correctly identified common bile duct stones in 37 patients with
      one false-positive exam (sensitivity = 92%; specificity = 99%). MRC also
      correctly identified distal biliary strictures in eight patients. In the
      remaining 70 patients, no definite biliary obstruction was identified by MRC, and
      in all patients the absence of mechanical obstruction was confirmed by invasive
      cholangiography or overall clinical course. CONCLUSIONS: This study demonstrates
      that MRC is able to accurately identify the level and cause of biliary
      obstruction in both malignant and benign disease. MRC may prove to be an
      important noninvasive tool in preoperative evaluation of patients with suspected
      biliary obstruction and identification of patients most likely to benefit from an
      invasive radiologic or surgical procedure.

PMID- 10401743
TI  - Thrombotic complications resulting from hypercoagulable states in chronic
      hemodialysis vascular access.
AB  - BACKGROUND: Vascular access-related complications are an important cause of
      morbidity, and they account for 14% to 17% of dialysis patients' hospitalizations
      with an annual cost in the United States of approximately $1 billion. Previous
      studies have related the major predisposing factor of thrombotic complications to
      stenosis of the graft anastomosis. Several recent reports suggest that
      antiphospholipid antibodies may cause frequent thrombotic complications. The
      broad spectrum of diseases that cause hypercoagulable states has not been
      correlated with frequent PTFE graft thrombosis. STUDY DESIGN: A retrospective
      case series study was performed to determine the frequency of hypercoagulable
      states in dialysis patients who had repeated thrombotic complications of their
      PTFE grafts. Between May 1996 and June 1998, 91 operations were performed on 34
      patients with end-stage renal disease. All arteriovenous fistulas were created
      with PTFE grafts and placed by a single surgeon. All patients were evaluated at
      operation for anastomotic stenosis, and the majority of patients were studied for
      hypercoagulable states. Patients with a documented hypercoagulable state were
      considered for warfarin therapy. RESULTS: Twenty-two individuals (64.7%)
      developed 67 thrombotic complications. Twelve of the 14 patients tested (85.7%)
      were shown to have hypercoagulable states of various causes and degrees. Thirteen
      patients developed multiple thrombotic complications, 11 (81.8%) were tested and
      proved to be hypercoagulable. Thirty-eight of the thrombotic complications had
      nonanatomic causes and 28 (41.8%) had hypercoagulability as the only determinable
      cause. Ten of the 12 hypercoagulable patients (83.3%) were relegated to
      intermediate to high-intensity warfarin therapy to reduce the incidence of
      thrombotic events. Hypercoagulable patients not receiving warfarin had a
      thrombosis rate of 4.0 events per year; patients on warfarin had a rate of 1.2
      events per year. Twenty-three thrombotic events occurred in the anticoagulated
      group all with an International Normalized Ratio (INR) less than 2.7. This
      incidence of vascular access thrombosis may be prevented when patients are
      maintained at an optimal INR of 2.7-3.0. CONCLUSIONS: Hypercoagulability has been
      a major etiologic factor in PTFE graft thrombosis. Hypercoagulable states are
      often found in patients with multiple graft thromboses and in patients with
      nonanatomic causes for thrombosis. Antiphospholipid antibodies are prevalent in
      the patients with PTFE graft thrombosis, as well as abnormalities in the Protein
      C, Protein-S, and Antithrombin III systems. PTFE graft thrombosis has been a
      frequent cause of morbidity in patients on hemodialysis, and diagnostic
      evaluation should include a hypercoagulability profile. Based on our data,
      warfarin therapy should be instituted when hypercoagulable states are found,
      unless otherwise contraindicated, and INR maintained at 2.7-3.0 to decrease
      morbidity and frequency of graft thrombosis.

PMID- 10401744
TI  - Dual kidney transplantation: older donors for older recipients.
AB  - BACKGROUND: Dual kidney transplantation, the transplantation of both donor
      kidneys into a single recipient, allows increased use of expanded criteria donors
      (eg, older donors with a history of hypertension) to alleviate the disparity
      between available donors and potential recipients. We evaluated outcomes in our
      dual kidney transplant program that started in 1995. STUDY DESIGN: A
      retrospective comparison of donor and recipient data between recipients of dual
      (n = 41) versus single (n = 199) cadaveric renal transplants from February 1,
      1995, to March 22, 1998, was performed. Dual kidney transplantation was
      selectively performed when the calculated donor admission creatinine clearance
      was less than 90 mL/min and the donor age was greater than 60 years, or if the
      donor had an elevated terminal serum creatinine. Every attempt was made to age-
      and size-match the donor and recipients. RESULTS: Recipients of dual kidneys had
      donors who were older than single kidney donors (59 +/- 12 versus 42 +/- 17 years
      respectively, p < 0.0001) and had more hypertension (51% versus 29%, p = 0.024).
      Average urine output was lower in the dual versus single kidney group (252 +/-
      157 versus 191 +/- 70 mL/hr, p = 0.036). Donors for dual kidney recipients had a
      lower donor admission creatinine clearance of 82 +/- 28 mL/min versus 105 +/- 45
      mL/min in the single kidney group (p = 0.005). Recipients of dual versus single
      kidneys were older (58 +/- 11 versus 47 +/- 12 years, p > 0.0001). Dual versus
      single kidney recipients had similar serum creatinines up to 2 years
      posttransplant (1.6 +/- 0.3 versus 1.6 +/- 0.7 mg/dL at 2 years, p = NS) and a
      comparable incidence of delayed graft function (24% versus 33%, p = NS) and 3
      month posttransplant creatinine clearance (54 +/- 23 versus 57 +/- 25 mL/min, p =
      NS). One-year patient and graft survival for single kidney transplantation was
      97% and 90%, respectively, and 98% and 89% for dual kidney transplantation (p =
      NS). CONCLUSIONS: Dual kidney donors were significantly older, had more
      hypertension, lower urine outputs, and lower donor admission creatinine
      clearance. Despite these differences, dual kidney recipients had comparable
      postoperative function, outcomes, and survival versus single kidney recipients.
      We believe selective use of dual kidney transplantation can provide excellent
      outcomes to recipients of kidneys from older donors with reduced renal function.

PMID- 10401745
TI  - Angiographic criteria reliably predict when carotid endarterectomy can be safely
      performed without a shunt.
AB  - BACKGROUND: Selective shunting during carotid endarterectomy is widely performed,
      but the optimal approach for predicting when a shunt is unnecessary remains
      uncertain. We evaluated the ability of preoperative cerebral angiography to
      predict when carotid endarterectomy could be safely performed without a shunt.
      STUDY DESIGN: Eighty-seven patients undergoing carotid endarterectomy between
      August 1991 and December 1997 had preoperative cerebral angiograms. The
      angiograms were evaluated for the presence of collateral flow from the
      contralateral carotid through the anterior communicating artery and from the
      posterior circulation through the posterior communicating artery. Patients then
      underwent endarterectomy and were selectively shunted based on somatosensory
      evoked potential changes. Internal carotid artery stump pressure was routinely
      measured in all patients. RESULTS: Nine patients (10%) had a shunt placed based
      on somatosensory evoked potential changes and none of the 87 patients had a
      perioperative (30 days) stroke. Angiography revealed that 36 patients (41%) had
      no cross-filling from the contralateral carotid through the anterior
      communicating artery. Nine of these patients (25%) required a shunt; none of the
      51 patients with adequate cross-filling (p < 0.001) did. Furthermore, 94% of the
      patients without cross-filling but with a patent ipsilateral posterior
      communicating artery did not require a shunt using somatosensory evoked potential
      changes as the standard for shunt insertion. Stump pressure measurements (> or =
      25 mmHg) or (> or = 50 mmHg) did not reliably exclude the need for a shunt. Only
      2 of 15 patients with contralateral carotid occlusion and 1 of 16 patients with a
      prior ipsilateral stroke required shunts. CONCLUSIONS: In the presence of cross
      filling from the contralateral carotid artery, shunt insertion was uniformly
      unnecessary. In addition, routine shunting of patients with previous ipsilateral
      strokes or contralateral carotid occlusion was not always necessary. Stump
      pressures were less sensitive than angiographic criteria in determining when a
      shunt was unnecessary. Evaluation of cross-filling from the contralateral carotid
      artery on preoperative angiography can predict with certainty which patients will
      not require a shunt.

PMID- 10401746
TI  - Endovascular graft repair of ruptured aortoiliac aneurysms.
AB  - BACKGROUND: The feasibility of endovascular graft (EVG) repair of ruptured
      aortoiliac aneurysms (AIAs) has yet to be demonstrated. There are inherent
      limitations in EVG repair, including the need for preoperative measurements of
      the aneurysmal and adjacent arterial anatomy to determine the appropriate size
      and type of graft and the inherent delay to obtain proximal occlusion. We
      developed an EVG system with broad versatility that largely eliminates these
      problems. STUDY DESIGN: Between 1993 and 1998, within an experience of 134
      endovascular AIA repairs, 12 ruptured AIAs were treated using EVGs that
      facilitated intraoperative customization and eliminated the need for preoperative
      measurements. The EVGs consisted of either a Palmaz stent and a PTFE graft
      deployed by a compliant balloon (n = 9) or a self-expanding covered stent graft
      (n = 3). Both grafts were cut to the appropriate length intraoperatively. The
      mean age of the patients was 72 years (range 40 to 86 years). The mean size of
      the aneurysms was 7.6 cm (range 3 to 16 cm). Preoperative symptoms were present
      in all patients and included abdominal or back pain (n = 9), syncope (n = 4), and
      external bleeding (n = 2). All patients were high surgical risks because of
      comorbid disease (n = 10) or previous abdominal operations (n = 6), and nine
      experienced hypotension. RESULTS: All EVGs were inserted successfully and
      excluded the aneurysms from the circulation. The mean operating time was 263
      minutes, the mean blood loss was 715 mL, and the mean length of hospital stay was
      6.5 days. There were two deaths (16%), one from the preexisting acute myocardial
      infarction and one from multiple organ failure. There were three minor
      complications (25%). Two patients required evacuation of an intraabdominal
      hematoma from the initial rupture. All but one of the grafts was functioning at a
      mean followup of 18 months. CONCLUSIONS: This study demonstrates the feasibility
      of EVG repair for ruptured AIAs using a graft that can be customized
      intraoperatively for each patient. Such repairs currently are valuable in
      patients with ruptured AIAs and serious comorbidities and may be applicable in
      other circumstances as well.

PMID- 10401748
TI  - Virtual reality surgical simulators: feasible but valid?

PMID- 10401747
TI  - Measuring and developing suturing technique with a virtual reality surgical
      simulator.
AB  - BACKGROUND: We have developed an interactive virtual reality (VR) surgical
      simulator for the training and assessment of suturing technique. The surgical
      simulator is comprised of surgical tools with force feedback, a 3-dimensional
      graphics visual display of the simulated surgical field, physics-based computer
      simulations of the tissues and tools, and software to measure and evaluate the
      trainee's performance. STUDY DESIGN: This study uses the simulator to measure and
      compare the skills of 8 experienced vascular surgeons versus 12 medical students
      when performing a virtual reality suturing task. Eight parameters of the suturing
      task were measured: total tissue damage, accuracy of needle puncture, peak tissue
      tearing force, time to complete the task, damage to the surface of the tissue,
      angular error in needle technique, total distance traveled by the tool tip, and a
      measure of overall error. Three test conditions (dominant hand, nondominant hand,
      and 3-dimensional needle guide) were tested. Statistical significance was defined
      as a univariate two-sided p value < or = 0.05. RESULTS: The surgeons' average
      performance was significantly better than the students' average performance for
      three of the measured parameters (total tissue damage, time to complete the task,
      and total distance traveled by the tool tip) for each of the test conditions. For
      the test condition most similar to surgery (using the dominant hand to suture)
      one additional parameter was also significantly different (the measure of overall
      error). The medical students showed improvements for 6 of the 7 parameters for
      which the users received feedback during the training process. The surgeons also
      had significant improvement for 4 of the 7 parameters. The students had a larger
      improvement than the surgeons for 6 of the parameters, but these differences were
      not statistically significant. CONCLUSIONS: Data indicate differences between
      surgeon and nonsurgeon performance and in improvement in performance with
      training. One possible explanation for the superior performance of the surgeons
      is that their suturing skills applied well to the simulated suturing task.
      Additional research is required to confirm or deny the similarity between actual
      and simulated surgical tasks and the relevance of virtual reality surgical
      simulation to surgical skill assessment and training.

PMID- 10401749
TI  - Pancreatic cancer: "true, false, or just a start?".

PMID- 10401750
TI  - Laparoscopic finger-assisted technique (fingeroscopy) for treatment of
      complicated appendicitis.

PMID- 10401751
TI  - Intraoperative dynamic fluoroscopic cholangiogram during laparoscopic
      cholecystectomy.

PMID- 10401752
TI  - A modification of the "components separation" technique for closure of abdominal
      wall defects in the presence of an enterostomy.

PMID- 10401753
TI  - Treatment with low molecular weight heparin needs anticoagulation monitoring.

PMID- 10401754
TI  - The immune privilege of corneal allografts.
AB  - BACKGROUND: Corneal transplantation is the oldest, most common, and arguably, the
      most successful form of tissue transplantation. In the United States alone, over
      40,000 corneal transplantations are performed each year. Less than 10% of the
      uncomplicated, first-time corneal grafts will undergo immune rejection even
      though HLA matching is not routinely performed and the use of immunosuppressive
      drugs is limited to the topical application of corticosteroids. The success of
      corneal transplantations predates the use of corticosteroids and further
      emphasizes the remarkable privilege of corneal allografts. METHODS: Several
      laboratories have used rat and mouse models of orthotopic corneal transplantation
      (keratoplasty) in an attempt to understand the basis for the immune privilege of
      corneal allografts. RESULTS: The time-honored explanation for the immune
      privilege of corneal allografts was based on the conspicuous avascularity of the
      cornea, which was believed to sequester the graft from the immune apparatus.
      However, results from several laboratories indicate that at least three
      additional features of the corneal graft contribute to its immune privileged
      status: (a) absence of donor-derived, antigen-presenting passenger Langerhans
      cells in the corneal graft; (b) expression of Fas ligand on the epithelium and
      endothelium of the corneal allograft; and (c) capacity of the corneal allograft
      to induce immune deviation of the systemic immune response. CONCLUSIONS: The
      immune privilege of corneal allografts is a product of at least three unique
      qualities of the corneal allograft that conspire to interfere with the induction
      and expression of allodestructive immune responses.

PMID- 10401755
TI  - The visualization of T cell responses.
AB  - Transplanting allogeneic grafts is still significantly hampered by the rejection
      process, despite the use of powerful immunosuppressive agents. The T cell is
      recognized as playing a central role in the process of rejection, and it is
      believed that graft tolerance will ultimately be achieved by immunological
      manipulation of this cell (1, 2). As immunologists strive to define the role of
      the T cell in the fundamental processes of immunity and tolerance, new methods
      are emerging that will facilitate visualization of the T cells directly involved
      in the rejection response (3, 4). This overview addresses the visualization of T
      cell responses as made possible by these technological developments.

PMID- 10401756
TI  - Anti-MHC-II preventing graft rejection.

PMID- 10401757
TI  - Cardiac allograft tolerance induced by intra-arterial infusion of recombinant
      adenoviral CTLA4Ig.
AB  - BACKGROUND: Systemic administration of soluble recombinant fusion protein of
      cytotoxic T lymphocyte antigen 4 (CTLA4Ig) induces blockade of the CD28/B7
      costimulatory pathway and promotes survival of allogeneic and xenogeneic grafts.
      We tested the efficacy of local expression of CTLA4Ig gene in the myocardium,
      induced by transduction with a recombinant adenovirus encoding the CTLA4Ig gene,
      on the survival of rat cardiac allografts. METHODS: The donor hearts were
      perfused ex vivo with recombinant adenovirus encoding CTLA4Ig cDNA (AdCTLA4Ig)
      via intra-aorta coronary artery before transplantation. The distribution and
      duration of CTLA4Ig transgene expression in the myocardium was assessed by
      reverse transcriptase polymerase chain reaction (RT-PCR) or in situ RT-PCR after
      transplantation. RESULTS: In situ RT-PCR demonstrated abundant expression of
      CTLA4Ig transgene in the endo-myocardium of AdCTLA4Ig-perfused cardiac grafts.
      Lewis and Brown Norway cardiac allografts transduced with AdCTLA4Ig survived
      indefinitely in nonimmunosuppressed Wistar Furth recipients. However, donor
      strain skin grafts were rejected by long-term recipients of cardiac allografts,
      which also triggered the rejection of the primary heart grafts. CONCLUSIONS: A
      single ex vivo intra-aortic infusion of recombinant adenovirus encoding the
      CTLA4Ig gene induced efficient transduction of the endo-myocardium and promoted
      the permanent survival of cardiac allografts in nonimmunosuppressed hosts.
      Despite the beneficial effect of local immunosuppression on cardiac allograft
      survival, the strategy failed to promote a state of donor-specific peripheral
      tolerance.

PMID- 10401758
TI  - Cellular and humoral mechanisms of vascularized allograft rejection induced by
      indirect recognition of donor MHC allopeptides.
AB  - INTRODUCTION: To investigate the role and mechanisms of indirect allorecognition
      in allograft rejection, we studied whether priming T cells with donor-derived MHC
      allopeptides could accelerate rejection in a vascularized allograft model.
      METHODS: Lewis recipients of fully mismatched Wistar Furth cardiac allografts
      were immunized before transplantation with donor MHC allopeptides. RESULTS:
      Animals immunized with immunogenic class II MHC allopeptides rejected their
      grafts in a significantly accelerated fashion compared with controls. Additional
      studies demonstrated that a single immunodominant RT1.D (HLA-DR like) allopeptide
      was responsible for accelerating the rejection process. Histological analysis of
      rejected allografts revealed marked vascular rejection in the accelerated,
      although not the control, group as well as severe cellular rejection. Peak
      production of IgM and IgG donor-specific alloantibodies was detected by flow
      cytometry 1 week earlier in the sera of the accelerated group compared with the
      control group. Immunohistological analysis of grafts from the accelerated
      compared with the control group showed increased endothelial deposition of IgG2b,
      C3, and fibrin, and up-regulation of class II MHC molecule expression. Increased
      intragraft expression of interferon-y and the interferon-gamma-induced
      chemokines, inducible protein-10 and Mig, and infiltration by activated
      mononuclear cells expressing CXCR3, the receptor for inducible protein-10 and
      Mig, was also seen. CONCLUSION: These novel data provide evidence of a definitive
      link between indirect allorecognition of donor-derived MHC class II peptides and
      the cellular and humoral mechanisms of vascularized allograft rejection.

PMID- 10401759
TI  - Long-term survival, morphology and in vitro function of isolated pig islets under
      different culture conditions.
AB  - BACKGROUND: Islet culture aims to optimize islet survival and to reduce islet
      immunogenicity. To achieve these objectives, culture periods at 37 degrees C and
      22-24 degrees C are mainly used. METHODS: This study compares the influence of
      donor age (juvenile vs. adult), temperature (22 degrees C vs. 37 degrees C), and
      serum supplementation (10% newborn calf serum [NCS] with 10% pig serum) on
      morphological integrity and in vitro function of porcine islets during long-term
      culture (LTC). RESULTS: After 21 days at 22 degrees C, the survival rate of
      cultured islets isolated from juvenile donors was lower than of adult islets
      (23+/-0.9% vs. 88+/-2.8%, P<0.001). Compared with 37 degrees C, LTC at 22 degrees
      C increased survival of adult islets and DNA recovery (92+/-2.5% vs. 45+/-4.8%,
      P<0.001; 72+/-4.1% vs. 30+/-5.1%, P<0.001) and reduced viability (62+/-8% vs.
      89+/-5%, P<0.05). LTC at 22 degrees C was associated with a reduction of insulin
      content (85+/-9 vs. 152+/-10 microU/islet equivalents [IEQ], P<0.01), 24 hr
      insulin secretion (82+/-7 vs. 552+/-91 microU/ day/IEQ, P<0.001), and integrated
      dynamic insulin response to glucose (1093+/-124 vs. 3074+/-708 microU/60 min/100
      IEQ, P<0.05), compared with 37 degrees C LTC. Histologic analysis revealed
      disintegration of islet periphery after 22 degrees C, whereas smoothly shaped
      islets were present after 37 degrees C LTC. Integrity after 14 days at 37 degrees
      C was significantly better preserved when medium CMRL 1066 was supplemented with
      10% porcine serum, compared with 10% NCS (40+/-2.3% vs. 21+/-6.7%, P<0.05),
      contrasting with 22 degrees C (52+/-4.0% vs. 59+/-3.7%, not significant).
      CONCLUSIONS: This study demonstrates that survival of cultured porcine islets is
      increased at 22 degrees C, whereas in vitro function and viability are better
      preserved at 37 degrees C. Survival at 37 degrees C can be improved by adding
      homologous serum to the medium.

PMID- 10401760
TI  - Inhibition of endothelin-converting enzyme attenuates transplant vasculopathy and
      rejection in rat cardiac allografts.
AB  - BACKGROUND: Transplant vasculopathy in kidney and heart allografts is associated
      with marked elevation of endothelin-1 (ET-1), but a role for ET-1 in the
      pathogenesis of transplant vasculopathy and chronic rejection has not been
      established. We, therefore, tested whether inhibition of ET-1-converting enzyme
      by phosphoramidon (PA) would attenuate rejection in a rat model of chronic
      cardiac allograft rejection (Lewis [LEW] to F344). METHODS: Donor LEW rats were
      pretreated 24 hr before transplantation with a bolus injection of vehicle (water)
      or PA. Twenty- four hour after transplantation, water or PA was continuously
      administered through an osmotic mini-pump. Plasma ET-1 levels in Fisher 344
      (F344) recipients were 0.8+/-0.1 pg/ml in water-treated rats and 0.2+/-0.2 pg/ml
      (P<0.01) in PA-treated rats, demonstrating that the PA treatment protocol
      effectively lowered ET-1 biosynthesis. RESULTS: LEW cardiac allografts treated
      with water survived (i.e., palpable heart beat) for 16.0+/-0.5 days (n=6).
      Inhibition of ET-1 secretion by PA improved allograft survival to 28.8+/-3.3 days
      (P<0.01, n=8). An analysis of cardiac arteries demonstrated that PA treatment
      attenuated transplant vasculopathy. A morphometric scale of neointima formation
      (0-5) was 1.4+/-0.2 and 3.6+/-0.2 in PA- or water-treated rats, respectively
      (P<0.01). The percent of luminal occlusion, as measured by microscopic image
      analysis, was 19+/-6% in PA-treated animals and 38+/-6% (P<0.01) in animals
      treated with water. PA treatment also reduced infiltration of ED-1-positive
      monocytes/macrophages into the vascular neointima. CONCLUSIONS: We conclude that,
      even in the absence of concomitant immunosuppression, inhibition of ET-1
      biosynthesis significantly attenuates transplant vasculopathy and improves
      survival of LEW to F344 cardiac allografts.

PMID- 10401761
TI  - Cytokine regulation of chronic cardiac allograft rejection: evidence against a
      role for Th1 in the disease process.
AB  - BACKGROUND: Transient depletion of CD4+ T cells in cardiac allograft recipients
      prolongs allograft survival; however, grafts exhibit signs of chronic rejection
      characterized by collagen deposition and neointima development. Although it is
      believed that Th1 cells promote acute graft rejection, the role of these cells in
      chronic rejection remains unclear. Hence, our study evaluated whether Th1 cells
      are associated with the development of chronic cardiac allograft rejection.
      METHODS: Splenocytes obtained from C57BL/6 recipients bearing BALB/c hearts with
      signs of chronic rejection were adoptively transferred into C57BL/6 SCID cardiac
      allograft recipients. As a measure of Th1 function, interferon-y production was
      determined after restimulation of recipient splenocytes with donor alloantigens.
      RESULTS: Transfer of splenocytes in SCID allograft recipients resulted in
      accelerated chronic rejection in the majority of mice. Characterization of these
      cells before transfer revealed hyporesponsive Th1 function. However, donor
      specific proliferative responses and precursor interleukin-2 producing helper and
      cytotoxic T lymphocyte frequencies were comparable to that of naive splenocytes.
      Further, splenocytes obtained from SCID recipients with advanced signs of chronic
      rejection remained deficient in Th1 function, suggesting that Th1 are not
      involved in this disease process. This possibility was further supported by the
      development of chronic rejection in IL-12 knockout recipients. Finally, when
      splenocytes used for adoptive transfer retained Th1 function, transfer of these
      cells into SCID recipients resulted in acute allograft rejection. CONCLUSIONS: We
      have established a model in which the mediators of chronic rejection may be
      further explored. In this system, the absence rather than the presence of donor
      reactive Th1 is associated with chronic rejection. These data indicate that Th1
      independent effector mechanisms are responsible for chronic rejection in this
      model.

PMID- 10401762
TI  - Videomicroscopic imaging of graft mucosa for monitoring immunosuppressive therapy
      after small intestinal transplantation in rats.
AB  - BACKGROUND: Early diagnosis of rejection and effective immunosuppressive
      treatment are essential after small intestinal transplantation. To date little is
      known about microscopic alterations of the intestinal mucosa of the graft during
      rejection. We attempted to determine whether videomicroscopic imaging of the
      graft mucosa is a suitable method for monitoring immunosuppressive therapy.
      METHODS: Real-time videomicroscopic imaging of an ileostoma was performed daily
      after allogeneic heterotopic small bowel transplantation in the rat (BN to LEW)
      with and without FK506 immunosuppression. Subsequently, the videomicroscopic
      findings were compared with the histologically determined grade of rejection.
      RESULTS: A semiquantitative staging system was established for the intravital
      mucosal changes during graft rejection. The earliest changes related to rejection
      appeared on POD 6 in the untreated allogeneic group. The mucosa developed patchy
      paleness and the mucosal architecture was interrupted in places. The crypts were
      slightly widened and their color turned dark red (stage I). These alterations
      spread progressively over the mucosa on POD 7 (stage II). On POD 9 the mucosa
      appeared pale, the villi were shortened, and the crypts appeared wide and rounded
      (stage III). In the animals treated with FK506 similar changes were observed, but
      with a delayed onset. When FK506 was administered as antirejection therapy at the
      onset of rejection, a temporary improvement of mucosal alterations was observed
      (stage II --> stage I). The video-microscopic stages correlated with the
      histological grade of rejection. CONCLUSIONS: The introduction of videomicroscopy
      has made computer-based high resolution imaging of mucosal microarchitecture
      possible. With videomi-croscopy beginning rejection can be detected, although it
      can still be reversed with antirejection therapy. This is a new noninvasive
      technique that might be of high clinical relevance.

PMID- 10401763
TI  - Rapidly progressive liver injury and fatal alcoholic hepatitis occurring after
      liver transplantation in alcoholic patients.
AB  - Alcohol-related liver disease (ALD) is a common indication for orthotopic liver
      transplantation (OLT) in adults. Although return to 'heavy drinking' post-OLT is
      believed to be uncommon, the prevalence and severity of alcohol-related liver
      injury in such patients is not well characterized. We retrospectively reviewed
      the records of 68 adult patients who underwent OLT for ALD to determine the
      incidence of return to heavy drinking and to assess their clinical outcome.
      Follow-up ranged from 8-99 months (mean 42) post-OLT; 54 patients were followed
      for > or = 12 months. Ten patients (15%) had evidence of coexisting viral
      hepatitis (hepatitis C in 9 and hepatitis B in 1) before OLT. Six of 68 patients
      (8%) returned to heavy drinking post-OLT, and three of those died of alcoholic
      hepatitis at nine months, 2.5 and 3.5 years after OLT. In two of these three
      patients, premortem liver biopsy showed histologic features of alcoholic
      hepatitis in addition to bridging fibrosis or cirrhosis. None of the three
      patients who died of ALD had coexisting viral hepatitis. Of the 57 patients
      surviving for > or = 3 months post-OLT, 4 of 8 patients (50%) with steatosis and
      Mallory bodies in their native livers returned to heavy drinking compared to only
      2/49 (4%) without these histologic findings (P<0.05). In conclusion, the
      incidence of heavy drinking post-OLT was uncommon, however, it was associated
      with fatal alcoholic hepatitis in 50% of patients. Rapidly progressive alcohol
      related liver injury was seen even in the absence of coexisting viral hepatitis.
      The presence of steatosis and Mallory bodies in the native liver, which suggests
      recent or ongoing alcohol-related liver injury, predicted a return to heavy
      drinking post-OLT.

PMID- 10401765
TI  - Extracorporeal liver perfusion system for successful hepatic support pending
      liver regeneration or liver transplantation: a pre-clinical controlled trial.
AB  - BACKGROUND: There is a well recognized need for a system capable of providing
      effective support for patients with hepatic failure pending liver regeneration or
      liver transplantation. Recent attempts of using bioartificial liver containing
      encapsulated porcine hepatocytes, the deployment of emergency whole liver, or
      hepatocyte transplantation are complex and not consistently successful. The
      technique of ex vivo hepatic perfusion developed and used clinically by Abouna in
      the 1970s, has now been redesigned in a perfusion circuitry that mimics the
      physiological conditions of a normal liver. Before clinical application of this
      system, a preclinical trial was carried out in dogs with induced hepatic failure.
      METHODS: Acute hepatic failure was induced in dogs by an end-to-side porto caval
      shunt, followed 24 hr later, by a 2-hr occlusion of the hepatic artery. All
      animals (n=18) were medically supported and were divided into three groups. In
      the control group (n=6) only medical support was used. In the experimental group
      (n=12) the animals were connected to the ex vivo liver support apparatus during
      acute hepatic failure via an AV shunt using a dog liver (n=6) or calf liver (n=6)
      (after a temporary extracorporeal bovine kidney transplant to remove preformed
      xeno antibody). Hepatic perfusion was carried out at 37 degrees C through the
      hepatic artery and portal vein at physiological pressures, and blood flow rate
      for 6-8 hr. RESULTS: All control animals died of progressive hepatic failure at
      14-19 hr after clamping the hepatic artery. The animals treated with ex vivo
      liver showed remarkable clinical and biochemical improvement. Five animals
      survived for 36-60 hr. Another seven animals recovered completely and became long
      term survivors with biochemical and histological evidence of regeneration of
      their own liver. Biopsy of the allogeneic ex vivo liver at the end of perfusion
      showed some interstitial edema. Similar biopsy of the xenogeneic calf liver
      showed only mild and delayed xenograft rejection, which was most likely due to
      removal of preformed xeno antibody by temporary transplantation of the calf
      kidney before liver perfusion. CONCLUSIONS: The observations and results obtained
      in this trial strongly confirm that extracorporeal perfusion through a whole
      liver, using the system described, is very successful and cost effective for the
      treatment of acute, but reversible hepatic failure, as well as serving as a
      bridge to liver transplantation. The time has come for this form of liver support
      technology to be reintroduced and widely used.

PMID- 10401764
TI  - Histological evidence of concomitant intramyocardial and epicardial vasculitis in
      necropsied heart allografts: a possible relationship with graft coronary
      arteriosclerosis.
AB  - BACKGROUND: The significance of medial lymphocytic vasculitis in intramural
      coronary vessels in heart transplantation is very poorly understood. This study
      was designed to identify histological evidence of an association between the
      presence of epicardial coronary lesions and the occurrence of intramyocardial
      vasculitis and/or myocardial ischemia. METHODS: We analyzed the frequency of
      medial vasculitis and other myocardial histological alterations in a
      retrospective study of 24 human cardiac allografts from patients who died of
      ischemic heart disease and/or myocardial rejection. RESULTS: Medial lymphocytic
      vasculitis in the myocardium was associated with vasculitis in the vasa vasorum
      of the epicardial coronary arteries and the presence of microfoci of acute
      myocardial infarction but was independent of the occurrence of myocardial fiber
      rejection. Chronic graft epicardial arteriopathy revealed two patterns of
      lesions. One pattern was similar to that of usual atherosclerosis, compromising
      mainly the proximal segments of the coronary artery, and was not associated with
      intramural vasculitis. The other pattern demonstrated diffuse involvement of the
      epicardial artery associated with vasculitis of its vasa vasorum and lymphocytic
      vasculitis of the intramural vessels. This second type of epicardial coronary
      lesion seemed to evolve to fibrotic arteries with thinned walls, frequently
      demonstrating aneurysmal dilatation with severe fibrosis of the adventitia and
      poor vasa vasorum. CONCLUSION: Medial vasculitis affecting intramyocardial
      vessels is associated with adventitial epicardial coronary vasculitis in the
      transplanted heart. The process of vasculitis may be involved in the development
      of chronic graft arteriosclerosis and is associated with ischemic myocardial
      lesions, but seems independent of myocardial fiber rejection.

PMID- 10401766
TI  - Interleukin-4 secretion by the allograft fails to affect the allograft-specific
      interleukin-4 response in vitro.
AB  - BACKGROUND: The role of the cytokine, interleukin (IL)-4, in allograft rejection
      and protection is not clear. We have previously shown that IL-4 transgenically
      expressed in a pancreas allograft does not protect the allograft from rejection.
      Here, we analyze the effect of the transgenically expressed IL-4 on the cytokine
      profile of the allograft-specific immune response. METHODS: C57BL/6SCID mice were
      infused with small numbers of spleen cells from C57BL/6 donors. The former
      received pancreas grafts from 1- to 2-day-old BALB/c donors which did or did not
      transgenically express IL-4 in the graft. Three weeks after the cell infusion,
      the spleens were removed and the splenocytes were restimulated in vitro with
      BALB/c APC, and third party BALB.K APC. IL-2 and IL-4 levels in the culture
      supernatants were measured. RESULTS: The presence of a pancreatic allograft
      induced an increase in the levels of both IL-2 and IL-4 in culture supernatants
      from splenocytes of mice receiving grafts compared with mice not receiving
      grafts. The presence of IL-4 transgenically expressed in the pancreas allograft
      had no effect on the in vitro cytokine profile. CONCLUSIONS: from these results
      we conclude that the failure of transgenically expressed IL-4 to protect the
      allograft was not associated with up-regulation of a graft antigen-specific IL-4
      response.

PMID- 10401767
TI  - The allogeneic response to cultured human skin equivalent in the hu-PBL-SCID
      mouse model of skin rejection.
AB  - BACKGROUND: Engineered tissues have been proposed for the treatment of a variety
      of conditions including the partial or complete replacement of human organs. To
      determine the basis for the rejection of these tissues, we analyzed the immune
      response to allogeneic human skin equivalent (HSE, also called Apligraf) in the
      humanized SCID mouse (hu-PBL-SCID). METHODS: Two models of hu-PBL-SCID were used
      for these studies. In one model, human skin or HSE was transplanted onto
      humanized mice so that graft survival could be analyzed. In the other model, skin
      grafts were allowed to heal on naive mice before humanization. This model was
      used to analyze the immunologic response to the vascularized skin allograft.
      Humanization was performed by adoptive transfer of human PBL into SCID mice by
      i.p. injection. RESULTS: Both human foreskin and HSE successfully engrafted onto
      naive SCID mice and remained stable for more than 6 months. In contrast, human
      foreskin was rejected by 21 days posttransplant in hu-PBL-SCID, whereas HSE
      consistently engrafted for more than 28 days. Treatment of HSE grafts with
      interferon-y for 5 days to induce maximal MHC class II molecule expression before
      grafting failed to induce rejection. HSE also engrafted onto hu-PBL-SCID mice
      that were exposed to alloantigen by prior injection with interferon-gamma-treated
      keratinocytes identical to those used to generate the HSE. In addition, we
      determined that humanization of SCID mice following engraftment and
      vascularization of human foreskin resulted in marked CD3+ T cell infiltrates and
      a lymphocyte-induced vasculitis. In contrast, the response in vascularized HSE
      was associated with minimal CD3+ T cell infiltration in the absence of vasculitis
      or morphological features of rejection. CONCLUSION: These results support the use
      of HSE and other allogeneic engineered tissues in humans provided that such
      tissues are limited in their antigen presenting capabilities. In addition, our
      findings suggest a critical function for the donor endothelial cell in rejection.

PMID- 10401768
TI  - Anti-major histocompatibility complex class II treatment prevents graft rejection
      in the hamster-to-rat cardiac xenograft.
AB  - BACKGROUND: Several groups have achieved graft acceptance in the concordant
      hamster to rat model by using a combination of anti-proliferative drugs and
      conventional immunosuppressive therapy. However, such aggressive treatment often
      leads to the recipient dying with a functional xenograft, as a result of
      opportunistic infections. This study aimed to investigate the effects of a short
      course of therapy with an anti-MHC class II monoclonal antibody treatment
      (chimeric OX6 [cOX6]) in combination with cyclosporin A (CyA) in a concordant
      hamster-to-rat xenograft model. METHODS: Rats receiving hamster cardiac
      xenografts were given CyA or cOX6 alone or in combination and were monitored
      daily to assess the effect of treatment on graft survival. Additional studies
      monitored the effect of treatment on the production of cytolytic anti-hamster
      antibodies by the recipient and the deposition of immunoglobulin (Ig)M and
      complement factors within the xenograft. RESULTS: Treatment with CyA only had no
      effect on graft survival, whereas treatment with cOX6 increased graft survival
      time by 2 days. The median graft survival time for cOX6+CyA was 76 days. cOX6
      treatment of rats having undergone transplants inhibited the rise in cytotoxic
      anti-hamster antibodies in peripheral blood until day 5, whereas combination
      therapy completely inhibited anti-hamster antibody formation. Fluorescence
      activated cell sorter analysis showed treatment with cOX6 significantly reduced
      circulating B cell numbers until day 5. Anti-MHC class II treatment also markedly
      reduced the deposition of both IgM and C3. Anti-MHC class II treatment with CyA
      gives long term survival in concordant xenografts without severe side effects.
      CONCLUSIONS: The mechanism of action of this combination is complex and could be
      caused by an initial inhibition of B cell function by the anti-MHC class II
      treatment and the subsequent inhibition of T cell dependent pathways by CyA.

PMID- 10401770
TI  - Prolongation of heart xenograft survival in a hamster-to-rat model after therapy
      with a rationally designed immunosuppressive peptide.
AB  - BACKGROUND: Modification of the aminoacid sequence of peptides derived from the
      HLA class I heavy chain in combination with computer rational design resulted in
      the development of a peptide, RDP1258, with enhanced immunosuppressive activity.
      METHODS: We evaluated the activity of this peptide, analyzing infiltrate by
      immunohistology and cytokine transcripts by reverse transcriptase-polymerase
      chain reaction method, in a hamster-to-rat xenograft model where recipients were
      treated with cobra venom factor (CVF) and peptide. RESULTS: Although CVF or
      peptide alone had no effect, a combination of CVF/peptide RDP1258 resulted in a
      significant prolongation of graft survival (7.9+/-1 vs. 4.5+/-0 and 3.5+/-0 days,
      P<0.001). This effect was associated with an increased expression of heme
      oxygenase 1 (HO-1) in spleen, a significant reduced graft infiltrate, and a
      decrease of tumor necrosis factor-alpha mRNA transcripts (P<0.05) compared with
      CVF-treated recipients (1.6+/-0.07 vs. 3.3+/-0.3%, P=0.001) on day 3 after
      transplantation. CONCLUSION: These observations are consistent with the
      observation that up-regulation of HO-1 results in inhibition of immune effector
      functions and suggest that the peptide acts, at least partially, through HO-1
      regulation.

PMID- 10401771
TI  - Successful myoblast transplantation in fibrotic muscles: no increased impairment
      by the connective tissue.
AB  - BACKGROUND: Implantation of normal myoblasts may eventually be a treatment for
      inherited myopathies such as Duchenne muscular dystrophy. METHODS: We report a
      comparative study of the effectiveness on myoblast implantation: (1) into the
      muscles of young (2 months) mdx mice nonirradiated and noninjected with notexin
      (group 1), (2) into muscles of old mdx mice (15 months) nonirradiated and
      noninjected with notexin (group 2), and (3) into muscles of 5 months mdx mice
      irradiated 3 months before the transplantation (group 3). Roughly 3 million cells
      were injected with bFGF in the Tibialis anterior. RESULTS: Although mice of
      groups 2 and 3 had significantly more (P<0.05) fibrotic tissue in their muscles
      than those of group 1, the transplantation success was not significantly
      different among the three groups. CONCLUSION: Therefore these results
      demonstrated that myoblast transplantation can be successful even when there is
      abundant fibrosis.

PMID- 10401769
TI  - Prolonged xenograft survival of islets infected with small doses of adenovirus
      expressing CTLA4Ig.
AB  - BACKGROUND: Systemic administration of the inhibitor of costimulation, CTLA4Ig,
      has been shown to prolong islet graft survival. The purpose of this study was to
      compare local and systemic expression of murine CTLA4Ig in transplants of rat
      islets into mice. METHODS: Murine CTLA4Ig was made by joining two polymerase
      chain reaction products, the extracellular portion of CTLA4 and the Fc portion of
      IgG2a. Recombinant adenovirus expressing CTLA4Ig (AdCTLA4Ig) was generated using
      the strategy of Cre-lox recombination. Isolated rat islets infected with
      AdCTLA4Ig at multiplicities of infection (MOIs) ranging from 0.1 to 10 were
      transplanted into streptozocin diabetic male B6AF1 mice. Control islets were mock
      infected or infected with AdLacZ or AdsIg, a recombinant adenovirus expressing
      only the Fc portion of IgG2a. Also, AdCTLA4Ig and control viruses were injected
      intramuscularly into mouse transplant recipients at the time of islet
      transplantation to provide CTLA4Ig systemically. RESULTS: Control islets
      transplanted into diabetic mice were rejected in 13-17 days. Islets infected with
      AdCTLA4Ig had dose-dependent prolongation of graft survival. Prolonged survival
      was even found with very low MOIs of 0.1 and 0.5, with survivals of 24+/-4.2 and
      25+/-2.2 days, respectively. Survival with an MOI of 10 was 39+/-8.7 days. With
      intramuscular injection, no prolongation was found at the lowest relative MOIs of
      0.2 and 1, but there was dose-dependent prolongation of graft survival with
      larger doses. At the highest relative MOI of 400, survival was prolonged to 58+/
      10 days. CONCLUSIONS: Rat islets infected with AdCTLA4Ig transplanted into mice
      had prolonged graft survival. Prolonged survival with MOIs as low as 0.1 and 0.5
      indicates that only a minority of islet cells need to express CTLA4Ig to exert an
      effect. Moreover, the results suggest that the improved islet graft survival is
      due to a local influence of CTLA4Ig.

PMID- 10401772
TI  - Nitric oxide production by bronchoalveolar cells during allograft rejection in
      the rat.
AB  - BACKGROUND: We reported the increased nitric oxide (NO) level in exhaled air of
      rat lung transplant recipients during acute rejection (AR). The aim of this study
      was to determine the site and level of NO production in the rejected graft.
      METHODS: Rat lung transplantation was performed in isografts and allografts.
      RESULTS: In isografts, no AR and no significant increase in NO production was
      identified. In allografts, grades I-II of AR was seen on postoperative day (POD)
      3 and grade III on POD 5. NO produced by BAL cells increased on both POD 3
      (11.8+/-2.0 parts per billion [ppb]) and POD 5 (115.3+/-66.9 ppb). There was a
      highly significant correlation between the level of NO and the severity of AR
      (p=0.862, P<0.005). BAL cells from allografts expressed iNOS mRNA. Among them,
      macrophages, lymphocytes and neutrophils were immunostained for iNOS. CONCLUSION:
      NO produced by BAL cells was detected in the early stages of rejection.
      Therefore, it may serve as a sensitive indicator of AR in lung transplantation.

PMID- 10401773
TI  - Angiogenesis in the huPBL-SCID model of human transplant rejection.
AB  - BACKGROUND: Angiogenesis is characteristic of chronic inflammatory reactions. The
      process of angiogenesis is reported to be proinflammatory in part due to enhanced
      adhesion events and in part due to increased perfusion and permeability to sites
      of inflammation. However, little is known about the association between
      angiogenesis and rejection. METHODS: Severe combined immune deficient mice are
      permissive for the growth of human skin allografts and human peripheral blood
      mononuclear cells (PBMC). Human PBMC were injected into mice by intravenous or
      intraperitoneal injection. The infiltration of cells and the associated
      angiogenesis reactions in the skin allografts were analyzed temporally by
      videomicroscopy and spatially by immunohistochemistry. RESULTS: Human
      alloreactive mononuclear cells migrated to human skin but not mouse skin within
      hours after the intravenous infusion of PBMC. Within 3 days, areas of
      angiogenesis were observed in the skin grafts at the sites of infiltrates. The
      vessel densities in skin grafts were 24+/-6 vessels per calibrated grid at
      baseline on the day of the infusion and increased to 55+/-16 vessels per
      calibrated field by day 10. Skin grafts harvested from humanized severe combined
      immune deficient mice 7-14 days after the intraperitoneal infusion of human PBMC
      showed a similar increased density of vessels that were spatially associated with
      mononuclear cell infiltrates. CONCLUSIONS: A significant angiogenesis response
      was associated with the cell infiltrates in the human skin allografts. The onset
      of angiogenesis appeared after the initial development of localized infiltrates
      and preceded the development of microvascular destruction. These findings suggest
      that alloreactive T cells and/or monocytes mediate the angiogenesis response in
      skin allografts.

PMID- 10401774
TI  - Chlamydia: a role for multiple sclerosis or more confusion?

PMID- 10401775
TI  - Chlamydia pneumoniae infection of the central nervous system in multiple
      sclerosis.
AB  - Our identification of Chlamydia pneumoniae in the cerebrospinal fluid (CSF) of a
      patient with multiple sclerosis (MS) led us to examine the incidence of this
      organism in the CSF from 17 patients with relapsing-remitting MS, 20 patients
      with progressive MS, and 27 patients with other neurological diseases (OND). CSF
      samples were examined for C pneumoniae by culture, polymerase chain reaction
      assays, and CSF immunoglobulin (Ig) reactivity with C pneumoniae elementary body
      antigens. C pneumoniae was isolated from CSF in 64% of MS patients versus 11% of
      OND controls. Polymerase chain reaction assays demonstrated the presence of C
      pneumoniae MOMP gene in the CSF of 97% of MS patients versus 18% of OND controls.
      Finally, 86% of MS patients had increased CSF antibodies to C pneumoniae
      elementary body antigens as shown by enzyme-linked immunosorbent assay absorbance
      values that were 3 SD greater than those seen in OND controls. The specificity of
      this antibody response was confirmed by western blot assays of the CSF, using
      elementary body antigens. Moreover, CSF isoelectric focusing followed by western
      blot assays revealed cationic antibodies against C pneumoniae. Infection of the
      central nervous system with C pneumoniae is a frequent occurrence in MS patients.
      Although the organism could represent the pathogenetic agent of MS, it may simply
      represent a secondary infection of damaged central nervous system tissue. A
      therapeutic trial directed at eliminating C pneumoniae from the central nervous
      system may provide additional information on its role in MS.

PMID- 10401776
TI  - Randomized trial of sildenafil for the treatment of erectile dysfunction in
      spinal cord injury. Sildenafil Study Group.
AB  - Erectile dysfunction is a common complication of spinal cord injury. This double
      blind, placebo-controlled, two-way crossover study assessed the efficacy and
      safety of oral sildenafil in men with erectile dysfunction caused by traumatic
      spinal cord injury. A total of 178 men (mean age, 38 years) received placebo or
      sildenafil 1 hour before sexual activity for 6 weeks; after a 2-week washout
      period, the men received the alternate treatment for 6 weeks. The 50-mg starting
      dose could be adjusted to 100 or 25 mg based on efficacy and tolerability.
      Efficacy was assessed by using global efficacy questions, the International Index
      of Erectile Function (IIEF), and a patient log of erectile activity. Of 143 men
      with residual erectile function at baseline, 111 (78%) reported improved
      erections and preferred sildenafil to placebo. For all men (including those who
      reported no residual erectile function at baseline), 127 of 168 (76%) reported
      improved erections and preferred sildenafil to placebo. For all men, 132 of 166
      (80%) reported that sildenafil improved sexual intercourse compared with 17 of
      166 men (10%) reporting improvement with placebo. IIEF questions assessing the
      ability to achieve and maintain erections and satisfaction with sexual
      intercourse demonstrated significant improvement with sildenafil. Sildenafil was
      well tolerated, with a low rate of discontinuation because of treatment-related
      adverse events (2% vs 1% for placebo). Oral sildenafil is an effective and well
      tolerated treatment for erectile dysfunction caused by spinal cord injury.

PMID- 10401777
TI  - Neuronal activity in the basal ganglia in patients with generalized dystonia and
      hemiballismus.
AB  - Microelectrode recording was performed in the basal ganglia of 3 patients with
      generalized dystonia and 1 patient with hemiballismus secondary to a brainstem
      hemorrhage. Neuronal activity was recorded from the internal and external
      segments of the globus pallidus and assessed for mean discharge rate and pattern
      of spontaneous activity. The responses of neurons in the internal segment of the
      globus pallidus to passive and active movements were also evaluated. Mean
      discharge rates of neurons in both segments of the pallidum in patients with
      dystonia and the patient with hemiballismus were considerably lower than those
      reported for patients with idiopathic Parkinson's disease. In addition, the
      pattern of spontaneous neuronal activity was highly irregular, occurring in
      intermittent grouped discharges separated by periods of pauses. Although
      receptive fields in the dystonia patients were widened and less specific than
      those reported in normal monkeys, neuronal responses to movement were uncommon in
      the hemiballismus patient. Before surgery, patients with dystonia experienced
      abnormal posturing and involuntary movements. Coactivation of agonist-antagonist
      muscle groups was observed both at rest and during the performance of simple
      movements. After pallidotomy there was a significant reduction in the involuntary
      movement associated with these disorders and a more normal pattern of
      electromyographic activity during rest and movement. Given the improvement in
      dystonic and hemiballistic movements in these patients after ablation of the
      sensorimotor portion of the internal segment of the globus pallidus, we suggest
      that pallidotomy can be an effective treatment for patients with dystonia and
      also for patients with medically intractable hemiballismus. Based on the finding
      of decreased neuronal discharge rates in pallidal neurons, we propose that
      physiologically dystonia most closely resembles a hyperkinetic movement disorder.
      A model for dystonia is proposed that incorporates the observed changes in the
      rate and pattern of neuronal activity in the pallidum with data from neuroimaging
      with positron emission tomography and 2-deoxyglucose studies.

PMID- 10401778
TI  - Hereditary auditory, vestibular, motor, and sensory neuropathy in a Slovenian
      Roma (Gypsy) kindred.
AB  - Members of a Roma (Gypsy) family with hereditary motor and sensory peripheral
      neuropathy (HMSN) and concomitant auditory and vestibular cranial neuropathies
      were identified in Kocevje, Slovenia. The illness begins in childhood with a
      severe and progressive motor disability and the deafness is delayed until the
      second decade. There are no symptoms of vestibular dysfunction. The family
      structure is consistent with an autosomal recessive pattern of inheritance and
      the genetic locus for the disorder is linked to the same region of chromosome
      8q24 as other Roma families with HMSN and deafness from Lom, Bulgaria (HMSN-Lom).
      The present study shows that the deafness is caused by a neuropathy of the
      auditory nerve with preserved measures of cochlear outer hair cell function
      (otoacoustic emissions and cochlear microphonics) but absent neural components of
      auditory brainstem potentials. The hearing loss affects speech comprehension out
      of proportion to the pure tone loss. Vestibular testing showed absence of caloric
      responses. Physiological and neuropathological studies of peripheral nerves were
      compatible with the nerve disorder contemporaneously affecting Schwann cells and
      axons resulting in both slowed nerve conduction and axonal loss. Genetic linkage
      studies suggest a refinement of the 8q24 critical region containing the HMSN-Lom
      locus that affects peripheral motor and sensory nerves as well as the cranial
      auditory and vestibular nerves.

PMID- 10401779
TI  - Seizure control and mortality in epilepsy.
AB  - Mortality rates are increased among people with epilepsy, and may be highest in
      those with uncontrolled seizures. Because epilepsy surgery eliminates seizures in
      some people, we used an epilepsy surgery population to examine how seizure
      control influences mortality. We tested the hypothesis that patients with
      complete seizure relief after surgery would have a lower mortality rate than
      those who had persistent seizures. Three hundred ninety-three patients who had
      epilepsy surgery between January 1986 and January 1996 were followed after
      surgery to assess long-term survival; 347 had focal resection or transection, and
      46 had anterior or complete corpus callosotomy. A multivariate survival analysis
      was performed, contrasting survival in those who had seizure recurrence with
      survival of those who remained seizure free. Standardized mortality ratios and
      95% confidence intervals were calculated. Overall, seizure-free patients had a
      lower mortality rate than those with persistent seizures. This was true for the
      subset of patients with localized resection or multiple subpial transection. No
      patients died among 199 with no seizure recurrence, whereas of 194 patients with
      seizure recurrence, 11 died. Six of the deaths were sudden and unexplained. Most
      patients who died had a substantial reduction in postoperative seizure frequency.
      The standardized mortality ratio for patients with recurrent seizures was 4.69,
      and the risk of death in these patients was 1.37 in 100 person-years, whereas
      among patients who became seizure free, there was no difference in mortality rate
      compared with the age- and sex-matched population of the United States.
      Elimination of seizures after surgery reduces mortality rates in people with
      epilepsy to a level indistinguishable from that of the general population,
      whereas patients with recurrent seizures continue to suffer from high mortality
      rates. This suggests that uncontrolled seizures are a major risk factor for
      excess mortality in epilepsy. Achieving complete seizure control with epilepsy
      surgery in refractory patients reduces the risk of death, so the long-term risk
      of continuing medical treatment appears to be higher than the risk of epilepsy
      surgery in suitable candidates.

PMID- 10401780
TI  - Mirror agnosia and mirror ataxia constitute different parietal lobe disorders.
AB  - We describe two new clinical syndromes, mirror agnosia and mirror ataxia, both
      characterized by the deficit of reaching for an object through a mirror in
      association with a lesion of either parietal lobe. Clinical investigation of 13
      patients demonstrated that the impairments affected both sides of the body. In
      mirror agnosia, the patients always reached toward the virtual object in the
      mirror and they were not capable of changing their behavior even after
      presentation of the position of the object in real visual space. In mirror ataxia
      (resembling optic ataxia) although some patients initially tended to reach for
      the virtual object in the mirror, they soon learned to guide their arms toward
      the real object, all of them producing many directional errors. Both patient
      groups performed poorly on mental rotation, but only the patients with mirror
      agnosia were impaired in line orientation. Only 1 of the patients suffered from
      neglect and 3 from apraxia. Magnetic resonance imaging showed that in mirror
      agnosia the common zone of lesion overlap was scattered around the posterior
      angular gyrus/superior temporal gyrus and in mirror ataxia around the postcentral
      sulcus. We propose that both these clinical syndromes may represent different
      types of dissociation of retinotopic space and body scheme, or likewise, of
      allocentric and egocentric space normally adjusted in the parietal lobe.

PMID- 10401781
TI  - Positron emission tomographic measurement of acetylcholinesterase activity
      reveals differential loss of ascending cholinergic systems in Parkinson's disease
      and progressive supranuclear palsy.
AB  - We measured brain acetylcholinesterase activity in 16 patients with Parkinson's
      disease (PD), 12 patients with progressive supranuclear palsy (PSP), and 13 age
      matched controls, using N-methyl-4-[11C]piperidyl acetate and positron emission
      tomography. Kinetic analysis was performed to calculate k3, an index of
      acetylcholinesterase activity. In PD patients, there was a significant reduction
      (-17%) of cerebral cortical k3 compared with normal controls, whereas there was
      only a nonsignificant reduction (-10%) of cortical k3 in PSP patients. However,
      there was a prominent reduction (-38%) of thalamic k3 in PSP patients compared
      with normal controls, whereas there was only a nonsignificant reduction (-13%) of
      thalamic k3 in PD patients. The results suggest that there is a loss of
      cholinergic innervation to the cerebral cortex in association with cholinergic
      innervation to the thalamus in PD, whereas there is a preferential loss of
      cholinergic innervation to the thalamus in PSP. When the thalamic to cerebral
      cortical k3 ratio was taken for each subject, PD and PSP were separated,
      suggesting that positron emission tomography measurement of acetylcholinesterase
      activity may be useful for differentiating the two similar disorders.

PMID- 10401782
TI  - Computed tomography and magnetic resonance imaging in mild to moderate head
      injury: early and late imaging related to outcome.
AB  - Serial magnetic resonance imaging (MRI) and computed tomographic (CT) studies
      were performed in mild to moderate head injury to evaluate whether early and late
      imaging have additional value in predicting outcome in this category of patients.
      During 1-year follow-up of a series of 67 patients, a CT scan on admission was
      performed together with MRI studies within 1 to 3 months and 6 to 12 months after
      injury. With CT, intracranial lesions were seen in 62% of patients compared with
      44% with early and 19% with late MRI, located predominantly in the frontal and
      temporal regions. More than half of the lesions revealed with CT resulted in
      focal atrophy on MRI. Outcome was found to be worse in patients with edema and
      lesions on CT. Likewise, abnormalities detected with MRI were associated with
      poor outcome scores. In multiple regression analysis, only lesions in the frontal
      regions detected with early MRI were found to be predictive of outcome. With late
      MRI, only focal atrophy in the frontotemporal regions was found to be predictive
      of outcome. The findings in this study suggests that MRI studies may be valuable
      for predicting long-term outcome in patients with mild to moderate HI.

PMID- 10401784
TI  - Diagnosis of subtle focal dysplastic lesions: curvilinear reformatting from three
      dimensional magnetic resonance imaging.
AB  - Focal cortical dysplasia is a frequent cause of medically intractable partial
      epilepsy. These lesions are being increasingly identified by high quality images
      provided by magnetic resonance imaging (MRI), resulting in improved seizure
      control of surgically treated patients. Small dysplastic lesions are often missed
      by conventional MRI methods. The identification of subtle structural
      abnormalities by rectilinear slices is often limited by the complex convolutional
      pattern of the brain. We developed a method of curvilinear reformatting of three
      dimensional MRI data that improves the anatomical display of the gyral structure
      of the hemispheric convexities. It also reduces the asymmetric sampling of gray
      white matter that may lead to false-positive results. We present 5 patients in
      whom conventional two-dimensional and three-dimensional MRI with multiplanar
      reformatting was initially considered normal. Subsequent studies using
      curvilinear reformatting identified lesions in all. Four patients underwent
      surgery with histological diagnosis of focal cortical dysplasia. Three patients
      are seizure-free and 1 had significant improvement in seizure control. These
      results indicate that an increase in the detection of subtle focal dysplastic
      lesions may be accomplished when one improves the anatomical display of the brain
      gyral structure by performing curvilinear reformatting.

PMID- 10401783
TI  - Neuronal damage in T1-hypointense multiple sclerosis lesions demonstrated in vivo
      using proton magnetic resonance spectroscopy.
AB  - Hypointense T1 lesions in multiple sclerosis patients correlate with axonal loss
      at autopsy and biopsy. We evaluated the chemical substrate of hypointense T1
      lesions by using in vivo proton magnetic resonance spectroscopy, and analyzed the
      spectroscopic correlate of increased T1-relaxation time measurements. Localized
      proton magnetic resonance spectroscopy and T1-relaxation time measurements were
      performed in lesions, selected on T1-weighted spin-echo magnetic resonance images
      according to degree of hypointensity, in normal appearing white matter (NAWM) and
      in normal white matter of controls. In NAWM, prolongation of T1-relaxation time
      and a decrease in N-acetylaspartate (NAA) were present, compared with normal
      white matter. Severely hypointense lesions showed a lower concentration of NAA
      and creatine compared with NAWM and a lower concentration of NAA compared with
      isointense to mildly hypointense lesions. NAA concentration correlated with
      degree of hypointensity of lesions and with T1-relaxation time within the
      spectroscopic voxel. Our results provide the first in vivo evidence of axonal
      damage in severely hypointense T1 lesions in multiple sclerosis patients. T1
      relaxation time correlates with the concentration of NAA in both multiple
      sclerosis lesions and NAWM, indicating that this parameter deserves further
      evaluation to monitor disease progression.

PMID- 10401785
TI  - Epileptogenic action of caffeine during anoxia in the neonatal rat hippocampus.
AB  - Excessive maternal caffeine consumption can lead to fetal and neonatal pathology,
      but the underlying mechanisms have not been determined. Here, we report that low
      doses of caffeine generate seizures when applied in conjunction with brief anoxic
      episodes in the hippocampus of neonatal rats in vitro. In control conditions,
      brief (4-6 minutes) anoxic episodes reversibly depressed evoked synaptic
      responses and blocked the physiological pattern of network activity. In the
      presence of caffeine (50 microM), similar anoxic episodes generated ictal (29%)
      or interictal (33%) epileptiform activities often followed during reoxygenation
      by recurrent spontaneous seizure activity that persisted for several hours. These
      effects are likely mediated by a blockade of adenosine receptors by caffeine
      because (1) in control conditions, caffeine antagonized the inhibitory effect of
      selective A1 receptor agonist N6-cyclopentyladenosine on excitatory synaptic
      responses, and (2) epileptogenic effects of caffeine were reproduced by selective
      A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine and theophylline. Our
      findings suggest that endogenous adenosine released during anoxia acting via A1
      receptors prevents seizures in the neonatal hippocampus and that the antagonism
      of these receptors by caffeine leads to epileptogenesis. This study suggests
      concerns about the safety of caffeine in the fetus and newborn.

PMID- 10401786
TI  - Levodopa induces a cytoplasmic localization of D1 dopamine receptors in striatal
      neurons in Parkinson's disease.
AB  - Parkinson's disease is characterized by a massive loss of nigral dopamine neurons
      that results in a reduction of dopamine concentrations in the striatum. The most
      commonly used treatment for this disease is levodopa therapy to restore striatal
      dopamine. This treatment is mediated by dopamine receptors, but the effect of
      treatment and the disease on receptor distribution is unknown. In this study, the
      distribution of D1 dopamine receptors was analyzed at the cellular and
      subcellular level in the striatum of 5 patients with Parkinson's disease (all
      treated with levodopa) and 4 control subjects. In the control brains, D1 dopamine
      receptors were mostly detected on the plasma membrane of medium-sized spiny
      neurons. The quantitative analysis performed at the ultrastructural level in
      patients with Parkinson's disease revealed an increase in immunostaining in the
      cytoplasm of medium-sized neurons. This effect was likely the result of the
      treatment rather than the dopaminergic denervation, as such changes were not
      observed in the striatum of rats with a unilateral 6-hydroxydopamine
      nigrostriatal lesion, but were present in normal or lesioned rats treated with a
      D1 dopamine agonist. Altered localization of D1 dopamine receptors may
      participate in the occurrence of side effects of levodopa therapy such as
      dyskinesia and fluctuations in motor performances.

PMID- 10401787
TI  - A de novo splice donor site mutation causes in-frame deletion of 14 amino acids
      in the proteolipid protein in Pelizaeus-Merzbacher disease.
AB  - Pelizaeus-Merzbacher disease (PMD) is a leukodystrophy associated with mutations
      in the proteolipid protein (PLP) gene. Jimpy is a mouse model of human PMD, and a
      splice site mutation in Jimpy causes the deletion of exon 5 from the PLP mRNA,
      producing a truncated form of PLP. We describe a de novo point mutation at the 5'
      splice donor site of exon 5 in a 17-year-old male with PMD, which results in the
      skipping of 42 base pairs of exon 5. The mutation removes only 14 amino acids in
      frame of PLP. This is a novel splice donor site mutation in the human PLP gene.
      Moreover, the results indicate that the 14-amino acid deletion in the PLP is
      responsible for oligodendrocyte cell death and the development of PMD.

PMID- 10401788
TI  - Homozygotes for oculopharyngeal muscular dystrophy have a severe form of the
      disease.
AB  - Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) usually begins with
      ptosis or dysphagia during the fifth or sixth decade of life. We studied 7
      patients with OPMD symptoms starting before the age of 36 years. All were found
      to be homozygotes for the dominant (GCG)9 OPMD mutation. On average, disease
      onset was 18 years earlier than in heterozygotes, and patients had a
      significantly larger number of muscle nuclei containing intranuclear inclusions
      (INIs) (9.4 vs 4.9%).

PMID- 10401789
TI  - Anti-myelin-associated glycoprotein antibodies predict the development of
      neuropathy in asymptomatic patients with IgM monoclonal gammopathy.
AB  - We examined 52 asymptomatic patients with IgM monoclonal gammopathy and
      correlated anti-myelin-associated glycoprotein (anti-MAG) IgM with the presence
      of subclinical neuropathy and, in 24 of these patients, with the development of
      symptomatic neuropathy during a follow-up interval of 40 to 144 months (mean,
      75.3 months). Three of 6 patients (50%) with high (>1/6,400) anti-MAG IgM had
      subclinical neuropathy at entry compared with 2 of 46 patients (4.3%) with low or
      no reactivity. At follow-up, a symptomatic neuropathy occurred in 3 of 4 patients
      with high reactivity and in 3 of 21 patients with low or no reactivity. The
      correlation of high anti-MAG IgM with the presence of subclinical neuropathy or
      the development of symptomatic neuropathy supports its pathogenetic role in the
      neuropathy.

PMID- 10401790
TI  - Increased iron in the dentate nucleus of patients with Friedrich's ataxia.
AB  - Friedreich's ataxia (FA) is the most frequently inherited ataxia. To test the
      hypothesis that iron is increased in the cerebellum of patients with FA, we
      developed a multigradient echo magnetic resonance sequence for the three
      dimensional imaging of brain iron-induced contrast. Relaxation rate (R2*) values
      in the unaffected globus pallidus were equal in FA patients and controls,
      although R2* values in the dentate nucleus of patients were significantly higher,
      which is most likely due to increased iron.

PMID- 10401791
TI  - Function of the cerebellum in Parkinsonian rest tremor and Holmes' tremor.
AB  - We describe a patient who developed Parkinson's disease (PD) 17 years after
      resection of his right cerebellum because of a Lindau tumor. He showed a classic
      4.3-Hz resting tremor on the left side but a 3.1-Hz resting, postural, and
      intention tremor on the right side compatible with midbrain tremor (Holmes'
      tremor). We conclude that the generator of the tremor in PD cannot be located
      within the olivocerebellar loop. The cerebellum, however, seems to modulate the
      tremor frequency of parkinsonian rest tremor and may prevent the rest tremor from
      transforming into a postural and goal-directed tremor.

PMID- 10401792
TI  - Remarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with
      sporadic amyotrophic lateral sclerosis.
AB  - To investigate the significance of peroxynitrite-mediated oxidative damage in the
      pathogenesis of sporadic amyotrophic lateral sclerosis (SALS), the concentrations
      of 3-nitrotyrosine and tyrosine in the cerebrospinal fluid (CSF) of patients with
      SALS were determined. The concentration of 3-nitrotyrosine and the 3
      nitrotyrosine/ tyrosine ratio in patients with SALS were approximately seven
      times those of controls. Thus, the present findings in living patients provide in
      vivo evidence for a possible role of peroxynitrite, a mediator of oxidative
      stress, and increased nitration of tyrosine residues in the pathogenesis of SALS.

PMID- 10401793
TI  - Guidelines for clinical trials of new therapeutic agents in multiple sclerosis:
      reporting extended results from phase III clinical trials. National Multiple
      Sclerosis Society Advisory Committee on Clinical Trials of New Agents in Multiple
      Sclerosis.

PMID- 10401794
TI  - Does increased superoxide dismutase activity really cause muscular dystrophy?

PMID- 10401795
TI  - Copper/zinc superoxide dismutase: more is not necessarily better!

PMID- 10401796
TI  - Lack of association between bleomycin hydrolase gene polymorphism and Alzheimer's
      disease in Japanese people.

PMID- 10401797
TI  - On dystrophin abundance and C-terminal missense mutations in dystrophinopathies.

PMID- 10401798
TI  - Cost-effective management of sore throat: it depends on the perspective.

PMID- 10401799
TI  - Comparison of soy-based formulas with lactose and with sucrose in the treatment
      of acute diarrhea in infants.
AB  - OBJECTIVE: To evaluate the effect of feeding infants a soy-based formula with
      lactose compared with a soy-based formula with sucrose during an acute diarrheal
      episode. PARTICIPANTS AND METHODS: Two hundred boys, aged 3 to 18 months, who
      were admitted to the hospital with acute diarrhea and signs of dehydration were
      randomly assigned to receive a soy-based formula with lactose or sucrose after
      initial rehydration. Intake and output (stool, urine, and vomit) were measured
      and recorded every 3 hours until diarrhea resolved. RESULTS: The stool output
      during the first 24 hours of maintenance therapy, the total stool output during
      maintenance therapy, and the stool output during the entire illness (measured in
      grams per kilograms) were significantly lower among patients who received the soy
      based formula with sucrose (P<.05, P<.001, and P<.001, respectively) than among
      patients who received the soy-based formula with lactose. The duration of
      diarrhea was significantly shorter among patients who received the soy-based
      formula with sucrose (P<.001). The relative risk of being withdrawn from the
      study increased to 1.95 (95% confidence interval, 0.65-9.2) and the relative risk
      of recurrence of dehydration after feeding was initiated increased significantly
      to 3.49 (95% confidence interval, 1.1-9.6; P<.01) in the group receiving the soy
      based formula with lactose. CONCLUSION: During diarrheal episodes, feeding
      infants a soy-based formula with sucrose has a better outcome (lower stool
      output, shorter duration of diarrhea, and lower failure rates) than feeding
      infants a soy-based formula with lactose.

PMID- 10401800
TI  - Management of sore throats in children: a cost-effectiveness analysis.
AB  - OBJECTIVE: To perform a cost-effectiveness analysis of treatment management
      strategies for children older than 3 years who present with signs or symptoms of
      pharyngitis. DESIGN: Decision model with 7 strategies, including neither testing
      for streptococcus nor treating with antibiotics; treating empirically with
      penicillin V; basing treatment on results of a throat culture (Culture); and
      basing treatment on results of enzyme immunoassay or optical immunoassay rapid
      tests, performed alone or in combination with throat cultures. In these 7
      strategies, all tests are performed in a local reference laboratory. In a
      sensitivity analysis, we examined the cost-effectiveness of 4 strategies
      involving office-based testing. We obtained data on event probabilities and test
      characteristics from our hospital's clinical laboratory and the literature; costs
      for the analysis were based on resource use. RESULTS: At a baseline prevalence of
      20.8% for streptococcal pharyngitis, the Culture strategy was the least expensive
      and most effective, with an average cost of $6.85 per patient. The outcome was
      sensitive to the prevalence of streptococcal pharyngitis, the rheumatic fever
      attack rate, the cost of the enzyme immunoassay test, and the cost of culturing
      and reporting culture results. The Culture strategy was also preferred if
      amoxicillin was substituted for oral penicillin. For office-based testing,
      Culture was the least costly strategy, but treatment based on results of the
      optical immunoassay test alone had an incremental cost-effectiveness ratio of
      $1.6 million per additional life saved. CONCLUSION: In a setting with adherent
      patients, children with sore throats should generally get throat cultures in lieu
      of rapid streptococcus antigen tests.

PMID- 10401801
TI  - Breast-feeding and environmental tobacco smoke exposure.
AB  - BACKGROUND: Exposure to environmental tobacco smoke is associated with adverse
      effects in infants and children. OBJECTIVE: To explore whether an increase in
      urinary cotinine fumarate level is caused by ingested nicotine and cotinine in
      breast-feeding infants. METHODS: We studied newborns at risk for developing
      asthma and allergies based on a strong family history. We measured urinary
      cotinine levels in the infants as a measure of environmental tobacco smoke
      exposure and cotinine levels in the breast milk of breast-feeding mothers.
      RESULTS: Of 507 infants, urinary cotinine levels during the first 2 weeks of life
      were significantly increased in infants whose mothers smoked. Breast-fed infants
      had higher cotinine levels than non-breast-fed infants, but this was
      statistically significant (P<.05) only if mothers smoked. Urinary cotinine levels
      were 5 times higher in breast-fed infants whose mothers smoked than in those
      whose mothers smoked but did not breast-feed. CONCLUSIONS: Mothers should be
      encouraged to not smoke, and parents must be advised of the potential respiratory
      and systemic risks of environmental tobacco smoke exposure to their child,
      including the potential for future addiction to smoking.

PMID- 10401802
TI  - Three-year maintenance of improved diet and physical activity: the CATCH cohort.
      Child and Adolescent Trial for Cardiovascular Health.
AB  - OBJECTIVE: To assess differences through grade 8 in diet, physical activity, and
      related health indicators of students who participated in the Child and
      Adolescent Trial for Cardiovascular Health (CATCH) school and family intervention
      from grades 3 through 5. DESIGN: Follow-up of the 4-center, randomized,
      controlled field trial with 56 intervention and 40 control elementary schools.
      PARTICIPANTS: We studied 3714 (73%) of the initial CATCH cohort of 5106 students
      from ethnically diverse backgrounds in California, Louisiana, Minnesota, and
      Texas at grades 6, 7, and 8. RESULTS: Self-reported daily energy intake from fat
      at baseline was virtually identical in the control (32.7%) and intervention
      (32.6%) groups. At grade 5, the intake for controls remained at 32.2%, while the
      intake for the intervention group declined to 30.3% (P<.001). At grade 8, the
      between-group differential was maintained (31.6% vs 30.6%, P = .01). Intervention
      students maintained significantly higher self-reported daily vigorous activity
      than control students (P = .001), although the difference declined from 13.6
      minutes in grade 5 to 11.2, 10.8, and 8.8 minutes in grades 6, 7, and 8,
      respectively. Significant differences in favor of the intervention students also
      persisted at grade 8 for dietary knowledge and dietary intentions, but not for
      social support for physical activity. No impact on smoking behavior or stages of
      contemplating smoking was detected at grade 8. No significant differences were
      noted among physiologic indicators of body mass index, blood pressure, or serum
      lipid and cholesterol levels. CONCLUSION: The original CATCH results demonstrated
      that school-level interventions could modify school lunch and school physical
      education programs as well as influence student behaviors. This 3-year follow-up
      without further intervention suggests that the behavioral changes initiated
      during the elementary school years persisted to early adolescence for self
      reported dietary and physical activity behaviors.

PMID- 10401803
TI  - The pediatric primary-specialty care interface: how pediatricians refer children
      and adolescents to specialty care.
AB  - OBJECTIVE: To describe how pediatricians refer patients to specialists, including
      frequency of referral decisions, reasons for referral, and types of referrals.
      DESIGN: We conducted a prospective study of visits (N = 58 771) made to 142
      pediatricians in a national primary care practice-based research network. During
      20 consecutive practice days, physicians and parents completed questionnaires for
      referred patients, and office staff kept logs of all visits. Physicians used
      medical records to complete questionnaires 3 months after referrals were made.
      RESULTS: Pediatricians referred patients to specialists during 2.3% of office
      visits. Referrals made during telephone conversations with parents accounted for
      27.5% of all referrals. The most common reason for referral was advice on
      diagnosis or treatment (74.3%). Referrals were made most commonly to surgical
      subspecialists (52.3%), followed by medical subspecialists (27.9%), nonphysicians
      (11.4%), and mental health practitioners (8.4%). Physicians requested a
      consultation or a referral with shared management in 75% of cases. Otitis media
      was the condition referred most often (9.2%). Fifty other conditions accounted
      for 84.3% of all referrals. CONCLUSIONS: About 1 in 40 pediatric visits result in
      referral. Getting advice from a specialist is the most common reason for
      referral. Pediatricians desire a collaborative relationship with specialists for
      most of their referred patients. Physician training to increase clinical
      competence may be most useful for the 50 most commonly referred conditions.
      Education concerning the referral process should focus on the respective roles of
      the referring physician and specialist, particularly as they pertain to
      successful approaches for comanaging referred patients.

PMID- 10401804
TI  - Pulmonary hemorrhage: clinical course and outcomes among very low-birth-weight
      infants.
AB  - OBJECTIVE: To describe the clinical course, neonatal morbidity, and
      neurodevelopmental outcomes of very low-birth-weight (<1500 g) children who
      develop pulmonary hemorrhage. DESIGN: A retrospective case-control study in which
      58 very low-birth-weight infants who developed pulmonary hemorrhage during 1990
      through 1994, of whom 29 survived, were each matched to the next admitted infant
      who required mechanical ventilation for respiratory distress syndrome and was of
      the same sex, race, and birth weight (within 250 g). SETTING: A regional tertiary
      neonatal intensive care unit and follow-up clinic for high-risk infants at
      University Hospitals of Cleveland, Cleveland, Ohio. MAIN OUTCOME MEASURES:
      Survival, neonatal morbidity, and neurodevelopmental outcome at 20 months'
      corrected age. RESULTS: Pulmonary hemorrhage occurred in 5.7% of the total
      population of very low-birth-weight infants. Despite similar severity of lung
      disease, significantly more infants who developed pulmonary hemorrhage received
      surfactant therapy compared with controls (91% vs 69%, P = .005). Infants with
      pulmonary hemorrhage who died had a lower birth weight and gestational age
      compared with those who survived (766 g vs 1023 g; 25 weeks vs 28 weeks, P<.001)
      and more received surfactant therapy (100% vs 83%, P = .05). Survivors with
      pulmonary hemorrhage did not differ significantly from controls in rates of
      oxygen dependence at 36 weeks corrected age (52% vs 38%), grade 3 to 4
      periventricular hemorrhage (28% vs 17%), or necrotizing enterocolitis (3% vs 7%),
      but tended to have more seizures (24% vs 3%, P = .05), periventricular
      leucomalacia (17% vs 0%, P = .06), and patent ductus arteriosus (79% vs 55%, P
      =.09). There were no significant differences in neurodevelopmental outcomes at 20
      months' corrected age, (cerebral palsy, 16% vs 14%; subnormal [<70] Bayley Mental
      Developmental Index, 59% vs 43%; and deafness, 13% vs 10%). CONCLUSION: Although
      mortality is high, pulmonary hemorrhage does not significantly increase the risk
      of later pulmonary or neurodevelopmental disabilities among those who survive.

PMID- 10401805
TI  - Current use of adequate preparticipation history forms for heart disease
      screening of high school athletes.
AB  - OBJECTIVE: To determine the proportion of US high schools using sports
      preparticipation evaluation (PPE) forms containing the 3 elements of the medical
      history currently recommended for screening young athletes for heart disease,
      including questions about exercise-related symptoms, previous diagnosis of heart
      murmur or high blood pressure, and family history of early myocardial infarction
      or sudden death. DESIGN: A random, population-based mail survey was conducted of
      500 US high schools. The survey was mailed to the athletic trainer at each
      school. Each trainer was asked to complete and return a brief survey along with a
      copy of the PPE form used at that school. PARTICIPANTS: High schools employing an
      athletic trainer who is a member of the National Athletic Trainers Association.
      MAIN OUTCOME MEASURE: The proportion of PPE forms containing all 3 components of
      the recommended cardiac screening history, RESULTS: Of the 500 high schools
      surveyed, 254 (50.8%) responded. Of the PPE forms received, 47 (25.3%) included
      questions about exercise-related symptoms, 97 (52.2%) included questions about a
      previous diagnosis of heart murmur or high blood pressure, and 57 (30.7%) had
      questions about a family history of early myocardial infarction or sudden death.
      Only 32 (17.2%) of the PPE forms received contained all 3 components of the
      recommended cardiac screening history. CONCLUSIONS: Only 17.2% of high schools in
      this nationwide survey use PPE forms that contain all the elements of the cardiac
      history recommended by the American Academy of Pediatrics for identifying young
      athletes at risk for sudden death.

PMID- 10401806
TI  - Rehospitalization of children with asthma.
AB  - BACKGROUND: Although some children with asthma experience multiple admissions,
      asthma is considered a preventable cause of hospitalization. OBJECTIVE: To assess
      whether components of medical histories, ambulatory care prior to
      hospitalization, or ambulatory care after discharge are associated with repeated
      hospitalizations for children admitted with asthma. DESIGN: Nested case-control
      study of a cohort of children hospitalized for asthma, comparing those who were
      rehospitalized within 1 year with those not rehospitalized. SETTING: Urban
      pediatric primary care clinic. PARTICIPANTS AND METHODS: Subjects were 119
      children, aged 0 to 14 years, who had an inpatient admission with a diagnosis of
      asthma between July 1, 1993, and June 30, 1995 (index hospitalization). Data
      sources included medical charts, computerized patient records, and administrative
      data. Use of health care services was compared among children who were
      rehospitalized within 1 year of the index admission and those who were not. MAIN
      OUTCOME MEASURE: Repeated hospitalizations. RESULTS: The proportions of children
      who received general pediatric, allergy, or pulmonary care in the year prior to
      the index hospitalization were 86%, 7%, and 8%, respectively. By report, half of
      all children did not receive prescribed therapies, more than half were exposed to
      cigarette smoke at home, and one fourth were not up-to-date with immunizations at
      the time of admission. Thirty-five of the 119 children hospitalized with asthma
      were subsequently readmitted with asthma within 1 year of the index
      hospitalization. Children readmitted did not differ from those with a single
      admission in terms of the above characteristics. However, significantly more
      children subsequently readmitted had a pulmonary consultation during the index
      admission (23% vs 4%; P = .001) or in the year following discharge (37% vs 12%; P
      = .002). In addition, children readmitted were more likely to have other chronic
      conditions (69% vs 49%; P= .048). CONCLUSION: Among low-income urban children,
      readmission for asthma is not associated with receipt of prescribed therapies or
      pediatric care.

PMID- 10401807
TI  - Pharmacy-based evaluation and treatment of minor illnesses in a culturally
      diverse pediatric clinic.
AB  - BACKGROUND: Among medically underserved immigrant parents, access to
      nonprescription medicines for home treatment of minor childhood illnesses may be
      limited by scarce financial resources or language barriers. OBJECTIVES: To design
      and implement a new clinical service for an urban ambulatory pediatric clinic
      with a large immigrant population that allows pharmacists to evaluate and to
      treat children and adolescents aged 6 months to 19 years with minor acute
      illnesses and to provide bilingual patient education materials. METHODS: We
      developed protocols and encounter forms for pharmacist evaluation of 5 pediatric
      conditions: cough/cold, fever, diaper rash, vomiting/diarrhea, and head lice. We
      published bilingual patient education materials for these conditions in 8
      commonly spoken languages. We assessed safety by thoroughly reviewing the medical
      records of all patients who returned within 1 week of a pharmacy encounter and by
      asking parents in a telephone survey to compare services received through the
      pharmacy and the acute care clinic for treatment of the common cold. RESULTS:
      During the first year of this pilot program, 191 patients were evaluated and
      treated, 145 (76%) for cough/cold. Seventy percent of the patients were
      immigrants. No unexpected or adverse outcomes were detected, although occasional
      deviations from established protocols were noted. Parent satisfaction with the
      pharmacy service was high, and similar to that received through the standard
      acute care clinic. Patients evaluated by pharmacists were more likely to be
      attended to promptly (< 15-minute wait) and were more likely to receive written
      information than patients evaluated by physicians for similar conditions.
      CONCLUSIONS: Pharmacist evaluation and treatment of minor pediatric illnesses
      seems to be both safe and well accepted. Further studies are needed to evaluate
      the cost-effectiveness of this service in diverse settings. In states that allow
      pharmacists to have prescriptive authority, pharmacy-based evaluation and
      treatment may improve access to care for children with minor illnesses.

PMID- 10401808
TI  - Sudden infant death syndrome among twins.
AB  - BACKGROUND: Sudden infant death syndrome (SIDS) is a major contributor to infant
      mortality. Previous studies have suggested that infants born of twin pregnancies
      are at greater risk for SIDS and that a twin who survives after a co-twin dies is
      at increased risk for SIDS. OBJECTIVE: To attempt to confirm the increased risk
      of SIDS among and within twin pairs through the use of US vital statistics data.
      METHODS: We analyzed data from the US-linked birth and infant death certificate
      tapes for the years 1987 through 1991 to determine the risk of SIDS in twin
      births compared with singleton births and to describe the characteristics of twin
      pairs in whom SIDS occurred. The analysis was limited to live births with weights
      of 500 g or more and gestational ages of 24 weeks or more. We used an algorithm
      to match co-twins (infants within a twin pair) to measure sex and birth weight
      concordancy, to identify twin pairs, in which one or both twins died of SIDS; and
      to examine, when both twins died, whether they died on the same day. RESULTS:
      There were 23464 singleton SIDS deaths and 1056 twin SIDS deaths during the 5
      year period. The crude relative risk for SIDS among twins compared with singleton
      births was 2.06 (95% confidence interval, 1.94-2.19). The adjusted relative risk
      independent of birth weight and sociodemographic variables was 1.13 (95%
      confidence interval, 0.97-1.31). We successfully matched the co-twins of 172029
      twin pregnancies. Of these, 767 were twin pregnancies in which one or both twins
      died of SIDS. Among the 767 twin pregnancies in which one or both twins
      experienced SIDS, there were only 7 in which both twins died of SIDS (rate ratio,
      4.0 per 100000 twin pregnancies). In only 1 of these 7 did both twins die on the
      same day (rate ratio, 0.58 per 100000 twin pregnancies). The relative risk for a
      second twin dying of SIDS was 8.17 (90% confidence interval, 1.18-56.67).
      CONCLUSIONS: Independent of birth weight, twins do not appear to be at greater
      risk for SIDS compared with singleton births. In addition, the occurrence of both
      twins dying of SIDS is uncommon, and the occurrence of both twins dying on the
      same day is extremely uncommon.

PMID- 10401809
TI  - Self-reported weight status and dieting in a cross-sectional sample of young
      adolescents: National Health and Nutrition Examination Survey III.
AB  - OBJECTIVE: To explore the relationship of self-reported weight status and dieting
      to actual weight and height in a cross-sectional nationally representative sample
      of young adolescents. METHODS: Weights and heights were obtained on 1932
      adolescents aged 12 to 16 years enrolled in the National Health and Nutrition
      Examination Survey III. Information on adolescents' perception of weight status,
      desired weight, and weight loss attempts was obtained by questionnaire. RESULTS:
      Adolescents' reports of whether they considered themselves overweight or normal
      weight correlated poorly with medical definitions of overweight: 52% of girls who
      considered themselves overweight were, in fact, normal weight (body mass index <
      or = 85th percentile), while only 25% of boys who considered themselves
      overweight were normal weight (P<.001). Adolescent white girls were significantly
      more likely to consider themselves overweight, even when their weight status was
      normal, than black girls (P<.001), black boys (P<.001), and white boys (P<.001).
      Adolescent white girls were also more likely to diet than black girls (P<.001),
      black boys (P<.001), and white boys (P<.001). Dieting behavior was associated
      with whether adolescents viewed themselves as overweight independent of whether
      they actually were overweight. Racial differences between dieting and self
      perceived weight status were limited to girls. There were no significant
      differences in self-perceived weight status (P = .28), dieting behaviors (P =
      .99), and desire to weigh less (P = .95) among black and white boys. CONCLUSIONS:
      Significant sex and racial differences existed in weight perception, desired
      weight, and dieting. A high proportion of normal-weight white girls consider
      themselves overweight and have attempted to lose weight.

PMID- 10401810
TI  - Impact of North Carolina's universal vaccine purchase program by children's
      insurance status.
AB  - OBJECTIVE: To examine the impact of a new universal purchase vaccine program on
      immunization rates of children with different types of insurance. DESIGN:
      Ecologic study using parent telephone interviews, medical chart abstraction in
      sites of outpatient care, and insurance verification with Medicaid and private
      insurers. SETTING: State of North Carolina. PARTICIPANTS: Of a random birth
      certificate sample of 4385 children born in North Carolina during 1994 and 1995,
      507 were excluded. A total of 2767 children had completed parent interviews; 95%
      of those had medical chart abstraction and insurance data. MAIN OUTCOME MEASURES:
      Immunization rates at each month during the first 2 years of age, site of
      delivery for immunizations and well-child visits, and insurance status. RESULTS:
      In month-by-month comparisons, children born in 1995 had immunization rates 4% to
      10% higher than their 1994 counterparts. By 24 months of age, 84% of the 1995
      cohort had completed the primary immunization series, compared with 79% of the
      1994 cohort (P<.001). In all insurance subgroups, 1995 immunization rates were
      higher than 1994 rates. The largest increases occurred among privately insured
      children with no well-child coverage, children who had periods of being
      uninsured, and children enrolled in Medicaid exclusively or with private
      insurance. More children in the 1995 cohort received immunizations in the private
      sector. CONCLUSIONS: Implementation of North Carolina's universal purchase
      program was associated with improved immunization rates, especially for children
      with inadequate insurance for well-child care. However, insurance status still
      influences the ability of children to receive immunizations on schedule.

PMID- 10401811
TI  - Effect of a longitudinal course on student performance in clerkships.
AB  - OBJECTIVE: To determine the effect that a 3-year primary-care course experience
      with family medicine, internal medicine, or pediatric preceptors would have on
      clerkship performance in pediatrics and internal medicine. DESIGN: In 1 academic
      year, third-year students were divided retrospectively into 3 groups based on
      preceptor type in the primary care course. An analysis of variance was conducted.
      When the analysis of variance showed statistical significance, a multiple
      comparison t test was performed. SETTING: University medical school with a
      longitudinal preceptor experience. PARTICIPANTS: One hundred nine third-year
      medical students who participated in the primary care course and completed the
      pediatric and internal medicine clerkships. Fifty-six students took part in the
      self-assessment portion of the study. MAIN OUTCOME MEASURES: Student performance
      scores in the pediatric clerkship and internal medicine clerkship were analyzed
      for significant differences based on preceptor type. Student self-assessment on
      pediatric objectives was analyzed for significant differences based on preceptor
      experience. RESULTS: Students with pediatric preceptors received higher clinical
      scores in the pediatric clerkship (P = .04) and perceived themselves as more
      advanced on 18 of the 39 pediatric curriculum pretest self-assessment items.
      Students with pediatric or internal medicine preceptors received significantly
      higher scores on the written patient medical history and physical examinations (P
      = .02). There were no significant differences on the pediatric written
      examination. There were no significant performance differences in the internal
      medicine clerkship. All hypothesis testing was conducted at the 95% confidence
      level. CONCLUSION: Experiences with pediatric preceptors in the early years of
      medical school may improve a student's performance and confidence in the
      pediatric clerkship.

PMID- 10401812
TI  - Radiological case of the month. Atypical cat-scratch disease.

PMID- 10401813
TI  - Radiological case of the month. Intermittent ileocolic intussusception caused by
      an unusual choristoma.

PMID- 10401814
TI  - Picture of the month. Keutel syndrome.

PMID- 10401815
TI  - Pathological case of the month. Neurocysticercosis.

PMID- 10401816
TI  - Post-lumbar puncture headache and backache in pediatrics: a case series and
      demonstration of magnetic resonance imaging findings.

PMID- 10401817
TI  - Use caution when determining "virginal" vs "nonvirginal" status.

PMID- 10401818
TI  - Reoperative parathyroid surgery in the era of sestamibi scanning and
      intraoperative parathyroid hormone monitoring.
AB  - HYPOTHESIS: Results of reoperative parathyroid surgery (RPS) have improved with
      the advent of sestamibi parathyroid subtraction scanning and intraoperative
      parathyroid hormone (IOPTH) monitoring. DESIGN: Retrospective review of patient
      histories, preoperative localization studies, operative data, including IOPTH
      monitoring, and outcomes for patients undergoing recent RPS at a single
      institution. Follow-up was complete (mean, 20 months). SETTING: Tertiary care
      referral center. PATIENTS: All patients undergoing RPS for benign persistent or
      recurrent primary hyperparathyroidism during the period 1989 to 1997. MAIN
      OUTCOME MEASURES: Overall cure rate and operative morbidity from RPS; sensitivity
      and accuracy of preoperative localization studies; and prediction of cure from
      IOPTH monitoring. RESULTS: The study group included 124 patients (87 women and 37
      men). Hypercalcemia was corrected in 109 patients (88%). Permanent recurrent
      laryngeal nerve injury occurred in 0.8% and permanent hypoparathyroidism in 13%
      of patients. Test sensitivities and accuracies, respectively, were as follows:
      ultrasound with biopsy, 90% and 82%; sestamibi parathyroid subtraction scanning,
      82% and 67%; and ultrasound alone, 75% and 65%. Level of IOPTH was predictive of
      cure in all patients with a 70% or greater fall from baseline at 20 minutes after
      excision. Persistent multigland disease was the major cause for reoperative
      failure (73%). CONCLUSIONS: Neither cure rates nor operative morbidity have
      changed appreciably over the past 2 decades, despite the introduction of
      sestamibi parathyroid subtraction scanning and IOPTH monitoring. Multigland
      disease continues to represent the principal cause of failure in RPS despite the
      routine use of preoperative localization studies. Thus far, increasing the
      stringency of IOPTH monitoring from a 50% to 70% decline from baseline levels has
      been predictive of cure, even in multigland disease. Most missed abnormal glands
      reside in normal anatomic locations, and the need for multiple operations, not
      just the reoperation, results in the increased morbidity seen with RPS.

PMID- 10401819
TI  - Surgical approaches to improving intestinal function in the short-bowel syndrome.
AB  - HYPOTHESIS: Nontransplantation surgical approaches to improve intestinal function
      in patients with the short-bowel syndrome have a satisfactory outcome in selected
      patients. PATIENTS: Ninety adult (aged >18 years) patients with intestinal
      remnants shorter than 180 cm were evaluated between 1980 and 1998. MAIN OUTCOME
      MEASURES: Clinical improvement (reduction in parenteral nutrition, resolution of
      anatomical problems, decreased symptoms, or improved oral intake) and
      postoperative morbidity and mortality rates. RESULTS: There were 17 deaths within
      30 days after resection. Thirty-seven (51%) of the surviving 73 patients
      underwent 43 procedures to improve intestinal function. Fourteen procedures (33%)
      were intended to expand intestinal surface area by restoring intestinal
      continuity (n = 10), recruiting additional length (n = 3), or longitudinal
      lengthening (n = 1). Twenty-six procedures (60%) aimed to alter intestinal
      function, either by relieving obstruction (n = 10), repairing fistulas (n = 8),
      slowing transit (n = 4), eliminating diseased bowel (n = 3), or improving
      motility (n = 1). Three patients had stomas created to improve oral intake and
      relieve perianal symptoms. Postoperatively, 2 anastomoses leaked, 2 fistulas
      recurred, and there was 1 death (mortality, 2%). Thirty-seven procedures (86%)
      resulted in clinical improvement. Eleven (46%) of the 24 patients receiving
      parenteral nutrition were able to discontinue it and 5 patients were able to
      reduce the amount of parenteral nutrition received. Twelve procedures that
      increased surface area (86%) and 22 procedures that addressed functional problems
      (85%) resulted in clinical improvement. Success was lowest (50%) in patients
      having procedures to prolong transit time. CONCLUSIONS: Various
      nontransplantation surgical procedures have a role in improving intestinal
      function in short-bowel syndrome. These procedures usually result in clinical
      improvement in properly selected patients. Success is lowest for procedures
      designed to prolong intestinal transit time; thus, these procedures should be
      used only in carefully selected patients.

PMID- 10401820
TI  - Histological correlation of microcalcifications in breast biopsy specimens.
AB  - HYPOTHESIS: Nonpalpable malignant-appearing microcalcifications discovered by
      mammography geographically target the location of the most important abnormality
      within the breast. Core needle or open biopsy of these microcalcifications will
      sample or remove underlying proliferative or invasive disease. DESIGN: A
      prospective database of 403 consecutive patients undergoing breast biopsy for
      nonpalpable abnormalities from July 1, 1994, to December 31, 1996, was reviewed
      to identify biopsies done for indeterminate microcalcifications. Specimens
      showing atypical hyperplasia, carcinoma in situ, or invasive carcinoma were
      identified and reviewed by 1 pathologist. The position of microcalcifications
      larger than 100 microm were recorded in reference to the histological findings.
      SETTING: A 450-bed referral community teaching hospital in rural Wisconsin.
      PATIENTS: Indeterminant microcalcifications were identified on mammograms in 167
      (41.4%) of 403 patients. Sixty-one (36.5%) of 167 biopsy specimens contained
      atypical hyperplasia, carcinoma in situ, or invasive carcinoma, and the slides of
      these 61 initial breast biopsy specimens were reviewed. MAIN OUTCOME MEASURES:
      Relationship of breast histopathological findings to microcalcifications.
      RESULTS: In these 61 specimens, 82 areas of atypical hyperplasia, carcinoma in
      situ, or invasive carcinoma were noted. The microcalcifications correlated with
      these areas in 43 (52%) of 82 areas on slide review and were present in the most
      important abnormality in 33 (54%) of 61 biopsy specimens. CONCLUSIONS:
      Indeterminant microcalcifications identified by mammography may not target the
      exact location of underlying breast disease. Careful evaluation of the entire
      biopsy specimen and close follow-up of patients with benign pathologic findings
      are recommended.

PMID- 10401821
TI  - Toupet fundoplication for gastroesophageal reflux in childhood.
AB  - HYPOTHESIS: Gastroesophageal reflux (GER) is a common condition in childhood that
      frequently requires operative treatment. The 360 degrees Nissen fundoplication
      (NF) has been the standard operation for GER, but is associated with substantial
      rates of recurrence, "gas bloat," gagging, and dysphagia. I believe that the
      Toupet fundoplication (TF), a 270 degrees posterior wrap originally described in
      conjunction with myotomy for achalasia, has fewer complications, and its longterm
      outcome in children compared with NF is favorable. DESIGN: Nonrandomized
      controlled trial. SETTING: Tertiary care children's hospital. PATIENTS: Two
      hundred fifty-six children (aged 3 months to 16 years) with GER disease
      unresponsive to nonoperative therapy who underwent either NF (n = 102) or TF (n =
      154). INTERVENTION: Operative repair of GER disease by either NF or TF. MAIN
      OUTCOME MEASURES: Time to first feeding, time to discharge from the hospital,
      postoperative dysphagia complications, recurrence, and rehospitalization and
      reoperation rates for each fundoplication technique. RESULTS: The 2
      fundoplication techniques had equivalent recurrence rates, but TF had
      significantly lower rates of postoperative dysphagia (P = .008) and
      rehospitalization/reoperation rates (P = .005) and significantly shorter times to
      discharge from the hospital (P = .01) and to the first feeding (P = .02).
      CONCLUSIONS: These data show that both NF and TF are effective procedures for GER
      in children, with acceptable recovery times and low recurrence rates. However, TF
      results in earlier feeding and discharge from the hospital and has a
      significantly lower incidence of dysphagia, gagging, and gas bloat, resulting in
      fewer rehospitalizations. In this population, TF seems to be superior to NF.

PMID- 10401822
TI  - Helicobacter pylori is not associated with the manifestations of gastroesophageal
      reflux disease.
AB  - HYPOTHESIS: Helicobacter pylori is not associated with gastroesophageal reflux
      disease and its complications, including adenocarcinoma of the esophagus and the
      gastroesophageal junction (GEJ). DESIGN: Retrospective analysis. SETTING:
      University tertiary referral center. PATIENTS: Two hundred twenty-nine patients
      with symptoms suggestive of foregut disease underwent esophageal manometry, 24
      hour pH monitoring, and upper gastrointestinal tract endoscopy, with biopsy
      specimens obtained from the gastric antrum, the GEJ, and the distal esophagus. In
      these and in an additional 114 patients with adenocarcinoma of the esophagus and
      the GEJ, the presence of H. pylori was determined by Giemsa stain. The presence
      of gastroesophageal reflux disease, defined by abnormal esophageal acid exposure,
      and its manifestations (carditis, erosive esophagitis, intestinal metaplasia
      limited to the GEJ, Barrett esophagus, and adenocarcinoma of the esophagus and
      GEJ) were correlated with the presence of H. pylori. RESULTS: Helicobacter pylori
      was found on the biopsy specimens of the gastric antrum in 14.0% (32/229) of the
      patients with benign disease. It was not related to the features of
      gastroesophageal reflux disease, including abnormal esophageal acid exposure,
      erosive esophagitis, or Barrett esophagus. The presence of inflamed cardiac
      mucosa at the GEJ or carditis was inversely related to H. pylori infection and
      strongly associated with increased esophageal acid exposure. There was no
      association between the presence of intestinal metaplasia and H. pylori
      infection. Helicobacter pylori was found in 22 (19.3%) of the 114 patients with
      esophageal adenocarcinoma, which was not different from the prevalence of H.
      pylori in patients with benign disease. CONCLUSION: Helicobacter pylori plays no
      role in the pathogenesis of gastroesophageal reflux disease or its complications.

PMID- 10401823
TI  - Effective use of percutaneous cholecystostomy in high-risk surgical patients:
      techniques, tube management, and results.
AB  - HYPOTHESIS: Percutaneous cholecystostomy (PC) is an effective, safe treatment in
      patients with suspected acute cholecystitis and severe concomitant comorbidity.
      DESIGN: Retrospective medical record review from March 1989 to March 1998.
      SETTING: Referral community teaching hospital (450 beds) in rural Wisconsin.
      PATIENTS: Twenty-two consecutive patients underwent PC tube placement over a 10
      year period. Twenty procedures were for acute cholecystitis (14 calculous, 6
      acalculous) and 2 were for diagnostic dilemmas. Nineteen (86%) of 22 patients
      were American Society of Anesthesiologists class 4; 3 (14%) were class 3.
      INTERVENTIONS: Pigtail catheters (8F-10F) placed by means of ultrasound or
      computed tomographic localization, with or without fluoroscopic adjunct. MAIN
      OUTCOME MEASURES: Thirty-day mortality, complications, clinical improvement as
      determined by fever and pain resolution, normalization of leukocytosis, further
      biliary procedures required, and outcome after drain removal. RESULTS: Twenty-two
      patients underwent PC for presumed acute cholecystitis based on ultrasound and
      clinical findings. All patients received antibiotics prior to PC for 24 or more
      hours. Thirty-day mortality was 36% (8 patients), reflecting severity of
      concomitant disease. Minor complications occurred in 3 of 22 patients. Clinical
      improvement occurred in 18 (82%) of 22 patients-15 (68%) within 48 hours. Follow
      up of fourteen 30-day survivors is as follows: 7 (50%) had drains removed because
      the gallbladder was stone free, 4 (29%) had drains remaining due to persistent
      stones, 2 (14%) underwent cholecystectomy, and 1 (7%) awaits scheduled surgery.
      Only 1 (12.5%) of 8 patients developed biliary complications after drain removal,
      requiring endoscopic retrograde cholangiopancreatography 9 months after drain
      removal. One patient required urgent cholecystectomy after failure to respond to
      PC. This patient died of a perioperative myocardial infarction. CONCLUSIONS:
      Percutaneous cholecystostomy is an effective, safe treatment in patients with
      suspected acute cholecystitis and severe concomitant comorbidity. Laparoscopic
      cholecystectomy is recommended as definitive treatment for patients whose risk
      for general anesthesia improves in follow-up. Drains can be safely removed once
      all gallstones are cleared. In patients with severe concomitant disease, drains
      can be left with a low incidence of complications if stones remain.

PMID- 10401824
TI  - Is laparoscopic reoperation for failed antireflux surgery feasible?
AB  - HYPOTHESIS: Laparoscopic techniques can be used to treat patients whose
      antireflux surgery has failed. DESIGN: Case series. SETTING: Two academic medical
      centers. PATIENTS: Forty-six consecutive patients, of whom 21 were male and 25
      were female (mean age, 55.6 years; range, 15-80 years). Previous antireflux
      procedures were laparoscopic (21 patients), laparotomy (21 patients), thoracotomy
      (3 patients), and thoracoscopy (1 patient). MAIN OUTCOME MEASURES: The cause of
      failure, operative and postoperative morbidity, and the level of follow-up
      satisfaction were determined for all patients. RESULTS: The causes of failure
      were hiatal herniation (31 patients [67%]), fundoplication breakdown (20 patients
      [43%]), fundoplication slippage (9 patients [20%]), tight fundoplication (5
      patients [11%]), misdiagnosed achalasia (2 patients [4%]), and displaced
      Angelchik prosthesis (2 patients [4%]). Twenty-two patients (48%) had more than 1
      cause. Laparoscopic reoperative procedures were Nissen fundoplication (n = 22),
      Toupet fundoplication (n = 13), paraesophageal hernia repair (n = 4), Dor
      procedure (n = 2), Angelchik prosthesis removal (n = 2), Heller myotomy (n = 2),
      and the takedown of a wrap (n = 1). In addition, 18 patients required crural
      repair and 13 required paraesophageal hernia repair. The mean +/- SEM duration of
      surgery was 3.5+/-1.1 hours. Operative complications were fundus tear (n = 8),
      significant bleeding (n = 4), bougie perforation (n = 1), small bowel enterotomy
      (n = 1), and tension pneumothorax (n = 1). The conversion rate (from laparoscopic
      to an open procedure) was 20% overall (9 patients) but 0% in the last 10
      patients. Mortality was 0%. The mean +/- SEM hospital stay was 2.3+/-0.9 days for
      operations completed laparoscopically. Follow-up was possible in 35 patients
      (76%) at 17.2+/-11.8 months. The well-being score (1 best; 10, worst) was 8.6+/
      2.1 before and 2.9+/-2.4 after surgery (P<.001). Thirty-one (89%) of 35 patients
      were satisfied with their decision to have reoperation. CONCLUSIONS: Antireflux
      surgery failures are most commonly associated with hiatal herniation, followed by
      the breakdown of the fundoplication. The laparoscopic approach may be used
      successfully to treat patients with failed antireflux operations. Good results
      were achieved despite the technical difficulty of the procedures.

PMID- 10401825
TI  - Ultrasound-guided central venous access.
AB  - HYPOTHESIS: Real-time ultrasound guidance should increase the success rate and
      lower the complication rate of central venous access in patients with relative
      contraindications to having the procedure performed. DESIGN: Prospective case
      series. SETTING: A community-based tertiary care hospital. PATIENTS: Fifty-two
      patients were studied. Relative risks to central venous catheter insertion
      included (1) thrombosis or stenosis of central veins, (2) inherent or acquired
      anticoagulation abnormalities, (3) inability to assume a supine position, (4)
      hypovolemia, (5) obesity or altered anatomy, and (6) severe respiratory
      compromise. INTERVENTIONS: Real-time ultrasound evaluation of the proposed vein
      to be cannulated, followed by real-time percutaneous central vein access. MAIN
      OUTCOME MEASURES: Successful cannulation of a central vein. RESULTS: All attempts
      at central vein cannulation were successful. No bleeding complications occurred.
      One pneumothorax occurred in an obese patient. CONCLUSIONS: Ultrasound-guided
      central venous access is a helpful technique to gain venous access in difficult
      cases. Surgeons who perform central venous access procedures should become
      acquainted with the techniques involved. The techniques should be incorporated
      into currently developing ultrasound instruction courses for surgeons.

PMID- 10401826
TI  - Field triage of the pulseless trauma patient.
AB  - HYPOTHESIS: Trauma patients who are pulseless at the scene of injury and whose
      electrical cardiac activity is less than 40 beats/min cannot be revived. DESIGN:
      Retrospective review. SETTING: University hospital, level I trauma center.
      PATIENTS: Pulseless trauma patients who had cardiopulmonary resuscitation at the
      scene, en route, or in the emergency department and presented between January 1,
      1991, and July 1, 1996. MAIN OUTCOME MEASURE: Survival after traumatic
      cardiopulmonary arrest. RESULTS: Sixteen thousand seven hundred twenty-four
      trauma patients were admitted. The study cohort comprised 604 victims of
      traumatic cardiopulmonary arrest, 304 as a result of blunt injury and 300 as a
      result of penetrating injury. Transport time for the study patients was 11+/-6.1
      minutes (mean +/- SD). Cardiopulmonary resuscitation was performed on them for
      22+/-11 minutes. Three hundred four patients (50%) had resuscitative thoracotomy
      in the emergency department; 160 patients were taken to the operating room for
      further resuscitation and treatment of their injuries. Sixteen patients (2.6%)
      survived to discharge from the hospital; 7 had severe neurologic disabilities. No
      patient (0/212) with electrical asystole survived. Five of 134 patients with an
      initial electrical heart rate between 1 and 39 beats/min survived long enough to
      reach the intensive care unit but died within 48 hours (4 died within 24 hours).
      No patient survived to leave the hospital if the initial electrical heart rate
      was less than 40 beats/min. All 16 survivors had an initial heart rate of 40
      beats/min or greater. CONCLUSION: Trauma victims who are pulseless and have
      asystole or agonal electrical cardiac activity (heart rate <40 beats/min) should
      be pronounced dead at the scene of injury.

PMID- 10401827
TI  - Esophageal pH monitoring abnormalities and gastroesophageal reflux disease in
      infants with intestinal malrotation.
AB  - HYPOTHESIS: Infants with rotational abnormalities of the midgut mesentery are at
      high risk for gastroesophageal reflux disease (GERD) and for sudden infant death
      (SID) from GERD. DESIGN: A survey of the prevalence of GERD and the risk factor
      for SID from GERD in a case series of infants treated for congenital anomalies
      that include intestinal malrotation. Eighty-one (89%) of the infants studied for
      GERD had a mean follow-up of 23.2 months (median, 12 months). SETTING: Patients
      treated in 2 tertiary care centers consisting of a children's hospital and a
      university medical center. PATIENTS: Two hundred eighty-six consecutive infants
      were treated for congenital anomalies from September 1, 1985, through May 31,
      1998. The patients selected for study were 91 infants who had 18- to 24-hour
      esophageal pH monitoring performed and no prior operation on the stomach or
      esophagus. The studied infants had intestinal malrotation either alone (n = 55)
      or associated with a repaired abdominal wall defect (n = 23) or congenital
      diaphragmatic hernia (n = 13). Of the 91 infants, 34 were asymptomatic at the
      time of esophageal pH monitoring. INTERVENTIONS: Eighteen- to 24-hour esophageal
      pH monitoring was used to determine the presence of GERD (abnormal pH score >2
      hours postcibal) and the risk factor for SID from GERD (type I or III reflux
      pattern in combination with a prolonged mean duration of sleep reflux). MAIN
      OUTCOME MEASURES: The prevalence of GERD and the risk factor for SID from GERD.
      The follow-up of GERD was reported as a combination of clinical outcome and
      subsequent extended esophageal pH monitoring. RESULTS: Of the 91 infants studied,
      80 (88%) had GERD and 26 (29%) had the risk factor for SID from GERD. Of 55
      infants with intestinal malrotation alone, 52 (95%) had GERD, and 20 (36%) had
      the risk factor for SID from GERD. Although GERD was found in 19 (83%) of 23
      patients with repaired abdominal wall defects, the prevalence of the risk factor
      for SID from GERD was significantly lower (13% [3 patients]; P = .03) than in
      patients with intestinal malrotation alone. The prevalence of GERD in infants
      with repaired congenital diaphragmatic hernia was significantly lower (69%
      [9/13]; P = .02) than in infants with intestinal malrotation alone but not for
      the prevalence of the risk factor for SID from GERD (23% [3/13]; P = .19). Both
      symptomatic and asymptomatic patients had similar prevalences of GERD (91%
      [52/57] vs. 82% [28/34], P = .17) and for the risk factor for SID from GERD (31%
      [18/57] vs. 24% [8/34]; P = .28). On follow-up, the prognosis for GERD in infants
      with intestinal malrotation was better in the infants who were asymptomatic than
      in those who were symptomatic at the initial extended esophageal pH monitoring.
      CONCLUSIONS: The prevalence of GERD in infants with intestinal malrotation is
      high, and the prevalence of the risk factor for SID from GERD is a significant
      concern. The prevalence of GERD is lower in infants with congenital diaphragmatic
      hernia. Infants with repaired abdominal wall defects have a lower prevalence of
      the risk factor for SID from GERD. We recommend careful evaluation and follow-up
      of infants with intestinal malrotation for problems, such as SID, from GERD.

PMID- 10401829
TI  - Traumatic disruption of the thoracic aorta in children.
AB  - HYPOTHESIS: This study was undertaken to identify mechanisms of injury,
      diagnostic modalities, surgical management, and outcome in children with
      traumatic aortic disruptions. DESIGN: Retrospective study. SETTING: University
      affiliated private hospital. PATIENTS: All patients younger than 17 years listed
      in the trauma registry. INTERVENTION: Operative repair of thoracic aortic
      injuries. MAIN OUTCOME MEASURES: There were 8 boys and 3 girls ranging in age
      from 12 to 17 years (mean, 14.8 years). Seven children were motor vehicle
      passengers; 3 were pedestrians struck by vehicles; and 1 was thrown from a bull.
      Aortic injuries were suspected on the basis of the mechanism of injury and
      abnormal chest x-ray films (mediastinal widening). Aortic injuries were confirmed
      in 9 patients by arch aortography and in 2 patients by computed tomography. The
      injuries involved the isthmus of the aorta in 9 patients (complete transections)
      and the aortic arch in 2 patients (avulsions of the great vessels). Isthmus
      injuries were repaired by means of left heart bypass with direct cannulation of
      the distal thoracic aorta in 8 patients and femoral venous to femoral arterial
      bypass in 1 patient. Arch injuries were repaired during hypothermic circulatory
      arrest. The injured aortic segments were replaced with interposition grafts.
      There were no direct complications of anticoagulation. Ten patients (91%)
      survived. The only death was caused by a severe closed head injury. There were no
      instances of paraplegia related to aortic repairs. CONCLUSION: Good outcomes
      resulted from early diagnosis based on mechanism of injury, prompt aortography,
      and computed tomography and operative management that included distal aortic
      perfusion with left heart bypass.

PMID- 10401828
TI  - Natural history of composite sequential bypass: ten years' experience.
AB  - BACKGROUND: We previously reported 48-month patency rates of composite sequential
      bypass (CSB) approaching 60%. Yet, extended patency and limb salvage rates are
      unknown. HYPOTHESIS: Long-term patency and limb salvage rates of CSB are affected
      by sex, bypass configuration, and warfarin therapy. DESIGN: Medical records of
      all patients who underwent CSB during a 10-year period were retrospectively
      reviewed. SETTING: A referral center for the Chicago, Ill, region. PATIENTS: One
      hundred consecutive patients (mean age, 68.8 years; 57% were men and 49% had
      diabetes) undergoing 102 CSBs for limb salvage (ulcer, 43%; rest pain, 39%; and
      gangrene, 18%) from January 1986 to January 1996 were identified. INTERVENTIONS:
      Warfarin was used after surgery by 72% of patients and aspirin was used by the
      remainder of them. MAIN OUTCOME MEASURES: Life table primary patency and limb
      salvage rates were compared for sex, diabetes mellitus status, location of distal
      prosthetic anastomosis (above knee vs. below knee), and anticoagulation drug
      therapy (warfarin sodium vs aspirin) with log-rank statistics. RESULTS: Primary
      patency of CSB was 56% at 24 months, 29% at 48 months, and 20% at 84 months (SE
      <10%; mean follow-up, 19.6 months [range, 1.0-110.0 months]). Limb salvage rates
      were 64% at 24 months, 30% at 48 months, and 23% at 84 months (SE <10%); 66% and
      90% of patients had failed grafts requiring amputation by 3 months and 1 year,
      respectively. CONCLUSIONS: Composite sequential bypass for limb salvage provides
      reasonable 2-year patency. However, patency rates steadily declined from year 2
      to year 5. After CSB failure, limb salvage rates are poor, with 90% of patients
      progressing to amputation within 1 year.

PMID- 10401830
TI  - The learning curve for sentinel node biopsy in breast cancer: practical
      considerations.
AB  - HYPOTHESIS: Performance of sentinel node biopsy (SNB) instead of full axillary
      lymph node dissection (ALND) by inexperienced surgeons will lead to understaging
      of some women with breast cancer and increased costs. DESIGN: A decision analysis
      model was used to investigate the implications of SNB vs. full ALND during the
      learning phase (60-80 procedures). This model simulates a randomized trial of
      10000 women in each arm. Data regarding the learning curve were obtained from
      published series. MAIN OUTCOME MEASURES: Percentage of women with inaccurate
      staging of their breast cancer, overall survival, quality-adjusted survival, and
      potential costs of SNB vs ALND. RESULTS: Performance of SNB instead of ALND
      results in inability to locate a sentinel node in 38% of attempts during the
      learning phase (compared with 10% in later cases) and understaging in 12% of
      patients during the learning phase (compared with 0% in later cases). This
      understaging is associated with a small decrement in survival (1%-2%) and an
      increased risk of axillary recurrence. Sentinel node biopsy is cost-effective
      only when the ability to detect sentinel nodes exceeds 80%; and the cost of SNB
      is less than 50% of the cost of ALND. CONCLUSIONS: To ensure accurate staging of
      patients with breast cancer, all surgeons should perform full ALND while learning
      SNB techniques. Only after documentation of accuracy of SNB (sensitivity >90%)
      should full ALND be omitted for women with negative sentinel nodes.

PMID- 10401831
TI  - Operative repair of bile duct injuries involving the hepatic duct confluence.
AB  - Injuries at the hepatic duct confluence present the surgeon with a technically
      demanding repair, often combined with life-threatening sequelae such as sepsis
      and portal hypertension. Moreover, the possibility of litigation is ever present,
      even for those not responsible for the initial injury. In this review, we discuss
      the approach to patients with proximal bile duct injuries, with emphasis on
      preoperative evaluation and the technical aspects of biliary reconstruction.

PMID- 10401832
TI  - Folk art portraiture of early American surgeons.

PMID- 10401833
TI  - Cochlear implantation in children with enlarged vestibular aqueducts.
AB  - OBJECTIVES: This report details our experience with cochlear implantation in
      children with both profound sensorineural HL (SNHL) and enlarged vestibular
      aqueducts (EVAs). It seeks to determine if the abnormal anatomy of EVA
      predisposes to any adverse events during or after cochlear implantation. STUDY
      DESIGN: A retrospective review. METHODS: Charts were reviewed for details of the
      procedure, complications, and audiologic outcome. RESULTS: Between 8/25/93 and
      9/16/98, 10 children with EVAs received cochlear implants, of whom 8 children (5
      males, 3 females; mean age 7.8 y) had audiologic follow-up of at least 6 months.
      The implant was inserted without difficulty in all patients. Pulsatile clear
      fluid via the cochleostomy was observed in five patients, but was easily
      controlled in each instance. There have been no major complications, although two
      patient had short-lived postoperative vestibular symptoms and one child has
      experienced an intermittent pulsing sensation in her head. Speech perception
      measures were obtained using a battery of tests that assessed the children's
      ability to perceive speech in both open- and closed-set formats. Two patients
      were excluded because the implant was placed within the last 6 months. Of the
      remaining eight children identified with EVAs, seven (86%) demonstrated open-set
      word recognition. CONCLUSIONS: These favorable results may be attributed in part
      to HL that occurs relatively late in childhood, allowing implantation in
      postlingual candidates. Cochlear implantation can be safely and effectively
      performed in children with SNHL associated with EVAs.

PMID- 10401834
TI  - Surgical techniques to facilitate endoscopic second-look mastoidectomy.
AB  - OBJECTIVES/HYPOTHESIS: Mastoidoscopy has shown to be a safe, effective
      alternative to traditional second-look mastoidectomy. This study was undertaken
      to review surgical modifications to facilitate successful mastoidoscopy. STUDY
      DESIGN: Retrospective database review of all surgical procedures performed by the
      senior author (T.J.H.) since January 1995. All surgeries were performed in a
      tertiary hospital setting. RESULTS: Fifteen second-look procedures were performed
      in this series. Five were performed endoscopically, 10 with traditional
      techniques. In the traditional surgeries five were prior to the use of endoscopy,
      five had contraindications to endoscopic mastoidectomy. There were six residual
      cholesteatomas in the series, one in the endoscopic cases (20%), and five in the
      traditional cases (50%). No cholesteatomas were identified with microscopic
      examination performed after endoscopy. There were no complications in the series.
      Mastoidoscopy gives limited access to the mesotympanum, eustachian tube and, in
      particular, the sinus tympani. The creation of a wide extended facial recess with
      removal of the buttress at the fossa incudis and removal of the incus and head of
      the maleus will facilitate inspection of the middle ear. Additional techniques
      are necessary to view the sinus tympani. The fallopian bridge technique, and the
      infratympanic extended facial recess technique may allow better visualization of
      the middle ear. CONCLUSION: Mastoidoscopy offers a safe alternative to
      traditional techniques for second-look surgery. The morbidity appears similar to
      traditional techniques.

PMID- 10401835
TI  - What your colleagues think of tympanostomy tubes--28 years later.
AB  - OBJECTIVE: Assess the changing opinions of otolaryngologists about tympanostomy
      tubes, including indications, tube material and shape and size, placement sites,
      and complications. STUDY DESIGN: Cross-sectional survey, compared to the same
      survey done 28 years earlier. METHODS: Questionnaires mailed to the 441 active
      fellows and 86 candidates of the Triological Society. Response rate 69.3%.
      RESULTS: The preference for polyethylene has decreased from 75% to 13% of
      respondents. Preferred insertion sites are more anterior. The proportion of
      respondents who have seen a permanent perforation as a consequence has increased
      from 26% to 93%. The proportion of respondents who have seen a tube-attributable
      cholesteatoma has increased from 8% to 38%. The average tube duration has
      increased from 4 months to 18 months. Teflon and Silastic are now the materials
      most often used. As 28 years earlier, about 19% of patients get a subsequent
      tympanostomy tube. Anesthetics most commonly used now are general or topical
      phenol. CONCLUSION: The consensus on several aspects of tympanostomy tubes has
      changed during 28 years. Controversy continues about the indications for using
      tubes. Although not a not cure-all for otitis media, tympanostomy tubes have
      proved useful.

PMID- 10401836
TI  - Use of the laryngeal mask airway in otologic surgery.
AB  - OBJECTIVE/HYPOTHESIS: The combination of intravenous sedation and local
      infiltration anesthesia is routinely utilized in otologic surgery. Advantages
      over general anesthesia with endotracheal intubation include ease and speed of
      induction and emergence, safety, and decreased postoperative discomfort. Anatomic
      and physiological patient constraints may preclude the use of intravenous
      sedation and anesthetists inexperienced in this technique may find it difficult
      to achieve a consistent level of anesthesia appropriate for major otologic
      surgery. Administration of anesthesia using the laryngeal mask airway (LMA) has
      been proposed to offer many of the advantages of intravenous sedation with less
      risk of oversedation and obstructive apnea. STUDY DESIGN: A retrospective chart
      review. METHODS: A review of 100 consecutive adult and pediatric patients
      undergoing major otologic procedures in which the LMA was utilized. RESULTS: All
      laryngeal masks were introduced without a laryngoscope and successful placement
      was accomplished on the first attempt in 98%. Procedures were performed under
      spontaneous ventilation and in only one instance was surgery temporarily
      interrupted because of patient movement. No major complications occurred and no
      patients required endotracheal intubation. Only three patients complained of mild
      throat discomfort in the immediate postoperative period. CONCLUSIONS: The
      laryngeal mask airway is a safe and effective means of providing anesthesia
      during major otologic surgery.

PMID- 10401837
TI  - Glutamate-like immunoreactivity during hair cell recovery after gentamicin
      exposure in the chinchilla vestibular sensory periphery.
AB  - OBJECTIVE: Determine the expression of glutamate by immunohistochemistry in
      normal and recovering vestibular hair cells in the chinchilla crista ampullaris
      after gentamicin ototoxicity. STUDY DESIGN: In five groups of three animals each,
      ototoxicity was produced by placing gentamicin (50 microg)-impregnated Gelfoam
      pellets within the perilymphatic space of the superior semicircular canal.
      Animals were sacrificed at 1, 2, 4, 8, and 16 weeks after treatment. A group of
      normal (n=3) animals was also processed. METHODS: For the detection of glutamate
      the inner ears of these animals were dissected, and the horizontal cristae
      ampullaris embedded in plastic. Two-micron-thick tissue sections were obtained
      and incubated with monoclonal antibodies against glutamate. The immunoreaction
      was detected using the avidinbiotinylated-complex technique and diaminobenzidine
      was the chromogen. RESULTS: Normal sensory epithelia demonstrated type I and type
      II hair cells with moderate glutamate-like immunoreactivity. Supporting cells
      demonstrated no glutamate-like immunoreactivity. Afferent nerve fibers and
      calyxes surrounding type I hair cells demonstrated strong glutamate-like
      immunoreactivity. At 1 and 2 weeks after treatment the few type II hair cells
      surviving ototoxic treatment (15%-18%) contained moderate glutamate-like
      immunoreactivity, supporting cells showed no immunoreactivity, and nerve
      terminals and fibers displayed strong immunoreactivity. At 4 and 8 weeks after
      treatment, recovered hair cells (80%) had greater glutamate-like immunoreactivity
      when compared with normal hair cells, supporting cells displayed no glutamate
      like immunoreactivity, and afferent fibers contained strong glutamate-like
      immunoreactivity. At 16 weeks, glutamate-like immunoreactivity in hair cells
      returned to normal level. CONCLUSION: Glutamate may be used as an indicator of
      hair cell differentiation and as an index of the molecular recovery of hair cells
      after ototoxicity.

PMID- 10401838
TI  - Cosmetic enhancement associated with surgery for obstructive sleep apnea.
AB  - OBJECTIVE: To document the capacity of surgery for obstructive sleep apnea (OSA)
      to incorporate techniques that incidentally improve the cosmetic features of the
      patients. STUDY DESIGN: Retrospective analysis of surgical outcomes at an
      academic practice. METHODS: Moderate to severe OSA usually requires multilevel
      pharyngeal surgery, including tongue base surgery. The surgical procedures,
      including hyoid myotomy and mandibular osteotomy with tongue advancement, afford
      the opportunity to address cosmetic deficits, such as microgenia and excessive
      submental skin and fat. Outcomes achieved using these procedures over a 4-year
      period were analyzed. RESULTS: Of 428 consecutive patients presenting for
      evaluation of sleep-related breathing disorders, 212 were deemed surgical
      candidates. Ninety-seven of these had office-based procedures for snoring, upper
      airway resistance syndrome, or mild OSA. The remaining 115 had formal surgical
      procedures done, and 68 of these had multilevel pharyngeal surgery. Of these, 12
      had defined cosmetic deficiencies that were addressed at the time of the sleep
      apnea surgery. There were 7 men and 5 women, with a mean age of 48.2 years. The
      group was moderately obese (mean BMI = 31.8) and had moderate to severe OSA (mean
      RDI = 37.0, mean LSAT = 78%). Cosmetic deficits identified included turkey
      gobbler deformity (n = 8), microgenia (n = 6), excessive submental fat (n = 2),
      and nasal deformity (n = 1); several patients had more than one addressable
      problem. All patients achieved an improved postoperative appearance.
      Representative photographs are presented. CONCLUSIONS: A surgical approach to the
      management of sleep apnea affords an opportunity to also address cosmetic
      deficiencies, including excessive submental skin and fat, microgenia, and nasal
      deformities.

PMID- 10401839
TI  - Orbital measurement in black and white populations.
AB  - OBJECTIVE: Obtain measurements of globe projection, intercanthal distance (ICD),
      interpupillary distance (IPD), palpebral fissure width (PFW), and palpebral
      fissure height (PFH) in a population of presumably normal white and black adults
      to determine if any significant differences exist between these groups. STUDY
      DESIGN: Prospective direct measurement of cohorts regarding orbital and globe
      measurements in a tertiary medical center. METHODS: Measurements of globe
      projection, ICD, IPD, PFW, and PFH were taken in 61 black adults and directly
      compared with measures taken from 65 white adults in an outpatient setting. Mean
      values and ranges were calculated and compared between races and sexes using an
      unpaired t test. RESULTS: A significant difference was found between races for
      globe projection, with black males demonstrating a mean projection of 18.23+/
      2.26 mm as compared with 17+/-2.65 mm for white males (P < .025). Black females
      demonstrated a mean projection of 17.27+/-1.44 mm as compared with 15.98+/-2.22
      mm for white females (P < .01). Similar differences were seen for measures of IPD
      and PFW, with greater mean values for black as compared with white adults. No
      racial differences existed for ICD or PFH. CONCLUSIONS: These findings suggest
      that racial differences exist for certain measures of globe and orbital position,
      i.e., projection, IPD, and PFW. Racial background should be considered when
      evaluating orbital anatomy.

PMID- 10401840
TI  - Test-retest reliability of computed tomography in the assessment of chronic
      rhinosinusitis.
AB  - OBJECTIVE: Computed tomography (CT) of the paranasal sinuses has emerged as the
      standard test for the assessment of chronic rhinosinusitis, as evidenced by the
      emergence of several CT-based staging systems. Despite its central role in the
      diagnosis and treatment planning for chronic rhinosinusitis, the sinus CT
      represents a "snapshot in time." This study was conducted to determine the
      reliability of the CT scan for chronic sinus disease: are the CT findings in
      chronic rhinosinusitis stable over time? METHODS: A prospective series of
      patients scheduled for endoscopic sinus surgery was evaluated. A total of 45
      patients received two CT scans: an initial scan obtained during routine
      diagnostic evaluation, and a second scan performed for use as part of an image
      guided sinus surgery protocol. No surgical intervention occurred between scans.
      The patients' scans were staged according to the Lund system by a blinded
      observer. The correlation between scans for each patient was determined using the
      matched pairs t test and the Pearson correlation coefficient. RESULTS: The mean
      time interval between scans was 122.6 days (range, 5364 d). The average Lund
      scores for the initial and second scans were 13.56 and 13.27, respectively. The
      Lund score for 5 patients remained the same, increased in 22 patients, and
      decreased in 18 patients. Overall, 75.6% of patients' second scans were within +/
      2 points of the first scan Lund score. The mean change in score between scans of 
      0.29 was not significant (P = .606, paired samples t test). The Pearson
      correlation coefficient between scans was 0.796 (P < .0001). CONCLUSIONS: CT scan
      assessment of chronic rhinosinusitis is a reliable test. The CT findings in
      patients with chronic rhinosinusitis remain consistent over time.

PMID- 10401841
TI  - The rhinology laboratory.
AB  - OBJECTIVES: This study seeks to develop a rhinology lab model and to assess its
      effectiveness for physicians-in-training. STUDY DESIGN: We established a
      rhinology lab at our institution with simple and affordable modifications to our
      temporal bone lab. Residents attended a seven-part lecture series and received a
      list of endoscopic and open procedures to perform on computed tomography (CT)
      scanned, vessel-injected cadaver heads. METHODS: After 2 years we asked
      participating residents to rate their lab experience on a 1-to-10 (disagree
      agree) scale. RESULTS: Cumulative scores indicated that residents
      enthusiastically perceived this additional training as worthwhile (micro=10),
      while increasing their efficiency (micro=9.5), safety (micro=9.875), and anatomic
      knowledge (micro=9.875). The lab has opened opportunities for rhinology research,
      as evidence by one resident publication and another project in progress. Survey
      feedback has helped develop guidelines for instructor participation in the lab as
      well as for assigned reading and independent study. CONCLUSIONS: Based on our
      preliminary experience, we recommend the rhinology lab to all residency programs
      as an important yet cost-effective means of maintaining education in step with
      rapidly changing technologies.

PMID- 10401842
TI  - Breaking the bad news of cancer: the patient's perspective.
AB  - OBJECTIVE: Head and neck cancers present a special challenge to the patient and
      the physician because they affect the quintessential aspects of living such as
      breathing, eating, and speaking. Numerous articles have described how the
      physician should perform the difficult task of conveying bad news, but only a
      small number of articles specifically assess the patients' perceptions when being
      told of a serious diagnosis. The purpose of this survey was to evaluate the
      thoughts and concerns of patients receiving diagnoses of head and neck cancer.
      STUDY DESIGN: Questionnaire survey. METHODS: A 41-item questionnaire was sent to
      head and neck cancer patients who have been treated for and remain free of
      disease for at least 2 years. RESULTS: All of the respondents felt that their
      diagnosis was adequately explained to them and that no further explanations were
      necessary. Eighty-one percent of the respondents did not wish to have anyone else
      present at the time of diagnosis. Additionally, 75% of the respondents did not
      want the physician to touch their hands or hug them when given the bad news. Only
      63% of the respondents had further discussions with family, friends, or other
      physicians after being told of their diagnosis. CONCLUSION: When patients are
      told of the diagnosis of head and neck cancer, they want their physician to be
      truthful, caring, and compassionate. The patients want their diagnosis in simple
      and direct terms without the incorporation of complex medical terminology. The
      results of this survey can provide insightful information to physicians when they
      are undertaking the difficult task of conveying bad news to their patients.

PMID- 10401843
TI  - Experimental nasal intubation: a study of changes in nasoantral mucosa and
      bacterial flora.
AB  - OBJECTIVES: To investigate the local effects in a nasal cavity and its adjacent
      sinuses of long-term detention of an endonasal tube, with special attention to
      inflammatory pathology and microbiology. STUDY DESIGN: Experimental rabbit study.
      METHODS: Four groups of 4 rabbits, in all 16, were unilaterally nasally intubated
      and evaluated macroscopically, histopathologically, and bacteriologically after
      1, 2, 4, and 8 weeks, respectively. RESULTS: At first, in the 1- and 2-week
      groups to the 4-week group, histopathology, such as degeneration of olfactory
      mucosa, squamous cell metaplasia, and polyp formations, was observed together
      with frequent opportunistic bacterial findings in the nasal cavity. Later, in the
      4- and 8-week groups, inflammatory mucosal changes, such as septal increase of
      connective tissue, goblet cell hyperplasia, and epithelial invaginations, were
      found in the nasal cavity containing a tube. A concomitant increase was found of
      commensal bacteria adjacent to the tube and the similar bacterial findings in the
      ipsilateral maxillary sinuses. However, there were no signs of inflammatory
      reactions in the sinuses. CONCLUSIONS: Our investigation points to the tube as
      the cause of local goblet cell hyperplasia with an increased mucus production,
      and as a food source for the commensals with a marked increase of the amount of
      bacteria. The positive bacterial cultures from the maxillary sinuses might be
      considered to be colonization. However, because of the possibility of
      contamination, improved sampling techniques are required, as are further studies.

PMID- 10401844
TI  - Repeated inflation does not prevent otitis media with effusion in a monkey model.
AB  - OBJECTIVE: Investigate the efficacy of repeated middle ear inflation with an
      inert gas (argon) for preventing the development of middle ear effusion in
      monkeys with functional eustachian tube obstruction. STUDY DESIGN: Prospective
      controlled trial of daily middle ear inflation with five monkeys assigned to the
      inflation group and four to the control group. METHODS: The right tensor veli
      palatini muscle of nine monkeys was paralyzed with botulinum toxin. Tympanometry
      was done before the procedure and then daily for 21 days. Presence and
      distribution of effusion were assessed before paralysis and on day 15 using
      magnetic resonance imaging (MRI). In five right ears inflation was done beginning
      at the first observation of negative middle ear pressure of < or =200 mm H2O and
      repeated on all days with pressures < or =-100 mm H2O. Four right ears served as
      uninflated controls. RESULTS: Right middle ear pressure decreased in all animals
      over the course of the study. Pressure returned to near-ambient levels
      immediately following the argon inflation but was decreased to control levels at
      the subsequent observation on the following day. MRI at day 15 documented
      effusion in all right ears with no quantifiable differences in amount or
      distribution between ears that were and were not inflated with argon.
      CONCLUSIONS: Repeated inflation with an inert gas does not prevent middle ear
      effusion in monkeys with functional eustachian tube obstruction.

PMID- 10401845
TI  - Preoperative antibiotics and steroids in vestibular schwannoma excision.
AB  - OBJECTIVE: To examine the benefits of preoperative admission for intravenous
      steroids and antibiotics for patients undergoing vestibular schwannoma excision.
      STUDY DESIGN: Retrospective cohort study. METHODS: One hundred twenty patients
      with pathologically confirmed vestibular schwannoma followed for at least 1 year
      after surgery were included. Sixty patients were assigned to the preoperative
      admission group and 60 patients to the same-day-admission surgery group. The
      preoperative admission group was given intravenous dexamethasone (0.1 mg/kg) and
      intravenous cefazolin (1 g) beginning 12 hours before surgery. The same-day
      surgery group received the same dosage of medication beginning at induction of
      anesthesia. OUTCOMES: Facial nerve function, meningitis, and wound infection
      rates, duration of hospital stay, and readmission rates were examined. RESULTS:
      There was no statistical difference in facial nerve function between the groups
      when controlling for tumor size. Likewise, there was no difference in meningitis
      or wound infection rates in the groups. As expected, hospital stay was
      significantly reduced but readmission rates were not affected. CONCLUSIONS: There
      are no apparent facial nerve function or infection control benefits to 1-day
      preoperative admission for intravenous steroids and antibiotics for patients
      undergoing vestibular schwannoma excision.

PMID- 10401846
TI  - Anti-endothelial autoantibodies in patients with sudden hearing loss.
AB  - OBJECTIVES/HYPOTHESIS: Sudden hearing loss (HL) can be caused by autoimmune
      disorders localized to the inner ear or secondary to systemic immune diseases.
      Studies in autoimmune animal strains showing HL have reported changes in the
      cochlear stria vascularis. The authors investigated the presence of
      antiendothelial cell antibodies (AECA) to see if immune-mediated vasculitis may
      play a role in human sudden HL. STUDY DESIGN: A prospective study in patients
      with sudden HL. METHODS: Fifteen consecutive patients (mean age, 32 y) affected
      by sudden HL and 14 normal subjects were included. Patients with familial
      deafness and metabolic diseases were excluded. Extensive audiovestibular,
      imaging, microbiological, immunological, and routine examinations were performed.
      AECA were detected on rat kidney tissue sections on the sera collected at -20
      degrees C. RESULTS: AECA were positive in 8 of 15 patients (53%) (2 of 5 men and
      6 of 10 women), thus differing significantly from the normal control population,
      in which only 2 of 14 tested AECA positive (P = .023). CONCLUSIONS: In patients
      with sudden HL, immune-mediated vascular damage can have a pathogenetic role and
      AECA might represent a serological marker of vasculitis.

PMID- 10401847
TI  - Ototoxicity of topical gentamicin preparations.
AB  - OBJECTIVE: To document that commercially available topical gentamicin-containing
      eardrops carry a risk of ototoxicity if they reach the middle ear through a
      tympanic membrane defect. STUDY DESIGN: Clinical study, retrospective case-note
      review. SETTING: Department of Otolaryngology, The Toronto Hospital, University
      of Toronto. PATIENTS: Sixteen patients were identified with well-documented
      histories, physical findings and laboratory investigations consistent with
      topical gentamicin-induced ototoxicity. One patient with incapacitating
      unilateral Meniere's disease underwent successful intentional vestibular ablation
      using topical gentamicin/steroid drops. RESULTS: In all cases of inadvertent
      ototoxicity, patients had used the drops for longer than 7 days (average 20.7 d)
      prior to symptoms developing. All patients developed vestibulotoxicity that was
      confirmed on ENG testing. Only 1 patient had a noticeable worsening of cochlear
      reserve. Deliberate and successful therapeutic ablation of vestibular function in
      a patient with unilateral Meniere's disease confirms the vestibulotoxic nature of
      commercially available topical gentamicin preparations. CONCLUSIONS: Physicians
      should consider the potential for ototoxicity if gentamicin-containing eardrops
      (and by extrapolation all topical aminoglycoside drops) are used for longer than
      7 days in patients with a tympanic membrane defect. These preparations should not
      be used in the presence of healthy middle ear mucosa and should be discontinued
      shortly after the discharge has stopped. It is important to recognize that
      toxicity is primarily vestibular rather than cochlear.

PMID- 10401848
TI  - Facial nerve function after petrosectomy.
AB  - OBJECTIVES: Evaluation of facial nerve function after petrosectomy in a patient
      series with facial nerve denudation-decompression, forward or backward rerouting,
      and facial nerve suture and grafting. STUDY DESIGN: Fifty-six patients with
      petrosectomies performed for 24 benign and 9 malignant tumors of the petrous
      bone, 13 malignant tumors of the parotid gland or of the infratemporal spaces
      with infiltration of the petrous bone, 8 traumatic facial nerve disruptions, and
      2 osteoradionecroses were retrospectively evaluated with respect to facial nerve
      function. Sixteen cases involved a partial, 25 a subtotal, and 15 an extended
      subtotal petrosectomy. METHODS: The treatment of the facial nerve included 15
      denudation-compressions, 23 denudation-compressions with rerouting, 4 primary
      sutures, and 14 nerve grafts. The House-Brackmann grading system was used for
      facial nerve evaluation. RESULTS: Normal or nearly normal facial nerve function
      was obtained in facial nerve denudation-decompression with and without rerouting
      (House-Brackmann Grade I or II) except in cases of malignant tumors and
      osteoradionecrosis, where preoperative impaired function remained. Satisfactory
      results were obtained with nerve suturing and nerve grafting after petrous bone
      fracture (Grade III or IV, in one case practically Grade II) except in a case of
      late repair 3 years after the trauma (Grade V). Variable results were obtained
      with nerve grafting in cases with tumor infiltration: Satisfactory results (5 of
      Grade III or IV) were obtained when the tumor was healed and also when
      postoperative radiotherapy was applied; poor results were obtained in the case of
      tumor recurrence (6 of Grade V or VI). CONCLUSIONS: Our results show that
      petrosectomy with denudation-decompression of the facial nerve with or without
      rerouting usually results in a normal mimic of the face. When the facial nerve is
      disrupted by trauma or when the nerve is infiltrated by tumor, early
      reconstruction with nerve suture or grafting mostly leads to a partial and quite
      acceptable reinnervation of the face.

PMID- 10401850
TI  - Nasal stuffiness during pregnancy.
AB  - OBJECTIVE: To investigate the occurrence of nasal stuffiness during pregnancy.
      STUDY DESIGN: Prospective longitudinal study, with collection of data during 1
      year in a cohort of 2,264 pregnant women. METHODS: Self-reported nasal stuffiness
      in gestational weeks 12, 20, 30, and 36 was correlated to age, parity, body mass
      index, and smoking habits. RESULTS: The prevalence of nasal stuffiness increased
      during pregnancy and occurred in 27% of the women at 12 weeks of gestation, in
      37% at 20 weeks, in 40% at 30 weeks and in 42% at 36 weeks. Sixty-five percent of
      the women reported stuffiness at some time when asked. It was commoner in
      multiparous than in nulliparous women. Age, body mass index, and smoking habits
      were not associated with nasal stuffiness. CONCLUSION: Self-reported nasal
      stuffiness for 3 or more weeks was common during pregnancy and could occur at any
      time in two thirds of the women. Treatment regimens to alleviate this symptom
      should be developed.

PMID- 10401849
TI  - Roles of cytokines and cell cycle regulating substances in proliferation of
      cholesteatoma epithelium.
AB  - OBJECTIVES: It can be surmised that the cell cycle must be involved in cell
      proliferation of the epithelium of middle ear cholesteatoma. Thus a comparative
      study was conducted of the levels of expression of cyclin-dependent kinase 2
      (cdk2) and cyclin-dependent kinase 4 (cdk4)-substances known to be involved in
      the cell cycle-in cholesteatoma epithelium and the normal epithelium of the bony
      region of the external ear canal. In addition, it has been reported that the
      expression of cytokines in the epithelium is accelerated in response to
      subepithelial inflammation. This suggests that an interaction between the
      epithelium and subepithelium, which is subject to paracrine regulation, is deeply
      involved in epithelial proliferation. Accordingly, attention was focused on
      interleukin-1alpha (IL-1alpha) and keratinocyte growth factor (KGF), cytokines
      which are found in the subepithelium, and experiments were conducted to elucidate
      their effects on the expression of the substances known to be involved in the
      cell cycle. METHODS: The expressions of cdk2 and cdk4 in the cholesteatoma
      epithelium and external ear canal epithelium were investigated by an
      immunohistochemical technique. In addition, cultured human keratinocytes were
      grown in medium containing IL-1alpha or KGF at concentrations of 0, 20, and 100
      ng/mL, and the differences in the expression of cdk2 and cdk4 were investigated
      and compared by Western blot analysis. RESULTS: In the cholesteatoma epithelium
      specimens, cdk2 and cdk4 were observed to be expressed in the basal and parabasal
      layers and in the upper layer (prickle layer and granular layer). Their
      expression tended to be increased compared with their expression in the normal
      external ear canal epithelium, and this tendency was marked in subepithelial
      sites showing severe inflammation. In addition, exposure of cultured human
      keratinocytes to IL-la or KGF resulted in accelerated expression of both cdk2 and
      cdk4, and this was especially striking in the case of addition of KGF.
      CONCLUSION: It can be surmised that, in cholesteatoma, accelerated expression of
      IL-1alpha and KGF by inflammatory cells at subepithelial sites of inflammation
      leads to upregulation of cdk2 and cdk4 in epithelial cells and to cell
      proliferation. It was concluded that this is at least one sequence of events
      involved in the mechanism causing epithelial proliferation in cholesteatoma.

PMID- 10401852
TI  - A new transnasal approach to endoscopic marsupialization of the nasolabial cyst.
AB  - OBJECTIVE: Nasolabial cyst is a mucus-secreting, nonodontogenic cyst in the
      nasofacial area. It is usually situated behind the ala nasi, extending backward
      beneath the nasal floor into the inferior meatus and forward into the labio
      gingival sulcus behind the upper lip. Patients with nasolabial cysts generally
      undergo surgical removal of the cyst via a transoral sublabial approach. This
      article reports a simple, less invasive surgical procedure for the treatment of
      nasolabial cysts. STUDY DESIGN: A transnasal endoscopic marsupialization method
      was designed to treat patients with nasolabial cysts. From 1996 through 1998, 16
      consecutive patients underwent this new surgical procedure. METHODS: With
      patients under local anesthesia, the roof of the cyst, which was firmly attached
      to the mucous membrane of the anterior nasal floor, was removed transnasally with
      a sickle knife and scissors. Under the guidance of a nasoendoscope, the opening
      of the cyst was widened with bite forceps. Meanwhile, the cut edges of the nasal
      mucosa and the epithelium lining of the cyst were adequately matched. The nose
      was then loosely packed. RESULTS: All but 1 of the 15 patients were successfully
      treated with this technique, and the whole surgical procedure was usually
      completed within 15 to 20 minutes. Postoperative endoscopic and radiological
      findings revealed that the cyst was replaced by an air-containing sinus with a
      persistent opening at the anterior or anterolateral nasal floor. There has been
      no evidence of mucus accumulation in the newly created sinus or recurrence of the
      cyst during a mean follow-up of 16 months. CONCLUSIONS: Transnasal endoscopic
      marsupialization is a simple and effective surgical procedure for treatment of
      nasolabial cysts.

PMID- 10401851
TI  - Is epistaxis evidence of end-organ damage in patients with hypertension?
AB  - OBJECTIVES/HYPOTHESIS: To study the association between history of mild to severe
      epistaxis with different stages of hypertension and with other evidence of target
      organ damage in a sample of patients attending an outpatient hypertension clinic,
      controlling for potential confounding factors. STUDY DESIGN: A survey of adult
      patients with hypertension. METHODS: A consecutive sample of 323 adults with
      hypertension was studied. The main outcome measures were history of adult
      epistaxis, high blood pressure, duration of hypertension, nasal abnormalities,
      and fundoscopic and electrocardiogram abnormalities. RESULTS: Ninety-four
      patients (29.1% of the whole sample) reported at least one episode of nosebleed
      after 18 years of age. Of these, 59 (62.8%) needed medical assistance to control
      at least one of the episodes. The history of epistaxis was not associated with
      blood pressure classified according to the World Health
      Organization/International Society of Hypertension paradigm or classified as
      severe or not severe. There was a trend of an association between history of
      epistaxis and duration of hypertension. The history of severe epistaxis
      (epistaxis that needed medical assistance) was not associated with blood pressure
      classified as severe or not severe and with duration of hypertension. More
      patients with left ventricular hypertrophy had a positive history of adult
      epistaxis. There was no association between history of epistaxis or history of
      severe epistaxis and fundoscopic abnormalities. Among the abnormalities detected
      at rhinoscopy, only the presence of enlarged septal vessels was associated with
      history of epistaxis. The presence of enlarged septal vessels was strongly and
      independently associated with history of epistaxis in the logistic regression
      model. Duration of hypertension and left ventricular hypertrophy showed a trend
      for an association with the history of epistaxis in the adult life. CONCLUSIONS:
      A definite association between blood pressure and history of adult epistaxis in
      hypertensive patients was not found. The evidence for an association of duration
      of hypertension and left ventricular hypertrophy with epistaxis suggests that
      epistaxis might be a consequence of long-lasting hypertension. The association
      between the presence of enlarged vessels at rhinoscopy with history of epistaxis
      in hypertensive patients is a novel observation that needs to be addressed in
      future observations.

PMID- 10401853
TI  - Transforming growth factor-alpha and rhinitis.
AB  - OBJECTIVES: Transforming growth factor-alpha (TGF-alpha) has been implicated in
      diverse physiologic and pathophysiologic functions including immunological,
      inflammatory, and neoplastic processes. TGF-alpha has been localized in the
      hyperproliferative, inflammatory environment of chronic otitis media,
      cholesteatoma, and asthmatic airways. TGF-beta1, which must be present with TGF
      alpha to transform fibroblasts, has been found in rhinitic mucosa and in asthma
      in prior studies. The authors sought to identify whether TGF-alpha also played a
      role in the inflammatory cascade and fibrosis of rhinitis. STUDY DESIGN: A
      nonrandomized, prospective study was carried out in which samples of inferior
      turbinate and nasal polyps from rhinitic and nonrhinitic patients were subjected
      to immunohistochemistry and Western blotting to determine the presence of TGF
      alpha. METHODS: Twenty-seven subjects undergoing surgery for rhinitis,
      obstructive sleep apnea, nasal fracture, and rhinoplasty were recruited for this
      study, the latter three groups acting as controls. Immunohistochemical and
      Western blotting techniques were employed to identify the presence of TGF-alpha
      in inferior-turbinate and nasal-polyp samples of rhinitic subjects. RESULTS:
      Immunohistochemistry demonstrated the selective staining of TGF-alpha in the
      basement membrane and extracellular matrix, including lymphatic, vascular, and
      glandular structures, in most turbinate samples and the absence of staining in
      corresponding controls. Further, TGF-alpha was isolated to a discrete 30-kD band
      in both inferior turbinate and polyp tissues by Western blotting without staining
      in the corresponding controls. CONCLUSIONS: These results suggest that TGF-alpha
      may play a role in the inflammatory derangement of rhinitis.

PMID- 10401854
TI  - Preservation of function and histologic appearance in the injured glottis with
      topical mitomycin-C.
AB  - OBJECTIVE: To evaluate the functional and histological effects of a single
      application of topical mitomycin-C after laser injury in the posterior canine
      glottis. STUDY DESIGN: A prospective, randomized study of 16 canines. METHODS: A
      supersaturated (1%) solution of topical mitomycin-C was applied to a unilateral,
      laser-induced injury near the cricoarytenoid joint in eight dogs. The mitomycin
      soaked pledget was placed immediately after induction of the injury and was left
      in contact with exposed cartilage for 3 minutes. The opposite side was not
      injured to provide an internal control. In eight additional dogs, the same laser
      injury was allowed to heal untreated. After 6 weeks, the animals were sacrificed
      and their larynges harvested. Arytenoid adduction sutures were placed
      bilaterally, and the force required to bring the vocal folds to midline was
      measured for each side using tensiometry. Gross and microscopic histological
      analysis was performed. Statistical analysis was accomplished using a two-tailed
      Student t test of unpaired samples, and the Wilcoxon Signed Rank Test where
      appropriate. RESULTS: The mitomycin-C treated larynges demonstrated improved
      cricoarytenoid joint mobility (P = .007), decreased granulation tissue
      development (P = .03), and complete prevention of secondary "vocal granuloma"
      formation (P = .0004) when compared with eight dogs with identical laser injuries
      allowed to heal untreated. No complications were noted. CONCLUSIONS: This study
      demonstrates functional preservation and improved histological appearance of the
      injured glottis after a single treatment with topical mitomycin-C. Potential
      applications of these findings include prophylactic use of topical mitomycin-C on
      glottic insults that commonly progress from granulation tissue formation to
      scarring and decreased vocal fold function.

PMID- 10401855
TI  - Use of endoscopically placed expandable nitinol tracheal stents in the treatment
      of tracheal stenosis.
AB  - OBJECTIVE: To evaluate the potential utility of a new endoscopically placed
      expandable tracheal stent in the treatment of benign symptomatic stenoses of the
      cervical trachea. STUDY DESIGN: Pilot study utilizing a prospectively followed
      case series. METHODS: An initial group of six patients undergoing stent placement
      was examined with rigid and flexible endoscopy under anesthesia immediately
      following stent placement and at postoperative 6 to 8 weeks. Subsequently each
      patient was followed clinically for a minimum of 6 months. RESULTS: All stents
      were well tolerated with no observed complications. Immediate reversal of
      symptomatic airway obstruction without the need for adjunctive tracheotomy was
      noted in every patient. At 6 weeks, endoscopic confirmation of complete
      intraluminal mucosalization without formation of any granulation tissue or scar
      bands within the stented areas was noted in each case. CONCLUSIONS: This
      preliminary pilot study supports the use of nitinol expandable tracheal stents as
      an alternative in the treatment of benign symptomatic tracheal stenoses.

PMID- 10401856
TI  - An external landmark for the anterior commissure.
AB  - OBJECTIVE: The ability to predict the level of the true vocal cords based on
      external landmarks is crucial to the success of many laryngeal surgical
      procedures. This study examines the reliability of one such landmark on the
      thyroid cartilage. METHODS: Twenty-four cadaver larynges were examined. A pin was
      placed through the landmark, best described as a small diamond shaped area of
      color change and surface depression along the anterior midline of each thyroid
      cartilage through which travels a very small unnamed artery. The endolaryngeal
      position of the pin was checked with a flexible nasopharyngoscope. RESULTS: In
      all 24 cadavers, the pin entered the larynx at the anterior commissure, just
      above or at the level of the true vocal cords. CONCLUSIONS: This external
      landmark reliably predicts the position of the true vocal cords. It serves as a
      useful adjunct to existing external landmarks used to direct thyroid cartilage
      cuts in laryngeal procedures.

PMID- 10401858
TI  - Hyaluronic acid (with fibronectin) as a bioimplant for the vocal fold mucosa.
AB  - OBJECTIVES: To measure the viscoelastic shear properties of hyaluronic acid, with
      and without fibronectin, and to compare them with those of the human vocal fold
      mucosa and other phonosurgical biomaterials. METHODS: Viscoelastic shear
      properties of various implantable biomaterials (Teflon, gelatin, collagen, fat,
      hyaluronic acid, and hyaluronic acid with fibronectin) were measured with a
      parallel-plate rotational rheometer. Elastic and viscous shear properties were
      quantified as a function of oscillation frequency (0.01-15 Hz) at 37 degrees C.
      RESULTS: The shear properties of hyaluronic acid were relatively close to those
      of human vocal fold mucosal tissues reported previously. Hyaluronic acid at
      specific concentrations (0.5%-1%), with or without fibronectin, was found to
      exhibit viscous shear properties (viscous shear modulus and dynamic viscosity)
      similar to those of the average male and female vocal fold mucosa. CONCLUSIONS:
      According to a theory that establishes the effects of tissue shear properties on
      vocal fold oscillation, phonation threshold pressure (a measure of the ease of
      phonation) is directly related to the viscous shear modulus of the vibrating
      vocal fold mucosa. Therefore, our findings suggest that hyaluronic acid, either
      by itself or mixed with fibronectin, may be a potentially optimal bioimplant for
      the surgical management of vocal fold mucosal defects and lamina propria
      deficiencies (e.g., scarring) from a biomechanical standpoint.

PMID- 10401857
TI  - Characterization of cyclooxygenase in laryngeal papilloma by molecular
      techniques.
AB  - OBJECTIVES: Demonstrate the induction of cyclooxygenase-2 (COX-2) in laryngeal
      papilloma Discuss the possible causal role of COX-2 in papilloma formation.
      Consider the potential for treatment of papilloma using selective COX-2
      inhibitors. STUDY DESIGN: Molecular biological analysis of COX-1 and COX-2 in
      laryngeal papilloma. METHODS: Tissue samples from five patients with recurrent
      respiratory papillomatosis (RRP) were analyzed by in situ hybridization,
      immunohistochemical staining, and reverse transcription polymerase chain reaction
      (RT-PCR) techniques. RESULTS: In situ hybridization to COX-2 mRNA showed strong
      autoradiographic signal surrounding fibrovascular cores. COX-1 autoradiographic
      signal was low intensity or nondetectable. Normal buccal mucosa biopsies showed
      low-density or nondetectable autoradiographic signal for both COX-1 and COX-2
      mRNAs. In situ hybridization results were corroborated by RT-PCR studies. Levels
      of COX-2 mRNA were 13-fold more than those in normal mucosa. Immunohistochemical
      staining for COX-1 and COX-2 showed a similar pattern to that seen with in situ
      hybridization in both normal and papilloma tissues. CONCLUSIONS: There is an
      elevation of COX-2 expression in papilloma tissues. This may represent a causal
      role of COX-2 in the formation and proliferation of laryngeal papilloma. There
      may also be a role for selective COX-2 inhibition for the treatment of

PMID- 10401859
TI  - Deterioration of olfaction and gustation as a consequence of total laryngectomy.
AB  - INTRODUCTION: After total laryngectomy the absence of a nasal airflow results in
      a decrease in olfaction and perception of flavors. MATERIALS AND METHODS: Odor
      perception was assessed in 63 laryngectomized patients with two different
      olfactory tests. The methods used by patients to smell were observed during
      olfactory testing. Patients' judgment about their olfaction and gustation was
      assessed by means of a structured questionnaire, semistructured interview, and
      self-rating. RESULTS: Based on the results of the olfactory tests, patients were
      categorized as "smellers" and "nonsmellers." Approximately one third of the
      patients were able to smell the odorous substances used in the olfactory tests.
      The smellers more often used a variety of methods to smell than the nonsmellers
      (P < .002); in most patients the method consisted of active use of facial
      muscles. Patients appeared well able to judge their own odor perception. Compared
      with the smellers, the nonsmellers judged their odor perception as worse (P <
      .003) and reported a more severe decrease in gustation after the operation (P <
      .033). The results of this study in laryngectomized patients confirm the
      interrelation between olfaction and gustation: the nonsmellers reported a poorer
      gustation and a more severe decrease in gustation and appetite than both the
      smellers and a reference group of elderly persons (P < .05). Patients who
      reported a deterioration of olfaction and gustation tended to experience negative
      consequences such as the inability to smell smoke, leaking gas, or agreeable
      odors. CONCLUSION: Olfaction and odor-related flavor sensation are seriously
      deteriorated after total laryngectomy.

PMID- 10401860
TI  - Effects of activated macrophages and fibroblast growth factor on random skin flap
      survival in swine.
AB  - OBJECTIVE: To examine the effect of application of activated autologous
      macrophages and basic fibroblast growth factor (FGF) on random skin flap survival
      in swine. DESIGN: A randomized nonblinded controlled trial. According to a
      standard design, six dorsally based, random-pattern skin flaps were raised in
      each of 12 Yorkshire pigs. METHODS: Twenty-five milliliters of blood is harvested
      from each animal 20 to 24 hours prior to flap creation. Monocytes are isolated,
      placed in culture medium, and then activated by the addition of platelet-derived
      growth factor (PDGF) and tissue growth factor beta (TGF-alpha). Following an 18
      hour incubation period, the monocytes are decanted and quantified, and their
      viability confirmed. These cells are then infused into the wound bed of the
      treatment flaps immediately following flap creation, and FGF is added prior to
      flap closure. The position of treatment and control flaps is systematically
      varied with regard to anterior-to-posterior and side-to-side flap positions
      within each animal. The area of superficial flap necrosis is evaluated on
      postoperative day 7, digitally scanned, and analyzed using graphics software.
      Control flaps are elevated similarly, but receive no placebo treatment. RESULTS:
      Two-way analysis of variance (ANOVA) demonstrated nonsignificant differences
      between pig side and anterior, middle, and posterior flap positions within
      treatment and control flap groups. Using side and position pooled data, a one-way
      ANOVA showed no statistically significant differences between treatment and
      control flaps. CONCLUSIONS: The cellular and biochemical events following
      creation of a surgical wound are complex and incompletely understood. Our attempt
      to augment the natural role of the macrophage in wound healing by employing
      cytokines to activate these cells and to accelerate their arrival by implanting
      them into the wound bed failed to enhance flap survival. Further study is
      warranted to ascertain the details of wound healing, particularly with respect to
      cytokine concentrations and the timing of their roles, if we are to find a
      clinically applicable means of enhancing flap survival.

PMID- 10401861
TI  - Treatment of the clinically negative neck in oral squamous cell carcinoma.
AB  - OBJECTIVE: To define the most effect treatment plan of patients with oral cavity
      squamous cell carcinoma with clinically negative (NO) neck staging. STUDY DESIGN:
      Retrospective review of 54 patients with NO neck staging who underwent resection
      of an oral cavity primary tumor with or without elective neck dissection between
      January 1982 and December 1992 and with a minimum follow-up of 3 years. METHODS:
      The records of 54 patients with previously untreated oral cavity squamous cell
      carcinoma and NO neck staging were retrospectively reviewed to determine the
      impact of elective neck dissection on patient outcomes including regional
      recurrence and overall survival. RESULTS: All patients underwent surgical
      resection of their oral cavity tumors, with 33 patients undergoing "watchful
      waiting" observation for the development of neck disease while 21 patients had
      elective neck dissections. The most controversial group of patients were those
      with intermediate-sized (T2 and T3) primary tumors. Eighteen of these patients
      underwent elective neck dissection, with two patients developing recurrent neck
      disease and an ultimate prognosis of 72%. Twelve patients had observation of
      their necks, with five of these patients subsequently requiring neck dissection.
      An additional seven patients did not undergo neck dissection, and this group had
      four survivors free of disease. The prognosis was 42% in patients not having
      elective neck dissections. CONCLUSIONS: T1 tumors do well with neck treatment
      other than careful observation. The data suggest that patients with T2 and T3
      oral squamous cell carcinoma should undergo surgical resection of their primary
      tumor site and elective neck dissection. Patients with T4 oral cavity lesions
      should routinely undergo neck dissection.

PMID- 10401862
TI  - Use of a laryngeal micro resector system.

PMID- 10401863
TI  - Myomucosal shunt plugging to prevent aspiration after near-total laryngectomy.

PMID- 10401864
TI  - Transnasal endoscopic examination of the subglottis and trachea using topical
      anesthesia in the otolaryngology clinic.

PMID- 10401865
TI  - Farming and prostate cancer.

PMID- 10401866
TI  - Studying the risks of ocean swimming.

PMID- 10401867
TI  - Epidemiology of cryptorchidism and hypospadias.

PMID- 10401868
TI  - The health effects of swimming in ocean water contaminated by storm drain runoff.
AB  - Waters adjacent to the County of Los Angeles (CA) receive untreated runoff from a
      series of storm drains year round. Many other coastal areas face a similar
      situation. To our knowledge, there has not been a large-scale epidemiologic study
      of persons who swim in marine waters subject to such runoff. We report here
      results of a cohort study conducted to investigate this issue. Measures of
      exposure included distance from the storm drain, selected bacterial indicators
      (total and fecal coliforms, enterococci, and Escherichia coli), and a direct
      measure of enteric viruses. We found higher risks of a broad range of symptoms,
      including both upper respiratory and gastrointestinal, for subjects swimming (a)
      closer to storm drains, (b) in water with high levels of single bacterial
      indicators and a low ratio of total to fecal coliforms, and (c) in water where
      enteric viruses were detected. The strength and consistency of the associations
      we observed across various measures of exposure imply that there may be an
      increased risk of adverse health outcomes associated with swimming in ocean water
      that is contaminated with untreated urban runoff.

PMID- 10401869
TI  - Risk factor patterns for cryptorchidism and hypospadias.
AB  - To evaluate the hypothesis of a common etiology for cryptorchidism and
      hypospadias, we conducted two case-control studies nested in a nationwide cohort
      in Sweden, using record linkage between the Inpatient and Birth Registries. Cases
      were 2,782 and 1,220 boys operated for cryptorchidism or hypospadias,
      respectively. Five matched controls per case were randomly selected. Pregnancy
      and perinatal data were prospectively recorded in the Birth Registry. Data were
      modeled through conditional logistic regression. Both cryptorchidism (odds ratio
      (OR) = 2.22) and hypospadias (OR = 2.75) were positively associated with other
      congenital malformations and inversely with maternal parity (OR = 0.77 and 0.52,
      respectively, for parity 4+ compared with primiparae). There is evidence that
      being born small-for-gestational-age and before the 33rd gestational week have a
      greater-than-additive effect with respect to both cryptorchidism (OR = 6.19 vs
      1.72 expected) and hypospadias (OR = 4.39 vs 2.60 expected) compared with non
      small-for-gestational-age boys born at term. Hypospadias was positively
      associated with severe preeclampsia (OR = 2.11). We conclude that the etiologies
      of the two conditions are partly shared.

PMID- 10401870
TI  - Prenatal methylmercury exposure as a cardiovascular risk factor at seven years of
      age.
AB  - Blood pressure in childhood is an important determinant of hypertension risk
      later in life, and methylmercury exposure is a potential environmental risk
      factor. A birth cohort of 1,000 children from the Faroe Islands was examined for
      prenatal exposure to methylmercury, and at age 7 years, blood pressure, heart
      rate, and heart rate variability were determined. After adjustment for body
      weight, diastolic and systolic blood pressure increased by 13.9 mmHg [95%
      confidence limits (CL) = 7.4, 20.4] and 14.6 mmHg (95% CL = 8.3, 20.8),
      respectively, when cord blood mercury concentrations increased from 1 to 10
      microg/liter cord blood. Above this level, which corresponds to a current
      exposure limit, no further increase was seen. Birth weight acted as a modifier,
      with the mercury effect being stronger in children with lower birth weights. In
      boys, heart rate variability decreased with increasing mercury exposures,
      particularly from 1 to 10 microg/liter cord blood, at which the variability was
      reduced by 47% (95% CL = 14%, 68%). These findings suggest that prenatal exposure
      to methylmercury may affect the development of cardiovascular homeostasis.

PMID- 10401871
TI  - Job strain and pregnancy-induced hypertension.
AB  - In a case-control study we assessed whether exposure to high job strain during
      the first 20 weeks of pregnancy increases the risk of preeclampsia and
      gestational hypertension. Cases (128 with preeclampsia and 201 with gestational
      hypertension) and controls (N = 401) were primiparous women who had a paid
      occupation for at least 1 week during the first 20 weeks of their pregnancy and
      who delivered between 1984 and 1986 in 10 hospitals of Quebec, Canada. Based on
      their job title, we assigned women scores of psychological demand and decision
      latitude derived from the National Population Health Survey and classified these
      women as exposed to high (high demand, low latitude) versus low (low demand, high
      latitude) job strain. Women exposed to high job strain were more likely to
      develop preeclampsia [adjusted odds ratio (aOR) = 2.1; 95% confidence interval
      (CI) = 1.1-4.1] than women exposed to low job strain. The risk was quite similar
      for women exposed to a full-time, high strain job (> or =35 hours per week) (aOR
      = 2.0) than in a part-time, high strain job (aOR = 1.8). High job strain
      increased the risk of gestational hypertension slightly (aOR = 1.3; 95% CI = 0.8
      2.2). These results indicate that women exposed to high job strain are at higher
      risk of developing preeclampsia and, to a lesser extent, gestational
      hypertension.

PMID- 10401872
TI  - Neural tube defects and drinking water disinfection by-products.
AB  - We conducted a population-based case control study of neural tube defects and
      drinking water contaminants, specifically, disinfection by-products. We used
      public monitoring records concurrent with the first month of gestation to assess
      exposure. The prevalence odds ratios (PORs) for the highest tertile of total
      trihalomethanes compared with the lowest was 1.6 (95% confidence interval [CI] =
      0.9-2.70). Surface water source was also associated with neural tube defects (POR
      = 1.5; 95% CI = 0.9-2.5). Sensitivity analyses restricted to isolated neural tube
      defect cases and mothers with known residence at conception yielded stronger
      associations [total trihalomethanes, POR = 2.1 (95% CI = 1.1-4.0); surface water,
      POR = 1.7 (95% CI = 0.9-3.2)]. Other major groups of disinfection by-products
      (haloacetic acids and haloacetonitriles) showed little relation to these defects.

PMID- 10401873
TI  - Association of serum uric acid with all-cause and cardiovascular disease
      mortality and incident myocardial infarction in the MONICA Augsburg cohort. World
      Health Organization Monitoring Trends and Determinants in Cardiovascular
      Diseases.
AB  - Because previous findings have been inconsistent, we explored the association of
      serum concentrations of uric acid with all-cause and cardiovascular disease
      mortality and myocardial infarction prospectively. We used data from 1,044 men
      who are members of the World Health Organization Monitoring Trends and
      Determinants in Cardiovascular Diseases (MONICA) Augsburg cohort. The men, 45-64
      years of age in 1984-1985, were followed through 1992. There were 90 deaths, 44
      of which were related to cardiovascular disease; 60 men developed incident
      nonfatal or fatal myocardial infarction. We estimated hazard rate ratios from Cox
      proportional hazard models. Uric acid levels > or =373 micromol/liter (fourth
      quartile) vs < or =319 micromol/liter (first and second quartile) independently
      predicted all-cause mortality [hazard rate ratio = 2.8; 95% confidence interval
      (CI) = 1.6-5.0] after adjustment for alcohol, total cholesterol/high-density
      lipoprotein cholesterol ratio, hypertension, use of diuretic drugs, smoking, body
      mass index, and education. The adjusted risk of cardiovascular disease mortality
      was 2.2 (95% CI = 1.0-4.8), and that of myocardial infarction was 1.7 (95% CI =
      0.8-3.3). Although residual confounding cannot be excluded, our results are among
      the few, in men, demonstrating a strong positive association of elevated serum
      uric acid with all-cause mortality. Future investigations may be able to evaluate
      whether uric acid contributes independently to the development of cardiovascular
      disease or is simply a component of the atherogenic metabolic condition known as
      the insulin resistance syndrome.

PMID- 10401874
TI  - Application of the case-specular method to two studies of wire codes and
      childhood cancers.
AB  - This paper presents the results of applying the case-specular method to two
      earlier studies of wire codes and childhood cancers (DA Savitz et al, Am J
      Epidemiol 1988;128:21-38, and SJ London et al, Am J Epidemiol 1991;9:923-937).
      The method compares the wire codes of case residences with the wire codes of
      specular residences constructed by switching the location of the case residence
      across the center of the street. The method was designed to discriminate between
      the magnetic field hypothesis, which postulates that childhood cancer is affected
      by magnetic fields and that wire codes are a proxy for magnetic fields, and the
      neighborhood hypothesis, which postulates that childhood cancer is affected by
      some characteristics of the neighborhood other than magnetic fields and that wire
      codes are a proxy for those characteristics. Although the results from the two
      applications of the method have limited precision, they support the results
      originally reported (odds ratios of around 2 for very high current configuration
      residences and childhood cancers) and do not support suggestions that the
      associations are due to confounding by socio-economic and neighborhood factors.
      The results leave open the question of whether or not control selection bias
      could have influenced the original associations, because there was no convincing
      evidence that the control-specular matrices were symmetric.

PMID- 10401875
TI  - Synergy between asbestos and smoking on lung cancer risks.
AB  - We have examined data from 12 epidemiologic studies for quantitative evidence of
      biologic synergy between asbestos and smoking on lung cancer risks. Estimates of
      the effect associated with joint exposure to the two agents exceeded the sum of
      their separate effects in each study. We explored the variations in the strength
      of the synergistic effect across the studies using three indices: the ratio of
      the combined effects to the sum of the separate effects of smoking and asbestos
      (S), the relative excess risk due to interaction (RERI), and the attributable
      proportion of risk due to interaction (AP). The weighted average of S across all
      studies was 1.64 (95% confidence interval = 1.33-2.03). The attributable
      proportion associated with this average S was estimated as 33%, that suggests
      that one-third of cancer cases among smokers who were exposed to asbestos can be
      attributed to the synergistic behavior of the two carcinogens, as distinct from
      their separate effects and those attributable to other ("background") factors.

PMID- 10401877
TI  - We should monitor human fecundity, but how? A suggestion for a new method that
      may also be used to identify determinants of low fecundity.
AB  - Human fecundity may be declining, and we may need ways to monitor it. The most
      simple monitoring is based on measuring waiting time to pregnancy retrospectively
      among pregnant women. Unfortunately, this design does not provide an estimate of
      fecundity, because infertile couples are excluded. We suggest a novel approach
      that combines the measurement of waiting time for pregnant women with information
      on the distribution of waiting time among women waiting to become pregnant. The
      method is based on principles from the case-cohort design.

PMID- 10401876
TI  - Effect of smoking cessation and tobacco type on the risk of cancers of the upper
      aero-digestive tract in Brazil.
AB  - Tobacco smoking has long been identified as the most important risk factor for
      upper aero-digestive tract cancers. To investigate the effect of different
      tobacco types and the benefit of smoking cessation, we analyzed data from a case
      control study of 784 cases of mouth, pharynx, and larynx cancers and 1,578 non
      cancer controls in three metropolitan hospital areas in Brazil. Subjects were
      interviewed as to their smoking and drinking habits, demographics, environmental
      exposures, occupational history, health characteristics, and diet. Controlling
      for total tobacco and alcohol consumption, risks for ex-smokers compared with
      current smokers decreased substantially with time since cessation of the habit.
      Compared with never smokers, ex-smokers of >20 years had a relative risk (RR) of
      1.98 [95% confidence interval (CI) = 1.0-3.8] for all upper aerodigestive tract
      cancers. RRs for long-term (>20 years) ex-smokers tended to be lower for mouth
      (RR = 1.61) and pharynx (RR = 1.52) than for larynx (RR = 3.63) cancers. The
      benefit of quitting was strongest for commercial cigarettes (RR = 1.45, 95% CI =
      0.7-3.0) for ex-smokers of >10 years, as compared with smoking of black tobacco
      (RR = 2.57, 95% CI = 1.4-4.6), cigars (RR = 2.59, 95% CI = 0.6-11.6), and pipe
      tobacco (RR = 3.40, 95% CI = 1.3-8.8).

PMID- 10401878
TI  - Fecundability in relation to body mass and menstrual cycle patterns.
AB  - Few studies have investigated the association between body mass index and
      fecundability, that is, the ability to conceive in a menstrual cycle, among
      fertile women with normal menstrual cycle pattern. We examined the independent
      and combined effects of duration and regularity of the menstrual cycle, body mass
      index, and fecundability from records on pregnant women attending antenatal care
      at Odense University Hospital, Denmark, between 1972 and 1987. We included only
      the first birth of each woman who had planned pregnancies and no pre-pregnancy
      disease (N = 10,903). We estimated the fecundability odds ratio (FR) as the odds
      of conception in a menstrual cycle. After adjusting for confounders, the
      fecundability for women with a body mass index >25 kg/m2 was lower than for women
      with a body mass index of 20-25 kg/m2 [FR = 0.77; 95% confidence interval (CI) =
      0.70-0.84]. FR was lower for women with long (>35 days) (FR = 0.74; 95% CI = 0.63
      0.87) or irregular cycles (FR = 0.78; 95% CI = 0.70-0.87), even when their body
      mass index was within the normal range (20-25 kg/m2) and/or their cycles were
      regular.

PMID- 10401879
TI  - The association of shift work and nitrous oxide exposure in pregnancy with birth
      weight and gestational age.
AB  - We examined the relation between shift work and occupational nitrous oxide
      exposure in the second trimester of pregnancy and birth weight and gestational
      age at delivery among the members of the Swedish Midwives Association. Eighty
      four per cent of members who were registered in 1989 responded to a postal
      questionnaire concerning occupational exposures, including work schedule and the
      use of nitrous oxide, in relation to each of their pregnancies. We obtained
      information on births from the Swedish Medical Birth Register. We used models
      with allowance for dependence between births for the same woman and found that
      night work was associated with preterm birth (<37 weeks) [odds ratio (OR) = 5.6;
      95% confidence limits (CL) = 1.9, 16.4] and to a lesser extent with low birth
      weight [OR = 1.9 (95% CL = 0.6, 5.8)]. Three-shift work schedule (day, evening,
      and night rotation) showed a possible association with preterm birth [OR = 2.3
      (95% CL = 0.7, 7.3)]. Exposure to nitrous oxide use was associated with reduced
      birth weight (-77 gm; 95% CL = -129, -24) and an increase in the odds of infants
      being small for gestational age (< or = 10th percentile of weight for gestational
      week) (OR = 1.8; 95% CL = 1.1, 2.8).

PMID- 10401880
TI  - No teratogenic effect after clotrimazole therapy during pregnancy.
AB  - We evaluated the potential teratogenic effects of vaginal and/or topical
      administration of clotrimazole in the large population-based dataset of the
      Hungarian Case-Control Surveillance of Congenital Abnormalities (1980-1992). The
      dataset included 18,515 case pregnancies and 32,804 control pregnancies; 7.1% of
      case and 7.7% of control women used clotrimazole during pregnancy. Clotrimazole
      use was not clearly associated with an increase in the total (fetal + birth)
      prevalence of any congenital abnormality group. There was, however, a suggestion
      that clotrimazole use was associated with a decrease in the prevalence of
      undescended testis (prevalence odds ratio = 0.72; 95% confidence interval = 0.54
      0.95).

PMID- 10401881
TI  - Maternal risk of breast cancer and birth characteristics of offspring by time
      since birth.
AB  - We examined the association between birth characteristics of offspring and the
      subsequent maternal risk of breast cancer in a population-based cohort of 998,499
      women, 13 to 48 years of age at entry. There were 9,495 incident cases of breast
      cancer during 12.8 million person-years of follow-up among these women. Compared
      with mothers of singleton infants, mothers having a multiple birth had an
      increased risk of breast cancer in the first 5 years after a birth (relative risk
      (RR) = 1.8; 95% confidence interval (CI) = 1.1-2.8). The risk for mothers having
      a heavy-weighted child (>3.75 kg), as compared with a child of light weight (< or
      =3 kg), was also slightly increased (RR = 1.2; 95% CI = 0.9-1.5). This latter
      effect was primarily due to an increased incidence of tumors larger than 2 cm at
      diagnosis (RR = 1.4; 95% CI = 0.9-1.9). Our findings are compatible with the
      hypothesis that the hormonal level during pregnancy influences the risk of breast
      cancer in the early years after delivery.

PMID- 10401882
TI  - Hormone replacement therapy and colon cancer among members of a health
      maintenance organization.
AB  - We investigated the association between hormone replacement therapy (HRT),
      primarily conjugated estrogens with or without medroxyprogesterone acetate, and
      colon cancer risk in a nested case-control study among women ages 55-79 years
      enrolled in Group Health Cooperative, a health maintenance organization in
      Washington state. Cases were diagnosed between 1984 and 1993. We selected
      controls randomly from enrollment files. HRT use was ascertained from a
      computerized database containing virtually all prescriptions dispensed since
      1977. Among subjects with at least 5 years of pharmacy database information
      before reference date (1 year before diagnosis date), there were 341 cases of
      incident colon cancer and 1,679 controls. Estrogen use during the 5 years before
      reference date was not associated with risk of colon cancer [odds ratio (OR) =
      0.85 and 95% confidence interval (CI) = 0.57-1.27 for 1-749 estrogen tablets; OR
      = 0.97 and 95% CI = 0.68-1.40 for > or =750 estrogen tablets]. An analysis
      including only women with at least 10 years of pharmacy database coverage found
      no association with use during the 10 years before reference date [OR = 1.07 (95%
      CI = 0.61-1.86) for 1-749 estrogen tablets; OR = 1.11 (95% CI = 0.69-1.80) for
      750 or more estrogen tablets]. These results do not support the hypothesis that
      recent HRT use substantially reduces risk of colon cancer.

PMID- 10401883
TI  - A cohort study of farming and risk of prostate cancer in Iowa.
AB  - Although farming has been linked to prostate cancer mortality, few investigations
      have addressed its association with prostate cancer incidence. We followed a
      population-based cohort of 1,177 cancer-free men for up to 9 years and identified
      81 incident prostate cancers. Men whose usual occupation was farmer were at an
      increased risk of prostate cancer after adjustment for age, smoking, alcohol, and
      dietary factors (RR = 1.7; 95% CI = 1.0-2.7). Exclusion of well-differentiated,
      localized tumors slightly strengthened the association (RR = 2.0; 95% CI = 1.1
      3.6). Risk was confined to older (age 70+ years) farmers (RR = 2.2; 95% CI = 1.1
      4.3); we found no evidence of an effect among younger farmers (RR = 1.0; 95% CI =
      0.4-2.1).

PMID- 10401884
TI  - Properties of the geometrically averaged ratio, an alternative standardized
      measure.
AB  - In epidemiology, the comparative mortality figure and the standardized mortality
      ratio are standardized measures in common use. Both are weighted averages of rate
      ratios (or observed/expected death count ratios) on the arithmetic scale. I
      propose a new standardized measure, the geometrically averaged ratio (GAR), which
      is defined through simple averaging on the logarithmic scale. I show that, in
      addition to providing a valid comparison between populations, the geometrically
      averaged ratio possesses the following desirable properties: (1) invertibility
      and invariance of standardized sex ratios and (2) interpopulational comparability
      with different standards.

PMID- 10401885
TI  - From hazard to habitat: rethinking environment and health.

PMID- 10401886
TI  - Childhood leukemia and electrical appliances.

PMID- 10401887
TI  - Adjustment for age at first birth in etiologic studies of breast cancer involving
      exposures that may effect age at first birth.

PMID- 10401888
TI  - Testosterone level as a potential selection bias for semen donors in assessing
      population fertility.

PMID- 10401889
TI  - An estimate of the tendency to repeat postterm delivery.

PMID- 10401890
TI  - The misinterpretation of study results based on statistical significance.

PMID- 10401891
TI  - Treatment satisfaction compared with outcome in severe dual disorders.
AB  - This paper examines patient (N = 75) ratings of treatment satisfaction and
      outcome for severely mentally ill dually diagnosed outpatients participating in
      long-term integrated dual focus treatment. In addition, it compares these ratings
      with case manager ratings of patient outcome over a one year period. Satisfaction
      ratings ranged from very good to excellent. Combined means of several outcomes
      ratings indicated that most patients rated themselves as improved. Satisfaction
      with over-all care and with case management was significantly, though weakly (r =
      .3 and .31, respectively, p < .05), related to patient ratings of overall
      outcome. While most patients rated that they had improved, satisfaction with
      treatment was only weakly related to either patient or case manager rated
      clinical outcomes. These findings indicate the relatively independent
      relationship of satisfaction with treatment outcome and caution against over
      generalizing the meaning of treatment satisfaction measures.

PMID- 10401892
TI  - Statewide replication of predictive validation for the Multnomah Community
      Ability Scale.
AB  - The Multnomah Community Ability Scale is a 17 item instrument that case managers
      can use to rate levels of functioning for clients with severe mental illness.
      Prior work in a large urban community mental health center showed that the
      instrument predicted subsequent involuntary hospitalization. The current project
      involved some 2,487 clients of community mental health programs throughout
      Oregon. This replication study again showed that low scores on the instrument
      predicted subsequent psychiatric hospitalization.

PMID- 10401893
TI  - Recovery as a psychological construct.
AB  - Mental health advocates have proposed recovery as a vision for severe mental
      illness. The purpose of this study is to examine psychometric characteristics of
      a measure of the psychological construct. Thirty-five participants in a partial
      hospitalization program were administered the Recovery Scale and measures of
      quality of life, social support, self-esteem, consumer empowerment, psychiatric
      symptoms, needs and resources, global functioning, and verbal intelligence.
      Results showed the scale to have satisfactory test-retest reliability and
      internal consistency. Analysis of the concurrent validity of the Recovery Scale
      showed recovery to be positively associated with self-esteem, empowerment, social
      support, and quality of life. It was inversely associated with psychiatric
      symptoms and age. Implications of these findings for a psychological model of
      recovery are discussed.

PMID- 10401895
TI  - Comparing practice patterns of consumer and non-consumer mental health service
      providers.
AB  - The practice patterns of consumer and non-consumer providers of assertive
      community treatment are compared using both quantitative and qualitative data
      collected as part of a randomized trial. Activity log data showed that there were
      few substantive differences in the pattern of either the administrative or direct
      service tasks performed by the two teams. In contrast, the qualitative data
      revealed that there were discernable differences in the "culture" of the two
      teams. The consumer team "culture" emphasized "being there" with the client while
      the non-consumer team was more concerned with accomplishing tasks.

PMID- 10401896
TI  - A comparison of consumer and provider preferences for research on homeless
      veterans.
AB  - Despite the dramatic growth of homelessness research, there have been no
      systematic assessments of consumer and provider preferences regarding the content
      of this research. Therefore, 87 clients and 28 staff of a homeless veterans
      program were administered a 15-item questionnaire requesting identification of
      the 5 "most" and 5 "least" important research topics. Staff and clients differed
      significantly on 6 items considered most important and 4 items considered least
      important. Clients wanted more research that focused on material needs, whereas
      staff preferences were more broadly distributed. The fact that appreciable data
      exist for many of the research topics that respondents identified as important
      raises concerns about the accessibility of homelessness research.

PMID- 10401894
TI  - Respite from stress and other service needs of homeless families.
AB  - This paper is a description of qualitative interviews with homeless mothers
      participating in an outdoor camp program designed as time out from the stressful
      conditions of shelter living. In addition to evaluation of family satisfaction
      with camp, the individual interviews and parental discussion groups offered at
      camp enabled the women to share stories about some of the obstacles they
      encounter in moving toward self-sufficiency and in parenting their children. Gaps
      in services to help overcome these obstacles ranged from learning to read to
      treatment of childhood sexual abuse and more comprehensive substance abuse
      treatment. Suggestions for expansion of the program to better meet needs of
      families included support groups and referrals to community mental health
      services.

PMID- 10401897
TI  - Orthopedic fellowships.

PMID- 10401898
TI  - Adjacent-segment degeneration after lumbar fusion: a review of clinical,
      biomechanical, and radiologic studies.
AB  - Lumbar fusion is commonly performed to relieve pain from degenerative conditions,
      including spinal stenosis and spondylolisthesis. While clinical studies have
      reported favorable fusion rates with limited complications, few have investigated
      the effect of fusion on the adjacent motion segment. A solid fusion alters the
      biomechanics at the adjacent level, resulting in increased mechanical demands.
      There have been reports of increased rates of adjacent-level pathologic lesions
      after fusion, but these have not accounted for the natural history of
      degenerative changes. Biomechanical and radiographic studies have shown increased
      forces, mobility, and intradiscal pressure in adjacent segments after fusion. It
      has been hypothesized that these changes lead to an acceleration in pathologic
      changes.

PMID- 10401899
TI  - Pronation and supination of the scaphoid.
AB  - The objective of this study was to identify and classify longitudinal rotations
      of the scaphoid on clinical radiographs of normal wrists. The concept of scaphoid
      recumbency was defined in terms of the orientation of the palmar tubercle.
      Pronation and supination of the scaphoid were identified in a set of 130
      posteroanterior films of structurally normal wrists in neutral position. Normal
      variations in scaphoid recumbency and lunate posture were classified. It was
      found that the scaphoid is in neutral recumbency in 62%, pronation in 32%, and
      supination in 7% of structurally normal wrists. Neutral scaphoid recumbency and
      neutral lunate posture occur together in 45% of normal wrists. Rarely, scaphoid
      supination and lunate flexion occurred together, simulating a collapse pattern
      often seen in inflammatory arthritis. Scaphoid supination and lunate extension
      did not occur together. An anatomic basis for this incompatibility of scaphoid
      recumbency and lunate posture is suggested. We conclude that longitudinal
      rotation of the scaphoid (ie, pronation and supination) may be seen on clinical
      radiographs of structurally normal wrists. These rotations are exaggerated in
      certain types of carpal instability.

PMID- 10401900
TI  - Hartshill spinal fixation in vertebral metastasis.
AB  - Spinal fusion by Hartshill rectangle frame was used in 10 patients with spinal
      cord compression secondary to vertebral metastasis in the thoracic and lumbar
      spine, occupying mainly the posterior elements. All patients presented with pain,
      bone collapse, and neurologic deficit. The procedure is built on a system of
      sublaminar wires passed under two to three lamina above and below the
      decompressed area and tightened to a prebent metal frame. This procedure was
      relatively simple, and the immediate stabilization achieved in our patients was
      good. All patients experienced immediate pain relief. While only two patients
      were able to walk before surgery, seven were able to do so at follow-up. During a
      follow-up period of at least 2 years in two patients, or until death in the other
      eight patients, one patient had a broken wire that did not affect the correction
      achieved at surgery. Partial loss of correction in the sagittal plane was found
      in two patients who had metastasis in the lumbar spine and in another patient who
      had metastasis in the ninth thoracic vertebra.

PMID- 10401901
TI  - Comparison of morphine patient-controlled analgesia with and without ketorolac
      for postoperative analgesia in pediatric orthopedic surgery.
AB  - The purpose of this prospective, randomized, double-blind, placebo-controlled
      clinical study was to determine whether the administration of intravenous
      ketorolac, coadministered with morphine patient-controlled analgesia (PCA),
      demonstrates an opioid-sparing effect, provides improved analgesia, and reduces
      the incidence of opioid-induced side effects in children after orthopedic
      surgery. The findings of enhanced analgesia with decreased opioid use suggest
      that coadministration of ketorolac with morphine PCA is beneficial for the
      treatment of pain in children after orthopedic surgery.

PMID- 10401902
TI  - Ring finger ray amputation: a 25-year follow-up.
AB  - The treatment of class III ring avulsion injuries remains controversial. This
      case report presents a 25-year follow-up of a class III ring avulsion injury
      treated with secondary ring finger ray amputation. This case shows long-term
      excellent functional and cosmetic results of ring finger ray resection without
      bony transposition.

PMID- 10401903
TI  - Use of a custom retrograde intramedullary rod for the management of distal
      femoral nonunion: a report of two cases.
AB  - Nonunion of the distal femur is a rare injury that is difficult to manage. A
      variety of surgical implants and techniques are available. We present an
      alternative mode of treatment for supracondylar femoral nonunion using a custom
      retrograde titanium femoral nail (Biomet; Warsaw, IN) to successfully achieve
      union in two cases. We believe the added length, custom modifications, and
      enhanced stability allowed better fixation in an osteopenic distal femur.

PMID- 10401904
TI  - Spinous process fractures in a jockey: a case report.
AB  - Spinous process fractures typically represent avulsion injuries involving the
      lower cervical spine. This case report describes the clinical and radiographic
      findings in a patient with spinous process fractures at the T-2, T-3, and T-4
      vertebral levels. The fractures, which were obscured on conventional radiographs
      by overlying osseous and soft-tissue structures, were optimally shown on axial
      and computer-reconstructed sagittal computed tomographic (CT) images. Although
      isolated spinous process fractures do not compromise spinal stability, chronic
      sequelae associated with fracture nonunion may occur if a fracture is not
      recognized and treated. Because conventional radiographic assessment of the
      thoracic posterior elements is often limited, cases of clinically suspected
      spinous process fracture often require CT evaluation to confirm the diagnosis.

PMID- 10401905
TI  - A 63-year-old man with neck pain and limb weakness.

PMID- 10401906
TI  - Chondral lesions of the knee: comparisons of treatments and treatment costs.

PMID- 10401907
TI  - Anonymous or confidential HIV counseling and voluntary testing in federally
      funded testing sites--United States, 1995-1997.
AB  - Human immunodeficiency virus (HIV) counseling and voluntary testing (CT) programs
      have been an important part of national HIV prevention efforts since the first
      HIV antibody tests became available in 1985. In 1995, these programs accounted
      for approximately 15% of annual HIV antibody testing in the United States,
      excluding testing for blood donation. CT opportunities are offered to persons at
      risk for HIV infection at approximately 11,000 sites, including dedicated HIV CT
      sites, sexually transmitted disease (STD) clinics, drug-treatment centers,
      hospitals, and prisons. In 39 states, testing can be obtained anonymously, where
      persons do not have to give their name to get tested. All states provide
      confidential testing (by name) and have confidentiality laws and regulations to
      protect this information. This report compares patterns of anonymous and
      confidential testing in all federally funded CT programs from 1995 through 1997
      and documents the importance of both types of testing opportunities.

PMID- 10401908
TI  - Progress toward poliomyelitis eradication--African Region, 1998-April 1999.
AB  - In 1988, the World Health Assembly resolved to eradicate poliomyelitis globally
      by 2000. To achieve this goal, the African Region (AFRO) of the World Health
      Organization (WHO) has accelerated polio eradication strategies, but the region
      remains one of the two major reservoirs for wild poliovirus transmission. This
      report summarizes progress toward polio eradication from 1998 through April 1999
      in AFRO, highlights supplementary vaccination activities (National Immunization
      Days [NIDs]) and acute flaccid paralysis (AFP) surveillance conducted in the
      region, and describes plans for program acceleration (intensified NIDs and
      mopping-up vaccinations) to meet the 2000 eradication target.

PMID- 10401909
TI  - Renal insufficiency and failure associated with immune globulin intravenous
      therapy--United States, 1985-1998.
AB  - Immune globulin intravenous (IGIV) is a sterile, highly purified immunoglobulin G
      (IgG) preparation made from pooled human plasma stabilized with glucose, maltose,
      glycine, sucrose, sorbitol, or albumin and is used as prophylaxis or therapy for
      various medical disorders. The Food and Drug Administration (FDA) first licensed
      IGIV in 1981 and has approved its use for six conditions: primary
      immunodeficiencies, immune-mediated thrombocytopenia, Kawasaki syndrome, recent
      bone marrow transplantation in patients aged > or =20 years, chronic B-cell
      lymphocytic leukemia, and pediatric human immunodeficiency virus type 1 (HIV-1)
      infection. In clinical practice, IGIV has been known to be used to treat 50-60
      unapproved conditions, including acute lymphoblastic leukemia, adult HIV
      infection, multiple sclerosis, Guillain-Barre syndrome, and chronic inflammatory
      demyelinating polyneuropathy. During June 1985-November 1998, FDA received
      approximately 120 reports worldwide of renal adverse events (RAEs) (i.e., acute
      renal failure or insufficiency) following IGIV administration. This report
      describes the epidemiology of IGIV-associated RAEs in the United States and
      emphasizes the importance of reviewing indications for IGIV use and implementing
      precautions during its administration.

PMID- 10401910
TI  - Update: hantavirus pulmonary syndrome--United States, 1999.
AB  - Hantavirus pulmonary syndrome (HPS) is a rodentborne viral disease characterized
      by severe pulmonary illness and a case-fatality ratio of 43%. Sin Nombre virus is
      the primary hantavirus that causes HPS in the United States, and the deer mouse
      (Peromyscus maniculatus) is its predominant carrier. CDC-sponsored studies of
      rodent populations since 1994 have yielded data that suggest an increased risk
      for infection for humans in some areas of the southwestern United States during
      the summer of 1999. This report describes increases in human cases during January
      May 1999, current hantavirus prevalence in rodent populations, the need for
      renewed attention to reduce the risk for hantavirus exposure, and the importance
      of physician awareness and early detection in the treatment of HPS.

PMID- 10401911
TI  - Antidepressants: the blue-chip psychotropic for the modern treatment of anxiety
      disorders.

PMID- 10401912
TI  - Novel antipsychotics: comparison of weight gain liabilities.
AB  - BACKGROUND: We performed a retrospective analysis of 122 clinical records of 92
      male patients with DSM-III-R schizophrenia to examine the relative weight gain
      liabilities of clozapine, risperidone, olanzapine, and sertindole compared with
      haloperidol. We hypothesized that the unique pharmacodynamic profiles of these
      agents would contribute to different amounts and patterns of weight gain. METHOD:
      Data were analyzed to determine differences in weight gain during treatment among
      patients receiving 5 different drug treatments (clozapine [N = 20], olanzapine [N
      = 13], risperidone [N = 38], haloperidol [N = 43], and sertindole [N = 8]).
      Measures of maximal weight gain, final weight, and duration to maximal weight
      gain were calculated. RESULTS: Repeated measures analyses of variance controlling
      for age, treatment duration, and initial weight revealed statistically
      significant differences between groups on all 3 measures. Clozapine and
      olanzapine had the greatest maximal weight gain liability (F = 4.13, df = 4,23; p
      = .01). Weight gain with clozapine, but not olanzapine or risperidone, appears to
      persist (as reflected by final weight) despite behavioral interventions (e.g.,
      nutritional consultation, suggested exercise regimen; F = 5.69, df = 4,23; p =
      .003). Clozapine- and olanzapine-treated subjects appeared to gain weight over a
      prolonged period of time, whereas risperidone-and sertindole-treated subjects had
      a more limited period of weight gain (F = 2.95, df = 4,25; p = .04). CONCLUSION:
      Clozapine and olanzapine caused the most weight gain, risperidone was
      intermediate, and sertindole had less associated weight gain than haloperidol.
      The relative receptor affinities of the novel antipsychotics for histamine H1
      appear to be the most robust correlate of these clinical findings.

PMID- 10401913
TI  - Clozapine and obsessions in patients with recent-onset schizophrenia and other
      psychotic disorders.
AB  - BACKGROUND: The increase or emergence of obsessions was compared in young
      patients with recent-onset schizophrenia or other psychotic disorders taking
      clozapine and other antipsychotic drugs. METHOD: We conducted a retrospective
      cohort study. Subjects were 121 consecutively admitted patients diagnosed with
      DSM-III-R schizophrenia, schizoaffective disorder, schizophreniform disorder, or
      psychotic disorder not otherwise specified. Obsessions were diagnosed according
      to DSM-IV criteria. RESULTS: More clozapine-treated subjects (20.6%) than
      subjects treated with other antipsychotic drugs (1.3%) experienced an emergence
      or increase of obsessions (p<.01). CONCLUSION: Use of clozapine is associated
      with the emergence or increase of obsessions in early-phase schizophrenia.

PMID- 10401914
TI  - Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic
      outpatients.
AB  - BACKGROUND: Nearly one third of patients suffering from schizophrenia do not
      fully respond to antipsychotic medication. Safe, effective, and cost-efficient
      methods to reduce symptoms are clearly needed; therefore, lithium as an adjunct
      to fluphenazine decanoate was tested in a placebo-controlled trial in outpatients
      who were part of the Treatment Strategies of Schizophrenia (TSS) study. METHOD:
      Forty-one patients with DSM-III schizophrenia or schizoaffective disorder were
      assigned to either adjunctive lithium or placebo after at least 6 months of
      fluphenazine decanoate treatment to stabilize symptoms had failed. The trial was
      designed for 8 weeks of treatment, and patients assigned to placebo could
      afterward be administered lithium in an 8-week, open-label study. RESULTS:
      Assessment of the intent-to-treat analysis revealed no significant differences in
      demographic variables between the lithium and placebo groups. Although both
      groups showed significant (p = .00135) improvement as measured by total scores on
      the Brief Psychiatric Rating Scale (BPRS), there were no significant differences
      in response between the lithium and placebo groups. Patients originally treated
      with placebo added to neuroleptic did not have significantly greater improvement
      when receiving open-label adjunctive lithium. CONCLUSION: Although success with
      lithium augmentation therapy for persistent psychosis has been reported in the
      past, this study of well-characterized patients showed no benefit for this common
      strategy, thus indicating that care be used in utilizing lithium augmentation.

PMID- 10401915
TI  - Risperidone use at a state hospital: a clinical audit 2 years after the first
      wave of risperidone prescriptions.
AB  - BACKGROUND: In spite of some inherent limitations, naturalistic data can provide
      information on populations that have greater heterogeneity than can controlled
      clinical trials and on functional outcomes that may be especially important in
      clinical practice. In the present retrospective naturalistic study, we evaluated
      key clinical outcomes among the first wave of risperidone-treated patients at a
      state psychiatric hospital. METHOD: Outcome data were extracted from the charts
      of 142 patients 2 years after initiation of treatment with risperidone. Their
      diagnoses included DSM-III-R schizophrenia (57%), schizoaffective disorder (22%),
      dementia and other organic conditions (7%), bipolar disorder (5%), and other
      psychiatric disorders (9%). RESULTS: During the 2-year period, 92 of 142 patients
      were discharged from the hospital: 61 (43%) were discharged on risperidone
      treatment and 31 (22%) were discharged on treatment with other drugs. At the time
      of the study, 50 of 142 patients were still in the hospital: of these, 18 (13%)
      were still receiving risperidone. The modal maximum daily dose of risperidone was
      4.1 mg in patients discharged on risperidone treatment and 7.5 mg in patients
      still in the hospital. All groups were granted more ward privileges after
      starting risperidone, the most being granted to patients discharged from the
      hospital on risperidone treatment (p<.05 versus patients discharged on treatment
      with other drugs) and those still receiving risperidone in the hospital.
      Significantly fewer patients discharged on risperidone treatment than on
      treatment with other drugs were readmitted to the hospital within 2 years after
      discharge (p<.01). CONCLUSION: Improved privilege levels and a reduced
      readmission rate indicate that risperidone was an effective antipsychotic agent
      among a heterogeneous patient population in a state hospital. These factors may
      be especially important to justify use of this agent in the current fiscal
      climate.

PMID- 10401916
TI  - Sensitivity to 35% carbon dioxide in patients with generalized anxiety disorder.
AB  - BACKGROUND: Panic disorder and generalized anxiety disorder (GAD) are both
      characterized by severe anxiety, but there is evidence that indicates a
      qualitative difference between these 2 anxiety disorders. To investigate the
      specificity of the association between carbon dioxide (CO2) hypersensitivity and
      panic disorder and the possible relationships between panic disorder and GAD, the
      responses to inhalation of a gas mixture of 35% CO2 and 65% oxygen (O2) were
      assessed. METHOD: Fifteen patients with panic disorder, 13 patients with GAD, and
      10 patients with comorbid GAD and panic disorder according to a consensus
      diagnosis using Diagnostic Interview Schedule Version III-R (DIS-R) and DSM-IV
      criteria, and 12 healthy controls inhaled 2 vital capacities: 1 of 35% CO2 and 1
      of compressed air. A double-blind, randomized, crossover design was used.
      RESULTS: GAD patients showed reactions to 35% CO2 that were similar to those of
      healthy controls and significantly weaker than that of panic disorder patients.
      Patients with comorbid panic disorder and GAD had anxiogenic reactions similar to
      those of subjects with panic disorder. CONCLUSION: The results of the present
      study support the idea that panic disorder and GAD are separate disorders that
      have at least some differences in pathogenetic mechanisms and suggest that the
      35% CO2 test might be a valid tool for discriminating between these 2 disorders.

PMID- 10401917
TI  - Response to missile attacks on civilian targets in patients with panic disorder.
AB  - BACKGROUND: The complex interaction that exists between biological and cognitive
      factors determines the reaction of panic-disorder patients to stressors. The
      current study was conducted to systematically assess the behavioral effects of a
      real, life-threatening event on panic-disorder patients. METHOD: Sixty-five panic
      disorder patients completed structured telephone interviews during the first 4
      weeks of the Persian Gulf War. Evaluation included frequency of panic attacks,
      anxiety levels, and function levels both during and between air raid alarms.
      RESULTS: The findings indicate that panic-disorder patients, despite high levels
      of anxiety, did not demonstrate an increased frequency of panic attacks during
      the Persian Gulf War. In addition, the majority of patients reported good-to-high
      levels of functioning during the crisis in both everyday and alarm-related
      functioning. Grouping of subjects according to proximity to risk or current
      antipanic treatment did not produce significant differences in the frequency of
      panic attacks or levels of anxiety. CONCLUSION: The findings suggest that
      vulnerability of patients with panic disorder to a "panic-stricken" response does
      not increase during real-life stressors. The lack of increased frequency of panic
      attacks observed under these circumstances provides additional support for the
      opinion that panic and fear are two distinct entities.

PMID- 10401918
TI  - Changes in adverse events reported by patients during 6 months of fluoxetine
      therapy.
AB  - BACKGROUND: Although a period of 6 to 12 months of antidepressant therapy is
      recommended for most patients with depression, systematic examinations of the
      course of adverse events over time, the resolution of early-onset events, and the
      possible emergence of later-onset events are limited. We examined the safety of
      fluoxetine, 20 mg/day, in a large, prospective, long-term treatment trial, and we
      report a comparison of early- and late-onset adverse events and the course of
      adverse events over 26 weeks of treatment. METHOD: Adverse events were recorded
      at each visit in a uniform format by open-ended questioning, regardless of
      perceived causality. New or worsened events reported in either the first 4 weeks
      of treatment (early-reporting interval) or weeks 22 through 26 of treatment (late
      reporting interval) were compared. RESULTS: Patients (N = 299) whose depression
      (DSM-III-R) remitted with 12 weeks of fluoxetine treatment entered continuation
      therapy, and 174 completed 26 weeks of therapy. All events that occurred in > or
      =5% of patients early in treatment decreased in frequency over time (p<.05), and
      no events occurred significantly more frequently during continuation therapy. No
      previously uncommon adverse events became common during long-term treatment.
      CONCLUSION: Common adverse events associated with initiating fluoxetine treatment
      in depressed patients, including nausea, insomnia, nervousness, and somnolence,
      resolve in the majority of patients and become significantly less frequent with
      continued treatment over a 6-month period. No adverse events present initially
      become more frequent late in treatment. Therapy with fluoxetine, 20 mg/day, is
      well tolerated over 6 months, and most adverse events observed early in treatment
      resolve.

PMID- 10401920
TI  - Reboxetine, a unique selective NRI, prevents relapse and recurrence in long-term
      treatment of major depressive disorder.
AB  - BACKGROUND: The long-term efficacy and tolerability of the antidepressant
      reboxetine, a unique selective norepinephrine reuptake inhibitor (selective NRI),
      were assessed in an international study. METHOD: Two hundred eighty-three
      patients with recurrent DSM-III-R major depression who responded to 6 weeks of
      reboxetine treatment (> or =50% decrease in Hamilton Rating Scale for Depression
      [HAM-D] total score) were randomly assigned to receive reboxetine or placebo for
      46 weeks in a double-blind phase. Relapse (> or =50% increase in HAM-D total
      score and/or a HAM-D total score > or =18) rate was the principal assessment
      criterion and included patients who experienced relapse or recurrence. Only
      patients who remained relapse-free at the end of the first 6-month treatment
      period were included in the relapse rate assessment at the end of the second 6
      month treatment period. RESULTS: Reboxetine was associated with a markedly lower
      relapse rate than placebo (22% vs. 56%; p<.001) and a greater cumulative
      probability of a maintained response (p = .0001) during long-term treatment.
      Patients in remission (HAM-D total score < or =10) at the time of random
      assignment were less likely to relapse (16% reboxetine, 48% placebo; p<.001). The
      proportion of patients who were relapse-free and therefore remained in the study
      was significantly (p< or =.001) higher among those on reboxetine treatment than
      on placebo at the end of the first (61% vs. 40%) and second (88% vs. 59%) 6
      months of treatment. Additional efficacy measures supported these findings. The
      incidence of adverse events with reboxetine was low and comparable with that for
      placebo. Discontinuation due to adverse events occurred infrequently. CONCLUSION:
      Reboxetine treatment over 1 year is more effective than placebo in the prevention
      of relapse in patients with recurrent depression. The low relapse rates at the
      end of the second 6 months of treatment further suggest that reboxetine
      effectively prevents recurrence of depressive symptoms following episode
      resolution. Reboxetine is well tolerated in long-term treatment of depression, a
      finding that bodes well for long-term patient compliance.

PMID- 10401919
TI  - Effect of cannabis use on cognitive functions and driving ability.
AB  - BACKGROUND: Neither experimental nor epidemiologic approaches have so far given
      definitive answers to the question of the potential effect of cannabis on driving
      ability. METHOD: To shed more light on this topic, we conducted a placebo
      controlled double-blind study including 60 healthy volunteers (a negative urine
      drug screening test was prerequisite). On the first day, baseline data were
      obtained from a physical examination and a psychological test battery for the
      investigation of visual and verbal memory as well as cognitive perceptual
      performance. On the second day, subjects received a regular cigarette or one
      containing 290 microg/kg body weight of tetrahydrocannabinol. Physical and
      psychological assessments were performed immediately (15 minutes) after subjects
      smoked their cigarettes. Twenty-four hours later, physical and psychological
      examinations were repeated. RESULTS AND CONCLUSION: Our results suggest that
      perceptual motor speed and accuracy, 2 very important parameters of driving
      ability, seem to be impaired immediately after cannabis consumption.

PMID- 10401921
TI  - Isotretinoin treatment of a woman with bipolar disorder.

PMID- 10401922
TI  - Seizures after discontinuation of low-dose lorazepam from originally seizure-free
      clozapine regimen: combined effects?

PMID- 10401923
TI  - Bipolar II disorder vs. premenstrual dysphoric disorder.

PMID- 10401924
TI  - SSRI-induced parkinsonism may be an early sign of future Parkinson's disease.

PMID- 10401925
TI  - Psychiatric features of 36 men convicted of sexual offenses.
AB  - BACKGROUND: To increase understanding of the relationship between sexual violence
      and mental illness, the authors assessed the legal histories and psychiatric
      features of 36 males convicted of sexual offenses. METHOD: Thirty-six consecutive
      male sex offenders admitted from prison, jail, or probation to a residential
      treatment facility received structured clinical interviews for DSM-IV Axis I and
      II disorders. The participants' legal histories, histories of sexual and physical
      abuse, and family histories of psychiatric disorders were also assessed. RESULTS:
      The participants' mean +/- SD age was 33+/-8 years. They had been convicted a
      mean of 1.8+/-1.4 times (range, 1-9 times) for sexual offenses and incarcerated a
      mean of 8+/-6 years (range, 0-22 years). Participants displayed high rates of
      lifetime DSM-IV Axis I disorders: 30 (83%) had a substance use disorder; 21
      (58%), a paraphilia; 22 (61%), a mood disorder (13 [36%] with a bipolar
      disorder); 14 (39%), an impulse control disorder; 13 (36%), an anxiety disorder;
      and 6 (17%), an eating disorder. Participants also displayed high rates of Axis
      II disorders, with 26 (72%) meeting DSM-IV criteria for antisocial personality
      disorder. In addition, subjects reported experiencing high rates of sexual (but
      not physical) abuse and high rates of Axis I disorders, especially substance use
      and mood disorders, in their first-degree relatives. Compared with subjects
      without paraphilias, subjects with paraphilias displayed statistically
      significantly higher rates of mood, anxiety, and eating disorders, as well as
      significantly higher rates of childhood sexual abuse. CONCLUSION: Recognition and
      treatment of major psychiatric disorders among sex offenders may increase chances
      for successful rehabilitation, reduce recidivism and public victimization, and
      produce significant public health and economic benefits. More studies in this
      area appear warranted to search for more effective interventions for this severe
      public health problem.

PMID- 10401926
TI  - Feedforward neural network with adaptive reference pattern layer.
AB  - A hybrid neural network architecture is investigated for modeling purposes. The
      proposed hybrid is based on the multilayer perceptron (MLP) network. In addition
      to the usual hidden layers, the first hidden layer is selected to be an adaptive
      reference pattern layer. Each unit in this new layer incorporates a reference
      pattern that is located somewhere in the space spanned by the input variables.
      The outputs of these units are the component wise-squared differences between the
      elements of a reference pattern and the inputs. The reference pattern layer has
      some resemblance to the hidden layer of the radial basis function (RBF) networks.
      Therefore the proposed design can be regarded as a sort of hybrid of MLP and RBF
      networks. The presented benchmark experiments show that the proposed hybrid can
      provide significant advantages over standard MLPs and RBFs in terms of fast and
      efficient learning, and compact network structure.

PMID- 10401927
TI  - Neural networks and linear programming for the satisfiability problem.
AB  - First a Linear Programming formulation is considered for the satisfiability
      problem, in particular for the satisfaction of a Conjunctive Normal Form in the
      Propositional Calculus and the Simplex algorithm for solving the optimization
      problem. The use of Recurrent Neural Networks is then described for choosing the
      best pivot positions and greatly improving the algorithm performance. The result
      of hard cases testing is reported and shows that the technique can be useful even
      if it requires a huge amount of size for the constraint array and Neural Network
      Data Input.

PMID- 10401928
TI  - Solving linear integer programming problems by a novel neural model.
AB  - The paper deals with integer linear programming problems. As is well known, these
      are extremely complex problems, even when the number of integer variables is
      quite low. Literature provides examples of various methods to solve such
      problems, some of which are of a heuristic nature. This paper proposes an
      alternative strategy based on the Hopfield neural network. The advantage of the
      strategy essentially lies in the fact that hardware implementation of the neural
      model allows for the time required to obtain a solution so as not depend on the
      size of the problem to be solved. The paper presents a particular class of
      integer linear programming problems, including well-known problems such as the
      Travelling Salesman Problem and the Set Covering Problem. After a brief
      description of this class of problems, it is demonstrated that the original
      Hopfield model is incapable of supplying valid solutions. This is attributed to
      the presence of constant bias currents in the dynamic of the neural model. A
      demonstration of this is given and then a novel neural model is presented which
      continues to be based on the same architecture as the Hopfield model, but
      introduces modifications thanks to which the integer linear programming problems
      presented can be solved. Some numerical examples and concluding remarks highlight
      the solving capacity of the novel neural model.

PMID- 10401929
TI  - A memory-based self-generated basis function neural network.
AB  - The paper presents a novel memory-based Self-Generated Basis Function Neural
      Network (SGBFN) that is composed of small CMACs. The SGBFN requires much smaller
      memory space than the conventional CMAC and has an excellent learning convergence
      property compared to multilayer neural networks. Each CMAC in the new structure
      takes a subset of problem inputs as its inputs. Several CMACs that have different
      subsets of inputs form a submodule and a group of submodules form a neural
      network. The output of a submodule is the product of its CMACs' outputs. Each
      submodule implements a self-generated basis function, which is developed during
      the learning. The output of the neural network is the sum of the outputs from the
      submodules. Using only a subset of inputs in each CMAC significantly reduces the
      required memory space in high-dimensional modeling. With the same size of memory,
      the new structure is able to achieve a much smaller learning error compared to
      the conventional CMAC.

PMID- 10401930
TI  - Synchronous and asynchronous brain-state-in-a-box information system neural
      models.
AB  - Synchronous and asynchronous information system neural models are proposed that
      are hybrids of Pawlak's information system and Brain-State-in-a-Box (BSB) neural
      models. The stability of the proposed models is studied using LaSalle's
      Invariance Principle. Applications to an analysis of the United Nations
      activities are presented as examples.

PMID- 10401931
TI  - Partial retraining: a new approach to input relevance determination.
AB  - In this article we introduce partial retraining, an algorithm to determine the
      relevance of the input variables of a trained neural network. We place this
      algorithm in the context of other approaches to relevance determination.
      Numerical experiments on both artificial and real-world problems show that
      partial retraining outperforms its competitors, which include methods based on
      constant substitution, analysis of weight magnitudes, and "optimal brain
      surgeon".

PMID- 10401932
TI  - Endotoxin-core antibodies: time for a reappraisal?

PMID- 10401933
TI  - Jugular bulb oximetry: the link between cerebral and systemic management of
      severe head injury.

PMID- 10401934
TI  - N-acetylcysteine administration in the critically ill.

PMID- 10401935
TI  - Relationship of antibodies to endotoxin core to mortality in medical patients
      with sepsis syndrome.
AB  - OBJECTIVES: To assess the prognostic value of determining anti-endotoxin core
      antibodies (EndoCab) immunoglobulin (Ig)G and IgM in medical patients with sepsis
      syndrome in order to identify patient subgroups that may profit from endotoxin
      neutralizing therapy. The findings were correlated with clinical outcome,
      endotoxin levels and sepsis score. DESIGN: Cohort study with a follow-up period
      of 30 days. SETTING: Medical intensive care units (2) of a university hospital.
      PATIENTS AND METHODS: Twenty-nine patients who fulfilled the criteria of sepsis
      syndrome and did not present with septic shock or had not been treated with
      antibiotics for more than 3 days were included in the study. Twenty-one intensive
      care patients without infections served as controls for antibody concentrations.
      INTERVENTIONS: Blood samples were obtained from indwelling arterial catheters or
      direct venipuncture on admission and daily thereafter until transfer to a regular
      unit. Sepsis scores were determined daily. RESULTS: The mortality rate at 30 days
      was 44.8% (13 out of 29). Sepsis patients had significantly lower initial EndoCab
      IgM and IgG concentrations than controls. Initial EndoCab IgG concentrations were
      significantly lower in non-survivors of sepsis syndrome but not in survivors
      compared to controls (median concentrations 51.5 vs 110.1 vs 245.4 MU/ml).
      EndoCab IgM and IgG were lower in non-survivors compared to survivors, though
      that difference failed to reach significance (p = 0.11 in both cases). Depletion
      of initial EndoCab IgM concentrations (defined as a value below the 10th
      percentile of a control population) was present in 15 patients, 9 of whom died,
      and depletion of IgG in five patients, four of whom died. EndoCab IgM and IgG
      concentrations rose concordantly in survivors and non-survivors in the course of
      the disease. Endotoxin levels were significantly higher in non-survivors compared
      to controls but not in survivors. A sepsis score of 21 and higher was associated
      with 90.9% mortality (specificity 93.8%, sensitivity 76.9%). CONCLUSIONS:
      Decreased EndoCab IgG concentrations are associated with increased mortality in
      medical patients with sepsis syndrome. The measurement of initial anti-endotoxin
      antibodies may provide a useful tool to identify septic patients who profit
      potentially from endotoxin neutralizing therapy, however considerable overlap of
      antibody concentrations warrants additional parameters. The sepsis score is easy
      to determine and useful in the evaluation of medical patients with sepsis.

PMID- 10401936
TI  - Early SjvO2 monitoring in patients with severe brain trauma.
AB  - OBJECTIVE: To investigate early cerebral variables after minimal resuscitation
      and to compare the adequacy of a cerebral perfusion pressure (CPP) guideline
      above 70 mmHg, with jugular bulb venous oxygen saturation (SjvO2) monitoring in a
      patient with traumatic brain injury (TBI). DESIGN: Prospective, observational
      study. SETTING: Anesthesiological intensive care unit. PATIENTS: 27 TBI patients
      with a postresuscitation Glasgow Coma Scale score less than 8. INTERVENTION:
      After initial resuscitation, cerebral monitoring was performed and CPP increased
      to 70 mmHg by an increase in mean arterial pressure (MAP) with volume expansion
      and vasopressors as needed. MEASUREMENTS AND RESULTS: MAP, intracranial pressure
      (ICP), CPP, and simultaneous arterial and venous blood gases were measured at
      baseline and after treatment. Before treatment, 37% of patients had an SjvO2
      below 55%, and SjvO2 was significantly correlated with CPP (r = 0.73, p <
      0.0001). After treatment, we observed a significant increase (p < 0.0001) in CPP
      (78+/-10 vs 53+/-15 mmHg), MAP (103+/-10 vs 79+/-9 mmHg) and SvjO2 (72+/-7 vs
      56+/-12), without a significant change in ICP (25+/-14 vs 25+/-11 mmHg).
      CONCLUSION: The present study shows that early cerebral monitoring with SjvO2 is
      critical to assess cerebral ischemic risk and that MAP monitoring alone is not
      sensitive enough to determine the state of oxygenation of the brain. SjvO2
      monitoring permits the early identification of patients with low CPP and high
      risk of cerebral ischemia. In emergency situations it can be used alone when ICP
      monitoring is contraindicated or not readily available. However, ICP monitoring
      gives complementary information necessary to adapt treatment.

PMID- 10401937
TI  - Mechanical ventilation of patients on long-term oxygen therapy with acute
      exacerbations of chronic obstructive pulmonary disease: prognosis and cost
      utility analysis.
AB  - OBJECTIVE: To analyze the prognosis and costs of mechanical ventilation in
      patients with exacerbations of chronic obstructive pulmonary disease (COPD)
      treated with long-term oxygen therapy. DESIGN: A prospective cohort study. Follow
      up at 1 and 5 years. Cost utility analysis. SETTING: A medical-surgical intensive
      care unit (ICU) in a university hospital. PATIENTS: 20 patients with previous
      COPD treated with long-term oxygen therapy and needing mechanical ventilation due
      to acute respiratory failure. MEASUREMENTS AND MAIN RESULTS: Mortality in the
      ICU, in-hospital mortality (ICU plus ward), and mortality at 1 and 5 years, and
      factors associated with prognosis and cost-utility were assessed. The mean Acute
      Physiology and Chronic Health Evaluation II score was 20 (median 20 range 12-36).
      Cumulative mortality was 35% in the ICU, 50% in hospital, 75% at 1 year, and 85%
      at 5 years. Factors significantly associated with mortality in the ICU were low
      levels of albumin (p = 0.05) and sodium (p = 0.01) at admission. Patients who
      died in hospital and in the first year after discharge had a lower forced
      expiratory volume in 1 s (FEV1) than survivors (p = 0.03 and p = 0.05,
      respectively). The cost per Quality Adjusted Life Year (QALY) was U.S. $26283 and
      U.S. $44602 in a "best" (cost/QALY calculated for the life expectancy in Spain)
      and a "worst case scenario" (cost/QALY calculated for a 68-year life expectancy),
      respectively. CONCLUSIONS: Applying mechanical ventilation to COPD patients
      treated with long-term oxygen therapy carries a high mortality and cost. Factors
      significantly associated with mortality in the ICU were albumin and sodium
      concentrations and FEV1 in hospital and in the first year after discharge.

PMID- 10401938
TI  - Noninvasive ventilation: experience at a community teaching hospital.
AB  - OBJECTIVE: To describe our hospital's experience with noninvasive positive
      pressure ventilation (bilevel positive airway pressure; BiPAP) for patients with
      respiratory failure (RF). DESIGN: Retrospective, observational study. SETTING: A
      300-bed community teaching hospital. METHODS: Medical records were analyzed for
      physiologic and outcome variables for all patients who received BiPAP for RF
      between January 1994 and December 1996. RESULTS: Eighty patients with a mean (+/-
      S.E.) age of 71.5+/-1.3 years and APACHE II score of 17.2+/-0.6 received BiPAP
      for RF during the study period. Thirty-one patients received BiPAP for hypoxemic
      RF, 25 for acute hypercapnic RF, 9 for chronic hypercapnic RF, 10 for
      postextubation RF and 5 could not be categorized. BiPAP success was defined as no
      need for invasive ventilation. BiPAP was successful in 47 of 75 cases that could
      be classified; all BiPAP successes lived whereas 18 of 28 BiPAP failures died. In
      the overall cohort, BiPAP success was associated with a lower ICU length of stay
      (5.8+/-0.9 versus 10.6+/-1.4 days, p < 0.01). The duration of BiPAP dependency in
      successful cases was 35.3+/-6.7 h. BiPAP was successful in 20 of 25 patients with
      acute hypercapnic RF and in 15 of 31 patients with hypoxemic RF. The risk of
      BiPAP failure was significantly greater (risk ratio = 2.6, 95% CI = 1.1-6.1) for
      patients with hypoxemic than for those with hypercapnic RF. BiPAP success was
      marked by increased PaO2/FIO2 in patients with hypoxemic RF and by increased pH
      and reduced PCO2 in patients with hypercapnic RF. BiPAP use was also successful
      in 8 of 10 patients who developed RF within 48 h of endotracheal extubation.
      CONCLUSIONS: BiPAP is highly effective in selected patients with RF during
      routine use in a community teaching hospital. The success rate is higher amongst
      patients presenting with hypercapnic than amongst those with hypoxemic RF and
      BiPAP failure is associated with an increased likelihood of in-hospital
      mortality. BiPAP may also be used successfully to temporize patients who develop
      RF in the period following endotracheal extubation. The duration of BiPAP
      dependency (35 h in this study) was shorter than in previous trials, and, though
      this is speculative, may have been minimized by our performing a trial of
      unassisted breathing each day.

PMID- 10401939
TI  - Metoclopramide improves gastric motility in critically ill patients.
AB  - OBJECTIVE: To assess the effect of metoclopramide on gastric motility in
      critically ill patients. DESIGN: Prospective, controlled, single-blind cross-over
      trial. SETTING: A 10-bed general intensive care unit. PATIENTS: Ten critically
      ill, enterally fed adult patients without renal failure. INTERVENTIONS: Each
      patient received enteral feeding with Enrich via a nasogastric tube at 50 ml/h
      throughout the 5-h study period on two consecutive days. Either normal saline
      (control) or 10 mg of metoclopramide (treatment) was administered intravenously
      at the start of the study period in random order with cross-over design.
      MEASUREMENTS AND RESULTS: Gastric motility was measured indirectly by analysis of
      the absorption over time of 1.5 g of paracetamol administered into the stomach at
      the start of the study period together with a 100 ml bolus of Enrich feed. The
      rate of gastric emptying is proportional to the area under the line plot of serum
      paracetamol concentration against time over 120 min (AUC120). Eight of the ten
      patients studied showed an increased AUC120 with metoclopramide compared to that
      with saline. Statistical analysis with the Wilcoxon signed rank test gave a p
      value of 0.04, indicating a significant increase in gastric emptying following
      administration of metoclopramide. CONCLUSIONS: The administration of intravenous
      metoclopramide improved gastric emptying in a heterogeneous group of critically
      ill patients. Metoclopramide is a useful prokinetic drug in this patient
      population.

PMID- 10401940
TI  - Bacterial sepsis-induced rhabdomyolysis.
AB  - OBJECTIVE: To describe the syndrome of rhabdomyolysis during bacterial sepsis
      with regard to incidence, blood bacteriology and complications and to examine the
      association between hyperosmolal state and rhabdomyolysis, evaluating the
      relationship between plasma osmolality (Posm) and serum creatine phosphokinase
      (CPK) levels. DESIGN: Prospective study including all patients admitted to the
      intensive care unit (ICU) for sepsis with positive blood culture and
      rhabdomyolysis over a 3-year period. SETTING: Seven-bed medical/surgical ICU of a
      teaching hospital. PATIENTS: 35 patients (group 1) with bacterial sepsis-induced
      rhabdomyolysis (15 males, 20 females; mean age 71+/-13 years) and 122 (group 2)
      bacteraemic septic patients without rhabdomyolysis (49 males, 73 females; mean
      age 68+/-15) were studied. Patients with rhabdomyolysis were divided into gram(+)
      and gram(-) subgroups according to the blood culture growth. RESULTS: From 491
      patients recorded, 35 fulfilled the inclusion criteria for bacterial sepsis
      induced rhabdomyolysis (7.1%). Gram-positive bacteria predominated in group 1
      (69%), while gram-negative predominated (60%) in group 2. There was a correlation
      between CPK and Posm levels in the rhabdomyolysis Group (r = 0.52, R2 = 0.27, p =
      0.003). There was a stronger correlation between these two variables (r = 0.67,
      R2 = 0.45, p = 0.001) in the gram(+).subgroup. Acute renal failure (68.5%) and
      electrolyte disorders such as hyperkalaemia (34%) and hypocalcaemia (48.5%) were
      the major complications in the rhabdomyolysis group. Sixteen (45.7%) patients in
      group 1 and 49 (40%) in group 2 died during their stay in the ICU from sepsis and
      multiple organ failure. Rhabdomyolysis was not considered a contributing factor
      to their death, as none of our patients died during or immediately after the
      syndrome. CONCLUSION: Bacterial sepsis-induced rhabdomyolysis results from
      certain types of microorganisms, mainly gram-positive and to a lesser extent gram
      negative. Hyperosmolality is a predisposing mechanism for rhabdomyolysis during
      bacteraemic sepsis from any type of bacterial microorganism.

PMID- 10401941
TI  - Trial of dexamethasone treatment for severe bacterial meningitis in adults. Adult
      Meningitis Steroid Group.
AB  - OBJECTIVE: To evaluate the clinical benefit of early adjunctive dexamethasone
      therapy for severe bacterial meningitis in adults. DESIGN: Multicenter, double
      blind, randomized trial initiated in emergency or intensive care units in France
      and Switzerland. Within 3 h after initiation of an aminopenicillin therapy,
      patients received dexamethasone (10 mg q.i.d.) or placebo for 3 days. The primary
      end-point was the rate of patients cured without any neurologic sequelae on day
      30. RESULTS: Sixty patients were enrolled, predominantly with a severe form since
      85% required ICU stay and 43% mechanical ventilation. Streptococcus pneumoniae
      accounted for 31 cases and Neisseria meningitidis for 18 cases. The study had to
      be stopped prematurely because of a new national recommendation of experts to use
      third generation cephalosporin and vancomycin as a result of the increasing rate
      of penicillin-resistant S. pneumoniae in France. After the third sequential
      analysis by the triangular statistical test, the difference of rate of cured
      patients without any neurologic sequelae was not statistically significant (p =
      0.0711) between the dexamethasone group (74.2%; n = 31) and the placebo group
      (51.7%; n = 29). Furthermore, the former group was younger and less sick at
      inclusion. CONCLUSION: Bacterial meningitis is still a severe disease in adults,
      since the overall observed rate of death or severe neurologic sequelae was 26.7%.
      The reported data are inconclusive regarding a systematic use of dexamethasone as
      an adjunctive therapy for bacterial meningitis in adults. Moreover this treatment
      impairs antibiotic penetration into the cerebrospinal fluid (CSF) that can lead
      to therapeutic failure, particularly in areas with high or increasing rates of
      penicillin-resistant S. pneumoniae.

PMID- 10401942
TI  - Central venous cannulation in patients with liver disease and coagulopathy--a
      prospective audit.
AB  - OBJECTIVE: To determine the incidence of vascular complications associated with
      central venous cannulation in patients with liver disease and coagulopathy.
      DESIGN: A prospective audit of all cannulation episodes in patients with liver
      disease and a prothrombin (INR) more than 1.5 and/or platelet count of 150 x
      10(9)/l or less. SETTING: A specialist liver unit between January 1996 and
      September 1997. PATIENTS: Patients with acute or chronic liver diseases and
      patients undergoing liver transplantation or other hepatobiliary surgery.
      MEASUREMENTS AND RESULTS: Vascular complications of central venous cannulation
      were classified as major (any haemodynamically significant haemorrhage) or minor
      (superficial oozing or haematoma). We recorded 658 cannulations (subclavian, 352,
      and internal jugular, 306). The median INR was 2.4 (range 1-16) in the subclavian
      group and 2.7 (1-17) in the internal jugular group (p < 0.05); median platelet
      counts were 81 x 10(9)/l (range 9-1088) and 83 x 10(9)/l (10-425), respectively
      (difference not significant). One patient developed a haemothorax after
      accidental subclavian artery puncture (INR was 1.5, platelets 68 and regional
      prostacyclin therapy was being given for haemofiltration). There were no other
      major vascular complications. Risk factors for minor vascular complications
      included internal jugular cannulation, more than one needle pass into the vein,
      failure to pass any guidewire, a high INR and low platelets for haematoma
      formation, and low platelets and heparin therapy for superficial oozing.
      CONCLUSIONS: The incidence of major vascular complications following central
      venous cannulation in patients with liver disease and coagulopathy was low in
      this audit. In liver disease the presence of a raised INR alone should not be
      considered a contra-indication to central venous cannulation.

PMID- 10401943
TI  - Pharmacokinetics of cefpirome during the posttraumatic systemic inflammatory
      response syndrome.
AB  - OBJECTIVE: To determine the pharmacokinetic parameters of cefpirome, a new so
      called fourth-generation cephalosporin, in previously healthy trauma patients
      with posttraumatic systemic inflammatory response syndrome (SIRS) and to compare
      them to parameters obtained in matched, healthy volunteers. DESIGN: A prospective
      study. SETTING: 12-bed surgical intensive care unit in a university hospital.
      PATIENTS: 9 severe [Injury Severity Score, median (range) 29 (16-50)] trauma
      patients on mechanical ventilation with proven or suspected cefpirome-susceptible
      nosocomial infection, with no renal or hepatic failure, and healthy volunteers
      matched for age (+/- 5 years), sex, and body surface area (+/- 10%) were
      enrolled. All were men. INTERVENTIONS: Cefpirome (2 g twice daily) was
      continuously infused over a 0.5 h period alone or concomitantly with
      ciprofloxacin (400 mg over 1 h, twice daily). MEASUREMENTS AND MAIN RESULTS:
      Antibiotic concentrations in plasma were measured by high-performance liquid
      chromatography; their pharmacokinetic parameters were evaluated at 12 time points
      after the first drug administration using a noncompartmental model. Cefpirome
      pharmacokinetic parameters for the two groups were similar despite a wider
      variation for trauma patients. Specifically, the median (range) time during which
      the cefpirome concentration in plasma remained over 4 mg/l (corresponding to the
      French lower cutoff determining cefpirome susceptibility) was 9.5 (7- > 12) and 9
      (8-12) h for trauma patients and healthy volunteers, respectively. In the group
      of five patients receiving combined antibiotic therapy, the interindividual
      variability of pharmacokinetics was wider for ciprofloxacin than for cefpirome.
      CONCLUSION: No major pharmacokinetic modification was noted when cefpirome was
      given to trauma patients with posttraumatic SIRS without significant organ
      failure, indicating that no dosage adjustment seems required in this population.
      However, larger studies including determination of antibiotic levels in tissues
      are warranted to confirm these results.

PMID- 10401944
TI  - Q.E.D. Alcohol test: a simple and quick method to detect ethanol in saliva of
      patients in emergency departments. Comparison with the conventional determination
      in blood.
AB  - OBJECTIVE: The aim of this pilot study was to assess whether ethanol
      concentrations in saliva are comparable to those in blood and to evaluate whether
      this new non-invasive saliva alcohol test is suitable for use in emergency
      departments. DESIGN: Prospective, open, non-randomised study. SETTING: University
      hospital emergency department. PATIENTS AND METHODS: 100 consecutive patients who
      were admitted to the emergency department whose smell and/or behaviour indicated
      alcohol abuse. Fifteen patients participated as a control group after they were
      asked to abstain from alcohol consumption for 24 h before the study.
      INTERVENTIONS: Blood and saliva samples were obtained at the same time for
      ethanol measurement. The Q.E.D. Alcohol Test A350 was used in order to measure
      the concentration of ethanol in saliva. Blood samples were analysed by the
      alcohol dehydrogenase method. RESULTS: The mean difference between the ethanol
      levels in blood and saliva was -0.1 mg/dl, whereas the values measured in saliva
      were on average 0.1 mg/dl higher than those measured in blood (p = 0.002).
      CONCLUSION: The Q.E.D. Alcohol Test A 350, which uses saliva, is well suited for
      quantitative determination of alcohol levels. The levels measured in saliva
      correlate well with those measured in blood at both the lower and the upper end
      of the scale. Because this test is quick and easy to perform by emergency room
      personnel and the results are accurate enough for clinical purposes, it should
      prove valuable to determine whether impaired consciousness is related to alcohol
      intoxication or to other likely causes.

PMID- 10401945
TI  - Partial liquid ventilation combined with kinetic therapy in acute respiratory
      failure in piglets.
AB  - OBJECTIVE: To investigate the effect of the combination of kinetic therapy (KT)
      with partial liquid ventilation (PLV) on gas exchange, lung mechanics and
      hemodynamics in acute lung injury (ALI). DESIGN: Prospective, randomized,
      controlled pilot study. SETTING: University research laboratory. SUBJECTS: Eleven
      piglets weighing 8.3+/-0.9 kg. INTERVENTION: ALI was induced by the infusion of
      oleic acid (0.08 ml/kg) and repeated lung lavages with 0.9% NaCl (20 ml kg(-1)).
      Thereafter the animals were randomly assigned either for PLV or a combination of
      PLV with KT (PLV/KT). The dose of perfluorocarbon administered was 30 ml/kg,
      evaporative losses were substituted with 5 ml/kg per h. MEASUREMENTS AND MAIN
      RESULTS: Airway pressures, tidal volumes, dynamic compliance (Cdyn), expiratory
      airway resistance and arterial blood gases were measured. Hemodynamic monitoring
      included right atrial, mean pulmonary artery, pulmonary capillary wedge and mean
      systemic arterial pressures, and continuous flow recording of the pulmonary
      artery. In both groups the induction of ALI significantly reduced PaO2/FIO2 Cdyn
      and cardiac output, and significantly increased pulmonary artery pressure. After
      the initiation of PLV there was a significant increase of PaO2/FIO2, and Cdyn,
      and a significant decrease of pulmonary artery pressure in both groups. Except
      the PaCO2, which showed significantly lower values in the PLV/KT group, no
      variables showed any differences between the two groups. CONCLUSION: The
      additional use of KT did not show beneficial effects on oxygenation and lung
      mechanics during PLV. However, at constant minute ventilation PaCO2 levels were
      significantly lower during PLV/KT, indicating some positive influence on the
      ventilation/perfusion distribution within the lung. Extreme body positions during
      PLV/KT did not show any significant hemodynamic side effects.

PMID- 10401946
TI  - Effect of inspiratory flow waveform on work on endotracheal tubes: a model
      analysis.
AB  - OBJECTIVE: This model analysis aimed to predict the impact of different
      inspiratory flow wave-forms, i. e., constant, sinusoidal, and two linearly
      decreasing flows, on the resistive work (Wres) performed on endotracheal tubes.
      DESIGN: Model analysis. RESULTS: Model analysis predicts that: (i) minimal Wres
      is obtained with the constant flow; (ii) for any given tidal volume/inspiratory
      duration (V(T)/T(I), mean inspiratory flow), Wres increases with decreasing tube
      size; (iii) for any given inspiratory flow waveform, Wres increases with
      increasing V(T)/T(I), being lowest with constant flow. CONCLUSIONS: These
      findings have major clinical implications: at any given ventilator setting, not
      only the size of the endotracheal tube but also the inspiratory flow waveform
      must be taken into account to interpret the values of Wres and hence of the total
      work of breathing.

PMID- 10401947
TI  - Evaluation of a new, rapid lactate analyzer in critical care.
AB  - OBJECTIVE: To determine the reliability, precision and clinical usefulness of a
      newly developed substrate-specific lactate/blood gas analyzer (Chiron M865).
      SETTING: A university hospital 31-bed mixed medical/surgical intensive care unit
      (ICU). PATIENTS: Seventeen critically ill patients with sepsis (n = 4), post
      cardiac surgery (n = 8), hepatic failure (n = 2) or acute respiratory failure (n
      = 3). MEASUREMENTS AND RESULTS: Lactate levels were measured in 17 critically ill
      patients on whole blood using the new Chiron M865, and on plasma by a stat
      lactate/glucose analyzer (Yellow Spring Instrument, YSI mode 2300) and a
      reference lactate/glucose/electrolyte/enzyme analyzer (Hitachi 911). The
      influences of temperature and storage on blood lactate levels were then
      evaluated. Mean lactate values obtained were 3.73+/-2.84 mmol/l with the Chiron,
      3.03+/-2.60 mmol/l with the YSI, and 3.59+/-2.92 mmol/l with the Hitachi. There
      was a strong correlation between the three analyzers (Chiron vs YSI r = 0.99;
      Chiron vs Hitachi 911 r = 0.98), and good agreement between the Chiron and the
      two other methods (Chiron/YSI bias was -0.65, SD 0.50 mmol/l; Chiron/Hitachi bias
      was 0.12, SD 0.55 mmol/l). The variability coefficients were 3.7% for the Chiron
      and 3.0% for the YSI. During short term storage, a continuous increase in lactate
      levels was observed at room temperature (2.36+/-1.68 mmol/l to 2.53+/-1.74
      mmol/l, p < 0.05), but when the samples were kept on ice there was just a small
      statistically significant, but not clinically significant, increase after 8 min
      (2.37+/-1.62 mmol/l to 2.39+/-1.63 mmol/l, p < 0.05). For longer storage times,
      samples on ice showed a small increase in lactate levels after 15 min (3.73+/
      2.90 mmol/l to 4.01+/-3.00 mmol/l, p < 0.05) but no further increase during the
      subsequent 45 min. CONCLUSIONS: The new Chiron lactate analyzer is reliable for
      serial whole blood lactate measurements in an intensive care stat laboratory.
      Samples should be kept on ice immediately after sampling to minimize in vitro
      erythrocyte production of lactate.

PMID- 10401948
TI  - Additional inspiratory work of breathing imposed by tracheostomy tubes and non
      ideal ventilator properties in critically ill patients.
AB  - OBJECTIVE: To determine the tracheostomy tube-related additional work of
      breathing (WOBadd) in critically ill patients and to show its reduction by
      different ventilatory modes. DESIGN: Prospective, clinical study. SETTING:
      Medical ICU of a university teaching hospital. INTERVENTION: Standard
      tracheostomy due to prolonged respiratory failure. MEASUREMENTS AND RESULTS: Ten
      tracheostomized, spontaneously breathing patients were investigated. As the tube
      resistance depends on gas flow, patients were subdivided according to minute
      ventilation into a low ventilation group (= 10 l/min; n = 5) and a high
      ventilation group (> 10 l/min; n = 5). The WOBadd due to tube resistance and non
      ideal ventilator properties was calculated on the basis of the tracheal pressure
      measured. Ventilatory modes investigated were: continuous positive airway
      pressure (CPAP), inspiratory pressure support (IPS) of 5, 10, and 15 cm H2O above
      PEEP, and automatic tube compensation (ATC). In the low ventilation group, WOBadd
      during CPAP was 0.382+/-0.106 J/l. It was reduced to below 15% of that value by
      ATC or IPS more than 5 cm H2O. In the high ventilation group WOBadd during CPAP
      increased to 0.908+/-0.142 J/l. In this group, however, only ATC was able to
      reduce WOBadd below 15% of the value observed in the CPAP mode. CONCLUSIONS: The
      results indicate that, depending on respiratory flow rate, (1) tracheostomy tubes
      can cause a considerable amount of WOBadd, and (2) ATC, in contrast to IPS, is a
      suitable mode to compensate for WOBadd at any ventilatory effort of the patient.

PMID- 10401949
TI  - Severe accidental hypothermia: rewarming strategy using a veno-venous bypass
      system and a convective air warmer.
AB  - OBJECTIVE: To study a rewarming strategy for patients with severe accidental
      hypothermia using a simple veno-venous bypass in combination with a convective
      air warmer. SETTING: Eighteen beds in a university hospital intensive care unit.
      PATIENTS: Four adults admitted with a core temperature less than 30 degrees C.
      Hypothermia was caused by alcoholic intoxication in three patients and by drug
      overdose in one patient. MEASUREMENTS AND MAIN RESULTS: All patients were
      rewarmed by a venovenous bypass and in three cases a convective air warmer was
      also used. At a bypass flow rate of 100-300 ml/min the mean increase in core
      temperature was 1.15 degrees C/h (Range: 1.1-1.2 degrees C/h). One patient died 2
      days after rewarming as a consequence of a reactivated pancreatitis. The other
      three patients survived without neurological sequelae. CONCLUSION: This rewarming
      technique seems safe and effective and allowed the controlled rewarming of our
      patients who suffered from severe accidental hypothermia

PMID- 10401950
TI  - Time course of activated coagulation time at various sites during continuous
      haemodiafiltration using nafamostat mesilate.
AB  - OBJECTIVE: To determine the adequate site of activated coagulation time (ACT)
      measurement during continuous haemodiafiltration (CHDF) using nafamostat
      mesilate. DESIGN: Prospective, consecutive, clinical study. SETTING: An intensive
      care unit of a general hospital. PATIENTS: Ten patients with acute organ failure
      including kidney, lung and liver, caused by sepsis after major surgery.
      INTERVENTIONS: A CHDF circuit with a haemofilter made of polymethylmethacrylate
      membrane was primed with 50 mg nafamostat in 500 ml saline, and was started at a
      circuit flow rate of 100 ml/min. Continuous injection of 0.5 mg/kg per h
      nafamostat, 700 ml/h of dialysis fluid and 1000 ml/h of filtrate fluid was set.
      MEASUREMENTS AND RESULTS: The circuit pressure at the inlet and outlet of the
      circuit were monitored, and ACT was measured every 2 h at the site of nafamostat
      injection, outlet, patient's artery and inlet until 24 h. A value of standard
      deviation of ACT at each site was regarded as the variation value of ACT. The
      circuit pressure did not change significantly. The ACT did not change
      significantly at any measurement site. The variation value of ACT at the inlet of
      the circuit was significantly lower than that at the site of nafamostat
      injection. CONCLUSIONS: The ACT value at the inlet of the circuit may be adequate
      to monitor anticoagulation during CHDF using nafamostat.

PMID- 10401951
TI  - Two cases of acute methanol poisoning partially treated by oral 4-methylpyrazole.
AB  - OBJECTIVE: Since the use of 4-methylpyrazole (4-MP) in the treatment of humans
      with methanol poisoning is poorly documented, we report two cases of acute
      methanol intoxication partially treated by this potent alcohol dehydrogenase
      (ADH) inhibitor. SETTING: Intensive Care Unit in a university hospital. PATIENTS:
      A 56-year-old man and an 18-year-old woman were observed, respectively, 41 and 16
      h after the voluntary ingestion of an unknown amount of methanol. INTERVENTION:
      In both cases, ethanol was used as the first antidote. In the first patient,
      hemodialysis was also performed on admission because a high methanol level (0.72
      g/l) and visual impairment were noted. In the second patient, ethanol therapy was
      withdrawn after 12 h when clinical and biological signs of acute pancreatitis
      became evident. Both patients received multiple oral doses of 4-MP. No recurrence
      of metabolic acidosis occurred and the 4-MP therapy was well tolerated.
      CONCLUSION: While the use of 4-MP is better documented in cases of ethylene
      glycol poisoning, it could also become an accepted option for the management of
      methanol poisoning since 4-MP offers advantages over ethanol therapy.

PMID- 10401952
TI  - Postpartum cerebral angiopathy associated with the administration of sumatriptan
      and dihydroergotamine--a case report.
AB  - Cerebral angiopathy of the postpartum period is a rare entity, sometimes promoted
      by vasoconstrictives drug prescription. Its clinical presentation includes
      headaches, seizures and focal neurological deficits, which develop shortly after
      a normal pregnancy. The diagnosis is based on clinical findings and angiography,
      showing multiple narrowing of the intracranial cerebral arteries. This
      neurological feature is reversible and the clinical outcome is good. We report a
      case of benign cerebral angiopathy in a 20-year-old woman in the postpartum
      period, occurring after administration of sumatriptan and ergot derivates.

PMID- 10401953
TI  - Bronchopleural fistula complicating group A beta-haemolytic streptococcal
      pneumonia. Use of a Fogarty embolectomy catheter for selective bronchial
      blockade.
AB  - A 36-year-old woman developed severe group A Streptococcal pneumonia, complicated
      by a bronchopleural fistula, ARDS and multi-organ failure. We describe the use of
      selective middle lobe bronchus blockade, with a Fogarty embolectomy catheter, to
      localise and control the air leak. This allowed effective mechanical ventilation
      and oxygenation on intensive care and during right middle lobectomy. The patient
      made a prolonged, but full recovery.

PMID- 10401954
TI  - Epidemiology in ARDS.

PMID- 10401955
TI  - Measurement of functional residual capacity in the critically ill. Relevance for
      the assessment of respiratory mechanics during mechanical ventilation.

PMID- 10401956
TI  - Mechanical cardiac assistance.

PMID- 10401957
TI  - Venovenous ECMO in life-threatening radiocontrast mediated-ARDS.

PMID- 10401958
TI  - Pulmonary dysfunction following primary bilateral femoral nailing--a case report.

PMID- 10401959
TI  - Life-threatening fluvoxamine overdose in a 4-year-old child.

PMID- 10401960
TI  - Nontraumatic seizure-associated bilateral fractures of the head of the humerus.

PMID- 10401961
TI  - Managing expectations before the cancer intensive care unit.

PMID- 10401962
TI  - Managed care and adolescents with eating disorders.

PMID- 10401963
TI  - Counseling of birth control patients.

PMID- 10401964
TI  - Preventing the high-risk sexual behavior of adolescents: focus on HIV/AIDS
      transmission, unintended pregnancy, or both?
AB  - Adolescents are at high risk for negative health outcomes associated with
      unprotected sexual intercourse including infection with human immunodeficiency
      virus/acquired immunodeficiency syndrome (HIV/AIDS) and unintended pregnancy.
      That unprotected sexual intercourse is the risk behavior common to both problems
      has not been fully capitalized on in prevention programs. Limited knowledge about
      the effects of type-of-outcome expectancy (i.e., disease vs. pregnancy) on the
      association between risk perceptions and precautionary or health-protective
      sexual behavior makes it difficult to determine what preventive approach would be
      most effective with adolescents. The literature suggests that pregnancy
      prevention is a greater concern for adolescents than disease prevention. This
      review focuses on the implications of these differential risk perceptions for
      HIV/AIDS prevention programs targeting adolescents.

PMID- 10401965
TI  - Comparability of a computer-assisted versus written method for collecting health
      behavior information from adolescent patients.
AB  - PURPOSE: To investigate the comparability of health behavior data obtained from
      adolescents via notebook computer versus those obtained via written
      questionnaire. METHODS: We interviewed adolescent patients (ages 13-20 years)
      receiving services at community adolescent health clinics. Participants
      anonymously completed either a computer-assisted self-interview (CASI) or a self
      administered questionnaire (SAQ), both assessing health-protective behaviors,
      substance use (i.e., tobacco, alcohol, marijuana) and sexual behaviors. From a
      pool of 671 adolescent participants (348 completing CASI, 323 completing SAQ), we
      matched 194 SAQ participants with 194 CASI participants on the basis of gender
      and race. We could not match individually on the basis of age, but were able to
      match each gender-race subgroup by mean age. RESULTS: Across the majority of
      health behaviors (i.e., all health-protective behaviors, tobacco use, sexual
      behaviors), mode of administration made no significant difference in the
      reporting of information by adolescents. However, girls reported a greater
      frequency of alcohol use and marijuana use on CASI than on SAQ, whereas boys
      reported a lower frequency of alcohol use and marijuana use on CASI than on SAQ.
      CONCLUSIONS: The findings of this study suggest that there may be gender-related
      differences between modes of anonymous collection of specific adolescent health
      behaviors such as alcohol and marijuana use. Future studies should incorporate
      direct questions regarding adolescents' attitude and comfort levels toward
      completing different modes of data collection.

PMID- 10401966
TI  - Screening for major depression disorders in adolescent medical outpatients with
      the Beck Depression Inventory for Primary Care.
AB  - PURPOSE: To ascertain the psychometric characteristics of the Beck Depression
      Inventory for Primary Care (BDI-PC) among adolescents (12-17 years old) scheduled
      for health maintenance examinations, and to determine the effectiveness of the
      BDI-PC in screening the adolescents for Diagnostic and Statistical Manual of
      Mental Disorders, Fourth Edition, major depression disorders (MDD). METHODS: The
      BDI-PC was administered to 50 male and 50 female adolescents who received
      pediatric health maintenance examinations. The diagnosis of MDD was established
      with the Mood Module from the Primary Care Evaluation of Mental Disorders.
      RESULTS: The internal consistency of the BDI-PC was high (Cronbach alpha = .88),
      and it was not significantly associated with gender, ethnicity, age, or having a
      medical disorder. A cutoff score of > or = 4 had both 91% sensitivity and
      specificity rates for identifying adolescents with and without MDD. CONCLUSIONS:
      The BDI-PC is a useful instrument for screening for clinical depression in
      adolescents receiving routine medical examinations.

PMID- 10401967
TI  - Ten years after: examination of adolescent screening questions that predict
      future violence-related injury.
AB  - PURPOSE: To determine which screening questions used in routine adolescent health
      care maintenance visits correlate with subsequent violence-related injury.
      METHODS: A prospective cohort study was undertaken of adolescents initially seen
      at the East Boston Neighborhood Health Center (EBNHC) in 1986. Risk factor data
      were collected based on the adolescent health intake form in the medical records.
      The primary outcome measure, time until first violence-related injury was
      determined through identification on chart review of the treatment of any such
      injuries at the urgent care center at EBNHC in the subsequent 10 years. Kaplan
      Meier survival statistics and Cox proportional hazards models were used to
      account for loss of patients to follow-up. RESULTS: Median follow-up for this
      sample was >5 five years. Male gender, cigarette smoking, alcohol use, other drug
      use, poor relationships with parents, not being in school or failing school, and
      history of fighting in the past year, predicted violence-related injury within
      the follow-up period. The number of fights in the past year appeared to have a
      dose-response effect on risk of subsequent violence-related injury. A simple
      screening instrument consisting of items concerning school status, drug use, and
      fighting history was used to stratify youth into low, moderate, and high risk of
      violence-related injury during the follow-up period. CONCLUSIONS: These results
      suggest that a simple three-item screening instrument may be used to stratify the
      risk of future injury at the time of adolescent health maintenance visits.
      Further research is indicated to validate this finding in other populations.
      Interventions designed to assist adolescents who are not in school or who have
      drug use problems should also incorporate violence prevention strategies.

PMID- 10401968
TI  - Low literacy and violence among adolescents in a summer sports program.
AB  - PURPOSE: To investigate the relationship between inadequate literacy and violent
      behavior among adolescents. METHODS: This descriptive study involved a
      convenience sample of 386 adolescents who participated in a summer track and
      field and literacy program serving youths in low-income neighborhoods in
      Shreveport, Louisiana, during 1994-1996. Self-reported violence was measured
      using the Youth Risk Behavior Survey (YRBS) and reading grade levels were
      measured by the Slosson Oral Reading Test-Revised (SORT-R). RESULTS: Youths
      ranged in age from 11 to 18 years; 66% were male, and 86% were African-American.
      Forty-three percent of adolescents tested had below-grade reading levels (> or =
      2 grades). Participants with below-grade reading skills had higher rates of self
      reported violent behaviors compared with those reading at grade level. When
      gender, race, and age were controlled for, adolescents reading below grade level
      were significantly more likely to report carrying weapons [odds ratio (OR) = 1.9;
      95% confidence interval (CI) 1.1-3.5], carrying guns (OR = 2.6; CI 1.1- 6.2), to
      have been in a physical fight at school (OR = 1.7; CI 1.1-2.6), and to have been
      in a physical fight resulting in injuries requiring treatment (OR = 3.1; CI 1.6
      6.1). In addition, youths reading below grade level were significantly more
      likely to be threatened at school with a weapon (OR = 2.1; CI 1.2-3.7) and to
      report missing days of school in the previous 30 days because they felt unsafe at
      school (OR = 2.3; CI 1.3-4.3). In characterizing the violence related behaviors,
      we found that low reading-level adolescents were more likely to be both
      aggressor/perpetrator and victim (44% vs. 32%; p = .02) and less likely to be
      only a victim (6% vs. 12%; p = .04) compared to adolescents with grade
      appropriate reading skills. CONCLUSIONS: Below-grade-level reading was
      significantly related to violence behaviors among adolescents who volunteered for
      a summer track and field program. Longitudinal studies are needed to further
      investigate the relationship of below-grade-level reading and
      aggressive/perpetrator and victim behaviors.

PMID- 10401969
TI  - Adolescent alcohol and drug abuse and health.
AB  - PURPOSE: To examine the relationship of adolescent alcohol and drug use over a 5
      year period to cumulative health problems in late adolescence and young
      adulthood. METHODS: We prospectively examined self-reported health problems in a
      sample of adolescents, some of whom received treatment for substance use
      disorders and had consistently poor substance use outcomes (n = 38), some of whom
      received treatment for substance use disorders and had positive substance use
      outcomes (n = 30), and a low alcohol and drug use community comparison group (n =
      48). Data regarding health-related problems of these adolescents (mean, 15.9
      years; 83% Caucasian; 56.5% female) were collected at 2, 4, and 6 years following
      initial assessments. RESULTS: Alcohol and/or drug involvement severe enough to
      warrant treatment during adolescence was associated with more cumulative health
      problems and severe health problems for girls and more cumulative health problems
      for boys. Protracted and continuous abuse of alcohol and drugs was associated
      with more cumulative and severe health problems for girls and more severe health
      problems for boys. CONCLUSIONS: These results suggest that significant health
      problems and concerns are related to both brief and protracted alcohol and drug
      abuse during adolescence. Health problems will likely become even more evident as
      early-onset, chronic substance abusers continue to age.

PMID- 10401970
TI  - Is there an increased clinical severity of patients with eating disorders under
      managed care?
AB  - OBJECTIVES: We sought to examine possible differences in medical status at
      presentation in 1996, compared to 1991, of adolescents with eating disorders
      (EDs) at a hospital-based multidisciplinary care program to reflect the
      increasing market penetration of managed care. DESIGN: Charts were reviewed for
      all new patients scheduled in a hospital-based outpatient ED program in 1996 and
      1991. The 92-item standardized data extraction form included information on
      demographics, indicators of illness severity at the first visit, and subsequent
      hospitalization. The need for primary care referral was verified using billing
      records. Data were analyzed with Student's t-test, Chi-square, Fisher's exact,
      and Mann-Whitney U tests using SPSS 7.5. RESULTS: Of the 153 total patients, 133
      kept their intake appointment and 130 (98%) of these had charts available for
      review. The age, racial/ethnic characteristics, and average length of disordered
      eating behaviors were not significantly different over the 5-year period.
      Referral from a primary care clinician was more commonly required in 1996 than
      1991 (59% vs. 11%; p < .0001). Eighteen percent of the patients seen in 1996 were
      admitted from the initial appointment for medical stabilization, compared to 1.5%
      in 1991 (p = .002). Comparing 1996 to 1991, a similar number of patients had
      symptoms consistent with anorexia nervosa, whereas fewer patients in 1996 gave a
      history of bingeing and purging (22% vs. 40%; p = .027). There were no
      significant differences in indicators of illness severity, treatment by primary
      care clinician prior to referral, or hospitalization rates for those patients
      with and without managed care. CONCLUSIONS: Patients in 1996 were more likely to
      require referrals, were less likely to have symptoms consistent with bulimia
      nervosa, and were more likely to be admitted for medical stabilization. There
      were no differences in patient presentation characteristics or initial
      hospitalization rates based on their managed care status. Further research is
      needed to investigate the changes in illness severity at presentation and to
      assess the role that managed care plays in the treatment of patients with eating
      disorders.

PMID- 10401971
TI  - Differential parental communication with adolescents who are disabled and their
      healthy siblings.
AB  - PURPOSE: To examine the levels of parental communication and differential
      conversational styles with adolescents who are disabled and their healthy
      siblings, to better understand why the adolescent who is disabled has a higher
      risk of psychosocial problems during the transition into adulthood. METHODS:
      Families who had a disabled adolescent and at least one other adolescent who was
      not disabled were videorecorded during dinner at home. Twenty adolescents (12
      girls and 8 boys) and their families participated. Analyses were conducted on the
      392 interactions. RESULTS: Not only did the healthy adolescents participate in
      family interactions at higher frequencies than the adolescents who were disabled
      F(1, 383) = 14.00, p < .001, but the interactions were also more meaningful with
      healthy adolescents, F(2, 383) = 5.25, p < .01. Furthermore, healthy siblings had
      significantly greater conversational control than did their siblings with
      disabilities, chi2 (1) = 14.36, p < .001. Parents responded more negatively when
      adolescents who were disabled initiated a topic in comparison with their response
      to the healthy siblings, F(2, 69) = 5.44, p < .01. Finally, adolescents with
      disabilities were ignored more often than their healthy siblings, z = -3.75, p <
      .001, and they did not monopolize the conversation as often as did their healthy
      siblings, z = -3.91, p < .001. CONCLUSION: These results suggest that adolescents
      who are disabled may be at a disadvantage when engaged in family interactions in
      contrast with their healthy siblings.

PMID- 10401972
TI  - Weight change in adolescents who used hormonal contraception.
AB  - PURPOSE: (a) To compare weight change at 1 year between adolescents 13-19 years
      old who were using either depot medroxyprogesterone acetate (DMPA) or oral
      contraceptives (OC), and (b) to determine if age, baseline body mass index (BMI),
      race/ethnicity, or weight gain at 3 months predicted which subjects would gain
      excessive weight. METHOD: The setting was a Planned Parenthood Teen Clinic with
      chart review of variables of interest. Excessive weight was defined as weight
      gain > 10%. RESULTS: Baseline variables were similar in the two groups, except
      that DMPA users (n = 44) had a greater mean BMI (t test, p = .05) than OC users
      (n = 86). Mean (standard deviation) and median weight gains at 1 year were 3.0
      (4.5) and 2.4 kg in the DMPA users and 1.3 (3.9) and 1.5 kg in the OC users
      (difference in medians not significant, Wilcoxon rank sum test, p = .10). Fifty
      six percent of DMPA and 70% of OC users lost weight or gained < 5% of their
      baseline weight (p = .17, Fisher exact test); 25% of DMPA users and 7% of OC
      users gained > 10% of their baseline weight (p = .006). Age, baseline BMI, or
      race/ethnicity did not affect the likelihood that either group would gain > 5% or
      > 10% of their baseline weight. Of adolescents who gained > 5% of baseline weight
      at 3 months, 13 of 14 (93%) gained even more weight at 12 months. CONCLUSIONS:
      The majority of adolescents who used hormonal contraception for 1 year lost
      weight or gained < 5% of baseline weight. DMPA users were more likely than OC
      users to gain > 10%. Subjects who gained > 5% of baseline weight at 3 months were
      at high risk (93%) of gaining even more weight by 1 year.

PMID- 10401973
TI  - Stigmatization, self-esteem, and coping among the adolescent children of lesbian
      mothers.
AB  - PURPOSE: To examine perceived stigma, coping, disclosure, and self-esteem among
      adolescents with lesbian mothers. METHOD: Interviews were conducted with 76
      adolescents ages 11-18 years. Standardized measures of self-esteem and coping
      skills were used. A measure of stigma was adapted for this study and a measure of
      disclosure was developed. The relationship between perceived stigma and self
      esteem was examined. General coping skills and level of disclosure about the
      adolescents' mothers' sexual orientation were assessed as potential moderators of
      the relationship between perceived stigma and self-esteem. RESULTS: Adolescents
      who perceived more stigma had lower self-esteem in five of seven self-esteem
      areas, compared to those who perceived less stigma. In addition, coping skills
      moderated the effect of stigma on self-esteem in three self-esteem areas.
      However, only one subtype of coping skills, that of decision-making coping, was
      found to moderate the relationship of perceived stigma and self-esteem in such a
      way that adolescents using more decision-making coping had higher self-esteem in
      the face of high perceived stigma. For social support coping, in the face of high
      perceived stigma, the adolescents with more effective coping skills had lower
      self-esteem. In the face of high perceived stigma, adolescents who disclosed more
      about their mother's sexual orientation had higher self-esteem in the subscale of
      close friendship than those who disclosed less. CONCLUSIONS: Results suggest that
      stigma is related to self-esteem among the adolescent children of lesbian
      mothers. The results indicate that this relationship is moderated by coping
      skills. These results have implications for intervention and prevention of
      stigmatization by the establishment of effective coping skills as well as through
      educational efforts to eradicate stigmatizing attitudes.

PMID- 10401974
TI  - Demographic characteristics of fathers of infants born to adolescent mothers in
      Taiwan.
AB  - It has been well accepted that effective programs for prevention of adolescent
      pregnancy should involve adolescent women and their partners. Using data from
      certificates of live births in Taichung County, Taiwan, in 1994, the demographic
      characteristics of fathers whose infants were born to adolescent women were
      compared with a matched group fathers whose infants were born to women aged > or
      =20 years. Most of the fathers of infants born to adolescent women were adults:
      57% of the fathers of infants born to women aged < or =15 years were > or =30
      years of age. Fathers of infants born to adolescent women had a lower educational
      level than that of matched fathers. These demographic characteristics of fathers
      should be carefully interpreted and taken into consideration in developing
      intervention programs.

PMID- 10401975
TI  - Service utilization among homeless and runaway youth in Los Angeles, California:
      rates and reasons.
AB  - PURPOSE: To describe the service utilization patterns of homeless and runaway
      youth in a "service-rich" area of Los Angeles, California; identify demographic
      and other correlates of utilization; and contextualize the findings with
      qualitative data. METHOD: During Phase 1 of this study, survey data were
      collected from an ethnically diverse sample of 296 youth aged 13-23 years,
      recruited from both service and natural "hang-out" sites using systematic
      sampling methods. During Phase 2, qualitative data were collected from 46 youth
      of varying ethnicities and lengths of time homeless. RESULTS: Drop-in centers and
      shelters were the most commonly used services (reported by 78% and 40%,
      respectively). Other services were used less frequently [e.g., medical services
      (28%), substance abuse treatment (10%) and mental health services (9%)].
      Utilization rates differed by ethnicity, length of time in Los Angeles, and city
      of first homeless episode (Los Angeles versus all others). Shelter use was
      strongly associated with use of all other services. Despite youths' generally
      positive reactions to services, barriers were described including rules perceived
      to be restrictive, and concerns youth had about confidentiality and mandated
      reporting. Youth suggested improvements including more targeted services, more
      long-term services, revised age restrictions, and more and/or better job training
      and transitional services to get them off the streets. CONCLUSIONS: Because
      shelters and drop-in centers act as gateways to other services and offer
      intervention potential for these hard-to-reach youth, it is vital that we
      understand the perceived barriers to service utilization.

PMID- 10401976
TI  - Improving the nutritional health of adolescents--position statement--Society for
      Adolescent Medicine.

PMID- 10401977
TI  - Expression of interleukin-1 genes and interleukin-1 receptors in the mouse brain
      after hippocampal injury.
AB  - In order to evaluate the role of IL-1 production in post-traumatic brain,
      transcripts for IL-1 (alpha, beta, RA) have been quantified following RT-PCR, in
      hippocampus and cortex after injury of either hippocampus (Hip) or striatum
      (Stri). Moreover, 125I IL-1alpha binding sites have been directly quantified
      using binding experiments on brain sections and quantitative autoradiography.
      Under basal conditions, levels of PCR products were very low. On day 1, IL-1RA
      transcripts only were strongly increased in the hippocampus after Hip-lesions and
      in cortex after Stri lesion. Transcripts were back to control values on day 7
      post-lesion. IL-1 receptor densities in the hippocampus (dentate gyrus) were
      decreased at day 1 around the site of the lesion (but not on the contralateral
      side) and were back to controls on day 7 indicating a transient and local IL-1
      production in the surroundings of the lesion. No changes were found following
      Stri lesion. This study provides further evidence of the role of the IL-1
      molecules family, notably IL-1RA, in the brain reaction to trauma.

PMID- 10401978
TI  - Bicuculline-resistant, Cl- dependent GABA response in the rat spinal dorsal horn.
AB  - Receptors for gamma-aminobutyric acid (GABA), the main inhibitory
      neurotransmitter in the mammalian central nervous system (CNS), have been divided
      into three subtypes. GABA(A) receptor is a ligand-gated chloride channel that is
      competitively antagonized by bicuculline, whereas GABA(B) receptor regulate Ca2+
      or K+ channels through G proteins. Recently, GABA(C) receptor has been identified
      in mammalian and fish retina. Unlike GABA(A) receptors, the GABA(C) receptor is a
      bicuculline-resistant chloride channel that is selectively activated by cis-4
      aminocrotonic acid (CACA), and antagonized by imidazole-4-acetic acid (I4AA) and
      to some extent by picrotoxin. We report here that bicuculline-resistant GABA
      responses mediated by chloride channels are also expressed in substantia
      gelatinosa (SG) neurons in the dorsal horn, which receive predominantly
      nociceptive inputs from periphery. The GABA responses are, however, not mimicked
      by CACA nor affected by I4AA, but abolished by picrotoxin. Moreover, these
      responses are modulated by benzodiazepines (flunitrazepam) and barbiturates
      (thiopental), although GABA(C) responses are not affected. Thus, the
      pharmacological characteristics of the GABA responses observed in SG neurons are
      distinct from those responses mediated by the known GABA receptors. These
      differences may reflect the presence of receptor subunits unique to SG neurons.

PMID- 10401979
TI  - Mouse semaphorin H inhibits neurite outgrowth from sensory neurons.
AB  - Mouse semaphorin H (M-semaH) was structurally similar to semaphorin III/D, a
      mammalian homologue of collapsin 1 which was identified as a collapsing factor
      for sensory nerves. In this study we investigated the expression patterns of M
      semaH mRNA and the protein binding sites in the trunk of mouse embryos. M-semaH
      mRNA was expressed in the mesenchymal tissues surrounding each dorsal root
      ganglia. These tissues include the caudal sclerotome and perinotochordal
      mesenchyme, which were thought to express factors repulsive to axons. M-semaH
      binding was detected on the spinal nerves. We further investigated, using in
      vitro co-culture assay, whether M-semaH acted as a chemorepulsive molecule on
      sensory axons. The results suggested that M-semaH was a candidate for a
      chemorepellent expressed in the mesenchyme surrounding the sensory ganglia, which
      is involved in the axonal guidance mechanism of sensory nerves in the trunk.

PMID- 10401980
TI  - Distribution of AP-2 subtypes in the adult mouse brain.
AB  - In the mammalian central nervous system (CNS), transcription factor activator
      protein 2 (AP-2) is one of the critical regulatory factors for neural gene
      expression and neural development. As AP-2 has diverged into several subtypes,
      i.e. AP-2alpha, -2beta, and 2.2, we investigated the distribution of the AP-2
      subtypes in the adult mouse brain by in situ hybridization using subtype-specific
      probes. Though AP-2 was essentially expressed in most regions of the brain, the
      hippocampus and cerebellum Purkinje cells exhibited a relatively high
      concentration of transcripts of any of the AP-2 subtypes. Among AP-2alpha
      variants, the expression of variant 1 was considerably lower than that of variant
      3. Hence, the expression pattern of AP-2alpha variant 3 is suggested to represent
      the major gene expression of AP-2alpha. On the other hand, the expression of AP
      2beta messenger RNA (mRNA) was higher than that of AP-2alpha in many regions.
      Especially, the olfactory bulb, hippocampus, cerebellum, and cerebral cortex
      contained an abundance of these mRNAs. Different from those of AP-2alpha, AP
      2beta mRNAs were detected in considerable amounts in the glanular cells as well
      as in Purkinje cells. AP-2.2 gene expression was weak throughout the brain.
      Consequently, we found that various AP-2 subtypes and variants were expressed in
      a similar distribution pattern with each having its own specific intensity but
      that their precise distribution profiles were not exactly the same. In the mature
      brain, AP-2 is thought to regulate neural gene expression through specific and
      redundant association with a target gene.

PMID- 10401981
TI  - Nitric oxide-enhanced excitotoxicity-independent apoptosis of glucose-deprived
      neurons.
AB  - Glucose deprivation has been shown to elicit neuronal death via extracellular
      glutamate accumulation. Here we report that immunostimulated glial expression of
      inducible nitric oxide synthase enhances the apoptotic death of glucose-deprived
      cerebellar granule cells (CGC) via the excitotoxicity-independent pathway. CGC
      cultures were immunostimulated by interferon-gamma (100 U/ml) and
      lipopolysaccharides (1 microg/ml) and 2 days later were challenged by glucose
      deprivation. Neither a 2-h Glucose deprivation nor a 2-day immunostimulation
      altered the viability of CGC. A 2-day immunostimulation, however, markedly
      enhanced the apoptotic death of CGC glucose-deprived for 1 h. The increased
      apoptotic death of glucose-deprived CGC after immunostimulation was mimicked by
      the nitric oxide (NO) releasing reagent 3-morpholinosydnonimine (200 microM, 30
      min) and was partially prevented by the NO synthase (NOS) inhibitor N(G)
      nitroarginine. The enhanced apoptotic death was not blocked by the N-methyl-D
      aspartate (NMDA) receptor antagonists D-2-amino-5-phosphovalerate (APV) and
      dizocilpine (MK-801) or the non-NMDA receptor antagonist 6-cyano-7
      nitroquinoxaline-2,3-dione (CNQX). Moreover, the NO-induced enhanced apoptotic
      death occurred without a significant increase of the concentration of glutamate
      in the bathing medium. Our data indicate that immunostimulated glial cells
      potentiate the apoptotic death of glucose-deprived CGC in part through the
      expression of inducible NOS but not through NMDA receptor activation.
      Potentiation of glucose-deprived CGC death by immunostimulated glial cells may be
      clinically implicated in the tendency of recurrent ischemic insults to be more
      severe and fatal than an initial ischemic insult.

PMID- 10401982
TI  - Physiological characterization of lip and tentacle nerves in Lymnaea stagnalis.
AB  - The lip and tentacle nerves of the pond snail, Lymnaea stagnalis, were
      characterized using electrophysiological techniques. When the activity of those
      nerves was induced in lip-tentacle preparations, aversive taste signals were
      transmitted through all the lip and tentacle nerves, but appetitive signals could
      be recorded only through the superior lip nerve. In the CNS immersed in high Mg2+
      -high Ca2+ saline, electrical stimuli applied to any of the nerves failed to
      induce action potentials in one of the regulatory neurons (cerebral giant cell:
      CGC) involved in feeding responses, implying that the signals are
      polysynaptically transmitted to the CGC. Intracellular recordings revealed that
      the CGCs in semi-intact half-body preparations received both appetitive and
      aversive taste signals not only through the superior lip nerve but also through
      the median lip nerve. In addition, an osphradium was ruled out as a candidate for
      appetitive reception. The present results, together with our preceding data
      arrived at by the histochemical analyses, indicate that the appetitive taste
      transduction responsible for generating feeding responses is performed through
      the superior lip nerve with some contribution of the median lip nerve. The data
      showing that the CGC can receive various taste signals suggests that it may play
      a crucial role in feeding behavior as demonstrated in the study of conditioned
      taste-aversion.

PMID- 10401983
TI  - Morphological plasticity and rearrangement of cytoskeletons in pituicytes
      cultured from adult rat neurohypophysis.
AB  - The adult rat neurohypophysis reveals drastic morphological plasticity of neuron
      glial organization during chronic physiological stimulation. Pituicytes are
      modified astrocytes in the neurohypophysis, and shape conversion of them largely
      contributes to the morphological plasticity. The present study aimed to
      investigate the receptor-mediated mechanism for shape conversion of the pituicyte
      morphology, particularly in relation with changes of cytoskeletal organization.
      The cultured pituicytes from adult rat neurohypophysis were mostly flat amorphous
      shape in normal salt solution. Histochemical experiments showed that thick bundle
      of microfilament (stress fibers) and fine fibers of microtubule distributed
      evenly within the pituicyte. When pituicytes were treated with adenosine (more
      than 1 microM), isoproterenol (IPR); beta-agonist, more than 10 nM), and
      dibutyryl cyclic AMP (dBcAMP, 1 mM), the pituicyte morphology changed from flat
      to stellate shape. Upon treatment with dBcAMP, stress fibers within pituicyte
      cytoplasm disappeared, and microtubule assembled in the cellular processes and
      cytoplasm surrounding the nucleus. Pretreatment with colchicine (microtubule
      disrupting agent, 25 microM) and orthovanadate (tyrosine phosphatase inhibitor, 1
      mM) prevented dBcAMP-induced stellation of the pituicyte morphology. Treatment
      with sphingosine (protein kinase C inhibitor, 10 microM), W-7 (calmodulin
      dependent protein kinase inhibitor, 40 microM), ML-9 (myosin light chain kinase
      inhibitor, 20 microM), and cytochalasinB (CytB; microfilament disrupting agent, 5
      microM), induced stellation of the pituicyte morphology. Treatment of endothelin
      1 (more than 0.1 nM) and endotheline-3 (more than 0.1 nM) reverted dBcAMP-induced
      stellation of the pituicyte morphology to original flat one and also reverted
      arrangement of cytoskeletons of stress fiber and microtubules as seen in control
      one. The present results reveal that pituicyte shape conversion is mediated via
      beta-adrenergic, adenosine and endotheline and depend on rearrangement of stress
      fibers and microtubules. In addition, the mechanism of shape conversion of
      pituicytes cultured from adult neurohypophysis is quite similar to that of
      astrocytes cultured from neonatal brains and possibly is useful for understanding
      morphological plasticity of adult brains.

PMID- 10401984
TI  - Irreversible impairment of inhibitory neurons and nitric oxide release in the
      neocortex produced by low temperature and hypoxia in vitro.
AB  - Brain ischemia causes irreversible hyperexcitability, which may be attributed to
      irreversible impairment of inhibitory neurons. However, the conditions required
      for selective and irreversible impairment of inhibitory interneurons in vitro are
      unknown. In this study, we found that a combination of low temperature and
      hypoxia produced hyperexcitability in the neocortex. Neocortical tissue blocks
      isolated from rats were exposed to low temperature (1-3 degrees C) for 45 min and
      subsequently to room temperature (21-23 degrees C) for 60 min in the non
      oxygenated medium. In experimental slices prepared from the processed blocks,
      hyperexcitability, similar to that elicited by an antagonist of GABA(A)
      receptors, was observed. Exposure of the neocortical tissue blocks to low
      temperature alone or room temperature alone did not elicit hyperexcitability. The
      excitability of pyramidal neurons, excitatory synaptic transmission and
      inhibitory effects of an agonist of GABA(A) receptors were normal in experimental
      slices. However, excitation of pyramidal neurons was inhibited after local
      stimulation of inhibitory neurons in control slices, but not in experimental
      slices. Nitric oxide (NO) release from cortical interneurons was also markedly
      reduced in experimental slices. These results indicate that irreversible
      impairment of neocortical inhibitory neurons was produced by low temperature
      combined with hypoxia produced in vitro.

PMID- 10401985
TI  - Neuronal substrates participating in attentional set-shifting of rules for
      visually guided motor selection: a functional magnetic resonance imaging
      investigation.
AB  - To investigate the neuronal substrates participating in attentional set-shifting
      for motor selection rules, a functional magnetic resonance imaging study was
      performed during hand-shape selection tasks. During the session, six right-handed
      subjects were required to make one of three hand-shapes using their right hands,
      in response to the hand-shape images on a video screen, following one of the
      three predefined rules of win, lose, and tie. The selection rules were
      consistently applied in three conditions (win, tie, and lose), and changed
      alternately in one condition (alternate win-lose). Thus the alternate win-lose
      condition requires the shift of rules for motor selection. This alternate
      condition compared with the win, tie, and lose conditions showed activation in
      the left middle frontal gyrus, the bilateral inferior frontal gyri, and the left
      posterior fusiform and lingual gyri. These activation patterns in the prefrontal
      cortex were similar to those observed during the performance of the Wisconsin
      Card Sorting Test (WCST), which requires a typical set-shifting ability from one
      perceptual dimension to another (Berman et al., 1995. Neuropsychologia 33, 1027
      1046; Nagahama et al., 1996. Brain 119, 1667-1675; Konishi et al., 1998. Nature
      Neuroscience 1, 80-84.). Our data may indicate that the dorsolateral prefrontal
      cortex including the middle and inferior frontal gyri are important in
      attentional set-shifting of both perceptual and non-perceptual characteristics.
      Another activation in the fusiform and lingual gyri may have reflected the
      increased attentional demand for visual processing in the light of a current rule
      for motor selection.

PMID- 10401986
TI  - p130cas is a cellular target protein for tyrosine nitration induced by
      peroxynitrite.
AB  - We found that the exposure of human neuroblastoma SH-SY5Y cells to the
      peroxynitrite donor 3-morpholinosydnonimine (SIN-1) induced tyrosine nitration of
      a 130-kDa protein, and prevented tyrosine phosphorylation of the 130-kDa protein.
      The focal adhesion protein p130cas was identified as a component of the 130-kDa
      protein using specific antibody. These results suggest that p130cas is a new
      target protein for nitration induced by SIN-1.

PMID- 10401987
TI  - Ileal and colonic contractions by endothelin-1 in experimentally induced
      paralytic ileus in rats.
AB  - The aim of the present study was to investigate the effect of endothelin-1 on the
      isolated distal ileum and proximal colon in an experimentally induced ileus in
      rats. Ileal and colonic contractions by endothelin-1, acetylcholine alone and
      with endothelin-1 were recorded both in normal and experimentally induced
      paralytic ileus in rats. In the control group, all the responses to acetylcholine
      were found to be potentiated significantly when used together with endothelin-1
      but in paralytic ileus group, no detectable change was observed in the responses
      of the amine after administration of acetylcholine together with endothelin-1.
      This study indicates that endothelin-1 might have an effect on gastrointestinal
      motility and postoperative paralytic ileus.

PMID- 10401989
TI  - Panax ginseng blocks morphine-induced thymic apoptosis by lowering plasma
      corticosterone level.
AB  - The effects of Panax ginseng on morphine-induced immune suppression were studied.
      Morphine (20 mg/kg, SC, 4 days) decreased body weight increment rate and caused
      atrophy of thymus and spleen. These changes were partly reversed by concomitant
      administration of ginseng total saponin (GTS, 100 mg/kg, oral, 9 days). Morphine
      elevated the serum corticosterone level and caused the DNA fragmentation of
      thymocytes. These sequential events were completely blocked by a concomitant
      administration of GTS. Flow cytometry analysis showed that GTS specifically
      blocked morphine-induced apoptosis of thymocytes.

PMID- 10401988
TI  - Effects of NRA0045, NRA0160, and NRA0215 on regional Fos-like immunoreactivity in
      the rat brain.
AB  - Pharmacological characteristics of NRA compounds, novel atypical antipsychotics,
      were compared with those of clozapine and haloperidol, in regard to modification
      of Fos-like immunoreactivity (FLI) in rats. (R)-(+)-2-Amino-4-(4-fluorophenyl)-5
      [1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045) and 2
      carbamoyl-4-phenyl-5-[2-[4-(4-fluorobenzylidene) piperidin-1-yl] ethyl] thiazole
      (NRA0215) have a high affinity for dopamine D4 receptors, serotonin2A receptors,
      and the alpha1 adrenoceptor. 2-Carbamoyl-4-(4-fluorophenyl)-5-[2-[4-(3
      fluorobenzylidene) piperidin-1-yl] ethyl] thiazole (NRA0160) has a selective and
      high affinity for dopamine D4 receptors. NRA0045 and clozapine (10 and 30 mg/kg,
      IP) produced significant increases in FLI in both the nucleus accumbens (N. Acc.)
      and the medial prefrontal cortex (mPFC) but not in the dorsolateral striatum
      (DLS). In contrast, NRA0160 and NRA0215 (10 and 30 mg/kg, IP) significantly
      increased FLI in the mPFC but not in the N. Acc. and the DLS. Haloperidol (0.1
      and 1 mg/kg, IP) significantly produced FLI in the N. Acc., the DLS, and the
      mPFC. These data indicate that the antagonistic effects of dopamine D4 receptors
      may contribute, at least in part, to the actions of NRA0045, NRA0160, and NRA0215
      in the mPFC.

PMID- 10401990
TI  - Ginsenosides that produce differential antinociception in mice.
AB  - Ginsenoside Rc, Rd, and Re induced antinociception in writhing and formalin tests
      among five representative ginsenosides: Rb1, Rc, Rd, Re, and Rg1. However, these
      ginsenosides had no effect in the tail-flick test. The antinociceptive effects
      induced by three ginsenosides were dose dependent. ED50 was 20.5 (7.3-57.4 mg/kg)
      for Rc, 17 (11.0-27.6 mg/kg) for Rd, and 3.5 (1-12 mg/ kg) for Re in the writhing
      test and 62 (42-90 mg/kg) for Rc, 45 (20.5-99.0 mg/kg) for Rd, and 82 (48-139
      mg/kg) for Re in the second phase of the formalin test. The antinociceptive
      effects were not blocked by the opioid receptor antagonist naloxone in the
      writhing and formalin tests. These three ginsenosides did not affect motor
      function. Ginsenoside Rc and Rd induced hypothermia for 30 to 60 min, and
      ginsenoside Rc induced hyperthemia after 150 min of treatment at doses of 100
      mg/kg. These results suggest that ginsenosides such as Rc, Rd, or Re inhibit
      mainly chemogenic pain rather than thermal pain by the nonopioid system in mice.

PMID- 10401991
TI  - Free-radical scavenging action of medicinal herbs from Ghana: Thonningia
      sanguinea on experimentally-induced liver injuries.
AB  - The antioxidant action of medicinal herbs used in Ghana for treating various
      ailments was evaluated in vitro and in vivo. Five plants, Desmodium adscendens,
      Indigofera arrecta, Trema occidentalis, Caparis erythrocarpus, and Thonningia
      sanguinea were tested for their free radical scavenging action by their
      interaction with 1,1-diphenyl-2-picrylhydrazyl (DPPH). Of these five plants, only
      Thonningia sanguinea was found to scavenge the DPPH radical. Lipid peroxidation
      in liver microsomes induced by H2O2 was also inhibited by T. sanguinea. The
      hepatoprotective effect of T. sanguinea was studied on acute hepatitis induced in
      rats by a single dose of galactosamine (GalN, 400 mg/kg, IP) and in mice by
      carbon tetrachloride (CCl4, 25 microl/kg, IP). GalN induced hepatotoxicity in
      rats as evidenced by an increase in alanine aminotransferase (ALT) and
      glutathione (GSH) S-transferase activities in serum was significantly inhibited
      when T. sanguinea extract (5 ml/kg, IP) was given to rats 12 hr and 1 hr before
      GalN treatment. The activity of liver microsomal GSH S-transferase, which is
      known to be activated by oxidative stress, was increased by the GaIN treatment
      and this increase was blocked by T. sanguinea pretreatment. Similarly, T.
      sanguinea pretreatment also inhibited CCl4-induced hepatotoxicity in mice. These
      data indicate that T. sanguinea is a potent antioxidant and can offer protection
      against GalN- or CCl4-induced hepatotoxicity.

PMID- 10401992
TI  - Serotonin induces four pharmacologically separable contractile responses in the
      pharynx of the leech Hirudo medicinalis.
AB  - Stimulation of the serotoninergic innervation of the leech pharynx or application
      of serotonin to the isolated pharynx induced four distinct types of contractile
      activity: an increase in basal tonus, large phasic contractions of 10-15 s in
      duration, smaller phasic contractions occurring at approximately 1 Hz, and a
      relaxation after washout of serotonin. Application to the isolated pharynx of the
      selective serotonin agonists (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin, N-(3
      trifluoromethylphenyl)piperazine, 1-(m-chlorophenyl)-piperazine, (+/-)-2,5
      dimethoxy-4-iodoamphetamine, 2-methyl-5-hydroxytrypamine, alpha-methyl-5
      hydroxytryptamine, and 5-methoxytryptamine induced distinct types of pharyngeal
      contractile activity. The results of this study suggest that the leech pharynx
      possesses more than one type of serotonin receptor.

PMID- 10401993
TI  - Activation of inducible nitric oxide synthase by Taraxacum officinale in mouse
      peritoneal macrophages.
AB  - The objective of the current study was to determine the effect of Taraxacum
      officinale (TO) on the production of nitric oxide (NO). Stimulation of mouse
      peritoneal macrophages with TO after the treatment of recombinant interferon
      gamma (rIFN-gamma) resulted in increased NO synthesis. TO had no effect on NO
      synthesis by itself. When TO was used in combination with rIFN-gamma, there was a
      marked cooperative induction of NO synthesis in a dose-dependent manner. The
      optimal effect of TO on NO synthesis was shown 6 h after treatment with rIFN
      gamma. This increase in NO synthesis was manifested as an increased amount of
      inducible NO synthase (iNOS) protein. NO production was inhibited by N(G)
      monomethyl-L-arginine. The increased production of NO from rIFN-gamma plus TO
      stimulated cells was decreased by treatment with a protein kinase C inhibitor
      such as staurosporin. In addition, synergy between rIFN-gamma and TO was mainly
      dependent on TO-induced tumor necrosis factor-alpha (TNF-alpha) secretion. All
      the preparations of TO were endotoxin free. These results suggest that the
      capacity of TO to increase NO production from rIFN-gamma-primed mouse peritoneal
      macrophages is the result of TO-induced TNF-alpha secretion.

PMID- 10401994
TI  - Correlation between degree of inhibition of parasympathetic reflex vasodilation
      and MAC value for various inhalation anesthetics.
AB  - Parasympathetic reflex vasodilation was elicited in the lower lip by stimulation
      of the central cut end of the lingual nerve in urethane plus alpha-chloralose
      anesthetized, vago-sympathectomized cats. A dose-related inhibition of this
      response was induced by the inhalation anesthetics isoflurane, halothane,
      sevoflurane, and enflurane, the ID50 values being 0.94%, 0.82%, 1.74%, and 2.0%,
      respectively. These results indicate that the ID50 value is approximately two
      thirds of the published MAC (for isoflurane, halothane, sevoflurane, and
      enflurane, 1.6%, 1.2%, 2.6%, and 2.4%, respectively) value for such anesthetics,
      suggesting that parasympathetic reflex vasodilation is more susceptible than
      somato-somatic reflexes to inhibition by inhalation anesthetics.

PMID- 10401996
TI  - The neuromuscular transmission fade (Wedensky inhibition) induced by L-arginine
      in neuromuscular preparations from rats.
AB  - L-Arginine (4.7-18.8 mM) and 3-(4-morpholinyl)-sydonone imine hydrochloride (SIN
      1; 1.15 mM) induced an increase in tetanic fade caused by indirect stimulation
      (180-200 Hz) of muscle. However, Wedensky inhibition, different from control, was
      not observed when the preparations treated with d-tubocurarine were directly
      stimulated by the same frequency. D-Arginine (9.4 mM) was ineffective in changing
      R values caused by indirect stimulation (180-200 Hz) of muscle. N(omega)-Nitro-L
      arginine (73 mM) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM)
      did not produce any effect on Wedensky inhibition but did antagonize the tetanic
      fade induced by L-arginine (9.4 mM). The SIN-1 effect was antagonized by previous
      administration of ODQ (108 microM), which alone did not produce any effects on R
      values. These results indicate that NO acting at the presynaptic level increases
      the Wedensky inhibition induced by high frequency of stimulation applied on motor
      nerves, and its effect may be produced through the cGMP-GC pathway.

PMID- 10401995
TI  - Cardioprotective effects of YM934, an ATP-sensitive potassium channel opener, on
      stunned myocardium in anesthetized dogs.
AB  - The effects of YM934 [2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)
      pyridine N-oxide], an adenosine triphosphate (ATP)-sensitive potassium channel
      opener, on stunned myocardium were examined. Forty eight anesthetized dogs were
      subjected to 15 min of left anterior descending (LAD) coronary artery occlusion
      followed by 3 hours of reperfusion. To elucidate the possible contribution of the
      cardioprotective property of YM934 to stunned myocardium, a nonhypotensive dose
      of YM934 was directly injected into the LAD coronary artery before the ischemic
      insults. Intracoronary artery infusion (i.c.) of YM934 (0.1 microg/kg/min)
      produced a marked improvement in post-ischemic regional contractile dysfunction.
      The effects were not associated with improvement of hemodynamics, including
      regional myocardial blood flow during ischemia, heart rate and mean arterial
      blood pressure. The anatomic areas at risk expressed as a percentage of the left
      ventricle and regional myocardial blood flow were not significantly different
      between groups. The cardioprotective effect of YM934 was completely blocked by
      pretreatment with an ATP-sensitive potassium channel blocker, glibenclamide (1.0
      mg/kg i.v. bolus). These results suggest that YM934 exerts cardioprotective
      effect on stunned myocardium through opening myocardial ATP-sensitive potassium
      channels.

PMID- 10401997
TI  - The action of flufenamic acid and other nonsteroidal anti-inflammatories on
      sulfate transport in the isolated perfused rat liver.
AB  - The influence of flufenamic acid and other nonsteroidal anti-inflammatories on
      sulfate transport in the liver was investigated. The experimental system was the
      isolated perfused rat liver. Perfusion was accomplished in an open,
      nonrecirculating system. The perfusion fluid was Krebs/Henseleit-bicarbonate
      buffer (pH 7.4), saturated with a mixture of oxygen and carbon dioxide (95:5) by
      means of a membrane oxygenator and heated to 37 degrees C. Sulfate transport
      (equilibrium exchange) was measured by employing the multiple-indicator dilution
      technique with simultaneous injection (impulse input) of [35S]sulfate.
      [3H]sucrose (indicator for the distribution of the sinusoidal transit times), and
      [3H]water (indicator for the total aqueous space). Analysis was accomplished by
      means of a space-distributed variable transit time model. Flufenamic acid and
      other anti-inflammatories inhibited sulfate transport in the liver. For a
      concentration of 100 microM, the following decreasing series of potency could be
      established: flufenamic acid (53.4 +/- 2.9%) > niflumic acid (41.1 +/- 1.4%) >
      mefenamic acid (35.6 +/- 3.3%) > piroxicam (16.6 +/- 1.9%) > naproxen (13.5 +/-
      8.4)%) nimesulide (11.6 +/- 5.8%). Inhibition of sulfate transport by flufenamic
      acid was clearly concentration dependent; 250 microM flufenamic acid produced
      more than 95% inhibition. Flufenamic acid in the range between 50 and 250 microM
      did not affect the mean transit times of tritiated water (t water) and
      [3H]sucrose (t suc), the same applying to all other anti-inflammatory agents (100
      microM) tested in this work. This means that these agents do not affect vascular
      and cellular spaces, even when present at high concentrations. The ratio of the
      intra- to extracellular sulfate concentrations ([C]i/[C]e), generally between 0.4
      and 0.5 under control conditions, was affected only by 250 microM flufenamic acid
      and 100 microM niflumic acid. In the first case, this phenomenon is possibly due
      to the high degree of transport inhibition (more than 95%), which does not allow
      a uniform tracer distribution over the whole cellular space during a single
      passage through the liver. The degree of inhibition of sulfate transport by 100
      microM flufenamic acid was a function of the concentration of nontracer sulfate.
      With sulfate in the range between 1.2 and 25 mM, the inhibition degree increased
      linearly with the concentration. In the presence of flufenamic acid, the
      saturation curve of equilibrium exchange showed a substrate inhibition-like
      phenomenon, which was absent in the control curve. As inhibitors of sulfate
      transport in hepatocytes, flufenamic and niflumic acids are less active than in
      erythrocytes by a factor of 10(2). This observation is most probably indicative
      of structural differences between the hepatic sulfate carrier and the anion
      carrier of erythrocytes. It is unlikely that the action of flufenamic acid and
      its analogs on sulfate transport is a consequence of energy metabolism
      inhibition. Nimesulide is as active as flufenamic or niflumic acid in inhibiting
      energy metabolism but considerably less efficient as an inhibitor of sulfate
      transport. Our results as well as literature data reveal that the interactions of
      the nonsteroidal anti-inflammatories with the liver membranes and intracellular
      structures are ample and complex. Even at high concentrations, however, these
      interactions are not so intense as to change the vascular and cellular spaces.

PMID- 10401998
TI  - Gated TI-201 myocardial perfusion SPECT: application of energy window
      optimization.
AB  - PURPOSE: TI-201 scintigraphy is plagued with poor image quality because of the
      low-energy photons of TI-201 decay. Traditionally, a narrow 20% window centered
      on 71-72 keV has been used to improve sensitivity. Recent studies indicate that
      better imaging may be possible by optimizing the energy window to 34% centered on
      77 keV. In this study, energy window optimization (EWO) was applied to gated TI
      201 myocardial perfusion SPECT, and myocardial functional parameters were
      compared for gated TI-201 SPECT and gated Tc-99m sestamibi (Tc-99m MIBI) SPECT.
      METHODS: Count statistics for standard and optimal TI-201 myocardial scintigraphy
      were noted in 25 patients by assessing the total counts in a mid-ventricular
      slice of a rest-gated TI-201 myocardial SPECT study. The feasibility of
      performing functional studies with the application of EWO to TI-201 was assessed
      using the count statistics of a mid-ventricular slice of an optimized gated TI
      201 SPECT study and a gated Tc-99m MIBI SPECT study. The functional parameters
      (ejection fraction, wall motion, and thickening) of TI-201 with EWO and Tc-99m
      MIBI were compared in 60 patients who underwent rest-gated TI-201 SPECT followed
      by poststress gated Tc-99m MIBI SPECT. The left ventricular ejection fraction was
      calculated using commercially available software, whereas wall thickness and
      motion were assessed by the consensus of two readers. RESULTS: The application of
      EWO increased available counts by more than 25%. It also resulted in sufficient
      counts being available to perform gated TI-201 SPECT without increasing
      acquisition times or the dose of TI-201. The average ejection fraction was 60.4%
      for gated TI-201 SPECT and 59.6% for gated Tc-99m MIBI SPECT (not significantly
      different). Overall, the image quality was rated excellent in 12% for TI-201 and
      Tc-99m MIBI and good in 50% and 62%, respectively, and poor in 38% and 26%,
      respectively. CONCLUSION: The application of EWO to TI-201 SPECT allows
      myocardial functional parameters to be assessed without having to increase the
      acquisition times or the administered dose of TI-201.

PMID- 10401999
TI  - The influence of differences in hydration on bone-to-soft tissue ratios and image
      quality in bone scintigraphy.
AB  - This prospective study evaluated the effects of different amounts of fluid intake
      on the bone-to-soft tissue (B:ST) ratio and image quality of bone scans performed
      using Tc-99m MDP. One hundred sixty patients with no renal disease were divided
      into three groups with different degrees of hydration in liters (group 1, 0.25 I;
      group 2, 1 I; group 3, 1.5 I), and image quality was assessed with a
      semiquantitative score. The B:ST ratio was calculated over the femoral diaphysis
      and adductor area, respectively. No significant differences in the B:ST ratio or
      image quality were demonstrated in all three patient groups with median values of
      1.90 (group 1), 1.93 (group 2), and 1.84 (group 3). A filled urinary bladder was
      associated with greater fluid intake. The B:ST and image quality were correlated
      directly with the postinjection time interval and inversely with age. When
      patients drink a large volume of fluid, B:ST ratios do not necessarily increase
      and bone scintigraphy image quality does not improve.

PMID- 10402000
TI  - The pitfalls of planar three-phase bone scintigraphy in nontraumatic hip
      avascular osteonecrosis.
AB  - PURPOSE: This study documented the previously reported lower sensitivity of
      routine planar three-phase bone scintigraphy (BS) performed using a high
      resolution parallel-hole collimator compared with MRI to diagnose nontraumatic
      avascular necrosis of the hip (AVN). METHODS: Six observers reviewed 143 bone
      scintigrams obtained in patients with nontraumatic hip pain (n = 120) or a
      control group (n = 23). All patients had a standard radiograph and MRI within 2
      months of the BS. Of 280 hips, 148 (53%) were painful on the day of the
      examination. The osteonecrosis group (AVN) consisted of 93 instances of AVN in 58
      patients. Although it departs from the clinical situation, this method evaluated
      the intrinsic performance of the imaging method. The data were analyzed using a
      receiver operating characteristic method. RESULTS: For the six observers, the
      A(z) values were 0.65, 0.67, 0.66, 0.67, 0.73, and 0.79, respectively, and 0.66,
      0.71, 0.75, 0.81, 0.81, 0.82, and 0.84 after removing hip diseases other than AVN
      through data manipulation. Bone marrow edema, as seen on MRI, was the most
      frequently reported misleading sign in false-positive diagnoses, especially in
      the early or late phases of the disease. False-negative diagnoses misclassified
      the scans as "asymptomatic hips" in 28 of 30 cases. Twenty-two of 30 scans
      appeared normal, but these AVN lesions were small (<25%) and were discovered by
      chance on MRIs that displayed bilateral involvement associated with radiographic
      evidence (stage 0 or 1). Thirteen of 20 patients were followed for 3 or more
      years, and only one worsened. CONCLUSIONS: BS is not indicated to diagnose
      possible contralateral AVN if the hip is asymptomatic. This study emphasizes the
      results from the literature; if indicated, a radionuclide hip investigation
      requires the use of a pin-hole collimator, a SPECT study with scatter correction
      and iterative reconstruction algorithms, or both.

PMID- 10402001
TI  - Fluorine-18 fluorodeoxyglucose imaging using dual-head coincidence positron
      emission tomography without attenuation correction in patients with head and neck
      cancer.
AB  - PURPOSE: An accurate, preoperative assessment of tumor extent and lymph node
      involvement is necessary to plan and tailor therapy for patients with head and
      neck cancer. Metabolic imaging with fluorine-18 fluorodeoxy-glucose (FDG) is a
      good method to detect primary tumors in the head and neck and to assess the
      involvement of lymph nodes, but it is not widely available because of the high
      cost of positron emission tomography (PET). Recently, an alternative method for
      using FDG was developed: coincidence detection PET (CoDe PET) using a gamma
      camera. The aim of this study was to evaluate the clinical utility of FDG CoDe
      PET using a gamma camera in patients with head and neck cancer. MATERIALS AND
      METHODS: Thirty FDG CoDe PET studies without attenuation correction were
      performed in seven patients before therapy and in 19 patients after therapy
      (ages: 25-79 years, mean, 50 +/- 13 years; 18 men, 8 women) with various head and
      neck cancers. All patients had fasted for 6 to 12 hours and were injected with
      111 to 370 MBq F-18 FDG 1 hour before imaging. Visually detectable focal FDG
      uptake in the primary tumor site or in the neck was considered positive except
      for physiologic uptake. The FDG CoDe PET studies were correlated with MRI. The
      gold standard for the presence of disease was the combination of repeated MRIs,
      endoscopic examination, and 3 months of follow-up clinical evaluation. RESULTS:
      FDG CoDe PET had a detection rate that was comparable to that of MRI in the
      pretherapy group. However, in the posttherapy group, FDG CoDe PET could
      differentiate residual tumor or tumor recurrence from radiation change more
      accurately than could MRI. However, it had a less accurate detection rate for
      cervical node metastases because of asymmetric neck muscle uptake. CONCLUSIONS:
      FDG CoDe PET is a sensitive and cost-effective method to detect primary tumor and
      lymph node involvement in primary head and neck cancers. It is also useful in
      differentiating residual tumor or tumor recurrence from posttherapy changes in
      patients with head and neck tumors.

PMID- 10402003
TI  - The diagnosis of segmental transplant renal artery stenosis by captopril
      renography.
AB  - The captopril renogram test has been shown to be a sensitive test for the
      diagnosis of renal artery stenosis in native and transplanted kidneys. Most
      reports have involved only stenosis of the main renal artery. Although segmental
      renal artery stenosis has been diagnosed successfully in native kidneys, it is
      not clear whether the captopril renogram test can diagnose segmental renal artery
      stenosis in a transplanted kidney. The authors report two cases of successful
      identification, by the captopril renogram test, of functionally significant
      stenosis in an intrarenal branch of a single transplant renal artery.

PMID- 10402002
TI  - Identification of bilateral breast sentinel lymph nodes draining primary melanoma
      of the back by preoperative lymphoscintigraphy and intraoperative mapping.
AB  - A 30-year-old white woman with a primary malignant melanoma of her right back at
      the Sappey line, 4 cm from the midline at the L2 level, underwent preoperative
      lymphoscintigraphy and intraoperative mapping of the sentinel lymph node using
      lymphazurin injection at the primary site and a hand-held gamma probe.
      Lymphoscintigraphy showed one sentinel lymph node in each breast and another one
      in the right axilla. These three sentinel lymph nodes were accurately identified
      using a hand-held gamma probe during operation. An additional sentinel and one
      nonsentinel lymph node from the right axilla were harvested. All four sentinel
      lymph nodes were blue and showed significantly elevated radioactivity compared
      with background. Histologic analysis showed that all these lymph nodes were
      negative for metastatic melanoma. She has been followed for a period of 26.7
      months since her selective sentinel lymphadenectomy and has been free of disease
      to date. This case illustrates the importance of preoperative lymphoscintigraphy
      in identifying in-transit sentinel lymph nodes in both breasts in addition to the
      clinically predictable sentinel lymph node(s) in the right axilla.

PMID- 10402004
TI  - Hepatic perfusion changes in patients with cirrhosis indices of hepatic arterial
      blood flow.
AB  - PURPOSE: This study used radionuclide angiography to evaluate semiquantitatively
      the hepatic arterial blood flow changes associated with cirrhosis. METHODS: The
      parameters of net arterial hepatic perfusion were estimated by analysis of first
      pass flow studies in 11 control participants and in 15 patients with cirrhosis
      (Child-Pugh classification B-C). Hepatic, renal, and splenic time-activity curves
      were generated, normalized per pixel, and corrected for background. The rate of
      hepatic arterial blood flow was compared with the reference kidney and spleen
      perfusion using the hepatorenal and hepatolienal perfusion indices, respectively.
      These indices were defined as: PI = area under hepatic curve limited by time of
      the renal (splenic) curve peak/area under renal (splenic) curve to its peak
      RESULTS: The values of both these perfusion indices are significantly greater in
      the patients with cirrhosis than in controls (hepatorenal perfusion index, P <
      0.01; hepatolienal perfusion index, P < 0.05). The values of the hepatic
      perfusion index (the ratio of the arterial to the total liver blood flow), which
      were also calculated, were elevated in the patients with cirrhosis (P < 0.01).
      CONCLUSIONS: The results confirm that the net hepatic arterial blood flow is
      increased in patients with cirrhosis. Radionuclide angiography accompanied by
      calculation of arterial perfusion indices may provide semiquantitative parameters
      of net hepatic arterial blood flow.

PMID- 10402005
TI  - Relapsing polychondritis diagnosed by Tc-99m MDP bone scintigraphy.
AB  - PURPOSE: Relapsing polychondritis is a generalized recurring disease of cartilage
      that involves joints, trachea, bronchi, laryngeal cartilages, costal cartilages,
      and cartilages of the ear and nose. It is associated with autoimmune diseases,
      including Hashimoto disease in some cases. METHODS: The authors evaluated a 29
      year-old man with relapsing polychondritis who had symptoms and signs of a common
      cold for 2 months and anterior chest pain near the sternum for 1 month. RESULTS:
      After the diagnosis, the authors found that the patient had a history of thyroid
      therapy for hyperthyroidism 15 years before. Tc-99m MDP bone scintigraphy
      performed to evaluate anterior chest pain showed diffusely increased accumulation
      of radioactivity in all costocartilages and sternoclavicular joints. Based on
      that information, relapsing polychondritis was diagnosed. Ga-67 citrate
      scintigraphy was preformed to determine the optimum biopsy site of the cartilage.
      The diagnosis was histologically supported by the results of the open biopsy.
      CONCLUSIONS: In this case, Tc-99m MDP bone scintigraphy was useful for diagnosing
      relapsing polychondritis, and Ga-67 citrate scintigraphy was helpful in
      determining the biopsy site.

PMID- 10402006
TI  - The reversibility of cardiac neuronal function after removal of a
      pheochromocytoma: an I-123 MIBG Scintigraphic Study.
AB  - PURPOSE: Twelve patients with proved pheochromocytoma evaluated in our
      institution between 1991 and 1997 are described. METHODS: The patients' urinary
      excretion rates and their metabolites (vanylmandelic acid and metanephrines) were
      significantly greater than normal before surgery. Echocardiography showed normal
      left ventricular ejection fractions (72% +/- 8%). All of the patients underwent
      planar I-123 metaiodobenzylguanidine (MIBG) scintigraphy to assess cardiac
      neuronal uptake 4 hours after and locate a pheochromocytoma 24 hours after
      intravenous injection of 185 MBq (3 mCi) I-231 MIBG. Ten patients with
      pheochromocytoma had positive tumoral findings with I-123 MIBG scintigraphy.
      Twelve patients had significant impairment of cardiac neuronal uptake of MIBG,
      with a heart:mediastinum ratio averaging 142% +/- 18% (normal value, 230% +/-
      30%, P < 0.05). Postoperative cardiac MIBG imaging was performed in all patients
      (at 6 +/- 3 months). RESULTS: After surgical removal of the pheochromocytoma,
      cardiac MIBG uptake and the heart:mediastinum uptake ratios improved
      significantly (197% +/- 20%, P < 0.05) in all the patients. Urinary excretion
      rates and metabolites returned to the normal range. However, no significant
      correlation was found between cardiac MIBG uptake and urinary excretion rates and
      metabolites after the tumors were removed. CONCLUSION: Removing a
      pheochromocytoma reversed cardiac neuronal function as assessed by MIBG
      scintigraphy.

PMID- 10402008
TI  - Loculated pericardial effusion detected on blood pool bone imaging.

PMID- 10402007
TI  - False-positive antimyosin imaging caused by cardioversion-induced skeletal muscle
      uptake.

PMID- 10402009
TI  - Detection of a cerebrospinal fluid pseudocyst on delayed imaging.

PMID- 10402010
TI  - Pain in the anterior pelvis and postoperative prostatectomy findings.

PMID- 10402011
TI  - Two meningiomas detected incidentally by Tc-99m HDP bone scintigraphy during a
      work-up for breast cancer.

PMID- 10402012
TI  - A "harness" distribution pattern on pediatric Ga-67 scintigraphy.

PMID- 10402014
TI  - Intraperitoneal renal transplant mobility: the transposed transplant.

PMID- 10402013
TI  - Thoracic actinomycosis imaging with fluorine-18 fluorodeoxyglucose positron
      emission tomography.

PMID- 10402015
TI  - Multiple extrapulmonary sites of accumulation of Ga-67 citrate in sarcoidosis.

PMID- 10402016
TI  - Focal hepatic "hot spot" in superior vena cava obstruction: correlation between
      radiocolloid hepatic SPECT and contrast-enhanced CT.

PMID- 10402017
TI  - The "backpack sign": abnormal findings on fluorine-18 fluorodeoxyglucose imaging.

PMID- 10402018
TI  - Hepatocellular carcinoma monitored by F-18 fluorodeoxyglucose positron emission
      tomography after laparoscopic microwave coagulation therapy.

PMID- 10402019
TI  - Three generations of amyotrophic lateral sclerosis in a family: SPECT brain
      perfusion findings.

PMID- 10402020
TI  - Covert persistence of mdx mouse myopathy is revealed by acute and chronic effects
      of irradiation.
AB  - To compare muscle fiber loss in young and old mdx mice, we have blocked
      regeneration in one leg with a high dose (18 Gy) of X-rays administered at two
      ages; 16 days, just prior to the onset of the myopathy, and 15 weeks, when the
      myopathy is considered to be quiescent. Mice were examined 4 days after
      irradiation to look for acute effects, or after 6 weeks to look for cumulative
      effects. Tibial length, muscle weight, muscle fiber size, fiber number and
      histological changes were recorded. Signs of acute damage to muscle fibers,
      leakage of Procion Orange dye into fibers and loss of creatine kinase from the
      fibers were also examined. Irradiation caused no acute or chronic damage to
      muscle fibers; on the contrary, in the youngest mdx mice, irradiation delayed the
      onset of the disease. However, in mdx but not in normal mice, there was a loss of
      muscle mass and fiber number in irradiated by comparison with the non-irradiated
      contra-lateral muscles. This loss, attributed to fiber necrosis in the absence of
      regeneration, was as great in animals irradiated at 15 weeks as in those
      irradiated at 16 days. Such persistence of muscle fiber necrosis contradicts the
      standard view of the mdx mouse and establishes it as a closer model of Duchenne
      muscular dystrophy than is generally appreciated.

PMID- 10402021
TI  - Anemic hypoxia in moderate intracerebral hemorrhage: the alterations of cerebral
      hemodynamics and brain metabolism.
AB  - To determine the influence of anemic hypoxia on cerebral hemodynamics and brain
      metabolism during pathological conditions of the brain, moderate-sized
      intracerebral hemorrhage (ICH) was created in canines with and without
      preoperatively inducing chronic anemia. The changes in cerebral perfusion
      pressure (CPP) and cerebral blood flow velocities (CBFv) were evaluated as well
      as the determinations for cerebral extraction fraction of oxygen (CEO2),
      arteriovenous oxygen content difference (AVDO2) and lactate (Lac) concentrations
      through the arterial and superior sagittal sinus (SSS) samples. Before ICH
      production, anemic animals (n = 8) showed a significant reduction in cerebral
      AVDO2 and arteriovenous Lac difference (AVDLac) but had higher CBFv as well as
      CEO2 than did nonanemic animals (n = 8). The CBFv began to decrease within 30 min
      after ICH in anemic but not in nonanemic animals, and the difference between the
      two groups was found to be significant at 2 h (P<0.05). Following ICH, anemic
      group also showed coupling reductions in CEO2 and AVDO2, indicating a decreased
      cerebral metabolic rate for oxygen (CMRO2) relative to the baseline data,
      compared with a constant CMRO2 in nonanemic group in which the CEO2, AVDO2, and
      CBFv remained relatively normal. Moreover, compared to the baseline data, a
      significant increase of the AVDLac was found in anemic but not in nonanemic
      group, although the former had lower Lac concentrations of the SSS than did the
      latter group throughout the whole observation period. We conclude that, in cases
      with chronically reduced Hct, cerebral hemodynamics and oxygenation remain in
      favorable conditions, thus decreasing Lac production of the brain. The findings
      suggest a lowered metabolic demand of the brain tissue due to reduced cerebral O2
      carrying capacity. During the early phase of moderate ICH, the regulation
      capacity in cerebral hemodynamics and brain oxygenation tend to deteriorate in
      profound anemic hypoxia, which consequently leads to enhancing at least modest
      anaerobic glycolysis.

PMID- 10402022
TI  - Effects of cholinergic blockers on auditory brain-stem evoked potentials in rats.
AB  - The pharmacology of auditory brain-stem evoked potentials (ABEP) pathways is
      poorly understood. There are anecdotal reports on the involvement of various
      neurotransmitters but they were not investigated systematically. The aim of this
      study was to investigate the effects on ABEP of muscarinic and nicotinic
      blockers, administered into the cerebral ventricles. Atropine sulfate, d
      Tubocurarine and saline were injected stereotactically into the lateral cerebral
      ventricle of anesthetized male rats. Auditory clicks were given at a rate of 20
      s(-1). ABEP recording was performed before and 30 min after injection. Pre- and
      post-injection peak latencies and peak-to-peak amplitudes of positive waves were
      compared for each animal. Atropine reduced the amplitudes of waves P1, P3 and P4
      and increased mildly the brain stem transmission time. d-Tubocurarine reduced the
      amplitudes of P1 and P4 with no significant effect on the peak latencies. Saline
      injection had no effect on any of the parameters. These results show that both
      cholinergic systems are involved in ABEP generation or transmission. Mechanism of
      action could be either direct inhibition of afferent pathways or indirect effect,
      via modulating efferent pathways.

PMID- 10402023
TI  - Differences in regional cerebral blood flow in two types of leuko-araiosis.
AB  - Cerebral blood flow and cerebrovascular acetazolamide reactivity were
      investigated in patients with periventricular hyperintensity and in patients with
      leuko-araiosis in centrum semiovale. Fifteen patients with periventricular
      hyperintensity, 15 patients with leuko-araiosis in centrum semiovale and 15 age
      matched controls without leuko-araiosis were studied. The regional cerebral blood
      flow was measured using the stable xenon CT method before and 20 min after
      intravenous injection of 17 mg/kg acetazolamide. The blood flow and the
      cerebrovascular acetazolamide reactivity in the area of leuko-araiosis were
      significantly lower in the periventricular hyperintensity group and the leuko
      araiosis in centrum semiovale group than the control group. The blood flow in the
      cerebral cortex was significantly lower in the leuko-araiosis in centrum
      semiovale group than in the periventricular hyperintensity group and the control
      group. The cerebrovascular acetazolamide reactivity in the cerebral cortex did
      not show any significant difference among the three groups. The blood flow in the
      cerebral cortex was decreased in patients with leuko-araiosis in centrum
      semiovale but the cerebrovascular acetazolamide reactivity in the cerebral cortex
      was normal in patients with leuko-araiosis.

PMID- 10402024
TI  - Autoantibodies to GM1b and GalNAc-GD1a: relationship to Campylobacter jejuni
      infection and acute motor axonal neuropathy in China.
AB  - IgG antibodies to the minor gangliosides GM1b and GalNAc-GD1a frequently are
      present in sera of Japanese patients with Guillain-Barre syndrome. The
      relationship between these autoantibodies and Campylobacter jejuni infection, the
      type of disease (acute motor axonal neuropathy [AMAN], or acute inflammatory
      demyelinating polyneuropathy [AIDP]) has yet to be established. Sera samples were
      obtained from 55 Chinese patients with clinically defined Guillain-Barre
      syndrome. An electrophysiology study showed nine AIDP, 28 had AMAN, and 18
      unclassified. C. jejuni serology was positively correlated with anti-GM1b and
      anti-GalNAc-GD1a IgG antibodies (respective P values, 0.007 and 0.02). The
      frequencies of positive anti-GM1b and anti-GalNAc-GD1a serology were greater in
      AMAN (32 and 21%) than in AIDP (11 and 0%), but the differences were not
      significant. Infection by C. jejuni may induce IgG anti-GM1b antibody in some
      patients and IgG anti-GalNAc-GD1a antibody in others. A larger population of
      patients must be studied to show whether there is a definite correlation.

PMID- 10402025
TI  - Visual event-related potential changes at two different tasks in nondemented
      Parkinson's disease.
AB  - A visual oddball paradigm and an S1-S2 paradigm were employed to evoke event
      related potentials (ERPs) in 38 nondemented Parkinson's disease (PD) patients and
      24 healthy elderly subjects. Delayed N200 and reduced P300 amplitude in the whole
      PD sample were only found in the S1-S2 paradigm. Delayed N200 and reaction time
      in PD with short duration of illness were found only after the S1-S2 paradigm,
      which might be an early sign of cognitive changes in PD. This is the first study
      to apply an S1-S2 paradigm for a visual P300 test in PD and proved the value of
      this paradigm for detecting minor cognitive abnormalities. ERP changes were
      correlated with clinical features. Reduced P300 amplitude for the S1-S2 paradigm
      was significantly correlated with WAIS-R scores and gait disturbance. The
      correlation between P300 amplitude and clinical scores has rarely been discussed
      before. P300 latency during the oddball paradigm in PD was influenced by age at
      test, age at onset, and duration of illness. This may explain why P300 results in
      nondemented PD have varied among previous authors.

PMID- 10402026
TI  - Short-term evolution of new multiple sclerosis lesions enhancing on standard and
      triple dose gadolinium-enhanced brain MRI scans.
AB  - We compared the short-term magnetic resonance imaging (MRI) evolution of new
      multiple sclerosis (MS) lesions enhancing after single dose (SD) (0.1 mmol/kg) or
      triple dose (TD) (0.3 mmol/kg) gadolinium-DTPA (Gd) to explore possible
      differences in the pathological substrates of acute MS lesions. Brain MRI scans
      were obtained at baseline and every 4 weeks for a 3-month period in 18 relapsing
      remitting MS patients. At each time point, using two separate sessions, we
      obtained dual echo and T1-weighted scans before and after SD and TD of Gd. New
      enhancing lesions detected at month 1 and 2 were entered into the analysis. The
      presence of corresponding hypointense lesions on unenhanced T1-weighted scans and
      hyperintense lesions on T2/proton density (PD)-weighted images was assessed on
      the same scan and on the scans performed 1 month before and 1 month after the new
      lesion development. Persistence of enhancement was evaluated on the SD and TD
      scans obtained 1 month after new lesion appearance. One-hundred and sixty lesions
      were studied. Of these, 97 lesions were enhancing after both SD and TD (group A)
      and 63 lesions only after TD (group B). Thirty (31%) of the lesions enhancing
      after both SD and TD and ten (16%) of the lesions enhancing only after TD had
      corresponding T1-weighted lesions (P = 0.03). Of these lesions, 87% in group A
      and 40% in group B (P = 0.003) were not hypointense on the previous scans. No
      differences were found in the frequencies of corresponding T2/PD-weighted
      abnormalities (92% in Group A vs. 87% in Group B lesions). Of these hyperintense
      areas, 62% in group A and 56% in group B were not present on the previous scans.
      On follow-up scans, 52% of the lesions enhancing after SD and TD and 70% of the
      lesions enhancing only after TD did not show enhancement after the injection of
      both the doses of Gd (P = 0.02). The frequencies of corresponding T2/PD and T1
      weighted abnormalities were higher in Group A than in Group B lesions, but the
      differences were not statistically significant. Our findings suggest that the
      pathological process is less severe in MS lesions enhancing only after TD
      injection than in those enhancing after the SD.

PMID- 10402028
TI  - R- and S-salsolinol are not increased in cerebrospinal fluid of Parkinsonian
      patients.
AB  - Various investigators address an augmented synthesis of tetrahydroisoquinolines,
      such as salsolinol (SAL), or an increased N-methylation of these compounds as
      putative pathophysiologic mechanisms in Parkinson's disease (PD). Objectives of
      this study were (1) the evaluation of a putative elevation of enantiomers (R-, S
      ) of SAL and (2) the investigation of relations between these metabolic
      precursors of neurotoxic N-methylated-SAL (NMSAL) and dopamine in cerebrospinal
      fluid of untreated de-novo Parkinsonian patients and age- and sex-matched healthy
      controls. Levels of R- and S-SAL and dopamine did not significantly (R-SAL: P =
      0.75, S-SAL: P = 0.69, dopamine: P = 0.46) differ and dopamine did not correlate
      to R-SAL and S-SAL in both groups. We conclude, that central accumulation of R
      NMSAL, which is neurotoxic to dopaminergic nigrostriatal neurons, is not due to
      elevated synthesis of R-SAL and/or S-SAL in PD.

PMID- 10402027
TI  - A new mitochondrial DNA mutation (A3288G) in the tRNA(Leu(UUR)) gene associated
      with familial myopathy.
AB  - We describe a family with a maternally inherited mitochondrial myopathy and an
      A3288G mutation in the tRNA(Leu(UUR)) gene. The proband had muscle cramping and
      mild weakness while her brother had long-standing limb and respiratory muscle
      weakness and her daughter had elevated serum CK. The mutation, which was nearly
      homoplasmic in muscle and heteroplasmic in blood, affects the TpsiC loop at a
      conserved site and was not found in 107 controls. This report confirms the
      frequent association of tRNA(Leu(UUR)) mutations with respiratory muscle
      involvement and bolsters the concept that tRNA(Leu(UUR)) is a hotspot for mtDNA
      mutations.

PMID- 10402029
TI  - Parkinson's disease and lower limb somatosensory evoked potentials: apomorphine
      induced relief of the akinetic-rigid syndrome and vertex P37-N50 potentials.
AB  - We evaluated brainstem P30, vertex-central P37-N50 and contralateral frontal N37
      somatosensory evoked potentials (SEPs) from the tibial nerve in 14 patients
      affected by Parkinson's disease (PD) with akinetic-rigid syndrome. In seven
      patients SEPs were recorded after administration of apomorphine. The cortical P37
      N50 complex was either absent (five patients, eight tested sides) or
      significantly smaller in patients as compared to the control group (n = 18).
      There was a relationship between abnormalities of early vertex potentials and
      degree of motor impairment. Administration of apomorphine was followed by an
      increase in amplitude of P37-N50 response, which was maximal after 15-30 min and
      then progressively returned to basal values in parallel with clinical
      improvement. Amplitude of brainstem P30 and frontal N37 responses was within
      normal values and did not vary following drug administration. These results
      suggest that the P37-N50 complex arises from independent cortical generators,
      probably located in the pre-rolandic cortex, which may be selectively affected by
      basal ganglia dysfunction. Amplitude decrease of the P37-50 complex may reflect
      an abnormal processing of somatosensory inputs within the pre-central cortex due
      to defective modulation exerted by basal ganglia circuitry on cortical
      excitability. SEP potentiation following apomorphine, besides indicating that
      this dysfunction is partly reversible, might suggest objective method to measure
      therapeutic efficacy.

PMID- 10402030
TI  - Epidermal innervation: changes with aging, topographic location, and in sensory
      neuropathy.
AB  - In previous work we demonstrated little effect of aging on the density and
      spatial pattern of epidermal innervation, however, this was restricted to two
      sites proximal and distal in the leg. To expand on these observations, we used
      punch skin biopsy in ten healthy controls to examine the variation in intra
      epidermal nerve fiber (IENF) density at multiple specific sites in the leg. There
      was a consistent gradient in IENF from proximal to distal sites in all subjects,
      but minimal effect of age was noted. In the older age group (> or =70 years), the
      IENF densities ranged from 28.6+/-1.9 IENF/mm at the trunk to 15.5+/-1.5 at the
      distal leg. In a group of six patients with painful sensory neuropathy, we
      confirmed a length-dependent reduction in IENF. We observed what may be a
      predegenerative change, namely increased branching of epidermal nerve fibers at
      clinically unaffected sites. These data suggest little age-related change in
      IENF, at least up to age 75 years, in healthy normals. The increased branching
      complexity noted in unaffected sites in patients with sensory neuropathies
      implies that this may be a predegenerative change, preceding the actual loss of
      nerve fibers. Skin biopsy may be a useful tool for assessing the topographic
      extent and degree of nerve fiber damage in sensory neuropathies and its
      quantitative interpretation should be little affected by aging changes.

PMID- 10402031
TI  - Corticospinal function in severe brain injury assessed using magnetic stimulation
      of the motor cortex in man.
AB  - We have assessed corticospinal function in 19 post-coma patients severely brain
      injured by anoxia or physical trauma. Eleven patients were unresponsive (Category
      1) and eight demonstrated minimal, non-verbal responses to simple commands
      (Category 2). Motor evoked potentials (MEPs) could be elicited in hand and leg
      muscles in nine Category 1 and all eight Category 2 patients in response to
      transcranial magnetic stimulation (TMS). In comparison with normal subjects,
      threshold to TMS was significantly elevated in Category 1 but not in Category 2.
      Central conduction times were within the normal range except for two patients
      (one in each category) in whom they were prolonged. The variability in MEP
      amplitude to constant TMS was not significantly different from normal in either
      category. The size of MEPs recorded simultaneously in different hand muscles were
      correlated in all three groups. The presence of H-reflexes in hand muscles was
      associated with an absence of MEPs or a high threshold to TMS. Variability of
      MEPs was substantially greater than that of H-reflexes. We conclude that brain
      injury of a severity that may preclude consciousness and voluntary movement does
      not invariably predicate a non-functional motor cortex and corticospinal system.

PMID- 10402032
TI  - Regional differences in genetic subgroup frequency in hereditary cerebellar
      ataxia, and a morphometrical study of brain MR images in SCA1, MJD and SCA6.
AB  - Molecular genetic assessments of 69 individuals in 44 families with hereditary
      cerebellar ataxia (HCA) were made to determine the relative frequencies of
      subtypes of HCA in Yamagata, Japan. Fifteen families (34%) had SCA1, none had
      SCA2, nine (20%) had MJD, five (11%) had SCA6 and nine (20%) had DRPLA. These
      findings differ markedly from those in other regions of Japan and the rest of the
      world. A morphometrical study of the brain MR images also was made on 38
      individuals with SCA1 (n = 14), MJD (n = 8) or SCA6 (n = 16). In SCA1, the
      ventral pons was atrophic in proportion to the amount of cerebellar atrophy. In
      MJD, both the pons and the cerebellum were atrophic, cerebellar atrophy being
      less pronounced than that in SCA1 and SCA6. While both the major and minor axes
      of the ventral pons were proportionally decreased in SCA1, the minor axis was
      more decreased than the major axis in MJD. In SCA6, a mild reduction in the ratio
      of the ventral pontine area to the posterior fossa area (Pv/PF) was observed as
      well as obvious cerebellar atrophy. These findings indicate that in MR images
      SCA1, MJD and SCA6 show different atrophic features of the cerebellum and
      brainstem.

PMID- 10402033
TI  - Encephalopathy caused by visceral larva migrans due to Ascaris suum.
AB  - We described a patient with encephalopathy associated with visceral larva migrans
      (VLM) caused by Ascaris suum. He suffered from drowsiness, quadriparesis,
      eosinophilia and elevated serum IgE levels. Brain magnetic resonance (MR) imaging
      revealed multiple cerebral cortical and white matter lesions. Serological tests
      indicated recent infection with A. suum. Pulse steroid therapy relieved the
      patient's central nervous system symptoms and marked improvement of lesions on
      brain MR images. We concluded that the encephalopathy in this patient was
      probably caused by VLM due to Ascaris suum.

PMID- 10402034
TI  - Tropical rain forest fragmentation, howler monkeys (Alouatta palliata), and dung
      beetles at Los Tuxtlas, Mexico.
AB  - In Neotropical rain forests, fresh mammal dung, especially that of howler
      monkeys, constitutes an important resource used by dung beetles as food and for
      oviposition and further feeding by their larvae. Tropical rain forest
      destruction, fragmentation, and subsequent isolation causing reductions in
      numbers of and the disappearance of howler monkeys may result in decreasing
      numbers of dung beetles, but this has not been documented. In this study, we
      present information on the presence of howlers and dung beetles in 38 isolated
      forest fragments and 15 agricultural habitats. Howler monkeys were censused by
      visual means, while dung beetles were sampled with traps baited with a mixture of
      howler, cow, horse, and dog dung. Results indicated that loss of area and
      isolation of forest fragments result in significant decrements in howlers and
      dung beetles. However, dung beetle abundance was found to be closely related to
      the presence of howler monkeys at the sites and habitats investigated. Scenarios
      of land management designed to reduce isolation among forest fragments may help
      sustain populations of howler monkeys and dung beetles, which may have positive
      consequences for rain forest regeneration.

PMID- 10402035
TI  - Pendular motion in the brachiation of captive Lagothrix and Ateles.
AB  - Pendular motion during brachiation of captive Lagothrix lagothricha lugens and
      Ateles fusciceps robustus was analyzed to demonstrate similarities, and
      differences, between these two closely related large bodied atelines. This is the
      first captive study of the kinematics of brachiation in Lagothrix.
      Videorecordings of one adult male of each species were made in a specially
      designed cage constructed at the DuMond Conservancy/Monkey Jungle, Miami, FL.
      Java software (Jandel Scientific Inc., San Rafael, CA) was used for frame-by
      frame kinematic analysis of individual strides/steps. Results demonstrate that
      the sequence of hand and tail contacts differ significantly between the two
      species with Lagothrix using a new tail hold with every hand hold, while Ateles
      generally utilizes a new tail hold with only every other hand hold. Stride length
      and stride frequency, even after adjusting for limb length, also differ
      significantly between the two species. Lagothrix brachiation utilizes short,
      choppy strides with quick hand holds, while Ateles uses long, fluid strides with
      longer hand holds. During brachiation not only is Lagothrix's body significantly
      less horizontal than that of Ateles but also, within Ateles, there are
      significant differences between steps depending on tail use. Because of the
      unique nature of tail use in Ateles, many aspects of body positioning in
      Lagothrix more closely resemble Ateles steps without a simultaneous tail hold
      rather than those with one. Overall pendulum length in Lagothrix is shorter than
      in Ateles. Tail use in Ateles has a significant effect on maximum pendulum length
      during a step. Although neither species achieves the extreme pendulum effect and
      long period of free-flight of hylobatids in fast ricochetal brachiation, in
      captivity both consistently demonstrate effective brachiation with brief periods
      of free-flight and pendular motion. Morphological similarities between ateline
      brachiators and hylobatids are fewer and less pronounced in Lagothrix than in
      Ateles. This study demonstrates that Lagothrix brachiation is also less hylobatid
      like than that of Ateles.

PMID- 10402036
TI  - Dominance in assamese macaques (Macaca assamensis).
AB  - A field study of 64 assamese macaques (Macaca assamensis) was conducted at a
      temple site in Assam, India. Focal and all occurrence scan techniques were used
      to collect data on agonistic, grooming, and sexual behavior. More than 1,000 hr
      of data were summarized into agonistic dominance, grooming, and mounting
      matrices. Rank hierarchies were constructed for all three and compared. We also
      directly compared each cell in each matrix with the corresponding cells in the
      other matrices. A nearly linear agonistic dominance hierarchy was found, but it
      did not correlate with the directionality of mounting or grooming. Adult males
      mounted females, generally were dominant to females and groomed females more
      often than they were groomed by females. Younger males groomed older males and
      were also generally subordinate to older males. These age and sex effects
      produced some inter-correlations among grooming, mounting, and dominance but only
      for specific age-sex classes. Theoretical models of social exchange were not
      considered useful in predicting the complex patterns of grooming, mounting, and
      dominance seen in the present group. Whereas such models may "explain" existing
      data for some groups and have gained widespread acceptance, they must be
      empirically tested.

PMID- 10402038
TI  - Urine as another potential source for template DNA in polymerase chain reaction
      (PCR).
AB  - This technical note examines the potential for preparing template DNA in
      polymerase chain reactions (PCR) from urine in Japanese macaques (Macaca
      fuscata). Microsatellite band patterns from urine samples showed close agreement
      with those of blood and fecal samples, and only a few hundred microl of urine
      yielded a template DNA for PCR. This research will increase the opportunity for
      scientists to examine the genetic backgrounds of their target animals by using
      non-invasive sample collection in the wild.

PMID- 10402037
TI  - A two-step extraction method to measure fecal steroid hormones in female
      cynomolgus monkeys (Macaca fascicularis).
AB  - We developed a two-step extraction method for measuring fecal steroid
      concentrations. In the first step, distilled water was used to extract steroids
      from fecal samples. In the second step, a mixture of organic solvents (hexane and
      ether) was used to re-extract water extracts that had been transferred to a glass
      tube. A portion of the upper layer of the organic solvents was transferred to
      separate assay-tubes for measurement of estradiol (E2) or progesterone (P), and
      the organic solvents were evaporated in vacuo. After phosphate-buffered saline
      was added to each tube, commercially supplied radioimmunoassay (RIA) kits were
      used to determine the steroids. We demonstrated the advantages and reliability of
      this method by using it to assay the steroid hormone concentrations in fecal
      samples and serum samples collected on the same day from female cynomolgus
      monkeys who showed normal menstrual cycles and from monkeys who had induced
      hyperfunction of ovarian steroidgenesis. Different fecal samples from each monkey
      were used to determine the recovery rate of each steroid in water extraction from
      the fecal samples and the reproductivity of hormone concentrations in the fecal
      samples. The results demonstrate that this two-step method is simple and
      effective for measuring fecal steroids for monitoring the reproductive status of
      cynomolgus monkeys, without having to collect serum samples.

PMID- 10402039
TI  - Food transfers in wild and reintroduced golden lion tamarins, Leontopithecus
      rosalia.
AB  - We collected data from wild and reintroduced golden lion tamarins (Leontopithecus
      rosalia) to describe the behavior of donor and recipient during food transfers,
      evaluate the effect of supplemental feeding on food transfer behavior, and
      examine various hypotheses concerning the function of food transfers in primates.
      Behavioral observations were conducted on 12 groups of tamarins with young (N =
      30) between the ages of 1 week and 1 year old. Results show that food transfers
      involve various behaviors, from steals by recipients to offers by donors;
      transfers mostly derive from adults and are directed at immature weaned young
      (between 3 and 9 months old); and that most items transferred were prey or fruits
      that require skill to process. Eleven percent of food transfers were preceded by
      an adult vocalization specific to that context, whereas 86% were preceded by
      conspicuous infant vocalizations and begging behavior. The most common
      vocalizations were loud and atonal (rasps) and broad banded frequency modulated
      (trills). Infants born to reintroduced parents vocalized less, whereas
      reintroduced adults vocalized more before transferring food than their wild
      counterparts. Reintroduced adults and young received more food transfers (4.4 per
      hr) than did wild-born adults and young (2.2 per hr). Our findings suggest that
      food transfer in golden lion tamarins is best understood as provisioning of young
      that have not fully developed foraging skills to ensure they get the necessary
      resources for growth and survival.

PMID- 10402040
TI  - Electrocardiographic left ventricular hypertrophy by five criteria among civil
      servants in Benin City, Nigeria: prevalence and correlates.
AB  - Although increasing hypertension rates have been reported in several African
      populations, little is known about the frequency of resulting hypertensive
      complications in these populations. We recorded the electrocardiograms of 482
      male and 284 female civil servants in Benin City, Nigeria. Five different
      criteria were used to detect the presence of electrocardiographic left
      ventricular hypertrophy. Associations between electrocardiographic left
      ventricular hypertrophy and demographic, anthropometric and blood pressure
      characteristics were assessed. The prevalence of electrocardiographic left
      ventricular hypertrophy ranged from 3 to 29% in the total population, depending
      on the criteria used, with four of the five criteria resulting in prevalence
      estimates of less than 10%. The prevalence of electrocardiographic left
      ventricular hypertrophy was significantly greater among those with hypertension
      (19% of the total population), ranging from 11 to 49%. The prevalence of
      electrocardiographic left ventricular hypertrophy increased with blood pressure
      level in both normotensives and hypertensives. Among hypertensives with systolic
      blood pressure > or =180 mm Hg or diastolic blood pressure > or =110 mm Hg, the
      prevalence exceeded 50% by four of the five criteria. We conclude that left
      ventricular hypertrophy may be affecting many hypertensives in this Nigerian
      population, potentially resulting in a substantial future burden of
      cardiovascular disease and death.

PMID- 10402041
TI  - Prediction of atrial fibrillation recurrence after cardioversion by P wave signal
      averaged electrocardiography.
AB  - The purpose of this report was to determine prospectively whether P wave signal
      averaged electrocardiography (ECG) is useful for the prediction of recurrences of
      atrial fibrillation after cardioversion. The P wave signal-averaged ECG was
      recorded in 73 patients after successful cardioversion. Duration of the filtered
      P wave and the root mean square voltages for the last 20 ms of the P wave were
      calculated. In addition to signal-averaged ECG P wave analysis, all patients were
      evaluated by echocardiography. During 6 months follow-up period recurrence of
      atrial fibrillation was observed in 31 (42.5%) patients and in 42 (57.5%)
      patients sinus rhythm was maintained. There was no difference in gender, age,
      presence of organic heart disease, left atrial diameter, left ventricular
      ejection fraction, use of antiarrhythmic drug, and duration of atrial
      fibrillation (P>0.05). The filtered P-wave duration was longer and the root mean
      square voltages for the last 20 ms of the P wave was lower in patients with
      recurrence of atrial fibrillation than in patients who maintained sinus rhythm
      (138.3+/-12.5 ms vs. 112.4+/-11.8 ms, P = 0.001; 1.9+/-0.7 microV vs. 2.5+/-0.6
      microV, P = 0.001). A filtered P-wave duration > or =128 ms associated with a
      root mean square voltage for the last 20 ms of the P wave < or =2.1 microV had a
      sensitivity of 70% and specificity of 76% for the detection of patients with
      recurrence of atrial fibrillation after successful cardioversion of atrial
      fibrillation. We found that the likelihood of recurrence of atrial fibrillation
      after cardioversion was increased 4.31-fold (95% confidence interval 2.08-9.83)
      if these parameters were used. These results suggest that P wave signal-averaged
      ECG could be useful to identify patients at risk for recurrence of atrial
      fibrillation after cardioversion.

PMID- 10402042
TI  - Sjogren autoantibodies modify neonatal cardiac function via M1 muscarinic
      acetylcholine receptor activation.
AB  - Isolated congenital heart block may be associated with primary Sjogren syndrome.
      In this work we describe circulating antibodies in the sera of primary Sjogren
      syndrome patients that are able to interact with neonatal myocardium by
      activating muscarinic acetylcholine receptors of M1 subtype. We report on the
      presence of autoantibodies against the second extracellular loop of human M1
      muscarinic acetylcholine receptors in primary Sjogren syndrome mothers whose
      children have congenital heart block using a synthetic peptide in indirect
      immunofluorescence technique. Autoantibodies from primary Sjogren syndrome
      patients gave positive image on neonatal atria but not on adult atria slices. The
      synthetic M1 peptide selectively abrogated indirect immunofluorescence
      recognition. The primary Sjogren syndrome-immunoglobulin G also displayed an
      'agonist like' activity modifying the intracellular events associated with
      muscarinic acetylcholine receptor activation. The mechanism appears to occur
      secondarily to stimulation of phosphoinositides turnover via phospholipase C
      activation. This, in turn, triggers cascade reactions involving
      calcium/calmodulin and leads to activation of nitric oxide synthase and soluble
      guanylate cyclase. All of these effects were selectively blunted by pirenzepine
      and neutralized by M1 synthetic peptide. These biological effects were not
      obtained using adult instead of neonatal rat atria and neither occurred with the
      sera of normal healthy women of childbearing age. It could be concluded that
      antibodies against neonatal M1 muscarinic acetylcholine receptor may be another
      serum factor to be considered in the pathophysiology of the development of
      congenital heart block associated with primary Sjogren syndrome mothers.

PMID- 10402044
TI  - Waist circumference and waist-to-hip ratio in Turkish adults: interrelation with
      other risk factors and association with cardiovascular disease.
AB  - OBJECTIVE: To investigate the distribution of waist circumference (WC) and waist
      to-hip ratio (WHR), their relationships with a number of established risk factors
      and their relevance to cardiovascular morbidity in a random sample of Turkish
      general adult population. DESIGN: Cross-sectional population-based study.
      SUBJECTS: The subjects comprised 958 men and 1014 women, aged 25-74 years.
      MEASUREMENTS: Waist circumference was measured midway between the lower rib and
      iliac crest while that of the hip at the level of trochanters. Mean of two blood
      pressure measurements was used for analysis. Plasma total cholesterol (Cho) and
      triglyceride (Trg) concentrations were measured by the enzymatic dry method with
      a Reflotron apparatus. RESULTS: Overall mean WC measured 93+/-12 cm in men, and
      88.6+/-13 cm in women. Mean WHR was 0.919+/-0.077 and 0.823+/-0.074,
      respectively, and a rise by about 0.001 was associated with each year of age. In
      multiple regression analysis a model was utilized that included age, body mass
      index (BMI), systolic and diastolic blood pressure (BP), plasma total Cho and Trg
      and category of smoking. This revealed age, BMI, and Trg as independent
      determinants of WHR in both genders, and diastolic BP in women alone. Age, BMI,
      and diastolic BP proved to be independently associated with WC in both genders,
      while Cho did so in men alone, Trg and systolic BP in women alone. Partial
      correlation coefficients on univariate analysis between all four variables of
      blood pressure and plasma lipids and either WC or WHR, controlled for age, were
      highly significant though moderately weak in both genders. These were stronger in
      men than in women, and stronger with respect to WC than to WHR. Cigarette smoking
      men and women had significantly lower WC or WHR than nonsmokers and ex-smokers,
      though these associations did not prove to be independent. When the relevance of
      WC and WHR to CHD risk was tested in this cohort (for the age bracket 45-74
      years) comprising 138 cases with a clinical diagnosis of CHD, only WHR in women
      proved to be significantly associated. Odds ratio for a value of >0.845 was 1.6.
      CONCLUSION: WC and WHR are strongly associated with BMI and age as well as with
      parameters reflecting insulin resistance such as diastolic blood pressure and
      plasma triglycerides. WHR was significantly associated with coronary heart
      disease in Turkish women.

PMID- 10402043
TI  - Comparison of diabetic and non-diabetic patients referred for coronary
      angiography.
AB  - AIM: To evaluate whether diabetic patients differ from non-diabetic patients when
      referred for coronary angiography regarding previous history, indication for and
      findings at coronary angiography, use of medication, exercise test results and
      mortality. METHODS: Data were prospectively collected on patients referred for
      consideration of coronary revascularization to seven of the eight public Swedish
      heart centers that performed approximately 92% of all bypass operations in Sweden
      in 1994. RESULTS: 2762 patients were included of whom 406 (15%) had a history of
      diabetes mellitus. There was no difference in age or sex in the two groups.
      Chronic stable angina was the most common indication (73% in both groups) and
      only 3% were admitted due to silent ischemia. Diabetic patients had more severe
      symptoms (Canadian Cardiovascular Society III-IV) than non-diabetic patients (66%
      vs. 58%, p<0.01). They more frequently used ACE-inhibitors (33% vs. 19%,
      p<0.0001) and calcium channel blockers (47% vs. 40%, p<0.01) and more often had a
      diagnosis of arterial hypertension than non-diabetic patients (50% vs. 33%,
      p<0.0001). Diabetic patients more often had depressed myocardial function
      (EF<35%); 12% and 8%, respectively (p<0.01), and more extensive coronary artery
      disease (left main/3-VD; 48% vs. 37%, p<0.001). The mortality during the
      subsequent 21 months was 7.9% among diabetic patients and 3.6% among non-diabetic
      patients (p<0.001). CONCLUSION: Among patients being referred for coronary
      angiography in Sweden, 15% were patients with a history of diabetes. They
      differed from patients without such a history by more often having severe
      symptoms and a higher prevalence of left main/triple vessel disease. Coronary
      angiography may thus be underused in diabetic patients with chest pain.

PMID- 10402045
TI  - Central and peripheral components of chronic heart failure: determinants of
      exercise tolerance.
AB  - This study sought to determine the relationship between myocardial dysfunction
      and peripheral haemodynamic disorders to exercise intolerance in patients with
      chronic heart failure (CHF). Seventeen patients with mild to moderate CHF (peak
      oxygen consumption (VO2) >16 ml/min/kg) and 13 with severe CHF (peak VO2 <16
      ml/min/kg) underwent invasive (Swan-Ganz) cardiopulmonary exercise testing and
      forearm venous occlusion plethysmography at rest and during maximal dilatation in
      reactive hyperaemia. There was a shift from central to peripheral haemodynamic
      factors limiting exercise, suggesting an increasing importance of peripheral
      factors in parallel to the progression of CHF. In mild to moderate CHF peak VO2
      was closely related to central haemodynamics (r = 0.57 for cardiac index at rest;
      r = 0.76 for cardiac index at maximal workload; r = -0.54 for right arterial
      pressure at maximal workload; all p<0.05) and poorly correlated with peripheral
      haemodynamics (blood flow, vascular resistance and venous tone). In contrast, in
      severe CHF peak VO2 was closely related to peripheral haemodynamic factors (r =
      0.79 for forearm blood flow; r = -0.82 for vascular resistance; r = -0.77 for
      venous tone; all p<0.05) and less to central ones. Thus, exercise tolerance of
      patients with mild to moderate CHF is predominantly determined by central
      haemodynamic factors, notably by the cardiac index. In severe CHF peripheral
      factors assume ever greater importance in the determining of exercise capacity.

PMID- 10402046
TI  - Plasma endothelin-1 levels in patients with left-to-right shunt with or without
      pulmonary hypertension.
AB  - The aim of this study was to evaluate the role of endothelin-1 (ET-1) in
      pathophysiology of pulmonary hypertension (PH) secondary to congenital heart
      disease with left-to-right shunt. Twenty-three children (12 male, 11 female) aged
      0.58-13 years were enrolled the study. Blood samples were drawn from superior
      vena cava, right atrium, right ventricle, pulmonary artery and pulmonary wedge or
      pulmonary vein during cardiac catheterization. Plasma ET-1 levels were assayed by
      ELISA. Patients were divided into two groups according to the presence or absence
      of PH. Plasma ET-1 levels of the study group were compared to the peripheral
      venous and arterial ET-1 levels of 11 healthy infants and children (aged 0.75-13
      years). Plasma ET-1 levels in patients with left-to-right shunt were found
      significantly higher than those of controls. However, plasma ET-1 levels were
      similar between the two groups of the patients. Pulmonary venous ET-1 levels were
      higher than the levels of superior vena cava, this suggested an increased
      production of ET-1 in pulmonary vascular bed in patients with PH. No correlations
      were found between plasma ET-1 levels and pulmonary arterial pressure, pulmonary
      vascular resistance and pulmonary blood flow in the patients. Plasma ET-1 levels
      of the patients with left-to-right shunt were increased independently from
      pulmonary arterial pressure and pulmonary vascular resistance. This increase was
      related to the production of ET-1 in pulmonary vascular bed in patients with PH.
      ET-1 could not be found to be directly related to the development of PH in the
      patients with left-to-right shunt.

PMID- 10402047
TI  - QT/corrected QT (QTc) intervals and QT/QTc dispersions in children with chronic
      renal failure.
AB  - We aimed to examine QT/corrected QT (QTc) intervals, QT/QTc dispersions
      (QTD/QTcD) and also the effect of different clinical and laboratory variables on
      these parameters in children with chronic renal failure. Serum biochemistry, 12
      lead electrocardiogram, telecardiogram, and echocardiography were performed in 50
      children with chronic renal failure (23 female and 27 male; aged 12.3+/-3.6
      years, range 5 to 20 years). None of them had symptoms related to arrhythmias.
      When compared with a control group (372 children, aged 7 to 18 years, mean 12.4+/
      2.6) patients with chronic renal failure had greater QT/QTc intervals and QT/QTc
      dispersion values (Patient: QT = 360.9+/-53.3; QTc = 438.5+/-33.2; QTD = 42.4+/
      20.8; QTcD = 57.5+/-23.8; CONTROL: QT = 325.9+/-24.1; QTc = 398.7+/-19.7; QTD =
      29.9+/-10.2; QTcD = 47.3+/-16.6; P<0.01). QT, QTc, and QTcD values were
      significantly greater in patients who had renal failure duration longer than 2
      years. Patients who had impaired left ventricular systolic function on
      echocardiogram had greater QTc, QTD, and QTcD values. It was found that sex,
      cardiomegaly on chest X-ray, and left ventricular hypertrophy on echocardiogram
      were not related to these parameters. It is concluded that, impaired cardiac
      systolic function and longer renal failure duration are related to an increase in
      QT, QTc, QTD, and QTcD values and hence these variables may be risk factors for
      ventricular arrhythmias in uremic patients.

PMID- 10402048
TI  - Mechanical complications of intra-aortic balloon counterpulsation.
AB  - Intra-aortic balloon counterpulsation (IABP) related complications in a
      heterogeneous group of patients who received an IABP before or after thrombolytic
      therapy and mechanical revascularization or in the management of refractory
      unstable angina and myocardial infarction related mechanical complications were
      evaluated prospectively. Ninety-one patients were enrolled to the study. Mean
      IABP duration was 4.3+/-2.4 days. While the IABP was in place, three patients
      (3.3%) had femoral artery emboli, four patients (4.4%) had lower extremity
      ischemia that resolved after the removal of the balloon, eight patients (8.8%)
      had groin hematoma requiring blood transfusion (< or =2 units) and four patients
      (4.4%) had intra-aortic balloon rupture. The relation of several risk factors to
      groin hematoma requiring < or =2 units blood transfusion, emboli, lower extremity
      ischemia and to total complications was evaluated. A chi-squared analysis showed
      that nadroparine use was more often complicated with emboli (P = 0.00005) and
      ischemic events (emboli and/or lower extremity ischemia) (three patients; 30% of
      nadroparine group vs. four patients; 4.9% of heparin group, P = 0.005) and
      hypercholesterolemia (>200 mg/dl) was more often complicated with lower extremity
      ischemia (P = 0.017). Forward conditional logistic regression analysis did not
      show any relation between the risk factors identified and emboli, lower extremity
      ischemia, ischemic events and groin hematoma (P>0.05), but an inverse relation
      was found between IABP duration and total complications (P = 0.0198). In
      conclusion, IABP related complications were found to remain unchanged but were
      not life-threatening and were inversely related to IABP duration and this
      suggests shorter periods of IABP use whenever possible and one must be cautious
      to use low molecular weight heparin in patients with an IABP in place.

PMID- 10402049
TI  - Radiofrequency catheter ablation of junctional ectopic tachycardia in adults.
AB  - Junctional ectopic tachycardia is an arrhythmia seen principally in infants and
      children, in adults it is even more rare and is difficult to treat with
      antiarrhythmic drugs and is associated with a poor prognosis. To our knowledge,
      there is not information about treatment with nonpharmacological methods in
      adults. We report two adult patients with junctional ectopic tachycardia who
      underwent successful radiofrequency catheter ablation of the automatic focus
      located in the His bundle region. The tachycardia was eliminated in both patients
      with AV block in one and the AV conduction was preserved in the other. After six
      and 48 months of follow-up both patients are asymptomatic and free of
      recurrences.

PMID- 10402050
TI  - Formation of a left atrial ball thrombus from a large mural thrombus 4 days after
      an embolic episode.
AB  - We present a case of basilar artery embolism originating from a left atrial mural
      thrombus. The thrombus was large and attached to the posterior left atrial wall,
      but decreased in size and detached forming a ball type thrombus over the next 4
      days without anticoagulant and/or antifibrinolytic therapy.

PMID- 10402051
TI  - Total occlusion of the left main coronary artery in a young cocaine user.
AB  - A young woman, currently user of cocaine, was admitted because of acute
      myocardial infarction with cardiogenic shock. The coronary arteriography revealed
      total occlusion of the left main coronary artery. Despite the use of an
      intraaortic counterpulsation balloon and successful percutaneous transluminal
      coronary angioplasty, she developed electromechanical dissociation, unresponsive
      to resuscitation manoeuvres.

PMID- 10402052
TI  - Neurobiology of slow coronary flow.

PMID- 10402053
TI  - Sympathetic nervous system, adrenergic receptors, and obesity.

PMID- 10402054
TI  - Effects of testosterone and growth hormone on muscle function.

PMID- 10402055
TI  - BRCA-associated cancer risk: molecular biology and clinical practice.

PMID- 10402056
TI  - Lipid peroxidation and atherosclerosis in type II diabetes.

PMID- 10402057
TI  - Sympathetic modulation of lipolysis in subcutaneous adipose tissue: effects of
      gender and energy restriction.
AB  - To investigate the differences in the regulation of lipolysis between male and
      female obese subjects in vivo, we used an in situ microdialysis technique before
      and after 3 weeks of energy restriction. Using this method, we examined glycerol,
      glucose, and lactate responses after 5 minutes of epinephrine stimulation in the
      adipose tissues. Glycerol releases after the perfusion of phentolamine,
      orciprenaline, and propranolol were also studied. Sixteen subjects were studied
      (8 men, 8 women, 35 to 45 years of age, body mass index 38 to 50 kg/m2). In
      women, epinephrine provoked a greater glycerol release than in men in both
      abdominal and femoral regions (P < .05). In men and women there was a significant
      decrease in the concentration of glucose and a significant increase in lactate
      concentration after epinephrine stimulation (P < .001). After 3 weeks of energy
      restriction, glycerol release after epinephrine stimulation was greater in both
      sexes than that observed before energy restriction (P < .05). Both phentolamine
      and orciprenaline stimulated the release of glycerol (P < .01); phentolamine had
      a higher effect in women, while propranolol had no effect on glycerol release in
      both sexes. In summary, we have demonstrated that epinephrine provoked a greater
      lipolytic response in obese women in both abdominal and femoral adipose tissues.
      The lipolytic response was further enhanced after 3 weeks of energy restriction
      in each gender. The decrease in glucose concentration suggests that glucose may
      be reutilized for synthesis into new triacylglycerol. Knowledge about the
      sensitivity to lipolytic agents in subcutaneous adipose tissue may provide
      potential new approaches for modulating the lipolytic responses of subcutaneous
      adipose tissue differently in men and women.

PMID- 10402058
TI  - Local and systemic responses to iron-dextran injected into a granuloma pouch in
      the rat.
AB  - Many inflammatory processes are accompanied by anemia and repeated hemorrhages,
      but the local and systemic effect of the iron present in the inflamed area and
      the availability of this iron are not known. The experimental model used to mimic
      the above situation was the carrageenan-induced granuloma in rats with
      simultaneous iron-dextran injection into the granuloma pouch. We studied the
      effect of iron-dextran on leukocytes from the inflammatory exudate and the
      location of iron in the granuloma tissue. We also evaluated the systemic
      responses by studying several iron parameters in blood and in iron-storage
      organs. The results showed a reduction in the number of leukocytes present in the
      exudate and a reduction in their viability and also extensive damage to the
      granuloma tissue, essentially to macrophages, caused by local iron-induced
      oxidative stress. A small percentage of iron reaches the systemic circulation,
      and this is eventually stored in the liver and spleen as hemosiderin, which is
      unlikely to have any effect on anemia. In spite of its local toxicity, the
      accumulation of iron in inflamed areas can be interpreted as a protective
      mechanism against systemic oxidative radical reactions induced by iron
      mobilization.

PMID- 10402059
TI  - Procalcitonin expression in human peripheral blood mononuclear cells and its
      modulation by lipopolysaccharides and sepsis-related cytokines in vitro.
AB  - Procalcitonin (PCT), the precursor of calcitonin, was recently put forward as a
      diagnostic marker of systemic bacterial infection and sepsis. The major PCT
      production site in sepsis still remains unclear. Because of a certain association
      between increased levels of PCT and leukocyte-derived cytokines during sepsis, we
      assessed the possible expression of PCT in human peripheral blood mononuclear
      cells (PBMCs) and the modulation of PCT by lipopolysaccharides (LPS) and various
      sepsis-related cytokines by reverse transcriptase-polymerase chain reaction (RT
      PCR) by using a novel primer set and flow cytometric analysis with intracellular
      staining with antibodies to the PCT components calcitonin and katacalcin. RT-PCR
      and flow cytometric analysis demonstrated that PBMCs express PCT both on mRNA and
      on protein levels. LPS and various proinflammatory cytokines (interleukin-1beta
      (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), IL-2) had pronounced
      stimulatory effects on the expression of PCT mRNA. Under identical experimental
      conditions the anti-inflammatory cytokine IL-10 had no effect on the expression
      of mRNA for PCT. Flow cytometric analysis demonstrated increased intracellular
      amounts of PCT components after LPS stimulation. Thus we demonstrate for the
      first time that PCT is expressed in PBMCs. This expression is modulated by
      bacterial LPS and sepsis-related cytokines. Therefore PBMCs may be among the
      sources of elevated PCT levels in patients with sepsis.

PMID- 10402060
TI  - Dipeptidyl peptidase activity of CD26 in serum and urine as a marker of
      cholestasis: experimental and clinical evidence.
AB  - Dipeptidyl peptidase IV (CD26) is a membrane-associated enzyme that is expressed
      on the surface of T cells and on the hepatocyte brush border. In a soluble form
      it is present in serum. CD26 has been implicated in the regulation of T cell
      activation and in the metabolism of hormones and cytokines. Dipeptidyl peptidase
      (DPP) activity is elevated in the urine and serum of patients with biliary
      atresia (BA). To clarify the role of cholestasis in the development of increased
      serum and urinary DPP/CD26 activity, we studied the mechanism of activity
      increase in experimentally induced cholestasis of CD26-deficient and wild-type
      rats. The clinical utility of serum and urinary DPP/CD26 activity measurements
      was tested in adult and pediatric patients with hepatobiliary diseases and in
      liver transplant recipients. The results establish CD26-associated serum DPP
      activity as a novel, clinically useful marker of cholestasis and demonstrate that
      in contrast with alkaline phosphatase levels, DPP levels do not change in
      metastatic bone disease. Additionally, DPP activity is useful as a urinary test
      of cholestasis in infants who are not receiving nephrotoxic medication.

PMID- 10402061
TI  - Prevalence of mixed infection by different hepatitis C virus genotypes in
      patients with hepatitis C virus-related chronic liver disease.
AB  - Multiple infection by different hepatitis C virus (HCV) genotypes may be of great
      clinico-pathologic interest. In this study we determined the effective prevalence
      of coinfections by two or more HCV genotypes in 213 subjects with HCV-positive
      chronic hepatitis by using genotype-specific polymerase chain reaction (PCR),
      genotype-specific probe hybridization, and direct sequencing. The most prevalent
      genotype was HCV-1b (54%). HCV-2 (a/c) was also prevalent (27%), and types 1a and
      3a were found in 5% and 3% of patients, respectively. A mixed infection was
      detected in 23 patients (10.8%): 4 out of 23 were coinfected by types 1a + 1b,
      while the remaining 19 patients had a b + 2 (a/c) mixed infection. Further
      analysis based on restriction fragment length polymorphism (RFLP) on type
      specific PCR products was used to verify genotyping results. Only four
      coinfections (1a + 1b in 2 patients and 1b + 2 (a/c) in the remaining 2 patients,
      respectively) were confirmed by enzyme cleavage. All patients with true
      coinfection had long-lasting infection and liver cirrhosis. Both true and false
      mixed infections resulting from RFLP analysis were confirmed by direct sequencing
      of type-specific amplification products. We also determined a recurrent C/T
      transversion at position 618 in all sequenced samples. In 4 cases another point
      mutation (G/A at position 626) was found, reducing the number of mismatches
      between HCV-2 and HCV-1b from 4 to 3 (or 2). Interestingly, all HCV-2 isolates
      sequenced showed the highest degree of nucleotide homology with HCV-2 subtype c,
      confirming the relatively high prevalence of this subtype in Italy. In
      conclusion, we showed the possibility of multiple infection by different HCV
      types in the general population of chronically infected patients without
      particular risk factors, even if in a low percentage of cases. Further studies
      are needed to assess the clinical relevance of chronic HCV infection with
      multiple genotypes.

PMID- 10402062
TI  - Segmental allergen challenge induces plasma protein leakage into the airways of
      asthmatic subjects at 4 hours but not at 5 minutes after challenge.
AB  - We have investigated whether increased plasma protein leakage is present early
      after segmental allergen challenge in allergic asthma. Seven asthmatic subjects
      with mild allergy (AA group) and 5 non-asthmatic subjects with allergy (ANA
      group) were challenged with allergen doses based on similar early skin reactions;
      5 healthy control subjects without allergy (C group) were challenged with the
      highest dose applied in the subjects with allergy. Bronchoalveolar lavage (BAL)
      fluid was obtained before, at 5 minutes after, and at 4 hours after challenge
      from different segments. Levels of albumin (Alb) and alpha2-macroglobulin (A2M)
      were measured in BAL fluid and serum. In addition, we calculated the relative
      coefficient of excretion as follows: RCE = ((A2M in BAL fluid)/(A2M in
      serum))/((Alb in BAL fluid)/(Alb in serum)). Also, levels of tryptase as a marker
      of mast cell activation and tumor necrosis factor-alpha (TNF-alpha), a possible
      inducer of plasma protein leakage, were determined. At 5 minutes after challenge,
      in none of the groups was a significant change found in the parameters for
      protein leakage. Levels of tryptase were increased in the subjects with allergy
      at 5 minutes after challenge only (P = .004). At 4 hours after challenge, levels
      of Alb (P = .03) and A2M (P = .04) and the RCE (P = .04) were increased in the AA
      group only. At 4 hours, levels of TNF-alpha were increased, with no significant
      differences among the three groups. In the asthmatic subjects with allergy,
      levels of TNF-alpha correlated with levels of Alb (r = 0.85, P = .02). In
      conclusion, at 4 hours after segmental allergen challenge, plasma protein leakage
      was increased in the asthmatic subjects only. The increase in levels of TNF-alpha
      in all groups indicates that the presence of TNF-alpha alone was not sufficient
      to cause plasma protein leakage within 4 hours after allergen challenge. Our
      results confirm the concept that plasma exudation after allergen exposure is a
      pathophysiologic event associated with asthma.

PMID- 10402063
TI  - Induction of apoptosis in rat hepatic stellate cells by disruption of integrin
      mediated cell adhesion.
AB  - Cell-matrix adhesion is recognized as a physiologic determinant of cell growth
      and survival. Integrin occupancy seems to be a primary role. We sought to
      investigate the signal transduction pathways for integrin effects on cell
      survival in hepatic stellate cells. Integrin function was antagonized by the
      soluble integrin recognition sequence pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) in
      primary cultures of rat hepatic stellate cells. Integrin antagonism with GRGDS
      peptide induced apoptosis. To investigate signal transduction mechanisms for the
      effect of integrins on cell survival in hepatic stellate cells, the expression of
      p53, Bcl-2, and Bax was analyzed. Incubation with soluble GRGDS peptide resulted
      in increased expression of p53 and decreased the Bcl-2/Bax ratio. In conclusion,
      these findings indicate that the abrogation of cell adhesion with soluble GRGDS
      peptide plays a critical role in the induction of apoptosis of rat hepatic
      stellate cells.

PMID- 10402064
TI  - Regulation of transforming growth factor-beta1 gene expression and cell
      proliferation in human hepatocellular carcinoma cells (PLC/PRF/5) by tamoxifen.
AB  - Hepatocellular carcinoma (HCC) is a common, potentially lethal tumor in human
      patients. Because the serum levels of transforming growth factor-beta1 (TGF
      beta1) correlate with outcome in patients with HCC and because TGFbeta1 mRNA
      expression is increased in HCC tissues, it raises the possibility that TGF-beta1
      may be of importance in the development, growth, and metastases of HCC. Tamoxifen
      has been used for the treatment of human HCC. However, clinical trials have
      produced conflicting results. To further delineate whether tamoxifen may be of
      benefit in altering the course of HCC, we documented the effects of 4
      hydroxytamoxifen and 17beta-estradiol on TGF-beta1 mRNA and protein levels and
      cell proliferation in a human HCC cell line. PLC/PRF/5 cells were treated with
      carrier (controls), 4-hydroxytamoxifen, 17beta-estradiol, or TGF-beta1. 4
      Hydroxytamoxifen and 17beta-estradiol decreased TGF-beta1 mRNA and protein levels
      in a time- and dose-dependent manner. TGF-beta1 significantly inhibited PLC/PRF/5
      cell proliferation, whereas both 4-hydroxytamoxifen and 17beta-estradiol
      stimulated PLC/PRF/5 cell proliferation. The stimulatory effects of 4
      hydroxytamoxifen on PLC/PRF/5 cell proliferation raise concerns regarding its use
      in the treatment of HCC in human patients and suggest that 4-hydroxytamoxifen may
      have no beneficial effects in some patients with HCC.

PMID- 10402065
TI  - Reproductive failure prior to the onset of clinical autoimmune disease.

PMID- 10402066
TI  - Should dehydroepiandrosterone replacement therapy be provided with
      glucocorticoids?
AB  - Adrenocorticotrophic hormone (ACTH) induces the concomitant secretion of
      glucocorticoids (GC) and dehydroepiandrosterone (DHEA) from the adrenal cortex.
      Whereas GC are catabolic, DHEA is anabolic. Long-term GC administration may
      result in some deleterious side-effects, such as muscular weakness, atrophy and
      necrosis, diabetes, fattiness, osteopenia, osteoporosis and avascular necrosis
      and susceptibility to infections. DHEA ameliorates some deleterious effects of
      GC, such as diabetes, amino acid deamination, fattiness, hypertension and
      susceptibility to viraemia. By its anabolic effects in muscles, bones and
      endothelium, DHEA may diminish the severity of GC-induced myopathy, osteopenia,
      osteoporosis and avascular necrosis. The natural concomitant secretion of DHEA
      with GC probably enables the latter to protect the body from ill-effects of
      stress without exerting their deleterious potency. DHEA secretion diminishes
      during aging and severe or chronic diseases such as rheumatoid arthritis (RA) and
      systemic lupus erythematosus (SLE). Anti-inflammatory and immunosuppressive
      effects of GC and androgens, including DHEA, are now well established. On the
      other hand, administration of GC inhibits ACTH secretion, involutes the adrenal
      cortex and results in further DHEA deficiency, particularly harmful in chronic
      autoimmune diseases (i.e. RA, SLE). Therefore, the deleterious side-effects of
      chronic administration of GC emerges from both their direct catabolic activity
      and the suppression of DHEA production. Whereas, in males, most androgens come
      from the testes, in females, under GC supplementation, DHEA deficiency leads to
      nullification of the androgen-dependent anabolism, leaving them exposed to the GC
      catabolic effects to a larger extent. The viewpoint presented here claims that
      under chronic GC supplementation, DHEA replacement therapy may reduce damage
      caused by GC administration.

PMID- 10402067
TI  - Interleukin-10 as an explanation for pregnancy-induced flare in systemic lupus
      erythematosus and remission in rheumatoid arthritis.

PMID- 10402068
TI  - Amyloidosis in a nationwide series of 1666 subjects with rheumatoid arthritis who
      died during 1989 in Finland.
AB  - OBJECTIVES: Virtually all studies dealing with the occurrence of amyloidosis in
      subjects with rheumatoid arthritis (RA) have been based on selected series
      collected from university clinics. The purpose of the study was to obtain
      information on the true prevalence of amyloidosis and the role of amyloidosis as
      a cause of death. METHODS: The study included all 1666 subjects (480 men and 1186
      women) who had died in 1989 and had been entitled under the national sickness
      insurance scheme to receive specially reimbursed medication for RA. RESULTS:
      Amyloidosis was regarded as an immediate cause or an intervening antecedent cause
      of death in 64 cases (3.8%) and as a contributory cause of death in 33 cases
      (2%), corresponding to a prevalence of 5.8%. Amyloidosis had been diagnosed
      during life in 89 instances and was detected at autopsy in eight instances.
      Twenty-three (4.8%) of the subjects were men and 74 (6.2%) were women (P = 0.25).
      Compared with the remaining subjects in the study series, the lifespan of the
      subjects with amyloidosis was shortened by 7.7 yr. CONCLUSIONS: The prevalence of
      amyloidosis was lower than apparent from most earlier studies. Monitoring
      information derived from the Finnish sickness insurance system is a useful way of
      following trends in the occurrence of amyloidosis complicating RA.

PMID- 10402069
TI  - Detection of mycoplasmal infections in blood of patients with rheumatoid
      arthritis.
AB  - OBJECTIVE: Mycoplasmal infections are associated with several acute and chronic
      illnesses. Some mycoplasmas can enter a variety of tissues and cells, and cause
      system-wide or systemic signs and symptoms. METHODS: Patients (14 female, 14
      male) diagnosed with rheumatoid arthritis (RA) were investigated for mycoplasmal
      infections in their blood leucocytes using a forensic polymerase chain reaction
      (PCR) procedure. Amplification was performed with genus- and species-specific
      primers, and a specific radiolabelled internal probe was used for Southern
      hybridization with the PCR product. Patients were investigated for the presence
      of Mycoplasma spp., and positive cases were further tested for infections with
      the following species: M. fermentans, M. hominis, M. pneumoniae and M. penetrans.
      RESULTS: The Mycoplasma spp. sequence, which is not entirely specific for
      mycoplasmas, was amplified from the peripheral blood of 15/28 patients (53.6%)
      and specific PCR products could not be detected in 13 patients (46.4%).
      Significant differences (P < 0.001) were found between patients and positive
      healthy controls in the genus test (3/32) and in the specific tests (0/32).
      Moreover, the incidence of mycoplasmal infections was similar in female and male
      patients. Using species-specific primers, we were able to detect infections with
      M. fermentans (8/28), M. pneumoniae (5/28), M. hominis (6/28) and M. penetrans
      (1/28) in RA patients. In 36% of the patients, we observed more than one
      Mycoplasma species in the blood leucocytes. All multiple infections occurred as
      combinations of M. fermentans with other species. CONCLUSIONS: The results
      suggest that a high percentage of RA patients have systemic mycoplasmal
      infections. Systemic mycoplasmal infections may be an important cofactor in the
      pathogenesis of RA, and their role needs to be explored further.

PMID- 10402070
TI  - Measurement of matrix metalloproteinases (MMPs) and tissue inhibitor of
      metalloproteinases-1 (TIMP-1) in patients with knee osteoarthritis: comparison
      with generalized osteoarthritis.
AB  - OBJECTIVES: To compare plasma levels of matrix metalloproteinase (MMP)-3, MMP-9
      and tissue inhibitor of metalloproteinases-1 (TIMP-1) between patients with knee
      osteoarthritis and normal subjects, to investigate whether the degree of knee
      joint involvement is related to those measurements, and to compare patients with
      and without generalized osteoarthritis. METHODS: Eighty-three women with knee
      osteoarthritis (OA patients) were studied. Plasma levels of MMP-3, MMP-9 and TIMP
      1 were measured by enzyme immunoassays. Knee and hand radiographs were taken of
      all patients. The joints of the knee and hand were graded from 0 to 4 according
      to Kellgren and Lawrence criteria. All OA patients were divided into a
      generalized OA (GOA) group (n = 37) and a knee OA (KOA) group (n = 46) according
      to Doherty's criteria. MMPs and TIMP were also measured in 19 normal subjects.
      RESULTS: Plasma levels of MMP-3 and TIMP-1 were significantly higher in OA
      patients than in normal subjects. In contrast, MMP-9 was lower in OA patients
      than in normal subjects. Plasma levels of MMP-3 and MMP-9 were not influenced by
      the grade of knee OA. TIMP-1 was influenced by the grade of knee OA. Plasma
      levels of MMP-3 were significantly elevated in GOA compared to KOA. In contrast,
      there were no significant differences in plasma levels of MMP-9 and TIMP-1
      between GOA and KOA. CONCLUSION: Since the plasma level of MMP-3 in GOA was
      higher than that in KOA patients, it may be a superior indicator for whole-joint
      degeneration.

PMID- 10402071
TI  - Association of Fas/APO-1 gene polymorphism with systemic lupus erythematosus in
      Japanese.
AB  - OBJECTIVES: This study was undertaken to investigate the possible association of
      Fas gene mutation(s) or polymorphism(s) with systemic lupus erythematosus (SLE)
      in Japanese. METHODS: Screening for structural defects of the Fas gene was
      performed by using reverse transcriptase-polymerase chain reaction (RT
      PCR)/single-strand conformation polymorphism (SSCP) analysis in 57 patients with
      SLE, followed by direct sequencing for the aberrantly migrating bands. The
      frequency of Fas polymorphism was determined by sequence-specific oligonucleotide
      probe (SSOP) hybridization in 82 SLE patients and 132 ethnically matched healthy
      individuals. RESULTS: We found a novel polymorphism at nucleotide 297 (T297C),
      which was linked to Fas polymorphism at nucleotide 416 (A416G). The 297C/416G
      genotype was present in four of the 132 (3.0%) healthy controls, none of whom was
      homozygous for the genotype. The allele frequency for 297C/416G in the controls
      was 1.5%. In contrast, 10 of the 82 (12.2%) SLE patients carried the 297C/416G
      allele, including one patient homozygous for the genotype. The allele frequency
      in SLE patients was 6.7%. The 297C/416G allele was significantly frequent in SLE
      patients (P = 0.01, chi2) with a relative risk of 5.00. CONCLUSION: As the
      polymorphism 297C/416G is silent at the amino acid level, it may affect the
      expression of Fas itself or be linked to a neighbouring genetic abnormality that
      is responsible for the pathogenesis of SLE.

PMID- 10402072
TI  - Predicting 'normal' grip strength for rheumatoid arthritis patients.
AB  - OBJECTIVE: An ability to predict accurately 'normal' grip strength in rheumatoid
      arthritis (RA) patients would facilitate a more accurate assessment of the degree
      of their functional loss. This, in turn, would allow the setting of more
      meaningful treatment goals aimed at restoring hand function towards normal. This
      study carefully measures three modalities of hand grip strength and their
      correlation with multiple simple anthropometric parameters in normal subjects. We
      aim to determine which of these parameters are best correlated to grip strength,
      and whether this correlation is strong enough to allow the accurate prediction of
      what normal grip strength should be in RA patients. METHODS: In 81 normal
      subjects (67 female), power, pinch and tripod grip strength measurements were
      made using an MIE digital pinch grip analyser. These strength data were
      correlated with specific local forearm anthropometric measurements: forearm
      circumference, forearm length, forearm volume, hand circumference, hand length,
      hand volume, hand and forearm volume, and various general anthropometric
      parameters (weight, height and age). These normal subjects had been chosen so as
      to be age and sex matched with 83 RA patients (67 female) in whom the same
      strength and anthropometric parameters were assessed and correlated. In patients,
      the grip strength results were additionally correlated with two markers of
      disease activity: a modified Ritchie Articular Index local to the hand and
      forearm (mRAI) and a visual analogue scale (VAS) assessing subjective pain
      severity. RESULTS: In normal subjects, clear correlations were demonstrated
      between hand grip strengths and all specific anthropometric variables, the
      strongest correlation being with forearm and hand volume (r = 0.729 and 0.638 for
      dominant and non-dominant hands, respectively; P < 0.01 for both). The patients
      were considerably weaker than normal subjects. Markers of disease activity showed
      a negative correlation with grip strength. In normal subjects, the dominant hand
      was significantly stronger than the non-dominant hand, and on average by 8%,
      while the opposite was true in patients, who were 20% weaker on the dominant
      side. CONCLUSION: Simple anthropometric measurements, and forearm and hand volume
      in particular, would be useful at baseline for predicting 'normal' hand grip
      strength in RA patients, both in the clinical setting and in research trials
      aimed at improving grip strength and hand function.

PMID- 10402073
TI  - Oxidative stress in systemic lupus erythematosus and allied conditions with
      vascular involvement.
AB  - OBJECTIVE: To evaluate the occurrence and clinical significance of lipid
      peroxidation (oxidative stress) in rheumatic diseases characterized by vascular
      involvement. PATIENTS AND METHODS: Plasma 8-epi-PGF2alpha (oxidative stress
      marker) was measured by gas chromatography-mass spectrometry in 36 patients with
      systemic lupus erythematosus (SLE), 13 with systemic sclerosis (SSc), 13 with
      systemic vasculitis [Wegener's granulomatosis (WG), n = 4; Churg Strauss syndrome
      (CSS), n = 3; Behcet syndrome, n = 6], 12 with rheumatoid arthritis (RA) and in
      23 healthy controls (n = 23). RESULTS: 8-epi-PGF2alpha levels were higher in
      patients with SLE (P = 0.007), SSc (P < 0.001) and vasculitis (P = 0.001) than in
      controls. In SLE, a positive Coombs' test and arterial hypertension independently
      predicted 8-epi-PGF2alpha concentrations (P = 0.004 and P = 0.001, respectively).
      SLE patients not taking prednisolone showed higher 8-epi-PGF2alpha concentrations
      than SLE patients on prednisolone (P = 0.02). In the latter group, a dose
      response relationship was noted between 8-epi-PGF2alpha and steroid dosage (r =
      0.6, P = 0.0003). In WG and CSS, 8-epi-PGF2alpha concentrations correlated with
      disease activity (r = 0.8, P = 0.01) and were higher than in patients with Behcet
      disease (P = 0.003). CONCLUSIONS: Oxidative stress may be pathogenetically
      relevant in some autoimmune rheumatic diseases with vascular involvement.
      Amelioration of some clinical manifestations of these diseases may be envisaged
      by targeting lipid peroxidation with dietary or pharmacological antioxidants.

PMID- 10402074
TI  - Development and validation of a self-administered systemic sclerosis
      questionnaire (SySQ).
AB  - OBJECTIVE: To develop a self-administered systemic sclerosis questionnaire (SySQ)
      covering condition-specific functional limitation and symptoms. METHODS An
      initial item pool was generated by open patient interviews. A preliminary
      questionnaire was devised using 62 systemic sclerosis (SSc; scleroderma)
      patients. Factor analysis was used for further selection and grouping of items
      into distinct scales. The retrieved scales were tested for internal consistency
      and test-retest reliability. Spearman's rank correlation and Wilcoxon's rank sum
      test were used to examine hypothesized associations of the SySQ with various
      clinical and laboratory features. RESULTS: Altogether 32 SySQ items were selected
      and aggregated into 12 scales addressing 'pain', 'stiffness', 'coldness',
      'complex functions', 'strength of hands', 'rising', 'walking', shortness of
      breath', 'upper airway symptoms', 'eating', 'swallowing' and
      'heartburn/regurgitation'. Internal consistency ranged from 0.93 ('complex
      functions') to 0.73 ('heartburn/regurgitation'); Spearman's correlation
      coefficient for test retest reliability ranged from 0.93 to 0.73 (P < 0.001).
      While the scales were associated with corresponding functional impairments, there
      was generally less association with morphological impairments. CONCLUSION: The
      SySQ is a valid and reliable condition-specific measure in patients with SSc.
      Individually applicable scales cover a wide spectrum of general and organ
      specific SSc symptoms and functional limitation. After further validation with
      respect to its ability to measure change, it may be used in clinical, health
      services and epidemiological research.

PMID- 10402075
TI  - Concordance between abdominal scintigraphy using technetium-99m
      hexamethylpropylene amine oxime-labelled leucocytes and ileocolonoscopy in
      patients with spondyloarthropathies and without clinical evidence of inflammatory
      bowel disease.
AB  - OBJECTIVE: To study the concordance between abdominal scintigraphy using
      technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO)-labelled leucocytes
      (ASTLL) and ileocolonoscopy in patients with spondyloarthropathies (SpA) and
      without clinical evidence of inflammatory bowel disease (IBD). PATIENTS AND
      METHODS: Fifteen patients with SpA (European Spondylarthropathy Study Group 1991
      criteria) without clinical evidence of IBD were studied prospectively with ASTLL
      and ileocolonoscopy. RESULTS: This cohort consisted of seven men and eight women
      aged 31.8+/-10.5 yr (18-47) [mean age +/- S.D. (range)] and with a disease
      duration of 6.0+/-4.4 yr (0.4-15). ASTLL showed abnormal uptake in four patients.
      Ileocolonoscopy was abnormal in five patients, showing acute inflammatory lesions
      in one patient with reactive arthritis, undifferentiated chronic inflammatory
      lesions in two cases, and features indistinguishable from those of Crohn's
      disease in two cases. ASTLL was negative in two cases in which ileocolonoscopy
      showed inflammatory lesions and was positive (terminal ileum) in one case with
      normal ileocolonoscopy. The concordance between the two examinations was
      statistically significant (kappa = 0.53; P = 0.008). CONCLUSION: ASTLL may be an
      interesting tool to detect subclinical gut inflammation in patients with SpA.

PMID- 10402076
TI  - Detection of mycobacteria in joint samples from patients with arthritis using a
      genus-specific polymerase chain reaction and sequence analysis.
AB  - OBJECTIVE: Mycobacteria have been implicated in the pathogenesis of various forms
      of arthritis. The aim of this study was to examine the diagnostic potential of
      molecular biological techniques as well as to investigate the pathogenetic role
      of mycobacteria in chronic arthritis. PATIENTS AND METHODS: DNA, extracted from
      synovial fluid and synovial tissue samples from patients with mycobacterial
      septic arthritis (n = 2), seronegative spondyloarthropathies (SpA) (n = 18),
      undifferentiated arthritis (UA) (n = 21) and rheumatoid arthritis (RA) (n = 40),
      was analysed using a mycobacterial genus-specific polymerase chain reaction (PCR)
      applied to amplify mycobacterial DNA. Subsequently, automated sequencing was
      performed for speciation. Samples from patients with either non-mycobacterial
      septic arthritis, osteoarthritis (OA), crystal arthritis or joint trauma served
      as negative controls (n = 19). RESULTS: Mycobacterium tuberculosis complex and
      Mycobacterium marinum were detected in the two patients with mycobacterial septic
      arthritis. The other species identified were Mycobacterium hodleri (in one RA
      patient), Mycobacterium smegmatis (in one OA patient and two RA patients) and
      Mycobacterium austroafricanum (in one crystal arthritis patient). All other
      samples were negative. CONCLUSIONS: The results suggest that the mycobacterial
      genus-specific PCR applied on DNA extracts isolated directly from joint samples
      may be employed as an additional diagnostic tool in the case of clinical
      suspicion of a mycobacterial infection. No evidence was obtained for a
      pathogenetic role of mycobacteria in SpA, UA or RA.

PMID- 10402077
TI  - Femoral intercondylar notch measurements in osteoarthritic knees.
AB  - METHODS: We measured the dimensions of the intercondylar notch of the femur in 32
      patients with primary severe osteoarthrosis (OA) of the knee and 54 embalmed
      cadaveric knees. RESULTS: There were 56 knees with morphologically normal
      anterior cruciate ligament (ACL), 11 knees with lax or partially ruptured ACL and
      19 knees with missing ACL. The average width of the intercondylar notch in knees
      with lax and missing ACL was significantly narrower than that of knees with
      normal ACL. In addition, knees with missing ACL had a significantly smaller notch
      depth than knees with normal ACL. In medial compartment OA (56 knees), the notch
      width and depth in knees with severe OA (37 knees) were significantly smaller
      than those in normal (19 knees) and mild to moderate OA groups (19 knees).
      CONCLUSION: Our results indicate that osteophyte growth in the femoral
      intercondylar notch seems to correlate with the progression of medial compartment
      OA of the knee.

PMID- 10402078
TI  - Pregnancy outcome and family size in systemic lupus erythematosus: a case-control
      study.
AB  - OBJECTIVE: To establish pregnancy outcomes and family size in a geographically
      defined population of systemic lupus erythematosus (SLE) patients. METHODS: One
      hundred and thirty-eight SLE patients (all women satisfying at least four
      American Rheumatism Association criteria) and 276 age-matched female controls,
      from the Nottingham area, were interviewed by a single investigator. Demographic
      details and maternity histories were obtained, and the data collected were
      analysed statistically to calculate odds ratios (ORs) for risk of fetal loss
      (through miscarriage, stillbirth and abortion). Family size was also determined
      in White and non-White cases and controls. RESULTS: Women with SLE are at greater
      risk of spontaneous fetal loss than their healthy counterparts (OR = 2.21, 95% CI
      1.46-3.35, P < 0.01) and they are more likely than controls to have a surgical
      abortion (OR 2.44, 95%, CI 1.22-4.87, P = 0.01). The excess risk of both of these
      outcomes exists both before and after diagnosis of SLE. The median number of
      children in White and non-White families of cases and controls is the same, i.e.
      two. White women with SLE, however, appear less likely than controls to have more
      than two children, whereas non-White lupus women tend to retain their propensity
      to have larger families, i.e. more than two children. CONCLUSIONS: We confirm
      that lupus women who have, or later develop, SLE are at greater risk of pregnancy
      loss by spontaneous or surgical means. We have also shown that race, and the
      inherent differences in social and cultural influences, appears to be an
      important determinant of ultimate family size; White women with SLE have fewer
      children than controls, whilst non-White lupus women tend to have larger
      families.

PMID- 10402079
TI  - Intra-articular absorption and distribution of ketoprofen after topical plaster
      application and oral intake in 100 patients undergoing knee arthroscopy.
AB  - OBJECTIVE: The primary objective of this study was to assess the kinetics of
      ketoprofen in synovial fluid and intra-articular tissues in relation to plasma.
      The secondary objective was to study whether intra-articular tissues act as
      reservoirs. METHODS: The ketoprofen concentration was analysed in plasma,
      synovial fluid and intra-articular tissues after single application of a 30 mg
      plaster (n = 40), multiple applications for 5 days (n = 30) or oral intake of 50
      mg (n = 30) in patients undergoing knee arthroscopy. RESULTS: Median CMax values
      after topical application were 12.8 ng/ml in synovial fluid, 56.7 ng/g in
      synovial tissue, 349.3 ng/g in meniscus and 568.9 ng/g in cartilage. CONCLUSION:
      Topical applications of ketoprofen allow the attainment of high intra-articular
      tissue concentrations.

PMID- 10402080
TI  - Skeletal muscle mitochondrial function in polymyalgia rheumatica and in giant
      cell arteritis.
AB  - OBJECTIVE: To ascertain whether mitochondrial function is impaired in polymyalgia
      rheumatica (PMR) and giant cell arteritis (GCA). PATIENTS AND METHODS: Thirteen
      patients suffering from isolated PMR, 19 from GCA (eight with and 11 without PMR)
      and 25 healthy people submitted to orthopaedic surgery were included. Skeletal
      muscle was obtained from the quadriceps by open biopsy. Mitochondrial
      histological abnormalities were assessed on Gomori's trichrome staining and on
      cytochrome c oxidase and succinic dehydrogenase reactions. Biochemical studies
      consisted of polarographic measurement of oxidative activity using complex I, II,
      III and IV substrates, and spectrophotometric determination of individual
      enzymatic activity of such complexes. RESULTS: We did not find differences among
      groups either with respect to the percentage of histological or histochemical
      abnormalities [P = not significant (NS) for all stainings and reactions],
      oxidative capacity (P = NS for all substrates) or individual enzymatic activities
      (P = NS for all complexes). CONCLUSION: Skeletal muscle mitochondria remain
      histologically and functionally unaffected in PMR and in GCA.

PMID- 10402081
TI  - Oral carriage of staphylococci in patients with rheumatoid arthritis.
AB  - OBJECTIVE: To determine the prevalence of oral staphylococcal carriage in
      patients with rheumatoid arthritis compared with healthy controls. METHODS: Fifty
      healthy adults, 25 healthy elderly volunteers and 25 patients with rheumatoid
      arthritis were studied. An oral rinse, tongue swab and nasal swab were collected
      for culture on blood agar and a range of selective agars. Isolates of
      staphylococci were identified and antibiotic sensitivity profiles determined by
      standard methods. RESULTS: Staphylococci were isolated from the mouths of 94% of
      the healthy adults, 24% of whom carried Staphylococcus aureus. All the healthy
      elderly carried oral staphylococci and 36% were colonized with S. aureus.
      Staphylococci were isolated from 96% of the rheumatoid arthritis patients and
      this group had the highest carriage rate of S. aureus (56%), significantly higher
      than the healthy adults (P < 0.05). In all three groups, Staphylococcus
      epidermidis was isolated from the mouths of > 80%. No methicillin-resistant
      strains of S. aureus were isolated. CONCLUSION: Oral carriage of S. aureus
      appears to be common in patients with rheumatoid arthritis and studies of the
      mouth as a source of infection in septic arthritis would be merited.

PMID- 10402082
TI  - False aneurysm of the internal carotid artery in Behcet's disease: successful
      combined endovascular treatment with stent and coils.

PMID- 10402083
TI  - Combination therapy in rheumatoid arthritis: a comment.

PMID- 10402084
TI  - Use of prophylaxis for corticosteroid-induced osteoporosis in hospital practice.

PMID- 10402085
TI  - An unusual cause of blindness in Wegener's granulomatosis.

PMID- 10402086
TI  - Alfuzosin is not associated with dermatomyositis.

PMID- 10402087
TI  - EEG alpha rhythm in infants.
AB  - The 'functional topography' approach has been applied to study alpha rhythms in
      infant twins during the second half-year of life. The experimental sample
      included 154 normal infants born at 32-41 weeks of gestational age. Their
      chronological age varied from 7.4 to 12.4 months. EEG was registered during
      wakefulness under two experimental conditions: sustained visual attention and
      dark homogenous visual field. During darkness as compared with visual attention
      the sharp increase of spectral amplitudes within 5.2-9.6 Hz band was observed
      over the occipital-parietal cortex. The properties of the 5.2-9.6 Hz occipital
      rhythmic activity comply with the classical properties of alpha rhythm. The
      distinct spectral peak in 6.0-8.8 Hz band at precentral recording sites was
      observed during sustained visual attention. This rhythmic component was
      suppressed under the condition of total darkness. Arguments in favour of homology
      between the infant central rhythm and adult sensorimotor mu rhythm are advanced.
      The group mean of alpha peak frequency increased from 6.24 +/- 0.45 Hz at 8
      months to 6.78 +/- 0.38 Hz at 11 months of chronological age. The frequency of
      infant alpha rhythm depended only on the period of extrauterine experience,
      regardless of gestational age at birth. This result points to the critical role
      of early visual experience in alpha rhythm development. The group mean of the
      peak frequency of mu rhythm also increased during the second half-year of life,
      from 7.03 +/- 0.47 Hz at 8 months to 7.42 +/- 0.46 Hz at 11 months. Unlike alpha
      rhythm, the peak frequency of mu rhythm depended on duration of both intra- and
      extrauterine development. We speculate that the development of sensorimotor mu
      rhythm is influenced by somatosensory stimulation, which, in sharp contrast to
      the visual input, is present in the uterus.

PMID- 10402088
TI  - Reliability of dipole models of epileptic spikes.
AB  - OBJECTIVE: In order to validate dipole-modeling results, we compared dipole
      localizations with the distribution of intracerebral potentials occurring
      simultaneously with scalp EEG paroxysms. METHODS: Firstly, scalp EEGs were
      recorded from 11 patients. Dipole sources were estimated on averaged spikes and
      projected on 3D-MRIs. Secondly, stereoelectroencephalography (SEEG) was recorded
      from implanted electrodes with direct identification onto MRI. Simultaneously
      with SEEG, control scalp electrodes were pasted where spikes peaked during the
      first session. SEEG was averaged, triggered by the main peak of scalp spikes.
      RESULTS: SEEG activity during scalp spikes always involved several contacts. In
      13 of 14 spikes, maximal fields occurred in neocortical regions. In 4 of 5 cases
      where intracerebral activity was simple, spikes could be modeled by one source.
      In all cases where intracerebral activity was complex, spikes had to be modeled
      by several sources. The main dipole source was 11 +/- 4.2 mm from the SEEG
      contact showing the maximal intracerebral potential. Early and late dipole
      localization and SEEG fields were concordant in two thirds of cases. CONCLUSION:
      Results indicate that in our group of patients scalp spikes reflect activity in
      large neocortical areas and never activity limited to mesial structures. Dipole
      locations and time activation were confirmed most often and were more reliable
      for sources representing the main negative component than for early or late
      sources.

PMID- 10402089
TI  - Generalized absence seizures with 10-15 Hz fast discharges.
AB  - OBJECTIVE: To report clinical and EEG features in 5 adults with unusual, fast
      rhythmic discharges accompanying absence seizures. DESIGN AND METHODS: The 5
      patients presented with uncontrolled seizures. All had EEG-video monitoring with
      recorded seizures. Video seizures were reviewed and ictal as well as interictal
      epileptiform activity was analyzed. The patients were followed up after
      appropriate therapy for a minimum of 6 months. RESULTS: There were 3 women and
      two men, with a mean age of 37 years (range: 23-59). Two patients had onset of
      absence seizures in childhood, one in adolescence and two after age 20. All
      patients also had generalized tonic-clonic seizures. Ictal EEG recordings showed
      generalized spike and wave (SW) discharges of variable dominant frequencies (2.5
      6 Hz) and intermingled 10-15 Hz generalized rhythmic discharges which also
      occurred in isolation or as the dominant activity. Interictal recordings showed
      similar but shorter 2.5-6 Hz generalized SW discharges. The background activity
      was normal in 3 patients and mildly slow in two who had very frequent absence
      seizures during the recording period. Four patients became seizure free and one
      had 75% improvement on appropriate antiabsence therapy. CONCLUSIONS: The fast 10
      15 Hz rhythmic discharges that we report appear to occur mostly in adult patients
      with absence, as well as, generalized tonic-clonic seizures. They can occur in
      isolation or be embedded in more typical SW discharges accompanying typical
      absence seizures. Their presence does not imply a poor prognosis for seizure
      control.

PMID- 10402090
TI  - Asynchronous pentobarbital-induced burst suppression with corpus callosum
      hemorrhage.
AB  - OBJECTIVE: We describe the electroencephalographic (EEG) findings in a 9-year-old
      girl, who presented with generalized tonic-clonic status epilepticus requiring
      pentobarbital anesthesia, and correlate these findings with clinicoradiologic
      evidence of a ruptured AVM with hemorrhage into the body of the corpus callosum.
      METHODS: EEG analysis accompanied by clinical assessment, CT and MRI scans, and
      cerebral angiography were performed. RESULTS: With pentobarbital coma, the EEG
      showed burst suppression with prominent interhemispheric asynchrony. Suppression
      epochs >2 s in duration and with amplitude <20 microV in all channels were
      identified. In 12 min of the EEG analyzed, 6 unilateral and 20 bilateral epochs
      occurred. Of the 20 bilateral suppression epochs, interhemispheric asynchrony of
      >1 s was noted at onset for 5 epochs and at offset for one. Chi-square analysis
      revealed an equal tendency for unilateral suppressions to occur over either
      hemisphere, and for suppression in one hemisphere to begin before the other.
      CONCLUSIONS: We conclude that the corpus callosum plays a critical role in
      interhemispheric synchronization of cortical neuronal electrical activity and
      propose that: (1) normally, the corpus callosum modulates interhemispheric
      synchronization of cortical inhibition; and (2) with corpus callosal disruption,
      cortical areas are 'released' from such synchronization.

PMID- 10402091
TI  - Visual P300 latency predicts treatment response to modafinil in patients with
      narcolepsy.
AB  - OBJECTIVE: To evaluate the hypothesis that visual P300 latency (VL) predicts
      treatment response to modafinil (a new wake-promoting agent) in patients with
      narcolepsy. METHODS:  DESIGN: Comparison of responders and non-responders in a
      double-blind randomized placebo-controlled trial. SETTING: Private practice
      referral sleep disorders center. PATIENTS: Twenty one patients with narcolepsy
      (ages 17-65 years). INTERVENTIONS: Auditory and visual P300 testing using 31
      evenly spaced scalp electrodes, and baseline polysomnograms and objective and
      subjective tests of daytime sleepiness, followed by modafinil treatment for 9
      weeks. Polysomnograms and tests of sleepiness were then repeated. MAIN OUTCOME
      MEASURE: The Maintenance of Wakefulness Test (MWT). Response defined as a final
      MWT > 7.3min (normative sample mean - 3 SD), plus an increase > 1SD based on
      normative sample (3.6 min) over baseline MWT. RESULTS: Non-responders had longer
      age-adjusted 31-electrode mean VL (448.4 ms vs. 410.8 ms, P = 0.024), and larger
      auditory P300 amplitude, with no topographical P300 differences. Non-responders
      and responders did not differ on any other baseline clinical variable. Using a
      cut-off of 0.5 SE from normal regression constant, shorter age-adjusted VL
      predicted modafinil response, with specificity of 0.71 and sensitivity of 0.86.
      CONCLUSIONS: VL predicts treatment response to modafinil in patients with
      narcolepsy.

PMID- 10402092
TI  - Parvocellular and magnocellular visual processing in spinocerebellar degeneration
      and Parkinson's disease: an event-related potential study.
AB  - OBJECTIVE: We recorded event-related potentials (ERPs) using appropriate visual
      stimuli to establish a non-invasive method that separately investigates the
      parvocellular (P) and magnocellular (M) visual functions, and to evaluate the
      visual function in spinocerebellar degeneration (SCD) and Parkinson's disease
      (PD). METHODS: Eight SCD and 10 PD patients were compared with 11 age-matched
      control subjects. In the P-task, subjects were required to discriminate
      equiluminant red (frequent) and green (rare) random dots. In the M-task, moving
      random dots on a rotating cylinder (frequent) and those moving irregularly (rare)
      were discriminated. RESULTS: Control subjects showed an endogenous positive
      component at 400 ms (P400(p)) with an early exogenous negative potential
      (N160(p)) in the P-task. In the M-task, N160(m) and P400(m) were recorded. A
      deuteranope lacked P400(p) with normal P400(m). In SCD, P400(p) latency and
      N160(p)-P400(p) interval were increased with normal N160(p) latency. N160(m)
      latency was also increased while N160(m)-P400(m) interval was normal. In PD,
      there were no significant changes in the P-task but P400(m) latency was increased
      with normal N160(m) latency. CONCLUSIONS: SCD patients may have not only abnormal
      higher processing in the P-pathway but abnormal fundamental processing in the M
      pathway. PD may have impaired higher processing of the M-pathway with the
      preserved P-function.

PMID- 10402093
TI  - Motoric response inhibition in finger movement and saccadic eye movement: a
      comparative study.
AB  - OBJECTIVE: To study cortical potentials associated with suppression of intended
      motoric actions. METHODS: Electro-encephalographic activity was recorded in a
      Go/NoGo reaction time paradigm. Subjects viewed computer-generated pacing
      stimuli, which provided information concerning the time at which an imperative
      Go/NoGo signal occurred. A motoric response was required following Go stimuli
      while motoric response inhibition was required following NoGo stimuli. To examine
      whether previously reported 'Go/NoGo effects' on event related potential (ERP)
      components may be generalized across movement modalities, the present
      experimental paradigm was performed with either finger movement or saccadic eye
      movement as required motoric response. RESULTS: For both movement modalities,
      comparable differences in the morphology, amplitude and scalp topography of ERP
      components were observed between Go trials, with proper movement execution, and
      NoGo trials, with complete suppression of motoric activity. In addition, for
      either movement modality a similar 'error related negativity' (ERN) was found for
      NoGo trials in which motoric activity was present. CONCLUSIONS: The results of
      the present study suggest that cortical activity underlying the Go/NoGo
      differences in ERP components represent general cortical processing associated
      with detection and/or suppression of inappropriate response behaviour,
      independent of movement modality.

PMID- 10402094
TI  - Localization and characterization of speech arrest during transcranial magnetic
      stimulation.
AB  - OBJECTIVE: To determine the anatomic and physiologic localization of speech
      arrest induced by repetitive transcranial magnetic stimulation (rTMS), and to
      examine the relationship of speech arrest to language function. METHODS: Ten
      normal, right-handed volunteers were tested in a battery of language tasks during
      rTMS. Four underwent mapping of speech arrest on a 1 cm grid over the left
      frontal region. Compound motor action potentials from the right face and hand
      were mapped onto the same grid. Mean positions for speech arrest and muscle
      activation were identified in two subjects on 3-dimensional MRI. RESULTS: All
      subjects had lateralized arrest of spontaneous speech and reading aloud during
      rTMS over the left posterior-inferior frontal region. Writing, comprehension,
      repetition, naming, oral praxis, and singing were relatively spared (P < .05).
      Stimulation on the right during singing abolished melody in two subjects, but
      minimally affected speech production. The area of speech arrest overlay the
      caudal portion of the left precentral gyrus, congruous with the region where
      stimulation produced movement of the right face. CONCLUSIONS: The site of
      magnetic speech arrest appears to be the facial motor cortex. Its characteristics
      differ from those of classic aphasias, and include a prominent dissociation among
      different types of speech output.

PMID- 10402095
TI  - Dissociation of somatosensory and motor evoked potentials in non-comatose
      patients after head injury.
AB  - OBJECTIVES: This study was performed to evaluate the clinical value of combined
      use of somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs)
      in patients with different brain lesions after head trauma. METHODS: A total of
      64 patients with minor and moderate head injury were investigated by means of
      SEPs recorded over the parietal and frontal areas and MEPs following single-pulse
      transcranial magnetic stimulation (sTMS) and slow-rate repetitive transcranial
      magnetic stimulation (rTMS). RESULTS: In almost 50% of the patients, a
      dissociated impairment of somatosensory and motor evoked potentials was found.
      This dissociation was related to different distribution of SEP and MEP
      abnormalities in head injury subgroups. The higher threshold to sTMS and
      increased variability of the MEP amplitude during slow-rate rTMS were the most
      prominent features in patients with focal brain contusions, suggesting impairment
      of the cortical excitability. SEP abnormalities, as well as central conduction
      impairments, were more noticeable in patients with diffuse brain injury.
      CONCLUSIONS: A combined analysis of SEPs and MEPs may improve the assessment of
      cortical dysfunctions and central conduction abnormalities in non-comatose
      patients with head injury. A slow-rate rTMS may be considered as a complementary
      technique to the evaluation of the threshold in assessment of the excitability of
      the motor cortex in minor and moderate head injury.

PMID- 10402096
TI  - Trigeminal sensory input elicited by electric or magnetic stimulation interferes
      with the central motor drive to the intrinsic hand muscles.
AB  - In 6 normal subjects, unilateral supraorbital magnetic or electric stimulation
      resulted in a consistent symmetrical inhibition of the motor evoked potentials
      (MEPs) of the relaxed and preactivated first dorsal interosseus (FDI) muscle. A
      supraorbital stimulus caused a significant reduction in amplitude when the
      trigeminal CS was given 30 to 65 ms before transcranial magnetic stimulation
      (TMS). In addition, supraorbital magnetic stimulation induced a bilateral EMG
      suppression of the isometrically contracting FDI muscles, starting about 40 to 50
      ms after the magnetic stimulus. In 4 subjects, MEPs evoked by transcranial
      electric stimulation or by TMS during slight muscle contraction showed a
      comparable trigeminomotor inhibition. These findings demonstrate that
      electromagnetic stimulation of trigeminal afferents interferes with the motor
      output to the intrinsic hand muscles inducing a bilateral inhibition which is
      probably mediated by a multisynaptic subcortical network. In all 6 subjects, TMS
      over the motor hand area or the cerebellum elicited a reproducible blink reflex.
      Since the blink reflex is a sensitive indicator of trigeminal excitation, one has
      to assume that TMS is associated with a significant excitation of trigeminal
      afferents. Therefore, trigeminomotor inhibition has to be considered in all TMS
      studies that use a conditioning-test design.

PMID- 10402097
TI  - The excitation site of the accessory nerve to the magnetic stimulation--the
      relationship between the orientation of the magnetic field and the excitation
      site.
AB  - OBJECTIVE: The relationship between the accessory nerve excitation site and the
      magnetic field direction was investigated to prove whether the cranial nerve
      excitation site to the transcranial magnetic stimulation is constant or not.
      METHODS: Compound muscle action potentials (CMAPs) elicited by the transcranial
      magnetic stimulation were recorded from the trapezius muscles of 7 adult cats.
      The waveforms of CMAPs were detected before craniectomy, after craniectomy, and
      after cutting the accessory nerve at the C1, at the jugular tubercle, and at the
      jugular foramen. The optimal orientation was determined by rotating the coil
      clockwise in increments of 22.5 degrees from the rostral direction. RESULTS: The
      accessory nerve was stimulated by the magnetic stimulation at the C1, at the
      jugular tubercle or at the jubular foramen, and these excitation sites varied
      with coil orientation. The average angles of the optimal orientation of the
      magnetic coil were 77.1 degrees for C1, 122.1-263.6 degrees for the jugular
      tubercle, and 308.6-32.1 degrees for the jugular foramen. CONCLUSIONS: The
      accessory nerve excitation site varied with the orientation of the magnetic coil.
      This study suggested the possibility of a variety of the cranial nerve excitation
      sites to the transcranial magnetic stimulation.

PMID- 10402098
TI  - Intracortical inhibition after paired transcranial magnetic stimulation depends
      on the current flow direction.
AB  - OBJECTIVES: To assess whether cortico-cortical inhibition (CCI) induced by paired
      pulse transcranial magnetic stimulation (TMS) is influenced by 'preferential' or
      'non-preferential' activation of the motor cortex. METHODS: Paired-pulse TMS
      (conditioning-test paradigm with interstimulus intervals of 2-5 ms) with a round
      coil centered over the vertex was performed in 10 normal subjects using opposite
      current flow directions. The amount of CCI in the opponens pollicis and first
      dorsal interosseus muscles was determined. RESULTS: When a clockwise current was
      induced in the brain (side A of the coil uppermost) a 'preferential' activation
      of the left hemisphere (right hand muscles) was observed, but the suppression of
      the test response by the conditioning stimulus (i.e. the CCI) was significantly
      greater in the left hand muscles. The situation was reversed when an
      anticlockwise current (side B of the coil uppermost) was induced in the brain.
      These effects occurred independently of the interstimulus interval, or of the
      absolute conditioning stimulus strength. CONCLUSIONS: CCI is more effective in
      the 'non-preferentially' stimulated hemisphere, and the neural elements
      generating the indirect I3 wave are more sensitive to intracortical inhibition
      than those generating the I1 wave.

PMID- 10402099
TI  - Are motoneurons involved in muscular dystrophy?
AB  - In the early seventies, a suggestion that even in muscular dystrophy a neurogenic
      factor may be involved, was formulated. The argument which followed this
      suggestion, resulted in eventual abandoning of this concept even by its author.
      This discussion however has never been supported by any systematic study of
      motoneuron activity in muscular dystrophy. We examined an activity of motoneurons
      supplying brachial biceps in eight controls and 26 patients affected by Duchenne
      muscular dystrophy by studying single motor unit (MU) potentials picked up by
      fine wire bipolar electrodes. In the majority of patients, MU firing rates were
      higher as compared to controls and increased more rapidly with increasing force
      level. The relationship between standard deviation of interspike intervals and
      their mean value, SD(x), was shifted towards the shorter intervals and lower SDs.
      The numerical values describing these changes were correlated with severity of
      the disease. There is evidence that the break-point of the function SD(x) is
      correlated with motoneuron properties, in particular with after-hyperpolarization
      duration. In muscular dystrophy, this break-point corresponds to the shorter
      interspike intervals. We suggest that the motoneurons in muscular dystrophy are
      altered either in response to the muscle degeneration, or as a result of the
      disease itself.

PMID- 10402100
TI  - An electrophysiological study of the corticospinal projections in amyotrophic
      lateral sclerosis.
AB  - OBJECTIVE: To elucidate the pattern of corticospinal tract involvement in
      patients with amyotrophic lateral sclerosis (ALS), we analyzed motor evoked
      potential (MEP) waveforms and their relationship to the behaviour of single motor
      units using the peristimulus time histogram (PSTH) technique. METHODS:
      Abnormality of the corticospinal pathways was studied in 35 ALS patients using
      MEPs. PSTHs were also constructed to assess the effect of magnetic cortical
      stimulation on the discharge pattern of a voluntarily activated motor unit.
      RESULTS: MEPs showed a complex waveform in 10 out of 18 (56%) ALS patients with
      upper motor neuron signs (UMN). PSTHs revealed double primary peaks (PPs), PP1
      and PP2, in 6 out of 16 motor units (38%) in ALS with UMN, as compared to only 2
      out of 16 (13%) motor units in multiple sclerosis or cerebrovascular disease with
      UMN. None of the patients with lower motor neuron diseases or ALS without UMN had
      these abnormalities. The late component of complex MEPs showed a good correlation
      to PP2 (P < 0.0001), both probably being mediated by relatively preserved slower
      conducting corticospinal volleys. CONCLUSIONS: These findings suggest
      preferential involvement of the fast conducting direct corticospinal tracts,
      sparing the slower or polysynaptic projections in ALS.

PMID- 10402101
TI  - Castleman's disease associated with chronic inflammatory demyelinating
      polyradiculoneuropathy: a clinical and electrophysiological follow-up study.
AB  - Castleman's disease (CD), or angiofollicular lymph node hyperplasia, is a rare
      lymphoproliferative disorder that can be associated with peripheral neuropathy.
      We report the long-term follow-up of a patient with a chronic inflammatory
      demyelinating polyradiculoneuropathy complicating the mediastinal form of classic
      CD who improved notably with immunosuppressive therapy. Our findings suggest that
      serial electrophysiological studies may be useful for monitoring treatment
      efficacy.

PMID- 10402103
TI  - Within patient variability of lower extremity muscle responses to transcranial
      electrical stimulation with pulse trains in aortic surgery.
AB  - Intraoperative recording of myogenic motor responses evoked by transcranial
      electrical stimulation is a method of controlling the integrity of the motor
      pathways during clamping of the aorta. It is important to know the within patient
      variability of the transcranial motor evoked potential (tcMEP), before changes
      within the variability range are interpreted as abnormal during the period of
      aortic cross clamping. Lower limb muscle responses were obtained in 11 patients,
      following transcranial electrical stimulation with pulse trains, of 4, 6 and 8
      pulses. Under the conditions of partial neuromuscular blockade and a stable low
      dose propofol/fentanyl/nitrous oxide anaesthetic state, this study shows that
      multipulse transcranial electrical stimulation reliably produces muscle responses
      of the lower limb in all patients tested with a coefficient of variation (CV) of
      around 20%. Eight pulses in the stimulation train produce neurophysiological
      facilitation that exceeds a 4 pulse train in terms of area under the curve (AUC)
      and response duration. The use of multipulse stimulation rather than double or
      single pulse stimulation is recommended in order to increase the clinical
      efficacy of tcMEP monitoring in aortic surgery.

PMID- 10402102
TI  - Effects of the amplitude threshold on the separability of neuropathic and
      myopathic from normal EMG using parameters of the turns/amplitude analysis.
AB  - OBJECTIVE: In this study, the relationship between the amplitude threshold used
      for the determination of the turns of the electromyographic (EMG) interference
      pattern and the parameters of the turns/amplitude analysis was examined. It was
      investigated whether the discrimination of myopathic and neuropathic from normal
      muscles could be optimized by an appropriate amplitude threshold. METHODS: The
      interference patterns of the tibialis anterior muscle of 15 patients with
      myopathies, 30 patients with neuropathies and 56 controls were recorded, using
      concentric needle electrodes. A computer program performed the Willison analysis,
      systematically varying the amplitude threshold between 10 microV and 200 microV.
      RESULTS: Amplitudes as well as the number of turns per second were non-linearly
      related to the amplitude threshold. The reduction of the amplitude threshold to
      30 microV resulted in a clearly better separation of the distributions of the
      number of turns of neuropathic, myopathic and normal EMG, compared to the
      traditional threshold value of 100 microV. The distributions of amplitude values,
      however, were not affected. The distance between the turns parameter
      distributions of neuropathic patients and controls and between the distributions
      of myopathic patients and controls, expressed by the Kolmogoroff-Smirnov
      distance, had a maximum at 30 microV. CONCLUSIONS: For the turns/amplitude
      analysis of the tibialis anterior muscle an amplitude threshold of 30 microV
      should be selected.

PMID- 10402104
TI  - The polar average reference effect: a bias in estimating the head surface
      integral in EEG recording.
AB  - A reference-independent measure of potential is helpful for studying the
      multichannel EEG. The potentials integrated over the surface of the body is a
      constant, i.e. inactive across time, regardless of the activity and distribution
      of brain electric sources. Therefore, the average reference, the mean of all
      recording channels at each time point, may be used to approximate an inactive
      reference. However, this approximation is valid only with accurate spatial
      sampling of the scalp fields. Accurate sampling requires a sufficient electrode
      density and full coverage of the head's surface. If electrodes are concentrated
      in one region of the surface, such as just on the scalp, then the average is
      biased toward that region. Differences from the average will then be smaller in
      the center of the region, e.g. the vertex, than at the periphery. In this paper,
      we illustrate how this polar average reference effect (PARE) may be created by
      both the inadequate density and the uneven distribution of EEG electrodes. The
      greater the coverage of the surface of the volume conductor, the more the average
      reference approaches the ideal inactive reference.

PMID- 10402105
TI  - GPIIbIIIa inhibitors as adjunctive therapy in acute myocardial infarction.
AB  - Thrombolytic therapy has proved useful in the treatment of acute myocardial
      infarction but is frequently associated with limited vessel reperfusion and early
      reocclusion. Local platelet aggregation and activation play a role in these
      pathological processes, explaining the benefit of aspirin, a weak antiplatelet
      agent. Recent interest has turned to GPIIbIIIa antagonists, a class of potent
      inhibitors of platelet aggregation. Their concomitant use with fibrinolytics, in
      rescue and primary angioplasty for acute myocardial infarction treatment is
      explored. Efficacy and safety issues are addressed and the potential pivotal role
      of these agents in the treatment of acute myocardial infarction is discussed.

PMID- 10402106
TI  - Statin + fibrate combination therapy fluvastatin with bezafibrate or ciprofibrate
      in high risk patients with vascular disease.
AB  - We evaluated the use of combination therapy (ciprofibrate 100 mg or bezafibrate
      400 mg plus fluvastatin 40 mg) in 23 patients (n = 13 in the ciprofibrate group)
      with established cardiovascular disease. Both treatments achieved a significant
      (P< or =0.01) decrease in the total cholesterol (TC) (32 and 21%), triglycerides
      (TG) (53 and 46%) and low-density lipoprotein (LDL) (36 and 26%) levels and the
      TC/high-density lipoprotein (HDL) (42 and 31%) and LDL/HDL (46 and 35%) ratios.
      HDL levels were increased (19% for both treatment groups), but this rise only
      achieved significance (P=0.01) in the ciprofibrate group. Although the two
      patient groups were not strictly matched, the reduction in serum TC and LDL
      levels was greater with ciprofibrate (32 and 36%, respectively; P< or =0.001)
      than with bezafibrate (21 and 26%, respectively; P< or =0.01). There was a
      significant reduction in plasma fibrinogen levels (36.4 and 13.5% in the
      ciprofibrate and bezafibrate group, respectively). None of the patients reported
      myalgia or had abnormal creatine kinase activity or liver function tests.
      Combination therapy is worth considering in high-risk patients because of the
      advantages associated with this option. Combination therapy is competitively
      priced when compared with high doses of statins. An end-point-based trial is
      needed.

PMID- 10402107
TI  - The relationship between diastolic function of the left ventricle and QT
      dispersion in patients with myocardial infarction.
AB  - Lack of synchronicity concerns not only the electrical but also the mechanical
      function of the left ventricle and causes impaired ventricular filling. To our
      knowledge a direct association between electrical dispersion and impairment of
      left ventricular filling has not been reported. The study group comprised 71
      patients with myocardial infarction. Echocardiographic Doppler studies and QT
      dispersion measurements from standard 12-lead electrocardiograms were performed
      during the second week of hospitalization. The study population was divided into
      high, intermediate and low QT dispersion groups. Differences in the left
      ventricular filling parameters between high and low QT dispersion groups were
      assessed. Patients with high QT dispersion had larger end-diastolic volume (134+/
      31 vs. 107+/-19 ml; P=0.049) and tended to have shorter E-wave deceleration time
      (155+/-18 vs. 175+/-20 ms; P=0.056) compared with patients with low QT
      dispersion. There was a negative correlation between E-wave deceleration time and
      QT dispersion (r=-0.248; P=0.05). We conclude that greater dispersion of
      repolarization is accompanied by changes in the left ventricular diastolic
      geometry and more 'restrictive' filling. The hypothesis that left ventricular
      filling abnormalities are caused by increased electrical dispersion deserves
      further study, especially under controlled, experimental conditions.

PMID- 10402109
TI  - Clinical and angiographic features in patients under 35 years with a first Q wave
      acute myocardial infarction.
AB  - Sixty patients less than 35 years with a first Q wave acute myocardial infarction
      were prospectively studied to evaluate their features, risk factors and evidence
      of any viral infection. Typical chest pain was present in 98.3% with Q waves and
      ST segment elevation in all. None had hypotension or cardiogenic shock. Smoking
      was the most common risk factor (81.7%). Mean total cholesterol was 5.74 (+/
      1.42) mmol/l. History of a viral illness was present in 28.3%, severe emotional
      stress in 21.7% and exhausting physical activity in 18.3%. Mean left ventricular
      diastolic and end systolic volumes were increased (90.11+/-22.5 ml/m2) and
      (46.62+/-20.46 ml/m2), respectively. The ejection fraction was depressed (49.71+/
      1.6%). Triple vessel disease was seen only in 6.8 and 26.7% had insignificant or
      no coronary artery disease. Left anterior descending artery was most frequently
      involved (66%). None had left main involvement. Coronary ectasia was present in
      11.7%, intracoronary thrombus in 28.3% and 40% had collaterals. Patients with no
      significant disease had no diabetes, a smaller number had a raised total
      cholesterol or smoked and had a lower ejection fraction. Patients from the Indian
      subcontinent who had fewer conventional risk factors, had more severe disease
      than those from the Arab world suggesting that other etiological factors need
      investigation.

PMID- 10402108
TI  - Differential coronary microvascular function in patients with left ventricular
      dysfunction of unknown cause--implication for possible mechanism of myocardial
      ischemia in early stage of cardiomyopathy.
AB  - To evaluate whether or not coronary microvascular dysfunction is associated with
      exercise-induced myocardial ischemia in left ventricular dysfunction of unknown
      cause, both the treadmill exercise test (TET) and coronary hemodynamics were
      studied in 20 patients with impaired left ventricular ejection fraction (<50% by
      radionuclide ventriculogram), normal cardiac size, normal coronary angiogram and
      no evidence of clinical heart failure. Ten subjects with atypical chest pain were
      studied as the control. Coronary hemodynamics were studied both at baseline and
      after dipyridamole infusion (0.56mg/kg, i.v. for 4'). There was no difference in
      age, gender, blood pressure, baseline great cardiac venous flow (GCVF) and
      coronary vascular resistance between ten patients with a positive TET and the
      other ten with a negative TET. At baseline, coronary sinus oxygen concentration
      was increased and myocardial oxygen consumption reduced in patients with a
      positive TET compared with those with negative a TET. After dipyridamole
      infusion, maximum GCVF (102+/-47 vs. 144+/-31 ml/min, P=0.027) and coronary flow
      reserve (2.31+/-0.49 vs. 3.00+/-0.61, P=0.012) were significantly reduced and
      minimum coronary vascular resistance was higher (1.00+/-0.42 vs. 0.63+/-0.12
      mmHg/ml/min, P=0.016) in patients with a positive TET than in those with a
      negative TET. At follow-up, 40% of patients with a positive TET and 10% of those
      with a negative TET developed clinical heart failure with a dilated left
      ventricle during a period of 45 months. Thus, coronary microvascular function is
      heterogeneous in patients with left ventricular dysfunction of unknown cause. In
      some of them, coronary microvascular dysfunction could be related to the presence
      of exercise-induced myocardial ischemia, suggesting that similar pathophysiology
      underlies the early stage of dilated cardiomyopathy and syndrome X.

PMID- 10402110
TI  - Effect of amiodarone and sotalol on the defibrillation threshold in comparison to
      patients without antiarrhythmic drug treatment.
AB  - AIM OF THE STUDY: It is generally accepted that chronic therapy with
      antiarrhythmic drugs might increase the defibrillation threshold at implantation
      of an implantable cardioverter defibrillator. A recently published animal study
      showed a minor effect of the class 1 antiarrhythmic drug lidocaine on the
      defibrillation threshold if biphasic shocks were used. METHODS AND RESULTS: We
      therefore performed a retrospective analysis in 89 patients who received an ICD
      capable of monophasic (n=18) or biphasic (n=71) shocks with a transvenous lead
      system. In all patients the defibrillation threshold was determined according to
      the same step down protocol. In the 18 patients with a monophasic device the
      effects of chronic therapy with amiodarone (n=7) on the defibrillation threshold
      were evaluated in comparison to a group without antiarrhythmic treatment (n=11).
      In those patients receiving a biphasic device the effects of chronic therapy with
      amiodarone (n=29), sotalol (n=20) or no antiarrhythmic medication (n=22) on the
      defibrillation threshold were evaluated. The groups receiving a monophasic device
      did not differ in respect to age, sex, underlying cardiac disease, clinical
      arrhythmia (VT/VF), clinical functional status, left ventricular ejection
      fraction and the number of patients with additional subcutaneous electrodes.
      These parameters as well as the type of implanted device were not different
      between patient groups receiving a biphasic device. Patients on chronic
      amiodarone therapy receiving a monophasic device had a significantly higher
      defibrillation threshold (29.1 +/- 8.8 J) than patients without antiarrhythmic
      treatment (19.1 +/- 5.1 J, P = 0.021). The groups did not differ significantly in
      respect to the impedance measured at the shocking lead (P = 0.13). In three
      patients on chronic amiodarone an epicardiac lead system had to be implanted due
      to an inadequate monophasic defibrillation threshold compared to no patient
      without antiarrhythmic drug treatment (P = 0.043). In the patients with a
      biphasic device the intraoperative defibrillation threshold was not significantly
      different between the three study groups (P = 0.44). No patient received an
      epicardiac lead system. The defibrillation threshold in the amiodarone group was
      15.3 +/- 7.3 J, in the sotalol group 14.4 +/- 7.2 J and in the patients without
      antiarrhythmic drug treatment 17 +/- 6.1 J. As well, no significant difference
      was seen between the groups in respect of the impedance of the high voltage
      electrode (P = 0.2). CONCLUSION: With the use of a biphasic device in combination
      with a transvenous lead system the intraoperative defibrillation threshold is not
      significantly different between patients on chronic amiodarone in comparison to
      patients without antiarrhythmic drug treatment or patients on chronic oral
      sotalol. This is in contrast to our findings with a monophasic device.

PMID- 10402111
TI  - Exercise electrocardiography test in patients with aortic stenosis. Differential
      features from that of coronary artery disease.
AB  - BACKGROUND AND AIM OF THE STUDY: Studies that have been conducted with an
      exercise test in patients with aortic stenosis (AS) have demonstrated that
      results of an exercise test can mimic that of coronary artery disease (CAD). The
      objective of our study was to investigate if there was any differential
      feature(s) of an exercise test in patients with AS compared to those with CAD.
      METHODS: We prospectively studied 42 patients with AS (AS group, age 37 +/- 23,
      range 8-75) with an averaged maximal gradient of 42 +/- 19 mmHg (range 26-95).
      All patients had undergone a coronary angiography within 1 week of the exercise
      test and none had CAD. Another 100 patients with CAD, diagnosis proven with
      coronary angiography, comprised our second group for the comparison (CAD group).
      Cornell protocol was used in all patients. RESULTS: ST-segment depression was
      observed in all patients (160 +/- 25 microV in AS group and 170 +/- 20 microV in
      CAD group, P>0.05). Thirty-four (81%) patients in AS group and 88 (88%) patients
      in CAD group exceeded the classical threshold for the test positivity (P>0.05).
      ST/HR slopes derived from heart rate adjustment to ST-segment level did not
      differ between the study groups (3.2 +/- 2.3 and 3.7 +/- 2.2 microV/beat/min, in
      AS and CAD groups, respectively, P>0.05). Recovery-phase patterns of ST-segment
      in heart rate domain were quite different between AS and CAD (clockwise loop: 86%
      vs. 0%; counterclockwise loop: 9% vs. 88% in AS group and CAD group,
      respectively, both P<0.0001). Percentage of intermediate loop was 5% in AS group
      and 12% in CAD group (P>0.05). CONCLUSIONS: Our study demonstrated that patients
      with AS could be distinguished from those with CAD with the method of rate
      recovery loop analysis.

PMID- 10402112
TI  - Prognostic significance of diabetes in acute myocardial infarction. Are the
      differences linked to female gender?
AB  - A prospective study of acute myocardial infarction was carried out in 1239
      patients in order to assess both the prognostic significance of diabetes mellitus
      and the clinical characteristics associated with age and gender. Diabetes
      mellitus (DM) was found in 386 cases, often associated with old age, female
      gender, and more prevalent history of angina, heart failure, and hypertension. DM
      patients were admitted later and they were less likely to receive thrombolytic
      therapy, 47.9 vs. 58.1% (P<0.001). Complications more often associated with DM
      were: heart failure, 45 vs. 24.5% (P<0.01), and early, in-hospital and 1-year
      mortalities, 7.2 vs. 3.9% (P<0.05), 17.6 vs. 9.1% (P<0.001), and 29.2 vs. 16.2%
      (P<0.001), respectively. Compared with diabetic men, diabetic women were older
      and had a more prevalent history of hypertension and congestive heart failure.
      Diabetic women also had a higher rate of heart failure during hospitalisation,
      and of mortality, than diabetic men: early: 11.7 vs. 4.5% (P<0.01); in-hospital:
      29.6 vs. 10.3% (P<0.001); and 1-year: 42.7 vs. 21.1% (P>0.001). DM was not
      selected by the multivariate analysis as a variable with independent prognostic
      value for mortality. In separate multivariate analysis for diabetic and non
      diabetic patients, female gender had independent prognostic value for mortality
      only in the case of the diabetic population.

PMID- 10402113
TI  - Chronic haemoptysis as delayed complication of ventricular aneurysmectomy.
AB  - Two patients developed a ventriculo-pulmonary fistula several years after
      original resection of a left ventricular aneurysm. Both presented with chronic
      mild haemoptysis. In the first case mild haemoptysis lasted nearly 19 months, and
      despite a battery of non invasive and invasive investigations, diagnosis was
      ultimately made via exploratory thoracotomy. In the second case mild haemoptysis
      lasted four months and finally manifested as a large haemoptysis. Diagnosis was
      made preoperatively using echocardiography. We recommend the use of
      echocardiography when haemoptysis occurs in a patient with a previous history of
      ventricular aneurysm repair.

PMID- 10402114
TI  - Extrauterine pelvic arteriovenous malformation mimicking the clinical
      presentation of structural heart disease.
AB  - A case is reported of an extrauterine pelvic arteriovenous malformation involving
      branches of the internal iliac arteries. Cardiomegaly and a rough cardiac murmur
      were the clinical presentations mimicking a structural heart disease. A
      continuous bruit could only be detected by the diaphragm of the stethoscope
      applied firmly to the left lower abdomen. Multiple blood samplings from inferior
      vena cava, and iliac and femoral veins for determination of oxygen saturation may
      be necessary for suspected cases. However, selective arteriography remains the
      best method for diagnosing the presence, extent, and multiplicity of the lesions
      before surgery or percutaneous arterial embolization.

PMID- 10402115
TI  - Variant of the beta3-adrenergic receptor gene and coronary atherosclerosis in
      Japanese subjects.
AB  - In the present study, we assessed the significance of the Trp64Arg mutation in
      the beta3-adrenergic receptor gene in 428 Japanese subjects, including 198
      subjects who underwent coronary angiography for possible ischemic heart diseases
      (IHD group) and 230 non-IHD subjects (control group). We conclude that the
      Trp64Arg polymorphism of the beta3-adrenergic receptor gene did not appear to
      have any pathophysiological significance in Japanese subjects.

PMID- 10402116
TI  - Recurrent meningitis in the pediatric patient--the otolaryngologist's role.
AB  - OBJECTIVE: To assess the etiology of recurrent meningitis in the pediatric
      patient. DESIGN: Retrospective case series and literature review. SETTING:
      Tertiary-care pediatric hospital. PATIENTS: Children (< 17-years-old) with
      recurrent meningitis, treated at Texas Children's Hospital (TCH) between 1984 and
      1995. RESULTS: A review of 463 cases of bacterial meningitis over an 11 year
      period revealed six children aged 3 months to 15 years with the diagnosis of
      recurrent meningitis. The patient's age, number of episodes of meningitis,
      diagnostic investigations performed and etiologies of recurrent meningitis were
      recorded. Fifteen episodes of meningitis were identified in these six patients;
      Streptococcus pneumoniae represented the bacteriology in 73% of the cases. Two
      patients were diagnosed with temporal bone abnormalities, two children with
      immunological deficiencies and no underlying etiology for the recurrent
      meningitis was identified in the remaining two patients. In this series, one
      third of patients had an otolaryngologic etiology for their recurrent meningitis.
      These six patients, along with a review of the recent literature, will highlight
      the need for otolaryngological assessment and the importance of considering
      immunological investigations when managing recurrent meningitis in the pediatric
      patient. CONCLUSION: We propose that children with recurrent meningitis of
      unknown etiology undergo: (1) an audiological evaluation; (2) a CT scan of the
      temporal bones, skull base and paranasal sinuses; and (3) an immunological
      evaluation.

PMID- 10402117
TI  - Ewing's sarcoma of the head and neck in children.
AB  - OBJECTIVE: The purpose of this paper was to review our experience with Ewing's
      sarcoma of the head and neck in children. DESIGN: Retrospective chart review.
      SETTING: The Hospital for Sick Children, Toronto, Ont., Canada. METHODS: Between
      1986 and 1996, 70 cases of Ewing's sarcoma were identified. The medical records,
      roentgenographic and pathology reports were reviewed retrospectively. The gender,
      age of presentation, location and clinical presentation of the tumor were noted
      in the cases involving the head and neck. The treatment and follow-up of these
      patients were recorded. RESULTS: Of the 70 cases of Ewing's, five involved the
      head and neck (7.1%). The age of presentation ranged from 7.5 to 14 years. An
      enlarging mass in the mandible was the mode of presentation in three of the five
      children. Two patients had metastases at initial presentation. All patients
      received combination treatment regimens with chemotherapy initially, followed by
      adjuvant surgery and/or radiation. Follow-up ranged from 2 to 11 years. Three of
      five patients died of metastatic disease. Two are alive and well with no evidence
      of disease. CONCLUSIONS: Ewing's sarcoma occurs infrequently in the head and neck
      in children. An enlarging mass in the mandible is the most frequent mode of
      presentation. This tumor is treated systemically with high dose chemotherapy and
      locally with surgical excision where possible. In lesions that are initially
      unresectable and/or show a poor response to chemotherapy, radiation is used for
      local control. A good prognosis can be expected if the disease has not
      metastasized.

PMID- 10402118
TI  - Chronic suppurative otitis media: prevalence and practices among rural South
      Indian children.
AB  - In order to determine the prevalence of chronic suppurative otitis media (CSOM)
      in rural South Indian children, a cross-sectional survey was conducted among 914
      children (484 boys and 430 girls) from four primary schools and 12 nurseries
      (balwadis; preschool), of adjacent villages of North Arcot District of Tamil Nadu
      state. The preschool children were aged 2-5 years, while the ages of the primary
      school children ranged from 6 to 10 years. The overall prevalence rate of CSOM
      was found to be 6%. The disease was equally prevalent in preschool children
      (5.7%) and primary school children (6.2%) (P = 0.94). Cholesteatomatous ear
      disease was observed in 1.2% of children, those of the older age group having a
      slightly higher prevalence rate (1.5%) than the younger age group (0.7%).
      Parental beliefs and existing practices with respect to the disease are also
      presented.

PMID- 10402119
TI  - Evaluation and management of benign, non-congenital tongue masses in children.
AB  - Lingual tumors are rare, primarily benign, lesions in the pediatric population.
      Congenital lesions, such as hemangiomas, lymphatic malformations, dermoids,
      hamartomas and thyroglossal ducts cysts, are seen more commonly. Primary, non
      congenital lingual neoplasms are less common in children. We present three
      patients with benign lingual neoplasms. Evaluation, management, pathology and
      follow-up are discussed.

PMID- 10402120
TI  - Congenital tracheoesophageal fistula without esophageal atresia.
AB  - The authors report a series of eight cases of isolated tracheoesophageal fistula
      without esophageal atresia (or an H type fistula), treated in three pediatric ENT
      departments. This is a rare malformation whose diagnosis requires investigation
      for associated anomalies. The clinical signs are mainly respiratory but also
      digestive and the symptomatology can be severe. The diagnosis can be made with a
      barium swallow combined with cineradiography, but a tracheoesophageal endoscopy
      remains the investigation of choice. The treatment is surgical. In most cases,
      the fistula is accessible by a right or left cervicotomy, depending on the
      surgeon's practice, with a much lower postoperative morbidity as compared to a
      thoracotomy. The postoperative management was straightforward in most of our
      cases. We discuss the role of gastro-esophageal reflux with respect to
      postoperative morbidity as well as systematic treatment for reflux peri
      operatively. The pros and cons of the various surgical approaches are also
      discussed.

PMID- 10402121
TI  - Risk factors of otitis media with effusion during infancy.
AB  - Associations of possible risk factors with prevalence of otitis media with
      effusion (OME) were prospectively studied in a cohort of 250 infants, aged 0-2
      years. In order to determine OME, otoscopy and tympanometry were performed at 3
      monthly intervals beginning at term date. Eighteen epidemiologically relevant
      features were inventoried by means of standardized questionnaires. Multivariate
      analysis controlled for possible confounding factors. Prevalence of OME was most
      strongly associated with age (P-value < 0.001). Other factors significantly
      associated with the prevalence of OME (P-value < 0.05) were gestational age,
      birth weight, breastfeeding, day-care attendance, number of siblings, season, and
      parent-reported ear infection, hearing loss, mouth breathing and common cold. No
      significance was found for gender, date of birth, passive smoking, family history
      of otitis media, parental socio-economic status and histories of snoring and
      consultation of a physician. IN CONCLUSION: both intrinsic and extrinsic factors
      appear to play an important role in the prevalence of OME. Some of the risk
      factors appeared to be time-dependent.

PMID- 10402122
TI  - Neuralgic amyotrophy presenting with bilateral vocal cord paralysis in a child: a
      case report.
AB  - Acute stridor and bilateral vocal cord paralysis is not uncommon in the neonate
      but is unusual in the older child. We report the first case of bilateral vocal
      cord paralysis secondary to neuralgic amyotrophy, a peripheral polyneuropathy, in
      a 5-year-old child. An extensive workup revealed a paralyzed right hemidiaphragm,
      arm weakness and an EMG pattern consistent with neuralgic amyotrophy. Neuralgic
      amyotrophy is an uncommon disorder in pediatric patients which may involve
      cranial and peripheral nerves including the phrenic nerves and rarely the
      recurrent laryngeal nerves. We propose that the diagnosis be considered in
      children who present with bilateral vocal cord paralysis and other associated
      neurologic findings.

PMID- 10402123
TI  - Superolateral subperiosteal orbital abscess complicating sinusitis in a child.
AB  - Orbital complications of sinusitis in children generally occur as a consequence
      of ethmoid sinusitis due to preferential spread across the lamina papyracea. A
      case is presented of a subperiosteal abscess (SPA) in the superolateral orbital
      wall complicating frontal sinusitis in a 6-year-old female. Congenital bony
      dehiscences exist in the lateral floor of the frontal sinus, which may allow
      direct spread of infection through to that region. While the general principles
      of managing orbital complications of sinusitis are applicable, the surgical
      approach for a SPA complicating frontal sinusitis differs from that of the
      typical medial SPA, and the clinician should be mindful of this variation when
      planning surgical treatment.

PMID- 10402124
TI  - Successful long-term endoscopic closure of a recurrent tracheoesophageal fistula
      with fibrin glue in a child.
AB  - We present an unusual case of recurrent tracheoesophageal fistula after primary
      surgical repair of congenital esophageal atresia. Traditionally, this disorder
      has required open-surgical correction, but successful endoscopic closure of these
      fistulas has been reported. This case report describes our experience using
      fibrin glue, applied endoscopically in a 6-year-old child, with encouraging long
      term results 4 years after treatment.

PMID- 10402125
TI  - Spurious diagnosis of a cervical mass due to a laryngeal mask airway.
AB  - The laryngeal mask airway (LMA) has become a popular alternative to endotracheal
      intubation. We report a case in which appropriate LMA placement resulted in an
      unrecognized neck mass and subsequent erroneous diagnosis of cervical
      lymphadenopathy. Otolaryngologists should be aware that the LMA may result in
      alterations of neck anatomy.

PMID- 10402126
TI  - Dystocia and caesarean sections: the importance of duration and good judgement.

PMID- 10402127
TI  - The science and art of angular limb deformity correction.

PMID- 10402128
TI  - New treatment technologies demand rigorous evaluation.

PMID- 10402129
TI  - Ultrasonographic anatomy of the accessory ligament of the superficial digital
      flexor tendon in horses.
AB  - The ultrasonographic anatomy of the accessory ligament of the superficial digital
      flexor tendon (AL-SDFT) in the horse is presented. Comparison between anatomical
      sections of isolated limbs and ultrasound scans of the distal antebrachium in
      sound horses enabled the authors to establish the normal reference
      ultrasonographic images of this structure. The AL-SDFT inserts 7-14 cm above the
      antebrachiocarpal joint on the palmaromedial aspect of the radius.
      Ultrasonographically it appears as an uniformly echogenic structure located deep
      to the median artery. The knowledge of ultrasonographic anatomy is essential for
      identification of abnormal images and assessment of AL-SDFT damage.

PMID- 10402130
TI  - Physeal growth retardation leads to correction of intracarpal angular deviations
      as well as physeal valgus deformity.
AB  - Retrospective analysis of the radiographs of horses with carpal valgus, presented
      to the Iowa State University Veterinary Teaching Hospital from 1987-1996, were
      used to compare 2 methods of geometric analysis for finding the total angle of
      deviation. The pivot point angle method and the individual joint angle method
      were found to be comparable for determining the total angle of deviation. The
      individual joint angle method was used to analyse individual carpal joint angles
      and physis angle in joints with carpal valgus, as well as the changes that
      occurred in response to surgical correction. Multiple joint involvement was
      common with carpal valgus; and surgical manipulation caused a change in angle at
      all joints. Use of the individual joint angle method for evaluating carpal valgus
      may aid the surgeon in making a more accurate prognosis.

PMID- 10402131
TI  - Comparison of bacteriology and cytology of tracheal fluid samples collected by
      percutaneous transtracheal aspiration or via an endoscope using a plugged,
      guarded catheter.
AB  - Cytological and bacteriological results from tracheal fluid samples obtained
      endoscopically using a telescoping, plugged catheter (TPC) were compared with
      results from samples collected by percutaneous transtracheal aspiration (PTA).
      The TPC technique and PTA were performed in random order on 9 healthy
      Standardbred geldings. Three weeks later the procedures were performed on the
      same horses in the reverse order. The presence of oropharyngeal contamination was
      determined by quantitative bacteriology and quantification of squamous epithelial
      cells (SEC)/ml sample. The relative numbers of macrophages, haemosiderophages,
      giant cells, neutrophils, lymphocytes and eosinophils did not differ between
      techniques. The number of SEC/ml was greater in samples with more colony forming
      units/ml indicating that quantification of SEC provides evidence of the probable
      degree of oropharyngeal contamination. Fifteen out of the 18 TPC samples were
      free of contamination, indicating that the TPC can provide adequate samples for
      bacteriology. The results also indicate that tracheoscopy sometimes results in
      oropharyngeal contamination of the trachea, but that this does not affect the
      results of the TPC sample.

PMID- 10402133
TI  - An evaluation of the haemostatic suture in hysterotomy closure in the mare.
AB  - This study was designed to evaluate the haemostatic suture as a means of
      preventing haemorrhage from the hysterotomy in mares after caesarean section. At
      2 university hospitals 1982-1994, 48 mares had caesarean section for dystocia, 10
      as an elective, and 8 mares concurrently with colic surgery. The haemostatic
      suture was used in 31 of 66 mares (47%) and surgery period was significantly
      (P<0.05) shorter when it was not applied. Anaemia (PCV<30%) was recorded in 13
      (22%) of 58 mares, excluding the colic group, and the haemostatic suture did not
      after this proportion of mares that had anaemia. Anaemia was 5 times more
      probable following caesarean section than vaginal delivery, evidence that
      bleeding from the hysterotomy is a serious and common complication of caesarean
      section in mares. Severe uterine haemorrhage was recorded in 3 mares that had an
      haemostatic suture (10%) and in 2 mares that did not (6%). The latter two mares
      died of haemorrhage. The suture, therefore did not eliminate post operative
      anaemia and severe uterine haemorrhage. If omitted, the hysterotomy should be
      closed with a full thickness pattern that is sufficiently tight to compress
      vessels in the uterine wall.

PMID- 10402132
TI  - Caesarean section and other methods for assisted delivery: comparison of effects
      on mare mortality and complications.
AB  - Data from 116 mares that had caesarean section or vaginal delivery at 2
      university hospitals were analysed in 5 groups, as follows: dystocia corrected by
      caesarean section, Group DCS (n = 48); elective caesarean section, Group ECS (n =
      10); caesarean section concurrently with colic surgery, Group CCS (n = 8);
      assisted vaginal delivery, Group AVD (n = 22); and controlled vaginal delivery
      under general anaesthesia, Group CVD (n = 28). Survival rate in all mares that
      had caesarean section, excluding Group CCS, was 88% (51/58). All mares in Group
      ECS survived and Group CCS had the lowest survival rate (38%). In 98 mares with
      dystocia, Groups DCS (15%) and AVD (14%) had significantly lower (P<0.05)
      mortality rates than Group CVD (29%). There were no differences between groups
      for duration of dystocia. The placenta was retained in 75 (65%) of 116 mares, and
      for a longer period following elective caesarean section than following assisted
      vaginal delivery. Multiple complications (> or = 3) were recorded in 6 mares in
      Group CVD but not in the other groups. Of the 102 foals delivered from 98 mares
      with dystocia, 11 (11%) were alive at delivery and 5 (5%) survived to discharge.
      Survival rate for foals was 38% in Group CCS, and 90% in Group ECS. Under
      conditions similar to those in this study, it is calculated that caesarean
      section is preferable to CVD if dystocia is protracted and great difficulty and
      trauma is involved, even if CVD allows delivery of the foal.

PMID- 10402135
TI  - Endoscopic examination of the tarsal sheath of the lateral digital flexor tendon
      in horses.
AB  - This study was designed to develop a reliable technique for endoscopic
      examination of the tarsal sheath of the lateral digital flexor tendon of horses.
      The anatomy of the tendon sheath and associated structures was studied in detail
      in cadavers before determining portals for the insertion of an arthroscope into
      the sheath. Approaches into the sheath through the proximal pouch and through the
      flexor retinaculum, at the level of the sustentaculum tali, were performed and
      compared in cadavers. The proximal pouch portal permitted visualisation only of
      the proximal half of the sheath, while the approach through the retinaculum
      allowed examination of the entire sheath. The normal endoscopic appearance of the
      tarsal sheath was studied. The endoscopic approach was subsequently used to
      examine and treat 5 horses with tarsal sheath tenosynovitis, including 2 cases of
      chronic, traumatic tenosynovitis and 3 of subacute septic tenosynovitis. Four of
      these horses had fragmentation of the sustentaculum tali. The technique allowed
      adequate examination of the sheath and debridement of adhesions and lesions
      within the lumen of the sheath. Fragments dorsal to the medioplantar edge of the
      sustentaculum tali could not be visualised endoscopically and had to be removed
      after widening of the wound. All 5 horses survived. Follow-up enquiries (8-31
      months) revealed that the horses were all reported to be sound. Four were
      performing at their previous level of activity, 1 was used for hacking. The 2
      cases presented with chronic tenosynovitis had residual sheath distension with no
      associated loss of function. A prospective study, including longer term follow-up
      investigation, is currently being performed.

PMID- 10402134
TI  - The role of prostanoids and nitric oxide in endotoxin-induced hyporesponsiveness
      of equine digital blood vessels.
AB  - Endotoxin has been implicated in the pathophysiology of acute laminitis. The aim
      of this study was to examine the direct effects of endotoxin on isolated equine
      digital blood vessels. Equine digital veins (EDV), incubated in Krebs-Henseleit
      solution containing lipopolysaccharide (LPS) (1 microg/ml) became hyporesponsive
      to 5-HT after 16 h. Cycloheximide and ibuprofen blocked this effect of LPS and
      increased the maximum response obtained to 5-HT when compared to control vessels.
      L-nitroarginine methyl ester (L-NAME) reversed the hyporesponsiveness caused by
      LPS. Vessels maintained in culture medium containing LPS also became
      hyporesponsive to 5-HT, an effect which was completely prevented by ibuprofen but
      only partially reversed by L-NAME. Measurements were made of 6-keto PGF1alpha and
      nitrite production by segments of equine digital artery and vein in culture
      medium alone or co-cultured with peripheral blood leucocytes. LPS did not
      stimulate nitrite production from vessel segments but increased nitrite release
      from leucocytes, an effect which was inhibited by cycloheximide and L-NAME.
      Lipopolysaccharide increased 6-keto PGF1alpha production by blood vessels, an
      effect which was inhibited by cycloheximide and ibuprofen but not L-NAME. No
      synergistic effect on release of nitrite or 6-keto PGF1alpha was noted in co
      cultures of blood vessels and leucocytes. These data suggest that induction of
      cyclo-oxygenase by LPS was a major cause of hyporesponsiveness of digital blood
      vessels to 5-HT. Release of nitric oxide was not detectable in LPS-stimulated
      blood vessels maintained in culture even in the presence of activated leucocytes
      yet L-NAME did protect against LPS-induced hyporesponsiveness indicating nitric
      oxide synthase induction may play some role in the effect of LPS. These findings
      are important in furthering our understanding of the pathophysiological
      mechanisms underlying the vascular changes which occur in acute laminitis.

PMID- 10402136
TI  - The effect of low level laser therapy (LLLT) on wound healing in horses.
AB  - Laser therapy is used in many countries, including South Africa, for the
      treatment of skin wounds. Low level galium aluminium arsenide (GaAlAs) laser was
      administered to full thickness skin wounds (3 x 3 cm) induced surgically on the
      dorsal aspect of the metacarpophalangeal joints of 6 crossbred horses in a
      randomised, blind, controlled study. Treated wounds that received a daily laser
      dosage of 2 J/cm2 were compared with nontreated control wounds on the opposite
      leg. There were no wound complications. Both groups of wounds were cleaned daily
      using tap water. Wound contraction and epithelialisation were evaluated using
      photoplanimetry. There were no significant differences in wound contraction or
      epithelialisation between the laser treated and the control wounds. It was
      therefore concluded that laser therapy had no clinically significant effect on
      second intention wound healing in this study.

PMID- 10402137
TI  - A method for determination of equine hoof strain patterns using photoelasticity:
      an in vitro study.
AB  - During impact, equine hooves undergo viscoelastic deformations which may result
      in potentially harmful strains. Previous hoof strain studies using strain gauges
      have been inconclusive due to arbitrary gauge placement. Photoelastic stress
      analysis (PSA) is a full-field technique which visually displays strains over
      entire loaded surfaces. This in vitro study identifies normal hoof strain
      patterns using PSA. Custom-made photoelastic plastic sheets were applied to the
      hoof surface. The hooves were axially loaded (225 kg) under level and
      varus/valgus conditions. Strain patterns were video-recorded through a
      polariscope. Strains were concentrated between middle and distal thirds of the
      hoof wall regardless of the loading conditions. This strain distribution appears
      to result from the differential expansion of the hoof wall under load. Increasing
      load resulted in higher strains and asymmetric loading resulted in an ipsilateral
      increase in strain magnitudes without altering strain locations. This study shows
      that PSA is a reliable method with which to evaluate hoof strains in vitro and is
      sensitive enough to reflect subtle load-related strain alterations.

PMID- 10402138
TI  - Distribution of substance P binding sites in equine airways.
AB  - Autoradiography with [125I]-Bolton Hunter substance P ([I]-BHSP) was used to
      detect substance P binding sites in the equine lung. Specific [I]-BHSP binding
      sites were very dense over small bronchial vessels, tracheobronchial glands and
      airway epithelium in large and small airways. The density of [I]-BHSP binding
      sites over airway smooth muscle was much lower than in the preceding tissues.
      Competition with an excess of either a specific neurokinin 1 receptor agonist, or
      a specific neurokinin 2 receptor agonist indicated that most specific [I]-BHSP
      binding sites in the equine lung represent neurokinin 1 receptors. The receptor
      mediated effects of substance P in the equine lung are most likely to involve
      regulation of vascular tone and airway secretions based upon the density of
      specific [I]-BHSP binding sites in these tissues. Activation of intrapulmonary
      afferent nerves containing Substance P by noxious stimuli such as inhaled
      allergens or irritants may lead to increased mucus secretion and decreased airway
      diameter due to vascular congestion.

PMID- 10402139
TI  - Expression of endothelin in equine laminitis.
AB  - Biosynthesis of endothelin-1 (ET-1), the most potent endogenous vasoconstrictor
      yet identified, is increased following myocardial infarction (MI) in man.
      Pathological events which occur in the connective tissues of the equine hoof
      during laminitis are similar in some respects, to changes occurring in the
      myocardial connective tissues following MI in man. The objective of this study
      was to determine whether ET-1 expression in connective tissues obtained from the
      hoof of laminitic horses is increased compared with tissues obtained from healthy
      horses. Expression of ET-1 in connective tissues of the equine hoof was measured
      following tissue extraction from 3 groups of horses: horses in which acute
      laminitis had been induced by the administration of starch; chronically foundered
      horses; nonlaminitic horses. The concentration of ET-1 in laminar connective
      tissues obtained from all laminitic horses (1573.0 +/- 392.8 pg/g of tissue; n =
      10) was increased when compared with tissues obtained from nonlaminitic horses
      (392.5 +/- 117.4 pg/g of tissue; n = 5) (P<0.05). The concentration of ET-1 in
      laminar connective tissues obtained from the experimentally induced, acute
      laminitic horses (1043.6 +/- 254.4 pg/g of tissue; n = 7) and from the
      spontaneously affected, chronic laminitic horses (2808.3 +/- 878.6 pg/g of
      tissue; n = 3) was increased compared with the control group (P<0.05, P<0.01,
      respectively). The concentration of ET-1 in laminar connective tissues obtained
      from the chronic laminitic horses was greater than that of the experimentally
      induced, acute laminitic group (P<0.05). It is suggested that the data provide a
      strong argument that increased ET-1 expression in the connective tissues of the
      equine hoof represent a potentially important and hitherto unrecognised component
      of the pathophysiology of equine laminitis. Further studies are needed to
      determine whether inhibitors of ET-1 converting enzyme or antagonists of ET-1
      receptors might be useful in the treatment and prevention of laminitis in horses.

PMID- 10402140
TI  - Prediction of first season stallion fertility of 3-year-old Dutch Warmbloods with
      prebreeding assessment of percentage of morphologically normal live sperm.
AB  - In the selection procedure to acquire a breeding licence, 3-year-old Dutch
      Warmblood stallions have to undergo a breeding soundness test It is questioned
      whether this evaluation is predictive of the stallion's fertility results in the
      first breeding season. Therefore, semen parameters at the beginning of their
      first breeding season were evaluated and correlated to nonreturn at first cycle
      and foaling rate of mares bred by stallions (n = 13). The total number of mares
      inseminated with chilled semen from those stallions was 1055. Semen parameters
      were recorded on 2 ejaculates, collected 1 h apart. Percentage progressive sperm
      motility, % morphologically normal from unstained spermatozoa (MNA), % sperm
      cells with abnormal acrosomes and the total number of spermatozoa were correlated
      with first cycle nonreturn rate and foaling rate. Mean motility at evaluation was
      72 +/- 6%. Mean MNA was 62 +/- 13%. Mean first cycle nonreturn rate and foaling
      rate were 58 +/- 15% and 69 +/- 12%, respectively. A significantly positive
      correlation (P<0.05) was found between the MNA and first cycle nonreturn rates.
      Foaling rates were not significantly correlated with semen characteristics and
      first cycle nonreturn rates. In conclusion, the breeding soundness test is of
      predictive value for the breeding results in the breeding season following the
      test. First cycle nonreturn rates reflect fertilising capacity better than
      foaling rates.

PMID- 10402141
TI  - Results of screw fixation combined with cortical drilling for treatment of dorsal
      cortical stress fractures of the third metacarpal bone in 56 Thoroughbred
      racehorses.
AB  - The purpose of this study was to evaluate screw fixation with cortical drilling
      as a surgical treatment for dorsal cortical stress fractures of MCIII in the
      Thoroughbred racehorse. Details of age, sex, limb affected, fracture assessment,
      and post operative recommendations were obtained from medical records and
      radiographs. Fracture healing was assessed radiographically at the time of screw
      removal. Performance evaluation was determined from race records obtained from
      The Jockey Club Information System, Lexington, Kentucky. Fifty-six Thoroughbred
      racehorses were treated surgically for stress fracture of MCIII with screw
      fixation and cortical drilling. Stress fractures occurred primarily in the left
      front limb of the male 3-year-olds, in the dorsolateral cortex of the middle
      third of MCIII. Ninety-seven percent of the fractures travelled in a dorsodistal
      to palmaroproximal direction. Median period to screw removal was 2.0 months.
      Evaluation at time of screw removal revealed 98% of single stress fractures of
      the left front limb were healed radiographically. Median period to resume
      training was 2.75 months (single stress fractures); median period to race was
      7.62 months. There was no statistically significant difference in earnings/start
      before and after surgical intervention. Of the 63 fractures treated, two
      recurred. There were no catastrophic failures, and no incisional infections.

PMID- 10402142
TI  - Serum cortisol concentrations in response to incremental doses of inhaled
      beclomethasone dipropionate.

PMID- 10402143
TI  - Assessment of bilateral infra-orbital nerve blockade and bilateral infra-orbital
      neurectomy in the investigation and treatment of idiopathic headshaking.

PMID- 10402144
TI  - Acute physiological and behavioral effects of oral cocaine in humans: a dose
      response analysis.
AB  - The present study was designed to assess the acute physiological and behavioral
      effects of a wide range of doses of oral cocaine HCL (placebo, 50, 100, 200, and
      300 mg). Nine volunteers (eight males and one female) with recent histories of
      cocaine use resided on a general inpatient psychiatry unit while they
      participated. Drug doses were administered in a double-blind fashion under
      medical supervision, but for safety purposes, they were administered in ascending
      order. The physiological, subject-rated, and performance effects of oral cocaine
      HCL were assessed before drug administration and periodically afterwards for 5 h.
      Oral cocaine HCL increased heart rate and blood pressure as a graded function of
      dose, but the magnitude of these effects were not clinically significant. Oral
      cocaine HCL produced positive subject-rated drug effects (e.g. increased ratings
      of good effects, like drug, and willing to take again), but did not affect
      performance. Consistent with the pharmacokinetics of oral cocaine HCL, drug
      effects were generally discernible from placebo 0.5-1 h after administration,
      peaked approximately 1 h after administration, and progressively abated during
      the remainder of the experimental session. The results of this experiment
      demonstrate that across a six-fold range of doses oral cocaine HCL is well
      tolerated by individuals with recent histories of cocaine use and can be safely
      administered under controlled laboratory and medical conditions.

PMID- 10402145
TI  - Increased specificity of ethanol's discriminative stimulus effects in an ethanol
      pentobarbital-water discrimination in rats.
AB  - Ethanol's modulation of a number of receptor systems results in a heterogeneous
      discriminative stimulus complex. A previous study found that these heterogeneous
      discriminative stimulus effects were seemingly diminished when rats were trained
      to discriminate ethanol (2.0 g/kg) from pentobarbital (10.0 mg/kg). The present
      experiment was designed to extend these findings by using a lower training dose
      of ethanol (1.0 g/kg). Adult male Long-Evans rats (n = 7) discriminated
      pentobarbital (10.0 mg/kg; intragastric (i.g.)) from ethanol (1.0 g/kg; i.g.)
      from water (2.3 ml; i.g.) in a 3 lever, food-reinforced task. Substitution tests
      were conducted following intraperitoneal (i.p.) administration of GABA(A)
      positive modulators, noncompetitive NMDA antagonists, 5-HT1 agonists and
      isopropanol. The GABA(A) positive modulators diazepam, midazolam and
      allopregnanolone completely substituted for pentobarbital. Isopropanol completely
      substituted for ethanol, while the NMDA antagonists dizocilpine and phencyclidine
      partially substituted for ethanol. The 5-HT agonists RU 24969 and CGS 12066B did
      not result in complete substitution for ethanol or pentobarbital, although RU
      24969 resulted in partial pentobarbital substitution. These data replicate and
      extend the previous findings that discriminating ethanol from pentobarbital
      attenuates the ethanol-like effects of GABA(A) positive modulators, NMDA
      antagonists and 5-HT1 agonists and results in a more specific ethanol cue. The
      outcome appears to be a conditional basis for the ethanol discrimination, where a
      full ethanol-like effect is produced only by drugs with pharmacological activity
      similar to the heterogenous effects of ethanol (e.g. other alcohols).

PMID- 10402146
TI  - Identifying methadone maintenance clients at risk for poor treatment response:
      pretreatment and early progress indicators.
AB  - Exhaustive searches have uncovered few demographic or other pretreatment factors
      that reliably predict performance in substance abuse treatments. In this study we
      evaluate whether early treatment response offers improved prediction of treatment
      response 6 and 9 months later. New admissions to methadone maintenance treatment
      (n = 59) were dichotomized into outcome groups based on treatment retention and
      ongoing drug use as revealed by urinalysis results 6 and 9 months after
      admission. Regression analyses revealed two early (week 2) performance measures,
      counseling attendance and opiate abstinence, could be used to correctly classify,
      the outcomes of more than 80% of the sample. Strikingly, of the 20 participants
      who neither submitted an opiate-negative urine sample in week 2 nor attended at
      least two scheduled counseling sessions by that time, not one achieved a superior
      6-month outcome. The odds of having a superior outcome increased considerably for
      those who submitted two opiate negative urine samples and attended two counseling
      sessions by week 2. Thus, 6-month outcomes were well predicted by treatment
      performance in week 2. Similar results are reported for month 9 outcomes.

PMID- 10402147
TI  - Feasibility of multidimensional substance abuse treatment matching: automating
      the ASAM Patient Placement Criteria. American Society of Addiction Medicine.
AB  - The Patient Placement Criteria published by the American Society of Addiction
      Medicine (ASAM Criteria) established a non-proprietary standard for matching
      substance use disorder patients to treatment settings. METHODS: Data from 593
      substance dependent adults who were assessed using the first computerized
      implementation of the ASAM Criteria were analyzed to determine whether the level
      of care assignments showed significant differences on a variety of clinical
      measures. RESULTS: The algorithm showed acceptable discrimination between each of
      three ASAM Levels of Care across numerous clinical subscales. CONCLUSIONS: It is
      feasible to implement complex, multidimensional criteria for substance abuse
      treatment that may improve reliability and facilitate validity studies.

PMID- 10402148
TI  - Job strain and non-medical drug use.
AB  - In this study, the Karasek demand/control formulation of job strain, initially
      used in research on cardiovascular health, has been extended to drug use. Full
      time nurses (n = 2375), all participants in a national anonymous mailed survey,
      were an estimated 1.5 times more likely to be a recent non-medical drug user if
      they had a high strain job as compared to nurses in low strain jobs. The
      psychosocial work environment might influence whether nurses become and remain
      non-medical drug users, over and above the risk-modifying functions related to
      nurses' individual vulnerabilities and their greater access to controlled
      substances.

PMID- 10402150
TI  - Characteristics of benzodiazepine abuse in methadone maintenance treatment
      patients: a 1 year prospective study in an Israeli clinic.
AB  - We aimed to study the prevalence patterns and course of benzodiazepine (BZD)
      abuse in an Israeli methadone maintenance (MMT) clinic using repeated random
      observed urine analysis as well as self-report data. Lifetime and current
      prevalence of BZD abuse were found in 66.3 and 50.8% patients, respectively. It
      was found that 44.6% of patients who abused BZDs during their first month of
      treatment ceased to do so after 1 year, while 27.4% who had not abused BZDs at
      the beginning of MMT did so after 1 year in treatment. Flunitrazepam was the most
      commonly abused BZD (92.9%), followed by diazepam (54.3%) and oxazepam (38.6%).
      Most of the patients swallowed BZDs (92.8%), 42.9% also smoked or snorted them
      while 8.6% injected BZDs intravenously. BZDs were used as self-medication for
      alleviating emotional problems rather than for recreational or other reasons. We
      conclude that BZD abuse is a significant clinical problem in heroin addicts both
      before entering and during MMT. MMT may have a positive as well as a negative
      influence on BZD abuse with the former being more prevalent.

PMID- 10402149
TI  - Demographic and substance use factors related to violent and accidental injuries:
      results from an emergency room study.
AB  - OBJECTIVE: The primary goal of this study was to identify demographic and
      substance use factors associated with violent injuries, accidental injuries, and
      medical conditions or illnesses (non-injured). METHOD: Data were examined from a
      sample of 1701 admissions to emergency rooms at two Canadian hospitals. These
      patients were interviewed and provided urine samples to detect the presence of
      drug metabolites for alcohol, THC, benzodiazepines, barbiturates, morphine, and
      codeine. RESULTS: Those with violent injuries were significantly (P<0.0001) more
      likely to be male and have lower incomes compared with both the accidental injury
      and non-injury groups. About 37% of violent injuries occurred at a bar or
      restaurant, which was significantly more than 3% for accidental injuries and 2%
      for non-injuries (P<0.00001). The violent injury group was significantly more
      likely than the other two groups to report feeling the effects of alcohol at the
      time of the injury and to report negative consequences of alcohol use
      (P<0.00001). Furthermore, about 42% of those with violent injuries had a blood
      alcohol level (BAL) over 80 mg% compared to only 4% with accidental injuries
      (P<0.00001) and 2% of non-injuries (P<0.00001). In terms of drug tests for other
      substances, the violent injury group was significantly more likely to test
      positive for benzodiazepines than the accidental injury group (P<0.01) while all
      between group comparisons for other drugs were not significant.

PMID- 10402151
TI  - Health-related service utilization and HIV risk behaviors among HIV infected
      injection drug users and crack smokers.
AB  - This study was designed to assess utilization of health-related services and HIV
      risk related behaviors by HIV infected drug users one year prior to and two years
      following the availability of Ryan White Title I funding. Using a cross-sectional
      design, a total of 777 drug injectors and crack smokers from five US cities were
      surveyed, over three waves of data collection, about their use of drug treatment,
      medical services, housing, mental health, and case management and about their sex
      and drug-related risk behaviors. For all service categories and in each wave,
      including the year prior to Title I funding, HIV risk behaviors were lower among
      those who used health-related services, with the exception of housing. Use of
      services did not increase significantly following the disbursement of Title I
      funds except for housing and case management. These findings suggest that it may
      be necessary to increase the attractiveness of health-related services, not just
      funding for services, for HIV infected substance abusers.

PMID- 10402152
TI  - Orally delivered methadone as a reinforcer: Effects of the opioid antagonist
      naloxone.
AB  - The effects of the opioid antagonist naloxone were studied with three monkeys
      under a mutually exclusive fixed-interval 15 s (FI 15 s) schedule of
      reinforcement. Under this schedule, at the end of each interval, the monkey could
      obtain one liquid delivery from either the spout that delivered methadone (0.8
      mg/ml) or the spout that delivered vehicle (deionized water). Naloxone doses from
      0.0125 to 0.2 mg/kg (IM daily 10 min prior to the session) were studied in an
      ascending then descending order. In the ascending series, low naloxone doses
      produced increases of methadone deliveries in the first hour of the session for
      three monkeys and increases over the entire 3-h session for two of the three
      monkeys. At higher doses naloxone decreased methadone deliveries in all three
      monkeys. Naloxone's effects were usually greater during the descending dose
      series than during the ascending series. These findings suggest that a history of
      naloxone injections is one determinant of response to the drug. Vehicle
      maintained responding was generally low and not changed by naloxone in a
      systematic way. The time course of methadone deliveries showed that naloxone's
      effects were greatest in the first hour of the session and were a direct function
      of dose. These experiments demonstrate that oral methadone reinforced behavior is
      sensitive to naloxone pretreatment and that the effects of naloxone are a direct
      function of dose.

PMID- 10402153
TI  - Effects of alcohol cues on cognitive processing in heavy and light drinkers.
AB  - The effects of alcohol-related visual cues on cognitive processing in heavy and
      light social drinkers were assessed. Participants were exposed to either alcohol
      or control cues while they completed a cognitively demanding emotional Stroop
      task that used alcohol-related and control words as potential distracters. Heavy
      drinkers exposed to alcohol cues had significantly slower reaction times on the
      Stroop task than: (a) heavy drinkers exposed to control cues; and (b) light
      drinkers exposed to either alcohol or control cues. Results indicate that the
      effects of alcohol cues on automatic cognitive processes previously found in
      dependent drinkers' also occur in social drinkers. The magnitude of these effects
      varies directly with social drinkers' level of habitual alcohol use.

PMID- 10402154
TI  - Does clinical case management improve outpatient addiction treatment.
AB  - This project evaluated whether clinical case managers (CCMs) could increase
      access and utilization of social services in the community; and thereby improve
      outcomes of addiction treatment. No case management (NoCM)--patients received
      standard, group-based, abstinence-oriented, outpatient drug abuse counseling,
      approximately twice weekly. Clinical case management (CCM)--patients were treated
      in the same programs but also were assigned a CCM who provided access to pre
      contracted, support services such as drug free housing, medical care, legal
      referral, and parenting classes from community agencies. CCM patients received
      more alcohol, medical, employment, and legal services than NoCM patients during
      treatment. At 6 month follow-up CCM patients showed significantly more
      improvement in alcohol use, medical status, employment, family relations, and
      legal status than NoCM patients. We conclude that CCM was an effective method of
      improving outcomes for substance abuse patients in community treatment programs.
      Essential elements for successful implementation included extensive training to
      foster collaboration; and pre-contracting of services to assure availability.

PMID- 10402155
TI  - Ecstasy use in Australia: patterns of use and associated harm.
AB  - This study explored patterns of ecstasy use and associated harm through the
      administration of a structured interview schedule to 329 ecstasy users, recruited
      from three Australian cities. A broad range of ecstasy users were interviewed,
      but on the whole, the sample was young, relatively well educated and most were
      employed or students. Patterns of use were varied, although extensive polydrug
      use was the norm. High rates of intravenous drug use were recorded, which may
      relate to an over-representation of chaotic intravenous polydrug users. Subjects
      had experienced an average of eight physical and four psychological side-effects,
      which they attributed to their ecstasy use in the preceding 6 months.
      Approximately 40% of the sample also reported financial, relationship and
      occupational problems. Young, female, polydrug users and those who binged on
      ecstasy for 48 h or more appeared most at risk of experiencing harm that they
      related to their ecstasy use. One-fifth of the sample had received treatment for
      an ecstasy-related problem, most often from a GP or natural therapist, and 7%
      were currently in treatment. One quarter wanted to reduce their use because of
      financial, relationship and psychological problems. A total of 15% wanted formal
      treatment for an ecstasy-related problem and 85% requested more information.
      These results have implications for the development of policies to respond to
      drug use among this population.

PMID- 10402156
TI  - Response patterns of the Spanish version of the 49-item short form of the
      Addiction Research Center Inventory after the use of sedatives, stimulants, and
      opioids.
AB  - This report examines the validity of the Spanish version of the 49-item short
      form of the Addiction Research Center Inventory (ARCI) for measuring subjective
      effects after the use of sedatives, stimulants, and opioids. Data from four
      clinical trials in which this questionnaire was used have been analyzed. The
      Spanish ARCI short form was found to be sensitive in measuring subjective effects
      after the administration of alcohol, triazolam, and flunitrazepam (sedatives),
      cocaine (stimulants), and morphine, pentazocine, and naloxone (opioids) and to
      distinguishing among them. The response patterns were similar to those previously
      reported for the same drugs with the English version of ARCI. It is concluded
      that Spanish version of the 49-item short form of ARCI is a valid instrument for
      assessing the subjective effects of psychoactive drugs in the Spanish-speaking
      population context.

PMID- 10402157
TI  - Cannabinoid receptor binding and mRNA levels in several brain regions of adult
      male and female rats perinatally exposed to delta9-tetrahydrocannabinol.
AB  - The present study was designed to elucidate whether perinatal delta9
      tetrahydrocannabinol (delta9-THC) exposure results in changes in cannabinoid
      receptor binding and mRNA levels in adulthood. Most of the brain areas studied,
      including the basal ganglia, the cerebellum, the limbic structures, and most of
      the hippocampal regions exhibited no changes in cannabinoid receptor binding and
      mRNA levels in adulthood as a consequence of the perinatal delta9-THC exposure.
      However, some subtle changes could be appreciated in specific regions, although
      their physiological relevance seems uncertain. For example, delta9-THC-exposed
      males exhibited a small decrease in binding in the superficial layer of the
      cerebral cortex, an effect that was not seen in delta9-THC-exposed females and in
      mRNA levels for both males and females. In the CA2 layer of the Ammon's horn,
      there was an increase in mRNA levels of delta9-THC-exposed animals, although this
      was statistically significant only in males. However, the more marked and
      probably relevant changes were seen in the arcuate nucleus, where delta9-THC
      exposed males exhibited an increase in binding, whereas this tended to decrease
      in delta9-THC-exposed females. In an additional experiment, we analyzed the motor
      response of these animals to a challenge with SR141716, a specific antagonist for
      cannabinoid receptors. The delta9-THC-exposed animals tended to show a higher
      response to SR141716 challenge, with changes apparently more marked in delta9-THC
      exposed females, although they did not reach statistical significance. In
      summary, perinatal cannabinoid exposure does not appear to significantly alter
      cannabinoid receptor binding and mRNA expression in the brain of adult rats, as
      well as the motor response caused by the blockade of these receptors with a
      specific antagonist. There were some changes in the status of cannabinoid
      receptors but they were very small and, hence, of debatable physiological
      relevance. The most significant of these effects was the increase in binding
      observed in the arcuate nucleus of delta9-THC-exposed males.

PMID- 10402158
TI  - Oral and intravenous methadone use: some clinical and pharmacokinetic aspects.
AB  - A sample of 15 patients participating in an injectable methadone trial and of 15
      patients in an oral methadone maintenance treatment, who admitted injecting part
      or all of their methadone take-home doses, were compared to 20 patients in
      maintenance treatment who use methadone exclusively by mouth. The present study
      confirms the poorer general health, the higher levels of emotional, psychological
      or psychiatric problems, the higher use of illicit drugs, and the higher number
      of problems related to employment and support associated with the use of the
      intravenous mode of administration of methadone. As expected, due to the shunt of
      metabolism in the gut wall and of the liver first-pass effect, higher
      concentration to dose ratios of (R)-methadone, which is the active enantiomer,
      were measured in the intravenous group (23% increase). This difference reached an
      almost statistically significant value (P = 0.054). This raises the question
      whether the effect of a higher methadone dose could be unconsciously sought by
      some of the intravenous methadone users.

PMID- 10402159
TI  - Substance use among a regional sample of female nurses.
AB  - We assessed the prevalence of licit (e.g. alcohol) and illicit (e.g. cocaine)
      drug use, as well as prescription (e.g. tranquillizers) and over-the-counter
      medications (e.g. analgesics), in a regional sample of female nurses. Surveys
      were mailed to a random sample of 4000 nurses in Western New York. The survey
      focused on lifetime and current use of substances, negative consequences of
      alcohol consumption and dependence. Three mailings resulted in a return of 2400
      (60%) surveys, of which 1951 (49%) were usable. We examined lifetime and current
      use in each of the four classes of substances in the context of nursing related
      factors (e.g. type of nurse, nursing specialty, work setting) and demographic
      characteristics (e.g. age, marital status). There were significant differences
      within each of the different groupings. Lifetime experience of negative
      consequences were relatively rare and few nurses reported dependence on
      substances other than tobacco and caffeine.

PMID- 10402161
TI  - Hormonal and behavioral homeostasis in boys at risk for substance abuse.
AB  - This study modeled the influences of cortisol reactivity, androgens, age
      corrected pubertal status, parental personality, family and peer dysfunction on
      behavioral self-regulation (BSR), in boys at high (HAR) and low average risk
      (LAR) for substance abuse. Differences between risk groups in cortisol and
      androgen concentrations, and cortisol reactivity were also examined. Subjects
      were 10- through 12-year-old sons of substance abusing fathers (HAR; n = 150) and
      normal controls (LAR; n = 147). A multidimensional construct of BSR was developed
      which utilized multiple measures and multiple informants. Boys reported on family
      dysfunction and deviant behavior among their peers. Parents reported on their
      propensity to physically abuse their sons, and their own number of DSM-III-R
      Antisocial Personality Disorder symptoms. Endocrine measures included plasma
      testosterone, dihydrotestosterone, and salivary cortisol. HAR boys, compared to
      LAR boys, had lower mean concentrations for testosterone, dihydrotestosterone,
      salivary cortisol prior to evoked related potential testing, and lower cortisol
      reactivity. The number of maternal Antisocial Personality Disorder symptoms,
      parental potential for physical abuse, degree of family dysfunction, and peer
      delinquency were significantly associated with BSR. Parental aggression
      antisocial personality symptoms and parental physical abuse potential are likely
      to influence sons' behavioral dysregulation and homeostatic stress reactivity.
      These key components of liability are posited to increase the likelihood of
      developing suprathreshold Psychoactive Substance Use Disorder (PSUD).

PMID- 10402160
TI  - Plasma concentrations of buprenorphine 24 to 72 hours after dosing.
AB  - BACKGROUND: This study evaluated plasma buprenorphine concentrations 24-72 h
      following sublingual administration of a dose of buprenorphine solution, ranging
      from 16 mg/70 kg to 44 mg/70 kg, administered on a daily or thrice-weekly
      schedule. Additionally, this study evaluated the effects of different thrice
      weekly buprenorphine dose schedules on opiate use and withdrawal symptoms.
      METHODS: Opiate dependent subjects (n = 10) were maintained in an outpatient
      clinic for two 3-week periods at each of three thrice-weekly buprenorphine dose
      schedules (providing a weekly total buprenorphine dose of 64, 84 and 112 mg) and
      for 1 week of a daily buprenorphine dose of 16 mg/70 kg. Plasma samples were
      obtained 24, 48 and 72 h following administration of buprenorphine. Urine samples
      were also collected and opiate withdrawal symptoms, agonist effects and the use
      of heroin, cocaine, alcohol and other drugs, were assessed. RESULTS: Plasma
      levels showed a wide range of intra- and inter-subject variability. Nonetheless,
      higher doses of buprenorphine resulted in higher plasma concentrations at each
      time point and plasma concentration decreased with time. There were no
      significant differences in heroin use across dosing. Rates of withdrawal symptoms
      were low and did not differ across dosing schedules. CONCLUSIONS: In the two
      highest dose schedules, plasma levels 72 h following the administration of the
      highest dose and at 48 h after the lower dose, were comparable to plasma
      concentrations at 24 h following daily administration of 16 mg/70 kg of
      buprenorphine.

PMID- 10402162
TI  - Level of education and injecting drug use among African Americans.
AB  - Drawing upon a nationally representative survey sample of African American (AA)
      drug injectors and non-injectors, this study tests for a suspected causal
      association between dropping out of school and the occurrence of injecting drug
      use (IDU), which remains a major cause of human immunodeficiency virus (HIV)
      transmission in this population. The data are from public use files of the
      National Household Surveys on Drug Abuse (NHSDA) conducted between 1991 and 1995.
      From within the NHSDA's nationally representative sample of adult household
      residents, a total of 389 AA adults with a history of IDU were matched on
      neighborhood of residence with 2253 AA adults with no history of IDU. The
      conditional form of multiple logistic regression was used to estimate the
      relative risk of having injected a drug for school dropouts relative to a
      reference category of AA who received the high school diploma but did not go to
      college. AAs who dropped out of high school were an estimated two times more
      likely to have injected drugs. With statistical adjustment for age, sex, and
      Hispanic background, the estimated association was 1.9 (95% confidence interval
      (C.I.) = 1.3-2.6, P<0.001). Contrary to our advance hypothesis, earning the
      graduate equivalency certificate (GED) did not seem to affect the magnitude of
      excess risk for having started IDU (adjusted odds ratio (aOR) = 2.3, 95% C.I. =
      1.4-3.8, P<0.001). Hence, school dropout prevention might reduce the risk of IDU
      per se, in addition to the many other general benefits of educational attainment.
      The issue of GED-associated reduced risk of IDU remains open for future study.

PMID- 10402163
TI  - Nuclear factor kappaB (NF-kappaB) pathway as a therapeutic target in rheumatoid
      arthritis.
AB  - Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by
      persistent joint swelling and progressive destruction of cartilage and bone.
      Current RA treatments are largely empirical in origin and their precise mechanism
      of action is uncertain. Increasing evidence shows that chronic inflammatory
      diseases such as RA are caused by prolonged production of proinflammatory
      cytokines including tumor necrosis factor (TNF) and interleukin 1 (IL-1). The
      nuclear factor kappaB (NF-kappaB) plays an essential role in transcriptional
      activation of TNF and IL-1. NF-kappaB is induced by many stimuli including TNF
      and IL-1, forming a positive regulatory cycle that may amplify and maintain RA
      disease process. NF-kappaB and enzymes involved in its activation can be a target
      for anti-inflammatory treatment. Aspirin and sodium salicylate inhibit activation
      of NF-KB by blocking IkappaB kinase, a key enzyme in NF-kappaB activation.
      Glucocorticoids suppress expression of inflammatory genes by binding
      glucocorticoid receptor with NF-kappaB, and increasing expression of inhibitory
      protein of NF-kappaB, IkappaBalpha. Sulfasalazine and gold compounds also inhibit
      NF-kappaB activation. Continuing advances in our understanding of action
      mechanism of antirheumatic agents will benefit the future development of RA
      regimens with greater efficacy and less toxicity.

PMID- 10402164
TI  - Air pollution and daily mortality in Inchon, Korea.
AB  - The association between total daily mortality and air pollution was investigated
      for a 1-year period (January 1995 to December 1995) in Inchon, Korea. The purpose
      of this study was to evaluate the relative importance of particulate and gaseous
      air pollution as predictors of daily mortality. Concentration of total suspended
      particulates (TSP), inhalable particles (PM10), and gaseous pollutants, such as
      sulfur dioxide, nitrogen dioxide, ozone, carbon monoxide, were measured daily
      during the study period. A generalized additive model was used to regress daily
      death counts on each air pollutant, controlling for time trend and meteorologic
      influences such as temperature or relative humidity. Total mortality was found to
      increase 1.2% (95% CI: 0.2 to 2.2%) for each 10 microg/m3 increase in 6-day
      moving average of TSP, and 1.2% (95% CI 0.2 to 2.1%) for each 10 microg/m3
      increase in 5-day moving average of PM10. The association is similar in magnitude
      to associations between particulate air pollution and mortality found in several
      other communities in America and Europe. Associations with gaseous pollutants
      were all statistically insignificant in the generalized additive model. The
      relative risk of death increased at particulate levels that were well below the
      current Korean Ambient Air Quality Standard.

PMID- 10402165
TI  - Time-dependent expression of ICAM-1 & VCAM-1 on coronaries of the heterotopically
      transplanted mouse heart.
AB  - To investigate the pathogenesis of accelerated graft atherosclerosis after
      cardiac transplantation, a genetically well-defined and reproducible animal model
      is required. We performed heterotopic intraabdominal heart transplantation
      between the two inbred strains of mice. Forty hearts from B10.A mice were
      transplanted into B10.BR mice. Recipients were sacrificed at 1, 3, 5, 7, 14, 28,
      and 42 days after implantation. The specimens from both donor and recipient were
      examined with fluorescent immunohistochemistry and the serial histopathologic
      changes were evaluated. In the donor hearts, ICAM-1 and VCAM-1 expressions were
      minimal at day 1 and they gradually increased, reaching their peaks on day 5 or 7
      and remained unchanged by day 42. However, there were very little expressions in
      the recipients' hearts. Mean percent areas of intima in the donor coronaries
      revealed progressive increase by day 42. However, those in the recipients
      occupied consistently less than 5% of the lumen. In conclusion, we demonstrated
      that a heterotopic murine heart transplantation model was a useful tool to
      produce transplantation coronary artery disease and that adhesion molecules on
      the cardiac allografts were activated very early and remained elevated at all
      time-points, nonetheless the arterial lesion was detected after day 28 and its
      progression was accelerated thereafter.

PMID- 10402166
TI  - Reflux esophagitis and its relationship to hiatal hernia.
AB  - We performed this study to evaluate the prevalence of reflux esophagitis and/or
      hiatal hernia in patients referred to a medical center and to examine the
      relationship between endoscopic reflux esophagitis and hiatal hernia. The study
      was carried out in 1,010 patients referred to Yong Dong Severance Hospital for
      upper gastrointestinal endoscopy because of symptoms related to the
      gastrointestinal tract from September 1994 to March 1996. The presence of hiatal
      hernia was defined as a circular extension of the gastric mucosa of 2 cm or more
      above the diaphragmatic hiatus. Reflux esophagitis was found in 5.3% of patients,
      hiatal hernia in 4.1%, duodenal ulcer in 7.2% and gastric ulcer in 8.2%. The
      prevalence rates of reflux esophagitis and hiatal hernia in males were
      significantly higher than those in females. Thirty-two percent of patients with
      reflux esophagitis had hiatal hernia. In patients without reflux esophagitis,
      hiatal hernia was found in only 2.5% (p<0.01). There was no significant
      association between the presence of hiatal hernia and the degree of esophagitis
      on endoscopy. Duodenal ulcer was the second most common endoscopic abnormality
      found in patients with reflux esophagitis. The prevalence rate of reflux
      esophagitis and/or hiatal hernia at a medical center is relatively low compared
      to peptic ulcer disease and other reports from the Western countries. Our study
      confirms the close association between reflux esophagitis and hiatal hernia.

PMID- 10402167
TI  - A pathologic study of abdominal lymphangiomas.
AB  - Abdominal lymphangiomas are uncommon angiomatous tumor occurring mainly in
      childhood. This is a retrospective clinicopathologic study of 17 cases of
      abdominal lymphangioma. The patients included are five children and 12 adults,
      with a mean age at initial presentation of 30.7 years (age ranges 3-63). The
      locations of the tumors were mesentery (5), retroperitoneum (4), colon (3),
      omentum (3), mesocolon (1) and gallbladder (1). Infiltrative growth was more
      common pattern than entirely circumscribed pattern. Masses were mostly
      multilocular cysts and contained chyle or serous fluid. On immunohistochemical
      staining, 16 cases were reactive for either CD31 or factor VIII-related antigen.
      These fact would suggest that intra-abdominal lymphangiomas simulate the
      immunohistochemical features of collecting lymphatics. Follow up was possible in
      12 cases for 3-50 months (mean 19 months) and only one patient showed local
      recurrence. Although abdominal lymphangiomas are rare in adulthood and correct
      preoperative diagnosis is difficult, awareness of such a possibility in adulthood
      will contribute to make a correct preoperative diagnosis.

PMID- 10402168
TI  - Correlation between expression of matrix metalloproteinase-2 (MMP-2), and matrix
      metalloproteinase-9 (MMP-9) and angiogenesis in colorectal adenocarcinoma.
AB  - Matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which
      degrade extracellular matrix, are believed to play a crucial role in tumor
      invasion and metastasis. Angiogenesis is also perceived as an important step in
      tumor growth and metastasis. To investigate the expression of MMPs and the
      correlation between the expression of MMPs and angiogenesis in colorectal
      adenocarcinoma, we studied 72 cases of colorectal adenocarcinoma in Inha
      University Hospital from 1996 to 1997. We evaluated the expression of MMPs by
      immunohistochemistry and angiogenesis by counting the microvessels. The
      expression of MMP-2 was increased according to the Astler-Coller stage (p< 0.05).
      Angiogenesis in the metastatic group was higher than that of the localized one
      (p<0.05). The expression of MMP-2 positively correlated with angiogenesis
      (p<0.05), and marked expression of MMP-9 positively correlated with angiogenesis
      (p<0.05). The present results suggest that the expression of MMP-2 provides clues
      for tumor progression and angiogenesis provides significant information to
      predict whether metastasis is present in colorectal adenocarcinoma.

PMID- 10402169
TI  - Adenovirus-mediated p53 tumor suppressor gene therapy against subcutaneous HuH7
      hepatoma cell line nodule of nude mice.
AB  - Mutations of the tumor-suppressor gene p53 have been found in 30-50% cases of
      hepatocellular carcinoma (HCC). In this study, E1-negative adenoviral vector
      encoding wild-type p53 under the control of the human cytomegalovirus promoter
      (AdCMV-p53w) was constructed to evaluate its therapeutic efficacy against tumor
      nodules developing after injection of HuH7 cell lines in ten nude mice. When each
      nodule had reached 10 mm in perpendicular diameter, 1.5 x 10(8) pfu of AdCMV-p53w
      per session was injected intratumorally as follows: In group I (n=3), five
      sessions were injected every other day. In group II (n=3), only one session.
      Group III (n=4) as negative controls. The mice were sacrificed at 28 days post
      AdCMV-p53w injection. Tumor growth was significantly suppressed and delayed in
      group I and II compared to group III as compared by tumor volume at the end of
      observation. These results suggest that AdCMV-p53w may not only be effective in
      treating HCCs expressing mutant p53, but also useful as a local injectable gene
      therapy.

PMID- 10402170
TI  - The metabolic effects of estriol in female rat liver.
AB  - The effects of estriol on oxygen uptake, glucose release, lactate and pyruvate
      production, beta-hydroxybutyrate and acetoacetate production in perfused rat
      liver as well as, carbon uptake in rat liver and intracellular calcium in
      isolated Kupffer cells were investigated. Basal oxygen consumption of perfused
      liver increased significantly in estriol or ethanol-treated rats. But these
      increased effects were blocked by gadolinium chloride pretreatment. In a
      metabolic study, pretreatment with estriol resulted in a decrease in glucose
      production and in glycolysis while an increase in ketogenesis. A more oxidized
      redox state of the mitochondria was indicated by increased ratios of perfusate
      [lactate]/[pyruvate] and decreased ratios of perfusate [beta
      hydroxybutyrate]/[acetoacetate]. Carbon uptake of Kupffer-cell increased
      significantly in estriol-treated rats. But these increased uptake were not shown
      in rats pre-treated by gadolinium chloride blocking phagocytosis. In isolated
      Kupffer cells from estriol-treated rats, intracellular calcium was more
      significantly increased after addition of lipopolysaccharide (LPS) than in
      controls. These findings suggest that the metabolic effects of estriol (two mg
      per 100 mg body wt) can be summarized to be highly toxic in rat liver, and these
      findings suggest that oral administration of estrogens may induce hepatic
      dysfunctions and play a role in the development of liver disease.

PMID- 10402171
TI  - Gallstone formation and gallbladder mucosal changes in mice fed a lithogenic
      diet.
AB  - To investigate the pathologic change of gallbladder mucosa related to gallstone
      formation, 52 mice were fed a lithogenic diet containing 1% cholesterol and 0.5%
      cholic acid and we evaluated the sequential morphologic changes in the
      gallbladder from two days to 40 weeks. Cholesterol gallstones began to appear
      after two weeks and all the mice had gallstones after eight weeks. At two days,
      the mitotic index was at its highest. The gallbladder mucosa showed progressive
      hyperplastic change with earlier papillary projection of the folds and later
      inward proliferation. At the same time of stone formation, mucous cells forming
      glands appeared. Their histochemical profile of mucin was different from that of
      normal epithelium. Numbers of mucous cells increased gradually until 24 weeks but
      slightly decreased afterward. These results suggest hyperplasia and metaplasia
      are closely related to the gallstone formation. Hyperplasia is probably reactive
      to irritating effect of lithogenic bile or stone. Metaplasia and cholesterol
      gallstone may develop simultaneously, and act synergistically.

PMID- 10402172
TI  - Crescentic glomerulonephritis: a clinicopathologic analysis of 17 cases with
      emphasis on glomerular and interstitial neutrophil infiltration.
AB  - In order to determine the extent to which specific forms of glomerulonephritis
      (GN) contribute to the pool of crescentic GN, renal tissues from 17 crescentic GN
      patients were examined with special attention to glomerular and interstitial
      neutrophil infiltration. Renal tissues from five normal kidneys served as normal
      controls. Renal biopsy tissues from five patients with postinfectious GN in which
      crescent formation was not observed were also examined as disease controls. The
      patients were put into both three groups according to immunofluorescence findings
      and two groups according to the active or inactive phase of the crescents: group
      1 with anti-glomerular basement membrane crescentic GN, one case; group 2 with
      immune complex crescentic GN, ten cases; and group 3 with pauci-immune crescentic
      GN, six cases. Four of the nine individuals tested were positive for anti
      neutrophil cytoplasmic antibody (44.4%). Glomerular and interstitial neutrophil
      infiltrations were prominent in both the active and inactive phase groups,
      compared to normal controls (p<.05). Glomerular neutrophil infiltration was
      significantly prominent in the active phase group, compared to the inactive phase
      group (p<.001). In both the active and inactive phase groups, interstitial
      neutrophil infiltration was prominent, compared to disease control groups
      (p<.05). These results support the concept of the participation of periglomerular
      leukocytes in the renal tissue damage of crescentic GN, although the role of
      neutrophils was not examined.

PMID- 10402174
TI  - The effects of peripheral leukocytes on the hippocampal neuronal changes in
      transient global ischemia and unilateral cerebral hemispheric infarction.
AB  - The participation of activated leukocytes and subsequent production of chemical
      mediators has been well accepted in the pathophysiology of hypoxic-ischemic
      injury. This study was performed to see the effects of leukocytes on hippocampal
      neuronal damage in transient global ischemia induced by 10-min occlusion of
      bilateral common carotid arteries (CCAs) with reperfusion for various times, and
      in complete unilateral ischemia induced by 24-hr ligation of left CCA. Leukopenia
      was induced by intraperitoneal injection of cyclophosphamide for 4 days. The
      results showed that hippocampal neuronal damages were worse at 6-hr reperfusion
      in leukopenic experimental group than in the control group. In comparison, 24-hr
      and 3-day reperfusion leukopenic groups showed less numbers of damaged neurons
      and milder changes. The 5-day reperfusion group showed inconsistent changes.
      Unilateral CCA occlusion showed extensive infarction in 83.3% of gerbils in the
      control group, compared to 25% of gerbils in the experimental group (p<0.05).
      These results strongly suggest that the number of peripheral leukocytes were
      closely related to the development of delayed neuronal damage of hippocampus in
      transient global ischemia and the incidence of infarction induced by 24-hr
      unilateral CCA ligation.

PMID- 10402173
TI  - Suppression of NF-kappaB activation in normal T cells by supernatant fluid from
      human renal cell carcinomas.
AB  - T lymphocytes from patients with renal cell carcinoma (RCC) show reduced immune
      function and impaired activation of the transcription factor, NF-kappaB. We
      determined the mechanism of NF-kappaB suppression in T cells of RCC patient and
      determined whether supernatant fluid from RCC explants (RCC-S) induced the same
      phenotype of NF-kappaB suppression in normal T cells that is observed in patient
      T cells. The pattern of kappaB-binding activity in T cells of RCC patient was
      altered as compared to that seen in T cells obtained from normal volunteers. In
      some patients, no activation of RelA/NFkappaB1-binding activity was detectable,
      while in others kappaB-binding activity was modestly induced but the duration was
      reduced. IkappaBalpha was degraded normally following stimulation in both normal
      controls and T cells from RCC patients. RCC-S did not alter the cytoplasmic
      levels of RelA and NF-kappaB1 but did suppress their nuclear localization and
      inhibited the activation of RelA/NF-kappaB1 binding complexes. These results show
      that RCC-S can induce in normal T cells the same phenotype of impaired NF-kappaB
      activation that is detected in T cells of RCC patient. It also appears that NF
      kappaB suppression by RCC-S may contribute to the immunosuppression of host
      immunity.

PMID- 10402175
TI  - Endobronchial actinomycosis simulating endobronchial tuberculosis: a case report.
AB  - We report a case of a 70-year-old woman who presented with mild exertional
      dyspnea and cough. Fiberoptic bronchoscopic findings revealed an endobronchial
      polypoid lesion with stenotic bronchus. The lesion was very similar to
      endobronchial tuberculosis. Histologic examination of the biopsy specimen
      demonstrated Actinomyces infection. There was a clinical response to intravenous
      penicillin therapy. Primary endobronchial actinomycosis must be considered in the
      differential diagnosis of an endobronchial lesion, especially endobronchial
      tuberculosis in Korea.

PMID- 10402176
TI  - Rheumatoid arthritis associated with myelodysplastic syndrome: a case report.
AB  - Myelodysplastic syndromes (MDS) are a group of refractory anemias resulting from
      a clonal stem cell disorder often associated with cytogenetic abnormalities.
      There is increasing recognition of immunological abnormalities in patients with
      MDS, including defective B- and T-cell function, hyper- or hypogammaglobulinemia
      and monoclonal gammopathy. MDS have been associated with Sjogren's syndrome,
      polymyalgia rheumatica, relapsing polychondritis and systemic lupus
      erythematosus. Although there may be various rheumatologic features, including
      acute arthritis in MDS, chronic inflammatory arthritis is uncommonly combined.
      There have been a few reports that described cases of rheumatoid arthritis (RA)
      concurrent with MDS, but advanced rheumatoid arthritis with typical joint
      deformities has rarely been reported. We report a case of rheumatoid arthritis
      with atlantoaxial subluxation combined with refractory anemia in a 31-year-old
      woman.

PMID- 10402177
TI  - Erdheim-Chester disease: a case report.
AB  - A 42-year-old man with Erdheim-Chester disease (EC) is presented. This is the
      first case of this disease reported in Korea. The patient complained of knee pain
      and plain roentgenogram of the bilateral legs revealed diffusely increased
      density, coarsened trabecular pattern, and cortical thickening in the diaphysis,
      and metaphysis as well as epiphysis. Magnetic resonance imaging revealed that the
      lesions showed low signal intensity on T1-weighted images and heterogeneously low
      and high signal intensity on T2-weighted images. Histological examination of the
      biopsy specimen showed a xanthogranulomatous lesion consisting aggregations of
      foamy histiocytes and Touton-type giant cells. Immunohistochemical staining
      showed positive reaction to anti-S-100 and lysozyme in the cytoplasm of the giant
      cells.

PMID- 10402178
TI  - Four cases of therapy-related leukemia.
AB  - Combination chemotherapy and radiation therapy have contributed to the successful
      treatment of various cancer patients. But the development of second malignancies
      is an inevitable complication of long-term cytotoxic treatment. The most serious
      and frequent of such complications is acute myelogenous leukemia (AML). Therapy
      related leukemia is generally fatal. Since the number of patients exposed to
      chemotherapy is increasing each year, the clinical significance of this entity
      cannot be underestimated. There have been many investigations of therapy-related
      leukemia, but in Korea published reports are rare. We describe four such cases,
      involving one older female with lung cancer and three children with acute
      lymphoblastic leukemia (ALL) and malignant lymphoma. Alkylating agents were used
      for chemotherapy, and in one case, topoisomerase II inhibitor. Irrespective of
      the causative agents, the latency periods were relatively short, and despite
      induction chemotherapy in two, all survived for only a few months. During the
      follow-up of patients treated for primary malignancies, the possibility of
      therapy-related leukemia should always be borne in mind.

PMID- 10402179
TI  - Intrapulmonary and gastric teratoma : report of two cases.
AB  - The lung and stomach are very unusual sites for teratoma. The histologic findings
      of intrapulmonary and gastric teratomas are not different from those arising in
      usual sites, such as the ovary or testis. However, preoperative diagnosis is
      sometimes difficult to make partly because of unusual location. We report here
      two cases of teratoma, one intrapulmonary teratoma and the other gastric. The
      intrapulmonary teratoma in our study had an endobronchial tumor growth, which
      rules out mediastinal teratoma. Meanwhile gastric teratomas usually present as a
      submucosal tumor and most cases are reported in infancy and childhood. Gastric
      teratoma in this study occurred in a 27-year-old man. To the best of our
      knowledge, this case of intrapulmonary teratoma is the eighth and the gastric
      teratoma is the first to be reported in Korea.

PMID- 10402180
TI  - Solid mesenchymal hamartoma of the liver in adult.
AB  - This paper presents an unusual solid mesenchymal hamartoma of the liver (MHL) in
      adult. A well defined solid mass in the left lobe of the liver was found in a 57
      year-old female. Preoperative radiologic examinations demonstrated solid mass
      with multifocal calcifications abutting the gallbladder. By light microscopy, the
      lesion was composed of dense fibrous stroma with hyalinization, bile ducts and
      thick-walled vessels without hepatocytes. The solid and hyalinized mesenchymal
      component would suggest an unusual degenerative change representing a burnt-out
      MHL.

PMID- 10402181
TI  - Sclerosing Mucoepidermoid carcinoma with eosinophilia of the thyroid glands: a
      case report with clinical manifestation of recurrent neck mass.
AB  - Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a recently
      recognized malignant neoplasm of the thyroid gland. About 14 cases of SMECE have
      been reported and this is the first reported case in Korea. A 57-year-old woman
      presented with right neck mass for 20 years. Total thyroidectomy was performed
      under the impression of thyroid carcinoma. The resected thyroid gland showed a
      poorly circumscribed hard mass. Histologically, the tumor consisted of solid
      nests of large atypical cells with dense fibrous stroma. The tumor cells showed
      squamoid appearance with abundant eosinophilic cytoplasm. There were also rare
      mucin-containing cells within the nests. Within the hyalinized stroma, numerous
      eosinophils were found. The surrounding thyroid parenchyma displayed Hashimoto's
      thyroiditis. There was metastasis in a regional lymph node. Two years after
      initial surgery, she underwent a modified radical neck dissection due to
      recurrent neck mass. After the radiation therapy for eight weeks, laryngectomy
      and esophagectomy were performed due to a recurrent carcinoma in the esophageal
      wall. We report an additional case of SMECE, with metastasis to regional lymph
      nodes and esophagus. The tumor appears to be more aggressive than previously
      reported and a correct diagnosis can be rendered by just examining the metastatic
      lesions.

PMID- 10402182
TI  - Non-typhoid Salmonella meningitis complicated by a infarction of basal ganglia.
AB  - A previously healthy 16-month-old Korean girl with symptoms of fever, vomiting,
      and generalized tonic seizure was diagnosed to have Group D non-typhoid
      Salmonella meningitis. The patient was treated with ceftriaxone (100 mg/kg/day)
      and amikin (22.5 mg/kg/day) initially and ciprofloxacin (30 mg/kg/day) was added
      later because of clinical deterioration and disseminated intravascular
      coagulation. Brain CT performed on the second day showed a well-demarcated low
      density lesion in the right lentiform nucleus and both caudate nuclei, without
      evidence of increased intracranial pressure. MRI performed on the 11th day
      confirmed CT scan findings as well as right subdural fluid collection, brain
      atrophy, and ventriculomegaly. She underwent subdural drainage and later
      ventriculo-peritoneal shunt operation. Despite receiving intensive treatment, she
      still has severe neurologic sequelae. Our case shows that infarctions of basal
      ganglia and thalami are not specific for tuberculous meningitis and that
      meningitis complicated by infarction is indicative of grave prognosis.

PMID- 10402183
TI  - Gliosarcoma: a case with unusual epithelial feature.
AB  - Astrocytic tumors, particularly gliosarcoma, may contain epithelial features in
      the form of trabecular, adenoid, papillary arrangement, and squamous metaplasia.
      A case of gliosarcoma with unusual epithelial feature is described. The patient
      was a 60-year-old male with frequent seizures. The mass was 4 cm and in the left
      frontal lobe. Trabecular or rarely adenoid arrangement of neoplastic astrocytes
      was present in the mucinous stroma, and there was a distinctive transition
      between the trabecular area and typical anaplastic astrocytoma. The tumor cells
      in the trabecular area showed positive immunostain for glial fibrillary acidic
      protein, but did not react with various kinds of cytokeratin. The sarcomatous
      area was undifferentiated and was not labeled by factor-VIII, desmin, and anti
      smooth muscle actin. Occurrence and histogenesis of epithelial features in
      gliosarcoma are reviewed. The importance to recognize the existence of epithelial
      feature in malignant astrocytic tumor is emphasized.

PMID- 10402185
TI  - The benefits of adding insult to injury.

PMID- 10402184
TI  - Learning something ORIGINal at the Drosophila neuromuscular junction.

PMID- 10402186
TI  - Alpha neurotoxins and their relatives: foes and friends?

PMID- 10402187
TI  - Potassium channels: some assembly required.

PMID- 10402188
TI  - Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity.

PMID- 10402189
TI  - Who tells one hand what the other is doing: the neurophysiology of bimanual
      movements.

PMID- 10402190
TI  - Genetic malformations of the human cerebral cortex.

PMID- 10402191
TI  - Alternatively spliced isoforms of nerve- and muscle-derived agrin: their roles at
      the neuromuscular junction.
AB  - Agrin induces synaptic differentiation at the skeletal neuromuscular junction
      (NMJ); both pre- and postsynaptic differentiation are drastically impaired in its
      absence. Multiple alternatively spliced forms of agrin that differ in binding
      characteristics and bioactivity are synthesized by nerve and muscle cells. We
      used surgical chimeras, isoform-specific mutant mice, and nerve-muscle cocultures
      to determine the origins and nature of the agrin required for synaptogenesis. We
      show that agrin containing Z exons (Z+) is a critical nerve-derived inducer of
      postsynaptic differentiation, whereas neural isoforms containing a heparin
      binding site (Y+) and all muscle-derived isoforms are dispensable for major steps
      in synaptogenesis. Our results also suggest that the requirement of agrin for
      presynaptic differentiation is mediated indirectly by its ability to promote
      postsynaptic production or localization of appropriate retrograde signals.

PMID- 10402193
TI  - latheo, a Drosophila gene involved in learning, regulates functional synaptic
      plasticity.
AB  - Mutations in the latheo (lat) gene disrupt associative learning in Drosophila ,
      but a role for LAT in regulating neuronal function has not been demonstrated.
      Here, we report that LAT plays a central role in regulating Ca2(+)- and activity
      dependent synaptic plasticity. Immunological localization of the LAT protein
      indicates it is present at synaptic connections of the larval neuromuscular
      junction (NMJ) and is enriched in presynaptic boutons. Basal synaptic
      transmission amplitude at the lat mutant NMJ is elevated 3- to 4-fold, and Ca2+
      dependence of transmission is significantly reduced. Multiple forms of synaptic
      facilitation and posttetanic potentiation (PTP) are strongly depressed or absent
      at the mutant synapse. Our results suggest that LAT is a novel presynaptic
      protein with a role in the Ca2(+)-dependent synaptic modulation mechanisms
      necessary for behavioral plasticity.

PMID- 10402192
TI  - latheo encodes a subunit of the origin recognition complex and disrupts neuronal
      proliferation and adult olfactory memory when mutant.
AB  - The Drosophila latheo (lat) gene was identified in a behavioral screen for
      olfactory memory mutants. The original hypomorphic latP1 mutant (Boynton and
      Tully, 1992) shows a structural defect in adult brain. Homozygous lethal lat
      mutants lack imaginal discs, show little cell proliferation in the CNS of third
      instar larvae, and die as early pupae. latP1 was cloned, and all of the above
      mentioned defects of hypomorphic or homozygous lethal lat mutants were rescued
      with a lat+ transgene. lat encodes a novel protein with homology to a subunit of
      the origin recognition complex (ORC). Human and Drosophila LAT both associate
      with ORC2 and are related to yeast ORC3, suggesting that LAT functions in DNA
      replication during cell proliferation.

PMID- 10402194
TI  - NUMB localizes in the basal cortex of mitotic avian neuroepithelial cells and
      modulates neuronal differentiation by binding to NOTCH-1.
AB  - The importance of lateral inhibition mediated by NOTCH signaling is well
      demonstrated to control neurogenesis both in invertebrates and vertebrates. We
      have identified the chicken homolog of Drosophila numb, which suppresses NOTCH
      signaling. We show that chicken NUMB (c-NUMB) protein is localized to the basal
      cortex of mitotic neuroepithelial cells, suggesting that c-NUMB regulates
      neurogenesis by the modification of NOTCH signaling through asymmetrical cell
      division. Consistent with this suggestion, we show (1) that c-NUMB interferes
      with the nuclear translocation of activated c-NOTCH-1 through direct binding to
      the PEST sequence in the cytoplasmic domain of c-NOTCH-1 and (2) that c-NUMB
      interferes with c-NOTCH-1-mediated inhibition of neuronal differentiation.

PMID- 10402195
TI  - Regeneration of dorsal column fibers into and beyond the lesion site following
      adult spinal cord injury.
AB  - Regeneration is abortive following adult mammalian CNS injury. We have
      investigated whether increasing the intrinsic growth state of primary sensory
      neurons by a conditioning peripheral nerve lesion increases regrowth of their
      central axons. After dorsal column lesions, all fibers stop at the injury site.
      Animals with a peripheral axotomy concomitant with the central lesion show axonal
      growth into the lesion but not into the spinal cord above the lesion. A
      preconditioning lesion 1 or 2 weeks prior to the dorsal column injury results in
      growth into the spinal cord above the lesion. In vitro, the growth capacity of
      DRG neurite is also increased following preconditioning lesions. The intrinsic
      growth state of injured neurons is, therefore, a key determinant for central
      regeneration.

PMID- 10402196
TI  - Role of alpha9 nicotinic ACh receptor subunits in the development and function of
      cochlear efferent innervation.
AB  - Cochlear outer hair cells (OHCs) express alpha9 nACh receptors and are contacted
      by descending, predominately cholinergic, efferent fibers originating in the CNS.
      Mice carrying a null mutation for the nACh alpha9 gene were produced to
      investigate its role(s) in auditory processing and development of hair cell
      innervation. In alpha9 knockout mice, most OHCs were innervated by one large
      terminal instead of multiple smaller terminals as in wild types, suggesting a
      role for the nACh alpha9 subunit in development of mature synaptic connections.
      Alpha9 knockout mice also failed to show suppression of cochlear responses
      (compound action potentials, distortion product otoacoustic emissions) during
      efferent fiber activation, demonstrating the key role alpha9 receptors play in
      mediating the only known effects of the olivocochlear system.

PMID- 10402197
TI  - lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in
      the mammalian CNS.
AB  - Elapid snake venom neurotoxins exert their effects through high-affinity
      interactions with specific neurotransmitter receptors. A novel murine gene,
      lynx1, is highly expressed in the brain and contains the cysteine-rich motif
      characteristic of this class of neurotoxins. Primary sequence and gene structure
      analyses reveal an evolutionary relationship between lynx1 and the Ly
      6/neurotoxin gene family. lynx1 is expressed in large projection neurons in the
      hippocampus, cortex, and cerebellum. In cerebellar neurons, lynx1 protein is
      localized to a specific subdomain including the soma and proximal dendrites.
      lynx1 binding to brain sections correlates with the distribution of nAChRs, and
      application of lynx1 to Xenopus oocytes expressing nAChRs results in an increase
      in acetylcholine-evoked macroscopic currents. These results identify lynx1 as a
      novel protein modulator for nAChRs in vitro, which could have important
      implications in the regulation of cholinergic function in vivo.

PMID- 10402198
TI  - The parahippocampal place area: recognition, navigation, or encoding?
AB  - The parahippocampal place area (PPA) has been demonstrated to respond more
      strongly in fMRI to scenes depicting places than to other kinds of visual
      stimuli. Here, we test several hypotheses about the function of the PPA. We find
      that PPA activity (1) is not affected by the subjects' familiarity with the place
      depicted, (2) does not increase when subjects experience a sense of motion
      through the scene, and (3) is greater when viewing novel versus repeated scenes
      but not novel versus repeated faces. Thus, we find no evidence that the PPA is
      involved in matching perceptual information to stored representations in memory,
      in planning routes, or in monitoring locomotion through the local or distal
      environment but some evidence that it is involved in encoding new perceptual
      information about the appearance and layout of scenes.

PMID- 10402199
TI  - Processing of visually presented sentences in Mandarin and English studied with
      fMRI.
AB  - Comprehension of visually presented sentences in fluent bilinguals was studied
      with functional magnetic resonance imaging (fMRI) using a set of conceptually
      similar sentences in two orthographically and phonologically distinct languages,
      Mandarin and English. Responses were monitored during scanning. Sentence
      comprehension in each language was compared to fixation in nine subjects and
      Tamil-like pseudo-word strings in five subjects. Spatially congruent activations
      in the prefrontal, temporal, and superior parietal regions and in the anterior
      supplementary motor area were observed for both languages and in both experiments
      at the individual and group levels of analysis. Proficient bilinguals exposed to
      both languages early in life utilize common neuroanatomical regions during the
      conceptual and syntactic processing of written language irrespective of their
      differences in surface features.

PMID- 10402200
TI  - Phospholipase C-gamma and phosphoinositide 3-kinase mediate cytoplasmic signaling
      in nerve growth cone guidance.
AB  - Expression of rat TrkA in Xenopus spinal neurons confers responsiveness of these
      neurons to nerve growth factor (NGF) in assays of neuronal survival and growth
      cone chemotropism. Mutational analysis indicates that coactivation of
      phospholipase C-gamma (PLC-gamma) and phosphoinositide 3-kinase (PI3-kinase) by
      specific cytoplasmic domains of TrkA is essential for triggering chemoattraction
      of the growth cone in an NGF gradient. Uniform exposure of TrkA-expressing
      neurons to NGF resulted in a cross-desensitization of turning responses induced
      by a gradient of netrin-1, brain-derived neurotrophic factor (BDNF), or myelin
      associated glycoprotein (MAG) but not by a gradient of collapsin-1/semaphorin
      III/D or neurotrophin-3 (NT-3). These results, together with the effects of
      pharmacological inhibitors, support the notion that there are common cytosolic
      signaling pathways for two separate groups of guidance cues, one of which
      requires coactivation of PLC-gamma and PI3-kinase pathways.

PMID- 10402201
TI  - Molecular determinants for subcellular localization of PSD-95 with an interacting
      K+ channel.
AB  - Ion channels and PSD-95 are colocalized in specific neuronal subcellular
      locations by an unknown mechanism. To investigate mechanisms of localization, we
      used biolistic techniques to express GFP-tagged PSD-95 (PSD-95:GFP) and the K(+)
      selective channel Kv1.4 in slices of rat cortex. In pyramidal cells, PSD-95:GFP
      required a single PDZ domain and a region including the SH3 domain for
      localization to postsynaptic sites. When transfected alone, PSD-95:GFP was
      present in dendrites but absent from axons. When cotransfected with Kv1.4, PSD
      95:GFP appeared in both axons and dendrites, while Kv1.4 was restricted to axons.
      When domains that mediate the interaction of Kv1.4 and PSD-95 were disrupted,
      Kv1.4 localized nonspecifically. Our results provide evidence that Kv1.4 itself
      may determine its subcellular location, while an associated MAGUK protein is a
      necessary but not sufficient cofactor.

PMID- 10402202
TI  - A novel presynaptic inhibitory mechanism underlies paired pulse depression at a
      fast central synapse.
AB  - Several distinct mechanisms may cause synaptic depression, a common form of short
      term synaptic plasticity. These include postsynaptic receptor desensitization,
      presynaptic depletion of releasable vesicles, or other presynaptic mechanisms
      depressing vesicle release. At the endbulb of Held, a fast central calyceal
      synapse in the auditory pathway, cyclothiazide (CTZ) abolished marked paired
      pulse depression (PPD) by acting presynaptically to enhance transmitter release,
      rather than by blocking postsynaptic receptor desensitization. PPD and its
      response to CTZ were not altered by prior depletion of the releasable vesicle
      pool but were blocked by lowering external calcium concentration, while raising
      external calcium enhanced PPD. We conclude that a major component of PPD at the
      endbulb is due to a novel, transient depression of release, which is dependent on
      the level of presynaptic calcium entry and is CTZ sensitive.

PMID- 10402203
TI  - Identification and mechanism of action of two histidine residues underlying high
      affinity Zn2+ inhibition of the NMDA receptor.
AB  - Zinc (Zn2+) inhibition of N-methyl-D-aspartate receptor (NMDAR) activity involves
      both voltage-independent and voltage-dependent components. Recombinant NR1/NR2A
      and NR1/NR2B receptors exhibit similar voltage-dependent block, but voltage
      independent Zn2+ inhibition occurs with much higher affinity for NR1/NR2A than
      NR1/NR2B receptors (nanomolar versus micromolar IC50, respectively). Here, we
      show that two neighboring histidine residues on NR2A represent the critical
      determinant (termed the "short spacer") for high-affinity, voltage-independent
      Zn2+ inhibition using the Xenopus oocyte expression system and site-directed
      mutagenesis. Mutation of either one of these two histidine residues (H42 and H44)
      in the extracellular N-terminal domain of NR2A shifted the IC50 for high-affinity
      Zn2+ inhibition approximately 200-fold without affecting the EC50 of the
      coagonists NMDA and glycine. We suggest that the mechanism of high-affinity Zn2+
      inhibition on the NMDAR involves enhancement of proton inhibition.

PMID- 10402204
TI  - A YAC mouse model for Huntington's disease with full-length mutant huntingtin,
      cytoplasmic toxicity, and selective striatal neurodegeneration.
AB  - We have produced yeast artificial chromosome (YAC) transgenic mice expressing
      normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental
      and tissue-specific manner identical to that observed in Huntington's disease
      (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities,
      indicating cytoplasmic dysfunction prior to observed nuclear inclusions or
      neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration
      of medium spiny neurons in the lateral striatum associated with the translocation
      of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in
      the absence of macro- or microaggregates, clearly showing that aggregates are not
      essential to initiation of neuronal death. These mice demonstrate that initial
      neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear
      translocation of htt N-terminal fragments, and selective neurodegeneration.

PMID- 10402206
TI  - Cellular response to Echinostoma caproni infection in Biomphalaria glabrata
      strains selected for susceptibility/resistance.
AB  - The Biomphalaria glabrata/Schistosoma mansoni system represented the only model
      available so far, for investigating snail resistance to parasites. A new host
      parasite model has been recently provided by selection of B. glabrata strains
      that are genetically resistant and susceptible to Echinostoma caproni. As a first
      approach in investigating resistance mechanisms in this model, we compared the
      hemocytic response and its effect on E. caproni development in a susceptible and
      a resistant strains. Histological analysis revealed that resistance does not
      prevent penetration or migration through the snail tissues. However, all mother
      sporocysts (MS) settled in the ventricle and the aorta of resistant snails were
      encapsulated and killed by 4 days post-exposure. MS abnormally settled in the
      pericardial cavity were not encapsulated and could survive for 5 days. Regardless
      of their level of encapsulation, all live MS observed during the first days of
      infection in resistant snails showed abnormal development and degeneration,
      raising the question of the possible role of humoral factors in the resistance to
      E. caproni. Finally, we observed an increased number of adherent hemocytes in the
      resistant as compared with the susceptible snails after parasite exposure. This
      different effect on circulating hemocyte subpopulations may reflect the failure
      of E. caproni to interfere with the hemocytic response of resistant snails.

PMID- 10402205
TI  - Molecular cloning and characterization of prophenoloxidase in the black tiger
      shrimp, Penaeus monodon.
AB  - A cDNA encoding shrimp, Penaeus monodon, prophenoloxidase (proPO) was obtained by
      screening a hemocyte library by plaque hybridization using a proPO cDNA fragment
      from freshwater crayfish, Pacifastaceus leniusculus, as a probe. The 3,002 bp
      cDNA contains an open reading frame of 2,121 bp and a 881 bp 3'-untranslated
      region. The molecular mass of the deduced amino acid sequence (688 amino acids)
      is 78,700 Da with an estimated pI of 5.8. Two putative copper binding sites are
      present and they have a highly conserved sequence around these sites. No signal
      peptide was detected in the shrimp proPO, as has been previously shown to be the
      case for all arthropod proPOs cloned so far. The cleavage site of zymogen
      activation is likely to be between Arg 44 and Val 45. A tentative complement-like
      motif (GCGWPQHM) is also present. Shrimp proPO mRNA is synthesized in the
      hemocytes and not in the hepatopancreas. Comparison of amino acid sequences
      showed that shrimp proPO is more closely related to another crustacean proPO,
      namely crayfish, than to the insect proPOs.

PMID- 10402207
TI  - Catfish Oct2 binding affinity and functional preference for octamer motifs, and
      interaction with OBF-1.
AB  - The DNA-binding (POU) domain of the catfish Oct2 transcription factor was shown,
      by electromobility shift assays and surface plasmon resonance techniques, to have
      an affinity for the consensus octamer motif (ATGCAAAT) that was slightly higher
      than its affinity for a variant motif (ATGtAAAT). This observation is consistent
      with the transcriptional activation potentials of catfish Oct2 alpha and Oct2
      beta, which were shown to activate transcription in catfish B and T cell lines to
      an equivalent extent from both the consensus and variant octamer motifs. When
      tested in a mouse plasmacytoma cell line, catfish Oct2 alpha and Oct2 beta, as
      well as mouse Oct2, showed higher transcriptional activation with the variant, as
      compared to the consensus, octamer motif. Catfish Oct2 was shown to function
      synergistically with the mammalian co-activator, OBF-1, activating octamer
      dependent transcription in catfish T cells. The strong transcriptional activity
      of OBF-1 in catfish cells was dependent on the presence of octamer motif(s) at
      the proximal (promoter) rather than the distal (enhancer) position.

PMID- 10402208
TI  - Analysis of localization and function of the COOH-terminal corresponding site of
      cytochrome b558 in fish neutrophils.
AB  - Using an antibody against the synthetic peptide corresponding to the COOH
      terminal region of human cytochrome b558 large subunit, a broad band was
      specifically detected in neutrophil lysates from 6 marine fish and 2 freshwater
      fish by western blotting. Immunofluorescence assay showed that the antibody
      recognized the epitopes in eel and tilapia neutrophils permeabilized with
      detergent. These results suggest that the cytochrome b large subunit universally
      exists in fish neutrophils and that the epitopes are exposed to the cytoplasmic
      side of fish neutrophils as well as human neutrophils. Furthermore, a synthetic
      peptide corresponding to the COOH-terminus of the large subunit apparently
      blocked superoxide production in a specific and dose-dependent fashion in eel and
      tilapia neutrophils, indicating that the region equivalent to the COOH-terminus
      of cytochrome b large subunit is responsible for superoxide generation in fish
      neutrophils.

PMID- 10402209
TI  - Antigen receptor-mediated activation of extracellular related kinase (ERK) in B
      lymphocytes of teleost fishes.
AB  - In mammalian B lymphocytes, engagement of the B cell antigen receptor (BCR)
      activates several parallel intracellular signaling pathways which ultimately lead
      to expression of differentiated functions such as cell proliferation and antibody
      production or to cellular apoptosis. BCR engagement stimulates the classical
      mitogen activated protein kinase (MAPK) pathway, also called the extracellular
      related kinase (ERK) pathway, resulting in activation of the signature terminal
      enzyme in the pathway, MAPK (or ERK). BCR signaling also activates the
      phosphatidyl inositol pathway and its key enzyme protein kinase C (PKC). To
      investigate the ERK pathway in cells of the teleost immune system, peripheral
      blood leukocytes from red drum or channel catfish were treated with PKC
      activators or antibodies which crosslink the BCR. Proteins were identified in
      both red drum and catfish B cells that resembled mammalian ERKs in molecular
      weight and in their possessing a distinctive pTEpY dual phosphorylation site. BCR
      mediated activation of these presumptive teleost ERKs depended in part (red drum)
      or in total (catfish) on PKC. To our knowledge this represents the first report
      of a functional MAPK kinase pathway in teleost fish.

PMID- 10402210
TI  - Light chain variable region diversity in Atlantic cod (Gadus morhua L.).
AB  - This study was undertaken to determine if a lack of V(L) domain variability could
      explain, in part, the failure of Atlantic cod to respond to immunization with the
      production of specific antibodies. The variability of cod V(L) regions was
      studied in 33 cDNA and two genomic clones. The variability of the CDRs was
      estimated by the Shannon entropy method and compared with that in other species.
      It was found to be lowest in the little skate (Raja erinacea), higher in cod, and
      highest in Xenopus and mouse. While the variability of the CDRs is slightly lower
      in cod than in Xenopus and mouse, it is spread over broader areas of the amino
      acid sequence. The length of CDR1 and CDR3 in cod is equal to or exceeds that
      found in skate, Xenopus, chicken and mammals. Isoelectric points and
      hydrophobicity vary substantially among the studied Ig light chain domains. Thus,
      neither the length, nor the variability, nor the physicochemical properties (pI
      and hydrophobicity) of the L chain CDRs can explain the absence of antibody
      response to immunization in cod.

PMID- 10402211
TI  - Natural and induced apoptosis during lymphocyte development in the axolotl.
AB  - Lymphocytes apoptosis was characterized in a urodele amphibian, the axolotl, by
      morphology using electron microscopy and by flow cytometry after propidium iodide
      staining, as well as by biochemical criteria with the detection of DNA ladders
      after glucocorticoid treatment. The morphological and biochemical features
      observed in treated axolotls are in accordance with the criteria of apoptosis
      found in different models of mammalian lymphocyte programmed cell death. The
      onset of natural apoptosis was then detected by DNA fragmentation in thymus and
      in spleen during lymphocyte development and ontogenesis. A typical DNA ladder
      characteristic of apoptosis is detectable in the thymus as early as 5 months;
      apoptosis increases and peaks at 8 months, and is no longer detected by 10 months
      or thereafter. The ability of a superantigen, Staphylococcus aureus enterotoxin B
      (SEB), to induce T lymphocyte apoptosis in larvae was investigated as well. In
      vivo exposure of young axolotl larvae to SEB induces, as in mammals, thymocyte
      apoptosis as indicated by the enhancement of DNA fragmentation. These last
      results, natural programmed cell death and SEB induced apoptosis during thymic
      ontogeny, are discussed in correlation with what is known during mammalian thymic
      selection and apoptosis.

PMID- 10402212
TI  - Treatment of the macrophage-like P388D.1 cells with bacterial lipopolysaccharide
      and interferon-gamma causes long-term alterations in calcium metabolism.
AB  - The intracellular calcium concentrations ([Ca2+]i) of P338D.1 macrophage-like
      cells, activated with interferon-gamma (IFN-gamma) and/or bacterial
      lipopolysaccharide (LPS) were determined using fura-2/AM and ratiometric imaging
      techniques. Treatment of macrophages with IFN-gamma and LPS resulted in
      significant downward shift in [Ca2+]i, 8, 16 and 24 h but not at 1 and 4 h after
      treatment. The decrease in [Ca2+]i also occurred when macrophages were treated
      with LPS only, but not after exposure of the cells to recombinant IFN-gamma,
      indicating that LPS was an essential signal in the observed changes in [Ca2+]i of
      activated macrophages. The IFN-gamma and/or LPS alteration in the [Ca2+]i,
      paralleled the in vitro nitric oxide production of the activated macrophages, 8,
      16 and 24 h after treatment. The decrease in the [Ca2+]i may be caused by
      vigorous buffering and storing of Ca2+ by macrophages to below the normal resting
      quantities, following the reported transient increase in Ca2+ during the priming
      stage of macrophage activation. Thus, the downward shift in [Ca2+]I may play a
      physiological role in the activation processes of macrophages for antimicrobial
      responses.

PMID- 10402213
TI  - Thromboxane receptors in human kidney tissues.
AB  - Thromboxane (TX) A2 effects in the kidneys include contraction of glomerular
      mesangial cells and intrarenal vascular tissue. A kidney cDNA encoding a TX
      receptor expressed in rat renal glomeruli and rat renal arterial smooth muscle
      cells has been reported. However, TXA2 receptors in human kidneys have not been
      documented. The purpose of this study was to identify and characterize TXA2
      receptors in glomeruli and intrarenal arteries isolated from human kidneys.
      Normal kidneys, not used for transplant because of technical reasons, were kept
      at -70 degrees C and used for research purposes. The glomeruli and intrarenal
      arteries were isolated from renal cortical tissue by a mechanical sieving
      technique. The equilibrium dissociation constant and receptor number were
      determined by nonlinear analysis of binding inhibition data. The data were
      generated in radioreceptor assays using [125I]-BOP, a stable analog of TXA2. The
      dissociation constants (mean +/- SEM) for binding of I-BOP to human glomeruli and
      intrarenal arterial membranes were 6.6 +/- 1.1 nM (n = 7) and 20 +/- 6 nM (n =
      7), respectively (p < 0.05). The receptor number was 311 +/- 91 fmol/mg protein
      (n = 7) in glomeruli and 74 +/- 16 fmol/mg protein (n = 7) in intrarenal arterial
      membranes (p < 0.04). The order of specificity of TXA2 analogs for [125I]-BOP
      binding sites was similar in glomeruli and in arterial membranes and was I-BOP >
      or = U46619 > or = pinane TXA2 > or = carbocyclic TXA2 > or = PGH2. These
      findings provide direct evidence for the presence of specific, high-affinity
      [125I]-BOP binding sites in human renal glomeruli and extraglomerular vascular
      tissue. These data also indicate that the human binding sites have higher
      affinity for the TXA2 agonist I-BOP than for PGH2.

PMID- 10402214
TI  - PGE2 induces its own secretion in vitro by bovine 270-day placenta but not by 200
      day placenta.
AB  - Two separate experiments were conducted to determine whether prostaglandin (PG)
      E2 stimulates the secretion of progesterone by 270- or 200-day Brahman placentas
      in vitro. Secretion of progesterone, PGF2alpha, pregnancy specific protein B, or
      estradiol-17beta by 270-day Brahman placentas was not affected (p > or = 0.05) by
      PGE2, during the 4-h incubation period at the doses tested. Indomethacin or
      meclofenamic acid decreased (p < or = 0.05) 270-day Brahman placental secretion
      of PGE and PGF2alpha by 98 and 60%, respectively. However, PGE2 induced (p < or =
      0.05) its own secretion, but not the secretion of PGF2alpha (p > or = 0.05), by
      270-day Brahman placentas, even in the presence of indomethacin or meclofenamic
      acid at a dose of 100 ng/mL. Also, secretion of 8-Epi-PGE2 by Day 270 Brahman
      placentas was increased (p < or = 0.05) by PGE2. Secretion of progesterone,
      estradiol-17beta, or pregnancy specific protein B by 200-day Brahman placentas
      was not affected by PGE2, 8-Epi-PGE2, PGF2alpha, estradiol-17beta, or
      trichosanthin during the 4- or 8-h incubation period (p > or = 0.05). Secretion
      of estradiol-17beta at 8 h was lower (p < or = 0.05) in all treatment groups and
      did not differ (p > or = 0.05) among the 8-h incubation treatment groups.
      Secretion of PGE by 200-day Brahman placentas was reduced (p < 0.05) by
      indomethacin 72 and 82% and by meclofenamic acid 72 and 96%, respectively, at 4
      and 8 h when compared to controls. Secretion of PGF2alpha was reduced (p < or =
      0.05) 71 and 86% by indomethacin or 89 and 89% by meclofenamic acid at 4 and 8 h,
      respectively, and did not differ (p > or = 0.05) between 4 and 8 h of incubation.
      PGE2 did not (p > or = 0.05) induce secretion of PGE above what was added in any
      treatment group. PGE in culture media was increased (p < or = 0.05) by 8-Epi
      PGE2, pregnancy specific protein B, and the 100 ng/mL PGF2alpha dose (p < or =
      0.05), but not by PGE2, progesterone, estradiol-17beta, 8-Epi-PGF2alpha, or
      trichosanthin. Secretion of PGF2alpha by 200-day Brahman placentas was not
      affected (p > or = 0.05) by 8-Epi-PGE2, progesterone, or estradiol-17beta, but
      PGF2alpha secretion was increased (p < or = 0.05) by trichosanthin or PGE2, even
      in the presence of indomethacin or meclofenamic acid. It is concluded that PGE
      does not affect secretion of progesterone by 200- or 270-day bovine placentas,
      but, pregnancy specific protein B may regulate placental secretion of PGE. Also,
      indomethacin and meclofenamic may affect enzymes converting PGH to PGE rather
      than acting only on cyclooxygenase because indomethacin and meclofenamic acid
      lowered PGE secretion by 270-day Brahman placentas more than they lowered
      PGF2alpha. In addition, it is concluded that PGE2 can induce bovine placental
      secretion of PGE, but this is dependent upon the stage of gestation.

PMID- 10402215
TI  - Effect of different classes of antibiotics on amniotic prostaglandin E release.
AB  - Our purpose was to investigate the effects of different classes of antibiotics,
      namely beta-lactamines, aminoglicosides, tetracyclines, macrolides, on amniotic
      prostaglandin E release to clarify their role in the treatment of premature
      labor. The effects of these antibiotics were tested also in combination with
      ampicillin, whose antiprostaglandinergic action had been demonstrated previously.
      Ceftriaxone and gentamicin significantly and reversibly inhibit both basal and
      arachidonic acid- or oxytocin-stimulated prostaglandin E release from amnion,
      although to a different extent. On the contrary, tetracycline and erythromycin do
      not influence prostaglandin E output. The inhibitory effect of ampicillin is
      potentiated, in an additive manner, by ceftriaxone, reduced by gentamycin, and
      eliminated by tetracycline and erythromycin. The finding that diverse classes of
      antibiotics and their combinations affect amniotic prostaglandin E release should
      be taken into account in the management of premature labor.

PMID- 10402217
TI  - Progesterone and estradiol secretion by porcine luteal cells is influenced by
      individual and combined treatment with prostaglandins E2 and F2alpha throughout
      the estrus cycle.
AB  - The present experiments were conducted to test whether the ratio of
      PGE2:PGF2alpha affects steroid secretion by porcine luteal cells. We examined the
      effect of separate and combined treatment with PGE2 and PGF2alpha on progesterone
      and estradiol secretion. Luteal cells were collected at three different stages of
      the luteal phase (1-3 days after ovulation; 10-12 days after ovulation and 14-16
      days after ovulation). PGE2 alone in a dose dependent manner increased
      progesterone production by cells collected from mature corpora lutea. On the
      other hand, PGF2alpha in a dose dependent manner decreased progesterone secretion
      by cells of the same origin. Progesterone secretion by cells isolated from mature
      and regressing corpora lutea and treated with both prostaglandins increased in
      comparison to PGF2alpha-treated cultures. However, in cells collected from
      regressing corpora lutea PGE2 and PGF2alpha in a ratio of 2:1 and 4:1 increased
      estradiol production when compared to control and both ratios increased estradiol
      secretion in comparison to PGF2alpha-treated cells. These data 1) confirm the
      luteotropic effect of PGE2 and the luteolytic effect of PGF2alpha; 2) demonstrate
      that when the ratio of PGE2 to PGF2alpha changed from 1:1 to 2:1 or 4:1 cells
      were protected against the inhibitory effects of PGF2alpha on progesterone
      secretion by cells collected during the mid- and late luteal phase; and 3)
      suggest that elevated estradiol production by luteal cells, isolated during late
      luteal phase, under the influence of increased doses of PGE2 may serve as an
      additional source of estradiol to blastocysts, during early pregnancy in the pig.

PMID- 10402216
TI  - Estrogen effects on platelet-activating factor and platelet-activating factor
      acetylhydrolase activity in rat uterus during the late stages of pregnancy.
AB  - The platelet-activating factor (PAF) concentration of the uterus spontaneously
      increased during pregnancy. When 17alpha-ethynylestradiol (0.25 mg/kg) was
      administered subcutaneously to pregnant rats for 3 days starting on Day 17 of
      pregnancy, some rats delivered prematurely on Day 20. However, none of the
      vehicle-treated (80% dimethylsulfoxide and 20% ethanol) pregnant rats delivered
      prematurely. The PAF concentration of the uterus in pregnant rats treated with
      17alpha-ethynylestradiol was significantly higher than in those treated with
      vehicle on Days 19 and 20. On the other hand, the specific activity of uterine
      PAF-acetylhydrolase (PAF-AH) in pregnant rats treated with 17alpha
      ethynylestradiol was significantly lower than in those treated with vehicle on
      Days 19 and 20, and the plasma PAF-AH activity in pregnant rats treated with
      estrogen was also significantly lower than in treated with vehicle on Days 18,
      19, and 20. These findings indicate that estrogen increases PAF concentrations in
      the rat uterus, and this was correlated with a decrease in PAF-AH in the uterus
      and plasma. The increase in PAF concentrations in the uterus may be related to
      premature delivery and labor caused by PAF's known effect on myometrial
      contraction.

PMID- 10402218
TI  - Key enzymes of prostaglandin biosynthesis and metabolism. Coordinate regulation
      of expression by cytokines in gestational tissues: a review.
AB  - Preterm labor is frequently associated with ascending intrauterine infection,
      accompanied by leukocytes infiltration and enhanced local production of cytokines
      and other inflammatory mediators. The resulting amplification of the inflammatory
      response, and of prostanoid production in particular, is postulated to be a
      principal mechanism of infection-driven preterm labor. In this review the effects
      of pro- and anti-inflammatory cytokines are discussed with respect to the
      expression of enzymes involved in three key steps of prostanoid biosynthesis and
      metabolism: liberation of arachidonic acid (AA), conversion of AA to bioactive
      prostanoids, and prostanoid catabolism. We suggest that by exerting coordinate
      actions on all three key steps, through multiple molecular mechanisms,
      inflammatory cytokines acutely up-regulate prostanoid production in intrauterine
      tissues.

PMID- 10402219
TI  - Effects of administration of oxytocin on embryonic survival in progestogen
      supplemented cattle.
AB  - Embryonic survival after administration of oxytocin (OT) was examined in 42 beef
      cows. All cows were bred (Day 0) and randomly assigned to receive either 25 mL
      saline (CON; n = 10), 100 IU OT + 20 mL saline (OT; n = 12), 100 IU OT + 1 g
      flunixin meglumine (OT + FM; inhibitor of prostaglandin endoperoxide synthase; n
      = 10), or 100 IU OT + lutectomy (OT + LUT; n = 10) administered (i.m.) at 8-h
      intervals on Days 5-8 after mating. Lutectomies were performed by transrectal
      digital pressure prior to initiation of treatments (0600, Day 5). All cows were
      fed 4 mg/head/day of melengesterol acetate (an orally administered exogenous
      progestogen) through Days 3-30 and were bled by jugular venipuncture at 0600 and
      0700 h on Day 5 for determination of 13,14-dihydro-15-keto-PGF2a (PGFM).
      Pregnancy rates, as determined by transrectal ultrasonography at Day 30, were
      reduced in OT (33.3%) and OT + LUT (30%) groups compared to CON and OT + FM (80%;
      p < or = 0.03). Number of short cycles were increased in OT (n = 6/12) group
      compared to CON (n = 0/10; p < or = 0.009) and OT + FM (n = 1/10; p < or =
      0.045). Mean change in PGFM from the 0600 to 0700 h bleed was different (p < or =
      0.01) between the OT + LUT (31.6 +/- 11.0 pg/mL) group versus CON (-11.2 +/- 10.6
      pg/mL) and OT + FM (-13.8 +/- 10.6 pg/mL) groups. Administration of oxytocin
      appears to decrease embryonic survival by stimulating uterine PGF2a. Thus,
      previous reports indicating that removal of the corpus luteum during progestogen
      supplementation and prior to PGF2a administration increases embryonic survival
      can be explained through interruption of the luteal oxytocin-uterine PGF2a
      feedback loop.

PMID- 10402220
TI  - Maternal cigarette smoking increases F2-isoprostanes and reduces prostacyclin and
      nitric oxide in umbilical vessels.
AB  - The objective of this study was to evaluate the influence of smoking on F2
      isoprostanes, prostacylin and nitric oxide in human umbilical vessels. Umbilical
      cords from 13 babies of smoking mothers and from 28 babies of non-smoking mothers
      were examined for levels of F2-isoprostanes, prostacyclin, L-arginine, and L
      citrulline. Forty-one umbilical arteries and eleven umbilical veins were
      analyzed. Statistical analysis of data was done using modified t-test. Cigarette
      smoking increased F2-isoprostane levels and reduced the generation of
      prostacyclin, L-arginine and L-citrulline comparably in umbilical arteries and
      veins. Notably, in umbilical cords of babies of non-smoking mothers the F2
      isoprostane level was significantly higher in arteries. Cigarette smoking
      correlates with a direct vasoconstrictive effect. We suggest that smoking might
      enhance the vasoconstrictory capacity in umbilical arteries by increased F2
      isoprostanes and by a simultaneous decrease in the production of the vasodilatory
      compounds, prostacyclin, and nitric oxide.

PMID- 10402221
TI  - Distinct mechanisms underlay DNA disintegration during apoptosis induced by
      genotoxic and nongenotoxic agents in neuroblastoma cells.
AB  - Exposure of mouse NB-2a neuroblastoma cells to genotoxic (etoposide or cytosine
      arabinoside) or nongenotoxic challenges (serum deprivation or okadaic acid)
      resulted in progressive cell death with biochemical and morphological
      characteristics typical of apoptosis. Apoptotic cell death induced by
      nongenotoxic agents was associated with the disintegration of nuclear DNA into
      high molecular weight (HMW) and oligonucleosomal-DNA fragments, while the
      formation of HMW-DNA fragments, but not oligonucleosomal-DNA ladder accompanied
      apoptosis induced by genotoxic agents. Combination of genotoxic and nongenotoxic
      insults, i.e. incubation of etoposide-treated cells in the serum-free medium,
      resulted in an additive effect on the profile of DNA disintegration, which
      involved both HMW fragmentation pattern as in etoposide alone treated cells and
      the oligonucleosomal-DNA ladder observed with serum-deprived cells. On the other
      hand, incubation of serum-deprived cells in the presence of Zn2+-ions led to the
      abrogation of internucleosomal DNA fragmentation but accumulation of HMW-DNA
      fragments. Differences in the pattern of DNA fragmentation were reproducible in a
      cell free apoptotic system after treatment of isolated normal nuclei with
      cytosolic extracts prepared from the cells treated with genotoxic or nogenotoxic
      apoptotic inducers. Cell free experiments also revealed that activities
      responsible for the formation of HMW- and oligonucleosomal-DNA fragments are
      separable in cytosolic extract prepared from the serum-deprived cells. Finally,
      DNA fragmentation induced by nongenotoxic apoptotic inducers was effectively
      prevented by cycloheximide and suramin, while both cycloheximide and suramin had
      only a slight inhibitory effect on DNA fragmentation induced by genotoxic agents.
      The results presented suggest that distinct pathways underlay disintegration of
      nuclear DNA during apoptosis induced by genotoxic and nongenotoxic inducers, and
      that the formation of HMW- and oligonucleosomal-DNA fragments proceeds via
      separate mechanisms in NB-2a neuroblastoma cells.

PMID- 10402223
TI  - Endothelin stimulates tyrosine phosphorylation of p125FAK and p130Cas in rat
      cerebral cortex.
AB  - Stimulation of rat cerebral cortex with endothelin-1 (ET-1) caused an increase in
      the tyrosine phosphorylation of several proteins. Two of these phosphoproteins
      were identified by the immunoprecipitation assays as being the focal adhesion
      kinase p125FAK and crk-associated substrate p130Cas. This effect was time- and
      dose-dependent, with an EC50 value of 3.9 x 10(-8) M. In addition, the cerebral
      cortex ET receptor subtype involved in this action was determined by using BQ-123
      and BQ-788, which are ET(A) and ET(B) receptor antagonists respectively. Our
      results indicate that the ET-1 effect on protein tyrosine phosphorylation
      occurred through ET(B) receptors. The requirement for extracellular Ca2+ on ET-1
      action was also studied. ET-1-stimulated tyrosine phosphorylation of both p125FAK
      and p130Cas was abolished in the absence of external Ca2+ or in the presence of
      nimodipine, a Ca2+ channel-blocker. These results suggest that the ET-1
      stimulated protein tyrosine phosphorylation was secondary to Ca2+ influx through
      the dihydropyridine Ca2+-channel. In slices where protein kinase C was inhibited,
      ET-1-stimulated tyrosine phosphorylation of both proteins was reduced. These
      results indicate that ET-1 modulates the tyrosine phosphorylation of specific
      proteins, which may be involved in adhesion processes in the brain.

PMID- 10402222
TI  - Cannabinoid receptor and WIN-55,212-2-stimulated [35S]GTPgammaS binding and
      cannabinoid receptor mRNA levels in several brain structures of adult male rats
      chronically exposed to R-methanandamide.
AB  - We and others have recently demonstrated that the pharmacological tolerance
      observed after prolonged exposure to plant and synthetic cannabinoids in adult
      individuals seems to have a pharmacodynamic basis, based on the observed down
      regulation of cannabinoid receptors in the brain of cannabinoid-tolerant rats.
      However, we were unable to elicit a similar receptor down-regulation after a
      chronic exposure to anandamide, the first discovered endogenous cannabinoid,
      possibly because of its rapid metabolic breakdown in arachidonic acid and
      ethanolamine. The present study was designed to progress in these previous
      studies, by using R-methanandamide, a more stable analog, instead anandamide. In
      addition, we examined not only cannabinoid receptor binding, but also WIN-55,212
      2-stimulated [35S]-GTPgammaS binding, by autoradiography, and cannabinoid
      receptor mRNA levels, by in situ hybridization. Results were as follows. The
      daily administration of R-methanandamide for a period of five days produced
      decreases in cannabinoid receptor binding in the lateral caudate-putamen,
      cerebellum, entopeduncular nucleus and substantia nigra. The remaining areas, the
      medial caudate-putamen, globus pallidus, cerebral cortex (layers I and VI),
      hippocampus (dentate gyrus and Ammon's horn) and several limbic structures
      (nucleus accumbens, septum nuclei and basolateral amygdaloid nucleus), exhibited
      no changes in cannabinoid receptor binding. Similarly, the levels of cannabinoid
      receptor mRNA expression decreased in the lateral and medial caudate-putamen and
      in the CA1 and CA2 subfields of the Ammon's horn in the hippocampus after the
      chronic exposure to R-methanandamide, whereas the remaining areas showed no
      changes. WIN-55,212-2-stimulated [35S]-GTPgammaS binding did not change in the
      lateral caudate-putamen, cerebral cortex (layer I), septum nuclei and hippocampal
      structures (dentate gyrus and Ammon's horn) of animals chronically exposed to R
      methanandamide, whereas a certain trend to decrease could be observed in the
      substantia nigra and deep layer (VI) of the cerebral cortex in these animals. In
      summary, as reported for other cannabinoid receptor agonists, the prolonged
      exposure of rats to R-methanandamide, a more stable analog of anandamide, was
      able to produce cannabinoid receptor-related changes in contrast with the absence
      of changes observed early with the metabolically labile anandamide. The observed
      changes exhibited an evident regional pattern with areas, such as basal ganglia,
      cerebellum and hippocampus, responding to chronic R-methanandamide treatment
      while regions, such as the cerebral cortex and limbic nuclei, not responding.

PMID- 10402224
TI  - Acetaminophen-induced antinociception via central 5-HT(2A) receptors.
AB  - Acetaminophen is one of the most widely used analgesic drugs. Although the
      mechanism of analgesic action of acetaminophen is still not known, the
      involvement of the central serotonin (5-hydroxytryptamine: 5-HT) system is one
      possibility. In the present study, we examined the antinociceptive effect of
      acute and chronic intraperitoneally (i.p.) administered acetaminophen by tail
      flick latency measurements in the rat. A significantly increased tail flick
      latency was observed in acute and 15-day acetaminophen-treated rats, but not in
      30-day acetaminophen-treated rats, at a dose of 400 mg/kg/day. To investigate the
      plasticity of receptors at postsynaptic membrane, we conducted a series of
      experiments by radioligand binding method on frontal cortex and brainstem
      membrane. The technique involved radioligand binding with [phenyl-4-3H]spiperone
      and ketanserin for studying 5-HT(2A) receptor characteristics. A significant
      decrease in the maximum number of 5-HT(2A) binding sites (Bmax) was demonstrated
      in all treatment groups with acetaminophen 300 and 400 mg/kg on frontal cortex
      membrane, whereas the value of the dissociation equilibrium constant (Kd)
      remained unchanged. The down-regulation of 5-HT(2A) binding sites in frontal
      cortex was of a lesser magnitude after 30 days of treatment and the tail flick
      latency was as in the control animals. These results suggest that down-regulation
      of 5-HT(2A) receptor in response to 5-HT release is a major step in the mechanism
      underlying analgesia produced by this agent. On the contrary, chronic use of
      acetaminophen may result in 5-HT depletion, which in turn produces re-adaptation
      of postsynaptic 5-HT(2A) receptors. These data provide further evidence for a
      central 5-HT-dependent antinociceptive effect of acetaminophen.

PMID- 10402225
TI  - Norepinephrine induced alpha-adrenoceptor mediated increase in rat brain Na-K
      ATPase activity is dependent on calcium ion.
AB  - It has been reported that norepinephrine increases Na-K ATPase activity by acting
      on alpha-1 adrenoceptors. The mechanism of such an increase was investigated. The
      norepinephrine induced increase in synaptosomal Na-K ATPase activity was
      prevented by pretreating the rat brain homogenate with either EDTA, a divalent
      cation chelator or prazosin, an alpha-1 adrenoceptor blocker. The norepinephrine
      and EGTA increased the Na-K ATPase activity in the synaptosome prepared from rat
      brain homogenate untreated with EDTA. The EGTA was ineffective in stimulating the
      enzyme activity if the synaptosome was prepared from homogenate treated with
      norepinephrine. However, the EGTA was effective in increasing the enzyme activity
      if the synaptosome was prepared from the homogenate treated with norepinephrine
      in the presence of prazosin. Thus, norepinephrine did not increase the Na-K
      ATPase activity in the presence of EDTA or alpha-1 adrenoceptor blocker.
      Similarly, the Ca++ chelator, EGTA, could not increase the enzyme activity if the
      homogenate was pretreated with norepinephrine alone. However, if norepinephrine
      action was blocked by alpha-1 antagonist prazosin, EGTA increased the enzyme
      activity possibly by chelation of Ca++. Further, chlorotetracycline fluorescence
      study showed that norepinephrine removes membrane bound Ca++. Thus, it is likely
      that norepinephrine acts on adrenoceptors and removes membrane bound Ca++ and
      thereby increases the Na-K ATPase activity in the synaptosome.

PMID- 10402226
TI  - Evidence of glutathione transporter in rat brain synaptosomal membrane vesicles.
AB  - Glutathione (GSH) transport was studied in synaptosomal membrane vesicles (SMV)
      of rat cerebral cortex. The present study shows that GSH uptake into SMV occurs
      very quickly in a time-dependent manner into an osmotically active intravesicular
      space. The initial rate of transport followed Michealis-Menten saturation
      kinetics with a Km 4.5+/-0.8 microM that shows a high affinity of the transporter
      for GSH. Therefore GSH uptake in SMV occurs by a mediated transport system which
      can be activated by either an inward gradient of cations, like Na+ or K+, or
      membrane depolarization. These results, together with those obtained by
      valinomycin-induced K+ diffusion potential, indicate that GSH synaptosomal
      transport is electrogenic by a negative charge transfer. The increase of GSH
      uptake measured by trans-stimulation experiments confirms a GSH bidirectional
      mediated transport which seems susceptible of modulation by changes in ionic
      fluxes and in the membrane potential. These results may indicate a possible
      involvement of this transporter in the role suggested for GSH in synaptic
      neurotransmission; also considering that GSH precursor of neuroactive aminoacids
      (glycine, glutamate), may contribute to regulate their level in synapses.
      Finally, a GSH transporter in synaptosomes may contribute to maintaining the GSH
      homeostasis in cerebral cortex, where decreases of GSH levels have been related
      to susceptibility to neuropathologies.

PMID- 10402227
TI  - Early changes in adenosine A1 receptors in cerebral cortex slices submitted to in
      vitro ischemia.
AB  - The effects of brain ischemia on the maximum binding capacity (Bmax) and affinity
      (Kd) of A1 receptors were studied in the rat cerebral cortex, with an in vitro
      approach. The results were correlated with changes in 3H-adenosine release,
      studied under identical experimental conditions. Fifteen minutes of in vitro
      'ischemia' (hypoxic, glucose-free medium) induced a significant increase in both
      Bmax (2398+/-132 fmol/mg protein, 151% of the control, P < 0.05) and in Kd
      (2.43+/-0.12 nM, 161% of the control, P < 0.01). At the same time, an increase in
      tritium efflux from [3H]-adenosine labeled cerebral cortex slices to 324% of the
      control was observed. A trend toward normalization was evident 5-15 min after
      'reoxygenation' (restoring normal medium), but the binding parameters were still
      altered after 60 min (Bmax 2110+/-82 fmol/mg protein, Kd 2.26+/-0.14 nM, P < 0.01
      vs the corresponding control) as was adenosine release (196% of the control).
      These findings suggest that the increased availability of adenosine and its
      receptors may be a defense mechanism against ischemic injury, while the reduced
      affinity of A1 receptors, possibly due to desensitization, may be a sign of
      ischemia-induced cellular damage.

PMID- 10402228
TI  - Unchanged levels of interleukins, neopterin, interferon-gamma and tumor necrosis
      factor-alpha in cerebrospinal fluid of patients with dementia of the Alzheimer
      type.
AB  - Several histopathological studies suggest that amyloidogenesis in dementia of the
      Alzheimer type is accompanied by activated glia and glia-derived cytokines,
      leading to chronic, self-propagating, cytokine-mediated molecular and cellular
      reactions. As studies regarding inflammatory changes in cerebrospinal fluid of
      patients with dementia of the Alzheimer type has been inconclusive, we set up a
      prospective study to assess cerebrospinal fluid levels of interleukin-1beta,
      interleukin-6, interleukin-10, interleukin-12, soluble interleukin-2 receptor,
      interferon-gamma, tumor necrosis factor-alpha and neopterin in 20 patients with
      dementia of the Alzheimer type and 20 age- and sex-matched controls. Comparing
      both groups, no significant differences in concentrations and specific activities
      could be revealed. An additional 22 patients were included to enlarge the study
      population. No statistically significant differences were shown comparing
      patients (n=42) with the control group (n=20). We conclude that the immune
      mediated inflammatory changes found in histopathological studies are not
      reflected in cerebrospinal fluid of patients with dementia of the Alzheimer type.
      Probably, cytokine production appears very localized in the central nervous
      system, not allowing representative detection in cerebrospinal fluid. Further
      studies assessing cytokine levels in various regions of central nervous system of
      patients with dementia of the Alzheimer type will be of interest to confirm this
      hypothesis.

PMID- 10402229
TI  - The administration schedule of cyclin-dependent kinase inhibitor gene therapy and
      etoposide chemotherapy is a major determinant of cytotoxicity.
AB  - Cyclin-dependent kinase inhibitors are potent suppressors of cell growth and have
      been proposed as targets for gene replacement therapy in cancer. Expression of
      either p16INK4a or p21WAF1 protected cells from the cytotoxic effects of the
      topoisomerase II inhibitor, etoposide. A lower level of p53 was induced in CDK
      inhibitor-expressing etoposide-exposed cells suggesting that protection may be
      due to lower levels of DNA damage in the growth arrested cells. Exposure of human
      osteosarcoma cells to either p16INK4a or p21WAF1 prior to and during etoposide
      therapy protected cells against etoposide-induced cell death. Infection of the
      cells by Ad-p16INK4a or Ad-p21WAF1 following exposure to etoposide resulted in
      loss of the protective effect with evidence of enhanced growth inhibition. The
      results suggest that the schedule of administration of DNA damaging etoposide
      chemotherapy and cell cycle inhibitory therapy is a major determinant of the
      resulting cytotoxicity.

PMID- 10402230
TI  - In situ analysis of tumor-specific CTL effector and memory responses elicited by
      tumor vaccination.
AB  - In this study tumor-specific CTL effector and memory responses were analyzed in
      normal mice, in tumor bearing mice and in animals treated by active specific
      immunotherapy (ASI) with an autologous virus modified tumor vaccine. In the well
      defined DBA/2 mouse lymphoma model ESb, the tumor specific CTL response requires
      interactions of four different cell types and recognition of MHC class I and
      class II restricted tumor antigens either on host antigen presenting cells (APCs)
      or on the tumor cells. The most effective in situ activation of syngeneic tumor
      specific CTL can be generated within no more than 9 days by primary immunization
      in the ear pinna and restimulation in the peritoneal cavity. Here we describe
      modulatory effects of either cytokines or of virus infection of tumor stimulator
      cells during restimulation in the peritoneal cavity on the CTL memory response.
      The in situ peritoneal effector cell (PEC) response was augmented when Newcastle
      Disease Virus (NDV) was used to infect tumor cells which expressed the correct
      tumor associated antigen of the memory response but not when a third party tumor
      cell was infected and admixed. A response could also be augmented by co
      administration of interferons-alpha, -beta or IL-2 and by pre-treatment with low
      dose cyclophosphamide. Therapeutic vaccination effects could be achieved in mice
      inoculated s.c. with this aggressive and metastatic tumor variant if the vaccine
      was given very early, i.e. 1-2 days after priming and when the vaccine was
      applied post-operatively, i.e. in situations of low tumor burden. A long-term CTL
      memory response could be demonstrated even two months after post-operative active
      specific immunotherapy with ESb-NDV vaccine.

PMID- 10402231
TI  - Adenovirus-mediated transfer of wild-type p53 gene results in apoptosis or growth
      arrest in human cultured gastric carcinoma cells.
AB  - We examined the susceptibility of six human gastric carcinoma cell lines to
      infection with recombinant p53 adenovirus vector (AxCA-p53). AxCA-p53 infection
      at a muliplicity of infection (MOI) of 50 resulted in apoptotic cell death (MKN-1
      cells), growth arrest (MKN-45, MKN-74 and KATO-III cells), or non-effectiveness
      (TMK-1 and OCUM-2M cells). Western blot analysis revealed increasing expression
      levels of p21/WAF1 protein after infection with AxCA-p53 in all the cell lines.
      After infection with AxCA-p53, the expression levels of bax or bcl-XL protein
      changed in MKN-1, but not in the other cell lines. These results suggest that the
      apoptotic pathway (dependence on the expressions of bcl-2 family proteins)
      dominates the growth arrest pathway (dependence on the expressions of p21/WAF1
      protein) after infection with AxCA-p53. Thus, the bcl-2 family might play a
      crucial role in p53-mediated growth arrest and apoptosis in human gastric
      carcinoma cells.

PMID- 10402232
TI  - Overexpression of protein kinase C epsilon in astroglial brain tumor derived cell
      lines and primary tumor samples.
AB  - Prognosis for astroglial brain tumors that are not amenable to surgical resection
      remains poor. Consequently, a need to identify new cellular targets and
      chemotherapeutics for the treatment of astroglial tumors remains. Important
      reports indicate that human astroglial cell lines express higher protein kinase C
      (PKC) activity in comparison to normal astrocytes. PKC designates a family of
      kinases that regulate many cellular functions including cell growth and
      differentiation. The tight regulation of PKC activity is crucial for maintaining
      normal cellular proliferation since excessive activity leads to uncontrolled
      growth and cellular transformation. PKCepsilon, one of the 11 known PKC isozymes,
      has been shown to function as an oncogene in rodent fibroblasts by enhancing c
      Raf-1 kinase activity leading to the stimulation of mitogen-activated protein
      (MAP) kinase pathway. We recently demonstrated that the ability of substance P
      (SP) neuropeptide to activate MAP kinase pathway in U-373MG astrocytoma cells
      correlates with its ability to selectively translocate PKCepsilon from cytosolic
      to membrane fraction, and that PKC inhibitors (e.g. CGP 41251) inhibit the
      activation of this pathway by SP or the PKC activator 12-O-tetradecanoyl phorbol
      13-acetate (TPA). In this study, we demonstrated that PKCepsilon is overexpressed
      in many astroglial cell lines (n=27 lines), thus providing new evidence as to the
      possible involvement of this isozyme in the pathology of astroglial tumors.
      Consistently, we demonstrated that PKCepsilon is overexpressed in primary
      pediatric anaplastic astrocytoma (grade III) tumor samples as well as in cell
      lines derived from them, and that glioblastoma multiforme (grade IV) and
      gliosarcoma tumor samples, but not pilocytic astrocytomas (grade I), also express
      high levels of PKCepsilon. Therefore, the reported increase in PKC activity in
      brain tumor derived cell lines may be, in part, attributed to the overexpression
      of PKCepsilon and possibly other PKC isozymes. Consequently, we propose that the
      use of PKCepsilon selective inhibitors may be beneficial in the treatment of
      astroglial brain tumors.

PMID- 10402233
TI  - Cell cycle effects and control of gene expression by resveratrol in human breast
      carcinoma cell lines with different metastatic potentials.
AB  - Trans-resveratrol, a polyphenol present in red wines and various human foods, is
      an antioxidant also with reported chemopreventive properties. However, whether
      resveratrol may exert different effects in malignant cells with a common
      anatomical origin yet displaying different invasive characteristics is not known.
      Since invasiveness and metastasis are considered to be the most insidious and
      life-threatening aspects for all cancers, we compared the ability of resveratrol
      to control growth and cell cycle transition in the highly invasive MDA-MB-435
      with the minimally invasive MCF-7 breast carcinoma cells. The data revealed that
      resveratrol exerted a greater inhibitory effect on the MDA-MB-435 cells. A
      diminution of percentage of cells in G1 phase and a corresponding accumulation of
      cells in S phase of the cell cycle was observed. We also studied the effect of
      resveratrol on a panel of MDA-MB-435 cells transfected with nm23-H1 and nm23-H2
      genes, which have been suggested to play a role in controlling metastasis in
      breast cancer cells. These cells are designated as Vbeta, 1beta, 1Tbeta, 2beta,
      and 2Tbeta, respectively. The control Vbeta consists of MDA-MB-435 cells
      transfected with bacterial beta-glucuronidase. Cells labeled 1beta and 1Tbeta
      correspond to those carrying beta-glucuronidase and overexpressed wild-type
      (His118) or mutant (Tyr118, catalytically inactive) nm23-H1 genes. The 2beta and
      2Tbeta refer to cells transfected with wild-type and mutant nm23-H2 genes. The
      responses of these cells to resveratrol were assessed by measuring proliferation,
      cell cycle phase distribution, and changes in expression of several genes. These
      studies have shown that resveratrol (25 microM, 3 days) reduced growth of all
      cell types by 60-80%. Overexpression of both wild-type and catalytically inactive
      nm23-H1 (1beta, 1Tbeta) but not nm23-H2 (2beta, 2Tbeta) reduced the proportion of
      cells in G1 phase, compared to the Vbeta control cells. Little changes in
      expression of PCNA, Rb, p53, and bcl-2 were observed in the five cell types
      treated with resveratrol, compared to untreated cells. Noted exceptions included
      reduced expression of Rb protein and increased expression of p53 in 2beta and
      2Tbeta cells, and increased expression of bcl-2 in 2beta cells, treated with
      resveratrol. In contrast, resveratrol upregulated expression of cathepsin D by 50
      100% in all cell lines except 1beta. These results suggest that the intrinsic
      metastatic potential of cancer cells may affect their responses to
      chemopreventive agents such as resveratrol.

PMID- 10402234
TI  - The relationship between p21/waf1 expression patterns and cell proliferation
      during the tumorigenesis of the bronchus.
AB  - Each developmental stage in the process towards bronchial squamous cell carcinoma
      (normal epithelium, squamous metaplasia and early stage squamous cell carcinoma
      including in situ carcinoma) was examined for p21/waf1 protein expression and
      cell proliferation using MIB1. P21/waf1 immunoreactivity was classified into four
      patterns: predominantly cytoplasmic staining, exclusively nuclear staining, both
      nuclear and cytoplasmic staining and negative. The cases with predominantly
      cytoplasmic staining showed suppression of cell proliferation. Most cases with
      either negative or exclusively nuclear staining revealed high cell proliferation.
      The simultaneous evaluation of p21/waf1 and cell proliferation is valuable for
      clinical determination of the high risk for malignant transformation.

PMID- 10402235
TI  - Oral administration of cholic acid promotes growth of liver tumors initiated by
      diethylnitrosamine in rats.
AB  - The effect of dietary administration of cholic acid on tumorigenesis in the liver
      was investigated in male Fischer-344 rats after carcinogenic initiation by
      diethylnitrosamine (DEN); progression of liver tumors was examined in the rats
      fed 0.4% cholic acid-containing diet (CA group) and the rats fed standard diet (C
      group) at 15, 20 and 25 weeks after administration of DEN. The total bile acids
      and cholic acid in serum of CA group were 150 nmol/ml and 117 nmol/ml, being 31
      fold and 51-fold higher than those in C group (p<0.0001, each). Serum AST and ALT
      were significantly higher in CA group than in C group at 15 weeks (p<0.01). Serum
      ALP was significantly higher in CA group than C group at each time point (p<0.01,
      each). Liver tumors, whose histology was hepatocellular carcinoma, developed at
      15 weeks in both CA and C groups. However, tumor volume and tumor weight were
      significantly increased in CA group, compared to those in C group at each time
      point (p<0.001, p<0. 001, p<0.01, p<0.001, p<0.01 and p<0.05). The percentage of
      apoptotic cells in CA group at each time point was significantly lower than C
      group (p<0.05, p<0.01 and p<0.05). The percentage of bcl-2 positive tumor cells
      in C group at 20 weeks was 1.88+/-2.59%. However, it dramatically increased to
      34.00+/-13.67% in CA group (p<0.0001). It was also higher in CA group than in C
      group at 15 and 25 weeks (p<0.05 and p<0.01). In addition, the bax-positive cells
      were higher in CA group than in C group at 20 weeks (p<0.05). These data suggest
      that oral administration of cholic acid promotes liver tumorigenesis initiated by
      DEN through reducing apoptosis mediated by overexpression of bcl-2.

PMID- 10402236
TI  - The association between a mutated ras gene and cyclooxygenase-2 expression in
      human breast cancer cell lines.
AB  - Cyclooxygenase (COX) is rate-limiting for arachidonic acid metabolism to the
      prostanoid family of eicosanoids. Some human breast cancers, notably those which
      are estrogen receptor (ER)-negative with high metastatic potential, produce high
      levels of prostaglandin E2 (PGE2). In some cell types, expression of the
      inducible COX-2 isoform occurred in association with a ras gene mutation. We
      determined COX-1 and COX-2 expression, and the corresponding PGE2 secretions, in
      4 ER-negative human breast cancer cell lines, the MCF10A breast epithelial cell
      line, and the same non-cancerous line transfected with a mutated ras gene. The
      highly invasive MDA-MB-231 and Hs578T cancer cell lines, which possess a mutated
      Ki-ras and H-ras, respectively, expressed constitutive and inducible COX-2, and
      produced high PGE2 levels; the less invasive MDA-MB-435 and SK-BR-3 lines,
      without a mutated ras, possessed only low levels of COX-2, and secreted
      correspondingly low PGE2 levels. Similarly, the ras transfectant, but not
      parental MCF10A cells, expressed inducible COX-2. Chemosuppression with a
      selective COX-2 inhibitor may be effective only in that minority of breast
      cancers which have a mutated ras gene.

PMID- 10402237
TI  - Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite
      oncogenic K-ras expression.
AB  - Activating mutations within the K-ras gene have been found in up to 90% of
      pancreatic carcinomas. Although multiple Ras effector pathways have been
      identified, the Raf protein kinases which are upstream regulators of the mitogen
      activated protein kinases (MAPK/Erk) are believed to be the primary mitogenic
      effectors. Constitutive upregulation of this pathway by oncogenic ras is thought
      to promote cellular transformation. To explore the biological effects of mutated
      K-ras, we analyzed the Ras signaling pathway in a panel of cell lines derived
      from human pancreatic carcinomas. We found that despite high levels of Ras-GTP in
      each cell line expressing mutant K-ras, elevated levels of active Erk1 and Erk2
      were not detectable under conditions of exponential growth or serum-starvation.
      Depending upon the cell line, the block in Erk signaling was observed to occur at
      either the level of Raf or Erk. Increased levels of active Erk1 and Erk2 were
      detected in only 2 out of 10 normal tissue-matched primary pancreatic tumors with
      mutated K-ras. Our results suggest that Erk signaling is not aberrantly
      upregulated in pancreatic cancers containing oncogenic K-ras mutations. The lack
      of Erk activation observed in both cell lines and primary tumor tissue suggests
      that constitutive Erk activation may not be required for tumor maintenance or
      progression in K-ras transformed pancreatic cells. We hypothesize that other Ras
      dependent signaling pathways or an unidentified Raf/Mek-dependent pathway may be
      important for carcinogenesis in the pancreas. These findings may have important
      implications for drug treatment strategies which currently target the MAP kinase
      branch of the Ras signaling pathway.

PMID- 10402238
TI  - Expression of full length or truncated epidermal growth factor precursor
      transforms NIH3T3 fibroblasts.
AB  - Epidermal growth factor (EGF) is derived from a large precursor (EGFP) of unusual
      structure. As EGFP remains unprocessed in certain tissues, it is of biological
      relevance to study its activity. Activation of the EGF receptor by EGF is
      involved in transformation of NIH3T3 fibroblasts. We isolated clones of NIH3T3
      expressing full length, cytoplasmic region deleted or EGF-repeats deleted EGFP.
      All clones formed colonies in soft agarose and tumors in nude mice. Two clones
      expressing EGF-repeats deleted EGFP formed more and larger colonies. To conclude,
      EGFP is biologically active. Deletion of the 8 EGF repeats may enhance anchorage
      independent growth in NIH3T3.

PMID- 10402239
TI  - E-cadherin and beta-catenin expression in breast medullary carcinomas.
AB  - The initial step of cancer invasion and metastasis is the escape of tumour cells
      from the primary site, involving disruption of normal cell-cell adhesion and E
      cadherin (E-cad) and beta-catenin (beta-cat) down-regulation, as shown in various
      types of human malignancies including breast carcinomas. Medullary carcinomas are
      high grade and poorly differentiated tumours with syncytial typical pattern, and
      prognosis unexpectedly better than that in high grade breast carcinomas. In a
      series of 55 breast typical medullary carcinomas diagnosed according to the
      strict use of Ridolfi et al (Cancer 40: 1365-1385, 1977) criteria, E-cad and beta
      cat were investigated using quantitative (SAMBA 2005 system) immunocytochemical
      assays on frozen sections. Results were compared to that obtained on paraffin
      sections and in a series (n=55) of grade 3 ductal carcinomas. It was shown that
      medullary carcinomas significantly (p<0.001) expressed more E-cad and beta-cat
      than grade 3 ductal carcinomas. E-cad and beta-cat correlated with high
      expression of P53, of c-erbB, and of Ki-67 antigens, and with lack of hormone
      receptors antigenic sites (p<0.001). It was concluded that favourable prognosis
      and syncytial pattern of typical breast medullary carcinomas likely results, at
      least partly, from a particular expression of cell-cell adhesion molecules,
      significantly limiting tumour growth and efficiently mastering the tumour cell
      dissemination, opposing to high proliferative activity (grade 3).

PMID- 10402240
TI  - Comparative analysis of HPLC profile of cytosolic thymidine kinase activity
      between hepatoma and regenerating liver in rat with reference to phosphorylation.
AB  - Thymidine kinase (TK) activity in rat hepatoma JB1 and AH136B was mainly due to
      cytosolic TK and was much higher than that in rat regenerating liver. Two forms
      of cytosolic TK, designated as TK-I and TK-II, were revealed in addition to
      mitochondrial TK in anion-exchange high performance liquid chromatography (HPLC)
      of the enzyme extract from hepatoma JB1. During incubation of the enzyme extract
      at 20 degrees C in the presence of phosphatase inhibitor NaF, TK-II activity
      remained while TK-I activity almost disappeared. Thus, TK-II appeared to be more
      stable than TK-I. In Western blot analysis, TK-II was much more phosphorylated
      and exhibiting higher specific activity than TK-I. Meanwhile, regenerating liver
      derived from the rat 24 h after partial hepatectomy showed only TK-I activity,
      which completely disappeared after incubation at 20 degrees C even in the
      presence of NaF. Consequently, the presence of TK-II might account for the higher
      TK activity in hepatomas than in regenerating liver.

PMID- 10402241
TI  - The level of tyrosine kinase activity regulates the expression of p21/WAF1 in
      cancer cells.
AB  - It is well documented that epidermal growth factor (EGF) inhibits proliferation
      of A431 and MDA-468 cells via activation of p21/WAF1. In the present study, we
      have shown that treatment of MDA-468 and A431 cells that express high levels of
      EGFR with 100 ng/ml of EGF leads to 14.9-fold increase in epidermal growth factor
      receptor (EGFR) autophosphorylation and high levels of p21/WAF1-induction (6. 7
      fold), down regulation of cdk2 activity and growth arrest. When MDA-468 or A431
      cells were simultaneously treated with 100 ng/ml EGF and RG13022, a relatively
      specific tyrosine kinase inhibitor, there was a significant reduction in p21/WAF1
      levels. In contrast, when MDA-468, A432 cells that are treated with low levels of
      EGF (10 ng/ml) or other cells which express low to moderate levels of EGFRs such
      as MCF-7, MCF-10A, MDA-231 and SKBR-3 breast cells were exposed to 100 ng/ml of
      EGF there was a 3.8-fold increase in EGFR autophosphorylation, leading to 1.6
      fold induction of p21/WAF1 and increased cell proliferation. These results
      suggest that the level of EGFR tyrosine kinase activity may regulate p21/WAF1
      induction in cancer cells.

PMID- 10402242
TI  - DLX-7 homeobox gene regulates c-myc and GATA-1 gene expression in different
      stages respectively.
AB  - Homeobox genes code for transcription factors with a highly conserved DNA binding
      motif, but their target genes are largely unknown. We have shown that inhibition
      of the DLX-7 homeobox gene by an antisense oligonucleotide decreased the
      expression of c-myc and GATA-1 genes. Nuclear run-on assay revealed decreased
      transcriptional activity of c-myc but not of GATA-1 after DLX-7 antisense
      treatment. Actinomycin D chase experiments demonstrated that GATA-1 mRNA became
      unstable as a result of DLX-7 inhibition, whereas c-myc mRNA stability was
      unaffected. These results suggest that DLX-7 may regulate c-myc and GATA-1 genes
      at transcriptional and post-transcriptional levels.

PMID- 10402243
TI  - Progression of diploid tumor cells in aneuploid head and neck squamous cell
      carcinomas.
AB  - The development of aneuploid clones from diploid progenitor cells is a regular
      characteristic of head and neck squamous cell carcinoma progression. While the
      significance of aneuploidy formation for the acquisition of invasive and
      metastatic behavior is well documented, little is known about the contribution of
      diploid tumor cells after aneuploid clones have emerged. To distinguish diploid
      cells of epithelial origin from benign cellular components, we applied
      multiparameter flow cytometry of DNA content and cytokeratin (CK) expression to
      36 primary tumors. Twenty-seven carcinomas accommodated aneuploid cell lines that
      stained positive for CK. All diploid cell populations obtained from aneuploid
      carcinomas contained CK-positive subpopulations as did all of nine tumors that
      consisted exclusively of diploid cells. The proportions of CK-positive diploid
      cells ranged between 6% and 80%, independent of whether they were achieved from
      entirely diploid or from aneuploid carcinomas. CK-gated diploid and aneuploid
      cell populations showed largely identical S-phase fractions. These results
      emphasize that diploid tumor cells regularly persist after the development of
      aneuploid clones and significantly contribute to local tumor progression. Despite
      the presence of diploid epithelial cells in aneuploid primary tumors, exclusively
      the aneuploid clones of eight corresponding lymph node metastases were CK
      positive. This provides further evidence of a largely reduced metastatic
      potential of diploid tumor cells.

PMID- 10402244
TI  - Tamoxifen in the treatment of metastatic malignant melanoma: still a controversy?
      (Review).
AB  - This review attempts to summarize the available preclinical and clinical evidence
      supporting the inclusion of tamoxifen (TAM) in the treatment of malignant
      melanoma, in the attempt to identify what role, if any, the antiestrogen could
      have in the present and future therapeutic approach to this disease. Emphasis has
      been given to the biological basis of the potential TAM mechanisms of action, as
      well as to the rational basis underlying the study design of the reported
      clinical experiences. Results to date show that TAM has no useful activity as a
      single agent in melanoma patients, most published response rates reaching less
      than 10%. A still controversial question is the inclusion of the antiestrogen in
      different active chemotherapy regimens, since clinical investigations on the role
      of TAM in combination therapy of advanced melanoma have produced inconclusive
      results. While several early trials suggested that TAM may improve the response
      rates when combined with different cytotoxic agents, the majority of subsequent
      reports, including recent randomized studies, did not show a significant benefit
      stemming from TAM addition to various single-agent or multi-agent combinations.
      Only one controlled trial showed a significant improvement in both response rate
      and survival for patients receiving dacarbazine plus TAM, an effect primarily
      noted in women, and confirmatory studies have not been reported. From a
      biological standpoint, why the activity of this poorly effective single-agent is
      potentiated when given in combination with some cytotoxic agents is not clearly
      understood, although preclinical and clinical experiences support a possible
      synergistic effect of TAM combined with cisplatin, particularly when the former
      is added at high doses. Of major interest is a body of experimental studies
      producing confirmatory data that induction of apoptosis, probably through the
      inhibition of protein kinase C, as well angiogenesis inhibition, at least in part
      mediated by TGF-beta stimulation, are alternative ways through which TAM
      suppresses tumor cell growth, independently of the expression of estrogen
      receptors. These findings also provide a model and rationale for combining TAM
      with agents which are able to modify cell biology in melanoma. The investigation
      on TAM-containing biological combinations appears to be a promising avenue to be
      explored in the near future. To this end, clinical research should incorporate
      biological studies to allow the selection of subgroups of patients who are most
      likely to benefit from TAM-based treatment.

PMID- 10402246
TI  - Increased acetylation of histones induced by diallyl disulfide and structurally
      related molecules.
AB  - In previous studies, diallyl disulfide induced differentiation in DS19 mouse
      erythroleukemic cells. A mechanism mediated by increased histone acetylation was
      investigated. Diallyl disulfide caused increased acetylation of H4 and H3
      histones in DS19 cells and K562 human leukemic cells. Diallyl disulfide was more
      effective than diallyl monosulfide and diallyl sulfone. Acetylation was also
      induced in rat hepatoma and human breast cancer cells by diallyl disulfide or its
      metabolite, allyl mercaptan. Allyl mercaptan was a more potent inhibitor of
      histone deacetylase than diallyl disulfide. Differentiation in erythroleukemic
      cells by diallyl disulfide and allyl mercaptan may be mediated through induction
      of histone acetylation.

PMID- 10402245
TI  - The impact of schedule on acute toxicity and dose-intensity of high-dose
      chemotherapy with epirubicin and cyclophosphamide plus colony stimulating factors
      in advanced breast cancer.
AB  - To increase the dose-intensity of two drugs in metastatic breast cancer, we
      tested the feasibility, in phase I studies, of two schedules of epirubicin (E)
      and cyclophosphamide (C) - sequential (E--> C) and alternating (E/C) - with
      respect to the standard combination (EC). Drugs were given at three planned-dose
      levels, plus either G-CSF or GM-CSF. Patients with metastatic (30), inoperable
      stage IIIb (2) or inflammatory (7) breast cancer were treated. The doses of EC,
      given every 21 days (4 cycles), were 75/1500, 82.5/2250, 90/3000 mg/m2. In the
      E/C schedule, epirubicin was given at cycles 1, 3 and 5, and cyclophosphamide at
      cycles 2, 4 and 6. In the E--> C schedule, three cycles of epirubicin then three
      cycles of cyclophosphamide were administered. In both experimental schedules,
      drugs were given every 14 days for 6 cycles at doses of 100, 110, 120 mg/m2 (E)
      and 2000, 3000, 4000 mg/m2 (C). The average relative dose-intensity was 1.2-fold
      and 2-fold greater with E/C and E--> C, respectively, than with EC. The third
      level dose was feasible with all schedules. Grade 4 leucopenia occurred in 77% of
      patients. Thrombocytopenia was absent in 6 cases and grade 4 in 12 (30.8%).
      Eighty-one percent of patients on experimental schedules required red blood cell
      support versus 44.4% of patients on EC. At the third level, platelet transfusions
      were more frequent among patients treated with EC (27. 8%). Non-haematological
      toxicity was mild: about 20% of patients experienced grade 3 vomiting,
      irrespective of schedule. Only 2 patients had grade 3 mucositis; no patient
      developed heart failure. Fever (61% of patients) and bone pain (55.5% of
      patients) were relevant in the GM-CSF treated groups and 12 patients shifted to G
      CSF. The overall response rate was 84.6%: 5/39 (12.8%) complete response and
      28/39 (71.8%) partial response. At 30/9/98, median survival was 29.5 months, with
      no difference between patients with metastatic and stage IIIb/inflammatory breast
      cancer. Median follow-up of surviving patients was 62 months (range 17-83). The 5
      year estimated survival was 19% (95% confidence intervals = 7-31%). Rapidly
      alternating or sequential cycles of epirubicin and cyclophosphamide with CSF
      support is a feasible strategy that allows a higher increase of dose-intensity of
      the single drugs. Hospitalization and anemia were more frequent with the
      experimental schedules, and thrombocytopenia with the standard schedule. Overall,
      this intensified therapy was very active.

PMID- 10402247
TI  - Lack of mutations in DNA polymerase beta of estradiol-induced hamster kidney
      tumors: sequence of hamster DNA polymerase beta cDNA.
AB  - We examined the effects of estradiol (E2), the natural estrogenic hormone, on the
      structure and expression of DNA polymerase beta (DNA pol beta), a DNA repair
      gene, from E2-induced primary kidney tumors of twelve Syrian hamsters, their
      metastases, and from kidney tissues surrounding the tumors. We sequenced the
      coding region of the hamster DNA pol beta and found it to differ from that of the
      human by 11%. No mutations were detected in the entire coding region including
      the catalytic domain of the DNA pol beta from E2-induced primary kidney tumors,
      their metastases, or from kidney tissues surrounding the tumors. The expression
      of the DNA pol beta mRNA was also not significantly altered in E2-induced kidney
      tumors or in kidney tissues surrounding the tumors compared to that of control
      kidney tissues. These results suggest that mutations in the DNA pol beta gene may
      not be involved in the induction or malignant progression of hamster kidney
      tumors induced by E2. The nucleotide sequence of the hamster DNA pol beta
      described here will be useful for the study of the structure and expression of
      this gene.

PMID- 10402248
TI  - Microsatellite instability and allelic losses in neuroendocrine tumors of the
      gastro-entero-pancreatic system.
AB  - Carcinoids are well differentiated tumors, able to secrete a variety of bioactive
      and hormonal products. Neuroendocrine tumors occur either sporadically or as part
      of familial syndromes (MEN1, MEN2). Defective DNA mismatch repair is implicated
      in a variety of gastrointestinal and other cancers; however, its role in the
      tumorigenesis of carcinoids has not been assessed. Formalin-fixed, paraffin
      embedded archivial pathology tissues from 16 neuroendocrine tumors and 9 related
      metastases were studied by microdissection and microsatellite analysis of
      extracted DNA to evaluate the degree of microsatellite instability, a marker of
      defective mismatch repair. The carcinoid tumors analyzed display no
      microsatellite instability, but, interestingly, show a number of allelic
      deletions scattered throughout the genome. Particularly, the vast majority of
      pancreatic derived tumors display loss of heterozygosity on the short arm of
      chromosome 8. These results suggest that genomic instability is probably not
      involved in neuroendocrine carcinogenesis and a tumor suppressor gene involved in
      pancreatic carcinoid tumorigenesis could probably be localized on chromosome 8p12
      22.

PMID- 10402249
TI  - A new tubulin polymerization inhibitor, auristatin PE, induces tumor regression
      in a human Waldenstrom's macroglobulinemia xenograft model.
AB  - Waldenstrom's macroglobulinemia (WM) is an uncommon lymphoproliferative disease
      which remains incurable with current treatment protocols. We have previously
      established a permanent WM cell line, WSU-WM, which grows as a xenograft in
      severe combined immune deficient (SCID) mice. In this study, we investigated the
      anti-tumor effects of auristatin PE (a structural modification of the marine,
      shell-less mollusk peptide constituent dolastatin 10). WSU-WM cells were cultured
      in RPMI-1640 at a concentration of 2x10(5) cells/ml using 24-well plates.
      Auristatin PE or dolastatin 10 were added to triplicate wells and cell count and
      viability were assessed after 24, 48 and 72 h. Results showed that both agents
      were active against WSU-WM, and were able to induce complete growth inhibition at
      100 pg/ml. The efficacy of these agents in vivo was evaluated using the WSU-WM
      SCID mouse xenograft model. Auristatin PE and dolastatin 10 were given i.v. via
      tail vein at 2.0 mg/kg and 0.2 mg/kg, respectively. The agents were given every
      second day for three injections which represent the maximum tolerated doses.
      Tumor growth inhibition (T/C), tumor growth delay (T-C), and log10 kill for
      auristatin PE and dolastatin 10 were 0%, 18 days, 2.83 and 67%, 2 days, 0.06,
      respectively. Based on these animal results, dolastatin 10 was inactive while
      auristatin PE was highly active. We therefore focused further investigation on
      auristatin PE to understand some of its mechanisms of action. Using two flow
      cytometry assays, propidium iodide for cell cycle analysis and 7-amino
      actinomycin D (7AAD) to detect apoptosis, we were able to demonstrate that
      auristatin PE at 10 pg/ml after 24 h arrested 50% of WSU-MW cells in G2M.
      Concomitantly, 31% of auristatin PE-treated cells entered apoptosis. By 72 h,
      greater than 75% of the cells became apoptotic. The activity of auristatin PE
      should be evaluated in other tumor types and in clinical trials.

PMID- 10402250
TI  - The transcriptional function of the hepatitis B virus X protein and its role in
      hepatocarcinogenesis (Review).
AB  - The hepatitis B virus (HBV) encodes a 16.5 kDa multifunctional protein termed pX
      or HBx, required for transcription of the viral genome and implicated in the
      development of hepatocellular carcinoma (HCC) in chronic HBV-infected patients.
      However, the mechanism of pX-mediated hepatocarcinogenesis remains unknown. pX is
      a multifunctional protein exhibiting a number of activities affecting
      transcription, cell growth, and apoptotic cell death. Although pX does not
      directly bind DNA, pX is regarded as a promiscuous transactivator, acting via a
      dual mechanism: in the cytoplasm, pX activates mitogenic signaling cascades; in
      the nucleus, pX interacts directly with members of the bZip class of
      transcription factors and with specific components of the basal transcriptional
      apparatus. The focus of this review is to describe the transactivation function
      of pX and its role in hepatocarcinogenesis.

PMID- 10402251
TI  - The efficacy of chemotherapy with docetaxel and paclitaxel in anthracycline
      resistant breast cancer (Review).
AB  - This review was performed to determine the efficacy of commonly used cytotoxic
      agents in the management of anthracycline-resistant breast cancer, using a
      stringent and uniform definition of drug resistance. We reviewed the reports of
      second- and third-line chemotherapy after anthracycline-containing regimens
      published over the last two decades. Only studies with sufficient information on
      the timing of progressive disease in relation to anthracycline therapy were
      considered. All assessable studies were reviewed individually, and the data
      obtained with taxanes in anthracycline-resistant breast cancer were also pooled
      to estimate the activity. The great majority of published studies on second- and
      third-line chemotherapy lack useful information about anthracycline resistance.
      Among the few studies with sufficient information about anthracycline resistance,
      several definitions were used. We reanalyzed those reports utilizing a uniform
      definition of anthracycline resistance: progression while receiving an
      anthracycline. Only studies using paclitaxel or docetaxel reported an activity in
      this anthracycline-resistant population, allowing a response rate between 6-50%
      and 32-57% for both agents respectively. The activity of other cytotoxic agents
      in anthracycline-resistant breast cancer could not be determined because a lack
      of accurate data using the stringent definition. Both paclitaxel and docetaxel
      have substantial antitumor activity in patients with clearly defined
      anthracycline-resistant breast cancer. The activity of other cytotoxic agents in
      this group of patients remains to be established.

PMID- 10402252
TI  - Upregulation of E2F transcription factors in chemically induced mouse skin
      tumors.
AB  - E2F family of transcription factors plays an important role in cell cycle
      regulation, oncogenesis and differentiation. E2Fs are a family of heterodimeric
      transcription factors composed of E2F-like and DP-like subunits. They regulate
      expression of specific genes controlling cellular proliferation by binding to
      specific sequences within the promoter regions of these target genes and
      affecting their transcription in a cell cycle dependent manner. Recent studies
      have suggested an essential role of Rb/E2F pathway in the passage of cells
      through the G1 phase of the cell cycle. To better understand the role of these
      transcription factors in epithelial tumorigenesis, we compared the expression of
      various proteins involved in the Rb/E2F pathway in epidermis and 7,12
      dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13
      acetate (TPA) promoted papillomas on SENCAR mouse skin. Western blot analysis
      data showed 3.0- to 7.6-fold upregulation of E2F-1, E2F-2, E2F-3, E2F-4 and E2F-5
      in tumors compared to normal epidermis. In tumors, the protein expression of DP-1
      did not show significant change whereas that of DP-2 showed a 2.2-fold increase.
      Compared to normal epidermis, a significant upregulation of pRb (6.3-fold) and
      p107 (13-fold) was also observed in tumors. The protein expression of p130 was
      not detectable either in normal epidermis or in tumors. These data suggest that
      the overexpression of E2F proteins may be involved in the G1-S phase
      dysregulation that occurs during mouse skin tumorigenesis.

PMID- 10402253
TI  - Sampling technique influences the detection of K-ras mutations in normal
      appearing mucosa of colorectal cancer patients.
AB  - Based on three colorectal cancer cell lines with specified K-ras status, a
      sensitive PCR-RFLP assay was established detecting one K-ras mutant among 106
      wild-type cells. Using this assay for tissues of 124 colorectal cancer patients,
      59 tumor (46%) and 11 mucosa samples (9%) were found to harbor a K-ras mutation.
      When using the same scalpel for collecting tumor and mucosa tissues (group A),
      18% of the patients had a matching K-ras mutation in both tissues, but this
      coincidence was seen in 3% of patients only, when separate scalpels were used
      (group B). Thus we conclude that the sampling technique used for collecting
      specimens is a major contributor to the detection of K-ras mutations in normal
      appearing mucosa when a highly sensitive detection technique is used.

PMID- 10402254
TI  - ERP manifestations of processing printed words at different psycholinguistic
      levels: time course and scalp distribution.
AB  - The aim of the present study was to examine the time course and scalp
      distribution of electrophysiological manifestations of the visual word
      recognition mechanism. Event-related potentials (ERPs) elicited by visually
      presented lists of words were recorded while subjects were involved in a series
      of oddball tasks. The distinction between the designated target and nontarget
      stimuli was manipulated to induce a different level of processing in each session
      (visual, phonological/phonetic, phonological/lexical, and semantic). The ERPs of
      main interest in this study were those elicited by nontarget stimuli. In the
      visual task the targets were twice as big as the nontargets. Words, pseudowords,
      strings of consonants, strings of alphanumeric symbols, and strings of forms
      elicited a sharp negative peak at 170 msec (N170); their distribution was limited
      to the occipito-temporal sites. For the left hemisphere electrode sites, the N170
      was larger for orthographic than for nonorthographic stimuli and vice versa for
      the right hemisphere. The ERPs elicited by all orthographic stimuli formed a
      clearly distinct cluster that was different from the ERPs elicited by
      nonorthographic stimuli. In the phonological/phonetic decision task the targets
      were words and pseudowords rhyming with the French word vitrail, whereas the
      nontargets were words, pseudowords, and strings of consonants that did not rhyme
      with vitrail. The most conspicuous potential was a negative peak at 320 msec,
      which was similarly elicited by pronounceable stimuli but not by nonpronounceable
      stimuli. The N320 was bilaterally distributed over the middle temporal lobe and
      was significantly larger over the left than over the right hemisphere. In the
      phonological/lexical processing task we compared the ERPs elicited by strings of
      consonants (among which words were selected), pseudowords (among which words were
      selected), and by words (among which pseudowords were selected). The most
      conspicuous potential in these tasks was a negative potential peaking at 350 msec
      (N350) elicited by phonologically legal but not by phonologically illegal
      stimuli. The distribution of the N350 was similar to that of the N320, but it was
      broader and including temporo-parietal areas that were not activated in the
      "rhyme" task. Finally, in the semantic task the targets were abstract words, and
      the nontargets were concrete words, pseudowords, and strings of consonants. The
      negative potential in this task peaked at 450 msec. Unlike the lexical decision,
      the negative peak in this task significantly distinguished not only between
      phonologically legal and illegal words but also between meaningful (words) and
      meaningless (pseudowords) phonologically legal structures. The distribution of
      the N450 included the areas activated in the lexical decision task but also areas
      in the fronto-central regions. The present data corroborated the functional
      neuroanatomy of word recognition systems suggested by other neuroimaging methods
      and described their timecourse, supporting a cascade-type process that involves
      different but interconnected neural modules, each responsible for a different
      level of processing word-related information.

PMID- 10402255
TI  - Electrophysiological signatures of visual lexical processing: open- and closed
      class words.
AB  - This paper presents evidence of the disputed existence of an electrophysiological
      marker for the lexical-categorical distinction between open- and closed-class
      words. Event-related brain potentials were recorded from the scalp while subjects
      read a story. Separate waveforms were computed for open- and closed-class words.
      Two aspects of the waveforms could be reliably related to vocabulary class. The
      first was an early negativity in the 230- to 350-msec epoch, with a bilateral
      anterior predominance. This negativity was elicited by open- and closed-class
      words alike, was not affected by word frequency or word length, and had an
      earlier peak latency for closed-class words. The second was a frontal slow
      negative shift in the 350- to 500-msec epoch, largest over the left side of the
      scalp. This late negativity was only elicited by closed-class words. Although the
      early negativity cannot serve as a qualitative marker of the open- and closed
      class distinction, it does reflect the earliest electrophysiological
      manifestation of the availability of categorical information from the mental
      lexicon. These results suggest that the brain honors the distinction between open
      and closed-class words, in relation to the different roles that they play in on
      line sentence processing.

PMID- 10402256
TI  - Patterns of brain activity during visual imagery of letters.
AB  - Cortical signals associated with visual imagery of letters were recorded from 10
      healthy adults with a whole-scalp 122-channel neuromagnetometer. The auditory
      stimulus sequence consisted of 20 different phonemes corresponding to single
      letters of the Roman alphabet and of tone pips (17%), delivered once every 1.5
      sec in a random order. The subjects were instructed to visually imagine the
      letter corresponding to the auditory stimulus and to examine its visuospatial
      properties: The associated brain activity was compared with activity evoked by
      the same stimuli when the subjects just detected the intervening tones. All
      subjects produced broad imagery-related responses over multiple cortical regions.
      After initial activation of the auditory cortices, the earliest imagery-related
      responses originated in the left prerolandic area 320 msec after the voice onset.
      They were followed within 70 msec by signals originating in the posterior
      parietal lobe close to midline (precuneus) and, 100 msec later, in the posterior
      superior temporal areas, predominantly in the left hemisphere. The activations
      were sustained and partially overlapping in time. Imagery-related activity in the
      left lateral occipital cortex was observed in two subjects, and weak late
      activity in the calcarine cortex in one subject. Real audiovisually presented
      letters activated multiple brain regions, and task-induced visuospatial
      processing of these stimuli further increased activity in some of these regions
      and activated additional areas: Some of these areas were activated during imagery
      as well. The results suggest that certain brain areas involved in high-level
      visual perception are activated during visual imagery and that the extent of
      imagery-related activity is dictated by the requirements of the stimuli and the
      task.

PMID- 10402257
TI  - The neurophysiology of backward visual masking: information analysis.
AB  - Backward masking can potentially provide evidence of the time needed for visual
      processing, a fundamental constraint that must be incorporated into computational
      models of vision. Although backward masking has been extensively used
      psychophysically, there is little direct evidence for the effects of visual
      masking on neuronal responses. To investigate the effects of a backward masking
      paradigm on the responses of neurons in the temporal visual cortex, we have shown
      that the response of the neurons is interrupted by the mask. Under conditions
      when humans can just identify the stimulus, with stimulus onset asynchronies
      (SOA) of 20 msec, neurons in macaques respond to their best stimulus for
      approximately 30 msec. We now quantify the information that is available from the
      responses of single neurons under backward masking conditions when two to six
      faces were shown. We show that the information available is greatly decreased as
      the mask is brought closer to the stimulus. The decrease is more marked than the
      decrease in firing rate because it is the selective part of the firing that is
      especially attenuated by the mask, not the spontaneous firing, and also because
      the neuronal response is more variable at short SOAs. However, even at the
      shortest SOA of 20 msec, the information available is on average 0.1 bits. This
      compares to 0.3 bits with only the 16-msec target stimulus shown and a typical
      value for such neurons of 0.4 to 0.5 bits with a 500-msec stimulus. The results
      thus show that considerable information is available from neuronal responses even
      under backward masking conditions that allow the neurons to have their main
      response in 30 msec. This provides evidence for how rapid the processing of
      visual information is in a cortical area and provides a fundamental constraint
      for understanding how cortical information processing operates.

PMID- 10402258
TI  - Testing a computational account of category-specific deficits.
AB  - Patients displaying mild symptoms of Alzheimer's disease sometimes have more
      difficulty naming items from an artifact than from a natural kind category;
      others displaying more severe symptoms almost always have more difficulty naming
      items from a natural kind than from an artifact category. This paper examined a
      computational model of this double dissociation (Devlin, Gonnerman, Andersen, &
      Seidenberg, 1998). Four basic tests of the model were proposed: The model should
      be able to generalize to new exemplars, the model should be expandable such that
      training sets of a realistic size can be used, the model's performance should not
      be unduly affected by small changes in architecture, and the learning algorithm
      should produce results that are not inconsistent with any major underlying factor
      of semantic organization. The model was found to be deficient in all four areas.
      Results reported from the model may therefore have been idiosyncratic to the
      model and not reflect general properties of a real semantic system.

PMID- 10402259
TI  - Accessory stimulus effects on response selection: does arousal speed decision
      making?
AB  - When an intense but task-irrelevant "accessory" stimulus accompanies the
      imperative stimulus in a choice reaction task, reaction times (RTs) are
      facilitated. In a similar previous study (Hackley & Valle-Inclan, 1998), we
      showed that this effect is not due to a reduction of the interval from onset of
      the lateralized readiness potential (LRP) until movement onset. In the present
      study, the RT task was modified to move a portion of the response selection stage
      into this time interval. The interval remained invariant, indicating that this
      late phase of the response selection process is not speeded by accessory
      stimulation. However, we observed amplitude modulation of the LRP on no-go trials
      in a condition with three alternative responses. This finding suggests that an
      earlier phase of response selection is influenced by accessory stimulation. In
      addition, a novel dependent measure was introduced to event-related potential
      research--the latency of spontaneous, post-trial blinking.

PMID- 10402260
TI  - Interview with George A. Ojemann.

PMID- 10402261
TI  - Introduction to histochemical studies on human fetal brain development.

PMID- 10402262
TI  - Cell proliferation and death: morphological evidence during corticogenesis in the
      developing human brain.
AB  - Cell proliferation and death account for the refinement of the cell number during
      corticogenesis. These processes have been investigated in the human developing
      telencephalon (12th-24th week of gestation) and cerebellum (16th-24th week). Only
      foetal brains, which had normal neuropathological examination, were utilised.
      Cell proliferation was analysed by classical histology and PCNA
      immunohistochemistry; cell death was investigated by the TUNEL method, which
      makes evident the different stages of apoptosis. High figures of mitotic nuclei
      were seen in the ventricular zone at the 12th-15th week of gestation, before
      sharply declining. The decrease of the proliferating cells occurs synchronously
      in both frontal and occipital germinal zones. Conversely, a slow increase of the
      number of the mitotic cells was observed in the more dorsal regions, probably due
      to the presence of proliferating glial elements. The amount of apoptotic nuclei
      was always remarkably low in the transient compartments of the wall of the
      telencephalon. The moderate number of apoptotic cells suggests that cellular
      mechanisms other than apoptosis are involved in the dissolution of the
      ventricular zone. Neither proliferating nor apoptotic cells were seen in the
      cortical plate. The topography of cell proliferation and death in the developing
      cerebellum did not account for a mutual relationship between the two events. The
      prolonged duration of the cell-cycle in the human developing CNS may explain its
      increased vulnerability to various DNA-damaging conditions, which can lead to
      either destructive lesions or malformations.

PMID- 10402263
TI  - Proliferative status of cells in adult human dentate gyrus.
AB  - Experiments in rodents and marmoset monkeys indicate that granule neurons of the
      dentate gyrus may be renewable throughout the entire life of the animal. Whether
      this occurs in larger primates remains a matter of contention. However, a recent
      study of brain samples from five adult humans who had been injected with the
      thymidine analog bromodeoxyuridine indicates that new neurons might indeed be
      produced in the dentate gyrus. In this study, hippocampus specimens removed from
      18 adult humans for treatment of epilepsy were examined. The cell cycle marker
      Ki67, which is expressed from late G1 to M phase, was demonstrated by
      immunohistochemistry, and H2b/H3/H4 histone mRNAs, which are expressed during S
      phase, were demonstrated by in situ hybridization. Only 0.17% of cells in the
      subgranular layer, the site of neuronal progenitor cells, were Ki67
      immunoreactive but the identity of these could not be proven. Although the
      histone in situ hybridization technique was shown to work in human fetal brain,
      no M phase cells could be demonstrated in the hippocampus. The generation of new
      granule neurons in the human hippocampus must occur at a very slow rate. The
      approaches used in this study are likely unsuitable for studying cell populations
      with low turnover rate. Further work is needed to determine the fate of newly
      generated cells in the dentate gyrus. This information is of importance to our
      understanding of the mechanisms of learning and memory.

PMID- 10402264
TI  - Colonisation of the developing human brain and spinal cord by microglia: a
      review.
AB  - Microglia are the immune effector cells of the nervous system. The prevailing
      view is that microglia are derived from circulating precursors in the blood,
      which originate from the bone-marrow. Colonisation of the central nervous system
      (CNS) by microglia is an orchestrated response during human fetal development
      related to the maturation of the nervous system. It coincides with
      vascularisation, formation of radial glia, neuronal migration and myelination
      primarily in the 4th-5th months and beyond. Microglial influx generally conforms
      to a route following white matter tracts to gray areas. We have observed that
      colonisation of the spinal cord begins around 9 weeks, with the major influx and
      distribution of microglia commencing around 16 weeks. In the cerebrum,
      colonisation is in progress during the second trimester, and ramified microglial
      forms are widely distributed within the intermediate zone by the first half of
      intra-uterine life (20-22 weeks). A distinct pattern of migration occurs along
      radial glia, white matter tracts and vasculature. The distribution of these cells
      is likely to be co-ordinated by spatially and temporally regulated, anatomical
      expression of chemokines including RANTES and MCP-1 in the cortex; by ICAM-2 and
      PECAM on radiating cerebral vessels and on capillaries within the germinal layer,
      and apoptotic cell death overlying this region. The phenotype and functional
      characteristics of fetal microglia are also outlined in this review. The need for
      specific cellular interactions and targeting is greater within the central
      nervous system than in other tissues. In this respect, microglia may additionally
      contribute towards CNS histogenesis.

PMID- 10402265
TI  - A novel peroxisomal enzyme, D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA
      dehydrogenase bifunctional protein: its expression in the developing human brain.
AB  - D-bifunctional protein, which is a newly recognized peroxisomal enzyme (D-3
      hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase), demonstrates a
      characteristic development of pattern in the human brain. At 13 gestational weeks
      (GW), D-bifunctional protein immunoreactivity first appeared in the brain. Each
      neuron exhibited increased immunoreactivity along with growth in size as age
      increased and size with age. Glial cells in the white matter showed
      immunoreactivity after 30 GW. On the other hand, the L-bifunctional protein
      immunoreactivity was reported in neurons from 23 or 25 GW and in the white matter
      from 12 or 14 GW. Because of polymicrogyria in conditions such as infantile
      Refsum disease and infantile adrenoleukodystrophy, peroxisomal enzymes are
      thought to play an important role in neuronal migration and possibly myelination.
      D-bifunctional protein may be relevant to neuronal migration and L-bifunctional
      protein may be involved in axonal growth and synaptic development. This study is
      designed to access the ontogeny of D-bifunctional protein in the human brain.

PMID- 10402266
TI  - Early appearance of acetylcholinergic, serotoninergic, and peptidergic neurons
      and fibers in the developing human central nervous system.
AB  - Animal experiments have already shown that neurotransmitters and neuropeptides
      are not only important for normal functioning of the adult central nervous system
      (CNS) but are also crucial to its development. However, information on the spatio
      temporal distribution of these endogenous substances in the developing human CNS
      is still scarce. With the use of immunocytochemical staining and a constant
      supply of properly fixed human abortuses from southern China, an early appearance
      of acetylcholinesterase, enkephalin, and substance P immunoreactivities was
      detected first in the spinal cord (weeks 5 to 7 of gestation), then in the
      brainstem nuclei (weeks 11 to 12). Their overlapping localizations in many
      regions of the CNS suggest possible interactions among neurons containing these
      substances, which are in turn important for the proper establishment of the
      neuronal circuitry. Immunoreactivity for neuropeptide Y appeared initially in the
      lateral region of upper segments of the spinal cord at week 12 of gestation, then
      spread latero-medially and cranio-caudally to the sacral region. In the
      hippocampus, neuropeptide Y neurons appeared from week 15 onwards. Serotoninergic
      neurons were found in the dorsal raphe nucleus at week 10 and then decreased in
      number as the fetus grew older. Somatostatin releasing inhibitory factor,
      vasopressin, and oxytocin were detected in the hypothalamus from weeks 12 to 14
      onwards, and monoamine oxidase, succinic dehydrogenase, parvalbumin, calbindin
      D28K, and vasoactive intestinal peptide were found in the visual cortex at
      midgestation. The early appearance and the abundance of the neurotransmitters and
      neuropeptides in the developing CNS indicate that they may play a key role in
      neuronal differentiation.

PMID- 10402267
TI  - Nitrinergic neurons in the developing and adult human telencephalon: transient
      and permanent patterns of expression in comparison to other mammals.
AB  - A subpopulation of cerebral cortical neurons constitutively express nitric oxide
      synthase (NOS) and, upon demand, produce a novel messenger molecule nitric oxide
      (NO) with a variety of proposed roles in the developing, adult, and diseased
      brain. With respect to the intensity of their histochemical (NADPH-diaphorase
      histochemistry) and immunocytochemical (nNOS and eNOS immunocytochemistry)
      staining, these nitrinergic neurons are generally divided in type I and type II
      cells. Type I cells are usually large, intensely stained interneurons, scattered
      throughout all cortical layers; they frequently co-express GABA, neuropeptide Y,
      and somatostatin, but rarely contain calcium-binding proteins. Type II cells are
      small and lightly to moderately stained, about 20-fold more numerous than type I
      cells, located exclusively in supragranular layers, and found almost exclusively
      in the primate and human brain. In the developing cerebral cortex, nitrinergic
      neurons are among the earliest differentiating neurons, mostly because the
      dominant population of prenatal nitrinergic neurons are specific fetal subplate
      and Cajal-Retzius cells, which are the earliest generated neurons of the cortical
      anlage. However, at least in the human brain, a subpopulation of principal
      (pyramidal) cortical neurons transiently express NOS proteins in a regionally
      specific manner. In fact, transient overexpression of NOS-activity is a well
      documented phenomenon in the developing mammalian cerebral cortex, suggesting
      that nitric oxide plays a significant role in the establishment and refinement of
      the cortical synaptic circuitry. Nitrinergic neurons are also present in human
      fetal basal forebrain and basal ganglia from 15 weeks of gestation onwards, thus
      being among the first chemically differentiated neurons within these brain
      regions. Finally, a subpopulation of human dorsal pallidal neurons transiently
      express NADPH-diaphorase activity during midgestation.

PMID- 10402268
TI  - Differential expression of calbindin and calretinin in the human fetal amygdala.
AB  - The distribution patterns of the calcium-binding proteins calbindin and
      calretinin, both expressed early during development within the various amygdaloid
      nuclei and areas, have been investigated. Anti-calbindin as well as anti
      calretinin mark immature, partly migrating neurons in the 5th gestational month;
      the number of calretinin-immunoreactive neurons is distinctly higher. In the 8th
      month, calbindin and calretinin are found in a small proportion of presumed
      pyramidal cells and in various types of non-pyramidal neurons. Small and large
      bipolar and small and large multipolar neurons are shown to express calbindin and
      calretinin. Double-labellings show that calbindin and calretinin are largely
      contained in different subsets of these neuronal types, which are considered to
      represent interneurons. These nerve cell classes are widespread within the
      amygdala with mainly moderate to high packing densities. Diffuse immunoreactive
      structures, which are found in different intensities in the various amygdaloid
      nuclei, display distinct redistribution during fetal development. The results
      show that during early fetal development calbindin and particularly calretinin
      may be involved in the regulation of neuronal migration. In later development,
      definite subsets of interneurons, which are likely to be functionally different,
      are marked by anti-calbindin and -calretinin. Different diffuse immunolabelling
      at various developmental stages probably indicates the sequential arrival of
      afferent input from brain areas containing calbindin- or calretinin
      immunoreactive nerve cells. With the exception that calretinin may be transiently
      expressed in pyramidal neurons, the distribution of calbindin- and calretinin
      immunoreactive structures to a large degree corresponds to that in the adult.
      Thus, little reorganisation is to be expected during proceeding development.

PMID- 10402269
TI  - Development of telencephalin in the human cerebrum.
AB  - Telencephalin (TLN) is a 130kDa, type 1 integral membrane glycoprotein of the
      immunoglobulin superfamily found in the mammalian central nervous system. TLN
      shows a molecular structure resembling intercellular adhesion molecules-1 and -3,
      and binds to the CD11a/CD18 leukocyte integrin. TLN was localized to neuronal
      dendrites in the telencephalic gray matter: cerebral cortex and basal ganglia. We
      studied immunohistochemically the expression of TLN in the developing human
      brain. In the hippocampus, TLN immunoreactivity appeared at 29 gestational weeks
      (GW), intensified subsequently, and persisted into adulthood. In the temporal
      cortex, labeling was weak and restricted to the cytoplasm of pyramidal neurons
      from 35 to 39 GW, but thereafter became diffuse and intense in the cortical
      layers, especially the molecular layer, by 5 months of postnatal age. The
      development of TLN was late compared to synaptophysin and microtubule-associated
      protein 2, suggesting its involvement in the functional maturation of neuronal
      dendrites and synapses.

PMID- 10402270
TI  - Distribution of the catecholaminergic neurons in the central nervous system of
      human embryos and fetuses.
AB  - The catecholaminergic cell groups in the human brain, denominated from A1 to A17,
      display some striking anatomical differences with those described in the rodent.
      These differences are essentially observed in the extent of the dopaminergic
      neurons and especially their axonal fields in the telencephalon.
      Immunocytochemistry for tyrosine-hydroxylase and dopamine-ss-hydroxylase allowed
      the visualization of the precocious human catecholaminergic groups as early as
      4.5 postovulatory weeks. Maps of tyrosine-hydroxylase positive neurons generated
      in the different rhombomeres, midbrain, and prosomeres are shown following the
      prosomeric model introduced by Puelles and Rubenstein [(1993) Trends Neurosci.
      16:472-476]. Such a description is convenient to compare catecholaminergic
      systems in different mammalian species and provide clear anatomical landmarks of
      the embryonic substantia nigra (midbrain and prosomeres 1 and 2), that are
      necessary for transplantation of neural tissue in Parkinson's disease. The
      development and early specification of the dopaminergic neurons expressing
      calbindin D28K phenotype in the substantia nigra and in the ventral tegmental
      area are described. The catecholaminergic axons enter the anlage of the cerebral
      cortex just after the formation of the cortical plate, from 7 postovulatory weeks
      on. They invade the subplate layer where they wait for 4 weeks before penetrating
      the cortical plate. At midgestation, the different areas and layers of the
      frontal cerebral wall are invaded by the catecholaminergic axons, before the
      layering of the cortex is completed, in a pattern of fiber distribution similar
      to that described in the adult human brain. The early pattern of development of
      the catecholamine systems appeared to be phylogenetically well preserved in
      mammals, but specific features emerging during the differentiation period are
      unique to humans.

PMID- 10402271
TI  - Expression of a kinase anchoring protein 79 in the human fetal amygdala.
AB  - The expression of AKAP (a kinase anchoring protein) 79 enriched in postsynaptic
      densities has been investigated in the human amygdaloid nuclei of the 8th
      gestational month. Nuclear specific diffuse and cellular immunostaining is
      observed. An outstanding feature of cellular immunostaining is the labelling of
      somata and dendritic trees in a manner that allows neuronal classification.
      Bipolar, multipolar, and pyramidal AKAP79-positive neurons are found throughout
      the amygdala; the highest packing density of immunostained neurons is seen within
      the central and lateral nucleus. Dense diffuse immunolabelling is observed in the
      lateral and accessory basal nucleus. The results indicate that AKAP79 is
      expressed in various neuronal types (projection as well as local circuit
      neurons). Diffuse staining does not always match with cellular labelling within a
      nucleus, thus, AKAP79 may be particularly enriched in dendrites in some nuclei.
      The widespread distribution of AKAP79 indicates its possible role in various
      amygdaloid circuitries; thus, AKAP79 does not seem to be restricted to definite
      functional systems in the 8th month.

PMID- 10402272
TI  - Evidence for developmental precursor lesions in epilepsy-associated glioneuronal
      tumors.
AB  - The etiology and pathogenesis of epilepsy-associated local lesions remain largely
      unknown. Histopathologically, the most frequent lesions comprise gangliogliomas
      and glioneuronal malformations, i.e., hamartias or hamartomas, with a preferred
      location in the temporal lobe of young patients. A characteristic
      histopathological admixture of glial and neuronal elements, the focal appearance
      and the benign clinical behaviour suggest a malformative nature. So far, no
      molecular genetic alterations specifically involved in the pathogenesis of these
      glioneuronal lesions have been identified. However, immunohistochemical analysis
      revealed distinct distribution patterns of oncofetal antigens. The embryonic form
      of the neural cell adhesion molecule is present within glioneuronal hamartias,
      indicating an early migrational disorder. Recently, we have observed
      immunoreactivity for the stem cell marker CD34 in the majority of gangliogliomas
      and glioneuronal hamartomas. Based on these findings, we propose a common origin
      of gangliogliomas and glioneuronal hamartomas from a bipotent precursor that
      undergoes abnormal glioneuronal development.

PMID- 10402273
TI  - Immunohistochemical survey of migration of human anterior pituitary cells in
      developmental, pathological, and clinical aspects: a review.
AB  - Developmentally pathological conditions of the anterior pituitary cells include
      failed separation of the primary pituitary gland into sellar and pharyngeal ones,
      ectopic migration into the subarachnoid space, and basophil invasion into the
      posterior lobe although the last is a physiological phenomenon with pathological
      potentiality in certain circumstances. Pituitary primordium appears at about 4
      weeks of gestation. One of the causes of the pituitary gland agenesis may be a
      formation of the primary hypothalamic ganglionic hamartoma just at the time of
      occurrence of the pituitary primordium, as analyzed in cases of Pallister-Hall
      syndrome. A double pituitary in a single individual is a rare malformation. Its
      pathogenesis is considered as a result of notochordal anomaly. In the 8th
      gestational week, the primary pituitary gland separates into sellar and
      pharyngeal parts. The disturbance of this histogenesis results in a rare
      pituitary malformation, a "pharyngosellar pituitary." Despite the failed
      separation in this case, differentiation of the pituitary cells proceeds and the
      hormone production of this malformed pituitary gland can be displayed
      immunohistochemically. In this case, the distribution of the different hormone
      producing cells was atypical, particularly in those of gonadotropic hormones and
      ACTH. Life-long existence of the pharyngeal pituitary is a normal anatomical
      state in humans. Cell differentiation (hormone production) in the pharyngeal
      pituitary occurs about 4-10 weeks later than in the sellar pituitary. In
      pharyngeal pituitary, all kinds of adenohypophyseal hormones are produced.
      Extracranial pituitary adenomas (with intact sellar pituitary), exclusively found
      in the nasopharynx, sphenoid sinus, and clivus, may occur from the pharyngeal
      pituitary while another tumorigenesis can develop from the residual tissue
      fragment in the craniopharyngeal canal. The "overshoot" of the adenohypophyseal
      cell migration in the distal part of the sellar pituitary is frequently observed
      in the leptomeninges of the peri-infundibular or peri-hypothalamic region as
      ectopic pituitary cell clusters that are apparently independent of the pars
      tuberalis. It is suggested that these cells, frequently found in "normal"
      individuals, may be one of the possible origins of the intracranial ectopic
      pituitary adenomas. However, the reason why a majority of the reported
      intracranial ectopic pituitary tumors are ACTH-adenomas remains unexplained,
      since the ectopic cells, found in "normal" individuals, consist of fairly
      different hormone-producing cells. A further enigmatic phenomenon is a "basophil
      invasion." ACTH-positive cells invade from the pars intermedia into the posterior
      lobe of the pituitary. This invasion increases in intensity and frequency
      according to increase in age. However, the invasion of ACTH cells is observed as
      early as in the fetal life. The invasive cells display occasionally cell atypia
      as well as mitotic activity. The origin of extremely rare pituitary adenomas
      inside the posterior lobe can be explained by the existence and proliferative
      activity of basophil invasion.

PMID- 10402274
TI  - Clinical and angiographic outcome of stenting following suboptimal results of
      percutaneous transluminal coronary angioplasty in small (<2.5 mm) coronary
      arteries.
AB  - The purpose of the present study was to evaluate the feasibility and efficacy of
      stenting following suboptimal percutaneous transluminal coronary angioplasty
      (PTCA) in angiographically small coronary arteries. The clinical and angiographic
      outcome of unplanned stenting in 33 patients with coronary arteries <2.5 mm in
      diameter was studied. Procedural success was achieved for 97.0% with a greater
      initial gain (1.79 +/- 0.60 vs. 1.34 +/- 0.58 mm, P < 0.05) and larger
      postprocedural minimal luminal diameter (2.19 +/- 0.43 vs. 1.57 +/- 0.57 mm, P <
      0.001) than that in the size-matched elective PTCA patients. Trends toward a
      lower restenosis rate and a significant reduction in target lesion
      revascularization (7.1% vs. 41.9%, P < 0.01) were observed in the stented
      patients, suggesting the feasibility and efficacy of stenting following
      suboptimal PTCA in small coronary arteries. Cathet. Cardiovasc. Intervent. 47:269
      276, 1999.

PMID- 10402275
TI  - Stenting small coronaries: size does matter.

PMID- 10402276
TI  - Coronary stenting in diabetics: immediate and mid-term clinical outcome.
AB  - Balloon angioplasty in diabetics is associated with acceptable immediate results
      but with high rates of restenosis, target vessel revascularization, and late
      mortality. The impact of coronary stenting on the outcome of these patients
      remains controversial. We reported the immediate and mid-term clinical outcome of
      272 consecutive diabetic patients, representing 12.5% of the population
      undergoing coronary stenting between May 1995 and April 1997. Diabetes mellitus
      was insulin-requiring in 58 patients and non-insulin-requiring in 214. Stenting
      performed on large vessels (mean diameter >/=3 mm) was successful in 99.2% of
      nondiabetic patients and in all cases in diabetics. During in-hospital stay, the
      complications rate, including mortality, nonfatal myocardial infarction,
      emergency coronary bypass surgery, and stent subacute thrombosis, was similar in
      nondiabetic patients, insulin-requiring, and non-insulin-requiring diabetics
      (2.55%, 0%, and 2.0%, respectively). No complication occurred in the insulin
      requiring group. One patient (0.5%) died from myocardial infarction and another
      (0.5%) presented a nonfatal myocardial infarction (subacute stent thrombosis) in
      the non-insulin-requiring group. The clinical follow-up (mean length 13 +/- 8
      months) was obtained in 93% and 97% of the insulin-requiring and non-insulin
      requiring diabetics, respectively. Overall mortality was significantly higher in
      insulin-requiring patients (9.3% vs. 2.4%). Nonfatal myocardial infarction and
      target lesion revascularization rates were similar in the two groups (0% vs. 0.5%
      and 8.2% vs. 10.5%). These results suggest that coronary stenting in diabetics
      could be performed with acceptable immediate and mid-term results. Cathet.
      Cardiovasc. Intervent. 47:279-284, 1999.

PMID- 10402277
TI  - Coronary intervention in the diabetic: therapeutic strategies for 1999 and
      beyond.

PMID- 10402278
TI  - Percutaneous transluminal myocardial revascularization with a holmium laser
      system: procedural results and early clinical outcome.
AB  - Surgical transmyocardial laser revascularization has been reported to improve
      clinical outcome in patients with refractory angina who are not candidates for
      angioplasty or bypass surgery. We investigated the feasibility and safety of a
      nonsurgical, percutaneous technique for laser channel creation using energy from
      a holmium:yttrium-aluminium-garnet (YAG) laser. The laser energy was directed
      through a fiber enclosed in a catheter to the ventricular myocardium creating
      channels between the blood pool and the myocardium. Thirty-five patients with
      angina and coronary anatomy not amenable to revascularization with coronary
      angioplasty or bypass surgery underwent percutaneous transluminal myocardial
      revascularization. A total of 15 +/- 5 channels were formed per patient. There
      was no procedure-related mortality. One patient developed cardiac tamponade
      requiring thoracotomy and another a minor self-limiting pericardial effusion.
      There was no worsening of regional wall motion function in any patient. All
      patients were discharged alive after a postprocedure hospital stay of 2.1 +/- 1.4
      days. Mean Canadian Cardiovascular Society (CCS) functional class declined from
      3.68 +/- 0.4 before procedure to 0.82 +/- 0.7 at 30 days (P < 0.01). At 3 months,
      mean angina class was 0.94 +/- 0.65 (n = 35; P < 0.01) and at 6 months, mean
      angina class was 1.08 +/- 0.58 (n = 26; P < 0.01). One patient required repeat
      revascularization after 5 months for progression of disease in a degenerated
      saphenous venous graft supplying different region of myocardium. We conclude that
      transmyocardial revascularization using holmium:YAG laser by percutaneous
      technique can be carried out safely with encouraging early results and a very low
      complication rate. The symptomatic relief seen up to 6 months has been excellent.
      The long-term effects of this technique on mortality and relief of angina,
      however, remain to be defined. Cathet. Cardiovasc. Intervent. 47:287-291, 1999.

PMID- 10402279
TI  - Holier than thou.

PMID- 10402281
TI  - Readministration of abciximab: weighing the risks and benefits 

PMID- 10402280
TI  - Abciximab readministration: A single-operator community-hospital experience.
AB  - Abciximab, a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor,
      reduces ischemic complications of coronary interventions after first
      administration. In this study, We sought to determine whether readministration of
      abciximab is associated with equal efficacy and safety. We retrospectively
      reviewed the charts of 35 patients who received two doses of abciximab at
      separate intervals. We monitored patients clinically for recurrent ischemia,
      bleeding complications, and thrombocytopenia. We measured hemoglobin and platelet
      counts before and after readministration of abciximab. There was no cardiac
      related death, myocardial infarction, or recurrent ischemia. No obvious bleeding
      occurred in any of the 35 patients, although 1 patient had a drop of hemoglobin
      >3 gm/dl. We observed one episode of severe thrombocytopenia without any
      complication, and this patient improved without requiring platelet transfusion.
      There was no profound thrombocytopenia. We conclude that readministration of
      abciximab was well tolerated without any evidence of altered efficacy or safety.
      Cathet. Cardiovasc. Intervent. 47:294-296, 1999.

PMID- 10402282
TI  - Intravascular ultrasound-guided balloon angioplasty for treatment of in-stent
      restenosis.
AB  - We investigated the usefulness of intravascular ultrasound (IVUS)-guided balloon
      angioplasty for in-stent restenosis in 37 lesions of 34 consecutive patients. We
      divided these patients into two groups: a group in which the balloon size was
      determined by quantitative coronary angiography (QCA group; 17 patients, 19
      lesions) and a group in which the balloon size was determined by IVUS (IVUS
      group; 17 patients, 18 lesions). We compared short-term and 6-month outcomes for
      these groups. In the IVUS group, we used a balloon of a size equal to 95% of the
      media-to-media diameter at the distal to the stent, as determined by IVUS. No
      significant differences were observed in patient or lesion characteristics
      between the two groups. The clinical success rate was 100% in both groups, and no
      clinical events were observed in either of the groups. The balloon/artery ratio
      was larger in the IVUS group than in the QCA group (1.33 +/- 0.35 vs. 1.16 +/-
      0.13, P < 0.05), and the recurrent restenosis rate was lower (17% vs. 53%, P <
      0.05). These results suggest that repeat balloon angioplasty using a balloon size
      determined by IVUS is useful for in-stent restenosis. Cathet. Cardiovasc.
      Intervent. 47:298-303, 1999.

PMID- 10402283
TI  - A prospective, randomized evaluation of nonsurgical closure of femoral
      pseudoaneurysm by compression device with or without ultrasound guidance.
AB  - Femoral artery pseudoaneurysm (PA) is a significant complication following
      diagnostic or therapeutic catheterization. The treatment of choice for femoral
      artery PA is freehand ultrasound-guided compression repair (UGCR). An alternative
      method is compression by mechanical devices. The study evaluated the mechanical
      compression device (FemoStop) with (G1) or without (G2) ultrasound guidance for
      initial placement in a randomized fashion. Thirty-eight patients (20 women, 18
      men) age 40 to 85 (mean 54) years with clinical signs of PA underwent diagnostic
      color Doppler ultrasound. Randomization yielded 19 patients each for G1 and G2.
      PA occurred after 12 diagnostic cardiac catheterizations, 18 coronary stent
      implantations or balloon angioplasties, 2 electrophysiology procedures, and 6
      peripheral percutaneous transluminal angioplasties. The G1 protocol was
      successful in 15 of 19 patients (79%), with a mean compression time of 28 min.
      The three other patients were treated successfully with UGCR. Only one patient
      needed vascular surgery. The G2 protocol was successful in 14 of 19 patients
      (74%) with a mean compression time of 33 min. The failed patients were treated
      successfully: three with UGCR and two with the same mechanical compression device
      now positioned under ultrasound control. Compression therapy with the compression
      device (FemoStop) for iatrogenic femoral pseudoaneurysm does not require
      ultrasound guidance for positioning. Cathet. Cardiovasc. Intervent. 47:304-309,
      1999.

PMID- 10402284
TI  - Stent implantation to create interatrial communications in patients with complex
      congenital heart disease.
AB  - A restrictive interatrial communication can complicate the management of complex
      congenital heart disease. The purpose of this report is to present a new
      technique to achieve a patent and reliable interatrial communication by using an
      endovascular stent. A stent was successfully implanted across a fenestrated
      extracardiac conduit in two patients with low cardiac output after Fontan
      operations and across the interatrial septum in a patient with double inlet left
      ventricle and severe left atrioventricular stenosis. The procedures were
      uncomplicated and all patients showed immediate hemodynamic improvement. Cathet.
      Cardiovasc. Intervent. 47:310-313, 1999.

PMID- 10402285
TI  - Are children worth it? the FDA thinks so, and so do we! 

PMID- 10402286
TI  - Snare-assisted vascular access: a new technique.
AB  - Access to the central circulation can be difficult in small infants, particularly
      when normal anatomic landmarks have been altered. We describe a new technique
      that utilizes any existing central catheter to establish additional sites of
      vascular access. A 4 Fr end hole catheter is advanced under fluoroscopic guidance
      to the desired site of new vascular access. A 10-mm Amplatz snare catheter is
      advanced through the end hole catheter and the loop opened within the target
      vessel lumen. The snare is then used to guide percutaneous placement of a Cope
      wire through a 21-gauge needle and then to pull the wire into the central
      circulation. New access is then achieved by introducing an additional catheter
      over the guidewire. This technique has now been successfully utilized 16 times in
      13 patients. Snare assistance is a safe and effective technique that provides a
      reliable means of establishing additional secure vascular access. Cathet.
      Cardiovasc. Intervent. 47:315-318, 1999.

PMID- 10402287
TI  - Percutaneous venous access: snares are for more than gooses.

PMID- 10402288
TI  - Right aortic arch with isolation of the left subclavian artery, moderate patent
      ductus arteriosus, and subclavian steal syndrome: A rare aortic arch anomaly
      treated with the Gianturco-Grifka vascular occlusion device.
AB  - We present the first described use of the Gianturco-Grifka Vascular Occlusion
      Device to close a moderate patent ductus arteriosus associated with the rare
      congenital condition of right aortic arch with isolation of the left subclavian
      artery. Left vertebral artery "steal" through the moderate patent ductus
      arteriosus was eliminated by this transcatheter technique. Cathet. Cardiovasc.
      Intervent. 47:320-322, 1999.

PMID- 10402289
TI  - Dislodged stent: a simple retrieval technique.
AB  - We report a technique for retrieval of a dislodged coronary stent using a stiff
      angioplasty wire positioned beside the initial stent guidewire. This two-wire
      technique provides a better platform to move and position the snare device
      without moving the dislodged stent and thus lessens the risk of embolization. If
      a larger femoral sheath is needed for stent removal, this method facilitates
      sheath exchange. Cathet. Cardiovasc. Intervent. 47:323-324, 1999.

PMID- 10402290
TI  - Retrieval techniques for dislodged stents.

PMID- 10402291
TI  - Right ventricular infarction complicating right coronary angioplasty.
AB  - We report a patient who developed anterior ST segment elevation following
      angioplasty of the right coronary artery in which a right ventricular branch
      became occluded. Several similar reports were found in the literature as well as
      a putative mechanism for the electrocardiographic changes. Cathet. Cardiovasc.
      Intervent. 47:327-330, 1999.

PMID- 10402292
TI  - Severe spasm of a radial artery coronary bypass graft during coronary
      intervention.
AB  - Coronary spasm is a well-recognized observation during coronary angiography. This
      report describes a patient who developed spasm of a radial artery bypass graft
      during coronary intervention. There are many reports on the angiographic follow
      up to confirm the surgical results for patency in radial arterial conduits. We
      share our experience with this first case in the literature noted to have severe
      vasospasm during PTCA. Cathet. Cardiovasc. Intervent. 47:331-335, 1999.

PMID- 10402293
TI  - Right-sided pulsus alternans in diastolic left ventricular dysfunction.
AB  - Pulsus alternans is usually found in patients with reduced systolic ventricular
      function. We describe a patient with shortness of breath, hypertension, and left
      ventricular hypertrophy, but with normal left and right systolic function. Pulsus
      alternans was demonstrated in the pulmonary wedge position, pulmonary artery, and
      right ventricle, but not in the aorta or left ventricle. Cathet. Cardiovasc.
      Intervent. 47:336-339, 1999.

PMID- 10402294
TI  - The significance of right-sided pulsus alternans.

PMID- 10402295
TI  - Occurrence of a saccular pseudoaneurysm formation two weeks after perforation of
      the left anterior descending coronary artery during balloon angioplasty in acute
      myocardial infarction.
AB  - We describe the occurrence of a localized saccular pseudoaneurysm in a 69-year
      old patient 2 weeks after perforation of the left anterior descending coronary
      artery during balloon angioplasty in acute myocardial infarction. The therapy of
      perforations requires prolonged balloon inflations, perfusion balloons, covered
      stents, or surgery. Coronary peudoaneurysm formations are rare; their therapy
      requires covered stents or surgery. Cathet. Cardiovasc. Intervent. 47:341-346,
      1999.

PMID- 10402296
TI  - Radiation safety in the cardiac catheterization laboratory: operational radiation
      safety.
AB  - The goal of the catheterization laboratory radiation safety program is to
      facilitate invasive cardiology while simultaneously reducing staff risks to an
      acceptable level. Achieving this goal requires a balance between the value of
      catheterization to the patient and the associated radiation risk to the staff.
      This article introduces the principles of radiation protection as applied in the
      catheterization laboratory. Prudent conformance to these principles will
      appropriately reduce radiation risk. Cathet. Cardiovasc. Intervent. 47:347-353,
      1999.

PMID- 10402297
TI  - Percutaneous transmyocardial laser revascularization: an overview.
AB  - Transmyocardial revascularization (TMR) is a novel strategy designed to improve
      anginal symptoms and enhance myocardial perfusion by applying laser energy
      directly into the ischemic myocardium. Preliminary surgical experiences using TMR
      have indicated a significant reduction in angina severity, improved quality of
      life, and some evidence of improved myocardial perfusion in refractory coronary
      ischemic syndromes. Possible mechanisms to explain the clinical benefit include
      stimulated angiogenesis, local myocardial denervation, or both. The goal of
      catheter-based TMR is to create nontransmural endomyocardial channels smaller in
      size but comparable in tissue effect to the surgical TMR procedure. At present,
      most percutaneous TMR experiences seem very promising, although derived from
      nonrandomized registries with a relatively small number of patients. More
      rigorous assessments of objective and subjective endpoints derived from ongoing
      larger randomized clinical trials are needed to render definitive conclusion
      about the validity of this therapeutic strategy in patients with refractory
      coronary ischemic syndromes. Cathet. Cardiovasc. Intervent. 47:354-359, 1999.

PMID- 10402298
TI  - Warming up to the reptilian heart.

PMID- 10402299
TI  - Stenting with a true bifurcated stent: acute and mid-term follow-up results.
AB  - Percutaneous therapy of coronary bifurcated lesions is associated with greater
      risk of acute complications and late restenosis. Numerous innovative techniques
      using various stent types have been proposed. We report the first clinical use of
      a truly bifurcated stent (Bard XT Carina). The implantation procedure, favorable
      medium-term angiographic and 1-year clinical follow-up of the first human use in
      a 43-year-old female are illustrated with angiography and intravascular
      ultrasound. As a single prosthesis that effectively covers the bifurcation, this
      stent presents appealing alternative for the treatment of coronary bifurcation
      lesions when compared to methods that involve multiple-stent implantation.
      Cathet. Cardiovasc. Intervent. 47:361-369, 1999.

PMID- 10402300
TI  - New self-expanding patent foramen ovale occlusion device.
AB  - Our purpose was to evaluate a new self-expanding device for closure of the patent
      foramen ovale (PFO). A transeptal catheter passage through the flap of the fossa
      ovalis was performed with a transeptal needle inside a catheter, creating a PFO
      in two minipigs. In an additional five animals, a naturally occurring PFO was
      found. The device is made from 0.005 inch nitinol wire mesh with polyester fabric
      inside, similar in construction to the Amplatzer atrial septal occluder. However,
      the left atrial disc is smaller (18 mm) than the right atrial disc (26 mm). Both
      discs are connected by a very short flexible waist (3 mm) that allows free
      movement of both retention discs. Pulmonary and right atrial angiography were
      performed after placement, at 1 month, and at 3 months follow-up. Placement of
      the device was technically successful in six animals. One animal died from
      ventricular fibrillation during placement. Pulmonary angiography and
      echocardiography showed complete occlusion of the PFO in six animals. Two animals
      were sacrificed after 1 month and four animals after 3 months. In the animals
      sacrificed at 1 month, histopathological examination showed partial (n = 2)
      endothelialization, and in the 3 months follow-up group (n = 4)
      endothelialization was complete. The device appears to be highly effective for
      occlusion of PFOs. This procedure may be performed as an outpatient procedure due
      to the small 7 Fr delivery system sheath. Cathet. Cardiovasc. Intervent. 47:370
      376, 1999.

PMID- 10402301
TI  - Percutaneous patent foramen ovale (PFO) closure: It can be done but should it?

PMID- 10402302
TI  - A new thrombectomy catheter device (AngioJet) for the disruption of thrombi: An
      in vitro study.
AB  - In this study we examined a new thrombectomy catheter device. Different kinds of
      in vitro generated thrombi and cadaver thrombi were disrupted in test tubes. The
      mean disruption rate (and disruption time for 1 g of thrombus) was 225 +/- 65
      mg/sec (5 +/- 2 sec) for whole-blood, 117 +/- 60 mg/sec (12 +/- 9 sec) for
      fibrin, 41 +/- 18 mg/sec (30 +/- 18 sec) for mixed, 70 +/- 42 mg/sec (17 +/- 5
      sec) for unorganized, 45 +/- 8 mg/sec (22 +/- 4 sec) for partly, and 5 +/- 1
      mg/sec (216 +/- 29 sec) for completely organized cadaver thrombi (P < 0.05). More
      than 99% of fragmented particles of whole-blood thrombi were 0-12 microm in
      diameter. The particle size of fibrin, mixed, and cadaver thrombi was similar,
      with 25%-40% of particles between 0-12 microm, 55%-71% >12-24 microm, and 2%-7%
      >24 microm. The device may be effectively used in the therapy of massive
      pulmonary embolism or acute peripheral and coronary artery syndromes when medical
      thrombolysis is contraindicated and organization of thrombus is absent. Further
      studies need to be performed to investigate the potential effects of particle
      microembolization. Cathet. Cardiovasc. Intervent. 47:381-389, 1999.

PMID- 10402303
TI  - The golden age of cardiology.

PMID- 10402304
TI  - Good news for egg lovers.

PMID- 10402306
TI  - Coenzyme Q-10 disappoints in rigorous study.

PMID- 10402305
TI  - Abdominal aortic aneurysms run in the family.

PMID- 10402307
TI  - Ask the doctor. I have diabetes and use insulin two, sometimes three, times a day
      to keep my sugar under control. My hope is that this will help me avoid a heart
      attack. Is this a reasonable goal?

PMID- 10402308
TI  - Ask the doctor. I am so confused by what I read about hormone-replacement
      therapy. I am 60 years old and do not have any heart problems now. Should I be
      taking these drugs?

PMID- 10402309
TI  - The physical exam. Close encounter of a medical kind.

PMID- 10402310
TI  - By the way, doctor... Last month I had a night of severe abdominal pain. My
      doctor ordered an ultrasound test, and it showed gallstones. She is recommending
      surgery to remove my gallbladder, but I'd rather not have an operation because of
      this one episode. Is it dangerous to hold off on surgery? Is there any diet to
      follow or medicine I can take to prevent another attack? I am 53 years old and
      healthy.

PMID- 10402311
TI  - Heat and health: when it's too darn hot.

PMID- 10402312
TI  - Nocturia. When nature calls at night.

PMID- 10402313
TI  - Vegetarianism. Should you or shouldn't you?

PMID- 10402314
TI  - Mitral myths.

PMID- 10402315
TI  - Memories lost and found - Part II.

PMID- 10402316
TI  - Insights: where biopsychiatry came from: a short history of somatic therapies
      from 1900 to the 1950s.

PMID- 10402317
TI  - Forum. Which aspects of nicotine addiction should concern mental health
      professionials?

PMID- 10402318
TI  - Treating prostate cancer: An overview.

PMID- 10402320
TI  - Heat wave.

PMID- 10402321
TI  - I understand there is a new artificial sweetener on the market. Is it any safer
      than others?

PMID- 10402322
TI  - Estrogen and breast cancer risk.

PMID- 10402323
TI  - Coronary heart disease. New guidelines for prevention.

PMID- 10402324
TI  - Ovarian disorders. Benign cysts.

PMID- 10402326
TI  - Low-fat diets for migraine headache.

PMID- 10402325
TI  - Weight control. Keeping pounds off.

PMID- 10402327
TI  - By the way, doctor. I read with interest your article regarding conventional Pap
      smears, PapNet, and AutoPap. Lately I've been reading about another test called
      ThinPrep. I'm not sure which one to request. Which of these techniques is better
      for detecting cervical cancer?

PMID- 10402328
TI  - Near infrared spectroscopy : an emerging non-invasive optical imaging technique.

PMID- 10402329
TI  - Neurological manifestations of malaria : an update.
AB  - Several neurological complications are associated with complicated and severe
      falciparum malaria. Cerebral malaria is one of the most dreaded complication. The
      children are particularly more vulnerable to have this complication. Despite
      availability of several potent antimalarial drugs in recent past, the mortality
      status has not changed. A large number of survivors are left with disabling
      neurological sequelae. Few patients may experience post-malaria neurological
      syndrome after recovery from complicated falciparum infection. Various
      psychiatric syndromes have been described either as early manifestation of
      cerebral malaria or part of post malaria neurological syndrome. From Indian
      subcontinent several patients of delayed cerebellar ataxia have also been
      described following recovery from clinical malaria. In paediatric patients,
      convulsions of cerebral malaria need to be differentiated from febrile
      convulsions. Falciparum malaria is also associated specifically with convulsions
      in uncomplicated patients of malaria. Several isolated case reports of various
      other neurological syndromes like peripheral neuropathies, various movement
      disorders, myelopathies and stroke like syndrome have been described. However
      association of these neurological manifestations with malaria remains doubtful.

PMID- 10402330
TI  - Bilateral optic nerve injury.
AB  - Bilateral optic nerve injury is a rare condition and is reported in 5-6 percent
      of all optic nerve injuries. However, there is no published series on bilateral
      optic nerve injury. Analysis of 31 cases of bilateral optic nerve involvement
      seen amongst 275 patients with optic nerve injury (11.5 percent) is discussed.
      Road traffic accident which is the most common cause of optic nerve injury, was
      recorded in 61 percent. Shotgun injury and blast in jury was the cause in 22.5
      percent of cases. All the patients except 4 received steroids. Anterior cranial
      fossa fracture and opacity of paranasal sinuses were recorded in a third of the
      patients. Visual evoked potentials were recorded in 27 patients. Improvement in
      vision was noticed in 23 patients (74 percent). However, among the 62 eyes, 39
      eyes showed improvement (62.8 percent). Possible reasons for better outcome in
      bilateral optic nerve injury are discussed.

PMID- 10402331
TI  - Trigeminal evoked potentials in patients with symptomatic trigeminal neuralgia
      due to intracranial mass lesions.
AB  - Trigeminal evoked potentials (TEP) were recorded by electrical stimulation of the
      lips in 7 patients with symptomatic trigeminal neuralgia due to CT proved mass
      lesions involving the trigeminal nerve. All the patients showed TEP abnormalities
      on the affected side. Chronic compression and irritation of the trigeminal nerve
      may be responsible for these changes. The results obtained were compared with
      other similar studies and TEP abnormalities observed in idiopathic trigeminal
      neuralgia. As all the patients had unequivocal compression of the trigeminal
      nerve and all of them had TEP changes, it can be concluded that TEP abnormality
      is an accurate predictor of trigeminal nerve compression. TEPs may be a valuable
      aid in demonstrating a compressive element in patients with trigeminal neuralgia.

PMID- 10402332
TI  - Epilepsy surgery : overview Of forty years experience.
AB  - Although many patients with epilepsy achieve control of their seizures with
      medication, a substantial number ultimately develop intractable epilepsy.
      Patients with intractable epilepsy form the group for whom surgical procedures
      may be beneficial. We retrospectively analyzed the clinical profile and outcome
      of 141 patients operated for intractable epilepsy at Vellore between 1949 and
      1990. The operative procedures done for suprasylvian epilepsy were topectomy (24
      cases) and lobectomy (2 cases). For temporal lobe epilepsy the surgical
      procedures done were topectomy (28 cases), temporal lobectomy with amygdalectomy
      (25 cases), temporal lobectomy with amygdalectomy and hippocampectomy (10 cases),
      amygdalectomy (15 cases) and topectomy with amygdalectomy in one case.
      Hemispherectomy was done for 12 cases with multilobe epilepsy. For multifocal
      epilepsy, four patients underwent stereotactic ansotomy. Post operative
      complications included infections (10 cases) and acute post operative haematoma
      in one patient. There was transient neurological deterioration in ten patients.
      Three patients operated prior to 1960 died due to peri operative complications.
      Follow up data of 80 patients, ranging from 1 to 42 years (mean 10 years) was
      analysed. Total or near total seizure control was obtained in 53% patients and a
      worthwhile outcome in 20% patients. Mental retardation, pre operative scalp
      electroencephalography and post excision electrocorticography has been shown to
      be predictors of outcome with respect to seizures.

PMID- 10402333
TI  - Effect of 'Mentat' on the pharmacokinetics of single and multiple doses o
      phenytoin in rabbits.
AB  - The effect of 'Mentat', a herbal preparation, was studied on pharmacokinetics of
      single and multiple doses of phenytoin in rabbits. No significant effect was
      found after single oral dose of 'Mentat' on single dose kinetics of phenytoin.
      However, 'Mentat' administration for 7 days increased the steady state kinetic
      parameters. Peak plasma phenytoin concentration, area under the implasma
      concentration and elimination half life were significantly increased and t-max
      was significantly reduced, indicating the suppression of phenytoin metabolism by
      'Mentat'.

PMID- 10402334
TI  - Somatosensory evoked potentials by paraspinal stimulation in acute transverse
      myelitis.
AB  - Somatosensory evoked potentials by paraspinal stimulation were studied in 6
      patients with acute transverse myelitis. In one patient in whom posterior tibial
      somatosensory evoked potentials were not recordable, a poorly formed response was
      seen with paraspinal stimulation. Slowing of conduction across the involved
      segment was seen in the remaining 5 patients and fairly correlated with the
      clinical localization.

PMID- 10402335
TI  - Posterior circulation abnormalities in moyamoya disease : a radiological study.
AB  - Moyamoya disease (MMD) is an uncommon entity outside Japan. Though the clinical
      and radiological features are well described, involvement of the posterior
      circulation has not been highlighted. Out of 10 patients of MMD studied, the
      posterior circulation was involved in 9 (3 bilateral, 6 unilateral). The P1
      segment was most commonly affected. Interestingly, no infarcts were seen in the
      territory of the posterior circulation in any patient. Five patients showed
      recent haemorrhages on scan. It was thalamic haemorrhage in four and subarachnoid
      in one patient. The posterior circulation is frequently involved in MMD as
      evident on angiography. However, ischaemic events of the posterior circulation
      are not frequent, as the posterior circulation acts as collateral pathway for the
      diseased anterior circulation till later stages of the disease.

PMID- 10402336
TI  - Intracranial pressure changes with different doses of lignocaine under general
      anaesthesia.
AB  - The effect of intravenous lignocaine on intracranial pressure (ICP) was studied
      on thirty patients of either sex, aged above 5 years and scheduled for elective
      ventriculoperitoneal shunt surgery. The patients were randomly divided into 3
      groups, which received intravenous lignocaine in the dose of 1 mg, 1.5 mg and 2
      mg/kg body weight respectively. Intracranial pressure, heart rate, ECG, arterial
      pressure and arterial blood gases were monitored at various intervals for a
      period of 30 minutes. Maximum decrease in ICP was seen at 2 minutes after IV
      lignocaine in all the three groups (p<0. 001). The fall in ICP was significantly
      more in group II and group III (35.65% and 37.5% respectively) as compared to
      group I (17.47%) (p<0.001). This fall in ICP in all the three groups persisted
      below the basal level, throughout the study period. None of the groups showed any
      significant change in the heart rate, but a statistically significant fall in
      arterial pressure was observed in group III (p<0. 05). In conclusion intravenous
      lignocaine, in a dose of 1.5 mg/kg, causes significant fall in ICP without
      causing any untoward cardiovascular effects and is recommended for routine
      clinical use.

PMID- 10402337
TI  - Antiphospholipid antibodies syndrome in 'Stroke in young'.
AB  - Antiphospholipid antibodies syndrome has emerged as an important entity
      responsible for stroke in young. Seven cases of young stroke (< 40 years of age)
      with mean age of 30.1 years (age range 25-39 years, 2 males and 5 females), who
      tested positive for antiphospholipid antibodies are being reported. All subjects
      had completed strokes. Six had arterial ischaemic and one patient had venous
      stroke. One patient suffered from four episodes, three ischaemic and one
      intracerebral haemorrhage. Two patients suffered from foetal loss. Generalised
      tonic clonic seizures occurred in three patients. Deep vein thrombosis was
      observed in one case. Thrombocytopenia was not observed in any case. All the
      patients had elevated anticardiolipin antibodies (aCL) IgM or IgG, while Lupus
      anticoagulant (LA) was elevated in 4 cases. Six cases belonged to primary
      antiphospholipid antibodies syndrome and one to lupus like illness. Oral
      anticoagulants were administered to maintain a high intensity international
      normalized ratio (INR). No recurrences were observed during a follow up period of
      6-18 months.

PMID- 10402338
TI  - Midline cerebellar cystic schwannoma : a case report.
AB  - An extremely unusual case of a cystic schwannoma in the region of the inferior
      vermis and posterior to the fourth ventricle in a fifteen year old boy is
      reported. The cystic tumour caused partial obstruction to the outflow of
      cerebrospinal fluid from fourth ventricle and resulted in development of
      supratentorial hydrocephalus. On investigations, the schwannoma simulated a Dandy
      Walker cyst. The boy presented with symptoms of increased intracranial pressure.
      On surgery, the lesion was not arising from any cranial nerve, nor was it
      attached to brain parenchyma, blood vessel or to the dura. The possible
      histogenesis of the cystic schwannoma in a rare location is discussed.

PMID- 10402339
TI  - Acute dysautonomia following mumps.
AB  - Pure acute or subacute dysautonomia is a rare entity. Its etiology is as yet
      unknown. However, majority of these cases have a preceding viral infection such
      as herpes simplex, infectious mononucleosis, rubella or coxsackie B. A unique
      patient in whom acute dysautonomia followed mumps is reported.

PMID- 10402340
TI  - Palatal myoclonus in postinfectious opsoclonus myoclonus syndrome : a case
      report.
AB  - An adult male presenting with acute onset opsoclonus, myoclonus and cerebellar
      ataxia is being reported. Patient had myoclonus involving limbs and palate. There
      are only a few reported cases associated with palatal myoclonus. Patient showed
      gradual spontaneous recovery. Possibility of underlying malignancy was excluded
      by detailed investigations.

PMID- 10402341
TI  - Familial gliomas : a case report.
AB  - Two non-twin brothers were found to have intracranial malignant neoplasms. The
      age of presentation was third and fourth decade but the onset was simultaneous,
      at the same time. Diagnosis in each of them was made by computed tomography and
      confirmed by histopathology. Elder among them had cellular ependymoma and the
      younger had oligodendroglioma. Both the brothers received radiotherapy post
      operatively and were surviving asymptomatically without any neurological deficit,
      leading active life as police constable, 12 months after surgical treatment.

PMID- 10402342
TI  - Primary progressive aphasia : a case report.
AB  - Primary progressive aphasia is due to focal left perisylvian degeneration and
      manifests with progressive decline in language function for two or more years.
      There is preservation of cognitive functions and activities of daily living
      continue to be normal. We report a case of progressive aphasia in a 65 year old
      lady.

PMID- 10402343
TI  - Glioblastoma multiforme following prophylactic cranial irradiation and
      intrathecal methotrexate in a child with acute lymphoblastic leukaemia : a case
      report.
AB  - A 12 year old boy with acute lymphoblastic leukaemia had received prophylactic
      cranial irradiation (2000 cGy/15 days) and intrathecal methotrexate. Six years
      later he was diagnosed to have glioblastoma in left temporoparietal region. There
      is a strong possibility that the glioma may have been radiation and/or
      chemotherapy induced.

PMID- 10402344
TI  - Suprasellar arachnoid cyst presenting with precocious puberty : report of two
      cases.
AB  - Suprasellar arachnoid cysts (SSAC) are uncommon intracranial lesions. Two
      patients of SSAC presenting with precocious puberty are described. In both the
      cases partial excision of the cyst wall, through a pterional craniotomy,
      establishing communication with the basal subarachnoid spaces was carried out.
      The endocrinological symptoms regressed after surgery. The clinical presentations
      of SSAC and the treatment options available are reviewed.

PMID- 10402345
TI  - CSF rhinorrhoea from unusual site : report of two cases.
AB  - CSF rhinorrhoea is associated with high morbidity and mortality. Bone and dural
      defects may result from trauma or enlarging 'pitholes' or breach in lateral
      recess of sphenoid sinus. Unless surgically corrected, they tend to cause
      meningitis and rhinorrhoea. Unusually delayed rhinorrhoea is a diagnostic
      problem.

PMID- 10402346
TI  - Plasma antithrombin III deficiency in ischaemic stroke in the young.
AB  - A deficiency of plasma antithrombin III has been identified as a potential risk
      factor for thrombosis. In a pilot study of 56 patients aged less than 40 years
      who presented with ischaemic stroke of unknown etiology, we detected only one
      case of plasma antithrombin III deficiency. Antithrombin III activity was
      estimated by a chromogenic assay. Hence, antithrombin III deficiency, though
      rare, should be considered while evaluating young patients with stroke of unknown
      etiology.

PMID- 10402347
TI  - Spinal epidural haematoma in an haemophiliac with HIV.

PMID- 10402348
TI  - Spontaneous spinal extradural haematoma.

PMID- 10402350
TI  - Regression of acromegaly following pituitary apoplexy.

PMID- 10402349
TI  - Neurobrucellosis presenting as acute meningoencephalitis.

PMID- 10402351
TI  - Mesial temporal sclerosis.

PMID- 10402352
TI  - Wine labels tout health benefits.

PMID- 10402353
TI  - Long-term statin therapy appears safe.

PMID- 10402354
TI  - Ask the doctor: I take a water pill for swelling of my legs. My doctor tells me
      to put my feet up to help the fluid drain, but he also tells me to be active and
      walk around, which of course requires putting my feet down. Aren't these
      instructions contradictory?

PMID- 10402355
TI  - Ask the doctor: I take a water pill for my high blood pressure, but just hate
      taking my potassium supplement - two teaspoons of a bitter liquid per day. Is
      there any better way to keep my potassium up?

PMID- 10402356
TI  - This bug and booze don't mix.

PMID- 10402357
TI  - Diet and exercise: a partnership that works.

PMID- 10402358
TI  - I was very surprised when my cardiologist sent me a bill for a telephone call. It
      was a long conversation, but I've never had to pay for advice before. Are most
      doctors charging for phone calls?

PMID- 10402359
TI  - New treatment for vertebral fractures.

PMID- 10402360
TI  - By the way, doctor. Recently, you advocated taking 800 IU of vitamin D as part of
      osteoporosis prevention. However, during the summer, I get a lot of vitamin D
      from sunlight. Am I in danger of getting too much vitamin D?

PMID- 10402361
TI  - A case of unpaired anterior cerebral artery occlusion producing akinetic mutism.

PMID- 10402362
TI  - Shunt surgery induced iatrogenic CSF cyst presenting as a mass lesion.

PMID- 10402363
TI  - Dr basil tarlatzis: chairman ESHRE (1997-1999) 

PMID- 10402364
TI  - Antisperm antibodies: detection assays for antisperm antibodies: what do they
      test?

PMID- 10402365
TI  - Detection of antisperm antibodies: an argument against therapeutic nihilism.

PMID- 10402366
TI  - What effect does hydrosalpinx have on assisted reproduction? What is the
      preferred treatment for hydrosalpines? The ovary's perspective.

PMID- 10402367
TI  - Effective treatment of subfertility: introducing the Cochrane Menstrual Disorders
      and Subfertility Group.
AB  - The last two decades have seen a rapid explosion in research surrounding
      subfertility treatments. This ever-increasing volume of research has made it a
      difficult task for health professionals involved in the management of the
      subfertility to be able to assimilate the information easily. There is an urgent
      need for the findings from research to be synthesized into simple easy to read
      reviews that are both of a high quality and are based on the best evidence
      available. The Menstrual Disorders and Subfertility Group of the Cochrane
      Collaboration is attempting to address these issues by collecting a register of
      all the randomized controlled trials in the field of reproductive medicine and
      preparing systematic reviews on topics that will be of interest to healthcare
      workers and consumers. Readers are invited to participate in this process by
      identifying published and unpublished data and by helping in the process of
      preparing protocols and systematic reviews for inclusion in the Cochrane Library.

PMID- 10402368
TI  - Variation of luteinizing hormone and androgens in oligomenorrhoea and its
      implications for the study of polycystic ovary syndrome.
AB  - We measured luteinizing hormone (LH) and androgen concentrations in patients at
      different phases of the oligomenorrhoeic cycle and compared the results with
      those of patients with normogonadotrophic amenorrhoea. Several blood samples
      separated by >/=7 days were obtained from each of 72 patients with
      oligomenorrhoea and 18 with normogonadotrophic amenorrhoea. The oligomenorrhoeic
      cycle was divided into five phases: the postmenstrual phase week 1 (day 1-7) and
      week 2 (day 8-14), the specific oligomenorrhoeic phase (SOP, day 15 after a
      menstruation to day 21 before the next menstruation), the possibly peri-ovulatory
      phase (days 21-11 before menstruation) and the premenstrual phase (days 10-1
      before menstruation). Samples obtained in the possibly peri-ovulatory phase were
      excluded. Within individuals LH concentrations were significantly higher during
      the SOP than during all other phases of the oligomenorrhoeic cycle (paired t
      test, P = 0.0001-0.03). In contrast to the other phases of the oligomenorrhoeic
      cycle, no significant differences in gonadotrophins, androgen or oestradiol
      concentrations were found between the SOP and normogonadotrophic amenorrhoea. In
      oligomenorrhoea timing of blood sampling influences the measurement of LH and
      androgen concentrations, and the accurate interpretation of these measurements
      requires that the dates of menstruation both before and after the sample is taken
      should be known. In patients with oligomenorrhoea blood samples should be
      obtained during the SOP, when the endocrinology is comparable with that of
      normogonadotrophic amenorrhoea.

PMID- 10402369
TI  - Adjuvant L-arginine treatment for in-vitro fertilization in poor responder
      patients.
AB  - The objective of the present study was prospectively and randomly to evaluate the
      role of L-arginine in improving uterine and follicular Doppler flow and in
      improving ovarian response to gonadotrophin in poor responder women. A total of
      34 patients undergoing assisted reproduction was divided in two groups according
      to different ovarian stimulation protocols: (i) flare-up gonadotrophin-releasing
      hormone analogue (GnRHa) plus elevated pure follicle stimulating hormone (pFSH)
      (n = 17); and (ii) flare-up GnRHa plus elevated pFSH plus oral L-arginine (n =
      17). During the ovarian stimulation regimen, the patients were submitted to
      hormonal (oestradiol and growth hormone), ultrasonographic (follicular number and
      diameter, endometrial thickness) and Doppler (uterine and perifollicular
      arteries) evaluations. Furthermore, the plasma and follicular fluid
      concentrations of arginine, citrulline, nitrite/nitrate (NO2-/NO3-), and insulin
      like growth factor-1 (IGF-1) were assayed. All 34 patients completed the study.
      In the L-arginine treated group a lower cancellation rate, an increased number of
      oocytes collected, and embryos transferred were observed. In the same group,
      increased plasma and follicular fluid concentrations of arginine, citrulline, NO2
      /NO3-, and IGF-1 was observed. Significant Doppler flow improvement was obtained
      in the L-arginine supplemented group. Three pregnancies were registered in these
      patients. No pregnancies were observed in the other group. It was concluded that
      oral L-arginine supplementation in poor responder patients may improve ovarian
      response, endometrial receptivity and pregnancy rate.

PMID- 10402370
TI  - Bioequivalence of subcutaneous injections of recombinant human follicle
      stimulating hormone (Puregon(R)) by Pen-injector and syringe.
AB  - A randomized, single-centre, cross-over study was designed to compare the
      bioavailability of two pharmaceutical formulations of recombinant human follicle
      stimulating hormone (recFSH; Puregon(R)): (i) a dissolved cake injected by a
      normal syringe; and (ii) a ready-for-use solution injected using a device
      referred to as Puregon(R)Pen. Twenty-two healthy female volunteers underwent one
      of two administration sequences: Puregon(R)Pen/syringe or syringe/Puregon(R)Pen,
      by which they received a single subcutaneous dose of recFSH (150 IU). Endogenous
      gonadotrophin production had been previously suppressed using an oral
      contraceptive (Lyndiol(R)). Pharmacokinetic parameters characterizing rate [peak
      concentration (Cmax) and time of peak concentration (tmax)] and extent [area
      under the curve (AUC) and clearance (CL)] of absorption were obtained from 20
      subjects. After injection with both formulations, serum FSH concentrations
      reached a peak of 3.4 IU/l at 13 h after injection. The elimination half-life was
      approximately 34 h, irrespective of formulation. A difference of approximately
      18% was found between serum FSH concentrations obtained using the two
      formulations, which was caused by differences between the anticipated and the
      actual volume injected with the normal syringe. After correction for injection
      losses by weighing the amount injected with a normal syringe, the two
      formulations were found to be bioequivalent with respect to Cmax, AUC and CL. For
      tmax, bioequivalence could not be proven due to high intra-subject variability
      and broad absorption peaks of FSH. Both methods were well tolerated, local
      reactions being generally mild and short-lived.

PMID- 10402372
TI  - Severe ovarian hyperstimulation syndrome following salvage of empty follicle
      syndrome.
AB  - We report a case of severe ovarian hyperstimulation syndrome (OHSS) following a
      rescue of empty follicle syndrome (EFS). This suggests that the risk of
      developing OHSS remains unaltered even in the presence of EFS. The case supports
      the possibility of obtaining oocytes that fertilize and cleave normally after a
      second dose of human chorionic gonadotrophin (HCG) and a repeat oocyte retrieval.
      It supports the suggestion that the follicles are not necessarily empty in EFS.
      It demonstrates further that OHSS cannot be prevented by aspiration of follicular
      fluid and patients with large numbers of follicles and EFS must be warned of this
      potential complication.

PMID- 10402371
TI  - Recurrent empty follicle syndrome successfully treated with recombinant human
      chorionic gonadotrophin.
AB  - We report a case of a patient with polycystic ovary syndrome and primary
      infertility who was admitted to our in-vitro fertilization (IVF)/intracytoplasmic
      sperm injection (ICSI) programme because of her partner's severe oligozoospermia
      and asthenozoospermia. Ovarian stimulation was accomplished in the three
      treatment cycles using gonadotrophin therapy after a dual approach with ovarian
      suppression using oral contraceptive pills followed by gonadotrophin-releasing
      hormone agonist therapy. Oocyte retrieval was unsuccessful in the first two
      treated cycles despite the fact that human chorionic gonadotrophin (HCG) from
      three different batches was used. In the third treatment cycle, recombinant HCG
      was used and five oocytes were retrieved. This is the first report of recurrent
      empty follicle syndrome despite the use of different batches of commercially
      available urinary HCG, and of its successful treatment using recombinant HCG.

PMID- 10402373
TI  - Human male infertility and Y chromosome deletions: role of the AZF-candidate
      genes DAZ, RBM and DFFRY.
AB  - Microdeletions in Yq11 overlapping three distinct 'azoospermia factors' (AZFa-c)
      represent the aetiological factor of 10-15% of idiopathic azoospermia and severe
      oligozoospermia, with higher prevalence in more severe testiculopathies, such as
      Sertoli cell-only syndrome. Using a PCR-based screening, we analysed Yq
      microdeletions in 180 infertile patients affected by idiopathic Sertoli cell-only
      syndrome and different degrees of hypospermatogenesis, compared with 50 patients
      with known causes of testicular alteration, 30 with obstructive azoospermia, and
      100 normal fertile men. In idiopathic severe testiculopathies (Sertoli cell-only
      syndrome and severe hypospermatogenesis), a high prevalence of microdeletions
      (34.5% and 24.7% respectively) was found, while milder forms were not associated
      with Yq alteration. No deletions were found in testiculopathies of known
      aetiology, obstructive azoospermia, normal fertile men and male relatives of
      patients with deletions. Deletions in the AZFc region involving the DAZ gene were
      the most frequent finding and they were more often observed in severe
      hypospermatogenesis than in Sertoli cell-only syndrome, suggesting that deletions
      of this region are not sufficient to cause complete loss of the spermatogenic
      line. Deletions in AZFb involving the RBM gene were less frequently detected and
      there was no correlation with testicular phenotype, with an apparent minor role
      for such gene in spermatogenesis. The DFFRY gene was absent in a fraction of
      patients, making it a candidate AZFa gene. Our data suggest that larger deletions
      involving more than one AZF-candidate gene are associated with a more severe
      testicular phenotype.

PMID- 10402374
TI  - Screening for microdeletions of Y chromosome genes in patients undergoing
      intracytoplasmic sperm injection.
AB  - The potential of assisted reproduction techniques to transmit genetic defects
      causing male infertility raises questions concerning the need for a systematic
      genetic screen and counselling. Deletions of the long arm of the Y chromosome are
      frequently associated with a failure of spermatogenesis. The search for Y
      specific sequences and for the gene families RNA binding motif (RBM) and deleted
      in azoospermia (DAZ) have been introduced in many laboratories. The incidence of
      Y microdeletions varies widely between studies, from 1-55%. These differences are
      mainly related to study design. The highest incidence of microdeletions has been
      reported in well selected idiopathic azoospermic patients. Since microdeletions
      have been reported also in non-idiopathic patients, it is important to define
      what is the deletion frequency in unselected patients. We report Y chromosome
      microdeletion screening in 134 unselected patients undergoing intracytoplasmic
      sperm injection (ICSI). In the first part of the study we tested six Y chromosome
      markers. We found three patients with microdeletions (2.2%). Subdivision of the
      study population revealed a deletion incidence of 4.7% in
      azoospermic/cryptozoospermic patients; an incidence of 7% in idiopathic patients
      and an incidence of 16% in idiopathic azoospermic/cryptozoospermic patients. The
      second part of the study consisted of a screen for the presence of the Y
      chromosome genes, DBY, CDY, XKRY, eIF-1A, DAZ and BPY2. No additional gene
      specific deletions were found. Further data on gene specific screening are needed
      especially for selected idiopathic patients.

PMID- 10402375
TI  - Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic
      sperm injection, but are likely to transmit the deletion and infertility.
AB  - Deletion of the AZFc region of the Y chromosome is the most frequent molecularly
      defined cause of spermatogenic failure. We report three unrelated men in whom
      azoospermia or severe oligozoospermia was caused by de-novo AZFc deletions, and
      who produced sons by intracytoplasmic sperm injection (ICSI). We employed
      polymerase chain reaction (PCR) assays to examine the Y chromosomes of their four
      infant sons. All four sons were found to have inherited the Y chromosome
      deletions. Such sons are likely to be infertile as adults. This likelihood should
      be taken into account when counselling couples considering ICSI to circumvent
      infertility due to severe oligozoospermia or non-obstructive azoospermia.

PMID- 10402376
TI  - The value of intra-operative cystoscopy at the time of laparoscopic hysterectomy.
AB  - The aim of this study was to determine the usefulness of routine intra-operative
      cystoscopy in documenting ureteral injury during total laparoscopic hysterectomy
      with vault suspension and to document the incidence of this complication in a
      large series. The charts of 118 patients who underwent laparoscopic hysterectomy
      with vault suspension from January 1992 to January 1998 were retrospectively
      reviewed. The patients underwent intra-operative cystoscopic evaluation to verify
      ureteral permeability and bladder integrity. Intra-operative ureteral obstruction
      occurred in four patients (3.4%). All complications were immediately fixed and
      there were no postoperative ureteral problems. No late ureteral complications
      were observed. Intra-operative cystoscopy allows for early recognition and
      treatment of obstructive ureteral injuries and may reduce the rate of late
      postoperative complications during advanced laparoscopic procedures.

PMID- 10402378
TI  - Myomectomy: a retrospective study to examine reproductive performance before and
      after surgery.
AB  - The aim of this retrospective study was to establish the impact of myomectomy on
      pregnancy outcome with particular reference to its effect on the incidence of
      pregnancy loss. Myomectomy was performed using microsurgical procedures upon 51
      women who had intramural or subserosal fibroids and wished to conceive. Overall,
      the conception rate following myomectomy was 57%. Multiple regression analysis
      showed that age was the only factor which influenced conception rate: </=35
      years, 74% (23/31); >/=36 years, 30% (6/20; P < 0.005). The pregnancy loss rate
      prior to myomectomy was 60% (24/40), which was reduced to 24% (8/33) after
      myomectomy (P < 0.001). There was no instance of premature labour or scar rupture
      among 25 live births. This retrospective study suggests that myomectomy for
      intramural and subserosal fibroids may significantly improve the reproductive
      performance of women presenting with infertility or pregnancy loss.

PMID- 10402377
TI  - Closure techniques for fetoscopic access sites in the rabbit at mid-gestation.
AB  - Operative fetoscopy may be limited by its relatively high associated risk of
      preterm prelabour rupture of membranes. The objective of this study was to study
      closure techniques of the access site for fetoscopy in the mid-gestational
      rabbit. A total of 32 does (288 amniotic sacs) at 22 days gestational age (GA;
      term = 32 days) underwent 14 gauge needle fetoscopy, by puncture through
      surgically exposed amnion. Entry site was randomly allocated to four closure
      technique groups: myometrial suture (n = 14), fibrin sealant (n = 15), autologous
      maternal blood plug (n = 13), collagen plug (n = 14); 16 sacs were left unclosed
      (positive controls), and the unmanipulated 216 sacs were negative controls.
      Membrane integrity, presence of amniotic fluid and fetal lung to body weight
      ratio (FLBWR) were evaluated at 31 days GA. Following fetoscopy without an
      attempt to close the membranes, amniotic integrity was restored in 41% of cases
      (amniotic integrity in controls 94%; P = 0.00001). When the access site was
      surgically closed, the amnion resealed in 20-44% of cases, but none of the tested
      techniques was significantly better than the others or than positive controls.
      Permanent amniotic disruption was associated with a significantly lower FLBWR in
      all groups. In conclusion, the rate of fetoscopy-induced permanent membrane
      defects in this model did not improve by using any of the closure techniques
      tested here.

PMID- 10402379
TI  - Laparoscopic hemi-hysterectomy in treatment of a didelphic uterus with a
      hypoplastic cervix and obstructed hemivagina.
AB  - Maldevelopment of the Mullerian duct system may result in various urogenital
      anomalies including didelphic uterus with a hypoplastic cervix and obstructed
      hemivagina. We report a patient with this anomaly who was treated by laparoscopic
      hemi-hysterectomy and hysteroscopic resection of hemivagina. A 17 year old
      patient who had complained of vaginal pus-like discharge on and off for 1 year
      was diagnosed by MRI to have a double uterus with obstructed right hemivagina and
      ipsilateral renal agenesis. After hysteroscopic identification of hypoplasia of
      the right uterine cervix, laparoscopic resection of the right uterus and right
      Fallopian tube and hysteroscopically assisted resection of the vaginal septa were
      performed successfully. From our experience, combined laparoscopy and
      hysteroscopy may be an efficacious alternative in the management and diagnosis of
      Mullerian anomalies.

PMID- 10402380
TI  - A rational approach to the management of low responders in in-vitro
      fertilization.

PMID- 10402381
TI  - Embryo development and pregnancies from in-vitro matured and fertilized human
      oocytes.
AB  - There is an increasing interest in retrieving immature oocytes in the absence of
      or with limited gonadotrophin exposure, with the aim of maturing them in vitro
      for embryo transfer purposes. The aim of this report is to present our experience
      of fertilization, embryonic development and pregnancies from in-vitro maturation
      cycles. A total of 18 patients underwent 21 cycles in which an average of 8.1
      immature oocytes was retrieved after limited exposure to human menopausal
      gonadotrophin (HMG) and no exposure to human chorionic gonadotrophin (HCG). In
      one cycle, no oocytes were recovered. The oocytes were cultured for 44 h and 121
      oocytes which reached MII were injected with a single spermatozoon. A total of 71
      oocytes showed two pronuclei and 53 zygotes cleaved. Forty-four embryos were
      transferred in 17 cycles. Five weeks after embryo transfer, ultrasound
      examination indicated the presence of one gestational sac and one fetal heart
      beat in two patients. The results suggest that in-vitro matured oocytes can
      undergo fertilization and the resulting embryos may result in pregnancies.
      However, the success rate was not sufficient to recommend widespread use of the
      technique without further research.

PMID- 10402382
TI  - Ovarian volume may predict assisted reproductive outcomes better than follicle
      stimulating hormone concentration on day 3.
AB  - This study was undertaken to compare ovarian volume with other factors which are
      important for the success of assisted reproduction. The first treatment cycle for
      261 patients meeting all entry criteria between September 1993 and June 1995 was
      considered. All cycles employed the same stimulation protocol and no
      interventions were based upon pre-treatment indicators. Pre-treatment ovarian
      volumes, cycle day 3 follicle stimulating hormone (FSH) and oestradiol
      concentrations, smoking status and age were compared to subsequent peak
      oestradiol concentrations, numbers of oocytes retrieved, cycle cancellation and
      occurrence of clinical pregnancy. Statistical evaluation was performed using
      simple and multiple logistic regression analysis to determine odds ratios. The
      resultant odds ratios suggest that age and small ovarian volume may predict
      retrieval of fewer mature oocytes, while the failure to achieve clinical
      pregnancy was predicted by current smoking and small ovarian volume. Day 3 FSH
      values failed to be a significant predictor when maternal age, smoking status and
      ovarian volume were known. It can be concluded that, like maternal age and
      smoking status, ovarian volume may be a clinically important predictor of
      reproductive success, being superior to cycle day 3 FSH or oestradiol
      concentrations as an assessment of ovarian reserve.

PMID- 10402383
TI  - Midazolam/ketamine sedative combination compared with
      fentanyl/propofol/isoflurane anaesthesia for oocyte retrieval.
AB  - Assisted reproduction may be associated with repeated occasions of surgical
      intervention. Propofol, which is frequently used for induction of anaesthesia in
      such procedures, has been suspected of damaging oocytes. We compared in a
      randomized prospective design the use of general anaesthesia with fentanyl 0.017
      mg/kg, propofol 2.5 mg/kg and isoflurane to that of sedation with midazolam 0.06
      mg/kg and ketamine 0.75 mg/kg for transvaginal oocyte retrieval in 50 patients
      with no premedication. Overall, patient satisfaction was not different between
      the groups. Sedated patients were more arousable than anaesthetized patients
      during the procedure and experienced less postoperative abdominal pain at 30 min.
      Despite some movement in response to pain, oocyte retrieval was conveniently
      feasible in all sedated patients, of which none required a switch to general
      anaesthesia. A comparable number of oocytes was retrieved per cycle, 10.8 (+/
      7.8) versus 9.6 (+/-10.9) with sedation and anaesthesia respectively. No patient
      recalled any pain sensation during the procedure. The rate of embryo transfers
      and pregnancies were not different between the two groups. We conclude that the
      sedative combination of midazolam and ketamine for oocyte retrieval may serve as
      an alternative for general anaesthesia.

PMID- 10402384
TI  - Perinatal and obstetric outcomes of donor insemination using cryopreserved semen
      in Victoria, Australia.
AB  - This study compared the perinatal and obstetric outcomes of 1552 donor
      insemination pregnancies in Victoria, Australia, with a control group of 7717
      normally conceived pregnancies from the general population. Data on the outcomes
      of pregnancies of at least 20 weeks gestation, for both groups, were obtained
      from the same population-based birth registry. The study showed that there were
      no significant differences between the donor insemination and control groups in
      the incidence of preterm birth, low birthweight, multiple birth, perinatal death
      and birth defects, or in the sex ratio. Pregnancies conceived by donor
      insemination were significantly more likely than controls to have an induced
      labour (OR = 1.6, 95% CI 1. 4-1.8), a forceps delivery (OR = 1.5, 95% CI 1.3-1.8)
      and/or a Caesarean section (OR = 1.6, 95% CI 1.4-1.9) and to develop pre
      eclampsia (OR = 1.4, 95% CI 1.2-1.8) after adjusting for maternal age, multiple
      birth, parity and presentation. Reasons for the higher rate of induced and
      operative deliveries are not clear. Overall, the study's findings are reassuring
      for couples considering infertility treatment with donor insemination. The study
      illustrates the importance of complete follow-up in studies of pregnancy outcomes
      after assisted conception and the use of appropriate population-based control
      groups with comparable ascertainment of outcomes.

PMID- 10402386
TI  - Pregnancies after activated oocyte transfer: a new option for infertility
      treatment.
AB  - In this preliminary report, we describe a new technique involving the same-day
      transfer of activated oocytes to the uterus after intracytoplasmatic sperm
      injection (ICSI). The technique, termed activated oocyte transfer (AOT), offered
      to 19 couples, yielded a pregnancy rate per cycle of about 30%, equivalent to
      traditional in-vitro fertilization (IVF) and ICSI in a laboratory setting. AOT is
      performed 4 h after oocyte retrieval, permitting the patient to undergo treatment
      as an out-patient procedure.

PMID- 10402385
TI  - Is waiting for an endogenous luteinizing hormone surge and/or administration of
      human chorionic gonadotrophin of benefit in intrauterine insemination?
AB  - This retrospective study was undertaken to investigate the observation that the
      probability of pregnancy was higher with intrauterine insemination (IUI) when
      human chorionic gonadotrophin (HCG) was administered after the onset of the
      luteinizing hormone (LH) surge. A total of 219 patients who had 524 IUI cycles
      was included in this study. IUI cycles were divided into three groups: group 1,
      patients who had an endogenous LH surge but no HCG; group 2, patients given HCG
      after an endogenous LH surge was observed; and group 3, patients given HCG before
      an endogenous LH surge could be demonstrated. The overall clinical pregnancy rate
      was 16%. Forty-two (19.2%) patients had 91 cycles with their partner's semen,
      while 177 (80.8%) used donor semen in 433 cycles; clinical pregnancy rates were
      12.1% and 16.9% respectively. There was no significant difference in pregnancy
      rate per cycle between patients in group 1 (12.7%) compared with those in groups
      2 (15.6%) or 3 (20.5%). We could not establish any benefit in waiting for a
      spontaneous LH surge before administering HCG in the presence of a mature
      follicle(s) in this study. This strategy avoids further monitoring to detect the
      LH surge, allowing treatment to be planned for a time convenient to the patient.

PMID- 10402387
TI  - Serum CA-125 values on the day of oocyte retrieval are not predictive of
      subsequent pregnancy with in-vitro fertilization.
AB  - In the clinical management of in-vitro fertilization (IVF) patients it would be
      very useful to know, before the embryo transfer, whether or not there is a
      significant chance of pregnancy in that cycle. If low, it would be better to
      freeze the embryos and postpone the embryo transfer to a subsequent cycle. For
      this reason, a retrospective study was carried out to investigate the
      correlations between the serum CA-125 values before embryo transfer and the
      clinical outcome of that IVF cycle. Women aged <40 years undergoing a complete
      infertility evaluation including laparoscopy and receiving gonadotrophin
      releasing hormone analogue (GnRHa) suppression followed by purified follicle
      stimulating hormone (FSH) for IVF-embryo transfer were entered into the study.
      Ninety-seven cycles qualified for evaluation (26 pregnant and 71 non-pregnant
      cycles). CA-125 concentrations on the day of oocyte retrieval were significantly
      lower in the pregnant versus non-pregnant cycles in both non-endometriosis and
      endometriosis patients. To evaluate the existence of a cut-off value of CA-125
      which would allow the prediction of a possible pregnancy with sufficient
      specificity and sensitivity, a receiver operating characteristic curve analysis
      was performed. This analysis demonstrated the absence of any predictive value of
      the subsequent pregnancy for CA-125 concentrations. For this reason, and in
      contrast with previous findings, CA-125 determinations before the embryo transfer
      in IVF patients do not appear to be a useful tool for clinicians to use in
      predicting the outcome of IVF in any given cycle.

PMID- 10402388
TI  - Treatment of autoimmune premature ovarian failure.
AB  - There is no known immunosuppressive therapy for autoimmune premature ovarian
      failure that has been proven safe and effective by prospective randomized placebo
      controlled study. Nevertheless, immunosuppression using corticosteroids has been
      used on an empirical basis for this condition. Here we present two cases of young
      women with premature ovarian failure who were treated with glucocorticoids in the
      hopes of restoring fertility. The first case illustrates the potential benefit of
      such therapy, and the second case illustrates a potential risk. The first patient
      with histologically proven autoimmune oophoritis was treated with alternate day
      glucocorticoid treatment. She had return of menstrual bleeding six times and
      ovulatory progesterone concentrations four times over a 16 week period. The
      second patient with presumed but unconfirmed autoimmune ovarian failure was
      referred to us after having been treated with a 9 month course of
      corticosteroids. During that treatment her menses did not resume. The
      corticosteroid treatment was complicated by iatrogenic Cushing syndrome and
      osteonecrosis of the knee. Identifying patients with autoimmune premature ovarian
      failure presents the opportunity to restore ovarian function by treating these
      patients with the proper immune modulation therapy. On the other hand, potent
      immune modulation therapy can have major complications. Corticosteroid therapy
      for autoimmune premature ovarian failure should be limited to use in placebo
      controlled trials designed to evaluate the safety and efficacy of such treatment.

PMID- 10402389
TI  - Viagra for temporary erectile dysfunction during treatments with assisted
      reproductive technologies.
AB  - During treatments with assisted reproductive technologies (ART), some men may
      have difficulties in producing spermatozoa on demand at the time of insemination,
      either for intrauterine insemination (IUI) or for in-vitro fertilization (IVF).
      This situation imposes tremendous stress on the couple and may cause cancellation
      of the treatment. Here we describe, for the first time, the use of sildenafil
      citrate (ViagraTM) for temporary erectile dysfunction in couples undergoing ART.
      The first case was a man who could not produce spermatozoa for the first IVF
      treatment after an exhausting trial for 12 h, despite the fact that he never had
      problems in providing sperm samples during previous IUI cycles. Using Viagra
      enabled him to provide spermatozoa, but the delay in oocyte insemination resulted
      in no embryonic development. This prompted us to be more alert to this option and
      to suggest the use of Viagra to men who had a history of erectile dysfunction
      during previous ART cycles. In these cases, the use of Viagra was planned in
      advance and it successfully solved any unpredictable erectile dysfunction on the
      day of insemination. Such cases emphasize the need to think in advance of this
      potential use of Viagra during ART.

PMID- 10402390
TI  - Testicular fine needle aspiration: the alternative method for sperm retrieval in
      non-obstructive azoospermia.
AB  - The objective of this prospective open study was to determine the feasibility of
      obtaining mature spermatozoa for intracytoplasmic sperm injection (ICSI) by
      testicular fine needle aspiration (TEFNA) in men diagnosed with non-obstructive
      azoospermia. TEFNA consisted of a mean of 15 punctures and aspirations in each
      testis, using 23 gauge butterfly needles, connected to a 20 ml syringe with an
      aspiration handle. Patients (n = 85) underwent 111 TEFNA cycles. Mature
      testicular spermatozoa were recovered in 65 (58.5%) cycles from 50 (58.8%)
      patients. The sperm recovery rate by testicular histology was 14 out of 29
      (48.3%) in patients with Sertoli cell-only, 13 out of 28 (46.4%) in patients with
      maturation arrest, 19 out of 20 (95%) in patients with hypospermatogenesis, four
      out of six (66.6%) in patients with tubular hyalinization due to non-mosaic
      Klinefelter's syndrome. No spermatozoa were found in two cases with post
      irradiation fibrosis. ICSI was performed in all 65 cycles. In 58 cycles in which
      only the husbands' spermatozoa were used, 406 mature oocytes were injected, and
      154 (37.9%) were normally fertilized. Of the 143 embryos that developed (92.8%),
      119 were transferred in 42 cycles resulting in 18 clinical pregnancies (42. 8%),
      with 31 gestational sacs, providing an implantation rate of 26%. One abortion of
      a singleton pregnancy occurred (5.6%). No major side-effects, such as haematoma
      or infection were recorded. In conclusion, we have found TEFNA to be efficient,
      easy to learn, safe and well tolerated by all patients. In our opinion, TEFNA
      should be considered the first choice whenever sperm recovery is attempted in
      patients with non-obstructive azoospermia.

PMID- 10402391
TI  - Effect of varicocelectomy on the abnormal retention of residual cytoplasm by
      human spermatozoa.
AB  - Abnormal retention of cytoplasmic residues by human spermatozoa is associated
      with the generation of reactive oxygen species (ROS) in semen and defective sperm
      function. We have examined the effect of varicocelectomy on the retention of
      residual cytoplasm by human spermatozoa. Clinical reports of 43 men who underwent
      microsurgical varicocelectomy at our institution during a 1 year period beginning
      July 1996 were reviewed. Standard semen parameters (concentration, motility and
      morphology) and residual cytoplasm retention (monitored by Papanicolaou stain)
      were assessed before and 6 months after varicocelectomy. The percentage of
      spermatozoa with residual cytoplasm decreased significantly following
      varicocelectomy compared to pre-operatively (25.8 versus 18.1% respectively). The
      percentages of motile spermatozoa and normal forms increased significantly (P =
      0.0003, P = 0.005 respectively) following varicocelectomy (22.6 versus 32.9% and
      46.4 versus 54.4% respectively). Our data suggest that varicocelectomy can
      improve the disposal of residual sperm cytoplasm by the testis and/or epididymis
      in infertile men with varicocele. These data also suggest that varicocelectomy
      reduces the potential for ROS generation by human spermatozoa in these men.

PMID- 10402392
TI  - Testicular sperm retrieval and cryopreservation prior to initiating ovarian
      stimulation as the first line approach in patients with non-obstructive
      azoospermia.
AB  - The potency for fertilization and successful implantation was compared between
      fresh and cryopreserved testicular spermatozoa obtained from the same patient
      with non-obstructive azoospermia. Spermatozoa cryopreserved at the outset were
      also evaluated. Non-obstructive azoospermic men (n = 55) underwent testicular
      sperm extraction (TESE); mature spermatozoa were found in 33 (60%) of them. Of 57
      intracytoplasmic sperm injection (ICSI) cycles in 25 patients, 15 used fresh
      spermatozoa (14 patients, group 1), 24 used the excess spermatozoa cryopreserved
      after 'fresh' ICSI (11 couples who did not conceive in the 'fresh' cycle, group
      2) and 18 cycles used cryopreserved spermatozoa at the outset (11 other patients,
      group 3). Fertilization, cleavage, embryo quality, implantation and take home
      baby rates were not significantly different in groups 1 and 2, and 6/14 couples
      ultimately had healthy babies (42.8% cumulative take home baby rate per TESE). In
      group 3, neither the fertilization rate, embryo development, pregnancy nor
      implantation rates per embryo transfer were significantly different from groups 1
      and 2. The cumulative delivery and ongoing pregnancy rate in this group was 36.
      4%. Cryopreservation did not impair the availability of motile spermatozoa for
      ICSI. When immotile spermatozoa were injected, however, fertilization rate
      decreased dramatically. Since criteria for predicting the presence of spermatozoa
      in the testicular tissue of patients with non-obstructive azoospermia are
      inadequate, it is suggested that TESE be performed prior to initiating ovarian
      stimulation.

PMID- 10402393
TI  - The intra- and inter-assay variation of the indirect mixed antiglobulin reaction
      test: is a quality control suitable?
AB  - The test most commonly used to detect sperm antibodies is the mixed antiglobulin
      reaction (MAR), standardized by the World Health Organization. The indirect MAR
      test detects soluble sperm antibodies in seminal plasma by using healthy donor
      spermatozoa as antigen. In this study we systematically investigated the
      influence of donor spermatozoa and the source of sperm antibodies upon the
      results of the indirect MAR test, and calculated the intra- and inter-assay
      variations. Using one individual seminal plasma and the same donor semen, results
      of the indirect MAR test are highly reproducible (low intra-assay variation). Two
      dimensions of inter-assay variation must be considered: (i) serial ejaculates of
      an individual donor may be used at different times; (ii) different donors may be
      applied to identical antibody sources. Donor spermatozoa strongly influenced the
      results of the indirect MAR test. Using multivariate statistical tests, highly
      significant main effects between the different donors (P < 0.001) and specific
      reciprocal effects between donor spermatozoa and seminal plasma samples (P <
      0.001) were observed. The high inter-assay variation of the indirect MAR test
      will lead to incorrect results. There is urgent need of a reliable and
      reproducible test for sperm antibody detection to improve quality control of the
      methods.

PMID- 10402394
TI  - Effect of immobilization stress on testicular germ cell apoptosis in rats.
AB  - The influence of immobilization stress on testicular germ cell apoptosis was
      investigated in rats. A transient increase in serum corticosterone and a
      transient decrease in serum testosterone were observed during each period of
      immobilization stress. Twenty-four hours after the last immobilization session,
      the testicular weight and serum concentrations of corticosterone and testosterone
      were the same between the immobilization stress and control groups. However, the
      percentages of apoptotic tubules and apoptotic cells in the stress group were
      significantly higher than those in controls (P < 0.001). These facts suggest that
      immobilization stress can enhance testicular germ cell apoptosis in rats.

PMID- 10402395
TI  - Acephalic spermatozoa and abnormal development of the head-neck attachment: a
      human syndrome of genetic origin.
AB  - A series of 10 young sterile men with acephalic spermatozoa or abnormal head-mid
      piece attachments is presented. Nine of these patients had 75-100% spermatozoa
      with minute cephalic ends and 0-25% abnormal head-middle piece attachments. Loose
      heads ranged between 0-35 for each 100 spermatozoa and normal forms were rare.
      Two patients were brothers. On ultrastructural examination, the head was
      generally absent and the middle piece was covered by the plasma membrane. When
      present, heads implanted at abnormal angles on the middle piece. A testicular
      biopsy showed abnormal spermiogenesis. The implantation fossa was absent and the
      flagellar anlage developed independently from the nucleus, resulting in abnormal
      head-middle piece connections. In one patient azoospermia was induced with
      testosterone to attempt to increase the normal sperm clone during the rebound
      phenomenon, but all newly formed spermatozoa were acephalic. In another patient
      with high numbers of defective head-mid-piece connections, microinjections of
      spermatozoa resulted in four fertilized oocytes, but syngamy and cleavage did not
      take place, suggesting an abnormal function of the centrioles. The findings
      indicate that acephalic spermatozoa arise in the testis as the result of an
      abnormal neck development during spermiogenesis. The familial incidence and the
      typical phenotype strongly suggest a genetic origin of the syndrome.

PMID- 10402396
TI  - The incidence of spontaneous acrosome reaction in homogeneous populations of
      hyperactivated human spermatozoa.
AB  - The incidence of spontaneous acrosome reaction occurring in 1314 individually
      selected hyperactivated (HA) human spermatozoa was compared to that occurring in
      8226 individually selected non-hyperactivated spermatozoa (non-HA) sampled over
      an incubation time course to allow for capacitation. Two-way analysis of variance
      showed a significant difference between HA and non-HA spermatozoa for the mean
      percent acrosome reacted (R), partially acrosome reacted (PR) and combined total
      (R+PR) (P < 0.001). One-way analysis showed that among the HA spermatozoa there
      were marked differences among the proportion showing R+PR at the various time
      points (P = 0.005). Using the same end point, there was no significant evidence
      of change with time for the non-HA spermatozoa. The overall data indicated that
      HA human spermatozoa have a greater propensity for spontaneous acrosomal loss
      than non-HA spermatozoa during incubation in synthetic culture media.

PMID- 10402397
TI  - British Andrology Society guidelines for the screening of semen donors for donor
      insemination (1999).
AB  - The British Andrology Society (BAS) guidelines for the screening of semen donors
      have undergone a recent review, and following consultation with members of the
      Society and with experts in the allied professions, the following revised
      guidelines have been issued. Major changes include the introduction of an upper
      age limit for semen donors (<40 years old) and the general exclusion of men who
      are seropositive for cytomegalovirus as donors. The BAS recommends the screening
      of prospective semen donors for chromosomal abnormalities and for cystic fibrosis
      carrier status. Following the report of cross-contamination of human cells with
      hepatitis B virus within a liquid nitrogen storage vessel, the BAS recommends
      that steps be taken to ensure the safe cryopreservation of donor gametes.

PMID- 10402399
TI  - Frequency of CFTR gene mutations in males participating in an ICSI programme.
AB  - A higher prevalence of cystic fibrosis transmembrane regulator (CFTR) gene
      mutations has been suggested both in men affected by congenital aplasia of the
      vas deferens, and in individuals presenting with reduced sperm quality. In this
      case, an increased risk for offspring being affected by cystic fibrosis (CF) can
      be expected in couples who are planning to undergo intracytoplasmic sperm
      injection (ICSI), since most of the male partners suffer from infertility. In
      order to determine the risk for these couples more precisely, we offered them a
      test for the most frequent CF mutations prevalent in the German population. The
      frequency of mutations within the CFTR gene in the female group was in the same
      range as expected for the general population (six out of 150). In 10 out of 207
      males tested, infertility could be explained by exogenous factors not related to
      CFTR. Among the remaining 197 males with idiopathic infertility, we detected 13
      heterozygotes for a mutation within the CFTR gene. This slightly, but
      significantly (P = 0.014), elevated rate could indicate that infertile males
      have, compared with the general population, an increased risk of being a carrier
      of a CFTR gene mutation.

PMID- 10402398
TI  - Lipid dynamics in the plasma membrane of fresh and cryopreserved human
      spermatozoa.
AB  - Preserving the integrity of the plasma membrane of spermatozoa is crucial for
      retention of their fertilizing capacity, especially after stressful procedures
      such as freezing and storage. In this investigation we have measured lipid
      diffusion in different regions of the plasma membrane of fresh and cryopreserved
      human spermatozoa using a sensitive, high resolution fluorescence photobleaching
      technique (FRAP) with 5-(N-octadecanyl)aminofluorescein as reporter probe.
      Results show that diffusion was significantly faster on the plasma membrane
      overlying the acrosome and decreased progressively in the postacrosome, midpiece
      and principal piece. The midpiece plasma contains a higher proportion of immobile
      lipids than other regions. In cryopreserved spermatozoa, lipid diffusion in the
      plasma membrane was significantly reduced on the acrosome, postacrosome and
      midpiece relative to fresh spermatozoa. Diffusion, however, could be restored to
      normal levels by washing spermatozoa in a medium containing 0.4%
      polyvinylpyrrolidine but not in medium alone or in medium containing 0.4%
      albumin. These results suggest that (i) lipid dynamics in the plasma membrane of
      human spermatozoa varies significantly between surface regions; (ii) in-plane
      diffusion is adversely affected by cryopreservation; and (iii) washing frozen
      spermatozoa in 0.4% polyvinylpyrrolidine restores membrane lipid fluidity to
      normal levels. The latter finding has important implications for improving the
      fertility of human spermatozoa following cryopreservation.

PMID- 10402400
TI  - Day-specific probabilities of clinical pregnancy based on two studies with
      imperfect measures of ovulation.
AB  - Two studies have related the timing of sexual intercourse (relative to ovulation)
      to day-specific fecundability. The first was a study of Catholic couples
      practising natural family planning in London in the 1950s and 1960s and the
      second was of North Carolina couples attempting to become pregnant in the early
      1980s. The former identified ovulation based on the ovulatory shift in the basal
      body temperature, while the latter used urinary assays of hormones. We use a
      statistical model to correct for error in identifying ovulation and to re
      estimate the length of the fertile window and day-specific fecundabilities. We
      estimate the same 6-day fertile interval in both studies after controlling for
      error. After adjusting for error both data sets showed the highest estimate of
      the probability of pregnancy on the day prior to ovulation and both fell close to
      zero after ovulation. Given that the fertile interval is before ovulation,
      methods that anticipate ovulation by several days (such as the assessment of
      cervical mucus) would be particularly useful for couples who want to time their
      intercourse either to avoid or facilitate conception.

PMID- 10402401
TI  - A hypothesis on the origin of germ cell mutation and evolutionary role of
      extraembryonic mutation.

PMID- 10402402
TI  - A prospective comparison of 'in house' and commercially prepared Earle's balanced
      salt solution in human in-vitro fertilization.
AB  - A prospective, randomized study was undertaken to compare the use of Earle's
      balanced salt solution (EBSS) prepared 'in house' with that produced
      commercially, in 448 cycles of therapeutic in-vitro fertilization. Outcome was
      assessed in terms of fertilization and cleavage rates, embryo morphology, and
      implantation rates following embryo transfer. The only differences that were
      found between the two media in any of the outcome parameters were in the number
      of cycles with failed fertilization (1/218 in 'in house' medium compared with
      10/230 in commercially prepared medium; P = 0.0186), and in the rate at which
      embryos cleaved. Thus, while the median number of blastomeres per embryo was no
      different in the two groups at 46-49 h post insemination (three in embryos
      cultured in 'in-house' medium, compared with four in those cultured in
      commercially prepared medium; P > 0.1), the number of embryos per cycle that had
      cleaved to the 4-cell stage by 46-49 h post insemination was significantly
      greater in the Medi-Cult than in the EBSS medium (P < 0.001).

PMID- 10402403
TI  - In-vitro maturation of human oocytes from regularly menstruating women may be
      successful without follicle stimulating hormone priming.
AB  - This prospective randomized study investigated whether the developmental
      potential of in-vitro matured (IVM) human oocytes is improved by follicle
      stimulating hormone (FSH) priming before aspiration. Normally cycling women were
      recruited among couples referred for in-vitro fertilization or intracytoplasmic
      sperm injection because of male factor and/or tubal disease. In the first
      experiment, 20 women were randomly allocated to either no stimulation (n = 10) or
      stimulation for 3 days with rec-FSH (Gonal-F, Serono) at a fixed dose of 150
      IU/day from day 3 (n = 10). The oocytes were aspirated when the follicle(s) was
      observed to be 10 mm and matured in vitro for 36 h. In experiment 2, 12 women
      received rec-FSH (150 IU/daily) from day 3. In five patients stimulation was
      given for 3 days and aspiration performed as in the first experiment; the
      remaining seven patients continued stimulation until follicles were 10 mm in
      diameter and aspiration was performed 72 h later. All the oocytes were cultured
      for 48 h. FSH priming did not increase the number of oocytes obtained per
      aspiration and did not improve on maturation to metaphase II, cleavage rate or
      embryo development. The implantation potential of IVM embryos may be improved by
      maturation for 36 h compared to 48 h. In the first experiment, five out of 20
      patients (25%) obtained a clinical pregnancy with an implantation rate of 15%
      (5/33). One has delivered a healthy boy and three pregnancies are ongoing beyond
      32 gestational weeks. In the second experiment, an implantation rate of 7% and a
      single pregnancy (8%) was obtained, with delivery of a healthy girl.

PMID- 10402404
TI  - Variability in the expression of trophectodermal markers beta-human chorionic
      gonadotrophin, human leukocyte antigen-G and pregnancy specific beta-1
      glycoprotein by the human blastocyst.
AB  - Improved culture conditions that support the development of human embryos to the
      blastocyst stage in vitro led to the prospect of blastocyst transfer to increase
      pregnancy rates. Thus, there is a need for characterization of possible
      biochemical markers able to predict the implantation potential of human
      blastocysts. In this study, the expression of three placental markers that are
      expressed prior to implantation, beta-human chorionic gonadotrophin (HCG), human
      leukocyte antigen (HLA)-G and pregnancy specific beta-1 glycoprotein (SP-1), was
      investigated. beta-HCG transcript could be detected as early as the two-cell
      stage, which is one to two cleavage divisions earlier than previously reported.
      Both beta-HCG and HLA-G transcripts could be detected in the majority of
      blastocysts, but their levels were highly variable. No association could be found
      between the amount of transcript for these genes, total cell number or cell death
      rate. Interestingly, there was a highly positive correlation between accumulation
      of beta-HCG and HLA-G transcripts. SP-1 protein concentrations were assessed in
      the culture medium of blastocysts using enzyme-linked immunosorbent assay. There
      was a significant positive correlation between SP-1 concentrations and blastocyst
      cell numbers. Moreover, synthetic oviductal medium enriched with potassium
      resulted in an SP-1 concentration twice as high as that observed using human
      tubal fluid medium. These data suggest that SP-1 may be used to select
      blastocysts with higher cell number, possibly resulting in higher pregnancy
      rates.

PMID- 10402405
TI  - In-vitro matured metaphase-I oocytes have a lower fertilization rate but similar
      embryo quality as mature metaphase-II oocytes after intracytoplasmic sperm
      injection.
AB  - About 4% of all the oocytes denuded prior to intracytoplasmic sperm injection
      (ICSI) are in metaphase-I (MI). Frequently, these oocytes achieve meiosis after a
      few hours of in-vitro culture and are available for ICSI on the day of oocyte
      retrieval. In this retrospective study, the aim was to evaluate the fertilization
      rate and the developmental capacity of these in-vitro matured MI oocytes. After
      controlled ovarian stimulation using human menopausal gonadotrophin (HMG) and
      human chorionic gonadotrophin (HCG) in 896 ICSI cycles, 1210 MI-to-MII-matured
      oocytes were injected approximately 4 h after in-vitro culture and 8803 MII
      oocytes were injected immediately, or later, after denudation. The fertilization
      rate of in-vitro matured oocytes was significantly lower than that of mature MII
      oocytes (52.7 and 70.8% respectively, P < 0.00l). Embryo quality was only
      slightly different as regards the numbers of good quality embryos: 47.4% good
      quality embryos were obtained in the in-vitro matured oocyte group, whereas 53.2%
      good quality embryos were obtained in the MII oocyte group (P < 0.05). The same
      proportions of excellent (5.7 and 7.0%, NS) and fair quality (17.6 and 15.3%, NS)
      embryos were obtained for in-vitro matured and mature oocytes respectively.
      Embryos derived from in-vitro matured oocytes were transferred only if they were
      of better quality or if there were not enough mature oocyte derived embryos
      available. Fifteen transfers involved only embryos derived from in-vitro matured
      oocytes: 11 single embryo transfers and four transfers of two embryos, resulting
      in one singleton pregnancy and the birth of a healthy baby. It may be concluded
      that in cycles with few MII oocytes it might be worthwhile to inject in-vitro
      matured MI oocytes in order to increase the number of embryos available for
      transfer.

PMID- 10402406
TI  - Maturation in vitro of human oocytes from unstimulated cycles: selection of the
      optimal day for ovum retrieval based on follicular size.
AB  - The potential use of immature oocytes for in-vitro fertilization (IVF) requires
      the conditions for successful maturation to be defined. This study focused on the
      day of oocyte retrieval. The selection of a dominant follicle may induce
      endocrine changes in the remaining cohort that may be detrimental to their
      subsequent fertilization and embryonic development. Natural cycles in volunteer
      donors were followed by measurement of serum oestradiol and by vaginal
      ultrasound, starting on day 3 of the cycle. Cycles were randomly allocated to one
      of two groups: group 1 (n = 10), in which follicles were aspirated before the
      leading follicle was 10 mm in diameter; and group 2 (n = 9), in which follicles
      were aspirated when a dominant follicle was clearly visible with diameter >10 mm.
      Oocytes were cultured in vitro to metaphase II (MII) stage, donated, and
      inseminated by intracytoplasmic sperm injection (ICSI) with husband's
      spermatozoa. Those that became fertilized within 24 h were further co-cultured in
      autologous endometrial epithelial cells up to the blastocyst stage, and
      cryopreserved. There was a significantly (P < 0.05) increased rate of oocyte
      retrieval in group 1 (70.8% of aspirated follicles) compared with group 2
      (50.5%). Maturation to MII and fertilization were similar between the groups.
      However, development to blastocyst stage was significantly (P < 0.05) higher in
      group 1 embryos (56.5%) compared with group 2 (35.7%). There was a positive
      correlation (r2 = 0.1978) between the appearance of the cumulus cells and the
      ability to develop to blastocyst stage when both parameters were analysed in
      group 1, whereas no such correlation was found in group 2. In conclusion, our
      data suggest the importance of retrieving immature oocytes before follicular
      selection, and define the conditions for the first stage in the use of immature
      oocytes. Further stages must be defined before this technique can be used
      clinically.

PMID- 10402407
TI  - Pregnancy and birth resulting from transfer of a blastocyst observed to have one
      pronucleus at the time of examination for fertilization.
AB  - This case report describes a successful full-term pregnancy and birth after the
      transfer of a zona-free blastocyst derived from an oocyte observed at
      fertilization check as having only one distinct pronucleus (PN). The patient had
      previously undergone four in-vitro fertilization (IVF) cycles and three frozen
      embryo transfer cycles, with one pregnancy resulting. In this IVF cycle, 7/19
      oocytes were fertilized exhibiting two distinct PN; however, all these oocyctes
      failed to develop in culture and had arrested or totally fragmented by day 6
      after insemination. One oocyte (1/19) displayed only one PN 18 h after
      insemination, but culture of this oocyte led to development of an early
      cavitating blastocyst by day 6. Since no other embryos were available for
      transfer to the patient, this embryo was transferred, resulting in a full-term
      pregnancy with delivery of a normal healthy boy. Observation of a single PN at
      the normal time of fertilization assessment would not appear to be an absolute
      indicator of developmental incompetence. In-vitro culture to 6 days post
      insemination provides the opportunity to assess embryological development after
      activation of the embryonic genome. Formation of a morphologically normal
      blastocyst may be an indicator of a fertilized embryo with normal developmental
      capacity.

PMID- 10402408
TI  - The factor V Leiden mutation in Japanese couples with recurrent spontaneous
      abortion.
AB  - Thrombosis of placental vessels can be a major cause of recurrent spontaneous
      abortion (RSA). The factor V Leiden (FVL) mutation, a single point mutation in
      the factor V gene, is the most common genetic predisposition to thrombosis in
      European countries and the United States. However, even among Caucasian
      populations, the association between the FVL mutation and RSA is still
      controversial. The objectives of the present study were to investigate the
      prevalence of the FVL mutation in Japanese women who have experienced RSA and to
      clarify the contribution of the FVL mutation to recurrent miscarriages. A total
      of 52 Japanese women with a history of three or more consecutive idiopathic first
      trimester miscarriages and 41 of their male partners were studied. The control
      group consisted of 55 parous women without obstetric complications. Peripheral
      blood cell DNA was examined for the presence of the FVL alleles by polymerase
      chain reaction with Mnl I restriction fragment length polymorphisms. None of the
      52 women with RSA and the 41 partners carried the mutation. We also found no
      subject carrying the FVL alleles in the control group. These results suggest that
      the FVL alleles are not concentrated in women with RSA at least to clinically
      significant levels and that there is no apparent association between the FVL
      mutation and RSA in our Japanese population.

PMID- 10402409
TI  - Early transvaginal embryo aspiration: a safer method for selective reduction in
      high order multiple gestations.
AB  - Assisted reproduction technologies and ovulation induction for treatment of
      infertility continue to cause high order multiple gestations. Increased perinatal
      morbidity and mortality, as well as maternal morbidity, may complicate these
      pregnancies. Selective fetal reduction, an acceptable therapeutic approach in
      these cases, is usually performed at or after the ninth week of gestation, with
      KCl injected in the vicinity of the fetal heart, and is associated with a total
      pregnancy loss rate of 11.7%. We report our experience with 90 women who
      underwent early (mean 7.5 weeks gestation, range 7. 0-8.0 weeks) transvaginal
      selective embryo aspiration. The mean number of viable embryos before and after
      reduction was 3.5 and 2.1 respectively. Six (6.7%) pregnancies were lost before
      24 gestational weeks. One miscarriage occurred at the tenth gestational week. The
      other five pregnancies were aborted at 17.3-21.6 weeks gestation. Additional
      interventions were performed in three of these pregnancies: genetic amniocentesis
      in two cases and cervical suture in one case. In the subset of 39 patients
      with>/=4 embryos, only one (2.6%) pregnancy loss was recorded. This loss rate is
      significantly lower (P < 0.05) than the 15.3% loss rate in patients with >/=4
      fetuses calculated from other work. Four (4.4%) other pregnancies were
      complicated by premature delivery (25-28 weeks gestation). Mean gestational age
      of delivered pregnancies in our series was 35.7 weeks. In conclusion, early
      transvaginal embryo aspiration is a simple and relatively safe method for
      multiple pregnancy reduction. The overall pregnancy loss rate associated with
      early embryo aspiration is similar to that of procedures performed at later
      gestational age, but is significantly lower when the initial number of embryos is
      four or greater.

PMID- 10402410
TI  - Maternal serum insulin-like growth factor binding protein-2 and -3 and fetal
      growth.
AB  - This was a prospective observational study of maternal insulin-like growth factor
      binding protein-2 and -3 and fetal growth in 141 pregnant women after 24 weeks
      gestation who were scanned and venesected fortnightly. Cases (birthweight <5th
      centile) were sub-divided into those with growth restriction due to placental
      dysfunction (n = 25) and normal small (n = 27) and there were 89 normally grown
      controls. Maternal binding protein-3 was measured by radioimmunoassay and the
      overall pattern of the binding proteins and their proteolytic modifications were
      assessed by Western ligand blotting and immunoblotting followed by densitometric
      analysis. In controls, there was no correlation between binding protein-3 and
      birthweight, and binding protein-3 was elevated in the normal small but not the
      placental dysfunction group. Complete proteolysis of the 40 kDa doublet of
      binding protein-3 was observed in all pregnancies. Maternal serum binding protein
      2 concentrations were unchanged in normal pregnancy compared to non-pregnant
      controls but elevated in the growth-restricted group and in all pregnancies
      binding protein-2 was predominantly present as a 14 kDa proteolysed fragment.
      These results suggest that compensatory changes in binding protein-2 and -3 or
      their proteolysis do not increase bioavailability and so do not confound the low
      maternal insulin-like growth factor-I in growth restricted pregnancies.

PMID- 10402411
TI  - Pregnancy is not associated with altered morphology of the femoral artery.
AB  - While pregnancy is associated with adjustments in cardiovascular function, the
      morphology of the vascular system during pregnancy has been generally viewed as
      being very stable. However, recently we have demonstrated that pregnancy remodels
      the aorta and the carotid artery. In the present study, we assessed the
      morphological characteristics of the guinea-pig femoral artery during different
      stages of pregnancy using light and electron microscopy. There were no
      significant differences between external and internal diameters, wall thickness,
      total cross-sectional area and cross-sectional areas of lumen, intima, media, and
      adventitia of femoral arteries from non-pregnant and early-, mid- and late
      pregnant guinea-pigs (n = 8-10). In previous studies, we have shown that the
      morphology of vascular smooth muscle and endothelial cells in the aorta and the
      carotid artery may be altered by pregnancy. Therefore, to test this possibility
      we measured diameters as well as cross-sectional areas of femoral arterial muscle
      and endothelial cells using electron microscopy. These parameters, at the
      electron microscopy level, were also not significantly changed by pregnancy (n =
      8-10). It is concluded that the morphology of the guinea-pig femoral artery is
      not altered during pregnancy. In this regard, this study demonstrated that
      pregnancy-induced vascular remodelling varies between blood vessels that undergo
      the same functional alterations. Therefore, this may suggest that pregnancy
      induced changes in blood flow through different vascular beds are not the most
      important factor involved in vascular remodelling observed during pregnancy.
      Rather, it is possible that haemodynamic-independent factors regulate pregnancy
      mediated structural changes of the vascular wall.

PMID- 10402412
TI  - Prenatal assessment of the Hyrtl anastomosis and evaluation of its function: case
      report.
AB  - The presence of a communicating vessel, the Hyrtl anastomosis, between the
      umbilical arteries is well described in pathological studies. Using different
      injection techniques, it has been speculated that this vessel acts as a pressure
      equalizing mechanism between the different lobes of the placenta. However, its
      detection during fetal life has never been reported. We report on two cases of
      ultrasonographic detection and Doppler assessment of the Hyrtl anastomosis during
      pregnancy. A pulsatile blood flow from the umbilical artery with higher
      resistance to that with lower resistance has been demonstrated at the level of
      the Hyrtl anastomosis, which was confirmed after delivery. In addition, this
      report supports the hypothesis that the anastomosis plays an important role in
      regulating the blood pressure in the placental lobes and in equalizing the blood
      pressure between umbilical arteries.

PMID- 10402413
TI  - Primary repair of cornual rupture occurring at 21 weeks gestation and successful
      pregnancy outcome.
AB  - The successful delivery in a 31 year old woman at 33 weeks gestation is reported,
      after repair to a cornual rupture which occurred at 21 weeks gestation. The
      patient exhibited acute abdominal pain and pending shock. Emergency laparotomy
      showed a cornual rupture and an intrauterine vital fetus having intact amnion
      membrane. On the patient's family's insistence, primary repair for a cornual
      rupture was performed and preservation of the fetus attempted. Postoperatively,
      tocolytic agent with ritodrine hydrochloride was administered and close follow-up
      of the patient was uneventful. The patient had a smooth obstetric course until 33
      weeks gestation when premature rupture of the membranes occurred, soon followed
      by the onset of labour. She underwent an elective Caesarean section and delivered
      a normal male fetus weighing 2140 g with Apgar scores at 1, 5 and 10 min of 6, 8,
      and 9 respectively. Because of this successful outcome, we suggest that primary
      repair for such an unusual patient should be accepted.

PMID- 10402414
TI  - Danish National In-Vitro Fertilization Registry 1994 and 1995: a controlled study
      of births, malformations and cytogenetic findings.
AB  - This paper reports data from the Danish in-vitro fertilization (IVF) registry
      from 1994 to 1995 including data on treatments and the results of these
      (perinatal outcome, cytogenetic findings and fetal malformations) in comparison
      with a control group matched for maternal age, parity, multiplicity and year of
      birth. There were 1756 deliveries of 2245 children (24.3% twins, 1.8% triplets).
      The rate of prematurity among IVF children was 23.8% (NS) [singletons 7. 3% (P <
      0.05), twins 41.2% and triplets 93.5%], 23.6% weighed <2500 g [singletons 7% (P <
      0.05), twins 42.2% and triplets 87.1%]. The perinatal mortality rate was 21.8 in
      the study group compared to 17. 4 in the control group (NS). In total, 13.2% of
      all clinical pregnancies and 15.4% of the pregnancies that resulted in a delivery
      had a prenatal genetic examination. Of all examined, 3.5% had an abnormal
      karyotype. In total, 107 (4.8%) children in the study group and 103 (4.6%) in the
      control group were born with malformations (NS), compared to 2.8% in the
      background population. Our results indicate that it is the characteristics of the
      patients and multiplicity of pregnancy, rather than the assisted reproductive
      technology that determines the fetal risks of IVF pregnancies compared to the
      background population.

PMID- 10402415
TI  - Subclinical depletion of primordial follicular reserve in mice treated with
      cyclophosphamide: clinical importance and proposed accurate investigative tool.
AB  - Studies have shown that ovarian failure is a common side-effect of chemotherapy
      treatment; however, continuation of regular menses post-treatment does not
      necessarily imply that the ovaries have escaped damage. This animal study
      measures directly the primordial follicle (PMF) loss following exposure to
      chemotherapy and evaluates reproductive outcome following significant destruction
      of the PMF population. Inbred Balb/c mice aged 5-6 weeks were administered
      different doses of an alkylating agent, cyclophosphamide, and the total number of
      PMF remaining in both ovaries was counted. Results show that cyclophosphamide
      causes PMF destruction in proportion to increasing dose (P = 0.0001).
      Reproductive performance was assessed after exposure to 75 mg/kg
      cyclophosphamide, a dose which destroys approximately 50% of PMF reserve, by
      evaluation of ovulation, mating and pregnancy rates. Reproductive potential of
      treated mice was not affected compared with controls despite the significant loss
      of PMF. Our results indicate that reproductive performance is not an accurate
      parameter for assessing ovarian injury. Rather, histological counting of PMF
      number more directly reflects the damage caused by chemotherapy to the ovary.
      This method can be used as a sensitive, inexpensive tool to gauge the damage to
      fertility caused by new chemotherapy agents or protocols.

PMID- 10402416
TI  - Successful pregnancy in an infertile patient with conservatively treated
      endometrial adenocarcinoma after transfer of embryos obtained by intracytoplasmic
      sperm injection.
AB  - A rare case of successful pregnancy in a woman with early-stage endometrial
      adenocarcinoma conservatively treated is presented. The patient, having
      polycystic ovaries, was initially diagnosed with hyperplasia of the endometrium
      and treated with several cycles of ovulation induction following intrauterine
      insemination. Then dilatation and curettage were carried out when hysteroscopy
      was performed. The histology report identified a well-differentiated
      adenocarcinoma of the endometrium. After repeated endometrial curettage, in-vitro
      fertilization and embryo transfer were introduced for immediate treatment of the
      patient's infertility in order to avoid the risk of recurrence of neoplastic
      endometrial lesions by oestrogens. A single pregnancy was achieved after transfer
      of the embryos obtained after intracytoplasmic sperm injection. This was
      performed due to the poor semen characteristics (asthenozoospermia). The patient
      delivered a healthy normal male infant at term. A transvaginal ultrasound
      examination 2 months after delivery showed a smooth, linear endometrium.
      Moreover, the histology report after endometrial biopsy was free of any
      malignancies. The patient now desires another pregnancy. We conclude that
      conservative treatment of early-stage endometrial adenocarcinoma in young women
      wishing to preserve fertility should be considered in carefully selected cases.
      Assisted reproductive technologies may be helpful for immediate achievement of
      pregnancy in such patients.

PMID- 10402417
TI  - The medical ethics of paid egg sharing in the UK.
AB  - Paid egg sharing occurs when infertile patients receive infertility treatment
      free or at reduced cost in exchange for sharing some of their eggs with patients
      who require donated eggs. This approach to treatment is discussed in the context
      of the four principles of medical ethics, namely respect for autonomy, justice,
      beneficence and non-maleficence. The implications of these ethical considerations
      for responsible practice and regulation are considered.

PMID- 10402418
TI  - Management of poor responders in IVF.

PMID- 10402419
TI  - Does i.v. albumin prevent ovarian hyperstimulation syndrome?

PMID- 10402420
TI  - Local reaction to s.c. injections of a recombinant gonadotrophin preparation
      possibly related to the osmolality of the reconstituted solution.

PMID- 10402421
TI  - Interfering with viral infection. Plants Do it too 

PMID- 10402422
TI  - A recessive Arabidopsis mutant that grows photoautotrophically under salt stress
      shows enhanced active oxygen detoxification.
AB  - Mutagenized Arabidopsis seedlings (ecotype Columbia) were screened for the
      ability to grow photoautotrophically on solid medium containing 200 mM NaCl. A
      novel mutant line, designated pst1 (for photoautotrophic salt tolerance1), was
      obtained. There were no significant differences between pst1 and wild-type plants
      with regard to their ability to induce proline as an osmoregulatory solute. In
      addition, the content of monovalent cations in pst1 plants grown with or without
      salt stress was equal to that in the wild type. We observed that light, even at
      moderate intensities, increased the effects of salt stress on wild-type plants.
      The pst1 seedlings were nearly 10 times more tolerant to methyl viologen than
      were wild-type seedlings. We also found that the activities of the active oxygen
      scavengers superoxide dismutase and ascorbate peroxidase were enhanced
      significantly in pst1 plants. The pst1 plants also were tolerant to other
      stresses, such as high light intensity and toxic monovalent cations. The
      recessive nature of the pst1 mutation indicates that the potential for salt
      stress tolerance is blocked in wild-type Arabidopsis.

PMID- 10402423
TI  - Gene silencing without DNA. rna-mediated cross-protection between viruses 
AB  - Previously, it was shown that the upper leaves of plants infected with
      nepoviruses and caulimoviruses are symptom free and contain reduced levels of
      virus. These leaves are said to be recovered. Recovery is associated with RNA
      mediated cross-protection against secondary virus infection. Here, by analyzing
      plants infected with viruses that are quite distinct from the nepovirus or
      caulimovirus groups, we demonstrate that this RNA-mediated defense is a general
      response to virus infection. Upon infection with a tobravirus, plants exhibited
      RNA-mediated cross-protection and recovery, as occurs in nepovirus-infected
      plants. However, upon infection with a potexvirus, plants exhibited RNA-mediated
      cross-protection without recovery. In both instances, a transient gene expression
      assay showed that RNA-mediated cross-protection was functionally equivalent to
      post-transcriptional gene silencing. Combined, these data provide direct evidence
      that post-transcriptional gene silencing of nuclear genes is a manifestation of a
      natural defense mechanism that is induced by a wide range of viruses.

PMID- 10402424
TI  - ANTHOCYANINLESS2, a homeobox gene affecting anthocyanin distribution and root
      development in Arabidopsis.
AB  - The ANTHOCYANINLESS2 (ANL2) gene was isolated from Arabidopsis by using the maize
      Enhancer-Inhibitor transposon tagging system. Sequencing of the ANL2 gene showed
      that it encodes a homeodomain protein belonging to the HD-GLABRA2 group. As we
      report here, this homeobox gene is involved in the accumulation of anthocyanin
      and in root development. Histological observations of the anl2 mutant revealed
      that the accumulation of anthocyanin was greatly suppressed in subepidermal cells
      but only slightly reduced in epidermal cells. Furthermore, the primary roots of
      the anl2 mutant showed an aberrant cellular organization. We discuss a possible
      role of ANL2 in the accumulation of anthocyanin and cellular organization of the
      primary root.

PMID- 10402426
TI  - Gnarley1 is a dominant mutation in the knox4 homeobox gene affecting cell shape
      and identity.
AB  - Maize leaves have a stereotypical pattern of cell types organized into discrete
      domains. These domains are altered by mutations in knotted1 (kn1) and knox (for
      kn1-like homeobox) genes. Gnarley (Gn1) is a dominant maize mutant that exhibits
      many of the phenotypic characteristics of the kn1 family of mutants. Gn1 is
      unique because it changes parameters of cell growth in the basal-most region of
      the leaf, the sheath, resulting in dramatically altered sheath morphology. The
      strongly expressive allele Gn1-R also gives rise to a floral phenotype in which
      ectopic carpels form. Introgression studies showed that the severity of the Gn1
      conferred phenotype is strongly influenced by genetic background. Gn1 maps to
      knox4, and knox4 is ectopically expressed in plants with the Gn1-conferred
      phenotype. Immunolocalization experiments showed that the KNOX protein
      accumulates at the base of Gn1 leaves in a pattern that is spatially and
      temporally correlated with appearance of the mutant phenotype. We further
      demonstrate that Gn1 is knox4 by correlating loss of the mutant phenotype with
      insertion of a Mutator transposon into knox4.

PMID- 10402425
TI  - A maize homolog of mammalian CENPC is a constitutive component of the inner
      kinetochore.
AB  - Genes for three maize homologs (CenpcA, CenpcB, and CenpcC) of the conserved
      kinetochore assembly protein known as centromere protein C (CENPC) have been
      identified. The C-terminal portion of maize CENPC shares similarity with
      mammalian CENPC and its yeast homolog Mif2p over a 23-amino acid region known as
      region I. Immunolocalization experiments combined with three-dimensional light
      microscopy demonstrated that CENPC is a component of the kinetochore throughout
      interphase, mitosis, and meiosis. It is shown that sister kinetochore separation
      occurs in two discrete phases during meiosis. A partial separation of sister
      kinetochores occurs in prometaphase I, and a complete separation occurs in
      prometaphase II. CENPC is absent on structures known as neocentromeres that, in
      maize, demonstrate poleward movement but lack other important features of
      centromeres/kinetochores. CENPC and a previously identified centromeric DNA
      sequence interact closely but do not strictly colocalize on meiotic chromosomes.
      These and other data indicate that CENPC occupies an inner domain of the maize
      kinetochore.

PMID- 10402427
TI  - Overexpression of Arabidopsis hexokinase in tomato plants inhibits growth,
      reduces photosynthesis, and induces rapid senescence.
AB  - Sugars are key regulatory molecules that affect diverse processes in higher
      plants. Hexokinase is the first enzyme in hexose metabolism and may be a sugar
      sensor that mediates sugar regulation. We present evidence that hexokinase is
      involved in sensing endogenous levels of sugars in photosynthetic tissues and
      that it participates in the regulation of senescence, photosynthesis, and growth
      in seedlings as well as in mature plants. Transgenic tomato plants overexpressing
      the Arabidopsis hexokinase-encoding gene AtHXK1 were produced. Independent
      transgenic plants carrying single copies of AtHXK1 were characterized by growth
      inhibition, the degree of which was found to correlate directly to the expression
      and activity of AtHXK1. Reciprocal grafting experiments suggested that the
      inhibitory effect occurred when AtHXK1 was expressed in photosynthetic tissues.
      Accordingly, plants with increased AtHXK1 activity had reduced chlorophyll
      content in their leaves, reduced photosynthesis rates, and reduced photochemical
      quantum efficiency of photosystem II reaction centers compared with plants
      without increased AtHXK1 activity. In addition, the transgenic plants underwent
      rapid senescence, suggesting that hexokinase is also involved in senescence
      regulation. Fruit weight, starch content in young fruits, and total soluble
      solids in mature fruits were also reduced in the transgenic plants. The results
      indicate that endogenous hexokinase activity is not rate limiting for growth;
      rather, they support the role of hexokinase as a regulatory enzyme in
      photosynthetic tissues, in which it regulates photosynthesis, growth, and
      senescence.

PMID- 10402429
TI  - Elevated glutathione biosynthetic capacity in the chloroplasts of transgenic
      tobacco plants paradoxically causes increased oxidative stress 
AB  - Glutathione (GSH), a major antioxidant in most aerobic organisms, is perceived to
      be particularly important in plant chloroplasts because it helps to protect the
      photosynthetic apparatus from oxidative damage. In transgenic tobacco plants
      overexpressing a chloroplast-targeted gamma-glutamylcysteine synthetase (gamma
      ECS), foliar levels of GSH were raised threefold. Paradoxically, increased GSH
      biosynthetic capacity in the chloroplast resulted in greatly enhanced oxidative
      stress, which was manifested as light intensity-dependent chlorosis or necrosis.
      This phenotype was associated with foliar pools of both GSH and gamma
      glutamylcysteine (the immediate precursor to GSH) being in a more oxidized state.
      Further manipulations of both the content and redox state of the foliar thiol
      pools were achieved using hybrid transgenic plants with enhanced glutathione
      synthetase or glutathione reductase activity in addition to elevated levels of
      gamma-ECS. Given the results of these experiments, we suggest that gamma-ECS
      transformed plants suffered continuous oxidative damage caused by a failure of
      the redox-sensing process in the chloroplast.

PMID- 10402428
TI  - Nuclear export in plants. Use of geminivirus movement proteins for a cell-based
      export assay.
AB  - The nuclear export of proteins and RNAs has been studied in heterokaryons or by
      microinjecting test substrates into nuclei of HeLa cells or Xenopus oocytes. We
      have previously shown that the two movement proteins BR1 and BL1 encoded by the
      plant pathogenic squash leaf curl virus act in a coordinated manner to facilitate
      virus cell-to-cell movement and that one of these (BR1) is a nuclear shuttle
      protein. By using a novel in vivo cell-based assay for nuclear export in which
      nuclear-localized BR1 is trapped by BL1 and redirected to the cortical cytoplasm,
      we demonstrate that residues 177 to 198 of BR1 contain a leucine-rich nuclear
      export signal (NES) of the type found in the Rev protein encoded by the human
      immunodeficiency virus and in Xenopus TFIIIA. We further show that the TFIIIA NES
      can functionally replace the NES of BR1 in both nuclear export and viral
      infectivity. These findings suggest that this basic pathway for nuclear export is
      highly conserved among plant and animal cells and in yeast.

PMID- 10402430
TI  - Environmental signals controlling sexual development of the corn Smut fungus
      Ustilago maydis through the transcriptional regulator Prf1.
AB  - Environmental signals induce and coordinate discrete morphological transitions
      during sexual development of Ustilago maydis. In this fungus, mating of two
      compatible haploid sporidia is a prerequisite for plant infection. Cell fusion is
      governed by the action of pheromones and receptors, whereas the subsequent
      pathogenicity program is controlled by the combinatorial interaction of
      homeodomain proteins. The U. maydis pheromone response factor (Prf1) is a central
      regulator of both processes. We have analyzed the regulation of the prf1 gene and
      demonstrate that pheromone and cAMP signaling regulate prf1 post
      transcriptionally. Transcriptional activation of prf1 was observed in the
      presence of carbon sources, such as glucose and fructose, allowing us to define
      the cis-acting element in the prf1 promoter that mediates these effects. The same
      element provides for negative control of prf1 gene transcription at high cAMP
      levels. A protein that specifically binds to this element was purified and
      analyzed for its role in prf1 gene regulation. On the basis of these results, we
      present a model in which prf1 integrates different environmental signals to
      control development in U. maydis.

PMID- 10402431
TI  - ANI1. A sex pheromone-induced gene in ceratopteris gametophytes and its possible
      role in sex determination.
AB  - Antheridiogen (ACE) is a pheromone that is required for the development of male
      gametophytes in the homosporous fern Ceratopteris richardii. Subtractive
      hybridization of cDNAs isolated from ACE-treated and non-ACE-treated gametophytes
      was used to isolate genes that are induced by the pheromone. The expression of
      one gene, ANI1 (for antheridiogen induced), was induced within 3 hr of ACE
      treatment, but its expression was transient. Patterns of ANI1 expression in wild
      type and mutant gametophytes show that ANI1 expression inversely correlates with
      the predicted activity of one of the sex-determining genes, TRANSFORMER5 (TRA5).
      These data suggest that ANI1 transcription or transcript accumulation is directly
      or indirectly prevented by TRA5 in the absence of ACE and that ACE inactivates
      the TRA5 gene or its product, leading to the upregulation of ANI1. Cycloheximide
      (no ACE) induced the expression of ANI1, also indicating that ANI1 expression is
      subject to negative regulation in the absence of ACE. The sequence and inferred
      protein structure of ANI1 suggest that it is a novel, extracellular protein. The
      secreted portion of the ANI1 protein potentially forms a beta barrel with
      superficial similarities to lipocalins, which bind small hydrophobic molecules
      such as pheromones, steroids, and odorants. ANI1 may be an extracellular carrier
      of ACE that is required to initiate the male program of development as the sexual
      fate of the young gametophyte is determined.

PMID- 10402432
TI  - Epigenetic interactions among three dTph1 transposons in two homologous
      chromosomes activate a new excision-repair mechanism in petunia.
AB  - Unstable anthocyanin3 (an3) alleles of petunia with insertions of the
      Activator/Dissociation-like transposon dTph1 fall into two classes that differ in
      their genetic behavior. Excision of the (single) dTph1 insertion from class 1 an3
      alleles results in the formation of a footprint, similar to the "classical"
      mechanism observed for excisions of maize and snapdragon transposons. By
      contrast, dTph1 excision and gap repair in class 2 an3 alleles occurs via a newly
      discovered mechanism that does not generate a footprint at the empty donor site.
      This novel mechanism depends on the presence of two additional dTph1 elements:
      one located in cis, 30 bp upstream of the an3 translation start in the same an3
      allele, and a homologous copy, which is located in trans in the homologous an3
      allele. Absence of the latter dTph1 element causes a heritable suppression of
      dTph1 excision-repair from the homologous an3 allele by the novel mechanism,
      which to some extent resembles paramutation. Thus, an epigenetic interaction
      among three dTph1 copies activates a novel recombination mechanism that
      eliminates a transposon insertion.

PMID- 10402433
TI  - The TRANSPARENT TESTA GLABRA1 locus, which regulates trichome differentiation and
      anthocyanin biosynthesis in Arabidopsis, encodes a WD40 repeat protein.
AB  - The TRANSPARENT TESTA GLABRA1 (TTG1) locus regulates several developmental and
      biochemical pathways in Arabidopsis, including the formation of hairs on leaves,
      stems, and roots, and the production of seed mucilage and anthocyanin pigments.
      The TTG1 locus has been isolated by positional cloning, and its identity was
      confirmed by complementation of a ttg1 mutant. The locus encodes a protein of 341
      amino acid residues with four WD40 repeats. The protein is similar to AN11, a
      regulator of anthocyanin biosynthesis in petunia, and more distantly related to
      those of the beta subunits of heterotrimeric G proteins, which suggests a role
      for TTG1 in signal transduction to downstream transcription factors. The 1.5-kb
      TTG1 transcript is present in all major organs of Arabidopsis. Sequence analysis
      of six mutant alleles has identified base changes producing truncations or single
      amino acid changes in the TTG1 protein.

PMID- 10402434
TI  - The presence of a heterotrimeric G protein and its role in signal transduction of
      extracellular calmodulin in pollen germination and tube growth 
AB  - The role of heterotrimeric G proteins in pollen germination, tube growth, and
      signal transduction of extracellular calmodulin (CaM) was examined in lily
      pollen. Two kinds of antibodies raised against animal Gzalpha, one against an
      internal sequence and the other against its N terminus, cross-reacted with the
      same 41-kD protein from lily pollen plasma membrane. This 41-kD protein was also
      specifically ADP ribosylated by pertussis toxin. Microinjection of the membrane
      impermeable G protein agonist GTP-gamma-S into a pollen tube increased its growth
      rate, whereas microinjection of the membrane-impermeable G protein antagonist GDP
      beta-S and the anti-Galpha antibody decreased pollen tube growth. The membrane
      permeable G protein agonist cholera toxin stimulated pollen germination and tube
      growth. Anti-CaM antiserum inhibited pollen germination and tube growth, and this
      inhibitory effect was completely reversed by cholera toxin. The membrane
      permeable heterotrimeric G protein antagonist pertussis toxin completely stopped
      pollen germination and tube growth. Purified CaM, when added directly to the
      medium of plasma membrane vesicles, significantly activated GTPase activity in
      plasma membrane vesicles, and this increase in GTPase activity was completely
      inhibited by pertussis toxin and the nonhydrolyzable GTP analogs GTP-gamma-S and
      guanylyl-5'-imidodiphosphate. The GTPase activity in plasma membrane vesicles was
      also stimulated by cholera toxin. These data suggest that heterotrimeric G
      proteins may be present in the pollen system where they may be involved in the
      signal transduction of extracellular CaM and in pollen germination and tube
      growth.

PMID- 10402436
TI  - Passing of the torch 

PMID- 10402437
TI  - Induction of nitric oxide synthase and dual effects of nitric oxide and
      cyclooxygenase products in regulation of arterial contraction in human septic
      shock.
AB  - BACKGROUND: The role of endogenous nitric oxide (NO) and cyclooxygenase
      metabolites was investigated in contractile responses of small omental arteries
      from patients with hyperdynamic septic shock. METHODS AND RESULTS: Expression of
      inducible NO synthase (immunostaining) and a high but variable level of NO
      production (NO spin trapping) was detected in arteries from patients with septic
      shock. In these vessels, ex vivo contractile responses to the thromboxane A2
      analogue U46619 and to low concentrations of norepinephrine (NE) (up to 10
      micromol/L) were not significantly different from controls. However, higher
      concentrations of NE caused pronounced fading of contraction in septic but not in
      nonseptic arteries. Exposure to either the NO synthase inhibitor NG-nitro-L
      arginine methyl ester or the cyclooxygenase inhibitor indomethacin had no effect
      in control vessels. However, both inhibitors increased the response to the
      contractile effects of the 2 agonists only in patients with septic shock. In
      contrast to NG-nitro-L-arginine methyl ester, which decreased the threshold
      concentration of the fading effect of NE, indomethacin abolished this effect in
      arteries from septic patients. CONCLUSIONS: These results provide direct evidence
      for the induction of NO synthase in small arteries from patients with septic
      shock. They suggest that in these arteries, increased production of NO, in
      conjunction with vasodilatory cyclooxygenase metabolites, contributes to
      counteract hyperreactivity to agonists and decreases the cyclooxygenase product
      mediated pronounced fading of contraction caused by a high concentration of NE.

PMID- 10402435
TI  - Molecular characterization of the maize Rp1-D rust resistance haplotype and its
      mutants.
AB  - The Rp1-D gene for resistance to maize common rust (Puccinia sorghi) is a member
      of a complex locus (haplotype) composed of Rp1-D and approximately eight other
      gene homologs. The identity of Rp1-D was demonstrated by using two independent
      gene-tagging approaches with the transposons Mutator and Dissociation. PIC20, a
      disease resistance (R) gene analog probe previously mapped to the rp1 locus,
      detected insertion of Dissociation in an Rp1-D mutation and excision in three
      revertants. Independent libraries probed with the PIC20 or Mutator probes
      resulted in isolation of the same gene sequence. Rp1-D belongs to the nucleotide
      binding site, leucine-rich repeat class of R genes. However, unlike the rust
      resistance genes M and L6 from flax, the maize Rp1-D gene does not encode an N
      terminal domain with similarity to the signal transduction domains of the
      Drosophila Toll protein and mammalian interleukin-1 receptor. Although the
      abundance of transcripts of genes from the rp1 complex changed with leaf age,
      there was no evidence of any change due to inoculation with avirulent or virulent
      rust biotypes. A set of 27 Rp1-D mutants displayed at least nine different
      deletions of Rp1-D gene family members that were consistent with unequal crossing
      over events. One mutation (Rp1-D*-24) resulted in deletion of all but one gene
      family member. Other unique deletions were observed in the disease lesion mimic
      Rp1-D*-21 and the partially susceptible mutant Rp1-D*-5. Different rp1
      specificities have distinct DNA fingerprints (haplotypes). Analysis of
      recombinants between rp1 specificities indicated that recombination had occurred
      within the rp1 gene complex. Similar analyses indicated that the rust R genes at
      the rp5 locus, 2 centimorgans distal to rp1, are not closely related to Rp1-D.

PMID- 10402438
TI  - Are electrophysiological changes induced by longer lasting atrial fibrillation
      reversible? :observations using the atrial defibrillator.
AB  - BACKGROUND: Studies in animal hearts have shown shortening of the atrial
      effective refractory period (AERP) and loss of the relation between the AERP and
      heart rate after prolonged periods of atrial fibrillation (AF). The purposes of
      this study were (1) to evaluate atrial electrophysiology after a long period of
      sinus rhythm in patients who had longer lasting recurrent AF that was
      successfully treated with the Metrix Atrioverter and (2) to analyze the effect of
      prompt cardioversion on subsequent AF episodes and the duration of sinus rhythm.
      METHODS AND RESULTS: Four patients with recurrent AF (duration, 3 to 21 years;
      mean+/-SD, 13+/-7.6 years) were studied after the implantation of an Atrioverter.
      The Atrioverter stores and analyzes 3 minutes of cardiac rhythm every hour.
      Before implantation, AERP was measured. During a mean follow-up of 14 months, 52
      spontaneous (39 treated and 18 nontreated) AF episodes occurred while the
      patients were on antiarrhythmic drugs. All patients were electrophysiologically
      studied after they had been in sinus rhythm for at least 1000 hours (range, 1052
      to 2675 hours). Before Atrioverter implantation, AF was induced by 1 atrial
      premature beat in 3 patients and not induced in the remaining patient. After a
      long period in sinus rhythm (>1000 hours), AF could be induced in the same 3
      patients in the same way as before implantation. In the patient in whom no AF was
      induced, right AERP values measured using the single extrastimulus technique at 3
      pacing cycle lengths (600, 500, and 430 ms) were similar to those before
      implantation. CONCLUSIONS: AF was still inducible by a single atrial premature
      beat after long episodes of sinus rhythm in 3 of 4 patients with previously
      longer lasting AF. In the patient in whom no AF was induced, AERP behaved like it
      did before implantation. In these patients with longer lasting recurrent AF, no
      return to "normal" atrial electrophysiology could be demonstrated.

PMID- 10402439
TI  - Improvement of impaired myocardial vasodilatation due to diffuse coronary
      atherosclerosis in hypercholesterolemics after lipid-lowering therapy.
AB  - BACKGROUND: Diminished myocardial vasodilatation (MVD) in hypercholesterolemics
      without overt coronary stenosis has been reported. However, whether the
      diminished MVD of angiographically normal coronary arteries in
      hypercholesterolemics can be reversed after lipid-lowering therapy is not known.
      METHODS AND RESULTS: A total of 27 hypercholesterolemics and 16 age-matched
      controls were studied. All patients had >1 normal coronary artery, and those
      segments that were perfused by anatomically normal coronary arteries were
      studied. Myocardial blood flow (MBF) was measured during dipyridamole loading and
      at baseline using positron emission tomography and 13N-ammonia, after which MVD
      was calculated before and after lipid-lowering therapy. Total cholesterol was
      significantly higher in hypercholesterolemics (263+/-33.8) than in controls
      (195+/-16.6), and it normalized after lipid-lowering therapy (197+/-19.9).
      Baseline MBF (ml. min-1. 100 g-1) was comparable among hypercholesterolemics
      (both before and after therapy) and controls. MBF during dipyridamole loading was
      significantly lower in hypercholesterolemics before therapy (189+/-75.4) than in
      controls (299+/-162, P<0.01). However, MBF during dipyridamole loading
      significantly increased after therapy (226+/-84.7; P<0.01). MVD significantly
      improved after therapy in hypercholesterolemics (2.77+/-1.35 after treatment
      [P<0.05] versus 2. 02+/-0.68 before treatment [P<0.01]), but it remained
      significantly higher in controls (3.69+/-1.13, P<0.01). There was a significant
      relationship between the percent change of total cholesterol and the percent
      change of MVD before and after lipid-lowering therapy (r=-0. 61, P<0.05).
      CONCLUSIONS: Diminished MVD of anatomically normal coronary arteries in
      hypercholesterolemics can be reversed after lipid-lowering therapy.

PMID- 10402440
TI  - Insulin resistance syndrome predicts coronary heart disease events in elderly
      nondiabetic men.
AB  - BACKGROUND: The role of a cluster of risk factors characteristic for the insulin
      resistance syndrome as a predictor for coronary heart disease (CHD) has not been
      studied previously. METHODS AND RESULTS: Clustering of cardiovascular risk
      factors was analyzed by factor analysis to investigate whether these clusters
      (factors) predict CHD events (CHD death or nonfatal myocardial infarction) in a
      nondiabetic population of 1069 subjects 65 to 74 years old from eastern Finland
      followed up for 7 years. There were 151 CHD events (92 for men, 59 for women)
      during the follow-up period. In men, factor 1 (the insulin resistance factor,
      which reflected primarily body mass index, waist-to-hip ratio, triglycerides,
      fasting plasma glucose, and insulin) (hazards ratio [HR] with 95% CI, 1.33, CI
      1.08, 1.65, P=0.008), factor 2 (alcohol consumption, high HDL cholesterol, low
      triglycerides) (HR 0.78, CI 0.63, 0.96, P=0.020), factor 3 (age, systolic blood
      pressure, urinary albumin/creatinine ratio, left ventricular hypertrophy) (HR
      1.52, CI 1.26, 1.83, P<0.001), and factor 4 (high total cholesterol and
      triglycerides) (HR 1.42, CI 1. 15, 1.77, P=0.002) predicted CHD events in
      multivariate Cox regression analysis. In women, the insulin resistance factor did
      not predict CHD events (HR 1.06, CI 0.82, 1.36), but factor 2 (previous stroke,
      low HDL cholesterol and high triglycerides) (HR 1.34, CI 1. 06, 1.69, P=0.014)
      and factor 3 (age, systolic blood pressure, urinary albumin/creatinine ratio,
      left ventricular hypertrophy) (HR 1.44, CI 1.15, 1.82, P=0.002) predicted CHD
      events. CONCLUSIONS: Our study supports the notion that the insulin resistance
      syndrome is a risk factor for CHD in elderly men.

PMID- 10402441
TI  - Nitrate resistance in platelets from patients with stable angina pectoris.
AB  - BACKGROUND: Hemodynamic resistance to nitrates has been previously documented in
      congestive heart failure. In patients with stable angina pectoris (SAP), we have
      observed a similar phenomenon: decreased platelet response to disaggregating
      effects of nitroglycerin (NTG) and sodium nitroprusside (SNP). METHODS AND
      RESULTS: In blood samples from normal subjects (n=32) and patients with SAP
      (n=56), we studied effects of NO donors (NTG and SNP) on ADP-induced platelet
      aggregation and on intraplatelet cGMP. NTG and SNP inhibited platelet aggregation
      in patients to lesser extents than in normal subjects (P<0.01). The cGMP
      elevating efficacy of NTG and SNP was diminished in platelets from patients in
      comparison with those from normals (P<0.001). Inhibition of the anti-aggregatory
      effects of NTG and SNP by ODQ, a selective inhibitor of NO-stimulated guanylate
      cyclase, was significantly less pronounced in patients than in normal subjects.
      Content of O2- was higher in blood samples from patients than in those from
      normal subjects (P<0. 01). In blood samples from patients with SAP, but not in
      normal subjects, the O2- scavenger superoxide dismutase (combined with catalase)
      suppressed platelet aggregation (P<0.01) and increased the extent of anti
      aggregatory effect of SNP (P<0.01). CONCLUSIONS: In patients with SAP, platelets
      are less responsive to the anti-aggregating and cGMP-stimulating effects of NO
      donors; this may reflect both reduction in guanylate cyclase sensitivity to NO
      and inactivation of the released NO by O2-. The implied impairment of anti
      platelet efficacy of endogenous NO (in the form of EDRF) may contribute to
      platelet hyperaggregability associated with angina pectoris.

PMID- 10402442
TI  - Cardiac sympathetic denervation after transmyocardial laser revascularization.
AB  - BACKGROUND: Transmyocardial laser revascularization (TMR) has been shown to
      improve refractory angina not amenable to conventional coronary interventions.
      However, the mechanism of action remains controversial, because improved
      myocardial perfusion has not been consistently demonstrated. We hypothesized that
      TMR relieves angina by causing myocardial sympathetic denervation. METHODS AND
      RESULTS: PET imaging of resting and stress myocardial perfusion with [13N]ammonia
      (NH3) and of sympathetic innervation with [11C]hydroxyephedrine (HED) was
      performed before and after TMR in 8 patients with class IV angina ineligible for
      CABG or PTCA. A mean of 50+/-11 channels were created in the left ventricle (LV)
      with a holmium:YAG laser. A semiautomated program was used to determine NH3
      uptake and HED retention in the LV. Perfusion and innervation defects were
      defined as the percentage of LV with tracer uptake or retention >2 SD below
      normal mean values. All patients experienced improvement in their angina by 2.4+/
      0.5 angina classes after surgery, P=0.008. Sympathetic innervation defects
      exceeded resting perfusion defects in all patients before TMR (34.6+/-27.3% for
      HED versus 9.4+/-10.8% for NH3, P=0.008). TMR did not significantly affect
      resting or stress myocardial perfusion but increased the extent of sympathetic
      denervation in 6 of 8 patients by 27.5+/-15.9%, P=0.03. In the remaining 2
      patients, both sympathetic denervation and stress perfusion defects decreased
      after surgery. CONCLUSIONS: TMR causes decreased myocardial HED uptake in most
      patients without significant change in resting or stress myocardial perfusion,
      suggesting that the improvement in angina may be at least in part due to
      sympathetic denervation.

PMID- 10402443
TI  - Prognostic value of myocardial ischemia and viability in patients with chronic
      left ventricular ischemic dysfunction.
AB  - BACKGROUND: Previous studies showed that thallium scintigraphy and dobutamine
      echocardiography were accurate, noninvasive ways of predicting contractile
      recovery after revascularization in patients with left ventricular (LV)
      dysfunction. However, the prognostic impact of such methods remains uncertain.
      METHODS AND RESULTS: We prospectively studied 137 consecutive patients with
      coronary disease and LV dysfunction who underwent exercise-redistribution
      reinjection thallium scintigraphy and dobutamine echocardiography to identify
      myocardial ischemia and viability. A total of 94 patients subsequently underwent
      revascularization, and 43 underwent medical treatment. The primary endpoint was
      cardiac mortality, and mean follow-up was 33+/-10 months. Twenty-four patients
      died of cardiac causes. By Cox's regression analysis, long-term survival was
      related to the extent of coronary disease, the presence of diabetes, type of
      treatment, the presence of ischemic myocardium as determined by thallium
      scintigraphy, and the presence of viable myocardium as determined by both tests.
      Three-year survival was greater in patients with ischemic myocardium (as
      determined by thallium scintigraphy) or viable myocardium (as determined by both
      tests) who underwent revascularization than in the other groups (P=0.018 with
      thallium; P<0.001 with dobutamine). Subgroup analyses indicated that among
      patients with 1- or 2-vessel disease, only those with ischemic or viable
      myocardium improved survival after revascularization, whereas in patients with 3
      vessel or left main diseases, revascularization always improved survival, albeit
      more in the presence of ischemic or viable myocardium. CONCLUSIONS: Among the
      parameters commonly available in patients with LV ischemic dysfunction, the
      presence of ischemic myocardium (as determined by thallium scintigraphy) and that
      of viable myocardium (as determined by dobutamine echocardiography) are
      independent predictors of subsequent mortality. These observations may be useful
      in the preoperative selection of patients for revascularization.

PMID- 10402444
TI  - Amiodarone-associated thyroid dysfunction: risk factors in adults with congenital
      heart disease.
AB  - BACKGROUND: Amiodarone is widely used in adults with congenital heart disease,
      but no systematic study has been published on its effects on thyroid function in
      these patients. A retrospective study was performed to examine the frequency of
      amiodarone-associated thyroid dysfunction in adults with congenital heart disease
      and to identify any contributing factors. METHODS AND RESULTS: All adults (16 to
      60 years old) with congenital heart disease were identified from a database if
      they had no preexisting thyroid disease, had taken amiodarone for >/=6 months,
      and were currently followed up by 1 consultant (J.S.). Ninety-two patients were
      found and evaluated for thyroid status and cardiac complications. A case-control
      analysis was performed, with patients matched for duration of amiodarone therapy.
      Of the 92 patients (age, 34.9+/-10.2 years; range, 18 to 60 years), 36% developed
      thyroid dysfunction: 19 became hyperthyroid and 14 hypothyroid. Female sex and
      complex cyanotic heart disease were significant risk factors for developing
      thyroid dysfunction (odds ratios, 3.0 and 7.00; P=0.04 and 0.01, respectively).
      Previous Fontan-type surgery also appeared to be a risk factor for developing
      thyrotoxicosis (odds ratio, 4.0; P=0.17), and amiodarone >200 mg/d a risk factor
      for thyroid dysfunction (odds ratio, 4.0; P=0.60). CONCLUSIONS: Amiodarone
      associated thyroid dysfunction is common in adults with congenital heart disease.
      Women and those with complex cyanotic lesions are at particular risk, as patients
      may be who have had Fontan-type surgery or are taking >200 mg/d of amiodarone.
      Amiodarone should be used only when other antiarrhythmics are ineffective or
      contraindicated. Vigilance is required to detect and treat thyroid dysfunction.

PMID- 10402445
TI  - Subunit expression of the cardiac L-type calcium channel is differentially
      regulated in diastolic heart failure of the cardiac allograft.
AB  - BACKGROUND: Left ventricular diastolic dysfunction is a major cause of cardiac
      allograft failure. Multimeric L-type calcium channels (alpha1-, alpha2/delta-,
      and beta-subunits) are essential for excitation/contraction coupling in the
      heart. Their gene expression was studied in allografts that developed diastolic
      heart failure. METHODS AND RESULTS: mRNA levels of calcium channel subunits were
      measured by competitive reverse transcriptase-polymerase chain reaction in
      microbiopsy samples from the interventricular septum. Size and tissue
      variabilities between biopsy samples were assessed by determination of cardiac
      calsequestrin mRNA levels. In the cardiac allografts studied, mRNA levels in
      microbiopsy samples were considered to represent left ventricular gene
      expression, because septal and left ventricular gene expression in Northern blots
      was equivalent, and left ventricles contracted homogeneously. Biopsy samples
      (n=72) were taken from allografts with normal left ventricular end-diastolic
      pressure (LVEDP; 8 to 13 mm Hg; n=30), moderately elevated LVEDP (14 to 18 mm Hg;
      n=26), and elevated LVEDP (19 to 28 mm Hg; n=16). Increased LVEDP was related to
      slowed diastolic relaxation determined by the time constant tau (r2=0.86),
      whereas systolic performance (dP/dt; ejection fraction) was preserved. With
      increasing LVEDP, mRNA levels of the pore-forming alpha1c-subunit (n=15) and of
      the regulatory alpha2/delta-subunit (n=17) remained unchanged but decreased
      exponentially (r2=-0.83) for the regulatory beta-subunit (n=40). Compared with
      cardiac allografts with normal LVEDP (n=15), beta-subunit mRNA level was reduced
      by 75% at elevated LVEDP (n=9; P=0.012). In an explanted, diastolically failing
      cardiac allograft, beta-subunit expression was reduced correspondingly by 72% and
      76% on the mRNA level in septal and left ventricular myocardium and by 80% on the
      protein level. CONCLUSIONS: The downregulated expression of the calcium channel
      beta-subunit might contribute to altered calcium handling in diastolically
      failing cardiac allografts.

PMID- 10402446
TI  - Limb blood flow and vascular conductance are reduced with age in healthy humans:
      relation to elevations in sympathetic nerve activity and declines in oxygen
      demand.
AB  - BACKGROUND: We tested the hypothesis that basal (resting) limb blood flow and
      vascular conductance are reduced with age in adult humans and that these changes
      are related to elevations in sympathetic vasoconstrictor nerve activity and
      reductions in limb oxygen demand. METHODS AND RESULTS: Sixteen young (28+/-1
      years; mean+/-SEM) and 15 older (63+/-1 years) healthy normotensive adult men
      were studied. Diastolic blood pressure and body fat were higher (P<0.005) in the
      older men, but there were no other age-related differences in subject
      characteristics. Femoral artery blood flow (Doppler ultrasound) was 26% lower in
      the older men (P<0.005), despite similar levels of cardiac output (systemic
      arterial blood flow) in the 2 groups. Femoral artery vascular conductance was 32%
      lower and femoral vascular resistance was 45% higher in the older men (P<0. 005).
      Muscle sympathetic nerve activity (peroneal microneurography) was 74% higher in
      the older men (P<0.001) and correlated with femoral artery blood flow (r=-0.55,
      P<0.005), vascular conductance (r=-0.65, P<0.001), and vascular resistance
      (r=0.61, P<0.001). The age-related differences in femoral hemodynamics were no
      longer significant after correction for the influence of muscle sympathetic nerve
      activity. There were no significant age-group differences in leg tissue mass (by
      dual-energy x-ray absorptiometry), but estimated leg oxygen consumption was 15%
      lower in the older men (P<0.001). Femoral artery blood flow was directly related
      to estimated leg oxygen consumption (r=0.78, P<0.001). The age-group differences
      in femoral artery blood flow were no longer significant after correction for
      estimated leg oxygen consumption by ANCOVA. CONCLUSIONS: (1) Basal whole-leg
      arterial blood flow and vascular conductance are reduced with age in healthy
      adult men; (2) these changes are associated with elevations in sympathetic
      vasoconstrictor nerve activity; and (3) the lower whole-limb blood flow is
      related to a lower oxygen demand that is independent of tissue mass.

PMID- 10402447
TI  - Increased incidence of periprocedural complications among patients with
      peripheral vascular disease undergoing myocardial revascularization in the bypass
      angioplasty revascularization investigation.
AB  - BACKGROUND: Risks of coronary artery bypass graft surgery (CABG) or percutaneous
      transluminal coronary angioplasty (PTCA) may be different in the presence of
      peripheral vascular disease (PVD). METHODS AND RESULTS: We analyzed outcomes of
      550 patients with PVD enrolled in the Bypass Angioplasty Revascularization
      Investigation randomized trial and registry. Compared with 1770 patients without
      PVD, those with PVD were older and had a greater prevalence of medical comorbid
      conditions. No significant differences in coronary anatomy or PTCA success rates
      were found. The risk of any major complication (death, myocardial infarction,
      stroke, coma, or emergency revascularization) after PTCA was significantly higher
      among patients with PVD (11.7% versus 7.8%, P=0.027). In multivariate analysis,
      this represented a 50% increase in the odds of having any major complication
      (multivariate odds ratio, 1.5; P=0. 032). Among patients undergoing CABG, the
      risk of major complications was found to be markedly higher for patients with PVD
      (12%) than those without (6.1%, P=0.003) even after controlling for baseline
      differences (multivariate odds ratio, 1.8; P=0.018). Major differences between
      the PTCA and CABG groups were related primarily to a higher risk of neurological
      complications in PVD patients who had CABG (multivariate odds ratio, 2.8;
      P<0.001). CONCLUSIONS: We conclude that patients with PVD are at high risk for
      periprocedural complications after myocardial revascularization, in particular
      neurological events.

PMID- 10402448
TI  - Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic
      rat hearts.
AB  - BACKGROUND: Ischemia followed by reperfusion in the presence of polymorphonuclear
      leukocytes (PMNs) results in cardiac contractile dysfunction as well as
      cardiomyocyte injury. These deleterious effects are due in large part to
      endothelial dysfunction leading to the upregulation of cell adhesion molecules
      and subsequent neutrophil-endothelium interaction. At clinically relevant doses,
      simvastatin, an HMG-CoA reductase inhibitor, has been shown to lower serum
      cholesterol levels and normalize endothelial cell function. We wanted to test the
      effects of simvastatin on neutrophil-mediated cardiac dysfunction in a controlled
      model of myocardial ischemia-reperfusion. METHODS AND RESULTS: This study
      examines the effects of simvastatin in a neutrophil-dependent isolated perfused
      rat heart model of ischemia (I) (20 minutes) and reperfusion (R) (45 minutes)
      injury. Administration of simvastatin 25 micrograms/rat improved coronary flow
      and preserved left ventricular developed pressure (LVDP) and dP/dtmax, indexes of
      cardiac contractile function. Final LVDP was 95+/-5 mm Hg in I/R hearts perfused
      with PMNs and simvastatin, compared with 49+/-4 mm Hg in PMN-perfused I/R hearts
      receiving only vehicle (P<0.001). In addition, simvastatin significantly reduced
      PMN accumulation in the ischemic myocardium (P<0.01). In PMN-perfused rat hearts
      after I/R, simvastatin also significantly attenuated P-selectin expression, CD18
      upregulation in rat PMNs, and PMN adherence to rat vascular endothelium.
      Significant, although less potent, effects were obtained with pravastatin.
      CONCLUSIONS: These results provide evidence that HMG-CoA reductase inhibitors are
      potent and effective cardioprotective agents that inhibit leukocyte-endothelial
      cell interactions and preserve cardiac contractile function and coronary
      perfusion after myocardial ischemia and reperfusion. Moreover, these effects are
      unrelated to the cholesterol-lowering action of this agent and appear to be
      mediated by enhanced endothelial release of NO.

PMID- 10402449
TI  - Relationship of elevated 23Na magnetic resonance image intensity to infarct size
      after acute reperfused myocardial infarction.
AB  - BACKGROUND: Elevated 23Na MR image intensity after acute myocardial infarction
      has previously been shown to correspond to high tissue [Na+] and loss of
      myocardial viability. In this study, we explored the potential of in vivo 23Na
      MRI to assess infarct size and investigated possible mechanisms for elevated 23Na
      image intensity. METHODS AND RESULTS: Thirteen dogs and 8 rabbits underwent in
      situ coronary artery occlusion and reperfusion and were imaged by 23Na MRI. For
      anatomically matched left ventricular short-axis cross sections (n=46), infarct
      size measured by in vivo 23Na MRI correlated well with triphenyltetrazolium
      chloride staining (r=0.87, y=0.92x+3.37, P<0.001). Elevated 23Na image intensity
      was observed in infarcted myocardium (206+/-37% of remote in dogs, P<0.001; 215+/
      58% in rabbits, P<0.002) but was not observed after severe but reversible
      ischemic injury (101+/-11% of baseline, P=NS). High-resolution ex vivo imaging
      revealed that regions of elevated 23Na image intensity appeared to be identical
      to those of infarcted regions (r=0.97, y=0.92x+1.52, P<0.001). In infarcted
      regions, total tissue [Na+] was elevated (89+/-12 versus 37+/-9 mmol/L in control
      tissue, 156+/-60% increase, P<0.001) and was associated with increased
      intracellular sodium (254+/-68% of control, P<0.005) and an increased
      intracellular sodium/potassium ratio (868+/-512% of control, P<0.002).
      Morphometric analysis demonstrated only a minor increase in extracellular volume
      (17+/-8% versus 14+/-5%, P<0.05) in the infarcted territory. CONCLUSIONS:
      Elevated 23Na MR image intensity in vivo measures infarct size after reperfused
      infarction in both a large and a small animal model. The mechanism of elevated
      23Na image intensity is probably intracellular sodium accumulation secondary to
      loss of myocyte ionic homeostasis.

PMID- 10402450
TI  - Survival, integration, and differentiation of cardiomyocyte grafts: a study in
      normal and injured rat hearts.
AB  - BACKGROUND: Cardiomyocyte grafting augments myocyte numbers in the heart. We
      investigated (1) how developmental stage influences graft survival; (2) whether
      acutely necrotic or healing cardiac lesions support grafts; and (3) the
      differentiation and integration of cardiomyocyte grafts in injured hearts.
      METHODS AND RESULTS: Cardiomyocytes from fetal, neonatal, or adult inbred rats
      were grafted into normal myocardium, acutely cryoinjured myocardium, or
      granulation tissue (6 days after injury). Adult cardiomyocytes did not survive
      under any conditions. In contrast, fetal and neonatal cardiomyocytes formed
      viable grafts under all conditions. Time-course studies with neonatal
      cardiomyocytes showed that the grafts recapitulated many aspects of normal
      development. The adherens junction protein N-cadherin was distributed
      circumferentially at day 1 but began to organize into intercalated disk-like
      structures by day 6. The gap junction protein connexin43 followed a similar but
      delayed pattern relative to N-cadherin. From 2 to 8 weeks, there was progressive
      hypertrophy and the formation of mature intercalated disks. In some hearts, graft
      cells formed adherens and gap junctions with host cardiomyocytes, suggesting
      electromechanical coupling. More commonly, however, grafts were separated from
      the host myocardium by scar tissue. Gap and adherens junctions formed between
      neonatal and adult cardiomyocytes in coculture, as evidenced by dye transfer and
      localization of cadherin and connexin43 at intercellular junctions. CONCLUSIONS:
      Grafted fetal and neonatal cardiomyocytes form new, mature myocardium with the
      capacity to couple with injured host myocardium. Optimal repair, however, may
      require reducing the isolation of the graft by the intervening scar tissue.

PMID- 10402451
TI  - Extracardiac ablation of the canine atrioventricular junction by use of high
      intensity focused ultrasound.
AB  - BACKGROUND: High-intensity focused ultrasound has been applied to internal organs
      from outside the body to ablate tissue. No published study has assessed the
      feasibility of ablating cardiac tissue within the beating heart by use of this
      type of therapeutic ultrasound. The purpose of this study was to determine
      whether high-intensity focused ultrasound can be used to ablate the
      atrioventricular (AV) junction within the beating heart. METHODS AND RESULTS: Ten
      dogs were anesthetized and underwent a thoracotomy. The heart was covered with a
      polyvinyl chloride membrane. The thorax above the membrane was perfused with
      degassed water, which functioned as a coupling medium for the ultrasound. A 7.0
      MHz diagnostic ultrasound probe was affixed to a spherically focused 1.4-MHz high
      intensity focused ultrasound transducer with a 1.1x8.3-mm focal zone 63.5 mm from
      the ablation transducer. The diagnostic ultrasound probe was calibrated such that
      the location of the focal zone of the ablation transducer was identifiable on the
      2-dimensional ultrasound image. Target sites were identified with the diagnostic
      ultrasound. The maximum ultrasound intensity for ablation (2.8 kW/cm2) was
      delivered to the AV junction only during electrical diastole and for a total of
      30 seconds. Complete AV block was achieved in each of the 10 dogs with 6.5+/-5.6
      (range, 3 to 21) 30-second applications of therapeutic ultrasound. Gross
      inspection showed that the mean lesion volume was 124+/-143 mm3, with a depth of
      6.7+/-3.6 mm, a length of 5.7+/-2.5 mm, and a width of 4.7+/-1.8 mm. Four hours
      after the dogs were killed, histopathological study demonstrated a well
      demarcated area of necrosis and early inflammation. CONCLUSIONS: High-intensity
      focused ultrasound produces well-demarcated lesions and appears to be a feasible
      energy source to create complete AV block within the beating heart without
      damaging the overlying or underlying cardiac tissue. This energy source may allow
      for a noninvasive approach to ablation of cardiac arrhythmias.

PMID- 10402452
TI  - Is this right? (...or is it left?).

PMID- 10402453
TI  - Spatial and temporal periodicity during atrial fibrillation.

PMID- 10402454
TI  - Ventricular septal defect patch causing right ventricular inflow tract
      obstruction.

PMID- 10402455
TI  - Kinetochore fibers are not involved in the formation of the first meiotic spindle
      in mouse oocytes, but control the exit from the first meiotic M phase.
AB  - During meiosis, two successive divisions occur without any intermediate S phase
      to produce haploid gametes. The first meiotic division is unique in that
      homologous chromosomes are segregated while the cohesion between sister
      chromatids is maintained, resulting in a reductional division. Moreover, the
      duration of the first meiotic M phase is usually prolonged when compared with
      mitotic M phases lasting 8 h in mouse oocytes.We investigated the spindle
      assembly pathway and its role in the progression of the first meiotic M phase in
      mouse oocytes. During the first 4 h, a bipolar spindle forms and the chromosomes
      congress near the equatorial plane of the spindle without stable kinetochore-
      microtubule end interactions. This late prometaphase spindle is then maintained
      for 4 h with chromosomes oscillating in the central region of the spindle. The
      kinetochore-microtubule end interactions are set up at the end of the first
      meiotic M phase (8 h after entry into M phase). This event allows the final
      alignment of the chromosomes and exit from metaphase. The continuous presence of
      the prometaphase spindle is not required for progression of the first meiotic M
      phase. Finally, the ability of kinetochores to interact with microtubules is
      acquired at the end of the first meiotic M phase and determines the timing of
      polar body extrusion.

PMID- 10402457
TI  - Mutations in the essential spindle checkpoint gene bub1 cause chromosome
      missegregation and fail to block apoptosis in Drosophila.
AB  - We have characterized the Drosophila mitotic checkpoint control protein Bub1 and
      obtained mutations in the bub1 gene. Drosophila Bub1 localizes strongly to the
      centromere/kinetochore of mitotic and meiotic chromosomes that have not yet
      reached the metaphase plate. Animals homozygous for P-element-induced, near-null
      mutations of bub1 die during late larval/pupal stages due to severe mitotic
      abnormalities indicative of a bypass of checkpoint function. These abnormalities
      include accelerated exit from metaphase and chromosome missegregation and
      fragmentation. Chromosome fragmentation possibly leads to the significantly
      elevated levels of apoptosis seen in mutants. We have also investigated the
      relationship between Bub1 and other kinetochore components. We show that Bub1
      kinase activity is not required for phosphorylation of 3F3/2 epitopes at
      prophase/prometaphase, but is needed for 3F3/2 dephosphorylation at metaphase.
      Neither 3F3/2 dephosphorylation nor loss of Bub1 from the kinetochore is a
      prerequisite for anaphase entry. Bub1's localization to the kinetochore does not
      depend on the products of the genes zw10, rod, polo, or fizzy, indicating that
      the kinetochore is constructed from several independent subassemblies.

PMID- 10402458
TI  - A visual screen of a GFP-fusion library identifies a new type of nuclear envelope
      membrane protein.
AB  - The nuclear envelope (NE) is a distinct subdomain of the ER, but few membrane
      components have been described that are specific to it. We performed a visual
      screen in tissue culture cells to identify proteins targeted to the NE. This
      approach does not require assumptions about the nature of the association with
      the NE or the physical separation of NE and ER. We confirmed that screening a
      library of fusions to the green fluorescent protein can be used to identify
      proteins targeted to various subcompartments of mammalian cells, including the
      NE. With this approach, we identified a new NE membrane protein, named nurim.
      Nurim is a multispanning membrane protein without large hydrophilic domains that
      is very tightly associated with the nucleus. Unlike the known NE membrane
      proteins, it is neither associated with nuclear pores, nor targeted like lamin
      associated membrane proteins. Thus, nurim is a new type of NE membrane protein
      that is localized to the NE by a distinct mechanism.

PMID- 10402459
TI  - Component specificity for the thylakoidal Sec and Delta pH-dependent protein
      transport pathways.
AB  - Prokaryotes and prokaryote-derived thylakoid membranes of chloroplasts share
      multiple, evolutionarily conserved pathways for protein export. These include the
      Sec, signal recognition particle (SRP), and Delta pH/Tat systems. Little is known
      regarding the thylakoid membrane components involved in these pathways. We
      isolated a cDNA clone to a novel component of the Delta pH pathway, Tha4, and
      prepared antibodies against pea Tha4, against maize Hcf106, a protein implicated
      in Delta pH pathway transport by genetic studies, and against cpSecY, the
      thylakoid homologue of the bacterial SecY translocon protein. These components
      were localized to the nonappressed thylakoid membranes. Tha4 and Hcf106 were
      present in approximately 10-fold excess over active translocation sites.
      Antibodies to either Tha4 or Hcf106 inhibited translocation of four known Delta
      pH pathway substrate proteins, but not of Sec pathway or SRP pathway substrates.
      This suggests that Tha4 and Hcf106 operate either in series or as subunits of a
      heteromultimeric complex. cpSecY antibodies inhibited translocation of Sec
      pathway substrates but not of Delta pH or SRP pathway substrates. These studies
      provide the first biochemical evidence that Tha4 and Hcf106 are specific
      components of the Delta pH pathway and provide one line of evidence that cpSecY
      is used specifically by the Sec pathway.

PMID- 10402460
TI  - A role for the vesicle tethering protein, p115, in the post-mitotic stacking of
      reassembling Golgi cisternae in a cell-free system.
AB  - During telophase, Golgi cisternae are regenerated and stacked from a
      heterogeneous population of tubulovesicular clusters. A cell-free system that
      reconstructs these events has revealed that cisternal regrowth requires interplay
      between soluble factors and soluble N-ethylmaleimide (NEM)-sensitive fusion
      protein (NSF) attachment protein receptors (SNAREs) via two intersecting pathways
      controlled by the ATPases, p97 and NSF. Golgi reassembly stacking protein 65
      (GRASP65), an NEM-sensitive membrane-bound component, is required for the
      stacking process. NSF-mediated cisternal regrowth requires a vesicle tethering
      protein, p115, which we now show operates through its two Golgi receptors, GM130
      and giantin. p97-mediated cisternal regrowth is p115-independent, but we now
      demonstrate a role for p115, in conjunction with its receptors, in stacking p97
      generated cisternae. Temporal analysis suggests that p115 plays a transient role
      in stacking that may be upstream of GRASP65-mediated stacking. These results
      implicate p115 and its receptors in the initial alignment and docking of single
      cisternae that may be an important prerequisite for stack formation.

PMID- 10402461
TI  - GBF1: A novel Golgi-associated BFA-resistant guanine nucleotide exchange factor
      that displays specificity for ADP-ribosylation factor 5.
AB  - Expression cloning from a cDNA library prepared from a mutant CHO cell line with
      Golgi-specific resistance to Brefeldin A (BFA) identified a novel 206-kD protein
      with a Sec7 domain termed GBF1 for Golgi BFA resistance factor 1. Overexpression
      of GBF1 allowed transfected cells to maintain normal Golgi morphology and grow in
      the presence of BFA. Golgi- enriched membrane fractions from such transfected
      cells displayed normal levels of ADP ribosylation factors (ARFs) activation and
      coat protein recruitment that were, however, BFA resistant. Hexahistidine-tagged
      GBF1 exhibited BFA-resistant guanine nucleotide exchange activity that appears
      specific towards ARF5 at physiological Mg2+concentration. Characterization of
      cDNAs recovered from the mutant and wild-type parental lines established that
      transcripts in these cells had identical sequence and, therefore, that GBF1 was
      naturally BFA resistant. GBF1 was primarily cytosolic but a significant pool
      colocalized to a perinuclear structure with the beta-subunit of COPI. Immunogold
      labeling showed highest density of GBF1 over Golgi cisternae and significant
      labeling over pleiomorphic smooth vesiculotubular structures. The BFA-resistant
      nature of GBF1 suggests involvement in retrograde traffic.

PMID- 10402462
TI  - A cell-free assay allows reconstitution of Vps33p-dependent transport to the
      yeast vacuole/lysosome.
AB  - We report a cell-free system that measures transport-coupled maturation of
      carboxypeptidase Y (CPY). Yeast spheroplasts are lysed by extrusion through
      polycarbonate filters. After differential centrifugation, a 125,000-g pellet is
      enriched for radiolabeled proCPY and is used as "donor" membranes. A 15,000-g
      pellet, harvested from nonradiolabeled cells and enriched for vacuoles, is used
      as "acceptor" membranes. When these membranes are incubated together with ATP and
      cytosolic extracts, approximately 50% of the radiolabeled proCPY is processed to
      mature CPY. Maturation was inhibited by dilution of donor and acceptor membranes
      during incubation, showed a 15-min lag period, and was temperature sensitive.
      Efficient proCPY maturation was possible when donor membranes were from a yeast
      strain deleted for the PEP4 gene (which encodes the principal CPY processing
      enzyme, proteinase A) and acceptor membranes from a PEP4 yeast strain, indicating
      intercompartmental transfer. Cytosol made from a yeast strain deleted for the
      VPS33 gene was less efficient at driving transport. Moreover, antibodies against
      Vps33p (a Sec1 homologue) and Vam3p (a Q-SNARE) inhibited transport >90%.
      Cytosolic extracts from yeast cells overexpressing Vps33p restored transport to
      antibody-inhibited assays. This cell-free system has allowed the demonstration of
      reconstituted intercompartmental transport coupled to the function of a VPS gene
      product.

PMID- 10402463
TI  - Pex22p of Pichia pastoris, essential for peroxisomal matrix protein import,
      anchors the ubiquitin-conjugating enzyme, Pex4p, on the peroxisomal membrane.
AB  - We isolated a Pichia pastoris mutant that was unable to grow on the peroxisome
      requiring media, methanol and oleate. Cloning the gene by complementation
      revealed that the encoded protein, Pex22p, is a new peroxin. A Deltapex22 strain
      does not grow on methanol or oleate and is unable to import peroxisomal matrix
      proteins. However, this strain targets peroxisomal membrane proteins to
      membranes, most likely peroxisomal remnants, detectable by fluorescence and
      electron microscopy. Pex22p, composed of 187 amino acids, is an integral
      peroxisomal membrane protein with its NH2 terminus in the matrix and its COOH
      terminus in the cytosol. It contains a 25-amino acid peroxisome membrane
      targeting signal at its NH2 terminus. Pex22p interacts with the ubiquitin
      conjugating enzyme Pex4p, a peripheral peroxisomal membrane protein, in vivo, and
      in a yeast two-hybrid experiment. Pex22p is required for the peroxisomal
      localization of Pex4p and in strains lacking Pex22p, the Pex4p is cytosolic and
      unstable. Therefore, Pex22p anchors Pex4p at the peroxisomal membrane. Strains
      that do not express Pex4p or Pex22p have similar phenotypes and lack Pex5p,
      suggesting that Pex4p and Pex22p act at the same step in peroxisome biogenesis.
      The Saccharomyces cerevisiae hypothetical protein, Yaf5p, is the functional
      homologue of P. pastoris Pex22p.

PMID- 10402464
TI  - Intracellular localization of proteasomal degradation of a viral antigen.
AB  - To better understand proteasomal degradation of nuclear proteins and viral
      antigens we studied mutated forms of influenza virus nucleoprotein (NP) that
      misfold and are rapidly degraded by proteasomes. In the presence of proteasome
      inhibitors, mutated NP (dNP) accumulates in highly insoluble ubiquitinated and
      nonubiquitinated species in nuclear substructures known as promyelocytic leukemia
      oncogenic domains (PODs) and the microtubule organizing center (MTOC).
      Immunofluorescence revealed that dNP recruits proteasomes and a selective
      assortment of molecular chaperones to both locales, and that a similar (though
      less dramatic) effect is induced by proteasome inhibitors in the absence of dNP
      expression. Biochemical evidence is consistent with the idea that dNP is
      delivered to PODs/MTOC in the absence of proteasome inhibitors. Restoring
      proteasome activity while blocking protein synthesis results in disappearance of
      dNP from PODs and the MTOC and the generation of a major histocompatibility
      complex class I-bound peptide derived from dNP but not NP. These findings
      demonstrate that PODs and the MTOC serve as sites of proteasomal degradation of
      misfolded dNP and probably cellular proteins as well, and imply that antigenic
      peptides are generated at one or both of these sites.

PMID- 10402465
TI  - Yeast homologues of tomosyn and lethal giant larvae function in exocytosis and
      are associated with the plasma membrane SNARE, Sec9.
AB  - We have identified a pair of related yeast proteins, Sro7p and Sro77p, based on
      their ability to bind to the plasma membrane SNARE (SNARE) protein, Sec9p. These
      proteins show significant similarity to the Drosophila tumor suppressor, lethal
      giant larvae and to the neuronal syntaxin-binding protein, tomosyn. SRO7 and
      SRO77 have redundant functions as loss of both gene products leads to a severe
      cold-sensitive growth defect that correlates with a severe defect in exocytosis.
      We show that similar to Sec9, Sro7/77 functions in the docking and fusion of post
      Golgi vesicles with the plasma membrane. In contrast to a previous report, we see
      no defect in actin polarity under conditions where we see a dramatic effect on
      secretion. This demonstrates that the primary function of Sro7/77, and likely all
      members of the lethal giant larvae family, is in exocytosis rather than in
      regulating the actin cytoskeleton. Analysis of the association of Sro7p and Sec9p
      demonstrates that Sro7p directly interacts with Sec9p both in the cytosol and in
      the plasma membrane and can associate with Sec9p in the context of a SNAP
      receptor complex. Genetic analysis suggests that Sro7 and Sec9 function together
      in a pathway downstream of the Rho3 GTPase. Taken together, our studies suggest
      that members of the lethal giant larvae/tomosyn/Sro7 family play an important
      role in polarized exocytosis by regulating SNARE function on the plasma membrane.

PMID- 10402466
TI  - DAP-kinase participates in TNF-alpha- and Fas-induced apoptosis and its function
      requires the death domain.
AB  - Death-associated protein (DAP)-kinase is a calcium/calmodulin regulated
      serine/threonine kinase that carries ankyrin repeats, a death domain, and is
      localized to the cytoskeleton. Here, we report that this kinase is involved in
      tumor necrosis factor (TNF)-alpha and Fas-induced apoptosis. Expression of DAP
      kinase antisense RNA protected cells from killing by anti-Fas/APO-1 agonistic
      antibodies. Deletion of the death domain abrogated the apoptotic functions of the
      kinase, thus, documenting for the first time the importance of this protein
      domain. Overexpression of a fragment encompassing the death domain of DAP-kinase
      acted as a specific dominant negative mutant that protected cells from TNF-alpha,
      Fas, and FADD/MORT1-induced cell death. DAP-kinase apoptotic function was blocked
      by bcl-2 as well as by crmA and p35 inhibitors of caspases, but not by the
      dominant negative mutants of FADD/MORT1 or of caspase 8. Thus, it functions
      downstream to the receptor complex and upstream to other caspases. The
      multidomain structure of this serine/threonine kinase, combined with its
      involvement in cell death induced by several different triggers, place DAP-kinase
      at one of the central molecular pathways leading to apoptosis.

PMID- 10402469
TI  - Age-related atrophy of motor axons in mice deficient in the mid-sized
      neurofilament subunit.
AB  - Neurofilaments are central determinants of the diameter of myelinated axons. It
      is less clear whether neurofilaments serve other functional roles such as
      maintaining the structural integrity of axons over time. Here we show that an age
      dependent axonal atrophy develops in the lumbar ventral roots of mice with a null
      mutation in the mid-sized neurofilament subunit (NF-M) but not in animals with a
      null mutation in the heavy neurofilament subunit (NF-H). Mice with null mutations
      in both genes develop atrophy in ventral and dorsal roots as well as a hind limb
      paralysis with aging. The atrophic process is not accompanied by significant
      axonal loss or anterior horn cell pathology. In the NF-M-null mutant atrophic
      ventral root, axons show an age-related depletion of neurofilaments and an
      increased ratio of microtubules/neurofilaments. By contrast, the preserved dorsal
      root axons of NF-M-null mutant animals do not show a similar depletion of
      neurofilaments. Thus, the lack of an NF-M subunit renders some axons selectively
      vulnerable to an age-dependent atrophic process. These studies argue that
      neurofilaments are necessary for the structural maintenance of some populations
      of axons during aging and that the NF-M subunit is especially critical.

PMID- 10402468
TI  - Drosophila roadblock and Chlamydomonas LC7: a conserved family of dynein
      associated proteins involved in axonal transport, flagellar motility, and
      mitosis.
AB  - Eukaryotic organisms utilize microtubule-dependent motors of the kinesin and
      dynein superfamilies to generate intracellular movement. To identify new genes
      involved in the regulation of axonal transport in Drosophila melanogaster, we
      undertook a screen based upon the sluggish larval phenotype of known motor
      mutants. One of the mutants identified in this screen, roadblock (robl), exhibits
      diverse defects in intracellular transport including axonal transport and
      mitosis. These defects include intra-axonal accumulations of cargoes, severe
      axonal degeneration, and aberrant chromosome segregation. The gene identified by
      robl encodes a 97-amino acid polypeptide that is 57% identical (70% similar) to
      the 105-amino acid Chlamydomonas outer arm dynein-associated protein LC7, also
      reported here. Both robl and LC7 have homology to several other genes from fruit
      fly, nematode, and mammals, but not Saccharomyces cerevisiae. Furthermore, we
      demonstrate that members of this family of proteins are associated with both
      flagellar outer arm dynein and Drosophila and rat brain cytoplasmic dynein. We
      propose that roadblock/LC7 family members may modulate specific dynein functions.

PMID- 10402467
TI  - Myosin light chain kinase functions downstream of Ras/ERK to promote migration of
      urokinase-type plasminogen activator-stimulated cells in an integrin-selective
      manner.
AB  - Urokinase-type plasminogen activator (uPA) activates the mitogen activated
      protein (MAP) kinases, extracellular signal-regulated kinase (ERK) 1 and 2, in
      diverse cell types. In this study, we demonstrate that uPA stimulates migration
      of MCF-7 breast cancer cells, HT 1080 fibrosarcoma cells, and uPAR-overexpressing
      MCF-7 cells by a mechanism that depends on uPA receptor (uPAR)-ligation and ERK
      activation. Ras and MAP kinase kinase (MEK) were necessary and sufficient for uPA
      induced ERK activation and stimulation of cellular migration, as demonstrated in
      experiments with dominant-negative and constitutively active mutants of these
      signaling proteins. Myosin light chain kinase (MLCK) was also required for uPA
      stimulated cellular migration, as determined in experiments with three separate
      MLCK inhibitors. When MCF-7 cells were treated with uPA, MLCK was phosphorylated
      by a MEK-dependent pathway and apparently activated, since serine-phosphorylation
      of myosin II regulatory light chain (RLC) was also increased. Despite the
      transient nature of ERK phosphorylation, MLCK remained phosphorylated for at
      least 6 h. The uPA-induced increase in MCF-7 cell migration was observed
      selectively on vitronectin-coated surfaces and was mediated by a beta1-integrin
      (probably alphaVbeta1) and alphaVbeta5. When MCF-7 cells were transfected to
      express alphaVbeta3 and treated with uPA, ERK was still phosphorylated; however,
      the cells did not demonstrate increased migration. Neutralizing the function of
      alphaVbeta3, with blocking antibody, restored the ability of uPA to promote
      cellular migration. Thus, we have demonstrated that uPA promotes cellular
      migration, in an integrin-selective manner, by initiating a uPAR-dependent
      signaling cascade in which Ras, MEK, ERK, and MLCK serve as essential downstream
      effectors.

PMID- 10402470
TI  - Genomic organization, expression, and analysis of the troponin C gene pat-10 of
      Caenorhabditis elegans.
AB  - We have cloned and characterized the troponin C gene, pat-10 of the nematode
      Caenorhabditis elegans. At the amino acid level nematode troponin C is most
      similar to troponin C of Drosophila (45% identity) and cardiac troponin C of
      vertebrates. Expression studies demonstrate that this troponin is expressed in
      body wall muscle throughout the life of the animal. Later, vulval muscles and
      anal muscles also express this troponin C isoform. The structural gene for this
      troponin is pat-10 and mutations in this gene lead to animals that arrest as
      twofold paralyzed embryos late in development. We have sequenced two of the
      mutations in pat-10 and both had identical two mutations in the gene; one changes
      D64 to N and the other changes W153 to a termination site. The missense
      alteration affects a calcium-binding site and eliminates calcium binding, whereas
      the second mutation eliminates binding to troponin I. These combined biochemical
      and in vivo studies of mutant animals demonstrate that this troponin is essential
      for proper muscle function during development.

PMID- 10402471
TI  - alpha-bungarotoxin receptors contain alpha7 subunits in two different disulfide
      bonded conformations.
AB  - Neuronal nicotinic alpha7 subunits assemble into cell-surface complexes that
      neither function nor bind alpha-bungarotoxin when expressed in tsA201 cells.
      Functional alpha-bungarotoxin receptors are expressed if the membrane-spanning
      and cytoplasmic domains of the alpha7 subunit are replaced by the homologous
      regions of the serotonin-3 receptor subunit. Bgt-binding surface receptors
      assembled from chimeric alpha7/serotonin-3 subunits contain subunits in two
      different conformations as shown by differences in redox state and other features
      of the subunits. In contrast, alpha7 subunit complexes in the same cell line
      contain subunits in a single conformation. The appearance of a second
      alpha7/serotonin-3 subunit conformation coincides with the formation of alpha
      bungarotoxin-binding sites and intrasubunit disulfide bonding, apparently within
      the alpha7 domain of the alpha7/serotonin-3 chimera. In cell lines of neuronal
      origin that produce functional alpha7 receptors, alpha7 subunits undergo a
      conformational change similar to alpha7/serotonin-3 subunits. alpha7 subunits,
      thus, can fold and assemble by two different pathways. Subunits in a single
      conformation assemble into nonfunctional receptors, or subunits expressed in
      specialized cells undergo additional processing to produce functional, alpha
      bungarotoxin-binding receptors with two alpha7 conformations. Our results suggest
      that alpha7 subunit diversity can be achieved postranslationally and is required
      for functional homomeric receptors.

PMID- 10402472
TI  - Recycling of E-cadherin: a potential mechanism for regulating cadherin dynamics.
AB  - E-Cadherin plays critical roles in many aspects of cell adhesion, epithelial
      development, and the establishment and maintenance of epithelial polarity. The
      fate of E-cadherin once it is delivered to the basolateral cell surface, and the
      mechanisms which govern its participation in adherens junctions, are not well
      understood. Using surface biotinylation and recycling assays, we observed that
      some of the cell surface E-cadherin is actively internalized and is then recycled
      back to the plasma membrane. The pool of E-cadherin undergoing endocytosis and
      recycling was markedly increased in cells without stable cell-cell contacts,
      i.e., in preconfluent cells and after cell contacts were disrupted by depletion
      of extracellular Ca2+, suggesting that endocytic trafficking of E-cadherin is
      regulated by cell-cell contact. The reformation of cell junctions after
      replacement of Ca2+ was then found to be inhibited when recycling of endocytosed
      E-cadherin was disrupted by bafilomycin treatment. The endocytosis and recycling
      of E-cadherin and of the transferrin receptor were similarly inhibited by
      potassium depletion and by bafilomycin treatment, and both proteins were
      accumulated in intracellular compartments by an 18 degrees C temperature block,
      suggesting that endocytosis may occur via a clathrin-mediated pathway. We
      conclude that a pool of surface E-cadherin is constantly trafficked through an
      endocytic, recycling pathway and that this may provide a mechanism for regulating
      the availability of E-cadherin for junction formation in development, tissue
      remodeling, and tumorigenesis.

PMID- 10402473
TI  - Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell
      motility: functional competition of collapsin-1 and vascular endothelial growth
      factor-165.
AB  - Neuropilin-1 (NRP1) is a receptor for two unrelated ligands with disparate
      activities, vascular endothelial growth factor-165 (VEGF165), an angiogenesis
      factor, and semaphorin/collapsins, mediators of neuronal guidance. To determine
      whether semaphorin/collapsins could interact with NRP1 in nonneuronal cells, the
      effects of recombinant collapsin-1 on endothelial cells (EC) were examined.
      Collapsin-1 inhibited the motility of porcine aortic EC (PAEC) expressing NRP1
      alone; coexpressing KDR and NRP1 (PAEC/KDR/NRP1), but not parental PAEC; or PAEC
      expressing KDR alone. The motility of PAEC expressing NRP1 was inhibited by 65
      75% and this inhibition was abrogated by anti-NRP1 antibody. In contrast, VEGF165
      stimulated the motility of PAEC/KDR/NRP1. When VEGF165 and collapsin-1 were added
      simultaneously to PAEC/KDR/NRP1, dorsal root ganglia (DRG), and COS-7/NRP1 cells,
      they competed with each other in EC motility, DRG collapse, and NRP1-binding
      assays, respectively, suggesting that the two ligands have overlapping NRP1
      binding sites. Collapsin-1 rapidly disrupted the formation of lamellipodia and
      induced depolymerization of F-actin in an NRP1-dependent manner. In an in vitro
      angiogenesis assay, collapsin-1 inhibited the capillary sprouting of EC from rat
      aortic ring segments. These results suggest that collapsin-1 can inhibit EC
      motility as well as axon motility, that these inhibitory effects on motility are
      mediated by NRP1, and that VEGF165 and collapsin-1 compete for NRP1-binding
      sites.

PMID- 10402474
TI  - IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal
      growth factor receptor-mediated calpain activity.
AB  - During wound healing, fibroblasts are recruited from the surrounding tissue to
      accomplish repair. The requisite migration and proliferation of the fibroblasts
      is promoted by growth factors including those that activate the epidermal growth
      factor receptor (EGFR). Counterstimulatory factors in wound fluid are postulated
      to limit this response; among these factors is the ELR-negative CXC chemokine,
      interferon inducible protein-10 (IP-10). We report here that IP-10 inhibited EGF-
      and heparin-binding EGF-like growth factor-induced Hs68 human dermal fibroblast
      motility in a dose-dependent manner (to 52% and 44%, respectively, at 50 ng/ml IP
      10), whereas IP-10 had no effect on either basal or EGFR-mediated mitogenesis (96
      +/- 15% at 50 ng/ml). These data demonstrate for the first time a
      counterstimulatory effect of IP-10 on a specific induced fibroblast response,
      EGFR-mediated motility. To define the molecular basis of this negative
      transmodulation of EGFR signaling, we found that IP-10 did not adversely impact
      receptor or immediate postreceptor signaling as determined by tyrosyl
      phosphorylation of EGFR and two major downstream effectors phospholipase C-gamma
      and erk mitogen-activated protein kinases. Morphological studies suggested which
      biophysical steps may be affected by demonstrating that IP-10 treatment resulted
      in an elongated cell morphology reminiscent of failure to detach the uropod; in
      support of this, IP-10 pretreatment inhibited EGF-induced cell detachment. These
      data suggested that calpain activity may be involved. The cell permeant agent,
      calpain inhibitor I, limited EGF-induced motility and de-adhesion similarly to IP
      10. IP-10 also prevented EGF- induced calpain activation (reduced by 71 +/- 7%).
      That this inhibition of EGF-induced calpain activity was secondary to IP-10
      initiating a cAMP-protein kinase A-calpain cascade is supported by the following
      evidence: (a) the cell permeant analogue 8-(4-chlorophenylthio)-cAMP (CPT-cAMP)
      prevented EGF-induced calpain activity and motility; (b) other ELR-negative CXC
      chemokines, monokine induced by IFN-gamma and platelet factor 4 that also
      generate cAMP, inhibited EGF-induced cell migration and calpain activation; and
      (c) the protein kinase A inhibitor Rp-8-Br-cAMPS abrogated IP-10 inhibition of
      cell migration, cell detachment, and calpain activation. Our findings provide a
      model by which IP-10 suppresses EGF-induced cell motility by inhibiting EGF
      induced detachment of the trailing edges of motile cells.

PMID- 10402476
TI  - Structure and function of the extracellular calcium-sensing receptor (Review).
AB  - The extracellular calcium-sensing receptor (CaR) originally cloned from bovine
      parathyroid gland is a G protein-coupled receptor. The physiological relevance of
      the cloned CaR for sensing and regulating the extracellular calcium concentration
      has been established by identifying hyper- and hypocalcemic disorders resulting
      from inactivating and activating mutations, respectively, in the CaR. The cloned
      CaR has been stably or transiently expressed in human embryonic kidney cells and
      significant progress has been made in elucidating its biochemical and functional
      features using physiological, biochemical and molecular biological methods. A
      large collection of naturally occurring CaR mutations offers a valuable resource
      for studies aimed at understanding the structure-function relationships of the
      receptor, including receptor-receptor interactions. In turn, characterization of
      these naturally occurring mutations has clarified the pathogenesis of clinical
      conditions involving abnormalities in the CaR, such as familial hypocalciuric
      hypercalcemia and neonatal severe hyperparathyroidism, and the physiology of
      certain cell types, such as keratinocytes.

PMID- 10402477
TI  - Genetic basis of hemophagocytic lymphohistiocytosis syndrome (Review).
AB  - The group of immune disorders which leads to the occurrence of hemophagocytic
      lymphohistiocytosis (HLH) syndrome presents a strange paradox in that patients
      with these conditions associate a dramatic immune response to infection with the
      failure to establish an effective immune response. During the last few years,
      significant progress was made in the characterization and the understanding of
      the molecular basis involved in these inherited immune disorders. The
      hemophagocytic lymphohistiocytosis syndrome which characterized the evolution of
      the Chediak-Higashi syndrome and the Griscelli disease results from defects
      affecting intracellular trafficking. A defective SH2 protein interacting with T
      lymphocyte intracellular signaling pathways is the cause of the X-linked
      lymphoproliferative disease, whereas at least three distinct genetic defects can
      lead to the familial hemophagocytic lymphohistiocytosis. The molecular
      characterization of these latter defects is in progress. This review summarizes
      the recent advances as well as their implications in the diagnosis and the
      understanding of the physiopathology of these disorders.

PMID- 10402475
TI  - Glypican-3-deficient mice exhibit developmental overgrowth and some of the
      abnormalities typical of Simpson-Golabi-Behmel syndrome.
AB  - Glypicans are a family of heparan sulfate proteoglycans that are linked to the
      cell surface through a glycosyl-phosphatidylinositol anchor. One member of this
      family, glypican-3 (Gpc3), is mutated in patients with the Simpson-Golabi-Behmel
      syndrome (SGBS). These patients display pre- and postnatal overgrowth, and a
      varying range of dysmorphisms. The clinical features of SGBS are very similar to
      the more extensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has
      been associated with biallelic expression of insulin-like growth factor II (IGF
      II), it has been proposed that GPC3 is a negative regulator of IGF-II. However,
      there is still no biochemical evidence indicating that GPC3 plays such a
      role.Here, we report that GPC3-deficient mice exhibit several of the clinical
      features observed in SGBS patients, including developmental overgrowth, perinatal
      death, cystic and dyplastic kidneys, and abnormal lung development. A proportion
      of the mutant mice also display mandibular hypoplasia and an imperforate vagina.
      In the particular case of the kidney, we demonstrate that there is an early and
      persistent developmental abnormality of the ureteric bud/collecting system due to
      increased proliferation of cells in this tissue element. The degree of
      developmental overgrowth of the GPC3-deficient mice is similar to that of mice
      deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator
      of IGF-II. Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3
      knockouts are similar to those of the normal littermates.

PMID- 10402478
TI  - Regulation of GCDFP-15 expression in human mammary cancer cells.
AB  - Gross cystic disease fluid protein 15 (GCDFP-15) is a major protein component of
      benign breast gross cysts. It is also found in approximately 50% of all breast
      cancer specimens. Androgen receptor (AR) mediated regulation of GCDFP-15
      expression was investigated in the AR-positive human mammary cancer cell lines
      MFM-223 and ZR-75-1. Proliferation of MFM-223 and ZR-75-1 cells is inhibited by
      androgens. Ten nM 5alpha-dihydrotestosterone stimulated the expression of GCDFP
      15 mRNA in MFM-223 (ca. 3-fold) and ZR-75-1 cancer cells (ca. 30-fold) as well as
      the secretion of GCDFP-15 into the culture medium. Competition experiments with
      DHT and the antiandrogens hydroxyflutamide and casodex confirmed the involvement
      of the AR in the regulation of GCDFP-15. Both antiandrogens inhibited GCDFP-15
      mRNA expression even in the absence of DHT. AR mRNA was down-regulated in MFM-223
      and ZR-75-1 cells (80 and 20% of the control, respectively) during incubation
      with DHT. Our data demonstrate the effective inhibition of GCDFP-15 expression by
      pure antiandrogens.

PMID- 10402479
TI  - Tyrosine phosphorylation in peripheral T cells of kidney transplant recipients:
      analyses of baseline levels and response to T cell receptor stimulation.
AB  - Impaired immunosurveillance in recipients of organ transplants has been
      attributed to alleviation of T cell functions. We analyzed the phosphorylation of
      tyrosine residues in T cells of peripheral blood, and after T cell receptor (TCR)
      stimulation. The TCR was stimulated by OKT3 monoclonal antibody (mAb) in non
      separated heparinized blood specimens of patients (n=64) and healthy controls
      (n=25). After fixation and red cell lysis, lymphocytes were permeabilized by
      saponin. Subsequently, intracellular phosphotyrosine residues and surface CD3
      antigen were stained simultaneously with specific mAbs. We analyzed transplant
      recipients and healthy donors for baseline levels of total cellular tyrosine
      phosphorylation and for increase in phosphotyrosine content following stimulation
      by OKT3. Phosphotyrosine levels were significantly lower in non-stimulated T
      cells of kidney transplant recipients compared to controls (p=0.004). There was a
      marked variability in the levels of tyrosine phosphorylation among transplanted
      patients (p=0.02). T cell receptor stimulation by OKT3 mAb in vitro led to a
      strong increase of tyrosine phosphorylation in all specimens of patients and
      healthy controls. In conclusion, we demonstrated decreased phosphotyrosine levels
      in T cells of kidney transplant recipients compared to healthy donors. However,
      increase in tyrosine phosphorylation was not impaired in all patients as a result
      of TCR stimulation.

PMID- 10402480
TI  - The mechanisms of antitumor effects of luteinizing hormone-releasing hormone
      agonist (buserelin) in 7, 12-dimethylbenz(a)anthracene-induced rat mammary
      cancer.
AB  - We evaluated the mechanism of antitumor effects of buserelin, which is one of LH
      RH agonists, on a hormone dependent breast cancer model, using 7,12
      dimethylbenz(a)anthracene (DMBA)-induced rat mammary cancer. Rats developing
      solid mammary tumors within 5-7 weeks following the DMBA administration were
      divided into groups weekly, and treated without delay. The tumor bearing rats
      were randomized into five groups with regard to tumor size or average weight (15
      rats per group). Each group received one of the following treatments during 4
      weeks: a) no treatment (NT); b) ovariectomy (Ovx); c) buserelin; d) Ovx and
      17beta-estradiol (E2) (Ovx+E2); e) Ovx+E2+buserelin. Tumor regression immediately
      began at one week after both buserelin treatment and ovariectomy. A significant
      reduction of tumor size was observed in both buserelin-treated rats and Ovx rats
      compared with NT rats (p<0.01). No significant difference of tumor size was
      observed between buserelin-treated rats and ovariectomized rats. No reduction of
      tumor size was observed in Ovx+E2 rats and Ovx+E2+buserelin rats. Although the
      mean uterine wet weight of the buserelin group was significantly higher than that
      of the Ovx group, it was significantly lower than that of the NT group. The mean
      uterine wet weight of the NT group, the Ovx+E2 group and the Ovx+E2+buserelin
      group was similar and was significantly higher than that of the Ovx group.
      Buserelin did not inhibit exogenous estrogen-dependent tumor growth in DMBA
      induced rat mammary cancers. These results suggest that buserelin has no direct
      effects on DMBA-induced rat mammary cancers, and the main mechanism of action of
      buserelin for tumor-reduction is due to ovarian estrogen deficiency.

PMID- 10402481
TI  - Glycyrrhizin protects mice from concanavalin A-induced hepatitis without
      affecting cytokine expression.
AB  - The administration of concanavalin A (Con A) to mice induces cytokine-dependent
      hepatitis. In the present study, the effect of glycyrrhizin on Con A-induced
      hepatitis was examined. Treatment of mice with Con A (0.2 mg/mouse, i.v.) induced
      elevation of the plasma transaminase activities at 24 h. Mice were treated with
      glycyrrhizin (100, 200 and 400 mg/kg, i.p.), and glycyrrhizin at the doses of 200
      and 400 mg/kg inhibited the Con A-induced elevation of the plasma transaminase
      activities. At 1 h after Con A treatment, interferon-gamma, tumor necrosis factor
      alpha, interleukin-2 and interleukin-6 proteins were released into the plasma.
      Although treatment with glycyrrhizin at 200 mg/kg inhibited Con A-induced
      hepatitis, it did not affect the release of any of these Con A-induced cytokines
      into the plasma. The present results clearly show that glycyrrhizin inhibited Con
      A-induced hepatitis without affecting cytokine expression.

PMID- 10402483
TI  - Potassium-current oscillation of rat megakaryocytes: As a model system for drug
      evaluation (Review).
AB  - Megakaryocytes respond to externally applied agonists showing a periodic K+
      current that reflects oscillation in cytoplasmic calcium concentration ([Ca2+]i).
      We have revealed several signal transducing factors that are involved in the K+
      current oscillation of megakaryocytes. In this megakaryocyte system, it is
      relatively easy to determine what point of the signal transduction pathway a drug
      affects. In addition, as a progenitor cell, megakaryocytes resemble platelets
      which have important roles in many diseases. Therefore, this experimental system
      can be used for evaluation of new drugs.

PMID- 10402482
TI  - Topological transition of the parametric expression site of tumor suppressor
      inactivation as a marker evidence of environmental hormone-oriented cancer risk
      increase.
AB  - The present study is an extension of our recent study in which we attempted
      statistical analysis of the data assembly of age-adjusted incidence rates (AAIRs)
      of a tumor without topological data manipulation for each of 20 individual tumors
      in scope, for each of 6 cancer registration areas in space, and for a period of
      early 1960's to mid 1980's in time. This time, a data assembly of log AAIR
      changes in time and space first passed through the process of topological data
      manipulation, and then underwent the sequential regression analysis so that we
      could assess the fitness of log AAIR changes either in space or in time to the
      equilibrium model of the law of mass action from the viewpoint of the interaction
      between oncogene activation and tumor suppressor gene inactivation. For the sake
      of comparison, the fitness of the cancer risk data to the equilibrium model was
      assessed in the framework of 3 sets of coordinates: a) the original (x org, y
      org) coordinates in which most of the log AAIR data assemblies in their data
      variations were classified as the oncogene activation type in the field of
      centripetal force (r seq=-1.000). b) The rect (X rect, Y rect) coordinates in
      which the log AAIR data assemblies were very often classified as the tumor
      suppressor gene inactivation type in the field of centrifugal force (r
      seq=+1.000). c) The para (X para, Y para) coordinates in which the log AAIR data
      assemblies were mostly classified as the intermediate type as regards the fitness
      to the equilibrium model. The rect-coordinates and the para-coordinates, 2
      variants of angular rotation of the original coordinates, were so designed as to
      allow their X-axes to run each at a right angle and parallel to the regression
      line of the original pair data block. The results obtained were as follows: a)
      poor fitness of the log AAIR changes in space to the equilibrium model in the
      rect-coordinates was found in male breast cancer, male thyroid cancer, female
      esophageal cancer, female laryngeal cancer and female lung cancer. The summation
      of the present study and the last study from our laboratory led to the conclusion
      that the members of low-risk gender in the tumor family with sex discrimination
      of cancer risk were inclined to show either failed expression of oncogene
      activation or failed expression of tumor suppressor gene inactivation or both. b)
      There was a subtle difference of the fitness of log AAIR data to the equilibrium
      model between the log AAIR changes in time and those in space in that the log
      AAIR changes in time within the framework of the rect-coordinates, which usually
      represented the field of centrifugal force or site of tumor suppressor gene
      inactivation expression, showed an increase in the number of oncogene activation
      type data sets as compared with the log AAIR changes in space. c) Upon further
      insight into the AAIR changes in time, consistent association of prominent cancer
      risk increase in time with the transition of tumor suppressor gene inactivation
      expression (r seq=+1.000) from the rect-coordinates to the para-coordinates was
      detected in skin cancer of both sexes, testicular tumor, liver cancer of both
      sexes and thyroid cancer of both sexes, all of which were related to the
      prevalence of environmental hormones as regards the recent boost of their cancer
      risks in the Western countries. In summary, the log AAIR, a cancer risk
      parameter, in its changes in time and space was found to provide useful
      information in assessing the interaction between the oncogene-tumor suppressor
      gene complex and the hormonal milieu of the host in the genesis of both
      environmental hormone-dependent and -independent human neoplasias. The
      significance of our statistical maneuver (the sequential regression analysis) is
      discussed in the light of the development of mathematics in early 19th century.

PMID- 10402484
TI  - Proliferative and apoptotic activity in lobular breast carcinoma.
AB  - Apoptotic and proliferative activity was studied in 25 invasive lobular breast
      carcinomas (ILC), and the relationship with conventional prognostic parameters
      [tumor size, nodal status, expression of estrogen (ER) and progesterone receptors
      (PR)] was investigated. Also 12 lobular carcinomata in situ (LCIS), 25 invasive
      ductal carcinomas (IDC) and 12 normal breast tissue controls were included. MIB-1
      growth fraction (GF), mitotic index (MI) and the number of argyrophilic nucleolar
      organizer regions (AgNOR) served as proliferative parameters. Apoptotic index
      (AI) was determined after visualization of apoptoses by the TUNEL method. All
      parameters increased in the following order: control tissue - LCIS - ILC - IDC.
      Except for a negative correlation between GF and ER expression, no other
      significant relationship between any of the kinetical parameters and any
      prognostic parameter could be found in ILC. However, a significant inverse
      correlation between the GF:AI ratio and both ER and PR expression was registered.
      We conclude from our results a) that transition from non-invasive to invasive
      growth in lobular breast cancer is associated with an increased cellular
      turnover, and b) that proliferative activity is significantly lower in ILC than
      in IDC. The GF:AI ratio may possibly provide additional prognostic information in
      lobular breast cancer.

PMID- 10402485
TI  - Effects of insulin-like growth factors I and II on oestrone sulphatase activity
      in human breast cancer cell lines.
AB  - Oestrogens play an important role in the development of breast cancer. A very
      important source of active oestrogens in the breast is oestrone sulphate which is
      converted to oestrone by oestrone sulphatase. The aim of this study was to assess
      the effects of IGF-I and IGF-II on oestrone sulphatase activity in, as well as
      cell growth of, MCF-7 and MDA-MB-231 human breast cancer cell lines. Cells were
      grown in supplemented DMEM and treated with varying concentrations of IGFs. At
      the end of the treatment period, intact cell monolayers were washed and assayed
      for oestrone sulphatase activity and the number of cell nuclei determined on a
      Coulter Counter. Oestrone sulphatase activity was significantly stimulated by IGF
      I and II at concentrations of 100 ng/ml and 200 ng/ml in MCF-7 cells. IGF-I had
      no effect on oestrone sulphatase activity in MDA-MB-231 cells over the range of
      concentrations tested. Significant inhibition of oestrone sulphatase was observed
      in MDA-MB-231 cells at higher concentrations of IGF-II (50 ng/ml, 100 ng/ml and
      200 ng/ml). Both IGF-I and IGF-II at higher concentrations (100 ng/ml and 200
      ng/ml) significantly inhibited MCF-7 and stimulated MDA-MB-231 cell growth. Since
      IGF-I and II have effects on cell growth and oestrone sulphatase activity in
      breast cancer cell lines they may play a role in the development and progression
      of human breast cancer.

PMID- 10402486
TI  - Influence of apolipoprotein E genotype on blood redox status of Alzheimer's
      disease patients.
AB  - The blood redox status of probable Alzheimer's Disease (AD) patients and control
      subjects with distinct Apo E genotypes was investigated. It was assessed by
      measuring the levels of hydroperoxides (MDA) in plasma and erythrocytes, the
      levels of the antioxidant defense system (enzymatic and non-enzymatic) in plasma,
      erythrocytes, platelets and leukocytes, the activities of catechol-O
      methyltransferase (COMT) in erythrocytes and monoamine oxidase-B (MAO-B) in
      platelets and also the activity of the mitochondrial respiratory chain in
      leukocytes. No significant differences were found between the Apo E genotype and
      MDA, uric acid, vitamin E and reduced-glutathione (GSH) levels in plasma; MDA,
      vitamin E, GSH, superoxide-dismutase (SOD), glutathione-peroxidase (GSH-Px) and
      COMT levels in erythrocytes; vitamin E levels in the platelets of AD patients and
      control subjects. However, the uric acid levels in plasma and the COMT levels in
      erythrocytes of AD patients and control subjects with the epsilon4 allele were
      significantly lower than those observed in control subjects without the epsilon4
      allele. Moreover, the duraquinol oxidation level in leukocytes of AD patients
      with the epsilon4 allele was significantly higher than that in AD patients
      without the epsilon4 allele and control subjects with and without the epsilon4
      allele. The meaning of these results is discussed in terms of involvement of
      oxidative stress in the etiopathogenesis of AD.

PMID- 10402487
TI  - In vitro interaction of serum protein with circulating DNA of lung cancer
      patient.
AB  - Circulating DNA and oncoproteins can be extracted from serum or plasma of cancer
      patients. In this study, using gel retardation analysis we observed circulating
      DNA obtained from plasma of a lung cancer patient complexed with serum proteins.
      p53 was identified by immunoblotting as one of the proteins present in the
      complex. Our finding suggests that the same interaction observed between p53 and
      DNA in intact cells occurs in serum of lung cancer patient. As far as we know
      this is the first evidence for such finding.

PMID- 10402488
TI  - Phosphorylation and disorganization of vascular-endothelial cadherin in
      interaction between breast cancer and vascular endothelial cells.
AB  - Adherens junctions of the endothelium play a key role in the maintenance of
      endothelial permeability and are composed of the vascular endothelial (VE)
      cadherin/catenin adhesion complex. We report that following tumour cell (MDA
      MB231 cells) adherence to the HUVECs, there was a rapid (within 5 min)
      redistribution of VE-cadherin, resulting in its transient loss from regions of
      endothelial cell-cell contact. The molecule gradually reorganised within the
      endothelial cell contacts after this time. It was further shown that the overall
      expression of VE-cadherin did not change, however, the amount of alpha- and beta
      catenins coprecipitated with VE-cadherin markedly decreased after 5 min of tumour
      cell adhesion to the HUVECs. Immunoprobing of these samples with anti
      phosphotyrosine antibodies demonstrated that the tyrosine phosphorylation of VE
      cadherin was significantly increased following 5 min of tumour cell adhesion.
      Together, these results suggest that the adhesion of tumour cells to HUVEC
      promotes the redistribution of VE-cadherin from interendothelial adherens
      junctions, an effect that may be attributed to the increase in tyrosine
      phosphorylation of members of the VE-cadherin/catenin adhesion complex. This, in
      turn, may increase vascular endothelial permeability and facilitate the
      transendothelial migration of tumour cells during extravasation.

PMID- 10402491
TI  - Association study of a polymorphism of nonerythroid alpha-spectrin gene with
      schizophrenia.
AB  - The specificity of cytoarchitectural abnormalities in limbic structures of
      patients with schizophrenia and their contributions towards the etiology of
      schizophrenia remain unknown. We have recently reported an increased breakdown of
      nonerythroid alpha-spectrin (fodrin), a major component of neuronal cytoskeletal
      proteins, in schizophrenic left superior temporal cortices [Kitamura et al.,
      1998: Biol Psychiatry 43:254-262], suggesting that polymorphisms of the alpha
      spectrin gene might contribute to the vulnerability to schizophrenia. We screened
      for genetic variations associated with schizophrenia through the C-terminus
      sequences of the human nonerythroid alpha-spectrin gene (SPTAN1) spanning two EF
      hands and also tested a possible contribution of the polymorphism to the
      development of schizophrenia by an association study. We found a polymorphic
      region of an intron located in the second EF-hand of SPTAN1 gene. There was no
      significant difference between patients with schizophrenia and controls in allele
      frequencies or genotype distribution. There is evidence that the Psh BI SPTAN1
      gene polymorphism does not play a major role in the genetic component of
      schizophrenia.

PMID- 10402490
TI  - Modulation of biological phenotypes for tumor growth and metastasis by target
      specific biological inhibitors in gastric cancer.
AB  - For tumor progression, a cascade of linked sequential biological events is
      essential. We tried to test whether biological therapy can modulate specific
      biological phenotypes and increase the anti-tumor effect when combined with
      chemotherapy. Five human gastric cancer cell lines (YCC-1, YCC-2, YCC-3, YCC-7,
      AGS) were used in these studies. Pentosan polysulfate (PPS) as a heparin-binding
      growth factor inhibitor, Tranexamic acid as a plasmin inhibitor, Lovastatin as an
      adhesion inhibitor and Adriamycin as a chemotherapeutic agent were selected. The
      effects of each drug on colony formation and tumor cell proliferation were
      evaluated by soft agar assay and cell proliferation assay, respectively to test
      direct anti-tumor effect. The expression of uPA, PAI-1 was determined by ELISA,
      while MMPs activity was evaluated by zymography. PPS suppressed the colony
      forming activity as much as Adriamycin did, but it showed only cytostatic effects
      in cell proliferation assay. Migration capacity using Boyden chamber assay was
      more closely correlated with adhesive capacity than uPA or MMP-2 expression. The
      motility inhibitory effect of Tranexamic acid was observed in the YCC-7 cell
      line, which expressed all the required biological phenotypes for migration. In
      AGS, with high cell motility and adhesiveness, the adhesion was inhibited by
      Lovastatin and most of the inhibitory effect was recovered by Mevalonate. When
      PPS was combined with Adriamycin on the Adriamycin-resistant, midkine (MK) gene
      expressing YCC-7 cell line, the growth inhibition rate increased up to 84%, while
      that for a single treatment of PPS or Adriamycin was 40% and 22%, respectively
      (p=0.001). When we combined Tranexamic acid and Adriamycin, we observed the
      synergistic effect in YCC-3 and YCC-7, while no combined effect was found in YCC
      1. The combination of Lovastatin and Adriamycin did not show any combined effects
      in any of the cell lines. In conclusion, a synergistic anti-proliferative effect
      (chemo-sensitization) with combined chemo-biotherapy was found in cancer cells
      with specific biological target, MK. The anti-motility effect was the greatest
      when the gastric cancer cells expressed all the specific biological phenotypes.

PMID- 10402489
TI  - Effects of low doses of carcinogen and different antibodies on the splenic
      lymphoid system of p53 transgenic mice: morphometric and immunohistochemical
      studies.
AB  - The role of the splenic immune system in the development of high sensitivity of
      p53 transgenic mice to low doses of carcinogen and vaccination was investigated
      immunohistochemically and morphometrically. Spleens were obtained from human p53
      promoter-chloramphenicol acetyl transferase transgenic mice, grouped as follows:
      1, untreated controls; 2, exposed to dimethylhydrazine (DMH); 3, and 4,
      vaccinated with polyclonal antibodies to soluble-53 kDa protein (s53); 5,
      vaccinated with monoclonal PAb DO1; 6, vaccinated with monoclonal PAb 421; 7,
      vaccinated with polyclonal alphaH-p53 antibody. Mice in groups 4-7 were treated
      with DMH after the course of vaccination. Six months later all the mice were
      tumor-free, but effects of the low dose carcinogen were distinct in the splenic
      immune system. They were mainly manifested in blast transformation: the total
      number of lymphocytes and lymphoblasts decreased to 56.5% of the controls. The
      total of lymphoid cells in the follicles (B zone) and periarterial lymph sheath
      (T zone) declined, reflecting moderate insufficiency of the spleen's lymphoid
      system. Vaccination of transgenic mice with antibodies to soluble-p53 elicited
      mainly a B system response, with lesser T system involvement. Only few signs of B
      system insufficiency were found in these mice. Vaccination of mice with different
      antibodies, with subsequent carcinogen treatment, caused changes in the spleen
      that were similar to those described for DMH alone, but varied with different
      anti-p53 antibodies. Vaccination with polyclonal antibodies to soluble-p53, or
      with monoclonal antibodies PAb DO1 or PAb 421, stimulated the splenic activity of
      T system, and therefore can decrease the tumorigenic effect of carcinogens.

PMID- 10402492
TI  - Dopamine D2 receptor gene not associated with symptomatology of mood disorders.
AB  - Dopamine D2 receptor gene (DRD2) variants have been implicated in the
      pathogenesis of psychiatric disorders. Many studies have, however, failed to
      replicate the original association of DRD2 with schizophrenia and mood disorders.
      A possible reason for this may lie in the definition of phenotype, which is
      traditionally based on psychiatric diagnosis. In this study we investigated the
      possibility that variants of the DRD2 gene might be associated with
      symptomatology in a sample of mood disorder subjects. Forty-seven inpatients
      affected by bipolar disorder (Diagnostic and Statistical Manual of Mental
      Disorders IV) were assessed at admission by the Operational Criteria for
      Psychotic Illness and were typed for DRD2 variants using polymerase chain
      reaction techniques. DRD2 was not associated with excitement, depression,
      delusion, and disorganization symptoms. Gender did not influence results
      significantly. Among early onset subjects DRD2*1 was associated with disorganized
      symptoms. In our sample DRD2 variants did not markedly influence psychopathology
      among mood disorder subjects. We observed a trend toward higher disorganization
      among DRD2*1 subjects.

PMID- 10402494
TI  - Novel polymorphism in the promoter region of the tumor necrosis factor alpha
      gene: No association with narcolepsy.
AB  - The striking evidence of almost 100% association of narcolepsy with human
      leukocyte antigens (HLA) DR2(DR15) antigen is an important clue to elucidate the
      molecular basis of this sleep disorder. The gene for tumor necrosis factor alpha
      (TNF alpha) is located in the HLA class II gene cluster. Recent studies have
      indicated that TNF alpha plays an important role in the regulation of normal
      human sleep, and regulation of this cytokine may be disturbed in narcolepsy. We
      searched for a mutation associated with narcolepsy in the promoter region of the
      TNF alpha gene by single-strand conformation polymorphism analysis. A novel
      polymorphism, C-850T, was found in narcoleptic patients. Genotype frequency was
      examined by restriction fragment length polymorphism method. No significant
      difference of genotype distribution was found between 92 patients with narcolepsy
      and 91 normal controls. These results do not support our hypothesis that genetic
      abnormality of TNF alpha production is pathogenetic for narcolepsy.

PMID- 10402493
TI  - Association study of schizophrenia among Indian families.
AB  - A putative association of schizophrenia with a Msc I restriction fragment length
      polymorphism at the dopamine D3 receptor gene locus (DRD3) was tested among
      Indian families, using haplotype relative risk analysis and the transmission
      disequilibrium test (n=66 families and 58 sets of transmissions, respectively). A
      significant association either with homozygosity or with allele 1 at the
      biallelic polymporphism could not be detected.

PMID- 10402495
TI  - Association analysis of exonic variants of the gene encoding the GABAB receptor
      and idiopathic generalized epilepsy.
AB  - The gene encoding the GABAB receptor (GABABR1) maps close to the HLA-F locus on
      chromosome 6p21.3 in the same region to which a major susceptibility locus for
      common subtypes of idiopathic generalized epilepsy (IGE), designated as EJM1, has
      been localized. Moreover, animal models suggest that the GABAB receptor plays a
      critical role in the epileptogenesis of absence seizures. Accordingly, the
      present association study tested the candidate gene hypothesis that genetic
      variants of the human GABABR1 gene confer susceptibility to common subtypes of
      IGE. Three DNA sequence variants in exons 1a1, 7, and 11 of the GABABR1 gene were
      assessed by PCR-based restriction fragment length polymorphisms in 248 unrelated
      probands of German descent, comprising 72 patients with juvenile myoclonic
      epilepsy (JME), 46 patients with idiopathic absence epilepsy (IAE), and 130
      control subjects without a history of epileptic seizures and lack of generalized
      spike-wave discharges in their electroencephalogram. The results revealed no
      evidence for an allelic association of any of the GABABR1 sequence variants with
      either JME or IAE (P > 0.18). Thus, we failed to demonstrate that any of the
      three exonic GABABR1 variants themselves, or other so-far unidentified mutations,
      which are in strong linkage disequilibrium with the investigated variants, are
      involved in the pathogenesis of common IGE subtypes.

PMID- 10402496
TI  - DNA polymorphism-diet-cofactor-development hypothesis and the gene-teratogen
      model for schizophrenia and other developmental disorders.
AB  - Three problems in identifying genes causing schizophrenia and other developmental
      disorders may be locus heterogeneity, high disease allele frequency, and unknown
      mode of inheritance. The DNA polymorphism-diet-cofactor-development (DDCD)
      hypothesis addresses the first two. The gene-teratogen model addresses the third.
      The DDCD hypothesis is that schizophrenia results in part from brain abnormality
      in utero from the aggregate effect of multiple mutations of small effect of genes
      related to important cofactors (e.g., folate, cobalamin, or pyridoxine)
      potentiated by maternal dietary deficiency of these cofactors and by pregnancy.
      The effect results from insufficiency of the cofactors and from resulting effects
      such as impaired DNA synthesis, immune deficiency, effects on niacin and
      serotonin metabolism, and teratogens, e.g., hyperhomocysteinemia. The hypothesis
      addresses all of the unusual features of schizophrenia: e.g., decreased brain
      gray matter, birth-month effect, geographical differences, socioeconomic
      predilection, association with obstetrical abnormalities, decreased incidence of
      rheumatoid arthritis, and association with famine and viral epidemics. In the
      gene-teratogen model, a teratogenic effect in utero produces a developmental
      disorder through a teratogenic locus and a modifying or specificity locus, as
      well as through environmental factors. An example is the major intrauterine
      effect seen in offspring of phenylketonuric mothers. Thus, the mode of
      inheritance of genes acting prenatally may in some cases be fundamentally
      different from that of genes acting postnatally. The model is interesting because
      it is simple and because teratogenic loci will be difficult to locate by
      conventional linkage mapping techniques due to misspecification of the affection
      status of both mother and affected children. A new study design is suggested for
      identifying teratogenic loci.

PMID- 10402497
TI  - Analysis of GNAZ gene polymorphism in bipolar affective disorder.
AB  - Evidence for a bipolar disorder (BPD) susceptibility locus on chromosome 22q11
      has been provided in several studies. One candidate gene that maps to this region
      is the G-protein alpha subunit gene Galphaz (GNAZ). We have identified a common
      silent polymorphism in GNAZ exon 2 by single strand conformation polymorphism
      analysis. The frequency of this polymorphism was determined in a control
      population (n=84) and in patients with BPD (n=88). The data showed a statistical
      trend toward a difference in the distribution of alleles in patients with BPD
      compared with control subjects (chi square=3.2, 1 df, P=0.073, two-tailed). No
      significant difference was detected when the GNAZ polymorphism was analyzed in
      control subjects and schizophrenia patients (n=63, P=0.92). These data continue
      to provide some support for a BPD susceptibility gene on 22q11, possibly in
      linkage disequilibrium with the GNAZ 309 polymorphism.

PMID- 10402498
TI  - Nightmares: familial aggregation and association with psychiatric disorders in a
      nationwide twin cohort.
AB  - We quantified the genetic influences affecting the liability to nightmares, and
      the association between nightmares and psychiatric disorders in a community-based
      sample. In 1990, 1,298 monozygotic (MZ) and 2,419 dizygotic (DZ) twin pairs aged
      33-60 years responded to a questionnaire study in the Finnish Twin Cohort.
      Structural equation modeling was used to estimate genetic and environmental
      components of variance in the liability to nightmares. Records on hospitalization
      and long-term antipsychotic medication were used to estimate the period
      prevalence of serious psychiatric disorders. Nightmares were reported more
      frequently in females both in childhood and as adults. The correlation between
      occurrence in childhood and as adults was 0.69 in males and 0.71 in females.
      Polychoric correlations of occurrence within the twin pairs were 0. 45 in MZ and
      0.21 in DZ pairs in childhood, and as adults 0.39 and 0. 18, respectively. The
      best fitting genetic model was that specifying additive genetic and unshared
      environmental effects. The estimated proportion of genetic effects in childhood
      was in males 44% (95% confidence interval [CI] 35-52%) and in females 45% (95% CI
      38-52%) of the phenotypic variance. As adults the values were in males 36% (95%
      CI 27-44%) and in females 38% (95% CI 31-45%). Nightmare frequency and
      psychiatric disorders were linearly associated. Among those with the most
      frequent nightmares odds ratios (95% CI) were 3. 67 (2.48-5.42) for childhood and
      5.87 (4.08-8.45) for adults compared with those never having nightmares.
      Nightmares are quite a stable trait from childhood to middle age. There are
      persistent genetic effects on the disposition to nightmares both in childhood and
      adulthood. Nightmares are significantly associated with psychiatric disorders.

PMID- 10402499
TI  - Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q.
AB  - Evidence for suggestive linkage to schizophrenia with chromosome 6q markers was
      previously reported from a two-stage approach. Using nonparametric affected sib
      pairs (ASP) methods, nominal p-values of 0.00018 and 0.00095 were obtained in the
      screening (81 ASPs; 63 independent) and the replication (109 ASPs; 87
      independent) data sets, respectively. Here, we report a follow-up study of this
      50cM 6q region using 12 microsatellite markers to test for linkage to
      schizophrenia. We increased the replication sample size by adding an independent
      sample of 43 multiplex pedigrees (66 ASPs; 54 independent). Pairwise and
      multipoint nonparametric linkage analyses conducted in this third data set showed
      evidence consistent with excess sharing in this 6q region, though the statistical
      level is weaker (p=0.013). When combining both replication data sets (total of
      141 independent ASPs), an overall nominal p-value=0.000014 (LOD=3. 82) was
      obtained. The sibling recurrence risk (lambdas) attributed to this putative 6q
      susceptibility locus is estimated to be 1.92. The linkage region could not be
      narrowed down since LOD score values greater than three were observed within a
      13cM region. The length of this region was only slightly reduced (12cM) when
      using the total sample of independent ASPs (204) obtained from all three data
      sets. This suggests that very large sample sizes may be needed to narrow down
      this region by ASP linkage methods. Study of the etiological candidate genes in
      this region is ongoing.

PMID- 10402500
TI  - Apo E genotypes and risk of dementia in Down syndrome.
AB  - The relationship between apo E genotypes and risk of dementia in Down syndrome is
      not clear. Accordingly, we have analysed this locus in 20 demented and 25
      nondemented individuals with Down syndrome and combined these data with other
      studies in a meta-analysis. The meta-analysis revealed an estimated odds ratio
      for dementia of 2.74 (95% CI 1.34-5.58) (P =.0004) for apo epsilon4 carriers
      compared with apo epsilon3/epsilon3, similar to that observed in late-onset
      Alzheimer's disease. An additional parallel with late-onset Alzheimer's disease
      was shown by the apo epsilon2 allele, which was associated with decreased
      dementia risk in Down syndrome (odds ratio for apo epsilon2/epsilon2 +
      epsilon2/epsilon3 = 0.37 (95% CI 0.14-0. 96)). Thus, apo E genotypes are
      associated with similar risk effects in Down syndrome dementia and late-onset
      Alzheimer's disease.

PMID- 10402501
TI  - Lack of linkage or association between schizophrenia and the polymorphic
      trinucleotide repeat within the KCNN3 gene on chromosome 1q21.
AB  - To determine the importance of a candidate gene KCNN3 (formerly named hSKCa3) in
      the susceptibility to schizophrenia, we have studied the genotypes of a (CAG)n
      polymorphism within this gene in the DNAs of the members of 54 multiplex families
      with this disease. Parametric and nonparametric linkage analysis did not provide
      evidence for linkage between KCNN3 (that we mapped to chromosome 1q21) and
      schizophrenia. Furthermore, we observed no difference in the distribution of the
      (CAG)n alleles between affected and normal individuals. These results do not
      support the hypothesis that larger KCNN3 alleles are preferentially associated
      with schizophrenia [Chandy et al. 1998 Mol Psychiatr 3:32-37] in individuals from
      multiply affected families.

PMID- 10402502
TI  - Trend for an association between schizophrenia and D3S1310, a marker in proximity
      to the dopamine D3 receptor gene.
AB  - There is considerable controversy regarding a putative association between
      schizophrenia and a biallelic BalI polymorphism in the first exon of the dopamine
      D3 receptor gene (DRD3), although meta-analyses of published data suggest an
      association. If such an association exists, it may be detectable at markers
      physically close to DRD3. Accordingly, we conducted a case-control association
      study using D3S1310, a short tandem repeat polymorphism located approximately 700
      kb telomeric to DRD3 on chromosome 3q13.3. The subjects were Swedish patients
      with schizophrenia (DSM III-R criteria, n = 110) and screened adult controls (n =
      83). A trend for a negative association with the 141 bp allele was detected (chi2
      = 7.6, d.f. = 1, P = 0.006; odds ratio 0.46, 95% confidence intervals 0.26,
      0.81). However, following corrections for multiple comparisons using subgroups (n
      = 15) the difference was not significant. Also, due to the risk for population
      stratification in case-control association studies the results must be treated as
      tentative. If replicated the results may lend further support for the proposition
      of an association between schizophrenia and DRD3 or a gene in close proximity to
      DRD3 on chromosome 3q.

PMID- 10402503
TI  - Studies of the 48 bp repeat polymorphism of the DRD4 gene in impulsive,
      compulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling,
      and substance abuse.
AB  - Prior studies have reported an association between the presence of the 7 repeat
      allele of the 48 bp repeat polymorphism of the third cytoplasmic loop of the
      dopamine D4 receptor gene (DRD4) and novelty seeking behaviors, attention deficit
      hyperactivity disorder (ADHD), Tourette syndrome (TS), pathological gambling, and
      substance abuse. However, other studies have failed to replicate some of these
      observations. To determine whether we could replicate these associations we
      genotyped 737 individuals from four different groups of control subjects, and 707
      index subjects from four different groups of impulsive, compulsive addictive
      behaviors including substance abuse, pathological gambling, TS, and ADHD. Chi
      square analysis of those carrying the 7 allele versus non-7 allele carriers was
      not significant for any of the groups using a Bonferroni corrected alpha of.0125.
      However, chi-square analysis of those carrying any 5 to 8 allele versus
      noncarriers was significant for pathological gambling (p <.0001), ADHD (p </=.01)
      and the total index group (p </=.0004). When the comparison included all 7
      alleles the results were significant for gamblers (p <.0001), TS (p </=.003),
      ADHD (p </=.003), and the total group (p </=.0002). There was a significant
      increase in the frequency of heterozygosity versus homozygosity for all alleles
      for pathological gamblers (p </=.0031) and the total index group (p </=.0015),
      suggesting that heterosis played a role. In the substance abuse subjects a
      quantitative summary variable for the severity of drug dependence, based on the
      Addiction Severity Index, showed that the scores varied by increasing severity
      across the following genotypes: 44 </= heterozygotes </= 77 </= 22. Studies of
      other quantitative traits indicated an important role for the 2 allele and the
      22, 24, and 27 genotypes. All studies indicated that the role of the DRD4 gene in
      impulsive, compulsive, addictive behaviors is more complex than a sole focus on
      the 7 versus non-7 alleles.

PMID- 10402504
TI  - Linkage analysis of a large Swedish kindred provides further support for a
      susceptibility locus for schizophrenia on chromosome 6p23.
AB  - Several reports have indicated genetic linkage between markers on the short arm
      of chromosome 6 and schizophrenia. However, significant threshold levels were not
      always achieved, and the chromosomal regions identified are large and different
      in different families. One way to decrease the problem of heterogeneity is to
      study a single extended pedigree. Here we report the analysis of a very large,
      previously undescribed pedigree from northern Sweden that includes 31 affected
      individuals. We typed 16 markers spanning 40 cM on the short arm of chromosome 6.
      Linkage analysis was performed only with the affected individuals. Suggestive lod
      scores (maximum 2.6) were obtained with markers on chromosome 6p23 in a single
      branch of the large pedigree indicating possible heterogeneity inside the family.
      A haplotype comprising markers from D6S309 to D6S1578 was found to segregate with
      the disease. This chromosomal region is included within a segment proposed to
      contain a susceptibility gene for schizophrenia by many other investigators. Our
      results thus give further support for a possible localization of a susceptibility
      locus for schizophrenia in 6p23 and help to narrow the candidate chromosomal
      region to the segment included between markers D6S309 and D6S1578.

PMID- 10402505
TI  - Genetic epidemiological study of maternal and paternal transmission of
      Alzheimer's disease.
AB  - Recent evidence for mitochondrial mutations associated with Alzheimers disease
      (AD) suggests the possibility of maternal transmission of this illness. We
      investigated this hypothesis by examining, in a variety of ways, the risk of a
      primary progressive dementia (PPD) in the parents (n = 650) and siblings (n =
      1,220) of 325 AD probands. The results did not support maternal transmission in
      AD: The mothers of AD probands were not at greater risk of PPD than the fathers
      or the sisters of AD probands; the offspring of affected mothers were not at
      greater risk than the offspring of affected fathers or families with no affected
      parent; and, after selecting those proband families with evidence for increased
      familial loading, such families did not more frequently have affected mothers
      than fathers. In contrast, the cumulative risk of PPD in fathers of AD probands,
      while similar to that of mothers, was significantly increased over the brothers
      of AD probands. In addition, the cumulative risk curve of PPD in the offspring of
      affected fathers was significantly higher than the offspring of no affected
      parents. While no evidence for maternal transmission in AD was observed,
      unexpectedly, we did find evidence of increased paternal transmission.

PMID- 10402507
TI  - Interrelationship of genetic and environmental influences on conduct disorder and
      alcohol and marijuana dependence symptoms.
AB  - Data from the Vietnam Era Twin (VET) Registry were analyzed to explore the degree
      to which the same genetic and environmental factors contribute to childhood
      conduct disorder symptoms and to alcohol and marijuana dependence symptoms. Data
      on conduct disorder and alcohol and marijuana dependence were obtained from
      administration of the Diagnostic Interview Schedule to 1,856 monozygotic and
      1,479 dizygotic male-male twin pair members of the VET Registry. Multivariate
      genetic models were compared to determine the genetic and environmental
      influences common and or specific to all three phenotypes. A full model that
      allowed for common genetic and environmental influences to all three phenotypes
      gave a good fit to the data, but the best fitting reduced model did not allow for
      a genetic influence on conduct disorder symptoms. Under the best fitting reduced
      model, genes explained 44.7% of the variance in risk for alcohol dependence
      symptoms. The genetic liability for symptoms of marijuana dependence was due to a
      36.3% specific contribution and a 7.6% contribution from genes common with
      alcohol dependence symptoms. Family environmental contributions common to all
      three phenotypes explained 46.7%, 11.9%, and 21.3% of variance in risk for
      symptoms of conduct disorder, alcohol dependence, and marijuana dependence,
      respectively. Common family environmental factors contribute to risk of conduct
      disorder symptoms and alcohol and marijuana dependence symptoms. Common genetic
      influences contribute to risk of symptoms of alcohol dependence and marijuana
      dependence. While our findings suggest genes do not contribute to co-morbid
      conduct disorder symptoms, comparisons with other twin studies suggest that the
      role of genes in risk for conduct disorder remains uncertain.

PMID- 10402506
TI  - Heritability of event-related brain potentials in families with a history of
      alcoholism.
AB  - Event-related brain potentials (ERPs) are altered in patients with a variety of
      psychiatric disorders and may represent quantitative correlates of disease
      liability that are more amenable to genetic analysis than disease status itself.
      Estimates of heritability are presented for amplitude and latency of the N1 and
      P3 components of the ERP measured at 19 scalp locations in response to visual and
      auditory stimuli for 604 individuals in 100 pedigrees ascertained as part of the
      Collaborative Study on the Genetics of Alcoholism. Significant heritabilities
      were found for visual P3 amplitude in response to all stimuli and for visual P3
      latency in response to target and novel, but not non-target, stimuli.
      Heritability of visual N1 latencies was uniformly low, whereas heritability of
      visual N1 amplitude was significant for all electrodes in response to the non
      target stimuli but only for posterior electrodes in the other two stimulus
      conditions. Heritabilities for auditory target P3 were similar to those of the
      visual stimuli, with auditory target P3 amplitudes and latencies both
      demonstrating significant heritability. For auditory P2 in response to non-target
      stimuli, peak amplitude was heritable, but latency was not. Auditory N1 amplitude
      and latency were significantly heritable for both target and non-target
      conditions and did not demonstrate the anterior/posterior patterning obtained for
      visual N1 amplitude. This study represents the first systematic assessment of
      heritability of these potential neurophysiological markers in families with a
      history of alcoholism and suggests that many of these ERP phenotypes have
      heritabilities strong enough to justify genomic screening for loci jointly
      influencing ERP abnormalities and liability to alcoholism.

PMID- 10402508
TI  - Analysis of the monoamine oxidase A (MAOA) gene in bipolar affective disorder by
      association studies, meta-analyses, and sequencing of the promoter.
AB  - Monoamine oxidases catalyse the oxidative degradation of biogenic amines
      including neurotransmitters such as noradrenaline, dopamine, and 5
      hydroxytryptamine (5-HT). Three groups have reported positive associations of the
      monoamine oxidase A (MAOA) gene with bipolar affective disorder although other
      studies have been negative. In an extension of a previous study [Rubinsztein et
      al., 1996: Human Molec Genet 5:779-782] we report association studies of MAOA
      polymorphic markers and affective disorders. The polymorphisms comprised a CA
      repeat microsatellite in intron 2 and a Fnu4HI G/T silent polymorphism at
      position 941 of the cDNA sequence. No significant differences were found when the
      control allele frequencies were compared with those in bipolar, unipolar, or
      combined bipolar + unipolar groups. Meta-analyses were then performed to include
      the data of all published studies using the MAOA microsatellite and Fnu4HI
      polymorphisms. Separate meta-analyses were performed for Caucasian and Japanese
      studies, as allele frequencies of the microsatellite in these populations were
      markedly different. Associations of bipolar affective disorder in pooled male and
      female groups were found with the MAOA microsatellite in both the Caucasian (P <
      0.02) and the Japanese (P < 0.02) meta-analyses. In view of these positive
      associations, and as previous results have shown that coding variants do not
      account for the normal population variation in MAOA activity, over 1,300 bp of
      the promoter were sequenced in 22 bipolar cases and 1 control. A novel
      polymorphic promoter variable number of tandem repeats (VNTR) located
      approximately 1,200 bp upstream from the translation start site was demonstrated.
      However, there was no association of this promoter VNTR with affective disorder.
      These results suggest that there may be functional variants in other regions of
      the MAOA gene or neighbouring genes that affect bipolar affective disorder risk.

PMID- 10402509
TI  - -141 C del/ins polymorphism of the dopamine receptor 2 gene is associated with
      schizophrenia in a British population.
AB  - Dopamine has long been hypothesised to be involved in the pathogenesis of
      schizophrenia. The dopamine D2 receptor is a major site of action of neuroleptic
      agents used in the treatment of schizophrenia. Arinami et al. [1997; Human Mol
      Genet 6:577-582] have recently sequenced the dopamine receptor 2 (DRD2) gene in
      Japanese individuals and identified a novel polymorphism: a single cytosine
      deletion at position -141 disrupting a BstN1 restriction site with a frequency of
      0.22 in their control group. They then found a strong association with this
      polymorphism and schizophrenia (p < 0.001) with an odds ratio of 0.60 in a
      Japanese population. We have attempted to verify their results by repeating the
      RFLP analysis on a sample of Scottish schizophrenics and controls. We then
      combined our data with those from another British sample recruited using similar
      procedures. The total combined sample size was 439 schizophrenics and 437
      controls. We obtained a significant association--p = 0.02 with an odds ratio of
      1.41. Schizophrenia is associated with the C insertion in the Japanese, but that
      association is reversed in Caucasians. Linkage disequilibrium with a causative
      polymorphism nearby is the most likely explanation for this reverse association.

PMID- 10402510
TI  - Lithium responsive bipolar disorder, unilineality, and chromosome 18: A linkage
      study.
AB  - Over the last three years several studies have investigated the hypothesis of
      linkage between bipolar disorder and markers on chromosome 18. Although
      independent groups have reported positive results, it is still not clear how
      these should be interpreted, as linkage spans a considerably large segment of the
      chromosome. In this study we have investigated linkage with chromosome 18 markers
      in 19 families of lithium-responsive bipolar patients, as a way to select a more
      homogeneous population. In addition, we have investigated whether there is
      evidence of a parent-of-origin effect as suggested by previous studies. Eleven
      markers spanning the whole chromosome were typed and linkage analysis was carried
      out using parametric and nonparametric methods. Analysis of the whole sample
      provided nonsignificant linkage results. However, when the sample included only
      unilineal families, and was further stratified according to parental origin, two
      chromosomal regions provided modestly positive lod scores. Maximum lod scores of
      1.04 (P = 0.001) at D18S53 and 0.87 (P = 0.045) at D18S61 were observed for
      maternal and paternal pedigrees, respectively. Nonparametric analysis yielded
      similar results. In conclusion, our results are congruent with previous reports
      that suggest an advantage of unilineal pedigrees in linkage analysis of bipolar
      disorder and cannot rule out a parent-of-origin effect in this genomic region.

PMID- 10402511
TI  - HLA and schizophrenia: refutation of reported associations with A9 (A23/A24),
      DR4, and DQbeta1*0602.
AB  - The aim of this study was to test previous hypotheses of association between
      schizophrenia and human leukocyte antigen (HLA) specificities A9 (A23/24), DR4,
      and allele DQbeta1*0602. Using sequence-specific oligonucleotide probes, 256
      familial schizophrenic patients and 261 unrelated controls were genotyped at
      polymorphisms for HLA-A, DRbeta1, and DQbeta1 loci. No significant (p < 0.05)
      differences in the allele frequencies between schizophrenics and controls were
      found, either when examining the sample as a whole or when subdivided by clinical
      subtype or gender. The present data do not support association between these HLA
      specificities and schizophrenia, and our review of previous studies suggests that
      reported associations may well be false positive results.

PMID- 10402512
TI  - Schizophrenia and HLA: No association with PCR-SSOP typed classical loci in a
      large Irish familial sample.
AB  - Susceptibility to autoimmunity is strongly influence by genes clustered in the
      MHC region, particularly class I and class II antigens. It has been proposed that
      there is an immune component in the aetiology of schizophrenia, and the
      distribution of human leukocyte antigens (HLA) in schizophrenic patients and
      controls has been investigated in numerous studies. Positive associations have
      been reported between schizophrenia and the HLA-A1, A2, A9, B5, Cw4, and DR8 and
      negative associations with HLA-DR4 and HLA-DQbeta*0602. Small sample size,
      variable diagnostic methodology, unreliable laboratory and statistical
      procedures, and possible mismatching of cases and controls may have contributed
      to a lack of consistency of results to date. Therefore, in this investigation we
      used a large and carefully diagnosed homogeneous Irish familial schizophrenic
      sample compared with ethnically matched controls. All alleles were determined
      using polymerase chain reaction amplification followed by short specific
      oligoprobes. We found no evidence of association with 80 HLA alleles (some
      previously not examined) from 4 genes. Our data therefore do not support the
      involvement of these classical HLA loci in the aetiology of schizophrenia at
      least in these Irish families. The remaining classical HLA loci (HLA-B and HLA-C)
      should be typed when reliable DNA-based methods become available.

PMID- 10402513
TI  - No association between serotonin transporter gene polymorphisms and personality
      traits.
AB  - Human family and twin studies have established considerable heritable components
      in personality traits as assessed by self-report questionnaires. Recently, an
      association between a functional polymorphism in the upstream regulatory region
      of the serotonin transporter gene and neuroticism-related personality traits was
      reported. Two different serotonin transporter polymorphisms including the
      previously associated variant were genotyped in two samples of healthy Swedish
      subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales
      of Personality (KSP) inventory. No statistically significant association between
      serotonin transporter polymorphisms and any of the eight neuroticism-related KSP
      scales was found. Thus, the previously reported association between serotonin
      transporter alleles and neuroticism-related personality traits could not be
      replicated in the present study.

PMID- 10402514
TI  - Genome scan for linkage to Gilles de la Tourette syndrome.
AB  - Gilles de la Tourette Syndrome (TS) is a neuropsychiatric disorder characterized
      by both motor and vocal tics. Despite clear evidence for a genetic predisposition
      to TS from family, twin, and adoption studies, there have been no confirmed
      linkage findings. In this article we test for linkage to TS in multigenerational
      families segregating TS using a panel of 386 markers with the largest interval
      between any two markers being 28 cM and an average distance between markers of 10
      cM. We tested for linkage using an autosomal dominant model with reduced
      penetrance and using nonparametric methods. No significant evidence for linkage
      was found with parametric analysis. A logarithm of the odds (LOD) score of
      greater or equal to one under the autosomal dominant model was observed in 24 of
      these markers in at least one of the families tested. No LOD scores greater than
      two were observed with any of the markers. For the nonparametric analysis, eight
      markers were observed with a P-value less than 0.00005 for significance evidence
      of linkage in at least one family. However caution should be used in the
      interpretation of the nonparametric analyses as this statistic (the affected
      pedigree-member method) is know to have a high false-positive rate. Further
      support for linkage in these regions is required before linkage can be assumed.

PMID- 10402515
TI  - Association between a functional polymorphism at the DRD2 gene and the liability
      to substance abuse.

PMID- 10402516
TI  - The vex and fuss about nasal vestibule cancer.

PMID- 10402517
TI  - Squamous cell carcinoma of the nasal vestibule.
AB  - BACKGROUND AND METHODS: Sixty patients were treated with radiation therapy alone
      (56 patients) or followed by surgery (4 patients) between 1970 and 1995 for
      squamous cell carcinoma of the nasal vestibule. RESULTS: Local control rates at
      five years after irradiation alone in 56 patients were: T1-T2, 94%; T4, 71%; and
      overall, 85%. Multivariate analysis revealed that tumor size and bone invasion
      significantly influenced local control. All four patients with extensive T4
      tumors treated with radiation therapy plus surgery were cured. Cause-specific
      survival rates at five years for 56 patients treated with radiation therapy alone
      were: T1-T2, 94%; T4, 86%; and overall, 91%. Multivariate analysis revealed that
      bone invasion and tumor size adversely influenced cause-specific survival. No
      patient treated with irradiation alone experienced a major complication, compared
      with three of four patients who underwent irradiation and surgery. CONCLUSIONS:
      Radiation therapy results in a high cure rate with good cosmesis. Patients with
      extensive T4 cancers have an improved chance of cure with radiation and surgery
      but more complications.

PMID- 10402518
TI  - The University of Washington head and neck cancer measure as a predictor of
      outcome following primary surgery for oral cancer.
AB  - BACKGROUND: The purpose of this study was to investigate the disease specific
      functional status of patients with oral cancer treated by primary surgery. The
      University of Washington head and neck cancer questionnaire (UW-QOL) was used,
      and outcome was compared against patient's age, sex, T category, site, surgical
      procedure, and adjuvant radiotherapy. METHODS: In the year 1995, consecutive
      patients with previously untreated squamous cell carcinoma of the oral region
      were recruited. Questionnaires were given at four time intervals: preoperatively
      and at 3, 6, and 12 months. RESULTS: Fifty patients underwent primary surgery for
      oral cancer between 4 January and 12 December 1995. Of 48 patients recruited, 41
      (85%) had microvascular free tissue reconstruction. Patients with T category 3 or
      4 tumors tended to report more severe problems than did patients with T category
      1 or 2 tumors; this was especially true for increased pain (p <.001). There was a
      marked fall in cumulative UW-QOL scores by 3 months, with some recovery to 12
      months. Of the initial 48 patients, 29 (60%) were alive and disease free at 1
      year, and there were 25 completed questionnaires. The trend at 1 year was for
      better scores in women, T category 1 and 2, anterior oral cavity, primary
      closure/laser treatments, and patients not requiring adjuvant radiotherapy.
      CONCLUSIONS: Patients undergoing surgery for oral cancer have a profound fall in
      quality of life scores by 3 months, and their scores approach pretreatment levels
      by 12 months. Clinical parameters are useful in predicting trends in UW-QOL
      outcome at 1 year and are also associated with differences in individual domain
      scores.

PMID- 10402519
TI  - The role of skull base surgery for the treatment of adenoid cystic carcinoma of
      the sinonasal tract.
AB  - BACKGROUND: Adenoid cystic carcinoma (ACC) of the sinonasal tract is an
      aggressive malignancy associated with a poor 5-year survival rate. The role of
      skull base surgery for the treatment of patients presenting with sinonasal ACC
      and its impact upon their survival has not previously been evaluated. METHODS: A
      retrospective review of 35 patients with ACC of the sinonasal tract who were
      treated with surgery and radiation therapy at the University of Pittsburgh
      Medical Center was performed to evaluate patient outcome. RESULTS: Local
      recurrence of tumor following surgery and radiation therapy was observed in 36%
      of the patients originally treated at the University of Pittsburgh Medical
      Center. Fourteen percent of these patients developed a regional tumor recurrence,
      and 21% developed distant metastases. We did not identify any tumor-related
      factors that predicted patient outcome. Local recurrences were treated with
      salvage surgical excision, and, despite aggressive management, only 1 of 17
      patients with local recurrence was considered cured (NED) at 24 months (follow-up
      after salvage surgery). Overall, disease-free survival was 46.4%, at a median
      follow-up of 40 months. CONCLUSIONS: ACC of the sinonasal tract is an aggressive
      malignancy. Skull base surgery has facilitated the gross total excision of
      advanced lesions that were deemed inoperable in the past, but has not resulted in
      an overall improvement in disease-free survival. Local recurrence portends a very
      poor prognosis, despite aggressive salvage regimens. Alternative therapies for
      local recurrences warrant further investigation. Prospective, randomized studies
      are necessary to evaluate the outcome of patients treated with aggressive
      multimodal treatment regimens, including chemotherapeutic regimens.

PMID- 10402520
TI  - Pattern of invasion and margin assessment in patients with oral tongue cancer.
AB  - BACKGROUND: Involvement of resection margins and the pattern of tumor invasion
      are reported to be important predictors of local recurrence and survival in
      surgically treated patients. In this study we have retrospectively assessed the
      significance of these two prognostic factors in a relatively homogeneous patient
      population. Patients and Methods This study was confined to 150 previously
      untreated patients who had surgery for squamous carcinoma of the oral tongue
      between 1987 and 1993. There were 82 men and 68 women who ranged in age from 25
      to 89 years (median 60 years). Glossectomy was peroral in 129, whereas 8 and 13,
      respectively, had a cheek flap or mandibulotomy approach. Some form of
      lymphadenectomy was performed in 109 (73%), and 51 patients (34%) received
      postoperative radiotherapy. Histologic slides from each primary tumor were
      reviewed to verify the margin status. In addition, the pattern of invasion was
      evaluated and graded from 1 to 4, varying from a consistently well-defined,
      "pushing" border (Grade 1) to diffuse infiltration and cellular dissociation
      (Grade 4). RESULTS: Intraoperative frozen section assessment of margins was
      accurate, whether positive or negative, in 118 of 133 patients (89%). Positive or
      close margins (within one high-power field) and an endophytic growth pattern were
      associated with a significant increase in local recurrence (p <0.003 and <0.04,
      respectively). With higher grades of infiltration (Grade 3 or 4; 82 patients),
      the tumors tended to be larger and the patients younger. Although the likelihood
      of nodal involvement and subsequent distant metastasis was significantly greater
      in those with Grade 3 or grade 4 patterns (p <0.0003 and <0. 01, respectively),
      there was no impact on local recurrence. Cumulative survival was similar whether
      or not the surgical margins were involved, but was significantly reduced when the
      pattern of tumor invasion was of higher grade (p <0.01). SUMMARY: Frozen section
      provided reasonably accurate information about margins in our patients, whether
      taken from the patient or the surgical specimen. Positive margins increased the
      likelihood of local recurrence, but did not impact on survival because subsequent
      surgery and/or irradiation controlled tumor recurrence in some patients. Grade 3
      or 4 patterns at the tumor/host interface were associated with an increased
      incidence of nodal and distant metastasis, as well as a significant decrease in
      survival.

PMID- 10402521
TI  - Proliferating cell nuclear antigen and c-erbB-2 oncoprotein expression in adenoid
      cystic carcinomas of the salivary glands.
AB  - BACKGROUND: Adenoid cystic carcinoma (ACC) of the salivary gland shows a variable
      clinical course. It would be helpful to discover reliable biologic markers in the
      management of patients with ACC. METHODS: We examined proliferating cell nuclear
      antigen (PCNA) and c-erbB-2 oncoprotein expression on 30 cases of ACC of the
      salivary glands. The immunohistochemical results, and size, location, and
      histologic grade of the tumors were compared with the clinical outcome of the
      patients. RESULTS: Mean PCNA positivity of ACCs was 15%, and was higher in solid
      than in cribriform/tubular areas. High PCNA value was significantly correlated
      with shorter disease-free and overall survival of the patients with ACC. c-erbB-2
      overexpression was observed in only five cases, focally in cribriform/tubular
      areas. High histologic grade, which was determined by the presence of solid
      components, showed a trend toward shorter survival. Size and location of ACC were
      not associated with patient outcome. CONCLUSIONS: The present study indicates
      that PCNA score may be one of the most useful prognostic factor of ACC.

PMID- 10402522
TI  - Smoking withdrawal and relapse in head and neck cancer patients.
AB  - BACKGROUND: Smoking withdrawal and relapse were characterized among newly
      diagnosed head and neck cancer patients participating in a physician-delivered
      smoking cessation intervention. METHODS: Patients completed questionnaires at
      baseline, 1, 6, and 12 months following intervention delivery. RESULTS:
      Significant baseline predictors of smoking relapse included medical treatment
      (XRT versus surgical treatment), stage of change/readiness to quit
      (precontemplators), age of initiation (younger), and greater addiction (smoking
      </=30 minutes after waking). Relapsers were significantly more likely to quit
      using gradual reduction versus cold turkey and had less confidence in remaining
      quit. Relapsers experienced significantly higher levels of anxiety and craving
      during withdrawal. Relapse was temporally delayed compared with healthy
      populations. CONCLUSION: Assistance with cessation efforts should be ongoing for
      one year and should include nicotine replacement therapy and psychotropic
      medications to address significant relapse triggers.

PMID- 10402523
TI  - Platysma muscle-cervical fascia-sternocleidomastoid muscle (PCS) flap for
      parotidectomy.
AB  - BACKGROUND: Parotidectomy is useful in the treatment of benign and malignant
      neoplasms of the parotid gland, but often leads to sequelae of facial deformity
      and Frey's syndrome. This paper presents a retrospective review of parotidectomy
      results in 21 consecutive patients treated with either traditional techniques or
      with the rotation and advancement of combined platysma muscle-cervical fascia
      sternocleidomastoid flap (PCS). METHODS: The surgical procedures utilized for
      removal and reconstruction are described. Information on appearance and function
      was obtained by analysis of hospital and office records and telephone
      questionnaire for patients with and without the flap. RESULTS: Of the 21 patients
      eligible for this study, only 9 of 10 patients with the PCS flap and 10 of 11
      patients without the flap provided sufficient data for analysis. In the flap
      group all 9 patients either noted a mild fullness on the operated side or no
      difference between sides. In the nonflap group, 4 patients felt they had a
      moderate depression, 2 patients noted a mild depression, and 4 patients noted no
      difference between sides. Frey's syndrome was classified as mild in 2 patients in
      the PCS group, whereas in the nonflap group, 4 patients thought it was mild and
      1, severe. Complications were rare in either group. CONCLUSION: The PCS flap
      prevents deformity and contributes to patient satisfaction following
      parotidectomy. The flap helps to prevent Frey's syndrome and is not associated
      with an increase in postoperative complications. The flap is recommended
      following removal of nonrecurrent or low-grade malignant parotid tumors.

PMID- 10402524
TI  - The importance of in situ light dosimetry for photodynamic therapy of oral cavity
      tumors.
AB  - BACKGROUND: Photodynamic therapy (PDT) is being evaluated for treatment of
      localized head and neck cancer. "Light dose" is usually prescribed as incident
      fluence, which takes no account of reflected and scattered light. This study
      investigates variations in total tissue fluence for a given incident fluence in
      the oral cavity. METHODS: Light dosimetry was performed in 19 patients treated
      with PDT for cancers in the oral cavity and in 5 volunteers. Illumination was
      with 652 nm laser light delivered via a microlens. In situ dosimetry was
      performed with isotropic probes held against the tissue in the illuminated area.
      RESULTS: Tissue fluences of 254% to 305% of the incident fluence were measured in
      the illuminated area in healthy volunteers. In the patient population tissue
      fluences were 133% to 545% of the incident fluence. CONCLUSION: The relationship
      between incident and total tissue fluence depended on the location and
      pigmentation of the target area and was not predictable. In situ dosimetry during
      cavity illumination allows for more controlled tissue illumination and should be
      employed as the basis for light dose prescription in PDT for head and neck
      cancer.

PMID- 10402525
TI  - Parathyroid biopsy to facilitate the preservation of functional parathyroid
      tissue during thyroidectomy.
AB  - BACKGROUND: The preservation of viable parathyroid tissue, either by preserving
      parathyroid glands in situ with an intact blood supply or by autotransplantation,
      is an integral element of thyroid surgery. There is a general impression that
      nonviable parathyroid glands can be recognized on the basis of black or purple
      black discoloration of the gland. We came to believe that this is not a reliable
      way to assess the viability of parathyroid glands because we observed that when
      we excised parathyroid glands (with the intention of reimplanting them) in
      situations where it was not feasible to preserve their blood supply, they did not
      become discolored. METHODS: To assess the status of the parathyroid blood supply,
      we performed incisional biopsies of suspected parathyroid glands during 14
      consecutive thyroid operations (9 hemithyroidectomies, 1 completion
      thyroidectomy, 4 total thyroidectomies), and observed the biopsy site for
      evidence of active bleeding. RESULTS: Thirty-four of 36 possible parathyroid
      glands were histologically confirmed. Seventeen bled actively from the biopsy
      site and were preserved in situ. The other 17 were felt to be nonviable: 5 were
      severely discolored (black) and either no bleeding or minor venous oozing was
      seen when they were biopsied; 12 with normal coloration (3 were harvested prior
      to biopsy), did not bleed actively following an incisional biopsy. Parathyroid
      glands that were judged to be devascularized were autotransplanted into the
      sternocleidomastoid muscle. CONCLUSIONS: The absence of discoloration is not a
      reliable way to determine whether the parathyroid blood supply is intact. Biopsy
      of the parathyroid glands during thyroid surgery facilitates the identification
      of devascularized parathyroid glands that can be salvaged with
      autotransplantation.

PMID- 10402526
TI  - Cervical lymph node metastases and squamous cell carcinoma of the lip.
AB  - BACKGROUND: Squamous cell carcinoma of the lip generally has a favorable outcome.
      The chance of long-term survival is significantly reduced if lymph node
      metastases develop. Any features that could identify patients having increased
      risks of occult lymph node metastases would allow more aggressive treatment and,
      possibly, a better outcome. METHODS: A chart review of lip cancer from this
      institution identified 1001 patients with squamous cell carcinoma of the lip.
      This database was used to identify the characteristics that are associated with
      occult lymph node metastases. RESULTS: Delayed cervical lymph node metastases
      developed in 40 patients. No significant differences were noted in the frequency
      of delayed lymph node metastases according to gender, lip subsite, or age less
      than 40 years. Significant differences were noted in association with the tumor
      size, tumor differentiation, and local recurrence. CONCLUSIONS: Elective cervical
      lymphadenectomy is justifiable for higher grade tumors and for locally recurrent
      tumors. An increase in delayed metastases was observed in patients with tumors
      greater than 3 cm, but the proportion is not great enough to justify elective
      neck dissections.

PMID- 10402527
TI  - Epstein-Barr virus infection and P53 expression in HIV-related oral large B cell
      lymphoma.
AB  - BACKGROUND: Head and neck non-Hodgkin's lymphomas in HIV positive patients are
      highly related with Epstein-Barr virus (EBV) infection. In general, viral agents
      can alter p53 protein levels by enhancing degradation of cellular p53 or by
      increasing its half-life by viral protein-p53 interaction. Moreover, it has been
      reported that modifications of p53 gene can modulate tumor cells' response to
      radio- and chemotherapy. METHODS: To assess a possible role of EBV infection, p53
      protein deregulation, and p53 gene alterations in exons 5 to 8, we have studied
      six cases of HIV-related primary oral large B-cell lymphoma. We used in situ
      hybridization (ISH) for EBV-DNA and EBV-encoded nuclear RNA-1 (EBER-1),
      immunohistochemistry (IHC) for EBV latent membrane protein -1 (LMP-1) and p53
      proteins expression, and single strand conformational polymorphism (SSCP)
      analysis to screen p53 gene mutations in exons 5 to 8. RESULTS: The EBV-DNA was
      present in all specimens, according to conventional DNA-ISH. No evidence for EBER
      1 was found by ISH. The presence of EBV-DNA was correlated with the LMP-1
      expression in all but one case. Moreover, p53 protein expression was negative in
      three cases and strongly positive in the others. However, mutational analysis of
      p53 gene in exons 5-8 showed no alteration. CONCLUSIONS: Our data may suggest
      that both EBV infection and LMP-1 expression may cause p53 loss of function even
      in the absence of p53 gene mutations, as assessed by SSCP. We speculate that the
      presence of EBV-infection and p53 protein deregulation may be responsible for
      radio- and chemotherapy resistance, by influencing apoptosis of cancer cells.

PMID- 10402528
TI  - Squamous cell carcinoma of temporal bone: reported on 33 patients.
AB  - BACKGROUND: This study assessed the treatment results of a series of 33 patients
      with squamous cell carcinoma (SCC) of the temporal bone and evaluated the
      efficacy of mastoidectomy combined with perioperative radiation therapy protocol.
      METHODS: Thirty-three patients with biopsy-proven SCC invaded to the temporal
      bone were reviewed retrospectively and staged into three subgroups according to
      the University of Pittsburgh TNM Staging System. There were 3 patients with Stage
      I and II disease(tumor confined to auditory canal), 17 patients with Stage III
      (tumor involving the middle ear or mastoid), and 13 patients with Stage IV(more
      extensive disease). Two patients were treated by surgery alone. Eleven patients
      received irradiation only, and the remaining 20 patients underwent combined
      surgery and perioperative radiotherapy. The surgical intervention included sleeve
      resection for patients with Stage I and II lesions and mastoidectomy for all
      patients with Stage III and IV lesions except 1 who had subtotal temporal bone
      resection. The radiation dose delivered was in the range of 3500 approximately 10
      000 cGy, with an average dose of 6560 cGy. RESULTS: The five-year survival rate
      for the whole series was 51.7% by the life-table analysis. After being staged
      into three subgroups (ie, Stage I + II, Stage III, and Stage IV), the estimated
      five-year survival rates were 100%, 68. 8%, and 19.6%, respectively (p = 0.04).
      Radiation alone yielded a 28. 7% five-year survival, while combined surgery and
      irradiation gave a result of 59.6% (p = 0.80). For patients treated with planned
      combined therapy, the actuarial five-year survival rates were 72.7% (8/11) for
      Stage III disease and 12.5% (1/8) for Stage IV disease (p = 0.02). Twelve
      patients who died of disease did so of local recurrence (10 cases), cervical
      metastases (1 case), and liver metastases (1 case), with 70% of succumbing to
      their diseases within two years. Complications include osteonecrosis (n = 1),
      osteitis (n = 3), radiation dermatitis (n = 2), facial nerve palsy (n = 2), and
      delayed healing (n = 2). Data on clinical presentation and treatment modality
      were also analyzed. CONCLUSION: The results of mastoidectomy with removal of all
      gross tumor, combined with planned perioperative irradiation therapy, seems to be
      a useful approach for SCC of the temporal bone. This gives at least as good, and
      possibly better, five-year survival than temporal bone resection. The
      mastoidectomy procedure creates less operative morbidity and mortality. To
      facilitate the development of more effective means of treating advanced disease,
      an accepted staging system and cooperative group investigation is necessary.

PMID- 10402529
TI  - Reactive oxygen metabolites, antioxidants and head and neck cancer.
AB  - This manuscript will review the probable role of reactive oxygen metabolites
      (ROM) in the etiopathogenesis of head and neck cancer (HNC). Cancer is a
      heterogeneous disorder with multiple etiologies including somatic and germ-line
      mutations, cellular homeostatic disturbances, and environmental triggers. Certain
      etiologies are characteristic of HNC and include infectious agents such as the
      Epstein-Barr virus, the use of tobacco, and consumption of alcohol. A large body
      of evidence implicates ROM in tumor formation and promotion. ROM species are
      formed in the process of cellular respiration, specifically during oxidative
      phosphorylation. These ubiquitous molecules are highly toxic in the cellular
      environment. Of the many effects of ROM, especially important are their effect on
      DNA. Specifically, ROM cause a variety of DNA damage, including insertions, point
      mutations, and deletions. Thus, it is hypothesized that ROM may be critically
      involved in the etiology of malignant disease through their possible impact on
      protooncogenes and tumor suppressor genes. Additionally, empirical evidence
      suggests that ROM may also affect the balance between apoptosis and cellular
      proliferation. If apoptotic mechanisms are overwhelmed, uncontrolled cellular
      proliferation may follow, potentially leading to tumor formation. Thus, this
      manuscript will critically review the evidence that supports the role of ROM in
      tumorigenesis. ROM scavengers and blockers have shown both in vivo and in vitro
      effects of attenuating the toxicity of ROM. Such compounds include the
      antioxidant vitamins (A, C, and E), nutrient trace elements (selenium), enzymes
      (superoxide dismutase, glutathione peroxidase, and catalase), hormones
      (melatonin), and a host of natural and synthetic compounds (lazaroids,
      allopurinol, gingko extract). Thus, this paper will also review the possible
      benefit derived from the use of such scavengers/blockers in the prevention of
      HNC.

PMID- 10402530
TI  - Transposition of the lingual thyroid: A new alternative technique.
AB  - BACKGROUND: In symptomatic lingual thyroid, surgical transposition of the gland
      with its vascular supply intact seems to have superior results to those obtained
      by surgical ablation and autotransplantation. However, the procedure should be
      simple, reproducible, reliable, and cause less morbidity as well as providing
      simple access to and evaluation of the gland postoperatively. METHODS: We present
      the case of a 33-year-old female with lingual thyroid who was treated by
      transposing the whole gland to the lateral pharyngeal wall through a lateral
      pharyngotomy incision. The transposed lingual thyroid was nourished by a random
      tongue muscle pedicle flap. RESULT: At the 5-month postoperative stage, iodine
      scanning reviewed the radioactivity uptake of the transposed gland. Even though
      the patient was not on postoperative thyroid hormone supplement, her thyroid
      function gradually returned to normal after initially showing hypothyroid
      postoperatively. CONCLUSION: This new technique for transposition of lingual
      thyroid is simple and reliable and should be considered as an alternative method
      in the management of symptomatic patients.

PMID- 10402531
TI  - A new role for magnetic resonance imaging in the diagnosis of laryngeal relapsing
      polychondritis.
AB  - BACKGROUND: Relapsing polychondritis involving the upper airway is a rare cause
      of airflow obstruction and hoarseness. The diagnosis of relapsing polychondritis
      depends on clinical signs, characteristic findings on cartilage biopsy, and
      response to treatment. Delays in diagnosis and treatment can increase the
      morbidity and mortality of the disease. METHODS: We present a case report of
      primary laryngeal relapsing polychondritis. RESULTS: Serologic testing, direct
      laryngoscopy, and endoscopic biopsy could not establish the diagnosis of
      relapsing polychondritis. Magnetic resonance imaging (MRI) examination
      demonstrated findings consistent with the histopathological diagnosis obtained on
      open biopsy. Follow-up MRI after treatment showed resolution of the initial
      findings. CONCLUSION: This case demonstrates the usefulness of MRI in the
      diagnosis and management of relapsing polychondritis involving the upper airway.

PMID- 10402532
TI  - Cancers of the pyriform sinus: right for the right reason.

PMID- 10402533
TI  - Submitral aneurysm is not a false aneurysm.

PMID- 10402534
TI  - Handling complexity in oxygen delivery in the univentricular circulation.

PMID- 10402535
TI  - Cardiopulmonary interactions after fontan operations 

PMID- 10402537
TI  - The new financial demands of home care management.

PMID- 10402536
TI  - Rn Delegation: the New Jersey Task Force recommendations.
AB  - Because licensure and delegation clauses are determined state by state, all
      statewide home care associations need to begin a dialogue concerning delegation
      and how it impacts the nurse's practice and the way agencies deliver care in the
      community. State organizations need to communicate with each other and share
      concerns and experiences with other state home care organizations. Nursing
      boards, nursing and home health aide associations, advocates for long-term care
      patients, and the older population also need to be involved in the discussion.
      This open dialogue between many different organizations concerning delegation
      will ensure that patients receive safe, quality care that is also cost effective.

PMID- 10402538
TI  - Conflicting incentives: managing a home health agency in 1998.

PMID- 10402539
TI  - My home health agency's worst patient (me).

PMID- 10402540
TI  - Ten tips for the successful managed care call.

PMID- 10402542
TI  - Using storyboards to make your performance improvement plan come alive.
AB  - The key to successfully using storyboarding within the PI plan is to create a
      storyboard for each activity as it is completed. Our agency waited until JCAHO
      was almost upon us. The historical preservation of activities as they occur will
      create an archive of activities for your PI committee and staff as well as for
      surveyors. The storyboard's second purpose is the communication of activities to
      the staff. Take the opportunity to use the boards as educational activities for
      the staff. Performance Improvement can many times be a frightening, or at best
      frustrating and uncomfortable activity for staff personnel. Bringing the PI plan
      alive through the use of storyboards accomplishes many goals as well as helps all
      staff see how Performance Improvement really makes a difference.

PMID- 10402541
TI  - Leadership on the battlefield.

PMID- 10402544
TI  - Personalities at work. Who is out there?

PMID- 10402543
TI  - Considering Title I of the ADA when hiring and interviewing.

PMID- 10402545
TI  - How to survive an ORT or wedge surgery.

PMID- 10402546
TI  - Helping staff become more independent.

PMID- 10402547
TI  - Bridges' model for managing transitions: a framework for assisting home care
      staff through the pre-merger period.

PMID- 10402549
TI  - Implementing standard precautions in home care.

PMID- 10402548
TI  - Creative ways to inform physicians and hospital colleagues about home care.

PMID- 10402550
TI  - Medicare coverage concerns.

PMID- 10402551
TI  - Effectively using your agency's incident reporting system.

PMID- 10402552
TI  - Oasis is coming--OASIS is here!

PMID- 10402553
TI  - Organize the orientee: crossing the threshold into home care.

PMID- 10402554
TI  - Reward + recognition = retention.

PMID- 10402555
TI  - Extrahepatic drug metabolizing enzymes.
AB  - Drug metabolizing enzymes are known to be present and active in most extrahepatic
      tissues. In this review, evidence is presented that expression and activity of
      several extrahepatic drug-metabolizing enzymes are regulated in unique ways,
      which may be associated with tissue functions and activities. In several
      instances evidence is offered that hormonal effects may be regulated through
      tissue specific distribution and/or responses of transcription factors.

PMID- 10402556
TI  - Effect of trichloroethylene on DNA methylation and expression of early
      intermediate protooncogenes in the liver of B6C3F1 mice.
AB  - Trichloroethylene (TCE) is a multimedia environmental pollution that is
      carcinogenic in mouse liver. The ability of TCE to modulate DNA methylation and
      the expression of immediate-early protooncogenes was evaluated. Female B6C3F1
      mice were administered 1000 mg/kg TCE by gavage 5 days/week and killed after 5,
      12, or 33 days of exposure. Methylation of DNA as 5-methylcytosine was decreased
      by 5 days of treatment with TCE and remained reduced for 33 days. TCE also
      decreased the methylation of the promoter regions for the protooncogenes, c-jun
      and c-myc. The expression of the mRNA for the two protooncogenes was increased
      between 60 and 120 minutes after administering the last dose of TCE and returned
      to control level by 24 hours. The expression of the mRNA for c-fos remained
      undetectable after administering TCE. Hence, TCE decreased the methylation both
      of total DNA and the promoters for the c-jun and c-myc genes and increased the
      expression of their mRNA. The decreased methylation and increased expression of
      the two immediate-early protooncogenes might be associated with TCE-induced
      increase in cell proliferation and promotion of tumors.

PMID- 10402557
TI  - Inhibition of DNA adduct formation of 2-amino-1-methyl-6-phenylimidazo[4,5
      b]pyridine and 2-amino-3-methylimidazo[4,5-f]quinoline by dietary indole-3
      carbinol in female rats.
AB  - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3
      methylimidazo[4,5-f]quinoline (IQ) are two important heterocyclic amines formed
      in proteinaceous foods during the cooking process. Both PhIP and IQ are
      carcinogenic in several strains of rats. PhIP induces mammary tumors in female
      F344 rats, while IQ induces principally mammary and liver tumors in female
      Sprague-Dawley rats. Both PhIP and IQ are activated enzymatically, first by N
      hydroxylation, catalyzed by CYP1A1 and CYP1A2, and subsequently by esterification
      (O-acetylation or sulfation), to yield DNA adducts. Such DNA adduct formation,
      and persistence of adducts, is related to initiation of carcinogenesis, while
      inhibition of this process leads to prevention of carcinogenesis. Indole-3
      carbinol (I3C), a constituent of cruciferous vegetables, has chemopreventive
      properties in various systems; it probably acts by induction of detoxification
      enzymes. We have examined the effect of dietary I3C on DNA adduct formation by
      PhIP in female F344 rats and on that by IQ in female Sprague-Dawley rats. In
      experiment 1, F344 rats were maintained on AIN-76A diet containing 0.1% (w/w) I3C
      and then given p.o. doses (10 or 50 mg/kg) of PhIP. These doses are known to
      induce CYP1A1 and CYP1A2. Groups of animals (4/time point) were euthanized 1, 2,
      6, and 16 days later, and their blood (for isolation of white blood cells),
      mammary glands, liver, stomach, small intestine, cecum, colon, heart, lungs,
      kidneys, and spleen were removed for DNA isolation and quantitation of PhIP-DNA
      adducts by 32P-postlabeling. PhIP-DNA adduct formation was inhibited (40-100%) by
      I3C in virtually all organs, including the mammary gland (the target organ), at
      both doses of PhIP, and at almost all time points. In a second experiment,
      Sprague-Dawley rats were fed either control AIN-76A diet or this diet containing
      0.02% I3C or 0.1% I3C for a total of 42 days. IQ was added to the diets (0.01%,
      w/w) from day 15 to day 42, after which all rats received diet free of IQ and
      I3C. Groups of animals (4/time point) were killed on days 43 and 57. In addition
      to the organs removed in experiment 1, the pancreas, uterus, and ovaries were
      also removed, and IQ-DNA adducts were quantitated by 32P-postlabeling. Both
      dietary concentrations of I3C inhibited IQ-DNA adduct formation in most organs
      (except in lungs, kidneys, and pancreas) on both days 43 and 57; in liver,
      stomach, mammary gland, and spleen, inhibition was evident only on day 43.
      Inhibitions ranged from 22.6 to 86.6% with the 0.02% I3C diet and from 32.2 to
      89.6% with the 0.1% I3C diet. I3C diets did not affect rate of adduct removal in
      either experiment. It is concluded that dietary I3C inhibits PhIP- and IQ-DNA
      adduct formation in both target and nontarget organs of female rats, even with
      high doses of PhIP when CYP1A1 and CYP1A2, the enzymes responsible for the
      initial activation (N-hydroxylation) of PhIP, are expected to be induced.

PMID- 10402559
TI  - Cyanide interaction with redox modulatory sites enhances NMDA receptor responses.
AB  - Activation of NMDA receptors plays an important role in cyanide neurotoxicity.
      Cyanide indirectly activates the receptor by inducing neuronal release of
      glutamate and also enhances receptor-mediated responses by a direct interaction
      with the receptor complex. This study investigated the mechanism in cerebellar
      granule cells by which cyanide enhances NMDA-induced Ca2+ influx. Cyanide (50
      microM) increased the influx of Ca2+ over the NMDA concentration range of 0.5-500
      microM. Experiments showed that cyanide does not interact with the receptor's
      glycine or PKC mediated phosphorylation regulatory sites. N-ethylmaleimide, a
      thiol alkylating agent which inactivates the redox regulatory sites of the
      receptor, blocked the enhancing effect of cyanide. Pretreatment of cells with 5,5
      dithio-bis-2-nitrobenzoic acid (DTNB), a compound that oxidizes the receptor
      redox sites, had no effect on the response to cyanide. On the other hand, the
      nonpermeant reducing agents, dithiothreitol or cysteine, further increased the
      cyanide effect. These observations can be explained by cyanide interacting with
      redox sensitive disulfide groups that are not accessible to the non-permeant
      reducing agents. It is proposed that cyanide interacts with a redox site(s)
      located either on the intracellular receptor domain or in the transmembrane
      hydrophobic domain. Furthermore the enhancement by cyanide of the excitotoxic
      actions of NMDA involves receptor sites that are sensitive to oxidation/reduction
      and this interaction contributes to the neurotoxic action of cyanide.

PMID- 10402558
TI  - Constitutive expression and induction of CYP1B1 mRNA in the mouse.
AB  - Previous studies appeared to indicate that CYP1B1 was not constitutively
      expressed in mouse liver. In our laboratory, we demonstrated using aromatic
      hydrocarbon-responsive receptor knock-out (AHR-(-)/-) mice that both piperonyl
      butoxide (PBO) and acenaphtyhlene (ACN) are AHR-independent inducers of murine
      CYP1A2 and CYP1B1 mRNA. In the current study, we demonstrate both constitutive
      levels and induction of CYP1B1 in mouse liver. The induction of CYP1B1 mRNA by
      PBO or ACN was higher in DBA/2 (Ahrd) than in C57BL/6 (Ahrb-1) mice, while 3
      methylcholanthrene induced CYP1B1 more in C57BL/6 than in DBA/2 mice. These
      results suggest that CYP1B1 may also be induced by more than one mechanism. In
      addition, constitutive expression of CYP1B1 was detected in liver, kidney, and
      lung of untreated C57BL/6 mice. There was no gender difference in CYP1B1
      expression; however, in C57BL/6 mice, the kidney contained less CYP1B1 than
      either liver or lung.

PMID- 10402560
TI  - Detoxication of paraoxon by rat liver homogenate and serum carboxylesterases and
      A-esterases.
AB  - Paraoxon, the active metabolite of parathion, can be detoxified through a
      noncatalytic pathway by carboxylesterases and a catalytic pathway by calcium
      dependent A-esterases, producing p-nitrophenol as a common metabolite. The
      detoxication patterns of carboxylesterases and A-esterases were investigated in
      vitro in the present study with a high tissue concentration (75 mg/mL rat liver
      homogenate or 50% rat serum solution) to more closely reflect enzyme
      concentrations in intact tissues. A final paraoxon concentration of 3.75 microM
      was used to incubate with liver homogenates or serum solutions for 5 seconds or
      3, 5, 15, or 25 minutes; also 0.625, 1.25, 2.5, 3.125, 3.75, or 5.0 microM
      paraoxon (final concentration) was incubated with liver homogenates or serum
      solutions for 15 minutes. Phenyl saligenin cyclic phosphate and EDTA were used to
      inhibit carboxylesterases and A-esterases, respectively. Significant amounts of p
      nitrophenol were generated with or without either inhibitor during a 15 minute
      incubation with paraoxon from low (0.625 microM) to high (5.0 microM)
      concentrations. The amount of p-nitrophenol generated via carboxylesterase
      phosphorylation was greater than via A-esterase-mediated hydrolysis in the
      initial period of incubation or when incubating with a low concentration of
      paraoxon. Plateau shape curves of p-nitrophenol concentration versus time or
      paraoxon concentration indicated that carboxylesterase phosphorylation was
      saturable. When incubated for long time intervals or with high concentrations of
      paraoxon, more p-nitrophenol was generated via A-esterase-mediated hydrolysis
      than from carboxylesterase phosphorylation. The ratio of paraoxon concentration
      to tissue amount used in in vitro assays of this study was equivalent to dosing a
      rat with toxicologically relevant dosages. These in vitro data suggest that both
      carboxylesterases and A-esterases detoxify paraoxon in vivo; carboxylesterases
      may be an important mode of paraoxon detoxication in initial exposures to
      paraoxon or parathion before they become saturated, whereas A-esterases may
      contribute to paraoxon detoxication in repeated exposures to paraoxon or
      parathion because they will not become inhibited and will remain catalytically
      active unlike the carboxylesterases. The importance of carboxylesterases in
      detoxication of paraoxon was verified by an in vivo study. In rats pretreated
      with tri-o-tolyl phosphate, an in vivo carboxylesterase inhibitor, brain
      acetylcholinesterase was significantly inhibited after intravenous exposure to
      parathion. No significant inhibition of brain acetylcholinesterase was observed
      in rats pretreated with corn oil.

PMID- 10402562
TI  - Microsomal deacetylation of ring-hydroxylated 2-(acetylamino)fluorene isomers:
      effect of ring position and molecular mechanics considerations.
AB  - Metabolism of arylamides such as 2-(acetylamino)fluorene to mutagenic products is
      catalyzed by various liver microsomal and cytosolic enzymes. Deacylation is
      believed to be a deactivating pathway, and the activity of the microsomal
      deacetylase toward N-hydroxy-2-AAF is exceedingly greater than toward the parent
      2-AAF. Another deactivating pathway is cytochrome P450-catalyzed ring
      hydroxylation. We have studied the effect of ring hydroxyl substitution on the
      activity of the liver microsomal deacetylase from Aroclor 1254-treated rats in
      vitro. The deacetylase activity was generally decreased toward ring-hydroxylated
      derivatives in the order of 2AAF approximately 1-OH-AAF > 3-OH-AAF > 7-OH-AAF > 5
      OH-AAF approximately 9-OH-AAF. The difference in activity between 2-AAF and 5-OH-
      and 9-OH-AAF was about eightfold. Molecular mechanics calculations reveal that
      structural and geometrical parameters are more important than the energies
      associated with the different isomers. We show that the greater the distance of
      the hydroxyl group on the fluorenyl ring structure from the acetylamino group,
      the slower the rate of deacetylation. The difference in reactivity between the 1
      hydroxy-2-AAF and the other hydroxy-2-AAF isomers is due to the lack of planarity
      of the 1-hydroxy isomer as compared to the essentially planar configuration of
      the other isomers. The relative contribution of microsomal ring hydroxylation and
      deacetylation to detoxification of arylamides remains to be established.

PMID- 10402561
TI  - Fatty acid anilides: in vivo formation and relevance to toxic oil syndrome.
AB  - Toxic oil syndrome (TOS), a multisystemic epidemic outbreak in 1981 in Spain, was
      caused by the ingestion of a cooking oil mixture containing rapeseed oil
      denatured with aniline. The mechanisms and causative agents responsible for the
      TOS are still not known. Although primary lesions observed in TOS patients could
      not be reproduced experimentally, the levels of fatty acid anilides (FAAs) and
      aniline in TOS-related cooking oil were considered proximate markers of TOS.
      Aniline, available from free aniline and FAAs ingested with TOS-related cooking
      oil, and its reconjugation with endogenous fatty acids could be an early event
      leading to TOS. Therefore, the present study was undertaken to determine the
      formation of FAAs following an oral dose of 2 mmol/kg aniline hydrochloride (AH)
      via gavage in rats. Here, 16:0, 18:0, 18:1, 18:2, 18:3, and 20:4 FAAs were
      analyzed in the whole blood, brown fat, liver, and pancreas at 0 (control), 0.25,
      0.5, 1, 3, 6, 12, 24, and 48 hours. Generally, 16:0 and 18:1 FAAs were detected
      in the whole blood, brown fat, and liver of AH-treated rats with highest mean
      levels at 0.25 or 0.5 hour, except 3 hours for the whole blood. Only 16:0 FAA was
      detectable in the pancreas of AH-treated animals. The 18:0 FAA was also detected
      frequently in the liver while other FAAs were either in trace amounts or not
      detectable in the tissues analyzed in the present study. Overall, highest
      formation of the 16:0 FAA was found in the liver followed by pancreas and of 18:1
      FAA in the whole blood and brown fat. These results indicate a rapid formation
      and further metabolism and disposition of FAAs in rat model and support our
      previous findings that 18:1 and 16:0 fatty acids are better substrates for the
      conjugation with aniline. Surprisingly, a small or trace amount of a few FAAs
      also detected in the tissues of control rats indicates their endogenous
      biosynthesis and/or presence. Results of 18:1 fatty acid incubation and aniline
      in the presence of fatty acid ethyl ester synthase, purified to homogeneity from
      rat liver microsome, suggest that formation of FAAs is catalyzed by an enzyme
      involved in the conjugation of fatty acids with xenobiotic alcohols. Because the
      FAAs are known to exert a wide range of toxicity in experimental animals and
      primary cell cultures, in vivo formation of FAAs could be an early event leading
      to TOS.

PMID- 10402563
TI  - Clinical ethics committees in the UK.

PMID- 10402564
TI  - Clinical pharmacology and therapeutics in a changing world.

PMID- 10402565
TI  - Lessons from dermatology--implications for future provision of specialist
      services.

PMID- 10402566
TI  - Motor neuron disease and its management.

PMID- 10402567
TI  - Autoimmune inflammatory neuropathy.

PMID- 10402568
TI  - Paraneoplastic neurological disorders.
AB  - Distinct syndromes are associated with a limited range of tumours. Autoantibodies
      are provoked by tumour (onconeural) antigens. Paraneoplastic antibodies to ion
      channels (VGCC, VGKC, AChR) are disease-inducing, but may also slow tumour growth
      in the case of LEMS. Antibodies to intracellular antigens in CNS disorders are
      probably not disease-inducing, but are valuable in diagnosis as disease markers.
      T cell mediated cytotoxicity is the likely effector mechanism in these latter
      disorders.

PMID- 10402569
TI  - Mechanisms and management of headache.

PMID- 10402570
TI  - The spectrum of dementia and its treatment.

PMID- 10402571
TI  - Maintaining good medical practice. Clinical governance and self regulation for
      physicians. A report of the Royal College of Physicians.
AB  - A high standard of medical practice is a prerequisite of good medical care and
      clinical governance is the means for ensuring that a high standard is maintained.
      In February of this year the College issued the following report to its Fellows
      and Members. The report states unequivocally the College's position on clinical
      governance and self-regulation and what it expects of individual physicians and
      their employers in implementing them. Some of the proposals have already been
      acted upon and are set in train; others will require additional resources and the
      commitment of the Department of Health and the Trusts.

PMID- 10402572
TI  - Provision of secondary care for dermatology within general practice. Guidelines
      from the Royal College of Physicians Dermatology Advisory Committee.

PMID- 10402573
TI  - Who will challenge evidence-based medicine?
AB  - Evidence based medicine (EBM), which lays special emphasis on the formal
      gathering and synthesis of research data by systematic review and meta-analysis,
      is intuitively attractive as a way of determining best treatments. However,
      questions remain unanswered about the underlying assumptions of EBM. There is
      little true dialogue between its critics and its advocates, although the latter
      have had considerable disagreements among themselves in the correspondence
      columns of medical journals about the precise way in which its methods should be
      used. EBM medicine is in danger of becoming a new and unchallengeable orthodoxy
      following its own political agenda.

PMID- 10402574
TI  - Lowering cholesterol in old age.
AB  - In arguing for a conservative view of the need for and wisdom of lowering plasma
      cholesterol, or low density lipoprotein cholesterol, in advanced age, three
      considerations are taken into account. These are: plasma cholesterol
      concentrations decrease spontaneously with age, as does their association with
      vascular disease; the absence of data to demonstrate the benefits of lowering
      cholesterol levels in the elderly; and conflicting priorities (including the cost
      of treatment) in the care of the elderly. Patients with known coronary heart
      disease who have received lipid-lowering treatment for some years could continue
      to be treated with these drugs beyond the age of 75, though even this decision
      should depend on clinical judgement.

PMID- 10402576
TI  - Computer generated discharge summaries and their use as a case mix sensitive
      audit engine. A tale of two cities.
AB  - BACKGROUND: An 'audit engine' allows critical appraisal of clinical practice
      without necessitating cumbersome data input, editing or analysis. This is
      achieved by capturing data from an otherwise necessary task, in this case writing
      discharge summaries, and using standardised analyses to illustrate the effects of
      operational changes. DESIGN AND SETTING: Retrospective analysis of clinical
      outcome of 1,829 sequential discharges from one consultant's team in two
      geriatric medicine departments. MAIN OUTCOME MEASURES: Mortality, discharge
      destination and functional performance. RESULTS: Median length of stay in the two
      departments differed significantly (8 vs 13 days; p < 0.0001), but patients in
      the latter department were more disabled, with almost twice as many needing
      domiciliary services after discharge and suffering impaired mobility or
      incontinence. Despite this disparity, a similar proportion of survivors was
      placed in institutional care (31/300 (10%) vs 94/1,100 (8%); NS). CONCLUSIONS:
      This audit engine demonstrated that apparently worse performance indicators were
      explained by adverse case mix in one department, and the similar
      institutionalisation rates suggest superior care there.

PMID- 10402575
TI  - Unexpected deaths and referrals to intensive care of patients on general wards.
      Are some cases potentially avoidable?
AB  - OBJECTIVES: (i) To determine the incidence of unexpected deaths occurring on
      general wards, and whether any were potentially avoidable; (ii) to assess whether
      the quality of care on general wards prior to admission to intensive care
      affected subsequent outcome. DESIGN: Six-month audit in teaching hospital. Review
      of medical, nursing and physiotherapy notes, bedside charts and laboratory data
      in ward patients either dying unexpectedly (i.e. not having a prior 'do not
      resuscitate' order) or requiring intensive care unit (ICU) admission. Panel
      assessment of quality of ward care prior to unexpected ward death or ICU
      admission. SUBJECTS: Adult general ward patients admitted to ICU or dying
      unexpectedly. OUTCOME MEASURES: ICU and hospital mortality. RESULTS: (i) In the
      six-month study period, 317 of the 477 hospital deaths occurred on the general
      wards, of which 20 (6%) followed failed attempts at resuscitation. Thirteen of
      these unexpected deaths were considered potentially avoidable: gradual
      deterioration was observed in physiological and/or biochemical variables, but
      appropriate action was not taken; (ii) in the same period, 86 hospital inpatients
      were admitted on 98 occasions to the ICU, 31 of whom received suboptimal care pre
      ICU admission due either to non-recognition of (the severity of) the problem or
      to inappropriate treatment. Both ICU (52% vs 35%) and hospital (65% vs 42%)
      mortality was significantly higher in these patients compared to well managed
      patients (p < 0.0001). CONCLUSIONS: Patients with obvious clinical indicators of
      acute deterioration can be overlooked or poorly managed on the ward. This may
      lead to potentially avoidable unexpected deaths or to a poorer eventual outcome
      following ICU admission. Early recognition and correction of abnormalities may
      result in outcome benefit, but this requires further investigation.

PMID- 10402577
TI  - Research based on archived information and samples. Recommendations from the
      Royal College of Physicians Committee on Ethical Issues in Medicine.
AB  - In 1996 the College published Guidelines on the Practice of Ethics committees in
      Medical Research involving Human Subjects (3rd edition) which includes a section
      on unintrusive research. The recommendations published here are intended to
      clarify the issues surrounding this category of research as they relate to
      consent to the use of archived information and samples.

PMID- 10402579
TI  - To South Sudan with operation lifeline Sudan and UNICEF.
AB  - The protracted civil war in the Sudan has had an immense human and economic cost.
      The consequent collapse of infrastructure in the south of the country has
      disrupted the provision of basic health care, and primary health care schemes to
      eradicate trypanosomiasis and dracunculiasis have been rendered impossible.
      Operation Lifeline Sudan, an official United Nations umbrella organisation, has
      been in a unique position to provide long-term medical, agricultural, livestock,
      fishery and emergency food aid in both government held and rebel held areas over
      about the past decade.

PMID- 10402578
TI  - Bugs and guts: it's good to talk?

PMID- 10402580
TI  - Academic medicine.

PMID- 10402581
TI  - What is meant by 'thrombolysis nurse'?

PMID- 10402582
TI  - Co-prescription of conventional and 'alternative' medicines.

PMID- 10402584
TI  - Clinical ethics committees.

PMID- 10402583
TI  - Smoking during pregnancy.

PMID- 10402585
TI  - The diagnosis of dying.

PMID- 10402586
TI  - Cardiovascular risk calculation on a pocket sized computer.

PMID- 10402587
TI  - Principal component analysis of the dynamic response measured by fMRI: a
      generalized linear systems framework.
AB  - Principal component analysis (PCA) is one of several structure-seeking
      multivariate statistical techniques, exploratory as well as inferential, that
      have been proposed recently for the characterization and detection of activation
      in both PET and fMRI time series data. In particular, PCA is data driven and does
      not assume that the neural or hemodynamic response reaches some steady state, nor
      does it involve correlation with any pre-defined or exogenous experimental design
      template. In this paper, we present a generalized linear systems framework for
      PCA based on the singular value decomposition (SVD) model for representation of
      spatio-temporal fMRI data sets. Statistical inference procedures for PCA,
      including point and interval estimation will be introduced without the constraint
      of explicit hypotheses about specific task-dependent effects. The principal
      eigenvectors capture both the spatial and temporal aspects of fMRI data in a
      progressive fashion; they are inherently matched to unique and uncorrelated
      features and are ranked in order of the amount of variance explained. PCA also
      acts as a variation reduction technique, relegating most of the random noise to
      the trailing components while collecting systematic structure into the leading
      ones. Features summarizing variability may not directly be those that are the
      most useful. Further analysis is facilitated through linear subspace methods
      involving PC rotation and strategies of projection pursuit utilizing a reduced,
      lower-dimensional natural basis representation that retains most of the
      information. These properties will be illustrated in the setting of dynamic time
      series response data from fMRI experiments involving pharmacological stimulation
      of the dopaminergic nigro-striatal system in primates.

PMID- 10402588
TI  - A hierarchical clustering method for analyzing functional MR images.
AB  - We introduce a novel method for detecting anatomic and functional structures in
      fMRI. The main idea is to divide the data hierarchically into smaller groups
      using k-means clustering. The separation is halted if the clusters contain no
      further structure that is verified by several independent tests. The resulting
      cluster centers are then used for computing the final results in one step. The
      procedure is flexible, fast to compute, and the numbers of clusters in the data
      are obtained in a data-driven manner. Applying the algorithm to synthetic fMRI
      data yields perfect separation of "anatomic," i.e., time-invariant, and
      "functional," i.e., time-varying, information for a standard off-on paradigm and
      a typical functional contrast-to-noise ratio of two and higher. In addition, an
      EPI-fMRI data set of the human motor cortex was analyzed to demonstrate the
      performance of this novel approach in vivo.

PMID- 10402589
TI  - A novel local PCA-based method for detecting activation signals in fMRI.
AB  - A novel local principal component analysis (LPCA) technique is presented for
      activation signal detection in functional magnetic resonance imaging (fMRI)
      without explicit knowledge about the shape of the model activation signal. Unlike
      the traditional PCA methods, our LPCA algorithm is based on a measure of
      separation between two clusters formed by the signal segments in active periods
      and inactive periods, which is computed in an eigen-subspace. In addition, we
      only applied PCA to the temporal sequence of each individual voxel instead of
      applying PCA to the fMRI data set. In our algorithm, we first applied a linear
      regression procedure to alleviate the baseline drift artifact. Then, the baseline
      corrected temporal signals were partitioned into active and inactive segments
      according to the paradigm used for the fMRI data acquisition. Principal
      components were computed from all these segments for each voxel by PCA. By
      projecting the segments of each voxel onto a linear subspace formed by the
      corresponding most dominant principal components, two separate clusters were
      formed from active and inactive segments. An activation measure was defined based
      on the degree of separation between these two clusters in the projection space.
      We show experimental results on the activation signal detection from various sets
      of fMRI data with different types of stimulation by using the proposed LPCA
      algorithm and the standard t-test method for comparison. Our experiments indicate
      that the LPCA algorithm in general provides substantial signal-to-noise ratio
      improvement over the t-test method.

PMID- 10402590
TI  - Dynamic contrast-enhanced 3D breath hold MRA using a multiple variable
      orientation slab acquisition.
AB  - With the conventional 3D MR angiographic sequences, it is difficult to prescribe
      multiple phases in different orientations, though multiple phases may be
      prescribed in the same orientation as the initial scan. Magnetic resonance
      angiography (MRA) was performed in which three slabs were prescribed in different
      orientations and were acquired in a sequential measurement. A fixed delay of 8 s
      between the slabs was used to prepare patients to hold their breath for
      subsequent measurements. All subjects tolerated the entire breath hold
      examination. The results were easily reproducible and yielded high-resolution 3
      dimensional images in various planes.

PMID- 10402592
TI  - Characterization of the calcaneal fat pad in diabetic and non-diabetic patients
      using magnetic resonance imaging.
AB  - It is well known that diabetic patients have a high incidence of foot ulceration.
      The purpose of this study was to determine whether magnetic resonance (MR)
      imaging can detect changes in the composition of the calcaneal fat pad in
      diabetic feet. MR data were collected in vitro from amputated specimens (eight
      from diabetic patients and eight from non-diabetic patients) as well as in vivo
      from age-matched diabetic and control subjects (four subjects each group.) Three
      types of images were acquired: spin lattice (T1), spin-spin (T2), and
      magnetization transfer (MT). The in vitro results showed statistically
      significant differences in the T1, T2, and MT parameters between the two disease
      groups. The same trends were shown in the study of live subjects but the
      differences were not statistically significant. The differences are believed to
      arise from changes in the composition of the tissues as a result of the
      progression of diabetes.

PMID- 10402591
TI  - Magnetic resonance arthrography (MRA) in the postoperative shoulder.
AB  - To evaluate changes in capsular mechanisms and the labroligamentous complex with
      magnetic resonance arthrography (MRA) after shoulder surgery and to establish
      possible criteria for the expected post-operative appearance of the shoulder. MRA
      of the shoulder was performed in 16 patients, before and 6 months after
      undergoing arthroscopic surgery for recurrent unidirectional dislocation. MR
      studies were performed after application of a constant amount of contrast
      solution (2 mmol Gd-DTPA). Axial and coronal oblique T1-weighted images were
      obtained with and without fat suppression techniques. Anterior (a) and posterior
      (p) capsular distances were measured, and the p/a ratio was established. Capsule
      thickness, capsular leaking, estimation of the volume of the axillary recess,
      appearance of the glenohumeral ligaments, and evidence of labral lesions were
      compared on pre- and postoperative images. Mean anterior capsular distance (a)
      decreased from 9.73 +/- 1.03 mm preoperatively to 5.27 +/- 2.49 mm
      postoperatively, whereas dorsal capsular distance (p) increased from 6.13 +/-
      2.36 to 8.93 +/- 2.37. The p/a ratio increased from 0.64 +/- 0.25 to 2.36 +/-
      2.54 (p = 0.007). Capsular leaking was suspected preoperatively in seven
      patients, but was not evident postoperatively. Capsular thickness and the
      estimated volume in the axillary recess did not change significantly. Contrast
      extension into pre-existent labral tears (nine patients) decreased or were not
      evident postoperatively. Changes in the appearance of the glenohumeral ligaments
      were found in six patients. Changes in capsular distances might be indicative of
      a decreased capsular laxity and could be a valuable criterion in the evaluation
      of the postoperative shoulder. Postoperative follow-up of labral tears is
      demonstrated by a decrease in contrast extension into or under a tear. Reactive
      capsular thickening or scar tissue formation can be reactive or preexistent.
      Changes in ligaments might be secondary to surgery. MRA may be helpful in the
      reevaluation of patients with suspected recurrent instability.

PMID- 10402593
TI  - Age-dependent changes in spatial and temporal blood velocity distribution of
      early left ventricular filling.
AB  - This study describes early diastolic inflow dynamics based on three-directional
      magnetic resonance velocity data and investigates age-dependent changes in early
      diastolic inflow characteristics. We examined 26 young healthy volunteers age 25
      (3) years (mean, SD), and 23 healthy older volunteers age 63 (8) years. Three
      directional magnetic resonance velocity mapping was performed in a long axis
      plane through the heart. Transverse velocity profiles were read in five different
      positions in the early diastolic inflow stream of the left ventricle. The size
      and timing of the maximum velocities at each level were recorded and the
      repeatability of the method was tested. Compared with the younger group, the
      older group was characterized by: 1) lower maximum velocity in all positions, 2)
      increased deceleration of blood downstream from the mitral leaflet tips, and 3)
      delayed velocity propagation. The described method was repeatable and enabled
      detection of the age-dependent differences between groups of normal subjects. In
      conclusion, the early diastolic inflow pattern changes with age, probably
      reflecting changes in the diastolic function of the myocardium.

PMID- 10402594
TI  - MRI of normal and abnormal duodenum using Half-Fourier Single-Shot RARE and
      gadolinium-enhanced spoiled gradient echo sequences.
AB  - The objective of this research was two-fold: First, to describe the normal and
      abnormal MR appearances of the duodenum using combined Half-Fourier Acquisition
      Single Shot RARE (HASTE) and gadolinium-enhanced standard and fat suppressed
      spoiled gradient echo (SGE) sequences. The second objective was to assess the
      ability of these combined sequences to detect and characterize duodenal diseases.
      MR examinations were performed on fifty consecutive patients with no clinical
      history of duodenal diseases, who were 1) imaged with HASTE and gadolinium
      enhanced standard and fat suppressed SGE sequences and 2) referred to MR
      examination for reasons other than duodenal diseases, and were reviewed
      retrospectively to determine the normal MR appearances of the duodenum. A second
      population of patients with abnormal duodenum who were imaged with the same MR
      sequences were included in the second part of this study. This population was
      composed of 20 consecutive patients with subsequently proven duodenal
      abnormalities, including: malrotation (2), diverticula (4), intussusception (1),
      sprue (1), polyps (2), neurofibroma (1), lymphoma (1), Zollinger Ellison syndrome
      (1), metastatic disease (1), Crohn's disease (1), and wall thickening and
      duodenitis (5). Normal measurements of the duodenum are described. Abnormalities
      of wall thickness and duodenal masses required combined HASTE and gadolinium
      enhanced SGE images to evaluate well. Abnormalities of the bowel lumen (e.g.,
      diverticula and intussusception), and developmental variants (e.g., malrotation),
      were sufficiently visualized on HASTE images alone. Bowel inflammation was best
      shown on gadolinium-enhanced fat suppressed SGE images. HASTE and gadolinium
      enhanced fat suppressed SGE sequences are complementary techniques for the
      demonstration of normal and abnormal duodenum. The combined use of both sequences
      allows evaluation of different aspects of bowel diseases; abnormalities of
      position, lumen, and contents are well shown on HASTE, while inflammation is best
      shown on gadolinium enhanced fat suppressed SGE, and wall thickening and masses
      are best evaluated with the combined use of both techniques.

PMID- 10402595
TI  - A study of rotationally invariant and symmetric indices of diffusion anisotropy.
AB  - This study investigated the properties of a class of rotationally invariant and
      symmetric (relative to the principal diffusivities) indices of the anisotropy of
      water self-diffusion, namely fractional anisotropy (FA), relative anisotropy
      (RA), and volume ratio (VR), with particular emphasis to their measurement in
      brain tissues. A simplified theoretical analysis predicted significant
      differences in the sensitivities of the anisotropy indices (AI) over the
      distribution of the principal diffusivities. Computer simulations were used to
      investigate the effects on AI image quality of three magnetic resonance (MR)
      diffusion tensor imaging (DTI) acquisition schemes, one being novel: the schemes
      were simulated on cerebral model fibres varying in shape and spatial orientation.
      The theoretical predictions and the results of the simulations were corroborated
      by experimentally determined spatial maps of the AI in a normal feline brain in
      vivo. We found that FA mapped diffusion anisotropy with the greatest detail and
      SNR whereas VR provided the strongest contrast between low- and high-anisotropy
      areas at the expense of increased noise contamination and decreased resolution in
      anisotropic regions. RA proved intermediate in quality. By sampling the space of
      the effective diffusion ellipsoid more densely and uniformly and requiring the
      same total imaging time as the published schemes, the novel DTI scheme achieved
      greater rotational invariance than the published schemes, with improved noise
      characteristics, resulting in improved image quality of the AI examined. Our
      findings suggest that significant improvements in diffusion anisotropy mapping
      are possible and provide criteria for the selection of the most appropriate AI
      for a particular application.

PMID- 10402596
TI  - The reduction of the sorting bias in the eigenvalues of the diffusion tensor.
AB  - One of the most intrinsic quantities when measuring the diffusion properties of a
      system is the set of principal diffusivities, which represents diffusion along
      the fibre axes. System noise is a well-known cause of systematic sorting bias
      when closely spaced diffusivities are ordered according to their magnitude and
      leads to their inaccurate estimation. This paper describes a new method for the
      ordering of the principal diffusivities in which local fibre directional
      coherence was used as a basis for sorting. The method was applied and tested in
      computer simulations and experimental data acquired in an isotropic water phantom
      and healthy human brain. Our results demonstrate that this method leads to
      significant reduction in the sorting bias in comparison to other techniques and
      thus a more accurate estimation of the eigenvalues. The method is advantageous
      over other proposed alternatives to the conventional magnitude sorting method
      because it is not reliant on a large region-of-interest averaging scheme.

PMID- 10402597
TI  - MRI-based quantification of cerebral edema in individual SHRSP rats using
      averaged criteria determined before the occurrence of edema.
AB  - This study evaluated whether it is possible with T2-weighted MRI to
      quantitatively relate image-outcome in a single, individual case with that of a
      standardized control group that did not show these pathologies. An animal model
      of hypertension-related cerebral damage, the salt-loaded, stroke-prone
      spontaneously hypertensive rat (SHRSP), was applied. Very similar values for
      cerebral edema were found when using either the individual or the averaged
      threshold. The values were positively correlated with each, as edema(averaged
      threshold) = 0.12 + 0.99 x edema(individual threshold) (Pearsons coefficient =
      0.99, p < 0.0001). This line was virtually congruent with the line of identity.
      Thus, by determination of the averaged threshold in the healthy salt-loaded
      SHRSP, a parameter was obtained to calculate cerebral edema with the specifically
      used T2-weighted MRI protocol, in any rat.

PMID- 10402598
TI  - Concentration and velocity field measurements by magnetic resonance imaging in
      aperiodic heterogeneous porous media.
AB  - Magnetic resonance imaging (MRI) techniques were investigated as a means to
      obtain concentration and velocity field measurements for the verification of a
      stochastic model for conservative chemical transport. MRI techniques were
      successfully applied to obtain one-dimensional breakthrough images and two
      dimensional velocity images along the length of an aperiodic heterogeneous porous
      medium. Experimental moment data showed the concentration field in the
      experimental model to be slightly positively skewed. Velocity images showed the
      velocity field to be relatively uniform with no channeling or preferential flow
      behavior. Measured covariance functions showed evidence of negative correlation
      in the velocity field. The detailed spatial information provided by these imaging
      experiments has demonstrated that MRI is a valuable tool for obtaining
      experimental data for the verification of existing theoretical models.

PMID- 10402599
TI  - Performance of 2D 1H spectroscopic imaging of the brain: some practical
      considerations regarding the measurement procedure.
AB  - This paper deals with some of the practical considerations in the planning and
      performance of chemical shift imaging (MRSI or CSI) of the brain. It contains
      some aspects of 1) the imaging procedure (MRI), i.e., suggestions of an imaging
      protocol useful for the spectroscopic planning, 2) the planning of the
      spectroscopic volume, i.e., size and position, 3) evaluation and judgment of the
      preparation results, and 4) evaluation of the MRSI images. The paper also
      contains suggestions of developmental work and quality assessment to be done
      before patient studies are begun. Examples are given for MRSI studies of temporal
      lobe epilepsy. Several of the aspects described are obvious for the experienced
      spectroscopist but may be useful in the initiation of MRSI. The goal of this
      paper was to share our experiences of how to achieve high quality MRSI,
      experiences that we would had been grateful for in our prelude of MRSI
      experiments.

PMID- 10402600
TI  - Idiopathic dilatation of the pulmonary artery: report of four cases.
AB  - Idiopathic dilatation of the pulmonary artery (IDPA) is a rare congenital disease
      which is usually detected fortuitously on chest x-ray, thus radiologists must be
      aware of this clinical entity. This report describes four cases to which Magnetic
      Resonance Imaging (MRI) played a major role in diagnosing IDPA and in detecting
      the concomitant findings observed in this disease. MRI is a non-invasive
      procedure with many advantages for the accurate and reproducible measurement of
      artery structures, which makes it the preferred option for combined use with
      echocardiography in the diagnosis and follow-up of patients with IDPA.

PMID- 10402602
TI  - Mitochondrial DNA sequence relationships of the newly described enigmatic
      Vietnamese bovid, Pseudonovibos spiralis.

PMID- 10402601
TI  - Proton MR spectroscopy in a child with pyruvate dehydrogenase complex deficiency.
AB  - The purpose of this study was the non-invasive quantitative determination by
      proton MR Spectroscopy (1H MRS) of alterations in cerebral metabolism in a 19
      month-old male infant with severe global developmental delay caused by a Pyruvate
      Dehydrogenase Complex (PDHC) deficiency due to a mutation at the thiamine binding
      site. Two investigations were performed at different CSF thiamine concentrations
      to assess the effect of thiamine supplementation. 1H MR spectra were collected at
      different echo times (20-270 ms) from a voxel located in the striatum;
      spectroscopic imaging was done on a larger region including occipital white
      matter. The tissue levels of N-acetylaspartate and choline were in the normal
      range, while creatine appeared elevated. Abnormally high lactate and alanine
      signals were observed both in and outside the striatum; the levels of these
      metabolites were higher during the second measurement at a lower thiamine
      concentration. Abnormal cerebral levels of alanine have only been described once
      before in PDHC deficiency. The 1H MRS profile of this patient reflects the
      diversity of brain metabolite alterations in patients with this genetically
      heterogeneous disease.

PMID- 10402603
TI  - Temporal segmentation of human short-term behavior in everyday activities and
      interview sessions.
AB  - Human behavior is structured by serial order and timing of functionally related
      groups of movements with a duration of a few seconds. These elementary action
      units have been described in ethological studies during unstaged everyday
      behavior, but not during interview sessions. Psychomotor alterations are relevant
      for differential diagnosis and treatment, and psychiatric patients are generally
      evaluated during interview sessions. Therefore the time structure of upper limb
      movements (n = 764) of healthy subjects (n = 22) were studied using videotaped
      interviews and frame-by-frame analysis and compared to movements (n = 530) of
      unstaged human everyday behavior (n = 154). The number of action units, but not
      their duration, was correlated inversely with self-reported impairment of mood
      and pleasure experience in healthy persons. The temporal distribution of
      movements in interview sessions did not differ from the time patterns of everyday
      behavior. This method could be a promising tool to investigate time patterns of
      movements and psychomotor alterations in psychiatric patients during interview
      sessions.

PMID- 10402604
TI  - What should we expect from drug abusers?

PMID- 10402605
TI  - The computerized lab alert system for patient management in clinical care.

PMID- 10402606
TI  - Seclusion and restraint: Congress reacts to reports of abuse.

PMID- 10402607
TI  - Public-sector managed behavioral health care: III. Meaningful consumer and family
      participation.

PMID- 10402608
TI  - Cognitive-behavioral therapy and clozapine for clients with treatment-refractory
      schizophrenia.

PMID- 10402609
TI  - Trends in psychiatric nursing graduate education.

PMID- 10402610
TI  - Community treatment of severely mentally ill offenders under the jurisdiction of
      the criminal justice system: a review.
AB  - OBJECTIVE: Very large numbers of severely mentally ill persons now fall under the
      jurisdiction of the criminal justice system. A number of conditions are placed on
      those who are returned to the community, including specific ones related to
      treatment. This paper reviews the principles and practice of forensic outpatient
      mental health treatment. METHODS: MEDLINE, Psychological Abstracts, and the Index
      to Legal Periodicals and Books were searched from 1978, and all pertinent
      references were obtained. RESULTS AND CONCLUSIONS: Community treatment of
      severely mentally ill offenders who fall under the jurisdiction of the criminal
      justice system has important differences from treatment of nonoffenders, which
      focuses on alleviation of symptoms. Patients must comply with legal restrictions
      on their behavior, and treatment first addresses a patient's risk of harm to the
      community. Mentally ill offenders are often resistant to treatment. The mental
      health system may be disinclined to treat them due to their resistance and their
      criminal history, especially a history of violence. It is critical to identify a
      treatment philosophy that strikes a balance between individual rights and public
      safety and includes clear treatment goals, a close liaison between treatment
      staff and the criminal justice system, adequate structure and supervision,
      treatment staff who are comfortable with using authority, interventions for
      managing violence, incorporation of the principles of case management,
      appropriate and supportive living arrangements, and a recognition of the role of
      family members and significant others in treatment.

PMID- 10402611
TI  - Termination of social security benefits among Los Angeles recipients disabled by
      substance abuse.
AB  - OBJECTIVES: Although a 1996 federal law terminated Social Security disability
      benefits to individuals disabled primarily by drug addiction and alcoholism, many
      were expected to successfully appeal for recertification based on mental illness.
      This study examined appeal and recertification in Los Angeles County. METHODS:
      Data for 2,001 persons receiving Social Security disability benefits in 1996
      because of substance abuse disability were obtained from the referral and
      monitoring agency, where each person had completed the Addiction Severity Index
      (ASI) during an initial visit in the past two years. Administrative data were
      obtained from the Social Security Administration. Severity of psychiatric
      symptoms--low, medium, or high--was based on the composite score on the ASI
      psychiatric subscale. Logistic regression analyses examined the relationship
      between severity and appeal and recertification status. RESULTS: Fifty-one
      percent of the subjects scored in the medium- or high-severity range. Appeals
      were made by 80 percent of the 506 recipients with high scores, 72 percent of the
      510 recipients with medium scores, and 74 percent of the 985 recipients with low
      scores. Recertification rates were 60 percent, 45 percent, and 47 percent,
      respectively. Compared with recipients who had low scores, those with high scores
      were more likely to appeal and to be recertified. However, benefits were
      terminated for 51 percent of recipients with high scores, including all those who
      did not appeal. CONCLUSIONS: Many recipients of Social Security disability
      benefits with comorbid psychiatric problems lost benefits either because they did
      not appeal or because their appeal was denied.

PMID- 10402612
TI  - Advance directives for mental health treatment.
AB  - Advance directives are designed to establish a person's preferences for treatment
      if the person becomes incompetent in the future or unable to communicate those
      preferences to treatment providers. Mental health advance directives are similar
      to the more commonly used directives for end-of-life medical decisions. A patient
      must be competent to execute a mental health advance directive, and the directive
      must clearly express the patient's wishes. Once directives are executed, steps
      must be taken to ensure compliance, including adequate dissemination to
      providers, and to ensure that proxy decisions are consistent with the patient's
      treatment preferences. Potential effects of mental health advance directives
      include enhanced consumer empowerment; improved functioning; improved
      communication between consumers, family members, and providers; increased
      tolerance for consumer autonomy at the organizational level in community mental
      health agencies; and reduced use of hospital services and judicial proceedings.
      Issues to be clarified in future research and practice include strategies for
      increasing awareness of advance directives in mental health, barriers to
      execution of legally and clinically effective directives, practitioners'
      concerns, providers' compliance with directives, effects of directives on
      consumers and providers, effects of managed care on implementation of directives,
      and stakeholders' perceptions of the value of directives.

PMID- 10402613
TI  - A randomized controlled study of two styles of group patient education about
      schizophrenia.
AB  - OBJECTIVE: The therapeutic specificity of patient education about schizophrenia
      was investigated in a randomized controlled study comparing the effects of two
      styles of group educational intervention. METHODS: Thirty-three adult inpatients
      with schizophrenia were assigned in a stratified random manner either to an
      experimental patient education group that used a didactic format to cover a range
      of topics on the characteristics and treatment of schizophrenia (N = 16) or to a
      control group in which participants discussed their subjective experiences with
      schizophrenia and its treatment (N = 17). Before and after the group
      interventions, participants responded to measures of knowledge about
      schizophrenia, insight into illness, and cognitions about medication intake.
      RESULTS: The two groups did not differ significantly in postintervention scores
      on measures. CONCLUSIONS: The benefits of patient education may not be due to
      specific active therapeutic educational ingredients but may be due instead to the
      presence of nonspecific treatment effects.

PMID- 10402614
TI  - Development of a vertically integrated program of services for persons with
      schizophrenia.
AB  - Economic pressures are changing the nature and quality of services available to
      individuals with chronic psychiatric disorders. Vertical integration of services
      has been proposed as a strategy for cost-effective merging of resources. This
      report describes the integration of inpatient, continuing day treatment, and
      ambulatory clinic services over an 18-month period into a service line for
      patients with schizophrenia. Key principles in implementing the integrated
      program included an open admission policy, continuity of care, use of criteria
      for level of care that were set by external review agencies, rapid transfers
      between services, and maintenance of the integrity of the treatment plan. Steps
      toward integration included evaluating and securing treatment resources,
      establishing core treatment approaches, fostering staff development, implementing
      outcomes assessment, and presenting the new program to clients, family members,
      and the community. The integrated program was 15 percent more productive than the
      combined services before integration, and inpatient length of stay dropped by 66
      percent. Vertical integration of services is cost-effective and offers the
      potential for significant clinical benefits.

PMID- 10402615
TI  - Use of public mental health services by Russian refugees.
AB  - OBJECTIVES: This study identifies the demographic characteristics and patterns of
      mental health service use among Russian refugees in New York State. METHODS: Data
      from a 1995 statewide survey of characteristics of patients served by the New
      York State mental health system were analyzed using chi square statistics and
      logistic regression. RESULTS: The demographic characteristics and service-use
      patterns of Russian refugees are different from those of non-Russian refugees and
      non-refugees. Russian refugees who used mental health services were likely to be
      older women with major depression who were enrolled in Medicaid and who were
      using those services for the first time. Relying heavily on themselves, family
      members, or friends as referral sources, they tended to use exclusively
      individual, outpatient services at voluntary, nonprofit agencies. CONCLUSIONS:
      Existing services systems must recognize the presence of Russian refugees. To
      improve access and service use, outreach efforts to the refugee community should
      be conducted, and services must be tailored to meet their mental health needs.

PMID- 10402616
TI  - The impact of a token economy on injuries and negative events on an acute
      psychiatric unit.
AB  - OBJECTIVE: Although the use of token economies has been shown to facilitate
      patient change and improve program functioning in numerous settings, token
      economies have received little attention in acute psychiatric settings. A token
      economy was introduced on an acute care unit in a rural hospital, and rates of
      negative events were compared before and after implementation. METHODS: Negative
      events were defined as patient and employee injuries that were not accidents.
      Unauthorized absences and use of emergency medications were also counted as
      negative events. Rates of negative events were calculated over two four-month
      periods, before and after the token economy was introduced on a 24-bed acute care
      unit that housed the hospital's neo-adult program for patients between the ages
      of 18 and 20. The unit also served as an admitting unit for patients over age 20.
      RESULTS: When the analysis controlled for unit census and the number of neo
      adults, an analysis of covariance indicated that the number of negative events
      fell significantly after the token economy was introduced, from 129 in the four
      months before implementation to 73 after implementation, a 43 percent reduction.
      Both staff and patient injuries were significantly reduced. A small increase in
      use of emergency medications was noted, but it was not statistically significant.
      CONCLUSIONS: Findings support the use of the token economy in acute settings to
      improve the unit milieu by reducing negative events.

PMID- 10402617
TI  - A survey of prescribing practices for monoamine oxidase inhibitors.
AB  - OBJECTIVE: A survey examined prescribing practices for monoamine oxidase
      inhibitors (MAOIs) and explored reasons for the widely noted decline in their
      use. METHODS: A one-page questionnaire was sent in 1997 to 1,129 members of the
      Michigan Psychiatric Association. A total of 717 responses were received, for a
      response rate of 64 percent. Only data from the 573 psychiatrists who were
      currently practicing were used. RESULTS: Twelve percent of the respondents never
      prescribed MAOIs, 27 percent had not prescribed them for at least three years,
      and 17 percent had prescribed them from one to three years ago. Thirty percent of
      the respondents had prescribed an MAOI within the past three months, and 14
      percent between three and 12 months ago. The most frequent reasons for not
      prescribing the drugs were side effects and interactions with other medications
      (46 percent), preference for other medications (30 percent), and dietary
      restrictions necessary for patients taking MAOIs (19 percent). Ninety-two percent
      of respondents believed that MAOIs were useful for atypical depression, 64
      percent for major depression, 54 percent for melancholic depression, 56 percent
      for panic disorder, 44 percent for social phobia, 27 percent for dysthymia, 12
      percent for obsessive-compulsive disorder, and 19 percent for posttraumatic
      stress disorder. However, only 2 percent said they would use MAOIs as their first
      line treatment in atypical depression, and only 3 percent would use them a first
      line treatment in social phobia. CONCLUSIONS: The results document the commonly
      held view that practicing psychiatrists believe MAOIs are efficacious but use
      them infrequently, primarily due to concerns about side effects and drug
      interactions.

PMID- 10402618
TI  - Cognitive-behavioral group therapy with medication for depressed gay men with
      AIDS or symptomatic HIV infection.
AB  - OBJECTIVE: The feasibility and effectiveness of a combination of group cognitive
      behavioral therapy and medication for the treatment of depression among gay men
      with AIDS or symptomatic HIV infection were evaluated. METHODS: Fifteen patients
      diagnosed with DSM-IV major depressive disorder or dysthymia were treated in one
      of two weekly therapy groups in which cognitive-behavioral therapy had been
      specially modified for the target population. The majority of these patients,
      including two who had been on medication before joining the groups, also received
      antidepressant medication. Thirteen of the 15 patients completed therapy,
      attending an average of 15 of the 20 therapy sessions. RESULTS: The group
      cognitive-behavioral therapy used in this project appeared to be attractive to
      most patients; retention, attendance, and therapy compliance were good.
      Depression scores showed substantial decreases from pre- to posttherapy, with
      further decreases at one-year follow-up. Patients' self-reports indicated that
      some aspects of the intervention, particularly the focus on cognitive
      restructuring, were especially valuable in alleviating their depression.
      CONCLUSIONS: The modified group cognitive-behavioral therapy described in this
      study report offers a reasonable option for treatment of this clinically
      challenging group of patients.

PMID- 10402619
TI  - Lessons from the first two years of Project Heartland, Oklahoma's mental health
      response to the 1995 bombing.
AB  - On April 19, 1995, a terrorist bombing in Oklahoma City killed 168 people and
      injured 853 others. The Oklahoma Department of Mental Health and Substance Abuse
      Services was the lead agency in crafting a community mental health response to
      reduce impairment of those affected. The Project Heartland program, which opened
      on May 15, 1995, was the first community mental health program in the U.S.
      designed to intervene in the short to medium term with survivors of a major
      terrorist event. The authors describe lessons learned in the areas of planning
      and service delivery, as well as the types and extent of services provided in the
      project's first two years.

PMID- 10402620
TI  - Mental health services for children in the first two years after the 1995
      Oklahoma City terrorist bombing.
AB  - Nineteen infants and children were killed in the 1995 terrorist bombing in
      Oklahoma City, and many were injured. More than 200 children lost one or both
      parents. These casualties focused attention on children in the disaster response
      efforts. This paper describes the development and implementation of a school
      based mental health program that provided accessible services to children
      affected by the bombing, with an emphasis on normalization. A clinical needs
      assessment of all children in the Oklahoma City public school system was carried
      out, and clinicians provided emergency and crisis services, counseling, and
      support groups.

PMID- 10402621
TI  - Validation of the empowerment scale with an outpatient mental health population.
AB  - The validity of the Empowerment Scale was examined in an adult outpatient mental
      health population. A survey was mailed to 2,000 consumers in the South Carolina
      outpatient public mental health system, and 283 completed surveys were received,
      a response rate of 16.5 percent. Reliability and factor analyses confirmed five
      subscales of empowerment: esteem, power, activism, anger, and control.
      Respondents with full-time jobs scored significantly higher on overall
      empowerment and on the esteem, anger, and power subscales. Respondents with
      college experience scored higher on overall empowerment and the power subscale.
      Results indicate adequate validity of the scale in this population and provide
      direction for research on empowerment as a process and outcome variable.

PMID- 10402622
TI  - Effects of client interviewers on client-reported satisfaction with mental health
      services.
AB  - A study at two outpatient facilities compared two methods of collecting data on
      client satisfaction with mental health services provided by case managers and by
      physicians. A satisfaction survey instrument was developed with input from
      clients. A total of 120 clients were randomly assigned to be interviewed by
      either a staff member or a client. Clients from both facilities reported high
      levels of satisfaction regardless of the type of interviewer. Clients gave a
      significantly greater number of extremely negative responses when they were
      interviewed by client interviewers. No difference between the two groups was
      found in overall satisfaction with services received from case managers or
      physicians.

PMID- 10402623
TI  - Adverse effects of poor behavior management of an inpatient's difficult
      behaviors.
AB  - Behavior therapy has been shown to improve the functioning of institutionalized
      clients, but front-line staff often have difficulty implementing behavior therapy
      techniques. In the case described in this report, staff with inadequate training
      in behavior therapy inconsistently used negative and positive reinforcement in
      the attempt to reduce the aggressive behavior of an inpatient diagnosed as having
      schizophrenia, and the interventions were associated with an increase in assaults
      and related behavior. The case illustrates the effects of poor behavior
      management and the importance of data collection in evaluating clinical
      interventions.

PMID- 10402624
TI  - Amnestic syndrome presenting as malingering in a man with developmental
      disability.
AB  - The authors report an unusual presentation of amnestic syndrome mislabeled as
      malingering in a man with mild developmental disability. The case highlights the
      challenges to medical personnel in treating persons who visit emergency rooms
      often, particularly individuals with mental retardation. Diagnostic overshadowing
      was a primary factor in the failure to diagnose amnestic syndrome. Overshadowing
      occurs when a patient's problematic behaviors are attributed to mental
      retardation, and no attempt is made to search for the root causes of the problem.
      The case also highlights the need for emergency room personnel to maintain links
      with agencies involved in the day-to-day care of persons with developmental
      disabilities.

PMID- 10402625
TI  - John Cade and lithium.

PMID- 10402626
TI  - Herbal medicines as a factor in delirium.

PMID- 10402627
TI  - Treatment compliance in first-episode schizophrenia.

PMID- 10402628
TI  - Female genital self-mutilation.

PMID- 10402629
TI  - Notes on the therapeutic role of the alliance.

PMID- 10402631
TI  - Numbers and psychoanalysis: reflections on the quest for certainty. 1.

PMID- 10402630
TI  - Archetype and interpretation.

PMID- 10402632
TI  - Mythic perspectives and perspectives on truth: approaching Winnicott by way of
      comparisons between Kohut and Freud.

PMID- 10402633
TI  - Optimal radiologic imaging of soft tissue sarcomas.
AB  - Radiologic evaluation of the patient with soft tissue sarcoma may include
      conventional radiography, scintigraphy, ultrasonography (US), computed tomography
      (CT), and magnetic resonance (MR) imaging. The radiologist also plays a critical
      role in the evaluation of the patient with soft tissue sarcoma by guiding and
      performing aspiration biopsies. This review discusses the use of radiological
      techniques to evaluate the primary lesion and to detect recurrences. In adults,
      soft tissue sarcoma most commonly occurs in the extremities, and this review
      emphasizes the role of MR imaging in the pre- and post-treatment evaluation of
      extremity soft tissue sarcomas. The role of imaging studies in the evaluation of
      soft tissue sarcomas in the abdomen, thorax, and the head and neck region is also
      discussed.

PMID- 10402634
TI  - New diagnostic modalities in soft tissue sarcoma.
AB  - Molecular and cytogenetic analysis of soft tissue sarcoma has provided a vast
      amount of new genetic information over the past 10 years. Recent advances in
      genetic technology, such as fluorescence in situ hybridization (FISH), reverse
      transcriptase-polymerase chain reaction (RT-PCR), and positional cloning
      techniques have greatly increased the rate of new discoveries and soon may bring
      cytogenetic and molecular analysis to standard pathology laboratories. Karotypic
      analysis of soft tissue tumors have demonstrated specific cytogenetic aberrations
      which have proved to be extremely useful diagnostically and have solidified and
      improved soft tissue tumor classification systems. Objective and reproducible
      prognostication in soft tissue sarcoma remains problematic. Presently, the grade
      and size of the sarcoma are the most important factors used to estimate risk of
      relapse and overall survival. Assigning a pathologic grade to an individual
      sarcoma as a means of predicting clinical behavior is often difficult with a 40%
      discordance rate even between expert sarcoma pathologists. There is mounting
      evidence that the composition of membrane phospholipid in tumor tissue is an
      important indicator of a tumor's cellularity, proliferative capacity, and
      differentiation state. However, there is a lack of information on the biochemical
      determinants of sarcoma proliferation and differentiation. To address these
      problems, novel quantitative ex vivo nuclear magnetic resonance (NMR) methods
      have been applied to determine the biochemical changes in tissue lipid for soft
      tissue sarcoma. The biochemical changes in tissue lipid have been found to
      correlate with sarcoma cellularity, growth rate, and differentiation. Continued
      prospective NMR analysis of tissue lipid biochemistry in soft tissue tumors will
      permit the development of a clinically relevant biochemical system of prognostic
      determinants for soft tissue sarcoma in the future.

PMID- 10402636
TI  - Contemporary radiotherapy for soft tissue sarcoma.
AB  - This review will detail the role of radiotherapy in the management of soft tissue
      sarcoma. Particular emphasis will be given to its role as an adjuvant to surgical
      excision for local curative management. The addition of radiotherapy permits a
      tissue-conserving operation to be performed, which has functional and cosmetic
      advantages yet produces local control equivalent to more radical surgery alone.
      The review will consider the historical evolution of treatment up through recent
      and contemporary practice. The principles of use will be outlined using available
      evidence and, where this is lacking, it will be acknowledged with suggestions for
      improvement. Finally, a brief overview of some technical issues about
      radiotherapy will be provided.

PMID- 10402635
TI  - Prognostic factors in soft tissue sarcoma.
AB  - The ability to accurately define the prognosis for patients with soft tissue
      sarcoma is a continuing challenge. Classically, this has been accomplished
      through assessments of tumor size, histologic grade, location, and the presence
      of nodal or distant metastases. These criteria are the basis of the currently
      utilized American Joint Commission on Cancer (AJCC) staging system. However,
      several other markers have been identified which have prognostic value. These
      newer markers are useful additions to the AJCC system. Such markers may not only
      improve our ability to prognosticate at diagnosis, but may also prove useful in
      selecting high-risk soft tissue sarcoma patients who could benefit from adjuvant
      therapy. This review will focus upon prognostic factors for patients with soft
      tissue sarcomas (STS). First, the components of the current AJCC staging system
      will be discussed; second, a summary of clinical prognostic factors which are not
      part of the staging system; and third, a discussion of newer and potential
      prognostic factors for STS patients.

PMID- 10402637
TI  - New chemotherapeutic strategies for soft tissue sarcomas.
AB  - Advanced soft-tissue sarcomas are still incurable in the vast majority of
      patients. The currently available standard methods of treatment such as surgery,
      radiation therapy, and chemotherapy have a very modest impact on the natural
      history of advanced soft tissue sarcomas. Nevertheless, until new strategies
      become widely available and applicable to this disease, we are obligated to
      optimize the current resources and make the best use of these modalities. We
      discuss the approaches of standard chemotherapy used in a dose-intensive fashion
      (especially in high-risk patients at an earlier stage), attempts to find new
      drugs with activity in this disease, and tests of the concepts of anti-angiogenic
      and differentiation therapy. To improve cure rates, patients and physicians must
      be encouraged to participate in multidisciplinary clinical trials.

PMID- 10402638
TI  - Reconstructive approaches in soft tissue sarcoma.
AB  - Plastic surgical techniques continue to evolve to deal with problem wounds
      following soft tissue sarcoma resection. Important advances in how tissue is
      transferred have allowed most wounds to be closed following extirpation; the
      emphasis is now placed on refining these transfers while minimizing donor site
      injury. Reconstructive microsurgery has emerged as a frequently preferred way to
      resurface wounds after sarcoma resection, particularly in patients who have
      received radiotherapy or previous surgery. Free flaps provide well-vascularized
      tissue to fill dead space, cover exposed vital structures, and provide structural
      support and contour. These procedures demonstrate a high success rate of over 90%
      and often can ensure a healed wound in a single-stage operation. Creative use of
      the versatile rectus abdominis or latissimus dorsi myocutaneous flaps can
      reconstruct the majority of breast, extremity, and head and neck soft tissue
      defects. Endoscopic harvest of muscle flaps has minimized donor morbidity and
      scarring. The use of "fillet flaps" is an important concept that spares a patient
      donor site. Composite free flaps, including bone, are routinely used to rebuild
      the mandible or other bony structures. The future holds great promise for sarcoma
      reconstruction because tissue engineering is rapidly closing in on techniques
      that can duplicate tissues in the laboratory for ultimate use in reconstruction,
      thus sparing the donor site from disease.

PMID- 10402640
TI  - Immunotherapeutic approaches to sarcoma.
AB  - In the last decade, the most important factor in the rekindled interest in immune
      therapy for cancer is the development of new methods to identify tumor antigens
      that can be recognized by T-cells and other immune effectors. In addition,
      greater knowledge about tolerance and mechanisms of tumor cell evasion from
      immune effectors has made the prospect of developing clinically effective immune
      therapies for cancer seem promising. Research in immune therapies for sarcoma has
      been limited, mainly because of the previous lack of defined tumor antigens in
      this disease and the low prevalence of sarcoma in the general population. We will
      review the fundamental concepts of tumor immunobiology, both cellular and
      humoral, and highlight the new, powerful methods for identifying novel tumor
      antigens. Further, we will focus on the unique situation presented by sarcoma as
      the only solid tumor in which many cytogenetic abnormalities have been
      characterized which encode for unique, tumor-specific fusion proteins that are
      ideal targets for immune-based therapy. We will review the specifics of vaccine
      therapy approach to this disease, with emphasis on strategies to improve the
      immunogenicity of newly defined tumor antigens in sarcoma.

PMID- 10402639
TI  - Chemoradiation treatment strategies for localized sarcoma: conventional and
      investigational approaches.
AB  - Current chemoradiation treatment strategies have largely evolved out of the
      experience reported by Eilber and colleagues from the University of California,
      Los Angeles (UCLA). The favorable local control rates they reported using intra
      arterial doxorubicin-based concurrent chemoradiation have been confirmed by
      several other groups with some groups reporting local control rates in excess of
      95% with this approach. This has led to further studies designed to evaluate: 1)
      the optimal route for chemotherapy administration--intra-arterial vs.
      intravenous, 2) the possible advantage of protracted infusion of the
      radiosensitizer vs. brief infusion, 3) the efficacy of other intravenous and oral
      radiation sensitizers, and 4) the efficacy of sequential chemoradiation using
      multi-agent chemotherapy alternating with radiotherapy. The results of these
      investigations are reviewed as the basis for ongoing research evaluating
      chemoradiation strategies for the treatment of patients with localized sarcoma.

PMID- 10402641
TI  - Preclinical experimental therapeutic approaches in soft tissue sarcoma.
AB  - Soft tissue sarcomas are relatively rare tumors that are generally treated with a
      multimodality approach including surgery, chemotherapy, and radiation therapy.
      Despite this aggressive tri-modality therapy, greater than 50% of soft tissue
      tumors will recur and result in diffuse metastatic spread of disease and
      ultimately death of the patient. It is this clinical scenario that drives the
      development of preclinical experimental studies designed to explore alternative
      treatments or enhance the effectiveness of existing therapies. Rapid developments
      in the field of molecular biology have led to the understanding of basic cellular
      processes governed by oncogenes and tumor suppressor genes. These cellular genes
      are sometimes overexpressed, mutated or even deleted from tumor cells.
      Cytogenetic analysis has led to the discovery of sarcoma fusion genes which
      encode for oncoproteins peculiar to specific subtypes of soft tissue sarcomas.
      These fusion genes have proved to be helpful in terms of diagnostic dilemmas and
      are now being used as targets in treatment strategies aimed at suppression of the
      cellular expression and action of these oncoproteins. Tumor suppressor genes such
      as p53 and the retinoblastoma tumor suppressor play important roles in growth
      inhibition and cell cycle progression. These tumor suppressors are often mutated
      or deleted in soft tissue sarcomas. Using gene therapy strategies, p53 can be
      reintroduced into sarcoma cells and has been shown to result in a dramatic
      decrease in cell survival. It also appears that p53 may sensitize these tumor
      cells to radiation and chemotherapy agents. Strategies which can drive tumor
      cells into programmed cell death pathways are also showing promise as novel
      treatment approaches to soft tissue sarcomas. This review will highlight some of
      the current research exploring novel treatment strategies aimed at molecular
      targets. Further development of these and other preclinical experimental programs
      are important in improving the outcome for patients with these rare soft tissue
      tumors.

PMID- 10402642
TI  - Effective follow-up strategies in soft tissue sarcoma.
AB  - The value of surveillance for detection of recurrences in patients with soft
      tissue sarcoma (STS) after definitive surgical resection of the primary tumor is
      based on the premise that early recognition and treatment of local or distant
      recurrence can prolong survival. Surveillance strategies should meet the criteria
      of easy implementation, accuracy, and cost-effectiveness. Although guidelines
      have been proposed for follow-up of patients with STS, there are few data in the
      medical literature on the effectiveness of these recommendations. We reviewed the
      effectiveness of a surveillance program for primary extremity STS in an effort to
      provide an evidence-based rationale for follow-up of STS. We concluded that
      clinical assessment of patient symptoms, chest X-ray imaging, and physical
      examination are effective strategies for follow-up of extremity STS. Chest X-ray
      imaging also appears to be cost-effective, at least for high-grade extremity STS.
      Imaging of the primary extremity site by computed tomography (CT) scan or
      magnetic resonance imaging (MRI) on an annual basis and routine laboratory blood
      tests were ineffective strategies for recurrence detection. However, certain
      patient characteristics such as body habitus, previous radiation therapy, and
      location of the primary tumor site may require the use of CT scans and MRI for
      adequate clinical assessment. The role of specific surveillance strategies for
      recurrence detection for sarcomas of the trunk, head and neck, retroperitoneum,
      and viscera has yet to be defined.

PMID- 10402643
TI  - [Effect of transition metal cations on Na+-Ca2+-exchange in cell membrane].
AB  - The possible mechanism of transient metals effect on Na(+)-CA2+ exchange of
      membrane in excitable and non-excitable cells has been examined on the basis of
      available literature and personal investigation. Different cations of transient
      metals can either inhibit or stimulate Na(+)-Ca2+ exchange depending on
      experimental conditions and their own properties. In some conditions these
      cations can even be translocated by the exchanger. Metal cations with the highest
      affinity to O-containing protein groups are able to inhibit the activity of
      exchanger due to the competition with Ca2+ within the transport site. Metal
      cations with the highest affinity of S-containing protein groups have stimulated
      the exchanger owing to their effect on the regulatory site. The total effect of
      different cations in each case is determined by the effectiveness of all these
      processes (inhibition, translocation and stimulation) which depends on the
      affinity of the cations to different protein functional groups. It has been
      assumed that complex investigation of the effect of different transient metals'
      cations is necessary for the revealing of Na(+)-Ca2+ exchange mechanism.

PMID- 10402644
TI  - [Mechanism of the antistressor and antiradiation action of plant phenol
      compounds].
AB  - The article analyses critically the date from literature as well as own date
      concerning appropriateness and mechanisms of antiradiation, capillary
      strengthening and antistress effect of plant phenolic compounds. Knowledge on
      antioxidant effect as the most fundamental mechanism being in the basic of the
      above mentioned biologic effects of plant phenolic compounds is grounded.

PMID- 10402645
TI  - [Plant metallothioneins].
AB  - The review is devoted to the problem of metal-binding proteins (metallothioneins)
      in plant objects. The chronology of studies, dealt with search of metallothionein
      like proteins in plant tissues is described. Data about the structure and
      function of metallothioneins, the features of metallothioneins-like gene
      expression in plants is shown. The role of metallothioneins as stress proteins,
      which are involved in formation of plant reaction on the influence of different
      stress factors, is discussed.

PMID- 10402646
TI  - [Effect of blood plasma inhibitors on activity of serine and cysteine
      proteinases].
AB  - Data on study of action plasma inhibitors on activity of pancreatic proteolytic
      enzymes (trypsin, chymotrypsin) and plant proteinases (papain, bromelain),
      included in composition of enzyme mixes, used for orally application are
      submitted. It is established, that serine proteases are more sensitive to
      inactivation of plasma inhibitors, than cysteine enzymes. Main inhibitor of the
      papain and bromelain is alpha-2-macroglobulin in complex with which they preserve
      significant part of initial activity. A high-sensitivity method of determination
      of activity enzyme combinations, enabling to detect nanograms of them in presence
      of plasma inhibitors is offered. It can be used for study pharmacokinetic and
      optimization of enzyme mixes application in clinical practice.

PMID- 10402647
TI  - [Inhibition of nuclear histone proteolysis by nucleotides].
AB  - Effects of nucleotides on the proteolysis of histones in nuclei incubated at 37
      degrees C during 1, 3 and 20 h were studied. It has been shown that the H1
      histone is removed first during proteolysis and then the H3 and H2B histones are
      digested. The H4 histone is not cleaved even after 20 h incubation. PMSF and ATP
      inhibit the H1 cleavage when its structure was not disturbed before ATP, CTP,
      ADP, NAD+, AMP and NADH inhibit the partial cleavage of the core histones H3 and
      H2B. ATP, CTP, AMP and NADH prevent the total digestion of H2B. ATP and, at lower
      extent, CTP prevent the H3 digestion. ATP, CTP, ADP and NAD+ inhibit the cleavage
      of the H2A histone in the experiments with 20 h incubation, when H4 is only
      resistant in the absence of nucleotides. The data obtained suggest an important
      role of ATP and other nucleotides in maintaining the structure of histones and
      chromatin.

PMID- 10402648
TI  - [In vitro study of regulation of rat liver xanthine oxidase activity by
      antioxidant reducing agents].
AB  - It was learned the regulation of xanthine oxidase activity from rat liver in the
      partly purified prepared by ascorbic acid, glutathione-SH, dithiothreitol,
      cysteine++ and hydrocortisone++. It was shown that ascorbic acid glutathione-SH,
      dithiothreitol, and cysteine++ can be activators and uncompetitor inhibitors of
      xanthine oxidase in dependence from concentration. As far as hydrocortisone is
      concerned, it is a powerful uncompetitor inhibitor of xanthine oxidase, that is
      bind with it. It was considered the mechanism of activation and inhibition of
      xanthine oxidase by these reductors-antioxidants.

PMID- 10402650
TI  - [Physico-chemical characteristics and functional properties of membrane-bound
      hemoglobin].
AB  - It was shown that fetal form of haemoglobin (Hb) is mainly connected with
      membrane of peripheral red blood corpuscles. Membrane-bound haemoglobin has
      relatively high affinity to O2, low Hill's coefficient, much higher peroxidase
      activity in comparison with cytosolic Hb.

PMID- 10402649
TI  - [Relationship between values of antioxidant enzyme system activity in various
      tissues of intact rats].
AB  - It was studied the relation between activities of ferments an antioxidant system:
      of superoxide dismutase, catalase and GSH-peroxidase in the homogenates of
      livers, lungs and cerebrum of intact rats. When activities were brought to
      identical units of measurement, it was determined that relation of activities can
      see with a point to view of chemical kinetics laws for consecutively-parallel
      reactions. It is followed from the result that the activity of catalase livers
      can be explained by the participation of catalases in other reactions, which were
      connected with forming a hydrogen peroxide. From the relations between ferments
      of antioxidant system it was discovered that GSH-peroxidase is the most important
      antioxidant enzyme for the cerebrum. Data of the relation of activities ferments
      of antioxidant system are stipulated by the tissues particularities and they are
      reflected a contribution of every biocatalyst in that system.

PMID- 10402651
TI  - [Effect of hypoxia on activity of glucose-6-phosphate dehydrogenase in red mullet
      and sea scorpion tissues].
AB  - 90 min hypoxia (50% initial saturation) does not change the level of glucose-6
      phosphate dehydrogenase activity in liver and brain of the red mullet. It is
      shown, that existence of the sea scorpion in environmental with low oxygen
      concentration (15% initial saturation) results in the increasing in this enzyme
      activity for 68% (p < 0.05). The rise of h values for NADP in 1.2-1.4 times and
      substrate-binding ability in 1.5-3 times are found for glucose-6-phosphate
      dehydrogenase from sea scorpion liver under hypoxia.

PMID- 10402652
TI  - [Photoperiodic changes of the glutathione system of the brain under acute
      hypoxia].
AB  - The effect of acute hypoxic hypobaric hypoxia on the content of reduced
      glutathione and the activity of glutathione peroxidase, glutathione reductase,
      glucose-6-phosphate dehydrogenase and glutathione S-transferase, as well as 5'
      nucleotidase in homogenates of juvenile male rats under conditions of varying
      photoperiodic duration: natural conditions of illumination, continuous
      illumination and continuous darkness were studied. Photoperiodic changes were
      revealed in the glutathione system of the control animals: the activity of
      glutathione peroxidase, glutathione reductase and glucose-6-phosphate
      dehydrogenase reduces under constant light, while the activity of glutathione
      peroxidase and glutathione S-transferase increases under conditions of constant
      darkness. The greatest inhibitory effect on the state of the glutathione system
      is brought about by constant light in case of acute hypoxia: the content of
      reduced glutathione decreases along with a sharp drop of the activity of
      glutathione S-transferase and glucose-6-phosphate dehydrogenase, observed against
      the background of decreased glutathione reductase activity. Permanent dark
      conditions eliminate partially or completely the negative effect of acute hypoxia
      on the glutathione system of the brain. The obtained results are indicator of a
      possibility of protecting role of melatonin in case of acute hypoxia.

PMID- 10402653
TI  - [Humoral link of autoimmune reactions to neuron-specific enolase in post
      radiation encephalopathy patients].
AB  - The purpose of this research was to study the humoral link of autoimmune response
      to the brain antigen i.e. neurospecific enolase (NSE) in liquidators of the
      Chernobyl accident aftereffects diagnosed as having "postradiation
      encephalopathy" (PREP). Determined in the PREP patients' serum were: NSE content,
      level of autoantibodies to NSE, concentration and size of the immune complexes
      (IC) as well as NSE content in the IC. The majority of PREP patients revealed
      high serum level of NSE and high level of autoantibodies to NSE. Concentration of
      small and middle-size IC was 2-3 times higher than normal. So the presence of
      circulating NSE and autoantibodies thereto in the liquidators' blood serum
      evidences of an organic lesion of the brain neurons, this causing the development
      of neurological syndromes. It is likely that at certain stages of the PREP
      pathogenesis there appear autoimmune responses to neuroantigens which prove the
      destructive effects of radiation on the CNS. Probably, in patients with PREP 2-3
      degrees the autoimmune processes become chronic due to pathogenic action of free
      autoantibodies to NSE and of small NSE-anti-NSE complexes which are known to be
      the most pathogenic and capable of being fixed on complementary brain structures
      promoting their damage.

PMID- 10402654
TI  - [Effect of surgical thread from the dura mater, modified with succinate, on the
      energy metabolism of white rat kidney mitochondria].
AB  - The activity of energy metabolism has been studied in the experiment with white
      rats, which had been carried out nephrotomia with following use for suture such
      absorbable surgical threads as catgut plain, biofil (of dura mater spinalis of
      the cattle) and biofil modified with succinate. The research proves the use of
      catgut plain decreases of energy quotient and such polarographic index as the
      rate of phosphorylating respiration of mitochondria of the kidneys in
      postoperative period. The greater activity of energy metabolism during this
      period has been stated with the use of biofil. The use of biofil modified with
      succinate results in the activation of bioenergy processes.

PMID- 10402655
TI  - [Effect of Arnica montana tincture on some hydrolytic enzyme activities of rat
      liver in experimental toxic hepatitis].
AB  - Effects of tinctura arnica on arginase, adenosine triphosphatase, glucose-6
      phosphatase and 5'-nucleotidase activities of rats liver in case of experimental
      toxic hepatitis have been studied. Toxic hepatitis was caused by 2 times
      interstomach administration of 0.25 ml oil solution of carbon tetrachloride per
      100 g of animal weight. 20 mkl/100 g of tinctura arnica was administered every
      day per os for 14 days. The enzyme activities have been investigated at 3, 7 and
      17 days. A significant demention of a studied hydrolytic enzyme activities in
      rats liver at intoxication of the body by CCI4 has been shown. It has been
      established that tinctura arnica administered per os to intoxicated animals sped
      up the normalization of hydrolytic enzyme activities in rat liver.

PMID- 10402656
TI  - [Inclusion of protein and nucleic acid precursors by staphylococci that are
      sensitive and resistant to antibiotics].
AB  - We have convey comparative study of including intensity of marking protein
      predecessors and nucleic acids by initial strains of Staphylococcus aureus
      sensitive to antibiotics and strains, which contain plasmids of resistance to
      different antibiotics. Shown including intensity increase of adenine, uridine,
      thymidine and marked amino acids by strains which contain plasmids of resistance
      to different antibiotics to compare with unplasmids variant. On the base of
      receiving results we may affirm that in general we observe intensification of
      protein synthesis and separate staves nucleic acid synthesis by observing staunch
      strains.

PMID- 10402657
TI  - [Effect of selenium on the functional state of white rat kidney in aluminum
      cadmium poisoning].
AB  - The breach of kidney's functional state and also the possibility of their
      selenite correction were researched after aluminium and cadmium intoxication.
      Aluminium chloride intensifies acid-secrete function of kidney. Cadmium chloride
      and its combination with aluminium chloride change the transport of sodium.
      Sodium selenite has aptitude for correction of the functional renal state in the
      case of aluminium and cadmium joint intoxication.

PMID- 10402658
TI  - [Age features of oxidative processes in rat liver caused by toxic damage from
      tetrachloromethane].
AB  - It has been studied the effect of tetrachlormethane on the activity of the
      processes of microsomal mitochondrial and free radical oxidation in 3.8-10 and 20
      24 month rats. The age peculiarities of the investigated processes have been
      ascertained. The introduction of CCl4 caused: the most increase of the level of
      free radical oxidation products in young animals. The activity of oxidative
      processes in microsomes were minimum in this group of animals. In old rats the
      contents of intermediate products of FRO increased in the least degree and end
      products--the same as young animals. The oxidative processes in mitochondria were
      decreased in the most degree in old rats. It has been concluded that the
      activation of free radical reactions by active metabolites of CCl4 plays the main
      role in progress of pathological processes in young animals and the covalent
      connection of low active radicals with proteins of membranes and enzymes in old
      rats.

PMID- 10402659
TI  - [Indicators of lipid peroxidation in rat liver mitochondria after exposing them
      to some xenobiotics and the action of low dose radiation].
AB  - The contents of primary and secondary products of lipid peroxidation in rat liver
      mitochondria through 1, 7 and 15 days after gamma-irradiation in a dose 0.5 Gy on
      a background of consumption of sodium nitrate, sodium nitrite and
      nitrosodiethylamine was investigated. Is was shown, that gamma-irradiation on a
      background of sodium nitrate, sodium nitrite and nitrosodiethylamine modified
      effects of nitrocompounds on speed of lipid peroxidation. Besides, combine action
      of sodium nitrate and gamma-irradiation has more effect in comparison with
      influencing of separate factors. The observed changes in quantity of lipid
      peroxidation products are rather stable and are kept during all terms of
      supervision.

PMID- 10402661
TI  - [Neurotrophic action of nicotinamide and nicotinoyl-GABA in rat brain in
      experimental Parkinsonism].
AB  - It was established, that the content of nicotinamide adenine dinucleotides and
      the binding of NAD by isolated brain cortex synaptic membranes under experimental
      parkinsonism are impaired. Treatment of the experimental results in the Scatchard
      plots for binding of [U-14C]NAD to the brain cortex synaptic membranes
      demonstrated that binding capacities lowered, without changes of affinities. NAD
      glycohydrolase involved in development of this pathology. The modulative effect
      of in vivo administered NAm and nicotinoyl-GABA supposes that NAm acts via NAD
      which binds specifically with synaptic membranes. Thus, NAm and nicotinoyl-GABA
      are involved in the regulation of the processes in the brain under experimental
      parkinsonism.

PMID- 10402660
TI  - [Disturbances in catecholamine metabolism during formation and development of
      chronic alcoholism].
AB  - There has been carried out an investigation dealing with catecholamines
      metabolism in the patients suffering from alcoholism in the first, second and
      third stage at the short-term remission. The first developed alcoholism stage was
      determined as a typical one for increasing the excretion with urine of DOPA,
      dopamine (DA), noradrenaline (NA) and adrenaline (A), as well as the blood levels
      of DA, NA and A. DA/NA rate evidences about an increased synthesis of NA with DA.
      The marked second alcoholism stage is characterized by an acute decrease of
      excreting with urine and blood levels of NA. Alongside with the latter. DA
      excretion with urine and its blood levels remained high. DA/NA rate indicates to
      the considerably low relative activity of NA with DA synthesis, both in relation
      to the control and to the developed first alcoholism stage. In the third
      alcoholism stage NA excretion with urine and its blood levels become lower
      relatively to the marked second stage. Simultaneously DA excretion with urine and
      its blood levels are lower than in the developed second stage, hower exceed the
      control values. DA/NA rate testifies the slight activation of NA and DA
      synthesis. The results obtained in the work indicate to the significant role of
      CA metabolism disturbances in the alcoholic dependence formation.

PMID- 10402662
TI  - [Change in the lipid status of the erythrocyte membrane in essential
      hypertension].
AB  - The erythrocyte ghosts fatty acid composition of 29 patients with essential
      hypertension of the II stage were investigated. The significant decrease of some
      saturated fatty acids as myristic, palmitic and stearic under hypertension was
      established. Simultaneously the percent of omega-6 arachidonic and docosatrienoic
      acids substantially increased. At the same time no changes in omega-3 fatty acids
      were observed. The possible relationship between hypercholesterolemia and
      erythrocyte membrane fatty acid profile under essential hypertension discussed.

PMID- 10402663
TI  - [Dynamics of the interaction of polyreactive immunoglobulins with immobilized
      antigens].
AB  - The kinetic of polyreactive immunoglobulins (PRIG) and immobilized antigen
      interaction was examined at different temperatures. It was shown that this
      process can be described by the so-called "competitive" model, and the relatively
      simple method for the rate constant determination for this process was developed.
      According to the "competitive" model PRIG molecule could be either in "active" or
      in "inactive" state and dynamic equilibrium exist between "active" and "inactive"
      molecules which strongly depend on incubation temperature. Only "active" PRIG can
      interact with antigens, and this is the reason of strong temperature dependence
      of PRIG-antigen interaction. The data also show that the mechanism of PRIG
      antigen interaction differ from that of antibody-antigen interaction.

PMID- 10402664
TI  - [A new graphic method for determining the rate constant for affinity of a ligand
      for its receptor].
AB  - A new method of determination of the equilibrium constant for a ligand binding to
      acceptor and evaluation of the number of binding sites on the acceptor molecules
      (or cells) is suggested. The method is simpler, more convenient, and more precise
      than Klotz's or Scatchard's method.

PMID- 10402665
TI  - [Delayed assessment of glucose level bioassays using a chemical stabilizer].
AB  - We have studied 36 chemical compounds. Moreover bromide 9,10
      bismethyltriphenylphosphoniumantracene has been found to stabilize bioassays and
      preserve their glucose content unchanged for a period of 75-990 days. Due to its
      use a delayed technique of a quantitative assessment of glucose in biologic
      objects has been elaborated characterized by universal novelty. It may be used
      with the aim of studying metabolic processes in the cosmonauts body, atomic
      submarine crews members of polar, alpine, desert, underwater, space and other
      expeditions which cannot be accompanied by a biochemical laboratory.

PMID- 10402666
TI  - [The possible H+-dependent functional connection between cell membrane and
      mitochondria in smooth muscle cells].
AB  - It has been found that Mg2, ATPase of the smooth muscle cells plasma membrane has
      the properties of an H(+)-sensitive enzymatic sensor which is characterized by a
      linear dependence between the initial maximal rate of the reaction, V0, and the
      pH value. The feasible role of plasma membrane Mg(2+)-ATPase in some reactions
      responsible for the control of proton and Ca2+ homeostasis in myometrium cells
      has been debated.

PMID- 10402667
TI  - Maternal and child health statistics: Russian Federation and United States,
      selected years 1985-95.
AB  - This report provides comparative maternal and child health data for recent years
      for the Russian Federation and the United States. Statistical data for Russia are
      from the Ministry of Health of Russia and from Goskomstat, the central
      statistical organization of Russia. Information for the United States comes from
      various data systems of the National Center for Health Statistics as well as
      other parts of the Department of Health and Human Services. A background section
      provides a description of each country's health care system and national
      guidelines for maternal and child health care. This information is intended to
      assist the reader in interpreting the subsequent sections on various aspects of
      maternal and child health. The report uses tables, figures, and commentary to
      present information on many different health measures for mothers, infants,
      children, and adolescents in the two countries. Topics covered include population
      size, prenatal and obstetrical care, abortions, natality, breastfeeding,
      mortality, immunization, communicable diseases, and other morbidity measures. The
      commentary includes a discussion of data quality issues that affect the accuracy
      and comparability of the information presented. Data are provided for selected
      years from 1985 to 1995. When available, additional detail is provided for key
      subgroups of each population: for the Russian Federation, urban and rural
      populations; for the United States, black and white racial groups. A glossary of
      terms at the end of the report provides additional information on definitions and
      data sources and limitations.

PMID- 10402668
TI  - Impaired retinol utilization in Adh4 alcohol dehydrogenase mutant mice.
AB  - Adh4, a member of the mouse alcohol dehydrogenase (ADH) gene family, encodes an
      enzyme that functions in vitro as a retinol dehydrogenase in the conversion of
      retinol to retinoic acid, an important developmental signaling molecule. To
      explore the role of Adh4 in retinoid signaling in vivo, gene targeting was used
      to create a null mutation at the Adh4 locus. Homozygous Adh4 mutant mice were
      viable and fertile and demonstrated no obvious defects when maintained on a
      standard mouse diet. However, when subjected to vitamin A deficiency during
      gestation, Adh4 mutant mice demonstrated a higher number of stillbirths than did
      wild-type mice. The proportion of liveborn second generation vitamin A-deficient
      newborn mice was only 15% for Adh4 mutant mice but 49% for wild-type mice. After
      retinol administration to vitamin A-deficient dams in order to rescue embryonic
      development, Adh4 mutant mice demonstrated a higher resorption rate at stage
      E12.5 (69%), compared with wild-type mice (30%). The relative ability of Adh4
      mutant and wild-type mice to metabolize retinol to retinoic acid was measured
      after administration of a 100-mg/kg dose of retinol. Whereas kidney retinoic acid
      levels were below the level of detection in all vehicle-treated mice (< 1
      pmol/g), retinol treatment resulted in very high kidney retinoic acid levels in
      wild-type mice (273 pmol/g) but 8-fold lower levels in Adh4 mutant mice (32
      pmol/g), indicating a defect in metabolism of retinol to retinoic acid. These
      findings demonstrate that another retinol dehydrogenase can compensate for a lack
      of Adh4 when vitamin A is sufficient, but that Adh4 helps optimize retinol
      utilization under conditions of both retinol deficiency and excess.

PMID- 10402669
TI  - Trophoblast giant cells express NF-kappa B2 during early mouse development.
AB  - To investigate whether transcription factors of the NF-kappa B family could play
      a role in early mammalian development, we have analyzed the expression of nfkb1,
      nfkb2, c-Rel, RelA, RelB, and bcl-3 from 6.5- to 10.5-day mouse embryo
      implantation sites. Our study shows that nfkb2 mRNA and protein are specifically
      localized in trophoblast giant cells throughout the stages analyzed. Trophoblast
      giant cells obtained upon in vitro cultures of 7.5-day ectoplacental cones
      display NF-kappa B DNA-binding activity that is supershifted by the anti-NF-kappa
      B2 antibody. Trophoblast giant cells are embryo-derived cells that form an
      interface between embryonic and maternal tissues during early mouse development;
      they are involved in decidual remodeling and expansion of the embryonic cavity,
      placenta formation, and possibly avoidance of maternal immune response to the
      embryo. Our study suggests that NF-kappa B2 could play a role in the modulation
      of genes expressed in trophoblast giant cells during the course of early
      embryogenesis, and therefore be relevant for tissue remodeling and morphogenesis
      of placenta.

PMID- 10402670
TI  - Constitutive and stress-inducible expression of the endoplasmic reticulum heat
      shock protein 70 gene family member, immunoglobulin-binding protein (BiP), during
      Xenopus laevis early development.
AB  - We have characterized the constitutive and stress-inducible pattern of
      immunoglobulin-binding protein (BiP) gene expression during Xenopus early
      development. Whole mount in situ hybridization analysis revealed that BiP mRNA
      was detected in unfertilized eggs, cleavage and blastula stage embryos. In
      gastrulae, BiP mRNA was present across the surface of the embryo, while in
      neurulae BiP mRNA was enriched in the neural plate, neural fold, and around the
      blastopore. In early and late tailbud embryos, BiP mRNA was found primarily in
      the dorsal region. Tunicamycin and A23187, the calcium ionophore, enhanced BiP
      mRNA accumulation first at the neurula stage, while heat shock induced BiP mRNA
      accumulation first at the gastrula stage. Compared to control, A23187- and heat
      shock-treated neurulae displayed relatively high levels of BiP mRNA in selected
      tissues, including the neural plate, neural folds, around the blastopore, and
      ectoderm. At the early tailbud stage, A23187 and heat shock enhanced BiP mRNA
      accumulation primarily in the head, somites, tail, and along the spinal cord. A
      similar situation was found with A23187- and heat shock-treated late tailbud
      embryos, except that heat-shocked embryos also displayed enhanced BiP mRNA
      accumulation in the epidermis. These studies demonstrate a preferential
      accumulation of BiP mRNA in selected tissues during development and in response
      to stress.

PMID- 10402671
TI  - Distal upstream tyrosinase S/MAR-containing sequence has regulatory properties
      specific to subsets of melanocytes.
AB  - A distal upstream regulatory element of the mouse tyrosinase gene has locus
      control region (LCR)-like activity and is required for position-independent
      expression of linked genes. It consists of a DNAse I hypersensitive site, which
      has enhancer activity in neural crest-derived melanocytes, embedded within a
      scaffold/matrix attachment region (S/MAR), both of which are necessary for LCR
      activity. To address the role of the S/MAR in position-independent expression, we
      assessed the ability of a fragment containing most of the S/MAR to insulate a
      transgene from position effects. The S/MAR sequence showed a striking cell type
      specificity in its function in all six multicopy transgenic lines, dampening
      position effects considerably in cutaneous melanocytes while allowing no
      expression in other neural crest-derived melanocytes, and causing elevated
      expression in ocular melanocytes derived from the neural tube. The specificity of
      transgene expression in the eye suggested the presence of both positive and
      negative regulatory elements in this enhancer/S/MAR region, which was confirmed
      by transient transfection analyses. This is the first known regulatory element to
      exhibit different activities in melanocytes of different developmental origins.

PMID- 10402672
TI  - Gene trap screening using negative selection: identification of two tandem,
      differentially expressed loci with potential hematopoietic function.
AB  - A fusion gene between Escherichia coli lacZ and herpes simplex virus thymidine
      kinase (HSV-tk) was constructed and used in a gene trap screen for hematopoietic
      loci in mouse embryonic stem (ES) cells. This gene, galtek, allowed both
      convenient histochemical detection of expression as well as ablation of
      expressing cells under 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil
      (FIAU) selection. Individual ES cell clones bearing gene trap insertions were
      differentiated in the presence of FIAU and scored for erythropoietic activity at
      day 9 of differentiation. Screening of a total of 235 independent gene trap lines
      identified one clone, F3, which consistently demonstrated FIAU-sensitive
      erythropoiesis during in vitro differentiation. Cloning of endogenous transcribed
      sequences from the F3 insertion site identified two distinct transcription units,
      F3-1 and F3-2, encoding mRNAs of approximately 1.3 kb and 3.35 kb, respectively.
      The transcripts were unrelated and did not exhibit similarity to known sequences.
      Both loci demonstrated similar relative levels of expression in the heart,
      testis, kidney, and lung as assessed by Northern blot hybridization. Whole-mount
      in situ hybridization detected F3-2 expression at multiple sites in embryonic day
      (E) 10.5 embryos, including the genital ridges, the aortic endothelium, and
      endothelium-associated cell clusters within the aortic lumen. Expression of F3-2
      in the aortic endothelium and endothelium-associated clusters overlapped that of
      gata-2, a gene required for hematopoietic development. The FIAU sensitivity of
      hematopoiesis in F3 embryoid bodies may result from expression of galtek during
      the formation of early hematopoietic cells, directed by regulatory signals from
      one or both of these endogenous loci.

PMID- 10402674
TI  - Aluminum speciation studies in biological fluids. Part 5. A quantitative
      investigation of A1(III) complex equilibria with desferrioxamine, 2,3
      dihydroxybenzoic acid, Tiron, CP20 (L1), and CP94 under physiological conditions,
      and computer-aided assessment of the aluminum-mobilizing capacities of these
      ligands in vivo.
AB  - While the involvement of environmental aluminum toxicity in the advent of senile
      dementias is still debated, acute aluminum toxicity of iatrogenic origin is well
      documented. So far, the only treatment available against it has been
      desferrioxamine (DFO), which induces major side effects. New drugs are thus
      highly desirable, and possible DFO substitutes have already been considered
      through various techniques. An important test for such new drugs is to assess
      their A1-mobilizing capacity in vivo. This can be done by computer-aided
      speciation provided formation constants for the corresponding A1(III) complexes
      are known beforehand. The present work reports an investigation of A1(III)
      complex equilibria with five sequestering ligands including DFO, and predicts the
      respective capacities of these to mobilize aluminum in vivo under normal and
      inflammatory conditions.

PMID- 10402673
TI  - tip genes act in parallel pathways of early Dictyostelium development.
AB  - Analysis of Dictyostelium strains carrying null mutations in tipA showed a
      primary defect in cell sorting and the formation of tips on the developing mound.
      To study the process affected in tipA- mutants further, other mutants with a
      similar phenotype were isolated and characterized. These studies showed three new
      Dictyostelium genes: tipB, tipC, and tipD. All the tip mutants aggregate into
      larger than average mounds, which split up and form many lips on their surfaces.
      Furthermore, each mutant exhibits reduced or aberrant cell-sorting behavior,
      never makes migrating slugs, and has severely reduced fruiting body and spore
      production. The mRNA of each tip gene is present in vegetative cells and does not
      vary significantly with development. Prespore and prestalk gene expression is
      reduced or delayed in the tip mutants indicating cell type differentiation is
      dependent on the function of these genes. Developing mutant cells in chimeric
      mixtures with wildtype cells demonstrated that the defects in each tip mutant
      behave cell autonomously. The overexpression of TipA in a tipB- background and
      the overexpression of TipB in a tipA- background significantly improved the
      morphogenesis of these mutants. These were the only situations in which the
      expression of one tip gene could compensate for the lack of a different tip gene.
      Except for the tipA-/tipB- strain, double mutations in the tip genes have
      additive effects, causing a more severe mutant phenotype with defects earlier in
      development than single mutants. The tipA-/tipB- double mutant does not show
      additive effects and is very similar to the tipA-single mutant. Analysis of the
      effects of double mutations and overexpression indicates that members of this
      class of genes appear to act through parallel pathways of differentiation and tip
      formation in early Dictyostelium development. Furthermore, TipA and TipB appear
      to have some overlapping functions or are involved in the same pathway. The
      multitipped phenotype observed in all the mutants may be a general result of
      perturbing early developmental events such as cell type differentiation and cell
      type proportioning.

PMID- 10402676
TI  - Synthesis and spectroscopic properties of copper(II) complexes derived from
      thiophene-2-carbaldehyde thiosemicarbazone. Structure and biological activity of
      [Cu(C6H6N3S2)2].
AB  - The synthesis, structure and spectroscopic properties on complexes with the
      formula [Cu(Lm)2] (1) and Cu(NO3)2(HLm)2 (2), where HLm = thiophene-2
      carbaldehyde thiosemicarbazone, have been developed. The molecular structure of
      compound 1 consists of monomeric entities. The copper(II) ions exhibit distorted
      square-planar geometry with both bidentate thiosemicarbazone ligands placed in a
      centrosymmetric way. Metal to ligand pi-backdonation is proposed to explain
      several structural and spectroscopic features in these complexes. The EPR spectra
      of compound 1 show an orthorhombic g tensor indicating the presence of weak
      magnetic exchange interactions. The reaction of compound 1 with glutathione
      causes the reduction of the metal ion and the substitution of the
      thiosemicarbazone ligand by the thiol ligand. This mechanism seems to be related
      to the cytotoxicity of this complex against Friend Erithroleukemia cells (FLC)
      and melanome B16F10 cells.

PMID- 10402675
TI  - Cr(IV) causes activation of nuclear transcription factor-kappa B, DNA strand
      breaks and dG hydroxylation via free radical reactions.
AB  - Electrophoretic mobility shift, DNA strand breakage assays and electron spin
      resonance (ESR) spin trapping were used to investigate the activation of nuclear
      transcription factor (NF)-kappa B, DNA strand breakage and 2'-deoxyguanosine
      hydroxylation induced by Cr(IV), as well the role of free radical reactions in
      these processes. Incubation of synthesized Cr(IV)-glutathione complex with
      cultured Jurkat cells resulted in activation of DNA binding activity of NF-kappa
      B. Cr(VI) is also able to induce NF-kappa B activation through Cr(V) and Cr(IV)
      intermediates generated during the reduction of Cr(VI) by the cells. Cr(III) did
      not cause observable NF-kappa B activation due to its inability to cross cell
      membranes. Cr(IV)-induced NF-kappa B activation is dose-dependent. Catalase
      inhibited the activation while superoxide dismutase enhanced it. The metal
      chelator, deferoxamine, and hydroxyl (.OH) radical scavengers, sodium formate and
      aspirin, also inhibited the NF-kappa B activation. Electrophoretic assays using
      lambda Hind III linear DNA showed that, in the presence of H2O2, Cr(IV) is
      capable of causing DNA strand breaks. Deferoxamine, sodium formate and aspirin
      inhibited the DNA strand breaks. HPLC measurements also show that .OH radical
      generated by the Cr(IV)-mediated reaction with H2O2 was capable of causing 2'
      deoxyguanosine (dG) hydroxylation to generate 8-hydroxyguanosine (8-OHdG). The
      relative magnitude of 8-OHdG formation correlated with the generation of .OH
      radicals. ESR spin trapping measurements showed that reaction of Cr(IV) with H2O2
      generated .OH radicals, which were inhibited by deferoxamine, sodium formate and
      aspirin. The results show that Cr(IV) can cause NF-kappa B activation, DNA strand
      breaks and dG hydroxylation through .OH radical-initiated reactions. This
      reactive chromium intermediate may play an important role in the mechanism of
      Cr(VI)-induced carcinogenesis. The results also suggest that the Cr(IV)
      glutathione complex may be used as a model compound to study the role of Cr(IV)
      in Cr(VI) carcinogenicity.

PMID- 10402677
TI  - A circular dichroism and fluorescence quenching study of the interactions between
      rhodium(II) complexes and human serum albumin.
AB  - Various divalent rhodium complexes Rh2(L)4 (L = acetate, propionate, butyrate,
      trifluoroacetate and trifluoroacetamidate) have been found to bind to non
      defatted human serum albumin (HSA) at molar ratios about 8:1. The circular
      dichroism measurements showed that the more liposoluble carboxylates, butyrate
      and trifluoroacetate, caused the major alterations of the secondary structure of
      HSA. Stern-Volmer constants for the fluorescence quenching of the buried Trp214
      residue by these complexes were also higher for the lipophilic metal compounds.
      In the case of the rhodium carboxylates it was observed that their denaturating
      and quenching properties could be explained in terms of their liposolubilities:
      the higher their lipophilic characters, the higher their abilities to penetrate
      inside the protein framework leading to structural alterations, and the closer
      they could get to the Trp residue causing fluorescence quenching. The liposoluble
      amidate complex, Rh2 (tfc)4, presented an intermediate quenching and did not
      cause structural alterations in the protein, presumably not penetrating inside
      the peptidic backbone. This study shows that it is possible to design new
      antitumor metal complexes which bind, to a large extent, to a transport protein
      causing little structural damage.

PMID- 10402678
TI  - Revisiting the past and back to the future: memory systems and the linguistic
      representation of social events.
AB  - Five studies were conducted to investigate the relationship between how people
      communicate about social events and how representations of these events are
      stored in memory. It was hypothesized that more distant events in memory would be
      described with more abstract linguistic predicates, and recent events with more
      concrete language. The 1st study supported this hypothesis. The 2nd and 3rd
      experiments demonstrated that abstract predicates used as prompts elicit memories
      that are significantly more removed in time than concrete predicates. Two final
      experiments showed that these outcomes are not merely a function of the type of
      semantic cue but an interaction between memory and preferential predicate use.
      The findings illustrate a link between memory and communicative behavior of a
      type that has not been previously studied. The results are discussed in terms of
      a recent, well-supported model of 2 separate fast-learning and slow-learning
      memory systems.

PMID- 10402679
TI  - The chameleon effect: the perception-behavior link and social interaction.
AB  - The chameleon effect refers to nonconscious mimicry of the postures, mannerisms,
      facial expressions, and other behaviors of one's interaction partners, such that
      one's behavior passively and unintentionally changes to match that of others in
      one's current social environment. The authors suggest that the mechanism involved
      is the perception-behavior link, the recently documented finding (e.g., J. A.
      Bargh, M. Chen, & L. Burrows, 1996) that the mere perception of another's
      behavior automatically increases the likelihood of engaging in that behavior
      oneself. Experiment 1 showed that the motor behavior of participants
      unintentionally matched that of strangers with whom they worked on a task.
      Experiment 2 had confederates mimic the posture and movements of participants and
      showed that mimicry facilitates the smoothness of interactions and increases
      liking between interaction partners. Experiment 3 showed that dispositionally
      empathic individuals exhibit the chameleon effect to a greater extent than do
      other people.

PMID- 10402680
TI  - Attachment and anger in an anxiety-provoking situation.
AB  - In this study, women were told they would engage in an anxiety-provoking
      activity. Women then waited with their dating partner for the activity to begin.
      During this 5-min "stress" period, each couple's interaction was videotaped
      unobtrusively. Each couple was then told that the woman would not have to do the
      stressful activity, and each couple was unobtrusively videotaped again during a 5
      min "recovery" period. The behavior of both partners was then coded during both
      periods. The major results revealed that more-avoidant men displayed greater
      anger during the stress period, especially if their partners were more anxious or
      distressed or sought more support from them. More-avoidant women also displayed
      greater anger, particularly if they were highly anxious or distressed and
      received little support or encountered anger from their partners. During the
      recovery period, highly ambivalent women behaved more negatively toward their
      partners if they had been more anxious in the stress period or had sought more
      support from their partners. These results are discussed in terms of attachment
      theory.

PMID- 10402681
TI  - The relation of rational and experiential information processing styles to
      personality, basic beliefs, and the ratio-bias phenomenon.
AB  - A new version of the Rational-Experiential Inventory (REI), which measures
      rational and experiential thinking styles and includes subscales of self-reported
      ability and engagement, was examined in two studies. In Study 1, the two main
      scales were independent, and they and their subscales exhibited discriminant
      validity and contributed to the prediction of a variety of measures beyond the
      contribution of the Big Five scales. A rational thinking style was most strongly
      and directly related to Ego Strength, Openness, Conscientiousness, and favorable
      basic beliefs about the self and the world, and it was most strongly inversely
      related to Neuroticism and Conservatism. An experiential thinking style was most
      strongly directly related to Extraversion, Agreeableness, Favorable Relationships
      Beliefs, and Emotional Expressivity, and it was most strongly inversely related
      to Categorical Thinking, Distrust of Others, and Intolerance. In Study 2, a
      rational thinking style was inversely related and an experiential thinking style
      was unrelated to nonoptimal responses in a game of chance. It was concluded that
      the new REI is a significant improvement over the previous version and measures
      unique aspects of personality.

PMID- 10402682
TI  - Changes in attractiveness of elected, rejected, and precluded alternatives: a
      comparison of happy and unhappy individuals.
AB  - In 3 studies the authors compared the responses of self-rated happy and unhappy
      students in situations involving choice. In Study 1, high school seniors
      evaluated colleges after applying for admission and then later after making their
      selections. Happy students tended to be more satisfied than unhappy ones with the
      colleges they ultimately chose and those they ultimately rejected, and they more
      sharply devalued the colleges that rejected them. Studies 2 and 3 dealt with
      postdecisional consequences of less consequential decisions about fancy desserts.
      In Study 2, unhappy participants sharply derogated the desserts they rejected or
      were denied, relative to those selected by or for them, whereas happy
      participants showed no such derogation. These group differences, moreover, proved
      to be largely independent of self-esteem and optimism. The design of Study 3
      helped explicate underlying mechanisms by inducing both groups to distract
      themselves or to self-reflect. Doing so eliminated all group differences.
      Implications of the results for the link between cognitive processes and hedonic
      consequences are discussed.

PMID- 10402683
TI  - Assertiveness predicts threat and challenge reactions to potential stress among
      women.
AB  - In this study assertiveness as a moderator of stress reactions among women was
      examined. Specifically, the experimenters examined how high and low assertive
      women cognitively appraised, affectively and physiologically responded to, and
      behaviorally coped with the stress of giving an impromptu speech. High assertive
      women appraised the speech stressor as challenging, whereas low assertive women
      appraised the stressor as threatening. High assertive women also had a challenge
      pattern of autonomic response during the task, compared with the threat response
      of low assertive women. Afterward, the high assertive women reported experiencing
      less stress and negative emotion and greater positive emotion than did the low
      assertive women. Overall, the high assertive women's stress-related reactions
      indicated challenge, whereas the low assertive women's reactions indicated threat
      (see J. Tomaka, J. Blascovich, R. M. Kelsey, & C. L. Leitten, 1993).

PMID- 10402684
TI  - Adult attachment style and the perception of others: the role of projective
      mechanisms.
AB  - In 3 reported studies the authors examined attachment-style differences in the
      perception of others and the hypothesis that projective mechanisms underlie these
      differences. In these studies, participants reported on their attachment style
      and generated actual-self-traits and unwanted-self-traits. Then, a 2nd session
      was conducted, in which impression formation about new persons (Study 1), the
      ease of retrieval of memories about known persons (Study 2), or memory inferences
      about learned features of fictional persons (Study 3) were assessed. Findings
      indicate that whereas anxious-ambivalent persons' impression formation, memory
      retrieval, and inferences about others reflected the projection of their actual
      self-traits, avoidant persons' responses reflected the projection of their
      unwanted-self-traits. Findings are discussed in terms of the regulatory goals and
      strategies that characterize the mental representations of each attachment style.

PMID- 10402685
TI  - Lesbian erotic role identification: behavioral, morphological, and hormonal
      correlates.
AB  - Lesbian scholars hotly debate the validity of "butch" and "femme" erotic roles.
      Although some dismiss them as social constructs, others maintain they are natural
      expressions of lesbian sexuality. The authors compared self-described butch and
      femme lesbians on gender-discriminating behavioral, morphological, and hormonal
      measures. Butch and femme lesbians did not differ from heterosexual women on sex
      role personality traits, depressive symptomology, eating disorders, or body
      dissatisfaction. Butch lesbians, however, recalled more childhood gender-atypical
      behavior and had higher waist-to-hip ratios, higher saliva testosterone levels,
      and less desire to give birth. These findings support the validity of butch-femme
      classification and suggest that butch lesbians are more male-typical compared to
      femme lesbians. The butch-femme classification may reflect a within-group
      difference caused by differential exposure to prenatal androgens.

PMID- 10402686
TI  - Memory bias in obsessive-compulsive disorder (OCD).
AB  - There is a memory bias associated with depression, and good reason to expect a
      memory bias associated with anxiety. However, the results of studies reported to
      date have been ambiguous. Accordingly, an experiment was conducted to assess
      memory for contamination in people with different types of anxiety. Memory for
      contaminated stimuli among participants who met DSM-IV criteria for obsessive
      compulsive disorder (OCD) and indicated a fear of contamination (n = 10) was
      compared to memory in a group of anxious controls (n = 10), and in undergraduate
      students (n = 20). Participants were shown 50 objects, 25 of which were
      contaminated by the experimenter and 25 which were touched but not contaminated.
      They then completed a neuropsychological memory assessment, after which the
      participants were asked to recall all of the objects touched by the experimenter.
      They were then asked to approach each object and to rate their anxiety about
      touching it. Finally, participants were asked about their perceptions of the
      cleanliness of each object. The OCD group had better memory for contaminated
      objects than for clean ones. Neither control group showed such a bias.
      Neuropsychological test scores indicated that this bias is not the result of
      differences in general memory ability. The results are discussed in terms of the
      memory-deficit theory of OCD and of behavioural and cognitive approaches to
      understanding the role of information processing in fear and anxiety.

PMID- 10402687
TI  - Avoidant personality disorder and implicit schema-congruent information
      processing bias: a pilot study with a pragmatic inference task.
AB  - Cognitive theory of personality disorders hypothesizes that each personality
      disorder is characterized by typical maladaptive schemes and that these schemas
      direct the processing of information resulting in schema-congruent biases. With
      regard to the avoidant personality disorder, these hypotheses were put to an
      initial test in a pilot study, using a self-report questionnaire to asses DSM-III
      R personality pathology, a belief questionnaire to assess avoidant schemas and a
      pragmatic inference task to assess schema-congruent implicit attributional bias.
      Participants were students (n = 57) who scored high or low on DSM-III-R avoidant
      personality pathology. As predicted from cognitive theory, DSM-III-R avoidant
      personality pathology was associated with avoidant beliefs (t(45.1) = 4.68, p <
      0.001) and avoidant beliefs were associated with schema-congruent information
      processing bias (t(55) = 2.17, p = 0.02, one-tailed test). However, DSM-III-R
      avoidant personality pathology was not associated with schema-congruent
      information processing bias (t(55) = 0.17, p = 0.43, one-tailed test). In
      addition to avoidant beliefs, low self-esteem was also related to the information
      processing bias. Social phobia and general personality pathology, two other
      control variables, were not. The findings warrant further study using the
      pragmatic inference task in a clinical group.

PMID- 10402688
TI  - Anxiety sensitivity and the five-factor model of personality.
AB  - Relations between anxiety sensitivity (AS) and the higher-order and lower-order
      dimensions of the 'Big Five' model of personality were examined in 317 university
      students. AS was significantly associated with a number of personality domains
      and facets of the NEO-PI-R. Regression analyses indicated that only the higher
      order domains of neuroticism and extraversion (negatively) and the lower-order N
      facets of anxiety and self-consciousness, significantly predicted AS. Three lower
      order factors within AS were identified and were also compared to NEO-PI-R
      domains and facets. In a hierarchical regression, the three AS factors
      significantly predicted variance in a measure of panic-related anxiety after the
      effects of the six N facets were statistically controlled. Results are discussed
      in the context of previous work with a Big Three taxonomy of personality and
      implications for understanding the nature and possible origins of AS are
      outlined.

PMID- 10402690
TI  - The observer perspective: biased imagery in social phobia, agoraphobia, and
      blood/injury phobia.
AB  - Clark and Wells' (1995): 'A cognitive model of social phobia'. In Social phobia:
      Diagnosis, assessment, and treatment (pp. 69-93), R. G. Heimberg, M. R.
      Liebowitz, D. A. & F. R. Hope (eds.); cognitive model of social phobia proposes
      that social phobics generate a negative impression of how they appear to others.
      This impression often occurs in the form of an image from an "observer"
      perspective in which social phobics can see themselves as if from another
      person's vantage point. This study investigated the specificity of the observer
      perspective among patients with social phobia, agoraphobia, and blood/injury
      phobia. All participants were asked to recall and imagine a recent anxiety
      provoking social situation and a non-social/non-anxiety-provoking situation, and
      rate their perspective for each. Consistent with predictions only patients with
      social-evaluative concerns (social phobics and agoraphobics) reported observer
      perspectives for anxiety-provoking social situations. Only social phobics showed
      a significant shift from an observer to a field perspective across the two
      conditions. The clinical implications of these findings are briefly discussed.

PMID- 10402689
TI  - Interpretive biases for ambiguous stimuli in social anxiety.
AB  - A growing body of literature suggests that individuals with high levels of
      general anxiety form threatening interpretations of ambiguous events. Although
      theoretical formulations of pathological social anxiety emphasize the importance
      of a negative interpretive-style in the etiology and maintenance of the disorder,
      we are unaware of any study that documents this presumed phenomenon. To address
      this issue, we assessed for possible interpretive biases in a group of high and
      low socially-anxious students. The results indicated that socially-anxious
      subjects showed more threatening interpretations of ambiguous, interpersonal
      events when compared to the low-anxious participants. However, this bias was
      marked not so much by an outright negative interpretation style, but rather by a
      failure of the socially-anxious subjects to show a positive interpretation as was
      evinced by the low-anxious individuals. These group differences in interpretive
      style appeared to be influenced by trait aspects of social anxiety rather than
      differences in current mood state. No group differences emerged in
      interpretations of events that involved non-personal stimuli suggesting there is
      content specificity in the interpretive biases associated with social-anxiety.

PMID- 10402691
TI  - Prediction of treatment outcome in social phobia: a cross-validation.
AB  - This study was a replication of a study on the prediction of treatment outcome in
      social phobic patients [Chambless, D. L., Tran, G. Q. Glass, C.R. (1997).
      Predictors of response to cognitive-behavioral group therapy for social phobia.
      Journal of Anxiety Disorders, 11 221-240]. Results at the posttest and the 18
      months follow-up were analyzed for DSM-III-R social phobic patients, with either
      a generalized social phobia (n = 50) or a nongeneralized fear, i.e. fear of
      blushing, trembling or sweating in social situations (n = 26). Predictors were
      pretreatment depression, personality disorder traits, clinician rated severity of
      impairment and frequency of negative self-statements during social interactions.
      The criterium variable was (the residual gain score of) self-reported avoidance
      of social situations. In line with Chambless et al., pretreatment depression
      showed some predictive value, but smaller and only at the posttest. Change in the
      frequency of negative self-statements paralleled, but did not predict, change in
      social phobia symptoms. In contrast with Chambless et al., clinician rated
      severity was (slightly) predictive for treatment outcome, whereas avoidant
      personality traits had reverse correlations with outcome in both subgroups. The
      results are discussed and directions for further research are given.

PMID- 10402692
TI  - Exploratory and confirmatory factor analytic investigations of the Illness
      Attitudes Scale in a nonclinical sample.
AB  - The Illness Attitudes Scale (IAS) assesses fears, beliefs and attitudes
      associated with hypochondriasis [Kellner, R. (1986). Somatization and
      hypochondriasis. New York: Praeger Publishers.]. Recent factor analytic
      investigations of the IAS in non-clinical samples have suggested a number of
      different factor solutions. In study 1, we used principal components analysis
      with both orthogonal and oblique rotation to better explore the structure of this
      measure. Using a random selection of 390 participants from a larger pool of 780,
      a five-factor solution was identified: (1) fear of illness, death, disease and
      pain, (2) effects of symptoms, (3) treatment experiences, (4) disease conviction
      and (5) health habits. In study 2, confirmatory factor analysis (CFA) of
      responses from the remaining 390 students evaluated: (a) a single-factor model,
      (b) Kellner's original nine-factor model, (c) a four-factor model proposed by
      Ferguson and Daniel [Ferguson, E. & Daniel, E. (1995). The Illness Attitudes
      Scale (IAS): a psychometric evaluation on a nonclinical population. Personality
      and Individual Differences, 18, 463-469.], (d) a different four-factor model
      proposed by Stewart and Watt [Stewart, S. H. & Watt, M. C. (1998). A psychometric
      investigation of the Illness Attitudes Scale (IAS) in a nonclinical young adult
      sample. Submitted for publication.] and (e) the five-factor model derived in
      study 1. Of these models, greatest support was obtained for our five-factor
      model. However, it was also clear that this model could be improved. Based on the
      results of the CFA, as well as previous research and theoretical considerations,
      we tested a revised model in which the health habits factor was deleted. Analysis
      of the revised model showed that it received the greatest support and could be
      conceptualized as either four distinct factors or as hierarchical in nature, with
      four lower-order factors loading on a single higher-order factor. Future
      directions for research as well as suggestions for scoring and using the IAS with
      nonclinical samples are discussed.

PMID- 10402693
TI  - The problem of structural indeterminacy in multidimensional symptom report
      instruments. The case of SCL-90-R.
AB  - The factor structure of SCL-90-R items and scales was analyzed using both
      exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Results
      of CFA studies at the item-level failed to support the original nine-factor
      model, as well as several alternative models and EFA suggested very different
      dimensionality, depending on which criteria were used. Analyses at the scale
      level (i.e. the nine original symptom dimensions) suggested that a one- or two
      factor model was satisfactory according to descriptive goodness of fit criteria.
      However, using the likelihood ratio test, specification of four factors was
      necessary to avoid rejection. According to the likelihood ratio test in a multi
      group analysis, a lack of factorial invariance across gender was indicated.
      Moreover, the factorial structure of the instrument was clearly different across
      levels of negative affectivity (NA); the dimensionality was substantially higher
      in the low-NA group as compared to the high-NA group. It is concluded that we are
      confronted with a profound structural indeterminacy problem and that factor
      analytic methods and model acceptance criteria alone are insufficient to solve
      this problem. The indeterminacy problem can be accounted for, at least in part,
      by the complex logical-semantical structure of SCL-90-R items and scales and the
      role of the NA trait as a structure generating factor.

PMID- 10402694
TI  - Anxiety disorders: why they persist and how to treat them.
AB  - Anxiety disorders are characterised by distorted beliefs about the dangerousness
      of certain situations and/or internal stimuli. Why do such beliefs persist? Six
      processes (safety-seeking behaviours, attentional deployment, spontaneous
      imagery, emotional reasoning, memory processes and the nature of the threat
      representation) that could maintain anxiety-related negative beliefs are outlined
      and their empirical status is reviewed. Ways in which knowledge about maintenance
      processes has been used to develop focussed cognitive therapy programmes are
      described and evaluations of the effectiveness of such programmes are summarized.
      Finally, ways of identifying the effective ingredients in cognitive therapy
      programmes are discussed.

PMID- 10402695
TI  - Understanding and treating obsessive-compulsive disorder.
AB  - The development of behaviour therapy for OCD and its evolution into cognitive
      behaviour therapy is described, highlighting the importance of a crucial series
      of experiments conducted by Rachman and colleagues in the mid-1970s. More
      recently, developments in cognitive theory suggest that the key to understanding
      obsessional problems lies in the way in which intrusive thoughts, images,
      impulses and doubts are interpreted. The important negative interpretations
      usually concern the idea that the person's action (or choice not to act) can
      result in harm to oneself or others. This responsibility interpretation has
      several consequences (such as motivating neutralising behaviour and other counter
      productive strategies, increasing selective attention, increased negative mood);
      these serve to maintain the negative beliefs and therefore the obsessive
      compulsive problem. Both general and specific aspects of cognitive-behavioural
      treatment are described. A number of treatment strategies which are specific to
      obsessional problems are described in clinical detail.

PMID- 10402696
TI  - Emotional processing, three modes of mind and the prevention of relapse in
      depression.
AB  - Rachman's (1980) analysis [Rachman, S. (1980). Emotional processing. Behaviour
      Research and Therapy, 18, 51-60] of emotional processing is extended and applied
      to the prevention of relapse and recurrence in depression. It is proposed that
      effective emotional processing leads to changes in the ability of triggering cues
      to reactivate depressogenic processing cycles at times of potential relapse.
      Available evidence supports the usefulness of the probe methodology of the
      emotional processing framework as a way to investigate processes mediating
      relapse prevention by cognitive therapy. It is proposed that effective emotional
      processing involves creation of modified affect-related schematic mental models
      and that this occurs most effectively only within certain processing
      configurations or modes of mind. Within the Interacting Cognitive Subsystems
      (ICS) framework, three modes of processing emotional material can be
      distinguished: 'mindless emoting'; 'conceptualising/doing' and 'mindful
      experiencing/being'. Only the last of these facilitates emotional processing; the
      second may prevent effective emotional processing and perpetuate depression by
      ruminative, conceptually dominated processing. This analysis suggests a further
      strategy to prevent relapse, in addition to modifying depressogenic schematic
      models, by teaching recovered depressed patients skills to switch processing
      modes by intentional redeployment of attention. Results of a recent trial of
      mindfulness-based cognitive therapy support the effectiveness of this novel
      alternative strategy.

PMID- 10402697
TI  - Cognitive behavior therapy for eating disorders: progress and problems.
AB  - Beginning with the application of operant conditioning principles as part of
      inpatient treatment, cognitive behavior therapy (CBT) for anorexia nervosa (AN)
      has been insufficiently studied. Its efficacy remains in question. By contrast,
      manual-based CBT is the first-line treatment of choice for bulimia nervosa (BN)
      although its effects are limited. More effective methods are needed for non
      responders to current therapy. Despite its well-established efficacy, CBT for BN
      is relatively rarely used in the US. Research on dissemination is a priority.
      Modified CBT and behavioral weight control programs seem comparably effective in
      reducing binge eating in Binge Eating Disorder (BED). Long-term maintenance of
      weight loss in these obese patients, however, remains a challenge. Self-help and
      other brief, cost-effective methods work for subsets of both BN and BED patients,
      demonstrating that treatment be administered within a stepped-care framework.

PMID- 10402698
TI  - Do personality disorders exist? On the validity of the concept and its cognitive
      behavioral formulation and treatment.
AB  - Since the introduction of personality disorders as important diagnostic
      categories in the DSM-III [APA (1980). Diagnostic and statistical manual of
      mental disorders (3rd ed.). Washington, DC: American Psychiatric Association] the
      concept of personality disorder (PD) has met both skepticism and enthusiasm. This
      paper addresses criticisms, reviews theoretical and empirical evidence for the
      concept of personality disorders (PD), critically discusses widespread clinical
      ideas about PDs, and reviews cognitive-behavioral models and treatments of PDs.
      It is concluded that there is enough evidence for the usefulness of PDs as
      diagnostic categories. A confirmatory factor analysis for instance yielded very
      reasonable evidence for the categories hypothesized by the DSM. Contradicting
      widespread ideas, research indicates that PDs are not a contraindication for
      cognitive-behavioral treatments of axis-I problems, and that there are even
      indications that PD pathology itself can be successfully treated using modified
      CBT methods. In stark contrast to the generally rich empirical history of CBT,
      research on cognitive models and treatment of PDs is virtually absent. However,
      the sparse attempts indicate that cognitive models may be fruitful in this area.
      Future research should be directed at further developing and testing cognitive
      conceptualizations and treatment models.

PMID- 10402699
TI  - Armies of idiots and idiosyncrasies: on reductions in experimental
      psychopathology.
AB  - Research requires reduction of complex phenomena to more basic ones. The degree
      of reduction seen in Behaviour Research and Therapy (BRAT) papers in general, and
      of Rachman's work in particular, meets with two types of criticism. First, it is
      argued that reduction is taken too far. This objection is typically heard from
      critics challenging the generalisability of outcome trials. Ignoring between
      patient differences in protocollisation of treatments in outcome studies is held
      to provide an underestimation of what individualised therapy has to offer.
      Alternatively, the strictness of inclusion/exclusion criteria in trials is held
      to give an overestimation of treatment effects in ordinary clinical practice.
      Scholars studying information processing or biological psychology/psychiatry
      argue that reduction has not been taken far enough. Convictions, beliefs,
      schemas, etc. are held not to explain behaviour or emotion. They should be
      reduced to perculiarities in information processing or, according to others, to
      neurophysiological processes. The objection that the reduction inherent in
      clinical trials hampers generalisation is obviously an empirical issue. It is
      argued that the objection that reduction has not been taken far enough is also an
      empirical issue. Given the present state of knowledge in psychopathology, and
      believing that degrees of reduction is an empirical rather than a philosophical
      issue, the conclusion is that both objections are empirically invalid and that
      the degree of reduction in Rachman's work has proved balanced and productive.

PMID- 10402700
TI  - The dissemination of empirically supported treatments: a view to the future.
AB  - An ideological and scientific struggle spanning decades has borne fruit with the
      development and documentation of psychological interventions for a variety of
      disorders and problems with proven efficacy. Termed variously 'empirically
      supported treatments' or 'evidence-based psychological practice' highly regarded
      scientific methods have established these interventions as effective as, and
      often more effective than, pharmacological treatments, particularly in the long
      run. In some cases, combined efficacious psychological and pharmacological
      treatments are most effective. Despite these developments, evidence exists that
      these psychological treatments are not readily available to the public who
      requires them, because they have not been effectively disseminated to the mental
      health professionals who deliver them. The variety of barriers to successful
      dissemination are outlined, and recent developments in clinical research and
      public health policy are described that may facilitate the advancement of
      evidence-based psychological practice.

PMID- 10402701
TI  - Footsteps on the road to a positive psychology.
AB  - We have argued that psychology as a field has been preoccupied with the negative
      side of life and has left us with a view of human qualities that is warped and
      one-sided. Psychology is literally 'half-baked'. We need to bake the other half
      now. It is time for us to become equally concerned with the qualities and
      experiences that make life most worthwhile. A balance is needed between work that
      strives to relieve damage and work that endeavors to build strength. This balance
      is beautifully exemplified by Jack Rachman's work over the past 40 years. As an
      astute and compassionate clinician and researcher, Jack developed and evaluated
      effective treatments for some of the most debilitating anxiety disorders. At the
      same time, he was impressed by the resiliency of his clients and the courage they
      exhibited daily. His observations and studies of courage have helped to launch a
      systematic science of human strengths. They are giant footsteps on the road to a
      positive psychology.

PMID- 10402702
TI  - Thought-starting: a review of new developments.
AB  - This paper discusses the work on thought-starting, a clinical technique developed
      by Durac, over many years. Much clinical work has taken place in using and
      further developing this approach, and some research has also been carried out.
      This paper attempts a review of these developments. A selective account of some
      of the major developments is given. The implications of these developments are
      also briefly discussed.

PMID- 10402703
TI  - Goonery in British clinical psychology: the Duracic spark.
AB  - Stanley Rachman, known to his colleagues as Jack Durac, has had a powerful
      influence on British clinical psychology. It is hypothesised that Duracic goonery
      has played a major role in the development of new treatments, as well as in the
      training of new clinical psychologists. Objective, historical evidence is
      assembled to support the view that this Duracic spark should be brought out into
      the field of scientific discourse and should not be hidden behind more
      comfortable jargon.

PMID- 10402705
TI  - Physical growth and fatness as related to physical activity in preadolescent
      girls.
AB  - The purpose of this study was to assess the relationship of physical activity
      with somatic growth and body fatness in preadolescent girls. One hundred twenty
      three girls ranging in age from 7 to 9 years (mean age = 8.2 +/- 1.4 yrs)
      participated in this study. Physical growth characteristics included height, body
      mass, 4 girths (arm, chest, thigh, calf) and 2 widths (knee, elbow). The sum of
      five skinfolds (triceps, biceps, subscapular, abdominal, medial calf) was
      calculated as the indicator of fatness. Physical activity was assessed by
      parental seven-day recall for the child. Somatic characteristics were non
      significantly (p > 0.05) related to physical activity. Body mass and sum of
      skinfolds were significantly negatively (p < 0.01; r = -0.27 and r = -0.39,
      respectively) related to moderate to vigorous physical activity (MVPA). After
      controlling for the effects of body size, the relationship between sum of
      skinfolds and MVPA remained significant (p < 0.01; r = -0.30). It was concluded
      that with exception of body mass and fatness, physical growth was not related to
      physical activity in preadolescent girls.

PMID- 10402704
TI  - Relationship between genetic anomalies of different levels and deviations in
      dermatoglyphic traits. Part 6: Dermatoglyphic peculiarities of males and females
      with cleft lip (with or without cleft palate) and cleft palate--family study.
AB  - The present study was carried out to evaluate the effect of polygenic morbidity
      with respect to Cleft Palate and Cleft Lip with or without Cleft Palate (CL) in
      males and females based on dermatoglyphic traits (DT) and indices of
      intraindividual diversity (Div), fluctuating (FA) and directional (DA) asymmetry.
      The main objectives of the present study were as follows: a) to find DT and FA
      indices, which could be "marker" traits and could indicate the degree of
      developmental instability of the organism; b) to explore the possibility of using
      DT, FA, Div and DA indices of CL patients and their parents and to predict the
      likelihood of the disease appearing in the offsprings of apparently healthy
      individuals. The samples were of 106 CL patients (59 males and 47 females) and
      156 of their parents (67 fathers and 89 mothers), all Israeli Jews. The prints
      were collected in the Beilinson (Petah-Tikva) and Rambam (Haifa) and Hadassah
      (Mount Scopus, Jerusalem) Hospitals, or in the abodes of the CL patients. The
      results were compared with the control group of healthy women and men whose data
      are detailed in our previous publication. Interpretation of the prints were done
      according to the methods and included identification of patterns, ridge counts
      and the measurements of distances and angles in the palms, 79 DT for every
      individual, 28 continuous traits, 9 discrete traits, 11 indices of Div, 15 DA
      indices and 16 FA indices. In CL groups increased FA indices values were found
      and a decreased sexual dimorphism in DT of the CL and parental groups as compared
      to the control--this both in terms of the number of significant differences, as
      well as in values of the traits (e.g. smaller differences between the male and
      female values). The above mentioned findings were partly confirmed also by the
      discriminant analysis. The values of DT parents were generally similar to those
      of the control. The best discrimination was obtained between the CL and control
      groups (70.44% between CL males and control males and 83.47% between CL females
      and control females). Over 50% of the DT variables were found to be suitable for
      including into the discriminant function.

PMID- 10402706
TI  - Nutritional status of the population in Dalmatia, Croatia.
AB  - Weight, stature, weight/stature (BMI), and triceps skinfold thickness were
      analysed in the population of Dalmatia in Croatia. Age- and sex-specific
      percentiles were obtained from 4.507 subjects, 18 to 74 years of age, and
      compared to the U.S. NHANES II reference data. Differences in BMI between the two
      populations were due to higher body weight of the Dalmatians. The triceps
      skinfold thickness indicated their lower body fatness. High BMI of the Dalmatians
      is attributable either to their more centralized fat patterning or larger body
      muscularity. Elucidation of these effects will provide information on the
      adequacy of NHANES data for the assessment of nutritional stat+us in Dalmatian
      population.

PMID- 10402707
TI  - Variations of body mass index in Croatian school children and adolescents.
AB  - The purpose of the study is to present the percentile distribution of body mass
      index in Zagreb school children and to assess whether it differs from those in
      other countries; in addition, to assess whether the values of mean BMI in Zagreb
      school children differ markedly from those in other regions in Croatia i.e. in
      Medimurje and Osijek. Data on height and weight have been derived from growth
      surveys organized or performed by the Andrija Stampar School of Public Health
      over the last decade. The results have shown the skewed distribution of data i.e.
      the agglomeration of high values of BMI in upper percentile positions. Percentile
      values of BMI for Zagreb school children were higher than the reference data for
      American white children and adolescents except at the upper percentile positions
      (85 and 95) for the older age groups. Mean values of BMI of Zagreb school boys
      and girls were in general higher than in their peers in other European countries.
      However, the means of BMI for two other groups of Croatian children--in Osijek
      and Medimurje--were lower. Regarding the association of overweight with risk
      factors for cardiovascular diseases, the results have pointed out a great
      importance of the respective health education programme for school children and
      adolescents. The presented results may also serve as a basis for a study of
      secular changes in variations of body mass index in the adolescent period.

PMID- 10402708
TI  - Lipoprotein (a) concentrations in school children and adolescents in Croatia.
AB  - Lipoprotein (a) concentrations in sera were determined on 536 healthy reference
      children and adolescents aged 8-19 years from Zagreb, Croatia. The frequency
      distribution showed that 20.4% boys and girls had lipoprotein (a) concentrations
      above 0.3 g/L what is considered as a cut-off value for the increased risk of
      early atherosclerosis. The results of correlation studies and factor analysis
      support the concept that the concentrations of lipoprotein (a) could be an
      independent risk factor and therefore may have a great value in the prediction of
      atherosclerosis early in life.

PMID- 10402709
TI  - Distribution of alleles at two microsatellite loci (D6S273 and TNFa) in Croatian
      population.
AB  - Polymorphism at the level of two microsatellite loci (D6S273 and TNFa) was
      studied in Croatian population. The most frequent alleles at D6S273 locus are
      D6S273 134 bp and 136 bp, while at TNFa locus two most frequent alleles are TNFa
      117 bp and 99 bp. This study confirms the irregularity in distribution of
      microsatellite alleles in different populations with the predominance of two or
      three alleles on these two investigated microsatellite loci.

PMID- 10402710
TI  - The analysis of population structure based on morphometric dimensions of
      metacarpal bones (the Island of Krk, Croatia).
AB  - The aim of this study was to investigate: 1) a possibility of using the
      morphometric dimensions of metacarpal bones for approximation of biological
      distances, and 2) a relationship of biological matrices, based on the
      morphometric dimensions of metacarpal bones to other biological (dermatoglyphic,
      genetic), bio-cultural (migration) and geographic variables. The morphometry of
      the metacarpal bones was performed according to Barnett and Nordin procedure and
      biological distances were estimated using Mahalanobis D2 method. Population
      structure was assessed through Mantel's permutation test using E2 genetic
      distances for classical serogenetic markers, DA genetic distances for HLA, DSW
      genetic distances for STRs, geographic distances expressed in kilometres, and
      migration kinship matrix estimated according to the method proposed by Malecot
      and modified by Morton. This study clearly indicated the need for applying
      factorial analytical approach to study the factor structure of morphometric
      variables that may be measured on six metacarpal bones as well as the need for
      conducting complex family and segregation analyses to address not only the
      intriguing issue of genetic vs. ecological impact onto the bone mineral turnover,
      but also to test the hypothesis of major gene control in determining bone mineral
      density.

PMID- 10402711
TI  - Anthropological cybernetic model of demographic structures in the Republic of
      Croatia.
AB  - Intentions of the present investigation were: a) to apply a cybernetic model in
      description of demography of the Republic of Croatia and b) to underline
      specificity of this type model application in anthrolpology based on definitions
      of systems theory as a reaction against reductionism. The cybernetic model is
      based on the idea that continuous processes of childbirth and ageing can be
      represented by compartment analysis. Compartment subpopulations were subjected
      to: a) the elimination by mortality and emigration described by constants Fi,0,
      and b) the enlargement by the immigration process described by constants F0,i.
      The consistency of the model is evaluated through the comparison between model
      data and census. The model prediction of the census and mortality for the period
      between 1953 to 1998 is fair enough (within +/- 2%). Application of this type of
      models provides a possibility that the anthropological fitness of regions could
      be quantified. The obtained data reveals that autoreproduction of the system and
      its fitness could be described by the chaos theory.

PMID- 10402712
TI  - Aspartat aminotransferase--a marker of periodontal disease activity.
AB  - Active and inactive periodontal pockets exist in periodontal disease and the
      progression of periodontitis is episodic and cyclical. Current diagnostic tests
      do not distinguish between active and inactive lesions. Objective assessment of
      disease activity could significantly affect periodontal therapy. Aspartat
      aminotransferase (AST) activity in gingival crevicular fluid is a potential
      quantitative marker of periodontal disease activity. Thirty-six patients with
      periodontitis, twenty with adult periodontitis and sixteen with rapidly
      progressive periodontitis were evaluated clinically prior to treatment and AST
      activity in periodontal pockets was determined prior to and after initial
      therapy. Clinical measures included plaque index, gingival inflammation degree
      and attachment loss. The results show that AST levels do not correlate with
      clinical indices and that they decrease after treatment. AST is a possible novel
      biochemical marker of periodontal disease activity independent of commonly used
      clinical measures. It could also be useful for early monitoring of treatment
      success.

PMID- 10402714
TI  - Computer analyses of two active plate modifications.
AB  - The aim of this study was to determine tooth movements in the upper dental arch
      using a simulated original model during the time of activation of two active
      plates modifications, symmetrically and asymmetrically cut plates. The changes of
      the dental arch dimensions and precise evaluation of the distribution of the
      forces produced by appliance were analysed by recording tooth movements. In order
      to register tooth movements more precisely two referral points were notched on
      each tooth thus creating 38 variables which defined weight and lengths of the
      dental arch. The symmetrically cut active plates used to obtain transversal
      expansion affect equally both sides and cause symmetrical movements of premolars,
      less of molars and canines, whereas they have no effect on incisors. The
      asymmetrically cut active plates used to obtain transversal expansion affect more
      the side of smaller active part of the plate. Movements are larger at the
      premolars than at molars and canines, and minimal at incisors. The results of
      this study confirm the data from the literature and a logical interdependence of
      the force and movements thus emphasising the importance of anchorage in
      orthodontic therapy.

PMID- 10402713
TI  - Inflammatory mediators in saliva of patients with rapidly progressive
      periodontitis during war stress induced incidence increase.
AB  - Rapidly progressive periodontitis (RPP) results from the interaction between the
      periodontal microflora and the host. Stress is believed to play an important role
      in determining host responses, and it has been proposed that hyperactivity of
      host defense mechanisms significantly increases tissue destruction typical for
      this disease. During a period of four months we have diagnosed 20 patients with
      acute RPP, all of them active participants in battles of the Croatian liberation
      war with posttraumatic stress disorder (PTSD) related symptoms. In these patients
      we analyzed biochemical parameters in unstimulated saliva and performed
      microbiological analyses of periodontal pockets. These findings were compared
      with those of patients with adult periodontitis (AP), edentulous and healthy
      persons, none of whom participated in the war. Persons with AP had reduced
      concentrations of host humoral defense factors in saliva (C-reactive protein, C3
      component of complement, and aplha alpha 2-macroglobulin), while patients with
      RPP had increased concentration of interleukin-6 (IL-6). IL-6 is released by host
      inflammatory cells and is a mediator of bone resorption. Actinobacillus
      actinomycetemcommitans and Peptostreptococcus were more frequently isolated from
      patients with RPP. We interpret these results as indicators of the importance of
      stress in the causation of RPP, with host inflammatory hyperactivity playing an
      important role in tissue destruction, specially alveolar bone resorption possibly
      caused by increased local levels of IL-6.

PMID- 10402715
TI  - Vomer as relevant factor in the mastication forces transmission system.
AB  - In the region of the posterior segment of bony palate and nasal cavities in both
      sides, the following three bones come together: the upper jaw, the palatal and
      the sphenoid bones. The perpendicular upper palate lamina laterally leans on the
      corpus of the upper jaw and on the wing process of the sphenoid bone. It is the
      posterior bony transmission system that has been selected as a separate study
      entity, which is otherwise a functionally inseparable part of the overall system
      of trajectories of mastication forces. It is a supporting element that begins at
      the dental alveolus of the wisdom tooth, ascends along the tuber maxillae and by
      the wing process of the sphenoid bone transmits the mastication load to the body
      of the sphenoid bone, i.e. into the mid-portion of the neurocranial base. By
      observing the characteristics of the vomer and measurement of distances between
      its morphological markings, or craniometric landmarks, together with its fitting
      into the harmonic analysis of face and head, the essential role of vomer has been
      established in regard to the trajectory system of mastication forces which has
      enabled us to create the basis for further biomechanical research of this
      phenomenon using photoelasticimetric procedures.

PMID- 10402716
TI  - Morphometric characteristics of toothless lower jaw ridge as a bed for total
      lower jaw prosthesis.
AB  - Analysis was made of 44 solid casts of toothless lower jaws.
      Stereophotogrammetry, a measurement procedure in photogrammetry, was used as a
      method in the measurement of solid casts. Adequate instruments and method of
      measurement made it possible to objectify anatomical and morphological structures
      of toothless lower jaws. The anterior width of the ridge in the region of canines
      was 22.70-35.50 mm. The posterior width in the first molars region was 43.30
      59.10 mm, with statistically significant difference between the genders. The
      width at the level of posterior ridge of mandibular tubercle was 52.10-70.00 mm,
      with statistically significant difference between the genders. The length of the
      alveolar ridge between the symphysis and the tangent line of posterior ridge of
      mandibular tubercle in the medial line was 34.70-49.00 mm, without statistically
      significant difference between the genders. The surface of the toothless ridge is
      at the same time the surface of the total lower prosthesis bed. The size of the
      surface depended on the resorption and relation between the alveolar ridge and
      the surrounding active structures; it ranged between 103.21-205.50 mm2. The mean
      value being 145.99 mm2. The values obtained in our study are in approximate
      accordance with the reference literature data. They are the results of accurate
      measurements of solid casts.

PMID- 10402717
TI  - Moire topography in measurement of the sagittal curvatures of the spine.
AB  - The purpose of the investigation was to establish the accuracy of moire
      topography in the analysis of the kyphotic spine. Using simplified
      instrumentation, moire topogram was performed in the 50 outpatients at the
      Department of Orthopaedic Surgery, School of Medicine, University of Zagreb.
      Lateral x-ray and meticulous clinical measurements of the spine were included as
      well. A correlation between the obtained results was established. A high
      correlation (r = 0.847) was found between the results obtained by means of X-rays
      and those obtained by means of moire topography. The authors concluded that the
      method is ideal for the determination of a morphotypology of the kyphotic spine
      and can significantly contribute to the differentiation between normal and
      pathological sagittal curvatures of the spine without the need for x-ray of the
      spine. The authors conclude that the application of moire topography in the
      biomechanical laboratories can contribute to the new cognition on kinematics of
      the spine. The investigation demonstrated that simple and nonexpensive apparatus
      can be used for the moire topography in the follow-up of the sagittal curvatures
      of the spine.

PMID- 10402718
TI  - Alterations in optic canal following resection of nerve in rats.
AB  - The authors have studied relations between bony optic canal and nerve elements
      resulting from lesion in the optic nerve. Experimental animals were divided in
      two groups: young adults and old adult rats; the non-operated sides of rat skulls
      were used as a control group. At the same time in control samples the changes in
      osseous openings resulting from ageing were studied. Four months after surgery
      the animals were sacrificed, their skulls macerated and morphometric measurements
      taken by photometric and planimetric techniques. The obtained results show no
      significant difference in size of bony openings between the operated and non
      operated sides. A significant difference has been found in the size of optic
      canal between the young and the old rats, regardless of the operated side. The
      authors have thus come to the conclusion that the size of bony canals in adult
      animals depends on their age in the first place. Narrowing of bony canaliculi,
      observed in the course of ageing, is most probably caused by primary osseous
      apposition, while atrophy of nerve elements may be considered as a secondary
      event.

PMID- 10402719
TI  - The comparison of isodose plans: radiotherapy techniques in the treatment of
      thyroid ophtalmopathy.
AB  - Thyroid ophthalmopathy is listed among benign disorders as the fourth indication
      for radiotherapy. Radiation reduces symptoms and signs of the disease in 46-93%
      of patients. Except for the lenses, the orbital content is resistant to the usual
      radiation dose of 20 Gy in 10 fractions. A number of radiotherapeutic techniques
      which avoid the lenses have been suggested. The testing of different techniques
      was performed on the same patient by using a computerized simulation of lateral
      alternating and crossed photon beams from a 6 MV and 18 MV linear accelerator or
      cobalt device. The radiation from a 6 MV linear accelerator using lateral beams
      angled at 5 degrees posteriori gave the best results. By this technique both
      lenses receive below 10% of the prescribed dose with a safety zone of 20% of the
      field size. Isodose distribution in clinical target volume is within the range of
      10%. The described technique is recommended as it enables a successful avoidance
      of both lenses with a satisfactory homogeneity of dose distribution in the
      clinical target volume.

PMID- 10402720
TI  - Color Doppler flow imaging (CDFI) of the vertebral arteries--the normal
      appearance, normal values and the proposal for the standards.
AB  - In order to assess mean diameters and blood flow velocities (BFV), Color Doppler
      Flow Imaging (CDFI) of vertebral arteries (VA) was performed. Five hundred and
      ninety six persons without carotid disease or symptoms related to vertebrobasilar
      system were analyzed by CDFI of VA. Mean right VA diameter was 3.37 +/- 0.6 mm
      and left 3.55 +/- 0.61 mm. Women had thinner VA (p < 0.05). Left VA was wider (p
      < 0.05). Mean right BFV was 48.31 +/- 14.09 cm/s and left 48.93 +/- 13.94 cm/s.
      Females had higher BFV (p < 0.05). BFV didn't very with age (p > 0.05). The VA
      hypoplasia was present in 2.34%, asymmetry in 15% (left VA dominant in 64%).
      Visualisation of V1 and V2 segment was possible in 100% and of the origin in
      81.7% on the right, and 80.7% on the left side. CDFI is a reliable method for
      evaluation of VA. Left VA was wider. Women had thinner VA. Hypoplasia was present
      in 2.34% and asymmetry in 15%.

PMID- 10402721
TI  - Influence of hyperglycemia on early embryonal growth in IDDM pregnant women.
AB  - The association between maternal diabetes mellitus and congenital anomalies is
      well established. Congenital malformations in the offspring of diabetic mothers
      account for approximately forty percent of perinatal deaths. The aim of the study
      was to identify incidence of early embryonal delay in diabetic and normal
      pregnancies, and to examine relationship between the HbA1c values and early
      embryonal growth delay. One hundred twenty IDDM and fifty and four healthy women
      enrolled into the study. Pregnancy duration was confirmed by beta-HCG
      measurements within a fortnight from the missed menstrual period. No statistical
      difference was detected between the studied groups for gestational age,
      prepregnancy weight, newborns' birthweight and sex. The risk of spontaneous
      abortion in IDDM pregnancy with delayed embryonal growth was eight times higher
      than in IDDM pregnancies with normal growth pattern. No fetal malformations were
      determined in fetuses or newborns of either groups. The mean value and standard
      deviation of HbA1c in the IDDM patients with normal embryonic growth was 7.3 +/-
      1.5%, and in the group of early embryonic growth, delay 9.39 +/- 2.37%
      respectively (F = 7.79; p = 0.006). This study confirmed the relationship between
      embryonal growth, spontaneous abortions and abnormal metabolic control of IDDM
      pregnancies.

PMID- 10402722
TI  - Preoperative tumor marker CA125 levels in relation to epithelial ovarian cancer
      stage.
AB  - The paper deals with 62 ovarian cancer patients observed from 1988 to 1997.
      Considering the ovarian cancer stage, the patients were divided in two groups.
      Group I consisted of 31 patients at the early stage of ovarian carcinoma (FIGO
      classification I and II), while group II included 31 patients with the advanced
      disease (FIGO classification III and IV). According to FIGO classification, a
      majority of group I and group II patients was classified as IA (61.3%) and IIIC,
      respectively. Ovarian carcinoma of the serous pathohistologic type accounting for
      48.4% prevailed in both groups, but there were also endometroid and mucinous
      types. Sensitivity to CA125 was observed in 93.5% of the group I and in 96.7% of
      the group II patients. In group I, the mean value of tumor marker CA125 read
      262.97 U/ml, median 93 U/ml, ranging from 13-2000 U/ml. In comparison with group
      I, the mean value of group II tumor marker CA125 was significantly higher reading
      1053.81 U/ml, median 365 U/ml, with CA125 levels ranging from 15-9960 U/ml. In
      relation to patients at the early stage of ovarian cancer, preoperative CA125
      serum levels were statistically more significant in the advanced ovarian cancer
      patients (statistically significant difference p = 0.002). When comparing CA125
      levels and tumor differentiation according to Broders, no statistically
      significant difference was observed in both group I (p = 0.6144) and group II (p
      = 0.6605). The statistically significant correlation (p = 0.00008) was confirmed
      between advanced ovarian carcinoma and less differentiated tumors (Broders
      differentiation III and IV).

PMID- 10402723
TI  - The usefulness of biochemical bone markers in predicting the response of hormone
      replacement therapy in perimenopausal cigarette smoking healthy women.
AB  - The purpose of our study was to evaluate the effects of orally administered
      combined sequential estradiol (2 mg 17 beta estradiol) with progestin (1 mg
      norethisteron acetate) daily during ( +/- SD) 15.34 +/- 13.89 months on bone
      markers in perimenopausal cigarette smoking women. The control group consisted of
      cigarette smoking perimenopausal women without hormone replacement therapy (HRT).
      The following biochemical bone markers were analyzed in hormone replacement users
      (N = 35) and non-users (N = 28): serum total calcium (Ca), total alkaline
      phosphatase (ALP), procollagen I C-terminal propeptide (PICP), cros-linked
      carboxyterminal collagen I telopeptide (ICTP) and osteocalcin (OC). When we
      compared the results of bone markers in the cigarette smoking current users and
      non cigarette smoking non-users, we found statistically significant lower levels
      of bone formation markers, ALP and OC, and lower level of bone resorption marker;
      ICTP in users than in non-users. In perimenopausal cigarette smoking women on HRT
      lower levels of new biological markers reflected less intensive bone remodelling
      and probable decrease in bone loss than in non-users. These results indicate that
      the measurement of biological bone markers are useful to identify risk women for
      osteoporosis who may have special benefit from the treatment with hormone
      replacement therapy, even when they smoke.

PMID- 10402724
TI  - Morphology of gonads in pure XY gonadal dysgenesis.
AB  - The authors gathered 20 patients having Swyer's syndrome and performed a
      bilateral gonadectomy and carried out a pathohistologic evaluation of the streak
      gonads. A more frequent occurrence of streak gonad tumors was found together with
      the possibility of tracing the merge gonadoblastoma into dysgerminoma (the
      youngest patient was 15 years old). In 95% of the streak gonads checked an ovary
      like stroma was found. In 11 of the patients (55%) one of the above mentioned
      tumors was found. A frequent finding was the presence of Leydig-type cells,
      calcifications and the remains of Wolffian canals. In three streak gonads, the
      corpora albicans-like formations were found.

PMID- 10402725
TI  - Influence of prolonged stress on risk factors for cerebrovascular disease.
AB  - The main purpose of this study was to analyze the influence of psychological and
      socio-economic factors on the frequency and characteristics of risk factors for
      cerebrovascular disease (CVD) among Croatians. A group of 120 war sufferers with
      signs of post-traumatic stress disorder and adaptation disturbances have been
      studied, and compared with a control group of 120 persons with no traumatic war
      experience. The risk factors for CVD were registered using epidemiological,
      clinical and functional measures, and level of the risk. In a displaced persons
      group a significant higher rates (p < 0.05) of arterial hypertension (AH),
      hyperlipidemia and obesity are found, with particularly higher rates of
      occurrence of AH and hyperlipidemia in younger individuals. Alcoholism was more
      frequent in the control group. Total risk for stroke was higher in the exposed
      group. The authors conclude that there is a need for undertaking intensive
      preventive measures in the risk population exposed to chronic stress and negative
      socioeconomic life conditions.

PMID- 10402726
TI  - The origin of ethics and social order in a society without state power.
AB  - How ethics and social order in a society without state power had originated and
      developed is one of enigmas which human beings have tried to solve for a long
      time. Several theories on the origin of social order have been proposed since the
      "Social Contract" theory of Thomas Hobbes. According to Hobbes, as a society
      without state power is in a condition called war, a social contract among men is
      the origin of social order in a society where every man is against every man.
      Rousseau says that when human beings reach the stage in which they live in a
      permanent neighborhood, a property system is introduced. Then, too much ambition
      and avarice of man who has possessions compel him to propose the formation of a
      political institution, providing social order which enables him to keep his
      possessions. According to Nietzsche, the principle of equilibrium, that is, an
      eye for an eye, a tooth for a tooth is an important concept for the oldest theory
      of low and morality as well as the basis of justice. The sense of superiority and
      nobility which a strong man brave enough to take revenge feels is the origin of
      the antithesis "good" and "bad". Girard says that the sacred violence wielded by
      the community to sacrifice a surrogate victim brings about social order in a
      society without state power. All the aforementioned theories seem to have failed
      to find out that a society without state power has its own ethics that had
      spontaneously developed on the pagan culture. Previously, I indicated that a
      society without state power or a society where state power cannot function well,
      such as the tribal society in northern Albania, has ethics which is based on the
      ancient concepts of "Guest-god", "food (commensality)" and "blood". In the
      present paper, I propose a new theory on the origin of ethics and social order,
      using the model of ethics of the Kanun.

PMID- 10402727
TI  - Understanding the role of nationalism in "new democracies".
AB  - The transition from communism to democracy has raised numerous discussions
      regarding the nature of postcommunism in Eastern Europe. According to the author,
      the two main approaches used to explain the collapse of communism--one that
      claims that resurrected civil society triumphed over totalitarianism, and, the
      other that avers Eastern Europe's propensity for irrationalism and a political
      behaviour based on ethnic exclusion and hatred--overlook the unique nature of
      postcommunism. In order to properly grasp the nature of this phenomena, the
      author argues that one must first understand the intrinsic nature of Eastern
      Europe's transformation. To do this requires an analysis of the social structures
      that drive political change and identifying the social group that is the main
      bearer of transformation. The author believes that though her analysis focuses
      primarily on the case of former Yugoslavia, and Croatia in particular, the
      conclusions she draws from it are also valid for other East European countries:
      that the nation is regarded as the principal catalyst for political change and
      that nationalism is the main legitimizing principle of emerging states. This
      analysis rejects the common view according to which nationalism is casually
      discounted as an irrational political movement that is fundamentally hostile to
      democracy and freedom. Quite the contrary. Throughout Eastern Europe nationalism
      has had a positive role in bringing down communism and creating a space for
      democracy to take root. Still, tension exists between nationalism and the
      democracy it spawned. To understand this paradox requires an extensive
      sociological and historical study of the particular conditions within which a
      particular community defines the goals of nationalism and the specific content of
      its main undergirding concepts like nation and state. Identifying the
      circumstances within which nationalism begins to act as an obstacle to the
      establishment of full-fledge democracy is key to understanding the political
      reality of today's Croatia and of many other East European "new democracies".
      Nationalism works differently in different socio-political conditions-
      differently in countries that recently achieved independence from countries with
      a long tradition of sovereign statehood, differently in countries with an
      underdeveloped or non-existent civil society from those with a strong civil
      society, differently in countries that are economically prosperous from those
      that are experiencing economic hardship. All these factors, not nationalism per
      se, determine the overall prospects for liberal democracy in Eastern Europe.

PMID- 10402728
TI  - Between symbolism and experience: Croatian glagolitic recipes (14th-15th
      centuries) dealing with ocular diseases.
AB  - In this paper Croatian Glagolitic recipes from the 14th and 15th century were
      elaborated as a part of the oldest such preserved sources in Croatia. Six recipes
      against ocular diseases were analyzed which were based mostly on empirical
      knowledge, and mostly herbal ingredients were suggested in preparation. In only
      one recipe traces of Christian belief were detected. Analysing the content of
      recipes, various strata of official medicine, empiry and religious symbolism were
      determined, as well as links with a wider Western European medical and cultural
      heritage.

PMID- 10402729
TI  - Ethnology as a play: a comparison of two schools of thought at the turn of the
      century.
AB  - The methods and theories of science are in a state of constant flux. With the
      perimeters of science changing so does the subject of inquiry. Ethnology, a
      relatively young science underwent a drastic change at the turn of the century as
      unillineal evolutionism of the preceding century became obsolete and gave away to
      diffusionism. In this paper I want to outline briefly the development of two
      institutes of cultural anthropology--at the University of California at Berkeley
      and the University of Vienna--at the turn of the century. It is not surprising
      that synchronous with this paradigmatic shift in ethnological inquiry the two
      institutes examined here found themselves in a time of great social as well as
      cultural upheaval. I took on the task of writing a kind of meta-ethnology, an
      inquiry into the socio-political and cultural forces that shape a scientific
      dogma, which in turn can and did change society. For my reader's as well as for
      my own benefit I used the metaphor of a "play" in describing such a complex
      process.

PMID- 10402730
TI  - The renewal of aristocratic principles.
AB  - The term of "aristocracy" has always risen various questions, such as its real
      meaning, its role, its types, its purposes, who composes aristocracy, etc. In
      this text, I have tried to give my point of view to those questions, not only in
      a historical and traditional line of development, but also applied to present
      systems, relations and sets of values. I have differentiated two types of
      aristocracy, so called "aristocracy of soul" and "aristocracy of property" and
      decsribed main features. Furthermore, there is a view to traditional role of
      aristocracy, its principles and laws of existence, together with its dangers.
      Based on those categories, further direction of development leads to the
      questions of aristocracy in democratic societies with all the contemporary
      "specificum". The last part deals with the matter of aristocracy in regard to
      politics and its wide range of application.

PMID- 10402732
TI  - Children and wives of deceased veterans--pride and suffering.
AB  - A widow is a women who lost her partner, Separation is what happened to her.
      Every separation is a big trauma and a possible source of psychopathology. The
      widow's children have experienced trauma as well, with all known consequences of
      separation. Admixture of pride partially reduces the intensity of frustration.
      However, this pride will soon lead to the sense of guilt and auto-aggressive
      component becomes dominant. Eighty nine widows, members of the Club "April 3,
      1992" in Valpovo, were examined by the means of a questionnaire. Due to the
      widow's anxiety, depression and thinking about their own death and children's
      psychosomatic disturbances there is the imperative of the long-term
      psychotherapeutic work with them which is aimed at the correction of possible
      psychopathology.

PMID- 10402731
TI  - Pro-longed exile and potential integration processes in Croatia.
AB  - The aim of this paper is to assess initial contact, social distance and
      interethnic attitudes between refugee/displaced groups and Croatian host society
      in Dalmatia as a predictor of possible integration processes. In spite of many
      similarities between the analyzed groups (Bosnian refugees, displaced persons
      from Eastern Slavonia and Dalmatian population), sharing a period of common
      history and linguistic features that should facilitate integration, the results
      reveal complex and ambivalent attitudes of these groups, socially differentiated
      by age, gender and education. The study indicates the need for major efforts in
      stimulating integration and enabling the development of intercultural identities
      as a prerequisite for social stability.

PMID- 10402733
TI  - Balint groups in the postwar period in Croatia (with regard to medical and social
      conditions).
AB  - The author tried to present social circumstances in the postwar period in
      Croatia, a period similar to other situations occurring after a war. Family
      doctors, and especially psychiatrists, exerted themselves to be present in these
      situations, and also they were alert to the sufferings of human beings as a
      consequence of the war. New conditions, new relations, as well as the previous
      war actions in which the patients had participated, made psychopathologic
      morbidity rather different from that appearing during the war and before the war.
      The doctors had to adapt or innovate, with more or less skill, Balint techniques
      in order to achieve better treatment results. In this they undertook particular
      precautions not to jeopardize classical forms of treatment and to be always in
      collusion with continuity of medical development and social changes. The author
      presents this adequately, having in mind all the levels with which a patient
      comes into contact. And, finally, it is concluded that only two active subjects
      in a treatment can make this treatment successful.

PMID- 10402735
TI  - Club as an integral approach to war veterans.
AB  - War veterans club "April 3, 1992" founded in Valpovo is aimed at providing an
      integral response to the numerous requirements of the war victims, participants
      of the patriotic war in Croatia. Apart from psychotherapists, the members of the
      club are: a priest, a social worker, pedagogists, nurses and a lawyer. The club
      offers a therapeutic work through its organisational form and the treatment
      conducted in it. One hundred and eighteen members of the veteran club in Valpovo
      have been examined by means of a questionnaire. Let us remind that there has been
      no attempted suicide since the club has started its work.

PMID- 10402734
TI  - Trauma and reconstruction in a large group of refugees.
AB  - The study is a continuation of a research which the expert team started in
      refugee and displaced persons' settlements in Croatia. By studying a group of
      refugees in its entirety we could not avoid noticing its extremely regressive
      position. Faced with the refugees' numerous existential problems we took the role
      of good, caring and tender mother (a good object) who will protect her children,
      give them security, meet their essential needs. Looking at the group dynamics, in
      the light of Melanie Klein's theory, we noticed the existence of schizo-paranoid
      and depressive position in the group, manifesting itself through the gap occuring
      as defense from its self-destructiveness, i.e. as the protection of introjected
      object which has be saved from destruction because the true "good object" was
      destroyed. Through the analysis of schizo-paranoid and depressive position of
      large group of refugees the aim of our work was to enable the group to gradually
      overcome the schizo-paranoid position and transfer into a more mature phase of
      development, thus creating a favorable atmosphere for maturation and self
      protection.

PMID- 10402736
TI  - Autogenous training--an anxiolytic and a factor contributing to the improvement
      of the quality of life.
AB  - Autogenous training in its narrow sense of meaning belongs to the group of
      supportive psychotherapeutic techniques. In fact, it is an autosuggestive
      relaxation. Autogenous training has been for decades successfully used as
      prevention to anxious reactions. Since anxiety is an etiological factor of
      numerous psychic and psychosomatic disturbances, positive implications of
      autogenous training have been considerably broadened. Life without anxiety
      belongs to a more qualitative form of life. Autogenous training directs the
      trainee towards introspection and self-analysis. Self-respect (self-esteem) is
      the consequence of our own work on ourselves.

PMID- 10402738
TI  - Lookback in angst.

PMID- 10402737
TI  - Underascertainment of infectious intestinal disease.

PMID- 10402739
TI  - Fifty years of influenza surveillance.

PMID- 10402740
TI  - We have some whole genome sequences. What now?

PMID- 10402741
TI  - The global impact of HIV infection and disease.
AB  - Patterns of HIV infection and disease are changing. HIV will soon enter the top
      five causes of death worldwide and is now believed to cause more deaths than
      malaria. Commonwealth countries account for around 60% of prevalent HIV
      infections worldwide. Around half of all global HIV transmissions are to people
      under 25 years of age. HIV is lowering life expectancy and reversing gains in
      child survival in east and central Africa. The incidence and prevalence of HIV
      infection have increased enormously in southern Africa recently. A more
      generalised pattern of heterosexual HIV transmission is emerging in parts of
      South and South East Asia. Injecting drug use and related HIV transmission is
      increasing in resource-poor countries. Countries where HIV prevalence is low but
      rising and there are high levels of other STIs offer particular opportunities for
      early intervention, as it is easier to intervene against HIV when it is entering
      a country than when it has become established. In countries with weak family and
      social networks there is inadequate care for the increasing numbers of parentless
      children. HIV is prejudicing tuberculosis control programme in most African
      countries and will do the same in Asia. AIDS mortality has fallen in
      industrialised countries but the prevalence of HIV infection and treatment costs
      are increasing. Countries that have used multisectoral approaches at an early
      stage and have had political support for HIV prevention early in their epidemics
      have been able to limit transmission. Others, intervening later, have been able
      to reduce transmission. Surveillance methods need to adapt to changing patterns
      of infection and disease.

PMID- 10402742
TI  - Weekly Returns Service of the Royal College of General Practitioners.
AB  - General practitioners in 69 practices in England and Wales monitor the spread of
      epidemic diseases in the community through the Weekly Returns Service (WRS) of
      the Royal College of General Practitioners, which has existed for over 30 years.
      Participating general practitioners summarise diagnoses and consultation/episode
      type (new episodes/ongoing consultations) for a defined population (currently
      about 570,000) and data are extracted to provide the 'weekly return', which
      includes age specific weekly incidence of new episodes of selected illnesses. The
      service has been used extensively to measure the burden of influenza and total
      acute respiratory illness in the community and the impact of enteric infections.
      It also provides information about illnesses for which there are no other major
      data sources--for example, chickenpox, scabies, and (historically) mumps. The
      entire network is electronically linked. Direct links with microbiological
      laboratories are being forged in order to integrate clinical and microbiological
      data in defined populations.

PMID- 10402744
TI  - A study of infectious intestinal disease in England: microbiological findings in
      cases and controls.
AB  - A study was undertaken to identify the microorganisms and toxins in stool
      specimens associated with infectious intestinal disease (IID) among cases in the
      community and presenting to general practitioners (GPs) and in asymptomatic
      controls. Population based cohorts were recruited from practice lists in 70
      practices and followed for 26 weeks (cohort component). Seven hundred and sixty
      one cases of IID identified from the cohorts, 2893 cases who presented to GPs in
      34 of the practices (GP component), and age/sex matched control subjects (555 and
      2264, respectively) submitted stool specimens by post for comprehensive
      microbiological examination. Campylobacter spp (12.2% of stools tested),
      rotavirus group A (7.7%), and small round structured virus (SRSV) (6.5%) were the
      organisms most commonly detected in the GP component. SRSV was identified in 7.0%
      of cases in the community cohort. No target microorganisms or toxins were
      identified in 45.1% and 63.1% of cases in the two components. Aeromonas spp,
      Yersinia spp, and some enterovirulent groups of Escherichia coli were detected as
      frequently in controls as in cases. The higher frequency of detection of
      campylobacter, salmonella, and rotavirus among cases who presented to GPs than
      among those in the community suggests that those pathogens cause more severe
      illness. No enteropathogens were detected from a large proportion of cases
      although comprehensive standard methods were used to seek them.

PMID- 10402743
TI  - A study of infectious intestinal disease in England: plan and methods of data
      collection.
AB  - The Committee on the Microbiological Safety of Food, set up in 1989 by the
      Department of Health in response to national epidemics of foodborne infection,
      considered the available evidence and commissioned a study of infectious
      intestinal disease (IID) in England. Seventy practices (with 489,500) patients
      overall) recruited from the Medical Research Council's General Practice Research
      Framework between August 1993 and January 1995 collected data for one year. The
      practice populations were representative of practices in England by area and
      urban/rural location, but with fewer small and affluent practices. There were
      five main components. i) A population cohort of 9776 (40% of those eligible) were
      enrolled to estimate the incidence and aetiology of IID in the community, and a
      large proportion were followed up. A median of 10% of patients on practice age
      sex registers had moved away or died. ii) A nested case control component based
      on cases ascertained in the cohort was used to identify risk factors for IID in
      the community. iii) In a case control component used to identify risk factors and
      to estimate the incidence and aetiology of IID presenting in 34 general practices
      70% of the 4026 cases returned risk factor questionnaires, 75% submitted stools,
      and matched controls were found for 75% of cases. iv) An enumeration component
      was used to estimate the incidence of IID presenting to general practitioners
      (GPs) in 36 practices and the proportion of specimens sent routinely for
      microbiological examination. v) In a socioeconomic costs component used to
      estimate the burden of illness of IID in the community and presenting to GPs 63%
      of those who returned a risk factor questionnaire also returned a socioeconomic
      questionnaire and were representative by age, sex, and social class. Despite
      variable enrolment and compliance the study sample had sufficient power for the
      multivariable analysis. The characteristics associated with low enrollment and
      compliance must be considered in the interpretation of the main study results.

PMID- 10402745
TI  - Microbiological investigation of halal butchery products and butchers' premises.
AB  - Halal butchers' premises were investigated as they had not been represented in a
      recent study of butchery products and butchers' premises conducted by the Local
      Authorities Coordinating Body on Food and Trading Standards and the PHLS. This
      study examined 183 raw prepared meats and 212 environmental samples from 105
      halal butcher premises. Only raw meats were prepared on 97 of the premises
      visited; and the types of meat prepared on the remaining eight premises was not
      specified. Four halal butchers sold cooked meats prepared elsewhere. Salmonella
      spp. and Campylobacter spp. were detected in 12 (7%) and 52 (28%) of the 183 raw
      meat products, respectively. Five raw prepared meats (3%) contained both
      salmonella and campylobacter. Vero cytotoxin producing Escherichia coli O157 was
      isolated from a raw meat product that also contained campylobacter. No cooked
      meat products were available for collection. The physical separation of raw and
      unwrapped cooked meat products in premises that prepared raw and sold cooked
      meats was not recorded. Apron cloths were the most heavily contaminated
      environmental samples examined; hygiene indicator microorganisms indicated an
      increased risk of cross contamination. Managers in 85 premises had received no
      food hygiene training and 88 premises had no hazard analysis system in place.
      Improvements are needed to reduce the risk of cross contamination.

PMID- 10402746
TI  - Leprosy in England and Wales.
AB  - This paper reviews cases of leprosy notified in England and Wales to the Central
      Leprosy Register since its inception in 1951. Leprosy remains a rare condition in
      England and Wales, with fewer than ten cases notified on average in recent years.
      No definite case of indigenously acquired leprosy has been reported since the
      disease became notifiable. Although only a small number of patients present each
      year, leprosy remains a debilitating disease, and the unfamiliarity of clinicians
      with this condition can lead to delays in diagnosis and undernotification.

PMID- 10402747
TI  - Enterovirus infections in England and Wales: laboratory surveillance data: 1975
      to 1994.
AB  - Microbiology laboratories in England and Wales reported 40,366 culture confirmed
      isolates of echovirus (24,628; 61%) and coxsackievirus (B 11,714; 29%, A 4024;
      10%) infections to the PHLS Communicable Disease Surveillance Centre (CDSC) in
      the 20 years from 1975 to 1994. Nearly half of the organisms were isolated from
      faeces, and 5741 were isolated from cerebrospinal fluid (75% of them echovirus,
      13% coxsackie B, and 12% coxsackie A). Isolation rates for all enteroviruses were
      highest among infants aged 1 to 2 months. Sixty per cent of patients were aged
      under 5 years, 10% 5 to 9 years, and only 6% 35 years or over. Predominant
      serotypes were similar to those reported in other countries including the United
      States, Finland, and Belgium. Seventy-one per cent of reports were made between
      July and mid December. Periodicity varied between groups and serotypes: some
      demonstrated peaks at intervals of two to five years. There was evidence of
      spread of epidemic serotypes across Europe in certain years. Data collected
      between March and May each year enabled the strains circulating in the following
      'season' to be predicted. Such information might be used to warn clinicians to
      anticipate particular clinical presentations.

PMID- 10402748
TI  - Are HIV lookbacks worthwhile? Outcome of an exercise to notify patients treated
      by an HIV infected health care worker. Incident Management Teams.
AB  - This report describes the management and outcome of one of the largest exercises
      undertaken in the United Kingdom to notify patients exposed to an HIV infected
      health care worker. Eighty-six per cent (1597/1852) of patients on whom the
      infected junior doctor in obstetrics and gynaecology had performed surgical
      procedures were contacted and 1180 women (64% of those exposed) elected to be
      tested. None was found to be positive. Of those tested, 651 had undergone
      procedures classified as 'higher risk' and 529 'low risk' procedures. These data
      provide further evidence that the overall risk of transmission from an infected
      health care worker to patients is likely to be very low. HIV lookbacks may be
      worthwhile but we consider that it would be justifiable to notify and offer HIV
      testing only to patients who have undergone higher risk procedures. The estimated
      cost to the NHS of this exercise exceeded 200,000 Pounds.

PMID- 10402749
TI  - Lessons from patient notification exercises following the identification of
      hepatitis B e antigen positive surgeons in an English health region.
AB  - The results of hepatitis B virus (HBV) serology from notification exercises
      conducted in cohorts of patients exposed to three surgeons positive for hepatitis
      B e antigen (HBeAg) identified in one English health region in 1994 and 1995 were
      reviewed. Of 777 patients notified, serology results at six months or more after
      exposure were available for 514 individuals who had not received post exposure
      prophylaxis. In one case DNA analysis confirmed transmission of HBV from surgeon
      to patient. Pre-existing natural immunity to HBV was found in a further 19
      patients, none of whom had evidence of recent infection, and in 13 patients
      (classified as cases of undetermined origin) transmission during surgery could
      not be excluded. The overall estimated transmission rate was 0.2% for confirmed
      cases (95% confidence interval (CI) 0.004-1.1) and 2.7% (95% CI 1.5-4.5) if cases
      of undetermined origin were included. The management of recall exercises should
      consider the risks of the operative procedures performed and the time that has
      elapsed since exposure.

PMID- 10402750
TI  - Outbreak of hepatitis B in an acupuncture clinic.
AB  - A retrospective cohort serological study identified five confirmed cases of acute
      hepatitis B virus (HBV) infection in three and a half years at an acupuncture
      clinic in London. These cases made up 1.7% of those treated by an acupuncturist
      who was a hepatitis B 'e' antigen (HBeAg) carrier. Virus subtyping and polymerase
      chain reaction--single strand conformation polymorphism assay (PCR-SSCPA) showed
      that strains of virus from the acupuncturist and two of the five patients for
      whom it was possible to perform the test were indistinguishable. Nine other
      patients who attended the same acupuncturist had antibody to the hepatitis B core
      antigen but had other risk factors for HBV infection. No obvious mode of
      transmission was identified but cross contamination of needles could not be ruled
      out in two cases. The fifth case was exposed to HBV after disposable needles were
      introduced. Routine immunisation of acupuncturists against HBV is recommended.

PMID- 10402751
TI  - Administration of time-expired yellow fever vaccine: public health response and
      results of a serological investigation.
AB  - The discovery that a local travel clinic had administered 101 doses of time
      expired yellow fever vaccine over a six month period prompted an immediate
      investigation in order to advise vaccinees about to travel to areas where yellow
      fever is endemic. No data were available to provide adequate reassurance about
      the potential efficacy of time-expired vaccine, so a rapid serological
      investigation was conducted, which provided evidence that the yellow fever
      vaccine had remained potent beyond its expiry date.

PMID- 10402752
TI  - Ascertainment of non-respiratory tuberculosis in five boroughs by comparison of
      multiple data sources.
AB  - The incidence of non-respiratory tuberculosis (TB) is known to be rising in many
      parts of the world. Examination of the ascertainment of non-respiratory TB in
      five Welsh boroughs by comparing multiple data sources showed that statutory
      notifications missed nearly half (38/81) of all cases over a period of 10 years,
      and illustrates an urgent need to improve surveillance.

PMID- 10402753
TI  - Follow up in north west England of cases of enteric fever acquired abroad, April
      1996 to March 1998.
AB  - Cases of enteric fever in the north west of England who acquired infection abroad
      between April 1996 and March 1998 were surveyed to determine the workload
      associated with the follow up of contacts of cases and the yield from their
      investigation. No asymptomatic secondary cases were detected, and it is argued
      that low risk asymptomatic contacts of cases of enteric fever acquired abroad do
      not need to be screened.

PMID- 10402754
TI  - Automation of the polymerase chain reaction. Part 2. Extraction--the foundation
      for success.

PMID- 10402755
TI  - Future accreditation of clinical microbiology laboratories.
AB  - Accreditation organisations in the United Kingdom (UK) are seeking to harmonise
      their practices to comply with internationally recognized standards. As
      organisations and laboratories work towards achieving alignment with the
      international accreditation standards, the standards currently applied in
      clinical microbiology laboratories are likely to change. The enforcement of
      international standards may demand extra resources to accommodate the necessary
      changes and it is important that laboratory staff become aware of the potential
      influence of international accreditation standards on clinical microbiology.

PMID- 10402756
TI  - Roles and responsibilities of safety officers and advisers.
AB  - Health and safety should be integrated into all practices and procedures at work.
      This article looks at the differences between safety officers/advisers, also
      known as safety practitioners and appointed safely representatives, examining
      their roles and responsibilities within working environments in general and
      specifically in microbiology laboratories and offices.

PMID- 10402757
TI  - Whooping cough notifications continue to fall: young unimmunised infants remain
      at highest risk.

PMID- 10402759
TI  - Prevalence of rotavirus diarrhoea among hospitalized children in Pune, India.
AB  - Rotavirus was detected in 266 (28.15%) out of 945 faecal specimens collected
      between July 1992 and June 1996 from children < or = 5 yr of age. Statistical
      analysis using odds ratios and multivariate logistic regression analysis revealed
      that seasonality had a strong influence on the number of rotavirus diarrhoea
      cases admitted to the hospital. Maximum cases occurred in the winter and minimum
      in the rainy season. Age was strongly associated with the prevalence of rotavirus
      diarrhoea. The age group of 6-24 months was the most susceptible. This disease
      was more predominant in males.

PMID- 10402758
TI  - Isolation & preliminary characterization of two HIV-2 strains from Pune, India.
AB  - Two HIV-2 strains were isolated from peripheral blood mononuclear cells of two
      HIV-2 seropositive patients with pulmonary tuberculosis by co-cultivating the
      cells with phytohaemagglutinin-P stimulated heterologous normal lymphocytes.
      Biological characterization of the isolates indicated that both isolates were
      syncytium inducing and induced cytopathic effect in the form of giant cells and
      syncytia formation in four T lymphoid cell lines. The isolates differed in their
      replication pattern. The isolates were confirmed as HIV-2 by nested PCR using HIV
      1 and HIV-2 specific oligonucleotide primers from the env region and by
      supplementary tests like indirect immunofluorescence assay, syncytium inhibition
      assay using reference and HIV-2 reactive patients' sera, western blot and
      electron microscopy. Neutralization of one isolate (TB1) with two Senegal
      reference sera also indicated that the isolate may be related to the Senegal
      strain. To our knowledge, this is the first report of isolation of HIV-2 in
      India.

PMID- 10402760
TI  - Biochemical characteristics & secretory activity of Aeromonas species isolated
      from children with gastroenteritis in Chennai.
AB  - An attempt was made to delineate the phenotypic markers for the detection of
      enterotoxigenic strains of Aeromonas. Eighteen Aeromonas species comprising one
      isolate of A. hydrophila, six isolates of A. sobria and 11 isolates of A. caviae
      were obtained from 379 children suffering from acute diarrhoea in Chennai. Nine
      of these isolates inclusive of three A. sobria and six A. caviae were found to
      produce secretory response in vitro in the rabbit intestinal mucosa mounted in
      the Ussing chambers as revealed by significant increases in the short circuit
      current. Eleven strains hydrolysed aesculin, 8 fermented arabinose, 6 produced
      acetyl methyl carbinol, 14 produced lysine decarboxylase, 3 fermented salicin, 9
      produced beta-haemolysin, 9 produced CAMP-like factor and only two isolates took
      up congo red dye. None of these phenotypic traits were found to correlate with
      the in vitro secretory activity.

PMID- 10402761
TI  - Vaccine potential of 56-66 kDa protease secreted by Entamoeba histolytica.
AB  - Excretory/secretory (ES) antigens and sub-cellular fractions of E. histolytica
      (HM1:IMSS strain) were tested for the presence of common proteases using
      substrate gel electrophoresis. We obtained two E. histolytica proteases (56-66
      kDa and 29 kDa) from ES material, soluble components and plasma membrane.
      Protease 56-66 kDa from ES antigen was selected for immunizing hamsters because
      it gave a consistent broad band. We observed 62.5 per cent protection in
      immunized animals, compared to 0 per cent in unimmunized controls. Although all
      vaccinated golden hamsters showed high antibody response, there was no
      correlation between antibody titres and protection. 56-66 kDa ES protease could
      thus prevent disease and could be a candidate molecular vaccine against
      amoebiasis.

PMID- 10402762
TI  - Association of the level of mosquito larvicidal activity with the growth &
      sporulation in Bacillus sphaericus H-5a5b strains.
AB  - The role of growth and sporulation in the production of mosquito larvicidal
      factors in B. sphaericus H-5a5b strains was investigated using 6 strains that
      differed in their larvicidal activity. Among these, strain B64 produced maximum
      biomass (15.5 g/l by 29th h) while B45 and B85 yielded the least (12.8 g/l by
      41st and 37th h respectively). Strains B43 and B42 reached the peak of viable
      cell count (4-6 x 10(10) cells/ml) 4 h earlier than B64 and 12 h earlier than the
      rest of the strains. Strains B42 and B43 produced higher number of heat resistant
      spores (4 x 10(8) spores/ml), while strains B45 and B57 produced the lowest
      numbers (2-4 x 10(5) spores/ml). Mosquitocidal toxin synthesis was noticed as
      early as the 5th and 9th h in the cultures of the strains B42 and B64
      respectively while in those of other strains it was detected by the 13th h or
      later. The results indicated that generally the highly and moderately toxic
      strains grew faster and sporulated better than the poorly toxic ones.

PMID- 10402763
TI  - Detection of glutamate dehydrogenase enzyme activity in Plasmodium falciparum
      infection.
AB  - We describe the separation of an active glutamate dehydrogenase [GDH (NADP+)]
      enzyme from the plasma of patients with P. falciparum infection using columns of
      sepharose anti-GDH (NADP+) of Proteus spp. The activity of this enzyme was also
      detected in P. falciparum culture supernatant. The parasitic origin of this
      enzyme was suggested by western blot analysis using anti-P. falciparum culture
      supernatant and anti-whole parasite antibodies. The differential inhibition of
      the P. falciparum GDH (NADP+) indicates that some epitopes recognised by the
      antibodies in both preparations may be different. The determination of P.
      falciparum GDH (NADP+) activity could be developed into a specific technique for
      the diagnosis of falciparum malaria.

PMID- 10402764
TI  - Changes in the composition of erythrocyte membrane during storage of blood in di
      (2-ethyl hexyl) phthalate [DEHP] plasticized poly vinyl chloride (PVC) blood
      storage bags.
AB  - Very little information is available on the changes in the erythrocyte membrane
      composition during storage of blood at 4 degrees C, particularly with respect to
      the glycosaminoglycans and glycoproteins. In view of this, a detailed study was
      carried out on the changes in the membrane proteins, glycosaminoglycans (GAG),
      carbohydrate components of glycoproteins, cholesterol, phospholipids and vitamin
      E in blood stored in glass bottles and a di-(2-ethyl hexyl) phthalate (DEHP)
      plasticized PVC bag (Penpol blood bag). Blood was collected in CPDA solution in
      glass bottles and in Penpol blood bags and kept at 4 +/- 1 degrees C. Analysis
      was made immediately after blood collection and after 28 and 42 days. Significant
      increase in the total protein in the erythrocyte membrane was observed during
      storage of whole blood in glass bottles and Penpol blood bag at 4 degrees C. This
      increase was progressively more with increase in storage time. Significant
      changes were also observed in GAG, carbohydrate components of glycoproteins,
      cholesterol, phospholipids and vitamin E in the erythrocyte membrane under these
      conditions. The protein:GAG ratio, protein:carbohydrate ratio,
      cholesterol:phospholipid ratio as well as protein:lipid ratio showed significant
      increase in the membrane. The extent of these changes was lower in the Penpol
      bag, indicating the stabilizing effect of DEHP on the erythrocyte membrane.

PMID- 10402765
TI  - Postoperative lung volume calculated by chest computed tomography in patients
      with esophageal cancer.
AB  - It has been reported that, due to the severe surgical stress of thoracotomy,
      respiratory function after esophagectomy under thoracotomy worsened as late as a
      month after surgery. To investigate the mechanism of the reduction of the
      respiratory function, we utilized chest CT to analyze separately the changes in
      the lung volume of the thoracotomized side and the other side. Here, we reported
      the results of our comparative study of lung volume and respiratory function,
      which was performed by spirogram before esophagectomy and 6 months afterwards. We
      selected twenty-three patients who had undergone esophagectomy under right
      thoracotomy. Fourteen of the selectees received standard thoracotomy, while the
      other nine had the anterior serratus muscle and the latissimus dorsi muscle
      preserved. Total lung volume was found to have decreased from a preoperative
      value of 4077 +/- 674 ml (mean +/- SD) to a postoperative value of 3964 +/- 774
      ml, and right-lung volume significantly decreased from 2229 +/- 397 to 2023 +/-
      397 ml, while left-lung volume tended to increase. While right-lung volume in
      standard thoracotomy displayed a significant decrease from 2264 +/- 334 to 1949
      +/- 424 ml, that in muscle-preserving thoracotomy showed almost no change.
      Spirogram revealed that vital capacity had decreased from 3574 +/- 601 to 2666 +/
      576 ml, and forced expiratory volume in the first second showed a significant
      decrease from 2680 +/- 500 to 2249 +/- 485 ml. Comparing the decreasing rate, the
      correlation coefficients between right-lung volume and %VC was 0.58. These
      results suggested that a change of lung volume in the thoracotomized side could
      play a role in the post-operative decrease of vital capacity and that muscle
      preserving thoracotomy might induce less surgical stress than standard
      thoracotomy.

PMID- 10402766
TI  - Does preoperative chemotherapy cause adverse effects on the perioperative course
      of patients undergoing esophagectomy for carcinoma?
AB  - The aim of this study was to clarify whether preoperative chemotherapy caused
      adverse effects on the perioperative course of patients undergoing esophagectomy.
      A total of 42 esophageal cancer patients were entered into a randomized trial and
      were analyzed. Twenty-one patients were assigned to immediate surgery (Surgery
      Group). The other 21 received two 5-day courses of chemotherapy comprising
      cisplatin (70 mg/m2) on day 1, and fluorouracil (700 mg/m2) and leucovorin (20
      mg/m2) on each of days 1 to 5 (chemotherapy group). Hospital mortality comprised
      of one patient (2.3%) who had undergone an operation in the beginning of this
      series at 21 days after chemotherapy. Thereafter, the interval between the
      chemotherapy and operation was prolonged, with the average being 35 +/- 7 days.
      Preoperatively, both the lymphocyte counts and serum albumin levels were not
      increased in the chemotherapy group of patients even though their body weights
      increased. In the chemotherapy group, the operation time and the blood loss were
      increased and, on the 1st postoperative day, the development of systemic
      inflammatory response syndrome was high but the level of C-reactive protein was
      low. The incidence of positive microbial cultures of sputum and/or wound
      discharge within 8 postoperative days was higher in the chemotherapy group
      (42.9%) than in the surgery group (4.8%). The host defense damage caused by
      chemotherapy may be prolonged and may show adverse effects in patients undergoing
      esophagectomy in the early postoperative period. Minimally, a 4-week interval
      between the completion of chemotherapy and operation is recommended for
      preventing surgical mortality related to the preoperative chemotherapy.

PMID- 10402767
TI  - Study of gene delivery in a rabbit vein graft model. Improvement of the
      efficiency of gene transfer into vein grafts.
AB  - Gene therapy is a therapeutic strategy in treating cardiovascular disease. Vein
      graft failure, the major limitation on coronary artery bypass surgery, may be
      amenable to gene approaches. Some studies describe gene therapies using
      functioning genes to prevent vein graft stenosis. Gene transfer efficiency
      remains a major issue. In this rabbit vein graft model, we studied gene delivery
      using a replication-deficit recombinant adenovirus to improve gene transfer
      efficiency into vein grafts. The adenovirus vector that contains the E.coli lacZ
      gene encoding beta gal was used because this vector is widely used and thought to
      be effective. Gene transfer was detected by X-gal staining. We hypothesized that
      dimethylsulfoxide and hyaluronidase, both drug delivery enhancers, would improve
      efficiency and that, in transfer to adventitia, direct injection would be more
      effective than dwelling. We studied 3 gene delivery methods to intima and media
      (controls, using dimethylsulfoxide and using hyaluronidase before transfection)
      and 2 delivery methods to adventitia (direct injection and dwelling). We used 6
      rabbits per delivery method. X-gal stained positive cell rates were counted using
      light microscopy. Our findings indicate that (1) dimethylsulfoxide increased the
      efficiency of transfection to media and intima, (2) hyaluronidase increased
      intimal transfection efficiency, (3) direct injection to adventitia was more
      effective than dwelling. These findings suggest that in vein grafting, our
      methods are feasible for improving gene transfer efficiency.

PMID- 10402768
TI  - Computed tomography-fluoroscopy guided injection of cyanoacrylate to mark a
      pulmonary nodule for thoracoscopic resection.
AB  - BACKGROUND: There have been several reports regarding aids to localize small
      and/or deeply situated peripheral pulmonary lesions thoracoscopically. However,
      we have found that they were not always reliable and have attempted to use a
      cyanoacrylate adhesive as an alternative. METHOD: We injected 0.1-0.2 ml of
      Histoacryl (n-butyl-2-cyanoacrylate) blue through a 22 gauge long needle to the
      lung parenchyma immediately beneath the pleural surface that was nearest to the
      target nodule. Following local anesthesia of the thoracic wall, we inserted the
      needle tip to the desired position under CT-fluoroscopic guidance. After
      retracting the syringe piston to confirm that no blood was aspirated, we injected
      the adhesive and immediately removed the needle. RESULTS: The adhesive
      polymerized immediately after its injection into the lung parenchyma to form a
      hard nodule. There was no complication except mild pneumothorax and slight pain
      at the puncture site. The adhesive nodule measured 1.0-1.5 cm in diameter and was
      hard enough to be easily located thoracoscopically in all the 8 patients/9
      nodules studied. The nodule was also recognizable by its blue color visible under
      the pleura. CONCLUSION: CT-fluoroscopy guided injection of Histoacryl blue
      provided a reliable marker for the localization of pulmonary nodules, especially
      in those patients with severe anthracosis in the pulmonary parenchyma.

PMID- 10402769
TI  - Developing bronchial fistulas as a late complication of extraperiosteal plombage.
AB  - A 65-year-old male, who underwent extraperiosteal plombage for pulmonary
      tuberculosis 46 years ago, was referred to our hospital due to relapsing
      hemosputa and pneumonia. A chest computed tomography scan revealed a bronchial
      fistula and a fluid collection in one Lucite ball. On May 20, 1996, a right
      anterior thoracotomy was performed in a supine position. Five Lucite balls were
      removed, and the empyema space was tightly filled with an omental pedicle flap.
      Although the bronchial fistulas were not sutured directly, the air leakage from
      the drainage tube ceased 12 days later. Two years postoperatively the patient has
      remained well. Our simple approach of combining an anterior thoracotomy and
      replacement of an empyema space with an omental pedicle flap in the same posture,
      without closing bronchial fistulas, would be an easy procedure, and therefore
      exploitable in patients who have a similar problem.

PMID- 10402770
TI  - Aortic valve stenosis with left ventricular outflow tract pressure gradient.
AB  - A 61-year-old man was diagnosed with severe aortic valve stenosis with left
      ventricular outflow tract pressure gradient due to systolic anterior movement of
      the mitral valve and a large poststenotic dilation of the ascending aorta. He
      underwent successful aortic root replacement and concomitant septal myectomy.

PMID- 10402771
TI  - Pulmonary artery aneurysm.
AB  - Main pulmonary artery aneurysm is an exceedingly rare entity. We present a case
      of main pulmonary artery aneurysm with patent ductus arteriosus in a sixty-year
      old woman. The aneurysm was successfully treated with aneurysmectomy and primary
      anastomosis of the defect of the main pulmonary artery, and the patent ductus
      arteriosus was divided. The etiology, operative indication and surgical
      intervention of main pulmonary artery aneurysm are discussed along with a review
      of the literature.

PMID- 10402772
TI  - Coronary artery bypass grafting in a case with severe aortic atheromatosis
      associated with abdominal aortic aneurysm.
AB  - A 69-year-old man with coronary artery disease associated with abdominal aortic
      aneurysm underwent a one-stage operation utilizing a low-flow cardiopulmonary
      bypass. Ordinary cardiopulmonary bypass was abandoned as a result of severe
      atheromatous finding in the entire aorta. However, coronary artery bypass
      grafting without cardiopulmonary bypass was hazardous as a result of heart
      enlargement and deteriorating function. Therefore, the abdominal aortic aneurysm
      was first replaced with a bifurcated graft. Coronary artery bypass grafting with
      two arterial grafts was then performed successfully on the beating heart with the
      support of a low-flow cardiopulmonary bypass connected to the bifurcated graft.

PMID- 10402773
TI  - Progressive pulmonary vascular disease after pulmonary artery banding and total
      correction in a case of ventricular septal defect and pulmonary hypertension.
AB  - A 7-month-old infant with ventricular septal defect and pulmonary hypertension
      underwent pulmonary artery banding, which resulted in a decrease in the pulmonary
      arterial peak pressure from 102 to 54 mmHg. Lung biopsy findings showed at most
      an early grade 3 Heath-Edwards classification, and an index of pulmonary vascular
      disease of 1.4, both of which indicated operability for total correction. Small
      pulmonary arteries less than 100 microns in diameter, however, showed marked
      hydropic changes in the medial smooth muscle cells. Total correction was
      performed at the age of 2 years, but the pulmonary arterial pressure failed to
      decrease. A lung biopsy taken just after the closure of the ventricular septal
      defect contraindicated operability due to progressive pulmonary vascular disease
      at a grade 6 Heath-Edwards classification and an index of pulmonary vascular
      disease of 2.4. The patient died at 8 months after the operation, and an autopsy
      revealed still more advanced pulmonary vascular disease at a grade 6 Heath
      Edwards classification and an index of pulmonary vascular disease of 2.8. The
      pathogenesis of arterial changes is discussed.

PMID- 10402774
TI  - Aortic valve replacement after retrosternal gastric tube reconstruction for
      esophageal cancer.
AB  - A 59-year-old man with a history of the thoraco-abdominal esophagus resection
      with retrosternal gastric tube reconstruction for esophageal cancer complicated
      by anastomosis leakage and purulent pericarditis was admitted for aortic
      regurgitation due to infective endocarditis. Floppy vegetation and worsening
      cardiac failure indicated aortic valve replacement. In a median sternotomy
      approach, the thickest adhesion between the cervical esophagus and posterior
      surface of the manubrium sternae was freed using an ultrasonic osteotome. Severe
      adhesions in the pericardium due to purulent pericarditis were found. Median
      sternotomy enabled minimal exposure of the aortic root, upper right atrium, and
      right superior pulmonary vein for instituting extracorporeal circulation and
      replacing the aortic valve. The patient's postoperative course was uneventful.
      For cardiac surgery in patients with a retrosternal gastric tube, left anterior
      or right thoracotomy may be considered to avoid gastric tube injury. Median
      sternotomy, however, is an alternative enabling safe heart exposure, and the
      ultrasonic osteotome was very useful in incising the sternum without injuring the
      cervical esophagus, which had no serosa.

PMID- 10402775
TI  - Thoracic and cardiovascular surgery in Japan during 1997. Annual report by the
      Japanese Association for Thoracic Surgery. Committee of Science.

PMID- 10402776
TI  - Open heart surgery in a patient with autoimmune hemolytic anemia.

PMID- 10402777
TI  - [Aortic valve operations through an upper partial sternotomy].
AB  - The median sternotomy has been accepted as the most common approach to the heart,
      because this approach is easily opened and closed, and easy access to the entire
      heart is possible. Following the pioneering work by Cosgrove and colleagues of
      using a parasternal incision for aortic and mitral valve operations, several
      reports suggested that modified minimal access procedures are likely to be
      associated with reduced postoperative discomfort and faster recovery. Since July
      1997, we have used an upper partial sternotomy and a limited skin incision for
      isolated aortic valve replacement (AVR) at our hospital. To demonstrate the
      benefits of this approach, we compared 14 AVR operations using our minimal access
      incision (group M) with 19 patients undergoing isolated AVR using a conventional
      sternotomy (group F). In the minimal access group of patients, a small skin
      incision was made from the second intercostal space to the fourth rib. The
      pectralis major and intercostal muscle was freed from the sternum, and then a
      transverse half sternotomy was made in the fourth intercostal space using a
      striker without injury to the right internal mammary artery. A median partial
      sternotomy from the supersternal notch to the level of the fourth intercostal
      space. Cardiopulmonary bypass was connected through the same access site to avoid
      cannulation of both groins. Conversion to median sternotomy was not necessary in
      any patient including reexploration for postoperative bleeding. There was no
      operative mortality, stroke, aortic dissection and perivalvular leaks due to
      technical factors. In group F, wound infection occurred in 1 patient. One patient
      in group M required reoperation to control postoperative bleeding. Although mean
      duration of operation, cardiopulmonary bypass, and cross clamp time in group M
      was not prolonged, the initiation of cardiopulmonary bypass and aortic crossclamp
      was delayed by difficulties of cannulations. The distance between the transverse
      sternotomy (lower edge of divided sternum) and the midpoint of aortic valve
      annulus was correlated with mean duration of cardiopulmonary bypass and cross
      clamp time. Our experience demonstrates that isolated AVR through an upper
      partial sternotomy allows the same quality operations as the full sternotomy,
      although more clinical experience is required to clarify the benefits of this
      approach. Excellent exposure of the aortic valve through a partial sternotomy may
      be attained, if an adequate approach can be selected by the position of aortic
      valve.

PMID- 10402778
TI  - [Stentless aortic root bioprosthesis (freestyle) to patients of bicuspid aortic
      valve with abnormal positioning of the coronary ostia].
AB  - Stentless aortic root bioprosthesis (Freestyle) was implanted to two patients of
      bicuspid aortic valve stenosis with anatomically abnormal positioning of the
      coronary ostia. In a patient of LR type bicuspid valve, the left coronary artery
      was located at 180 degrees against the right coronary ostium. To match the
      Valsalva sinus of the patient with bioprosthesis, the left half of the native
      annulus, 23 mm in the diameter, was plicated corresponding to the one third of
      the Freestyle inflow, 21 mm in the diameter. In the other patient of AP type
      bicuspid valve, both coronary ostia were closely positioned at 90 degrees. To
      keep both ostia in the sinus of bioprosthesis, careful trimming and suturing were
      required in the narrow part of both ostia. Their postoperative courses were
      uneventful and no regurgitation has been observed in either case.

PMID- 10402779
TI  - [A case of tracheal fistula after operation for esophageal cancer].
AB  - We have experienced a case of mediastinal abscess and tracheal fistula after
      operation for esophageal cancer and successfully closed by using intercostal
      muscle pedicle flap. A 61-year-old male underwent esophagectomy for advanced
      esophageal cancer. On the 12th postoperative day, mediastinal abscess caused by
      leakage was detected, and drainage of the mediastinal and thoracic cavity was
      performed. On the 29th postoperative day, tracheal fistula was detected, and
      operation was performed in order to close the fistula by using of intercostal
      muscle pedicle flap. His postoperative course was fair and general condition was
      improvement, esophageal reconstruction using of free jejunal graft was performed
      and oral ingestion was started.

PMID- 10402780
TI  - [The evaluation of ischemia by the tangential magnetocardiogram in a patient
      underwent coronary artery bypass grafting].
AB  - We tried to evaluate myocardial ischemia in a patient who underwent coronary
      artery bypass grafting by the measurement of tangential magnetocardiogram. For
      the visualization of ischemia, we introduced isointegral maps during
      depolarization and repolarization reconstructed from tangential magnetography. We
      found different patterns in isointegral maps of the IHD patient compared with
      those in normal subjects. Post operative isointegral maps showed recovery from
      ischemia as increase of current volume.

PMID- 10402781
TI  - [Mitral valve annuloplasty with U-shaped flexible band using Duran ring].
AB  - To preserve the physiologic function and correct annular dilatation, U-shaped
      flexible band was applied for mitral valve annuloplasty in 6 cases. U-shaped
      flexible band was made by cutting Duran ring to the proper length of posterior
      annulus using Carpentier-Edwards ring sizer. Echocardiographic mitral
      regurgitation decreased from 3.8 +/- 0.4 to 0.7 +/- 0.5 after repair. All
      patients discharged without any complications. This annuloplasty method is
      effective for mitral insufficiency.

PMID- 10402782
TI  - [Surgical repair of postinfarction ventricular septal defect: modified Komeda
      David procedure].
AB  - Since Cooley first reported surgical repair of postinfarction ventricular septal
      defect in 1957, there have been technical improvements in this procedure.
      However, the outcome of surgery has not been gratifying thus far. In 1990, Komeda
      and associates reported a single patch of bovine pericardium sutured to the
      healthy myocardium around the infarcted area on the left side of the septum that
      excludes the infarcted myocardium from the left ventricular cavity; a procedure
      based on a completely different idea. Since the satisfactory outcome of the
      surgical treatment in this procedure was obtained in a series of 12 patients,
      this surgical procedure has been in widespread use in Japan. On the other hand,
      this procedure has a drawback that there is a difficulty in suturing the patch
      and may lead to a postoperative residual shunt. We investigated a modified
      surgical procedure that could overcome this difficulty and would like to report
      it in this paper. At first, the perforated area should be covered with a felt
      strip and closed with mattress sutures. Secondly, the infarcted myocardium from
      the left ventricular cavity should be obliterated using a two-patch method. The
      primary advantage of this procedure is that it achieves a broader range of vision
      than a single patch method and enables easy suturing. Additionally, the
      development of a residual shunt can be prevented owing to the closure of
      perforation even if sutures fail to hold and leakage occurs. The tow-patch method
      has the advantage of avoiding tension against sutures since the patch is not
      everted around the sutures. However, the question arises whether only the healthy
      myocardium can be picked out and sutured without fail. In order to make the two
      patch method more reloable the perforation should be closed in advance.

PMID- 10402783
TI  - [Assessment of internal thoracic artery grafts using duplex scanning].
AB  - In an effort to develop a noninvasive method to evaluate flow characteristics of
      the internal thoracic artery grafts (ITAG) after coronary artery bypass grafting,
      we performed duplex scanning of ITAGs of 51 patients who underwent bypass
      grafting. The ITAG was visualized with a duplex scanner of 7.5 MHz through the
      first or second left intercostal space. The visualization of the ITAG was
      adequate to make reliable measurements in 47 patients (92.2%). The diameter of
      the vessel, systolic peak velocity, and diastolic peak velocity were recorded,
      and systolic flow volume, diastolic flow volume, velocity ratio, flow volume
      ratio, and diastolic flow volume fraction were calculated. The velocity ratio,
      flow volume ratio, and diastolic flow volume fraction were markedly higher in the
      unstenotic subjects than in the stenotic subjects. In the group in which severe
      LAD stenosis were recognized preoperatively, both systolic and diastolic flow
      volumes were increased compared with moderately stenotic group. No differences in
      flow characteristics could be demonstrated between the subjects with old anterior
      myocardial infarction and without it. In 10 patients in whom flow pattern was
      abnormal or not identified, angiography revealed graft stenosis or predominant
      native coronary arterial flow. Duplex scanning is thought to be a reliable,
      sensitive, and noninvasive technique for the assessment of the ITAG.

PMID- 10402784
TI  - [New screening method for coagulation abnormality including AT III deficiency
      during CABG].
AB  - In our institute, 1 ml of heparin is administered to the patients undergoing CABG
      before dissection and mobilization of the internal thoracic arteries (ITAs)
      and/or right gastroepiploic artery (GEA) to prevent possible thrombosis or
      coagulation tendency. Two patients with AT III deficiency underwent CABG and one
      of them died. The aim of this study is to know whether ACT check before and after
      administration of 1 ml of heparin is useful as a screening test of coagulation
      abnormalities including AT III deficiency. One hundred patients (84 males and 16
      females) undergoing CABG were studied. Age ranged from 41 to 79 years (mean 64.8
      +/- 8.0 years). One ml of heparin was administered to all the patients before
      ITAs and/or GEA were dissected and mobilized. ACT was doubly checked before
      (control ACT: c-ACT) and after (heparinized ACT: h-ACT) administration of
      heparin. ACT extension was defined as follows: ACT extension = (c-ACT)-(h-ACT).
      Mean c-ACT was 124 +/- 12 sec., h-ACT 188 +/- 26 sec. and ACT extension 64 +/- 24
      sec. There were only 3 cases which ACT extension were less than 30 sec.: two of
      them were combined with AT III deficiency and the other was due to insufficient
      administration of heparin. In conclusion, examination of ACT after 1 ml
      administration of heparin is new, simple and convenient screening method for
      coagulation abnormalities including AT III deficiency during CABG.

PMID- 10402785
TI  - [Total anomalous of pulmonary venous connection in infants less than 3 months
      old].
AB  - We examined the surgical results of total anomalous pulmonary venous connection
      (TAPVC) retrospectively in 6 infants, who were less than 3 months old and
      underwent a total repair at Ehime Prefectural Central Hospital between May, 1993
      through May, 1998, in terms of the pre, peri, and postoperative management, the
      site of connection, and the surgical procedures. Aged at operation ranged from 1
      day to 86 days (mean 39 days), and body weight ranged from 2.4 kg to 5.5 kg (mean
      3.4 kg). All 6 patients had echocardiographic diagnosis and cardiac
      catheterization but one. In operative procedure, cut back method was done in a
      patient of paracardiac type of Darling's classification and posterior approach
      was used in total correction for 4 supracardiac and 1 infracardiac type. There
      were 3 hospital deaths who had poor conditions before operation, but no late
      deaths. Surgical results of TAPVC might have been improved with advances in non
      invasive diagnosis by echocardiography, and pre and perioperative management. And
      we should take care of these patients of TAPVC in long term period to make sure
      that they have no pulmonary venous obstruction.

PMID- 10402786
TI  - [Methicillin-resistant Staphylococcus aureus (MRSA) mediastinitis after
      cardiovascular operations].
AB  - We described three cases of poststernotomy mediastinitis caused by MRSA. The
      first case 74-year-old woman who had undergone emergent CABG was treated by
      continuous closed irrigation and consecutive omental transfer. She was suffered
      from multiple organ failure and died. The other two cases 50-year-old woman and
      66-year-old man after double valves replacement and total aortic arch replacement
      were managed successfully with simultaneous combination of surgical debridement
      and placement of omental flap. It was seemed that early aggressive surgical
      procedures before deterioration of general conditions associated with improvement
      of mortality. Additionally, it was considered that to avoid residual dead space
      in presternum as well as in mediastinum was essential to decrease the morbidity
      and hospital stay, especially in case of MRSA infection.

PMID- 10402787
TI  - [Mitral valve replacement under cardiopulmonary bypass which complicated by
      multiple sclerosis: a case report].
AB  - The 60-year-old women who complicated by multiple sclerosis was referred to our
      hospital under diagnosis of mitral valve stenosis and tricuspid valve
      regurgitation. The mitral valve replacement and the tricuspid valve annuloplasty
      were performed under cardiopulmonary bypass. In the state of multiple sclerosis,
      even an operation by general anesthesia could become a cause of abrupt change,
      but by appropriate management during and after surgery, the post operative course
      was uneventful without any complications, and the patient discharged on the 35th
      post operative day.

PMID- 10402789
TI  - [A case of mitral valve replacement and left atrial plication for infantile
      Marfan syndrome with giant left atrium due to mitral valve regurgitation].
AB  - In Marfan syndrome, there is a subset, called infantile Marfan syndrome, in which
      the disease is diagnosed during infancy and cardiac lesions including mitral
      regurgitation and aortic root dilatation tend to be deteriorated rapidly. In
      infantile Marfan syndrome, respiratory function is sometimes impaired when
      skeletal abnormalities such as scoliosis and pectus excavatum are severe. In this
      report, we describe a 2-year and 4-months old boy with infantile Marfan syndrome
      who presented with severe mitral regurgitation and the collapsed left lung. In
      addition to the impairment of respiratory function due to severe scoliosis, the
      left lung was collapsed because of the compression of the left bronchus by the
      enlarged left atrium. The patient required mitral valve replacement concomitantly
      with left atrial plication, resulting in the decompression of the left bronchus
      and the re-expansion of the left lung. Characteristics and surgical management of
      infantile Marfan syndrome are discussed in this report.

PMID- 10402790
TI  - [A case of supravalvular mitral ring].
AB  - A two-year-old girl with supravalvular mitral ring successfully underwent the
      excision of the ring. The preoperative echocardiogram showed supravalvular mitral
      ring and almost normal mitral leaflets. We paid attention not to injury mitral
      valve at the excision of the ring because supravalvular mitral ring adhered to
      the mitral valve.

PMID- 10402788
TI  - [A case of mitral valve replacement combined with idiopathic thrombocytopenic
      purpura (ITP)].
AB  - We conducted mitral valve replacement (MVR) in a patient with mitral
      regurgitation (MR) complicated with idiopathic thrombocytopenic purpura (ITP).
      The patient was a 62-year-old male who was diagnosed to have grade IV MR.
      However, a decrease in platelet count was noted (5.6 x 10(4)/microliter) when he
      has admitted to this hospital for operation. After detailed examination, he was
      diagnosed to have ITP. Though mass intravenous infusion of gamma-globulin (400
      mg/kg/day, for 5 days) was done before the operation, the treatment was not
      successful and splenectomy was consequently conducted. In view of the influence
      of invasive splenectomy, the change in platelet count was carefully observed
      thereafter. The count subsequently increased to reach a peak (26.9 x
      10(4)/microliter) after 2 weeks from the splenectomy. MVR was conducted when the
      count started to decrease again after the peak. The operation was safely
      completed without any complication such as hemorrhage during and after the
      operation. Since gamma-globulin treatment and splenectomy are sometimes
      ineffective in ITP, it is advisable to wait an operation until the effects of
      these treatments are clarified.

PMID- 10402791
TI  - [A case of intracardiac repair for anatomically corrected malposition of the
      great arteries (S, D, L)].
AB  - A 5-year-old boy with anatomically corrected malposition of the great arteries
      (Van Praah's {S, D, L} arrangement type) associated with ventricular septal
      defect (malalignment conus type) and pulmonary stenosis underwent a biventricular
      repair. Subpulmonary stenosis was repaired by muscle resection of narrowing
      muscular subpulmonary conus through the right ventricle. The postoperative
      catheterization showed that the pressure ratio of right ventricle/left ventricle
      was 0.4. There was no complication during follow-up period of 6 years.

PMID- 10402792
TI  - [A one-staged operation for mitral regurgitation and giant bulla in a patient
      with severe pulmonary hypertension: report of a case].
AB  - A 57-year-old woman was admitted to our hospital for the treatment of mitral
      regurgitation and giant bulla with severe pulmonary hypertension. A dobutamine
      induced test performed preoperatively resulted in a decrease of the systolic
      pulmonary artery pressure by 30 mmHg. Subsequently, mitral valve replacement and
      bullectomy were performed concomitantly. The patient recovered from heart
      failure, and the pulmonary artery pressure clearly decreased during the
      perioperative period. This case report serves to demonstrate the effectiveness of
      performing a one-staged operation for mitral regurgitation and giant bulla with
      severe pulmonary hypertension.

PMID- 10402793
TI  - [A case of pulmonary dirofilariasis].
AB  - A 58-year-old man was admitted to our hospital for detailed examination of
      continuous cough. On a chest X-ray film, abnormal shadow was detected in the
      right lower lung field. Preoperative examination findings didn't lead to a
      definitive diagnosis. Under thoracoscopy partial resection of the lung was
      performed to rule out a malignant lesion. Intraoperative pathologic finding
      revealed a granulomatous lesion. And, final pathological diagnosis showed to be a
      pulmonary dirofilariasis. His postoperative course was not eventful. On 20 th day
      he discharged postoperatively. Now, under the Pet-boom the disease has been
      reported increasingly. But it is difficult to find the disease preoperatively.
      So, it is real to be operated for differentiate from a malignant lesion. Recently
      in many cases open lung biopsy, has been undergone with less invasive procedure
      such as thoracoscopy and VATS. It will be mainstream in future.

PMID- 10402794
TI  - [Complete disruption of thoracic descending aorta without widening of the
      pseudoaneurysm].
AB  - A 41-year-old male was transported to our emergency room 25 minutes after blunt
      chest trauma. The chest X-ray film and CT scanning demonstrated left pulmonary
      atelectasis, hemothorax, and widening of mediastinum possibly due to hematoma.
      Hundred and fifty minutes after arrival to the hospital, we were rush to bring
      him to the operation theater suspecting serious injury of the thoracic organs in
      association with bleeding from left thoracic drainage tube without detection of
      the aortic rupture. The left standard thoracotomy disclosed no injury of the left
      lung, good continuity and no dilatation of the thoracic descending aorta. But
      visual blood flow observed through the adventitia of the aortic isthmus led us to
      the final diagnosis of the aortic rupture. After aortic clamping, the intima of
      the injured aorta was found to be completely disrupted for a length of 6 cm and
      was repaired with a vascular prosthesis under the partial cardiopulmonary bypass
      using a centrifugal pump. His postoperative course was uneventful. We reported a
      case of complete circumferential aortic rupture without widening of the
      pseudoaneurysm in the acute stage of the disease.

PMID- 10402795
TI  - [Beta-blockers in heart failure. From contraindicated therapy to the best
      documented one].

PMID- 10402796
TI  - [Spiritual values can make the suffering meaningful and manageable. Existential
      questions are of current interest in palliative care].

PMID- 10402797
TI  - [Must "noisy Kalle" have a diagnosis to be placed correctly?].

PMID- 10402798
TI  - [Limited use of dormicum has its place in the care of critically ill patients].

PMID- 10402799
TI  - [Why not a scientific approach in connection with reorganizations?].

PMID- 10402801
TI  - [Which diseases are to be prioritized?].

PMID- 10402800
TI  - [The development of primary health care in Tanzania].

PMID- 10402802
TI  - [New methods of joint replacement in the hand yield better function and pain
      relief].
AB  - Arthroplasty of the hand has hitherto been performed with rather simple methods
      such as the interposition of soft tissue or silicone implants. Surface
      replacement techniques, both cemented and cementless, currently routine methods
      in orthopaedic surgery, are becoming more and more commonly used in hand surgery.
      The article consists in a review of old and new methods for the replacement of
      wrist and finger joints, and a report of the results of osseo-integrated titanium
      implants in metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints,
      and of short-term outcome of non-constrained implants in wrist and PIP joints.

PMID- 10402804
TI  - [Tranexamic acid reduces the blood loss in knee arthroplasty--if it's
      administered at the right time].
AB  - Blood loss in total knee arthroplasty is some-times profuse and often
      necessitates transfusion which is associated with a risk of disease transmission
      and immunological burden to the recipient. The fibrinolytic system is activated
      during surgery, an activation augmented by the tourniquet often used in knee
      arthroplasty. We have found tranexamic acid, a well-known fibrinolytic inhibitor,
      to reduce blood loss by half in total knee arthroplasty, and the need of
      transfusion by two thirds. For optimal efficacy, the tranexamic acid should be
      administered as prophylaxis before release of the tourniquet. We have found no
      adverse effects of the drug.

PMID- 10402803
TI  - [Reduced frequency of resistant pneumococci in Southern Sweden. Community based
      disease control projects to minimize antibiotic resistance].
AB  - In an attempt to limit the spread of penicillin non-susceptible pneumococci
      (PNSP) in southern Sweden, early in 1995 an intervention project was launched,
      using a combination of traditional communicable disease control measures and
      actions aimed at reducing antibiotics consumption. Patients carrying PNSP
      (penicillin G MIC (0.5 mg/L) are monitored with nasopharyngeal cultures until
      PNSP-negative. Pre-school children are kept home from group day-care facilities.
      Previous antibiotic consumption was identified as a risk factor for PNSP
      carriage. Antibiotics sales decreased during the study period, and
      epidemiological findings suggest the dissemination of PNSP in the area to have
      been reduced by the intervention project.

PMID- 10402805
TI  - [Patients with diabetes search facts about their disease on the net. More
      information in Swedish is needed].

PMID- 10402806
TI  - [A case report. Reperfusion in thrombolysis of pulmonary embolism can be measured
      with capnography].

PMID- 10402807
TI  - [Toulouse-Lautrec and Pean would have happily exchanged their professions].

PMID- 10402808
TI  - [To use the stethoscope correctly is not easy. The intricate art of auscultation
      should receive more attention in medical education].
AB  - Although the stethoscope is used daily by almost every physician, the full
      potential of the art of stethoscopy is seldom tapped. It has been replaced by
      newer and more costly techniques. In the article it is argued that more time in
      medical education should be allocated to stethoscopy, so that it can be used in
      selecting patients who will benefit most from examination with modern diagnostic
      tools. The medical technological background of stethoscopy is also reviewed, as
      are the reasons why it is difficult to give sound advice on the choice of
      stethoscope.

PMID- 10402809
TI  - [Gastrointestinal ischemia in patients undergoing coronary artery bypass surgery-
      comparison of two methods for gastric intramucosal PCO2 monitoring].
AB  - To assess the adequacy of gastrointestinal mucosal perfusion perioperatively, the
      gastric intramucosal PCO2 (PiCO2) was monitored in ten patients undergoing
      elective coronary artery bypass grafting operation. Extracorporeal circulation
      was performed with mild hypothermia (temperature between 30 degrees C and 32
      degrees C) and nonpulsatile flow. Plasma levels of interleukin-6 and endothelin-1
      remained elevated up to twelve hours after surgery. The PiCO2 using the ion
      sensitive field effect transistor (ISFET) sensor, attached to the tip of a
      nasogastric tube, increased significantly to 64 +/- 9 mmHg (mean +/- SD) at 6th
      postoperative hour from a baseline value of 48 +/- 7 mmHg. A similar trend was
      observed in PiCO2 as measured by capnographic gas tonometry. Although there was a
      close correlation between these two techniques (r2 = 0.4923), values with ISFET
      sensor were significantly higher (11-16 mmHg) than those by capnographic gas
      tonometry. Gastrointestinal mucosal ischemia, probably related to systemic
      inflammatory response, was observed during the immediate postoperative period.
      The PiCO2, measured directly and continuously with ISFET sensor, may be a more
      sensitive indicator compared with capnographic gas tonometry in evaluating the
      development of gastrointestinal mucosal injury.

PMID- 10402810
TI  - [Effect of vasodilators on femoral-to-radial arterial pressure gradient after
      cardiopulmonary bypass].
AB  - In 57 adult patients undergoing valve replacement surgery or valve plastic
      surgery, pressure gradient between the femoral and radial artery was evaluated
      after cardiopulmonary bypass (CPB). During CPB, the rectal temperature was kept
      at mild or moderate hypothermia. Nitrates and prostaglandin E1 were administered
      in all patients during operation. Patients were divided into two groups; Group A
      of 31 patients who had history of hypertension and received some vasodilators up
      to the operation, and Group B of 27 patients who had no history of such
      medication. There was no difference in patient's characteristics, anesthetic
      time, CPB time and aortic cross clamping time between the two groups. There was a
      significant difference between the pre-CPB and post-CPB in hematocrit data.
      Systemic vascular resistance (SVR) decreased significantly from the pre-CPB level
      to the post-CPB level. There was no significant difference between Group A and
      Group B in SVR, but a higher femoral-to-radial artery pressure gradient was
      observed in Group A until the end of operation. Hypertension and the use of
      vasodilator change the tone of peripheral blood vessels and intensify femoral-to
      radial artery pressure gradient after CPB.

PMID- 10402811
TI  - [Antinociceptive effects of intrathecally administered GABA agonists at the
      spinal cord level].
AB  - The present study was designed to investigate antinociceptive effect of GABA
      agonists regarding visceral as well as somatic noxious stimuli. Following the
      approval by the institutional animal care committee, an intrathecal catheter was
      implanted in the subarachnoid space at the L 4/5 level in male Sprague-Dawley
      rats. The tail flick (TF) test and the colorectal distension test (CD) were used
      to measure responses to somatic and visceral stimuli, respectively. Threshold in
      TF test and CD test were measured at 5, 10, 15, 20, 30, 60, 90, 120 and 180 min
      after the intrathecal injection of 0.1, 1, 5, 20 micrograms of muscimol, 0.01,
      0.1, 0.3, 1 microgram of baclofen or normal saline. Percent of maximum possible
      effect (%MPE) and %area under the curve (%AUC) were calculated by transforming
      response threshold in TF and CD tests. Repeated measure ANOVA followed by
      Fisher's PLSD test were used for statistical analysis. Muscimol 0.1 microgram
      increased mean %MPE in TF test at 10 min to 15% but not in CD test. Muscimol 1, 5
      and 20 micrograms significantly increased %MPE at 5 min in TF and CD tests.
      Muscimol 20 micrograms produced 100%MPE for 180 min after drug injection.
      Baclofen 0.1, 0.3 and 1 microgram significantly increased %MPE at 5 min in TF and
      CD test. Antinociceptive effect in TF test seems to be greater than that in CD
      test. Muscimol caused motor disturbance but baclofen did not. It is concluded
      that intrathecally administered muscimol and baclofen produced somatic and
      visceral antinociception in a dose dependent fashion.

PMID- 10402812
TI  - [The influence of ketamine on the bispectral index, the spectral edge frequency
      90 and the frequency bands power during propofol anesthesia].
AB  - To investigate the influence of ketamine on the bispectral index (BIS), the
      spectral edge frequency 90 (SEF 90) and relative power in four frequency bands
      (beta, alpha, theta, sigma), we studied 13 patients (ASA I-II) undergoing
      elective surgery. In the first study (n = 7), we administered ketamine (1.0 mg.kg
      1, bolus, i.v.) during propofol anesthesia. Thirty minutes after the
      administration, BIS, SEF 90 and relative beta power increased significantly. In
      the second study (n = 6), bolus administration of ketamine (0.5 mg.kg-1 i.v.)
      followed by continuous infusion was started during propofol anesthesia. The
      infusion rate of ketamine was 0.5 mg.kg-1.h-1 for 30 minutes and then increased
      to 1.0 mg.kg-1.h-1. BIS, SEF 90 and relative beta power increased significantly
      after ketamine administration, but the parameters did not change in dose-related
      manner. We conclude that further investigation is necessary to use
      electroencephalographic parameters as an indicator of the anesthesia depth during
      propofol/ketamine anesthesia.

PMID- 10402813
TI  - [A clinical dose finding study of propofol in continuous total intravenous
      anesthesia].
AB  - Total intravenous anesthesia (TIVA) is recommended in view of avoiding air
      pollution. However, intermittent administration of anesthetic agents has a
      disadvantage of delayed emergence time. We have suggested continuous TIVA with
      propofol, ketamine, vecuronium and buprenorphine (PKBp), and reported that the
      elder or the patients anesthetized for a long time show delayed emergence from
      continuous TIVA. In this study, after induction with propofol, ketamine,
      vecuronium and buprenorphine, the subjects were maintained with continuous
      intravenous administration of propofol corresponding to the age using twice step
      down method with ketamine (240 micrograms.kg-1.h-1), vecuronium (80 micrograms.kg
      1.h-1) and buprenorphine (0.4 microgram.kg-1.h-1). Emergence was evaluated from
      the 2nd step down of propofol to awareness. There was a linear relationship
      between the emergence (2nd step down time of propofol to awareness) (Y) and the
      anesthetic time (X); Y = 0.175X + 3.00. We conclude that the last 1/6 (= 0.175)
      of anesthetic time is the point to reduce maintenance doses of propofol to
      achieve more rapid emergence.

PMID- 10402814
TI  - [Changes of arterial blood pressure and heart rate during induction of anesthesia
      with propofol--efficacy of propofol titration using bispectral index as an
      indicator].
AB  - Bispectral index (BIS) is a processed EEG parameter that measures the hypnotic
      effects of anesthetic and sedative agents on the brain. We studied whether
      propofol titration using BIS allows us to prevent hemodynamic changes during
      induction of anesthesia and endotracheal intubation. Thirty patients without
      hypertension and obesity were studied. In the titration group (n = 15), BIS was
      maintained at 40 during induction of anesthesia with propofol. In the bolus
      group, anesthesia was induced with a bolus infusion of propofol 2 mg.kg-1 (n =
      15). Arterial blood pressure and heart rate were recorded before induction of
      anesthesia, during induction of anesthesia, immediately after, and 1 min, 2 min,
      and 3 min after intubation. Diastolic blood pressure and heart rate increased
      significantly after endotracheal intubation in both groups. Systolic blood
      pressure significantly increased immediately after intubation in the bolus group,
      but was unchanged in the titration group. These results suggest that BIS is
      useful to prevent significant increases in systolic blood pressure associated
      with endotracheal intubation during induction of anesthesia with propofol.

PMID- 10402815
TI  - [Perioperative change of ionized magnesium concentration--effect of blood
      transfusion].
AB  - In order to evaluate the effect of intra-operative blood transfusion on post
      operative decrease of ionized Mg (Mg2+), we performed following studies. 1) We
      measured ionized Mg (Mg2+), total Mg, ionized Ca (Ca2+), total Ca and citrate
      before and after operation in 70 patients. 2) We evaluated the effect of citrate
      on Mg2+ and Ca2+ in vitro. 3) We also measured these values during blood
      transfusion in 8 patients. There was no significant difference between post
      operative Mg2+ of 45 patients without blood transfusion (0.49 +/- 0.07 mmol.l-1,
      % decrease from pre-operative value was 13.4 +/- 9.2%; mean +/- SD), and that of
      25 patients with blood transfusion (0.48 +/- 0.09 mmol.l-1, 17.9 +/- 10.2%). Mean
      value of post-operative citrate concentration of patients with blood transfusion
      was 0.15 +/- 0.11 mmol.l-1, and this value decreased Mg2+ about 2% in in vitro
      study. During blood transfusion, Mg2+ (0.41 +/- 0.05 mmol.l-1) and ionized %
      (54.5 +/- 8.3%) decreased significantly just like Ca2+ with elevated citrate
      concentration (0.95 +/- 0.59 mmol.l-1). In conclusion, intra-operative blood
      transfusion had minor effect on the post-operative decrease of Mg2+, and the
      major cause was thought to be the dilution of extracellular fluid by Mg-free
      fluid administered during operation.

PMID- 10402816
TI  - [Monitored anesthesia care for a patient with malignant pheochromocytoma].
AB  - Monitored anesthesia care (MAC) is being increasingly used in the 1990s for a
      wide variety of diagnostic and therapeutic procedures. The primary objective in
      providing MAC is to ensure patients' comfort and safety, whether in the operating
      room or in other places. We experienced MAC for a patient with pheochromocytoma.
      A 63-year-old man with hepatic metastasis of malignant pheochromocytoma, received
      transcatheter arterial embolization (TAE) in the angiographic room. Hypertension
      and ventricular arrhythmia occurred during the hepatic arterial embolization.
      However, we successfully controlled the hemodynamic changes using phentolamine
      and propranolol under the close monitoring. He showed an uneventful recovery
      during postoperative period except for mild hypotension on the third day which
      needed temporary norepinephrine infusion.

PMID- 10402817
TI  - [Anesthetic management for mitral valve replacement in a patient with mitral
      stenosis and dilated cardiomyopathy].
AB  - A 42-year-old man with dilated cardiomyopathy and rheumatic mitral stenosis
      underwent mitral valve replacement. Prior intravascular fluid administration and
      infusion of dopamine and dobutamine stabilized hemodynamics during the induction
      of anesthesia. High-dose fentanyl at pre-cardiopulmonary bypass period and
      circulatory assist with milrinone and intraaortic balloon pumping after the
      bypass enabled us to obtain stable hemodynamics. Preoperative dobutamine stress
      test provided us the effective information for circulatory management in this
      patient.

PMID- 10402818
TI  - [A case of cardiac arrest after torsades de pointes due to prolonged QT interval
      syndrome possibly associated with subarachnoid hemorrhage].
AB  - An 58-year-old woman with prolonged QT interval syndrome possibly associated with
      subarachnoid hemorrhage underwent clipping for cerebral artery aneurysm.
      Anesthesia was induced with diazepam, fentanyl and vecuronium, and maintained
      with nitrous oxide (66%)-oxygen and sevoflurane (1%) with fentanyl. However,
      three hours after the start of operation, torsades de pointes suddenly appeared
      and cardiac arrest was followed. After cardiopulmonary resuscitation, sinus
      rhythm was restored. At that time, serum potassium was decreased to 2.7 mEq.l-1.
      Five days after the operation, she died despite cardiopulmonary resuscitation for
      frequent episodes of ventricular tachycardia including torsades de pointes.
      Ventricular tachycardia including torsades de pointes may have been caused by
      decreased serum potassium.

PMID- 10402819
TI  - [Successful management of a patient with pulmonary arteriovenous fistula using a
      continuous intra-arterial blood gas monitoring system].
AB  - We successfully anesthetized a patient with pulmonary arteriovenous fistula who
      received partial pulmonary resection and pulmonary arteriovenous plastic
      operation under one lung ventilation anesthesia, using a continuous intra
      arterial blood gas monitoring system. During anesthesia including one lung
      ventilation, the patient did not experience any fatal hypoxemia. The continuous
      intra-arterial blood gas monitoring system was useful in a patient with pulmonary
      arteriovenous fistula under one lung ventilation anesthesia.

PMID- 10402820
TI  - [Efficacy of the cuffed oropharyngeal airway in spontaneously breathing
      patients].
AB  - A cuffed oropharyngeal airway (COPA) was used in 20 adult patients for airway
      management under epidural and brachial plexus block supplemented with light
      general anesthesia. Insertion of a COPA was successful at first attempt in 17 of
      20 patients (85%). Sore throat developed in one patient (5%). Aspiration
      regurgitation, or laryngospasm was not observed. We conclude that a COPA can be
      an efficient airway device is spontaneously breathing patients under anesthesia.

PMID- 10402821
TI  - [Bilateral pneumothorax following lower neck and upper mediastinal surgery].
AB  - A 46-year-old male underwent resection of parathyroid tumor under general
      anesthesia. The preoperative chest radiography was normal. Arterial blood
      pressure, heart rate, and arterial oxygen saturation (SpO2) were stable during
      the operation. Because the tumor was in the mediastinum, incision was made behind
      the sternum and a drainage catheter was placed. At the completion of the surgery,
      spontaneous breathing began immediately. The neuromuscular blockade was reversed,
      and severe bucking was noted. Although the patient was not fully recovered from
      anesthesia, he was extubated because of his stable respiration and SpO2. Soon
      after the extubation, the patient developed cyanosis and the SpO2 declined to
      less than 50%. Chest radiography revealed bilateral pneumothorax, which was
      successfully treated by inserting bilateral chest tubes. Injury of parietal
      pleura, which might have been associated with the surgery and/or postoperative
      bucking, may be the main cause of the pneumothorax. Anesthetists should be aware
      of the occurrence of pneumothorax during neck surgery and have to avoid bucking
      postoperatively.

PMID- 10402822
TI  - [A posterior horn syndrome presumably due to direct trauma to the sacral cord: a
      rare complication of epidural anesthesia].
AB  - I report here a case of a posterior horn syndrome presumably due to sacral cord
      injury during the procedure of epidural anesthesia. A 43-year-old female
      underwent hysterectomy for myoma uteri. The operation was initially planned to be
      performed under epidural anesthesia. When a needle was inserted at the level of
      Th 12/L 1, she felt severe pain in the medial aspect of the left thigh. After the
      operation under general anesthesia, intolerable pain continued in the buttocks,
      the medial aspect of the left thigh, and the posterolateral aspect of the left
      lower leg. Lumbar MR images demonstrated slight disc hernia but no intra- and
      extramedullary hematomas. Seven weeks after the operation, she was referred to my
      clinic for neurologic evaluation. Motor functions were intact. Knee jerks on both
      sides were hyperactive; other tendon reflexes were normal. Plantar reflexes were
      indifferent. Thermal and pin-prick sensations were lost in the left S1 dermatome,
      and moderately impaired in the left S2 dermatome. Light touch and vibration sense
      showed no remarkable changes. Her sensory disturbance could have been caused by a
      lesion involving the left posterior horn and lateral spinothalamic tract within
      the S1 segment of the spinal cord.

PMID- 10402823
TI  - [Postoperative recurrent laryngeal nerve palsy following a transesophageal
      echocardiography].
AB  - The postoperative recurrent laryngeal nerve palsy (RLNP) following
      transesophageal echocardiography (TEE) was retrospectively evaluated in 175 adult
      patients after cardiac surgery. The incidence of RLNP was not significantly
      different between TEE group and non TEE group, but the incidence in female TEE
      group was higher than that in female non TEE group. The mechanism of RLNP
      following TEE as well as the insertion of nasogastric tube may be compression
      injuries of the branches of the posterior division of the recurrent laryngeal
      nerves. The incidence of RLNP in female TEE group was higher because of the
      narrow female larynx. TEE is a useful monitor during cardiac surgery, but we must
      be careful about RLNP following TEE.

PMID- 10402824
TI  - [Anesthetic management using extracorporeal circulation of a patient with severe
      tracheal stenosis by thyroid cancer].
AB  - A 64-year-old male with tracheal stenosis by thyroid cancer was scheduled for the
      emergency management of airway maintenance and total thyroidectomy. Dyspnea and
      orthopnea appeared suddenly on the admission for operation. Cervical CT and
      bronchial fiberscope examination revealed the trachea oppressed at the frontal
      neck by thyroid tumor. The trachea diameter was nearly 5 mm at the narrowest
      part. Therefore it seemed to be of high risk of perform tracheal intubation and
      tracheostomy. Extracorporeal circulation was adopted for the respiratory
      management at anesthesia induction. At first, the femoral artery and vein were
      cannulated with local anesthesia for cardiopulmonary bypass (CPB). After
      confirming CPB pump working, intravenous anesthetic agents were infused. Thyroid
      tumor was partially resected and tracheostomy was done under CPB. After the
      tracheostomy, a spiral tracheal tube was inserted. Anesthesia was maintained with
      sevoflurane and managed with controlled ventilation. Thereafter operation and
      anesthesia were uneventful. After the operation, pleural bloody effusion was
      noticed. Blood in effusion seemed to be due to the heparinization in
      extracorporeal circulation. We conclude that anesthetic management with
      extracorporeal circulation is one of useful methods for managing severe tracheal
      stenosis.

PMID- 10402825
TI  - [Anesthesia in a patient with epidermolysis bullosa].
AB  - Epidermolysis bullosa hereditaria, a rare inherited disorder presents clinically
      with recurrent cutaneous blister formation with possible involvement of mucous
      membrane and organs following minimal trauma. The sequelae of this disease pose
      significant anesthetic problems to operating room staffs. We describe the
      anesthetic management of a 32-year old woman with epidermolysis bullosa
      hereditaria who underwent palmar skin graft using regional anesthesia, and
      discuss the problems associated with this disease.

PMID- 10402826
TI  - [A study visit to three hospitals in Cairns, Australia].

PMID- 10402827
TI  - [The Japan industrial standard and the history of the Committee for
      Standardization of Anesthetic Equipment of the Japanese Society for
      Anesthesiologist].

PMID- 10402828
TI  - [Light-guided tracheal intubation using a Trachlight: causes of difficulty and
      skill acquisition].
AB  - We studied the reasons why tracheal intubation using a lighted stylet
      (Trachlight) was sometimes difficult for unexperienced intubators. We also
      examined light-guided intubation skill acquisition in inexperienced
      anesthesiologists. Two anesthesiologists, with no prior experience in using a
      Trachlight, performed orotracheal intubation using a Trachlight in 60
      anesthetized patients (30 patients each). During intubation, an assistant
      observed the advancement of the tracheal tube using a fiberscope passed nasally
      and recorded the reason for difficulty in intubation. The time to successful
      intubation was also measured. Data were divided into epochs of 10 cases, and the
      intubation time and the incidence of difficult cases were compared between the
      groups. Tracheal intubation was successful using the Trachlight in 59 of 60
      patients. The incidence of difficult cases, defined as cases requiring two or
      more attempts, was 31.7%. Fiberscopy showed that when the tube tip was located in
      the vallecula or in the esophagus, it was sometimes difficult to determine the
      position of the tube tip by transillumination of the soft tissues of the neck,
      and this results in the need for multiple attempts. Both the intubation time and
      the incidence of difficult cases decreased significantly between the first and
      last epoch. The present study confirms that light-guided intubation is sometimes
      difficult when the tube tip is advanced to the vallecula or to the esophagus. An
      acceptable level of skill in light-guided intubation is achieved within 30 uses.

PMID- 10402829
TI  - [Problems with employment of a staff anesthesiologist in a local hospital].
AB  - Yukiguni Yamato General Hospital (199 beds) is one of main local hospitals of
      Minamiuonuma area in Niigata prefecture. From June 1997, an anesthesiologist has
      been employed as a staff of this hospital instead of parttimers. We examined
      whether employment of an anesthetic staff was useful for a local hospital or not,
      in terms of clinical and cost advantages. There were benefits in explaining the
      nature of anesthesia, possible risks, operating room and pre-postoperative
      procedures to the patients. And there were advantages in reducing anesthetic
      management fee, in shortening the staying time in operating room. We conclude
      that there are many benefits in obtaining an anesthesiologist for a local
      hospital staff, but there are some drawbacks in having to work alone.

PMID- 10402830
TI  - [Comparison of five patient-controlled analgesia drug delivery devices].
AB  - We report the performance and our impression of five patient-controlled analgesia
      (PCA) drug delivery devices commercially available; Atom PCA Pump 500, AP-II,
      Deltec CADD-PCA 5800, Sabratek 6060 and Verifuse. Each of these devices has
      unique features for PCA. However, these devices still leave some room for
      improvement. Especially, we hope that future devices will be lighter to carry and
      use dry batteries more economically. In order to use these devices effectively
      for the management of pain, it is important to understand their characteristics.

PMID- 10402831
TI  - Active-controlled versus placebo-controlled trials.

PMID- 10402833
TI  - A glimpse into diagnostic radiology today.

PMID- 10402832
TI  - What hath brazen science wrought?

PMID- 10402834
TI  - Advances in nuclear medicine: current concepts.
AB  - As described above, many scintigraphic studies have recently become available
      which provide vital clinical information in a wide variety of diseases. The
      future of nuclear medicine also appears bright. Modifications to current gamma
      cameras will likely occur in the next few years to replace sodium iodide crystals
      with new scintillators like oxyorthosilicates which have better imaging
      characteristics for both single photon and positron-emitting radionuclides.
      Ongoing computer improvements will allow improved reconstruction and processing
      with newer systems already capable of advanced iterative reconstruction
      algorithms. Development of new radiopharmaceuticals is progressing at a rapid
      pace, with emphasis on new tracers that can provide information about diseases at
      the molecular level, such as receptor imaging agents. In addition, radiolabeled
      tracers for therapeutic purposes will continue to progress, including monoclonal
      antibodies labeled with beta emitters. Overall, nuclear medicine will continue to
      evolve in many new directions and provide useful functional imaging data about a
      variety of different organ systems and diseases.

PMID- 10402835
TI  - Evaluation of pulmonary emboli: current concepts.
AB  - While radionuclide lung V/Q scanning remains the standard initial pulmonary
      imaging test in suspected pulmonary emboli, other modalities may be useful,
      particularly in those patients with intermediate probability V/Q scans.
      Compression US of the lower extremities, spiral CT angiography, and conventional
      pulmonary anteriography may help to establish the diagnosis of pulmonary
      embolism.

PMID- 10402837
TI  - Imaging the patient with acute abdominal pain: current concepts.
AB  - The development of improved imaging technology, specifically development of
      helical CT and improvement in ultrasound, has revolutionized the work-up of
      patients with abdominal pain. It is important to remember that the type of
      examination performed depends on the suspected clinical diagnosis. In particular,
      the CT exam prescription by the radiologist varies significantly depending on the
      type of pathology suspected. The route of the administration of gastrointestinal
      contrast (oral or per rectum), the use of intravenous contrast, slice
      collimation, the field of view and other parameters can significantly improve the
      accuracy of the study. Thus, accurate communication with the examining physician
      is critical. When used properly, radiologic examinations can significantly impact
      on patient care and management.

PMID- 10402836
TI  - Emergency abdominal ultrasound in children: current concepts.
AB  - As equipment and techniques in ultrasonography improve, its role in the
      evaluation of infants and children has increased. Besides the traditional uses in
      the solid viscera and biliary tract, US can be a primary modality in the workup
      of pediatric gastrointestinal disease.

PMID- 10402838
TI  - Innovations in neuroimaging and neurointerventional radiology.

PMID- 10402839
TI  - Radiofrequency ablation: an outpatient percutaneous treatment.

PMID- 10402840
TI  - From twisted ankles.

PMID- 10402841
TI  - Breast cancer screening in Rhode Island: modest improvement, significant
      challenge.

PMID- 10402842
TI  - Operating characteristics of outpatient fluoroscopic systems.

PMID- 10402843
TI  - Hepatitis C virus (HCV): a silent epidemic.

PMID- 10402844
TI  - [Infectious diseases in Poland in 1997].
AB  - Decreasing of number of cases as well as incidence rate of hepatitis type B and
      type A, and increasing of pertussis, leptospirosis, encephalitis and some other
      diseases was noted in Poland in 1997. The biggest percentage of deaths was caused
      by tuberculosis--43.1%, sepsis--over 21.9% and hepatitis--10.6%. Introduction of
      ICD-10 as well as strikes of health workers in Poland in 1997 caused
      undernotification especially of deaths.

PMID- 10402845
TI  - [Measles in 1997].
AB  - Since 1990, the decrease of measles morbidity rates and the increase of the areas
      with limited measles transmission are observed in Poland. In 1997, 338 measles
      cases was reported, the lowest number of measles cases ever reported. This
      represents 47% decrease from the number of measles cases (639) reported in 1996.
      The increase of the number of measles incidence during last two month of 1997 may
      forecast epidemic 1998 year. The laboratory confirmation of suspected measles,
      especially sporadic cases should be implemented in all voivodeships in Poland.

PMID- 10402846
TI  - [Pertussis in 1997].
AB  - In 1997 an epidemic increase of pertussis was observed in Poland. The incidence
      was 5.4/100,000 population and was more than six times higher than in the
      preceding year. No clear reason for a sudden increase in pertussis incidence was
      found, in particular the vaccination coverage rates have remained high. In
      December 1997 the DTP vaccine coverage rate for children below two with four
      doses of DTP was 97.5%. The distribution of cases according to age during the
      last 20 years was analysed and it was shown that since the beginning of the '90 a
      growing proportion of cases occurs among fully vaccinated children and the
      average age of the cases has a steadily growing tendency. A hypothesis was put
      forward that the come-back of pertussis is presently due to waning of short-term
      immunity following immunisation, in cohorts of children who grew up in conditions
      of very low B. pertussis natural transmission. An open question remains whether
      to introduce to the immunisation calendar an additional booster dose of pertussis
      vaccine in school-aged children.

PMID- 10402847
TI  - [Scarlet fever in 1997].
AB  - In 1997, two years after the last epidemic peak of scarlet fever, the speed of
      decrease of the number of registered cases has been slower than after earlier
      epidemics. However, the seasonal distribution of cases does not forecast an
      increase of incidence of scarlet fever in the near future. The age, sex,
      urban/rural distribution of scarlet fever remain stable. The highest incidence
      rates are noted in 7-8-year old children. Scarlet fever cases are hospitalized in
      1%.

PMID- 10402848
TI  - [Mumps in 1997].
AB  - In 1997 83,558 cases of mumps were reported and attack rate of 216.3/100,000 was
      two times higher than in the previous year. Four percent of cases were admitted
      to hospitals (3,327) and the percentage of hospitalised children ranged from 0.3%
      in Chelm voivodeship to 12.9% in Konin voivodeship. Mostly affected were children
      in the age group 5 to 9 years old in which attack rates ranged from 1,602 to
      2,293 per 100,000. Patients in this age group constituted 59% of total number of
      mumps. MMR vaccine is still not included into the national programme of
      immunization; instead monovalent measles vaccine is used. MMR vaccine is used on
      voluntary basis.

PMID- 10402849
TI  - [Influenza in 1997].
AB  - The number of cases of influenza and influenza-like illness registered in Poland
      in 1997 amounted to 1,578,494. This number of cases is 41.8% lower when compared
      with the previous year 1996. The incidence of influenza amounted to 4,084 per
      100,000 inhabitants. The number of influenza cases registered in children aged up
      to 14 years was 557,033. This is 35.6% of total number of cases. The incidence of
      influenza in this group amounted to 6,828.7 per 100,000 and was 67% higher than
      total incidence. In the beginning of January 1997 six strains of A (H3N2)
      influenza virus were isolated in the National Influenza Center WHO, Dept. of
      Virology, National Institute of Hygiene. These isolates were similar to
      A/Wuhan/359/95 and A/Johannesburg/33/94 strains and were obtained from patients
      aged 5, 6, 45, 50, 75 and 85 living in Warsaw. In February 1997 next six strains
      A (H3N2) similar to A/Wuhan/359/95 were isolated. Four of them were obtained from
      patients aged 9, 10, 11 and 14 living in Lublin. One strain was isolated from
      patient aged 14 living in Kielce and the last one was obtained from patient aged
      70 from Warsaw. In general, ten strains isolated in 1997 were similar to the
      vaccine strain A/Wuhan/359/95 recommended for the epidemic season 1996/97, while
      two isolates were antigenically similar to the strain included in the vaccine in
      the previous epidemic season, i.e. 1995/96.

PMID- 10402850
TI  - [Rubella in 1997].
AB  - A cyclical epidemic of rubella has been noted in Poland in 1997. The relatively
      high incidence rate persistent in the last interepidemic period and local
      outbreaks in some areas in 1995-1996 caused smaller range of 1997 epidemic. The
      incidence was much lower than in 1986 and 1992 when the biggest registered
      rubella outbreaks were noted. The last epidemic outbreak of rubella didn't change
      significantly the existing relation between the incidence, age, gender and place
      of residence (rural, urban). The percentage of hospitalized cases was similar to
      past (0.2%).

PMID- 10402851
TI  - [Meningitis and encephalitis in 1997].
AB  - In 1997, 4,409 cases of meningitis and 632 cases of encephalitis were reported in
      Poland. Meningitis incidence rate was 11.4 per 100,000, and was 3-times lower
      than in 1996. The etiology of meningitis cases was as follows: 2,713 (61.5%) were
      due to viral agents (ECHO 30 dominated), 1,351 (30.7%) were caused by bacterial
      agents: 144 meningococcal (3.3%) and 1,207 other bacterial. The bacterial
      etiology was following: 33.2% were due to Streptococcus pneumoniae, 27.6% were
      cased by Haemophilus influenzae type b, and 11.6% by Staphylococci. Encephalitis
      incidence rate was 1.6 per 100,000. There were 201 cases of tick-borne
      encephalitis, found mainly in endemic areas of Bialystok and Suwalki
      voivodeships.

PMID- 10402852
TI  - [Hepatitis A in 1997].
AB  - Until 1997, hepatitis was registrated in Poland under the headings: hepatitis B
      and hepatitis non-B. In 1997, for the first time, the obligatory registration of
      hepatitis A cases was introduced. In the year 1997--4,045 cases of hepatitis A
      were notified in Poland. The incidence rate was 10.5 per 100,000 population with
      considerable differences in various voivodships. The incidence rate in rural
      areas was 2.5 higher than among urban population. The highest incidence rates
      were registered in the northern and north-eastern parts of the country. The 23%
      of reported cases occurred among children age 10-14.

PMID- 10402853
TI  - [Hepatitis B and C in 1997].
AB  - In 1997, 4,896 cases of hepatitis B were notified in Poland, including 66 mixed
      infections with B and C virus. The number of cases notified was 1,539 less than
      in 1996. The incidence rate was 12.7/100,000, which was lower by 4.0 than in the
      proceeding year (16.7), what means a decline in the incidence rate of hepatitis B
      by 24%. 1997 was the fifth consecutive year when a decline in incidence rate
      hepatitis B was observed, since the intensive program of hepatitis B prevention
      was introduced in 1993 Hepatitis B incidence rate was greater in urban areas
      (14.1/100,000) than in villages (10.4/100,000). In urban area, the incidence rate
      was proportional to the number of habitants (fig. 1). The immunisation programme
      is the main reason of falling incidence among children aged 0-3. In 1997, 36
      cases were notified in children aged 0-3 while in 1990 129 cases were registered.
      The incidence rate has fallen from 9.5/100,000 to 2.5/100,000 in this age group,
      which means a drop of 74%. The analysis of notified cases shows that the program
      of hepatitis B prevention is effective. Positive trends from previous years were
      maintained in 1997 although the declining trend has been slightly sloved. In 1997
      hepatitis C has become a statuatory notificable disease in Poland. 1,064 cases
      were notified, with an overall incidence of 2.75/100,000.

PMID- 10402854
TI  - [Salmonellosis in 1997].
AB  - The gradual decline of number salmonellosis cases has observed since 1988. In
      1997, 23,206 cases of salmonellosis were reported to the sanitary epidemiological
      stations in the whole country. Incidence rate was 60 per 100,000 inhabitants and
      was lower than 1996 and median 1991-1995 rates. Most of cases (19,611) was
      confirmed by isolation of Salmonella strains. The prevalent serotypes distributed
      at least in 30 of 49 voivodships, were: S. enteritidis (90% of all cases), S.
      typhimurium --3%, S. infantis--1.3%, S. virchow--1.2% and S. hadar--1%. Rates
      were highest in children aged under five years. The most serious clinical
      syndromes and complications were seen in the 49 oldest patients above 50 years
      old (septicaemia, meningitis, arthritis, osteomyelitis and abscesses). Five of
      them had died.

PMID- 10402855
TI  - [Dysentery in 1997].
AB  - Notifications of dysentery fell to their lowest yearly total since 1918. The 1997
      total figure of 439 was 18% lower than in 1996 (534 cases) and of 1353 cases
      (75%) lower than the median yearly figure in 1991-95 (1894 cases). Incidence rate
      in 1997 was 1.1/100,000 inhabitance, the lowest ever notified. In 1996 incidence
      rate was 1.4 for 100,000 inhabitants and median incidence rate in 1991-1995 was
      4.9. Dysentery was not diagnosed in 24% administrative regions of Poland. No case
      of dysentery has been notified in 5/49 regions, only one single patients in 7/49
      regions. 80% of patients were children 0-19 years old. The highest incidence rate
      (15.0 per 100,000) was found in children 3 years old and in children 4 years old
      (8.9/100,000)-residents of towns. Only bacteriological confirmed Shigella
      infection was notified as dysentery. In 1997 bacteriological examination for such
      purpose stopped to be done free of charge. Except one outbreak dispensed in
      Wroclaw all other outbreaks were limited to the children institution: schools,
      kindergartens or social care institutions. There were 12 outbreaks, 11 due to S.
      sonnei infection, and one to S. flexneri 1b. The quality control test performed
      by bacteriological laboratories of Sanitary Epidemiological Service revealed that
      not all of them used bacteriological media efficient for all types of Shigella.

PMID- 10402856
TI  - [Foodborne infections and food poisoning in 1997].
AB  - In total were registered 27,922 cases of foodborne infections and intoxications
      in 1997 (salmonelloses of animal source, staphylococcal, botulism, other
      bacterial and caused by undetermined agents). Morbidity amounted 72.7/100,000. In
      274 outbreaks of collective illnesses (4 people and more) 4,817 cases were
      registered altogether. Salmonella enteritidis caused 95.5% causes in outbreaks.
      The main vehicle of foodborne infections and intoxications in outbreaks was food
      prepared from raw materials of animal source, which caused 91.2% cases in
      outbreaks, in which dishes from eggs brought about 47.4% of these cases. Among
      the places of the ready made food production, private homes prevailed (57.9% of
      the whole amount of outbreaks). There epidemics numbering above 100 cases each
      were registered in 1997.

PMID- 10402857
TI  - [Botulism in 1997].
AB  - In 1997 81 cases of botulism in Poland were registered. The morbidity amounted
      0.21/100,000. In the rural regions were registered 55, and in urban regions 26
      cases. The morbidity in the rural regions amounted 0.37, and in urban regions
      0.13. The morbidity of men (0.23) outnumbered the morbidity of women (0.19). In
      1997 there were 8 outbreaks of two people noted, 2 outbreaks of three people and
      2 of four people. Among the vehicles of the botulinum toxin dishes from meat
      remained on the first position (65.4% of cases), and in these numbers prevailed
      wecks of home production (19.8%). No deaths caused by botulinum toxin were noted
      in 1997.

PMID- 10402858
TI  - [Intoxications caused by plant protection chemicals in 1997].
AB  - In 1997 were registered 140 cases of intoxications caused by chemicals used for
      plant protection. The most of the intoxications occurred after the intake of
      pesticides (70.7% of diseases). Accidental intake made 36.4% of the total number
      of cases, and intended intake was 34.3%. During the agricultural labour it came
      to exposure in 28.6% of cases. Insecticides caused 68.6% of the total number of
      intoxications by pesticides. In rural regions 79.3% of the sick people were
      submitted to intoxication and 20.7% in the urban regions. The morbidity of men
      was almost three times higher than morbidity of women (respectively 0.54 and
      0.20). In 1997 three outbreaks of intoxication by pesticides were noted: two of
      three people and one of two people. Because of intoxication by chemicals for
      plant protection 10 people died.

PMID- 10402859
TI  - [Tetanus in 1997].
AB  - In 1997, 37 cases of tetanus were registered in Poland. The incidence rate of
      tetanus was 0.1/100,000 population. No neonatal tetanus cases were recorded. The
      last neonatal tetanus case had been reported in this country 14 years ago and the
      last death from neonatal tetanus over 30 years ago. Two tetanus cases occurred in
      persons aged 20 and 28, who underwent a full course of tetanus vaccination and
      received their last booster dose of tetanus vaccine not more than 10 years ago.
      70% of cases occurred in persons aged 60 and over. Case-fatality rate associated
      with tetanus was 27%. By the end of 1997, 97.8% of children born in 1996 have
      been immunized with at least three doses of DTP vaccine. High vaccine coverage
      rates in Poland maintained since many years are an effective means of eliminating
      tetanus in the population. Since many years a decreasing number of tetanus cases
      are registered.

PMID- 10402860
TI  - [Rabies in Poland in 1997].
AB  - Mass oral vaccination of wild animals against rabies introduced in 1993, shows a
      positive impact on the epizootic situation of rabies in Poland. In parallel to
      the decreasing number of rabies cases in animal, the number of persons exposed to
      rabid parallel animals declines. No case of rabies in human beings has been
      reported in Poland since 1986. Of 7566 persons vaccinated in Poland against
      rabies only 1492 (19.7%) were bitten by or were in contact with a rabid animal.
      Main reason of vaccination against rabies were contact with animals of category C
      (rabies not excluded) (68.8%) and with animals healthy during the exposition
      (category D) (11.5%).

PMID- 10402861
TI  - [Brucellosis in 1997].
AB  - The registered human brucellosis in Poland constitute chronically ill
      professional persons, mainly veterinarians, who had been for many years involved
      in the control of animal brucellosis in the past. New acute or subacute
      infections are imported from Mediterranean areas.

PMID- 10402862
TI  - [Trichinosis in 1997].
AB  - The decreasing trend in human trichnellosis can be observed during last years in
      Poland, what is the result of proper meat control. The presence of Trichinella
      endemic areas in the north-east part of the country still determines the
      necessity of the meat survey against Trichinella spiralis in Poland.

PMID- 10402863
TI  - [Cestode infections in 1997].
AB  - In 1997, 736 intestinal cestode cases were registered in Poland. Among them 634
      were caused by T. saginata, 6 by T. solium, 63 by Taenia sp, 15 by Hymenolepsis
      sp, and 2 by D. latum and D. caninum. Moreover, 27 cases of larval cestode
      infections were also registered. Four of them were caused by larvae of T. solium
      and the remaining ones bz E. granulosus. The obtained results confirmed the
      decreasing frequency of infections with intestinal cestodes in Poland.

PMID- 10402864
TI  - [Malaria in Poland in 1997].
AB  - In 1997 37 malaria cases were registered in Poland. All of them were imported,
      mainly from Africa (26), and some from Asia. Plasmodium falciparum infection was
      confirmed in 23 cases. Among 37 malaria cases 31 were men. The majority of
      malaria cases (27) were in 20 to 49 year old group. Eighteen persons travelled
      abroad in the connexion with their job (especially as sailors and agropilots) and
      eleven--as missionaries. Three men (44, 47 and 70 years old) with P. falciparum
      malaria died.

PMID- 10402865
TI  - [AIDS and HIV infections in 1997].
AB  - In Poland 114 AIDS cases and 579 newly discovered HIV infections have been
      registered in 1997. Annual numbers of diagnosed and notified AIDS cases and HIV
      infections were rather stable during last years. The nearest future of HIV/AIDS
      epidemiological situation will depend on medical and social care, personal
      behaviours and preventive activities.

PMID- 10402866
TI  - [Changes in the epidemiological situation of hepatitis B in Kielce region, after
      introduction of vaccination of infants against hepatitis B].
AB  - The study presents epidemiology of hepatitis B in the region Kielce in the
      central part of Poland. The number of registrated cases and their age
      distribution were analyzed in the prevaccination period of 1990-92 and 1995-97
      when the obligatory vaccination of infants against hepatitis B was introduced.
      The significant decrease in the number of cases among young, below 4 years old
      children was recorded. There were no new cases of hepatitis B in the group of
      vaccinated children during hitherto 4-year period of observation. The analysis of
      the role of hospital contacts in the spread of infection, suggest that still more
      than half of infections occurred in hospitals, although the role of surgical
      departments in the spread of infections has been reduced in last three years.

PMID- 10402867
TI  - [Standardization. Sterilization standards and their impact on hospital services].
AB  - The European commission produced series of Directives which were aimed at
      harmonizing the European market whilst maintaining high standards to protect the
      citizens. Within each directive drafted Essential Requirements which had to be
      satisfied in order to market throughout Europe. The Medical Device Directive
      (93/42/EEC) covers the vast majority of medical devices including active non
      implantable and non-active implantable medical devices. Demonstration of
      compliance to harmonized European Standards (EN) was proof of compliance with
      Essential Requirements of the Directives. The European Standards Body (CEN)
      created a series of European Standards which would enable to demonstrate
      compliance with Essential Requirements. The CEN organisation has a pyramidal
      structure. Standards are produced in the CEN Technical Committees (TC's) composed
      of representatives from each country's own standards organization. The Technical
      Committee in turned created a series of Working Groups (WG), who's job it was to
      actually generate the text of the standards. Two of standards committees are
      working to generate standards which relate to sterilizers and sterilization:
      TC102--the standards emanating from this committee are product related, TC 204-
      the standards relate to sterilization practice. In Poland, the standarisation
      activity is provide by Polish Committee of Standardisation. From 5th June 1997
      operate Problem Commission number 272 for sterilization affairs. The job of the
      commission consist on translation of European'offs Standards and transform them
      to Polish Standards. After accede Poland to European Union, Polish hospitals will
      have to adjust to European Standards.

PMID- 10402868
TI  - [Validation of sterilization processes].
AB  - Sterilization is a special process, where the results of processes (efficacy of
      sterilization) cannot be verified by subsquent inspection and testing of the
      product (the items sterilized). For this reason sterilization process must be
      validated. Validation of sterilization processes is required by Medical Devices
      Directive 93/42 EEC and GMP. Also the sterilization processes in the hospitals
      shall be validated. The validation of sterilization of processes as described in
      European Standards: EN 550--for ethylene oxide EN 554--for moist heat.

PMID- 10402869
TI  - [Ischemic stroke during sepsis and bacterial meningoencephalitis: a case report].
AB  - A case of acute ischaemic stroke in a woman aged 49 years during sepsis and
      purulent, bacterial meningoencephalitis was described. Diagnosis was based on
      clinical examination and repeatedly CT scans. Attention is called to diagnostic
      difficulties in this complication of central nervous system bacterial infections.

PMID- 10402870
TI  - [Fight against acute infectious diseases in Poland in the first year of
      independence (1918-1919)].
AB  - In the first year of its independence (1918-1919), the main priority of the young
      state was the fight against ramp epidemics of acute infectious diseases. The most
      important task of the newly organized Ministry of Health was the organization of
      the control of infectious diseases, and especially typhus. Up to the mid-1919,
      the authorities organized 44 mobile epidemic hospitals with 2,200 beds, 103
      communal hospitals with 4,400 beds, and 35-mobile disinfection and disinfection
      units. Twenty three specially trained epidemic doctors collaborated with district
      physicians. The difficult conditions associated with continuing war, starting
      migration and repatriation which caused huge movements of population, weak
      hospital infrastructure, a serious shortage of medical personnel, sanitary
      materials, drugs, solap and hospital infrastructure did not facilitate the
      control of epidemic infectious diseases in the first year of independence.

PMID- 10402871
TI  - Irritable bowel syndrome and recurrent abdominal pain. A comparative review.
AB  - Clinical findings on irritable bowel syndrome in adults and recurrent abdominal
      pain in children are reviewed to determine if what is known about each disorder
      can illuminate our understanding of the other. The evidence reveals striking
      similarities between the disorders in prevalence, course, medical and psychiatric
      comorbidity, family medical and psychiatric history, and association with life
      events. Continuity between the two disorders is also suggested by the results of
      follow-up and follow-back studies. The review shows the importance of a
      developmental perspective for understanding functional bowel disorders in adults
      and points to areas where further research would be useful.

PMID- 10402872
TI  - Depression in coronary heart disease. What is the appropriate diagnostic
      threshold?
AB  - The purpose of this study was to determine the threshold at which depression
      becomes important for the daily functioning of patients with heart disease. Data
      from a 1-year prospective cohort study of health maintenance organization
      patients undergoing coronary angiography for coronary heart disease were analyzed
      for differences in a standardized composite measure of functioning. Patients with
      major depression (N = 19) and patients with minor depression (N = 28) were
      significantly more functionally impaired at baseline and at 1-year follow-up than
      those with no depression (N = 110). The major and minor depression groups did not
      differ significantly. The significance of the depression group differences was
      reduced, but not eliminated, when controlling for differences in reported heart
      symptoms.

PMID- 10402873
TI  - Psychiatric disorders and survival after lung transplantation.
AB  - The 30 patients who underwent lung transplantation between 1990 and 1996 were
      included in this study, and data were analyzed to find predictors of 1-year
      survival posttransplantation. All patients were followed throughout the
      posttransplantation period. Fifteen patients had a pretransplantation diagnosis
      of an anxiety and/or depressive disorders. Of the 30 patients transplanted, 19
      survived 12 months or more, and 11 died less than 12 months posttransplantation.
      The > 12-month survival group had a mean age of 45.2 years at transplantation,
      compared with a mean age of 43.0 years in the < 12-month group (NS). The mean
      Psychosocial Assessment of Candidates for Transplant score and premorbid history
      of smoking did not differ between the groups. The > 12-month survival group had
      more psychiatric illness pretransplantation than the < 12-month survival group
      (56% vs. 27%, P < 0.05). The recipients with a psychiatric history (N = 15) were
      more likely to survive 1 year posttransplantation than the recipients without a
      psychiatric history (80% vs. 47%, P < 0.05) and were not significantly different
      from the recipients without a psychiatric history in terms of episodes of
      rejection, bronchiolitis obliterans, or noncompliance with treatment. Depression
      and anxiety are treatable disorders that occur frequently in patients with end
      stage lung disease, and a premorbid history of either did not predict a worse
      outcome posttransplantation in this study of lung transplantation recipients.

PMID- 10402874
TI  - Cardiac ventricular support. Considerations for psychiatry.
AB  - Cardiac ventricular support is fostering additional roles for psychiatric
      consultation with this vulnerable end-of-life cardiac group. Incidence of
      premorbid and postsurgical psychiatric disorders (Axis I), psychotropic use,
      neurologic events, and mortality was obtained for 21 Novacor left-ventricular
      assist system patients prospectively and 13 Abiomed left/right ventricular-assist
      device patients retrospectively. This fragile patient population and their
      families warrant involvement for psychiatry because of the extreme conditions and
      consequences associated with mechanical cardiac assistance. The authors address
      psychiatric morbidity and neurobehavioral modifications associated with
      ventricular support.

PMID- 10402875
TI  - Iatrogenic acute estrogen deficiency and psychiatric syndromes in breast cancer
      patients.
AB  - The change of estrogen function, represented by amenorrhea or hot flashes, that
      results from breast cancer treatment may increase the risk of major depressive
      disorder in those women undergoing treatment for breast cancer. This pilot study
      describes the course of menopausal symptoms and the incidence of depression in 21
      patients who were likely to become acutely estrogen deficient during treatment
      for breast cancer. These included women who lost menses during chemotherapy, who
      suddenly stopped estrogen replacement therapy (ERT), or who started tamoxifen.
      Eight patients (38%) developed major depressive disorder, the majority within 6
      months of starting treatment. Twenty patients (95%) had dysphoria and/or
      insomnia. Fourteen patients (66%) had hot flashes. While this is only pilot data,
      these data suggest that breast cancer patients whose treatment precipitates
      menopausal symptoms should be targeted for diagnosis of depression and treated if
      diagnosed.

PMID- 10402876
TI  - Quality of life in hospice patients. A pilot study.
AB  - The general public and the medical community often perceive dying patients'
      quality of life (QOL) as rapidly deteriorating before death. However, with
      appropriate palliative services, this effect may be positively modified.
      Objective data are lacking on the true experience of dying from the point of view
      of the patient that this pilot study begins to address. Patients caregivers, and
      staff in our hospice program completed questionnaires evaluating the patient's
      QOL every 2 weeks until the patient's death. This pilot study found that patients
      QOL was relatively high and stable over time. Primary caregivers rated the
      patient's QOL lower than patient self-ratings, whereas the hospice staff
      evaluated the patient's QOL similarly to the patient. Many dying patients suffer
      and are perceived as having no QOL in the final days by their caregivers. This
      perception may be modified to maintain one's QOL with the help of palliative
      medical services, thereby relieving the suffering of those who are actively
      facing death.

PMID- 10402877
TI  - PRISM: Pictorial Representation of Illness and Self Measure. A brief nonverbal
      measure of illness impact and therapeutic aid in psychosomatic medicine.
AB  - The burden of illness is important for patients but complex and difficult to
      describe, let alone measure. A novel instrument is described that, according to
      preliminary data, measures what in German is termed Leidensdruck--the perceived
      burden of suffering due to illness. The measure--Pictorial Representation of
      Illness and Self Measure (PRISM)--takes less than 5 minutes to complete and is
      unusual in relying only minimally on language. The PRISM is being developed as a
      research tool and has been used effectively in routine clinical practice. To
      illustrate the latter application, three case vignettes are presented,
      demonstrating how the PRISM can enhance the patient's description and
      understanding of his/her illness and circumstances, facilitate patient-clinician
      communication, and help to monitor salient changes with treatment.

PMID- 10402878
TI  - Delivering mental health care to HIV-positive individuals. A comparison of two
      models.
AB  - Data on initial psychiatric evaluations performed in 1995 were compared to assess
      whether psychiatric consultation for human immunodeficiency virus (HIV)
      positive/acquired immunodeficiency syndrome (AIDS) patients provided on-site in
      an infectious disease (ID) clinic improved compliance and were preferred by staff
      to evaluations performed in a specialized AIDS psychiatric program. Compliance
      with initial appointments remained below 50% in both settings, but more patients
      seen in the ID clinic had received prior psychiatric treatment and medication and
      they were more likely to receive a psychotropic prescription at this initial
      visit. The ID clinic staff preferred on-site consultations. Stationing
      psychiatric consultants in the ID clinic may reach a more impaired population but
      did not improve compliance with the initial visit.

PMID- 10402879
TI  - Diagnosing demoralization in consultation psychiatry.
AB  - Demoralization, a normal response to adversity, is commonly seen in medical and
      surgical patients referred for psychiatric consultation. Demoralization should be
      distinguished from adjustment disorders and other pathological conditions--a
      process that would be facilitated if demoralization, like grief, were given a V
      code in DSM. Although the primary responsibility for treating demoralization
      rests with the patient's physician, the consulting psychiatrist must make an
      accurate diagnosis and begin the process of supportive psychotherapy.

PMID- 10402880
TI  - Somatization in primary care. Prevalence, health care utilization, and general
      practitioner recognition.
AB  - To study the prevalence of somatoform disorders (SDs) in primary care, a
      questionnaire including the modified 25-item version of the Symptom Checklist-90
      was administered to 191 patients consecutively consulting their family physician.
      A stratified sample of the patients was interviewed with the Schedules for
      Clinical Assessment in Neuropsychiatry. The study showed that 22.3% (confidence
      interval [CI]: 95%: 16.4-28.1) of the patients fulfilled the diagnostic criteria
      for an International Classification of Diseases--10th Revision (ICD-10) SD,
      excluding SD, unspecified, and 57.5% (CI: 95%: 50.5-64.5) for DSM-IV SD. But
      30.3% met the criteria (CI: 95%: 23.8-36.9) when the DSM-IV Not Otherwise
      Specified (NOS) diagnostic group is excluded. The most frequent ICD-10 diagnosis
      was autonomous dysfunction, for which 14.1% of the patients fulfilled the
      criteria, whereas the prevalence of the other somatoform diagnosis was between
      3.0% and 8.1%. The most frequent DSM-IV diagnoses were SD NOS and
      undifferentiated SD, which 29.93% and 27.3% of the interviewed patients,
      respectively, received, whereas the prevalence of the other diagnoses was between
      1.0% and 8.1%. A high comorbidity between SDs and other mental disorders was
      found. The general practitioners identified between 50% and 71% of the patients
      with an ICD-10 SD and between 36% and 48%, according to DSM-IV criteria. Patients
      with SDs used more nonpsychiatric health care facilities than other patients (P =
      0.01).

PMID- 10402881
TI  - Blindness, fear of sight loss, and suicide.
AB  - Numerous studies have examined the emotional impact exerted by sight loss.
      Research has tended to focus on clinical-diagnostic rather than therapeutic
      preventive aspects. Blindness and sight restoration have been reported to induce
      both temporary and longer term psychopathology, usually followed by psychosocial
      readjustment. However, in some cases, readjustment may not occur and suicide may
      result. Together with an extensive review of available literature, the authors
      present cases taken from their psychological autopsy study database. When
      compared with a hearing-impaired control group, impaired sight alone can acutely
      affect otherwise psychologically healthy individuals. Ophthalmologists need to be
      aware of this problem and to develop closer collaboration with mental health
      professionals. Serious consideration of this problem and definition of clear
      guidelines may prevent suicidal behaviour.

PMID- 10402882
TI  - Integrating medical and psychiatric treatment in an inpatient medical setting.
      The type IV program.
AB  - This study compares the treatment of patients with comorbid medical and
      psychiatric illness admitted to a high-acuity (Type IV) integrated medicine and
      psychiatry inpatient program with patients having psychiatric symptoms on general
      internal medicine wards (IMWs). More patients in the Type IV program had
      agitation, suicidal ideation, or psychosis as psychiatric admission behaviors
      when compared to IMW patients. Medical symptom improvement was comparable in the
      two settings, whereas, psychiatric symptoms improved more in the Type IV Program
      than on the IMWs despite more significant illness and comparable lengths of stay.
      Integrated care on the Type IV unit allowed shorter total lengths of stay for
      medical patients with serious psychiatric illness than would have occurred had
      the traditional sequential approach to care been used. The integrated Type IV
      medicine and psychiatry treatment program represents an efficient and effective
      process improvement in the way that medical patients with comorbid medical and
      psychiatric illness can be treated.

PMID- 10402883
TI  - Ketamine dependence in anesthesia providers.

PMID- 10402884
TI  - Visual hallucinations in mild dementia. A rare occurrence of Lhermitte's
      hallucinosis.

PMID- 10402885
TI  - The possible role of seasonal mood changes in the seasonal distribution of acute
      myocardial infarction.

PMID- 10402886
TI  - Cancer therapeutics beyond 2000--more rationality, less empiricism.

PMID- 10402887
TI  - Why doctors should learn counselling and psychotherapeutic skills.

PMID- 10402888
TI  - Pharyngocutaneous fistula after laryngectomy--incidence, predisposing factors and
      outcome.
AB  - AIMS: The occurrence of pharyngocutaneous fistula in a totally laryngectomised
      patient is a serious complication as it increases patient morbidity and
      mortality. This paper aims to determine the incidence of the problem in our
      patients, to identify factors which may contribute to fistula formation and to
      analyse our results in managing this complication. METHODS: The case records of
      69 patients who underwent total laryngectomy between April 1990 and July 1997
      were assessed. RESULTS: There were 11 cases of pharyngocutaneous fistula out of
      69 patients with total laryngectomy, giving an incidence of 15.9%. Our findings
      showed that fistula formation was significantly more common in patients who had
      received pre-operative radiotherapy (p = 0.001) or who had tumour involved
      surgical resection margins (p = 0.018). The development of fistula delayed
      hospital discharge, and in 1 patient, contributed to sepsis and death. Of the 11
      patients with fistula, 4 required surgical intervention for closure. There was a
      trend towards surgical repair when the size of the fistula was large (> 2 cm).
      CONCLUSION: This paper identifies the patients at high risks for developing
      pharyngocutaneous fistula and also discusses our experience with managing this
      complication.

PMID- 10402889
TI  - A study of defaulters of treatment for diabetic retinopathy.
AB  - BACKGROUND AND AIM OF STUDY: Diabetic retinopathy needing Argon Laser
      Photocoagulation requires multiple sessions of treatment and follow-up. It is not
      uncommon for patients to default laser treatment for various social, economic or
      medical reasons. This paper aims to examine the common reasons for defaulting and
      to evaluate the effectiveness of a "no-show" compliance programme in reducing the
      rate of defaultment. MATERIALS AND METHODS: A "no-show" defaulters' compliance
      programme was introduced in July 1994. It was designed to recall defaulters for
      counselling and further laser treatment. We examined retrospectively a group of
      1377 patients scheduled for Argon Laser Photocoagulation treatment at the
      Singapore National Eye Centre in the period July-December 1994 and compared it to
      another group of 1332 patients scheduled in the corresponding period in 1995 to
      assess the effectiveness of this programme. The common reasons for defaulting for
      the two periods were also reviewed and compared. RESULTS: The results were
      analysed using the Chi-square test and there was a significant decrease in the
      default rate in 1995; p < 0.01. CONCLUSION: The results showed that the "no-show"
      programme significantly decreased the number of defaulters over the period under
      study. In time, this will result in a decrease in diabetic blindness.

PMID- 10402890
TI  - Long-term benzodiazepine users--characteristics, views and effectiveness of
      benzodiazepine reduction information leaflet.
AB  - OBJECTIVE: The authors looked at the clinical characteristics of long-term
      benzodiazepine users and how they viewed their use of benzodiazepine. We also
      examined the effectiveness of a self-help leaflet on reducing benzodiazepine use.
      METHOD: One hundred and nine long-term benzodiazepine users (daily use for more
      than 1 year) were assessed. Their perceived beneficial and undesirable effects of
      benzodiazepine and intention to reduce benzodiazepine use were studied and their
      history of benzodiazepine use was obtained. Psychiatric diagnosis and medical
      history were reviewed. A self-help leaflet was provided to 56 users whose anxiety
      symptoms were assessed to have been under control. We re-examined these 56 users
      3 months later on their use of benzodiazepine and anxiety levels. RESULTS: The
      109 long-term benzodiazepine users used a therapeutic dose of benzodiazepine
      (median: 10 mg diazepam equivalent) regularly for a median of 9 years (range: 1
      40). Most of the users found benzodiazepine helpful and only 11% of them reported
      undesirable side effects. Half of the 109 subjects refused to reduce the dosage.
      Most of the subjects still experienced significant anxiety despite the use of
      benzodiazepine. Fourteen of the 56 subjects provided with a self-help leaflet
      were able to reduce a median of 2.5 mg of diazepam equivalent when re-examined
      after 3 months. CONCLUSION: The results are compared with previous studies in
      Western societies and are discussed in the light of clinical management of
      patients with anxiety disorders.

PMID- 10402891
TI  - Postoperative vomiting (POV) in the paediatric outpatient general surgical
      population.
AB  - AIM: To determine the incidence of postoperative vomiting (POV) in the paediatric
      outpatient general surgical population, the factors affecting POV and the
      incidence of unplanned admissions contributed by POV. METHOD: One hundred and
      ninety-nine children below 13 yeas of age undergoing elective outpatient general
      surgical procedures were enrolled into this prospective study. Anaesthesia was
      induced either intravenously or via the inhalational route. It was then
      maintained with nitrous oxide, oxygen and isoflurane or halothane. The age, sex,
      body weight, duration of fasting, administration of trimeprazine, type of general
      surgical procedure, maintenance technique for general anaesthesia, duration of
      general anaesthesia, the administration of opiods or local anaesthetics and the
      incidence of POV were noted. The results were analysed initially with chi-squared
      test and subsequently subjected to multivariate logistic regression analysis and
      stepwise variable selection method. RESULTS: The incidence of POV was 8.5%.
      Duration of general anaesthesia greater than one hour was associated with a
      significantly higher incidence of POV. Postoperative emesis did not contribute to
      unplanned admissions in these day surgical patients.

PMID- 10402893
TI  - Management and short-term outcome of persistent hyperinsulinaemic hypoglycaemia
      of infancy (nesidioblastosis).
AB  - BACKGROUND/AIM OF STUDY: Persistent hyperinsulinaemic hypoglycaemia is a rare
      metabolic disorder of glucose regulation. It is however the most common cause of
      persistent hypoglycaemia in the neonatal period. Various drugs have been used
      with generally poor results, but diazoxide and a long-acting somatostatin
      analogue, octreotide, have been found to be rather successful. When medical
      therapy fails, early pancreatectomy is recommended to maintain euglycaemia. Since
      pancreatectomy seems to carry the long-term risk of diabetes mellitus, some
      authors recommend long-term medical therapy as an alternative to surgery. The
      outcome of treatment seems to correlate with neurological status prior to
      surgery. Even in early recognised and treated patients, publications suggest that
      a subtle neurological deficit may be present despite apparently normal
      intelligence. In view of the varying recommendations on treatment and the
      variations in outcome, we reviewed our experience over a period of three years
      (1992-1995) to determine whether we could formulate a rational approach to the
      management. METHODS: From our records, we identified 8 children who fullfilled
      the criteria for the diagnosis of persistent hyperinsulinaemic hypoglycaemia of
      infancy and retrospectively reviewed their documents. We also included 2 more who
      presented to us during the study period. RESULTS: Two out of the 10 were born
      premature and four were considered large for gestational age, mean birth weight
      was 3679 gms (range 2580-4400 gms). All except three were symptomatic by day two
      of life. All except one were given hydrocortisone prior to transfer to our care
      at a mean age of 22 days (range 8-52 days). Our regime included a trial of
      diazoxide and octreotide. Near total pancreatectomy was performed in nine
      patients, seven following a short trial of octreotide. Our two most recent cases
      were given a longer trial of medical therapy of 9 and 6 months respectively prior
      to pancreatectomy. Our two early cases in the series had recurrence of
      hypoglycaemia within a week post-pancreatectomy. One still needed insulin therapy
      5 months post-surgery. Seven were available for outcome assessment; while
      longitudinal growth is normal in all, three were developmentally delayed.
      CONCLUSION: Based on our experience with short and prolonged course of
      somatostation analogue, we conclude that early pancreatectomy should be performed
      on those with inadequate maintenance of euglycaemia while prolonged course of
      medical therapy is feasible only in selected cases.

PMID- 10402892
TI  - Cutaneous vasculitis seen at a skin referral centre in Singapore.
AB  - OBJECTIVE: To study the clinical features and course of patients presenting to a
      skin referral centre with cutaneous vasculitis. METHOD: A retrospective review of
      patients presenting to the National Skin Centre from 1993 to 1995 with cutaneous
      vasculitis was done. All patients included in the study had histologically proven
      vasculitis on skin biopsy. The clinical manifestations and laboratory
      investigations of the patients were recorded. The response to the various drugs
      given as first line therapy and course of the disease 1 year after initial
      presentation was reviewed. RESULTS: Forty-seven patients were included in this
      study. Females outnumbered males in a ratio of approximately 2:1 (32 females
      versus 15 males). The age of the patients ranged from 14 to 78 years, with a mean
      of 36 years. The aetiology remained elusive in 70% of cases. Of the known
      secondary causes, drugs and streptococcal infections were the most frequently
      implicated. The lower limbs were involved in more than 90% of cases. Cutaneous
      lesions took the form of palpable purpura, ulcers, nodules and urticaria.
      Extracutaneous manifestations were present in 47% of patients. The main
      extracutaneous manifestations were arthralgia/arthritis (21%), microscopic
      haematuria (16%) and abdominal pain (8%). Direct immunofluorescence on lesional
      skin was positive in 65% of cases. A raised erythrocyte sedimentation rate was
      observed in 40% of patients. Positive antinuclear antibodies were detected in 30%
      of cases. Most patients who were given systemic corticosteroids responded
      predictably well. The response to other modalities of treatment was more
      variable. At 1 year follow-up, complete remission was recorded in 47% of the
      patients, while in 53% of the patients, the disease continued to run a chronic
      relapsing course.

PMID- 10402894
TI  - Hyperthyroidism due to papillary carcinoma of the thyroid--a case report.
AB  - A rare case of papillary carcinoma of the thyroid producing hyperthyroidism is
      presented. A young patients presented seven years after a thyroid operation with
      metastatic disease in the cervical lymph nodes and a history of deteriorating
      vision in the left eye. He also had a lesion in the base of the skull which could
      not be established to be metastasis from the thyroid cancer. There was clinical
      and biochemical evidence of hyperthyroidism. Radionuclide scan revealed uptake in
      the residual thyroid tissue and patchy uptake by the cervical lymph nodes. The
      patient underwent a complete thyroidectomy and radical neck dissection of the
      left side and 'berry-picking' of the lymph nodes on the right side. Although the
      patient became euthyroid post-operatively, his general condition deteriorated and
      he rapidly lost vision in both eyes before any ablative therapy could be
      instituted for the tumour in the base of the skull. The patient was lost to
      follow-up.

PMID- 10402895
TI  - Retroperitoneal and mesenteric cysts.
AB  - Retroperitoneal and mesenteric cysts are rare abdominal tumours. This report is a
      presentation of three cases. One patient had large retroperitoneal cyst which was
      accidentally discovered, another patient had mesenteric cyst presenting with
      abdominal pain, and the third patient had emergency admission due to infection of
      a large mesenteric cyst. The literature on this condition is reviewed.

PMID- 10402896
TI  - Hospital resuscitation of cardiac arrest patients.
AB  - Resuscitation of collapsed cardiac patients is often a not-too-successful affair.
      It has been repeatedly emphasised that the most important aspect of cardiac
      resuscitation is early access, early recognition of ventricular fibrillation and
      early defibrillation in patients with ventricular fibrillation. However, the co
      ordination of the various phases of cardiac resuscitation itself, which is often
      forgotten, would need a good organisation so that a systematic assessment of the
      patient can be done while resuscitation is in progress. In this report, we
      describe a case of successful prolonged cardiac resuscitation with emphasis on
      the organisation of resuscitation as well as early defibrillation. We would also
      like to emphasise that all procedures that were done were performed correctly and
      their effects on the monitored patient were assessed frequently so as to maximise
      efficiency, myocardial salvage and patient survival.

PMID- 10402897
TI  - Mirizzi syndrome--a report of 3 cases with a review of the present
      classifications.
AB  - We report three cases of Mirizzi syndrome, two with external compression of the
      common hepatic duct and another with cystobiliary fistula. All patients presented
      with jaundice. The diagnosis was suggested by ultrasonography and confirmed by
      endoscopic retrograde cholangiography (ERC). All three had the stones removed
      surgically, one through a choledochotomy, another through an opening in the gall
      bladder and the third at the time of subtotal cholecystectomy. We would like to
      propose a simple classification of Mirizzi syndrome, based on surgical procedures
      necessary for the correction of the pathological anatomy. If it involves the
      removal of calculi with some form of cholecystectomy, we consider it as Type I,
      whereas Type II involves the construction of a hepaticojejunostomy apart from the
      removal of calculi.

PMID- 10402898
TI  - Negative pressure pulmonary oedema caused by biting and endotracheal tube
      occlusion--a case for oropharyngeal airways.
AB  - A patient had general anaesthesia for laparoscopic surgery. She bit on and
      occluded her endotracheal tube during recovery from anaesthesia. Strong
      inspiratory efforts during airway obstruction caused negative pressure pulmonary
      oedema. The pulmonary oedema resolved within 24 hours. Use of an oropharyngeal
      airway as a bite block could have prevented this complication.

PMID- 10402899
TI  - Multiple organ failure and septic shock in disseminated tuberculosis.
AB  - The diagnosis of disseminated tuberculosis should be entertained in all patients
      with unexplained fever associated with hepatomegaly and/or splenomegaly with or
      without anomalies in liver function tests and haemogram. It should be considered
      as a possible cause of septic shock especially in patients with typical risk
      factors such as advanced age, diabetes, alcoholism or immunosuppression. Prompt
      therapy could be life saving in an otherwise potentially fatal condition. It is
      therefore appropriate to initiate anti-tuberculosis treatment as soon as such a
      diagnosis is suspected and not await final confirmation.

PMID- 10402900
TI  - Temporomandibular disorders--an overview.
AB  - Temporomandibular disorders (TMD) have been an area of increased clinical and
      scientific inquiry in dentistry. This is due to increased patient awareness and
      desire for treatment as well as scientific advances in the fields of
      epidemiology, neurobiology and diagnostic imaging. This article sets out to
      introduce this disorder and describes its aetiology and management.

PMID- 10402902
TI  - What you need to know--objective assessment of nasal patency--why it is
      important.

PMID- 10402901
TI  - Clinics in diagnostic imaging (35). Metastases to the breasts, skin and bone.
AB  - A 46-year-old woman presented with multiple skin lumps and right hip pain.
      Multiple nodules were palpable in the skin over the chest and abdominal wall, and
      in both breasts. Bilateral mammograms showed multiple solid masses, while
      ultrasound demonstrated multiple subcutaneous nodules. An osteolytic lesion was
      seen on the right hip radiograph. Excisional biopsy of a subcutaneous nodule
      revealed metastatic adenocarcinoma. The diagnosis of metastases to the breast is
      discussed, together with imaging features of other multiple breast lesions, such
      as fibroadenomas and cysts.

PMID- 10402903
TI  - [Infectious diseases in refugees from Kosovo].

PMID- 10402904
TI  - [Ways to a better spine].

PMID- 10402905
TI  - [Prioritization in theory and practice].

PMID- 10402906
TI  - [Physician as assessor and gatekeeper].

PMID- 10402907
TI  - [From valium to the happy pill?].
AB  - The National Health Insurance started to refund expenditure on selective
      serotonin reuptake inhibitors in 1994. Questions have been raised if a
      significant portion of benzodiazepine users would transfer to these new drugs
      when they were described in the literature as also being used for light anxiety,
      but not carrying the addiction risk associated with benzodiazepines. The study
      looks at changes over a four-year period in the prescription of benzodiazepines
      and selective serotonin reuptake inhibitors dispensed from two pharmacies in Vest
      Agder County with a total customer base of 17,800. For four years we also
      followed the prescription of drugs in these two groups to 1,125 patients who had
      been prescribed benzodiazepines in 1994. Our data show that only 5% of those
      receiving benzodiazepines in 1994, whom we were able to track, changed to a
      selective serotonin reuptake inhibitor-only therapy. 18% used a combination of
      the two groups of drugs and 77% continued to use benzodiazepines as before. The
      increase in the number of patients receiving selective serotonin reuptake
      inhibitors during the study period is far greater than the increase measured by
      number of daily doses. Selective serotonin reuptake inhibitors seem to have
      little influence on the use of benzodiazepines in our pharmacies' area. Our
      findings indicate that instead of "from Valium to Prozac" the change during the
      years 1994-97 can be described as "from Valium to Valium and Prozac".

PMID- 10402908
TI  - [Patients surgically treated for aortic coarctation].
AB  - The aim of this study was to evaluate the results of surgical treatment of
      coarctation of the aorta. All patient files on patients operated at Haukeland
      Hospital, Bergen, Norway, in the period 1975-95 (n = 102) were surveyed. We sent
      a questionnaire to all patients alive in 1996 (n = 84), and 82 (98%) responded.
      Six patients (6%) died within 30 days of surgery, and 12 (12%) died later. These
      mortality numbers were smaller among patients operated in the period 1988-95.
      Among patients with associated heart defects (n = 28) the numbers were 14% and
      25%, respectively. Four patients required reoperation and three patients balloon
      dilatation. Six of these patients were operated in the period 1975-87. Among the
      82 patients that responded to the questionnaire, clinical follow-up by a
      cardiologist had been discontinued in 35 cases. 31 patients (38%) were not
      satisfied with the follow-up. Many patients reported muscle fatigue in the legs
      (30%), reduced exercise performance (29%), headache (26%), general fatigue (22%),
      and leg pain (17%). 38% did not report any symptoms. Our results are in
      accordance with previously reported studies, and the mortality numbers were
      reduced in the second period. The number of recurrences was also reduced in this
      period. The symptoms reported by many patients may be caused by recoarctation or
      an abnormal blood pressure. This group of patients should, therefore, be
      monitored systematically for abnormal blood pressure, recoarctation and aortic
      valve disease.

PMID- 10402909
TI  - [Communication between general practitioners and hospital interns at emergency
      admissions].
AB  - Communication between general practitioners and hospital interns serves as basis
      for the first in-hospital treatment of emergency admitted patients. The purpose
      of this study is to describe how this communication currently functions in
      Norway. The study was carried out by personal and focus group interviews with
      general practitioners and hospital interns, and questionnaire responses from 532
      doctors. Both general practitioners (93%) and hospital interns (84%) claim that
      the general practitioner's information is usually valuable for the initial
      hospital treatment. 89% of the general practitioners and 65% of the interns (p <
      0.01) responded affirmatively to general statements characterising the existing
      communication as good. However, 58% of the interns are of the opinion that there
      are many unnecessary referrals to the hospitals, and 47% respond that the general
      practitioners often refer a patient in order to get rid of a problem they should
      have been able to handle themselves. The interns single out simple problems with
      the referral letters, such as illegible handwriting, and left-out or unsorted
      information. This critical view can in part be explained by the sense of
      isolation, lack of autonomy and high work load that interns experience in their
      obligatory hospital year. We recommended that interns are invited to participate
      when hospital doctors and general practitioners meet.

PMID- 10402910
TI  - [The first telephone call at emergency admissions--the role of nurses].
AB  - The article focuses on whom in the hospital the general practitioners first
      inform when referring emergency patients. The study is based on interviews with
      general practitioners and hospital interns, and questionnaires answered by 532
      doctors, selected from hospital areas where the primary doctor on call usually is
      an intern. Three fourths of the respondents state that the general practitioner
      when referring patients usually gives the clinical information directly by phone
      to an intern. The remaining state that general practitioners normally inform a
      hospital nurse about emergency admissions. The quality of communication, and the
      respect developed between general practitioners and interns is perceived as being
      better when there is a direct communication between the general practitioner and
      the hospital doctor, bypassing the nurse. The interns respect the admission
      decisions of the general practitioners to a significantly larger degree, and
      claim that necessary information about the patient is easier to obtain when they
      routinely communicate with the general practitioners. In our opinion, the present
      study gives reason to recommend a direct telephone contact between the referring
      general practitioner and the hospital intern as part of emergency admissions.

PMID- 10402911
TI  - [General practitioners and patients' social status].
AB  - The claim has been made that general practitioners known their patients' social
      context well. We aimed to explore the mechanisms by which this context comes to
      the doctors' attention and leads to a change in management. This paper summarizes
      the results of four papers published in international journals. A questionnaire
      survey was conducted, in which doctors and patients answered mirrored questions.
      1,401 patients visiting 89 general practitioners during one practice day were
      included. 1,217 patients responded (87%). Work-related problems were often
      recognized, financial problems not, while the results for interpersonal problems
      were intermediate. Sociodemographic characteristics of the patients and the
      general practitioners' previous general knowledge of the patients influenced the
      doctors' recognition of problems. Doctors and patients select certain subjects,
      particularly those related to occupational life, as more relevant than others.
      The doctors' recognition is influenced by presuppositions. A lasting doctor
      patient relationship facilitates the transmission of intimate information.

PMID- 10402912
TI  - [Applications for disability benefits before and after the 1991 restrictions].
AB  - In 1991, the eligibility criteria for disability benefits were restricted in
      Norway. Some effects are described in the present evaluation. Based on documents,
      first time applicants in 1990 and in 1993 in two counties were analysed according
      to social and medical variables. "Social security careers" before application are
      described, and proposals from physicians and the local social security office are
      compared with the decisions made by the county social security administration.
      Over a three-month period, applications decreased from 2.2 per 1,000 inhabitants
      in 1990 to 1.4 in 1993, a 39% decrease. About the same decrease was observed in
      all social and diagnostic groups. The proportion on vocational rehabilitation
      before application increased from 19% to 23% (p = 0.02). The certifying
      physicians proposed refusals in 9% and 8% in the two samples, and the local
      social security office did so in 12% and 13%. The refusal rate increased from 8%
      in 1990 to 21% in 1993. Refusals were mostly given to women, the middle-aged,
      those living alone, those with short education, and applicants with medically
      unclear conditions. It is pointed out that the restrictions on disability
      benefits in 1991 had the greatest impact on applicants with few resources.

PMID- 10402913
TI  - [Sources of income after being denied disability pension].
AB  - Restrictions in eligibility criteria for disability pension were introduced in
      Norway in 1991. The effect of these restrictions on sources of income is an
      important question in social policy. 157 first time applicants from two counties
      who were denied disability pension before (1990) and after (1993) the
      restrictions were studied three years later. Sources of income were established
      through searches in registers of wages and social security benefits. NOK 3,000
      per month was set as the lowest income allowing economic independence. Of the
      applicants in 1990, 14% were in the workforce three years later. In the post
      restriction 1993 sample, this proportion was 21% (p = 0.29). The proportions
      receiving disability pension were 25% and 22% respectively. The spouse supported
      33% of the 1990 applicants, and 22% in the 1993 sample (p = 0.13). Social welfare
      was the main source of income for 6% and 10% (p = 0.25). Changes in main sources
      of income following the restriction were relatively small. The main result of
      this study is that family support is the most prevalent source of income when
      disability benefits are denied. This is not in accordance with the Government's
      policy of promoting gainful employment.

PMID- 10402914
TI  - [Medical judgment and legal security. Physicians as gatekeepers in the
      distribution of public goods].
AB  - We wanted to explore general practitioners' discretionary judgments about the
      eligibility of patients applying for disability pension, and to examine if
      variations in such judgments are correlated with the physicians' personal values
      and moral standards. Data were collected by a postal questionnaire, which
      included two vignettes focusing on whether the "applicant" fulfils the
      eligibility criteria for disability benefit. Variations in judgments were then
      analysed in correlation to the GP's view on normative questions concerning the
      physicians' role as gatekeepers, the disability pension as a source of income,
      and an indicator of the GP's scepticism to the disability pension. 360 general
      practitioners from eight different counties in Norway participated. The response
      rate was 62 per cent. The assessment of the vignettes revealed great variation.
      Four out of ten general practitioners concluded that the first vignette fulfilled
      the medical eligibility criteria, while three out of ten came to the opposite
      conclusion. For the second vignette the results were reversed. For both
      vignettes, three out of ten were not able to answer "yes" or "no" because of
      uncertainty. Further, the variation in judgments was correlated with an indicator
      of the GPs' personal values and moral standards. The stronger expressed
      disability pension scepticism, the more restrictive interpretation of the medical
      eligibility criteria. A decision on entitlement to disability pension pertains to
      the distribution of public goods. The general practitioners' discretionary
      judgments are crucial in this decision-making. When doctors let their political
      and moral standards influence their judgment, they act arbitrarily and in
      conflict with ideals of equal treatment and legal security.

PMID- 10402915
TI  - [High admission rates--deficient communication between primary and secondary
      health care levels?].
AB  - GPs in Lofoten in the county of Nordland, Norway, were asked to consider and to
      propose suggestions for reducing the admission rates to the Department of
      Internal Medicine, Lofoten Hospital. The main suggestions were to open an
      outpatient clinic for emergency patients, improve the continuity among the GPs in
      primary care, increase the number of beds in nursing homes, and to establish a
      new forum where GPs and hospital doctors could meet. All suggestions, directly or
      indirectly expressed a need of closer collaboration and a better dialogue between
      doctors in primary and secondary health care. Only half of the GPs believed it
      would be possible to reduce the number of admissions to the hospital. This view
      might reflect some scepticism concerning the current organisation of the
      Norwegian health care services, and if so, there is a challenge to experiment
      with other organisation models.

PMID- 10402917
TI  - [A 70-year old male with prolonged paralysis after spinal anesthesia].

PMID- 10402916
TI  - [Testing of a standard referral form in Sor-Trondelag].
AB  - January 1st 1998 Norwegian health authorities introduced a standard referral form
      to be used for all referrals to specialists. The form had been developed by a
      working group in the Norwegian Board of Health. The group also was responsible
      for testing out the form. One test was performed by use of a medical audit method
      in Sor-Trondelag County in September 1997. The evaluation from the specialists
      who received the referrals was positive with regard to the information needed for
      appraisal of the referral. The general practitioners who participated had a more
      varied evaluation; in 90% of the cases the form was evaluated as good or
      serviceable, but only in 30% of the cases was it considered an improvement. At
      the closing workshop the participating doctors had many proposals for changes and
      improvements of the form. The most important conclusion of the pilot study is
      that efforts to improve communication between doctors must be closely linked to
      developments in computer software for medical practice.

PMID- 10402918
TI  - [Recommendations on care of back pain problems].
AB  - Back problems are a common cause of disability. There are important variations in
      the care provided, suggesting that some patients receive suboptimal treatment.
      Several Western countries have developed practice guidelines to improve this
      state of affairs. If guidelines are to improve the outcome for patients seeking
      care, they must give valid recommendations. In this article I compare ten
      practice guidelines for back problems. The guidelines are from nine Western
      countries and were published in the ten-year period 1987-97. There are
      significant variations in the recommendations given. The guidelines were
      developed according to different methods. A systematic, evidence-based approach
      is less prone to bias than an informal expert-based consensus. I conclude that
      the systematically developed US guideline (AHCPR 1994) and the British guideline
      (RCGP 1996) are the ones giving valid recommendations and are therefore the best
      options for practitioners.

PMID- 10402919
TI  - [Clinical management of low back pain in primary health care].
AB  - Diagnostic differentiation seems crucial in the treatment of patients with low
      back pain. We must try to distinguish between pain originating from the moving
      segments or the soft tissue in the columna, and differentiate between radicular
      pain and referred pain to the leg. Principles of treatment for the acute and
      recurrent low back pain attacks are dealt with, as well as the treatment of
      patients with acute chronic sciatica and spinal stenosis. The special problems
      concerning treatment of degenerative disc disease and patients with back pain
      caused by psychosocial problems are further discussed.

PMID- 10402920
TI  - [Radiography of the lumbosacral spine--do the referrals conform to clinical
      recommendations?].
AB  - The aim of this study was to evaluate how referrals from Norwegian general
      practitioners for plain radiography of the lumbosacral spine conform to clinical
      recommendations. The clinical information given in 274 referral letters was
      compared with Norwegian and British recommendations. We also interviewed 99 of
      the patients about symptoms and prior radiographs, and performed a new comparison
      using all available information. Only 27% (43%) of the 274 referrals conformed to
      the Norwegian (British) recommendations, 36% (41%) did not conform, and 37% (16%)
      were considered uncertain, mainly because of lack of pertinent information in the
      referral letters. Of 143 referrals which were in disagreement with the Norwegian
      and/or the British recommendations, only four resulted in "important" findings
      (osteoporotic fractures in two patients, uncertain sacroiliac joint arthritis in
      one patient, and probably benign bony sclerosis in one patient). In the interview
      group, the proportion of non-conforming referrals decreased from 40% (47%) to 31%
      (29%) when the additional clinical information was considered. Nevertheless, we
      conclude that a substantial proportion of referrals for plain radiography of the
      lumbosacral spine do not conform to clinical recommendations. Referrals outside
      the advised criteria yield few relevant findings and could probably be cancelled.

PMID- 10402921
TI  - [Chronic low back pain in 40-year olds in 12 Norwegian counties].
AB  - In this study, a questionnaire and a short interview were used to estimate the
      prevalence of chronic low back pain alone and low back pain together with other
      musculo-skeletal pains among 40-year-old women and men in 12 Norwegian counties
      (a total of 67,338 persons). On average 2.4% of men and 1.7% of women had only
      chronic low back pain, while 5.7% of men and 9.2% of women in addition had other
      pains as well. Persons with low back pain only were approximately equally
      distributed across the counties. Greater variations across the counties and
      between the sexes were found in persons with additional pain. The duration of the
      pain did not vary significantly between the sexes or across the counties, but the
      duration was on average two years longer in cases of multi-cause pain. Reduced
      capacity for work because of pain was approximately equally distributed between
      the sexes and the groups. More women than men were unable to do their daily work.
      About one third in both groups (more men than women) had been absent from work
      because of pain during the last year. More women than men in both groups received
      national insurance benefits. Persons with only low back pains were approximately
      equally represented across all levels of education and regardless of marital
      status, while people with multi-cause pain were overrepresented among those with
      low levels of education and among the divorced.

PMID- 10402922
TI  - [A close meeting with chronic fatigue syndrome].

PMID- 10402923
TI  - [Medicine is not mathematics--can anything substitute for professional
      judgment?].

PMID- 10402924
TI  - [Social inequality and health from a historical point of view].

PMID- 10402925
TI  - [Back pain, confusion and pessimism].

PMID- 10402926
TI  - [Distal renal tubular acidosis or only renal failure and diuretics-induced
      hypokalemia?].

PMID- 10402928
TI  - [To nail in the coffin of medicine].

PMID- 10402927
TI  - [When clinical medicine becomes post-modern].

PMID- 10402929
TI  - [Early diagnosis of cancer].

PMID- 10402930
TI  - [Spontaneous regression of malignant tumors].

PMID- 10402931
TI  - [Clinical pharmacology--what for?].

PMID- 10402932
TI  - [Forensic anthropology].

PMID- 10402933
TI  - [Telomere terminals and telomerase. The biological aging clock?].

PMID- 10402934
TI  - [Photodynamic therapy. A new method for the treatment of cancer].
AB  - This therapy is best understood as light activated chemotherapy. The
      chemotherapeutic agents, so-called photosensitizers, are relatively harmless
      without light. The photosensitizer is given systemically and is concentrated or
      retained in malignant tissue, the activating light is applied locally. The
      therapy is approved in The United States of America, Canada, The Netherlands,
      France, Germany and Japan for treatment of certain malignancies. An approval is
      pending at The Danish National Board of Health. Photodynamic therapy is
      potentially curative for many superficial or luminal tumours, and can eradicate
      micrometastases in the tumour bed.

PMID- 10402935
TI  - [Metaphyseal chondrodysplasia].
AB  - Metaphyseal chondrodysplasia (MCD) is a heterogeneous group of diseases
      characterised by defective enchondral ossification, leading to metaphyseal
      changes. The different types of MCD can be distinguished by clinical findings,
      radiology and genetic tests. Based on a case story with MCD, pancreatic
      insufficiency and granulocytopenia (Shwachman's syndrome), we review the most
      common types of MCD with regard to clinical manifestations, radiological
      findings, and genetic background.

PMID- 10402936
TI  - [Spontaneous remission of breast cancer. A literature review].
AB  - Some patients combine conventional treatment with alternative treatment forms and
      it has been claimed that some alternative treatment forms have an antineoplastic
      effect. Data from the first part of this century suggest that breast cancer has a
      very variable natural course, and a small fraction of patients survive 10-15
      years without treatment. An exceptional course could be misinterpreted as
      effective alternative treatment in the absence of strict criteria. We have
      therefore investigated the natural history of breast cancer and the degree of
      spontaneous remission. On the basis of international literature we found 32 cases
      of spontaneous remission of breast cancer. Six cases were sufficiently documented
      regarding histological confirmation of the diagnosis. The phenomenon is therefore
      very rare and the natural course is very variable.

PMID- 10402937
TI  - [Clinical pharmacological drug information. Well over one year's experience].
AB  - Clinical pharmacology was established quite recently in Denmark as a medical
      specialty. It comprises--among other items--clinical pharmacological drug
      information service, the primary aim of which is to provide service to health
      personnel with clinical responsibility involving drugs and specific patient
      related questions. Questions forwarded to the clinical pharmacological drug
      information service at two Copenhagen hospitals have been summarized. The
      questions were categorized according to the profession and the affiliation to the
      health care system of the inquirer as well as the nature of the question. At the
      two hospitals, 118 and 77 questions were answered from January 1st 1997 to June
      1st 1998, respectively. Physicians employed at hospitals were responsible for the
      majority of the questions. Most questions concerned adverse drug reactions,
      choice of therapy/drug, and therapy during pregnancy or breast feeding.

PMID- 10402938
TI  - [Glucose-galactose malabsorption. The first reported case in Denmark].
AB  - The first diagnosed case of glucose-galactose malabsorption (GGM) in Denmark is
      presented. GGM is an autosomal recessive disorder characterized by neonatal debut
      of severe osmotic diarrhoea. Untreated, GGM is potentially fatal. The disease is
      chronic and caused by a defect in the Na+/glucose co-transporter, SGLT1, located
      on the jejunal brush border. Diagnosis is based upon oral glucose tolerance test,
      stool reducing substances, and may be substantiated by genetic analysis.
      Treatment consists in eliminating alimentary glucose and galactose. Nurtured on
      this diet the patient will develop normally.

PMID- 10402939
TI  - [Vascular prosthesis infected with Salmonella. A rare complication of Salmonella
      sepsis].
AB  - A case of vascular graft infection secondary to Salmonella septicaemia is
      described. The patient was a 69 year old man with an aortic bifurcation graft and
      a femoropopliteal bypass. Despite antibiotics treatment, operation was necessary.
      An especially long extra-anatomical bypass was used.

PMID- 10402940
TI  - [Angiogenesis in malignant blood diseases].

PMID- 10402941
TI  - [Future of scientific journals. News from the meeting of the Council of Biology
      Editors in Montreal 22-26 May 1999 and the Vancouver group meeting in Ottawa 27
      28 May 1999].

PMID- 10402942
TI  - [The FREJA research program in biology and medicine].

PMID- 10402943
TI  - [An editorial about an editorial].

PMID- 10402944
TI  - [Diagnosis and treatment of vitamin D deficiency].

PMID- 10402945
TI  - [Beta-interferon will be transformed by Foldspang].

PMID- 10402946
TI  - [Treatment of Crohn disease with anti-tumor necrosis factor alpha].

PMID- 10402947
TI  - [Lung damage after use of conditioner sprays for leather and textiles].
AB  - A series of poisoning cases have been caused by private spraying of leather and
      textiles with a conditioner. Symptoms and signs from the airways as well as
      general symptoms have not been explained by any of the ingredients. Spray
      impregnation should be carried out where efficient ventilation is available.

PMID- 10402948
TI  - [Is male fertility declining?].
AB  - In the lay press, a worldwide decline in male fertility is often accepted. In
      fact, this assumption is based on a meta-analysis of "normal sperm parameters" in
      the medical literature between 1938-1998 and based on retrospective studies from
      several centers. Other studies, however, have not shown a decrease of sperm
      parameters. Some have even shown an increase of sperm parameters. Some have even
      shown an increase of sperm parameters. A critical analysis of all these studies
      shows great differences between studies in selection of normal men, measurement
      of sperm parameters, analysis of data, ... Also, unexplained geographical
      differences in sperm density exist that may influence the analysis. In
      conclusion, a worldwide decline of sperm quality or male fertility has not been
      scientifically proved.

PMID- 10402949
TI  - [A strategy for the prevention of male infertility].
AB  - Since 1990 there has been a simultaneous reduction of natality in Flanders (by
      approximately 12%) with increased demand for assisted reproduction, while sperm
      quality, mostly motility and morphology, have clearly deteriorated over recent
      decades. This evolution has been ascribed to the deleterious effects of hormone
      disrupting substances in the environment, synergistically enhancing unfavorable
      influences from life style and possible genito urinary diseases that can impair
      the function of the testes and accessory sex glands. It is probable that this
      synergistic effect is exerted through the intermediate of free oxygen radicals
      (also called reactive oxygen species) that damage both the sperm membrane and
      sperm DNA, which could allow certain minimal inborn genetic defects (such as
      point lesions) to come to expression. Both pseudo- or xeno-estrogens (such as
      certain organo chlorides, alkyl phenols, phthalates, etc.) and anti-androgens are
      held responsible for prenatal testicular damage and increased prevalence of
      testicular carcinoma and oligozoospermia, for anatomical malformations, as well
      as postnatal depression of testicular function and spermatogenesis. However,
      methods presently available to detect hormone disrupters are tedious and not
      fully adequate. A first strategic goal is to develop a simple method for the
      detection of these substances so that environmental pollution can be mapped.
      Fazing out the production and application of hormone disrupters, and removing
      them from the environment are the second strategic step. Also, a health food is
      being developed that will inhibit the absorption of these chemicals from the
      intestinal tract. In addition it is projected to detect and treat common genital
      diseases that can cause infertility, such as varicocele and infection of the
      urinary tract and accessory sex glands. The first could be organized to take
      place during medical examinations at school, whereas the second requires correct
      medical treatment of any cysto urethritis in adolescents. Non surgical treatment
      of varicocele by means of transcatheter embolization offers a cost effective
      approach, with minimal risk and complications, and high level of efficacy.
      Improving food quality and educational efforts aimed at a healthier life style
      should score high priority. The suggested strategy uses several entries in order
      to address the multifactorial mechanisms involved in the pathogenesis of male
      infertility. Preliminary epidemiological and biological data suggest that the
      proposed strategy can, indeed, be successful within a relatively short lapse of
      time.

PMID- 10402950
TI  - [Can T-cell immunity in an adult be regenerated?].
AB  - In man, normal peripheral T cell function depends on thymopoiesis during the
      foetal and perinatal period (up to 3 months). In humans, studies have shown that
      declines in thymic T-cell regenerative capacity begins relatively early in life,
      resulting in a limited capacity for T-cell regeneration by young adulthood. These
      limitations in T-cell regeneration have significant clinical implications in the
      setting of HIV infection and bone marrow transplantation. Recent studies have
      reported that the human thymus can generate new cells throughout life, and even
      late, into adult life. Patients infected with HIV can generate new peripheral T
      cells after anti-viral therapy. In view of a continuous role of thymopoiesis in
      man, there is a growing need for relevant models of human thymopoiesis. Using a
      hybrid human-mouse FTOC model, we have shown that IL-7 is an essential growth
      factor for thymocytes and that certain genes of HIV interfere with the normal
      production of thymocytes. These studies allow the selection for products active
      in therapeutic restoration or maintenance of thymic function.

PMID- 10402951
TI  - Brains and brawn: plectin as regulator and reinforcer of the cytoskeleton.
AB  - Plectin is a 580 kDa intracellular protein, previously shown to link intermediate
      filaments with microtubules, actin filaments, and membrane components. Disruption
      of the plectin gene in humans and in mice results in severe skin blistering and
      muscular degeneration, consistent with plectin's structural role in stabilizing
      cells against mechanical force. However, recent work by Andra et al.
      characterizing cells from plectin-deficient mice demonstrates that in addition to
      this structural role, plectin also modulates the dynamics of the actin
      cytoskeleton. This makes plectin unusual in that it serves both to reinforce and
      crosslink intermediate filament attachments to membranes and other cytoskeletal
      polymers and to regulate actin dynamics in cells.

PMID- 10402952
TI  - Competent steps in determination of cell fate.
AB  - Competence is an active state that defines the way in which cells respond to an
      inductive signal. A challenge of developmental biology is to explain not just the
      nature of the signalling molecules that promote cell specification or
      differentiation, but also how cells acquire competence to respond to these
      signals and what that reflects in molecular terms. A recent paper by Carmena et
      al. has revealed how several signalling mechanisms are used sequentially and in
      specific combinations to specify two mesodermal lineages in Drosophila.

PMID- 10402953
TI  - How to grow a gut: ontogeny of the endoderm in the sea urchin embryo.
AB  - Gastrulation is the process of early development that reorganizes cells into the
      three fundamental tissue types of ectoderm, mesoderm, and endoderm. It is a
      coordinated series of morphogenetic and molecular changes that exemplify many
      developmental phenomena. In this review, we explore one of the classic
      developmental systems, the sea urchin embryo, where investigators from different
      backgrounds have converged on a common interest to study the origin,
      morphogenesis, and developmental regulation of the endoderm. The sea urchin
      embryo is remarkably plastic in its developmental potential, and the endoderm is
      especially instructive for its morphological and molecular responsiveness to
      inductive cell interactions. We start by examining and integrating the several
      models for the morphogenetic mechanisms of invagination and tissue elongation,
      the basic processes of endoderm morphogenesis in this embryo. We next critique
      the proposed mechanisms of inductive gene regulation in the endoderm that
      exemplifies a concept of modular transcriptional regulation. Finally, we end with
      an examination of the current molecular models to explain cell fate determination
      of the endoderm. Recent progress at the molecular level should soon allow us to
      explain the seminal experimental observations made in this embryo over a hundred
      years ago.

PMID- 10402954
TI  - Segment polarity genes in neuroblast formation and identity specification during
      Drosophila neurogenesis.
AB  - The relatively simple central nervous system (CNS) of the Drosophila embryo
      provides a useful model system for investigating the mechanisms that generate and
      pattern complex nervous systems. Central to the generation of different types of
      neurons by precursor neuroblasts is the initial specification of neuroblast
      identity and the Drosophila segment polarity genes, genes that specify regions
      within a segment or repeating unit of the Drosophila embryo, have emerged
      recently as significant players in this process. During neurogenesis the segment
      polarity genes are expressed in the neuroectodermal cells from which neuroblasts
      delaminate and they continue to be expressed in neuroblasts and their progeny.
      Loss-of-function mutations in these genes lead to a failure in the formation of
      neuroblasts and/or specification of neuroblast identity. Results from several
      recent studies suggest that regulatory interactions between segment polarity
      genes during neurogenesis lead to an increase in the number of neuroblasts and
      specification of different identities to neuroblasts within a population of
      cells.

PMID- 10402955
TI  - Muscle pattern diversification in Drosophila: the story of imaginal myogenesis.
AB  - There are two phases of somatic muscle formation in Drosophila. During embryonic
      development, one phase of myogenesis generates larval muscle elements that
      mediate the relatively simple behavioural repertoire of the larva. During pupal
      metamorphosis, a diverse pattern of muscle fibres are assembled, and these
      facilitate the more elaborate behavioural patterns of the adult fly. In this
      review, we discuss the current status of understanding of the cellular, genetic,
      and molecular mechanisms of pattern formation during the second phase, imaginal
      muscle development. We briefly compare aspects of embryonic and adult myogenesis
      in Drosophila and muscle development in vertebrates and highlight conserved
      themes and disparities between these diverse myogenic programmes.

PMID- 10402956
TI  - Integrins: alternative splicing as a mechanism to regulate ligand binding and
      integrin signaling events.
AB  - Integrins are a family of transmembrane proteins composed of heterodimers of
      alpha and beta subunits. With their extracellular domain they bind extracellular
      matrix proteins or other cell surface molecules, and their cytoplasmic domain
      binds to cytoskeletal and signaling proteins. Thus, they are in an ideal position
      to transfer information from the extracellular environment to the interior of the
      cell and vice versa. For several integrin subunits, alternative splicing of mRNA
      leads to variations in the sequence of both extracellular and cytoplasmic
      domains. Many integrin splice variants have specific expression patterns, but for
      some time, functional differences between these variants were not evident. Recent
      experiments using transfected cell lines and gene targeting of specific splice
      variants have contributed significantly to our understanding of the function of
      these splice variants. The results indicate that alternative splicing is a
      mechanism to subtly regulate the ligand binding and signaling activity of
      integrins.

PMID- 10402957
TI  - Leishmania major infection of inbred mice: unmasking genetic determinants of
      infectious diseases.
AB  - Leishmania major infection of inbred mice leads to a major dichotomous response-
      death or survival--that depends on the strain of mice. This finding has motivated
      efforts to locate genetic determinants of disease susceptibility. Genotyping
      studies have confirmed a complex multilocus trait, but studies directed at the
      biology of the response suggest identifiable components of susceptibility that
      may direct the genetic investigations. A confluence of parasite variables-
      residence in macrophages class II-dependent immunity, and avoidance of early IL
      12 induction--with host factors--a prominent helper T-cell precursor frequency to
      a dominant parasite epitope and a bias in IL-4 gene activation--conspires to
      drive an aberrant immune response in animals that suffer fatal disease. These
      insights may lead to an understanding of factors that focus responses on dominant
      antigens and that mold the naive T-cell repertoire. Collectively, such factors
      might contribute to the pathogenesis of other infectious and autoimmune diseases.

PMID- 10402958
TI  - Does the immune system of a mouse age faster than the immune system of a human?
AB  - One of the characteristics of all somatic cells is a finite life span. Cells may
      proliferate until they reach a point after which, although they are metabolically
      active, they can no longer produce daughter cells. This observation is central to
      the clonal exhaustion hypothesis, a mechanism cited to explain age-associated
      immune dysfunction. In this hypothesis, repeated division of lymphocytes leads to
      a replicative limit, after which they enter the senescent phase but are not lost
      from the pool of T cells. Advancing age would then be associated with an increase
      in the number of T cells that are unable to proliferate to a stimulus which
      induces a proliferative response in T cells from younger individuals. This
      hypothesis seems both logical and reasonable and is supported by data from both
      humans and mice with the demonstration of an age-related accumulation of
      senescent T cells in both species. However, there is an apparent paradox. The
      paradox arises because the onset of immunosenescence appears to be more closely
      linked to the life span of the animal rather than the life span of the
      lymphocyte.

PMID- 10402959
TI  - The first pure embryonic inducing factor.
AB  - This is a personal account of the discovery of the mesoderm-inducing activity of
      fibroblast growth factors. The background is my work on the dorsalising signal in
      early amphibian embryos that was done at the imperial Cancer Research Fund in
      London. I became interested in mesoderm induction because of the embryologic work
      of Nieuwkoop and the partial purification of a "vegetalising factor" by
      Tiedemann. Although, initially, we expected inducing factors to be novel
      substances, it gradually became clear that the impure preparations we were
      studying had properties in common with growth factors. This opened the way to the
      testing of candidate factors, resulting in the conclusion that some inducing
      factors and growth factors,in fact, were the same molecules despite being
      discovered through different routes and assayed using different methods. After a
      slow start looking at the molecular biology of fibroblast growth factors in
      Xenopus, we eventually found that their most interesting functions in early
      development lay not at the stage of mesoderm induction but, rather, in the
      anteroposterior patterning of the body, which occurs during gastrulation.

PMID- 10402960
TI  - British Association of Urological Surgeons (BAUS) annual meeting. Glasgow, United
      Kingdom, 21-25 June 1999. Abstracts.

PMID- 10402961
TI  - Association of Surgeons of Great Britain and Ireland and Surgical Research
      Society joint meeting. Brighton, United Kingdom, 4-7 May 1999. Abstracts.

PMID- 10402962
TI  - [XIX Forum on Cancer. Paris, France, 30 May-1 June 1999. Abstracts].

PMID- 10402963
TI  - VIII Congress Spanish Association for Cancer Research (ASEICA), VII Congress
      Spanish Association for Medical Oncology (SEOM), I Joint meeting ASEICA-SEOM.
      Barcelona, Spain, 19-23 April 1999. Abstracts.

PMID- 10402964
TI  - 28th Annual meeting of the International Society for Experimental Hematology.
      Monte Carlo, Principality of Monaco, July 10-14, 1999. Abstracts.

PMID- 10402965
TI  - XIX International Symposium on Cerebral Blood Flow, Metabolism and Function, IV
      International Conference on Quantification of Brain Function with PET.
      Copenhagen, Denmark, June 13-17, 1999. Abstracts.

PMID- 10402966
TI  - Commercial sector partnerships for malaria control.

PMID- 10402967
TI  - Evidence for an association between hookworm infection and cognitive function in
      Indonesian school children.
AB  - The association between helminth infection and cognitive and motor function was
      investigated in school-age children in Java, Indonesia. 432 children from 42
      primary schools participated in the study. Children were stratified by age and
      sex into two age groups, 8-9 years and 11-13 years. Children infected with
      hookworm performed significantly worse than children without hookworm infection
      in 6 of the 14 cognitive or motor tests. After controlling for school (as a
      random effect) plus age, socio-economic status and parental education, sex,
      stunting (height-for-age < - 2sd), body mass index, haemoglobin concentration and
      the presence of A. lumbricoides and T. trichiura infections, infection with
      hookworm explained significantly lower scores on tests of Fluency (P < 0.01),
      Digit-Span Forwards (P < 0.01), Number Choice (P < 0.01), Picture Search (P <
      0.03), Stroop Colour Word (P < 0.02) and Mazes (P < 0.001). In 4 of the 6-tests
      (Fluency, Number Choice, Picture Search and Mazes), there was a significant
      interaction between hookworm infection and age (P < 0.03), indicating that the
      association between hookworm and lower test scores increased with age. No
      associations were observed between hookworm infection and scores in tests of
      Digit-Span Backwards, Corsi-Block, Stroop Colour, Stroop Interference, Free
      Recall, Verbal Analogies, Bead Threading or the Pegboard (P > 0.05). Tests
      associated with helminths represented various functions of working memory. No
      significant associations between helminth infection and motor function were
      observed that could not be explained by chance. The results suggest that hookworm
      infection can have a significant adverse effect on children's working memory
      which may have consequences for a child's reasoning ability and reading
      comprehension. Although the results are only associational, the fact that
      differences in cognition were observed at baseline imply that preventing
      infection with helminths in school-age children could be of benefit.

PMID- 10402968
TI  - Parameters associated with Schistosoma haematobium infection before and after
      chemotherapy in school children from two villages in the coast province of Kenya.
AB  - We evaluated the impact of praziquantel therapy (40 mg/kg body weight) on
      indicators of infection with Schistosoma haematobium by following a cohort of
      infected children from schools located 12 km apart in the Coast province of
      Kenya, at 0, 2, 4, 6, 12 and 18 months after treatment. Within this period,
      measurements of infection parameters pertaining to egg counts and haematuria
      (micro-, macro- and history) were evaluated at all time points. The initial
      prevalence of 100% dropped significantly 8 weeks after treatment with a similar
      trend in the intensity of infection. Microhaematuria followed the same trend as
      observed for egg counts while macrohaematuria remained low after treatment.
      Reinfection following successful therapy differed significantly between schools;
      in one school the children were reinfected immediately while those in the other
      remained uninfected despite similar starting prevalences, intensities of
      infection and cure rates. Transmission between the two areas looked homogeneous
      before treatment but when both groups were treated, contrasting transmission
      patterns became evident. In a regression model we evaluated factors that might be
      associated with reinfection, and after allowing for pretreatment infection level,
      age and sex, area (school) remained a highly significant predictor.

PMID- 10402969
TI  - Characterization of secretory acetylcholinesterase from Setaria cervi
      microfilariae: a potential antigen for diagnosis of human filariasis.
AB  - Acetylcholinesterase (AChE) is released to the external medium when microfilariae
      (m.f.) of Setaria cervi, a bovine filarial parasite, are maintained in vitro.
      Intense enzyme staining at amphids, excretory pores, anal vesicle and phasmids
      suggest an active secretion of AChE from m.f. Excretory-secretory products of
      m.f. displayed two electromorphic variants of AChE when resolved by 6%
      nondenaturing PAGE. The two isoforms of AChE (A and B) were separated on the
      basis of charge by DEAE sepharose CL 6B column following gel filtration. The two
      isoforms showed differing kinetic properties with respect to substrate
      specificity and inhibitor sensitivity. Anti-Nippostrongylus brasiliensis AChE
      antibodies cross-reacted with the affinity purified secretory AChE in ELISA.
      Immunoblotting of purified AChEs with cross-reacting anti-AChE antibodies
      revealed the presence of an approximately 75 kD protein in the isoenzyme A and an
      approximately 45 kD protein in B, whereas both proteins were present in the
      enzyme purified via affinity chromatography on edrophonium sepharose column.

PMID- 10402971
TI  - Distribution of fluoride and fluorosis in Ethiopia and prospects for control.
AB  - A review and mapping of fluoride test data for 270 water sources in 126
      communities and examination of the literature of fluorosis distribution in
      Ethiopia show that this health problem extends beyond the Rift Valley into some
      highland communities. Fluoride concentrations above 5.0 mg/l in the Rift Valley
      were found mostly in hot springs (100% of all sources), lakes (78%), shallow
      wells (54%) and boreholes (35%) and the lowest concentrations (below 1.5 mg/l) in
      springs and rivers. Analysis of hydrochemical, economic and demographic factors
      in the spatial distribution of high-fluoride domestic water sources indicates
      that the fluorosis problem has become more serious in the Rift Valley in recent
      decades. Considerable spatial variation in the occurrence of fluoride, even
      within the same communities, and the presence of some low-fluoride water sources
      in the Rift Valley offer possibilities for geochemical exploration for acceptable
      domestic sources. The defluoridation programme in the Wonji irrigation scheme
      illustrates the problems faced by a large rural community in a developing
      country. Possibilities for control are examined and recommendations made for the
      development of alternative water sources and promising defluoridation methods
      using locally available materials and technologies.

PMID- 10402970
TI  - The burden of mucocutaneous conditions and the association with HIV-1 infection
      in a rural community in Uganda.
AB  - OBJECTIVE: To determine the prevalence of mucocutaneous conditions and their
      association with HIV-1 infection in a rural community in Uganda. METHODS: In a
      prospective cohort study, participants were recruited from a large population
      study and invited to attend a clinic every 3 months for a detailed medical
      interview and a thorough physical examination. All findings including
      mucocutaneous findings were coded onto a standard questionnaire. RESULTS: By the
      end of 1996, 436 participants had provided 1450 person years of observation
      (pyo); 646 pyo in HIV-positives and 804 pyo in HIV-negatives. Overall, 70% of
      participants had a skin condition during follow-up, and although skin conditions
      were significantly more common in HIV-positive subjects, the background level in
      HIV-negative subjects was high (77.3% and 63.6%, respectively). Herpes zoster,
      thin/sparse hair, maculo-papular rash and prurigo were significantly more common
      in the HIV-positives. Kaposi sarcoma, palmar/plantar rash and herpes zoster had
      positive predictive values for HIV infection of over 80%. Oral conditions were
      found in over 40% of participants and were significantly more common in HIV
      positive subjects. Oral candidiasis and Kaposi sarcoma were significantly more
      frequent among HIV-positives. CONCLUSION: HIV infection increases the already
      high burden of mucocutaneous diseases in this rural population. We identified
      some conditions that are more common in HIV and others that can be used as
      indicators of HIV infection.

PMID- 10402972
TI  - Prevalence of GB virus C/hepatitis G virus among blood donors in north-eastern
      Brazil.
AB  - We tested 70 blood donors from Fortaleza (Ceara state, Brazil) for GB virus
      C/hepatitis G virus (GBV/HGV) infection by polymerase chain reaction and
      detection of antienvelope antibodies. Twenty-seven (38.6%) showed signs of an
      active or resolved infection. Sixty-four percent of those with indications of
      other blood-borne viral infections showed signs of GBV-C/HGV infection also.

PMID- 10402973
TI  - Evaluation of the SPf66 vaccine for malaria control when delivered through the
      EPI scheme in Tanzania.
AB  - BACKGROUND: Malaria control programmes need to protect young children, who bear
      the brunt of malaria disease and death in Africa. The development of a vaccine is
      a priority if improved and sustained malaria control is to be achieved. The best
      use of a vaccine in Africa will be achieved if it can be delivered through the
      expanded programme of immunization (EPI). We conducted a trial designed to
      evaluate the efficacy of SPf66 vaccine for malaria control when delivered through
      the EPI scheme in Tanzania. METHODS: The study was a two-arm, double blind,
      individually randomized placebo controlled trial involving 1207 infants. The
      primary objective of the trial was to estimate the efficacy of three doses of
      SPf66 given at 1, 2 and 7 months of age in preventing clinical episodes of
      malaria. These were documented through a health facility-based passive case
      detection system. RESULTS: Among 1207 randomized children, overall compliance for
      third dose was 91%. SPf66 was safe, immunogenic and did not interfere with the
      humoral immune responses to EPI vaccines. There were 294 children among SPf66
      recipients and 288 among placebo recipients with at least one malaria episode,
      yielding a vaccine efficacy estimate of 2% (95% CI: -16, 16; P = 0.84).
      CONCLUSION: This has been the first trial of a malaria vaccine among very young
      infants. It provides information on the safety of peptide vaccines administered
      at this early age as well as their capacity to induce immune responses without
      negatively interacting with EPI vaccines. Given the modest protection previously
      documented in older age groups and the lack of efficacy in younger infants, this
      vaccine in its current alum-based formulation does not appear to have a role in
      malaria control in sub-Saharan Africa. The lack of efficacy found in this trial
      also raises concerns about potential difficulties of inducing protective immune
      responses against malaria through immunization in infants.

PMID- 10402974
TI  - Safety in infants of SPf66, a synthetic malaria vaccine, delivered alongside the
      EPI.
AB  - The most likely mechanism to deliver a malaria vaccine in African countries is
      through the Expanded Program of Immunization (EPI). So far only SPf66, a
      multistage synthetic peptide, has shown any evidence of protection in Phase III
      field trials. In Tanzania, SPf66 reduced the risk of clinical malaria by 31% in
      children aged 1-5 years. In order to progress in the critical path of vaccine
      development and testing towards the implementation of a new vaccine in malaria
      control programs, we carried out a randomized double-blind placebo controlled
      efficacy trial of SPf66 when given alongside the EPI scheme. Monitoring of safety
      and reactogenicity during this trial included detailed clinical and laboratory
      assessments on 98 infants and assessment of adverse effects within 1 h of
      vaccination for all 1207 children vaccinated. Surveillance systems monitored
      attendances as outpatients, admissions to hospital and fatal events in the
      community. No serious adverse effects were detected more frequently amongst SPf66
      recipients compared to placebo. This first assessment in very young infants of a
      synthetic vaccine provides evidence of a good safety profile.

PMID- 10402975
TI  - Changing home treatment of childhood fevers by training shop keepers in rural
      Kenya.
AB  - BACKGROUND: Malaria control in Africa relies primarily on early effective
      treatment for clinical disease, but most early treatments for fever occur through
      self-medication with shop-bought drugs. Lack of information to community members
      on over-the-counter drug use has led to widespread ineffective treatment of
      fevers, increased risks of drug toxicity and accelerating drug resistance. We
      examined the feasibility and measured the likely impact of training shop keepers
      in rural Africa on community drug use. METHODS: In a rural area of coastal Kenya,
      we implemented a shop keeper training programme in 23 shops serving a population
      of approximately 3500, based on formative research within the community. We
      evaluated the training by measuring changes in the proportions of drug sales
      where an adequate amount of chloroquine was purchased and in the percentage of
      home-treated childhood fevers given an adequate amount of chloroquine. The
      programme was assessed qualitatively in the community following the shop keeper
      training. RESULTS: The percentage of drug sales for children with fever which
      included an antimalarial drug rose from 34.3% (95% CI 28.9%-40.1%) before the
      training to a minimum of 79.3% (95% CI 71.8%-85.3%) after the training. The
      percentage of antimalarial drug sales where an adequate amount of drug was
      purchased rose from 31.8% (95% CI 26.6%-37.6%) to a minimum of 82.9% (95% CI
      76.3%-87.3%). The percentage of childhood fevers where an adequate dose of
      chloroquine was given to the child rose from 3.7% (95% CI 1.2%-9.7%) before the
      training to a minimum of 65.2% (95% CI 57.7%-72.0%) afterwards, which represents
      an increase in the appropriate use of over-the-counter chloroquine by at least
      62% (95% CI 53.7%-69.3%). Shop keepers and community members were strongly
      supportive of the aims and outcome of the programme. CONCLUSIONS: The large
      shifts in behaviour observed indicate that the approach of training shop keepers
      as a channel for information to the community is both feasible and likely to have
      a significant impact. Whilst some of the impact seen may be attributable to
      research effects in a relatively small scale pilot study, the magnitude of the
      changes support further investigation into this approach as a potentially
      important new strategy in malaria control.

PMID- 10402976
TI  - Renal involvement in Gambian children with cerebral or mild malaria.
AB  - Kidney function was studied in 80 Gambian children with cerebral malaria, 73
      children with mild malaria, and in 19 children with other febrile illnesses.
      Serum creatinine was measured, and the excretion in urine of immunoglobulin G,
      transferrin, albumin and alpha 1 microglobulin was determined. Twenty-five
      percent of children with cerebral malaria, and 4% of children with mild malaria
      had an elevated serum creatinine above 62 mumol/l. Increased urinary protein
      excretion was frequent: 53% of children with cerebral malaria had a glomerulo
      tubular pattern of protein excretion, and 46% a tubular pattern. Median
      albuminuria was 68 mg/l in children with cerebral malaria, 18 mg/l in children
      with mild malaria, and 9 mg/l in febrile children with other diseases (P <
      0.0001). There was no significant association between the proteinuria and height
      of fever or the degree of parasitaemia, and there was no significant association
      between death and signs of renal impairment. Renal involvement is common in
      children with malaria in The Gambia, with prerenal, glomerular, and tubulo
      interstitial factors contributing. It is more pronounced in children with
      cerebral malaria than in those with mild malaria. However, renal dysfunction is
      relatively mild and does not indicate a worse prognosis.

PMID- 10402977
TI  - Latent class analysis permits unbiased estimates of the validity of DAT for the
      diagnosis of visceral leishmaniasis.
AB  - BACKGROUND: Substantial uncertainty surrounds the specificity of the Direct
      Agglutination Test (DAT) for visceral leishmaniasis (VL) in clinical suspects,
      since no good gold standard exists for unequivocally identifying diseased
      subjects. We explored the Latent Class Analysis (LCA) modelling technique to
      circumvent this problem. PATIENTS AND METHODS: Data on 149 clinical suspects
      recruited in 1993-96 during a multicentre study in Sudan were re-examined.
      Clinical data, lymph node and bone marrow aspirate and DAT results were
      available. IFAT was performed in 1997 on stored filter paper blood of 80
      individuals. Classical Validity Analysis (CVA) in a 2 x 2 contingency table with
      parasitology as a gold standard was compared with the parameter estimates
      produced by the best fitting LCA model. RESULTS: The sensitivity estimates of DAT
      produced by CVA (98% (89%-100%)) were almost exactly reproduced by LCA. The
      specificity estimates by LCA were substantially higher than those obtained in
      CVA. Specificity of DAT depended, however, on whether the subject was treated for
      VL before. In subjects without prior treatment, CVA estimated DAT specificity at
      68% (56%-79%), whereas LCA estimated it at 85% (63%-100%). CONCLUSION: LCA
      modelling proved a useful tool, as it gave consistent estimates of test
      characteristics and allowed for control of confounding factors and interaction
      effects. Since VL is a life-threatening disease for which expensive but effective
      and safe treatment exists, a clinical suspect in an endemic area should be
      treated on the basis of a positive DAT result.

PMID- 10402978
TI  - Viewpoint: management of malaria--working with the private sector.
AB  - Recent reviews have demonstrated that a substantial proportion of cases of
      malaria are managed in the private sector, and international policy initiatives
      routinely emphasize the need for malaria control programmes to collaborate with
      the private sector. However, information on how to develop successful
      partnerships between the public and private sectors remains limited. This paper
      reviews the current knowledge about the management of malaria by private
      providers, considers the potential of different strategies for influencing the
      quality of care provided, and identifies processes for facilitating public
      private sector collaborations. We contend that public sector-led interventions,
      such as training of private providers or the distribution of prepackaged
      antimalarials through the private sector, are unlikely to scale up to sustainable
      national level programmes if they do not take into account a wide range of needs
      and concerns, represented by private provider organizations and other interest
      groups, including service users. These groups should be involved at key stages
      including the design and piloting of interventions, through to the dissemination
      and implementation of findings. Research priorities are outlined for the
      development of tools to facilitate public-private partnerships for improving the
      management of malaria.

PMID- 10402979
TI  - Short course of azithromycin/artesunate against falciparum malaria: no full
      protection against recrudescence.

PMID- 10402980
TI  - Parotid selective lymphadenectomy in malignant melanoma.
AB  - Malignant melanoma of the head and neck can metastasize to lymph nodes within the
      parotid gland. Selective lymphadenectomy is the modern method of staging regional
      lymph node basins in clinically localized melanoma. This procedure involves
      intraoperative lymphatic mapping and directed, selective removal of the first
      draining nodes or sentinel lymph nodes (SLNs). Historically, the assessment of
      parotid lymph nodes would involve a superficial parotidectomy with facial nerve
      dissection. Since 1993, 28 patients with localized melanoma of the head and neck
      have demonstrated lymphatic drainage to parotid lymph nodes on preoperative
      lymphoscintigraphy. The overall success rate of parotid selective lymphadenectomy
      is 86% (24 of 28 patients). Of the 28 patients, there were 6 early patients in
      whom blue dye alone was utilized intraoperatively, and the success rate is 50% (3
      of 6 patients). When blue dye and radiocolloid mapping techniques are combined,
      the parotid selective lymphadenectomy is successful in 95% of patients (21 of 22
      patients). Four of the 24 patients (17%) had metastases to the SLNs and underwent
      therapeutic superficial parotidectomy and/or modified radical neck dissection.
      After completion of the therapeutic superficial parotidectomy, 1 of the 4
      patients was found to have an additional parotid (nonsentinel) node with melanoma
      metastases. None of the patients incurred injury to the facial nerve by parotid
      selective lymphadenectomy. To date, 2 of 28 patients (7%) have had regional
      recurrence to the parotid gland. Failure of the SLN technique may occur when blue
      dye alone is used, when human serum albumin (not sulfur colloid) is the
      radiocolloid, when prior wide excision and skin graft is present before lymphatic
      mapping, and when all SLNs are not retrieved. We conclude that parotid selective
      lymphadenectomy is a safe and reliable alternative to superficial parotidectomy
      for staging clinically localized melanoma of the head and neck.

PMID- 10402981
TI  - Clinical experience with the lateral thoracodorsal flap in breast reconstruction.
AB  - The lateral thoracodorsal flap is a local fasciocutaneous flap used for breast
      reconstruction. From 1986 to 1994 the authors used this flap in 157 breast
      reconstructions in 152 patients. The patients who had been treated with
      postmastectomy radiotherapy (N = 40) had significantly more (p < 0.01) early
      complications, such as necrosis and infection. Irradiated patients also required
      more operations due to secondary complications, such as capsular contracture (p <
      0.05). A patient questionnaire (response rate, 91%) was sent to 121 patients and
      showed that, although a majority of patients felt the reconstructed breast was
      less sensitive to touch and harder than the contralateral breast, they still
      regarded the reconstructed breast as a natural part of themselves. More than 90%
      of patients did not regret the reconstruction and 80% would recommend it to a
      friend.

PMID- 10402982
TI  - Reverse neurofasciocutaneous flaps for soft-tissue coverage of the lower leg.
AB  - The evolution of neurocutaneous flaps has created a new concept in reconstructive
      surgery. These flaps, based on the arterial network around the superficial
      sensory nerves, are gaining popularity in soft-tissue coverage. Various flaps can
      be planned based on the neurocutaneous perforators. These kinds of flaps are
      available for extremity reconstruction. In the lower leg, reverse neurocutaneous
      flaps have been used successfully. Although these flaps in the lower leg are
      called neurocutaneous, they have been elevated with the underlying fascia like
      fasciocutaneous flaps, and thus the authors call these flaps neurofasciocutaneous
      flaps. They have used 11 reverse neurofasciocutaneous flaps (6 saphenous and 5
      sural) since 1995. All flaps survived completely, and stable coverage of soft
      tissue defects of the lower leg was achieved in all patients.

PMID- 10402983
TI  - Repair of high-energy-induced tissue defects of the dorsal foot by free muscle
      transfer and skin graft.
AB  - Various alternative methods have been used for repair of extensive dorsal foot
      defects due to high-energy-induced injuries. The authors reconstructed such
      defects with free muscle transfers and skin grafts in 9 male patients (average
      age, 21.7 years) between the years 1995 and 1998. Patients (right foot, 5; left
      foot, 4) presented with injuries due to military rifle gunshot (N = 4), mine
      explosion (N = 2), high-voltage electricity (N = 2), and traffic accident (N =
      1). The patient injured in a traffic accident was treated with skin grafting
      only, and experienced osteomyelitis and skin breakdown. The other 8 patients were
      injured acutely and were hospitalized within 3 weeks of injury. After serial
      debridement of necrotic tissues, surgery was performed at an average of 6 weeks
      postinjury. Metatarsal bone defects of 5 cm in 3 patients were repaired by iliac
      (N = 2) and fibular (N = 1) bone grafts. Free muscle latissimus dorsi (N = 4) and
      rectus abdominis (N = 5) flaps were transferred microsurgically. The transferred
      muscle flaps were covered with split-thickness skin grafts. Mean operation
      duration was 5 hours 12 minutes. All flaps survived. The average area of soft
      tissue defect repaired was 93 cm2 (range, 36-231 cm2). Average follow-up was 25
      months. No symptoms of osteomyelitis and skin breakdown were encountered in the 8
      acutely injured patients. Monofilament sensory tests revealed diminished
      protective sensation in 5 patients and absence of protective sensation in 4
      patients. Partial resorption of bone grafts occurred in 2 patients. Thinning of
      the flaps was performed by tangential excision in 2 patients whose muscle flaps
      did not diminish in thickness. All patients were able to wear normal shoes. The
      authors suggest the use of free muscle transfer in reconstructing extensive soft
      tissue defects of the dorsal foot.

PMID- 10402985
TI  - Breast reconstruction in ectodermal dysplasia.
AB  - Patients with ectodermal dysplasia may request breast reconstruction. In addition
      to abnormalities of other ectodermally derived structures, the breast and nipple
      areolar complex may be absent or hypoplastic. Although this group of patients may
      have concerns with hair, nails, teeth, or even upper limb malformations, this
      report focuses on reconstruction of the breast anomalies. Four unrelated patients
      with ectodermal dysplasia who have undergone breast reconstruction are discussed.

PMID- 10402984
TI  - Risk factors for predicting surgical salvage of sternal wound-healing
      complications.
AB  - A retrospective study was performed to determine whether clinical factors can
      predict which complicated poststernotomy wounds can be managed successfully by
      debridement and reclosure, and which wounds require a muscle flap for healing.
      Between January 1990 and December 1996, 3,435 median sternotomies were performed
      at Indiana University Medical Center and affiliated hospitals. A total of 91
      patients (2.6%) were reoperated for sternal wound-healing complications. Seventy
      six patients (83.5%) underwent debridement and rewiring, and 15 patients (16.5%)
      underwent primary flap coverage. Of the 76 patients who underwent initial
      rewiring, 45 (59%) healed and 31 (41%) required additional operative procedures.
      Of the 31 rewiring failures, 26 patients (84%) were healed with muscle flaps and
      4 patients (13%) were managed with a second successful rewiring. The following
      clinical factors were correlated with operative procedure and outcome: history of
      smoking, chronic obstructive pulmonary disease, steroid use, previous sternotomy,
      age, diabetes, harvest of the left or right internal mammary artery (IMA),
      emergency operation, operation time, pump time, cross-clamp time, ischemic time,
      coronary artery bypass grafting alone versus combined with a valve replacement,
      positive wound cultures, positive blood cultures, elevated white blood cell
      count, and fever. When comparing patients with successful rewiring with those who
      had a failed rewiring, positive wound and blood cultures were significant risk
      factors (p < 0.05) on univariate analysis. Presence of a positive wound culture
      was significant on multivariate analysis. When comparing risk factors in patients
      who were rewired successfully versus all patients who had muscle flap coverage,
      the presence of a positive blood culture was significant on both univariate and
      multivariate analyses. We conclude patients most likely to fail rewiring and to
      require muscle flap closure are those with infected wounds, positive blood
      cultures, and possibly left IMA bypasses.

PMID- 10402986
TI  - Use of fascial grafts as an interface in flap prefabrication: an experimental
      study.
AB  - An experimental study was conducted to investigate whether a fascial graft can be
      used as an interface between a vascular pedicle and target tissue to augment
      tissue survival in a prefabricated flap. Thirty-six male Sprague-Dawley rats were
      divided into three experimental groups according to the type of the recipient bed
      prepared for the vascular implantation. The left saphenous vascular pedicle was
      used as the vascular source. A 9 x 9-cm inferiorly based peninsular abdominal
      flap was elevated in each animal. In group I, the pedicle was tacked beneath the
      abdominal flap, in which the epigastric fascial layer was untouched. In group II,
      a 3 x 5-cm graft of epigastric fascia was harvested from the abdominal flaps
      under loupe magnification. The graft was sutured back into its original position
      after a 180-deg rotation. The vascular pedicle was then implanted just beneath
      the center of the fascial graft. In group III, the same size of epigastric fascia
      was removed in the same manner as group II, exposing the subcutaneous layer for
      pedicle implantation. Four weeks later, abdominal flaps were raised as island
      flaps connected only to the saphenous pedicle and were sutured in place. Flap
      viability was assessed visually on day 7. Overall, the ultimate flap survival in
      group I was the largest, with some necrotic areas at the periphery of the flaps.
      In group II, flap survival was typically centralized over the fascial graft, and
      crescent-shaped necrosis was noted superiorly. In group III, an almost linear
      pattern of survival overlying the vascular pedicle was observed. The mean
      surviving flap area of group I (12.13 +/- 1.615 cm2) was statistically greater
      than that of group II (8.83 +/- 0.663 cm2, p < 0.001) and group III (6.3 +/-
      0.815 cm2; p < 0.001). There was a statistically significant difference between
      the mean flap survival in groups II and III (p < 0.001). Vascular arborization
      was examined by microangiography, and specimens were processed for histological
      staining. In group II, vascularization was distributed in a larger area along the
      fascial graft in comparison with limited vascularization around the pedicle in
      group III. In this study it was revealed that the interposition of a fascial
      graft as an interface between the vascular source and the target tissue seems to
      increase the size of the prefabricated flap.

PMID- 10402987
TI  - The ultrastructure and resorptive pattern of cancellous onlay bone grafts in the
      craniofacial skeleton.
AB  - The authors' laboratory has shown cancellous onlay bone grafts to resorb faster
      than cortical grafts. To understand the nature of cancellous bone grafts beyond
      volumetric measurements, a temporal analysis of the internal microarchitecture of
      these grafts was performed. Their hypothesis is that the forces of remodeling and
      resorption cause cancellous onlay bone grafts to develop a denser, more
      interconnected, and a more mechanically stable microarchitecture. Twenty-five
      adult New Zealand White rabbits were used in this study and were divided into
      three groups. Microcomputed tomography (MCT) was performed on all cancellous bone
      grafts to obtain detailed information regarding the microarchitecture of the
      cancellous bone. Bone graft specimens were examined histologically, and
      histomorphometric analysis was also performed. Their results show that cancellous
      onlay bone grafts develop a higher bone volume fraction, mean trabecular
      thickness, connectivity, and degree of anisotropy. Furthermore, cancellous onlay
      bone grafts developed a lower bone surface area-to-volume ratio and mean
      trabecular separation. The unique combination of MCT technology and
      histomorphometric techniques proved to be effective in providing a qualitative
      and quantitative ultrastructural analysis of cancellous onlay bone grafts over
      time. The authors were able to show changes in the internal microarchitecture of
      cancellous onlay bone grafts as they were remodeled and resorbed. Specifically,
      they found the cancellous onlay bone grafts to develop a more dense, less
      trabecular, more organized, and more interconnected internal ultrastructure over
      time. Their findings have helped to provide a reproducible description of the
      temporal sequence of changes in bone microarchitecture, revascularization, and
      internal remodeling.

PMID- 10402988
TI  - Microcirculatory response to halothane and isoflurane anesthesia.
AB  - Microcirculatory hemodynamics are often used to monitor tissue and organ
      survival. This study investigated the effect of halothane and isoflurane
      anesthesia on peripheral microcirculation using the cremaster muscle during
      intravital microscopy. Twenty-three Sprague-Dawley rats were studied in four
      groups. Two groups served as controls and did not undergo flap isolation but did
      receive halothane (N = 6) or isoflurane (N = 5). After induction with a single
      dose of intraperitoneal pentobarbital (40 mg per kilogram), rats were ventilated
      with either 2 minimum alveolar concentration (MAC) halothane or 2 MAC isoflurane.
      Esophageal temperature, electrocardiography, central venous pressure, mean
      arterial pressure, and blood gases were measured over 4 hours. In groups
      receiving surgery with either halothane (N = 6) or isoflurane (N = 6), the
      cremaster muscle was isolated on the neurovascular pedicle. Microcirculatory
      responses to both halothane and isoflurane anesthesia were evaluated by measuring
      red blood cell (RBC) velocity, vascular diameters in arterioles (A1, A2-1, A2-2,
      and A3) and the main venule (V1), functional capillary perfusion, and leukocytic
      endothelial interactions in postcapillary venules (rolling, adherent, and
      transmigrating leukocytes). Hemodynamic variables were compared among all four
      groups, and microcirculatory variables were compared between the two surgical
      groups. During isoflurane anesthesia in animals with flaps, significantly higher
      (p < 0.05) RBC velocities were recorded in arterioles A1 (24.4%), A2-2 (28.2%),
      and A3 (17.4%). Capillary perfusion was significantly higher in animals with
      flaps and halothane anesthesia (17.8%; p < 0.05). The number of rolling
      leukocytes (39.4%) was significantly higher during isoflurane anesthesia in
      animals with flaps (p < 0.05). Better flow hemodynamics in the peripheral
      microcirculation were seen during halothane anesthesia, and were confirmed by
      greater functional capillary perfusion and fewer activated leukocytes. In the
      isoflurane group, RBC velocity alone cannot serve as an indicator of
      microcirculatory function.

PMID- 10402989
TI  - Investigation of metabolism and perfusion in arterialized venous replantation:
      experimental study in rabbits.
AB  - Replantation of amputated digits at distal levels is difficult because the
      vessels are either too small or absent in the amputated part. Clinically
      unconventional anastomoses have been tried in such instances. Arterialization of
      the venous system in the amputated part was also utilized for this purpose. In
      this study, a digital replantation model utilizing the amputated rabbit ear was
      used to evaluate the survival, metabolism, and perfusion of unconventionally
      replanted parts. Mean survival areas were measured and perfusion studies with
      technetium 99m, blood gases, pH, blood glucose and lactate levels, tissue glucose
      and lactate levels, and histological evaluations were performed. Surviving areas
      did not reveal a significant difference. Perfusion of the arterialized venous
      replants were not as good as the conventionally replanted ears. The blood glucose
      and lactate levels in the afferent vein were initially near normal arterial
      levels but almost reached normal venous levels in the samples taken 24 hours
      after the arterialized venous replantation. Tissue glucose levels were lower than
      the conventionally perfused tissue, and the lactate levels were higher, but these
      two metabolite levels were normalized in later samples. The results of the
      metabolic and perfusion studies are interpreted to elucidate the survival
      mechanisms in the arterialized venous replants. As a result, arterialized venous
      replantation may be supported by the favorable results of metabolic and perfusion
      studies in our experimental model.

PMID- 10402990
TI  - Prenatal pressure necrosis of the scalp.
AB  - A case of full-thickness pressure necrosis of the scalp in a newborn is reported.
      This is a rare injury, with only four similar prior reports found in the
      literature. The presumed mechanism of injury is pressure of the infant's head
      against the mother's bony pelvis. A spectrum of injury can be seen, from
      temporary alopecia to complete scalp necrosis. Risk factors include prolonged
      ruptured membranes and prolonged labor.

PMID- 10402991
TI  - Serratus anterior free fascial flap for dorsal hand coverage.
AB  - Reconstruction of the dorsal surface of hand defects requires thin, pliable, well
      vascularized tissue with a gliding surface for the extensor tendon course.
      Fasciocutaneous or fascial flaps are the two surgical options. Fascial flaps
      present the advantages of thinness and low donor site morbidity. The authors
      present 4 cases of serratus anterior free fascial flap (SAFFF) used to cover the
      dorsum of the hand. The SAFFF with skin graft has many advantages for a fascial
      flap: long, constant vascular pedicle; very thin, well-vascularized tissue; low
      donor site morbidity; and the possibility of simultaneous donor and recipient
      site dissection. Furthermore, it can be associated with other flaps of the
      subscapular system for complex reconstructions. Of the 4 observations described,
      2 used associated flaps, 1 used the SAFFF with a latissimus dorsi flap, and 1
      used a scapular bone flap with the SAFFF. One flap was lost due to an electrical
      lesion to the forearm vessels.

PMID- 10402992
TI  - Free jejunal patch to reconstruct oral scar contracture following caustic
      ingestion.
AB  - Reconstruction of oral scar contracture is often a challenging problem due to the
      complex structures and functions of the oral cavity. This report describes the
      treatment of a patient who sustained extensive oral scar contracture following
      caustic liquid soda ingestion. Surgical release of the scar contracture formed an
      S-shaped, thin, long defect that was difficult to cover with a conventional flap
      or skin graft. A jejunal segment was transferred microsurgically as a patch to
      reconstruct the defect. It sustained a sufficient oral space to provide full
      opening of the mouth and good movement of the tongue. A free jejunal flap, used
      occasionally for reconstruction following oral cancer resection, has significant
      advantages for restoration of function after release of an oral scar contracture.

PMID- 10402993
TI  - A simple distraction device for finger lengthening.
AB  - A simple, light distraction device was developed for digital lengthening.
      Materials for this device are one piece of 1.5-mm K-wire, two five-hole
      miniplates, one one-hole miniplate, two bolts and nuts, and a nonabsorbable
      suture or surgical wire. These components are easily obtainable, and the device
      can be assembled easily for each patient during surgery. The principle of
      distraction using this device is unique: A distal bone segment is pulled straight
      forward by a suture or surgical wire. This minimizes scar formation on the
      finger. Finger elongation using commercially available distraction devices needs
      two transfixations of K-wires, two each for the proximal and distal bone
      segments, which create scars where the K-wires move. The authors report a
      clinical application in which their distraction device was used.

PMID- 10402994
TI  - A safe and rapid technique for modified neck dissection.
AB  - The technique of modified neck dissection presented here, by the very limited
      anatomic area it addresses of necessity shares aspects of techniques described by
      other authors. Developed over many years of teaching residents, it provides, if
      carefully followed, a simple, safe, and relatively rapid method of carrying out
      the procedure, having been used by the senior author and his residents in scores
      of patients both at our institution and in many overseas operations under rather
      primitive conditions without modification. It is not a new way of doing the
      procedure, but rather a combination of some of the simplest approaches and
      aspects which may be especially helpful to those without wide experience.

PMID- 10402995
TI  - Once is enough.

PMID- 10402996
TI  - The life span of silicone gel breast implants and a comparison of mammography,
      ultrasonography, and magnetic resonance imaging in detecting implant rupture: a
      meta-analysis.

PMID- 10402997
TI  - Re: The life span of silicone gel breast implants and a comparison of
      mammography, ultrasonography, and magnetic resonance imaging in detecting implant
      rupture: a meta-analysis.

PMID- 10402998
TI  - A case of lipoma associated with a supernumerary nipple-areola complex.

PMID- 10402999
TI  - A new method to facilitate skin graft harvest with minimal assistance.

PMID- 10403000
TI  - Use of a vein graft as a tendon sheath substitute following tendon repair: an
      innovative technique in tendon surgery.

PMID- 10403001
TI  - X-shaped meatoplasty and uretheral advancement for distal hypospadias treatment.

PMID- 10403002
TI  - Fomes pectinatis: an aeroallergen in India.
AB  - This work is focused on the aerobiology and allergenicity of Fomes pectinatis in
      India. The atmospheric concentration of Fomes basidiospores was recorded and the
      antigens were prepared from spore (FSE) and whole body (FWBE) materials. The
      intradermal (ID) and prick (PT) skin tests were conducted on 172 patients having
      respiratory allergy. The period from July to October has been recorded as having
      a higher concentration of Fomes spores. The maximum counts (67 spores/m3) were
      observed from the North Delhi site in the month of July, 1989, compared with 550
      spores/m3 in the South Delhi site. Marked skin positivity (2+ and above) varied
      from 9.8% to FSE to 22% to FWBE. Nine out of twelve ID positive patients (2+ to
      3+) to FSE also gave PT positive response. For FWBE, similar ID and PT response
      was obtained in 80% of cases. The soluble protein content of FSE was 0.37 mg/ml,
      whereas, for FWBE it was 0.70 mg/ml. It was observed through ELISA that almost
      all patients had significantly raised FP specific IgE levels in their sera. The
      current study, therefore, indicates that Fomes pectinatis may be a prevalent
      aeroallergen in India.

PMID- 10403003
TI  - Prevalence of allergic sensitization to regional inhalants among allergic
      patients in Jakarta, Indonesia.
AB  - Sensitization towards a panel of eight regional inhalant allergens was evaluated
      among 107 patients with allergic rhinitis and/or asthma. A total of 32 children
      (age 5-13 years, mean 9 years; 18 male, 14 female), 75 adolescents and adults
      (aged 14-66 years, mean 32 years; 21 male, 54 female) and 20 normal control
      volunteers (aged 16-46, mean 30 years; 4 male, 16 female) were evaluated via skin
      prick test. A weal response of 3 x 3 mm or greater was taken to be positive. The
      sensitization rates among individuals to these allergens were: house dust mites,
      Dermatophagoides pteronyssinus (77.57%), Blomia tropicalis (71.96%),
      Austroglycyphagus malaysiensis (33.64%), pollen, palm oil Elaeis guineensis
      (22.43%), Acacia auriculiformis (12.15%), fern spore, resam Dicranopteris spp
      (11.21%), fungal spores: Curvularia fallax (8.41%) and Exserohilum rostratum
      (13.08%). There were significantly higher frequencies of sensitization to these
      allergens among allergic individuals compared to normal controls, and among
      atopic individuals with two allergy manifestations (rhinitis and asthma) compared
      to those with only one. No difference was noted between children and adults in
      the allergic group. In conclusion, the allergic patients were highly sensitized
      to dust mites and sensitization to regional pollen and spores was also
      documented. They should be considered as relevant and be included in skin test
      batteries in Indonesia.

PMID- 10403004
TI  - Role of allergy in nasal polyps of Thai patients.
AB  - As distinct from many countries, allergy in Thailand is of the perennial type
      which may play a role in the formation of nasal polyps. Forty consecutive
      patients with nasal polyps and 30 normal subjects as control were studied at the
      Allergy Clinic, Department of Otolaryngology, Pramongkutklao Hospital. A positive
      clinical history and skin allergy testing are diagnostic criteria for allergy. In
      the nasal polyps group, these were 28 males and 12 females, aged between 12-65
      years, with an average age of 38.5 years. In the control group, there were 18
      males and 12 females, aged between 15-53 yeas, with an average age of 34 years.
      All had received prick skin testing with 6 common aeroallergens. The prick skin
      test was considered positive when the wheal was > or = 3 mm with surrounding
      erythema. Twenty-four of 40 patients (60%) with nasal polyps had a positive prick
      skin test, while 6 in the 30 control cases (20%) had a positive prick skin test.
      This difference was statistically significant (P = 0.0019), Odd's ratio = 6.0
      which means allergic persons were 6 times more prone to have polyps form than
      normal persons.

PMID- 10403005
TI  - Immunophenotyping of acute lymphoblastic leukemia in pediatric patients by three
      color flow cytometric analysis.
AB  - Immunophenotyping of acute lymphoblastic leukemia (ALL) in children using three
      color flow cytometry was carried out at Chulalongkorn Hospital, Bangkok,
      Thailand. Of 38 patients with acute lymphoblastic leukemia, 65.8% were identified
      as common ALL, 15.8% were B-ALL, and 18.4% were T-ALL. Of these 38 cases, there
      were 4 cases of infantile leukemia. Relapsed cases of leukemia were found most in
      B-ALL up to 3 out of 6 cases and to a lesser extent in T-ALL (1 of 7 cases) and c
      ALL (1 of 25 cases). Our data showed the CD markers expression for common ALL (c
      ALL) were CD19+/10+ (100%), CD20+ (24%), CD22+ (100%), HLA-DR+ (70.1%), and CD34+
      (58.8%). CD markers expression for B-ALL were CD19+ (100%), CD20+ (33.3%), CD22+
      (80%), and HLA-DR+ (80%). CD markers expression for T-ALL were CD3+ (42.9%), CD5+
      (100%), CD7+ (85.7%). Myeloid aberrant expressions were found in c-ALL (25
      37.5%), B-ALL (20%), and T-ALL (14.3%). The significance of the aberration is
      discussed. The immunophenotyping classification of ALL as c-ALL, B-ALL, and T-ALL
      is useful in prognosis and treatment.

PMID- 10403006
TI  - Antiparasite adherence activity in Thai individuals living in a P. falciparum
      endemic area.
AB  - Two types of antimalaria antibodies in the serum of 54 villagers living in a
      malaria endemic area of Thailand were determined by indirect immunofluorescence
      assay in order to define the status of malaria immunity within the group.
      Antibodies to parasite-derived antigens in the membrane of ring stage-infected
      erythrocytes were very high (> or = 1:1,250) in 44%, moderate to low (< or =
      1:250) in 37% of the sera, and the rest did not have the antibody. However, all
      the sera had antibodies to antigens of the intraerythrocytic mature parasites,
      showing a very high level in 65% and moderate to low levels in 37% of the sera.
      Sera with high antibody titers to either type of antigen significantly inhibited
      cytoadherence of P. falciparum-infected erythrocytes. All the sera variably
      inhibited rosette formation of the parasites but showed no association with the
      antibody titers. These results suggest that the antibodies to cytoadherence and
      rosette formation can be elicited and sustained in the malaria experienced host
      while living in the endemic area. This may be a natural preventive mechanism
      against the severity of P. falciparum infection in the infected host. How long
      the antiparasite adherence activity will last remains to be investigated.

PMID- 10403007
TI  - Characterization of a phase 1-d epitope on Salmonella typhi flagellin and its
      role in the serodiagnosis of typhoid fever.
AB  - A monoclonal antibody (MAb) directed against Salmonella typhi 52 kDa flagellin
      protein has been previously produced by our group. In this study, we have
      demonstrated that the epitope specific to the MAb is unique to phase 1-d. To map
      the epitope, plasmids encoding different regions of S. typhi flagellin gene were
      constructed. Analysis of protein produced from each recombinant plasmid indicated
      that the epitope specific to the MAb resided within amino acids 171-303 (region
      IV) of S. typhi flagellin protein. The recombinant region IV flagellin was used
      to develop an ELISA for the detection of IgM antibody to S. typhi in serum. In
      the hemoculture-positive typhoid group, the developed ELISA was positive in 77 of
      92 cases. In patients with non-typhoidal Salmonella, gram-positive and gram
      negative bacteria or dengue virus, the ELISA was negative in all 78 cases. Two
      from 116 healthy control subjects had positive reactions with the assay. The
      calculated sensitivity, specificity, positive and negative predictive values of
      the test were 83.7%, 99.0%, 97.5% and 92.8%, respectively. With such high
      validity together with the requirement of only a single serum specimen and one
      day for performing the test, the developed ELISA should become a valuable
      diagnostic test for typhoid fever.

PMID- 10403008
TI  - Detection of Salmonella contamination in food samples by dot-ELISA, DNA
      amplification and bacterial culture.
AB  - A dot-blot enzyme-linked immunosorbent assay (dot-ELISA) employing a genus
      Salmonella specific monoclonal antibody (MAb) was used for detection of the
      bacteria in food samples in comparison with the conventional culture method and
      the DNA amplification. Among the 200 chicken and pork samples (100 each) tested,
      9% and 33%, 7% and 20% and 7 and 23% were positive for salmonellae by the dot
      ELISA, the culture method and the DNA amplification, respectively. Statistical
      analyses revealed that the sensitivity, specificity, efficacy, and positive and
      negative predictive values of the detection of Salmonella in the food samples by
      dot-ELISA compared with the culture method were 93.33%, 91.76%, 92%, 66.66% and
      98.73%, respectively. Comparison of the DNA amplification and the culture method
      revealed the sensitivity, specificity, efficacy, and positive and negative
      predictive values of 100%, 91.58%, 92%, 65.21% and 100%, respectively. The dot
      ELISA and the DNA amplification results were in a better agreement when the two
      assays were compared. The sensitivity, specificity, efficacy, positive and
      negative predictive values of the dot-ELISA compared to the DNA amplification
      were 91.3%, 100%, 98%, 100% and 97.5%, respectively. From this study, the dot
      ELISA is rapid, simple, sensitive, specific at low cost with limited amount of
      infectious waste to be disposed and offers another advantage in that it detects
      only the smooth LPS of Salmonella which implies the possible presence of the
      virulent organisms.

PMID- 10403009
TI  - Identification of circulating antibodies in fasciolosis and localization of 66
      kDa antigenic target using monoclonal antibodies.
AB  - We identified three specific circulating antibodies in serum of cattle naturally
      infected with Fasciola gigantica. Two of the antibodies were found to react
      specifically to 97 and 66 kDa antigenic molecules of adult worm tegumental
      membrane extract. The third antibody was identified by the reaction with 26-28
      kDa molecule of the excretory/secretory antigens. Monoclonal antibody against 66
      kDa protein was developed and used for localization of its antigenic target in
      adult worm frozen sections. The experiment demonstrated that 66 kDa protein is a
      component on the outer surface membrane and on the membrane lining of the caecal
      epithelial of adult worm. The 66 kDa antigen was considered as a promising
      candidate for immunodiagnosis and vaccine.

PMID- 10403010
TI  - Effect of IVIG on the hair regrowth in a common variable immune deficiency
      patient with alopecia universalis.
AB  - Common variable immune deficiency (CVID) is associated with a variety of
      autoimmune diseases. Alopecia universalis (AU), believed to have an autoimmune
      basis, has been found in 1.6% of patients with CVID. Intravenous immunoglobulin
      (IVIG) therapy is used in various immunodeficiency disorders including CVID, and
      benefit has been shown in the therapy of autoimmune diseases. We report a patient
      with CVID and AU treated with IVIG who experienced significant hair regrowth. An
      8-year-old girl with CVID and AU was treated with IVIG 400 mg/kg every 4 weeks.
      Since her second dose of IVIG, regrowth of eyelashes, eyebrows, body and scalp
      hair was observed in this patient. At present, about 1 year treat-meant of IVIG,
      significant hair regrowth is noted with 5-6 cm of scalp hair. We believe that
      IVIG may be beneficial in the treatment of AU, at least in patients with CVID.

PMID- 10403011
TI  - Incomplete nigrostriatal dopaminergic cell loss and partial reductions in
      striatal dopamine produce akinesia, rigidity, tremor and cognitive deficits in
      middle-aged rats.
AB  - The present study was conducted to determine if the full array of parkinsonian
      symptoms could be detected in rats with nigrostriatal cell loss and striatal
      dopamine depletions similar to levels reported in the clinical setting, and to
      determine if older rats exhibit more robust parkinsonian deficits than younger
      rats. Young (2 months old) and middle-aged (12 months old) rats received
      bilateral striatal infusions of 6-OHDA, over the next 3 months they were assessed
      with a battery of behavioral tests, and then dopaminergic nigrostriatal cells and
      striatal dopamine and DOPAC levels were quantified. The results of the present
      study suggest that: (1) the full array of parkinsonian symptoms (i.e. akinesia,
      rigidity, tremor and visuospatial cognitive deficits) can be quantified in rats
      with incomplete nigrostriatal dopaminergic cell loss and partial reductions in
      striatal dopamine levels (2) parkinsonian symptoms were more evident in middle
      aged rats with 6-OHDA infusions, and (3) there was evidence of substantial
      neuroplasticity in the older rats, but regardless of the age of the animal,
      endogenous compensatory mechanisms were unable to maintain striatal dopamine
      levels after rapid, lesion-induced nigrostriatal cell loss. These results suggest
      that using older rats with nigrostriatal dopaminergic cell loss and reductions in
      striatal dopamine levels similar to those in the clinical condition, and
      measuring behavioral deficits analogous to parkinsonian symptoms, might increase
      the predictive validity of pre-clinical rodent models.

PMID- 10403012
TI  - Behavioral disinhibition following basal forebrain excitotoxin lesions: alcohol
      consumption, defensive aggression, impulsivity and serotonin levels.
AB  - Research on alcoholism have identified a subgroup in which the drinking problem
      is associated with high rates of violence, an impulsive disposition and signs of
      reduced serotonin functioning in the brain. The present study reports that male
      Wistar rats with ibotenic acid-induced (5 micrograms/0.5 microliter) neuron loss
      in the basal forebrain (ventral striatum, septal area and adjacent structures)
      showed behavioral and neurochemical signs not unlike this subtype of alcoholics.
      Thus, rats with this lesion exhibited excessive 6% alcohol drinking in a two
      bottle choice test and showed augmentation of certain defensive behaviors,
      including defensive aggression and increased activity-during signal. In the
      punished drinking test, a passive avoidance task which taps psychological
      mechanisms underlying impulsivity [56], experimental rats were not different from
      sham-operated controls with regard to the number of punished licks, but
      punishment evoked less disruption of ongoing behavior in subjects with basal
      forebrain damage. The virtual absence of food hoarding in the face of normal
      feeding may constitute yet another sign of increased impulsivity, indicating as
      it does a diminished influence of future rewards on behavior. As expected, in
      view of ibotenic acid's selectivity for neuronal perikarya, the concentrations of
      dopamine, serotonin and norepinephrine were normal in the lesioned area. However,
      the levels of serotonin and norepinephrine in the cortex were reduced. A separate
      experiment examined the extent to which serotonin depletion alone reproduced the
      behavioral profile induced by basal forebrain neuron loss. However, measures of
      alcohol consumption, defensive behavior and impulsivity were not different from
      controls in rats given intracerebroventricular 5,7-DHT (150 micrograms/20
      microliters), except for a modest increase in defensive aggression.

PMID- 10403013
TI  - Nicotine enhancement of contextual fear conditioning.
AB  - Nicotine has been suggested to have cognitive enhancing effects. The present
      study examined the effects of nicotine and the nicotinic antagonist mecamylamine
      on contextual fear conditioning in C57BL/6 mice. The fear conditioning task was
      chosen because the task examines two types of learning: contextual learning, and
      conditioned stimulus (CS)-unconditioned stimulus (US) learning. Multiple doses of
      nicotine were tested and 0.5 mg/kg nicotine, given on both training and testing
      days, improved contextual learning but had no effect on formation of an auditory
      CS-US association. No effect was found at lower doses or when nicotine was given
      on training day only, or testing day only. The nicotinic receptor antagonist
      mecamylamine (1 and 2 mg/kg) did not alter contextual fear conditioning but
      mecamylamine did prevent the nicotine-associated increase in contextual learning.
      A higher dose of nicotine (1 mg/kg, training day only) interfered with contextual
      conditioning when the context was paired with both the CS and US, but had no
      effect on the auditory CS-US association. This effect of 1 mg/kg nicotine on
      contextual learning disappeared when mice were trained without the CS. The
      present results indicate that nicotine enhancement of contextual fear
      conditioning is dose-dependent, but the presence of nicotine is required both
      during training and testing.

PMID- 10403014
TI  - Olfaction and peripheral olfactory connections in methimazole-treated rats.
AB  - Methimazole has been reported to produce extensive degenerative changes in
      olfactory epithelium and a severe deficit in odor detection [Genter BM, Owens DM,
      Carlone HB, Crofton KM. Fundam. Appl. Toxicol. 1996;29:71-77; Genter BM, Owens
      DM, Deamer NJ, Blake BL, Wesley DS, Levi PE. Toxicol. Pathol. 1995;23:477-486.].
      To examine this further, rats were tested on olfactory detection and
      discrimination problems before and after intraperitoneal injection of 300 mg/kg
      methimazole. In the first 2 days after treatment, experimental rats had nasal
      congestion and a modest decrement on odor detection and odor mixture
      discrimination tasks. They performed almost as well as control rats on the third
      post injection day. In a separate group of rats, anterograde transport of
      horseradish peroxidase from olfactory epithelium to the bulb was examined 1, 2,
      3, and 5 days after administration of methimazole. The treatment produced a
      modest but progressive disruption of bulbar input: 2 days after administration
      only approximately 10% of bulbar glomeruli had reduced levels of reaction product
      while 30-40% of glomeruli had little or no reaction product in 3-5 day survival
      rats. These results indicate that methimazole is not a particularly effective
      olfactotoxin and does not produce anosmia or even a severe hyposmia.

PMID- 10403015
TI  - Gastric mucosal erosion produced by NMDA microinfusions in the lateral
      hypothalamus: effect of selective knife cuts.
AB  - Bilateral infusions of N-methyl-D-aspartate (NMDA) into the lateral hypothalamus
      (LH) produce gastric erosions in rats. The present study attempted to determine
      the neural pathways that mediate this effect. In order to interrupt axonal
      transmission, knife cuts (KC) were made in different planes adjacent to the LH.
      In separate groups of rats, KC were made anterior, posterior or lateral to the LH
      just prior to bilateral NMDA infusions (20 micrograms/microliter). The incidence
      of gastric erosions was measured 24 h after NMDA infusions. Animals receiving
      sham KC and infused with NMDA exhibited significantly more gastric erosions than
      those infused with vehicle. Lateral parasagittal KC blocked the occurrence of
      gastric erosions produced by NMDA, whereas anterior coronal KC significantly
      increased the incidence of erosions produced by NMDA. Posterior coronal KC did
      not alter the incidence of gastric erosions produced by NMDA infusions into the
      LH. These results suggest that intrinsic LH neurons with gastric function project
      axons laterally and probably descend through the internal capsule to brainstem
      medullary nuclei. The results of the anterior KC suggest that the LH sends and/or
      receives inhibitory projections from neural structures (possibly the amygdaloid
      complex) anterior to the plane of the KC.

PMID- 10403016
TI  - Effects of electrolytic lesions of the lateral pallidum on motor coordination,
      spatial learning, and regional brain variations of cytochrome oxidase activity in
      rats.
AB  - In view of recent theories suggesting a role for basal ganglia circuits in motor
      control and cognition, rats with bilateral electrolytic lesions of the lateral
      part of the globus pallidus were compared with control rats on motor coordination
      tasks and spatial learning in the Morris water maze. By comparison with sham
      operated controls, rats with lesions of the lateral pallidum were impaired during
      acquisition of the rotorod task. Deficits were observed in a wooden beam task,
      but not in hole-board and suspended string tests. In addition, lesioned rats were
      impaired during acquisition of place learning but not of visuomotor guidance in
      the Morris water maze. Alterations of brain metabolism, as assessed by cytochrome
      oxidase activity, were found in three regions of lesioned rats, the subthalamic
      nucleus, the superior colliculus, and the centromedial thalamus of lesioned rats,
      probably as a result of interrupted neocortico-basal ganglia circuitry as a
      secondary consequence of the primary lesion.

PMID- 10403017
TI  - Cognitive performance and biochemical markers in septum, hippocampus and striatum
      of rats after an i.c.v. injection of streptozotocin: a correlation analysis.
AB  - In the present study we evaluated the effects of an intracerebroventricular
      injection of streptozotocin on cognitive behavior and biochemical markers in the
      brain of middle-aged Wistar rats. Intracerebroventricular injected streptozotocin
      has previously been reported to decrease the central metabolism of glucose. We
      found that streptozotocin-treated rats showed an impaired cognitive performance
      in the delayed non-matching to position task and the Morris water escape task.
      Glial fibrillary acidic protein, an indicator of reactive astroglial changes, was
      measured in three different (soluble, Triton X-100 soluble and crude
      cytoskeletal) protein fractions and its content in the fractions of the septum,
      hippocampus and striatum of streptozotocin-treated rats was increased.
      Furthermore, the glial fibrillary acidic protein response of each protein
      fraction to streptozotocin treatment appeared to be differently regulated. In
      streptozotocin-treated rats the choline acetyltransferase activity was decreased
      in the hippocampus only, which was correlated with the hippocampal glial
      fibrillary acidic protein contents of all three hippocampal protein fractions,
      thus suggesting that the cholinergic deficit is a consequence of direct damage to
      the hippocampus. The cognitive deficits in both tasks were related to the
      increased glial fibrillary acidic protein contents, especially of the soluble and
      cytoskeletal fraction, and the decreased choline acetyltransferase activity in
      the hippocampus. Taken together, these findings indicate that it is important to
      take into account which protein fraction has been used for measuring the glial
      fibrillary acidic protein response to a stressor. Furthermore,
      intracerebroventricular injected streptozotocin may provide a relevant model for
      studying neurodegenerative changes due to a metabolic insufficiency and testing
      neuroprotective effects of substances.

PMID- 10403019
TI  - Long-term reversal of hemispheric specialization for visual memory in a split
      brain macaque.
AB  - Accuracy of response and pattern of ocular fixations in three split-brain
      macaques were used to evaluate performance of each hemisphere in a continuous
      visual recognition task. The animal indicated by ocular fixation upon response
      points whether a displayed image or face was 'NEW' or 'OLD'. An inadvertent
      lesion of cingulate gyrus severely reduced contralateral fixations and impaired
      performance of the affected hemisphere in one animal, confirming the inferred
      relation between hemisphere and laterality of fixations. The hemispheres in the
      other two animals were initially remarkably similar in accuracy with human faces
      and with images; but the right hemisphere was significantly superior to the left
      for macaque faces. Parallel to this, in the one animal tested while
      simultaneously using both eyes/hemispheres, fixations were made primarily on the
      left half of human and macaque faces (right hemispheric control), whereas for
      images the ocular fixations were predominantly focused on the right half.
      However, after further, extensive training the left hemisphere performed with
      significantly greater accuracy than the right on all material and this shift was
      accompanied and further corroborated by a reversal of the fixational pattern to
      favor the right half of faces, as continued to be the case with images. Thus,
      over the long term both the pattern of ocular fixations and the accuracy of
      performance demonstrate a migration from right to left hemispheric dominance as
      familiarity with the task increased. Performance of the initially superior
      hemisphere actually diminished with this shift, presenting a uniquely puzzling
      question of hemispheric balance in the absence of the forebrain commissures.

PMID- 10403018
TI  - The effects of gonadal hormones on the development and expression of the
      stimulant effects of morphine in male and female rats.
AB  - Previous studies have shown that the behavioral activating effects of the
      stimulant drug amphetamine are augmented in female rats by estradiol. Here we
      studied the effects of gonadectomy and gonadal hormone replacement on the
      stimulant effects of morphine in both females and males. Groups of intact,
      ovariectomized (Ovex), and Ovex females given estradiol benzoate (EB) (5
      micrograms), and groups of intact, castrated, and castrated males given
      testosterone propionate (30 micrograms) were administered five injections of
      morphine sulphate (10 mg/kg, i.p.) or saline at 3-day intervals. Activity was
      monitored on each occasion for 2 h. Among females treated with morphine, intact
      and Ovex-EB animals showed progressive enhancement of activity over sessions,
      whereas Ovex animals showed no change. Three days after the last pre-exposure
      session, all animals received 5 mg/kg morphine in a test for sensitization. In
      spite of the lower levels of activity in Ovex animals, animals from all groups
      previously exposed to morphine showed a sensitized response to morphine compared
      with those receiving morphine for the first time. These findings are virtually
      identical to our previous findings in female rats treated with amphetamine. Among
      males, only intact animals showed a progressive increase in morphine-induced
      activity and only in the second hour of testing, but, overall, there was no
      significant effect of either group or drug during the pre-exposure phase. On the
      test for sensitization, as seen in females, those males that had been exposed to
      morphine previously showed a sensitized responses to morphine. There were,
      however, no differences in activity levels between the groups of males. We
      conclude that although gonadal hormones, and in particular estradiol, may modify
      the magnitude of the response to amphetamine and morphine, they appear not to be
      involved in those neurochemical and neuronal changes that occur during and
      following repeated drug exposures, and that underlie the enhanced sensitivity to
      the stimulant effects of a drug seen when such animals are compared with animals
      receiving the drug for the first time.

PMID- 10403020
TI  - Motor learning by imagery is differentially affected in Parkinson's and
      Huntington's diseases.
AB  - Studies of motor imagery and motor learning have thus far been concerned only
      with its effects on healthy subjects. Therefore, in order to investigate the
      possible involvement of the basal ganglia, the effectiveness of motor imagery in
      the acquisition of motor constants in a graphomotor trajectorial learning task
      was examined in 11 non-demented mildly affected Huntington's disease (HD)
      patients and 12 non-demented Parkinson's disease (PD) patients. The patients
      received, after baseline, 10 min of motor imagery training, followed by a motor
      practice phase. Additionally, a test battery for visual imagery abilities was
      administered in order to investigate possible relations between visual and motor
      imagery. The results showed that imagery training alone enabled the HD patients
      to achieve a significant approach to movement isochrony, whereas the PD patients
      showed no marked improvements, either with motor imagery or with motor practice.
      Furthermore, the PD patients had more difficulties than the HD patients in
      solving the visual imagery tasks. Subsequent correlational analysis revealed
      significant relationships between the degree of caudate atrophy in the HD
      patients and their performance in the visual imagery tasks. However, there were
      no substantial correlations between the performance on the visual imagery tasks
      and the improvement of motor performance through motor imagery, which indicates
      that visual and motor imagery are independent processes. It is suggested that the
      dopaminergic input to the basal ganglia plays an important role in the
      translation of motor representations into motor performance, whereas the caudate
      nucleus atrophy of the HD patients does not seem to affect motor imagery, but
      only the visual imagery process. Furthermore, the deficits found in PD patients
      might also be related to their limited attentional resources and difficulties in
      employing predictive motor strategies.

PMID- 10403021
TI  - 'Putting your foot in it'! A window into clumsy behaviour.
AB  - Intra-modal matching by 7-year-old children diagnosed as having hand-eye co
      ordination problems (HECP) and a control group of children without such problems
      was tested using a target location and matching task. The 'foot-hand' task
      required the children to locate a target pin with the 'big-toe' (felt target) and
      match the located target position with the hand, without vision. There were four
      conditions: location via right foot-matching the located target with the right
      hand (RfRh) and left hand (RfLh) and location via left foot-matching the located
      target with the left hand (LfLh) and right hand (LfRh). Both groups demonstrated
      better performance in the intra- as compared to the inter-hemispheric conditions,
      suggesting that the corpus callosum is not yet fully mature at this age. The HECP
      children showed inferior performance to the control children in three of the four
      conditions, the conditions where the right hemisphere was involved and/or
      information had to be transported across the corpus callosum (RfLh; LfLh; LfRh).
      Two possible explanations of these findings are put forward and discussed: right
      hemisphere insufficiency with or without dysfunctional corpus callosum.

PMID- 10403022
TI  - Effects of mammillary body lesions on spatial reference and working memory tasks.
AB  - This work examines the effects of electrolytic mammillary body (MB) lesions on
      the performance of rats in different spatial memory tasks in the Morris water
      maze. The first experiment assessed the effect of MB lesion on performance in a
      spatial reference memory task (place learning with multiple trials). The second
      experiment examined the effect of a lesion in this nucleus on performance in a
      spatial working memory task (single-trial place learning). The results show that
      lesion of the MB impairs the animals performance in spatial working memory tasks
      but does not impair acquisition in spatial reference memory tasks (place
      learning, transfer task, reversal task) or in a visual-cued task. However, the
      deficit in the spatial working memory task does not appear to vary with the delay
      between acquisition and retention trials (30 s and 5 min). Our results
      demonstrate a clear role of the mammillary bodies in the processing of spatial
      information in a working memory task. Lesion of the MB impairs performance in a
      working memory task but does not affect reference memory processes.

PMID- 10403023
TI  - Enhanced conditioned approach responses in transgenic mice with impaired
      glucocorticoid receptor function.
AB  - The long-term consequences of impaired glucocorticoid receptor (GR) function on
      reward-related learning were studied in transgenic mice with impaired GR function
      in a series of experiments taxing conditioned and unconditioned approach
      responses to stimuli predictive of food. There was a double-dissociation in that
      transgenic mice with impaired GR activity showed enhanced conditioned exploration
      in situations when stimuli predicted reward, while free-feeding food consumption
      over 24 h was reduced. Previous experiments have shown altered accumbens
      dopaminergic activity in these animals. In line with these findings, we observed
      an enhanced behavioural stimulation of transgenic mice following administration
      of d-amphetamine (2 mg/kg). This suggests that the increase in preparatory
      responses in transgenic mice may be mediated via an enhanced accumbens
      dopaminergic activity, possibly secondary to alterations in other brain systems.

PMID- 10403024
TI  - Presumed 'prefrontal cortex' lesions in pigeons: effects on visual discrimination
      performance.
AB  - The posterodorsolateral neostriatum (PDLNS) in pigeons may be an equivalent of
      the prefrontal cortex (PFC) in mammals. Here we report that lesions of this brain
      region in pigeons have a detrimental effect on various learned visual
      discriminations. Pigeons with lesions of the overlying area corticoidea
      dorsolateralis (CDL) served as controls. Both the postoperative re-learning to
      criterion of a preoperatively learned simultaneous double visual mirror pattern
      discrimination and the learning of a simple successive go, no-go discrimination
      were impaired by the PDLNS lesions. The PDLNS and CDL groups did not differ
      significantly in the postoperative learning of a reversal of the simultaneous
      discrimination. The results are discussed in relation to the presumed equivalence
      between the avian PDNLS and the mammalian PFC.

PMID- 10403025
TI  - Exploratory behaviour after intra-accumbens histamine and/or histamine
      antagonists injection in the rat.
AB  - The possible role of histamine locally applied into the nucleus accumbens on
      exploratory behaviours measured in 'conflictive' and 'non-conflictive'
      environments was studied in adult male rats. It was assumed that in conflictive
      environments the brain mechanisms involved in processing incentive environmental
      clues (novelty) were interacting with mechanisms involved in the processing of
      fearful or 'anxiogenic' environmental clues. As a model of conflictive
      environment, the elevated asymmetric-plus maze (APM) was used. As a model of a
      non-conflictive environment, a modified holebroad enriched with an object (OVM)
      was used. The exploration score in any of the arms of the APM was considered an
      approximate index of exploratory motivation. The permanency score (non
      exploratory behaviours) was considered an inverse approximate index of
      emotionality. Other variables such as the frequency of entries into any arm, the
      latency time and central activity were also measured. In the OVM, the general
      motor activity and head-dipping, vertical rearing and focalized exploration were
      measured. Results show that histamine in the APM had a dual effect. On the one
      hand, an increase of exploration was observed in those arms considered more
      'anxiogenic'. On the other hand, a decrease in exploration occurred in one of the
      arms considered less 'anxiogenic'. No changes of permanency was observed in the
      'anxiogenic' arms, and a decrease of permanency took place in the arms considered
      less 'anxiogenic'. In the OVM, histamine did not change the overall motor
      activity, but head-dipping was inhibited by the imidazolamine treatment.
      Histamine effects on exploration parameters were counteracted by pre-treatment
      with H1- and H2-histamine antagonists. Nevertheless, some behaviours were not
      blocked by the histamine receptor antagonists. The present results give support
      to the role of the nucleus accumbens in the exploratory motivation mechanisms and
      suggest that histamine might be an endogenous regulator.

PMID- 10403026
TI  - Learning versus performance impairments following regional administration of MK
      801 into nucleus accumbens and dorsomedial striatum.
AB  - To further ascertain the relative contributions of nucleus accumbens (NAC) and
      dorsomedial striatum (DS) to cognitive behaviors, the comparative effects in rats
      of MK-801 microinjections into these regions on a multiple schedule of repeated
      learning (RL) and performance (P) were examined. The RL component required
      learning of a new three-member response sequence during each experimental
      session, while the P component required rote performance of a pre-learned
      response, thus permitting a more precise delineation of treatment-related
      cognitive vs. non-cognitive changes. MK-801 decreased overall accuracy in both
      the RL and P components of the schedule in both brain regions, indicating that in
      neither NAC nor DS are NMDA receptors exclusively involved in mediating
      acquisition processes. Decreases in overall accuracy were primarily due to
      increased perseverative errors which may have been the result of excessively
      accelerated responding, a type of motoric alteration. MK-801 administered into
      NAC also resulted in an additional increase in skipping errors at the 2.5
      micrograms dose, a finding which could be consistent with disrupted learning
      resulting from an inability to encode spatial relationships. Collectively these
      findings suggest that NAC and DS mediate some behavioral functions in common, but
      that additional cognitive-related spatial processes are mediated by NAC.

PMID- 10403028
TI  - Oral operant ethanol self-administration in 5-HT1b knockout mice.
AB  - The present experiment examined oral ethanol self-administration in 5-HT1b
      knockout (KO) mice and 5-HT1b wide-type (WT) control mice using a continuous
      access operant procedure. After lever press training, adult 5-HT1b KO and 5-HT1b
      WT mice were placed in operant chambers on a 23 h per day basis with access to
      food (FR1), 10% v/v ethanol (FR4), and water from a sipper tube. KO mice
      displayed higher rates of responding on the ethanol-associated lever compared to
      WT mice. KO mice also consumed greater amounts of water. Food responding was the
      same in both genotypes. Following 30 sessions, ethanol concentration was altered
      every 5 days. Response patterns were determined using 0, 5, and 20% v/v ethanol
      concentrations. Ethanol responding (0, 5, 10, and 20% v/v) was also examined
      after the addition of 0.15% saccharin. KO mice and WT mice showed similar
      response rates for all ethanol concentrations. Since KO mice showed greater
      levels of ethanol responding only for unsweetened 10% v/v ethanol, and showed
      modest ethanol self-administration overall, the present results are not
      consistent with the notion that 5-HT1b KO have a generally greater preference for
      ethanol than 5-HT1b WT mice.

PMID- 10403027
TI  - Effects of the competitive N-methyl-D-aspartate receptor antagonist, CPP, on the
      development and expression of conditioned hyperactivity and sensitization induced
      by cocaine.
AB  - This study used novel behavioral measures to examine the effects of the
      competitive N-methyl-D-aspartate (NMDA) receptor antagonist, CPP, on the
      development and expression of conditioned hyperactivity and sensitization
      produced with cocaine. The first experiment confirmed that horizontal locomotor
      activity measured in the central zone of an activity enclosure could be increased
      by 10.0 mg/kg cocaine. This increased activity showed sensitization after
      repeated cocaine injections, and it could be conditioned to the test environment.
      Subsequent experiments demonstrated that CPP (0.2 and 0.4 nmol, i.c.v.) could
      block the development, but not the expression, of conditioned hyperactivity and
      sensitization in the central zone. These findings confirm that NMDA receptors are
      critically involved in the development of conditioned hyperactivity and
      sensitization, but indicate that such receptors may not be necessary for the
      expression of these neurobehavioral adaptations.

PMID- 10403029
TI  - Modifications of HIV-1 retrovirus-like particles to enhance safety and
      immunogenicity.
AB  - HIV-1 retrovirus-like particles can be produced in VERO cells that have been
      transfected with an expression construct encoding HIV-1 structural proteins. The
      particles are entirely non-infectious although structurally they resemble
      infectious virus particles. This makes them a promising candidate for use as an
      HIV-1 vaccine. In order to ensure their safety and enhance their immunogenicity,
      the retrovirus-like particles were modified in a number of ways. A large deletion
      in the HIV-1 pol gene has eliminated reverse transcriptase and integrase
      activities. Deletion of RNA packaging signals in the RNA untranslated leader
      sequence and in Gag reduced packaged RNA to 5% of that in HIV-1 virus.
      Replacement of the existing HIV-1LAI envelope protein with that of HIV-1MN has
      ensured that immune responses to the particles are relevant to those against the
      majority of HIV-1 clade B isolates. In addition to these changes in particle
      composition, yields of the modified particles were increased using a superior
      method of inducing the expression construct promoter, and an effective scheme for
      particle purification was developed. Immunization of non-human primates
      demonstrated that the particles were capable of generating anti-HIV-1
      neutralizing antibodies. The technological refinements reported here will permit
      retrovirus-like particles to be tested safely in humans, and the change in
      envelope proteins should allow a more realistic evaluation of the immunogenicity
      of these particles. Experience gained in engineering these refinements will
      greatly facilitate other modifications that may be required to achieve maximum
      efficacy as a vaccine against HIV-1.

PMID- 10403031
TI  - Effect of some variables on the in vivo determination of scorpion and viper venom
      toxicities.
AB  - An adequate assessment of scorpion and snake venom LD50 is an important step for
      accurate evaluation of antivenom sera potencies and the optimization of
      serotherapy. The LD50 variation of Tunisian scorpion (Androctonus australis
      garzonii: Aag and Buthus occitanus tunetanus: Bot) venoms with body weight, sex
      and strain (Swiss or C57BI/6) of mice used, the route of venom injection, the
      venom-milking procedures (manually or electrically) and the venom batches have
      been studied over a 7-year period (1990-1996). Aag venom is 3-4 times more toxic
      than Bot venom. However for both venoms, the LD50 determined in C57BI/6 mice, in
      small body weight animal or by intraperitoneal route were respectively
      significantly lower than those determined in Swiss mice, in high body weight or
      by subcutaneous route. Significant LD50 variations (25-50%) were also seen from
      one electrically prepared batch to another. A good correlation (r = 0.982) was
      observed between the concentrations of the crude venom toxic fraction determined
      by ELISA and LD50 values when assessed in vivo. The LD50 variation of Tunisian
      viper (Cerastes cerastes: Cc and Vipera lebetina: VI) venoms with the strain
      (Swiss or BALB/c), sex and body weight of mice used, the season and the year of
      venom milking were also investigated over a 3-year period (1990-1992). No
      significant LD50 variations were observed with the mouse strain, the sex or the
      season of venom milking. However, LD50 varies significantly with the year of the
      venom collection and the body weight of mice used. Furthermore, SDS-PAGE analysis
      shows annual variation for VI venom composition where no such variations were
      observed for Cc venom. These results stress the need either for the
      standardization of the venom LD50 evaluation or of the venom quality used for the
      development of an efficient antivenom.

PMID- 10403030
TI  - Virus validation of pH 4-treated human immunoglobulin products produced by the
      Cohn fractionation process.
AB  - To assess the virus reducing capacity of Cohn's cold ethanol fractionation
      process for the production of intravenous (IVIg) and intramuscular (IMIg)
      immunoglobulin products, and treatment of these products at pH 4, a validation
      study of virus removal and/or inactivation was performed using both lipid
      enveloped viruses [human immunodeficiency virus (HIV), bovine viral diarrhoea
      virus (BVDV) and pseudorabies virus (PSR)], and non-lipid-enveloped viruses
      [(simian virus 40 (SV40) and encephalomyocarditis virus (EMC)]. For the cold
      ethanol fractionation process, overall reduction factors of 3.0 logs, > or = 2.6
      (< 5.5) logs, 4.6 logs, 5.8 logs and > or = 2.6 (< 6.2) logs were found for HIV,
      BVDV, PSR, SV40 and EMC, respectively. For all tested viruses the precipitation
      of fraction III from fraction II + III was the most effective step. From the
      overall reduction factors it appears that cold ethanol fractionation, although
      capable of reducing viral infectivity to a significant extent, is not sufficient
      to meet the requirements of regulatory bodies for viral safety of immunoglobulin
      products. However, pH 4 treatment contributes effectively to the viral safety of
      the final products. Treatment at pH 4.05 and 37 degrees C for 16 h, as is applied
      to IVIg, yields reduction factors of > or = 8.4 logs, > or = 4.0 logs, > or = 7.1
      logs, 4.8 logs and 1.4 logs for HIV, BVDV, PSR, SV40 and EMC, respectively. The
      effectiveness of this process step could be enhanced by extending incubation to
      40 h at pH 4.25 compared to 16 h at pH 4.05. The extended incubation, as applied
      in the production of IMIg, yields a reduction of infectivity of SV40 by > or =
      5.5 (< 8.0) logs and of EMC by > or = 4.1 (< 7.1) logs. Storage of IMIg, which is
      formulated as a solution, at 2-8 degrees C also contributes to virus safety. For
      storage periods of 8 weeks or longer, reduction factors of 2 to 6 logs were found
      for all viruses, except for BVDV which remained unaffected. These data indicate
      that the production processes for IVIg and IMIg as described here have sufficient
      virus reducing capacity to achieve a high margin of virus safety.

PMID- 10403032
TI  - Estimation of the neurovirulence of poliovirus by non-radioisotope molecular
      analysis to quantify genomic changes.
AB  - Mutant analysis by polymerase chain reaction and restriction enzyme cleavage
      (MAPREC) has been developed for poliovirus to determine quantitatively for the
      presence of genomic changes in particular nucleotide sequences correlate with the
      characteristic of neurovirulence for monkeys. Currently the MAPREC is scheduled
      to be used as a routine safety test for oral poliomyelitis vaccine (OPV).
      Radioisotopes (RI) are used in MAPREC for quantitative determinations, a
      circumstance likely to limit its use. We investigated the possibility of
      developing a modified MAPREC, which did not require the use of radioisotopes, and
      developed a procedure designated NON-RI MAPREC. Conventional MAPREC and NON-RI
      MAPREC were then used in a series of studies in which analyses were performed on
      Sabin type 1 and Sabin type 3 attenuated vaccine polioviruses prepared under
      various conditions. Under the experimental conditions used, the stability of the
      genome of type 1 virus was shown to be markedly greater than that of the type 3
      virus, and the frequency of mutants was observed to vary in relation to both the
      virus strain and the virus inoculum used. The results of the studies relating to
      the two analytical procedures used indicated that the reproducibility of both
      methods was of a similarly high order, but that MAPREC had a somewhat broader
      range of sensitivity than NON-RI MAPREC. As the quantity of genomic changes in
      OPV relating to neurovirulent properties are within the range of detection by NON
      RI MAPREC, this procedure can be used as a quality control test for OPV.

PMID- 10403033
TI  - Immunogenicity and safety in adults of a new chromatographically purified Vero
      cell rabies vaccine (CPRV): a randomized, double-blind trial with purified Vero
      cell rabies vaccine (PVRV).
AB  - Recent improvements in chromatographic purification procedures have made it
      possible to develop a new chromatographically purified rabies vaccine (CPRV) by
      further purifying the current rabies vaccine prepared from Vero-cell culture
      (Verorab; Pasteur Merieux Connaught). The immunogenicity and safety of primary
      immunization, followed by a booster at one year, with CPRV was compared to that
      of the purified Vero cell vaccine (PVRV) in a randomized, double-blind study
      carried out at four veterinary schools in France. A total of 330 healthy, male
      and female, first-year veterinary students, aged at least 18 years and who
      required pre-exposure rabies prophylaxis, were enrolled in this study. Included
      subjects were randomly assigned either CPRV (n = 163) or PVRV (n = 167) to be
      given as a primary immunization series of three intramuscular injections (D0, D7,
      D28), followed by a booster after 1 year (D365). Blood samples for serological
      analysis were taken at D0 (before first injection), D28, D42, D180, D365 (before
      booster) and D379. All subjects developed a strong immune response to the primary
      series, and at D42, all subjects had seroconverted for rabies neutralizing
      antibody (serum titre > or = 0.5 IU/ml). The rabies virus-neutralizing antibody
      GMT value at D42 in the CPRV group (23.0 IU/ml) was non-inferior to that in the
      PVRV group (29.6 IU/ml), according to a one-sided non-inferiority test. While
      antibody titres tended to decrease over the period of follow-up, at D365 (before
      booster), 97.5% subjects in the CPRV group and 98.8% of subjects in the PVRV
      group remained seroconverted. After booster, although the rabies antibody GMT
      value in the CPRV group was lower than that in the PVRV group, all subjects in
      both groups were seroconverted, and the difference is probably not clinically
      important. The incidence of local and systemic reactions tended to decrease with
      each dose during the primary immunization series, followed by a slight increase
      after booster (significant time-effect in an exploratory logistic regression
      analysis). Although mild or moderate local reactions tended to be more frequent
      after injection with CPRV compared to PVRV, systemic reactions were reported less
      often (significant group-effects in exploratory logistic regression analyses).
      One serious adverse event possibly related to vaccine occurred during this study
      (severe asthenia after the third dose of PVRV). This comparative study in healthy
      young adults demonstrates that the new chromatographically purified rabies
      vaccine is as immunogenic as PVRV, and seems to be associated with fewer systemic
      reactions.

PMID- 10403034
TI  - Stability of 17D yellow fever virus vaccine using different stabilizers.
AB  - To optimize the thermostability of lyophilized 17D vaccine, the authors
      investigated parameters important for the freeze-drying process. Six different
      stabilizers with different sugars and amino acids were analysed in a freeze-thaw
      cycle for their crystallization characteristics and their stabilizing effect
      under thermal treatment conditions of 37 degrees C for 28 days. This test
      indicated that three out of six stabilizers (B, C, F) kept the vaccine
      significantly more stable than the three others (A, D, E). Under storing
      conditions of 4 degrees C over 96 days stabilizers A, B and C produced the lowest
      decrease in titre of about 10% in contrast to stabilizers D, E and F with a
      higher decrease in infectivity titre. Analysing the stability of the 17D vaccine
      using five different reconstitution solutions, we found that 90% D2O shows the
      best stabilizing effect under thermal treatment of 37 degrees C up to 24 h.

PMID- 10403035
TI  - Safety of viral DNA in biological products.
AB  - Data from studies of the infectivity of DNA injected directly into laboratory
      animals are used to estimate the potential infectivity risk of residual DNA in
      biological products. The potential for some novel products to contain infectious
      quantities of residual cellular DNA is discussed, and further study of this
      subject is suggested.

PMID- 10403036
TI  - Removal of viruses from human intravenous immune globulin by 35 nm
      nanofiltration.
AB  - Viral safety is an important prerequisite for clinical immunoglobulin
      preparations. A common manufacturing practice is to utilize several virus
      removal/inactivation process steps to ensure the safety of human intravenous
      immunoglobulin (IVIg). In this regard, we examined the use of Planova 35 nm
      filters to reduce potential loads of both non-enveloped and enveloped viruses
      prior to end-stage solvent detergent treatment. The nanofiltration process was
      validated for removal of a variety of enveloped and non-enveloped viruses ranging
      in size from 70 nm to 18 nm including: Sindbis virus, Simian Virus 40 (SV40),
      Bovine Viral Diarrhoea virus (BVDV), Feline Calicivirus, Encephalomyocarditis
      virus (EMC), Hepatitis A virus (HAV), Bovine Parvovirus (BPV) and Porcine
      Parvovirus (PPV). The filtration procedure was carried out by first spiking a 7%
      solution of IVIg with < 10(8) virus. The spiked IVIg solution was then filtered
      through a 75 nm Planova filter followed by two Planova 35 nm filters in series
      (75/35/35). The 75 nm prefilter is incorporated into this process to increase the
      capacity of the 35 nm viral removal filters. As a result of the inclusion of the
      75 nm pre-filtration step it was possible to assess the removal of virus by the
      35 nm filters independent of possible aggregation of the initial viral spiking
      material. Samples were collected at each step and immediately titred by viral
      plaque assay. A process control sample of the spiked load solution was held at
      the same conditions for the duration of the filtration process and then titred to
      determine the extent to which antibody neutralization may have contributed to
      overall viral reduction. Control assays of spiked IVIg were performed to
      establish the degree of toxicity of the IVIg solution to the indicator cell lines
      and the extent to which the IVIg interfered with plaque formation in the assay
      system. This combined data was used to establish assay sensitivity for the
      calculation of log removal by the filtration process. It was noted that
      toxicity/interference effects could have a significant effect upon apparent log
      reductions, and these effects could vary greatly, even within viruses of the same
      family. The results of these studies indicate that 35 nm filtration is very
      effective for removing substantial quantities of both non-enveloped and enveloped
      viruses from IVIg. Complete clearance (to the limits of detection of the assay)
      was obtained for all viruses larger than 35 nm. Interestingly, viruses reported
      to have mean diameters of less than 35 nm (EMC and HAV) were at least partially
      removed by the filtration (4.3 and > 4.7 logs removal, respectively). Even small
      viruses such as PPV were to some extent removed from the IVIg solution by the
      filters (2.6 logs removal). Reduction of BPV would not be assessed due to
      extensive neutralization and interference with plaque formation by the IVIg.
      Sindbis and SV40 also were subject to neutralization and assay interference due
      to the IVIg, though to a lesser extent. We conclude from these studies that the
      35 nm mean pore size is functionally efficient in removal of smaller size viruses
      from spiked IVIg concentrates.

PMID- 10403038
TI  - A comparison of two serological methods for detecting the immune response after
      rabies vaccination in dogs and cats being exported to rabies-free areas.
AB  - Levels of rabies virus neutralizing antibody in sera from dogs and cats were
      titrated to endpoint by the Rapid Fluorescent Focus Inhibition Test (RFFIT) and
      retested by the RFFIT and the Fluorescent Antibody Virus Neutralization test
      (FAVN). The two tests were compared for their ability to detect the 0.5
      international units/ml (I.U.) of antibody required by the World Health
      Organization and the Office International des Epizooties as the minimum response
      for proof of rabies immunization. No difference was observed in sensitivity or
      specificity for either method in tests of 168 sera from unvaccinated animals or
      70 sera from vaccinated animals with high levels of neutralizing antibody (an
      initial RFFIT titre of > or = 1.0 I.U.). Test to test variation occurred for
      results obtained by both RFFIT and FAVN for 95 sera from vaccinated animals with
      low to moderate levels of neutralizing antibody (RFFIT titre < 1.0 I.U.). No
      significant differences were detected for the 95 sera in the frequency for one
      methodology more often than the other to have a positive response (> or = 0.5
      I.U.), nor were significant differences detected for the symmetry (P = 0.43) or
      the marginal homogeneity (P = 0.39) of results obtained by the two methods. Both
      methods can adequately identity unvaccinated animals, but false positive and
      false negative results are possible for either method when a single test is used
      to measure the antibody response of low-responding vaccinated animals. Nucleotide
      sequence analysis identified several amino acid differences in stocks of the
      challenge rabies virus from different laboratories. The small differences in
      neutralizing antibody titre that may result from mutations in the challenge virus
      are not important for evaluating immunity induced by vaccines which are
      themselves prepared from a variety of different rabies virus strains, but
      differences in the challenge virus, rather than differences in methodology, may
      account for at least some of the discrepant results reported in inter-laboratory
      surveys. Comparative studies of serological methods for measuring rabies
      antibodies should use well-characterized unpassaged virus stocks obtained from a
      single reference laboratory.

PMID- 10403037
TI  - Recombinant human albumin as a stabilizer for biological materials and for the
      preparation of international reference reagents.
AB  - Recombinant human albumin expressed in Saccharomyces cerevisiae was compared with
      native human serum albumin in its physicochemical properties and in its use as a
      stabilizer in lyophilized preparations of thyroid-stimulating hormone (TSH),
      interleukin 15 (IL-15) and granulocyte colony-stimulating factor (G-CSF).
      Advantages of recombinant albumin include its lack of potential human
      contaminants and infectious agents. When used at concentrations of 0.1-0.2%
      (w/v), recombinant albumin was equivalent to native serum albumin in its capacity
      to protect immunological, biological and biochemical properties of TSH, IL-15 and
      G-CSF. Physicochemical characteristics of the two forms of albumin including
      their binding to fatty acids were also similar. The recombinant form of albumin
      used in this study should be considered as a suitable stabilizer in the
      preparation of lyophilized products and reference reagents.

PMID- 10403039
TI  - Informal workshop on potential regulatory and 2 licensing issues for pneumococcal
      conjugate vaccines. 13 June 1998, Helsingor, Denmark.
AB  - (1) It is likely that a seven-valent pneumococcal conjugate vaccine will be
      licensed in the next few years based on efficacy studies. Licensure of nine- or
      11-valent vaccines will be sought soon thereafter. Further studies of nine- or 11
      valent vaccines which can evaluate efficacy of the added serotypes will be
      unlikely. (2) Licensure of other vaccines (including those with additional
      serotypes), will depend on evaluation of surrogates for efficacy. (3) The most
      accepted surrogate of efficacy at this point is some combination of functional
      assay (e.g. opsonophagocytosis), and/or serology of anticapsular antibody by
      ELISA or RIA that correlates closely with the functional test. (4) An additional
      important correlate of immunity for polysaccharide conjugate vaccines may be
      measurement of the booster response. (5) Although effect on nasopharyngeal
      carriage may be developed into a useful correlate of efficacy in the future, much
      additional work must be done before carriage data can be interpreted usefully for
      this purpose. (6) Testing for consistency of production of pneumococcal conjugate
      vaccines will follow lines similar to that for Hib conjugate vaccines. Thus,
      instead of one set of universally applicable lot release criteria, vaccine
      specific criteria must be developed collaboratively between industry and national
      control authorities.

PMID- 10403040
TI  - WHO consultation on the development of new/improved brucellosis vaccines. 17
      December 1997, Geneva, Switzerland.

PMID- 10403041
TI  - Animal sera, animal sera derivatives and substitutes used in the manufacture of
      pharmaceuticals. 5-6 May 1998, Strasbourg, France.

PMID- 10403043
TI  - Zirconia-fluorapatite materials produced by HIP.
AB  - Composites of tetragonal zirconia and fluorapatite were sealed in steel tubes and
      hot isostatically pressed at 1200 degrees C. The phases formed in the samples
      were evaluated by X-ray powder diffraction. When the composites contained larger
      amounts of fluorapatite, the tetragonal zirconia changed gradually into the cubic
      phase with decreasing zirconia content. These phase changes occurred due to a
      transfer of calcium from fluorapatite, which acted as an additional dopant in
      zirconia. Small amounts of monoclinic zirconia were also present in all samples.
      The cell dimension in fluorapatite was changed with the composition of the
      composite. However, decomposition of the fluorapatite was not possible to detect.
      Vickers hardness and fracture toughness were measured and ranged from 5.1 to 10.8
      GPa and 0.9-5.5 MPam1/2, respectively. Microstructures in the composites were
      studied with scanning electron microscopy.

PMID- 10403042
TI  - Histological study of tissue reactions to epsilon-caprolactone-lactide copolymer
      in paste form.
AB  - In previous studies, epsilon-caprolactone-lactide copolymer in solid form has
      been used in experimental animals as suture material, and as a biodegradable
      nerve guide. The aim of the study reported here was to assess tissue reactions to
      epsilon-caprolactone-lactide copolymer in paste form, histologically, and to
      compare bone healing at the sites of implantation versus that at control sites.
      The other purpose of the study was to evaluate the properties of the implanted
      material as a filling material for bone defects. Resorption time and intensity of
      inflammatory reaction were also evaluated. Material was implanted into the
      abdominal walls and femurs of 34 rats. Follow-up times were from 2 weeks to 1
      year. The results showed that epsilon-caprolactone-lactide copolymer in paste
      form induces a severe inflammatory reaction when placed in muscle, and moderate
      inflammation when implanted into bone. The resorption time was more than 1 year.
      Bone healing at sites of implantation was slower than at control sites.

PMID- 10403044
TI  - Visualization of in vitro protein-rejecting properties of PEGylated stealth
      polycyanoacrylate nanoparticles.
AB  - The in vitro protein-rejecting properties of PEG-coated polyalkylcyanoacrylate
      (PACA) nanoparticles were for the first time visualized after freeze-fracture of
      the nanoparticles pre-incubated with fibrinogen as a model blood protein. The
      reduced protein association to the nanoparticles was evidenced also by two
      dimensional PAGE after incubation of the nanoparticles with human plasma. In vivo
      experiments showed the 'stealth' long-circulating properties of the PEGylated
      nanoparticles after intravenous administration to mice. Thus, the images obtained
      after nanoparticle-protein incubation were predictive of the behavior observed in
      vivo. In conclusion, freeze-fracture analysis represents a novel and original
      qualitative approach to investigate the interactions between proteins and
      particulate systems.

PMID- 10403045
TI  - Functionalized nanoparticles for endotoxin binding in aqueous solutions.
AB  - Nanoparticles consisting of a polystyrene core and a polyglycidyl methacrylate
      shell were prepared by a two-step emulsion polymerization. The size and surface
      properties of the particles were characterized by scanning electron microscopy,
      dynamic light scattering and polyelectrolyte titration techniques. Particles were
      found to be monodisperse with a mean diameter of about 85 nm. Parent particles
      were modified with a number of different ligands including diamines of increasing
      chain length, amino acids and corresponding amines and higher molecular weight
      ligands like polymyxin B. The modified particles were tested for their endotoxin
      (ET) binding capacity in water and physiological sodium chloride solution with
      the Limulus amebocyte lysate (LAL) assay. It was found that the ET binding
      properties of the different ligands depend both on the ability of the ligand to
      form Coulomb- and van der Waals-interactions with the ET molecule influenced by
      the nature of the suspension medium. Therefore, the choice of ligands for
      particle modification has to consider minutely the conditions under which ET has
      to be removed, e.g. removal from pure water, dialysis fluids, plasma or blood.

PMID- 10403046
TI  - Reliability theory for load bearing biomedical implants.
AB  - At present, load-bearing implants are designed on a deterministic basis in which
      the structural strength and applied loading are given fixed values, and global
      safety factors are applied to (i) cover any uncertainties in these quantities,
      and (ii) to design against failure of the component. This approach will become
      increasingly inappropriate as younger and more active patient demands become more
      exacting and as devices become more complex. The present work describes a
      preliminary investigation in which a scientific and probabilistic technique is
      applied to assess the structural integrity of the knee tibial tray. It is
      envisaged that by applying such a technique to other load bearing biomedical
      devices, reliability theory may aid in future lifing procedures and
      materials/design optimisation.

PMID- 10403048
TI  - Fluoridated apatite synthesized using a multi-step fluoride supply system.
AB  - Fluoridated apatite was synthesized at 80 +/- 1 degrees C, pH 7.4 +/- 0.2, using
      a 5-step fluoride supply system. During the synthesis experiment, 0, 5, 10, 15
      and 20 mmol/l of fluoride were each supplied for one-fifth of the experimental
      period with calcium and phosphate. X-ray diffraction analysis showed a typically
      apatitic pattern, although the (3 0 0) reflection was broader than that of
      homogeneous fluorapatite. Scanning electron micrographic observation indicated
      that the apatite was composed of needle-like crystals similar to hydroxyapatite
      and fluorapatite. High-resolution transmission electron microscopy showed a
      slender hexagonal shape similar to homogeneous hydroxyapatite in cross-sections
      perpendicular to the c-axis and the structural damage in the core of the crystal,
      although no boundary of step-like layers was observed. The apparent solubility in
      0.5 mol/l acetate buffer solution (37 degrees C and pH 4.0) was 12.1 +/- 0.2
      mmol/l, much less than that of homogeneous hydroxyapatite 32.3 +/- 1.9 mmol/l,
      and similar to that of heterogeneous two-layer fluoridated apatite with an outer
      fluoride-rich layer 12.5 +/- 0.6 mmol/l, which was synthesized previously by
      supplying fluoride during the latter half of the experimental period.

PMID- 10403047
TI  - The effect of poly-L-lactic acid with parallel surface micro groove on osteoblast
      like cells in vitro.
AB  - In this study we evaluated the behavior of rat bone marrow (RBM) cells on
      microgrooved poly-L-lactic acid (PLA) and polystyrene (PS) surfaces. The applied
      groove depth was 0.5, 1.0 or 1.5 microns, with a groove and ridge width of 1, 2,
      5 or 10 microns. Scanning electron microscopical examination showed that a
      collagen-rich mineralized layer of extracellular matrix (ECM) was deposited.
      Alignment of the cells and matrix to the surface grooves was observed as
      described before. Quantitative evaluation, using a tetracycline labeling assay,
      revealed that more mineralized ECM was formed on the PLA than on the PS. Further,
      PLA surfaces with a groove depth of 1.0 micron and groove widths of 1 and 2
      microns induced most mineralized ECM. Finally, alkaline phosphatase activity was
      also higher on most microgrooved PLA surfaces, compared with the other materials.
      On the basis of these observations, we concluded that microtextured surfaces are
      able to influence the differentiation of osteoblast-like cells and the deposition
      of mineralized matrix. Probably, this phenomenon can be used to increase the bone
      regeneration around oral implants.

PMID- 10403049
TI  - Bone modeling and cell-material interface responses induced by nickel-titanium
      shape memory alloy after periosteal implantation.
AB  - The purpose of this study was to evaluate the new bone formation, modeling and
      cell-material interface responses induced by nickel-titanium shape memory alloy
      after periosteal implantation. We used a regional acceleratory phenomenon (RAP)
      model, in which a periosteal contact stimulus provokes an adaptive modelling
      response. NiTi has thermal shape memory and superelasticity properties uncommon
      in other implant alloys. So far, there are insufficient data concerning the
      biocompatibility of NiTi as a bone implant. NiTi was compared to stainless steel
      (stst) and Ti-6Al-4V. The test implant was placed in contact with the intact
      femur periosteum, but it was not fixed inside the bone. Histomorphometry with
      digital image analysis was used to determine the bone formation and resorption
      parameters. The ultrastructural features of cell-material adhesion were analysed
      with scanning electron microscopy (FESEM). A typical peri-implant bone wall
      modelation was seen due to the normal RAP. The maximum new woven bone formation
      started earlier (2 weeks) in the Ti-6Al-4V group than in the NiTi (P < 0.01)
      group, but also decreased earlier, and at 8 weeks the NiTi (P < 0.05) and stst (P
      < 0.005) groups had greater cortical bone width. At 12 and 26 weeks no
      statistical differences were seen in the histomorphometric values. The
      histological response of the soft tissues around the NiTi implant was also
      clearly non-toxic and non-irritating. Cell adhesion and focal contacts were
      similar between the materials studied by FESEM. We conclude that NiTi had no
      negative effect on total new bone formation or normal RAP after periosteal
      implantation during a 26-week follow-up.

PMID- 10403050
TI  - Cell surface characteristics of microbiological isolates from human percutaneous
      titanium implants in the head and neck.
AB  - Percutaneous implants are commonly associated with several problems, and
      different failure modes have been described. Infections constitute one serious
      complication which may lead to the removal of the implant. In contrast to
      infections around polymer implants, infections around skin-penetrating titanium
      implants anchored in the temporal bone are often cured by local treatment.
      Coagulase-negative staphylococci are the most common etiological agents in
      infections related to polymers whereas Staphylococcus aureus is considered as the
      main pathogen in infections around metallic implants. Microbial adhesion is a
      prerequisite for an infection. In the present study, the cell surface of microbes
      isolated from the skin around skin-penetrating titanium implants, with and
      without signs of infection, was characterized with respect to expression of cell
      surface hydrophobicity and to binding of immobilized fibronectin, vitronectin and
      collagen type 1 which could mediate adhesion. Expression of protein binding was
      similar in strains isolated from the two groups. No strain expressed a
      hydrophobic cell surface as determined by two-phase separation, and we conclude
      that the microenvironment around a titanium implant promotes expression of a
      hydrophilic rather than a hydrophobic cell surface which in turn makes many
      infections around a titanium implant curable by local treatment.

PMID- 10403051
TI  - The influence of sample dimensions on fluoride ion release from a glass ionomer
      restorative cement.
AB  - The fluoride release from a commercial, restorative glass ionomer cement was
      found to be strongly dependent on sample surface area rather than volume. This
      was noted for disc, cylindrical- and bar-shaped specimens over periods ranging
      from 1 day to 3 yr. Release from all shapes of specimen followed the established
      pattern of an initial non-linear region followed by one where release was
      proportional to the square root of time. If fluoride levels in the cement matrix
      of specimens were artificially increased by incorporation during the mixing then
      the release pattern during the first few months was altered. The initial release
      increased for some specimen sizes and decreased for others. The dependency on
      surface area was greatly reduced for several months. By the time a year had
      elapsed the correlation between fluoride ion release and surface area had been re
      established. The influence of additional fluoride during setting can therefore
      act to perturb the normal release pattern and may in some instances reduce the
      initial fluoride release. Release should be quoted in terms of, or with
      measurements of, the surface area of specimens under investigation.

PMID- 10403052
TI  - Fabrication of porous gelatin scaffolds for tissue engineering.
AB  - A novel method which employs water present in swollen hydrogels as a porogen for
      shape template was suggested for preparing porous materials. Biodegradable
      hydrogels were prepared through crosslinking of gelatin with glutaraldehyde in
      aqueous solution, followed by rinsing and washing. After freezing the swollen
      hydrogels, the ice formed within the hydrogel network was sublimated by freeze
      drying. This simple method produced porous hydrogels. Irrespective of any rinsing
      and washing processes, water was homogeneously distributed into the hydrogel
      network, allowing the hydrogel network to uniformly enlarge and the ice to act as
      a porogen during the freezing process. Different porous structures were obtained
      by varying the freezing temperature. Hydrogels frozen in liquid nitrogen, had a
      two-dimensionally ordered structure, while the hydrogels prepared at freezing
      temperatures near -20 degrees C, showed a three-dimensional structure with
      interconnected pores. As the freezing temperature was lowered, the hydrogel
      structure gradually became more two-dimensionally ordered. These results suggest
      that the porosity of dried hydrogels can be controlled by the size of ice
      crystals formed during freezing. It was concluded that the present freeze-drying
      procedure is a bio-clean method for formulating biodegradable sponges of
      different pore structures without use of any additives and organic solvents.

PMID- 10403053
TI  - Irreversible adsorption of human serum albumin to hydrogel contact lenses: a
      study using electron spin resonance spectroscopy.
AB  - Human serum albumin (HSA) was specifically spin labelled with 4-maleimido-tempo
      (MSL) at its cysteine 34 residue (HSA-MSL). The irreversible adsorption of HSA
      MSL to hydrogel contact lenses (etafilcon A, tefilcon and vifilcon A) was
      investigated using electron spin resonance (ESR) spectroscopy. Changes in ESR
      spectral characteristics of adsorbed HSA-MSL as compared to HSA-MSL in solution
      displayed an additional immobilisation of the spin label due to the adsorption.
      This immobilisation of MSL corresponds to a large conformational alteration of
      the HSA-MSL near the modified Cys 34 residue. For both etafilcon A and tefilcon,
      the rate of irreversible adsorption was relatively slow compared with that of
      vifilcon A where the maximum state of immobilisation and hence conformational
      change occurred within the first hour of adsorption. Furthermore, tefilcon
      produced markedly different ESR spectra where a strong conformational change to a
      less mobile protein was apparent. This supported a model where the direct
      irreversible adsorption of HSA from solution dominated on tefilcon as opposed to
      conversion of the adsorbed protein from the reversible to the irreversible state
      on both etafilcon A and vifilcon A. HSA-MSL adsorption onto hydrophobic
      poly(methylmethacrylate) (PMMA) and hydrophilic poly(N-ter-butylacrylamide)
      (PTBAM) latex beads was also investigated. The spin label MSL was found to be
      less mobile when HSA was adsorbed onto PMMA compared with PTBAM beads. It was
      also found that the rate of irreversible adsorption of HSA is far higher onto
      PMMA surfaces than onto PTBAM surfaces.

PMID- 10403054
TI  - Building a bilayer model of the neuromuscular synapse.
AB  - Progress over the past 10 years has made it possible to construct a simple model
      of neurotransmitter release. Currently, some models use artificially formed
      vesicles to represent synaptic vesicles and a planar lipid bilayer as a
      presynaptic membrane. Fusion of vesicles with the bilayer is via channel proteins
      in the vesicle membrane and an osmotic gradient. In this paper; a framework is
      presented for the successful construction of a more complete model of synaptic
      transmission. This model includes real synaptic vesicles that fuse with a planar
      bilayer. The bilayer contains acetylcholine receptor (AChR) channels which
      function as autoreceptors in the membrane. Vesicle fusion is initiated following
      a Ca2+ flux through voltage-gated Ca2+ channels. Key steps in the plan are
      validated by mathematical modeling. Specifically, the probability that a
      reconstituted AChR channel opens following the release of ACh from a fusing
      vesicle, is calculated as a function of time, quantal content, and number of
      reconstituted AChRs. Experimentally obtainable parameters for construction of a
      working synapse are given. The inevitable construction of a full working model
      will mean that the minimal structures necessary for synaptic transmission are
      identified. This will open the door in determining regulatory and modulatory
      factors of transmitter release.

PMID- 10403055
TI  - Exonucleases and the incorporation of aranucleotides into DNA.
AB  - The polymerization of nucleotide analogs into DNA is a common strategy used to
      inhibit DNA synthesis in rapidly dividing tumor cells and viruses. The mammalian
      DNA polymerases catalyze the insertion of the arabinofuranosyl analogs of dNTPs
      (aranucleotides) into DNA efficiently, but elongate from the 3' aranucleotides
      poorly. Slow elongation provides an opportunity for exonucleases to remove
      aranucleotides. The exonuclease activity associated with DNA polymerase delta
      removes araCMP from 3' termini with the same efficiency that it removes a paired
      3' deoxycytosine suggesting that the proofreading exonucleases associated with
      DNA polymerases might remove aranucleotides inefficiently. A separate 30 kDa
      exonuclease has been purified from mammalian cells that removes araCMP from 3'
      termini. The activity of this enzyme in the cell could remove aranucleotides from
      3' termini of DNA and decrease the efficacy of the analogs. Inhibition analysis
      of the purified exonuclease shows that this enzyme is inhibited by thioinosine
      monophosphate (TIMP) with a Ki = 17 microM. When high TIMP levels are generated
      in HL-60 cells, incorporation of araC in DNA is increased about 16-fold relative
      to total DNA synthesis. This increased araC in DNA is likely a result of
      exonuclease inhibition in the cell. Thus, exonucleases in cells might play an
      important role in removing aranucleotides inserted by DNA polymerases.

PMID- 10403056
TI  - Characterization of arachidonic acid-induced apoptosis.
AB  - Tumor necrosis factor (TNF) can induce apoptosis in a number of different cell
      types. This response often depends on the activity of cytosolic phospholipase A2
      (cPLA2), which catalyzes the release of arachidonic acid from the sn-2 position
      of membrane phospholipids. In this study, we investigate the ability of
      arachidonic acid itself to cause cell death. We show that in assays with 10%
      fetal bovine serum (FBS) arachidonic acid will not kill, nor does act
      synergistically with TNF. In contrast, by lowering the concentration of FBS to
      2%, it is possible to use arachidonic acid to induce cell death. Arachidonic acid
      induced cell death was judged to be apoptotic based on morphology and the
      cleavage of poly(ADP)ribose polymerase. Arachidonic acid was able to kill all
      cell lines tested including two human melanoma-derived cell lines, and
      susceptibility to arachidonic acid was not influenced by adenovirus gene products
      that control susceptibility to TNF. Finally, we show that arachidonic acid is
      unique among 20 carbon fatty acids for its ability to induce apoptosis and that
      several other unsaturated, but not saturated fatty acids can also induce
      apoptosis.

PMID- 10403057
TI  - Protein tyrosine kinase-mediated pathways in G protein-coupled receptor
      signaling.
AB  - Abundant evidence has indicated that protein tyrosine kinases (PTKs) convey
      signals from G protein-coupled receptors (GPCRs) to regulate cell proliferation,
      migration, adhesion, and potentially cellular transformation. Molecular
      mechanisms by which PTKs regulate such diverse effects in GPCR signaling are not
      well understood. Recently, an unifying theme has emerged where both growth
      factors and GPCRs utilize protein tyrosine kinase activity and the highly
      conserved Ras/MAP kinase pathway to control mitogenic signals. Additionally, PTKs
      are also involved in the regulation of signal transmission from GPCRs to
      activation of the JNK/SAPK kinase pathway. Furthermore novel insights in
      chemokine receptor-activated PTKs and their role in mediating cell functions are
      discussed in this review.

PMID- 10403058
TI  - How many is enough? Exploring the myosin repertoire in the model eukaryote
      Dictyostelium discoideum.
AB  - The cytoplasm of eukaryotic cells is a very complex milieu and unraveling how its
      unique cytoarchitecture is achieved and maintained is a central theme in modern
      cell biology. It is crucial to understand how organelles and macro-complexes of
      RNA and/or proteins are transported to and/or maintained at their specific
      cellular locations. The importance of filamentous-actin-directed myosin-powered
      cargo transport was only recently realized, and after an initial explosion in the
      identification of new molecules, the field is now concentrating on their
      functional dissection. Direct connections of myosins to a variety of cellular
      tasks are now slowly emerging, such as in cytokinesis, phagocytosis, endocytosis,
      polarized secretion and exocytosis, axonal transport, etc. Unconventional myosins
      have been identified in a wide variety of organisms, making the presence of actin
      and myosins a hallmark of eukaryotism. The genome of S. cerevisiae encodes only
      five myosins, whereas a mammalian cell has the capacity to express between two
      and three dozen myosins. Why is it so crucial to arrive at this final census? The
      main questions that we would like to discuss are the following. How many distinct
      myosin-powered functions are carried out in a typical higher eukaryote? Or, in
      other words, what is the minimal set of myosins essential to accomplish the
      multitude of tasks related to motility and intracellular dynamics in a
      multicellular organism? And also, as a corollary, what is the degree of
      functional redundancy inside a given myosin class? In that respect, the choice of
      a model organism suitable for such an investigation is more crucial than ever.
      Here we argue that Dictyostelium discoideum is affirming its position as an ideal
      system of intermediate complexity to study myosin-powered trafficking and is or
      will soon become the second eukaryote for which complete knowledge of the whole
      repertoire of myosins is available.

PMID- 10403059
TI  - A potentially exhaustive screening strategy reveals two novel divergent myosins
      in Dictyostelium.
AB  - In recent years, the myosin superfamily has kept expanding at an explosive rate,
      but the understanding of their complex functions has been lagging. Therefore,
      Dictyostelium discoideum, a genetically and biochemically tractable eukaryotic
      amoeba, appears as a powerful model organism to investigate the involvement of
      the actomyosin cytoskeleton in a variety of cellular tasks. Because of the
      relatively high degree of functional redundancy, such studies would be greatly
      facilitated by the prior knowledge of the whole myosin repertoire in this
      organism. Here, we present a strategy based on PCR amplification using degenerate
      primers and followed by negative hybridization screening which led to the
      potentially exhaustive identification of members of the myosin family in D.
      discoideum. Two novel myosins were identified and their genetic loci mapped by
      hybridization to an ordered YAC library. Preliminary inspection of myoK and myoM
      sequences revealed that, despite carrying most of the hallmarks of myosin motors,
      both molecules harbor features surprisingly divergent from most known myosins.

PMID- 10403060
TI  - Uptake of reconstituted Na,K-ATPase vesicles by isolated lymphocytes measured by
      FACS, confocal microscopy and spectrofluorometry.
AB  - Na,K-ATPase (EC 3.6.1.37, Na,K-ATPase) is a fundamental vital membrane transport
      and receptor system which, after biosynthesis, is exported to the plasma membrane
      in inside-out vesicles. Na,K-ATPase can be extracted form the natural membrane
      and inserted into artificially formed phosphatidylcholine vesicles (liposomes).
      The ultrastructure of the reconstituted vesicles has been fully described. In the
      present work, the Na,K-ATPase-vesicles were labeled with fluorescent tracers
      either in their water or membrane phase, incubated with freshly isolated human
      lymphocytes, and the resulting cellular fluorescence measured with fluorescence
      activated cell sorting (FACS), confocal microscopy and spectrofluorometry. The
      FACS data show that all lymphocytes take up Na,K-ATPase-vesicles in a dose- and
      temperature-dependent fashion. Three-dimensional analysis of the fluorescence by
      confocal microscopy reveals that the fluorescence is contained within the cells.
      Quantitative determination by spectrofluorometry indicates that depending on the
      vesicle/cell ratio, a single lymphocyte takes up 650 to 36,500 vesicles within 30
      min at 37 degrees C together with up to about 200,000 renal Na,K-ATPase
      molecules.

PMID- 10403061
TI  - Migrainous visual phenomena in the general population.

PMID- 10403062
TI  - Characteristics and prevalence of transient visual disturbances indicative of
      migraine visual aura.
AB  - The objective of this study was to estimate the prevalence of and to compare the
      characteristics of transient visual disturbances (TVDs) of possible migraine
      origin in a clinical and a general population. Data were obtained in interviews
      from 100 consecutive female migraine patients (17-69 years) and 245 women (40-75
      years) from the general population. The lifetime prevalences were 37% and 13%,
      respectively. We did not detect any differences in characteristics of TVDs
      between patients and women in the general population. A gradual onset of five or
      more minutes was stated by as few as 45% and 46%, respectively. The typical
      headache phase in conjunction with a TVD had more migrainous features in
      patients. We conclude from our data that the TVDs in this study, which do not
      fulfill the IHS criteria for migraine with aura, more likely represent poorly
      described or abortive migraine phenomena, rather than phenomena of other origin.

PMID- 10403063
TI  - Dynamic changes of cognitive habituation and serotonin metabolism during the
      migraine interval.
AB  - Migraine patients show a specific cognitive processing with a loss of habituation
      in the interval and a normal habituation in the attack as measured by event
      related potentials (ERPs). It is unknown whether the loss of habituation changes
      during the migraine interval or is a stable state. Serotonin (5HT) metabolism is
      involved in the pathophysiology of migraine and also in the generation of ERPs.
      We enrolled 14 patients with regular migraine attacks in order to measure
      visually evoked ERPs repetitively during the migraine interval and in the
      migraine attack. Cognitive habituation was evaluated by analysis of P3 latency.
      Platelet serotonin content and free serotonin plasma level were measured at the
      same time points. The loss of habituation increased continuously during the
      migraine interval and abruptly normalized in the migraine attack (p < 0.05, time
      series analysis). The platelet 5HT content decreased significantly in the
      migraine attack (p < 0.03) and was at its maximum in the middle of the interval.
      The P3 latency was significantly increased in the attack (p < 0.01) and was
      significantly inversely correlated with the platelet 5HT content (r = -0.44, p <
      0.001). Free 5HT plasma levels did not show any significant change. Our findings
      suggest that loss of cognitive habituation continuously increases during the
      migraine interval until its normalization in the migraine attack. This phenomenon
      cannot be attributed to serotonergic transmission. In patients with regular
      changes of cognitive habituation before the migraine attack, it might be possible
      to predict the attack by analysing ERPs.

PMID- 10403064
TI  - Transcranial Doppler evaluation of cerebral hemodynamics in migraineurs during
      prophylactic treatment with flunarizine.
AB  - Transcranial Doppler (TCD) recording was used to evaluate the mean flow velocity
      (MFV) and cerebrovascular reactivity to CO2 in 21 migraineurs during the
      interictal phase. Nine were affected by migraine with aura (MwA) and 12 by
      migraine without aura (MwoA). During each session the middle cerebral artery
      (MCA) flow velocity was examined in basal conditions, in hypocapnia after a 3-min
      period of hyperventilation, in basal conditions a second time, and in hypercapnia
      after breath-holding. The same procedure was followed in a group of 21 age- and
      sex-matched volunteers. Recordings were performed before (T1), during (T2), and
      after (T3) prophylactic treatment with flunarizine (10 mg/day for 2 months) to
      assess the possible effect of this drug on cerebral hemodynamics. In basal
      condition, increased MFV values were found in both MwA and MwoA patients. In MwA
      patients the reactivity index (RI) to hypocapnia was significantly increased in
      T1 (p < 0.05). This abnormal cerebrovascular reactivity disappeared during
      flunarizine treatment (T2) and in the post-therapy period (T3).

PMID- 10403065
TI  - Validation of a migraine work and productivity loss questionnaire for use in
      migraine studies.
AB  - Migraine symptoms and therapy side effects cause significant functional
      disability that can result in work and productivity losses. Effective, well
      tolerated migraine therapy with rapid onset of relief could decrease work and
      productivity losses. The Migraine Work and Productivity Loss Questionnaire
      (MWPLQ) evaluates the impact of migraine and migraine therapy on paid work. Data
      from a randomized, open-label extension study were collected over 3 months.
      Migraineurs were randomized to either rizatriptan (5HT1B/1D receptor agonist) or
      their usual migraine therapy. Data were analyzed from 164 patients who
      experienced at least one work-related migraine. Internal consistency (Cronbach's
      alpha) for the work difficulty domains ranged from 0.80 to 0.95. Work loss and
      work difficulty were moderately correlated (r = 0.39-0.58) with migraine severity
      and functional ability. Differences were found favoring rizatriptan for
      absenteeism (1.3 vs 2.4 h), effectiveness at work (62% vs 49%), and difficulty
      with work-related tasks (p < 0.01). The MWPLQ demonstrated favorable measurement
      characteristics in this study and could be an important research tool for future
      evaluations of migraine-related work disability.

PMID- 10403066
TI  - Incremental absenteeism due to headaches in migraine: results from the Mig-Access
      French national cohort.
AB  - OBJECTIVE: To assess the costs of headache-related absenteeism of community
      dwelling migraineurs, and to compare the amount of absenteeism between
      migraineurs aged 18 and older and age, sex, and occupation-matched nonheadache
      prone subjects. DESIGN: Follow-up over a 3-month period. SAMPLES: 385 migraineurs
      and 313 nonheadache subjects representative of the setting. METHODS: Every day,
      the participants recorded the presence of headache, if any, and the work
      situation (unemployment, holiday, weekend, medical reason, nonmedical reason).
      Sickness-related absenteeism was the number of workdays missed or interrupted for
      medical reasons. Headache-related absenteeism was the sickness-related
      absenteeism during workdays with headaches. The annual headache-related
      absenteeism costs in France were extrapolated from these data in accordance with
      the mean income per occupational category. The incremental absenteeism and
      related costs were the difference between the two samples. RESULTS: Of working
      migraineurs, 20% had at least one period of absenteeism. During the 3 months,
      they missed or interrupted on average 1.4 days for medical reasons, 0.25 of which
      for headaches. Sickness-related absenteeism was statistically higher in
      migraineurs than in nonheadache-prone subjects. This difference was due to a
      higher absenteeism for comorbidity reasons, not for headache reasons,
      representing 20% of all sickness-related absenteeism. Migraineurs avoided sick
      leave for headache reasons. As an incremental total, 1.68 days or approximately
      0.7% of the annual number of working days are lost on average per individual with
      migraine. The annual incremental headache-related absenteeism cost was 5.22
      billions, i.e. 1,551 FF (US$240) per migraineur.

PMID- 10403067
TI  - Migraine prescription density and recommendations. Results of the PCAOM Study.
AB  - We estimate the extent to which recommendations on the prevention and treatment
      of migraine issued by professional medical bodies are implemented in medical
      practice in Germany. Computerized data (MediPlus, IMS Health) were analyzed in
      4,636 male and 16,573 female migraineurs from 383 primary care practices 1994
      through 1996 (Primary Care of Migraine, PCAOM study). A total of 90,540 drug
      prescriptions with a documented diagnosis of migraine were issued in 45,669
      person-years (1,492 prescriptions [DM 40.99] per person-year to men, 2,109
      prescriptions [DM 62.01] per person-year to women). Approximately three of every
      four prescriptions were incompatible with the recommendations of the German
      Migraine and Headache Society (DMKG), amounting to extrapolated costs of DM 49
      million per year borne by the German statutory health insurance fund for
      combination migraine preparations. The density of non-DMKG therapies for
      diagnosed migraine followed a sigmoid curve with increasing patient age, while
      DMKG-compliant therapies described a bell-shaped curve. Referrals to neurological
      care specialists were not associated with subsequent primary care focus on
      recommended therapies. We conclude that medication prescribed for migraine is
      largely not according to long-standing recommendations by medical societies in
      Germany.

PMID- 10403068
TI  - Primary headache care delivery by nonspecialists in Brazil. Brazilian Headache
      Care Cooperative Group.
AB  - Headaches are common disorders usually examined by nonneurologists. In order to
      assess how primary headache patients (IHS groups 1, 2, and 3) are generally
      managed by nonspecialists, 414 patients were asked about their previous headache
      care. Correct diagnosis had previously been made in only 44.9%, 6.7%, and 26.7%
      of the migraine, tension-type headache, and cluster headache patients,
      respectively. The patients underwent 501 investigative procedures motivated by
      the headache, averaging 1.21 examinations per patient, mostly EEGs. Preventive
      treatment was largely overlooked irrespective of the headache type. It is
      concluded that scientific improvements in headache care may be ineffective unless
      educational programs improve headache knowledge in general.

PMID- 10403069
TI  - Efficacy and safety of rizatriptan wafer for the acute treatment of migraine.
      Rizatriptan Wafer Protocol 049 Study Group.
AB  - Rizatriptan is a potent, highly selective 5HT1B/1D agonist with rapid onset of
      action for acute treatment of migraine. Rizatriptan wafer is a novel, freeze
      dried dosage formulation of rizatriptan which rapidly disintegrates on the
      tongue, is swallowed with saliva, and may be taken without liquids. The efficacy
      and tolerability of rizatriptan wafer were examined in a placebo-controlled,
      double-blind, outpatient study in 555 migraineurs. The primary efficacy endpoint
      was pain relief at 2 h. From 30 min onwards, significantly more patients
      experienced pain relief and became pain-free after rizatriptan 10-mg wafer
      compared to placebo. At 2 h, the percentage of patients with pain relief was
      significantly higher after rizatriptan 10-mg wafer (74%), 5-mg wafer (59%)
      compared with placebo (28%). Rizatriptan 10-mg wafer was superior to rizatriptan
      5-mg wafer on pain relief at 1.5 and 2 h (p < 0.05). Significantly more patients
      were pain-free at 2 h after rizatriptan 10-mg wafer (42%), 5-mg wafer (35%)
      compared with placebo (10%). Both doses of rizatriptan wafer were well tolerated.
      Rizatriptan wafer is a convenient, highly effective new formulation for acute
      treatment of migraine.

PMID- 10403070
TI  - Use of amitriptyline and fluoxetine in prophylaxis of migraine and tension-type
      headaches.

PMID- 10403071
TI  - Coincidence of familial hemiplegic migraine and hemicrania continua? A case
      report.
AB  - A case is presented of a 39-year-old woman with a history of simultaneous
      Familial hemiplegic migraine (FHM) and hemicrania continua (HC). The family
      history of the patient revealed different types of migraine and cyclic syndromes
      in childhood in four generations. The possible links between FHM and HC are
      discussed. The pedigree gives further evidence that cyclic syndromes in childhood
      belong to the spectrum of migraine.

PMID- 10403072
TI  - Vasoconstrictive properties of the 5HT1B/1D agonists: response to Dahlof and
      Mathew.

PMID- 10403073
TI  - Hematologic values and appearances in the healthy fetus, neonate, and child.
AB  - Morphologic and laboratory aspects of diagnostic pediatric hematology are
      reviewed, including developmental hematopoiesis in normal fetal blood, the
      principal morphologic features unique to examination of pediatric blood samples,
      special preanalytic considerations for the laboratory, and important analytic
      interferences common in the pediatric setting.

PMID- 10403074
TI  - The influence of developmental haemostasis on the laboratory diagnosis and
      management of haemostatic disorders during infancy and childhood.
AB  - The physiology of the hemostatic system in children is different from that in
      adults. Reference ranges for components of the hemostatic system are age
      dependent. During early childhood, physiologic values may overlap with values
      observed in congenital deficiencies of acquired pathological conditions.
      Physiologically decreased plasma concentrations of hemostatic components also
      influence the response to antithrombotic therapy. The relevance of developmental
      hemostasis for the laboratory diagnosis and management of hemorrhagic and
      thrombotic disorders during childhood is discussed.

PMID- 10403075
TI  - Quantitative and qualitative platelet disorders.
AB  - Platelet disorders are common during childhood. Those conditions that are
      clinically significant are generally diagnosed with ease. Qualitative platelet
      disorders rarely cause clinical problems. The armamentarium of diagnostic tests,
      although limited, is usually satisfactory to allow for accurate diagnosis and
      effective treatment of those children with platelet disorders who are at risk of
      hemorrhage.

PMID- 10403076
TI  - Hemolytic anemia in children.
AB  - This article provides an overview of hemolytic anemia in children. Main focus
      areas include acquired immune-mediated hemolysis, hemolytic anemia due to
      hereditary RBC disorders, hereditary hemolytic disorders caused by enzyme
      abnormalities, and hereditary hemolytic anemia due to hemoglobin abnormalities.

PMID- 10403077
TI  - Bone marrow failure syndromes.
AB  - Laboratory diagnosis of inherited bone marrow failure syndromes includes general
      evaluations, such as blood counts, examination of the peripheral blood smear for
      morphology, and bone marrow aspirates and biopsies, which may help the clinician
      classify the patient, particularly if there are no characteristic physical
      anomalies. Specific diagnoses require unique tests that are only available for a
      few of the diagnoses. The most useful is chromosome breakage in the diagnosis of
      FA, with gene mutation analysis or mapping about to become the gold standard when
      all of the FA genes have been cloned. The diagnosis of DC remains clinical at
      this time, although linkage to Xq28 and skewed maternal X inactivation may be
      helpful in some families. Laboratory proof of SD may be provided by decreased
      serum trypsinogen or other evidence of exocrine pancreatic insufficiency. CHH is
      substantiated when absent central pigment in hair is found and when it is mapped
      to 9p21-p13. The only mitochondrial syndrome, PS, is proved with demonstration of
      deleted mitochondrial DNA. RD is diagnosed from blood and marrow studies that
      demonstrate lack of lymphoid as well as myeloid activity. Amega requires absent
      or abnormal marrow megakaryocytes; if radii are also absent, the diagnosis is
      TAR. DBA usually has elevated red-cell ADA, and the DBA locus may map to 19q13.
      KS is diagnosed in patients who have congenital nonimmune severe neutropenia.
      Clinical suspicion of particular diagnoses can often be substantiated by
      laboratory tests of varying specificity.

PMID- 10403078
TI  - The histiocytoses.
AB  - The histiocytoses, systemic disorders of the dendritic or macrophage lines, are
      an enigmatic group of disorders. It is hoped that by better understanding and
      identification of the responsible cells in each of the various conditions, their
      biological nature will become apparent. Because they are unusual, only multi
      institutional groups, such as the Histiocyte Society, will be able to collect
      enough examples and bring a standardized approach to their evaluation. Those
      interested in joining the Histiocyte Society are invited to apply by contacting
      the Histiocyte Society, 302 N Broadway, Pitman, NJ 08071.

PMID- 10403079
TI  - Transient myeloproliferative disorder (transient leukemia) and hematologic
      manifestations of Down syndrome.
AB  - Transient Myeloproliferative Disorder (Transient Leukemia) is found in
      approximately 10% of newborn infants with Down Syndrome. It is characterized by
      the large numbers of megakaryoblasts in the peripheral blood, variable
      thrombocytopenia and, in a minority of cases, by a lethal course with hydrops
      fetalis or progressive hepatic fibrosis. Evidence is presented that this disease
      is truly leukemia, which, in most cases, recovers spontaneously. There is
      evidence that hematopoiesis is abnormal in Down Syndrome children who do not have
      leukemia. These abnormalities of red cells, platelets, and granulocytes are
      reviewed.

PMID- 10403080
TI  - Acute lymphoblastic leukemia.
AB  - This article reviews the laboratory methodologies used to evaluate acute
      lymphoblastic leukemia (ALL) in children and their role in establishing a
      diagnosis and prognosis of this disease. These methodologies are: morphology,
      flow cytometry, cytogenetics, and molecular diagnostics. Additionally,
      immunophenotypic classifications of ALL and criteria for establishing a diagnosis
      of ALL independent of morphology are described.

PMID- 10403081
TI  - Diagnosis of childhood acute myeloid leukemia.
AB  - Since 1985, our knowledge of the biology of acute leukemias has been greatly
      enhanced by new investigative tools and techniques. This new information in turn
      has produced improved diagnostic criteria, new classifications, and tailored
      therapeutic approaches for the acute leukemias. The intent of the following
      article is to present the clinical and laboratory features that facilitate a
      diagnosis of AML and provide insight into the biologic basis and treatment of
      these disorders.

PMID- 10403082
TI  - Intrauterine fetal diagnosis for hematologic and other congenital disorders.
AB  - Advances in prenatal diagnostic techniques allow for earlier, more rapid, and
      more effective detection of congenital disorders. The indications, diagnostic
      accuracy, and risks for invasive diagnostic techniques including amniocentesis,
      chorionic villus sampling, and fetal blood sampling are reviewed. Recent advances
      in non-invasive detection methods, such as fetal ultrasound and the isolation of
      fetal cells in the maternal circulation are discussed. Additionally, the
      intrauterine diagnosis of congenital infections and chromosomal and Mendelian
      disorders, as well as hematologic disorders are summarized.

PMID- 10403083
TI  - Methodological issues in longitudinal epidemiologic studies of dental caries.
AB  - As longitudinal epidemiologic studies of dental caries address increasingly
      complex research questions, approaches to analysis of data from those studies
      have become more sophisticated. This review examines methods available for
      analyzing and reporting data from such studies. Traditional analytic methods
      utilize the DMFS increment as the outcome measure in longitudinal studies of
      caries. However, two other outcome measures may be needed to address some
      research issues: cumulative incidence, which quantifies caries risk; and
      incidence density, which quantifies caries rate. Four major analytic decisions
      have to be addressed when computing DMFS increment: examiner misclassification
      ("reversals"), teeth lost due to caries, findings from more than two
      examinations, and multiple events such as caries initiation and progression. We
      present a uniform approach for enumerating caries events that permits the same
      analytic decisions made in calculating DMFS increment to be applied to cumulative
      incidence and incidence density calculations. In view of the variety of analytic
      decisions that must be made when enumerating events in longitudinal studies of
      caries, authors should specify how all potential changes in caries status were
      handled. Furthermore, if a study uses more than one outcome measure, the same
      decisions for enumerating events should be used when computing those measures.

PMID- 10403084
TI  - The shortened dental arch concept and its implications for oral health care.
AB  - The minimum number of teeth needed to satisfy functional demands has been the
      subject of several studies. However, since functional demands--and consequently
      the number of teeth needed--can vary from individual to individual, this minimum
      number cannot be defined exactly. In general, occlusion of a complete dental arch
      is preferable. However, this goal might be neither attainable, for general,
      dental or financial reasons, nor necessary. Many studies demonstrate that
      shortened dental arches comprising the anterior and premolar regions can meet the
      requirements of a functional dentition. Consequently, when priorities have to be
      set, restorative therapy should be aimed at preserving the most strategic parts
      of the dental arch: the anterior and premolar regions. This also implies that in
      cases of a shortened dental arch, the prompt replacement of absent posterior
      molars by free-end removable partial dentures leads to overtreatment and
      discomfort. The shortened dental arch concept is based on circumstantial
      evidence: it does not contradict current theories of occlusion and fits well with
      a problem-solving approach. The concept offers some important advantages and may
      be considered a strategy to reduce the need for complex restorative treatment in
      the posterior regions of the mouth.

PMID- 10403085
TI  - Dental fluorosis among persons exposed to high- and low-fluoride drinking water
      in western Norway.
AB  - The aim of this project was to study the prevalence and severity of dental
      fluorosis among persons exposed to moderate- to high- or low-fluoride drinking
      water in western Norway, and to assess the risk factors involved. Subjects aged 5
      to 18 years who had been lifelong consumers of moderate- to high-fluoride
      groundwater (> or = 0.50 mg F/L) were selected for the study (n = 113). A
      comparison group (n = 105) was chosen among consumers of low-fluoride surface
      water (approximately 0.10 mg F/L) in the same district. The Thylstrup-Fejerskov
      (TF) Index was used to score dental fluorosis. A questionnaire was used to obtain
      information on fluoride exposure and other relevant factors. Among the consumers
      of low-fluoride water 14.3% showed dental fluorosis (TF score 1-2) as compared to
      78.8% in the group consuming moderate- to high-fluoride water (TF scores 1-7).
      Premolars were most frequently affected, but severe cases (TF scores 3-7) were
      equally prevalent in maxillary central incisors and first molars. In logistic
      regression analysis with TF score 0 or TF score > or = 1 as the dependent
      variable, only fluoride concentration in the drinking water was associated with a
      statistically increased risk of dental fluorosis (odds ratio: 18.9; 95% CI: 8.85
      40.44). In the study area, which was characterised by multiple fluoride sources,
      uncontrolled groundwater with moderate to high fluoride content was the most
      important factor in the development of dental fluorosis. In order to prevent
      dental fluorosis, groundwater wells should routinely be analysed for fluoride.

PMID- 10403086
TI  - Perceptions of susceptibility to oral health hazards: a study of women in
      different cultures.
AB  - People typically attribute lower health risks to themselves than to others, a
      phenomenon called unrealistic optimism. OBJECTIVES: The purpose of this study was
      to investigate how women's perceived susceptibility to tooth decay is related to
      information from various sources, trust in these sources and personal experience
      with risk factors. Comparative risk judgments for oral health hazards were also
      investigated. METHODS: Two samples of women were included. In 1997, a random
      sample of adults (n = 1190) aged 25 years, from three counties of western Norway,
      were invited to complete postal questionnaires at home. A total of 735 adults
      (62%) responded, of whom 374 (51%) were women. During July 1997, a convenient
      sample of 140 women, aged 15-40 years, participated in a structured interview at
      a Maternal Child Health clinic in Arusha town, Tanzania. RESULTS: Among the
      Tanzanian women, information from health workers and media, trust in these
      sources, symptoms of tooth decay and intake of sugared foods were significantly
      related to perceived risk for tooth decay. Pearson's correlation coefficients
      varied from r = 0.47, P < 0.001 (trust in health workers) to r = 0.20, P < 0.05
      (intake of sugared foods). In both groups of women all mean ratings of
      comparative risk differed significantly (P < 0.001) from the midpoint of the
      scales (marked same risk as others), as tested by one sample t-test (test value =
      0). The range of t-values was from t = -12.7 (dental fluorosis) to t = -18.2
      (tooth decay) and from t = -4.9 (gum disease) to t = -8.3 (loss of teeth) among
      the Tanzanian and Norwegian women, respectively. CONCLUSIONS: When judging their
      susceptibility for tooth decay, Tanzanian women seem to consider both information
      from health workers and their personal risk experience. Optimism in comparative
      risk judgments for oral health hazards was evident among both the Tanzanian and
      the Norwegian women investigated. These findings are discussed in the context of
      implications for oral health education.

PMID- 10403087
TI  - Geographic variations in dental services provided to older adults in Ontario,
      Canada.
AB  - In an initial study, Leake et al. (J Public Health Dent 1996; 52: 182-90) found
      that older Ontarians living in metropolitan communities received almost twice the
      amount of dental care than older Ontarians living in non-metropolitan
      communities. Since data were collected for the 2 years prior to the enrollment of
      subjects in a longitudinal study, factors responsible for this variation could
      not be explored. This paper extends these findings by examining the volume of
      dental services received by these subjects in the 3 years between the baseline
      and follow-up phases of the longitudinal study. During this 3-year period,
      geographic variations in the volume of services provided were also observed. In a
      regression analysis, geographic location remained a significant predictor of the
      number of services received after controlling for six other explanatory
      variables: insurance coverage, number of teeth, restorative treatment need, self
      rated oral health, regular dental visits and use of specialist services.
      Together, these explained only 24% of the variance in service provision. Since
      patient-reported outcomes were better in the communities with higher volumes of
      provision, further research concerning the patient and dentist factors
      influencing treatment provision is warranted.

PMID- 10403088
TI  - The occurrence of toothwear in users of Ecstasy (3,4
      methylenedioxymethamphetamine).
AB  - Ecstasy users have reported that dry mouth, jaw tension and tooth grinding were
      common side effects of its use although the influence of these effects upon
      toothwear have not been previously investigated. OBJECTIVE: This study aimed to
      compare incisal and occlusal toothwear in Ecstasy users and a group of non-users
      of Ecstasy but users of other drugs. METHODS: Groups were established by a
      snowball peer information network from visitors to the "drop-in" Maryland Centre
      in Liverpool. Volunteers completed a questionnaire about social life, drug use
      and diet. Clinical examination for wear on the incisal edges and on canine tips
      was conducted with a mirror and probe, whereas occlusal wear was recorded in
      impressions and subsequently scored from stone replica casts. The degree of
      toothwear was scored according to the criteria of the Tooth Wear Index (Smith &
      Knight, Br Dent J 1984;157:16). RESULTS: Ecstasy users (n = 30) were compared
      with non-users (n = 28). Toothwear through the enamel into the underlying dentine
      occurred in 18 (60%) Ecstasy users but in only three (11%) non-users. The overall
      mean toothwear score in Ecstasy users was 0.63 compared with 0.16 in non-users (t
      = 4.34, P < 0.001). Dry mouth was reported by 93% of Ecstasy users whilst 89%
      stated that they clenched or ground their teeth after taking the drug. Tooth
      grinding commonly continued into the following morning. Carbonated (acidic)
      beverages were consumed by 93% of the users with a mean of three cans per "trip".
      CONCLUSION: The severity of toothwear and the number of teeth affected were
      greater in Ecstasy users than in a group of non-users. The occlusal surfaces were
      more commonly affected than the incisal, which may indicate jaw clenching rather
      than grinding as a feature of Ecstasy-induced muscle hyperactivity.

PMID- 10403089
TI  - Fluoride intake from foods, beverages and dentifrice by young children in
      communities with negligibly and optimally fluoridated water: a pilot study.
AB  - While the level of fluoride intake that affords optimal cariostatic efficacy
      without causing dental fluorosis is not precisely known, it has been suggested
      that the threshold of fluoride exposure above which fluorosis may occur is
      between 0.05 and 0.07 mg/kg/day. OBJECTIVE: To monitor and compare fluoride
      intake from diet and dentifrice use (theoretical F: 0.10-0.11%) by three groups
      of 16- to 40-month-old children: two groups living in the negligibly water
      fluoridated communities of San Juan, Puerto Rico, and Connersville, Indiana, and
      the third group residing in the optimally water-fluoridated region of
      Indianapolis, Indiana. METHODS: Fluoride intake from diet was monitored by the
      "duplicate plate" method, and fluoride ingested from dentifrice was determined by
      subtracting the amount of fluoride recovered after brushing from the amount
      originally placed on the child's toothbrush. RESULTS: The mean combined amount of
      fluoride ingested daily by children living in the negligibly fluoridated
      communities was not significantly different from that ingested by children in the
      fluoridated community. The major component of fluoride ingested by children in
      the negligibly fluoridated communities came from fluoridated dentifrice, and in
      the fluoridated area children ingested as much fluoride from toothpaste as they
      did from beverages. In San Juan mean daily fluoride intake was within the
      estimated range for safe fluoride exposure; however, in the "halo" community of
      Connersville and in Indianapolis, daily fluoride ingested by many of the children
      may have exceeded this level. CONCLUSION: Attention needs to be given, in
      negligibly water-fluoridated as well as in optimally water-fluoridated
      communities, to reducing the daily intake of fluoride by young children in order
      to avoid putting them at risk of developing dental fluorosis.

PMID- 10403090
TI  - The role of age- and population-based differences in the attitudes, knowledge and
      infection control practices of Canadian dentists.
AB  - OBJECTIVES: To investigate age- and population-based differences in dentists'
      infection control practices and willingness and refusal to treat patients with
      HIV. METHODS: A national mailed survey of a stratified random sample of dentists
      in Canada (n = 6444) with three follow-up attempts. Pearson's chi-square test and
      multiple logistic regression were used for data analysis. Predictor variables
      included population, age, gender, marital status, specialty, number of patients
      treated per day and continuing education on HIV/AIDS. RESULTS: The adjusted
      response rate was 66.4%. The best predictors of willingness to treat patients
      with HIV were younger age (compared with dentists > or = 60 years of age: < 30
      years, OR = 8.6, 30-39, OR = 3.4; 40-49, OR = 2.7; 50-59, OR = 1.6), attending
      continuing education on HIV/AIDS in the past 2 years (> 10 hours, OR = 1.6
      compared with zero hours), practicing in small population centres < 10,000 (OR =
      1.6 compared with > 500,000) and gender (male OR = 1.3). The best predictors of
      refusal to treat patients with HIV were older age (compared with dentists < 30
      years of age: > or = 60, OR = 6.1; 50-59, OR = 4.1; 40-49, OR = 3.0; 30-39, OR =
      2.6); and practicing in population centres > 500,000 (OR = 1.5 compared with <
      10,000). However, the latter group also reported treating more HIV patients than
      respondents in smaller communities. Infection control practices varied
      significantly with age and population centre. Dentists in communities of < 10,000
      were more compliant with HBV vaccination, but less compliant with handwashing
      after degloving and the use of infection control manuals. Similarly, dentists >
      60 years of age were the least compliant with HBV immunization, routine use of
      barriers and sterilization of handpieces, but reported the highest compliance
      with handwashing. CONCLUSIONS: Age- and population-based differences need to be
      considered in planning educational interventions to improve both access to care
      for patients with HIV and dentists' compliance with recommended infection control
      procedures.

PMID- 10403091
TI  - Estimation of the fraction of an ingested dose of fluoride excreted through urine
      in pre-school children.
AB  - OBJECTIVE: To determine the fraction of an ingested fluoride dose of 1 mg in 50
      mL orange juice that is excreted through the urine (FUEF) of children aged 3-5
      years. METHODS: Eighty-eight controlled determinations involving 24-hour urinary
      collections from a total of 48 children were carried out during consecutive
      control and test days. Net fluoride urinary excretion due to the ingested dose
      was calculated as the difference between the total amount of fluoride excreted by
      each child on test and control days. RESULTS: Excretion of the fluoride ingested
      from the single fluoride dose presented an average value of 30.7% (95% CI: 28.9
      32.5%). No significant associations were found between individual FUEF values
      with either anthropometrical variables or urinary pH values. The average FUEF
      value found in the present study lies between previously reported values for
      infants and young adults. The epidemiological usefulness of the FUEF values in
      estimating daily fluoride dose in pre-school children is discussed.

PMID- 10403092
TI  - Beta-blocker therapy in heart failure: pathophysiology and clinical results.

PMID- 10403093
TI  - Prenatal diagnosis of complicated abdominal wall defects.
AB  - The accurate prenatal diagnosis of anterior abdominal wall defects is important
      because it affects patient management and prognosis. The pathophysiology of each
      defect leads to key characteristics that make it possible to differentiate one
      entity from another. Among these features are the location of the defect in
      relation to cord insertion, the size and contents of the defect, and the
      associated anomalies. This article reviews the underlying defects, the
      characteristic ultrasound findings, the associated anomalies, and the prognosis
      of simple and complicated abdominal wall defects. The basic features of simple
      abdominal wall defects (i.e., omphalocele and gastroschisis) were used as the
      initial points of assessment. A comparison of the different features of these
      abnormalities and how they differ from one another resulted in the development of
      criteria that facilitated the understanding of the different ultrasound
      manifestations of these anomalies.

PMID- 10403095
TI  - Practical approach to the identification of clinically relevant Enterococcus
      species.
AB  - Enterococci have become important nosocomial pathogens, with Enterococcus
      faecalis and then Enterococcus faecium predominating. Because of the emergence of
      glycopeptide (vancomycin and teicoplanin) resistance in enterococci, laboratories
      have been required to screen for resistant strains and to identify them to the
      species level. This has resulted in the need for accurate identification of
      species less commonly associated with clinical infections, such as Enterococcus
      casseliflavus and Enterococcus gallinarum, which are inherently resistant to the
      glycopeptides. Studies evaluating commonly used commercial identification
      systems, have found error rates for enterococcal species identification of 2-21%
      for E. faecalis, 5-9% for E. faecium, and 14-79% for other species. Reporting
      errors may have adverse effects on the management of clinical infections, as well
      as in the control of multidrug-resistant strain outbreaks. The purpose of this
      document is to present a simplified approach to the identification of
      Enterococcus species that uses a combination of rapid, readily available, and
      inexpensive tests.

PMID- 10403094
TI  - Phenotypic and genotypic characterizations of Chinese strains of Escherichia coli
      producing extended-spectrum beta-lactamases.
AB  - Twenty-three multi-resistant strains of Escherichia coli were isolated at a
      single hospital in Beijing, China between January 1997 and May 1998. All isolates
      produced extended spectrum beta-lactamases (ESBLs) as detected by the double disk
      synergy test and the Etest ESBL strip (AB BIODISK, Solna Sweden). Additional
      antimicrobial susceptibility testing showed that most isolates were resistant to
      gentamicin, tobramycin, tetracycline, trimethoprim/sulfamethoxazole,
      ciprofloxacin, and cefepime. All isolates remained susceptible to imipenem with
      MICs of < or = 0.5 microgram/ml. The isolates each produced several beta
      lactamases (range 1-4 enzymes/strain) with pI values ranging from 5.2-8.4.
      Molecular epidemiologic typing revealed four ribotypes and eight pulsed field gel
      electrophoresis (PFGE) patterns with subgroups among the 23 isolates. Clusters of
      isolates with the same DNA type were observed as follows (ribotype/PFGE): Wards A
      (242-5/2, and 242-5/3a), B (242-5/4), and C (880-1/1a). Moreover, similar
      molecular types were observed in patients from two or more different wards.
      Further use of isoelectric focusing results and co-resistance patterns produced
      evidence of potential nosocomial dissemination of strains in only two instances
      (two identical strains on one ward and two identical strains on different wards).
      There were also strong similarities in beta-lactamase pIs and co-resistances
      among many of the strains throughout this medical center. These data document the
      wide genetic diversity among E. coli producing ESBLs, and a potential for
      nosocomial spread of these highly resistant organisms requiring increasingly more
      sophisticated molecular-based techniques and local interventions.

PMID- 10403096
TI  - Improved Legionella selective media by the addition of fluconazole: results of in
      vitro testing and clinical evaluation.

PMID- 10403097
TI  - Detection of Candida albicans in blood by PCR in a rabbit animal model of
      disseminated candidiasis.
AB  - A model of acute disseminated Candida albicans infection in New Zealand rabbits
      was developed to determine the sensitivity and accuracy of polymerase chain
      reaction (PCR) assay compared with the lysis-centrifugation blood culture method.
      Primers used amplify a DNA fragment from the multicopy gene coding for the small
      subunit rRNA, highly conserved in fungi. The sensitivity of PCR achieved in
      rabbit blood samples spiked with Candida albicans was 10-50 CFU/100 microL. A
      nested-PCR increased the limit of detection 10-fold. The sensitivity achieved
      exclusively with the lysis-centrifugation method (37.5%) was higher than that
      obtained with PCR (25%), but lower than nested PCR (52.5%). The combination of
      both techniques, lysis-centrifugation and nested PCR, increased the overall
      sensitivity rate to 62.5%. These results have demonstrated that, globally, the
      nested PCR was more sensitive than both single PCR and lysis-centrifugation
      culture in detecting C. albicans in blood from immunecompetent rabbits with acute
      disseminated candidosis. PCR could be a useful complementary technique to
      traditional methods in the early diagnosis of candidemia.

PMID- 10403098
TI  - Antimicrobial susceptibility of coagulase-negative staphylococci and
      characterization of isolates with reduced susceptibility to glycopeptides.
AB  - The antimicrobial susceptibility of 239 coagulase-negative staphylococci (CNS)
      isolates consecutively collected from blood culture in patients admitted in a 600
      bed teaching hospital was evaluated. The isolates were identified to the species
      level by conventional methods and the MicroScan Positive Combo Panel type 6
      system, and their susceptibility to vancomycin, teicoplanin, and oxacillin were
      tested by agar dilution, disk diffusion, and MicroScan-WalkAway system. The
      species distribution was as follows: Staphylococcus epidermidis 120 (50.2%), S.
      hominis 29 (12.1%), S. haemolyticus 24 (10.0%), S. cohnii 14 (5.9%), and isolates
      from other CNS species 52 (21.8%). The percentage of resistance to oxacillin was
      74.5% by agar dilution. The highest percentages of oxacillin resistance were
      found among S. haemolyticus (95.8%) and S. epidermidis (80.8%). Teicoplanin
      resistance (MIC > or = 32 micrograms/mL) was detected in five S. haemolyticus
      isolates, whereas intermediate resistance (MIC = 16 micrograms/mL) was detected
      in nine strains. These isolates with reduced susceptibility to teicoplanin were
      resistant to oxacillin, but remained susceptible to vancomycin (MIC < or = 4
      micrograms/mL). Two isolates, one S. haemolyticus and one S. epidermidis, showed
      a vancomycin MIC of 8 micrograms/mL, and both MicroScan and disk diffusion
      methods classified these isolates as susceptible. Our results showed that
      glycopeptide resistance is emerging among CNS isolates in our institution and the
      disk diffusion method may not detect isolates with decreased susceptibility to
      these antimicrobial agents.

PMID- 10403099
TI  - Controversies on diagnosis and prevention of ventilator-associated pneumonia.
AB  - Ventilator-associated pneumonia (VAP) is the most frequent infection among
      intensive care patients. There is a great deal of controversy about the methods
      for diagnosis and prevention of this infection. VAP is usually diagnosed on a
      combination of clinical, microbiological, and radiographic criteria. Although
      these criteria have a high sensitivity, specificity is low, resulting in
      unnecessary antibiotic use in many patients. Bronchoscopic techniques, suh as
      protected specimen brush and bronchoalveolar lavage, in combination with
      quantitative culture techniques, do have a higher specificity. However, whether
      implementation of these techniques influences patient care, and to what costs,
      remains to be determined. Prevention of VAP relies on basic infection control
      practices. Many specific strategies interfering with colonization routes have
      been studied. So far, only the use of topical nonabsorbable antibiotics, either
      of the whole digestive tract or the oropharynx only, consistently reduced the
      incidence of VAP. However, the effects on patient survival were disappointing and
      the possibility of selection of antibiotic-resistant bacteria limit the
      widespread use of these strategies.

PMID- 10403100
TI  - Interventional antimicrobial therapy in febrile neutropenic patients.
AB  - In febrile neutropenic patients, prompt empiric antimicrobial intervention is
      mandatory. Numerous studies have demonstrated the benefit of broad-spectrum beta
      lactams active against Gram-negative aerobes as well as against streptococci and
      Staphylococcus aureus in this setting. With this interventional strategy, a
      reduction of infection-related mortality to < or = 10% of patients undergoing
      intensive remission induction or consolidation chemotherapy could be obtained.
      Thereby, subgroups of patients have been identified who require an empiric
      modification of antimicrobial treatment, e.g., patients with catheter-related
      infections, with pulmonary infiltrates, or with unexplained fever (FUO) not
      responding to first-line antibacterials. In two consecutive, prospectively
      randomized trials conducted by the German Paul Ehrlich Society it could be shown
      that empiric antifungal therapy is beneficial for second-line treatment in
      patients with persistent FUO and improves first-line treatment results in
      patients with lung infiltrates. The addition of glycopeptides, however, should be
      restricted to patients with catheter-related infections due to coagulase-negative
      staphylococci or with infections due to multiresistant Gram-positive pathogens.

PMID- 10403101
TI  - Nosocomial fungal infections: candidemia.
AB  - Candida species are frequently encountered as part of the human commensal flora.
      Colonization mostly precedes candidemia and is an independent risk factor for the
      development of candidemia. Genotyping methods showed the similarity between
      colonizing and infecting strains, thus making endogenous origin likely, though
      exogenous sources like total parenteral nutrition also have been described.
      Health care workers (HCWs) play an important role in the transmission of yeasts.
      Candida species are frequently isolated from the hands of HCWs and can be
      transmitted from hands to patients. Granulocytopenia and damage of the mucosal
      lining resulting from intensive chemotherapy due to cancer, the increasing use of
      broad spectrum antibiotics, and the use of intravenous catheters are other
      important risk factors for the development of candidemia. Candidemia is
      associated with a high mortality and prolonged hospitalization. Therefore, and
      because of the high frequency of dissemination, all candidemias should be
      treated. Amphotericin B was considered the standard drug for the systemic
      treatment of candidemia. Fluconazole has been shown to be an effective and safe
      alternative in non-neutropenic patients. 5-Fluorocytosine has been used in
      combination with amphotericin B in the treatment of deep-seated infections.
      Liposomal formulations of amphotericin B and other new antifungal drugs currently
      are under investigation. C. albicans is the most frequently isolated Candida
      species, although the proportion of infections caused by non-C. albicans species
      is increasing. Also, there are reports of development of resistance to
      amphotericin B. C. lusitaniae is known for primary resistance and the development
      of resistance to amphotericin B. Development of resistance to fluconazole is
      mainly seen in AIDS patients with recurrent oropharyngeal candidiasis who receive
      longer courses of therapy.

PMID- 10403102
TI  - Epidemiology of nosocomial fungal infections: invasive aspergillosis and the
      environment.
AB  - The incidence rates of invasive aspergillosis have increased dramatically during
      the last two decades, and, despite all diagnostic and therapeutic efforts,
      outcome is often fatal. Therefore, preventive measures are of major importance in
      the control of invasive aspergillosis, and require full understanding of the
      epidemiology of this devastating disease. The environment has been suggested to
      play a crucial role in the epidemiology of invasive aspergillosis. Aspergillus
      spores are released in the air and may remain airborne for prolonged periods. As
      a result, spores are ubiquitously found in air and contaminate anything in
      contact with air. It has been hypothesized that the inhalation of airborne
      Aspergillus spores, either directly or through intermediate nasopharyngeal
      colonization, is a direct cause of pulmonary infection in immunocompromised
      patients. Recently, water has been suggested as an additional source of
      "airborne" Aspergillus spp. This review summarizes the current knowledge on the
      role of the environment in the epidemiology of invasive aspergillosis.

PMID- 10403103
TI  - Epidemiology and diagnosis of Shiga toxin-producing Escherichia coli infections.
AB  - Shiga toxin-producing Escherichia coli (STEC) have been identified as a worldwide
      cause of serious human gastrointestinal disease and the life-threatening
      hemolytic uremic syndrome. The most common serotype implicated is E. coli O157:
      H7, but infections involving various non-O157 serotypes have been found with
      increasing frequency in many countries. Food-borne outbreaks caused by STEC can
      affect large numbers of people and cause serious morbidity, making the bacteria
      one of the most important emerging pathogens. Because there is no specific
      treatment of the disease currently available, there is an urgent need for
      effective preventive measures based on a detailed understanding of the
      epidemiology of STEC infections. Such measures will also be dependent on the
      availability of rapid, sensitive, and simple procedures for the detection of the
      pathogens both in human samples and in samples of nonhuman origin such as food.
      This review summarizes the current knowledge on the epidemiology of STEC
      infection and presents a survey of laboratory methods currently available for
      diagnosis of STEC. Special attention is given to new diagnostic procedures for
      the less readily detectable non-O157 STEC strains and to simple procedures,
      usually based on commercially available kits, that can be used in routine
      clinical microbiological laboratories.

PMID- 10403104
TI  - Cryptosporidia and microsporidia--waterborne diseases in the immunocompromised
      host.
AB  - Cryptosporidia and microsporidia are emerging parasitic pathogens in
      immunocompetent and immunocompromised individuals. Cryptosporidium infects
      several wild and domestic animals that excrete oocysts into the environment and
      contaminated water represents the major source of infection for humans.
      Waterborne transmission of Cryptosporidium is a major risk for humans and
      appropriate measures have to be taken to protect immunocompetent and
      immunocompromised individuals to become infected. For microsporidia, the sources
      and ways of transmission are not well documented. Although several animal hosts
      have been identified recently, the relevant reservoirs of human microsporidia are
      still unknown. Also, the routes of spreading are unknown. Is microsporidiosis a
      zoonotic disease that will be transmitted through close contact with infected
      animals or is contaminated surface water responsible for transmission and
      represents a relevant reservoir? This review is designed to give information on
      these two emerging intestinal parasites in a format that will be useful to
      clinical microbiologists, physicians interested in infectious diseases, and
      public health personnel.

PMID- 10403105
TI  - Chlamydia pneumoniae infection and ethnic origin.
AB  - OBJECTIVES: To test the association of Chlamydia pneumoniae infection with ethnic
      origin. DESIGN: A prospective study by micro-immunofluorescence of antibodies to
      C. pneumoniae in patients admitted to one hospital with a variety of non
      pulmonary, non-cardiovascular disorders. SETTING: A large district general
      hospital serving a multi-ethnic inner-city population in Birmingham, UK.
      SUBJECTS: There were 1518 patients, 1061 of whom were Caucasian, 290 Asian and
      167 Afro-Caribbean. Each of 169 Asians and 141 Afro-Caribbeans was matched with
      two Caucasians for age, sex, smoking habit, steroid medication and date of
      admission, and logistic regression methods were used to compare the effects on C.
      pneumoniae antibody levels of ethnic origin, these confounding variables,
      diabetes mellitus and social deprivation. OUTCOME MEASURES: Serological evidence
      of acute C. pneumoniae infection or reinfection (defined by titres of IgM > or =
      8, a four-fold rise in IgG or IgG > or = 512) and previous infection (IgG 64-256
      or IgA > or = 8). RESULTS: Results showed 4.8% of Caucasians, 6.6% of Asians and
      10.2% of Afro-Caribbeans had antibody titres suggesting acute (re)infection; and
      11.2% of Caucasians, 13.4% of Asians and 21.0% of Afro-Caribbeans had titres
      suggesting previous infection. On chi 2 analysis, the distributions of the three
      possible serological outcomes (acute, previous and no infection) differed
      significantly (p < 0.05) between the Afro-Caribbean and Caucasian groups, but not
      between Asians and Caucasians or between Afro-Caribbeans and Asians. After
      adjusting for possible confounding variables, odds ratios for Afro-Caribbean
      versus Caucasian origin were 5.5 (95% confidence intervals 2.0-15.0) for acute
      (re)infection and 1.9 (1.0-3.7) for previous infection. CONCLUSIONS: Our results
      suggest that C. pneumoniae infection may be more prevalent among Afro-Caribbean
      than among Caucasian people, and that Asians may lie somewhere between them in
      this respect. The behaviour of this pathogen in different ethnic groups deserves
      further investigation. Future studies of this organism should give due attention
      to the ethnic origins of patients.

PMID- 10403106
TI  - Does vitamin D deficiency account for ethnic differences in tuberculosis
      seasonality in the UK?
AB  - OBJECTIVES: Notifications of tuberculosis in England and Wales are reported to
      peak in the summer season. The purpose of this study was to confirm that finding
      and to determine to what extent patients of Indian Subcontinent (ISC) ethnic
      origin contributed to the seasonality. The clinical presentation of the disease
      is presumed to occur some months following reactivation of the endogenous latent
      focus of tuberculosis infection. There arises the possibility of vitamin D
      deficiency producing immunological inadequacy at the end of winter and beginning
      of spring. PATIENTS AND METHODS: Monthly (or 4-weekly) aggregated data over 7
      years were collected from the three countries of mainland Britain, England,
      Wales, Scotland and from the city of Birmingham in England. The notifications
      from Birmingham were divided into those of ISC ethnic origin and 'whites'. The
      presence or absence of seasonality was determined by fitting a sinusoidal curve
      by the technique called 'cosinor analysis'. In this method amplitude gives a
      measure of the extent of the seasonal variation. RESULTS: The summer peak of
      clinical diagnosis was confirmed in the UK series from England, Wales and
      Scotland. In England and Wales without Scotland a larger seasonal variation was
      present. Scotland, with a lower proportion of population of ISC ethnic origin,
      was examined separately and the results in Scotland alone failed to confirm
      seasonality. In the data from Birmingham, seasonality was confirmed with a
      greater amplitude, particularly in those over 60 years of age. The finding was
      influenced by those of ISC ethnic origin, seasonality not being present in the
      'white' population. CONCLUSION: The results from Birmingham are very striking,
      but there were almost three times as many patients in the ISC ethnic group as in
      indigenous 'white' patients. A series with larger numbers of 'white' patients
      would be necessary to confirm the absence of seasonality in the 'white'
      population. The discussion reviews the evidence that vitamin D may have an
      important hormonal role in immunological defence in the prevention of
      tuberculosis.

PMID- 10403107
TI  - Parasuicide: a Singapore perspective.
AB  - OBJECTIVES: This study was undertaken to determine whether there were ethnic and
      social variations in parasuicide in the population of Singapore. METHODS: All
      hospital records of parasuicide from a teaching hospital between 1991 and 1995
      were reviewed. Demographic data, reasons precipitating the suicide attempt and
      the psychiatric diagnoses were recorded. Altogether 814 patients were identified.
      RESULTS: There was a general upward trend of cases admitted from 1991 to 1995.
      Young females appear to be the most vulnerable accounting for 60.5% of the study
      population. The Indian community has significantly higher risk of parasuicide
      compared to the Chinese and Malays. Overdose of medication was the most common
      method with paracetamol being implicated in 48.1% of all overdoses. CONCLUSION:
      Differences in parasuicide rates amongst the three ethnic communities can be
      attributed to various socio-cultural factors. The phenomenon of parasuicide is of
      increasing importance as it particularly involves adolescents and young adults.
      Suicide prevention will continue to present a challenge for mental health
      professionals in the foreseeable future.

PMID- 10403108
TI  - Social environment and substance misuse: a study of ethnic variations among inner
      London adolescents.
AB  - OBJECTIVES: To explore ethnic variations in drug, tobacco and alcohol use and
      their correlation with other factors which operate through peer, familial and
      religious influences. DESIGN: Semi-structured interviews with 132 12-13-year-old
      young people from four ethnic groups attending secondary schools in two inner
      London boroughs and a follow-up interview completed approximately 17 months
      later. RESULTS: The data was analysed using chi-square and McNemar tests.
      Familial, religious and peer influence closely correlated with ethnicity.
      Bangladeshi young people showed lower levels of peer and higher levels of
      religious and familial involvement and lower levels of substance use. White young
      people reported higher levels of peer, lower levels of religious and familial
      involvement, and a higher level of substance use. Black African and Black
      Caribbean young people lay between the two extremes. CONCLUSION: The findings
      suggest that young people with lower levels of familial and religious influence,
      or higher levels of peer influence, have higher levels of substance consumption
      than other young people. Health education initiatives need to promote personal
      decision-making skills within the context of the young people's individual
      culture. Cultural diversity should be recognised within local health education
      needs assessment.

PMID- 10403109
TI  - Gender, marital status and ethnicity. A Swedish retrospective study of
      criminality, morbidity and mortality among victims of non-fatal firearm injuries.
AB  - OBJECTIVE: To study gender and ethnic aspects in a population consisting of
      patients treated for non-fatal firearm injuries at public hospitals in Stockholm,
      Sweden, during a period of 21 years. DESIGN: Retrospective study. Ethnicity was
      defined as being a foreign-born individual or a native Swede. The morbidity and
      criminality data were analysed with unconditional logistic regression and the
      mortality data were analysed by a proportional hazard model. RESULTS: Females and
      foreign-born persons were more often victims of attempted murder than males or
      native Swedes. Attempted suicide was more common among native Swedes. Male
      patients, single persons and Finnish immigrants treated for a firearm injury all
      showed an increased risk of being registered for criminality or committing a
      violent crime. There was no difference between native Swedes and foreign-born
      persons concerning the number of hospitalisations during the follow-up period.
      Living alone and being of male gender were associated with an increased risk of
      hospitalisation. Firearm victims, independently of ethnicity, had an increased
      mortality rate compared to a Swedish population; the standardised mortality ratio
      (SMR) for males was almost 3 and for females almost 8 compared to the SMR of 1
      for the whole Swedish population. CONCLUSION: Firearm victims constitute a
      population at risk from social, psychological as well as from medical points of
      view. The present study shows an association between gender, ethnicity,
      criminality, and morbidity among firearm victims underlining the importance of
      ethnic- and gender-specific violence prevention strategies.

PMID- 10403110
TI  - The Health Belief Model and HIV risk behaviours: a causal model analysis among
      Anglos, African-Americans and Mexican-Americans.
AB  - A causal model of the Health Belief Model (HBM) is empirically evaluated which
      emphasizes possible indirect paths linking distal demographic and
      seriousness/susceptibility variables to HIV risk behaviours among Anglo, African
      American, and Mexican-American adults. A specific focus of the paper is upon
      alcohol-related expectancies (anticipation of disinhibitory effects of alcohol
      upon sexual behavior) as a 'barrier' to preventive behaviours. Ethnic comparisons
      stem both from the paucity of available research on the HBM in minority
      populations and from recent questions regarding the applicability of rational
      models such as the HBM among minority groups. Analyses of data from a community
      sample of 1390 adults indicate relatively consistent direct effects of barriers
      for males and benefits for females upon HIV risk behaviors. The analyses suggest
      distinct paths operative among males and females. The susceptibility-barriers
      risk behaviours path among males may suggest that alcohol-related expectancies
      (barriers in this model) may be more strongly related to risk behaviours among
      males than minority females.

PMID- 10403111
TI  - Ageing and ethnicity.
AB  - A project entitled 'Initiative for aged immigrants' was part of a programme of
      development to create centres for the aged, which was undertaken in the Oslo
      inner city area in 1996 by the Norwegian Ministry for Health and Social Affairs.

PMID- 10403112
TI  - Robert Fuelgen (1884-1955) - some biographical thoughts.

PMID- 10403113
TI  - The Feulgen reaction 75 years on.
AB  - The Feulgen reaction proposed by Feulgen and Rossenbeck 75 years ago is one of
      the cytohistochemical reactions most widely used in biology and medicine. It
      allows DNA in situ to be specifically stained based on the reaction of Schiff or
      Schiff-like reagents with aldehyde groups engendered in the deoxyribose molecules
      by HCl hydrolysis. The staining intensity is proportional to the DNA
      concentration. Current applications of the Feulgen reaction are mainly concerned
      with DNA quantification in cell nuclei by image cytometry for ploidy evaluation
      in tumor pathology. From the morphological point of view, specific demonstration
      of DNA in cell structures at the light microscopic level is very little used
      nowadays. On the other hand, application of the Feulgen principles to electron
      microscopy have recently allowed specific DNA-staining procedures to be developed
      for the study of the structural organization of DNA in situ.

PMID- 10403114
TI  - Cisplatin-induced apoptosis in human proximal tubular epithelial cells is
      associated with the activation of the Fas/Fas ligand system.
AB  - The role of Fas and Fas ligand (Fas-L) in the apoptotic cell death process in
      cisplatin (CP)-treated human proximal tubular epithelial cells (PTECs) was
      examined. The human PTECs were treated with various concentrations (20-80 microM)
      of CP for 24 h, and the incidence of apoptosis in CP-treated cells was assessed
      by trypan blue staining, propidium iodide staining, in situ end labeling, and
      electron microscopy. The expression of Fas and Fas-L was detected by
      immunofluorescence microscopy. The results showed that: (1) CP-treatment resulted
      in a decreased number of live human PTECs and an increased number of dead cells,
      (2) CP-treated human PTECs showed an increased rate of apoptosis with its typical
      morphological features, and (3) expression of both Fas and Fas-L was upregulated
      in CP-treated human PTECs. These results indicate that CP treatment induces
      apoptosis in human PTECs and the activation of the Fas/Fas-L system may play an
      active role in the induction of the apoptotic cell death process.

PMID- 10403115
TI  - Presence of anti-Mullerian hormone correlates with absence of laminin alpha5
      chain in differentiating rat testis and ovary.
AB  - The distribution of anti-Mullerian hormone (AMH) and laminin (Ln) alpha5 chain in
      differentiating rat testis and ovary were studied by immunohistochemistry. In the
      incipient embryonic male gonad a weak reaction for Ln alpha5 chain, but not for
      AMH, was detected. With further prenatal development, Ln alpha5 chain rapidly
      disappeared from the basement membrane (BM) of the incipient testicular cords in
      parallel with the appearance of AMH in the Sertoli cells. After birth, Ln alpha5
      chain reappeared in the BMs of the cords with the decline and disappearance of
      AMH from the respective Sertoli cells. In the corresponding stages of the ovary,
      Ln alpha5 chain was present in the BM of the prenatal gonadal cords and in
      postnatal primordial follicles. The cells of those epithelia were negative for
      AMH. With the growth of the follicles, Ln alpha5 chain disappeared from the BM
      when AMH appeared in the epithelial follicular cells. The present results show
      that male and female gonadal epithelia negative for Ln alpha5 chain were positive
      for AMH, and that epithelia positive for Ln alpha5 chain were negative for AMH.
      Thus, epithelial Ln alpha5 chain and AMH as a product of the same cell seemed to
      exclude each other. The results require an explanation why Ln alpha5 chain has to
      be excluded from the BM of the epithelia during the secretion of AMH chain
      through the basal cell membrane to the surrounding tissues where it executes its
      important biological functions. These observations suggest a hypothesis that the
      production of both components is regulated by the same gene and factor system.

PMID- 10403116
TI  - Dehydroepiandrosterone increases the zone [correction of in zone] of glutamine
      synthetase-positive hepatocytes in female rat liver: a putative androgenic
      effect.
AB  - The adrenal steroid dehydroepiandrosterone (DHEA) is a hepatocarcinogen and
      peroxisome proliferator in the rat, producing an increase in peroxisomes mainly
      in perivenular parts of the liver lobule. Glutamine synthetase (GS) is expressed
      exclusively in hepatocytes that directly surround the central terminal vein in
      rat liver. The GS-positive zone is wider in males than in females, covering about
      two to three cell layers in males and one to two cell layers in females.
      Treatment of rats with DHEA at a concentration of 0.6% in the diet for 4, 20, 32,
      70 and 84 weeks resulted in an enlargement of the GS-positive zone in females,
      whereas no change was observed in males. In females treated for up to 32 weeks
      with DHEA, the relative mean width (RMW) of the GS-positive zone was as large as
      that observed in males. The increase in the RMW was paralleled by an increase in
      the number of GS-positive hepatocytes. Upon longer treatment, the width of GS
      expression decreased to that observed in untreated controls. The findings suggest
      an androgenic effect of DHEA. The areas of peroxisome proliferation, identified
      in haematoxylin and eosin- and periodic acid-Schiff-stained sections, and GS
      expression were not identical. Furthermore, preneoplastic and neoplastic liver
      lesions induced by DHEA were all negative for GS, indicating that they do not
      derive from the perivenular cells which show the most pronounced peroxisomal
      proliferation.

PMID- 10403117
TI  - Immunohistochemical localisation of pterin-4alpha-carbinolamine dehydratase in
      rat peripheral organs.
AB  - The bifunctional protein PCD/DCoH is both a pterin-4alpha-carbinolamine
      dehydratase (PCD) involved in the recycling of tetrahydrobiopterin (BH4) and a
      dimerisation cofactor (DCoH) of the hepatic nuclear factor 1alpha (HNF-1alpha).
      An antiserum raised against rat PCD/DCoH was used to localise the protein in
      peripheral organs. In liver, all the hepatocytes but not the other cell types are
      immunoreactive. In kidney, the protein is prevalent in the proximal and distal
      convoluted tubules. In adrenals, all the cells of the medulla are labelled.
      Positive nerve cells occur in myenteric ganglia of the whole gastrointestinal
      tract and in the intestinal submucous ganglia. Many positive endocrine cells are
      present in the epithelium. The immunoreactivity is either cytoplasmic
      (hepatocytes, convoluted tubules of the kidney and part of the gastrointestinal
      endocrine cells) or prominently nuclear (kidney collecting tubules, adrenals,
      intestinal neural plexuses and part of the gastrointestinal endocrine cells). Our
      results show that PCD/DCoH is present in cells expressing enzymes that use BH4 as
      a cofactor and/or HNF-1alpha. In addition, PCD/DCoH is present in other cells,
      for example, neurons in the submucosal plexus. This fact and the prominent
      nuclear immunoreactivity found in all the positive cells derived from the neural
      crests argue in favour of a new, still unknown function for the protein.

PMID- 10403118
TI  - Distribution of alcohol dehydrogenase isoenzymes in the human liver acinus.
AB  - By the use of a newly developed technique of ultrathin-layer electrophoresis,
      class I and class II alcohol dehydrogenase activity could be demonstrated in
      microdissected samples of the periportal, intermediate, and perivenous zones of
      the liver acinus in men and women. It could be demonstrated that both classes
      exhibit low activity in the periportal zone. From there, a rising gradient in the
      direction of the perivenous end was apparent. This increase, however, was found
      to be significant only in women. The analysis of class I alcohol dehydrogenase
      isoenzymes showed that the expression of alpha-, beta-, and gamma-containing
      isoforms did not differ in relation to the intraacinar position. The constant
      proportions of the isoenzymes to the maxima and minima of the total alcohol
      dehydrogenase activity support the view that the adult liver-specific isoenzyme
      pattern is determined during postnatal development.

PMID- 10403119
TI  - Expression of the transmembrane protein tyrosine phosphatase RPTPalpha in human
      oral squamous cell carcinoma.
AB  - Little is known about the role of protein-tyrosine phosphatases (PTPs), the
      cellular counterparts of protein-tyrosine kinases, both for normal growth
      regulation and for its dysregulation in cancer. The receptor-like PTPalpha
      (RPTPalpha) may play a positive role in growth regulation and has been shown to
      be overexpressed in colon carcinoma. An RNA/RNA in situ hybridisation protocol
      for RPTPalpha as well as RPTPalpha immunohistochemistry was developed to evaluate
      RPTPalpha expression in oral squamous cell carcinomas (OSCCs) of different
      histological grade and to reveal the synthetically active cells and their tissue
      distribution. In well-differentiated OSCC (G1), RPTPalpha mRNA could be detected
      by in situ hybridisation exclusively in stroma cells (fibro/myofibroblasts and
      inflammatory cells). A higher histological grade (G2/G3) was associated with an
      increased number of RPTPalpha-synthesising carcinoma cells haphazardly
      distributed within invading tumour areas. Consistent results were obtained by
      immunocytochemistry. Thus, both carcinoma dedifferentiation and stroma
      recruitment and activation seem to be associated with an upregulation of
      RPTPalpha expression in OSCC. The results speak in favour of the important role
      of activation of stroma fibro/myofibroblasts influencing the biological behaviour
      of epithelial tumours and also suggest that elevated RPTPalpha expression may be
      a more general marker for proliferating or dedifferentiated cells.

PMID- 10403120
TI  - Dynamics of RNA polymerase II localization during the cell cycle.
AB  - Mitosis is characterized by condensation of chromatin, cessation of RNA
      transcription, and redistribution of nuclear proteins. We investigated the
      distribution of the hypo- and hyperphosphorylated forms of RNA polymerase II in
      mitotic cells from different cell lines by immunofluorescence. In interphase
      cells, the hyperphosphorylated RNA polymerase II (Pol IIO) is present in speckles
      and diffusely throughout the nucleoplasm. In prophase, when speckles disappear,
      Pol IIO concentrates at the surface of chromosomes and, in addition, localizes in
      small spots throughout the cytoplasm. The association of Pol IIO with the surface
      of chromosomes is visible until the chromosomes start to decondense during late
      anaphase/early telophase. In telophase cells, Pol IIO is absent in newly formed
      nuclei but present in the cytoplasm, while Pol IIO disappears nearly completely
      in late telophase cells. In early G1 cells, when cell nuclei increase in size,
      Pol IIO becomes present in the nucleus, first in small spots and later diffusely
      and in speckles. The hypophosphorylated form of RNA polymerase II (Pol IIA) is
      nearly absent in mitotic cells suggesting that Pol IIA is hyperphosphorylated at
      the onset of mitosis. Because Pol IIO, unlike Pol IIA, cannot assemble in
      transcription preinitiation complexes, the conversion of Pol IIA to Pol IIO and
      the lining of chromosomes with Pol IIO might be underlying a mechanism by which
      mitotic cells repress their transcriptional activity.

PMID- 10403121
TI  - In situ polymerase chain reaction and cycling primed in situ amplification:
      improvements and adaptations.
AB  - Ethanol fixation combined with microwave pretreatment allows rapid and simple
      detection of signals produced by cycling primed in situ (PRINS) amplification,
      which uses a single primer, and in situ polymerase chain reaction (ISPCR) in
      intact cells. After thermal cycling, signals remain as discrete subnuclear spots
      in the region of amplification and are clearly distinguishable from non-specific
      background labelling. These methods are applicable to routine blood smears, even
      after Giemsa staining or immunocytochemistry, and cellular morphology is
      retained. Chromosome enumeration by cycling PRINS is demonstrated using primers
      for repeat DNA sequences, whilst single copy sequence detection is demonstrated
      using bcl-2, CFTR and chromosome 21 specific primer pairs in ISPCR. We show that
      ethanol fixation supports efficient extension of cycling PRINS products to
      approximately 550 bp using up to 70 rounds of thermal cycling.

PMID- 10403122
TI  - Application of temperature-sensitive mutations to oncogene studies in Drosophila.
AB  - Recessive oncogenes are genetic functions important in the regulation of tissue
      growth and differentiation. These genetic functions are defined on the basis of
      the phenotype expressed by homozygotes. Defining the role of these genes in
      normal developmental and physiological processes is important to the development
      of accurate models of the normal regulation of growth and differentiation.
      Drosophila can be a good system to investigate the neoplastic mechanism of
      oncogenes and provide a greater understanding in the developmental progression of
      both invertebrates and vertebrates. The lethal (2) giant larvae gene is a
      recessive oncogene of Drosophila and temperature sensitive mutations of this gene
      have been isolated. Here, the application of temperature-sensitive mutations in
      Drosophila oncogene studies is discussed.

PMID- 10403123
TI  - Aloesin and arbutin inhibit tyrosinase activity in a synergistic manner via a
      different action mechanism.
AB  - In this study, we present evidence that cotreatment of aloesin and arbutin
      inhibits tyrosinase activity in a synergistic manner by acting through a
      different action mechanism. Aloesin or arbutin similarly inhibited enzyme
      activity of human- and mushroom-tyrosinases with an IC50 value of 0.1 or 0.04 mM,
      respectively. Lineweaver-Burk plots of the enzyme kinetics data showed that
      aloesin inhibited tyrosinase activity noncompetitively with a Ki value of 5.3 mM,
      whereas arbutin did it competitively (Maeda, 1996). We then examined whether
      cotreatment of these agents inhibits the tyrosinase activity in a synergistic
      manner. The results showed that 0.01 mM aloesin in the presence of 0.03 mM
      arbutin inhibited activity of mushroom by 80% of the control value and the
      reverse was also true. The inhibitory effects were calculated to be synergistic
      according to the Burgi method. Taken together, we suggest that aloesin along with
      arbutin inhibits in synergy melanin production by combined mechanisms of
      noncompetitive and competitive inhibitions of tyrosinase activity.

PMID- 10403124
TI  - An endogenous proteinacious inhibitor for S-adenosyl-L-methionine-dependent
      transmethylation reactions; identification of S-adenosylhomocystein as an
      integral part.
AB  - A proteinacious inhibitor with a molecular weight of 1,600 Da which inhibits S
      adenosyl-L-methionine-dependent transmethylation reactions was purified from
      porcine liver to homogeneity by procedures including boiling, Sephadex G-25
      column chromatography and repeated HPLC. Employing both Nuclear Magnetic
      Resonance (NMR) and Fast Atom Bombardment-Mass (FAB-Mass) spectroscopy, S
      adenosylhomocysteine was conclusively identified as an integral part of the
      inhibitor. The purified S-adenosylhomocysteine was competitive with S-adenosyl-L
      methionine with Ki value of 6.3x10(-6) M towards protein methylase II.

PMID- 10403125
TI  - Developmental patterns of GalBeta1,3(4)GlcNAc alpha2,3-sialyltransferase (ST3Gal
      III) expression in the mouse: in situ hybridization using DIG-labeled RNA probes.
AB  - Sialic acids are key determinants for biological processes, such as cell-cell
      interaction and differentiation. Sialyltransferases contribute to the diversity
      in carbohydrate structure through their attachment of sialic acid in various
      terminal positions on glycolipid and glycoprotein (N-linked and O-linked)
      carbohydrate groups. Galbeta 1,3(4)GlcNAc alpha2,3-sialyltransferase (ST3Gal III)
      is involved in the biosynthesis of sLe(x)and sLe(a) known as selectin ligands and
      tumor-associated carbohydrate structures. The appearance and differential
      distribution of ST3Gal III mRNA during mice embryogenesis [embryonic (E) days;
      E9, E11, E13, E15] were investigated by in situ hybridization with digoxigenin
      labeled RNA probes coupled with alkaline phosphatase detection. On E9, all
      tissues were positive for ST3Gal III mRNA expression, whereas ST3Gal III mRNA on
      E11 was not detected throughout all tissues. On E13, ST3Gal III mRNA was
      expressed in different manner in various tissues. In this stage, ST3Gal III mRNA
      was positive only in the liver, pancreas and bladder. On E15, specific signal for
      ST3Gal III was detected in the liver, lung and forebrain. These results indicate
      that ST3GAI III is differently expressed at developmental stages of mice embryo,
      and this may be importantly related with regulation of organogenesis in mice.

PMID- 10403126
TI  - Conversion of glycosylphosphatidylinositol (GPI)-anchored alkaline phosphatase by
      GPI-PLD.
AB  - Enzymatic conversion of brain glycosylphosphatidylinositol-linked alkaline
      phosphatase (GPI-AP), amphiphilic, was examined. When GPI-AP was incubated with
      glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD), a negligible
      conversion of GPI-AP to hydrophilic form was observed. The inclusion of
      monoacylglycerols enhanced the enzymatic conversion, although the action of
      monoacylglycerols differed greatly according to the size of acyl group; the
      enzymatic conversion was enhanced considerably in the presence of
      monoacylglycerols possessing acyl group of longer chain length (C10-C18), while
      monoacylglycerols with acyl moiety of shorter length (C4-C8) did fail to augment
      the enzymatic conversion. Noteworthy, monooleoylglycerol was much more effective
      than the other monoacylglycerols in promoting the enzymatic conversion,
      indicating a beneficial role of the unsaturation in acyl chain. Meanwhile, ionic
      amphiphiles such as monohexadecyllysophosphatidylcholine and palmitoyl-carnitine
      decreased the enzymatic conversion of GPI-AP in a concentration-dependent manner,
      with monohexadecyllysophosphatidylcholine being more inhibitory than
      palmitoylcarnitine. Separately, when GPI-AP was exposed to various oxidants prior
      to the incubation with GPI-PLD, a remarkable decrease of the enzymatic conversion
      was observed with hypochlorite and peroxynitrite generators, but not H2O2. In
      further study, hypochlorite was found to inactivate GPI-PLD at low concentrations
      (3 to approximately 100 microM). From these results, it is suggested that the
      enzymatic conversion of GPI-AP by GPI-PLD may be regulated in vivo system.

PMID- 10403127
TI  - Effect of biphenyl dimethyl dicarboxylate on the cellular and nonspecific
      immunosuppressions by ketoconazole in mice.
AB  - The effect of biphenyl dimethyl dicarboxylate (PMC) on the cellular and
      nonspecific immunosuppressions by ketoconazole (KCZ) was investigated in ICR
      mice. PMC at a dose of 6 mg/kg was administered orally to mice daily for 14
      consecutive days. KCZ was suspended in RPMI 1640 medium and orally administered
      at 160 mg/kg/day 2 hrs after the administration of PMC. Immune responses of the
      delayed-type hypersensitivity (DTH) reaction to sheep red blood cells (SRBC),
      phagocytic activity and natural killer (NK) cell activity were evaluated. DTH
      reaction to SRBC was enhanced to normal level by the combination of PMC and KCZ,
      compared with treatment of KCZ alone. In the combination of PMC and KCZ, as
      compared with the treatment of KCZ alone, there were also significant increases
      in activities of natural killer (NK) cells and phagocytes along with circulating
      leukocytes. These findings indicate that PMC shows a significant restoration from
      the immunotoxic status induced by KCZ.

PMID- 10403128
TI  - Preparation of dopamine transporter-specific antibodies using molecular cloned
      genes.
AB  - Dopamine transporter (DAT) plays the most important role in terminating the
      actions of dopamines released into the synaptic cleft. DAT is also the target of
      various psychotropic drugs such as cocaine and amphetamine. In this study we
      prepared DAT-specific antibodies using the 2nd extracellular loop of rat DAT as
      an antigen. The 2nd extracellular loop of the rat DAT was expressed in bacteria
      as a fusion protein with glutathione-S-transferase, and injected into rabbits to
      raise antibodies. Produced antibodies clearly recognized the rat DAT in ELISA,
      immunoblotting, and immunoprecipitation. As expected from the high sequence
      homology between the rat and human DAT, the antibodies raised for the rat DAT
      cross-reacted with the human DAT in the immunoblotting. Considering the
      specificity for DAT with wide range of applications such as ELISA,
      immunoblotting, and immunoprecipitation, these antibodies would be valuable tool
      for understanding the pharmacological actions of dopamine transporter and drug
      addiction.

PMID- 10403129
TI  - Enhanced macrophage antitumor effects of protein A in combination with IFN-gamma.
AB  - In this study we examined the potential for the synergistic augmentation of the
      antitumor activity of inflammatory mouse peritoneal macrophages by stimulation
      with protein A combined with IFN-gamma. The moderate augmentative effect induced
      by preincubation with protein A was demonstrated to be concentration-dependent,
      whereas IFN-gamma had a very low activating effect. Following preincubation with
      both protein A and IFN-gamma, a marked enhancement of macrophage activity was
      noted. In addition, based on the utilization of neutralizing antibody to TNF
      alpha or the inhibition of NO production, TNF-alpha and NO were proven to be
      involved as mediators during the activation of tumoricidal macrophages by protein
      A in combination with IFN-gamma. We also demonstrated that supernatants from
      macrophages treated with protein A plus IFN-gamma contained both TNF-alpha and NO
      at markedly increased levels. Thus, tumor cell lysis in the combined system was
      mediated via TNF-alpha or NO. These results demonstrate the synergistic effects
      on mouse peritoneal macrophage function of protein A in combination with IFN
      gamma and suggest that combinations of such agents may serve as the basis for
      future in vivo immunotherapy.

PMID- 10403130
TI  - Expression of the recombinant Klebsiella aerogenes UreF protein as a MalE fusion.
AB  - Expression of the active urease of the enterobacterium, Klebsiella aerogenes,
      requires the presence of the accessory genes (ureD, ureE, ureF, and ureG) in
      addition to the three structural genes (ureA, ureB, and ureC). These accessory
      genes are involved in functional assembly of the nickel-metallocenter for the
      enzyme. Characterization of ureF gene has been hindered, however, since the UreF
      protein is produced in only minute amount compared to other urease gene products.
      In order to overexpress the ureF gene, a recombinant pMAL-UreF plasmid was
      constructed from which the UreF was produced as a fusion with maltose-binding
      protein. The MBP-UreF fusion protein was purified by using an amylose-affinity
      column chromatography followed by an anion exchange column chromatography.
      Polyclonal antibodies raised against the fusion protein were purified and shown
      to specifically recognize both MBP and UreF peptides. The UreF protein was shown
      to be unstable when separated from MBP by digestion with factor Xa.

PMID- 10403131
TI  - A novel approach to the discovery of non-systemic anti-inflammatory steroids;
      antedrug.
AB  - Therapeutic use of anti-inflammatory steroids is limited due primarily to their
      systemic suppressive effects on pituitary function and the immune system. To
      overcome the clinical limitation, a new approach toward the discovery of non
      systemic anti-inflammatory steroids is based upon the antedrug concept introduced
      by this laboratory. The new concept describes locally active agents which are
      designed to undergo a predictable biotransformation to inactive metabolites upon
      entry into systemic circulation from the applied site. Thus, true antedrugs are
      devoid of systemic adverse effects. In a continuing effort, 16alpha-carboxylate
      and isoxazoline derivatives of prednisolone have been synthesized and screened.
      In the croton oil-induced ear edema bioassay, the following relative potencies
      were obtained setting hydrocortisone=1.0; 3a, 1.5; 3b, 3.1; 4a, 4.0; 4b, 12.2;
      5b, 8.2; 6b, 11.2; 7a, 1.9; 7b, 4.1; 8a, 3.3; 8b, 6.8; 9a, 0.7; 9b, 8.6; 10a,
      2.6; 10b, 7.4. Results of the five-day bioassay indicated that, in contrast to
      the parent compound, the novel steroidal antedrugs did not significantly alter
      body weight gain, thymus weights, adrenal weights or plasma corticosterone
      levels. Taken together, the antedrug concept appears to be a fundamentally sound
      strategy for the separation of local anti-inflammatory activity from systemic
      adverse effects.

PMID- 10403132
TI  - The application of ion chromatographic method for bioavailability and stability
      test of iron preparations.
AB  - Postabsorptive serum iron level was determined after oral administration of the
      compounds to human. In serum and whole blood, Fe3+ was measured by ion
      chromatography (IC) using a pyridine-2,6-dicarboxylic acid (PDCA) as an eluent.
      The serum sample solutions were pretreated with I N HCI and 50% TCA. The whole
      blood sample solutions were treated with 3 N HCI for 30 min at 125 degrees C. The
      limit of detection (LOD) of the IC technique is 0.2 microM for Fe2- and 0.1
      microM for Fe3+. The area under concentration (AUC) can be obtained by the above
      analytical condition. In addition, to compare the stability of Fe2+ to that of
      Fe3+ in pharmaceutical preparations, accelerated stability test was carried out.
      After storing the samples under 40 degrees C, 75%RH in light-resistant container
      for various time intervals, the contents of iron of different valencies were
      determined separately by the IC technique and the change and/or the interchange
      of among those iron species in preparations was investigated. Iron raw materials
      are stable, but Fe2+ in Fe3+ source materials was slightly converted to Fe3+ by
      oxidation. Fe2+ in Fe3+ source raw materials and Fe3+ in Fe2+ raw materials are
      determined as impurities. Therefore, IC technique is found to be an appropriate
      method for comparative evaluation of dissimilar bioavailability of Fe2+ and Fe3+,
      stability of Fe2+ and Fe3+ raw materials and preparations.

PMID- 10403133
TI  - Improved fluorescent determination method of cellular sphingoid bases in high
      performance liquid chromatography.
AB  - Precolumn orthophthaldehyde (OPA) labeling method of sphingoid bases, sphingosine
      and sphinganine, was investigated to obtain high fluorescent detectability. In
      order to improve the fluorescent yield, we investigated the optimal solubility of
      sphingoid bases for five pre-incubation solvents by incorporating the heating
      procedure before OPA derivatization. The pre-incubation in ethanol prominently
      increased the fluorescent peak height of OPA derivative for each sphingoid bases
      in high performance liquid chromatography. About ten-fold increase of
      detectability was archived by pre-incubating lipid extracts pellets in ethanol at
      60 degrees C for 30 min. Optimal derivatization was performed in 30 min at
      ambient temperature and the fluorescent intensity of OPA derivative was stable
      for two weeks at 4 degrees C. The detection limit of sphingosine was 0.1 pmol as
      injected amount. This method was applied to the determination of cellular
      sphingosine and sphinganine in various human lung cancer cells. This OPA
      procedure was prospective to be useful for quantitating the amount of sphingoid
      bases in other cancer cells.

PMID- 10403134
TI  - Stereoselective synthesis of (+/-)-epibatidine analog:(+/-)-2beta-(2-chloro-5
      pyridinyl)-8-azabicyclo[3.2.1] octane.
AB  - Stereoselective synthesis of (+/-)-epibatidine analog 2, which contains the 8
      azabicyclo[3.2.1]octane ring system, was achieved by using palladium-catalyzed
      Heck-type coupling reaction from 3.

PMID- 10403135
TI  - Synthesis of 4-hydroxy-1-thiocoumarin derivatives-1: an efficient synthesis of
      thioflocoumafen.
AB  - An efficient procedure for the preparation of 4-hydroxy-3-{1,2,3,4-tetra-hydro-3
      [4-(4-triflu-oromethylbenzyl oxy)phenyl]-1-naphthyl}thiocoumarin
      (thioflocoumafen, 1a and 1b) is described. The key step in the synthesis involves
      the condensation reaction of 3-(4-methoxyphenyl)-1-tetralol (2) with 4-hydroxy-1
      thiocoumarin (3).

PMID- 10403136
TI  - Enzymatic synthesis of a dihydrobenzofuran neolignan by oxidative coupling.
AB  - The oxidative dimerization of ferulic acid has been carried out using horse
      radish peroxidase as catalyst to give a dihydrobenzofuran neolignan (1), the
      structure of which was elucidated as (2SR,3RS)-2,3-dihydro-2-(4-hydroxy-3
      methoxyphenyl)-3-n-buto xycarbonyl-5-(2E-carboxyethenyl)-7-methoxybenzofuran by
      spectroscopic analyses. This compound showed more potent cytotoxicity against
      several tumor cell lines than the starting material.

PMID- 10403137
TI  - Inhibition of aromatase activity by flavonoids.
AB  - In searching for potent cancer chemopreventive agents from synthetic or natural
      products, 28 randomly selected flavonoids were screened for inhibitory effects
      against partially purified aromatase prepared from human placenta. Over 50% of
      the flavonoids significantly inhibited aromatase activity, with greatest activity
      being demonstrated with apigenin (IC50: 0.9 microg/mL), chrysin (IC50: 1.1
      microg/mL), and hesperetin (IC50: 1.0 microg/mL).

PMID- 10403138
TI  - Inhibition of mouse ear edema by steroidal and triterpenoid saponins.
AB  - Certain steroids and triterpenoids isolated from diverse plant families were
      known to possess anti-inflammatory activity. In the course of finding new anti
      inflammatory natural products, some steroidal and triterpenoid saponins were
      isolated and evaluated for their anti-inflammatory activity using in vivo mouse
      ear edema test. At the oral dose of 100 mg/kg, several steroidal saponins and
      triterpenoid saponins such as hederagenin glycosides showed significant
      inhibition of ear edema (20-37% inhibition), though less potent than indomethacin
      and hydrocortisone.

PMID- 10403139
TI  - In vitro anticomplementary activity of hederagenin saponins isolated from roots
      of Dipsacus asper.
AB  - Anticomplementary activity of hederagenin and related saponins isolated from
      Dipsacus asper was investigated in vitro. HN saponin F (3) was most potent with
      IC50 value of 3.7x10(-5) M followed by 3-O-beta-D-glucopyranosyl-(1->3)-alpha-L
      rhamnopyranosyl-(1->2)-beta-L-+ ++arabi nopyranosyl hederagenin 28-O-beta-D
      glucopyranosyl-(1->6)-beta-D-glucopyrano side (8), 3-O-beta-L-arabinopyranosyl
      hederagenin 28-O-beta-D-glucopyranosyl-(1->6)-beta-D-glucopyranoside (5),
      dipsacus saponin A (4), and hederagenin (1) on the classical pathway (CP) of
      complement system, while the saponins 3-5 did not show the inhibition of
      hemolysis and rather increase the hemolysis on the alternative pathway (AP).
      However, all of C-3 monodesmosides [prosapogenin CP (2), dipsacus saponin B (6),
      and dipsacus saponin C (7)] evoked hemolysis directly on the erythrocytes.

PMID- 10403140
TI  - Anti-allergic actions of the leaves of Castanea crenata and isolation of an
      active component responsible for the inhibition of mast cell degranulation.
AB  - The anti-allergic actions of the leaves of Castanea crenata (Fagaceae) were
      studied. The water extract demonstrated potent anti-allergic actions in in vivo
      and in vitro experiments. The oral or intraperitoneal administration of the
      extract (100 or 200 mg/kg) caused a significant inhibition of the 48 hr-PCA (up
      to 90%) and the vascular permeability induced by histamine or serotonin in rats
      (about 80%). The anaphylactic release of beta-hexosaminidase from RBL-2H3 cells
      was also significantly inhibited by the extract in a dose-dependent manner with
      an IC50 value of 230 microg/ml. The activity-guided fractionation of the extract,
      based on the determination of inhibitory effect upon the release of beta
      hexosaminidase, led to the isolation of quercetin as an active principle
      responsible for the inhibition of degranulation.

PMID- 10403141
TI  - Inhibitory activity of monoamine oxidase by coumarins from Peucedanum japonicum.
AB  - Four coumarins were isolated from chloroform extract of the root of Peucedanum
      japonicum and identified as praeruptorin A(1), xanthotoxin (2), psoralen (3) and
      bergapten (4) on the basis of spectroscopic methods. The inhibitory activities of
      these coumarins on monoamine oxidase prepared by mouse brain were tested. The
      IC50 values of them were shown to be 27.4 microM (1), 40.7 microM (2), 35.8
      microM (3), and 13.8 microM (4), in vitro.

PMID- 10403142
TI  - Is psychotherapy an effective treatment for melancholia and other severe
      depressive states?
AB  - The treatment of severe depression with psychotherapy, alone, is controversial.
      In this paper, we review the historical, conceptual, and empirical contexts of
      this controversy. In addition to work by others, we review recent work from our
      institute which has examined the psychobiological substrates of response to
      treatment in depressive subtypes. We examine the traditional categories that
      describe severe depressions. The features and psychobiological correlates of
      melancholia are discussed, as is the relationship between melancholia and aging.
      Research on treatment of melancholia and other severe depressive states with
      psychotherapies such as cognitive behavior therapy (CBT) and interpersonal
      psychotherapy (IPT) is reviewed in detail. We conclude that although some
      melancholic patients are responsive to IPT or CBT, there is not yet compelling
      evidence that melancholic patients respond to psychotherapy as well as they do to
      medications. The potentially mediating effects of hypercortisolism, alterations
      of sleep neurophysiology, and disturbances of information processing and regional
      cerebral metabolism represent fertile grounds for future investigation. We
      discuss the practical implications of the literature reviewed.

PMID- 10403143
TI  - Thoughts of harming infants in depressed and nondepressed mothers.
AB  - BACKGROUND: Thoughts of harming the infant and other disturbing cognitions are
      frequently described in anecdotal reports on postpartum depression. These
      cognitions have not been examined empirically. METHODS: 100 clinically depressed
      mothers with a child under 3 years were evaluated and compared to a control group
      of 46 nondepressed mothers. RESULTS: 41% of depressed mothers compared to 7% of
      control mothers admitted to thoughts of harming their infant. Fear of being alone
      with the infant and inability to care for the infant were assessed only in
      depressed mothers and occurred less frequently. More than half of depressed
      mothers had problems in one of these three areas. CONCLUSIONS: Thoughts of
      harming the infant are common in depressed mothers. Demographic variables,
      psychosocial stressors and psychiatric variables do not help predict which
      mothers are likely to experience thoughts of harm or fear of being alone with the
      infant. These cognitive and affective disturbances may be one pathway by which
      maternal depression affects infants. LIMITATIONS: The control group was not given
      the full diagnostic interview. Consequently, the groups were not selected by
      identical procedures. Also fear of being alone with the infant and difficulty
      caring for the infant were not assessed in the control group.

PMID- 10403144
TI  - Early deficient parenting in depressed outpatients is associated with personality
      dysfunction and not with depression subtypes.
AB  - BACKGROUND: We investigated the associations between recollected levels of
      parental care and current symptomatology, axis I and axis II comorbidity and
      family psychiatric history in 248 depressed outpatients. METHODS: The sample was
      divided into three approximately equal groups according to PBI scores. Current
      symptomatology was assessed with the SCL-90, SAS and HAM-17. Axis I and axis II
      comorbidity were assessed with the SCID-P and SCID-II respectively. RESULTS:
      Deficient parenting was not associated with melancholia, age of onset or severity
      of depression. Significant linear associations were found for recurrent
      depression, comorbid substance disorder, current symptomatology and, of most
      significance, personality disorders. CONCLUSION: Personality dysfunction may
      mediate the relation between early parental deprivation and adult
      psychopathology. LIMITATIONS: Possible limitations include retrospective recall
      of parental care and the state effects of depression on assessment.

PMID- 10403145
TI  - A Canadian multicenter, double-blind study of paroxetine and fluoxetine in major
      depressive disorder.
AB  - BACKGROUND: Recent studies have suggested clinical differences among selective
      serotonin reuptake inhibitors. In a 12-week randomized, multicenter, double-blind
      trial, the antidepressant and anxiolytic efficacy of the selective serotonin
      reuptake inhibitors paroxetine and fluoxetine was compared in patients with
      moderate to severe depression. METHODS: A total of 203 patients were randomized
      to fixed doses (20 mg/day) of paroxetine or fluoxetine for the first six weeks of
      therapy. From week 7-12, dosing could be adjusted biweekly, as required
      (paroxetine 20-50 mg/day, and fluoxetine 20-80 mg/day). The mean prescribed doses
      were paroxetine 25.5 mg/day (range 20.0-40.2 mg/day), and fluoxetine 27.5 mg/day
      (range 20.0-59.5 mg/day). Emergence of motor nervousness or restlessness was
      assessed using the ESRS scale for akathisia. RESULTS: Both active treatments
      demonstrated comparable antidepressant efficacy (HAM-D, CGI). Anxiolytic activity
      of the two drugs (COVI, STAI, HAM-D) was also comparable. However, paroxetine was
      found to be superior to fluoxetine on two subscore measures at week 1 of therapy
      (HAM-D Agitation item, p < 0.05; Psychic Anxiety item, p < 0.05), with no
      differences detected after week 2. The overall incidence of adverse effects was
      comparable in the two treatment groups. Constipation, dyspepsia, tremor, sweating
      and abnormal ejaculation were more common in paroxetine-treated subjects, whereas
      nausea and nervousness were more frequent in fluoxetine-treated patients. Weight
      loss was more common in the fluoxetine versus paroxetine group (11.88% versus
      2.94%, respectively). ESRS scores for akathisia were low throughout the study and
      showed little change. LIMITATIONS: Differences observed between the two drugs in
      antianxiety effects were limited to two measures of anxiety among several others.
      DISCUSSION: The data indicate that paroxetine and fluoxetine have comparable
      antidepressant and anxiolytic efficacy. Paroxetine appears to produce an earlier
      improvement in agitation and psychic anxiety symptoms compared with fluoxetine.

PMID- 10403146
TI  - First admissions for depression: is the 'no-treatment interval' a critical
      predictor of time to remission?
AB  - BACKGROUND: This study aimed to replicate findings that length of episode prior
      to adequate antidepressant treatment (the 'no-treatment interval') and premorbid
      neuroticism predict time to remission from the institution of adequate treatment
      for depression. METHODS: Eighty-three inpatients meeting ICD-10 criteria for a
      depressive illness were entered into an 18-month prospective follow-up study of
      illness course. Subjects were assessed using the Schedules for Clinical
      Assessment in Neuropsychiatry, Maudsley Personality Inventory (MPI) and the
      Hamilton Rating Scale for Depression (HRSD). Remission was defined as an HRSD
      score of < 8 for 2 consecutive weeks. RESULTS: Twenty-two patients (27%) remained
      depressed 12 months after the onset of adequate treatment. Significantly longer
      times to remission were predicted by a longer no-treatment interval and higher
      premorbid neuroticism scores. LIMITATIONS: Adequate antidepressant treatment was
      commenced prior to admission in half the cases, requiring a retrospective
      assessment of illness course prior to study entry. Twenty-four patients (29%) had
      not remitted at the time of completion of the MPI. CONCLUSIONS: These results
      replicate previous findings identifying a longer time to treatment and higher
      neuroticism scores as predictors of chronicity in depression.

PMID- 10403147
TI  - Temperament traits in seasonal affective disorder, suicide attempters with non
      seasonal major depression and healthy controls.
AB  - BACKGROUND: Very few studies have compared the temperament traits in matched
      suicidal and non-suicidal patients with major depression. METHODS: We compared
      the temperament traits in two matched groups of patients with major depressive
      disorder (MDD), MDD with seasonal subtype (SAD) without any suicide attempt (n =
      23) and MDD without seasonal variation who attempted suicide (non-SAD SA), and
      compared the patients to matched healthy controls by using the Karolinska Scales
      of Personality (KSP) and the Marke-Nyman Temperament (MNT) questionnaires.
      RESULTS: Both the SAD and non-SAD SA groups showed significantly higher Somatic
      Anxiety, Muscular Tension, Psychasthenia, Irritability, Suspicion, and lower
      Socialization and Validity than the controls. The non-SAD SA group also showed
      significantly higher Psychic Anxiety, Detachment and Guilt as compared to
      controls. When the SAD and the non-SAD SA were compared, we found significantly
      higher Somatic Anxiety, Psychic Anxiety and Muscular Tension for the non-SAD SA
      group. CONCLUSIONS: Both SAD and non-SAD SA patients display different
      temperament profiles compared to controls and in comparison with each other and
      the suicide attempters show especially high trait anxiety and hostility. CLINICAL
      RELEVANCE: The results suggest that trait anxiety and hostility, but not
      impulsivity, are associated with suicidal behavior in major depression.

PMID- 10403148
TI  - Rapid cycling affective disorder: a descriptive study from North India.
AB  - A series of 33 (4.29%) cases of rapid cycling affective disorder (RCAD ICD-10
      DCR) out of a pool of 770 consecutive cases of ICD-10 affective disorder (AD) was
      collected over a period of 5 years. All cases of RCAD belonged to bipolar
      affective disorder. RCAD when compared with non-rapid cycling bipolar affective
      disorder (BPAD) revealed a significantly longer mean duration of illness, greater
      number of total episodes, greater number of hospitalizations and stronger family
      loading of bipolar affective disorder. These findings implicate RCAD as a severe
      form of bipolar affective disorder.

PMID- 10403149
TI  - The relationship of dysfunctional attitudes to personality in depressed patients.
AB  - AIM: To examine the relationship between dysfunctional attitudes and personality
      in depressed patients. METHOD: One hundred depressed patients completed both the
      Dysfunctional Attitudes Scale (DAS) and the Temperament and Character Inventory
      (TCI). RESULTS: Scores on the DAS correlated with duration of depression, age of
      onset of depression, age, harm avoidance and self-directedness. In a multiple
      regression analysis three measures explained 45% of the DAS score. These were
      duration of depression, reward dependence and self-directedness. In both the
      univariate analyses and multiple regression the strongest predictor of
      dysfunctional attitudes was the character dimension of self-directedness.
      CONCLUSION: The character dimension of self-directedness in the TCI which
      assesses an individuals' self-concept, relates highly with the dysfunctional
      attitudes score on the DAS. Given that the TCI assesses personality within a
      broader framework of a psychobiologic and developmental model, self-directedness
      may have a wider application as a measure of self-concept than the DAS.

PMID- 10403150
TI  - Rates of electroconvulsive therapy use in Edinburgh (1992-1997).
AB  - BACKGROUND: The number of ECT treatments given each year is a topic of interest
      for psychiatrists, users and politicians, but there are major methodological
      problems in reported studies of rates of ECT use in the British Isles. The aim
      was to establish whether or not the use of ECT had fallen between 1992 and 1997.
      METHOD: A computerised database of ECT treatments in Edinburgh and relevant
      population data were used to calculate annual indices of ECT usage. These indices
      were calculated separately for the population aged 18-64 years and those 65 years
      or older. RESULTS: In the general adult population, the rate of ECT use fell
      progressively and significantly (p < 0.01) from 2.90 to 1.37 treatments per 1000
      population. This fall was commensurate with the falls in other indices of ECT
      use. Among the elderly population, the rate of ECT use was three times that in
      the general adult population. There was no significant change, although the
      number of courses of treatment fell by 40% (p = 0.06). CONCLUSIONS: There
      continues to be a progressive fall in the use of ECT in general adult psychiatry.
      ECT is used substantially more often in the elderly. Reports of ECT use ought to
      include numbers of both treatments and patients treated. LIMITATIONS: There was
      no investigation of the possible causes of the fall in ECT use. The extent to
      which these findings can be generalised to the rest of the British Isles will
      require further study.

PMID- 10403151
TI  - Lithium prophylaxis of recurrent bipolar affective disorder: long-term outcome
      and its psychosocial correlates.
AB  - BACKGROUND: Discrepancy between efficacy of prophylactic lithium and its
      effectiveness in ordinary clinical practice necessitates long-term follow-up data
      from specialised lithium clinics. Also, role of psychosocial factors in
      influencing the outcome is unclear. METHODS: One hundred and eighteen patients of
      bipolar affective disorder attending a lithium clinic were followed-up for
      approximately 11 years (range 2-27 years). Demographic and clinical data,
      measures of social support and psychosocial stress were obtained at the intake in
      1989-1990. Study design combined retrospective chart-review (till the time of
      intake) with prospective follow-up till July 1995. RESULTS: On lithium, the
      patients had a mean of 0.43 relapses per year (manic, 0.26; depressive, 0.17)
      which was significantly less (p < 0.01) than the pre-lithium episode frequency.
      The figure for entirely relapse-free patients was 24%, and 62% had relapses up to
      one episode per year (median = 0.3 per year). Fifty-eight (49%) patients were
      good responders to lithium (relapses < or = 0.30 per year). In comparison to good
      responders, partial/poor responders had a significantly greater number of pre
      lithium depressive episodes, poor lithium compliance, more psychosocial stress
      and lower social support at intake. These variables correlated well with relapses
      and explained 32% of the variance of the data. CONCLUSIONS: Lithium had a
      definite prophylactic effect on long-term outcome. Social support and stressful
      life events are significant correlates of response to lithium. CLINICAL
      IMPLICATIONS: Lithium prophylaxis of bipolar affective disorders seems justified
      though psychosocial factors appear to modulate its effectiveness. LIMITATIONS:
      Other psychotropic medications were used during relapse and the assessment of
      psychosocial factors was cross-sectional.

PMID- 10403152
TI  - Seasonal variations in mood and behaviour: epidemiological findings in the north
      tropics.
AB  - BACKGROUND: There has been no epidemiological study of seasonal affective
      disorder (SAD) in the north tropics. METHODS: The investigators randomly mailed
      the Seasonal Pattern Assessment Questionnaire (SPAQ) to 520 residents in Chiang
      Mai Municipality. RESULTS: The prevalence rates of summer SAD, subsyndromal
      summer SAD and winter SAD are 6.19%, 8.25% and 1.03%, respectively. CONCLUSIONS:
      The epidemiological study of SAD in the north tropics finds a high prevalence of
      summer SAD, low prevalence of winter SAD and the correlation between 'feel worst'
      response and temperature. LIMITATIONS: The reliability and validity of SPAQ in
      diagnosing summer SAD is probably low. The response rate from the studied sample
      is low. CLINICAL RELEVANCE: The prevalence of summer SAD in the tropics is much
      higher than that in the temperate zone and may relate to temperature.

PMID- 10403153
TI  - The validity of diagnosis of melancholic depression according to different
      diagnostic systems.
AB  - BACKGROUND: Melancholic versus nonmelancholic depression dichotomy is perhaps the
      most widely accepted distinction in categorization of depression. This research
      aims to compare RDC, DSM-III, DSM-III-R, DSM-IV and ICD-10
      melancholic/endogenous/somatic and nomelancholic/nonendogenous/nonsomatic
      depressive patients with regards to biological variables thyroid stimulating
      hormone (TSH), basal and post dexamethasone cortisol levels, age, age of onset of
      depression, psychosocial stressors, and severity of depression. METHODS: Sixty
      five patients who had been diagnosed as having major depression according to DSM
      III-R, using SCID were included in this study. Patients were divided into
      melancholic and nonmelancholic subtypes using RDC, DSM-III, DSM III-R, DSM-IV and
      ICD-10 criteria and groups were compared on the basis of biological variables, as
      well as age, psychosocial stressors and the severity of depression. RESULTS: RDC
      endogenous depressives were older, more severely depressed and had higher
      cortisol levels then RDC nonendogenous depressives. DSM III-R melancholics were
      older, more severely depressed, reported fewer numbers of psychosocial stressors
      and had lower levels of TSH than nonmelancholics. DSM-IV melancholics were more
      severely depressed, had higher basal and post dexamethasone cortisol levels and
      lower TSH levels. The ICD 10 somatic depression group contained more severe,
      older depressives with lower TSH levels. CONCLUSION: The results of this research
      show that different criteria may identify different groups of patients as having
      melancholic depression. They also partly support the hypothesis that endogenous
      or melancholic depression have a biological basis. LIMITATIONS OF STUDY: The
      study involved a relatively small sample size from a single centre and the
      results are based on this relatively small sample.

PMID- 10403154
TI  - Differential clinical features of early-onset panic disorder.
AB  - BACKGROUND: Although panic disorder (PD) begins typically in adulthood, an
      earlier onset is not uncommon. Recent studies on early-onset PD indicate that
      this subgroup of patients may display distinct clinical characteristics.
      OBJECTIVE: To compare a subgroup of early-onset PD patients with the rest of the
      sample. METHOD: A consecutive series of 442 patients with PD were included.
      Family histories were investigated, and clinical assessment employed the
      following instruments: Hamilton's scales, Global Functioning Scale, Marks
      Mathews' Fears and Phobia Scale, and Panic-Associated Symptom Scale. The age
      threshold for 'early-onset' was considered at 18 years. RESULTS: A total of 45
      patients (10.2%) exhibited early-onset PD, with a mean age at onset of 14.6. They
      were younger and had a longer duration of illness than later-onset patients. No
      differences were found in severity of panic symptoms, anxiety or depressive
      symptoms, and social functioning. They had more comorbidity with simple phobia,
      social phobia, and substance dependence. Rates of PD among first-degree relatives
      were higher in the early-onset group. CONCLUSION: Early-onset PD patients
      displayed a greater familial loading, but clinical severity of their panic
      agoraphobia symptoms was not higher. Comorbidity was greater with phobic and
      substance-related disorders.

PMID- 10403155
TI  - On the validity of the Bech-Rafaelsen Melancholia Scale (BRMS).
AB  - BACKGROUND: The findings published to date on convergent validity of the BRMS are
      mainly concerned with the correlation with other observer-rating scales for
      depression. In many studies on the evaluation of therapeutic interventions self
      rating scales are used in connection with observer-rating scales. Therefore,
      findings on the relations among instruments of both groups are necessary in order
      to justify the combination of a particular observer-rating scale with a
      particular self-rating scale. In the ICD-10 three different degrees of severity
      of depressive episodes are distinguished. No data on the discriminant validity of
      the BRMS with respect to this new diagnostic classification are available till
      now. METHODS: 45 depressed inpatients were assessed with two observer-rating
      scales (BRMS and DEPRES of the AMDP system) and two self-rating scales (BDI and
      DS). RESULTS: The discriminant validity with reference to the three degrees of
      severity of depressive episodes as defined in ICD-10 is at r = 0.80 very high.
      The convergent validity of the BRMS is high at r = 0.70, related to the DEPRES.
      The correlations between the BRMS and the BDI as well as the DS were clearly
      lower, at 0.53 and 0.32 each. CONCLUSIONS: The only moderate convergent validity
      between self-rating and observer-rating scales is a strong argument for a multi
      methodological approach in the context of therapy evaluation.

PMID- 10403156
TI  - Differences in adrenal steroid profile in chronic fatigue syndrome, in depression
      and in health.
AB  - BACKGROUND: Hyperactivity and hypoactivity of the HPA have been forwarded as of
      pathophysiological relevance in major depressive disorder and chronic fatigue
      syndrome (CFS), respectively. METHODS: This study examines cortisol levels in the
      two disorders, and also assesses levels of the adrenal androgens,
      dehydroepiandrosterone (DHEA) and its sulphate derivative (DHEA-S), and 17-alpha
      hydroxyprogesterone; 15 subjects with CFS diagnosed according to CDC criteria, 15
      subjects with DSM III-R major depression and 11 healthy subjects were compared.
      RESULTS: DHEA and DHEA-S levels were significantly lower in the CFS compared to
      the healthy group; DHEA-S levels, but not DHEA, were lower in the depressives;
      cortisol and 17-alpha-hydroxyprogesterone did not differ between the three
      groups. CONCLUSIONS: A potential role for DHEA, both therapeutically and as a
      diagnostic tool, in CFS, is suggested.

PMID- 10403157
TI  - Psychological predictors of single and recurrent major depressive episodes.
AB  - AIM: To examine for differential psychological risk factors in a nonclinical
      sample having single or recurrent episodes of major depression. METHODS: A cohort
      of 164 subjects was assessed initially in 1978 in their last year of teacher
      training, and at five-yearly intervals in 1983, 1988 and 1993. Experience of
      episodes of DSM major depression and anxiety disorders from each wave were summed
      and three groups (nil, one, and two or more episodes of major depression) were
      derived. The cohort also completed a series of self-report measures including
      neuroticism, state and trait depression, self-esteem, dependency, childhood
      parental environment and social support. RESULTS: The group with two or more
      episodes were distinctly more likely to have met lifetime criteria for an anxiety
      disorder and to have had multiple anxiety disorder diagnoses over their lifetime.
      Groups with one or more episodes reported higher mean scores for trait
      depression, neuroticism and maternal overprotection and lower mean scores for
      paternal care and self esteem at baseline in 1978, but these variables did not
      predict differences between groups with single and recurrent episodes. At 1993,
      those with two or more episodes differed from those with none and single episodes
      in reporting lower trait depression scores and decreased perception of
      satisfactory social support over time, suggesting a psychological scarring effect
      for those with repeated episodes.

PMID- 10403158
TI  - Religious climate and geographical distribution of depressive symptoms in older
      Dutch citizens.
AB  - This study examines whether the degree of conservatism of the religious climate
      affects the geographical distribution of late life depressive symptoms. A U
      shaped relationship is hypothesized: high levels of depressive symptoms at the
      extremes (both a-religious and hyperconservative), and a low level in the middle
      (moderate-conservative). Subjects are 3051 older Dutch citizens (55-85 years),
      living in 11 municipalities. Depressive symptoms are assessed using the CES-D.
      Religious climate is estimated on the municipality level, using percentages votes
      on political parties with a Christian background (moderate-conservative versus
      hyperconservative). Using multi-level analysis, the results support the U-curve
      hypothesis.

PMID- 10403159
TI  - Structure of depressive symptoms in pregnancy and the postpartum period.
AB  - BACKGROUND: The present study investigated the structure of depressive symptoms
      in the perinatal period. METHOD: The Zung Self-Rating Depression Scale (SDS) was
      administered to a total of 1329 women in early, middle and late pregnancy and 5
      days, 1 month, 6 months, 12 months and 18 months after the delivery. RESULTS: A
      number of somatic items and the suicidal ideation item of the SDS made low
      contributions to the evaluation of the severity of depression, and as a
      consequence these were excluded in the principal component analysis. Three
      factors were interpretable as "Cognitive", "Affective insomnia" and "Attentional"
      emerged at all eight assessment points. The goodness-of-fit index (GFI) generated
      by confirmatory factor analyses (LISREL 7.20) proved sufficiently high on all
      eight occasions. LIMITATION: The present study investigated only one self-rating
      scale and the sample comprised Japanese mothers only. CONCLUSION: The three
      factor model of the SDS in the perinatal period was derived from exploratory and
      confirmatory factor analyses. It is noteworthy that the same three-factor
      structure emerged at all eight collection points in the present study.

PMID- 10403160
TI  - One year clinical and psychosocial outcomes of early-onset chronic depression.
AB  - BACKGROUND: Results from short-term treatment studies have demonstrated the
      efficacy of antidepressant medications for outpatients with early-onset chronic
      depression. However, scant data exists regarding the long-term outcome of these
      patients treated for this disorder. METHODS: The author conducted a one-year
      naturalistic follow-up study of 50 outpatients with early-onset, chronic
      depression, who were treated in a university-based psychopharmacology research
      clinic. Assessments were conducted blind to the patients' histories. RESULTS:
      Forty-eight percent of the total sample reported 9-12 months of sustained
      euthymia (Months Well). Among the patients who recovered, 50% relapsed.
      LIMITATIONS: The major limitations of this study were its small sample size and
      lack of a comparison group. CONCLUSIONS: These results data demonstrate that
      despite initial response, many outpatients with chronic depression seem to
      relapse after leaving university-based psychopharmacology centers.

PMID- 10403162
TI  - Symptomatologic analysis of psychotic and non-psychotic depression.
AB  - BACKGROUND: The aim of the present study is to evaluate the symptomatologic
      presentation of delusional compared to non-delusional major depressive episodes.
      METHODS: Two hundred and eighty-eight subjects suffering from mood disorder (144
      bipolar, 133 unipolar) were assessed at admission by the Hamilton Depression
      Rating Scale (HAMD-21). RESULTS: Depressive symptomatology was more severe in the
      delusional sample, even after the exclusion of the items directly involved with
      delusional symptoms (P = 0.00002). CONCLUSIONS: Our data support the hypothesis
      of delusional depression as a more severe form of mood disorder.

PMID- 10403161
TI  - Marital and family relations and depression in married elderly Finns.
AB  - BACKGROUND: The aim was to describe the relationships between poor marital and
      family relations and depression, and the predictive value of these factors for
      the subsequent occurrence of depression. METHODS: The population for the cross
      sectional study consisted of the married elderly (N = 498) living in Ahtari,
      Finland, in 1989. The series of the longitudinal study was composed of married
      persons nondepressed in the epidemiological study in 1984-1985, and followed up
      until 1989-1990 (N = 347). RESULTS: In men, impaired functional abilities (OR
      5.0) and poor family relations (OR 2.9), and in women, impaired functional
      abilities (OR 3.9), family violence (OR 4.2), age 70 years or over (OR 3.0) and a
      loss of father in childhood or youth (OR 2.5) were independently related to
      depression. Poor marital relations tended to be related to depression in both men
      (OR 2.1) and women (OR 2.2). In both sexes, poor self-appreciation (OR men 3.9;
      women 7.1) and age 70 years or over (OR men 2.9; women 4.2), and in women, a loss
      of father in childhood or youth (OR 4.5) were independent predictors of
      subsequent depression. CONCLUSIONS: The poor marital or family relations
      experienced by many depressed elderly persons are usually consequences rather
      than predictors of depression. Family violence may be a consequence of depression
      or even a risk factor for depression. CLINICAL IMPLICATIONS: Problems in spouse
      pairs and families should be inquired and solved when treating depressed elderly
      persons. LIMITATIONS OF THE STUDY: Due to the unknown validity of the measure
      concerning marital relations, the results are suggestive.

PMID- 10403163
TI  - Double-blindness procedure did not mask giving of medication in panic disorder.
AB  - BACKGROUND: The purpose of this study was to measure the degree to which patients
      and their treating physicians correctly guessed whether patients were on an
      active treatment (paroxetine or clomipramine) or pill-placebo, and whether
      correctness of these guesses was related to treatment outcome. METHODS: Ninety
      five panic disorder patients, randomized to receive double-blind treatment with
      paroxetine, clomipramine or placebo for twelve weeks, were asked half-way through
      this period to classify treatment as active or placebo. Medical doctors were
      asked the same. RESULTS: Both patients and physicians guessed correctly to a
      degree much greater than would be expected by chance whether the patient was on
      an active treatment. Neither patients nor physicians were good at estimating
      correctly whether a patient was on a placebo. There was a trend approaching
      significance for patients on a placebo, whose physicians believed that they were
      on active treatment, to have a higher rating of symptom improvement than those
      patients who were correctly guessed to be on placebo. CONCLUSION: The 'double
      blindness' procedure did not mask the giving of antidepressive medication in
      panic disorder. There is some evidence that physicians who incorrectly classify
      patients on a placebo as receiving active treatment relate this to better
      treatment outcome.

PMID- 10403164
TI  - Family physicians and the risk of suicide in the depressed elderly.
AB  - BACKGROUND: Depression is the most frequent psychiatric disorder in the elderly.
      It is the reason for most suicides in this age group. METHOD: We performed a
      representative survey in primary care. Two written case vignettes were presented
      to 170 family physicians in face-to-face interviews which took place in their
      practices. The case vignettes described either (Case 1) a mildly depressed
      otherwise healthy old patient or a severely depressed patient (Case 2) with
      somatic comorbidity. Afterwards the interviewers asked standardized open
      questions. The physicians were not let into the mental health focus of the study.
      RESULTS: The response rate was 77.6%. Depression was considered for primary or
      differential diagnosis by 91.2% of the physicians in Case 1 and by 70% in Case 2
      (chi2-test; p < 0.01). For further anamnesis, only 2.4% of the physicians were
      interested in suicidal ideation of the patient. When directly asked at the end of
      the interview, 76.9% of the physicians said they would talk about suicide. Those
      who would not, thought that the patient would communicate suicidal intent
      himself/herself, or they feared to induce suicide by asking directly. CONCLUSION:
      Thinking of suicidality and its prevention is not uppermost in the physicians'
      mind. Therefore, and also with regard to the relatively high rate of depression
      recognition, we conclude that educational means should not only focus on the
      recognition and screening of depression, but also on the management--'how to talk
      about...'--of complex problems like suicide in the elderly, in order to change
      suicide rates.

PMID- 10403165
TI  - Trace lithium in mood disorders.
AB  - BACKGROUND: Variations in trace (endogenous) lithium exchanges have been
      postulated to play a role in the pathophysiology of affective diseases. This
      prospective study aimed to check whether plasma, erythrocytes and urine trace
      lithium levels were altered in mood disorders. METHODS: Trace lithium was
      determined by atomic absorption spectrophotometry in patients without mood
      stabilizing drugs or somatic diseases, hospitalized for bipolar affective
      disorders, major depressive episodes, and other psychiatric disorders with
      depressive features. Patients admitted for psychotic disorders without mood
      alterations and healthy volunteers served as controls. RESULTS: There were no
      differences in trace lithium status between the groups. Erythrocytes/plasma
      ratios appeared higher than described on therapeutic lithium (1.6+/-0.7, N =
      199). LIMITATIONS: The study had sufficient power to detect clinically
      significant differences in whole body lithium handling between the groups.
      However, it did not address alterations of lithium exchanges across neuronal
      membranes or the blood-brain barrier. CONCLUSIONS: Alterations of membrane
      exchanges hypothetically associated with mood disorders are not reflected in
      plasma or erythrocytes trace lithium levels. The occurrence of mood disorders
      seems not to be related to abnormalities in endogenous lithium.

PMID- 10403166
TI  - Source memory in major depression.
AB  - BACKGROUND: Research demonstrating episodic memory deficits in clinical
      depression has dealt with item memory exclusively. The present research sought to
      determine whether memory for source is differentially affected by depression.
      METHODS: Patients with major depression and normal control subjects were examined
      in item memory and two types of source memory, requiring discriminations between
      (e.g. something that the subject said and something another person said) and
      within (e.g. something that one person said and something another person said)
      classes. RESULTS: Depression-related deficits in item memory were exacerbated in
      source memory. However, deficits in source memory in depressed patients were
      restricted to those conditions requiring within-class discriminations.
      CONCLUSION: The overall pattern of results may reflect that those symptoms of
      major depression that affect the individuals basic processing resources (e.g.
      concentration difficulties, lack of effort, loss of energy) results in an
      impairment of episodic memory, particularly when the demands of differentiating
      perceptual and cognitive information are high.

PMID- 10403167
TI  - The role of pubertal progress in the development of depression in early
      adolescence.
AB  - BACKGROUND: Lack of longitudinal studies on the relationship between pubertal
      progress and changes in depression during adolescence. METHODS: Changes in the
      Anxious/Depressed scores of the Child Behavior Checklist and Youth Self-Report
      were predicted from pubertal progress. Subjects were young adolescents from the
      Dutch general population, aged 10-12 years at T1 and 12-14 years at T2. From the
      1327 parent reports, 207 showed a change that exceeded the cut-off for inclusion
      in the analyses. From the 1414 self-reports, 476 exceeded the cut-off. RESULTS:
      Apart from increase, decrease in depression was common. Pubertal progress was
      inversely related to the parent reports of boys' depression only. CONCLUSION:
      Self-perceptions of depressive symptoms change independently from pubertal
      progress, whereas changes observable to parents are inversely related to it in
      boys. LIMITATIONS: Progress was not measured across the whole pubertal
      development. CLINICAL RELEVANCE: One can expect parents to observe a decrease in
      boys' depression in the period when most pubertal progress is made. More
      attention should be paid to decreases in depressive symptomatology.

PMID- 10403168
TI  - Unipolar-bipolar dichotomy of mood disorders is supported by noradrenergic
      brainstem system morphology.
AB  - BACKGROUND: The biological basis of unipolar-bipolar dichotomy of mood disorders
      was investigated in this postmortem study by morphological comparison of the
      locus coeruleus (LC) as the main source of noradrenergic transmission in the
      brain. METHODS: Numbers and the rostro-caudal as well as ventro-dorsal
      distribution of neuromelanin-containing neurones in the LC were determined in
      brainstem of 12 patients with bipolar disorder (n = 6) or major depression (n =
      6), and 12 normal comparison subjects. RESULTS: Bipolar patients had
      significantly more neurones on both sides of the LC as a whole than patients with
      major depression. Topographical analysis revealed that this difference was
      restricted to the rostral two thirds and the dorsal part of the LC, in which
      bipolar patients showed at least a trend to higher neurone numbers as compared to
      unipolar patients or to controls. LIMITATIONS: Small case numbers. CONCLUSIONS:
      Results suggest differences of innervation arising from the LC of bipolar
      patients as compared to patients with major depression. These first data of
      brainstem transmitter system morphology in unipolar and bipolar disorder are in
      line with neuroanatomical studies of other brain regions indicating a biological
      basis of the unipolar-bipolar dichotomy of mood disorders.

PMID- 10403169
TI  - Depression: an inability to adapt to one's perceived life distress?
AB  - A comprehensive biopsychosocial distress adaptation model of depression in which
      neurochemical shortages are awarded a necessary but insufficient status is
      proposed. In context of this model, depression is seen as a function of
      inadequate behavioural, psychological, socioenvironmental and biological coping
      resources (all of which may be partly a function of genetic factors) for managing
      one's individually appraised level of life distress. It is further hypothesized
      that the physiological symptoms of depression arise as a result of a lack of
      available neurotransmitters to contend with stressors as well as maintain the
      normal functioning of the individual. Unlike many other theories, this distress
      adaptation model may account for several of the demographics of depression.

PMID- 10403170
TI  - Signaling pathways involved in thyroid hyperfunction and growth in Graves'
      disease.
AB  - The elucidation of the multiple signaling cascades coupled to the TSH receptor
      has offered new approaches in the understanding of the pathogenesis of Graves'
      disease. Here we review findings showing that immunoglobulins from Graves'
      patients are heterogeneous, bind to different epitopes and, similarly to TSH,
      activate different signaling pathways, including adenylyl cyclase, phospholipase
      C and phospholipase A2. Evidence that the multiplicity of signals correlates with
      the different manifestations of the disease is also summarized. We believe that
      the dissection of the molecular mechanisms involved in the pathogenesis of
      Graves' disease offers the basis for developing novel therapeutical approaches to
      this disease.

PMID- 10403171
TI  - The screening for mutations in the thyroglobulin cDNA from six patients with
      congenital hypothyroidism.
AB  - The six patients described in this study were clinically diagnosed with
      congenital hypothyroidism. Based on clinical and pathophysiological parameters,
      the cause of the thyroid dyshormonogenesis was suspected to be a defect in the
      synthesis of thyroglobulin, the matrix protein for thyroid hormone synthesis in
      the thyroid gland. After RNA isolation from six goitrous tissues and control
      thyroid tissues, RT-PCR was used to amplify 20 overlapping thyroglobulin (TG)
      cDNA fragments. Two alternative splice transcripts were identified: a transcript
      with a deletion of nucleotides 177-274 and a transcript with a deletion of
      nucleotides 3430-3736 that result in frame shifts and the introduction of
      premature stop codons. Two alternatively spliced transcripts not changing the
      reading frame were also identified: a transcript containing a deletion of
      nucleotides 4529-4699 and a transcript with a deletion of nucleotides 7301-7561.
      All these transcripts were expressed in thyroid tissue of both patients and
      controls. Nucleotide sequence analysis and comparison to the revised TG sequence
      (1997) revealed one revision and eight polymorphisms that did not result in amino
      acid changes and four polymorphisms that did change amino acid codons. In three
      patients a homozygous mutation was present at nucleotide position 229, causing a
      glycine to serine amino acid substitution. The clinical description
      'thyroglobulin synthesis defect' in this population cannot be explained by major
      mutations in the coding region of the TG gene. Furthermore, the presence and
      level of expression of the alternatively spliced transcripts do not co-segregate
      with thyroid dyshormonogenesis, since in normal thyroid tissue the same
      alternatively spliced transcripts are present.

PMID- 10403172
TI  - Cloning, chromosomal localization and identification of polymorphisms in the
      human thyroid transcription factor 2 gene (TITF2).
AB  - The human gene encoding the thyroid transcription factor 2 (TTF-2) was cloned and
      mapped to human chromosome 9q22. Three polymorphisms were identified in the gene
      by SSCP and direct sequencing: two consist of a third base substitution in the
      triplet encoding Leu129 and Ser273, and the third is an alanine stretch that
      varies from 12 to 17 residues. TTF-2 plays a critical role during thyroid
      morphogenesis in mice, and in man the TITF2 gene is associated with congenital
      hypothyroidism and cleft palate with thyroid dysgenesis. The polymorphisms
      identified in this study can be used as markers to study the role of the TITF2
      gene in other cases of thyroid dysgenesis, especially in familial cases.

PMID- 10403173
TI  - Colloidal aggregates of insoluble inclusions in human goiters.
AB  - To shed some light on the physicochemical properties of the thyroid follicular
      colloid, we have screened retrospectively the autoradiographs of 60 human nodular
      goiters labeled 17 h preoperatively with 100 microCi 125I for evidence of colloid
      compartmentalization. In 87% (52/60) of all goiters examined, sporadic or
      multiple colloidal inclusions ('colloid stones') not mixing with newly labeled Tg
      were detected. The detailed analysis of 17 goiters revealed a mean incidence of
      0.09+/-0.11 'colloid stones' of variable size per follicle ranging from 0.02+/
      0.01 (10) to 0.43+/-0.09 (5) (mean values +/- S.D., number of sections examined
      in brackets). In this study we did not find a clear-cut association of incidence
      of 'colloid stones' with sex, age or nosologic group (hyperthyroid, preclinically
      hyperthyroid, euthyroid). The existence of different colloidal compartments as
      demonstrated in this and other studies is of considerable importance for thyroid
      function, interpretation of iodine kinetics, and studies on the role of iodine on
      growth and function of the thyrocytes. Different thyroidal iodine compartments
      could well be of functional relevance, for example in the adaptation of thyroid
      hormone secretion to antithyroid drugs or in severe and prolonged iodine
      deficiency, when very slow compartments become an important source of minimal
      quantities of iodine and thyroid hormone. 'Colloid stones', for example, may well
      explain the repeatedly observed, surprisingly large total iodine store in human
      endemic goiters, even in the presence of severe iodine deficiency. It is evident
      that the existence of multiple iodine compartments and, in particular, of
      particulate slow-turnover pools complicates the interpretation of total glandular
      iodine measurements with modern techniques such as X-ray fluorescence and
      positron emission tomography.

PMID- 10403174
TI  - Combined ultrasonographic and cytological studies in the diagnosis of thyroid
      nodules.
AB  - Many aspects of thyroid nodule evaluation and management remain controversial.
      Widespread application of ultrasonography has resulted in frequent discovery of
      incidental nodules in the general population which has created a management
      dilemma for physicians. In this paper we have introduced a novel approach for
      evaluation of solid nodules, using an index derived from ultrasonographic and
      cytologic studies. Briefly thyroid nodules were classified ultrasonographically
      into four grades, with increasing score numbers (1-4) as progression to
      malignantly suspicious lesions was present. Similarly, four grades of a cytologic
      classification of fine needle biopsy aspirates were introduced with scores of 1-6
      (benign to malignant diagnosis). The sum of the ultrasonographic and cytologic
      scores were the basis of a diagnostic index: benign (2-4), doubtful (5),
      suspicious (6) and malignant (7-10). Sixty patients with an index equal or higher
      than 6 were submitted to thyroidectomy and the prevalence of thyroid cancer (n =
      46) in the excised nodules was 76.6%. Most series report a 10% to 30% incidence
      of malignancy in excised nodules with suspicious diagnosis. We concluded that
      using an index derived from combined ultrasonographic and cytologic studies will
      result in a better patient selection for surgery.

PMID- 10403175
TI  - Tissue-specific patterns of changes in 3,5,3'-triiodo-L-thyronine concentrations
      in thyroidectomized rats infused with increasing doses of the hormone. Which are
      the regulatory mechanisms?
AB  - We have measured 3,5,3'triiodothyronine (T3) in 12 tissues from thyroidectomized
      (Tx) rats infused with increasing doses of T3, and related them to their
      corresponding plasma levels. Young adult Wistar rats were surgically Tx. After 4
      weeks, the animals were infused with placebo or T3 (0.25, 0.50, 0.75, 1.00 or
      2.00 microg/100 g body weight/day). Placebo-infused intact rats served as
      euthyroid controls. Plasma and samples of cerebral cortex, cerebellum, brown
      adipose tissue (BAT), pituitary, liver, heart, lung, kidney, spleen, skeletal
      muscle, ovary and adrenal were obtained after 12-13 days of infusion. We
      determined plasma T3 and thyrotropin (TSH), and tissue T3 and thyroxine (T4), the
      latter being virtually undetectable. Results were compared with the relationships
      between tissue and plasma T3 in Tx rats on T4 infusions. Most tissues presented
      changes which paralleled those in plasma T3, irrespective of its source (infusion
      of T3, or generation from infused T4). However, at similar plasma T3
      concentrations, cerebral cortex, cerebellum and BAT (containing type II 5'
      iodothyronine deiodinase (DII) activity), reached much lower T3 levels in the T3
      infused Tx rats, than in Tx rats on T4, and required elevated plasma T3 levels
      for normal tissue T3. In these tissues, and in the pituitary, T3 concentrations
      were always lower than expected from plasma T3 levels. On the contrary, the lung
      and ovary of the T3-infused Tx rats contained more T3 than expected from plasma
      T3. Unexpectedly, both the ovary and adrenal attained higher tissue T3
      concentrations in Tx rats on T3 than on T4 at comparable plasma T3 levels. In
      conclusion, the patterns of changes of the concentrations of T3 as a function of
      increasing plasma T3 are not only tissue-specific when T4 is provided, but also
      when circulating T3 is the only source of this iodothyronine. Further studies are
      needed to identify the mechanisms involved in the regulation of tissue T3
      concentrations.

PMID- 10403176
TI  - Serum and tissue thyroglobulin measurement: clinical applications in thyroid
      disease.
AB  - Since the first demonstration by Van Herle et al. that thyroglobuling (Tg), the
      main iodo-protein of the thyroid gland, was detectable in the circulation of
      normal subjects by using specific radioimmunoassay, an impressive amount of
      papers has been produced, describing several clinical applications of Tg
      measurements. Now, measurement of Tg is the mainstay in the post-surgical follow
      up of differentiated thyroid cancer and an integral part in the diagnostic
      evaluation of patients with benign thyroid diseases. In this article we will
      review the most relevant clinical application of Tg measurements in the blood and
      in other biological material, including: a) serum Tg in perinatal age and
      congenital hypothyroidism; b) serum Tg measurements in thyrotoxicosis factitia
      and in other thyrotoxic conditions associated with low iodine uptake; c)
      differential diagnosis of thyroid and parathyroid cysts; and d) clinical
      relevance of Tg measurement in thyroid cancer.

PMID- 10403178
TI  - Expression of integrins of the beta1 family in thyroid cells from patients with
      Graves' disease in vivo and in vitro.
AB  - The expression of the beta1 family of integrins was determined in thyroid
      follicular cells from patients with Graves' disease (GD). Integrin expression was
      quantitated by flow fluorocytometry of single cell suspensions with antibodies
      against the common beta1 chain and the alpha1-alpha6 subunits. Results indicated
      that also in thyroid glands of GD, as previously observed in nodular goiters, two
      follicular cell populations with different patterns of beta1 integrin expression
      coexist (VLAalpha3beta1 and VLAalpha1,3,5,6beta1). The VLAalpha1,3,5,6beta1
      thyrocyte population in GD was more abundant than in nodular goiters, ranging
      from 40 to 70% of the total follicular cells and the overall expression of the
      beta1 integrins was a two-fold higher. In thyrocytes from patients with GD
      cultured in vitro, alpha3 and alpha2 expression was regulated by cell-to-cell
      contact as previously described in normal thyroid cells, while the expression of
      alpha1, alpha5 and alpha6 was quickly lost during the culture. Our data suggest
      that the integrin profile of the VLAalpha1,3,5,6beta1 thyrocyte population in GD
      is induced by micro-environmental conditions rather than being the expression of
      a constitutive phenotype.

PMID- 10403177
TI  - Mutations in the sodium/iodide symporter (NIS) gene as a cause for iodide
      transport defects and congenital hypothyroidism.
AB  - The ability to concentrate iodide actively is a characteristic feature of the
      thyroid gland and several other tissues. This function is mediated through the
      sodium iodide symporter (NIS), a protein that is located in the basolateral
      membrane of the thyrocyte. A defect in the NIS (iodide trapping defect) can
      result in hypothyroidism, the severity of which is variable and influenced, in
      part, by the amount of iodine supply. The molecular cloning of NIS and
      characterization of its genomic organization allowed the identification of NIS
      gene mutations in patients expressing the phenotype of iodide trapping defect.
      Six mutations (G93R, Q267E, C272X, T354P, Y531X and G543E) have been so far
      identified and their properties have been partially characterized. G93R, Q267E
      and Y531X were found in a compound heterozygous individual with NIS defect, C272X
      and G543E were detected in a homozygous state and T354P has been identified in
      both homozygotes and heterozygotes in combination with G93R. Heterozygous family
      members, expressing one normal allele, are clinically not affected. This was
      confirmed by in vitro analysis where all six mutants produced NISs with virtually
      no biological activity that did not interfere with the wild-type NIS function
      when cotransfected in mammalian cells. While the precise mechanisms by which
      mutant NISs cause iodide trapping defect are still unknown, preliminary data
      suggest that 354P interferes with the iodide transport function rather than
      targeting to the cell membrane.

PMID- 10403179
TI  - Effects of iodine repletion on thyroid morphology in iodine and/or selenium
      deficient rat term fetuses, pups and mothers.
AB  - It has been suggested that selenium deficiency aggravates the iodine-induced
      thyroid inflammation and necrosis in iodine-deficient Wistar rats and possibly in
      man. Studies were carried out to determine whether large amounts of iodine given
      to iodine-deficient pregnant Sprague-Dawley rats with or without selenium
      deficiency would induce inflammation and necrosis in their term fetal thyroids.
      Iodine deficiency was induced in the dams by a low iodine diet or perchlorate in
      the drinking water and iodine excess was achieved by iodinated drinking water
      during pregnancy or daily subcutaneous injections of iodine from days 20 to 22 of
      pregnancy, 1 day after perchlorate was discontinued. Studies were also carried
      out in 30-day-old pups whose nursing mothers were iodine-deficient (perchlorate)
      with or without selenium deficiency from conception onward. The administration of
      iodine restored the morphologic changes in the thyroid induced by iodine
      deficiency, irrespective of selenium status, toward normal without inflammatory
      changes or necrosis. Possible explanations for these unexpected findings are
      discussed.

PMID- 10403180
TI  - Thyroglobulin binding and TSH regulation of the RHL-1 subunit of the
      asialoglycoprotein receptor in rat thyroid.
AB  - The ability of asialo-thyroglobulin to bind the thyroid RHL-1 subunit of the
      asialoglycoprotein receptor has been investigated. Ligand blot assays show that
      the recombinant carbohydrate recognition domain of the thyroid RHL-1 subunit
      specifically interacts with rat desialated thyroglobulin. Moreover, RT-PCR and
      Western blot assays show that TSH deprivation decreases RHL-1 expression in PC
      C13 thyroid differentiated cells whereas insulin deprivation does not have any
      effect. The simultaneous absence of both TSH and insulin dramatically decreases
      the level of RHL-1 expression.

PMID- 10403181
TI  - Depletion of divalent cations within the secretory pathway inhibits the terminal
      glycosylation of complex carbohydrates of thyroglobulin.
AB  - Newly synthesized thyroglobulin transiting the secretory pathway is
      posttranslationally modified by addition of oligosaccharides to asparagine N
      linked residues. The effect of divalent cation depletion on oligosaccharide
      processing of Tg was studied in FRTL-5 cells. Treatment with an ionophore,
      A23187, or thapsigargin, an inhibitor of the sarcoplasmic/endoplasmic reticulum
      ATPases delayed Tg secretion. These effects were accompanied by a normal
      distribution of the marker of the endoplasmic reticulum protein disulfide
      isomerase. Analysis of the thyroglobulin oligosaccharides by Bio-gel P4
      chromatography showed that in the presence of A23187 and thapsigargin the
      addition of peripheral sialic acid and possibly galactose is inhibited. These
      findings were strengthened by experiments of exoglycosidase digestion and SDS
      PAGE analysis of the resulting products. These results reveal a cellular
      mechanism of production of thyroglobulin with incompletely processed complex
      chains, i.e., the ligand of the recently described GlcNAc and asialoglycoprotein
      receptors of the thyroid. Since A23187 and thapsigargin inhibit biosynthetically
      the addition of peripheral sugars on N-linked oligosaccharides chains, the
      thyroglobulin molecules secreted in the presence of A23187 and thapsigargin
      should greatly facilitate studies on the function of the GlcNAc and
      asialoglycoprotein receptors of the thyroid.

PMID- 10403182
TI  - The importance of thyroglobulin structure for thyroid hormone biosynthesis.
AB  - Thyroglobulin (Tg) is the most important protein in the thyroid because it
      provides the matrix for thyroid hormone biosynthesis. Here we review experimental
      work, principally from our laboratory, on the relationship between Tg structure
      and hormonogenesis. Early work showed that Tg's most important hormonogenic site
      was located in a fragment of approximately 26 kDa obtained on chemical reduction.
      With the establishment of the cDNA sequence of Tg, this and other major sites
      could be localized within Tg's polypeptide chain. The four major hormonogenic
      sites, designated A, B, C, and D, are located respectively at tyrosyls 5, 2553,
      2746, and 1290. In most species, site A accounts for about 40% of Tg's hormone,
      and site B for about 25%. Site C is associated with increased T3, at least in
      some species. Site D is prominent in guinea pigs and rabbits, and TSH favors
      hormonogenesis at it in these species. Sequential iodination of low iodine human
      Tg shows three consensus sequences associated with early iodination and with T4
      formation. Recent work has identified Tyr130 in beef Tg as donor of an outer
      iodothyronine ring, most likely to Tyr5, the most important hormonogenic site. In
      addition to its biochemical importance, Tg has clinical interest in familial
      goiter and autoimmune thyroid disease. Further elucidation of Tg structure and
      its relation to thyroid hormone synthesis will contribute to thyroid physiology
      and to its clinical application.

PMID- 10403183
TI  - Models to study the pathogenesis of thyroid autoimmunity.
AB  - In vitro and in vivo models to study the pathogenesis of thyroid autoimmunity are
      reviewed. Animal models with experimentally induced or spontaneously developed
      autoimmune thyroid disease as well as transplantation models have been used
      extensively in these studies, but also the use of thyroid cell cultures from both
      humans and animals has contributed to the present state of knowledge. Cytokines
      may play a role in the pathogenic mechanism in thyroid autoimmunity. The major in
      vitro and in vivo effects of for example interleukin-1, tumour necrosis factor
      and gamma-interferon on differentiated thyroid cell functions are inhibitory. The
      advantage of using cell cultures has been the possibility of studying an
      influence on thyrocytes from a single agent individually, such as cytokines,
      hormones or growth factors. The disadvantage is that an organism is under the
      influence of a multitude of factors that can only be investigated in vivo in
      intact organisms. Both types of models have therefore been important in the
      understanding of thyroid autoimmunity.

PMID- 10403184
TI  - The disulfide bond pattern between fragments obtained by the limited proteolysis
      of bovine thyroglobulin.
AB  - The comparative analysis of the products of the limited proteolysis of bovine
      thyroglobulin with trypsin by SDS-polyacrylamide gel electrophoresis in non
      reducing and reducing conditions revealed the presence of disulfide linkages
      between some of the fragments. In order to define the disulfide bond pattern
      between the proteolytic fragments of thyroglobulin, these were isolated by SDS
      polyacrylamide gel electrophoresis in non-reducing conditions and electrophoretic
      transfer onto polyvinylidene difluoride membranes. Individual bands were desorbed
      from the membranes and re-analyzed by SDS-polyacrylamide gel electrophoresis in
      reducing conditions. The resulting peptides were identified by comparison with
      the peptides directly obtained by SDS-electrophoresis in reducing conditions, and
      characterized by amino-terminal peptide sequencing either in this study or in a
      previous investigation (Gentile F., Salvatore G., Eur. J. Biochem. 218 (1993) 603
      621). The analysis revealed that several fragments, produced by cleavages within
      the context of various cysteine-rich repeats of type 1 and within cysteine-rich
      repeat 3b.1, did not separate in the absence of reduction. On the other hand, the
      products of the cleavages at the carboxy-terminal extremity of the linker between
      type 2 and type 3 cysteine-rich repeats, and in the middle of the
      acetylcholinesterase-similar domain of thyroglobulin separated freely, with no
      need for reduction. On the base of these data, a model is presented in which
      distinct subsets of cysteine-rich repeats and the carboxy-terminal,
      acetylcholinesterase-similar domain of thyroglobulin form sequentially aligned
      subdomains with internal disulfide linkages.

PMID- 10403185
TI  - The trace element selenium and the thyroid gland.
AB  - Apart from the essential trace element iodine, which is the central constituent
      of thyroid hormones, a second essential trace element, selenium, is required for
      appropriate thyroid hormone synthesis, activation and metabolism. The human
      thyroid gland has the highest selenium content per gram of tissue among all
      organs. Several selenocysteine-containing proteins respectively enzymes are
      functionally expressed in the thyroid, mainly in thyrocytes themselves: three
      forms of glutathione peroxidases (cGPx, pGPx, and PH-GPx), the type I 5
      deiodinase, thioredoxin reductase and selenoprotein P. The thyroidal expression
      of type II 5-deiodinase still is controversial. As thyrocytes produce H2O2
      continuously throughout life an effective cell defense system against H2O2 and
      reactive oxygen intermediates derived thereof is essential for maintenance of
      normal thyroid function and protection of the gland. In experimental animal
      models long-term and strong selenium deficiency leads to necrosis and fibrosis
      after high iodide loads. Combined iodide and selenium deficiency such as in
      central Zaire is thought to cause the myxedematous form of endemic cretinism.
      Inadequate selenium supply and prediagnostically low serum selenium levels are
      significantly correlated with the development of thyroid carcinoma and other
      tumors. Though selenium supply controls expression and translation of
      selenocysteine-containing proteins no direct correlation is found between
      selenium tissue content and expression of various thyroidal selenoproteins,
      indicating that other regulatory factors contribute to or override selenium
      dependent expression control, e.g., in thyroid adenoma, carcinoma or autoimmune
      disease. As both trace elements, iodine and selenium, were washed out from the
      upper layers of the soil during and after the ice ages in many regions of the
      world adequate supply with these essential compounds needs to be provided either
      by a balanced diet or supplementation.

PMID- 10403186
TI  - Mutation of the Secys residue 266 in human type 2 selenodeiodinase alters 75Se
      incorporation without affecting its biochemical properties.
AB  - Type 2 deiodinase (D2) is a low Km iodothyronine deiodinase that metabolizes
      thyroxine (T4) to the active metabolite T3. We have recently shown that the cDNA
      for the human D2 coding region contains two in-frame selenocysteine (TGA) codons.
      The 3' TGA is seven codons 5' to a universal stop codon, TAA. The human D2
      enzyme, transiently expressed in HEK-293 cells, can be in vivo labeled with 75Se
      as a doublet of approximately 31 kDa. This doublet is consistent with the
      possibility that the carboxy-terminal TGA codon can either encode selenocysteine
      or function as a stop codon. To test this hypothesis we mutagenized the second
      selenocysteine codon to a cysteine (TGC) or to an unambiguous stop codon (TAA).
      While the selenium incorporation pattern is different between the wild-type and
      mutant proteins, the deiodination properties of the enzyme are not affected by
      mutating the 3'TGA codon. Thus, we conclude that neither this residue nor the
      remaining seven carboxy-terminal amino acids are critical for the deiodination
      process.

PMID- 10403187
TI  - Evolving concepts of thyroid hormone action.
AB  - The past 25 years have witnessed dramatic changes in our concepts of thyroid
      hormone action. Progress in this area was made possible by the recognition of the
      central role of triiodothyronine in mediating thyroid hormone action and the
      recognition of specific nuclear receptors in target tissues as demonstrated by
      displacement studies. The cloning of the receptors and receptor variants has
      enabled investigators to undertake detailed analyses of the biochemical events
      which underlie the physiological and pathological action of thyroid hormone.

PMID- 10403188
TI  - Altered thyroid hormone binding to plasma lipoproteins in the syndrome of
      resistance to thyroid hormones.
AB  - Lipoproteins, especially HDL, are carriers of a small fraction of the thyroid
      hormones in plasma and participate in the intracellular transport of T4. In
      previous work we showed that a brief period of hypothyroidism alters the hormone
      distribution among the lipoproteins, causing a decrease in VLDL and LDL binding
      despite a relative increase in VLDL and LDL cholesterol, an increase in HDL
      binding, and a reversal of T4 and T3 binding to the smallest HDL size subgroup.
      The present study of three patients with thyroid hormone resistance and largely
      compensated hypothyroidism showed thyroid hormone distribution that differed
      markedly from both normal and hypothyroid subjects. The most striking difference
      was a much lower binding of both T4 and T3 to HDL and a much higher binding to
      LDL. If confirmed in a larger group of patients, this might serve as a marker for
      thyroid hormone resistance.

PMID- 10403189
TI  - Selective endocytosis of thyroglobulin: a review of potential mechanisms for
      protecting newly synthesized molecules from premature degradation.
AB  - In 1976 Cortese, Schneider and Salvatore (Eur. J. Biochem. 68 (1976) 121-129)
      showed that the thyroid gland protects newly synthesized, iodine and hormone poor
      thyroglobulin from immediate degradation. Since then there has been substantial
      progress in understanding the mechanism by which this selectivity of degradation
      occurs. Thyroglobulin in the follicular lumen is internalized mainly by receptor
      specific endocytosis. Recycling of immature, poorly iodinated thyroglobulin back
      to the follicular lumen is the pathway most likely responsible for selectivity.
      Since additional carbohydrate groups are added to the immature thyroglobulin, it
      appears that this recycling occurs via the Golgi compartment. The molecular
      signal for recycling most likely involves the complex carbohydrates and probably
      is exposed GlcNAc groups. A thyroid-specific GlcNAc receptor has been identified
      and cloned. Other Tg-binding sites have been identified in the thyroid, but their
      physiological role remains to be determined.

PMID- 10403190
TI  - Molecular evolution of thyroid peroxidase.
AB  - Thyroid peroxidase is a member of a family of mammalian peroxidases that includes
      myeloperoxidase, lactoperoxidase, eosinophil peroxidase, and salivary peroxidase.
      Protein sequences showing a high degree of sequence similarity with mammalian
      peroxidases have recently been observed in several invertebrate species. A
      multiple sequence alignment prepared with five mammalian and six invertebrate
      peroxidases shows complete conservation of amino acid residues considered to be
      important in the formation of peroxidase compound 1. These include the distal and
      proximal histidines, a catalytic arginine residue, and an asparagine residue
      hydrogen bonded to the proximal histidine. TPO-2, an alternatively spliced form
      of TPO, lacks the essential asparagine (Asn 579). It is now possible to speak
      more broadly of the family of animal peroxidases, rather than mammalian
      peroxidases. The animal peroxidases comprise a group of homologous proteins that
      differ markedly from the plant/fungal/bacterial peroxidases in primary, secondary
      and tertiary structure, but which share with them a common function. Animal
      peroxidases probably arose independently of the plant/fungal/bacterial peroxidase
      superfamily and most likely belong to a different gene family. The relationship
      between animal and non-animal peroxidases probably represents an example of
      convergent evolution to a common enzymatic mechanism.

PMID- 10403191
TI  - Hormone synthesis and storage in the thyroid of human preterm and term newborns:
      effect of thyroxine treatment.
AB  - Iodine and thyroglobulin concentrations, as well as iodine, T3, T4 and sialic
      acid contents of thyroglobulin, were measured in thyroid glands collected
      postmortem from 42 human premature or term newborns and infants. Three groups
      were considered: very preterm newborns (24-32 postmenstrual weeks, < 5 days
      postnatal life), preterm and term newborns (34-41 postmenstrual weeks, < 5 days
      postnatal life) and infants (born at term, postnatal age 1-8 months). Five very
      preterm and seven preterm newborns received a daily dose of 10 microg/kg L-T4 for
      at least 3 days. Thyroid weight and sialic acid content of thyroglobulin
      progressed with maturation. Intrathyroidal concentrations of iodine and
      thyroglobulin did not increase significantly before the 42nd week of
      postmenstrual age. The level of thyroglobulin iodination increased during the
      postnatal life, except in the very preterm neonates. T4 and T3 content of
      thyroglobulin was directly proportional to its degree of iodination and
      positively related to its sialic acid content. L-T4 treatment of preterm newborns
      increased thyroglobulin iodination and T4-T3 content, without increasing
      thyroglobulin concentration in the thyroid. It was concluded that the storage of
      thyroglobulin and iodine in the thyroid develops around term birth. This,
      associated with the resulting rapid theoretical turnover of the intrathyroidal
      pool of T4 in Tg, could be an important factor of increased risk of neonatal
      hypothyroxinemia in the premature infants. The L-T4 treatment of preterm newborns
      does not accelerate the maturational process of the thyroid gland.

PMID- 10403192
TI  - A hyperglycinergic rat model for the pathogenesis of schizophrenia: preliminary
      findings.
AB  - There is evidence of high glycine concentrations in the brains and periphery of
      schizophrenics. In the forebrain, glycine plays a major role as a co-agonist with
      glutamate at the excitatory N-methyl-D-aspartate (NMDA) receptors. This activity
      of glycine is involved in the normal functioning of the brain in adulthood and
      during neurodevelopment, and it may also cause neurotoxicity and brain
      abnormalities when its concentrations are high. To test the hypothesis that the
      high glycine concentrations observed in schizophrenics play an etiologic role in
      schizophrenia, an animal model was tested where rats were made hyperglycinic from
      life in utero to adulthood. The hyperglycinic rats showed abnormalities in
      sensory gating mechanisms, enlarged cerebral ventricles and diminished
      hippocampal dimensions. All of these abnormalities closely parallel observations
      reported in patients with schizophrenic psychoses. These results from a rat model
      suggest an etiologic role for high glycine concentration in the behavior and
      brain abnormalities of schizophrenic patients.

PMID- 10403193
TI  - Reduced hippocampal N-acetylaspartate without volume loss in schizophrenia.
AB  - Quantitative magnetic resonance imaging (MRI) can measure total gray matter
      volume but cannot discriminate between neurons and glia. Proton magnetic
      resonance spectroscopic imaging (1H MRSI) measures N-acetylaspartate (NAA) which
      is a selective marker of neuronal loss or neuronal dysfunction. The objective of
      this study was to obtain quantitative measures of hippocampal volume and
      hippocampal NAA to determine if there was evidence for hippocampal neuronal
      dysfunction or neuronal loss in schizophrenia. Quantitative MRI and 1H MRSI was
      performed on the right and left hippocampal regions in 23 chronic schizophrenic
      patients and 18 control subjects. Relative to the control group, the patients
      with schizophrenia demonstrated no change in hippocampal volumes bilaterally, but
      significantly decreased NAA in the hippocampal regions bilaterally. There was
      also no correlation between hippocampal volumes and NAA in either the
      schizophrenics or controls. These findings suggest that: (1) hippocampal NAA may
      be a more sensitive measure of neuronal loss than volumetric measurements; and
      (2) reduced hippocampal NAA may be measuring neuronal dysfunction or damage
      rather than neuronal loss in this sample of schizophrenics.

PMID- 10403194
TI  - Early age of onset, brain morphological changes and non-consistent motor
      asymmetry in schizophrenic patients.
AB  - Previous data suggest abnormalities in the consistence of motor dominance in
      schizophrenia (e.g. mixed-handedness, poor correlation between hand, eye and foot
      preferences and an increase of hand-eye crossed dominance). The aim of this work
      is to examine the clinical significance of hand-eye and hand-foot crossed
      dominance in a sample of 61 right-handed schizophrenic patients. The application
      of multivariate analysis revealed that 23 right-handed and non-right-eyed
      patients (crossed hand-eye dominant group) had a significant earlier clinical
      onset and smaller brain size, global and frontal area, than 38 right-handed and
      right-eyed schizophrenics (consistent hand-eye dominance group). These findings
      are discussed within the context of neurodevelopmental disorders.

PMID- 10403195
TI  - Geographical variation in rate of schizophrenia in rural Ireland by place at
      birth vs place at onset.
AB  - This study examined geographical variation in rate of occurrence of schizophrenia
      by place at birth vs place at onset, among a rural Irish catchment area
      population of unusual stability and socioeconomic homogeneity. Within a catchment
      area of 21,520 persons, all cases of schizophrenia were sought using current
      inpatient and outpatient records and key informants active in the community.
      Suspected cases were interviewed personally and diagnosed using DSM-III-R
      criteria. Place at birth and place at onset of psychosis were specified among the
      32 District Electoral Divisions constituting the study region. For the 72 cases
      ascertained, an unremarkable overall prevalence rate/morbid risk obscured
      substantial and significant geographical variations therein between District
      Electoral Divisions. Particularly after controlling for high-density families,
      men demonstrated prominent geographical variation both by place at birth and by
      place at onset, with most men remaining unmarried and becoming ill at their place
      of birth; conversely, women demonstrated prominent variation by place at birth
      but more limited variation by place at onset, despite more frequent transitions
      from the parental home to the marital home before onset. Even when cases changed
      their location before the onset of psychosis, geographical variation in rate of
      occurrence of schizophrenia remained associated more strongly with factors
      related to the place of their birth.

PMID- 10403196
TI  - The relationship between affect expression and affect recognition in
      schizophrenia.
AB  - To examine the relationship between affect expression and affect recognition, we
      assessed 30 clinically stable, medicated schizophrenic inpatients. Affect
      expression was assessed using both a standard clinical rating scale (SANS) and a
      computerized acoustic voice analysis (VOXCOM). Affect recognition was assessed
      using the Florida Affect Battery (FAB). The schizophrenics' performance on the
      FAB was impaired, indicating broad deficits in affect recognition (p<0.05). There
      were no significant correlations between measures of affect expression and affect
      recognition, suggesting that the expressive impairment in schizophrenia is not
      related to their ability to discern emotions in others. SANS Inappropriate
      Affect, however, was negatively correlated with facial affect recognition (p =
      0.001), suggesting that raters' impression of inappropriate affect may indicate a
      failure in the process of affect attunement.

PMID- 10403197
TI  - Comparison of set-shifting ability in patients with chronic schizophrenia and
      frontal lobe damage.
AB  - Neuropsychological studies of patients with schizophrenia have consistently
      identified deficits on tests sensitive to frontal lobe function. One paradigm
      that has been widely used is that of attentional set-shifting using the Wisconsin
      Card Sorting Test (WCST). In the present study, patients with chronic
      schizophrenia and with frontal lobe lesions were assessed on a computerised set
      shifting task that provides a componential analysis of the WCST by distinguishing
      between intra-dimensional and extra-dimensional set-shifting. Out of 51 patients
      with schizophrenia, those with high IQ (n =24) were compared with patients with
      lesions in prefrontal cortex (n = 22) and with normal control subjects (n= 18).
      These three groups were well matched for age, sex and National Adult Reading Test
      (NART) IQ. The schizophrenic group showed a significantly higher rate of
      attrition at the intra-dimensional shift stage of learning compared with the
      other two groups. At the extra-dimensional shift stage, both the schizophrenic
      and frontal lesioned groups showed greater attrition than controls. Further,
      patients with schizophrenia who were able to learn the intradimensional reversal
      stage required more trials and made significantly more errors at that stage than
      the other two groups. In comparison with high IQ patients with schizophrenia,
      those with low IQ performed at a lower level but showed a qualitatively similar
      pattern of performance, providing further evidence that the set-shifting deficits
      were not simply explained by any global intellectual decline. Patients with
      schizophrenia who dropped out at the extradimensional shift stage had higher
      negative symptom scores compared with patients dropping out at previous learning
      stages, while patients failing at the intra-dimensional shift stage had lower
      scores for bradyphrenia (slowness of thought). The results suggest that patients
      with chronic schizophrenia fail to 'learn set' and are impaired at both set
      shifting and concept formation. The relevance of these findings to understanding
      the nature of prefrontal cortical deficits in chronic schizophrenia is discussed.
      The implication of these findings to the rehabilitation of these patients is
      considered.

PMID- 10403198
TI  - Dinucleotide repeat polymorphism in the neurotrophin-3 gene and hippocampal
      volume in psychoses.

PMID- 10403199
TI  - Effects of conditioned stimulus presentation on diminution of the unconditioned
      response in aversive classical conditioning.
AB  - The purpose of this experiment was to study whether conditioned diminution of the
      unconditioned response (UR) is a phenomenon with an associative basis.
      Discriminative electrodermal conditioning was used with an interval between the
      conditioned stimulus (CS) and unconditioned stimulus (US; aversive white-noise)
      of 8 s. Fifty-nine volunteer subjects received discrimination training in which
      one CS was reinforced (CS+ /US) and a second CS was non-reinforced (CS-). After
      this discriminative training phase, participants were tested using intermixed
      trials in which a US was preceded by either a CS+, a CS-, or a neutral stimulus
      (NS). The results indicated that the skin conductance response amplitude of the
      UR was lower when the US was preceded by the CS+ than when the US was preceded by
      the CS- or the NS. However, NS/US presentations elicited URs of greater amplitude
      than those of the CS- /US presentations. The results can be explained in terms of
      orienting reflex reinstatement. In addition, it is argued that conditioned
      diminution has an associative basis.

PMID- 10403200
TI  - Mood and spatial memory: emotion and right hemisphere contribution to spatial
      cognition.
AB  - Depressed persons show an impairment of spatial cognition that may reflect the
      influence of affective arousal on right hemisphere cognition. We examined normal
      university students to determine whether individual differences in mood and
      arousal levels would be related to performance on a spatial memory task. Right
      hemisphere specialization for this spatial memory task was confirmed by a left
      field advantage for the targets and this field asymmetry was enhanced as task
      difficulty was increased. Event-related brain potentials (ERPs), assessed with a
      64-channel sensor array, showed a processing negativity contralateral to the
      target in the P300 interval (300-500 ms after the target appeared). This effect
      increased as task difficulty was increased. A stronger posterior negativity for
      good (rather than bad) targets may suggest that attention was allocated toward
      the good locations. A suggestion of right hemisphere sensitivity to mood in this
      normal sample was a tendency for the subjects high in Negative Arousal not to
      show the normal right hemisphere (left field) superiority for the spatial memory
      task. Interestingly, a medial frontal lobe negativity was elicited in the ERPs by
      the bad targets, perhaps paralleling the error-related negativity observed in
      other paradigms. This medial frontal negativity was also seen in response to the
      feedback stimulus for the bad targets. Motivation may be important to this
      frontal effect: It was enhanced for subjects describing themselves as high in
      either positive or negative affective arousal during the task.

PMID- 10403201
TI  - Hypertension and pain sensitivity: effects of gender and cardiovascular
      reactivity.
AB  - Repeatedly, hypertensives have been found to appraise physical stressors as less
      aversive than normotensives. The main aim of the present study was to examine the
      effects of gender and cardiovascular reactivity in the relationship between
      hypertension and appraisal of pain. Forty-two unmedicated hypertensives and 21
      normotensive controls of both genders were exposed to an electric current
      stimulus, while various cardiovascular parameters and prestressor anxiety were
      measured. In general, hypertensive women, but not men, showed diminished pain
      sensitivity compared to their normotensive counterparts. When the analyses were
      repeated with controlling for cardiovascular reactivity, the between-group
      effects were no longer significant. The results indicate that (i) profound gender
      differences exist in hypertension-related pain sensitivity and (ii) these effects
      seem to be mediated, at least partly, by cardiovascular reactivity.

PMID- 10403202
TI  - P300 and personality: an investigation with the Cloninger's model.
AB  - The relationships between P300 and personality have been explored mainly in
      reference to the model of personality described by Eysenck because of its
      biological bases. Recently, Cloninger and his colleagues have proposed a model of
      personality based on four temperaments and three characters. The Temperament and
      Character Inventory (TCI) is a 226-item self-questionnaire developed to assess
      these seven dimensions of personality. In the present study, the relationships
      between these dimensions of personality and P300 have been investigated in 43
      normal subjects. The results show that P300 amplitude is positively correlated
      with the novelty seeking dimension and negatively correlated with the harm
      avoidance dimension. In contrast, the other dimensions of the TCI were not
      related to P300 amplitude. Moreover, P300 latency and reaction time were not
      associated with the TCI dimensions of personality. This study confirms that
      personality is related to P300.

PMID- 10403203
TI  - Cortical malformations and epilepsy: new insights from animal models.
AB  - In the last decade, the recognition of the high frequency of cortical
      malformations among patients with epilepsy especially children, has led to a
      renewed interest in the study of the pathophysiology of cortical development.
      This field has also been spurred by the recent development of several
      experimental genetic and non-genetic, primarily rodent, models of cortical
      malformations. Epileptiform activity in these animals can appear as spontaneous
      seizure activity in vivo, in vitro hyperexcitability, or reduced seizure
      susceptibility in vitro and in vivo. In the neonatal freeze lesion model, that
      mimics human microgyria, hyperexcitability is caused by a reorganization of the
      network in the borders of the malformation. In the prenatal methylazoxymethanol
      model, that causes a diffuse cortical malformation, hyperexcitability is
      associated with alteration of firing properties of discrete neuronal
      subpopulations together with the formation of bridges between normally
      unconnected structures. In agreement with clinical evidence, these experimental
      data suggest that cortical malformations can both form epileptogenic foci and
      alter brain development in a manner that causes a diffuse hyperexcitability of
      the cortical network.

PMID- 10403204
TI  - Vagus nerve prolonged stimulation in cats: effects on epileptogenesis (amygdala
      electrical kindling): behavioral and electrographic changes.
AB  - PURPOSE: To analyze the effect of prolonged (daily) electrical vagus nerve
      stimulation (VNS) on daily amygdaloid kindling (AK) in freely moving cats.
      METHODS: Fifteen adult male cats were implanted in both temporal lobe amygdalae,
      both lateral geniculate bodies, and prefrontal cortices. A bipolar hook (5-mm
      separation) stainless steel electrode also was implanted in the unsectioned left
      vagus nerve. AK only was performed on five of the cats as a control. The
      remaining 10 cats were recorded under the following experimental conditions: VNS
      (1.2-2.0 mA, 0.5-ms pulses, 30 Hz) for 1 min along with AK (1-s train, 1-ms
      pulses, 60 Hz, 300-600 microA), followed by VNS alone for 1 min, four times
      between 11:00 a.m. and 2 p.m. At different times, VNS was arrested, and AK was
      continued until stage VI kindling was reached. RESULTS: The behavioral changes
      evoked by VNS were as follows: left miosis, blinking, licking, abdominal
      contractions, swallowing, and eventually yawning, meowing, upward gaze, and short
      head movements. Compulsive eating also was present with a variable latency.
      Outstanding polygraphic changes consisted of augmentation of eye movements and
      visual evoked potentials while the animal was awake and quiet, with immobility
      and upward gaze. An increase of the pontogeniculooccipital (PGO) wave density in
      rapid eye movement (REM) sleep also was noticeable. AK was completed (to stage
      VI) in the control animals without a vagus nerve implantation in 23.4+/-3.7
      trials. In animals with VNS, the AK was significantly delayed, remaining for a
      long time in the behavioral stages I-III and showing a reduction of
      afterdischarge duration and frequency. Stage VI was never reached despite 50 AK
      trials, except when the vagus nerve electrodes were accidentally broken or vagal
      stimulation was intentionally arrested. Under these circumstances, 24.4+/-8.16 AK
      trials alone were necessary to reach stage VI of kindling. CONCLUSIONS: Our
      results indicate that left, electrical VNS interferes with AK epileptogenesis.
      This anticonvulsant effect could be related to the increase of REM sleep.

PMID- 10403205
TI  - Nitric oxide and glutamate interaction in the control of cortical and hippocampal
      excitability.
AB  - PURPOSE: We investigated the role of nitric oxide (NO) as a new neurotransmitter
      in the control of excitability of the hippocampus and the cerebral cortex, as
      well as the possible functional interaction between NO and the glutamate systems.
      METHODS: The experiments were performed on anesthetized rats. The bioelectrical
      activities of the somatosensory cortex and the CA1 region of the hippocampus of
      these rats were recorded. Pharmacologic inhibition of NO synthase (NOS) through
      the nonselective and brain-selective inhibitors, N-nitro-L-arginine methyl ester
      (L-NAME) and 7-nitroindazole (7-NI), was performed. RESULTS: The treatments
      caused the appearance of an interictal discharge activity in both the structures.
      The latency of induction and the duration of the interictal discharge activity
      were strictly related to the dose of NOS inhibitor used. In some cases, after L
      NAME treatment at high doses, it was possible to note spike and wave
      afterdischarge activity in the hippocampus. All the NOS inhibitor-mediated
      excitatory effects were abolished by intraperitoneal (i.p.) pretreatment with the
      N-methyl-D-aspartic acid (NMDA) receptor antagonists (DL-2-amino-5
      phosphonovaleric acid, 2-APV; dizolcipine, MK-801) and partly suppressed after
      the i.p. injection of the non-NMDA antagonist (6-cyano-7-nitroquinoxaline-2,3
      dione; CNQX). CONCLUSIONS: All data showed that the reduction of NO levels in the
      nervous system causes the functional prevalence of the excitatory
      neurotransmission, which is probably due to an NMDA overactivity caused by the
      absence of the NO-mediated modulatory action. Thus, it is possible to hypothesize
      a neuroprotective role for NO, probably through a selective desensitization of
      the NMDA receptors.

PMID- 10403206
TI  - Symptomatology of epileptic seizures in the first three years of life.
AB  - PURPOSE: Few data are available concerning symptomatology of epileptic seizures
      in infants. METHODS: We reviewed 296 videotaped seizures from 76 patients aged 1
      35 months (mean, 15.1 months) who underwent video-EEG monitoring at our
      institution from 1988 to 1998. Seizure symptomatology was first classified based
      on observable behavioral and motor manifestations and then correlated with ictal
      EEG. RESULTS: Four seizure types accounted for 81% of all seizures seen in this
      group: epileptic spasms (24%), clonic seizures (20%), tonic seizures (17%), and
      hypomotor seizures (20%; characterized by arrest or significant decrease of
      behavioral motor activity with indeterminate level of consciousness). The
      remaining seizures included small numbers of myoclonic, atonic, and versive
      seizures. All 12 focal motor seizures and all five versive seizures were
      associated with focal EEG seizure patterns, seen in the contralateral hemisphere
      in all but one patient with versive seizures. Generalized motor seizures
      (clinically generalized at onset) were accompanied either by focal (19 of 51;
      37%) or generalized (32 of 51; 63%) EEG seizures. Hypomotor seizures also were
      associated with focal (14 of 20; 70%) or generalized (six of 20; 30%) EEG
      seizures. Four patients with generalized epileptic spasms had generalized EEG
      seizures in the setting of focal epilepsy based on neuroimaging, interictal EEG,
      and in two cases also on postresection seizure freedom. Seizure types not seen in
      this age group included auras, seizures with prominent automatisms (except in one
      case), and classic generalized tonic-clonic seizures. CONCLUSIONS: The repertoire
      of seizure manifestation in the first 3 years of life appears to be limited. In
      infants, focal motor seizures are reliably associated with focal EEG seizures in
      the contralateral hemisphere, whereas generalized motor and hypomotor clinical
      seizures may be either focal or generalized on EEG. Epileptic spasms may be seen
      in focal as well as generalized epilepsies. Video-EEG monitoring and neuroimaging
      may be critical for clarifying the focal or generalized nature of the epilepsy in
      infants.

PMID- 10403207
TI  - Localized pain associated with seizures originating in the parietal lobe.
AB  - PURPOSE: Ictal pain is a rare symptom of seizures. Epileptic pain may be
      experienced unilaterally (lateral/ peripheral), cephalically, or in the abdomen.
      Painful seizures have been associated with seizure origin in both the parietal
      and the temporal lobes. We report on the different types of epileptic pain and
      discuss its etiology and possible localizing value. METHODS: We reviewed the
      records of patients referred to our epilepsy program over the last 6 years. Eight
      (1.4%) of 573 patients had pain as an early prominent symptom of their seizures.
      RESULTS: Pain was predominantly unilateral in three patients, cephalic in two,
      and abdominal in three patients. Seizure onset was in or involving the parietal
      lobe in all patients, and when the painful symptoms were lateralized, they were
      contralateral to the side of seizure origin. Parietal lobe seizure origin was
      determined by both intracranial EEG recording and neuroimaging [magnetic
      resonance imaging (MRI), ictal single photon emission computed tomography
      (SPECT)] in five patients, and by both scalp EEG and neuroimaging in three
      patients. CONCLUSIONS: We conclude that ictal pain is a rare symptom of parietal
      lobe seizure origin with lateralizing potential.

PMID- 10403208
TI  - Patients with epileptic seizures and cerebral lesions who underwent lesionectomy
      restricted to or associated with the adjacent irritative area.
AB  - PURPOSE: To analyze the best surgical procedure for patients with epileptic
      seizures and cerebral lesions-i.e., resection restricted to the lesion or
      resection associated with the adjacent irritative area-based on the clinical
      evolution of patients' seizure outcome and electroencephalographic (EEG) and
      electrocorticographic (ECoG) findings. METHODS: This study comprised 37 patients
      with epileptic seizures and cerebral lesions, ranging in age from 9 to 66 years.
      Patients were divided into two groups: Group 1 consisted of 21 patients with
      medically intractable epilepsy, Group 2 of 16 patients with medically controlled
      epilepsy. Eleven of the 21 patients in Group 1 (Subgroup A) underwent surgical
      resection of the cerebral lesion and adjacent irritative area as shown by ECoG.
      For the remaining 10 patients in Group 1 (Subgroup B), the resection was
      restricted to the lesion. The 16 patients in Group 2 all underwent
      lesionectomies. RESULTS: Of the 11 patients in group 1 who underwent resection of
      the cerebral lesion and adjacent irritative area, 91% became seizure free. Sixty
      percent of the remaining patients in group I whose resections were restricted to
      the lesion also became seizure free, as did all the patients in group 2. An
      overall analysis of the EEGs for all patients showed a statistically significant
      decrease in paroxysmal activity. CONCLUSIONS: In patients with uncontrolled
      seizures, resection of the cerebral lesion associated with the irritative area
      shows a tendency to obtain better seizure-outcome results than restricted
      lesionectomy.

PMID- 10403209
TI  - A particular type of epilepsy in children with congenital hemiparesis associated
      with unilateral polymicrogyria.
AB  - PURPOSE: Polymicrogyria (PMG) is often associated with symptomatic focal epilepsy
      and neurologic dysfunction. We investigated the clinical and laboratory features
      of a group of children with congenital hemiparesis, unilateral polymicrogyria on
      magnetic resonance imaging (MRI), and a peculiar epileptic syndrome. METHODS:
      Twelve patients (seven girls and five boys) with a mean age of 7.8 years (range,
      5-13 years) were studied. All patients underwent clinical evaluation, computed
      tomography (CT) and MRI scanning, and neuropsychological assessment at initial
      examination. Patients were followed up from 1 to 7 years (mean, 4.5 years).
      RESULTS: Partial motor seizures with secondary generalization with onset between
      age 1 and 6 years (mean age, 2 years) were recorded in all patients. The course
      of epilepsy was similar in all patients with development of atypical absences,
      negative myoclonus, and gait difficulties. EEG recording demonstrated continuous
      spike-wave or bilateral abnormality throughout. Frequent relapses of the atonic
      and myoclonic seizures were seen in seven patients. However, during follow-up,
      seven patients were seizure free, and the others have not developed this
      particular seizure pattern. A single case underwent cortical resection 23 months
      ago and has had no seizures since then. Mental retardation was mild in nine and
      moderate in three patients. CONCLUSIONS: Children with unilateral polymicrogyria
      may develop a syndrome of negative myoclonus seizures that appears to be age
      specific and responsive to antiepileptic drug (AED) treatment. Despite limited
      follow-up time, a good outcome was observed in most cases.

PMID- 10403210
TI  - Metabolic changes in neuronal migration disorders: evaluation by combined MRI and
      proton MR spectroscopy.
AB  - PURPOSE: To assess the role of 1H-magnetic resonance spectroscopy (MRS) in
      detecting biochemical abnormalities in neuronal migration disorders (NMDs).
      METHODS: We performed 1H-MRS studies on 17 brain NMD areas [five polymicrogyria,
      eight subcortical heterotopia, and four cortical dysplasia on magnetic resonance
      imaging (MRI)]. The study group consisted of 15 patients, all but one affected by
      partial epileptic seizures. Spectra were acquired from volumes of interest
      localized on NMDs and contralateral sides and compared with those obtained on
      gray and white matter of 18 neurologic controls. RESULTS: NMD lesions were
      characterized by lower N-acetylaspartate to creatine (NAA/Cr) and choline to Cr
      (Cho/Cr) ratios than those of the white (p = 0.002 and p = 0.004) and gray matter
      (p = 0.03 and p = 0.06) of neurologic controls. In addition, the normal-appearing
      contralateral sides to the NMD lesions showed a significant decrease of Cho/Cr
      ratio when compared with those of white (p = 0.003) and gray matter (p = 0.05) of
      neurologic controls. No relation was found between NAA/Cr decrease, EEG
      abnormalities, and NMD sides, or between NAA/Cr ratios, duration of epilepsy, and
      frequency of seizures. Lactate signal was detected in the spectra of four
      patients who had an epileptic seizure a short time before MR examination.
      CONCLUSIONS: NAA/Cr decrease may be related more to structural and functional
      alteration of the NMD sides than to epileptic activity in these lesions. Low
      Cho/Cr may be related to a more extensive diffuse hypomyelination than suggested
      by the MRI findings. An activation of anerobic glycolysis during and after
      seizures could account for the presence of lactate. These data confirm that H-MRS
      is an advanced technique that may provide useful biochemical information in vivo
      on neurobiologic processes underlying NMDs.

PMID- 10403211
TI  - Prediction of surgical outcome by interictal epileptiform abnormalities during
      intracranial EEG monitoring in patients with extrahippocampal seizures.
AB  - PURPOSE: Ictal intracranial EEG recordings obtained during continuous
      preoperative monitoring are often used to localize the region of seizure onset
      for purposes of surgical resection in patients with extrahippocampal seizures.
      Whether interictal epileptiform abnormalities during long-term monitoring can
      predict surgical outcome in this group is not established. METHODS: Intracranial
      EEGs of patients who underwent extrahippocampal resective epilepsy surgery were
      reviewed for interictal epileptiform abnormalities before medication
      discontinuation or first seizure occurrence. Interictal abnormalities were
      categorized as within or beyond the confines of surgical resection. We correlated
      these findings with the region of seizure onset, the pathologic substrate, and
      surgical outcome (by using Engel criteria) at 1-year minimum follow-up. RESULTS:
      Of 13 patients with interictal epileptiform abnormalities, six patients had
      interictal epileptiform discharges extending beyond the confines of surgical
      resection. These patients all had poor surgical outcome even if the region of
      electrographic seizure onset was resected. Seven patients had focal interictal
      epileptiform discharges, the entire extent of which were resected. All had good
      outcomes. All patients with structural lesions had focal interictal epileptiform
      abnormalities and good surgical outcomes. The spatial extent of interictal
      epileptiform discharges varied among patients with nonstructural lesions.
      However, those whose regions of interictal epileptiform abnormality were included
      in surgical resection also had good surgical outcome. CONCLUSIONS: The presence
      of interictal epileptiform discharges extending beyond the area of resection
      correlates with poor surgical outcome in patients with extrahippocampal epilepsy.
      In contrast, patients with focal interictal epileptiform discharges included in
      surgical resection have good surgical outcomes.

PMID- 10403212
TI  - Intracranial EEG with very low frequency activity fails to demonstrate an
      advantage over conventional recordings.
AB  - PURPOSE: Conventional scalp and intracranial EEG is recorded within a limited
      band of frequencies (0.3-70 Hz) based on the premise that clinically relevant
      cerebral activity occurs within this frequency range. Ikeda et al. recently
      demonstrated focal very low frequency activity (VLFA), <0.3 Hz, at seizure onset
      for both intra- and extracranial recordings. The purpose of this investigation
      was prospectively to study VLFA during seizures in intracranial recordings to
      determine whether activity in this frequency range provides useful information
      regarding localization of seizure onset and spread. METHODS: Patients undergoing
      intracranial electrode implantation were studied by using a high-pass filter of
      0.01 Hz. The timing, location, and pattern of seizure onset were first determined
      by using a digital high-pass filter of 0.3 Hz (conventional seizure onset).
      Seizures were then reviewed without digital filters and the presence of VLFA
      recorded, along with its timing and location. RESULTS: Forty-seven seizures were
      recorded in four patients. VLFA was not observed in 29 seizures and, in one other
      case, VLFA occurred simultaneous with movement. Of seizures with VLFA (n = 17),
      the timing and location of VLFA were not consistent with those of conventional
      seizure onset or propagation. CONCLUSIONS: Our study failed to demonstrate any
      clinical advantage of intracranial telemetry recordings with a high-pass filter
      of 0.01 Hz over conventional recordings with regard to determining the timing and
      location of seizure onset and propagation.

PMID- 10403213
TI  - Seizure frequency and duration of epilepsy are not risk factors for postoperative
      seizure outcome in patients with hippocampal sclerosis.
AB  - PURPOSE: Despite accurate localization of the seizure focus, not all patients are
      seizure free after temporal lobectomy. This study determined risk factors for
      seizure recurrence in patients with proven hippocampal sclerosis. METHODS: The
      outcome from surgery was assessed in 56 consecutive patients with proven
      hippocampal sclerosis. The age at surgery, duration of epilepsy, history and age
      of febrile seizures, age of onset of epilepsy, sex ratio, laterality of seizure
      focus, and seizure frequency were compared between patients seizure free and
      those not seizure free, and those seizure and aura free and those with seizure
      recurrence including auras. RESULTS: During a mean follow-up of 38 months, 48
      (86%) of 56 are seizure free. The mean age at surgery (37 vs. 36 years), duration
      of epilepsy (26 vs. 22 years), age (1.6 vs. 1.1 years), and occurrence (58 vs.
      75%) of febrile seizures, age of onset of epilepsy (11 vs. 14 years), sex ratio
      (50 vs. 75% female), laterality of seizure focus (42 vs. 50% left), greater than
      weekly seizures (40 vs. 38%), and a history of (69 vs. 75%) and frequency of
      (2.10 vs. 2.38 per year) secondarily generalized seizures did not differ
      significantly between the two groups. Similarly there was no significant
      difference between patients seizure and aura free and those with seizure
      recurrence including auras. CONCLUSIONS: Clinical factors such as seizure
      frequency and duration of epilepsy are not risk factors for postoperative seizure
      recurrence.

PMID- 10403214
TI  - Learning and memory impairment in patients with temporal lobe epilepsy: relation
      to the presence, type, and location of brain lesion.
AB  - PURPOSE: To study the influence of epileptogenic lesions on learning and memory
      alterations in patients with temporal lobe epilepsy (TLE). METHODS: We studied
      131 patients (55 with left and 39 with right lesional TLE; 22 with left and 15
      with right cryptogenic TLE) and 36 healthy subjects. We compared these groups by
      using a battery of tests to assess verbal and visual learning, delayed recall,
      and recall after the imposition of interfering activity. RESULTS: Compared with
      the controls and patients with right TLE, the patients with left TLE were
      significantly impaired on all verbal tests. On visual tests, patients with right
      TLE were impaired compared with controls but not more so than patients with left
      TLE. Separate multivariate analyses of variance (MA-NOVAs) of patients' verbal
      and visual test scores, taking the TLE side and morphologic features of the
      temporal lobes (i.e., normal, hippocampal sclerosis, low-grade glioma, or
      cavernous angioma) as independent factors, did not show any significant effect of
      these features. Separate comparisons of verbal and visual test scores of patients
      with lesional TLE, taking the side and location (mesial or lateral) of the
      epileptogenic lesion as independent factors, did not show any significant effect
      of location. CONCLUSIONS: Our findings show that some learning and memory
      abilities are impaired in patients with TLE irrespective of the presence of overt
      damage. This supports the theory that focal epileptic discharges, rather than the
      lesions themselves, affect these functions. The pathologic characteristics and
      intratemporal location of an associated lesion do not seem to play an important
      role in determining learning and memory impairment when clinical and treatment
      related factors are taken into account.

PMID- 10403215
TI  - Hemodynamic and metabolic aspects of photosensitive epilepsy revealed by
      functional magnetic resonance imaging and magnetic resonance spectroscopy.
AB  - PURPOSE: To study in humans the hemodynamic and metabolic consequences of both
      photic stimulation-triggered and spontaneous generalized epileptiform discharges.
      METHODS: Simultaneous EEG, functional magnetic resonance imaging (fMRI) and MR
      spectroscopy were performed in a 1.5-T scanner in 16 patients with generalized
      epilepsy, including nine with photosensitive epilepsy, and 12 normal subjects.
      RESULTS: With a flash stimulation duration of 2 s, prominent visual cortex
      activation was seen in all normals and patients. There were no fMRI-registered
      hemodynamic abnormalities found in relation to the brief photoparoxysmal spike
      wave activity evoked in the photosensitive patients. However, irrespective of the
      presence of a spike-wave response to the photic stimulation, the photosensitive
      patients showed four unique findings compared with normals: (a) slightly, but
      significantly, increased lactate levels in the occipital cortex in the resting
      state, (b) an increased area of visual cortical activation with photic
      stimulation, (c) simultaneous with the occipital cortex stimulus-induced
      increased fMRI signal there were noncontiguous areas of signal attenuation most
      prominent in perirolandic regions, and (d) a marked decrement (undershoot) of
      fMRI signal intensity immediately after the photic stimulation in the occipital
      cortex and in the region of the posterior cingulate gyrus. CONCLUSIONS: These
      findings suggest abnormal interictal metabolism and increased vascular reactivity
      in the photosensitive patients.

PMID- 10403216
TI  - [18F]FDG-PET and whole-scalp MEG localization of epileptogenic cortex.
AB  - PURPOSE: To evaluate combined [18F]fluorodeoxyglucose (18F-FDG) positron emission
      tomography (PET) and 122-channel whole-scalp magnetoencephalography (MEG) in
      lateralizing the epileptogenic cortex in patients whose routine presurgical
      evaluations gave discordant results about the location of the epileptic focus.
      METHODS: Nine patients (five women, four men) aged 13-40 years were studied.
      Subdural EEG (SEEG) was recorded from eight patients. Six patients were operated
      on. RESULTS: In seven of nine patients, PET and MEG agreed in localizing the
      epileptogenic cortex. When PET and MEG were in congruence, SEEG agreed with the
      findings. In five of six operated-on patients, PET and MEG results were
      congruent, and the outcome of the operation was successful. Two patients had
      discordant PET and MEG results. In one patient, PET showed bitemporal
      hypometabolism, whereas MEG showed epileptiform activity in the right parietal
      lobe. The surgical outcome of the palliative temporal lobectomy was poor. Another
      patient had unilateral temporal hypometabolism in PET and bitemporal activity in
      MEG. She was not operated on. CONCLUSIONS: In most patients, PET and MEG were
      congruent in locating the epileptogenic cortex. Thus the combination of these
      techniques may provide useful support for the localization of the seizure onset
      and reduce the need for invasive procedures.

PMID- 10403217
TI  - A comparison of magnetoencephalography, MRI, and V-EEG in patients evaluated for
      epilepsy surgery.
AB  - PURPOSE: To determine the efficacy and relative contribution of several
      diagnostic methods [ictal and interictal scalp and intracranial EEG, magnetic
      resonance imaging (MRI), and magnetoencephalography (MEG)] in identifying the
      epileptogenic zone for resection. METHODS: This was a prospective study using a
      masked comparison-to-criterion standard. Fifty-eight consecutive patients with
      refractory partial epilepsy from two university comprehensive epilepsy programs
      were studied. Patients who were evaluated for and underwent epilepsy surgery were
      recruited. The main outcome measure was the efficacy of each diagnostic method to
      identify the resected epileptogenic zone, when referenced to surgical outcome.
      RESULTS: MEG (52%) was second only to ictal intracranial V-EEG in predicting the
      epileptogenic zone for the entire group of patients who had an excellent surgical
      outcome (seizure free or rare seizure). In a subanalysis, for patients who had
      temporal lobe surgery, this same relation was seen (MEG, 57%, ictal intracranial
      V-EEG, 62%). With extratemporal resection, ictal (81%) and interictal (75%)
      intracranial EEG were superior to MEG (44%) in predicting the surgery site in
      those patients with an excellent outcome. Finally, for all patients who had a
      good surgical outcome, MEG (52%) was better than ictal (33%) or interictal (45%)
      scalp VEEG in predicting the site of surgery. CONCLUSIONS: These results indicate
      that MEG is a very promising diagnostic method and raise the possibility that it
      may obviate the need for invasive EEG in some cases or reduce the length of scalp
      EEG evaluation in others.

PMID- 10403218
TI  - Familial paroxysmal kinesigenic choreoathetosis: an electrophysiologic and
      genotypic analysis.
AB  - PURPOSE: We report a pedigree of familial paroxysmal kinesigenic choreoathetosis
      (PKC) in which five of 18 members are affected. The pathophysiologic basis for
      PKC is still uncertain; reflex epilepsy versus dysfunction of basal ganglia. We
      examined (a) whether there were ictal discharges during the attacks, and (b) a
      linkage between PKC and possible DNA markers linked to several familial epileptic
      or movement disorders. METHODS: Video-monitoring EEG was performed in two
      patients with PKC during attacks elicited by movements of the lower extremities.
      Blood samples for DNA studies were obtained from 15 members of the pedigree.
      Fourteen polymorphic markers on chromosomes 1p, 2q, 6p, 10q, and 20q were
      genotyped, and two-point lod scores were calculated for each marker under a
      dominant model. RESULTS: No ictal discharges were found during the attacks in
      both patients. We could not obtain significant linkage of PKC with any marker
      examined. CONCLUSIONS: The video-monitoring EEG findings in our cases strongly
      suggested that the etiology of PKC should be considered distinct from that of
      reflex epilepsy. However, the patients in this pedigree had experienced
      generalized convulsions in their infancies; thus we could not deny the
      possibility of an epileptogenic basis for PKC. There was no strong evidence for a
      linkage of the gene for PKC with the candidate regions on 1p, 2q, 6p, 10q, or
      20q.

PMID- 10403219
TI  - Treatment of infantile spasms: results of a population-based study with
      vigabatrin as the first drug for spasms.
AB  - PURPOSE: The efficacy of a protocol consisting of vigabatrin (VGB) as the first
      and adrenocorticotropic hormone (ACTH) or valproate (VPA) as the second drug was
      studied in the treatment of newly diagnosed infantile spasms (IS) during 1994 to
      1997 in a population-based design. METHODS: Only total disappearance of the
      spasms with a minimal duration of 1 month was accepted as a response. The
      treatment response was confirmed by video-EEG study. All infants were studied by
      magnetic resonance imaging (MRI) or computed tomography (CT) for etiology.
      RESULTS: Altogether 42 infants, 10 with cryptogenic and 32 with symptomatic
      etiology, were treated. Eleven (26%) responded to VGB, five (50%) with
      cryptogenic, and six (19%) with symptomatic etiology; 91% of infants responded to
      a dose of 50-100 mg/kg/day, and 82% of them within 1 week. ACTH was offered in
      combination with VGB to 22 and VPA to four infants for whom VGB failed. Eleven
      responded to ACTH and one to VPA. In total, 26 (62%) infants responded to the
      treatment protocol; all (100%) with cryptogenic etiology and 16 (50%) with
      symptomatic etiology. ACTH treatment was associated with more severe side effects
      than VGB or VPA. Only one infant relapsed after a spasm-free period with VGB of
      >4 months, but none after ACTH was combined with VGB. CONCLUSIONS: We suggest VGB
      as a first drug to all infants with IS. After a treatment trial of 10-14 days
      with increasing dose from 50 to 150 mg/kg, ACTH should be considered.

PMID- 10403220
TI  - Acute effects of vigabatrin on brain GABA and homocarnosine in patients with
      complex partial seizures.
AB  - PURPOSE: The acute, subacute, and chronic effects of vigabatrin (VGB) were
      studied in patients with refractory complex partial seizures. VGB increases human
      brain gamma-aminobutyric acid (GABA) and the related metabolites, homocarnosine
      and 2-pyrrolidinone. METHODS: In vivo measurements of GABA and homocarnosine were
      made of a 14-cc volume in the occipital cortex by using 1H spectroscopy with a
      2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients
      (three women) were studied serially during the initiation and maintenance of VGB
      as adjunct therapy. RESULTS: The first, 3 g dose of VGB increased brain GABA by
      2.0 micromol/g within 81 min of oral administration. After 2 h, median edited
      GABA remained essentially the same for 2 days. The response to the second, 3-g
      dose of VGB given at 48 h was considerably less than that to the first dose, with
      a median increase of 0.5 micromol/g within 72 min. After 2-3 months,
      rechallenging patients taking 1.5-g VGB twice daily with 6 g increased GABA by
      0.4 micromol/g within 87 min. Homocarnosine increased more gradually than GABA to
      above-normal levels after a week of VGB therapy. CONCLUSIONS: VGB promptly
      elevates brain GABA and presumably offers partial protection against further
      seizures within hours of the first oral dose. Once-a-day dosing is sufficient to
      increase GABA. Patients may be expected to experience the effects of increased
      homocarnosine within 1 week.

PMID- 10403221
TI  - Safety and tolerability of gabapentin as adjunctive therapy in a large,
      multicenter study.
AB  - PURPOSE: To evaluate the tolerability and safety of gabapentin (GBP) as add-on
      therapy for seizure control. METHODS: Conducted in an outpatient setting and
      reflecting usual practice, this study compared tolerability of GBP dosages < or =
      1,800 versus >1,800 mg/day, when these doses were required to achieve the most
      effective seizure control. Two analyses of adverse events are presented:
      tolerability and safety. In the tolerability analysis, each patient served as his
      or her own control to compare the occurrence of adverse events at GBP < or =1,800
      versus >1,800 mg/day. The safety analysis required patients to receive at least
      one dose of GBP and have a follow-up contact. RESULTS: A total of 2,216 patients
      enrolled in this open-label, 16-week study and were evaluable for safety. Of
      these, 74.0% completed the 16-week study, and 281 met the tolerability criteria.
      Within these 281 patients, two mutually exclusive groups were compared (a) those
      reporting adverse events at only < or =1,800 mg/day (low dose); and (b) those
      reporting adverse events at only >1,800 mg/day (high dose). Three adverse events
      (asthenia, headache, and dizziness) were observed in a statistically
      significantly larger number of patients at only the low dose than in the group
      reporting these same adverse events at only the high dose, suggesting that
      patients who tolerated GBP at < or = 1,800 mg/day did not experience a
      significant increase in adverse events with dosages >1,800 mg/day. Overall, 10.6%
      of the 2,216 patients in the safety population prematurely withdrew because of
      adverse events, and 3.5% discontinued because of lack of efficacy. Safety and
      tolerability of GBP was rated as excellent or good for 78.5% of all patients.
      CONCLUSIONS: Gabapentin doses >1,800 mg/day were as well tolerated as doses < or
      =1,800 mg/day and were not associated with more adverse events.

PMID- 10403222
TI  - Lamictal (lamotrigine) monotherapy for typical absence seizures in children.
AB  - PURPOSE: To investigate whether lamotrigine (LTG) monotherapy is effective and
      safe for newly diagnosed typical absence seizures in children and adolescents
      (aged 3-15 years, n = 45). METHODS: A "responder-enriched" study design was used:
      open-label dose escalation was followed by placebo-controlled, double-blind
      testing of LTG. Conventional hyperventilation testing with EEG recording was used
      to confirm diagnoses and assess treatment success defined as complete freedom
      from seizures. Ambulatory 24-h EEG recordings provided supporting evidence of
      effectiveness. Safety was assessed by evaluation of adverse events, vital signs,
      and physical, neurologic, and laboratory examinations. Plasma samples were taken
      to evaluate the pharmacokinetics of LTG. RESULTS: During initial open-label dose
      escalation, 71.4% of patients (intent-to-treat) or 82% (per protocol analysis)
      became seizure free; individual patients responded at doses ranging from 2 to 15
      mg/kg/day (median, 5.0). In the placebo-controlled, double-blind phase of the
      study, statistically significantly more patients remained seizure free when
      treated with LTG (62%) than with placebo (21%; p < 0.02; for the intent-to-treat
      analysis). Mean plasma concentrations of LTG, were linearly related to dose,
      although there was substantial interindividual variation. No patients were
      withdrawn from the study for any safety-related reason. CONCLUSIONS: LTG
      monotherapy is effective for typical absence seizures in children and is
      generally well tolerated.

PMID- 10403223
TI  - Prothrombin and PIVKA-II levels in cord blood from newborn exposed to
      anticonvulsants during pregnancy.
AB  - PURPOSE: To determine whether anticonvulsant exposure during human pregnancy
      caused an increase of the abnormal form of prothrombin, known as PIVKA-II
      (prothrombin induced by vitamin K absence for factor II), and a decrease in total
      prothrombin, in the blood of the newborn. METHODS: Cord blood was collected from
      the placenta at the time of parturition from 12 women who had received
      anticonvulsant therapy during pregnancy and from 11 control women. RESULTS: PIVKA
      II was present in cord blood from control mothers at low or nondetectable levels.
      In the same samples, total prothrombin concentrations were approximately 50% of
      adult levels, but there was wide variation between individuals. Exposure to
      carbamazepine (CBZ) alone during pregnancy was associated with markedly increased
      PIVKA-II levels in four of six samples and decreased total prothrombin levels for
      the whole group. High PIVKA-II levels also were recorded in one cord blood sample
      from a mother who received phenytoin (PHT) and vigabatrin (VGB). Two cases of PHT
      alone and one of valproic acid (VPA) alone were not associated with increased
      PIVKA-II levels. CONCLUSIONS: These results are consistent with the hypothesis
      that some anticonvulsants (particularly CBZ) interfere with vitamin K metabolism
      during pregnancy and may result in hematologic signs of vitamin K deficiency in
      the newborn.

PMID- 10403225
TI  - REM sleep components predict the response to initial treatment of infantile
      spasms.
AB  - PURPOSE: The phasic inhibition index (PII) is the rate of the simultaneous
      occurrence of rapid eye movement bursts (RBs) and phasic chin muscle activity
      (PCMA) during rapid eye movement sleep (REMS). PII is low insofar as
      physiologically occurring REM-related phasic inhibition acts on chin muscles.
      Previously we found that PII was significantly higher in patients with infantile
      spasms (ISs) who had a recurrence of convulsions than in patients with ISs who
      exhibited no recurrence. We aimed to predict the response of patients with ISs to
      conventional anticonvulsants (AEDs) by means of REMS components including PII,
      expecting to facilitate avoidance of potentially hazardous hormonal therapy.
      METHODS: REMS, recorded before the beginning of any medication, was
      retrospectively examined in 15 patients with ISs. The patients were classified
      into two groups according to the response to initial treatment with conventional
      AEDs. Conventional AEDs were enough to control the spasms in six good responders
      (GRs), whereas further hormonal therapy was required in nine poor responders
      (PRs) to control the spasms. RESULTS: The amount of REMS was significantly lower
      in patients with ISs than in controls. GRs had less REMS than did PRs, although
      no significant difference was observed. Although the frequencies of RB and PCMA
      showed no significant differences among GRs, PRs, and controls, the average PII
      value in PRs (12.6+/-3.4; mean+/-SD) was significantly (p < 0.001) higher than
      that in GRs (6.1+/-1.7). CONCLUSIONS: PII is a useful parameter for
      differentiating GRs from PRs.

PMID- 10403226
TI  - Epileptic seizures induced by animated cartoon, "Pocket Monster".
AB  - PURPOSE: A large number of children had fits while watching the animated cartoon
      television (TV) program "Pocket Monster." To elucidate the seizures associated
      with the TV program, we administered a questionnaire survey in Aichi Prefecture,
      Japan. METHODS: The questionnaires were sent to 75 hospitals located in and
      around Aichi prefecture. The presence of epileptic seizures and the types of
      seizures were determined by three pediatric neurologists. RESULTS: Sixty-one
      hospitals responded to the questionnaire survey. Among 95 patients living in
      Aichi prefecture for whom enough information on seizure manifestations and EEG
      was available, < or =93 patients were considered to have epileptic seizures while
      watching the TV program. Most seizures occurred at a scene in which red and blue
      frames alternated at 12 Hz. Sixty-nine (74%) patients had no history of epilepsy.
      Thirty-nine patients had generalized seizures, and 49 patients had partial
      seizures. Partial seizures occurred more frequently in the younger age group than
      did generalized seizures. The EEG revealed a photoparoxysmal response (PPR) in
      43% of patients. PPR was present not only in patients with a history of epilepsy
      (54%) but also in those with no history of epilepsy (38%). CONCLUSIONS: Almost
      all seizures induced by the TV program "Pocket Monster" were epileptic, and
      partial seizures were induced more frequently than generalized seizures. The
      incidence of this "Pocket Monster"-induced seizures was roughly estimated as > or
      =1 in 4,923 individuals aged 6-18 years.

PMID- 10403227
TI  - Nonconvulsive status epilepticus in childhood localization-related epilepsy.
AB  - PURPOSE: To report on three children with localization-related epilepsy who
      exhibited minor seizures (atypical absences, brief atonic, and myoclonic) and
      nonconvulsive status epilepticus (NCSE) consisting of these minor seizures, and
      to elucidate their significance. METHODS: We studied the electroclinical
      characteristics of these children. Ictal electroencephalograms (EEGs) of NCSE
      were evaluated by using simultaneous video-EEG-electromyogram (EMG) polygraphic
      recordings. RESULTS: All patients began to have partial seizures between the ages
      of 6 months and 2 years 7 months, with minor seizures appearing later, between
      the ages of 1 year 11 months and 6 years 6 months. These minor seizures evolved
      into NCSE. Complex partial seizures remained after suppression of the minor
      seizures. Interictal EEGs taken when the minor seizures appeared showed excessive
      diffuse epileptic discharges in addition to multifocal spike-waves. Before and
      after suppression of the minor seizures, focal epileptic discharges predominated
      on the EEGs. On ictal EEGs of brief atonic and myoclonic seizures, diffuse spike
      wave and polyspike-wave bursts were detected. Ictal EEGs of the atypical absences
      revealed diffuse spike-wave bursts mixed with irregular high-voltage slow waves,
      often interspersed with brief atonic and myoclonic seizures. When atypical
      absences lasted for a long time, patients manifested NCSE. Polytherapy might be
      related to the occurrence of minor seizures and NCSE, because all patients were
      treated with polytherapy at their appearance, and simplification of antiepileptic
      drug (AED) therapy seemed to be effective. CONCLUSIONS: We concluded that this
      NCSE is a type of atypical absence status which is an age-dependent, transient,
      electroclinical condition. The mechanism of occurrence of these minor seizures
      might be related to secondary bilateral synchrony.

PMID- 10403224
TI  - Lamotrigine-associated rash: risk/benefit considerations in adults and children.
AB  - PURPOSE: Lamotrigine (LTG) is an antiepileptic drug (AED) recently released in
      several countries. It is effective for a variety of seizure types in adults and
      children both as an add-on agent and in monotherapy, and is generally well
      tolerated. This report reviews the apparent risk factors for rash associated with
      LTG to determine whether and how the risk of serious rash can be minimized in
      practice. METHODS: The panel of experts reviewed all published and unpublished
      data related to the incidence and risk factors for serious rash with LTG.
      RESULTS: An allergic skin reaction occurs in approximately 10% of patients,
      usually in the first 8 weeks. Rashes leading to hospitalization, including
      Stevens-Johnson syndrome and hypersensitivity syndrome, occurred in approximately
      one of 300 adults and one of 100 children in clinical trials and appeared to be
      increased with overrapid titration when starting therapy and with concurrent
      valproate (VPA). CONCLUSIONS: Recommendations are made for both minimizing the
      likelihood of serious rash and for management of rash in patients taking LTG.
      Risk of serious rash may possibly be lessened by strict adherence to
      manufacturer's dosing guidelines, particularly in patients who are at higher
      risk: those on concurrent VPA and in the pediatric population.

PMID- 10403228
TI  - Prevalence of childhood epilepsy in Estonia.
AB  - PURPOSE: To establish the prevalence rate (PR) and main characteristics of
      childhood epilepsy in Estonia. METHODS: We performed a population-based case
      ascertainment of all the possible sources of medical care in seven counties of
      Estonia from January 1995 to December 1997. Only cases of patients from 1 month
      to 19 years of age with active epilepsy (i.e., at least one seizure during the
      last 5 years, regardless of treatment) were included. All patients were examined
      by a pediatric neurologist. RESULTS: Five hundred sixty cases met the study
      criteria on the prevalence day, December 31, 1997. The total PR was 3.6 per 1,000
      population (boy/girl ratio, 1.2:1.0). The PR was the highest-4.3 per 1,000-in the
      5-to-9-year-old age group. The prevalence declined markedly in children age 14
      years and on. The correlation between age and PR was negative (-0.542, p <
      0.0001) by regression analyses. The most frequent seizure types in the total
      group were primarily generalized seizures-PR 2. 1/1,000 [rate ratio (RR) 1.4, 95%
      confidence interval (CI) 1.2, 1.6]. The predominance of generalized seizures was
      significant in those younger than 10 years. In 14.8% of cases, there was a
      history of epilepsy among first- and second-degree relatives. Benign rolandic
      epilepsy-PR 0.2/1,000-was the most frequent among idiopathic syndromes, and
      Lennox-Gastaut syndrome-PR 0.08/1,000-was the most frequent among cryptogenic
      ones. Perinatal factors-PR 0.8/1,000 were the most frequently found cause of
      epilepsy. In 304 cases (54.2%), additional medical problems existed. CONCLUSIONS:
      The prevalence of childhood epilepsy was comparable with that found in developed
      countries. Generalized seizures predominated, and the main cause was perinatal
      factors.

PMID- 10403229
TI  - Study on the early-onset variant of benign childhood epilepsy with occipital
      paroxysms otherwise described as early-onset benign occipital seizure
      susceptibility syndrome.
AB  - PURPOSE: We studied the early-onset variant of benign childhood epilepsy with
      occipital paroxysms (EVBCEOP) proposed by Panayiotopoulos, to confirm whether his
      five criteria are sufficient to delineate EVBCEOP as a new epileptic syndrome, as
      well as to predict a good outcome prospectively at the time of the first
      examination. SUBJECTS: The subjects were 649 children with localization-related
      epilepsies (LREs) observed in our hospital for >4 years. METHODS: We applied the
      International Classification of Epilepsies and Epileptic Syndromes to the 649
      patients and identified patients who had EVBCEOP from among those with
      nonspecific idiopathic LRE. The inclusion criteria were to satisfy all five
      criteria and all but one criterion (i.e., either ictal vomiting or occipital EEG
      paroxysms). We were blind as to the outcomes and selected patients who satisfied
      the following three of the five criteria at the time of the first examination,
      (a) normal development before the onset, (b) epilepsy onset age between 2 and 8
      years, and (c) occipital EEG foci. We attempted to determine whether the outcome
      can be predicted prospectively, and whether the presence or absence of ictal
      vomiting affects the prognosis. RESULTS: We identified 19 patients who satisfied
      all five criteria, 22 who exhibited all but occipital EEG foci, and 21 who
      exhibited all but ictal vomiting. The incidence of status convulsivus was higher
      in those with ictal vomiting than in those without ictal vomiting (p < 0.05).
      Interictal EEG performed every 6 months showed shifting and multiplication of EEG
      foci in 42 and 52% of all subjects, respectively. We identified 57 patients, 42
      (74%) of whom were in remission by age 12 years. The number of patients who
      experienced remission did not differ significantly between those with (76%, n =
      25) and without (72%, n = 32) ictal vomiting (p > 0.05). CONCLUSIONS:
      Nosologically, EVBCEOP appears to constitute the earliest form of idiopathic
      epileptic syndrome different from classic BCEOP. However, its clinical spectrum,
      ranging from the absence of ictal vomiting to a combination of extraoccipital and
      multifocal EEG foci, is broad, such that further prospective study is expected to
      reveal the exact prerequisite criteria for determining the border of this
      epileptic syndrome and for clarifying the clinical spectrum within this syndrome.

PMID- 10403230
TI  - A case of startle epilepsy and SSMA seizures documented with subdural recordings.
AB  - PURPOSE: To study the mechanisms of startle-induced supplementary sensorimotor
      area (SSMA) seizures. METHODS: We present a patient investigated with indwelling
      subdural grid electrodes covering both the SSMA and the dorsolateral frontal
      lobe. RESULTS: We found a simultaneous seizure onset in the right dorsolateral
      premotor cortex and the right SSMA. High-resolution magnetic resonance imaging
      (MRI) showed a small subcortical lesion adjacent to the right SSMA. The patient
      became seizure free after resection of the lesion and the ictal-onset zone.
      CONCLUSIONS: We conclude that an extended region of abnormally excitable tissue
      within the frontal lobe could facilitate the generation of startle-induced
      seizures. We speculate that a widespread epileptogenic zone could help to explain
      why some patients with SSMA or dorsolateral frontal lobe seizures are more likely
      to have startle-induced seizures.

PMID- 10403231
TI  - Fatal liver failure associated with valproate therapy in a patient with
      Friedreich's disease: review of valproate hepatotoxicity in adults.
AB  - PURPOSE: Valproate (VPA)-associated hepatotoxicity is usually considered a
      problem of young children with polytherapy, mental retardation, and underlying
      metabolic defects. METHODS: An adult patient with fatal liver failure during
      treatment with VPA is presented, and a review of the literature on other adult
      patients is given. RESULTS: A 29-year-old female patient with Friedreich's ataxia
      and partial seizures with acute liver failure during VPA treatment is reported.
      The first symptoms of liver failure (i.e., apathy during febrile upper airway
      infection) occurred 2 months after starting VPA therapy. VPA was discontinued 10
      days later on hospital admission, when she had hepatic encephalopathy and severe
      bleeding diathesis. The patient died of severe liver failure and bronchopneumonia
      after 4 weeks of supportive treatment. CONCLUSIONS: Twenty-six adult patients
      (>17 years) with VPA-associated fatal hepatotoxicity have been reported in the
      literature. Of the 26 adult patients, three were receiving VPA monotherapy. The
      age ranged between 17 and 62 years. The duration of VPA treatment before the
      first symptom varied between 7 days and 6 years. Twelve of the 26 affected adults
      had no underlying disease or a clearly nonmetabolic and non-hepatic disease.
      Therefore VPA-associated severe side effects also must be considered in adult
      patients without any evidence of a metabolic defect or underlying neurologic
      disease.

PMID- 10403232
TI  - Epilepsy and its treatment in the ancient cultures of America.
AB  - Epilepsy was a well-recognized disease in pre-Columbian America, as appears from
      the reports of the Spanish chroniclers of the sixteenth century. Both the Aztecs
      and the Incas strongly associated epilepsy with magic and religion, which is
      evident from their ideas about the pathogenesis and treatment of the disease.
      Apart from treatment of epilepsy by magic means, the Incas and especially the
      Aztecs used in addition a large number of botanic medicines; the use of these
      medicines probably had an empiric nature.

PMID- 10403233
TI  - Gore's humanitarianism loses out to strong-arm tactics.

PMID- 10403235
TI  - Expert group to look at UK cloning law.

PMID- 10403234
TI  - Sweden sets ethical standards for use of genetic 'biobanks'.

PMID- 10403237
TI  - Japan to launch ambitious genome project.

PMID- 10403236
TI  - As US DNA advisory body redefines itself.

PMID- 10403238
TI  - European Union tightens GMO regulations. Genetically modified organisms.

PMID- 10403239
TI  - Secondary metabolism and the risks of GMOs.

PMID- 10403240
TI  - Making sense of GM tomatoes. Genetically modified.

PMID- 10403241
TI  - Taking stock of new flavours.

PMID- 10403243
TI  - Malaria. Tying the conductor's arms.

PMID- 10403242
TI  - Cell cycle. A snip separates sisters.

PMID- 10403244
TI  - Genetic link to cervical tumours.

PMID- 10403245
TI  - Isochores result from mutation not selection.

PMID- 10403246
TI  - Life-sustaining planets in interstellar space?

PMID- 10403247
TI  - Sister-chromatid separation at anaphase onset is promoted by cleavage of the
      cohesin subunit Scc1.
AB  - Cohesion between sister chromatids is established during DNA replication and
      depends on a multiprotein complex called cohesin. Attachment of sister
      kinetochores to the mitotic spindle during mitosis generates forces that would
      immediately split sister chromatids were it not opposed by cohesion. Cohesion is
      essential for the alignment of chromosomes in metaphase but must be abolished for
      sister separation to start during anaphase. In the budding yeast Saccharomyces
      cerevisiae, loss of sister-chromatid cohesion depends on a separating protein
      (separin) called Esp1 and is accompanied by dissociation from the chromosomes of
      the cohesion subunit Scc1. Here we show that Esp1 causes the dissociation of Scc1
      from chromosomes by stimulating its cleavage by proteolysis. A mutant Scc1 is
      described that is resistant to Esp1-dependent cleavage and which blocks both
      sister-chromatid separation and the dissociation of Scc1 from chromosomes. The
      evolutionary conservation of separins indicates that the proteolytic cleavage of
      cohesion proteins might be a general mechanism for triggering anaphase.

PMID- 10403249
TI  - Motion streaks provide a spatial code for motion direction.
AB  - Although many neurons in the primary visual cortex (V1) of primates are direction
      selective, they provide ambiguous information about the direction of motion of a
      stimulus. There is evidence that one of the ways in which the visual system
      resolves this ambiguity is by computing, from the responses of V1 neurons,
      velocity components in two or more spatial orientations and then combining these
      velocity components. Here I consider another potential neural mechanism for
      determining motion direction. When a localized image feature moves fast enough,
      it should become smeared in space owing to temporal integration in the visual
      system, creating a spatial signal-a 'motion streak'-oriented in the direction of
      the motion. The orientation masking and adaptation experiments reported here show
      that these spatial signals for motion direction exist in the human visual system
      for feature speeds above about 1 feature width per 100 ms. Computer simulations
      show that this psychophysical finding is consistent with the known response
      properties of V1 neurons, and that these spatial signals, when appropriately
      processed, are sufficient to determine motion direction in natural images.

PMID- 10403248
TI  - Ectoparasite infestation and sex-biased local recruitment of hosts.
AB  - Dispersal patterns of organisms are a fundamental aspect of their ecology,
      modifying the genetic and social structure of local populations. Parasites reduce
      the reproductive success and survival of hosts and thereby exert selection
      pressure on host life-history traits, possibly affecting host dispersal. Here we
      test experimentally whether infestation by hen fleas, Ceratophyllus gallinae,
      affects sex-related recruitment of great tit, Parus major, fledglings. Using sex
      specific DNA markers, we show that flea infestation led to a higher proportion of
      male fledglings recruiting in the local population in one year. In infested
      broods, the proportion of male recruits increased with brood size over a three
      year period, whereas the proportion of male recruits from uninfested broods
      decreased with brood size. Natal dispersal distances of recruits from infested
      nests were shorter than those from uninfested nests. To our knowledge, this study
      provides the first evidence for parasite-mediated host natal dispersal and local
      recruitment in relation to sex. Current theory needs to consider parasites as
      potentially important factors shaping life-history traits associated with host
      dispersal.

PMID- 10403250
TI  - Mox2 is a component of the genetic hierarchy controlling limb muscle development.
AB  - The skeletal muscles of the limbs develop from myogenic progenitors that
      originate in the paraxial mesoderm and migrate into the limb-bud mesenchyme.
      Among the genes known to be important for muscle development in mammalian embryos
      are those encoding the basic helix-loop-helix (bHLH) myogenic regulatory factors
      (MRFs; MyoD, Myf5, myogenin and MRF4) and Pax3, a paired-type homeobox gene that
      is critical for the development of limb musculature. Mox1 and Mox2 are closely
      related homeobox genes that are expressed in overlapping patterns in the paraxial
      mesoderm and its derivatives. Here we show that mice homozygous for a null
      mutation of Mox2 have a developmental defect of the limb musculature,
      characterized by an overall reduction in muscle mass and elimination of specific
      muscles. Mox2 is not needed for the migration of myogenic precursors into the
      limb bud, but it is essential for normal appendicular muscle formation and for
      the normal regulation of myogenic genes, as demonstrated by the downregulation of
      Pax3 and Myf5 but not MyoD in Mox2-deficient limb buds. Our findings show that
      the MOX2 homeoprotein is an important regulator of vertebrate limb myogenesis.

PMID- 10403251
TI  - Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic
      cells.
AB  - The malaria parasite Plasmodium falciparum is one of the most successful human
      pathogens. Specific virulence factors remain poorly defined, although the
      adhesion of infected erythrocytes to the venular endothelium has been associated
      with some of the syndromes of severe disease. Immune responses cannot prevent the
      development of symptomatic infections throughout life, and clinical immunity to
      the disease develops only slowly during childhood. An understanding of the
      obstacles to the development of protective immunity is crucial for developing
      rational approaches to prevent the disease. Here we show that intact malaria
      infected erythrocytes adhere to dendritic cells, inhibit the maturation of
      dendritic cells and subsequently reduce their capacity to stimulate T cells.
      These data demonstrate both a novel mechanism by which malaria parasites induce
      immune dysregulation and a functional role beyond endothelial adhesion for the
      adhesive phenotypes expressed at the surface of infected erythrocytes.

PMID- 10403252
TI  - Eph receptors and ephrins restrict cell intermingling and communication.
AB  - Eph proteins are receptors with tyrosine-kinase activity which, with their ephrin
      ligands, mediate contact-dependent cell interactions that are implicated in the
      repulsion mechanisms that guide migrating cells and neuronal growth cones to
      specific destinations. Ephrin-B proteins have conserved cytoplasmic tyrosine
      residues that are phosphorylated upon interaction with an EphB receptor, and may
      transduce signals that regulate a cellular response. Because Eph receptors and
      ephrins have complementary expression in many tissues during embryogenesis,
      bidirectional activation of Eph receptors and ephrin-B proteins could occur at
      interfaces of their expression domains, for example at segment boundaries in the
      vertebrate hindbrain. Previous work has implicated Eph receptors and ephrin-B
      proteins in the restriction of cell intermingling between hindbrain segments. We
      therefore analysed whether complementary expression of Eph receptors and ephrins
      restricts cell intermingling, and whether this requires bidirectional or
      unidirectional signalling. Here we report that bidirectional but not
      unidirectional signalling restricts the intermingling of adjacent cell
      populations, whereas unidirectional activation is sufficient to restrict cell
      communication through gap junctions. These results reveal that Eph receptors and
      ephrins regulate two aspects of cell behaviour that can stabilize a distinct
      identity of adjacent cell populations.

PMID- 10403253
TI  - DNA-dependent protein kinase is not required for the p53-dependent response to
      DNA damage.
AB  - Damage to DNA in the cell activates the tumour-suppressor protein p53, and
      failure of this activation leads to genetic instability and a predisposition to
      cancer. It is therefore crucial to understand the signal transduction mechanisms
      that connect DNA damage with p53 activation. The enzyme known as DNA-dependent
      protein kinase (DNA-PK) has been proposed to be an essential activator of p53,
      but the evidence for its involvement in this pathway is controversial. We now
      show that the p53 response is fully functional in primary mouse embryonic
      fibroblasts lacking DNA-PK: irradiation-induced DNA damage in these defective
      fibroblasts induces a normal response of p53 accumulation, phosphorylation of a
      p53 serine residue at position 15, nuclear localization and binding to DNA of
      p53. The upregulation of p53-target genes and cell-cycle arrest also occur
      normally. The DNA-PK-deficient cell line SCGR11 contains a homozygous mutation in
      the DNA-binding domain of p53, which may explain the defective response by p53
      reported in this line. Our results indicate that DNA-PK activity is not required
      for cells to mount a p53-dependent response to DNA damage.

PMID- 10403254
TI  - DNA protection by stress-induced biocrystallization.
AB  - The crystalline state is considered to be incompatible with life. However, in
      living systems exposed to severe environmental assaults, the sequestration of
      vital macromolecules in intracellular crystalline assemblies may provide an
      efficient means for protection. Here we report a generic defence strategy found
      in Escherichia coli, involving co-crystallization of its DNA with the stress
      induced protein Dps. We show that when purified Dps and DNA interact, extremely
      stable crystals form almost instantaneously, within which DNA is sequestered and
      effectively protected against varied assaults. Crystalline structures with
      similar lattice spacings are formed in E. coli in which Dps is slightly over
      expressed, as well as in starved wild-type bacteria. Hence, DNA-Dps co
      crystallization is proposed to represent a binding mode that provides wide-range
      protection of DNA by sequestration. The rapid induction and large-scale
      production of Dps in response to stress, as well as the presence of Dps
      homologues in many distantly related bacteria, indicate that DNA protection by
      biocrystallization may be crucial and widespread in prokaryotes.

PMID- 10403255
TI  - Solution structure of the catalytic domain of GCN5 histone acetyltransferase
      bound to coenzyme A.
AB  - Gene transcription requires the release of inactive DNA from its packaging of
      histone proteins. Following the discovery of the first transcription-associated
      histone acetyltransferase, tetrahymena GCN5, it was shown that yeast GCN5 is
      recruited to the promoter and causes hyper-acetylation of histones and
      transcriptional activation of target genes, establishing a direct connection
      between histone acetylation and transcriptional activation. Many other important
      transcription regulators have been found to have histone acetyltransferase
      activity, including TAFII230/250, p300/CBP and its associated factor PCAF. Here
      we present the solution structure of the catalytic domain of tGCN5 (residues 47
      210) in complex with coenzyme A. The structure contains two domains; the amino
      terminal domain is similar to those of other GCN5-related N-acetyltransferases
      but the carboxy-terminal domain is not. Coenzyme A binds in a deep hydrophobic
      pocket between the two domains. Chemical shift changes upon titration with
      histone H3 peptides indicate a binding site at the domain boundary opposite to
      the coenzyme A site. The structural data indicate a single-step acetyl-transfer
      reaction mechanism catalysed by a hydrogen bond to the backbone amide group of
      leucine 126 and the side-chain carboxyl group of a conserved acidic residue.

PMID- 10403256
TI  - International consensus statement on preliminary classification criteria for
      definite antiphospholipid syndrome: report of an international workshop.

PMID- 10403257
TI  - Stiff-man syndrome: from the bedside to the bench.
AB  - The study of SMS, a rare disease, has resulted in a better understanding of a
      more common disorder, IDDM, and has allowed investigators to gain insights into
      the molecular mechanisms of autoimmunity. Many unanswered questions remain, such
      as the specific site of disease activity in SMS, both at the bedside (cortex,
      brain stem, or spinal cord) and at the bench (neuronal cytoplasma or synapse).
      The association of SMS with neoplastic disease and the development of
      autonomicdysfunction are not understood. The next decade may provide answers to
      these puzzling issues.

PMID- 10403258
TI  - Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate
      and leflunomide in patients with active rheumatoid arthritis.
AB  - OBJECTIVE: To examine the safety and pharmacokinetics of and clinical response to
      leflunomide, a de novo pyrimidine synthesis inhibitor, when administered to
      patients with active rheumatoid arthritis (RA) who have been receiving long-term
      methotrexate therapy. METHODS: This was an open-label, 52-week study in which 30
      patients with RA that remained active despite therapy with methotrexate at 17+/-4
      mg/week (mean +/- SD) for > or =6 months were given leflunomide, 10-20 mg/day.
      Patients were assessed for adverse effects, pharmacokinetic measurements of
      leflunomide and methotrexate, and clinical response by American College of
      Rheumatology (ACR) 20% response criteria. RESULTS: Twenty-three patients
      completed 1 year of treatment. No significant pharmacokinetic interactions
      between leflunomide and methotrexate were noted. This combination therapy was
      generally well tolerated clinically, with the exception of elevations of liver
      enzyme levels. Seven patients withdrew from the treatment regimen: 2 withdrawals
      were voluntary, 3 were due to persistent elevation of plasma transaminase levels,
      and 2 were due to lack of efficacy. Of the patients, 16 (53%) met ACR 20%
      response criteria. Two met ACR criteria for remission after 1 year. CONCLUSION:
      The combination of methotrexate and leflunomide has therapeutic potential in RA.

PMID- 10403259
TI  - HLA-DRB1 alleles associated with susceptibility or resistance to rheumatoid
      arthritis, articular deformities, and disability in Mexican Americans.
AB  - OBJECTIVE: To study the genetics (HLA-DRB1 allele associations) of rheumatoid
      arthritis (RA) susceptibility and severity among Mexican Americans, an important,
      but understudied, US population. METHODS: HLA-DRB1 alleles were compared between
      141 Mexican American patients with RA and 54 unrelated Mexican Americans without
      RA, and the association of these alleles with articular deformities and
      disability was examined. HLA-DRB1 alleles were typed using polymerase chain
      reaction-sequence-specific primer amplification and were classified according to
      the 1996 World Health Organization nomenclature. RESULTS: Of the 141 patients,
      105 (74%) had at least 1 copy of the shared epitope (SE) sequence, compared with
      29 (54%) of the 54 controls (P = 0.007). A significant gene-dose effect was
      observed, with 31 patients (22%) being homozygous for the SE compared with 1 (2%)
      of the controls (P = 0.004). In terms of disease severity, only 3% of RA patients
      who were "null" for the SE were outliers in the rate of development of articular
      deformities, compared with 10% of heterozygotes and 27% of homozygotes (P =
      0.002). Patients who were DRB1*08 positive had significantly fewer deformities
      per year of disease and a slower rate of development of disability than did
      patients with other DRB1 alleles. CONCLUSION: HLA-DRB1 alleles containing the SE
      are associated with susceptibility to RA in Mexican Americans, and may also be
      associated with a more rapid development of articular deformities and disability.
      HLA-DRB1*08 appears to have a protective influence on RA susceptibility and
      disease severity in Mexican Americans.

PMID- 10403260
TI  - Estimating the incidence of rheumatoid arthritis: trying to hit a moving target?
AB  - OBJECTIVE: To examine the effect of delay between symptom onset and notification
      to an arthritis register and the effect of application of the American College of
      Rheumatology (ACR; formerly, the American Rheumatism Association) 1987 criteria
      in a cumulative manner on estimates of the incidence of rheumatoid arthritis
      (RA). METHODS: General practitioners and/or hospital consultants in the Norwich
      Health Authority, Norfolk, UK, notified the Norfolk Arthritis Register (NOAR) of
      all patients who had onset of inflammatory polyarthritis (swelling of > or =2
      joints) during 1990. The patients were assessed within 2 weeks of notification
      and annually thereafter. The ACR 1987 criteria for RA were applied at each
      assessment. Age- and sex-specific incidence rates were calculated. RESULTS: If up
      to 12 months elapsed from symptom onset to notification to NOAR and the ACR
      criteria were applied at the baseline assessment, RA incidence estimates, age
      adjusted to the population of England and Wales, were 30.8/100,000 for women and
      12.7/100,000 for men. If up to 5 years elapsed from symptom onset to
      notification, these estimates rose by 45% for women and 36% for men. If up to 5
      years elapsed between symptom onset and notification and the criteria were
      applied cumulatively, the estimates rose by 75% and 93% for women and men,
      respectively, compared with the 1-year data, reaching 54.0/100,000 for women and
      24.5 per 100,000 for men. CONCLUSION: Accurate estimation of the incidence of RA
      requires long-term followup of patients who present with undifferentiated
      inflammatory polyarthritis. The highest age-adjusted estimates from this study
      are probably the best that are available.

PMID- 10403261
TI  - Strong association of autoantibodies to human nuclear lamin B1 with lupus
      anticoagulant antibodies in systemic lupus erythematosus.
AB  - OBJECTIVE: To determine the frequency and clinical significance of high titers of
      IgG autoantibodies to nuclear lamin B1 in a large number of unselected and well
      characterized systemic lupus erythematosus (SLE) patients, disease controls, and
      normal healthy controls. METHODS: A cross-sectional study of anti-lamin B1
      autoantibodies, as measured by enzyme-linked immunosorbent assay using human
      recombinant lamin B1 autoantigen, was performed on serum samples obtained at
      first evaluation of 238 consecutive French Canadian adults: 61 healthy control
      subjects, 20 patients with osteoarthritis, 22 with ankylosing spondylitis, 11
      with autoimmune hepatitis, 30 with rheumatoid arthritis, and 94 with SLE. SLE
      patients were studied for 57 disease manifestations. A case-control study was
      performed to analyze the relationship between anti-lamin B1 status and thrombotic
      manifestations between SLE onset and last followup. RESULTS: High titers of anti
      lamin B1 were strikingly restricted to a subset of 8 SLE patients (8.5%). The
      mean anti-lamin B1 titer was higher in this subset than in the other SLE patients
      or any control group (P<0.001). By univariate analysis and stepwise multiple
      logistic regression, the most striking association of anti-lamin B1 was with
      lupus anticoagulant (LAC) antibodies (P = 0.00001). Although LAC were
      significantly associated with thrombosis in our SLE patients, anti-lamin B1 was
      not. The frequency of thrombosis in SLE patients expressing both LAC and anti
      lamin B1 was similar to that in patients without LAC (P = 1.0). However, patients
      expressing LAC without anti-lamin B1 had a greater frequency of thrombosis (P =
      0.018). CONCLUSION: High titers of IgG anti-lamin B1 autoantibodies are highly
      specific for a subset of SLE patients whose clinical characteristics include the
      presence of LAC and other laboratory manifestations of the antiphospholipid
      syndrome. The presence of LAC without anti-lamin B1 may define a subset of SLE
      patients at greater risk for thrombosis.

PMID- 10403262
TI  - Sensitivity of the Systemic Lupus Erythematosus Disease Activity Index, British
      Isles Lupus Assessment Group Index, and Systemic Lupus Activity Measure in the
      evaluation of clinical change in childhood-onset systemic lupus erythematosus.
AB  - OBJECTIVE: To investigate whether 3 disease activity indices commonly used to
      evaluate systemic lupus erythematosus (SLE) in adults are sensitive to clinical
      change in children, and thus suitable for the use in the management of childhood
      onset SLE. METHODS: Thirty-five SLE patients who were newly diagnosed between
      1993 and 1997, had an age at onset of 6-16 years (26 female and 9 male), and were
      currently being followed up at The Hospital for Sick Children (followup of 9
      months to 4 years) were reviewed. The SLEDAI (Systemic Lupus Erythematosus
      Disease Activity Index), BILAG (British Isles Lupus Assessment Group index), and
      SLAM (Systemic Lupus Activity Measure) were applied at up to 4 occasions during
      the disease course: at the time of diagnosis, 6 months postdiagnosis, at the time
      of a flare (a deterioration in clinical presentation or laboratory results
      requiring initiation or increase of either corticosteroids or "second-line"
      drugs), and 6 months postflare. The sensitivity of the 3 measures to change, as
      gauged by the effect size (ES), effect size index (ESI), standard response mean
      (SRM), responsiveness statistic (RS), and relative efficiency index (REI), were
      compared. RESULTS: All 3 tools were very sensitive to change in disease activity
      (ES >0.8, ESI >2.3, SRM >0.6, RS >0.86, REI >0.72), but were ranked differently
      depending on the statistic used for comparison. CONCLUSION: All 3 measures of
      disease activity are highly sensitive to clinical change in children; none showed
      an overall superiority. The SLEDAI, BILAG, and SLAM can all be used to study
      response to treatment in children with SLE.

PMID- 10403263
TI  - Effectiveness of exercise therapy in patients with osteoarthritis of the hip or
      knee: a systematic review of randomized clinical trials.
AB  - OBJECTIVE: To review the effectiveness of exercise therapy in patients with
      osteoarthritis (OA) of the hip or knee. METHODS: A computerized literature search
      of Medline, Embase, and Cinahl was carried out. Randomized clinical trials on
      exercise therapy for OA of the hip or knee were selected if treatment had been
      randomly allocated and if pain, self-reported disability, observed disability, or
      patient's global assessment of effect had been used as outcome measures. The
      validity of trials was systematically assessed by independent reviewers. Effect
      sizes and power estimates were calculated. A best evidence synthesis was
      conducted, weighting the studies with respect to their validity and power.
      RESULTS: Six of the 11 assessed trials satisfied at least 50% of the validity
      criteria. Two trials had sufficient power to detect medium-sized effects. Effect
      sizes indicated small-to-moderate beneficial effects of exercise therapy on pain,
      small beneficial effects on both disability outcome measures, and moderate-to
      great beneficial effects according to patient's global assessment of effect.
      CONCLUSION: There is evidence of beneficial effects of exercise therapy in
      patients with OA of the hip or knee. However, the small number of good studies
      restricts drawing firm conclusions.

PMID- 10403264
TI  - Tramadol allows reduction of naproxen dose among patients with naproxen
      responsive osteoarthritis pain: a randomized, double-blind, placebo-controlled
      study.
AB  - OBJECTIVE: To demonstrate that in patients receiving naproxen for the pain of
      osteoarthritis (OA), the addition of tramadol will allow a reduction in the
      naproxen dosage without compromising pain relief. METHODS: This trial consisted
      of a 5-week open-label run-in and an 8-week double-blind phase. Patients with at
      least moderate pain (> or =40 mm on a 100-mm visual analog scale) of OA of the
      knee after a 1-week medication washout were treated with naproxen 500 mg/day for
      1 week. Patients whose pain scores were reduced to <20 mm were discontinued. The
      remaining patients received naproxen 1,000 mg/day for 3 weeks. Tramadol 200
      mg/day was added during the third week. Patients were then randomized in a double
      blind manner to continue tramadol 200 mg/day or to begin placebo in addition to
      naproxen. Randomization was stratified based on response to naproxen 1,000
      mg/day. During the double-blind phase, the naproxen dose was reduced by 250 mg
      every 2 weeks. The primary efficacy end point was the minimum effective naproxen
      dose (MEND). The MEND was defined as 250 mg above the naproxen daily dosage at
      which pain relief was no longer adequate. Patients discontinuing the double-blind
      phase of the study for reasons other than lack of efficacy were assigned a MEND
      equal to the last naproxen dose received. If the effect of treatment between the
      responder and nonresponder groups was statistically different, the difference in
      the MEND was assessed separately within the groups. RESULTS: Of 236 patients
      randomized (mean age 61 years; 147 females), 90 were stratified as naproxen
      responders and 146 as naproxen nonresponders. There was a significant difference
      (P = 0.040) in the treatment effect between the naproxen responders and
      nonresponders, thus demonstrating a difference in the way responders and
      nonresponders react to a decrease in naproxen dosage after the addition of
      tramadol. Among naproxen responders, the MEND was significantly lower in patients
      receiving tramadol (n = 36) than in patients receiving placebo (n = 54), 221 mg
      versus 407 mg, respectively (P = 0.021). For the naproxen nonresponders, the mean
      MEND was 419 mg in the tramadol group and 396 mg in the placebo group (P =
      0.706). CONCLUSION: In patients with painful OA of the knee responding to
      naproxen 1,000 mg/day, the addition of tramadol 200 mg/day allows a significant
      reduction in the dosage of naproxen without compromising pain relief.

PMID- 10403265
TI  - Osteoarthritis and risk of falls, rates of bone loss, and osteoporotic fractures.
      Study of Osteoporotic Fractures Research Group.
AB  - OBJECTIVE: To examine the association between osteoarthritis (OA), as defined by
      radiographic evidence and self report, and osteoporotic fractures, falls, and
      bone loss in a cohort of elderly white women. METHODS: A cohort of 5,552 elderly
      women from the Study of Osteoporotic Fractures was followed up prospectively for
      a mean of 7.4 years. Self-reported, physician-diagnosed OA was recorded at
      interview, and radiologic OA of the hip and hand were defined from pelvis and
      hand radiographs obtained at baseline by validated techniques. Prevalent and
      incident vertebral fractures were detected by vertebral morphometry, and data on
      incident fractures and falls were collected by postcard surveys; fractures were
      confirmed by radiography. Bone mineral density (BMD) was measured on 2 occasions
      at the hip, lumbar spine, and calcaneus, and rates of bone loss were calculated.
      RESULTS: Women with radiographic hip OA had a reduced risk of recurrent falls in
      the first year (relative risk [RR] 0.7, 95% confidence interval [95% CI] 0.5
      0.95). However, those with self-reported OA had an increased risk of falls (RR
      1.4, 95% CI 1.2-1.5). Radiographic hip OA was associated with reduced bone loss
      in the femoral neck compared with controls (mean +/- SD -0.29+/-0.09%/year versus
      -0.51+/-0.03%/year; P = 0.018). However, radiographic hip OA showed
      nonsignificant trends toward increased bone loss at the calcaneus and lumbar
      spine. There was no significant association between self-reported OA or
      radiographic hand OA with bone loss. No definition of OA was associated with
      incident nonvertebral fracture, hip fracture, or vertebral fracture. CONCLUSION:
      Despite having increased BMD compared with controls, subjects with OA did not
      have a significantly reduced risk of osteoporotic fracture, although there was a
      trend toward a reduced risk of femoral neck fractures in subjects with severe
      radiographic OA. The failure of the observed increase in BMD to translate into a
      reduced fracture risk may be due, in part, to the number and type of falls
      sustained by subjects with OA. Patients with OA should not be considered to be at
      a lower risk of fracture than the general population. Physicians should be aware
      that a high BMD in patients with OA may be falsely reassuring.

PMID- 10403266
TI  - No benefit of long-term ciprofloxacin treatment in patients with reactive
      arthritis and undifferentiated oligoarthritis: a three-month, multicenter, double
      blind, randomized, placebo-controlled study.
AB  - OBJECTIVE: To investigate the effect of long-term antibiotic treatment in
      patients with reactive arthritis (ReA) and undifferentiated oligoarthritis.
      METHODS: One hundred twenty-six patients were treated with ciprofloxacin (500 mg
      twice a day) or placebo for 3 months, in a double-blind, randomized study. Of
      these patients, 104 (48 treated with ciprofloxacin and 56 treated with placebo)
      were valid for clinical evaluation: 55 were diagnosed as having ReA with a
      preceding symptomatic urogenic or enteric infection and 49 as having
      undifferentiated oligoarthritis. These 2 groups were randomized separately. The
      triggering bacterium was sought by serology and/or culture. The percentage of
      patients in remission after 3 months of treatment was chosen as the primary
      efficacy parameter. RESULTS: A triggering bacterium could be identified in 52
      patients (50%): Chlamydia trachomatis in 13, Yersinia in 14, and Salmonella in
      25. No patient was positive for Campylobacter jejuni or for Shigella. No
      difference in outcome was found between treatment with ciprofloxacin or placebo
      in the whole group or in subgroups of patients with ReA or undifferentiated
      oligoarthritis. No difference was seen in patients with a disease duration <3
      months. Ciprofloxacin was not effective in Yersinia- or Salmonella-induced
      arthritis but seemed to be better than placebo in Chlamydia-induced arthritis.
      This difference was not significant, however, which might be due to the small
      sample size. CONCLUSION: Long-term treatment of ReA with ciprofloxacin is not
      effective; however, it might be useful in the subgroup of patients who have
      Chlamydia-induced arthritis. This has to be proven in a bigger study focusing on
      patients with Chlamydia-induced arthritis.

PMID- 10403267
TI  - The association between tender points, psychological distress, and adverse
      childhood experiences: a community-based study.
AB  - OBJECTIVE: To examine the hypothesis that characteristics of somatization and
      illness behavior, and their childhood antecedents, are associated with the
      presence of multiple tender points. METHODS: Two hundred eighty-nine subjects who
      had demonstrated psychological distress (General Health Questionnaire score > or
      =2) had a tender point examination and in-depth psychological evaluation. In
      addition, subjects were interviewed about a number of adverse childhood
      experiences. The 99 subjects with 5 or more tender points were compared with the
      remaining 190 subjects. RESULTS: A high tender point count (> or =5) was
      associated with low levels of self-care (odds ratio [OR] 2.4, 95% confidence
      interval [95% CI] 1.1-5.0), reports of a greater number of somatic symptoms (OR
      2.2, 95% CI 1.0-4.9), high levels of fatigue (OR 3.3, 95% CI 1.7-6.3), and a
      pattern of illness behavior characterized by increased medical care usage (OR
      4.2, 95% CI 2.1-8.4). Those with high tender point counts were substantially more
      likely to report adverse childhood experiences, including loss of parents (OR
      2.1, 95% CI 1.1-3.9) and abuse (OR 6.9, 95% CI 2.0-24.6). These results were not
      explained by the presence of chronic pain. CONCLUSION: These data add further
      weight to the hypothesis that tender points, as part of the fibromyalgia
      syndrome, are strongly associated with specific components of psychological
      distress as well as characteristics of somatization and its antecedents. It is
      possible that these features contribute to the development of the syndrome of
      fibromyalgia.

PMID- 10403268
TI  - Fat conversion of femoral marrow in glucocorticoid-treated patients: a cross
      sectional and longitudinal study with magnetic resonance imaging.
AB  - OBJECTIVE: To study the changes in hematopoietic marrow in patients given
      glucocorticoid (steroid) therapy. METHODS: In a cross-sectional study, high
      resolution T1-weighted magnetic resonance imaging (MRI) images of the proximal
      femur were obtained in an unselected series of 29 premenopausal female patients
      with systemic lupus erythematosus (SLE) and in a series of 29 age-matched healthy
      female subjects. In a longitudinal analysis, 2 MRI studies were performed 19
      months apart in 11 patients with SLE (including 9 patients from the cross
      sectional study who were evaluated before treatment) and in 7 patients with
      rheumatoid arthritis (RA). The percentage of fat marrow and the index of marrow
      conversion (IMC) were derived from the MRI images to estimate the degree of
      transformation of hematopoietic into fatty marrow in the area of the femoral
      neck. Values observed in the cross-sectional study and their changes over time
      were correlated with treatment data. RESULTS: The cross-sectional study performed
      in SLE patients indicated that their mean (+/- SD) percentage of fat marrow (48+/
      36%) and IMC (82+/-12) were significantly more elevated than those in the healthy
      control subjects (18+/-16% and 75+/-6, respectively) (P<0.01). The magnitude of
      fat conversion correlated positively with the mean daily dose of oral
      prednisolone, and was higher in patients with ischemic bone lesions. The
      longitudinal study performed in SLE and RA patients revealed that IMC changes
      over time correlated positively with daily prednisolone intake (r = 0.71; P =
      0.001), fat conversion occurring exclusively in patients receiving a mean
      prednisolone dose < or =7.5 mg/day. CONCLUSION: MRI indicates that fat conversion
      occurs in the proximal femur of steroid-treated patients. The magnitude of fat
      conversion correlates with steroid intake and is higher in patients with ischemic
      bone lesions.

PMID- 10403269
TI  - Dendritic cell presentation of antigens from apoptotic cells in a proinflammatory
      context: role of opsonizing anti-beta2-glycoprotein I antibodies.
AB  - OBJECTIVE: To verify whether opsonization of apoptotic cells skews the outcome of
      apoptotic cell antigen presentation by dendritic cells (DCs). METHODS: RMA cells,
      which were engineered with a mutant ovalbumin (OVA) protein and were devoid of
      the leader secretory sequence (OVA-RMA), underwent ultraviolet irradiation to
      induce apoptosis. Binding of anti-beta2-glycoprotein I antibodies (anti-beta2GPI)
      and phagocytosis of apoptotic cells were assessed by flow cytometry and confocal
      microscopy. Presentation of processing antigens and major histocompatibility
      complex (MHC) class II-restricted or MHC class I-restricted antigens was assessed
      using OVA-specific T cell hybridomas. RESULTS: Anti-beta2GPI facilitated
      presentation of epitopes from internalized apoptotic cells to MHC class II
      restricted, but not to class I-restricted, T lymphocytes. DCs challenged with
      supernatants of apoptotic cells did not activate OVA-specific T cells, making it
      unlikely that anti-beta2GPI complexed with antigen released from dying cells
      plays a role in antigen presentation. DCs challenged with low numbers of anti
      beta2GPI-opsonized apoptotic cells secreted interleukin-1beta (IL-1beta), tumor
      necrosis factor alpha, and IL-10 in an autocrine/paracrine manner. CONCLUSION:
      Opsonization influences the outcome of the disposal of low numbers of apoptotic
      cells by DCs. This implies that soluble factors bound to apoptotic cells modulate
      their immunogenicity.

PMID- 10403270
TI  - Monoclonal anti-endothelial cell antibodies from a patient with Takayasu
      arteritis activate endothelial cells from large vessels.
AB  - OBJECTIVE: To create monoclonal anti-endothelial cell antibodies (mAECA) from a
      patient with Takayasu arteritis to evaluate their ability to activate human
      umbilical vein endothelial cells (HUVEC), and to characterize the mechanism of EC
      activation. METHODS: A panel of mAECA was generated from peripheral blood
      lymphocytes of a patient with Takayasu arteritis, using Epstein-Barr virus
      transformation. Activity against macrovascular EC (HUVEC) and microvascular EC
      (human bone marrow EC immortalized by SV40) antigens was detected by enzyme
      linked immunosorbent assay. Inhibition studies were used to select the monoclonal
      antibodies (mAECA) which share the same EC epitope binding specificity as the
      total IgG-AECA from the Takayasu arteritis patient. The binding of the mAECA to
      human aortic EC was studied by immunohistochemistry. The secretion levels of
      interleukin-6 (IL-6) and von Willebrand factor (vWF) were determined, to serve as
      markers for EC activation. The activated EC were examined for the adherence of a
      monocytic cell line (U937), as well as for expression of vascular cell adhesion
      molecule 1, intercellular adhesion molecule 1, and E-selectin. In addition,
      nuclear extracts of the mAECA-treated EC were analyzed for the induction of
      translocation of nuclear factor kappaB (NF-kappaB), using a specific NF-kappaB
      oligoprobe in an electrophoretic mobility shift assay. RESULTS: Six mAECA were
      selected, the mixture of which produced 100% inhibition of binding of the
      original IgG (from the patient with Takayasu arteritis) to HUVEC. All mAECA
      possessed high activity against macrovascular EC, but none had significant
      antimicrovascular EC activity. The mAECA, but not normal human IgG, had anti
      human aortic EC activity. Four of the 6 mAECA activated EC, manifested by
      increased IL-6 and vWF secretion. The 4 mAECA induced EC expression of adhesion
      molecules and increased adhesion of U937 monocytic cells to EC. In addition,
      these mAECA stimulated the nuclear translocation of the NF-kappaB transcription
      factor. CONCLUSION: Our findings suggest that AECA may directly stimulate EC in
      Takayasu arteritis through elevation of adhesion molecule expression associated
      with NF-kappaB activation and adhesion of monocytes, and may therefore play a
      pathogenic role in the development of the vasculopathy in Takayasu arteritis.

PMID- 10403272
TI  - Reexpression of type IIA procollagen by adult articular chondrocytes in
      osteoarthritic cartilage.
AB  - OBJECTIVE: To test for the reexpression of the chondroprogenitor splice variant
      of the gene COL2A1, type IIA procollagen (containing a cysteine-rich NH2
      propeptide), in adult articular chondrocytes in osteoarthritic (OA) joint
      disease. METHODS: In situ hybridization and immunohistochemical localization were
      performed on normal and OA articular cartilage specimens. The presence of type
      IIA procollagen messenger RNA (mRNA) expression was confirmed by Northern blot
      analysis. RESULTS: In normal articular cartilage, no expression of mRNA or
      presence of type IIA procollagen was found. In OA articular cartilage, focally
      intense staining for type IIA protein was detected. Consistent with this,
      chondrocytes, particularly in the middle zones of articular cartilage, expressed
      type IIA procollagen mRNA. OA repair cartilage typically showed a broad zone of
      cells expressing type IIA mRNA and protein. CONCLUSION: Type IIA procollagen is
      reexpressed by adult articular chondrocytes in OA cartilage degeneration,
      indicating the potential reversion of the cells to a chondroprogenitor cellular
      phenotype. The absence of type IIA mRNA and protein in normal adult articular
      cartilage and its onset in the diseased state suggests type IIA procollagen as a
      marker of OA.

PMID- 10403271
TI  - Stable transfection of human fetal chondrocytes with a type II procollagen
      minigene: expression of the mutant protein and alterations in the structure of
      the extracellular matrix in vitro.
AB  - OBJECTIVE: To perform stable transfections of human chondrocytes under conditions
      that allow the maintenance of the chondrocyte-specific phenotype, and to examine
      the effects of the stable transfection of a mutated type II procollagen gene
      (COL2A1) on the structure of the cartilaginous extracellular matrix produced in
      vitro. METHODS: A type II procollagen minigene that lacks exons 16-27 was stably
      transfected into human fetal epiphyseal chondrocytes in vitro. Expression of the
      minigene was detected by reverse transcriptase-polymerase chain reaction, and the
      encoded protein was identified by Western blot with a human type II collagen
      specific antibody. The cartilaginous extracellular matrix produced by the
      cultured transfected chondrocytes was characterized using histochemical staining,
      polarized light microscopy analysis, and transmission electron microscopy.
      RESULTS: A shortened type II collagen encoded by the transfected minigene was
      biosynthesized and produced in the cultures of transfected cells. Histologic
      analyses demonstrated a more dense, negatively charged cartilaginous matrix in
      control cultures. In contrast, COL2A1 minigene-transfected cultures were more
      cellular, were populated with cells of irregular shape and less-chondrocytic
      appearance, contained abundant intracellular dense granules, and were surrounded
      by a less-dense matrix. Polarized light microscopy and transmission electron
      microscopy revealed a well-organized collagen fibrillar matrix in untransfected,
      control chondrocyte cultures, while the matrix in the transfected cultures was
      less birefringent and contained numerous truncated collagen fibrils. CONCLUSION:
      The findings illustrate the feasibility of gene transfer into human fetal
      chondrocytes under conditions that allow the preservation of their specific
      phenotype, and also shed light on the function of type II collagen in the
      maintenance of the structural integrity of articular cartilage matrix.

PMID- 10403273
TI  - Identification of multiple, differentially expressed messenger RNAs in dermal
      fibroblasts from patients with systemic sclerosis.
AB  - OBJECTIVE: To simultaneously identify several genes whose expression is altered
      in dermal fibroblasts from patients with systemic sclerosis (SSc). METHODS: Total
      RNA was prepared from fibroblasts derived from clinically affected and unaffected
      skin of patients with SSc. The RNA samples were analyzed using differential
      display reverse transcription-polymerase chain reaction (DDRT-PCR). Complementary
      DNA (cDNA) fragments corresponding to differentially expressed messenger RNAs
      (mRNAs) were eluted, cloned, and sequenced. The differential expression of the
      corresponding mRNAs was confirmed by ribonuclease protection assay. RESULTS: We
      identified 21 differentially expressed mRNAs. Their corresponding cDNAs were
      sequenced and the sequences obtained were compared with those of known genes
      entered into the EMBL/GenBank database. Three of the sequences corresponded to
      transcripts of yet-unidentified genes. Some of the mRNAs shared partial homology
      with extracellular matrix components, cellular receptors, enzymes, and nuclear
      factors. Others corresponded to known mRNAs such as those of fibronectin,
      fibronectin receptor, laminin receptor homolog, beta-tubulin, insulin-like growth
      factor binding protein 5, KIAA0179 protein, and protease nexin 1. CONCLUSION: The
      application of DDRT-PCR to scleroderma research has identified many mRNAs whose
      altered expression in scleroderma has not yet been described, thus providing new
      information for further investigation and potential targets for the development
      of novel therapies.

PMID- 10403274
TI  - High prevalence of T cell type I protein kinase A deficiency in systemic lupus
      erythematosus.
AB  - OBJECTIVE: To estimate the prevalence of protein kinase A type I isozyme (PKA-I)
      deficiency in a cohort of systemic lupus erythematosus (SLE) patients, and to
      establish whether the isozyme deficiency is associated with SLE disease activity.
      METHODS: Thirty-five SLE patients and 35 age-, sex-, and race-matched normal
      controls were studied. Fifteen subjects were restudied on at least 3 occasions
      over a 4-year interval. Clinical disease activity was estimated by the Systemic
      Lupus Erythematosus Disease Activity Index (SLEDAI), and the T cell activation
      markers CD25+ and HLA-DR+ were quantified by flow cytometry. PKA-I isozyme
      activities were quantified in enriched T cells. Statistical analyses were
      performed by Student's t-test, Mann Whitney U test, and Pearson product moment
      test. RESULTS: The mean PKA-I activity in SLE T cells (540 pmoles/minute/mg of
      protein) was significantly lower than that in control T cells (1,578 pmoles/
      minute/mg of protein) (P<0.001). The prevalence of isozyme deficiency in this
      cohort was 80%. During a 4-year interval, PKA-I activities remained significantly
      reduced, whereas SLEDAI scores significantly improved. There was no relationship
      between deficient PKA-I activity and either SLEDAI scores or the proportion of T
      cells bearing CD25+ or HLA-DR+ activation markers. CONCLUSION: There is a high
      prevalence of deficient T cell PKA-I isozyme activity in SLE that persists over
      time and is independent of SLE disease activity.

PMID- 10403275
TI  - Lymphoma development in Sjogren's syndrome: novel p53 mutations.
AB  - OBJECTIVE: Sjogren's syndrome (SS) is a chronic autoimmune disease characterized
      by lymphocytic infiltrations of the exocrine glands. Disease progression may lead
      to uncontrolled clonal proliferation of B lymphocytes and development of
      lymphoma. This study was undertaken to examine the possible involvement of the
      cell cycle checkpoint genes p53 and p21 in the pathophysiology of the syndrome.
      METHODS: Protein expression of p53 and p21 was studied, by immunohistochemistry
      and Western blot analysis, in minor salivary gland (MSG) biopsy specimens from 7
      patients with SS and 5 control subjects. In addition, sequence analysis of the
      p53 gene was performed on DNA samples obtained from MSG biopsy samples of the
      same 7 patients with SS and from 4 patients with SS and in situ non-Hodgkin's
      lymphoma (NHL). RESULTS: The study revealed increased protein expression of p53
      and p21 in MSG biopsy specimens from patients as compared with controls, while
      sequence analysis showed that the p53 gene was of the wild type. Furthermore,
      sequence analysis of the p53 gene from patients with SS and in situ NHL revealed
      2 novel mutations in exon 5 of the p53 gene. These mutations are single-base
      substitutions and appear to be functional since exon 5 is included in the coding
      region of the p53 gene. CONCLUSION: This is the first report on wild-type p53
      gene activation in SS. Our findings indicate a probable role for the DNA damage
      response genes in the pathogenesis of this syndrome. The novel mutations of the
      p53 gene implicate dysregulation of this tumor suppressor gene as a possible
      mechanism for lymphoma development in SS.

PMID- 10403276
TI  - Detection of Borrelia burgdorferi sensu stricto by reverse line blot in the
      joints of Dutch patients with Lyme arthritis.
AB  - OBJECTIVE: To analyze the presence of Borrelia burgdorferi sensu lato in synovial
      samples from the knee joint of patients with Lyme arthritis by polymerase chain
      reaction, and to differentiate the species by reverse line blot (RLB). METHODS:
      Synovial fluid (SF) and synovial tissue (ST) samples were obtained from patients
      with Lyme arthritis (n = 4) and from patients with various other forms of
      arthritis (n = 9). DNA extracted from synovial samples was amplified by using, as
      a target, the spacer region between the 5S and 23S ribosomal RNA genes of B.
      burgdorferi sensu lato. Subsequently, 4 species-specific DNA probes were used in
      the RLB for specific hybridization. RESULTS: DNA from B. burgdorferi sensu
      stricto DNA was detected in the SF and ST from 3 patients with Lyme arthritis. B.
      burgdorferi sensu lato DNA was not detected in the synovial samples from 9
      control patients. CONCLUSION: The relationship between different species of B.
      burgdorferi sensu lato and arthritis can be studied using direct analysis of
      extracted DNA from joint samples. This method can be used to study the
      association between particular clinical manifestations of Lyme disease and
      different species of B. burgdorferi sensu lato.

PMID- 10403277
TI  - Distinct vascular patterns of early synovitis in psoriatic, reactive, and
      rheumatoid arthritis.
AB  - OBJECTIVE: To examine the macroscopic vascular pattern of early synovitis in
      psoriatic arthritis (PsA), reactive arthritis (ReA), and rheumatoid arthritis
      (RA) and to assess the reliability of the grading features for synovitis.
      METHODS: Forty-four patients (14 PsA, 12 ReA, and 18 RA) with knee synovitis who
      were undergoing arthroscopy were assessed. Video recordings of the examination
      were scored independently by 3 arthroscopists who were blinded to the patient's
      identity and clinical details. Features of vascularity, villous formation,
      pannus, granularity, and capillary hyperemia were recorded and kappa values (
      1<kappa<1) were calculated to assess interobserver reliability. RESULTS: The
      interobserver reliability between experienced observers was high (kappa> or =0.8)
      for features of vascularity, villous hypertrophy, and pannus. Seventy-three
      percent of the PsA and ReA patients had predominantly tortuous, bushy vessels;
      89% of the RA patients had mainly straight, branching vessels. CONCLUSION: The
      distinct vascular patterns in PsA and ReA compared with those in RA may reflect
      different specific vascular factors in the pathogenesis of these arthritides.
      Vascularity and villous hypertrophy are the most reliable features of synovitis
      grading.

PMID- 10403278
TI  - Synovial Epstein-Barr virus infection increases the risk of rheumatoid arthritis
      in individuals with the shared HLA-DR4 epitope.
AB  - OBJECTIVE: To investigate the presence of the Epstein-Barr virus (EBV) in
      rheumatoid arthritis (RA) synovium and its correlation with the HLA genotype in
      an attempt to elucidate the role of EBV in the pathogenesis of RA. METHODS: EBV
      DNA/RNA was investigated by polymerase chain reaction (PCR) analysis of synovial
      tissue from 84 patients with RA and from 81 patients with non-RA arthritis
      (controls) and was correlated with the patients' HLA genotype. RESULTS: EBV DNA
      and EBV-encoded RNA 1 transcripts were significantly more frequently present in
      synovial tissue from the RA patients (29 of 84) than in that from the non-RA
      patient controls (8 of 81). EBV DNA-positive individuals had a 5.47 times higher
      risk of presenting with RA than did EBV DNA-negative individuals. In HLA
      DRB1*0401,0404,0405,0408-positive or shared epitope-positive patients, the risk
      was further increased (odds ratio for EBV and HLA-DR4 approximately 41, for EBV
      and the shared epitope approximately 15) compared with those who lacked both EBV
      DNA and RA-linked HLA genotypes. CONCLUSION: EBV seems to function as an
      environmental risk factor for RA, particularly in patients with the RA-linked HLA
      DRB1 alleles.

PMID- 10403280
TI  - Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes
      from patients with rheumatoid arthritis.
AB  - OBJECTIVE: To examine the ability of fibroblast-like synoviocytes in rheumatoid
      arthritis (RA) to produce interleukin-7 (IL-7) and IL-15, and the ability of
      these cytokines to induce the proliferation of synovium-infiltrating T cells.
      METHODS: Messenger RNA (mRNA) and protein levels of IL-7 and IL-15 in synovial
      tissue cells and fibroblast cell lines were determined by reverse transcriptase
      polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. T
      cell-enriched populations from RA synovial tissues were isolated by deleting
      adherent cells after a 14-hour incubation in plastic dishes or by expanding T
      cells during a 14-day incubation of tissue cells with IL-2 alone, and their
      proliferative responses to IL-7, IL-15, and IL-2 were measured by 3H-thymidine
      incorporation. RESULTS: Freshly isolated cells from RA synovial tissues more
      strongly expressed mRNA for both IL-7 and IL-15 compared with the cells from
      osteoarthritis tissues, and could spontaneously release greater amounts of these
      cytokine proteins in culture. Fibroblast cell lines prepared from RA patients
      were able to produce large amounts of IL-15 and small amounts of IL-7 at both the
      transcriptional and protein levels, and their cytokine production was
      significantly elevated when stimulated with IL-1 and tumor necrosis factor alpha.
      Purified synovial tissue macrophages spontaneously released IL-15 but not IL-7,
      and synovial T cells did not produce either cytokine. IL-7 and IL-15, similar to
      IL-2, stimulated the proliferation of synovial tissue T cells from RA patients;
      IL-7 was less potent than IL-15 or IL-2. CONCLUSION: These results indicated that
      fibroblast-like synoviocytes are an important source of the cytokines with IL-2
      like activity, IL-15 and IL-7, in RA joints, and that IL-15 may be mainly
      responsible for local T cell activation and expansion in the presence of
      deficient IL-2 production by T cells.

PMID- 10403279
TI  - T cell responses to a human cartilage autoantigen in the context of rheumatoid
      arthritis-associated and nonassociated HLA-DR4 alleles.
AB  - OBJECTIVE: To analyze the CD4+ T cell responses to the human cartilage antigen
      glycoprotein-39 (HCgp-39) in the context of rheumatoid arthritis (RA)-associated
      (DRalphabeta1*0401) and nonassociated (DRalphabeta1*0402) HLA class II molecules.
      METHODS: Large numbers of HCgp-39-specific T cell hybridomas were generated
      following immunization of HLA-DR4/human CD4 transgenic, murine major
      histocompatibility complex class II deficient mice with native HCgp-39. Fine
      epitope mapping of DRalphabeta1*0401-and DRalphabeta1*0402-restricted T cell
      hybridomas was performed using overlapping synthetic peptides. Antigen-specific
      cytokine production by lymph node T cells was evaluated after immunization with
      native antigen. Proliferative T cell responses of healthy human subjects were
      compared with the T cell responses of patients with active RA using HCgp-39
      epitopes defined in HLA-DR4 transgenic mice. RESULTS: CD4+ T cells from
      DRalphabeta1*0401 and DRalphabeta1*0402 transgenic mice identified completely
      different immunodominant peptide epitopes of HCgp-39, and this was not explained
      by known DR4-binding motifs or direct peptide-binding studies. DRalphabeta1*0401
      restricted, antigen-specific T cells produced significantly more interferon-gamma
      and tumor necrosis factor a in response to HCgp-39 than did T cells from
      DRalphabeta1*0402 transgenic mice. Finally, HCgp-39 peptides defined in
      DRalphabeta1*0401 transgenic mice stimulated T cells from HLA-DR4 positive human
      subjects and RA patients, but not T cells from HLA-DR4 negative individuals.
      CONCLUSION: T cell epitopes of HCgp-39 that were defined in HLA-DR4 transgenic
      mice stimulated T cells from human subjects carrying RA-associated HLA-DR4
      alleles. HLA-DR4 molecules may influence the disease process in RA both by
      presentation of selected peptide epitopes and by promoting the production of
      proinflammatory cytokines in synovial joints.

PMID- 10403281
TI  - Characterization of collagenase 3 (matrix metalloproteinase 13) messenger RNA
      expression in the synovial membrane and synovial fibroblasts of patients with
      rheumatoid arthritis.
AB  - OBJECTIVE: To study the localization and cell type-specific expression of
      collagenase 3 messenger RNA (mRNA) in the synovial membrane, its regulation in
      primary synovial fibroblasts, and the correlation with systemic markers of
      inflammation and radiographic damage in rheumatoid arthritis (RA). METHODS: The
      expression of collagenase 3 mRNA was characterized by Northern blot analysis,
      reverse transcriptase-polymerase chain reaction, and in situ hybridization.
      Immunohistochemical detection of cell type-specific antigens was used in
      combination with in situ hybridization of collagenase 3 mRNA to characterize the
      cellular origin of collagenase 3 mRNA expression. RESULTS: Collagenase 3 mRNA was
      detected in synovial membrane specimens of 21 of 36 RA patients (58%) and
      correlated with an increase in erythrocyte sedimentation rate (P<0.05) and C
      reactive protein levels (P<0.005). Collagenase 3 mRNA was localized in fibroblast
      like cells of the lining and sublining layers, and at the synovial membrane
      cartilage interface. Four of 10 primary synovial fibroblast cell cultures showed
      basal expression of collagenase 3 mRNA, which was stimulated 2-4-fold upon
      interleukin-1beta or tumor necrosis factor alpha treatment and, in contrast to
      interstitial collagenase mRNA, 5-10-fold by increasing the intracellular level of
      cAMP. The stimulation by cAMP analogs was completely abolished by protein kinase
      A inhibitors. CONCLUSION: Some RA patients show collagenase 3 mRNA expression in
      the synovial membrane, which correlates with elevated levels of systemic markers
      of inflammation in these patients. In synovial fibroblasts, the expression of
      collagenase 3 and interstitial collagenase mRNA is differentially regulated by
      distinct protein kinase signal transduction pathways.

PMID- 10403282
TI  - Apoptotic chondrocyte death in rheumatoid arthritis.
AB  - OBJECTIVE: Recently, chondrocytes were shown to undergo apoptosis by the addition
      of nitric oxide and by coupling of Fas/Fas ligand in vitro, suggesting the
      possibility that chondrocytes have an inherent programmed cell death pathway that
      operates in adult cartilage. Chondrocyte apoptosis was verified in situ in
      articular cartilage samples from humans with osteoarthritis (OA) and from an
      animal model of OA. The present study investigates apoptotic chondrocyte death
      and the expression of Bcl-2 and Fas in rheumatoid arthritis (RA) cartilage.
      METHODS: Cartilage samples were obtained from 13 RA patients at the time of joint
      replacement surgery and from 8 normal subjects at autopsy. Apoptotic chondrocytes
      were observed and counted in hematoxylin and eosin-stained cartilage specimens.
      Apoptosis was verified by TUNEL, electron microscopy, and DNA ladder assay. Bcl-2
      and Fas expression were evaluated by immunohistochemistry. RESULTS: Apoptotic
      cells were frequently observed in RA cartilage, whereas normal cartilage rarely
      showed apoptotic cells (3.01% versus 0.15%, respectively), a finding that was
      further confirmed by TUNEL staining. On electron microscopy, numerous apoptotic
      cells with typical chromatin condensation were observed in RA cartilage. DNA from
      RA cartilage also revealed 180-basepair nucleosome ladders on electrophoresis.
      Bcl-2 expression was significantly lower in RA cartilage than in normal cartilage
      (23.3% versus 43.1%, respectively), whereas Fas expression was not statistically
      different. CONCLUSION: Apoptotic chondrocyte death and decreased Bcl-2 expression
      were verified in RA cartilage. They might provide a novel model system for the
      research of cartilage breakdown and joint destruction in RA.

PMID- 10403284
TI  - Octreotide treatment of chronic intestinal pseudoobstruction secondary to
      connective tissue diseases.
AB  - Chronic intestinal pseudoobstruction (CIPO) is a rare syndrome that may occur in
      association with connective tissue diseases (CTD). Effective management is a
      major challenge. We report 3 cases in which subcutaneous octreotide was
      efficacious in the treatment of digestive symptoms in CIPO. In 2 of the 3 cases,
      previous treatment with domperidone, cisapride, or erythromycin had been
      unsuccessful. All 3 patients underwent a regimen of oral antibiotics along with
      octreotide to stimulate small bowel motility. The effects of octreotide were
      evident within 48 hours after the first injection in all patients. In 2, the
      efficacy seemed to decrease after 1 week and 6 months respectively, but
      increasing the dosage led to another remission. CIPO in CTD is a severe condition
      that can evolve regardless of the underlying disease activity. Octreotide appears
      to be efficacious in improving both clinical symptoms and manometric patterns.
      When its therapeutic effect diminishes, increasing the dosage can be useful.

PMID- 10403283
TI  - Inhibitory effect of annexin I on synovial inflammation in rat adjuvant
      arthritis.
AB  - OBJECTIVE: Annexin I is an endogenous antiinflammatory mediator, expressed in
      rheumatoid arthritis (RA) synovium, the contribution of which to autoregulation
      of the synovial inflammatory response has not been examined in models of RA. We
      investigated the antiinflammatory role of annexin I in rat adjuvant arthritis.
      METHODS: Rats with adjuvant-induced arthritis (AIA) were treated with a specific
      anti-annexin I monoclonal antibody (mAb), isotype control IgG, and/or
      dexamethasone. Clinical outcomes and synovial synthesis of tumor necrosis factor
      alpha (TNFalpha), prostaglandin E2 (PGE2), and nitric oxide were examined, and
      annexin I expression was assessed by flow cytometry and reverse transcription
      polymerase chain reaction. RESULTS: Anti-annexin I mAb reversed the effects of
      dexamethasone on the clinical features of AIA and exacerbated AIA in the absence
      of exogenous glucocorticoid. Clinical exacerbation of AIA by anti-annexin I mAb
      was accompanied by significantly increased synovial TNFalpha and PGE2, suggesting
      that annexin I tonically inhibits the production of these mediators. Anti-annexin
      I mAb treatment was associated with significantly reduced leukocyte intracellular
      annexin I, despite increased annexin I messenger RNA expression, consistent with
      a depletion effect of extracellular mAb via the cell surface. CONCLUSION: Annexin
      I is a key endogenous inhibitory mediator of arthritis via mechanisms that
      include inhibition of cytokine and effector molecule production. Moreover, a
      synthesis-independent depletion of intracellular annexin I by extracellular
      antibody supports the hypothesis that externalization of annexin I is involved in
      its mode of action.

PMID- 10403285
TI  - Clinical images: Early diagnosis of Takayasu arteritis using gadolinium-enhanced
      magnetic resonance imaging.

PMID- 10403286
TI  - Femoral head osteonecrosis in a child with hemophilia.

PMID- 10403287
TI  - A preliminary definition of the term "cure" as applied to systemic lupus
      erythematosus.

PMID- 10403288
TI  - An update on HLA association of Mi-2 autoantibodies: the association with a
      tryptophan at position 9 of the HLA-DRbeta chain is strong but not absolute.

PMID- 10403289
TI  - Rheumatic diseases in Ayurveda: a historical perspective.

PMID- 10403290
TI  - Dose-loading with hydroxychloroquine in rheumatoid arthritis: comment on the
      article by Furst et al.

PMID- 10403291
TI  - Methodologic issues for the assessment of reproducibility: comment on the article
      by Genant et al.

PMID- 10403292
TI  - Correlation analysis versus Bland-Altman analysis: comment on the article by
      Genant et al.

PMID- 10403293
TI  - Lymphoma infiltrate or hyperparathyroidism? Comment on the clinical image by
      Drosos and Bai.

PMID- 10403294
TI  - Systemic lupus erythematosus in patients native to West and Central Africa:
      comment on the article by Bae et al.

PMID- 10403295
TI  - Can HLA-DR explain the varying frequency of synovitis in polymyalgia rheumatica?
      Comment on the article by Salvarani et al.

PMID- 10403296
TI  - Primary melanocytic neoplasms of the central nervous systems.
AB  - Primary melanocytic neoplasms of the central nervous system (CNS) consist of a
      spectrum ranging from well-differentiated melanocytoma to its overtly malignant
      counterpart, melanoma. Diagnostically difficult intermediate lesions lie between
      these extremes. Clinicopathologic features of 33 cases were studied to define
      histologic appearances, diagnostic criteria, and the clinical behavior of lesions
      along this spectrum. Seventeen cases were well-differentiated, solitary
      leptomeningeal tumors classified as melanocytomas. They contained variably
      pigmented melanocytic cells arranged in tight nests, sheets, or fascicles.
      Mitotic rates ranged from zero to one per 10 high-power fields (HPFs), with most
      having zero per 10 HPFs. All tumors were immunoreactive for HMB-45 and S-100
      protein and negative for epithelial membrane antigen. MIB-1 staining was low (<1
      2%). Nuclei were regular, often with small, eosinophilic nucleoli. These lesions
      arose predominantly in the spinal canal (65%) in patients ranging in age from 17
      to 73 years. None recurred after surgical resection. In contrast to these benign
      lesions, there were 13 cases with histologic and cytologic features consistent
      with those of malignant melanoma. These cases contained larger, cytologically
      atypical, pigmented tumor cells growing in loose nests or sheets, often with CNS
      invasion or necrosis. Some contained bizarre, pleomorphic nuclei; others were
      densely cellular and mitotically active, but less pleomorphic. Mitotic rates
      (mean, 5.7 per 10 HPFs) and MIB-1 labeling indices (mean, 8.1%) were higher than
      those of melanocytomas. Melanomas occurred at spinal (38%), posterior fossa
      (38%), and supratentorial (23%) levels in patients ranging in age from 15 to 71
      years. After resection, 8 of 13 lesions recurred, with four being fatal (mean
      survival, 14 months). Of five totally resected melanomas, four did not recur
      (mean follow-up, 26 months). Three intermediate-grade melanocytic tumors could
      not be classified as melanocytoma or melanoma. All showed sheetlike growth
      patterns, microscopic CNS invasion, and occasional mitoses. MIB-1 staining ranged
      from 1% to 4%. One tumor recurred after 17 months; one patient was lost to follow
      up after 5 months; and the third died after surgery. Although melanocytic tumors
      represent a spectrum of lesions, certain histopathologic features are helpful in
      predicting biologic behavior.

PMID- 10403297
TI  - Leiomyosarcoma of soft tissue in children: clinicopathologic analysis of 20
      cases.
AB  - Leiomyosarcoma in the pediatric age group is uncommon and incompletely
      characterized. A series of 20 primary leiomyosarcomas of soft tissue occurring in
      children younger than 16 years is presented. No significant gender predilection
      was observed (11 girls and 9 boys). Patient age ranged from 4 to 15 years
      (median, 12 years). Tumor size ranged from 0.5 to 13 cm (median, 2.5 cm);
      subcutaneous and deep locations were equally represented. Tumors were evenly
      distributed among the trunk (30%), head and neck (25%), lower limbs (25%), and
      upper limbs (20%). All lesions showed at least focally typical features of smooth
      muscle differentiation, principally in the form of fascicles of eosinophilic
      spindle cells with cigar-shaped nuclei. An unusual whorled growth pattern was
      seen in two cases. Morphologic variants including inflammatory leiomyosarcoma
      (one case), granular cell leiomyosarcoma (two cases), giant-cell rich
      leiomyosarcoma (two cases), and epithelioid leiomyosarcoma (one case) were seen.
      Dystrophic calcifications were present in two cases. Most lesions (85%) were low
      grade. Immunohistochemical staining showed positivity for alpha-smooth muscle
      actin in 89% of the cases, HHF-35 in 87%, and desmin in 61%. Positivity for
      cytokeratins, observed in 6 (43%) of 14 cases tested, was usually strong and was
      diffuse in two cases. Follow-up data, available in 15 (75%) patients (median
      duration, 49 months), showed late local recurrence in only two cases, one with
      progression to a higher grade lesion, and no metastasis. These results show that,
      although extremely rare, soft-tissue leiomyosarcomas do occur in children, in
      whom they usually present as small morphologically low-grade lesions that seem to
      behave in a relatively indolent fashion, although longer follow-up data are
      needed. Differential diagnosis in this setting includes infantile
      myofibromatosis, leiomyoma, monophasic synovial sarcoma, and spindle cell
      rhabdomyosarcoma.

PMID- 10403298
TI  - Villous adenoma of the urinary tract: a report of 23 cases, including 8 with
      coexistent adenocarcinoma.
AB  - Villous adenoma originating in the urinary tract is uncommon. We present the
      first study of a large number of cases of villous adenoma of the urinary tract
      with clinical follow-up. Our series consisted of 15 patients with isolated
      villous adenoma and 8 patients with coexistent adenocarcinoma. The tumors
      occurred in elderly patients and had a predilection for the urachus, dome, and
      trigone of the urinary bladder. The typical clinical presentation was hematuria
      and irritative symptoms, and endoscopic examination usually identified a tumor
      growth. There was no gender predominance. Light microscopic examination showed
      morphologic similarity to colonic villous adenoma in all cases. Each tumor was
      composed of pointed or blunt finger-like processes lined by pseudostratified
      columnar epithelium. The epithelial cells displayed nuclear stratification,
      nuclear crowding, nuclear hyperchromasia, and occasional prominent nucleoli and
      mitotic figures. There was intense carcinoembryonic antigen immunoreactivity on
      the luminal surfaces (89%). Most cases (78%) contained cytoplasmic acid mucin,
      demonstrated by Alcian blue periodic acid-Schiff stain. Cytokeratin 20 was
      positive in all cases, cytokeratin 7 was positive in 56% of cases, and epithelial
      membrane antigen was positive in 22% of cases. Recurrence or invasive
      adenocarcinoma did not develop in any patient with isolated villous adenoma
      during a mean follow-up of 9.9 years. Lung metastasis developed in one patient
      with coexistent adenocarcinoma and multiple recurrences in another (mean follow
      up, 3 years). We conclude that the prognosis is excellent in patients with
      isolated villous adenoma, and complete surgical resection is curative. Patients
      with coexistent adenocarcinoma may experience recurrence or distant metastasis,
      and more aggressive treatment may be indicated.

PMID- 10403299
TI  - Oncocytoid renal cell carcinoma after neuroblastoma: a report of four cases of a
      distinct clinicopathologic entity.
AB  - Four children who developed oncocytoid renal cell carcinoma (RCC) after
      neuroblastoma are reported. One patient had multiple, bilateral RCCs. The mean
      age at time of diagnosis of RCC was 8.8 years (range, 5-13 years). The mean
      interval between neuroblastoma and RCC was 7.15 years (range, 3.1-11.5 years).
      The histologic findings of these RCCs did not fit within the spectrum of known
      renal epithelial neoplasms. Most of the neoplastic cells in all cases had
      eosinophilic, oncocytoid cytoplasm and were arranged in solid and papillary
      growth patterns. A subset of cells with reticular cytoplasm was also present.
      Immunohistochemical studies demonstrated keratins 8 and 18 in all neoplasms and
      keratin 20 in two cases. DNA ploidy analysis revealed that two of three neoplasms
      assessed were aneuploid. Cytogenetic studies revealed 45, XX, add or dup
      (7)(q32q36) in one neoplasm, and 83-89, XXXX, -1 ,-3, del (3)(q11.1q2?1),
      der(4)t(4;?22) (q32;q11.2), -14, -22 in a second tumor. Microsatellite polymerase
      chain reaction analysis detected no abnormalities in one neoplasm and allelic
      imbalance of chromosomes 2p31-32.2, 8p22, 9p22-24, 13q22, 20q13, and 22q11 in a
      second tumor. In case 4, two different RCCs excised 6 months apart were analyzed.
      The initial neoplasm showed allelic imbalance of chromosomes 2q31-32.2, 5q22,
      5q31, 10p13-14, 13q22, 14q31, and 20q13. The subsequent neoplasm showed allelic
      imbalance of chromosomes 3p21.3, 14q31, and 20q13. The common presence of 14q31
      and 20q13 abnormalities suggests that these two neoplasms were genetically
      related. In aggregate, these findings are distinctive, are not found in known
      types of RCC, and support the morphologic impression that oncocytoid RCC after
      neuroblastoma is a distinct clinicopathologic entity.

PMID- 10403300
TI  - Does prostatic ductal adenocarcinoma exist?
AB  - Prostatic ductal (endometrioid) adenocarcinoma has been considered a distinct
      pathologic and clinical entity since it was first described more than 30 years
      ago. Its current status as a unique neoplasm is controversial, however, because
      it has considerable histologic overlap with typical acinar adenocarcinoma,
      particularly in small specimens such as needle biopsies. There are also
      conflicting views regarding its clinical behavior. We recently encountered a
      series of typical peripheral zone cancers of the prostate gland with prominent
      papillary or cribriform pattern that apparently did not involve the large
      periurethral prostatic ducts or verumontanum. To determine the incidence of these
      "ductal features" in nonductal carcinoma, we reviewed the findings in 338
      consecutive totally embedded whole-mount prostatectomy specimens with typical
      clinical and pathologic features of acinar carcinoma. We defined carcinoma with
      significant "ductal features" as one that displayed papillary or cribriform
      pattern involving an arbitrarily defined aggregate focus at least 5 mm in
      diameter. Anti-keratin 34beta-E12 immunohistochemical staining for basal cells
      allowed exclusion of areas of papillary or cribriform pattern of high-grade
      prostatic intraepithelial neoplasia. We identified carcinoma with ductal features
      (papillary or cribriform growth) in 17 prostatectomy specimens (5% of cases)
      exclusively in the peripheral zone without involving the periurethral region.
      Papillary pattern was present in 11 of these cases (65%) and cribriform pattern
      in 10 (59%), including 4 cases (24%) with both patterns. Of 11 needle biopsy
      specimens available for examination from these 17 cases, 4 (36%) contained at
      least focal papillary or cribriform pattern of carcinoma. We conclude that
      adenocarcinoma arising in the peripheral zone of the prostate gland may display
      ductal carcinoma features (papillary or cribriform growth) classically associated
      with ductal adenocarcinoma. These findings, together with the recognized near
      constant association of prostatic ductal adenocarcinoma and typical prostate
      cancer, suggest that ductal adenocarcinoma results from spread of typical
      prostatic acinar carcinoma into the large accommodating periurethral ducts and
      stroma, and that there are no unique histologic features other than site of
      growth. Identification of papillary or cribriform growth of cancer in prostate
      needle biopsies usually results from peripheral zone adenocarcinoma and not
      ductal adenocarcinoma.

PMID- 10403301
TI  - Desmoplastic (sclerotic) nevus: an underrecognized entity that resembles
      dermatofibroma and desmoplastic melanoma.
AB  - Desmoplastic (sclerotic) nevus, a benign melanocytic neoplasm characterized by
      predominantly spindle-shaped nevus cells within a fibrotic stroma, can be
      confused with fibrous lesions and other melanocytic proliferations, including
      desmoplastic melanoma. We compared the histologic and immunohistochemical
      features of 16 desmoplastic nevi, nine desmoplastic melanomas, four hypopigmented
      blue nevi, and six dermatofibromas. The similarities between desmoplastic nevi
      and dermatofibromas included epidermal hyperplasia (12 of 16), presence of
      keloidal collagen (15 of 16), hypercellularity (16 of 16), and increased numbers
      of factor XIIIa-positive dendritic cells (12 of 12). The absence of adnexal
      induction (0 of 16), the rarity of lesions with multinucleated cells (3 of 16) or
      epidermal hyperpigmentation (2 of 16), and the presence of S-100 immunoreactivity
      (16 of 16) and melanocytic proliferation (9 of 16) helped differentiate
      desmoplastic nevi from dermatofibromas. The similarities between desmoplastic
      nevi and desmoplastic melanomas included the presence of atypical cells (16 of
      16) and HMB-45 expression in the superficial portion of the lesions (11 of 16).
      The infrequent location on the head or neck (1 of 16), the absence of mitotic
      figures (0 of 16), a significantly lower number of Ki-67-reactive cells, and a
      decrease in HMB-45 expression in the deep area of the lesions (8 of 11) helped
      distinguish desmoplastic nevi from desmoplastic melanoma. Desmoplastic nevi had
      overlapping features with hypopigmented blue nevi, but features tending to favor
      the latter included a predominance of ovoid nuclei, higher numbers of atypical
      cells, and homogeneous staining with HMB-45. We conclude that a combination of
      histologic and immunohistochemical criteria facilitates the reliable diagnosis of
      desmoplastic nevus from its simulators.

PMID- 10403302
TI  - Renal cell carcinomas in children and young adults: increased incidence of
      papillary architecture and unique subtypes.
AB  - Renal cell carcinomas in children and young adults are rare, and the pathologic
      features of these tumors have not been well described. We reviewed 24 renal cell
      carcinomas in children and young adults ages 6 to 29 years, 14 of whom were
      younger than 18 years of age. Fourteen were female. In 19 (79%) of 24 cases, the
      tumor met histologic criteria for papillary renal cell carcinoma, with at least
      50% papillary architecture. Four of the remaining five cases were typical clear
      cell tumors in patients known to have von Hippel Lindau syndrome, and one case
      was of chromophobe type. In the papillary tumors, calcifications, high nuclear
      grade, extracapsular extension (American Joint Commission on Cancer stage T3),
      and lymph node metastases were common. Among these papillary tumors, four
      distinct histologic patterns could be identified. Collecting duct-like tumors
      (two cases) involved the large collecting ducts, were multifocal and
      predominantly papillary, and had focal tubular and solid areas. These tumors were
      reactive for epithelial membrane antigen (EMA) and keratins, including CK7, but
      negative for Ulex europeaus and high molecular weight keratin 34BE12. Voluminous
      cell tumors (four cases) were composed of cells with extremely voluminous clear
      cytoplasm and, although predominantly papillary, had areas that also resembled
      clear cell tumors. These tumors were reactive for keratins AE1/AE3 but were
      otherwise negative for all other keratins, EMA, and U. europeaus. One of these
      tumors showed an X;7 translocation. Adult type tumors (12 cases) resembled
      papillary tumors of adults. These tumors were reactive for EMA and keratins,
      including CK7, and all but one were negative for U. europeaus and keratin 34BE12.
      This last case had trisomies of chromosomes 7, 16, 17, and 20. The final
      neuroendocrinelike case was multifocal, organoid, and composed of nests of small
      cells in a neuroendocrinelike pattern. Three of 13 patients were alive with
      disease at last follow-up, and three additional patients died of disease, all
      within 2 years. Progression was highly associated with lymph node involvement at
      the time of resection. We conclude that the clinicopathologic features of renal
      cell carcinomas in children and young adults differ from those arising in older
      adults. These tumors are characteristically high-grade, high-stage, papillary
      tumors with numerous calcifications, and several subtypes can be identified based
      on histologic, immunohistochemical, and cytogenetic features. Some subtypes
      appear to be unique to this age group.

PMID- 10403303
TI  - Prevalence and distribution of prostatic intraepithelial neoplasia in salvage
      radical prostatectomy specimens after radiation therapy.
AB  - High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor
      of prostate cancer. The effect of radiation therapy (RT) on the prevalence of PIN
      is uncertain. We studied 86 patients who underwent salvage radical prostatectomy
      after irradiation failure at the Mayo Clinic. The prevalence, volume,
      multicentricity, spatial proximity to cancer, and architectural patterns of PIN
      were evaluated. High-grade PIN was identified in 53 (62%) of 86 prostatectomy
      specimens. Multiple architectural patterns were usually observed, including
      tufting in 87%, micropapillary in 66%, cribriform in 38%, and flat in 17%. The
      mean volume of PIN was 0.12 cm3 (range, 0.05-1.20 cm3). PIN was usually
      multicentric (70%), with a mean number of PIN foci of 2.5 (range, 1-10). Ninety
      four percent of PIN foci were located within 2 mm of invasive cancer. There was
      no correlation between PIN and pathologic stage, surgical margin, tumor size, DNA
      ploidy, post-RT Gleason score, time interval from RT to biopsy-proven recurrence,
      postoperative prostate-specific antigen level, distant metastasis-free survival,
      or cancer-specific survival. Our examination of salvage radical prostatectomy
      specimens indicated that the prevalence and extent of PIN appeared to be reduced
      after RT compared to published studies of prostatectomies without prior RT.

PMID- 10403304
TI  - Cluster of uterine mullerian adenosarcoma in the Washington, DC metropolitan area
      with high incidence of sarcomatous overgrowth.
AB  - Mullerian adenosarcoma is an uncommon variant of uterine sarcoma. Twelve uterine
      adenosarcomas were diagnosed during a 42-month period at the Washington Hospital
      Center in Washington, DC. Based on estimated incidence data derived from the US
      Department of Defense beneficiary population, an estimated relative risk of 15.4
      (95% confidence interval, 7.7-31.0) was calculated, indicating a significantly
      increased incidence of adenosarcoma in the population studied (p<0.0000001).
      Among 10 patients who underwent hysterectomy, six (60%) of their tumors had
      sarcomatous overgrowth. In comparison with the previously reported proportion of
      adenosarcomas with sarcomatous overgrowth, approximately 16%, the proportion with
      sarcomatous overgrowth was significantly higher than expected (p<0.01). Mullerian
      adenosarcoma with sarcomatous overgrowth was first described in 1989 and suggests
      that the cluster of adenosarcomas reported herein may be due in part to the
      current classification of some uterine tumors as adenosarcoma with sarcomatous
      overgrowth that previously would have been classified as other types of uterine
      sarcoma. Nonetheless, even after reviewing and updating the classification of all
      sarcomas diagnosed at the Washington Hospital Center from 1985 to 1998, the ratio
      of adenosarcomas to uterine adenocarcinomas during the 1994-1998 period was 4.7
      times (p<0.005) that of the 1985-1993 period, suggesting a more modest but real
      increase in the occurrence of this tumor. Correct classification of mullerian
      adenosarcomas with sarcomatous overgrowth is important because the limited
      available data suggest that the prognosis is notably worse than that for
      adenosarcomas without sarcomatous overgrowth.

PMID- 10403305
TI  - Osteosarcomatous differentiation in phyllodes tumors.
AB  - Osteosarcomatous differentiation in phyllodes tumors is uncommon. The
      clinicopathologic features of 22 such cases in our files were retrospectively
      reviewed to evaluate the prognostic significance of this rare neoplasm. All
      patients were women between 40 and 83 years of age (mean, 60 years). Most (73%)
      presented with a palpable mass. None had prior irradiation to the breast or chest
      region. Patients were treated with excisional biopsy (N = 4), partial mastectomy
      (N = 1), or mastectomy (N = 17). All axillary nodes, dissected in 11 patients,
      were free of tumor. Two patients had extramammary spread at diagnosis. The
      neoplasms measured 1.9-15 cm (mean, 6.4 cm); 54% were grossly circumscribed or
      multilobulated. The osteosarcomatous component was classified as fibroblastic (N
      = 11), osteoclastic (N = 6), or osteoblastic (N = 5) and occupied a variable
      percentage of the phyllodes' stroma ranging from -25% to essentially 100% of the
      neoplasm. Of 21 patients with available follow-up, 11 (52%) were alive at a
      median follow-up of 44 months. Nine patients (43%) developed locally recurrent (N
      = 1) or metastatic (N = 8) disease. Metastases were clinically apparent within 1
      year of diagnosis in all eight patients; seven died within 12 months of detection
      of initial metastasis. By univariate analysis, gross tumor size and osteosarcoma
      subtype significantly correlated with prognosis. In a multivariate analysis,
      neither of these factors were independent prognosticators. Phyllodes tumors with
      an osteosarcomatous component are potentially aggressive neoplasms, particularly
      when large (>5 cm) or associated with an osteoclastic or osteoblastic
      osteosarcoma. Complete excision without axillary dissection is advised.

PMID- 10403306
TI  - Detection of melanoma micrometastasis in sentinel nodes by reverse transcription
      polymerase chain reaction correlates with tumor thickness and is predictive of
      micrometastatic disease in the lymph node basin.
AB  - The sentinel node has been reported to be representative for the presence or
      absence of metastatic melanoma in the draining lymph node basin. In this study,
      for the first time sentinel nodes and adjoining nonsentinel nodes were analyzed
      for micrometastatic disease using tyrosinase reverse transcription-polymerase
      chain reaction (RT-PCR) in comparison with standard immunohistochemistry.
      Successful identification of the sentinel nodes using a gamma probe-guided
      surgery was achieved in 73 (92%) of 79 patients with cutaneous stage I and II
      melanoma (tumor thickness > or =0.75 mm). A total of 794 regional lymph nodes,
      148 sentinel nodes, and 646 adjoining nonsentinel nodes were evaluated.
      Tyrosinase RT-PCR was shown to increase the sensitivity for melanoma cell
      detection in sentinel nodes significantly (49% positivity) as compared with
      immunohistochemistry using antibodies against HMB-45 antigen and S-100 protein
      (18% positivity). Examination of sentinel nodes was highly predictive in
      determining the presence of regional lymph node micrometastasis by
      immunohistochemistry (99%) and RT-PCR (89%). Interestingly, detection of nodal
      micrometastasis by RT-PCR showed a strong positive correlation with tumor
      thickness of primary cutaneous melanoma. These results suggest the clinical
      significance and emphasize the importance of tyrosinase RT-PCR for detection of
      melanoma micrometastasis in sentinel nodes.

PMID- 10403307
TI  - Reversible monoclonal lymphadenopathy in autoimmune lymphoproliferative syndrome
      with functional FAS (CD95/APO-1) deficiency.
AB  - The FAS (CD95/APO-1) receptor and its ligand play an important role in the
      initiation of apoptosis under many physiologic conditions. Loss of function
      mutations of the FAS gene have been described in lpr mice and in humans with
      autoimmune phenomena, recurrent lymphadenopathies, and hepatosplenomegaly. This
      syndrome is now called autoimmune lymphoproliferative syndrome type I (ALPS I).
      Recently, patients with similar clinical symptoms due to a functional FAS
      deficiency without FAS gene mutations have been distinguished. This disease has
      been termed autoimmune lymphoproliferative syndrome type II (ALPS II) or
      autoimmune lymphoproliferative disease (ALD). This report is the first
      description of the lymph node pathology and immunohistochemistry in a patient
      with ALPS II. After recurrent bacterial infections, a 4-year-old child developed
      cervical giant lymphadenopathy suggesting lymphoma. Lymph node histology
      resembled the findings in Epstein Barr virus-associated posttransplant atypical
      lymphoproliferations. Confluent sheets of immunoblasts, however, showed a
      monoclonal expression of IgG/lambda and a monoclonal rearrangement of the JH
      chain. The same clone was also present in the peripheral blood. Although high
      grade lymphoma could not be excluded, the patient's parents insisted on the
      patient's leaving the hospital with only antibiotic treatment. Surprisingly, the
      giant lymphadenopathy completely resolved within 7 weeks, and the clone was no
      longer detectable in the peripheral blood. Twelve months later the patient was
      still free from lymphoma and was doing well. Retrospectively, transient
      monoclonal B-cell populations could be identified in an archival frozen blood
      sample taken when the patient was 3 years old. Increased FAS-independent
      spontaneous apoptosis was a feature of the patient's lymphocytes and could be the
      molecular basis for self-elimination of B-cell clones. We conclude that the
      diagnosis of a FAS-FAS-L deficiency should be considered in children with an
      otherwise unexplained atypical lymphoproliferation and that a diagnosis of
      lymphoma in patients with functional FAS deficiency should be made with
      considerable reservation.

PMID- 10403308
TI  - Motilin-producing liver and bone metastases evidenced 14 years after resection of
      a rectal polyp.
AB  - A 62-year-old man with a history of a resected rectal polyp was diagnosed 14
      years later with right liver and multiple bone metastases. The liver biopsy
      showed a malignant epithelial tumor that was positive for neuron-specific enolase
      immunostaining and negative for chromogranin. Electron microscopy was
      characteristic of that for an endocrine tumor. Most circulating hormonal peptide
      levels were within normal ranges and only motilin level was elevated. On the
      right hepatectomy, the three large metastases had a histologic picture suggestive
      of an endocrine tumor. Immunohistochemistry revealed in some areas numerous tumor
      cells expressing motilin, and a few cells were strongly positive for pancreatic
      polypeptide and somatostatin. The retrospective analysis of the rectal polyp
      showed a similar histology and immunohistochemical profile, indicating that this
      lesion was the primary tumor. Motilin-positive cells from one of the hepatic
      lesions were identified on semithin sections and further processed for electron
      microscopy. Neurosecretory granules were numerous in all cells. Immunoelectron
      localization enabled us to characterize the motilin-containing neurosecretory
      granules, which had a mean diameter of 168.3x38.1 nm. Although not all tumor
      cells were motilin-positive, a diagnosis of motilinoma for the rectal polyp and
      its hepatic and bone metastases was proposed.

PMID- 10403309
TI  - Cerebellar papillary meningioma in a 3-year-old boy: the usefulness of electron
      microscopy for diagnosis.
AB  - We report one case of papillary meningioma located in the posterior fossa in a 3
      year-old boy. Despite a gross total resection, a major recurrence occurred 6
      months later that was operated on. Eight months later, another recurrence was
      observed with intracranial metastases and dissemination throughout the
      cerebrospinal fluid. The tumor had a papillary architecture more obvious in the
      recurrence. Areas of necrosis were numerous. Tumor cells had large clear atypical
      nuclei. Many mitotic figures were seen and Ki-67 labeling index was high. The
      tumor cells were immunoreactive for vimentin and polysialylated neural cell
      adhesion molecule only, ruling out a diagnosis of ependymoma or medulloblastoma.
      Diagnosis of meningioma was done by electron microscopy, which showed
      interdigitating cytoplasmic processes and cell junctions. Cytogenetic study
      revealed unusual karyotypic abnormalities.

PMID- 10403310
TI  - Cutaneous sclerosing perineurioma with cryptic NF2 gene deletion.
AB  - Sclerosing perineurioma is a recently described variant of perineurioma that
      characteristically occurs in the fingers and palms of young adults. We report a
      cutaneous sclerosing perineurioma with preservation of the axons and Schwann
      cells in the center of the whorls of perineurial cells, a feature that previously
      was reported to be typically absent in these lesions. Additionally, clonal
      chromosomal abnormalities of chromosome 10 and a cryptic deletion of the 5'BCR
      and NF2 loci on chromosome 22 were present. These findings further support the
      hypothesis that a gene on chromosome 22 may play a role in the pathogenesis of
      perineurioma. The NF2 gene is a logical candidate because of its involvement in
      other nerve sheath tumors.

PMID- 10403311
TI  - Primary smooth muscle tumor of the liver encasing hepatobiliary cystadenoma
      without mesenchymal stroma.
AB  - We describe a 59-year-old Japanese woman with a large mass of her liver encasing
      cystic components. Radiologic imaging showed the mass to be hypervascular, and
      surgical resection disclosed a white tumor. The solid portion was
      immunohistochemically characterized as a smooth muscle tumor. The cystic
      components were multilocular and lined with columnar epithelium, consistent with
      a hepatobiliary cystadenoma. The epithelium strongly stained for CA19-9. The
      subepithelial space was occupied by collagenous connective tissue interspersed
      with a small number of spindle-shaped cells. The cystic lesions lacked the
      mesenchymal stroma between the epithelium and connective tissue layer. There have
      been no previous reports of a hepatic smooth muscle tumor encasing a
      hepatobiliary cystadenoma. Because of the pathogenesis of the cystadenoma, it is
      possible to assume that the smooth muscle tumor also arose from the cells
      composing the biliary duct in association with the development of the
      cystadenoma.

PMID- 10403312
TI  - Apoptosis.

PMID- 10403313
TI  - Peritumoral muciphage.

PMID- 10403314
TI  - Identification of a novel strain of Borrelia hermsii in a previously undescribed
      northern California focus.
AB  - An epizootiologic investigation testing for the presence of tick-borne relapsing
      fever spirochetes in rodent and tick hosts was conducted at Eagle Lake in Lassen
      County, California. Six of 211 O. hermsii ticks and none of 180 rodents were
      polymerase chain reaction (PCR)-positive for Borrelia spirochetes. Sequencing of
      the PCR-amplified flagellin gene fragment suggests that the spirochetes from
      Eagle Lake represent a previously undescribed strain of Borrelia hermsii.

PMID- 10403315
TI  - Tick-borne rickettiosis in Guadeloupe, the French West Indies: isolation of
      Rickettsia africae from Amblyomma variegatum ticks and serosurvey in humans,
      cattle, and goats.
AB  - Twenty-seven rickettsiae were isolated and/or detected from 100 Amblyomma
      variegatum ticks collected on Guadeloupe in the French West Indies. In this
      study, the polymerase chain reaction procedure appeared to be more sensitive in
      detecting rickettsiae in ticks than the shell-vial technique. Sequencing a
      portion of the outer membrane protein A-encoding gene showed that these
      rickettsiae appeared to be identical to Rickettsia africae, a member of the
      spotted fever group rickettsiae recently described as an agent of African tick
      bite fever occurring in sub-Sahelian Africa. A high seroprevalence of antibodies
      to R. africae was demonstrated among mammals, particularly humans, cattle, and
      goats. These results and a recently reported case of an infection due to R.
      africae on Guadeloupe demonstrate that R. africae is present on this island.
      Although this disease has been underdiagnosed there, it may be frequent and may
      exist on other Caribbean islands where A. variegatum has propagated dramatically
      over recent years.

PMID- 10403316
TI  - Serologic evidence of rickettsialpox (Rickettsia akari) infection among
      intravenous drug users in inner-city Baltimore, Maryland.
AB  - We tested single serum samples from 631 intravenous (i.v.) drug users from inner
      city Baltimore, Maryland for serologic evidence of exposure to spotted fever
      group rickettsiae. A total of 102 (16%) individuals had titers > or = 64 to
      Rickettsia rickettsii by an indirect immunofluorescence assay. Confirmation that
      infection was caused by R. akari was obtained by cross-adsorption studies on a
      subset of serum samples that consistently resulted in higher titers to R. akari
      than to R. rickettsii. Current i.v. drug use, increased frequency of injection,
      and shooting gallery use were significant risk factors for presence of group
      specific antibodies reactive with R. rickettsii. There was a significant inverse
      association with the presence of antibodies reactive to R. rickettsii and
      antibodies reactive to the human immunodeficiency virus. This study suggests that
      i.v. drug users are at an increased risk for R. akari infections. Clinicians
      should be aware of rickettsialpox, as well as other zoonotic diseases of the
      urban environment, when treating i.v. drug users for any acute febrile illness of
      undetermined etiology.

PMID- 10403317
TI  - Outbreak of histoplasmosis among cavers attending the National Speleological
      Society Annual Convention, Texas, 1994.
AB  - In June 1994, 18 people developed serologically confirmed histoplasmosis
      following cave exploration associated with the annual National Speleological
      Society Convention in Bracketville, Texas. Six others had an undiagnosed illness
      suspected to be histoplasmosis. Two persons were hospitalized. We conducted a
      survey of convention attendees and a nested case-control study of those entering
      caves. We also conducted a histoplasmin skin test survey of a subgroup of the
      society, the Texas Cavers Association, who were attending a reunion in October
      1994. Among the national convention attendees, exposure to two caves was
      identified as responsible for 22 (92%) of the 24 cases; 12 (75%) of 16 people
      exploring one cave (Cave A) and 10 (77%) of 13 exploring a separate cave (Cave B)
      developed acute histoplasmosis. Additional risk-factors included fewer years of
      caving experience, longer time spent in the caves, and entering a confined crawl
      space in Cave A. Of 113 participants in the separate skin test survey, 68 (60%)
      were found to be skin test positive, indicating previous exposure to Histoplasma
      capsulatum. A positive skin test was significantly associated with male sex and
      more years of caving experience. Those less experienced in caving associations
      should be taught about histoplasmosis, and health care providers should pursue
      histories of cave exposure for patients with bronchitis or pneumonia that does
      not respond to initial antibiotic therapy.

PMID- 10403319
TI  - Evaluation of malaria surveillance using retrospective, laboratory-based active
      case detection in four southwestern states, 1995.
AB  - The global resurgence of malaria has raised concerns of the possible
      reintroduction of indigenous transmission in the United States. The Centers for
      Disease Control and Prevention's National Malaria Surveillance System, using data
      supplied by state and local health departments (SLHDs), is maintained to detect
      local malaria transmission and monitor trends in imported cases. To determine the
      completeness of reporting of malaria cases to SLHDs, cases identified by local
      surveillance systems were compared with those identified through active case
      detection conducted at all laboratories that receive clinical specimens from 11
      metropolitan areas in Arizona, California, New Mexico, and Texas. Of the 61
      malaria cases identified through either local surveillance or active case
      detection, 43 (70%) were identified by SLHDs (range by metropolitan area = 50
      100%) and 56 (92%) through active case detection. High percentages of cases were
      identified by SLHDs in New Mexico (80%) and San Diego County (88%), where
      laboratories are required to send positive blood smears to the SLHD laboratory
      for confirmation. Completeness of reporting, calculated using the Lincoln
      Peterson Capture-Recapture technique, was 69% for SLHD surveillance systems and
      89% for laboratory-based active case detection. The high percentage of cases
      identified by the 11 SLHDs suggests that the National Malaria Surveillance System
      provides trends that accurately reflect the epidemiology of malaria in the United
      States. Case identification may be improved by promoting confirmatory testing in
      SLHD laboratories and incorporating laboratory-based reporting into local
      surveillance systems.

PMID- 10403318
TI  - Type-3 dengue viruses responsible for the dengue epidemic in Malaysia during 1993
      1994.
AB  - To characterize the dengue epidemic that recently occurred in Malaysia, we
      sequenced cDNAs from nine 1993-1994 dengue virus type-3 (DEN-3) isolates in
      Malaysia (DEN-3 was the most common type in Malaysia during this period). Nucleic
      acid sequences (720 nucleotides in length) from the nine isolates, encompassing
      the precursor of membrane protein (preM) and membrane (M) protein genes and part
      of the envelope (E) protein gene were aligned with various reference DEN-3
      sequences to generate a neighbor-joining phylogenetic tree. According to the
      constructed tree, the nine Malaysian isolates were grouped into subtype II, which
      comprises Thai isolates from 1962 to 1987. Five earlier DEN-3 virus Malaysian
      isolates from 1974 to 1981 belonged to subtype I. The present data indicate that
      the recent dengue epidemic in Malaysia was due to the introduction of DEN-3
      viruses previously endemic to Thailand.

PMID- 10403320
TI  - Effect of schistosomiasis and hepatitis on liver disease.
AB  - Infection with hepatitis C virus (HCV) has become the most important public
      health problem in Egypt. In Egypt, viral hepatitis along with infection with
      Schistosoma mansoni is the major cause of chronic liver disease and liver
      cirrhosis. Although HCV infection is highly prevalent in Egypt, very little
      information is available on the distribution of the different genotypes of HCV.
      Our aims in this study were first to determine the prevalence of viral and
      parasite infections in patients with chronic liver disease and then to assess the
      distribution of HCV genotypes in these patients. In the present study, 151
      individuals (50 with chronic liver disease, 51 with chronic diseases of organs
      other than the liver, and 50 apparently healthy persons) were investigated. The
      last 2 groups served as control groups. These individuals were subjected to
      routine liver function tests and detection of serum antibodies to bilharziasis,
      hepatitis B surface antigen (HBsAg), and HCV. Furthermore, the presence of
      hepatitis G virus (HGV) and HCV in the serum samples were tested for by a reverse
      transcription polymerase chain reaction (RT-PCR). Prevalence of different
      genotypes of HCV in patients positive for HCV were determined by RT-PCR using
      type-specific primers. Results of the study revealed that 84, 74, 12, and 20% of
      patients with chronic liver disease were positive for Schistosoma mansoni, HCV,
      HBsAg, and HGV, respectively, as compared to 51, 43.1, 2, and 4% of patients with
      other chronic diseases and 22, 6, 0, and 0% of apparently healthy individuals.
      One hundred percent of patients with chronic liver disease, 72.5% of those with
      other diseases, and 26% of normal controls were shown to have at least one of the
      studied infectious agents. Two or more of the agents were highly coincident in
      patients with chronic liver disease. In Egypt, HCV genotype 4a is highly
      prevalent, where it contributed 85% of the tested samples in comparison to 10,
      2.5, and 2.5% for subtypes 1b, 2a, and 3a, respectively. In conclusion, these
      results suggest that in Egypt, HCV along with schistosomal parasite infection is
      the major risk factor for chronic liver disease. In most Egyptian patients, HCV
      genotype 4 is highly prevalent.

PMID- 10403321
TI  - Genetic analysis of susceptibility to infection with Ascaris lumbricoides.
AB  - Epidemiologic studies of helminthic infections have shown that susceptibility to
      these parasites frequently aggregates in families, suggesting the possible
      involvement of genetic factors. This paper presents a genetic epidemiologic
      analysis of Ascaris lumbricoides infection in the Jirel population of eastern
      Nepal. A total of 1,261 individuals belonging to a single pedigree were assessed
      for intensity of Ascaris infection at two time points. Following an initial
      assessment in which all individuals were treated with albendazole, a follow-up
      examination was performed one year later to evaluate reinfection patterns. Three
      measures of worm burden were analyzed, including eggs per gram of feces, direct
      worm counts, and worm biomass (weight). For all traits, variance component
      analysis of the familial data provided unequivocal evidence for a strong genetic
      component accounting for between 30% and 50% of the variation in worm burden.
      Shared environmental (i.e., common household) effects account for between 3% and
      13% of the total phenotypic variance.

PMID- 10403322
TI  - Evidence for a long-term effect of a single dose of praziquantel on Schistosoma
      mansoni-induced hepatosplenic lesions in northern Uganda.
AB  - Treatment with praziquantel reduces the prevalence and intensity of Schistosoma
      mansoni infection. However, reversibility of periportal fibrosis of the liver,
      which potentially leads to fatal complications, is not unequivocally
      substantiated. In the Nile District of Uganda, 460 patients were
      parasitologically (Kato-Katz method) and ultrasonographically examined during
      October 1991, October 1992, and May 1994. Treatment with praziquantel at a dosage
      of 40 mg per kilogram of body weight was given in October 1991 and October 1992
      to 460 individuals (group A). Another 192 patients were seen during the baseline
      study in October 1991 and missed the follow-up in October 1992 but took part in
      the second follow-up in May 1994. Thus, they received praziquantel only once in
      October 1991 (group B) and had an interval of 2.7 years until the next
      investigation in May 1994. Periportal thickening (PT) of the liver was assessed
      by ultrasound at each time point. Praziquantel therapy reduced the prevalence of
      S. mansoni in group A from 84% in 1991 to 31% in 1992 and 30% in 1994. The
      respective intensities of infection (geometric means of egg output) were 81 eggs
      per gram (epg) of stool in 1991, 31 epg in 1992, and 30 epg in 1994. Periportal
      thickening was found in 46% of patients in 1991, 32% of patients in 1992, and 35%
      of patients in 1994. Reversibility of PT was influenced by age (markedly lower
      reversibility in individuals older than 30 years) and sex (women and girls
      responded less favorably than did men and boys). Surprisingly, no significant
      difference was detected between group A and group B with respect to reversibility
      of PT The outcome between the 2 groups did not differ significantly. This may
      indicate that a single dose of praziquantel (as given to group B) may have a
      longer lasting effect than previously thought, that is, more than 2.5 years.

PMID- 10403323
TI  - Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated
      from Egyptian villagers.
AB  - Recent evidence suggest that resistance to praziquantel (PZQ) may be developing.
      This would not be surprising in countries like Egypt where the drug has been used
      aggressively for more that 10 years. The classic phenotype of drug resistance is
      a significant increase in the 50% effective dose value of isolates retrieved from
      patients not responding to the drug. In a previous publication, we reported that
      such phenotypes have been isolated from humans infected with Schistosoma mansoni.
      Since the action of PZQ may be dependent upon the drug and host factors, most
      notably the immune system, we analyzed the quantitative effects of PZQ on single
      worms that differed in their response to PZQ when maintained in mice. Our
      hypothesis was that the in vitro action of the drug would correlate with it in
      vivo action. We confirmed this hypothesis and conclude that the in vitro action
      of the drug is related to its in vivo action. Knowing this relationship will
      assist in our ability to detect or survey for the PZQ resistant phenotype in
      human populations.

PMID- 10403324
TI  - Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug
      resistant Plasmodium falciparum malaria.
AB  - The new oral fixed combination artemether-lumefantrine (CGP 56697) has proved to
      be an effective and well-tolerated treatment of multi-drug resistant Plasmodium
      falciparum malaria, although cure rates using the four-dose regimen have been
      lower than with the currently recommended alternative of artesunate-mefloquine.
      Two six-dose schedules (total adult dose = 480 mg of artemether and 2,880 mg of
      lumefantrine) were therefore compared with the previously used four-dose regimen
      (320 mg of artemether and 1,920 mg of lumefantrine) in a double-blind trial
      involving 359 patients with uncomplicated multidrug-resistant falciparum malaria.
      There were no differences between the three treatment groups in parasite and
      fever clearance times, and reported adverse effects. The two six-dose regimens
      gave adjusted 28-day cure rates of 96.9% and 99.12%, respectively, compared with
      83.3% for the four-dose regimen (P < 0.001). These six-dose regimens of
      artemether-lumefantrine provide a highly effective and very well-tolerated
      treatment for multidrug-resistant falciparum malaria.

PMID- 10403325
TI  - The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in
      vitro activity against Plasmodium falciparum and a non-antifolate mode of action
      of the prodrug.
AB  - We have studied the reversal of activity against Plasmodium falciparum of
      WR99210, a triazine antimalarial drug, and of the pro-drug PS-15 by folic acid
      (FA) and folinic acid (FNA). Folic acid and FNA inhibit the growth of P.
      falciparum in vitro at concentrations > 10(-4.5) and 10(-3.5) mol/L,
      respectively. The activity of pyrimethamine against Kenyan strains M24 and K39 is
      reduced 10-12-fold by 10(-5) mol/L of FA, and virtually eliminated by 10(-5)
      mol/L of FNA. Folates do not antagonise the action of WR99210 against Kenyan
      strains, and only partially antagonize the action of WR99210 action against the
      Southeast Asian strains V1/S and W282. Similarly, FA and FNA exerted weak or no
      antagonism of the action of PS-15. The inability of folates to antagonize the
      action of WR99210 can be explained in terms of high drug-enzyme affinity, but
      this does not account for the inability of FA and FNA to antagonize PS-15. These
      results suggest that action of PS-15 against P. falciparum is primarily due to a
      non-folate mechanism.

PMID- 10403326
TI  - Detection of specific antibodies to Plasmodium falciparum in blood bank donors
      from malaria-endemic and non-endemic areas of Venezuela.
AB  - Malaria antibody detection is valuable in providing retrospective confirmation of
      an attack of malaria. Blood bank screening is another area were malaria serology
      is potentially useful. In the present study, we tested the presence of antibodies
      to Plasmodium falciparum in sera from blood bank donors of non-endemic and
      malaria-endemic areas of Venezuela. Sera from 1,000 blood donors were tested by
      an indirect immunofluorescent antibody (IFA) assay and an IgG-ELISA for the
      presence of malaria antibodies using a synchronized in vitro-cultured Venezuelan
      isolate of P. falciparum as the antigen source. A selected group of positive and
      negative sera (n = 100) was also tested by a dot-IgG-ELISA. Positive results
      (reciprocal titer > or = 40) were found in 0.8% and 3.8% of blood donors when
      tested by the IFA assay and in 0.8% and 2% (optical density > or = 0.2) when
      tested by the IgG-ELISA in Caracas (non-endemic area) and Bolivar City (endemic
      area), respectively. The presence of anti-malarial antibodies in some sera from
      non-endemic areas such as Caracas reflects the increased potential risk of post
      transfusional malaria in those areas due to the mobility of the blood donors. The
      data obtained indicate the need to implement new blood donor policy in blood
      banks in developing areas. Our results also indicate that the IFA assay is the
      most reliable test to use in malaria serodiagnosis.

PMID- 10403327
TI  - Hepatosplenic morbidity in schistosomiasis japonica: evaluation with Doppler
      sonography.
AB  - In Southeast Asia, schistosomiasis japonica is an important cause of hepatic
      fibrosis and gastrointestinal hemorrhage. Reliable methods to investigate portal
      hypertension (PHT) clinically and epidemiologically on community level are
      lacking. Doppler sonography is an established tool for investigating PHT in
      hospital settings. In Leyte, The Philippines, 137 individuals underwent color
      Doppler sonography, stool examination, and serology for hepatitis B and C, liver
      cell injury and cholestasis. A total of 85% of the study population had been
      infected with Schistosoma japonicum. Sonographically, periportal liver fibrosis
      was seen in 25% and reticular echogenicities (network pattern) in 44%. Portal
      blood flow was decreased or portosystemic collaterals were present in 10% (adults
      throughout) and correlated with periportal fibrosis, but not with network
      lesions. Chronic viral hepatitis was rare. Thus, hepatic lesions are frequent in
      adults but not in children in areas endemic for S. japonicum. Periportal liver
      fibrosis indicates a risk of PHT, and network pattern fibrosis apparently does
      not. Doppler sonography is suitable for research under tropical field conditions.

PMID- 10403328
TI  - Application of immunodiagnostic assays: detection of antibodies and circulating
      antigens in human schistosomiasis and correlation with clinical findings.
AB  - In an initial cross-sectional survey, serum, urine, and stool samples were
      collected from 370 participants representing about 10% of the population (n =
      4,438) in Behbeet village, 50 km south of Cairo, Egypt, an area well known to be
      endemic solely for Schistosoma haematobium. Diagnosis was approached in two
      parallel ways. The first approach, which simulated actual conditions in many
      endemic areas in Egypt, was based on physical examination and urine and stool
      microscopic analysis. The second approach was based on two advanced
      immunodiagnostic assay systems. One system detected antibodies to species
      specific microsomal antigens, the other detected circulating schistosomal
      antigens. Microsomal antigens from S. haematobium and S. mansoni were used to
      detect antibodies in the Falcon assay screening test (FAST)-ELISA and the enzyme
      linked immunoelectrotransfer blot (EITB). Circulating anodic antigen (CAA) and
      circulating cathodic antigen (CCA) were quantified in serum and urine samples in
      a sandwich ELISA using monoclonal antibodies. Parasitologically, the prevalence
      of S. haematobium was 7.01% in females and 25.82% in males, giving an overall
      prevalence of 15.8%. The combination of urine CCA and serum CAA for detecting
      circulating antigens and the combination of the S. haematobium adult worm
      microsomal antigens (HAMA) FAST-ELISA and the HAMA EITB for detecting antibodies
      significantly improved the sensitivity of detecting S. haematobium circulating
      antigens and antibodies. Also, including a medical examination as an integral
      part of field studies and correlating immunodiagnostic results with other
      clinical and investigational data allowed us to calculate an accurate estimation
      of S. haematobium prevalence in this area of low endemicity.

PMID- 10403329
TI  - Fluctuations of larval excretion in Strongyloides stercoralis infection.
AB  - Follow-up stool examinations were carried out on two groups of the subjects who
      were screened negative (group 1) or positive (group 2) for Strongyloides
      stercoralis by the agar plate culture. This technique could detect S. stercoralis
      larvae in 87.5-96.4% of the subjects in group 2 and 0-5.9% of the subjects in
      group 1 on various days of the eight-week and four-week follow-up periods,
      respectively. The detection rate on each day of examination was not statistically
      different from that on the first day in both groups. Quantitative measurement of
      S. stercoralis larvae excreted in the feces of the subjects in group 2 by the
      standard direct smear method of Beaver and others revealed slight to marked
      fluctuations of the larval output in individual subjects. From the results of
      both stool examination methods, it could be implied that 52% of S. stercoralis
      infected individuals had low-level infection.

PMID- 10403330
TI  - Induction of histamine release in parasitized individuals by somatic and
      cuticular antigens from Onchocerca volvulus.
AB  - The host immune response in onchocerciasis is believed to contribute to the
      clinical manifestations of infection. Mazzotti and chronic inflammatory reactions
      might be mediated by mechanisms involving specific IgE and reactivity of mast
      cells and basophils to the parasite antigens. In this report, we show that
      Onchocerca volvulus antigens are capable of inducing histamine release. Three
      types of extracts were prepared from the parasite: soluble total, surface, and
      cuticular collagen. Soluble extracts released histamine in all individuals with
      onchocerciasis at significantly higher levels (P < 0.05) than those found in
      endemic controls, but similar levels to those found in patients with
      mansonellosis. However, cuticular collagen induced significantly (P < 0.01)
      higher histamine release in patients with onchocerciasis than in those with
      mansonellosis. No reactivity against human type IV collagen was observed.
      Implications derived from the presence of sensitized basophils in the
      pathogenesis of onchocerciasis are discussed.

PMID- 10403331
TI  - Analysis of renal function in onchocerciasis patients before and after therapy.
AB  - The occurrence of renal abnormalities was investigated in patients with
      onchocerciasis in comparison to individuals without onchocerciasis in Guinea.
      Serum creatinine levels, excretion of urinary marker proteins, and kidney size by
      ultrasound were determined. A high prevalence of glomerular as well as tubular
      dysfunctions was observed; however, no association with onchocerciasis could be
      detected. We also hypothesized that patients with hyperreactive onchocerciasis
      might be prone to develop immune-mediated glomerular disorders; however, this
      could not be verified. Following treatment with ivermectin, a slight but
      significant increase in the excretion of urinary albumin and alpha1-microglobulin
      was seen five days after treatment in all treated patients, whereas levels of
      proteinuria were significantly higher five days after treatment only in patients
      with high microfilarial densities. Our results indicate that ivermectin can cause
      glomerular and tubular disturbances in patients with onchocerciasis; however,
      these are minor and do not seem to be clinically relevant.

PMID- 10403332
TI  - A simian model of human granulocytic ehrlichiosis.
AB  - Following intravenous inoculation with horse blood-infected with the agent of
      human granulocytic ehrlichiosis (HGE) from a human fatality, two rhesus macaques
      (Macaca mulatta) exhibited pyrexia and lethargy on days 4-12 postinfection (PI).
      Hematology revealed neutropenia, thrombocytopenia, and anemia, with ehrlichial
      morulae in monocytes and neutrophils on days 4-12. Blood was polymerase chain
      reaction (PCR)-positive on days 4-12 and bone marrow was PCR-positive on day 11.
      There was a minor increase in gamma-glutamyl transpeptidase on day 12 and serum
      interferon-gamma levels increased by day 18. Seroconversion occurred on day 20 PI
      to a titer of 100 by day 22. Western blot bands characteristic of HGE included 25
      , 44-, 80-, 94-, 105-, and 125-kD bands. There was generalized lymphohistiocytic
      infiltration in the liver, spleen, lymph nodes, and other tissues. The liver had
      focal hepatocyte apoptosis. There was HGE DNA (by PCR) only in the spleen.
      Comparable findings were not observed in a monkey that received uninfected horse
      blood as a control. This animal model of human disease is important for further
      studies of HGE diagnosis, management, and pathogenesis.

PMID- 10403333
TI  - Cloning and characterization of the merozoite surface antigen 1 gene of
      Plasmodium berghei.
AB  - Merozoite surface antigen 1 (MSA1) is a promising candidate for vaccine
      development against malaria parasites. Here, we report the complete nucleotide
      sequence of the gene encoding the precursor to this major surface antigen of
      Plasmodium berghei strain ANKA using cDNA library screening and polymerase chain
      reaction techniques. A single open reading frame of 5,376 basepairs encoding a
      protein with a calculated molecular mass of 197 kD was defined. The protein
      contains a putative signal peptide of 19 amino acids, a membrane anchor sequence
      of 18 residues, and shows two epidermal growth factor-like domains rich in Cys
      residues at the C-terminus. There are four repeat sequences of oligopeptides in
      the molecule: tetrapeptide (Ser-Thr-Thr-Thr), tripeptide (Pro-Thr-Pro and Pro-Ala
      Ala), and dipeptide (Ser-Gly). Furthermore, three nine-residue stretches of a
      motif (Ala-Ser-Asn-Pro-Gly-Ala-Ser-Ala-Ser) are located near each other. All of
      these repeat sequences are unexceptionally located in the variable regions when
      compared with other MSA1 molecules. The molecule displays 79% overall identity to
      the analogous antigen of P. yoelii yoelii strain YM, 70% to that of P. chabaudi
      chabaudi strain AS, and 38% to that of P. falciparum strain Wellcome.

PMID- 10403334
TI  - High amounts of genetic differentiation between populations of the malaria vector
      Anopheles arabiensis from West Africa and eastern outer islands.
AB  - Polymorphism at nine microsatellite loci was examined to assess the level of
      genetic differentiation between four Anopheles arabiensis populations from
      Senegal, the high plateau of Madagascar, and Reunion and Mauritius islands. Eight
      of nine loci showed great polymorphism (2-16 alleles/locus) and significant
      genetic differentiation was revealed between all four populations by F- and R
      statistics, with Fst estimates ranging from 0.080 to 0.215 and equivalent Rst
      values ranging between 0.022 and 0.300. These high amounts of genetic
      differentiation are discussed in relation to geographic distance including large
      bodies of water, and history of mosquito settlement, and insecticide use on the
      islands. The results suggest that historical events of drift rather than mutation
      are probably the forces generating genetic divergence between these populations,
      with homogenization of the gene pool by migration being drastically restricted
      across the ocean.

PMID- 10403335
TI  - Population structure and genetic divergence in Anopheles nuneztovari (Diptera:
      Culicidae) from Brazil and Colombia.
AB  - Anopheles nuneztovari is considered an important vector of human malaria in
      several localities in Venezuela and Colombia. Its status as a vector of human
      malaria is still unresolved in areas of the Brazilian Amazon, in spite of have
      been found infected with Plasmodium sp.. For a better understanding of the
      genetic differentiation of populations of A. nuneztovari, electrophoretic
      analysis using 11 enzymes was performed on four populations from Brazil and two
      from Colombia. The results showed a strong differentiation for two loci: alpha
      glycerophosphate dehydrogenase (alpha-Gpd) and malate dehydrogenase (Mdh) from 16
      loci analyzed. Diagnostic loci were not detected. The populations of A.
      nuneztovari from the Brazilian Amazon showed little genetic structure and low
      geographic differentiation, based on the F(IS) (0.029), F(ST) (0.070), and
      genetic distance (0.001-0.032) values. The results of the isozyme analysis do not
      coincide with the indication of two lineages in the Amazon Basin by analysis of
      mitochondrial DNA, suggesting that this evolutionary event is recent. The mean
      F(ST) value (0.324) suggests that there is considerable genetic divergence among
      populations from the Brazilian Amazon and Colombia. The genetic distance among
      populations from the Brazilian Amazon and Colombia is ranges from 0.047 to 0.148,
      with the highest values between the Brazilian Amazon and Sitronela (SIT) (0.125
      0.148). These results are consistent with those observed among members of
      anopheline species complexes. It is suggested that geographic isolation has
      reduced the gene flow, resulting in the genetic divergence of the SIT population.
      Dendrogram analysis showed three large groups: one Amazonian and two Colombia,
      indicating some genetic structuring. The present study is important because it
      attempted to clarify the taxonomic status of A. nuneztovari and provide a better
      understanding of the role of this mosquito in transmission of human malaria in
      northern South America.

PMID- 10403336
TI  - Risk factors for gametocyte carriage in uncomplicated falciparum malaria.
AB  - The factors affecting the development of patent Plasmodium falciparum
      gametocytemia were assessed in 5,682 patients entered prospectively into a series
      of antimalarial drug trials conducted in an area of low and seasonal transmission
      on the western border of Thailand. Of the 4,565 patients with admission thick
      smear assessments, 110 (2.4%) had gametocytemia. During the follow-up period 170
      (3%) of all patients developed patent gametocytemia, which in 89% had developed
      by day 14 following treatment. In a multiple logistic regression model five
      factors were found to be independent risk factors at presentation for the
      development or persistence of gametocytemia during follow up; patent
      gametocytemia on admission (adjusted odds ratio [AOR] = 7.8, 95% confidence
      interval [CI] = 3.7-16, P < 0.001), anemia (hematocrit <30%) (AOR = 3.9, 95% CI =
      2.3-6.5, P < 0.001), no coincident P. vivax malaria (AOR = 3.5, 95% CI = 1.04
      11.5, P < 0.04), presentation with a recrudescent infection (AOR = 2.3, 95% CI =
      1.3-4.1, P < 0.004), and a history of illness longer than two days (AOR = 3.3,
      95% CI = 1.7-6.6, P < 0.001). Patients whose infections responded slowly to
      treatment or recrudesced subsequently were also more likely to carry gametocytes
      than those who responded rapidly or were cured (relative risks = 1.9, 95% CI =
      1.3-2.7 and 2.8, 95% CI = 2.0-4.0, respectively; P < 0.001). These data provide
      further evidence of important epidemiologic interactions between P. falciparum
      and P. vivax, and drug resistance and transmission potential.

PMID- 10403337
TI  - Does the availability of blood slide microscopy for malaria at health centers
      improve the management of persons with fever in Zambia?
AB  - Some Ministries of Health in Africa plan to make blood slide microscopy available
      in peripheral health centers to improve malaria diagnosis over the current
      practice, which relies solely on clinical findings. To assess whether microscopy
      improves the management of febrile persons in health centers, we prospectively
      reviewed medical records of all outpatients visiting six health centers with
      laboratories in Zambia during a 2-3-day period. Staff interviews and a blinded
      review of a series of blood slides from each facility by two expert microscopists
      were also conducted. Of 1,442 outpatients, 655 (45%) reported fevers or had a
      temperature > or = 37.5 degrees C. Blood slide microscopy was ordered in 28-93%
      of patients with fever (mean = 46%). Eighty-eight (35%) patients without
      parasitemia were prescribed an antimalarial drug. Antimalarial drugs were
      prescribed with equal frequency to those who were referred for a blood slide
      (56%) and those not referred (58%). The sensitivity of microscopy was 88% and the
      specificity was 91%. Use of malaria microscopy varied widely, indicating that
      clinicians are not using standard criteria for ordering this test. Although
      diagnosis by microscopy was generally accurate, it appeared to have had little
      impact on the treatment of persons with fever. Guidelines for using blood slide
      microscopy are needed and prescription of antimalarial drugs should be
      discouraged when slide results are negative.

PMID- 10403338
TI  - Prevalence and immune response to Entamoeba histolytica infection in preschool
      children in Bangladesh.
AB  - Entamoeba histolytica infection was present in 5% and E. dispar in 13% of
      asymptomatic 2-5-year-old children from an urban slum of Dhaka, Bangladesh.
      Entamoeba dispar-infected children were no more likely than uninfected children
      to have serum antibodies to lectin. In contrast, all children infected with E.
      histolytica had serum antibodies to lectin. This anti-lectin response included
      antibodies against the carbohydrate recognition domain, which have been
      demonstrated in animal models to confer passive protection from amebiasis.
      Antibodies to lectin persisted in the sera of 17 children with E. histolytica
      infection over one year of follow-up, during which time E. histolytica infection
      cleared without treatment in 15, and with anti-amebic medication in two. We
      conclude that half of the children in this population have serologic evidence of
      amebiasis by five years of age, and that an anti-lectin serum antibody response
      is associated with limitation of E. histolytica infection to the colon.

PMID- 10403339
TI  - Establishing a laboratory for surveillance of invasive bacterial infections in a
      tertiary care government hospital in a rural province in the Philippines.
AB  - A clinical bacteriologic laboratory was established in a tertiary care government
      hospital in The Philippines, where expert bacteriologic laboratories do not
      usually exist at this level of health care. The laboratory was jointly
      established by the Research Institute for Tropical Medicine (RITM) (Manila, The
      Philippines) and the National Public Health Institute (KTL) (Helsinki, Finland).
      The laboratory was planned, its personnel were trained, and its functioning was
      continuously supported by the RITM and KTL. The following aspects were of utmost
      importance in establishing the laboratory and launching its work: 1) the support
      of the RITM bacteriologic laboratory, with back-up and consultations from KTL; 2)
      creation and maintenance of personal contacts between clinicians and laboratory
      staff with an emphasis on clinical relevance and rapid reporting of laboratory
      results; 3) the consideration of the quality aspects of the work from the start;
      and 4) keen follow-up of the bacteriologic results and their clinical
      significance and use, of practical laboratory work, and of quality assurance
      aspects. In the first two years of its operation, the laboratory identified
      Streptococcus pneumoniae and Haemophilus influenzae as the most important causes
      of severe pneumonia, sepsis or meningitis in children less than two years of age,
      and Salmonella typhi as the most frequent significant isolate from the blood
      cultures, being found most often in school age children and young adults.

PMID- 10403340
TI  - Limited potential for mosquito transmission of genetically engineered, live
      attenuated Venezuelan equine encephalitis virus vaccine candidates.
AB  - In an attempt to improve the current live-attenuated vaccine (TC-83) for
      Venezuelan equine encephalitis (VEE), specific mutations associated with
      attenuation of VEE virus in rodent models were identified. These mutations were
      inserted into full-length cDNA clones of the Trinidad donkey strain of VEE virus
      by site-directed mutagenesis, and isogenic virus strains with these mutations
      were recovered after transfection of baby hamster kidney cells with infectious
      RNA. We evaluated 10 of these strains for their ability to replicate in and be
      transmitted by Aedes taeniorhynchus, a natural vector of epizootic VEE virus. Two
      vaccine candidates, one containing a deletion of the PE2 furin cleavage site, the
      other a combination of three separate point mutations in the E2 glycoprotein,
      replicated in mosquitoes and were transmitted to hamsters significantly less
      efficiently than was either parental (wild type) VEE virus or TC-83 virus.
      Although the attenuated strains were transmitted to hamsters by mosquitoes, after
      intrathoracic inoculation, there was no evidence of reversion to a virulent
      phenotype. The mutations that resulted in less efficient replication in, or
      transmission by, mosquitoes should enhance vaccine safety and reduce the
      possibility of environmental spread to unintentional hosts.

PMID- 10403341
TI  - Comparison of the immunogenicity and safety of two 17D yellow fever vaccines.
AB  - As part of the clinical validation process of a new working seed of a licensed
      yellow fever vaccine (new working seed PV26, Stamaril; Pasteur Merieux Connaught,
      Lyon, France), the immunogenicity and safety of two batches of this vaccine (PM
      YF) were compared with those of another commercially available vaccine (Arilvax;
      Evans Medical-Wellcome, Liverpool, United Kingdom) in 211 healthy adults. While
      the geometric mean titer values at days 10-14 and day 28 after vaccination were
      higher in the PM-YF group, the vaccines provided equivalent seroprotection
      (titers > or = 1/10) one month after a single vaccine dose (100% PM-YF versus 99%
      W-YF; P = 0.001, by one-sided equivalence test). Both vaccines were safe. There
      were no serious local or systemic reactions reported, nor any clinically
      significant hepatic function abnormalities associated with the use of either
      vaccine. These two 17D yellow fever vaccines from different European vaccine
      manufacturers were highly immunogenic and safe, and provided equivalent
      seroprotection.

PMID- 10403342
TI  - First do no harm: making oral rehydration solution safer in a cholera epidemic.
AB  - Oral rehydration solution (ORS) is lifesaving therapy for cholera and pediatric
      diarrhea. During a cholera epidemic in Guinea-Bissau, we evaluated the
      microbiologic quality of ORS prepared at a hospital and tested a simple
      intervention using special vessels for disinfecting tap water with bleach and for
      preparing, storing, and dispensing ORS. Few coliform bacteria and Escherichia
      coli were recovered from tap water; however, pre-intervention ORS contained
      numerous bacteria including E. coli and toxigenic Vibrio cholerae O1. In
      contrast, ORS samples from intervention vessels had few or no coliform bacteria,
      no E. coli, and no V. cholerae. Mean pre-intervention counts of coliform bacteria
      (3.4 x 10(7) colony-forming units [cfu]/100 ml) and E. coli (6.2 x 10(3) cfu)
      decreased significantly during the intervention period to 3.6 x 10(2) cfu and 0
      cfu, respectively (P < 0.001). This simple system using bleach disinfectant and
      special storage vessels prevents bacterial contamination of ORS and reduces the
      risk of nosocomial transmission of cholera and other enteric pathogens.

PMID- 10403343
TI  - Prevention of cerebral malaria in children in Papua New Guinea by southeast Asian
      ovalocytosis band 3.
AB  - Southeast Asian ovalocytosis (SAO) occurs at high frequency in malarious regions
      of the western Pacific and may afford a survival advantage against malaria. It is
      caused by a deletion of the erythrocyte membrane band 3 gene and the band 3
      protein mediates the cytoadherence of parasitized erythrocytes in vitro. The SAO
      band 3 variant may prevent cerebral malaria but it exacerbates malaria anemia and
      may also increase acidosis, a major determinant of mortality in malaria. We
      undertook a case-control study of children admitted to hospital in a malarious
      region of Papua New Guinea. The SAO band 3, detected by the polymerase chain
      reaction, was present in 0 of 68 children with cerebral malaria compared with six
      (8.8%) of 68 matched community controls (odds ratio = 0, 95% confidence interval
      = 0-0.85). Median hemoglobin levels were 1.2 g/dl lower in malaria cases with SAO
      than in controls (P = 0.035) but acidosis was not affected. The remarkable
      protection that SAO band 3 affords against cerebral malaria may offer a valuable
      approach to a better understanding of the mechanisms of adherence of parasitized
      erythrocytes to vascular endothelium, and thus of the pathogenesis of cerebral
      malaria.

PMID- 10403344
TI  - Short report: prevention of Schistosoma mansoni infections in mice by the insect
      repellents AI3-37220 and N,N-diethyl-3-methylbenzamide.
AB  - N,N-diethyl-3-methylbenzamide (DEET) has recently been reported to kill cercariae
      of Schistosoma mansoni in vitro. In addition, it blocked cercarial entry into
      mouse tail skin. We confirmed these results and compared the efficacy of DEET to
      a second insect repellent, 1-(3-Cyclohexen-1-yl-carbonyl)-2-methylpiperidine (AI3
      37220), in preventing S. mansoni infections in mice. Both AI3-37220 and DEET
      conferred 100% protection against S. mansoni infection via percutaneous exposure
      to cercariae.

PMID- 10403345
TI  - Assessing continuing medical education.

PMID- 10403347
TI  - Factors associated with unplanned hospital readmission among patients 65 years of
      age and older in a Medicare managed care plan.
AB  - PURPOSE: Unplanned hospital readmission within 30 days of discharge is considered
      a "sentinel event" for poor quality. Patients at high risk for this adverse event
      could be targeted for interventions designed to reduce their risk of readmission.
      The purpose of this study was to identify patient characteristics and risk
      factors at discharge associated with unplanned readmission within 30 days of
      hospital discharge. SUBJECTS AND METHODS: We performed a matched case-control
      study among patients in a Medicare managed care plan who had been admitted to an
      academic hospital. The cases were patients aged 65 years or older who were
      urgently or emergently readmitted to the hospital within 30 days of discharge.
      One control patient who was not readmitted within 30 days was matched to each
      case by principal diagnosis. The medical records of the first admission of the
      cases and the admission of the controls underwent review (blinded to case-control
      status) to determine the patient's baseline demographic characteristics, comorbid
      conditions, previous health care utilization, and functional status. The records
      were also reviewed to assess risk factors on discharge, including clinical
      instability, inability to ambulate and feed, mental status changes, number of
      discharge medications, and discharge disposition. RESULTS: Five factors were
      independently associated (P < 0.05) with unplanned readmission within 30 days.
      These included four baseline patient characteristics: age 80 years or older [odds
      ratio = 1.8; 95% confidence interval (CI), 1.02-3.2], previous admission within
      30 days (odds ratio = 2.3; 95% CI, 1.2-4.6), five or more medical comorbidities
      (odds ratio = 2.6; 95% CI, 1.5-4.7), and history of depression (odds ratio = 3.2;
      95% CI, 1.4-7.9); and one discharge factor: lack of documented patient or family
      education (odds ratio = 2.3; 95% CI, 1.2-4.5). CONCLUSIONS: If validated, these
      factors may identify patients at high risk of readmission. They suggest that
      interventions, such as improved discharge education programs, may reduce
      unplanned readmission.

PMID- 10403346
TI  - Variation in length of hospital stay in patients with community-acquired
      pneumonia: are shorter stays associated with worse medical outcomes?
AB  - PURPOSE: To assess the variation in length of stay for patients hospitalized with
      community-acquired pneumonia and to determine whether patients who are treated in
      hospitals with shorter mean stays have worse medical outcomes. SUBJECTS AND
      METHODS: We prospectively studied a cohort of 1,188 adult patients with community
      acquired pneumonia who had been admitted to one community and three university
      teaching hospitals. We compared patients' mean length of stay, mortality,
      hospital readmission, return to usual activities, return to work, and pneumonia
      related symptoms among the four study hospitals. All outcomes were adjusted for
      baseline differences in severity of illness and comorbidity. RESULTS: Adjusted
      interhospital differences in mean length of stay ranged from 0.9 to 2.3 days (P
      <0.001). When the risk of each medical outcome was compared between patients
      admitted to the hospital with the shortest length of stay and those admitted to
      longer stay hospitals, there were no differences in mortality [relative risk (RR)
      = 0.7; 95% CI, 0.3 to 1.7], hospital readmission (RR = 0.8; 95% CI, 0.5 to 1.2),
      return to usual activities (RR = 1.1; 95% CI, 0.9 to 1.3), or return to work (RR
      = 1.2; 95% CI, 0.8 to 2.0) during the first 14 days after discharge, or in the
      mean number of pneumonia-related symptoms 30 days after admission (P = 0.54).
      CONCLUSIONS: We observed substantial interhospital variation in the lengths of
      stay for patients hospitalized with community-acquired pneumonia. The finding
      that medical outcomes were similar in patients admitted to the hospital with the
      shortest length of stay and those admitted to hospitals with longer mean lengths
      of stay suggests that hospitals with longer stays may be able to reduce the mean
      duration of hospitalization for this disease without adversely affecting patient
      outcomes.

PMID- 10403348
TI  - Low incidence of cardiac abnormalities in treated trichinosis: a prospective
      study of 62 patients from a single-source outbreak.
AB  - PURPOSE: The reported incidence of cardiac involvement in trichinosis is highly
      variable, ranging from 21% to 75%. This study sought to determine the incidence
      and type of cardiac lesions in trichinosis using serial echocardiographic
      examinations. SUBJECTS AND METHODS: Sixty-two consecutive patients admitted to
      the Banja Luka Medical Center during an outbreak of trichinosis (November to
      December 1996) were included in the study. Diagnosis was made by typical clinical
      presentation, positive epidemiologic history, serologic testing, and the
      detection of Trichinella larvae in contaminated meat. All patients underwent
      serial electrocardiograms and two-dimensional and Doppler echocardiographic
      examinations within 20 days after the onset of symptoms. Repeated
      echocardiographic examinations were performed weekly during the hospital stay in
      all patients with electrocardiographic abnormalities or an abnormal initial
      echocardiogram. RESULTS: Cardiac involvement (electrocardiographic and/or
      echocardiographic changes) was detected in 8 (13%) of the 62 patients.
      Nonspecific transient electrocardiographic ST-T changes were found in 6 patients
      (10%); 1 patient had frequent premature ventricular complexes. Echocardiographic
      examinations revealed pericardial effusions in 6 patients (10%), 5 of whom had
      minimal effusions without impairment of global and regional left ventricular
      systolic function. One patient had hypokinesis of the interventricular septum
      with a small pericardial effusion, both of which resolved within 2 weeks. Only 2
      of the patients with electrocardiographic abnormalities lacked echocardiographic
      evidence of cardiac involvement. At 6-month follow-up, none of the patients had
      electrocardiographic or echocardiographic abnormalities. CONCLUSIONS: The
      incidence of cardiac involvement in trichinosis appears to be lower than
      previously reported. Pericardial effusion is the most common manifestation of
      cardiac involvement, and nonspecific transient electrocardiographic changes,
      traditionally ascribed to myocarditis, more frequently reflect pericarditis.

PMID- 10403349
TI  - Upper and lower gastrointestinal evaluation of elderly inpatients who are iron
      deficient.
AB  - PURPOSE: Iron deficiency anemia is commonly caused by chronic gastrointestinal
      blood loss, and a thorough examination of the gastrointestinal tract has become
      standard practice. In contrast, iron deficiency without anemia has hardly been
      studied, and its causes are less certain. The aim of the present study was to
      determine the diagnostic value of upper and lower gastrointestinal evaluation in
      elderly hospitalized patients with iron deficiency, irrespective of the
      hemoglobin level. PATIENTS AND METHODS: In a prospective study, 151 consecutive
      elderly patients with iron deficiency (serum ferritin level < 50 microg/L at two
      separate occasions) were investigated using esophagogastroduodenoscopy with
      colonoscopy (n = 90) or barium enema (n = 61). RESULTS: A potential upper
      gastrointestinal tract lesion was found in 47 (49%) of the 96 anemic patients and
      in 31 (56%) of the 55 nonanemic patients (P = 0.38). Nonanemic patients had a
      greater prevalence of erosive gastritis or duodenitis. Anemic patients (72%) were
      more frequently investigated with a colonoscopy than nonanemic patients (38%, P =
      0.001), and a lower gastrointestinal lesion was found in 32% of the anemic
      patients and 16% of the nonanemic patients (P = 0.03). Cancer was the most common
      lesion in the colon; 11 of the 18 patients were asymptomatic. Site-specific
      symptoms, fecal occult blood loss, and the use of nonsteroidal anti-inflammatory
      drugs (NSAIDs) were not associated with the detection of gastrointestinal
      lesions. In 9.5% of the patients with a benign upper gastrointestinal lesion, a
      synchronous colonic tumor was found. CONCLUSION: Elderly patients with iron
      deficiency should undergo endoscopic examination, irrespective of the hemoglobin
      level. The presence of gastrointestinal symptoms, a positive fecal occult blood
      test, and the use of NSAIDs are of limited value in guiding the diagnostic
      procedure.

PMID- 10403350
TI  - Population-based screening for hemochromatosis using phenotypic and DNA testing
      among employees of health maintenance organizations in Springfield, Missouri.
AB  - BACKGROUND: Hemochromatosis reportedly affects 3 to 8 persons per 1,000 and is
      associated with an elevated risk of morbidity and mortality. We sought to
      ascertain its prevalence in a community and to assess the association between
      phenotype and genotype. METHODS: All health maintenance organization employees
      were invited to participate in hemochromatosis screening using a repeated
      elevation of the transferrin saturation test as the case definition (> or = 50%
      in women and > or = 60% in men with no other cause). Iron overload from
      hemochromatosis was defined as serum ferritin concentration > or = 95th
      percentile and mobilizable iron > or = 99th percentile for age and sex, or
      hepatic iron index > or = 1.9. The HFE gene was analyzed for mutations. RESULTS:
      Participation among employees was 28% (1,653 of 6,000); 83% were women. The
      prevalence of hemochromatosis was 8 per 1,000 (13 of 1,653), and the prevalence
      of iron overload from hemochromatosis was 4 per 1,000 (5 of 1,653). Compared with
      those who had no HFE mutation, the relative risk (RR) for hemochromatosis was
      greatest for C282Y homozygotes (RR = 147), compound heterozygotes (RR = 19), and
      H63D homozygotes (RR = 9). Overall, 38% of participants had at least one HFE
      mutation. Screening based on an initial elevated transferrin saturation test had
      the best sensitivity, whereas DNA testing offered the best specificity and
      predictive value positive for iron overload disease. CONCLUSIONS: In this
      population, we found a greater than expected prevalence of hemochromatosis and
      demonstrated a clear association with the HFE genotype. Promotion of screening is
      complicated by controversies in case definition and the large number of persons
      who will be detected before they have clinically significant iron loading, in
      whom the risk of clinical disease is unknown. Larger screening studies in more
      diverse populations are necessary to characterize the burden of disease and to
      follow those at risk (based on HFE or iron status measures) to establish the
      natural history of hemochromatosis.

PMID- 10403351
TI  - Does a year make a difference? Changes in physician satisfaction and perception
      in an increasingly capitated environment.
AB  - BACKGROUND: Although capitation has become an increasingly common method of
      payment for heath care, little is known about changes in physician satisfaction
      as they become more experienced working in a capitated environment. METHODS: We
      surveyed the members of a physician hospital organization at an urban teaching
      hospital in the summers of 1996 and 1997. In 1996, fully capitated contracts
      covered <5% of patients under 65 years of age, but that figure increased to
      nearly 25% by 1997. We assessed physicians' satisfaction with their practice,
      compared satisfaction under fee-for-service and capitated payment, and evaluated
      ethical issues related to capitation. RESULTS: In 1996, we surveyed 587
      physicians with direct patient care responsibilities, of whom 62% responded; 51%
      of 520 physicians responded in 1997. Overall satisfaction was 57% in 1996 and 71%
      in 1997. Among physicians who responded in both years, overall satisfaction was
      unchanged, but increases in satisfaction were noted for patient load (an increase
      of 0.5 points on a five-point scale, P <0.01), time to discuss patient needs (an
      increase of 0.3 points, P <0.01), and helpfulness of care coordination (an
      increase of 0.5 points, P = 0.02). In a direct comparison between fee-for-service
      and capitation, physicians were more satisfied with both methods of payment in
      1997 than they were in 1996, but they were much more satisfied with fee-for
      service in both years. For many individual indicators, the difference in
      satisfaction between fee-for-service and capitation increased between 1996 and
      1997. CONCLUSION: When introduced to capitation, physicians had strong negative
      perceptions about it. After a year's experience, satisfaction with capitation
      improved, but perceived differences between capitation and fee-for-service grew
      even larger. Thus, physicians have serious concerns about capitation that may not
      be alleviated by experience with it.

PMID- 10403352
TI  - Determinants of retinopathy progression in type 1 diabetes mellitus.
AB  - PURPOSE: To determine the risk factors for retinopathy progression in type 1
      (insulin-dependent) diabetes mellitus in a prospective cohort study. SUBJECTS AND
      METHODS: Subjects were 485 participants in the Sorbinil Retinopathy Trial, a
      randomized trial of aldose reductase inhibition among patients aged 18 to 56
      years with type 1 diabetes mellitus (duration of 1 to 15 years) and no or only
      mild retinopathy. Retinopathy progression, assessed by seven-field stereoscopic
      fundus photography, was defined as worsening by two or more levels on a
      standardized grading scale at the end of follow-up (median, 41 months). RESULTS:
      The relative risks for retinopathy progression according to successively greater
      quintiles of total glycosylated hemoglobin level at baseline, after adjusting for
      age, diabetes duration, sorbinil assignment, and other variables, were 1.0, 2.0,
      1.6, 3.7, and 4.4 (P trend <0.0001). Risk increased with greater baseline
      diastolic blood pressure: 1.0 for <70 mm Hg, 1.2 for 70 to 79 mm Hg, and 1.8 for
      > or =80 mm Hg (P for trend = 0.04). Diastolic blood pressure was a significant
      risk factor for progression in participants with mild baseline retinopathy (P for
      trend <0.02) but not in those without retinopathy at entry. Systolic blood
      pressure, by comparison, was not associated with progression. Baseline total
      cholesterol level was a marginally significant predictor of retinopathy
      progression when examined as a categorical variable (relative risks for
      increasing quartiles; 1.0, 1.6, 1.8, 1.9; P for trend = 0.03) but not when it was
      examined as a continuous variable or when hypercholesterolemic patients were
      compared with those with normal levels. Furthermore, when cholesterol levels were
      updated in subsequent visits, it was not a significant predictor of progression,
      and low density lipoprotein (LDL) cholesterol levels did not predict progression
      no matter how analyzed. Smoking was not associated with progression of
      retinopathy. CONCLUSIONS: Levels of hyperglycemia and diastolic blood pressure
      predicted progression of retinopathy in type 1 diabetes mellitus. We found only a
      suggestion of an association between total cholesterol level (but not of LDL
      cholesterol level) and progression of retinopathy; resolution of this issue will
      require additional studies with larger sample sizes and longer follow-up.

PMID- 10403353
TI  - Evidence-based organ allocation.
AB  - BACKGROUND: There are not enough cadaveric kidneys to meet the demands of
      transplant candidates. The equity and efficiency of alternative organ allocation
      strategies have not been rigorously compared. METHODS: We developed a five
      compartment Monte Carlo simulation model to compare alternative organ allocation
      strategies, accommodating dynamic changes in recipient and donor characteristics,
      patient and graft survival rates, and quality of life. The model simulated the
      operations of a single organ procurement organization and attempted to predict
      the evolution of the transplant waiting list for 10 years. Four allocation
      strategies were compared: a first-come first-transplanted system; a point system
      currently utilized by the United Network of Organ Sharing; an efficiency-based
      algorithm that incorporated correlates of patient and graft survival; and a
      distributive efficiency algorithm, which had an additional goal of promoting
      equitable allocation among African-American and other candidates. RESULTS: A 10
      year computer simulation was performed. The distributive efficiency policy was
      associated with a 3.5%+/-0.8% (mean +/- SD) increase in quality-adjusted life
      expectancy (33.9 months vs 32.7 months), a decrease in the median waiting time to
      transplantation among those who were transplanted (6.6 months vs 16.3 months),
      and an increase in the overall likelihood of transplantation (61% vs 45%),
      compared with the United Network of Organ Sharing algorithm. Improved equity and
      efficiency were also seen by race (African-American vs other), sex, and age (<50
      or > or =50 years). Sensitivity analyses did not appreciably change the
      qualitative results. CONCLUSION: Evidence-based organ allocation strategies in
      cadaveric kidney transplantation would yield improved equity and efficiency
      measures compared with existing algorithms.

PMID- 10403355
TI  - A practical approach to familial and hereditary colorectal cancer.
AB  - Recent genetic research has isolated the primary genetic defect underlying many
      of the hereditary colorectal cancer syndromes. Obtaining a detailed family
      history is the first step in identifying individuals at increased risk of
      developing colorectal cancer. Once identified, individuals and their families may
      benefit from earlier, more intensified surveillance, prophylactic surgery, cancer
      risk assessment and education, and genetic testing. Clinicians, especially those
      with many patients with colorectal cancer in their practice, must be able to
      address the complex issues associated with the familial and hereditary colorectal
      cancer syndromes. A well-integrated partnership among colorectal surgeons,
      gastroenterologists, oncologists, and medical geneticists is necessary to address
      these complex issues and provide comprehensive medical care.

PMID- 10403354
TI  - Antibiotics in acute bronchitis: a meta-analysis.
AB  - PURPOSE: Most patients with acute bronchitis who seek medical care are treated
      with antibiotics, although the effectiveness of this intervention is uncertain.
      We performed a meta-analysis of randomized, controlled trials to estimate the
      effectiveness of antibiotics in the treatment of acute bronchitis. SUBJECTS AND
      METHODS: English-language studies published January 1966 to April 1998 were
      retrieved using MEDLINE, bibliographies, and consultation with experts. Only
      randomized trials that enrolled otherwise healthy patients with a diagnosis of
      acute bronchitis, used an antibiotic in the treatment group and a placebo in the
      control group, and provided sufficient data to calculate an effect size were
      included. RESULTS: We identified eight randomized controlled trials that
      satisfied all inclusion criteria. These studies used one of three antibiotics
      (erythromycin, doxycycline, trimethoprim/sulfamethoxazole). The use of
      antibiotics decreased the duration of cough and sputum production by
      approximately one-half day (summary effect size 0.21; 95% CI, 0.05 to 0.36). For
      specific symptoms, there were nonsignificant trends favoring the use of
      antibiotics: a decrease of 0.4 days of purulent sputum (95% CI, -0.1 to 0.8), a
      decrease of 0.5 days of cough (95% CI, -0.1 to 1.1), and a decrease of 0.3 days
      lost from work (95% CI, -0.6 to 1.1). CONCLUSION: This meta-analysis suggests a
      small benefit from the use of the antibiotics erythromycin, doxycycline, or
      trimethoprim/sulfamethoxazole in the treatment of acute bronchitis in otherwise
      healthy patients. As this small benefit must be weighed against the risk of side
      effects and the societal cost of increasing antibiotic resistance, we believe
      that the use of antibiotics is not justified in these patients.

PMID- 10403356
TI  - Acute pancreatitis in human immunodeficiency virus-infected patients: a review.
AB  - Acute pancreatitis is a clinical condition that develops when active pancreatic
      inflammation is induced by stimuli noxious to the pancreas. Patients infected
      with human immunodeficiency virus (HIV) often have histologic abnormalities of
      the pancreas, and acute pancreatitis is much more common in HIV-infected patients
      than in the general population. This article reviews the epidemiology and
      etiology of acute pancreatitis in HIV-infected patients. The clinical
      presentation and treatment of acute pancreatitis in HIV-infected patients are
      also reviewed.

PMID- 10403358
TI  - Gelatinous transformation of the bone marrow: an uncommon manifestation of
      intestinal lymphangiectasia (Waldmann's disease)

PMID- 10403359
TI  - Guillain-Barre syndrome occurring as a complication of acute nonlymphoblastic
      leukemia.

PMID- 10403360
TI  - Silver coating of medical devices for catheter-associated infections?

PMID- 10403357
TI  - Cellular adhesion molecules and atherogenesis.

PMID- 10403361
TI  - Hyperparathyroidism in congestive heart failure.

PMID- 10403362
TI  - Postmenopausal hormone therapy increases risk of deep vein thrombosis and
      pulmonary embolism.

PMID- 10403363
TI  - CuI-semiquinone radical species in plant copper-amine oxidases.
AB  - The intermediate CuI-semiquinone radical species in the catalytic mechanism of
      copper-amine oxidase from Lens esculenta and Pisum sativum seedlings has been
      studied by optical, Raman resonance and ESR spectroscopies and by stopped-flow
      and temperature-jump measurements. Treatment of highly purified enzyme
      preparations with good, poor or suicide substrates, under anaerobic and aerobic
      conditions, at different pH values and temperatures, makes it possible to
      generate, detect and characterize this free radical intermediate.

PMID- 10403364
TI  - New substrates of DNA polymerases.
AB  - Bis-(2'-deoxynucleoside) 5',5'-tetraphosphates and bis-(2'-deoxynucleoside) 5',5'
      triphosphates were shown to be a new type of substrate for several DNA
      polymerases of human, bacterial and viral origin. Their substrate properties
      depend both on their structure and on the nature of the enzyme. They are
      incorporated by both termini in correspondence with the template nucleotide
      program in the active center. The results obtained support the mechanism of their
      direct incorporation rather than prior hydrolysis to dNTP. The highest activity
      of these compounds was observed for HIV reverse transcriptase. The probable
      biological significance of the reaction is discussed.

PMID- 10403365
TI  - Fourier-transform resonance Raman spectra of cation carotenoid in photosystem II
      reaction centres.
AB  - Resonance Raman spectra of the cation form of a redox-active carotenoid in
      photosystem II are presented. These results have implications for the nature of
      the carotenoid radical and in particular the localisation of the hole on this
      molecule.

PMID- 10403366
TI  - Formation of adenosine 5'-tetraphosphate from the acyl phosphate intermediate: a
      difference between the MurC and MurD synthetases of Escherichia coli.
AB  - The mechanism of the Mur synthetases of peptidoglycan biosynthesis is thought to
      involve in each case the successive formation of an acyl phosphate and a
      tetrahedral intermediate. The existence of the acyl phosphates for the MurC and
      MurD enzymes from Escherichia coli was firmly established by their in situ
      reduction by sodium borohydride followed by acid hydrolysis, yielding the
      corresponding amino alcohols. Furthermore, it was found that MurD, but not MurC,
      catalyses the synthesis of adenosine 5'-tetraphosphate from the acyl phosphate,
      thereby substantiating its existence and pointing out a difference between the
      two enzymes.

PMID- 10403367
TI  - The small GTPases Rab5a, Rab5b and Rab5c are differentially phosphorylated in
      vitro.
AB  - Rab GTPases play a fundamental role in the regulation of membrane traffic. Three
      different Rab5 isoforms have been reported but no differences in their function
      in endocytosis have been discovered. As the Rab5 isoforms show a conserved
      consensus site for Ser/Thr phosphorylation, we investigated whether this site was
      phosphorylated. Here, we report that the three Rab5 proteins are differentially
      recognized by different kinases. Rab5a is efficiently phosphorylated by
      extracellular-regulated kinase 1 but not by extracellular-regulated kinase 2,
      while cdc2 kinase preferentially phosphorylates Ser-123 of Rab5b. These findings
      strongly suggest that phosphorylation could be important to differentially
      regulate the function of the Rab5 isoforms.

PMID- 10403368
TI  - The lipoate synthase from Escherichia coli is an iron-sulfur protein.
AB  - Lipoate synthase catalyzes the last step of the biosynthesis of lipoic acid in
      microorganisms and plants. The protein isolated from an overexpressing
      Escherichia coli strain was purified from inclusion bodies. Spectroscopic (UV
      visible and electron paramagnetic resonance) properties of the reconstituted
      protein demonstrate the presence of a (2Fe-2S) center per protein. As observed in
      biotin synthase, these clusters are converted to (4Fe-4S) centers during
      reduction under anaerobic conditions. The possible involvement of the cluster in
      the insertion of sulfur atoms into the octanoic acid backbone is discussed.

PMID- 10403369
TI  - Biochemical analysis of the interaction between elongation factor 1alpha and
      alpha/beta-tubulins from a ciliate, Tetrahymena pyriformis.
AB  - The interaction between elongation factor 1alpha (EF-1alpha) and alpha/beta
      tubulins has been analyzed in vivo and in vitro. An association of both alpha-
      and beta-tubulins with EF-1alpha in the lysate of Tetrahymena pyriformis was
      detected by co-immunoprecipitation analysis. In contrast, in vitro biomolecular
      interaction analysis with glutathione S-transferase (GST) fusion proteins
      revealed that GST-beta-tubulin, but not GST-alpha-tubulin, can bind to GST-EF
      1alpha. Two beta-tubulin binding sites have been identified to reside in the
      domains I and III of EF-1alpha. In addition, beta-tubulin itself seems to have
      two distinct interaction sites for each of the domains. Since domain II of EF
      1alpha did not interact with beta-tubulin, we have re-evaluated the phylogenetic
      status of ciliates using EF-1alpha sequences devoid of domain II. The
      phylogenetic tree thus obtained was significantly different from that inferred
      from the whole sequence of EF-1alpha, suggesting the presence of functional
      constraints on the molecular evolution of EF-1alpha.

PMID- 10403371
TI  - Coupling of a targeting peptide to plasmid DNA by covalent triple helix
      formation.
AB  - The nuclear localization signal (NLS) of the SV40 large T antigen efficiently
      induces nuclear entry of proteins. We have developed a strategy for covalent
      coupling of one or a controlled number of NLS peptides to plasmid DNA at a
      specific site by triple helix formation. A psoralen-oligonucleotide-NLS peptide
      conjugate was synthesized and characterized by proteolysis with trypsin. This
      conjugate was used to covalently associate one NLS peptide to plasmid DNA by
      triple helix formation and photoactivation. The oligonucleotide-NLS peptide
      conjugate interacted with the NLS-receptor importin alpha. The reporter gene was
      expressed after transfection of the modified plasmid in NIH 3T3 cells, indicating
      no loss of the gene expression functionality of the plasmid. On the other hand,
      no increase in expression was observed as a result of the NLS peptide. This site
      specific coupling technology can be used to couple to a plasmid other ligands
      targeting to a specific receptor.

PMID- 10403370
TI  - Sequence of subunit a of the Na(+)-translocating F1F0-ATPase of Acetobacterium
      woodii: proposal for residues involved in Na+ binding.
AB  - Na+ transport through the F0 domain of Na(+)-F1F0-ATPases involves the combined
      action of subunits c and a but the residues involved in Na+ liganding in subunit
      a are unknown. As a first step towards the identification of these residues, we
      have cloned and sequenced the gene encoding subunit a of the Na(+)-F1F0-ATPase of
      Acetobacterium woodii. This is the second sequence available now for this subunit
      from Na(+)-F1F0-ATPases. A comparison of subunit a from Na(+)-F1F0-ATPases with
      those from H(+)-translocating enzymes unraveled structural similarity in a C
      terminal segment including the ultimate and penultimate transmembrane helix.
      Seven residues are conserved in this region and, therefore, likely to be involved
      in Na+ liganding.

PMID- 10403373
TI  - Mutational analysis of a conserved tetraloop in the 5' untranslated region of
      hepatitis C virus identifies a novel RNA element essential for the internal
      ribosome entry site function.
AB  - The 5' untranslated region of hepatitis C virus RNA forms an extensive secondary
      structure including several hairpin motifs and mediates translation initiation by
      an internal ribosome entry site-dependent pathway. We report, here, an extensive
      mutagenesis analysis of a highly conserved tetraloop in the 5' untranslated
      region of hepatitis C virus, namely hairpin IIIe (295'-GAUA-298'). Our results
      demonstrate that hairpin IIIe is essential for the internal ribosome entry site
      function. Moreover, they indicate the importance of the primary structure of this
      motif because mutations in all four nucleotides of the loop caused a severe loss
      of internal ribosome entry site activity. These data represent the first
      experimental evidence for the functional significance of tetraloops in internal
      ribosome entry site-driven translation of hepatitis C virus.

PMID- 10403372
TI  - Two novel delta-endotoxin gene families cry26 and cry28 from Bacillus
      thuringiensis ssp. finitimus.
AB  - Genes cry26Aal and cry28Aal were cloned from Bacillus thuringiensis ssp.
      finitimus strain B-1166 VKPM. This strain forms insecticidal crystal bodies
      either outside or inside the exosporium. The deduced amino acid sequence of the
      cry26Aal gene product included seven residues determined to be an N-terminal part
      of a chymotrypsin-treated delta-endotoxin isolated from the same strain. Earlier
      this protein was detected in both free and spore-associated types of crystals
      [Revina et al., Biokhimia (1999) in press]. Neither BtI nor BtII promoter
      sequences were found upstream of the open reading frames in both genes. Southern
      hybridization has shown that the surroundings of both genes at least 3 kb
      upstream and downstream of the open reading frames are unique. We suggest that
      the protein Cry26Aal in both types of crystal bodies is synthesized under the
      control of one and the same genomic locus.

PMID- 10403374
TI  - The glucose repressor CRE1 from Sclerotinia sclerotiorum is functionally related
      to CREA from Aspergillus nidulans but not to the Mig proteins from Saccharomyces
      cerevisiae.
AB  - We isolated the putative glucose repressor gene cre1 from the phytopathogenic
      fungus Sclerotinia sclerotiorum. cre1 encodes a 429 amino acid protein 59%
      similar to the carbon catabolite repressor CREA from Aspergillus nidulans. In
      addition to the overall amino acid sequence relatedness between CRE1 and CREA
      proteins, cre1 can functionally complement the A. nidulans creAd30 mutation as
      assessed by repression of the alcohol dehydrogenase I gene expression. The CREI
      region carrying the two zinc fingers is also very similar to the DNA binding
      domains of the Saccharomyces cerevisiae glucose repressors Mig1p and Mig2p.
      Despite the presence in the CRE1 protein of several motifs involved in the
      regulation of Miglp activity, cre1 cannot complement mig deficiencies in S.
      cerevisiae. These data suggest that glucose repression pathways may have evolved
      differently in yeasts and filamentous fungi.

PMID- 10403375
TI  - The 3' non-coding region of the Drosophila melanogaster HeT-A telomeric
      retrotransposon contains sequences with propensity to form G-quadruplex DNA.
AB  - HeT-A elements are non-long terminal repeat retrotransposons added onto the
      Drosophila chromosome ends. We have investigated the formation in vitro of higher
      order structures by oligonucleotides derived from the 3' non-coding region of HeT
      A elements and found that they are capable of forming G-quadruplex DNA. These
      results suggest that the 3' repeat region of HeT-A may structurally behave as the
      telomeric repeats common to a majority of eukaryotes. The presence of structural
      motifs shared by telomeres and centromeres and the implications of these findings
      for chromosome evolution are discussed.

PMID- 10403376
TI  - Dual effects of suppressor of cytokine signaling (SOCS-2) on growth hormone
      signal transduction.
AB  - A family of suppressors of cytokine signaling (SOCS) has recently been identified
      of which two members have been shown to block growth hormone (GH) signaling. Dose
      response experiments were conducted in 293 cells and SOCS-1 and SOCS-3 were shown
      to inhibit the transcriptional activation of a GH-responsive element and
      suppressed Jak2 tyrosine kinase activity. SOCS-2 had two opposite effects: at low
      concentrations it inhibited GH-induced STAT5-dependent gene transcription, but
      restoration of GH signaling was observed at higher concentrations. In
      cotransfection studies, SOCS-2 was able to block the inhibitory effect of SOCS-1
      but not that of SOCS-3 on GH signaling. These findings suggest that a major
      function for SOCS-2 is to restore the sensitivity to GH by overcoming the initial
      inhibitory effects of other endogenous SOCS molecules.

PMID- 10403378
TI  - Calcium release from InsP3-sensitive internal stores initiates action potential
      in Chara.
AB  - Neomycin and U73122 are known to suppress inositol 1,4,5-trisphosphate (InsP3)
      production by inhibition of phospholipase C. We studied the effects of these
      inhibitors on the excitatory currents, Iex, in Chara corallina under voltage
      clamp conditions. Computer simulations of the experimental effects by a minimum
      model for the excitatory reaction pathway allow the assignment of the inhibitory
      effects to one specific reaction step, i.e. the release of Ca2+ from InsP3
      sensitive internal stores. In contrast, the inhibitory effect of La3+ on Iex
      suggests inactivation of Cl- channels. Furthermore, ryanodine-sensitive Ca2+
      stores seem to be irrelevant for electrical excitation in Chara.

PMID- 10403377
TI  - Regulation of Fas antibody induced neutrophil apoptosis is both caspase and
      mitochondrial dependent.
AB  - Resolution of neutrophil mediated inflammation is achieved, in part, through
      induction of neutrophil apoptosis. This constitutively expressed programme can be
      delayed by inflammatory mediators and induced by ligation of the Fas receptor.
      However, functional activation of the neutrophil results in resistance to Fas
      signalled death. We evaluated the effects of Fas antibody engagement on caspase
      activation and mitochondrial permeability, and the impact of co-stimulation by
      lipopolysaccharide (LPS) or granulocyte macrophage-colony stimulating factor (GM
      CSF) on these events. Fas engagement by an agonistic anti-Fas antibody resulted
      in enhanced caspase 3 and 8 activity and increased mitochondrial permeability.
      Studies with pharmacological inhibitors of caspase activity showed that
      activation of caspase 8 occurred before, and activation of caspase 3 occurred
      after mitochondrial disruption. The mitochondrial stabilising agent bongkrekic
      acid also inhibited caspase activation and apoptosis. LPS, GM-CSF and increased
      glutathione stabilised the mitochondria and inhibited caspase 3. Caspase 8
      activity was also inhibited by co-stimulation through a mechanism independent of
      mitochondrial stabilisation. Glutathione directly inhibited caspase 3 and 8
      activity. We conclude inhibition of Fas antibody induced apoptosis by
      inflammatory proteins is associated with augmented mitochondrial stability and
      reduced caspase 3 activity that may be glutathione mediated.

PMID- 10403379
TI  - Ca2(+)-dependent interaction of N-copine, a member of the two C2 domain protein
      family, with OS-9, the product of a gene frequently amplified in osteosarcoma.
AB  - N-copine is a novel two C2 domain protein that shows Ca2(+)-dependent
      phospholipid binding and membrane association. By using yeast two-hybrid assays,
      we identified OS-9 as a protein capable of interacting with N-copine. We further
      revealed that the second C2 domain of N-copine bound with the carboxy-terminal
      region of OS-9. Their interaction in vivo was also confirmed by co
      immunoprecipitation from 293E cells co-expressing transfected N-copine and OS-9.
      In vitro binding assays showed that this interaction was Ca2(+)-dependent. By
      Northern blot analysis, N-copine and OS-9 were co-expressed in the same regions
      of human brain. These results reveal that OS-9 is a potential target of N-copine.

PMID- 10403380
TI  - Polyunsaturated fatty acids potentiate interleukin-1-stimulated arachidonic acid
      release by cells overexpressing type IIA secretory phospholipase A2.
AB  - By analyzing human embryonic kidney 293 cell transfectants stably overexpressing
      various types of phospholipase A2 (PLA2), we have shown that polyunsaturated
      fatty acids (PUFAs) preferentially activate type IIA secretory PLA2 (sPLA2-IIA)
      mediated arachidonic acid (AA) release from interleukin-1 (IL-1)-stimulated
      cells. When 293 cells prelabeled with 13H]AA were incubated with exogenous PUFAs
      in the presence of IL-1 and serum, there was a significant increase in [3H]AA
      release (in the order AA > linoleic acid > oleic acid), which was augmented
      markedly by sPLA2-IIA and modestly by type IV cytosolic PLA2 (cPLA2), but only
      minimally by type VI Ca2(+)-independent PLA2, overexpression. Transfection of
      cPLA2 into sPLA2-IIA-expressing cells produced a synergistic increase in IL-1
      dependent [3H]AA release and subsequent prostaglandin production. Our results
      support the proposal that prior production of AA by cPLA2 in cytokine-stimulated
      cells destabilizes the cellular membranes, thereby rendering them more
      susceptible to subsequent hydrolysis by sPLA2-IIA.

PMID- 10403381
TI  - Identification of the protein components of mismatch binding complexes in human
      cells using a gel-shift assay.
AB  - In eukaryotes, mismatch recognition is thought to be mediated by two
      heterodimers, hMutSalpha (hMSH2+hMSH6), which preferentially binds to base-base
      mismatches and hMutSbeta (hMSH2+hMSH3), which binds to insertion/deletion loops.
      We studied these mismatch binding activities in several human cell lines with a
      gel-shift assay using various mismatch oligonucleotides as substrates. Both
      hMutSalpha and hMutSbeta activities could be detected in various human cell
      lines. In cells with amplified copies of the hMSH3 gene, a large increase in
      hMutSbeta and a reduction in hMutSalpha were observed. To identify the
      composition of each mismatch binding complex, the protein-DNA complexes were
      transferred from gel-shift polyacrylamide gel to a polyvinylidene difluoride
      membrane and were subjected to immunoblot analysis with an enhanced
      chemiluminescence protein detection system. The results clearly demonstrated that
      hMutSalpha detected by the gel-shift assay was composed of hMSH2 and hMSH6, while
      hMutSbeta was composed of hMSH2 and hMSH3. Our data, therefore, support a model
      whereby formation of hMutSalpha and hMutSbeta is mutually regulated. Combination
      of a gel-shift assay with immunoblotting (shift-Western assay) proved to be a
      highly sensitive technique and should be useful for studying the interactions
      between DNA and binding proteins, including DNA mismatch recognition.

PMID- 10403382
TI  - Energetics of the proposed rate-determining step of the glyoxalase I reaction.
AB  - The proposed rate-limiting step of the reaction catalyzed by glyoxalase I is the
      proton abstraction from the C1 carbon atom of the substrate by a glutamate
      residue, resulting in a high-energy enolate intermediate. This proton transfer
      reaction was modelled using molecular dynamics and free energy perturbation
      simulations, with the empirical valence bond method describing the potential
      energy surface of the system. The calculated rate constant for the reaction is
      approximately 300-1500 s(-1) with Zn2+, Mg2+ or Ca2+ bound to the active site,
      which agrees well with observed kinetics of the enzyme. Furthermore, the results
      imply that the origin of the catalytic rate enhancement is mainly associated with
      enolate stabilization by the metal ion.

PMID- 10403383
TI  - Exploiting retrograde transport of Shiga-like toxin 1 for the delivery of
      exogenous antigens into the MHC class I presentation pathway.
AB  - Shiga-like toxin 1 (SLT) from Escherichia coli O157:H7 enters mammalian cells by
      endocytosis from the cell surface to the endoplasmic reticulum before
      translocating into the cytosol. Here, SLT was engineered at its N- or C-terminus
      to carry a peptide derived from influenza virus Matrix protein for delivery to
      major histocompatibility complex (MHC) class I molecules. We show that SLT N-Ma
      was capable of sensitising cells for lysis by appropriate cytotoxic T-lymphocytes
      whilst no killing of SLT-resistant cells was observed. Our results demonstrate
      that peptide was liberated intracellularly and that retrograde transport of a
      disarmed cytotoxic protein can intersect the MHC class 1 presentation pathway.

PMID- 10403384
TI  - Introducing transglycosylation activity in a liquefying alpha-amylase.
AB  - By mutating Ala-289 by Phe or Tyr in the Bacillus stearothermophilus alpha
      amylase, we induced this enzyme to perform alcoholytic reactions, a function not
      present in the wild-type enzyme. This residue was selected from homology analysis
      with neopullulanase, where the residue has been implicated in the control of
      transglycosylation [Kuriki et al. (1996) J. Biol. Chem. 271, 17321-173291. We
      made some inferences about the importance of electrostatic and geometrical
      modifications in the active site environment of the amylase to explain the
      behavior of the modified enzyme.

PMID- 10403385
TI  - NMR analysis of cardiac troponin C-troponin I complexes: effects of
      phosphorylation.
AB  - Phosphorylation of the cardiac specific amino-terminus of troponin I has been
      demonstrated to reduce the Ca2+ affinity of the cardiac troponin C regulatory
      site. Recombinant N-terminal cardiac troponin I proteins, cardiac troponin I(33
      80), cardiac troponin I(1-80), cardiac troponin I(1-80)DD and cardiac troponin
      I(1-80)pp, phosphorylated by protein kinase A, were used to form stable binary
      complexes with recombinant cardiac troponin C. Cardiac troponin I(1-80)DD, having
      phosphorylated Ser residues mutated to Asp, provided a stable mimetic of the
      phosphorylated state. In all complexes, the N-terminal domain of cardiac troponin
      I primarily makes contact with the C-terminal domain of cardiac troponin C. The
      nonphosphorylated cardiac specific amino-terminus, cardiac troponin I(1-80), was
      found to make additional interactions with the N-terminal domain of cardiac
      troponin C.

PMID- 10403386
TI  - DNA conformational dynamics in the presence of catanionic mixtures.
AB  - DNA conformational behavior in the presence of non-stoichiometric mixtures of two
      oppositely charged surfactants, cetyltrimethylammonium bromide and sodium octyl
      sulfate, was directly visualized in an aqueous solution with the use of a
      fluorescence microscopy technique. It was found that in the presence of cationic
      rich catanionic mixtures, DNA molecules exhibit a conformational transition from
      elongated coil to compact globule states. Moreover, if the catanionic mixtures
      form positively charged vesicles, DNA is adsorbed onto the surface of the
      vesicles in a collapsed globular form. When anionic-rich catanionic mixtures are
      present in the solution, no change in the DNA conformational behavior was
      detected. Cryogenic transmission electron microscopy, as well as measurements of
      translational diffusion coefficients of individual DNA chains, supported our
      optical microscopy observations.

PMID- 10403387
TI  - Calpain controls the balance between protein tyrosine kinase and tyrosine
      phosphatase activities during platelet activation.
AB  - Protein phosphorylation was studied during platelet stimulation in two ranges of
      ionized [Ca2+]. At ionized [Ca2+]i< or = 1 microM, proteins were phosphorylated.
      At ionized [Ca2+]i > or = 4 microM, phosphoproteins disappeared. Protein
      dephosphorylation was prevented by the combined action of calpeptin and
      phosphatase inhibitors. Protein tyrosine phosphatase activity was stimulated
      regardless of the ionized [Ca2+] level. Protein tyrosine kinase activity was
      stimulated at ionized [Ca2+]i < or =1 microM, whereas at ionized [Ca2+]i > or =4
      microM, no protein tyrosine kinase activity was observed except in the presence
      of calpeptin. Thus, the massive tyrosine phosphoprotein disappearance observed at
      a high ionized [Ca2+]i resulted not only in protein tyrosine phosphatase
      activation, but also in calpain-induced protein tyrosine kinase inactivation.

PMID- 10403388
TI  - N-acetylcysteine protects epithelial cells against the oxidative imbalance due to
      Clostridium difficile toxins.
AB  - Toxins A and B from the anaerobic bacterium Clostridium difficile are the
      causative agents of the antibiotic-associated pseudomembraneous colitis. At the
      subcellular level, they inhibit the Rho family GTPases, thus causing alterations
      of the actin cytoskeleton. The cytoskeletal integrity is also controlled by the
      redox state of cells. Therefore, we have evaluated whether an oxidative imbalance
      could be involved in the toxin-induced cytopathic effects. Our results indicate
      that both toxins induce oxidative stress with a significant depletion of protein
      SH-groups. These responses and the cytoskeleton-dependent cell retraction and
      rounding are significantly counteracted by N-acetylcysteine but not by alpha
      tocopherol. Our study provides the first evidence that the thiol supplier N
      acetylcysteine impairs the cellular intoxication by acting on the cytoskeleton
      integrity. This also suggests a possible beneficial role for this drug during
      therapeutic intervention.

PMID- 10403389
TI  - Novel anti-inflammatory chalcone derivatives inhibit the induction of nitric
      oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages.
AB  - In a previous work, we tested a series of chalcone derivatives as possible anti
      inflammatory compounds. We now investigate the effects of three of those
      compounds, CHI, CH8 and CH12, on nitric oxide and prostanoid generation in mouse
      peritoneal macrophages stimulated with lipopolysaccharide and in the mouse air
      pouch injected with zymosan, where they showed a dose-dependent inhibition with
      inhibitory concentration 50% values in the microM range. This effect was not the
      consequence of a direct inhibitory action on enzyme activities. Our results
      demonstrated that chalcone derivatives inhibited de novo inducible nitric oxide
      synthase and cyclooxygenase-2 synthesis, being a novel therapeutic approach for
      inflammatory diseases.

PMID- 10403390
TI  - Cloning of a novel kinase (SIK) of the SNF1/AMPK family from high salt diet
      treated rat adrenal.
AB  - PCR-coupled cDNA subtraction hybridization was adapted to identify the genes
      expressed in the adrenocortical tissues from high salt diet-treated rat. A novel
      cDNA clone, termed salt-inducible kinase (SIK), encoding a polypeptide (776 amino
      acids) with significant similarity to protein serine/ threonine kinases in the
      SNF1/AMPK family was isolated. An in vitro kinase assay demonstrated that SIK
      protein had autophosphorylation activity. Northern blot revealed that SIK mRNA
      levels were markedly augmented by ACTH treatment both in rat adrenal glands and
      in Y1 cells. SIK may play an important role in the regulation of adrenocortical
      functions in response to high plasma salt and ACTH stimulation.

PMID- 10403391
TI  - Induction of terminal differentiation and apoptosis in human colonic carcinoma
      cells by brefeldin A, a drug affecting ganglioside biosynthesis.
AB  - An appreciable increase in G(M3) with a concomitant decrease in some neolacto
      series gangliosides was observed during differentiation of human colonic
      carcinoma HCT 116 cells induced by a differentiating agent. When the cells were
      treated with brefeldin A (BFA), a striking increase in de novo biosynthesis of
      G(M3) and a decrease in biosynthesis of neolactoseries gangliosides were observed
      after 6 h. Clear morphological changes to differentiated epithelial cells and an
      arrest of cells in the G0/G1 phase of the cell cycle were observed after 1 day of
      treatment. Then the cells were led to apoptosis. This activity was not affected
      by forskolin, which antagonizes the effects of BFA on protein transport and the
      Golgi apparatus. These results suggest that the differentiation-inducing activity
      of BFA might be due to its modulatory effect on ganglioside biosynthesis, and
      that a specific change in ganglioside pattern is an essential prerequisite for
      induction of differentiation, providing a novel target for differentiation
      therapy of cancer.

PMID- 10403392
TI  - Permutation of modules or secondary structure units creates proteins with basal
      enzymatic properties.
AB  - The RNase activity of barnase mutants obtained by the permutation of modules or
      secondary structure units was investigated. Four of the 45 mutants had weak but
      distinct RNase activity, and they had unique optimum pHs and temperatures like
      natural enzymes. One of the active mutants had an ordered conformation, but the
      others did not. An active mutant having disordered conformation formed an ordered
      conformation in the presence of GMP, which is an inhibitor of this mutant. These
      results indicate that the amino acid sequences derived from barnase have
      sufficient plasticity to be rearranged into different proteins with basal
      enzymatic properties.

PMID- 10403393
TI  - Lack of c-Jun activity increases survival to cisplatin.
AB  - Antineoplasic agents such as cisplatin and adriamycin execute their
      pharmacological role by triggering apoptosis. We have studied the mechanism of
      apoptosis induction by cisplatin and adriamycin. Both drugs activated JNK with
      slow and persistent kinetics. Adriamycin activated caspase-3 before the rise in
      JNK activity, while the response to cisplatin occurs hours after JNK activation.
      The increase in JNK activity was necessary for cisplatin-mediated apoptosis but
      it was dispensable for adriamycin-induced cell death. Cells derived from c-jun
      knock out mice were more resistant to cisplatin cell death than normal cells, but
      no difference was observed in response to adriamycin. Activation of JNK and cell
      death by cisplatin is mediated by the MEKK1/SEK1 cascade, since expression of
      dominant negative expression vectors of these kinases blocked both processes. p38
      was also activated by cisplatin with similar kinetics as JNK. AP-1 complexes were
      activated by cisplatin including mainly c-jun/ATF-2 heterodimers suggesting that
      AP-1-dependent transcription partially mediated cisplatin-induced apoptosis.

PMID- 10403394
TI  - Spin-trapping agent alpha-phenyl N-tert-butylnitrone binds to trypsin and
      enhances heparin-induced inhibition of amidolytic activity and structural
      degradation of the enzyme.
AB  - The effects of heparin on trypsin have recently been demonstrated to involve
      inhibition of catalytic activity and degradation of the enzyme by means of an
      oxidative mechanism. The possibility that alpha-phenyl N-tert-butylnitrone
      protects heparin-induced radical formation on trypsin was investigated by
      measuring amidolytic activity and changes in the structure of trypsin in the
      presence of heparin with and without alpha-phenyl N-tert-butylnitrone. The
      results show that alpha-phenyl N-tert-butylnitrone does not only prevent, but it
      even significantly enhances effects of heparin on the enzyme. This is due to the
      unique property of alpha-phenyl N-tert-butylnitrone, independently of spin
      trapping capacity, to modify the trypsin structure by binding irreversibly to the
      catalytic triad, at sites distinct from those to which heparin binds.

PMID- 10403395
TI  - Di-, tri- and tetrameric single chain Fv antibody fragments against human CD19:
      effect of valency on cell binding.
AB  - Single chain variable fragments (scFv) of the murine monoclonal antibody HD37
      specific to human B-cell antigen CD19 were constructed by joining the VH and VL
      domains with linkers of 18, 10, 1 and 0 residues. ScFv-18 formed monomers, dimers
      and small amounts of tetramers; scFv-10 formed dimers and small amounts of
      tetramers; scFv-1 formed exclusively tetramers; scFv-0 formed exclusively
      trimers. The affinities of the scFv-10 (diabody) and scFv-1 (tetrabody) were
      approximately 1.5- and 2.5-fold higher, respectively, than that of the scFv-0
      (triabody). The tetrabody displayed a significantly prolonged association with
      cell-bound antigen (t1/2 cell surface retention at 37 degrees C of 26.6 min)
      compared to both the diabody (13.3 min) and triabody (6.7 min). This increase in
      avidity of the tetrabody combined with its larger size could prove to be
      particularly advantageous for imaging and the immunotherapy of B-cell
      malignancies.

PMID- 10403396
TI  - The N-terminal 77 amino acids from tobacco N-acetylglucosaminyltransferase I are
      sufficient to retain a reporter protein in the Golgi apparatus of Nicotiana
      benthamiana cells.
AB  - In order to investigate sequences of tobacco N-acetylglucosaminyltransferase I
      (GnTI), involved in targeting to and retention in the plant Golgi apparatus the
      cytoplasmic transmembrane stem (CTS) region of the enzyme was cloned in frame
      with the cDNA of the green fluorescent protein (gfp) and subsequently transiently
      expressed in Nicotiana benthamiana plants using a tobacco mosaic virus (TMV)
      based expression vector. Confocal laser scanning microscopy showed small
      fluorescent vesicular bodies in CTS-gfp expressing cells, while gfp alone
      expressed in control plants was uniformly distributed in the cytoplasm. The CTS
      gfp fusion protein colocalised with immunolabelling observed by an antibody
      specific for the Golgi located plant Lewis a epitope. Furthermore, treatment with
      brefeldin A, a Golgi specific drug, resulted in the formation of large
      fluorescent vesiculated areas. These results strongly suggest a Golgi location
      for CTS-gfp and as a consequence our findings reveal that the N-terminal 77 amino
      acids of tobacco GnTI are sufficient to target to and to retain a reporter
      protein in the plant Golgi apparatus and that TMV based vectors are suitable
      vehicles for rapid delivery of recombinant proteins to the secretory pathway.

PMID- 10403397
TI  - Actinomycin D as a novel SH2 domain ligand inhibits Shc/Grb2 interaction in B104
      1-1 (neu*-transformed NIH3T3) and SAA (hEGFR-overexpressed NIH3T3) cells.
AB  - Actinomycins, a family of bicyclic chromopeptide lactones with strong
      antineoplastic activity, were screened as inhibitors of Shc/Grb2 interaction in
      in vitro assay systems. To investigate the effects of actinomycin D on Shc/Grb2
      interaction in cell-based experiments, we used SAA (normal hEGFR-overexpressed
      NIH3T3) cells and B104-1-1 (neu*-transformed NIH3T3) cells, because a large
      number of the Shc/Grb2 complexes were detected. Associated protein complexes
      containing Shc were immunoprecipitated from actinomycin D-treated cell lysates
      with polyclonal anti-Shc antibody. Then the association with Grb2 was assessed by
      immunoblotting with monoclonal anti-Grb2 antibody. The result of the
      immunoblotting experiment revealed that actinomycin D inhibited Shc/Grb2
      interaction in a dose-dependent manner in both B104-1-1 and EGF-stimulated SAA
      cells. The inhibition of Shc/Grb2 interaction by actinomycin D in B104-1-1 cells
      also reduced tyrosine phosphorylation of MAP kinase (Erk1/Erk2), one of the major
      components in the Ras-MAP kinase signaling pathway. These results suggest that
      actinomycin D could be a non-phosphorylated natural and cellular membrane
      permeable SH2 domain antagonist.

PMID- 10403398
TI  - Mutation of the mitochrondrially encoded ATPase 6 gene modeled in the ATP
      synthase of Escherichia coli.
AB  - Defects of respiratory chain protein complexes and the ATP synthase are becoming
      increasingly implicated in human disease. Recently, mutations in the ATPase 6
      gene have been shown to cause several different neurological disorders. The
      product of this gene is homologous to the a subunit of the ATP synthase of
      Escherichia coli. Here, mutations equivalent to those described in humans have
      been introduced into the a subunit of E. coli by site-directed mutagenesis, and
      the effects of these mutations on the ATPase activity, ATP synthesis and ability
      of the enzyme to pump protons studied in detail. The effects of the mutations
      varied considerably. The mutation L262P (9185 T-C equivalent) caused a 70% loss
      of ATP synthesis activity, reduced DCCD sensitivity, and lowered proton pumping
      activity. The L207P (8993 T-C equivalent) reduced ATP synthesis by 50%, affected
      DCCD sensitivity, while proton pumping was only marginally affected when measured
      by the standard AMCA quenching assay. The other mutations studied affected the
      functioning of the ATP synthase much less. The results confirm that modeling of
      these point mutations in the E. coli enzyme is a useful approach to determining
      how alterations in the ATPase 6 gene affect enzyme function and, therefore, how a
      pathogenic effect can be exerted.

PMID- 10403399
TI  - Defective regulation of Ca2+/calmodulin-dependent protein kinase II in gamma
      irradiated ataxia telangiectasia fibroblasts.
AB  - Recent indirect evidence suggests that a Ca2+/ calmodulin-dependent pathway,
      which may involve calmodulin-dependent protein kinase II (CaMKII), mediates the S
      phase delay manifested by gamma-ray-exposed human fibroblasts. This pathway is
      severely impaired in ataxia telangiectasia (A-T) cells [Mirzayans et al. (1995)
      Oncogene 11, 15971. To extend these findings, we assayed CaMKII activity in
      irradiated normal and A-T fibroblasts. The radiation treatment induced the
      autonomous activity of the kinase in normal cells. In contrast, this activity was
      not elevated in either (i) normal cells pretreated with the selective CaMKII
      antagonist KN-62 or (ii) gamma-irradiated A-T cells. Moreover, A-T fibroblasts,
      unlike normal cells, failed to mobilize intracellular Ca2+ upon mitogenic
      stimulation. These findings identify a novel role for CaMKII in radiation-induced
      signal transduction and suggest its involvement in effecting the S-phase delay.
      The data also implicate ATM, the product of the gene responsible for A-T, as a
      key mediator of both intracellular Ca2+ mobilization and CaMKII activation in
      response not only to genotoxic stress but also to physiological stimuli.

PMID- 10403400
TI  - The combination of polymorphisms within interferon-gamma receptor 1 and receptor
      2 associated with the risk of systemic lupus erythematosus.
AB  - Genetic factors seem to play a significant role in susceptibility to systemic
      lupus erythematosus (SLE). We previously described the amino acid polymorphism
      (Val14Met) within the IFN-gamma receptor 1 (IFN-gammaRI), and that the frequency
      of the Metl4 allele in SLE patients was significantly higher than that of the
      healthy control population [Tanaka et al. (1999) Immunogenetics 49, 266-271]. We
      also found an amino acid polymorphism (Gln64Arg) within IFN-gamma receptor 2 (IFN
      gammaR2). Since the IFN-gamma receptor is a complex consisting of IFN-gammaR1 and
      IFN-gammaR2, we searched for the particular combination of two kinds of amino
      acid polymorphisms found within the IFN-gamma receptor which plays a prominent
      role in susceptibility to SLE. The greatest risk of the development of SLE was
      detected in the individuals who had the combination of IFNGR1 Met14/Val14
      genotype and IFNGR2 Gln64/Gln64 genotype.

PMID- 10403401
TI  - Cytokine-inducible CD40 gene expression in vascular smooth muscle cells is
      mediated by nuclear factor kappaB and signal transducer and activation of
      transcription-1.
AB  - The interaction of T-lymphocytes expressing the CD40 ligand (CD154) and cells of
      the vessel wall expressing the corresponding receptor protein (CD40) may play an
      important role in chronic inflammation including arteriosclerosis. One way of
      interfering with CD40-CD154 signalling is to prevent CD40 expression, the
      regulation of which, however, has yet to be elucidated. Therefore, we studied
      CD40 expression in rat aortic cultured smooth muscle cells. Both CD40 mRNA and
      protein expression in these cells was markedly enhanced as early as 6 h after
      exposure to different pro-inflammatory cytokines. Experiments with actinomycin D
      and subsequent run-on analyses revealed that CD40 expression in response to these
      cytokines was regulated at the level of transcription. Moreover, electrophoretic
      mobility shift analyses along with the employment of transcription factor decoy
      oligodeoxynucleotides demonstrated that tumor necrosis factor alpha via nuclear
      kappaB and interferon-gamma via signal transducer and activator of transcription
      1 up-regulate CD40 gene expression in rat aortic cultured smooth muscle cells.

PMID- 10403402
TI  - The kynurenine metabolic pathway in the eye: studies on 3-hydroxykynurenine, a
      putative cataractogenic compound.
AB  - The rabbit lens has an elevated content of 3-hydroxykynurenine (30HKYN) in spite
      of a very low activity of the enzymes leading to its synthesis. The iris/ciliary
      body, on the contrary, has very high activity of 30HKYN synthesizing enzymes but
      a content of 30HKYN lower than that of the lens. These observations suggest that
      30HKYN is formed in the iris/ ciliary body, released into the aqueous humor and
      then taken up into the lens where it may be used for the synthesis of UV
      filtering products. An excessive accumulation of 30HKYN in the lens has been
      associated with cataract formation. We found that available selective inhibitors
      of kynurenine hydroxylase reduced 30HKYN synthesis in both the lens and the
      iris/ciliary body.

PMID- 10403403
TI  - Mechanism of cytochrome P450 reductase from the house fly: evidence for an FMN
      semiquinone as electron donor.
AB  - The interaction of recombinant house fly (Musca domestica) P450 reductase with
      NADPH and the role of the FMN semiquinone in reducing cytochrome c have been
      investigated. House fly P450 reductase can rapidly oxidize only one molecule of
      NADPH, whereas the rate of oxidation of a second molecule of NADPH is too slow to
      account for the observed rates of catalysis. This demonstrates that house fly
      P450 reductase does not require a priming reaction with NADPH for catalysis.
      Kinetics of cytochrome c reduction and EPR spectroscopy revealed that the enzyme
      forms two types of neutral FMN semiquinone. One serves as the catalytic
      intermediate of cytochrome c reduction, and another one is an 'airstable'
      semiquinone, which reduces cytochrome c 3000 times more slowly. The results show
      that the reduction state of the house fly P450 reductase during catalysis cycles
      in a 0-2-1-0 sequence.

PMID- 10403404
TI  - Uncoupling protein-3 gene expression in skeletal muscle during development is
      regulated by nutritional factors that alter circulating non-esterified fatty
      acids.
AB  - Uncoupling protein-3 gene expression in skeletal muscle is up-regulated during
      postnatal development of mice. A high-carbohydrate diet at weaning induces a
      decrease in uncoupling protein-3 mRNA levels that does not occur when mice were
      weaned onto a high-fat diet. Uncoupling protein-3 mRNA levels do not increase in
      response to fasting in young pups. Only after day 15 of life, when fasting
      increases serum non-esterified fatty acids, uncoupling protein-3 mRNA is up
      regulated by starvation. Over-nutrition or under-nutrition during lactation
      increases or decreases, respectively, uncoupling protein-3 mRNA expression in
      skeletal muscle. Regulation of uncoupling protein-3 gene expression in skeletal
      muscle during development is mediated by ontogenic and nutritional factors
      determining changes in circulating non-esterified fatty acids.

PMID- 10403405
TI  - Enlargement of the endoplasmic reticulum membrane in Saccharomyces cerevisiae is
      not necessarily linked to the unfolded protein response via Ire1p.
AB  - Conditions that stress the endoplasmic reticulum (ER) in Saccharomyces cerevisiae
      can elicit a combination of an unfolded protein response (UPR) and an inositol
      response (IR). This results in increased synthesis of ER protein-folding factors
      and of enzymes participating in phospholipid biosynthesis. It was suggested that
      in cells grown on glucose or galactose medium, the UPR and the IR are linked and
      controlled by the ER stress sensor Ire1p. However, our studies suggest that
      during growth on oleate the IR is controlled both by an Ire1p-dependent pathway
      and by an Ire1p-independent pathway.

PMID- 10403406
TI  - Functional roles of the two cyclic AMP-dependent forms of cyclic AMP receptor
      protein from Escherichia coli.
AB  - The cyclic AMP receptor protein activates transcription in Escherichia coli, only
      when complexed with cyclic AMP. The cyclic AMP receptor protein-cyclic AMP
      complex formed at low concentrations of cyclic AMP has a different conformation
      from either cyclic AMP receptor protein alone or its complex with cyclic AMP
      formed at high cyclic AMP concentrations. Various biophysical data suggest that
      the latter complex resembles free cyclic AMP receptor protein. We have examined
      the conformational and biological properties of cyclic AMP receptor protein as a
      function of cyclic AMP concentrations, using the gal operon of E. coli. A
      biphasic behavior is observed. It is shown that only the complex formed at lower
      concentrations of cyclic AMP is the transcriptionally active form. This
      difference between the complexes at different levels of cyclic AMP arises from a
      decreased ability of the cyclic AMP receptor protein-cyclic AMP complex at high
      cyclic AMP concentrations to bind to DNA at specific sites.

PMID- 10403407
TI  - The SNF1 kinase complex from Saccharomyces cerevisiae phosphorylates the
      transcriptional repressor protein Mig1p in vitro at four sites within or near
      regulatory domain 1.
AB  - Mig1p is a zinc finger protein required for repression of glucose-regulated genes
      in budding yeast. On removal of medium glucose, gene repression is relieved via a
      mechanism that requires the SNF1 protein kinase complex. We show that Mig1p
      expressed as a glutathione-S-transferase fusion in bacteria is readily
      phosphorylated by the SNF1 kinase in vitro. Four phosphorylation sites were
      identified, i.e. Ser-222, Ser-278, Ser-311 and Ser-381. The latter three are
      exact matches to the recognition motif we previously defined for SNF1 and lie
      within regions shown to be required for SNF1-dependent derepression and nuclear
      to-cytoplasmic translocation.

PMID- 10403409
TI  - Micellar catalysis for oxidation of nitric oxide (NO) in the multi-phase systems
      in vivo.
AB  - The equation of the dependence of the third-order reaction acceleration due to
      concentrating the reagents in a small volume of the hydrophobic phase on the
      partition coefficients of reagents (Q) and on the lipophilic phase fraction (x),
      [k(app)/ k2 = H(Q(NO),Q(O2),x)] was analyzed. It was demonstrated that the
      numeric value of dH/dx at x-->0 could not be used in order to calculate the
      efficiency of catalysis from the experimental data. It was shown that, unlike in
      two-phase systems (with an aqueous and a hydrophobic phase), the dependence of H
      on Q in multi-phase systems, that include all in vivo systems, is different. The
      multiple phase state of the systems has a determining role for a regulation of NO
      dependent processes and in the realization of conditions of 'NO catastrophes'.

PMID- 10403408
TI  - Hyperphosphorylated tau in SY5Y cells: similarities and dissimilarities to
      abnormally hyperphosphorylated tau from Alzheimer disease brain.
AB  - Unlike normal tau, abnormally hyperphosphorylated tau (AD P-tau) from Alzheimer
      disease (AD) does not promote but instead inhibits microtubule assembly and
      disrupts already formed microtubules. Tau in the human neuroblastoma cell line SH
      SY5Y is hyperphosphorylated at several of the same sites as AD P-tau, and
      accumulates in the cell body without any association to the cellular microtubule
      network. The aim of the present study was to elucidate why the SY5Y tau does not
      affect the viability of the cells. We found that, like AD P-tau, SY5Y tau because
      of hyperphosphorylation does not bind to microtubules and inhibits the tau
      promoted assembly of microtubules. However, the tau/HMW MAP ratio is about 10
      times less in SY5Y cells than in AD brain. These findings suggest that the
      hyperphosphorylated tau from SY5Y cells has similar biological characteristics as
      AD P-tau from AD brain, but is not lethal to the SY5Y cells because of its low
      tau/HMW MAP ratio.

PMID- 10403410
TI  - Do antiseptics and disinfectants select for antibiotic resistance?

PMID- 10403411
TI  - Comparison of a commercial test for serotyping heat-stable antigens of
      Campylobacter jejuni with genotyping by pulsed-field gel electrophoresis.
AB  - A new commercial serotyping set based on heat-stable Penner's antigens was
      compared with pulsed-field gel electrophoresis (PFGE) with SmaI and SacII
      restriction endonucleases. Among 50 isolates of Campylobacter jejuni from Finnish
      patients, which represented predominant PFGE patterns selected from isolates from
      sporadic cases and isolates associated with small outbreaks, 11 different
      serotypes were demonstrated from 43 typable isolates. Several PFGE patterns could
      be found within one serotype; on the other hand, several serotypes could be
      demonstrated within one PFGE type. Most isolates originated from sporadic cases;
      however, some isolates were epidemiologically associated and showed identical
      serotypes and PFGE patterns. Although the new serotyping set would have been
      useful in the few epidemic cases studied, several isolates (14%) representing the
      major PFGE patterns remained untypable or gave weakly positive agglutination
      reactions only suggesting a plausible serotype (18%). This might restrict the use
      of the novel serotyping set, at least in Finland.

PMID- 10403412
TI  - Investigation of the types and characteristics of the proteolytic enzymes formed
      by diverse strains of Proteus species.
AB  - Many diverse clinical isolates of Proteus mirabilis (48 strains), P. penneri
      (25), P. vulgaris biogroup 2 (48) and P. vulgaris biogroup 3 (21) from man were
      examined for their ability to produce proteolytic enzymes and the nature and
      characteristics of the proteases were studied. All the P. penneri isolates, most
      (94-90%) of the P. mirabilis and P. vulgaris biogroup 2 isolates, but only 71% of
      the P. vulgaris biogroup 3 isolates, secreted proteolytic enzymes. These were
      detected most readily at pH 8 with gelatin as substrate. A strong correlation was
      found between the ability of a strain to form swarming growth and its ability to
      secrete proteases. Non-swarming isolates invariably appeared to be non
      proteolytic. However, some isolates, particularly of P. vulgaris biogroup 3, were
      non-proteolytic even when they formed swarming growth. Analysis of the secreted
      enzymes of the different Proteus spp. on polyacrylamide-gelatin gels under
      various constraints of pH and other factors showed that they were all EDTA
      sensitive metalloproteinases. Analysis of the kinetics of production of the
      proteases revealed the formation of an additional protease of undefined type and
      function that was cell-associated and formed before the others were secreted. The
      secreted protease was subsequently modified to two isoforms whose mass (53-46
      kDa) varied with the Proteus spp. and the strain. There was no evidence that the
      secreted proteases of strains of Proteus spp. were of types other than
      metalloproteinases.

PMID- 10403413
TI  - Fur and iron transport proteins in the Brazilian purpuric fever clone of
      Haemophilus influenzae biogroup aegyptius.
AB  - The Brazilian purpuric fever (BPF) clone of Haemophilus influenzae biogroup
      aegyptius causes a fatal septicaemic disease, resembling fulminant meningococcal
      sepsis, in children. When isolate F3031 was grown under iron-limiting conditions,
      the presence of several iron-regulated proteins of 38-110 kDa was revealed by
      electrophoretic analysis and a Fur homologue was shown by immunoblotting. Dot
      blot assays and immunoblotting indicated that BPF cells bound human transferrin
      and contained transferrin-binding proteins in the outer membrane. However, the
      binding activity and the biosynthesis of these proteins were detected even under
      iron-rich conditions. Immunoblot analysis demonstrated the presence of a
      periplasmic protein related to the ferric iron-binding protein A (FbpA), the
      major iron-binding protein described in Neisseria spp. However, the FbpA
      homologue in strain F3031 was constitutively expressed and was smaller than the
      periplasmic protein detected in H. influenzae type b strain Eagan. The periplasm
      of strain F3031 also contained a protein related to the Streptococcus parasanguis
      FimA protein which recently has been shown to be involved in iron acquisition in
      Yersinia pestis. Although the Eagan and F3031 FimA homologues had a similar mol.
      wt, of 31 kDa, the expression of the BPF fimA-like gene was not regulated by the
      iron concentration of the culture medium.

PMID- 10403414
TI  - Bactericidal activity of rat lung lavage fluid against Bordetella pertussis.
AB  - Cell-free lung lavage fluid (LLF) from healthy normal rats killed phase I (wild
      type, virulent) Bordetella pertussis at 37 degrees C in vitro. B. parapertussis
      was also killed by the LLF, but phase IV (avirulent mutant) B. pertussis and some
      other common bacterial species, including B. bronchiseptica, were not.
      Transmission electron microscopy of thin sections of the phase I B. pertussis
      showed extensive structural damage and cell lysis. None of the other mammalian
      species tested had LLF with bactericidal activity against B. pertussis as high as
      that of the rat. Rats killed with halothane yielded LLF with higher bactericidal
      activity than when CO2 was used. Ultracentrifugation of LLF at 55,000 g gave a
      surfactant (pellet) fraction that had c. 95% of the bactericidal activity and
      which was biochemically distinct from the 5% of activity in the supernate
      fraction. Phospholipids and fatty acids appeared to be involved in LLF
      bactericidal activity, but not complement or lysozyme. Arachidonic acid was the
      most active of the fatty acids tested. Artificial surfactant, as used in
      premature infants, had no bactericidal effect on B. pertussis.

PMID- 10403415
TI  - Evidence for the presence in Burkholderia pseudomallei of a type III secretion
      system-associated gene cluster.
AB  - Burkholderia pseudomallei, the causative agent of melioidosis, contains a cluster
      of putative genes homologous to those encoding HpaP, HrcQ, HrcR, HrcS and HrpV in
      the plant pathogen Ralstonia solanacearum. In R. solanacearum, these genes form
      part of a type III secretion-associated pathogenicity island. The order of the
      genes in B. pseudomallei is directly equivalent to that found in R. solanacearum.
      The B. pseudomallei proteins share 49.5% (HpaP), 52.6% (HrcQ), 80.0% (HrcR),
      72.1% (HrcS) and 46.7% (HrpV) similarity, respectively, with their equivalent R.
      solanacearum proteins. The presence of type III secretion-associated genes in B.
      pseudomallei pathogens suggests a possible role for type III secretion systems in
      the pathogenicity of this organism.

PMID- 10403416
TI  - Analysis of fliC variation among clinical isolates of Burkholderia cepacia.
AB  - PCR and restriction fragment length polymorphism (RFLP) typing of flagellin genes
      (fliC) from 57 clinical isolates of Burkholderia cepacia indicated that only type
      11 flagellins were present. Twenty-two isolates previously identified as the
      epidemic UK cystic fibrosis strain were indistinguishable by this method, as were
      11 isolates from a pseudo-outbreak in Senegal. Other clinical isolates, including
      19 from disparate sources in Malaysia, were separated into nine fliC RFLP groups,
      exhibiting a large degree of divergence. When isolates were indistinguishable by
      fliC genotyping, their similarity was confirmed by whole genome macro-restriction
      analysis with pulsed-field gel electrophoresis following XbaI digestion. The
      variation in fliC sequences of B. cepacia was far greater than that with B.
      pseudomallei, supporting the view that 'B. cepacia', as currently defined, may
      comprise several different genomic species.

PMID- 10403417
TI  - In-vitro resistance to azoles associated with mitochondrial DNA deficiency in
      Candida glabrata.
AB  - A commercially available disk diffusion procedure was used in a large-scale study
      to evaluate the susceptibility of a wide range of Candida isolates to polyenes
      and azoles. With almost all isolates of C. glabrata resistant colonies were
      present within the inhibition zones for the azole compounds fluconazole,
      ketoconazole and miconazole, and less frequently for isoconazole, econazole and
      clotrimazole. Ten randomly selected isolates were cloned by limiting dilution and
      the susceptibility of the resulting strains to polyenes and azoles was
      determined. All strains presented a similar susceptibility pattern with
      sensitivity to polyenes and the presence of resistant colonies for all azole
      compounds except tioconazole. For each strain and each antifungal agent, one of
      these resistant colonies was subcultured and studied for antifungal
      susceptibility. All these colonies showed similar properties regardless of which
      antifungal agent allowed their selection, with increased sensitivity to polyenes
      and cross-resistance to the azole compounds except tioconazole. Similar results
      were obtained on Shadomy's modified medium and on synthetic medium. Likewise,
      determination of MICs by the Etest method confirmed the resistance to
      fluconazole. Comparative growth studies revealed a respiratory deficiency in the
      mutants caused by mitochondrial DNA (mtDNA) deletions. In addition, 'petite'
      mutants were obtained from a wild-type strain by exposure to ethidium bromide,
      and these respiratory mutants were shown to be resistant to azoles. These results
      demonstrate the relationship between mtDNA deficiency and resistance to azoles,
      and provide an interesting model to study the mechanisms of action of these
      antifungal agents.

PMID- 10403419
TI  - Usefulness of rat-derived antigen in the serodiagnosis of Pneumocystis carinii
      infection.
AB  - Sera from patients with likely and possible Pneumocystis carinii pneumonia (PCP)
      on the basis of clinical information and laboratory investigations were tested by
      immunoblotting to assess the usefulness of trophozoites in the serodiagnosis of
      PCP. IgG antibodies to 50-60- kDa proteins were demonstrated with cyst antigen,
      but antibodies to additional proteins of 61, 70, 82, 95, 99 and 116 kDa were
      found with trophozoite antigen. These bands were not demonstrated with control
      sera. IgG antibody to the 116-kDa protein was found in 18 (46%) of 39 sera from
      patients with possible PCP compared with 5 (17%) of 30 sera from patients with
      likely PCP. There was no other significant difference between the two patient
      groups in detection of these proteins. Sera with higher indirect
      immunofluorescence assay (IFA) IgG titres were more likely to be immunoblot
      positive. Only 4 of 16 patients with likely PCP were IgG negative in the IFA;
      three of these were IgG immunoblot positive. In 4 of 10 patients with likely PCP
      and 6 of 15 patients with possible PCP, demonstration of IgM or IgA, or both, by
      IFA or immunoblotting provided evidence suggestive of current infection. This
      study confirms the usefulness of rat-derived antigen, especially trophozoite
      antigen, in PCP serology. The IgG IFA remains the most useful test, but IgM and
      IgA testing and immunoblotting can support the diagnosis.

PMID- 10403418
TI  - Role of dimorphism in the development of Candida albicans biofilms.
AB  - Two model biofilm systems, involving growth on disks of catheter material or on
      cylindrical cellulose filters, were used to investigate the structure of Candida
      albicans biofilms. To assess the importance of dimorphism in biofilm development,
      biofilms produced by two wild-type strains were compared with those formed by two
      morphological mutants, incapable of yeast and hyphal growth, respectively.
      Scanning electron microscopy and thin sections of biofilms examined by light
      microscopy revealed that biofilms of the wild-type strains formed on catheter
      disks consisted of two distinct layers: a thin, basal yeast layer and a thicker,
      but more open, hyphal layer. The hypha- mutant produced only the basal layer,
      whereas the yeast- mutant formed a thicker, hyphal biofilm equivalent to the
      outer zone of the wild-type structures. Biofilms of the yeast- mutant were more
      easily detached from the catheter surface than the others, suggesting that the
      basal yeast layer has an important role in anchoring the biofilm to the surface.
      Biofilms formed on cylindrical cellulose filters were quite different in
      appearance. The hypha- mutant and both wild types produced exclusively yeast-form
      biofilms whereas the yeast- mutant generated a dense hyphal mat on the top of the
      filter. All these biofilms, irrespective of morphological form, were resistant to
      the antifungal agent, amphotericin B. Overall, these results indicate that the
      structure of a C. albicans biofilm depends on the nature of the contact surface,
      but that some surfaces produce biofilms with a layered architecture resembling to
      that described for bacterial systems.

PMID- 10403420
TI  - In-vitro anti-chlamydial activities of free and liposomal tetracycline and
      doxycycline.
AB  - The purpose of this study was to evaluate the anti-chlamydial activities in vitro
      of liposome-encapsulated doxycycline (Dox) and tetracycline (Tet) in comparison
      with free Dox and Tet. Dox and Tet encapsulated in cationic (CAL), anionic (ANL)
      and neutral (NTL) liposomes by sonication, were quantified by high-performance
      liquid chromatography. Anti-chlamydial activities were determined by addition of
      serial dilutions of antibiotics (MIC 0.12-0.007 mg/L; MBC 4-0.25 mg/L) to HeLa
      229 cell monolayers inoculated with Chlamydia trachomatis L2/434/Bu (10(3)
      ifu/well). After incubation for 72 h at 37 degrees C, chlamydial inclusions were
      stained by the May-Grunwald Giemsa method to establish MICs. MBCs were determined
      in chlamydial agent-free medium after second passages. Dox-encapsulation
      efficiencies were 28.6 SEM 6.4% in cationic (CAL-Dox), 49.1 SEM 6.7% in anionic
      (ANL-Dox) and 21.0 SEM 0.8% in neutral (NTL-Dox) liposomes. Tet-encapsulation
      efficiencies were 3.5 SEM 0.3% in anionic (ANL-Tet) and 2.2 SEM 0.6% in neutral
      (NTL-Tet) liposomes; no Tet was detected in cationic (CAL-Tet) liposomes. MIC
      values were 0.06 mg/L for Dox, 0.12 mg/L for Tet, 0.03 mg/L for CAL-Dox, NTL-Dox
      and NTL-Tet, and 0.01 mg/L for ANL-Dox and ANL-Tet. MBCs were 4 mg/L for Tet, 0.5
      mg/L for CAL-Dox and NTL-Dox, and 1 mg/L for Dox, ANL-Dox, ANL-Tet, NTL-Tet and
      NTL-Tet. For MICs, the relative increase in anti-chlamydial activity observed
      with liposomal formulations compared to the corresponding free antibiotic ranged
      from 2- to 6-fold with Dox and from 4- to 10-fold with Tet. For MBCs, the
      relative increases in anti-chlamydial activity were 2- and 4-fold with liposome
      encapsulated Dox and Tet, respectively. Dox was better encapsulated than Tet in
      all liposomes. Liposome-encapsulated drugs showed greater anti-chlamydial
      activities than their free forms; thus, these drug formulations have potential in
      the treatment of chlamydial infections.

PMID- 10403421
TI  - Identification of clinically isolated vancomycin-resistant enterococci:
      comparison of API and BBL Crystal systems.
AB  - Twenty-eight phenotypically separate strains of clinically isolated vancomycin
      resistant enterococci have been investigated with two API identification kit
      systems (20 Strep and Rapid ID 32 Strep) and two BBL Crystal kits (Gram Positive
      and Rapid Gram Positive). All strains were identified as Enterococcus faecium by
      a reference laboratory. The Rapid ID 32 kit positively identified 15 of 28
      strains (54%), but only two (7%) were identified correctly: 11 were identified as
      'doubtful' or 'to genus level' and two gave 'unacceptable' profiles. The API 20
      Strep kit identified 27 strains (96%), but only 16 (57%) were identified
      correctly as E. faecium. The Rapid ID 32 kit erred by either positively
      misidentifying vancomycin-resistant E. faecium as E. casseliflavus or E.
      gallinarum, or indicated that this was the most likely identification, while the
      API 20 Strep kit more commonly produced a misidentification as E. casseliflavus.
      The Crystal Gram Positive and Rapid Gram Positive kits correctly identified 26
      (93%) and 27 (96%) of the strains, respectively.

PMID- 10403422
TI  - Microbiology of retroperitoneal abscesses in children.
AB  - Samples of pus from 41 children with retroperitoneal abscess treated between 1974
      and 1994 yielded a total of 125 organisms (3.0 isolates/specimen); 58 isolates
      were aerobic and facultative species (1.4/specimen) and 67 were anaerobic
      (1.6/specimen). Aerobic bacteria only were isolated from 7 (17%) abscesses,
      anaerobic bacteria only from 3 (7%) and mixed aerobic and anaerobic bacteria from
      31 (76%); 34 (83%) infections were polymicrobial. The predominant aerobic and
      facultative isolates were Escherichia coli (19 isolates) and Staphylococcus
      aureus (6), and the predominant anaerobes were Peptostreptococcus spp. (18
      isolates), Bacteroides spp. (22) and Prevotella spp. (5).

PMID- 10403423
TI  - Use of a low nutrient culture medium for the identification of bacteria causing
      severe ocular infection.
AB  - A low nutrient culture medium was used to identify the pathogens in four cases of
      persisting ocular infection. Bacto R2A agar was used in addition to conventional
      liquid- and solid-phase media to culture pathogenic bacteria from one case of
      recurrent keratitis, one case of suture-related keratitis with endophthalmitis
      and two eyes (two patients) with post-operative endophthalmitis. In each case, a
      pathogen was identified solely with R2A agar after culture for 6 days. Species
      isolated were Pseudomonas aeruginosa (one), Propionibacterium acnes (two) and
      Staphylococcus aureus (one). Antibiotic therapy was tailored to conform to the
      sensitivity of the cultured organism in each case. The use of Bacto R2A low
      nutrient agar should be considered in culture negative eyes not showing clinical
      improvement, or for chronic cases where bacteria may have become adapted to more
      stringent ocular environments.

PMID- 10403424
TI  - Inhibitory effect of rose oil products on Helicobacter pylori growth in vitro:
      preliminary report.

PMID- 10403425
TI  - Ciliary neurotrophic factor protects hippocampal neurons from excitotoxic damage.
AB  - The loss of neurons is responsible for many acute neurological disorders as well
      as chronic neurodegenerative diseases. This cell loss might be prevented by a
      direct delivery of neurotrophic factors. Therefore, we investigated the capacity
      of ciliary neurotrophic factor (CNTF) and nerve growth factor (NGF) as well as
      the combination of both growth factors on the glutamate-induced excitotoxic
      damage in hippocampal cultures. The exposure of hippocampal neuronal/glial co
      cultures to 0.5 mM L-glutamate for 1 h induced pronounced neurotoxicity evaluated
      18 h later by trypan blue staining and morphological criteria. The damaged
      neurons showed both apoptotic and necrotic features. However, CNTF (1-1000 pg/ml)
      reduced neuronal degeneration when administered 6 and 24 h before induction of
      injury and remained in contact with the cells until evaluation of neuronal
      damage. Furthermore, NGF (1 ng/ml) also rescued the hippocampal neurons under the
      same experimental conditions and with a similar to CNTF potency. However, the co
      administration of NGF and CNTF (but not either factor alone) restored the
      neuronal survival to control levels. Our results support the hypothesis that
      administering neurotrophic factors could represent an alternative strategy for
      the treatment of acute and chronic brain disorders.

PMID- 10403427
TI  - Differential regulation of glutamate, aspartate and gamma-amino-butyrate release
      by N-methyl-D-aspartate receptors in rat striatum after partial and extensive
      lesions to the nigro-striatal dopamine pathway.
AB  - The in vivo microdialysis methodology was used to assess the effect of N-methyl-D
      aspartate (NMDA) receptor ligands on glutamate (GLU), aspartate (ASP) and gamma
      aminobutyrate (GABA) extracellular levels in the striatum of anaesthetized rats,
      after damage to the dopamine (DA) nigrostriatal pathway by injections of
      different doses of 6-hydroxydopamine (6-OH-DA) seven days earlier. The 6-OH-DA
      treated rats were divided into two groups, corresponding to animals with 20-80%
      (partial) and 85-99% (extensive) striatal DA tissue depletion, respectively. In
      rats with partial DA depletion, the striatal extracellular ASP levels
      significantly increased after intrastriatal dialysis perfusion with MK-801 (100
      microM), an antagonist of NMDA receptors. In addition, a change in the pattern of
      local NMDA (500 microM)- induced efflux of ASP was observed in the striatum of
      these rats. However, in these partially DA-depleted striata no changes were found
      in basal extracellular levels of GLU, ASP and GABA or in NMDA- and MK-801
      mediated effluxes of GLU and GABA relative to striata from sham rats. In
      contrast, rats with extensive striatal DA depletion exhibited a significant
      increase in ASP and GABA extracellular striatal levels, after intrastriatal
      dialysis perfusion with NMDA. In addition, the MK-801-mediated stimulation of
      extracellular ASP levels was accentuated along with the appearance of a MK-801
      mediated increase in extracellular striatal GLU. Finally, basal extracellular
      levels of ASP, but not of GLU and GABA, were found to increase in extensive DA
      depleted striata when compared to sham and partially DA-depleted striata. Thus, a
      differential regulation of basal and NMDA receptor-mediated release of
      transmitter amino acids occur seven days after partial and extensive DA-depleted
      striatum by 6-OH-DA-induced lesions of the nigrostriatal DA pathway. These
      findings may have implications as regards the participation of NMDA receptors in
      the compensatory mechanisms associated with the progress of Parkinson's disease,
      as well as in the treatment of this neurological disorder.

PMID- 10403426
TI  - Increased expression of glyceraldehyde-3-phosphate dehydrogenase in cultured
      astrocytes following exposure to manganese.
AB  - Manganism is a disorder characterized by hyperintensities in basal ganglia
      structures on magnetic resonance imaging which may be the consequence of
      manganese deposition in these areas. Since manganese is taken up avidly into
      astrocytes and is known to interfere with cerebral energy metabolism, we studied
      the effect of this metal on the expression and activity of the glycolytic enzyme
      glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in primary cultures of
      astrocytes. Treatment with 100 microM manganese for 7 days increased both the
      Vmax and Km values for GAPDH which was not reproducible with other divalent
      metals. Using RT-PCR, increased GAPDH expression was detected in cells exposed to
      manganese compared with controls. No changes in cytochrome oxidase activity or
      ATP levels were observed, and lactate production was unaffected, in manganese
      treated cells. These findings provide evidence of a possible role for GAPDH in
      the mediation of the effects of manganese on central nervous system function.

PMID- 10403428
TI  - A linear endothelin-1 analogue: solution structure of ET-1[Aib1,3,11,15, Nle7] by
      nuclear magnetic resonance spectroscopy and molecular modelling.
AB  - Two-dimensional nuclear magnetic resonance techniques and a combination of
      distance geometry and molecular dynamics calculations were utilised to determine
      the three dimensional solution structure of an ET-1 analogue, ET-1[Aib1,3,11,15,
      Nle7], in a methanol-d3/water co-solvent. The modelled structure shows that the
      peptide folds into a consistent alpha-helical conformation between residues Ser4
      His16 while the C-terminus prefers no fixed conformation. Our studies confirm
      that the disulphide links which are normally associated with the endothelin
      family of neuropeptides are not important for the formation of a helical
      conformation in solution. This full length, modified, synthetic linear ET-1
      analogue plays a vital role towards designing endothelin receptor agonists.
      Structure activity relationships are discussed in terms of the conformational
      features of the calculated structure.

PMID- 10403429
TI  - NGF mediates the neuroprotective effect of the beta2-adrenoceptor agonist
      clenbuterol in vitro and in vivo: evidence from an NGF-antisense study.
AB  - Previous studies in our laboratory suggested that neuroprotective effects of the
      beta2-adrenoceptor agonist clenbuterol in vitro and in vivo occurred due to
      enhanced synthesis of nerve growth factor. The aim of the present study was to
      evaluate the effects of a phosphothioated NGF oligodeoxynucleotide on
      neuroprotection by clenbuterol in vitro and in vivo. After clenbuterol treatment
      (1-100 microM) an increase in nerve growth factor mRNA and protein levels (200
      300% of control) was observed in primary cultures of rat cortical astrocytes.
      Nerve growth factor antisense oligonucleotide (0.3-1 microM for 3 days) reduced
      the content of nerve growth factor protein in the medium of the astrocytes
      concentration-dependently to 20% of control level. Nerve growth factor content in
      the medium of mixed hippocampal cells was reduced to 55% of sister cultures
      receiving the vehicle or a random control oligonucleotide. In mixed hippocampal
      cultures pretreated with random oligonucleotide (1 microM, 30 h), clenbuterol (10
      microM) reduced the percentage of damaged neurons after glutamate exposure (0.5
      mM, 1 h) to 17%. Pretreatment with nerve growth factor antisense oligonucleotide
      (1 microM) for 30 h before glutamate incubation blocked the protective effect of
      clenbuterol. In vivo, clenbuterol (0.01-0.1 mg/kg) reduced the infarct volume in
      a rat model of permanent focal cerebral ischemia dose-dependently. Nerve growth
      factor antisense oligonucleotides injected into the cortical tissue before
      ischemia abolished the cerebroprotective effect of clenbuterol. Our results
      indicate that the nerve growth factor antisense oligonucleotide presented in this
      study is a useful tool to investigate the effects of nerve growth factor knock
      down. By using the nerve growth factor antisense oligonucleotide we could
      demonstrate that nerve growth factor mediated the neuroprotective effects of the
      beta2-adrenoceptor agonist clenbuterol in vitro and in vivo.

PMID- 10403430
TI  - Modest cholinergic deafferentation fails to alter hippocampal G-proteins.
AB  - The integrity of hippocampal G-protein mediated signalling following ibotenate
      induced lesion of the medial septum was examined. The lesion was confined
      histologically to the septum and induced a 23% reduction in hippocampal choline
      acetyltransferase (ChAT) activity and G-proteins levels and related enzyme
      activities were measured in the hippocampus following a 21 day survival period.
      The relative levels of five G-protein subunits (Gbeta, G(alpha)o, G(alpha)i1,
      G(alpha)i2, and G(alpha)s-L), basal GTPase, the degree of carbachol- or baclofen
      stimulated GTPase activities, and the basal and fluoroaluminate-stimulated
      adenylate cyclase activities were apparently unaffected. To determine if our
      assay methodology was sensitive to changes in pre-synaptic signalling, we
      compared G-protein density in synaptosomes with total hippocampal homogenates.
      The concentration of G(alpha)q/11, G(alpha)i1, and G(alpha)i2. were significantly
      lower in synaptosomes, while G(alpha)o, was only marginally reduced. Thus, modest
      lesions of the medial-septal nucleus fail to alter G-protein signalling. However,
      our findings that G-protein density is lower in synaptosomal membranes than in
      total homogenates, indicates that the analysis of signalling events in
      synaptosomes following deafferentation could clarify adaptive changes which may
      occur at the presynaptic level.

PMID- 10403431
TI  - Lipid mediated gene delivery in the adult rat brain: quantitative analysis of
      expression.
AB  - Gene transfer into the adult brain is potentially an attractive alternative to
      commonly employed transgenic approaches. DNA-lipid complexes have been used to
      obtain brain gene transfer, but data are sparse to indicate to what extent this
      results in significant expression of functional protein. Here, an expression
      construct encoding the functional reporter, chloramphenicol-acetyl-transferase
      (CAT), was complexed to a novel biodegradable lipid, and delivered into the rat
      brain. CAT-activity was assayed in tissue extracts to allow a precise
      quantitation of functional enzyme protein. Following bilateral intraventricular
      (i.c.v.) injection, robust enzyme activity was found in all brain regions
      studied, peaking at 4 weeks. Other routes of administration, e.g. intra
      parenchymal injection or chronic infusion of complexes, resulted in marginal or
      no activity. Presence of CAT mRNA and plasmid DNA in tissue extracts was
      confirmed at 4 weeks post i.c.v. administration. In agreement with previous
      studies, labelled lipid-DNA complexes were mainly found in the ventricular
      ependyma. Present data support the feasibility of lipid mediated brain gene
      transfer, and outline some of its anatomical and temporal limitations.

PMID- 10403432
TI  - Regional distribution and relative amounts of glutamate decarboxylase isoforms in
      rat and mouse brain.
AB  - The levels of the two isoforms of glutamate decarboxylase (GAD) were measured in
      12 regions of adult rat brain and three regions of mouse brain by sodium
      dodecylsulfate-polyacrylamide gel electrophoresis and immunoblotting with an
      antiserum that recognizes the identical C-terminal sequence in both isoforms from
      both species. In rat brain the amount of smaller isoform, GAD65, was greater than
      that of the larger isoform, GAD67, in all twelve regions. GAD65 ranged from 77
      89% of total GAD in frontal cortex, hippocampus, hypothalamus, midbrain,
      olfactory bulb, periaqueductal gray matter, substantia nigra, striatum, thalamus
      and the ventral tegmental area. The proportion of GAD65 was lower in amygdala and
      cerebellum but still greater than half of the total. There was a strong
      correlation between total GAD protein and GAD activity. In the three mouse brain
      regions analysed (cerebellum, cerebral cortex and hippocampus) the proportion of
      GAD65 (35,47, and 51% of total GAD) was significantly lower than in the
      corresponding rat-brain regions. The amount of GAD67 was greater than the amount
      of GAD65 in mouse cerebellum and was approximately equal to the amount of GAD65
      in mouse cerebral cortex and hippocampus.

PMID- 10403433
TI  - Chronic D1 and D2 dopaminomimetic treatment of MPTP-denervated monkeys: effects
      on basal ganglia GABA(A)/benzodiazepine receptor complex and GABA content.
AB  - The effect of various chronic dopaminergic treatments in 1-Methyl-4-phenyl
      1,2,3,6-tetrahydropyridine (MPTP) monkeys on the brain gamma-aminobutyric acid
      type A (GABA(A)) /benzodiazepine receptor complex and GABA content was
      investigated in order to assess the GABAergic involvement in dopaminomimetic
      induced dyskinesia. Three MPTP monkeys received for one month pulsatile
      administrations of the D1 dopamine (DA) receptor agonist SKF 82958 whereas three
      others received the same dose of SKF 82958 by continuous infusion. A long acting
      D2 DA receptor agonist, cabergoline, was given to another three animals.
      Untreated MPTP as well as naive control animals were also included. Pulsatile SKF
      82958 relieved parkinsonian symptoms but was also associated with dyskinesia in
      two of the three animals whereas animals treated continuously with SKF 82958
      remained as untreated MPTP monkeys. Chronic cabergoline administration improved
      motor response with no persistent dyskinesia. MPTP treatment induced a decrease
      of 3H-flunitrazepam binding in the medial anterior part of caudate-putamen and an
      increase in the internal segment of globus pallidus (GPi) which was in general
      unchanged by pulsatile or continuous SKF 82958 administration. Throughout the
      striatum, binding of 3H-flunitrazepam remained reduced in MPTP monkeys treated
      with cabergoline but was not significantly lower than untreated MPTP monkeys.
      Moreover, cabergoline treatment reversed the MPTP-induced increase in 3H
      flunitrazepam binding in the GPi. GABA concentrations remained unchanged in the
      striatum, external segment of globus pallidus and GPi following MPTP denervation.
      Pulsatile but not continuous SKF 82958 administration decreased putamen GABA
      content whereas cabergoline treatment decreased caudate GABA. No alteration in
      GABA levels were observed in the GPe and GPi following the experimental
      treatments. These results suggest that: (1) D2-like receptor stimulation with
      cabergoline modulates GABA(A) receptor density in striatal subregions
      anatomically related to associative cortical afferent and (2) the absence of
      dyskinesia in dopaminomimetic-treated monkeys might be associated with the
      reversal of the MPTP-induced upregulation of the GABA(A)/benzodiazepine receptor
      complex in the Gpi.

PMID- 10403435
TI  - International standards for rodent quality.

PMID- 10403434
TI  - Mousepox: a threat to U.S. mouse colonies.

PMID- 10403436
TI  - Spontaneous ophthalmic lesions in young Swiss mice.
AB  - BACKGROUND AND PURPOSE: Outbred mice are frequently used in toxicity evaluation.
      Due to their small size, ophthalmologic examination of such animals is difficult
      with regard to restraint and use of instruments designed for human medicine. The
      clinical appearance and incidence of spontaneous ophthalmic lesions should be
      helpful in selecting mice for toxicity studies and allow distinction between
      intercurrent spontaneous ocular changes and those attributable to drugs or
      chemicals. METHODS: Pretest ophthalmologic examinations of about 3,000 4- to 5
      week-old Swiss mice, Crl:CD1 (ICR)BR, conducted in 1995 and 1996, provided
      information about spontaneous ocular changes and their incidence. Eye evaluations
      were performed after pupil dilatation (0.5% tropicamide instillation), using
      indirect ophthalmoscopy, and when indicated, a portable slit lamp. RESULTS:
      Lenticular opacities and heterogeneity/prominence were the most common findings
      (up to 19%) in the anterior segment. Abnormalities of the cornea and iris were
      detected in up to 4% of mice. Hyaloid artery remnant, as well as isolated cases
      of floating bodies or hemorrhage, was observed in the vitreous of 12 to 17% of
      mice. Approximately 2 to 4% of mice had colobomatous fundus, retinal fold, or
      retinal atrophy. A few mice had chorioretinal atrophy, hemorrhage, or abnormal
      pattern of the retinal vasculature. Remaining findings consisted of incomplete
      palpebral fissure, microphthalmia, exophthalmia, ophthalmic hemorrhage, and
      scleral mass. CONCLUSIONS: Due to severity of the condition or interference with
      ocular examination, affected mice should be eliminated from experimental studies.
      Hence, pretest ocular examinations of mice are indicated in safety-assessment
      toxicity studies.

PMID- 10403437
TI  - Neuroendocrine (ECL cell) differentiation of spontaneous gastric carcinomas of
      cotton rats (Sigmodon hispidus).
AB  - BACKGROUND AND PURPOSE: Female inbred cotton rats develop adenocarcinomas in the
      oxyntic mucosa. Since a female preponderance is typical for enterochromaffin-like
      (ECL) cell tumors, we examined such tumors for ECL cells. Gastrin plays a
      decisive role in ECL cell tumorigenesis, so blood gastrin concentration and
      gastric mucosal pH were measured. METHODS: The stomachs from six female cotton
      rats (6 to 8 months old) were studied histologically, and at euthanasia, gastric
      mucosal pH was determined. Euthanasia was performed on 15 other female cotton
      rats of similar age for determination of blood gastrin values by radioimmunoassay
      (RIA) and gastric mucosal pH. Rats were classified macroscopically to have normal
      or thick oxyntic mucosa, with or without tumor. RESULTS: Among the six cotton
      rats studied histologically, two 6-month-old rats had normal and two others had
      thick gastric mucosa, whereas two 8-month-old rats had thick mucosa with tumors.
      The ECL cells were markedly hyperplastic in all rats with thick mucosa, and ECL
      cells were found in the neoplastic parenchyma. All cotton rats with normal
      appearing gastric mucosa had pH <2.5, whereas 14 rats with thick mucosa had pH
      >3.1 and hypergastrinemia. CONCLUSIONS: Gastrin may play a major role in ECL cell
      hyperplasia and, perhaps, in adenocarcinoma genesis.

PMID- 10403438
TI  - Effect of respiratory tract disease on pharmacokinetics of tilmicosin in rats.
AB  - BACKGROUND AND PURPOSE: In rats, murine respiratory mycoplasmosis is caused by
      Mycoplasma pulmonis. Tilmicosin, a macrolide antibiotic, has good tissue
      penetration and reaches high concentration in the lungs. Therefore, a model for
      studying the effects of disease on pharmacokinetics of tilmicosin was developed,
      using LEW rats. METHODS: Seventy-two LEW rats were assigned at random to two
      groups: one group was inoculated with M. pulmonis, and the other served as an
      uninoculated control group. On postinoculation day 31, all rats received a single
      dose of tilmicosin (20 mg/kg of body weight, subcutaneously). RESULTS:
      Concentration of tilmicosin in the lungs of both groups of rats was significantly
      higher than serum tilmicosin concentration at all times. Infected rats had
      significantly higher lung tilmicosin concentration than did noninfected rats. No
      correlation was found between pH of the lungs and tilmicosin concentration in the
      lungs in either treatment group, nor did treatment have any effect on pH of the
      muscle. CONCLUSION: Tilmicosin accumulates in the lungs, and
      infection/inflammation further improves its tissue penetration.

PMID- 10403439
TI  - Characterization of the interaction of Escherichia coli heat-stable enterotoxixn
      (STa) with its intestinal putative receptor in various age groups of mice, using
      flow cytometry and binding assays.
AB  - BACKGROUND AND PURPOSE: Enterotoxigenic Escherichia coli heat-stable enterotoxin
      (STa) is a major cause of diarrhea in young animals. Age-dependent variation in
      the density and affinity of the mouse enterocyte receptors specific for STa was
      investigated. METHODS: Four age groups (2-day-, 1- and 2-week-, and 2-month-old)
      of Swiss Webster mice were studied (8 to 10 mice/group). Flow cytometry and
      radiolabeled STa (125I-STa) assays were used as reliable quantitative measures
      for characterization of STa-enterocyte receptor interaction. RESULTS AND
      CONCLUSIONS: Interaction of STa with its putative receptor was stronger for
      enterocytes of 2-day-old mice. Scatchard analysis of 125I-STa-receptor
      interaction suggested that STa-receptors exist at higher numbers on enterocytes
      from 2-day-old (7.2 nmol/mg) than older (0.30, 0.36, and 0.40 nmol/mg for 1-week
      , 2-week-, and 2-month-old mice, respectively). Additionally, receptors from 2
      day-old mice had greater affinity for STa (Kd = 75 nM) than did receptors from
      older mice (Kd = 125, 1,430, and 1,111 nM for 1-week-, 2-week-, and 2-month-old
      mice, respectively). Density of STa receptors on enterocytes and their affinity
      to STa may determine extent of binding and severity of the secretory response,
      and may explain the high susceptibility of newborn animals and human infants to
      STa-mediated diarrhea.

PMID- 10403440
TI  - Radiographic, histologic, and cytologic lesions associated with mutations in the
      fitness1(4226SB) locus of mice.
AB  - BACKGROUND AND PURPOSE: Previous investigation of fitness1(4226SB) mice revealed
      growth retardation and microcytic, hypochromic anemia with functional iron
      deficiency. Serum biochemical analysis suggested protein-losing enteropathy and
      liver dysfunction. METHODS: Radiography was done to assess lumbar bone lesions in
      mice hemizygous for fitness1 (fit1) [c fit1(4226SB/Df(c Mod2 sh1)26DVT] and age
      matched sibling controls [c(ch)+/c(ch)+] at 40 or 60 days of age. Macroscopic and
      microscopic lesions were evaluated at necropsy. Bone marrow was examined
      cytologically to evaluate hematopoietic lesions. RESULTS: Mice hemizygous for
      fit1 had radiographically evident lumbar vertebral abnormalities, including
      various degrees of vertebral body fusion, with loss of intervertebral disk spaces
      and mild, generalized osteopenia. All mutant mice had scoliosis. Several mutant
      mice had lordosis and/or kyphosis of variable severity and mild subluxation at
      the lumbosacral junction. Marked splenomegaly and mild cardiomegaly were evident,
      and bone marrow color ranged from normal to slightly pale. The spleen had marked
      extramedullary hematopoiesis; lumbar vertebrae contained microscopic lesions that
      corresponded to the radiographic lesions. Cytologic examination of bone marrow
      revealed normocellular to hypocellular status, with mild to moderate erythroid
      hypoplasia characterized by mild increase in the myeloid-to-erythroid cell ratio,
      decreased percentage of erythroid precursors, and slight increase in percentage
      of myeloid precursor cells. CONCLUSIONS: Mutations in fit1 directly or indirectly
      cause alteration(s) in blood, organs of hematopoiesis (bone marrow, spleen, and
      liver), heart, and vertebral column, and suggest that this mouse may be a good
      model for study of scoliosis and relationships between iron metabolism and bone
      growth.

PMID- 10403441
TI  - The FLS mouse: a new inbred strain with spontaneous fatty liver.
AB  - BACKGROUND AND PURPOSE: A new strain of mouse, named FLS (fatty liver Shionogi),
      which develops spontaneous fatty liver without obesity, was established by
      inbreeding. Morphologic, physiologic, and genetic characterization of the strain
      was done. METHODS: Characteristics of male FLS mice were compared with those of
      the sister strain, dd Shionogi (DS), which does not develop spontaneous fatty
      liver. A genetic cross experiment was performed by mating FLS with C3H/He/Shi
      mice. RESULTS: The hepatocytes of neonatal FLS mice contained fine lipid droplets
      throughout the lobules, and large lipid droplets appeared as mice aged. Liver
      triglyceride concentrations of FLS mice were fivefold higher than those of DS
      mice, but serum lipid concentrations and the lipoprotein profile did not indicate
      abnormalities. Higher plasma aspartate transaminase and alanine transaminase
      activities in FLS, compared with DS mice, suggested hepatocellular lesions. The
      genetic cross experiment suggested that the fatty liver formation is a complex
      polygenic trait. CONCLUSION: The FLS mice develop a progressive hepatic steatosis
      without obesity and diabetes. The FLS mouse might be a good model for
      investigating hepatic disorders accompanied by fatty liver unrelated to
      alcoholism or obesity.

PMID- 10403442
TI  - Statistical method for characterization of hypertrophic cardiomyopathy by use of
      morphologic and pathologic measurements in pigs (Sus scrofa domestica).
AB  - BACKGROUND AND PURPOSE: Hypertrophic cardiomyopathy (HCM) is characterized by
      symmetric or asymmetric hypertrophy of the left and/or right ventricle.
      Morphologic and pathologic indices (MI and PI) of hearts were established for
      classification of HCM in pigs. METHODS: Fifty on-farm-performance-tested pigs
      (average body weight, 104.3 kg; age, 224.5 days) were randomly selected. Heart
      weight, length, width, heart-to-body weight ratio, and thickness of the cranial
      and middle portions of ventricular septum and left ventricular free wall were
      measured. Myocyte disorganization and necrosis, myocardial and endocardial
      fibrosis, and intramural coronary arterial occlusion were scored. Principal
      component analysis and stepwise regression analysis were used to establish MI and
      PI. RESULTS: MI was established by using the first principal component as the
      dependent variable and applying stepwise regression analysis. Hearts were
      classified as morphologically normal, suspicious, and hypertrophic according to
      the range of MI. The same statistical method was used to find PI. Hearts were
      classified as pathologically normal, moderately affected, or seriously affected
      according to the range of PI. Combining MI and PI, hearts could be classified
      into five groups: no hypertrophy with minor lesion (normal); hypertrophy but with
      rare lesion; no hypertrophy but seriously affected; suspicious; and hypertrophy
      and seriously affected (heart with HCM). Another 119 hearts were collected and
      classified. The variation of heart measurements was consistent with the original
      purpose of classification. CONCLUSIONS: Using fewer measurements for
      identification of HCM objectively in pigs seems to have practical application.

PMID- 10403444
TI  - Behavioral effects of ivermectin in mice.
AB  - BACKGROUND AND PURPOSE: Ivermectin is a common anthelmintic drug, widely used in
      laboratory rodents for treatment of pinworm and mite infestations. We evaluated
      the action of ivermectin on sensitive behavioral tasks in mice during treatment
      for mites within a barrier facility. METHODS: A total of 21 (5 males, 16 females)
      mice (129/SvEv) were used for measuring body weight, open field locomotor
      activity, and rotarod motor coordination. For acoustic startle and prepulse
      inhibition, 20 C57BL/6J and 29 AKR/J mice were studied. For the Morris water
      task, the same 20 C57BL/6J mice were studied. Ivermectin (0.08% sheep drench) was
      administered in the drinking water of the home cage for 8 weeks. Control groups
      received normal tap water in identical bottles. RESULTS: Ivermectin did not
      affect general health, body weight, motor coordination, swimming behavior, or
      spatial learning in several inbred strains of mice. However, it induced a small
      but significant effect on some sensitive behaviors. CONCLUSIONS: A cautious
      approach to initiating ivermectin treatment in mice should be used for sensitive
      behavioral experiments.

PMID- 10403443
TI  - Model of Staphylococcus aureus central venous catheter-associated infection in
      rats.
AB  - BACKGROUND AND PURPOSE: Staphylococcus aureus is an important cause of
      intravascular catheter-associated bacteremia. We developed a rat central venous
      catheter (CVC)-associated infection model to study pathogenesis and treatment.
      METHODS: A silastic lumen-within-lumen catheter and rodent-restraint jacket were
      designed. Subcutaneously tunneled catheters were inserted in the jugular vein of
      20 male Sprague Dawley rats. Twelve rats (group 1) were inoculated with S. aureus
      via the CVC; three rats (group 2) were inoculated with S. aureus via the tail
      vein, five rats (group 3) served as uninfected controls; and three rats (group 4)
      were inoculated with S. aureus via the tail vein but did not undergo CVC
      insertion. Five to eight days after inoculation, animals were euthanized, CVCs
      were aseptically removed, and quantitative culture was done. Quantitative culture
      also was performed on blood, heart, liver, lungs, and kidneys. RESULTS:
      Infection, characterized by bacteremia and metastatic disease, was observed in
      all rats inoculated via the CVC with as few as 100 colony-forming units (CFU) of
      S. aureus. Rats of group 2 were not as likely to develop CVC-associated
      infection, and none of the animals of groups 3 or 4 developed infection.
      CONCLUSIONS: This model of CVC-associated infection should prove suitable for
      studying pathogenesis and treatment of the condition.

PMID- 10403446
TI  - Ventricular pressure and dimension measurements in mice.

PMID- 10403445
TI  - Light-emitting diodes and cool white fluorescent light similarly suppress pineal
      gland melatonin and maintain retinal function and morphology in the rat.
AB  - BACKGROUND AND PURPOSE: A novel light-emitting diode (LED) light source for use
      in animal-habitat lighting was evaluated. METHODS: The LED was evaluated by
      comparing its effectiveness with that of cool white fluorescent light (CWF) in
      suppressing pineal gland melatonin content and maintaining normal retinal
      physiology, as evaluated by use of electroretinography (ERG), and morphology.
      RESULTS: Pineal melatonin concentration was equally suppressed by LED and CWF
      light at five light illuminances (100, 40, 10, 1, and 0.1 lux). There were no
      significant differences in melatonin suppression between LED and CWF light,
      compared with values for unexposed controls. There were no differences in ERG a
      wave implicit times and amplitudes or b-wave implicit times and amplitudes
      between 100-lux LED-exposed rats and 100-lux CWF-exposed rats. Results of retinal
      histologic examination indicated no differences in retinal thickness, rod outer
      segment length, and number of rod nuclei between rats exposed to 100-lux LED and
      100-lux CWF for 14 days. Furthermore, in all eyes, the retinal pigmented
      epithelium was intact and not vacuolated, whereas rod outer segments were of
      normal thickness. CONCLUSION: LED light does not cause retinal damage and can
      suppress pineal melatonin content at intensities similar to CWF light
      intensities.

PMID- 10403447
TI  - Natural and experimentally induced infection of Syrian hamsters with a newly
      recognized parvovirus.

PMID- 10403448
TI  - Identification of pseudocysts of Tritrichomonas muris in Armenian hamsters and
      their transmission to mice.

PMID- 10403449
TI  - Carbon dioxide-induced anesthesia has no effect on brain biogenic amine
      concentrations in mice.

PMID- 10403451
TI  - Spontaneous low-virulence mouse hepatitis virus infection in severe combined
      immunodeficiency mice.

PMID- 10403452
TI  - Percutaneous intravenous injection in neonatal mice.

PMID- 10403450
TI  - Body condition scoring: a rapid and accurate method for assessing health status
      in mice.

PMID- 10403453
TI  - Rat model for dual opportunistic pathogen prophylaxis: Cryptosporidium parvum and
      Pneumocystis carinii.

PMID- 10403454
TI  - Tradition-based dental care and evidence-based dental care.

PMID- 10403455
TI  - Tony Melcher's contributions to the regeneration of the periodontium.
AB  - The impact of Tony Melcher's scientific work on periodontal regeneration is
      discussed in light of his interests in cellular domains and bone healing, the
      physiology of the periodontal ligament, and his development of organ and cell
      culture methods. Collectively, his scientific accomplishments have pointed us in
      new directions for approaching periodontal regeneration and have helped to create
      new research opportunities, many of which were previously unrecognized. Tony's
      scientific ideas are insightful, numerous, and compelling; his ability to make
      these ideas come alive and relevant to clinical problems has been a major
      influence in shaping our current thinking on the biology of the periodontium and
      on periodontal regeneration.

PMID- 10403456
TI  - Effect of moist vs. dry bonding to normal vs. caries-affected dentin with
      Scotchbond Multi-Purpose Plus.
AB  - Recent research in dentin bonding demonstrated the superiority of moist bonding
      over dry bonding on normal dentin, but it is unclear if this technique is also
      superior in bonding to caries-affected dentin. The purpose of this study was to
      evaluate the SEM appearance and bond strength of Scotchbond Multi-Purpose Plus
      (SMPP) to normal vs. caries-affected dentin bonded under moist vs. dry
      conditions, with and without polyalkenoic acid in the primer. Extracted carious
      human third molars were ground down by means of 600-grit SiC paper until the
      carious dentin no longer stained with caries detector solution. The flat surfaces
      were then primed, bonded, and built up with resin composite. After soaking in
      water for 1 day, the teeth were serially sectioned vertically into 5 or 6 slabs
      0.7 mm thick. The bonded caries-affected areas were isolated by means of an
      ultrafine diamond bur to create an hourglass configuration with a cross-sectional
      area of 0.9 mm2. Bonded normal dentin was isolated the same way. Each specimen
      was attached to a Bencor device and tested in tension to failure. SMPP bonds to
      dry, normal dentin were only half as strong (21+/-10 MPa, x +/- SD) as those made
      to moist, normal dentin (42+/-9 MPa, p<0.01). There was no significant difference
      between bonds made to normal vs. caries-affected dentin by means of the moist
      technique (42+/-9 vs. 48+/-4 MPa, respectively). Removal of the polyalkenoic acid
      from the primer lowered (p<0.05) the bond strength of SMPP to caries-affected
      dentin (38+/-8 MPa). The benefits of moist bonding extend to caries-affected
      dentin. The polyalkenoic acid in the SMPP primer contributes to the high bond
      strength that can be achieved to caries-affected dentin.

PMID- 10403457
TI  - Dental composite resins containing silica-fused ceramic single-crystalline
      whiskers with various filler levels.
AB  - Currently available direct-filling composite resins are susceptible to fracture
      and hence are not recommended for use in large stress-bearing posterior
      restorations involving cusps. The glass fillers in composites provide only
      limited reinforcement because of the brittleness and low strength of glass. The
      aim of the present study was to use ceramic single-crystalline whiskers as
      fillers to reinforce composites, and to investigate the effect of whisker filler
      level on composite properties. Silica particles were fused onto the whiskers to
      facilitate silanization and to roughen the whiskers, thereby improving retention
      in the matrix. The composite flexural strength, elastic modulus, hardness, and
      degree of polymerization conversion were measured as a function of whisker filler
      mass fraction, which ranged from 0% to 70%. Selected composites were polished
      simulating clinical procedures, and the surface roughness was measured with
      profilometry. The whisker composite with a filler mass fraction of 55% had a
      flexural strength (mean +/- SD; n = 6) of 196+/-10 MPa, significantly higher than
      83+/-14 MPa of a microfill and 120+/-16 MPa of a hybrid composite control (family
      confidence coefficient = 0.95; Tukey's multiple comparison). The composite
      modulus and hardness increased monotonically with filler level. The flexural
      strength first increased, then plateaued with increasing filler level. The degree
      of conversion decreased with increasing filler level. The whisker composite had a
      polished surface roughness similar to that of a conventional hybrid composite
      (p>0.1; Student's t). To conclude, ceramic whisker reinforcement can
      significantly improve the mechanical properties of composite resins; the whisker
      filler level plays a key role in determining composite properties; and the
      reinforcement mechanisms appear to be crack pinning by whiskers and friction from
      whisker pullout resisting crack propagation.

PMID- 10403458
TI  - Stoichiometry of the leaching process of fluoride-containing aluminosilicate
      glass-ionomer glasses.
AB  - Dental glass-ionomer cements (GIC) set by an acid-base reaction between a
      polyalkenoic acid and an ion-leachable glass. The exact relationship between the
      glass composition and the setting and final properties of GIC is not yet fully
      elucidated. As part of a systematic study of this relationship, we studied the
      leaching stoichiometry of glasses used in commercial formulations to correlate
      the glass composition with its leaching properties. The leaching experiments were
      performed in acetic acid solutions at pH = 3.4 by means of a pH-stat method.
      After predetermined time intervals, the suspension was filtered and the filtrate
      was analyzed for the glass constituents. The usefulness of the pH-stat method for
      the determination of glass reactivity was corroborated. The deviation of the
      leaching stoichiometry with respect to the pure glass stoichiometry decreased
      with increasing relative content of mono- and bivalent glass network dwellers and
      modifiers. Indications were found that the latter can be leached out
      independently and preferentially, while the leaching of network dwellers is
      coupled with the aluminum release. The F content as well as the reactivity of the
      glass affect the amount of fluoride available for release from a set GIC. It
      could be concluded that the leaching stoichiometry of GIC glasses can be
      correlated with their absolute and relative composition.

PMID- 10403459
TI  - Longevity of extensive class II open-sandwich restorations with a resin-modified
      glass-ionomer cement.
AB  - Several new techniques have been introduced for use in the esthetic restoration
      of posterior cavities to substitute for the presumed toxicity of amalgam.
      Composite-laminated glass-ionomer cement restorations, the sandwich technique,
      have been recommended for caries-risk patients. Clinical evaluation of the use of
      conventional glass-ionomer cements in the open-sandwich restoration has shown a
      high failure rate. The aim of this study was to evaluate the durability and
      cariostatic effect of a modified open-sandwich restoration utilizing a resin
      modified glass-ionomer cement (RMGIC) in large cavities. The materials consisted
      of 274 mostly extensive Class II Vitremer/Z100 restorations performed by four
      dentists in 168 adults. Six experimental groups were investigated. In four groups
      a thick and in two groups a thin layer of cement was placed. Cavity conditioning
      before application of the RMGIC self-etching primer was done in 3 groups with
      polyacrylic acid and in one group with maleic acid; in two groups, only water
      rinsing was performed. The restorations were evaluated at baseline and after 6,
      12, 24, and 36 months according to modified USPHS criteria (van Dijken, 1986).
      After 3 years, 239 restorations were evaluated. Twelve (5%) were estimated as non
      acceptable. Two were replaced, and seven were repaired with resin composite.
      Tooth fractures were observed in 2.5%. Slight erosion of the RMGIC part was seen
      in 4%, and in one case operative treatment was indicated. Post-operative
      sensitivity was reported for 9 teeth. Forty-three percent of the patients were
      considered as caries-risk patients. Only one restoration showed secondary caries.
      The three-year results indicated that the modified open-sandwich restoration is
      an appropriate alternative to amalgam including extensive restorations.

PMID- 10403460
TI  - Kinetics of enamel demineralization in vitro.
AB  - Previously, we reported that the rate (R) of hydroxyapatite dissolution in
      acetic, lactic, and phosphoric acid solutions is a function of the degree of
      saturation with respect to the dissolving mineral, DS (defined as the ratio of
      the mean ionic activity product for hydroxyapatite [Ca5OH(PO4)3] in solution to
      its solubility product constant), and the sum of the acid activities (sumBiH) in
      solution: R = K(1-DS)m(sumBiH)n. The present study was undertaken to explore the
      general validity of this model in describing the kinetics of enamel
      demineralization. Thin sections of human enamel were exposed to partially
      saturated 0.1 mol/L lactic acid solutions, at two different DS levels, and at pH
      values of 4.3 to 6.0. Thin sections of human enamel were also exposed to
      solutions with four different concentrations of acetic and lactic acids (pH 4.3)
      with three different DS values and, at one DS value, to solutions of propionic
      acid. Mineral loss was monitored by quantitative microradiography. In solutions
      with pH values of 4.3 and 5.0, "lesions" were formed with well-defined surface
      layers, whereas, in solutions with pH 6.0, "lesions" were produced with no
      apparent surface layers. The formation of relatively intact surface layers was
      consistent with predicted phase transformations. Rates of mineral loss were found
      to be inversely proportional to both the degree of saturation with respect to
      enamel mineral, DS(En), and the pH of the solution and increased with increased
      activities of each organic acid, consistent with the proposed model. However, at
      the same DS(En) and acid activity, rates of demineralization were the same in the
      acetic and propionic acid solutions, whereas rates of demineralization in lactic
      acid were greater. It is suggested that specific interactions of acid species
      with enamel mineral may modify the rate of enamel demineralization. These in
      vitro findings suggest that relatively small differences in DS(En) values found
      in plaque fluid may result in very significant differences in the rate of enamel
      demineralization in vivo.

PMID- 10403461
TI  - Influence of clenching intensity on bite force balance, occlusal contact area,
      and average bite pressure.
AB  - It has been difficult for investigators to simultaneously and reliably evaluate
      bite force in the intercuspal position with the area and location of occlusal
      contacts. This study was designed to investigate the variations in these
      parameters with respect to two factors: three levels of clenching and the
      preferred chewing side. Human subjects with normal occlusion were examined with a
      recently developed system (Dental Prescale Occluzer, Fuji Film, Tokyo, Japan).
      The three levels of clenching intensity were assessed by masseteric EMG activity
      and included the maximum voluntary contraction, and 30% and 60% of the maximum.
      The results indicated that the bite force and occlusal contact area on the whole
      dental arch increased with clenching intensity. In contrast, the average bite
      pressure, obtained by dividing the bite force by the contact area, remained
      unchanged regardless of the clenching intensity. As the clenching intensity
      increased, the medio-lateral position of the bite force balancing point shifted
      significantly (P<0.01) from the preferred chewing side toward the midline. The
      antero-posterior position remained stable in a range between the distal third of
      the first molar and the mesial third of the second molar. The bite force and
      occlusal contact area, which were mainly on the molars, increased with the
      clenching intensity, whereas the proportions of these two variables on each upper
      tooth usually did not change significantly. The exception was the second molar on
      the non-preferred chewing side. When comparisons were made between pairs of
      specific upper teeth of same name, usually no significant difference was found in
      bite force or occlusal contact area, regardless of the clenching level. Again,
      the exception to this observation was the second molar on the preferred chewing
      side, which had a larger area at the 30% clenching level. The results in normal
      subjects suggest that as the clenching intensity increases in the intercuspal
      position, the bite force adjusts to a position where it is well-balanced. This
      adjustment may prevent damage and overload to the teeth and temporomandibular
      joints.

PMID- 10403462
TI  - Expression of cell cycle and apoptosis-related proteins in sporadic odontogenic
      keratocysts and odontogenic keratocysts associated with the nevoid basal cell
      carcinoma syndrome.
AB  - Odontogenic keratocysts are occasionally (4-5%) associated with the nevoid basal
      cell carcinoma syndrome, a pleiotropic, autosomal disorder presenting a spectrum
      of developmental abnormalities and a predisposition for the development of
      different neoplasms. The aim of this study was to establish whether keratocysts
      showing clinically aggressive behavior associated with nevoid basal cell
      carcinoma syndrome reflect differences in cellular proliferation rate and/or in
      the expression of oncoproteins and tumor suppressor genes. For this reason,
      formalin-fixed paraffin-embedded sections of odontogenic keratocysts associated
      with the nevoid basal cell carcinoma syndrome (16 cases) and sporadic odontogenic
      keratocysts (16 cases) were compared for expression of proliferating cell nuclear
      antigen (PCNA) and p53, bcl-2, and bcl-1 (cyclin D1) onco-proteins. Most of the
      epithelial lining of odontogenic keratocysts associated with the nevoid basal
      cell carcinoma syndrome showed nuclear immunopositivity for p53 protein and
      overexpression of cyclin D1 with various degrees of staining intensity. All
      sporadic odontogenic keratocysts were negative for p53 and cyclin D1. The
      expressions of bcl-2 oncoprotein were found to be substantially similar between
      the two groups of lesions, with a cytoplasmic immunopositivity localized only in
      the resting reserve basal layer of the epithelium. PCNA expression showed no
      statistically significant difference between the two groups of lesions. In
      conclusion, the finding of cyclin D1 and p53 overexpression in odontogenic
      keratocysts associated with the nevoid basal cell carcinoma syndrome could be
      considered a hallmark of a mutated cellular phenotype, thus leading to the
      hypothesis that their aggressive clinical behavior could be due to a
      dysregulation of the expression of cyclin D1 and p53 proteins, involved in a
      check-point control of cellular proliferation.

PMID- 10403463
TI  - 92K-GL (MMP-9) and 72K-GL (MMP-2) are produced in vivo by human oral squamous
      cell carcinomas and can enhance FIB-CL (MMP-1) activity in vitro.
AB  - Previous studies have shown a correlation between the production of certain
      matrix metalloproteinases (MMPs), especially the gelatinases, by malignant tumors
      and the progression of these cancers as they invade and metastasize through the
      extracellular matrix and basement membranes. However, very few of these studies
      examined this relationship in human oral cancer in vivo, and none addressed the
      issue of how combinations of the MMPs may further enhance tumor progression. To
      determine which MMPs are produced in vivo by human oral cancers, we used specific
      anti-human-MMP antibodies and immunocytochemistry (ICC) methods to examine oral
      cancer tissue specimens from 20 surgery patients. The ICC data indicated that 72
      kDa (72K-GL) and 92-kDa gelatinases (92K-GL) were produced in vivo by discreet
      clusters of tumor cells and by stromal fibroblasts, vascular endothelial cells
      (72K-GL), and PMNs (92K-GL). Some stromal fibroblasts near the tumors also
      appeared to produce fibroblast-type collagenase (FIB-CL), a finding confirmed by
      Western blot analysis of media conditioned by oral tumor explant cultures. ICC
      results indicated that 5 of the 20 tumors coincidentally produced all three MMPs.
      To examine how the two gelatinases and FIB-CL may interact in vitro to degrade
      fibrillar type I collagen, a major structural component of the extracellular
      matrix, we used a modified FIB-CL activity assay. Combinations of the gelatinases
      and FIB-CL were incubated with a 3H-collagen substrate, with the results compared
      with the combination of stromelysin-1 (SL-1, a superactivator of FIB-CL) and FIB
      CL. 92K-GL caused a nine-fold increase in collagenase activity, equivalent to SL
      1, while 72K-GL produced a four-fold increase. These results indicate that human
      oral cancers produce 92K-GL, 72K-GL, and FIB-CL in vivo and that the gelatinases
      and FIB-CL cooperate to enhance collagen degradation greatly in vitro.

PMID- 10403464
TI  - Detection and quantification of MUC7 in submandibular, sublingual, palatine, and
      labial saliva by anti-peptide antiserum.
AB  - The large carbohydrate moiety of low-Mr salivary mucin MUC7 (originally referred
      to as MG2) is subject to variations. Biochemical analysis and quantification of
      MUC7 in saliva samples require recognition tools that are independent of the
      carbohydrate moiety. Therefore, we have evoked three antisera to synthetic
      peptides of MUC7. One of these (CpMG2), raised against the C-terminal peptide,
      recognized native MUC7 in saliva and was characterized further. Recognition of
      MUC7 by CpMG2 turned out to be specific, resistant to dissociating and reductive
      treatments, and independent of glycosylation differences, as indicated by Western
      analysis and ELISA. The antiserum could be used to monitor MUC7 during
      purification procedures. MUC7 was demonstrated in small volumes of saliva from
      all (sero)mucous glands, including the palate and lip. Analysis with antibodies
      and lectins indicated large variations in amount as well as in glycosylation of
      MUC7. An ELISA was developed to determine the relative quantity of MUC7 in the
      glandular salivas: mean values of approximately 220, 980, and 100 microg mucin
      per mL were found in submandibular, sublingual, and palatine saliva,
      respectively.

PMID- 10403465
TI  - Growth of Viridans streptococci on human serum alpha1-acid glycoprotein.
AB  - Viridans streptococci have emerged as major opportunistic pathogens. We suggest
      that for these bacteria to proliferate in vivo and cause disease, they must
      utilize host tissue components. We have therefore examined the ability of all
      recognized species of viridans streptococci to liberate and utilize the
      constituent sugars of the glycans of the extensively sialylated human serum
      alpha1-acid glycoprotein (AGP) as the sole source of carbohydrate to support in
      vitro growth. Analysis of residual glycans following bacterial growth was
      performed by high-pH anion exchange chromatography with pulsed amperometric
      detection and matrix-assisted laser desorption ionization time-of-flight mass
      spectrometry. Only those species which produced sialidase-namely, Streptococcus
      oralis, S. intermedius, and S. defectivus--grew on AGP. The extent of degradation
      of glycans was dependent on the particular glycosidases produced by the bacteria.
      S. defectivus produced only a sialidase which released the terminal N
      acetylneuraminic acid residues of the glycans, and the liberated sugar was
      utilized. S. intermedius also produced beta-galactosidase and beta-N
      acetylglucosaminidase, which removed galactose and N-acetylglucosamine from
      desialylated glycans, all of which again were utilized by the organism. S. oralis
      produced beta-galactosidase, beta-N-acetylglucosaminidase, and alpha-fucosidase
      and novel alpha- and beta-mannosidases which were apparent only from the analysis
      of the residual sugars of AGP. S. oralis cleaved all the sugars from AGP except
      for 22% of the N-acetylglucosamine. The residual N-acetylglucosamine residues
      remaining were those linked to the asparagine of the peptide backbone. All the
      monosaccharides released by S. oralis from AGP, with the exception of fucose,
      were utilized. Sialidase production may be a key factor for growth of these
      species of viridans streptococci on glycoproteins in vivo, since they are
      commonly associated with extra-oral diseases, with S. oralis emerging as an
      important pathogen.

PMID- 10403466
TI  - The role of taxanes in the management of breast cancer.

PMID- 10403468
TI  - Evidence-based paradigms and opinions in clinical management and cancer research.
AB  - Clinical management involves values, the recognition of a patient's unique
      circumstances, and information. Given strong biases in the way we all process
      experience, clinical decision making must acknowledge the results of formal
      research. Evidence-based clinical management requires that we take account of the
      whole body of available evidence, not a potentially biased "biopsy" of it.
      Systematic literature review is therefore a central element. Such an approach is
      time consuming and requires skills in literature search and data evaluation,
      which physicians frequently have not been taught. Computing and library
      facilities are an important aid, as is the development of evidence-based
      resources such as the Cochrane Library Collection. Practice guidelines can prove
      useful and acceptable to clinicians if they are both evidence- and practice
      based. The largest single obstacle to evidence-based clinical management is the
      bias against the reporting of studies with negative findings. This can be
      overcome by compulsory trial registration.

PMID- 10403467
TI  - The academic global virtual concept in clinical cancer research and its
      application to breast cancer: The Breast Cancer International Research Group.
AB  - In contrast to previous decades, the 1990s have witnessed an increase of new
      agents with significant activity in breast cancer, including chemotherapy,
      hormone therapy, and, more recently, biologic modifiers. All information appears
      to confirm that such a trend will persist and even accelerate in the coming
      decades. Unless clear strategies of development for new drugs are strictly
      followed, it will become difficult to adequately assess the many new agents with
      potentially important activity against breast cancer, and patient access may
      become a limiting key factor. The academic, global virtual concept is calling for
      the definition of a new relationship between the pharmaceutical industry and
      clinical researchers. The main aspect is related to the creation of partnerships
      with an academically controlled global strategy of development for promising new
      agents, in which the quality and independence of processes (adjuvant setting, for
      example) are critical. The means are based on the globalization of patient access
      (worldwide network) and the virtuality of the approach (modern means of
      communication as well as access to subgroups of patients). The Breast Cancer
      International Research Group is the first academic global virtual cooperative
      group in breast cancer and is making contributions in the development of new
      drugs, such as taxanes, new antiestrogens, and new cytokines.

PMID- 10403469
TI  - Single-agent paclitaxel in the treatment of breast cancer: phase I and II
      development.
AB  - In oncology, the 1990s has in many respects been the decade of the taxanes,
      particularly in breast cancer therapy. Preclinical data suggested that scheduling
      was an important determinant of the antitumor activity of paclitaxel. Initial
      phase I/II studies established a variety of schedules (based on different doses
      and infusion durations) for the administration of this drug, with neutropenia or
      neuropathy being the dose-limiting toxicities. More recently, a regimen in which
      paclitaxel is infused weekly over 1 hour at doses up to 90 mg/m2 produced little
      myelosuppression, but substantial antitumor activity. It is hypothesized that
      this uncoupling of the drug from its expected major toxicity arises due to the
      shorter period of time in which the plasma paclitaxel concentrations are above a
      critical level. Along with other approaches, the dose-dense administration of
      paclitaxel is now subject to randomized, controlled trials.

PMID- 10403470
TI  - Phase I-II studies of docetaxel as a single agent in the treatment of metastatic
      breast cancer.
AB  - Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) is highly effective in
      the first-line treatment of metastatic breast cancer, achieving an objective
      response rate of 61% (95% confidence interval, 52% to 69%). This rate of response
      is seen in patients with poor prognostic factors such as liver metastases and
      multiple organ involvement. In previously treated metastatic disease, docetaxel
      is also highly active, with an overall objective response rate of 41% in patients
      with strictly defined anthracycline-resistant disease. Phase II data suggest that
      docetaxel is the most active agent yet available in the treatment of advanced
      breast cancer; this conclusion is now supported by the results of randomized
      phase III trials. These data justify the further investigation of docetaxel alone
      and in combination chemotherapy.

PMID- 10403471
TI  - Paclitaxel activity, dose, and schedule: data from phase III trials in metastatic
      breast cancer.
AB  - Results from phase III trials comparing paclitaxel with doxorubicin suggest that
      although it is an effective first-line treatment for patients with metastatic
      breast cancer, paclitaxel cannot be considered an alternative to doxorubicin.
      Phase III trials are ongoing to define the role of paclitaxel/anthracycline
      containing regimens. In these trials, the combination of paclitaxel and
      anthracycline is compared with standard anthracycline-based combinations in
      advanced breast cancer patients receiving first-line treatments. Results are
      eagerly awaited for the year 2000. Data from randomized trials are available to
      define the best dose and schedule of paclitaxel for patients with metastatic
      breast cancer. From these trials it can be concluded that the dose of 175 mg/m2
      is better tolerated and as effective as higher doses. With regard to the duration
      of paclitaxel infusion, although a trend to an amelioration of response rates may
      be observed with a prolonged infusion, a similar time to treatment failure and
      overall survival and a more complex support required for prolonged infusion
      discourage this practice; therefore, the 3-hour infusion should still be
      considered as the standard schedule.

PMID- 10403472
TI  - Phase III randomized trials of docetaxel in patients with metastatic breast
      cancer.
AB  - In a randomized phase III trial in which docetaxel was compared with doxorubicin
      in metastatic breast cancer patients who had failed prior alkylating
      chemotherapy, docetaxel proved more active, achieving responses at a
      significantly higher rate (complete + partial responses, 48% v 33%). The risk to
      benefit ratio favors docetaxel. The higher response rate was achieved without the
      risk of potentially fatal cardiac toxicity evident in patients who received
      doxorubicin and with a lower risk of infection and febrile neutropenia. In a
      second phase III study, patients with metastatic breast cancer who had failed
      prior anthracycline therapy were randomized to receive either docetaxel or a
      standard salvage regimen of mitomycin C plus vinblastine. Those assigned to
      docetaxel lived significantly longer (median survival, 11.4 v 8.7 months),
      experienced a longer time before disease progression (19 weeks v 11 weeks), and
      achieved a higher overall response rate (30% v 11.6%). The toxicity profile of
      both regimens was manageable. These phase III studies confirmed the activity
      observed with docetaxel in the phase II trials and support the view point that
      docetaxel is one of the most active agents available for the treatment of breast
      cancer.

PMID- 10403473
TI  - Paclitaxel and anthracycline combination chemotherapy for metastatic breast
      cancer.
AB  - Numerous clinical trials have demonstrated that the combination of paclitaxel and
      doxorubicin is extremely active in metastatic breast cancer. Overall response
      rates of 42% to 94% and complete response rates of 4% to 41% have been reported.
      However, several trials with the highest response rates were associated with the
      development of congestive heart failure (CHF) in approximately 20% of patients.
      These early findings resulted in reducing the maximum permitted cumulative
      dosages of doxorubicin in subsequent trials, with a corresponding decrease in
      cardiac toxicity being noted. Several subsequent series suggest that with
      cumulative dosing of 360 mg/m2 doxorubicin, the rate of CHF can be reduced to
      approximately 5%. A recently completed Eastern Cooperative Oncology Group phase
      III randomized trial comparing paclitaxel versus doxorubicin versus combination
      therapy with paclitaxel and doxorubicin noted an overall response rate of 33% and
      34% in each single-agent arm, respectively, and a response rate of 46% with the
      combination therapy. There was an acceptable incidence of CHF. However, no
      difference in overall survival was noted with the combination therapy compared
      with the single-agent treatment. Losoxantrone, an anthrapyrazole in clinical
      development, has shown promising single-agent activity in metastatic breast
      cancer. An initial phase III randomized clinical trial comparing treatment with
      either paclitaxel alone versus losoxantrone and paclitaxel was recently
      completed. With no maximal cumulative dosage of losoxantrone incorporated into
      this trial design, an overall incidence of CHF of 4.9% was noted with combination
      therapy. Other hematologic and nonhematologic toxicities were overall acceptable
      with this new regimen as well. Additionally, preliminary analyses of clinical
      efficacy suggest that this new combination is promising therapy for the treatment
      of patients with metastatic breast cancer.

PMID- 10403474
TI  - Docetaxel and anthracycline polychemotherapy in the treatment of breast cancer.
AB  - Given the single-agent activity of docetaxel and doxorubicin in metastatic breast
      cancer and their potential non-cross-resistance, several phase I/II pilot studies
      of either docetaxel/doxorubicin (TA) or TA plus cyclophosphamide (TAC) were
      conducted. The results of these studies show that the main toxicity is related to
      neutropenia and its consequences, although documented infections are rarely
      reported. Other toxicities are mild, while docetaxel-specific toxicities (fluid
      retention, nail changes, etc) are seldom seen. No significant cardiotoxicity,
      even when patients are exposed to a cumulative doxorubicin dose greater than 360
      mg/m2, has been observed. In terms of efficacy, response rates in the range of
      70% to 80% were noted in all studies, even for patients with visceral metastases.
      Preliminary data suggest that the combination of docetaxel with epirubicin is
      also feasible, with manageable toxicities and significant activity. Several phase
      III randomized trials using TA or TAC are presently being performed in first-line
      metastatic breast cancer and, most importantly, in the adjuvant setting to assess
      whether TA-based combinations will change the natural history of breast cancer.

PMID- 10403475
TI  - C1 inhibitor in anti-inflammatory therapy: from animal experiment to clinical
      application.
AB  - Potentially life-threatening consequences due to severe inflammatory tissue
      destruction are often closely associated with an excessive activation of the
      complement system. Various clinical disorders, including capillary leak syndrome,
      septic shock, multiple organ failure and hyperacute graft rejection are at least
      in part driven by an overactivated complement system. Therapeutic support of
      complement regulation appears to be a logical approach to reduce undesirable
      inflammatory reactions. C1 inhibitor, a multifunctional regulator of all major
      kinin-generating protein cascade systems, is frequently observed to be reduced in
      patients suffering from severe inflammation, due to ligand-induced inactivation
      of the regulatory protein. After C1 inhibitor has for many years been proven
      beneficial in acute treatment of hereditary angioedema, a growing number of
      reports now suggests that C1 inhibitor provides an effective means to protect
      against complement-mediated inflammatory tissue damage. These studies not only
      include pathophysiologically relevant animal models but also first attempts to
      prove the benefits of C1 inhibitor as a novel therapeutic approach in clinical
      trials.

PMID- 10403476
TI  - Phosphorylation of plasma proteins with emphasis on complement component C3.
AB  - Phosphorylation of complement component C3 by different protein kinases in vitro
      has been demonstrated to alter the functional properties of the protein.
      Extracellular phosphorylation mediated by activated platelets is a newly
      described mechanism by which the function of plasma proteins can be regulated.
      Upon activation of platelets a casein kinase is released concomitant with large
      amounts of ATP and Ca2+. These components are sufficient to phosphorylate
      proteins e.g., C3 extracellularly. In vivo, in patients with SLE, the phosphate
      content in plasma proteins, including C3 has been demonstrated to increase during
      exacerbation. The changes were linked to platelet activation by a covariation
      with the levels of beta-thromboglobulin. The purpose of this review is to
      summarise the findings in this field.

PMID- 10403477
TI  - Factor H and disease: a complement regulator affects vital body functions.
AB  - Factor H is a multidomain and multifunctional protein. As a complement regulator
      factor H determines the fate of newly formed C3b and controls formation and
      stability of C3 convertases both in the fluid phase and on cell surfaces. In
      addition, this plasma protein displays functions outside complement control as it
      has been suggested to act as an adhesion protein, to be a ligand for the cellular
      integrin receptor CR3 (CD11b/CD18) and to display chemotactic activity. Genetic
      and pathophysiological analyses describe a role for factor H in vital body
      functions. Depletion or the absence of factor H due to genetic reasons leads to
      unrestricted C3 consumption. A reduced amount of factor H in plasma or mutations
      within the factor H gene may lead to glomerulonephritis (type II MPGN) or
      hemolytic uremic syndrome (HUS). Certain pathogenic organisms have been shown to
      evade complement attack by binding factor H from the host. Such specific factor H
      binding components have been demonstrated on the surface of microbes, e.g.,
      Streptococcus pyogenes and Neisseria gonorrhoeae. Here, we summarize the current
      knowledge how abnormalities in function of the central complement regulator
      factor H are associated with human diseases.

PMID- 10403478
TI  - Evasion of pathogens by avoiding recognition or eradication by complement, in
      part via molecular mimicry.
AB  - Most pathogens invading the human body are attacked by the host immune system
      directly following entry and usually also during most stages of the disease,
      especially when they are in contact with the blood. However, pathogens have
      developed an effective battery of specific strategies to overcome immune defense.
      This, far from being complete, review concentrates on evasion of pathogens by
      avoiding recognition or eradication by complement. The latter is achieved by
      removal of complement either by shedding it off the microbial surface, by
      consuming it away from the target membrane or by destroying it. Alternative
      procedures of avoiding eradication are the inhibition of complement activation or
      the employment of complement proteins via several highly sophisticated
      mechanisms, including the imitation of complement-like proteins (molecular
      mimicry).

PMID- 10403479
TI  - Complement-endothelial cell interactions: pathophysiological implications.
AB  - The function of the endothelial cells can be modulated by humoral factors present
      in the circulation and in the extravascular fluid, including proteins of the
      complement system. This review examines the multiple interactions between the
      complement system and the endothelial cells and their functional consequences on
      inflammation, coagulation and regulation of vascular tone. The implications of
      these interactions in the induction and progression of the vascular lesions
      occurring in atherosclerosis, ischemia/reperfusion and xenotransplantation and
      the possible therapeutic approaches in terms of complement regulation are also
      discussed.

PMID- 10403480
TI  - Xenotransplantation: how to overcome the complement obstacle?
AB  - The xenotransplantation research is driven by the shortage of allografts for
      transplantation of patients with end-stage organ failure and by lack of success
      in developing suitable artificial organs. Pigs are now generally accepted to be
      the donor species of choice, although a possible risk for transmission of
      xenozoonoses, particularly pig endogenous retroviruses, should be born in mind. A
      vascular xenograft from pig to human is usually rejected hyperacutely due to
      naturally occurring antibodies and complement. This hyperacute rejection can be
      prevented by manipulating with either of these systems. In this review we briefly
      describe the hyperacute rejection and how it can be prevented by complement
      modulation. Pigs made transgenic for human complement regulatory proteins seem
      very promising for future clinical experiments. Control of fluid-phase complement
      activation should be obtained as well. The latter is discussed based on our own
      recent studies in this field.

PMID- 10403481
TI  - Cross-reactivity and epitope analysis of Pru a 1, the major cherry allergen.
AB  - A high percentage of birch pollen allergic patients experiences food
      hypersensivity after ingestion of fresh fruits and vegetables. The cross
      reactivity of the major allergens of sweet cherry (Pru a 1), apple (Mal d 1),
      pear (Pyr c 1), celery tuber (Api g 1) and carrot (Dau c 1) is due to structural
      similarities which are reflected by high amino acid sequence identities with Bet
      v 1a, the major birch pollen allergen. Apart from a strong cross-reactivity to
      Bet v 1a, IgE inhibition experiments with Mal d 1, Pru a 1 and Api g 1
      demonstrated the presence of common and different epitopes among the tested food
      allergens. Secondary structure prediction of all investigated allergens indicated
      the presence of almost identical structural elements. In particular, the 'P-loop'
      region is a common domain of the pollen related food allergens and of
      pathogenesis related proteins. To identify the IgE binding epitopes, five
      overlapping recombinant Pru a 1 fragments representing the entire amino acid
      sequence with lengths of approximately 60-120 residues were investigated. Weak
      IgE binding capacity was measured exclusively with Pru a IF4 (1-120) by
      immunoblotting, whereas none of the fragments showed allergenicity in the rat
      basophil leukaemia cell mediator release assay. Site-directed mutagenesis
      experiments with Pru a 1 revealed that amino acid S112 is critical for IgE
      binding of almost all patients sera tested. This reduced IgE binding was also
      observed with a single point mutant of Bet v 1a (S112P) and thus indicated serine
      112 as an essential residue for preserving the structure of a cross-reactive IgE
      epitope. Moreover, two Pru a 1 mutants with an altered 'P-loop' region, showed a
      lowered IgE binding capacity for IgE from a subgroup of allergic patients. The
      investigation of essential features for preserving cross-reactive IgE-epitopes
      provides the structural basis for understanding the clinically observed cross
      allergenicity between pollen and fruits. Moreover, non-anaphylactic allergen
      fragments or variants derived from the IgE-inducing pollen allergens may serve as
      useful tools for a new strategy of specific immunotherapy.

PMID- 10403483
TI  - Serum starvation induced secondary V lambda J lambda rearrangement in a human
      plasma B cell line.
AB  - HB4C5 is a human antibody producing plasma B cell line that expresses the
      recombination activating gene-1 (RAG-1) and RAG-2 constitutively, but undergoes
      few secondary immunoglobulin gene rearrangements when cultured in fetal bovine
      serum-containing medium. Here, we found that depletion of serum from the culture
      media induces secondary VlambdaJlambda rearrangement in this cell line. To
      investigate the induction mechanism of secondary VlambdaJlambda rearrangement, we
      assessed the expression levels of RAG-1 and RAG-2 products, Vlambda germline
      transcription level and the amount of Vlambda signal broken ends (SBE) in HB4C5
      cells cultured in serum-supplemented or serum-free medium. Western-blot analysis
      showed that the expression level for the RAG-1 and RAG-2 proteins was not
      affected by the serum depletion. Vlambda germline transcript was found to be
      constitutively expressed in HB4C5 cell line and this transcription level was not
      affected by the lack of serum. On the other hand, the amount of Vlambda SBE was
      shown to be increased in HB4C5 cells cultured in serum-free medium, suggesting
      that this increased formation of Vlambda SBE at least partly contributed to the
      enhanced occurrence of secondary VlambdaJlambda rearrangement in HB4C5 cells
      cultured in the serum-free condition. These results indicate that expression of
      RAG proteins and Vlambda germline transcription is not enough to undergo
      secondary VlambdaJlambda rearrangement in this cell line.

PMID- 10403482
TI  - Characterization of mutated protein encoded by partially duplicated fibrillin-1
      gene in tight skin (TSK) mice.
AB  - Fibrillin-1 (Fbn-1) is a ubiquitous protein present in the extracellular matrix
      of various organs and it is a major component of microfibrils embedded in the
      core of elastic fibers. In humans, mutations or deletions of the Fbn-1 gene are
      associated with several genetic diseases. In addition, several microsatellite
      alleles near Fbn-1 gene were found associated with diffuse scleroderma. In TSK/+
      mice, which develop a scleroderma-like syndrome, the Fbn-1 gene exhibits an
      inframe duplication of exons 17-40. In this study, we report that the synthesis
      and secretion of wild-type Fbn-1 in TSK/+ is higher than that of the mutated Fbn
      1 protein excluding the possibility that TSK genetic defect is due to a loss of
      the wild allele. We also demonstrate for the first time that TGF-beta, which
      plays a crucial role in skin fibrosis, binds to both wild-type and mutated Fbn-1.
      The amount of bound TGF-beta was higher in mutated than wild-type Fbn-1 and
      appears related to the number of TGF-beta binding motifs.

PMID- 10403484
TI  - An intact NF-kappa B signaling pathway is required for maintenance of mature B
      cell subsets.
AB  - Members of the NF-kappaB/Rel transcription factor family are expressed
      constitutively during B cell development and are further induced by mitogen
      activation. Mice harboring germline disruptions in individual NF-kappaB subunits
      exhibit distinct defects in B lymphocyte activation and survival. However, the
      role of NF-kappaB in the production and maintenance of B cell subsets has been
      difficult to dissect in these knockout animals due to functional impairment of
      other immune cells. To directly address the cell autonomous requirements for NF
      kappaB in humoral immune compartments, transgenic mice were generated that
      express a transdominant form of Ikappa-Balpha in B lineage cells. Whereas
      expression of the inhibitor had only modest effects on basal or LPS-induced
      levels of NF-kappaB, transgenic B cells were significantly impaired for cellular
      proliferation and NF-kappaB induction in response to B cell receptor (BCR)
      crosslinking. Furthermore, the trans-dominant inhibitor produced a dose-dependent
      reduction in the population of mature splenic B cells. This cellular defect was
      more pronounced in long-lived B lymphocyte subsets that recirculate to the adult
      bone marrow. Together, these results indicate that BCR-mediated signaling must
      maintain NF-kappaB levels above a stringent threshold for proper regulation of B
      cell homeostasis.

PMID- 10403485
TI  - CD28-mediated regulation of the c-jun promoter involves the MEF2 transcription
      factor in Jurkat T cells.
AB  - Within a few minutes of T-cell activation, transcription of a set of genes
      including c-fos and c-jun is activated. For maximal induction of c-jun, at least
      two major signal pathways are required. One can be triggered by T-cell receptor
      engagement or phorbol esters and the other by anti-CD28 engagement. The c-jun
      promoter region between -117 and -50 contains binding sites for the transcription
      factors Spl, CTF, ATF/CREB, and MEF2. In this study, we sought to map the
      sequences in the c-jun promoter responsible for CD28-mediated induction in
      activated Jurkat T cell by point mutational analysis. We found that mutation of
      the c-jun MEF2 site strongly reduces CD28 induction of the promoter in Jurkat T
      cells and that MEF2D is the major binding molecule to the c-jun MEF2 site in
      Jurkat T cells. Mutation of the c-jun ATF site also partially reduced CD28
      induction of the promoter. In addition, pretreatment with an endolysomotropic
      agent NH4Cl, an acidic sphingomyelinase inhibitor, completely inhibited the
      activation of the c-jun promoter by anti-CD28 antibody treatment, whereas
      pretreatment with wortmannin, a PI3-kinase inhibitor, did not affect the
      induction of the c-jun promoter. These results suggest that CD28 signaling
      leading to the c-jun promoter involves acidic sphingomyelinase, but not PI3
      kinase, to activate factors binding to the MEF2 and ATF sites.

PMID- 10403486
TI  - Replacements in the exposed loop of the T15 antibody VH CDR2 affect carrier
      recognition of PC-containing pathogens.
AB  - A panel of mutant antibodies of the phosphocholine (PC)-binding antibody, T15,
      was tested for binding to PC-protein, Streptococcus pneumoniae, Trichinella
      spiralis and Ascaris suum. Relative to wildtype T15, all the mutant antibodies
      showed differential recognition of the panel of PC-associated antigens. These
      mutant antibodies contain amino acid replacements in the CDR2 region of the heavy
      chain variable region, indicating the importance of CDR2 in recognition of
      carrier determinants. A model of T15 is shown that illustrates the strategic
      placement of mutations that could allow interaction with determinants associated
      with PC. A direct implication of this finding is that the T15 antibody combining
      site accommodates structures larger than phosphocholine and that recognition of
      associated carrier determinants could be a significant force in shaping the
      immune response to PC-containing pathogens.

PMID- 10403488
TI  - Endothelins and asthma.
AB  - In the decade since endothelin-1 (ET-1) and related endogenous peptides were
      first identified as vascular endothelium-derived spasmogens, with potential
      pathophysiological roles in vascular diseases, there has been a significant
      accumulation of evidence pointing to mediator roles in obstructive respiratory
      diseases such as asthma. Critical pieces of evidence for this concept include the
      fact that ET-1 is an extremely potent spasmogen in human and animal airway smooth
      muscle and that it is synthesised in and released from the bronchial epithelium.
      Importantly, symptomatic asthma involves a marked enhancement of these processes,
      whereas asthmatics treated with anti-inflammatory glucocorticoids exhibit
      reductions in these previously elevated indices. Despite this profile, a causal
      link between ET-1 and asthma has not been definitively established. This review
      attempts to bring together some of the evidence suggesting the potential mediator
      roles for ET-1 in this disease.

PMID- 10403487
TI  - N-glycosylation influences epitope expression and receptor binding structures in
      human IgE.
AB  - Although human IgE is relatively rich in carbohydrates, there are few studies
      concerning their structural and functional importance. The low serum
      concentration of IgE has limited carbohydrate characterisation to a few IgE
      myeloma proteins. Four to six of the seven potential N-glycosylation sites in the
      constant region of the epsilon chain seem occupied together with some residual
      microheterogeneity. We have used a panel of 28 anti-Cepsilon2, 7 anti-Cepsilon3
      and 18 anti-Cepsilon4 domain-specific anti-IgE mAbs, and rFcepsilonRIalpha to
      examine the effect of N-glycosylation on epitope expression of human IgE. Myeloma
      proteins IgE(DES)-kappa, IgE(ND)-lambda and IgE(UD)-kappa as well as polyclonal
      IgE were deglycosylated with PNGF and/or sialidase and tested in different ELISA.
      In all ELISA approaches, the reactivity of most domain-specific anti-IgE mAbs was
      independent of the glycosylation state of IgE(DES), except for one-third of the
      anti-Cepsilon2 mAbs. These mAbs reacted better with deglycosylated IgE(DES) in
      the order of treatment PNGF/sialidase > PNGF > or = sialidase > buffer control.
      In sharp contrast, the reactivity of IgE(DES) with rFcepsilonRIalpha was not
      influenced by sialidase but markedly reduced following PNGF or PNGF/sialidase
      treatment. These findings were neither myeloma restricted nor caused by
      aggregation, since monomeric IgE demonstrated the same reactivity pattern. Thus.
      N-glycosylation seems to influence both structure and function of human IgE. The
      oligosaccharides modulate epitope expression, mainly in the Cepsilon2-domain, as
      revealed by a subset of mAbs. They also promote subtle changes in the Cepsilon3
      domain, leading to a reduced FcepsilonRIalpha binding. These findings suggest
      physiological implications of carbohydrates in human IgE.

PMID- 10403489
TI  - Specific binding and effects of dehydroepiandrosterone sulfate (DHEA-S) on
      skeletal muscle cells: possible implication for DHEA-S replacement therapy in
      patients with myotonic dystrophy.
AB  - Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are the most abundant
      steroidal products and major circulating steroids in humans. The serum
      concentrations of DHEA-S are lower in patients with myotonic dystrophy (DM) than
      normal controls, and possible improvement of myotonia and muscle weakness was
      recently reported following DHEA-S replacement therapy. However, the molecular
      mechanism of action of DHEA-S remains unknown. To understand the reported anti-DM
      action of DHEA-S, we investigated DHEA-S binding in skeletal muscle cells in
      vitro. We identified two populations of DHEA-S binding sites (Kd = 5-9 microM and
      35-40 microM) in C2C12 myocytes. Similar binding sites were also identified in
      human skeletal muscles. The Kd value of the high-affinity site was within the
      range of serum concentrations of DHEA-S in adult humans. Our results suggest that
      DHEA-S might act directly on skeletal muscles under normal physiological
      conditions in humans.

PMID- 10403491
TI  - Metabolic acidosis inhibits pyruvate oxidation in chick liver by decreasing
      activity of pyruvate dehydrogenase complex.
AB  - Replacement of drinking water with NH4Cl (1.5%) solution significantly reduced
      blood pH on the 2nd d in chicks and thereafter. Concomitant with this reduction,
      oxidation rate of state 3 with pyruvate in liver mitochondria was also decreased
      in acidotic animals when compared with control animals. No significant
      differences between the two groups were observed in the state 4 oxidation at any
      feeding period. The ADP/O ratio did not appear to be affected by the treatment.
      The successive experiments of gavage-feeding for 4 d were also employed to ensure
      an equivalent intake of diet and the amount of NH4Cl given. As a result, the
      higher the NH4Cl provided, the lower the oxidation rate of state 3 with pyruvate
      in liver mitochondria, and the actual activity of pyruvate dehydrogenase complex,
      as expressed as units of produced CO2 per g wet weight of liver, which were
      accompanied by the lower pH in blood. This study provides the first evidence for
      a critical role of pyruvate dehydrogenase complex in the regulation of pyruvate
      catabolism in the liver from acidotic chicks induced by NH4Cl.

PMID- 10403490
TI  - Alpha-adrenoceptor-mediated glucose release from perifused catfish hepatocytes.
AB  - In fish liver catecholamines bind to beta-adrenoceptors (AR) and increase glucose
      release via cAMP augmentation. Alpha1-AR have recently been shown to mediate IP3
      and Ca2+ elevation in catfish and eel hepatocytes, although their coupling to a
      physiological response has remained doubtful. We have perifused isolated catfish
      hepatocytes in Bio-Gel P4 columns with epinephrine in the presence of prazosin
      and/or propranolol, alpha- and beta-AR antagonists, respectively. Ten nM
      epinephrine stimulated glucose release approximately 3-fold, and this effect was
      completely antagonized by the simultaneous presence of both alpha- and beta-AR
      blockers. The two AR antagonists separately inhibited about one-third and two
      third of the total stimulation, respectively. Through alpha-AR occupancy,
      epinephrine provoked a significant increase of glucose release whereas no
      stimulation was detected in Ca2+-depleted hepatocytes. Glucose release was
      strongly elevated by both ionomycin and dibutyryl cAMP. These results represent
      the first direct evidence that alpha-AR transduction pathway is involved in
      epinephrine-induced glucose release from fish hepatocytes.

PMID- 10403492
TI  - Inhibition of 2-P-mercaptophenyl-1,4-naphthoquinone on human platelet function.
AB  - As widely assumed, platelets and coagulation system heavily influence the
      pathogenesis and progression of cardiovascular diseases. Some 1,4-naphthoquinone
      derivatives, such as vitamin K3, have been reported to increase the synthesis of
      coagulation proteins. In this study, we examine how 2-p-mercaptophenyl -1,4
      naphthoquinone (NTP), a newly synthesized 1,4-naphthoquinone derivative, affects
      the platelet function in humans. A tapered parallel plate chamber which provided
      a range of shear stress covering the entire physiological range in human
      circulation is used to assess platelet adhesiveness on fibrinogen coated-surface.
      In addition, platelet aggregation and thromboxane B2 (TXB2) production by
      inducers are evaluated by the turbidimetric method and enzyme immunoassay kit,
      respectively. Moreover, platelets [Ca2+]i are measured using a dual-wavelength
      fluorescence spectrophotometer. Analysis results indicate that 1) NTP decreases
      the percentages of attached platelets at the locations in various shear stresses
      and the levels of platelet adhesiveness, denoted as the slope; 2) NTP can inhibit
      the platelet aggregation by ADP (2 microM) and collagen (25 microg/ml), and the
      IC50 are: 0.32 and 26.83 microg/ml, respectively; and 3) NTP markedly inhibits
      TXB2 formation and platelet [Ca2+]i elevation caused by ADP and collagen.
      Therefore, we conclude that NTP may inhibit platelet adhesiveness on fibrinogen
      coated-surface, aggregability, [Ca2+]i, and thromboxane production, and that it
      may be used as an antiplatelet agent.

PMID- 10403493
TI  - Activity of voltage-gated K+ channels is associated with cell proliferation and
      Ca2+ influx in carcinoma cells of colon cancer.
AB  - Cell proliferation of carcinoma cells DLD-1 derived from colon cancer as measured
      by [3H] thymidine incorporation was drastically reduced in the presence of 4
      aminopyridine, an inhibitors of voltage-gated K channel. A number of nonspecific
      K+ channel inhibitors including TPeA, TEA, verapamil and diltiazem also inhibited
      [3H] incorporation at the concentration reported to inhibit voltage-gated K+
      channels. The presence of voltage-gated K+ channels was confirmed by reverse
      transcription-PCR and cDNA sequencing. Charybdotoxin and iberiotoxin, inhibitors
      for Ca2+-sensitive K+ channel, and glibenclamide, a specific inhibitor for ATP
      sensitive K+ channel, did not have effect on cell proliferation. These
      experiments suggested a critical role of voltage-gated K+ channels in
      proliferation of colon cancer cells. Mechanism of action of K+ channel activity
      in cell proliferation was explored by studying the relationship between the K+
      channel activity and Ca2+ entry. The results from experiments indicated that K+
      channel inhibitors blocked [Ca2+]i influx. Therefore, it is likely that K+
      channel activity may modulate Ca2+ influx into colon cancer cells, and
      subsequently modulate the proliferation of these cells.

PMID- 10403494
TI  - Inhibition of glucose transporter gene expression by antisense nucleic acids in
      HL-60 leukemia cells.
AB  - Glucose is the basic source of energy for mammalian cells. The energy-independent
      transport of glucose down its concentration gradient is mediated by the
      facilitative glucose transporter family (GLUT). It has long been recognised that
      glucose transporter genes are overexpressed in many human cancer cells, to help
      provide extra energy for the rapid growth of cancer cells. In the present study,
      antisense oligonucleotides and plasmid-derived antisense RNA against GLUT-1 gene
      were synthesized and transfected into human leukemia HL-60 cells to investigate
      the effect of these antisense nucleic acids on tumour growth. Our results show
      that antisense nucleic acids inhibited the proliferation of HL-60 cells by 50-60%
      and the mRNA expression of GLUT-1 gene was suppressed as detected by Northern
      hybridization.

PMID- 10403496
TI  - Effects of wheatgerm agglutinin and aging on the regional brain uptake of HIV
      1GP120.
AB  - HIV-1 is associated with infection and altered functions of the CNS, especially
      in the elderly. Most studies indicate that HIV-1 is not evenly distributed
      throughout the CNS but is concentrated in deep brain nuclei. This study examined
      whether regional or age-related differences in the permeability of the blood
      brain barrier to gp120, the viral coat of HIV-1, exist. The initial concentration
      of gp120 in 10 brain regions correlated with vascular content in young and old
      mice. Susceptibility to wheatgerm agglutinin (WGA)-induced uptake of gp120, which
      relates to endothelial cell internalization, varied regionally, with no induction
      of uptake into the striatum or hypothalamus but with large increases in the
      cerebellum, cortex, and midbrain. Transport across the BBB, as measured by the
      unidirectional influx rate (Ki), also varied regionally with the hypothalamus,
      hippocampus, and pons-medulla showing the highest values for Ki and the striatum
      the lowest. These regional variations in the permeability of the BBB to gp120
      could contribute to the inhomogeneous distribution of HIV-1 within the CNS
      whereas the failure to see differences with aging suggests other causes underlie
      the susceptibility of the elderly to the CNS manifestations of AIDS.

PMID- 10403495
TI  - Dolichol and retinol content of rat liver sinusoidal cells after chronic monensin
      treatment.
AB  - Aim of this study was to ascertain whether an impairment of communication between
      parenchymal and non-parenchymal liver cells involves vitamin A intercellular
      transport. The following approach was adopted: liver cells were isolated from
      rats treated chronically with the hydrophobic ionophore monensin i.p. for 3, 5,
      and 7 weeks and their retinol and dolichol content was assessed. Monensin, which
      alters membrane flow, was used because it had previously been reported to induce
      liver steatosis, cholestasis and glycogenolysis after acute treatment and, by
      preliminary morphological examination, to impair vitamin A transport between
      stellate cells and hepatocytes. Dolichol was chosen as a biochemical marker
      because it is a membrane lipid that modulates the fluidity and permeability of
      the membranes that retinol must cross. After monensin treatment, a load of
      vitamin A was given to rats three days before sacrifice, to ascertain whether its
      uptake by sinusoidal liver cells was altered. The main result was a dolichol
      decrease in hepatocytes and in the Ito-1 subfraction. In this latter, monensin
      induced a decrease in dolichol content only after vitamin A load. Moreover, while
      the hepatocytes were able to take up a load of vitamin A normally, the Ito-1
      subfraction was no longer able to store retinol. Therefore the polarised
      transport of retinol between hepatocytes and stellate cells seemed impaired. The
      behaviour of sinusoidal endothelial cells and Kupffer cells might be ascribed to
      the functions of these cells and is not significantly modified by monensin. In
      conclusion, the altered cross-talk between sinusoidal cells in liver pathology
      might involve retinol as well as cytokines. Different pools of dolichol might
      have a role in this membrane process in a hydrophobic environment.

PMID- 10403497
TI  - Galanin in the lizard oviduct: its distribution and relationships with estrogen,
      VIP and oviposition.
AB  - The distribution of neurons containing galanin immunoreactivity (Gal/IR) has been
      detected in the oviduct of the lizard Podarcis s. sicula during the main phases
      of its sexual cycle and after 17beta-estradiol treatment. Indirect
      immunofluorescence technique was applied both to cryostatic sections and whole
      mount preparations, and Western blot analysis, with an antibody directed against
      mammalian galanin (Gal), was performed with lizard oviduct extracts.
      Colocalization of Gal with vasoactive intestinal polypeptide (VIP) was also
      studied as well as Gal effects on egg deposition. In the quiescent oviduct of non
      reproductive females, scanty Gal/IR fibres were found in the uterine-vaginal
      segment. During the reproductive period a gradual increase of positive nerve
      fibres and cell bodies were found distally in the lizard oviduct and the vagina
      revealed a reactive nerve population denser than elsewhere. Gal-IR nerve
      structures were present either in the musculature or mucosa and in the
      intermuscular layer they were organized in a nerve network. In the oviduct of non
      reproductive females, 17beta-estradiol administration induced a significant
      increase of neurons containing Gal/IR. This hormone could be involved in the egg
      laying by means of galanin action and this hypothesis is supported by the
      induction of premature oviposition in pre-ovulatory females after Gal
      administration. Western blot analysis validates this peptide as true Gal,
      recognising one protein band with a molecular weight (3.2 kDa), similar to that
      of porcine Gal. Double labelling studies showed the co-presence of Gal and VIP in
      some neurons.

PMID- 10403498
TI  - Low frequency-dependent mechanism of the M2 receptor function on vagally mediated
      bronchoconstriction in rabbits in vivo.
AB  - The present study was carried out to investigate whether there is the difference
      between low and high frequencies of vagal stimulation on the functional
      appearance of M2 receptors in the rabbit. The animals were anesthetized,
      artificially ventilated and bilaterally vagotomized. Bilateral vagus nerve
      stimulation (5 to 30 Hz) for 30 sec caused bronchoconstriction (measured as an
      increase in R(L) and a decrease in Cdyn) in a frequency-dependent manner. The
      bronchoconstriction evoked by ACh injection (1 and 3 microg/kg) was dose
      dependent. Although administration of methoctramine (50 and 300 microg/kg), a
      selective M2 receptor antagonist, had no significant effect on ACh-induced
      bronchoconstriction, methoctramine dose-dependently augmented the R(L) and Cdyn
      responses to vagal stimulation at 5-15 Hz but did not potentiate
      bronchoconstrictive responses to the stimulation at 30 Hz. Administration of [D
      Pro2, D-Try(7,9)]-SP (0.5 mg/kg, a selective tachykinin receptor antagonist) that
      had no significant effect on the R(L) and Cdyn responses to vagal stimulation (5
      15 Hz) attenuated the bronchoconstrictive response to the stimulation at 30 Hz.
      Conversely, thiorphan (2 mg/kg, a neutral endopeptidase inhibitor) potentiated
      the bronchoconstriction evoked by vagal stimulation at 30 Hz only. These results
      suggest that M2 receptors function as the inhibitory receptors in the
      bronchoconstrictive response to vagal stimulation at the lower frequencies (5-15
      Hz), but that the M2 receptor antagonism is diminished when vagal stimulation at
      a higher frequency (30 Hz) results in the release of SP from the lungs.

PMID- 10403499
TI  - Effect of single neonatal vitamin K1 treatment (imprinting) on the binding
      capacity of thymic glucocorticoid and uterine estrogen receptors of adolescent
      and adult rats.
AB  - Neonatal single treatment with vitamin K1 (50 microg/animal) significantly
      increased the density (Bmax) of thymic glucocorticoid receptors of the adolescent
      (6 weeks old) and uterine estrogen receptors of adult (10 weeks old) females. The
      same tendency was observed in the thymus of males and adult females, however
      without significance. Receptor affinity was (not significantly) influenced in the
      same direction. Considering that the steroid receptor imprinting effect of
      vitamins A and D as well as the imprinting-like effect of vitamin E was
      demonstrated earlier, the ability for neonatal steroid receptor imprinting of the
      whole lipid-soluble vitamin group is now justified.

PMID- 10403500
TI  - Methylphenidate and cocaine have a similar in vivo potency to block dopamine
      transporters in the human brain.
AB  - The reinforcing effects of cocaine and methylphenidate have been linked to their
      ability to block dopamine transporters (DAT). Though cocaine and methylphenidate
      have similar in vitro affinities for DAT the abuse of methylphenidate in humans
      is substantially lower than of cocaine. To test if differences in in vivo potency
      at the DAT between these two drugs could account for the differences in their
      abuse liability we compared the levels of DAT occupancies that we had previously
      reported separately for intravenous methylphenidate in controls and for
      intravenous cocaine in cocaine abusers. DAT occupancies were measured with
      Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal
      controls for the methylphenidate study and in 17 active cocaine abusers for the
      cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum
      to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of
      DAT availability. Parallel measures were obtained to assess the cardiovascular
      effects of these two drugs. Methylphenidate and cocaine produced comparable dose
      dependent blockade of DAT with an estimated ED50 (dose required to block 50% of
      the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both
      drugs induced similar increases in heart rate and blood pressure but the duration
      of the effects were significantly longer for methylphenidate than for cocaine.
      The similar in vivo potencies at the DAT for methylphenidate than for cocaine are
      in agreement with their reported relative in vitro affinities (Ki 390 nM and 640
      nM respectively), which is likely to reflect the similar degree of uptake (8-10%
      of the injected dose) and regional distribution of these two drugs in the human
      brain. Thus, differences in the in vivo potency of these two drugs at the DAT
      cannot be responsible for the differences in their rate of abuse in humans. Other
      variables i.e. longer duration of methylphenidate's side effects may
      counterbalance its reinforcing effects.

PMID- 10403501
TI  - Ligands for opioid and sigma-receptors improve cardiac electrical stability in
      rat models of post-infarction cardiosclerosis and stress.
AB  - The effects of the extremely selective mu-opioid receptor agonist, [D-Arg2,Lys4]
      dermorphin-(1-4)-amide (DALDA), the mu-opioid receptor agonist morphine, the
      mu/delta agonist D-Ala2, Leu5, Arg6-enkephalin (dalargin), the kappa-opioid
      receptor agonist spiradoline, and the sigma1-receptor antagonist DuP 734 on
      ventricular fibrillation threshold (VFT) was investigated in an experimental post
      infarction cardiosclerosis model and an immobilization stress-induced model in
      rats. Both models produced a significant decrease in VFT. The postinfarction
      cardiosclerosis-induced decrease in VFT was significantly reversed by intravenous
      administration of dalargin (0.1 mg/kg), DALDA (0.1 mg/kg), or morphine HCl (1.5
      mg/kg). Pretreatment with naloxone (0.2 mg/kg) completely eliminated the increase
      in cardiac electrical stability produced by DALDA. Both spiradoline (8 mg/kg,
      i.p.) and DuP 734 (1 mg/kg, i.p.) produced a significant increase in VFT in rats
      with post-infarction cardiosclerosis. This effect of spiradoline was blocked by
      nor-binaltorphimine. The immobilization stress-induced decrease in VFT was
      significantly reversed by administration of either DALDA, spiradoline or DuP 734.
      In conclusion, activation of either mu- or kappa1-opioid receptors or blockade of
      sigma1-receptors reversed the decrease in VFT in both cardiac compromised models.
      Since DALDA and dalargin essentially do not cross blood brain barriers, their
      effects on VFT may be mediated through peripheral mu-opioid receptors.

PMID- 10403502
TI  - Anti-inflammatory effects of the products from Wilbrandia ebracteata on
      carrageenan-induced pleurisy in mice.
AB  - Wilbrandia ebracteata Cogn. (Cucurbitaceae) is commonly known in Brazil as
      "Taiuia". The roots are employed in folk medicine for the treatment of several
      diseases, such as rheumatic disease. This study has evaluated the anti
      inflammatory action of dicloromethane fraction (F-DCM), purified fraction (PFIII)
      and Cucurbitacin B extracted from crude extract of W. ebracteata in experimental
      models in vivo. The F-DCM (0.3 to 10 mg.kg(-1), i.p. or 3 to 30 mg.kg(-1) p.o.)
      produced significant but not dose-dependent inhibition of the carrageenan-induced
      cell influx and exsudate leakage in the pleural cavity of mice. The F-DCM 0.01 to
      10 mg.kg(-1), i.p. or 0.1 to 10 mg.kg(-1) p.o.) decreased the levels of PGE2 in
      the exsudate leakage induced by carrageenan in the pleural cavity after 4 h with
      a calculated ID50 of 0.01 (0.002-0.09, i.p.) and 0.29 (0.05-1.45, p.o.) mg.kg(
      1). The PFIII (3 mg.kg(-1), i.p.) inhibited 80% of cell migration (1.50 +/- 0.09
      x 10(6) cells/cavity) and exsudate leakage by about 50% (3.09 +/- 0.71 microg/ml)
      in relation to the control group. Cucurbitacin B (0.1 mg.kg(-1), i.p.), the main
      compound of PFIII, reduced significantly the levels of PGE2 in the exsudate
      leakage by 40.7% (10.41 +/- 2.67 ng.ml(-1)). These data show that the active
      principle(s) present in the F-DCM of W. ebracteata elicited pronounced anti
      inflammatory effects when assessed by i.p. or p.o. routes, as well as PFIII. The
      F-DCM was also able to prevent PGE2 formation in exsudate leakage induced by
      carrageenan, as well as Cucurbitacin B, its active principle. These results
      indicate that the anti-inflammatory activity of Wilbrandia ebracteata can be
      related with the inhibition of the production of PGE2.

PMID- 10403503
TI  - Impact of a cholesterol enriched diet on maternal and fetal plasma lipids and
      fetal deposition in pregnant rabbits.
AB  - Pregnancy is associated with a hypercholesterolemic and a hyperlipidemic state.
      The totality of the essential fatty acids and 50% of the lipids needed by the
      fetus are transferred by the placenta from the maternal circulation. The
      hypothesis of this study is that an augmentation of the maternal plasmatic
      cholesterol is modifying the fetal lipids accumulation and development during
      rabbit pregnancy. To demonstrate the impact of a cholesterol enriched diet on
      plasma lipids during rabbit's pregnancy and on their fetus, we have established
      two groups: control and hypercholesterolemic rabbits (fed with a 0.2% cholesterol
      diet). Blood samples were collected before mating and at each trimester of
      pregnancy for analysis of lipid fractions and their lipoproteins. Plasma analysis
      shows that starting the 10th day of pregnancy the concentration of total
      cholesterol and lipoproteins decreases for both groups. We have demonstrated that
      for the hypercholesterolemic group, concentrations of total-cholesterol (631%)
      and lipoproteins are significantly higher at the end of pregnancy than those for
      the control group. For both groups, after 20 days of pregnancy, triglycerides
      metabolism was biphasic showing a significant increase followed by a diminution
      in their concentration. In both groups, free fatty acids increases significantly
      at the end of the pregnancy (537.5% for the control group and 462.5% for the
      hypercholesterolemic group). Furthermore, the offsprings of hypercholesterolemic
      dams manifest a lower birth weight (15.5%) than those of control group. Our
      results demonstrate that a cholesterol enriched diet modifies greatly the fetal
      development and lipid metabolism during rabbit's pregnancy. These modifications
      could be useful for the understanding of the interaction between diet and fetal
      development in rabbit and probably during human pregnancy.

PMID- 10403504
TI  - Interleukin-1beta-induced nitric oxide production in rat aortic endothelial
      cells: inhibition by estradiol in normal and high glucose cultures.
AB  - Expression of inducible nitric oxide synthase (iNOS) and the resultant increased
      nitric oxide (NO) production are associated with septic shock, atherosclerosis,
      and cytokine-induced vascular injury. Estrogen is known to impact vascular injury
      and vascular tone, in part through regulation of NO production. In the current
      study, we examined the effect of physiological concentrations of estradiol on
      interleukin-1beta (IL-1beta)-induced NO production in rat aortic endothelial
      cells (RAECs). 17Beta-estradiol significantly decreased IL-1beta-induced iNOS
      protein levels and reduced NO production in RAECs. High glucose (25 mM) elevated
      the increase in IL-1beta-induced iNOS protein and NO production. Nevertheless,
      estradiol still inhibited IL-1beta-induced iNOS and NO production even in the
      presence of high glucose. These data suggest that estradiol may exert its
      beneficial effects in part by inhibiting induction of endothelial iNOS, a
      possible mechanism for the protective effect of estradiol against diabetes
      associated cardiovascular complications.

PMID- 10403505
TI  - Nitric oxide synthase inhibitors enhance 5-HT2 receptor-mediated behavior, the
      head-twitch response in mice.
AB  - The purpose of this study was to characterize behavioral interactions between
      nitric oxide synthase (NOS) inhibitors and serotonergic 5-HT2 receptors. In the
      present study, NOS inhibitors, N(G)-nitro-L-arginine, N(G)-nitro-L-arginine
      methylester, N(G)-monomethyl-L-arginine, 7-nitroindazole, trifluoperazine and NO
      scavenger, methylene blue markedly enhanced 5-hydroxytryptamine (5-HT)-induced
      selective serotonergic behavior, the head twitch response (HTR), in mice. However
      NO generators, sodium nitroprusside, 3-morpholinosydnonimine and S-nitroso-N
      acetylpenicillamine as well as NO precursor, L-arginine markedly inhibited 5-HT
      induced HTR in mice. In the previous study, it was demonstrated that the N-methyl
      D-aspartate (NMDA) receptor antagonists markedly enhanced 5-HT-induced selective
      serotonergic behavior, HTR, whereas NMDA itself inhibited 5-HT-induced HTR in
      mice. In the present study, it was demonstrated that the inhibition by a NMDA
      receptor agonist, NMDA of 5-HT-induced HTR was reversed by the treatment with NOS
      inhibitors, N(G)-nitro-L-arginine and N(G)-nitro-L-arginine methylester. The
      suppressive action by a NO generator, S-nitroso-N-acetylpenicillamine of 5-HT
      induced HTR was also reversed by the treatment with NMDA receptor antagonists, MK
      801 and dextromethorphan. These results have shown that the NO system is located
      down stream of NMDA receptors involved in modulation of 5-HT2-mediated HTR.
      Therefore, the enhanced effects of NOS inhibitors on 5-HT-induced HTR support
      experimental evidence for the NO/5-HT2 as well as NMDA/5-HT2 receptor
      interactions indicating that NO plays an important role in the glutamatergic
      modulation of the serotonergic function at the 5-HT2 receptor.

PMID- 10403506
TI  - Cyclic GMP regulates cromakalim-induced relaxation in the rat aortic smooth
      muscle: role of cyclic GMP in K(ATP)-channels.
AB  - Recent studies have shown that nitric oxide (NO) modulates K+-channel activity
      which play an important role in controlling vascular tone. The formation of
      cyclic guanosine 3',5'-monophosphate (cyclic GMP) has also been recognized to be
      associated with the vasodilatory effect of NO. Both cyclic GMP and NO increase
      whole-cell K+-current by activating Ca2+-activated K+-channels (K(Ca)-channels).
      Here, we show evidence that activators of soluble guanylyl cyclase sodium
      nitroprusside or 3-morpholino-sydnonimine (SIN-1), and an analogue of cyclic GMP
      8-bromo-cyclic GMP enhance the relaxation induced by cromakalim which is blocked
      by glibenclamide (a specific inhibitor of ATP-sensitive K+-channels [K(ATP)
      channels]), and partially attenuated by methylene blue (an inhibitor of cyclic
      GMP formation). However, this is not due to the increase of cyclic GMP level by
      cromakalim itself because the relaxation induced by cromakalim is not associated
      with the changes of cyclic GMP level formed in the aortic smooth muscle. Thus, it
      is most likely that cyclic GMP also modulates activity of K(ATP)-channels, in
      addition to K(Ca)-channels, in the rat aorta.

PMID- 10403507
TI  - Hypoxanthine-guanine phosphoribosyltransferase deficiency and erythrocyte
      synthesis of pyridine coenzymes.
AB  - Purine and pyridine metabolism were studied in ten Lesch-Nyhan patients, with
      virtually no hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity in
      erythrocytes. Increased NAD erythrocyte concentrations were found in all
      patients. Raised activities of two enzymes catalysing NAD synthesis from
      nicotinic acid (nicotinic acid phosphoribosyltransferase: NAPRT, and NAD
      synthetase: NADs) was found in erythrocyte lysates from all patients. The two
      enzymes had normal apparent Km for their substrates and increased Vmax. The rate
      of synthesis of pyridine nucleotides from nicotinic acid by intact erythrocytes
      in vitro was also increased in most patients. These findings suggest that raised
      NAD concentrations in HPRT- erythrocytes are due to enhanced synthesis as a
      result of increased enzyme activities.

PMID- 10403508
TI  - H2O2 induces apoptosis in bovine tracheal epithelial cells in vitro.
AB  - Oxidants play an important role in the pathogenesis of various airway diseases.
      Oxidants have been shown to induce two distinct types of cell death, i.e.,
      apoptosis and necrosis. However, whether oxidants induce apoptosis in airway
      epithelial cells remains unclear. To address this question, we evaluated the
      effect of H2O2 exposure on bovine tracheal epithelial cells cultured under
      different conditions. When tracheal epithelial cells were isolated and exposed to
      H2O2 in suspension cultures, they underwent apoptosis as demonstrated by
      characteristic ultrastructural changes and DNA fragmentation. Interestingly,
      apoptosis occurred in single cells but not in aggregated cells. In addition,
      apoptosis was seen in many ciliated and in fewer mucous cells. When tracheal
      epithelial cells were allowed to attach to the substrate and grow, they became
      resistant to apoptosis induced by H2O2. These results suggest that H2O2 can
      induce apoptosis in airway epithelial cells.

PMID- 10403509
TI  - Effect of intragastric ammonia on gastrin-, somatostatin-and somatostatin
      receptor subtype 2 positive-cells in rat antral mucosa.
AB  - Somatostatin suppresses gastrin and somatostatin secretion via somatostatin
      receptors (SSTRs). Ammonia produced by Helicobacter pylori has been reported to
      modify gastric gastrin and somatostatin levels. We investigated the distribution
      of SSTR-subtype 2 (SSTR-2) in relation to gastrin- and somatostatin-containing
      cells and the effect of ammonia solution (0.01%-0.1%) administered orally for 2
      to 4 weeks on these cells in rat antral mucosa by immunohistochemistry. The
      majority of SSTR-2 peptide [31-41]-positive cells were located in the basal third
      of the glands. Double staining experiments revealed that SSTR-2 peptide [31-41]
      positive cells are co-localized in 85.0 +/- 2.2% of the gastrin-containing cells
      and in 34.4 +/- 4.8% of the somatostatin-containing cells. Ammonia solution
      significantly decreased the number of somatostatin-containing cells and increased
      the proportion of SSTR-2 peptide [31-41]-labeling in the somatostatin-containing
      cells in a duration-dependent manner. Maximum changes were observed in rats
      treated with ammonia solution at the lowest level of 0.01% accompanied by an
      increase in serum gastrin levels in the portal vein. Sodium hydroxide at the
      similar pH to 0.01% ammonia solution had no effect. These findings suggest that
      SSTR-2 are localized in antral endocrine cells and that ammonia solution mainly
      decreases somatostatin-containing cells without SSTR-2 expression, resulting in
      an increase in gastrin secretion into the portal vein.

PMID- 10403510
TI  - Secretion and clearance of the mature form of adrenomedullin in humans.
AB  - In the biosynthesis of adrenomedullin (AM), glycine-extended AM, an intermediate
      form (iAM) processed from proAM is converted to AM[1-52]-NH2, the bioactive
      mature form of AM (mAM), by enzymatic amidation. We earlier showed that both
      molecular forms of AM circulate in human plasma. In the present study, to
      investigate the secretion and clearance sites of mAM and iAM in humans, we
      examined the plasma mAM and iAM concentrations in the femoral artery and vein (FA
      and FV), the aortic root and coronary sinus (AO and CS), and the pulmonary artery
      and capillary (PA and PC) of patients with ischemic heart disease. Plasma mAM in
      FV was significantly (p<0.001) higher than in FA. There also was a significant
      (p<0.001) step-up in the plasma mAM of the CS as compared to the AO. In contrast,
      plasma mAM was significantly (p<0.001) reduced in the PC as compared to the PA.
      However, such differences were not observed in plasma iAM levels. These findings
      suggest that in humans the vasculature of the lower extremities and the heart
      produce and secrete mAM and that the lung is a clearance site of circulating mAM.

PMID- 10403512
TI  - The tumor promoting effect of constant light exposure on diethylnitrosamine
      induced hepatocarcinogenesis in rats.
AB  - The hypothesis that light-induced circadian clock suppression exerts a promoting
      effect on liver carcinogenesis was investigated in rats. Sixty-five male Wistar
      rats were given diethylnitrosamine (DEN, 10 mg/kg/day p.o.) for 6 weeks and were
      randomized into 3 groups. Rats from group 1 (N=20) received DEN only. Rats from
      group 2 (N=22) also received phenobarbital (pheno, 30 mg/rat/day p.o.) for 4
      weeks as a promoting agent and rats from group 3 (N=23) were exposed to
      continuous light. Three months after starting DEN treatment, urinary 6
      sulfatoxymelatonin (alphaMT6s) excretion, a marker of circadian clock function,
      had lost its circadian rhythmicity in the LL group, with a 4-fold lower 24 h mean
      than that found in the LDpheno and LD groups (8.0 +/- 3.2 ng/ml, 33.6 +/- 3.1
      ng/ml and 34.3 +/- 2.4 ng/ml respectively; p from ANOVA <0.001). Laparotomy was
      then performed. The proportion of rats with macroscopic nodules on liver surface
      was 72% (LD group), 89% (LDpheno group) and 95% (LL group) (p from chi2 = 0.1).
      Nodules were more numerous and larger both in the LL group and in the LDpheno one
      as compared to the LD group (p from chi2 <0.05). All the rats died with
      hepatocellular carcinomas, with a median survival of 5 months, similar in all 3
      groups. Light-induced circadian clock suppression exerted a promoting effect
      similar to that caused by phenobarbital in this model, yet through different
      effects on circadian system function.

PMID- 10403511
TI  - Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to
      LDL oxidation and polyunsaturated fatty acids.
AB  - Wine polyphenols were examined for their capacity to protect the lipid and
      protein moieties of porcine low density lipoproteins (LDL) during oxidation. The
      efficiency of resveratrol (3, 4', 5, trihydroxystilbene) and defined flavonoids
      was compared to that of a wine extract (WE) containing 0.5 g/g proanthocyanidols.
      The efficiency of resveratrol for protecting polyunsaturated fatty acids (PUFA)
      was higher than that of flavonoids in copper-induced oxidation and lower in AAPH
      (radical initiator)-induced oxidation. The LDL receptor activity was evaluated by
      flow cytometry using LDL labeled with fluorescein isothiocyanate (FITC) and
      Chinese hamster ovary cells (CHO-K1). The incubation of CHO-K1 with FITC-LDL
      oxidized for 16 h reduced the proportion of fluorescent cells from 97% to 4%. At
      a concentration of 40 microM, resveratrol and flavonoids completely restored the
      uptake of copper-oxidized LDL and AAPH-oxidized LDL respectively. Total
      fluorescence could also be obtained with 20 mg/L of WE with both oxidation
      systems. These data are consistent with previous findings relative to the
      formation of degradative products from PUFA. They confirm that resveratrol was
      more effective than flavonoids as a chelator of copper and less effective as a
      free-radical scavenger. Moreover, they show that WE, which contained monomeric
      and oligomeric forms of flavonoids and phenolic acids, protected LDL by both
      mechanisms.

PMID- 10403513
TI  - Synaptophysin is phosphorylated in rat cortical synaptosomes treated with
      botulinum toxin A.
AB  - Phosphorylation and dephosphorylation of neuronal proteins have been implicated
      in regulation of synaptic transmission. Studies were performed to determine if
      synaptophysin was phosphorylated or dephosphorylated during exposure of
      synaptosomes to botulinum toxin A (BoTX/A). Cholinergic-enriched synaptosomes
      were preincubated in the presence of 3H-choline to label newly synthesized
      acetylcholine (3H-ACh). This was followed by incubation with low or high
      potassium to stimulate release of newly synthesized 3H-ACh. BoTX/A inhibited
      total Ach release by 15-19% and inhibited release of newly synthesized 3H-ACh by
      35%. A 165% increase in synaptophysin phosphorylation occurred in a dose
      dependent manner over a range of doses (0.2 nM, 2 nM, 20 nM, 100 nM) of BoTX/A.
      When 4-Aminopyridine was added to synaptosomes that were BoTX/A treated,
      synaptophysin was dephosphorylated to control levels. Synaptosomes incubated with
      BoTX/A exhibited an inhibition of potassium stimulated ACh release and an
      increase in synaptophysin phosphorylation. Synaptophysin phosphorylation may be
      involved in inhibition of acetylcholine release.

PMID- 10403514
TI  - Selectivity of omega-CgTx-MVIIC toxin from Conus magus on calcium currents in
      enteric neurons.
AB  - Whole-cell perforated patch clamp recordings were used to analyze selectivity of
      omega-CgTx-MVIIC toxin for voltage-dependent calcium currents in cultured
      myenteric neurons from guinea-pig small intestine. Omega-CgTx-MVIIC (300 nM)
      blocked 37 +/- 9% of the peak current activated from -80 mV in 15 neurons by
      mostly affecting the plateau phase of the current. The toxin suppressed peak
      current activated from -30 mV dose-dependently with an IC50 of 70 +/- 8 nM. The
      blockade was complete at toxin concentrations of 1 microM. Thus, it appears that
      omega-CgTx-MVIIC blocks high voltage activated (HVA) calcium channels in the
      myenteric neurons unselectively as well as other types of HVA Ca2+ channels
      including P and Q channels.

PMID- 10403515
TI  - Suppression of resistance to drugs targeted to human immunodeficiency virus
      reverse transcriptase by combination therapy.
AB  - There are currently thirteen drugs approved for the treatment of human
      immunodeficiency virus (HIV)-infected individuals. Seven of them are targeted
      against the virus-encoded reverse transcriptase (RT). Appearance of drug
      resistant virus strains under the selective pressure of anti-HIV chemotherapy
      rapidly occurs as a consequence of the low fidelity of the RT-catalyzed DNA
      polymerisation reaction and the massive viral turnover. Resistance-associated
      mutations appear in the RT of virus strains that are under selective pressure of
      both nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs).
      A variety of these mutations cause cross-resistance to several other NRTIs or
      NNRTIs and consequently may hamper the effectiveness of the other drugs. Other RT
      mutations are quite specific and selective in their drug-resistance spectrum and
      do not influence the potency of the majority of other available drugs. Moreover,
      drug-specific mutations are identified that are able to restore drug sensitivity
      again when concomitantly present with other drug-specific mutations. Combination
      therapy has proven to be able to markedly suppress virus replication (and
      subsequent appearance of drug resistance) for a relatively long time period.
      However, in a number of cases, multiple drug combination therapy results in the
      appearance of a different mutation spectrum than is expected to emerge under
      monotherapy. Also, it has been shown that drugs that alter cellular
      deoxynucleotide pools not only are able to potentiate the antiviral efficacy of
      some RT inhibitors, but also may influence the resistance spectrum of certain
      anti-HIV drugs. All available information argues for the use of a rational
      combination of different anti-HIV inhibitors with different resistance spectra to
      suppress virus replication efficiently and to delay the emergence of drug
      resistant virus as long as possible, but it also indicates that there is a strong
      need for additional drugs to further optimize and improve the efficacy of long
      term HIV treatment.

PMID- 10403516
TI  - Inductive and inhibitory effects of non-ortho-substituted polychlorinated
      biphenyls on estrogen metabolism and human cytochromes P450 1A1 and 1B1.
AB  - The effects of a series of non-ortho-substituted polychlorinated biphenyls (PCBs)
      on human cytochrome P450 1A1 (CYP1A1), a 17beta-estradiol (E2) 2-hydroxylase, and
      P450 1B1 (CYP1B1), an E2 4-hydroxylase, were investigated in HepG2 and MCF-7
      cells. Elevated rates of 2- and 4-methoxyestradiol (2- and 4-MeOE2) formation in
      PCB-treated cultures were measured as activities of CYP1A1 and CYP1B1,
      respectively. Of the congeners investigated, 3,4,4',5-tetrachlorobiphenyl (PCB
      81), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and 3,4',5-trichlorobiphenyl (PCB
      39) caused marked stimulation of E2 metabolism in both cell lines. Northern blot
      analyses confirmed that exposure of MCF-7 cells to PCBs 81, 126, and 39 caused
      highly elevated levels of the CYP1A1 and CYP1B1 mRNAs. Exposure of MCF-7 cells to
      3,3',4,4',5,5'-hexachlorobiphenyl (PCB 169) resulted in elevated levels of the
      CYP1A1 and CYP1B1 mRNAs, but did not cause elevated rates of E2 metabolism;
      rather, 4-MeOE2 production was depressed to below control levels in PCB 169
      treated cultures. PCB 169 also inhibited the 2,3,7,8-tetrachlorodibenzo-p-dioxin
      (TCDD)-induced 4-MeOE2 and, to a lesser extent, 2-MeOE2 production in MCF-7
      cells, as did PCB 126 and several other congeners. In microsomal assays,
      inhibition of cDNA-expressed human CYP1B1 by PCBs 169 and 126 was demonstrated.
      These studies with one subgroup of PCBs, the non-ortho-substituted congeners,
      underscore the complexity and diversity of effects of PCBs, as individual
      congeners were found both to induce expression and to inhibit activity of human
      CYP1B1 and CYP1A1.

PMID- 10403517
TI  - Kinetic control of guanine nucleotide binding to soluble Galpha(q).
AB  - Binding of guanine nucleotides to heterotrimeric G proteins is controlled
      primarily by kinetic factors, such as the release of bound GDP, rather than by
      affinity alone. Detergent-solubilized Galpha(q) displays unusual guanine
      nucleotide binding properties in comparison with other G protein alpha subunits.
      Under conditions where most G proteins bind nearly stoichiometric GTPgammaS in 5
      30 min at micromolar nucleotide concentrations, GTPgammaS binding to Galpha(q) is
      slow (>1 hr to completion), markedly substoichiometric, and dependent upon high
      concentrations of nucleotide (0.1 to 0.2 mM). Although the latter two properties
      suggest low affinity, GTPgammaS dissociation is immeasurably slow under commonly
      used conditions. We found that purified Galpha(q) can bind stoichiometric
      GTPgammaS, but that binding is controlled kinetically by a combination of
      factors. GDP (or IDP) dissociated slowly from Galpha(q), but the dissociation
      rate increased linearly with the concentration of (NH4)2SO4 up to 0.75 M
      (approximately 20-fold acceleration). The resulting GDP-free Galpha(q) was labile
      to rapid and irreversible denaturation, however (rate constant > or = 1 min(-1)
      at 20 degrees). Denaturation competed kinetically with relatively slow GTPgammaS
      association, such that stoichiometric binding was only attained at 100 microM
      GTPgammaS. These findings reconcile the slowly reversible binding of GTPgammaS to
      Galpha(q) with the other behaviors that suggested lower affinity, and point out
      that events subsequent to GDP dissociation can markedly influence the rates and
      extents of guanine nucleotide binding to G protein alpha subunits. Understanding
      these interactions allowed the direct, accurate quantitation of active Galpha(q)
      by a simple GTPgammaS binding assay in the presence of (NH4)2SO4, and similarly
      can prevent underestimation of the concentrations of other G proteins.

PMID- 10403518
TI  - A novel function of emodin: enhancement of the nucleotide excision repair of UV-
      and cisplatin-induced DNA damage in human cells.
AB  - Nucleotide excision repair (NER) is the main pathway by which mammalian cells
      remove carcinogenic DNA lesions caused by UV light and many other common
      mutagens. To explore the effect of emodin on NER, its influence on the repair of
      UV- and cisplatin-induced DNA damage in human fibroblast cells (WI38) was
      evaluated. Emodin increased unscheduled DNA synthesis (UDS) of UV-treated cells
      and reduced cisplatin-induced DNA adducts in WI38 in a concentration-dependent
      manner, indicating that emodin might promote NER capability in cells. The
      resultant NER complex is a cooperative assembly of XPF, ERCC1, XPA, RPA, and XPG
      subunits. The gene regulations of the subunits after emodin treatment were
      determined by reverse transcription-polymerase chain reaction (RT-PCR) using
      specific primers. Among the subunits, the expression of ERCC1 in WI38 cells was
      up-regulated significantly after emodin treatment. All other expressions remained
      essentially unchanged. In addition, calcium influx in WI38 was increased in
      proportion to the concentration of emodin. Since UV-induced NER is Ca2+
      dependent, elevation of calcium influx may be another mechanism by which emodin
      facilitates DNA repair. In conclusion, emodin can increase the repair of UV- and
      cisplatin-induced DNA damage in human cells, and elevated ERCC1 gene expression
      and Ca2+-mediated DNA repair processes may be involved in the repair mechanism of
      emodin.

PMID- 10403519
TI  - Kinetics of inhibition of glutathione-mediated degradation of ferriprotoporphyrin
      IX by antimalarial drugs.
AB  - We have shown previously that chloroquine and amodiaquine inhibit the glutathione
      dependent degradation of ferriprotoporphyrin IX (FP). We have also demonstrated
      that treatment of human erythrocytes infected with Plasmodium falciparum with
      chloroquine or amodiaquine results in a dose- and time-dependent accumulation of
      FP in the membrane fraction of these cells in correlation with parasite killing.
      High levels of membrane FP are known to perturb the barrier properties of
      cellular membranes, and could thereby irreversibly disturb the ion homeostasis of
      the parasite and cause parasite death. We here report on the effect of various 4
      aminoquinolines, as well as pyronaridine, halofantrine and some bis-quinolines,
      on glutathione-mediated destruction of FP in aqueous solution, when FP was bound
      non-specifically to a protein, and when it was dissolved in human erythrocyte
      ghost membranes. We showed that all drugs were capable of inhibiting FP
      degradation in solution. The inhibitory efficacy of some drugs declined when FP
      was bound non-specifically to protein. Quinine and mefloquine were unable to
      inhibit the degradation of membrane-associated FP, in line with their inability
      to increase membrane-associated FP levels in malaria-infected cells following
      drug treatment. The discrepancy between chloroquine and amodiaquine on the one
      hand, and quinine and mefloquine on the other, is discussed in terms of the
      particular location of drugs and FP in the phospholipid membrane, and may suggest
      differences in the mechanistic details of the antimalarial action of these drugs.

PMID- 10403520
TI  - Attenuation by glutathione of hsp72 gene expression induced by cadmium in
      cisplatin-resistant human ovarian cancer cells.
AB  - Intracellular GSH has some effects on protecting cells against cadmium and is
      involved in the development of resistance to cisplatin (CDDP). To determine the
      effects of intracellular GSH on expression of the heat shock genes (hsp) induced
      by cadmium in CDDP-resistant cancer cells, we used two human ovarian cancer cell
      lines: CDDP-sensitive A2780 and its CDDP-resistant derivative A2780CP. The
      concentration of intracellular GSH was significantly higher in A2780CP than in
      A2780 cells. A2780CP cells were more resistant to CdCl2 exposure than A2780
      cells. The treatment of the two cell lines with 50 microM CdCl2 induced hsp72,
      hsp32 and metallothionein (MT-II) mRNAs, and the induction level of each mRNA did
      not differ in the two cell lines. However, the treatment with 20 microM CdCl2
      induced the hsp72 and hsp32 mRNAs in A2780CP cells less than in A2780 cells,
      while the MT-II mRNA was induced to similar levels in the two cell lines. The DNA
      binding activity of the heat shock factor (HSF) in response to 20 microM CdCl2
      exposure was also significantly lower in A2780CP cells. The treatment of A2780
      cells with N-acetyl-L-cysteine increased the intracellular GSH concentration, and
      profoundly suppressed hsp72 mRNA induction and HSF activation by CdCl2. These
      results indicate that the regulation of the hsp72 gene expression induced by
      CdCl2 was more suppressive in A2780CP than in A2780 cells. Our findings suggest
      that increased GSH biosynthesis in CDDP-resistant cancer cells may be involved in
      the attenuation of HSF activation by CdCl2.

PMID- 10403521
TI  - Oxidizing effects of vanadate on calcium mobilization and amylase release in rat
      pancreatic acinar cells.
AB  - The effects of vanadate were examined by monitoring intracellular free calcium
      concentration ([Ca2+]i) and amylase secretion in collagenase-dispersed rat
      pancreatic acinar cells. Vanadate increased [Ca2+]i by mobilizing calcium from
      agonist-releasable intracellular calcium stores, since this increase was observed
      in the absence of extracellular calcium and vanadate failed to increase [Ca2+]i
      after treatment with thapsigargin in calcium-free medium. Moreover, pretreatment
      of acinar cells with vanadate prevented the cholecystokinin octapeptide (CCK-8)
      induced signal of [Ca2+]i, whereas co-incubation with CCK-8 potentiated the
      plateau phase of calcium response to CCK-8 without modifying the transient
      calcium spike. The effects of vanadate on calcium mobilization were reversed by
      the presence of the sulfhydryl reducing agent dithiothreitol. Vanadate also
      activated the calcium influx, since an additional enhancement of calcium influx
      induced by thapsigargin-evoked intracellular store depletion was observed and
      vanadate reversed the inhibitory effect of lanthanum (an inhibitor of calcium
      entry) into acinar cells. In addition, vanadate evoked a concentration-dependent
      release of amylase from pancreatic acinar cells and moreover, reduced the
      secretory response to CCK-8. We conclude that, in pancreatic acinar cells,
      vanadate releases calcium from the agonist-releasable intracellular calcium pool
      and consequently induces amylase secretion. These effects are likely due to the
      oxidizing effects of this compound.

PMID- 10403522
TI  - Specific dual effect of cycloheximide on B lymphocyte apoptosis: involvement of
      CPP32/caspase-3.
AB  - Cycloheximide (CHX) is known to stimulate or to prevent apoptosis, according to
      the cell type used. We found that CHX, in a dose-dependent way, exerted the two
      opposite effects in B lymphocytes. CHXhigh (2.5 microg/mL) inhibited protein
      synthesis (>90%) and greatly increased B cell apoptosis but failed to prevent
      apoptosis induction by dexamethasone (DEX) or dibutyryl-cAMP (dbcAMP), which is
      in opposition with CHX activity in thymocytes. On the contrary, CHXlow (0.05
      microg/mL), modestly inhibited protein synthesis (<15%) and reduced spontaneous
      as well as drug-induced apoptosis and further augmented the protection conferred
      by interleukin-4 or lipopolysaccharide. To examine the role of caspases in CHX
      effects, we used the broad spectrum peptide caspase inhibitor Z-VAD-fmk: it
      totally abrogated spontaneous as well as drug- and CHXhigh-induced cell death.
      Apoptosis was associated with CPP32/caspase-3 activation, since cleavage of
      CPP32/caspase-3 and caspase-3 activity were increased by DEX, dbcAMP as well as
      by CHXhigh treatment. Meanwhile, caspase-3 activity was reduced by CHXlow
      treatment. Therefore, CHX exerts opposite effects on B lymphocyte apoptosis which
      are associated with a dual action on caspase-3 activation.

PMID- 10403523
TI  - Cell cycle-dependent distribution and specific inhibitory effect of vectorized
      antisense oligonucleotides in cell culture.
AB  - Factors limiting the use of antisense phosphodiester oligodeoxynucleotides (ODNs)
      as therapeutic agents are inefficient cellular uptake and intracellular transport
      to RNA target. To overcome these obstacles, ODN carriers have been developed, but
      the intracellular fate of ODNs is controversial and strongly depends on the means
      of vectorization. Polyamidoamine dendrimers are non-linear polycationic cascade
      polymers that are able to bind ODNs electrostatically. These complexes have been
      demonstrated to protect phosphodiester ODNs from nuclease degradation and also to
      increase their cellular uptake and pharmacological effectiveness. We studied the
      intracellular distribution of a fluorescein isothiocyanate-labeled ODN vectorized
      by a dendrimer vector and found that intracellular ODN distribution was dependent
      on the phase of the cell cycle, with a nuclear localization predominantly in the
      G2/M phase. In addition, in order to evaluate the relevance of ODN vectors in
      enhancing the inhibition of the targeted genes' expression, we developed a rapid
      screening system which measures the transient expression of two reporter genes,
      one used as target, the other as control and vice versa. This system was
      validated through investigating the effect of the dendrimer vector on ODN
      biological activity. Antisense sequence-specific inhibition of more than 70% of
      one reporter gene was obtained with a chimeric ODN containing four
      phosphorothioate groups, two at each end.

PMID- 10403524
TI  - Protection of mitochondrial respiration activity by bilobalide.
AB  - Mitochondria alteration is an early event in ischemia-induced damage, and its
      prevention improves tissue survival upon reperfusion. Adenine translocase and
      complex I activities are rapidly affected by ischemia. Ginkgo biloba extract
      demonstrates anti-ischemic properties attributable to the terpenoid fraction,
      mainly due to the presence of bilobalide. The mechanism of the protection
      afforded by bilobalide is not yet known. In this work, the effects of bilobalide
      on mitochondrial respiration were investigated. Mitochondria isolated from rats
      treated with bilobalide (2 to 8 mg/kg) showed a dose-dependent increase in the
      respiratory control ratio, due to a lower oxygen consumption during state 4.
      Bilobalide also decreased the sensitivity of oxygen consumption to inhibition of
      complex I by Amytal or to inhibition of complex III by antimycin A or
      myxothiazol. There was no protection of complexes IV and V. It also increased the
      activity of complex I but not of adenine translocase. Similar effects were also
      obtained in vitro when control mitochondria were preincubated for 1 hr with 0.8
      microg/mL bilobalide. Treatment of the rats with 8 mg/kg bilobalide also
      prevented the ischemia-induced decrease in state 3 of the mitochondrial
      respiration and thus the decrease in RCR. The protective effect of bilobalide on
      cellular ATP content observed under ischemic conditions can be correlated with
      the above observations. By protecting complex I and III activities, bilobalide
      allows mitochondria to maintain their respiratory activity under ischemic
      conditions as long as some oxygen is present, thus delaying the onset of ischemia
      induced damage. This mechanism provides a possible explanation for the anti
      ischemic properties of bilobalide and of Ginkgo biloba extract in therapeutic
      interventions.

PMID- 10403525
TI  - Inhibition of protein kinase C activator-mediated induction of p21CIP1 and
      p27KIP1 by deoxycytidine analogs in human leukemia cells: relationship to
      apoptosis and differentiation.
AB  - Events accompanying sequential exposure of U937 leukemic cells to the
      deoxycytidine (dCyd) analogs 1-[beta-D-arabinofuranosyl]cytosine (ara-C) or 2',2'
      difluorodeoxycytidine (gemcitabine; dFdC) followed by two protein kinase C (PKC)
      activators [bryostatin 1 (BRY) or phorbol 12'-myristate 13'-acetate (PMA)]
      exhibiting disparate differentiation-inducing abilities were characterized. A 24
      hr exposure to 10 nM BRY or PMA after a 6-hr incubation with 1 microM ara-C or
      100 nM dFdC resulted in equivalent increases in apoptosis, caspase-3 activation,
      and polyADP-ribose polymerase degradation, as well as identical DNA cleavage
      patterns. BRY and PMA did not modify retention of the lethal ara-C metabolite ara
      CTP or alter ara-CTP/dCTP ratios. Unexpectedly, pretreatment of cells with ara-C
      or dFdC opposed BRY- and PMA-related induction of the cyclin-dependent kinase
      inhibitors (CDKIs) p21CIP1 and/or p27KIP1. These effects were not mimicked by the
      DNA polymerase inhibitor aphidicolin or by VP-16, a potent inducer of apoptosis.
      Inhibition of PKC activator-induced CDKI expression by ara-C and dFdC did not
      lead to redistribution of proliferating cell nuclear antigen but was accompanied
      by sub-additive or antagonistic effects on leukemic cell differentiation.
      Sequential exposure of cells to ara-C followed by BRY or PMA led to substantial
      reductions in clonogenicity that could not be attributed solely to apoptosis.
      Finally, pretreatment of cells with ara-C attenuated PMA- and BRY-mediated
      activation of mitogen-activated protein kinase, an enzyme implicated in CDKI
      induction. Collectively, these findings suggest that pretreatment of leukemic
      cells with certain dCyd analogs interferes with CDKI induction by the PKC
      activators PMA and BRY, and that this action may contribute to modulation of
      apoptosis and differentiation in cells exposed sequentially to these agents.

PMID- 10403526
TI  - Critical role of sulfenic acid formation of thiols in the inactivation of
      glyceraldehyde-3-phosphate dehydrogenase by nitric oxide.
AB  - The relationship between possible modifications of the thiol groups of
      glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by nitric oxide (NO) and
      modified enzyme activity was examined. There are 16 free thiols, including 4
      active site thiols, in a tetramer of GAPDH molecule. NO donors, sodium
      nitroprusside (SNP), and S-nitroso-N-acetyl-DL-penicillamine (SNAP) decreased the
      number of free thiols with a concomitant inhibition of GAPDH activity in a
      concentration- and time-dependent manner. After treatment for 30 min, free thiols
      were maximally decreased to 8-10 per GAPDH tetramer and enzyme activity was also
      inhibited to 5-10% of control activity. In the presence of 30 mM dithiothreitol
      (DTT), these effects were completely blocked. Since similar results were obtained
      in the case of hydrogen peroxide (H2O2) treatment, which is known to oxidize the
      thiols, these effects of nitric oxide donors were probably due to modification of
      thiol groups present in a GAPDH molecule. On the other hand, DTT posttreatment
      after the treatment of GAPDH with SNP, SNAP, or H2O2 did not completely restore
      the modified thiols and the inhibited enzyme activity. DTT posttreatment after
      the 30-min-treatment with these agents restored free thiols to 14 in all
      treatments. In the case of SNAP treatment, all 4 active sites were restored and
      enzyme activity reached more than 80% of the control activity, but in two other
      cases one active site remained modified and enzyme activity was restored to about
      only 20%. Therefore, all 4 free thiols in the active site seem to be very
      important for full enzyme activity. DTT posttreatment in the presence of sodium
      arsenite, which is known to reduce sulfenic acid to thiol, almost completely
      restored both thiol groups and enzyme activity. These findings suggest that
      nitric oxide inhibits GAPDH activity by modifications of the thiols which are
      essential for this activity, and that the modification includes formation of
      sulfenic acid, which is not restored by DTT. S-nitrosylation, which is one type
      of thiol modification by NO, occurred when GAPDH was treated with SNAP but not
      SNP. Analysis of thiol modification showed that SNAP preferentially nitrosylated
      the active site thiols, the nitrosylation of which fully disappeared by DTT
      posttreatment. It seems that SNAP nitrosylates the active site thiols of GAPDH to
      prevent these thiols from oxidizing to sulfenic acid.

PMID- 10403527
TI  - Reversal by flunarizine of the decrease in hippocampal acetylcholine release in
      pentylenetetrazole-kindled rats.
AB  - The aim of our study was to evaluate the effect of the non-selective calcium
      antagonist flunarizine on hippocampal acetylcholine (ACh) release with the
      microdialysis technique in freely moving rats after long-term concomitant
      administration of pentylenetetrazole (PTZ) in comparison with rats treated long
      term with PTZ (kindled animals). The basal extracellular concentration of ACh in
      the hippocampus of rats treated with PTZ alone was significantly reduced relative
      to that of vehicle-treated rats (2.04+/-0.2 vs 3.94+/-0.3 pmol per 20-min sample;
      P < 0.01). Administration of flunarizine (7.5 mg/kg i.p.) before each PTZ
      injection prevented this decrease in basal ACh output (3.75+/-0.4 pmol per 20-min
      sample). On the contrary, the expression of PTZ-induced kindling was not
      prevented by administration of flunarizine. The specific antagonistic effect of
      flunarizine on the kindling-induced decrease in hippocampal ACh release is shared
      by the selective antagonist of the L-type calcium channel, nifedipine, but not by
      the dopamine D2 antagonist, (-)-sulpiride, suggesting that the decrease in Ca2+
      overload by a blockade of the L-type calcium channel may be responsible for the
      protective action on cholinergic neurons exerted by flunarizine. These data also
      suggest a potential therapeutic role for flunarizine in counteracting impairment
      of hippocampal cholinergic activity.

PMID- 10403528
TI  - Effects of desferrithiocin and its derivatives on peripheral iron and striatal
      dopamine and 5-hydroxytryptamine metabolism in the ferrocene-loaded rat.
AB  - Iron overload disorders, such as beta-thalassaemia, are currently treated with
      the iron chelator desferrioxamine (DFO) or 1,2-dimethyl-3-hydroxypyridin-4-one
      (L1), which is currently under clinical evaluation. However, DFO is inactive
      orally and needs to be administered by intramuscular infusion, whilst there are
      concerns over the long-term effectiveness and toxicity of L1. In addition, both
      DFO and L1 affect brain dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolism.
      In this study, the 3,5,5-trimethylhexanoyl ferrocene rat model of iron overload
      was used to compare the iron-chelating capabilities of a novel orally active
      siderophore, desferrithiocin (DFT) and its desmethyl derivatives DFT-D and DFT-L,
      to that of DFO, along with their ability to affect brain DA and 5-HT metabolism.
      Chronic administration of ferrocene produced a 12-fold increase in liver iron
      levels, as assessed by electrothermal atomic absorption. Subsequent treatment
      with DFT over a two-week period produced a 37% reduction in liver iron levels,
      whereas similar treatment with DFT-D and DFT-L produced a more marked reduction
      in these levels (65% and 59%, respectively) in the ferrocene-treated animals. In
      contrast, using the same dosing regimen, DFO and L1 only produced a 16% and 18%
      reduction, respectively, in liver iron levels. Both DFT and its derivatives
      failed to affect either striatal DA or 5-HT metabolism when assessed by HPLC. In
      view of the previously described oral bioavailability of DFT, the marked ability
      of DFT and its derivatives to chelate hepatic iron, and their inability to affect
      brain DA or 5-HT metabolism, such siderophores appear potentially useful clinical
      iron chelators.

PMID- 10403529
TI  - Cellular localization of hepatic cytochrome 1B1 expression and its regulation by
      aromatic hydrocarbons and inflammatory cytokines.
AB  - Cytochrome P450 1B1 (CYP1B1) is an activator of several xenobiotics and is
      induced in the liver upon experimental exposure to aromatic hydrocarbons. Since
      its cellular localization and regulation are incompletely clarified, Cyp1B1
      expression and inducibility by 9,10-dimethyl-1,2-benzanthracene (DMBA) and
      inflammatory cytokines were investigated in different rat liver cell populations
      in vitro and in the liver during hepatocellular injury. Expression of Cyp1B1 was
      studied by Northern blot analysis in hepatic stellate cells (HSCs),
      myofibroblasts (MFs), Kupffer cells (KCs), and hepatocytes at various time points
      of primary cultures and in acutely damaged rat liver (carbon tetrachloride
      model). Enzyme inducibility was assessed by incubation of cells with DMBA as well
      as, in the case of HSCs, with tumor necrosis factor-alpha (TNF-alpha) and
      transforming growth factor beta1 (TGFbeta1). Cyp1B1 messengers were expressed at
      high levels by HSCs and MFs, whereas constitutive expression was not detectable
      in KCs or in hepatocytes. Cyp1B1-specific mRNA were expressed at highest levels
      in HSCs at an early stage of activation (2 days after plating) and were
      diminished upon further activation. DMBA strongly enhanced Cyp1B1 gene expression
      in HSCs, MFs, and in hepatocytes at day 3 of primary cultures, but not in
      hepatocytes at day 1, or in KCs. The inflammatory cytokine TNF-alpha enhanced the
      Cyp1B1 gene expression in HSCs, either when administered alone or in addition to
      DMBA, while TGFbeta1 did not affect Cyp1B1 expression, even after DMBA induction.
      We conclude that HSCs and MFs seem to be the major cellular sources of hepatic
      Cyp1B1 expression and that the constitutive expression of the Cyp1B1 gene and the
      responsiveness to DMBA stimulation differ between mesenchymal and parenchymal
      liver cells, indicating a cell-specific regulation of Cyp1B1 gene expression.
      Interestingly, TNF-alpha is a potent stimulator of the Cyp1B1 gene in HSCs and
      acts in concert with DMBA.

PMID- 10403530
TI  - Initiation of a process of differentiation by stable transfection of ob17
      preadipocytes with the cDNA of human A1 adenosine receptor.
AB  - A process of differentiation was observed when ob17 preadipocyte cells were
      stably transfected with a vector containing the cDNA of the human A1 adenosine
      receptor of adipose tissue. Growth of the cell lines continued but was slowed
      relative to untransfected cells and cells transfected with vector alone, never
      attaining confluence. During this process, cells were observed to differentiate
      morphologically and to accumulate lipid droplets in their cytoplasm, droplets
      that stained with Oil red-O. During that same period of time, cells transfected
      with vector alone multiplied rapidly, attained confluence, and showed no signs of
      differentiation. We conclude that expression of the A1 adenosine receptor
      initiated a differentiation process that resembled aspects of the normal
      differentiation of preadipocytes. If so, a role for the A1 receptor in normal
      preadipocyte differentiation should be considered, perhaps after cell-to-cell
      contact occurs at confluence.

PMID- 10403531
TI  - Protective effects of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a
      superoxide dismutase mimetic, in paw oedema induced by carrageenan in the rat.
AB  - In the present study we investigated the therapeutic efficacy of Mn(III)tetrakis
      (4-benzoic acid) porphyrin (MnTBAP), a superoxide dismutase mimetic which
      possesses peroxynitrite scavenging effects, in rats subjected to carrageenan
      induced paw oedema. Local administration of MnTBAP (5, 25, and 50 microg/paw)
      significantly and dose dependently reduced carrageenan-induced paw oedema at all
      time points. MnTBAP also caused a significant dose-dependent reduction in paw
      myeloperoxidase activity and lipid peroxidation, as well as preventing
      histological injury. Immunohistochemical analysis for nitrotyrosine revealed a
      positive staining in paw from carrageenan-treated rats. No positive nitrotyrosine
      staining was found in the paws of the carrageenan-treated rats that received
      MnTBAP. Our study demonstrates that MnTBAP exerts protective effects in
      carrageenan-induced paw oedema. Part of these anti-inflammatory effects may be
      related to: 1) reduction of superoxide formation due to the superoxide dismutase
      like activity of the compound; and 2) scavenging of peroxynitrite.

PMID- 10403532
TI  - Pneumadin-evoked intracellular free Ca2+ responses in rat aortic smooth muscle
      cells: effect of dexamethasone.
AB  - The direct vascular effect of pneumadin (PN) was determined by studying the
      changes in intracellular free calcium ([Ca2+]i) levels in cultured rat aortic
      smooth muscle cells maintained between the second and fifth passages. PN evoked a
      rapid, concentration-dependent, biphasic increase in [Ca2+]i. The [Ca2+]i level
      rose from a basal value of 108 nM to a maximum increase in peak value of 170 nM.
      Although the level of maximal [Ca2+]i response evoked by PN was less than with
      other vasoactive agonists, it was more potent (EC50 0.5 nM) than even endothelin
      1 (EC50 3.1 nM). At concentrations > 100 nM, [Ca2+]i elevations induced by PN
      above basal levels were no longer observed. Pretreatment with dexamethasone (100
      nM for 24 hr) resulted in a significant increase (P < 0.01) in the peak [Ca2+]i
      response (310 nM) to PN. However, the biphasic pattern in the peak [Ca2+]i
      responses encountered with increasing concentrations of PN remained unaffected.
      The exaggerated [Ca2+]i response to PN was abolished by preincubation of cells
      with either the glucocorticoid antagonist mifepristone (RU 486) or the protein
      synthesis inhibitor cycloheximide. Inclusion of either an AT1 antagonist
      (losartan), a V1 selective vasopressin antagonist (d(Ch2)5 Tyr (Me) AVP), or an
      alpha-adrenoceptor antagonist (phentolamine) failed to affect the increases in
      [Ca2+]i induced by PN. PN-evoked increases in inositol 1,4,5-trisphosphate levels
      paralleled the [Ca2+]i changes. These data suggest that PN increases Ca2+
      mobilization in rat aortic smooth muscle cells via activation of phospholipase C
      coupled receptors. This effect is up-regulated by dexamethasone.

PMID- 10403533
TI  - Doxazosin treatment and peroxidation of low-density lipoprotein among male
      hypertensive subjects: in vitro and ex vivo studies.
AB  - Doxazosin is an antihypertensive drug that gives rise to 6- and 7
      hydroxydoxazosin during hepatic metabolism. The structures of the
      hydroxymetabolites suggest that they may possess antioxidative properties. The
      aim of the present study was to examine whether doxazosin and 6- and 7
      hydroxydoxazosin were able to scavenge free radicals and whether these compounds
      might protect low-density lipoprotein (LDL) against in vitro and ex vivo
      oxidation. Both 6- and 7-hydroxydoxazosin showed radical scavenging capacity as
      assessed by measuring scavenging of 1,1-diphenyl-2-picrylhydrazyl radicals. In
      vitro incubation with 10 microM 6- and 7-hydroxydoxazosin significantly reduced
      human mononuclear cell-mediated oxidation of LDL, measured as the formation of
      lipid peroxides and the relative electrophoretic mobility of LDL (to 10 and 6% of
      the control, respectively). Furthermore, formation of conjugated dienes in LDL
      during Cu2+-induced oxidation was significantly reduced in the presence of 5
      microM 6- and 7-hydroxydoxazosin (to 28% of tmax [time to maximum] of control).
      However, treatment of hypertensive patients with increasing doses of doxazosin
      (from 1 to 8 mg/day) for 8 weeks altered neither Cu2+-catalyzed, 2,2'azobis-(2
      amidinopropane hydrochloride)-initiated, nor cell-mediated oxidation of patient
      LDL ex vivo. Furthermore, the total antioxidative capacity of plasma was
      unaffected by treatment. In conclusion, the present study shows that 6- and 7
      hydroxydoxazosin have radical scavenging properties and protect LDL against in
      vitro oxidation. However, treatment of hypertensive male subjects with increasing
      doses of doxazosin for 8 weeks did not affect ex vivo oxidation of LDL.

PMID- 10403534
TI  - Differential apoptosis by indomethacin in gastric epithelial cells through the
      constitutive expression of wild-type p53 and/or up-regulation of c-myc.
AB  - Nonsteroidal anti-inflammatory drug (NSAID)-induced apoptosis is considered to be
      an important mechanism in the antineoplastic effects and damage produced by the
      drugs in the gastrointestinal tract. In this study, two different gastric cancer
      cell lines, MKN28 (mutant-type p53) and AGS (wild-type p53), were compared as to
      growth inhibition, apoptosis, and cell cycle and apoptosis-related gene
      expression in response to indomethacin treatment. Cell growth was measured by MTT
      (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Apoptosis
      was characterized by acridine orange staining and DNA fragmentation, and cell
      cycle kinetics by flow cytometry. The mRNA and protein levels of p53,
      p21waf1/cip1, and c-myc were determined by Northern and Western blotting. The
      results showed that indomethacin initiated growth inhibition and apoptosis in
      both cell lines without cell cycle shifting. AGS cells were more sensitive to
      growth inhibitory activity and apoptosis of indomethacin than MKN28 cells. In
      MKN28 cells, the levels of p53, p21waf1/cip1, and c-myc mRNA remained unchanged
      over the 24-hr treatment with indomethacin, but the p53 protein level was
      elevated after 4 hr. There was no change in the p21waf1/cip1 and c-myc protein
      levels in the MKN28 cells. In AGS cells, a progressive increase in c-myc mRNA and
      protein levels was noted, while p53 and p21waf1/cip1 remained unchanged. It can
      be concluded that wild-type p53 and/or up-regulation of c-myc is associated with
      indomethacin-mediated differential apoptosis in gastric epithelial cells.

PMID- 10403535
TI  - Resveratrol, an antioxidant present in red wine, induces apoptosis in human
      promyelocytic leukemia (HL-60) cells.
AB  - Resveratrol, a triphenolic stilbene present in grapes and other plants, has
      striking antioxidant and anti-inflammatory activities which have been considered
      to be responsible for the beneficial effects of red wine consumption on coronary
      heart disease. Recent studies reveal that resveratrol can inhibit each step of
      multistage carcinogenesis. However, the molecular mechanisms underlying anti
      tumorigenic or chemopreventive activities of this phytochemical remain largely
      unknown. In the present work, we have found that resveratrol reduces viability
      and DNA synthesis capability of cultured human promyelocytic leukemia (HL-60)
      cells. The growth inhibitory and antiproliferative properties of resveratrol
      appear to be attributable to its induction of apoptotic cell death as determined
      by morphological and ultrastructural changes, internucleosomal DNA fragmentation,
      and increased proportion of the subdiploid cell population. Resveratrol treatment
      resulted in a gradual decrease in the expression of anti-apoptotic Bcl-2. These
      results, together with previous findings, suggest the cancer therapeutic as well
      as chemopreventive potential of resveratrol.

PMID- 10403536
TI  - Detection of genomically-tagged cancer cells in different tissues at different
      stages of tumor development: lack of correlation with the formation of
      metastasis.
AB  - Genetic detection of tumor cells in blood, lymphatic nodes or bone marrow using
      reverse transcription and polymerase chain reaction (PCR) is quite attractive
      because it allows the early diagnosis of cancer dissemination. Unfortunately,
      this type of detection strategy cannot be applied to solid parenchymas, because
      they usually share with tumor cells the mRNA markers. To avoid this impediment,
      we have developed an experimental model of cancer using cells with a genome
      associated tag. DHD/K12-PROb cancer cells were stably transfected with
      pcDNA3.1CAT. Approximately 10(6) transfected cells (DHD-CAT cells) were injected
      subcutaneously into the chest of BD-IX rats. Animals were divided into 11 groups
      according to the time between injection of tumor cells and euthanasia. An
      additional 'untagged group' was injected with untransfected cells (DHD-Wild).
      Blood and tissues samples were collected after euthanasia. Macroscopic and
      microscopic analysis was done. To detect circulating tumor cells or their
      presence in peripheral organs, we performed PCR with nested primers to amplify
      chloramphenicol acetyl transferase-encoding (CAT-encoding) DNA sequences. The
      minimum number of cells that yielded detectable cells routinely was 2 in 10(6).
      No modification of cancer aggressiveness was observed in DHD-CAT cells. DHD-CAT
      cells were detected by PCR in lung from the 1st week after inoculation, in liver,
      spleen and kidney from the 3rd week and in the blood from the 5th week. All
      animals analyzed 12 weeks after injection showed lung metastases. Metastases in
      liver, spleen or kidney, either microscopic or macroscopic, were never detected.
      We have developed an experimental model of cancer based on genomic tagging of
      tumor cells that allows the detection of small numbers of cells in all organs and
      the blood. The presence of cancer cells in parenchymas detected with molecular
      technology does not correlate with the development of clinically relevant
      metastases.

PMID- 10403537
TI  - Potent suppressive effect of a Japanese edible seaweed, Enteromorpha prolifera
      (Sujiao-nori) on initiation and promotion phases of chemically induced mouse skin
      tumorigenesis.
AB  - Potent antigenotoxic and anti-tumor promoting activities of a Japanese edible
      seaweed, Enteromorpha prolifera (Sujiao-nori in Japanese) were previously
      identified using an in vitro cell culture experiment (Y. Okai, K. Higashi-Okai,
      S. Nakamura, Y. Yano, S. Otani, Cancer Lett. 87 (1994) 25-32). However, in vivo
      anti-carcinogenic activity of this seaweed has not been elucidated until now. In
      the present study, the anticarcinogenic activity of E. prolifera was analyzed
      using an initiation and promotion model experiment of mouse skin tumorigenesis
      caused by 7,12-dimethylbenz[a]anthracene (initiator) and 12-O
      tetradecanoylphorbol-13-acetate (promoter). (1) Application of the extract of E.
      prolifera prior to the treatment with a tumor initiator or promoter caused a
      significant suppression against skin tumorigenesis, and the combined application
      of the extract prior to both treatments with initiator and promoter exhibited
      much stronger suppression against the same skin tumorigenesis. (2) As a possible
      active principle for the anticarcinogenic activity of the extract, we propose a
      chlorophyll-related compound, pheophytin-a, which has been recently identified in
      the extract of this alga as an antigenotoxic substance (Y. Okai, K. Higashi-Okai,
      J. Sci. Food Agric. 74 (1997) 531-535), and showed significant suppressive
      effects in the same tumorigenesis experiment. These results suggest that E.
      prolifera has a potent suppressive activity against chemically induced mouse skin
      tumorigenesis through the suppression at the initiation and promotion phases, and
      that pheophytin-a might be partially associated with the in vivo anticarcinogenic
      activity.

PMID- 10403538
TI  - Correlation of aromatase and cyclooxygenase gene expression in human breast
      cancer specimens.
AB  - Aromatase, the enzyme system catalyzing estrogen biosynthesis, is found in
      stromal tissue in the breast. The increased expression of the aromatase CYP19
      gene in breast cancer tissues was recently associated with a promoter region
      regulated through cAMP-mediated pathways. PGE2, derived from cyclooxygenase,
      increases intracellular cAMP levels and stimulates estrogen biosynthesis. This
      association suggest that local production of PGE2 via cyclooxgenase isozymes may
      influence estrogen biosynthesis. The present study represents the first to
      examine the levels of mRNA expression of CYP19, COX-1, and COX-2 genes in human
      breast cancer specimens and normal breast tissue samples using semi-quantitative
      RT-PCR methods. Positive correlations were observed between CYP19 and COX-2 and
      the greater extent of breast cancer cellularity. Linear regression analysis using
      a bivariate model shows a strong linear association between CYP19 expression and
      the sum of COX-1 and COX-2 expression. This significant relationship between the
      aromatase and cyclooxygenase enzyme systems suggests that autocrine and paracrine
      mechanisms may be involved in hormone-dependent breast cancer development via
      growth stimulation from local estrogen biosynthesis.

PMID- 10403539
TI  - A diacetylenic spiroketal enol ether epoxide, AL-1, from Artemisia lactiflora
      inhibits 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion possibly by
      suppression of oxidative stress.
AB  - The inhibitory effects of the diacetylenic spiroketal enol ether epoxide AL-1
      from Artemisia lactiflora on a variety of tumor promoter-induced biological
      responses such as oxidative stress as well as tumor promotion in ICR mouse skin
      were investigated. AL-1 inhibited TPA-induced intracellular peroxide formation in
      differentiated HL-60 cells, suggesting that this suppression might be
      attributable to the inhibition of O2- generation. In a double TPA application
      system in mouse skin, double pretreatments of AL-1 (810 nmol) significantly
      suppressed double TPA application-induced H2O2 generation. Pretreatment of AL-1
      only before the second TPA treatment was sufficient to inhibit, while only with
      first treatment was not. From these results we concluded that AL-1 is a specific
      inhibitor of the activation phase in H2O2 production induced by double TPA
      treatments. In addition, AL-1 strongly inhibited tumor promoter-induced Epstein
      Barr virus (EBV) activation in Raji cells (IC50 = 0.5 microM), which was
      comparable to or even stronger than that of curcumin, a well-known antioxidative
      chemopreventer from turmeric. In a two-stage carcinogenesis experiment with TPA
      (topical application at 1.6 nmol) and 7,12-dimethylbenz[a]anthracene (DMBA, at
      0.19 micromol) in ICR mouse skin, topical application of AL-1 (at 160 nmol)
      significantly reduced tumor incidence, the numbers of tumors per mouse, and edema
      formation by 58% (P < 0.01 in t-test), 20% (P < 0.005 in chi2-test) and 42% (P <
      0.01), respectively. These results together indicate that an inhibitor of O2
      generation is an effective chemopreventer of mouse skin carcinogenesis by their
      antioxidative property.

PMID- 10403540
TI  - Distribution and activity of transglutaminase in rat brain carcinogenesis and in
      gliomas.
AB  - Tissue transglutaminase is a calcium-dependent enzyme which may influence cell
      morphology, cytoskeletal processes and membrane functions. During rat brain
      carcinogenesis induced by transplacental administration of N-ethyl-N-nitrosourea
      to BD IX rats, cytosolic tissue transglutaminase activity was increased by about
      140% at 30 days of extrauterine life and returned towards the control values at 3
      5 months. In the particulate fraction, enzyme activity progressively increased,
      reaching values similar to those present in the developed gliomas. Tissue
      transglutaminase activity in gliomas had a behavior inverse to that observed in
      controls, with a decrease (about 50%) in the cytosol and a marked increase (380%)
      in the particulate fraction, indicating a redistribution of enzyme activity.

PMID- 10403541
TI  - G6PD activity and gene expression in leukemic cells from G6PD-deficient subjects.
AB  - In the present study we examined gene expression and glucose-6-phosphate
      dehydrogenase (G6PD) activity in leukemic cells isolated from G6PD normal and
      deficient subjects. The results have shown that G6PD activity strongly increases
      in G6PD normal leukemic cells as well as in G6PD deficient leukemic cells when
      compared to peripheral blood mononuclear cells (PBMC). Higher levels of G6PD gene
      expression were observed in leukemic cells from G6PD deficient patients compared
      to G6PD normal. A similar pattern of gene expression was also observed for 3
      hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase. These results support the
      hypothesis that G6PD deficient cell, in order to sustain their growth, must
      respond to the low activity of their mutant enzyme with an increase in quantity
      through an induction of gene expression.

PMID- 10403543
TI  - Glucose uptake in the human gastric cancer cell line, MKN28, is increased by
      insulin stimulation.
AB  - The expression of the insulin-responsive glucose transporter (GLUT) 4 was studied
      in three histologically different human gastric cancer cell lines, MKN28, MKN45,
      and STSA. RT-PCR demonstrated GLUT1 and GLUT4 mRNA in all three cell lines. MKN28
      cells expressed GLUT4 protein more than MKN45 and STSA cells by
      immunohistochemistry. Insulin stimulation of MKN28 cells resulted in a 22%
      increase in glucose uptake over that found under basal conditions (0.60 +/- 0.05
      fmol/cell per min after insulin stimulation versus 0.53 +/- 0.07 fmol/cell per 3
      min at basal). No increase in glucose uptake occurred with insulin stimulation in
      MKN45 or STSA cells. We conclude that the insulin responsive GLUT4 is expressed
      in MKN28, MKN45, and STKM1 human gastric cancer cell lines, albeit in different
      amounts. The greater expression of this transporter in MKN28 cells is likely
      responsible for the cell's ability to increase glucose uptake with insulin
      stimulation. However, the role played by GLUT4 in regulating the amount of
      glucose uptake would not be large in those human gastric cancer cell lines.

PMID- 10403542
TI  - Genetic properties for the suppression of development of putative preneoplastic
      glutathione S-transferase placental form-positive foci in the liver of carcinogen
      resistant DRH strain rats.
AB  - The post-initiation stage of hepatocarcinogenesis was investigated in carcinogen
      resistant inbred DRH rats and the parental strain, carcinogen-sensitive Donryu
      rats. Male rats at 5 weeks of age from both strains were treated with N
      nitrosodiethylamine (200 mg/kg i.p.) followed by feeding with a diet containing
      3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) from 2 weeks later and were then
      subjected to partial hepatectomy at 1 week later. At 8 weeks after the start of
      treatment, the mean area occupied by glutathione S-transferase placental form
      (GST-P)-positive lesions was about 30% in Donryu rats but less than 4% in DRH
      rats despite the presence of comparable numbers of foci in the livers of both
      strains. These observations suggested that clonal expansion of GST-P-positive
      foci in DRH rat liver was significantly suppressed under these conditions.
      Furthermore, this genetic property was dominantly inherited in the F1 rats by
      crosses of DRH and carcinogen-sensitive inbred F344 rats; that is, the induction
      of GST-P mRNA in the livers of F344 x DRH F1 rats was dominantly suppressed after
      administration of 3'-Me-DAB for 8 weeks as compared with parental F344 rats under
      the same conditions. We compared the intrinsic properties related to growth
      potential of liver cells between adult DRH and Donryu rats. DRH rat liver showed
      retarded and/or reduced DNA synthesis after partial hepatectomy or a single i.v.
      injection of lead nitrate and lower activity of telomerase induced by 3'-Me-DAB
      administration for 1 week, as compared with the Donryu rat liver. The intrinsic
      properties observed in this study may be related, at least in part, to the low
      incidence of liver tumors induced by hepatocarcinogens in DRH rats.

PMID- 10403544
TI  - Insulin receptor substrate-1 is over-expressed in glycogenotic but not in
      amphophilic preneoplastic hepatic foci induced in rats by N-nitrosomorpholine and
      dehydroepiandrosterone.
AB  - Insulin receptor substrate-1 (IRS-1) is over-expressed in preneoplastic
      glycogenotic hepatic foci (GSF) and is gradually down-regulated during
      progression of these lesions, via mixed cell foci (MCF), to the basophilic
      neoplastic phenotype. The aim of the present study was to investigate the effect
      of dehydroepiandrosterone (DHEA), a weak hepatocarcinogen and tumour enhancer, on
      IRS-1 expression. Hepatocellular lesions were induced by N-nitrosomorpholine
      followed by DHEA. Under these conditions, many glycogen-poor amphophilic (APF)
      and intermediate cell foci (ICF) appear, in addition to GSF and MCF. IRS-1 was
      over-expressed in 215 out of 295 GSF, in 50 out of 53 MCF and in a glycogen-rich
      mixed cell adenoma. IRS-1 expression was not shown in 147 APF, 51 ICF and 5
      amphophilic hepatocellular adenomas, and 3 out of 5 hepatocellular carcinomas
      showed a weak IRS-1 expression. The results suggest a close association of IRS-1
      over-expression with the glycogenotic hepatocellular phenotype. The modulation
      and enhancement of tumour progression by DHEA is associated with a shift from
      glycogenosis to amphophilia and basophilia, and a down-regulation of IRS-1
      expression.

PMID- 10403545
TI  - Decreased expression of Bax is correlated with poor prognosis in oral and
      oropharyngeal carcinoma.
AB  - We investigated the expression of apoptosis-related factors, p53, Bax, Bcl-2, and
      spontaneous apoptosis in 57 cases of oral and oropharyngeal squamous cell
      carcinoma (SCC) by immunochemical staining and ApopTag kit. Positive expression
      of Bax was inversely associated with advanced tumor stage (P = 0.0225), lymph
      node metastasis (P = 0.0225), clinical stage (P = 0.0083) and poor prognosis (P =
      0.0478). Positive expression of p53 was related to poor prognosis (P = 0.0445)
      and was associated with negative expression of Bax (P = 0.0439). The apoptosis
      index did not correlate with clinical outcome. These results suggest that
      abnormality of Bax expression plays an important role in tumor progression in
      oral and oropharyngeal SCC.

PMID- 10403547
TI  - Expression of the cyclin D1 gene in rat colorectal aberrant crypt foci and tumors
      induced by azoxymethane.
AB  - Cyclin D1 is a cell cycle regulator which is overexpressed in a variety of human
      cancers. We examined overexpression of cyclin D1 in several stages of rat
      colorectal carcinogenesis induced by azoxymethane (AOM) treatment. The level of
      cyclin D1 in 13 aberrant crypt foci (ACF) (atypical hyperplasias), 22 colorectal
      tumors (14 non-invasive adenocarcinomas and eight invasive adenocarcinomas) was
      assessed by immunostaining using a polyclonal antibody. Cell proliferation of
      these samples was investigated by measurement of 5-bromo-2'-deoxyuridine-labeling
      index. Indices of cyclin D1-positive cells in adenocarcinomas and atypical
      hyperplasias were significantly higher than that in normal crypts (P < 0.05).
      Moreover, cyclin D1-positive rates in the two types of adenocarcinomas were
      significantly higher than that in atypical hyperplasias (P < 0.05). Staining of
      nuclear cyclin D1 was very strong in almost all adenocarcinomas and four ACF.
      Comparisons of BrdU-positive indices in colorectal lesions showed similar results
      to the cyclin D1-positive indices. These results suggested that overexpession of
      cyclin D1 occurs early in the multistep carcinogenesis, and plays an important
      role in rat colorectal carcinogenesis.

PMID- 10403546
TI  - Increased production of interferon-gamma by tumour infiltrating T lymphocytes in
      nasopharyngeal carcinoma: indicative of an activated status.
AB  - Undifferentiated nasopharyngeal carcinomas (UNPC) are characterised by an
      association with Epstein-Barr virus and an abundant lymphoid stroma. We studied
      the functional status of the infiltrating T cells in ten UNPC biopsies using an
      immunohistochemical approach. Twelve non-NPC biopsies were included as controls.
      Tumour cells of UNPC were positive for HLA class I (10/10) and II (8/10), LMP1
      (3/10), and CD86 (6/10). Tumour infiltrating T cells (TILs) were detected with
      antibodies directed at CD3, CD4, and CD8, and shown to be comparable to that in
      the control biopsies. Although expression of CD28 was shown to be decreased in
      TILs, expression of CD25 and IFN-gamma at a relatively high percentage could be
      consistently detected in the UNPC biopsies. These data suggest that TILs in UNPC
      are in an activated status, and this T cell response is possibly directed at the
      tumour cells.

PMID- 10403548
TI  - Inositol hexaphosphate reduces 12-O-tetradecanoylphorbol-13-acetate-induced
      ornithine decarboxylase independent of protein kinase C isoform expression in
      keratinocytes.
AB  - High-fiber diets have been shown to have beneficial effects on preventing
      tumorigenesis. Inositol hexaphosphate (InsP6 or phytic acid) which is a fiber
      associated component of cereals and legumes has been demonstrated to inhibit cell
      proliferation and enhance cell differentiation, indicating its potential for
      chemopreventive roles. In this study, we investigated the effect of InsP6 on 12-O
      tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC)
      activity, an essential event in tumor promotion in HEL-30 cells, a murine
      keratinocyte cell line and SENCAR mouse skin. ODC activity was significantly
      reduced by 0.5 mM InsP6 in keratinocytes (P < 0.01). Furthermore, when mouse skin
      was treated with 10 mM InsP6, ODC induction was significantly inhibited (P <
      0.05). In addition, the expression of TPA-induced c-myc mRNA was significantly
      inhibited by the same InsP6 treatments in HEL-30 cells and CD-1 mouse skin (P <
      0.01). No changes in protein kinase C (PKC) isoform expression and phorbol
      dibutyrate binding due to InsP6 treatment were found in HEL-30 cells. These
      results indicate that InsP6 reduces TPA-induced ODC activity independent of PKC
      isoform expression.

PMID- 10403549
TI  - Protein kinase C-dependent anti-apoptotic mechanism that is associated with high
      sensitivity to anti-Fas antibody in ovarian cancer cell lines.
AB  - We compared the sensitivities to apoptosis via anti-Fas antibody of two human
      ovarian cancer cell lines, NOS4 and SKOV-3, both of which strongly express the
      Fas antigen on their cell surface. Treatment with anti-Fas antibody induced
      extensive DNA fragmentation in NOS4 cells but none in SKOV-3 cells. However; both
      cell lines underwent apoptosis in response to calcium ionophore A23187 or
      sphingomyelinase, demonstrating that the latter cell line is capable of DNA
      fragmentation. DNA fragmentation was not induced in either cell line by treatment
      with PKC activator PMA, however treatment with protein kinase C (PKC) inhibitor H
      7 induced extensive DNA fragmentation in NOS4 cells, but again none in SKOV-3
      cells. Protein kinase A inhibitor HA1004 treatment did not induce DNA
      fragmentation in either cell line. Correspondingly, treatment of cells with PMA
      before anti-Fas antibody or A23187 treatment partially inhibited induction of DNA
      fragmentation in NOS4 cells but not in SKOV-3 cells. Both NOS4 and SKOV-3 cell
      lines expressed isozymes of PKC at comparable levels. These results suggest the
      presence of a PKC-dependent anti-apoptotic mechanism in association with high
      sensitivity to anti-Fas antibody in these ovarian cancer cell lines.

PMID- 10403550
TI  - Effect of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-
      quinolinone (vesnarinone) on the growth of gastric cancer cell lines.
AB  - Vesnarinone (OPC-8212; 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]
      2(1H)-quinolinone ) is a synthetic oral cardiotonic agent that has been used for
      the treatment of patients with congestive heart failure. Six days of treatment
      with 30 microg/ml of vesnarinone induced 20-80% growth inhibitions in five out of
      six gastric carcinoma cell lines examined. Cell cycle analysis revealed that the
      vesnarinone-sensitive TMK-1 gastric cancer cell line exhibited a significant G0
      G1 arrest without evidence of apoptotic cell death induction after 48 h of
      treatment. Interestingly, this phenomenon was preceded by a marked reduction in
      the expression of cyclin A, D1 and E as well as cyclin-dependent kinase 2 (CDK2).
      On the other hand, no significant change was observed in the expression of
      p21(Waf1/Cip1), p27Kip1 nor various growth factors and their receptor genes.
      Overall these results indicate that vesnarinone inhibits the growth of gastric
      cancer cells by down-regulating G1 cyclins and CDK2 to induce G0-G1 arrest
      through a pathway different from that of cyclin inactivation by p21(Waf1/Cip1) or
      p27Kip1.

PMID- 10403551
TI  - Promoting effects of intravesical instillation of saline on bladder lesion
      development in rats pretreated with N-butyl-N-(4-hydroxybutyl) nitrosamine are
      inhibited by bacillus Calmette-Guerin.
AB  - The promoting effects of intravesical instillation of saline and the efficacy of
      bacillus Calmette-Guerin (BCG) for prophylaxis of bladder carcinogenesis were
      assessed. Rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for
      10 weeks; they were then given 6 weekly intravesical instillations of BCG, saline
      or distilled water starting 1 week or 15 weeks after the BBN treatment. At 32
      weeks, both the incidences and numbers of bladder cancers were elevated in
      animals receiving the saline. An exception was the early phase BCG group.
      Significant increases in tumor size were also noted for the saline, but not the
      distilled water group. The results indicate that intravesical instillation of
      saline promotes urinary bladder carcinogenesis. However, the inhibitory influence
      of BCG was suggested if administered at the early, but not the late phase, of
      carcinogenesis.

PMID- 10403552
TI  - Combination effects of tamoxifen plus 5-fluorouracil on gastric cancer cell lines
      in vitro.
AB  - We tested the effect of tamoxifen alone and tamoxifen plus 5-fluorouracil (5-FU)
      on proliferation of two different types of gastric cancer cell lines using the
      WST-1 method. A high dose of tamoxifen suppressed the proliferation of KATOIII
      cells (poorly differentiated adenocarcinoma), but MKN28 cells (well
      differentiated adenocarcinoma) were not affected. The combination of the two
      drugs resulted in a synergistic anti-proliferative activity on KATOIII cells. On
      the other hand, in the combination therapy, tamoxifen stimulated MKN28 cells to
      proliferate in a dose-dependent manner. TGF-beta1 secretion was not changed in
      KATOIII cells by tamoxifen plus 5-FU treatment but was down-regulated in MKN28
      cells. Both cancer cell lines were judged as intracellular estrogen receptor (ER)
      negative. These data suggest that the anti-proliferative effects of tamoxifen
      plus 5-FU on KATOIII cells were not dependent on ER expression or TGF-beta1
      secretion. On the other hand, their proliferative effects on MKN28 cells might
      be, in part, caused by the reduced secretion of TGF-beta1.

PMID- 10403553
TI  - Extracellular matrix regulates steady-state mRNA levels of the proliferation
      associated protein Ki-67 in endometrial cancer cells.
AB  - We investigated whether components of the extracellular matrix have the potential
      to regulate the proliferative activity of endometrial adenocarcinoma cells.
      Culturing of cells on the reconstituted basement membrane matrigel down-regulated
      the steady-state mRNA levels of the proliferation associated protein, Ki-67, in
      the endometrial adenocarcinoma cell lines HEC 1B(L) and Ishikawa after 48-96 h of
      culture on the matrix substrate. Proliferation of Ishikawa was stimulated again
      if cells were cultured on matrigel and challenged by proteins representing
      functional domains of tenascin-C, a mesenchymal glycoprotein. The fibronectin
      type-III-like repeats 6-8 of tenascin-C were found to be the most potent. In
      summary, evidence is provided that components of both epithelial and stromal
      extracellular matrices can function as regulators of cell growth.

PMID- 10403554
TI  - Effects of lipo prostaglandin E1 on distribution of cis-diamminedichloroplatinum
      in lung metastasis derived from Dunn osteosarcoma cell-inoculated mouse foot-pad.
AB  - This study was designed to determine the effect of lipid microspheres containing
      prostaglandin E1 (lipo PGE1) on cis-diamminedichloroplatinum (CDDP) accumulation
      in primary and lung metastatic lesions. Sixty mice were divided into four groups,
      depending on whether or not an intra-foot-pad injection of Dunn osteosarcoma
      cells had been administered and on whether or not an intraperitoneal injection of
      lipo PGE1 had been administered. CDDP was injected intraperitoneally into all the
      mice 6 weeks after the inoculation. Tumor colonies of spontaneous metastases in
      the left lung were found in 21 out of 30 tumor-inoculated mice at autopsy. Tissue
      platinum concentrations in the lungs with metastatic colonies and in the foot-pad
      tumors were significantly higher in the lipo PGE1-administered mice than in those
      without treatment. Terminal deoxytransferase-mediated dUTP nick end labeling
      (TUNEL) assay showed marked localization of dying cells in the lung metastatic
      lesions of the lipo PGE1-administered mice. The results of this study showed that
      pretreatment with lipo PGE1 may augment the antitumor effects of CDDP at the
      tumor site.

PMID- 10403555
TI  - Enhancing effect of tumor necrosis factor (TNF)-alpha, but not IFN-gamma, on the
      tumor-specific cytotoxicity of gammadeltaT cells from glioblastoma patients.
AB  - Adoptive immunotherapy using tumor-specific killer cells can be beneficial in
      inducing regression of advanced cancer. The roles of cytokines on effector cells
      in inducing maximal killing activity and the accompanying side-effects should be
      investigated in vitro and fully understood prior to their clinical use. The
      present study indicates that the gammadeltaT cells involved in autologous tumor
      specific killing consist of several populations in terms of their T cell receptor
      (TCR) repertoire, but predominantly express the products of the Vgamma9/Vdelta2
      gene locus of the TCR. We then examined the effect of TNF-alpha and IFN-gamma on
      these tumor-specific gammadeltaT cells for possible clinical use in cancer
      patients. TNF-alpha alone, at concentrations of 0.01-1.0 microg/ml, caused
      increased gammadeltaT cell cytotoxicity against autologous glioblastoma cells,
      whereas IFN-gamma alone had no effect. The combination of TNF-alpha (1 microg/ml)
      with IL-2 (50 units/ml) resulted in further enhancement of cytotoxicity. TNF
      alpha, but not IFN-gamma, marginally inhibited the proliferative response of
      gammadeltaT cells; a similar result was seen when the cytokines were combined.
      TNF-alpha may, therefore, be one cytokine capable of inducing increased
      autologous tumor-specific activity in gammadeltaT cells, bearing mainly
      Vgamma9/Vdelta2 chains, which can be enhanced when combined with other cytokines.

PMID- 10403556
TI  - Loss of heterozygosity in actinic keratosis, squamous cell carcinoma and sun
      exposed normal-appearing skin in Japanese: difference between Japanese and
      Caucasians.
AB  - Actinic keratosis (AK) has been considered to be a precursor of squamous cell
      carcinoma (SCC). However, based on epidemiological and molecular studies, it has
      become questionable to regard AK as a precancerous lesion. We analyzed 37 AKs and
      14 sporadic SCCs using six microsatellite markers in order to elucidate if any
      genetic instability or loss of heterozygosity (LOH) was implicated in
      tumorigenesis and progression of non-melanocytic skin tumor. Microsatellite
      instability (MSI) was not found in any of the AKs or SCCs indicating that genetic
      instability has little implication in the tumorigenesis of sporadic non
      melanocytic skin tumor. LOH was found in seven of 37 lesions of AK, but in only
      one of 14 lesions of SCC. The significantly lower frequency of LOH than that
      previously reported in Caucasians suggested that the molecular pathogenesis of
      AKs and SCCs might be different between Japanese and Caucasians. The higher
      frequency of LOH in AKs than in SCCs in the present study supported the previous
      epidemiological and molecular studies that AK was not likely to proceed to SCC.
      LOH was also demonstrated in histologically normal-appearing skin in three cases
      suggesting that genetic alteration occurs before histological change appears in
      the sun-exposed skin.

PMID- 10403557
TI  - Antitumor activity of 4-phenyl-1-arylsulfonylimidazolidinone, DW2143.
AB  - We examined the ability of sulfonylurea derivative, DW2143 (4-phenyl-1-[1-(4
      aminobenzoyl)-indoline-5-sulfonyl]-4,5-dihydro-2-imida zolone hydrochloride), to
      inhibit the growth of tumor cells in vitro and in vivo. When its anti
      proliferative activities were tested on five murine tumor (B 16, Colon26, E1-4,
      3LL and P388) and nine human tumor (BxPC-3, HepG2, Lovo, MCF-7, NCI-H69, SW480,
      WiDR, KB and KBV20C) cells of diverse tissue origins, the in vitro antitumor
      activities of DW2143 were comparable to those of doxorubicin against all tumor
      cell lines. In addition, the anti-proliferative activities of DW2143 against
      KBV20C, a vincristine-resistant cell line, are similar or superior to those of
      doxorubicin. When the in vivo antitumor activities using three murine tumor cells
      were tested after oral administration of DW2143, a wide range of tumor growth
      inhibition was observed. Tumor growth inhibition against 3LL at doses of 50 and
      100 mg/kg DW2143 was 84.3% and 47.2%, respectively, which was comparable or
      superior to those of doxorubicin (5 mg/kg). Tumor growth inhibition of B16 at a
      dose of 100 mg/kg in the DW2143-treated group was 42% as compared to 54% for
      doxorubicin (5 mg/kg). When mice implanted with Colon26 were tested, tumor growth
      inhibition at a dose of 80 mg/kg DW2143 was 36% as compared with 37% for
      doxorubicin (5 mg/kg). Taken together, these results indicate that the novel
      sulfonylurea derivative, DW2143, is an attractive candidate for further
      development as a useful oral anticancer drug.

PMID- 10403558
TI  - Phospholipid metabolism and resistance to glucocorticoid-induced apoptosis in a
      human leukemic cell line: a 31P-NMR study using a phosphonium analog of choline.
AB  - In order to evaluate any connection between phospholipid metabolism and the
      dexamethasone resistance in CEM-C1-15 leukemic cells, a phosphonium analog of
      choline was used to study the phospholipid metabolism in dexamethasone-sensitive
      and dexamethasone-resistant leukemic cells using 31P-NMR spectroscopy.
      Measurements were done on the two cell lines in the presence and absence of
      dexamethasone, a synthetic glucocorticoid steroid. Dexamethasone was found to
      cause a significant reduction in the phospholipid metabolism of the dexamethasone
      sensitive CEM-C7-14 cells. In contrast, dexamethasone caused a significant
      enhancement of the phospholipid metabolism in the dexamethasone-resistant CEM-C1
      15 cells, indicating a significant difference between the two cell lines in
      phospholipid metabolism during apoptosis. The results of this study suggest the
      involvement of phospholipid metabolism in the mechanism of dexamethasone
      resistance in the CEM-C1-15 cells.

PMID- 10403559
TI  - Antitumor activity of four macrocyclic ellagitannins from Cuphea hyssopifolia.
AB  - We evaluated the antitumor activities of four macrocyclic hydrolyzable tannin
      dimers, cuphiin D1, cuphiin D2, oenothein B and woodfordin C isolated from Cuphea
      hyssopifolia (Lythraceae). All significantly inhibited the growth of the human
      carcinoma cell lines KB, HeLa, DU-145, Hep 3B, and the leukemia cell line HL-60,
      and showed less cytotoxicity than adriamycin against a normal cell line (WISH).
      All four compounds inhibited the viability of S-180 tumor cells in an in vitro
      assay and an in vivo S-180 tumor-bearing ICR mice model. Oenothein B demonstrated
      the greatest cytotoxicity (IC50 = 11.4 microg/ml) against S-180 tumor cells in
      culture, while cuphiin D1 resulted in the greatest increase in survival on S-180
      tumor-bearing mice (%ILS = 84.1%). Our findings suggest that the antitumor
      effects of these compounds are not only related to their cytotoxicity on
      carcinoma cell lines, but also depended on a host-mediated mechanism; they may
      therefore have potential for antitumor applications.

PMID- 10403560
TI  - Correlation of tumor necrosis factor alpha (TNF alpha) with high Caspase 3-like
      activity in myelodysplastic syndromes.
AB  - Increased intramedullary apoptotic death of hematopoietic cells is thought to
      contribute to the ineffective hematopoiesis in myelodysplastic syndromes (MDS).
      Furthermore, high amounts of tumor necrosis factor alpha (TNF alpha) have
      previously been correlated with apoptosis in MDS marrows. The present studies
      were undertaken to examine the status of two key downstream effectors of TNF
      alpha signaling, i.e. Caspase 1 and Caspase 3 enzymes, using a fluorometric assay
      in the bone marrow aspirate mononuclear cells (BMMNC) in relation to apoptotic
      DNA fragmentation detected by in situ end-labeling (ISEL) of DNA and with
      localization of TNF alpha in the corresponding biopsies from 14 MDS patients.
      Both Caspase 1 and 3 were detectable in freshly harvested BMMNC, albeit median
      Caspase 3 levels (47.5 units/mg protein) being almost 10 times higher than
      Caspase 1 (4.0 units/mg protein). Upon short-term culture for 4 h in a serum
      supplemented medium in vitro a significant increase was seen in Caspase 3
      activity (58.8 +/- 13.9 at 0 h vs. 177.8 +/- 55.2 units/mg protein at 4 h, n =
      14, P = 0.017) and in percent cells labeled by ISEL (apoptotic index or AI%:
      0.76% +/- 0.25% vs. 3.99% +/- 1.1%, n = 14, P = 0.004, respectively). Caspase 1
      activity increased after 15 min in culture. Interestingly, TNF alpha levels
      measured by immunohistochemistry correlated with the net increase in Caspase 3
      activity after 4 h (p = 0.517, n = 13, P = 0.07) and the starting levels of
      Caspase 1 at 0 h correlated with the Caspase 3 levels attained at 4 h (p = 0.593,
      n = 13, P = 0.033). Additionally when TNF alpha-positive bone marrows (8/14) were
      compared with the negative marrows (6/14) the Caspase 3 levels were significantly
      higher in the TNF alpha-positive marrows (189.6 +/- 66.2 vs. 25.0 +/- 14.6
      units/mg protein, respectively, P = 0.043). The increase in AI%, though not
      statistically significant, was also higher in the TNF alpha-positive marrows.
      Finally in HL60 cells the effects of different Caspase inhibitors and
      pentoxifylline (PTX) (interferes with lipid signaling of cytokines) on TNF alpha
      induced apoptosis were evaluated. TNF alpha treatment significantly increased AI%
      (P < 0.003) as compared to the untreated controls. A co-treatment with three
      Caspase inhibitors, zVAD.FMK (inhibitor of Caspases 1 and 3, 10 microM/l),
      Ac.YVAD.FMK (Caspase 1 inhibitor, 1 microM/l), Ac.DEVD.FMK (Caspase 3 inhibitor,
      10 microM/l) as well as PTX (250 microM/l) significantly curtailed the AI%
      induced by TNF alpha. The present studies thus identify the downstream effectors
      of TNF alpha-inducible apoptosis in MDS and so also the suppressors of TNF alpha
      apoptotic signaling. These results may have significant clinical implications in
      the therapy of MDS in the future.

PMID- 10403561
TI  - Combination radioimmunotherapy with local hyperthermia: increased delivery of
      radioimmunoconjugate by vascular effect and its retention by increased antigen
      expression in colon cancer xenografts.
AB  - Hyperthermia (HT) may increase tumor targeting of a radiolabeled antibody by its
      effects on tumor vasculature and antigen expression. Expression of a 45-kDa
      glycoprotein antigen on LS180 colon cancer cells was 2.7-fold enhanced 2 days
      after heating at 43 degrees C for 1 h. Preferential tumor accumulation of 125I-A7
      recognizing this antigen was doubled and the antitumor effect of 131I-A7 was
      significantly improved by HT. Hyperthermia also increased tumor uptake of an
      irrelevant antibody but its radioactivity was rapidly cleared. These results
      indicate that HT increased the initial delivery of an antibody to a tumor by its
      vascular effect, and radioactivity was retained in tumors by increased specific
      binding, resulting in a better radioimmunotherapy outcome.

PMID- 10403562
TI  - Identification of a novel gene, DAM1, amplified at chromosome 1p13.3-21 region in
      human breast cancer cell lines.
AB  - Screening for differentially expressed genes in cancer cell lines by the RNA
      differential display (DD) technique identified a novel mRNA that encodes a 26-kDa
      protein and is up-regulated in MCF-7 and BT-20 breast cancer cells. The predicted
      amino acid sequence showed 38% homology to Caenorhabditis elegans T12A2.7
      protein, indicating that this is a possible human homologue for C. elegans
      T12A2.7 protein. The mRNA, designated DAM1 (DNA amplified in mammary carcinoma),
      was mapped at the 1p13.3-21 region, which is frequently altered in human breast
      cancer. By Southern blot analysis, we confirmed that the up-regulation of this
      novel gene is associated with gene amplification in MCF-7 (10-fold) and BT-20 (5
      fold) cells. Our findings suggest that the DAM1 gene is a novel gene up-regulated
      by amplification in human breast cancer cell lines.

PMID- 10403563
TI  - Identification of a novel gene, LDOC1, down-regulated in cancer cell lines.
AB  - By screening for differentially expressed genes in cancer cells, using the RNA
      differential display (DD) technique, we identified a novel cDNA, LDOC1, that is
      down-regulated in some cancer cell lines. A Northern blot analysis revealed no
      expression in pancreatic and gastric cancer cell lines but ubiquitous expression
      in normal human tissues. This new gene was mapped on chromosome Xq27 and the
      predicted protein sequence showed no similarity to known sequences in the
      database except for a leucine zipper-like motif at the N-terminal region and a
      proline-rich region that shares marked similarity to an SH3-binding domain. In an
      enhanced green fluorescent protein (EGFP) assay, the EGFP-LDOC1 fusion protein
      was localized in the nucleus. Although the function of LDOC1 is still unknown,
      our results suggest that this novel gene codes for a nuclear protein, and down
      regulation of LDOC1 may have an important role in the development and/or
      progression of some cancers.

PMID- 10403565
TI  - The role of arachidonic acid on LH-stimulated steroidogenesis and steroidogenic
      acute regulatory protein accumulation in MA-10 mouse Leydig tumor cells.
AB  - Metabolic pathways leading to the production of arachidonic acid (AA) and its
      metabolites have been reported to have modulatory effects on steroidogenesis in a
      number of cell types. To examine the importance of the arachidonic acid pathway
      in steroid production and steroidogenic acute regulatory (StAR) protein
      expression, luteinizing hormones (LH) or N6-2-o-dibutyryl-adenosine-3:5-cyclic
      monophosphate-(Bt2cAMP) stimulated MA-10 mouse Leydig tumor cells were treated
      with various concentrations of quinacrine (an inhibitor of arachidonic acid
      production). Incubation of the cells with quinacrine resulted in dose-dependent
      decreases in steroid production and StAR protein. Twenty micromolars quinacrine
      inhibited 92 and 91% of LH-induced progesterone and StAR protein, respectively,
      and 98 and 90% of Bt2cAMP-induced progesterone and StAR protein. Reversal of this
      inhibition was obtained by incubation of quinacrine-treated cells with various
      levels of AA, which resulted in a dose-dependent increase in both steroid and
      StAR protein levels. Two hundred micromolars of AA rescued 57 and 60% of the LH
      induced steroid production and StAR protein, respectively, and 52 and 89% of
      Bt2cAMP-induced steroid production and StAR protein. These results suggest that
      the effect of AA on LH- and cAMP-stimulated steroidogenesis is associated with
      the modulation of StAR protein expression.

PMID- 10403566
TI  - Glucose rapidly decreases plasma membrane GLUT4 content in rat skeletal muscle.
AB  - We have previously demonstrated that chronic hyperglycemia per se decreases GLUT4
      glucose transporter expression and plasma membrane content in mildly
      streptozotocin- (STZ) diabetic rats (Biochem. J. 284, 341-348, 1992). In the
      present study, we investigated the effect of an acute rise in glycemia on muscle
      GLUT4 and GLUT1 protein contents in the plasma membrane, in the absence of
      insulin elevation. Four experimental groups of rats were analyzed in the
      postabsorptive state: 1. Control rats. 2. Hyperglycemic STZ-diabetic rats with
      moderately reduced fasting insulin levels. 3. STZ-diabetic rats made
      normoglycemic with phlorizin treatment. 4. Phlorizin-treated (normoglycemic) STZ
      diabetic rats infused with glucose for 40 min. The uniqueness of the latter model
      is that glycemia can be rapidly raised without any concomitant increase in plasma
      insulin levels. Plasma membranes were isolated from hindlimb muscle and GLUT1 and
      GLUT4 proteins amounts determined by Western blot analysis. As predicted, STZ
      diabetes caused a significant decrease in the abundance of GLUT4 in the isolated
      plasma membranes. Normalization of glycemia for 3 d with phlorizin treatment
      restored plasma membrane GLUT4 content in muscle of STZ-diabetic rats. A sudden
      rise in glycemia over a period of 40 min caused the GLUT4 levels in the plasma
      membrane fraction to decrease to those of nontreated STZ-diabetic rats. In
      contrast to the GLUT4 transporter, plasma membrane GLUT1 abundance was not
      changed by the acute glucose challenge. It is concluded that glucose can have
      regulatory effect by acutely reducing plasma membrane GLUT4 protein contents in
      rat skeletal muscle. We hypothesize that this glucose-induced downregulation of
      plasma membrane GLUT4 could represent a protective mechanism against excessive
      glucose uptake under hyperglycemic conditions accompanied by insulin resistance.

PMID- 10403564
TI  - Abnormal cell calcium homeostasis in type 2 diabetes mellitus: a new look on old
      disease.
AB  - Cumulative evidence reveals that diabetes is a condition in which cell Ca2+
      homeostasis is impaired. Defects in cell Ca2+ regulation were found in
      erythrocytes, cardiac muscle, platelets, skeletal muscle, kidney, aorta,
      adipocytes, liver, osteoblasts, arteries, lens, peripheral nerves, brain
      synaptosomes, retinal tissue, and pancreatic beta cells, confirming that this
      defect in cell Ca2+ metabolism is a basic pathology associated with the diabetic
      state. Though different defects in a variety of functions that regulate cell Ca2+
      homeostasis were described in diabetes, the most common finding is an increase in
      [Ca2+]i levels. However, it is not clear whether the defect in cell Ca2+
      metabolism in diabetes precedes or succeeds the overt diabetic condition. It is
      also not clear which of the multiple functions involved in cell Ca2+ regulation
      has the primary defect. Defects in cell Ca2+ metabolism may be significant for
      the observed pathologies in insulin secretion and insulin action in diabetes.
      They may also play an important role in the vascular complications seen in this
      condition, such as hypertension, atherosclerosis, and microangiopathy. Therefore,
      better understanding of the impairment in cell Ca2+ metabolism in diabetes may
      markedly enhance our understanding of this condition.

PMID- 10403567
TI  - Tumor necrosis factor alpha inhibition of follicle-stimulating hormone-induced
      granulosa cell estradiol secretion in the human does not involve reduction of
      cAMP secretion but inhibition at post-cAMP site(s).
AB  - Tumor necrosis factor alpha (TNF) inhibits follicle-stimulating hormone-
      (FSH)induced estradiol secretion by granulosa cells in several species, including
      humans. One major inhibitory effect of TNF in rat granulosa cells is at the level
      of stimulatable adenylyl cyclase, resulting in reduced cAMP concentrations. The
      purpose of the present study was to investigate whether a reduction in cAMP
      secretion could account for the inhibitory effects of TNF on FSH-induced
      estradiol in human granulosa cells. Granulosa cells were taken from ovaries of
      premenopausal women undergoing oophorectomy for reasons unrelated to ovarian
      pathology. Women in this study were in various stages of the menstrual cycle or
      exhibited irregular cycles. Granulosa cells from follicles ranging from 5 to 10
      mm diameter were subjected to culture for 48 and 96 h. Granulosa cells were
      cultured with human FSH (2 ng/mL) and testosterone (1 microM) in the presence and
      absence of human TNF (20 ng/mL). Media were collected at 48 h, fresh media and
      hormones added, and cultures continued for an additional 48 h. Accumulation of
      cAMP, progesterone, and estradiol in media were determined by radioimmunoassay
      (RIA). FSH induced significant increases in cAMP, progesterone, and estradiol by
      96 h of culture. TNF inhibited the secretion of estradiol at 96 h without
      reducing the accumulation of cAMP and progesterone in media. Similar results were
      observed in the presence of 0.1 mM isobutylmethylxanthine (D3MX), a
      phosphodiesterase inhibitor that would prevent metabolism of cAMP to AMP. To
      determine whether TNF would inhibit the ability of cAMP to induce estradiol and
      progesterone secretion, granulosa cells were incubated with 0.1 mM cAMP in the
      presence and absence of TNF. TNF consistently inhibited the ability of cAMP to
      increase estradiol secretion. These results indicate that a pathway for TNF
      inhibition of FSH- or cAMP-induced estradiol secretion in human granulosa cells
      is at post-cAMP sites rather than inhibition of FSH-stimulatable adenylyl
      cyclase.

PMID- 10403568
TI  - A specifically radiolabeled somatostatin analog with strong antitumor activity
      induces apoptosis and accumulates in the cytosol and the nucleus of HT29 human
      colon carcinoma cells.
AB  - The new heptapeptide somatostatin analog TT-232 decreases proliferation of HT-29
      human colon carcinoma cells in vitro by reducing mitotic and increasing apoptotic
      activity. We have synthesized and characterized a specifically tritium labeled 3H
      Tyr3-TT-232 (30 Ci/mmol) to investigate the effect and the fate of this antitumor
      peptide on human colon tumor cells. 3H-labeled TT-232 could be detected on the
      cell surface, on cytoplasmic membranes and also in the nucleus of HT-29 cells, 1
      6 h after the administration of 0.5 and 50 microg/mL [3H]TT-232. Binding and
      internalization of TT-232 to human colon tumor cells at a relatively high dose
      provide further evidence for the existence of low-affinity somatostatin receptors
      in such cells, which might mediate the apoptosis-inducing effect. Our data
      suggest the possible use of TT-232 in the treatment of human colon tumors.

PMID- 10403569
TI  - Cell-to-cell communication and expression of gap junctional proteins in human
      diabetic and nondiabetic skin fibroblasts: effects of basic fibroblast growth
      factor.
AB  - Wound healing involves the interactions of many cell types, and is controlled in
      part by growth factors. Intercellular communication mediated by gap junctions is
      considered to play an important role in the coordination of cellular metabolism
      duringthe growth and development of tissues and organs. Basic fibroblast growth
      factor (bFGF), known to be important in wound healing, has been found to increase
      Cx43 expression and intercellular communication in endothelial cells and cardiac
      fibroblasts. It has been proposed that an increased coupling is necessary for the
      coordination of these cells in wound healing and angiogenesis, and that one of
      the actions of bFGF is to modulate intercellular communication. The aim of our
      study was to evaluate the effects of bFGF on gap junctional intercellular
      communication (GJIC) in vitro, and the presence of gap junctional proteins
      connexin (Cx) 26, Cx32, and Cx43 in fibroblasts of diabetic and nondiabetic
      individuals. Fibroblast cell lines (n = 10) were cultured for 3 d in serum-free
      media with or without bFGF (3 ng/mL). Cells were evaluated for the rate of GJIC
      by using laser cytometry, and for the presence of Cx26, Cx32, and Cx43 by
      immunohistochemical and Western analyses. All cell types communicated via contact
      dependent mechanisms. The rate of GJIC was greater (p < 0.01) for diabetic than
      for nondiabetic fibroblasts (4.1 +/- 0.01 vs 3.3 +/- 0.01%/min). bFGF increased
      (p < 0.01) the rate of GJIC for diabetic (4.9 +/- 0.01 vs 4.1 +/- 0.01%) and
      nondiabetic (4.1 +/- 0.01 vs 3.3 +/- 0.01%) fibroblasts. Immunohistochemistry
      identified Cx26 in the cytoplasm, Cx32 was not detected, and Cx43 was present on
      the cellular borders in all cultures. Image analysis of immunofluorescent
      staining demonstrated that bFGF increased (p < 0.05) Cx43 expression in diabetic
      and nondiabetic fibroblasts. Western immunoblot analysis revealed bands at 43-46
      kD that were similar in volume for diabetic and nondiabetic fibroblasts. Thus,
      gap junctions involving Cx43 and GJIC among fibroblasts appear to be targets for
      bFGF. Fibroblasts of diabetic individuals appear to have an increased rate of
      cell-cell coupling, correlating with a decreased rate of proliferation.

PMID- 10403570
TI  - Expression of gap junctional proteins connexin 43, 32, and 26 throughout
      follicular development and atresia in cows.
AB  - Detection of connexin (Cx) proteins has been used as an indicator of the presence
      of structural and functional gap junctions in tissues. To examine the role of gap
      junctions during follicular growth and atresia, the presence of three major
      connexins, Cx43, Cx32, and Cx26, was evaluated in bovine ovaries by using
      immunohistochemistry and Western immunoblot analysis. Cx43 was not present in
      primordial follicles, but was present in granulosa cells of primary/secondary and
      antral follicles. Cx43 also was present on the borders between granulosa cells
      and the oocyte. Expression of Cx43 increased in healthy developing antral
      follicles, but decreased during follicular atresia. Cx32 was not present in
      healthy follicles but was present in granulosa cells of atretic antral, and
      especially small antral follicles. Cx26 was present in the oocyte of primordial
      and primary/secondary follicles, and in the granulosa and/or thecal cell layers
      of healthy antral follicles. The percentage of healthy antral follicles that
      expressed Cx26 also increased during follicular development, but decreased during
      atresia. Cx32 and Cx26 also were detected in ovarian blood vessels and in stromal
      tissues adjacent to the tunica albuginea in some ovaries. The pattern of
      expression of these Cx indicates that gap junctional proteins may be involved in
      the control of follicular growth and atresia in cows.

PMID- 10403571
TI  - Acute and early effects of triiodothyronine administration on serum markers of
      bone and mineral metabolism.
AB  - There have been few studies on acute changes of bone metabolism in humans by
      thyroid hormone. This study aimed to examine the effects of triiodothyronine on
      serum markers of bone and mineral metabolism during a 7-d course of daily 75
      microg therapy in 14 normal volunteers by drawing blood on 1, 2, 3, 5, and 7 d of
      therapy. Serum calcium concentrations did not significantly change during the
      course of therapy, while serum phosphorus concentrations were significantly (p <
      0.05) decreased from 3.21 +/- 0.43 mg/dL (mean +/- SD) to 2.85 +/- 0.46 mg/dL on
      the 7th d. Serum PTH concentrations were significantly decreased from 339 +/- 116
      pg/mL to 316 +/- 29 pg/mL. Serum concentrations of alkali-phosphatase and bone
      specific alkali-phosphatase were not significantly changed, but serum osteocalcin
      concentrations were significantly increased from 5.71 +/- 1.98 mg/dL to 6.73 +/-
      2.24 mg/dL. Serum carboxy-terminal propeptide of type I collagen concentrations
      were significantly decreased from 137.8 +/- 33.7 microg/L to 119.2 +/- 33.6
      microg/L. Serum pyridinoline cross-linked telopeptide domain of type I collagen
      concentrations, a bone resorption marker, were significantly increased from 3.40
      +/- 0.77 to 3.87 +/- 1.05 microg/L, and such significant increase was obtained
      from the 3rd day. The results indicate that some of bone and mineral markers
      change rapidly in response to triiodothyronine-induced acute thyrotoxicosis, but
      the manner of change is not the same as that of chronic thyrotoxicosis.

PMID- 10403572
TI  - Physiologic and endocrinologic characterization of male sex-biased diabetes in
      C57BLKS/J mice congenic for the fat mutation at the carboxypeptidease E locus.
AB  - The fat gene in mice represents a recessive mutation at the carboxypeptidase E
      (Cpe) locus. The mutant allele (Cpe(fat)) encodes a highly unstable enzyme and
      produces an obesity phenotype characterized by attenuated processing of
      prohormones such as proinsulin that require this exopeptidase for full
      maturation. This article presents a preliminary physiologic and endocrinologic
      characterization of the stock of C57BLKS/LtJ-Cpe(fat)/Cpe(fat) mice at the
      backcross generation (N10) currently distributed by The Jackson Laboratory.
      Although previously reported not to be diabetogenic at N5, an additional five
      backcrosses to the C57BLKS/J background resulted in a male-biased development of
      both obesity and diabetes. Major differences distinguishing this mutant stock
      from the phenotypes produced by either the diabetes (Lepr(db)) or obese (Lep(ob))
      mutations on the same inbred strain background are lack of hyperphagia and
      hypercorticism, sensitivity of diabetic males to exogenous insulin, and a milder
      and male-biased diabetes syndrome that is not associated with widespread beta
      cell necrosis and islet atrophy, and that often remits with age.

PMID- 10403574
TI  - GH kinase activity in bovine anterior pituitary subcellular fractions.
AB  - Growth hormone (GH) and prolactin (PRL) share significant structural homology. We
      have previously characterized the phosphorylation of bovine PRL and wish to
      determine whether a similar kinase activity phosphorylates bovine GH.
      Phosphorylation of bovine GH was performed using [alpha-32P]ATP labeling of
      subcellular fractions. Bovine GH phosphorylation was dependent on Zn2+ or Cu2+
      with apparent Km's of 0.9 and 1.0 mM, respectively, and a pH maxima of 7.0. The
      apparent Km's of bovine GH kinase activity for exogenous bovine GH and ATP were
      30 microM and 376 microM, respectively. Exogenous bovine PRL served as a
      competitive substrate, increasing the apparent Km for bovine GH by threefold
      compared to the Km determined without exogenous bovine PRL. We conclude: 1) in
      vitro phosphorylation of bovine GH occurs under conditions that are consistent
      with those found in anterior pituitary cells, and 2) a similar kinase activity
      phosphorylates both bovine PRL and GH.

PMID- 10403573
TI  - Negative regulation of N-cadherin-mediated cell-cell adhesion by the estrogen
      receptor signaling pathway in rat pituitary GH3 cells.
AB  - The ability of the estrogen receptor signaling pathway to regulate cell-cell
      adhesion, and N-cadherin and beta-catenin expression was examined in rat
      somatolactotropic GH3 cells cultured in serum-free, phenol red-free medium (SFM).
      Estradiol-17beta (E2) promoted a nonadherent phenotype, whereas the steroidal
      antiestrogen, ICI 182,780, induced the formation of tightly adherent aggregates
      of cells. The antiestrogen-induced cell-cell adhesion was associated with the
      presence of adherens junctions, and was Ca2+-dependent. E2 reduced surface N
      cadherin protein to barely detectable levels, whereas ICI 182,780-treated cells
      displayed abundant punctate immunoreactive N-cadherin. Antiestrogen failed to
      induce adhesion in the presence of a blocking antibody to N-cadherin. ICI 182,780
      increased the protein levels for N-cadherin and the cadherin-binding protein,
      beta-catenin, by twofold over SFM controls or E2-treated samples. ICI 182,780
      also increased the mRNA levels for N-cadherin and beta-catenin by two- to
      fivefold. In GH3 cells cultured in growth medium, ICI 182,780 increased N
      cadherin and beta-catenin levels by twofold over untreated controls, and
      inhibited cell proliferation by 53%. These results provide the first
      demonstration of the regulation of N-cadherin-mediated cell-cell adhesion by the
      estrogen receptor (ER) signaling pathway in pituitary somatolactotrophs through
      the coordinate regulation of N-cadherin and beta-catenin expression. The inverse
      relationship between ICI 182,780-induced adhesion and proliferation raises the
      possibility that these two processes are functionally related.

PMID- 10403576
TI  - Energy density of the diet, food volume and energy intake by age and sex in a
      healthy population.
AB  - OBJECTIVE: To assess the changes in energy intake (EI), food intake volume (FV)
      and energy density (ED) related to age and gender in a population in the
      Mediterranean area of Spain, and to determine the different role of FV and ED on
      the consecution of the adequate EI throughout lifespan. SUBJECTS: One thousand
      and eighty-eight individuals (1-65 y) randomly selected from the population
      census. DESIGN: Cross-sectional study in which food intake was quantified by 24 h
      dietary recall, three non-consecutive days. Height and weight measurements were
      taken in 885 individuals. RESULTS: EI, FV and ED increased progressively (P <
      0.001) between 1-2 y and 10-12 y of age in both sexes. At 1-2 y the EI is 5.8+/
      1.5 MJ/d, FV 1195+/-275 g/d and ED 4.8+/-0.9 kJ/g. Between 1-2 and 3-4 y,
      coinciding with an EI that increased up to 7.2+/-1.5 MJ/d, there was an increase
      in ED up to 6.1+/-0.8 kJ/g (P < 0.001), while the FV did not vary significantly.
      At the start of puberty, between 7-9 and 10-12 y, when the EI increased to 9.7+/
      0.9 MJ/d (P < 0.001) in males, the ED rose to 7.1+/-0.9 kJ/g (P < 0.001) while
      the FV did not vary significantly. At this age, a significant difference between
      the genders was observed in the EI (P = 0.04), and in the ED (P = 0.02) but not,
      as yet, in the FV. During adulthood, a significant trend towards decrease (P <
      0.001 in both sexes) was observed in EI and ED. However, FV decreased
      significantly only in females. CONCLUSIONS: The changes in energy intake that
      were observed with respect to age and gender were accommodated-for by changes in
      the ED of the diet rather than by variations in food volume intake.
      Autoregulation of the ED of the diet, sufficient for energy intake requirement
      changes, appears to be an essential human capacity for efficient nutrition.

PMID- 10403575
TI  - Repression of the rat steroidogenic acute regulatory (StAR) protein gene by
      PGF2alpha is modulated by the negative transcription factor DAX-1.
AB  - The steroidogenic acute regulatory protein (StAR) is thought to mediate the rapid
      increase in steroid hormone biosynthesis by facilitating cholesterol transport to
      the inner mitochondrial membrane. Recent studies indicate that StAR gene
      expression is enhanced by gonadotropins, whereas prostaglandin F2alpha
      (PGF2alpha) appears to suppress both basal and gonadotropin-stimulated StAR mRNA
      levels. While studies have demonstrated that steroidogenic factor 1 (SF-1)
      mediates transcriptional activation of the StAR gene, the mechanism for the
      reduction in StAR expression requires analysis. Recent studies have shown that
      DAX-1 (Dosage-sensitive sex reversal adrenal hypoplasia congenita critical region
      on the X-chromosome, gene-1), a negative transcription factor, inhibits
      transcription of reporter genes in vitro. To determine whether DAX-1 could
      negatively regulate expression of the StAR gene, approx 2 kb of the rat StAR
      promoter was linked to a luciferase reporter gene (creating p-1862 StAR) and
      cotransfected into Y1 adrenal tumor cells and HTB9 human bladder carcinoma cells
      with vectors which encode DAX-1 and SF-1. Luciferase levels were significantly
      increased in both cell types when SF-1 was present. In contrast, when DAX-1 was
      cotransfected with the StAR promoter, Y1 adrenal and HTB9 cell luciferase
      activities were reduced to levels that were 57% and 24% of basal promoter levels,
      respectively. Furthermore, when dibutyryl-cAMP (dbcAMP) was added to the DAX-1
      expressing cells, cAMP responsiveness was repressed 50% and 75% in Y1s and HTB9s
      respectively, relative to the non-DAX-1 expressing dbcAMP-treated cells. The
      inhibition of StAR gene transcription by DAX-1 was dose-dependent reducing
      transcription to 6% of control levels. Consistent with the possibility that
      PGF2alpha regulates ovarian StAR expression via DAX-1, Western blot analysis
      indicated a three- and fivefold increase in rat ovarian DAX-1 levels at 2 and 4 h
      following PGF2alpha injection (250 microg). The increase in DAX-1 protein
      corresponded to a 50% reduction in StAR mRNA levels concomitant with a 39%
      reduction in serum progesterone levels. Truncation of the DAX-1 protein at the C
      terminal end caused a loss of inhibition of transcriptional activity. Deletion of
      bp -95 to -50 within the StAR promoter, a proposed DAX-1 binding site, did not
      alter the ability of wild-type DAX-1 to inhibit transcription. In a mammalian two
      hybrid system, cotransfection of DAX-1 and SF-1 caused a 25-fold induction in
      luciferase activity demonstrating that these proteins interact in the two-hybrid
      assay. This study is the first to demonstrate that the rat StAR promoter is
      regulated by DAX-1 and that DAX-1 reduces StAR promoter responsiveness to cAMP.
      The enhanced level of DAX-1 following PGF2alpha administration is consistent with
      DAX-1 having a role in controlling both basal, gonadotropin-stimulated, and
      PGF2alpha-mediated StAR gene expression. These results imply that DAX-1 has an
      important role in regulating ovarian steroidogenesis by repressing StAR
      transcription.

PMID- 10403577
TI  - Waist circumference values in Spanish children--gender related differences.
AB  - OBJECTIVE: To obtain reference values of the waist circumference in Spanish
      children, and to investigate their dependence on age and gender. DESIGN: Cross
      sectional study. SETTING: General school-age population. SUBJECTS: A
      representative sample of the schools in Zaragoza, Spain, was drawn from seven
      schools. The population selected comprised 1728 children with ages ranging from
      6.0-14.9y. Of the original sample, 368 children (21.29%) were excluded because of
      chronic diseases or refusal. Finally, 1360 children and adolescents: 701 boys and
      659 girls, were studied. INTERVENTIONS: Waist and hip circumferences were
      measured with an unelastic tape. RESULTS: Waist circumference tended to be higher
      in males than in females and this difference was significant after 11.5y. In
      general, hip circumference was higher in females than in males (statistically
      significant differences at 7.5, 10.5, 12.5 and 13.5 y). In general, percentile
      values of waist circumference were higher in males than in females, especially
      after 12.5 y. Difference between males and females on percentile 95 at 14.5 y was
      7.6 cm. Hip was greater than waist in both sexes, and the two curves run nearly
      parallel in males. In females, while hip enlarges continuously, waist shows the
      reverse tendency between 11.5 and 14.5 y. CONCLUSIONS: Waist circumference showed
      higher values in boys than in girls, especially after 11.5 y, and waist values
      increase with age both in males and females. These findings justify the use of
      age and gender specific reference standards.

PMID- 10403578
TI  - Resting metabolic rate, body composition and aerobic fitness comparisons between
      active and sedentary 54-71 year old males.
AB  - OBJECTIVE: To test the hypothesis that 55-70 y old male longterm exercisers (LE)
      have higher resting metabolic rates (RMR) than longterm nonexercisers (LNE).
      DESIGN: A power analysis demonstrated that this cross-sectional study required 12
      subjects per group to detect a 10% RMR difference (kJ x kg FFM(-1) x d(-1))
      between the LE and LNE (power = 0.8;alpha = 0.05). SUBJECTS: Twelve LE (X +/-
      s.d.; 63.5+/-3.4 y; 1.75+/-0.06 m; 69.01+/-8.24 kg; 20.4+/-4.9 %BF) and 12 LNE
      (63.6+/-5.6 y; 1.72+/-0.07 m; 79.44 12.4 kg; 29.6 4.4 %BF) were recruited from
      advertisements placed in a newspaper and on university and community
      noticeboards. INTERVENTIONS: Measurements were conducted for: RMR using the
      Douglas bag technique; body composition via a four compartment model which is
      based on determination of body density, total body water and bone mineral mass;
      and aerobic fitness using a submaximal work test on a cycle ergometer. RESULTS:
      The LE (93.00+/-7.16 kJ x kg(-1) x d(-1)) registered a significantly greater (P =
      0.04) RMR than the LNE (84.70+/-11.23 kJ x kg(-1) x d(-1)) when energy
      expenditure was expressed relative to body mass, but this difference disappeared
      (P = 0.55) when the data were corrected for the non-zero intercept of the graph
      of RMR (MJ/d) against body mass. ANCOVA with FFM as the covariate also indicated
      that the RMR (MJ/d) difference between the groups was not statistically
      significant (P = 0.28). The adjusted means for the LE and LNE were 6.39 and 6.62
      MJ/d, respectively. CONCLUSIONS: There are no RMR (MJ/d) differences between LE
      and LNE 54-71 y old males when statistical control is exerted for the effect of
      FFM and the higher value of the former group for RMR normalised to body mass
      disappears when this ratio is corrected for statistical bias.

PMID- 10403580
TI  - High performance liquid chromatography method for the determination of pyridoxal
      5-phosphate in human plasma: how appropriate are cut-off values for vitamin B6
      deficiency?
AB  - OBJECTIVES: Application of a HPLC (high performance liquid chromatography)
      method, using cyanide derivatisation, to the determination of plasma pyridoxal-5
      phosphate (PLP) concentrations as an indicator of vitamin B6 adequacy. SETTING:
      The study was performed at the Institute of Food Research, Norwich, UK. Blood
      samples were taken at the Institute, at Health Centres, or in the volunteer's
      home. SUBJECTS: 51 adolescent, 131 adult, 68 non-institutionalized elderly and 44
      aged (>73 y) volunteers were recruited from local authority schools, local Health
      Centres and General Practitioners. RESULTS: The mean PLP recovery was 92.8%. The
      intra- and inter-assay coefficients of variation were 2.8% and 5.2% respectively.
      Mean PLP concentrations for males and females, respectively, were: adolescents
      (13-14 y), 36.4 and 43.5 nM; adults (20-64 y), 39.2 and 40.0 nM; elderly (68-73
      y), 34.8 and 35.3 nM; aged (>73 y), 57.8 and 49.0 nM. Percentages of subjects
      with PLP concentrations <34.4 nM were over 26% in all population groups. Mean
      vitamin B6 intakes (microg/g protein intake), as assessed by weighed dietary
      records, were all above reference nutrient intakes (15 microg/g protein).
      CONCLUSIONS: An HPLC method, using cyanide derivitisation, has been applied to
      the determination of plasma PLP. Comparisons of results for local population
      groups with current cut-off values for plasma PLP, show large numbers of
      volunteers at risk of vitamin B6 deficiency although this is not reflected by
      vitamin B6 intakes calculated from food tables. The 34.4 nM cut-off value for
      value for plasma PLP, indicating deficiency, is questioned.

PMID- 10403579
TI  - The quantitation of lipoprotein lipase mRNA in biopsies of human adipose tissue,
      using the polymerase chain reaction, and the effect of increased consumption of n
      3 polyunsaturated fatty acids.
AB  - OBJECTIVE: To examine the effects of the consumption of fish oils on the gene
      expression of lipoprotein lipase (LPL, EC 3.1.1.34) in human adipose tissue. In
      order to measure LPL mRNA in adipose tissue samples obtained by needle biopsy
      from human volunteers a competitive, reverse transcriptase PCR (RT-PCR) protocol
      was developed. DESIGN: A randomised controlled, single blind cross over dietary
      study which compared the effects of a low level n-3 polyunsaturated fatty acids
      (PUFA) using normal foods enriched with eicosapentaenoic (EPA) and
      docosahexaenoic (DHA) (test diet), with non-enriched but otherwise identical
      foods (control). The diets were consumed for a period of 22 d with a wash out
      period of 5 months between the diets. SETTING: Free-living individuals associated
      with the University of Surrey. SUBJECTS: Six male subjects with a mean (+/- sd)
      age of 51.2+/-3.6 y were recruited. MAJOR OUTCOME MEASURES: Pre- and postprandial
      blood samples were taken for the measurement of triacylglycerol (TAG),
      postheparin LPL activity and adipose tissue samples for the measurement of LPL
      mRNA levels. RESULTS: Mean LPL expression values were 4.12 x 10(5) molecules of
      LPL mRNA per ng total RNA on the control diet and 4.60 x 10(5) molecules of LPL
      mRNA per ng total RNA on the n-3 PUFA enriched (test) diet. There was no
      significant difference between the levels of LPL expression following each diet,
      consistent with the lack of change in TAG levels in response to increased dietary
      n-3 PUFA intake. However, the change in LPL expression (Test-Control diet)
      correlated significantly with the change in fasting TAG levels (P = 0.03, R = 
      0.87 and R2 = 0.75) and with the total area under the TAG-time response curve (P
      = 0.003, R = -0.96 and R2 = 0.92) in individuals. CONCLUSIONS: These findings,
      although based on a small number of subjects, suggest that LPL expression may be
      a determinant of plasma TAG levels. The development of this methodology should
      allow further elucidation of the effects of dietary manipulation and disease
      processes on lipid clearance and regulation in human subjects.

PMID- 10403581
TI  - Risk of linear growth retardation during the first two years of life: a new
      approach.
AB  - OBJECTIVE: Estimate the risk of linear growth retardation during the first two
      years of life as a result of household social vulnerability. SETTING: Families
      who participated in the National Supplementary Feeding Program in the Health
      Units of the metropolitan area of the city of Sao Paulo, Brazil. SUBJECTS: Four
      hundred and thirty-one index-babies, weighing more than 2500 grams and who had at
      least one young sibling under the age of five who participated in the Program for
      a minimum of two years. DESIGN: The index-babies were divided into two cohorts:
      74.9% coming from 'non-stunted families' (those with normal height siblings) and
      25.1% from 'stunted families' (those with stunted siblings). The study design
      allowed the observation of growth patterns over a period of time and over a
      childhood growth range. It also allowed the estimation of the stunting and the
      recovery probabilities at each moment, not only within a given age range. The
      transition probabilities between 'stunted' and 'non-stunted' index-babies were
      estimated. The relative risk ratio (RR) was also calculated. RESULTS: The
      prevalence of stunting in the index-babies at 12 and 24 months of age was
      significantly greater in 'stunted families' (P < 0.001). Probabilities of
      becoming stunted began to differ from the fourth month on (confidence intervals
      non-superposed), and were higher for index-babies from 'stunted families'. The
      recovery probability of a stunted child was smaller in the 'stunted families'
      cohort after the 12th month of age. From the third month on, the (RR) was always
      above 1.5. CONCLUSION: The family context exposes children to failure in growth
      in the first two years of life when there are already stunted children in the
      household.

PMID- 10403582
TI  - Influence of educational level and marital status on dietary intake, obesity and
      other cardiovascular risk factors in a Hong Kong Chinese population.
AB  - OBJECTIVES: To examine the influence of education and marital status on dietary
      intake, body mass index, waist hip ratio, blood pressure, fasting and 2 h
      glucose, and lipid profile in adult Hong Kong Chinese. DESIGN: Randomized age and
      sex stratified survey. SUBJECTS: One thousand and ten subjects aged 25-74 y (500
      men, 510 women) recruited for the 1995-96 Hong Kong Dietary and Cardiovascular
      Risk Prevalence Survey. MEASUREMENTS: Dietary intake was estimated using a food
      frequency method. Information on education level and marital status was included
      in the questionnaire. Anthropometry and biochemical parameters were measured
      using standard methods. RESULTS: After adjustment for age, higher levels of
      education are associated with higher percentage protein intake in men, higher
      percentage fat intake in women, higher nutrient density of fibre and calcium in
      both men and women, and higher nutrient density of protein, fat, niacin, vitamin
      D, and polyunsaturated fatty acid in women. Consumption of fruits was also higher
      in women, and that of dairy products higher in men. Body mass index and waist-hip
      ratio were lower with increasing levels of education in women, while lower mean
      systolic BP was observed in men. Single women had lower nutrient densities of
      vitamin D and iron, and lower consumption of vegetables and fish, compared with
      married women. Body mass index was lower in both single men and women. Single men
      had a better cardiovascular risk factor profile, in that diastolic BP,
      triglycerides and cholesterol/HDL ratio were lower, in addition to a lower body
      mass index. CONCLUSION: Higher education level is associated with a healthier
      diet and lower prevalence of overweight.

PMID- 10403583
TI  - Differences in the relationship between body fat and body mass index between two
      different Indonesian ethnic groups: the effect of body build.
AB  - OBJECTIVE: To study the relationship between body fat percent (BF%) and body mass
      index (BMI) in two different Indonesian ethnic groups (Malays and Chinese) and to
      relate differences in the relationship to differences in body build and
      slenderness. DESIGN: Cross-sectional study. SUBJECTS: Except for ethnicity, not
      specially selected populations living on Java (Depok, south of Jakarta: Malay
      Indonesians, n = 117) and on Sulawesi (Makale, north of Ujung Pandang: Chinese
      Indonesians, n = 109). MEASUREMENTS: Weight, height, sitting height, waist and
      hip circumferences and skeletal widths were measured. BMI was calculated and BF%
      was predicted from BMI, age and sex using a (Dutch) Caucasian prediction formula.
      Slenderness was expressed as the ratio of weight: sum of knee and wrist width.
      BF% assessed by deuterium oxide dilution was used as a reference. RESULTS: BF% in
      the male and female Malay Indonesians was 24.6+/-7.0 and 35.6+/-5.6% respectively
      which was not significantly different from the values in the male and female
      Chinese Indonesians (24.0+/-4.3 and 33.8+/-6.9%). BMI and age were significantly
      lower in the Malay Indonesians. Malay Indonesians had a more slender body build
      in terms of skeletal widths compared to the Chinese Indonesians, and they had a
      higher slenderness index. BF% predicted from BMI using a Caucasian prediction
      formula was underestimated by 5.8+/-4.8% and 7.7+/-3.8% in the male and female
      Malay Indonesians but only by 1.3+/-3.0% and 1.7+/-3.7% in the male and female
      Chinese Indonesians. After correction for differences in age, sex and BF% the
      Malay Indonesians had a 1.7+/-0.3 kg/m2 (P < 0.0001) lower BMI than the Chinese
      Indonesians. After correcting for body build and relative sitting height the
      difference lowered to 0.9+/-0.4 kg/m2 (P < 0.02). CONCLUSIONS: The study
      confirmed the results of an earlier study that Indonesians have a higher BF% at
      the same BMI compared to Caucasians, but that there are apparently also
      differences among Indonesian subgroups. These differences are at least partly
      related to differences in body build.

PMID- 10403584
TI  - Diets high and low in glycemic index versus high monounsaturated fat diets:
      effects on glucose and lipid metabolism in NIDDM.
AB  - OBJECTIVE: To examine the relative effects of high and low glycemic index (GI)
      carbohydrates, and monounsaturated fats on blood glucose and lipid metabolism in
      NIDDM subjects. SUBJECTS: Fourteen male and seven female variably controlled
      NIDDM subjects recruited by advertisement. SETTING: Free living outpatients.
      RESEARCH DESIGN: A repeated measures, within-subject design was used such that
      each subject consumed three diets: (a) a high-GI diet (53% CHO -21% fat, 63 GI
      units (glucose= 100)); (b) a low-GI diet (51% CHO -23% fat, 43 GI units); and (c)
      a high-mono high-GI diet (42% CHO -35% fat, 59 GI units) in random order and
      cross-over fashion for four weeks. Approximately 45% energy was provided as key
      foods which differed in published GI values and specifically excluded legumes.
      Dietary fibre intake was > 30 g/d on each diet. At the end of each dietary
      intervention, we measured fasting plasma lipids, glucose, insulin, total glycated
      plasma protein, fructosamine, LDL and HDL particle size as well as 24 h urinary
      excretion of glucose and C-peptide. RESULTS: HDL-cholesterol was higher on the
      low-GI and high-mono high-GI diets compared to the high-GI diet (P < 0.05 for
      overall diet effect). There were no other significant differences in metabolic
      control between diets, even when adjusted for BMI, glucose control or gender.
      Body weight and saturated fat intake remained stable between dietary
      interventions. CONCLUSION: High-mono high-GI and high-CHO, low-GI diets are
      superior to high-CHO, high-GI diets with respect to HDL metabolism but no effect
      was noted on glucose metabolism in variably controlled NIDDM subjects.

PMID- 10403585
TI  - Gender specific alterations of body composition in patients with inflammatory
      bowel disease compared with controls.
AB  - OBJECTIVE: To assess body hydration and the distribution of the body water
      compartments in defined populations of patients with inflammatory bowel disease
      (IBD) compared with those of matched healthy controls. SUBJECTS: Fifty-two
      patients with IBD at time of diagnosis (20 patients with Crohn's disease (CD-new)
      and 32 patients with ulcerative colitis (UC-new)), 40 patients with long-standing
      CD (CD-long) and 2 matched healthy control groups (n = 52 and n = 40) were
      recruited for the study. METHODS: Total body water (TBW) and extracellular water
      (ECW) were measured by deuterium oxide and bromide dilution, respectively.
      Intracellular water (ICW) was calculated as TBW-ECW. In addition, hydration of
      fat-free mass (FFM) and the ECW:ICW ratio were calculated. FFM, body fat (BF) and
      % body fat (%BF) were assessed by dual energy X-ray absorptiometry. RESULTS: In
      female IBD patients, the ECW:ICW ratio was significantly (P < 0.05) higher than
      in controls (CD-new: 0.89+/-0.11 vs 0.79+/-0.08, P < 0.01; UC-new: 0.85+/-0.15 vs
      0.77+/-0.10, P < 0.05; CD-long: 0.86+/-0.14 vs 0.80+/-0.10, P < 0.05). In these
      female patients, the ICW:FFM ratio was significantly (P < 0.05) lower than in
      controls. Fluid shifts were especially pronounced in female patients with
      recently diagnosed CD. In male patients with recently diagnosed UC and in those
      with long-standing CD, body weight, body mass index, BF and %BF were
      significantly (P < 0.05) lower than in controls. No differences in body hydration
      or body water distribution were observed between male patients and controls.
      CONCLUSIONS: An altered body water distribution and body hydration was observed
      in female IBD patients, especially in female patients with recently diagnosed CD.

PMID- 10403586
TI  - Trace element transfer from the mother to the newborn--investigations on triplets
      of colostrum, maternal and umbilical cord sera.
AB  - OBJECTIVE: To investigate the trace element transfer from the mother to the
      newborn. DESIGN: The concentrations of the eight essential elements calcium (Ca),
      cobalt (Co), copper (Cu), magnesium (Mg), manganese (Mn), molybdenum (Mo), tin
      (Sn), and zinc (Zn), and of the non-essential and toxic elements barium (Ba),
      beryllium (Be), bismuth (Bi), cadmium (Cd), cesium (Cs), lanthanum (La), lithium
      (Li), lead (Pb), rubidium (Rb), antimony (Sb), strontium (Sr), and thallium (Tl)
      were determined in umbilical cord (n = 29) and corresponding maternal sera (n =
      29) as well as in colostrum (n = 27). RESULTS: Umbilical cord serum
      concentrations of Ca, Mn, and Zn were 120%, 150%, and 148% of the maternal value,
      respectively. Maternal sera had twice the Cu concentrations found in healthy
      adults and five-times higher Cu than umbilical cord sera. Concentration ratios
      colostrum/maternal serum and colostrum/umbilical cord serum were approximately
      one for Co, 1.4 for Mg, two for Ca, Mn, and Sn, five for Cu (maternal serum),
      eight for Mo, and ten for Zn. Concentrations of the toxic elements Cd and Pb
      decreased in the order colostrum (Pb 2.6 microg/L; Cd 0.6 microg/L), maternal
      sera (0.8 microg/L; 0.3 microg/L), umbilical cord sera (0.4 microg/L; 0.2
      microg/L). Maternal serum Ba and Rb was 182% and 66% of the umbilical cord value.
      For Sr and Li, an almost perfect correlation between umbilical cord and maternal
      sera was found. For Ba, Co, Cu, Mn, Zn none, and for Ca, Cs, Mn, Mo, Rb only weak
      positive correlations between these two compartments could be established.
      CONCLUSIONS: The results of this study indicate that an active transport
      mechanism for the transport of Ca, Mn, Rb, and Zn from the mother to the newborn
      exists, whereas Cs, Li, and Sr follow concentration gradients. As regards Cu, the
      placenta showed to have a blocking effect on the transfer from the mother to the
      baby.

PMID- 10403587
TI  - Satiety related to 24 h diet-induced thermogenesis during high
      protein/carbohydrate vs high fat diets measured in a respiration chamber.
AB  - OBJECTIVE: Assessment of a possible relationship between perception of satiety
      and diet-induced thermogenesis, with different macronutrient compositions, in a
      controlled situation over 24 h. DESIGN: Two diets with different macronutrient
      compositions were offered to all subjects in randomized order. SETTING: The study
      was executed in the respiration chambers at the department of Human Biology,
      Maastricht University. SUBJECTS: Subjects were eight females, ages 23-33 y, BMI
      23+/-3 kg/m2, recruited from University staff and students. INTERVENTIONS:
      Subjects were fed in energy balance, with protein/carbohydrate/fat: 29/61/10 and
      9/30/61 percentage of energy, with fixed meal sizes and meal intervals, and a
      fixed activity protocol, during 36 h experiments in a respiration chamber. The
      appetite profile was assessed by questionnaires during the day and during meals.
      Diet induced thermogenesis was determined as part of the energy expenditure.
      RESULTS: Energy balance was almost complete, with non-significant deviations.
      Diet-Induced-Thermogenesis (DIT) was 14.6+/-2.9%, on the high
      protein/carbohydrate diet, and 10.5+/-3.8% on the high fat diet (P < 0.01). With
      the high protein/high carbohydrate diet, satiety was higher during meals (P <
      0.001; P < 0.05), as well as over 24 h (P < 0.001), than with the high fat diet.
      Within one diet, 24 h DIT and satiety were correlated (r = 0.6; P < 0.05). The
      difference in DIT between the diets correlated with the differences in satiety (r
      = 0.8; P < 0.01). CONCLUSION: In lean women, satiety and DIT were synchronously
      higher with a high protein/high carbohydrate diet than with a high fat diet.
      Differences (due to the different macronutrient compositions) in DIT correlated
      with differences in satiety over 24 h.

PMID- 10403588
TI  - Current status and future priorities for rotavirus vaccine development,
      evaluation and implementation in developing countries.

PMID- 10403589
TI  - Diphtheria booster vaccination: one or two injections?
AB  - In a prospective, controlled, randomized, multicenter study the immunogenicity
      and tolerance of a single vaccination (day 0) and two (day 0, 28) booster
      vaccinations against diphtheria were compared in subjects who had received their
      last diphtheria vaccination more than 10 years ago. 415 subjects received the
      first booster vaccination, and 203 were vaccinated twice. The geometric mean
      diphtheria antitoxin concentration after the first booster (day 28) was 2.354
      I.U./ml, and after the second booster (day 56) 2.238 I.U./ml. Prior to the first
      vaccination 48.9% of the subjects had a diphtheria antitoxin level below 0.1
      I.U./m; after the first and second boosters 95.4% and 97.5% of subjects,
      respectively, showed a level of at least 0.1 I.U./ml. A clear serological effect
      of a second booster 4 weeks after the first one could not be demonstrated.

PMID- 10403590
TI  - Intranasal immunization with recombinant gD2 reduces disease severity and
      mortality following genital challenge with herpes simplex virus type 2 in guinea
      pigs.
AB  - The ability of a genetically detoxified mutant of heat labile enterotoxin (LTK63)
      to act as a mucosal adjuvant following intranasal immunization with recombinant
      gD2 has previously been reported in mice [Ugozzoli M, O'Hagan DT, Ott GS.
      Intranasal immunization of mice with herpes simplex virus type 2 recombinant gD2:
      the effect of adjuvants on mucosal and serum antibody responses. Immunol
      1998;93:563-571.]. In the current studies, these observations were extended to
      the guinea pig model. Immunized guinea pigs were subsequently challenged
      intravaginally with HSV-2. Intranasal immunization with gD2 and LTK63 induced a
      significant reduction in disease severity and a reduction in mortality. However,
      only intramuscular immunization with a potent adjuvant (MF59) induced protection
      against the incidence of disease.

PMID- 10403591
TI  - Modified M2 proteins produce heterotypic immunity against influenza A virus.
AB  - Vaccination with the influenza A transmembrane protein M2 provides enhanced viral
      clearance and recovery from influenza A virus infection in mice. However, the
      high degree of hydrophobicity of the protein limits its purification for vaccine
      purposes. We have attempted to alter the structure of the M2 protein to allow
      high level recombinant expression in Escherichia coli, to reduce its
      hydrophobicity and improve protein solubility, thus improving its properties as a
      vaccine subunit candidate. Constructs investigated include deletion of the
      transmembrane domain of M2 (residues 26-43) and an extended deletion (residues 26
      55). A full-length M2 protein was not pursued because of poor expression, even in
      the presence of amantadine. Expressed as glutathione S-transferase fusion
      proteins and used to vaccinate mice, either deletion construct was found to raise
      M2-specific serum antibodies and enhance viral clearance in mice challenged with
      homologous and heterologous influenza A viruses. Enzymatic cleavage from the GST
      fusion domain produces soluble protein giving similar results. The results
      demonstrate that large alterations of M2 protein structure can improve its
      isolation and purification characteristics without detracting from its
      immunogenic properties.

PMID- 10403592
TI  - Antibody responses to DNA vaccination of horses using the influenza virus
      hemagglutinin gene.
AB  - Equine influenza virus infection remains one of the most important infectious
      diseases of the horse, yet current vaccines offer only limited protection. The
      equine immune response to natural influenza virus infection results in long-term
      protective immunity, and is characterized by mucosal IgA and serum IgGa and IgGb
      antibody responses. DNA vaccination offers a radical alternative to conventional
      vaccines, with the potential to generate the same protective immune responses
      seen following viral infection. Antigen-specific antibody isotype responses in
      serum and mucosal secretions were studied in ponies following particle-mediated
      delivery of hemagglutinin (HA)-DNA vaccination on three occasions at
      approximately 63-day intervals. One group of four ponies were vaccinated at skin
      and mucosal sites and the another group were vaccinated at skin sites only. All
      ponies were subjected to a challenge infection 30 days after the third
      vaccination. Skin and mucosal vaccination provided complete protection from
      clinical signs of infection, while skin vaccination provided partial protection;
      DNA vaccination provided partial protection from viral shedding. DNA vaccination
      generated only IgGa and IgGb antibody responses, which occurred with a higher
      frequency in the skin and mucosa vaccinated ponies. No mucosal IgA response was
      generated prior to challenge infection and IgA responses were only detected in
      those ponies which shed virus postchallenge. These results demonstrate that HA
      DNA vaccination induces IgG(a) and IgG(b) antibody responses which are associated
      with protection in the absence of mucosal IgA responses. In addition, additional
      DNA vaccinations of mucosal sites increased protection and the frequency of
      seroconversion in ponies.

PMID- 10403593
TI  - Primary and booster immune responses to SA14-14-2 Japanese encephalitis vaccine
      in Korean infants.
AB  - Attenuated SA14-14-2 Japanese encephalitis (JE) vaccine has been administered
      safely and effectively to more than 100 million children in China since 1988 and
      recently, licensure of the vaccine in Korea has been sought. In the first
      clinical evaluation of the vaccine outside of China, we monitored side effects in
      84 children and evaluated antibody responses to a single dose given as primary JE
      vaccination in 68 children, 1-3 years old (mean age 27 months). No significant
      adverse events were noted. Neutralizing antibodies (geometric mean titer [GMT] of
      188) were produced in 96% of the 68 subjects. In 10 other children who previously
      had been immunized with two or three doses of inactivated JE vaccine, the booster
      administration of SA14-14-2 vaccine produced an anamnestic response in all, with
      a GMT of 3378. In a comparison group of 25 children previously immunized with two
      doses of inactivated vaccine, neutralizing antibody titers were detected in 16
      (64%). Viral specific IgM was detected in nine primary vaccinees (13%) but in
      others, IgM may have declined to undetectable levels in the four week
      postimmunization sample. Live attenuated SA14-14-2 JE vaccine is a promising
      alternative to the only commercially available JE vaccine for national childhood
      immunization programs in Asia.

PMID- 10403594
TI  - Baculovirus-derived hemagglutinin vaccines protect against lethal influenza
      infections by avian H5 and H7 subtypes.
AB  - Baculoviruses were engineered to express hemagglutinin (HA) genes of recent avian
      influenza (AI) isolates of the H5 and H7 subtypes. The proteins were expressed as
      either intact (H7) or slightly truncated versions (H5). In both cases purified HA
      proteins from insect cell cultures retained hemagglutination activity and formed
      rosettes in solution, indicating proper folding. Although immunogenic in this
      form, these proteins were more effective when administered subcutaneously in a
      water-in-oil emulsion. One or two-day-old specific pathogen free (SPF) White Rock
      chickens, free of maternal AI antibodies, responded with variable serum HI
      titers, but in some cases the titers were comparable to those achieved using
      whole virus preparations. Vaccination of three-week-old chickens with 1.0 microg
      of protein per bird generated a more consistent serum antibody response with an
      average geometric mean titer (GMT) of 121 (H5) and 293 (H7) at 21 days
      postvaccination. When challenged with highly pathogenic strains of the
      corresponding AI subtypes, the vaccinated birds were completely protected against
      lethal infection and in some cases exhibited reduced or no cloacal shedding at 3
      days postinfection. Vaccine protocols employing these recombinant HA proteins
      will not elicit an immune response against internal AI proteins and thus will not
      interfere with epidemiological surveys of natural influenza infections in the
      field.

PMID- 10403595
TI  - Low-level transforming activity of an activated Ras gene under the control of a
      vaccinia virus p40 promoter is abrogated by truncation of the Ras cDNA.
AB  - Many human cancers have been shown to contain activated forms of the Ras proto
      oncogene. Mutations comprising amino acid changes at codons 12, 13 and 61
      therefore represent unique targets for cancer immunotherapy. Recombinant Vaccinia
      viruses encoding point mutated Ras oncogenes have raised issues concerning the
      safety and transforming ability of these recombinant vaccines. Vaccinia virus, a
      representative of the orthopox virus genus, is a large DNA virus that is
      cytopathogenic and that replicates in the cytoplasm of the infected cell.
      However, it remains unclear whether orthopox viruses are capable of genetic
      interactions with infected cells. Our studies show that DNA isolated from cells
      infected with a recombinant Vaccinia virus expressing mutated Ras constituted a
      poor reagent for transfection into NIH3T3 cells for transformation analysis.
      Stable integration of a recombinant Vaccinia virus expressing mutant Ras DNA was
      not detected in recipient cells. This study also demonstrates that the crossover
      plasmids used to generate the recombinant virus where the activated Ras gene is
      under the control of a Vaccinia virus early promoter had low but detectable
      transforming efficiency in the NIH3T3 transformation assay. Analysis of the
      transfected cells indicated that Ras transcription was initiated upstream of the
      Vaccinia virus promoter. The introduction of wobble mutations as well as the
      truncation of the Ras protein removed the transforming capabilities of the
      crossover vector. This study demonstrates the potential problems and solutions in
      the use of point mutated oncogenes in live vectors for cancer vaccine
      development.

PMID- 10403596
TI  - Paradoxical response to a novel influenza virus vaccine strain: the effect of
      prior immunization.
AB  - BACKGROUND: repeated influenza immunization does not appear to adversely affect
      the serum antibody response to new influenza strains. OBJECTIVE: to determine
      whether the immune response to a new influenza strain was inferior in persons
      previously vaccinated compared with persons not previously vaccinated. DESIGN:
      randomized, double-blind clinical trial. SETTING: university affiliated community
      teaching hospital. PATIENTS: 139 healthy adult men and women, mean age 38 years.
      INTERVENTION: subjects were vaccinated as part of another study. They received
      influenza vaccines containing influenza strains A/Texas/36/91 (H1N1),
      A/Nanchang/933/95 (H3N2) and B/Beijing/184/93. One group received a licensed
      influenza vaccine while the other group received a similar vaccine except the
      A/Nanchang strain had a diminished potency. MEASUREMENTS: serum hemagglutination
      inhibition (HAI) antibody titers were determined prior to vaccination and two
      weeks afterward. If patients had a low postvaccination titer, they were
      revaccinated and HAI titers were determined two weeks later. RESULTS: 68 adults
      received the licensed vaccine and 70 received the subpotent vaccine. The groups
      were similar with regards to baseline characteristics. Those previously
      vaccinated had significantly lower postvaccination HAI geometric mean titers
      (GMTs) for all three vaccine strains (A/Texas--127 vs. 359, p < 0.001, A/Nanchang
      -31 vs. 93, p < 0.001 and B/Beijing--140 vs. 205, p < 0.05). The percentage of
      subjects with a presumed protective HAI titer of > or =40 was significantly lower
      among the previously vaccinated groups only for the new influenza strain,
      A/Nanchang (55% vs. 80%, p < 0.05). For the other two vaccine strains, the
      percentage with an HAI titer > or =40 was greater than 90% for both groups.
      CONCLUSIONS: the decrease in serologic response to influenza vaccine among
      healthy, young adults who were previously vaccinated appears to be unique for
      this year's influenza vaccine. Further studies are required to determine the
      frequency and clinical significance of this phenomenon observed in younger
      healthy adults, and whether it is a general one. Based on its proven efficacy,
      influenza vaccine should continue to be given on an annual basis to high risk
      children and adults and to all those 65 years or older.

PMID- 10403597
TI  - Comparison of immunogenicity of two hepatitis A vaccines--VAQTA and HAVRIX--in
      young adults.
AB  - Two new hepatitis A vaccines have been developed, and their immunogenicity tested
      using different immunoassays. The present study was designed to compare the
      immunogenicity of these two hepatitis A virus (HAV) vaccines--VAQTA and HAVRIX-
      as determined by seroconversion rates and anti-HAV titers, and using the same
      immunoassay. Healthy volunteers (15-30 y), seronegative for anti-HAV, were
      randomized in an open single center study to four groups of 20-21 vaccinees each,
      to receive either a 25 U or a 50 U dose of VAQTA, or HAVRIX at 720 EU or 1440
      EU/dose, administered at 0, 1 and 6 m or at 0 and 6 m, respectively. Four weeks
      after primary immunization, seroconversion rates were 100% for VAQTA and 95% for
      HAVRIX, following injection of 50 U or 1440 EU, respectively (p = NS) and anti
      HAV GMTs were 40 and 37 mIU/ml for VAQTA and HAVRIX, respectively. At 6 months,
      prior to the booster dose, seroconversion rates were 100% for both vaccines, with
      anti-HAV GMTs of 111 and 70 mIU/ml for VAQTA and HAVRIX, respectively (P < 0.05).
      At month 7, four weeks after the only booster injection, using the two dose
      regimen, anti-HAV titers were 2212 and 1511 mIU/ml for VAQTA and HAVRIX,
      respectively (P < NS). Using three doses of 25 U/dose of VAQTA or 720 EU/dose of
      HAVRIX at 0, 1 and 6 m did not produce any clinically evaluable advantage over
      the two dose regimen for either vaccine. No significant adverse events were
      observed using either vaccine. In summary, both vaccines have similar
      immunogenicity demonstrated using identical immunoassays for evaluation. These
      results also confirm the outstanding immunogenicity of a single dose of either of
      the HAV vaccines and support their use in pre- and possibly postexposure
      prophylaxis against hepatitis A virus infection.

PMID- 10403598
TI  - Immunogenicity and protective efficacy of a gE, gG and US2 gene-deleted bovine
      herpesvirus-1 (BHV-1) vaccine.
AB  - The efficacy and safety of a gene-deleted bovine herpesvirus-1 (BHV-1) vaccine
      was determined in a bovine herpesvirus challenge trial in calves. Three different
      doses of the vaccine were administered intramuscularly at 10(5), 10(6) and 10(7)
      PFU/ml and compared to a commercial vaccine and non vaccinated control calves.
      Challenge was performed by intranasal aerosolization with the Cooper strain of
      BHV-1 (3 x 10(4) PFU/ml). The non-vaccinated calves shed significantly (P < 0.05)
      more virus than all other groups on days 4, 8 and 10 post challenge. By day 14
      post challenge, antibody titers for BHV-1 of calves vaccinated with 10(7) PFU/ml
      were significantly (P < 0.05) higher than the commercial or non-vaccinated
      calves. Clinical scores of non-vaccinated calves were significantly (P < 0.05)
      higher than all other groups on days 4-14 post challenge. With both
      radioimmunoprecipitation and competitive enzyme-linked immunosorbent assays (C
      ELISA), calves in the gene-deleted vaccine groups mounted comparable specific
      responses against gB, gC and gD post vaccination as calves in the commercial
      vaccine group, but in a dose dependent manner. These data suggest that the gene
      deleted BHV-1 vaccine tested may be used as an effective vaccine in controlling
      BHV-1 infections.

PMID- 10403599
TI  - Induction of resistance against Schistosoma mansoni infection by passive transfer
      of an IgG2a monoclonal antibody.
AB  - Monoclonal antibodies can confer resistance to schistosome infections. This has
      led to identification of several protective antigens. An IgG2a monoclonal
      antibody designated BRL4 mAb identified a 74-kDa antigen in antigenic extract of
      Schistosoma mansoni adult worms. The target antigen was localized in gut and
      tegument. In 3 passive transfer experiments, the BRL4 mAb conferred 51.6, 41.9
      and 53.8% protection levels into female Swiss mice. Histopathological examination
      revealed a marked decrease in number, size, collagen and reticular fibers of the
      liver granulomas. Further experiments using purified 74-kDa-target antigen as a
      candidate vaccine will be performed.

PMID- 10403600
TI  - The V3 loop based multi-epitope polypeptide TAB9 adjuvated with montanide ISA720
      is highly immunogenic in nonhuman primates and induces neutralizing antibodies
      against five HIV-1 isolates.
AB  - In a previous work we selected montanide ISA720 (M-ISA720) among different
      adjuvants for the vaccination with a V3 loop based multi-epitope polypeptide
      TAB9. In this paper we present the evaluation of the toxicity and immunogenicity
      of this formulation in non-human primates. TAB9 in M-ISA720 was highly
      immunogenic in macaques (Macaca fascicularis) inducing antibodies against TAB9 in
      all animals after one inoculation and a strong anamnestic response after booster
      injections. Furthermore 97% of the V3 peptides included were recognized by TAB9
      sera. No differences between doses of 200 microg and 1 mg of TAB9 in M-ISA720
      were observed after four immunizations. Neutralizing antibodies against five HIV
      1 isolates were detected in most animals. Animals remain healthy throughout the
      study and did not show lesions at the inoculation site.

PMID- 10403601
TI  - Clinical value of ambulatory blood pressure monitoring.
AB  - Ambulatory blood pressure monitoring (ABPM) has now become an established
      clinical tool. It is appropriate to take stock and assess the situation of this
      technique. UPDATE ON EQUIPMENT: Important improvements in equipment have
      occurred, with reductions in weight, in awkwardness and in noisiness of the
      machines, better acceptability and tolerance by the patients, and better
      reliability. Validation programmes have been proposed and should be referred to.
      Limitations of the technique persist with intermittent recording in current
      practice. The reproducibility is limited in the short-term while recording over
      24 h is acceptable. DIAGNOSIS AND PROGNOSIS: White-coat effect (WCE) is
      manifested as a transient elevation in blood pressure during the medical visit
      The frequency of this phenomenon, the size of the effect, age, sex and level of
      blood pressure (BP) or the situation of occurrence (general practitioner,
      specialist or nurse) have been interpreted differently. It does not seem that WCE
      predicts cardiovascular morbidity or mortality. White-coat hypertension (WCH) is
      diagnosed on the evidence of abnormal clinical measures of BP and normal ABPM.
      The latest upper limits of normality by ABPM recommended by the JNCVI are <
      135/85 mmHg while patients are awake and < 120/75 mmHg while patients are asleep.
      If we accept these upper limits of normality in ABPM, WCH does not appear to be a
      real problem as regards risk factors or end-organ effects. In terms of prognosis,
      data are limited. Cardiovascular morbidity seems low in WCH but identical to that
      of hypertensive subjects in these studies. However, further studies are needed to
      confirm these results. WCH does not appear to benefit from anti-hypertensive
      treatment. It is obvious that the lower the BP regarded as the limit of
      normality, the less likely the occurrence of secondary effects of metabolism, or
      end-organ effects or complications in those classified as hypertensive. 24 HOUR
      CYCLE: One of the most specific characteristics of ABPM is the possibility of
      being able to discover modification or alteration of the 24 h cycle of BP. Non
      dippers are classically defined as those who show a reduction in BP of less than
      10/5 mmHg or 10% between the day (06.00-22.00 h) and the night, or an elevation
      in BP. In contrast, extreme dippers are those in whom the BP reduction is greater
      than 20%. CARDIOVASCULAR SYSTEM: The data remain inconclusive with regard to the
      existence of a consistent relationship between the lack of a nocturnal dip in
      blood pressure and target organ damage. As regards prognosis, it seems that an
      inversion of the day-night cycle is of pejorative significance. CEREBROVASCULAR
      SYSTEM: Almost all studies have shown that non-dippers had a significantly higher
      frequency of stroke than dippers. In contrast, too great a fall in nocturnal BP
      may be responsible for more marked cerebral ischaemia. RENAL SYSTEM: Non-dippers
      have a significantly elevated median urinary excretion of albumin. There is a
      significant correlation between the systolic BP and nocturnal diastolic BP, and
      urinary excretion of albumin. Various studies have confirmed the increased
      frequency of change in the 24 h cycle in hypertensive subjects at the stage of
      renal failure. DIABETES: BP abnormalities should be considered as markers of an
      elevated risk in diabetic subjects but cannot be considered at present as
      predictive of the appearance of micro-albuminuria or other abnormalities. ABPM is
      thus of interest in type I or type II diabetes both in the initial assessment and
      in the follow-up and adaptation of treatment. PHARMACO-THERAPEUTIC USES: The
      introduction of ABPM has truly changed the means and possibilities of approach to
      the study of the effects of anti-hypertensive medications, with new possibilities
      of analysis such as trough-peak ratio smoothness index, etc.

PMID- 10403602
TI  - Value of blood pressure self-monitoring as a predictor of progression of diabetic
      nephropathy.
AB  - OBJECTIVE: To determine the impact of self-monitoring of blood pressure values
      (BP(S)) as compared with office blood pressure measurements (BP(O)) on the
      progression of diabetic nephropathy. DESIGN: Long-term, follow-up cohort study.
      SUBJECTS AND METHODS: Hypertensive, type 1 diabetic patients with overt diabetic
      nephropathy were investigated. Patients initially participated in a hypertension
      treatment and teaching programme including extensive advice on blood pressure
      self-monitoring. Self-monitoring and office blood pressure values were
      continuously assessed during the entire follow-up period. Progression of diabetic
      nephropathy over the study period was individually assessed as the mean decline
      of glomerular filtration rate (GFR) per patient per year. Baseline and follow-up
      parameters were included in stepwise multiple regression analyses with the
      decline of GFR per year as the dependent variable. RESULTS: Seventy-seven type 1
      diabetic patients (37 women, 40 men) were followed for a mean period of 6.2 +/-
      2.8 years (mean +/- SD; range 2-12) resulting in a total of 481 patient-years.
      During the follow-up period, mean BP(O) decreased from 166/95 at baseline to
      154/89 mmHg during follow-up, and mean BP(S) fell from 159/93 to 138/83 mmHg. The
      mean decline of GFR was 4.1 +/- 5.6 ml/min per year. Loss of kidney function was
      significantly correlated with proteinuria, blood pressure and glycosylated
      haemoglobin values. In the multiple regression analyses, BP(S) predicted the loss
      of renal function better than BP(O) (R2 = 0.52 versus 0.42). The simple
      correlation between BP(S) and GFR decline was higher compared to BP(O) and GFR (r
      = -0.42; P < 0.0001 versus -0.33; P < 0.004). CONCLUSION: Blood pressure self
      monitoring values are a better predictor of progression of diabetic nephropathy
      when compared with office blood pressure measurements.

PMID- 10403603
TI  - Haemodynamic responses to obstructive sleep apnoeas in premenopausal women.
AB  - OBJECTIVES: Obstructive apnoeas during sleep are associated with marked cyclical
      blood pressure fluctuations in men with obstructive sleep apnoea (OSA).
      Haemodynamic responses to OSA in women are largely unknown. We aimed to
      investigate haemodynamics during apnoeic events in women with OSA and to assess
      the influence of the menstrual cycle on these responses. DESIGN AND METHODS: Full
      overnight polysomnography and continuous non-invasive blood pressure monitoring
      was performed in 13 women with OSA during follicular and luteal phases of the
      menstrual cycle. Change in blood pressure (deltaBP) from pre- to post-apnoea
      termination was measured for each apnoeic cycle. RESULTS: Only 10 of 13 subjects
      ovulated. In women who ovulated, pressor responses to apnoea termination occurred
      in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, but
      substantially increased during the luteal phase of ovulatory cycles [NREM change
      in mean arterial pressure (deltaMAP) 12 +/- 3 mmHg during the follicular phase
      and 20 +/- 3 mmHg during the luteal phase, P < 0.001; REM deltaMAP 11 +/- 3 mmHg
      during the follicular phase and 23 +/- 3 mmHg during the luteal phase, P <
      0.001]. Sleep apnoea severity did not change during the cycle in NREM sleep, but
      was reduced in REM during the luteal phase. Changes in pressor responses were
      absent in non-ovulating subjects. CONCLUSIONS: Obstructive apnoeas in women were
      associated with marked blood pressure changes, similar to those previously
      reported in men. While respiratory events improved slightly in the luteal phase,
      blood pressure responses to these events increased by approximately 100%. Thus,
      the menstrual cycle has discordant effects on the respiratory and cardiovascular
      effects of OSA in women.

PMID- 10403604
TI  - Relationship between hypercholesterolaemia, endothelial dysfunction and
      hypertension.
AB  - OBJECTIVES: We have previously shown that in the rat a diet high in cholesterol
      and deficient in vitamin E and selenium results in hypercholesterolaemia and
      increased lipid oxidation. We utilized this model to determine whether rats given
      this diet develop impaired endothelium-dependent relaxation mediated by nitric
      oxide (NO) in mesenteric and in renal vessels. In addition, we tested whether the
      impairment is due to (i) decreased endothelial NO synthase activity, (ii)
      increased NO inactivation and/or (iii) increased production of the endothelium
      derived constricting factors thromboxane A2/prostaglandin H2 and endothelin-1. We
      also investigated whether endothelial dysfunction induced by dyslipidaemia
      increases the sensitivity for the development of hypertension in response to high
      dietary salt. METHODS: Male Dahl salt-sensitive (DSS) rats were divided into
      three groups and received a standard diet (control group), a high (4%)
      cholesterol diet (HChol), or a high cholesterol diet deficient in the anti
      oxidants vitamin E and selenium (HChol-Def). The NaCl content of these diets was
      0.5%. After 18 weeks we studied endothelium-dependent relaxation in response to
      acetylcholine (ACh) in aortas and in isolated perfused preparations of mesenteric
      arteries and kidneys. In some experiments, ifetroban, a thromboxane
      A2/prostaglandin H2 receptor antagonist, was added to the organ bath or the
      perfusion buffer. Vascular responses to endothelin-1 as well as to BQ-123, an
      endothelin A receptor blocker, were studied in the isolated perfused kidneys. In
      addition, two extra groups of rats were fed a diet high in sodium chloride (2%):
      one of the groups received the normal cholesterol diet whereas the other group
      received the diet high in cholesterol and deficient in vitamin E and selenium.
      RESULTS: Compared to normocholesterolemic rats, responses to ACh were
      significantly impaired in aortas, mesenteric arteries and kidneys of HChol-Def
      rats (P < 0.01). Endothelial NO synthase activity (conversion of [14C]L-arginine
      to [14C]L-citrulline) was similar in aortas of control, HChol and HChol-Def rats;
      thus suggesting that impaired endothelium-dependent relaxation in the HChol-Def
      rats was not due to decreased cNOS catalytic activity. Ifetroban improved the
      impaired endothelium-dependent relaxation in mesenteric vessels, but not in
      aortas and kidneys. Endothelin-1 (ET-1: 10(-13)-10(-11) mol/l) elicited NO
      mediated relaxations in kidneys of control rats but not in kidneys of HChol-Def;
      blockade of ET-1 with BQ-123, an ET(A) receptor blocker, did not improve NO
      mediated relaxation of HChol-Def. Despite impaired endothelium-dependent
      relaxation in renal and mesenteric vessels, HChol-Def DSS rats failed to develop
      hypertension (systolic blood pressure 144 +/- 1 in control and 150 +/- 2 mmHg in
      HChol-Def) but manifested a significant increase in sensitivity to the pressor
      effects of a high (2% NaCl) dietary salt content during the initial 10 weeks of
      the study, although the final blood pressure at 18 weeks was similar in both
      groups. CONCLUSION: These studies support the notion that (i) products of lipid
      oxidation may reduce NO bioactivity without affecting endothelial NO synthase
      mass or catalytic activity, (ii) the mechanisms involved in the endothelial
      dysfunction induced by hypercholesterolaemia and oxidized lipids may differ among
      vascular beds, and (iii) decreased NO bioavailability does not necessarily result
      in systemic hypertension, but it may enhance the sensitivity to the
      hypertensinogenic effect of dietary salt.

PMID- 10403605
TI  - Uptake and proteolytic activation of prorenin by cultured human endothelial
      cells.
AB  - OBJECTIVE: To investigate the mechanisms of vascular uptake of prorenin and renin
      and to explore the possibility of vascular activation of prorenin. DESIGN AND
      METHODS: Human umbilical vein endothelial cells (HUVECs) cultured in a chemically
      defined medium were incubated with recombinant human prorenin or renin in the
      presence or absence of putative inhibitors of renin internalization. Cell surface
      bound and internalized prorenin or renin were separated by the acid-wash method
      and were quantified by enzyme-kinetic assays. The activation of prorenin was also
      monitored by a direct immunoradiometric assay (IRMA) with use of a monoclonal
      antibody directed against the -p24-Arg to -1p-Arg C-terminal propeptide sequence
      of prorenin. RESULTS: Prorenin and renin were internalized at 37 degrees C in a
      dose-dependent manner; with 1000 microU prorenin/ml medium, the quantity of cell
      associated prorenin after 3 h of incubation was 9.3 +/- 1.0 microU/4 x 10(5)
      cells, and with 75,000 microU/ml medium it was 670 +/- 75 microU/4 x 10(5) cells
      (mean +/- SD; n = 5). Results for renin were similar. Prorenin that had been
      treated with endoglycosidase H to remove N-linked oligosaccharides was not
      internalized. Addition of mannose 6-phosphate (M-6-P) to the medium caused a dose
      dependent inhibition of renin and prorenin internalization. Fifty per cent
      inhibition was observed at 70 micromol/M-6-P, whereas mannose 1-phosphate,
      glucose 6-phosphate and alpha-methylmannoside at this concentration had no effect
      Ammonium chloride (50 mmol/l) and monensin (10 micromol/l) also inhibited
      internalization. Prorenin was activated by HUVECs, and cell-activated prorenin
      was only found in the internalized fraction, whereas the surface-bound prorenin
      remained inactive. Thus, it appears that the activation of prorenin took place at
      the time of its internalization or thereafter. The results of the prorenin IRMA
      indicated that activation was associated with proteolytic cleavage of the
      propeptide. CONCLUSIONS: Our findings provide evidence for M-6-P receptor
      dependent endocytosis of (pro)renin and proteolytic prorenin activation by
      vascular endothelial cells.

PMID- 10403606
TI  - Racial differences in aortic stiffness in normotensive and hypertensive adults.
AB  - OBJECTIVE: To investigate whether differences exist in the mechanical properties
      of large arteries between white and black subjects. DESIGN: Eighty-two white (49
      normotensive and 33 untreated hypertensive) and 38 black (24 normotensive and 14
      untreated hypertensive) adult male volunteers were studied in a cross-sectional
      study. METHODS: Carotid-femoral pulse wave velocity was measured as an index of
      arterial stiffness, using a recently developed non-invasive automatic device, and
      compared between white and black subjects before and after the adjustment for
      age. The slope of regressions for pulse wave velocity and systolic blood pressure
      were also compared between racial groups. RESULTS: In the normotensive group,
      white subjects presented higher mean values of pulse wave velocity than blacks
      while the opposite behavior was found in the hypertensive group. After adjustment
      for age, significant differences in pulse wave velocity between whites and blacks
      became evident in the normotensive (whites 8.15 +/- 0.04 versus blacks 7.75 +/-
      0.02 m/s; P < 0.001) and hypertensive (whites 8.88 +/- 0.02 versus blacks 9.30 +/
      0.17 m/s; P < 0.001) groups. Linear regression analysis for age-adjusted pulse
      wave velocity and systolic blood pressure showed that the slope was significantly
      greater in blacks than in whites (0.040 +/- 0.002 versus 0.019 +/- 0.001 m/s; P <
      0.001). CONCLUSION: These data indicate that there is a greater pressure
      dependent increase in aortic stiffness in blacks than in whites. This finding
      points towards major differences in mechanical properties of large arteries
      between these racial groups.

PMID- 10403607
TI  - Polymorphisms of the gamma subunit of the epithelial Na+ channel in essential
      hypertension.
AB  - OBJECTIVE: The gamma subunit of the epithelial Na channel (gammaENaC) has been
      implicated in Liddle's syndrome. The objective of this study was to examine its
      status in essential hypertension. DESIGN AND METHODS: The search for molecular
      variants was performed using the SSCP technique after determination of the intron
      exon boundaries of the transcribed sequence. We found an additional 205 bp intron
      splitting the published exon 10 in two. The last exon of gammaENaC was tested
      with samples from a series of 245 normotensive patients and 453 hypertensive
      subjects (383 Caucasians, 70 Afro-Caribbeans), all probands of hypertensive
      families in the HYPERGENE data set. The search was extended to the other 11
      transcribed exons in a subset of 65 patients with low-renin profile. RESULTS:
      Four neutral polymorphisms were detected, three in the third exon of the gene
      (T387C, T474C, C549T) and one in the last exon (C1990G). These four variants were
      found with similar frequencies in hypertensive and normotensive Caucasian
      subjects as well as in patients with low-renin profile. Hypertensive Caucasians
      and hypertensive subjects of African ancestry also had similar frequencies.
      Lastly, we found two rare mutations, one the insertion of a proline residue at
      position 594 of the mature protein (594insP), the other an Arg-to-His
      substitution at position 631 (R631H). Compared to wild-type (1.00 +/- 0.42, n =
      26), expression of the 594insP (1.10 +/- 0.43, n = 26) and R631H (0.97 +/- 0.43,
      n = 26) variants in Xenopus oocytes produced no significant increase in Na+
      current. CONCLUSIONS: Screening of the entire coding sequence of gammaENaC does
      not suggest that this subunit is frequently involved in essential hypertension.

PMID- 10403608
TI  - Genetic determinants of plasma ACE and renin activity in young normotensive
      twins.
AB  - OBJECTIVE: We investigated the determinants of plasma renin activity (PRA) and
      plasma levels of angiotensin-converting enzyme (pACE), including the effect of
      the D/I polymorphism of the angiotensin-converting enzyme (ACE) gene, in
      monozygotic (MZ) and dizygotic (DZ) twins. METHODS: Sixty-nine pairs of twins
      underwent measurements of blood pressure, pACE and ACE D/I genotyping. In
      addition, in 30 pairs ambulatory blood pressure (ABP) monitoring was carried out.
      To ascertain twin's zygosity, some highly discriminating variable number of
      tandem repeats micro- and mini-satellite systems were analysed by polymerase
      chain reaction (PCR) followed by polyacrylamide gel electrophoresis and silver
      staining. The D/I polymorphism was assessed by PCR; pACE was measured in
      triplicate with a colorimetric assay, and PRA by a commercial kit. In DZ twins,
      identity by descent of the D/I alleles was examined by PCR amplification of a
      highly polymorphic simple sequence repeat at the human growth hormone gene.
      RESULTS: pACE levels were significantly (P < 0.01) higher in DD (9.27 +/- 2.60
      IU/l, mean +/-SD) than in II (6.68 +/- 3.0), with DI having intermediate levels
      (7.93 +/- 2.7). No difference of PRA between different D/I genotypes was found.
      Twin data analysis showed a statistically significant heritability of pACE, but
      not of PRA. No differences between MZ and DZ twins in PRA, pACE and the
      relationship of the D/I genotype with pACE was found. Besides showing that the
      D/I genotype was the most important predictor of pACE, a multivariate analysis
      demonstrated that identity by descent of the D/I allele, as assessed by growth
      hormone (GH) genotyping, also significantly affected pACE. CONCLUSIONS: In this
      study of normotensive twins, pACE and not PRA showed significant heritability,
      the former being tightly associated with the D/I ACE gene polymorphism, and/or
      with a quantitative trait locus in linkage disequilibrium with it.

PMID- 10403609
TI  - A population study of ethnic variations in the angiotensin-converting enzyme I/D
      polymorphism: relationships with gender, hypertension and impaired glucose
      metabolism.
AB  - BACKGROUND: The presence of the deletion allele of the angiotensin-converting
      enzyme (ACE) I/D polymorphism is associated with an excess risk of vascular
      disease and diabetic nephropathy. OBJECTIVE: To examine the importance of this
      polymorphism as a determinant of hypertension and impaired glucose metabolism in
      a population-based study of three ethnic groups and assess the potential
      modifying effect of gender. DESIGN: Population-based cross-sectional study in
      South London. The population-based sample of 1577 men and women, age 40-59 years,
      was obtained from stratified random sampling of general practice lists where 25%
      of the residents were born outside the UK. The ACE I/D polymorphism was
      determined for 1366 individuals (86.6%): 462 whites, 462 of African descent and
      442 of South Asian origin. RESULTS: The genotype frequency within each ethnic
      group was in Hardy-Weinberg equilibrium. The frequencies were similar in whites
      and those of African descent (II, ID, DD: 18.4%, 49.6%, 32.0% for whites and
      18.4%, 50.5%, 30.9% for those of African descent), but there was a much higher
      frequency of the II genotype in those of South Asian origin (39.8%, 41.8%, 18.3%;
      chi2 = 77.6; P < 0.0001). There was no association between the I/D polymorphism
      and impaired glucose metabolism in any ethnic group. There were also no
      significant associations between the I/D polymorphism and hypertension in whites
      and in those of South Asian origin. This contrasts with a highly significant
      association between the D allele and hypertension in women of African descent (OR
      = 2.54; 95% CI 1.38-4.65; P = 0.003) but not in men of African descent (0.79;
      0.36-1.72) (test for differences between sexes P = 0.023). CONCLUSIONS: These
      observations provide estimates of the frequency distribution of the ACE I/D
      polymorphism in whites, in people of African descent and in people of South Asian
      origin. Moreover, these results highlight the potential importance of gender
      dependent interactions between genetic background and expression of hypertensive
      phenotype.

PMID- 10403610
TI  - Internally quenched fluorogenic substrates for angiotensin I-converting enzyme.
AB  - OBJECTIVE: Development of internally quenched fluorogenic substrates for
      sensitive and continuous assays of angiotensin I-converting enzyme (ACE). DESIGN:
      We synthesized internally quenched fluorogenic bradykinin-related peptides
      introducing Abz (ortho-aminobenzoic acid) and EDDnp (N-[2,4-dinitrophenyl]
      ethylenediamine) at their N- and C-terminal groups, respectively, and these were
      assayed as ACE substrates. We examined two series of peptides, Abz-GFSPFRX-EDDnp
      and Abz-GFSPFXQ-EDDnp (X, various amino acids). METHODS: Hydrolysis of the
      fluorogenic substrates by ACE was followed by continuous recording of the rising
      fluorescence (lambda(em) = 420 nm and lambda(ex) = 320 nm). The peptides were
      obtained by solid-phase synthesis or by classical solution methods. RESULTS:
      Despite of the blocked C-terminal sequences, the internally quenched bradykinin
      related peptides were hydrolysed by ACE. The best substrates for plasma guinea
      pig ACE were Abz-GFSPFRA-EDDnp and Abz-GFSPFFQ-EDDnp, in which the fluorescence
      appeared after the first cleavage that occurred at R-A and F-Q bond,
      respectively. This ACE activity was sensitive to NaCl concentration and the
      optimum pH is greater than 8.0. Measurements of ACE activity with Hip-His-Leu and
      Abz-GFSPFFQ-EDDnp in the serum of 20 healthy patients correlated closely (r =
      0.959). Complete inhibition of the hydrolysis of Abz-GFSPFFQ-EDDnp by human serum
      was observed with captopril and lisinopril. CONCLUSIONS: We describe internally
      quenched fluorogenic substrates for ACE devoid of free C-terminal carboxyl group.
      They are convenient tools for ACE studies as they permit continuous fluorimetric
      measurements of the enzymatic activity, even in human serum.

PMID- 10403611
TI  - Mechanisms underlying arginine vasopressin-induced relaxation in monkey isolated
      coronary arteries.
AB  - OBJECTIVE: The present study was undertaken to examine whether arginine
      vasopressin (AVP) relaxes primate coronary artery and to analyse the mechanisms
      of its action in reference to endothelial nitric oxide and AVP receptor subtype.
      METHODS: Isometrical tension responses to AVP and desmopressin were recorded in
      isolated monkey coronary arteries. RESULTS: AVP (10(-9) to 10(-7) mol/l) induced
      a concentration-related relaxation; endothelium-denudation abolished the
      response. Treatment with N(G)-nitro-L-arginine, but not the D-enantiomer,
      abolished the endothelium-dependent relaxation, which was restored by L-arginine.
      Treatment with SR49059 and [Pmp1,Tyr(Me)2]-Arg8-vasopressin, selective inhibitors
      of V1 receptor subtype, attenuated the relaxant response to AVP, whereas the
      relaxation induced by sodium nitroprusside was not affected by SR49059.
      Desmopressin, a V2 receptor agonist, up to 10(-8) mol/l did not elicit
      relaxation. CONCLUSIONS: It is concluded that AVP-induced monkey coronary
      arterial relaxation is mediated via nitric oxide synthesized from L-arginine in
      association with stimulation of V1 receptor subtypes in the endothelium.

PMID- 10403612
TI  - Influence of treated blood pressure on progression of silent cerebral infarction.
AB  - PURPOSE AND METHODS: To examine whether treatment for hypertensive patients
      prevents the progression of cerebral infarction, we performed magnetic resonance
      imaging (MRI) repeatedly at mean intervals of 22 months on 117 Japanese subjects
      aged 65-89 (mean 74 years), including 84 hypertensive patients. The patients were
      given various anti-hypertensive agents, and the blood pressure of each patient
      was monitored periodically during the observation period. Depending on the
      average blood pressure at the end of the follow-up period, hypertensive patients
      were classified into three subgroups: normotension (N), borderline (B) and
      hypertension (H). None had a prior history of symptomatic cerebral infarction and
      neurological abnormalities. The number of infarcted lesions were determined on
      brain MRI by two independent observers. RESULTS: Silent cerebral infarction (SCI)
      lesions were observed in 42 hypertensive subjects (50.0%) and in eight control
      subjects (24.2%) on enrollment. The numbers of SCI lesions increased in 33
      hypertensive subjects (39.3%) and three control subjects (9.1%) during the
      observation period. In the hypertensive subjects, an increased number of
      infarcted lesions was found in six of 28 subjects in group N (21.4%), 17 of 44 in
      group B (38.6%), and 10 of 12 in group H (83.3%). Thus, blood pressure controlled
      to the normal level appears to result in a lower incidence of progression of
      infarcted areas in patients with hypertension (N versus H, P < 0.001).
      CONCLUSION: Our data indicate that an appropriate anti-hypertensive treatment
      reduces the risk of a cerebrovascular accident in hypertensive patients.

PMID- 10403613
TI  - Myocardial diastolic impairment caused by left ventricular hypertrophy involves
      basal septum more than other walls: analysis by pulsed Doppler tissue imaging.
AB  - OBJECTIVE: To assess regional diastolic function in patients with hypertension
      with or without left ventricular hypertrophy using Doppler tissue imaging, a new
      tool that analyzes myocardial wall motion 'on-line'. METHODS: Ten normotensive
      subjects, 20 hypertensive patients without hypertrophy and 20 with hypertrophy
      (left ventricular mass index >50 g/m2.7), all men, underwent Doppler
      echocardiography and Doppler tissue imaging, which was performed in apical view
      by placing pulsed sample volume at the level of the basal and middle septum,
      basal and middle lateral wall, and infero-posterior wall. Peak velocities and
      time-velocity integrals of myocardial early (Em) and late (Am) waves and their
      ratios, regional deceleration time and regional relaxation time were measured in
      each segment. RESULTS: Transmitral peak E/A ratio was 1.37 in normotensive
      subjects, 1.01 in hypertensive patients without hypertrophy and 0.77 in those
      with hypertrophy (P < 0.00001). The myocardial diastolic indexes derived by
      Doppler tissue imaging worsened at all levels in hypertensive patients without
      hypertrophy compared with normotensive subjects. In hypertensive patients with
      hypertrophy, the majority of myocardial diastolic indexes were further impaired
      at the basal septal level, but only marginal differences were found in other
      regions, compared with indexes in hypertensive patients without hypertrophy. The
      main diastolic indexes were found, using separate intra-group analyses, to be
      more compromised at the basal septum than at other levels only in hypertrophic
      hypertensive patients. The prevalence of regions having peak Em/Am ratios < 1
      increased significantly from normotensive subjects to hypertensive patients
      without hypertrophy, but not significantly from these to the hypertrophic group.
      Among pooled hypertensive patients, after adjusting for heart rate and diastolic
      blood pressure using multivariate models, the septal wall thickness was shown to
      be an independent determinant of the diastolic indexes of the basal and middle
      septum. CONCLUSIONS: In hypertensive patients without hypertrophy, diastolic
      dysfunction is uniform along the ventricular walls, whereas in those with
      hypertrophy it is more evident at the basal septal level than in other walls.
      Overall among hypertensive patients, the diastolic properties of the
      interventricular septum worsen as the thickness of the septal wall increases, in
      the presence and in the absence of hypertrophy.

PMID- 10403614
TI  - Renal-protective effect of non-depressor dose of cicletanine in streptozotocin
      diabetic rats.
AB  - OBJECTIVE: To assess the renal benefits of cicletanine (CIC) in diabetic rats
      with renal impairment. METHODS: Hemi-nephrectomized streptozotocin-diabetic
      Wistar-Kyoto Izmo rats (WKYIzm) (10 weeks old) were randomly assigned to receive
      vehicle or a low or high dose of CIC (30 or 100 mg/kg per day, orally) for 12
      weeks. RESULTS: The blood pressure was raised slightly but not significantly in
      this model. An anti-hypertensive effect of CIC was not significantly observed.
      However, the sub-depressor doses of CIC significantly and dose-dependently
      decreased urinary albumin excretion. These results were confirmed by
      morphological analysis of kidneys in each group of rats. CIC treatment
      significantly and effectively protected against an increase in the percentage of
      focal glomerular sclerosis. CIC did not affect urinary and blood glucose
      concentrations at either dose. CONCLUSIONS: These results suggest that CIC has a
      renal-protective action, which is not related to improvement of diabetes or of
      high blood pressure in this model. The action might be due to the reduction of
      intraglomerular capillary pressure, although the mechanism remains to be further
      investigated.

PMID- 10403615
TI  - Is it possible to develop drugs that act more selectively on large arteries?
AB  - BACKGROUND: Patients with high pulse pressures have an increased risk for
      cardiovascular events. Drugs that selectively decrease high pulse pressure may be
      of interest for these patients. Such drugs have a more pronounced effect on large
      arteries than on resistance vessels. OBJECTIVE: To compare the selectivity to
      large arteries of the new nitric oxide donor sinitrodil with the classic nitrate
      isosorbide dinitrate in healthy young men in order to investigate whether it is
      possible to develop drugs that act more selectively on large arteries. DESIGN:
      The study had a double-blind, 5-way cross-over design. In randomized order,
      subjects received a single oral dose of 10 mg sinitrodil, 20 mg sinitrodil, 40 mg
      sinitrodil, isosorbide dinitrate and placebo. Measurements were performed before
      and 45 min after administration of the drugs. Between each drug administration,
      at least 3 days of wash-out was allowed. METHODS: The effects of the drugs on
      large arteries and resistance vessels were assessed by their effects on brachial
      artery compliance and total peripheral resistance, respectively. RESULTS:
      Brachial artery compliance increased gradually with increasing doses of
      sinitrodil (by 10, 20 and 27% with 10, 20 and 40 mg sinitrodil, respectively).
      Total peripheral resistance index decreased with isosorbide dinitrate (by 11%)
      and 40 mg sinitrodil (by 7%), while it remained unchanged with 10 mg and 20 mg
      sinitrodil. CONCLUSIONS: The results of this study show that it may be possible
      to develop drugs with a higher selectivity for large arteries. Such drugs may be
      good candidates to decrease high pulse pressure without substantially decreasing
      mean and diastolic blood pressures.

PMID- 10403616
TI  - Comparison of verapamil versus felodipine on heart rate variability in
      hypertensive patients.
AB  - OBJECTIVE: We evaluated the effect of two calcium channel blockers, verapamil and
      felodipine, on heart rate variability in hypertensive patients. DESIGN: Time and
      frequency domain measures of heart rate variability were obtained from 24 h
      Holter recording in 25 previously untreated hypertensive patients without left
      ventricular hypertrophy, before and after 3 months of verapamil slow-release
      treatment (240 mg once daily) or felodipine extended-release treatment (10 mg
      once daily). RESULTS: Blood pressure values decreased with both drugs. Measures
      of heart rate variability, comparable at baseline in the two groups, were
      unchanged after felodipine. After verapamil, the average RR interval, the square
      root of the mean of the squared differences between all adjacent normal RR
      intervals (r-MSSD) and the percentage of differences between all adjacent normal
      RR intervals > 50 ms (pNN50), measures of vagal modulation of heart rate,
      increased (from 735 +/- 67 to 827 +/- 84 ms, P < 0.001; from 30 +/- 10 to 44 +/-
      15 ms, P < 0.001; and from 3 +/- 2 to 7 +/- 6%, P < 0.01, respectively) and were
      higher than after felodipine. The coefficient of variation, a measure that
      compensates for heart rate effects, increased only after verapamil (from 5.8 +/-
      1.3% to 6.6 +/- 1.0%; P < 0.05). High frequency power and its coefficient of
      component variance, both representing the vagal modulation of heart rate,
      increased after verapamil (from 5.33 +/- 0.29 to 5.80 +/- 0.27 In units, P <
      0.001 and from 1.9 +/- 0.3 to 2.2 +/- 0.25%; P < 0.05). Finally, the low to high
      frequency power ratio, an indicator of sympathovagal balance, with a high value
      suggesting a sympathetic predominance, decreased after verapamil (from 2.16 +/-
      0.41 to 1.36 +/- 0.35; P < 0.001), confirming the improvement in vagal modulation
      of heart rate. CONCLUSION: In hypertensive patients, despite a comparable anti
      hypertensive effect, verapamil, but not felodipine, has favourable effect on
      cardiac autonomic control.

PMID- 10403618
TI  - Seasonal influences on ambulatory blood pressure. An insight from the HARVEST
      study. Hypertension and Ambulatory Monitoring Venetia Study.

PMID- 10403617
TI  - Sodium transport and exchange in spontaneously hypertensive rats.

PMID- 10403619
TI  - Inhibition of glutamine transport in rat brain mitochondria by some amino acids
      and tricarboxylic acid cycle intermediates.
AB  - Glutamine transport into rat brain synaptic and non-synaptic mitochondria has
      been monitored by the uptake of [3H]glutamine and by mitochondrial swelling. The
      concentration of glutamate in brain mitochondria is calculated to be high, 5-10
      mM, indicating that phosphate activated glutaminase localized inside the
      mitochondria is likely to be dormant and the glutamine taken up not hydrolyzed.
      The uptake of [3H]glutamine is largely stereospecific. It is inhibited by
      glutamate, asparagine, aspartate, 2-oxoglutarate and succinate. Glutamate
      inhibits this uptake into synaptic and non-synaptic mitochondria by 95 and 85%,
      respectively. The inhibition by glutamate, asparagine, aspartate and succinate
      can be explained by binding to an inhibitory site whereas the inhibition by 2
      oxoglutarate is counteracted by aminooxyacetic acid, which indicates that it is
      dependent on transamination. The glutamine-induced swelling, a measure of a very
      low affinity uptake, is inhibited by glutamate at a glutamine concentration of
      100 mM, but this inhibition is abolished when the glutamine concentration is
      raised to 200 mM. This suggests that the very low affinity glutamine uptake is
      competitively inhibited by glutamate. Furthermore, glutamine-induced swelling is
      inhibited by 2-oxoglutarate, succinate and malate, similarly to that of the
      [3H]glutamine uptake. The properties of the mitochondrial glutamine transport are
      not identical with those of a recently purified renal glutamine carrier.

PMID- 10403620
TI  - Three TRH-like molecules are released from rat hypothalamus in vitro.
AB  - TRH-like immunoreactivity distinct from TRH is present in various tissues and
      fluids. In order to determine whether TRH-like molecules are secreted by the
      hypothalamus, we analyzed tissues and media from hypothalamic slices incubated in
      Krebs Ringer bicarbonate. Media from basal or high KCl conditions contained 3 TRH
      like molecules evidenced by reverse phase high performance liquid chromatography
      followed by TRH radioimmunoassay. Peak I corresponded to authentic TRH (73% of
      total immunoreactivity) and peaks II and III had a higher retention time. These
      additional TRH-like forms were neither detected in hypothalamic tissue nor in
      tissue or medium from olfactory bulb. Gel filtration analysis of hypothalamic
      media revealed only one TRH-like peak eluting as TRH, suggesting that the
      molecular weights of peaks II and III are similar to that of TRH. Peak II
      retention time was similar to that of pglu-phe-proNH2. We analysed if they could
      be produced by post secretory metabolism of TRH. Incubation of hypothalamic
      slices with [3H-Pro]-TRH did not produce radioactive species comigrating with
      peaks II or III. However, it induced rapid degradation to [3H-Pro]-his
      prodiketopiperazine ([3H]-HPDKP). Inhibitor profile suggested that pyroglutamyl
      aminopeptidase II, but not pyroglutamyl aminopeptidase I, is responsible for [3H]
      HPDKP production. These data are consistent with the hypothesis that pyroglutamyl
      aminopeptidase II is the main aminopeptidase degrading TRH in hypothalamic
      extracellular fluid. Furthermore, we suggest that the hypothalamus releases
      additional TRH-like molecules, one of them possibly pglu-phe-proNH2, which may
      participate in control of adenohypophyseal secretions.

PMID- 10403621
TI  - Different changes in concentrations of monoamines and their metabolites and amino
      acids in various brain regions by the herbal medicine/Toki-Shakuyaku-San between
      female and male senescence-accelerated mice (SAMP8).
AB  - Due to it's estrogen-secreting qualities, a Japanese herbal medicine, Toki
      Shakuyaku-San may have a potential role for Alzheimer's disease in women. The
      effect of treatment with Toki-Shakuyaku-San testing on concentrations of
      monoamines, their metabolites and amino acids in the cortex, hippocampus and
      striatum of senescence accelerated mice (SAMP8) was examined and sex differences
      of SAMP8 and ddY mice was studied. In the female SAMP8, concentrations of gamma
      aminobutyric acid, alanine, and glycine were elevated in three regions after
      treatment. The concentration of glutamate was decreased in the cortex,
      hippocampus, and striatum of female and male SAMP8 and not in female and male ddY
      mice. These results suggest that different effects of Toki-Shakuyaku-San
      treatment on concentrations of monoamines, their metabolites and amino acids in
      the brain tissue may be due to its stimulation of secreted estrogen on neurons.

PMID- 10403622
TI  - Reduced palmitate turnover in brain phospholipids of pentobarbital-anesthetized
      rats.
AB  - Our laboratory has reported that pentobarbital-induced anesthesia reduced the
      incorporation of intravenously injected radiolabeled palmitic acid into brain
      phospholipids. To determine if this decrease reflected a pentobarbital-induced
      decrease in palmitate turnover in phospholipids, we applied our method and model
      to study net flux and turnover of palmitate in brain phospholipids (1). Awake,
      light and deep pentobarbital (25-70 mg/kg, iv) anesthetized rats were infused
      with [9,10-3H]palmitate over a 5 min period. Brain electrical activity was
      monitored by electroencephalography. An isoelectric electroencephalogram
      characterized deep pentobarbital anesthesia. Net incorporation rates (J(FA,i))
      and turnover rates (Fi) of palmitate were calculated. J(FA,i) for palmitate
      incorporated into phospholipids was dramatically reduced by pentobarbital
      treatment in a dose-dependent manner, by 70% and 90% respectively for lightly and
      deeply anesthetized animals, compared with awake controls. Turnover rates for
      palmitate in total phospholipid and individual phospholipid classes were
      decreased by nearly 70% and 90% for lightly and deeply anesthetized animals,
      respectively. Thus, pentobarbital decreases, in a dose-dependent manner, the
      turnover of palmitate in brain phospholipids. This suggests that palmitate
      turnover is closely coupled to brain functional activity.

PMID- 10403623
TI  - Nomega-nitro-L-arginine, a nitric oxide synthase inhibitor, antagonizes
      quinolinic acid-induced neurotoxicity and oxidative stress in rat striatal
      slices.
AB  - Nitric oxide (NO) is a potential contributor to neurotoxicity following
      overactivation of N-methyl-D-aspartate (NMDA) receptors. In this work we
      investigated the effect of Nomega-nitro-L-arginine (L-NARG 25, 50, or 100
      microM), a selective inhibitor of nitric oxide synthase (NOS) -the synthetic
      enzyme of NO- on quinolinic acid (QUIN 100 microM)-induced neurotoxicity
      (measured as lactate dehydrogenase (LDH) leakage) in rat striatal slices.
      Oxidative stress was also measured both as lipid peroxidation and as the levels
      of reduced (GSH) and oxidized (GSSG) glutathione, in an effort to elucidate a
      possible participation of NO in the toxic mechanisms involved in NMDA receptor
      mediated neuronal injury. The action of L-arginine (L-ARG 100 or 200 microM), a
      well-known NO precursor, was also tested on QUIN-induced neurotoxicity and
      oxidative stress. Results showed that QUIN produced significant changes in both
      cell damage (177%) and oxidative injury (203% in lipid peroxidation, 68% in GSH,
      and 123% in GSSG) as compared to control values. All these effects were
      antagonized by adding L-NARG to the incubation media, whereas L-ARG alone, or in
      combination with QUIN, significantly enhanced both lipid peroxidation and LDH
      leakage. Moreover, the protective effects of L-NARG on QUIN-induced lipid
      peroxidation were reversed by addition of an excess of L-ARG to the media. These
      findings indicate that NO is probably mediating the mechanism of neurotoxicity
      produced by QUIN, which may be of potential value to explain the molecular basis
      of neurodegenerative processes linked to QUIN-mediated NMDA receptor
      overactivation.

PMID- 10403624
TI  - Endogenous dopamine increases extracellular concentrations of glutamate and GABA
      in striatum of the freely moving rat: involvement of D1 and D2 dopamine
      receptors.
AB  - Interactions between endogenous dopamine, glutamate, GABA, and taurine were
      investigated in striatum of the freely moving rat by using microdialysis.
      Intrastriatal infusions of the selective dopamine uptake inhibitor nomifensine
      (NMF) were used to increase the endogenous extracellular dopamine. NMF produced a
      dose-related increase in extracellular dopamine and also increased extracellular
      concentrations of glutamate, GABA, and taurine. Extracellular increases of
      dopamine were significantly correlated with extracellular increases of glutamate
      and GABA, but not taurine. To investigate whether the increased extracellular
      dopamine produced by NMF was responsible for the concomitant increase of
      glutamate and GABA, D1, and D2 receptor antagonists were used. Dopamine receptor
      antagonists D1 (SCH23390) and D2 (sulpiride) significantly attenuated the
      increases of glutamate and GABA produced by NMF. These data suggest that
      endogenous dopamine, through both D1 and D2 dopamine receptors, plays a role in
      releasing glutamate and GABA in striatum of the freely moving rat.

PMID- 10403625
TI  - Bifemelane hydrochloride protects against cytotoxicity of hydrogen peroxide on
      cultured rat neuroblastoma cell line.
AB  - Free radicals are involved in neuronal damage. Bifemelane hydrochloride has been
      reported to protect neural tissues against ischemic damage and age-related
      neurodegeneration. We examined the protective effects of bifemelane HCl and the
      relation between its effectiveness and free radical formation in hydrogen
      peroxide (H2O2)-induced cytotoxicity using cultured rat neuroblastoma cell line
      (B50). Cytotoxicity was examined by using the lactate dehydrogenase (LDH) assay
      and cell viability by the WST-1 assay. H2O2 reduced the survival of B50 cells in
      a dose-dependent manner, and treatment of these cells with 75 microM or 100
      microM H2O2 reduced their viability by 50% relative to the control group. B50
      cells were treated with 5 or 10 microM bifemelane for 2 days followed by
      treatment with 75 microM or 100 microM H2O2. H2O2 cytotoxicity was reduced by
      pretreatment with bifemelane. We also examined the effect of bifemelane on lipid
      peroxide formation in B50 cells using thiobarbituric acid reactive substances
      assay. Pretreatment of B50 cells with 10 microM bifemelane for 2 days reduced
      lipid peroxide formation to approximately 54% of the control group. Our results
      suggest that bifemelane hydrochloride provides a protective effect against H2O2
      cytotoxicity partly due to its anti-oxidative properties.

PMID- 10403626
TI  - Nitric oxide synthetase activity in cerebral post-ischemic reperfusion and
      effects of L-N(G)-nitroarginine and 7-nitroindazole on the survival.
AB  - Nitric Oxide (NO) mediates a series of physiological processes including
      regulation of vascular tone, macrophage-mediated cytotoxicity, platelet
      aggregation, learning and long-term potentiation, neuronal transmission. Although
      NO mediates several physiological functions, overproduction of NO can be
      detrimental and play multiple roles in the pathophysiology of focal cerebral
      ischemia. In the present study NOS activities were evaluated in cerebellum and
      cerebral cortex of ischemic and post-ischemic reperfused rats using an
      experimental model of partial cerebral ischemia; moreover, the effects of L
      N(G)Nitroarginine (NA, nonselective NOS inhibitor) or 7-Nitroindazole (7-NI,
      selective neuronal NOS inhibitor) administration were assayed on percentage
      survival of ischemic rats. An increase of NOS activity in the cerebellum and in
      cerebral cortex of ischemic and post-ischemic reperfused rats was observed. NA
      administration failed to induce neuroprotective effects, by increasing percentage
      of mortality of treated ischemic rats with respect to control group. In contrast,
      the treatment with the selective neuronal NOS inhibitor, 7-NI, induced a
      significant neuroprotective effect.

PMID- 10403627
TI  - Gene structure and amino acid sequence of Latimeria chalumnae (coelacanth) myelin
      DM20: phylogenetic relation of the fish.
AB  - The structure of Latimeria chalumnae (coelacanth) proteolipid protein/DM20 gene
      excluding exon 1 was determined, and the amino acid sequence of Latimeria DM20
      corresponding to exons 2-7 was deduced. The nucleotide sequence of exon 3
      suggests that only DM20 isoform is expressed in Latimeria. The structure of
      proteolipid protein/DM20 gene is well preserved among human, dog, mouse, and
      Latimeria. Southern blot analysis indicates that Latimeria DM20 gene is a single
      copy gene. When the amino acid sequences of DM20 were compared among various
      species, Latimeria was more similar to tetrapods than other fishes including
      lungfish, confirming the previous finding by immunoreactivity (Waehneldt and
      Malotka 1989 J. Neurochem. 52:1941-1943). However, when phylogenetic trees were
      constructed from the DM20 sequences, lungfish was clearly the closest to
      tetrapods. Latimeria was situated outside of lungfish by the maximum likelihood
      method. The apparent similarity of Latimeria DM20 to tetrapod proteolipid
      protein/DM20 is explained by the slow amino acid substitution rate of Latimeria
      DM20.

PMID- 10403628
TI  - Effect of 2,6-diisopropylphenol and halogenated anesthetics on
      tetraphenylphosphonium uptake by rat brain synaptosomes: determination of
      membrane potential.
AB  - The effect of 2,6-diisopropylphenol (propofol) in comparison to that of the
      halogenated anesthetics enflurane, isoflurane, and halothane on
      tetrapenylphosphonium uptake by rat brain synaptosomes was studied. A direct
      method to separately measure the synaptosomal and the mitochondrial transmembrane
      potential by using the tetraphenylphosphonium cation (TPP+) was utilized. The
      latter is a lipophylic charged molecule which distributes between two
      compartments according to the transmembrane electrical potential in the presence
      or absence of 60 mM KCl as a synaptosomal membrane depolarizing agent. After
      previously reporting the damages induced by general anesthetics on isolated
      mitochondria, the aim of this paper was to study their possible action on the
      synaptosomal membrane potential and whether or not drugs concentrations damaging
      isolated mitochondria are also effective on synaptosomal mitochondria. The
      results indicated that, in the presence of glucose, mitochondria included in
      synaptosomes were able to maintain a transmembrane potential of 202+/-8 mV (mean
      +/- SD) while the synaptosomal membrane showed a potential of 78+/-8 mV (mean +/-
      SD). When anesthetic concentrations (0.6-1 mM propofol, 10-40 microM enflurane,
      30-50 microM isoflurane, 8-15 microM halothane) that impair mitochondrial energy
      metabolism were used, the synaptosomal transmembrane potential was maintained
      and, in addition, a slight increase of the TPP+ taken up was observed as the
      anesthetic concentration was increased.

PMID- 10403629
TI  - Factors influencing the carcinogenicity of food chemicals.
AB  - The relationship between food and cancer is extremely complex. It is generally
      accepted that diet is a contributory factor in the aetiology of a large
      proportion of cancers, but with very few exceptions, we are unable to identify
      specific causal agents. Many food components have genotoxic potential and more
      are produced endogenously during digestion. Conversely, there is increasing
      evidence that consumption of some foods may decrease the risk of cancer, and a
      number of plant constituents have been shown to have the potential to inhibit
      various stages of the carcinogenic process. Yet we have little understanding of
      the interactions between the different food-related genotoxic and protective
      factors. A further complication is the variation in individual susceptibility and
      vulnerability. As a result we are still not able to determine the optimal diet
      for minimising cancer risk. In recognition of these issues, the UK Ministry of
      Agriculture, Fisheries and Food (MAFF) is funding a number of projects aimed at
      providing greater mechanistic understanding of the links between food and cancer,
      in order to offer detailed advice to the public. This report summarises the
      proceedings of a workshop entitled 'Factors influencing the carcinogenicity of
      food chemicals', held in London on 1 June 1998, providing overviews of some of
      the key issues, and demonstrating how the MAFF-funded research is contributing to
      advances in these areas. It includes discussion of genetic polymorphisms and how
      they may contribute to individual susceptibility and help to identify causal
      links between food components and colorectal cancer. Biomarkers of DNA damage in
      human studies and of inhibition of carcinogen activation and endogenous formation
      of genotoxic reactive nitrogen species are examined. Also considered are the
      potential uses of physiologically based pharmacokinetic modelling techniques for
      providing more accurate estimates of risk and reducing the uncertainty in
      extrapolation between species and doses. Research now in progress will help to
      establish the critical risk and protective factors involved in diet-related
      colorectal cancers, in order to provide a sound scientific basis for formulation
      of dietary advice to the public.

PMID- 10403630
TI  - Doxorubicin-resistant LoVo adenocarcinoma cells display resistance to apoptosis
      induction by some but not all inhibitors of ser/thr phosphatases 1 and 2A.
AB  - LoVo adenocarcinoma cells are fairly sensitive to cytostatic drugs, e.g.
      doxorubicin, but can develop drug resistance by expression of a P-glycoprotein
      mediated MDR1 phenotype. LoVo cells respond with apoptosis to nanomolar
      concentrations of okadaic acid and micromolar concentrations of cantharidic acid.
      Interestingly, LoVoDx cells which had become about 10-fold less sensitive to
      doxorubicin by incubation in increasing concentrations of this cytostatic drug
      were also less sensitive to the toxicity of okadaic acid. Resistance to both
      agents was lost or significantly reduced by incubation in drug-free medium for
      about 4 months. On the other hand, LoVoDx cells did not lose responsiveness to
      the structurally different phosphatase inhibitor cantharidic acid but were about
      twofold more sensitive to the cytotoxic effect of this agent. Thus, MDR
      expression protects LoVo cells from the toxicity of phosphatase inhibitors that
      presumably are substrates of the P-glycoprotein, e.g. okadaic acid and its
      derivatives but not cantharidic acid, despite the fact that both agents are
      potent inducers of apoptotic cell death via ser/thr phosphatase inhibition.

PMID- 10403631
TI  - The antioxidant EPC-K1 attenuates NO-induced mitochondrial dysfunction, lipid
      peroxidation and apoptosis in cerebellar granule cells.
AB  - In this study we investigated the effects of nitric oxide (NO) on cultured
      cerebellar granule cells. Exposure to NO donors, S-nitrosoglutathione (GSNO; 250
      microM) or sodium nitroprusside (SNP; 500 microM), triggered apoptosis in
      immature cultures of cerebellar granule cells, which was characterized by
      chromatin condensation, nuclei fragmentation, and DNA laddering. Exposure of
      cerebellar granule cells to NO donors led to a decrease in the mitochondrial
      transmembrane potential and intracellular ATP content, which suggested that NO
      treatment caused mitochondrial dysfunction. NO treatment also induced oxidative
      stress in cerebellar granule cells as measured by thiobarbituric acid (TBA)
      assay. Pretreating cells with L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl
      2-(4,8,12-trimethyltridecyl)-2H -1-benzopyran-6-yl-hydrogen phosphate] potassium
      salt (EPC-K1), a novel antioxidant, attenuated NO-induced mitochondrial
      dysfunction and oxidative stress to some extent, and prevented the cells from
      apoptosis. The results of the present investigation suggest that a
      superoxide/peroxynitrite-mediated oxidative stress may be an important pathway
      leading to NO-associated neuronal damage. Pretreating cells with the antioxidant
      EPC-K1 attenuated NO-induced neurotoxicity by scavenging superoxide/peroxynitrite
      and/or its breakdown products.

PMID- 10403633
TI  - Environmental lead exposure and activity of delta-aminolevulinic acid dehydratase
      (ALA-D) in maternal and cord blood.
AB  - The hypothesis that environmental lead exposure measured from blood (Pb-B)
      inhibits delta-aminolevulinic acid dehydratase activity (ALA-D) from whole blood
      was tested in 241 urban mothers and their newborns. Geometric means and (5th and
      95th Percentiles) for maternal and cord Pb-B were 6.4 microg dl(-1) (3.4-11.9)
      and 4.6 microg dl(-1) (2.8-9.2). Spearman correlations between mother and cord Pb
      B and ALA-D were all negative but statistically significant only for cord Pb-B
      and mother ALA-D. A potential lead threshold, was identified between 3.2 and 4.8
      microg dl(-1), above which ALA-D may be inhibited by lead, and below which ALA-D
      may be insensitive or even activated. In conclusion, low environmental exposure
      to lead is responsible for a demonstrable biochemical effect. This potential ALA
      D inhibition may lead to neurotoxic effects, especially in newborns who have high
      level of neurogenesis.

PMID- 10403632
TI  - Evidence for the presence of a microsomal NADH-dependent enzyme system that can
      bioactivate aromatic amines in the liver of rats and mice.
AB  - Experimental evidence is presented for the presence in the liver of rats and mice
      of an Aroclor 1254-inducible, NADH-dependent enzyme system that can catalyse the
      bioactivation of aromatic and heterocyclic amines to genotoxic metabolites. It
      differs from the established microsomal cytochrome P450 and flavin monooxygenase
      systems in its response to treatment with cytochrome P450 inducing agents,
      optimum protein concentration and in vitro modulation by DMSO. The mutagenic
      metabolites generated by the NADH-supported system appear to be similar to those
      generated by the NADPH-mediated systems. Mutagenicity of the aminocompounds in
      the presence of either cosubstrate was less pronounced in an O-acetyltransferase
      deficient bacterial strain, implying the presence of hydroxylamines. Moreover,
      glutathione potentiated the mutagenic response of both the NADH- and NADPH
      generated metabolites. Cytochrome c suppressed markedly the NADPH-dependent
      mutagenicity of aromatic amines but had no such effect in the presence of NADH.
      Similarly, antibodies to cytochrome P450 reductase markedly inhibited the NADPH-,
      but not the NADH-dependent bioactivation of the aromatic amine 2-aminoanthracene.
      The cytochrome P450 suicide inhibitor, 1-aminobenzotriazole, decreased the
      mutagenicity of both, the NADH- and NADPH-mediated bioactivation of the
      aminocompounds. The above findings raise the possibility that a cytochrome P450
      like protein, that can receive electrons from NADH, possibly through cytochrome
      b5 reductase, is present in the hepatic microsomes of rats and mice, and is
      capable of catalysing the bioactivation of aromatic amines through N
      hydroxylation. Such a hypothesis is supported by the findings that NADH could
      support the O-dealkylation of 7-methoxy- and 7-ethoxy-resorufin, in the absence
      of NADPH. Finally the NADH-dependent bioactivation of aromatic amines was induced
      markedly by Aroclor 1254 and benzo(a)pyrene in Ah responsive, but not Ah
      nonresponsive, mice indicating that it is associated with the Ah locus.

PMID- 10403634
TI  - Binding of the potent allergen hexahydrophthalic anhydride in the mucosa of the
      upper respiratory and alimentary tract following single inhalation exposures in
      guinea pigs and rats.
AB  - Hexahydrophthalic anhydride (HHPA; CAS No. 13149-00-3) is a highly allergenic
      compound commonly used in the chemical industry. Guinea pigs and rats were
      exposed to [3H2]HHPA by inhalation for 3-8 h and were killed at various intervals
      during 7 days. The tissue distribution of non-volatile and covalently bound
      radioactivity was studied by autoradiography. Tissue bound radioactivity was
      mainly found in the mucosa of the upper respiratory airways, whereas negligible
      levels were observed in the lungs. In addition, tissue bound radioactivity was
      present in the gastrointestinal tract and conjunctiva. Moreover, in the cortex of
      the kidneys in rats, but not in guinea pigs, a low level of tissue bound
      radioactivity was found. The radioactivity in the tissues persisted for at least
      7 days after the end of exposure. Plasma proteins and soluble proteins from
      trachea, lung, and kidney from [3H2]HHPA-exposed animals were separated by gel
      filtration. The radioactivity in dialysed plasma was mainly found in the same
      fractions as albumin. The soluble proteins from trachea, lung, and kidney in both
      rats and guinea pigs showed a similar pattern as found in blood. The
      radioactivity in dialysed plasma from both guinea pigs and rats seemed to decay
      according to a two-compartment model. The non-extractable binding of [3H2]HHPA in
      the upper respiratory airways and conjunctiva may be of relevance for symptoms in
      workers with allergy, since they mainly develop symptoms and signs from the nose
      and eyes.

PMID- 10403635
TI  - Success of pyridostigmine, physostigmine, eptastigmine and phosphotriesterase
      treatments in acute sarin intoxication.
AB  - The acute toxicity of organophosphorus (OP) compounds in mammals is due to their
      irreversible inhibition of acetylcholinesterase (AChE) in the nervous system,
      which leads to increased synaptic acetylcholine levels. The protective actions of
      intravenously (i.v.) administered pyridostigmine, physostigmine, eptastigmine,
      and an organophosphate hydrolase, phosphotriesterase, in acute sarin intoxication
      were studied in mice. The acute intragastric (i.g.) toxicity (LD50) of sarin with
      and without the pretreatments was tested by the up-and-down method. The mice
      received pyridostigmine (0.06 mg/kg body weight), physostigmine (0.09 mg/kg body
      weight), the physostigmine derivative eptastigmine (0.90 mg/kg body weight) or
      phosphotriesterase (104 U/g, 10.7 microg/g body weight) 10 min prior to the i.g.
      administration of sarin. Physostigmine was also administered with
      phosphotriesterase. Phosphotriesterase was the most effective antidote in sarin
      intoxication. The LD50 value for sarin increased 3.4-fold in mice receiving
      phosphotriesterase. Physostigmine was the most effective carbamate in sarin
      exposure. The protective ratios of physostigmine and pyridostigmine were 1.5- and
      1.2-1.3-fold, respectively. Eptastigmine did not give any protection against
      sarin toxicity. Both the phosphotriesterase and physostigmine treatments
      protected the brain AChE activities measured 24 h after sarin exposure. In
      phosphotriesterase and physostigmine-treated mice, a 4- and 2-fold higher sarin
      dose, respectively, was needed to cause a 50% inhibition of brain AChE activity.
      Moreover, the combination of phosphotriesterase-physostigmine increased the LD50
      value for sarin 4.3-fold. The animals pretreated with phosphotriesterase
      ephysostigmine tolerated four times the lethal dose in control animals,
      furthermore their survival time was 2-3 h in comparison to 20 min in controls. In
      conclusion, phosphotriesterase and physostigmine were the most effective
      treatments against sarin intoxication. However, eptastigmine did not provide any
      protection against sarin toxicity.

PMID- 10403636
TI  - Dose-response hapatotoxicity of the peroxisome proliferator, perfluorodecanoic
      acid and the relationship to phospholipid metabolism in rats.
AB  - Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator that causes
      hepatotoxicity but lacks tumor-promoting activity in rats. We previously showed
      that a single dose of PFDA at 50 mg/kg (approximately LD50) causes an elevation
      in liver phosphocholine (PCho) and other effects related to phospholipid
      metabolism. In this study, we examined metabolic effects in the dose range 2-50
      mg/kg in rats. At doses < or =20 mg/kg, PFDA is significantly less hepatotoxic
      than the LD50 as manifested by electron microscopy and measurements of daily food
      consumption and body weight. At 50 mg/kg rat serum tumor necrosis factor (TNF)
      alpha concentration was increased 8-fold, while at 15 mg/kg there was no apparent
      increase in this cytokine. This lower dose, however, induces metabolic effects
      similar to those seen at the LD50. Liver fatty acyl-CoA oxidase activity showed a
      dose-dependent increase from 5-25 mg/kg PFDA. Treatments at 15 and 50 mg/kg
      caused a significant increase in liver phosphatidylcholine (28 and 66%) and
      phosphatidylethanolamine (31 and 74%). Both doses caused a significant increase
      in liver PCho but did not affect liver ATP levels, as manifested in 31P nuclear
      magnetic resonance (NMR) spectra from rat livers in vivo. These data suggest that
      the increase in liver [PCho] observed following PFDA exposure in rats represents
      a specific metabolic response, rather than a broad-range hepatotoxic effect.

PMID- 10403637
TI  - Cytokines, growth factors, and oxidative stress in HepG2 cells treated with
      ethanol, acetaldehyde, and LPS.
AB  - Inflammatory mediators, including cytokines, growth factors, and reactive oxygen
      species, are associated with the pathology of chronic liver disease. In the
      liver, cytokine and growth factor secretion are usually associated with
      nonparenchymal cells, particularly Kupffer cells. In the present studies, the
      effect of 24 and 72 h administration of ethanol (50 mM). acetaldehyde (175
      microM), and LPS (1 microg/ml) were studied on the expression and secretion of
      TNF-alpha, IL-1beta, IL-6, and TGF-beta3, lipid peroxidation damage and
      glutathion content in HepG2 cell cultures. A 24 h exposure to ethanol induced the
      expression of TNF-alpha and TGF-beta1, and the secretion of IL-1beta and TGF
      beta1. With the same period of treatment, acetaldehyde markedly increased TNF
      alpha expression, and stimulated IL-1beta secretion, while LPS exposure induced
      the expression of TNF-alpha, IL-6, and TGF-beta1, and the secretion of IL-1beta,
      IL-6, and TGF-beta1. A reduced in TNF-alpha response and TGF-beta1 expression
      were observed after 72 h exposure to ethanol. A 72 h acetaldehyde exposure
      decreased markedly TNF-alpha expression and stimulated a previously absent TGF
      beta1 response. With the same time of exposure, LPS reduced slightly TGF-beta1
      expression, and decreased its secretion. IL-1beta and IL-6 were not detected
      under 72 h exposure conditions. Lipid peroxidation damage was increased in all
      treatments, but higher values were found in 72 h treatments. Glutathion content
      diminished in all treatments. These findings suggest that HepG2 cells,
      independent of other cells such as Kupffer or macrophages, participate in a
      differential cytokine, growth factor and oxidative stress response, which differs
      according to the toxic agent and the time of exposure.

PMID- 10403638
TI  - The role of caspases in development, immunity, and apoptotic signal transduction:
      lessons from knockout mice.

PMID- 10403639
TI  - The M cell as a portal of entry to the lung for the bacterial pathogen
      Mycobacterium tuberculosis.
AB  - M. tuberculosis accesses the terminal lung and is phagocytosed by alveolar
      macrophages. Utilizing a mouse intratracheal challenge model, we demonstrate that
      M. tuberculosis rapidly enters through M cells as well. From there, bacilli are
      deposited within associated intraepithelial leukocytes and subsequently conveyed
      to the draining lymph nodes early after infection. Osteopetrotic
      (Csfm(op)/Csfm(op)) mice, null mutants for macrophage colony-stimulating factor,
      possess diminished numbers of circulating monocytes and tissue macrophages.
      Csfm(op)/Csfm(op) mice were highly susceptible to challenge with M. tuberculosis.
      In contrast to controls, tubercle bacilli were not conveyed to draining lymph
      nodes early after infection but were instead retained within the mucosa. These
      results indicate that M cells represent an alternate portal of entry for M.
      tuberculosis, which may contribute to the rapid development of protective lung
      immune responses.

PMID- 10403640
TI  - Interleukin 10-mediated immunosuppression by a variant CD4 T cell epitope of
      Plasmodium falciparum.
AB  - The immunodominant CD4 T cell epitope region, Th2R, of the circumsporozoite
      protein of Plasmodium falciparum is highly polymorphic. Such variation might be
      utilized by the parasite to escape from or interfere with CD4 T cell effector
      functions. Here, we show that costimulation with naturally occurring altered
      peptide ligands (APL) can induce a rapid change from IFNgamma production to the
      immunosuppressive mediator interleukin 10 (IL-10). This mechanism may contribute
      to the low levels of T cell responses observed to this pathogen in malaria
      endemic areas.

PMID- 10403641
TI  - The selective downregulation of class I major histocompatibility complex proteins
      by HIV-1 protects HIV-infected cells from NK cells.
AB  - To avoid detection by CTL, HIV encodes mechanisms for removal of class I MHC
      proteins from the surface of infected cells. However, class I downregulation
      potentially exposes the virus-infected cell to attack by NK cells. Human lymphoid
      cells are protected from NK cell cytotoxicity primarily by HLA-C and HLA-E. We
      present evidence that HIV-1 selectively downregulates HLA-A and HLA-B but does
      not significantly affect HLA-C or HLA-E. We then identify the residues in HLA-C
      and HLA-E that protect them from HIV down-regulation. This selective
      downregulation allows HIV-infected cells to avoid NK cell-mediated lysis and may
      represent for HIV a balance between escape from CTL and maintenance of protection
      from NK cells. These results suggest that subpopulations of CTL and NK cells may
      be uniquely suited for combating HIV.

PMID- 10403642
TI  - The telomerase catalytic subunit is a widely expressed tumor-associated antigen
      recognized by cytotoxic T lymphocytes.
AB  - The discovery of tumor-associated antigens (TAA) in certain human malignancies
      has prompted renewed efforts to develop antigen-specific immunotherapy of cancer.
      However, most TAA described thus far are expressed in one or a few tumor types,
      and, among patients with these types of tumors, TAA expression is not universal.
      Here, we characterize the telomerase catalytic subunit (hTERT) as a widely
      expressed TAA capable of triggering antitumor cytotoxic T lymphocyte (CTL)
      responses. More than 85% of human cancers exhibit strong telomerase activity, but
      normal adult tissues, with few exceptions, do not. In a human system, CD8+ CTL
      specific for an hTERT peptide and restricted to MHC HLA-A2 lysed hTERT+ tumors
      from multiple histologies. These findings identify hTERT as a potentially
      important and widely applicable target for anticancer immunotherapeutic
      strategies.

PMID- 10403643
TI  - Presentation of out-of-frame peptide/MHC class I complexes by a novel translation
      initiation mechanism.
AB  - Immune surveillance by CD8 T cells requires that peptides derived from
      intracellular proteins be presented by MHC class I molecules on the target cell
      surface. Interestingly, MHC molecules can also present peptides encoded in
      alternate translational reading frames, some even without conventional AUG
      initiation codons. Using T cells to measure expression of MHC bound peptides, we
      identified the non-AUG translation initiation codons and established that their
      activity was at the level of translational rather than DNA replication or
      transcription mechanisms. This translation mechanism decoded the CUG initiation
      codon not as the canonical methionine but as the leucine residue, and its
      activity was independent of upstream translation initiation events. Naturally
      processed peptide/MHC complexes can thus arise from "noncoding" mRNAs via a novel
      translation initiation mechanism.

PMID- 10403644
TI  - The molecular characterization of the fetal stem cell marker AA4.
AB  - We have identified and characterized the stem cell antigen AA4. This molecule is
      a type I transmembrane protein whose overall structure suggests a role in cell
      adhesion. During fetal ontogeny (days 9-14 of development), AA4 is expressed in
      three major cell types: vascular endothelial cells, aorta-associated
      hematopoietic clusters, and primitive fetal liver hematopoietic progenitors. In
      the adult, AA4 is abundant in lung, heart, and whole bone marrow. In the adult
      hematopoietic compartment, aa4 transcripts are present in bone marrow CD34(-/lo)
      Lin- Sca-1+ c-Kit+ and CD34hi Lin- Sca-1+ c-Kit+ stem and progenitor cell
      subsets. Our observations suggest that AA4 plays a role in cell-cell interactions
      during hematopoietic and vascular development.

PMID- 10403645
TI  - Biochemical association of CD45 with the T cell receptor complex: regulation by
      CD45 isoform and during T cell activation.
AB  - CD45 is the predominant transmembrane tyrosine phosphatase in lymphocytes and is
      required for the efficient induction of T cell receptor signaling and activation.
      However, the regulation of CD45 activity and substrate specificity are poorly
      understood. In the present study, we demonstrate a basal biochemical association
      of CD45 with the T cell receptor complex that is regulated in part by CD45
      isoform expression. Further, maintenance of CD45/TCR association is
      differentially regulated following TCR ligation with peptide: a partial agonist
      peptide induces CD45/TCR dissociation while an agonist peptide promotes sustained
      association in a CD4-dependent manner. These data suggest that T cell receptor
      signaling pathways may be modulated by altering access of CD45 to TCR-associated
      substrates involved in T cell activation.

PMID- 10403646
TI  - Distinct signals mediate maturation and allelic exclusion in lymphocyte
      progenitors.
AB  - Successful in-frame rearrangement of immunoglobulin heavy chain genes or T cell
      antigen receptor (TCR) beta chain genes in lymphocyte progenitors results in
      formation of pre-BCR and pre-TCR complexes. These complexes signal progenitor
      cells to mature, expand in cell number, and suppress further rearrangements at
      the immunoglobulin heavy chain or TCRbeta chain loci, thereby ensuring allelic
      exclusion. We used transgenic expression of a constitutively active form of c-Raf
      1 (Raf-CAAX) to demonstrate that activation of the Map kinase pathway can
      stimulate both maturation and expansion of B and T lymphocytes, even in the
      absence of pre-TCR or pre-BCR formation. However, the same Raf signal did not
      mediate allelic exclusion. We conclude that maturation of lymphocyte progenitors
      and allelic exclusion require distinct signals.

PMID- 10403647
TI  - A developmental switch from TCR delta enhancer to TCR alpha enhancer function
      during thymocyte maturation.
AB  - V(D)J recombination and transcription within the TCR alpha/delta locus are
      regulated by three characterized cis-acting elements: the TCR delta enhancer
      (Edelta), TCR alpha enhancer (Ealpha), and T early alpha (TEA) promoter. Analysis
      of enhancer and promoter occupancy and function in developing thymocytes in vivo
      indicates Edelta and Ealpha to be developmental-stage-specific enhancers, with
      Edelta "on" and Ealpha "off" in double-negative III thymocytes and Edelta "off"
      and Ealpha "on" in double-positive thymocytes. Edelta downregulation reflects a
      loss of occupancy. Surprisingly, Ealpha and TEA are extensively occupied even
      prior to activation. TCR delta downregulation in double-positive thymocytes
      depends on two events, Edelta inactivation and removal of TCR delta from the
      influence of Ealpha by chromosomal excision.

PMID- 10403648
TI  - Reactive oxygen species regulate activation-induced T cell apoptosis.
AB  - Reactive oxygen species (ROS) mediate apoptosis in a number of cell types. We
      studied the role that ROS play in activated T cell apoptosis by activating T
      cells in vivo and then culturing them for a short time. Activated T cells died
      independently of Fas and TNF alpha. Their death was characterized by rapid loss
      of mitochondrial transmembrane potential (delta psi(m)), caspase-dependent DNA
      fragmentation, and superoxide generation. A superoxide dismutase mimetic, Mn
      (III) tetrakis (5, 10, 15, 20-benzoic acid) porphyrin (MnTBAP), protected T cells
      from superoxide generation, caspase-dependent DNA loss, loss of delta psi(m), and
      cell death. These results indicate that ROS can regulate signals involved in
      caspase activation and apoptosis and may contribute to peripheral T cell
      deletion.

PMID- 10403649
TI  - The transcription factor c-Maf controls the production of interleukin-4 but not
      other Th2 cytokines.
AB  - IL-4 promotes the differentiation of naive CD4+ T cells into IL-4-producing T
      helper 2 (Th2) cells. Previous work provided suggestive but not conclusive
      evidence that the transcription factor c-Maf directed the tissue-specific
      expression of IL-4. It was not known whether c-Maf controlled the transcription
      of other Th2 cytokine genes. To elucidate the role of c-Maf in vivo, we examined
      cytokine production in mice lacking c-Maf (c-maf(-/-)). CD4+ T cells and NK T
      cells from c-maf(-/-) mice were markedly deficient in IL-4 production. However,
      the mice produced normal levels of IL-13 and IgE, and, when differentiated in the
      presence of exogenous IL-4, c-maf(-/-) T cells produced approximately normal
      levels of other Th2 cytokines. We conclude that c-Maf has a critical and
      selective function in IL-4 gene transcription in vivo.

PMID- 10403650
TI  - SHIP recruitment attenuates Fc gamma RIIB-induced B cell apoptosis.
AB  - Fc gammaRIIB is an inhibitory receptor that terminates activation signals
      initiated by antigen cross-linking of the BCR through the recruitment of SHIP. Fc
      gammaRIIB can also signal independently of BCR coligation to directly mediate an
      apoptotic response, requiring only an intact transmembrane domain. Failure to
      recruit SHIP, either by deletion of SHIP or mutation of Fc gammaRIIB, results in
      enhanced Fc gammaRIIB-triggered apoptosis. Thus, in the germinal center, where
      ICs are retained by FDCs, Fc gammaRIIB may be an active determinant in the
      negative selection of B cells whose BCRs have reduced affinity for antigen as a
      result of somatic hypermutation. Selection of B cells may represent the sum of
      opposing signals generated by the interaction of ICs with the BCR and Fc
      gammaRIIB through pathways modulated by SHIP.

PMID- 10403651
TI  - One of two unstructured domains of Ii becomes ordered in complexes with MHC class
      II molecules.
AB  - We studied the role of the invariant chain (Ii) protein's structure in its
      ability to form complexes with major histocompatibility complex class II
      molecules. Multidimensional nuclear magnetic resonance experiments demonstrated
      that Ii contains two unstructured, flexible domains: a 39 residue sequence that
      contains a region (CLIP) critical for Ii/class II complex formation and becomes
      rapidly ordered when Ii/class II complexes are assembled, and a 30 residue
      sequence that contains the insertion point for a protease inhibitor domain
      included in an alternative splice form of Ii. Mobility of these domains
      guarantees accessibility to CLIP and the inhibitor insert, and ordering of the
      CLIP-containing domain may provide protection against proteolysis and contribute,
      along with Ii's compact 118-192 domain, to allotype-independent class II binding.

PMID- 10403652
TI  - Mandates to develop non-mammalian models for chemical immunotoxicity evaluation:
      are fish a viable alternate to rodents?

PMID- 10403653
TI  - Intracellular oxidation/reduction status in the regulation of transcription
      factors NF-kappaB and AP-1.
AB  - The eukaryotic cell contains a multitude of pathways coupling environmental
      stimuli to the specific regulation of gene expression. Two early response
      transcriptional complexes, NF-kappaB and AP-1, appear to respond to environmental
      stressors by inducing the expression of response specific downstream genes. Both
      are well-characterized transcriptional regulatory factors that are induced by a
      wide variety of seemingly unrelated exogenous and endogenous agents and serve
      important roles in cell growth and differentiation, immunity, inflammation, and
      other preprogrammed cellular genetic processes. The activities of NF-kappaB and
      AP-1 are also affected following exposure to chemicals, drugs, or other agents
      that appear to alter the cellular oxidation/reduction (redox) status. From these
      observations, it has been suggested that changes in cellular oxidation/reduction
      status, communicated via a series of cellular redox-sensitive signaling circuitry
      employing metal- and thiol-containing proteins, serve as common mechanisms
      linking environmental stressors to adaptive cellular responses. As such, these
      transcription factors are ideal paradigms to study the mechanism and possible
      physiological significance of early response genes in the cellular response to
      changes in cellular redox status. In this article we summarize the evidence
      suggesting that cellular redox regulates these transcription factors.

PMID- 10403655
TI  - Glutathione reduces the toxicity associated with antitumor therapy of ascites
      fluid adsorbed over Staphylococcus aureus Cowan I in tumor bearing mice.
AB  - It has been well documented in the literature that the removal of circulatory
      immune complexes (CICs) from the host circulation leads to the immunopotentiation
      as well as generation of antitumor responses in a variety of tumors in rats,
      cats, dogs and human patients. CICs are the major immunosuppressive factors in
      tumor bearing host. Protein A (PA) has been extensively used for the removal of
      these CICs from the sera/plasma of tumor bearers, because PA has the ability to
      bind with the Fc portion of mammalian immunoglobulins. Previously, we reported
      for the first time a potent antitumor response by the inoculation of cell free
      Ehrlich's ascites fluid adsorbed in vitro over PA containing Staphylococcus
      aureus Cowan I (SAC) in Ehrlich's ascites tumor model. However, there was
      toxicity associated with this form of therapy in terms of early death of treated
      animals and the depletion of hepatic glutathione pool as well as phase I
      biotransformation enzyme and increase in glutathione-S-transferase (GST)
      activities. In the present investigation, tumor bearing animals were treated
      intraperitoneally (i.p.) on alternate days for 15 days with adsorbed ascites
      fluid (ad-ASF) (0.1 ml) and glutathione (GSH) (250 mg/kg body weight) separately.
      We found that GSH supplementation increases mean survival time of GSH and ad-ASF
      treated mice up to 37.2 days in comparison with 19.9 days for only ad-ASF treated
      animals, while percent increase in body weight was found to be not affected by
      the GSH substitution, which remains significantly lower (P < 0.01) in comparison
      to the tumor control animals. GSH supplementation causes a significant decrease
      (P < 0.05) of glutathione-S-transferase and restoration of aniline hydroxylase
      activity (P < 0.05) and aminopyrine-N-demethylase activity. We have also observed
      that GSH supplementation does not alter the tumor cell viability and tumor cell
      counts in ad-ASF treated animals in comparison to only ad-ASF treated animals,
      which indicates that GSH supplementation does not alter the antitumor effect of
      the therapy. Treatment of Ehrlich's ascites tumor bearing mice with ad-ASF and
      glutathione increased their survival, but did not reduce the mortality of animals
      because of tumor.

PMID- 10403654
TI  - Mechanisms for xenobiotic transport in biological membranes.

PMID- 10403656
TI  - Effects of hexachlorobenzene on phospholipid and porphyrin metabolism in
      Harderian glands: a time-course study in two strains of rats.
AB  - Hexachlorobenzene, one of the most persistent environmental pollutants, induces
      uroporphyria and phospholipid alterations in rat liver. Harderian glands produce
      a secretion that is rich in lipids and accumulate large amounts of
      protoporphyrin. The aim of the present study was to determine if
      hexachlorobenzene administration to rats affects phospholipid and porphyrin
      metabolisms in Harderian glands and if these effects are strain dependent. For
      this purpose, a time-course study (2, 3 and 4 weeks of hexachlorobenzene
      treatment) of phospholipid pattern and porphyrin content was performed
      comparatively in two strains of rats (Wistar and Chbb THOM) which differ in their
      susceptibility to develop HCB-induced porphyria. Hexachlorobenzene produced
      decreases in several phospholipid contents, but no changes in phosphatidylcholine
      levels. While the sphingomyelin/phosphatidylcholine molar ratio remained
      essentially constant until the third week in Chbb THOM rats, it showed a constant
      drop in Wistar rats, suggesting a more pronounced alteration of membrane fluidity
      in the later strain. In regard to porphyrin metabolism, Wistar rats showed an
      increase in the porphyrin content of the gland, while Chbb THOM animals showed a
      decrease. The study revealed that not only are the normal parameters of
      phospholipid and porphyrin metabolism in rat Harderian glands strain dependent,
      but the response to hexachlorobenzene is also.

PMID- 10403657
TI  - Prevention of chromosomal aberration in mouse bone marrow by indole-3-carbinol.
AB  - In this study, we report the protective effect of indole-3-carbinol (I3C), one of
      the glucobrassicin derivative isolated from cruciferous vegetables against
      cyclophosphamide induced chromosomal aberrations in mouse bone marrow cells. The
      three test doses namely 1000,500 and 250 mg/kg b.wt. of I3C provided protection
      when given 48 h prior to the single i.p. administration of cyclophosphamide (50
      mg/kg). I3C alone did not induce chromosomal aberrations at the test doses of
      1000 and 500 mg/kg b.wt.. Thus tested glucobrassicin derivative seems to have a
      preventive potential against cyclophosphamide induced chromosomal aberrations in
      Swiss mouse bone marrow cells at the doses tested.

PMID- 10403658
TI  - The UDP-glucuronyltransferase inducers, phenobarbital and pregnenolone-16alpha
      carbonitrile, enhance thyroid-follicular cell apoptosis: association with TGF
      beta1 expression.
AB  - Exposure to certain UDP-glucuronosyltransferase (UDP-GT) inducers leads to
      follicular cell hyperplasia, and ultimately thyroid gland tumors. These compounds
      decrease thyroid hormones, which increases serum concentrations of thyroid
      stimulating hormone (TSH). This induction of TSH enhances thyroid-follicular cell
      proliferation. In addition, treatment with classical goitrogenic compounds, such
      as propylthiouracil (PTU) and methimazole (MMI), induces TGF-beta1 in thyroid
      follicular cells, presumably through increased TSH. In other tissues, increases
      in TGF-beta1 induce apoptosis, a particular form of programmed cell death. In
      this experiment, we sought to determine whether the UDP-GT inducers,
      phenobarbital (PB) and pregnenolone-16alpha-carbonitrile (PCN) modulate thyroid
      follicular cell apoptosis. If so, are the induction of apoptosis and TGF-beta1
      possibly linked? An additional group of rats treated with the thyroid goitrogen,
      PTU was included. Male Sprague-Dawley rats were treated with thyroid hormone
      disrupting doses of PB, PCN, or PTU for 3, 7, 14, 21, 28, 45, or 90 days. In this
      study, PTU treatment increased apoptosis and TGF-beta1 immunoreactive thyroid
      follicular cells. PTU treatment of rats produced both a large increase number of
      TGF-beta1-positive cells (detected by immunohistochemistry), and apoptotic
      thyroid-follicular cells (detected by morphology). In PB- and PCN-treated rats, a
      moderate increase in apoptosis coincided with similar increases in TGF-beta1
      immunoreactive thyroid-follicular cells. In summary, PB and PCN increase
      apoptosis and the percentage of TGF-beta1 positive thyroid-follicular cells.
      Thus, treatment with UDP-GT-inducing chemicals may increase the expression of TGF
      beta1 and apoptosis in the thyroid to compensate for the thyroid hypertrophy and
      hyperplasia.

PMID- 10403659
TI  - Glutathione depletion and oxidative damage in mitochondria following exposure to
      cadmium in rat liver and kidney.
AB  - The dose-dependent effects of cadmium (Cd) on mitochondria and post-mitochondrial
      supernatant (PMS) of liver and kidney were investigated in adult male albino
      rats. Two groups of rats were injected intraperitoneally with 0.1 mg Cd/kg body
      weight and 1 mg/kg body weight, respectively, for a period of 3 months (5
      days/week). This resulted in a significant decrease in total glutathione (GSH)
      levels, irrespective of the doses, in mitochondrial as well as in PMS fractions
      of liver and kidney. In contrast, end products of lipid and protein were
      significantly increased in a dose-dependent manner in subcellular fractions of
      liver and kidney. These results suggest that the depletion of tissue glutathione
      levels is not a primary reason of the observed oxidative damage in liver and
      kidney caused by Cd.

PMID- 10403660
TI  - Hepatic cytochrome P450 and flavin-containing monooxygenase in male Nts:Mini rat,
      a transgenic rat carrying antisense RNA transgene for rat growth hormone.
AB  - We investigated the characteristics of hepatic cytochrome P450s and flavin
      containing monooxygenase 1 (FMO1) in male Nts:Mini rats, a Wistar/Jcl-derived
      transgenic rat strain showing less plasma GH concentration than the parental
      strain. The total hepatic P450 contents of Mini rats were significantly reduced.
      A suppression was observed in the activities and protein expression of male
      specific P450s (CYP3A and CYP2C11) and was speculated to be a potential cause of
      the reduction in total P450 contents. The activity and protein expression of
      CYP2B1 were suppressed and those of CYP2E1 and CYP2B2 were enhanced. With the
      exception of our data on CYP2B1, these results largely agreed with previous
      reports concerning GH-depletion rat models (hypophysectomized rats, rats
      neonatally treated with glutamate, and dwarf rats), implying that the changes in
      Mini rats were caused by GH insufficiency. The liver FMO1 protein expression in
      Mini rats was higher than that in Wistar rats but the activity was comparable,
      suggesting that GH is not a positive regulator of FMO expression. With their
      insufficient but not depleted levels of plasma GH, Mini rats may thus become
      another candidate for use in the investigation of GH regulation of hepatic mixed
      function monooxygenases.

PMID- 10403661
TI  - Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers:
      choice of an experimental model capable of testing the hepatotoxicity of low
      molecular weight compounds.
AB  - The aim of this work on rat hepatic P450 2E1 activity was to seek the most
      suitable experimental model to study the role of cytochrome P450 2E1 in the
      metabolism of industrial chemicals. Two sets of experiments were devoted to
      selecting the age and sex of animals and to estimating the response of male and
      female rats to different inducers. In the first set, the effect of three inducers
      (fasting; ethanol; acetone) was studied in male rats aged 5, 7 and 9 weeks. In
      the second set, the effect of different inducers, namely beta-naphthoflavone
      (BNF), phenobarbital (PB), ethanol, acetone and pyridine, on PNP and
      chlorzoxazone (CLZO) hydroxylase activities was studied in 7 week old male and
      female rats. The results demonstrate firstly that microsomal p-nitrophenol (PNP)
      hydroxylase activity significantly decreases in control male rats in inverse
      function of age, and secondly that induction by ethanol decreases with age. The
      PNP hydroxylase activity level of controls and the significant increases in PNP
      hydroxylase activity observed in 7 week old male rats show that this is the most
      suitable age for the second set of experiments. In this second set, it was shown
      that P450 1A (induced by BNF) is involved in CLZO hydroxylase activity only. PB
      increased the hydroxylase activities in male and female rats by about 1.5 and 1.7
      times those of the controls, respectively. The effects of P450 2E1 inducers in
      function of sex show that male rats exhibited more significant increases in PNP
      and CLZO hydroxylase activities than female. The specificity of these two
      substrates is discussed. Neither of these two reactions was specifically
      catalysed by P450 2E1, but PNP may be considered as the most specific and the
      least sensitive substrate. In addition, the linear relationship observed between
      the two substrates (PNP and CLZO) showed a good correlation between their
      activities (r = 0.90, P < 0.001). In conclusion, these results suggest the use of
      the 7 week old male rat as the experimental model to study the role of cytochrome
      P450 2E1 in the hepatotoxicity of low molecular weight industrial chemicals.

PMID- 10403662
TI  - Absence of neurovisual effects due to tissue and blood cholinesterase depression
      in a chronic disulfoton feeding study in dogs.
AB  - Technical grade disulfoton (DiSyston) was fed to Beagle dogs (four animals per
      sex and treatment level) at nominal concentrations of 0, 0.5, 4 and 12 ppm for 1
      year. The purpose of this study was to characterize the potential general and
      neurovisual toxicity according to routine Environmental Protection Agency (EPA)
      guideline requirements, and by use of ancillary ocular and neurologic tests
      established in this Laboratory. Ophthalmological tests included: ocular tissue
      cholinesterase and histopathology, electroretinography (ERG), tracking,
      refractivity, intraocular pressure and pachymetry (corneal thickness)
      measurements. Neurological examinations included; peripheral and cranial reflex
      tests, task performance tests, gait and behavioral observations, and rectal
      temperature measurements. Plasma, erythrocyte and corneal cholinesterase were
      significantly depressed at 4 and 12 ppm in both sexes. Brain cholinesterase was
      depressed at 4 and 12 ppm in females. Retinal cholinesterase was depressed at 4
      ppm in females and at 12 ppm in males. Ciliary body cholinesterase was depressed
      at 12 ppm in both sexes. Despite these cholinergic effects, there were no
      ophthalmologic findings in measurements of ERG, tracking, refractivity,
      intraocular pressure or pachymetry. There were no clinical neurology findings
      related to compound administration. We conclude that 0.5 ppm was a no-observable
      effect level (NOEL), and effects were limited to cholinesterase changes that had
      no detectable physiologic impact. This study demonstrates that special
      mechanistic investigations incorporated within guideline studies, enhances
      scientific integrity and can minimize the need for dedicated organ system
      studies.

PMID- 10403663
TI  - Peroxidase-catalyzed in vitro formation of polychlorinated dibenzo-p-dioxins and
      dibenzofurans from chlorophenols.
AB  - Chlorophenols (CP) are transformed in vitro to polychlorinated dibenzo-p-dioxins
      and dibenzofurans (PCDD/F) by a peroxidase-catalyzed oxidation. This is shown for
      2,4,5-tri-, 2,3,4,6-tetra- and pentachlorophenol with plant horseradish
      peroxidase and with myeloperoxidase recovered from human leukocytes, each in the
      presence of hydrogen peroxide. The yield, the reaction and the PCDD/F-pattern
      found are dependent on the CP. The amounts of PCDD/F formed within 4 or 24 h are
      in the micromol/mol-range for all substrates and both peroxidases. The
      experiments suggest that biochemical formation of PCDD/F from precursors such as
      CPs can take place in the human body and that this metabolic pathway may lead to
      a higher inner exposure to PCDD/F than up to now assumed based on intake data for
      PCDD/F.

PMID- 10403664
TI  - Methyl methanesulfonate and hydrogen peroxide differentially regulate p53
      accumulation in hepatoblastoma cells.
AB  - Genotoxic chemicals not only damage cellular DNA, but may also induce cell
      apoptosis if they are lethal to the cell. p53, Bcl-2 and Bax play important roles
      in the regulation of genotoxic chemical induced cell apoptosis. Since the
      mechanisms by which cellular DNA damaged by different DNA-damaging chemicals may
      not be the same, we studied the involvement of p53, Bcl-2 and Bax in apoptosis
      induced by methyl methanesulfonate (MMS) and hydrogen peroxide (H2O2). H2O2
      damages DNA by free radical generation and MMS damages DNA by DNA methylation. At
      non-lethal doses, both H2O2 and MMS induced high level of p53 protein
      accumulation. Nevertheless, while the amount of p53 protein increased with the
      dose of MMS and the occurrence of apoptotic cell death events, H2O2 doses that
      induce cell apoptosis attenuated the p53 protein accumulation level. Lethal MMS
      treatment also increased Bax, but not Bcl-2 expression, whereas in H2O2 induced
      apoptosis, the level of both Bcl-2 and Bax declined. These results indicate that
      toxic chemicals differentially regulate the accumulation of p53 protein. Thus,
      the pathways of toxic chemicals induced cell apoptosis are different and
      independent.

PMID- 10403665
TI  - Protein oxidation in thyroid hormone-induced liver oxidative stress: relation to
      lipid peroxidation.
AB  - The influence of thyroid hormone administration (daily doses of 0.1 mg of 3,3',5
      triiodothyranine (T3)/kg for 1-3 consecutive days) on rat liver protein oxidation
      was investigated in relation to the calorigenic and lipid peroxidative actions of
      the hormone. T3 treatment elicited a progressive enhancement in the serum levels
      of the hormone, the rectal temperature of the animals, and in the rate of O2
      uptake of the liver, changes that are significantly correlated and evidence the
      development of thyroid calorigenesis. Liver lipid peroxidation was augmented by
      T3 administration as determined by the tissue content of thiobarbituric acid
      reactants, with a maximal effect (3.1-fold increase) being found at 2 days after
      treatment, whereas protein oxidation measured by the content of protein hydrazone
      derivatives exhibited a maximal 88% increase at 3 days. Maximal rates of lipid
      peroxidation occur at 1 day after the administration of T3, whereas those of
      protein oxidation are attained after treatment with three daily doses of T3, time
      at which the former levels off. It is concluded that T3 administration induces a
      substantial enhancement in hepatic protein oxidation, in addition to lipid
      peroxidation, that seems to be due to the higher oxidative stress status
      conditioned in the liver by thyroid calorigenesis. Both processes exhibit a
      differential time course of changes, that may represent differences in the
      susceptibility of target molecules to free radical attack and/or in the
      efficiency of repair mechanisms.

PMID- 10403666
TI  - Na+ :H+ exchange inhibition induces intracellular acidosis and differentially
      impairs cell growth and viability of human and rat hepatocarcinoma cells.
AB  - Amiloride and its more potent analog, hexamethylene amiloride (HMA), inhibits Na+
      :H+ exchange and decreases intracellular pH in a concentration-dependent way in
      two human hepatocarcinoma cell lines and in a rat hepatocarcinoma cell line that
      differs in its phenotypic characteristics, resembling the clinical situation
      encountered in human hepatocarcinomas. After 24 h of exposure, DNA synthesis and
      cell protein content of the cultures decreases according to the concentration of
      the drugs and in parallel to Na+ exchange inhibition and the drop in pHi
      promoted. RNA and protein syntheses are less sensitive to its action. The above
      effects induced by HMA are accompanied by an abrupt decrease in cell viability
      and lysosomal integrity at 24 h. These effects develop gradually with the
      exposure time as does the increase in free radical production. Decreased
      viability is totally or partially restored by N-acetylcysteine or deferoxamine,
      but the degree of intracellular acidification produced is not. These results tend
      to suggest that intracellular acidification can diminish cell growth and provoke
      cytotoxic cell death by diminishing reduced glutathione (GSH) levels and
      impairing lysosomal integrity, reflecting the sensitivity of hepatocarcinoma
      cells to Na+ exchange inhibition and intracellular acidosis.

PMID- 10403667
TI  - Cisplatin-induced toxicity in LLC-PK1 kidney epithelial cells: role of
      basolateral membrane transport.
AB  - Cytotoxicity of cisplatin was evaluated after apical and/or basolateral treatment
      of LLC-PK1 cell monolayers grown on porous membrane filters with 300 microM
      cisplatin. When LLC-PK1 cells were exposed from basolateral side for 0.5-4 h,
      lactate dehydrogenase (LDH) release into culture medium was markedly stimulated.
      However, apical treatment of the cells with cisplatin for 0.5 h did not stimulate
      LDH release. gamma-Glutamyltransferase activity and amount of protein in the cell
      homogenate were markedly decreased by basolateral treatment with cisplatin.
      However, in the apical treatment with cisplatin, these changes were relatively
      small, suggesting that degrees of the toxicities were different between
      basolateral and apical treatment with cisplatin. Cellular platinum level after
      basolateral treatment with cisplatin was higher compared to that following apical
      treatment. Furthermore, both accumulation and toxicity of cisplatin in LLC-PK1
      cells were decreased by treatment with cisplatin at 4 degrees C. These results
      suggested that there were specific mechanisms mediating cisplatin uptake at the
      basolateral membranes of LLC-PK1 cells.

PMID- 10403668
TI  - Immune responses to contact allergens: novel approaches to hazard evaluation.
AB  - Progress in our understanding of the immunobiological mechanisms that cause skin
      sensitization and allergic contact dermatitis has facilitated consideration of
      alternative approaches to hazard evaluation. One such is the murine local lymph
      node assay in which, in contrast to more traditional guinea pig tests,
      sensitizing activity is measured as a function of events associated with the
      induction, rather than the elicitation, phase of contact hypersensitivity.
      Activity in the local lymph node assay is dependent upon all of those
      immunological events that are initiated following first encounter with chemical
      allergen and which result in the stimulation of T lymphocyte proliferative
      responses in lymph nodes draining the site of exposure. In this respect the assay
      embraces in an holistic way the induction of skin sensitization. With the
      objective of developing in vitro approaches to hazard identification,
      consideration has been given to discrete immunological responses that
      characterize the induction of skin sensitization. Most attention has focused upon
      the changes induced by chemical allergens in the phenotype and function of
      epidermal Langerhans cells and in cytokine expression. In addition, attempts have
      been made to identify contact allergens as a function of their ability to provoke
      in vitro specific responses by unprimed T lymphocytes. These novel approaches to
      skin sensitization testing and their potential utility in the context of
      toxicological evaluations are reviewed in this article.

PMID- 10403669
TI  - Absence of correlation between telomerase activity and hepatic neoplasia in
      B6C3F1 mice.
AB  - Telomeres are the physical ends of eukaryotic chromosomes, which maintain
      chromosome stability and are progressively shortened with aging in somatic cells.
      The enzyme telomerase elongates telometric DNA and while not usually detectable
      in human somatic cells is expressed in most human tumors. The present study was
      conducted to determine if telomerase activity is a marker for spontaneous hepatic
      neoplastic changes in B6C3F1 mice, a strain frequently used in rodent
      carcinogenicity studies. Telomerase activity was generally higher in
      microscopically normal liver tissue from 8-week-old compared to aged mice (110
      week-old); however, telomerase activity was not consistently increased in
      hepatocellular adenomas and carcinomas. It is proposed that, while elevated
      telomerase activity may modulate human tumor development, modulation of
      telomerase activity is not a feature of hepatic tumors in B6C3F1 mice and
      therefore is unlikely to have utility as a molecular marker for hepatic neoplasia
      in this mouse strain.

PMID- 10403670
TI  - Quantification of recombinant core-like particles of bluetongue virus using
      immunosorbent electron microscopy.
AB  - Immunosorbent electron microscopy was used to quantify recombinant baculovirus
      generated bluetongue virus (BTV) core-like particles (CLP) in either purified
      preparations or lysates of recombinant baculovirus-infected cells. The capture
      antibody was an anti-BTV VP7 monoclonal antibody. The CLP concentration in
      purified preparations was determined to be 6.6 x 10(15) particles/l. CLP
      concentration in lysates of recombinant baculovirus-infected cells was determined
      at various times post-infection and shown to reach a value of 3 x 10(15)
      particles/l of culture medium at 96 h post-infection. The results indicated that
      immunosorbent electron microscopy, aided by an improved particle counting method,
      is a simple, rapid and accurate technique for the quantification of virus and
      virus-like particles produced in large scale in vitro systems.

PMID- 10403671
TI  - Development of a nested PCR assay for the detection of canine coronavirus.
AB  - A diagnostic test for canine coronavirus (CCV) infection based on a nested
      polymerase chain reaction (n-PCR) assay was developed and tested using the
      following coronavirus strains: CCV (USDA strain), CCV (45/93, field strain),
      feline infectious peritonitis virus (FIPV, field strain), transmissible
      gastroenteritis virus (TGEV, Purdue strain), bovine coronavirus (BCV, 9WBL-77
      strain), infectious bronchitis virus (IBV, M-41 strain) and fecal samples of dogs
      with CCV enteritis. A 230-bp segment of the gene encoding for transmembrane
      protein M of CCV is the target sequence of the primer. The test described in the
      present study was able to amplify both CCV and TGEV strains and also gave
      positive results on fecal samples from CCV infected dogs. n-PCR has a sensitivity
      as high as isolation on cell cultures, and can therefore be used for the
      diagnosis of CCV infection in dogs.

PMID- 10403672
TI  - TCID50 determination by an immuno dot blot assay as exemplified in a study of
      storage conditions of infectious pancreatic necrosis virus.
AB  - Some cell lines are difficult to grow in confluent monolayers and, therefore, the
      plaque assay cannot be applied since plaques may be hard to distinguish from
      other blank areas of the cell monolayers. To avoid this problem a rapid and
      sensitive immuno dot blot TCID50 method was developed using antibodies against
      virus antigens to detect infection and virus production. An alternative
      statistical method was developed to treat the scoring data and thereby obtained a
      coefficient of variation of 10%. To speed up the total procedure and to increase
      the proliferation rate of cells grown in 96-well cell culture plates, the plates
      were pretreated for 4 h at 4 degrees C with growth medium obtained from cell
      culturing flasks containing confluent cell monolayers. This immuno dot blot
      TCID50 method was applied for a study of the infectivity maintenance upon storage
      of infectious pancreatic necrosis virus (IPNV). Storage of IPNV at -70 degrees C
      with a cryoprotective agent (10% glycerol) preserved the TCID50 level even after
      as many as ten cycles of freezings and thawings, whereas the infectivity
      decreased by four orders of magnitude after storage at 4-8 degrees C for 2 months
      in the salt buffer used commonly.

PMID- 10403673
TI  - Genetic polymorphism near HIV-1 reverse transcriptase resistance-associated
      codons is a major obstacle for the line probe assay as an alternative method to
      sequence analysis.
AB  - The performance of the line probe assay (LIPA) for the detection of mutations
      conferring resistance to nucleoside inhibitors of HIV-1 reverse transcriptase was
      evaluated in comparison with sequence analysis. The tests were undertaken on
      plasma samples from 63 patients (61 receiving combination therapy and 2 without
      treatment at the time of inclusion). In 27 cases (43%) which included codons 41,
      69, 70, 74, 184 and 215, the sequence of the RT gene was distinct from the
      hybridization probes used in LIPA. Correspondingly, LIPA gave uninterpretable
      results in 15, 30 and 41% of cases for codons 184, 215 and 41, respectively.
      Overall, the concordance between LIPA and sequence analysis varied from 52%
      (codons 41 and 215) to 85% (codon 70). These data show that the polymorphism of
      the nucleotide sequence near resistance-associated codons is a major shortcoming
      of LIPA.

PMID- 10403674
TI  - Screening for HBV, HCV and HIV genomes in blood donations: shortcomings of
      pooling revealed by a multicentre study simulating real-time testing.
AB  - This study was undertaken in order to determine whether screening of viremic
      blood donations by testing of pooled donor samples could constitute a technically
      feasible transfusional safety measure. A pilot study of real-time simulation, on
      a day-to-day basis, of screening of three viral genomes (hepatitis B virus (HBV),
      hepatitis C virus (HCV) and human immunodeficiency virus (HIV)) was conducted by
      five French Blood Centers on plasma samples collected from blood donors and
      studied within undiluted samples and within sample pools of various sizes. This
      study was carried out within time conditions compatible with the release of
      platelets. For the detection of HCV and HIV genomes, the five laboratories
      achieved a sensitivity that decreased with the size of the sample pool. Four were
      successful in detecting all undiluted samples. In the 1/10 diluted samples, four
      failed to detect one HIV or HCV sample. In the 1/100 diluted samples, all
      laboratories failed to detect one or more HIV or HCV samples. For HBV genome, no
      participating laboratories detected all of the samples of the panel, even
      undiluted samples, and the sample pooling considerably affected sensitivity. The
      improvement and standardization of assays needs to be attained, and training of
      laboratories appears to be a step crucial for routine screening of viral genomes
      in blood donations.

PMID- 10403675
TI  - Serotyping of foot-and-mouth disease virus by antigen capture reverse
      transcriptase/polymerase chain reaction.
AB  - The technique of capturing of foot-and-mouth disease virus (FMDV) from clinical
      material in microcentrifuge tubes coated with type-specific antibodies and
      amplifying the viral sequences by RT/PCR in the same tube, promoted the detection
      and serotyping of FMDV with high sensitivity and specificity. The efficiency of
      antigen capturing and shelf life of the coated tubes was improved by
      glutaraldehyde fixation of antibodies to the tubes. Virus in infected tissues,
      even after storage for 25-30 years at 70 degrees C, could be successfully typed
      by this method. Conserved sequences flanking the variable region of
      immunoreactive VP1 gene of FMDV were used as primers in the assay and hence the
      nucleotide sequence analysis of the product could reveal the strain variation.
      The test has been found to be at least 125-fold more sensitive than type specific
      ELISA and of comparable sensitivity as other protocols for detection of FMDV by
      RT/PCR.

PMID- 10403677
TI  - Comparison of the plaque test and reverse transcription nested PCR for the
      detection of FMDV in nasal swabs and probang samples.
AB  - In order to compare the sensitivity of assays for the diagnosis of foot-and mouth
      disease (FMD), a cell suspension plaque test on BHK21-CT cells and a reverse
      transcription nested PCR (RT-nPCR) were used to examine 485 nasal swabs and 227
      probang samples obtained from FMDV-infected cattle during vaccine potency tests.
      In nasal swabs, FMDV could be detected by both tests before the onset of clinical
      symptoms. However, after two weeks p.i., FMDV was only detected routinely in the
      probang samples. Examination of nasal swabs revealed a higher number of infected
      animals using RT-nPCR than by the use of the plaque test. Both tests gave
      approximately equivalent results with the probang samples.

PMID- 10403676
TI  - Prevalence of GBV-C/hepatitis G virus viraemia among blood donors, health care
      personnel, chronic non-B non-C hepatitis, chronic hepatitis C and hemodialysis
      patients in Egypt.
AB  - A new RNA virus, designated GBV-C/hepatitis G virus (HGV) has been identified
      recently. To evaluate the prevalence of GBV-C/HGV infection among Egyptians, five
      groups were enrolled in this study: group I, healthy blood donors (82); group II,
      health care personnel (30); group III, chronic non-B non-C hepatitis patients
      (63); group IV, chronic hepatitis C patients (100); group V, renal dialysis
      patients (79). GBV-C/HGV-RNA was detected by nested reverse transcription
      polymerase chain reaction (RT-PCR) using primers derived from 5'-non coding
      region of GBV-C/HGV. GBV-C/HGV-RNA was detected in 57 of 354 tested sera with an
      overall prevalence of 16.1%. Meanwhile, isolated GBV-C/HGV infection was detected
      in 16/57 (28.1%), GBV-C/HGV coinfection with hepatitis C virus (HCV) in 37/57
      (64.9%) and with hepatitis B virus (HBV) in 4/57 (7.6%) of cases. The highest
      prevalence was encountered among dialysis patients reaching 30% followed by
      chronic hepatitis C (14%), blood donors (12.2%), chronic non-B non-C hepatitis
      (11.1%), whereas the lowest prevalence rate of 6.6% was detected among health
      care personnel. Nucleotide sequence analysis in three Egyptians confirmed that
      these PCR products were derived from GBV-C/HGV genome and all isolates classified
      into US/European type (type 2) of GBV-C/HGV genotypes. The risk factors of all
      cases were non-transfusion parenteral exposure, e.g. reusing syringes, dental
      treatment, surgery, invasive medical maneuvers, with an exception of renal
      dialysis patients who have had repeated blood transfusion. It is concluded that
      there is a relatively high prevalence of GBV-C/HGV-RNA among different Egyptian
      groups compared to international figures. The main risk factors were direct
      percutaneous exposure rather than blood transfusion. The Egyptian GBV-C/HGV
      isolates are very similar to the American isolate PNF 2161.

PMID- 10403678
TI  - Typing of porcine circovirus in clinical specimens by multiplex PCR.
AB  - A multiplex PCR assay was developed to detect and differentiate between the
      porcine circovirus (PCV) infecting persistently the PK 15 cell line (PCV type I)
      and the PCV associated with postweaning multisystemic wasting syndrome (PMWS)
      (PCV type II). DNA products with unique sizes characteristic of each type of PCV
      were obtained. Sequencing of these products demonstrated that the nucleotide
      sequences were type-specific. Tissue samples from a total of 42 field cases from
      Quebec were studied, among which 41 were collected in 1997-1998 and one which had
      been previously collected in 1994. These 42 cases found previously to be PCV
      positive by PCR were tested in the present study by a multiplex PCR assay to
      determine the type of PCV in each case. From these 42 field cases, 40 cases were
      PCV type II-positive, one case was PCV type I-positive and one case was positive
      for both PCV types I and II. PCV type II was identified in typical PMWS field
      cases, but also in field cases submitted for various clinical histories, some of
      which were not suggestive of PMWS. In the field case where PCV type I was
      detected, there was no clinical evidence nor histological lesions suggestive of
      PMWS. The demonstration of PCV type II in a total of 41/42 field cases in the
      present study suggests that PCV type II may be the main type of PCV circulating
      in pigs. Furthermore the detection of PCV type II in a field case dating back to
      1994 indicates that this PCV type was circulating in pigs in Quebec several years
      before the report of clinical PMWS in this province.

PMID- 10403679
TI  - A high throughput assay of the hepatitis C virus nonstructural protein 3 serine
      proteinase.
AB  - A simple assay was developed based on intramolecular fluorescence resonance
      energy transfer for detection of the activity of hepatitis C virus (HCV) serine
      proteinase. Two quenched-fluorogenic substrates, (7-methoxycoumarin-4-yl)acetyl
      (Mca) Asp-Asp-Ile-Val-Pro-Cys-Ser-Met-Ser-(2,4-dinitrophenyl, Dnp) Lys (Mca-Asp
      Asp-Ile-Val-Pro-Cys-Ser-Met-Ser-Lys[Dnp], QF-1) and Mca-Asp-Asp-Ile-Val-Pro-Cys
      Ser-Met-Lys(Dnp)-Arg-Arg (QF-2), which derived from the NS5A/5B junction of the
      HCV polyprotein, were designed. Kinetic studies revealed that QF-1 and QF-2 had
      high affinity for a recombinant enzyme which is a fusion protein of maltose
      binding protein and almost entire nonstructural protein (MBP-NS3), with Km values
      comparable to that of longer substrate based on the same cleavage site. QF-1 and
      QF-2 were cleaved by MBP-NS3 efficiently with kcat values of 7.5 and 4.2 min(-1),
      respectively. QF-2 was also found to be a good substrate of deltaNS3 which
      contained serine proteinase part of NS3 with kcat value of 4.3 min(-1). The
      cleavage reaction is detected continuously by the elevation of the fluorescence
      due to release from quenching. The fluorescence of the substrates increases in
      proportion to progress of the cleavage reaction under the standard conditions.
      This method was applied for screening of HCV serine protease inhibitors using a
      fluorescence multiwell plate reader. A group of natural occurring products,
      flavonoids, was subjected to be screened. Two flavonoids out of 25 were found to
      inhibit the enzyme moderately at a concentration of 100 microM. The data agreed
      with those obtained by high-performance liquid chromatography (HPLC). This method
      is suited to sensitive quantitation of the enzyme reaction as well as the high
      throughput analysis of the inhibitors.

PMID- 10403680
TI  - A screening assay for antiviral compounds targeted to the HIV-1 gp41 core
      structure using a conformation-specific monoclonal antibody.
AB  - The human immunodeficiency virus type 1 (HIV-1) gp41 plays an important role in
      membrane fusion between viruses and target cells. The gp41 ectodomain contains
      two heptad repeat regions adjacent to the N and C-termini. Peptides derived from
      these two regions, designated N and C-peptides, are potent inhibitors of HIV-1
      infection and can interact with each other to form a six-stranded coiled-coil,
      representing the fusogenic core structure of gp41. A monoclonal antibody was
      generated, designated NC-1, which specifically binds to the complex formed by the
      N and C-peptides, but not to the individual peptides. An enzyme linked
      immunosorbent assay (ELISA) was developed using NC-1 for detecting complex formed
      by N and C-peptides and for screening of organic compounds for antiviral agents
      that may interfere with complex formation and inhibit HIV-1 infection. Single
      point mutations in the C-peptides abolish the complex formation also eliminate
      their anti-HIV-1 activity. A phenylazo-naphthalene sulfonic acid derivative,
      designated ADS-J1, was found to inhibit both formation of NC-1 detectable complex
      and HIV-1-mediated membrane fusion, suggesting that the described ELISA is
      applicable to rapid screening of libraries of organic compounds for HIV-1
      inhibitors targeted to the HIV-1 gp41 core structure.

PMID- 10403681
TI  - Serological detection of hepatitis B virus genotypes by ELISA with monoclonal
      antibodies to type-specific epitopes in the preS2-region product.
AB  - An ELISA was developed for serological determination of the six genotypes of
      hepatitis B virus (HBV) designated A, B, C, D, E, and F. Monoclonal antibodies
      were raised against genotype-specific epitopes in the preS2-region product, and
      labeled with horseradish peroxidase. Hepatitis B surface antigen (HBsAg) in sera
      was captured by immobilized antibodies against the common determinant, and
      evaluated for reactivity with genotype-specific monoclonal antibodies labeled
      with the enzyme. Serological genotyping was in complete accord with genotypes
      determined by S-gene sequences in a panel of 68 sera containing HBV/HBsAg of
      different genotypes. Of 514 sera with HBsAg from Japan, 507 (98.6%) were
      genotyped serologically: genotype A was identified in 24 (4.7%); B in 196
      (38.1%); C in 282 (54.9%); D in 2 (0.4%); and F in 3 (0.6%). There were no sera
      containing HBV of genotype E. Likewise, 425 of 446 (95.3%) sera with HBsAg from
      Brazil, China, India, Indonesia, Kenya, Korea, Nepal, Papua New Guinea, the
      Philippines, and Thailand were classified into A (25.6%), B (24.2%), C (33.9%),
      and D (11.7%) genotypes; there were no sera with HBsAg of genotype E or F among
      them. Some sera unclassifiable by ELISA revealed mixed infection with HBV of
      distinct genotypes, or contained HBsAg deprived of genotype-specific epitopes by
      point mutations. The ELISA would be useful for large-scale surveys, because it
      allows serological detection of HBV genotypes without sequencing nucleotides.

PMID- 10403682
TI  - Platelet dense granules: structure, function and implications for haemostasis.
AB  - The advances that have been made over the last decade in microscopic,
      biochemical, molecular, and genetic techniques have led to substantial
      improvement in our understanding of platelet dense granule structure and
      function, and the implications of dense granule deficiencies for haemostasis.
      However, much has still to be learned. For example, what is the specific
      mechanism of docking and fusion that occurs during dense granule exocytosis? What
      are the roles of dense granule membrane proteins during exocytosis or after
      expression on the surface of activated platelets? Finally, how do the genetic
      defects identified in HPS and CHS result in the clinical phenotype of these
      diseases, and what does this tell us about the origin and function of the
      affected subcellular organelles?

PMID- 10403683
TI  - Comparative study of antiplatelet drugs in vitro: distinct effects of cAMP
      elevating drugs and GPIIb/IIIa antagonists on thrombin-induced platelet
      responses.
AB  - Among various categories of antiplatelet drugs, cAMP-elevating agents and GP
      IIb/IIIa antagonists have been reported to inhibit platelet aggregation
      stimulated by a wide variety of platelet agonists. To clarify the qualitative
      difference between these two agents, their effects on various platelet responses
      in washed platelets evoked by thrombin (0.05 U/mL) were compared in vitro. Two
      types of cAMP-elevating drugs, cilostazol (a phosphodiesterase III inhibitor) and
      prostaglandin E1 (an adenylate cyclase activator), both inhibited platelet
      aggregation, thromboxane A2 formation, and platelet factor 4 release in a
      concentration-dependent manner. In addition, both agents suppressed intracellular
      Ca++ elevation induced by thrombin. However, two classes of GP IIb/IIIa
      antagonists, abciximab (Fab fragment of antibody) and tirofiban (a synthetic
      compound), showed no inhibitory effects against thromboxane A2 formation and
      platelet factor 4 release, although these drugs inhibited platelet aggregation.
      Essentially the same results were obtained in platelet-rich plasma stimulated
      with high concentration (100 microM) of thrombin receptor activating peptide. In
      contrast to these different profiles on thromboxane A2 formation and release
      reaction, both cAMP-elevating agents and GP IIb/IIIa antagonists potently
      suppressed procoagulant activity in thrombin-stimulated platelets. These results
      suggest that the development of platelet procoagulant activity induced by
      thrombin is exclusively dependent on platelet aggregation or aggregation
      dependent processes. These observations also indicate that cAMP-elevating agents
      possess wider inhibitory effects on platelet responses evoked by strong agonists
      than GP IIb/IIIa antagonists.

PMID- 10403684
TI  - The influence of a vegetarian diet on haemostatic risk factors for cardiovascular
      disease in Africans.
AB  - Dietary habits have been implicated in the occurrence of cardiovascular diseases.
      Elevated plasma fibrinogen levels and decreased fibrinolytic activity have been
      identified as major independent cardiovascular risk factors. In this study, we
      compared the blood pressure, plasma fibrinogen concentration, and fibrinolytic
      activity of 40 nonvegetarians (NON-VEGs) with 36 vegetarians (8 VEGs and 28 SEMI
      VEGs). The latter group consisted of students and lecturers of the Adventist
      Seminary Institute of West Africa, Ilishan Remo. All subjects had blood pressures
      below 140/90 mmHg, no underlying haemostatic disorders and were not on any
      medical treatment. The NON-VEGs had significantly decreased fibrinolytic activity
      (p<0.001) and increased plasma fibrinogen levels (p<0.001) compared with the SEMI
      VEGs and VEGs. There were no significant differences between the blood pressure
      levels of the three groups, although the NON-VEGs had lower diastolic blood
      pressures. It is concluded that black African Seventh-Day Adventists who follow a
      vegetarian diet may be protected against premature cardiovascular disease because
      of beneficial dietary effects on plasma fibrinogen levels and fibrinolytic
      activity.

PMID- 10403687
TI  - Beta2-glycoprotein I-dependent anticardiolipin antibody is reactive to both beta2
      glycoprotein I/oxidized as well as beta2-glycoprotein I/reduced cardiolipin.

PMID- 10403685
TI  - Association of plasma levels of activated protein C with recanalization of the
      infarct-related coronary artery after thrombolytic therapy in acute myocardial
      infarction.
AB  - Protein C is one of the most important antithrombotic components. After
      activation by the thrombin-thrombomodulin complex on endothelial cells, activated
      protein C (APC) inactivates factors Va and VIIIa, which leads to the inhibition
      of thrombin formation. We examined the association of plasma levels of APC with
      the responsiveness to coronary thrombolytic therapy of the infarct-related
      coronary artery in patients with acute myocardial infarction (AMI). Plasma levels
      of APC, thrombin-antithrombin III complex (TAT), and plasminogen activator
      inhibitor (PAI) activity were measured in 32 consecutive AMI patients who
      underwent coronary angiography followed by thrombolytic therapy, and compared to
      the measurements in 23 control subjects. On admission, APC levels (ng/mL) were
      significantly elevated in patients with AMI, as compared with controls (2.5+/-0.4
      vs. 1.2+/-0.2, 1.3+/-0.2, respectively, p<0.01). At discharge, plasma levels in
      AMI patients decline to values not significantly different from those in
      controls. (1.2+/-0.2, 1.3+/-0.2, respectively). TAT levels (ng/mL) were different
      among the groups in a fashion similar to that of APC (14.1+/-3.1 on admission vs.
      3.3+/-0.4 at discharge, 1.8+/-0.1 in the control subjects, respectively, p<0.01).
      PAI activity levels (IU/mL) were higher on admission than at discharge and higher
      than the control subjects (19.7+/-1.8 vs. 10.5+/-1.0, 5.4 +/- 0.7, respectively,
      p<0.01). Thirty-two patients with AMI were classified into two groups according
      to the results of thrombolysis: the success group (24 patients) and the failure
      group (eight patients). APC levels were higher in the failure group than in the
      success group (5.1+/-0.7 vs. 1.6+/-0.2, p<0.01). TAT levels were also higher in
      the failure group than in the success group (30.8+/-9.6 vs. 8.6+/-1.7, p<0.01).
      PAI activity levels (IU/mL) were lower in the failure group than in the success
      group (13.5+/-3.1 vs. 21.7+/-2.1, p<0.05). There were correlations between APC
      and TAT levels both on admission (r=0.75, p<0.0001) and at discharge (r=0.71,
      p<0.0001). Elevated APC was thought to correlate with increased thrombin
      generation in patients with AMI. This study demonstrated that there was a
      significant relation between plasma APC level and the responsiveness to
      thrombolytic therapy of the infarct artery. This study may also indicate that
      increased thrombin generation is a cause of the resistance to thrombolytic
      therapy.

PMID- 10403686
TI  - Comparison of the antithrombotic effects and bleeding risk of fractionated aurin
      tricarboxylic acid and the GPIIb/IIIa antagonist GR144053 in a hamster model of
      stenosis.
AB  - The present study compared the antithrombotic properties of fractionated aurin
      tricarboxylic acid (ATA), an inhibitor of platelet glycoprotein (GP) Ib, and
      GR144053, a GPIIb/IIIa antagonist, in a hamster model of stenosis. Endothelial
      cell injury in the hamster carotid artery was achieved by a 2F modified catheter.
      Arterial blood flow in the control groups was interrupted 5.4+/-0.9 minutes after
      the injury. When ATA (0.01, 0.03, 0.1, 0.3, and 1.0 mg/kg per hour) or GR144053
      (0.1, 0.3, and 1.0 mg/kg per hour) were continuously infused intravenously, the
      time elapse before the vessel completely occluded was prolonged in a dose
      dependent manner. However, all arteries in the ATA-treated groups ultimately
      occluded during the observation period even if the aggregation of platelets ex
      vivo and induced by botrocetin was completely inhibited. When either ATA (0.1
      mg/kg per hour) or GR144053 (0.3 mg/kg per hour) were infused via an implanted
      osmotic pump together with tissue-type plasminogen activator (tPA), late patency
      of the reperfused artery was improved compared to that of arteries treated with
      TPA alone. However, the cyclic reflow pattern after reperfusion on days 0 and 1
      was not reduced by the ATA treatment. The bleeding time was significantly
      prolonged when either ATA or GT144053 was coadministered with tPA. The treatment
      with ATA showed an especially marked prolongation of the bleeding time. In
      conclusion, both inhibition of platelet activation by ATA or GR144053 prevent
      arterial thrombosis and enhance the thrombolytic effect of tPA, but GR144053 was
      more protective in its antithrombotic effect and more effective during
      thrombolytic therapy than ATA.

PMID- 10403688
TI  - Short-term chemotherapy and palliative radiotherapy for elderly patients with
      stage IV non-small cell lung cancer: a phase II study.
AB  - Optimal treatment in elderly (> 70 years) with stage IV non-small cell lung
      cancer (NSCLC) is not known. In order to define it, concurrent short-term
      chemotherapy (CHT) and palliative radiotherapy (RT) was evaluated in this patient
      population. Between January 1988 and June 1993, a total of 50 patients entered
      into a study that used two cycles of carboplatin (CBDCA), 300 mg/m2, days 1 and
      29 and oral etoposide, 50 mg/m2, days 1-21 and 29-42. RT was administered with
      dose of 14 Gy in two fractions given with 1 week split, days 1 and 8. Of 47
      patients evaluable for the response, there were three (6%) complete response
      (CR), and ten (21%) partial response (PR), making the overall response rate of 13
      (28%). Response duration ranged 2-8 months (median, 5 months; mean, 5 months).
      Median survival time (MST) for all 50 patients was 7 months and 1-3 year survival
      rates were 31, 4.1, and 2%, respectively. There were only nine (19%) patients
      experiencing hematological grade 3 toxicity, all other CHT-induced toxicity being
      grade 1 or 2. Of RT-induced high-grade toxicity, grade 3 esophageal was observed
      in nine (19%) patients while only four (9%) patients experienced grade 3
      bronchopulmonary toxicity. No grade 4 or 5 toxicity occurred during this study.
      Short-course CHT and palliative RT in elderly patients with stage IV NSCLC was
      well tolerated with mild to moderate toxicity. Together with results obtained
      this way, they warrant further studies evaluating the effectiveness of this
      approach and possible CHT- and/or RT-dose escalation in elderly patients with
      stage IV NSCLC.

PMID- 10403690
TI  - Relationship between quality of life and clinical outcomes in advanced non-small
      cell lung cancer: best supportive care (BSC) versus BSC plus chemotherapy.
AB  - In a prospective randomized study, 287 patients with advanced non-small cell lung
      cancer (NSCLC) stage IIIb or IV with ECOG performance status (PS) 0-1 or 2 were
      randomly assigned to receive either best supportive care (BSC) or supportive care
      plus combination chemotherapy (IEP regimen: ifosfamide 3 gm/m2 IV with mesna
      uroprotection, epirubicin 60 mg/m2 IV on day 1 and cisplatin 60 mg/m2 IV on day
      2; or MVP regimen: mitomycin-C 8 mg/m2, cisplatin 100 mg/m2 IV on day 1,
      vinblastine 4 mg/m2 IV on days 1 and 15). Serial assessment of Karnofsky
      performance status (KPS), modified Functional Living Index-Cancer (T-FLIC) and
      modified Quality of Life-Index (T-QLI) were used to estimate the quality of life.
      Interviews were done at entry, at the third month and at 2 months post complete
      treatment. At least two courses of chemotherapy were considered to be adequate
      for response evaluation. Patients were treated for a total of four to six courses
      or until progression of disease. Partial response rates were 40 and 41.7% in IEP
      and MVP arms. Median survival durations were 5.9 and 8.1 months for the IEP and
      MVP chemotherapy arms, and 4.1 months for BSC (log-rank test: P = 0.0003). One
      year survival was 13, 29.8 and 39.3% for the BSC, IEP and MVP regimens,
      respectively. Two years survival was 7.8, 6.4 and 13.1% for the BSC, IEP and MVP
      regimens, respectively. Improvement in quality of life (QOL) scores at the first,
      second and third interview were seen in chemotherapy arms only, not in the BSC
      arm. We conclude that combination chemotherapy improves the quality of life as
      well as prolonging the survival of patients with advanced NSCLC.

PMID- 10403689
TI  - Immunohistochemical analysis of nm23-H1 gene product in node-positive lung cancer
      and lymph nodes.
AB  - The nm23-H1 gene product has been considered as an anti-metastatic protein and
      the level of its expression has been reported to correlate inversely with
      metastatic potential in some cancers. However, the expression of nm23-H1 gene
      product in the metastatic sites have not been studied in detail. We examined the
      expression of nm23-H1 gene product in surgically resected 46 pairs of primary
      lung cancers and metastatic lymph nodes by immunohistochemistry. The positive
      staining of nm23-H1 gene product in primary cancers and metastatic lymph nodes
      were observed in 56.5 and 67.4%, respectively. The heterogeneity of nm23-H1 gene
      product expression between primary cancers and metastatic lymph nodes was
      observed in 41.3%. No correlations were found between the nm23-H1 gene product
      expression in lung cancers and the patients survival. No significant association
      was also observed between nm23-H1 gene product expression in lymph nodes and the
      patients survival. There was, furthermore, no correlation between the
      heterogeneity of nm23-H1 gene product expression and the patients survival. In
      conclusion, the level of nm23-H1 gene product expression does not significantly
      reveal prognostic value in node-positive lung cancers. Expression of nm23-H1 gene
      product in metastatic lymph nodes was also unrelated to patients survival.

PMID- 10403692
TI  - Estimation of tumor control probability model parameters from 3-D dose
      distributions of non-small cell lung cancer patients.
AB  - Tumor control probability (TCP) model calculations may be used in a relative
      manner to evaluate and optimize three-dimensional (3-D) treatment plans. Using a
      mathematical model which makes a number of simplistic assumptions, TCPs can be
      estimated from a 3-D dose distribution of the tumor given the dose required for a
      50% probability of tumor control (D50) and the normalized slope (gamma) of the
      sigmoid-shaped dose-response curve at D50. The purpose of this work was to derive
      D50 and gamma from our clinical experience using 3-D treatment planning to treat
      non-small cell lung cancer (NSCLC) patients. Our results suggest that for NSCLC
      patients, the dose to achieve significant probability of tumor control may be
      large (on the order of 84 Gy) for longer (> 30 months) local progression-free
      survival.

PMID- 10403691
TI  - Shift in the IgG subclass distribution in patients with lung cancer.
AB  - Lung cancer patients have been reported to have generalized immune dysfunction of
      the cell-mediated immune response. In contrast, little is known about the humoral
      immune function in these patients. Therefore, we examined the IgG subclass
      distribution (IgG1-lgG4) in 67 lung cancer patients (23 adenocarcinoma, 29
      squamous cell carcinoma, 15 small cell carcinoma), 13 patients with inflammatory
      lung diseases, seven patients with pulmonary metastasis and 23 healthy controls
      using a commercial available ELISA. We found a significant increase in the
      percentage of IgG1 in adenocarcinoma, compared with squamous cell and small cell
      lung carcinoma (P < 0.05). Small cell lung cancer patients showed an increase in
      IgG2, IgG3 and IgG4 compared with all other groups (P < 0.05, respectively).
      IgG1/lgG2, IgG1/lgG3 and IgG1/lgG4 ratios in adenocarcinoma were higher than in
      small cell lung cancer (P < 0.05). In the squamous cell carcinoma there was no
      difference in IgG subclass distribution compared to controls. Our study
      demonstrates that the different histological subtypes of lung carcinoma influence
      the IgG subclass distribution. Whether this phenomenon is the result of a direct
      influence on B-cell activity by the tumor needs further investigation.

PMID- 10403693
TI  - Ifosfamide in malignant mesothelioma: a phase II study.
AB  - Malignant mesothelioma is a rare malignancy with a median survival, ranging from
      4 to 18 months in untreated patients. In a phase II study of patients with
      mesothelioma, the efficacy and toxicity of ifosfamide and mesna was evaluated.
      Twenty-nine previously untreated patients, with histologically proven and
      unresectable mesothelioma, entered the study. Three patients were later excluded
      from the study due to revision of the diagnoses. The patients had to have
      bidimensionally measurable disease by CT scans and a WHO performance status < or
      = 3. Eligible patients received ifosfamide 3000 mg/m2 per day for 3 days as a 1-h
      infusion and mesna 1800 mg/m2 per day for 3 days every third week. Dose
      modifications were made according to the degree of hematologic, neurologic and
      renal toxicity. Response to treatment was evaluated in accordance with WHO
      criteria. The median age of patients was 59 years (range 39-68), 18 patients
      (69%) had a history of asbestos exposure and the median of treatment cycles was
      four (range 1-10). No complete responses were observed. One patient obtained a
      partial response after five cycles with a duration of response of 25 months. Nine
      patients (35%) had stable disease, while 13 (54%) progressed. The median survival
      for all patients was 10 months. The toxicity of the treatment was considerable.
      Thirteen patients (50%) had grade 4 leucopenia, ten patients (38%) had grade 3 or
      4 reversible neurotoxicity and ten patients (38%) had grade 3 or 4 nausea and
      vomiting. Eleven patients (42%) went off the study due to the toxicity of the
      treatment. In conclusion, ifosfamide did not show any substantial activity of
      relevance in malignant mesothelioma at the dose level investigated, in spite of
      considerable toxicity.

PMID- 10403694
TI  - Re: 'Effect of cigarette smoking on major histological types of lung cancer' SA
      Khuder, HH Dayal, AB Mutgi et al., Lung Cancer 1998;22:15-21.

PMID- 10403695
TI  - A comparative analysis of the phosphorylation and biochemical properties of wild
      type and host range variant DNA binding proteins of human adenovirus 5.
AB  - Specific mutation of the DNA binding protein (DBP) of human adenovirus types 2
      and 5 can extend the host range of these viruses to simian cells. These mutations
      replace histidine at position 130 in the highly phosphorylated N-terminal domain
      of DBP with a potentially phophorylatable tyrosine residue. To investigate the
      possibility that alternative phosphorylation might contribute to the functional
      differences between wild type (wt) and host range (hr) DBP molecules,
      radiolabeled proteins were compared by partial proteolysis and tyrosine
      phosphorylation was analyzed. These studies confirmed the previous tentative
      assignment of a chymotrypsin-sensitive site at position 121 of DBP. No host range
      specific tyrosine phosphorylation was detected, and no gross difference in the
      extent of phosphorylation between wt and hr DBP was observed. However, the
      cleaved N-terminal domains of wt and hr DBP exhibited different sensitivities to
      further chymotryptic digestion in vitro and different fragmentation patterns,
      suggesting that they might have different conformations. Such a difference could
      underlie the differing ability of these proteins to support Ad replication in
      simian cells.

PMID- 10403696
TI  - Genetic analysis of pestiviruses at the 3' end of the genome.
AB  - Specific PCR primers were selected for each pestivirus genotype which flanked the
      3'-part of the NS5B gene and more than three quarters of the 3'-UTR. PCR products
      were sequenced in both directions using an automatic sequencing device and
      analyzed by computer package program DNASTAR. A comparative analysis of the 3'
      untranslated region (3'-UTR) of 82 viruses, representing the four genotypes of
      the Pestivirus genus, provided a similar phylogenetic grouping as other genomic
      regions. Intertypic recombination was not observed, but Border disease virus
      (BDV) and Bovine viral diarrhoea virus type I (BVDV I) showed great
      intragenotypic variability. In most pestiviruses the stop codon is TGA, but BDV
      isolates were found to have either a TAG or a TAA stop codon. Various deletions
      and insertions were observed in the 3'-UTR region. Viruses of the BVDV lb group
      contained a characteristic deletion of 41 nucleotides. Compared to the 5'-UTR,
      the 3'-UTR was less conserved. The first 50-60 nucleotides were particularly
      variable, whilst the most conserved part was found at the 3' end of the studied
      region. All 82 viruses contained AT-rich stretches, the positions and sizes of
      which differed between the genotypes.

PMID- 10403697
TI  - Expression of envelope proteins of endogeneous C-type retrovirus on the surface
      of mouse and human oocytes at fertilization.
AB  - Retrovirus genomes express, among other products, the envelop (env) proteins SU
      (gp70) and TM (p15E). They coexist at the viral surface membrane and are able to
      promote immunosuppression and membrane fusion. In mouse oocytes, endogeneous
      retroviruses (ERV) genomes are expressed at fertilization, and antigen epitopes
      of the Moloney murine leukemia virus (MuLV) env protein gp70 are recognized in
      the cytoplasm of the oocytes before but not after fertilization. By using a panel
      of monoclonal antibodies (mAbs) raised against env components, we checked with
      laser scanning confocal microscopy (LSCM) whether gp70 and p15E were expressed
      also on the oocyte surface membrane (oolemma). Since we found that both mouse and
      human unfertilized oocytes expressed these ERV proteins on the oolemma and that
      the expression enfeebled significantly after fertilization, we assume that ERV
      genomes could play a role at the sperm-egg binding and fusion.

PMID- 10403698
TI  - A defective RNA associated with bamboo mosaic virus and the possible common
      mechanisms for RNA recombination in potexviruses.
AB  - A naturally occurring 1.1 kb RNA was isolated from purified virions of bamboo
      mosaic potexvirus isolate S (BaMV-S). This RNA is a defective RNA (D RNA) derived
      from a single internal deletion of the BaMV genome. A cDNA clone representing the
      complete nucleotide sequence of the BaMV-S D RNA was generated and its nucleotide
      sequence was determined. The BaMV D cDNA is 1015 nts in length [excluding the
      poly(A) tail] and consists of two regions corresponding to 867 nts of the 5'
      terminus and 148 nts of the 3' terminus of the BaMV genomic RNA. BaMV D cDNA
      contains a single open reading frame (ORF) encoding a putative 29.7 kDa protein
      comprised of a fusion of the first 258 amino acids of BaMV ORF 1 and the last 2
      amino acids of coat protein. The coding capacity of D RNA was verified by in
      vitro translation of native BaMV-S D RNA and of 1.1 kb RNA transcribed in vitro
      from the full-length D cDNA. BaMV D RNA can be reproducibly generated by serial
      passages of BaMV-S in Nicotiana benthamiana and is the first D RNA in the
      potexvirus group shown to be generated de novo. Alignments of sequences
      surrounding the 5' and 3' junction borders of reported potexvirus D RNAs reveal a
      65.2-84.6% sequence identity, suggesting that common mechanisms for viral RNA
      recombination are involved in the generation of potexvirus D RNAs.

PMID- 10403699
TI  - Complete nucleotide sequence of bean pod mottle virus RNA1: sequence comparisons
      and evolutionary relationships to other comoviruses.
AB  - The complete nucleotide sequence of bean pod mottle comovirus (BPMV) RNA 1 was
      determined. It is 5983 nucleotides long, excluding the poly(A) tail, and encodes
      a polyprotein of 1850 amino acid (aa) residues. Multiple alignments of the
      deduced aa sequence of BPMV polyprotein with those of cowpea mosaic virus (CPMV),
      red clover mottle virus (RCMV) and cowpea severe mosaic virus (CPSMV) indicated
      that BPMV RNA1 encodes the predicted set of five mature proteins: the equivalent
      of CPMV 32K protease cofactor, 58K putative helicase, VPg, 24K protease and 87K
      putative RNA-dependent RNA polymerase. Of the four proposed cleavage sites in
      BPMV RNA1 polyprotein, the one at the 32K/58K site (Q/A) is distinct for BPMV
      polyprotein and those at the 58K/VPg and VPg/24K junctions (Q/S and Q/M,
      respectively) are identical in all four comovirus polyproteins. Sequence
      comparison and phylogenetic analysis revealed that BPMV RNA1 is more closely
      related to CPSMV than to CPMV or to RCMV.

PMID- 10403700
TI  - Cloning of E6 and E7 genes of human papilloma virus type 18 and transformation
      potential of E7 gene and its mutants.
AB  - E6 and E7 genes of human papilloma virus type 18 have been subcloned from plasmid
      pC7, carrying an insert of DNA from squamous cell carcinoma of cervix. Both genes
      in comparison to prototype variant contain one mutation that changes asparagine
      to leucine. In the case of E6 gene this mutation is mapped in codon 129, in the
      case of E7 the same change AAC to AAA mapped in codon 92. In addition both genes
      contain few point mutations that do not change the aminoacid sequences of the
      protein. Two mutants of E7 gene have been constructed by site directed
      mutagenesis based on PCR technology-one in codon 10 (change Asp to Asn) and one
      in codon 24 (change Asp to Gly). The first type of mutation did not influence the
      transformation potential of the E7 gene in comparison to the parental one with
      mutation in codon 92. The mutation in codon 24 (region responsible for the
      interaction with Rb protein) eliminate the transformation potential of the gene.
      The cells transformed with E7 mutants in codons 10 and 92 were tumorigenic for
      syngenic rats.

PMID- 10403701
TI  - The genome of cowpox virus contains a gene related to those encoding the
      epidermal growth factor, transforming growth factor alpha and vaccinia growth
      factor.
AB  - Cowpox virus (CPV) is a member of the Orthopoxvirus genus and has the genetic
      capacity to encode a multitude of genes that interfere with the host inflammatory
      and immune response or modulate the physiological state of infected and non
      infected cells. Among these CPV factors are receptors homologous to interferon
      and tumor necrosis factor receptors and also a viral cellular serine-proteinase
      analog. Here we describe the detection of a CPV gene that encodes a protein
      homologous to epidermal growth factor, transforming growth factor alpha and
      poxvirus growth factors, such as the vaccinia growth factor (VGF). The VGF and
      other poxvirus growth factors are produced early in the infection and are
      secreted into the medium where they bind to the EGF receptors, generating mytotic
      responses. The cowpox growth factor (CGF) gene was detected in three copies on
      the virus genome by PCR, and by northern and southern blot hybridization using
      VGF nucleotide sequences as primers and probes. The CPV gene has a strong
      nucleotide and predicted amino acid similarity with VGF, and is also produced
      early in the infection.

PMID- 10403702
TI  - Capsid protein-encoding (P1) sequence of foot and mouth disease virus type Asia 1
      ind 63/72.
AB  - Variations in the amino acid sequence of Foot-and-Mouth Disease Virus (FMDV)
      structural proteins are the basis for the antigenic diversity of the virus.
      Majority of antigenic sites for the virus neutralization are present on VP1, the
      major immunogenic protein. However, a few conformational epitopes are present on
      the structural proteins VP2 and VP3. The nucleotide sequence encoding all the
      four structural proteins (P1 region) of FMDV type Asia 1 Ind 63/72 was
      determined. The nucleotide and the deduced amino acid sequence of P1 of Asia 1 of
      Indian strain was compared with that of Asia 1 Israel strain. Differences were
      observed at 284 (14%) nucleotide positions resulting in 69 (10%) amino acid
      changes. The variation in the derived amino acid sequence is the highest in VP1
      (14.4%) followed by VP2 (10%), VP3 (6.4%) and VP4 (3%). Deletion of two amino
      acids, which was observed in the case of Indian strain as well as in Israel
      strain indicated that these deletions are specific for type Asia 1. The P1
      sequence was also compared with the corresponding region of the other serotypes
      O1K, A12, Cl and SAT-1. The sequence has been submitted to EMBL data bank, under
      accession number Y09949.

PMID- 10403704
TI  - Molecular cloning and sequence analysis of the phosphoprotein (P) gene of the
      lapinized rinderpest virus.
AB  - We determined the nucleotide sequence of the coding region for the phosphoprotein
      (P) gene of the L strain of rinderpest virus (RPV). The gene encodes two
      overlapping open reading frames of 1521 and 531 nucleotides. Use of the first ATG
      would produce a P polypeptide of 507 amino acids, while use of the second ATG
      would produce a C polypeptide of 177 amino acids. In addition, the insertion of
      an extra G residue at the editing site generates an alternative mRNA potentially
      encoding the V protein of RPV. Homology comparisons of the P, C and V proteins
      among various viruses suggest that RPV is closer to measles virus (MV) than to
      canine distemper virus (CDV). Alignment of the sequences unique to the V protein
      revealed that the cysteine residues are well conserved among RPV, MV and CDV, and
      form a "zinc finger"-like motif.

PMID- 10403703
TI  - Molecular characterization of HCV 1b intra-familiar infection through three
      generations.
AB  - Vertical transmission is an uncommon route of hepatitis C virus (HCV) infection.
      Little is known about the way of virus spread between relatives. Furthermore, the
      nucleotide sequence variability studies that can be used for the definition of
      cases of HCV transmission still need accurate standardization. In this study, we
      analyzed the HCV positive sera from subjects belonging to one family. Five out of
      seven individuals were positive both for anti-HCV and HCV-RNA. The
      epidemiological data, in our knowledge, excluded the possible risk of parenteral
      exposure to HCV for the members of the family. The genetic relatedness of the
      viruses infecting the members of this family was demonstrated by the phylogenetic
      analysis of sequences from E1 genome region. The analysis included the
      calculation of the genetic divergence specific index, based on the ratio of
      synonymous/non-synonymous mutations. By the analysis of this genome region, we
      demonstrated the occurrence of HCV transmission among family members. In 2 cases
      out of 3, Mother-to-Infant transmission was demonstrated that involved three
      generations of the family. Transmission by sexual route was absent. A method of
      sequence analysis of E1 HCV genome region is proposed as molecular approach for
      the definition of transmission cases of HCV.

PMID- 10403705
TI  - Mutational analysis of human immunodeficiency virus type 1 vif gene.
AB  - Mutations were introduced into scattered regions of the HIV-1 vif gene. The
      twelve in-frame mutants generated were evaluated for the replication potentials
      in cells by transfection and infection experiments. All the mutants produced a
      normal level of progeny virions upon transfection, indicating the absence of the
      late function of HIV-1 Vif protein. The infectivity of virions obtained was
      monitored in H9 cells, which are non-permissive for HIV-1 without the Vif
      function. Most of the mutations in various parts of the vif gene, including those
      in the three conserved regions among HIV/SIV, abrogated the infectivity of the
      virus. In contrast, the cysteine residue at position 133, which was reported to
      be critical for viral infectivity, was found not to be essential. In addition,
      the C-terminal eight amino acid residues (185-192) in the Vif protein could be
      deleted with no effects on viral growth potential.

PMID- 10403706
TI  - Compatibility of Vpu-like activity in the four groups of primate immunodeficiency
      viruses.
AB  - Env-minus mutants of the viruses of major four human and simian immunodeficiency
      viruses (HIVs and SIVs) were monitored for their progeny virion production upon
      transfection into the cells, which are dependent on the HIV-1 Vpu for efficient
      particle release. Of the env mutants of HIV-1 (one mutant), HIV-2/SIVmac (three
      mutants), SIVagm (one mutant), and SIVmnd (one mutant) examined, the mutant of
      SIVmnd generated a very low level of progeny virions similar to that by the HIV-1
      Vpu-minus mutant. This effect of the mutation was not observed in the cells which
      are independent on the Vpu for virion release. The Env of SIVmnd efficiently
      enhanced virion release of heterologous viruses like the HIV-1 Vpu.

PMID- 10403707
TI  - Judgments about estrogen replacement therapy: the role of age, cognitive
      abilities, and beliefs.
AB  - This study investigated age, cognitive abilities, health beliefs, and other
      factors in women's judgments about effective treatments for menopause. Women (N =
      102) ranging in age from 20 to 79 read a vignette about a woman facing a decision
      about Estrogen Replacement Therapy (ERT) and then made judgments about what
      should be done. Participants also completed a battery of questions pertaining to
      ERT and cognitive abilities. Path-analytic techniques were used to determine the
      role of specific cognitive abilities and the representation of menopause and its
      treatment in making judgments about ERT treatments. Cognitive abilities had
      direct effects on treatment decisions. Education affected the number of perceived
      options for treatment. Age and education indirectly affected treatment decisions,
      operating through cognitive abilities. Factors related to the mental
      representation of menopause had no direct effects and few indirect effects on
      treatment decisions. Potential mechanisms that can help older adults compensate
      for declines in cognitive abilities in medical decisions are discussed.

PMID- 10403708
TI  - Season's greetings: adults' social contacts at the holiday season.
AB  - Close friends and family play an important role in adults' lives, but little is
      known about the implications of infrequent or peripheral social ties that adults
      maintain. Eighty-seven adults, ranging in age from 24 to 87 years (M = 51.25)
      provided information about their holiday card networks. Participants completed
      surveys for up to 25 cards that they received during one holiday season (n =
      1,405 surveys completed) and provided the holiday greetings as well, if they were
      willing (n = 1,152 cards). Over half of the cards participants received were from
      individuals whom participants did not consider to be close friends or family
      members and whom they had not seen in over a year. Adults of all ages described
      emotional reactions to approximately one third of the cards they received.
      Younger adults tended to view their holiday greetings as a means of maintaining
      or building new social ties, whereas older adults were more likely to view their
      holiday greetings as a link to their personal past. Receiving a greater number of
      holiday cards and receiving cards from close social contacts were associated with
      increased feelings of social embeddedness. Similarities and differences between
      peripheral ties and close social ties are considered.

PMID- 10403709
TI  - Change in depressive symptoms among daughter caregivers: an 18-month longitudinal
      study.
AB  - This longitudinal study investigates, over an 18-month period, the caregiving
      experience of a probability sample of 115 daughters who provided care to an aging
      parent. The levels of depressive symptoms manifested by these daughters were
      relatively low, with only 23.5% scoring in the clinical range during the study.
      Nevertheless, there was substantive change in depressive symptoms among the
      daughters during the 18 months. Daughters with higher levels of mastery were more
      likely to use problem-focused coping strategies, which led to reductions in
      depression, whereas daughters with lower levels of mastery were more likely to
      use emotion-focused coping, which led to increased levels of depression. Mastery
      was higher when the caregiving role was shared with a sibling: it was lower if
      the daughter had other caregiving responsibilities and if the parent care
      recipient had elevated levels of behavior problems.

PMID- 10403710
TI  - Reducing gist-based false recognition in older adults: encoding and retrieval
      manipulations.
AB  - Using a categorized pictures paradigm, Koutstaal and Schacter (1997) reported
      high levels of false recognition of lures that were categorically related to
      presented items. Although also shown by younger adults, false recognition was
      markedly higher for older adults. To probe the factors underlying this age
      difference, these experiments required participants to engage in more careful
      scrutiny of the items at retrieval or to notice specific differentiating
      perceptual features of the objects during encoding. False recognition was reduced
      with each of these manipulations, but neither manipulation, either separately or
      together, eliminated the age difference in false recognition. Older adults can
      considerably reduce false recognition if encouraged to use more stringent
      decision criteria. Persistent difficulty in opposing familiarity-based responding
      and comparatively more generic encoding may contribute to residual deficits.

PMID- 10403711
TI  - Self-appraisal, life satisfaction, and retrospective life choices across one and
      three decades.
AB  - This research investigated the relationship of a self-appraisal of having lived
      up to one's intellectual abilities at midlife (average age of 49 years) with life
      satisfaction and retrospective life choices 1 and 3 decades later among 383
      participants in the Terman Study of the Gifted. Study 1 showed that participants
      who reported living up to their intellectual abilities were higher in
      satisfaction with occupational success, satisfaction with family life, and joy in
      living 11 years later. Study 2 showed that participants who reported living up to
      their abilities were higher in overall life satisfaction and were less likely to
      report that they would make different life choices in work or family life 3
      decades later. In an integrative structural equation model, the relation between
      the midlife self-appraisal of having lived up to intellectual abilities and
      overall satisfaction at age 80 was mediated by life satisfaction discrepancy at
      age 61.

PMID- 10403712
TI  - Use it or lose it: engaged lifestyle as a buffer of cognitive decline in aging?
AB  - Data from the Victoria Longitudinal Study were used to examine the hypothesis
      that maintaining intellectual engagement through participation in everyday
      activities buffers individuals against cognitive decline in later life. The
      sample consisted of 250 middle-aged and older adults tested 3 times over 6 years.
      Structural equation modeling techniques were used to examine the relationships
      among changes in lifestyle variables and an array of cognitive variables. There
      was a relationship between changes in intellectually related activities and
      changes in cognitive functioning. These results are consistent with the
      hypothesis that intellectually engaging activities serve to buffer individuals
      against decline. However, an alternative model suggested the findings were also
      consistent with the hypothesis that high-ability individuals lead intellectually
      active lives until cognitive decline in old age limits their activities.

PMID- 10403713
TI  - Age-related decline in prospective memory: the roles of cue accessibility and cue
      sensitivity.
AB  - In two experiments the authors evaluated the hypothesis that age-related decline
      in prospective memory reflects momentary lapses of intention (MLIs), and explored
      two factors, cue sensitivity and accessibility, that may contribute to MLIs. MLIs
      were reliably greater than zero in Experiment 1, indicating that performance
      fluctuated over the course of the task. Analysis of the response latency data
      (RL) revealed that older adults demonstrated elevated RL for missed prospective
      cues and were much slower to respond correctly to prospective cues than younger
      adults. These findings indicate preserved cue sensitivity in later adulthood and
      an age-related decline in cue accessibility. Experiment 2 demonstrated that cue
      sensitivity did not result from an orienting response to the perceptual novelty
      associated with the prospective cues.

PMID- 10403714
TI  - Neuroticism, coping strategies, and negative well-being among caregivers.
AB  - Neuroticism was incorporated into a model for predicting the well-being of family
      caregivers. Using data from 596 women with an adult child with a chronic
      disability, the model hypothesizes direct effects of neuroticism on a caregiver's
      perceptions of the stressor, on her wishful-escapism and problem-focused coping,
      and on psychological well-being. Results indicate that neuroticism exerts direct
      and indirect effects on negative well-being. Results also indicate that stressors
      have direct effects on both wishful-escapism coping and problem-focused coping.
      Burden had direct effects on negative psychological well-being. Diagnosis
      influences the model by having direct effects on stressors and wishful-escapism
      coping but not on problem-focused coping or burden. Inclusion of individual level
      variables, such as neuroticism, results in a substantial amount of explained
      variance in negative well-being.

PMID- 10403715
TI  - Age differences in implicit memory: fragmented object identification and category
      exemplar generation.
AB  - In a cross-sectional study of 164 participants aged 21 to 91, the authors
      examined age differences on two implicit tests, fragmented object identification
      (FOI) and category exemplar generation (CEG), and on tests of explicit memory,
      attention, and verbal fluency. FOI results revealed impaired perceptual skill
      learning in those over 60 and a decrease in perceptual priming across young,
      middle-aged, and older groups. CEG priming was impaired in those over 80.
      Regression analysis revealed explicit contamination of priming on both the FOI
      and CEG tests. Across the three implicit measures, age accounted for 4 to 13% of
      the variance when explicit memory was controlled. Semantic fluency predicted CEG
      priming, suggesting possible frontal lobe involvement on the test. Altogether,
      results indicate that age has a small but reliable influence on implicit memory.

PMID- 10403717
TI  - Inhibition in the processing of garden-path sentences.
AB  - The Hartman and Hasher (1991) garden-path sentence completion task has been used
      in several studies to assess the efficiency of the deletion function of
      inhibition (e.g., L. Hasher, R. Zacks, & C. P. May, 1999 ), with results
      suggesting that younger adults are efficient at suppressing once relevant but no
      longer appropriate information, whereas older adults generally are not (e.g., M.
      Hartman & L. Hasher, 1991: L. Hasher. M. B. Quig, & C. P. May, 1997; C. P. May &
      L. Hasher, 1998). An alternative interpretation of patterns of access to relevant
      and no-longer-relevant sentence endings focuses on the difficulty of selecting
      final words for sentence frames and on integration effects in implicit memory (M.
      Hartman, 1995). This alternative is considered and found wanting on the basis of
      both new and old empirical data. On the basis of present data and related
      findings, it is concluded that the task does measure inhibitory efficiency.

PMID- 10403716
TI  - Neuropsychological function and apolipoprotein E genotype in the preclinical
      detection of Alzheimer's disease.
AB  - Nondemented older adults genotyped for the Apolipoprotein E (ApoE) epsilon4
      allele (n = 43) were neuropsychologically compared to participants without a copy
      of the epsilon4 allele (n = 90). At baseline, the groups did not differ on age,
      education, gender, or global cognitive status. ApoE-epsilon4 participants
      demonstrated significantly poorer mean performances on delayed recall, but no
      significant group differences emerged on attention, language, constructional
      skills, psychomotor speed, or executive function. Significantly more ApoE
      epsilon4 participants developed probable or questionable Alzheimer's disease (AD)
      compared with non-epsilon4 participants, suggesting that the group differences
      resulted from a preponderance of preclinical AD cases within the epsilon4 group
      and not from a direct influence of ApoE genotype on cognition. Cox proportional
      hazards analysis, adjusting for age, years of education, and global cognitive
      status, revealed that ApoE-epsilon4 allele status and measures of recall
      performance were significant and independent predictors of conversion to AD.
      Results support the importance of specific episodic memory changes and possession
      of the ApoE-epsilon4 allele in the preclinical detection of AD.

PMID- 10403718
TI  - The locus of adult intelligence: knowledge, abilities, and nonability traits.
AB  - Some intelligence theorists (e.g., R. B. Cattell, 1943; D. O. Hebb, 1942) have
      suggested that knowledge is one aspect of human intelligence that is well
      preserved or increases during adult development. Very little is known about
      knowledge structures across different domains or about how individual differences
      in knowledge relate to other traits. Twenty academic and technology-oriented
      tests were administered to 135 middle-aged adults. In comparison with younger
      college students, the middle-aged adults knew more about nearly all of the
      various knowledge domains. Knowledge was partly predicted by general
      intelligence, by crystallized abilities, and by personality, interest, and self
      concept. Implications of this work are discussed in the context of a
      developmental theory that focuses on the acquisition and maintenance of
      intelligence-as-knowledge, as well as the role of knowledge for predicting the
      vocational and avocational task performance of adults.

PMID- 10403719
TI  - Effects of divided attention and time course on automatic and controlled
      components of memory in older adults.
AB  - The relation between attention available at encoding and automatic and
      consciously controlled aspects of memory was investigated within a single task
      using the process-dissociation procedure (L. L. Jacoby, 1991). Sixty-four older
      adults and 64 young adults studied a word list in either a full or a divided
      attention condition. Recall cued with word stems was tested immediately and at 20
      minute and 60-minute delays. In contrast to consciously controlled influences of
      memory, automatic influences of memory (a) showed generally no reliable age
      differences, (b) remained invariant across the manipulation of attention, and (c)
      remained relatively invariant across the 60-minute time course. Furthermore, age
      did not interact with the attentional manipulation or the time course factor.

PMID- 10403720
TI  - Hepatitis C and liver transplantation.

PMID- 10403721
TI  - Helicobacter pylori and dyspepsia: trick or treat?

PMID- 10403722
TI  - The pill: safe sex and Crohn's disease?

PMID- 10403723
TI  - Gall bladder and bowel: the links multiply.

PMID- 10403725
TI  - HBV + HCV = HCC?

PMID- 10403724
TI  - Cyclosporin and chronic pancreatitis: a supermodel?

PMID- 10403726
TI  - Nuclear factor kappaB in liver disease.

PMID- 10403727
TI  - Endoscopic assessment of oesophagitis: clinical and functional correlates and
      further validation of the Los Angeles classification.
AB  - BACKGROUND: Endoscopic oesophageal changes are diagnostically helpful and
      identify patients exposed to the risk of disease chronicity. However, there is a
      serious lack of agreement about how to describe and classify the appearance of
      reflux oesophagitis AIMS: To examine the reliability of criteria that describe
      the circumferential extent of mucosal breaks and to evaluate the functional and
      clinical correlates of patients with reflux disease whose oesophagitis was graded
      according to the Los Angeles system. METHODS: Forty six endoscopists from
      different countries used a detailed worksheet to evaluate endoscopic video
      recordings from 22 patients with the full range of severity of reflux
      oesophagitis. In separate studies, Los Angeles system gradings were correlated
      with 24 hour oesophageal pH monitoring (178 patients), and with clinical trials
      of omeprazole treatment (277 patients). RESULTS: Evaluation of circumferential
      extent of oesophagitis by the criterion of whether mucosal breaks extended
      between the tops of mucosal folds, gave acceptable agreement (mean kappa value
      0.4) among observers. This approach is used in the Los Angeles system. An
      alternative approach of grouping the circumferential extent of mucosal breaks as
      occupying 0-25%, 26-50%, 51-75%, 76-99%, or 100% of the oesophageal
      circumference, gave unacceptably high interobserver variation (mean kappa values
      0-0.15) for all but the lowest category of extent (mean kappa value 0.4).
      Severity of oesophageal acid exposure was significantly (p<0.001) related to the
      severity grade of oesophagitis. Preteatment oesophagitis grades A-C were related
      to heartburn severity (p<0.01), outcomes of omeprazole (10 mg daily) treatment
      (p<0.01), and the risk for symptom relapse off therapy over six months (p<0.05).
      CONCLUSIONS: Results add further support to previous studies for the clinical
      utility of the Los Angeles system for endoscopic grading of oesophagitis.

PMID- 10403728
TI  - Corpus gastritis is protective against reflux oesophagitis.
AB  - BACKGROUND: Gastric acid is important in the pathogenesis of reflux oesophagitis.
      Acid production by the gastric corpus is reduced in corpus gastritis. AIMS: To
      determine whether corpus gastritis protects against reflux oesophagitis. METHODS:
      Patients presenting for elective oesophagogastroduodenoscopy were studied. Two
      biopsy specimens were taken from the antrum, corpus, and cardia and stained with
      haematoxylin/eosin and Diff-Quick II stains. The presence and severity of
      gastritis were graded according to a modified updated Sydney classification.
      RESULTS: Of 302 patients, 154 had endoscopic signs of reflux oesophagitis. There
      was no difference between patients with and controls without oesophagitis in the
      overall infection rates with Helicobacter pylori. Acute or chronic corpus
      gastritis occurred less often in patients with than those without reflux
      oesophagitis. Compared with controls, corpus gastritis was less severe in
      patients with reflux oesophagitis. The presence of acute or chronic gastritis in
      the corpus was significantly correlated with either type of gastritis in other
      areas of the stomach. In a multivariate logistic regression, age, sex, smoking
      status, and the presence of chronic corpus gastritis all exerted a significant
      influence on the presence of reflux oesophagitis. Chronic corpus gastritis was
      associated with a 54% reduced risk for reflux oesophagitis. CONCLUSIONS: While
      infection with H pylori alone may not affect the occurrence of reflux
      oesophagitis, the development of chronic corpus gastritis seems to be protective.

PMID- 10403729
TI  - A prospective randomised trial of a "test and treat" policy versus endoscopy
      based management in young Helicobacter pylori positive patients with ulcer-like
      dyspepsia, referred to a hospital clinic.
AB  - BACKGROUND: Management of dyspepsia remains a controversial area. Although the
      European Helicobacter pylori study group has advised empirical eradication
      therapy without oesophagogastroduodenoscopy (OGD) in young H pylori positive
      dyspeptic patients who do not exhibit alarm symptoms, this strategy has not been
      subjected to clinical trial. AIMS: To compare a "test and treat" eradication
      policy against management by OGD. PATIENTS: Consecutive subjects were
      prospectively recruited from open access OGD and outpatient referrals. METHODS: H
      pylori status was assessed using the carbon-13 urea breath test. H pylori
      positive patients were randomised to either empirical eradication or OGD.
      Symptoms and quality of life scores were assessed at baseline and subsequent
      reviews over a 12 month period. RESULTS: A total of 104 H pylori positive
      patients aged under 45 years were recruited. Fifty two were randomised to receive
      empirical eradication therapy and 52 to OGD. Results were analysed using an
      intention to treat policy. Dyspepsia scores significantly improved in both groups
      over 12 months compared with baseline; however, dyspepsia scores were
      significantly better in the empirical eradication group. Quality of life showed
      significant improvements in both groups at 12 months; however, physical role
      functioning was significantly improved in the empirical eradication group.
      Fourteen (27%) in the empirical eradication group subsequently proceeded to OGD
      because of no improvement in dyspepsia. CONCLUSIONS: This randomised study
      strongly supports the use of empirical H pylori eradication in patients referred
      to secondary practice; it is estimated that 73% of OGDs in this group would have
      been avoided with no detriment to clinical outcome.

PMID- 10403730
TI  - Synergistic effects of interferon gamma and tumour necrosis factor alpha on T84
      cell function.
AB  - BACKGROUND: Inflammatory bowel disease (IBD) is characterised by chronic
      intestinal inflammation and increased epithelial permeability. Both tumour
      necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) have been
      implicated in IBD. AIMS: To understand better the effects of these cytokines on
      epithelial cell function. METHODS: T84 cells were cultured with IFN-gamma and TNF
      alpha and changes in transepithelial resistance (TER), fluorescein isothiocyanate
      (FITC) dextran flux, short circuit current (I(sc)), cystic fibrosis transmembrane
      conductance regulator (CFTR) protein levels, cell morphology, TNF receptor gene
      expression, and apoptosis were assayed. RESULTS: Relative to controls,
      significant changes (p<0.05) occurred in cells incubated with IFN-gamma for two
      days: TER was decreased to 20 (6.2)%, FITC-dextran flux was increased by 109 (19)
      fold, cAMP and Ca dependent I(sc) were decreased to 51 (6.4)% and 24 (2.2)%,
      respectively, and CFTR levels were decreased to 47 (11)%. Cell morphology was
      altered but cell death was not induced. TNF receptor mRNA levels were increased.
      When added with IFN-gamma, TNF-alpha accelerated IFN-gamma dependent changes.
      Relative to controls, significant changes occurred after one day of culture with
      IFN-gamma plus TNF-alpha: TER was decreased to 27 (3.5)%, FITC-dextran flux was
      increased by 185 (45)-fold, and cAMP and Ca dependent I(sc) were decreased to 66
      (12)% and 35 (6.8)%, respectively. TNF-alpha also enhanced IFN-gamma dependent
      changes in cell morphology but did not induce cell death. CONCLUSION: IFN-gamma
      alters T84 cell epithelial properties and TNF-alpha can enhance these effects,
      perhaps due to IFN-gamma dependent increases in TNF receptor gene expression.
      Overall, these studies suggest that in IBD, TNF-alpha may have synergistic
      effects on IFN-gamma mediated alterations of epithelial cell function.

PMID- 10403732
TI  - Strictures in Crohn's disease are characterised by an accumulation of mast cells
      colocalised with laminin but not with fibronectin or vitronectin.
AB  - BACKGROUND/AIMS: Intestinal fibrosis and stricture formation is an unresolved
      problem in Crohn's disease. The aim of this study was to investigate whether mast
      cells accumulate in these tissues and whether their localisation is associated
      with extracellular matrix components. METHODS: Mast cells were visualised by
      immunohistochemical staining of the mast cell specific proteases chymase and
      tryptase. Their localisation in relation to extracellular matrix components was
      shown by immunohistochemical double labelling. RESULTS: In strictures in Crohn's
      disease, a striking accumulation of mast cells was seen particularly in the
      hypertrophied and fibrotic muscularis propria, with a mean (SEM) mast cell number
      of 81.3 (14.9) v 1.5 (0.9)/mm(2) in normal bowel (p<0.0005). All mast cells in
      the muscularis propria were colocalised with patches of laminin. In contrast, in
      the submucosa, laminin was exclusively found in the basal lamina of blood vessels
      where many adherent mast cells were seen. No colocalisation of mast cells was
      found with fibronectin or vitronectin. CONCLUSIONS: The large accumulation of
      mast cells in the muscle layer of strictured bowel suggests a functional role for
      these cells in the hypertrophic and fibrotic response of the smooth muscle cells.
      The colocalisation with laminin indicates a mechanism of interaction between
      smooth muscle cells and mast cells that may be important in the role of mast
      cells in the process of fibrosis.

PMID- 10403731
TI  - Reduced oxidative and nitrosative damage in murine experimental colitis in the
      absence of inducible nitric oxide synthase.
AB  - BACKGROUND: Oxidative and nitrosative stress have been implicated in the
      pathogenesis of inflammatory bowel diseases. AIMS: To study the role of nitric
      oxide (NO) derived from inducible NO synthase (iNOS) in an experimental model of
      murine enterocolitis. METHODS: Trinitrobenzene sulphonic acid (TNBS) was
      instilled per rectum to induce a lethal colitis in iNOS deficient mice and in
      wild type controls. The distal colon was evaluated for histological evidence of
      inflammation, iNOS expression and activity, tyrosine nitration and
      malondialdehyde formation (as indexes of nitrosative and oxidative stress),
      myeloperoxidase activity (as index of neutrophil infiltration), and tissue
      localisation of intercellular adhesion molecule 1 (ICAM-1). RESULTS: TNBS
      administration induced a high mortality and weight loss associated with a severe
      colonic mucosal erosion and ulceration, increased myeloperoxidase activity,
      increased concentrations of malondialdehyde, and an intense staining for
      nitrotyrosine and ICAM-1 in wild type mice. Genetic ablation of iNOS gene
      conferred to mice a significant resistance to TNBS induced lethality and colonic
      damage, and notably reduced nitrotyrosine formation and concentrations of
      malondialdehyde; it did not, however, affect neutrophil infiltration and
      intestinal ICAM-1 expression in the injured tissue. CONCLUSION: Data show that
      activation of iNOS is required for nitrosative and oxidative damage in
      experimental colitis.

PMID- 10403733
TI  - Oral contraceptive use and the clinical course of Crohn's disease: a prospective
      cohort study.
AB  - BACKGROUND: Women with Crohn's disease are usually advised not to take oral
      contraceptives, but, unlike smoking, there is no clear association between
      current oral contraceptive use and more severe disease. AIM: To assess the effect
      of oral contraceptive use on the clinical course of Crohn's disease. PATIENTS:
      331 women, aged 16-50 years, with Crohn's disease and Crohn's disease activity
      index <200, were enrolled consecutively during a one year period. Patients were
      classified at inclusion as oral contraceptive users or non-users and smokers or
      non-smokers. METHODS: A prospective 12-18 month cohort study was used. The main
      outcome measures were flare up rate and time to flare up. RESULTS: In total, 134
      women used oral contraceptives, in most cases low oestrogen formulations. During
      the study period, 61 oral contraceptive users (46%) developed a flare up,
      compared with 85 non-users (43%). The hazard ratio for oral contraceptive use was
      1.11 (95% confidence interval 0.80 to 1.55). Variables associated with flare up
      were smoking status, recently active disease, baseline Crohn's disease activity
      index, and presence of anoperineal lesions. The same results were obtained when
      the analysis was restricted to patients eligible for a relapse prevention trial.
      CONCLUSION: Unlike smoking, oral contraceptives have no effect on Crohn's disease
      activity.

PMID- 10403734
TI  - Gut origin of sepsis: a prospective study investigating associations between
      bacterial translocation, gastric microflora, and septic morbidity.
AB  - AIMS: To investigate the "gut origin of sepsis" hypothesis. METHODS: Prospective
      controlled study of 279 surgical patients in which cultures of nasogastric
      aspirates were compared with those obtained from mesenteric lymph nodes taken at
      laparotomy and the organisms cultured from subsequent septic complications.
      Bacterial translocation was confirmed if positive cultures were obtained from
      mesenteric lymph nodes. Postoperative sepsis was defined as any positive culture
      in the postoperative period. Bacterial species obtained in gastric microflora,
      mesenteric lymph nodes, and postoperative septic complications were compared.
      RESULTS: Only 85/279 patients (31%) had a sterile nasogastric aspirate; the most
      frequently identified organism was Candida spp. (54%) and the most common enteric
      organism cultured was E coli (20%). Multiple organisms were isolated in 39% and
      occurred more frequently in patients aged over 70 years, those undergoing non
      elective surgery, and in those requiring proximal gastrointestinal surgery.
      Postoperative sepsis was more common in these patients. Bacterial translocation
      occurred in 21% and was significantly more frequent in those with multiple
      organisms in their nasogastric aspirates. E coli was the commonest organism
      isolated from the lymph node specimens (48%) and septic foci (53%). Fungal
      translocation did not occur. An identical genus was identified in the nasogastric
      aspirate and the septic focus in 30% of patients, in the nasogastric aspirate and
      the lymph node in 31%, and in the lymph node and a postoperative septic focus in
      45%. CONCLUSIONS: Proximal gut colonisation is associated with both increased
      bacterial translocation and septic morbidity. The commonality of organisms
      identified supports the gut origin of sepsis hypothesis.

PMID- 10403735
TI  - Intestinal crypt cell apoptosis in murine acute graft versus host disease is
      mediated by tumour necrosis factor alpha and not by the FasL-Fas interaction:
      effect of pentoxifylline on the development of mucosal atrophy.
AB  - BACKGROUND: Murine T cell mediated acute semiallogeneic graft versus host disease
      (GVHD) is characterised by lymphocytic infiltrates, crypt hyperplasia, and
      villous atrophy. It has been shown that programmed cell death (apoptosis) of the
      crypt epithelium takes place during the intestinal manifestation of acute GVHD.
      AIMS: To investigate which of the two most investigated inductors of apoptosis
      (Fas ligand (FasL) and tumour necrosis factor alpha (TNF-alpha)) is responsible
      for the induction of apoptosis in this animal model. METHODS: Animals undergoing
      acute semiallogeneic GvH reaction were treated with neutralising anti-TNF-alpha,
      two different anti-FasL antibodies, or pentoxifylline. RESULTS: Anti-TNF-alpha
      application inhibited the appearance of apoptotic cells in the intestinal mucosa,
      whereas anti-FasL antibodies had no influence on mucosal apoptosis. In addition,
      the transfer of FasL deficient (gld) donor lymphocytes still induced crypt cell
      apoptosis, villous atrophy, and crypt hyperplasia. Furthermore, when the animals
      were treated with pentoxifylline, a known inhibitor of TNF-alpha secretion in
      vitro and in vivo, there was significant normalisation of the intestinal
      morphology accompanied by inhibition of epithelial apoptosis. CONCLUSIONS: The
      FasL-Fas interaction is not involved in the induction of apoptosis during acute
      GVHD. However, neutralisation of TNF-alpha by an antibody or by pentoxifylline
      inhibits the occurrence of apoptosis and of mucosal atrophy in this animal model.
      These results have implications for the treatment of immunologically mediated
      human atrophic gut diseases-for example, diet refractory cases of coeliac
      disease.

PMID- 10403736
TI  - Structural, neuronal, and functional adaptive changes in atrophic rat ileum.
AB  - BACKGROUND: Inactivity of the gut leads to atrophic changes of which little is
      known. AIMS: To investigate structural, neuronal, and functional changes
      occurring in bypassed rat ileum. METHODS: Morphometry was used to characterise
      the atrophic changes. The numbers of enteric neurones, their expression of
      neurotransmitters, and the presence of interstitial cells of Cajal were studied
      using immunocytochemistry and in situ hybridisation. Motor activity was studied
      in vitro. RESULTS: Adaptive changes in bypassed ileum include atrophy and
      remodelling of the gut wall. The total numbers of submucous and myenteric
      neurones per unit length increased one and four weeks after bypass but were
      identical to sham operated intestine 10 weeks after bypass. Neurones expressing
      vasoactive intestinal peptide, neuropeptide Y, or pituitary adenylate cyclase
      activating peptide decreased gradually in number in bypassed ileum. Nitric oxide
      synthase expressing neurones were increased, particularly in the myenteric
      ganglia. No change in the frequency and distribution of interstitial cells of
      Cajal was noted. The contractile response elicited by electrical stimulation of
      sham operated ileum consisted of a fast cholinergic twitch followed by a slower
      non-adrenergic, non-cholinergic contraction. In the bypassed ileum an identical
      biphasic contraction was elicited; however, the entire response was non
      adrenergic, non-cholinergic. The relaxatory response to electrical stimulation in
      sham operated ileum was nitric oxide mediated; after bypass it was non-nitrergic.
      CONCLUSIONS: Notable atrophic changes were seen in the rat ileum after bypass.
      The enteric nervous system reacted with neuronal cell death and plasticity in
      terms of release and expression of neurotransmitters.

PMID- 10403737
TI  - Interleukin 1 and interleukin 1beta converting enzyme (caspase 1) expression in
      the human colonic epithelial barrier. Caspase 1 downregulation in colon cancer.
AB  - BACKGROUND: Interleukin (IL) 1beta converting enzyme (now known as caspase 1) is
      able to process pro-IL-1beta into its active form and is involved in proapoptotic
      signalling. AIMS: To characterise IL-1 and caspase 1 expression in human colonic
      epithelial cells. METHODS: Intracellular IL-1 content (IL-1alpha and IL-1beta)
      was measured by ELISA in freshly isolated human normal colonocytes. Caspase 1
      expression was determined both at the mRNA level using in situ hybridisation and
      reverse transcription polymerase chain reaction, and at the protein level by
      immunoblotting experiments using antibodies specific for the proform of caspase 1
      and for its cleavage forms. RESULTS: Low amounts of IL-1beta were found in nearly
      all preparations (92%), and IL-1alpha was detected in only 45% of human
      colonocyte preparations. The normal colonic epithelium strongly expressed caspase
      1, both at the mRNA level and at the protein level in its latent form. In
      contrast, caspase 1 was not expressed in colon cancer (primary colonic
      adenocarcinomas and cancer cell lines). CONCLUSIONS: The demonstration that the
      human colonic epithelial barrier is able to express caspase 1 and its substrate
      IL-1beta reinforces the concept that, under certain conditions, the epithelium
      could trigger an inflammatory reaction. In addition, the finding that caspase 1
      was downregulated in colonic adenocarcinomas supports the concept that disrupted
      apoptosis pathways may be involved in tumour formation and/or may confer
      resistance to treatment.

PMID- 10403738
TI  - Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal
      cancers.
AB  - BACKGROUND/AIM: Matrilysin is one of the matrix metalloproteinases that has a
      critical role in tumour invasion, and is often expressed in gastrointestinal
      cancers. The aim of this study was to examine the role of matrilysin in
      metastasis of human colorectal cancers. PATIENTS (SUBJECTS)/METHODS: The relation
      between matrilysin expression and Dukes's type was investigated
      immunohistochemically in 83 surgically resected colorectal cancers, including
      five with liver metastasis. Moreover, the effects of matrilysin on the in vivo
      invasive and metastatic potential of colon cancer cells transfected with
      matrilysin cDNA were examined after subcutaneous injection into SCID mice.
      RESULTS: In 46% of primary and all of metastatic liver tumours, over 10% of
      cancer cells were stained positively for matrilysin. The expression of matrilysin
      correlated significantly with the presence of nodal or distant metastases
      (p<0.05). In addition, matrilysin transfectants formed invasive tumours and
      multiple liver metastases in SCID mice, without producing any significant
      difference in the subcutaneous tumour growth from mock transfectants. Casein
      zymography showed that the invading and metastasised tumours showed conspicuous
      matrilysin activity, which correlated with the number of metastatic lesions
      (p<0.001). CONCLUSIONS: Matrilysin showed a correlation with metastasis in a
      cohort of 83 colorectal cancer patients and marked metastatic potentiation in
      human colorectal cancer xenografts, indicating that it may play a critical role
      in the metastatic pathway of colorectal cancers.

PMID- 10403739
TI  - Polymerase chain reaction based human leucocyte antigen genotyping for the
      investigation of suspected gastrointestinal biopsy contamination.
AB  - BACKGROUND: Mislabelling or contamination of surgical specimens may lead to
      diagnostic inaccuracy, particularly within gastrointestinal pathology when
      multiple small mucosal biopsy specimens are commonly taken, and where a tiny
      fragment of foreign tissue may be indistinguishable from true biopsy material
      using histological assessment alone. AIMS: To assess the utility of polymerase
      chain reaction (PCR) based human leucocyte antigen (HLA) genotyping techniques
      for the investigation of potentially mislabelled or contaminated gastrointestinal
      biopsy specimens. PATIENTS: Ten cases (28 samples) in which mislabelling or
      contamination was suspected, comprising four upper gastrointestinal tract
      biopsies and six colonoscopic biopsy series. METHODS: Direct and nested PCR
      sequence specific primer (SSP) based HLA class II genotyping was performed on DNA
      extracted from formalin fixed and paraffin wax embedded tissue (23 samples) or
      peripheral blood leucocytes (five samples). RESULTS: A full HLA-DRB1 genotype was
      determined in all 28 samples. In seven cases the HLA-DRB1 genotype of the
      putative contaminant was different to that of the corresponding reference tissue,
      confirming different individual origins for the contaminant and reference
      material. In one case the contaminant tissue was shown to possess the same HLA
      DRB1 alleles as a second patient (probable source). In the remaining three cases
      the same HLA-DRB1 alleles were detected within the potential contaminant and
      reference tissues. CONCLUSIONS: PCR based HLA class II genotyping is a valuable
      tool for investigating potential contamination or mislabelling within
      gastrointestinal biopsy specimens and this report has confirmed contamination in
      seven of ten cases studied.

PMID- 10403740
TI  - Gall bladder emptying in severe idiopathic constipation.
AB  - BACKGROUND: It has been suggested that slow transit constipation (STC) may be
      part of a panenteric motor disorder. AIM: To evaluate motility of an upper
      gastrointestinal organ, the gall bladder, in 16 patients with STC and 20 healthy
      controls. METHODS: Gall bladder emptying (ultrasonography) was studied in
      response to neural, cephalic-vagal stimulation with modified sham feeding (MSF)
      for 90 minutes and in response to hormonal stimulation with cholecystokinin (CCK,
      0.5 IDU/kg/h) for 60 minutes. RESULTS: Fasting gall bladder volume in patients
      with STC (17 (2) cm(3)) was significantly (p<0. 01) reduced compared with that in
      controls (24 (2) cm(3)). Gall bladder emptying in response to MSF was
      significantly reduced in patients with STC expressed both as percentage emptying
      (11 (5)% versus 22 (3)%; p<0.05) and as absolute emptying (2.1 (0.7) cm(3) versus
      4.9 (0.7) cm(3); p<0.02). However, percentage gall bladder emptying in response
      to CCK was not different between patients and controls (73 (4)% versus 67 (4)%)
      although the absolute reduction in gall bladder volume was significantly (p<0.05)
      smaller in patients (10.7 (1.1) cm(3) versus 15.3 (1.4) cm(3)). CONCLUSIONS:
      Patients with slow transit constipation have smaller fasting gall bladder
      volumes, impaired gall bladder responses to vagal cholinergic stimulation, but
      normal gall bladder responses to hormonal stimulation with CCK. These results
      point to abnormalities in gastrointestinal motility proximal from the colon in
      slow transit constipation and more specifically, impaired neural responsiveness.

PMID- 10403742
TI  - Iron overload in urban Africans in the 1990s.
AB  - BACKGROUND: In a previously described model, heterozygotes for an African iron
      loading locus develop iron overload only when dietary iron is high, but
      homozygotes may do so with normal dietary iron. If an iron loading gene is
      common, then homozygotes with iron overload will be found even in an urban
      population where traditional beer, the source of iron, is uncommon. AIMS: To
      determine whether iron overload and the C282Y mutation characteristic of
      hereditary haemochromatosis are readily identifiable in an urban African
      population. METHODS: Histological assessment, hepatocellular iron grading, and
      dry weight non-haem iron concentration were determined in post mortem tissue from
      liver, spleen, heart, lungs, and skin. DNA of subjects with elevated hepatic iron
      indexes was analysed for the C282Y mutation. Iron concentrations in other tissues
      were compared. RESULTS: A moderate increase (>30 micromol/g) in hepatic iron
      concentrations was found in 31 subjects (23%; 95% confidence interval 15.9 to
      30.1%), and they were considerably elevated (>180 micromol/g) in seven subjects
      (5.2%; 95% confidence interval 1.5 to 8.9%). Appreciably elevated hepatic iron
      concentrations were associated with heavy iron deposition in both hepatocytes and
      macrophages, and either portal fibrosis or cirrhosis. All were negative for the
      C282Y mutation. Very high concentrations were uncommon in subjects dying in
      hospital. Concentrations of iron in spleen, heart, lung, and skin were
      significantly higher in subjects with elevated hepatic iron. CONCLUSIONS: Iron
      overload is readily identified among urban Africans and is associated with
      hepatic damage and iron loading of several tissues. The condition is unrelated to
      the genetic mutation found in hereditary haemochromatosis.

PMID- 10403741
TI  - Myofibroblast proliferation, fibrosis, and defective pancreatic repair induced by
      cyclosporin in rats.
AB  - BACKGROUND: Full recovery is always achieved after caerulein induced
      pancreatitis. Cyclosporin stimulates transforming growth factor beta (TGF-beta)
      and may interfere with pancreatic regeneration. AIM: To investigate the effects
      of cyclosporin after caerulein induced pancreatitis or after caerulein injury.
      METHODS: Protocol A: rats received cyclosporin daily (20 mg/kg) and caerulein
      pancreatitis was induced on days 2 and 8. Protocol B: six courses of caerulein
      pancreatitis were induced at weekly intervals. Cyclosporin was administered on
      induction and the day before. Rats recovered for two weeks before being killed.
      Control groups received saline, cyclosporin, or caerulein alone. RESULTS:
      Protocol A: plasma TGF-beta1 and tissue collagenase rose after pancreatitis but
      decreased towards baseline values on day 15, matching a low collagen content.
      Morphology disclosed minimal inflammatory infiltration and some interstitial
      cells immunoreactive for smooth muscle alpha-actin (SMA). TGF-beta1 increased,
      and remained high in cyclosporin treated groups (cyclosporin alone and
      cyclosporin plus caerulein). Rats treated with cyclosporin and caerulein showed
      severe pancreatic weight reduction, abundant inflammatory infiltrates, increased
      SMA immunoreactive interstitial cells, high collagen content, and delayed
      collagenase response. No SMA immunoreactive cells were detected in normal rats.
      Cyclosporin alone also increased SMA immunoreactive cells, despite the absence of
      inflammatory infiltration and fairly conserved pancreatic structure. Protocol B:
      the combined pulse treatment induced appreciable collagen deposition and resulted
      in a smaller pancreas than controls. Morphological examination showed atrophy,
      fibrosis, fibroblast proliferation, and mononuclear infiltrates. CONCLUSION:
      Cyclosporin greatly distorts pancreatic repair, transforming caerulein induced
      pancreatitis into a fibrotic chronic-like disease. The mechanism involves TGF
      beta, myofibroblasts, and defective collagenase activation.

PMID- 10403743
TI  - High prevalence of anti-hepatitis B virus serological markers in patients with
      hepatitis C virus related chronic liver disease in Japan.
AB  - BACKGROUND/AIMS: Evidence is accumulating that hepatitis B virus (HBV) is present
      in patients who are hepatitis B surface antigen negative but have antibody to
      hepatitis B core antigen (anti-HBc). Furthermore, recent studies have shown that
      patients with hepatocellular carcinoma who have antibody to hepatitis C virus
      (HCV) often possess HBV related serological markers. Data on the seroprevalence
      of HBV infection in patients with HCV related chronic liver disease were
      collected to evaluate the significance of the presence of antibodies to HBV.
      METHODS: The prevalence of HBV related serological markers was analysed in a
      total of 2014 Japanese patients with HCV infection. The control group comprised
      352 subjects without liver disorder. RESULTS: A large number of patients (49.9%)
      with HCV related chronic liver disease including hepatocellular carcinoma were
      positive for anti-HBc. In addition, the prevalence of anti-HBc closely correlated
      with the clinical stage of the liver disease. There was no relation between a
      past history of blood transfusion and the prevalence of anti-HBc. Notably, anti
      HBc was the only serological marker for HBV infection in a significant number of
      patients with HCV related chronic liver disease (24.1%). CONCLUSIONS: Our data
      provide further evidence for the high prevalence of anti-HBc in patients with HCV
      related chronic liver disease, particularly those with hepatocellular carcinoma,
      suggesting that HBV infection, probably including latent infection, may play an
      important role in carcinogenesis in these patients.

PMID- 10403744
TI  - Familial occurrence of nodular regenerative hyperplasia of the liver: a report on
      three families.
AB  - BACKGROUND/AIMS: Nodular regenerative hyperplasia of the liver is a histological
      lesion usually associated with systemic diseases, haematological malignancies, or
      drugs. Its prognosis depends on portal hypertension, which usually is well
      tolerated and requires medical management only. PATIENTS: Three unrelated
      families, in which two sibling adult male patients presented with nodular
      regenerative hyperplasia of the liver, were studied. METHODS: Complete clinical
      charts and liver biopsy specimens were available for all patients. In addition,
      explanted livers were available for examination for the two transplanted
      patients. RESULTS: There was no evidence of any of the various clinical
      situations known to be associated with nodular regenerative hyperplasia of the
      liver. Portal hypertension was severe, requiring surgical treatment in two cases.
      Renal lesions were present in three patients. In two patients, progressive
      evolution to liver atrophy and hepatic failure, associated with renal failure,
      led to combined liver and renal transplantation. CONCLUSIONS: This report
      describes the existence of familial cases of nodular regenerative hyperplasia of
      the liver, occurring without underlying or associated systemic disease,
      characterised by a poor clinical course and often associated with progressive
      renal failure.

PMID- 10403745
TI  - Development of a disease specific questionnaire to measure health related quality
      of life in patients with chronic liver disease.
AB  - BACKGROUND AND AIMS: To develop and assess a disease specific instrument for
      measuring health related quality of life (HRQL) in patients with chronic liver
      disease (CLD). METHODS: Based on responses from 60 patients with chronic liver
      disease, from 20 liver experts, and from a Medline search of the literature,
      items potentially affecting the HRQL of these patients were identified. A
      separate sample of 75 patients identified which items they found problematic and
      rated their importance. Results were explored using factor analysis; domains were
      chosen and items placed within domains. Redundant questions were eliminated and
      the final questionnaire was pretested in 10 patients. Using this instrument, HRQL
      was assessed in a further 133 patients with various types and stages of liver
      disease. RESULTS: Patients, experts, and the literature search identified 156
      items of potential importance. Of these, 35 proved important to over 50% of 75
      respondents in the item reduction sample. The factor analysis suggested six
      domains. After eliminating redundancies, the Chronic Liver Disease Questionnaire
      (CLDQ) included 29 items in the following domains: fatigue, activity, emotional
      function, abdominal symptoms, systemic symptoms, and worry. In pretesting,
      patients found the CLDQ clear and easy to complete in 10 minutes. In another 133
      patients, the CLDQ showed a gradient between patients without cirrhosis, Child's
      A cirrhosis, and those with Child's B or C cirrhosis. CLDQ has evidence for
      moderate reliability at six months and seems to be responsive. CONCLUSION: The
      CLDQ is short, easy to administer, produces both a summary score and domain
      scores, and correlates with the severity of liver disease.

PMID- 10403747
TI  - Selection of hepatitis B surface "escape" mutants during passive immune
      prophylaxis following liver transplantation: potential impact of genetic changes
      on polymerase protein function.
AB  - CASE REPORT: A patient is described who developed hepatitis B virus (HBV)
      reinfection five months following liver transplantation. Failure of hepatitis B
      immunoglobulin prophylaxis was associated with the emergence of mutations. HBV
      gene sequencing identified nucleotide substitutions associated with amino acid
      changes, one within the major hydrophilic region (MHR) of the HBV surface antigen
      at amino acid position 144 and one outside the MHR. Because of the overlapping
      reading frames of surface and polymerase genes, the latter surface antigen change
      was associated with an amino acid change in the polymerase protein. The patient
      developed significant allograft hepatitis and was treated with lamivudine (3TC)
      100 mg daily. Rapid decline of serum HBV DNA was observed with loss of HBV e
      antigen and HBV surface antigen from serum. There was normalisation of liver
      biochemistry, and liver immunohistochemistry showed a reduction in HBV core and
      disappearance of HBs antigen staining. CONCLUSION: Surface antigen encoding gene
      mutations associated with HBIg escape may be associated with alteration of the
      polymerase protein. The polymerase changes may affect sensitivity to antiviral
      treatment. Selection pressure on one HBV reading frame (for example, HBIg
      pressure on HBsAg, or nucleoside analogue pressure on polymerase protein) may
      alter the gene product of the overlapping frame. Such interactions are relevant
      to strategies employing passive immune prophylaxis and antiviral treatment.

PMID- 10403746
TI  - Spur cell anaemia and hepatic iron stores in patients with alcoholic liver
      disease undergoing orthotopic liver transplantation.
AB  - BACKGROUND: Following orthotopic liver transplantation (OLT) histological
      examination of explant livers from patients with alcoholic liver disease (ALD)
      sometimes shows extensive iron deposits in a distribution suggestive of
      homozygous haemochromatosis. AIMS: To use haemochromatosis gene (HFE) assays to
      distinguish between ALD with notable siderosis and hereditary haemochromatosis.
      To evaluate the possible influence of spur cell haemolytic anaemia on hepatic
      iron loading. PATIENTS: Thirty seven patients with ALD were abstinent for at
      least six months prior to OLT. Twenty three patients had transferrin saturations
      greater than 55%, 16 also had increased serum ferritin (>350 micrograms/l). Eight
      of 37 (22%) explant livers had grade 3 or 4 hepatic iron deposition,
      predominantly in hepatocytes. Of these, four had a hepatic iron index greater
      than 1. 9 and most seemed to have spur cell haemolytic anaemia. METHODS: Mutation
      analysis for C282Y and H63D mutations was performed on DNA extracts from
      peripheral blood or explant liver. Spur cell haemolytic anaemia was diagnosed
      when the haemoglobin was 105 g/l in the presence of notable acanthocytosis.
      RESULTS: None of the eight patients with grade 3 or 4 hepatic iron had evidence
      of the C282Y mutation. Two of the eight were heterozygous for H63D. None of the
      remaining 28 patients tested showed homozygous HFE mutations. Spur cell anaemia
      was present in six of the eight patients with heavy iron deposition and only one
      of the remaining patients. CONCLUSIONS: The HFE mutation was not present in these
      patients with advanced ALD and heavy iron loading. Spur cell haemolytic anaemia
      provides an alternative potential mechanism for the heavy iron loading.

PMID- 10403748
TI  - A woman who bled after a decade of dyspnoea.

PMID- 10403750
TI  - Cardiac-specific overexpression of Galphaq alters excitation-contraction coupling
      in isolated cardiac myocytes.
AB  - Transgenic mice with cardiac-specific overexpression of G alpha q exhibit a
      biochemical and physiological phenotype of load-independent cardiac hypertrophy
      with contractile dysfunction. To elucidate the cellular basis for altered
      contractility, we measured cellular contraction, Ca(2+)transients, and l -type
      Ca(2+)channel currents (I(Ca)) in left ventricular (LV) myocytes isolated from
      non transgenic (NT) controls or G alpha q hearts. Although baseline contractile
      function (% shortening) and the amplitude of Ca(2+)transients in G alpha q
      myocytes were similar to NT myocytes, the rates of cellular shortening and
      relengthening and the duration of Ca(2+)transients were prolonged in G alpha q
      myocytes. Myocytes from G alpha q hearts had larger cell capacitance but no
      change in I(Ca)density, voltage-dependence of activation and inactivation. The
      responses of I(Ca)to dihydropyridine drugs and a membrane permeable cAMP analog,
      8-(4-chlorophenylthio) cAMP, were not altered; however, the time course of
      I(Ca)inactivation was significantly slower in G alpha q myocytes compared to NT
      myocytes. The kinetic difference in inactivation was abolished when Ba(2+)was
      used as the charge carrier or when the sarcoplasmic reticulum (SR) Ca(2+)was
      depleted by ryanodine, suggesting that Ca(2+)-dependent inactivation is reduced
      in G alpha q myocytes due to altered SR Ca(2+)release. Consistent with this
      hypothesis, the function of SR as assessed by the maximal Ca(2+)uptake rates and
      the apparent affinity of SR Ca(2+)-ATPase for Ca(2+)was reduced in ventricles of
      G alpha q heart. These results suggest that the reduced SR function contributes
      to the depressed contractility associated with this form of cardiac hypertrophy.

PMID- 10403749
TI  - The role of infection in acute pancreatitis.

PMID- 10403751
TI  - Myocardial glucose transporter GLUT1: translocation induced by insulin and
      ischemia.
AB  - Myocardial glucose transport is not only facilitated by the insulin sensitive
      glucose transporter (GLUT) 4 but also by GLUT1. It was recently demonstrated that
      ischemia induces GLUT4 translocation by a mechanism distinct from the insulin
      induced signaling pathway. However, the role of ischemia-mediated GLUT1
      translocation and the signaling pathway involved is not yet defined. This study
      investigated the effects of wortmannin, a phosphatidylinositol-3 kinase
      (PI3kinase) inhibitor, on basal, ischemia- and insulin-stimulated GLUT1
      redistribution. PI3kinase is known to participate in insulin-mediated GLUT4
      translocation. Rat hearts were perfused with Krebs-Henseleit buffer containing 10
      mmol/l glucose according to Langendorff and treated with/without 1 micromol/l
      wortmannin, 100 nmol/l insulin and 15 min no-flow ischemia. Relative subcellular
      distribution of GLUT1 protein was analysed using membrane fractionation and
      subsequent Western blotting. Both ischemia and insulin significantly increased
      the relative amount of GLUT1 in the plasma membrane (PM) compared to controls
      (41.6+/-2.8% in controls v 46.0+/-2.3% in ischemic and 51.4+/-3.9% in insulin
      hearts, both P<0.05) with a concomitant decrease of GLUT1 in intracellular
      membranes. However, the increases were moderate in view of the more than 2-fold
      stimulated GLUT4 translocation shown for ischemia and insulin. Although
      wortmannin completely inhibited insulin-induced GLUT1 translocation (42.0+/-2.0%
      GLUT1 on PM), it had no effect on the ischemia-induced translocation of GLUT1
      (45. 4+/-1% GLUT1 on PM). Treatment with the inhibitor alone did not influence
      basal GLUT1 distribution. Results show that in the perfused rat heart, PI3 kinase
      is involved in the insulin-induced signaling leading to GLUT1 translocation but
      not in the ischemia-mediated signaling and basal GLUT1 trafficking. This suggests
      two different pathways for ischemia- and insulin-induced GLUT1 translocation as
      recently shown for GLUT4.

PMID- 10403753
TI  - Palmitoyl carnitine increases intracellular calcium in adult rat cardiomyocytes.
AB  - Earlier studies have demonstrated that palmitoyl carnitine (PC), a long chain
      acyl carnitine, accumulates in the ischemic myocardium. Although perfusion of
      hearts with PC is known to induce contractile dysfunction which resembles
      ischemic contracture, the mechanisms underlying this derangement are not clear.
      In this study, we examined the effect of exogenous PC on the intracellular
      concentration of calcium ([Ca(2+)](i)) in freshly isolated cardiomyocytes from
      adult rat hearts. The results showed that PC elevated [Ca(2+)](i)in a dose
      dependent (5-20 microm) manner; 15 microm PC evoked a marked and reversible
      increase in [Ca(2+)](i)without having any significant action on cell viability.
      The PC (15 microm)-induced increase in [Ca(2+)](i)was slightly depressed but
      delayed in the absence of extracellular Ca(2+). Pre-incubation of cardiomyocytes
      with sarcolemmal (SL) l -type Ca(2+)-channel blockers, verapamil or diltiazem,
      and inhibitors of SL Na(+)-Ca(2+)exchanger such as Ni(2+)or amiloride, depressed
      the PC-evoked increase in [Ca(2+)](i)significantly. Ouabain, a Na(+)-K(+)ATPase
      inhibitor, and low concentrations of extracellular Na(+)enhanced the PC-induced
      increase in [Ca(2+)](i). Depletion of the sarcoplasmic reticulum (SR)
      Ca(2+)stores by low micromolar concentrations of ryanodine (a SR Ca(2+)-release
      channel activator) or by thapsigargin (a SR Ca(2+)-pump ATPase inhibitor)
      depressed the PC-mediated increase in [Ca(2+)](i). Combined blockade of the l 
      type Ca(2+)channel, Na(+)-Ca(2+)exchanger and the SR Ca(2+)-pump had an additive
      inhibitory effect on the PC response. These observations suggest that the PC
      induced increase in [Ca(2+)](i)is dependent on both Ca(2+)-influx from the
      extracellular space and Ca(2+)-release from the SR stores. Thus, the accumulation
      of PC in the myocardium may be partly responsible for the occurrence of
      intracellular Ca(2+)overload in ischemic heart.

PMID- 10403754
TI  - Duration of ischaemic preconditioning and importance of size of area at risk in
      pigs.
AB  - An explanation of the preconditioning phenomenon must account for the biology of
      the phenomenon. Here we provide a more thorough characterization of ischaemic
      preconditioning (IPC), examining temporal characteristics and the importance of
      the size of area at risk. IPC was induced by two 10-min LAD occlusions separated
      by 30 min reperfusion in pentobarbital anaesthetized open-chest pigs. The last
      brief occlusion was followed by either 30 min, 2 h or 4 h of reperfusion. The
      degree of protection was evaluated by measuring infarct size after either 45 or
      60 min LAD occlusion followed by 2 h of reperfusion. To examine the importance of
      the size of area at risk, the occlusion site on LAD was varied between pigs. IPC
      followed by 30 min and 2 h of reperfusion reduced infarct size from 58+/-2% of
      area at risk to 15+/-4% (P<0.05) and 15+/-6% (P<0.05), respectively, by 45 min of
      LAD occlusion. After 4 h of reperfusion the infarct size-limiting effect of IPC
      was still prominent when a test ischaemic period of 45 min was used (47+/-5%vs
      13+/-1%P<0.05). IPC was paralleled by an increased incidence of ventricular
      fibrillation during the early phase of the prolonged LAD occlusion after 30 min,
      2 h and 4 h of reperfusion. Although no correlation was found between infarct
      size (as a percentage of area at risk) and area at risk (as a percentage of
      ventricular weight) in control pigs, a positive correlation was found between
      these variables in preconditioned pigs. We conclude that the infarct size
      limiting effect of IPC lasts at least 4 h and that it is paralleled by
      profibrillatory effects in open-chest pigs. Furthermore, the infarct size
      limiting effect of IPC depends on the size of area at risk, being most pronounced
      when area at risk is small.

PMID- 10403752
TI  - Mechanical stretch induces platelet-activating factor receptor gene expression
      through the NF-kappaB transcription factor.
AB  - In this study, we used the platelet-activating factor (PAF) receptor gene as a
      model of a mechano-sensitive gene to investigate how mechanical stimuli regulate
      gene expression and cell function. We utilized a culture system of pulmonary
      artery smooth muscle cells and a well-defined in vitro mechanical device that
      imparts an equibiaxial strain repeatedly to cells attached to an elastomeric
      membrane. Northern blot and immunohistochemical analyses revealed increased PAF
      receptor expression at both the mRNA and protein levels after 1 h exposure of the
      cells to a 5% strain at a frequency of 1 Hz. To investigate the mechanism of
      activation of this gene by stretch, we performed transfection experiments with a
      luciferase reporter gene linked to segments of the 5' flanking region of the
      receptor gene promoter. Expression of the transfected reporter gene bearing a 1.1
      kb fragment of the promoter was enhanced in mechanically stretched cells
      indicating a direct effect on transcriptional activity. When truncated to leave
      the nucleotides between -610 to +27, the promoter-reporter construct lost stretch
      inducibility suggesting that the region between -1099 and -610 was required for
      stretch responsiveness. This region contains four copies of NF-kappaB binding
      sites. These elements are in close proximity to one another and can form a
      complex with nuclear proteins derived from stretched cells as demonstrated by gel
      mobility shift assay. Moreover, in experiments using cycloheximide, we found that
      de novo protein synthesis was not necessary for the induction of the PAF receptor
      gene expression by mechanical stretch. Conversely, preincubation of the cells
      with protein kinase C inhibitors suppressed mechanical stretch-induced PAF
      receptor gene expression at the mRNA levels and abrogated upstream events of NF
      kappaB activation in the cytoplasm. These data strongly suggest that stretch
      induced PAF receptor gene expression is mediated by NF-kappaB binding to the PAF
      receptor gene promoter and that protein kinase C activation is among the
      molecular features of NF-kappaB activation and translocation into the nucleus in
      mechanically stretched cells.

PMID- 10403755
TI  - Reduced sarcoplasmic reticulum Ca(2+)-uptake and expression of phospholamban in
      left ventricular myocardium of dogs with heart failure.
AB  - The purpose of this study was to examine the sarcoplasmic reticulum (SR) Ca(2+)
      uptake and the expression of phospholamban (PLB) and Ca(2+)-ATPase (CAA) in left
      ventricular (LV) and right ventricular (RV) myocardium of 6 normal (NL) dogs and
      6 dogs with chronic heart failure (HF). In addition, gene expression of PLB and
      CAA was also examined in LV myocardium of NL and HF dogs. HF (LV ejection
      fraction 23+/-2%) was produced by multiple sequential intracoronary
      microembolizations. Oxalate-dependent Ca(2+)-uptake was measured in isolated
      membrane vesicles. Using specific dog myocardial monoclonal antibody, the
      expression of CAA, PLB and calsequestrin (CSQ) were measured in sodium dodecyl
      sulfate extract prepared from LV and RV tissue. Steady-state mRNA levels were
      determined by Northern hybridization using specific cDNA clones of PLB, CAA, CSQ,
      and glyceraldehyde-3-phosphate dehydrogenase (GADPH), a house keeping gene. SR
      Ca(2+)-uptake of NL and HF dogs increased with increasing Ca(2+)concentrations
      and reached a plateau at 3 microm in both LV and RV. Total capacity (134+/-9 v
      224+/-10 nmol(45)Ca/mg protein/10 min, P<0.05) and maximal velocity (15+/-2 v 2
      nmol(45)Ca/mg protein/min, P<0.05) of the SR to sequester Ca(2+)was significantly
      lower in LV myocardium of HF dogs compared to NL, whereas the Hill coefficient
      and the affinity of the Ca(2+)-pump for Ca(2+)were unchanged. LV tissue levels of
      the PLB and CAA, normalized to noncollagen protein or to CSQ and the PLB and CAA
      mRNA levels, normalized to CSQ or GADPH mRNA, were also significantly lower in HF
      dogs compared to NL. In RV myocardial tissue, no significant differences in total
      capacity of SR to sequester Ca(2+), maximal velocity of SR Ca(2+)-uptake, the
      affinity and Hill Coefficient of the Ca(2+)-pump for Ca(2+), or tissue levels of
      PLB and CAA were observed between NL dogs compared to HF dogs. We conclude that
      SR Ca(2+)-uptake and SR PLB and CAA protein and gene expression levels are
      reduced in LV myocardium of dogs with chronic HF. These abnormalities can lead to
      Ca(2+)-overload and subsequent global LV dysfunction.

PMID- 10403756
TI  - Lysophosphatidylcholine, a metabolite which accumulates early in myocardium
      during ischemia, reduces gap junctional coupling in cardiac cells.
AB  - Lysophosphatidylcholine (LPC) is a metabolite that accumulates rapidly during
      cardiac ischemia in animal and human hearts. LPC induces electrophysiological
      changes including action potential alterations and cardiac arrhythmias. Since
      there is increasing evidence that disrupted cell coupling can contribute to the
      generation of cardiac arrhythmias under ischemic conditions, this study was
      designed to assess the effects of LPC on gap junction coupling between cardiac
      cell pairs using the dual whole-cell voltage-clamp technique. To measure gap
      junction resistance (r(j)), both cells of a pair were first clamped to a common
      holding potential and then, one cell was stepped to various voltages (20 mV steps
      from -50 to +50 mV). Junctional conductance (g(j)=1/r(j)) was derived from the
      junctional current recorded in the non-stimulated cell divided by the trans
      junctional voltage. Extracellular medium was set to minimize non-junctional
      membrane conductance. LPC induced a decrease in g(j)after about 3, 8 and 12 min
      superfusion, respectively, for 50, 10 and 5 micromol/l. When LPC was continuously
      superfused (no washout), no steady-state was observed but a complete uncoupling
      (i.e. when the junctional resistance is infinitely high) after a delay of 7.3+/
      1.2 min, 11.3+/-6.0 min, 15. 2+/-5.5 min and 23.3+/-6.0 min, respectively, for
      LPC 50 (n=5), 20 (n=4), 10 (n=5) and 5 (n=3) micromol/l. Mg(2+(out))at a
      concentration of 5 mmol/l exerted protective effects against LPC-induced
      uncoupling. In conclusion, LPC, at concentrations measured in situ during cardiac
      ischemia, is a potent inhibitor of gap junction communications between cardiac
      cells. Impaired junctional communications due to LPC accumulation early during
      ischemia could decrease electrical conduction and contribute to the genesis of
      malignant arrhythmias.

PMID- 10403757
TI  - Acanthamoeba castellanii: characterization of an adhesin molecule.
AB  - Acanthamoeba castellanii is a free-living protozoan that causes keratitis in
      humans and has been associated with pneumonia and granulomatous amebic
      encephalitis in dogs, sheep, and other species. Adherence of the Acanthamoeba to
      epithelial cells is critical to the pathogenesis of this disease. In this study,
      several mouse monoclonal antibodies (MAb) generated to whole Acanthamoeba
      trophozoites identified surface membrane epitopes by ELISA and IFA. Nine
      antibodies inhibited adherence of [(35)S]-methionine-labeled Acanthamoeba
      trophozoites to hamster corneal epithelial cells by 27-90%. Sodium periodate
      treatment, but not proteinase K digestion, of whole Acanthamoeba destroyed
      epitopes recognized by adherence-inhibiting antibodies such as MAb 7H6,
      suggesting that the adherence epitopes are carbohydrates. Other antibodies, MAb
      2A8 for example, recognized surface membrane peptide epitopes that were
      proteinase K sensitive and sodium periodate resistant. Purified MAb 2A8 was used
      in an antigen-capture ELISA with peroxidase-labeled MAb 7H6 and demonstrated that
      the carbohydrate adhesion molecule was linked to the peptide recognized by MAb
      2A8. Both MAbs 7H6 and 2A8 recognized a >207-kDa band on a Western blot of eluant
      from a MAb 2A8 immunoaffinity column, confirming that MAb 7H6 and MAb 2A8
      recognize different epitopes on the same adherence molecule. MAbs 7H6 and 2A8
      also identified the adhesion molecule in soluble Acanthamoeba membrane
      preparations and MAb 2A8 immunoaffinity column eluant by ELISA and Western blot.
      Neither of these antibodies were inhibited from binding to whole trophozoites nor
      membrane extracts by mannose or mannan in competitive binding assays. When our
      Acanthamoeba membrane preparations were electrophoresed and immunoblotted with
      alpha-d-mannosylated-biotin albumin, no bands were recognized in the >207 kDa
      range by our adherence-associated antibodies. These results suggest that the
      Acanthamoeba adhesin is not identical to the mannose binding protein of
      Acanthamoeba but rather is a distinct surface membrane glycoprotein.

PMID- 10403758
TI  - Hymenolepis diminuta: praziquantel removal of adult tapeworms is followed by
      apoptotic down-regulation of mucosal mastocytosis.
AB  - The rat tapeworm, Hymenolepis diminuta, induces mastocytosis, hypertrophy of
      enteric smooth muscle, alteration of enteric myoelectric activity, and slowed
      enteric transit of the rat host's intestine. This report examines the resolution
      of both tapeworm-induced mastocytosis and tissue changes during the period
      following removal of the tapeworm with Praziquantel (PZQ). The dynamics of the
      mucosal mast cell (MMC) population following removal of the tapeworms was
      assessed by histochemical identification of MMC and morphometric techniques. As a
      possible mechanism of MMC population regulation, MMC apoptosis was examined over
      the same experimental period using the in situ nick end labeling of fragmented
      DNA (TUNEL). Shifts in MMC numbers were correlated with functional and
      morphological changes of the intestine following removal of the adult-stage
      tapeworm. Ileal tissues from rats infected 32 days with H. diminuta (the
      beginning of plateau phase of tapeworm-induced chronic mastocytosis) were
      harvested 1, 2, 3, and 4 weeks after the PZQ treatment. Control ilea were
      obtained either from rats which were never infected and never treated with PZQ or
      from rats infected with H. diminuta for 32 days but not treated with PZQ. In
      order to detect MMC and apoptosis, tissue sections of ileum were doubled stained
      sequentially with Astra blue for MMC granules followed by a modification of the
      TUNEL technique. No alteration in MMC numbers were observed in PZQ-treated
      animals until 3 weeks after the removal of the tapeworms. The decline of MMC
      occurred in the mucosa and submucosa. MMC numbers first approached uninfected
      control levels at 4 weeks posttreatment. Coincident with the decline in mucosal
      MMC numbers, the rate of MMC entering apoptosis also declined. Simultaneously,
      ileal smooth muscle layers, hypertrophied by infection, and mucosal structures
      began the process of involution and atrophy. Apoptosis of MMC in the submucosa
      and muscularis mucosa was not detected. In conclusion, H. diminuta-elicited
      mastocytosis and increased thickness of both mucosa and muscularis externa do not
      begin a decline toward control values until 3 weeks after the parasites are gone
      and normal intestinal motility is restored. These data are consistent with the
      lack of MMC mediation of altered motility, and the decline in the rate of MMC
      apoptosis at 3 weeks post-PZQ suggests that apoptosis may play an important role
      in the involution of tapeworm-induced mastocytosis.

PMID- 10403759
TI  - Leishmania: overexpression and comparative structural analysis of the stage
      regulated meta 1 gene.
AB  - The meta 1 gene of Leishmania major is upregulated in metacyclic promastigotes
      and encodes an 11.5-kDa protein with no significant similarities to other
      proteins in the existing databases. In this paper, we characterize the homologous
      meta 1 genes in L. amazonensis and L. donovani. Proteins encoded by this gene in
      all three species present a high degree of identity. The meta 1 gene cannot be
      replaced by gene targeting in L. major, suggesting an essential role for the
      protein, at least in promastigotes. Overexpression of the meta 1 protein in L.
      amazonensis generates parasites that are more virulent than wild-type organisms
      in vivo.

PMID- 10403760
TI  - Haemonchus contortus: effects of glutamate, ivermectin, and moxidectin on inulin
      uptake activity in unselected and ivermectin-selected adults.
AB  - Using [(3)H]inulin uptake as a measure of pharyngeal pumping activity, we have
      investigated and compared the effects of glutamate, ivermectin, and moxidectin on
      inulin uptake in susceptible and ivermectin-selected Haemonchus contortus. Inulin
      uptake is inhibited by glutamate, ivermectin, and moxidectin, at biologically
      relevant concentrations. Glutamate influences the responses to both ivermectin
      and moxidectin, suggesting that these three substances share a common mechanism
      of action. The effects of ivermectin on inulin uptake, but not moxidectin, are
      significantly altered as a result of selection with ivermectin. These results
      suggest that ivermectin and moxidectin may differ, to some extent, in their mode
      of action responses or mechanisms of resistance.

PMID- 10403761
TI  - Dietary nucleosides and nucleotides reduce Cryptosporidium parvum infection in
      dexamethasone immunosuppressed adult mice.
AB  - Numerous studies have demonstrated that dietary sources of nucleosides and
      nucleotides are important for the maintenance of cellular and humoral immune
      responses. To determine the immunological effects of feeding a nucleoside
      nucleotide mixture to dexamethasone-immunosuppressed C57BL/6 adult mice infected
      with Cryptosporidium parvum, we examined fecal oocyst shedding,
      lymphoproliferative responses to concanavalin (Con) A, and C. parvum antigen,
      interleukin (IL-2), and gamma-interferon (IFN-gamma) production by cultured
      spleen cells. Mice were fed a nucleotide-free 20% casein diet (control group) or
      this diet supplemented with a 0. 5% nucleoside-nucleotide mixture before and
      after inoculation with C. parvum. Spleens from mice receiving the supplemented
      diet had higher (P < 0.05) Con A and antigen-specific induced cell proliferation
      than those from control mice. In addition to the increased cell proliferation,
      the spleen cells from the supplemented mice produced significantly more IL-2 (P <
      0.002) and significantly more IFN-gamma (P <; 0.004) than cells from the control
      mice. Mice fed the supplemented diet excreted fewer (P < 0.05) C. parvum oocysts
      in the feces than control mice. The cumulative survival rate in the nucleoside
      nucleotide mixture-fed group was higher compared with the control group (P <
      0.05). We conclude that nucleosides and nucleotides may partially counteract the
      immunosuppressive effects of dexamethasone in C. parvum-challenged mice.

PMID- 10403762
TI  - The use of anti-Pfs 25 monoclonal antibody for early determination of Plasmodium
      falciparum oocyst infections in Anopheles gambiae: comparison with the current
      technique of direct microscopic diagnosis.
AB  - Experimental infections of laboratory-reared anopheline mosquitoes were carried
      out with 57 Plasmodium falciparum gametocyte carriers from Cameroon. Prevalence
      of infected mosquitoes and oocyst intensity were determined by two independent
      methods. Young P. falciparum oocysts were detected on day 2 after feeding using
      an immunofluorescent assay, and the results were compared with direct microscopic
      examination of midgut oocysts on day 7 postinfection. The immunofluorescent assay
      was based on a FITC-labeled anti-25-kDa monoclonal antibody, while the direct
      microscopy was performed on midguts stained with 2% mercurochrome. Young oocysts
      were easily detected by their typical and bright green-fluorescing Pfs25 positive
      coat and their characteristic pattern of pigment granules under transmitted white
      light examination. The agreement between the results of the two methods was
      assessed using the Kappa coefficient on prevalences of positive infections and
      the interclass correlation coefficient on arithmetic mean oocyst load per
      infected midgut. The results indicated a low agreement between the two methods
      for the comparison of prevalences of infected mosquitoes. However, this agreement
      was near perfect for the comparison of mean oocyst intensities. Prevalences of
      positive infections and the overall number of parasites per positive gut were
      significantly correlated for both methods. Thus, the immunofluorescent test could
      be an appropriate tool for early determination of malaria infection in
      mosquitoes, particularly under laboratory conditions. The possible applications
      of this immuno-fluorescent technique are discussed.

PMID- 10403763
TI  - Trypanosoma avium: large minicircles in the kinetoplast DNA.

PMID- 10403764
TI  - Entamoeba dispar contains but does not secrete acid phosphatase as does Entamoeba
      histolytica.

PMID- 10403765
TI  - Molecular basis underlying functional pleiotropy of cytokines and growth factors.
AB  - Cytokines and growth factors play pivotal roles in cell growth, differentiation,
      and cell survival. Ligand binding to the receptors induces dimerization or
      oligomerization of the receptors, resulting in the activation of a variety of
      signal transduction pathways. The interplay among these multiple signals is
      critically involved in the biological activities of cytokines and growth factors.
      In this minireview, I discuss two models. One is the "receptor conversion model":
      The complex of cytokine and its soluble form of receptor acts like a cytokine
      with novel target specificity. The other is the "orchestrating model": Cytokines
      can simultaneously generate contradictory signals in the same target cells and
      the balance of each contradictory signal may determine the final output of
      cytokine signals to express unified biological activity. These mechanisms are
      part of the molecular basis underlying functional pleiotropy of cytokines and
      growth factors.

PMID- 10403766
TI  - BCR binds to the xeroderma pigmentosum group B protein.
AB  - The BCR gene is involved in the formation of the BCR-ABL oncogene responsible for
      the pathogenesis of Philadelphia chromosome-positive human leukemias. We have
      previously shown that P210 BCR-ABL binds to the xeroderma pigmentosum group B
      protein (XPB) through the portion of BCR that is homologous to the catalytic
      domain of GDP-GTP exchangers such as yeast CDC24 and Dbl. In the baculovirus
      overexpression system which facilitates binding of coexpressed proteins, we now
      show that XPB binds to the intact BCR protein efficiently but not to CDC24 or
      Dbl, suggesting specificity of this interaction. The binding of endogenous BCR
      and XPB proteins was also detected in Hela cells, and this was inhibited by a
      blocking peptide. Full-length (1-782) XPB and its truncated form (203-782), which
      does not contain the nuclear localization signal, were tagged with glutathione S
      transferase (GST) and were expressed in Rat1 fibroblasts. GST-XPB(203-782) was
      localized predominantly in the cytoplasm and bound to BCR but not to p62, one of
      the other components in TFIIH. GST-XPB(1-782) was largely in the nucleus and
      bound to p62 and BCR. Although the biological significance of the binding remains
      to be uncovered, BCR binds to the XPB/p62 complex.

PMID- 10403767
TI  - Inosine(15.1) hammerhead ribozymes for targeting the transthyretin-30 mutation.
AB  - The most common cause of hereditary amyloidosis (HA) is the val30met mutation in
      the transthyretin protein (TTR-met30). The mutation is caused by a mononucleic
      substitution from G to A (GUC to AUC) in the transthyretin gene resulting in the
      exchange for the amino acids valine to methionine in the corresponding protein
      sequence. The aim of our work was the development of a specific cleavage of TTR
      30 mRNA using hammerhead ribozymes. We chemically modified nuclease stable
      hammerhead ribozymes to target the TTR-30 mRNA with high specificity. The
      exchange of adenosine(15.1) with inosine(15.1) in the catalytic core of the
      hammerhead ribozyme resulted in a change of the cleavable target sequence from
      N(16.2)U(16.1)H(17) to N(16. 2)C(16.1)H(17) without loss in ribozymal activity
      (Nucleic Acids Res. 26, 2279-2285, 1998). This modification allowed a specific
      cleavage of the TTR-30 mutation ("gCC Gug" to "gCC Aug"). In vitro experiments
      with TTR-30 mRNA demonstrated that the RNase stable inosine(15.1) hammerhead
      ribozyme cleaved the TTR-30 mRNA with 100% specificity and with a velocity of
      0.23 min(-1), whereas no cleavage occured in the wildtype mRNA of TTR. In
      conclusion, the development of this NCH specific hammerhead ribozyme represents a
      promising tool for future in vivo therapeutic application for TTR-met30 induced
      hereditary amyloidosis.

PMID- 10403768
TI  - Expression of ADAMTS homologues in articular cartilage.
AB  - Articular chondrocytes possess the capacity to express a number of ADAM (A
      Disintegrin And Metalloproteinase) family members, thereby implicating a role for
      such proteins in the turnover of cartilage extracellular matrix molecules.
      Recently, the sequence for the human orthologue of an "aggrecanase" isolated from
      bovine nasal cartilage has been elucidated, and the recombinant protein product
      shown to be capable of cleaving aggrecan specifically at the relevant peptide
      bonds which are hydrolyzed in situ during cartilage degradation. The sequence for
      the human "aggrecanase" exhibits homology with that of murine ADAMTS-1, an ADAM
      with thrombospondin type I motifs. In the present study we have identified
      additional ADAMTS homologues and have examined their mRNA expression profiles in
      freshly excised human articular cartilage and in human cartilage explant cultures
      stimulated with IL-1, TNF-alpha, or retinoic acid, agents which enhance
      "aggrecanase" activity in vitro. Significantly, cartilage exposed to retinoic
      acid showed a marked increase in the release of "aggrecanase"-generated aggrecan
      catabolites with no concomitant increase in mRNA levels for any of the ADAMTS
      homologues investigated. These findings indicate that enhanced "aggrecanase"
      activity, which may be attributed to known ADAMTS homologues, may be
      predominantly regulated by post-transcriptional mechanism(s), and may raise the
      possiblility for the existence of other as yet unidentified "aggrecanase(s)."

PMID- 10403770
TI  - ICSAT overexpression is not sufficient to cause adult T-cell leukemia or multiple
      myeloma.
AB  - ICSAT (Interferon Consensus Sequence binding protein for Activated T cells) is a
      lymphocyte-specific member of the interferon regulatory factor (IRF) family of
      transcription factors, originally identified through Southwestern screening of
      the ATL(Adult T-cell leukemia)-16T expression library. In this study, we created
      transgenic mice overexpressing ICSAT in lymphocytes. Although spontaneous
      tumorigenesis was not observed, IL-2 production with Concanavalin A stimulation
      was significantly increased in transgenic mice overexpressing ICSAT. ICSAT
      overexpression in lymphocytes seems insufficient for the leukemogenesis of ATL or
      multiple myeloma (MM), however, it may regulate T cell activation and its
      overexpression may lead to leukemogenesis via controlling IL-2 production.

PMID- 10403769
TI  - Conjugation of plasmid DNAs with lactose via diazocoupling enhances resistance to
      restriction enzymes and acquires binding affinity to galactose-specific lectin.
AB  - Oligosaccharide-plasmid DNA conjugates were synthesized simply and effectively
      via the diazocoupling method. Plasmids (pUC19, pTRI-beta-actin, and pEGFP-C1)
      were treated with an N-beta-lactoside-substituted diazonium salt to yield
      diazocoupling products with degree of substitutions of 2.5-3.1 mol% of overall
      nucleobases. The lactose-pUC19 conjugate was found to resist restriction enzymes
      more strongly than the nonconjugated plasmid DNA and to acquire a strong binding
      affinity to galactose-specific lectin RCA(120). The diazocoupling modification of
      pTRI-beta-actin plasmid DNA little influenced in vitro transcription with T7 RNA
      polymerase. When lactose-pEGFP-C1 conjugate was transfected to baby hamster
      kidney (BHK) cells by means of cationic lipids, transduced gene was expressed in
      BHK cells similarly with the nonconjugated pEGFP-C1. The modification of plasmid
      DNA with carbohydrate enhanced the resistance to restriction enzymes and
      developed a strong binding affinity to galactose-specific lectin.

PMID- 10403771
TI  - Protein aging by carboxymethylation of lysines generates sites for divalent metal
      and redox active copper binding: relevance to diseases of glycoxidative stress.
AB  - Aging and age-related diseases are associated with the production of reactive
      oxygen species which modify lipids, proteins and DNA. Here we hypothesized the
      glyco- and lipoxidation product N(epsilon)-(carboxymethyl)lysine (CML) in
      proteins should bind divalent and redox active transition metal binding. CML-rich
      poly-L-lysine and bovine serum albumin (BSA) were chemically prepared and found
      to bind non-dialyzable Cu(2+), Zn(2+) and Ca(2+). CML-BSA-copper complexes
      oxidized ascorbate and depolymerized protein in the presence of H(2)O(2). CML
      rich tail tendons implanted for 25 days into the peritoneal cavity of diabetic
      rats had a 150% increase in copper content and oxidized ascorbate three times
      faster than controls. CML-rich proteins immunoprecipitated from serum of uremic
      patients oxidized four times more ascorbate than control and generated spin
      adducts of DMPO in the presence of H(2)O(2). The chelator DTPA suppressed
      ascorbate oxidation thereby implicating transition metals in the process. In
      aging and disease, CML accumulation may result in a deleterious vicious cycle
      since CML formation itself is catalyzed by lipoxidation and glycoxidation.

PMID- 10403772
TI  - Structure of mouse calpastatin isoforms: implications of species-common and
      species-specific alternative splicing.
AB  - Mouse calpastatin cDNAs were cloned by the method of RT-PCR using RNA isolated
      from myoblast C2C12 cells. Nucleotide sequencing of the isolated clones revealed
      an in-frame ATG codon upstream of the previously assigned translation initiation
      methionine. Except for the N-terminal segment, the new translatable region
      (domain XL) was similar to the sequence of bovine calpastatin in which domain XL
      was first identified. Among the isolated mouse calpastatin cDNA clones, three
      isoforms (mCS-a, mCS-b, and mCS-c) were identified. In domain L, mCS-b had a
      deletion of the region corresponding to exon 3 of the human calpastatin gene. RT
      PCR analyses of various mouse tissues revealed that mCS-b was the major form and
      that the content of mCS-a, nondeleted form, was 5-10% in tissues including
      skeletal muscle, liver, brain, etc. and about 30% in the myoblast C2C12 cells.
      Unlike human and rat cDNAs, no other deletions were detected in mouse calpastatin
      domain L. Isolation of the cDNA clone of mCS-c, which lacked regions
      corresponding to exons 3 and 12, was obtained by chance because its expression
      level was under the detectable level in the mouse tissues and even in C2C12
      cells.

PMID- 10403773
TI  - Tumor vascular targeting using a tumor-tissue endothelium-specific monoclonal
      antibody as an effective strategy for cancer chemotherapy.
AB  - In this study, we attempted to develop tumor vascular targeting with a tumor
      tissue endothelium-specific monoclonal antibody. TES-23, which strongly and
      selectively recognizes tumor tissue endothelial cells, was chemically conjugated
      with Neocarzinostatin (NCS), and the anti-tumor effect was examined. The
      immunoconjugate, TES-23-NCS, showed, through the use of tumor hemorrhagic
      necrosis, a marked anti-tumor effect on KMT-17 tumors in rats at a dosage of 17
      micrograms/kg (NCS equivalent) without any side effects, probably due to specific
      tumor vascular injury. By contrast, TES-23 alone (107 micrograms/kg), NCS alone
      (17 micrograms/kg), and Mopc-NCS (Mopc, 107 micrograms/kg; NCS, 17
      micrograms/kg), the immunoconjugate of control antibody, did not have any anti
      tumor activities. By tissue distribution analysis, TES-23 and TES-23-NCS showed
      high accumulation in KMT-17 tumors 1 h after intravenous administration. Moreover
      TES-23 also accumulated in Sarcoma-180 tumors in mice 1 h after intravenous
      administration. These results suggest that TES-23 may be a candidate for a
      potential tumor vascular targeting agent that is applicable to a wide variety of
      tumor types.

PMID- 10403774
TI  - GTPase and transglutaminase are associated in the secretion of the rat anterior
      prostate.
AB  - We have found that in the secretion of rat anterior prostate, a hydrolyzing
      activity on GTP is present with a high affinity for the substrate; ATP, GDP, and
      ADP are not substrates for enzymatic activity. At the same time we have shown
      that GTP is a negative modulator for the well-known type IV transglutaminase
      activity present in the prostatic secretion. The hydrolyzing activity on GTP
      appears to be due to two molecular species: a high-molecular-weight GTPase,
      having electrophoretical mobility higher than 100 kDa, and a low-molecular-weight
      GTPase, of about 30 kDa. The two enzymatic activities are associated in the
      prostatic secretion with the transglutaminase (type IV). We describe an
      experimental procedure to separate them.

PMID- 10403776
TI  - Hypoxia up-regulates telomerase activity via mitogen-activated protein kinase
      signaling in human solid tumor cells.
AB  - Solid tumor cells are often exposed to hypoxia in vivo, which has been suggested
      to promote genetic instability in those cells. Telomere elongation by telomerase
      is implicated in chromosome stabilization in immortal cells. Here we found that
      hypoxia enhanced telomerase activity in the solid tumor A2780 and HT-29 cells but
      not in the leukemia U937 cells. The telomerase activation correlated with
      activation of mitogen-activated protein kinase (MAPK) and c-fos expression. The
      MEK1 inhibitor PD98059 repressed telomerase activation in the hypoxic cells.
      Consistently, a dominant negative MEK1 inhibited telomerase activation by
      hypoxia. Finally, we found a good correlation between telomerase activation and
      resistance to apoptotic cell death under hypoxic conditions. These findings
      indicate that hypoxia up-regulates telomerase activity via MAPK cascade signaling
      especially in solid tumor cells and suggest that solid tumor cells might enhance
      the telomerase activity as a stress response against genotoxicity induced by
      hypoxia.

PMID- 10403775
TI  - Structure, genetic localization, and identification of the cardiac and skeletal
      muscle transcripts of the human integrin alpha7 gene (ITGA7).
AB  - We have determined the structure and the exon size pattern of the human integrin
      alpha7 subunit gene (ITGA7), which has been shown to be affected in a form of
      congenital myopathy. The gene is composed of at least 27 exons spanning a region
      of about 22.5 kb. The sequence of all exon/intron boundaries was determined and
      conforms to the GT/AG splicing consensus. We investigated the different splicing
      forms previously described in human and rodents. The major cytoplasmic variants
      alpha7A and alpha7B, which are developmentally regulated and tissue specific,
      were identified in human tissues, as well as the extracellular isoforms X1 and
      X2. The recently described D variant was detected in adult tissues by RT-PCR but
      not the C variant. We localized ITGA7 on chromosome 12q13 by high-resolution
      radiation hybrid mapping between D12S312 and D12S90 and identified a new CA
      repeat microsatellite in intron 1.

PMID- 10403777
TI  - Regulation of endothelial cell adherens junctions by a Ras-dependent signal
      transduction pathway.
AB  - Adherens junctions, consisting of transmembrane cadherin molecules and their
      associated cytoplasmic alpha-, beta-, and gamma-catenin proteins, are thought to
      be critical for the development of stable cell adhesion and subsequent 3
      dimensional tissue organization. In human endothelial cells there is a marked
      induction of gamma-catenin levels when cells reach confluence. We demonstrate
      that expression of a dominant negative ras gene product (N17ras) via adenoviral
      mediated gene transfer inhibits the confluent-dependent rise in gamma-catenin
      mRNA and protein levels. Consistent with its effects on overall gamma-catenin
      levels, expression of N17ras also reduces the amount of gamma-catenin associated
      with the adherens junction. Finally, although expression of N17ras under normal
      culture conditions produces no clear morphological phenotype, endothelial cells
      expressing a dominant negative ras gene product fail to form 3-dimensional,
      vascular-like structures when plated on reconstituted extracellular matrix.

PMID- 10403779
TI  - Expression of the heterogenous nuclear ribonucleoprotein complex K protein and
      the prolyl-4-hydroxylase alpha-subunit in atherosclerotic arterial smooth muscle
      cells.
AB  - Smooth muscle cells (SMC) play a major role in the formation of atherosclerotic
      lesions found on major blood vessels. SMC proliferation, migration, and protein
      synthesis promote the progression of the early lesion, the fatty streak, into a
      complex myointimal fibrous plaque. To investigate altered gene expression in SMC
      during atherogenesis, we characterized differences between SMC from normal
      rabbits, rabbits fed a 2% cholesterol diet, and Watanabe Heritable Hyperlipidemic
      rabbits (WHHL). We detected and isolated a 501 bp cDNA fragment representing the
      A isoform of heterogenous nuclear ribonucleoprotein complex K (hnRNP-K) and a 281
      bp cDNA fragment representing the prolyl-4-hydroxylase alpha-subunit (alphaPH)
      mRNAs. hn-RNP-K was upregulated in SMC from cholesterol-fed rabbits isolated in
      primary culture, as well as in SMC medial tissue from both the cholesterol-fed
      and WHHL rabbits. alphaPH was upregulated in SMC from the cholesterol-fed rabbits
      isolated in primary culture and in the tissue from WHHL rabbits. These data
      demonstrate genes consistent with increased proliferation and collagen production
      are upregulated in SMC during atherogenesis and may shed new light on gene
      expression changes and corresponding phenotype changes in SMC during
      atherogenesis.

PMID- 10403778
TI  - Evidence for the presence of a functional pregnane X receptor response element in
      the CYP3A7 promoter gene.
AB  - Pregnane X Receptor (PXR) has been recently shown to regulate the inducible
      expression of CYP3A genes in response to xenobiotics and steroids. PXR forms a
      heterodimer with the retinoic acid receptor (RXR) and this complex binds to and
      transactivates an 18bp region containing two everted repeats TGA(A/C)CT separated
      by 6 nucleotides (ER6) and located at approximately -150 in the CYP3A4 promoter.
      In this work we have isolated and sequenced the proximal 5'-flanking region of
      CYP3A7 from two different human genomic libraries. In contrast to a previously
      reported sequence (Itoh et al., 1992), we did not observe any mutation in the 3'
      half of the CYP3A7 ER6 element. Using electrophoretic mobility shift assays and
      cotransfection experiments we show that this element is able to bind the PXR:RXR
      complex and transactivates the expression of a down stream promoter in response
      to rifampicin, clotrimazole, and RU-486, three compounds known to specifically
      activate the human PXR. This is consistent with the fact that CYP3A7 mRNA is
      inducible in several primary cultures of human hepatocytes from different
      patients, as well as in two hepatocarcinoma cell lines HuH7 and HepG2, in
      response to these compounds. In contrast to a previous report (Blumberg et al.,
      1998), based on the sequence published by Itoh et al., we conclude that CYP3A7,
      like CYP3A4, is inducible in response to xenobiotics and presumably in a large
      proportion of the population.

PMID- 10403780
TI  - Characterization in vitro and in vivo of hammerhead ribozymes directed against
      murine tumor necrosis factoralpha.
AB  - A hammerhead ribozyme directed against murine TNFalpha (mTNFalpha) mRNA has been
      constructed. In vitro studies showed that this ribozyme was released from the
      parent molecule by flanking cis-acting hammerhead and hairpin ribozymes. This
      same anti-mTNFalpha ribozyme specifically cleaved both synthetically derived
      substrate RNA and mTNFalpha mRNA within a pool of total cellular RNA. Endogenous
      delivery of this anti-mTNFalpha ribozyme via the self-cleaving cassette reduced
      mTNFalpha mRNA and protein levels in lipopolysaccharide (LPS)-stimulated, stably
      transfected murine macrophage RAW 264.7 cells. When complexed to liposomes and
      exogenously delivered to mouse peritoneal macrophages, the same ribozyme, with
      and without the cis-acting ribozymes, reduced mTNFalpha protein levels. However,
      an irrelevant ribozyme delivered in an identical fashion was also effective at
      reducing mTNFalpha protein levels. These data suggest that anti-mTNFalpha
      ribozymes can be constructed which efficiently cleave mTNFalpha mRNA, but
      irrelevant RNA/liposome complexes also effectively limit TNFalpha mRNA expression
      and can mimic functional ribozyme activity under in vitro conditions.

PMID- 10403781
TI  - APOBEC-2, a cardiac- and skeletal muscle-specific member of the cytidine
      deaminase supergene family.
AB  - APOBEC-1, which mediates the editing of apolipoprotein (apo) B mRNA, is the only
      known member of the C (cytidine)-->U (uridine) editing enzyme subfamily of the
      cytidine deaminase supergene family. Here we report the cloning of APOBEC-2,
      another member of the subfamily. Human and mouse APOBEC-2 both contain 224 amino
      acid residues, and their genes are mapped to syntenic regions of human chromosome
      6 (6p21) and mouse chromosome 17. By phylogenetic analysis, APOBEC-2 is shown to
      be evolutionarily related to APOBEC-1, and analysis of substitution rates
      indicates that APOBEC-2 is a much better conserved gene than APOBEC-1. APOBEC-2
      mRNA and protein are expressed exclusively in heart and skeletal muscle. APOBEC-2
      does not display detectable apoB mRNA editing activity. Like other editing
      enzymes of the cytidine deaminase superfamily, APOBEC-2 has low, but definite,
      intrinsic cytidine deaminase activity. The identification of APOBEC-2 indicates
      that APOBEC-1 is not the only member of the C-->U editing enzyme subfamily,
      which, like the A (adenosine)-->I (inosine) subfamily of editing enzymes, must
      encompass at least two and possibly more different deaminase enzymes. It suggests
      that the C-->U editing affecting apoB mRNA and other RNAs is not an isolated
      event mediated by a single enzyme but involves multiple related proteins that
      have evolved from a primordial gene closely related to the housekeeping enzyme
      cytidine deaminase.

PMID- 10403783
TI  - Differential membrane antioxidant effects of immediate and long-term estradiol
      treatment of MCF-7 breast cancer cells.
AB  - Previous studies have documented the direct antioxidant effects of estradiol, and
      it is tempting to ascribe the antiapoptosis effects of estradiol to its
      scavenging of reactive oxygen species. However, recent reports have also
      demonstrated that long-term exposure of MCF-7 human breast cancer cells to
      estradiol results in estrogen receptor- and estradiol dose-dependent
      overexpression of the antiapoptosis gene, bcl-2. We have used the pattern of
      protection of membrane phospholipids from oxidation as a probe to separate these
      direct and indirect effects of estradiol from one another. Immediate exposure to
      estradiol non-specifically protects all membrane phospholipids from oxidation by
      the diazo radical initiator, AMVN. This implies the direct antioxidant activity
      of estradiol in this system. In contrast, long-term exposure, with associated
      increased expression of bcl-2, protects only phosphatidylserine, the oxidation of
      which is a critical component of the final common pathway for apoptosis. This bcl
      2-mediated indirect effect of estradiol is accompanied by prevention of apoptosis
      in MCF-7 cells.

PMID- 10403782
TI  - MBP-1 physically associates with histone deacetylase for transcriptional
      repression.
AB  - MBP-1, a c-myc promoter binding protein, is a mammalian transcription factor with
      intriguing properties including transcriptional repression of cellular genes.
      Recently, we have identified and characterized two different repressor domains of
      MBP-1. In this report, we have demonstrated that MBP-1 physically associates with
      histone deacetylase (HDAC), thus promoting formation of neucleosomes that inhibit
      transcription. Trichostatin A, an inhibitor of histone deacetylase, significantly
      reduces MBP-1-mediated transcriptional repression. However, MBP-1-mediated
      repression on c-myc promoter is resistant to histone deacetylase activity. Our
      results suggest that MBP-1 represses transcription by recruiting histone
      deacetylase as one of the mechanisms, whereas the other mechanism is resistant to
      HDAC activity and probably related to direct binding of promoter sequences or
      interaction through yet unidentified factor.

PMID- 10403784
TI  - The human apM-1, an adipocyte-specific gene linked to the family of TNF's and to
      genes expressed in activated T cells, is mapped to chromosome 1q21.3-q23, a
      susceptibility locus identified for familial combined hyperlipidaemia (FCH).
AB  - The human adipocyte-specific apM-1 gene encodes a secretory protein of the
      adipose tissue that has been suggested to play a role in the pathogenesis of
      obesity. The regulation of apM-1 was studied along adipocyte differentiation.
      While apM-1-mRNA and apM-1 protein were absent in preadipocytes and in 48 h
      differentiated adipocytes, they were found upregulated from day 4 to day 9 of
      adipocyte differentiation as shown by RNase protection assay and Western blot
      analysis. These data indicate that apM-1 may be a late marker of adipocyte
      differentiation. In human sera apM-1 protein is also detectable by Western blots
      using a polyclonal antibody raised against a synthetic peptide sequence of the
      human apM-1. The genomic structure of the human apM-1 gene together with a total
      of 2.7 kb of the 5'-flanking region with putative transcription factor binding
      sites is presented. Interestingly, sequence comparisons link the apM-1 gene to
      the family of TNF's and to genes expressed in activated T-cells. The chromosomal
      localization of apM-1 was investigated by FISH and mapped to human chromosome
      1q21.3-1q23, a region that was identified as a susceptibility locus for Familial
      Combined Hyperlipidaemia (FCH) and polygenic NIDDM. These data and the
      chromosomal localization on chromosome 1q21.3-q23 raises the possibility that apM
      1 as an adipocyte-specific secretory protein may play a role in the pathogenesis
      of FCH and associated insulin resistance. Exon- and intron-specific primer
      sequences are presented as a basis for mutation screening of patients affected
      with FCH.

PMID- 10403785
TI  - Neural network in planarian revealed by an antibody against planarian
      synaptotagmin homologue.
AB  - In order to investigate the neural connection of planarian, it is imperative to
      produce an antibody that specifically stains axons. To identify axon-specific
      genes, we constructed a cDNA library from a single eye by using a single cell PCR
      method, in which visual neurons are major components, and sequenced one thousand
      independent clones. We succeeded in the identification of a planarian homologue
      of synaptotagmin, Djsyt, whose specific expression in neurons was confirmed by in
      situ hybridization. The antibody against DjSYT specifically stained axons
      although its mRNA is distributed in the cell bodies. By using anti-DjSYT, we
      succeeded in the visualization of neural connections in planarians by whole mount
      staining. The anti-DjSYT antibody will become a powerful tool to analyze the
      molecular mechanisms underlying neural network formation in planarian.

PMID- 10403786
TI  - Tooth-specific expression conferred by the regulatory sequences of rat dentin
      sialoprotein gene in transgenic mice.
AB  - We have isolated a 3.8-kb DNA fragment containing the 5' flanking region, 1st
      exon, and 1st intron of the rat dentin sialoprotein (rDsp) gene and produced
      transgenic mice carrying a LacZ reporter gene under the control of this fragment.
      Expression of the transgene transcript and beta-galactosidase activity were
      restricted to dentin and odontoblasts with spatial and temporal patterns
      comparable to those of the endogenous mouse Dsp transcript, although beta
      galactosidase activity could not be detected visually during embryonal stages.
      Other tissues tested, such as alveolar bones, ameloblasts and dental pulps, did
      not express the transgene. This indicates that the regulatory elements necessary
      for tooth-specific expression are present in the fragment, which contains a TATA
      box and several consensus sequences for binding sites of transcription factors
      related to tooth development, such as TCF-1/LEF-1, MSX-1 and Dlx-1. The
      regulatory sequences and the transgenic mice described here provide useful
      information for the study of tooth development.

PMID- 10403787
TI  - Cytodifferentiation potentiates aFGF-induced p21(ras)/Erk signaling pathway in
      rat cultured astrocytes.
AB  - MBP kinase detection assay revealed that acidic FGF (aFGF) augmented MBP kinase
      activity in a dose-dependent manner in astrocytes (AC). The molar potency of this
      action of aFGF in dibutyryl cyclic AMP (DBcAMP)-treated AC was significantly
      higher than that in quiescent AC. Consistently, the molar potency of accumulation
      of p21(ras)-GTP by aFGF was significantly higher in DBcAMP-treated AC than in
      quiescent AC. However, binding study showed that B(max) and K(D) for [(125)I]aFGF
      in DBcAMP-treated AC were quite similar to those in quiescent AC. Furthermore,
      the expression levels of Grb2, SOS, and p21(ras) were not changed by treatment of
      AC with DBcAMP. These results suggest that cytodifferentiation potentiates the
      p21(ras)/Erk signaling pathway in AC in response to aFGF without changing the
      expression levels of signaling molecules mediating from the FGF receptor to
      p21(ras).

PMID- 10403788
TI  - Association of prokaryotic and eukaryotic chaperone proteins with the human
      1alpha,25-dihydroxyvitamin D(3) receptor.
AB  - Steroid hormone receptors (SHR) form complexes with heat shock proteins (hsps).
      The 1alpha,25-dihydroxyvitamin D(3) receptor (VDR) has not been previously shown
      to interact with hsps. During expression and purification of VDR-glutathione S
      transferase (VDR-GST) fusion proteins encompassing full-length, DNA, and ligand
      binding domains of the VDR (FL-VDR, DBD-VDR, and LBD-VDR), we observed binding of
      bacterial hsps with VDR-GST constructs. All VDR constructs bound DnaK in amounts
      greater than GST alone and bound smaller amounts of DnaJ or GrpE. GroEL bound
      only to FL-VDR. GroES did not bind to VDR. When VDR-GST constructs were incubated
      with a reticulocyte lysate system that has been used previously to examine SHR
      hsp interactions, eukaryotic hsc70 was detected bound to FL-VDR and DBD-VDR.
      Binding of hsp90 to VDR was not detected. However, geldanamycin, an hsp90
      inhibitor, reduced 1alpha,25-dihydroxyvitamin D(3)-mediated gene activation in
      osteoblasts. Our data show that the bacterial and eukaryotic hsps associate with
      the VDR and might be involved in VDR function.

PMID- 10403789
TI  - Pokeweed antiviral protein isoforms PAP-I, PAP-II, and PAP-III depurinate RNA of
      human immunodeficiency virus (HIV)-1.
AB  - Pokeweed antiviral protein (PAP) is a naturally occurring broad-spectrum
      antiviral agent with potent anti-human immunodeficiency virus (HIV)-1 activity by
      an as yet undeciphered molecular mechanism. In the present study, we sought to
      determine if PAP is capable of recognizing and depurinating viral RNA.
      Depurination of viral RNA was monitored by directly measuring the amount of the
      adenine base released from the viral RNA species using quantitative high
      performance liquid chromatography. Our findings presented herein provide direct
      evidence that three different PAP isoforms from Phytolacca americana (PAP-I from
      spring leaves, PAP-II from early summer leaves, and PAP-III from late summer
      leaves) cause concentration-dependent depurination of genomic RNA (63 to 400
      pmols of adenine released per micrograms of RNA) purified from human
      immunodeficiency virus type-I (HIV-I), plant virus (tobacco mosaic virus (TMV),
      and bacteriophage (MS 2). In contrast to the three PAP isoforms, ricin A chain
      (RTA) failed to cause detectable depurination of viral RNA even at 5 microM,
      although it was as effective as PAP in inhibiting protein synthesis in cell-free
      translation assays. PAP-I, PAP-II, and PAP-III (but not RTA) inhibited the
      replication of HIV-1 in human peripheral blood mononuclear cells with IC(50)
      values of 17 nM, 25 nM, and 16 nM, respectively. These findings indicate that the
      highly conserved active site residues responsible for the depurination of rRNA by
      PAP or RTA are not sufficient for the recognition and depurination of viral RNA.
      Our study prompts the hypothesis that the potent antiviral activity of PAP may in
      part be due to its unique ability to extensively depurinate viral RNA, including
      HIV-1 RNA.

PMID- 10403790
TI  - Identification and expression of a novel family of bHLH cDNAs related to
      Drosophila hairy and enhancer of split.
AB  - In this report we describe the initial characterization of murine, human, and
      Drosophila hesr-1 (for hairy and enhancer of split related-1) a novel
      evolutionary conserved family of hairy/enhancer of split homologs. Hesr-1 cDNAs
      display features typical of hairy and enhancer of split-type bHLH proteins
      including a N-terminal bHLH domain a conserved orange domain immediately C
      terminal to the bHLH region. Despite their similarity to known hairy/enhancer of
      split homologs, hesr-1 cDNAs are divergent members of the hairy and enhancer of
      split bHLH family since the degree of sequence identity within the bHLH and their
      nearest homologs are relatively low. Moreover, the tetrapeptide motif, WRPW,
      which is found in all hairy and enhancer of split family members, is not present
      in hesr-1. Rather, a variant of this motif, YRPW, is found. Analysis of embryonic
      murine hesr-1 expression by in situ hybridization reveals strong expression in
      the somitic mesoderm, the central nervous system, the kidney, the heart, nasal
      epithelium, and limbs indicating a role for hesr-1 in the development of these
      tissues. Like the enhancer of split cDNAs in Drosophila, we show that hesr-1
      expression depends critically on signaling through the notch pathway in murine
      embryos, suggesting that aspects of hesr-1 regulation and function might also be
      evolutionary conserved.

PMID- 10403791
TI  - Genomic organization and chromosomal localization of the human CD163 (M130) gene:
      a member of the scavenger receptor cysteine-rich superfamily.
AB  - The human protein CD163 (M130) is a member of the scavenger receptor cysteine
      rich (SRCR) superfamily, which is exclusively expressed by monocytes and
      macrophages. Here, we investigated the genomic organization and the chromosomal
      localization of the human CD163 gene. The CD163 gene is composed of 17 exons and
      16 introns and spans over 35 kb. Each of its nine SRCR domains is encoded by a
      separate exon, which is similar to other members of the group B SRCR subfamily.
      Two cytoplasmic variants of CD163 arise from alternative splicing of intron 15,
      while a truncated and an extracellular variant results from alternative splicing
      of intron 5 or intron 7, respectively. Using fluorescence in situ hybridization
      we mapped this gene to the human chromosome 12p13. The transcription initiation
      sites of the CD163 gene were determined and the 5'-flanking region was sequenced.
      The nucleotide analysis revealed several putative binding sites for transcription
      factors, which have been shown to play an important role in myeloid specific gene
      expression. In addition, we identified a L1 element located 1.4 kb upstream of
      the major transcription initiation site.

PMID- 10403792
TI  - Hematopoietic development of primordial germ cell-derived mouse embryonic germ
      cells in culture.
AB  - Induction of hematopoiesis in an embryonic germ (EG) cell line derived from mouse
      primordial germ cells (PGCs) was examined. When single undifferentiated EG-1
      cells were inoculated directly into the methylcellulose medium, both primitive
      and definitive erythropoiesis were seen in embryoid bodies derived from the EG
      cells as observed in ES cells, and production of myeloid cell lineages was
      stimulated by IL-3. These results indicate that EG cells acquired in vitro
      potency to differentiate toward hematopoietic cells, although they were derived
      from PGC and are distinct from inner cell mass-derived ES cells with regard to
      gene expression and patterns of DNA methylation corresponding to genomic
      imprinting. It turns out that they are useful for study of cell differentiation
      in the animals whose ES cells are not available.

PMID- 10403793
TI  - EGF-Induced receptor autophosphorylation in primary hepatocytes isolated from
      phenobarbitone-treated mice.
AB  - Phenobarbitone (PB) treatment of mice causes a decrease in the growth factor
      responsiveness of hepatocytes. Here, epidermal growth factor receptor (EGFR)
      expression and receptor autophosphorylation was determined in hepatocytes
      isolated from control and PB-treated mice. There was a decrease in the level of
      EGFR expression in hepatocytes isolated from mice following PB administration
      when compared to controls. EGF caused an approximate 20-fold increase of the 170
      kD phosphotyrosine band in control hepatocytes, which was inhibited by the EGFR
      specific tyrosine kinase inhibitor 4, 5-dianilinopthalamide. Following PB
      treatment, the degree of basal receptor phosphorylation (in the absence of EGF)
      was significantly greater and therefore the fold rise in EGFR phosphorylation in
      isolated hepatocytes was lower than in controls. However, the overall extent of
      EGF-induced receptor phosphorylation was not diminished in hepatocytes isolated
      from PB-treated mice. Therefore the reduction in responsiveness to growth factors
      seen in hepatocytes ex vivo or the cessation of proliferation observed in vivo
      following PB administration is unlikely to be attributed to a decrease in ligand
      binding and subsequent receptor autophosphorylation.

PMID- 10403794
TI  - Loss of function mutations of the human melanocortin 1 receptor are common and
      are associated with red hair.
AB  - The melanocortin 1 receptor is a G-protein-coupled receptor that acts as a
      control point for control of the eumelanin/phaeomelanin ratio in mouse hair. MC1
      receptor loss of function mutations lead to an increase in the ratio of
      phaeomelanin/eumelanin in many mammals resulting in yellow or red coat colours.
      We have previously shown that several common point mutations in the human MC1
      receptor are overrepresented in North European redheads and in individuals with
      pale skin. In order to determine the functional significance of these changes we
      have carried out transfection and binding studies. Expression of the Val60Leu,
      Arg142His, Arg151Cys, Arg160Trp, and Asp294His receptors in COS 1 cells revealed
      that these receptors were unable to stimulate cAMP production as strongly as the
      wild type receptor in response to alpha-melanocyte-stimulating hormone
      stimulation. None of the mutant receptors displayed complete loss of alphaMSH
      binding, with only the Arg142His and Asp294His displaying a slight reduction in
      binding affinity.

PMID- 10403795
TI  - Characterization of a novel form of angiopoietin-2 (Ang-2B) and expression of
      VEGF and angiopoietin-2 during chicken testicular development and regression.
AB  - The complex process of angiogenesis is controlled by the vascular endothelial
      growth factor (VEGF) and its receptors and by the recently isolated angiopoietin
      1 (Ang-1) and angiopoietin-2 (Ang-2) that signal through the transmembrane
      endothelial receptor tyrosine kinase Tie2. We report here the characterization of
      a novel form of Ang-2 (Ang-2B) with a truncated amino-terminal domain resulting
      from an alternative splicing of the gene. While previous reports have found the
      expression of Ang-2 limited to the embryo, female reproductive organs, and tumor
      tissues, we have observed striking changes in Ang-2 expression during chicken
      testicular development and regression. The expression of Ang-2 and VEGF is
      abundant in prepuberal testis and low in quiescent adult testis. Testicular
      regression is accompanied by high expression of Ang-2 and very low expression of
      VEGF. These observations are in accordance with the proposal that Ang-2 induces
      angiogenesis in the presence of VEGF and vascular regression in its absence.

PMID- 10403797
TI  - A serpentine receptor-dependent, Gbeta- and Ca(2+) influx-independent pathway
      regulates mitogen-activated protein kinase ERK2 in Dictyostelium.
AB  - Ca(2+) influx and mitogen-activated protein (MAP) kinase activation are important
      phenomena in signal transduction, which are often interconnected. We investigated
      whether serpentine receptor-dependent, Gbeta-independent activation of MAP kinase
      ERK2 by chemoattractant cyclic AMP (cAMP) is mediated by Ca(2+) influx in the
      social amoeba Dictyostelium discoideum. We generated a D. discoideum double
      mutant, which harbours a temperature-sensitive Gbeta subunit and expresses the
      apoaequorin protein. Utilizing this mutant, we demonstrate that cAMP induced
      Ca(2+) influx into intact D. discoideum cells can be blocked completely at both
      the permissive and the restrictive temperature, by using either gadolinium ions
      or Ruthenium Red. Under the same experimental conditions, these substances do not
      abolish cAMP stimulation of ERK2 at either temperature. We conclude that there is
      a Gbeta- and Ca(2+) influx-independent pathway for the receptor-dependent
      activation of MAP kinase ERK2 in D. discoideum.

PMID- 10403796
TI  - Alteration of SREBP activation in liver of trisomy 21 fetuses.
AB  - We previously reported that trisomy 21 (T21) fetuses have an intrinsic lipid
      metabolism abnormality resulting in higher serum cholesterol levels than their
      matched controls. In an attempt to clarify the biochemical basis of this
      derangement we analyzed the liver cholesterol levels and activation of the sterol
      regulatory element binding proteins SREBP-1 and SREBP-2. We report here for the
      first time that SREBP-1 and SREBP-2 are present in human fetal liver and their
      activation follows a different regulatory pattern. Moreover T21 fetuses show a
      peculiar pattern of SREBP activation which, at variance from control fetuses,
      involves sterol-independent maturation of SREBP-1. Multiple defects accompanied
      the lipid derangement in T21, resulting in high circulating and tissue
      cholesterol. This may serve as an early biochemical marker of an unknown,
      possibly genetically determined mechanism, whose consequence on lipid homeostasis
      during postnatal and adult life is still not understood.

PMID- 10403799
TI  - Cross-linking of plasmalemmal cholesterol in lymphocytes induces capping,
      membrane shedding, and endocytosis through coated pits.
AB  - By use of a nicked and biotinylated perfringolysin O (BCtheta), which binds to
      cholesterol specifically, we studied consequences of cross-linking cholesterol in
      lymphocytes. When bound with BCtheta and then with labeled avidin or
      streptavidin, capping occurred in most cells within 30 min at 37 degrees C. It
      was inhibited by cytochalasin D or NaN3, but not by nocodazole. When BCtheta
      cholesterol was capped, Thy-1 and transferrin receptor, a GPI-anchored protein
      and a transmembrane protein, respectively, remained evenly distributed. By
      fluorescence and electron microscopy, a cluster of small vesicles bound with
      BCtheta were observed in the cap. They were then shed in the medium or
      internalized through coated pits. The result indicates that cross-linking of
      cholesterol in lymphocytes induces capping, but does not affect distribution of
      membrane proteins, and that the capped cholesterol molecules are either shed as
      vesicles or endocytosed.

PMID- 10403798
TI  - Multiple splicing variants of cdc25B regulate G2/M progression.
AB  - Progression through G2 phase into mitosis is regulated by the activation of the
      mitotic cyclin/cdk complexes, which are in turn activated cdc25B and cdc25C
      phosphatases. Here we report that alternate splicing produces at least five
      variants of cdc25B, although only cdc25B2 and cdc25B3 are detectable as proteins.
      Analysis of these two variants shows that cdc25B2 is expressed at lower levels
      relative to cdc25B3 in all cell lines tested, and the expression of both
      increased markedly during G2 and mitosis. Overexpression of the catalytically
      inactive version of either cdc25B variant produced a G2 arrest implicating both
      in regulating G2/M progression.

PMID- 10403800
TI  - Regulation of Bcl-2 protein expression during oxidative stress in neuronal and in
      endothelial cells.
AB  - The relationship between oxidative stress and Bcl-2 expression was investigated
      in two different experimental models of oxidative stress. Acute oxidative stress
      was assessed by measuring, with fluorescence microscopy and cytofluorimetry, the
      increase in fluorescence of the oxidation-sensitive probe dihydrorhodamine 123,
      both in retinal rod receptor cells exposed to bright light (0.32 mW/cm(2) for 15
      minutes) and in human endothelial cells treated with the immunosuppressant
      cyclosporin A (200 microM for 21 h). In both cell types, acute oxidative stress
      reduced Bcl-2 expression and also caused a significant increase in the level of
      nucleosomes. Interestingly, chronic treatment with clinical concentrations of
      cyclosporin A (0.5-2.5 microM for 8 days) led to a significant increase in Bcl-2
      expression, while nucleosomes were similar to control level. This suggests that
      up-regulation of Bcl-2 protein by low levels of oxidants may represent a critical
      factor in cellular adaptation to drug toxicity.

PMID- 10403801
TI  - Real time analysis of interaction between inositol 1,4, 5-trisphosphate receptor
      type I and its ligand.
AB  - Inositol 1,4,5-trisphosphate (IP(3)) is an important second messenger that
      releases intracellular Ca(2+) by binding to its specific receptor, inositol 1,4,5
      trisphosphate receptor (IP(3)R), in a wide range of cellular processes. We report
      here large-scale expression and purification of N-terminal 604 amino acids of
      IP(3)R type 1 (T604) expressed in E. coli, which contains the ligand binding
      domain. Surface plasmon resonance biosensor studies showed that purified T604
      could bind to its ligands with binding specificity identical to that of full
      length native IP(3)R type 1. Kinetic parameters of T604 for IP(3) consisted of a
      fast association rate constant (K(ass) = 1.2 x 10(6) M(-1) s(-1)) and a rapid
      dissociation rate constant (k(diss) = 1 s(-1)), and the equilibrium dissociation
      constant was determined to be 336 nM, at 150 mM NaCl and pH 7.4. However,
      association and dissociation patterns depended on the pH level and ionic
      strength. These results pave the way toward detail analysis of structure-function
      analysis of the ligand binding domain of IP(3)R type 1 for its ligands.

PMID- 10403802
TI  - L-Asparaginase inhibits the rapamycin-targeted signaling pathway.
AB  - L-Asparaginase is widely used in the treatment of acute lymphoblastic leukemia. L
      Asparaginase preparation derived from E. coli converts asparagine (Asn) and
      glutamine (Gln) to aspartate (Asp) and glutamate (Glu), respectively, and causes
      rapid depletion of Asn and Gln. It thus suppresses growth of malignant cells that
      are more dependent on an exogenous source of Asn and Gln than are normal cells.
      It remains unclear, however, which signaling events in leukemic cells are
      affected by L-asparaginase. Recently, amino acid sufficiency has been
      demonstrated to selectively regulate p70 S6 kinase (p70(s6k)) and eukaryotic
      initiation factor 4E-binding protein 1 (4E-BP1), both of which are targeted by
      the anti-proliferative drug rapamycin. Here we demonstrate that addition of L
      asparaginase to human leukemic cells inhibits activity of p70(s6k) and
      phosphorylation of 4E-BP1, but not activities of other cell growth-related
      serine/threonine kinases. The rate and kinetics of p70(s6k) inhibition by L
      asparaginase were comparable to those seen by deprivation of Asn and/or Gln from
      cell culture media, suggesting that the effect of L-asparaginase on p70(s6k) is
      explained by depletion of Asn and/or Gln. Moreover, L-Asparaginase as well as
      rapamycin selectively suppressed synthesis of ribosomal proteins at the level of
      mRNA translation. These data indicate that L-asparaginase and rapamycin target a
      common signaling pathway in leukemic cells.

PMID- 10403803
TI  - Inhibition of EGF-dependent calcium influx by annexin VI is splice form-specific.
AB  - Annexin VI is a widely expressed calcium- and phospholipid-binding protein that
      lacks a clear physiological role. We now report that A431 cells expressing
      annexin VI are defective in their ability to sustain elevated levels of cytosolic
      Ca(2+) following stimulation with EGF. Other aspects of EGF receptor signaling,
      such as protein tyrosine phosphorylation and induction of c-fos are normal in
      these cells. However, EGF-mediated membrane hyperpolarization is attenuated and
      Ca(2+) entry abolished in cells expressing annexin VI. This effect of annexin VI
      was only observed for the larger of the two annexin VI splice forms, the smaller
      splice variant had no discernable effect on either cellular phenotype or growth
      rate. Inhibition of Ca(2+) influx was specific for the EGF-induced pathway;
      capacitative Ca(2+) influx initiated by emptying of intracellular stores was
      unaffected. These results provide the first evidence that the two splice forms of
      annexin VI have different functions.

PMID- 10403804
TI  - Uncoupling protein-3 mRNA levels are increased in white adipose tissue and
      skeletal muscle of bezafibrate-treated rats.
AB  - Fibrates are hypolipidemic drugs that are also able to improve glucose tolerance
      in animals and diabetic patients through an unknown mechanism. Since uncoupling
      proteins (UCP) seem to play an important role in the pathogenesis of non-insulin
      dependent diabetes mellitus (NIDDM), we examined whether treatment of rats with
      bezafibrate for 3, 7, or 15 days modified UCP mRNA levels. Using RT-PCR, we
      observed a weak ectopic expression of UCP-1 and a 2-fold increase in UCP-3 mRNA
      levels in white adipose tissue after 7 and 15 days of treatment. Moreover,
      bezafibrate administration caused a 1. 7-fold induction in UCP-3 mRNA levels in
      skeletal muscle on day 7. Since UCP-3 mRNA levels are reduced in skeletal muscle
      of diabetic patients, this effect may be involved in the improvement of insulin
      sensitivity caused by bezafibrate in NIDDM.

PMID- 10403805
TI  - Characterization of an oxygen/redox-dependent degradation domain of hypoxia
      inducible factor alpha (HIF-alpha) proteins.
AB  - Hypoxia-inducible factors are heterodimeric DNA-binding complexes that control
      the hypoxia responses of several genes and regulate the adaptive responses to the
      lack of oxygen. The complex is composed of two b-HLH protein subunits, HIF-1beta
      (ARNT), that is constitutively expressed, and a HIF-alpha subunit, that is
      present only in hypoxic cells. HIF-alpha proteins are continuously synthesized,
      but are rapidly degraded by the ubiquitin-proteasome system under oxic
      conditions. Hypoxia, transition metals, iron chelators, and several antioxidants
      stabilize the HIF-alpha proteins, allowing the formation of the transcriptionally
      active HIF complex. However, the sequences and mechanisms involved in the
      regulated degradation of the alpha protein subunits are poorly understood.
      Analysis of the available cloned sequences of human and mouse members of the HIF
      alpha family of proteins revealed an area of about 15 amino acids with strong
      sequence conservation between all the members. This area corresponds to the
      region encompassing amino acids 557-571 of the hHIF-1alpha subunit. Fragments of
      HIF-1alpha and HIF-3alpha proteins containing this conserved sequence were able
      to confer hypoxia regulation when expressed as fusion proteins in Hep-3B cells.
      Regulation was observed with all the known hypoxia "mimics," including the
      reducing thiol donor N-mercaptopropionylglycine (NMPG). Selective alanine
      substitutions of amino acids 561-568 stabilized the protein in normoxic
      conditions. Furthermore, transfection with an expression vector containing a
      fragment of hHIF-1alpha comprising amino acids 540-580 enhanced transactivation
      activity of the full-length hHIF-1alpha protein. These results suggest that the
      above-mentioned conserved sequences are likely involved in the hypoxic
      stabilization of HIF-alpha proteins. The mechanisms and the interacting ubiquitin
      ligases involved in the selective degradation process remain unknown.

PMID- 10403806
TI  - Doxycycline induces Fas/Fas ligand-mediated apoptosis in Jurkat T lymphocytes.
AB  - Tetracyclines have been used in the treatment of chronic inflammatory diseases
      associated with local infiltration of inflammatory cells and matrix destruction
      as observed in rheumatoid arthritis and periodontal disease. Fas/Fas ligand
      (FasL)-mediated apoptosis plays an important role in maintaining T lymphocyte
      homeostasis and modulating immune response. The present study demonstrates that
      doxycycline inhibits Jurkat T lymphocyte proliferation and induces apoptosis. The
      phytohemagglutinin (PHA)-activated Jurkat cells are more susceptible to
      doxycycline-induced apoptosis. Furthermore, doxycycline-induced apoptosis is
      associated with increased Fas/FasL expression in Jurkat cells. The increase of
      apoptosis in Jurkat cells treated with doxycycline is consistent with the
      increase of FasL expression. These results suggest that doxycycline may
      downregulate the inflammatory process in certain diseases by eliminating
      activated T lymphocytes through Fas/FasL-mediated apoptosis.

PMID- 10403807
TI  - Flavonoids are potential inhibitors of glucose uptake in U937 cells.
AB  - Flavonoids are a group of polyphenolic compounds ubiquitously found in plants
      including fruits, and vegetables. Broad ranges of the biological activities of
      flavonoids have been reported using in vitro studies. I report that several
      natural flavonoids blocked glucose uptake in myelocytic U937 cells. Although
      there were some variations in the blocking activity of individual flavonoids,
      approximately half of the glucose uptake was blocked by flavonoids at the
      concentrations of 8-50 microM. The decreasing order of the blocking activity was
      fisetin >/= myricetin >/= quercetin >/= apigenin > genistein > cyanidin >
      daidzein >/= hesperetin > naringenin > catechin. Fisetin showed approximately 50%
      inhibition of glucose uptake at a concentration of 8 microM. Similar patterns of
      the inhibition were observed in lymphocytic Jurkat cells. Fisetin and quercetin
      inhibited glucose transport in a competitive manner. K(i) values for fisetin and
      quercetin were proximately 9 and 12 microM, respectively. This study showed that
      some types of natural flavonoids block glucose uptake in U937 cells and that
      natural flavonoids could be used as alternative blockers of glucose uptake in
      vitro.

PMID- 10403808
TI  - Cell-specific differences in the regulation of IL-6 expression by PMA.
AB  - We have studied the regulation of IL-6 expression in human blood monocytes and
      lymphocytes. LPS and IFN-gamma induced IL-6 gene expression with a similar
      qualitative profile in both cell types. Treatment of monocytes and lymphocytes
      with PMA resulted, instead, in different effects: monocytes accumulated IL-6 and
      its message, while lymphocytes were inhibited either in the absence or the
      presence of LPS and IFN-gamma. These results suggest that the signal transduction
      pathways triggered by LPS and IFN-gamma are similar in both cell types, while PMA
      may activate a tissue-specific pathway which leads to opposite responses.

PMID- 10403809
TI  - The C-terminus of bax is not a membrane addressing/anchoring signal.
AB  - It has been suggested that BCL-2 family members associate with certain organelles
      through their hydrophobic C-terminus which in the case of bcl-2, appears to play
      a key role in the regulation of apoptosis. We have investigated the association
      of bax with microsomal, nuclear and mitochondrial membranes using a cell-free
      system and found, contrary to bcl-2, that bax binds poorly to these organelles.
      Deletion of the C-terminal of bax (baxDeltaC) or exchanging the C-terminal ends
      of bax and bcl-XL suggests that the bax C-terminus is not an addressing/anchoring
      signal. In agreement with this observation, HL-60 cells transfected with either
      bax or baxDeltaC show no difference in sensitivity to an apoptotic signal. In the
      cell-free system, at low pH, bax becomes associated with mitochondria after a
      change of conformation, a result consistant with its structural homology with
      certain bacterial toxins. In HL-60 cells, as observed in the cell-free system,
      bax acquired a protease resistant conformation upon its translocation from the
      cytosol to the mitochondria after the induction of apoptosis.

PMID- 10403810
TI  - Nociceptin binding sites in frog (Rana esculenta) brain membranes.
AB  - The recently discovered natural heptadecapeptide nociceptin (orphanin FQ) shares
      some homology with the opioid peptides but it binds to a distinct receptor type,
      termed nociceptin receptor. This study demonstrates the presence of specific
      nociceptin recognition sites in brain membrane fractions of an amphibian, Rana
      esculenta. Para-iodo-Phe(1)-nociceptin-amide was radiolabelled by catalytic
      dehalotritiation, resulting in p[(3)H]Phe(1)-nociceptin-amide of 25 Ci/mmol
      specific radioactivity. Specific binding of [(3)H]nociceptin-amide to frog brain
      membranes was found to be saturable and of high affinity with equilibrium K(d)
      values in the low nanomolar range. A single set of binding sites with about 180
      fmol/mg protein maximal binding capacity was obtained in saturation and
      competition experiments. [(3)H]Nociceptin-amide binding could easily be inhibited
      by synthetic nociceptin compounds but not by opioid ligands. Both sodium ions and
      5'-guanylylimidodiphosphate decreased the binding of the radioligand by
      transferring the receptor to a lower affinity state. Nociceptin dose-dependently
      stimulated the binding of the nonhydrolysable, radiolabeled GTP-analogue
      guanosine-5'-O-(3-thio)triphosphate ([(35)S]GTPgammaS) to G-proteins in frog
      brain membranes. Addition of 1 microM naloxone caused no significant change in
      the curves, indicating that nociceptin-mediated activation of G-proteins occurred
      through nonopioid mechanism.

PMID- 10403811
TI  - Rotation of Escherichia coli F(1)-ATPase.
AB  - By applying the same method used for F(1)-ATPase (TF(1)) from thermophilic
      Bacillus PS3 (Noji, H., Yasuda, R., Yoshida, M., and Kinosita, K., Jr. (1997)
      Nature 386, 299-302), we observed ATP-driven rotation of a fluorescent actin
      filament attached to the gamma subunit in Escherichia coli F(1)-ATPase. The
      torque value and the direction of the rotation were the same as those observed
      for TF(1). F(1)-ATPases seem to share common properties of rotation irrespective
      of the sources.

PMID- 10403812
TI  - Transcription factor NF1 mediates repression of the GLUT4 promoter by cyclic-AMP.
AB  - Prolonged treatment of 3T3-L1 adipocytes with 8-Br-cAMP decreases expression of
      GLUT4, the insulin-responsive glucose transporter. Expression of a promoter
      reporter gene construct that contained 785 base pairs of 5'-flanking region of
      the murine GLUT4 gene was down regulated by 8-Br-cAMP (p < 0.001), whereas
      expression of constructs that contained 641 or 469 base pairs of 5'-flanking
      region was not. A reporter gene construct in which bases -706 to -676 were
      deleted was not repressed by 8-Br-cAMP, thereby identifying a 30 bp region as
      necessary for repression of the GLUT4 promoter by 8-Br-cAMP. Mutations in this
      regulatory element that disrupt binding of the transcription factor NF1 abolish
      the 8-Br-cAMP-induced repression of the gene. Although insulin and cAMP both
      repress the GLUT4 promoter through this cis-element, they appear to do this
      through different mechanisms, as treatment with 8-Br-cAMP does not induce the
      phosphorylation of NF1 that is induced by insulin treatment.

PMID- 10403813
TI  - Nuclear localization of C-terminal domains of the kinesin-like protein MKLP-1.
AB  - The successful execution of mitosis in mammalian cells requires the activities of
      numerous kinesin-like proteins. The Mitotic Kinesin-Like Protein-1 (MKLP-1)
      localizes to the spindle equator and is believed to participate in the separation
      of spindle poles during anaphase B. Injection of antibodies against MKLP-1 into
      dividing cells results in cell cycle arrest, suggesting that MKLP-1 is essential
      for mitosis. To further characterize MKLP-1, constructs encoding C-terminal
      domains of MKLP-1 were expressed as fusions to the green fluorescent protein and
      localized in HeLa cells. All constructs localized to the nucleus indicating the
      presence of at least one nuclear localization sequence in the C-terminus of the
      protein. C-terminal domains of MKLP-1 expressed in insect cells also localized to
      the nucleus as shown by subcellular fractionation. These proteins remained
      tightly associated with the nucleus following both detergent and salt extraction,
      suggesting a tight interaction with a component of the nucleus.

PMID- 10403815
TI  - Sphingosine and phorbol ester modulate protein kinase C activity and modify ATP
      evoked calcium mobilization in glioma C6 cells.
AB  - The effect of sphingosine and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on ATP
      evoked Ca(2+) mobilization in glioma C6 cells was studied with the Fura-2 video
      imaging technique. Treatment of the cells with TPA, an activator of protein
      kinase C, reduced the ATP-evoked release of Ca(2+) from the intracellular stores,
      whereas sphingosine, known from in vitro studies as a protein kinase C inhibitor,
      potentiated Ca(2+) release synergistically with ATP. ATP-induced Ca(2+)
      mobilization was also enhanced by a specific protein kinase C inhibitor, GF
      109203X. Pretreatment of the cells with GF 109203X prevented TPA action, whereas
      TPA diminished the stimulatory effect of sphingosine. However, this sphingosine
      effect was only observed after a short (1 min) treatment, whereas a longer
      treatment (5 min) reduced ATP-evoked Ca(2+) release. It is therefore concluded
      that sphingosine has two apparent actions: it inhibits protein kinase C providing
      a positive feedback regulation of receptor signals and it releases Ca(2+) from
      intracellular stores by an unknown mechanism, possibly independent of protein
      kinase C.

PMID- 10403814
TI  - Evidence for direct binding of fatty acids and eicosanoids to human peroxisome
      proliferators-activated receptor alpha.
AB  - The alpha isoform of peroxisome proliferators-activated receptor (PPAR) is
      activated by fatty acids, their metabolites, and the fibrate class of lipid
      lowering agents. To test the ability of these activators to directly bind the
      ligand-binding domain of human PPARalpha, we performed a competitive binding
      assay using radiolabeled [(3)H]KRP-297, a known ligand for human PPARalpha. Long
      chain fatty acids and eicosanoids were even more potent ligands for human
      PPARalpha than the hitherto most potent PPARalpha ligand WY-14,643. Moreover,
      these natural ligands avidly activated this receptor in a transient
      transcriptional assay. This study provides the direct evidence that human
      PPARalpha is activated through the direct binding of fatty acids and eicosanoids,
      as well as of a fibrate, to its ligand-binding domain.

PMID- 10403816
TI  - Heat shock proteins 70 and 90 increase calcineurin activity in vitro through
      calmodulin-dependent and independent mechanisms.
AB  - We have shown that heat shock proteins (HSPs) associated with steroid receptor
      complexes are involved in the activation of calcineurin by aldosterone and
      dexamethasone. To determine whether HSPs directly interact with calcineurin, we
      measured the effect of HSPs 90, 70 and 56 on calcineurin activity in a cell-free,
      in vitro system using a calcineurin-specific substrate. HSP-90 (75 or 100 nM)
      significantly increased calcineurin V(max) in the presence of calmodulin, while
      maximal stimulation by HSP-70 occurred at 50 nM. Bovine serum albumin (BSA) and
      actin did not change basal calcineurin activity indicating that HSP-90 and HSP-70
      specifically activate calcineurin. Neither HSP-70, HSP-56, nor ATP augmented HSP
      90-induced activation of calcineurin. In the absence of calmodulin, HSP-90
      restored calcineurin activity to basal levels while higher concentrations (333
      and 500 nM) increased calcineurin activity. In contrast, HSP-70 failed to
      activate calcineurin activity in the absence of calmodulin. Immunoprecipitation
      of HSP-90 from in vitro mixtures as well as protein extracts from LLCPK-1 cells
      demonstrates that calcineurin co-precipitates with HSP-90. In summary: (1) HSP-90
      and 70 stimulate calcineurin V(max) in vitro; (2) non-specific protein
      interactions do not activate calcineurin activity; (3) HSP-70 and HSP-56 do not
      enhance HSP-90-induced activation of calcineurin; (4) HSP-70 and HSP-90 activate
      calcineurin via a calmodulin-dependent and independent pathways; (5) Calcineurin
      co-precipitates with HSP-90 from LLCPK-1 cells as well as cell-free in vitro
      preparations.

PMID- 10403817
TI  - A factor from pancreatic and colonic cancer cells stimulates glucose uptake and
      lactate production in myoblasts.
AB  - Patients with cancer cachexia exhibit increased glucose flux and lactate
      production in skeletal muscle. The aim of this study was to examine the direct
      effect of cancer cell-conditioned media on glucose metabolism in L6 myoblasts.
      Media from PANC-1 and Colo 320 cells caused a marked time-dependent and
      concentration-dependent increase of 2-deoxyglucose uptake in GLUT-4 transfected
      L6 myoblasts. This effect was greater than maximal acute stimulation by insulin
      and the effect of insulin was additive. Glucose utilization and lactate
      production increased in parallel to glucose uptake. The effect was inhibited by
      the protein synthesis inhibitor, cycloheximide and the glucose transport
      inhibitor, cytochalasin B. The bioactive factor had a molecular weight of
      approximately 5,000 and the biological activity was destroyed by proteinase K
      digestion. Radioimmunoassay and immunoneutralization studies indicated the major
      factor involved is not TNFalpha, IL-1beta, insulin, IGF-I or IGF-II. Further
      purification and characterization are needed to reveal the identity of this novel
      factor or factors which may have other metabolic effects that contribute to the
      cancer cachexia and insulin resistance.

PMID- 10403819
TI  - Protocadherin 2C: a new member of the protocadherin 2 subfamily expressed in a
      redundant manner with OL-protocadherin in the developing brain.
AB  - Using cDNA of human protocadherin 2A (pc2A; originally known as protocadherin 2)
      as a probe, we cloned a new member of the protocadherin 2 subfamily from mouse
      brain cDNA libraries and named it protocadherin 2C (pc2C). It was similar to pc2A
      throughout its entire coding region, and its C-terminal region was highly
      conserved. The locus of the pc2C gene was on the mouse chromosome 18C where the
      pc2A gene is located, suggesting that genes of the pc2 subfamily form a gene
      cluster. The expression of pc2C was restricted to the nervous system, and the
      expression started in the embryonic stage and increased up to the adult stage.
      The expression pattern was quite similar to that of OL-protocadherin, a distinct
      class of protocadherin, although the timing and relative strength of expression
      were different. These results suggest that pc2C may be involved in neural
      development along with other classes of protocadherins.

PMID- 10403818
TI  - Involvement of the 92-kDa gelatinase (matrix metalloproteinase-9) in the ceramide
      mediated inhibition of human keratinocyte growth.
AB  - Triggering the ceramide pathway by exogenous treatment with neutral
      sphingomyelinase (Smase) inhibited human keratinocyte growth rate, while having
      no influence on cell apoptosis. Increasing the ceramide content of keratinocytes
      with Smase (100 U/ml) or C6-ceramide (1 microM) enhanced matrix metalloproteinase
      (MMP)-9 production. On the contrary, levels of MMP-2 secretion were unchanged.
      The inhibition of keratinocyte growth rate induced by ceramide could be
      annihilated by a peptide hydroxamate MMP inhibitor or an MMP-9 blocking antibody.
      In addition, inhibiting MMP-9 activity in control keratinocyte culture was found
      to stimulate keratinocyte proliferation. These data suggest a pivotal function of
      MMP-9 in the control of keratinocyte growth.

PMID- 10403820
TI  - Neuronal expression of a Caenorhabditis elegans elav-like gene and the effect of
      its ectopic expression.
AB  - We examined the expression of a Caenorhabditis elegans (C. elegans) elav-like
      gene, which we designated elr-1. The elr-1 gene encodes a predicted 456-amino
      acid protein containing three putative RNA-binding domains and belongs to the
      ELAV family, which is functionally involved in neuronal differentiation. Northern
      blot analysis suggested that the levels of elr-1 mRNA are regulated
      developmentally. A elr-1::gfp reporter gene under the control of the elr-1
      promoter was expressed specifically in the ring ganglia near the nerve ring, the
      ventral nerve cord (VNC), and the pre-anal and lumbar ganglia. In the VNC, GFP
      positive cells were shown to be acetylcholine-producing motor neurons which
      increased in number as development proceeded, suggesting that elr-1 is expressed
      in mature neurons. Ectopic expression of ELR-1 protein at the L4 larval and adult
      stages, but not earlier stages, caused irreversible death, accompanied by
      uncoordinated movement (Unc), clear (Clr), and egg-laying defective (Egl)
      phenotypes, which are often observed in mutants with neuronal defects. These
      results suggest that ELR-1 may have important functions in specific mature
      neurons in C. elegans.

PMID- 10403821
TI  - Hyperleptinemia depletes fat from denervated fat tissue.
AB  - Adenovirus-mediated transfer of the leptin gene causes severe hyperleptinemia
      with rapid disappearance of visible body fat. To determine if this dramatic
      lipopenic action is mediated by neurotransmitted signals from the central nervous
      system, we transplanted the right epididymal fat pad of normal rats to the
      anterior abdominal wall. Four weeks later, rats were infused with either
      adenovirus-leptin cDNA (AdCMV-leptin) or adenovirus-beta-galactosidase (AdCMV
      beta-gal). Eight days later, plasma leptin averaged 23 +/- 12 ng/ml in the former
      and 1.2 +/- 0.4 ng/ml in the latter. The fat transplant was intact in all 4 AdCMV
      beta-gal-infused rats but had disappeared in all 4 hyperleptinemic rats. Tyrosine
      hydroxylase staining of the fat pad remnant was negative, excluding regrowth of
      sympathetic nerves. Thus, the lipopenic action of severe hyperleptinemia on
      adipocytes is not mediated by neurotransmitters, but must have resulted either
      from direct action of leptin and/or from leptin-mediated neurohormones.

PMID- 10403822
TI  - Casein kinase 2 binds to and phosphorylates BRCA1.
AB  - The BRCA1 gene encodes a complex protein that appears to be involved in some
      aspects of DNA repair, transcription, or cell cycle regulation. The
      phosphorylation of BRCA1 is enhanced following episodes of DNA damage or during
      cell cycle progression, indicating that phosphorylation may be an important
      regulatory mechanism. Through a yeast two hybrid assay, we found that the beta
      subunit of casein kinase 2 (CK2) associated with a carboxy-terminal region of
      BRCA1. This association was much weaker with the same fragment bearing a missense
      mutation (M1775R) that has been identified in breast tumors. The interaction was
      also evident in Sf9 cells. Subsequent studies showed that BRCA1 was
      phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1
      showed that in vitro phosphorylation by CK2 required a serine at aa1572. These
      data implicate CK2 as a potential mediator of BRCA1 activity.

PMID- 10403823
TI  - Purification and characterization of brevinase, a heterogeneous two-chain
      fibrinolytic enzyme from the venom of Korean snake, Agkistrodon blomhoffii
      brevicaudus.
AB  - A fibrinolytic enzyme, designated as brevinase, was purified from the venom of
      Korean snake, Agkistrodon blomhoffii brevicaudus. Brevinase cleaved both the
      Aalpha- and Bbeta-chains of fibrinogen but did not affect the gamma-chain. It
      showed beta-fibrinogenase activity devoid of fibrinogen clotting and caseinolytic
      activity. The fibrinolytic activity was completely inhibited by PMSF, DFP,
      Pefabloc, and DTT, indicating brevinase is a serine protease requiring disulfide
      bridge(s) for its activity. It kept 80% of the initial activity after heating at
      100 degrees C for 3 min, showed an equal maximum activity in the pH range from
      5.5 to 8.5, and was inactivated by Zn(2+). Brevinase consists of two polypeptide
      chains of 16.5 and 17 kDa linked by disulfide bridge(s). The N-terminal amino
      acid sequences of 16.5 and 17 kDa chains showed homology to the N-terminal and
      the internal (central region) amino acid sequences of single-chain fibrinolytic
      enzymes in snake venom, respectively.

PMID- 10403824
TI  - CAPN 8: isolation of a new mouse calpain-isoenzyme.
AB  - Recent molecular biological approaches indicate that calpain, also named CANP for
      calcium-activated neutral protease and originally characterized as an
      intracellular cytoplasmatic nonlysosomal cysteine protease that requires calcium
      ions for activity, constitutes a large superfamily consisting of ubiquitous and
      tissue specific homologues, which are widely distributed in cells of various
      organisms from human to fungus. Due to the increasing number of substrates along
      with the involvement of calpain isoenzymes in mammalian diseases, especially in
      malignancies, members of the calpain superfamily seem to be important
      biomodulators in physiological as well as pathological cell function. Here we
      report the characterisation of a new calpain, named CAPN 8 with a different C
      terminal domain, implicating a putative new regulatory mechanism. Northern blot
      analysis revealed an ubiquitous expression with different RNA levels in all
      tissues examined. Highest levels were found in brain, kidney, and digestive
      tract, suggesting a specific regulatory function of CAPN 8 in these tissues.

PMID- 10403825
TI  - Human prostate CYP3A5: identification of a unique 5'-untranslated sequence and
      characterization of purified recombinant protein.
AB  - We have isolated a cDNA clone coding for CYP3A5 from a human prostate cDNA
      library. The human prostate CYP3A5 cDNA had a unique 5'-untranslated sequence,
      suggesting that the prostate specific regulation of CYP3A5 is different from
      liver. Hybridization screening using a human genomic BAC library yielded four
      positive clones, two of which were shown to contain the unique 5'-untranslated
      sequence by Southern blot analysis. The CYP3A5 recombinant protein expressed in
      Escherichia coli using the pCWOri expression vector was purified to an almost
      electrophoretically homogeneous state with a specific content of 4.4 nmol of
      P450/mg of protein. This P450 exhibited 6beta-hydroxylation activity toward both
      testosterone and progesterone. No polar metabolite of 5alpha-dihydrotestosterone
      (DHT) was detected. The apparent K(m) values for testosterone and progesterone
      6beta-hydroxylation were 143 and 114 microM, respectively, with V(max) values of
      0.48 and 0. 21 nmol/min/nmol of P450, respectively. This is the first report that
      a particular form of P450, CYP3A5, has been isolated from human prostate and that
      the purified recombinant protein of CYP3A5 has been shown to be active in the
      metabolism of sex hormones.

PMID- 10403826
TI  - Daphnetin, one of coumarin derivatives, is a protein kinase inhibitor.
AB  - Protein kinases play key roles in the control of cell proliferation,
      differentiation and metabolism. In this work, we studied the effect of coumarin
      and its derivatives, including daphnetin, esculin, 2-OH-coumarin, 4-OH-coumarin
      and 7-OH-coumarin, on the activity of protein kinases. It was found that, in
      these compounds, only daphnetin was a protein kinase inhibitor. This compound
      inhibited tyrosine-specific protein kinase, EGF receptor (IC(50) = 7.67 microM),
      and serine/threonine-specific protein kinases, including cAMP-dependent protein
      kinase (PKA) (IC(50) = 9.33 microM) and protein kinase C (PKC) (IC(50) = 25.01
      microM) in vitro. The inhibition of EGF receptor tyrosine kinase by daphnetin was
      competitive to ATP and non-competitive to the peptide substrate. The inhibition
      of EGF-induced tyrosine phosphorylation of EGF receptor by daphnetin was not
      observed in human hepatocellular carcinoma HepG2 cells. The structural comparison
      of daphnetin with coumarin and other coumarin derivatives suggests that the
      hydroxylation at C8 may be required for daphnetin acting as a protein kinase
      inhibitor.

PMID- 10403827
TI  - Lipopolysaccharides induce p8 mRNA expression in vivo and in vitro.
AB  - Systemic LPS endotoxin is associated with acute pancreatic damage. Whether damage
      results from direct interaction of LPS with pancreatic cells is unknown. We
      addressed that question by monitoring p8 expression in reponse to LPS, in vivo
      and in vitro, because overexpression of the p8 protein is a sensitive marker of
      pancreatic agression. For in vivo studies, rats were sacrificed at different
      times after a single intraperitoneal injection of LPS, and pancreas, liver,
      kidney, lung, brain, and intestine were processed for RNA preparation. In vitro,
      pancreatic acinar AR4-2J cells were cultivated with 0.1, 1, or 10 micrograms/ml
      LPS for 6, 12, or 24 h. p8 mRNA expression was monitored by Northern blotting. In
      vivo, it was strongly increased in the pancreas after 12 h of treatment and
      remained elevated after 24 h. It was also induced in kidney and liver, with a
      maximum at 6 and 12 h, respectively, but not in lung, brain, or intestine. In AR4
      2J cells, basal p8 mRNA expression was very low and increased in a time- and dose
      dependent manner after treatment with LPS. LPS-induced overexpression of p8 mRNA
      in vivo confirmed the adverse effect of endotoxemia on pancreas and its
      overexpression in vitro demonstrated a direct interaction of LPS with pancreatic
      cells.

PMID- 10403828
TI  - Functional characterization of a purified, recombinant NF-kappaB/IkappaB complex.
AB  - The NF-kappaB signal transduction pathway involves the interaction of several NF
      kappaB and IkappaB family members that are activated by a diverse range of
      extracellular signals and that stimulate many different cellular responses. The
      biochemical regulation of this cascade can be studied by establishing a cell-free
      system using purified proteins. As a first step toward establishing an in vitro
      model incorporating multiple combinations of NF-kappaB and IkappaB proteins, we
      produced purified human p65 (RelA) and human IkappaBalpha proteins and tested
      their functionality. Full-length RelA and IkappaBalpha proteins were overproduced
      by coinfection of TN5-JE cells with two recombinant baculoviruses. RelA and
      IkappaBalpha formed a stable complex that could be purified to >95% homogeneity.
      Protein-protein interactions, protein-DNA binding, and protein phosphorylation
      were similar to the native proteins.

PMID- 10403829
TI  - Epidermal growth factor stimulates 3-hydroxy-3-methylglutaryl-coenzyme A
      reductase expression via the ErbB-2 pathway in human breast adenocarcinoma cells.
AB  - HMG-CoA reductase is the key enzyme for the biosynthesis of isoprenoid compounds
      essential for cell growth and differentiation. Its tyrosine kinase-dependent
      modulation has recently been suggested and described in the ErbB-2 overexpressing
      cell line SKBR-3 [Asslan et al. (1998) Biochem. J. 330, 241-246]. Epidermal
      growth factor (EGF) increased the HMG-CoA reductase activity, protein, and mRNA
      levels only in ErbB-2-expressing cells (SKBR-3 and MCF-7) but not in MDA-MB-468
      cells that do not express ErbB-2 even though their EGF receptor was efficiently
      phosphorylated. Tyrphostin AG 879, a specific inhibitor of ErbB-2 tyrosine kinase
      activity, decreased HMG-CoA reductase activity only in cells that expressed ErbB
      2. A functional EGF receptor appeared to be necessary since its inhibition by the
      specific tyrphostin AG 1478 abolished the EGF effects. Phosphatidylinositol 3
      kinase (PI 3-kinase) might be a crucial enzyme in the signaling pathway since the
      specific inhibitor, LY 294002, was shown to inhibit HMG-CoA reductase activity
      and to completely abolish the stimulation by EGF in SKBR-3 cells.

PMID- 10403830
TI  - Dynamic expression pattern of Ca(2+)/calmodulin-dependent protein kinase II gene
      in the central nervous system of Drosophila throughout development.
AB  - Calcium/calmodulin-dependent protein kinase II (CaM KII) is thought to be
      involved in the majority of the neuronal functions mediated by intracellular free
      Ca(2+), and has been implicated in long-term potentiation, learning, and memory.
      In this work, we have examined in detail the RNA expression pattern for the
      Drosophila CaM KII gene by in situ hybridization, during embryonic, larval,
      pupal, and adult stages. Our results indicate that expression of CaM KII was
      homogeneous in early embryos, but that during development the gene transcription
      rapidly became restricted to neuroblasts and their progeny in the nervous system.
      This predominant expression in the nervous system is maintained during late
      embryogenesis and post-embryonic development. A signal compartmentalization
      appeared in the larval central nervous system, where the CaM KII expression
      became progressively concentrated in the anterior ganglia. In the adult brain, a
      specific expression was more abundant in a subset of neurons around the central
      brain, particularly the mushroom bodies and the central complex, structures that
      play an important role in learning and memory.

PMID- 10403832
TI  - Insulin receptor substrate 4 supports insulin- and interleukin 4-stimulated
      proliferation of hematopoietic cells.
AB  - Signaling from the activated insulin receptor is initiated by its tyrosine
      phosphorylation of the insulin receptor substrates (IRSs). The IRSs then act as
      docking/effector proteins for various signaling proteins containing src homology
      2 domains. Four members of the IRS family, designated IRS-1 through IRS-4, have
      been identified. Although these IRSs show considerable structural homology, the
      extent to which they overlap in functions has not been explored in detail. The
      32D hematopoietic cell line, which contains no detectable amounts of any IRS,
      provides a system in which to determine whether an IRS supports cell
      proliferation. Previous studies have shown that introduction of IRS-1 or -2 into
      32D cells overexpressing the insulin and IL-4 receptors (32D-R cells) enables the
      cells to undergo mitogenesis in response to insulin and IL-4. In the present
      study, we have examined IRS-4, a member of the IRS family that we recently
      discovered, in this system. Expression of IRS-4 in 32D-R cells permitted the
      cells to undergo mitogenesis and continuous proliferation in response to insulin
      and IL-4. Immunoblotting of phosphotyrosine proteins showed that insulin and IL-4
      elicited the tyrosine phosphorylation of IRS-4 in these cells. Thus, IRS-4, like
      IRS-1 and -2, can function in the signal transduction pathways linking insulin
      and IL-4 receptors to cell proliferation.

PMID- 10403831
TI  - Is green fluorescent protein toxic to the living cells?
AB  - Green fluorescent protein (GFP) has become more popular to be used as a living
      marker for positively transfected clones in many studies. To establish stable
      cell lines constitutively expressing GFP, three GFPs expressed from plasmid
      pBIEGFP, pSG5GFP, and pRSGFP were introduced into NIH/3T3, BHK-21, Huh-7, and
      HepG2 cells. All the GFPs we used are the mutant forms of a common wild
      phenotype. The pBIEGFP expressed enhanced GFP (EGFP). The pRSGFP and pSG5GFP
      expressed red shift GFP (RSGFP). The RSGFP gene in pSG5GFP was driven by a strong
      SV40 promoter and showed at least 20-fold higher RSGFP expression by western blot
      analysis. Despite of the variation in the levels of GFP expression, many GFP
      expressing cells contracted, rounded-up, and died, which was confirmed by
      decreasing luciferase activity. CPP32 activity and flow cytometric analyses
      further demonstrate that cells expressing GFP underwent apoptosis. Our
      observation is contradictory to other reports that GFP is nontoxic to the cells.
      Most importantly, this paper shows for the first time the link between expression
      of GFP and induction of apoptosis. This finding should promote studies of GFP
      cytotoxicity and attempts to isolate new non-toxic mutants of GFP.

PMID- 10403833
TI  - Expression, purification, and characterization of the cytoplasmic domain of the
      human IGF-1 receptor using a baculovirus expression system.
AB  - The cytoplasmatic domain of the beta-subunit of the human IGF-1 receptor
      (residues 929-1337) has been overexpressed in insect cells using the baculovirus
      expression system. Synthesis of the soluble protein (IGFK, M(r) 46 kDa) in
      Spodoptera frugiperda (Sf9) cells was detected 24 h after infection and maximal
      accumulation was achieved 40-48 h postinfection. Rapid purification to near
      homogeneity (>/=95% pure protein) was accomplished by sequential chromatography
      on Resource-Q and phenyl-Sepharose with a specific activity of 142 nmol/min/mg
      using poly[Glu:Tyr] as substrate. The purified IGFK showed a preference for
      Mn(2+) ions and a linear incorporation of (32)P from [gamma-(32)P]ATP over a 20
      fold dilution of the protein and was stimulated 20-fold by the polycation poly-L
      lysine. Interestingly, the kinase autophosphorylated on tyrosine and serine
      residues. In contrast, a kinase-negative mutant, IGFK-K1003A, did not undergo
      phosphorylation on tyrosine or serine residues, respectively, suggesting that IGF
      1 receptor kinase is a dual specific kinase.

PMID- 10403834
TI  - 9-cis-retinoic acid decreases the level of its cognate receptor, retinoid X
      receptor, through acceleration of the turnover.
AB  - In this study, we investigated the ligand-mediated regulation of retinoid X
      receptor (RXR) in two human cell lines (HepG2 and JEG-3 cells), which have been
      reported to express RXRalpha predominantly. Western blot analysis revealed that a
      treatment with 1 microM 9-cis-retinoic acid (9-cis RA) for 24 h decreased
      RXRalpha protein level to 72 +/- 9 and 75 +/- 7% in HepG2 and JEG-3 cells,
      respectively, when the levels in the non-treated cells were expressed as 100%.
      The decrease was not due to the changes in steady-state level of RXRalpha mRNA or
      its stability as revealed by Northern blot analysis. However, the 9-cis RA
      treatment decreased the half-life of RXRalpha protein as determined by pulse
      chase analysis. It was thus demonstrated that 9-cis RA downregulates RXRalpha by
      increasing the turnover of the protein in the two cell lines. The ligand
      dependent downregulation of RXRalpha protein may be important for several
      hormonal signalings, in which the receptors heterodimerize with RXR.

PMID- 10403835
TI  - Release of soluble ICAM-1 from human lung fibroblasts, aortic smooth muscle
      cells, dermal microvascular endothelial cells, bronchial epithelial cells, and
      keratinocytes.
AB  - We determined effects of IL-1alpha, TNFalpha and IFNgamma on sICAM-1 release in
      culture media from human aortic smooth muscle cells (AOSMC), dermal microvascular
      endothelial cells (DMEC), keratinocytes (KC), bronchial epithelial cells (BEC)
      and lung fibroblasts (LF) as determined by ELISA. Under basal conditions of
      cultures for 20 h, low concentrations of sICAM-1 were only detected in the
      culture media of two (DMEC and BEC) of these cell types. IL-1alpha, TNFalpha and
      IFNgamma stimulated sICAM-1 from these cells. IFNgamma stimulated more shedding
      from AOSMC, BEC and KC than IL-1alpha or TNFalpha. TNFalpha enhanced more sICAM-1
      release from DEMC than from AOSMC, BEC and LF. IL-1alpha and IFNgamma or TNFalpha
      and IFNgamma acted synergistically to enhance shedding of sICAM-1 from these
      cells. The levels sICAM-1 in pathophysiological conditions may influence
      leukocyte-vascular cell interactions to block leukocyte transmigration to tissue
      injury sites as a negative feedback mechanism.

PMID- 10403836
TI  - Marked expression of glutathione S-transferase A4-4 detoxifying 4-hydroxy-2(E)
      nonenal in the skin of rats irradiated by ultraviolet B-band light (UVB).
AB  - Enzyme, Western blot, and immunohistochemical analyses indicated that rat skin
      cytosol contained no detectable level of the homodimeric, alpha-class glutathione
      S-transferase (rGST) A4-4 which catalyzes the GSH conjugation of the toxic
      product, 4-hydroxy-2(E)-nonenal (HNE), nonenzymatically formed from n-6
      polyunsaturated fatty acid residues of lipids by lipid peroxidation. Rats
      irradiated by single doses (4000-24,000 mJ/cm(2)) of ultraviolet B-band light
      (UVB, 200 mJ/cm(2)/min) markedly expressed rGSTA4-4 in the skin at a level one
      fifth that of the liver in apparent specific activity toward HNE at a single dose
      of 24,000 mJ/cm(2). Skin rGSTA4-4 was isolated, purified to homogeneity, and
      identified with hepatic rGSTA4-4 by reverse-phase partition HPLC and by amino
      acid sequence analysis of its CNBr fission peptides. Immunohistochemistry with
      polyclonal antibody raised against rGSTA4-4 demonstrated the selective expression
      of rGSTA4-4 in epidermis and sebaceous glands localized in dermis after UVB
      irradiation.

PMID- 10403837
TI  - Decrease in GTP cyclohydrolase I gene expression caused by inactivation of one
      allele in hereditary progressive dystonia with marked diurnal fluctuation.
AB  - Hereditary progressive dystonia with marked diurnal fluctuation (HPD; dopa
      responsive dystonia, DRD) have been recently found to be caused by a genetic
      defect in the GTP cyclohydrolase I (GCH1) gene. In this study, we quantified the
      mRNA level of GCH1 in phytohemagglutinin (PHA)-stimulated mononuclear blood cells
      from one Japanese family that do not have a mutation in the coding region or
      splice junctions of the gene. The results showed that the amounts of the GCH1
      mRNA were decreased to about 40% of the normal level in both patients and
      carriers. In addition, we found that the GCH1 mRNA was transcribed from only one
      allele, indicating that the other allele was in an inactive state. These results
      suggest that some novel mutations should exist on one of the alleles in some
      unknown region of the GCH1 gene, and may decrease the GCH1 mRNA causing the
      HPD/DRD symptoms.

PMID- 10403838
TI  - Influence of a cap site element on tissue-restricted expression of the
      glycoprotein hormone alpha-subunit gene.
AB  - Little is known of the transcriptional regulators important for expression of the
      glycoprotein hormone alpha-subunit (GPHalpha) gene in nonendocrine tumors, which
      secrete free alpha-subunit at an incidence of 25-80%. Consequently, attempts were
      made to define cis-regulatory elements and their cognate trans-acting factors
      that modulate promoter activity in epithelial cell types that do not normally
      express the glycoprotein hormones. DNA-mediated transient expression of promoter
      reporter constructs was used to identify a novel negative regulatory element
      located at the GPHalpha gene transcription start site. Mutagenesis of this
      element produced a 2- to 10-fold increase in promoter activity, depending on the
      particular mutation and the transfected tumor cell line. Electrophoretic mobility
      shift analysis detected a protein that binds specifically to a DNA motif
      encompassing the cap site. It was present at different levels in a variety of
      cell types. Significantly, the degree to which activity of the wild-type promoter
      was suppressed relative to that of the mutant promoter was proportional to the
      level of cap site binding protein in the collection of cell lines examined. These
      results indicate that a negative regulatory element centered at the GPHalpha gene
      cap site and its cognate DNA-binding protein make a significant contribution to
      the production of alpha-subunit in a variety of tumor tissues. A detailed
      understanding of this cis/trans pair may further suggest a mechanism to explain,
      at least in part, how this gene becomes activated in nonendocrine tumors.

PMID- 10403839
TI  - Characterization of three splice variants and genomic organization of the mouse
      BMAL1 gene.
AB  - The BMAL1 gene encodes a member of the basic helix-loop-helix/PER-ARNT-SIM
      (bHLH/PAS) family of transcription factors. It is a key regulator of circadian
      rhythms. Using sequence information from human BMAL1 (hBMAL1) cDNAs previously
      reported by our laboratory, we have isolated and characterized cDNAs encoding
      three splice variants of the mouse BMAL1 (mBMAL1) gene. Of the three splice
      variants, mBMAL1b extends for 1878 bp in the coding sequence, which is 91%
      identical to that of hBMAL1b; its deduced amino acid sequence is 626 residues
      long and is 98% identical to that of hBMAL1b, and sequence identities in the
      bHLH, PAS-A, and PAS-B regions are 98, 100, and 100%, respectively. mBMAL1b'
      arises from alternative usage of exon 2, which results in a 7-amino-acid
      insertion and alternative splice acceptor usage at the intron 9/exon 10 splice
      junction, which causes an alanine residue deletion. mBMAL1b' encodes 632 amino
      acids and contains the bHLH/PAS domains. mBMAL1g' is generated by alternative
      splice acceptor usage at the intron 6/exon 7 splice junction, which results in a
      28-bp deletion adjacent to the 5' end of the PAS domain. Since the 28-bp deletion
      shifts the reading frame, mBMAL1g' is predicted to encode a product of only 222
      amino acids that lacks the PAS domain. The tissue distributions of the three
      splice variants showed some variation. The variations in the tissue distributions
      and predicted amino acid sequences suggest that the three splice variants may
      have different functions. Direct sequencing of the genomic mBMAL1 clones
      indicated that the coding sequence of mBMAL1 spans 32 kb and includes 17 exons.
      An unusual exon/intron donor sequence was found in intron 14, which begins with
      GC at the 5' end. Comparison with the bHLH/PAS family genes revealed that the
      intron/exon splice pattern of mBMAL1 most closely matches that of the mAhr, which
      suggests that BMAL1 and Ahr belong to the same subclass and may be derived from a
      common primordial gene.

PMID- 10403841
TI  - Redistribution of activated caspase-3 to the nucleus during butyric acid-induced
      apoptosis.
AB  - The colonic epithelial cells near the top of the crypt and in the lumen have been
      shown to undergo apoptosis. Since butyric acid is the major short-chain fatty
      acid produced by fermentation of dietary fiber in the large bowel, it has been
      proposed that it could act as an important regulator of apoptosis in colorectal
      cancer. Here we report that in cells treated with butyric acid, the cleavage of
      DNA-PKcs was paralleled or preceded by the induction of activation of caspase-3,
      and these events were inhibited by Bcl-2 overexpression. We also demonstrated the
      redistribution of activated caspase-3 to the nuclear compartment where it locally
      cleaves DNA-PKcs and poly(ADP-ribose) polymerase, and cleaved fragments were
      released in the cytosolic compartment. The observed activation of caspase-3 and
      nuclear cleavage of its substrates and their subsequent release into the cytosol
      were inhibited by a specific caspase-3 inhibitor, the tetrapeptide DEVD-CHO.
      These findings suggest that relocalization of activated caspase-3 to the nucleus
      may constitute an important apoptotic signal during butyric acid-induction of
      apoptosis human colorectal cancer cells.

PMID- 10403840
TI  - Characterization of novel inhibitors of cyclin-dependent kinases.
AB  - In epithelial cells progression through the G1 phase of the cell cycle and
      preparing the cell for the S phase is regulated by cyclin D1-cdk4. Cells that
      express the retinoblastoma protein (pRb) are dependent on cyclin D1-cdk4 activity
      for their proliferation while cells that do not express pRb are not.
      Overexpression of cyclin D1 and/or cdk4, and loss of expression of p16 (the
      natural inhibitor of cyclin D1-cdk4 activity), have been implicated in several
      cancers. These data suggest that the aberrant activity of cyclin D1-cdk4
      correlates with the tumor phenotype. Hence, blocking cyclin D1-cdk4 activity may
      prove to be an effective anticancer therapy for pRb(+) tumors. In this paper, we
      report the identification of four novel compounds that selectively inhibit cyclin
      D1-cdk4 activity to various degrees. We further demonstrate that two of these
      compounds also selectively inhibit the target, pRb(+) tumor cells. The
      implications of these discoveries and their utility as anticancer agents are
      discussed.

PMID- 10403842
TI  - Snare protein expression and adenoviral transfection of amphicrine AR42J.
AB  - The amphicrine AR42J acinar cell line is an excellent model to study both
      exocrine and neuroendocrine exocytotic mechanisms. As a first step toward this
      goal, we determined the specific isoforms of the v- and t-SNARE and Munc18
      families expressed in these cells. In addition, we show that dexamethasone
      induced differentiation toward the exocrine phenotype causes an upregulation of
      several of these proteins. AR42J is notoriously difficult to transfect, limiting
      its usefulness as a model. However, we have now overcome this obstacle by
      acheiving high efficiency expression of a beta-galactosidase reporter gene and
      truncated SNAP-25 gene using adenoviral infection techniques. The AR42J cells can
      now be used to pursue and elucidate the distinct functions of individual SNARE
      isoforms used in endocrine and exocrine secretion within a single cell line.

PMID- 10403843
TI  - DNA binding activity of the fetal Alz-50 clone 1 (FAC1) protein is enhanced by
      phosphorylation.
AB  - Fetal Alz-50 clone 1 (FAC1) is a novel DNA binding protein with altered
      expression and subcellular localization during neuronal development and
      degeneration. FAC1 localizes to the cell body and neurites in undifferentiated
      neurons during development and in degenerating neurons during Alzheimer's disease
      progression. In the normal adult brain FAC1 is present predominantly in the
      nucleus of cortical neurons. When in the nucleus FAC1 has been shown to repress
      transcription by binding a specific DNA sequence. In the present study we
      demonstrate that the affinity of FAC1 for the identified DNA sequence is
      dramatically enhanced when FAC1 is phosphorylated. Phosphatase treatment of
      neuroblastoma nuclear extracts reduces FAC1 DNA binding affinity. Finally,
      inhibition of cellular serine/threonine phosphatases results in increased FAC1
      DNA binding activity. These data suggest that FAC1 DNA binding activity is
      dependent upon and regulated by phosphorylation signals in the cell.

PMID- 10403844
TI  - Selective association of the tyrosine kinases Src, Fyn, and Lyn with integrin
      rich actin cytoskeletons of activated, nonaggregated platelets.
AB  - Integrin-mediated interactions between cytoskeletal proteins and extracellular
      fibrinogen are required for platelet adhesion. We have previously demonstrated
      that the major platelet integrin, alpha(IIb)beta(3), becomes incorporated into
      the actin cytoskeleton of platelets in an activation-dependent, aggregation
      independent manner. To determine if regulatory molecules are also associated with
      these integrin-rich cytoskeletal complexes, we examined actin cytoskeletons for
      the presence of kinases and phosphoproteins. Western immunoblot analysis revealed
      that the tyrosine kinases Src, Fyn, and Lyn are specifically associated with
      actin cytoskeletons of activated, nonaggregated platelets. However, as noted by
      others, the cytoskeletal association of focal adhesion kinase depends on platelet
      aggregation. Actin cytoskeletons isolated from (32)P-labeled platelets also
      contain a number of phosphorylated proteins. Interestingly, an approximately 18
      kDa phosphoprotein was uniquely present in activated platelet cytoskeletons.
      Collectively, our results demonstrate that actin cytoskeletons of activated,
      nonaggregated platelets contain not only integrins, but also kinases and
      phosphoproteins that could regulate platelet adhesion and transmembrane
      communication.

PMID- 10403845
TI  - Oligomerized Ced-4 kills budding yeast through a caspase-independent mechanism.
AB  - In Caenorhabdtis elegans, Ced-3, Ced-4, and Ced-9 are components of a cell
      suicide program. Ced-4 facilitates the proteolytic activation of the caspase, Ced
      3, while Ced-9 opposes Ced-3/Ced-4 killing. To examine the interactions among
      these proteins they were expressed in Saccharomyces cerevisiae. Ced-3 and Ced-4
      were lethal when expressed alone, revealing an intrinsic Ced-4 killing activity.
      Coexpression of Ced-9 blocked Ced-3- and Ced-4-induced killing, showing Ced-9 can
      independently antagonize the action of both proteins. Ced-3- but not Ced-4
      toxicity was attenuated by coexpression of the caspase inhibitors, CrmA and p35.
      Thus, besides its Ced-3- and Ced-9-dependent action in C. elegans, Ced-4 has an
      additional Ced-9-dependent, Ced-3-independent killing mechanism in yeast. Two
      hybrid analysis confirmed that Ced-4 formed heteromers with Ced-9. In addition,
      Ced-4 formed homomers and mutation of its nucleoside triphosphate binding motif
      eliminated both homomerization and cell killing. We suggest the caspase
      independent lethality of Ced-4 in yeast is mediated by a Ced-4 homomer.

PMID- 10403846
TI  - A novel apoptotic cascade mediated by CDK4 in rat pheochromocytoma PC12 cells.
AB  - Apoptosis induced by serum withdrawal in pheochromocytoma PC12 cells is promoted
      by overexpression of cyclin-dependent kinase 4 (CDK4). We compared CDK4-promoted
      apoptosis with that induced by serum withdrawal alone in PC12 cells. Protein
      synthesis inhibitors did not prevent apoptosis in parental cells, but prevented
      the promotion of apoptosis by CDK4 overexpression. Nerve growth factor, basic
      fibroblast growth factor, and Bcl-2 proteins protected both parental and CDK4
      overexpressing cells from apoptosis. However, insulin-like growth factor-I and
      Bcl-X(L) protein only partially inhibited apoptosis in the CDK4-overexpressing
      cells. Bcl-2 or Bcl-X(L) had no significant effect on CDK4 kinase activity in
      both cell lines. These results suggest a novel CDK4-mediated apoptotic cascade
      which is normally restrained, but which is activated by CDK4 overexpression. This
      apoptotic cascade should eventually converge with the cascade induced by serum
      withdrawal in normal PC12 cells. We discuss the interactions among these
      apoptotic cascades and the points where anti-apoptotic agents act.

PMID- 10403848
TI  - Ontogeny and species differences in the pancreatic expression and localization of
      the CCK(A) receptors.
AB  - We have evaluated the presence and localization of the CCK(A) receptor in rat,
      mouse, pig and human fetal pancreas by Northern, Western blots and
      immunofluorescence techniques. In the rat, parallelism exists between development
      of the CCK(A) receptor mRNA and protein with maximal peaks of expression during
      the suckling period. In the course of pancreatitis induction, CCK(A) receptor
      mRNA were maximally expressed and sustained during the gland's regeneration. In
      the rat and mouse pancreas, the CCK(A) receptor protein is localized around the
      acinar cells and beta cells of the islets of Langerhans. In the adult pig and
      fetal human pancreas, the CCK(A) receptor proteins were detected by Western blot.
      By immunofluorescence, its detection was possible only in the islet of Langerhans
      of the pig pancreas. These new findings support the views that CCK plays
      important and various roles in specific physiological systems of the pancreas of
      different species.

PMID- 10403847
TI  - Reactive oxygen species as a risk factor in verotoxin-1-exposed rats.
AB  - It has been suggested the the interaction of Escherichia coli O157-derived
      verotoxins (VTs) with the vascular endothelium plays a central role in the
      pathogenesis of the thrombotic microangiopathy and ischemic lesions
      characteristic of hemolytic uremic syndrome (HUS) and E. coli O157-associated
      hemorrhagic colitis. Intravenous administration of both E. coli O157-derived VT1
      and lipopolysaccharide (LPS) in the rat induced a synergistic increase in
      thiobarbituric acid (TBA) values in those animal's plasma, as compared with that
      injected with VT1 or LPS alone. We then hypothesized that an increase in lipid
      peroxidation in the rat plasma was due to an enhanced production of endothelial
      cell-derived reactive oxidant. Based on determination of rat sera and cultured
      human aortic endothelial cells (HAECs), VT1 had little if any effect on LPS
      stimulated increase of nitric oxide and the resultant peroxynitrite generations.
      Both RT-PCR and Western blot studies of reactive oxygen species-related enzymes
      showed that VT1 markedly decreased the expression of catalase mRNA and protein in
      HAECs, but caused less alteration in the levels of Cu, Zn-superoxide dismutase,
      and NADPH oxidase mRNA. Further studies by spin trapping analysis using 5, 5
      dimethyl-1-pyrroline-N-oxide (DMPO) revealed a time-dependent increase in
      hydroxyl radicals by VT1 in HAECs. The accumulated data thus suggest that
      bacterial VT1 reduces mainly catalase levels in endothelial cells, which is
      synergistically potentiated by LPS, and that the resulting hydroxyl radical
      participates in endothelium injury through a marked enhancement of lipid
      peroxidation, leading to HUS.

PMID- 10403849
TI  - Hepatocyte nuclear factor 1 binds to and transactivates the human but not the rat
      CYP7A1 promoter.
AB  - Cholesterol 7alpha-hydroxylase (CYP7A1), a liver-specific enzyme, catalyzes the
      rate-limiting step in the degradation pathway of cholesterol to bile acids, and
      thus plays a key role in cholesterol homeostasis. To elucidate the mechanisms
      that control hepatic expression of the human CYP7A1 gene, we are studying the
      promoter region. Initially, we observed that up to 40% of the overall
      transcriptional activity of the promoter in HepG2 cells was associated with DNA
      sequences from -65 to -1 of the human gene. Within this region, a binding site
      for the liver-enriched transcription factor HNF-1 (-56 to -49) has been
      identified. Binding of HNF-1 to this site leads to transcriptional activation of
      the human promoter. The corresponding segment from the rat CYP7A1 gene does not
      bind HNF-1; instead, it is bound by the orphan receptors ARP-1 (COUP-TFII) and
      LXRalpha, that are implicated in dietary regulation.

PMID- 10403850
TI  - Neostigmine for the treatment of acute colonic pseudo-obstruction.
AB  - BACKGROUND: Acute colonic pseudo-obstruction -- that is, massive dilation of the
      colon without mechanical obstruction -- may develop after surgery or severe
      illness. Although it may resolve with conservative therapy, colonoscopic
      decompression is sometimes needed to prevent ischemia and perforation of the
      bowel. Uncontrolled studies have suggested that neostigmine, may be an effective
      treatment. METHODS: We studied 21 patients with acute colonic pseudo-obstruction.
      All had abdominal distention and radiographic evidence of colonic dilation, with
      a cecal diameter of at least 10 cm, and had had no response to at least 24 hours
      of conservative treatment. We randomly assigned 11 to receive 2.0 mg of
      neostigmine intravenously and 10 to receive intravenous saline. A physician who
      was unaware of the patients' treatment assignments recorded clinical response
      (defined as prompt evacuation of flatus or stool and a reduction in abdominal
      distention), abdominal circumference, and measurements of the colon on
      radiographs. Patients who had no response to the initial injection were eligible
      to receive open-label neostigmine three hours later. RESULTS: Ten of the 11
      patients who received neostigmine had prompt colonic decompression, as compared
      with none of the 10 patients who received placebo (P<0.001). The median time to
      response was 4 minutes (range, 3 to 30). Seven patients in the placebo group and
      the one patient in the neostigmine group without an initial response received
      open-label neostigmine; all had colonic decompression. Two patients who had an
      initial response to neostigmine required colonoscopic decompression for
      recurrence of colonic distention; one eventually underwent subtotal colectomy.
      Side effects of neostigmine included abdominal pain, excess salivation, and
      vomiting. Symptomatic bradycardia developed in two patients and was treated with
      atropine. CONCLUSIONS: In patients with acute colonic pseudo-obstruction who have
      not had a response to conservative therapy, treatment with neostigmine rapidly
      decompresses the colon.

PMID- 10403851
TI  - Association of aortic-valve sclerosis with cardiovascular mortality and morbidity
      in the elderly.
AB  - BACKGROUND: Although aortic-valve stenosis is clearly associated with adverse
      cardiovascular outcomes, it is unclear whether valve sclerosis increases the risk
      of cardiovascular events. METHODS: We assessed echocardiograms obtained at base
      line from 5621 men and women 65 years of age or older who were enrolled in a
      population-based prospective study. On echocardiography, the aortic valve was
      normal in 70 percent (3919 subjects), sclerotic without outflow obstruction in 29
      percent (1610), and stenotic in 2 percent (92). The subjects were followed for a
      mean of 5.0 years to assess the risk of death from any cause and of death from
      cardiovascular causes. Cardiovascular morbidity was defined as new episodes of
      myocardial infarction, angina pectoris, congestive heart failure, or stroke.
      RESULTS: There was a stepwise increase in deaths from any cause (P for trend,
      <0.001) and deaths from cardiovascular causes (P for trend, <0.001) with
      increasing aortic-valve abnormality; the respective rates were 14.9 and 6.1
      percent in the group with normal aortic valves, 21.9 and 10.1 percent in the
      group with aortic sclerosis, and 41.3 and 19.6 percent in the group with aortic
      stenosis. The relative risk of death from cardiovascular causes among subjects
      without coronary heart disease at base line was 1.66 (95 percent confidence
      interval, 1.23 to 2.23) for those with sclerotic valves as compared with those
      with normal valves, after adjustment for age and sex. The relative risk remained
      elevated after further adjustment for clinical factors associated with sclerosis
      (relative risk, 1.52; 95 percent confidence interval, 1.12 to 2.05). The relative
      risk of myocardial infarction was 1.40 (95 percent confidence interval, 1.07 to
      1.83) among subjects with aortic sclerosis, as compared with those with normal
      aortic valves. CONCLUSIONS: Aortic sclerosis is common in the elderly and is
      associated with an increase of approximately 50 percent in the risk of death from
      cardiovascular causes and the risk of myocardial infarction, even in the absence
      of hemodynamically significant obstruction of left ventricular outflow.

PMID- 10403852
TI  - Ehrlichia ewingii, a newly recognized agent of human ehrlichiosis.
AB  - BACKGROUND: Human ehrlichiosis is a recently recognized tick-borne infection.
      Four species infect humans: Ehrlichia chaffeensis, E. sennetsu, E. canis, and the
      agent of human granulocytic ehrlichiosis. METHODS: We tested peripheral-blood
      leukocytes from 413 patients with possible ehrlichiosis by broad-range and
      species-specific polymerase-chain-reaction (PCR) assays for ehrlichia. The
      species present were identified by species-specific PCR assays and nucleotide
      sequencing of the gene encoding ehrlichia 16S ribosomal RNA. Western blot
      analysis was used to study serologic responses. RESULTS: In four patients,
      ehrlichia DNA was detected in leukocytes by a broad-range PCR assay, but not by
      assays specific for E. chaffeensis or the agent of human granulocytic
      ehrlichiosis. The nucleotide sequences of these PCR products matched that of E.
      ewingii, an agent previously reported as a cause of granulocytic ehrlichiosis in
      dogs. These four patients, all from Missouri, presented between May and August
      1996, 1997, or 1998 with fever, headache, and thrombocytopenia, with or without
      leukopenia. All had been exposed to ticks, and three were receiving
      immunosuppressive therapy. Serum samples obtained from three of these patients
      during convalescence contained antibodies that reacted with E. chaffeensis and E.
      canis antigens in a pattern different from that of humans with E. chaffeensis
      infection but similar to that of a dog experimentally infected with E. ewingii.
      Morulae were identified in neutrophils from two patients. All four patients were
      successfully treated with doxycycline. CONCLUSIONS: These findings provide
      evidence of E. ewingii infection in humans. The associated disease may be
      clinically indistinguishable from infection caused by E. chaffeensis or the agent
      of human granulocytic ehrlichiosis.

PMID- 10403853
TI  - Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in
      pseudohypoaldosteronism.
AB  - BACKGROUND: Active sodium absorption is the dominant mechanism of ion transport
      in airway epithelium, but its role in pulmonary physiology and airway host
      defense is unknown. To address this question, we studied the function of airway
      epithelial cells and determined the frequency of pulmonary symptoms in patients
      with systemic pseudohypoaldosteronism, a salt-losing disorder caused by loss-of
      function mutations in the genes for the epithelial sodium channel. METHODS: In
      nine patients 1.5 to 22 years of age who had systemic pseudohypoaldosteronism, we
      tested for mutations in the genes for the epithelial sodium channel, estimated
      the rate of sodium transport in the airway, determined the volume and ion
      composition of airway surface liquid, reviewed clinical features, collected
      laboratory data pertinent to pulmonary function, and, in three adults, measured
      mucociliary clearance. RESULTS: The patients with systemic
      pseudohypoaldosteronism had loss-of-function mutations in the genes for the
      epithelial sodium-channel subunits, no sodium absorption from airway surfaces,
      and a volume of airway surface liquid that was more than twice the normal value.
      The mean (+/-SE) mucociliary transport rate was higher in the 3 adult patients
      than in 12 normal subjects (2.0+/-0.7 vs. 0.5+/-0.3 percent per minute, P=0.009).
      Young patients (those five years of age or less) all had recurrent episodes of
      chest congestion, coughing, and wheezing, but no airway infections with
      Staphylococcus aureus or Pseudomonas aeruginosa. Older patients (those more than
      five years of age) had less frequent respiratory symptoms. CONCLUSIONS: Patients
      with systemic pseudohypoaldosteronism fail to absorb liquid from airway surfaces;
      the result is an increased volume of liquid in the airways. These results
      demonstrate that sodium transport has a role in regulating the volume of liquid
      on airway surfaces.

PMID- 10403854
TI  - Images in clinical medicine. Cystic lymphoma of the brain.

PMID- 10403855
TI  - The biology of chronic myeloid leukemia.

PMID- 10403856
TI  - Hemangiomas in children.

PMID- 10403857
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 21-1999. A 69-year-old man with exposure to talc and a pulmonary
      mass.

PMID- 10403858
TI  - Management of acute colonic pseudo-obstruction.

PMID- 10403859
TI  - Aortic sclerosis--a window to the coronary arteries?

PMID- 10403860
TI  - Ehrlichiosis--ticks, dogs, and doxycycline.

PMID- 10403861
TI  - What's the price of a research subject? Approaches to payment for research
      participation.

PMID- 10403862
TI  - Vaporisers.

PMID- 10403863
TI  - A comparison of hospital and critical-care activity.
AB  - When compared with changes in hospital activity, corresponding fluctuations in
      critical-care activity are not clear. Therefore, trends in hospital activity were
      compared with those of the critical-care services and simple patient demographic
      details. The results suggest that while the size of hospitals remained static,
      hospital admissions and outpatient attendances increased by 5% each year. During
      the same period, the number of critical-care beds increased by 21.4%. Despite
      this increase in capacity, the activity of the critical-care services continued
      to increase by a similar 5% per annum, indicating a huge surge in critical-care
      workload. The results indicate that the increase in the rate of activity in
      hospitals and critical-care services is similar but the workload of the critical
      care services is increasing much faster. This suggests that the demand for
      critical care may be generated from within hospitals.

PMID- 10403864
TI  - Physiological values and procedures in the 24 h before ICU admission from the
      ward.
AB  - Physiological values and interventions in the 24 h before entry to intensive care
      were collected for admissions from hospital wards. In a 13-month period, there
      were 79 admissions in 76 patients who had been in hospital for at least 24 h and
      had not undergone surgery within 24 h of admission to intensive care. Thirty-four
      per cent of patients underwent cardiopulmonary resuscitation before intensive
      care admission. Using Acute Physiology and Chronic Health Evaluation II scoring
      to quantify abnormal physiology in the group as a whole, a significant
      deterioration in respiratory function before admission was found. During the 6-h
      period immediately before intensive care admission, 75% of patients received
      oxygen, 37% underwent arterial blood gas sampling, and oxygen saturation was
      measured in 61% of patients, 63% of whom had an oxygen saturation of less than
      90%. Overall hospital mortality in the study group was 58%. Information collected
      on the wards identified seriously ill patients who may have benefited from
      earlier expert treatment.

PMID- 10403865
TI  - Effect of maternal ambulation on labour with low-dose combined spinal-epidural
      analgesia.
AB  - Two hundred and twenty-nine nulliparous women who requested regional analgesia
      during labour were given a combined spinal-epidural block. They were randomly
      allocated to stay in bed or spend at least 20 min of every hour out of bed. There
      was no significant difference in duration of labour, analgesia requirements, mode
      of delivery or condition of the baby between the groups. Ambulation appeared to
      be safe for the mother and baby. Maternal satisfaction with the low-dose combined
      spinal-epidural was high in both groups.

PMID- 10403866
TI  - Low-dose bupivacaine: a comparison of hypobaric and near isobaric solutions for
      arthroscopic surgery of the knee.
AB  - The results of studies on the effect of volume, concentration or total dose of
      local anaesthetic on the spread of spinal anaesthesia are inconclusive. Most
      support the assumption that the total dosage is more important than the volume.
      We compared low-dose bupivacaine (6 mg) in 0.5% and 0.18% solutions as sole
      anaesthetic to achieve predominantly unilateral spinal anaesthesia for knee
      arthroscopy. Sixty patients were randomly allocated to two groups to receive
      either 1.2 ml 0.5% bupivacaine (6 mg) (n = 30) or 3.4 ml 0.18% hypobaric
      bupivacaine (6.1 mg) (n = 30). Drugs were administered at the L3-4 interspace
      with the patient in the lateral position. Patients remained in this position for
      20 min before being turned supine for the operation. Spinal block was assessed by
      pinprick and modified Bromage scale and compared between the operated and
      nonoperated sides. No significant changes were found in the spread or duration of
      sensory or motor block (p > 0.05). The haemodynamic changes were also similar
      between the groups. The same pinprick level of analgesia, degree of motor block
      and duration of spinal anaesthesia was obtained with bupivacaine (6 mg) in low
      (1.2 ml) or high (3.4 ml) volumes.

PMID- 10403867
TI  - The reinforced laryngeal mask in paediatric outpatient dental surgery.
AB  - One hundred and twenty ASA I and II grade children aged 2-9 years scheduled for
      outpatient dental extractions under general anaesthesia were studied. They were
      allocated randomly to one of three groups for airway management: group R had
      anaesthesia with a reinforced laryngeal mask airway, group L with a standard
      laryngeal mask airway and group N with a nasal mask. Anaesthesia was induced in
      all children using halothane in 50% nitrous oxide with oxygen and maintained on
      halothane in 67% nitrous oxide with oxygen. An Ayre's T-piece with Jackson-Rees
      modification was used. The incidence of airway obstruction was significantly
      lower and surgical access significantly better with the reinforced laryngeal mask
      airway when compared with the standard laryngeal mask airway. However, the
      reinforced laryngeal mask airway was significantly more difficult to insert when
      compared with the standard laryngeal mask airway. On comparing the reinforced
      laryngeal mask airway with the nasal mask, there were significantly fewer
      episodes of airway obstruction, better oxygen saturation, less increase in heart
      rate and fewer arrhythmias in the reinforced laryngeal mask airway group. Total
      time for the procedures was the same for all three groups. Thus, the reinforced
      laryngeal mask airway was found to be a favourable alternative to the standard
      laryngeal mask airway and nasal mask for paediatric outpatient dental
      extractions.

PMID- 10403868
TI  - The use of breathing system filters as oxygen-delivery devices.
AB  - A breathing system filter can remain connected to a laryngeal mask airway during
      recovery from anaesthesia. The Luer-lock monitoring port on the filter could be
      used for the delivery of supplementary oxygen. The efficacy of this technique was
      assessed in vitro by comparing the performance of two filters with four other
      devices, including a T-piece with a 40% oxygen injector. The minimum inspired
      oxygen fraction and pressure drop were measured over a range of ventilatory
      conditions and oxygen flows. The minimum inspired oxygen fraction measured with
      the remaining devices was greater than with the T-piece at an oxygen flow of 10
      l.min-1. The pressure drop was greater with the breathing system filters than
      with the T-piece. A potential advantage in using filters is that no additional
      equipment is required. However, if using the filters as oxygen supplementation
      devices, there is only one port open to the atmosphere in the system and
      inadvertent obstruction of this port could cause barotrauma. It must be
      remembered that the nonstandard use of such equipment contravenes the recently
      introduced Medical Device Directive regulations.

PMID- 10403869
TI  - Prevention of tracheal aspiration using the pressure-limited tracheal tube cuff.
AB  - A new design of tracheal tube cuff, the pressure-limited cuff, used with a
      constant-pressure inflation system, was compared with a high-volume low-pressure
      cuffed tracheal tube for leakage of dye placed in the subglottic space into the
      trachea. Patients requiring ventilation on the intensive care unit were randomly
      allocated into two groups, one for each type of cuff, and blue food dye was
      instilled daily via a fine catheter above the cuff into the subglottic space.
      There were eight patients in the high-volume low-pressure group and seven in the
      pressure-limited cuff group. Dye leaked into the trachea in seven (87%) of the
      high-volume low-pressure group compared with none (0%) of the pressure-limited
      cuff group (p < 0.01). This study demonstrates that the pressure-limited cuffed
      tracheal tube, in combination with a constant-pressure inflation device, prevents
      leakage of fluid into the lungs that occurs with high-volume low-pressure cuffs
      in the critically ill, intubated patient.

PMID- 10403870
TI  - Acute cardiac herniation after radical pleuropneumonectomy.
AB  - Acute cardiac herniation after radical pneumonectomy is extremely rare and is
      associated with an immediate mortality greater than 50%. We report a patient in
      whom cardiac herniation produced no signs or symptoms. The heart was returned to
      its correct position and the pericardial defect was repaired.

PMID- 10403871
TI  - Hypokalaemic, hyperchloraemic metabolic acidosis requiring ventilation.
AB  - A 16-year-old patient required intermittent positive pressure ventilation for
      hypokalaemic muscle weakness resulting from metabolic complications of combined
      colonic bladder augmentation and incomplete voiding via a prosthetic sphincter.
      Catheter re-establishment of urinary flow and electrolyte replacement produced
      dramatic metabolic and clinical improvement allowing the return of adequate
      spontaneous respiration.

PMID- 10403872
TI  - Anaesthesia for Conn's syndrome.
AB  - We describe the peri-operative management of two patients undergoing bilateral
      adrenalectomy for Conn's syndrome; one using an open surgical approach and the
      other a laparoscopic technique. The first patient, aged 64 years, died of a
      myocardial infarction 5 days postoperatively; the second, aged 29 years, had an
      uneventful recovery. The pre-operative preparation, peroperative management and
      postoperative care of these patients are detailed, and the pathophysiology and
      clinical management of Conn's syndrome are reviewed.

PMID- 10403873
TI  - The story of the gauge.
AB  - Gauges are old measures of thickness. They originated in the British iron wire
      industry at a time when there was no universal unit of thickness. The sizes of
      the gauge numbers were the result of the process of wire-drawing and the nature
      of iron as a substance. Gauges were measured and described in fractions of an
      inch during the 19th century. In the UK, one gauge was standardised and legally
      enforced as the Standard Wire Gauge. One important reason for the standardisation
      of the gauge was the convenience of craftsmen. In the 20th century, the gauge was
      to be replaced with the introduction of the International System of Units.
      However, within the field of anaesthesia at the threshold of the 21st century,
      the gauge seems hard to remove from the minds of craftsmen like anaesthetists.

PMID- 10403874
TI  - The accuracy of visual estimation of weight and height in pre-operative supine
      patients.
AB  - Four observers estimated the weight and height of 38 patients who were lying
      covered on operating theatre trolleys. Regression analysis of the results was
      performed for each observer. The results showed marked variation in ability to
      assess these characteristics accurately.

PMID- 10403875
TI  - Decontamination of laryngoscopes: a survey of national practice.
AB  - We conducted a postal questionnaire to survey methods of laryngoscope cleaning in
      units throughout Great Britain. We found that there was great variation in
      practice. Most units autoclave laryngoscope blades at some time, but less than
      one-quarter do so between each case. A wide range of methods is used to clean the
      blade in units where autoclaving was not undertaken. Most units had no guidelines
      relating to laryngoscope treatment between uses.

PMID- 10403876
TI  - The effect of cerebral palsy on the action of vecuronium with or without
      anticonvulsants.
AB  - Patients with cerebral palsy who are treated with anticonvulsant medication are
      resistant to vecuronium. We examined the contributions to vecuronium resistance
      made by cerebral palsy and anticonvulsants in a study of children with cerebral
      palsy and a control group. The acceleromyographic responses of the following
      three groups of children were studied: children with cerebral palsy not taking
      anticonvulsant medication (n = 11); children with cerebral palsy taking
      anticonvulsant medication (n = 8); and a control group of children who did not
      have cerebral palsy and were not taking anticonvulsant treatment (n = 10). Using
      a standardised technique, general anaesthesia was induced and maintained with 0.5
      1. 5% isoflurane in a 60/40 nitrous oxide in oxygen mixture. After a
      stabilisation period which was performed with supramaximal train-of-four stimuli
      (2 Hz every 15 s) an intubating dose of vecuronium 0.1 mgkg-1 was administered.
      The first twitch of the train-of-four response (T1), the onset time, the times to
      25, 50, 75 and 90% recovery of T1, recovery index, and the time to 70% recovery
      of train-of-four ratio were recorded. Recovery times to T1 and train-of-four
      responses were reduced significantly in both groups of children with cerebral
      palsy compared with the control group. These results suggest that children with
      cerebral palsy display resistance to vecuronium whether or not they are taking
      anticonvulsant drugs.

PMID- 10403878
TI  - Explaining the variable effect on laryngeal view obtained with the McCoy
      laryngoscope.

PMID- 10403877
TI  - The effects of EMLA and a topical formulation of 4% amethocaine (Ametop) on pain
      associated with retrobulbar injection.
AB  - Retrobulbar block is commonly performed to provide anaesthesia for cataract
      extraction. This technique can cause significant discomfort. A prospective,
      randomised, placebo-controlled trial was carried out to investigate the efficacy
      of a eutectic mixture of local anaesthetics (EMLA) and a 4% amethocaine topical
      formulation (Ametop) in reducing the pain of retrobulbar injection. Ametop and
      EMLA proved to be of similar efficacy, both being superior to a placebo in
      alleviating the discomfort of retrobulbar block. No significant side-effects were
      observed with the use of either formulation.

PMID- 10403879
TI  - Solutions to the problem of difficult tracheal tube passage associated with the
      paraglossal straight laryngoscopy technique.

PMID- 10403880
TI  - The left-handed laryngoscope.

PMID- 10403881
TI  - The reinforced LMA - what is needed is less flexibility.

PMID- 10403882
TI  - Capnography and the differentiation between tracheal and oesophageal intubation.

PMID- 10403883
TI  - Filters in breathing systems.

PMID- 10403884
TI  - Filters in breathing systems 

PMID- 10403885
TI  - Retrospective soliloquy: rationalising practice through prospective audit.

PMID- 10403887
TI  - Propofol/midazolam coinduction 

PMID- 10403886
TI  - Anaphylactic reaction following intravenous adenosine.

PMID- 10403889
TI  - Analgesia for spinal puncture 

PMID- 10403888
TI  - Target-controlled infusions.

PMID- 10403890
TI  - Avoiding a dural tap.

PMID- 10403891
TI  - Pumps for epidural catheters.

PMID- 10403892
TI  - The 'whoosh' test.

PMID- 10403893
TI  - An unusual presentation of paraneoplastic neuropathy.

PMID- 10403895
TI  - A problem with a triple-lumen central line.

PMID- 10403894
TI  - Position of CVP lines.

PMID- 10403897
TI  - Hazard notice MDA SN1999(11) march 1999. Heartstart Defibrillation Electrodes,
      Part No. 902402, Lot codes: ALL.

PMID- 10403899
TI  - The in vitro effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate on
      Sertoli cell morphology.
AB  - The objective of the present study was to examine the effects of the well-known
      tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) on the morphology of
      cultured Sertoli cells from immature rats. The cells were cultured for 5 days and
      the TPA was added at the end of the culture period for 8 h at a concentration of
      10-7 M. Viability tests showed that controls as well as TPA-treated cells
      remained viable during the culture period and no deleterious effects were
      observed as a result. Application of computerized morphometry at both light and
      electron microscopic levels revealed that TPA caused important changes in cell
      morphology in vitro. Statistical analysis of the results indicated that compared
      to the controls, Sertoli cells treated with TPA exhibited fewer astrocytic-type
      cytoplasmic extensions and a smaller size. Our results support the conclusion
      that the tumor promoter TPA, when applied to immature Sertoli cells in vitro,
      causes significant morphological alterations.

PMID- 10403896
TI  - Peri-orbital bruising as a complication of taping eyes.

PMID- 10403898
TI  - Genetic and epigenetic changes of intercellular communication genes during
      multistage carcinogenesis.
AB  - During multistage carcinogenesis, the functions of several key genes involved in
      cell growth control must be damaged. Such genes include not only those involved
      in cell cycle control of individual cells, but also those involved in the
      coordination of cell growth throughout a given tissue through cell-cell
      communication. The most intimate form of intercellular communication is mediated
      by gap junctions. Gap junctional intercellular communication (GJIC) is known to
      transfer small water soluble molecules, including cAMP and IP3, from the
      cytoplasm of one cell to that of its neighbors; the growth of a given GJIC
      associated cell is thus kept in check by other GJIC-connected cells. Most tumor
      cells have a reduced ability to communicate among themselves and/or with
      surrounding normal cells, confirming the importance of intact GJIC in growth
      control. When connexin (gap junction protein) genes are transfected into such
      cells, normal cell growth control is often recovered. Certain dominant-negative
      mutant connexin genes can reverse such tumor suppression. While these results
      suggest that connexin genes form a family of tumor suppressor genes, so far we
      have found no connexin gene mutations in human tumors; only two connexin gene
      mutations were found in chemically induced rat tumors. On the other hand, our
      recent studies suggest that connexin genes may be inactivated by hypermethylation
      of their promoter regions, suggesting that epigenetic inactivation of connexin
      genes may be a mechanism of GJIC disturbance in certain tumors. However, in many
      tumor cells connexins are normally expressed but aberrantly localized. The
      mechanisms of aberrant localization of connexins include lack of an appropriate
      cell-cell recognition apparatus and aberrant phosphorylation of connexins. These
      results suggest that GJIC disorders may occur not only because of aberrant
      expression of connexin genes themselves, but also as a result of disruption of
      various control mechanisms of the protein functions.

PMID- 10403900
TI  - Percutaneous progesterone use and risk of breast cancer: results from a French
      cohort study of premenopausal women with benign breast disease.
AB  - Percutaneous progesterone topically applied on the breast has been proposed and
      widely used in the relief of mastalgia and benign breast disease by numerous
      gynecologists and general practitioners. However, its chronic use has never been
      evaluated in relation to breast cancer risk. The association between percutaneous
      progesterone use and the risk of breast cancer was evaluated in a cohort study of
      1150 premenopausal French women with benign breast disease diagnosed in two
      breast clinics between 1976 and 1979. The follow-up accumulated 12,462 person
      years. Percutaneous progesterone had been prescribed to 58% of the women. There
      was no association between breast cancer risk and the use of percutaneous
      progesterone (RR = 0.8; 95% confidence interval 0.4-1.6). Although the combined
      treatment of oral progestogens with percutaneous progesterone significantly
      decreased the risk of breast cancer (RR = 0.5; 95% confidence interval 0.2-0.9)
      as compared with nonusers, there was no significant difference in the risk of
      breast cancer in percutaneous progesterone users versus nonusers among oral
      progestogen users. Taken together, these results suggest at least an absence of
      deleterious effects caused by percutaneous progesterone use in women with benign
      breast disease.

PMID- 10403901
TI  - Nm-23, c-erbB-2, and progesterone receptor expression in invasive breast cancer:
      correlation with clinicopathologic parameters.
AB  - Downregulation of nm-23 antimetastasis gene has been associated with disease
      progression in some human tumors. NPD kinase A is the product of the H1 isotype
      of the nm23 gene and its value as a marker of metastatic potential is well worth
      investigating. The expression of the nm23-H1 gene peptide was
      immunohistochemically evaluated in 191 primary mammary cancer tissues. A three
      step immunoperoxidase staining procedure was performed and any association of our
      results with several classical clinicopathologic indicators, including hormonal
      status and c-erbB-2 oncoprotein membrane immunoexpression, was examined. NDP
      kinase A-positive cytoplasmic immunolabeling was noticed in 64% of all specimens
      (123/191) which frequently demonstrated positive progesterone receptor (PgR)
      status (p = 0.001) and were furthermore characterized by high PgR
      immunoreactivity rates. This association was significant by both univariate and
      multivariate statistical analysis. The double nm23-H1 (+)/PgR(+) phenotype was
      more frequently detected than any other combined phenotype of these markers. The
      nm23-H1 gene peptide was generally detected in a remarkable proportion of
      malignant cells, either in the invasive or the intraductal tumor components.
      Notably, large-cell ductal carcinomas in situ were characterized by lower nm23-H1
      immunoreactivity rates when compared with other in situ cancer types.
      Quantitatively increased nm23-H1 immunopositive staining was more frequently
      observed in special histologic types of infiltrating cancers, in high nuclear
      grade tumors, as well as in carcinomas with high PgR levels (p = 0.05). The nm23
      H1 (-)/c-erbB-2(+) phenotype was more often detected in the cancers of this study
      than the nm23-H1(+)/c-erbB-2(+) one. The former phenotype was correlated to
      postmenopausal ages as well as to extensive axillary nodal involvement by
      univariate statistical analysis. It is noteworthy that nm23-H1(-) status, on its
      own, was not statistically associated either with the presence or with a high
      number of involved lymph nodes. On the contrary, nm23-H1 immunopositivity was,
      paradoxically, more frequently observed in tumors of relatively increased TN
      tumor stage. Tumor progression is thus more likely to depend on the c-erbB-2
      gene's overexpression. Possibly, any favorable outcome in nm23-H1(+) cases might
      be due to the fact that they also express PgR, which is a marker of a more
      functionally differentiated phenotype.

PMID- 10403902
TI  - Neuron-specific enolase, thymidine kinase, and tissue polypeptide-specific
      antigen in diagnosis and response to chemotherapy of small-cell lung cancer.
AB  - The clinical usefulness of neuron-specific enolase (NSE), thymidine kinase (TK),
      and tissue polypeptide-specific antigen (TPS) was investigated in 41 patients (53
      80 years old) with recently discovered small-cell lung cancer (SCLC). Eleven
      patients exhibited limited disease (LD) and 30 extensive disease (ED). Serum
      samples for NSE, TPS (immunoradiometric assay), and TK (radioenzymatic assay)
      evaluations were drawn from all patients at the time of diagnosis and before each
      cycle of chemotherapy in the treated patients. Therapy consisted of i.v.
      carboplatin 300 mg/m2 on the first day and i.v. etoposide 120 mg/m2 from the
      first to the third day every 3 weeks. Nine patients refused or were not eligible
      for chemotherapy. Five patients received only one course and showed no response
      (NR); 9 patients received two courses; 18 patients received three or more
      courses. In the last group, complete remission (CR) was obtained in 9 cases,
      partial remission (PR) in 18 cases. The tumor markers studied did not show any
      significant difference in distinguishing LD from ED. NSE and TPS were
      significantly more often abnormal than TK, either at the time of diagnosis (p <
      0.05) or in PR or NR patients (p < 0.05). In relation to chemotherapy response,
      NSE and TPS serum patterns were shown to be more reliable than TK in PR (p <
      0.05) and NR patients (computed error between 10% and 15%). No significant
      difference was observed between serum NSE and TPS patterns. Serum NSE and TPS
      seem to be more useful in the diagnosis and follow-up of SCLC patients undergoing
      chemotherapy. Further trials are necessary to ascertain whether the associated
      assessment of NSE and TPS can add useful information to that provided by the
      assessment of NSE alone.

PMID- 10403903
TI  - Prostate cancer screening: promise and peril--a review.
AB  - This review summarizes the current status of and recommendations for prostate
      cancer screening with prostate-specific antigen in light of recent reductions in
      prostate cancer incidence and mortality. It describes how the uncertain
      effectiveness of aggressive treatment for prostate cancer and a reservoir of
      unsuspected indolent cancers make prostate cancer fit poorly into conventional
      screening models. The large proportion of men with unsuspected prostate cancers
      that may not cause morbidity or mortality and are unlikely to benefit from
      aggressive treatment decrease the effectiveness of a screening program. In
      addition, indolent, unsuspected prostate cancers in the screening population
      accentuate the detrimental effects of length bias on studies evaluating the
      effectiveness of prostate cancer screening. Screening tests for prostate cancer
      will continue to improve, but chemoprevention or nutritional prevention with
      vitamins and micronutrients such as tocopherols or selenium may prove to be
      effective methods of reducing prostate cancer incidence and should be
      aggressively investigated.

PMID- 10403904
TI  - A receptor tyrosine kinase, UFO/Axl, and other genes isolated by a modified
      differential display PCR are overexpressed in metastatic prostatic carcinoma cell
      line DU145.
AB  - We have used a modified differential display PCR protocol for isolating 3'
      restriction fragments of cDNAs specifically expressed or overexpressed in
      metastatic prostate carcinoma cell line DU145. Several cDNA fragments were
      identified that matched to milk fat globule protein, UFO/Axl, a receptor tyrosine
      kinase, human homologue of a Xenopus maternal transcript, laminin and laminin
      receptor, human carcinoma-associated antigen, and some expressed sequence tags.
      The transcript for milk fat globule protein, a marker protein shown to be
      overexpressed in breast tumors, was elevated in DU145 cells. The expression of
      UFO/Axl, a receptor tyrosine kinase, was considerably higher in DU145 cells as
      compared to normal prostate cells and prostatic carcinoma cell line PC-3. The
      overexpression of UFO oncogene in DU145 cells is discussed in the context of
      prostate cancer metastasis.

PMID- 10403905
TI  - Prospects of immunotherapy for the treatment of prostate carcinoma--a review.
AB  - The treatment of prostate carcinoma is dependent on the stage of the disease.
      Patients who present with clinically localized cancer or locally advanced tumors
      can be potentially cured by radical prostatectomy, radiation, and hormonal
      therapy. However, disease progression can occur in 30-50% of patients diagnosed
      with clinically localized cancer. The bone is the predominant site of metastases.
      Metastatic prostate cancer is first treated by androgen blockade but within a few
      months becomes hormone refractory. Hormone refractory metastatic prostate cancer
      is not responsive to conventional treatments, and patients have an expected
      survival of less than a year. It is essential to develop new approaches for the
      treatment of hormone refractory metastatic disease. Immunotherapy, based on
      enhancement of the host immune response against the tumor, has been used as an
      alternative therapy for the treatment of metastatic cancers refractory to
      conventional therapy in particular for melanoma and renal cell carcinoma. In this
      review, we will summarize various immunotherapeutic approaches developed over the
      last 18 years, and we will address the potential of immunotherapy for the
      treatment of metastatic prostate carcinoma by reviewing preclinical studies and
      initial clinical trials performed in this field.

PMID- 10403906
TI  - Daunorubicin-induced pathology in the developing hamster molar tooth germ in
      vitro.
AB  - The aim of this study was to evaluate, under organ culture conditions, the
      cytotoxic effects of daunorubicin on tooth development. Three-day-old maxillary
      hamster second molars were exposed for 24 h in vitro to 108-10-4 M daunorubicin
      and then evaluated biochemically and histologically. At 10-6 M daunorubicin dose
      dependently decreased tooth germ dry weight, cell proliferation ([3H]thymidine
      uptake), and insoluble [32P] phosphate uptake (phosphorylation of
      macromolecules). [45Ca]calcium uptake, a marker for mineralization, was
      significantly affected only at the highest concentration (10-4 M) tested.
      Histologically, 10-6 M daunorubicin induced necrosis of the proliferating but not
      the differentiated protein-secreting cells. At 10-4 M, however, all cells were
      dead. These results indicate that daunorubicin is particularly toxic to the
      proliferating cells of the tooth germ. Thus, it can be postulated that children
      treated with daunorubicin may develop defects in the erupted teeth mainly
      associated with those regions that were in the proliferating stage at the onset
      of anticancer chemotherapy.

PMID- 10403907
TI  - 5-aminolevulinic acid-mediated photodynamic therapy of intraepithelial neoplasia
      and human papillomavirus of the uterine cervix--a new experimental approach.
AB  - The aim of this study was to treat patients for ectocervical dysplasia [cervical
      intraepithelial neoplasia (CIN) grades 1 and 2] and associated human papilloma
      virus (HPV) infections with photodynamic therapy (PDT). In 20 patients, 5
      aminolevulinic acid (5-ALA, 12% w/v) was applied topically with a cervical cap 8
      h prior to illumination. A thermal light source (150 W halogen lamp) emitting a
      broadband red light (total energy: 100 J/cm2, fluence rate: 90 mW/cm2) was used
      for superficial illumination of the portio. In addition, an Nd:YAG pumped dye
      laser (652 nm) was used to illuminate the cervical canal (total energy: 50 J/cm2,
      fluence rate: 300 mW/cm2). Preliminary results of follow-ups at 1, 3, 6, and 9
      months posttherapy showed a cytological improvement in the grading of the PAP
      smears in 19 patients and the eradication of cervical HPV in 80%. These results
      demonstrate that ectocervical dysplasia and associated HPV infections can be
      treated by PDT.

PMID- 10403908
TI  - Impaired expression of MHC class II molecules in response to interferon-gamma
      (IFN-gamma) on human thymoma neoplastic epithelial cells.
AB  - A human thymoma is a neoplasm derived from the thymic epithelial cell, and is
      well known for its association with autoimmune diseases, especially myasthenia
      gravis. The neoplastic epithelial cells of thymoma clearly retain thymic
      epithelial functions, but the development of T cells in thymoma is somewhat
      impaired. In this study, we quantified by flow cytometry the in vitro expression
      of MHC molecules on neoplastic epithelial cells precultured with IFN-gamma. While
      MHC class I expression was comparable with that on normal thymic epithelial
      cells, the level of MHC class II molecules on neoplastic epithelial cells was
      lower than in controls, and also varied greatly from case to case. Additionally,
      there was a significant positive correlation between the expression level of MHC
      class II and the proportion of mature CD3+ cells in the CD4+CD8- subset. Thus,
      accumulation of CD3-CD4+CD8- cells in thymoma may result from impaired expression
      of the MHC class II molecules, suggesting that the function of the neoplastic
      epithelial cells might determine the maturation and the positively selected
      repertoire of T cells in thymomas.

PMID- 10403909
TI  - Reduced IL-4 and interferon-gamma (IFN-gamma) expression by CD4 T cells in
      patients with chronic lymphocytic leukaemia.
AB  - CD7 co-expression by CD4 T cells has been reported to be higher in the Th1
      compared with the Th2 functional subset. Clinical immunodeficiency and immune
      dysregulation are more prevalent in the advanced stages of B cell chronic
      lymphocytic leukaemia (B-CLL). To analyse this further 25 patients with B-CLL and
      11 healthy subjects were examined for cell surface CD7 and intracellular IFN
      gamma and IL-4 expression in the peripheral blood CD4+ T helper cell population.
      Significantly decreased CD7, IFN-gamma and IL-4 expression was observed in the
      patients with B-CLL (P < 0.001). While CD7 negativity and IL-4 expression were
      more frequent in the later stages of the disease, this did not attain statistical
      significance. These results suggest a possible explanation for the reduced
      cellular and humoral immunity in B-CLL.

PMID- 10403910
TI  - Analysis of human C4A and C4B binding to an immune complex in serum.
AB  - Previous studies using isolated complement proteins have shown that more C4A than
      C4B binds to certain types of immune complexes. However, the in vivo binding of
      the C4 isoforms to an immune complex has not been investigated in detail and may
      differ from events when measured with the isolated proteins. We report here the
      binding of C4A and C4B to an immune complex of bovine serum albumin (BSA) anti
      BSA as it occurs in serum. We found that when using the isolated C4 proteins more
      C4A than C4B bound to the complex, but in serum similar amounts of C4A and C4B
      were found to bind. Furthermore, these results were not explainable by a
      difference in activity between isoforms. In an attempt to explain these results a
      number of unexpected observations were noted. First C4A, but not C4B, bound
      specifically to a yet unidentified 38-kD serum protein. Second, when both
      covalent and non-covalent binding was assessed, we found that as serum
      concentration increased there followed a concomitant decrease in covalent binding
      and C4B was more affected than C4A. The potential biological significance of
      these findings is discussed.

PMID- 10403911
TI  - Rarity of autoantibodies to a major autoantigen, thyroid peroxidase, that
      interact with denatured antigen or with epitopes outside the immunodominant
      region.
AB  - The nature of the autoantibody repertoire to the dominant autoantigen in human
      autoimmune thyroid disease is controversial. There is evidence that
      autoantibodies to thyroid peroxidase (TPO) interact with overlapping
      conformational epitopes in an immunodominant region and binding to denatured (DN)
      protein is decreased. Contrary data demonstrate TPO autoantibody reactivity with
      DN-TPO or polypeptide fragments. However, none of the TPO-specific, human
      monoclonal autoantibodies isolated to date preferentially recognize denatured
      autoantigen. We therefore searched an immunoglobulin gene phage display library
      for human autoantibodies that bind TPO denatured by reduction and alkylation (DN
      TPO). Thyroid-infiltrating B cells from a typical TPO autoantibody-positive
      patient were the source of mRNA for library construction. Surprisingly, the
      library enriched after panning on DN-TPO, as well as a panel of individual
      clones, preferentially bound native (N)-TPO. Of 13 clones selected using DN-TPO
      or N-TPO, 12 clones recognized the TPO immunodominant region. Moreover,
      regardless of selection with N-TPO or DN-TPO, their heavy and light chains were
      encoded by similar VDJ and Vkappa combinations. One clone (DN4), isolated using
      DN-TPO, did not interact with the TPO immunodominant region and its H chain
      derives from a different VH gene. Although DN4 binds specifically to TPO, its
      affinity is low, unlike the high affinities of other human TPO autoantibodies. In
      conclusion, human monoclonal autoantibodies that preferentially recognize
      denatured TPO could not be isolated from an immunoglobulin gene library despite
      selection with denatured protein. Our findings demonstrate the bias of the human
      B cell repertoire towards recognition of an immunodominant region on the
      conformationally intact form of a major thyroid autoantigen.

PMID- 10403912
TI  - T cell response pattern to glutamic acid decarboxylase 65 (GAD65) peptides of
      newly diagnosed type 1 diabetic patients sharing susceptible HLA haplotypes.
AB  - Autoantibodies and autoreactive T lymphocytes directed against several pancreatic
      beta cell proteins such as GAD65 have been identified in the circulation before
      and at the onset of clinical type 1 (insulin-dependent) diabetes. Using GAD65
      synthetic peptides, we studied the proliferative response of peripheral blood
      mononuclear cells (PBMC) either from recently diagnosed type 1 diabetic patients,
      of whom the majority share the disease-associated HLA class II haplotype (DR4
      DQB1*0201 or DR3-DQB1*0302), or from HLA-matched control subjects. We found that
      67% (14/21) of the type 1 diabetic patients and 39% (9/23) of the control
      subjects exhibited a positive proliferative response. Compared with control
      subjects, however, PBMC from diabetic patients proliferated more frequently (P <
      0.05) in the presence of peptide pools from the C-terminal region of GAD65 (amino
      acids 379-585). Diabetic patients with the same HLA-DQ or HLA-DR alleles showed
      partially identical T cell reactivity, but no clear correlation could be made
      between MHC class II specificity and T cell epitopes because of multiple
      combinations of class II alleles. In addition, by flow cytometry, we studied the
      direct binding of GAD65 peptides to MHC class II molecules of Epstein-Barr virus
      (EBV)-transformed B (EBV-B) cells obtained from a diabetic patient. We found that
      11 GAD peptides were able to bind to the highly susceptible haplotype
      DRB1*0301/0401-DQA1*0301/0501-DQB1*0302/0201 on the surface of EBV-B cells in
      partial correlation with the results obtained in the proliferation assays.

PMID- 10403913
TI  - Transfer of dendritic cells (DC) ex vivo stimulated with interferon-gamma (IFN
      gamma) down-modulates autoimmune diabetes in non-obese diabetic (NOD) mice.
AB  - The NOD mouse has been used to explore the many features of insulin-dependent
      diabetes mellitus (IDDM) that is caused by the destruction of insulin-producing
      beta cells in the islets of Langerhans of the pancreas. Self-reactive T cells
      have been considered to mediate IDDM in the NOD mouse, and antigen-presenting
      cells like DC and macrophages are expected to be involved in the processes from
      their role in generating regulatory or effector T cells. The present study shows
      that transfer of IFN-gamma-stimulated DC of the NOD or ICR mouse into the NOD
      mouse did not accelerate IDDM onset but afforded long-lasting protection against
      clinical and histological signs of IDDM in the recipient mice. The anti
      diabetogenic ability was unique to IFN-gamma-stimulated DC when compared with
      unstimulated DC. A considerable proportion of the injected IFN-gamma-stimulated
      DC was demonstrated to migrate into the pancreas and its associated lymphoid
      tissues, suggesting the DC exert their anti-diabetogenic effects there. These
      findings suggest that development of autoimmune diabetes in the NOD mouse is
      under the control of DC, and that IDDM onset could be controlled by appropriately
      manipulating DC systems in vivo, which may open the gate for the therapeutic
      application of ex vivo-conditioned DC to human IDDM.

PMID- 10403914
TI  - Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced
      insulitis and diabetes.
AB  - In certain animal models of autoimmunity the isoxasol derivative leflunomide has
      been reported to exert a protective effect against autodestruction. In the
      present study, the immunomodulatory potential of the main metabolite of
      leflunomide, A77 1726, in experimentally induced autoimmune diabetes was
      investigated. The disease was induced in genetically susceptible CBA/H mice by
      multiple low doses of streptozotocin (MLD-SZ, 40 mg/kg per day, given
      intraperitoneally for 5 consecutive days). Effects of leflunomide were evaluated
      by two treatment protocols: mice treated with MLD-SZ were injected
      intraperitoneally with A77 1726 for 10 consecutive days, either during the first
      10 days of the disease (early treatment), or starting from day 10 after disease
      induction (late treatment). Disease manifestations defined by hyperglycaemia,
      mononuclear infiltration into pancreas, expression of interferon-gamma (IFN
      gamma) and inducible nitric oxide synthase (iNOS) and destruction of the islets
      of Langerhans were reduced in a dose-dependent fashion after early treatment with
      A77 1726 (dose range of 5-35 mg/kg per day). Moreover, late treatment with the
      high dose of the drug (25 mg/kg per day), started when the autoimmune disease was
      already apparent, arrested progression of ongoing inflammatory response. Analysis
      of the effects of A77 1726 on the adhesive interactions of spleen-derived or
      peripheral blood-derived mononuclear cells from MLD-SZ-treated and normal mice
      demonstrated that the drug inhibits both ex vivo and in vitro spontaneous
      mononuclear cell aggregation, thus suggesting that an important component of
      leflunomide's immunomodulatory action is suppression of adhesive interactions.
      These results demonstrate both preventive and therapeutic effects of leflunomide
      in a model of MLD-SZ-induced diabetes and suggest that the drug may be considered
      a potent therapeutic tool for autoimmune inflammatory disorders, including
      diabetes.

PMID- 10403915
TI  - Changing jejunal gamma delta T cell receptor (TCR)-bearing intraepithelial
      lymphocyte density in coeliac disease.
AB  - The function of jejunal intraepithelial gamma delta+ T cells is obscure, but they
      are commonly implicated as playing a role in inflammatory and autoimmune
      conditions. In coeliac disease (CoD), there are controversial reports as to
      gluten dependency of these cells. We have now studied the small bowel mucosal
      intraepithelial T cell densities, and the ratios of gamma delta+ to CD3+ T cells
      and gamma delta+ to alpha beta+ T cells during early disease development and on a
      gluten-free diet. Nine children initially excluded for CoD were followed up and
      rebiopsy after 0.8-4.5 years showed mucosal deterioration. Further, 21 biopsy
      specimens from newly diagnosed CoD patients were studied, together with 20
      specimens taken from children on a gluten-free diet. During CoD development the
      density of gamma delta+ and alpha beta+ T cells as well as the ratios of gamma
      delta+ to CD3+ T cells and gamma delta+ to alpha beta+ T cells increased. In the
      latent stage of CoD when the small bowel mucosal architecture was still normal,
      two children had clearly normal densities of gamma delta+ (< 2.5 cells/100
      epithelial cells) and alpha beta+ (< 25.0 cells/100 epithelial cells) T cells,
      and low ratios as well. In patients with newly diagnosed CoD the densities
      decreased significantly on a long-term gluten-free diet. We conclude that the
      density of intraepithelial gamma delta+ T cells as well as alphabeta+ T cells in
      CoD is gluten-dependent. CoD can develop in a child ingesting normal amounts of
      gluten and having normal jejunal mucosal morphology on biopsy and a normal
      density of gamma delta+ T cells.

PMID- 10403916
TI  - Inhibition of apoptosis by ionomycin and zinc in peripheral blood mononuclear
      cells (PBMC) of leprosy patients.
AB  - PBMC from tuberculoid (BT/TT) and lepromatous leprosy (BL/LL) leprosy patients
      showed spontaneous apoptosis when cultured in the absence of mitogen for 24 h,
      which was inhibited by anti-tumour necrosis factor-alpha (TNF-alpha) antibodies.
      Apoptosis was also inhibited by ionomycin and zinc, which also increased IL-2 and
      decreased TNF-alpha production. The increase in IL-2 production suggests a
      mechanism whereby dietary supplements with zinc might alter the cell-mediated
      immunity response in leprosy patients.

PMID- 10403917
TI  - Protective role of NK1.1+ cells in experimental Staphylococcus aureus arthritis.
AB  - In a model of Staphylococcus aureus-induced septic arthritis in C57Bl/6 mice we
      investigated the role of natural killer (NK) cells in the development of disease.
      Depletion of NK1.1+ cells was achieved by repeated injections of the PK136
      antibody, whereas control mice received an irrelevant monoclonal antibody,
      O1C5.B2. Both groups of mice then received injections intravenously with 2 x 107
      live S. aureus LS-1 secreting toxic shock syndrome toxin-1 (TSST-1). The mice
      were evaluated for 16 days with regard to weight, mortality and arthritis. Nine
      days after bacterial injection, 9/19 mice depleted of NK cells had developed
      arthritis compared with 1/17 in the control group (P = 0.01). The experiment was
      repeated twice with the same outcome. NK cell-depleted and control mice displayed
      the same degree of histopathological signs of arthritis at day 16. Depletion of
      NK cells did not affect uptake of bacteria by phagocytic cells in vitro, or
      bacterial clearance in vivo. In NK cell-depleted mice there was a tendency to
      increased levels of antibodies to TSST-1, whereas total immunoglobulin levels
      were similar to those in controls. NK cell depletion of non-infected mice did not
      affect the magnitude of inflammatory response during the T cell-dependent
      cutaneous DTH reaction to oxazolone, or during granulocyte-mediated inflammation.
      However, specific antibody responses to oxazolone were greatly increased in
      depleted animals. In conclusion, our study demonstrates that NK cells protect
      against arthritis during S. aureus infection. This outcome does not seem to be
      due to an influence on bacterial clearance, but could be due to an interaction
      with the host anti-inflammatory mechanisms.

PMID- 10403918
TI  - Inducible nitric oxide synthase is expressed in joints of goats in the late stage
      of infection with caprine arthritis encephalitis virus.
AB  - We have studied the expression of the inducible form of nitric oxide synthase
      (iNOS) in joints of goats infected with the caprine arthritis encephalitis virus
      (CAEV). Nitric oxide generated by iNOS is thought to play an important role in
      the pathogenesis of various types of arthritis, especially rheumatoid arthritis
      (RA) in humans. Surprisingly, iNOS immunoreactivity was found only in joints of
      long-term infected goats with severe clinical arthritis, whereas-despite the
      presence of high numbers of inflammatory cells in the synovial tissue-no iNOS
      immunoreactivity was detected in mildly arthritic and in short-term
      experimentally infected goats. Most iNOS-positive cells expressed neither MHC
      class II nor CD68, which suggests that they were fibroblast-like synoviocytes. In
      situ hybridization studies showed that there was no correlation between iNOS
      immunoreactivity and detectable virus expression in the joint. In addition,
      infection of macrophages in vitro-the major host cells of CAEV in vivo-did not
      lead to increased iNOS mRNA expression. In response to stimulation, similar
      levels of iNOS expression were observed in infected and in uninfected
      macrophages. These findings suggest that the expression of iNOS is a feature of
      late-stage chronic arthritis and is not involved in the development of the
      inflammatory lesions. Both the lack of co-localization of iNOS protein and viral
      transcripts in the joint and the finding that CAEV does not stimulate the
      expression of iNOS in vitro further suggest that iNOS is not directly induced by
      the virus or the anti-viral immune response in the joint, that it may well,
      however, be involved in tissue remodelling or scar formation.

PMID- 10403920
TI  - Dysregulation of B7.2 (CD86) expression on monocytes of HIV-infected individuals
      is associated with altered production of IL-2.
AB  - T helper (Th) responses are mediated in part by immunoregulatory cytokines and
      the signals delivered by the costimulatory CD28-B7 pathway. In this study, we
      have investigated the relationship between the regulation of B7 isoform
      expression on antigen-presenting cells from HIV+ individuals and the production
      of Th cytokines. The level of expression of both B7.1 and B7.2 isoforms as
      measured by mean channel fluorescence was significantly decreased on freshly
      isolated monocytes from HIV+ individuals compared with HIV- controls. However,
      the levels of expression of B7.1 and B7.2 on both B cells and monocytes increased
      significantly following culture in HIV+ individuals compared with HIV- controls.
      B7 expression is subject to regulation by immunoregulatory cytokines. Therefore,
      we analysed the regulation of B7 expression by cytokines, namely IL-10 and tumour
      necrosis factor-alpha (TNF-alpha), the production of which is enhanced in HIV
      infection and have similar inhibitory effects on B7 expression. Two groups of
      HIV+ individuals were distinguished on the basis of the inhibitory effect of IL
      10 and TNF-alpha on monocyte B7.2 expression. IL-10 inhibited B7.2 expression on
      monocytes from some HIV+ individuals (termed responders) like the HIV- controls.
      However, in a subset of HIV+ individuals (non-responders) this inhibitory effect
      was lost. Loss of inhibition of B7.2 expression by IL-10 was associated with
      significantly reduced IL-2 production by phytohaemagglutinin (PHA)- stimulated
      peripheral blood mononuclear cells (PBMC). These observations showing an
      association of B7 dysregulation on monocytes and B cells with altered production
      of IL-2 may have implications in HIV immunopathogenesis.

PMID- 10403919
TI  - Enhancing of anti-viral activity against HIV-1 by stimulation of CD8+ T cells
      with thymic peptides.
AB  - HIV-1 can be neutralized by soluble factors produced and secreted by activated
      CD8+ T cells. Production of such anti-viral CD8 factors (including chemokines)
      can be induced with IL-2 or phytohaemagglutinin (PHA). In addition to PHA or IL
      2, we have co-stimulated CD8+ T cells with PHA/IL-2 and a mixture of thymic
      peptides (TP) of molecular weights below 10 kD. For the activation, CD8+ T cells
      were purified from peripheral blood mononuclear cells of HIV-1- individuals and
      any resultant anti-viral activity was monitored using an HIV-1 neutralization
      assay. Using HIV-1 isolates highly resistant to chemokine inhibition we detected
      significantly higher levels of HIV-1 neutralizing activity in CD8+ T cell culture
      supernatants which had been co-activated with TP. When the TP-induced anti-viral
      activity was monitored, neutralization of both non-syncytia-inducing (NSI) and
      syncytia-inducing (SI) patient isolates was enhanced by 38% (NSI, PHA +/- TP),
      66% (SI, PHA +/- TP), 28% (NSI, IL-2 +/- TP), and 57% (SI, IL-2 +/- TP) compared
      with the anti-viral activity present in supernatants from CD8+ T cell cultures
      stimulated only with PHA or IL-2. Peptide sequence analysis of purified TP showed
      that the TP mixture predominantly contains peptides with homology to human
      histone and collagen sequences. Our data demonstrate that CD8+ T cells are
      additionally activated by a mixture of TP. In this way, the production of HIV-1
      neutralizing CD8 factors can be enhanced.

PMID- 10403921
TI  - Phenotypic and functional characterization of lymphocytes derived from normal and
      HIV-1-infected human lymph nodes.
AB  - Lymph nodes are the major site of cell-to-cell transmission and replication of
      HIV-1. Trafficking of CD4+ T lymphocytes into lymph nodes provides a continual
      supply of susceptible target lymphocytes, and conversely, recruitment of CD8+ T
      lymphocytes may be critical for the host response that attempts to control HIV-1
      replication. The present study was undertaken as no detailed assessment of
      lymphocyte subpopulations in HIV-1-infected lymph nodes has previously been
      reported. Peripheral blood and single-cell suspensions prepared from lymph nodes
      of patients with HIV-1 and control subjects were analysed using three-colour flow
      cytometry. Approximately 80% of the lymphocytes in control lymph nodes were CD3+
      T lymphocytes, of which over 65% were CD4+. The majority of the CD4+ and CD8+ T
      lymphocytes obtained from both lymph nodes and blood of control subjects were
      immunologically naive (CD45RA+). By contrast, in HIV-1-infected patients there
      was a significant reduction in the proportion of CD4+ T lymphocytes and an
      expansion of the CD8+ T lymphocyte subset in both lymph nodes and peripheral
      blood. Furthermore, a high proportion of these T lymphocytes displayed a marker
      for immunological memory (CD45RO+). T lymphocytes derived from HIV-1-infected
      lymph nodes also showed altered expression of the adhesion molecules, L-selectin
      and very late antigen-4 (VLA-4), but not leucocyte function-associated antigen-1
      (LFA-1). In an in vitro adhesion assay, lymphocytes from HIV-1-infected nodes
      were significantly more adhesive than control lymphocytes on fibronectin, as well
      as recombinant human intercellular adhesion molecule-1 (ICAM-1) and vascular cell
      adhesion molecule-1 (VCAM-1) substrates. This combination of altered lymphocyte
      subpopulations in the HIV-1-infected lymph nodes, as well as enhanced adhesion
      phenotype and function, suggests that T lymphocyte traffic to lymph nodes in HIV
      disease may be an important determinant of pathogenesis.

PMID- 10403922
TI  - Comparison of enterovirus-specific cellular immunity in two populations of young
      children vaccinated with inactivated or live poliovirus vaccines.
AB  - Enterovirus-specific cellular immunity was studied in Estonian and in Finnish
      children at the age of 9 months. The aim was to evaluate the level of
      responsiveness in two neighbouring countries with different poliovirus
      immunization practices and striking differences in the incidence of insulin
      dependent diabetes mellitus (IDDM), a disease in which early enterovirus
      infections are an aetiological risk factor. The Estonian children immunized with
      live attenuated polio vaccine had stronger T cell responses to coxsackievirus B4
      and poliovirus type 1 when compared with Finnish children immunized with
      inactivated polio vaccine (median stimulation indices 10.4 and 6.3 in Estonian
      children and 1.9 and 2.9 in Finnish children, respectively; P < 0.05).
      Lymphocytes stimulated by poliovirus type 1 antigen expressed interferon-gamma
      (IFN-gamma) mRNAs, which strongly correlated with the level of proliferation
      responses. Lymphocytes of Estonian children had a tendency towards stronger
      expression of IFN-gamma upon poliovirus challenge when compared with Finnish
      children. The number of children who had experienced coxsackievirus B infections,
      as determined by the presence of neutralizing antibodies, did not differ between
      Estonian and Finnish children. The results show that Finnish children have weaker
      cellular immunity against enteroviruses at the age of 9 months compared with
      Estonian children at the same age. This is most probably due to the difference in
      polio vaccination schedules; in Estonia live poliovirus vaccine is used and given
      at earlier ages than the inactivated vaccines in Finland. This leads to stronger
      T cell immunity which cross-reacts with other enterovirus serotypes. This may
      explain the lower incidence of IDDM in Estonia by providing effective protection
      against diabetogenic enterovirus strains in Estonian children.

PMID- 10403923
TI  - DNA vaccination favours memory rather than effector B cell responses.
AB  - Following priming and boosting of mice with a DNA vector pEE6DeltaS-hCGss
      expressing sequences encoding a transmembrane version of the beta-chain of human
      chorionic gonadotropin (hCGbeta), we failed to detect appreciable levels of
      specific antibody. However, subsequent challenge with hCG protein in Ribi
      adjuvant elicited a strong and rapid secondary immune response. This response was
      of comparable magnitude to that produced following priming, boosting and
      challenge with protein in adjuvant. Thus, DNA vaccination with this vector is as
      efficient in generating B cell memory as is conventional immunization, but the
      memory generation occurs in the absence of an overt effector response. Despite an
      overall similar level of specific antibody, the DNA-vaccinated mice produced hCG
      specific antibodies biased towards IgG2a and IgG2b isotypes, whereas the protein
      vaccinated mice produced higher levels of IgG1 antibodies. Both Th1 and Th2
      cytokines (interferon-gamma (IFN-gamma) and IL-4) were lower in the spleens of
      the DNA-immunized animals compared with the protein-Ribi-immunized animals,
      possibly suggesting a different level of helper T cell response to the two
      different modes of immunization.

PMID- 10403924
TI  - Interferon-gamma (IFN-gamma)-dependent protection and synthesis of
      chemoattractants for mononuclear leucocytes caused by IL-12 in the lungs of mice
      infected with Cryptococcus neoformans.
AB  - We have recently demonstrated that IL-12 induced cellular inflammatory responses
      consisting mainly of accumulation of mononuclear leucocytes in the lungs of mice
      infected with Cryptococcus neoformans and protected mice against fulminant
      infection. We examined the involvement of endogenously synthesized IFN-gamma in
      such a response by investigating the effects of a neutralizing monoclonal
      antibody against this cytokine. The latter treatment completely abrogated the
      positive effects of IL-12 on survival of infected mice and prevented IL-12
      induced elimination of microbials from the lungs. Histopathological examination
      showed that accumulation of mononuclear leucocytes in the infected lungs caused
      by IL-12 was clearly inhibited by anti-IFN-gamma MoAb. We also examined the local
      production of mononuclear cell-attracting chemokines such as monocyte chemotactic
      protein-1 (MCP-1), regulated upon activation, normal T cell expressed and
      secreted (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta
      and IFN-gamma-inducible protein 10 (IP-10) in the lungs using a reverse
      transcriptase-polymerase chain reaction (RT-PCR) method. We found that these
      chemokines were not synthesized in the infected lungs, while IL-12 treatment
      markedly induced their production. Interestingly, neutralizing anti-IFN-gamma
      MoAb strongly suppressed IL-12-induced production of these chemokines. Similar
      results were obtained with MCP-1 and MIP-1alpha when their synthesis was measured
      at the protein level using respective ELISA kits. Our results indicate that IFN
      gamma plays a central role in the protective effects of IL-12 by inducing
      mononuclear leucocyte-attracting chemokines and cellular inflammatory responses.

PMID- 10403926
TI  - Prenatal immune priming in onchocerciasis-onchocerca volvulus-specific cellular
      responsiveness and cytokine production in newborns from infected mothers.
AB  - This study investigated the effect of maternal Onchocerca volvulus infection on
      humoral and cellular responsiveness in newborn children and their mothers.
      Onchocerca volvulus-specific IgG isotypes and IgE were significantly elevated in
      infected mothers and their infants. One year post partum, O. volvulus-specific
      IgG4 was strongly reduced in children of infected mothers, while IgG1 responses
      weakened only slightly. Umbilical cord mononuclear blood cells (UCBC) and
      peripheral blood cells (PBMC) from mothers proliferated in response to
      phytohaemagglutinin (PHA), concanavalin A (Con A), and the bacterial antigens
      streptolysin-O (SL-O) or purified protein derivative (PPD). UCBC from neonates
      born to O. volvulus-infected mothers responded lower (P < 0.01) to Con A (at 5
      micrograms/ml), PPD (at 10 and 50 micrograms/ml) and O. volvulus-derived antigens
      (OvAg) (at 35 micrograms/ml), and in parallel, a diminished cellular reactivity
      (P < 0.01) by PBMC was observed to OvAg in mothers positive for O. volvulus.
      Several Th1-type (IL-2, IL-12, interferon-gamma (IFN-gamma) and tumour necrosis
      factor-alpha (TNF-alpha)) and Th2-type (IL-4, IL-5, IL-10, IL-13) cytokines were
      secreted by UCBC and PBMC in response to OvAg, bacterial SL-O and PHA. OvAg did
      not stimulate IL-2 and none of the mitogens or antigens induced production of IL
      4 in neonates. In response to OvAg, substantially elevated (P < 0.01) amounts of
      IFN-gamma were produced by UCBC from newborns of O. volvulus-infected mothers.
      UCBC secreted low levels of IL-5 and IL-13, while higher amounts of IL-10 were
      found (P < 0. 01) in newborns from onchocerciasis-free mothers. In conclusion,
      maternal O. volvulus-infection will sensitize in utero parasite-specific cellular
      immune responsiveness in neonates and activate OvAg-specific production of
      several Th1- and Th2-type cytokines.

PMID- 10403925
TI  - Depletion of peritoneal CD5+ B cells has no effect on the course of Leishmania
      major infection in susceptible and resistant mice.
AB  - The mouse peritoneal cavity contains a unique self-renewing population of B cells
      (B-1) derived from fetal liver precursors and mainly producing polyreactive
      antibodies. Since B-1 cells are a potential source of IL-10, it has been
      suggested that these cells may contribute to the susceptibility of BALB/c mice to
      Leishmania major infection by skewing the T helper cell network towards a Th2
      phenotype. Accordingly, L. major infection of B cell-defective BALB/c Xid mice
      (lacking B-1 cells) induces less severe disease compared with controls. However,
      in addition to the lack of B-1 cells, the Xid immune deficiency is characterized
      by high endogenous interferon-gamma (IFN-gamma) production. In the present study,
      the role of B-1 cells during L. major infection was investigated in mice
      experimentally depleted of peritoneal B-1 cells. Six weeks old C57Bl/6 and BALB/c
      mice were lethally irradiated and reconstituted with autologous bone marrow which
      allows systemic depletion of B-1 cells. Untreated BALB/c, C57Bl/6 as well as
      BALB/c Xid mice were used as controls. After reconstitution, mice were injected
      with L. major amastigotes and progression was followed using clinical,
      parasitological and immunological criteria. As previously reported, BALB/c Xid
      mice showed a significant reduction in disease progression. In contrast, despite
      the dramatic reduction of B-1 cells, B-1-depleted BALB/c mice showed similar or
      even worse disease progression compared with control BALB/c mice. No differences
      were found between B-1-depleted or control C57Bl/6 mice. Our data suggest that
      the B-1 cells do not contribute to the susceptibility of BALB/c mice to L. major
      infection.

PMID- 10403927
TI  - CD95 expression and function on lymphocyte subpopulations in common variable
      immunodeficiency (CVID); related to increased apoptosis.
AB  - Apoptosis is now recognized as a central process of development and disease, and
      it has been proposed as one of the mechanisms that may account for the
      lymphopenia seen in some diseases. In this study we measured spontaneous
      apoptosis and CD95 expression on different cell subpopulations from CVID
      patients, using flow cytometric techniques. We divided our patients into two
      groups according to their CD4+ and CD4+CD45RA+ cell counts. Our results clearly
      show increased spontaneous apoptosis and CD95 expression on the CD4+ and
      CD4+CD45RA+ subsets from lymphopenic CVID patients compared with normal subjects
      and disease controls. Interestingly, our lymphopenic CVID patients presented a
      profound reduction in absolute counts, mainly affecting the CD4+CD45RA+
      subpopulation. We also found a statistically significant direct correlation
      between absolute numbers of CD4+CD45RA+ T cells and spontaneous apoptosis on the
      same subset in CVID patients, but attempts to induce CD95-mediated apoptosis were
      unsuccessful despite increased CD95 expression on CD4+ T cells. These findings
      suggest that apoptosis could be one of the mechanisms implicated in the
      significant lymphopenia present in these patients.

PMID- 10403928
TI  - Spontaneous labour at term is associated with fetal monocyte activation.
AB  - The aetiology of both term and preterm labour remains incompletely understood.
      Maternal infectious diseases as well as intra-uterine infections were shown to be
      a well established cause of uncontrollable preterm delivery, indicating that
      inflammatory reactions, regulated by maternal immunecompetent cells, are
      implicated in labour-promoting mechanisms. To investigate the possibility that
      the activation of the fetal immune system may be involved in labour induction, we
      examined cytokine production patterns of different cord blood cell populations
      obtained from neonates after spontaneous onset of normal term labour and vaginal
      delivery (n = 25), vaginal delivery but induced term labour (n = 17), and preterm
      delivery because of uncontrollable labour (n = 27, 20 patients received corticoid
      treatment for fetal lung maturation), in comparison with cells obtained from
      neonates after elective term caesarean delivery in the absence of labour (n =
      15). Our results demonstrate that spontaneous term labour, but not induced term
      labour, was associated with significantly increased IL-6 production by
      myelomonocytic cell populations. Preterm delivery due to uncontrollable labour
      with resistance to tocolysis was not associated with increased IL-6 production by
      fetal myelomonocytic cells. Two-colour flow cytometry combined with intracellular
      cytokine staining was used to identify fetal monocytes as sources of labour
      associated IL-6 release at term. We did not find any activation of cord blood T
      cells in association with spontaneous term or uncontrollable preterm labour.
      Therefore, fetal T cell responses may not cause monocyte activation. Our results
      suggest that increased release of IL-6 from fetal monocytes is involved in
      mechanisms promoting normal term, but not preterm labour, and that mechanisms
      inducing term and preterm labour are completely different.

PMID- 10403929
TI  - Soluble CD40 in the serum of healthy donors, patients with chronic renal failure,
      haemodialysis and chronic ambulatory peritoneal dialysis (CAPD) patients.
AB  - CD40 and its ligand CD40L are key players in T cell-B cell interaction and T cell
      antigen-presenting cell (APC) interaction. Inhibition of CD40-CD40L interaction
      leads to severe humoral and cellular immunodeficiency. In this study we examined
      the presence of soluble CD40 (sCD40) in the serum of haemodialysis (HD) patients,
      CAPD patients, chronic renal failure (CRF) patients and healthy donors in order
      to evaluate the possible involvement of CD40 in uraemic immunodeficiency. Soluble
      CD40 was detected in the serum of healthy donors (n = 41) with a mean of 0.14 +/-
      0.12 ng/ml and in the urine of healthy donors with a mean of 1.80 +/- 0.74 ng/ml.
      Soluble CD40 was highly elevated in all patients with impaired renal function. HD
      patients (n = 22) had up to 100-fold elevated sCD40 levels with a mean
      concentration of 8.32 +/- 4.11 ng/ml, whereas CAPD patients (n = 10) had
      considerably lower levels of sCD40 with a mean of 3.58 +/- 2.40 ng/ml. A strong
      correlation between sCD40 and serum creatinine levels was noted in CRF patients
      (n = 66). The highly elevated levels of sCD40 may point to the involvement of
      CD40 and its ligand CD40L in the clinical manifestation of uraemic
      immunodeficiency.

PMID- 10403930
TI  - Augmented production of chemokines (monocyte chemotactic protein-1 (MCP-1),
      macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta) in patients
      with systemic sclerosis: MCP-1 and MIP-1alpha may be involved in the development
      of pulmonary fibrosis.
AB  - To determine the role of chemokines in the pathogenesis of systemic sclerosis
      (SSc), we examined serum levels, spontaneous production by peripheral blood
      mononuclear cells (PBMC), and histological distribution in the affected skin, of
      MCP-1, MIP-1alpha and MIP-1beta in SSc patients. Serum levels of these chemokines
      were examined by ELISA in 58 patients with SSc and 20 normal controls. The levels
      of these chemokines in culture supernatants from PBMC were also measured by
      ELISA. Serum levels and spontaneous production levels by PBMC of MCP-1, MIP
      1alpha, and MIP-1beta were significantly elevated in patients with SSc compared
      with normal controls. Elevated serum levels of MCP-1 and MIP-1alpha significantly
      correlated with the presence of pulmonary fibrosis. MCP-1 expression in the skin
      of SSc was immunohistochemically examined using anti-MCP-1 MoAb. MCP-1 was
      strongly expressed in the epidermis, inflammatory mononuclear cells, and vascular
      endothelial cells in the sclerotic skin of SSc patients, but not expressed in any
      control skin. Furthermore, the MCP-1 expression in inflammatory mononuclear cells
      and endothelial cells significantly correlated with earlier onset of SSc. Thus,
      MCP-1, MIP-1alpha and MIP-1beta may be involved in the disease process, possibly
      by augmenting leucocyte migration into the affected tissues in SSc. Furthermore,
      MCP-1 and MIP-1alpha may play an important role in the development of pulmonary
      fibrosis in SSc.

PMID- 10403931
TI  - Oligoclonal T cell expansions in patients with Behcet's disease.
AB  - Behcet's disease (BD) is a multisystem disorder with oral and genital ulcers,
      mucocutaneous, ocular, joint, vascular and central nervous system involvement. In
      this study, the peripheral T cell repertoire was analysed in patients with BD
      with MoAbs against T cell receptor (TCR) Vbeta gene products in CD4+ and CD8+ T
      cell compartments, and these were compared with rheumatoid arthritis (RA)
      patients and healthy controls (HC). In the CD4+ T cell compartment, oligoclonal
      TCR Vbeta expression was observed in 56% of BD (10/18), 71% of RA (5/7) patients
      and 21% (3/14) of HC. In the CD8+ T cell group 50% of BD (9/18), 57% of RA
      patients and 28% of HC (4/14) had an oligoclonal TCR repertoire. An increase of
      TCR Vbeta5.1 subset was observed in five BD patients among CD8+ T cells. Other
      elevations of TCR Vbeta subsets were heterogeneously distributed with one to
      three different Vbeta subsets. Our results suggest an antigen-driven oligoclonal
      increase of T cells in BD. There was no overall increase in any Vbeta group to
      suggest a superantigen effect. Analysis of the responsible antigens causing the
      increase in T cell subsets may give insights into the aetiopathogenesis of BD and
      immunomodulation of these T cells may lead to new treatments.

PMID- 10403932
TI  - Peripheral blood mononuclear cells from patients with rheumatoid arthritis
      spontaneously secrete vascular endothelial growth factor (VEGF): specific up
      regulation by tumour necrosis factor-alpha (TNF-alpha) in synovial fluid.
AB  - This study was designed to investigate VEGF production from peripheral blood
      mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA) compared
      with healthy controls and to identify the predominant cellular source in PBMC
      isolated from RA patients. The regulation of PBMC VEGF production by cytokines
      and synovial fluid (SF) was studied. PBMC were isolated from RA patients and
      healthy controls and stimulated with lipopolysaccharide (LPS), IL-1beta, IL-4, IL
      6, IL-8, IL-10, TNF-alpha and transforming growth factor-beta (TGF-beta) isoforms
      for varying time points up to 72 h at 37 degrees C/5% CO2. The effect of SF on
      VEGF secretion by PBMC was also studied. Supernatant VEGF levels were measured
      using a flt-1 receptor capture ELISA. RA patients had significantly higher
      spontaneous production of VEGF compared with controls, and monocytes were
      identified as the predominant cellular source. RA PBMC VEGF production was up
      regulated by TGF-beta isoforms and TNF-alpha and down-regulated by IL-4 and IL
      10, with no effect observed with IL-1beta, IL-6 and IL-8. Antibody blocking
      experiments confirmed that TNF-alpha and not TGF-beta isoforms in SF increased
      VEGF secretion by RA PBMC. These results emphasize the importance of monocytes as
      a source of VEGF in the pathophysiology of RA. Several cytokines known to be
      present in SF can modulate the level of VEGF secretion, but the predominant
      effect of SF in VEGF up-regulation is shown to be dependent on TNF-alpha.

PMID- 10403933
TI  - Presence of circulating abnormal CD34+ progenitors in adult Langerhans cell
      histiocytosis.
AB  - Langerhans cell histiocytosis (LCH) is related to the proliferation of cells,
      which are similar to Langerhans cells (LC) but possess many abnormal
      characteristics. Lesions are widespread and this fact suggests that LCH cells or
      their precursors are present in the blood of patients. In five adult patients, we
      have isolated and cultured CD34+ blood progenitors of dendritic cells. We studied
      their phenotype by flow cytometry and their functional properties in mixed
      culture with heterologous lymphocytes and with autologous lymphocytes in the
      presence of tri-nitro-phenyl antigen (TNP). The amount of CD34+ precursors was
      dramatically higher than controls but a high mortality occurred during the in
      vitro differentiation. The phenotype of surviving cells was similar to LC
      phenotype (CD1a+, CD83+, Lag+) but some of them expressed CD2. These cells were
      able to induce T cell proliferation in mixed culture. They could not initiate
      primary response to TNP, except in a patient treated with thalidomide. In our
      hands, these CD34+ cells may be precursors of LCH cells.

PMID- 10403934
TI  - Heat treatment of normal human sera reveals antibodies to bactericidal
      permeability-inducing protein (BPI).
AB  - Heat treatment of normal sera to 56 degrees C for 30 min, a common procedure for
      the inactivation of viruses, e.g. HIV, reveals the presence of antibodies to
      neutrophil cytoplasm antigens (ANCA), as detected by indirect immunofluorescence
      on ethanol-fixed human neutrophils and by antigen-specific ELISA for BPI.
      Reactivity was not seen to the other common vasculitis-associated antigens
      proteinase 3 (PR3) or myeloperoxidase (MPO). The effect of temperature was
      maximal at 56 degrees C, with substantial antibody demonstrable after only 5 min
      at this temperature. In experiments using polyethylene glycol (PEG)6000 to remove
      immune complexes, the effect of heating could be abrogated by preincubation with
      8% PEG, which suggested that these anti BPI antibodies might be complexed in
      sera. After passage of normal plasma over a protein G column, the acid-eluted
      fraction contained elevated levels of antibodies to BPI but not to other
      vasculitis-associated antigens such as PR3 or MPO, nor to glomerular basement
      membrane (GBM), the Goodpasture antigen which is recognized by the pathogenically
      important human antibodies shown to mediate nephritis in transfer experiments.
      Moreover the levels of anti-BPI in the IgG fraction could be augmented by
      preincubation with glycine pH 2.5 for 30 min. This anti-BPI activity could be
      inhibited by addition of the unbound material from the protein G column and this
      inhibitory material was not heat-labile at 56 degrees C. The molecular
      specificity of this autoreactivity was confirmed using recombinant BPI in
      coincubation experiments and the epitope localized to the C or N terminal
      moieties by the use of recombinant fusion proteins.

PMID- 10403974
TI  - Nursing education for the millennium.

PMID- 10403935
TI  - Anti-idiotype immunomodulation of experimental anti-phospholipid syndrome via
      effect on Th1/Th2 expression.
AB  - Mice with experimental anti-phospholipid syndrome (APS), induced by active
      immunization with a human anti-cardiolipin MoAb (H-3), were treated with mouse
      anti-idiotypic MoAb (anti-H3, named S2.9) and with an irrelevant anti-idiotype.
      The immunized mice produced high titres of mouse anti-cardiolipin antibodies
      along with clinical manifestations of experimental APS: prolonged activated
      partial thromboplastin time (aPTT), thrombocytopenia and high rate of fetal loss.
      Treatment with the specific anti-Id (S2.9) as a whole molecule or F(ab)2
      fraction, resulted in a decrease in serum levels of the anti-cardiolipin
      antibodies, rise in platelet count, shortened aPTT and reduced rate of fetal
      loss. The anti-Id effect was associated with a rise in the number of IL-2 and
      interferon-gamma (IFN-gamma)-secreting cells (Th1) and reduction in IL-4- and IL
      6-secreting cells (Th2). The beneficial effect of the anti-Id treatment in mice
      with experimental APS induced by active immunization with an idiotype further
      supports the idiotypic aetiology of experimental APS and points to the role of
      Th1 cytokines in suppression of its manifestations.

PMID- 10403975
TI  - Evidence for nursing practice: a clarification of the issues.
AB  - There has been considerable confusion and unease within the nursing profession
      about the emphatic push for all healthcare to be 'evidence-based'. In particular,
      there has been anxiety that the emphasis on evidence ignores practitioners'
      skills and individual patient preferences. This paper attempts to clarify the
      main issues surrounding evidence-based nursing. These include its epidemiological
      origins and purpose, the meaning and limits of 'evidence', the need for
      individual skills and expertise in the use of evidence, and the strengths and
      weaknesses of different kinds of evidence. It aims to debunk the misconception
      that randomized controlled trials are synonymous with evidence, and to increase
      critical awareness of the nature of evidence in nursing.

PMID- 10403976
TI  - Evidence-based nursing: a stereotyped view of quantitative and experimental
      research could work against professional autonomy and authority.
AB  - In recent years, there have been calls within the United Kingdom's National
      Health Service (NHS) for evidence-based health care. These resonate with long
      standing calls for nursing to become a research-based profession. Evidence-based
      practice could enable nurses to demonstrate their unique contribution to health
      care outcomes, and support their seeking greater professionalization, in terms of
      enhanced authority and autonomy. Nursing's professionalization project, and,
      within this, various practices comprising the 'new nursing', whilst sometimes not
      delivering all that was hoped of them, have been important in developing certain
      conditions conducive to developing evidence-based practice, notably a critical
      perspective on practice and a reluctance merely to follow physicians' orders.
      However, nursing has often been hesitant in its adoption of quantitative and
      experimental research. This hesitancy, it is argued, has been influenced by the
      propounding by some authors within the new nursing of a stereotyped view of
      quantitative/experimental methods which equates them with a number of
      methodological and philosophical points which are deemed, by at least some of
      these authors, as inimical to, or problematic within, nursing research. It is
      argued that, not only is the logic on which the various stereotyped views are
      based flawed, but further, that the wider influence of these viewpoints on nurses
      could lead to a greater marginalization of nurses in research and evidence-based
      practice initiatives, thus perhaps leading to evidence-based nursing being led by
      other groups. In the longer term, this might result in a form of evidence-based
      nursing emphasizing routinization, thus--ironically--working against strategies
      of professional authority and autonomy embedded in the new nursing. Nursing
      research should instead follow the example of nurse researchers who already
      embrace multiple methods. While the paper describes United Kingdom experiences
      and debates, points raised about the importance of questioning stereotyped views
      of research should have international relevance.

PMID- 10403936
TI  - No association between neutrophil FcgammaRIIa allelic polymorphism and anti
      neutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis.
AB  - ANCA, implicated as having a pathogenic role in systemic vasculitis, can activate
      tumour necrosis factor-alpha (TNF-alpha)-primed neutrophils by cross-linking
      surface-expressed ANCA antigens with neutrophil FcgammaRIIa receptors to release
      reactive oxygen species. The FcgammaRIIa receptor exists as polymorphic variants,
      R131 and H131, which differ in their ability to ligate human IgG2 and IgG3.
      Neutrophils homozygous for the FcgammaRIIa-H131 allotype bind more efficiently to
      IgG3 than the FcgammaRIIa-R131 allotype and are the only human FcgammaR which
      bind IgG2. Our aim was to determine whether the homozygous FcgammaRIIa-H131
      individuals are more susceptible to developing ANCA-associated systemic
      vasculitis and nephritis due to differential IgG binding and activation.
      FcgammaRIIa allotype was determined by both allele-specific polymerase chain
      reaction (PCR) and Southern blotting with allele-specific oligonucleotide probes
      end-labelled with 32P-gammaATP, after PCR amplification of genomic FcgammaRIIa
      DNA in 107 Caucasian patients with ANCA+ vasculitis (of whom 89 had renal
      disease) and 100 ethnically matched controls. Phenotyping of neutrophil
      FcgammaRIIa alleles was confirmed in some patients by quantitative flow cytometry
      using murine MoAbs 41H16 and IV.3. Of the patients with ANCA+ systemic
      vasculitis, 75 had ANCA with specificity for proteinase 3 and 32 with specificity
      for myeloperoxidase. Overall, no skewing in FcgammaRIIa allotypes was seen in
      patients compared with controls. No significant increase of the FcgammaRIIa-H131
      allotype was found amongst patients irrespective of ANCA specificity, and no
      association between the FcgammaRIIa allotype and nephritis was found. Our data
      suggest that the FcgammaRIIa receptor allotype is not a major factor predisposing
      to the development of ANCA+ systemic vasculitis, or to nephritis.

PMID- 10403977
TI  - Quantitative measurement of caring.
AB  - Caring is a difficult, elusive concept not only to define but also to measure.
      Eleven different quantitative instruments designed to measure caring are
      reviewed. Out of these 11 caring instruments, seven are Likert scales, two are
      visual analogue scales, one is a checklist, and one is a Q-sort. For each of
      these instruments the following information is provided: description of the tool,
      such as number of items and length of time to administer; conceptual definition
      of caring upon which it is based; reported reliability and validity; and the
      instrument's use in research studies. Comparison of these instruments revealed
      that different aspects of caring are measured by these tools such as caring
      behaviours, satisfaction with caring behaviours, ability to care, and response to
      caring behaviours. Some caring instruments are designed to be completed by
      patients only, by nurses only, or by either patients or nurses. Multiple factors
      need to be taken into consideration by nurse researchers in deciding which
      instrument to use to measure caring.

PMID- 10403978
TI  - Patients' views on quality of care: do they merely reflect their sense of
      coherence?
AB  - The aim was to explore the relationship between patients' perceptions of the
      quality of care and their sense of coherence. The sample consisted of 782 Swedish
      in-patients at a gynaecological, a medical, an orthopaedic, and a surgical
      department. The median age was 59 years and 55% of the patients were women. Data
      were collected using the Quality from the Patient's Perspective (QPP)
      Questionnaire and the Sense of Coherence Questionnaire. The QPP consists of 61
      items designed to measure the following four quality dimensions: the medical
      technical competence and the degree of identity-orientation in the actions of the
      caregivers, the physical-technical conditions and the socio-cultural atmosphere
      of the care organization. Each question is posed in two different ways in the
      QPP; one measures perceived reality of the item in question and one the
      subjective importance the patient ascribes to it. Results showed that patients'
      ratings of perceived reality covaried systematically with their sense of
      coherence. This was particularly the case on questions rated by experts to be
      more abstract and emotionally loaded. Patients' ratings of the subjective
      importance of the items were weakly related to their sense of coherence. The
      results are discussed in terms of negative affectivity and culturally shared
      ideals regarding quality of care.

PMID- 10403980
TI  - A systematic review of the relationships between written manual nursing care
      planning, record keeping and patient outcomes.
AB  - A systematic review of research literature published in English between 1987 and
      1997 was carried out to test the hypothesis that care planning and/or record
      keeping in nursing practice has no measurable effect on patient outcomes. The
      study was limited to research applicable to acute in-patient care and to non
      information technology based recording. A search strategy was agreed with the
      steering group and search terms refined as the study progressed. Using the
      guidelines from the University of York National Health Service Centre for Reviews
      and Dissemination (NHS Centre for Reviews 1995), a data extraction proforma was
      constructed. An initial search revealed approximately 300 possible abstracts for
      discussion. Further analysis limited this to 43 studies, of which 30 were
      rejected as having too little information. Of the remaining 13 studies, none was
      sufficiently robust to be included in the review. The hypothesis can be neither
      accepted nor rejected. This has important consequences for nursing practice and
      management and for research. A multi-centre rigorous study is recommended.

PMID- 10403979
TI  - Clinical guidelines in nursing, midwifery and the therapies: a systematic review.
AB  - BACKGROUND: While nursing, midwifery and professions allied to medicine (PAMs)
      are increasingly using clinical guidelines to reduce inappropriate variations in
      practice and ensure higher quality care, there have been no rigorous overviews of
      their effectiveness in relation to these professions. We identified 18
      evaluations of guidelines which met established quality for evaluations of
      interventions aimed at changing professional practice. This paper describes
      characteristics of guidelines evaluated and the effectiveness of different
      dissemination and implementation strategies used. METHODS: Guideline evaluations
      conducted since 1975 which used a randomized controlled trial, controlled before
      and-after, or interrupted time-series design, were identified using a combination
      of database and hand searching. FINDINGS: It is mostly impossible to tell whether
      the guidelines evaluated were based on evidence. The most common method of
      guideline dissemination was the distribution of printed educational materials.
      Three studies compared different dissemination and/or implementation strategies:
      findings suggest educational interventions may be of value in the dissemination
      of guidelines and confer a benefit over passive dissemination.

PMID- 10403981
TI  - A conceptual framework for evaluating the nurse practitioner role in acute care
      settings.
AB  - The conceptualization and enactment of the ACNP role varies across settings,
      potentially leading to variability in outcome achievement. A conceptual framework
      for evaluating the ACNP role is proposed. The framework is an adaptation of the
      Nursing Role Effectiveness Model which was developed to facilitate the
      identification and investigation of nursing-sensitive outcomes. The framework
      represents the complex system of interrelated factors that are present in the
      ACNP practice situation and that affect role effectiveness. It includes three
      components: (i) structure--encompassing patient, ACNP and organizational
      variables; (ii) process--consisting of the ACNP role components (clinician,
      educator, researcher and administrator) and the ways in which the role is
      enacted; and (iii) outcomes--including patient- and cost-related outcomes. The
      framework proposes specific relationships among the structure, process and
      outcomes components. Empirical support for the framework propositions is
      provided, based on a review of pertinent literature. Implications for future ACNP
      impact studies are discussed.

PMID- 10403982
TI  - Observations on positivism and pseudoscience in qualitative nursing research.
AB  - In this paper I will examine the boundaries between positivism, interpretivism
      and pseudoscience, arguing that some qualitative researchers may risk the
      credibility of nursing research by utilizing concepts from the margins of
      science. There are two major threats to the perceived rigour and credibility of
      qualitative research in its many forms. First is a trend in some work towards a
      mystical view of both the methods and the content of the qualitative enterprise.
      This can be detected, I will argue, in the work of Rosemary Parse in particular.
      The second potentially damaging trend is almost its epistemological opposite,
      towards excessive reliance on precise procedures, strict definitions and
      verification exemplified by Juliet Corbin and others. I will suggest that this is
      nothing to fear, but something to be clear about. This is not social
      constructionism or interpretivism but a 'qualitative' version of positivism. The
      paper concludes that students and researchers should be cautious in the
      uncritical acceptance of theories and 'research' which approach the boundaries of
      pseudoscience on the one hand, and 'hard' science on the other.

PMID- 10403983
TI  - The theory-practice relationship in nursing: the practitioners' perspective.
AB  - Within contemporary scholarly discourse, there are a number of distinctive
      approaches to understanding the theory-practice relationship. Carr identifies
      four principal approaches, each of which is sustained within explicit views about
      the nature of theory. Carr terms these approaches the 'common-sense' approach,
      the 'applied-science' approach, the 'practical' approach and the 'critical'
      approach. Each approach is recoverable from the explicit and implicit content of
      scholarly literature. The study reported here sought to uncover the ways in which
      practising nurses understand the relationship between theory and practice and to
      establish the extent to which their explicit and implicit understandings accord
      with Carr's typology. The study involved in-depth interviews with six practising
      nurses. The purpose of the interviews was to prompt each study participant to
      enter into a reflective mode in a way that would generate narrative information,
      which would illustrate the various ways in which each theorized with respect to
      the theory-practice relationship. In this reflective theorizing, the study
      participants indicated that they understood the theory-practice relationship in
      ways that accorded with elements of Carr's typology. A brief discussion considers
      the limitations of the study and the implications for further research into the
      theory-practice relationship.

PMID- 10403984
TI  - On the phenomenology of empathy in nursing: empathy or sympathy?
AB  - In her recent phenomenological study Baillie attempted to describe the essential
      structure of empathy in surgical nursing. The study is important in that it
      utilizes a qualitative research method to investigate the phenomena of empathy,
      in contrast to previous quantitative studies. Although the phenomenological
      approach is clearly identified and ascribed to Husserl as the founder of the
      phenomenological movement, as well as utilizing the peculiarly Husserlian notion
      of bracketing, or epoche, in an attempt to describe the essence (another
      Husserlian objective) of the phenomenon under investigation (empathy), the
      research method does not reflect Husserl's philosophy. The results reflect
      nurses' subjective views on empathy, an exercise consistent with the nurse
      phenomenologists quoted, who without exception, all believe Husserlian
      phenomenology concerns itself with subjective experience. However, in seeking the
      essence of phenomena unclouded by subjective opinion, Husserl stands in contrast
      to nursing interpretations of phenomenology's famous catch phrase, 'back to the
      things themselves' (zu den Sachen selbst). Nurse-phenomenologists have
      misunderstood the intention of Husserlian phenomenology, and despite their
      opposition to traditional scientific methods, are still mired in the Kantian
      notion of science as a reality independent of mind. A theme consistent with the
      'things-in-themselves', not the things themselves. As such, nursing's use of the
      phenomenological method is questionable, and therefore the research findings on
      the phenomenon of empathy need to be reformulated. Interestingly, the phenomenon
      of empathy challenges us to question such underlying assumptions on how we view
      the world.

PMID- 10403985
TI  - The moral metaphors of nursing.
AB  - The essence of metaphor is understanding and experiencing one thing in terms of
      another. Metaphorical concepts structure and reflect what we perceive, how we
      act, and how we relate to other people. In nursing ethics, several metaphors have
      emerged which have had a great impact on nursing practice. These metaphors
      include the military metaphor which exemplified nursing during the 1800s, the
      advocacy and academic metaphors which became a philosophical basis for nursing
      during the 1960s, and the individualist and community as caring metaphors which
      have emerged more recently. Although beneficial in some ways, these metaphors may
      be obscuring the complex moral reality of nursing practice. This article defines
      a moral metaphor, critiques nursing's moral metaphors, and provides an historical
      overview of their development with examples of how they have and do affect
      nursing practice.

PMID- 10403986
TI  - Still attractive after all these years? Magnet hospitals in a changing health
      care environment.
AB  - This paper examines the research base for 'magnet hospitals'--hospitals that have
      a good reputation for recruitment and retention of registered nurses. It also
      assesses the extent to which the concept of the magnet hospital continues to have
      relevance to nursing in the United Kingdom (UK). The study reviews previous
      research, examines recent trends in nursing employment, and reports on case
      studies conducted as fieldwork research. The early research on magnet hospitals,
      conducted in the 1980s in the United States of America (USA), is reassessed in
      the light of subsequent cost containment driven changes in the USA nursing labour
      market and in the organization of USA hospitals. Many of these changes have
      impacted on nursing staff, with increases in workload, and with changes in skill
      mix, particularly as a result of increased use of care assistants. Similar
      developments have been happening in the UK. The paper examines the extent to
      which the concept of the magnet hospital can retain validity in this changing
      health care environment. Case studies in 14 USA magnet hospitals were conducted
      in 1997. The results highlight that, as a result of hospital reorganization and
      merger, some of these hospitals no longer exhibit core characteristics of
      'magnetism', whilst others have retained these characteristics despite
      organizational change. The paper concludes by cautioning that the concept of the
      magnet hospital continues to have a relevance to the management of nursing
      resources, but that the research base, with some notable exceptions, continues to
      be weak and that there is a need for monitoring and a process of re-
      accreditation to maintain a 'live' register of magnet hospitals.

PMID- 10403987
TI  - The global distribution of physicians and nurses.
AB  - AIM: To explore the global distribution of physicians and nurses and the
      influence of gross national product per capita on this distribution, using
      available United Nations' (UN) sources. OBJECTIVES: to compare the international
      distribution of physicians and nurses by country; to examine the influence of
      gross national product per capita (GNP) on the global distribution of physicians
      and nurses; to explore the assumptions underlying the recommendations of The
      World Development Report 1993 Investing in Health for health workforce
      substitution; and to consider the implications for future studies of global
      health labour distribution. DESIGN: A database was compiled from various UN
      sources on 147 countries. Using some of the variables from this database, a
      general linear regression model for log GNP per capita on each of the two
      dependent variables (log nurses and log physicians per 1000 population) was
      produced. Standardized residuals obtained from these bivariate regressions were
      calculated and plotted against each other to determine the relationship between
      the global distribution of physicians to population and that of nurses. From this
      analysis outlying countries could also be identified. RESULTS: Ratios of
      physicians to population by country varied from 0. 02 to 4.4 per 1000 population
      (or from 1 to 227 and 1-50,000 population), and nurses from 0.03 to 16.4 (or from
      1 to 61 and 1-33, 000 population). There was a positive correlation (r = 0.84, P
      < 0. 001) between the number of physicians per 1000 population and the number of
      nurses per 1000 population. GNP explained 49% of the variation in physicians and
      40% in nurses. Ranking of countries according to their standardized deviation
      from mean regression lines for GNP against health personnel in countries with
      both the lowest incomes and lowest numbers of health personnel, resulted in
      little change from the original rankings of ratios of physicians and nurses
      relative to population. For some of the wealthiest countries, there was a marked
      fall in global ranking and for some middle income countries a marked improvement
      in ranking. CONCLUSION: 70% of the distribution of nurses globally can be
      explained by the distribution of physicians, and the influence of GNP per capita
      on the global distribution of physicians and nurses appears to be substantial. In
      only a minority of the world's very poorest countries is there evidence to
      suggest that higher numbers of nurses substitute for low numbers of physicians.
      Standardization of the distributions by GNP demonstrates that many countries (but
      not the poorest) regress to within one standard deviation of the mean expected
      distribution. This suggests that countries could set optimum levels of physicians
      and nurses within the limits of their GNP. More realistically, the findings
      suggest that recommendations for modification of the structure of countries'
      health labour forces as a component of health care reform may be more difficult
      to achieve than at first appears. The potential unreliability of the data sources
      used, and the implications for the accuracy of the findings, are discussed.

PMID- 10403988
TI  - The contingent nature of advanced nursing practice.
AB  - This paper examines the issues faced by advanced nurse practitioners in the
      United Kingdom as they attempt to implement a new role in practice. The
      discussion draws on evidence gathered during a longitudinal study of a small
      number of graduates from a Master's degree programme who subsequently took up
      posts as advanced nurse practitioners. The paper focuses on one of the key
      findings to emerge from the inquiry, that of the identification of the contingent
      nature of advanced nursing practice. The data for the study were collected over a
      2-year period via interviews, observation of clinical practice and self-report
      role development diaries. Following analysis it was revealed that, whilst the
      passage from experienced nurse to advanced nurse practitioner can be considered
      to be highly individual and complex, practitioners appear to move through three
      discrete stages during the transitional process. The first of the three stages is
      represented by a state of 'idealism' on the part of advanced practitioners.
      During the second phase, termed 'organizational governance', practitioners
      discover that, in contrast to their initial optimism, the orientation, goal and
      delivery of their role is controlled by key stakeholders within the organization.
      The final stage, 'resolution', is only reached when practitioners have been in
      post for more than 1 year and can be summarized as a state of acquiescence and
      compromise. A conceptual model is presented which illustrates the contingent
      nature of advanced nursing practice.

PMID- 10403989
TI  - Incompatible skills and ideologies: the impediment of gender attributions on
      nursing research.
AB  - The evidence-based care culture requires that ritualistic treatment interventions
      are subjected to scientific scrutiny, with the ultimate intention that clinical
      practice should have empirical rather than historical justification. Despite
      initiatives to increase research output, there is evidence for a continued
      research/practice rift. One explanation for this that has relevance for the
      present paper is the perceived conflict between the skills and ideologies
      associated with clinical nursing and research. More specifically, it would seem
      that the characteristics demanded by high quality nursing are diametrically
      opposed to those required by research, such that research activities may be
      perceived to be inappropriate within the traditional nursing role. Formal gender
      role schemata may also contribute to the theory-practice gap, insofar as nursing
      embodies qualities that are essentially female-associated, while research
      requires attributes associated with masculinity. These conceptualizations are
      derived from two studies based on central trait theory, which involved
      participants in making assumptions about a range of qualities of hypothetical
      candidates for a nursing post, who were described either as a good researcher or
      a good clinician. The hypothetical candidates in the first study were female, but
      in the second were male; in both cases the participant raters were female. It is,
      however, conceivable that rater-gender impacts upon assumptions of personal and
      professional attributes of clinical and research nurses. In order to investigate
      this contention, the present paper manipulated the gender of the raters, whilst
      replicating the previous studies in every other way. Analysis of the data using a
      series of 3-way ANOVAS suggested that there were some significant effects of
      rater and candidate gender, as well as of clinical/research descriptors,
      especially in terms of ascribed kindness, compassion, ambition and success. The
      results are discussed in relation to gender role stereotypes and nursing
      research.

PMID- 10403990
TI  - Passivity vs. militancy: a Q methodological study of nurses' industrial relations
      on Merseyside (England).
AB  - This paper describes a Q methodological study of accounts of nurses' industrial
      relations expressed by a sample of nurses (n = 60) drawn from the geographical
      area of Merseyside, United Kingdom (UK). The participants completed a 65-item Q
      sort made up of statements which could be ranked in terms of their relevance to
      an understanding of their industrial relations situation. Of interest was the
      importance of the narrative accounts which nurses draw upon in making sense of
      their employment relations, having the potential to underpin or delimit their
      actions. The notion of industrial action was an important focus of this research.
      Q methodology was chosen to allow the meaningful investigation of such
      subjectivity, with interesting tensions between differing notions of
      professionalism and militancy apparent from the analysis. Six accounts of
      industrial relations, which are available to be drawn on by nurses, are described
      and interpreted within a social constructionist framework. Some implications for
      the conduct of nurses' industrial relations in the UK are contemplated.

PMID- 10403991
TI  - The changing nature of nurses' job satisfaction: an exploration of sources of
      satisfaction in the 1990s.
AB  - This paper focuses on the changing nature of nurses' job satisfaction. It
      compares the major sources of satisfaction and dissatisfaction experienced by
      acute ward nurses in the English National Health Service (NHS) in the early
      1990s, with sources identified in previous research. In the light of findings
      from a pilot study, the suitability of existing research approaches and
      measurement tools for portraying nurses' contemporary work experiences is
      examined. The study comprised content analysis of a random sample of 130 nurses'
      comments about ward organizational issues, collected as part of a national
      survey. Findings suggest that new measurement tools need to be developed, because
      new sources of satisfaction and dissatisfaction emerged, directly associated with
      change arising out of the introduction of the NHS internal market. These include
      pressures associated with new roles, role conflict, lack of job security, 'tight'
      resources, using new technology, a perceived lowering of standards of patient
      care, coping with increased amounts of paperwork, and the experience of working
      in a rapidly and constantly changing environment. Findings also suggest that the
      nature of nurses' job satisfaction is increasingly being shaped by their position
      within the organization, denoted by clinical grade, and the organizational
      culture of individual NHS Trusts. Ward leaders experience dissatisfaction as a
      result of role conflict and strain, while nurses of lower clinical grades are
      increasingly concerned with managerial and resource constraints on their ability
      to provide good quality care. Nurses' satisfaction with management and morale
      were found to be significantly different between NHS Trusts. While findings may
      be specific to England, it is argued that they have relevance for the wider,
      international nursing community. This is because developing an understanding of
      the changing nature of nurses' job satisfaction may help to resolve recruitment
      and retention problems.

PMID- 10403992
TI  - 'Levels' of attainment in nursing practice: reality or illusion?
AB  - In earlier research based on an analysis of course documentation, it had been
      found that there was little consensus among nurse educators concerning the
      parameters which distinguish levels of practice skills, particularly those which
      differentiate diploma and degree qualifications in the United Kingdom. This
      result was confirmed and strengthened in the current study. Lecturers in nursing,
      when presented with a sorting task using 40 statements derived from course
      documentation selected from the earlier study, were unable to distinguish
      statements describing diploma level from those describing degree level practice.
      Possible reasons for the difficulty are discussed. It is concluded that the
      attempt to represent practice skill in a hierarchy of assessment for degree or
      diploma qualifications is premature since the parameters of practice remain
      unreliably specified.

PMID- 10403993
TI  - The cost and value of pre-registration clinical placements for Project 2000
      students.
AB  - The research outlined in this article was commissioned by the Sheffield and North
      Trent College of Nursing and Midwifery to explore the cost implications of pre
      registration clinical placements in the context of Project 2000. The authors
      outline the methodology and findings of an exercise designed to collect relevant
      cost information which was not readily available. On the basis of these findings,
      they suggest that: at 1995/1996 pay and prices, clinical placements cost the
      education provider approximately pound 890 per student per annum; in terms of
      real resources, the value to service providers of the service contribution made
      by second- and third-year nursing and midwifery students on ward-based placements
      outweighs the value of the time spent by qualified staff on their supervision and
      education. Once the funding assumptions underlying the introduction of Project
      2000 have been taken into account, second- and third-year nursing and midwifery
      students benefit the service provider by on average pound 3.46 for every hour
      they spend in an unrostered ward-based placement. The service contribution made
      by students in community-based clinical placements cannot free staff time in the
      same way as on the wards and, because qualified staff in these areas are
      generally more highly graded, the value of the time they spend on the supervision
      and education of students on placement is higher than in ward-based placements.
      Second- and third-year students therefore appear to cost the service provider on
      average pound 0.48 for each hour they spend in a community-based placement. It
      was not possible to determine whether this cost translates into a reduction in
      patient contacts.

PMID- 10403994
TI  - The clinical role of the nurse teacher: a conceptual framework.
AB  - A small scale qualitative study explored the clinical role of the nurse teacher
      and concluded by proposing a conceptual framework that seeks to illustrate how
      nurse teachers manage the clinical aspect of their work. Three conceptual
      categories (role clarity, fitting in and role justification) are proposed as a
      means of describing how the respondents approached their clinical role.

PMID- 10403995
TI  - Nursing and the research assessment exercise: past, present and future.
AB  - In this paper we examine approaches to undertaking nursing research and building
      research capacity in higher education institutions in the United Kingdom (UK).
      First we review some of the main responses in the literature to the last two
      Research Assessment Exercises (RAE), then we report findings from a small study
      of nursing departments which entered the last RAE and finally we speculate on the
      likely future of nursing research in the light of recent education and health
      policy. We suggest that many of the difficulties experienced are an effect of
      contradictory health and education policies and rival ways of assessing research
      performance. Nursing education is caught in the 'pincer movement' of stringency
      in both sectors. In addition, the challenges of the RAE and the necessity to earn
      income from contracting with National Health Service (NHS) education and training
      consortia for teaching represent an outworking of two rival views of the role of
      higher education, broadly an elitist view and one that sees higher education as a
      supplier of the workforce needs of industry. In addition to this, the NHS R&D
      (research and development) strategy provides an alternative arena for
      collaboration, funding and reputation to that constructed by the RAE.

PMID- 10403996
TI  - Determinants of parental decisions on 'drop out' from cancer treatment for
      childhood cancer patients.
AB  - Little is known about the psychosocial process of parental decisions on 'drop
      out' from cancer treatment for paediatric patients in Taiwan. This study, based
      on structured in-depth interviews, attempted to document the determinants of
      parental decisions on drop out. A total of 19 parents of paediatric cancer
      patients who dropped out from a cancer treatment for at least a month within 3
      years since first treatment were interviewed. Content analysis of qualitative
      data revealed six categories of determinants associated with parental decisions:
      suffering severe pain from medical treatments and adverse side-effects; desire
      for better and less painful treatments; adverse effect of other patients'
      experiences; searching for possible explanations for disease after prolonged
      denial of diagnosis; lack of empathy from health care professionals; and
      misinterpretation of improved prognostics. These findings reflected the
      deficiency of psychological and emotional support for parents from health care
      professionals prior to and during cancer treatment.

PMID- 10403998
TI  - The quality of mothers' solutions to child-rearing problems: what difference does
      setting internal or external to the family make?
AB  - In this study we examined the difference the setting of a child-rearing problem,
      either internal or external to the family, made for mothers' generation of
      solutions likely to assist a child's development of problem-solving competencies.
      In addition, the direct effect of a mother's personal resources (age, education,
      number of children parented, and verbal ability) and the direct and mediating
      effect of the extent to which a mother took the child's perspective on her
      generation of assistive solutions were explored. Adult mothers (n = 128) of
      children ranging in age from 1 month to 18 years were interviewed by telephone
      concerning eight hypothetical child-rearing problems. Mothers generated a greater
      proportion of assistive solutions and took the child's perspective more often for
      external problems than for internal problems. For internal problems, a mother's
      verbal ability made a significant contribution to the proportion of assistive
      solutions generated. For external problems, number of children made a significant
      negative contribution. For external problems, perspective taking had a mediating
      effect on the relationship of number of children with the proportion of assistive
      solutions generated. The nature of a mother's perspective taking and the function
      that it has in solution generation for child-rearing problems merit exploration.

PMID- 10403997
TI  - Early parental interactions with and perceptions of multiple birth infants.
AB  - The perceptions and interactions of mothers and fathers of seven sets of twins
      and one set of triplets were compared to those of parents of 49 singleton
      infants. Couples were typically interviewed together three times during the
      pregnancy and at 1 week and 3 months post-partum. Two-weekly observations of
      mother-father-infant interactions were conducted after the first postnatal
      interview. Three major themes were apparent in the interviews--the positive and
      negative specialness for multiple births, difficulties involved in managing more
      than one infant, and attachment issues--that were also evident during the
      observations. Although there were few differences in care-giving and interactive
      behaviours between the multiple birth and singleton parents, the logistics of
      caring for more than one infant dictated that multiple birth infants were left
      alone more and looked at, talked to and held less often. Couples used different
      strategies to care for their infants, varying in both the extent to which they
      interacted preferentially with the infants and in the relative involvement of the
      mother, father and others.

PMID- 10403999
TI  - The role of the child primary mental health worker.
AB  - The purpose of the study was to explore how the child primary mental health
      worker role, as defined in the Health Advisory Service document, has been
      interpreted in each of the mental health trusts in England. Studies have
      indicated there is a deficit in recognition and treatment skills, by primary care
      workers, of psychological difficulties presented by children and young people,
      which could be supported by specialist mental health workers. A postal
      questionnaire was sent to 169 English mental health trusts. There were 98 returns
      (59%) indicating that 22 child mental health services had established this new
      role and a further 42 were planning to develop it in the near future. The child
      primary mental health workers were spending on average 35% of their time in
      primary care offering consultation and training to health professionals, rather
      than direct work with children and families. This development was found to be a
      growing area of advanced practice for nurses. Given the stated intention of the
      majority of services to develop or retain this role, further evaluation studies
      will be needed.

PMID- 10404000
TI  - The integration of comprehensive psychiatric/mental health care into the primary
      health system: diagnosis and treatment.
AB  - This research study was funded by the Health Systems Trust in Cape Town through
      the University of Natal in Durban. OBJECTIVES. The objectives of this study were
      to teach primary health care nurses to diagnose and treat common psychiatric
      conditions, to refer those patients whom they cannot handle, and to evaluate the
      implementation of these functions in their primary health care practice. METHODS.
      Twenty nurses from six clinics in one province of South Africa were trained, and
      implementation was studied. History taking, diagnosis, pharmacological treatment
      and referral were studied through record reviews. Record reviews were done by two
      independent psychiatrists, who achieved an inter-rater reliability of 0.68.
      RESULTS. Record reviews showed that at the end of the project nurses could take
      substantially complete psychiatric histories in 89% cases, five axis diagnoses
      were correct in 63% of cases, and when STAT medication was prescribed it was
      appropriate in 92% of cases. Appropriate long-term medication was prescribed in
      60% of cases. ETHICAL ISSUES. Permission was obtained from the provincial office,
      the Municipal Offices and participating clinics. Informed consent was obtained by
      the registered nurses from all participating clients. LIMITATIONS. The sample for
      the clinics was not representative of all clinics in the Eastern Cape but a
      representation of rural-urban settings sampled from 20 clinics in a region. The
      sample of consumers was convenient and may not represent the client population in
      each clinic. For this reason the findings may not be a true reflection of the
      entire region, and generalization of the findings should be made at the utmost
      discretion of the reader.

PMID- 10404001
TI  - Investigating and implementing change within the primary health care nursing
      team.
AB  - Primary care is developing rapidly with significant impacts on the nursing team.
      Such changes have brought inter-professional team-working into sharper focus,
      particularly community care and collaborative working. This paper: examines the
      nursing roles within a general practice; describes the perspectives of service
      users; identifies areas of change; clarifies core and specialist skills; defines
      new roles among the primary health care nursing team; proposes a new model of
      working; and identifies appropriate education. The project was set in a general
      practice in south-west England and used an action research methodology. The
      objectives were to create a change in practice and to develop and refine existing
      theory to underpin nursing roles. Throughout the research regular team meetings
      allowed reflection and discussion about research findings and progress. Data were
      collected from multiple sources, including team workshops, patient focus group
      interviews, and individual interviews with GPs, practice managers and area
      managers. Reflective diaries and a patient survey were also used. The analysis of
      the quantitative and qualitative data collected from patients formed a basis for
      practice development and facilitated the team's reflection on the areas of
      change. Overall high satisfaction with services and care was expressed in the
      patient interviews and the questionnaire. The themes from the data highlighted
      areas important for patients and helped in shaping the new roles and
      responsibilities for team members. Regarding the team perspective, the data
      indicated many areas that could be considered for development. The community
      nursing team decided to concentrate on three key areas: child health, leg ulcer
      management, and cardiovascular health. The research concludes that action
      research presents some problems and challenges but is a useful approach to
      developing team-working in primary health care.

PMID- 10404002
TI  - Power, self-care and health in women living in urban squatter settlements in
      Karachi, Pakistan: a test of Orem's theory.
AB  - This was a study of health in women living in urban squatter settlements in
      Karachi, Pakistan. The study grew out of the author's concern for the generally
      poor health status of Pakistani women. Orem's nursing theory was selected to
      examine health in these women. The purpose of the study was to examine
      relationships among basic conditioning factors, self-care agency (specifically,
      perception of power as a foundational capability of self-care agency and the
      enabling capabilities of self-care agency), self-care, and selected health
      outcomes of Pakistani women. Four hypotheses were developed and tested. They were
      that in a group of Pakistani women: (1) perception of power as a foundational
      capability and enabling capabilities of self-care agency and self-care will be
      related to selected basic conditioning factors; (2) perception of power, as a
      foundational capability of self-care agency, will be directly and positively
      related to enabling capabilities of self-care agency; (3) perception of power as
      a foundational capability and enabling capabilities of self-care agency will have
      a direct and positive relationship with self-care; and (4) self-care will be
      related to selected health outcomes. Hypotheses one, two and three were
      supported. Findings indicate that the basic conditioning factors, socioeconomic
      variables, ethnicity and roles, were predictive of perception of power, enabling
      capabilities of self-care agency, self-care and health. Hypothesis four was not
      supported; basic conditioning factors had more influence on health than self
      care.

PMID- 10404003
TI  - An evaluation of the nurse practitioner role in a major rural emergency
      department.
AB  - The purpose of this pilot study was to investigate whether nurse practitioners
      are able to provide a level of primary health service applicable to
      remote/isolated settings in wound management and treatment of blunt limb trauma.
      It was hypothesized that there would be no significant difference in the quality
      of care, or the level of client satisfaction, provided by the medical officers
      and the nurse practitioners in the study. Two groups participated in the study,
      nurse practitioners and medical officers. The study used a randomized trial
      design. Data were collected using quantitative and qualitative methods. Two
      hundred and thirty-two clients participated in the study. Of this number 63 were
      supervised cases in the pilot trial. In the randomized trial participants were
      distributed between nurse practitioners and medical officers (n = 169), of which
      91 were randomized to medical officers and 78 to nurse practitioners. Telephone
      interviews were conducted to evaluate client satisfaction. The majority of study
      participants were surveyed for client satisfaction (n = 132). This represents
      approximately 78% of the randomized sample and multivariate analysis was carried
      out on the data. Study results indicate that there were no significant
      differences between the two groups in relation to client satisfaction. Very
      positive outcomes of treatment were consistent across groups in the study. The
      study also found that there was strong support for the role of the nurse
      practitioner in the rural emergency setting. Recommendations include further
      research to measure the efficacy of nurse practitioners utilizing the selected
      competencies in remote/isolated settings.

PMID- 10404004
TI  - Future Direction for Nursing in Scotland. Royal College of Nursing Scotland
      annual conference, held at Stakis Grosvenor Hotel, Edinburgh, Scotland, 26-27
      February 1999.

PMID- 10404005
TI  - New developments in the pathogenesis and treatment of steroid-induced
      osteoporosis.

PMID- 10404006
TI  - Targeted expression of calcitonin gene-related peptide to osteoblasts increases
      bone density in mice.
AB  - The neuropeptide calcitonin gene-related peptide (CGRP) is concentrated in fine
      sensory nerve endings innervating all tissues, including bone. CGRP inhibits
      osteoclasts, stimulates insulin-like growth factor I and inhibits tumor necrosis
      factor alpha production by osteoblasts in vitro. To investigate the role of CGRP
      in bone in vivo, mice were engineered to express CGRP in osteoblasts by placing
      the human CGRP gene under the control of the rat osteocalcin promoter (Ost-CGRP
      tg+ mice). Calvaria cultures from transgene positive (tg+), but not tg- mice,
      produced bioactive CGRP. Trabecular bone density and bone volume, determined by
      peripheral quantitative computed tomography and bone histomorphometry,
      respectively, were higher in tg+ than tg- littermates. This increase in bone
      volume was associated with an increased bone formation rate. Trabecular bone
      density decreased in tg+ mice as a result of ovariectomy, but remained higher
      than in sham tg- mice. Targeting CGRP to osteoblasts appears to favor the
      establishment of a higher trabecular bone mass in mice.

PMID- 10404008
TI  - Mechanical tension-stress induces expression of bone morphogenetic protein (BMP)
      2 and BMP-4, but not BMP-6, BMP-7, and GDF-5 mRNA, during distraction
      osteogenesis.
AB  - Bone lengthening with osteotomy and gradual distraction was achieved in 57 rats,
      and the effect of mechanical tension-stress on gene expression of bone
      morphogenetic proteins (BMPs) was investigated by in situ hybridization and
      Northern blot analysis using probes of BMP-2, BMP-4, BMP-6, BMP-7, and
      growth/differentiation factor (GDF)-5. There was a lag phase for 7 days after
      femoral osteotomy until gradual distraction was carried out for 21 days at a rate
      of 0. 25 mm/12 h using a small external fixator. The signals of the above BMPs
      mRNA were not detected in the intact rat bone but they were induced after
      osteotomy except those for BMP-7. By 4 days after osteotomy, BMP-2 and BMP-4
      mRNAs were detected in chondrogenic precursor cells in the subperiosteal immature
      callus. BMP-6 and GDF-5 mRNA were detected in more differentiated cells in
      chondroid bone. By 7 days after osteotomy, cartilaginous external callus and bony
      endosteal callus were formed. Meanwhile, the signals of BMP-2 and BMP-4 mRNAs
      declined to preoperative levels, whereas the signals of BMP-6 and GDF-5 mRNAs
      were rather elevated. As distraction was started, the callus elongated and
      eventually separated into proximal and distal segments forming a fibrous
      interzone in the middle. Expression of BMP-2 and BMP-4 mRNAs was markedly induced
      at this stage. Their signals were detected widely among chondrogenic and
      osteogenic cells and their precursor cells sustaining mechanical tension-stress
      at the fibrous interzone. BMP-6 and GDF-5 mRNAs were detected exclusively in
      chondrogenic cells at both ends of the fibrous interzone, where endochondral
      ossification occurred. But neither mRNA was detected in terminally differentiated
      hypertrophic chondrocytes. As distraction advanced, the cartilage was
      progressively resorbed from both ends and new bone was formed directly by
      intramembranous ossification. There was no new cartilage formation in the
      advanced stage of distraction. The signals of BMP-6 and GDF-5 mRNA declined by
      this stage, while those of BMP-2 and BMP-4 were maintained at high level for as
      long as distraction was continued. After completion of distraction, the fibrous
      interzone fused and the lengthened segment was consolidated. BMP-2, BMP-4, BMP-6,
      nor GDF-5 was expressed at this stage. The signals of BMP-7 were not detected
      throughout the experiment. The present results suggest that excellent and
      uninterrupted bone formation during distraction osteogenesis owes to enhanced
      expression of BMP-2 and BMP-4 genes by mechanical tension-stress. Abundant gene
      products of BMP-2 and BMP-4 could induce in situ bone formation by paracrine and
      autocrine mechanisms.

PMID- 10404009
TI  - A novel T cell cytokine stimulates interleukin-6 in human osteoblastic cells.
AB  - Rheumatoid arthritis (RA) is an autoimmune disease characterized by a heavy
      lymphocytic infiltration into the synovial cavity, resulting in the secretion of
      a variety of cytokines which ultimately leads to destruction of joint tissue.
      Among the infiltrating cells are activated T cells which produce specific
      cytokines capable of osteoclast progenitor cell expansion, fusion, and
      activation. Cultures of activated human T cells and human osteoblasts (hOBs) were
      used to study the possibility that lymphokines may act on osteoblasts to produce
      the osteoclastogenic factor interleukin-6 (IL-6). Purified T cells were activated
      with a combination of anti-CD3 and anti-CD28 antibodies, cocultured with hOBs in
      direct physical contact or separated by a transwell system, and conditioned media
      (CM) were assayed for IL-6 production. After a 72 h incubation period, activated
      T cell-hOB interaction resulted in a 100-fold increase of IL-6 production over
      basal levels. The immunosuppressant cyclosporine A (CsA) inhibited T cell tumor
      necrosis factor alpha and IL-6 production but did not inhibit the T cell
      induction of IL-6 from hOB. Assay of activated T-cell CM on hOB revealed that a
      soluble factor, not cell-cell contact, was the major inducer of IL-6. The
      induction of IL-6 mRNA by both activated T cell CM and CsA-treated activated T
      cell CM was confirmed by Northern blot analysis. Neutralizing antibodies to IL-13
      and IL-17 did not affect IL-6 production. These findings suggest that activated T
      cells produce a novel, potent, IL-6 inducing factor that may be responsible for
      the bone loss observed in RA patients.

PMID- 10404007
TI  - Collagen integrin receptors regulate early osteoblast differentiation induced by
      BMP-2.
AB  - Studies in several cell types indicate that the actions of integrin receptors for
      extracellular matrix and receptors for growth factors are synergistic in
      regulating cellular differentiation and function. We studied the roles of the
      alpha1beta1 and alpha2beta1 integrin collagen receptors in regulating the
      differentiation of 2T3 osteoblastic cells in response to bone morphogenetic
      protein (BMP)-2. The immortalized 2T3 cell line was established from the calvaria
      of mice transgenic for a BMP-2 promoter driving SV40 T-antigen. These cells
      require exogenous BMP-2, as well as ascorbic acid and beta-glycerolphosphate, for
      expression of a mature osteoblast phenotype and formation of a mineralized
      matrix. To determine how integrin receptors for collagen-I affect BMP-2
      signaling, function-perturbing anti-rat alpha1 and/or alpha2 integrin subunit, or
      anti-type I collagen (Col-I), antibodies were added to human recombinant (hr)BMP
      2-treated 2T3 cultures at confluence (C0) or at 4 or 8 days postconfluence (C4,
      C8). After 4 days of exposure to the antibodies, cultures were assayed for
      alkaline phosphatase (ALP) mRNA levels and enzyme activity and for cAMP
      production in response to parathyroid hormone. Addition of anti-collagen-I or
      both anti-integrin-alpha1 and -alpha2 antibodies to C0 cultures blocked
      expression of these early osteoblast markers by more than 90%, and also blocked
      mineralization (0.5-1.8% control) of these cells. In all cases, adding anti
      alpha1 or anti-alpha2 antibodies separately produced partial effects, while their
      combined effect approached that of anti-collagen-I. When antibodies were added to
      more differentiated 2T3 cells, the inhibitory effects decreased. 2T3 cells
      carrying constitutively active BMP receptor (caBMPR-IB) showed elevated ALP
      activity without hrBMP-2; this constitutive activity was also suppressed by
      alpha1 and alpha2 integrin antibodies and by anti-Col-I antibody. Together, our
      data suggest that a signal(s) from collagen integrin receptors regulates the
      response to BMP downstream of BMPR-IB and upstream of the regulation of ALP mRNA
      and other early markers of osteoblast differentiation.

PMID- 10404010
TI  - Glucocorticoids decrease interleukin-6 levels and induce mineralization of
      cultured osteogenic cells from children with fibrous dysplasia.
AB  - Fibrous dysplasia (FD) is a progressive bone disease in which abnormal fibroblast
      proliferation results in the replacement of normal cancellous bone with an
      immature fibrous tissue that is poorly mineralized. The disease manifests itself
      in the monostotic form in which only one bone is involved and the polyostotic
      form in which multiple bones at different sites are affected. The McCune-Albright
      syndrome is a variation of the polyostotic form in which patients demonstrate a
      greater extent of bone involvement and a variety of endocrinopathies. Somatic
      activating mutations in the GNAS gene have been demonstrated in the fibrotic
      lesions of patients affected with either monostotic or polyostotic FD. The
      increased cAMP levels caused by the G-protein mutations lead to increased
      interleukin-6 (IL-6) levels in the affected tissues, resulting in abnormal
      osteoblast differentiation and increased osteoclastic activity. Utilizing cell
      culture techniques that have been developed for mammalian bone marrow stromal
      cells, we have successfully cultured osteogenic stem cells from the affected
      stroma of 11 FD patients. Cells cultured from patients with polyostotic FD showed
      a high frequency of the Gsalpha mutation, whereas cells from monostotic FD
      patients showed a low frequency of the mutation. Both the normal and FD cells
      displayed the osteogenic phenotype when exposed to medium containing
      glucocorticoids. Glucocorticoids also caused a dramatic inhibition of IL-6 mRNA
      and protein levels in osteogenic cells cultured from the FD patients. These
      findings suggest that chemical alteration of cellular function may lead to new
      treatment options for patients with FD.

PMID- 10404011
TI  - Age-related osteogenic potential of mesenchymal stromal stem cells from human
      vertebral bone marrow.
AB  - Mesenchymal stem cells (MSCs) residing in bone marrow (BM) are the progenitors
      for osteoblasts and for several other cell types. In humans, the age-related
      decrease in bone mass could reflect decreased osteoblasts secondary to an age
      related loss of osteoprogenitors. To test this hypothesis, BM cells were isolated
      from vertebral bodies of thoracic and lumbar spine (T1-L5) from 41 donors (16
      women and 25 men) of various ages (3-70 years old) after death from traumatic
      injury. Primary cultures were grown in alpha modified essential medium with fetal
      bovine serum for 13 days until adherent cells formed colonies (CFU-Fs). Colonies
      that stained positive for alkaline phosphatase activity (CFU-F/ALP+) were
      considered to have osteogenic potential. BM nucleated cells were plated (0.5, 1,
      2.5, 5, or 10 x 106 cells/10-cm dish) and grown in dexamethasone (Dex), which
      promotes osteoblastic differentiation. The optimal plating efficiency using BM
      derived cells from donors of various ages was 5 x 106 cells/10-cm dish. BM
      derived cells were also grown in the absence of Dex at this plating density. At
      the optimal plating density, in the presence of Dex, the number of CFU-F/ALP+
      present in the BM of the younger donors (3-36 years old) was 66.2 +/- 9.6 per 106
      cells (mean +/- SEM), but only 14.7 +/- 2.6 per 106 cells in the older donors (41
      70 years old). With longer-term culture (4-5 weeks) of these BM cells in medium
      containing 10 mM beta-glycerophosphate and 100 microg/ml ascorbic acid, the
      extracellular matrix mineralized, a result consistent with mature osteoblastic
      function. These results demonstrate that the number of MSCs with osteogenic
      potential (CFU-F/ALP+) decreases early during aging in humans and may be
      responsible for the age-related reduction in osteoblast number. Our results are
      particularly important in that the vertebrae are a site of high turnover
      osteoporosis and, possibly, the earliest site of bone loss in age-related
      osteoporosis.

PMID- 10404012
TI  - Mechanical strain stimulates nitric oxide production by rapid activation of
      endothelial nitric oxide synthase in osteocytes.
AB  - Previous studies have indicated that physiological levels of dynamic mechanical
      strain produce rapid increases in nitric oxide (NO) release from rat ulna
      explants and primary cultures of osteoblast-like cells and embryonic chick
      osteocytes derived from long bones. To establish the mechanism by which loading
      induced NO production may be regulated, we have examined: nitric oxide synthase
      (NOS) isoform mRNA and protein expression, the effect of mechanical loading in
      vivo on NOS mRNA expression, and the effect of mechanical strain on NO production
      by bone cells in culture. Using Northern blot analyses, in situ hybridization,
      and immunocytochemistry we have established that the predominant NOS isoform
      expressed in rat long bone periosteal osteoblasts and in a distinct population of
      cortical bone osteocytes is the endothelial form of NOS (eNOS), with little or no
      expression of the inducible NOS or neuronal NOS isoforms. In contrast, in non
      load-bearing calvariae there are no detectable levels of eNOS in osteocytes and
      little in osteoblasts. Consistent with these observations, ulnar explants release
      NO rapidly in response to loading in vitro, presumably through the activation of
      eNOS, whereas calvarial explants do not. The relative contribution of different
      bone cells to these rapid increases in strain-induced NO release was established
      by assessment of medium nitrite (stable NO metabolite) concentration, which
      showed that purified populations of osteocytes produce significantly greater
      quantities of NO per cell in response to mechanical strain than osteoblast-like
      cells derived from the same bones. Using Northern blot hybridization, we have
      also shown that neither a single nor five consecutive daily periods of in vivo
      mechanical loading produced any significant effect on different NOS isoform mRNA
      expression in rat ulnae. In conclusion, our results indicate that eNOS is the
      prevailing isoform expressed by cells of the osteoblast/osteocyte lineage and
      that strain produces increases in the activity of eNOS without apparently
      altering the levels of eNOS mRNA.

PMID- 10404013
TI  - Midkine is expressed during repair of bone fracture and promotes chondrogenesis.
AB  - Midkine (MK) is a heparin-binding growth/differentiation factor implicated in the
      control of development and repair of various tissues. Upon fracture of the murine
      tibia, MK was found to be transiently expressed during bone repair. MK was
      immunohistochemically detected in spindle-shaped mesenchymal cells at the
      fracture site on day 4 after fracture and in chondrocytes in the area of
      endochondral ossification on day 7. MK expression was decreased on day 14 and
      scarcely seen on day 28 when bone repair was completed. This mode of MK
      expression is reminiscent of MK expression during development. MK was expressed
      in hypertrophic chondrocytes of the prebone cartilage rudiments on embryonic day
      14 in mouse embryos. MK was also strongly expressed in the epiphyseal growth
      plate. MK was localized intracellularly during both bone repair and development,
      and this localization was confirmed by immunoelectron microscopy for embryonic
      chondrocytes. When MK cDNA was transfected into ATDC5 chondrogenic cells and
      overexpressed, the majority of transfected cells with strong MK expression showed
      enhanced chondrogenesis as revealed by increased synthesis of sulfated
      glycosaminoglycans, aggrecan, and type II collagen. These results suggest that MK
      plays important roles in chondrogenesis and contributes to bone formation and
      repair.

PMID- 10404014
TI  - Localization of Smads, the TGF-beta family intracellular signaling components
      during endochondral ossification.
AB  - Members of the transforming growth factor-beta (TGF-beta) family transduce
      signals from the cell membrane to the nucleus via specific type I and type II
      receptors and Smad proteins. Smad1 and Smad5 mediate intracellular signaling of
      bone morphogenetic protein (BMP), whereas Smad2 and Smad3 transduce TGF-beta
      signaling. Smad4 is a common mediator required for both pathways. Smad6 and Smad7
      inhibit signaling by members of the TGF-beta superfamily. Here, we examined the
      expression of Smad1 to Smad7 proteins during endochondral ossification of
      epiphyseal plate of growing rats using immunohistochemical techniques. The
      expression of Smad proteins was correlated with the expression of TGF-beta1 and
      its receptors, and BMP-2/4 and BMP receptors. The results show that TGF-beta1 and
      BMP-2/4 were actively expressed in chondrocytes that are undergoing proliferation
      and maturation, which overlaps with expression of their corresponding type I and
      type II receptors. The Smads, however, exhibited a distinct expression pattern,
      respectively. For example, Smad1 and Smad5 were highly expressed in proliferating
      chondrocytes and in those chondrocytes that are undergoing maturation. The TGF
      beta/activin-restricted Smads were also expressed in a nearly complementary
      fashion; Smad2 was strongly expressed in proliferating chondrocytes, whereas
      Smad3 was strongly observed in maturing chondrocytes. Smad4 was broadly expressed
      in all zones of epiphyseal plate. Inhibitory Smads, Smad6 and Smad7, were
      strongly expressed in the zone of cartilage that contained mature chondrocytes.
      Our findings show a colocalization of the pathway-restricted and inhibitory Smads
      with activating ligands or ligands whose action they antagonize and their
      receptors in various zones of epiphyseal growth plate, suggesting that TGF-beta
      superfamily Smad signaling pathways plays a morphogenic role during endochondral
      bone formation.

PMID- 10404015
TI  - Dietary conjugated linoleic acids alter serum IGF-I and IGF binding protein
      concentrations and reduce bone formation in rats fed (n-6) or (n-3) fatty acids.
AB  - A study was designed to examine the effects of dietary conjugated linoleic acid
      (CLA) on serum concentrations of insulin-like growth factor-I (IGF-I) and IGF
      binding proteins (IGFBP) and the relationship of these factors to bone
      metabolism. Weanling male rats were fed AIN-93G diet containing 70 g/kg of added
      fat for 42 days. Treatments included 0 g/kg or 10 g/kg of CLA and soybean oil
      (SBO) or menhaden oil + safflower oil (MSO) following a 2 x 2 factorial design.
      Serum IGFBP was influenced by dietary polyunsaturated fatty acid (PUFA) type ((n
      6) and (n-3)) and CLA (p = 0.01 for 38-43 kDa bands corresponding to IGFBP-3).
      CLA increased IGFBP level in rats fed SBO (p = 0.05) but reduced it in those fed
      MSO (p = 0.01). Rats fed MSO had the highest serum IGFBP-3 level. Both (n-3)
      fatty acids and CLA lowered ex vivo prostaglandin E2 production in bone organ
      culture. In tibia, rats given CLA had reduced mineral apposition rate (3.69 vs.
      2.79 microm/day) and bone formation rate (BFR) (0.96 vs. 0.65
      microm3/microm2/day); however, the BFR tended to be higher with MSO. Dietary
      lipid treatments did not affect serum intact osteocalcin or bone mineral content.
      These results showed that dietary PUFA type and CLA modulate local factors that
      regulate bone metabolism.

PMID- 10404016
TI  - The human vitamin D receptor gene (VDR) is localized to region 12cen-q12 by
      fluorescent in situ hybridization and radiation hybrid mapping: genetic and
      physical VDR map.
AB  - The vitamin D receptor (VDR) is a member of the steroid hormone receptor
      superfamily of ligand-activated transcription factors. The VDR gene was
      previously mapped to human chromosome 12q13-12q14, but its precise physical and
      genetic localization are unknown. The present study reports the mapping of the
      human VDR gene by radiation hybrid (RH) analysis, the isolation of a bacterial
      artificial chromosome (BAC) containing this gene, and physical mapping of the VDR
      gene by fluorescent in situ hybridization (FISH). RH analysis placed the VDR gene
      locus at chromosome 12cen-q12, flanked by Stanford Human Genome Center (SHGC)
      30216 and SHGC 9798 (D12S1892) markers. FISH analysis of a BAC containing the VDR
      gene confirmed its centromeric location. Thus, we have identified a BAC and
      genetic markers which can be used in the genetic analysis of the VDR gene and
      investigation of its involvement in osteoporosis and related disorders. We
      conclude that the VDR gene is centromeric to its previously reported locus on
      chromosome 12.

PMID- 10404017
TI  - Direct three-dimensional morphometric analysis of human cancellous bone:
      microstructural data from spine, femur, iliac crest, and calcaneus.
AB  - The appearance of cancellous bone architecture is different for various skeletal
      sites and various disease states. During aging and disease, plates are perforated
      and connecting rods are dissolved. There is a continuous shift from one
      structural type to the other. So traditional histomorphometric procedures, which
      are based on a fixed model type, will lead to questionable results. The
      introduction of three-dimensional (3D) measuring techniques in bone research
      makes it possible to capture the actual architecture of cancellous bone without
      assumptions of the structure type. This requires, however, new methods that make
      direct use of the 3D information. Within the framework of a BIOMED I project of
      the European Union, we analyzed a total of 260 human bone biopsies taken from
      five different skeletal sites (femoral head, vertebral bodies L2 and L4, iliac
      crest, and calcaneus) from 52 donors. The samples were measured three
      dimensionally with a microcomputed tomography scanner and subsequently evaluated
      with both traditional indirect histomorphometric methods and newly developed
      direct ones. The results show significant differences between the methods and in
      their relation to the bone volume fraction. Based on the direct 3D analysis of
      human bone biopsies, it appears that samples with a lower bone mass are primarily
      characterized by a smaller plate-to-rod ratio, and to a lesser extent by thinner
      trabecular elements.

PMID- 10404018
TI  - Apolipoprotein E polymorphism: A new genetic marker of hip fracture risk--The
      Study of Osteoporotic Fractures.
AB  - Hip fractures are common and devastating events. The apolipoprotein E*4 (APOE)
      allele, associated with Alzheimer's disease, has also been associated with
      osteoporosis in hemodialysis patients. We prospectively studied 1750 women, age
      >/=65 years, who underwent measurements of hip and calcaneal bone mineral density
      (BMD), were typed for APOE and followed for approximately 7.0 years for the
      occurrence of fractures and falls. Women with at least one APOE*4 allele had an
      increased risk of hip fracture, relative hazard (RH) (95% confidence interval) =
      1.90 (1.05-3.41) and wrist fracture, RH = 1.67 (1.01-2.77) compared with women
      without APOE*4, even after adjusting for age, cognitive function, falling, and
      BMD. The effect of APOE*4 on hip fracture was greatest among women with
      additional (>/=3) other risk factors. Women with an APOE*4 allele were also
      likely to report a maternal history of fracture. The average number of falls per
      year did not differ by APOE*4: 0.46 for APOE*4 women and 0.41 for women without
      an APOE*4 allele. Women with an APOE*4 allele experienced greater weight loss
      which contributed to faster rates of bone loss. We conclude that women with the
      APOE*4 polymorphism are at substantially increased risk of hip and wrist fracture
      that is not explained by bone density, impaired cognitive function, or falling.
      Possible alternate explanations include an effect of APOE on vitamin K, bone
      turnover, or weight loss. The APOE polymorphism may be a candidate gene for hip
      fractures among community dwelling nondemented women.

PMID- 10404019
TI  - Oral administration of the growth hormone secretagogue MK-677 increases markers
      of bone turnover in healthy and functionally impaired elderly adults. The MK-677
      Study Group.
AB  - Growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover
      and stimulates osteoblast activity when given to elderly subjects. Probably a
      major effect of GH on bone is mediated through stimulation of either circulating
      or locally produced insulin-like growth factor I (IGF-I). We determined the
      effect of chronic administration of the GH secretagogue, MK-677, on serum IGF-I
      and markers of bone turnover in 187 elderly adults (65 years or older) enrolled
      in three randomized, double-blind, placebo-controlled clinical studies lasting 2
      9 weeks. Urine was collected for determination of N-telopeptide cross-links
      (NTXs), a marker of bone resorption, and blood was collected for determination of
      serum osteocalcin and bone-specific alkaline phosphatase (BSAP), as bone
      formation markers, and serum IGF-I levels pre- and post-treatment. Dose response
      data were initially obtained in healthy elderly subjects who received oral doses
      of 10 mg or 25 mg of MK-677 or placebo for 2 weeks (n = 10-12/group). Treatment
      with 10 mg and 25 mg of MK-677 for 2 weeks increased mean urine NTXs 10% and 17%,
      respectively (p < 0.05 vs. placebo). Additionally, 50 healthy elderly subjects
      received either placebo (n = 20) for 4 weeks or 25 mg of MK-677 (n = 30) daily
      for 2 weeks followed by 50 mg daily for 2 weeks. MK-677 increased mean serum
      osteocalcin by 8% (p < 0.05 vs. placebo). In both studies, MK-677 increased serum
      IGF-I levels significantly (55-94%). Subsequently, the biological effects of MK
      677 were studied in 105 elderly subjects who met objective criteria for
      functional impairment. Subjects were randomized to receive oral doses of placebo
      for 9 weeks or either 5, 10, or 25 mg of MK-677 daily for an initial 2 weeks
      followed by 25 mg of MK-677 daily for the next 7 weeks(n = 63 on MK-677 and n =
      28 on placebo completed 9 weeks of therapy). Treatment with MK-677 (all MK-677
      groups combined) for 9 weeks increased mean serum osteocalcin by 29.4% and BSAP
      by 10.4% (p < 0.001 vs. placebo) and mean urinary NTX excretion by 22.6% (p <
      0.05 vs. placebo). The change from baseline serum osteocalcin correlated with the
      change from baseline serum IGF-I in the MK-677 group (r = 0.37; p < 0.01). In
      conclusion, once daily dosing with MK-677, an orally active GH secretagogue,
      stimulates bone turnover in elderly subjects based on elevations in biochemical
      markers of bone resorption and formation.

PMID- 10404020
TI  - A PCR analysis of ERalpha and ERbeta mRNA abundance in rats and the effect of
      ovariectomy.
AB  - To study the relative abundance and the changes of both estrogen receptor alpha
      (ERalpha) and ERbeta mRNA before and after ovariectomy in major organs important
      to the regulation of calcium homeostasis, we compared the degree of mRNA
      expression of ERalpha to that of ERbeta in rat tissues by performing competitive
      reverse transcription polymerase chain reaction (RT-PCR) with internal standards.
      Both ERalpha and ERbeta were highly expressed in the ovary {ERalpha[(2.2 +/-
      0.33) x 10(7) copies/microg of total RNA] > ERbeta[(1.2 +/- 0.33) x 10(5)
      copies/microg of total RNA]} as we expected. The bone marrow and renal cortex
      were very important target organs of estrogen because ERalpha was highly
      expressed approximately 2 x 10(5) copies/microg of total RNA, but marrow cells
      revealed only a very weak expression of ERbeta [(0.7 +/- 0.21) x 10(2)
      copies/microg of total RNA]. Both ERalpha and ERbeta were expressed in the
      trabecular bone [(3.2 +/- 0.56) x 10(3) copy/microg of RNA] and [(2.8 +/- 0.21) x
      102 copy/microg of RNA], respectively. However, they were not detected in the
      cortical bone. In the jejunum, the expression of ERalpha was not detectable,
      while ERbeta was expressed very weakly [(1.1 +/- 0.24) x 10(2) copies/microg of
      total RNA]. The thyroid gland expressed low copy numbers of ERbeta [(6.0 +/-
      0.23) x 10(2) copies/microg of total RNA], but the parathyroid gland was negative
      for both ERalpha and ERbeta mRNA. In cultured stromal cells, ERalpha and ERbeta
      mRNAs were not detected after a 24-h culture; however, the rates of mRNA
      expression of ERalpha and ERbeta reached approximately 105 copies/microg of total
      RNA and approximately 10(2) copies/microg of total RNA, respectively, after 9-,
      11-, and 13-day cultures. After ovariectomy, the expression of ERalpha mRNA
      decreased abruptly in the bone marrow and renal cortex, and both ERalpha and
      ERbeta were barely detected in the trabecular bone. In conclusion, ERalpha might
      be the main ER in organs important for calcium homeostasis, except in the
      jejunum. The mRNA expression of ERalpha in the bone marrow and renal cortex
      decreased abruptly after ovariectomy, which may partially explain why the effect
      of estrogen deficiency can be amplified and why trabecular bone loss is more
      predominant than cortical bone loss shortly after surgical or natural menopause.

PMID- 10404021
TI  - Estrogen regulation of intestinal calcium absorption in the intact and
      ovariectomized adult rat.
AB  - Studies were carried out to examine the mechanism of action of estrogen on
      intestinal calcium absorption in the rat. Three-month-old Wistar rats were sham
      operated or ovariectomized (OVX). They were fed a diet containing 0.4% Ca, 0.4%
      P, and 2000 IU vitamin D3/kg. Eight weeks after operation, both OVX and sham
      operated rats were randomly assigned to eight treatment groups. Five groups
      received per 100 g of body weight 12.5 ng calcitriol (1, 25-dihydroxyvitamin D3);
      7.5 microg of estradiol-benzoate; 7.5 microg of estradiol-benzoate and 0.1 mg of
      ICI 182780; 12.5 ng of calcitriol and 0.1 mg of ICI 182780; and 0.1 mg of ICI
      182780, respectively. Three groups received the various vehicles used. Intestinal
      calcium absorption was measured in vivo using single pass perfusion of the
      duodenum. OVX did not change intestinal calcium absorption. A pharmacological
      dose of estradiol-benzoate caused a significant increase in intestinal absorption
      of calcium, which was comparable to that of a pharmacological dose of calcitriol
      in both OVX and sham-operated rats. Estrogen-induced rise in intestinal calcium
      absorption was completely blocked to basal level by the pure estrogen receptor
      (ER) antagonist ICI 182780. In contrast, ICI 182780 did not antagonize calcitriol
      enhanced intestinal calcium absorption. Our findings suggest that estrogen
      stimulates intestinal calcium absorption via an ER.

PMID- 10404022
TI  - Age-related changes in bone turnover in men.
AB  - Biochemical markers of bone turnover can be used to study the pathophysiology of
      osteoporosis. So far there have been few such studies in men. The aims of this
      study were to determine the effect of aging on bone turnover and to identify
      which hormones might regulate bone turnover in men. We studied 178 healthy
      Caucasian men, ages 20-79 years (30 per decade). The data for the effect of age
      on bone turnover was best fit by a quadratic function (nadirs at age 56, 57, 53,
      39, and 58 years for intact propeptide of type I procollagen, osteocalcin, bone
      alkaline phosphatase, free deoxypyridinoline, and cross-linked N-telopeptides of
      type I collagen, respectively). For most markers, bone turnover tended to be
      highest in the third decade, lowest in the fifth and sixth decade, with a small
      increase in some markers in the eighth decade. Insulin-like growth factor-I (IGF
      I), insulin-like growth factor binding protein-3, dehydroepiandrosterone sulfate,
      testosterone, estradiol, and free androgen index all decreased significantly with
      age (54, 17, 76, 26, 33, and 57%, respectively), while sex hormone binding
      globulin and parathyroid hormone increased significantly with age (62% and 43%).
      IGF-I and sex hormones were positively correlated with bone turnover, and this
      association was stronger in young men than older men. In conclusion, increased
      IGF-I and sex hormones may be associated with increased bone turnover in young
      men, with less influence on bone turnover in older men.

PMID- 10404023
TI  - Lactulose stimulates calcium absorption in postmenopausal women.
AB  - Animal studies have indicated that calcium absorption is increased by lactulose,
      a synthetic disaccharide. Therefore, the influence of lactulose on calcium
      absorption was measured in postmenopausal women who may benefit from the possible
      enhancing effect of lactulose on calcium absorption. Twelve postmenopausal women
      drank 100 ml of water containing 5 or 10 g of lactulose or a reference substance
      at breakfast for 9 days. The three treatments were given according to a
      randomized, double-blind, cross-over design, separated by two 19-day wash-out
      periods. On the 8th day of each treatment period, 44Ca dissolved in orange juice
      was drunk immediately after the solution with the study substance and just before
      a standard breakfast with 162 mg of carrier calcium. Within half an hour, 48Ca
      was given intravenously. Based on isotope ratios measured in urine collected
      before and until 36 h after isotope administration, true fractional calcium
      absorption was calculated. Calcium absorption during the treatments with the
      reference substance, 5 g and 10 g of lactulose was (mean +/- SD) 27.7 +/- 7.7,
      30.0 +/- 7.6, and 32.2 +/- 7.0, respectively. A significant difference in calcium
      absorption was found between the highest dose of lactulose and the reference
      treatment (p < 0.01). A significant linear trend was found between the dose of
      lactulose and its positive effect on calcium absorption. In conclusion, in
      postmenopausal women a 9-day consumption of lactulose increases calcium
      absorption in a dose-response way. More research is warranted to explore how
      lactulose stimulates calcium absorption and whether it is able to improve calcium
      balance and/or to attenuate the rate of aging bone loss.

PMID- 10404024
TI  - Hormone replacement therapy prevents osteoclastic hyperactivity: A
      histomorphometric study in early postmenopausal women.
AB  - In a randomized, double blind, clinical prospective trial comprising 35 women
      treated with either hormone replacement therapy (HRT) (cyclic
      estradiol/norethisterone acetate) or placebo we performed histomorphometric
      studies on paired bone biopsies obtained before and after 2 years of treatment.
      Untreated women developed a progressively more negative balance at individual
      bone multicellular units (BMUs) (i.e., wall thickness-erosion depth) (2.2 +/- 1.7
      microm vs. -5.7 +/- 1.4 microm; p < 0.01), while women on HRT displayed
      preservation of bone balance (2.4 +/- 2.4 microm vs. 2.5 +/- 2.5 microm; NS). No
      significant differences in wall thickness between the two groups were
      demonstrable, but the untreated women developed a pronounced increase in erosion
      depth over 2 years (46.9 +/- 1.8 microm vs. 52.0 +/- 1.9 microm; p < 0.05), while
      the HRT group revealed no change (47.8 +/- 2.7 microm vs. 44.6 +/- 1.7 microm;
      NS). Furthermore, the placebo group displayed an increased osteoclastic erosion
      depth (17.8 +/- 1.6 microm vs. 25.0 +/- 1.7 microm; p < 0.001), compared with
      unchanged values in the HRT group (20.0 +/- 1.6 microm vs. 16.9 +/- 1.4
      microm/day; NS). While the placebo group revealed a slight increase in volume
      referent resorption rate (35 +/- 8% vs. 38 +/- 8%; NS) the HRT group revealed a
      pronounced decrease (46 +/- 8% vs. 28 +/- 5%; p < 0.05). No significant changes
      in marrow star volume (an index of trabecular perforations) were demonstrable in
      either group. Our results demonstrate that bone remodeling in early
      postmenopausal women is characterized by progressive osteoclastic hyperactivity,
      which is reduced by cyclic HRT. This reduction of resorptive activity at the BMU
      level after HRT seems to precede the reduction in activation frequency
      demonstrated in previous studies on older postmenopausal women.

PMID- 10404025
TI  - Effects of high-impact exercise on ultrasonic and biochemical indices of skeletal
      status: A prospective study in young male gymnasts.
AB  - Physical activity has been proposed as one strategy to enhance bone mineral
      acquisition during growth. The aim of this study was to determine whether
      frequent impact loading associated with gymnastics training confers a skeletal
      benefit on pre- and peripubertal male gymnasts. We measured broadband ultrasonic
      attenuation (BUA, dB/MHz) at the calcaneus (CBUA); ultrasound velocity (m/s) at
      the calcaneus (CVOS), distal radius (RVOS) and phalanx (PVOS); serum osteocalcin
      (OC); total alkaline phosphatase (ALP) and insulin-like growth factor-I (IGF-I)
      every 3-4 months over an 18-month period in elite male gymnasts and matched
      normoactive controls (pubertal stage </=2). Ground reaction forces of common
      gymnastics maneuvers were determined using a force platform and loading histories
      of the upper and lower extremities approximated from video recordings. Ultrasound
      results were expressed as a standardized score (Z score) adjusted for age,
      height, and weight. At baseline, no differences were detected between the
      gymnasts (n = 31) and controls (n = 50) for CBUA, although ultrasound velocity at
      each site was higher in the gymnasts (0.6-1.5 SD) than the predicted mean in
      controls (p </= 0. 001). Over 18 months, CBUA Z scores increased significantly in
      the gymnasts from baseline (0.3 vs. 1.0, p < 0.05, n = 18). In contrast,
      ultrasound velocity did not increase in either group, although CVOS and RVOS
      remained significantly higher in gymnasts compared with controls (range p < 0.01
      and < 0.001). No differences between groups were found for OC, ALP, or IGF-I at
      any time. Gymnastics training was associated with on average 102 and 217 impacts
      per session on the upper and lower extremities, respectively, with peak
      magnitudes of 3.6 and 10.4 times body weight. These results suggest that frequent
      high-impact, weight-bearing exercise during the pre and peripubertal period may
      enhance the mechanical competence of the skeleton, perhaps offering an important
      strategy for osteoporosis prevention if the benefits are maintained.

PMID- 10404026
TI  - Long-term recreational gymnastics, estrogen use, and selected risk factors for
      osteoporotic fractures.
AB  - The purpose of this cross-sectional study was to examine whether long-term
      participation in recreational gymnastics or folk dancing or estrogen replacement
      therapy (ERT) is associated with mechanically more competent bones and improved
      muscular strength and body balance. One hundred and seventeen healthy, female
      postmenopausal recreational gymnasts (mean age 62.1 [SD 4.7] years) and 116
      sedentary controls (mean age 61.5 [4.6] years) were enrolled in the study. Bone
      mineral content (BMC) of the distal radius, femoral neck, and trochanter were
      measured with dual-energy X-ray absorptiometry. BMC of the midshaft and distal
      tibia and trabecular density (TrD) of the distal tibia were measured with
      peripheral computed quantitative tomography. Maximal isometric strength, muscular
      power, cardiorespiratory fitness, and body balance of the participants were also
      assessed. The cardiorespiratory fitness, muscular strength, and dynamic balance
      of the recreational gymnasts and folk dancers combined were significantly better
      than those of the controls, the average group difference ranging from 7.5% (95%
      confidence interval 5.0-9.9%) in dynamic balance to 12.8% (6.6-19. 4%) in dynamic
      muscular power. ERT was not associated with the fitness indicators, muscular
      power, or balance, but was significantly associated with the BMC at all the
      measured bone sites, the mean group difference between estrogen users and
      nonusers ranging from 6.5% (3.7-9.3%) for the tibial shaft to 11.8% (6.4-17. 0%)
      for the distal radius. Recreational gymnastics, in turn, was significantly
      associated with higher BMC at the tibia only, the mean group difference being
      3.9% (0.9-6.9%) for the tibial shaft and 7.7% (3.7-11.9%) for the distal tibia.
      Recreational gymnastics was also associated with higher TrD at the distal tibia
      (5.2%; 1.2-9.2%), whereas estrogen usage did not show such association. The
      results indicate that ERT seems especially effective in preventing postmenopausal
      bone loss, whereas recreational gymnastics and folk dancing improve muscular
      performance and body balance in addition to increased bone mass and bone size in
      the tibia. All these factors are essential in prevention of fall-related
      fractures of the elderly.

PMID- 10404027
TI  - Identification and characterization of a novel protein, periostin, with
      restricted expression to periosteum and periodontal ligament and increased
      expression by transforming growth factor beta.
AB  - We had previously identified the cDNA for a novel protein called osteoblast
      specific factor 2 (OSF-2) from an MC3T3-E1 cDNA library using subtraction
      hybridization and differential screening techniques. Here we describe the
      localization, regulation, and potential function of this protein.
      Immunohistochemistry using specific antiserum revealed that in adult mice, the
      protein is preferentially expressed in periosteum and periodontal ligament,
      indicating its tissue specificity and a potential role in bone and tooth
      formation and maintenance of structure. Based on this observation and the fact
      that other proteins have been called OSF-2, the protein was renamed "periostin."
      Western blot analysis showed that periostin is a disulfide linked 90 kDa protein
      secreted by osteoblasts and osteoblast-like cell lines. Nucleotide sequence
      revealed four periostin transcripts that differ in the length of the C-terminal
      domain, possibly caused by alternative splicing events. Reverse transcription-
      polymerase chain reaction analysis revealed that these isoforms are not expressed
      uniformly but are differentially expressed in various cell lines. Both purified
      periostin protein and the periostin-Fc recombinant protein supported attachment
      and spreading of MC3T3-E1 cells, and this effect was impaired by antiperiostin
      antiserum, suggesting that periostin is involved in cell adhesion. The protein is
      highly homologous to betaig-h3, a molecule induced by transforming growth factor
      beta (TGF-beta) that promotes the adhesion and spreading of fibroblasts. Because
      TGF-beta has dramatic effects on periosteal expansion and the recruitment of
      osteoblast precursors, this factor was tested for its effects on periostin
      expression. By Western blot analysis, TGF-beta increased periostin expression in
      primary osteoblast cells. Together, these data suggest that periostin may play a
      role in the recruitment and attachment of osteoblast precursors in the
      periosteum.

PMID- 10404029
TI  - Osteoclast isolation: new developments and methods.

PMID- 10404030
TI  - Neurochemical alterations during age-related anorexia.
AB  - Unexplained weight loss during the latter stages of aging is commonly preceded by
      a spontaneous diminution in food intake. Multiple etiologies of age-related
      anorexia in humans, ranging from social isolation to impaired gastrointestinal
      function, have been proposed. The observation of this phenomenon in older
      laboratory animals suggests that physiological changes play a significant causal
      role. A continually expanding body of information on the neurochemical control of
      food intake supports a contribution of altered neurochemistry to dysregulated
      feeding behavior. This review provides an update on the relationship between
      declining food intake during advanced age and physiological (specifically
      neurochemical) function. The complexity of the control of food intake as well as
      the variety of investigative methods used in this field of study render the
      identification of definitive causes difficult. Evidence presented here is
      evaluated and possible etiologic factors are suggested.

PMID- 10404031
TI  - Hemodynamic and renal effects of ProANF31-67 in hypertensive rats.
AB  - It has been demonstrated previously that the atrial natriuretic factor prohormone
      fragment 31-67 (ProANF31-67) circulates in animals and possesses natriuretic and
      vasodilating actions. Although the plasma levels of the peptide are reportedly
      elevated in patients with high blood pressure, its role and actions in
      hypertension are unknown. In the present study, synthetic human ProANF31-67 was
      infused intravenously at doses of 0, 10, 30, and 100 ng/kg/min into respective
      groups of anesthetized normotensive and spontaneously hypertensive rats. Mean
      arterial pressure (MAP), urine flow rate (UV), and sodium excretion (UNaV) were
      measured during two consecutive 30-min periods. In both strains of rats,
      reductions in MAP with ProANF31-67 were similar in magnitude and dose-related.
      Sodium excretion responses to the peptide infusions also were remarkably similar
      in both normotensive and hypertensive rats, and the responses demonstrated 3- to
      5-fold (P < 0.05) increments compared to control at the doses of 10 and 30
      ng/kg/min. However, in the two strains of rats, attenuation of natriuresis
      occurred with the highest infusion dose of 100 ng/kg/min and was probably related
      to the large decreases in MAP of 17-23 mmHg at this dose of the peptide. The
      present results indicate the ProANF31-67 has important hemodynamic and renal
      effects in hypertension and may represent one compensatory mechanism involved in
      this disease.

PMID- 10404033
TI  - Immune function in transgenic mice overexpressing growth hormone (GH) releasing
      hormone, GH or GH antagonist.
AB  - Effects of life-long exposure to high levels of homologous or heterologous growth
      hormone (GH) and effects of GH resistance on selected parameters of immune
      function were studied in adult male transgenic mice overexpressing GH releasing
      hormone (GHRH), bovine (b) GH or an antagonistic bGH analog. In metallothionein I
      (MT)-bGH transgenic mice with high peripheral levels of bovine GH, there were
      significant increases in the absolute weight of the thymus and the spleen and in
      the mitogenic responses of splenocytes to concanavalin A (ConA),
      lipopolysaccharide (LPS) and phytohemagglutinin (PHA), as compared to age-matched
      normal animals. There were no significant differences between MT-bGH transgenic
      and normal mice in splenocyte viability or in delayed-type hypersensitivity
      measured by the allergic contact dermatitis response to oxazolone. Similar
      results, including significant stimulation of splenocyte responses to ConA, LPS,
      and PHA, were obtained in MT-hGHRH transgenic mice in which overexpression of
      GHRH leads to striking pituitary enlargement and massive elevation of peripheral
      levels of homologous (mouse) GH. In MT-bGH-antagonist transgenic mice in which
      overexpression of an antagonistic bGH analog interferes with the actions of
      endogenous GH, spleen weight was reduced but proliferative responses of
      splenocytes to ConA, LPS, and PHA were not affected. It is concluded that
      overexpression of heterologous or homologous GH in transgenic mice can lead to
      significant stimulation of some parameters of immune function, whereas antagonism
      of GH action by expression of an antagonistic GH analog does not affect
      splenocyte responses to mitogens.

PMID- 10404032
TI  - Serum leptin concentrations in response to acute exercise in postmenopausal women
      with and without hormone replacement therapy.
AB  - The purpose of the study was to examine the effects of acute exercise and hormone
      replacement therapy on serum leptin concentrations in postmenopausal women.
      Subjects were 15 healthy, postmenopausal women, 8 on hormone replacement therapy
      (HRT) and 7 not on hormone replacement therapy (NHRT). Group comparisons
      indicated no significant differences between HRT and NHRT groups with respect to
      age, height, weight, BMI, sum of skinfolds, or VO2max, and verified significant
      differences in estradiol and FSH concentrations. After an overnight fast, each
      subject completed 30 min of treadmill exercise at approximately 80% VO2max. Over
      2 hr and 10 min, baseline, exercise, and recovery blood samples were collected
      from an intravenous catheter. A control session conducted a month later consisted
      of the same blood sampling protocol without exercise. Leptin concentrations
      declined significantly over the course of both the exercise and control sessions,
      gradually decreasing from baseline levels to -1.54 +/- 0.49 ng. ml-1
      postexercise, and continuing to decline to a low of -2.89 +/- 0.59 ng. ml-1 at
      the end of the session. There was no significant difference between groups with
      respect to this decline. This is the first study to document that diurnal changes
      in leptin concentrations in postmenopausal women are not altered by acute
      treadmill exercise or HRT status. The study underscores the need to account for a
      diurnal reduction in leptin over the course of an exercise trial.

PMID- 10404035
TI  - Atrial natriuretic-like peptide and its prohormone within metasequoia.
AB  - Metasequoia glyptostroboides was one of the dominant conifers in North America,
      Asia, and Europe for more than 100 million years since the late Cretaceous Albian
      Age, but Quaternary glaciations drove the Metasequoia population to apparent
      extinction. A small pocket of Metasequoia, however, was found in central China in
      the 1940s representing the only surviving population of this "living fossil"
      species. Atrial natriuretic peptide, a 28-amino-acid peptide hormone that causes
      sodium and water excretion in animals, has been found to be part of the first
      peptide hormonal system in lower plants. The existence of this hormonal system
      has never been examined within trees of any genus. High-performance gel
      permeation chromatography of the leaves and stems (i.e., branches) of Metasequoia
      followed by atrial natriuretic peptide radioimmunoassay revealed an ANP-like
      peptide and its prohormone (i.e., approximately 13,000 mol wt) were present in
      both leaves and stems of this conifer. The elution profile of ANP-like peptide in
      stems of Metasequoia had a shoulder to the left of where pure synthetic ANP
      elutes suggesting the possibility of a slightly larger peptide eluting within
      this shoulder secondary to alternate processing of the ANP-like prohormone and
      similar to what occurs with the kidney of animals. The elution profile of ANP
      like peptide in the leaves of Metasequoia revealed two peaks; one where ANP
      elutes and a second peak suggesting a smaller peptide that has been metabolically
      processed. The presence of the ANP-like prohormone strongly suggests that ANP
      like gene expression is occurring in both leaves and stems of Metasequoia since
      this prohormone is the gene product of this hormonal system. The presence of the
      ANP-like hormonal system in trees implies that this hormonal system may have been
      present early in land plant evolution to allow trees to reach heights of greater
      than 30 feet where a water flow-enhancing substance is absolutely necessary for
      water flow to occur to these heights.

PMID- 10404034
TI  - Nifedipine does not impede clenbuterol-stimulated muscle hypertrophy.
AB  - The mechanism(s) responsible for beta2-adrenergic receptor-mediated skeletal
      muscle and cardiac hypertrophy remains undefined. This study examined whether
      calcium influx through L-type calcium channels contributed to the development of
      cardiac and skeletal muscle (plantaris; gastrocnemius; soleus) hypertrophy during
      an 8-day treatment with the beta2-adrenergic receptor agonist clenbuterol.
      Concurrent blockade of L-type calcium channels with nifedipine did not reverse
      the hypertrophic action of clenbuterol. Moreover, nifedipine treatment alone
      resulted in both cardiac and soleus muscle hypertrophy (6% and 7%, respectively),
      and this effect was additive to the clenbuterol-mediated hypertrophy in the heart
      and soleus muscles. The hypertrophic effects of nifedipine were not associated
      with increases in total beta-adrenergic receptor density, nor did nifedipine
      reverse clenbuterol-mediated beta-adrenergic receptor downregulation in either
      the left ventricle or soleus muscle. Both nifedipine and clenbuterol-induced
      hypertrophy increased total protein content of the soleus and left ventricle,
      with no change in protein concentration. In conclusion, our results support the
      hypothesis that beta2-adrenergic receptor agonist-induced muscle hypertrophy is
      mediated by mechanisms other than calcium influx through L-type calcium channels.

PMID- 10404036
TI  - Modification of physical movement in old C57BL/6 mice by DHEA and melatonin
      supplementation.
AB  - As old age results in reduced physical activity as well as less
      dehydroepiandrosterone (DHEA) and melatonin (MLT) production, low hormone levels
      may be a component of inactivity. Therefore, we studied the effects of DHEA
      and/or MLT supplementation on movement and resting in young and old female C57
      black mice. Our results showed for the first time that old female C56BL/6 mice
      have significantly decreased physical activity. Their average speed and resting
      time were significantly higher than in young mice, whereas ambulatory time,
      distance traveled, and body movements when stationary (stereo time) were lower.
      DHEA supplementation significantly increased stereo time in old mice, while
      decreasing ambulatory time and distance traveled. MLT supplementation of old mice
      decreased average speed, resting time, and stereo time compared to untreated, old
      mice. Supplementation with MLT or DHEA, whose production is reduced in aging,
      restored physical activity levels in old mice. MLT also increased ambulatory time
      and distance traveled while reducing body movements of young mice.

PMID- 10404037
TI  - Opposing actions of dehydroepiandrosterone and corticosterone in rats.
AB  - The purpose of this study was to determine the impact of dehydroepiandrosterone
      (DHEA) and corticosterone (CORT) treatment, using implants as a route of
      administration, on specific hormones, metabolites, and enzymes involved in energy
      metabolism. Sixty male Sprague-Dawley rats, 325 g initial weight, were implanted
      subcutaneously for 3 weeks with time-release pellets containing either DHEA or
      CORT at doses of 0, 10, 25, 50, or 100 mg in this 2 x 5 factorial experiment. In
      general, body weights and food intakes decreased as the level of steroid hormones
      increased. In contrast to DHEA treatment, rats receiving the 50- and 100-mg doses
      of CORT had lighter thymus glands and spleens and heavier epididymal and
      retroperitoneal fat pads than their controls. Rats treated with 100 mg of DHEA
      had lowered serum levels of triglycerides and lipid hydroperoxides whereas rats
      treated with 100 mg of CORT had higher levels of these blood lipids compared to
      their respective controls. In contrast to DHEA treatment, there was a dose
      dependent increase in liver lipid content and the specific activities of the
      hepatic lipogenic enzymes glucose-6-phosphate dehydrogenase, malic enzyme, and
      fatty acid synthase in response to CORT treatment. Rats treated with 100 mg of
      DHEA had higher serum levels of IGF-1 than control rats. Conversely, rats treated
      with 100 mg of CORT had lower serum levels of IGF-1 and higher serum levels of
      testosterone, progesterone, and insulin than their controls. These data
      demonstrate the lipogenic actions of corticosterone in rats. Conversely, DHEA
      treatment reduced serum and hepatic lipids. Furthermore, these data suggest that
      using implants instead of bolus injections of steroids may be a more
      physiological approach for studying the influence of these steroids on lipid
      metabolism.

PMID- 10404038
TI  - Estrogen receptor mRNA in uteri of normal estrous cycling and ovariectomized rats
      by in situ hybridization.
AB  - Biological effects of estrogen are mediated via its binding to the estrogen
      receptor (ER), the contents of its protein and mRNA varying during the estrous
      cycle. In the present study, the ERalpha mRNA expression in different cell
      components of the uterus was investigated in normal estrous cycling rats using
      nonisotopic in situ hybridization. Additionally, ovariectomized (OVX) rats
      treated with 17beta-estradiol (E2: 5 microg/kg, sc injection daily) were also
      investigated to clarify the effects of exogenous E2. At proestrus and diestrus,
      and especially the former, the luminal and glandular epithelial (LE and GE) cells
      were strongly positive, along with stromal cells beneath the luminal epithelium.
      At estrus, the expression was slightly diminished in LE cells, but almost
      completely lacking in GE cells. At metestrus, positive signals appeared again in
      GE cells. In the myometrium, ER mRNA was demonstrated to be constantly positive
      in all estrous cycle stages. OVX rat uteri underwent marked atrophy, but ER mRNA
      still remained in all cell types. After 2 consecutive days of E2 treatment,
      markedly increased intensity was observed, especially in LE and GE cells. The
      uteri of OVX rats treated with E2 for 14 days, however, showed slightly
      diminished expression, whereas the serum concentration of E2 was comparable to
      that in rats after 2 days. These results provide evidence that cell-type specific
      patterns of ER mRNA expression characterize the uteri of both normal estrous
      cycling rats and OVX rats after estrogen treatment.

PMID- 10404039
TI  - Efficacy of providing nicotine in a liquid diet to rats.
AB  - To determine if rats would consume nicotine at psychoactive levels, a
      nutritionally balanced diet with 0, 20, 60, or 200 mg of nicotine tartrate per kg
      of diet was provided. Diet consumption and body weight differences were recorded
      for 14 days after which, following 16 hr of withdrawal, animals were given access
      to a two-bottle choice of the previously presented diet and a nicotine-free diet.
      Spontaneous horizontal motor activity was recorded 8, 16, and 24 hr after
      withdrawal. By Day 14, all animals showed a significant increase in diet
      consumption and significant weight gain compared to Day 1. Animals consumed an
      average of 2.1, 6.8, or 19.5 mg/kg/day of nicotine on the low, medium, and high
      nicotine diets, respectively. However, animals receiving the high-nicotine diet
      consumed less diet and gained less weight than the control, low, and medium
      nicotine groups. During only the first 4 hr of the two-bottle choice (16-20 hr
      postwithdrawal), the high-nicotine group consumed significantly higher amounts of
      nicotine base than the other groups, but also consumed more of the control diet
      during the first 2 hr. In a replicate experiment, animals receiving the medium
      nicotine diet showed an increased consumption of the nicotine diet and increased
      preference for nicotine following a 14-day exposure compared to the control-fed
      animals and compared to a baseline preference test. Also, this group showed
      differences in locomotor activity consistent with other studies using an
      injection regimen or subcutaneuos pumps to induce dependence. Finally, animals in
      all three groups exhibited high plasma nicotine and cotinine (a major nicotine
      metabolite) levels. Because animals in all groups tolerated the diet well, gained
      weight, selected the nicotine diet in a choice test, and showed withdrawal
      symptoms, we conclude that the liquid diet proved to be a satisfactory method of
      inducing nicotine dependence in rats.

PMID- 10404040
TI  - Comparison of verapamil and felodipine treatment on lipid and glucose metabolism
      in obese female SHHF/Mcc-facp rats.
AB  - Calcium channel blockers, verapamil or felodipine, were given to genetically
      obese 6 and 11-month-old female SHHF/Mcc-facp (SHHF: Spontaneous Hypertension
      Heart Failure) rats for 8 weeks to investigate their effects on glucose and lipid
      metabolism and obesity. Both antihypertensive agents significantly decreased
      systolic blood pressure. In 11-month-old rats, verapamil treatment significantly
      decreased body weight after 4 weeks whereas with felodipine it was only
      significantly reduced after 8 weeks. In 6-month-old rats, verapamil significantly
      curtailed body weight gain. Subcutaneous fat depots were smaller, and abdominal
      fat depots were larger in verapamil rats compared to felodipine or control rats.
      Oral glucose tolerance tests in the 6-month-old verapamil and the 11-month-old
      felodipine groups showed improved glucose tolerance compared to their respective
      control groups. After 8 weeks of treatment, fasting plasma glucose levels were
      lower in 6-month-old verapamil rats compared to felodipine and control rats and
      were decreased by both verapamil and felodipine treatments as compared to control
      in 11-month-old rats. During the oral glucose tolerance test in 6-month-old rats,
      both fasting plasma insulin and the area under the insulin curve were increased
      in verapamil compared to both control and felodipine groups. When compared to
      controls, plasma cholesterol was increased by verapamil in both age groups, but
      was significantly decreased by felodipine after 8 weeks of treatment in the 11
      month-old group. Plasma triglycerides increased in all control rats compared to
      initial levels; however, verapamil and felodipine groups showed lower
      triglycerides in both age groups. In 6-month-old rats, the percentages of plasma
      HDL significantly increased in both treatment groups as compared to control. This
      study shows that verapamil and felodipine depressed body weight gain in the young
      rats, reduced body weight in the old rats, improved lipid parameters and glucose
      tolerance, but had the opposite effects on body fat distribution and insulin
      levels in obese female SHHF rats.

PMID- 10404041
TI  - Changes in ryanodine receptor-mediated calcium release during skeletal muscle
      differentiation.
AB  - We have observed a disparity between the actions of caffeine and ryanodine, two
      agents known to affect the same site of intracellular calcium (Ca2+) release in
      muscle. The site of intracellular Ca2+ release, the ryanodine receptor (RyR), is
      established as the route of Ca2+ movement from the sarcoplasmic reticulum (SR) to
      the cytosol during excitation-contraction coupling. We measured Ca2+ release
      fluorimetrically in both saponin-permeabilized and intact L6 cells, in response
      to known modulators (i.e., caffeine and ryanodine), during differentiation in
      vitro. The undifferentiated L6 cells showed little response to caffeine. However,
      a substantial caffeine-induced calcium release (caffCR) was evident by Day 3 of
      differentiation, and was nearly maximal by Day 7 of differentiation. By contrast,
      ryanodine failed to stimulate Ca2+ release until Day 4, lagging behind the
      caffeine response. Ryanodine-stimulated Ca2+ release was also maximal by Day 7.
      Higher concentrations of ryanodine, known to inhibit Ca2+ release, only began to
      affect caffCR at Day 4, indicating that cells were insensitive to both ryanodine
      stimulation and ryanodine inhibition prior to this time. Most of the results
      could be obtained both in permeabilized and intact cells. Using intact cells, we
      measured the time course of K+ -dependent (i.e., depolarization-induced) Ca2+
      release. This time course matched caffeine and not ryanodine-induced Ca2+ release
      suggesting the action of caffeine was not due to Ca2+ release unrelated to
      excitation-contraction coupling. These findings suggest that ryanodine binding
      sites on the RyR may not be functional at early stages of muscle development,
      that ryanodine sensitivity is a poor indicator of Ca2+ flux through the RyR, or
      that other proteins are involved in Ca2+ release under certain circumstances.

PMID- 10404042
TI  - Regulation of preB cell apoptosis by aryl hydrocarbon receptor/transcription
      factor-expressing stromal/adherent cells.
AB  - Polycyclic aromatic hydrocarbons (PAH) are environmental chemicals that mediate
      immunosuppression. In long-term bone marrow B-cell lymphopoiesis models, PAH
      induce apoptosis in immature (preB) lymphocytes. Since the biologic function of
      PAH is often mediated by the aryl hydrocarbon receptor/transcription factor
      (AhR), the role of the AhR or AhR-regulated genes was assessed in preB cell
      apoptosis. Specifically, a bone marrow-derived preB cell line (BU-11) was
      cultured on monolayers of the AhR + bone marrow-derived stromal cell line BMS2,
      hepatoma sublines that express various levels of AhR activity (Hepa-1c1c7 and
      variants), AhR+ thymic epithelial cells, and primary bone marrow stromal cells
      from wildtype or AhR-/- mice. Cultures were treated with one of two prototypic
      PAH, 7,12-dimethylbenz[a] anthracene (DMBA) or benz[a]pyrene (B[a]P), and the
      percentage of cells undergoing apoptosis measured. The data demonstrated that: 1)
      bone marrow- and hepatic-derived stromal/adherent cells support preB cell growth
      and regulate apoptosis induced by DMBA or B[a]P; 2) B[a]P is more effective than
      DMBA when preB cells are maintained on Hepa-1c1c7 monolayers than when maintained
      on BMS2 monolayers; 3) DMBA is more effective than B[a]P when preB cells are
      cultured on BMS2 monolayers; 4) alpha-naphthoflavone, an AhR antagonist and
      cytochrome P-450 inhibitor, blocks preB cell apoptosis in both BU-11/Hepa-1c1c7
      and BU-11/BMS2 cultures; 5) although preB cells grow well in Hepa-1c1c7 or BMS2
      supernatants, addition of PAH in the absence of hepatic- or bone marrow-derived
      adherent cells does not result in preB cell apoptosis; 6) preB cell apoptosis is
      dependent on AhR activity in adherent hepatic- or bone marrow-derived stromal
      cells; and 7) apoptosis is induced by DMBA when preB cells are maintained on
      primary bone marrow stromal cell monolayers from wildtype but not from AhR-/-
      mice. Collectively, the data indicated that AhR-regulated activities in the
      hematopoietic microenvironment influence the susceptibility of immature
      lymphocytes to low-dose PAH exposure.

PMID- 10404043
TI  - Differential depressant effects of general anesthetics on the cardiovascular
      response to cocaine in mice.
AB  - In recent years, murine models have gained increasing importance for studies of
      cardiovascular physiology and pharmacology, largely due to the development of
      transgenic strains with specific alterations in phenotype. Differential effects
      of general anesthetic agents on the cardiovascular responses to cocaine have been
      reported in larger mammals; therefore, we studied the effects of commonly used
      anesthetics on heart function and on blood pressure responses to cocaine in Swiss
      Webster mice. We positioned a polyethylene catheter (PE-10) in the right carotid
      artery or left ventricle of mice anesthetized with equivalent anesthetic dose of
      either ketamine-xylazine (KX, 40 mg/kg + 5 mg/kg), pentobarbital (PEN, 40 mg/kg)
      or alpha-chloralose-urethane (CU, 80 mg/kg + 100 mg/kg). Cocaine (0.3 mg/kg, 1
      mg/kg and 3 mg/kg) was administrated via the left jugular vein by bolus
      injection. In the KX group, the basal mean arterial pressure (MAP) and systolic
      left ventricular pressure (LVP) were 110 +/- 12 and 120 +/- 13 mmHg,
      respectively, close to conscious values. However, PEN and CU significantly
      decreased the basal parameters (P < 0.01 compared to the KX group). The lowest
      dose of cocaine (0.3 mg/kg) elicited minimal changes. Significant responses were
      obtained with a 1-mg/kg dose of cocaine (P < 0.01 compared to baseline). However,
      at 3 mg/kg, a toxic effect of cocaine appeared in all three anesthetic groups.
      Compared to published conscious animal data, anesthetic agents attenuated the
      cardiovascular effects of cocaine. Taken together, our results indicate that
      minimally effective doses of general anesthetics may significantly alter the
      basal hemodynamic state and the responses to sympathomimetic agents in the murine
      model, as has been reported in larger mammalian species. We concluded that
      anesthesia with ketamine-xylazine provides baseline hemodynamic values close to
      reported values in conscious animals, but also attenuates the hemodynamic
      response to cocaine.

PMID- 10404044
TI  - Change in the Th1/Th2 phenotype of memory T-cell clones from rheumatoid arthritis
      synovium.
AB  - The stability of established memory T helper (Th)1/Th2 cells in chronic
      inflammatory diseases is not clear, and a shift of the cytokine balance could
      control chronic inflammation. In order to study the regulation of the Th
      phenotype of memory T cells, polyclonal T-cell lines and clones with a Th1, Th0
      or Th2 phenotype were developed from rheumatoid synovial tissue. Th1 [interleukin
      (IL)-12 + anti-IL-4] and Th2 (IL-4 + anti-IL-12) promoting environments and IL-2
      were used to manipulate the cytokine profile. Polyclonal T-cell lines of
      predominantly Th1 type could be shifted to produce Th2 cytokines, and polyclonal
      Th2/Th0 lines could be shifted to produce Th1 cytokines. However, this shift was
      due to an amplification of CD8+ T cells with a memory phenotype and a loss of the
      CD4+ T cells, giving Tc2 or Tc1 profiles, respectively. Th2 clones cultured
      repeatedly with IL-2 switched to either a Th0 or a Th1 phenotype, while both Th1
      and Th0 memory clones kept a stable phenotype. Addition of Th2-promoting
      conditions strongly reduced the production of both interferon-gamma and IL-17,
      while Th1-promoting conditions increased the production of these cytokines. These
      results demonstrate that RA Th2 clones readily switch, while Th1 and Th0 clones
      are stable. However, induction of Th2 cytokines can be obtained in polyclonal
      polarized memory T cells due to amplification of Tc2 cells.

PMID- 10404045
TI  - Why so many coinhibitory receptors?
AB  - Receptors that display negative signalling functions on lymphocytes and other
      cells of the reticuloendothelial system now number about 30. These negative
      receptors are transmembrane glycoproteins activated by phosphorylation of a
      tyrosine residue in immunoreceptor tyrosine-based inhibitory motifs that bind
      various phosphatases to induce dominant negative signals. Since these receptors
      are armed by the action of activating receptors and inhibit signalling by
      activating receptors, we have termed them coinhibitory receptors and the negative
      outcome is coinhibition. Coinhibitory receptors and some inhibitory mediators
      include FcgammaRIIB, CTLA-4, CD5, CD22, p58/70/140 KIR, gp49B1/gp91, PIRB1-5,
      LAIR-1, NKB1, Ly49 A/C/E/F/G, NKG2-A/B APC-R, CD66, CD72, PD-1, SHPS-1, SIRP
      alpha1, ILT1-5, MIR7, 10, hMIR(HM18), hMIR(HM9), LIR1-3,5,8, Fas (CD95), TGFbeta
      R, TNF-R1, IFNgamma-R (alpha and beta chains), mast cell function Ag, H2-M, HLA
      DM, CD1, CD1-d, CD46, c-cbl, Pyk2/FADK2, P130 Ca rel prot, PGDF-R, LIF, LIF-R,
      CIS, SOCS13 and 5, and others are being defined regularly. This long list
      suggests that coinhibitors are needed not only for self-nonself discrimination,
      but also for control of ongoing responses to foreign antigens so that infectious
      agents are ideally dealt with by an appropriate level of immune responses to
      nonself and an appropriate amount of immunopathology and sickness behaviour.

PMID- 10404046
TI  - Molecular characterization of the VH1-specific variable region determinants
      recognized by anti-idiotypic monoclonal antibodies G6 and G8.
AB  - Mutational analysis was used to determine the structural basis for the binding of
      the murine anti-idiotypic (anti-Id) monoclonal antibodies (MoAb) G6 and G8 to VH1
      encoded antibodies. The MoAb G6 binds a cross-reactive idiotope present on the
      heavy (H) chains of immunoglobulins (Ig) encoded by 51p1-related gene segments,
      but not those encoded by hv1263-related gene segments. Gene segments 51p1 (DP-10)
      and hv1263 differ by only four amino acids; three in complementarity-determining
      region 2 (CDR2), and one in framework region 3 (FR3). The MoAb G8 also binds 51p1
      related sequences, although it is undetermined whether G8 can bind hv1263-related
      sequences. In order to localise the Ids recognized by MoAbs G6 and G8 on 51p1
      encoded antibodies, recombinant antibodies containing H-chain mutants were
      expressed in insect cells. Idiotypic analysis on the expressed recombinant
      proteins definitively localised the reactivity in each molecule. These studies
      should be important in the structural appreciation for critical serological
      reagents.

PMID- 10404047
TI  - Immunoglobulin-secreting cells in cord blood: effects of Epstein-Barr virus and
      interleukin-4.
AB  - The contribution of cord blood B lymphocytes to the immune response has been
      under considerable investigation. Cord blood B cells produce almost no antibodies
      except of the immunoglobulin (Ig)M isotype, indicating immaturity of the cells or
      the environment they reside in. The aim of this study was to investigate the
      number of circulating IgA-, IgM-, IgG-, and IgE-producing cells in cord blood in
      comparison to adult peripheral blood using the ELISPOT method. Moreover, we
      studied the effect of transformation with the Epstein-Barr virus (EBV) on the
      proportion of cells producing different isotypes with or without interleukin (IL)
      4. Cord blood had IgM-producing cells circulating predominantly, but also some
      IgA- and IgG-producing cells, whereas adult peripheral blood contained high
      amounts of circulating IgA-producing cells and some IgM- and IgG-producing cells.
      No circulating IgE-producing cells were found in either group. Transformation by
      EBV caused significant expansion of IgA-, IgM-, and IgG-producing cells in adult
      peripheral blood, but almost only of IgM-producing cells in cord blood. A low but
      detectable expansion of IgA- and IgG-producing cells was found. Cells producing
      IgE were still not found, even after EBV transformation. However, EBV
      transformation in the presence of IL-4 increased the numbers of IgE-producing
      cells significantly both in cord blood and adult peripheral blood. These findings
      indicate that cord blood contains some circulating IgA- and IgG-producing cells
      that are expanded to some extent after EBV infection. They also indicate that
      cord blood B cells have a similar capacity for IgE production to adult peripheral
      blood B cells when appropriately stimulated.

PMID- 10404049
TI  - The influence of age and breeding conditions on the number and proliferation of
      intraepithelial lymphocytes in pigs.
AB  - The number and subset composition of intraepithelial lymphocytes (IEL) were
      studied in pigs in different age groups ranging from 1 day to 4.5 years. There
      were no major differences between the numbers of IEL in the jejunum and ileum.
      The postnatal increase of IEL largely depended on the breeding conditions: in
      germ-free animals there was a constant level, while in conventionally bred pigs
      the numbers increased more obviously than in specified pathogen-free (SPF) pigs.
      As the numbers of IEL can rise due to increased influx from other organs,
      decreased emigration, decreased apoptosis or local proliferation, the
      incorporation of the DNA precursor bromodeoxyuridine (BrdU) by IEL was studied
      after different labelling protocols. There were low but definite numbers of BrdU+
      IEL 1 h after BrdU, indicating in-situ proliferation in conventional animals with
      a tendency to a higher index in the jejunum than the ileum. Repetitive labelling
      protocols for 14 days resulted in 12-20% BrdU+ IEL, which may be caused by local
      proliferation and immigration of lymphocytes produced in other lymphoid organs as
      documented for the pig. Future studies need to focus on the factors regulating
      local proliferation and the migration of IEL in different species.

PMID- 10404048
TI  - Detection of B cells and proinflammatory cytokines in atherosclerotic plaques of
      hypercholesterolaemic apolipoprotein E knockout mice.
AB  - Atherosclerosis, the main lethal disease in the Western world, is associated with
      a cellular immune response in the arterial lesions and a humoral immune response
      directed towards oxidized lipoproteins, certain microbes and other antigens. The
      local immune response is dominated by macrophages and T cells, while to date, the
      role of B cells in lesions has been unclear. We analysed B-cell involvement in
      lesions using the apolipoprotein E knockout mouse, an experimental model that
      develops accelerated atherosclerosis when fed a lipid-rich diet. Both early fatty
      streak-type lesions and full-blown atherosclerotic plaques of these mice
      contained CD22+ B cells. They accumulated predominantly in the base of lesions,
      where high expression levels of vascular cell adhesion molecule-1 (VCAM-1) were
      observed in other cells. Cells expressing interleukin-6 and tumour necrosis
      factor-alpha were also detected and IgM was abundant in this region. These data
      show that B cells participate in atherosclerosis in this experimental model; the
      data also suggest that these cells may accumulate through VCAM-1 expression by
      surrounding cells and may produce antibodies and proinflammatory cytokines. These
      factors are likely to be important in the pathogenesis of atherosclerosis.

PMID- 10404050
TI  - Inflammation and severe demyelination in the peripheral nervous system induced by
      the intraneural injection of recombinant mouse interleukin-12.
AB  - Inflammatory cytokines appear to be involved in damage to Schwann cells, myelin
      and axons, although the exact role of the different cytokines is uncertain. The
      direct injection model offers a new and simplified way of examining the
      mechanisms of early inflammation in the peripheral nervous system. The present
      study was performed to assess the direct effects of interleukin (IL)-12 on rat
      sciatic nerves injected with recombinant mouse IL-12. Histological and
      immunohistochemical examination 24 h after injection showed early inflammation as
      well as demyelination within the injected nerve fibres. By 4 days the
      inflammatory and demyelinating changes were significantly increased. Seven days
      after injection, the endoneurium still contained significant numbers of
      inflammatory cells and the demyelination was even more severe. Control rats
      injected with sterile phosphate-buffered saline exhibited no such inflammatory
      and demyelinating response. These changes are similar to those seen in
      inflammatory and demyelinating disorders of the peripheral nervous system and
      suggest that IL-12 could be relevant to the pathogenesis of demyelinating
      diseases such as Guillain-Barre syndrome.

PMID- 10404051
TI  - Low responsiveness to immunization with immunoglobulin E/antigen and
      immunoglobulin G/antigen complexes in H-2Ab mice.
AB  - Immunoglobulin (Ig)E and IgG antibodies specific for 2,4, 6-trinitrophenyl (TNP)
      are able to enhance the carrier-specific antibody response to TNP-conjugated
      soluble proteins such as bovine serum albumin (BSA). We have recently reported
      that mice carrying the MHC class II Ab molecule are low responders to
      immunization with IgE/antigen complexes and now show that H-2Ab mice are also low
      responders to IgG/antigen complexes. In addition, we found that spleen cells from
      naive low- and high-responder mice captured IgE/antigen complexes exclusively on
      B cells, and that the binding was completely inhibited by monoclonal antibodies
      (MoAbs) against the low-affinity receptor for IgE (FcepsilonRII or CD23). The
      IgG/antigen complexes were targeted both to B cells and macrophages. The binding
      of IgG/antigen to B cells primarily seemed to be dependent on the low-affinity
      receptor for IgG (FcgammaRII or CD32), although some influence of complement
      receptor 2 (CR2 or CD21) was seen. Capture of IgG/antigen complexes on
      macrophages was partially blocked by MoAbs against FcgammaRII/III. There was no
      difference in expression of FcepsilonRII, FcgammaRII/III, CR1, CR2, and CR3
      between low- and high-responder strains, thus excluding low levels of these FcRs
      and CRs as a reason for low responsiveness in H-2Ab mice.

PMID- 10404052
TI  - Expression of activation and costimulatory elements by human intestinal
      intraepithelial lymphocytes.
AB  - It is unclear whether human intestinal intraepithelial T lymphocytes (iIEL) are
      resting or activated cells. To address this question, an improved isolation
      procedure was developed for small bowel iIEL, which were analysed by two-colour
      flow cytometry and compared with resting and mitogen-activated peripheral blood
      lymphocytes. iIEL expression of CD44 isoforms, Bcl-2 and Ki67 antigen was also
      determined in tissue sections. iIEL expressed CD69 at levels comparable with 48
      72 h phytohaemagglutinin blasts, but did not express CD25 or CD95. iIEL were Bcl
      2+ but not Ki67+. alphaEbeta7 and alpha4B7 expression was relatively high,
      whereas alphaLbeta2, CD5 and CD28 were expressed at low density. Isolated iIEL
      expressed CD44 (core epitopes) at lower levels than peripheral blood lymphocytes,
      although almost all CD44 contained splice variant 6 (CD44v6). Peripheral blood
      lymphocytes expressed CD44 at very high density, but little CD44v6, even after
      activation. However, in tissue sections, iIEL showed differential labelling with
      CD44 core epitope antibodies and no detectable CD44v6, implying CD44 receptor
      occupancy or epitope masking in situ. Thus, normal iIEL express a quasi-activated
      phenotype with unusual patterns of adhesion receptors, which may act as
      costimulatory elements. These may permit iIEL to assume effector functions, with
      absence of CD25 preventing entry into the cell cycle, thereby maintaining an
      apoptosis-resistant phenotype.

PMID- 10404053
TI  - Interleukin-12 regulates the production of Bacille Calmette-Guerin-induced
      interferon-gamma from human cells in a CD40-dependent manner.
AB  - Interferon (IFN)-gamma is a cytokine which plays a critical role in the host
      defence against human tuberculosis infection. There is evidence that interleukin
      (IL)-12 can exert a potent effect in stimulating the production of IFN-gamma, and
      it is well known that a costimulatory signal provided by CD40 may enhance IL-12
      production by monocytes/macrophages. However, it is unclear whether CD40-CD40L
      stimulation is able to regulate the production of mycobacterial-induced IFN-gamma
      through an IL-12-dependent pathway. In this study, we investigated the capacity
      of the Bacille Calmette-Guerin (BCG) strain of Mycobacterium bovis to induce the
      production of interferon-gamma through IL-12 and/or CD40 costimulation from human
      cells. Our data demonstrate that anti-IL-12 antibodies markedly reduced the
      levels of IFN-gamma produced by the BCG-stimulated human cells, while exogenous
      recombinant (r)IL-12 up-regulated the production of IFN-gamma. In addition, the
      stimulatory effect of IL-12 on BCG-induced IFN-gamma secretion was specific, as
      it was significantly abolished in the presence of anti-IL-12 antibodies. We also
      observed that the presence of an anti-CD40L monoclonal antibody significantly
      inhibited the production of IL-12 and IFN-gamma by human cells activated with
      BCG. In contrast, an isotype control antibody showed no effect on cytokine
      production. Furthermore, the presence of a trimeric soluble CD40L agonist (CD40T)
      in cultures increased the production of IL-12 and IFN-gamma. Importantly, the
      stimulatory capacity of CD40T on BCG-induced IFN-gamma secretion was blocked by a
      monoclonal antibody against IL-12, indicating that the effect of CD40T on T cells
      was mediated through IL-12. Together, these studies are the first to demonstrate
      that BCG-induced IFN-gamma production by human cells appears to be mediated by IL
      12 in a CD40-dependent manner and suggest that CD40-CD40L activation may be a
      critical mediator in regulating the immune response to stimulation with BCG.

PMID- 10404054
TI  - Increased expression of down-regulatory CTLA-4 molecule on T lymphocytes from
      rheumatoid synovial compartment.
AB  - Since the CTLA-4 molecule expressed on activated T lymphocytes has recently been
      suggested to be an important negative regulator in autoimmune diseases, this
      study was undertaken to investigate the expression and function of CTLA-4 on
      synovial T cells from patients with rheumatoid arthritis. CTLA-4-expressing T
      cells were detected using a dual fluorescence flow cytometric method. Only a
      small percentage of peripheral blood T cells from patients with rheumatoid
      arthritis had detectable surface CTLA-4 expression (mean +/- SD, 1. 89 +/-
      1.92%). However, the levels of CTLA-4-positive T cells was increased
      significantly in rheumatoid synovial fluids (5.44 +/- 4. 96%) and synovial
      membranes (28.76 +/- 14.30%). To explore the role of CTLA-4 molecule in the
      inflammation of rheumatoid joints, CTLA-4 was blocked with anti-CTLA-4 antibody
      to assess its effects on the production of tumour necrosis factor alpha and
      interleukin 1beta in synovial fluid mononuclear cell culture. The addition of
      anti-CTLA-4 antibody enhanced the production of tumour necrosis factor alpha and
      interleukin 1beta in a dose-dependent manner. The data suggest that the
      expression of CTLA-4 plays a down-regulatory role in rheumatoid articular
      inflammation. We thus concluded that CTLA-4 was up-regulated on synovial T cells
      from patients with RA, and the increased CTLA-4 expression might exert a down
      regulation effect on tumour necrosis factor alpha and interleukin 1beta
      production.

PMID- 10404055
TI  - Prophylactic intravenous immunoglobulin treatment influences serum immunoglobulin
      M repertoire development after allogeneic bone marrow transplantation.
AB  - Patients treated with allogeneic bone marrow transplantation (BMT) suffer from a
      deficient humoral immunity during the post-transplant period. To prevent
      infections patients may receive prophylactic intravenous immunoglobulin (IVIG)
      therapy from 1 week before to 3 months after BMT. We have studied the effect of
      IVIG treatment on reconstitution of immunoglobulin repertoires in transplanted
      patients. Sera obtained from 13 IVIG-treated and 31 non-IVIG-treated patients
      before and at different time points after BMT, ranging from 3 days to 3 years,
      and from 18 healthy controls, were analyzed using a quantitative immunoblot
      system. The average immunoglobulin (Ig)M and IgG reactivity profiles against
      antigens derived from human liver, muscle and skin as well as Staphylococcus
      epidermidis protein extracts were similar in both patient groups and in controls.
      Both IgG and IgM reactivity profiles are, however, less heterogeneous among the
      individuals in the IVIG-treated patient group. Around 1 year after BMT the
      heterogeneity of the IgM reactivity profiles against allogeneic protein extracts
      is much lower in the IVIG-treated group compared to the non-IVIG-treated group
      and the healthy controls. This effect remains months to years after the IVIG
      treatment has been completed. Our results suggest that IVIG influences selection
      of the natural antibody repertoire mediated by the variable (V)-region during
      reconstitution after BMT.

PMID- 10404056
TI  - Specific immune response to human immunodeficiency virus (HIV)-1 in patients
      assessed through the production of interferon-gamma and interleukin-4 in HIV-1
      p24-activated whole blood cultures: relationship with the viral load in plasma.
AB  - We studied the in vitro HIV-1 antigen-stimulated production of IFN-gamma and IL-4
      in HIV-1-infected patients and its relationship with viral replication as
      assessed through the plasma level of HIV-1 RNA. The levels of IFN-gamma and IL-4
      were higher in supernatants of stimulated whole blood cultures than in stimulated
      peripheral blood mononuclear cell cultures, therefore whole blood cultures were
      used in the rest of the study. Specific IFN-gamma and IL-4 responses to HIV-1 p24
      antigen were observed in HIV-1-infected patients but not in healthy controls (n =
      23). A lower proportion of individuals with a positive IFN-gamma response to HIV
      1 p24 was observed in patients at a declining clinical stage: 62% in asymptomatic
      patients (CDC group A, n = 16) versus 19% in symptomatic patients (CDC groups B
      and C, n = 21; P = 0.007, chi2 testing), whereas the proportion of individuals
      with a positive IL-4 response to HIV-1 p24 was almost similar in both groups of
      patients (25% versus 23.8%). Increased IL-4 production by HIV-1 p24-activated
      immunocompetent cells of patients and a predominant IL-4 response to HIV-1 p24
      (with IL-4/IFN-gamma > 1) were positively correlated with an increased viral
      load. In contrast, there was no correlation between the mitogen-stimulated
      production of IL-4 and IFN-gamma and the viral load in plasma. The CD8 T cells
      from whole blood of patients, but not from controls played a significant role in
      the HIV-1 p24-activated production of IFN-gamma and IL-4. In conclusion, HIV-1
      antigen-stimulated whole blood appears to be a valuable tool to study the
      production of IL-4 in HIV-1-infected patients. The cytokine profile pattern in
      response to epitopes of HIV-1 gag p24 may play an important role in the host
      immune response to HIV-1.

PMID- 10404057
TI  - Aspirin protects against gastric cancer: results of a case-control study from
      Moscow, Russia.
AB  - A case-control study of stomach cancer which includes 448 cases and 610 hospital
      controls has been conducted in Moscow, Russia. Information on life-style habits,
      such as smoking, alcohol consumption, diet, medical history and use of different
      medications including aspirin and other non-steroidal anti-inflammatory drugs
      (NSAIDs) was collected using a self-administered structured questionnaire. Venous
      blood was drawn from 361 cases and 441 controls. A serological test for
      Helicobacter pylori immunoglobulin G was performed to detect infected
      individuals. Use of aspirin and other NSAIDs was associated with protection
      against cancer of the stomach (OR = 0.60, 95% CI 0.41-0.90). Analysis by subsite
      revealed that aspirin did not affect the risk of cancer of the gastric cardia but
      had a protective effect for non-cardia gastric cancer. The OR associated with use
      of aspirin adjusted for age and education for both sexes combined was 0.49 (95%
      CI 0.31-0.77). A decrease in relative risk was statistically significant for men
      (OR = 0.48, 95% CI 0.25-0.92) and women (OR = 0.52, 95% CI 0.28-0.97).
      Controlling for major risk factors did not attenuate the reduction in risk. The
      observed associations were also present in individuals who were H. pylori
      immunoglobulin G-positive. There was no reduction in risk associated with aspirin
      and/or non-aspirin NSAIDs among non-infected subjects.

PMID- 10404058
TI  - Detection of tenascin-C isoforms in colorectal mucosa, ulcerative colitis,
      carcinomas and liver metastases.
AB  - The glycoprotein tenascin-C is up-regulated in inflammatory and neoplastic
      diseases. Most available data on tissue tenascin-C content do not distinguish its
      various isoforms. We have quantified tissue tenascin-C signals in colorectal
      mucosa, ulcerative colitis, colorectal carcinomas and liver metastases using 5
      monoclonal antibodies (MAbs) with different binding sites. Tenascin-C of tissue
      extracts was analyzed by a standardized Western blot technique and densitometry.
      As a reference MAb, K8 displayed tenascin-C tissue concentrations of 4.1 +/- 2.3
      microgram/mg total protein in normal mucosa, 13.8 +/- 4.7 microgram/mg in
      ulcerative colitis, 28.8 +/- 14.5 microgram/mg in colorectal carcinomas and 25.6
      +/- 8.9 microgram/mg in liver metastases. The optical density values per
      microgram protein tissue extract of the 5 MAbs reflect the levels of the
      corresponding tenascin-C epitopes. Various signal intensities indicate a distinct
      diagnostic usefulness of the MAbs in detecting colorectal carcinomas. The binding
      characteristics of MAb J1/tn2 point to an under-representation of the TNfnD
      domain in metastasizing colorectal carcinomas, while MAb 19H12 showed an
      increased binding rate on the TNfnA1,2,4 region. Our comparative study of
      tenascin-C in inflammatory and neoplastic diseases of the colon mucosa
      substantiates the occurrence of large differences in the diagnostic value of
      tenascin-C MAbs. The detected alterations of tenascin-C in metastasizing
      colorectal carcinomas might indicate a prognostic value of specific tenascin-C
      isoforms.

PMID- 10404059
TI  - Physical activity, water intake and risk of colorectal cancer in Taiwan: a
      hospital-based case-control study.
AB  - The age-adjusted mortality rates of colorectal cancer have been rising in Taiwan
      over the past 2 decades, and colorectal cancer is now the third leading cause of
      cancer mortality in the country. We conducted a hospital-based case-control study
      to clarify the nature of the association between physical activity, water intake
      and colorectal-cancer risk in Taiwan. A total of 163 subjects (aged 33-80 years)
      with histologically confirmed primary colorectal cancer and 163 hospital controls
      were enrolled during 1992. Dietary intake, physical activity and other lifestyle
      activities were assessed using a comprehensive food-frequency and lifestyle
      activity questionnaire. Adjusted odds ratios (OR) and 95% confidence intervals
      (CI) were estimated using conditional logistic-regression analysis. A strong
      inverse dose-response relation between increased water intake and rectal cancer
      was found among men after adjustment for other risk factors (p for trend =
      0.0005). The OR for rectal cancer among men in the highest tertile of water
      intake was 0.08 (95% CI, 0.02-0.35) compared with that among men in the lowest
      tertile (OR = 1). Similar but not significant trends were seen among women (p =
      0.29). The OR for colon cancer among men with active leisure-time physical
      activity was 0.19 (95% CI, 0.05-0.77) times that among sedentary men (p for trend
      = 0.03). However, physical activity was not associated with colon-cancer risk
      among women (p = 0.48). No differences in the amount of water intake were found
      related to level of physical activity. These findings add to the evidence that
      leisure-time activity may reduce colon-cancer risk, not only in high-risk but
      also in low-risk populations, and support the potential beneficial effect of
      increased water intake in reducing colorectal-cancer risk.

PMID- 10404060
TI  - High frequency of inactivation of the imprinted H19 gene in "sporadic"
      hepatoblastoma.
AB  - Embryonal tumors such as Wilms' tumor (WT), embryonal rhabdomyosarcoma (eRMS) and
      hepatoblastoma have been thought to have a common pathogenetic mechanism. H19 was
      found to be inactivated in WT and eRMS either by loss of heterozygosity or by
      hypermethylation of the maternal allele. We show here that the expression of the
      H19 gene is inactivated by maternal allelic loss or hypermethylation in 7 out of
      8 "sporadic" hepatoblastomas. Furthermore, we analyzed expression of the IGF2
      gene. Loss of imprinting of the IGF2 gene was detected and linked to inactivation
      of the H19 gene in 2 hepatoblastomas. However, 2 sporadic cases demonstrated
      monoallelic expression of the IGF2 gene with inactivation of the H19 gene. Our
      results suggest that H19 may play a role as a common imprinted tumor suppressor
      gene in "sporadic" hepatoblastomas but may at times work independently of IGF2
      expression.

PMID- 10404061
TI  - Detection of recurrent chromosomal gains and losses in primary nasopharyngeal
      carcinoma by comparative genomic hybridisation.
AB  - Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China but rare in
      Western countries. To search for genetic alterations in NPC, we examined a series
      of 20 primary tumours with comparative genomic hybridisation. The identified
      common chromosomal alterations included gain of chromosomes 1q, 8, 12, 19 and 20
      as well as loss of chromosomes 1p, 3p, 9p, 9q, 11q, 13q, 14q and 16q. In
      concordance with our previous loss of heterozygosity studies in primary NPC, a
      high incidence of loss was detected on chromosomes 3p (75%), 11q (70%) and 14q
      (65%). Losses of 9q (60%), 13q (50%) and 16q (40%) were also identified. Novel
      chromosomal gains were observed on chromosome 12, with a high frequency (70%).
      Current analysis has revealed a comprehensive profile of the chromosomal regions
      showing losses and gains in primary NPC. Our findings may provide an entry point
      for conducting further investigations to locate the putative tumour-suppresser
      genes and oncogenes that may be involved in the tumourigenesis of NPC.

PMID- 10404062
TI  - beta-catenin expression in primary and metastatic colorectal carcinoma.
AB  - beta-catenin plays a fundamental role in the regulation of the E-cadherin-catenin
      cell adhesion complex. It also functions in growth signalling events,
      independently of the cadherin-catenin complex, and these signalling pathways are
      disturbed in colorectal cancer. Mutations in either the APC or beta-catenin genes
      in colorectal cancer cells result in up-regulation of protein expression and
      subsequent cytoplasmic and nuclear distribution of beta-catenin. In this study,
      we examined beta-catenin expression in 47 primary colorectal tumors and the
      corresponding liver metastases. Immunohistochemical studies demonstrated loss of
      membranous beta-catenin expression in 26% of primary tumors and 60% of liver
      metastases and a concomitant increase in cytoplasmic and nuclear staining.
      Widespread nuclear expression of beta-catenin was found in 64% of primary tumors
      and 21% of liver metastases. No associations were found between any form of beta
      catenin expression and either tumor stage or tumor grade. Cellular distribution
      of beta-catenin was also examined by detergent extraction and Western blot
      analysis in 16 primary tumors and 23 liver metastases. This analysis showed that
      most tumors demonstrated reduced beta-catenin in the cytoskeletal fraction and
      increased beta-catenin in the cytosolic fraction. Furthermore, 3 liver metastases
      were found to contain a truncated beta-catenin protein of approximately M(r)
      80,000. Immunoprecipitation studies showed that the truncated beta-catenin
      proteins only bound weakly to E-cadherin and beta-catenin compared with non
      truncated beta-catenin. These results demonstrate gross alterations in the
      cellular distribution of beta-catenin in primary colorectal cancers with
      metastatic potential, as well as in the metastatic tumors. These changes may be
      the consequence of APC or beta-catenin gene mutations, or possibly result from a
      post-translational modification of the E-cadherin-catenin complex.

PMID- 10404063
TI  - Predominant germ-line mutation of the hMSH2 gene in Japanese hereditary non
      polyposis colorectal cancer kindreds.
AB  - By means of PCR-SSCP and direct sequencing, we detected 12 germ-line mutations of
      hMSH2 or hMLH1 in 37 Japanese hereditary non-polyposis colorectal cancer (HNPCC)
      kindreds, of whom 15 satisfied the Amsterdam and 22 the Japanese criteria. The
      germ-line mutation detection rate of hMSH2 was much higher than that of hMLH1
      (11/37 vs. 1/37). The total mutation detection rate of hMSH2 and hMLH1 in the
      Amsterdam criteria group was significantly higher than that in the Japanese
      criteria group (9/15 vs. 3/22). Furthermore, the mean age of the HNPCC patients
      in the mutation-positive group was lower than that in the mutation-negative one;
      the rates of both vertical transmission and multiplicity of tumors in the
      mutation-positive group were higher than those in the mutation-negative one. In
      addition, the number of patients with microsatellite instability-positive cancers
      in the mutation-positive group was higher than that in the mutation-negative one.
      Our results suggest firstly that the hMSH2 gene plays a much more important role
      than hMLH1 in the carcinogenesis of Japanese HNPCC patients, secondly that the
      rate of hMSH2 and hMLH1 mutations is high in the kindreds satisfying the
      Amsterdam criteria and thirdly that both the clinical phenotypes (early onset,
      vertical transmission and multiplicity of tumors) and the microsatellite
      instability status are important for the genetic screening of HNPCC.

PMID- 10404064
TI  - Gene-environment interaction in hereditary nonpolyposis colorectal cancer with
      implications for diagnosis and genetic testing.
AB  - Hereditary nonpolyposis colorectal cancer (Lynch syndrome) is an autosomal
      dominant disease caused by mutations in the mismatch repair genes in particular
      in MLH1, MSH2 and MSH6. The disease is characterized by the development of
      colorectal, endometrial cancer and several other cancers. There is evidence that
      the clinical expression of the disease varies from one country to another. This
      variation might affect not only the application of criteria proposed to identify
      families but also clinical risk factors reported to predict the outcome of
      genetic testing. Data on site of the cancer, age at diagnosis and pathology were
      collected from 155 families with suspected HNPCC known at the Korean and Dutch
      HNPCC registries. DGGE, SSCP and DNA-sequencing were performed to identify MSH2,
      MLH1 and MSH6 mutations. A total of 33 Korean and 42 Dutch families met the
      clinical criteria for HNPCC. Germline mutations in the MMR-genes were found in 23
      Korean and 24 Dutch families. In families that met the Amsterdam criteria, and
      also in those associated with MLH1 mutations, more cancers of the stomach and
      pancreas were observed in the Korean families than in the Dutch HNPCC families;
      in relative terms, the incidence of cancers of the endometrium in the Korean
      families was lower. Multivariate analysis showed that an early age at diagnosis,
      and the occurrence of pancreatic cancer were independent predictive factors of
      germline mutations in MLH1, MSH2 and MSH6 in the Korean subset of families.

PMID- 10404065
TI  - Role of Helicobacter pylori cagA(+) strains and specific host immune responses on
      the development of premalignant and malignant lesions in the gastric cardia.
AB  - The incidence rates of gastric cardia and esophageal adenocarcinomas are
      increasing, but data suggest that carriage of cagA(+) Helicobacter pylori strains
      may protect against development of Barrett's esophagus and esophageal
      adenocarcinoma. Our aims were to examine the relationship between pre-malignant
      and malignant lesions in the gastric cardia and serum antibodies to H. pylori
      antigens in patients with and without complications of Barrett's esophagus. The
      prevalence of carditis was 40% in controls compared with 13% in patients with
      complicated or uncomplicated Barrett's esophagus and cardia adenocarcinoma (p <
      0.001). Cardia intestinal metaplasia (IM) and atrophy were present and concordant
      in 28% of controls but less frequent in patients with Barrett's alone or with
      dysplasia/adenocarcinoma (0% for each, p < 0.001). Carriage of cagA(+) strains
      was present in 34% of patients with carditis and significantly associated with
      increased frequency and severity of cardia inflammation, IM, and atrophy but not
      with adenocarcinoma. IgA and HspA seropositivity were significantly increased in
      H. pylori-colonized patients with carditis compared to persons with normal cardia
      histology (p </= 0.005) but not in persons with esophageal disease or cardia
      adenocarcinoma. We conclude that carriage of cagA(+) H. pylori strains and
      induction of particular serological responses are significantly associated with
      marked histological findings in the gastric cardia but not with adenocarcinoma of
      either the gastric cardia or esophagus.

PMID- 10404066
TI  - Relative cytotoxic activity of immunotoxins reactive with different epitopes on
      the extracellular domain of the c-erbB-2 (HER-2/neu) gene product p185.
AB  - Different epitopes on the extracellular domain of the HER-2 receptor can serve as
      distinct targets for immunotoxins. To determine the optimal epitope target for
      immunotoxin therapy, 7 anti-HER-2 ricin A chain murine monoclonal immunotoxins,
      each reactive with different epitopes of HER-2 receptor, were tested for
      cytotoxic activity. The immunotoxins produced 1.2-4.6 logs of cytotoxicity in
      limiting dilution clonogenic assays with 2 breast cancer cell lines that
      overexpressed HER-2. Cytotoxicity did not correlate with immunoglobulin isotype,
      binding affinity, relative position of epitopes or internalization of the anti
      HER-2 immunotoxins. Interestingly, the most and least effective immunotoxins
      bound to epitopes in very close proximity. Competitive binding assays with
      unconjugated antibodies have previously indicated that our antibodies recognized
      epitopes that are arranged in a linear array. To orient this relative epitope
      map, deletions were prepared in the HER-2/neu gene and these mutant constructs
      were expressed in NIH3T3 cells. Epitope expression was determined by antibody
      binding and radioimmunoassay. Epitopes targeted by the PB3, 454C11 and NB3
      antibodies are localized N-terminal to the epitopes recognized by ID5, BD5, 741F8
      and 520C9 antibodies. The 2 non-conformational epitopes PB3 and NB3 were
      localized to regions corresponding to amino acides 78-242 of the p185(HER-2)
      protein.

PMID- 10404067
TI  - Immunotherapy with effector cells and IL-2 of lymph node metastases of human
      squamous-cell carcinoma of the head and neck established in nude mice.
AB  - We have previously reported that immune anti-tumor effector cells, both cytotoxic
      T lymphocytes (CTLs) and IL-2-activated natural killer (A-NK) cells, are
      effective at eliminating human head-and-neck cancer (HNC) targets in vitro and in
      vivo in xenograft models. In this study, these 2 types of human effector cell
      were compared for the ability to prevent the development of lymph node metastases
      in a metastasis model of human squamous-cell carcinoma of the head and neck
      (SCCHN) established in nude mice. A tumor cell line, OSC-19, was injected into
      the floor of the mouth in nude mice, and the tumor grew progressively and
      metastasized to cervical lymph nodes by day 21. As effector cells, a human HLA-A2
      restricted CTL line recognizing a shared antigen on OSC-19 and human non-MHC
      restricted A-NK cells were used. Both types of effector cell mediated high levels
      of lysis against OSC-19 targets in 4-hr (51)Cr-release assays. Administration of
      human CTLs or A-NK cells and IL-2 to the site of tumor growth in mice with 7-day
      OSC-19 tumors resulted in significant reduction of the number of lymph node
      metastases relative to untreated or sham-operated controls or to mice treated
      with IL-2 without the effector cells. Our results suggest that in a xenograft
      model of human SCCHN implanted in the oral cavity of nude mice, the development
      of lymph node metastases can be successfully controlled by adoptive transfer of
      human SCCHN-specific CTLs or SCCHN-reactive A-NK cells plus IL-2.

PMID- 10404068
TI  - Treatment of neoplastic meningeal xenografts by intraventricular administration
      of an antiganglioside monoclonal antibody, 3F8.
AB  - Leptomeningeal (LM) neoplastic metastases are painful, debilitating and
      inevitably lethal. Intrathecal (IT) anti-tumor antibodies may have therapeutic
      potential. We evaluated 3F8, an anti-G(D2) murine IgG(3) monoclonal antibody
      (MAb) in the treatment of human melanoma (SKMEL-1) and neuroblastoma (NMB7)
      xenografts in athymic rats. Both tumors were lysed efficiently in vitro by 3F8 in
      the presence of rat neutrophils or rat complement. Antibody-dependent cellular
      cytotoxicity (ADCC) was not augmented by recombinant human GM-CSF (rhGM-CSF), rhG
      CSF, recombinant rat MIP-2 (rrMIP-2) or lipopolysaccharide (LPS). In vivo,
      continuous intraventricular administration of 3F8 and LPS prevented tumor
      engraftment, retarded tumor growth and eradicated 3-day-old established
      xenografts whereas 3F8 alone, LPS alone or F(ab)'(2) plus LPS had no or only
      marginal effects. Tumor establishment in brain was completely prevented in 36% of
      animals implanted with SKMEL-1 and 65% of animals implanted with NMB7. Twenty
      percent of established xenografts around the brain were eradicated but all
      animals had persistent tumor in the lumbosacral meninges despite treatment.
      Continuous intraventricular infusion of LPS produced a variable polymorphonuclear
      (PMN) pleocytosis that was dose-dependent. Continuous intraventricular infusion
      of 3F8 produced immunohistochemically detectable attachment to 86% of persistent
      brain deposits of tumor but <1% of spinal lumbosacral deposits. We conclude that
      regional therapy with anti-G(D2) MAb could target neutrophils to inhibit LM tumor
      growth. However, optimal activation and mobilization of neutrophils into the
      cerebrospinal fluid (CSF) and improved penetration of MAb to tumor sites remain
      critical variables.

PMID- 10404069
TI  - Acquired immunity in nude mice induced by expression of the IL-2 or IL-4 gene in
      human pancreatic carcinoma cells and anti-tumor effect generated by in vivo gene
      transfer using retrovirus.
AB  - We have examined the anti-tumor effect in nude mice caused by human pancreatic
      cancer cells (AsPC-1) modified to secrete IL-2 or IL-4. Loss of tumorigenicity of
      cytokine-producing, but not wild-type, cells was observed despite their unaltered
      in vitro proliferation rates; and these anti-tumor effects were dependent on the
      amount of cytokine released. Wild-type cells inoculated into mice which had
      rejected IL-2- or IL-4-producer cells showed significant growth retardation,
      while no retardation was detected when unrelated human colon carcinoma cells were
      inoculated. Histological examination of regressing IL-2- or IL-4-producing AsPC-1
      tumors in nude mice revealed infiltration by CD11b-, but not CD90-, positive
      cells around the tumors. Treatment of nude mice with anti-asialoGM(1) antibody
      did not affect loss of tumorigenicity. Mice injected i.p. with IL-2- or IL-4
      producing AsPC-1 cells did not die, in contrast to mice inoculated with wild-type
      cells. Injection of retrovirus-bearing IL-2, but not beta-galactosidase, gene
      into mice which had wild-type cells in the peritoneal cavity also significantly
      prolonged survival. Thus, expression of the IL-2 or IL-4 gene in AsPC-1 cells may
      generate tumor-specific acquired immunity, even in mature T cell-deficient
      conditions. An anti-tumor response can be induced by in vivo transfer of the IL-2
      gene.

PMID- 10404070
TI  - 6-thioguanine resistance in a human colon carcinoma cell line with unaltered
      levels of hypoxanthine guanine phosphoribosyltransferase activity.
AB  - Cell populations resistant to high doses (30 microM) of 6-thioguanine (6-TG, 6
      TG(r) cells) were selected from a human colon carcinoma cell line, LoVo. This
      cell line, which lacks hMSH2, a component of the human mismatch binding
      heterodimer hMutSalpha, is resistant to low doses of 6-TG. The level of activity
      of hypoxanthine-guanine phosphoribosyltransferase, the enzyme responsible for the
      phosphoribosylation of the thiopurine, was comparable to that expressed in the
      parental cells. No significant difference was found in the levels of enzyme
      activities involved in the conversion of 6-TG or its derivatives into non-toxic
      compounds. In contrast, a significant difference was found in the uptake kinetics
      of 6-TG in the 2 cell types. Net uptake of 6-TG ceased after 100-sec incubation
      in the 6-TG(r) cells, while it appeared to continue throughout the 10-min
      incubation in the wild-type cells. As a consequence, after 10-min incubation, the
      total amount of 6-TG taken up by the parental LoVo cells was approximately 3
      times higher than that present in the 6-TG(r) cells.

PMID- 10404071
TI  - Mutated cytochrome b as a determinant of a new monoclonal antibody (H8.98) on
      renal carcinoma cell lines recognized by a Vgamma3Vdelta1(+) T-cell clone.
AB  - We generated a monoclonal antibody (MAb), H8.98, that recognizes an antigen
      shared by 50% of examined renal carcinoma cell (RCC) lines and is susceptible to
      lysis by a Vgamma3Vdelta1(+) T-cell clone derived from RCC tumor-infiltrating
      lymphocytes. H8.98 inhibited Vgamma3Vdelta1(+ )T-cell clone-mediated lysis of RCC
      lines. It did not stain normal kidney lines, melanomas, fibroblasts, Burkitt's
      lymphoma or Epstein-Barr virus-transformed B-cell lines but it did stain 2 of 4
      tested breast cancer lines. Through screening of a renal carcinoma cDNA library
      using H8.98, we isolated a cDNA clone which, upon sequencing, was found to be
      cytochrome b with 2 point mutations.

PMID- 10404072
TI  - Antigen-specific cytotoxicity and cell number of adoptively transferred T cells
      are efficiently maintained in vivo by re-stimulation with an antigen/interleukin
      2 fusion protein.
AB  - In order to maintain in vivo anti-tumor efficacy of antigen (Ag)-specific T cells
      in adoptive immunotherapy for a prolonged period, we constructed a fusion protein
      (OVA/IL-2) containing ovalbumin (OVA) as a model tumor Ag, co-valently linked to
      murine interleukin-2 (IL-2). The OVA/IL-2 protein produced in a baculovirus
      expression system displayed potent IL-2 bio-activity. Immunization with the
      OVA/IL-2 protein after adoptive transfer of OVA-specific T cells maintained the
      OVA-specific cytotoxicity and cell number of adoptively transferred T cells long
      term in vivo, while a simple mixture of recombinant OVA (rOVA) and rIL-2 did not.
      The response was dependent on the injection doses and times of the OVA/IL-2
      protein. Furthermore, weekly re-stimulation of adoptively transferred OVA
      specific T cells with the OVA/IL-2 protein cured 70% of tumor-bearing mice. In
      contrast, re-stimulation with a mixture of rOVA and rIL-2 could not significantly
      prolong the survival period of tumor-bearing mice. These studies suggest that the
      co-valent linkage between IL-2 and antigen confines the effect of IL-2 to antigen
      specific T cells, leading to efficient maintenance of the anti-tumor activity of
      adoptively transferred T cells.

PMID- 10404073
TI  - Anti-sense inhibition of small-heat-shock-protein (HSP27) expression in MCF-7
      mammary-carcinoma cells induces their spontaneous acquisition of a secretory
      phenotype.
AB  - This work was aimed at testing the hypothesis (hitherto supported only by
      indirect evidence) that, besides contributing to resistance to stress, the small
      heat-shock-protein HSP27 might be involved in the control of growth and
      differentiation in mammary-tumour cells, where it is known to be oestrogen
      regulated. Therefore, MCF-7 cells were transfected with a modulatable human hsp27
      anti-sense cDNA. Clones of transfectants (designated alphahsp27) were selected
      which, upon expression of the anti-sense, exhibited a decline in HSP27
      accumulation, associated with a decrease in resistance to heat shock and in
      proliferation rate, the degree of the latter reflecting their respective
      reduction in HSP27 content. The effects of anti-sense inhibition of HSP27
      production were similar to those exerted on parental cells by phorbol myristate
      (TPA). Both resulted in growth inhibition, accumulation of lipid droplets in the
      cytoplasm, formation of secretory microvesicles with internal microvilli and
      increased release of several proteins, including the isoforms of a 52-kDa
      protein, which we identified as the oestrogen-regulated protein cathepsin D, all
      this without noticeable change in actin organization. These data constitute the
      first direct support for the hypothesis that, at least in some cell types, HSP27
      might play a modulatory role in cell differentiation and (perhaps by this) in
      proliferation. While allowing dissociation of this role from the known action of
      HSP27 on actin polymerization, they suggest similar modulation of the function of
      some protein(s) implicated in the acquisition of the secretory phenotype by MCF-7
      cells, with HSP27 also exerting an inhibitory action that can be alleviated
      either by its phosphorylation (as occurs with TPA) or by inhibition of its
      production.

PMID- 10404074
TI  - Lack of p73 mutations and late occurrence of p73 allelic deletions in melanoma
      tissues and cell lines.
AB  - A novel gene, termed p73 with significant homology to p53, has been identified at
      1p36, a chromosomal region which is frequently deleted in malignant melanoma. To
      determine whether p73 is involved in melanoma development we analyzed 8 benign
      melanocytic nevi, 17 primary melanomas, 34 melanoma metastases and 9 melanoma
      cell lines for p73 alterations. Allelic loss at the p73 locus was observed in 2
      of 10 cases (20%) and occurred only in metastatic tumors. Mutation analysis of
      the DNA-binding domain of p73 revealed no somatic mutations in the tumor
      specimens and melanoma cell lines analyzed, whereas the p53 gene was mutated in 5
      of 9 melanoma cell lines. Expression analysis of p73 using semiquantitative RT
      PCR demonstrated that p73 is not expressed or at exceedingly low levels in benign
      melanocytic nevi, primary melanomas and lymph node metastases, but at various
      levels in melanoma cell lines. Our data indicate that p73 does not play a role as
      a tumor suppressor in melanoma development.

PMID- 10404075
TI  - Expression of fas ligand in human hepatoma cell lines: role of hepatitis-B virus
      X (HBX) in induction of Fas ligand.
AB  - It has been postulated that tumor cells expressing Fas ligand (FasL) can evade
      immune surveillance by inducing apoptosis in T cells expressing Fas. In this
      study, we investigated FasL expression in 13 human hepatoma cell lines. Strong
      FasL expression was detected by reverse transcription-polymerase chain reaction
      or immunofluorescence in Hep G2.2.15, in which the hepatitis-B-virus (HBV) genome
      was transfected, and in SNU-354, which showed HBx transcripts. To determine the
      biological activity of FasL, Hep G2.2. 15 was co-cultured with MOLT-4, T-cell
      leukemia cells. Hep G2.2.15 induced apoptosis in MOLT-4 and this was inhibited by
      the antagonistic anti-Fas antibody, ZB4. For further analysis of the role of HBx
      in the induction of FasL, PLC/PRF/5 cells were transfected transiently with the
      HBV genome, or HBx, or the frameshift mutant of HBx. In PLC/PRF/5 cells
      transfected with the HBV genome or HBx but not in cells transfected with the
      frameshift mutant of HBx, FasL expression was detected. Our data suggest that HBx
      plays a role in the induction of FasL in hepatoma cells and in the escape from
      immune surveillance.

PMID- 10404076
TI  - Inhibition of growth of MX-1, MCF-7-MIII and MDA-MB-231 human breast cancer
      xenografts after administration of a targeted cytotoxic analog of somatostatin,
      AN-238.
AB  - Since somatostatin (sst) receptors are expressed in a high percentage of human
      breast cancers, we studied the effects of a targeted cytotoxic somatostatin
      analog (AN-238) formed by linking the highly active doxorubicin (DOX) derivative
      2-pyrrolino-DOX (AN-201) to octapeptide RC-121 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys
      Thr-NH(2)) in 3 human breast cancer models. The models included estrogen
      independent MDA-MB-231 and MX-1 and estrogen-sensitive MCF-7-MIII tumors. Nude
      mice bearing xenografts of these cancers were injected i.v. with 250 nmol/kg
      doses of cytotoxic radical AN-201, cytotoxic analog AN-238 or the unconjugated
      mixture of AN-201 and sst analog RC-121. Significant inhibition of growth of MDA
      MB-231, MX-1 and MCF-7-MIII tumors was observed 1 week after injection of a
      single dose of cytotoxic analog AN-238. The volume of MDA-MB-231 tumors remained
      significantly decreased 3 weeks after treatment. The volumes and weights of MCF-7
      MIII tumors continued to be significantly reduced 60 days after therapy with AN
      238. AN-238 also caused complete regression of MX-1 tumors in 5 of 10 animals,
      which remained tumor-free 60 days after treatment. In contrast, after treatment
      with cytotoxic radical AN-201, MDA-MB-231 and MCF-7-MIII tumors grew steadily and
      the regression of MX-1 tumors was only transitory in most animals. Toxicity of AN
      201 was much greater than that of AN-238, as measured by animal deaths, loss of
      body weight and leukopenia. High-affinity sst receptors and mRNA for both sst(2)
      and sst(5) subtypes were found in all 3 tumor lines. Expression of sst receptors
      was not significantly affected by treatment with AN-238. Our results indicate
      that the cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of
      human breast cancers expressing sst receptor subtypes 2 and 5.

PMID- 10404077
TI  - Adult T-cell leukemia cells over-express the multidrug-resistance-protein (MRP)
      and lung-resistance-protein (LRP) genes.
AB  - Adult T-cell leukemia (ATL) is a T-cell malignancy caused by human T-cell
      leukemia-virus-I (HTLV-I) infection. ATL comprises 4 clinical forms: acute,
      chronic, smoldering and lymphoma types. ATL is usually resistant to conventional
      chemotherapy and has a relatively poor prognosis; however, the resistance
      mechanisms remain undetermined. To explore the multidrug-resistance (MDR)
      mechanisms of ATL, we examined the expression and functional activity of MDR
      related genes in peripheral-blood mononuclear cells (PBMC) from ATL patients by
      semi-quantitative RT-PCR and FACScan with calcein-AM. PBMC from ATL patients
      expressed similar or higher levels of MRP, LRP and cMOAT mRNAs, as compared with
      normal PBMC. In normal controls and ATL patients, MDR1 mRNA expression was
      undetectable in this study. PBMC from acute and chronic ATL patients expressed
      significantly higher levels of MRP and LRP mRNA than did normal PBMC (p < 0.01
      and p < 0.05 respectively). In chronic ATL, positive correlations were apparent
      between levels of MRP and LRP mRNA expression (r = 0.759, p = 0.018), and between
      each mRNA level and the absolute number of abnormal lymphocytes in peripheral
      blood. Probenecid, an inhibitor of the MRP pump, significantly increased the
      accumulation of calcein in PBMC from 3 chronic ATL patients. Our findings suggest
      that the MRP and LRP genes in ATL are often activated by HTLV-I infection and may
      confer MDR of ATL cells in vivo. Combined chemotherapy with inhibitors of these
      MDR genes may be promising in the treatment of ATL.

PMID- 10404078
TI  - Synovial sarcoma specific translocation associated with both epithelial and
      spindle cell components.
AB  - The biphasic subtype of synovial sarcoma consists of both epithelial and spindle
      cell components. To address the relationship between the different cellular
      components found in synovial sarcoma, we deduced the presence of the synovial
      sarcoma-specific der(X)t(X;18)(p11.2;q11.2), and involvement of the SSX1 gene in
      both the epithelial/glandular and spindle cell components of 3 biphasic synovial
      sarcomas with wide ranging proportions of each of the 2 elements. This has been
      achieved using a 2-color fluorescence in situ hybridization (FISH) methodology
      that we had developed recently for analysis paraffin-embedded material. The
      presence of the rearrangement could be deduced in histologically defined regions
      and the results showed clearly that the rearrangement was present in both
      cellular components. This finding provides direct genetic evidence for biphasic
      synovial sarcomas being clonal and truly biphasic.

PMID- 10404079
TI  - Increased resistance to apoptosis by bone marrow CD34(+)progenitor cells from
      tumor-bearing mice.
AB  - Tumors, such as the murine Lewis lung carcinoma (LLC), produce granulocyte
      macrophage colony-stimulating factor (GM-CSF), which increases the proportion of
      CD34(+) hematopoietic progenitor cells in the bone marrow and in the periphery.
      This increase in peripheral CD34(+) cells had been attributed to the growth
      promoting and mobilizing effects of the tumor-derived GM-CSF. However, the
      possibility that the CD34(+) cells of tumor bearers might have enhanced survival
      abilities had not been considered. The present studies showed a significant
      baseline level of apoptotic cells in short-term (5-day) cultures of normal
      CD34(+) cells containing GM-CSF plus stem cell factor (SCF), and a markedly
      greater level of apoptosis in cytokine-deficient cultures. In contrast, CD34(+)
      cells from tumor bearers did not undergo such levels of apoptosis, even in the
      absence of cytokines. This resistance to apoptosis could be conferred to normal
      CD34(+) cells by culture with LLC-conditioned medium. Studies to elucidate
      possible mechanisms for the resistance to apoptosis by tumor-exposed CD34(+)
      cells showed increased levels of the pro-life gene product bcl-2. Finally, the
      resistance of tumor-exposed CD34(+) cells to ligation of the Fas receptor, a
      known apoptotic trigger in hematopoietic cells, was compared with that of control
      CD34(+) cultures. Whereas approximately half of the normal CD34(+) cells
      underwent apoptosis in response to Fas ligation, the tumor-exposed CD34(+) cells
      resisted apoptosis, even though their surface Fas expression was greater than
      that of normal CD34(+) cells. Thus, our results show that the increased level of
      CD34(+) cells in tumor bearers is due not only to an increased growth and
      mobilization of CD34(+) cells as previously thought, but also may be due to an
      increased resistance to apoptosis that is conferred by tumor-derived products and
      is associated with increased expression of bcl-2.

PMID- 10404080
TI  - Papillomavirus and p53 codon 72 polymorphism.

PMID- 10404081
TI  - Carbohydrates and risk of stomach cancer in Uruguay.

PMID- 10404082
TI  - Relationship between Fas-ligand expression on carcinoma cell and cytotoxic T
      lymphocyte response in lymphoepithelioma-like cancer of the stomach.
AB  - The Fas/Fas-ligand (Fas-L) system is involved in the induction of apoptosis and
      mediates T-cell cytotoxicity. We investigated the Fas/Fas-L system and cytotoxic
      T lymphocytes (CTLs) in 30 lymphoepithelioma-like cancer of the stomach (LECS) in
      order to understand the immune evasion of the tumor cells. Epstein-Barr virus
      (EBV) was detected in 15 cases in 30 LECSs. The expressions of Fas and Fas-L in
      tumor cells, and TIA-1, CD4, CD8 and CD56 in lymphocytes were examined by
      immunohistochemical staining. Apoptosis of tumor cells and lymphocytes was
      detected by the terminal deoxynucleotidyl-mediated dUTP-nick end labeling method
      (TUNEL). Expression of Fas and Fas-L was detected in tumor cells in 10 and 17
      LECS, respectively. CTL consisted predominantly of CD8 (CD8(+) > CD4(+)), whereas
      natural killer (NK) cells were detected in 4 cases only. In Fas-L-positive
      tumors, the TIA-1-positive lymphocyte count was significantly lower (p < 0.05)
      and the number of apoptotic lymphocytes was significantly higher (p < 0.05) than
      in Fas-L-negative cases. The number of TIA-1-positive lymphocytes in EBV(+) cases
      was significantly higher than that in the EBV(-) tumors (p < 0.05). The number of
      apoptotic tumor cells in EBV(+) tumors was significantly lower than in EBV(-)
      cases (p < 0.01). Our results suggest that in LECS, tumor cells expressing Fas-L
      may evade the immune attack by killing lymphocytes through the Fas/Fas-L system.
      However, in EBV(+) LECS tumors, our results indicate that a high number of CTL is
      associated with a reduction in the number of apoptotic tumor cells. Our findings
      indicate that the Fas/Fas-L system plays a role in immune evasion of tumor cells
      in EBV(+) tumors. Int. J. Cancer (Pred. Oncol.) 84:339-343, 1999.

PMID- 10404083
TI  - DNA amplification on chromosome 6p12 in non small cell lung cancer detected by
      arbitrarily primed polymerase chain reaction.
AB  - Gene amplification is clearly an important aspect of tumour growth and
      development and has prognostic significance in certain tumours. The
      identification and genetic characterisation of new areas of amplification in
      human malignancy remains an important goal in understanding the underlying
      genetic lesions within these tissues. In the present work, arbitrarily primed-PCR
      (AP-PCR) has been applied to detect and characterise amplified DNA fragments in
      human non small cell lung cancer (NSCLC). Our results show that gains of genomic
      sequences occur at high frequency (64% of all genomic changes analysed).
      Moreover, we succeeded in detecting a genomic sequence that is highly amplified
      in one of the tumours analysed. The amplification intensity of this DNA fragment
      was also increased in 29 (45%) of the 65 NSCLC patients from our study. The
      amplified DNA fragment was isolated and identified as a 600 bp sequence mapped to
      chromosome 6p12. This sequence did not show significant homology with known human
      DNA sequences. Interestingly, a gene related to cancer processes, the pim-1
      oncogene, is placed neighbouring to this region on chromosome 6. Survival studies
      revealed that disease-free interval of NSCLC patients was shorter in patients
      bearing the amplified sequence (p = 0.05 by the Breslow test). Our findings
      suggest that the amplified sequence located on chromosome 6 might be relevant in
      the pathogenesis of human NSCLC. Int. J. Cancer (Pred. Oncol.), 84:344-349, 1999.

PMID- 10404084
TI  - Association between CYP17 gene polymorphism and risk of breast cancer in young
      women.
AB  - Long-term exposure to oestrogens is a well-recognised risk factor for breast
      cancer, whereas little is known about the influence of polymorphisms of genes
      involved in oestrogen biosynthesis and metabolism. A candidate, containing a
      single bp polymorphism, T-->C, (designated, A2 allele), might be the CYP17 gene,
      which codes for an enzyme involved in oestrogen synthesis. This polymorphism
      creates an additional Sp1-type promoter site (CCACC box), which has been shown to
      be associated with increased serum oestrogen levels. We performed a case-control
      study, to evaluate association of the CYP17 gene polymorphism with risk of breast
      cancer in young women (younger than 37 years). We found a statistically
      significant increased risk in carriers of at least 1 A2 allele [odds ratio (OR),
      2.0; 95% confidence interval (CI), 1.1-3.5, p = 0.027], and a trend toward a gene
      dose effect illustrated by a slightly higher risk for A2-homozygous subjects (OR,
      2.8) than for heterozygous women (OR, 1. 9). Furthermore, when we investigated
      the CYP17 genotype in relation to tumour characteristics, breast cancer patients
      with 1 or 2 A2 alleles tended to have lower oestrogen receptor levels (risk
      ratio, 0.70; CI, 0.41-1.2, p = 0.44). Our findings suggest that CYP17 gene
      polymorphism influences breast carcinogenesis in young women. Int. J. Cancer
      (Pred. Oncol.) 84:350-353, 1999.

PMID- 10404085
TI  - Effect of c-erbB(2) and estrogen receptor status on survival of women with
      primary breast cancer treated with adjuvant
      cyclophosphamide/methotrexate/fluorouracil.
AB  - We have investigated the relationship between c-erbB(2) status, estrogen receptor
      (ER) status and outcome in 274 women with node-positive breast cancer who,
      following excision and axillary clearance, were randomized to receive either 6
      cycles of cyclophosphamide/methotrexate/fluorouracil (CMF) (n = 129) or no such
      treatment (n = 145). Follow-up data (median 13.3 years) were available on all
      patients. CMF improved relapse-free and overall survival of all women. The
      greatest benefit was seen in women with ER-negative tumors; the median overall
      survival of those given CMF was 11.6 years compared with only 2 years for the
      control group. For the women with ER-positive tumors the median overall survival
      of the CMF-treated women was 11.3 years compared with 7.7 years in the control
      group. When benefit from CMF was examined in relation to c-erbB(2) status, the
      women with c-erbB(2)-negative tumors who received CMF had a median overall
      survival of 12.7 years compared with only 7.3 years for the c-erbB(2)-negative
      women in the control group. The improvement in survival was less marked in the
      women with c-erbB(2)-positive tumors; median overall survival was 6.1 years for
      those who received CMF compared with 4.4 years for women in the control group.
      All women benefited from adjuvant CMF chemotherapy, those with ER-negative tumors
      benefiting the most. Int. J. Cancer (Pred. Oncol.) 84:354-359, 1999.

PMID- 10404086
TI  - Blood-based reverse transcriptase polymerase chain reaction assays for prostatic
      specific antigen: long term follow-up confirms the potential utility of this
      assay in identifying patients more likely to have biochemical recurrence (rising
      PSA) following radical prostatectomy.
AB  - Reverse transcriptase polymerase chain reaction (RT-PCR) assay is a sensitive
      technique to detect circulating cells expressing prostate-specific antigen (PSA)
      in blood or bone marrow from patients with prostate cancer. When applied to
      prostate cancer patients at our institution, this technique identifies those
      patients with a greater likelihood of extra-prostatic disease. We evaluated RT
      PCR PSA as a predictor of PSA recurrence and compared it with pre-operative
      (serum PSA, digital rectal examination, Gleason score on biopsy) and post
      operative parameters (pathological findings). Three hundred nineteen men
      scheduled for radical prostatectomy had an enhanced RT-PCR PSA assay before
      surgery. The enhanced RT-PCR PSA protocol has been previously described. PSA
      recurrence was defined as any serum PSA value above 0.2 microgram/l. Forty-six
      patients had PSA recurrence. The mean follow-up was 25.4 months. Recurrence free
      survival was 53% for patients with positive RT-PCR PSA vs. 84% if RT-PCR PSA was
      negative. By using multivariate analyses, RT-PCR PSA status was not an
      independent predictor of PSA recurrence compared to pathological stage pT3,
      Gleason score on prostate specimen and serum PSA. If only pre-operative
      parameters were studied, serum PSA and RT-PCR PSA status were 2 independent pre
      operative predictors of PSA recurrence compared with Gleason score on biopsy and
      digital rectal examination. Int. J. Cancer (Pred. Oncol.) 84:360-364, 1999.

PMID- 10404087
TI  - Stage-independent expression and genetic analysis of tp73 in neuroblastoma.
AB  - The tp73 gene, a tp53 homologue, has been sub-regionally mapped at 1p36.3, a
      chromosomal region frequently deleted in neuroblastoma. Due to its chromosomal
      localization and to the mono-allelic expression observed in some neuroblastoma
      cell lines, it was proposed that tp73 might be involved in the pathogenesis of
      neuroblastoma. Functional assays have demonstrated that tp73 can inhibit cell
      proliferation and induce apoptosis. The role of this gene in tumorigenesis,
      however, is still unclear. We analyzed tp73 expression in 95 sporadic
      neuroblastoma samples by RT-PCR and we detected the tp73 transcript in 46 cases
      (48.4%), without significant correlation with age, clinical stage or 3-year
      overall survival. A genetic polymorphism in the 2nd exon of tp73 was utilized to
      identify the transcribed allele in tumor-cell samples. Expression from only one
      of the tp73 alleles was found in 13 out of 16 heterozygous tumors, while in 3
      samples both alleles were present. Genotype analysis of 73 patients and 150
      controls showed a significant deviation (p = 0.0308) from the Hardy-Weinberg
      equilibrium for a tp73 allele only among neuroblastoma patients. The absence of
      correlation between tp73 expression and clinical stage, age and survival suggests
      that this gene does not play an essential function in the clinical course of the
      disease. However, the distribution of genomic tp73 alleles in patients indicates
      that a role of this gene in the development of neuroblastoma cannot be completely
      ruled out. Int. J. Cancer (Pred. Oncol.) 84:365-369, 1999.

PMID- 10404088
TI  - Different patterns of chromosomal imbalances in metastasising and non
      metastasising primary breast carcinomas.
AB  - In an attempt to identify chromosomal abnormalities that may be associated with a
      metastatic phenotype, we investigated the pattern of chromosomal gains and losses
      in 66 node-positive and 63 node-negative primary breast carcinomas. For both
      subgroups of tumours, losses were more common than gains and the losses were most
      often the result of structural aberrations. The exceptions were the long arm of
      chromosome 1, and chromosomes 7, 8, 12, 18 and 20, which were more often gained
      than lost. Node-negative tumours were preferentially characterised by loss of
      6q10-21 and loss of 16q, whereas loss of chromosome 18 was significant for node
      positive tumours. Other aberrations that tended to be associated with one of the
      phenotypes, though not statistically significant, were gain of chromosome 18 and
      loss of chromosome 10 in node-negative tumours, and gain of chromosome 14 and
      loss of 12p in node-positive tumours. Our data show that there are differences
      among the genetic lesions present in node-negative and node-positive breast
      tumours. Int. J. Cancer (Pred. Oncol.) 84:370-375, 1999.

PMID- 10404089
TI  - Expression of the HMGI(Y) gene in human colorectal cancer.
AB  - Expression of HMGI(Y), a nucleoprotein that binds to A/T rich sequences in the
      minor groove of the DNA helix, is observable in neoplastically transformed cells
      but not in normal cells. We have analyzed HMGI(Y) expression in colorectal cancer
      and evaluated its clinicopathologic significance. HMGI(Y) mRNA was measured by
      CRT-PCR (competitive reverse transcription-polymerase chain reaction).
      Immunohistochemical staining for HMGI(Y), p53 and Ki-67 was performed in the same
      colon cancer tissues, and the results in colorectal tissues were similar to those
      of RT-PCR. HMGI(Y) expression evidenced by RT-PCR was observed in 63 of 64
      (98.4%) colorectal cancer samples, and 2 of 5 (40%) adenomatous polyps, whereas
      21 normal colon samples were negative (p<0.001). High HMGI(Y) expression using
      CRT-PCR was found in colon cancers with a high Ki-67 labeling index (p<0.001).
      There was no significant correlation between the levels of HMGI(Y) expression and
      stage, tumor size, lymph node metastasis, histologic grade and
      immunohistochemical status of p53. Our results indicate that the HMGI(Y)
      expression may occur at an early stage of carcinogenesis and correlate with cell
      proliferation. Int. J. Cancer (Pred. Oncol.), 84:376-380, 1999.

PMID- 10404090
TI  - Correlation of numerical and structural status of chromosome 16 with histological
      type and grade of non-invasive and invasive breast carcinomas.
AB  - Loss of heterozygosity on chromosome arm 16q frequently occurs in human breast
      carcinomas regardless of the histological grade or type. To reveal whether the
      status of chromosome 16 corresponds to the histology of breast carcinomas, we
      examined the signal number of 16cen, 16q breakpoints and 1;16 fusions in the
      interphase nuclei of 185 breast carcinomas using fluorescence in situ
      hybridization to detect the loci D16Z2 (16cen), D16Z3 (16q11), D16S154 (16q24)
      and D1Z1 (1q12). A 16q loss associated with a proximal or distal breakage was
      identified as a discrepancy between the modal signal counts of the D16Z2, D16Z3
      and D16S154 loci in each tumor. Clonal 16cen aneusomy, proximal breakages, distal
      breakages and 1;16 fusion were detected in 62%, 35%, 34% and 38% of the
      carcinomas respectively. Each of these alterations correlated with the histology
      of both non-invasive and invasive carcinomas; 16cen aneusomy was more frequent in
      carcinomas of high histologic grade, proximal breakage was more frequent in
      invasive ductal carcinomas (IDCs) of the strand or solid types and in grade-2 and
      -3 carcinomas, and distal breakage was more frequent in tubular/cribriform type
      IDCs and grade-1 carcinomas. 1;16 fusion correlated with the tubular/cribriform
      type of non-invasive or invasive carcinomas and invasive lobular carcinomas.
      Proximal breakage correlated with 16cen aneusomy, whereas the distal breakage
      correlated with 16cen disomy. These structural and numerical chromosome
      alterations appeared to occur in association with each other, and their specific
      combinations appeared to be involved in the establishment of morphological
      variety among breast carcinomas. Int. J. Cancer (Pred. Oncol.) 84:381-387, 1999.

PMID- 10404091
TI  - Activity of O(6)-methylguanine-DNA methyltransferase in relation to p53 status
      and therapeutic response in ovarian cancer.
AB  - The DNA-repair protein O(6)-methylguanine-DNA methyltransferase
      (alkyltransferase; MGMT) is a major determinant of resistance of cells to various
      alkylating cytostatic drugs. Its expression in tissues is highly variable,
      indicating complex regulatory mechanisms involved. Transfection-mediated
      expression of wild-type p53 has been shown to negatively regulate basal promoter
      activity of MGMT in vitro. To elucidate whether p53 is involved in regulation of
      MGMT in tumor tissue, we examined MGMT expression and the p53 status of 140
      primary ovarian carcinomas and analyzed the data as to the correlation between
      MGMT and p53, as well as the survival response of the patients after
      chemotherapy. We show that MGMT expression is highly variable in ovarian
      carcinomas, ranging from zero level up to 2500 fmol/mg protein. MGMT activity was
      significantly lower in tumors with wild-type p53 (p53wt) than in tumors with
      mutant p53 (p53mt) (p = 0.045). As expected, the percentage of tumors with p53mt
      increased with increasing histologic grade of the tumors. Thus, p53mt was
      observed in 4, 45 and 64% of grades 1, 2 and 3 tumors, respectively (p = 0.001).
      Increase in p53mt was accompanied by an increase in MGMT activity, which was, on
      average, 460 +/- 66, 624 +/- 63 and 662 +/- 60 fmol/mg protein in grades 1, 2 and
      3 tumors, respectively (p = 0.047). In addition, MGMT activity as well as p53mt
      were associated with the FIGO stage of the tumors. Mean MGMT activity was 472 +/-
      48 fmol/mg for patients with FIGO stages I and II, as compared with 675 +/- 50
      fmol/mg for patients with FIGO stages III and IV, (p = 0.0179). The percentage of
      p53mt was 27% and 54% in ovarian tumors with FIGO stages I/II and FIGO stages
      III/IV, respectively (p = 0.004). Thus, progression of ovarian tumors was clearly
      associated with increase of both MGMT activity and the percentage of p53mt. In
      tumors expressing low MGMT (<100 fmol/mg), p53mt was very rarely found. No
      significant association was observed between MGMT level in ovarian carcinomas and
      the survival of patients treated with cyclophosphamide and carboplatin. On the
      other hand, a clear correlation was found between histological type, grading,
      residual tumor mass and p53wt expression and duration of the patient's survival.
      The finding that p53wt expression was associated with low MGMT level in primary
      ovarian cancer supports the view that down-regulation of basal MGMT promoter
      activity by p53wt is also relevant in tumor cells in vivo. Int. J. Cancer (Pred.
      Oncol.) 84:388-395, 1999.

PMID- 10404092
TI  - Elevated serum levels of transforming growth factor beta1 in Epstein-Barr virus
      associated nasopharyngeal carcinoma patients.
AB  - Nasopharyngeal carcinomas (NPCs) of non-keratinizing type are strongly associated
      with Epstein-Barr virus (EBV). EBV and its gene products induce the synthesis
      and/or release of transforming growth factor beta1 (TGF-beta1) from human cells
      and platelets. TGF-beta1 is an immunosuppressive cytokine, and many tumors are
      known to secrete it, to counter the host immune response. To determine the
      potential role of this cytokine in the pathogenesis of NPC, 53 serum samples from
      patients with EBV-associated NPC and 20 from healthy donors were analyzed for
      total and active TGF-beta content using ELISA. Serum samples for TGF-beta content
      were also analyzed from NPC patients at different clinical stages of the tumors.
      Significantly higher (p < 0.01) levels of active and total TGF-beta were found in
      the sera of NPC patients than in control sera. The ratio of active:total TGF-beta
      was also significantly (p < 0.01) increased in the NPC sera. Levels of this
      cytokine were also significantly higher (p < 0.05) in the sera of patients with
      advanced stages of tumor compared to patients with earlier stages. Furthermore,
      higher levels were seen in patients with relapsing than with remitting tumors;
      even higher levels were observed in NPC patients who died of the tumor. Our data
      suggest a role of this cytokine in the pathogenesis of NPC; therefore, it may
      prove to be a valuable biomarker molecule for the diagnosis and prognosis of NPC.
      Int. J. Cancer (Pred. Oncol.) 84:396-399, 1999.

PMID- 10404093
TI  - Overexpression of cyclooxygenase-2 protein is less frequent in gastric cancers
      with microsatellite instability.
AB  - Overexpression of cyclooxygenase-2 (COX-2) has been reported in gastric cancers.
      However, the relationship between expression of COX-2 and clinico-pathological or
      genotypic features has not been elucidated. To address the issue, expression of
      COX-2 protein was analyzed in 100 gastric cancers as well as 7 gastric cancer
      cell lines by using immunoblot analysis. Overexpression of COX-2 in cancer
      tissues compared with matched non-cancerous tissues was found in 70% of cases and
      was significantly associated with lymphatic involvement, lymph node metastasis
      and advanced tumor stage. Interestingly, overexpression of COX-2 was less
      frequent in gastric cancers with microsatellite instability (MSI) than in those
      without MSI (8/20 vs. 62/80, p < 0.01). Expression of COX-2 protein was detected
      in some gastric cancer cell lines without MSI at various levels, but not in those
      with MSI. Our results suggest that overexpression of COX-2 may play an important
      role in tumor progression of gastric cancer and also support the notion that
      gastric cancers with and without MSI represent distinctive pathways of
      carcinogenesis. We also observed a reduction of MSI phenotype after aspirin or
      sulindac treatment in a hMLH1-defective gastric cancer cell line SNU-1, which
      lacks COX-2 expression. Int. J. Cancer (Pred. Oncol.) 84:400-403, 1999.

PMID- 10404094
TI  - Genomic instability and alterations in Apc, Mcc and Dcc in Hong Kong patients
      with colorectal carcinoma.
AB  - Our aim was to reveal the significance of tumor-suppressor genes and genomic
      instability in 99 Hong Kong Chinese colorectal carcinoma (CRC) patients by PCR
      LOH analysis and PCR-PTT assay. The frequencies of allelic loss of Apc, Mcc and
      Dcc and of APC truncation were 31.3% (15/48), 11.6% (5/43), 44.4% (20/45) and
      46/93 (49.5%), respectively. The frequency of Apc LOH was similar to, the Mcc LOH
      was lower than, and the Dcc LOH was higher than that reported for Caucasians and
      Japanese. In Hong Kong CRC patients, the replication error-positive (RER(+))
      phenotype occurred with a frequency of 10% (10/99), which was similar to other
      results using microsatellite markers where RER(+) frequencies ranged from 11% to
      28%. The rates of genetic alteration in RER(+) tumors were lower in tumors
      harboring p53, Mcc and Dcc alterations; similar in Apc; and higher in Ki-ras
      tumors compared with RER(-) tumors, though these differences did not achieve
      statistical significance. None of the biomarkers examined were predictive of
      survival independently, but strong trends confirming earlier observations of
      associations between RER(+) phenotypes with proximal tumor location and poorly
      differentiated tumor status were noted. The RER(+) phenotype was correlated
      significantly to the less aggressive Duke's stage B and improved prognosis.
      Additionally, tumors with RER(+) phenotypes were positively correlated with young
      age and sex. Our results support the observation that a subset of younger male
      CRC patients in Hong Kong may develop CRC via the RER pathway and show
      differences in RER status and sex. A significantly higher percentage of older
      Hong Kong Chinese CRC patients had APC truncations. Int. J. Cancer (Pred. Oncol.)
      84:404-409, 1999.

PMID- 10404095
TI  - Microsatellite analysis and response to chemotherapy in head-and-neck squamous
      cell carcinoma.
AB  - Molecular studies have revealed that microsatellite instability and loss of
      heterozygosity occurred in head-and-neck cancer, suggesting the involvement both
      of suppressor and of mutator pathways in head-and-neck carcinogenesis. There is
      evidence for relations between tumor phenotype and clinical parameters. Indeed,
      replication-error phenotype, characterized by microsatellite instability, was
      associated with decreased sensitivity to chemotherapeutic agents in cell lines.
      Loss of heterozygosity is a frequent mechanism of inactivation of tumor
      suppressor genes, which might be implicated in resistance to chemotherapy. In
      head-and-neck cancer, chemosensitivity is inconstant, and no marker is available
      to predict response to treatment. In order to evaluate the role of tumor
      phenotype on resistance to chemotherapy, we analyzed 56 primary head-and-neck
      squamous-cell carcinomas collected at time of diagnosis and a sub-group of 23
      resistant tumors collected after chemotherapy at 22 microsatellite loci. At time
      of diagnosis, only one tumor showed MSI-H phenotype. Loss of heterozygosity (LOH)
      was observed in 75% of tumors, indicating the dominant role of the suppressor in
      comparison with the mutator pathway in HNSCC carcinogenesis. No change in
      microsatellite patterns was observed after treatment, suggesting that
      chemotherapy did not select mismatch-repair-deficient clones. Univariate analyses
      showed that LOH at 9p or 17p was significantly associated with drug resistance.
      In a multivariate analysis, only LOH at 17p remains predictive of low response to
      chemotherapy, with a relative risk of 3.7 and 95% CI of 1.1-13, indicating that
      p53 alterations could play a role in chemotherapy resistance in HNSCC. Int. J.
      Cancer (Pred. Oncol.) 84:410-415, 1999.

PMID- 10404096
TI  - O(6)-methylguanine-DNA methyltransferase gene (MGMT) expression in human
      glioblastomas in relation to patient characteristics and p53 accumulation.
AB  - Repair of cytotoxic DNA damage by O(6)-methylguanine-DNA methyltransferase (MGMT)
      is a potentially important factor of chemoresistance to chloroethylnitrosoureas
      (CENUs), commonly used in the treatment of glioblastoma multiforme (GBM). The
      value of p53 as a prognostic factor in GBMs remains unclear, but a possible
      relationship between MGMT gene expression and p53 has been suggested. To further
      examine these GBM characteristics in vivo, we assessed MGMT gene expression using
      semi-quantitative RT-PCR and p53 alteration by immuno-histochemistry on a series
      of 39 GBMs. MGMT gene expression was inversely correlated with age (p < 0.03),
      consistent with the results of others. Interestingly, tumors from male patients
      had higher MGMT mRNA amounts than tumors from female patients (p < 0.03). No
      prognostic implication was observed either for MGMT gene expression or for p53
      accumulation. However, MGMT gene expression was significantly lower in p53
      altered GBM, regardless of the percentage of positive cells (p < 0.01). Our
      observation suggests that in human glial tumors, a low level of MGMT gene
      expression might promote p53 alteration, probably via mutation of its gene. Int.
      J. Cancer (Pred. Oncol.) 84:416-420, 1999.

PMID- 10404097
TI  - Prognostic value of immunohistochemical expression of the c-erbB-2 oncoprotein in
      metastasic prostate cancer.
AB  - It is well established that the activation of proto-oncogenes could trigger
      uncontrolled cell growth and cancer development. Although this correlation has
      already been evidenced in several human tumors, no conclusive studies have
      related oncogene activation with the development of prostatic neoplasia.
      Nevertheless, some reports suggest that c-erbB-2, which is a prognostic marker in
      breast cancer, could be implicated in the development of prostatic
      adenocarcinoma. We have studied the expression of the c-erbB-2 oncoprotein in
      primary prostatic tissue in a series of 70 patients with metastasic disease, by
      means of immunohistochemistry. The NCL-B 11 anti-c-erbB-2 monoclonal antibody was
      used, and the immunoreactivity was quantified by image analysis. The overall rate
      of prostatic-tissue sections presenting positive c-erbB-2 immunostaining was
      64.3%. No significant relation was observed between histological grade and c-erbB
      2 over-expression or severity of the disease, based on the extent of metastases.
      The average specific survival in patients with c-erbB-2 over-expression was 33
      months, while it was 54 in patients with c-erbB-2 negativity; p < 0. 034. These
      results, as well as the logistic-regression analysis, suggest that expression of
      c-erbB-2 oncoprotein would be considered as an independent prognostic factor of
      metastatic prostate cancer. Moreover, it could discriminate between the prognosis
      of patients with Gleason score 2 to 7 and those with score 8 to 10. Our results
      suggest that the expression of c-erbB-2 oncoprotein in primary prostatic tissue
      could have a prognostic value in patients with metastatic prostate cancer. Int.
      J. Cancer (Pred. Oncol.) 84:421-425, 1999.

PMID- 10404098
TI  - Differential telomerase activity, expression of the telomerase catalytic sub-unit
      and telomerase-RNA in ovarian tumors.
AB  - Telomerase activity has been found in a variety of malignant tumors but only
      rarely in benign tumors or normal tissues. In this study, we investigated
      telomerase activation in 37 ovarian tumors, including benign, borderline and
      malignant neoplasms. Telomerase activity was detected using the telomeric repeat
      amplification protocol (TRAP) in 13/16 ovarian carcinomas, 9/10 borderline tumors
      and 3/11 cystadenomas/fibromas. mRNA expression of the putative human telomerase
      catalytic sub-unit gene (hTERT) was detected by RT-PCR in 14/15 ovarian
      carcinomas, 8/10 borderline tumors and 4/11 cystadenomas/fibromas. In situ
      hybridization was performed to evaluate telomerase-RNA (hTR) expression in the
      corresponding paraffin-embedded tumors. Variable expression levels of hTR were
      found over neoplastic tumor cells. The highest levels of hTR expression were
      found predominantly in ovarian carcinomas. Although the amount of telomerase
      activity varied, significantly high levels of telomerase activity were found
      predominantly in ovarian carcinomas. hTERT mRNA expression was closely associated
      with telomerase activity. These findings suggest that up-regulation of hTERT and
      hTR is important for telomerase activation during malignant-tumor progression.
      Telomerase activation might therefore be a valuable diagnostic parameter that
      could help to identify potentially progressive lesions. However, the diagnostic
      and therapeutic implications of telomerase activation need to be clarified in
      clinical trials. Int. J. Cancer (Pred. Oncol.) 84:426-431, 1999.

PMID- 10404099
TI  - Loss of heterozygosity at 10q in tumors of the upper respiratory tract is
      associated with poor prognosis.
AB  - Frequent loss of a specific chromosomic region in cancers is often associated
      with inactivation of a tumor-suppressor gene. The long arm of chromosome 10 is
      deleted in several types of tumor, among them squamous-cell carcinomas of the
      head and neck (HNSCC). To determine the role of 10q deletions in the
      tumorigenesis of the upper respiratory tract, 47 HNSCCs were examined for loss of
      heterozygosity (LOH) at 10q: 43% of the cases analyzed showed LOH at 10q, and 2
      distinct hot spots of deletion were identified, at 10q22-23 and 10q25-26. The
      possible involvement of pTEN/MMAC1, a tumor-suppressor gene mapped at 10q23, was
      also evaluated. No mutation, homozygous deletion or loss of expression of
      pTEN/MMAC1 was detected, indicating that inactivation of this gene plays a minor
      role in HNSCC development. Interestingly, the frequency of deletion at 10q was
      greater in invasive carcinoma than in adjacent carcinoma in situ, and a
      significant association between LOH and poor prognosis was observed. Taken
      together, our results suggest the presence in the long arm of chromosome 10 of
      (a) tumor-suppressor gene(s) other than pTEN/MMAC1 and presumably involved in the
      malignant progression of tumors of the upper respiratory tract. Int. J. Cancer
      (Pred. Oncol.) 84:432-436, 1999.

PMID- 10404100
TI  - Changing role of 3 screening modalities in the European randomized study of
      screening for prostate cancer (Rotterdam).
AB  - A randomized screening trial was started in Europe to show the effect of early
      detection and treatment of prostate cancer on mortality (European Study on
      Screening of Prostate Cancer). In one centre (Rotterdam), the screening protocol
      initially consisted of 3 screening tests for all men: prostate-specific antigen
      (PSA), digital rectal examination (DRE) and transrectal ultrasonography (TRUS). A
      PSA value of >/=4 ng/ml and/or an abnormality on DRE and/or TRUS were taken to
      indicate that biopsy was required. In this study, we examined the possibilities
      for a more efficient screening protocol. A logistic-regression model was used to
      predict the number of cancers for PSA < 4 ng/ml if all men were biopsied
      (predictive index, PI). Effects of a change in PSA cut-off on the screening
      results were explored. Weights were applied to procedures and cancers to explore
      the possibility of expressing differences between protocols in one overall
      figure. Biopsies in men with PSA < 1 ng/ml and a positive DRE or TRUS were very
      inefficient. Applying DRE and TRUS only in the PSA ranges 1.5 to 3.9 and 2 to 3.9
      ng/ml to determine whether a biopsy was required would result in a decrease of 29
      to 36% in biopsies and a decrease of 5 to 8% in cancers. However, the results of
      DRE and TRUS could not be duplicated entirely. A protocol with only PSA >/= 3
      ng/ml as a direct biopsy indicator resulted in a decrease of detected cancers by
      7.6% and of biopsies by 12%, also a much simpler screening procedure. Use of the
      PI would give more efficient protocols, but this should be viewed as a
      preliminary finding, with the disadvantage of necessitating many additional
      screening visits. Since the results of DRE and TRUS could not be duplicated, a
      change in protocol towards PSA >/= 3 ng/ml appears acceptable. If this proves
      effective, a final judgement about the optimal combination of screening tests may
      be made. Int. J. Cancer (Pred. Oncol.) 84:437-441, 1999.

PMID- 10404101
TI  - Detection of Epstein-Barr virus (EBV) genomes in the serum of patients with EBV
      associated Hodgkin's disease.
AB  - DNA from malignant cells is present in the serum/plasma of cancer patients and
      DNA from this source is amenable to analysis by polymerase chain reaction (PCR).
      In the present study, we evaluated whether Epstein-Barr virus (EBV) DNA is
      present in the serum of patients with EBV-associated Hodgkin's disease (HD).
      Using conventional PCR, EBV DNA was detected in serum from 30/33 patients with
      EBV-associated HD but in only 6/26 patients with non-EBV-associated disease (p <
      0.001). Samples from healthy individuals were negative and only 5/12 infectious
      mononucleosis samples were positive. Real-time quantitative PCR was subsequently
      employed to determine the concentration of EBV DNA present in serum; among
      positive samples the level ranged from 1 to 705 copies per 125 microliter of
      serum. Post-treatment samples from 5/14 cases with EBV-associated HD contained
      detectable EBV DNA; analysis of this small group of cases suggests that
      positivity in post-treatment samples correlates with risk factors indicative of a
      poor prognosis. Overall, our results are consistent with the notion that DNA from
      Reed-Sternberg cells is present in the serum of HD patients, and further suggest
      that serum EBV should be evaluated as a prognostic marker. Int. J. Cancer (Pred.
      Oncol.) 84:442-448, 1999.

PMID- 10404102
TI  - Epstein-barr virus in Hodgkin's disease: frequency of a 30-bp deletion in the
      latent membrane protein (LMP-1) oncogene in South African patients.

PMID- 10404103
TI  - What's in a citation impact factor? A journal by any other measure.

PMID- 10404104
TI  - Antibody to calretinin stains AII amacrine cells in the rabbit retina: double
      label and confocal analyses.
AB  - The AII or rod amacrine cell is a critical interneuron in the rod pathway of
      mammalian retinae. In this report, it is shown that commercially available
      antibodies to the calcium binding protein calretinin may be used to label the
      population of AII amacrine cells selectively. Calretinin-positive amacrine cells
      had the morphological attributes of AII amacrine cells. Double-labeling
      procedures showed that calretinin-positive somata were surrounded by dopaminergic
      varicosities and that calretinin-positive dendrites enclosed rod bipolar
      terminals, both as previously described for AII amacrine cells. By analyzing the
      surrounding kernel for each labeled pixel in the rod bipolar image, it is shown
      here that AII processes are adjacent to rod bipolar terminals at a level that far
      exceeds the random overlap present in images in which one label was rotated out
      of phase. Such a spatial relationship is indicative of synaptic connections, as
      well described for rod bipolar input to AII amacrine cells. AII amacrine cells
      also were double-labeled for calretinin and parvalbumin; however, a scattergram
      analysis of red versus green intensity showed that the parvalbumin antibody
      stained additional unidentified amacrine cells. In conclusion, at the appropriate
      dilution, calretinin antibodies are a useful marker for AII amacrine cells in the
      rabbit retina.

PMID- 10404105
TI  - AII amacrine cells limit scotopic acuity in central macaque retina: A confocal
      analysis of calretinin labeling.
AB  - We have used calretinin antibodies to label selectively the mosaic of AII
      amacrine cells in the macaque retina. Confocal analysis of double-labeled
      material indicated that AII dendrites spiral down around descending rod bipolar
      axons before enveloping the synaptic terminals. Processes from a previously
      observed dopaminergic plexus in the inner nuclear layer were observed to contact
      the somata of calretinin-positive AII somata. Intracellular neurobiotin injection
      revealed that AII amacrine cells are tracer coupled to other AII amacrine cells
      and to some unidentified cone bipolar cells. An analysis of the retinal
      distribution of macaque AII amacrine cells, including an area in and around the
      fovea, showed a peak density of approximately 5,000 cells/mm(2) at an
      eccentricity of 1.5 mm. Staining of AII amacrine cells in central retina with
      antibodies to calretinin was confirmed by confocal microscopy. These results
      indicate that calretinin antibodies can be used to label the AII amacrine cell
      population selectively and that primate AII amacrine cells share many of the
      features of previously described mammalian AII amacrine cells. The peak AII cell
      density closely matched the peak sampling rate of scotopic visual acuity.
      Calculations suggest that, in central macaque retina, where midget ganglion cells
      are more numerous, AII amacrine cells form the limit of scotopic visual acuity
      (Wassle et al. [1995] J. Comp. Neurol. 361:537-551). As the ganglion cell density
      falls rapidly away from the fovea, there is a cross-over point at around 15
      degrees eccentricity that matches the inflection point in a psychophysically
      derived plot of scotopic visual acuity versus eccentricity (Lennie and Fairchild
      [1994] Vision Res. 34:477-482). The correspondence between the anatomic and
      psychophysical data supports our interpretation that the anatomic sampling rate
      of AII amacrine cells limits central scotopic acuity.

PMID- 10404106
TI  - Afferents to the red nucleus in the lizard Podarcis hispanica: putative pathways
      for visuomotor integration.
AB  - The afferents to the red nucleus from visual and nonvisual forebrain centers have
      been investigated in the lizard Podarcis hispanica by using both retrograde and
      anterograde transport of tracers. Because the red nucleus constitutes a key
      structure in the limb premotor system, these sensory afferents probably are
      involved in visuomotor and other forms of sensorimotor integration. After tracer
      injections aimed at the red nucleus, retrograde labeling was found in the
      reticular thalamus, the subthalamus, the nucleus of the posterior commissure, as
      well as in two retinorecipient nuclei, namely, the ventral lateral and pretectal
      geniculate nuclei, where labeled cells are especially abundant. These
      geniculorubral projections have been confirmed by means of anterograde tracing
      with dextranamine injections. On the other hand, small injections of tracers in
      the retina demonstrated that its projections to the ventral lateral and pretectal
      geniculate nuclei are organized in a point-to-point fashion. Moreover, small
      tracer injections into the optic tectum of Podarcis indicated that the ventral
      lateral geniculate nucleus also receives a precisely organized tectal afferent.
      Taken together, these results strongly suggest that geniculorubral projections
      might constitute the neuroanatomical substrate for the generation of quick
      locomotor responses to appropriate visual stimuli. Additional ventral thalamic,
      subthalamic, and pretectal afferents to the red nucleus are likely to subserve
      other kinds of sensorimotor integration. These results help to clarify the
      organization of the reptilian motor system, including the telencephalic control
      of motor responses, and to unravel some of the major trends in the evolution of
      the limb premotor network of tetrapodian vertebrates.

PMID- 10404107
TI  - Preprotachykinin-A mRNA expression in the human and monkey brain: An in situ
      hybridization study.
AB  - The mRNA expression for preprotachykinin-A (PPT-A) was studied throughout the
      human and cynomolgus monkey brain to assess the neuroanatomical expression
      pattern of the PPT-A gene in primates. In situ hybridization showed that the PPT
      A mRNA is expressed highly in specific regions of the postmortem human brain,
      including the striatum, islands of Calleja, hypothalamus (posterior,
      premammillary, medial mammillary, and ventromedial nuclei), superior and inferior
      colliculi, periaqueductal gray, and oculomotor nuclear complex. PPT-A mRNA
      expressing neurons also were present in the paranigralis (ventral tegmental area)
      and were scattered in the bed nucleus stria terminalis throughout the
      sublenticular substantia innominata region, including the diagonal band of Broca
      and the nucleus basalis of Meynert. In the hippocampus, high PPT-A mRNA
      expression was localized predominantly to the polymorphic layer of the dentate
      gyrus; no labeled cells were present in the granular layer. Positively labeled
      cells also were found scattered in the CA regions as well as in the amygdaloid
      complex. Neocortical expression of PPT-A mRNA was localized mainly to the deep
      laminae (layers V/VI), except for the striate cortex (labeling was seen also in
      superficial layers). The subiculum, thalamus, globus pallidus, ventral pallidum,
      substantia nigra pars compacta, red nucleus, pontine nuclei, and cerebellum were
      characterized by very weak to undetectable expression of PPT-A mRNA. An
      expression pattern was evident in the monkey forebrain similar to that observed
      in the human, except for the absence of PPT mRNA-expressing cells in the medial
      mammillary nucleus despite intense expression in supramammillary, lateral
      mammillary, and premammillary nuclei. Overall, more similarities than differences
      are apparent between primate species in the expression pattern of the PPT-A gene.
      J. Comp. Neurol. 411;56-72, 1999.

PMID- 10404108
TI  - Abducens internuclear and ascending tract of Deiters inputs to medial rectus
      motoneurons in the cat oculomotor nucleus: neurotransmitters.
AB  - The abducens internuclear and ascending tract of Deiters (ATD) pathways are the
      principal excitatory inputs to medial rectus motoneurons in the oculomotor
      nucleus and are related to the control of conjugate horizontal eye movements.
      Differences in the morphology and soma-dendritic distribution of abducens
      internuclear and ATD synaptic endings are correlated with known differences in
      the physiological properties of these independent inputs. The present study
      extends these observations to the ultrastructural localization of the excitatory
      amino acid neurotransmitters, glutamate and aspartate, using a postembedding
      immunogold procedure combined with the pre-embedding immunoperoxidase
      localization of anterogradely transported biocytin from the abducens nucleus and
      the ventral lateral vestibular nucleus. Consistent with their spheroidal synaptic
      vesicle content and the asymmetric pre/postsynaptic membrane profile, both the
      abducens internuclear and ATD synaptic endings are labeled with glutamate and
      aspartate. However, quantitative analysis of the density of colloidal gold
      particles associated with mitochondria versus synaptic vesicles/axoplasmic matrix
      reveals significant differences in the metabolic versus neurotransmitter pools of
      the amino acids in the two populations of synaptic endings. The findings indicate
      that both aspartate and glutamate, possibly co-localized, are the excitatory
      neurotransmitters utilized by abducens internuclear synaptic endings whose burst
      tonic physiological activity conveys information related to eye position to
      medial rectus motoneurons. By contrast, glutamate is the excitatory
      neurotransmitter associated with ATD synaptic endings whose high frequency burst
      activity is related to head velocity.

PMID- 10404109
TI  - NGF facilitates the developmental maturation of the previously committed
      cholinergic interneurons in the striatal matrix.
AB  - Although all of the cholinergic interneurons of the striatum are generated early
      in development, the maturation of these neurons depends on striatal compartmental
      localization. The majority of the cholinergic neurons in the patches turn on
      choline acetyltransferase (CHAT) embryonically, whereas the majority of
      cholinergic neurons in the matrix turn on CHAT postnatally. To determine whether
      CHAT expression can be induced earlier in the cholinergic neurons and whether the
      facilitation is compartment specific, we infused nerve growth factor (NGF) into
      the lateral ventricle of either embryonic day 19 embryos or postnatal day 1 pups.
      We simultaneously marked the patch compartment by injecting the retrograde
      fluorescent tracer True Blue into the substantia nigra at the times of the NGF
      infusions. After a 2-day survival time, NGF induced a dramatic increase in the
      number of CHAT-immunoreactive neurons in the matrix compartment (up to adult
      levels), whereas the NGF infusions did not increase the number of CHAT neurons in
      the patch compartment. Analyses of the compartmental distributions of the p75 and
      trkA NGF receptors themselves do not provide an explanation for the differential
      cholinergic maturation in the compartments of the control striatum or for the
      upregulation of CHAT in the striatal matrix after the NGF infusion. We conclude
      that NGF infusion is capable of facilitating the normally slow cholinergic
      maturation of the cholinergic neurons in the matrix, whereas the cholinergic
      maturation of the CHAT cells in the patch compartment seems to be largely
      independent of NGF signalling.

PMID- 10404110
TI  - Projection patterns of single mossy fibers originating from the lateral reticular
      nucleus in the rat cerebellar cortex and nuclei.
AB  - Projection of neurons in the lateral reticular nucleus (LRN) to the cerebellar
      cortex (Cx) and the deep cerebellar nuclei (DCN) was studied in the rat by using
      the anterograde tracer biotinylated dextran amine (BDA). After injection of BDA
      into the LRN, labeled terminals were seen bilaterally in most cases in the
      vermis, intermediate zone, and hemisphere of the anterior lobe, and in various
      areas in the posterior lobe, except the flocculus, paraflocculus, and nodulus.
      Areas of dense terminal projection were often organized in multiple longitudinal
      zones. The entire axonal trajectory of single axons of labeled LRN neurons was
      reconstructed from serial sections. Stem axons entered the cerebellum through the
      inferior cerebellar peduncle (mostly ipsilateral), and ran transversely in the
      deep cerebellar white matter. They often entered the contralateral side across
      the midline. Along the way, primary collaterals were successively given off from
      the transversely running stem axons at almost right angles to the Cx and DCN, and
      individual primary collaterals had longitudinal arborizations that terminated as
      mossy fibers in multiple lobules of the Cx. These collaterals arising from single
      LRN axons terminated bilaterally or unilaterally in the vermis, intermediate
      area, and sometimes hemisphere, and in different cerebellar and vestibular nuclei
      simultaneously. The cortical terminals of single axons appeared to be distributed
      in multiple longitudinal zones that were arranged in a mediolateral direction.
      All of the LRN axons examined (n = 29) had axon collaterals to the DCN. All of
      the terminals observed in the DCN and vestibular nuclei belonged to axon
      collaterals of mossy fibers terminating in the Cx.

PMID- 10404111
TI  - Intrinsic determinants of retinal axon collateralization and arborization
      patterns.
AB  - Permanent, novel retinal projections to the principal thalamic somatosensory
      (ventrobasal) or auditory (medial geniculate) nuclei can be produced in adult
      hamsters if the superior colliculus is ablated bilaterally and the somatosensory
      and auditory lemniscal axons are transected unilaterally on the day of birth. We
      studied the development of those novel projections by labeling retinal axons with
      the fluorescent tracer 1,1'-dioctadecyl-3,3,3', 3'-tetramethylindocarbocyanine
      perchlorate to examine the relative roles of intrinsic factors and axon-target
      interactions in the specification of retinal axon connections. Our principal
      findings are as follows: (1) In hamsters operated on the day of birth to produce
      the novel retinal projections, retinal ganglion cell axons projecting to the
      ventrobasal or medial geniculate nuclei develop in three morphologically distinct
      stages, i.e., elongation, collateralization, and arborization, as do retinal
      axons projecting to the dorsal lateral geniculate nucleus, the principal thalamic
      visual nucleus, in normal hamsters. (2) In both the ventrobasal and medial
      geniculate nuclei of operated hamsters, as in the dorsal lateral geniculate
      nucleus of normal hamsters, collateral branches were initially formed by retinal
      ganglion cell axons in both the superficial and internal components of the optic
      tract and only collaterals from the superficial component formed permanent
      projections. (3) The retinofugal axon terminal arbors in the ventrobasal and
      medial geniculate nuclei of mature, operated hamsters resemble the same three
      morphologic classes that are observed in the lateral geniculate nucleus of normal
      hamsters, although their absolute size appears to be altered. These data suggest
      that both superficial and internal optic tract axons can produce thalamic
      collaterals during development but that only superficial optic tract axons can
      permanently retain thalamic collaterals. Furthermore, the same morphologic types
      of retinofugal axons appear to contribute to normal and surgically induced
      retinal projections.

PMID- 10404112
TI  - Distribution of bulbospinal gamma-aminobutyric acid-synthesizing neurons of the
      ventral respiratory group of the rat.
AB  - Spinal respiratory motoneuron activity is controlled primarily by excitatory and
      inhibitory neurons in the medulla oblongata. To identify bulbospinal inhibitory
      neurons, immunohistochemistry for glutamic acid decarboxylase (GAD) was combined
      with retrograde labeling of projections to the C(4) ventral horn with Fluoro
      Gold. GAD-immunoreactive bulbospinal neurons were located in the ventrolateral
      portion of the intermediate reticular nucleus, the ventral portion of the medial
      reticular nuclei, and the raphe and spinal vestibular nuclei. Small numbers of
      bulbospinal ventral respiratory group neurons were GAD immunoreactive. These
      neurons were distributed throughout the rostral ventral respiratory group and the
      Botzinger complex. Surprisingly, low numbers of Botzinger neurons, a population
      thought to be exclusively inhibitory, were GAD immunoreactive. These results
      suggest that the rostral ventral respiratory group and the Botzinger complex both
      contain heterogeneous bulbospinal neuron populations, only some of which have
      gamma-aminobutyric acid (GABA)-mediated inhibitory control over phrenic
      motoneurons. Furthermore, the ventral respiratory group contained many GABAergic
      neurons that lacked bulbospinal projections.

PMID- 10404113
TI  - Interactions between limbic, thalamo-striatal-cortical, and central autonomic
      pathways during epileptic seizure progression.
AB  - We used immunocytochemistry to determine the regional and temporal distribution
      of Fos protein expression in awake and unrestrained rats after a unilateral
      stereotaxic microinjection of a cholinergic agonist, carbachol, in the thalamic
      ventroposterolateral and reticular nuclei, previously shown to cause limbic and
      generalized convulsive seizures. The microinjection of carbachol elicits
      behavioral alterations including immobilization, staring, facial and jaw clonus,
      rearing, and falling, followed by recurrent generalized convulsive seizures, and
      a pattern of c-fos expression throughout the brain. In addition to the
      hypothalamic paraventricular and supraoptic nuclei, the initial induction of c
      fos expression was observed as early as 15 minutes after the carbachol
      microinjection, in the piriform and entorhinal cortices, the thalamic
      paraventricular, the supramammilary, the lateral parabrachial nuclei, and the
      central gray. From 30 minutes to 2 hours, corresponding to the occurrence of
      motor expression of limbic and recurrent generalized convulsive seizures, Fos
      immunoreactivity was seen in a number of functionally related brain regions
      including the hippocampus, the amygdala, and the anterior thalamic nucleus
      (limbic system); the thalamus, the basal ganglia, and the cortex (thalamo
      striatal-cortical system); and the hypothalamus, the central nucleus of the
      amygdala, the pons, and the medulla (central autonomic system). On the basis of
      the present results showing regional and temporal c-fos expression and well known
      neuroanatomical connections, we have constructed a neural network relating the
      limbic, thalamo-striatal-cortical, and central autonomic systems. This analysis
      provides, for the first time, neuronal circuits and pathways relating epilepsy
      elicited behavioral expression of convulsive seizures and adaptive homeostatic
      responses and could serve as a basis for studying central autonomic regulation
      during epileptic disorders.

PMID- 10404114
TI  - Integrin family of cell adhesion molecules in the injured brain: regulation and
      cellular localization in the normal and regenerating mouse facial motor nucleus.
AB  - Integrins are a large family of heterodimeric glycoproteins that play a crucial
      role in cell adhesion during development, inflammation, and tissue repair. In the
      current study, we investigated the localization of different integrin subunits in
      the mouse facial motor nucleus and their regulation after transection of the
      facial nerve. In the normal mouse brain, there was clear immunoreactivity for
      alpha5-, alpha6-, and beta1-integrin subunits on blood vessel endothelia and for
      alphaM- and beta2-subunits on resting parenchymal microglia. Facial nerve
      transection led to an up-regulation of the beta1-subunit on the axotomized
      neurons and an increase in the alpha4-, alpha5-, alpha6-, beta1-, alphaM-, alphaX
      , and beta2-subunits on the adjacent, activated microglia. Quantification of the
      microglial integrins revealed two different expression patterns. The subunits
      alpha5 and alpha6 showed a monophasic increase with a maximum at day 4, the
      alphaM-subunit a biphasic regulation, with an early peak at day 1 and an elevated
      plateau between day 14 and 42. At day 14, there was also an influx of lymphocytes
      immunoreactive for the alpha4beta1- and alphaLbeta2-integrins, which aggregated
      at sites of neural debris and phagocytotic microglia. This finding was
      accompanied by a significant increase of the alpha5beta1-integrin on blood vessel
      endothelia. In summary, facial axotomy is followed by a strong and cell-type
      specific expression of integrins on the affected neurons and on surrounding
      microglia, lymphocytes, and vascular endothelia. The presence of several,
      strikingly different temporal patterns suggests a selective involvement of these
      molecules in the different adhesive events during regeneration in the central
      nervous system.

PMID- 10404115
TI  - Effects of thermal acclimation on the relaxation system of crucian carp white
      myotomal muscle.
AB  - Many cyprinid fish are able to compensate for a decrease in ambient temperature
      by process of physiological adaptation in the function of muscles. In the winter
      habitat of crucian carp (Carassius carassius L.), low temperature is associated
      with simultaneous oxygen shortage. Because of the oxygen deprivation, there is
      probably little space for compensatory adaptation because positive thermal
      compensation would increase energy demand and accelerate depletion of glycogen
      reserves. Thus, we assumed that the crucian carp, unlike many other cyprinid
      fish, would not show positive thermal compensation but either no compensation or
      inverse compensation in muscle function. To test this hypothesis in the
      relaxation system of skeletal muscles, we determined the parvalbumin content and
      the activity of sarcoplasmic reticular (SR) Ca-ATPase in white myotomal muscle of
      winter- and summer-acclimated crucian carp. In the laboratory, the winter fish
      were kept at 2 degrees C and the summer fish at 22 degrees C for a minimum of 3
      weeks before the experiments. The specific activity of SR Ca-ATPase at low
      experimental temperature (2 degrees C) was similar in summer- and winter
      acclimated fish (0.26 +/- 0.04 vs. 0.25 +/- 0.04 mM/mg/min; P > 0.05). Because of
      the bigger Q(10) of cold-acclimated carp, the enzyme activity at 30 degrees C was
      higher in cold-acclimated winter fish than in warm-acclimated summer fish (7.42
      +/- 0.90 vs. 5.18 +/- 0.53 mM/mg/min; P < 0.05). In contrast, the yield of SR
      protein was 70% higher in summer than winter fish (0.315 +/- 0.045 vs. 0.187 +/-
      0.017 mg/g; P < 0.001). Because of these opposing changes, total Ca-ATPase
      activity of SR (per gram muscle weight) remained relatively constant. Similarly,
      the parvalbumin content of the myotomal muscle was not different between summer
      (4.09 +/- 0.95 mg/g) and winter (3.70 +/- 0.60 mg/g) fish. Although there were no
      seasonal changes in the total relaxing system of the crucian carp white myotomal
      muscle, the same activity of SR Ca-ATPase in winter fish was obtained with less
      amount of SR pump protein, owing to the increased catalytic activity of the
      enzyme. The higher catalytic activity of winter fish SR Ca-ATPase might be caused
      by differences in fatty acid composition noted in membrane lipids; i.e., fewer
      saturated fatty acids and more n-6 polyunsaturated fatty acids (PUFAs), at the
      expense of n-3 PUFAs, were present in the SR of cold-acclimated winter fish.
      Temperature-induced changes in enzyme protein, however, cannot be excluded. Thus,
      the present results indicate the absence of positive thermal compensation in the
      relaxing system of crucian carp white muscle. It seems, however, that lipid
      composition of SR membranes and temperature dependence of SR Ca-ATPase are
      altered by seasonal acclimation.

PMID- 10404117
TI  - Mudskipper periophthalmodon schlosseri can repay oxygen debts in air but not in
      water 
AB  - We determined aerial and aquatic oxygen uptake rates (&Mdot;o(2)) of
      Periophthalmodon schlosseri at rest and after exhaustive exercise at 30 degrees
      C. Resting &Mdot;o(2) in air (3.16 +/- 0.10 [SE] &mgr;mol/g/hr) was significantly
      higher than that in air saturated water (2.41 +/- 0.06 &mgr;mol/g/hr). When the
      fish was placed in air after 2 min exhaustive exercise, &Mdot;o(2) immediately
      increased about 2.5 times, thereby repaying oxygen debt of 5.0 &mgr;mol/g. In
      contrast, &Mdot;o(2) failed to show any significant elevation from the resting
      level as long as the fish was confined in water after exercise. However, when the
      fish was subsequently emerged, &Mdot;o(2) did increase above the resting level,
      amounting to an excess oxygen uptake of 5.5 &mgr;mol/g. These results
      demonstrated that the gas transport system of P. schlosseri is better adapted to
      air breathing and the mode of adaptation limited the capability for water
      breathing. J. Exp. Zool. 284:265-270, 1999. Copyright 1999 Wiley-Liss, Inc.

PMID- 10404116
TI  - Effects of laparotomy, cage type, gestation period and spaceflight on abdominal
      muscles of pregnant rodents.
AB  - We studied the effects of four variables on the histological properties of three
      body wall muscles-rectus abdominis (RA), transversus abdominis (TA), and external
      oblique (EO)-from pregnant rats. The variables examined were (1) gestation
      period; (2) cage design; (3) the effect of a midline laparotomy, performed to
      determine fetus numbers; and (4) exposure to a nine-day spaceflight. We measured
      fiber cross-sectional area (CSA), metabolic enzyme levels (succinate
      dehydrogenase, glycerophosphate dehydrogenase), and myosin heavy chain (MHC)
      immunoreactivity in samples from each muscle. A major effect of spaceflight was
      an increase of 42-171% in fibers double-labeled for MHC in all three muscles.
      Based on fiber CSA, the TA and RA muscles showed signs of stretching with
      increased gestation; i.e., the CSA decreased 11-12% over a nine-day period. The
      EO, a torso rotator, hypertrophied by 9% in rats group-housed in cages with a
      complex 3-D structure, compared to controls housed singly in standard flat-bottom
      cages. The TA and EO, whose contractions would pull on the suture line, showed
      signs of atrophy in laparotomized animals, exhibiting a 12% decrease in muscle
      fiber CSA. Exposure to weightlessness is known to induce atrophy in most skeletal
      muscles. Surprisingly, the EO actually hypertrophied 11% in our flight animals;
      however, this can be explained by the fact that those rats actively rotated their
      torsos seven times more often than ground controls. The flight rats also had
      twice as many contractions as controls. However, they were still able to give
      birth on time postflight.

PMID- 10404118
TI  - Glycogen repletion following burst activity: a carbohydrate-sparing mechanism in
      animals adapted to arid environments?
AB  - The Western chestnut mouse (Pseudomys nanus ferculinus) is one of several native
      rodent species adapted to the arid environments of Australia. Since these
      environments are often associated with a paucity in dietary carbohydrate, the
      problem arises as to the mechanism whereby these rodents replete their stores of
      muscle glycogen when recovering from high intensity physical activity. This is an
      important issue since the maintenance of adequate stores of muscle glycogen is
      crucial to support the energy demands associated with 'flight or fight'
      responses. Whilst it is known that food ingestion post-exercise is required for
      the total repletion of muscle glycogen in rats and humans, our findings indicate
      that the Western chestnut mouse has the impressive capacity to replete completely
      its stores of muscle glycogen, even in the absence of food intake. Indeed during
      recovery from burst activity which results in the massive breakdown of the stores
      of muscle glycogen, the levels of glycogen return back to pre-exercise levels
      within only 50 minutes despite the absence of food intake. This capacity is
      important in the broader context of nutritional adaptation to arid/seasonally
      arid regions since it allows muscles to replete their fuel stores even when food
      is not available. How common is this strategy among desert-adapted mammal species
      is a question yet to be answered.

PMID- 10404119
TI  - Enzymatic capacities for beta-oxidation of fatty fuels are low in the gill of
      teleost fishes despite presence of fatty acid-binding protein.
AB  - A variety of circulating fuels can support the work of the teleost gill. Previous
      work indicates, however, that unlike other aerobic tissues from teleosts, the
      gill may have a limited capacity to oxidize fatty fuels. We determined capacities
      for catabolism of carbohydrate, fatty acids, and amino acids in four species of
      temperate marine or euryhaline teleosts representing distinct lineages. In
      addition, we assessed the capacity for fatty acid oxidation in the gill from an
      Antarctic species. Activities of rate-limiting or regulatory enzymes from
      pathways of energy metabolism were measured at physiological temperatures (15
      degrees or 1 degrees C). In the temperate species, ATP yields from glucose are 3-
      to 30-fold greater (varying with species) than ATP yields from a monounsaturated
      fatty acid, while ATP generation from glutamate is 2-50 times greater than
      similar capacities for the lipid fuel. Like the temperate species, capacity for
      beta-oxidation of fatty acids is limited in the Antarctic species. A positive
      linear correlation between activities of citrate synthase (central pathway of
      oxidative metabolism) and hexokinase (glycolysis) adds further support to the
      hypothesis that glucose is a preferred metabolic fuel in gill. Our results also
      demonstrate that fatty acid-binding protein is present in the gill of teleost
      fishes. It is likely that this protein plays a more important role facilitating
      anabolic pathways in lipid metabolism rather than fatty acid oxidation in the
      gill of teleost fishes.

PMID- 10404121
TI  - Hyperplastic development and hypertrophic growth of muscle fibers in the white
      seabass (Atractoscion nobilis) 
AB  - Because skeletal muscle is the main contributor to body weight in most fish, it
      is probable that the size of a fish is limited by the growth of this tissue.
      Several aspects of both somatic size and skeletal muscle growth were investigated
      in white seabass (Atractoscion nobilis). One hundred and four subjects ranging in
      size from 1.3-91.8 cm standard length were examined to discern growth patterns
      throughout the entire life span of this species. Relationships of somatic growth
      were evaluated by weight, length, and age comparisons while muscle growth was
      assessed from cross-sectional area measurements of white muscle fibers. The
      average cross-sectional fiber area increased from approximately 150 &mgr;m(2) to
      4300 &mgr;m(2) as the fish increased in size, indicating that hypertrophy plays
      an important role in growth. Hyperplastic fiber recruitment accounted for
      approximately 93% of muscle growth in recently hatched fish and gradually
      decreased with fish length. Although the contribution of hyperplasia declined to
      less than 1% in the largest subject, the persistence of hyperplasia at standard
      lengths equal to or greater than 91.8 cm as observed in the white seabass has yet
      to be documented in other fish species. This sustained fiber recruitment may be
      responsible for the impressive ultimate standard length of 133 cm (41 kg) that
      white seabass are capable of attaining. The white seabass currently represents
      the largest marine fish species for which the dynamics of muscle fiber growth
      have been described. J. Exp. Zool. 284:299-308, 1999. Copyright 1999 Wiley-Liss,
      Inc.

PMID- 10404120
TI  - Hsp70 and a 54 kDa protein (Osp54) are induced in salmon (Salmo salar) in
      response to hyperosmotic stress.
AB  - Hsp70 and a 54 kDa osmotic stress protein (osp54) were induced in isolated
      tissues of anadromous Atlantic salmon (Salmo salar) upon exposure to hyperosmotic
      conditions. Incubation of branchial lamellae, hepatic tissue, and erythrocytes in
      medium supplemented with 200-600 mM NaCl dramatically reduced protein synthesis.
      Although general protein synthesis remained depressed following transfer of
      tissues from 450 mM supplemental NaCl to iso-osmotic medium, hsp70 was
      prominently induced in branchial lamellae and hepatic tissue. Accumulation of
      hsp70 mRNA and a decrease in actin mRNA suggest preferential upregulation of the
      hsp70 gene. Induction of osp54 was observed in branchial lamellae and
      erythrocytes, but not in hepatic tissue, during exposure to 75-125 mM
      supplemental NaCl. Use of glycerol in place of NaCl to create hyperosmotic
      conditions stimulated induction of hsp70 in branchial lamellae. Substitution with
      mannitol resulted in induction of osp54 in both branchial lamellae and
      erythrocytes. The solute-specific and temporal patterns of response suggest that
      hsp70 and osp54 might function in concert to restore osmotic homeostasis and
      renature proteins destabilized or denatured during the early stages of osmotic
      shock.

PMID- 10404122
TI  - Characterization of a monoclonal antibody specific to rainbow trout thrombocytes.
AB  - A monoclonal antibody (MAb) specific for rainbow trout thrombocytes was produced
      and its reactivity was demonstrated by flow cytometry and immuno-electron
      microscopy. Flow cytometry analysis showed that this MAb (TTL-7D11) reacted
      positively with about 30% of the peripheral blood leucocytes (PBL) and about 1%,
      2%, and 11% of the pronephros, mesonephros, and spleen cells, respectively.
      Electron microscopy using immunogold labeling demonstrated that this MAb reacted
      strongly with thrombocytes, where gold beads could be seen attached only to the
      membrane and canalicular system of these cells. Positive and negative leucocytes
      for this MAb were obtained by magnetic cell separation. In the positive fraction,
      96% of the cells were thrombocytes, while in the negative fraction no more than
      3% were, which clearly showed a high purity of the positive fraction. Aggregation
      studies showed that about 75% of the positive fraction cells aggregated after
      being mixed with U-46619 thromboxane-mimetic, whereas in the negative fraction
      only 10% of the cells did so. Thus, utilizing the TTL-7D11 we have succeeded in
      isolating a pure thrombocyte population, and this would facilitate further
      studies, particularly on their characteristics and function(s).

PMID- 10404123
TI  - Retinoic acid stimulates development of adult-type chromatophores in the
      flounder.
AB  - Premetamorphic flounder larvae were administered different doses of 9-cis
      retinoic acid (9cRA). 9cRA at 25 nM (the highest dose) not only stimulated adult
      type (ad-) chromatophore development on the ocular (eyed) side, but also induced
      the development of ad-chromatophores on the blind (non-eyed) side of the
      metamorphosed fish. The ad-chromatophore development was stimulated by 9cRA only
      when administered to the larvae that were at late premetamorphosis and at early
      prometamorphosis. Ad-chromatophores actually appear much later, at the end of
      metamorphosis. 9cRA was not effective at later stages of metamorphosis. These
      results suggest that 9cRA stimulated the development or determination of the
      developmental fate of neural crest cells for chromatophores. The present results
      also suggest the presence of immature chromatophores or neural crest cells on
      both sides of the larval body of the flounder and that the ad-chromatophore
      development is somehow inhibited on the blind side in spontaneous metamorphosis.
      All-trans retinoic acid (atRA) had a similar effect on the ad-chromatophore
      development. In addition, both types of RAs affected the development of fin rays
      of the fish, resulting in deformity of fins when administered at high doses early
      in metamorphosis. The teratogenic effect of atRA was greater than that of 9cRA.

PMID- 10404124
TI  - Gene expression during estivation in spadefoot toads, Scaphiopus couchii:
      upregulation of riboflavin binding protein in liver.
AB  - A cDNA library constructed from liver of 2-month estivating female spadefoot
      toads, Scaphiopus couchii, was differentially screened to reveal genes that were
      induced or upregulated during estivation. After two rounds of screening a clone
      was isolated that showed 60% higher expression in liver of estivating, versus
      control, toads. The clone possessed a 1.0 kb insert which annealed to a single
      0.7 kb band on Northern blots. Sequencing revealed a 1053 nucleotide full-length
      cDNA; the largest potential open reading frame was 708 nucleotides which encoded
      a protein of 235 amino acids. A homology search in Genbank indicated that the
      protein was a riboflavin binding protein (RfBP), a monomeric phosphoglycoprotein
      produced by the liver of female birds, reptiles, and mammals that functions to
      bind plasma riboflavin and load the vitamin into eggs or fetus. To our knowledge,
      this is the first demonstration that RfBP is also present in amphibians. Toad
      RfBP showed 50% of residues identical with the chicken or turtle liver proteins
      and many essential structural features were conserved in the toad protein
      including 18 cysteine residues, two asparagine glycosylation sites, and 6
      tryptophan residues. However, a region with eight phosphoserines in the chicken
      or turtle proteins that functions in RfBP binding to the oocyte membrane
      contained only three serine residues in toad RfBP, suggesting that recognition
      and binding to oocyte receptors must be different in toads. Northern
      hybridization showed that toad RfBP was largely liver-specific; no mRNA
      transcripts were detected in brain, gut, heart, or kidney but low message levels
      occurred in hind leg skeletal muscle of estivating, but not control, toads.
      Upregulation of RfBP in liver of estivating toads may be linked with maturation
      of eggs in preparation for the explosive breeding that occurs immediately upon
      emergence from estivation but might also have a role for the adult in "caching"
      riboflavin to maintain an endogenous vitamin pool over the 9-10 months of each
      year that toads are dormant.

PMID- 10404125
TI  - Diel rhythms of basal and stress-induced corticosterone in a wild, seasonal
      vertebrate, Gambel's white-crowned sparrow.
AB  - Glucocorticoids have a wide array of actions in vertebrates. Daily fluctuations
      in basal levels of glucocorticoids are thought to regulate homeostatic
      mechanisms. In contrast, elevated levels secreted in response to stress stimulate
      changes in physiology and behavior. These changes are thought to aid an animal in
      avoiding chronic stress or death. Twenty-four-hour rhythms in basal and stress
      induced glucocorticoids have been detected in laboratory mammals, but studies in
      wild, seasonal vertebrates are rare. Identification of plasticity in hormone
      secretion in wild vertebrates is critical to understanding the effects of
      hormones on physiology and behavior, and therefore the success of an animal in
      its natural environment. In the present study, we characterized diel patterns of
      basal and stress-induced corticosterone (the avian glucocorticoid) under two
      photoperiods in Gambel's white-crowned sparrow (Zonotrichia leucophrys gambelii).
      In contrast to previous findings in the white-crowned sparrow, we demonstrated a
      robust rhythm in basal corticosterone secretion, in which corticosterone reaches
      peak levels at the end of the inactive period, and has returned to trough levels
      just after the active period has begun. We also demonstrated a diel rhythm in
      secretion of corticosterone in response to a stressor, showing the greatest
      response at the beginning of the active period. Patterns of CORT secretion were
      similar under both photoperiods. These patterns show interesting similarities and
      differences to classical mammalian rhythms.

PMID- 10404126
TI  - Immunocytochemical and histological studies on the hypophyseal-gonadal system in
      the freshwater nile tilapia, oreochromis niloticus (L.), during sexual maturation
      and spawning in different habitats 
AB  - The activities of the hypophyseal-gonadal system of O. niloticus in different
      habitats were investigated using immunocytochemical and histological techniques.
      The observed physico-chemical results indicated that Lake Nasser water
      characteristics are within the allowed and desired safety baseline levels. In
      contrast, Lake Manzalah exhibited high levels of Ca(2+), Mg(2+), SO(4)(2-) and
      heavy metals (Zn, Pb, and Cd). These water conditions affected the activity of
      the hypophyseal-gonadal axis of tilapia. The secretory and the synthetic
      activities of GTH and SL cells in the pituitary gland, in general, underwent
      obvious normal changes during gonad maturation and spawning of O. niloticus in
      Lake Nasser. In Lake Manzalah, the secretory activity of GTH and SL cells
      declined. This may be due to the effect of the high levels of heavy metals which
      interfere with the release of hormones and disturb the feedback mechanisms. In
      addition, the activity of both PRL and GH cells in Lake Nasser was higher than
      that of Lake Manzalah, but the synthetic activity of the ACTH and MSH cells was
      higher in Lake Manzalah. This may be related to the increased stress on fishes
      and the dark polluted water in Lake Manzalah. Both the environmental and the
      endocrine impacts in Lake Manzalah caused a decline in the gonadal activity as
      reflected by the decrease of sperm amount in the ripe testis, the appearance of
      oocytes in the testis and the degeneration of ripe oocytes (atresia) during the
      spawning season. J. Exp. Zool. 284:343-354, 1999. Copyright 1999 Wiley-Liss, Inc.

PMID- 10404127
TI  - Morphological alterations in mouse testis by a single dose of malathion.
AB  - Malathion((R)) is a widely used organophosphorate agropesticide. In spite of its
      low toxicity for mammalian cells, it provokes cytogenetic and genotoxic damage
      both in vivo and in vitro. The effect of Malathion was analyzed in CF-1 young
      adult male mice. Commercial Malathion (96.6% purity) was injected
      intraperitoneally in a single dose (250 mg/kg body weight corresponding to 1/12
      LD50). Four, 14, 18, and 26 days after injection animals were sacrificed to study
      epididymal sperm (count and morphology), testicular histology (percentage of
      depleted seminiferous tubules), and ultrastructural alterations in the germinal
      epithelium. The effect of Malathion on different germinal cell populations was
      studied. Teratozoospermia was induced by Malathion at all times studied.
      Spermatozoa midpiece and flagella were the most affected and at day 18 we
      observed less alterations of the head. The sperm count at different time
      intervals was significatively increased compared to controls and there was a
      parallel increase in depletion of the seminiferous tubules. In conclusion, all
      germinal cell populations studied were affected by Malathion. Malathion has a
      teratogenic effect on mice spermatid differentiation, which compromises mostly
      the flagella, perhaps due to an alkylating effect that disturbs the normal
      assembling of tail structural protein components. Apparently, the pachytene
      spermatocyte stage may be relatively more resistant to the pesticide. The Sertoli
      cells were affected by the insecticide and their damage at an ultrastructural
      level is highly significant. Cytoplasmatic vacuolization probably revealed
      metabolic alteration of these cells.

PMID- 10404128
TI  - Management of the axilla in early stage breast cancer: will sentinel node biopsy
      end the debate?

PMID- 10404129
TI  - Doubling time of serum CA 19-9 in the clinical course of patients with pancreatic
      cancer and its significant association with prognosis.
AB  - BACKGROUND AND OBJECTIVES: Pancreatic cancer is generally a disease with a poor
      prognosis, and relationship between change of serum CA 19-9 level and progression
      of this disease was investigated with regard to clinical pace of disease and
      tumor growth. METHODS: CA 19-9 doubling time was examined in 75 patients with
      pancreatic cancer, including 41 inoperable cases. Then, its relation with their
      prognosis and change in tumor was evaluated. RESULTS: The doubling time of CA 19
      9 and CEA could be calculated in 90.2% and 58.5% of patients with inoperable
      pancreatic cancer. CA 19-9 doubling time was clearly associated with survival
      time in inoperable and palliatively operated cases, but not with sex, age, site
      of the lesion, or liver metastasis, and was significantly correlated with the
      tumor volume doubling time. CONCLUSIONS: Examination of CA 19-9 doubling time may
      be useful in clinical evaluation of the prognosis for patients with pancreatic
      cancer and could possibly prove valuable in terms of the analysis of the growth
      process in this disease.

PMID- 10404130
TI  - Expression of p27Kip1 and cyclin D1 proteins is inversely correlated and is
      associated with poor clinical outcome in human gastric cancer.
AB  - BACKGROUND AND OBJECTIVES: p27Kip1 is an inhibitor of cyclin-dependent kinases
      and is speculated to be a potential prognostic indicator in numerous human
      cancers. We investigated expression of p27Kip1 along with cyclin D1 in gastric
      cancer to estimate the clinical utility of p27Kip1. METHODS: Immunohistochemical
      assay for p27Kip1 and cyclin D1 proteins was performed in 64 patients with
      primary gastric cancer. Correlation between p27Kip1 expression and clinical
      biological parameters including patient survival was analyzed. RESULTS: p27Kip1
      expression was suppressed in 40 (62.5%) of 64 gastric cancer patients and cyclin
      D1 was overexpressed in 22 (34.4%) out of 64. Expression of p27Kip1 was
      significantly reduced in poorly differentiated cancers (82.1%, 23/28; P = 0.015)
      and was also reduced in the tumors with high S-phase fraction (86.7%, 26/30)
      compared with tumors showing low S-phase fraction (41.2%, 14/34; P = 0.0002).
      Expression of p27Kip1 and cyclin D1 was inversely correlated (P = 0.021). In
      univariate analysis, extent of the disease (P < 0.001), expression of cyclin D1
      (P = 0.0001), and reduced expression of p27Kip1 (P = 0. 0006), were statistically
      significant to predict patient's outcome, but depth of invasion (P = 0.008) and
      pathologic stage (P = 0.009) emerged as significant prognostic indicators in
      multivariate analysis. CONCLUSION: Expression of p27Kip1 is closely linked with
      cell proliferation and differentiation of human gastric cancer. p27Kip1 seems to
      have potential as a prognostic marker in the management of gastric cancer
      patients.

PMID- 10404131
TI  - Treatment and local control of primary extremity soft tissue sarcomas.
AB  - BACKGROUND AND OBJECTIVES: Modern series of adult extremity soft tissue sarcomas
      utilize combinations of modalities in all patients. Remaining questions: 1) is it
      necessary to strive for wide margins in the multimodality era; 2) to use adjuvant
      therapy in every high-grade sarcoma? 3) Does previous partial or marginal
      resection seriously interfere with the definitive resection? METHODS: In a
      retrospective review of 194 extremity soft tissue sarcomas (1977-1994), limb
      preservation was possible in 181/194 (93%) of cases. Patients with narrow margins
      received adjuvant radiation. Some patients were referred after partial (n = 39)
      or "complete" (n = 63) excision. RESULTS: Local recurrence was observed in
      181/141 (13%) of patients treated with wide or compartmental resection, and in 10
      of 42 (24%) of those treated with conservative resection plus radiation (P =
      0.14). The 5-year survival rate for grade III, >/=5-cm sarcomas was not
      significantly different (P = 0.82) with adjuvant (46%) or without (48%) adjuvant
      systemic chemotherapy. Five-year survival varied (P = 0.0001) according to grade.
      Patients referred with partial, or "complete" (63%, 38/63, had residual tumor at
      reoperation) excision had a local recurrence rate of 8% and 6%, and 5-year
      survival rates of 75% and 84%, respectively. CONCLUSIONS: 1) It is important to
      strive for wide margins even when adjuvant radiation is intended. 2) When a wide
      margin is possible, adjuvant radiation may not be necessary. 3) Adjuvant systemic
      chemotherapy may be considered for high-grade tumors, preferably within a
      prospective protocol. 4) A partial or "complete" excision of the tumor before
      referral to a tertiary center does not appear to compromise the limb
      preservation, local control, or survival rates of these patients.

PMID- 10404132
TI  - Axillary lymph node involvement in stage III breast cancer: treatment
      implications.
AB  - BACKGROUND AND OBJECTIVES: The introduction of multimodal therapy has improved
      the prognosis in stage III breast cancer. A knowledge of the likely axillary
      lymph node status at presentation is important, both to plan surgical therapy to
      the axilla and to establish the effect of induction therapy on the axillary
      nodes. METHODS: The study involved a chart review of 114 patients with stage III
      breast cancer who were treated by modified radical mastectomy without prior
      systemic therapy. A standard method was used for axillary dissection and numbers
      and levels of pathologically involved lymph nodes were recorded. The incidence of
      lymph node metastases was correlated with tumour size, grade, and clinical T
      stage. The accuracy of clinical axillary staging and the relationship between
      level III invasion and the number of level I and II nodes invaded was also
      assessed. RESULTS: Overall, 96 of 114 (84%) patients had axillary nodal
      metastases, and 37 of 114 (32%) patients had level III metastases. Eighteen of 43
      tumours (42%) 30 mm or less had level III metastases and 27% of larger tumours
      had level III metastases (6/25 31-49-mm tumours, and 12/42 50+-mm tumours). Of 98
      gradable cancers, only 1 out of 10 well-differentiated tumours had level III
      metastases, but the rate in moderately and poorly differentiated tumours was 36%
      (19/53) and 37% (13/35), respectively. Clinical node staging was unreliable. A
      group of patients with a low likelihood of level III metastases who might benefit
      from an axillary procedure less than level III dissection could not be identified
      preoperatively. CONCLUSIONS: Patients with stage III breast cancer have a high
      incidence of level III axillary lymph node metastases. A subgroup with a low
      incidence of level III metastases could not be identified in this study. Until
      axillary downstaging has been convincingly demonstrated with induction therapy, a
      less than complete axillary procedure may leave the patient at high risk of
      axillary relapse.

PMID- 10404133
TI  - Carboplatin and etoposide for recurrent malignant glioma following surgical and
      radiotherapy failure: A clinical study conducted at the Northern Israel Oncology
      Center.
AB  - BACKGROUND AND OBJECTIVES: We conducted a phase II study using carboplatin and
      etoposide on patients with recurrent malignant glioma to investigate tumor
      response. METHODS: From January 1995 to March 1997, 21 patients with recurrent
      malignant glioma were treated with a carboplatin (300 mg/m(2), day 1)/etoposide
      (100 mg/m(2), days 1-3) regimen every 3-4 weeks. The following radiologic
      parameters were evaluated: tumor size, central lucency, degree of contrast
      enhancement, and mass effect. No patient had received chemotherapy previously.
      Dose escalation corresponded to hematologic tolerance and to general and
      neurologic performance status. Most patients were treated postoperatively with
      involved field radiotherapy followed by a boost to the tumor area, as defined on
      the presurgery computed tomography scan or on magnetic resonance imaging. Mean
      interval to introduction of chemotherapy was 8.8 months (range, 7-36 months).
      Patients received a mean of four cycles [range, 2-8 cycles]. RESULTS: Only 2
      patients showed moderate radiological response, while 12 patients died of
      progressive disease. Mean time to progression following discontinuation of
      chemotherapy was 5.8 months (range, 1-11 months). The other patients survived
      with persistent disease and are being treated palliatively. Toxicity was
      manageable (1, neutropenic sepsis; 1, thrombocytopenia (45,000/mm(3)); 2,
      temporarily elevated transaminase level; 2, steroid-induced erosive gastritis).
      CONCLUSIONS: This phase II regimen proved to be ineffective in recurrent
      malignant glioma. Further studies incorporating innovative drug regimens and
      schedules are warranted. J. Surg. Oncol., 1999;71:167-170.

PMID- 10404134
TI  - Pancreatic cancer: total costs and utilization of health services.
AB  - BACKGROUND AND OBJECTIVES: Pancreatic cancer ranks 11th in incidence, and fifth
      in cancer deaths, with 29,000 affected annually. Accurate estimates of the cost
      of pancreatic cancer are unavailable; existing estimates are variable or not
      generalizable. This paper presents detailed cost estimates for pancreatic cancer
      by service, age, and gender. METHODS: Direct and indirect societal costs are
      determined using a prevalence-based, human capital approach. RESULTS: Total
      annual costs are $4.9 billion, (men: $3.0 billion, women: $1.9 billion). Total
      direct costs are $881 million, with 71% ($627.1 M/$881.3 M) for those over 65
      years. Total hospital costs are 77% ($679.5 M/$881.3 M) of total direct costs.
      Total indirect costs are $4.0 billion, with 63% ($2,518.43 M/$4,018 M) for those
      45 to 64 years. Mortality costs are $3.7 billion, 93% ($3,739 M/$4,018 M) of
      indirect costs. CONCLUSIONS: This paper presents cost estimates that are precise
      and generalizable to the general population. The surgical cost burden may be less
      than indicated previously, with most hospitalizations not including a major
      procedure, and average operating room costs accounting for only 9%
      ($1,045/$11,055) of hospital costs. Women have significantly less cancer-directed
      surgery than men.

PMID- 10404135
TI  - Recurrent ductal carcinoma in situ after total mastectomy.
AB  - A case report is presented of a woman with recurrent DCIS occurring several years
      following a total mastectomy, the diagnosis of which was aided by a subpectoral
      saline implant. A discussion of factors associated with recurrence and a review
      of the literature is provided. A role for selective use of mammography in
      screening postmastectomy reconstructed breasts in patients at high risk for
      recurrence is suggested.

PMID- 10404136
TI  - Tracheal injury during transhiatal mobilization of the esophagus.
AB  - In 50 transhiatal esophageal mobilizations done from 1988 to 1998 at the Cancer
      Institute (W.I.A.) in Chennai, India, injuries to the trachea were detected on 3
      occasions: 1 in a woman with carcinoma of the hypopharynx and 2 in patients (1
      male, 1 female) with squamous cell carcinoma of the esophagus. The incidence of
      tracheal injuries during esophageal mobilization varies in different series. This
      is usually on the membranous posterior wall of the trachea. When recognized on
      the table, repair of the rent must be carried out. Persistent air leak through
      the intercostal tube or surgical emphysema developing over the face and neck in
      the postoperative period indicates an injury to the airway. A bronchoscopy will
      reveal the site of injury. If the lung is fully expanded and the stomach abuts
      the rent completely, the patient may be observed. However, if the lung is
      collapsed and does not expand on applying negative suction to the intercostal
      tube or the injury is in the bronchi, the patient is best reexplored to close the
      rent. With proper case selection and careful dissection of the esophagus, the
      problem of tracheal injuries can be avoided.

PMID- 10404137
TI  - Distribution of gland-like structures in human gallbladder adenocarcinomas
      possesses fractal dimension.
AB  - BACKGROUND AND OBJECTIVES: Epithelial cells form tissue patterns of higher order
      such as gland-like structures. A question arises whether distribution of those
      patterns in adenocarcinomas is subject to certain regularity. METHODS: Due to the
      pilot nature of this study, gallbladder adenocarcinomas were preselected by
      histopathological, immunohistochemical, and morphometric analysis to ensure
      relative homogeneity of the patterns analyzed. A box-counting method was applied
      to investigate a relationship between a number of gland-like structures and a
      radius of the expanding family of the concentric circles. RESULTS: The
      coefficient of linear regression characterizing that relationship possesses
      noninteger value. It is 1. 585 (well-differentiated adenocarcinomas, standard
      deviation (SD) = 0.038, n = 100 sections), and 1.340 (moderately differentiated
      adenocarcinomas, SD = 0.044, n = 100 sections). While both nuclear area and
      nucleo-cytoplasmic ratio in those tissues remain within a similar range (Analysis
      of Variance (ANOVA), F(0) = 0.791 < F(alpha) = 3.84, P = 3 x 10(-3) and F(0) =
      0.077 < F(alpha) = 3.84, P = 10(-6), respectively, for k = 20,000 cells, in which
      F(0) is a value of the test function, F(alpha) is a critical, limit value of the
      F-test at the constant confidence value alpha = 0.05), a difference of fractal
      dimension is significant (F(0) = 3.94 > F(alpha) = 0.693, n = 100 sections, P = 2
      x 10(-3)). Also, variablity of fractal dimension between tumor sections is
      significant (moderately differentiated adenocarcinomas, F(0) = 1.9856 > F(alpha)
      = 1.4262, n = 100 sections, P = 0.189). CONCLUSIONS: There is fractal regularity
      in distribution of gland-like structures in human gallbladder adenocarcinomas.
      Fractal dimension is a holistic parameter which can be applied to evaluate tumor
      grading in a quantitative manner.

PMID- 10404138
TI  - Avoidance of rectovaginal fistula as a complication after low anterior resection
      for rectal cancer using a double-stapling technique.

PMID- 10404140
TI  - International union against cancer 17th international cancer congress:
      presentation of the third musio athayde cancer prize 

PMID- 10404139
TI  - Biological considerations with pelvic neoplasms.
AB  - The strategy of therapy for any neoplasm is determined to a significant degree by
      the biological characteristics of the neoplasm. The ones benefited most by
      surgical ablation are the cancers that grow locally but never metastasize. The
      second group is composed of neoplasms with exceedingly slow growth rates
      permitting long periods of symptom-free survival before recidivation. Many such
      cancers occur in pelvic structures requiring understanding of the nature of the
      cancers and then techniques necessary for their resection. The review provides an
      introduction to some of the relevant biological considerations.

PMID- 10404141
TI  - On acceptance of the third musio athayde cancer prize 

PMID- 10404142
TI  - Telomere length measurements using digital fluorescence microscopy.
AB  - BACKGROUND: The ends of chromosomes (telomeres) are important to maintain
      chromosome stability, and the loss of telomere repeat sequences has been
      implicated in cellular senescence and genomic instability of cancer cells. The
      traditional method for measuring the length of telomeres (Southern analysis)
      requires a large number of cells (>10(5)) and does not provide information on the
      telomere length of individual chromosomes. Here, we describe a digital image
      microscopy system for measurements of the fluorescence intensity derived from
      telomere repeat sequences in metaphase cells following quantitative fluorescence
      in situ hybridization (Q-FISH). METHODS: Samples are prepared for microscopy
      using Q-FISH with Cy3 labeled peptide nucleic acid probes specific for
      (T(2)AG(3))(n) sequences and the DNA dye DAPI. Separate images of Cy3 and DAPI
      fluorescence are acquired and processed with a dedicated computer program (TFL
      TELO). With the program, the integrated fluorescence intensity value for each
      telomere, which is proportional to the number of hybridized probes, is calculated
      and presented to the user. RESULTS: Indirect tests of our method were performed
      using simulated as well as defined tests objects. The precision and consistency
      of human telomere length measurements was then analyzed in a number of
      experiments. It was found that by averaging the results of less than 30 cells, a
      good indication of the telomere length (SD of 10-15%) can be obtained.
      CONCLUSIONS: We demonstrate that accurate and repeatable fluorescence intensity
      measurements can be made from Q-FISH images that provide information on the
      length of telomere repeats at individual chromosomes from limited number of
      cells.

PMID- 10404143
TI  - High-resolution cytometry of FISH dots in interphase cell nuclei.
AB  - BACKGROUND: Flow cytometry (FCM) and laser scanning cytometry (LSCM) provide
      indispensable tools for measuring large number of cells with low resolution.
      Confocal microscopy, on the other hand, is used for measuring small number of
      cells with high resolution. In this paper, we present a reasonable compromise
      between the two extremes. METHODS: We have developed a completely automated, high
      resolution system (high-resolution cytometer, HRCM) capable of analyzing
      microscope slides with FISH-stained interphase nuclei in two dimensions as well
      as in three dimensions using a fully motorized epi-fluorescence microscope and a
      cooled digital CCD camera fully controlled by a high-performance computer which
      performs both acquisition and related on-line image analysis. The images of
      different dyes are acquired sequentially using highly specific filters and
      superimposed in computer memory. For each nucleus and each hybridization dot,
      user-selected attributes (such as position, size, intensity, etc.) are computed
      off-line using another processor or computer connected with a network. RESULTS:
      Using HRCM, it is possible to analyze multi-color preparations including UV
      excited dyes as well as repeatedly hybridized preparations reacquiring individual
      nuclei. The speed of the acquisition and analysis is about 50 nuclei per minute
      in two dimensions and 1 nucleus per minute in three dimensions, but depends on
      the density of nuclei on the slide; the precision of the lateral and axial
      measurements is approximately 100 nm. CONCLUSIONS: Thus, using overnight
      acquisition, quantities comparable to those of FCM or LSCM measurements can be
      analyzed with an accuracy comparable to confocal microscopy. HRCM is suitable for
      a number of clinical and scientific tasks: routine diagnostics, follow-up of
      therapy, studies of chromatin structure, and many other different aspects of cell
      research.

PMID- 10404144
TI  - Detection of rare MCF-7 breast carcinoma cells from mixtures of human peripheral
      leukocytes by magnetic deposition analysis.
AB  - BACKGROUND: The presence of malignant breast cancer cells in bone marrow or
      peripheral blood is a prognostic factor. We tested the capacity of a novel
      magnetic cell analyzer to detect rare cancer cells in mixtures with human
      peripheral leukocytes. METHODS: Human peripheral leukocytes were spiked with
      cells of the MCF-7 line, and the cell mixture was labeled with anti-epithelial
      membrane antigen antibody and a magnetic colloid. The MCF-7 cells were
      selectively captured on a magnetic deposition substrate from the flowing
      leukocyte and MCF-7 cell mixture. RESULTS: The recovery of the MCF-7 cells from
      the original mixture ranged from 20% to 60%. The limit of detection of the MCF-7
      cells was 10(-6) (n = 9). The morphology of the captured cancer cells was well
      preserved and comparable to that observed in cytospin smears. All deposited cells
      were located in a small area of 1.4 mm x 6 mm and could be quickly identified
      with an optical microscope following Wright's staining. CONCLUSIONS: This is a
      proof-of-principle study using a simplified model of rare cancer cells in a
      leukocyte mixture. The clinical relevance of the method will be tested in the
      future by extension to patient bone marrow samples and using antibody cocktails
      to increase specificity against the breast carcinoma cells.

PMID- 10404145
TI  - Effects of thermal exposure on immunophenotyping combined with in situ PCR,
      measured by flow cytometry.
AB  - BACKGROUND: The combination of in situ PCR and cell phenotyping by antibody
      labeling (ISPCR/Flow) allows for the identification of cell subsets carrying a
      particular genetic sequence. ISPCR utilizes thermal cycling for genetic
      amplification, which can reduce the effectiveness of surface antibody labeling.
      This study explored and characterized the effects of thermal exposure on antibody
      labeling using CD4 and CD45. METHODS: Single temperature incubations and thermal
      cycling exposures were performed on leukocytes labeled with either direct
      antibody conjugates or with biotinylated antibodies and PE-streptavidin. RESULTS:
      Fluorescence emission decreased above 70 degrees ( )C when cells were stained
      with directly conjugated antibodies or a biotinylated antibody and PE
      streptavidin prior to high heat exposure. If counter stained with PE-streptavidin
      after heat, fluorochrome fluorescence was detectable. We tested a second CD4
      clone, that provided poor results under similar labeling conditions, suggesting
      the combination of fixation and heat may have an epitope specific effect for the
      same cellular antigen. CONCLUSIONS: Immunophenotyping can be combined with ISPCR,
      but each antibody must be tested to determine its efficacy. The denaturation of
      protein above 70 degrees C appears to be the main reason for loss of
      fluorescence. The best procedure is to first stain cells with a biotinylated
      antibody to an epitope that survives fixation and thermocycling. The cells are
      then subjected to the desired PCR procedure. Finally they are stained with a
      fluorochrome conjugated streptavidin.

PMID- 10404146
TI  - Phototoxicity of the fluorescent membrane dyes PKH2 and PKH26 on the human
      hematopoietic KG1a progenitor cell line.
AB  - BACKGROUND: The phototoxic effects of the well-known fluorescent membrane dyes
      PKH2 and PKH26 have been unknown, although their use in cell tracking experiments
      has increased dramatically. To eliminate the phototoxicity-induced alteration in
      cell function and morphology, it is essential to examine the suspicious
      phototoxicity of these dyes. METHODS: Chemical and phototoxic effects of PKH dyes
      on the human hematopoietic KG1a cell line were examined. To minimize
      phototoxicity in long-term cell tracking experiments lasting up to 18 h with a
      fluorescence microscope system, time-lapse monitoring with different time
      intervals and exposure times was introduced. RESULTS: There were no significant
      effects of the two PKH dyes on cell viability and growth when using dye
      concentrations up to 5 microM. However, when stained cells were exposed to
      excitation light, cell viability decreased dramatically, showing the
      phototoxicity of the PKH dyes. More than 60% of cells stained with 5 microM PKH26
      died after 5 min of continuous light exposure. The phototoxic effect was more
      extensive in cells stained with higher concentrations of the dyes. CONCLUSIONS:
      We present guidelines for the optimal use of these dyes by using a defined
      hardware configuration.

PMID- 10404147
TI  - Separation of sperm and vaginal cells based on ploidy, MHC class I-, CD45-, and
      cytokeratin expression for enhancement of DNA typing after sexual assault.
AB  - BACKGROUND: Successful DNA typing after rape is limited when only a few sperm and
      numerous vaginal cells are recovered from a swab, resulting in an extremely
      unfavorable ratio of male to female DNA. The goal of this study was to develop a
      protocol involving sperm cell sorting with flow cytometry based on differences in
      ploidy, major histocompatibility (MHC) class I, CD45 and cytokeratin expression.
      METHODS: Vaginal lavages were mixed with serially diluted ejaculate. After
      immunostaining and stoichiometric nuclear staining, spermatocytes were isolated
      by fluorescence-activated cell sorting. All sorted cells were used for DNA
      extraction and subsequent quantitative fluorescent multiplex polymerase chain
      reaction. The preferential lysis was performed for comparison. RESULTS: The
      sorting procedure was superior to the preferential lysis method within all tested
      dilutions. One documented case of rape was examined with both procedures and only
      after cell sorting with flow cytometry was the male DNA identified. CONCLUSIONS:
      We were able to show that separation of sperm and vaginal cells using cell
      sorting with flow cytometry may be crucial when there is only a few sperm
      detectable after rape.

PMID- 10404148
TI  - Bacterial fingerprinting by flow cytometry: bacterial species discrimination.
AB  - BACKGROUND: A flow cytometric measurement (FCM) technique has been developed to
      size DNA fragments. Individual fragments of a restriction digest of genomic DNA,
      stained with an intercalating dye, are passed through an ultrasensitive
      cytometer. The measured fluorescence intensity from each fragment is proportional
      to the fragment length. METHODS: The isolation of bacterial genomic DNA and
      digestion by restriction enzymes were performed inside an agarose plug. Rare
      cutting enzymes were employed to produce a manageable number of DNA fragments.
      Electroelution was used to move the DNA fragments from the agarose plug into a
      solution containing polyamines to protect the DNA from shear-induced breakage.
      The DNA was stained with the bisintercalating dye thiazole orange homodimer and
      introduced into our ultrasensitive flow cytometer. A histogram of the
      fluorescence intensities (fingerprint) was constructed. RESULTS: Gram-positive
      Bacillus globigii and gram-negative bacteria Escherichia coli and Erwinia
      herbicola were distinguished by the fingerprint pattern of restriction fragments
      of their genomic DNA. DNA sizes determined by FCM are in good agreement with
      pulsed-field gel electrophoresis (PFGE) analysis. Flow cytometry requires only
      picogram quantities of purified DNA and takes less than 10 min for data
      collection and analysis. When the total sample preparation time is included, the
      analysis times for PFGE and FCM are similar ( approximately 3 days). CONCLUSIONS:
      FCM is an attractive technique for the identification of bacterial species. It is
      more sensitive and potentially much faster than PFGE.

PMID- 10404149
TI  - Analysis with flow cytometry of green fluorescent protein expression in leukemic
      cells.
AB  - BACKGROUND: The measurement of DNA content with propidium iodide (PI) in cells
      transfected with expression vectors encoding the green fluorescent protein (GFP)
      is a useful tool in studying a variety of biological functions of proteins within
      cells. The purpose of this study was to determine conditions of formaldehyde
      fixation that permit intracellular GFP fluorescence and adequate DNA histograms
      to be generated following transient transfection of cells with a GFP-encoding
      plasmid. Cell cycle analysis was also performed in GFP-positive cells. METHODS:
      The murine myeloid leukemic cell line, 32Dcl3, was used as the model system.
      Cells were transfected with a GFP-encoding plasmid (pEGFPC1). Following fixation
      in different formaldehyde concentrations and permeabilization with 70% ethanol,
      cells were stained with PI and analyzed by flow cytometry for GFP fluorescence
      and DNA content. Transfected cells were also analyzed for GFP fluorescence and
      DNA content following release from nocodazole block. RESULTS: Fixing cells in
      0.51-1.75% formaldehyde concentrations prior to ethanol permeabilization resulted
      in 14-19% of transfected cells being GFP-positive, with acceptable coefficients
      of variation on the G(1) peak of DNA histograms. Analysis of cells synchronized
      to and released from the G(2)-M phase by nocodazole suggested that GFP-positive
      cells, when compared to GFP-negative cells, did not appear to progress out of
      G(2)-M following release from nocodazole block. Simultaneous detection of GFP
      fluorescence and DNA content by PI staining is possible following transient
      transfection of cells with a single expression vector encoding GFP. Our results
      demonstrate that GFP expression can be detected, using flow cytometry to perform
      cell cycle analysis in murine leukemic cells.

PMID- 10404150
TI  - Quantitative measurement of mast cell degranulation using a novel flow cytometric
      annexin-V binding assay.
AB  - BACKGROUND: Mast cells are primary mediators of allergic inflammation. Antigen
      mediated crosslinking of their cell surface immunoglobulin E (IgE) receptors
      results in degranulation and the release of proinflammatory mediators including
      histamine, tumor necrosis factor-alpha, and leukotrienes. METHODS: Mast cells
      were stimulated to degranulate by using either IgE crosslinking or ionophore
      treatment. Exogenously added annexin-V was used to stain exocytosing granules,
      and the extent of binding was measured flow cytometrically. Release of the enzyme
      beta-hexosaminidase was used for population-based measurements of degranulation.
      Two known inhibitors of degranulation, the phosphatidylinositol 3 kinase
      inhibitor wortmannin and overexpression of a mutant rab3d protein, were used as
      controls to validate the annexin-V binding assay. RESULTS: Annexin-V specifically
      bound to mast cell granules exposed after stimulation in proportion to the extent
      of degranulation. Annexin-V binding was calcium dependent and was blocked by
      phosphatidylserine containing liposomes, consistent with specific binding to this
      membrane lipid. Visualization of annexin-V staining showed granular cell surface
      patches that colocalized with the exocytic granule marker VAMP-green fluorescent
      protein (GFP). Wortmannin inhibited both annexin-V binding and beta
      hexosaminidase release in RBL-2H3 cells, as did the expression of a dominant
      negative rab3d mutant protein. CONCLUSIONS: The annexin-V binding assay
      represents a powerful new flow cytometric method to monitor mast cell
      degranulation for functional analysis.

PMID- 10404151
TI  - Fluoro-Gold: An alternative viability stain for multicolor flow cytometric
      analysis.
AB  - BACKGROUND: The viability stains propidium iodide (PI) and 7-amino-actinomycin D
      (7-AAD) are excited at 488 nm, as are the commonly used antibody conjugates
      fluorescein isothiocyanate (FITC), phycoerythrin (PE), and cyanine 5 dye
      covalently coupled to R-phycoerythrin (RPE-Cy5). When excited by a single laser,
      spectral overlap in the emission of PI and 7-AAD with RPE-Cy5 precludes the use
      of these viability stains for three-color immunophenotyping, particularly when
      evaluating low levels of marker expression in viable target cells. The
      ultraviolet excitable dye hydroxystilbamidine methanesulfonate (Fluoro-Gold, or
      FG) binds to DNA at the A-T-rich regions of the minor groove in permeabilized or
      dead cells. We assessed the suitability of this dye as a viability stain.
      METHODS: The ability of FG to detect nonviable cells in fresh and cryopreserved
      human apheresed peripheral blood cells was compared with that of PI and 7-AAD.
      The stability of FG staining and the effects of dye and cell concentration on the
      discrimination of nonviable cells was determined by measuring changes in the
      median fluorescence of viable and nonviable cells. RESULTS: FG labeling at dye
      concentrations of 2-8 microM is stable for at least 3 h over a wide range of cell
      concentrations (4 x 10(5) to 4 x 10(7) cells/ml). Costaining studies and linear
      regression analysis show that cell viability as determined by FG is strongly
      correlated with estimates using PI (r = 0.9636) and 7-AAD (r = 0.9879).
      CONCLUSIONS: FG is a reliable, alternative viability stain that can be used in
      conjunction with fluorochromes including FITC, PE, and RPE-Cy5 for multicolor
      analysis using dual-laser instruments.

PMID- 10404152
TI  - The use of chloromethyl-X-rosamine (Mitotracker red) to measure loss of
      mitochondrial membrane potential in apoptotic cells is incompatible with cell
      fixation.
AB  - BACKGROUND: A recent report by Macho et al. (Cytometry 25: 333-340, 1996)
      described the use of chloromethyl-X-rosamine (CMX-Ros) as a fixable probe for
      detection of loss of mitochondrial membrane potential (psi(mit)), an early event
      in many models of apoptosis. However, this previous report lacked a description
      of any direct comparisons between pre- and post-fixation analyses of normal and
      apoptotic cells stained with CMX-Ros. METHODS: Using a variety of cell types, we
      investigated the effect of paraformaldehyde fixation on cellular retention of CMX
      Ros and the implications of this for the subsequent analysis of changes in
      psi(mit) in cells undergoing apoptosis. RESULTS: We found that following
      fixation, the resolution between normal cells with polarized mitochondria and
      apoptotic cells with depolarized mitochondria is reduced to the extent that
      accurate discrimination between the cell types is no longer possible.
      CONCLUSIONS: Overall, our results are consistent with CMX-Ros being a valid probe
      for psi(mit) in intact cells but only when the cells are stained and analyzed
      immediately. Thus, our results suggest that the proposed applications for CMX-Ros
      in multiple parameter analysis of fixed cells are inappropriate and will lead to
      spurious results.

PMID- 10404153
TI  - Detection of apoptosis and changes in mitochondrial membrane potential with
      chloromethyl-X-rosamine.

PMID- 10404154
TI  - Plant ferritin and human iron deficiency.

PMID- 10404155
TI  - Deal making for growth.

PMID- 10404156
TI  - The long arm of DNA.

PMID- 10404157
TI  - Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural
      stem cells by type 1 astrocytes.
AB  - The implementation of neural stem cell lines as a source material for brain
      tissue transplants is currently limited by the ability to induce specific
      neurochemical phenotypes in these cells. Here, we show that coordinated induction
      of a ventral mesencephalic dopaminergic phenotype in an immortalized multipotent
      neural stem cell line can be achieved in vitro. This process requires both the
      overexpression of the nuclear receptor Nurr1 and factors derived from local type
      1 astrocytes. Over 80% of cells obtained by this method demonstrate a phenotype
      indistinguishable from that of endogenous dopaminergic neurons. Moreover, this
      procedure yields an unlimited number of cells that can engraft in vivo and that
      may constitute a useful source material for neuronal replacement in Parkinson's
      disease.

PMID- 10404158
TI  - Vaccination with carbohydrate peptide mimotopes promotes anti-tumor responses.
AB  - Tumor-associated carbohydrate (TAC) antigens are important targets in cancer
      vaccine efforts. Carbohydrates are, however, frequently poor immunogens, in that
      they are T-cell-independent antigens. Molecular mimicry of TAC by peptides is an
      alternative approach to generating anti-carbohydrate immune responses. Here we
      demonstrate that peptide mimotopes can elicit antibody responses that cross-react
      with representative human TAC antigens. Primary immunization with such a multiple
      antigenic peptide, along with QS-21 as adjuvant, elicits cytotoxic antibodies
      reactive with naturally occurring forms of TAC expressed on tumor cells, and
      vaccination of mice with peptide mimotopes reduced tumor growth and prolonged
      host survival in a murine tumor model.

PMID- 10404159
TI  - Therapeutic antibodies elicited by immunization against TNF-alpha.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is critically involved in the
      pathogenesis of several chronic inflammatory diseases. Monoclonal antibodies
      against TNF-alpha are currently used for the treatment of rheumatoid arthritis
      and Crohn's disease. This report describes a simple and effective method for
      active immunization against self TNF-alpha. This vaccination approach leads to a
      T-cell-dependent polyclonal and sustainable anti-TNF-alpha autoantibody response
      that declines upon discontinuation of booster injections. The autoantibodies are
      elicited by injecting modified recombinant TNF-alpha molecules containing foreign
      immunodominant T-helper epitopes. In mice immunized with such molecules, the
      symptoms of experimental cachexia and type II collagen-induced arthritis are
      ameliorated. These results suggest that vaccination against TNF-alpha may be a
      useful approach for the treatment of rheumatoid arthritis and other chronic
      inflammatory diseases.

PMID- 10404160
TI  - Antibodies engineered with IgD specificity efficiently deliver integrated T-cell
      epitopes for antigen presentation by B cells.
AB  - We have developed a strategy for improving the stimulation of T cells during
      immune responses by constructing recombinant antibodies that enhance the delivery
      of antigen to antigen-presenting cells, such as B cells. These antibodies have
      variable regions specific for surface molecules on B cells, and a constant region
      with an inserted antigen. In vitro, such antibodies make B cells approximately
      1000-fold more efficient at presenting antigen and stimulating specific T cells.
      In vivo, the antibodies turn B cells of the spleen into potent stimulators of T
      cells. This approach may be useful for the generation of new vaccines.

PMID- 10404161
TI  - Direct analysis of protein complexes using mass spectrometry.
AB  - We describe a rapid, sensitive process for comprehensively identifying proteins
      in macromolecular complexes that uses multidimensional liquid chromatography (LC)
      and tandem mass spectrometry (MS/MS) to separate and fragment peptides. The
      SEQUEST algorithm, relying upon translated genomic sequences, infers amino acid
      sequences from the fragment ions. The method was applied to the Saccharomyces
      cerevisiae ribosome leading to the identification of a novel protein component of
      the yeast and human 40S subunit. By offering the ability to identify >100
      proteins in a single run, this process enables components in even the largest
      macromolecular complexes to be analyzed comprehensively.

PMID- 10404162
TI  - An in vivo library-versus-library selection of optimized protein-protein
      interactions.
AB  - We describe a rapid and efficient in vivo library-versus-library screening
      strategy for identifying optimally interacting pairs of heterodimerizing
      polypeptides. Two leucine zipper libraries, semi-randomized at the positions
      adjacent to the hydrophobic core, were genetically fused to either one of two
      designed fragments of the enzyme murine dihydrofolate reductase (mDHFR), and
      cotransformed into Escherichia coli. Interaction between the library polypeptides
      reconstituted enzymatic activity of mDHFR, allowing bacterial growth. Analysis of
      the resulting colonies revealed important biases in the zipper sequences relative
      to the original libraries, which are consistent with selection for stable,
      heterodimerizing pairs. Using more weakly associating mDHFR fragments, we
      increased the stringency of selection. We enriched the best-performing leucine
      zipper pairs by multiple passaging of the pooled, selected colonies in liquid
      culture, as the best pairs allowed for better bacterial propagation. This
      competitive growth allowed small differences among the pairs to be amplified, and
      different sequence positions were enriched at different rates. We applied these
      selection processes to a library-versus-library sample of 2.0 x 10(6)
      combinations and selected a novel leucine zipper pair that may be appropriate for
      use in further in vivo heterodimerization strategies.

PMID- 10404163
TI  - Rapid protein-folding assay using green fluorescent protein.
AB  - Formation of the chromophore of green fluorescent protein (GFP) depends on the
      correct folding of the protein. We constructed a "folding reporter" vector, in
      which a test protein is expressed as an N-terminal fusion with GFP. Using a test
      panel of 20 proteins, we demonstrated that the fluorescence of Escherichia coli
      cells expressing such GFP fusions is related to the productive folding of the
      upstream protein domains expressed alone. We used this fluorescent indicator of
      protein folding to evolve proteins that are normally prone to aggregation during
      expression in E. coli into closely related proteins that fold robustly and are
      fully soluble and functional. This approach to improving protein folding does not
      require functional assays for the protein of interest and provides a simple route
      to improving protein folding and expression by directed evolution.

PMID- 10404164
TI  - Directed evolution of the surface chemistry of the reporter enzyme beta
      glucuronidase.
AB  - The use of the Escherichia coli enzyme beta-glucuronidase (GUS) as a reporter in
      gene expression studies is limited due to loss of activity during tissue fixation
      by glutaraldehyde or formaldehyde. We have directed the evolution of a GUS
      variant that is significantly more resistant to both glutaraldehyde and
      formaldehyde than the wild-type enzyme. A variant with eight amino acid changes
      was isolated after three rounds of mutation, DNA shuffling, and screening.
      Surprisingly, although glutaraldehyde is known to modify and cross-link free
      amines, only one lysine residue was mutated. Instead, amino acid changes
      generally occurred near conserved lysines, implying that the surface chemistry of
      the enzyme was selected to either accept or avoid glutaraldehyde modifications
      that would normally have inhibited function. We have shown that the GUS variant
      can be used to trace cell lineages in Xenopus embryos under standard fixation
      conditions, allowing double staining when used in conjunction with other
      reporters.

PMID- 10404165
TI  - Resistance to rice yellow mottle virus (RYMV) in cultivated African rice
      varieties containing RYMV transgenes.
AB  - The disease caused by rice yellow mottle virus (RYMV) is a serious problem for
      African rice growers in large-scale irrigated programs. As there are very few
      suitable natural sources of RYMV resistance, we have investigated a transgenic
      approach using widely grown, RYMV-susceptible cultivars of rice and a transgene
      encoding the RNA-dependent RNA polymerase of RYMV. Transformed lines were
      resistant to RYMV strains from different African locations. In the most extreme
      examples there was complete suppression of virus multiplication. Resistance was
      stable over at least three generations. Subject to satisfactory field testing,
      these transgenic lines may be suitable for introduction into RYMV-affected rice
      growing areas. In the most resistant line, transcription analysis indicated that
      the resistance derives from an RNA-based mechanism associated with
      posttranscriptional gene silencing.

PMID- 10404166
TI  - Ectopic expression of a tobacco invertase inhibitor homolog prevents cold-induced
      sweetening of potato tubers.
AB  - We have transformed potato with Nt-inhh cDNA, encoding a putative vacuolar
      homolog of a tobacco cell wall invertase inhibitor, under the control of the CaMV
      35S promoter. In transgenic tubers, cold-induced hexose accumulation was reduced
      by up to 75%, without any effect on potato tuber yield. Processing quality of
      tubers was greatly improved without changing starch quantity or quality, an
      important prerequisite for the biotechnological use of Nt-inhh for potato
      transformation.

PMID- 10404167
TI  - Dinitroaniline herbicide-resistant transgenic tobacco plants generated by co
      overexpression of a mutant alpha-tubulin and a beta-tubulin.
AB  - Dinitroaniline herbicides are used for the selective control of weeds in arable
      crops. Dinitroaniline herbicide resistance in the invasive weed goosegrass was
      previously shown to stem from a spontaneous mutation in an alpha-tubulin gene. We
      transformed and regenerated tobacco plants with an alpha/beta-tubulin double gene
      construct containing the mutant alpha-tubulin gene and showed that expression of
      this construct confers a stably inherited dinitroaniline-resistant phenotype in
      tobacco. In all transformed lines, the transgene alpha- and beta-tubulins
      increased the cytoplasmic pool of tubulin approximately 1.5-fold while repressing
      endogenous alpha- and beta-tubulin synthesis by up to 45% in some tissues.
      Transgene alpha- and beta-tubulin were overexpressed in every plant tissue
      analyzed and comprised approximately 66% of the total tubulin in these tissues.
      Immunolocalization studies revealed that transgene alpha- and beta-tubulins were
      incorporated into all four microtubule arrays, indicating that they are
      functional. The majority of the alpha/beta-tubulin pools are encoded by the
      transgenes, which implies that the mutant alpha-tubulin and the beta-tubulin can
      perform the majority, if not all, of the roles of microtubules in both juvenile
      and adult tobacco plants.

PMID- 10404168
TI  - Neuroscience in China.

PMID- 10404169
TI  - Real-time control of a robotic arm by neuronal ensembles.

PMID- 10404170
TI  - Caspases land on APP: one small step for apoptosis, one giant leap for
      amyloidosis?

PMID- 10404171
TI  - Do animals see what we see?

PMID- 10404173
TI  - Singing in the brain: song learning in adult zebra finches.

PMID- 10404172
TI  - The origin of confabulations.

PMID- 10404174
TI  - Flies by night.

PMID- 10404175
TI  - Improving educational efficiency.

PMID- 10404177
TI  - A new transparent motion aftereffect.

PMID- 10404176
TI  - Selective localization of cardiac SCN5A sodium channels in limbic regions of rat
      brain.

PMID- 10404178
TI  - Can molecules explain long-term potentiation?

PMID- 10404180
TI  - 'Sideways' laryngeal mask airways.

PMID- 10404179
TI  - Ionic interactions in the Drosophila serotonin transporter identify it as a
      serotonin channel.
AB  - Serotonin transporters (SERTs) are targets for drugs such as Prozac that increase
      serotonin (5HT) levels by blocking 5HT reuptake. Although SERTs saturate in the
      micromolar range, synaptic 5HT may exceed 1 mM. To examine SERT's response to
      high 5HT concentrations, we expressed Drosophila SERT (dSERT) in Xenopus oocytes
      and found that transport continued to increase with concentration up to 0.3 mM
      5HT. As 5HT is a monovalent cation, its entry through an ion channel in SERT
      might explain uptake at high concentrations. We therefore investigated dSERT
      using traditional ion channel methods, including mole-fraction experiments under
      voltage clamp. We propose that SERTs may function as 5HT-permeable channels, and
      that this mechanism may be important for clearance of the neurotransmitter at
      high concentrations.

PMID- 10404181
TI  - A trainer for placement of double-lumen tracheal tubes.

PMID- 10404182
TI  - Bronchofibrescopic jet ventilation - an aid to percutaneous tracheostomy.

PMID- 10404183
TI  - Interactions between beta 2-syntrophin and a family of microtubule-associated
      serine/threonine kinases.
AB  - A screen for proteins that interact with beta 2-syntrophin led to the isolation
      of MAST205 (microtubule-associated serine/threonine kinase-205 kD) and a newly
      identified homologue, SAST (syntrophin-associated serine/threonine kinase).
      Binding studies showed that beta 2-syntrophin and MAST205/SAST associated via a
      PDZ-PDZ domain interaction. MAST205 colocalized with beta 2-syntrophin and
      utrophin at neuromuscular junctions. SAST colocalized with syntrophin in cerebral
      vasculature, spermatic acrosomes and neuronal processes. SAST and syntrophin were
      highly associated with purified microtubules and microtubule-associated proteins,
      whereas utrophin and dystrophin were only partially associated with microtubules.
      Our data suggest that MAST205 and SAST link the dystrophin/utrophin network with
      microtubule filaments via the syntrophins.

PMID- 10404184
TI  - Alpha-2 receptor agonists and a species-specific mechanism of hypoxaemia.

PMID- 10404185
TI  - Propofol/midazolam coinduction.

PMID- 10404186
TI  - Comparison of 0.75% levobupivacaine with 0.75% racemic bupivacaine for peribulbar
      anaesthesia.

PMID- 10404187
TI  - Analgesia for spinal puncture.

PMID- 10404189
TI  - Prolonged intrathecal catheterisation after inadvertent dural taps in labour.

PMID- 10404190
TI  - An unexpectedly shallow epidural space.

PMID- 10404191
TI  - Local anaesthetic loss during simulated spinal anaesthesia.

PMID- 10404193
TI  - Amniotic fluid embolism in a patient with SC sickle cell disease.

PMID- 10404195
TI  - The epidural potato - and beyond.

PMID- 10404192
TI  - Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic
      mechanism.
AB  - We investigated long-term potentiation (LTP) at mossy fiber synapses on CA3
      pyramidal neurons in the hippocampus. Using Ca2+ imaging techniques, we show here
      that when postsynaptic Ca2+ was sufficiently buffered so that [Ca2+]i did not
      rise during synaptic stimulation, the induction of mossy fiber LTP was prevented.
      In addition, induction of mossy fiber LTP was suppressed by postsynaptic
      injection of a peptide inhibitor of cAMP-dependent protein kinase. Finally, when
      ionotropic glutamate receptors were blocked, LTP depended on the postsynaptic
      release of Ca2+ from internal stores triggered by activation of metabotropic
      glutamate receptors. These results support the conclusion that mossy fiber LTP
      and LTP at other hippocampal synapses share a common induction mechanism
      involving an initial rise in postsynaptic [Ca2+].

PMID- 10404194
TI  - A problem with a triple-lumen central line 

PMID- 10404196
TI  - Modulation of a pacemaker current through Ca(2+)-induced stimulation of cAMP
      production.
AB  - Brief increases in [Ca2+]i can result in prolonged changes in neuronal
      properties. A Ca(2+)-dependent modulation of the hyperpolarization-activated
      cation current (Ih) controls the slow recurrence of synchronized thalamocortical
      activity. Here we show that the persistent activation of Ih is initiated by
      rapidly increased [Ca2+]i and subsequent production of cAMP. The modulation is
      maintained via a facilitated interaction of cAMP with open (voltage-gated) h
      channels, inducing prolonged activation of Ih that may outlast the presence of
      increased free [Ca2+]i and [cAMP]i. This persistent Ih activation may control the
      presence and periodicity of both normal and abnormal synchronized thalamocortical
      rhythms.

PMID- 10404197
TI  - Timing of cochlear feedback: spatial and temporal representation of a tone across
      the basilar membrane.
AB  - Electromotile outer hair cell (OHC) feedback provides the sensitivity and sharp
      frequency tuning of the cochlea. Basilar membrane displacements in response to
      characteristic frequency (CF) tones were measured with an interferometer at up to
      15 locations across the basilar membrane width in the basal turn of the guinea
      pig cochlea. For CF tones, basilar membranes vibrations were largest beneath the
      OHCs; these phase-led vibrations beneath outer pillar cells and adjacent to the
      spiral ligament by approximately 90 degrees. Post mortem, responses measured
      beneath the OHCs were reduced by up to 65 dB, and the basilar membrane moved with
      similar phase across its entire width. We suggest OHCs amplify basilar membrane
      responses to CF tones when the basilar membrane moves at maximum velocity.

PMID- 10404198
TI  - Loss of autoreceptor functions in mice lacking the dopamine transporter.
AB  - Autoreceptors provide an important inhibitory feedback mechanism for dopamine
      neurons by altering neuronal functions in response to changes in extracellular
      levels of dopamine. Elevated dopamine may be a component of several
      neuropsychiatric disorders. However, evidence concerning the state of
      autoreceptors in such conditions has remained elusive. The function of dopamine
      autoreceptors was assessed in mice lacking the dopamine transporter (DAT).
      Genetic deletion of the DAT gene in mice results in a persistent elevation in
      levels of extracellular dopamine. Direct assessment of impulse-, synthesis- and
      release-regulating autoreceptors in these mice reveals a nearly complete loss of
      function. These findings may provide insight into the neurochemical consequences
      of hyperdopaminergia.

PMID- 10404199
TI  - Neural bases of an auditory illusion and its elimination in owls.
AB  - Humans and owls localize sounds by detecting the arrival time disparity between
      the ears. Both species determine the interaural time difference by finding the
      delay necessary to match the leading signal with the lagging one. This method
      produces ambiguity with periodic signals, because the two signals can be matched
      by delaying either one or the other. As predicted, owls localized periodic
      signals in illusory directions, whereas they always perceived the real source
      when signal bandwidth exceeded a certain value. This bandwidth also enabled
      higher-order auditory neurons to discriminate between real and illusory sources.

PMID- 10404200
TI  - Perception and neuronal coding of subjective contours in the owl.
AB  - Robust form perception and underlying neuronal mechanisms require generalized
      representation of object boundaries, independent of how they are defined. One
      visual ability essential for form perception is reconstruction of contours absent
      from the retinal image. Here we show that barn owls perceive subjective contours
      defined by grating gaps and phase-shifted abutting gratings. Moreover, single
      neuron recordings from visual forebrain (visual Wulst) of awake, behaving birds
      revealed a high proportion of neurons signaling such subjective contours,
      independent of local stimulus attributes. These data suggest that the visual
      Wulst is important in contour-based form perception and exhibits a functional
      complexity analogous to mammalian extrastriate cortex.

PMID- 10404201
TI  - Real-time control of a robot arm using simultaneously recorded neurons in the
      motor cortex.
AB  - To determine whether simultaneously recorded motor cortex neurons can be used for
      real-time device control, rats were trained to position a robot arm to obtain
      water by pressing a lever. Mathematical transformations, including neural
      networks, converted multineuron signals into 'neuronal population functions' that
      accurately predicted lever trajectory. Next, these functions were electronically
      converted into real-time signals for robot arm control. After switching to this
      'neurorobotic' mode, 4 of 6 animals (those with > 25 task-related neurons)
      routinely used these brain-derived signals to position the robot arm and obtain
      water. With continued training in neurorobotic mode, the animals' lever movement
      diminished or stopped. These results suggest a possible means for movement
      restoration in paralysis patients.

PMID- 10404202
TI  - The physiological basis of attentional modulation in extrastriate visual areas.
AB  - Selective attention to color or motion enhances activity in specialized areas of
      extrastriate cortex, but mechanisms of attentional modulation remain unclear. By
      dissociating modulation of visually evoked transient activity from the baseline
      for a particular attentional set, human functional neuroimaging was used to
      investigate the physiological basis of such effects. Baseline activity in motion-
      and color-sensitive areas of extrastriate cortex was enhanced by selective
      attention to these attributes, even without moving or colored stimuli. Further,
      visually evoked responses increased along with baseline activity. These results
      are consistent with the hypothesis that attention modulates sensitivity of
      neuronal populations to inputs by changing background activity.

PMID- 10404203
TI  - Spontaneous confabulators fail to suppress currently irrelevant memory traces.
AB  - Human actions require integration of past experiences, ongoing percepts and
      future concepts. To adapt behavior to reality, the brain must identify mental
      representations of current relevance. Occasional amnesic subjects act according
      to invented stories ('spontaneous confabulations'), disregarding present reality.
      We used repeated runs of a continuous recognition task to measure the ability to
      distinguish currently relevant from previously encountered but currently
      irrelevant information. Spontaneous confabulators detected target items as
      accurately as nonconfabulating amnesics, but increasingly failed to suppress
      false-positive responses, confusing presentation in previous runs with
      presentation in the current run. Lesions involved the anterior limbic system:
      medial orbitofrontal cortex, basal forebrain, amygdala and perirhinal cortex or
      medial hypothalamus. We suggest that the anterior limbic system represents 'now'
      in human thinking by suppressing currently irrelevant mental associations.

PMID- 10404204
TI  - The modern RNA world.

PMID- 10404205
TI  - Thinking outside the box: new insights into the mechanism of GroEL-mediated
      protein folding.

PMID- 10404206
TI  - The bromodomain: a chromatin-targeting module?

PMID- 10404207
TI  - Where U and I meet.

PMID- 10404208
TI  - Prelude to NMR studies of protein folding.

PMID- 10404209
TI  - Gramicidin channel controversy--the structure in a lipid environment.

PMID- 10404211
TI  - Gramicidin channel controversy - reply.

PMID- 10404210
TI  - Gramicidin channel controversy--revisited.

PMID- 10404212
TI  - Picture story. Mopping up histamine.

PMID- 10404213
TI  - Electrostatic contribution of phosphorylation to the stability of the CREB-CBP
      activator-coactivator complex.

PMID- 10404214
TI  - Immunoglobulin motif DNA recognition and heterodimerization of the PEBP2/CBF Runt
      domain.
AB  - The polyomavirus enhancer binding protein 2 (PEBP2) or core binding factor (CBF)
      is a heterodimeric enhancer binding protein that is associated with genetic
      regulation of hematopoiesis and osteogenesis. Aberrant forms of PEBP2/CBF are
      implicated in the cause of the acute human leukemias and in a disorder of bone
      development known as cleidocranial dysplasia. The common denominator in the
      natural and mutant forms of this protein is a highly conserved domain of
      PEBP2/CBF alpha, termed the Runt domain (RD), which is responsible for both DNA
      binding and heterodimerization with the beta subunit of PEBP2/CBF. The three
      dimensional structure of the RD bound to DNA has been determined to be an S-type
      immunoglobulin fold, establishing a structural relationship between the RD and
      the core DNA binding domains of NF-kappaB, NFAT1, p53 and the STAT proteins. NMR
      spectroscopy of a 43.6 kD RD-beta-DNA ternary complex identified the surface of
      the RD in contact with the beta subunit, suggesting a mechanism for the
      enhancement of RD DNA binding by beta. Analysis of leukemogenic mutants within
      the RD provides molecular insights into the role of this factor in leukemogenesis
      and cleidocranial dysplasia.

PMID- 10404215
TI  - Molecular insights into PEBP2/CBF beta-SMMHC associated acute leukemia revealed
      from the structure of PEBP2/CBF beta.
AB  - PEBP2/CBF is a heterodimeric transcription factor essential for genetic
      regulation of hematopoiesis and osteogenesis. DNA binding by PEBP2/CBF alpha is
      accomplished by a highly conserved DNA binding domain, the Runt domain (RD),
      whose structure adopts an S-type immunoglobulin fold when bound to DNA. The
      supplementary subunit beta enhances DNA binding by the RD in vitro, but its role
      in the control of gene expression has remained largely unknown in vivo.
      Chromosome 16 inversion creates a chimeric gene product fusing PEBP2/CBF beta to
      a portion of the smooth muscle myosin heavy chain (PEBP2/CBF beta-SMMHC) that is
      causally associated with the onset of acute myeloid leukemia in humans. The three
      dimensional structure of PEBP2/CBF beta has been determined in solution and is
      shown to adopt a fold related to the beta-barrel oligomer binding motif. Direct
      analysis of a 43.6 kD ternary RD-beta-DNA complex identifies the likely surface
      of beta in contact with the RD. The structure of PEBP2/CBF beta enables a
      molecular understanding of the capacity of PEBP2/CBF beta-SMMHC to sequester
      PEBP2/CBF alpha in the cytoplasm and therefore provides a molecular basis for
      understanding leukemogenic transformation.

PMID- 10404216
TI  - Solution structure of core binding factor beta and map of the CBF alpha binding
      site.
AB  - The core binding factor beta subunit (CBF beta) is the non-DNA binding subunit of
      the core-binding factors, transcription factors essential for multiple
      developmental processes including hematopoiesis and bone development. Chromosomal
      translocations involving the human CBFB gene are associated with a large
      percentage of human leukemias. The N-terminal 141 amino acids of CBF beta
      contains the heterodimerization domain for the DNA-binding CBF alpha subunits,
      and is sufficient for CBF beta function in vivo. Here we present the high
      resolution solution structure of the CBF beta heterodimerization domain. It is a
      novel alpha/beta structure consisting of two three-stranded beta-sheets packed on
      one another in a sandwich arrangement, with four peripheral alpha-helices. The
      CBF alpha binding site on CBF beta has been mapped by chemical shift perturbation
      analysis.

PMID- 10404217
TI  - Treponema pallidum TroA is a periplasmic zinc-binding protein with a helical
      backbone.
AB  - The crystal structure of recombinant TroA, a zinc-binding protein component of an
      ATP-binding cassette transport system in Treponema pallidum, was determined at a
      resolution of 1.8 A. The organization of the protein is largely similar to other
      periplasmic ligand-binding proteins (PLBP), in that two independent globular
      domains interact with each other to create a zinc-binding cleft between them. The
      structure has one bound zinc pentavalently coordinated to residues from both
      domains. Unlike previous PLBP structures that have an interdomain hinge composed
      of beta-strands, the N- and C-domains of TroA are linked by a single long
      backbone helix. This unique backbone helical conformation was possibly adopted to
      limit the hinge motion associated with ligand exchange.

PMID- 10404218
TI  - Structure of the most conserved internal loop in SRP RNA.
AB  - The signal recognition particle (SRP) directs translating ribosomes to the
      protein translocation apparatus of endoplasmic reticulum (ER) membrane or the
      bacterial plasma membrane. The SRP is universally conserved, and in prokaryotes
      consists of two essential subunits, SRP RNA and SRP54, the latter of which binds
      to signal sequences on the nascent protein chains. Here we describe the solution
      NMR structure of a 28-mer RNA composing the most conserved part of SRP RNA to
      which SRP54 binds. Central to this function is a six-nucleotide internal loop
      that assumes a novel Mg2+-dependent structure with unusual cross-strand
      interactions; besides a cross-strand A/A stack, two guanines form hydrogen bonds
      with opposite-strand phosphates. The structure completely explains the
      phylogenetic conservation of the loop bases, underlining its importance for SRP54
      binding and SRP function.

PMID- 10404219
TI  - 3D reconstruction of the ATP-bound form of CCT reveals the asymmetric folding
      conformation of a type II chaperonin.
AB  - The type II chaperonin CCT (chaperonin containing Tcp-1) of eukaryotic cytosol is
      a heteromeric 16-mer particle composed of eight different subunits. Three
      dimensional reconstructions of apo-CCT and ATP-CCT have been obtained at 28 A
      resolution by cryo-electron microscopy. Binding of ATP generates an asymmetric
      particle; one ring has a slightly different conformation from the apo-CCT ring,
      while the other has undergone substantial movements in the apical domains. Upon
      ATP binding the apical domains rotate and point towards the cylinder axis, so
      that the helical protrusions present at their tips could act as a lid closing the
      ring cavity.

PMID- 10404220
TI  - EF-G-dependent GTP hydrolysis induces translocation accompanied by large
      conformational changes in the 70S ribosome.
AB  - Cryo-electron microscopy has been used to visualize elongation factor G (EF-G) on
      the 70S ribosome in GDP and GTP states. GTP hydrolysis is required for binding of
      all the domains of EF-G to the pretranslocational complex and for the completion
      of translocation. In addition, large conformational changes have been identified
      in the ribosome. The head of the 30S subunit shifts toward the L1 protein side,
      and the L7/L12 stalk becomes bifurcated upon EF-G binding. Upon GTP hydrolysis,
      the bifurcation is reversed and an arc-like connection is formed between the base
      of the stalk and EF-G.

PMID- 10404221
TI  - Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat.
AB  - Members of the inhibitor of apoptosis (IAP) family of proteins are able to
      inhibit cell death following viral infection, during development or in cell lines
      in vitro. All IAP proteins bear one or more baculoviral IAP repeats (BIRs). Here
      we describe the solution structure of the third BIR domain from the mammalian IAP
      homolog B (MIHB/c-IAP-1). The BIR domain has a novel fold that is stabilized by
      zinc tetrahedrally coordinated by one histidine and three cysteine residues. The
      structure consists of a series of short alpha-helices and turns with the zinc
      packed in an unusually hydrophobic environment created by residues that are
      highly conserved among all BIRs.

PMID- 10404222
TI  - Rational design of a GCN4-derived mimetic of interleukin-4.
AB  - In this work we describe the rational design of two helix coiled coil peptide
      mimetics of interleukin-4 (IL-4) which are able to recognize and bind its high
      affinity receptor (IL-4R alpha). We have used the leucine-zipper domain of the
      yeast transcription factor GCN4 as a scaffold into which the putative binding
      epitope of IL-4 for IL-4R alpha was transferred in a stepwise manner, using
      computer-aided molecular modeling. The resulting molecules bind IL-4R alpha with
      affinities ranging from 2 mM to 5 microM, depending on the fraction of the IL-4
      binding site incorporated and on their stability. To our knowledge this is the
      first time a molecule capable of binding a cytokine receptor has been
      successfully designed in a rational manner.

PMID- 10404223
TI  - The GYF domain is a novel structural fold that is involved in lymphoid signaling
      through proline-rich sequences.
AB  - T cell activation through the CD2 cell surface receptor is transmitted by proline
      rich sequences within its cytoplasmic tail. A membrane-proximal proline-rich
      tandem repeat, involved in cytokine production, is recognized by the
      intracellular CD2 binding protein CD2BP2. We solved the solution structure of the
      CD2 binding domain of CD2BP2, which we name the glycine-tyrosine-phenylalanine
      (GYF) domain. The GYF sequence is part of a structurally unique bulge-helix-bulge
      motif that constitutes the major binding site for the CD2 tail. A hydrophobic
      surface patch is created by motif residues that are highly conserved among a
      variety of proteins from diverse eukaryotic species. Thus, the architecture of
      the GYF domain may be widely used in protein-protein associations.

PMID- 10404224
TI  - Structure of EVH1, a novel proline-rich ligand-binding module involved in
      cytoskeletal dynamics and neural function.
AB  - The Ena-VASP homology (EVH1) domain is a protein interaction module found in
      several proteins that are involved in transducing migratory and morphological
      signals into cytoskeletal reorganization. EVH1 specifically recognizes proline
      rich sequences in its binding partners and directs the localization and formation
      of multicomponent assemblies involved in actin-based motile processes and neural
      development. The structure of the complex between an EVH1 domain and the target
      peptide sequence EFPPPPT identifies the interactions responsible for recognition
      and distinguishes it from other proline-rich binding modules, including SH3 and
      WW domains. Surprisingly, the EVH1 domain has structural similarity to pleckstrin
      homology (PH), phosphotyrosine-binding (PTB) and ran-binding (RanBD) domains.

PMID- 10404225
TI  - Profilin binds proline-rich ligands in two distinct amide backbone orientations.
AB  - The actin regulatory protein profilin is targeted to specific cellular regions
      through interactions with highly proline-rich motifs embedded within its binding
      partners. New X-ray crystallographic results demonstrate that profilin, like SH3
      domains, can bind proline-rich ligands in two distinct amide backbone
      orientations. By further analogy with SH3 domains, these data suggest that non
      proline residues in profilin ligands may dictate the polarity and register of
      binding, and the detailed organization of the assemblies involving profilin. This
      degeneracy may be a general feature of modules that bind proline-rich ligands,
      including WW and EVH1 domains, and has implications for the assembly and activity
      of macromolecular complexes involved in signaling and the regulation of the actin
      cytoskeleton.

PMID- 10404226
TI  - A protein taxonomy based on secondary structure.
AB  - Does a protein's secondary structure determine its three-dimensional fold? This
      question is tested directly by analyzing proteins of known structure and
      constructing a taxonomy based solely on secondary structure. The taxonomy is
      generated automatically, and it takes the form of a tree in which proteins with
      similar secondary structure occupy neighboring leaves. Our tree is largely in
      agreement with results from the structural classification of proteins (SCOP), a
      multidimensional classification based on homologous sequences, full three
      dimensional structure, information about chemistry and evolution, and human
      judgment. Our findings suggest a simple mechanism of protein evolution.

PMID- 10404227
TI  - GroEL accelerates the refolding of hen lysozyme without changing its folding
      mechanism.
AB  - The chaperonin GroEL binds folding intermediates of four-disulfidehen lysozyme
      transiently within its central cavity. Using stopped flow fluorescence we show
      that GroEL binds early intermediates in folding and accelerates the slow kinetic
      phase that reflects the reversal of non-native interactions involving tryptophan
      residues and the formation of the native state. Pulsed hydrogen exchange
      monitored by electrospray ionization mass spectrometry demonstrates that GroEL
      does not alter the folding mechanism, nor are protected species unfolded by the
      chaperonin. The data suggest a mechanism for GroEL-assisted folding in which the
      reorganization of non-native tertiary interactions is facilitated but domain
      folding is unperturbed.

PMID- 10404228
TI  - Structure-based identification of a novel NTPase from Methanococcus jannaschii.
AB  - Almost half of the entire set of predicted genomic products from Methanococcus
      jannaschii are classified as functionally unknown hypothetical proteins. We
      present a structure-based identification of the biochemical function of a protein
      with an as yet unknown function from a M. jannaschii gene, Mj0226. The crystal
      structure of Mj0226 protein determined at 2.2 A resolution reveals that the
      protein is a homodimer and each monomer folds into an elongated alpha/beta
      structure of a new fold family. Comparisons of Mj0226 protein with protein
      structures in the database, however, indicate that one part of the protein is
      homologous to some of the nucleotide-binding proteins. Biochemical analysis shows
      that Mj0226 protein is a novel nucleotide triphosphatase that can efficiently
      hydrolyze nonstandard nucleotides such as XTP to XMP or ITP to IMP, but not the
      standard nucleotides, in the presence of Mg2+ or Mn2+ ions.

PMID- 10404230
TI  - Forming and inhibiting PRT active sites.

PMID- 10404229
TI  - Co-translational domain folding as the structural basis for the rapid de novo
      folding of firefly luciferase.
AB  - The 62 kDa protein firefly luciferase folds very rapidly upon translation on
      eukaryotic ribosomes. In contrast, the chaperone-mediated refolding of chemically
      denatured luciferase occurs with significantly slower kinetics. Here we
      investigate the structural basis for this difference in folding kinetics. We find
      that an N-terminal domain of luciferase (residues 1-190) folds co
      translationally, followed by rapid formation of native protein upon release of
      the full-length polypeptide from the ribosome. In contrast sequential domain
      formation is not observed during in vitro refolding. Discrete unfolding steps,
      corresponding to domain unfolding, are however observed when the native protein
      is exposed to increasing concentrations of denaturant. Thus, the co-translational
      folding reaction bears more similarities to the unfolding reaction than to
      refolding from denaturant. We propose that co-translational domain formation
      avoids intramolecular misfolding and may be critical in the folding of
      multidomain proteins.

PMID- 10404231
TI  - Quantification of cellular properties from external fields and resulting induced
      velocity: cellular hydrodynamic diameter.
AB  - An experimental technique is discussed in which the size distribution of a
      population of cells is determined by calculating each cell's settling velocity.
      The settling velocity is determined from microscopically obtained images which
      were recorded on SVHS tape. These images are then computer imaged and processed,
      and the cell's location and velocity are determined using a computer algorithm
      referred to as cell tracking velocimetry (CTV). Experimental data is presented
      comparing the distribution of human lymphocytes and a human breast cancer cell
      line, MCF-7, determined using a Coulter counter and the CTV approach.

PMID- 10404232
TI  - Quantification of cellular properties from external fields and resulting induced
      velocity: magnetic susceptibility.
AB  - An experimental technique is discussed in which the magnetic susceptibility of
      immunomagnetically labeled cells can be determined on a cell-by-cell basis. This
      technique is based on determining the magnetically induced velocity that an
      immunomagnetically labeled cell has in a well-defined magnetic energy gradient.
      This velocity is determined through the use of video recordings of microscopic
      images of cells moving in the magnetic energy gradient. These video images are
      then computer digitized and processed using a computer algorithm, cell tracking
      velocimetry, which allows larger numbers (>10(3)) of cells to be analyzed.

PMID- 10404233
TI  - Quantitative structure-activity relationship (QSAR) analysis of surfactants
      influencing attachment of a Mycobacterium sp. to cellulose acetate and aromatic
      polyamide reverse osmosis membranes.
AB  - A series of 23 neutral, anionic, and zwitterionic surfactants were tested at a
      concentration of 0.1% wt/vol for their influence on attachment of a Mycobacterium
      sp. to cellulose acetate (CA) and polyamide (PA) reverse osmosis (RO) membranes.
      Four cell attachment bioassays were used: (1) semiconcurrent addition of
      surfactant and bacteria to RO coupons (standard assay); (2) surfactant
      pretreatment of RO membranes (membrane pretreatment assay); (3) surfactant
      treatment of adsorbed cells (detachment assay); and (4) surfactant pretreatment
      of mycobacteria (cell pretreatment assay). Seventeen surfactants inhibited
      attachment to PA membranes, whereas 15 inhibited attachment to CA in standard
      assays and, in 13 cases, the same surfactant inhibited attachment to both PA and
      CA. Despite greater cell attachment to PA than CA, surfactants were typically
      more effective in the former membrane system. More surfactants were effective in
      impairing cell attachment than in promoting detachment and a number enhanced
      attachment in membrane pretreatment assays, suggesting surface modification of RO
      membranes. Cell pretreatment inhibited attachment to CA membranes, suggesting the
      bacterial surface was also a target for detergent activity. Multivariate
      regression and cluster analyses indicated that critical micellar concentration
      (CMC) was positively correlated with Mycobacterium attachment in CA and PA
      standard assays. Surfactant dipole moment and octanol/water partitioning (LogP)
      also contributed to detergent activity in the PA system, whereas dipole moment,
      molecular topology (i.e., connectivity indices), and charge properties influenced
      activity in the CA system. Influential variables in membrane pretreatment assays
      included the LogP, topology indices, and charge properties, whereas CMC played a
      diminished role. Surfactant dipole moment was most influential in CA membrane
      detachment assays. Increasing system ionic strength by LiBr addition strengthened
      inhibition of cell attachment to CA membranes by dodecylbenzene sulfonic acid
      (DBSA) and promoted DBSA adsorption to CA surfaces as indicated by attenuated
      total reflection Fourier-transform infrared spectrometry. Results indicate that
      inhibition of bacterial attachment to RO membranes may be maximized by
      manipulating surfactant molecular structure to optimize surface adsorption
      behavior.

PMID- 10404234
TI  - Fourier-transform infrared spectroscopy study of dehydrated lipases from candida
      antarctica B and pseudomonas cepacia 
AB  - Fourier-transform infrared (FT-IR) spectroscopy was employed to investigate
      potential lyophilization-induced changes in the secondary structure of lipases
      from Candida antarctica B and Pseudomonas cepacia. The secondary structure
      elements were determined by curve fitting of the amide III bands of the two
      lipases in the lyophilized state in KBr pellets and in solution. It was found
      that lyophilization decreased the alpha-helix and increased the beta-sheet
      content. However, FT-IR analysis of crosslinked enzyme crystals of Pseudomonas
      cepacia lipase also indicated an increase in the beta-sheet content, which
      appears despite the fact that the enzyme, being in the crystallized state, should
      possess native conformation. This result partially questions the suitability of
      FT-IR for analysis of the structure of solid proteins, at least as far as the
      beta-sheet content is concerned, because it is possible that the method
      overestimates the beta-sheets by measuring other hydrogen-bonded nonperiodic
      intermolecular structures. No significant modification was observed when lipase
      from Pseudomonas cepacia was lyophilized in the presence of methoxypoly(ethylene
      glycol). Copyright 1999 John Wiley & Sons, Inc.

PMID- 10404235
TI  - Scale-up of citric acid fermentation by redox potential control 
AB  - To obtain high citric acid productivity in Aspergillus niger fermentation on beet
      molasses substrate, a certain redox potential profile with two maxima (260 and
      280 mV) and two minima (180 and 80 mV) must be maintained. The most effective
      regulation of redox potential is by regulation of aeration and agitation. It has
      been shown that control of redox potential by aeration and agitation is a most
      successful method for scale-up from 10-L laboratory scale to the 100- and 1000-L
      pilot-plant scale, even in geometrically dissimilar stirred-tank reactors.
      Copyright 1999 John Wiley & Sons, Inc.

PMID- 10404236
TI  - Modelling and parameter estimation of the enzymatic synthesis of oligosaccharides
      by beta-galactosidase from bacillus circulans 
AB  - The aim of this research is to develop a model to describe oligosaccharide
      synthesis and simultaneously lactose hydrolysis. Model A (engineering approach)
      and model B (biochemical approach) were used to describe the data obtained in
      batch experiments with beta-galactosidase from Bacillus circulans at various
      initial lactose concentrations (from 0.19 to 0.59 mol.kg(-1)). A procedure was
      developed to fit the model parameters and to select the most suitable model. The
      procedure can also be used for other kinetically controlled reactions. Each
      experiment was considered as an independent estimation of the model parameters,
      and consequently, model parameters were fitted to each experiment separately.
      Estimation of the parameters per experiment preserved the time dependence of the
      measurements and yielded independent sets of parameters. The next step was to
      study by ordinary regression methods whether parameters were constant under the
      altering conditions examined. Throughout all experiments, the parameters of model
      B did not show a trend upon the initial lactose concentration when inhibition was
      included. Therefore model B, a galactosyl-enzyme complex-based model, was chosen
      to describe the oligosaccharide synthesis, and one parameter set was determined
      for various initial lactose concentrations. Copyright 1999 John Wiley & Sons,
      Inc.

PMID- 10404237
TI  - Biotechnology for the production of nutraceuticals enriched in conjugated
      linoleic acid: I. Uniresponse kinetics of the hydrolysis of corn oil by a
      pseudomonas sp. lipase immobilized in a hollow fiber reactor 
AB  - The kinetics of the hydrolysis of corn oil in the presence of a lipase from
      Pseudomonas sp. immobilized within the walls of a hollow fiber reactor can be
      modeled in terms of a three-parameter rate expression. This rate expression
      consists of the product of a two-parameter rate expression for the hydrolysis
      reaction itself (which is of the general Michaelis-Menten form) and a first-order
      rate expression for deactivation of the enzyme. Optimum operating conditions
      correspond to 30 degrees C and buffer pH values of 7.0 during both immobilization
      of the enzyme and the hydrolysis reaction. Under these conditions, the total
      fatty acid concentration in the effluent oil stream for a fluid residence time of
      4 h is approximately 1.6 M. This concentration corresponds to hydrolysis of
      approximately 50% of the glyceride bonds present in the feedstock corn oil. The
      fatty acid of primary interest in the effluent stream is linoleic acid. Copyright
      1999 John Wiley & Sons, Inc.

PMID- 10404238
TI  - Cardiac tissue engineering: cell seeding, cultivation parameters, and tissue
      construct characterization.
AB  - Cardiac tissue engineering has been motivated by the need to create functional
      tissue equivalents for scientific studies and cardiac tissue repair. We
      previously demonstrated that contractile cardiac cell-polymer constructs can be
      cultivated using isolated cells, 3-dimensional scaffolds, and bioreactors. In the
      present work, we examined the effects of (1) cell source (neonatal rat or
      embryonic chick), (2) initial cell seeding density, (3) cell seeding vessel, and
      (4) tissue culture vessel on the structure and composition of engineered cardiac
      muscle. Constructs seeded under well-mixed conditions with rat heart cells at a
      high initial density ((6-8) x 10(6) cells/polymer scaffold) maintained structural
      integrity and contained macroscopic contractile areas (approximately 20 mm(2)).
      Seeding in rotating vessels (laminar flow) rather than mixed flasks (turbulent
      flow) resulted in 23% higher seeding efficiency and 20% less cell damage as
      assessed by medium lactate dehydrogenase levels (p < 0.05). Advantages of
      culturing constructs under mixed rather than static conditions included the
      maintenance of metabolic parameters in physiological ranges, 2-4 times higher
      construct cellularity (p &le 0.0001), more aerobic cell metabolism, and a more
      physiological, elongated cell shape. Cultivations in rotating bioreactors, in
      which flow patterns are laminar and dynamic, yielded constructs with a more
      active, aerobic metabolism as compared to constructs cultured in mixed or static
      flasks. After 1-2 weeks of cultivation, tissue constructs expressed cardiac
      specific proteins and ultrastructural features and had approximately 2-6 times
      lower cellularity (p < 0.05) but similar metabolic activity per unit cell when
      compared to native cardiac tissue.

PMID- 10404240
TI  - A special reactor design for investigations of mixing time effects in a scaled
      down industrial L-lysine fed-batch fermentation process 
AB  - A specially designed model reactor based on a 42-L laboratory fermentor was
      equipped with six stirrers (Rushton turbines) and five cylindrical disks. In this
      model reactor, the mixing time, Theta(90), turned out to be 13 times longer
      compared with the 42-L standard laboratory fermentor fitted with two Rushton
      turbines and four wall-fixed longitudinal baffles. To prove the suitability of
      the model reactor for scaledown studies of mixing-time-dependent processes,
      parallel exponential fed-batch cultivations were carried out with the leucine
      auxotrophic strain, Corynebacterium glutamicum DSM 5715, serving as a microbial
      test system. L&HYPHEN;Leucine, the process-limiting substrate, was fed onto the
      liquid surface of both reactors. Cultivations were conducted using the same
      inoculum material and equal oxygen supply. The model reactor showed reduced sugar
      consumption (-14%), reduced ammonium consumption (-19%), and reduced biomass
      formation (-7%), which resulted in a decrease in L-lysine formation (-12%). These
      findings were reflected in less specific enzyme activity, which was determined
      for citrate synthase (CS), phosphoenolpyruvate carboxylase (PEP-C), and aspartate
      kinase (AK). The reduced specific activity of CS correlated with lower CO(2)
      evolution (-36%) during cultivation. The model reactor represents a valuable tool
      to simulate the conditions of poor mixing and inhomogeneous substrate
      distribution in bioreactors of industrial scale. Copyright 1999 John Wiley &
      Sons, Inc.

PMID- 10404239
TI  - On-line detection of acetate formation in Escherichia coli cultures using
      dissolved oxygen responses to feed transients.
AB  - Recombinant protein production in Escherichia coli can be significantly reduced
      by acetate accumulation. It is demonstrated that acetate production can be
      detected on-line with a standard dissolved oxygen sensor by superimposing short
      pulses to the substrate feed rate. Assuming that acetate formation is linked to a
      respiratory limitation, a model for dissolved oxygen responses to transients in
      substrate feed rate is derived. The model predicts a clear change in the
      character of the transient response when acetate formation starts. The predicted
      effect was verified in fed-batch cultivations of E. coli TOPP1 and E. coli
      BL21(DE3), both before and after induction of recombinant protein production. It
      was also observed that the critical specific glucose uptake rate, at which
      acetate formation starts, was significantly decreased after induction. On-line
      detection of acetate formation with a standard sensor opens up new possibilities
      for feedback control of substrate feeding.

PMID- 10404242
TI  - The use of lectins to select subpopulations of insect cells 
AB  - Lectins have been used in glycoprotein purification, oligosaccharide analysis,
      and in cell-selection processes. Here, we utilize lectins in a rational attempt
      to select a subpopulation of insect cells (Estigmene acrea, EAA) with more
      complete glycosylation capacity by selecting cells that display more complex-type
      cell-surface oligosaccharides than the general population of cells. A lectin
      (ECA) from Erythrina cristagalli, specific for galactose beta(1-4)N
      acetylglucosamine, was found to be useful in recognizing a small subpopulation of
      Sf-21 and EAA cells. Cell selections were performed by lectin affinity
      chromatography and by selective agglutination. Analysis by lectin blots of cell
      lysates and a quantitative agglutination assay did not reveal significant
      differences in regard to the level of complex glycosylation between the
      negatively and positively selected subpopulations of EAA cells. Statistically
      significant differences in binding the fluorescently labeled lectin, ECA-TRITC
      were observed even 30 passages post-selection between EAA subpopulations that
      were negatively and positively selected by lectin affinity chromatography. There
      were no differences in the two subpopulations in the ECA quantitative
      agglutination assay. Thus, the hypothesis that a subpopulation differing in
      glycosylation capacity exists and that such a subpopulation can be identified by
      the character of cell-surface oligosaccharides is plausible. However, these
      differences appear to be too small to be of practical use. Copyright 1999 John
      Wiley & Sons, Inc.

PMID- 10404241
TI  - Genetically controlled cell lysis in the yeast Saccharomyces cerevisiae.
AB  - The cell wall of the yeast Saccharomyces cerevisiae is a tough, rigid structure,
      which presents a significant barrier to the release of native or recombinant
      proteins from this biotechnologically important organism. There is hence a need
      to develop inexpensive and efficient methods of lysing yeast cells in order to
      release their intracellular contents. To develop such a method, a tightly
      regulated promoter, pMET3, has been used to control three genes involved in cell
      wall biogenesis: PDE2, SRB1/PSA1, and PKC1. Two of these regulation cassettes,
      pMET3-SRB1/PSA1 and pMET3-PKC1, have been integrated at the chromosomal loci of
      the respective genes in order to overcome problems of plasmid instability.
      Although repression of PDE2 did not cause cell lysis, cells depleted of
      Srb1p/Psa1p gradually lost their viability and integrity, releasing about 10% of
      total protein into the medium. Repression of PKC1 led to extensive cell lysis,
      accompanied by the release of 45% of cellular protein into the medium. A double
      mutant, carrying both pMET3-SRB1/PSA1 and pMET3-PKC1 cassettes in place of
      SRB1/PSA1 and PKC1, was constructed and found to permit the efficient release of
      both homologous and heterologous proteins. &copy 1999 John Wiley & Sons, Inc.,

PMID- 10404243
TI  - Isolation of a novel microorganism, pestalotia heterocornis, producing paclitaxel
AB  - Pestalotia heterocornis was isolated from soil collected in yew forest and was
      shown to produce paclitaxel in semisynthetic liquid media. The presence of
      paclitaxel in the fungal extract was confirmed by FAB mass spectrometry and NMR
      spectroscopy. The maximum yield of paclitaxel was 31 &mgr;g per liter. Optimal
      paclitaxel production occurred after 5-7 days in a 20-liter scale fermentation at
      23 degrees C. These results indicate that P. heterocornis is an excellent
      candidate for consideration in fermentation technology. Copyright 1999 John Wiley
      & Sons, Inc.

PMID- 10404244
TI  - Spectroscopic investigation of lipase from pseudomonas cepacia solubilized in 1,4
      dioxane by non-covalent complexation with methoxypoly(ethylene glycol) 
AB  - Lipase from Pseudomonas cepacia was made soluble in 1,4-dioxane by lyophilization
      of the enzyme from aqueous solutions containing methoxypoly(ethylene glycol)
      (PEG). The solubility of the enzyme-PEG complex depended both on protein
      concentration and PEG protein ratio. Intrinsic protein fluorescence and far- and
      near-UV circular dichroism revealed that not only did the enzyme not unfold in
      the organic solvent, but rather became more compact. This was seen by the slight
      quenching of fluorescence intensity and by the enhancement of the near-UV
      circular dichroism negative signals, which are indicative of stronger
      interactions of tryptophanyl and/or tyrosyl residues among themselves or with
      other parts of the enzyme molecule. The specific activity of the lipase-PEG
      complex in the organic solvent was at least 2 orders of magnitude higher than
      that of the enzyme powder. This can be attributed both to the maintenance of
      native conformation and to enzyme dissolution in the reaction medium which should
      minimize possible limitations to enzyme-substrate interactions. &copy 1999 John
      Wiley & Sons, Inc.,

PMID- 10404245
TI  - Demonstration of efficient trichloroethylene biodegradation in a hollow-fiber
      membrane bioreactor 

PMID- 10404246
TI  - Scientific conduct and publication: the Journal takes a stand.

PMID- 10404247
TI  - Distribution of preprovasopressin mRNA in the rat central nervous system.
AB  - Vasopressin released in the central nervous system has been shown to be involved
      both in homeostatic mechanisms (e.g., water balance, thermoregulation,
      cardiovascular regulation, metabolism, and antinociception) and in higher brain
      functions (e.g., social recognition and communication, and learning and memory).
      Many nuclear groups have been proposed to synthesize vasopressin, but available
      data are conflicting. We have used a sensitive in situ hybridization technique to
      identify the distribution of the neurons that may be the origin of the
      vasopressin in the central nervous system of the male Sprague-Dawley rat.
      Vasopressin mRNA-expressing neurons were most abundant in the hypothalamus (e.g.,
      the paraventricular, supraoptic, and suprachiasmatic nuclei) but were also seen
      in the medial amygdaloid nucleus, the bed nucleus of stria terminalis, and the
      nucleus of the horizontal diagonal band. Previously unreported vasopressinergic
      neurons were seen in the entorhinal and piriform cortices, the ventral lateral
      portion of the parabrachial nucleus, the pedunculopontine nucleus, and the
      rostral part of the ventral periaqueductal gray matter and the adjacent portion
      of the mesencephalic reticular nucleus. Vasopressin mRNA expression suggestive of
      neuronal labeling was seen in the pyramidal layer of the CA1-3 fields and the
      dentate gyrus of the hippocampus. In addition, vasopressin mRNA expression,
      probably representing axonal mRNA, was detected over the hypothalamopituitary
      tract. No or insignificant preprovasopressin mRNA expression was present in the
      cerebellum, locus coeruleus, subcoeruleus, or the spinal cord. These findings
      provide novel information on the distribution of vasopressin neurons that are
      important for our understanding of how vasopressin acts in the brain.

PMID- 10404248
TI  - Spinal cord-projecting vasopressinergic neurons in the rat paraventricular
      hypothalamus.
AB  - The paraventricular hypothalamic nucleus (PVH) is a key structure for the
      maintenance of homeostasis. Homeostatic regulation includes modulation of
      signaling in the spinal cord. This may be exerted by neurons in the PVH with
      spinal projections. However, the PVH is not a homogeneous structure, but consists
      of anatomically and functionally distinct subdivisions. In this study, we have
      analyzed the distribution of spinal cord-projecting PVH neurons that express
      vasopressin, an important neuropeptide in autonomic regulation. Vasopressinergic
      neurons were identified with a radiolabeled riboprobe complementary to
      vasopressin mRNA combined with immunohistochemical labeling of retrogradely
      transported cholera toxin subunit b in spinally projecting neurons. More than 40%
      of the spinally projecting neurons in the PVH of naive Sprague-Dawley rats were
      found to express vasopressin mRNA. The lateral parvocellular subdivision and the
      ventral part of the medial parvocellular subdivision contained the densest
      distribution of spinal cord-projecting vasopressin mRNA-expressing neurons. The
      magnocellular subdivisions displayed large numbers of vasopressin mRNA-expressing
      neurons, but very few of those projected to the spinal cord. The dorsal
      parvocellular subdivision contained a large number of spinally projecting
      neurons, but very few of those expressed vasopressin mRNA. These findings show
      that the PVH gives rise to a major vasopressinergic projection to the spinal cord
      and that the spinal cord-projecting vasopressinergic neurons are parceled into
      anatomically distinct cell groups. This provides an anatomical basis for a
      selective activation of functionally different groups in the PVH as part of a
      behaviorally adaptive response, including modulation of autonomic activity and
      pain processing at the spinal level.

PMID- 10404249
TI  - Dendritic arbors and central projections of physiologically characterized
      auditory fibers from the saccule of the toadfish, Opsanus tau.
AB  - Neurobiotin was injected iontophoretically into saccular afferents of toadfish
      (Opsanus tau) after intracellular recording to examine dendritic arbors and
      central projections with respect to the physiological and directional response
      properties of the cells. Dendritic arbors of 36 afferents were examined in
      detail. Maximum diameter of the arbor and the number of terminal points were
      positively correlated with each other, but neither was predictive of spontaneous
      activity or sensitivity. Best azimuths were centered around 30 degrees -40
      degrees, which corresponds to the angle of the saccule with respect to the fish's
      midline. In general, best elevations for afferents corresponded to hair cell
      orientations in the region innervated; unexpectedly low elevations obtained from
      afferents innervating the middle saccule may reflect curvature of the sensory
      epithelium against the otolith. Three efferent cells were filled partially. The
      location and large size of the efferent projections indicate that activity along
      the saccule could be modulated by a single efferent. All afferents projected to
      the dorsal zone of the descending octaval nucleus (dDON); many afferents
      bifurcated to terminate in the anterior octaval nucleus, and a few of those also
      had terminal fields in the medial zone of DON. All afferent projections into the
      dDON consisted of multiple axon collaterals projecting to numerous sites along
      the rostral-caudal extent of the nucleus. Variation in terminal field sites also
      was noted in the medial to lateral axis of the dDON; however, there were no
      consistent correlations between terminal field locations, physiology, and best
      directions of the saccular afferents.

PMID- 10404251
TI  - Development of afferent fiber lamination in the infrapyramidal blade of the rat
      dentate gyrus.
AB  - In the rat dentate gyrus, the lateral perforant path, the medial perforant path,
      and the major part of the hilar projection to the molecular layer share the
      lamination domain, mainly in the outer one-third of the molecular layer, the
      middle one-third, and the inner one-third, respectively. To reveal the order of
      the afferent fiber lamination and to have an indication of how the synaptic sites
      on dendrites are determined, we investigated the ontogeny of afferent fiber
      lamination in the dorsal hippocampus by injecting 1, 1'-dioctodecyl-3,3,3',3'
      tetramethylindocarbocyanine perchlorate (DiI) into the entorhinal cortex and
      hippocampus in vivo. Fibers from the contralateral hilar region were found under
      the pia mater of the infrapyramidal blade at postnatal day 3 (P3), whereas the
      entorhinal afferent fibers were absent in the infrapyramidal blade. Then the
      medial and the lateral perforant path appeared under the pia mater in the
      infrapyramidal blade as riding on top of the preexisting laminae by P7 and by
      P11, respectively. Based on the established knowledge that most entorhinal layer
      II neurons simultaneously innervate both the suprapyramidal blade and
      infrapyramidal blade by branching, it is assumed that the medial and lateral
      perforant path in the suprapyramidal blade await an appropriate timing for
      sprouting of interstitial branches into the infrapyramidal blade. The granule
      cells in the infrapyramidal blade had dendritic growth cones by P11. Calretinin
      immunohistochemistry revealed Cajal-Retzius cells in the infrapyramidal blade
      even at P14. Under the pia mater, axon growth cones of ingrowing afferent fibers
      may interact with the dendritic growth cones or the Cajal-Retzius cells, and
      determines the synaptic sites on the granule cell dendrites.

PMID- 10404250
TI  - Melanin-concentrating hormone-producing neurons in birds.
AB  - The peptidergic melanin-concentrating hormone (MCH) system was investigated by
      immunocytochemistry in several birds. MCH perikarya were found in the
      periventricular hypothalamic nucleus near the paraventricular organ and in the
      lateral hypothalamic areas. Immunoreactive fibers were very abundant in the
      ventral pallidum, in the nucleus of the stria terminalis, and in the
      septum/diagonal band complex, where immunoreactive pericellular nets were
      prominent. Many fibers innervated the whole preoptic area, the lateral
      hypothalamic area, and the infundibular region. Some fibers also reached the
      dorsal thalamus and the epithalamus. The median eminence contained only sparse
      projections, and the posterior pituitary was not labeled. Thus, in birds, a
      neurohormonal role for MCH is not likely. Immunoreactive fibers were observed in
      other regions, such as the intercollicular nucleus, stratum griseum
      periventriculare (mesencephalic tectum), central gray, nigral complex (especially
      the ventral tegmental area), reticular areas, and raphe nuclei. Although no
      physiological investigation concerning the role of MCH has been performed in
      birds, the distribution patterns of the immunoreactive perikarya and fibers
      observed suggest that MCH may be involved in functions similar to those described
      in rats. In particular, the projections to parts of the limbic system
      (ventropallidal ganglia, septal complex, hypothalamus, dorsal thalamus, and
      epithalamus) and to structures concerned with visceral and other sensory
      information integration suggest that MCH acts as a neuromodulator involved in a
      wide variety of physiological and behavioral adaptations (arousal) with regard to
      feeding, drinking, and reproduction.

PMID- 10404252
TI  - Cerebellar Purkinje cell loss during life span of the heterozygous staggerer
      mouse (Rora(+)/Rora(sg)) is gender-related.
AB  - The staggerer mutation causes dysgenesis of the cerebellar cortex in the
      homozygous mutant (Rora(sg)/Rora(sg)). The mutation acts intrinsically within the
      Purkinje cells (PCs), leading to cytological abnormalities and a severe deficit
      in the number of these cells. In contrast, in the heterozygous staggerer
      (Rora(+)/Rora(sg)), the cytoarchitecture of the cerebellar cortex appears to be
      normal, but quantitative studies have revealed a significant loss of cerebellar
      neurons with advancing age. In the heterozygous reeler (+/rl), another mutant
      presenting a PC loss with age, we have found that only males were affected (Hadj
      Sahraoui et al., 1996). In the present study, we have investigated whether a
      similar gender effect exists in the heterozygous staggerer during life span. PCs
      were counted on cerebellar sagittal sections in male and female Rora(+)/Rora(sg)
      and in their Rora(+)/Rora(+) littermates at 1, 3, 9, 13, 18, and 24 months of
      age. In the Rora(+)/Rora(+), the number of PCs remained stable until 18 months,
      but there was a 25% significant loss in 24- month-old mice of both genders.
      During life span, Rora(+)/Rora(+) males had slightly more PC than females. In the
      Rora(+)/Rora(sg) of both genders, the deficit in PC number was similar at 13
      months but it appeared earlier in males, beginning between 1 and 3 months, and
      was aggravated regularly up to 13 months. By contrast, the decline was delayed
      and more abrupt in Rora(+)/Rora(sg) females, from a value still normal at 9
      months to its maximal extent at 13 months. In view of these results, the
      heterozygous (Rora(+)/Rora(sg)) mouse offers an interesting model to test the
      interaction between sex, age, and genetic background on the development and
      maintenance of cerebellar neuronal populations.

PMID- 10404253
TI  - Topographic organization of serotonergic and dopaminergic neurons in the cerebral
      ganglia and their peripheral projection patterns in the head areas of the snail
      Helix pomatia.
AB  - The distribution of monoaminergic neurons within the cerebral ganglia was
      investigated in the pulmonate snail Helix pomatia. Simultaneous serotonin and
      tyrosine hydroxylase double immunostaining revealed that the immunoreactive cell
      groups are concentrated in a putative monoaminergic center on the ventral surface
      of the cerebral ganglia. Simultaneous cobalt (Co)- and nickel (Ni)-lysine
      backfills of cerebral nerves were combined with 5, 6-dihydroxytryptamine pigment
      labelling of serotonergic neurons, or with fluorescence immunocytochemistry of
      dopaminergic neurons. This showed that the serotonergic and dopaminergic cell
      groups can be divided into smaller subgroups on the basis of their axonal
      projections into different cerebral nerves. These subgroups show a topographic
      organization within the serotonergic and dopaminergic neuronal clusters. In the
      serotonergic system, the different regions of the head are represented in a
      rostrocaudal direction, whereas a caudorostral organization is characteristic for
      the dopaminergic system. No serotonin- or dopamine-immunoreative cell bodies but
      numerous fibers were observed in the head areas, indicating that these are
      innervated by cerebral monoaminergic neurons and show different innervation
      patterns. Serotonin-immunoreactive fibers mostly innervate muscle fibers, whereas
      dopamine-immunoreactive processes do not innervate effector cells, but terminate
      within the nerve branches of the head areas. On the basis of their innervation
      pattern, we suggest that dopaminergic neurons may take part in en route
      modulation of sensory afferent and efferent processes in an as yet unknown
      manner. The serotonergic neurons, on the other hand, may play a direct role in
      the modulation of muscle function.

PMID- 10404254
TI  - Regional patterning of reticulospinal and vestibulospinal neurons in the
      hindbrain of mouse and rat embryos.
AB  - The dispositions and axonal trajectories of bulbospinal neurons in the pons and
      medulla of mouse and rat embryos is described from the earliest times these
      projections can be labelled retrogradely from the cervical spinal cord.
      Reticulospinal and vestibulospinal neurons are clustered into identifiable
      groups, each with a characteristic combination of spatial domain and axon
      trajectory. The various groups can be labelled retrogradely in a specific
      developmental sequence. The position of some groups shifts from medial to lateral
      with development, apparently through cell migration. These observations show that
      the basic regional organization of the reticulospinal and vestibulospinal
      projections is similar in mouse and rat and is already established during early
      stages of axon outgrowth.

PMID- 10404255
TI  - Cellular localization of adenosine A1 receptors in rat forebrain:
      immunohistochemical analysis using adenosine A1 receptor-specific monoclonal
      antibody.
AB  - Monoclonal antibodies were generated against the adenosine A1 receptor (A1R)
      purified from rat brain. In immunoblot analyses of purified or partially purified
      A1R preparations from rat brain, these antibodies recognized a solitary band, the
      size of which corresponded to that expected for A1R. These antibodies recognized
      not only the native form of A1R but also the deglycosylated form of A1R.
      Immunocytochemical analysis of Chinese hamster ovarian cells that were
      transfected stably with rat A1R cDNA showed that their cell bodies were stained
      intensely by these antibodies, whereas nontransfected Chinese hamster ovarian
      cells were not. These antibodies detected the A1R naturally present in the
      DDT(1)( )MF-2 smooth muscle cells. One of these antibodies (the 511CA antibody)
      was then used to examine the immunohistochemical distribution of A1Rs in rat
      forebrain. On light microscopy, A1R immunoreactivity was observed in the cerebral
      cortex, septum, basal ganglia, hippocampal formation, and thalamus. However, in
      some regions of the forebrain, regional differences in staining intensity were
      found as follows: In the cerebral cortex, the strongest immunoreactivity was
      found in the large pyramidal neurons of layer V. This immunoreactivity was
      detected in the pyramidal cell bodies, dendrites, and axon initial segments. In
      the hippocampus, A1R immunoreactivity was detected mainly in the stratum
      pyramidale. The pyramidal cells in fields CA2-CA3 of the hippocampus were stained
      more intensely or more clearly than those in field CA1 or the dentate gyrus. More
      intense A1R immunoreactivity of the apical dendrites was detected in field CA2
      compared with other hippocampal fields and the dentate gyrus. Many interneurons
      of the hippocampus were stained by the 511CA antibody. The subcellular
      distribution of A1Rs in the forebrain was examined by using a digital
      deconvolution system and electron microscopy. In the cerebral cortex, the view
      obtained by removing the background haze by deconvolution revealed that the
      immunofluoresence-labeled A1Rs were distributed on the surfaces of the cell
      bodies and dendrites and in the cytoplasm of layer V neurons as small spots. In
      field CA1, immunoreactivity was detected in the areas surrounding pyramidal
      cells. Electron microscopy revealed the presence of A1R-immunoreactive products
      in both the presynaptic terminals and the postsynaptic structures. The specific
      cellular distribution of A1Rs is consistent with the physiological premise that
      endogeneously released adenosine exerts control over the excitability of
      forebrain neurons at both presynaptic and postsynaptic sites through A1Rs.

PMID- 10404256
TI  - Rhombomere development in a reptilian embryo.
AB  - Rhombomere development was investigated in a reptile, Alligator mississippiensis,
      using a variety of methodologies: cytoarchitecture (cresyl violet),
      histochemistry (peanut agglutinin), immunocytochemistry (antibodies to acetylated
      tubulin, vimentin, calretinin, and acetylcholinesterase), and external and
      internal morphology of wholemount embryos. Rhombomere boundaries form
      sequentially until 8 rhombomeres are present at stage 8. From stage 11 onwards,
      rhombomere borders fade. When present, boundaries of rhombomeres 2 through 5 were
      distinct. In all embryos, except the earliest stages, neural tissue was divided
      between the caudal end of the mesencephalon and the rostral end of the
      rhombencephalon. This area of transection was designated as the isthmus. For
      these technical reasons, a distinct border between the midbrain and the first
      rhombomere was not seen and the isthmic rhombomere could not be identified. The
      interrhombomeric boundary between rhombomere 7 and rhombomere 8 and between the
      most caudal rhombomere and the spinal cord was not nearly as clear as were the
      boundaries of rhombomeres 2 through 5. Development of rhombomeres 2 through 5 was
      investigated in wholemount preparations between stages 5/6 and 11. Qualitative
      and quantitative observations were made. In these rhombomeres, r2 through r5,
      rostrocaudal caudal expansion occurs at a slower rate than mediolateral
      development. This differential growth sculpts the morphology of rhombomeres 2
      through 5. Rhombomere development in Alligator shares several features in common
      with hindbrain segmentation in chick. The identification of rhombomeres in a
      multitude of vertebrates from a variety of classes suggests that segmentation is
      a feature common to hindbrain development in all vertebrates.

PMID- 10404257
TI  - Pattern formation by retinal afferents in the ferret lateral geniculate nucleus:
      developmental segregation and the role of N-methyl-D-aspartate receptors.
AB  - The projection from the retina to the lateral geniculate nucleus (LGN) in ferrets
      segregates during development into eye-specific layers and ON/OFF sublayers. The
      projection pattern and the morphology of single axons was examined at several
      postnatal ages. The axons progress from a simple, sparsely branched morphology at
      birth to crude arbors at postnatal day 7 (P7). At P14-P15, axons have terminal
      arbors that span one eye-specific layer. By P19-P21, retinal afferents in the A
      layers have segregated into inner and outer sublaminae that correspond to ON- and
      OFF-center cells. Sublaminae form mainly by directed growth of terminal arbors in
      appropriately positioned regions of the LGN, along with elimination of extraneous
      branches in inappropriate regions. From P28 to P35, the LGN assumes an adult-like
      shape, and retinogeniculate axons form terminal boutons on branch endings. During
      the period between P14 and P21, when retinogeniculate axons segregate into ON/OFF
      sublaminae, N-methyl-D-aspartate (NMDA) receptors were blocked with chronic
      infusion of specific antagonists into the LGN. NMDA receptor blockade prevents
      the retinal afferent segregation into ON/OFF sublaminae. Some individual
      retinogeniculate axons have arbors that are not restricted appropriately, and
      most are restricted in size but are located inappropriately within the eye
      specific laminae. Thus, NMDA receptor blockade prevents the positioning of
      retinogeniculate arbors that lead to the formation of ON/OFF sublaminae in the
      LGN. These results indicate that the activity of postsynaptic cells, and the
      activation of NMDA receptors in particular, can influence significantly the
      patterning of inputs and the structure of presynaptic afferents during
      development.

PMID- 10404258
TI  - Identification and characterization of estrogen receptor alpha-containing neurons
      projecting to the vicinity of the gonadotropin-releasing hormone perikarya in the
      rostral preoptic area of the rat.
AB  - Gonadal steroids exert a powerful regulatory influence upon the functioning of
      gonadotropin-releasing hormone (GnRH) neurons despite the apparent absence of
      gonadal steroid receptors in these cells. By using retrograde-tracing techniques
      combined with dual-labeling immunocytochemistry, we show here that distinct
      populations of estrogen receptor alpha (ERalpha)-containing neurons located in
      the hypothalamus and caudal brainstem project to the vicinity of the GnRH
      perikarya located in the rostral preoptic area (rPOA). The strongest estrogen
      receptive afferent projection to this area originated from neurons located in the
      anteroventral periventricular and medial preoptic nuclei of the preoptic area.
      Approximately 50% of arcuate nucleus neurons projecting to the rPOA were
      demonstrated to synthesize either neuropeptide Y or beta-endorphin, but little
      evidence was found for ERalpha immunoreactivity in either of these specific
      subpopulations. Over 80% of all tyrosine hydroxylase-expressing neurons in the
      arcuate nucleus expressed ERalpha, but none projected to the rPOA. In the caudal
      brainstem, the A1 and A2 norepinephrine neurons comprised nearly all of the
      retrogradely labeled neurons. However, only the A2 afferents expressed ERalpha
      immunoreactivity, whereas the A1 afferents coexpressed neuropeptide Y. These
      observations, combined with the anterograde labeling data of others, provide
      neuroanatomical evidence for the existence of specific estrogen-receptive
      neuronal cell populations that project to the rPOA and may be involved in the
      estrogen-dependent transsynaptic regulation of GnRH neurons in the rat.

PMID- 10404260
TI  - Aggregation and species coexistence of ectoparasites of marine fishes.
AB  - Interspecific interaction may lead to species exclusion but there are several
      ways in which species can coexist. One way is by reducing the overall intensity
      of competition via aggregated utilisation of fragmented resources. Known as the
      'aggregation model of coexistence', this system assumes saturation and an
      equilibrium number of species per community. In this study we tested the effects
      of interspecific aggregation on the level of intraspecific aggregation among
      ectoparasites of marine fishes (36 communities of gill and head ectoparasite
      species). If parasite species are distributed in a way that interspecific
      aggregation is reduced relative to intraspecific aggregation then species
      coexistence is facilitated. We found a positive relationship between parasite
      species richness and fish body size, controlling for host phylogeny. A positive
      relationship between infracommunity species richness and total parasite species
      richness was also found, providing no evidence for saturation. This result
      supports the view that infracommunities of parasites are not saturated by local
      parasite residents. The observed lack of saturation implies that we are far from
      a full exploitation of the fish resource by parasites. Ectoparasites were
      aggregated at both population and species levels. However, only half of the
      ectoparasite communities were dominated by negative interspecific aggregation. We
      found that infracommunity parasite species richness was positively correlated
      with the level of intraspecific aggregation versus interspecific aggregation.
      This means that intraspecific aggregation increases compared with interspecific
      aggregation when total parasite species richness increases, controlling fish size
      and phylogeny. This supports one assumption of the 'aggregation model of
      coexistence', which predicts that interspecific interactions are reduced relative
      to intraspecific interactions, facilitating species coexistence.

PMID- 10404259
TI  - Characterisation of Fasciola hepatica cytochrome c peroxidase as an enzyme with
      potential antioxidant activity in vitro.
AB  - Cytochrome c peroxidase oxidises hydrogen peroxide using cytochrome c as the
      electron donor. This enzyme is found in yeast and bacteria and has been also
      described in the trematodes Fasciola hepatica and Schistosoma mansoni. Using
      partially purified cytochrome c peroxidase samples from Fasciola hepatica we
      evaluated its role as an antioxidant enzyme via the investigation of its ability
      to protect against oxidative damage to deoxyribose in vitro. A system containing
      FeIII-EDTA plus ascorbate was used to generate reactive oxygen species superoxide
      radical, H2O2 as well as the hydroxyl radical. Fasciola hepatica cytochrome c
      peroxidase effectively protected deoxyribose against oxidative damage in the
      presence of its substrate cytochrome c. This protection was proportional to the
      amount of enzyme added and occurred only in the presence of cytochrome c. Due to
      the low specific activity of the final partially purified sample the effects of
      ascorbate and calcium chloride on cytochrome c peroxidase were investigated. The
      activity of the partially purified enzyme was found to increase between 10 and
      37% upon reduction with ascorbate. However, incubation of the partially purified
      enzyme with 1 mM calcium chloride did not have any effect on enzyme activity. Our
      results showed that Fasciola hepatica CcP can protect deoxyribose from oxidative
      damage in vitro by blocking the formation of the highly toxic hydroxyl radical
      (.OH). We suggest that the capacity of CcP to inhibit .OH-formation, by
      efficiently removing H2O2 from the in vitro oxidative system, may extend the
      biological role of CcP in response to oxidative stress in Fasciola hepatica.

PMID- 10404261
TI  - Population biology of Schistosoma mansoni in the black rat: host regulation and
      basic transmission rate.
AB  - A simple mathematical model was built to investigate the population biology of
      Schistosoma mansoni in its natural definitive host, the black rat (Rattus
      rattus). Prevalence and parasite abundance over 13 years from field studies and
      data from laboratory experiments were used to set up the model. Sensitivity
      analysis showed that the abundance of parasites is strongly influenced by
      variation in the values of infection parameters. The model shows that the
      parasite is able to control populations of definitive hosts. We discuss the
      factors that may explain the long-term persistence of S. mansoni among its
      natural definitive host, R. rattus and its intermediate host, the snail
      Biomphalaria glabrata in Guadeloupe (French West Indies). The impact of the
      parasite does not appear to explain the apparent persistence of the host-parasite
      association over a 13 year period. Our results seem to support the influence of
      environmental factors, which may act on the infection process by reducing, or
      increasing, the rate of encounters between hosts and free-living stages of the
      parasite.

PMID- 10404263
TI  - Effects of the excretory/secretory products of Trichostrongylus colubriformis on
      the growth of different cell lines.
AB  - The effects of the excretory/secretory (ES) products of the parasitic nematode
      Trichostrongylus colubriformis were examined on the proliferation of seven cell
      lines derived from a digestive or non-digestive origin. The excretory/secretory
      products of T. colubriformis were incorporated in the culture medium of the
      different cell lines and cell proliferation was measured by means of the 5-bromo
      2'-deoxy-uridine (Brdu) assay. An increase in cell numbers was found with the
      three epithelial intestinal cells (RIC, IEC-6, IRD-98) and with epithelial kidney
      cells (MDCK). In contrast, an inhibition in the proliferation of epithelial
      ovarian cells (CHO) and fibroblasts (3T3) was observed with the addition of the
      excretory/secretory products and no effect was detected on the cell growth of
      hepatocytes (HepG2). These data are discussed with respect to the tissue
      specificity of the existing mitogenic effect of the worms on the intestinal crypt
      cells during parasitism.

PMID- 10404262
TI  - Use of a pre-selected epitope of cathepsin-L1 in a highly specific peptide-based
      immunoassay for the diagnosis of Fasciola hepatica infections in cattle.
AB  - A peptide-based indirect ELISA to detect cattle antibodies against Fasciola
      hepatica was developed and evaluated for its sensitivity and specificity. An
      immunogenic antigen released in vitro by F. hepatica was purified. After
      purification the sequence of the first 20 N-terminal aa of this protein showed
      considerable homology with cathepsin L-like proteinase. Based on its homology
      with cathepsin-L1, we further focused on this protein for diagnostic purpose.
      Predicted B-cell epitopes of cathepsin-L1 were synthesised as single synthetic
      peptides and tested with respect to their diagnostic potential. An indirect ELISA
      based on one of these peptides was (i) evaluated further and (ii) compared to the
      potential of an indirect ELISA with excretion/secretion antigens from adult F.
      hepatica, or (iii) purified cathepsin-L1. Specificity and sensitivity of the
      three ELISAs were assessed using sera from calves experimentally infected with
      pure isolates of Dictyocaulus viviparus, Ostertagia ostertagi, Cooperia
      oncophora, Nematodirus helvetianus, Schistosoma mattheei, Ascaris suum, Taenia
      saginata or F. hepatica, respectively, and sera from parasite-naive calves. In
      addition, sera were analysed from calves naturally infected with F. hepatica. The
      sensitivities of all three ELISAs were also very high, 98.9% (i), 100% (ii) and
      100% (iii). The specificity of the peptide ELISA was very high, 99.8%, whereas
      specificities of the ES antigens and cathepsin-L1 ELISAs were only 82.8% and
      94.6%. In experimentally infected cattle, F. hepatica-specific antibodies were
      first detected between days 21 and 28 p.i. with all three ELISAs, and the
      antibody levels persisted in the peptide ELISA until day 183 p.i. All sera from
      naturally infected calves were positive in the peptide ELISA. These results
      demonstrate that the peptide-based F. hepatica ELISA is a useful method for
      detecting antibodies in the sera from cattle infected with F. hepatica. This type
      of immunodiagnostic will therefore contribute to more accurate diagnosis and to
      timely curative treatment of animals.

PMID- 10404264
TI  - Enzyme immunoassay detection of Cryptosporidium parvum inhibition by sinefungin
      in sporozoite infected HCT-8 enterocytic cells.
AB  - Complete parasite development was obtained in differentiated human enterocytic
      HCT-8 cells infected at confluence with Cryptosporidium parvum sporozoites, and
      evaluated in a quantitative enzyme immunoassay. Forty-eight hours after
      infection, a linear correlation was found between optical density values and the
      number of parasites determined in an immunofluorescent assay. Sinefungin exerted
      an inhibitory effect when added within 4 h after sporozoite addition to HCT-8
      cultures (MIC50 = 38 mumol L-1), while the inhibitory effects of paromomycin and
      pentamidine dimethanesulfonate were also easily detected (MIC50 = 0.87 mumol L-1
      and 0.27 mumol L-1, respectively). Except for high pentamidine dimethanesulfonate
      concentrations, no alteration in optical microscopy morphology or trypan blue
      exclusion of HCT-8 cells was observed in the presence of anticryptosporidial
      agents, which suggests that they were primarily active against developing
      parasites. Data suggest that EIA detection of C. parvum development in sporozoite
      infected HCT-8 cells provides an accurate and convenient model for in vitro
      evaluation of parasite infectivity, growth and response to anticryptosporidial
      agents.

PMID- 10404265
TI  - Long-term survival of Cryptosporidium parvum oocysts in seawater and in
      experimentally infected mussels (Mytilus galloprovincialis).
AB  - Transmission of infectious oocysts of Cryptosporidium parvum via surface- and
      drinking-water supplies has been reported and many surface waters flow into the
      sea, potentially causing runoff of animal-infected faeces. Eating raw mussels is
      a common practice in many countries, increasing the public's risk of acquiring
      enteric pathogens. The aims of the present study were to estimate how long C.
      parvum oocysts remain infectious in artificial seawater, to determine if the
      oocysts are retained in mussel tissues (Mytilus galloprovincialis), and how long
      they maintain their infectivity. Oocysts were incubated in artificial seawater at
      6-8 degrees C under moderate oxygenation and the infectivity of oocysts was
      tested five times, over a 12 month period after incubation in seawater, in BALB/c
      mice. Each pup was inoculated per os with 10(5) oocysts and killed 5 days p.i.
      Oocysts remained infectious for 1 year. Forty mussels held in an aquarium
      containing artificial seawater filtered out more than 4 x 10(8) oocysts in a 24 h
      period. Oocysts were detected in the gill washing up to 3 days p.i., in the
      haemolymph up to 7 days p.i., and in the intestinal tract up to 14 days p.i.
      Oocysts collected from the gut of mussels 7 and 14 days p.i. were observed to
      have infected mice. These results suggest that C. parvum oocysts can survive in
      seawater for at least 1 year and can be filtered out by benthic mussels,
      retaining their infectivity up to 14 days, so seawater and molluscs are a
      potential source of C. parvum infection for humans.

PMID- 10404266
TI  - Simple blood-spot sampling with nested polymerase chain reaction detection for
      epidemiology studies on Brugia malayi.
AB  - In the absence of a suitable Brugia malayi antigen detection assay, PCR remains
      one of the more sensitive alternatives to Giemsa-stained thick blood films for B.
      malayi detection. The need for refrigerated storage and transportation of blood
      has limited the use of PCR for large-scale epidemiology studies in remote endemic
      areas. Here we report simple finger-prick blood-spot collection, a one-tube DNA
      template extraction method and the development of a B. malayi-specific nested PCR
      assay. The assay was tested on 145 field samples and was positive for all 30
      microscopy-positive samples and for an additional 13 samples which were
      microscopy-negative.

PMID- 10404267
TI  - Expression and characterisation of a Plasmodium falciparum protein containing
      domains homologous to sarcalumenin and a tyrosine kinase substrate, eps15.
AB  - We have identified in Plasmodium falciparum a novel gene encoding a putative bi
      functional protein, termed PfPast-1, from genomic and cDNA libraries. Analysis
      indicated that the sequence encodes a 62 kDa protein of 529 amino acid residues
      with two distinctive domains: a sarcalumenin-like domain of approximately 320
      amino acids at the amino half of the molecule, which shares homology to a major
      sarcoplasmic reticulum lumenal protein, sarcalumenin, and an eps15 homology
      domain of about 90 amino acids located at the carboxyl terminus. The eps15
      homology domain, first identified in a tyrosine kinase substrate, eps15, and
      found in increasing numbers of mammalian proteins, has recently been suggested as
      a protein-protein interaction domain involved in intracellular sorting. Genomic
      sequences encoding similar proteins containing both the sarcalumenin-like and
      eps15 homology domains have been identified in humans and Drosophila. RNA blot
      analysis revealed the presence of a single messenger RNA transcript approximately
      3.7 kb in size, which is expressed in all the developmental stages examined with
      the highest level in extracellular gametes followed by erythrocytic asexual
      stages, and the lowest in the gametocytes. In the attempt to define its
      biological function, we have expressed a full-length recombinant PfPast-1 protein
      in Escherichia coli. Specific immune serum directed against the recombinant
      protein recognised a approximately 55 kDa protein in the parasite lysate. Further
      characterisation of PfPast-1 may help in elucidation of its functions in P.
      falciparum.

PMID- 10404268
TI  - Analysis of the 60 S ribosomal protein L27a (L29) gene of Trypanosoma brucei.
AB  - The Trypanosoma brucei gene encoding the 60 S ribosomal protein L27a (L29)
      homologue has been cloned and characterised. The complete open reading frame
      encodes a small basic protein of 145 amino acids with a predicted molecular
      weight of 15,950. The L27a amino acid sequence shares 45-58% identity with other
      L27a (L29) homologues. Southern blot hybridisation suggests that the gene is
      present in multiple copies. Northern blot analysis of RNA from three T. brucei
      life cycle stages show that mRNA levels are two-fold higher in procyclic than in
      early or late bloodstream stages. This infers that this highly conserved
      ribosomal protein may play an important role in translational regulation through
      the life cycle of trypanosomes.

PMID- 10404269
TI  - gamma delta T-cells may interfere with a productive immune response in Plasmodium
      yoelii infections.
AB  - Mice lacking alpha beta T-cells or gamma delta T-cells were infected with
      Plasmodium yoelii 17X NL (non-lethal) and followed for parasitaemia and cytokine
      production. While the parasitaemia in wild type mice resolved after reaching a
      peak value of 30 to 50%, it persisted in the -alpha beta T-cell mice until death.
      However, in the -gamma delta T-cell mice the peak parasitaemia was 12.5% of the
      levels seen in the wild type and -alpha beta T-cell mice and resolved faster than
      in the wild type mice. Higher levels of IL-10 and IFN-gamma were consistently
      found in the wild type and -gamma delta T-cell mice but not in the -alpha beta T
      cell mice.

PMID- 10404270
TI  - Eicosanoid production by adult Fasciola hepatica and plasma eicosanoid patterns
      during fasciolosis in sheep.
AB  - Fasciola hepatica infection in sheep is known to cause anaemia, fever and
      elevated levels of liver enzymes. It was hypothesised that eicosanoids play a
      role in these pathophysiological changes, so the pattern of plasma eicosanoids
      during the course of acute and chronic fasciolosis was studied in sheep infected
      with a single dose of 800 F. hepatica metacercariae. Blood plasma was collected
      weekly until week 17 p.i. from infected sheep, and from uninfected controls.
      Adult F. hepatica were then recovered from bile ducts and incubated for
      production of ES products. Eicosanoids were determined by enzyme immuno-assay in
      blood plasma, fluke homogenates and ES products after chromatographic
      purification of the samples. Fever and anaemia were seen from 3 to 12 weeks p.i.
      and from 8 to 17 weeks p.i., respectively. Onset of fever was accompanied by
      elevated liver enzyme activities (aspartate amino transferase and gamma glutamyl
      transferase) in the plasma. In general, the plasma levels of prostaglandin E2
      (PGE2), prostaglandin I2 (PGI2) and leukotriene B4 (LTB4) were reduced during the
      acute and chronic stages of the infection, whereas thromboxane B2 (TXB2) was
      reduced only at 8 weeks p.i. The TXB2/PGI2 ratio was increased in favour of TXB2
      at 3 and 11 weeks p.i. Additionally, TXB2, PGI2, PGE2 and LTB4 were detected both
      in ES products and in homogenates of F. hepatica. It was concluded that
      eicosanoid depletion in the plasma is caused by parasite-induced liver damage.
      The changes in eicosanoid levels are highly correlated to the clinical signs of
      the disease. Changes in the pattern of host plasma eicosanoids during
      fasciolosis, as well as parasite-derived eicosanoids, may reflect or contribute
      to the pathology of the disease.

PMID- 10404271
TI  - The taxonomic position and evolutionary relationships of Trypanosoma rangeli.
AB  - This paper presents a re-evaluation of the taxonomic position and evolutionary
      relationships of Trypanosoma (Herpetosoma) rangeli based on the phylogenetic
      analysis of ssrRNA sequences of 64 Trypanosoma species and comparison of mini
      exon sequences. All five isolates of T. rangeli grouped together in a clade
      containing Trypanosoma (Schizotrypanum) cruzi and a range of closely related
      trypanosome species from bats [Trypanosoma (Schizotrypanum) dionisii, Trypanosoma
      (Schizotrypanum) vespertilionis] and other South American mammals [Trypanosoma
      (Herpetosoma) leeuwenhoeki, Trypanosoma (Megatrypanum) minasense, Trypanosoma
      (Megatrypanum) conorhini] and an as yet unidentified species of trypanosome from
      an Australian kangaroo. Significantly T. rangeli failed to group with (a) species
      of subgenus Herpetosoma, other than those which are probably synonyms of T.
      rangeli, or (b) species transmitted via the salivarian route, although either of
      these outcomes would have been more consistent with the current taxonomic and
      biological status of T. rangeli. We propose that use of the names Herpetosoma and
      Megatrypanum should be discontinued, since these subgenera are clearly
      polyphyletic and lack evolutionary and taxonomic relevance. We hypothesise that
      T. rangeli and T. cruzi represent a group of mammalian trypanosomes which
      completed their early evolution and diversification in South America.

PMID- 10404272
TI  - Molecular analyses suggest monospecificity of the genus Sarcoptes (Acari:
      Sarcoptidae).
AB  - To clarify the taxonomic status of mites of the genus Sarcoptes, the second
      internal transcribed spacer (ITS-2) of the rRNA gene, as well as phenotypic
      characters, were investigated in 23 isolates from nine host species in four
      continents. Phenotypic differences among isolates were observed, but the range of
      variation within each isolate precluded the differentiation of individual mites.
      Genotypically, there was no delimitation between distinct genotypic groups and no
      correlation with host species or geographic origin was evident. These results
      support the conspecificity of the mites investigated and confirm the view that
      the genus Sarcoptes consists of a single, heterogenous species.

PMID- 10404274
TI  - Comparison of 18S and ITS-1 rDNA sequences of selected geographic isolates of
      Myxobolus cerebralis.
AB  - Myxobolus cerebralis, the myxosporean parasite-causing salmonid whirling disease,
      was first reported among rainbow trout (Oncorhynchus mykiss) in Germany in 1903.
      The parasite was reported for the first time in North America in 1958 among
      hatchery-reared trout in the eastern USA, presumably arriving with frozen trout
      shipments from Europe. A comparison of 18S and ITS-1 ribosomal DNA sequences was
      conducted to identify potential strain differences between selected geographic
      isolates of this parasite from Europe and North America. Only fourteen of 1700
      base pairs were different in the 18S rRNA gene from isolates obtained from
      California and West Virginia in the USA, and the Federal German Republic. No
      evidence for strain differences was obtained from ITS-1 sequences that were found
      to be identical among all parasite isolates. This finding is consistent with the
      hypothesis that the parasite was recently introduced to the USA from Europe.

PMID- 10404273
TI  - Genetic and phenotypic intraspecific variation in the microsporidian
      Encephalitozoon hellem.
AB  - Encephalitozoon hellem is a microsporidian species that causes disseminated
      infections in HIV-positive patients. Identical genotypes of E. hellem, as
      assessed by the sequence of the rDNA internal transcribed spacer, have been
      identified in isolates from humans and from a psittacine bird. However, by
      analysing the rDNA ITS of four E. hellem isolates from Switzerland (three) and
      Tanzania (one), two new genotypes were identified. Differences among the E.
      hellem isolates were also detected by Western blot analysis, but there was no
      absolute match between ITS genotype and antigen profile. Hence, strain variation
      exists in E. hellem and the ITS sequence seems a valuable marker in obtaining
      further insight into the epidemiology of this pathogen.

PMID- 10404275
TI  - The curvilinear relationship between worm length and fecundity of Teladorsagia
      circumcincta.
AB  - The variation among sheep in fecundity of Teladorsagia (Ostertagia) circumcincta
      was estimated by dividing the faecal egg count by the worm number following
      deliberate infection of mature Scottish Blackface lambs. Fecundity was skewed and
      ranged from 0 to 350 eggs per worm per day. Most animals had relatively low worm
      fecundities, but a small number of individuals had relatively high worm
      fecundities. However, as fecundity is a ratio of two imprecise estimates, extreme
      values may be statistical artefacts. Following both deliberate and natural
      infection, differences in worm fecundity were associated with differences in
      adult female worm length. In both infections, fecundity varied with worm length
      to the power 0.4. This relationship should assist the measurement of fecundity in
      studies of host immunity, in epidemiological modelling and in estimating the
      influence of density-dependent relationships.

PMID- 10404276
TI  - Resistance of field isolates of Trichostrongylus colubriformis and Ostertagia
      circumcincta to ivermectin.
AB  - Twelve Romney lambs and 10 Angora goats were infected with 7000 infective third
      stage larvae (89% Trichostrongylus, 11% Ostertagia) collected from goats
      suspected of harbouring ivermectin-resistant nematodes. On 28 days p.i., the
      lambs and goats were divided into treatment and control groups of six and five
      animals, respectively. The animals in the treatment groups were treated with
      ivermectin (0.2 mg/kg) and necropsied 35 days p.i. Faecal egg counts were
      estimated on days 28 and 35 p.i. and larval development assays (LDAs) were
      conducted on 22, 24, 26, 28, 30, 32, 34 and 35 days p.i. The ivermectin treatment
      reduced Trichostronglus colubriformis burdens by 39% and 13% and Ostertagia
      circumcincta by 33% and 0% in lambs and goats, respectively. When compared with a
      susceptible strain, the LDAs indicated a resistance factor before treatment in
      lambs for T. colubriformis of 2.6 and 1.5 with ivermectin and avermectin B2,
      respectively, which rose to 3.4 and 2.0 after treatment. The LD50 values of the
      two control groups were relatively constant throughout the experiment. Prior to
      ivermectin treatment the LD50 values of the treated groups were similar (P >
      0.05) to the control groups but following ivermectin treatment their LD50 values
      increased steadily until the animals were killed on 35 days p.i. The LD50 values
      for ivermectin and avermectin B2 of sheep were always slightly higher and
      significantly different (P < 0.01) than those of goats indicating a host effect
      on this parameter. The greater reduction in worm counts in goats suggests a
      difference in the efficacy of ivermectin between lambs and goats. This is the
      first confirmed report of ivermectin resistance in a field strain of T.
      colubriformis.

PMID- 10404277
TI  - An experimental, NADPH-diaphorase histochemical and immunocytochemical study of
      Mesocestoides vogae tetrathyridia.
AB  - In order to test the role of nitric oxide in flatworms, Mesocestoides vogae
      tetrathyridia were incubated together with L-arginine, which is the substrate for
      nitric oxide synthesis, or with NG-nitro-L-arginine, which is an irreversible
      inhibitor of nitric oxide synthase. Normally, tetrathyridia attach to each other
      with the aid of their suckers, forming clusters. The rate of cluster formation
      was followed during the incubations. L-Arginine stimulated, and NG-nitro-L
      arginine clearly inhibited, the cluster formation. This is the first time that an
      effect of nitric oxide has been observed in a flatworm. In addition, the pattern
      of the NADPH-diaphorase histochemical reaction in the nervous system and the
      pattern of F-actin filaments in the musculature stained with TRITC-labelled
      phalloidin were studied. NADPH-d staining occurred in the brain and the main
      nerve cords but also followed the muscle fibres stained with phalloidin. The
      pattern of the NADPH-d reaction was compared with that of 5-HT immunoreactivity.
      The implications of the results are discussed in relation to the background of
      data on neuronal signal substances in M. vogae.

PMID- 10404278
TI  - Phylogenetic analysis of Sarcocystis spp. of mammals and reptiles supports the
      coevolution of Sarcocystis spp. with their final hosts.
AB  - Sequences of the small subunit rRNA genes were obtained for two coccidians,
      Sarcocystis dispersa and an unnamed Sarcocystis sp. which parasitise the European
      barn owl and an African viperid snake as their final host, respectively, and
      share mouse as their intermediate host. Phylogenetic analysis of the sequence
      data showed that Sarcocystis sp. from the viperid snake is most closely related
      to another Sarcocystis sp. isolated from an American crotalid snake, while S.
      dispersa grouped with other bird-transmitted species. The available dataset
      failed to resolve the evolutionary relationships among four major branches into
      which all Sarcocystidae and Isospora spp. were split. However, within these
      branches, the phylogenetic relationships of the majority of analysed members of
      the genus Sarcocystis reflected coevolution with their final, rather than
      intermediate hosts.

PMID- 10404279
TI  - The Nesbit operation for congenital curvature of the penis.
AB  - OBJECTIVE: To assess the results of the correction of congenital penile curvature
      using the Nesbit operation. PATIENTS AND METHODS: The records of 106 patients who
      had a Nesbit operation to correct a congenital penile curvature between 1977 and
      1992 were reviewed. RESULTS: An excellent (78.3%) or satisfactory (17.9%) result
      was achieved representing an overall success rate of 96.2%. The reasons for a
      poor or satisfactory result were either an impaired erection--7 (6.6%) [all
      psychogenic] or a residual deformity of 10 degrees--16 (15.1%). There were no
      major complications although five patients (5.3%) needed a further Nesbit
      operation. CONCLUSION: The Nesbit operation is a simple and effective technique
      for the correction of a congenital penile curvature.

PMID- 10404280
TI  - Effects of diabetes on nitric oxide synthase and growth factor genes and protein
      expression in an animal model.
AB  - Erectile dysfunction occurs frequently in humans with diabetes mellitus; the
      molecular basis of this phenomenon is not known. We investigated the effects of
      diabetes on penile erection, nitric oxide synthase and growth factors expression
      in an animal model. Forty male rats were divided into two groups: the
      experimental group (n = 30) received intraperitoneal injection of Streptozotocin
      (STZ) dissolved in citrate buffer to induce diabetes; ten age-matched control
      rats received injection of citrate buffer vehicle only. Before euthanization at
      eight weeks, erectile function was assessed by electrostimulation of the
      cavernous nerves. NADPH diaphorase staining was used to identify NOS and
      immunostaining technique was used to identify nNOS in the penile nerve fibers. RT
      PCR was used to identify mRNA expression of nNOS, eNOS, iNOS, ER-beta, ER-alpha,
      NGF, IGF-I, TGF-beta 1, and AR. Western blot was used to identify nNOS, IGF-I,
      NGF, and TFG-beta protein expressions. In the diabetic group, there was: (1) a
      significant decrease in NOS containing nerve fibers in the dorsal and
      intracavernosal nerves; (2) a significant lower maximal intracavernosal pressure.
      RT-PCR showed down-regulation of nNOS (large form), iNOS and ER-beta mRNA
      expression, Immunoblot showed down-regulation of nNOS protein expression and nNOS
      immunostaining showed less positive staining in the dorsal and intracavernous
      nerves in the diabetic group. These molecular changes may provide the basis for
      further studies to explore the association between diabetes and impotence.

PMID- 10404282
TI  - Definition and classification of erectile dysfunction: report of the Nomenclature
      Committee of the International Society of Impotence Research.

PMID- 10404281
TI  - The penis is not protected--in hypertension there are vascular changes in the
      penis which are similar to those in other vascular beds.
AB  - In hypertension, small arteries in a variety of vascular beds undergo structural
      changes that increase resistance. To assess whether there are differential
      structural changes in the penis that accompany hypertension, we began with
      determining structurally-based vascular resistance properties in penile and
      hindlimb vascular beds of adult spontaneously hypertensive rats (SHR) and Sprague
      Dawley (SD) rats. In anesthetized SHR, the penile and hindlimb vasculature were
      isolated and perfused, maximum dilation was induced, and a flow-pressure
      assessment and alpha 1-adrenoceptor agonist concentration-response curves were
      generated. Both the baseline and maximum constrictor responses were similar in
      the two beds of each strain, and overall the maximum structurally-based vascular
      resistance in SHR was higher than in SD rats. Our data suggests that the penile
      vasculature is not protected from the structural changes that take place in the
      other vascular beds in hypertension. There does not appear to be an underlying
      functional control mechanism that protects the penile vasculature from structural
      changes that may have a negative impact on penile blood flow.

PMID- 10404283
TI  - Intracavernosal self-injection therapy in men with erectile dysfunction:
      satisfaction and attrition in 119 patients.
AB  - This study describes a 12-24 month follow-up on 119 ED patients in an attempt to
      understand satisfaction with and dropout from ICI use. Results indicate 40%
      attrition, attributed primarily to a lack of efficacy of ICI, but also to
      spontaneous return of erectile function and to negative reactions surrounding the
      injection procedure. Multivariate analyses indicated that ICI dropouts were more
      likely to have co-existing premature ejaculation, low responses during
      psychophysiological screening, a lack of spontaneous erections prior to ICI, and
      an etiology that included an organogenic component. These same factors, along
      with low satisfaction with their sex life, were related to attrition due
      specifically to a lack of drug efficacy. In contrast, attrition due to recovery
      of spontaneous erections was associated with high sexual satisfaction. Among
      ongoing users, dissatisfaction was associated with higher age, shorter erections
      during ICI use, and low satisfaction with sex life. These findings identify a
      number of factors related to attrition and satisfaction, emphasizing the
      importance of specifying the cause for ICI attrition and, demonstrating that a
      substantial portion of patients who dropout do so for positive reasons.

PMID- 10404284
TI  - Perineal floor efficiency in sexually potent and impotent men.
AB  - Given the knowledge that the ischiocavernous and bulbocavernous muscles are
      involved in the erection of the penis, we studied the voluntary contractile
      activity of the perineal floor muscles in sexually potent and impotent men to
      investigate whether or not a different muscular efficiency can be found in these
      subjects. The activity of perineal floor muscles was studied in 76 sexually
      potent men and in 97 impotent men matched by age. A further group of 217 older
      impotent men was also studied to verify the impact of age on the efficiency of
      perineal floor contraction. The average myoelectrical activity of 24 maximized
      contractions of the perineum was measured in microV by anal plug
      electromyography. Perineal floor muscle contraction was significantly higher (P =
      0.0007) in potent than in impotent men matched by age. In addition, in older
      impotent men the less perineal floor efficiency was also negatively correlated to
      age (r = -0.21, P = 0.002). Our results clearly demonstrated that a reduction of
      contractile activity of perineal muscles may be related to erectile dysfunction
      in younger men and an additional influence of age on perineal floor efficiency
      can be present in older impotent men.

PMID- 10404285
TI  - Elevated low-density lipoprotein cholesterol (LDL-C) enhances pro-erectile
      neurotransmission in the corpus cavernosum.
AB  - Hypercholesterolaemia is thought to foster atherosclerosis and impotence through
      its effects on vascular endothelium. In this study, we investigated the
      pharmacological changes in rabbit corpus cavernosum (CC) secondary to incubation
      with lysolecithin and hypercholesterolaemia. A daily egg yolk dietary supplement
      induced gross hypercholesterolaemia in our rabbits. Group A of test animals (n
      12) was fed with the yolk content of single egg and group B (n-6), that from two
      eggs for eight weeks. Serum level estimation revealed a progressive elevation of
      cholesterol to 15 and 30 times respectively, in the two treated groups as
      compared to values in the control group (n-6). Early histological manifestations
      of atherosclerosis were perceived as fat cell lesions in the cavernosum of
      treated animals. In vitro pharmacological studies on CC strips from both groups
      of test animals demonstrated a profound accentuation of the contractile responses
      to noradrenaline and histamine and attenuation of relaxant response to
      acetylcholine. However, in contrast to single-egg treated group, which
      demonstrated a reduction in the relaxant response to electrical field stimulation
      (EFS), there was a marked and statistically significant potentiation of this
      nitrergic transmission, in the two-eggs group. Prior incubation of CC strips of
      normolipidaemic rabbits (n-7) with lysolecithin, reproduced similar exaggerated
      response to EFS. Therefore, from the results of our study, it is concluded that
      oxidised LDL or its major amphiphile lysolecithin, at some critical level or
      beyond, may be capable of reverting at least some of the adverse effects of
      hypercholesterolaemia on erectile function, through its mediating effect on
      nitrergic transmission.

PMID- 10404286
TI  - Bulbocavernosus-reflex latencies and pudendal nerve SSEP compared to penile
      vascular testing in 669 patients with erectile failure and other sexual
      dysfunction.
AB  - The purpose of this current study was to find out the coincidence of pathological
      penile vascular supply with pathological data in Bulbocavernosusreflex latency
      (BCR-L) measurements and Pudendal Nerve SSEP (PudSSEP) recordings. Six hundred
      and sixty-nine males (642 with erectile dysfunction, 27 with different sexual
      disturbances) (mean age 49.3 y, range 17-76 y) underwent consecutively a battery
      of neurophysiological investigations together with pharmacotesting of cavernous
      bodies combined with duplex sonography of penile arteries. Pathological vascular
      findings were indicated in 286 men (43%), pathological neurophysiological
      findings in 264 men (39%). Normal findings in both investigations (vascular and
      neurophysiological) were encountered in 252 men (38%); 131 men (19%) revealed
      pathological data exclusively in the neurophysiological parameters, 153 (23%)
      exclusively in the vascular parameters and 133 (20%) in both. The highest
      percentages of pathological findings were observed in patients with diabetes
      mellitus (110 out of 131, 88%) and patients who had sustained pelvic trauma or
      surgery (36 out of 44, 82%), in contrast to the lowest percentage in patients
      with a proven psychogenic etiology (10 out of 38, 26%). Somewhat surprising was
      the rather high proportion of vascular impairment in patients with defined
      neurological diseases such as alcohol abuse (20 out of 51, 43%), polyneuropathy
      (PNP) of various etiology (9 out of 19, 47%), lumbosacral radiculopathies (26 out
      of 65, 40%), and CNS diseases (24 out of 52, 46%), about half of them coinciding
      with pathological neurophysiological findings. Even if the validity of BCR-L
      measurement and PudSSEP recordings in the assessment of neurogenic impotence was
      controversely discussed, we conclude that in a large number of impotent males
      both neurogenic and vascular factors are responsible for the onset of erectile
      dysfunction.

PMID- 10404287
TI  - The sexual health inventory for men (IIEF-5)

PMID- 10404288
TI  - Transacting self-preservation: a grounded theory of the spiritual dimensions of
      people with terminal cancer.
AB  - This study describes the spiritual meanings people with terminal cancer give to
      their everyday life-experiences. Transcriptions from semi-structured, in-depth
      interviews of 19 adults who had a diagnosis of cancer and who were living in
      Queensland and New South Wales, Australia, were analysed using the constant
      comparative approach of grounded theory. The study found that people with
      terminal cancer develop a spiritual perspective that strengthens their approaches
      to life and death. Their discovery of spiritual meaning is enacted through a
      process of transacting self-preservation. This process incorporates three phases,
      taking it all in, getting on with things and putting it all together. As people
      with terminal cancer move through these phases they transact self-preservation by
      discovering deeper levels of understanding self. This discovery of self
      incorporates a higher level of spiritual growth, spiritual perspective, spiritual
      awareness and spiritual experiences. The study indicates that nurses can help
      people with terminal cancer develop coping strategies that allow them to engage
      in the process of transacting self-preservation. This study also shows that there
      needs to be more emphasis on spirituality, spiritual issues and the role of
      spiritual caring in nursing curricula and practice.

PMID- 10404289
TI  - A study of the perceptions of hospice day care patients: my phenomenological
      methodology.
AB  - This paper describes the phenomenological methodology used to evaluate a hospice
      day care service from the perspective of twelve patients attending a UK hospice
      in June/July 1996. It briefly compares and contrasts a variety of
      phenomenological methodologies, then gives an account of the development and
      application of the phenomenological methodology used for the study.

PMID- 10404290
TI  - Needs of parents of the child hospitalised with acquired brain damage.
AB  - This paper describes the findings of a descriptive study into needs of parents of
      children with Acquired Brain Damage during hospitalisation. Thirty four parents
      of 28 children treated at a tertiary referral pediatric hospital were
      interviewed. Parents described their experiences during their child's
      hospitalisation and identified needs which, when met, enabled them to care for
      their children and cope with the sudden illness and disabilities. Three themes
      were identified: services that optimised the child's recovery, services which
      supported parents cope with child's illness and services assisting in maintenance
      of family functioning and stability. An emerging model of parental needs and
      nursing interventions to meet these are identified.

PMID- 10404291
TI  - A European perspective on psychiatric nursing and violent incidents: management,
      education and service organisation.
AB  - The topic of violent incidents and its importance to inpatient psychiatric
      nursing practice is well recognised in the academic literature. However the
      awareness and profile of the issue in different European countries is highly
      variable. In this paper five European countries are compared: Italy, Norway, the
      Netherlands, Sweden and the UK. Contextual factors are likely to determine the
      perception, recognition and acknowledgement of the problem. Those described in
      detail here are the organisation of psychiatric inpatient services, the training
      of psychiatric nurses, and the methods used by those nurses to control and
      contain disturbed patients. For each of these factors large variations exist
      between the countries considered. The conclusion is drawn that there is much
      scope for useful comparative research.

PMID- 10404292
TI  - Effects of cognitive-behavioral interventions on quality of life in persons with
      HIV.
AB  - This study explored the effects of cognitive-behavioral interventions on quality
      of life in persons with HIV. In a randomized, 3 x 3 block design, 69 participants
      were assigned to a guided imagery, progressive muscle relaxation or control
      group. Following brief instruction, subjects practiced their respective
      intervention over six weeks. Post intervention, perceived health status, but not
      quality of life, was significantly different across treatment groups. Findings
      suggested differential effects for guided imagery and progressive muscle
      relaxation, with larger effects for those at mid-stage disease and for low
      frequency users of guided imagery.

PMID- 10404293
TI  - The effect of expressive physical touch on patients with dementia.
AB  - This study explored the effect of expressive physical touch with verbalization
      (EPT/V) on anxiety and dysfunctional behavior in patients with dementia using a
      one group repeated measures design. The study findings are that (1) anxiety is
      lower immediately following EPT/V and (2) EPT/V causes decreasing episodes of
      dysfunctional behavior. Therefore, it behooves caregivers and family members to
      use expressive physical touch and verbalization when caring for these patients,
      since it is cost-effective, simple to learn and practice and it is most effective
      in improving and maintaining patient's high quality of life.

PMID- 10404295
TI  - Coping with chronic illness: a qualitative study of coping with postpolio
      syndrome.
AB  - The study describes how 24 people with postpolio syndrome (PPS) cope with their
      problems. Two qualitative interviews were conducted, 6 weeks apart. The
      interviews were analysed inductively. It was found that the participants
      experienced many types of illness-related problems in their everyday lives.
      Furthermore, they describe the progressive deterioration in terms of a general
      weakness, fatigue and pain--these adding to the emotional stress. A variety of
      coping strategies are employed and the result of the analysis shows it to be
      impossible to carry out a clearly differentiated grouping into problem-focused
      and emotion-focused. By and large the participants have learnt to live with the
      changes and feel that they have 'a good life in spite of everything'.

PMID- 10404294
TI  - Help seeking behaviour and health and social services utilisation by people
      suffering from urinary incontinence.
AB  - It is estimated that urinary incontinence can effect up to 23% of the population
      at some time during their adult years, with 9% currently experiencing symptoms.
      This study found that the majority of sufferers had spoken to or had contacted
      their GP about their incontinence, and that people currently suffering from
      incontinence were significantly more likely to have seen their GP within the last
      month than those who were continent. Help seeking behaviour was also influenced
      by the severity of incontinence, with people suffering from severe incontinence
      significantly more likely to have sought help than those with light to moderate
      incontinence. Two thirds of sufferers who did not seek help were too embarrassed
      to do so. Significantly more people who were incontinent that did not seek help
      in a health authority without an established continence service did not know that
      health services were available, compared with those in a health authority having
      an established continence service. It is important for health care providers to
      ensure that the public knows what services are on offer and how to access them.
      Significantly more incontinence sufferers in the health authority with an
      established continence service chose not to seek help from a health professional
      compared with those in the health authority without service, which could indicate
      there was an element of informed choice in not accessing the services available.
      Significantly more people who were incontinent than continent required help with
      their activities of daily living and personal self care. They were also
      significantly more likely than those who were continent to require formal and
      informal contacts provided by health services, local authority, the church or
      voluntary sector. It is important that people suffering from incontinence have
      their health and social needs assessed so that services can be effectively
      targeted.

PMID- 10404297
TI  - Shared governance: a literature review.
AB  - This paper sets out to establish what is meant by shared governance, analyses the
      literature on shared governance implementation, and discusses emergent issues.
      The paper is based on research funded by the Department of Health (England) and
      by North Staffordshire NHS Trust. A literature search was undertaken using the
      terms 'shared governance' and 'empowerment', restricted to English language. The
      databases used were CINAHL, British Nursing Index, Medline, Social Sciences
      Citation Index and FirstSearch, and the search period was January 1988-May 1998.
      Initially, nearly 500 articles were identified. This search also highlighted
      articles describing participative management, professional practice models, and
      self-managed work teams. For the purposes of this review, only published articles
      which either described and/or evaluated the implementation of shared governance
      were analysed. According to these criteria, 48 studies, which were obtained by
      the cut-off date, were included for detailed assessment.

PMID- 10404296
TI  - Factors related to fatigue; priority of interventions to reduce or eliminate
      fatigue and the exploration of a multidisciplinary research model for further
      study of fatigue.
AB  - A growing interest in the health problem presented by fatigue, both in clinical
      practice and research, coupled with a decreasing number of reported studies on
      fatigue in the last decade, make an updated and systematic review of factors
      related to fatigue necessary. A search of the literature, comprising 53 studies,
      was therefore undertaken to explore the following research questions: Which
      significantly social-demographic, cure-related, and care-related factors are
      significantly correlated with fatigue? And which nursing interventions need
      priority in experimental research to reduce or eliminate fatigue? Reported
      factors related to fatigue in analysed studies show that the correlations between
      the specific cure- and care-related factors and fatigue are similar among the
      various investigated (patient) populations. This result supports the concept of
      the non-specific character of fatigue. The intervention of primary effectiveness
      most suggested in this study is 'energy management'. Interventions of secondary
      importance which emerge are those of 'emotional support', 'activity therapy' and
      'coping enhancement'. This study makes clear that the exploration of a research
      model for fatigue, with social-demographic, cure- and care-related factors is
      useful and that care-related factors have their own effects on fatigue not
      necessarily dependent upon the presence of medical diseases or cure-related
      factors. In general, multi-related factors could be assessed. Implications and
      relevant questions for further research on fatigue are also given.

PMID- 10404298
TI  - Evaluating the effectiveness of a smoking cessation intervention designed for
      nurses.
AB  - The purpose of this study was to evaluate the effectiveness of offering an
      individualised approach to smoking cessation to qualified nurses and student
      nurses in Northern Ireland. Twenty-two qualified nurses and 32 student nurses
      enrolled in the intervention. A further 23 qualified nurses and 33 student nurses
      expressed interest in giving up smoking, but did not wish to be included in the
      intervention. They were assigned to the comparison group. Objective verification
      utilising salivary cotinine measurements of continuous abstinence at 6 months and
      1 year demonstrated that 24% of student and qualified nurses in the intervention
      groups stopped smoking compared with 7% of those in the comparison groups. Both
      of these differences are statistically significant (Fisher's Exact Probability
      Test p = < 0.05). This suggests that the individualised approach as used in this
      study is an appropriate method of helping motivated nurses to quit.

PMID- 10404299
TI  - Quality of life, coping and concerns in Chinese patients after renal
      transplantation.
AB  - This study aims to identify the coping methods used by patients to deal with
      stress after renal transplantation and to assess patients' perceived quality of
      life at two different time intervals after the transplant. The study conducted in
      one transplant centre in Hong Kong and 101 survivors participated. The Chinese
      Coping Scale (CCS) and the Hong Kong Chinese version of the WHOQOL scale were
      used together with an open question inquiring about stressors or concerns
      experienced by patients posttransplant. The results revealed that the main
      stressors identified were fear of rejection, compliance with medication and side
      effects of medication, uncertainty about the future, fear of infection and the
      cost factor. Not statistically significant differences were found in all the CCS
      subscales measuring internal coping or external coping between patients within
      one year posttransplant (n = 23) and patients more than one year posttransplant
      (n = 78). Overall, patients used more internal locus of coping to deal with
      stress. Not statistically significant differences were also found in all the
      quality of life subscales between the two groups of patients. The results showed
      that quality of life was moderate in the Chinese renal transplant patients in
      Hong Kong. The findings of this study would enable renal nurses to design
      interventions to help transplant recipients to cope with the demands of life with
      a renal graft.

PMID- 10404300
TI  - Developing the role of the generic healthcare support worker: phase 1 of an
      action research study.
AB  - This paper reports on the first phase of an action research practice development
      project to explore, develop and evaluate the role of the generic healthcare
      support worker in a high dependency rehabilitation service. The project is being
      jointly conducted by staff from the University of Southampton, the University of
      Portsmouth and the Isle of Wight Healthcare NHS Trust and phase 1 is supported by
      a grant from the NHS Executive (South and West). The aim of phase 1 of the
      project is to explore the attitudes of staff towards the implementation of the
      role of the generic healthcare support worker, particularly regarding the
      practical, professional and ethico-legal problems of the role. Professional and
      support staff from different parts of the service were interviewed in groups and
      the interviews were tape recorded, transcribed and subjected to a simple thematic
      analysis. Four themes emerged from the data relating to the challenge to
      professional boundaries, being a generic worker, outcomes for service and
      patients and implementing the role. As an action research project, the aim was
      not to produce findings that are generalizable beyond the practice areas in which
      they were generated, but it is nevertheless hoped that the reader might be able
      to apply some of the conclusions to his or her own setting.

PMID- 10404301
TI  - Barriers to nurses' use of research: an Australian hospital study.
AB  - Although research is recognised as an essential basis for nursing knowledge and
      practice development, there is considerable agreement that nurses do not use
      research as often as they could. The question is, what factors are perceived by
      nurses in Australia to interfere with their ability to use research in their
      clinical practice? Using factor analysis procedures, barriers to the use of
      research by 149 nurses working in an Australian hospital were grouped under three
      main factors, viz. the perceived usefulness of research to clinical practice; the
      perceived ability of the practitioner to generate change to practice based on
      research and the accessibility of research to the practitioner. The three most
      frequently cited barriers to using research were insufficient time on the job to
      implement research findings, insufficient time to read research and a lack of
      awareness of research findings. In order to improve the ability of nurses to
      apply research to their practice, fundamental changes need to occur within the
      education system, so as to improve the teaching of research to students of
      nursing and qualified practitioners, within the health care system where nursing
      research is expected to be applied and among clinical nurses.

PMID- 10404302
TI  - Contribution of basic sciences to academic success in nursing education.
AB  - The present study set out to examine the contribution of basic sciences to
      academic success in nursing education. A number of regression analysis models
      were used to analyze the relationships among predictor and criterion variables.
      Data analyses showed that basic sciences and grade point average of nursing
      courses in year 3 and 4 contributed significantly to student success in the
      program (p < 0.001). The cumulative grade point average was the only significant
      predictor of the licensure examination success. These results suggested that the
      content in science courses may have unique relevance to nursing and, therefore,
      may have a factor in their predictive value.

PMID- 10404303
TI  - Characterization of ureteral lesions associated with impacted stones.
AB  - BACKGROUND: Few studies have addressed the various types of ureteral lesions
      apparent in patients treated for ureteral stones, especially in those with
      impacted stones. Macroscopic and microscopic analyses of ureteral lesions
      associated with impacted stones were therefore undertaken. METHODS: From May 1994
      to October 1996, 36 patients with ureteral stones, 21 of whom showed stone
      impaction, were treated with transurethral ureterolithotripsy. After
      ureteroscopic examination, biopsied specimens were obtained from six patients
      with impacted stones and were examined microscopically by conventional
      hematoxylin and eosin staining. RESULTS: Ureteroscopy revealed two types of
      mucosal lesions in the patients with impacted stones: Type 1 lesions were defined
      as edematous or cystic hemispheric lesions and occurred in 18 patients, whereas
      type 2 lesions had a villous appearance and were present in three patients.
      Microscopically, type 1 lesions appeared as submucosal edema without specific
      findings, whereas type 2 lesions appeared as columnar mesenchymal tissue coated
      with several layers of transitional epithelium. With regard to factors that might
      contribute to lesion formation, duration of stone presence was significantly
      greater for patients with impacted stones than for those with-non-impacted
      stones. However, no differences in such parameters were apparent between patients
      with type 1 lesions and those with type 2 lesions. CONCLUSIONS: Two types of
      ureteral lesions associated with impacted stones were confirmed microscopically.
      The duration of stone presence is a potential contributing factor in the
      development of ureteral lesions, but factors that determine the type of ureteral
      lesion remain unclear.

PMID- 10404304
TI  - Expression of transitional cell-specific genes, uroplakin Ia and II, in bladder
      cancer: detection of circulating cancer cells in the peripheral blood of
      metastatic patients.
AB  - BACKGROUND: Uroplakins (UP), urothelium-specific transmembrane proteins, are
      present only in urothelia and may be good candidates as tumor markers specific
      for transitional cell carcinomas (TCC). We investigated the expression of UP-Ia
      and UP-II genes in the tissues and peripheral blood of patients with TCC.
      METHODS: We investigated UP-Ia and UP-II gene expression in tissues from 12
      patients with TCC by reverse transcription-polymerase chain reaction (RT-PCR).
      HT1197, a TCC cell line, was used as an indicated cell line to assess a detection
      system for the UP-II gene-expressing cancer cells by nested RT-PCR. We also
      investigated UP-II gene expression in the peripheral blood of 12 other patients
      with TCC by nested RT-PCR. RESULTS: Prior to the investigation of UP-Ia and UP-II
      gene expression, a partial nucleotide sequence of human UP-II gene cDNA was
      determined to prepare the primers for RT-PCR. Uroplakin genes were expressed in
      both cancerous and non-cancerous urothelia taken from all patients examined by RT
      PCR. The detection sensitivity of our assay showed that one cancer cell could be
      detected in 5 mL peripheral blood. UP-II gene-expression was detected in the
      peripheral blood from all three patients with metastatic TCC but not from the
      nine patients with non-metastatic TCC nor the three healthy volunteers.
      CONCLUSIONS: Uroplakins may be employed as tumor markers for transitional cell
      cancer, because they are highly conserved and well expressed, not only in non
      cancerous cells but also in cancer cells. Furthermore, detection of UP-II gene
      expression in blood by nested RT-PCR may provide helpful information in the
      diagnosis and management of TCC.

PMID- 10404305
TI  - Endorectal ultrasonography for the assessment of rectal wall invasion in
      intrapelvic tumor: a preliminary report.
AB  - BACKGROUND: The purpose of the present study was to determine the usefulness of
      endorectal ultrasonography (ERUS) in assessing rectal wall involvement in
      intrapelvic tumors. METHODS: Rectal wall invasion was assessed in 16 patients; 14
      with deeply invasive bladder tumors, one with prostatic leiomyosarcoma, and one
      with prostatic leiomyoma. Computed tomography (CT), magnetic resonance (MR)
      imaging and ERUS with a flexible-type radial scanner (7.5 MHz) were used and the
      results were compared with the histopathologic findings in surgical specimens.
      RESULTS: The normal rectum was shown by ERUS to be a five- or seven-layer
      structure. Characteristic abnormal ERUS findings included disappearance of the
      perirectal fat tissue layer with or without disruption of the propria muscle
      layer. Endorectal ultrasonography accurately assessed rectal wall involvement in
      all four patients who had two bladder tumors, plus the one patient with prostatic
      leiomyoma and the one with prostatic leiomyosarcoma. However, ERUS overstaged one
      of 12 bladder tumors with no rectal wall involvement, which was strongly adhesive
      to the rectum because of an inflammatory change but had no tumor invasion. There
      were no cases of understaging by ERUS. In comparison, CT accurately assessed
      rectal wall involvement in two patients, but overstaged in three and understaged
      in two. Magnetic resonance imaging, which was performed in 14 patients,
      accurately assessed rectal wall involvement in two patients, but overstaged in
      three and understaged in one. CONCLUSION: This preliminary study suggests that
      ERUS more accurately assesses rectal wall involvement in intrapelvic tumor than
      CT or MRI.

PMID- 10404306
TI  - The value of gamma-seminoprotein in combination with prostate specific antigen in
      detecting prostate cancer.
AB  - BACKGROUND: The present study was undertaken to investigate the value of gamma
      seminoprotein (gamma-Sm) and the gamma-Sm/prostate specific antigen (PSA) ratio
      in combination with serum PSA in detecting prostate cancer. METHODS: Prostate
      specific antigen, gamma-Sm and the gamma-Sm/PSA ratio were evaluated in 112
      patients with untreated prostate cancer and 90 patients without prostate cancer
      who had serum PSA and gamma-Sm levels above their respective detection limits.
      RESULTS: When data for all of the patients were analyzed, serum PSA and gamma-Sm
      levels were significantly higher and the gamma-Sm/PSA ratio was significantly
      lower in patients with prostate cancer than patients without prostate cancer. The
      serum PSA and gamma-Sm levels significantly increased and the gamma-Sm/PSA ratio
      significantly decreased with advancing clinical stage in patients with prostate
      cancer. Among the patients with serum PSA levels ranging from 1.8 to 6 ng/mL, the
      gamma-Sm/PSA ratio was significantly lower (P < 0.05) and gamma-Sm levels were
      lower (P = 0.054) in the patients with prostate cancer than in those without
      prostate cancer, but serum PSA levels were not significantly different (P =
      0.53). A receiver operating characteristic (ROC) analysis demonstrated that the
      areas under the ROC curves were 0.54 for PSA, 0.65 for gamma-Sm and 0.69 for the
      gamma-Sm/PSA ratio for prediction of prostate cancer in the PSA range from 1.8 to
      6 ng/mL, although the ROC analysis suggested that the gamma-Sm/PSA ratio does not
      provide significant advantage over PSA in detecting prostate cancer when all of
      the patients were analyzed. CONCLUSIONS: These results suggest that the gamma
      Sm/PSA ratio and gamma-Sm may facilitate differentiation between patients with
      and without prostate cancer who have intermediate PSA levels.

PMID- 10404307
TI  - The significance of resections for residual masses after chemotherapy in
      metastatic testicular tumors.
AB  - BACKGROUND: After chemotherapy for metastatic testicular tumors, masses may
      remain, often in the metastatic sites. This study analyses the role of resections
      for the residual masses. METHODS: Seventy-seven patients with advanced (stage II,
      III) testicular tumors were treated. Of these, 38 patients, including eight with
      seminoma and 30 patients with non-seminomatous germ cell tumors, underwent
      resection of residual masses after chemotherapy and have been followed for a
      median of 41.5 months (range 2-138) after the resection. RESULTS: Residual masses
      were necrosis/fibrosis in 19 patients, mature teratoma in 11 and cancer in eight.
      The ratio of cancer in stage III (41.2%) was significantly higher than that in
      stage II (4.8%). Ten of 38 (26.3%) patients experienced recurrences in sites
      other than the resected sites, and five of 10 patients have died of cancer. Most
      recurrences (80%) occurred within two years. Recurrences after resection were
      detected in 4.8% of stage II patients, 52.9% of stage III, 16.7% of
      necrosis/fibrosis and mature teratoma, and 62.5% of cancer. The survival rate of
      patients with cancer was significantly lower in spite of adjuvant chemotherapy
      after surgery. CONCLUSIONS: Resection for residual masses after chemotherapy in
      metastatic testicular tumors was useful in confirming the tissue and in
      controlling the metastatic sites. Recurrences were often found in patients with
      cancer in the residual mass and the prognosis of patients with cancer was poor,
      therefore the development of more effective therapy for patients with cancer is
      required to improve the prognosis.

PMID- 10404308
TI  - The effect of papaverine on morphologic differentiation, proliferation and
      invasive potential of human prostatic cancer LNCaP cells.
AB  - BACKGROUND: Intracellular cyclic adenosine monophosphate (AMP) level changes are
      thought to play an important role in inhibiting cell proliferation and inducing
      differentiation in several types of cells. It has been reported that cyclic AMP
      analogs induce terminal differentiation in human prostate cancer cells.
      Consequently, phosphodiesterase inhibitors may be useful in delineating the role
      of cyclic AMP in the differentiation of these cells. Therefore, the effect of
      phosphodiesterase inhibitors on morphologic differentiation, proliferation and
      invasive potential of human prostate cancer cells was investigated. METHODS:
      Three human prostate cancer cell lines PC-3, DU145 and LNCaP were treated with
      one of the phosphodiesterase inhibitors, papaverine, 3-isobutyl-1-methylxanthine
      (IBMX) or theophylline, for 6 days. Morphologic changes of these cells induced by
      phosphodiesterase inhibitors were observed by microscopy. Intracellular cyclic
      AMP levels in LNCaP cells were measured by radioimmunoassay using a cyclic AMP
      assay kit. The effect of papaverine on the proliferation and invasive potential
      of LNCaP cells were measured by cell counting and the Matrigel invasion chamber
      assay. RESULTS: Of the three agents, examined papaverine (10(-5) mol/L) is the
      most effective inducer of morphologic change and also raised intracellular cyclic
      AMP levels in LNCaP cells. However, unlike LNCaP cells, PC-3 and DU145 cells
      treated with phosphodiesterase inhibitors, including papaverine, showed little
      change in morphology. Additionally, proliferation and invasive potential of LNCaP
      cells were significantly inhibited by papaverine. CONCLUSION: The results suggest
      that papaverine induces terminal differentiation in LNCaP cells, which is
      correlated with an intracellular cyclic AMP-mediated pathway.

PMID- 10404309
TI  - A case of ileal ureter with proximal antireflux system.
AB  - BACKGROUND: The initial experience of constructing a new antirefluxing valve at
      the uretero-ileal junction with ileal substitution is reported. METHODS: A new
      antirefluxing valve was constructed at the uretero-ileal junction with ileal
      substitution by fixing the distal part of the ureter between the psoas muscle and
      ileal segment (the ileo-psoas tunnel technique). DISCUSSION: The valve created by
      the technique has been working effectively for preventing the ileo-ureteral
      reflux. Pre-operative hydronephrosis was improved and the renal function has been
      well preserved. CONCLUSION: The ileo-psoas tunnel technique is worthwhile when
      ileal substitution of the ureter is indicated.

PMID- 10404310
TI  - Vesicoureteral reflux in a boy presenting with difficulty in walking.
AB  - BACKGROUND: We report an uncommon case who presented himself at our hospital with
      main complaints of high fever and difficulty in walking due to pain on extension
      of his right lower extremity. METHODS: He was diagnosed, through investigation of
      his urinary tract, as having secondary psoas pyomyositis spread from acute
      pyelonephritis caused by vesicoureteral reflux. RESULTS: He was successfully
      managed firstly by antibiotic therapy, followed by the correction of reflux by
      ureteroneovesicostomy.

PMID- 10404311
TI  - A case of complete testicular feminization: laparoscopic orchiectomy and analysis
      of androgen receptor gene mutation.
AB  - BACKGROUND: Analysis of an androgen receptor gene mutation and a bilateral
      laparoscopic orchiectomy were performed on a 19-year-old patient diagnosed as a
      case of complete testicular feminization. METHODS: DNA sequencing of an androgen
      receptor gene mutation and laparoscopic orchiectomy were performed. RESULTS: A
      novel point mutation substituting a proline residue (CCG) for a leucine residue
      (CTG) was observed in codon 892 of exon 8 in the hormone-binding domain of the
      androgen receptor gene. Bilateral intra-abdominal testes were resected
      uneventfully by means of laparoscopic orchiectomy. CONCLUSION: We conclude that
      genetic analysis of androgen receptor gene mutation is essential for diagnosis of
      teon and laparoscopic orchiectomy is a useful therapeutic alteration as a
      minimally invasive treatment.

PMID- 10404312
TI  - The treatment of Legionnaires' disease.

PMID- 10404313
TI  - The role of the rdxA gene in the evolution of metronidazole resistance in
      Helicobacter pylori.
AB  - It was recently demonstrated that inactivation of the rdxA gene, which encodes an
      oxygen-insensitive NADPH nitroreductase, is associated with the development of
      resistance to metronidazole by Helicobacter pylori. In order to further evaluate
      the contribution of rdxA to metronidazole resistance, the sequence of the rdxA
      gene was determined for a series of metronidazole-sensitive and -resistant
      isolates derived from a single, metronidazole-sensitive strain using an H. pylori
      mouse model. These strains were cultured from the stomachs of mice experimentally
      infected with H. pylori strain SS1 and then treated orally with metronidazole.
      The sequence of the rdxA gene of all 10 sequenced metronidazole-sensitive and two
      (7%) of the 27 metronidazole-resistant isolates was identical to that of the
      parental strain. In contrast, the rdxA gene of the other 25 metronidazole
      resistant isolates contained between one and three frameshift or missense
      mutations. This suggests that while the development of metronidazole resistance
      in H. pylori is frequently associated with mutational inactivation of the rdxA
      gene, other mechanisms of resistance are likely to exist in this bacterium.

PMID- 10404314
TI  - Reduced glutaraldehyde susceptibility in Mycobacterium chelonae associated with
      altered cell wall polysaccharides.
AB  - Glutaraldehyde-resistant Mycobacterium chelonae have been isolated from endoscope
      washer disinfectors and endoscope rinse water. The mechanism of glutaraldehyde
      resistance is not well understood. Two spontaneous, glutaraldehyde-resistant
      mutants of the sensitive type strain, NCTC 946, were investigated. The colony
      morphology of the two mutants differed from that of the the type strain: colonies
      of the former were dry and waxy whereas those of the latter were smooth and
      shiny. Increased resistance to glutaraldehyde of the mutants was matched by small
      increases in the MICs of rifampicin and ethambutol but not isoniazid. Both
      mutants showed increased surface hydrophobicity. No changes were identified in
      the extractable fatty acids or the mycolic acid components of the cell wall but a
      reduction in each of the resistant strains in the arabinogalactan/arabinomannan
      portion of the cell wall was detected.

PMID- 10404315
TI  - 5-Fluorocytosine antagonizes the action of sterol biosynthesis inhibitors in
      Candida glabrata.
AB  - The concentration-dependent antagonistic interaction between 5-fluorocytosine and
      a sterol biosynthesis inhibitor (SBI) was studied using intact cells and cell
      free extracts of Candida glabrata. 5-Fluorocytosine promoted incorporation of
      radioactivity into 4-desmethylsterols (P < 0.01), and enhanced the relative and
      absolute increases of ergosterol (P < 0.05) in C. glabrata incubated aerobically
      with an SBI (miconazole or amorolfine). Further aerobic incubation of C. glabrata
      with combinations of a nucleic acid or protein synthesis inhibitor (rifampicin or
      chlortetracycline) and an SBI (miconazole) promoted a similar increase in
      ergosterol biosynthesis. In contrast, 5-fluorocytosine reduced the incorporation
      of radioactivity into 4,4-dimethylsterols (P < 0.01), but had no obvious effect
      on the absolute ergosterol level in C. glabrata incubated statically with
      miconazole. In cell-free extracts of cultures previously incubated with 5
      fluorocytosine, ergosterol synthesis was less sensitive to the action of
      miconazole. Antagonism between 5-fluorocytosine and the SBI is thus mediated by a
      reversal of inhibition of intracellular ergosterol synthesis. The possible
      mechanisms underlying antagonism between 5-fluorocytosine and SBIs that inhibit
      different sites of the sterol biosynthesis pathway, as well as its clinical
      relevance to combination therapy, are discussed.

PMID- 10404316
TI  - Differences between the activity of penicillin, amoxycillin, and co-amoxyclav
      against 5,252 Streptococcus pneumoniae isolates tested in the Alexander Project
      1992-1996.
AB  - A number of published studies have shown that the MICs of amoxycillin and/or co
      amoxyclav are lower than those of ampicillin and/or penicillin for Streptococcus
      pneumoniae. Other published studies have concluded that the activities of
      amoxycillin and co-amoxyclav are comparable with that of penicillin for S.
      pneumoniae. A collection of 5252 S. pneumoniae isolates obtained during a 5 year
      period (1992-1996) was analysed to determine differences between the MICs of
      penicillin, amoxycillin and co-amoxyclav. Among the isolates analysed, 3788 (72%)
      were penicillin-susceptible, 615 (12%) were penicillin-intermediate and 849 (16%)
      were penicillin-resistant. Differences between the agents were assessed by
      examination of MIC distribution functions and simultaneous 95% CIs. In addition,
      penicillin-intermediate and -resistant isolates were analysed to determine the
      number and percentage of isolates which had an amoxycillin and co-amoxyclav MIC
      less than, equal to, or greater than the penicillin MIC. Results showed that the
      amoxycillin and co-amoxyclav MIC90s were one two-fold dilution lower than those
      of penicillin for all isolates collected between 1992-1993 and 1994-1996.
      Simultaneous 95% CIs showed that the mean differences between MICs of amoxycillin
      and penicillin, and between MICs of co-amoxyclav and penicillin, were less than
      zero. The majority of the penicillin-intermediate and penicillin-resistant
      isolates had an amoxycillin and co-amoxyclav MIC less than the penicillin MIC. In
      conclusion, amoxycillin and co-amoxyclav MICs were shown to be lower than the
      penicillin MICs for the S. pneumoniae isolates analysed in this study.

PMID- 10404317
TI  - Prevalence of resistance to MLS antibiotics in 20 European university hospitals
      participating in the European SENTRY surveillance programme. Sentry Participants
      Group.
AB  - Macrolide, lincosamide and streptogramin (MLS) antibiotics are chemically
      distinct inhibitors of bacterial protein synthesis. Resistance to MLS antibiotics
      may be constitutive or inducible. The purpose of this study is to update our
      understanding of the prevalence of different forms of MLS resistance in Europe.
      The analysis of 3653 clinical pneumococcal, staphylococcal and enterococcal
      isolates exhibited an average percentage of 21.3% and 6.2% intermediate and high
      level penicillin-resistant Streptococcus pneumoniae, 21.8% methicillin-resistant
      Staphylococcus aureus and 11% vancomycin-resistant Enterococcus faecium.
      Geographical differences in erythromycin and clindamycin resistance in isolates
      of S. pneumoniae and S. aureus strongly reflect geographical variations in
      susceptibility to penicillin and methicillin, respectively. A very narrow range
      of MICs was obtained with quinupristin/dalfopristin, with no S. pneumoniae, S.
      aureus and E. faecium isolate having an MIC of > 4 mg/L, indicating a possible
      role of quinupristin/dalfopristin in the treatment of infections by multi
      resistant Gram-positive bacteria.

PMID- 10404318
TI  - The antileishmanial activity of novel oxygenated chalcones and their mechanism of
      action.
AB  - Our previous studies have shown that licochalcone A, an oxygenated chalcone, has
      antileishmanial and antimalarial activities, and alters the ultrastructure and
      function of the mitochondria of Leishmania spp. parasites. The present study was
      designed to investigate the antileishmanial activity and the mechanism of action
      of a group of new oxygenated chalcones. The tested oxygenated chalcones inhibited
      the in-vitro growth of Leishmania major promastigotes and Leishmania donovani
      amastigotes. Treatment of hamsters infected with L. donovani with intraperitoneal
      administration of two oxygenated chalcones resulted in a significant reduction of
      parasite load in the liver and the spleen compared with untreated control
      animals. The oxygenated chalcones also inhibited the respiration of the parasite
      and the activity of mitochondrial dehydrogenases. Electron microscopic studies
      illustrated that they altered the ultrastructure of the mitochondria of L. major
      promastigote. The data clearly indicate that this group of oxygenated chalcones
      has a strong antileishmanial activity and might be developed into a new
      antileishmanial drug. The antileishmanial activity of oxygenated chalcones might
      be the result of interference with function of the parasite mitochondria.

PMID- 10404319
TI  - The postantibiotic effect of N-chlorotaurine on Staphylococcus aureus.
      Application in the mouse peritonitis model.
AB  - This study was designed to investigate the delay of regrowth (postantibiotic
      effect) in the presence of N-chlorotaurine (NCT), an endogenous active N-chlorine
      compound, of Staphylococcus aureus, strain Smith diffuse. The low reactivity of
      NCT enabled clear temporal separation of the postantibiotic and killing effect to
      be defined. Delay of regrowth proved to be dependent both on concentration of
      NCT, and incubation time. The maximum delay was 3 h. Using the model of lethal
      staphylococcal peritonitis in mice, in-vivo delay of regrowth of bacteria
      pretreated with N-chlorotaurine could be demonstrated to correlate with survival.
      It is concluded that the postantibiotic effect of N-chlorotaurine could be an
      important factor on decreasing virulence of bacteria. This effect was observed
      after relatively short incubation times.

PMID- 10404320
TI  - Pharmacodynamics of trovafloxacin in a mouse model of cephalosporin-resistant
      Streptococcus pneumoniae pneumonia.
AB  - Trovafloxacin is a potentially useful agent for treatment of infections caused by
      cephalosporin-resistant Streptococcus pneumoniae. We studied the effectiveness of
      trovafloxacin therapy and examined the correlation between pharmacodynamic
      indices in serum and lung, and bacterial killing. Immunocompetent Balb/c mice
      were infected by intranasal inoculation of a cephalosporin-resistant S.
      pneumoniae isolate (MIC of ceftriaxone and trovafloxacin 2 and 0.06 mg/L,
      respectively). Trovafloxacin 10-30 mg/kg/day in one or three divided doses was
      started 15 h after infection. Serum and lung drug concentrations were measured at
      multiple time points for 24 h. Serum concentrations peaked at 30-60 min and lung
      concentrations approximately 30 min later. The serum T1/2 was approximately 9 h
      and lung T1/2 varied from 5 to 9 h. Lung AUC and Cmax values were 2-3 times
      greater than those in serum. At the start of therapy lung bacterial
      concentrations were 8.4 +/- 0.3 log10 cfu/mL and 24 h later had decreased by 3.5
      +/- 0.2, 4.0 +/- 0.2, 0.8 +/- 0.3 and 1.0 +/- 1.2 log10 cfu/mL with 30 mg/kg x 1,
      10 mg/kg x 3, 10 mg/kg x 1 and 3.3 mg/kg x 3 regimens, respectively. Although the
      larger dosages were more effective (P < 0.001) the differences between divided
      and single dosage regimens were not significant. Trovafloxacin serum AUC/MIC
      ratio correlated best with bacterial killing in the lungs over 24 h.
      Trovafloxacin is likely to be useful in the treatment of cephalosporin-resistant
      S. pneumoniae pneumonia.

PMID- 10404321
TI  - Fluconazole, with or without dexamethasone for experimental cryptococcosis:
      impact of treatment timing.
AB  - The time of initiation of fluconazole treatment with or without dexamethasone,
      and the impact on mycological outcome and drug pharmacokinetics were assessed in
      a murine model of disseminated cryptococcosis. Non-infected mice and mice with
      disseminated cryptococcosis were given saline, dexamethasone, or fluconazole +/-
      dexamethasone, 1 or 8 days after infection. Cfus were counted in tissues, and
      fluconazole concentrations were determined in plasma and tissues by HPLC and a
      bioassay. Despite fluconazole tissue and plasma concentrations which were above
      the minimal inhibitory concentration, the numbers of cfus in brain and lung
      tissues were reduced after early (P = 0.002 and 0.04, respectively), but not
      after late fluconazole treatment. The administration of dexamethasone did not
      have a deleterious effect on the number of cfus, fluconazole pharmacokinetics or
      antifungal activity. In conclusion, the size of the fungal burden influences the
      effective level of fluconazole activity in lung and brain. These results strongly
      suggest that potential antifungal agents should be studied following both early
      and late administration in experimental cryptococcosis.

PMID- 10404322
TI  - Comparative in-vitro activity of moxifloxacin, minocycline and azithromycin
      against Chlamydia spp.
AB  - The in-vitro activity of moxifloxacin, a new 8-methoxyquinolone, was compared
      with minocycline and azithromycin against 40 strains of Chlamydia trachomatis,
      Chlamydia pneumoniae and Chlamydia psittaci. Both the MIC and the MBC of
      moxifloxacin ranged from 0.03 to 0.125 mg/L. MICs of minocycline ranged from
      0.015 to 0.06 mg/L and MBCs between 0.03 and 0.25 mg/L. MICs of azithromycin
      ranged from 0.03 to 0.125 mg/L and the MBCs between 0.06 and 0.5 mg/L. MBC values
      of moxifloxacin were the same as MICs in 32 (80%) of 40 strains tested, whereas
      those of minocycline and azithromycin were two to four times higher than their
      MICs. These data confirm those previously obtained indicating that quinolones
      kill chlamydial strains at concentrations equivalent to their MICs.

PMID- 10404323
TI  - Use of a clinical Escherichia coli isolate expressing lux genes to study the
      antimicrobial pharmacodynamics of moxifloxacin.
AB  - Escherichia coli isolate 16,906 expressing lux genes was used for real-time
      monitoring of moxifloxacin effects on bacterial metabolism compared with effects
      on cell replication. Viable counts showed concentration-dependent killing by
      moxifloxacin; real-time measurement of bioluminescence on the same cultures
      showed metabolic activity over 54 h, but with greater inhibition at 1 x MIC than
      with higher MIC multiples. Post-antibiotic effect was longer when determined
      using bioluminescence than by viable counts. The control-related effective
      regrowth time was consistent with both methods. Bioluminescent bacteria provide a
      rapid and sensitive means for measuring antimicrobial effects on bacterial
      metabolism.

PMID- 10404324
TI  - Comparative in-vitro activity of moxifloxacin, penicillin, ceftriaxone and
      ciprofloxacin against pneumococci isolated from meningitis.
AB  - Minimum inhibitory concentrations of penicillin, ceftriaxone, ciprofloxacin, and
      moxifloxacin (BAY 12-8039), a new 8-methoxyquinolone, were determined for 60
      cerebrospinal fluid isolates of Streptococcus pneumoniae collected during January
      1997-April 1998 at Italian medical centres. Three reference isolates with
      predetermined MIC values (two penicillin- and multidrug-resistant isolates, one
      uniformly susceptible to all antibiotics) were also tested with the same
      antibiotics. The MIC90 of penicillin was < or = 0.03 mg/L (range < or = 0.03-2
      mg/L), of ceftriaxone 0.06 mg/L (range < or = 0.03-0.5 mg/L), of ciprofloxacin 2
      mg/L (range 0.5-8 mg/L) and of moxifloxacin 0.06 mg/L (range 0.03-0.12 mg/L).
      Moxifloxacin was effective against all the penicillin-resistant isolates tested,
      with an MIC of 0.06 mg/L. Moxifloxacin was 32-fold more active than ciprofloxacin
      and was not affected by penicillin and cephalosporin resistance. These results
      indicate that moxifloxacin could be useful for the treatment of both penicillin
      sensitive and -resistant S. pneumoniae meningitis.

PMID- 10404325
TI  - Antibacterial effect of garlic and omeprazole on Helicobacter pylori.
AB  - The antibacterial effect of a home-made raw garlic extract and commercial garlic
      tablets alone and in combination with antibiotics or omeprazole was determined
      against clinical isolates of Helicobacter pylori. MIC values of raw garlic
      extract and three types of commercial garlic tablets ranged from 10,000 to 17,500
      mg/L. When MIC values of the commercial tablets were based on the allicin
      content, no differences between the three types were observed. The combination of
      garlic and omeprazole, studied with killing curves, showed a synergic effect
      which was concentration dependent. Further clinical evaluation of garlic in
      combination with the conventional agents for H. pylori treatment seems warranted.

PMID- 10404326
TI  - Factors associated with trimethoprim-resistant bacteria isolated from urine
      samples.
AB  - Urine samples with trimethoprim-resistant or trimethoprim-sensitive Gram-negative
      bacteria and samples with no bacterial growth (NG) were identified. Age-sex
      matched community controls were generated with each trimethoprim-resistant case.
      These four groups were evaluated for exposure. Prior trimethoprim use was
      significantly more common in the trimethoprim-resistant group when compared with
      the trimethoprim-sensitive or the NG group. Prior hospitalization was
      significantly less common in the trimethoprim-resistant than the trimethoprim
      sensitive group, but not with the NG group. Prior oestrogen exposure was
      associated with trimethoprim resistance. There were no associations found for
      diabetes or prior corticosteroid exposure. Community controls were found to be
      inappropriate controls for the study of trimethoprim-resistant bacteria in urine
      samples.

PMID- 10404327
TI  - Electron microscopy studies of the bactericidal effects of
      quinupristin/dalfopristin on Staphylococcus aureus.

PMID- 10404328
TI  - Emergence of heterogeneous intermediate vancomycin resistance in Staphylococcus
      aureus isolates in the Dusseldorf area.

PMID- 10404329
TI  - The susceptibility of Streptococcus pneumoniae to levofloxacin and other
      antibiotics.
AB  - The aim of this study was to determine the in-vitro susceptibility of
      Streptococcus pneumoniae to levofloxacin, ciprofloxacin, sparfloxacin, ofloxacin,
      amoxycillin, cefepime and cefuroxime. In total, 105 isolates (clinical blood and
      sputum isolates from 1995-96) were selected from the collection of the Department
      of Clinical Microbiology of the Chaim Sheba Medical Centre. MICs were determined
      with an agar dilution method according to NCCLS guidelines. The MIC ranges with
      the test antibiotics against the pneumococcal isolates were: 0.5 mg/L,
      levofloxacin; 0.12-0.5 mg/L, sparfloxacin; 0.5-2 mg/L, ciprofloxacin; 0.5-1 mg/L,
      ofloxacin; < 0.03-2 mg/L, amoxycillin; < 0.03-2 mg/L, cefepime; < 0.03-2 mg/L,
      cefuroxime. The results indicated that although all isolates were susceptible to
      all the fluoroquinolone agents except ciprofloxacin, some isolates had reduced
      susceptibility to amoxycillin, cefepime and cefuroxime. We conclude that all S.
      pneumoniae isolates tested were susceptible to levofloxacin, ofloxacin and
      sparfloxacin. However, about 85% were susceptible to amoxycillin and the other
      beta-lactam antibiotics tested.

PMID- 10404330
TI  - A comparative study of the in-vitro activity of levofloxacin against
      Streptococcus pneumoniae.
AB  - In this study, the in-vitro activity of levofloxacin against Streptococcus
      pneumoniae was compared with the activities of a range of other antibiotics. In
      total, 320 penicillin-susceptible and 30 penicillin-intermediate clinical
      isolates of S. pneumoniae were collected in Germany between 1992 and 1994 from
      patients with bacteraemic pneumonia. MICs were determined using the agar dilution
      methodology recommended by the NCCLS and the results with levofloxacin compared
      with those with ofloxacin, D-ofloxacin, ciprofloxacin, amoxycillin, cefpodoxime,
      cefixime, cefuroxime, faropenem, erythromycin and tetracycline. Levofloxacin
      (MIC50 1 mg/L) was approximately twice as active against the isolates as
      ofloxacin (MIC50 2 mg/L). D-ofloxacin (MIC90 32 mg/L) showed no activity, while
      beta-lactam antibiotics showed elevated MIC90 values against penicillin
      intermediate strains (amoxycillin, 1 mg/L; cefpodoxime, 2 mg/L; cefixime, 32
      mg/L; cefuroxime, 8 mg/L) in comparison with the MIC90 obtained with penicillin
      susceptible strains (amoxycillin, 0.015 mg/L; cefpodoxime, 0.03 mg/L; cefixime,
      0.5 mg/L; cefuroxime, 0.03 mg/L). Faropenem showed good activity against
      pneumococcal isolates (penicillin-susceptible strains, MIC90 0.016 mg/L;
      penicillin-intermediate strains, MIC90 0.25 mg/L). Erythromycin (MIC90 8 mg/L)
      and tetracycline (MIC90 64 mg/L) were also less active against penicillin
      intermediate pneumococcal isolates. In conclusion, levofloxacin and faropenem may
      be useful in the treatment of pneumococcal infections caused by organisms with
      decreased susceptibility to penicillin.

PMID- 10404331
TI  - In-vitro bacteriostatic activity of levofloxacin and three other fluoroquinolones
      against penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae.
AB  - The purpose of this study was to investigate the in-vitro bacteriostatic activity
      of levofloxacin in comparison with that of ofloxacin, sparfloxacin and
      ciprofloxacin against 205 strains of Streptococcus pneumoniae (101 penicillin
      susceptible, 51 penicillin-intermediate and 53 penicillin-resistant). The
      isolates were provided between September 1996 and October 1996 by French
      hospitals participating in the National Co-operative Survey of Pneumococcal
      Infections. The determination of MICs (mg/L) was made by the agar dilution
      method. The MIC50 and MIC90 values of the four fluoroquinolones for the three
      classes of S. pneumoniae (penicillin-susceptible, penicillin-intermediate and
      penicillin-resistant) were not significantly different. In contrast, the
      differences in in-vitro activity observed among the four fluoroquinolones against
      the 205 strains allowed them to be separated into three groups: sparfloxacin
      (MIC50/90 0.25 mg/L); ciprofloxacin and levofloxacin (MIC50 0.5 and 1 mg/L
      respectively, MIC90 1 mg/L); and ofloxacin (MIC50 1 mg/L, MIC90 2 mg/L). A total
      of 204 of the strains had a levofloxacin MIC between 0.25 mg/L and 1 mg/L, and
      only one of the 205 strains was highly resistant (MIC 16 mg/L). Whatever the
      level of susceptibility to penicillin, the relative bacteriostatic activity was,
      in descending order of activity, sparfloxacin, levofloxacin/ciprofloxacin and
      ofloxacin. These results suggest levofloxacin has potential for the treatment of
      pneumococcal infections.

PMID- 10404332
TI  - In-vitro activity of levofloxacin against Streptococcus pneumoniae with various
      levels of penicillin resistance.
AB  - This in-vitro study was designed to compare the activity of levofloxacin with
      that of ciprofloxacin, ofloxacin, erythromycin, penicillin, amoxycillin,
      loracarbef, cefaclor, cefpodoxime, ceftriaxone, trimethoprim-sulphamethoxazole,
      clindamycin and vancomycin against a collection of 202 Streptococcus pneumoniae
      isolates (56% susceptible to penicillin, 34% intermediate, 10% resistant). The
      isolates (60% nasopharyngeal, 40% middle ear) were obtained from otherwise
      healthy children at child care centres in urban and rural Nebraska, and at a
      paediatric clinic in rural Kentucky. MICs were determined by NCCLS agar dilution
      methodology using an inoculum of 10(4) cfu/spot. Using NCCLS breakpoints, the
      percentage of penicillin-intermediate and -resistant strains susceptible to the
      evaluable agents were, respectively, as follows: levofloxacin (99%, 100%),
      ofloxacin (87%, 100%), erythromycin (52%, 65%), ceftriaxone (93%, 25%),
      trimethoprim-sulphamethoxazole (7%, 0%), clindamycin (93%, 100%) and vancomycin
      (100%, 100%). Without NCCLS interpretive criteria, no conclusions could be made
      concerning the susceptibility of penicillin-intermediate and -resistant strains
      to the other study drugs. All beta-lactam antibiotics, erythromycin and
      trimethoprim-sulphamethoxazole were less active against penicillin-resistant
      strains, indicating that these may be suboptimal agents for empirical therapy for
      suspected S. pneumoniae infections in these patient populations. However,
      levofloxacin, ofloxacin, clindamycin and vancomycin were equally active against
      penicillin-susceptible and -resistant strains. These data suggest that the
      efficacy of levofloxacin should be examined in both adult and paediatric S.
      pneumoniae infections involving body sites where levofloxacin concentrations > 2
      mg/L can be achieved safely.

PMID- 10404333
TI  - In-vitro activity of levofloxacin, a new fluoroquinolone: evaluation against
      Haemophilus influenzae and Moraxella catarrhalis.
AB  - The in-vitro activity of levofloxacin was studied against 10 beta-lactamase
      negative and 93 beta-lactamase-positive Moraxella catarrhalis isolates, and 65
      beta-lactamase-negative and 35 beta-lactamase-positive Haemophilus influenzae
      isolates. The MICs of levofloxacin were determined by agar dilution on Mueller
      Hinton agar (with the addition of 5% horse blood for M. catarrhalis) or on
      Haemophilus Test Medium for H. influenzae, and were compared with those of
      ofloxacin, ciprofloxacin and sparfloxacin, as well as pefloxacin and D-ofloxacin
      for M. catarrhalis. The fluoroquinolones showed similar activity against isolates
      of H. influenzae and M. catarrhalis, irrespective of beta-lactamase production.
      Levofloxacin (MIC50/90 0.06 mg/L) was 64 times more active against M. catarrhalis
      than D-ofloxacin (MIC50/90 4/8 mg/L) and twice as active as ofloxacin (MIC50/90
      0.125 mg/L). Ciprofloxacin had an MIC50/90 of 0.03/0.06 mg/L and sparfloxacin
      showed an MIC50/90 of 0.015 mg/L against M. catarrhalis irrespective of the
      resistance phenotype of the isolates. Against H. influenzae, levofloxacin was
      twice as active as ofloxacin (MIC90 values 0.03 mg/L versus 0.06 mg/L), while the
      MIC90s of ciprofloxacin and sparfloxacin were both 0.015 mg/L. Our results
      therefore suggest that levofloxacin has potential for treating respiratory tract
      infections caused by H. influenzae and M. catarrhalis.

PMID- 10404334
TI  - In-vitro activity of levofloxacin, ofloxacin and D-ofloxacin against coryneform
      bacteria and Listeria monocytogenes.
AB  - The objective of this study was to evaluate the in-vitro activity of
      levofloxacin, ofloxacin and D-ofloxacin compared with ciprofloxacin, norfloxacin
      and sparfloxacin against coryneform bacteria and Listeria monocytogenes isolated
      from clinical samples. The following organisms (and number of strains) were
      studied: Corynebacterium jeikeium (20), Corynebacterium urealyticum (20),
      Corynebacterium minutissimum (20), Corynebacterium striatum (20), Corynebacterium
      amycolatum (30), Brevibacterium spp. (15) and Listeria monocytogenes (15).
      Antimicrobial activity was determined by microdilution using cation-adjusted
      Mueller-Hinton broth supplemented with 0.5% Tween 80 when testing C. jeikeium or
      C. urealyticum. Fluoroquinolones were used in the range 0.015-16 mg/L. Plates
      were incubated in air at 35 degrees C for 18-20 h (24 h when testing C. jeikeium
      or C. urealyticum). The following MIC50 values were obtained for all 140
      organisms tested: levofloxacin, 1 mg/L; ofloxacin, 2 mg/L; D-ofloxacin, > 16
      mg/L; ciprofloxacin, 1 mg/L; norfloxacin, 16 mg/L; sparfloxacin, 1 mg/L. MIC90
      values were > 16 mg/L for all test antibiotics with the exception of
      levofloxacin, which had an MIC90 value of 16 mg/L. At a concentration of 2 mg/L,
      levofloxacin inhibited all L. monocytogenes strains and 35-93% of the remaining
      species. MIC90 values of ofloxacin were one dilution step higher than those of
      levofloxacin against C. minutissimum, C. striatum, Brevibacterium spp. and L.
      monocytogenes. Levofloxacin showed similar (C. jeikeium, C. urealyticum, C.
      amycolatum and Brevibacterium spp.) or greater (C. minutissimum and C. striatum)
      activity than ciprofloxacin and sparfloxacin, and higher than D-ofloxacin or
      norfloxacin against all species studied. In conclusion, levofloxacin was the most
      active of the six fluoroquinolones evaluated against coryneform bacteria isolated
      from clinical samples and could therefore be a promising treatment option in this
      setting.

PMID- 10404335
TI  - Comparative in-vitro activity of levofloxacin, other fluoroquinolones,
      doxycycline and erythromycin against Ureaplasma urealyticum and Mycoplasma
      hominis.
AB  - The susceptibility of 56 Ureaplasma urealyticum and 57 Mycoplasma hominis strains
      to levofloxacin, ofloxacin, ciprofloxacin, fleroxacin, doxycycline and
      erythromycin was determined by an agar dilution method. The reference strain used
      was M. hominis PG 21. Agar plates containing serial dilutions of antibiotics
      (range 0.03-16 mg/L), and control plates (without antibiotics) were inoculated
      with bacteria suspended in modified Shepard's broth using a multipoint
      inoculator. Levofloxacin showed greater activity against all U. urealyticum and
      M. hominis strains compared with all other antibiotics tested. The MIC90 values
      for U. urealyticum were as follows: levofloxacin, 1 mg/L; ofloxacin, 2 mg/L;
      ciprofloxacin, 4 mg/L; fleroxacin, 4 mg/L; doxycycline, 1 mg/L; erythromycin, 8
      mg/L. The MIC90s for M. hominis were: levofloxacin, 1 mg/L; ofloxacin, 2 mg/L;
      ciprofloxacin, 4 mg/L; fleroxacin, 4 mg/L; doxycycline, 4 mg/L; erythromycin, >
      or = 16 mg/L. In conclusion, the results of this study suggest that levofloxacin
      may be useful in the treatment of mycoplasma genital infections.

PMID- 10404336
TI  - Comparative in-vitro activity of levofloxacin against isolates of bacteria from
      adult patients with community-acquired lower respiratory tract infections.
AB  - This study was conducted to evaluate the activity of levofloxacin in comparison
      with a range of antibacterial agents against recent isolates obtained
      consecutively from patients with community-acquired pneumonia (CAP) or acute
      exacerbation of chronic bronchitis (AECB) during the period 1995 to 1996.
      Susceptibility testing was carried out by either microdilution or the Etest, and
      interpreted according to NCCLS breakpoints. The activity of levofloxacin was
      compared with that of amoxycillin, amoxycillin-clavulanate, cefuroxime, cefixime,
      erythromycin, roxithromycin, clarithromycin, azithromycin, ofloxacin and
      ciprofloxacin. Clinically significant numbers of bacteria were recovered from 31
      CAP and 94 AECB specimens. The predominant bacterial species in the CAP specimens
      were Streptococcus pneumoniae (21 isolates) and Haemophilus influenzae (four
      isolates). The AECB isolates mainly consisted of S. pneumoniae (38%), Moraxella
      catarrhalis (26%), H. influenzae (19%) and Pseudomonas aeruginosa (10%). The
      overall percentage susceptible of the isolates for each antibiotic was:
      amoxycillin, 64%; amoxycillin-clavulanate, 89%; cefuroxime, 87%; cefixime, 78%;
      erythromycin, 85%; roxithromycin, 87%; clarithromycin, 87%; azithromycin, 85%;
      ofloxacin, 95%; ciprofloxacin, 95%; and levofloxacin, 97%. The activities of
      levofloxacin and the other agents were also compared against 40 S. pneumoniae
      isolates, of which 20 were penicillin-non-susceptible, recovered from CAP and
      AECB specimens during the period 1994 to 1996. These strains were all susceptible
      to levofloxacin, but only 50% were susceptible to ciprofloxacin and 80% to
      ofloxacin. Twenty M. catarrhalis, 20 H. influenzae and 20 methicillin-susceptible
      S. aureus isolates were also all susceptible to levofloxacin. Furthermore, 20
      community-acquired P. aeruginosa isolates showed similar percentage susceptible
      rates to levofloxacin and ciprofloxacin. These in-vitro results suggest that
      levofloxacin may be useful in the treatment of community-acquired lower
      respiratory tract infections.

PMID- 10404337
TI  - In-vitro antibacterial activity of levofloxacin against hospital isolates: a
      multicentre study.
AB  - The objective of this study was to evaluate the activity of the fluoroquinolone,
      levofloxacin, against hospital isolates of bacteria. MICs of levofloxacin were
      determined for 2154 strains by agar dilution. Breakpoints for susceptibility
      testing were calculated using the agar diffusion technique with 5 micrograms
      discs. The activity of levofloxacin against nalidixic acid- and pefloxacin
      susceptible Enterobacteriaceae (n = 668) was higher (MIC50/90 0.06-0.12 mg/L)
      than previously reported for ofloxacin. As seen with other fluoroquinolones, this
      activity was reduced against nalidixic acid-resistant and pefloxacin-intermediate
      and -resistant strains (MIC 1-8 mg/L). MICs for Pseudomonas aeruginosa (n = 104)
      were between 0.12 and 128 mg/L. Levofloxacin had good activity against nalidixic
      acid- and pefloxacin-susceptible Acinetobacter baumannii (n = 12; MIC 0.06-0.25
      mg/L), but the activity was reduced against nalidixic acid- and pefloxacin
      resistant strains (n = 80; MIC 1-32 mg/L). Haemophilus influenzae (n = 70),
      Haemophilus parainfluenzae (n = 47) and Moraxella catarrhalis (n = 64) were
      inhibited by low concentrations of levofloxacin (MICs 0.016-0.03 mg/L, 0.03-0.12
      mg/L) and 0.03-0.12 mg/L, respectively). Clostridium perfringens (n = 23; MIC
      0.25-1 mg/L) was more susceptible than Bacteroides fragilis (n = 60; MIC 0.5-4
      mg/L). Levofloxacin showed superior activity compared with ofloxacin against
      methicillin-susceptible staphylococci (n = 107; MIC 0.03-0.5 mg/L); the resistant
      strains (MICs 2-32 mg/L) were usually also resistant to methicillin. Levofloxacin
      was less effective against enterococci (n = 105; MIC 1-32 mg/L), but streptococci
      (n = 192) and pneumococci (n = 129), including 58 penicillin-non-susceptible
      strains, were inhibited by low concentrations (MICs 0.5-2 mg/L). According to the
      regression curve, zone diameters were usually 20-22 mm, 17-19 mm and 15-16 mm for
      MICs of 1, 2 and 4 mg/L, respectively. In conclusion, this study, performed on a
      large number of strains, confirms the superior anti-bacterial activity of
      levofloxacin compared with ofloxacin, especially against pathogens isolated from
      respiratory tract infections.

PMID- 10404338
TI  - Susceptibility to levofloxacin of clinical isolates of bacteria from intensive
      care and haematology/oncology patients in Switzerland: a multicentre study.
AB  - The objective of this study was to examine the susceptibility of clinical
      isolates to levofloxacin, a fluoroquinolone with extended activity against Gram
      positive bacteria, and other antibiotics in 12 Swiss clinical microbiology
      laboratories using the NCCLS disc diffusion technique. Isolates were
      prospectively collected from intensive care units (ICUs (59%), oncology wards
      (7%) and other units with haematology/oncology patients (34%) from June 1995 to
      March 1996. The levofloxacin breakpoints used were as recommended by the
      manufacturer. A total of 310 Gram-positive and 580 Gram-negative isolates from
      the respiratory tract (36%), skin/wounds (12%), blood (16%), urine (17%) and
      other sources (19%) were tested. The percentage of isolates susceptible to
      levofloxacin was 100% for Enterococcus spp. (38 strains), Streptococcus
      agalactiae (13), Streptococcus pneumoniae (65), Acinetobacter spp. (11),
      Citrobacter diversus (6), Citrobacter freundii (17), Klebsiella oxytoca (39),
      Morganella morganii (16), Proteus mirabilis (20), Proteus vulgaris (23), Serratia
      spp. (19), Stenotrophomonas maltophilia (10) and Haemophilus influenzae (41). The
      percentage of isolates susceptible to levofloxacin for Staphylococcus aureus (95
      strains, including 2% MRSA) was 94%, coagulase-negative staphylococci (85) 65%,
      Enterobacter spp. (75) 99%, Escherichia coli (111) 97%, Klebsiella pneumoniae
      (45) 98% and Pseudomonas aeruginosa (124) 87%. In conclusion, levofloxacin is a
      new fluoroquinolone to which the most common clinical isolates in Switzerland are
      susceptible. The susceptibility of Enterococcus spp. and S. pneumoniae to
      levofloxacin was particularly remarkable. This compound appears to be a promising
      therapeutic alternative for the treatment of Gram-positive infections.

PMID- 10404339
TI  - Relative potential for selection of fluoroquinolone-resistant Streptococcus
      pneumoniae strains by levofloxacin: comparison with ciprofloxacin, sparfloxacin
      and ofloxacin.
AB  - The aim of this study was to evaluate the relative potential of levofloxacin to
      select for resistance in Streptococcus pneumoniae in comparison with
      ciprofloxacin, sparfloxacin and ofloxacin. Two S. pneumoniae strains were
      studied; HBD 153 (parental strain, serotype 3) and HBD 964 (selected from the
      parental strain in an experimental mouse peritonitis infection model). MICs for
      the two strains were, respectively: 2 and 2 mg/L for ciprofloxacin; 2 and 4 mg/L
      for ofloxacin; 0.5 and 1 mg/L for sparfloxacin; 2 and 2 mg/L for levofloxacin. In
      vitro, with 4 x MIC as the selection concentration, no mutant was obtained with
      strain HBD 153 (mutation frequency < 10(-8). With HBD 964, the mutation frequency
      was 9 x 10(-7) for ofloxacin, 10(-7) for ciprofloxacin, 4 x 10(-5) for
      sparfloxacin and < 10(-8) for levofloxacin. In an immunosuppressed mouse
      peritonitis model (20 mice per dose), the S. pneumoniae strains were studied with
      sc doses of ciprofloxacin, sparfloxacin and ofloxacin at 50 mg/kg od, and with sc
      levofloxacin at a dose of 10 and 50 mg/kg od, or 10 and 50 mg/kg bid. The MICs
      for strains isolated after antibiotic treatment and the mutation frequencies at 4
      x MIC were determined. Against HBD 153, sparfloxacin was the most active
      treatment, followed by levofloxacin 10 mg/kg and 50 mg/kg bid, but strains
      identical to HBD 964 (showing a resistant variant at 4 x MIC) were selected by
      sparfloxacin. Against HBD 964, levofloxacin (10 mg/kg and 50 mg/kg) was the most
      active drug. Highly resistant mutants were selected by ofloxacin and
      ciprofloxacin, but not by sparfloxacin and levofloxacin. In conclusion, the
      relative potential of levofloxacin to select for fluoroquinolone-resistant S.
      pneumoniae is lower than that of ciprofloxacin, ofloxacin and sparfloxacin both
      in vitro and in vivo.

PMID- 10404340
TI  - Serum bactericidal activity of levofloxacin against Streptococcus pneumoniae.
AB  - The objective of this study was to determine the serum bactericidal activity
      (SBA) of levofloxacin against Streptococcus pneumoniae strains with various
      degrees of susceptibility to penicillin and cefotaxime. Serum samples of
      volunteers (n = 12) who had received levofloxacin 500 mg as a single po dose were
      provided in blinded fashion. SBA was determined, using the microdilution method,
      in Todd-Hewitt broth supplemented with lysed horse blood inoculated with an
      overnight culture diluted to yield a final concentration of approximately 10(5)
      cfu/mL. The serum bactericidal titre was defined as the highest dilution of serum
      showing no growth (> 99.9% reduction of inoculum). The duration of SBA ranged
      from 0.75 to 6.3 h (mean 3.85 h), and was independent of the susceptibility of
      the strains to penicillin and cefotaxime. In conclusion, a single po dose of 500
      mg levofloxacin achieved serum concentrations which were bactericidal against
      penicillin-resistant S. pneumoniae for a mean period of 3.85 h.

PMID- 10404341
TI  - Levofloxacin: serum bactericidal activity against methicillin-resistant
      Staphylococcus aureus isolates.
AB  - The aim of this study was to assess the serum bactericidal activity (SBA) of
      levofloxacin compared with that of ofloxacin against methicillin-resistant
      Staphylococcus aureus (MRSA) isolates. Serum from 10 healthy volunteers (seven
      females, three males) was collected after a single oral dose of either
      levofloxacin (500 mg) or ofloxacin (400 mg). Subjects were allocated randomly to
      treatment after at least a 1 week interval between antibiotic regimens. Three
      well-defined MRSA strains were tested, each susceptible to levofloxacin and
      ofloxacin, with different levels of resistance to methicillin (HBD 456, HBD 3 and
      HBD 2; class 1, 2 and 3 Tomasz heterogeneous resistance, respectively) together
      with a methicillin-susceptible (MSSA) reference strain (S. aureus ATCC 25,923).
      SBA was tested in vitro by a microtitration method 15 min before dosing and at 1,
      4, 8 and 12 h after drug absorption. Levofloxacin was significantly more
      bactericidal than ofloxacin against all strains of S. aureus tested (SBA > or =
      1:2). An SBA was recorded for only a short period with ofloxacin, and thereafter
      only bacteriostatic activity remained. This study, therefore, confirms the
      superior activity of levofloxacin over that of ofloxacin against MSSA and MRSA.

PMID- 10404342
TI  - Bactericidal activity of levofloxacin against Streptococcus pneumoniae in an in
      vitro model simulating serum pharmacokinetic parameters.
AB  - The objective of the current study was to evaluate the bactericidal activity of
      levofloxacin against Streptococcus pneumoniae at concentrations equivalent to
      those present in serum after a po dosage of 500 mg. Nine S. pneumoniae strains
      (one penicillin G-resistant, one penicillin G-intermediate resistant, and two
      penicillin G- and cefotaxime-resistant) were exposed to a levofloxacin
      concentration of 6 mg/L diluted at a terminal half-life (t1/2) of 8 h. Surviving
      S. pneumoniae (cfu/mL) were quantified up to 24 h by the membrane filtration
      method. Levofloxacin was rapidly bactericidal and reduced the quantity of
      inoculum to below the detection level of 10 cfu/mL within 2.5-5.15 h,
      irrespective of susceptibility to penicillin G or cefotaxime. No viable S.
      pneumoniae could be detected at the end of the observation period (24 h). All
      strains except one (strain 17134) had an MIC < 1.0 mg/L, and the minimum
      bactericidal concentrations (MBCs) were, at the most, one dilution higher than
      the respective MICs. The inoculum was high, ranging from 2.9 x 10(5) to 7.5 x
      10(6) cfu/mL. The time required to achieve 99% death ranged from 0.9 to 3.1 h,
      and was longest for strain 17134 which had an MIC of 1.0 mg/L and an MBC of 2.0
      mg/L. A 99.9% reduction in inoculum was achieved within 1.5-4.15 h. At a serum
      concentration achievable after a single po dosage of 500 mg, levofloxacin showed
      rapid and complete bactericidal activity against the S. pneumoniae strains
      tested.

PMID- 10404343
TI  - Pharmacodynamics of levofloxacin and ofloxacin against Streptococcus pneumoniae.
AB  - The aim of this study was to compare the bactericidal efficacy of levofloxacin
      and ofloxacin against Streptococcus pneumoniae at different dosage regimens for
      both agents. An in-vitro pharmacodynamic model was used. Levofloxacin kinetics of
      500 mg, administered od or bd, were compared with ofloxacin kinetics of 400 mg od
      or bd. Killing by 3 log10 (99.9%) was achieved up to an MIC of 0.5 mg/L (500 mg
      od) or 1 mg/L (500 mg bd). For levofloxacin killing of S. pneumoniae was
      unimpaired in mixed cultures with Haemophilus influenzae. For ofloxacin, killing
      by 2 log10 was achieved up to an MIC of 0.5 mg/L for 400 mg od and up to an MIC
      of 1 mg/L for 400 mg bd. Killing by 3 log10 was not achievable by 400 mg od, but
      was achieved up to an MIC of 0.5 mg/L for 400 mg bd. Killing of S. pneumoniae
      with identical MICs of levofloxacin was not influenced by their susceptibility to
      penicillin G. These data, together with the two-fold higher activity of
      levofloxacin in comparison with ofloxacin, indicate good therapeutic perspectives
      for levofloxacin over ofloxacin in the treatment of S. pneumoniae infections.

PMID- 10404344
TI  - Clinical effectiveness of levofloxacin in patients with acute purulent
      exacerbations of chronic bronchitis: the relationship with in-vitro activity.
AB  - The objective of this randomized, double-blind study was to compare the clinical
      efficacy of levofloxacin at two different dosages with that of cefuroxime axetil
      in patients with acute purulent exacerbations of chronic bronchitis and, in
      particular, to assess the impact of the susceptibility to levofloxacin on the
      clinical findings. In total, 124 evaluable patients were treated for 7 days with
      oral levofloxacin 250 mg or 500 mg od, or cefuroxime axetil 250 mg bd. Sputum
      cultures were monitored pre-treatment, and at 1 and 7 days after the end of
      treatment. The susceptibility of Streptococcus pneumoniae isolates was tested by
      agar dilution in Columbia blood agar and by disc diffusion, but all other
      isolates were tested solely by the disc diffusion method. A greater number of
      infections were eradicated by levofloxacin than by cefuroxime axetil: infections
      were eradicated in 68% of patients receiving the 500 mg dosage and in 63% of
      those taking 250 mg levofloxacin, whereas the eradication rate with the
      comparator drug was much lower (48%). Against all pre-treatment S. pneumoniae
      isolates (n = 39), the MICs of levofloxacin were between 0.25 and 2 mg/L
      (geometric mean 0.95 mg/L), similar to those of the post-treatment strains (n =
      32; mean 1.11 mg/L). All except one of the S. pneumoniae isolates were
      susceptible to penicillin G (MIC < or = 0.06 mg/L), and the remaining isolate was
      inhibited by 0.5 mg/L of penicillin G, but was fully susceptible to levofloxacin.
      Some pretreatment strains of Pseudomonas aeruginosa were resistant to
      levofloxacin, but many more resistant strains were encountered afterwards. All
      strains of Moraxella catarrhalis and Haemophilus influenzae were highly
      susceptible to levofloxacin in the disc diffusion tests. All the antimicrobial
      agents used in the study were well tolerated: only two patients discontinued
      treatment because of adverse drug effects. The results of this study indicated
      that, although there were some failures in patients with S. pneumoniae and P.
      aeruginosa infections, resistance to levofloxacin did not emerge rapidly among
      strains of S. pneumoniae during therapy with levofloxacin, and that natural
      resistance among pneumococci, H. influenzae and M. catarrhalis was rare.

PMID- 10404345
TI  - The angiotensin receptor blockers.

PMID- 10404346
TI  - Analysis of trends in hospitalizations for heart failure.
AB  - BACKGROUND: Over the past 10 years, efforts have been made to control the cost of
      care for patients with congestive heart failure (CHF) through reducing
      hospitalizations and shortening lengths of stay. Few data are available regarding
      the effectiveness of these intervention strategies on a community basis. METHODS
      AND RESULTS: We analyzed the Oregon hospital discharge database. Multivariable
      methods were used to assess trends while controlling for confounding factors,
      such as age, sex, and comorbidity. The hospital admission rates for CHF were
      stable over time in all age groups. The age- and sex-standardized admission rate
      among people aged 65 years or older decreased slightly from 13.9/1,000 in 1991 to
      12.9/1,000 in 1995. The annual hospital readmission rate remained constant over
      time, with an average rate of 15.3%. The average length of hospital stay
      decreased from 5.01 days in 1991 to 3.95 days in 1995. The in-hospital mortality
      rate decreased from 6.9% in 1991 to 4.7% in 1995, independent of length of stay.
      CONCLUSION: We observed stable hospital admission and readmission rates for CHF,
      accompanied by a decreasing trend in the length of hospital stay and in-hospital
      mortality. Our findings raise the possibility of improved care management for
      heart failure over time.

PMID- 10404347
TI  - Patient preferences for heart failure treatment: utilities are valid measures of
      health-related quality of life in heart failure.
AB  - BACKGROUND: Current standards hold that cost-effectiveness analyses should
      incorporate measures of both quantity and quality of life, and that quality of
      life in this context is best measured by a utility. We sought to measure utility
      scores for patients with heart failure and to assess their validity as measures
      of health-related quality of life (HRQL). METHODS AND RESULTS: We studied 50
      patients with heart failure. We measured utilities with the time trade-off
      technique, exercise capacity with a 6-minute walk test, and HRQL with the
      Minnesota Living With Heart Failure questionnaire, the Medical Outcomes Study
      Short Form-36 (SF-36) questionnaire, and a visual analogue score. Validity was
      assessed by establishing correlation between utilities and these other measures.
      Mean utility score was 0.77 +/- 0.28. There were significant (P < .05)
      curvilinear relationships between utility score and visual analogue score, the
      physical function summary scale of the SF-36, 6-minute walk distance, and the
      Living With Heart Failure score. Utility scores on retest at 1 week were
      unchanged in a subset of 12 patients. Utilities did not vary systematically with
      age, sex, or ethnicity. CONCLUSION: Utilities are valid measures of HRQL in
      patients with heart failure, and cost-effectiveness analyses of heart failure
      treatments incorporating utilities in the outcome measure can be meaningful.

PMID- 10404348
TI  - Physiological significance of early deceleration time prolongation in
      asymptomatic elderly subjects.
AB  - BACKGROUND: Alterations in Doppler-derived diastolic filling patterns are common
      among elderly persons, but their physiological and prognostic significance
      remains uncertain, particularly in asymptomatic older persons without overt
      cardiac disease. This study was designed to determine whether early mitral inflow
      deceleration time (DT) prolongation is of physiological significance in
      asymptomatic elderly subjects. METHODS AND RESULTS: In 15 asymptomatic patients
      aged 60 to 93 years with no history of heart failure (HF) or edema, we performed
      two-dimensional and Doppler echocardiography and 60-minute head-out, isothermic
      water immersion to produce circulatory volume expansion. Plasma levels of atrial
      natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured
      immediately before and after water immersion. Seven of 15 patients had a normal
      mitral early DT (160 to 240 milliseconds; group 1) and 8 of 15 patients had DT
      prolongation (> 240 milliseconds; group 2). Group 2 subjects had significantly
      smaller chamber sizes and increased relative wall thickness without increased
      left ventricular mass. Head-out water immersion produced greater increases in
      plasma ANP levels in group 2 subjects with longer DTs despite similar degrees of
      circulatory volume expansion in each group. In contrast, plasma BNP levels did
      not increase significantly with water immersion in either group. CONCLUSION:
      Early DT prolongation in asymptomatic elderly subjects is associated with
      increased relative wall thickness and enhanced ANP increments after central
      volume expansion. Such exaggerated responses suggest that, in the elderly, a
      prolonged DT has physiological significance and may represent a precursor to
      symptomatic diastolic HF, a condition known to be associated with advancing age.

PMID- 10404349
TI  - Interval-force relation is unaffected by the presence of cardiomyopathy or
      coronary artery disease in patients with atrial fibrillation.
AB  - BACKGROUND: We tested the hypothesis that cycle length-dependent cardiac
      contractility in atrial fibrillation is primarily governed by the negative
      interval-force relation in patients with normal and depressed systolic function.
      METHODS AND RESULTS: We performed two-dimensional guided M-mode echocardiography
      in 41 patients (mean age, 69 +/- 4 years; range, 48 to 92 years; 19 men, 11
      women). Twelve patients had objective evidence of left ventricular systolic
      dysfunction (CMP; mean ejection fraction, 37% +/- 7%) in the absence of coronary
      artery disease (CAD), 13 patients had documented CAD (mean ejection fraction, 43%
      +/- 6%), and 16 patients had normal resting left ventricular systolic function
      (mean ejection fraction, 58% +/- 7%). Simultaneous beat-to-beat blood pressure,
      end-systolic and end-diastolic dimension, circumferential velocity of fiber
      shortening (Vcf), and end-systolic wall stress (ESWS) were calculated for all
      patients. All three groups showed a significant linear relation between beat-to
      beat Vcf and Vcf corrected for afterload (represented as the Vcf/ESWS ratio) and
      preceding cycle length. There was, however, no significant difference in the
      relation between either of these variables and cycle length among the three
      groups. There was also no difference in the rate of change in either Vcf or Vcf
      corrected for afterload (Vcf/ESWS ratio) from beat-to-beat among the three
      groups. Control patients with normal systolic function showed greater Vcf at any
      given cycle length compared with patients with CMP or CAD. CONCLUSION: Our data
      show that, for each beat in atrial fibrillation, Vcf and Vcf/ESWS ratio are
      decreased after shorter cycle lengths and increased after long cycles, but there
      is no significant attenuation of this effect in patients with systolic
      dysfunction with or without coronary disease compared with controls. Thus, the
      negative interval-force relation, the predominant determinant of beat-to-beat
      variation in contractility in atrial fibrillation, is preserved in patients with
      CAD or reduced left ventricular systolic function.

PMID- 10404350
TI  - Hemodynamic changes and neurohumoral regulation during development of congestive
      heart failure in a model of epinephrine-induced cardiomyopathy in conscious
      rabbits.
AB  - BACKGROUND: The present study was designed to study the progression of heart
      failure in rabbits with catecholamine-induced cardiomyopathy. METHODS AND
      RESULTS: We investigated the effects of three repetitive applications (at 16-day
      intervals) of high-dose epinephrine (first infusion, 5 micrograms/kg/min for 60
      minutes; second and third infusions, 4 micrograms/kg/min for 60 minutes) on
      hemodynamics, echocardiographic parameters, and plasma hormone levels in eight
      conscious rabbits chronically instrumented with a Doppler flow probe around the
      proximal abdominal aorta and a catheter in the right atrium. Mean arterial
      pressure and blood flow velocity, as well as the acceleration of blood flow
      velocity (df/dt) in the proximal abdominal aorta were progressively reduced, and
      right atrial pressure was significantly elevated. On echocardiography,
      progressive left ventricular (LV) dilatation with depressed LV systolic function
      and an increase in LV mass were observed. Plasma atrial natriuretic peptide level
      was enhanced approximately fourfold after each epinephrine infusion, with a
      tendency to return to baseline values. Plasma renin activity (PRA) was increased
      after the first epinephrine application (3.0 +/- 0.5 to 6.4 +/- 0.9 ng
      angiotensin I (AI)/mL/h; P < .05), followed by a return to control levels. After
      the second epinephrine infusion, a significant decrease to 1.0 +/- 0.3 ng AI/mL/h
      (P < .05) was observed. After the third catecholamine treatment, PRA levels
      insignificantly increased. Plasma vasopressin level significantly increased from
      0.5 +/- 0.2 to 1.1 +/- 0.5 pg/mL (P < .05) after the second epinephrine infusion.
      CONCLUSION: Repetitive infusions of high doses of epinephrine induce a
      cardiomyopathy with progressive hemodynamic deterioration, LV dilatation and
      hypertrophy, depressed systolic function, and different stages of neurohumoral
      compensation. This model appears to be suitable to study the progression of
      chronic heart failure by serial measurements in a small animal preparation.

PMID- 10404351
TI  - Left and right ventricular collagen type I/III ratios and remodeling post
      myocardial infarction.
AB  - BACKGROUND: Types I and III collagen have different physical properties, and an
      increase of type I/III ratio can have a deleterious impact on myocardial
      compliance and left and right ventricular diastolic function. Post-myocardial
      infarction, these changes in collagen types may be relevant to the remodeling
      process and the development of heart failure. METHODS AND RESULTS: In the rat
      coronary ligation heart failure model, we studied the time course of changes in
      types I and III and total collagen levels over 10 weeks postinfarction. Collagen
      types were separately quantified in the left (LV) and right ventricles (RV) by
      computerized morphometry and standard immunohistochemistry techniques, and also
      by hydroxyproline analysis, and these were correlated with hemodynamic changes.
      Compared with sham-operated rats, total collagen level increased 2.5- to 2.9-fold
      and 1.7- to 2.9-fold in the noninfarcted areas (NIAs) of the LV and RV,
      respectively, over the 10-week period and showed a good relation with changes in
      hydroxyproline content (r2 = 0.62; P < .0001). In the NIAs of both the LV and RV,
      type III collagen level showed a transient twofold increase at 2 weeks, which
      declined to normal at 4 weeks. Type I collagen level increased twofold at 4 weeks
      in the NIA of the LV and remained elevated at 10 weeks. In the RV, type I
      collagen level increased 2.7-fold to a peak at 4 weeks and declined gradually to
      1.7 times baseline at 10 weeks. The patterns of change in type I collagen level
      in the RV correlated with the changes in LV end-diastolic pressure (r = 0.73; P <
      .0001) and RV weight to body weight ratio (r = 0.73; P < .0001). CONCLUSION:
      There is a relative greater increase of type I collagen level in the NIA and RV
      postinfarction, and this may lead to left and right ventricular dysfunction.
      Separate mechanisms might be involved in the induction of the different types of
      collagen deposition, with type I collagen levels apparently closely correlating
      with hemodynamic stress.

PMID- 10404352
TI  - Peripheral vascular remodeling in chronic heart failure: clinical relevance and
      new conceptualization of its mechanisms.
AB  - Increased peripheral vascular tone is a critical factor in the deterioration of
      clinical stage and symptoms in chronic congestive heart failure (CHF) because of
      increased cardiac afterload and decreased nutritive skeletal muscle blood flow.
      Endothelial function as represented by nitric oxide (NO) production shows
      significant attenuation with the progression of clinical severity of CHF as
      determined by New York Heart Association class and exercise capacity parameters.
      This endothelial dysfunction emerges in the early stages of CHF. In the advanced
      stage of the condition, both endothelium-dependent and endothelium-independent
      dilator mechanisms are impaired in limb resistance vessels. This occurs because
      vascular endothelial function, especially NO production, is an important factor
      in the regulation of vasodilatory function, as well as making an important
      contribution to vascular structure. Furthermore, although such vasodilatory
      circulating factors as natriuretic polypeptides and newly discovered
      adrenomedullin are increased in heart failure, the vasodilatory potency of these
      polypeptide hormones in the limb vascular bed is significantly blunted. These
      observations suggest that peripheral circulatory failure in CHF is caused not
      only by simple arterial muscle constriction, but also by structural and
      functional changes, including receptor and postreceptor levels in the
      vasculature. This vascular remodeling may be an important mechanism underlying
      vasodilatory failure in both limb conduit and intraskeletal muscle vessels and
      may contribute significantly to left ventricular dysfunction and exercise
      intolerance in patients with heart failure.

PMID- 10404353
TI  - Angiotensin II and sympathoactivation in heart failure.
AB  - Excessive activity of the sympathetic nervous system (SNS) contributes to the
      development and progression of the syndrome of congestive heart failure (CHF) in
      patients with decreased left ventricular function. The factors underlying chronic
      sympathoactivation are poorly understood, particularly in stable patients. This
      review summarizes both clinical and experimental data regarding the effects of
      angiotensin II (A-II) on the activity of the SNS. The focus is on both the direct
      effects of A-II on the SNS and an indirect effect medicated through alteration in
      function of the baroreflex. Available evidence is consistent with a potentially
      important effect of A-II on SNS activity, perhaps most likely via the baroreflex.
      Important issues regarding the direct effect of A-II on regional SNS activity,
      and on the physiological relevance of effects seen only at high plasma
      concentration of A-II remain to be fully elucidated.

PMID- 10404354
TI  - Effects of losartan versus captopril on mortality in patients with symptomatic
      heart failure: rationale, design, and baseline characteristics of patients in the
      Losartan Heart Failure Survival Study--ELITE II.
AB  - BACKGROUND: In the Evaluation of Losartan in the Elderly (ELITE) heart failure
      study, a survival benefit (primarily because of a reduction in sudden deaths) was
      observed in symptomatic patients treated with losartan compared with captopril.
      METHODS AND RESULTS: The Losartan Heart Failure Survival Study--ELITE II
      (currently ongoing) is a double-blind, randomized clinical trial being conducted
      in 45 countries at 288 sites. ELITE II formally tests the hypotheses that
      losartan, compared with captopril, will reduce all-cause mortality (primary end
      point) and sudden cardiac death and/or resuscitated cardiac arrest (secondary end
      point). In addition, all-cause mortality and/or hospitalizations and
      cardiovascular mortality and/or hospitalizations will be evaluated. The trial has
      90% power to detect a 25% treatment difference in all-cause mortality (event
      driven, 510 deaths). Substudies are examining quality of life, health care
      resource utilization, and mechanisms related to the reduction in sudden death.
      During recruitment (June 1997 to May 1998), 3,152 patients aged 60 years or older
      (mean age, 71.6 years), with New York Heart Association classes II (51%), III
      (44%), and IV (5%), and left ventricular ejection fraction of 40% or less (mean,
      31%) were randomized to receive either 12.5 mg of losartan, titrated as tolerated
      to 50 mg once daily, or 12.5 mg of captopril, titrated as tolerated to 50 mg
      thrice daily. Randomization was stratified by clinical site and for baseline beta
      blocker use. CONCLUSION: The ELITE II study will further define the role of
      losartan in the treatment of patients with symptomatic heart failure relative to
      the angiotensin-converting enzyme inhibitor captopril, an agent from a class
      currently considered standard treatment for this disease.

PMID- 10404355
TI  - Rationale and design of the Valsartan Heart Failure Trial: a large multinational
      trial to assess the effects of valsartan, an angiotensin-receptor blocker, on
      morbidity and mortality in chronic congestive heart failure.
AB  - BACKGROUND: To investigate the role of persistent angiotensin activity despite
      angiotensin-converting enzyme inhibitor therapy in the progression of heart
      failure, the Valsartan Heart Failure Trial has been designed to investigate the
      effect of the angiotensin-receptor blocker, valsartan, on morbidity and
      mortality. METHODS AND RESULTS: Nearly 5,000 patients with New York Heart
      Association classes II to IV heart failure, while receiving all standard therapy,
      are being randomized to treatment with valsartan, 160 mg twice daily, or placebo
      in a worldwide study. Follow-up will be continued until 906 deaths have been
      recorded. Additional end points will include the need for hospitalization, other
      major morbid events, quality--of life measurement, changes in neurohormone
      levels, and changes in left ventricular size and function. Substudies will
      explore exercise tolerance, arrhythmias, and magnetic resonance imaging.
      CONCLUSION: This study should help establish the role of angiotensin-receptor
      blockade in the treatment of heart failure.

PMID- 10404356
TI  - Cataract surgery and its effect on intraocular pressure.

PMID- 10404357
TI  - LASIK after PRK for myopic regression.

PMID- 10404358
TI  - Tissue-plasminogen activator fibrinolysis.

PMID- 10404359
TI  - Globe rupture after peribulbar anesthesia.

PMID- 10404360
TI  - Method for safer penetrating keratoplasty in patients with low scleral rigidity.
AB  - In eyes with low scleral rigidity, penetrating keratoplasty (PKP) is a high-risk
      procedure because forward movement of the lens-iris diaphragm can result in
      prolapse of intraocular contents, expulsive choroidal hemorrhage, and damage to
      the crystalline lens. We developed a method for safer PKP in eyes with low
      scleral rigidity. In this technique, the host cornea is incompletely excised and
      remains attached at the 6 and 12 o'clock positions while the cardinal sutures to
      secure the donor button over the host are placed. Donor endothelium is protected
      by an intervening layer of viscoelastic material. After the first 3 cardinal
      sutures are placed, the host button is completely excised and removed and the
      donor cornea is sutured. This technique prevents the unopposed forward movement
      of the lens-iris diaphragm and may reduce the risk of expulsive choroidal
      hemorrhage and spontaneous extrusion or damage to the crystalline lens during PKP
      in patients with low scleral rigidity.

PMID- 10404362
TI  - Blood-retinal barrier and autofluorescence of the posterior polar retina in long
      standing pseudophakia.
AB  - PURPOSE: To study the physiological state of the retina in long-standing
      pseudophakic eyes using blood-retinal barrier (BRB) disruption and
      autofluorescence as parameters. SETTING: Miyake Eye Hospital, Nagoya, Japan.
      METHOD: This retrospective, case-controlled study sought to determine whether
      ultraviolet (UV)-light-filtering and blue-light-filtering intraocular lenses
      (IOLs) had different outcomes in severity of BRB disruption and autofluorescence
      of the posterior polar retina than clear (untreated) IOLs. RESULTS: Mean sodium
      fluorescein transmittance in eyes with untreated IOLs was 3.7 ng/mL +/- 2.2 (SD)
      3 years after surgery (n = 40) and 3.5 +/- 1.8 ng/mL 8 years after surgery (n =
      18). In eyes with a UV-filtering IOL, the values were 2.4 +/- 1.5 ng/mL (n = 39)
      and 2.6 +/- 2.0 ng/mL (n = 14), respectively. Eyes with a UV-filtering IOL had
      significantly lower transmittance (P < .01-< .05). Mean transmittance 5 years
      after surgery was 4.2 +/- 1.9 ng/mL in eyes with an untreated IOL (n = 31), 3.2
      +/- 2.1 ng/mL in eyes with a UV-filtering IOL (n = 30), 2.8 +/- 1.9 ng/mL in eyes
      with a Menicon blue-light-filtering IOL (n = 20), and 2.6 +/- 1.8 ng/mL in eyes
      with a Hoya blue-light-filtering IOL (n = 21). The eyes with a UV-filtering and
      the blue-light-filtering IOLs had significantly lower transmittance than those
      with an untreated IOL (P < .01-< .05); the eyes with a Hoya IOL had a
      statistically lower mean than those with the UV-filtering IOL (P < .05). Mean
      autofluorescence was 44.9 +/- 6.8 (n = 14), 49.5 +/- 6.1 (n = 6), 53.0 +/- 11.9
      (n = 15), and 64.5 +/- 13.2 (n = 7) at 1, 4, 9, and 14 years after surgery,
      respectively; there was a significant difference between 1 and 9 years and
      between 1 and 14 years (P < .05). CONCLUSION: Eyes with a UV-filtering or blue
      light-filtering IOL had a lower incidence of BRB disruption than eyes with an
      untreated IOL. Autofluorescence increased with age, even in eyes with UV
      filtering IOLs.

PMID- 10404361
TI  - Long-term changes in intraocular pressure after clear corneal
      phacoemulsification: normal patients versus glaucoma suspect and glaucoma
      patients.
AB  - PURPOSE: To compare the effects of clear corneal phacoemulsification on
      intraocular pressure (IOP) in patients without glaucoma, glaucoma suspects, and
      patients with glaucoma. SETTING: Urban, multisubspecialty private practice.
      METHODS: A retrospective analysis of patients who had clear corneal
      phacoemulsification with a minimum of 12 months follow-up was performed. The
      patients were divided into 3 groups: no glaucoma (NG), glaucoma suspects (GS),
      and glaucoma (GG). None had a history of prior surgery. Glaucoma suspects
      included patients with elevated IOPs, abnormal discs, pseudoexfoliation syndrome,
      or pigment dispersion syndrome on no medications and with no field defects.
      Glaucoma patients had received only medical treatment. Two-tailed, homoscedastic
      t tests were used for statistical analysis. RESULTS: There were 143 patients (164
      eyes) in the NG group, 65 (75) in the GS group, and 61 (71) in the GG group. The
      mean preoperative IOP was 16.42 mm Hg +/- 2.77 (SD), 17.59 +/- 4.15 mm Hg, and
      16.97 +/- 4.86 mm Hg in the 3 groups, respectively. At 1 year, the mean IOP was
      lower in all groups: 14.37 +/- 2.97 mm Hg, 15.68 +/- 3.38 mm Hg, and 15.86 +/-
      4.00 mm Hg, respectively. The change was statistically significant in the NG and
      GS groups. Glaucoma patients showed a statistically significant reduction in the
      number of glaucoma medications postoperatively. CONCLUSION: Clear corneal
      phacoemulsification was associated with a statistically significant long-term
      reduction in IOP.

PMID- 10404363
TI  - Comparison of contact lens overrefraction and standard keratometry for measuring
      corneal curvature in eyes with lenticular opacity.
AB  - PURPOSE: To assess the accuracy of corneal power measurement by contact lens
      overrefraction in patients with normal corneas and to determine the suitability
      of this method for use in intraocular lens (IOL) calculations. SETTING: General
      ophthalmology clinic at a public hospital (Ben Taub General Hospital, Houston,
      Texas, USA). METHODS: Using contact lens overrefraction (CLO), and standard
      keratometry, the corneal power in 33 eyes of 20 normal patients and patients
      scheduled for cataract extraction was prospectively measured. The eyes were
      divided into 3 groups based on their best spectacle-corrected visual acuity: (1)
      20/20 to 20/40, (2) 20/50 to 20/70, and (3) 20/80 to 20/400. For each group, the
      means (absolute and arithmetic), standard deviations, and ranges of differences
      in corneal power as measured by CLO and keratometry were calculated. These values
      were used to estimate the induced variance in refractive outcome for IOL
      calculations. RESULTS: The mean absolute differences in corneal power by group
      were 0.35 diopter (D) +/- 0.18 (SD), 0.54 +/- 0.33 D, and 0.77 +/- 0.28 D,
      respectively. The mean arithmetic differences in corneal power were -0.05 +/-
      0.39 D, +0.37 +/- 0.51 D, and +0.17 +/- 0.80 D, respectively. CONCLUSIONS: In
      eyes of patients with good visual acuity (20/20 to 20/40), corneal power
      measurements by CLO and keratometry were similar. The accuracy of the CLO-derived
      value decreased with increasing media opacity but was still acceptable with
      acuity of 20/70. Contact lens overrefraction may be a viable alternative to
      refractive history and videokeratography for estimating true corneal power in
      patients with surgically altered or irregular corneas.

PMID- 10404364
TI  - Diurnal fluctuations in corneal topography 10 years after radial keratotomy in
      the Prospective Evaluation of Radial Keratotomy Study.
AB  - PURPOSE: To correlate clinically observed fluctuations in manifest refraction,
      visual acuity, keratometry, and intraocular pressure (IOP) with changes in the
      anterior corneal surface as measured by videokeratography in patients 10 years
      after radial keratotomy (RK). SETTING: Four clinical centers in the United States
      that participated in the Prospective Evaluation of Radial Keratotomy (PERK)
      study. METHODS: Thirty-two eyes of 20 PERK patients who noted diurnal
      fluctuations in vision had clinical examination and videokeratography (TMS-1,
      Computed Anatomy Inc.) in the morning and evening of the same day a mean of 10.3
      years (range 7.8 to 11.7 years) after RK. The videokeratographs were analyzed in
      terms of various indexes generated by custom-designed software. Morning-to
      evening changes in the means of the various clinical and videokeratographic
      values were assessed using pairwise methods. RESULTS: The mean increase in myopia
      was 0.36 diopters (D) +/- 0.58 (SD) from morning to evening (P < .01). Analysis
      of the videokeratographs showed a corresponding increase in average corneal power
      (ACP), reflecting a steepening of 0.52 +/- 0.45 D (P < .001). The change in ACP
      was correlated with a change in the manifest spherical equivalent refraction (R =
      0.39, P = .03) and a change in best spectacle-corrected visual acuity (R = 0.38,
      P = .03) over the same period. Similarly, simulated keratometry (SimK) readings
      correlated with the change in the manifest spherical equivalent refraction (R =
      0.38, P = .03 for SimK1; R = 0.37, P = .35 for SimK2; R = 0.4, P = .02 for
      average SimK), although the standard clinical keratometric data did not (P = .26
      for K1, P = .11 for K2, and P = .09 for the mean K). The elevation depression
      magnitude, a measure of the low-frequency irregularities of the cornea, showed a
      decrease of 0.32 +/- 1.59, which also correlated with the change in the manifest
      spherical equivalent refraction (R = 0.37, P = .04). Intraocular pressure tended
      to decrease from morning to evening (mean change of -0.97 +/- 3.29 mm Hg), but
      the difference was not significant. Variations in IOP in individual patients,
      however, were correlated with changes in the manifest spherical equivalent
      refraction (R = 0.37, P = .04). CONCLUSIONS: Diurnal fluctuations in corneal
      topographic indexes can be used to evaluate the diurnal fluctuations in
      refraction and visual acuity after RK. The study findings provide statistical
      support for the idea that IOP contributes to the diurnal fluctuation in visual
      acuity after RK.

PMID- 10404365
TI  - One year clinical results of photoastigmatic refractive keratectomy for compound
      myopic astigmatism.
AB  - PURPOSE: To evaluate the efficacy, predictability, and safety of excimer laser
      photoastigmatic refractive keratectomy (PARK) to correct compound myopic
      astigmatism. SETTING: Departments of Ophthalmology, Robert Debre Hospital and
      Rothschild Foundation, Paris, France. METHODS: This retrospective study included
      27 eyes with compound myopic astigmatism treated with a Nidek EC 5000 excimer
      laser. The refractive results were measured at 1 year, and the cylindrical
      component was analyzed by the Alpins method. Mean preoperative myopia was -4.50
      diopters (D) (range -0.75 to -4.00 D) and mean preoperative cylinder, -1.64 D
      (range -0.75 to -4.00 D). RESULTS: At 1 year, the spherical equivalent was -0.47
      D (range +1.00 to -3.00 D) and residual subjective astigmatism, -0.40 (range 
      0.25 to -1.50 D). Uncorrected visual acuity of 20/40 or better was obtained in 22
      of the 27 eyes; 21 eyes were within +/- 1.0 D of emmetropia. Vector analysis
      showed a mean coefficient adjustment of 1.50 D +/- 0.53 (SD), a mean axis shift
      of 2.64 +/- 12.10 degrees, and a mean magnitude of error of 0.45 +/- 0.56 D. Haze
      was absent in 22 eyes and grade 1+ in 5 eyes. Five eyes gained 1 line of best
      corrected visual acuity and 3 lost 1 line. No patient lost more than 1 line.
      CONCLUSION: Excimer laser PARK successfully corrected low and moderate myopia
      combined with up to 4.0 D of astigmatism with a low mean angle of error. To
      increase the accuracy of toric ablation, specific algorithms for the cylinder
      component are needed.

PMID- 10404366
TI  - Use of a polylysine-saporin conjugate to prevent posterior capsule opacification.
AB  - PURPOSE: To determine the feasibility of applying a polylysine-saporin (PLS)
      conjugate to the lens capsule at surgery to prevent lens epithelial cell (LEC)
      proliferation and posterior capsule opacification (PCO). SETTING: Department of
      Research & Development, Bausch & Lomb Surgical, and Department of Ophthalmology,
      Saint Louis University, St. Louis, Missouri, USA. METHODS: Fluorescein-labeled
      polylysine was applied to the lens capsule of rabbits after phacoemulsification
      and analyzed histologically to determine the extent of binding to the lens
      capsule and surrounding tissues. The cytotoxin saporin was conjugated to
      polylysine using bifunctional cross-linkers. This PLS conjugate was applied to
      LECs in culture and to the lens capsules of rabbits. These eyes were monitored
      for PCO. RESULTS: Polylysine primarily bound to the lens capsule membranes, with
      little or no binding to surrounding tissues. When PLS was added to LECs in
      culture, it was internalized and destroyed the cells. Of 9 rabbit eyes treated
      with PLS during surgery, 1 remained free of PCO for the life of the animal (40
      weeks), while 6 showed a delay of cortical regrowth approximately 2 to 3 times
      that of control eyes. CONCLUSIONS: Polylysine bound selectively to the lens
      capsule membrane. The PLS conjugation resulted in a toxic agent that targeted the
      lens capsule and destroyed proliferating LECs. The application of a PLS conjugate
      during surgery may prevent PCO.

PMID- 10404367
TI  - Fibrous membrane formation at the capsular margin in capsule contraction
      syndrome.
AB  - PURPOSE: To determine whether the pathogenesis of capsule contraction syndrome
      involves the outgrowth of the fibrous membrane from the anterior capsule margin.
      SETTING: Department of Ophthalmology, Keio University School of Medicine, Tokyo,
      and the Ando Eye Clinic, Kanagawa, Japan. METHODS: A retrospective review of
      medical records and slitlamp photographs was conducted in 12 eyes (10 patients)
      that had required treatment for a narrowed anterior capsule opening after
      cataract surgery. All patients had had continuous curvilinear capsulorhexis and
      phacoemulsification with implantation of an intraocular lens in the capsular bag.
      Specimens of surgically removed fibrous membrane were examined by
      histopathological methods. RESULTS: Fibrous membrane on the inner surface of the
      anterior capsule and the linear folds of the anterior capsule were present in
      each eye. In 10 eyes of 8 patients, the fibrous membrane was on the outer surface
      of the anterior capsule and covered the capsular folds at its margin.
      Pathological study showed that this fibrous membrane consisted of the flattened
      lens epithelial cells that proliferated on the inner and outer surfaces of the
      shrunken anterior capsule. The outgrowth of this membrane from the margin of the
      anterior capsule to the center of the opening of the anterior capsule was noted.
      CONCLUSION: In this study, capsule contraction syndrome involved contraction of
      the fibrous membrane as well as its outgrowth from the capsule margin.

PMID- 10404368
TI  - Visual, refractive, and subjective outcomes after photorefractive keratectomy for
      myopia of 6 to 10 diopters using the Nidek laser.
AB  - PURPOSE: To analyze the results of photorefractive keratectomy (PRK) for myopia
      of 6.0 to 10.0 diopters (D) using the Nidek laser and compare them with those in
      other series, including LASIK, and to analyze the subjective aspects of vision.
      SETTING: Remuera Eye Clinic, Auckland, New Zealand. METHOD: One hundred ninety
      two eyes of 162 consecutive PRK patients with a 6 month follow-up were studied.
      All had myopia in the range of 6.0 to 10.0 D by spherical equivalent. Astigmatism
      of up to 3.5 D was treated by laser simultaneously. At 6 months, uncorrected
      visual acuity, best spectacle-corrected visual acuity, residual refractive error,
      and corneal haze were recorded. After the 6 month examination, a questionnaire
      was sent to all patients. RESULTS: Uncorrected visual acuity of 20/20 was
      achieved in 59% of eyes and of 20/40 or better in 94%. The accuracy of correction
      was +/- 0.5 D of emmetropia in 77% and +/- 1.0 D in 94%. In 2 eyes (1.0%),
      corneal haze was assessed as 2+ and 2 Snellen lines of best corrected visual
      acuity were lost. The questionnaire revealed that 45% of patients had
      difficulties with night vision. This was better than before surgery in 35% but
      worse in 31%. Halos were seen around lights by 52%, but these were less than
      before surgery in 21% and worse in 26%. There was undue sensitivity to glare in
      29%, but this was better than before surgery in 19% and worse in 28%. The overall
      quality of vision was better than before surgery in 60% and worse in 17%. Seventy
      seven percent did not need spectacles. Ninety-eight percent said they would have
      the surgery again. CONCLUSIONS: As long as the patients are informed of the
      limitations of PRK for myopia, the results are acceptable.

PMID- 10404369
TI  - Refractive lensectomy to correct ametropia.
AB  - PURPOSE: To assess the postoperative outcome of refractive lensectomy for
      ametropia. SETTING: Pacific Eye Center, Brisbane, Australia. METHODS: One hundred
      thirty-eight cases of refractive lensectomy performed from September 1994 to
      September 1997 by 1 surgeon were analyzed retrospectively. Preoperative
      refractive spherical equivalent (SE) ranged from -0.25 to -23.75 diopters (D) in
      the myopic group and from +0.25 to +11.62 D in the hyperopic group. In all cases
      with a low SE, the astigmatism was greater than -2.00 D. Eyes were divided into 6
      groups by the preoperative SE. RESULTS: Overall, 90.0% of eyes achieved an
      uncorrected visual acuity of 20/40 or better; 81.2% achieved 20/30 or better.
      Postoperative SE was within +/- 2.0 D of emmetropia in 93.5% of eyes and within
      +/- 1.0 D in 78.3%. The postoperative incidence of retinal detachment was 0.7%;
      intraocular lens (IOL) exchange, 2.8%; late uveitis, 0.7%; piggyback IOL, 2.1%;
      and neodymium: YAG capsulotomy, 8.0%. No cystoid macular edema, capsule tear, or
      endophthalmitis was seen. CONCLUSION: Refractive lensectomy can achieve excellent
      visual acuity and refractive outcomes with few complications. The surgery can be
      considered in selected patients with myopia, hyperopia, and astigmatism and to
      correct residual ametropia after refractive surgery.

PMID- 10404370
TI  - Refractive astigmatism after oblique clear corneal phacoemulsification cataract
      incision.
AB  - PURPOSE: To determine the astigmatic effect of a supero-oblique clear corneal
      phacoemulsification cataract incision. SETTING: A university-based general
      ophthalmology practice. METHODS: All eyes having supero-oblique
      phacoemulsification cataract surgery using the right hand of a single surgeon
      between April 17, 1997, and July 24, 1997, were prospectively included. There
      were 52 eyes of 52 consecutive patients. Manifest refraction was performed
      preoperatively and 1, 3, and at least 6 months postoperatively. A Fourier method
      of vector analysis was used. RESULTS: Mean refractive error (Fourier corrected)
      for all eyes and all ages preoperatively was -1.422 + 0.085 x 35.85. At 6 months,
      it was -0.620 + 0.190 x 14.2. There was little difference between right and left
      eyes. Patients older than 80 years had greater induced astigmatism. CONCLUSION:
      This study provides evidence that making a supero-oblique clear corneal
      phacoemulsification incision while sitting in the more natural superior position
      does not induce a clinically important amount of oblique astigmatism.

PMID- 10404371
TI  - Comparison of the effects of viscoelastic agents on clinical properties of the
      Unfolder lens injection system.
AB  - PURPOSE: To evaluate the effect of 7 viscoelastic materials on the physical
      properties of the Unfolder lens injection system. SETTING: John A. Moran Eye
      Center, University of Utah School of Medicine, Salt Lake City, Utah, USA.
      METHODS: New sterile SI-40NB intraocular lenses (IOLs) were loaded into the
      Unfolder (AMO PhacoFlex II SofTip insertion system (Allergan) using 7
      viscoelastic materials: sodium hyaluronate 1.0% (Healon, Provisc), sodium
      hyaluronate 1.4% (Healon GV), sodium hyaluronate 1.6% (Amvisc Plus),
      hydroxypropyl methylcellulose 2.0% (Occucoat), sodium chondroitin 4.0%--sodium
      hyaluronate 3.0% (Viscoat), and hyaluronate 3.0% (Vitrax). The IOLs were then
      injected after 10 or 120 seconds in the chamber (chamber dwell time) and 10, 60,
      or 180 seconds in the barrel of the Unfolder cartridge (barrel dwell time).
      Torque values (g/cm) required to extrude the lenses were measured with a torque
      gauge, and the cartridges and IOLs were inspected for damage. RESULTS: Longer
      chamber dwell times resulted in lower torque values to extrude the IOLs (P <
      .001). Conversely, longer barrel dwell times resulted in higher torque
      requirements for IOL extrusion (P < .001). Furthermore, rates of adverse events,
      such as nondelivery, IOL damage, or Unfolder cartridge damage, were higher with
      shorter chamber dwell times and longer barrel dwell times (P < .001). However,
      IOL damage was avoided when the manufacturer's recommended chamber and barrel
      times were used. CONCLUSION: Increasing chamber dwell time and decreasing barrel
      dwell time resulted in lower torque values to extrude IOLs from the Unfolder and
      increased successful use. Moreover, dispersive viscoelastic agents tended to be
      more forgiving of changing dwell times and therefore had lower torque values and
      adverse event rates overall.

PMID- 10404372
TI  - Final clear corneal incision size for AcrySof intraocular lenses.
AB  - PURPOSE: To evaluate clear corneal incision size variation in phacoemulsification
      surgery after the implantation of 2 models of AcrySof intraocular lenses (IOLs).
      SETTING: Departamento de Oftalmologia, Clinica Universitaria de Navarra,
      Universidad de Navarra, Pamplona, Spain. METHODS: This prospective study
      comprised 108 eyes that had phacoemulsification and implantation of an Acrysof
      IOL model MA60BM (56 eyes) or MA30BA (52 eyes). Wound incision size was
      quantified using the Nordan incision size measurer. The incision size for each
      IOL model was evaluated before and after implantation and its relationship with
      the complications during implantation analyzed. RESULTS: Mean incision size
      varied from 3.7 mm +/- 0.14 (SD) before implantation to 3.9 +/- 0.11 mm after
      implantation for the MA60BM model (P = .001) and from 3.3 +/- 0.15 mm to 3.4 +/-
      0.13 mm for the MA30BA model (P = .001). Intraoperative complications occurred in
      14 eyes, and difficulty during IOL implantation, in 23 eyes. There was no
      association between final incision size and complications. CONCLUSIONS: Incision
      size increased after the implantation of the 2 AcrySof IOL models used in this
      study. Modifications to model MA30BA have led to an average decrease in wound
      size of 0.5 mm with respect to the MA60BM model. Most difficulties encountered
      were attributable to improper IOL unfolding.

PMID- 10404374
TI  - Small incision nucleus capture: results of 200 cases.
AB  - PURPOSE: To compare the learning curve in a series of 200 cataract surgeries
      performed using small incision nucleus capture with that of phacoemulsification
      as reported in the literature. SETTING: Department of Ophthalmology, University
      of Genoa, Genoa, Italy. METHODS: Two hundred eyes of 163 consecutive patients
      with cataract had small incision nucleus capture, a relatively new cataract
      surgery technique that allows small incisions and in-the-bag intraocular lens
      implantation. Patients were divided into 4 groups of 50 each according to when
      they had surgery between August 1996 and October 1997. The incidence of
      intraoperative complications (capsule break with or without vitreous loss,
      capsulorhexis tears, Descemet's detachment, transient iris damage) and
      postoperative complications (raised intraocular pressure, corneal epithelial
      edema, Descemet's folds, and permanent iris damage) were evaluated at the
      different time points. Also recorded was final visual acuity. These results were
      compared with those obtained with phacoemulsification. RESULTS: The study
      comprised 92 women and 71 men with an age range of 41 to 93 years. Overall final
      results showed that the learning curve of nucleus capture is comparable to that
      of phacoemulsification. CONCLUSION: Nucleus capture cataract extraction resulted
      in a low incidence of complications and good visual recovery that was comparable
      to that obtained with phacoemulsification.

PMID- 10404373
TI  - Effect of small incision cataract surgery on ocular blood flow in cataract
      patients.
AB  - PURPOSE: To evaluate the effect of small incision cataract surgery using
      peribulbar anesthesia on ocular blood flow in patients with senile cataract.
      SETTING: Department of Ophthalmology, University of Vienna, Vienna, Austria.
      METHODS: In 33 eyes of 33 consecutive patients scheduled for cataract surgery,
      ocular hemodynamics were measured preoperatively and 1 day, 1 week, and 1 month
      postoperatively. Measurements included fundus pulsation amplitude (FPA) with a
      laser interferometric method that assessed the pulsatile choroidal blood flow,
      mean blood flow velocity (MFV), and resistive index (RI) in the ophthalmic artery
      (OA) and the central retinal artery (CRA) with Doppler sonography. Systemic
      hemodynamics and intraocular pressure (IOP) also were measured. RESULTS: The FPA,
      MFV, and RI in the OA and the CRA did not change postoperatively from baseline
      values. Systemic hemodynamics, IOP, and as a consequence ocular perfusion
      pressure, also remained unchanged. CONCLUSION: Uneventful small incision cataract
      surgery using peribulbar anesthesia did not affect ocular blood flow in patients
      with senile cataract between 1 day and 1 month postoperatively.

PMID- 10404375
TI  - Toxicity of topical anesthetic agents to human keratocytes in vivo.
AB  - PURPOSE: To test the potential toxicity on human keratocytes of topical
      anesthetic agents used after photorefractive keratectomy (PRK) to reduce or
      eliminate pain. SETTING: Department of Ophthalmology, Doheny Eye Institute,
      University of Southern California, Los Angeles, California, USA. METHODS:
      Cultured human keratocytes were incubated with commercially available tetracaine
      and proparacaine at reduced concentrations of 0.001%, 0.01%, 0.1%, and 0.25%.
      Evaluations were performed by phase-contrast microscopy and tetrazolium salt
      colorimetric assay every 2 hours for 12 hours after adding 1 of the anesthetic
      agents to the media. RESULTS: After time of incubation and concentration were
      adjusted, both drugs reduced overall cell viability; however, tetracaine produced
      a larger decrease in cell viability than proparacaine (P = .008). For both drugs,
      significant differences were found among concentrations for and across time (P <
      .001 and P = .004, respectively). CONCLUSION: Both tetracaine and proparacaine
      had toxic effects on stromal keratocytes related not only to drug concentrations
      but also to time exposure. These findings underscore the widespread concern that
      anesthetic drugs may affect corneal stromal wound healing after PRK.

PMID- 10404376
TI  - Vitreous opacification after neodymium:YAG posterior capsulotomy.
AB  - PURPOSE: To describe the clinical picture in eyes that developed vitreous
      opacification behind the intraocular lens (IOL) after neodymium:YAG (Nd:YAG)
      laser posterior capsulotomy and determine whether this type of opacification
      tends to occur in patients with diabetes. SETTING: Shinjo Eye Clinic, Miyazaki,
      Japan. METHODS: The clinical course in 728 eyes that had Nd:YAG posterior
      capsulotomy was reviewed. RESULTS: After Nd:YAG posterior capsulotomy,
      opacification developed in the vitreous in contact with the IOL in 9 eyes (1.2%).
      All occurred in diabetic patients, and the vitreous opacification developed
      within 1 month after the capsulotomy. A vitrectomy was performed in 8 eyes and in
      1, the opacification spontaneously absorbed. Vitreous opacification occurred in
      8.9% of 101 eyes of diabetic patients, and the prevalence in diabetic eyes was
      significantly higher than in nondiabetic eyes (P < .0001). Nine of the diabetic
      eyes were opaque and 92 nonopaque. In the opaque eyes, the prevalence of
      panretinal photocoagulation was higher than in the nonopaque eyes (P = .013), and
      hemoglobin Alc (P = .030) was higher; the interval between cataract surgery and
      Nd:YAG capsulotomy was shorter (P = .047) and the final visual acuity, lower (P =
      .045). CONCLUSION: The prevalence of vitreous opacification after Nd:YAG laser
      posterior capsulotomy was significantly higher in diabetic than in nondiabetic
      eyes. Viterectomy was effective for this type of opacification.

PMID- 10404377
TI  - Complications of phacoemulsification on the first postoperative day: can follow
      up be safely changed?
AB  - PURPOSE: To establish the rate of complications detected on the first
      postoperative day and therefore the need for evaluation on that day. SETTING:
      Hinchingbrooke Hospital, Huntingdon, England. METHODS: Complications detected on
      the first day after phacoemulsification cataract surgery were retrospectively
      reviewed over 8 months. Ophthalmic nurse practitioners performed the 1 day
      postoperative examination and kept a log of patients seen, recording
      complications detected and whether referral to a physician was required. All
      patients had had routine phacoemulsification with intraocular lens implantation
      without anterior vitrectomy or trabeculectomy, as identified from the log book
      and cross-checked with operating theater records. Notes were reviewed if a
      complication or referral was recorded. Most cases were performed under local
      anesthesia as day cases using a temporal corneal approach. Sections were
      routinely left unsutured unless enlarged or closure was not satisfactory at the
      conclusion of surgery. RESULTS: The review yielded 392 patients. Six (1.53%) had
      intraocular pressure (> or = 30 mm Hg) requiring treatment, 1 (0.26%) had
      painless iris prolapse, 11 (2.81%) had corneal abrasions, and 7 (1.78%) were
      given a more intensive steroid regime. No cases of fibrinous uveitis were
      recorded. CONCLUSIONS: Potentially sight-threatening complications present on the
      first postoperative day, albeit infrequently. With our current practice and case
      mix, the need for this review persists. It is possible to reduce the demand on
      physician time by using appropriately trained nonmedical practitioners.

PMID- 10404378
TI  - Evaluating cataract surgery gains by assessing patients' quality of life using
      the VF-7.
AB  - PURPOSE: To describe the development and performance of a questionnaire designed
      to measure functional impairment caused by cataract. SETTING: Department of
      Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland. METHODS:
      The results of a visual-functioning index (VF-14) of 168 patients with first-eye
      cataract surgery were analyzed. Patients with significant comorbidity were
      excluded, leaving 142 patients for the final analysis. Snellen visual acuity
      measurements and complete preoperative and 4 month postoperative clinical status
      were performed by ophthalmologists. Outcome measures, including the VF-14,
      patient perception of trouble with vision, patient satisfaction with vision, and
      the cataract symptom score, were taken by nurses at the preoperative clinical
      examinations and at the 4 month postoperative visit. The Spearman rank
      correlation was used to determine which items of the VF-14 best correlated with a
      change in patient satisfaction. RESULTS: Seven items of the VF-14 that best
      correlated with patient satisfaction were selected for inclusion in a new 7-item
      index (the VF-7). Based on the Spearman rank correlation, the items from best to
      worst were nighttime driving; reading small print; watching television; seeing
      steps, stairs, or curbs; reading traffic, street, or store signs; cooking; and
      doing fine handwork. The correlation among changes in the VF-7 score and visual
      acuity in the operated eye was 0.17, while the correlation among changes in the
      VF-7 and patient satisfaction caused by cataract surgery was high (r = .56).
      CONCLUSION: The VF-7 was a strong predictor of change in patient satisfaction
      caused by cataract surgery.

PMID- 10404379
TI  - Observations on the optical effects of a cataract.
AB  - PURPOSE: To describe and measure the optical effects seen by a person with a
      cataract and to use these observations to deduce physical changes in the
      crystalline lens caused by the cataract formation. SETTING: Humphrey Systems,
      Dublin, California, USA. METHODS: Caustic patterns created on the retina by a
      bright point source of white light as that source is viewed at various far-point
      distances ranging from the anterior focal point of the eye to +15.00 diopters
      were observed. The subtended retinal angle of a diffractive ring of light created
      by a small bright source of white light was observed and measured. RESULTS: Three
      optical effects were seen and measured: multiple-image formation at certain far
      point positions; a diffractive light ring surrounding small bright sources; a
      radial needle of bright light surrounding a small bright-white source. With a
      point source of light positioned at the anterior focal point of the eye, the Y
      sutures of the lens could be visualized. With the point source at other
      distances, characteristic caustic patterns could be visualized, allowing
      assessment of the lens' optical character. The subtended retinal angle of the
      diffractive ring was measured so the periodic lens structure could be evaluated.
      CONCLUSIONS: The lens acted refractively as if it were divided into 3 elements
      with noncoincident optical axes. These 3 segments were associated with areas
      defined by the Y sutures, causing 3 images to be formed at certain distances. The
      caustic patterns indicate that each segment is slightly toroidal with axes at
      about 120 degrees apart combined with overcorrected spherical aberration. The
      period structure creating the diffractive ring had a period of 10 microns,
      approximately the width of a cortical lens cell, indicating that fluid between
      the cells likely creates a diffractive phase grating.

PMID- 10404380
TI  - Culture-negative ulcerative keratitis after laser in situ keratomileusis.
AB  - A 40-year old man, highly myopic in both eyes, had laser in situ keratomileusis
      (LASIK) in the left eye in November 1996. Corneal melting and ulceration and fine
      striae-like interface infiltrates were noticed 1 day postoperatively. There was
      no response to intensive topical antibiotics in the form of hourly ofloxacin 3%
      (Tarivid), and satellite lesions developed on day 4. Corneal scrapings for gram
      stain and culture were done twice. No bacterial or fungal organisms were
      identified. Intensive topical fortified vancomycin (50 mg/mL) was added, and the
      lesions resolved gradually over the ensuing 2 weeks. Eighteen months after LASIK,
      refraction was -1.50 - 0.75 x 105 in the left eye, and uncorrected visual acuity
      was 20/70, correctable to 20/25 with spectacles.

PMID- 10404381
TI  - Interface fluid associated with diffuse lamellar keratitis and epithelial
      ingrowth after laser in situ keratomileusis.
AB  - We report a case in which diffuse interface keratitis began 1 week after
      bilateral uneventful laser in situ keratomileusis (LASIK). A layer of fluid in
      the interface with epithelial ingrowth was noted in the left eye 20 days
      postoperatively. The same complication occurred in the right eye 5 months after
      LASIK. Dry-eye syndrome and steroid-induced intraocular pressure elevation
      occurred in this patient with pre-existing ocular hypertension. A long course of
      interface inflammation was resistant to topical steroids. Surgical removal of the
      epithelial ingrowth and drainage of the fluid, combined with medical treatment,
      resulted in resolution of the inflammation. The cytopathologic examination of the
      fluid showed epithelial cells without signs of inflammation. The clinical
      features of this case represent a new complication of LASIK.

PMID- 10404383
TI  - Bilateral microcornea and unilateral macrophthalmia resulting in incorrect
      intraocular lens selection.
AB  - A 79-year-old man with symmetrical microcornea and a dense unilateral nuclear
      sclerotic cataract had cataract extraction by phacoemulsification. The SRK/T
      formula suggested a 10.0 diopter (D) intraocular lens (IOL) for emmetropia (axial
      length 26.58 mm). The non-cataract eye required a 25.0 D IOL for emmetropia
      (axial length 21.51 mm). Biometric measurements were rechecked, and an 18.0 D IOL
      was implanted (axial length 24.02 mm). The 6 week postoperative refraction of 
      13.0 + 2.0 x 25 necessitated IOL exchange (10.0 D). Six weeks postexchange, the
      refraction was -3.75 + 2.5 x 30. This illustrates that symmetrical anterior
      microphthalmos does not always coexist with symmetrical posterior microphthalmos.
      Awareness of the association of symmetrical microcornea and unilateral
      colobomatous macrophthalmia may aid appropriate IOL selection in future cases.

PMID- 10404382
TI  - Complete capsulorhexis opening occlusion despite capsular tension ring
      implantation.
AB  - An 89-year-old woman and an 86-year-old woman had continuous curvilinear
      capsulorhexis, phacoemulsification, and implantation of a silicone plate-haptic
      intraocular lens. Because of presumed weak zonules (high age, pseudoexfoliation),
      a poly(methyl methacrylate) capsular tension ring was also implanted. Despite
      this, both patients reported deterioration in visual acuity that was the result
      of complete occlusion of the anterior capsule opening by fibrotic tissue 4 and 3
      months postoperatively, respectively.

PMID- 10404384
TI  - Accumulation of milky fluid: a late complication of cataract surgery.
AB  - We describe 3 patients who presented with an accumulation of homogeneous milky
      fluid in the capsular bag several years after continuous curvilinear
      capsulorhexis, phacoemulsification, and posterior chamber intraocular lens (IOL)
      implantation. In each case, the entire edge of the anterior capsule opening was
      tightly attached to the peripheral IOL optic. The milky fluid was present in the
      closed chamber between the IOL optic and the posterior capsule. The fluid was
      sampled in 2 patients, and its concentration of sodium hyaluronate was determined
      by high-performance liquid chromatography. The concentration of sodium
      hyaluronate resembled that in normal aqueous humor. In 1 case, the protein
      concentration was measured and found to be elevated. Electrophoresis showed that
      human serum albumin was the main protein constituent. While the outcome was
      favorable in all 3 patients, this delayed complication of cataract surgery merits
      further study to clarify its etiology and pathogenesis.

PMID- 10404385
TI  - Reassembling proteins and chaperones in human nuclear matrix protein fractions.
AB  - To detect putative filament forming components, nuclear matrix proteins were
      searched for proteins extensively reassembling from urea solution. Eight
      proteins, ubiquitously occurring in various human cell types, but not apparent in
      the cytosol, were registered by means of two-dimensional gel electrophoresis.
      They consisted of a protein exhibiting a novel amino acid sequence; of nuclear
      lamin B2, RbAp46, and RbAp48; and of four as yet unknown proteins. Furthermore,
      partial sequencing, mass spectrometry, and immunodetection of proteins
      demonstrated the presence of molecular chaperones and protein folding catalysts
      in the nuclear matrix fractions. In addition to a TCP-1-related protein, certain
      members of the heat shock, PDI, and calreticulin family of proteins were
      detected. On the basis of the absence of several other heat shock proteins in the
      nuclear matrix fraction, a general contamination by cytoplasmic chaperones
      appears unlikely.

PMID- 10404386
TI  - Cell cycle-dependent nuclear location of the matricellular protein SPARC:
      association with the nuclear matrix.
AB  - Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein
      that inhibits cellular adhesion and proliferation. In this study, we report the
      detection of SPARC in the interphase nuclei of embryonic chicken cells in vivo.
      Differential partitioning of SPARC was also noted in the cytoplasm of these cells
      during discrete stages of M-phase: cells in metaphase and anaphase exhibited
      strong cytoplasmic immunoreactivity, whereas cells in telophase were devoid of
      labeling. Immunocytochemical analysis of embryonic chicken cells in vitro
      likewise showed the presence of SPARC in the nucleus. Furthermore, elution of
      soluble proteins and DNA from these cells indicated that SPARC might be a
      component of the nuclear matrix. We subsequently examined cultured bovine aortic
      endothelial cells, which initially appeared to express SPARC only in the
      cytoplasm. However, after elution of soluble proteins and chromatin, we also
      detected SPARC in the nuclear matrix of these cells. Embryonic chicken cells
      incubated with recombinant SPARC were seen to take up the protein and to
      translocate it to the nucleus progressively over a period of 17 h. These
      observations provide new information about SPARC, generally recognized as a
      secreted glycoprotein that mediates interactions between cells and components of
      the extracellular matrix. The evidence presented in this study indicates that
      SPARC might subserve analogous functions in the nuclear matrix.

PMID- 10404387
TI  - Monoclonal antibody specific to a subclass of polyproline-Arg motif provides
      evidence for the presence of an snRNA-free spliceosomal Sm protein complex in
      vivo: implications for molecular interactions involving proline-rich sequences of
      Sm B/B' proteins.
AB  - The human spliceosomal Sm B/B' proteins are essential for the biogenesis of the
      snRNP particles. B/B' proteins contain several clusters of the PPPPGM/IR
      sequence, which occurs within the C-terminus of Sm B/B'. This sequence is very
      similar to the PPPPPGHR sequence of the cytoplasmic tail of the CD2 receptor and
      closely resembles the class II of SH3 ligands, suggesting a similarly important
      role. We report that a monoclonal antibody (3E10) against the PPPPPGHR sequence
      recognizes spliceosomal Sm B/B' proteins. Proteins that are specifically
      immunoprecipitated by 3E10 include Sm B, B', D1, D2, D3, E, F, and G. However,
      unlike Y12 and other anti-Sm immunoprecipitates, 3E10 immunoprecipitates appear
      to lack the U1 snRNP-specific proteins A and C and U snRNAs. These findings
      indicate that 3E10 recognizes a subset of Sm protein core and suggest the
      presence of snRNA-free Sm protein complex(es) in vivo. We propose that the
      epitope binding for 3E10 may become unaccessible upon interactions of Sm proteins
      and their subsequent incorporation into the core particles. The Sm proline-rich
      sequences may have an important role in mediating protein-protein interactions
      necessary for the proper snRNP core assembly or function, or both. To our
      knowledge, 3E10 is the first well characterized mAb specific for a subclass of
      polyproline-arg motif recognizing Sm B/B' and CD2 proteins. 3E10 antibody can be
      used to further characterize the nature of protein components in the snRNA-free
      Sm subcore protein complex(es) that are formed during the snRNP core assembly
      steps.

PMID- 10404388
TI  - Interaction of plasma lipoprotein subfractions with differentiating 3T3-L1 and
      human mammary preadipocytes in culture.
AB  - Differentiating 3T3-L1 preadipocytes (murine fatty fibroblasts) and human
      preadipocytes interact with human lipoprotein subfractions (HDL2 and LDLII/III)
      at all stages of the differentiation program, displaying saturable binding
      behavior. Both cell types interact similarly with LDLII/III as differentiation
      proceeds, showing increased binding affinities and capacities and maximal rates
      of uptake in the mature cells, as compared with the preadipocyte stage. These
      changes coincide with the intracellular appearance of lipid droplets. However,
      with regard to HDL2, a markedly different pattern of interaction is evident in
      both cell types. For 3T3-L1 cells, lowered binding and uptake affinities and
      capacities are apparent in the fully differentiated state for HDL2, as compared
      with LDLII/III. Human preadipocytes displayed two distinct affinity binding sites
      for HDL2 during the early stages of differentiation (days 2 and 3), as compared
      with a single affinity site for LDLII/III at all stages. However, in the fully
      differentiated human cells, only a single affinity site, indistinguishable from
      the high-affinity site present on day 2, is evident, and probably represents the
      only binding site of physiological significance in these cells. All the cellular
      developments appear to be largely unaffected by exposure of both preadipocyte
      types to added lipoproteins (HDL + LDL) in the medium during the early stages of
      the conversion process.

PMID- 10404389
TI  - Upregulation of the RAS-GTPase activating protein (GAP)-binding protein (G3BP) in
      proliferating RPE cells.
AB  - Cultured human retinal pigment epithelial (RPE) cells of different passages (P0
      and P3) were used as a model system to examine changes in gene expression in
      proliferating RPE cells by polymerase chain reaction (PCR)-based differential
      expressed mRNA analysis (DEmRNA-PCR). DEmRNA-PCR showed enhanced expression of a
      specific RNA in P3 compared with P0. Sequence alignment displayed its identity
      with the 3'-end of the coding sequence of the human RAS-GTPase activating protein
      (GAP)-binding protein (G3BP). Confirmation of the induced expression of G3BP was
      performed by gene-specific reverse transcription-polymerase chain reaction (RT
      PCR) of freshly prepared human RPE cells and of cultured cells of P0, P3 and P8
      and by immunohistochemistry of cultivated retinal pigment epithelial cells in an
      artificial lesion assay. The expression of G3BP mRNA increased with the number of
      passages. G3BP protein expression increased in cells repopulating the artificial
      lesion. DEmRNA-PCR in RPE cells with subsequent sequence analysis led to the
      characterization of dedifferentiation- and proliferation-dependent expression of
      a previously undetected gene product in cultured RPE cells with a possible role
      in modifying signal transduction responses that may have implications on the
      treatment of proliferative vitreoretinopathy.

PMID- 10404390
TI  - Developmental changes in isoform expression of Ca2+/calmodulin-dependent protein
      kinase II delta-subunit in rat heart.
AB  - In the heart, Ca2+/calmodulin-dependent protein kinase II is critically involved
      in the regulation of Ca2+ homeostasis. Previously the predominant expression of a
      subclass of Ca2+/calmodulin-dependent protein kinase II delta-subunit, containing
      a second variable domain, was demonstrated in cardiac tissue. Here we report on
      the expression pattern of the non-neuronal members of this delta-subunit
      subclass, delta 2, delta 3, delta 4, and delta 9 in the developing heart of the
      rat. By semiquantitative RT-PCR isoform delta 3 was shown to be typically
      expressed in the heart, whereas delta 4 was expressed in skeletal muscle of adult
      rat. From embryonic day 14 up to the adult state of rat ventricular muscle,
      amounts of delta 9 transcripts remained unchanged, transcript levels of isoforms
      delta 2 and delta 3 were significantly increased, whereas level of delta 4
      transcript was significantly decreased. Immunoblotting, using an antibody
      recognizing specifically those delta-isoforms containing the second variable
      domain, revealed three separated protein signals at about 59 kDa, 58 kDa, and 56
      kDa. The immunoreaction at about 59 kDa, corresponding to the predicted molecular
      mass of delta 4, was dramatically diminished, whereas a significant increase in
      the signal at about 58 kDa was assumed to represent an increase in isoform delta
      3. The protein signal at about 56 kDa, close to the predicted molecular mass of
      isoform delta 2, was high in the embryonic heart and significantly decreased
      after birth. Our data suggest the predominant expression of isoform delta 2 in
      the embryonic heart, establish delta 3 to be the typical isoform in the adult
      heart and define the skeletal muscle form delta 4 to be characteristic for fetal
      and neonatal stages of the heart.

PMID- 10404392
TI  - DNA bending is induced by binding of vitamin D receptor-retinoid X receptor
      heterodimers to vitamin D response elements.
AB  - The ability of vitamin D receptor-retinoid X receptor (VDR-RXR) heterodimers to
      induce a DNA bend upon binding to various vitamin D response elements (VDRE) has
      been investigated by circular permutation and phasing analysis. Recombinant rat
      VDR expressed in the baculovirus system and purified recombinant human RXR beta
      have been used. The VDREs were from 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3)
      enhanced genes (rat osteocalcin, rOC; mouse osteopontin, mOP, and rat 1,25
      dihydroxyvitamin D3-24-hydroxylase, r24-OHase), and a 1,25-(OH)2D3 repressed gene
      (human parathyroid hormone, hPTH). As shown by circular permutation analysis, VDR
      RXR induced a distortion in DNA fragments containing various VDREs. Calculated
      distortion angles were similar in magnitude (57 degrees, 56 degrees, 61 degrees,
      and 59 degrees, respectively for rOC, mOP, r24-Ohase, and hPTH). The distortions
      took place with or without a 1,25-(OH)2D3 ligand. The centers of the apparent
      bend were found in the vicinity of the midpoint of all VDREs, except for rOC VDRE
      which was found 4 bp upstream. Phasing analysis was performed with DNA fragments
      containing mOP VDRE and revealed that VDR-RXR heterodimers induced a directed
      bend of 26 degrees, not influenced by the presence of hormone. In this study we
      report that similar to other members of the steroid and thyroid nuclear receptor
      superfamily, VDR-RXR heterodimers induce DNA bending.

PMID- 10404391
TI  - Induction of transcription factor interferon regulatory factor-1 by interferon
      gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) in FRTL-5 cells.
AB  - While it is well known that interferon-gamma (IFN gamma) and tumor necrosis
      factor-alpha (TNF alpha) play a role in the regulation of thyroid growth and
      differentiated functions, the cellular and molecular mechanisms involved in
      mediating the effects of IFN gamma and TNF alpha on thyroid function are unknown.
      In the present study, we used FRTL-5 rat thyroid cells to examine the effects of
      IFN gamma and TNF alpha on gene expression of transcription factor interferon
      regulatory factor-1 (IRF-1), which is involved in mediating the effects of these
      cytokines in a number of cell types. Northern blot analysis of FRTL-5 mRNA showed
      a single IRF-1 mRNA at 2.2 Kb. In quiescent FRTL-5 cells, IRF-1 mRNA levels were
      low but detectable by Northern analysis. Incubation of FRTL-5 cells with IFN
      gamma or TNF alpha resulted in a dose- and time-dependent increase in IRF-1 mRNA
      levels. We have shown that TNF-alpha and IFN-gamma act synergistically to block
      the TSH-induced increase in type I 5'-deiodinase(5'D-I) activity and 5'D-I gene
      expression in FRTL-5 rat thyroid cells. Incubation of FRTL-5 cells with IFN gamma
      and TNF alpha in combination, however, did not synergistically increase IRF-1
      mRNA levels. Electrophoretic mobility shift assay (EMSA) revealed that IFN gamma
      induced the formation of a single complex to a IFN gamma activation site (GAS)
      probe in a dose dependent manner. Several lines of evidence suggest that TNF
      alpha activates transcription factor nuclear factor-kappa B (NF kappa B) through
      activation of protein kinase C (PKC) or the hydrolysis of sphingomyelin to
      ceramide in a number of cell types. Here we demonstrate that hydrolysis of
      sphingomyelin to ceramide by sphingomyelinase (SMase), but not activation of PKC
      by 12-O-tetradecanoylphorbol 13-acetate (TPA), was involved in the activation of
      NF kappa B in FRTL-5 cells. Similarly, hydrolysis of sphingomyelin to ceramide,
      but not activation of PKC, resulted in an increased in IRF-1 mRNA levels in FRTL
      5 cells. The present data demonstrate that IFN gamma and TNF alpha increase IRF-1
      mRNA levels in FRTL-5 cells through activation of GAS and NF kappa B binding
      proteins, respectively. Thus, our results suggest that upregulation of IRF-1 may
      play a role in mediating the effects of IFN gamma and TNF alpha on thyroid
      function. Our results also suggest that the induction of IRF-1 mRNA by IFN gamma
      and TNF alpha is not the cellular mechanism involved in the synergistic effect of
      these cytokines on thyroid function.

PMID- 10404393
TI  - Centrosome and microtubule instability in aging Drosophila cells.
AB  - Several cytoskeletal changes are associated with aging which includes alterations
      in muscle structure leading to muscular atrophy, and weakening of the microtubule
      network which affects cellular secretion and maintenance of cell shape. Weakening
      of the microtubule network during meiosis in aging oocytes can result in
      aneuploidy or trisomic zygotes with increasing maternal age. Imbalances of
      cytoskeletal organization can lead to disease such as Alzheimer's, muscular
      disorders, and cancer. Because many cytoskeletal diseases are related to age we
      investigated the effects of aging on microtubule organization in cell cultures of
      the Drosophila cell model system (Schneider S-1 and Kc23 cell lines). This cell
      model is increasingly being used as an alternative system to mammalian cell
      cultures. Drosophila cells are amenable to genetic manipulations and can be used
      to identify and manipulate genes which are involved in the aging processes.
      Immunofluorescence, scanning, and transmission electron microscopy were employed
      for the analysis of microtubule organizing centers (centrosomes) and microtubules
      at various times after subculturing cells in fresh medium. Our results reveal
      that centrosomes and the microtubule network becomes significantly affected in
      aging cells after 5 days of subculture. At 5-14 days of subculture, 1% abnormal
      out of 3% mitoses were noted which were clearly distinguishable from freshly
      subcultured control cells in which 3% of cells undergo normal mitosis with
      bipolar configurations. Microtubules are also affected in the midbody during cell
      division. The midbody in aging cells becomes up to 10 times longer when compared
      with midbodies in freshly subcultured cells. During interphase, microtubules are
      often disrupted and disorganized, which may indicate improper function related to
      transport of cell organelles along microtubules. These results are likely to help
      explain some cytoskeletal disorders and diseases related to aging.

PMID- 10404394
TI  - Sodium butyrate-mediated induction of the glycoprotein hormone alpha-subunit
      gene: requirement for continued protein synthesis, identification of a butyrate
      responsive element, and inhibition of promoter activation by 2-deoxyglucose.
AB  - Production of the glycoprotein hormone alpha-subunit (GPH alpha) was enhanced by
      sodium butyrate (Btr) in HeLa cells. Induction of the HeLa alpha-subunit gene by
      Btr was inhibited by the simultaneous addition of cycloheximide (CHX), indicating
      a requirement for continued protein synthesis. Transient expression assays using
      plasmids containing the GPH alpha gene promoter fused to the chloramphenicol
      acetyltransferase (CAT) reporter gene demonstrated that the GPH alpha promoter is
      inducible by Btr in HeLa cells, and this induction could be prevented by 2
      deoxyglucose (dGlc). CAT production driven by the SV-40 early promoter, the
      cytochrome P-450-IA1 promoter, and the Rous sarcoma virus long terminal repeat
      was also enhanced by Btr, but the augmented synthesis was not inhibited by the
      addition of dGlc, demonstrating that the effect is restricted only to some
      promoters. CAT synthesis could be induced by Btr when the GPH alpha promoter
      extended upstream to position -169 (relative to the transcription start site at
      +1) but not when the promoter terminated at -150, classifying the DNA between
      these termini as a Btr-responsive element (BRE). This region overlaps the
      composite trophoblast-specific enhancer. Inactivation of enhancer subdomains by
      site-directed mutagenesis confirmed the deletion analysis and ranked their
      response to Btr as CRE < TSE < URE < alpha ACT. Electrophoretic mobility shift
      analysis failed to detect any significant difference among several enhancer
      binding proteins in nuclear extracts from untreated and Btr-treated cells.
      Together, these results suggest that Btr-mediated induction of the alpha-subunit
      gene in HeLa cells is manifest either through the synthesis of a new
      transcription factor(s), which is inhibited by CHX but required for increased
      transcription from the GPH alpha gene promoter, or through the activity of
      existing factors that may require glycosylation or phosphorylation by a
      modification system that is inducible by Btr and inhibited by dGlc and CHX. These
      results further suggest that the factor is not an enhancer-binding protein or
      that Btr increases its transactivation potential without altering its DNA-binding
      activity.

PMID- 10404395
TI  - Human skin fibroblasts express m2, m4, and m5 subtypes of muscarinic
      acetylcholine receptors.
AB  - Previous studies have demonstrated that muscarinic acetylcholine receptors
      (mAChRs) are expressed by human skin fibroblasts (HSF). We have identified the
      molecular subtypes of these receptors by reverse transcription-polymerase chain
      reaction (RT-PCR), using m1-m5 subtype-specific primers. These experiments showed
      that only mRNAs for m2, m4, and m5 mAChR subtypes are present in HSF. The RT-PCR
      products were characterized by restriction analysis and Southern blotting.
      Northern blot analysis showed the presence of m2 and m4 mAChR RNA. Rabbit
      antibodies were raised using a synthetic peptide as immunogen corresponding to
      the C-terminus of the m2 protein and were used to visualize fibroblast mAChRs.
      Cell membranes of HSF in cell culture and specimens of normal human skin had a
      unique staining pattern specific for anti-m2 antibody, as well as for antibodies
      against m4 and m5. In Western blots of fibroblast proteins, the antibodies
      visualized the m2 receptor at 65 kDa, m4 at 70 kDa, and m5 at 95 kDa. The
      function of fibroblast mAChRs was examined by measuring muscarinic effects on
      intracellular free Ca2+ concentration ([Ca2+]i). Muscarine increased transiently
      [Ca2+]i in cultured HSF. This effect could be abolished by the muscarinic
      antagonist atropine. Thus, the results of this study showed that HSF express m2,
      m4, and m5 mAChR subtypes, and that fibroblast mAChRs are coupled to the
      regulation of [Ca2+]i.

PMID- 10404396
TI  - Ethanol inhibits prolactin-induced activation of the JAK/STAT pathway in cultured
      astrocytes.
AB  - Alcohol consumption has multiple effects in the central nervous system (CNS).
      Whereas, alcohol is an immunosuppressive drug the effect of alcohol on the
      neuroimmune system, remains unclear. In cultured astrocytes, prolactin (PRL)
      induces mitogenesis and the expression of inflammatory cytokines, including tumor
      necrosis factor-alpha (TNF alpha). We have recently shown that whereas ethanol
      does not inhibit PRL receptor binding, it markedly inhibits PRL-induced
      mitogenesis and TNF alpha secretion in cultured astrocytes. It is clear that PRL
      activates the tyrosine phosphorylation of several proteins, including members of
      a novel family of protein tyrosine kinases, the Janus Kinases (JAKs). The aims of
      this study were to characterize PRL-induced activation of the JAK/STAT (signal
      transducers and activators of transcription) pathway, and to determine if ethanol
      affects JAK/STAT activation in cultured astrocytes. We found that PRL
      specifically increases the tyrosine phosphorylation of JAK2, but not JAK1, JAK3,
      or Tyk2, and the subsequent phosphorylation of STAT1 alpha, STAT5a, and STAT5b.
      Preincubation of astrocytes with ethanol markedly inhibited phosphorylation of
      JAK2, STAT1 alpha, STAT5a, and STAT5b. In PRL-stimulated astrocytes, ethanol
      inhibited binding of nuclear proteins to oligonucleotides corresponding to the
      gamma-interferon activated sequence (GAS). Further, ethanol blocked PRL-induced
      increases in interferon regulatory factor-1 (IRF-1) mRNA, a PRL/cytokine
      inducible transcription factor involved in the regulation of a number of cytokine
      inducible genes. The inhibition of tyrosine phosphorylation by ethanol was not a
      general effect, however, as we found that ethanol increased basal and NGF-induced
      tyrosine phosphorylation of extracellular signal-activated protein kinase-1 (ERK
      1). These data indicate that ethanol inhibits PRL-induced tyrosine
      phosphorylation of the JAK/STAT pathway resulting in decreased nuclear GAS DNA
      binding and inhibition of the PRL inducible gene, IRF-1. Thus, suggesting that
      ethanol-induced inhibition of JAK2 phosphorylation may be one mechanism though
      which ethanol could after the brain's response to injury or infection.

PMID- 10404397
TI  - Evidence on the participation of protein kinase C alpha in the proliferation of
      cultured myoblasts.
AB  - There is evidence involving protein kinase C (PKC) in the signal transduction
      pathways that regulate the differentiation of myoblasts into mature
      multinucleated muscle cells (myotubes). In order to obtain information on the
      possible role of individual PKC isozymes in myogenesis, in the present work we
      investigated the differential expression of PKC isoforms alpha, beta, delta,
      epsilon, and zeta during muscle cell development in vitro. Chick embryo myoblasts
      cultured from 1 to 6 days were used as experimental model. Morphological
      characterization and measurement of specific biochemical parameters in cultures,
      e.g., DNA synthesis, creatine kinase activity, and myosin levels, revealed a
      typical muscle cell developmental pattern consisting of an initial proliferation
      of myoblasts followed by their differentiation into myotubes. PKC activity was
      high at the proliferation stage, decreased as myoblasts elongated and fused, and
      increased again in differentiated myotubes. In proliferating myoblasts, the PKC
      inhibitors calphostin C and bisindolylmaleimide I decreased DNA synthesis whereas
      in myoblasts undergoing differentiation they exerted the opposite effect,
      suggesting that PKC plays a role at both stages of myogenesis. Western blot
      analysis of changes in the expression of PKC isoforms during muscle cell
      development showed high levels of PKC alpha in the proliferating phase which
      markedly decreased as myoblasts differentiated. Treatment with TPA of
      proliferative myoblasts inhibited DNA synthesis and selectively down-regulated
      PKC alpha, suggesting that this isozyme may have an important role in maintaining
      myoblast proliferation. On the other hand, an increase in the expression of PKC
      beta, delta, and epsilon was detected during myogenesis, suggesting that one or
      more of these isoforms may participate in the differentiation process of
      myoblasts.

PMID- 10404398
TI  - Aggregation of Dictyostelium discoideum is dependent on myristoylation and
      membrane localization of the G protein alpha-subunit, G alpha 2.
AB  - The heterotrimeric G protein, G2, from the eukaryotic organism Dictyostelium
      discoideum participates in signal transduction pathways which are essential to
      Dictyostelium's developmental life cycle. G2 is activated by cell surface cAMP
      receptors and in turn is required for the activation of a host of effectors,
      including adenylyl cyclase, guanylyl cyclase, and phospholipase C. Myristoylation
      of G protein alpha-subunits is known to affect alpha-subunit association with the
      beta gamma subunits and membrane localization. The putative site for N-terminal
      myristoylation of G alpha 2 was mutated from Gly to Ala (G2A) and expressed in
      the g alpha 2-null cell line, MYC2. Transformants expressing G alpha 2-G2A
      exhibit physiological and biochemical changes from wild-type cells. G alpha 2-G2A
      expressing cells fail to rescue the aggregation-minus phenotype of MYC2 cells on
      developmental agar plates. G alpha 2-G2A expressing cells are also not
      chemotactic to cAMP in a standard drop assay. G alpha 2-WT is found in both the
      pellet and supernatant fractions following lysis of the cells. G alpha 2-G2A
      however is found almost exclusively in the lysate supernatant. G alpha 2 is
      radiolabeled upon incubation of cells in [3H]myristate, while G alpha 2-G2A is
      not labeled. Examination of activation of the effectors adenylyl cyclase and
      guanylyl cyclase reveals that G alpha 2-G2A expressing cells partially activate
      adenylyl cyclase but show no cAMP-stimulation of guanylyl cyclase. The
      physiological deviations from wild-type can be explained by the variations in
      effector activation, possibly due to improper localization of the non
      myristoylated G alpha 2-G2A to the cytosol.

PMID- 10404399
TI  - Superantigens in human disease.
AB  - Superantigens have been implicated in a wide variety of human diseases. Yet,
      solid evidence for their role in pathogenesis is available only for Toxic Shock
      Syndrome and a few other conditions. This evidence is critically reviewed herein.

PMID- 10404400
TI  - Natural autoantibody to galectin-9 in normal human sera.
AB  - Antibodies to certain self-antigens are detected in normal individuals as well as
      in patients with autoimmune diseases. Natural autoantibodies found in normal
      human sera are thought to act as an immune regulator, a functional controller of
      specific proteins, or the first-line defense against pathogenic microorganisms.
      In the course of screening human pancreatic islet cDNA library with human sera,
      we found that autoantibodies to galectin-9 and its unique isoform are present in
      normal healthy individuals. Galectin-9 antibody was detected in all 44 human sera
      tested by the immunoprecipitation assays, suggesting a widespread presence of
      galectin-9 autoantibodies in humans. The reactivity of the sera to galectin-9 was
      not inhibited by lactose or endoglycosidase treatment, indicating that the
      reactivity was not due to a nonspecific lectin-carbohydrate interaction. We also
      demonstrated by RT-PCR that galectin-9 and its isoform are expressed in a variety
      of human tissues such as pancreatic islets, liver, lung, and tonsils as well as
      HeLa and Jurkat cell lines. Thus, although it has been reported previously that
      human galectin-9 is expressed mainly in immune cells and tissues, the current
      work suggests that the expression of galectin-9 and its isoform is not tissue
      restricted and natural autoantibodies against them are present in normal human
      sera. The significance of these autoantibodies needs to be studied further.

PMID- 10404401
TI  - Centrosome proteins: a major class of autoantigens in scleroderma.
AB  - Autoantibodies to intracellular antigens are a hallmark of autoimmune diseases,
      although their role in disease pathogenesis is unclear. Centrosomes are
      organelles involved in the organization of the mitotic spindle and they are
      targets of autoantibodies in systemic sclerosis (SSc). We used recombinant
      centrosome autoantigens, centrosome-specific antibodies, and immunoassays to
      demonstrate that a significant proportion of SSc patients exhibited centrosome
      reactivity. Two centrosome proteins cloned in our laboratory were used to screen
      129 SSc sera by Western blotting. The same sera were screened by
      immunofluorescence using centrosome-specific antibodies to distinguish
      centrosomes from nuclear speckles commonly stained by SSc sera. Using these
      criteria, 42.6% of SSc patients were autoreactive to centrosomes, a larger
      percentage than reacted with all other known SSc autoantigens. Most centrosome
      positive sera reacted with both centrosome proteins and half were negative for
      other routinely assayed SSc autoantibodies. By these criteria, we have identified
      a novel class of SSc autoreactivity. Only a small percentage of normal
      individuals and patients with other connective tissue diseases had centrosome
      reactivity. These results demonstrate that centrosome autoantibodies are a major
      component of autoreactivity in SSc and thus have potential in disease diagnosis.
      Centrosome autoantigens may be useful in studying the development of
      autoantibodies and chronic inflammation in SSc and perhaps other autoimmune
      diseases.

PMID- 10404402
TI  - Diet modulates Th-1 and Th-2 cytokine production in the peripheral blood of lupus
      prone mice.
AB  - Calorie restriction or fish oil extends life span. To investigate the potential
      mechanism(s) involved, young (4-month) and old (9-month) NZB x NZW(F1) mice were
      fed 5% (w/w) corn oil (CA) or fish oil (FA) ad libitum or 40% restricted (CR and
      FR, respectively). Peripheral blood T-lymphocytes were analyzed for Th-1 (IL-2,
      IFN-gamma) and Th-2 (IL-5, IL-10) production. CR and FA partially blunted while
      FR completely abolished the decline in aged CD4+ T lymphocytes. In contrast, both
      CR and FR abolished the decline in CD8+ T lymphocytes with age, while FA had no
      effect. In aged mice, both CR and FR blunted the increase in Th-1 (IL-2, IFN
      gamma) cytokine production, while FA was only partially effective. Only FR
      completely blunted the age-related increase in Th-2 (IL-5, IL-10) cytokine
      production. These data suggest that FR delays the onset of autoimmune kidney
      disease by suppressing both Th-1 and Th-2 cytokine production.

PMID- 10404403
TI  - Flow cytometric analysis of in vitro proinflammatory cytokine secretion in
      peripheral blood from multiple sclerosis patients.
AB  - The cytokines, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF
      alpha), and interleukin-2 (IL-2) are important endogenous proinflammatory
      proteins and have been linked to disease activity in multiple sclerosis. In this
      study, we use flow cytometric methodology to compare the secretion of IFN-gamma,
      IL-2, and TNF-alpha from peripheral blood-derived T cells of multiple sclerosis
      patients to the secretion in healthy controls. The percentages of IFN-gamma, IL
      2, and TNF-alpha secreting cells are not significantly different between multiple
      sclerosis patients and controls. However, the TNF-alpha secreting CD3 cell
      percentage is correlated with the IFN-gamma and IL-2 secreting CD3 cell
      percentages in multiple sclerosis patients. In the controls, only the TNF-alpha
      secreting CD3 cell percentage is correlated with IFN-gamma. These findings show
      that correlated secretion of cytokines occurs in multiple sclerosis and suggest
      that concerted intercytokine interactions may play an important role in the
      disease.

PMID- 10404404
TI  - Identification of an adhesion molecule expressed on adult T cell leukemia cells
      derived from a patient with gastrointestinal involvement: implication for a
      possible role of integrin beta 7 in leukemic cell infiltration into intestinal
      mucosa.
AB  - Patients with adult T cell leukemia (ATL) often manifest leukemic cell
      infiltration into various organs such as lung, liver, skin, and gut. To analyze
      the mechanism of intestinal infiltration of ATL cells, we made mAbs against ATL
      43T, a human T cell line derived from an ATL patient with severe intestinal
      mucosal infiltration. One of the mAbs, named H920, was noted for a high and
      relatively specific reactivity with ATL-43T. Molecular cloning was done to
      identify this molecule and disclosed that the Ag molecule was identical to
      integrin beta 7. Since integrin beta 7 and its ligand MAdCAM-1 had been reported
      to mediate homing of lymphocytes to endothelial cells in intestinal mucosa, we
      next examined wither ATL-43T cells could adhere to MAdCAM-1+ cells. Human MAdCAM
      1 transfectants of MMCE, a mouse epithelial cell line, were made and used to
      evaluate cell adhesion mediated by integrin beta 7 and MAdCAM-1. Considerable
      levels of cell adhesion were observed between ATL-43T and the transfectant cells,
      which was inhibited by H920 mAb in a dose-dependent manner. Furthermore,
      peripheral blood leukemic cells or lymphoma cells from 10 ATL patients were
      examined for expression of integrin beta 7 with regard to organ involvement.
      Samples from three patients with gastrointestinal tract involvement showed
      considerably higher expression of integrin beta 7. These results suggest that
      integrin beta 7 may play a role in adhesion and subsequent infiltration of a
      certain type of ATL cells into intestinal mucosa.

PMID- 10404405
TI  - Medial prefrontal cortices are unified by common connections with superior
      temporal cortices and distinguished by input from memory-related areas in the
      rhesus monkey.
AB  - Medial prefrontal cortices in primates have been associated with emotion, memory,
      and complex cognitive processes. Here we investigated whether the pattern of
      cortical connections could indicate whether the medial prefrontal cortex
      constitutes a homogeneous region, or if it can be parceled into distinct sectors.
      Projections from medial temporal memory-related cortices subdivided medial
      cortices into different sectors, by targeting preferentially caudal medial areas
      (area 24, caudal 32 and 25), to a lesser extent rostral medial areas (rostral
      area 32, areas 14 and 10), and sparsely area 9. Area 9 was distinguished by its
      strong connections with premotor cortices. Projections from unimodal sensory
      cortices reached preferentially specific medial cortices, including a projection
      from visual cortices to area 32/24, from somatosensory cortices to area 9, and
      from olfactory cortices to area 14. Medial cortices were robustly interconnected,
      suggesting that local circuits are important in the neural processing in this
      region. Medial prefrontal cortices were unified by bidirectional connections with
      superior temporal cortices, including auditory areas. Auditory pathways may have
      a role in the specialization of medial prefrontal cortices in species-specific
      communication in non-human primates and language functions in humans.

PMID- 10404406
TI  - Effects of aging and axotomy on the expression of neurotrophin receptors in
      primary sensory neurons.
AB  - Aging is accompanied by declined sensory perception, paralleled by widespread
      dystrophic and degenerative changes in both central and peripheral sensory
      pathways. Several lines of evidence indicate that neurotrophic interactions are
      of importance for a maintained plasticity in the adult and aging nervous system,
      and that changes in the expression of neurotrophins and/or their receptors may
      underpin senile neurodegeneration. We have here examined the expression of
      neurotrophin receptor (p75NTR, trkA, trkB, and trkC) mRNA and protein in intact
      and axotomized primary sensory neurons of young adult (3 months) and aged (30
      months) rats. To examine possible differences among primary sensory neuron
      populations, we have studied trigeminal ganglia (TG) as well as cervical and
      lumbar dorsal root ganglia (DRG). In intact aged rats, a decrease in trk (A/B/C)
      mRNA labeling densities and protein-like immunoreactivities was observed. The
      decrease was most pronounced in lumbar DRG. In contrast, a small, not
      statistically significant, increase of p75NTR expression was observed in aged DRG
      neuron profiles. After axotomy, a down-regulation of mRNA and protein levels was
      observed for all neurotrophin receptors (p75NTR, trkA, trkB and trkC) in both
      young adult and aged rats. Consistent with the higher expression levels of
      neurotrophin receptors in unlesioned young adult primary sensory neurons, the
      relative effect of axotomy was more pronounced in the young adult than aged rats.
      Although a decrease in mean cell profile cross-sectional areas was found during
      aging and after axotomy, the characteristic distribution of neurotrophin receptor
      expression in different populations of NRG neurons was conserved. The present
      findings suggest an attenuation of neurotrophic signaling in primary sensory
      neurons with advancing age and that the expression of p75NTR and trks is
      regulated differently during aging. A similar dissociation of p75NTR and trk
      regulation has previously been reported in other neuronal systems during aging,
      suggesting that there may be a common underlying mechanism. Decreased access to
      ligands, disturbed axon function and systemic changes in androgen/estrogen levels
      are discussed as inducing and/or contributing factors.

PMID- 10404407
TI  - NADPH diaphorase histochemistry in the thoracic ganglia of locusts, crickets, and
      cockroaches: species differences and the impact of fixation.
AB  - The NADPH diaphorase (NADPHd) reaction is widely used as a histochemical marker
      for nitric oxide synthase (NOS). In this study on locusts, crickets, and
      cockroaches, we demonstrate 1) that related species can differ considerably in
      the fixation sensitivity of putatively NOS-related NADPHd; and 2) that prolonged
      fixation can induce NADPHd activity in cells that are diaphorase negative under
      mild fixation regimes. These two phenomena reconcile previous, contradictory
      reports on the distribution of NADPHd in locusts and crickets. In locusts,
      neuronal NADPHd is found exclusively in interneurones. The projection neuropiles
      of the exteroceptors contain a dense NADPHd-positive fibre meshwork, but sensory
      afferents do not stain. In crickets, staining has been reported in sensory
      afferents, in motor neurones and dorsal unpaired median (DUM) neurones, and in a
      non-fibrous distribution throughout the sensory neuropiles. We demonstrate that
      this widespread, non-selective staining is induced by strong formaldehyde
      fixation. Weak fixation resulted in a highly selective labelling of a few
      individual interneurones and of a fibre meshwork in the projection neuropiles of
      the exteroceptive afferents. Staining was absent in the afferents themselves, in
      motor neurones, and in efferent DUM neurones. Thus, after weak fixation, the
      staining pattern closely matched that in the locust. The similar distribution of
      putatively NOS-related NADPHd in the thoracic nervous systems of orthopteroid
      insects suggests a species-independent role for nitric oxide in the processing of
      mechanosensory information. Histopharmacological techniques such as permanganate
      oxidation, or incubation in the NOS inhibitors methylene blue or
      dichlorophenolindophenol, did not allow discrimination between the selective and
      the fixation-induced staining. The species-specific impact of different fixation
      regimes may necessitate reconsideration of results obtained in other cross
      species comparisons.

PMID- 10404408
TI  - Quantitative analysis of neuronal nitric oxide synthase-immunoreactive neurons in
      the mouse hippocampus with optical disector.
AB  - A detailed quantitative analysis of immunocytochemically identified nonprincipal
      neurons containing neuronal nitric oxide synthase (nNOS) was performed on the
      mouse hippocampus, with particular reference to the dorsoventral gradient. The
      present study applied two variations of a stereologic technique, the optical
      disector--one that used confocal laser-scanning microscope optical sections to
      examine colocalization of nNOS and glutamic acid decarboxylase 67 (GAD67), and
      the other that used conventional thick sections to examine numerical densities
      (NDs) and cell sizes of nNOS-immunoreactive (IR) neurons. Colocalization analysis
      indicated that practically all nNOS-IR neurons (97.6%) were GAD67-IR, whereas a
      part of the GAD67-IR neurons (about 30%) were nNOS-IR in the whole hippocampus at
      both dorsal and ventral levels. The percentages of GAD67-IR neurons containing
      nNOS were higher in the dentate gyrus (DG, about 50%), and lower in the Ammon's
      horn (about 20%). Laminar analysis revealed that the majority of GAD67-IR neurons
      contained nNOS in the stratum lacunosum-moleculare of the CA3 region (about 60%)
      and in the molecular layer of the DG (about 80%). The NDs of nNOS-IR neurons in
      the whole hippocampus showed a dorsoventral gradient, which increased from dorsal
      (1.6 x 10(3)/mm3) to ventral (2.2 x 10(3)/mm3) levels. The NDs were relatively
      higher in the principal cell layers, where about 40% of nNOS-IR neurons were
      situated both in the Ammon's horn and DG. The mean cell sizes of nNOS-IR neurons
      showed no remarkable laminar differences or dorsoventral gradient in the Ammon's
      horn, but they were extensively larger in the hilus of the DG than in other
      layers. These results indicate that nNOS-IR neurons in the mouse hippocampus
      represent a subpopulation of gamma-aminobutyric acid (GABA)ergic neurons and
      suggest that the laminar distributions of nNOS-IR neurons related to possible
      functional heterogeneity of GABAergic neurons in each hippocampal layer.

PMID- 10404409
TI  - Morphology of single pontine reticulospinal axons in the lumbar enlargement of
      the cat: a study using the anterograde tracer PHA-L.
AB  - The fine morphology of single pontine reticulospinal axons in the lumbar
      enlargement was investigated by using an anterograde Phaseolus vulgaris
      leucoagglutinin (PHA-L) tracing technique. Localized injections of PHA-L were
      made into the nuclei reticularis pontis oralis and caudalis in four cats.
      Following survival periods of 8-9 weeks, PHA-L-labeled axons were found
      throughout the lumbar enlargement from segments L4 to S2, in which the diameter
      of labeled axons was 0.6-2.5 microns. From serial transverse sections (50
      microns), trajectories of 21 single pontine reticulospinal axons were traced in
      continuity over distances of 18.9-36.3 mm, corresponding to three to six
      segments, respectively. All the identified axons gave off multiple (two to nine)
      axon collaterals along their courses, with mean intercollateral distances of
      approximately 5-6 mm. Detailed reconstruction of the collateral arborization in
      the lumbar enlargement showed a high degree of similarity to that of single axons
      in the cervical enlargement previously reported (Matsuyama et al. [1997] J. Comp.
      Neurol. 377:234-250). First, axon collaterals arising from a majority (n = 18) of
      identified axons innervated the gray matter unilaterally, ipsilateral to the
      parent axons, whereas those from the remaining three axons innervated the gray
      matter bilaterally. Second, collateral projections terminated mainly in laminae
      VIII and VII, with the arborization field confined to a narrow rostrocaudal
      extent (< 1 mm). Third, the termination fields of axon collaterals arising from a
      given reticulospinal axon were similar at each segmental level and differed from
      one stem axon to another. These results suggest that the long descending pontine
      reticulospinal pathway is composed of different types of axons that may innervate
      the cervical and lumbar enlargements in continuity in a similar manner.

PMID- 10404410
TI  - Location of muscarinic type 2 receptors within the synaptic circuitry of the cat
      visual thalamus.
AB  - A cholinergic projection from the parabrachial region (PBR) of the brainstem to
      the visual thalamus has been studied in great detail during the past 20 years. A
      number of physiological studies have demonstrated that this projection causes a
      dramatic change in thalamic activity during the transition from sleep to
      wakefulness. Additionally, the PBR may mediate more subtle changes in thalamic
      activity as attentional levels fluctuate during the waking state. The synaptic
      circuitry underlying these events has been identified in the cat thalamus.
      However, there is currently no anatomical information regarding the distribution
      of cholinergic receptors in relation to this circuitry. To begin to understand
      how the PBR projection modulates thalamic activity, we used immunocytochemical
      techniques to examine the distribution of muscarinic type 2 (M2) receptors in the
      visual thalamus of the cat. The distribution of M2 receptors correlates well with
      previous reports of the distribution of cholinergic terminals in the visual
      thalamus. At the light microscopic level, dense M2 staining was seen in the
      neuropil of the dorsal lateral geniculate nucleus (dLGN) and pulvinar nucleus and
      in somata and proximal dendrites of cells in the thalamic reticular nucleus
      (TRN). In the dLGN and pulvinar nucleus, we quantitatively analyzed the
      distribution of M2 receptors using electron microscopy. Postembedding
      immunocytochemistry for gamma aminobutyric acid (GABA) was used to determine
      whether M2 receptors are present on interneurons or thalamocortical cells. In
      particular, we examined the distribution of M2 receptors with respect to the
      known sites of PBR terminations. The dendrites of both thalamocortical cells and
      interneurons were stained for the M2 receptors in both the glomerular and
      extraglomerular neuropil. However, the densest staining was found in glomerular
      GABAergic profiles that displayed the morphology associated with interneuron
      dendritic terminals (F2 profiles). Our data suggest that M2 receptors play an
      important role both in blocking thalamic spindle oscillations and in increasing
      the efficacy of signal transmission during increased attentional states.

PMID- 10404412
TI  - Spatiotemporal gradients of differentiation of chick retina types I and II
      cholinergic cells: identification of a common postmitotic cell population.
AB  - The chick retina has three types of cholinergic amacrine cells. We have found
      that Types I and II differentiate from a common population of postmitotic cells
      temporarily located in the inner plexiform layer (IPL cells). Golgi staining and
      immunocytochemistry for choline acetyltransferase (ChAT) and gamma-aminobutyric
      acid (GABA) were used to trace the development and fate of IPL cells.
      Transformation of the shape of IPL cells into those typical of both conventional
      amacrine cells and those displaced to the ganglion cell layer are seen. All IPL
      cells are doubly immunoreactive, for ChAT and GABA, from the time they appear as
      a cell population within the inner plexiform layer (IPL) until their separation
      into the two amacrine cell populations. Polarization and early stages of shape
      differentiation of both types occur while they are in the IPL, starting in the
      dorsocentral area in the temporal retina and spreading to the rest of the retina.
      Three spatial gradients of differentiation are observed: from central-to
      peripheral, dorsal-to-ventral, and temporal-to-nasal retina. Our findings suggest
      that the fate of both types of cells in the chick is determined locally, whereas
      their postmitotic precursors are within the IPL. The presence of GABA and
      acetylcholine in both types of amacrine cells at early stages of their
      morphogenesis, well before they have synaptic interactions, suggests a
      morphogenetic role for these molecules in inner retinal differentiation.

PMID- 10404411
TI  - Mechanosensory pegs constitute stridulatory files in grasshoppers.
AB  - Stridulatory files on the inner face of hindleg femora were shown to consist of
      mechanosensory pegs in males and females of Syrbula montezuma (Saussure) and in
      males of Chorthippus biguttulus (L.). Females of Chorthippus had stiff
      protuberances on their stridulatory files, with an innervated tubercle instead of
      pegs. Pegs and tubercles of adult grasshoppers were shown to develop from
      innervated tubercular hairs present from the first instar onward in Chorthippus.
      In adults of Chorthippus, two sensory cells innervated each peg of males and each
      tubercle of females. Central projections of these afferents from the stridulatory
      files were very similar to those of the neighboring tactile hairs on the femur.
      The afferents from pegs in Syrbula responded to deflection and pressure
      introduced via the widened cuticular cap. In both species, selective stimulation
      of femoral cuticular receptors elicited antagonistic reflex responses in a coxal
      retractor muscle: pegs inhibited and neighboring hairs raised the efferent tonic
      discharges. Apparently, in these two distantly related grasshopper species,
      stridulatory files function as both sound-producing and proprioceptive organs.

PMID- 10404413
TI  - Projections from striate and extrastriate visual cortices of the cat to the
      reticular thalamic nucleus.
AB  - We have studied the pattern of connectivity of the visual cortical areas 17, 18,
      19, 20a, 21a, posteromedial lateral (PMLS), and the posterolateral lateral (PLLS)
      suprasylvian areas with the reticular thalamic nucleus (RTN) of the cat ventral
      thalamus. Three cortical areas per hemisphere were injected iontophoretically
      with either 4% wheat germ agglutinin-horseradish peroxidase, 4% dextran
      fluororuby, or 4% dextran-biotin. The visual field representations of the
      injection sites were determined by reference to previously published visuotopic
      maps of the cortex. The locations of labelled fibres, presumed terminals and cell
      bodies were determined with the aid of a camera lucida attachment and computer
      aided stereometry. In the ventral thalamus, the primary visual cortices (areas 17
      and 18) project in a topographic manner to both the perigeniculate nucleus (PGN)
      and the RTN. By contrast, the "higher" visual cortical areas (areas 19, 21a, 20a,
      PMLS, and PLLS) project only to the RTN. Our experiments demonstrate the
      existence of a single, albeit coarse, visuotopic map within the RTN but do not
      support the notion of separate subregions within the RTN that can be related
      specifically to a particular visual cortical area. The putative single visuotopic
      map in the RTN appears to be organised in such a way that the vertical meridians
      are represented along the rostrocaudal axis of the RTN, whereas the horizontal
      meridians are mapped within the dorsoventral axis of the nucleus. The upper
      visual field is represented within regions of the RTN adjacent to the caudal part
      of the dorsal lateral geniculate nucleus (LGNd), whereas the lower visual field
      is represented in the parts of the RTN rostral to the LGNd. The map also shows a
      ventrodorsal shift along the rostrocaudal axis of the RTN such that in the
      rostral RTN the representation of vertical meridian is placed more ventrally than
      that in the caudal part of the nucleus.

PMID- 10404414
TI  - Mucosa of the guinea pig gastric corpus is innervated by myenteric neurones with
      specific neurochemical coding and projection preferences.
AB  - The present study identified and characterised myenteric neurones involved in the
      innervation of the gastric mucosa. We applied retrograde neuronal tracing methods
      by using the dye DiI (1,1'-didodecyl-3,3,3',3'-tetramethylindocarbocyanine
      perchlorat) in combination with the immunohistochemical demonstration of choline
      acetyltransferase (ChAT), enkephalin (ENK), neuropeptide Y (NPY), nitric oxide
      synthase (NOS), substance P (SP), and vasoactive intestinal peptide (VIP). This
      method showed distinct neurochemical coding of DiI-labelled neurones with
      projections to the mucosa (mucosa neurones): ChAT/- (indicating the presence of
      ChAT only, 32%), ChAT/NPY/ +/- VIP (22%), NOS/NPY/ +/- VIP (19%), ChAT/SP/ +/-
      ENK (12%), NOS/- (indicating the presence of NOS only, 8%), or ChAT/ENK (4.6%).
      DiI-labelled mucosa neurones did not contain calretinin, serotonin, or
      somatostatin. All ChAT population had primarily ascending projections, whereas
      the NOS populations had mainly descending projections. Both were further
      classified as longitudinally and circumferentially projecting neurones, the
      latter having projection preferences towards the lesser or greater curvature. All
      subpopulations exhibited projection preferences. Nitrergic projections primarily
      arose from cell bodies located at the lesser curvature. ChAT/- projections, which
      dominated the cholinergic pathway, mainly arose from cell bodies located at the
      greater curvature. The other major cholinergic pathway with the code ChAT/NPY/ +/
      VIP consisted of neurones located mainly at the lesser curvature. The results
      suggest specific coding of gastric myenteric neurones with projections to the
      mucosa. Polarised projections consisted of ascending cholinergic and descending
      nitrergic neurones; the additional presence of NPY/VIP was a prominent feature in
      both pathways. Chemical coding, polarity, and projection preferences of enteric
      pathways to the gastric mucosa are remarkably different from those of other
      regions in the gut.

PMID- 10404415
TI  - Temporal and spacial relationships between PSA-NCAM-expressing, newly generated
      granule cells, and radial glia-like cells in the adult dentate gyrus.
AB  - The granule cell layer of the adult dentate gyrus possesses two characteristics
      of an immature nervous system. The first is that granule cells continue to be
      generated in the innermost region of the granule cell layer, and newly generated
      and developing granule cells in the adult express highly polysialylated neural
      cell adhesion molecule (PSA-NCAM). PSA-NCAM-expressing apical dendrites have
      dynamically unstable processes such as irregular shafts and many stick-like or
      fan-shaped fine processes. The second is that radial glia-like cells expressing
      glial fibrillary acidic protein (GFAP) remain in a similar region of the granular
      layer. The numbers of PSA-NCAM-expressing granule cells and GFAP-expressing
      radial glia-like cells show a parallel age-dependent decrease during aging.
      Moreover, by using confocal laser scanning microscopy and immunoelectron
      microscopy, we demonstrated that PSA-NCAM-expressing dendrites and GFAP
      expressing radial processes are partly in contact with each other, and
      occasionally the radial glial processes envelop the PSA-NCAM-positive dendritic
      processes. The temporal and spatial relationship between the two immature
      elements suggests that the processes of the radial glia-like cells are closely
      associated with the dendritic growth of the newly generated granule cells in the
      adult dentate gyrus and that these two immature features of neurons and glia in
      the dentate gyrus diminish with age.

PMID- 10404416
TI  - Ethnopharmacobotanical studies of the Tuscan Archipelago.
AB  - From an ethno-pharmacobotanical point of view, Tuscany is a region with very rich
      and interesting traditions. The Tuscan Archipelago, particularly due to its
      geographical position and its history, presents a large variety of plant species
      used in popular medicine in numerous pathologies, including several viral
      infections. Over 100 species of plants are used in popular medicine in this
      region.

PMID- 10404417
TI  - Ocular toxicity of Afromomum melegueta (alligator pepper) on healthy Igbos of
      Nigeria.
AB  - Afromomum melegueta is an ubiquitous specie of the family Zingiberaecea. It is a
      very popular spice used mainly as food, in brewing, and in veterinary and
      traditional medicines. The effect of acute consumption of A. melegueta seeds on
      some visual parameters was studied with a view to determining the adverse ocular
      effects. Results showed that bolus consumption of 0.35 g of A. melegueta seeds by
      10 healthy male Igbos age 30-35 and body weight 60-68 kg increased the near point
      of convergence (NPC) by 17.2% and reduced the amplitude of accommodation (AA) by
      9.2% without affecting the pupil size and the visual acuity. The increased NPC
      leads to doubling of vision while the reduction or loss of accommodation would
      lead to blurring of vision both synergising to impair vision at least
      transiently. Non-specific mechanism of action or papaverine-like activity is
      suggested.

PMID- 10404418
TI  - Insects and other arthropods used as drugs in Korean traditional medicine.
AB  - Insects and other arthropods appear in pharmacopoeias of Korean traditional
      medicine, but little was known about their use in modern South Korea. Interviews
      were conducted with 20 traditional medicine doctors at clinics in South Korea's
      Kyeong Dong Shijang in Seoul--one of the world's largest traditional drug markets
      -to learn about current patterns of usage. Seventeen products are prescribed and
      the use of arthropod drugs is stable or increasing. Centipedes (Scolopendra spp.)
      used primarily to treat arthritis and the silk moth fungus (Beauveria bassiana,
      which infects silk moth larvae) used mostly to treat stroke, are the most
      frequently prescribed and medically important arthropod drugs. Most of the
      arthropod drugs were traditionally collected or reared on the Korean Peninsula,
      but now they are imported, mainly from China. Folk logic appears to be the basis
      for some arthropod drug uses (i.e. centipedes, which have many legs, are used for
      leg problems). But many of the arthropods have venom and other defensive
      chemicals which are biologically active. The South Korean use of arthropods as
      drugs (as well as for food and enjoyment) is due, in part, to more positive
      attitudes towards these animals compared to many cultures. Arthropods appear to
      be an unexplored and unexploited source of drugs for modern medicine.

PMID- 10404419
TI  - Antiulcer action of Microgramma squamulosa (Kaulf.) Sota.
AB  - Microgramma squamulosa (Kaulf.) Sota (Polypodiaceae) is commonly used as an
      antiulcer agent in the state of Sao Paulo, mainly in the upper land. The present
      work aims to study the antiulcer action of the crude extract of the plant rhizome
      and its toxicity. The effective dose was determined through acute ulcer induction
      test by stress. Using a determined dose, we performed a test against ulcer
      through acute induction by ethanol and hydrochloric acid, using cimetidine and
      misoprostol as reference drugs in both tests. The same extract, its ethanol and
      ethanol + water (1:1) fractions and the reference drug cimetidine were tested
      through subchronic induction test with acetic acid. The subchronic toxicity test
      was performed using a dose of 800 mg/kg of the crude extract, orally administered
      for 30 days. Finally the extracts and fractions were analysed in order to
      determine the main chemical groups of substances.

PMID- 10404420
TI  - Healing with animals in Feira de Santana City, Bahia, Brazil.
AB  - This paper discusses the use of animals prescribed as medicines by herbalists
      from Feira de Santana city in the State of Bahia, Northeastern Brazil. Data were
      obtained by undergraduates of the Biology course of Feira de Santana State
      University, who performed open interviews with herbalists at Centro de
      Abastecimento, the main local market. The medicinally used faunistic resources
      are echinoderms, arthropods, fish, reptiles, birds and mammals. Folk remedies are
      administered as teas, syrups or plasters. Respiratory affections predominated and
      fat was the most common zootherapeutic. It was observed that some of the useful
      species are in danger of extinction. It is suggested that the rearing of these
      species in traditional farming systems will allow their conservation, while at
      the same time they will also results in people's life improvement. Traditional
      knowledge on folk medicine is to be studied in order to lead to the discovery of
      new sources of drugs.

PMID- 10404421
TI  - The effect of sour tea (Hibiscus sabdariffa) on essential hypertension.
AB  - Considering the high prevalence of hypertension, its debilitating end organ
      damage, and the side effects of chemical drugs used for its treatment, we
      conducted this experimental study to evaluate the effect of sour tea (Hibiscus
      sabdariffa) on essential hypertension. For this purpose, 31 and 23 patients with
      moderate essential hypertension were randomly assigned to an experimental and
      control group, respectively. Patients with secondary hypertension or those
      consuming more than two drugs were excluded from the study. Systolic and
      diastolic blood pressures were measured before and 15 days after the
      intervention. In the experimental group, 45% of the patients were male and 55%
      were female, and the mean age was 52.6 +/- 7.9 years. In the control group, 30%
      of the patients were male, 70% were female, and the mean age of the patients was
      51.5 +/- 10.1 years. Statistical findings showed an 11.2% lowering of the
      systolic blood pressure and a 10.7% decrease of diastolic pressure in the
      experimental group 12 days after beginning the treatment, as compared with the
      first day. The difference between the systolic blood pressures of the two groups
      was significant, as was the difference of the diastolic pressures of the two
      groups. Three days after stopping the treatment, systolic blood pressure was
      elevated by 7.9%, and diastolic pressure was elevated by 5.6% in the experimental
      and control groups. This difference between the two groups was also significant.
      This study proves the public belief and the results of in vitro studies
      concerning the effects of sour tea on lowering high blood pressure. More
      extensive studies on this subject are needed.

PMID- 10404423
TI  - Pharmacokinetics of Hoasca alkaloids in healthy humans.
AB  - N,N-Dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine (THH) are
      the characteristic alkaloids found in Amazonian sacraments known as hoasca,
      ayahuasca, and yaje. Such beverages are characterized by the presence of these
      three harmala alkaloids, where harmine and harmaline reversibly inhibit monoamine
      oxidase A (MAO-A) while tetrahydroharmine weakly inhibits the uptake of
      serotonin. Together, both actions increase central and peripheral serotonergic
      activity while facilitating the psychoactivity of DMT. Though the use of such
      'teas' has be known to western science for over 100 years, little is known of
      their pharmacokinetics. In this study, hoasca was prepared and administered in a
      ceremonial context. All four alkaloids were measured in the tea and in the plasma
      of 15 volunteers, subsequent to the ingestion of 2 ml hoasca/kg body weight,
      using gas (GC) and high pressure liquid chromatographic (HPLC) methods.
      Pharmacokinetic parameters were calculated and peak times of psychoactivity
      coincided with high alkaloid concentrations, particularly DMT which had an
      average Tmax of 107.5 +/- 32.5 min. While DMT parameters correlated with those of
      harmine, THH showed a pharmacokinetic profile relatively independent of
      harmine's.

PMID- 10404422
TI  - Antinociceptive, anti-inflammatory and antipyretic effects of ethanol extract of
      Clerodendron serratum roots in experimental animals.
AB  - The alcoholic extract (50, 100 and 200 mg/kg, p.o) of Clerodendron serratum roots
      produced a significant antinociceptive, anti-inflammatory and antipyretic
      activities in animal models. The results support the traditional claims of C.
      serratum as a remedy for pain, inflammation and fever.

PMID- 10404424
TI  - Biochemical evaluation of antitumor effect of muthu marunthu (a herbal
      formulation) on experimental fibrosarcoma in rats.
AB  - Natural products from plants are rich sources used for treating a number of
      diseases. Many of the pharmacological principles of the currently used anticancer
      agents have been initially isolated from plants. Most of the herbal drugs are a
      mixture of a number of plant ingredients. Their cumulative effect increases the
      efficacy of the drug in curing the diseases. Muthu Marunthu is a herbal
      formulation comprising of eight various plant ingredients, and has been claimed
      to possess antitumor effect. Therefore, attention has been focused on studying
      the various plant ingredients in the drug as a whole for its antitumor effects.
      It was observed that the growth rate in rats was normal and there was no change
      in blood parameters such as glucose, urea, proteins, cholesterol and also in the
      activities of pathophysiological enzymes such as lactate dehydrogenase (LDH),
      glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT),
      alkaline and acid phosphatase after Muthu Marunthu administration. The tumor
      weight was found to be reduced in methylcholanthrene induced fibrosarcoma rats
      after Muthu Marunthu treatment. Elevated levels of glycocomponents of
      glycoproteins such as hexose, hexosamine, sialic acid and fucose in plasma of
      fibrosarcoma rats decreased significantly after Muthu Marunthu treatment. The DNA
      and RNA levels of liver and kidney, which were increased in fibrosarcoma rats,
      returned to near normal levels after Muthu Marunthu treatment. The vitamins such
      as A, C and E in plasma were decreased in fibrosarcoma rats but increased
      significantly after Muthu Marunthu treatment. The altered levels of copper, zinc
      and selenium in plasma have also been corrected after Muthu Marunthu treatment.
      These observations clearly suggested the antitumor potency of Muthu Marunthu in
      experimentally induced fibrosarcoma in rats.

PMID- 10404425
TI  - Structure-activity relationship of cardiotonic flavonoids in guinea-pig papillary
      muscle.
AB  - Sixteen flavonoids were tested for a positive inotropic effect (PIE) on guinea
      pig papillary muscle paced at 0.2 Hz in a Krebs-Henseleit solution at 30 degrees
      C. The structure-activity relationship was investigated by determining both the
      pD2 value and the intrinsic activity in the case of ten flavonols, three
      flavones, one flavanone and two catechins. Quercetin showed the most potent
      intrinsic activity, and produced the strongest inotropic responses among the 16
      compounds. The relative order of potency of the tested flavonoids was quercetin >
      morin = kaempferol = HEPTA > luteolin = apigenin > natsudaidain = fisetin =
      galangin. Those that did not produce any PIE were 3-hydroxyflavone, flavone,
      glycosides of quercetin (rutin and hyperin), flavanones (naringenin) and
      catechins. With respect to the essential flavonoid nucleus for PIE development,
      the presence of a hydroxy group at C-4', an alpha, beta-unsaturated ketone on the
      C-ring and a reasonable lipophilic moiety in the molecule are required.
      Pharmacological analyses suggest that there is a common mechanism for the PIE and
      it is cyclic AMP dependent.

PMID- 10404426
TI  - Immunosuppressive activity of Achillea talagonica on humoral immune responses in
      experimental animals.
AB  - In this study the aqueous extract of Achillea talagonica consisting of a mixture
      of alkaloids, terpenoids and flavonoids was used. This genus has long been used
      in Iran for treatment of fever, skin inflammation, asthma and liver ailments.
      Effects of this plant were studied on humoral antibody responses in BALB/c mice
      and albino rabbits. Intraperitoneal administration of 0.25, 0.5, 1.0 and 2.0 g/kg
      x 7 days in mice prior to immunization with sheep red blood cells, resulted in a
      significant dose dependent decrease in haemagglutinating antibody (HA) titre. By
      decreasing the dosage, a significant decrease in HA titre was also observed. In
      rabbits after intrascapular injection of 0.5 g/kg, in primary response, a
      significant decrease in anti-HD titre was found, but no change observed in
      secondary response.

PMID- 10404427
TI  - Antioxidant activity of Tinospora cordifolia roots in experimental diabetes.
AB  - We made an attempt to study the antioxidant properties of Tinospora cordifolia
      roots, an indigenous plant used in Ayurvedic medicine in India in alloxan
      diabetic rats. Oral administration of an aqueous T. cordifolia root extract
      (TCREt) (2.5 and 5.0 g/kg) for 6 weeks resulted in a decrease in the levels of
      plasma thiobarbituric acid reactive substances, ceruloplasmin and alpha
      tocopherol in alloxan diabetic rats. The root extract also causes an increase in
      the levels of glutathione and vitamin C in alloxan diabetes. The root extract at
      a dose of 5.0 g/kg showed the highest effect. The effect of TCREt was more
      effective than glibenclamide. Insulin restored all the parameters to near normal
      levels.

PMID- 10404428
TI  - A natural flavonoid present in unripe plantain banana pulp (Musa sapientum L.
      var. paradisiaca) protects the gastric mucosa from aspirin-induced erosions.
AB  - The active anti-ulcerogenic ingredient was extracted from unripe plantain banana
      by solvent fractionation and identified by chromatography, spectroscopy and high
      performance liquid chromatography as the flavonoid leucocyanidin. Dried unripe
      plantain banana powder, the extracted leucocyanidin and a purified synthetic
      leucocyanidin demonstrated a significant (P < 0.05) protective effect against
      aspirin-induced erosions.

PMID- 10404429
TI  - Induction of cytotoxic T lymphocytes with peptides in vitro: identification of
      candidate T-cell epitopes in hepatitis B virus X antigen.
AB  - Cytotoxic T lymphocytes (CTL) have been suggested to contribute to viral
      clearance during hepatitis B virus (HBV) infection. To induce effective CTL
      against viral infection by peptide vaccination, it is essential to identify the
      epitope peptides recognized by CTL. Here, 15 peptide sequences that contain HLA
      A2.1-restricted CTL binding consensus motif were identified on hepatitis B virus
      X (HBx) protein and synthesized for further characterization. In the binding
      assay, 8 of 15 synthetic peptides enhanced the expression of HLA-A2.1 molecules
      on the surface of T2 cells, a human transport-associated antigen processing
      deficient cell line. This result implies that these eight peptides are able to
      bind to the HLA-A2.1 molecules. These peptides were further tested for their
      ability to activate CTL from peripheral blood mononuclear cells (PBMCs) isolated
      from HBV chronic carriers. Five of eight tested peptides activated PBMC-derived T
      cells, resulting in the lysis of the target T2 cells pulsed with the same
      peptide. Furthermore, the CTL responses to HBx antigen in HBV chronic carriers
      were shown to be polyclonal, multispecific, and mediated mainly by CD8+ T cells.
      In contrast, these responses were not detected in uninfected healthy blood
      donors. Although the five CTL epitope peptides identified in this study have not
      been proven to be the naturally processed epitopes in HBV-infected hepatocytes,
      they could be candidates for peptide-based immunotherapy against HBV infection.

PMID- 10404430
TI  - Antitumor immunization with a minimal peptide epitope (G9-209-2M) leads to a
      functionally heterogeneous CTL response.
AB  - The goal of experimental clinical protocols using peptide antigen for active
      vaccination and treatment of patients with metastatic cancer is to induce a
      vigorous cytotoxic T lymphocyte (CTL) response against the immunizing antigen,
      and thereby against tumor cells expressing the antigen. However, the magnitude
      and breadth of human CTL responses induced by peptide immunization, and in
      particular against antigens expressed by normal tissues as well as tumors, is not
      well characterized. This issue was examined by characterizing CTL cloids derived
      from peripheral blood mononuclear cells of three patients who received peptide
      immunization as treatment for metastatic melanoma. All patients received G9-209
      2M peptide, a modified epitope of the gp100 melanoma-associated antigen. The
      results indicated that the CTL response induced by this peptide antigen was
      highly heterogeneous both in terms of avidity toward the peptide antigen and
      recognition of tumor cell lines. Furthermore, avidity of each CTL cloid for the
      native peptide was highly predictive of tumor reactivity. These results are
      discussed in terms of their implications for peptide vaccination and adoptive
      tumor immunotherapy.

PMID- 10404431
TI  - Large-scale production of natural cytokines during activation and expansion of
      human T lymphocytes in hollow fiber bioreactor cultures.
AB  - We studied the large-scale production of a variety of natural cytokines during
      the activation and expansion of human T lymphocytes in a hollow fiber bioreactor
      culture system. Peripheral blood mononuclear cells (PBMC) were activated using
      phytohemagglutinin plus recombinant interleukin-2 (IL-2). Phytohemagglutinin was
      either present in the hollow fiber bioreactor during the entire 15-16-day culture
      period or only during the 20-h preactivation of the PBMC in culture bags. The
      expanding T lymphocytes were mainly CD3+,8+ and exerted maximal natural,
      activated, bispecific monoclonal antibody-redirected and lectin-dependent
      cytolytic activities between days 9 and 13 of culture. IL-1 and IL-4 were only
      produced in low amounts. IL-8 and lymphotoxin were primarily produced during the
      first week of culture. Harvest of the hollow fiber bioreactor culture supernatant
      at the time of peak cytokine concentration would have yielded per 10(8) PBMC
      input between 3.7 and 4.9 micrograms of IL-8 (at days 2 or 3), and between 0.02
      and 0.5 microgram of lymphotoxin (at days 6 or 7). Tumor necrosis factor-alpha
      and IL-6 were produced during the entire culture period of 15 or 16 days: per
      10(8) PBMC input, between 0.1 and 0.4 microgram of tumor necrosis factor-alpha
      (at days 2 or 3) and between 0.03 and 0.5 microgram of IL-6 (at days 15 or 16).
      Production of interferon-gamma and granulocyte-macrophage colony-stimulating
      factor started from initiation of cultures onwards to reach peak levels at the
      end of the 15- or 16-day culture period, yielding at that time between 2.1 and
      17.7 micrograms/ml of interferon-gamma and between 0.4 and 4.2 micrograms of
      granulocyte-macrophage colony-stimulating factor per 10(8) PBMC input. The
      production of tumor necrosis factor-alpha, IL-6, interferon-gamma, and
      granulocyte-macrophage colony-stimulating factor was proportional to the extent
      of lymphocyte multiplication. These results demonstrate the usefulness of hollow
      fiber bioreactor cultures to produce natural cytokines during the activation and
      expansion of predominantly CD3+,8+ T lymphocytes.

PMID- 10404432
TI  - Immunotherapy for lung metastases of murine renal cell carcinoma: synergy between
      radiation and cytokine-producing tumor vaccines.
AB  - We investigated the combination therapy of local radiation of lung metastasis and
      vaccination with autologous tumor cells that produced interleukin (IL)-2,
      interferon-gamma (IFN-gamma), and granulocyte-macrophage colony-stimulating
      factor (GM-CSF) using the mouse Renca pulmonary metastasis model. Wild-type Renca
      (W/Renca) were transfected with pEF-BOS vector incorporating cDNAs for IL-2, IFN
      gamma, or GM-CSF to express these cytokines. W/Renca, IL-2-producing Renca
      (Renca/IL-2), and IFN-gamma-producing Renca (Renca/IFN-gamma) produced
      subcutaneous tumor at the injection site in eight of eight, one of eight, and two
      of eight mice, respectively. No tumors were found in the GM-CSF-producing Renca
      (Renca/GM-CSF) group (zero of eight). Renca/IFN-gamma produced subcutaneous
      (s.c.) tumors in all Balb/c nude mice, but Renca/IL-2 and Renca/GM-CSF did not.
      To test the elicitation of antitumor activity, Balb/c mice were injected
      intravenously with 1 x 10(5) W/Renca on day 0, vaccinated, s.c., with 1 x 10(6)
      cells each of 5,000 rad preirradiated Renca/IL-2, Renca/IFN-gamma, and Renca/GM
      CSF or 3 x 10(6) cells of preirradiated W/Renca on days 1, 7, and 14, and
      radiated with 300 rad to both lungs on day 5. The animals were killed on day 21
      and tumor nodules in the lungs were enumerated. Neither local irradiation alone
      nor the combination of lung radiation and multiple vaccination with irradiated
      W/Renca significantly reduced the number of lung tumors. In contrast, the
      combination of lung radiation and the multiple vaccinations with cytokine
      producing Renca cells significantly reduced the number of lung tumors. This
      regimen was more effective than the multiple vaccinations with cytokine-producing
      Renca cells alone. These studies demonstrate the efficacy of vaccination with
      autologous tumor cells expressing these cytokines and sensitization of the tumor
      target with radiation.

PMID- 10404433
TI  - Local secretion of IFN-gamma induces an antitumor response: comparison between T
      cells plus IL-2 and IFN-gamma transfected tumor cells.
AB  - Previously we described that the adoptive transfer of tumor-infiltrating
      lymphocytes (TIL) + interleukin-2 (IL-2) leads to eradication of established
      methylcholanthrene (MCA)-105 fibrosarcoma pulmonary metastases in a congenic
      murine model. The in vivo efficacy of TIL was associated with their ability to
      secrete interferon-gamma (IFN-gamma), and to a lesser extent granulocyte
      macrophage colony-stimulating factor. The local secretion of these cytokines
      resulted in recruitment of naive host immune cells to the tumor and eventually in
      a successful host antitumor immune response. In the present study, to further
      evaluate the role of IFN-gamma in the induction of a host antitumor immune
      response, we compared the treatment efficacy of adoptively transferred T cells
      and IFN-gamma gene transfected tumor cells (MCA-105/IFN-gamma) as delivery
      systems of IFN-gamma. Treatment with TIL-IL-2 or irradiated MCA-105/IFN-gamma
      induced a similar reduction in pulmonary metastases of MCA-105 tumor. In
      contrast, irradiated wild-type MCA-105 or TIL from IFN-gamma gene knockout mice
      did not cause tumor eradication. MCA-105 tumor-bearing mice treated with MCA
      205/IFN-gamma showed a partial reduction in the number of pulmonary metastases.
      Histologically, lungs of successfully treated mice showed that initially
      activated macrophages expressing inducible nitric oxide synthase (iNOS) and
      dendritic cells infiltrated the tumor bed. Subsequently, CD4+ and CD8+ T cells
      infiltrated tumors. The therapeutic efficacy of IFN-gamma transfected tumor cells
      was eliminated when either CD4+ T cells or CD8+ T cells were depleted. These
      results suggest that local secretion of IFN-gamma induces a tumor-specific host
      antitumor immune response mediated through activated macrophages, dendritic
      cells, and tumor-specific T cells. This may be a common component of successful
      immunotherapy.

PMID- 10404434
TI  - Neuroblastoma cells expressing mature IL-18, but not proIL-18, induce a strong
      and immediate antitumor immune response.
AB  - Retroviral constructs were designed to express the novel cytokine interleukin 18
      (IL-18), also known as interferon-gamma-inducing factor, in a murine
      neuroblastoma cell line [neuro-2a (N-2a)] to examine the effects of IL-18
      expression on tumorigenicity. N-2a cells expressing proIL-18 (N-2a/IL-18p) were
      as tumorigenic as parental N-2a cells, whereas N-2a cells engineered to secrete
      mature IL-18 (N-2a/IL-18m) were nontumorigenic. Inoculation of mice with N-2a/IL
      18m generated immediate immunity to parental N-2a. N-2a/IL-18m formed tumors in
      mice depleted of CD4+ and CD8+ T cells, suggesting that the antitumor immune
      response was T cell mediated. The resulting T-helper (Th) immune response was
      also characterized in vitro and had a large Th1 component based on in vitro
      production of the cytokines IFN-gamma and granulocyte macrophage colony
      stimulating factor in response to tumor cells and IL-18.

PMID- 10404435
TI  - T cells coactivated with immobilized anti-CD3 and anti-CD28 as potential
      immunotherapy for cancer.
AB  - This report describes the generation of T cells with characteristics that may
      prove useful for the immunotherapy of cancer. Peripheral blood mononuclear cells
      obtained from healthy donors were cultured in the presence of anti-CD3/anti-CD28
      mAb-coated beads (3/28 beads) at a 3:1 bead to cell ratio. The 3/28 beads were
      removed after 14 days of culture. Optimal growth conditions for CD3/CD28
      coactivated T cells (COACTS) were determined to be X-VIVO 15 containing 5% human
      AB serum and 100 IU/ml of interleukin-2. The median fold expansion after 14 days
      was 84-fold. Flow cytometric analyses demonstrated that all cultures were > 90%
      CD3+ with an increase in the proportion of CD8+ cells. CD28 expression was
      maintained at very high levels on CD4+ cells and augmented on CD8+ cells. COACTS
      were induced to secrete high levels of Th1-type cytokines (IFN-gamma and TNF
      alpha) after a 24-h restimulation with fresh 3/28 beads and displayed nonmajor
      histocompatibility complex-restricted lytic activity against a variety of human
      tumor cell lines in standard 51Cr-release assays. Bead removal from COACT
      cultures before day 14 greatly enhanced the cell growth and cytokine production
      without significantly affecting the lytic potential. In summary, large numbers of
      T cells can be generated by coactivation with anti-CD3/anti-CD28-coated beads for
      14 days. This method may provide an advantage over current forms of cellular
      immunotherapy for cancer because of the ability of COACTS to secrete tumoricidal
      cytokines and generate antitumor cytotoxicity.

PMID- 10404436
TI  - Expression and purification of prostate-specific membrane antigen in the
      baculovirus expression system and recognition by prostate-specific membrane
      antigen-specific T cells.
AB  - Antigen-specific immunotherapy of cancer depends on a consistent source of well
      defined protein antigen. Production of recombinant protein offers the obvious
      solution to this problem but few comparisons of recombinant and native proteins
      in cellular immune assays have been reported. We report expression of a putative
      immunotherapy antigen, prostate-specific membrane antigen (PSMA), in insect cells
      using a baculovirus vector. T cells stimulated with recombinant PSMA or native
      PSMA derived from the LNCaP cell line recognized both native PSMA and
      recombinant, baculoviral PSMA. These data indicate that PSMA produced in Sf9
      cells is immunologically cross-reactive with native PSMA and therefore suitable
      for immunotherapy as it is recognized by both cellular and humoral immune
      responses.

PMID- 10404437
TI  - Brain metastasis after immunotherapy in patients with metastatic melanoma or
      renal cell cancer: is craniotomy indicated?
AB  - The purpose of this study was to evaluate the outcome of surgical treatment of
      brain metastasis in patients with metastatic melanoma or renal cell cancer after
      interleukin-2 (IL-2) therapy. A retrospective analysis was conducted at the
      Surgery Branch, National Cancer Institute. All patients with a diagnosis of
      metastatic melanoma or renal cell cancer who received IL-2 from January 1, 1985
      to January 1, 1996 (n = 1385) were screened for the development of brain
      metastasis. Forty patients underwent surgical treatment of brain metastasis that
      developed after initiating IL-2 therapy. Thirty-six were rendered free of disease
      after resection of a single metastasis and were the focus of this study. Twenty
      two of the 36 patients achieved a clinical response (10 complete responses and 12
      partial responses) at extracranial sites of disease after IL-2-based
      immunotherapy and before the development of brain metastasis. The median disease
      free interval in the brain after resection of a single metastasis was 21, 7, and
      3 months for patients achieving a complete response, partial response, and no
      response (CR, PR, and NR) to IL-2 therapy, respectively. The median survival
      after craniotomy for these three groups of patients was 23, 17, and 7 months,
      respectively. The disease-free interval in the brain and the overall survival
      after craniotomy were significantly longer for patients achieving a CR to
      previous immunotherapy when compared with patients achieving a PR or NR. Of the
      10 patients who had achieved a prior CR, 8 remained disease free in the brain at
      last follow-up, 6 remained alive beyond 1 year, and 3 > 4 years. Twenty-five
      patients experienced neurologic symptoms before craniotomy and all had complete
      resolution of their symptoms after surgery. Surgical treatment of single brain
      metastasis in patients with metastatic melanoma or renal cell cancer is indicated
      in carefully selected patients. The benefits of resection include palliation of
      symptoms and the potential for a prolonged disease-free interval in the brain.

PMID- 10404438
TI  - The modulatory impact of recombinant human interleukin-6 on the immune system of
      cancer patients.
AB  - To investigate the immunomodulatory impact of low-dose recombinant human
      interleukin-6 (rhIL-6), we examined 15 patients with metastatic renal cell
      carcinoma or malignant melanoma receiving rhIL-6 as an antitumor agent in a phase
      II trial. RhIL-6 (150 micrograms) was administered subcutaneously (s.c.) once
      daily for 42 consecutive days. Immunologic parameters were measured throughout
      therapy and at follow-up. No changes in white blood cell counts were noted.
      Lymphocyte subsets did not alter, nor did their expression of CD25 and HLA-DR.
      Immunoglobulins were unaffected. Levels of granulocyte-macrophage colony
      stimulating factor, tumor necrosis factor-alpha and IL-1 beta remained below
      detection limits. Theoretically, subtle immunologic alterations might have been
      masked by increases in plasma volume, known to occur after start of therapy.
      Using previously published data concerning plasma volume changes in these
      patients, part of immunologic data were corrected for concurrent hemodilution,
      showing a 39% +/- 17% increase in monocytes (mean change +/- SEM [standard error
      of mean]; p < 0.03) within 1 week of therapy, while lymphocytes tended to
      increase. However, the absence of appreciable increases in cell activation
      markers and in monokine levels indicates insufficient immune activation, probably
      underlying the lack of objective antitumor responses (6 x stable, 9 x progressive
      disease) in these patients. In conclusion, the immunomodulatory impact of rhIL-6,
      if present at all, remains very limited.

PMID- 10404440
TI  - Atopic eczema: its social and financial costs.
AB  - Atopic dermatitis is a disorder with considerable social and financial costs. A
      recent Australian study indicates that the family stress related to the care of a
      child with moderate or severe atopic dermatitis is significantly greater than
      that of care of children with insulin-dependent diabetes mellitus. The factors
      contributing to family stress include: sleep deprivation; loss of employment;
      time taken for care of atopic dermatitis; and financial costs. An estimate of the
      yearly financial costs for a family and community (which includes medical,
      hospital, direct costs of treatments and indirect costs from loss of employment),
      range from $A1142 per child per year with mild atopic dermatitis, to $A6099 per
      year for a child with severe atopic dermatitis. As the current prevalence of
      atopic dermatitis in Australia is 10-15%, this indicates a considerable financial
      burden on the community. It is possible that appropriate interventions directed
      to reducing trigger factors, may produce worthwhile savings, in addition to
      benefits for the individuals and families. Atopic dermatitis should not be
      regarded as a minor skin disorder but as a condition which has the potential to
      be a major handicap involving considerable personal, social and financial
      consequences both for the family and for the community.

PMID- 10404439
TI  - A pilot trial of GM-CSF and MDX-H210 in patients with erbB-2-positive advanced
      malignancies.
AB  - MDX-H210 is a chemically, cross-linked, half-humanized bispecific antibody
      composed of F(ab') fragment from monoclonal antibody (mAb) H22 that binds to the
      high-affinity receptor Fc gamma RI and F(ab') of mAb 520C9 that recognizes the
      erbB-2 (HER2/neu) oncoprotein. In a previous trial, the murine bispecific, MDX
      210 at a dose of 7 mg/m2, was well tolerated and activated monocytes and
      macrophages in vivo in doses as low as 0.35 mg/m2. In our multidose trial,
      granulocyte-macrophage colony-stimulating factor, which increases and activates
      potential effector cells, was given on days 1-4 at 250 micrograms/m2 s.c. and MDX
      H210 was given on day 4 weekly for 4 consecutive weeks. Thirteen patients were
      treated at dose levels of 1, 3.5, 7, 10, 15, and 20 mg/m2 without dose-limiting
      toxicity. Fever, chills, and rigors occurred during and up to 2 h postinfusion
      and correlated with the time to peak levels of tumor necrosis factor-alpha
      (median 88.2 pg/ml; range 15.6-887 pg/ml) and interleukin-6 (median 371 pg/ml;
      range 175-2,149 pg/ml). By the fourth consecutive week of treatment the side
      effects and cytokine levels decreased significantly. Human antibispecific
      antibody (HABA) levels were increased by 200- to 500-fold above pretreatment
      levels in 5 of 11 evaluable patients after 3 weeks of treatment. The monocyte and
      granulocyte population increased on days 4 and 11 (median 44%; range 18-68% and
      42%; 19-71%), respectively, for monocytes and (60%; 43-75% and 74%; 54-82%) on
      days 4 and 11 for granulocytes. There was a significant decrease in the monocyte
      populations immediately after MDX-H210 administration (median decrease 73%; range
      42-94%) and (52%; 12-72%) on days 4 and 11, respectively. Ten patients completed
      4 weeks of treatment. One patient had a 48% reduction in an index lesions and six
      patients had stable disease at the time of evaluation. Three patients progressed
      before the fourth week. The therapy was generally well tolerated with toxicity,
      primarily, limited to the days of treatment.

PMID- 10404441
TI  - Paediatrica philatelica.
AB  - The world's nations issue postage stamps with themes that their governments
      regard as being of significant national and international importance. The
      philatelic record, thus, parallels each nation's history, its themes of
      contemporary pride and its aspirations for the future. As children's health is
      one of the most important of all issues of public and political life, it is not
      surprising that paediatricians are permanently commemorated in many of the
      world's postage stamps. Hippocrates is portrayed on many of the world's stamps,
      as are children's illnesses and children's doctors. Paediatricians are portrayed
      on stamps from New Zealand, Papua New Guinea, Australia, the United States of
      America, the nations of Africa, Europe and the United Nations. Themes permanently
      recorded in the philatelic record encompass every discipline within paediatrics,
      including portraits of Dr Virginia Apgar (of the Apgar score), Dr Truby King (New
      Zealand) who was responsible for the introduction of universal postnatal nursing
      visits for every child, and Dr Janusz Korczak (1879-1942), the Polish
      paediatrician who gave his life at Treblinka in World War II in order that his
      child patients might not die alone. The paediatric philatelic record is thus an
      international repository of the chronology of child care.

PMID- 10404442
TI  - A randomized, controlled trial of nurse home visiting to vulnerable families with
      newborns.
AB  - OBJECTIVE: This project aimed to evaluate the impact of a home visiting programme
      that targeted families where the child, for environmental reasons, was at great
      risk of poor health and developmental outcomes. METHODOLOGY: Women in the
      immediate postpartum period were recruited to a randomized double-blind
      controlled trial on the basis of self-reported vulnerability factors and were
      randomly assigned to receive either a structured programme of nurse home
      visiting, supported by a social worker and paediatrician (n = 90), or assigned to
      a comparison group receiving standard community child health services (n = 91).
      Parenting stress and maternal depression were measured at enrollment and at 6
      weeks. Preventive health behaviour, service satisfaction and home environment
      outcomes were tested at 6 weeks, as were child health outcomes. RESULTS: At six
      weeks, women receiving the home-based programme had significant reductions in
      postnatal depression screening scores as well as improvements in their experience
      of the parental role and improvement in the ability to maintain their own
      identity. Maternal-infant interactions were more likely to be positive, with
      significantly higher (better) scores in aspects of the home environment related
      to optimal development in children, particularly maternal-infant secure
      attachment. Intervention group mothers were significantly more satisfied with the
      community child health service. CONCLUSIONS: This form of intervention for
      families is effective in promoting secure maternal-infant attachment, preventing
      maternal mood disorder and is welcomed by the families receiving it. These
      findings may predict long-term benefits for the healthy development of children
      otherwise at risk of a range of poor health and development outcomes.

PMID- 10404443
TI  - The role of palliative care in advanced muscular dystrophy and spinal muscular
      atrophy.
AB  - OBJECTIVE: This study examines the potential role for palliative care services in
      the care of individuals with muscular dystrophy and spinal muscular atrophy, and
      the support of their families. METHODOLOGY: Semistructured interviews were
      conducted in South Australia with nine bereaved and four current family members
      of individuals with muscular dystrophy or spinal muscular atrophy. Issues
      explored during interview included: (i) the family perceptions of the
      difficulties in caring; (ii) the psychological and physical resources which were
      available to assist them; and (iii) family recall of the management of the
      terminal phase of the illness. RESULTS: Significant issues identified included:
      (i) a lack of coordination of care and access to skilled, competent carers; (ii)
      a lack of support for siblings; (iii) inadequate bereavement care; and (iv)
      limited discussion of options of ventilatory support and advance directives.
      CONCLUSIONS: The terminal care for individuals with muscular dystrophy and spinal
      muscular atrophy and their families requires improvement. Although many
      individuals with these conditions will die following an acute event, palliative
      care services may be appropriate for those who require a period of terminal care
      at home.

PMID- 10404444
TI  - Asthma: communication between hospital and general practitioners.
AB  - OBJECTIVE: To assess whether efforts to actively involve General Practitioners
      (GPs) in the postdischarge care of their paediatric asthma patients improved
      their satisfaction with communication with hospital staff. METHODOLOGY:
      Randomized controlled trial involving 60 patients admitted to the Royal
      Children's Hospital, Melbourne, with acute asthma and an identifiable GP. The GPs
      of the intervention patients were telephoned during the admission. Intervention
      patients and their GPs received printed information detailing the care the
      patient received in hospital and the recommended postdischarge care, as well as
      standardized educational booklets about asthma. Follow-up appointments were made
      for intervention patients to attend their GPs. RESULTS: The GPs of intervention
      patients were more satisfied when compared to the GPs receiving a standard level
      of communication (96.4% vs 48.3% of the intervention and control GPs,
      respectively, described the communication as good or extremely good, P = 0.0001).
      The intervention group GPs believed they were more involved after discharge
      (75.0% vs 44.8%, P = 0.005) and had greater understanding of their patient's
      hospitalisation (96.4% vs 62.1%, P = 0.005). These differences were noted despite
      there being no difference in the rate of follow-up attendance with GPs for
      intervention and control patients (85.7% vs 72.4%, P = 0.2). Qualitative data
      supported these findings with GPs expressing approval of the intervention used.
      CONCLUSION: Efforts to actively involve GPs in the postdischarge care of their
      paediatric patients with asthma resulted in a marked improvement in their
      satisfaction with the communication with medical staff at the Royal Children's
      Hospital, Melbourne. The study had insufficient power to demonstrate a difference
      in morbidity.

PMID- 10404445
TI  - Changing mortality and causes of death in infants 23-27 weeks' gestational age.
AB  - OBJECTIVE: To contrast the mortality rates and changes in the causes of death of
      very preterm infants (23-27 weeks), before and after the introduction of
      exogenous surfactant in 1991, and to identify any preventable causes of death
      remaining in the 1990s. METHODOLOGY: This was a cohort study on consecutive
      preterm infants of 23-27 weeks' gestational age born in the Royal Women's
      Hospital, Melbourne, a level III perinatal centre. The infants were livebirths
      free of lethal anomalies from two distinct eras, 1983-90, and 1992-96, inclusive.
      The main outcome measures were mortality during the primary hospitalization and
      the causes of death before and after the introduction of exogenous surfactant in
      1991. RESULTS: In 1983-90, 261 of 508 livebirths (51.4%) of 23-27 weeks'
      gestational age died, a significantly higher proportion than the 109 of 384
      (28.4%) livebirths who died in the period 1992-96. The mortality rate fell
      significantly with increasing gestational age and was lower at each week of
      gestational age in 1992-96. More infants who died in 1992-96 were treated
      intensively in the neonatal intensive care unit (NICU). Of the group of infants
      who died or who were treated intensively in NICU, respiratory causes of death
      predominated. However, the causes of death changed over time. In 1992-96
      proportionally fewer infants died from respiratory causes (1983-90, 82.5%; 1992
      96, 60.0%; odds ratio (OR) 0.31, 95%; confidence interval (CI) 0.16-0.57), but
      more from septic causes (1983-90, 14.3%; 1992-96, 43.8%; OR 4.9, 95%; CI 2.6
      9.2). CONCLUSIONS: As the mortality rate has fallen over time, respiratory causes
      of death have diminished, but septic causes of death have increased. Further
      advances in the use of exogenous surfactant and respiratory support may reduce
      respiratory deaths. Effective strategies to reduce nosocomial infections are
      urgently required.

PMID- 10404446
TI  - Chronic diarrhoea in infants and young children: causes, clinical features and
      outcome.
AB  - OBJECTIVES: To review the causes, clinical features and outcomes of Malaysian
      children who had chronic diarrhoea. METHODOLOGY: A prospective study was
      performed on children with diarrhoea of more than 14 days' duration who were
      managed at the Department of Paediatrics, University of Malaya Medical Centre,
      Kuala Lumpur from 1 January 1996 to 31 December 1997. RESULTS: Twenty-seven
      patients (14 boys and 13 girls) were studied. The median age of onset of
      diarrhoea was 6 months and the mean duration of symptoms before referral was 66.5
      days. The underlying causes of diarrhoea were found to be: (i) prolonged
      diarrhoea due to well-defined entities (intestinal lymphangiectasia, two cases;
      congenital glucose-galactose malabsorption, one case; post-small bowel resection,
      one case; (ii) postenteritis diarrhoea (cow's milk protein intolerance, eight
      cases; secondary lactose intolerance, four cases; transient monosaccharide
      intolerance, one case; (iii) gastrointestinal infections (nontyphoid Salmonella
      gastroenteritis, three cases; trichuriasis, two cases; amoebiasis, one case;
      adenovirus, one case; (iv) cases in which a firm diagnosis could not be
      established (three cases). The mean duration of hospital admission was 63 days.
      Sixteen cases required a change in diet, while nine cases required total
      parenteral nutrition. One death occurred. CONCLUSIONS: Chronic childhood
      diarrhoea in Malaysia had a variety of aetiologies. A specific diagnosis could be
      established in 90% of cases. Making a diagnosis was important because this led to
      appropriate therapy and a good outcome in 96% of cases.

PMID- 10404447
TI  - Factors associated with medium-term response to psychostimulant medication.
AB  - OBJECTIVE: To determine, in a sample of children first prescribed
      psychostimulants for attention deficit hyperactivity disorder (ADHD) between 1992
      and 1994, which child and family factors, components of assessment, and aspects
      of management, were associated with a favourable treatment response, and with
      parental satisfaction with management. METHODOLOGY: Data were obtained by mail
      survey in March 1995. Factors considered potentially significant to treatment
      response and parental satisfaction were entered in a three-step hierarchical
      multiple regression equation. RESULTS: Responses were received from 788 (59.7%)
      of a possible 1319 parents. Items making a significant individual contribution to
      both improvement and parental satisfaction were: younger age of the child; amount
      of information provided by the clinician; shorter interval between review
      appointments; continued use of medication; and fewer treatment side effects.
      items contributing only to treatment response were: longer time taken over
      establishing the diagnosis; and the use of parent and teacher checklists in
      assessment. CONCLUSIONS: These data support early intervention for ADHD. A
      considered approach to assessment which includes the use of parent and teacher
      checklists is recommended. Providing adequate information to parents and children
      is essential. Review intervals of less than 6 months appear to foster better
      outcomes.

PMID- 10404448
TI  - Chemotherapy reduces the prevalence of asthma symptoms in children with cancer:
      implications for the role of airway inflammation in asthma.
AB  - OBJECTIVE: Asthma is common in Australian children, with a prevalence of 30%.
      Airway inflammation is an important determinant of asthma symptoms. Chemotherapy
      used for the treatment of many childhood cancers suppresses inflammation. The
      prevalence of asthma symptoms in children treated with chemotherapy is unknown.
      METHODOLOGY: We therefore performed a survey of symptoms of asthma in children
      attending the oncology clinic at John Hunter Children's Hospital during the first
      6 months of 1996. RESULTS: Fifty children aged 1-17 years were surveyed. Thirty
      two of the children were in remission and had completed treatment with
      chemotherapy and 18 were currently undergoing treatment with chemotherapy. There
      was no significant difference in the prevalence of asthma in children before,
      during and after chemotherapy (26%, 22% and 34%), or in the prevalence of asthma
      in their siblings (28%). No child was classified as having persistent asthma
      while on chemotherapy and there was a significant reduction in the requirement
      for preventive asthma drugs 12% versus 0% (P = 0.03) being reported during
      chemotherapy. CONCLUSION: The prevalence of asthma in children who develop cancer
      is similar to their siblings and the same as the population as a whole. While
      asthma symptoms do not disappear completely during chemotherapy, the severity of
      asthma symptoms is less, with no need for asthma preventive treatment. The
      immunosuppressive side effects of the chemotherapy used in the treatment of
      childhood cancer appear to induce a remission in asthma symptoms. The ongoing
      requirement for bronchodilator therapy in patients whilst on chemotherapy
      suggests airway hyperreactivity persists in children while they are on
      chemotherapy. Prospective study of the airways of this group of patients promises
      to provide insights into the relationships between airway hyperreactivity, airway
      inflammation and asthma.

PMID- 10404449
TI  - Early linear growth retardation in Chongqing, China.
AB  - OBJECTIVES: The objectives of this study were to investigate early linear growth
      retardation and to identify potential risk factors for it. METHODOLOGY: A
      community-based prospective study was performed in Chongqing, China, with infants
      being examined at 12 and 15 months of age. A total of 101 infants were examined
      twice. Supine length, bodyweight, lower leg length, head circumference, middle
      upper arm circumference and biceps skinfold thickness were measured. RESULTS: The
      prevalence of short stature (length-for-age standard deviation score, < -2) was
      22% and 23% at 12 and 15 months of age, respectively, while the incidence of
      growth stunting (low growth velocity) between 12 and 15 months of age was 24%,
      using the stunting screening method. A mother having a history of abortion and
      infants having current episodes of diarrhoea were identified as risk factors for
      growth stunting. CONCLUSIONS: We conclude that both short stature and growth
      stunting are common in the population studied. The stunting screening method used
      is applicable in developing communities.

PMID- 10404450
TI  - National birthweight percentiles by gestational age for twins born in Australia.
AB  - OBJECTIVE: To develop national charts of birthweight percentiles by gestational
      age and infant sex for liveborn twins born in Australia. METHODOLOGY: National
      data on live twin births to non-Indigenous Australian-born mothers during 1991-94
      were derived from perinatal data collected by midwives in each State and
      Territory. RESULTS: During 1991-4 there were 20,075 liveborn twin infants. Of
      these births, missing data included: birthweight 36 (0.2%) births, gestational
      age 95 (0.5%) births, and sex (missing or indeterminate) 13 (0.06%) births. These
      births were excluded from the study. An additional 0.6% births were excluded
      because the recorded birthweights were extreme outliers for the recorded
      gestational ages. Forty-seven per cent of live twin births were preterm (< 37
      weeks). At all gestational ages, the median birthweight of male twins was higher
      than that of female twins. At model gestational age of 38 weeks, the difference
      in the median birthweight was 130 g. CONCLUSIONS: The charts produced as a result
      of the study provide birthweight percentiles by gestational age for twins based
      on national data in Australia. They provide current population norms for the use
      of Australian clinicians and researchers.

PMID- 10404451
TI  - Once versus twice daily amikacin in neonates: prospective study on toxicity.
AB  - OBJECTIVE: To compare the potentially toxic effects in fullterm neonates of
      amikacin administered once daily, versus amikacin administered twice daily.
      METHODOLOGY: A controlled, randomized, prospective study in which one group of
      fullterm neonatal patients received amikacin 15 mg/kg per dose once daily (n =
      20), and the other received amikacin 7.5 mg/kg per dose twice daily (n = 20).
      Impairment of renal glomerular function was defined as a decline of less than 50%
      of the expected physiological drop in serum creatinine over time. Brainstem
      auditory evoked potentials were also evaluated and amikacin blood levels taken.
      RESULTS: Fifteen patients in the once-daily group and 12 patients in the twice
      daily group demonstrated at least one period of renal function impairment while
      in hospital. This decreased to five of 16 and four of 16 patients during follow
      up. These differences were not statistically significant. Brainstem auditory
      evoked potentials did not find signs of ototoxicity at any time. CONCLUSION: In
      fullterm neonatal patients, once daily dosing of amikacin is no more toxic than
      the twice daily regimen.

PMID- 10404452
TI  - Viral aetiology of lower respiratory tract infection in young Malaysian children.
AB  - OBJECTIVE: To study the viral aetiology of lower respiratory tract infection
      (LRTI) in young Malaysian children. METHODOLOGY: A retrospective review was
      performed of LRTI patients aged less than 24 months who were admitted to the
      University Malaya Medical Centre between 1982 and 1997. Respiratory viruses in
      their nasopharyngeal secretion were identified by indirect immunofluorescence,
      viral culture, or both. RESULTS: A total of 5691 children were included in the
      study. The mean age was 8.6 +/- 6.6 months and the M:F ratio was 1.6:1. The most
      common diagnosis was pneumonia (52%) followed by bronchiolitis (45%) and croup
      (2%). Positive viral isolation rate was 22.0%. Respiratory syncytial virus (RSV)
      was the commonest virus isolated (84%), followed by parainfluenza virus (8%),
      influenza virus (6%) and adenovirus (2%). Patients with positive virus isolation
      were younger (7.8 +/- 6.2 vs 8.7 +/- 6.7 months, P = 0.0001) and were more likely
      to have bronchiolitis. CONCLUSION: Young Malaysian children admitted with LRTI
      had a 22% viral isolation rate and RSV was the commonest virus isolated.

PMID- 10404453
TI  - Laparotomy for necrotizing enterocolitis: intensive care nursery compared with
      operating theatre.
AB  - OBJECTIVE: To determine whether neonates requiring laparotomy for necrotizing
      enterocolitis (NEC) are more stable perioperatively and have less disruption of
      physiological parameters if surgery is performed in the neonatal intensive care
      unit (NICU) compared with the operating theatre (OR). METHODOLOGY: A
      retrospective case review was performed on 233 neonates referred for further
      surgical management of severe NEC in the period January 1989 to December 1997.
      Mortality and morbidity were compared by calculating the score for neonatal acute
      physiology (SNAP) and its attendant risk of mortality score. Thirty-six separate
      physiological variables were also compared pre- and postoperatively and the mean
      postoperative change was calculated. RESULTS: For neonates weighing less than
      1500 g, mortality was linked to illness severity, as measured by SNAP, rather
      than operative location. Specific adverse events associated with secondary
      transfer to the OR included hypothermia, deterioration in oxygenation parameters,
      ventilation parameters and platelet count. The liberal use of blood products,
      albumin and bicarbonate in perioperative resuscitation may have obscured other
      effects. CONCLUSIONS: The use of the neonatal intensive care nursery for surgery
      on neonates weighing less than 1500 g with severe NEC can be justified and such
      use should be encouraged. In contrast, secondary transport of neonates weighing
      less than 1500 g to the OR for laparotomy is associated with significant
      deterioration in a number of physiological parameters, which may impact on
      morbidity.

PMID- 10404454
TI  - Why do mothers still sun their infants?
AB  - OBJECTIVE: To determine the prevalence of maternal beliefs about the therapeutic
      uses of sunlight in infancy in tropical Australia. METHODOLOGY: Data were
      collected by interviewing 114 post-partum patients in Townsville (19 degrees
      16'S), Queensland. Each woman was asked a series of open-ended and set-response
      questions about ancestry, pigmentation, residential history, parity, maternal and
      paternal education, and beliefs regarding the reputed therapeutic uses of
      sunlight. RESULTS: Half of the women had at least one risky belief about the
      perceived benefits of sunning their baby. Thirty-six per cent were in favour of
      using sunlight to treat neonatal jaundice; 20.2% believed it was necessary to
      intentionally sun their baby to prevent vitamin D deficiency; and 10.5% thought
      sunlight was a good remedy for nappy rash. Independent predictors of one or more
      of these beliefs included maternal age and education level, and having another
      child that had been treated for jaundice. Forty per cent of multiparous women had
      sunned a child to treat neonatal jaundice. In most cases, advice to mothers to
      sun their baby had been given by a midwife/nurse (41% or a doctor/paediatrician
      (28%). CONCLUSIONS: Post-parturient women had a high prevalence of beliefs that
      may result in their infant being intentionally exposed to sunlight, and which
      could increase their child's future risk of skin neoplasia. Midwives and doctors,
      including paediatricians, were identified as the major professional sources of
      these beliefs. Professional education is needed to change the beliefs of health
      professionals who recommend therapies involving sunlight.

PMID- 10404455
TI  - Epidemiology of Cryptosporidium parvum in symptomatic paediatric oncology
      patients.
AB  - BACKGROUND: Although Cryptosporidium parvum is known to cause significant
      morbidity in immunocompromised individuals, including adults with cancer, the
      epidemiology of this pathogen in paediatric oncology patients is not known.
      OBJECTIVE: We prospectively investigated the incidence of symptomatic C. parvum
      infection in children receiving treatment for malignancy. METHODOLOGY: Over a 9
      month period, all oncology inpatients with diarrhoea had stool analysis for C.
      parvum oocysts. The incidence of cryptosporidiosis was also recorded in non
      oncology patients who had a stool analysed for C. parvum during the 6 years of
      the study period. RESULTS: None of the 149 stool samples from 60 oncology
      patients analysed contained C. parvum oocysts. Thirteen per cent of 173 samples
      from non-oncology patients were positive for C. parvum oocysts. CONCLUSIONS: In
      contrast to studies of adult oncology patients, paediatric oncology patients in
      our institution appear at low risk of cryptosporidiosis.

PMID- 10404456
TI  - An epidemiological survey of recurrent abdominal pain in a rural Malay school.
AB  - OBJECTIVE: To study the prevalence of complaints of recurrent abdominal pain
      (RAP) among school children aged 11-12 years in a rural setting in Malaysia.
      METHODOLOGY: Questionnaires were distributed to all parents and teachers of
      children aged 11-12 years who attended a small rural school in which all the
      children were Malays. Complaints of RAP were defined as at least three such
      complaints occurring over a period of at least 3 months. RESULTS: One hundred and
      sixty questionnaires were distributed, of which 148 were returned, giving a
      response rate of 92.5%. Sixty-one children (41.2%) had RAP. Approximately 45.2%
      of girls and 35.9% of boys reported having RAP. Compared with children without
      RAP, there was a significantly larger number of children with RAP (85.2%) who had
      at least one stress factor (P = 0.0109). There were no significant associations
      between RAP and total family income (P = 0.0573), a history of abdominal pain in
      at least one parent (P = 0.1686), a history of abdominal pain in at least one
      sibling (P = 0.0617), academic performance (P = 0.9967) or the degree of sports
      participation (P = 0.8469). There was an increased incidence of other systemic
      complaints in children with RAP when compared with children without RAP.
      CONCLUSION: Recurrent abdominal pain was found to be common among 11- to 12-year
      old children in a rural Malay school. There was a significant association found
      between RAP and the presence of stressful events, as well as with the presence of
      other systemic complaints.

PMID- 10404457
TI  - Severe congenital absence of skin in a preterm infant.
AB  - A severe case of aplasia cutis congenita in a preterm infant is described.
      Although major problems with thermoregulation and fluid balance were anticipated,
      these parameters were relatively easy to control once the patient was stabilized.
      Meticulous skin care and rapid formation of a membranous-like fibrous tissue
      layer covering the denuded areas probably played an important role in minimizing
      excessive fluid and heat loss. The prognosis in aplasia cutis congenita is
      determined by the underlying associated anomalies, the severity of skin lesions
      and, in our case, the maturity of the infant who died from complications of
      prematurity.

PMID- 10404458
TI  - Myocardial infarction complicating neonatal enterovirus myocarditis.
AB  - A 10-week-old, 31-week gestation preterm boy re-presented with heart failure
      after an initial episode of neonatal aseptic meningitis with positive CSF
      enterovirus polymerase chain reaction. Investigation demonstrated global
      myocardial dysfunction with left ventricle posterolateral myocardial infarction.
      The boy's heart failure was controlled with medical treatment but his myocardial
      dysfunction persisted 9 months after presentation.

PMID- 10404459
TI  - Survival of a 30-week baby with congenital myotonic dystrophy initially
      ventilated for 55 days.
AB  - In previous reports, duration of initial ventilation exceeding 1 month almost
      always predicts non-survival of babies with congenital myotonic dystrophy.
      However, a baby with this condition survived beyond infancy after 55 days'
      ventilation. We describe this case in detail, explain why the baby survived and
      highlight the importance of individualized assessment, in addition to applying
      general prognostic terms described in the literature.

PMID- 10404460
TI  - Multiple neonatal endocrinopathies in McCune-Albright syndrome.
AB  - Two cases of McCune-Albright syndrome (MAS) are reported who presented in the
      neonatal period with profound failure to thrive, cardio-respiratory distress,
      precocious puberty and Cushing's syndrome for which both underwent bilateral
      adrenalectomy. Both girls had also bilateral nephrocalcinosis; in one case that
      may have been attributed to Cushing's syndrome, but in the second case the cause
      remained obscure with no obvious abnormality of calcium metabolism. The first
      girl had hydrocephalus which is uncommon in this condition and the second girl
      still failed to thrive at the age of 6 years, despite adequate caloric intake and
      hormonal manipulation. A constellation of other abnormal features are described.
      These cases illustrate the complexity of MAS which can become a life-threatening
      or a debilitating disorder.

PMID- 10404461
TI  - Meningitis or madness: a delicate balance.
AB  - A child with meningitis who developed a psychosis 2 weeks after commencing
      treatment with antituberculous therapy is described here. The psychosis resolved
      with cessation of isoniazid, but the meningitis returned. The meningitis was
      treated by re-introduction of daily doses of isoniazid, but the psychosis
      recurred. Successful treatment of the meningitis, with minimal psychotic
      symptoms, eventually was achieved using isoniazid at 48 h dose intervals. The
      psychosis resolved completely after completion of therapy for tuberculous
      meningitis and cessation of isoniazid. This is the first case of isoniazid
      associated psychosis reported in a child.

PMID- 10404462
TI  - Neonatal Marfan syndrome: a case report.
AB  - A case of neonatal Marfan syndrome is presented. The patient was noted to have
      cardiomegaly and tricuspid regurgitation on antenatal ultrasound scan. She was
      born with long, slender fingers and toes, an aged appearance and non-paralytic
      hypotonia. Echocardiogram revealed a dilated right atrium, right ventricle,
      dysplastic tricuspid valve and severe tricuspid regurgitation. She subsequently
      died of severe heart failure. Post-mortem examination showed the pathological
      features of lobar emphysema and cystic medial necrosis of the aorta. These
      features supported the diagnosis of neonatal Marfan syndrome. Nucleotide
      sequencing showed substitution of G by A at codon 1032 in exon 25 located in the
      long arm of chromosome 15. This resulted in the substitution of a cysteine by a
      tyrosine. A de novo mutation is suggested by the absence of affected family
      members.

PMID- 10404463
TI  - Neutrophil function in glucose-6-phosphate dehydrogenase deficient neonates.

PMID- 10404464
TI  - Medication in young children.

PMID- 10404465
TI  - Evaluating the effects of critical illness in children and their parents.

PMID- 10404466
TI  - Cyclical vomiting syndrome.

PMID- 10404467
TI  - Maternal distress and congenital malformations: do mothers of malformed fetuses
      have more problems?
AB  - As compared with 580 randomly chosen pregnant women without malformed offspring.
      161 women with malformed offspring at the index pregnancy had a more frequent
      history of previous multiple offspring deaths and somewhat increased maternal age
      but were not different on social class, marital or cohabitation status or parity.
      As compared with demographically similar reproducing women (n = 54) interviewed,
      malformation cases (n = 98) reported having had significantly more strong stress
      before identification of the malformation, as well as a clear tendency toward
      less appropriate timing of the pregnancy. Women with malformed offspring
      represent a psychosocially vulnerable group and should receive special clinical
      and personal support.

PMID- 10404468
TI  - Regulation of glucocorticoid receptor-mRNA in human blood cells by amitriptyline
      and dexamethasone.
AB  - Recent research suggests that antidepressants exert their clinical action in
      depression via the restoration of glucocorticoid receptor (GR) function with a
      subsequent normalization of the altered feed-back regulation of the hypothalamic
      pituitary adrenocortical (HPA) system. We, therefore, studied the effects of
      amitriptyline, a standard antidepressant, and of the glucocorticoid
      dexamethasone, which has recently been reported to possess antidepressive
      properties, on glucocorticoid receptor mRNA (GR-mRNA) derived from blood cells of
      healthy male volunteers. Whole blood samples were exposed in vitro for 24 h to
      amitriptyline and dexamethasone, the mRNA was extracted, transcripts of the
      'house-keeping gene' glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the GR
      gene were subjected to reverse transcriptase-polymerase chain reaction (RT-PCR)
      and semiquantitatively determined by subsequent densitometry. In a concentration
      of 10 nM, amitriptyline induced a significant increase in GR-mRNA (GR/GAPDH
      ratio) to 186 +/- 31% of the control condition, while a concentration of 10
      microM of amitriptyline resulted in an increase of GR-mRNA (GR/GAPDH ratio) to
      165 +/- 36%. Dexamethasone also up-regulated blood cell GR-mRNA (GR/GAPDH ratio)
      levels at a concentration of 10 nM to 184 +/- 29%, whereas an incubation with 10
      microM apparently resulted in toxic effects on blood cells with a decreased
      amount of total mRNA samples recovered. In conclusion, we here show an increase
      of GR-mRNA in human blood cells after treatment with amitriptyline and
      dexamethasone, pointing to a direct action of these substances on GR-gene
      expression in a human system.

PMID- 10404469
TI  - Adrenergic receptor function in panic disorder. II. Neutrophil beta 2 receptors:
      Gs protein coupling, effects of imipramine treatment and relationship to
      treatment outcome.
AB  - Panic attacks are associated with increased autonomic symptoms, suggesting
      increased beta 2-adrenergic receptor (beta 2AR) function in PD. Tricyclic
      antidepressants downregulate beta AR function. Previous studies on beta AR
      function in PD, however, are inconsistent. We recently found increased beta AR
      coupling and density in neutrophils of symptomatic drug-free PD patients. This
      study evaluated beta AR coupling to Gs protein in 28 controls, 25 drug-free PD
      patients and 8 PD imipramine-treated patients. PD patients had significantly
      higher coupling and receptor density, particularly in the high-conformational
      state. Differences were more pronounced in patients with less depressive
      symptomatology. Treatment with imipramine was associated with decreased beta AR
      coupling and density in the high-conformational state. Several beta AR binding
      parameters were related to severity of anxiety symptoms and treatment outcome.
      Antidepressants downregulate beta AR density and induce uncoupling from Gs
      protein in PD. Future studies may investigate beta AR coupling in relationship to
      treatment outcome and the role of beta AR kinase in PD.

PMID- 10404470
TI  - Effect of bupropion on immunodensity of putative imidazoline receptors on
      platelets of depressed patients.
AB  - A substantial number of studies have demonstrated increased imidazoline receptors
      (I1 binding sites) on platelets of depressed patients and downregulation
      following antidepressant treatments. Herein, imidazoline receptor binding protein
      (IRBP) antiserum was used to quantify imidazoline receptors on platelets of
      depressed patients before and after treatment with the atypical aminoketone
      antidepressant, bupropion. Western blots revealed an increase in IRBP
      immunodensity (p = 0.01, two-tailed) in a 33 kDa protein band in untreated
      depressed patients (n = 21) as compared with controls (n = 17). This band has
      been positively correlated with I1 binding sites on platelets. Following 6 weeks'
      treatment with bupropion, IRBP-immunodensity was downregulated in depressed
      patients (p = 0.03, paired t-test); predominantly in responders (p = 0.005).
      Patients non-responsive to bupropion (n = 5) were significantly different from
      responders (p = 0.05) by exhibiting no elevation in IRBP-immunodensity at pre
      treatment and no downregulation of the 33 kDa band after treatment. IRBP
      immunodensity was negatively correlated (r = -0.79, p = 0.01) with plasma
      concentrations of bupropion and its metabolites at week-4 of BUP treatment. Thus,
      a 33-kDa IRBP on platelet plasma membranes is elevated in depression and
      normalized in responders to bupropion.

PMID- 10404471
TI  - Immune parameters in rapid cycling bipolar patients before and after lithium
      treatment.
AB  - This study investigates immune function in rapid cycling bipolar patients and
      normal volunteers before and after 30 days of lithium treatment. Previous small
      studies in symptomatic bipolar patients suggested that nonspecific immune
      activation might be present. While studies of the effects of lithium on immune
      function found that lithium increased serum SIL-2RS in normal volunteers and
      seemed to normalize immune function in bipolar patients. We hypothesized that the
      immune profile of rapid cycling bipolar patients would also manifest immune
      activation that lithium treatment might normalize. The more stable serum immune
      measures (SIL-2RS and SIL-6RS) were increased in symptomatic rapid cycling
      patients and did normalize with lithium treatment. Lithium treatment increased IL
      2, SIL-2RS and SIL-6RS in normal volunteers. These data suggest that rapid
      cycling bipolar patients may have mild immune activation which seems to normalize
      with lithium treatment.

PMID- 10404472
TI  - Further evidence for unconscious learning: preliminary support for the
      conditioning of facial EMG to subliminal stimuli.
AB  - This study investigated the predictive validity of facial electromyograms (EMGs)
      in a subliminal conditioning paradigm. Two schematic faces (pleasant; CS- and
      unpleasant; CS+), were presented to eight right-handed males during supraliminal
      pre- and postconditioning phases. Subliminal conditioning consisted of 36 energy
      masked presentations of each face pairing the CS+ with an aversive shock 800 ms
      poststimulus. A forced-choice recognition task established that the energy mask
      effectively precluded conscious recognition of stimuli. For the obicularis oculi
      and corrugator EMGs, significant face x condition interactions were found at 20
      100 ms and 400-792 ms poststimulus. The results demonstrate the existence of an
      expressive motoric response related to affect operating in response to a learned
      but unconscious event. Subjects were not aware of a contingency between the CS+
      and the US, suggesting emotional contingencies can be unconsciously acquired.

PMID- 10404474
TI  - The prevalence of mitral valve prolapse in children with anxiety disorders.
AB  - Studies in adults have suggested a comorbidity of mitral valve prolapse and
      anxiety disorders, especially panic disorder. The nature of the association
      between these disorders is yet unclear. In the last years, case studies have
      appeared, reporting on the comorbidity of anxiety disorders and mitral valve
      prolapse in children. The present study evaluated the prevalence of mitral valve
      prolapse in children with anxiety disorders as compared to normal controls. The
      study group consisted of 52 children, 6-18 years old, with a diagnosis of panic
      disorder (9.6%), separation anxiety disorder (65.4%) and/or overanxious disorder
      (61.5%). Fifty-one normal age- and gender-matched healthy children served as
      controls. All participants were evaluated for the presence of mitral valve
      prolapse by cardiac auscultation and echocardiography. None of the 52 children
      with anxiety disorder and one of the 51 control children (1.96%) had mitral valve
      prolapse. There appears to be no association between childhood anxiety disorders
      and mitral valve prolapse. Whether children with panic disorder proper show a
      greater prevalence of mitral valve prolapse remains an open question.
      Implications to the association of mitral valve prolapse and panic disorder are
      discussed.

PMID- 10404473
TI  - Osteopenia in anorexia nervosa: specific mechanisms of bone loss.
AB  - Osteopenia is a well recognized medical complication of anorexia nervosa (AN).
      The mechanism of bone loss is not fully understood and there is uncertainty about
      its management. New markers of bone turnover have been developed. C-terminal type
      1 propeptide (PICP) is a measure of bone formation and urinary pyridinolines such
      as deoxypyridinoline (DPYRX) and serum carboxyterminal crosslinked telopeptide
      (ICTP) are markers of bone resorption. The aim of this study was to examine these
      bone markers in patients with AN. Twenty female patients with AN and 12 healthy
      controls were included in the study. Bone mineral density (BMD) of AN patients
      was measured by dual energy X-ray absorptiometry (DEXA). Lumbar bone density was
      significantly reduced in the AN group compared to standardised values of thirty
      year old adults (t-score 83.2%, S.D. 12.1). Femoral neck bone density showed an
      even greater reduction (t-score 79.4%, S.D. 13.5). We found a significant
      negative correlation between femoral BMD and the duration of the illness. Femoral
      BMD correlated significantly with minimal body weight (r(16) = 0.504, p = 0.033).
      The markers of bone resorption were significantly higher in the patients with AN
      compared to the values of the control group (ICTP t(30) = -2.15, p = 0.04, DPYRX
      t(25) = -2.26, p = 0.033), whereas the markers of bone formation did not differ
      significantly between the groups. AN appears to be a low turn over state
      associated with increased bone resorption without concomitant bone formation.
      This pattern differs from osteopenia in menopausal women and should, therefore,
      lead to the development of specific therapeutic strategies in AN associated
      osteopenia. Hormone replacement therapy as well as calcium and vitamine D
      supplementation are so far discussed controversially. Long-term treatment studies
      are warranted.

PMID- 10404475
TI  - The role of ambulatory cardiovascular psychophysiology in the study of stress.

PMID- 10404476
TI  - Attentional reactions to an MI: the impact of mood state, worry, and coping
      style.
AB  - This study investigated the possible development of an attentional bias to
      cardiac-related words in subjects who recently experienced a myocardial
      infarction (MI). It was hypothesized that cardiac-related stimuli would have
      attention-capturing characteristics for post-MI subjects, and this bias would be
      moderated by level of anxiety, degree of cardiac-related worry, and the subject's
      coping style. Post-MI subjects (n = 33) and matched controls (n = 31)
      participated in an attentional search task. The post-MI subjects failed to show
      the predicted group increases in attention allocated to cardiac stimuli, but a
      difference between groups still occurred as the control group exhibited directed
      inattention to cardiac stimuli. Subsequent analysis indicated those post-MI
      subjects who did evince an attentional bias toward cardiac stimuli had higher
      monitoring scores on a self-report measure of coping style. Level of emotional
      distress and cardiac-related worry failed to predict attentional bias for the
      post-MI subjects.

PMID- 10404477
TI  - Glycemic control and major depression in patients with type 1 and type 2 diabetes
      mellitus.
AB  - The current study evaluated the association of glycemic control and major
      depression in 33 type 1 and 39 type 2 diabetes mellitus patients. Type 1 patients
      with a lifetime history of major depression showed significantly worse glycemic
      control than patients without a history of psychiatric illness (t = 2.09; df =
      31, p < 0.05). Type 2 diabetes patients with a lifetime history of major
      depression did not have significantly worse control than those with no history of
      psychiatric illness. Findings from this study indicate different relationships
      between lifetime major depression and glycemic control for patients with type 1
      and type 2 diabetes. Treatment implications for glycemic control in type 1 and
      type 2 diabetes patients are discussed.

PMID- 10404478
TI  - Measurement of depressive symptoms in cancer patients: evaluation of the Center
      for Epidemiological Studies Depression Scale (CES-D).
AB  - The Center for Epidemiological Studies Depression Scale (CES-D) is commonly used
      to measure depressive symptomatology in cancer patients, yet there is little
      known about the psychometric properties of the measure when applied to a cancer
      population. The aim of this study was to examine the psychometric properties of
      the CES-D with cancer patients. For purposes of comparison, the psychometric
      properties of the CES-D were assessed both in women undergoing treatment for
      breast cancer and women with no history of cancer. The CES-D and other study
      measures were administered to women undergoing treatment for breast cancer on two
      occasions: prior to treatment and midway through treatment. The measures were
      also administered to a group of women similar in age to the cancer patients who
      had no history of any type of cancer. These healthy comparison subjects were also
      assessed on two separate occasions. The CES-D was found to have good internal
      consistency, with alpha coefficients > 0.85 for both groups, as well as adequate
      test-retest reliability in both groups. Construct validity was demonstrated in
      two ways, via comparisons between the groups and by comparing the CES-D with
      measures of fatigue, anxiety, and global mental health functioning. The CES-D was
      established as a valid and reliable measure of depressive symptomatology in this
      sample of breast cancer patients. This measure may be appropriate for use in
      clinical psychosocial research with cancer patients, yet further research is
      needed to evaluate its usefulness in other cancer populations. The importance of
      measuring psychological symptoms with standard measures that have been validated
      with cancer patients is highlighted.

PMID- 10404479
TI  - Menstrual cycle, race and task effects on blood pressure recovery from acute
      stress.
AB  - This study examined cardiovascular recovery from two standardized laboratory
      stressors in 68 healthy black and white normotensive women and men (mean age 33
      years). Women were studied in a randomized order at the same time of day on two
      separate occasions, once during the follicular phase (days 7 to 10 following
      menses) and once during the luteal phase (days 7 to 10 following the leutenizing
      hormone surge) of the menstrual cycle. Men were studied twice approximately 6
      weeks apart. There were differential effects of the tasks on blood pressure
      recovery (change scores) with a mirror star task yielding poorer diastolic blood
      pressure recovery (p = 0.004) and an interpersonal speaking task yielding poorer
      systolic blood pressure recovery (p = 0.003). Across both tasks, blacks evidenced
      greater diastolic blood pressure recovery as compared to whites (p = 0.02). Black
      women showed greater diastolic blood pressure recovery in the luteal as compared
      to the follicular phase (p = 0.01), whereas white women evidenced no such change
      across the menstrual cycle. Correlation analysis across testing sessions
      generally revealed comparable temporal stability values for recovery as compared
      to reactivity measures. The findings support prior studies indicating racial
      differences in recovery from acute stress and extend these findings by suggesting
      that the menstrual cycle may differentially affect recovery in black versus white
      women.

PMID- 10404480
TI  - Anxiety and depression disorders 5 years after severe injuries: a prospective
      follow-up study.
AB  - Individuals with severe injuries were investigated 5 years after the traumatic
      events, and predictors of anxiety and depression disorders were identified.
      Trauma victims were selected who had an Injury Severity Score of > or = 16 and
      were brought to all hospitals in the Mersey region and North Wales over 1 year.
      The 212 patients aged > or = 15 years who left the hospital alive and lived
      within an accessible distance of the study hospital in Warrington were contacted
      5 years later and 158 (74.5%) received follow-up assessment. Thirty-eight
      subjects (36.9%) reported "definite" anxiety and/or depression disorders and, of
      these, only 21.1% reported taking psychotropic medications. Factors associated
      with anxiety and/or depression disorders at follow-up were: sequelae of head
      injury (i.e., cognitive problems, posttraumatic seizures, facial pain): writing
      impairment: disability due to thorax problems; and a new trauma during follow-up.
      Initial severity or types of injuries and overall residual disability rated by
      the investigator were not strong predictors of anxiety and/or depression
      disorders at follow-up.

PMID- 10404481
TI  - Body size perception in anorexia nervosa: a signal detection approach.
AB  - This study investigated whether individuals with anorexia nervosa (AN) visualize
      themselves as fatter than they are because they perceive themselves as fatter.
      Females with AN who overestimated their own body size judged size differences
      between pictures of their own body, and then again of someone else's body. Signal
      detection analysis of the results showed no differences in perceptual sensitivity
      between the AN and normal and thin control groups. No significant correlations
      were found between body size estimates and perceptual sensitivity. The anorexic
      group did, however, show a bias to report seeing "thin" differences, which was
      opposite to that of thin controls. Because bias differences between the groups
      were significant while sensitivity differences were not, it was concluded that
      abnormalities of body image most probably arise during reconstruction of the
      visual body image, rather than during perception of the body.

PMID- 10404482
TI  - Incidence of and preoperative predictors for delirium after cardiac surgery.
AB  - Incidence of and preoperative predictors for postoperative delirium were studied
      in 296 patients (age 26-83 years, mean age 63 years) undergoing elective cardiac
      surgery. Delirium occurred in 40 (13.5%) patients. Predictors included old age,
      low level of albumin, poor physical condition, use of nifedipine, and a high
      ratio of the amino acids phenylalanine to the sum of isoleucine, leucine, valine,
      tyrosine, and tryptophan. These findings suggest that preoperative physical
      condition and amino acid disturbances may be related to delirium after cardiac
      surgery in the elderly.

PMID- 10404483
TI  - What is your diagnosis?Splenic torsion.

PMID- 10404484
TI  - Bordetella bronchiseptica infection in the cat.
AB  - Feline Bordetella bronchiseptica infection had received little consideration
      until recent years when it has been increasingly documented in association with
      respiratory disease. This article reviews current knowledge on the organism; its
      epidemiology, pathogenesis, and clinical, diagnostic and therapeutic features.

PMID- 10404485
TI  - Radiographic pelvimetry for assessment of dystocia in bitches: a clinical study
      in two terrier breeds.
AB  - Radiographic pelvimetry was used to assess the role of pelvic anatomy in
      obstructive dystocia in bitches. Based on the history of previous whelpings, 20
      Boston terrier and 14 Scottish terrier bitches were divided into two equal
      groups: normally whelping bitches and bitches with obstructive dystocia.
      Additional whelpings during the period of study were closely observed and the
      pups were immediately weighed and measured. The bitches were clinically examined
      and the pelvis was radiographed in ventrodorsal and lateral projections.
      Measurements from the radiographs showed a significantly smaller pelvic size in
      the bitches with obstructive dystocia compared to the normally whelping bitches.
      Fetal-pelvic disproportion in the Scottish terrier was mainly due to a
      dorsoventrally flattened pelvic canal, whereas in the Boston terrier it arose
      from the combination of a dorsoventrally flattened pelvic canal and big fetuses
      with large heads. These results suggest that radiographic pelvimetry could be
      used to predict a disposition for dystocia in individual bitches, and as a basis
      for selection of breeding animals.

PMID- 10404486
TI  - Therapy of difficult cases of canine pyoderma with marbofloxacin: a report of 39
      dogs.
AB  - Thirty-nine dogs with severe and/or recurrent lesions of pyoderma were treated
      with marbofloxacin at an average dosage of 2.12 mg/kg bodyweight, once daily, for
      time periods varing from 10 to 213 days. Forty-seven strains of bacteria,
      isolated from 34 cultures, were tested for sensitivity to various antibiotics. At
      day 0, no resistance to marbofloxacin was found, but one refractory case, a
      strain of Staphylococcus intermedius resistant to marbofloxacin, was cultured at
      day 28. Thirty-three dogs (84.6 per cent) showed an excellent response (cure),
      one (2.6 per cent) a clear improvement and one (2.6 per cent) a smaller
      improvement, while the remaining four dogs showed no response after 11 to 60
      days. Fifteen dogs (45.5 per cent) relapsed over the follow-up period of three to
      191 days, but none of the dogs in the study exhibited any adverse effects.

PMID- 10404487
TI  - Concurrent central diabetes insipidus and panhypopituitarism in a German shepherd
      dog.
AB  - This report describes a German shepherd dog that was presented with proportionate
      dwarfism and coat changes typical of hypopituitarism but that was also profoundly
      polydipsic and polyuric. Investigations established a diagnosis of concurrent
      central diabetes insipidus. Treatment with desmopressin was successful in
      managing the polyuria and polydipsia.

PMID- 10404488
TI  - Ultrasonographic diagnosis of a laryngeal cyst in a cat.
AB  - The ultrasonographic appearance, surgical treatment and pathological
      classification of a laryngeal cyst in a four-year-old cat is described. This is
      the first description of such a cyst diagnosed with the help of ultrasonography.
      The cat presented with dyspnoea and respiratory noise. An intraluminal fluid
      filled cyst attached to the vocal cord was identified by ultrasonography and
      drained under ultrasound guidance. The cyst recurred three weeks later and
      ultrasonography showed an increase in size compared to the previous examination.
      There was no evidence of recurrence of the lesion 18 months after surgical
      removal.

PMID- 10404489
TI  - Diagnostic imaging of foreign body reactions in dogs with diffuse back pain.
AB  - Six hunting dogs were investigated after showing signs of diffuse back pain. In
      three of the dogs, prodromal signs included coughing. Swelling in the dorsal
      lumbar region was noted in four of the dogs, but in two there was no visible or
      palpable swelling. Initial radiographs of the lumbar region were normal in two of
      the dogs and showed mild to moderate ventral periosteal reactions in the L1 to L4
      region in the remaining four. On ultrasonography and magnetic resonance imaging,
      changes were seen in the sublumbar muscles (e.g., abnormal echogenicity and
      increased signal intensity) in five dogs examined. Exploratory surgery revealed
      plant material foreign bodies in the sublumbar muscles in the L1 to L4 region in
      five of the six dogs. The concurrent infections were caused predominantly by
      anaerobic bacteria common to the mucous membranes of the oropharyngeal and
      respiratory tracts. All dogs recovered, with restored hunting ability. The mean
      follow-up period was five years (range 1.3 to 7.8 years). It is proposed that the
      plant parts were inhaled, and then migrated along either diaphragmatic crus to
      lodge in the sublumbar muscles.

PMID- 10404491
TI  - Plexiform vascularisation of a retropharyngeal lymph node in a cat.
AB  - Plexiform vascularisation of a retropharyngeal lymph node is described in an
      adult cat. The cat presented with a chronic history of inspiratory stridor and a
      slowly growing mass in the cranial cervical area. Clinical signs resolved after
      excision of the affected node. This appears to be the first clinical report of
      plexiform vascularisation of a retropharyngeal lymph node and its treatment in a
      cat.

PMID- 10404490
TI  - Genitourinary dysplasia in a cat.
AB  - A six-month-old kitten had congenital urethral sphincter mechanism incompetence
      due to urethral hypoplasia and associated uterine hypoplasia and vaginal aplasia.
      Diagnosis was based on radiographic examination, surgical exploration and
      histological examination of the lower urinary tract. Surgical correction resulted
      in a marked clinical improvement. The cat became fully continent following
      treatment with phenylpropanolamine.

PMID- 10404492
TI  - Exercise and cardiovascular events: a double-edged sword?

PMID- 10404493
TI  - Nasal splinting effects on breathing patterns and cardiorespiratory responses.
AB  - The aim of this study was to compare the effects of nasal splinting during
      different modes of breathing on breathing patterns and cardiorespiratory
      responses. Ten healthy subjects (4 males, 6 females) performed five maximal
      treadmill tests while breathing through the nose, nose + dilator, mouth, nose +
      mouth, and nose + mouth + dilator. Repeated-measures analysis of variance and
      Tukey HSD revealed no significant differences between trials for maximal oxygen
      consumption, minute ventilation at an oxygen consumption of 30 ml.kg-1.min-1,
      carbon dioxide production, respiratory exchange ratio, tidal volume, dead space
      to tidal volume ratio, or completed treadmill stages to exhaustion. No
      significant difference was found in subjective dyspnoea ratings between stages of
      nose versus nose + dilator breathing. Minute ventilation, ventilatory equivalent
      for oxygen, and breath frequency for nose and nose + dilator versus mouth, nose +
      mouth, and nose + mouth + dilator were significantly lower. Ventilatory
      equivalent for carbon dioxide was significantly lower for nose versus mouth, and
      nose + dilator versus nose + mouth + dilator breathing. End-tidal carbon dioxide
      was significantly higher in nose versus mouth, nose + mouth, and nose + mouth +
      dilator breathing, and in nose + dilator versus mouth breathing. Nose breathing
      revealed a significantly lower heart rate versus nose + dilator, mouth, nose +
      mouth, and nose + mouth + dilator breathing. These results suggest that nasal
      splinting during exercise has minimal effects when nasal breathing and no effects
      when oronasal breathing.

PMID- 10404494
TI  - Upper extremity augmentation of lower extremity kinetics during countermovement
      vertical jumps.
AB  - Twenty-five volleyball players (14 males, 11 females) were videotaped (60 Hz)
      performing countermovement vertical jumps with and without an arm swing. Ground
      reaction force and video-based coordinate data were collected simultaneously. The
      resultant joint force and torque at the hip, knee, ankle and shoulder for two
      trials per subject per condition were computed and normalized. Average kinematic,
      resultant joint force and torque data were compared using repeated-measures
      analysis of variance. Larger values were recorded for the vertical velocity of
      the centre of mass at take-off in the jumps with (mean 2.75, s = 0.3 m.s-1)
      versus without (mean 2.44, s = 0.23 m.s-1) an arm swing. The jumps with no arm
      swing produced larger torques at the hip during the first third of the propulsive
      phase (from zero to maximum vertical velocity of the centre of mass). During the
      final two-thirds of the propulsive phase, the arm swing augmented hip extensor
      torques by slowing the rate of trunk extension and placing the hip extensor
      muscles in slower concentric conditions that favoured the generation of larger
      forces and resultant joint torques. During the first two-thirds of the propulsive
      phase, knee extensor torque increased by 28% in the jumps with an arm swing, but
      maintained a relatively constant magnitude in the jumps with no arm swing.

PMID- 10404495
TI  - Power laws and athletic performance.
AB  - In a previous study, we showed that the 1992 men's world record running times in
      the 100 m to 200 km could be represented accurately by the equation T = cDn,
      where T is the calculated record time for distance D, and c and n are positive
      constants. Here, we extend that to cover the years 1925-65 at 10-year intervals
      and 1970-95 in 5-year intervals for distances of 100 m to 10 km. Values of n for
      all years lie along a straight line with a small negative slope. A regression
      analysis yields an equation for values of n covering the period 1925-95. Values
      of c from 1925 to 1995 were fitted by a quadratic equation. These two equations
      define a surface in three-dimensional space (log(T), log(D), data) for all men's
      world record runs over the 70-year period for distances of 100 m to 10 km. We
      also demonstrated previously that event times, t, do not scatter randomly with
      respect to the values of T but form a consistent pattern about the straight lines
      in log(T) versus log(D) plots. In this study, we show that the pattern of (t-T)/t
      as a function of date has remained constant for the past 70 years.

PMID- 10404496
TI  - Energy system contributions in middle-distance running events.
AB  - The aim of this study was to estimate the energy contributions in middle-distance
      running events for male and female university athletes. The oxygen uptake (VO2)
      response during high-speed running was measured directly during exhaustive
      treadmill tests. Muscle mass was estimated using anthropometry. Each athlete
      completed an average of three races over 400 m, 800 m or 1500 m. Five minutes
      after each race, they provided a blood sample for determination of blood lactate
      concentration. For each race, energy cost, which was expressed as oxygen
      equivalents, was calculated as the sum of the aerobic and anaerobic components.
      The aerobic contribution was calculated as the sum of oxygen stores (2.3 ml O2.kg
      body mass-1) and total VO2 (based on the VO2 response to treadmill running). The
      anaerobic contribution was calculated as the sum of the energy available from
      phosphocreatine stores (37 ml O2.kg muscle mass-1) and the energy from glycolysis
      (3.0 ml O2.kg body mass-1 per mmol.l-1 increase in blood lactate concentration).
      For the women, the anaerobic energy contributions for the 400 m, 800 m and 1500 m
      averaged 62%, 33% and 17%, respectively. For the men, the anaerobic contributions
      averaged 63%, 39% and 20%, respectively. This information will help coaches and
      sport scientists to design and implement individualized training programmes.

PMID- 10404497
TI  - Erythropoietin concentration and arterial haemoglobin saturation with
      supramaximal exercise.
AB  - The aim of this study was to determine if the hypoxaemic stimulus generated by
      intense exercise results in the physiological response of increased
      erythropoietin production. Twenty athletes exercised for 3 min at 109 +/- 2.8%
      (mean +/- s) maximal oxygen consumption. Estimated oxyhaemoglobin saturation was
      measured by reflective probe pulse oximetry (Nellcor N200) and was validated
      against arterial oxyhaemoglobin saturation by CO-oximetry in eight athletes.
      Serum erythropoietin concentrations-as measured using the INCSTAR Epo-Trac
      radioimmunoassay-increased significantly by 28 +/- 9% at 24 h post-exercise in 11
      participants, who also had an arterial oxyhaemoglobin saturation < or = 91% (P <
      0.05). Decreased ferritin levels and increased reticulocyte counts were observed
      at 96 h post-exercise. However, no significant changes in erythropoietin levels
      were observed in nine non-desaturating athletes and eight non-exercise controls.
      Good agreement was shown between arterial oxyhaemoglobin saturation and percent
      estimated oxyhaemoglobin saturation (limits of agreement = -3.9 to 3.7%). In
      conclusion, short supramaximal exercise can induce both hypoxaemia and increased
      erythropoietin levels in well-trained individuals. The decline of arterial
      hypoxaemia levels below 91% during exercise appears to be necessary for the
      exercise-induced elevation of serum erythropoietin levels. Furthermore,
      reflective probe pulse oximetry was found to be a valid predictor of percent
      arterial oxyhaemoglobin saturation during supramaximal exercise when percent
      estimated oxyhaemoglobin saturation > or = 86%.

PMID- 10404498
TI  - Physiological responses and perceptions of exertion in a step aerobics session.
AB  - The aims of this study were to establish the cardiovascular and metabolic demands
      of a university step aerobics session entitled 'Uni-Step' performed at three step
      heights, and to evaluate the use of heart rate and ratings of perceived exertion
      for the estimation of exercise intensity during this mode. Ten female
      participants in step aerobics (mean VO2max = 47.7, s = 6.8 ml.kg-1.min-1)
      performed a 40-min Uni-Step routine on steps of height 6, 8 and 10 inches (15.2,
      20.3 and 25.4 cm). Oxygen uptake, heart rate and ratings of perceived exertion
      were recorded throughout each test. Maximum oxygen uptake (VO2max) and maximum
      heart rate were measured using a continuous treadmill protocol. The mean
      intensities were 45.6%, 51.6% and 56.2% VO2max for the 6-, 8- and 10-inch steps
      respectively. The mean percent heart rate reserves were 57.2%, 63.6% and 70.1% at
      these three heights respectively. Correlations indicated a weak relationship
      between %VO2max and ratings of perceived exertion for the 6- and 8-inch steps (r
      = 0.61 and 0.66 respectively) but a stronger one for the 10-inch step (r = 0.79).
      Uni-Step performed on the two highest steps was of a sufficient relative
      intensity to improve or maintain the cardiovascular fitness of participants in
      this study. The lowest step may be useful for participants of lower fitness.
      Heart rate overestimated the metabolic cost of Uni-Step at all three step heights
      and therefore caution is advised if used to predict intensity. Low correlations
      between %VO2max and ratings of perceived exertion at the two lower step heights
      indicate that ratings of perceived exertion may have limited utility in
      prescribing training intensity.

PMID- 10404499
TI  - Confirmatory factor analysis of the Competitive State Anxiety Inventory-2.
AB  - The aim of this study was to evaluate the factor structure of the Competitive
      State Anxiety Inventory-2 (CSAI-2) using confirmatory factor analysis. Volunteer
      participants (n = 1213) completed the CSAI-2 approximately 1 h before competition
      and the data were analysed in two samples. The hypothesized model showed poor fit
      indices in both samples independently (Robust Comparative Fit Index: sample A =
      0.82, sample B = 0.84) and simultaneously (Comparative Fit Index = 0.83),
      suggesting that the factor structure proposed by Martens et al. is flawed. Our
      findings suggest that a limitation of the Cognitive Anxiety scale derives from
      phrasing items around the word 'concerned' rather than 'worried'. We suggest that
      being concerned about an impending performance does not necessarily mean that an
      athlete is experiencing negative thoughts, but that the athlete is acknowledging
      the importance and difficulty of the challenge and is attempting to mobilize
      resources to cope. The present results question the use of the CSAI-2 as a valid
      measure of competitive state anxiety.

PMID- 10404500
TI  - The effect of moderate alcohol ingestion on blood coagulation and fibrinolysis at
      rest and in response to exercise.
AB  - The effect of alcohol ingestion before exercise on blood haemostasis is not
      known. The present study examined the effects of moderate alcohol ingestion on
      blood haemostatic variables at rest and in response to exercise. Eleven normal
      healthy individuals randomly performed two tests separated by 7 days. A moderate
      dose of ethanol (0.5 g.kg-1) was administered before one test, whereas an equal
      volume of an alcohol-free drink was administered before the other. Forty-five
      minutes after the ingestion of either drink, the participants cycled at 65%
      VO2max for 30 min followed by a 5-min all-out performance. Venous blood samples
      were obtained before and 45 min after the ingestion of both drinks, and also
      immediately after exercise. Exercise induced a significant increase in tissue
      type plasminogen activator activity and antigen, and factor VIII procoagulant
      activity. The post-exercise data also showed a significant decrease in
      plasminogen activator inhibitor activity and soluble fibrin, with a significant
      shortening in prothrombin time and activated partial thromboplastin time, but not
      thrombin time. No significant changes were observed in antithrombin III. Although
      no significant differences were found between trials in the haemostatic and
      fibrinolytic variables at rest, a significant decrease in fibrinogen
      concentration was observed after exercise in the alcohol trial. This suggests
      that ingesting a moderate dose of alcohol does not alter blood coagulation and
      fibrinolysis at rest. Apart from fibrinogen concentration, which was
      significantly decreased after exercise in the alcohol trial, most of the
      haemostatic and fibrinolytic variables were not affected by alcohol. The
      mechanism responsible for the decrease in fibrinogen following exercise in the
      alcohol trial remains unknown, but might be related to inhibition of fibrinogen
      synthesis by the liver or an enhanced rate of its catabolism.

PMID- 10404501
TI  - Tumors of the thymus.
AB  - Thymic neoplasms are a common cause of an anterior mediastinal mass and may be
      benign or malignant. Thymic cysts are congenital or acquired and may be
      associated with a thymic malignancy. True thymic hyperplasia and thymic lymphoid
      hyperplasia may enlarge the thymus and simulate a neoplasm. Thymoma and thymic
      carcinoma are epithelial malignancies with distinct clinicopathologic features.
      Thymic carcinoid is a rare aggressive neuroendocrine malignancy associated with
      multiple endocrine neoplasia 1. Thymolipoma is a benign neoplasm. Hodgkin and non
      Hodgkin lymphoma may primarily or secondarily involve the thymus. Primary
      mediastinal germ cell tumors may arise primarily within the thymus and include
      mature teratoma, seminoma, and non-seminomatous malignant germ cell tumors.

PMID- 10404502
TI  - Perilobular pulmonary opacities: high-resolution CT findings and pathologic
      correlation.
AB  - This pictorial essay illustrates the high-resolution CT and histologic findings
      of various disease processes that involve the perilobular interstitium.

PMID- 10404503
TI  - Correlation of chest radiographic findings with biopsy-proven acute lung
      rejection.
AB  - The purpose of this study was to determine the chest radiographic findings of
      acute rejection and the accuracy of chest radiography in making this diagnosis in
      patients undergoing lung transplantation. For each of 100 transbronchial biopsies
      performed on 25 lung transplant recipients (single lung in three, double lung in
      22), chest radiographs obtained within 24 hours before the biopsy were reviewed
      retrospectively without knowledge of clinical or biopsy information.
      Transbronchial biopsy revealed 42 instances of acute rejection in 17 patients and
      58 instances of no acute rejection (normal, n = 43; other processes, n = 15). All
      pulmonary parenchymal radiographic abnormalities were assessed. Acute rejection
      was associated with the presence of middle or lower lung reticular interstitial
      or airspace disease in 21 lungs (sensitivity = 0.50 [21/42]). This pattern was
      seen in 18 lungs without acute rejection (specificity = 0.69 [40/58]). There was
      no difference in the appearance of the lungs between grades 1 and 2 acute
      rejection. Normal lungs were noted in 20 instances of acute rejection (48%). The
      authors conclude that chest radiograph findings are abnormal in about 50% of
      instances of biopsy-proven acute rejection. Because the appearance of acute
      rejection is similar to that of other conditions, the diagnosis cannot be made
      accurately by chest radiography.

PMID- 10404504
TI  - Thoracic computed tomography of patients infected with the human immunodeficiency
      virus: relevance for the course of disease.
AB  - To determine the diagnostic accuracy and prognostic implications of thoracic
      computed tomography (CT) in patients with human immunodeficiency virus infection
      (HIV), CT scans of 154 HIV-infected patients (mean age, 41 years; range 23-65
      years; 18 female) with suspicion of pulmonary disease were retrospectively
      reviewed for signs of disease by two investigators blinded to clinical data other
      than positive HIV serology. Abnormal CT features were correlated with CD4-T
      lymphocyte count, histologic or microbiologic diagnosis, and survival. Computed
      tomography detected features of pulmonary disease in 133 patients. A recent chest
      film was available in 96 patients, and it was normal in 16. In 17 of 99 patients
      (17%) with histologic or microbiologic correlation, pathologic CT features could
      be demonstrated, though histologic and microbiological studies were unrevealing.
      Median survival was 649 days. Confluent pulmonary infiltrates and bilateral
      masses on CT indicated advanced disease with a median survival of 115 days (n =
      11, p = 0.0005) and 174 days (n = 15, p < 0.0001), respectively. The authors
      concluded that thoracic CT detects pulmonary lesions in an appreciable portion of
      HIV-infected patients in whom chest radiographs, microbiologic methods, or
      histology failed to establish a diagnosis, and that CT findings allow for an
      estimation of patient survival in acquired immunodeficiency syndrome.

PMID- 10404505
TI  - Transthoracic needle aspiration biopsy: value in the diagnosis of mycobacterial
      lung opacities.
AB  - The purpose of this study was to assess the value of transthoracic fine-needle
      aspiration in the diagnosis of mycobacterial infection as the cause of focal lung
      opacities. Six hundred twelve fine-needle aspiration biopsies were performed from
      1985 to 1997 in 587 patients with solitary or multiple lung opacities. Initial
      procedures, including sputum analysis and bronchoscopy, had been nondiagnostic.
      Fluoroscopic or computed tomography guidance was used, and a pathologist was
      present. A diagnosis of mycobacterial infection was established when acid-fast
      bacilli were demonstrated in the aspirate. In 487 patients, a malignant cause was
      confirmed, and six other patients had carcinoid tumor. Of 94 nonmalignant
      opacities, 24 (26%) were determined to have a mycobacterial cause. Fine-needle
      aspiration biopsy detected acid-fast bacilli in 15 of 24 cases (sensitivity,
      62.5%; specificity, 100%). Radiologic findings included upper lobe involvement
      (17 of 24 cases), single opacities (12 of 24 cases), satellite nodules (4 of 12
      cases with single opacities), irregular borders (19 of 24), eccentric
      calcification (2 of 24), and cavitation (8 of 24). The authors conclude that fine
      needle aspiration biopsy must be processed for acid-fast bacilli when
      nonmalignant cytologic findings result, even if the results of sputum smears,
      cultures, and bronchoscopy are negative.

PMID- 10404506
TI  - Radiologic findings: pulmonary infections after bone marrow transplantation.
AB  - Pulmonary infections are a significant source of morbidity and mortality in the
      bone marrow transplant population. This pictorial essay reviews the typical time
      period and imaging findings associated with common pulmonary pathogens that
      affect bone marrow transplant recipients.

PMID- 10404507
TI  - Granulomatous interstitial pneumonitis in association with primary
      hypogammaglobulinemia: computed tomography appearances.
AB  - The authors describe the computed tomographic appearances of nonspecific
      granulomatous interstitial pneumonitis in two patients with primary
      hypogammaglobulinemia. Their purpose is to show that it is important to consider
      this entity in the differential diagnosis of multiple pulmonary nodules in
      patients with this disease.

PMID- 10404508
TI  - Mucormycosis of the central airways: CT findings in three patients.
AB  - Computed tomographic (CT) findings are described in three diabetic patients with
      central airways mucormycosis. The CT findings of the tracheobronchial
      mucormycosis include enhancing areas of mural thickening (n = 3), luminal
      narrowing (n = 3), intramural air (n = 3), low-attenuation nonenhancing bronchial
      wall thickening (n = 2), and bronchonodal fistula formation (n = 1). These CT
      features in a diabetic patient should raise a high index of suspicion for
      tracheobronchial mucormycosis, particularly when typical radiographic features of
      pulmonary tuberculosis are absent.

PMID- 10404509
TI  - Spontaneous tension pneumopericardium complicating staphylococcal pneumonia.
AB  - The authors describe a patient with spontaneous pneumopericardium complicating
      staphylococcal pneumonia and empyema that resulted in cardiac tamponade.
      Spontaneous pneumopericardium is an unusual disorder. The causes and clinical
      findings of pneumopericardium are reviewed, as are the radiographic features that
      differentiate this condition from pneumomediastinum. Early recognition of
      pneumopericardium is important, because emergent pericardiocentesis may be
      required if there is clinical evidence of tamponade.

PMID- 10404510
TI  - Pulmonary sarcoidosis: calcified micronodular pattern simulating pulmonary
      alveolar microlithiasis.
AB  - A case of sarcoidosis demonstrating an unusual pattern of profuse micronodular
      calcification is presented. The striking similarity with the so-called
      pathognomonic appearance of pulmonary alveolar microlithiasis and the progressive
      deterioration of pulmonary function are emphasized.

PMID- 10404513
TI  - C-terminal maturation fragments of presenilin 1 and 2 control secretion of APP
      alpha and A beta by human cells and are degraded by proteasome.
AB  - BACKGROUND: Most early-onset forms of Alzheimer's disease are due to missense
      mutations located on two homologous proteins named presenilin 1 and 2 (PS1 and
      PS2). Several lines of evidence indicate that PS1 and PS2 undergo various post
      transcriptional events including endoproteolytic cleavages, giving rise to 28-30
      kD N-terminal (NTF) and 18-20 kD C-terminal (CTF) fragments that accumulate in
      vivo. Whether the biological activity of presenilins is borne by the processed
      fragments or their holoprotein precursor remains in question. We have examined
      the putative control of beta APP maturation by CTF-PS1/PS2 and the catabolic
      process of the latter proteins by the multicatalytic complex, proteasome.
      MATERIALS AND METHODS: We transiently and stably transfected HEK293 cells with
      CTF-PS1 or CTF-PS2 cDNA. We examined these transfectants for their production of
      A beta 40, A beta 42, and APP alpha by immunoprecipitation using specific
      polyclonals. The effect of a series of proteases inhibitors on the
      immunoreactivity of CTF-PS1/PS2 was examined by Western blot. Finally, the
      influence of proteasome inhibitors on the generation of beta APP fragments by CTF
      expressing cells was assessed by combined immunoprecipitation and densitometric
      analyses. RESULTS: We showed that transient and stable transfection of CTF-PS1
      and CTF-PS2 cDNAs in human cells leads to increased secretion of APP alpha and A
      beta, the maturation products of beta APP. Furthermore, we demonstrated that two
      proteasome inhibitors, lactacystin and Z-IE(Ot-Bu)A-Leucinal, prevent the
      degradation of both CTFs. Accordingly, we established that proteasome inhibitors
      drastically potentiate the phenotypic increased production of APP alpha and A
      beta elicited by CTF-PS1/PS2. CONCLUSION: Our data establish that the C-terminal
      products of PS1 and PS2 maturation exhibit biological activity and in particular
      control beta APP maturation upstream to alpha-and beta/gamma-secretase cleavages.
      This function is directly controlled by the proteasome that modulates the
      intracellular concentration of CTFs.

PMID- 10404512
TI  - Glycine-extended gastrin exerts growth-promoting effects on human colon cancer
      cells.
AB  - BACKGROUND: Since human colon cancers often contain significant quantities of
      progastrin-processing intermediates, we sought to explore the possibility that
      the biosynthetic precursor of fully processed amidated gastrin, glycine-extended
      gastrin, may exert trophic effects on human colonic cancer cells. MATERIALS AND
      METHODS: Binding of radiolabeled glycine-extended and amidated gastrins was
      assessed on five human cancer cell lines: LoVo, HT 29, HCT 116, Colo 320DM, and T
      84. Trophic actions of the peptides were assessed by increases in [3H]thymidine
      incorporation and cell number. Gastrin expression was determined by northern blot
      and radioimmunoassay. RESULTS: Amidated gastrin did not bind to or stimulate the
      growth of any of the five cell lines. In contrast, saturable binding of
      radiolabeled glycine-extended gastrin was seen on LoVo and HT 29 cells that was
      not inhibited by amidated gastrin (10(-6) M) nor by a gastrin/CCKB receptor
      antagonist (PD 134308). Glycine-extended gastrin induced a dose-dependent
      increase in [3H]thymidine uptake in LoVo (143 +/- 8% versus control at 10(-10) M)
      and HT 29 (151 +/- 11% versus control at 10(-10) M) cells that was not inhibited
      by PD 134308 or by a mitogen-activated protein (MAP) or ERK kinase (MEK)
      inhibitor (PD 98509). Glycine-extended gastrin did stimulate jun-kinase activity
      in LoVo and HT 29 cells. The two cell lines expressed the gastrin gene at low
      levels and secreted small amounts of amidated gastrin and glycine-extended
      gastrin into the media. CONCLUSIONS: Glycine-extended gastrin receptors are
      present on human colon cancer cells that mediate glycine-extended gastrin's
      trophic effects via a MEK-independent mechanism. This suggests that glycine
      extended gastrin and its novel receptors may play a role in colon cancer cell
      growth.

PMID- 10404514
TI  - Transgenic mice expressing Shb adaptor protein under the control of rat insulin
      promoter exhibit altered viability of pancreatic islet cells.
AB  - BACKGROUND: The Src-homology 2 domain-containing adaptor protein Shb was recently
      cloned as a serum-inducible gene in the insulin-producing beta-TC1 cell line.
      Subsequent studies have revealed an involvement of Shb for apoptosis in NIH3T3
      fibroblasts and differentiation in the neuronal PC12 cells. To assess a role of
      Shb for beta-cell function, transgenic mice utilizing the rat insulin promoter to
      drive expression of Shb were generated. MATERIALS AND METHODS: A gene construct
      allowing the Shb cDNA to be expressed from the rat insulin 2 promoter was
      microinjected into fertilized mouse oocytes and implanted into pseudopregnant
      mice. Mice containing a low copy number of this transgene were bred and used for
      further experimentation. Shb expression was determined by Western blot analysis.
      The insulin-positive area of whole pancreas, insulin secretion of isolated islets
      and islet cell apoptosis, glucose tolerance tests, and in vivo sensitivity to
      multiple injections of the beta-cell toxin streptozotocin were determined in
      control CBA and Shb-transgenic mice. RESULTS: Western blot analysis revealed
      elevated islet content of the Shb protein. Shb-transgenic mice displayed enhanced
      glucose-disappearance rates in response to an intravenous glucose injection. The
      relative pancreatic beta-cell area neonatally and at 6 months of age were
      increased in the Shb-transgenic mice. Islets isolated from Shb-transgenic mice
      showed enhanced insulin secretion in response to glucose and increased insulin
      and DNA content. Apoptosis was increased in islets isolated from Shb-transgenic
      mice compared with control islets both under basal conditions and after
      incubation with IL-1 beta + IFN-gamma. Rat insulinoma RINm5F cells overexpressing
      Shb displayed decreased viability during culture in 0.1% serum and after exposure
      to a cytotoxic dose of nicotinamide. Shb-transgenic mice injected with multiple
      doses of streptozotocin showed increased blood glucose values compared with the
      corresponding controls, suggesting increased in vivo susceptibility to this
      toxin. CONCLUSION: The results suggest that Shb has dual effects on beta-cell
      growth: whereas Shb increases beta-cell formation during late embryonal stages,
      Shb also enhances beta-cell death under certain stressful conditions and may thus
      contribute to beta-cell destruction in type 1 diabetes.

PMID- 10404516
TI  - Gene expression pattern in human monocytes as a surrogate marker for systemic
      inflammatory response syndrome (SIRS).
AB  - BACKGROUND: Systemic inflammatory response syndrome (SIRS) is a mild inflammatory
      episode which, in a minority of patients, may deteriorate into septic shock. In
      the mouse, injection of bacteria or bacterial endotoxin induces systemic
      inflammation through the activation of blood monocytes, which leads to lethal
      shock. A number of intervention strategies have been shown to prevent progression
      to shock in mouse model systems. However, recent clinical trials of a number of
      these therapeutic strategies in patients have been uniformly disappointing. In
      contrast to the situation in the mouse models, there may be many different ways
      to initiate systemic inflammation in patients and not all of them need
      necessarily involve activation of blood monocytes. If there is no unifying
      mechanism behind the induction of systemic inflammation in patients and no common
      rules governing its development, then it is unlikely that generally applicable
      therapeutic strategies will be found that can prevent progression into shock.
      MATERIALS AND METHODS: We used differential display to compare gene expression
      patterns in monocytes of recent-admission multi-trauma patients with clinically
      diagnosed SIRS to the patterns in monocytes of healthy controls. RESULTS: Of
      seven differentially displayed bands that were recovered and sequenced, five were
      associated with SIRS and two were preferentially expressed in the monocytes of
      healthy controls. CONCLUSION: The data show that monocytes of SIRS patients are
      in an activation state that is different from that of monocytes from the healthy
      controls, that monocytes from many individual patients share similar patterns of
      differentially expressed sequences, and that by this criterion, the multi-trauma
      SIRS patients are a remarkably coherent group.

PMID- 10404517
TI  - [Prevalence of dementia syndromes].
AB  - A survey is presented of epidemiological data on the prevalence of dementia
      syndromes. Most studies have demonstrated that the prevalence index of dementia
      is doubled after the age of 60 years at intervals of 5.1 years. The data on
      Alzheimer's disease point out that its prevalence after the age of 65 years is
      between 1.9% and 5.8%. In the study of the population of the Mokotow City
      District of Warsaw aged 65-84 years the prevalence of dementia was 5.7%.

PMID- 10404515
TI  - An essential role for macrophage migration inhibitory factor (MIF) in
      angiogenesis and the growth of a murine lymphoma.
AB  - BACKGROUND: Macrophage migration inhibitory factor (MIF) has been shown to
      counterregulate glucocorticoid action and to play an essential role in the
      activation of macrophages and T cells in vivo. MIF also may function as an
      autocrine growth factor in certain cell systems. We have explored the role of MIF
      in the growth of the 38C13 B cell lymphoma in C3H/HeN mice, a well-characterized
      syngeneic model for the study of solid tumor biology. MATERIALS AND METHODS:
      Tumor-bearing mice were treated with a neutralizing anti-MIF monoclonal antibody
      and the tumor response assessed grossly and histologically. Tumor capillaries
      were enumerated by immunohistochemistry and analyzed for MIF expression. The
      effect of MIF on endothelial cell proliferation was studied in vitro, utilizing
      both specific antibody and antisense oligonucleotide constructs. The role of MIF
      in angiogenesis also was examined in a standard Matrigel model of new blood
      vessel formation in vivo. RESULTS: The administration of anti-MIF monoclonal
      antibodies to mice was found to reduce significantly the growth and the
      vascularization of the 38C13 B cell lymphoma. By immunohistochemistry, MIF was
      expressed predominantly within the tumor-associated neovasculature. Cultured
      microvascular endothelial cells, but not 38C13 B cells, produced MIF protein and
      required its activity for proliferation in vitro. Anti-MIF monoclonal antibody
      also was found to markedly inhibit the neovascularization response elicited by
      Matrigel implantation. CONCLUSION: These data significantly expand the role of
      MIF in host responses, and suggest a new target for the development of anti
      neoplastic agents that inhibit tumor neovascularization.

PMID- 10404518
TI  - [Biology of memory].
AB  - The memory phenomenon is described and characterized giving also definitions
      connected with it--engrams and learning. Several classifications of memory are
      reviewed discussing differences between instant and "processed" memory, and
      memory declarative and procedural. Theories are presented briefly of the nature
      of memory, the hypothesis of closed neuronal circuits, synaptic plasticity,
      neurochemical theory, and Fuster's new network theory, including arguments for
      and against them. Attention is called to the possibility of "watching" of the
      mechanisms of memory, provided by the introduction of neurovisual methods PET and
      MRI. Finally, observations are mentioned indicating that subconscious learning
      occurs more frequently than it is supposed, and the mechanisms of knowledge
      acquiring in this way are diverse.

PMID- 10404519
TI  - [Clinical pattern of early phase of Alzheimer's disease].
AB  - Modern views are presented on the sequence of neuropathological changes in
      Alzheimer's disease and their correlation with clinical symptoms in early phase
      of that process. Attention is called to difficulties in interpretation of the
      influence of morphotic changes, such as neurofibrillary degeneration and senile
      plaques, on the progression of clinical symptoms. Data are compared as published
      by various authors suggesting a diversity of neuropsychological abnormalities
      manifesting themselves in the early phases of the disease. Genetic studies seem
      also to confirm the complexity of the Alzheimer process and they may explain the
      imperfection of clinical diagnostic methods used as yet.

PMID- 10404520
TI  - [Depression and Alzheimer's disease].
AB  - Despite numerous studies the relationship between depression and Alzheimer's
      disease has not yet been clarified. The high prevalence of depression in
      Alzheimer's disease has been confirmed but the data on its incidence vary.
      Generally, depressed mood is the most prevalent symptom in 0-86% of dementia
      syndrome, minor depression, dysthymia is considered to be present in 20-30% of
      patients and major depression is least frequent. It seems confirmed that
      depression may be considered to be a risk factor for dementia, but the
      coincidence of these two diseases remains still unknown. Since the symptoms of
      depression and dementia are very similar, the clinical picture brings other
      controversies. Loss of energy, speech paucity, poor attention and concentration,
      diminished interest and psychomotor slowness cannot differentiate dementia from
      depression, the disability level seems to be the only differentiating factor.
      Depression may be suspected in case of changes in functional level, complaints
      about pain and diurnal variation of symptoms. From the practical point of view
      the type of contact and the willingness of perform tests are among the crucial
      symptoms. Sometimes, it is difficult to separate apathy and pathological crying
      from depression. The pathomechanism of depression in dementia is not known. The
      role of serotoninergic and cholinergic transmission changes, alterations of
      glucocorticoid cascade and presence of apoE are considered but without evident
      results.

PMID- 10404521
TI  - [Differential diagnosis of early dementia].
AB  - The principles of differential diagnosis are discussed of dementia in Alzheimer's
      disease against similar syndromes of other origin. Among the syndromes which
      should be differentiated from Alzheimer's disease those are considered: syndromes
      erroneously diagnosed as dementia, potentially reversible dementia, vascular
      dementia and dementia in certain degenerative diseases. In the differential
      diagnosis history data, results of neurological and neuropsychological
      examinations are helpful, while among laboratory investigations brain imaging by
      CT, MRI and SPECT are most important.

PMID- 10404522
TI  - [Early diagnosis of Alzheimer's disease by neuroimaging methods].
AB  - Visual examinations of the brain, MRI in particular, are very important but
      always only auxiliary methods in the diagnosis of Alzheimer's disease. Since
      several years the results obtained in them could have been confirmed objectively
      by introduction of various methods for measurement of cerebral structures
      undergoing atrophy. The development of functional MRI programmes, particularly
      those of regional blood flow in capillaries, has helped in detection of early
      Alzheimer lesions. The main difficulty in these diagnostic methods is the
      continuum of lesions resulting from physiological senescence and those being
      pathological atrophy of Alzheimer type.

PMID- 10404523
TI  - [Jumex in the treatment of Alzheimer's disease].

PMID- 10404524
TI  - Cancer deaths after 131I therapy for thyrotoxicosis.

PMID- 10404525
TI  - Differentiation between recurrent brain tumour and post-radiation necrosis: the
      value of 201Tl SPET versus 18F-FDG PET using a dual-headed coincidence camera--a
      pilot study.
AB  - The aim of this study was to determine whether it is possible to differentiate
      between recurrent disease and post-treatment necrosis in patients treated for a
      primary brain tumour. This prospective study was designed to compare the
      sensitivity and specificity of 201Tl single photon emission tomography (SPET) and
      18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) using a dual
      headed coincidence camera. Sixteen patients suspected of having recurrent brain
      tumour (10 men, 6 women) (mean age 39.5 years, range 21-57 years) were studied.
      201Tl SPET and 18F-FDG PET studies were performed on the same day. An increase in
      activity was considered indicative of tumour recurrence. The images were also
      quantified using a thallium index and an FDG index. The 18F-FDG PET images were
      also assessed visually using a 5-point scale. The diagnosis of tumour recurrence
      was based on clinical course and/or follow-up computed tomography or magnetic
      resonance imaging. The sensitivity of 201Tl SPET and 18F-FDG PET was 92% (11/12)
      and 62% (7/12) respectively. One patient initially assessed as having necrosis
      showed a recurrence 9 months after both studies. McNemar's analysis of these
      results showed a statistically significant difference (P = 0.023) in the ability
      of the two methods to separate with accuracy tumour from radiation necrosis. No
      correlation was found between the thallium index and the FDG index (r = 0.36). We
      conclude that 201Tl SPET is a sensitive modality for the detection of brain
      tumour recurrence. 18F-FDG imaging using a dual-headed coincidence camera gave
      significantly poorer results compared to 201Tl SPET. Our results do not justify
      continuation of this prospective comparative study.

PMID- 10404526
TI  - Bone marrow content measured in radioimmune bone marrow scintigraphy: intra- and
      inter-observer variability.
AB  - The aim of this study was to assess the possible quantification of vertebral
      residual bone marrow content relative to the bone marrow content of a non
      irradiated vertebra. This method is based on the vertebral count activity,
      measured using radioimmune bone marrow scintigraphy. First, however, we had to
      evaluate intra- and inter-observer variability. In three patients who underwent
      radioimmune bone marrow scintigraphy, two independent observers measured the
      count density in 51 (15 lumbar and 36 thoracic) vertebrae using a manually drawn
      region of interest. To evaluate intra- and inter-observer variability, we
      calculated the means and standard deviations of the differences between
      measurements. Bland-Altman plots were drawn for all vertebrae as well as for
      three subgroups of vertebrae (the upper thoracic spine, D1-D6; the lower thoracic
      spine, D7-D12; and the lumber spine, L1-L5). For all vertebrae, the mean (+/-
      S.D.) difference, expressed as a percentage of the overall mean, was -0.44 +/-
      3.3% for observer 1 and -0.3 +/- 2.1% for observer 2 for intra-observer
      variability; inter-observer variability varied from 0.55 +/- 3.9% to 1.28 +/-
      3.7%. On the Bland-Altman plots, the data points were evenly distributed above
      and below the 0-line and the linear regression equations matched the line of
      equality almost perfectly. This pattern was observed for all the vertebrae as
      well as for the subgroups of vertebrae. In conclusion, our results show that the
      intra- and inter-observer variabilities are not great, confirming that this
      technique is simple and robust and can be used for further quantification of bone
      marrow content in the axial skeleton.

PMID- 10404527
TI  - Left ventricular function at rest and during bicycle exercise in normal subjects:
      assessment by ECG-gated myocardial perfusion SPET with 99Tcm-tetrofosmin.
AB  - 99Tcm-labelled myocardial perfusion tracers allow simultaneous assessment of
      myocardial perfusion and left ventricular function using ECG-gated SPET. The aim
      of this study was to evaluate left ventricular performance during exercise by
      means of ECG-gated myocardial perfusion SPET. After the administration of 99Tcm
      tetrofosmin (555-740 MBq), eight healthy volunteers aged 27-49 years underwent
      ECG-gated myocardial perfusion SPET at rest and during supine submaximal exercise
      (75 and 125 W), for 3 min each. Using ECG-gated SPET data, left ventricular end
      diastolic volume (LVEDV) demonstrated a biphasic response during exercise (from
      106.4 +/- 17.5 to 119.9 +/- 19.9 to 108.1 +/- 19.2 ml). In contrast, left
      ventricular end-systolic volume decreased gradually and significantly during
      exercise (from 47.1 +/- 11.9 to 41.5 +/- 8.9 to 36.1 +/- 10.1 ml; P < 0.05), and
      left ventricular ejection fraction continued to increase at higher workloads
      (from 56.1 +/- 6.0 to 63.0 +/- 2.7 to 67.0 +/- 4.3; P < 0.01) despite a fall in
      LVEDV. There was a progressive increase in cardiac output during exercise, which
      reached a peak of 7.2 +/- 0.9 l.min-1. We conclude that ECG-gated myocardial
      perfusion SPET can assess left ventricular function during exercise and may
      provide useful information for the evaluation of patients with ischaemic heart
      disease.

PMID- 10404528
TI  - Uptake of liposome-encapsulated 99Tcm-MIBI by sensitive and multidrug-resistant
      tumour cell lines.
AB  - It is well established that accumulation of 99Tcm-sestamibi (99Tcm-MIBI) is much
      higher in sensitive than multidrug-resistant tumour cells expressing the
      permeability glycoprotein 170 (Pgp 170) as well as a multidrug-resistance related
      protein (MRP). Thus 99Tcm-MIBI is a good candidate for diagnosing the multidrug
      resistance phenotype by in vivo imaging. However, the blood clearance of 99Tcm
      MIBI is too rapid to achieve optimal accumulation in tumours and uptake in the
      liver, spleen, heart and muscle is too high for it to be an excellent in vivo
      tumour tracer. One way of prolonging the bioavailability of 99Tcm-MIBI is to use
      liposomes which do not affect its accumulation in tumour cells. We explored this
      possibility in vitro using two sensitive and five resistant cell lines, two of
      them expressing Pgp 170 and three others over-expressing MRP. 99Tcm-MIBI was
      incorporated into liposomes prepared by thin film hydration with phosphate
      buffered saline using distearoyl phosphatidyl choline, distearoyl phosphatidyl
      ethanolamine and cholesterol in a ratio of 1.85:0.15:1.00. Liposome diameter was
      97.9 +/- 4.5 nm as determined by dynamic light scattering. 99Tcm-MIBI uptake was
      quantified by measuring radioactivity retained in the cells incubated at 37
      degrees C with liposome-encapsulated 99Tcm-MIBI or with free radiotracer in the
      presence of empty liposomes. In both experimental cases, 99Tcm-MIBI accumulation
      was similar to that obtained in the presence of free 99Tcm-MIBI only: it was much
      higher in sensitive than in resistant Pgp 170-positive and MRP-positive cells.
      Encapsulation in liposomes does not alter the potency of 99Tcm-MIBI to
      distinguish the sensitive and resistant tumour cells. Our results suggest that
      future studies should assess the usefulness of the encapsulated form of 99Tcm
      MIBI for in vivo imaging of tumours.

PMID- 10404529
TI  - Artefacts in the thin-layer chromatographic analysis of 99Tcm-tetrofosmin
      injections.
AB  - In an evaluation of techniques for dispensing 99Tcm-tetrofosmin injections,
      variability in radiochemical purity measured by the recommended 'cut-and-count'
      thin-layer chromatographic (TLC) analytical technique was observed. This was due
      to inconsistency in the position of the 99Tcm-tetrofosmin on the chromatography
      plate. An investigation was therefore undertaken to identify the factors which
      influence the Rf value of 99Tcm-tetrofosmin and the subsequent effect on the
      values obtained in the measurement of radiochemical purity. TLC was performed on
      an ITLC/SG stationary phase with a mobile phase of dichloromethane:acetone
      (65:35). On a satisfactory chromatogram, the main peak had an Rf of approximately
      0.5 and the radiochemical purity was measured at > 90%. The Rf of the main peak
      and the measured radiochemical purity were found to increase as the size of the
      sample applied to the plate was increased. Force-drying the sample spot after
      application to the TLC plate gave a single peak with an Rf of 0. The dimensions
      of the tank and the time allowed for mobile phase saturation did not affect the
      outcome of the analysis. Small variations in the composition of the mobile phase
      affected the Rf of the main peak but not the measured radiochemical purity. TLC
      plates that were dried at 11 degrees C before use were found to give distorted
      chromatograms and unreliable measurements of radiochemical purity. In conclusion,
      when using TLC to measure the radiochemical purity of 99Tcm-tetrofosmin, the
      following precautions should be observed: (1) the sample spot applied to the TLC
      plate should be in the range 10-20 microliters; (2) the spot should not be force
      dried with air; and (3) ITLC/SG plates should not be dried before use.

PMID- 10404530
TI  - 111In-labelled platelets for assessment of thrombogenicity of new haemodialysis
      vascular access.
AB  - Using platelet scintigraphy to evaluate early thrombogenicity, we examined 39 new
      vascular accesses 4 weeks and 3 months after surgery. We found a significant
      association between platelet deposition and Doppler flow (P < 0.01) and blood
      pressure (P < 0.01). Compared with arteriovenous fistulae, prosthetic grafts
      showed significantly higher platelet uptake (after 4 h: 2.4 +/- 1.1 vs 1.2 +/-
      1.1 eU, P < 0.05; after 24 h: 2.1 +/- 1.0 vs 0.6 +/- 0.8 eU, P < 0.01) and a
      higher Doppler flow (1184 +/- 202 vs 609 +/- 342 ml.min-1, P < 0.001). In 8 of 39
      accesses, a thrombosis occurred. Accumulation of activity was not related to
      shunt thrombosis (specificity 61%, sensitivity 71%). We conclude that 111In
      platelet scintigraphy is not suitable for the early detection of shunt thrombosis
      or for identifying patients at risk.

PMID- 10404531
TI  - 13C-urea versus 14C-urea breath test: is there still a need for 14C-urea?

PMID- 10404532
TI  - Adaptogenic properties of six rasayana herbs used in Ayurvedic medicine.
AB  - Plants from all over the world such as Eleutherococcus senticosus, Panax ginseng,
      Raponticum carthamoides, Rhodiola rosea, Withania somnifera and Ocimum sanctum
      have been extensively evaluated for their adaptogenic potential. However, none of
      them has been successfully introduced as an adaptogen in the clinic. This paper
      discusses some of the problems in evaluation of adaptogens which have precluded
      their inclusion as clinically useful drugs. We further discuss our results with
      six rasayana plants from Ayurveda, which were studied for their adaptogenic
      potential. The whole, aqueous, standardized extracts of selected plants
      (Tinospora cordifolia, Asparagus racemosus, Emblica officinalis, Withania
      somnifera, Piper longum and Terminalia chebula) were administered orally to
      experimental animals, in a dose extrapolated from the human dose, following which
      they were exposed to a variety of biological, physical and chemical stressors.
      These plants were found to offer protection against these stressors, as judged by
      using markers of stress responses and objective parameters for stress
      manifestations. Using a model of cisplatin induced alterations in
      gastrointestinal motility, the ability of these plants to exert a normalizing
      effect, irrespective of direction of pathological change was tested. All the
      plants reversed the effects of cisplatin on gastric emptying, while Tinospora
      cordifolia and Asparagus racemosus also normalized cisplatin induced intestinal
      hypermotility. Tinospora cordifolia was also tested for its ability to modulate
      the changes occurring in the phagocytic activity of peritoneal macrophages after
      exposure of rats to either carbon tetrachloride or horse serum. It was found to
      normalize the phagocytic function irrespective to the direction of change,
      complying to the definition of an adaptogen. All the plant drugs were found to be
      safe in both acute and subacute toxicity studies. Studies on the mechanisms of
      action of the plants revealed that they all produced immunostimulation. The
      protection offered by Tinospora cordifolia against stress induced gastric mucosal
      damage was lost if macrophage activity was blocked. Emblica officinalis
      strengthened the defence mechanisms against free radical damage induced during
      stress. The effect of Emblica officinalis appeared to depend on the ability of
      target tissues to synthesize prostaglandins. Recent data obtained with Tinospora
      cordifolia suggest that it may induce genotypic adaptation, further opening the
      arena for more research and experimentation.

PMID- 10404534
TI  - Evaluation of the destructive effect of khaya gum on Bacillus subtilis spores
      during tableting.
AB  - The destructive effect of khaya gum used as a binding agent in a paracetamol
      formulation on Bacillus subtilis spores during tableting has been investigated,
      in comparison with the effects of two standard binders-polyvinylpyrrolidone and
      gelatin. The destructive effect of khaya gum was generally similar to those of
      the standard binders. Significant (p < 0.001 in each case) inverse linear
      relationships of log % survival of the B. subtilis spores with compression
      pressure and with concentration of binder, were established. The effect of the
      binding agent was significantly dependent (p < 0.001 in each case) on both
      compression pressure and the binder concentration. However, there was no
      significant interaction (p > 0.05) between the destructive effects of compression
      pressure and binder concentration. The results suggest that khaya gum and the
      standard binders would be useful in the destruction of microorganisms during
      tableting.

PMID- 10404533
TI  - Studies on the antidiarrhoeal properties of pentaclethra macrophylla leaf
      extracts.
AB  - The aqueous (WE) and ethanol (EE) leaf extracts of Pentaclethra macrophylla were
      tested for antidiarrhoeal activity using experimental animal models. The i.p.
      LD50 values were established to be 770 mg/kg and 280 mg/kg for the aqueous (WE)
      and ethanol (EE) extracts, respectively. Antidiarrhoeal potential of the extracts
      was evidenced by a significant reduction in faecal output and protection from
      castor oil-induced diarrhoea in rats treated with the extracts. In addition the
      extracts significantly (p < 0.05) decreased propulsive movement of
      gastrointestinal contents in mice. On isolated tissue preparations, the extracts
      significantly reduced in a non-specific manner contractions evoked by
      acetylcholine, nicotine and histamine. The extracts inhibited the growth of
      common pathogenic microorganisms. The antispasmodic as well as the antimicrobial
      effects of the extracts may explain the rationale for the use of the plant in
      traditional medicine as a popular antidiarrhoeal recipe.

PMID- 10404535
TI  - Antioxidant activity of AO-8, a herbal formulation in vitro and in vivo
      experimental models.
AB  - The effect of AO-8, a herbal formulation was evaluated for free radical
      scavenging activity using in vitro and in vivo experimental models. AO-8 dose
      dependently inhibited ferric ion induced lipid peroxidation in vitro at 125-1000
      micrograms. AO-8 was investigated at dose levels of 250, 500 and 750 mg/kg p.o.
      in isoproterenol-induced myocardial infarction and CCl4-induced hepatotoxicity in
      rats. The levels of serum GOT and LDH, cardiac glutathione, SOD and catalase were
      estimated following induction of myocardial infarction with isoproterenol. The
      estimation of parameters such as SGOT, SGPT, liver glycogen and lipid
      peroxidation were carried out in CCl4-induced hepatotoxicity. Treatment with AO-8
      for 15 days at a dose of 500 and 750 mg/kg offered marked protection in both in
      vivo models. The reversal of increased serum enzymes in both the models may be
      due to the prevention of leakage of the intracellular enzymes by its membrane
      stabilizing activity. The inhibition of lipid peroxidation and enhancement of
      antioxidant enzymes by AO-8 may be due to the direct free radical scavenging
      activity which could be attributed to the antioxidant potential of various
      ingredients present in the formulation. Thus it can be concluded that AO-8 is an
      effective free radical scavenger and could prove beneficial in the treatment of
      various disorders associated with the involvement of free radicals.

PMID- 10404536
TI  - Cytotoxic activity of marine macro-algae on Artemia salina (brine shrimp).
AB  - A total of 22 ethanol extracts of seaweed species (13 brown, 6 green and 3 red)
      collected from the Karachi coast were investigated for brine shrimp cytotoxicity.
      Of all the species, only six namely Stoechospermum marginatum, Sargassum
      swartzii, S. binderi, Spatoglossum asperum, Stokeyia indica (brown) and Caulerpa
      racemosa (green) showed significant activity. n-Hexane-soluble fractions of the
      ethanol extract of S. marginatum and S. swartzii were found to be responsible for
      the activity, whereas the methanol-soluble fractions of S. asperum and S. binderi
      were most active. The water extract of S. indica and C. racemosa exhibited the
      most prominent activity (LC50 value below 70 micrograms/mL) when compared with
      the ethanol extracts and their fractions. Cytotoxic activity may be due to the
      compounds differing in polarity.

PMID- 10404537
TI  - Dominant lethal study of alpha-asarone in male and female mice after sub-chronic
      treatment.
AB  - Dominant lethal studies were conducted in male and female mice with alpha
      asarone, the active hypolipidaemic component of Guatteria gaumeri Greenman, by
      per os sub-chronic treatment (10 and 20 mg/kg, 5 days/week, for 8 weeks) and
      subsequent mating. alpha-Asarone did not produce germinal mutations in either
      males or females. Epididymal sperm examination of male mice immediately after
      treatment failed to reveal any alteration in sperm count on shape. No significant
      alterations were observed in testicular or epididymal weights or testicular
      histology.

PMID- 10404538
TI  - Muscarinic agonist properties of the hydrobutanol extract from aerial parts of
      Waltheria viscosissima St. Hil. (Sterculiaceae) in rats.
AB  - The cardiovascular effects of the hydrobutanol phase of the ethanolic extract
      from the aerial parts (HBWV) of Waltheria viscosissima A. St. Hil.
      (Sterculiaceae) were tested in rats by using a combined (in vivo and in vitro)
      approach. HBWV (5, 7.5, 10, 15 and 20 mg/kg, randomly) induced a significant and
      dose-dependent hypotension and bradycardia in conscious freely moving
      normotensive rats. Both hypotensive and bradycardic effects evoked by a
      submaximal dose of HBWV (10 mg/kg) were inhibited by pre-treatment of the animals
      with atropine (2 mg/kg, i.v.). In anaesthetized animals, electrocardiogram
      recordings revealed second and third degree sinoatrial and atrioventricular
      blockade induced by the extract (10 mg/kg, i.v.), which were inhibited by cardiac
      muscarinic blockade (atropine, 2 mg/kg, i.v.). In isolated rat aortic rings,
      increasing concentrations of HBWV (50, 100, 200 and 400 micrograms/mL) were able
      to antagonize the contractile effects of noradrenaline (1 microM). This effect
      was inhibited by pre-incubation of the aortic rings with atropine (1 microM), by
      removal of the vascular endothelial tissue or by nitric oxide synthase blockade.
      These results suggest that both cardiac and peripheral actions induced by HBWV
      are probably mediated by stimulation of cardiac and endothelial muscarinic
      receptors, respectively.

PMID- 10404539
TI  - Efficacy of curcumin in the management of chronic anterior uveitis.
AB  - Curcumin, obtained from rhizomes of Curcuma longa, was administered orally to
      patients suffering from chronic anterior uveitis (CAU) at a dose of 375 mg three
      times a day for 12 weeks. Of 53 patients enrolled, 32 completed the 12-week
      study. They were divided into two groups: one group of 18 patients received
      curcumin alone, whereas the other group of 14 patients, who had a strong PPD
      reaction, in addition received antitubercular treatment. The patients in both the
      groups started improving after 2 weeks of treatment. All the patients who
      received curcumin alone improved, whereas the group receiving antitubercular
      therapy along with curcumin had a response rate of 86%. Follow up of all the
      patients for the next 3 years indicated a recurrence rate of 55% in the first
      group and of 36% in the second group. Four of 18 (22%) patients in the first
      group and 3 of 14 patients (21%) in the second group lost their vision in the
      follow up period due to various complications in the eyes, e.g. vitritis, macular
      oedema, central venous block, cataract formation, glaucomatous optic nerve damage
      etc. None of the patients reported any side effect of the drug. The efficacy of
      curcumin and recurrences following treatment are comparable to corticosteroid
      therapy which is presently the only available standard treatment for this
      disease. The lack of side effects with curcumin is its greatest advantage
      compared with corticosteroids. A double blind multi-centric clinical trial with
      this drug in CAU is highly desirable to further validate the results of the
      present study.

PMID- 10404540
TI  - Mechanism of antiviral activity of triterpenoid saponins.
AB  - Triterpenoid saponins are naturally occurring sugar conjugates of triterpenes
      possessing various biological activities, including antiviral action. Two
      substances isolated from natural sources were tested against herpes simplex virus
      type 1 replication. They did not show evidence of cytotoxicity under antiviral
      test conditions. The triterpenoid saponin, isolated from a Brazilian plant (s21),
      represents the oleanane group and inhibited herpes simplex virus type 1 DNA
      synthesis. The triterpenoid saponin, isolated from a Chinese plant (s17),
      represents the ursane group and seemed to inhibit viral capsid protein synthesis
      of herpes simplex virus type 1.

PMID- 10404541
TI  - Antimicrobial components of some cruciferae plants (Diplotaxis harra Forsk. and
      Erucaria microcarpa Boiss.)
AB  - The total herb of Diplotaxis harra Forsk. on treatment with myrosinase produces
      isopropyl isothiocyanate and 3- butenyl isothiocyanate in addition to (the non
      volatile) 2-hydroxy-3-butenyl isothiocyanate which could be obtained as 5-vinyl-2
      oxazolidinethione (goitrin) and methyl 4-isothiocyanatobutyrate (Erypestrin). On
      treating Erucaria microcarpa Boiss, herb with myrosinase, it produces isopropyl
      isothiocyanate, butyl isothiocyanate and benzyl isothiocyanate in addition to the
      non-volatile 8-methylsulphinyloctyl isothiocyanate (hirsutin). The plant extracts
      contain high percentages of arachidonic and palmitic acids, nonadecane,
      cholesterol, stigmasterol and B-sitosterol. The volatile constituents of D. harra
      and E. microcarpa showed higher activity against yeasts than Gram +ve, Gram -ve
      bacteria and fungi. The nonmethylated fatty acids of the two herbs showed higher
      activity against Gram +ve and Gram -ve bacteria than yeasts and fungi.

PMID- 10404542
TI  - An investigation into the antioxidant activity of Allium nutans L.
AB  - Antioxidants are important species which possess the ability to protect the body
      from damage caused by free radical-induced oxidative stress. There is currently
      much interest in the antioxidant role of fruit, vegetables, wines and teas. In
      this study the antioxidant activity of leaf, bulb and root of Allium nutants L.
      was investigated. Biochemical parameters were also determined: activities of
      antioxidant enzymes (superoxide dismutase, catalase, peroxidase, glutathione
      peroxidase), quantities of malonyldialdehyde, superoxide and hydroxyl radicals
      and reduced glutathione and contents of total flavonoids, chlorophylls a and b
      carotenoids, vitamin C and soluble proteins. Our results indicated that Allium
      nutants L. exhibits antioxidant ability in all investigated plant organs. The
      highest antioxidant ability was observed in the leaves where all investigated
      antioxidant enzymes were active and quantities of malonyldialdehyde and OH. low.
      Reduced glutathione, pigments and carotenoids present in the leaves contribute to
      the high antioxidant activity. ESR investigation conducted with Allium nutans L.
      phosphate buffer (pH 7) extract showed that the signal DMPO-OH spin adducts in
      the presence of Allium nutans L. extract was reduced by 78.48%.

PMID- 10404543
TI  - Inhibition of oncogene product enzyme activity as an approach to cancer
      chemoprevention. Tyrosine-specific protein kinase inhibition by purpurogallin
      from Quercus sp. nutgall.
AB  - Inhibitors of oncogene product enzyme activity were sought as a prescreen for
      potential cancer chemopreventive agents. Purpurogallin, a polyphenol from Quercus
      sp. nutgall, was found to inhibit the tyrosine-specific protein kinase of the
      human erb-b oncogene product (epidermal growth factor receptor) for both
      autophosphorylation (IC50 = 27.5 microM) and phosphorylation of an exogenous
      substrate (IC50 = 45.3 microM). An examination of enzyme kinetics indicated that
      purpurogallin is a competitive inhibitor of both ATP (Ki = 54.9 microM for
      autophosphorylation, Ki = 33.9 microM for phosphorylation of exogenous substrate)
      and the tyrosine-containing acceptor substrate poly(glutamate, alanine, tyrosine)
      6:3:1 (Ki = 83.7 microM).

PMID- 10404544
TI  - Immunomodulatory effect of IM-133.
AB  - The immunomodulatory effect of IM-133, a polyherbal formulation, has been
      investigated. Treatment with IM-133 enhanced the delayed type hypersensitivity
      (DTH) response in mice. IM-133 enhanced the in vitro response of splenocytes to
      mitogenic challenge. The in vivo treatment also stimulated the ex vivo lymphocyte
      proliferation, while the humoral response to sheep RBCs (SRBCs) was unaffected.
      The preferential stimulation of the components of cell mediated immunity (CMI)
      indicate that treatment with IM-133 affords non-specific immune stimulation.

PMID- 10404545
TI  - Biological effects of Myristica fragrans (nutmeg) extract.
AB  - The chloroform extract of nutmeg has been evaluated for antiinflammatory,
      analgesic and antithrombotic activities in rodents. The extract inhibited the
      carrageenan-induced rat paw oedema, produced a reduction in writhings induced by
      acetic acid in mice and offered protection against thrombosis induced by
      ADP/adrenaline mixture in mice.

PMID- 10404546
TI  - An investigation into the biochemical basis of the observed hyperglycaemia in
      rats treated with ethanol root extract of plumbago zeylanica.
AB  - The effects of the ethanol extract of the root of Plumbago zeylanica on key
      enzymes of glycolysis and other biochemical parameters were studied in the rat.
      The results show that thigh muscle hexokinase, phosphofructokinase, pyruvate
      kinase and lactate dehydrogenase activities were significantly reduced (p < 0.05)
      by 12.07%, 51.02%, 24.32% and 25.16% respectively in rats treated with the
      ethanol extract of Plumbago zeylanica when compared with the controls. Serum
      pyruvate and lactate were significantly lowered in the experimental rats by
      23.64% and 46.29%, respectively. The difference between the supernatant protein
      means was not statistically different (p > 0.05) suggesting the preservation of
      protein synthesis in the muscle of the extract-treated rats. The reduction in the
      activities of the key enzymes of glycolysis and its end-products suggests a
      reduction in flux across the glycolytic pathway in the extract-treated rats. This
      may be a result of impaired delivery to, and utilization of, glucose by the
      peripheral tissue, thus substantiating the reported hyperglycaemia in the extract
      treated rats.

PMID- 10404547
TI  - Antimicrobial activity of the essential oil of Calamintha nepeta and its
      constituent pulegone against bacteria and fungi.
AB  - The chemical composition of the essential oil of Calamintha nepeta and its
      antimicrobial activity against Listeria monocytogenes, Bacillus cereus,
      Salmonella veneziana, S. paratyphi B. S. typhimurium, Fusarium moniliforme,
      Botrytis cinerea, Aspergillus niger and Pyricularia oryzae have been studied.
      Moreover the main constituents of the oil (limonene, menthone, pulegone, menthol)
      have been tested against the same microorganisms. Only pulegone showed
      antimicrobial activity, particularly against all the Salmonella species.

PMID- 10404548
TI  - Antiinflammatory activity and acute toxicity (LD50) of the juice of Kalanchoe
      brasiliensis (Comb.) leaves picked before and during blooming.
AB  - Kalanchoe brasiliensis Comb. (Cassulaceae) extracts from leaves picked before and
      during plant blooming (extracts 1 and 2, respectively) were tested for their
      antiinflammatory effect on carrageenin-induced rat paw oedema and for acute
      toxicity (LD50). Oral doses of 0.25, 0.5 and 1.0 g/kg of extract 1 significantly
      inhibited the paw oedema during the first 4 h after injection of 2% carrageenin,
      while oral doses of 0.5, 1.0 and 2.0 g/kg of extract 2 had no inhibitory activity
      on the paw oedema induced by carrageenin. The results indicate an
      antiinflammatory effect of extract 1 and a proinflammatory effect of extract 2.
      K. brasiliensis extracts 1 and 2 presented no acute toxicity on mice at the doses
      of 0.25 to 5 g/kg administered intraperitoneally.

PMID- 10404549
TI  - Antimicrobial activity of extracts from the cell cultures of some Turkish
      medicinal plants.
AB  - Twenty-four callus, and eleven cell suspension, cultures were established from
      Turkish medicinal plants, and crude extracts prepared from them tested against
      microorganisms to assess their antimicrobial activities in vitro. Of the extracts
      tested, those belonging to the cell cultures of five of the plant species showed
      antibacterial activity against mainly three bacteria and a yeast. No activity was
      observed against herpes simplex viruses, HSV-I and II, but an extract from
      Hypericum capitatum showed a slight anti-retroviral activity against HIV-I.

PMID- 10404551
TI  - A message from Preventive Medicine and your physician.

PMID- 10404550
TI  - University students' knowledge and awareness of HPV.
AB  - BACKGROUND: The purpose of this study was to evaluate the knowledge, attitudes,
      and behaviors of university students regarding the human papillomavirus (HPV).
      METHODS: A random sample of 500 university students was mailed a self
      administered questionnaire that elicited their knowledge and awareness about HPV
      and compared their knowledge and attitudes with those of other sexually
      transmitted diseases (STDs). Among the 480 deliverable addresses, 289 students
      responded (response rate 60%). RESULTS: Only 37% of respondents had ever heard of
      HPV, and the median score on a 13-item knowledge scale was only 3. Of seven STDs
      assessed, respondents indicated they knew the least about HPV and perceived that
      this STD has received the least educational effort. In multivariate analyses,
      predictors of lower knowledge and awareness about HPV were male gender and sexual
      behavior (having multiple partners, not using condoms). CONCLUSIONS: Despite the
      high prevalence of HPV among young adults, most students knew very little about
      this infection. Implementing HPV educational programs and measuring their
      effectiveness should be a priority.

PMID- 10404552
TI  - Population-based recruitment for quit-smoking programs: an analytic review of
      communication variables.
AB  - BACKGROUND: Attempts to reduce the prevalence of smoking through quit-smoking
      programs have been unsuccessful because they have not attracted large numbers of
      smokers to participate in them. METHOD: An analytic review of the literature was
      conducted to identify potential communication variables that might enhance
      recruitment for community-based quit-smoking programs. Recruitment was defined as
      the number of smokers who enroll in a quit-smoking program divided by the
      estimated number of smokers in the target population. RESULTS: Thirty-three
      publications reporting the results of 40 recruitment campaigns were located. The
      median recruitment rate was 2.0%. Logistic regression was used to examine the
      effect of six variables on recruitment rate: the type of program sponsor, the
      type of program, program costs, use of participation incentives, whether messages
      were segmented by stage of change, and the type of channel used to send messages.
      The only significant predictor of recruitment rate was channel type (i.e., the
      method used to deliver a message). Studies that used interactive recruitment
      channels (telephone, interpersonal communication) were 66.5 times more effective
      than those using passive recruitment strategies (mass media, direct mail).
      Results examining the segmentation of messages by stage of change on recruitment
      were inconclusive. CONCLUSIONS: Results suggest that researchers and
      practitioners interested in population-based smoking cessation programs should
      pay more attention to recruitment methods. The use of interpersonal channels has
      been underused and appears to be particularly promising for improving the
      population impact of quit-smoking programs.

PMID- 10404553
TI  - Dietary associates of serum total, LDL, and HDL cholesterol and triglycerides in
      patients with coronary heart disease.
AB  - BACKGROUND: Diet-lipid associations established in clinical trials have in
      general been weak or nonexistent in cross-sectional studies within a population.
      Our objective was to analyze the dietary associates of serum lipids in patients
      with coronary heart disease (CHD) not using lipid-lowering medication. METHODS:
      Patients with coronary bypass grafting (n = 49), balloon angioplasty (n = 46),
      acute myocardial infarction (n = 79), and acute myocardial ischemia (n = 79)
      participated in a survey (EUROASPIRE). Patients were selected from hospital
      records at least 6 months after hospitalization. Diet was assessed by a food
      record, a short questionnaire, and fatty acid composition of serum cholesteryl
      esters (CE). RESULTS: Neither the intake of total fat nor that of saturated,
      monounsaturated, or polyunsaturated fatty acids was associated with serum lipids.
      Use of soft margarine on bread (though not in cooking or baking) and high intake
      of fiber and cereal products were associated with low total cholesterol. Linoleic
      acid in CE was inversely associated with total cholesterol and triglycerides, and
      eicosapentaenoic acid was inversely associated with triglycerides and positively
      associated with HDL cholesterol. CONCLUSIONS: In the present study use of soft
      margarine on bread (though not in cooking or baking) and high intake of fiber and
      cereal products were associates of lowered serum cholesterol concentrations in
      CHD patients. Fatty acid composition of CE reflected dietary fatty acid intake
      involved in cholesterol lowering better than food records.

PMID- 10404554
TI  - Relationship between cigarette dose and perceived risk of lung cancer.
AB  - BACKGROUND: Most people are aware that smoking cigarettes increases the risk of
      ill health, in particular of lung cancer. The precise way in which they relate
      amount of exposure to smoke and level of health risk has not, however, been
      determined. METHODS: A convenience sample of 155 French adolescents and adults
      ages 15 to 75 rated the risk of "smoker's cancer"--the popular term for lung
      cancer--in 24 scenarios depicting eight levels of daily cigarette consumption of
      three concentrations of nicotine. The data were analyzed according to functional
      measurement methodology to ascertain the forms of the relationship between
      exposure and perceived risk. RESULTS: All subjects perceived that the risk of
      smoker's cancer increased as smoking increased. Yet at high levels of
      consumption, additional cigarettes were generally judged to result in decreasing
      increments of risk, regardless of the nicotine content of the cigarettes and the
      sex and smoking status of the participants. Adolescents, however, were more
      likely than adults to perceive a linear, rather than a negatively accelerated,
      relationship. CONCLUSIONS: The actual form of the relationship between the dose
      of cigarette smoke and risk of lung cancer is either linear or positively
      accelerated. Public health educators and physicians should be aware that, at
      least in France, many people, particularly adults, incorrectly perceive this
      relationship as negatively accelerated.

PMID- 10404555
TI  - Screening mammography and late-stage breast cancer: a population-based study.
AB  - BACKGROUND: Among 50- to 69-year-old women, randomized clinical trials show
      breast cancer mortality reductions from screening mammography. However, few
      studies examine the long-term health effects and outcomes from screening
      mammography in community practice. The purpose of this study was to evaluate one
      approach for determining the effectiveness of screening mammography, as it is
      practiced in community settings, and to measure the prevalence of prior screening
      mammography among women with incident breast cancer. METHODS: This study was a
      population-based survey of the general community. Participants were 406 women
      with breast cancer diagnosed in 1993. The main outcome measure was breast cancer,
      late stage at diagnosis or fatal within 2 to 3 years of diagnosis. RESULTS: Sixty
      four (57.7%) of 111 women with late-stage and 123 (42.1%) of 292 women with early
      stage breast cancer did not have a screening mammogram in the 4 calendar years
      (1989-1992) before diagnosis. Relative to women with early-stage breast cancer,
      mammography nonuse in 1989-1992 was significantly more frequent among women with
      late-stage breast cancer (age-adjusted odds ratio 2.3, 95% confidence interval
      1.3-4.3). Prior mammography was particularly infrequent among 42 women with
      breast cancer incident in 1993 and fatal before January 1996. CONCLUSIONS: Prior
      mammography among women with late-stage or fatal breast cancer was relatively
      infrequent. Late-stage or fatal breast cancer lacking prior mammography
      constitutes a missed public health opportunity. Also, this population-based study
      showed the expected association between prior mammography and late-stage or fatal
      breast cancer. These results are consistent with the effective practice of
      mammography in a community setting. The results illustrate and validate a public
      health approach that uses prior mammography histories among women with incident
      breast cancer to evaluate mammography penetration and quality in defined
      communities.

PMID- 10404556
TI  - Characteristics associated with exposure to and participation in a televised
      smoking cessation intervention program for women with high school or less
      education.
AB  - OBJECTIVES: This paper estimates the prevalence of exposure to and participation
      in a televised smoking cessation intervention targeting women with high school or
      less education and describes characteristics related to exposure and
      participation. METHODS: A random sample of the population of female smokers with
      high school or less education in the Chicago metropolitan area was used to
      estimate the prevalence of exposure to a targeted smoking cessation intervention
      with television and booklet components (n = 722). Multiple logistic regression
      analysis was used to examine characteristics related to exposure to each
      component and participation, defined as simultaneous use of both components, in a
      sample of population and registrants combined (n = 1,727). RESULTS: About one of
      every four women in the target population either saw the television series or
      called for the booklet (24.5%); 17.5% saw the television series, 9.4% called for
      the booklet, and 2.4% both saw the television series and called for the booklet.
      Independent predictors of booklet exposure were black, older age, annual income
      $40,000 or less, heavier smoking, and higher stage of readiness to quit.
      Adjusting for booklet exposure, independent predictors of television exposure
      were older age and nonblack. Independent predictors of participation were black,
      older age, and higher stage of readiness to quit. CONCLUSIONS: The intervention
      reached a substantial portion of low-educated female smokers. Women who were
      older, black, or at higher stages of readiness to quit were most likely to be
      exposed and to participate. Heavier smokers or lower income women were most
      likely to be exposed but not necessarily to participate.

PMID- 10404557
TI  - Hazards of smoking initiation among Asian American and non-Asian adolescents in
      California: a survival model analysis.
AB  - BACKGROUND: Information about the risk of smoking initiation among whites,
      African Americans, and Latino Americans has provided an important information
      base for smoking prevention programs among adolescents from these ethnic
      backgrounds. Unfortunately, there is a lack of such information for Asian
      Americans, a fast-growing ethnic minority group with much internal diversity.
      METHOD: This study used cross-sectional data from 20,482 subjects 12-17 years of
      age, randomly sampled in California, to describe and compare the risk of smoking
      initiation for adolescents by age among Asian American and other non-Asian ethnic
      groups, using survival analysis. Computer-aided telephone interview techniques
      were used in data collection. RESULT: The risk of early smoking initiation among
      Asian American adolescents is about a third of that of Caucasians. However, the
      risk among Asian Americans continues to increase throughout adolescence, while
      the same risk among Caucasians and African Americans plateaus around 14-15 years
      of age. Significant differences in the levels and patterns of smoking initiation
      among Asian American subgroups were observed, with Chinese Americans showing the
      lowest risk of smoking initiation and Filipino Americans the highest, Japanese
      and Korean Americans being in-between. CONCLUSION: Asian American adolescents may
      be especially at risk of smoking initiation later in adolescence, even though
      they are at lower risk early in adolescence. Smoking prevention programs for
      Asian Americans should continue throughout adolescence and early adulthood.

PMID- 10404558
TI  - A pill for all by the year 2000?

PMID- 10404559
TI  - Perceived barriers to physical activity among high school students.
AB  - BACKGROUND: Perceived barriers to physical activity, the factor structure of
      perceived barriers, and the relationship between perceived barriers and
      participation in vigorous physical activity were examined. METHODS: A two-stage
      cluster sample of high school students (N = 1,041) in a large Metropolitan
      Toronto school district was used. Students completed a questionnaire (response
      rate 81.4%) dealing with participation in physical activity in three settings.
      Factor analysis was used to examine the dimensionality of perceived barriers.
      Multiple regression analysis was then used to examine the relationship between
      perceived barriers and participation. RESULTS: Time constraints due to school
      work, other interests, and family activities were three of the four barriers
      considered most important. Females cited consistently higher levels of perceived
      barriers than males. Two empirically distinct and theoretically meaningful
      factors emerged from the analysis--perceived internal barriers and perceived
      external barriers. Perceived internal barriers were predictive of physical
      activity in overall activity and outside of school activity. Perceived external
      barriers were predictive of overall physical activity and other school activity,
      but in the direction opposite to that hypothesized. CONCLUSIONS: It was concluded
      that perceived barriers may be predictive of physical activity participation
      among high school students only under specific conditions.

PMID- 10404560
TI  - Re: Turkish smokeless tobacco "Maras Powder".

PMID- 10404561
TI  - Proton magnetic resonance spectroscopy: clinical applications in children with
      nervous system diseases.
AB  - With the use of software modifications of existing magnetic resonance imaging
      technology, proton magnetic resonance spectroscopy yields insight noninvasively
      regarding brain biochemistry. Biochemical information can be obtained directly
      both regionally and longitudinally. This article summarizes the technological
      basis for magnetic resonance spectroscopy as well as its established applications
      to disorders of interest to the pediatric neurologist. Future directions for
      magnetic resonance spectroscopy study and advances to be expected in the near
      future are also highlighted.

PMID- 10404562
TI  - Functional magnetic resonance imaging in children.
AB  - Functional magnetic resonance imaging (fMRI) allows for the noninvasive mapping
      of the anatomical location of disparate functional brain activities. The means
      for carrying out fMRI involves the use of existing MR technology coupled with a
      special software image acquisition program or the use of a specially designed
      head coil. Thus far in pediatric neurology, fMRI has assisted in the presurgical
      localization of critical functions and the investigation of various developmental
      activities. The technique of fMRI, its applications in pediatric neuroscience,
      and future potential are outlined in this article.

PMID- 10404563
TI  - Diffusion-weighted magnetic resonance imaging: theory and potential applications
      to child neurology.
AB  - Magnetic resonance imaging (MRI) is an excellent tool for the investigation of
      neurological disorders in children. Diffusion-weighted MRI (DWI) is sensitive to
      the diffusion (or molecular displacement) of water in tissue. The purpose of this
      article is to describe briefly the basic theory behind DWI and to discuss its
      potential applications to neurological disorders in children. We demonstrate that
      DWI is a sensitive technique for the detection of acute brain injury, and that it
      is well suited for monitoring brain development, particularly myelination and
      white matter changes.

PMID- 10404564
TI  - New technologies in pediatric neurology. Near-infrared spectroscopy.
AB  - Near-infrared spectroscopy (NIRS) is a relatively new technology that offers the
      enormous advantage of making measurements in vivo of changes in cerebral
      hemodynamics and oxygenation. Because NIRS is noninvasive and portable, it can
      provide real-time measurements of these changes at the bedside. Thus NIRS is
      ideally suited to the study of many physiological and pathological processes
      affecting the brain, particularly in the infant or young child in the intensive
      care unit or operating room. This review outlines the basic principles,
      advantages, and limitations of the current state of NIRS technology. An emphasis
      is placed on the animal and clinical studies that are relevant to the field of
      child neurology, with an eye to the future evolution and potential applications
      of this promising technique.

PMID- 10404565
TI  - Positron emission tomography in pediatric neurology.
AB  - Positron emission tomography (PET) is an accurate and relatively noninvasive way
      of studying brain activity using systemically administered tracers labeled with
      positron emitting isotopes. In pediatric neurology, it has great scope not only
      to elucidate the complexities of the developing brain but also to understand
      disease processes and characterize biological risk factors. Its greatest clinical
      utility lies in the field of epilepsy where it is used (in patients with
      intractable partial epilepsy) to localize epileptogenic foci for surgical
      resection. In addition, functional brain mapping using PET is increasingly being
      used to reliably and accurately identify speech and sensory-motor areas to
      minimize postoperative morbidity. PET is also useful in evaluating
      neurodegenerative disorders and cognitive abnormalities when magnetic resonance
      imaging scans are unrevealing. The technology continues to progress rapidly
      through improvements in imaging and radiopharmacology with potential applications
      in neurooncology, cerebral vascular disease, and metabolic diseases.

PMID- 10404566
TI  - Computerized EEG monitoring.
AB  - Monitoring of central nervous system function in the intensive care unit is
      becoming more widely accepted as an integral part of critical care. The history
      of developments in electroencephalogram (EEG) technology is reviewed to better
      appreciate the rate of technological developments and their application to
      clinical practice. Basic concepts of digital EEG are reviewed. Principals of
      intensive care unit monitoring as they apply to clinical neurophysiological
      techniques are examined to better understand the goals for an "ideal central
      nervous system monitor." Some current advances and directions for future
      development in computerized EEG monitoring are discussed.

PMID- 10404567
TI  - Stability of the whole lumbar spine after multilevel fenestration and discectomy.
AB  - STUDY DESIGN: An investigation of the in vitro biomechanical effects of
      multilevel fenestrations and discectomies on the behavior of whole lumbar spine
      motion, using a material testing system (Instron 1341, Instron Limited, High
      Wycombe, England) and Elite three-dimensional motion analysis system (BTS,
      Milano, Italy). OBJECTIVES: To investigate the effects of multilevel
      fenestrations and discectomies on the stability of the whole lumbar spine,
      including segmental stiffness and sagittal (horizontal and vertical) translation.
      SUMMARY OF BACKGROUND DATA: In the management of lumbar spinal stenosis, wide
      decompressive laminectomy with partial or total facetectomy has been the standard
      procedure for multilevel nerve decompression. Main complications with these
      procedures have been instability and chronic pain syndrome. Multilevel
      fenestration with undermining enlargement of the spinal canal has been selected
      for multilevel nerve decompression in recent years. However, the biomechanical
      effects of multilevel fenestration and discectomy have been controversial and
      difficult to validate. This study investigated the in vitro biomechanical effects
      of multilevel fenestrations and discectomies on motion behavior of the whole
      lumbar spine. METHODS: Seven fresh human specimens from L1 to sacrum were used in
      this study. The fenestrations and discectomies consisted of L3-L4 bilateral
      fenestration, L4-L5 bilateral fenestration, L5-S1 bilateral fenestration, L4-L5
      discectomy, and L5-S1 discectomy. Flexion, lateral bending, and axial rotation
      (torsion) loading were applied. Ranges of motion were determined two
      dimensionally by the Elite system with an infrared camera. The postoperation
      results were compared with the intact conditions. RESULTS: After multiple
      fenestrations, the sagittal ranges of motion at L4-L5 increased by 18%
      anteroposteriorly and 16% vertically under the flexion loads. At L5-S1, the
      motions increased by 19% and 45%, respectively. After fenestrations and
      discectomies, the ranges of motion in the sagittal plane increased by 28%
      horizontally and 71% vertically at L4-L5, and 14% and 166% at L5-S1. Motion
      increases were statistically significant (P < 0.05) in vertical translations.
      However, after the multilevel surgeries, no significant motions were found in
      each of the lumbar segments during lateral bending and axial rotation.
      CONCLUSIONS: The results demonstrate that multilevel fenestrations and
      discectomies affect lumbar spinal stability in flexion, but have no effect on the
      stability of the lumbar spine in lateral bending or axial rotation.

PMID- 10404568
TI  - Evaluation of cervical laminectomy and laminoplasty. A longitudinal study in the
      goat model.
AB  - STUDY DESIGN: An evaluation of the longitudinal radiologic changes up to 6 months
      induced by multilevel laminectomy and laminoplasty and the biomechanical
      responses in the goat model, complemented by biomechanical studies of intact
      specimens. OBJECTIVES: To determine the long-term radiographic differences and
      biomechanical responses of laminectomy and laminoplasty in an in vivo animal
      model. SUMMARY OF BACKGROUND DATA: Previous clinical and laboratory studies have
      indicated that multilevel laminectomy can cause increased flexibility in the
      cervical spinal column. Although the potential for laminoplasty to resolve these
      changes has been suggested, other evaluations have not supported this contention.
      Clarification of this controversy with long-term in vivo studies has not been
      performed. METHODS: Ten adult goats were divided into two groups, one undergoing
      C3-C5 laminectomy and the other open-door laminoplasty. Lateral cervical spine
      radiographs were obtained at 4-week intervals for a 6-month period. After the
      goats were killed, biomechanical testing was performed using pure moment loading
      on the surgically treated specimens and on three intact (without surgery)
      cervical spinal columns. RESULTS: In the laminectomy preparations, the cervical
      curvature index was noted to decrease by 59% at 16 weeks (P < 0.028) and by 70%
      at 24 weeks (P < 0.002), whereas the decrease in laminoplasty was not
      significantly different. Biomechanical testing indicated a significantly
      increased sagittal-plane slack motion in the laminectomy group (55 degrees)
      compared with that in intact specimens (39 degrees), but no significant
      difference between the laminoplasty and intact groups with respect to this
      motion. Laminectomy was found to be significantly stiffer (36%) in flexion than
      in extension, whereas the contrary was true for laminoplasty (37%). CONCLUSIONS:
      Radiographic and biomechanical results in the goat model suggest that
      laminoplasty is superior to laminectomy in maintaining cervical alignment and
      preventing postoperative spinal deformities.

PMID- 10404569
TI  - Development of the Neck Pain and Disability Scale. Item analysis, face, and
      criterion-related validity.
AB  - STUDY DESIGN: The development and testing of a new comprehensive measure of neck
      pain and disability, the Neck Pain and Disability Scale. OBJECTIVES: To provide
      an initial evaluation of the Neck Pain and Disability Scale's reliability and
      validity. SUMMARY OF BACKGROUND DATA: Although several measures exist for
      generalized pain and disability, none is specific for neck pain. More specific
      measurements should improve assessment of treatments and clinical research aimed
      at cervical pain syndromes. METHODS: The Neck Pain and Disability Scale was
      designed using the Million Visual Analogue Scale as a template and consists of 20
      items that assess neck pain. In this study, 100 patients with neck pain, 52
      patients with lower back and leg pain, and 27 pain-free volunteers were rated by
      the Neck Pain and Disability Scale. In addition, a subset of the 47 patients with
      neck pain were rated by several other established psychometric instruments.
      RESULTS: An item analysis showed a high degree of internal consistency among the
      20 items on the Neck Pain and Disability Scale (r = 0.93), and face validity was
      established by comparing patients who had neck pain as well as lower back and leg
      pain with a pain-free group. The Neck Pain and Disability Scale scores correlated
      with the Oswestry Disability Questionnaire, the Pain Disability Index, and
      psychological measures of depression and neuroticism. CONCLUSIONS: The results
      suggest a highly reliable instrument for evaluating neck pain with at least four
      underlying dimensions. Further work to address the predictive validity of this
      new tool are under way.

PMID- 10404570
TI  - Anterior interbody fusion of the cervical spine with coralline hydroxyapatite.
AB  - STUDY DESIGN: A nonrandomized, retrospective human study of patients requiring
      anterior discectomy and reconstruction from C3 to T1. The pattern of
      incorporation, presence or absence of disc space collapse, maintenance of
      correction, and clinical outcomes were considered. OBJECTIVE: To determine the
      efficacy of coralline hydroxyapatite as a bone replacement in anterior interbody
      fusions of the cervical spine used in conjunction with rigid plate fixation.
      SUMMARY OF THE BACKGROUND DATA: Autograft is the gold standard for anterior
      interbody fusion of the cervical spine. Reported complication and morbidity rates
      with the use of autograft are as high as 21%. Using allograft instead of
      autograft presents numerous problems including lower rates of fusion. Other bone
      substitutes such as ceramics and polymethylmethacrylate are ineffective for
      fusion. METHODS: Twenty-six skeletally mature patients underwent anterior
      decompression, stabilization, microdiscectomy, and reconstruction with Pro Osteon
      200 (Interpore Cross International, Irvine, CA) coralline hydroxyapatite and AO
      anterior cervical locking plates. Iliac crest autograft, local bone, and
      allograft were not used. RESULTS: The minimum follow-up period was 2 years
      (average, 30 months). There was no evidence of plate breakage, screw breakage,
      resorption of the implant, or pseudarthrosis. Two patterns of incorporation were
      identified. The implant incorporated totally in 100% of the disc spaces. Average
      hospital stay was 1.6 days. The average decrease in pain was 75.8%. There was no
      evidence of nonunion. CONCLUSIONS: The use of Pro Osteon 200 with rigid anterior
      plating seems promising as a bone replacement in the cervical spine. The
      incorporation rate is exceedingly high, and the complication rate nonexistent.

PMID- 10404571
TI  - Process measures and patient/parent evaluation of surgical management of spinal
      deformities in patients with progressive flaccid neuromuscular scoliosis
      (Duchenne's muscular dystrophy and spinal muscular atrophy).
AB  - STUDY DESIGN: Fifty-four consecutive patients with flaccid neuromuscular
      scoliosis (33 with Duchenne's muscular dystrophy, 21 with spinal muscular
      atrophy) who had undergone surgery for their disorder between 1985 and 1995 were
      sent questionnaires to evaluate function, self-image, cosmesis, pain, pulmonary
      status, patient care, quality of life, and satisfaction. Forty-eight patients
      returned the questionnaires. OBJECTIVE: To assess patient/parent satisfaction and
      clinical/functional ways in which spinal fusion helped or did not benefit these
      patients and to assess complications and the ultimate radiographic result.
      SUMMARY OF BACKGROUND DATA: There are only a few reports of results of spinal
      fusion and segmental instrumentation for flaccid neuromuscular disorders. There
      are no published reports regarding patient/parent evaluation of the procedure.
      METHODS: Results of the questionnaire were tallied, graded, and divided into
      eight categories. The questionnaire was validated by a Cronbach's alpha analysis,
      a test-retest, and a comparison with questionnaire answers from patients with
      idiopathic scoliosis. Radiographic data and complications also were accumulated.
      The follow-up periods after surgery ranged from 2 to 12.6 years (average, 7.8
      years). RESULTS: Except for two patients who died within 3 months of surgery, all
      patients seemed to have benefited from the surgery. Cosmesis, quality of life,
      and overall satisfaction rated the highest. CONCLUSION: These data indicate that
      spinal fusion with segmental spinal instrumentation benefits most patients with
      Duchenne's muscular dystrophy or spinal muscular atrophy with spinal deformities
      in terms of all categories assessed, even though these diseases have a
      progressively deteriorating course.

PMID- 10404572
TI  - Kinematics of the chest cage and spine during breathing in healthy individuals
      and in patients with adolescent idiopathic scoliosis.
AB  - STUDY DESIGN: The lung function test by a Plethysmograph enabled calculations to
      be made of the total lung capacity and vital capacity. A Motion Analysis System
      (Elite, BTS Inc., Milano, Italy) was used to observe and record chest cage and
      spinal movements and as to correlate lung function with the chest cage and spine
      kinematics. OBJECTIVES: To determine the three-dimensional kinematics and the
      shape and size changes of the chest cage and thoracic spine motion during deep
      breathing in healthy and scoliotic individuals. SUMMARY OF BACKGROUND DATA:
      Lateral flexion plus rotation of the involved vertebrae around a vertical axis
      causing a decrease in lung function is the main disfigurement of scoliosis.
      Reports show that even after spinal fusion, reduced vital capacity associated
      with an increased residual volume are detected. Factors such as angle of
      scoliosis, length of the spinal column involved, and duration of the deformity
      influence pulmonary function but do not significantly affect its reduction.
      Mechanical inefficiency during breathing has not been studied. METHODS: Three
      dimensional kinematics of the chest cage and spine during breathing were studied
      in 41 scoliotic patients and in 20 healthy individuals. Three-dimensional chest
      cage motions relative to the spine and thoracic spine motions relative to T12
      were calculated. To examine stiffness of the spine, lateral bending angles were
      calculated. The lung function test, which including spirometry and lung
      subdivision, also was performed for the scoliotic patients. RESULTS: Significant
      differences (P < 0.05) were found in the movements of the upper level of the
      chest cage in anteroposterior and vertical directions, ranging from 16.7 to 28.6
      mm in healthy individuals and from 12.1 to 24.2 mm in scoliotic patients. The
      thoracic spine displayed two-dimensional movements posteriorly and vertically
      during breathing, whereas less movement was seen in scoliotic patients. In
      addition, overall the scoliotic spine showed signs of stiffness in lateral
      bending. CONCLUSIONS: The range of movement of the chest cage and spine is more
      limited in the scoliotic cases. This overall stiffness of the chest cage and the
      spine may contribute to the mechanical inefficiency and impairment of pulmonary
      function found in scoliotic patients.

PMID- 10404573
TI  - Recurrent low back pain and early disc degeneration in the young.
AB  - STUDY DESIGN: A prospective 9-year follow-up study involving randomized matched
      subgroups of 15-year-old schoolchildren with or without low back pain at
      baseline. OBJECTIVES: To evaluate the long-term persistence of initially reported
      recurrent low back pain, and to examine the significance of abnormalities found
      in magnetic resonance imaging of lumbar discs in individuals 15 and 18 years of
      age as possible contributors to persistently recurrent low back pain. SUMMARY OF
      BACKGROUND DATA: In surveys among children and teenagers during the past few
      years, as many as half of all children in a community report a history of low
      back pain. The current results, in accordance with previous findings, indicate
      that there is a subgroup of adolescents with more chronic symptoms which, in the
      authors' opinion, deserves more attention. Disc disease accompanying low back
      pain is a key issue both in research and clinical practice. The significance of
      early degenerative findings in the lumbar discs is not known. METHODS: In the
      survey of 14-year-olds (n = 1503), a subgroup (7.8%) with recurrent low back pain
      was found. A random sample of individuals with recurrent low back pain (n = 40)
      and an equal number of completely asymptomatic control subjects were selected for
      a comparative study. The selected groups were examined by magnetic resonance
      imaging at 15 and 18 years of age. The participation rate of youth at 14, 18, and
      23 years of age for all three questionnaires was 82% (29 boys and 33 girls).
      Imaging data were interpreted by two blinded radiologists experienced in low
      field-strength magnetic resonance imaging. In calculations of relative risks, the
      participants reporting recurrent low back pain in all phases of the study were
      compared with participants who had no persistently recurrent pain. RESULTS:
      Eleven participants (35%) in the original group with low back pain persistently
      reported recurrent pain. In 15-year-old participants with disc degeneration, the
      relative risk of reporting recurrent low back pain up to the age of 23 years was
      16 (95% confidence interval 2.2-118) compared with those having no disc
      degeneration. In addition, disc protrusion and Scheuermann-type changes at 15
      years contributed to the risk of persistently recurrent low back pain.
      CONCLUSIONS: The authors' earlier findings already favored the hypothesis of a
      causal relation between the early evolution of a degenerative process of lower
      lumbar discs and recurrent low back pain in the near future. The current results
      further strengthen this hypothesis, indicating that individuals with disc
      degeneration soon after the phase of rapid physical growth not only have an
      increased risk of recurrent low back pain at this age, but also a long-term risk
      of recurrent pain up to early adulthood.

PMID- 10404574
TI  - The effect of lumbar fatigue on the ability to sense a change in lumbar position.
      A controlled study.
AB  - STUDY DESIGN: A cross-sectional study in patients with recurrent/chronic low back
      trouble and healthy control subjects. OBJECTIVE: To evaluate the effect of
      paraspinal muscle fatigue on the ability to sense a change in lumbar position.
      SUMMARY OF BACKGROUND DATA: Protection against spinal injury requires proper
      anticipation of events, appropriate sensation of body position, and reasonable
      muscular responses. Lumbar fatigue is known to delay lumbar muscle responses to
      sudden loads. It is not known whether the delay is because of failure in the
      sensation of position, output of the response, or both. METHODS: Altogether, 106
      subjects (57 patients with low back trouble [27 men and 30 women] and 49 healthy
      control subjects [28 men and 21 women]) participated in the study. Their ability
      to sense a change in lumbar position while seated on a special trunk rotation
      unit was assessed. A motor rotated the seat with an angular velocity of 1 degree
      per second. The task in the test involved reacting to the perception of lumbar
      movement (rotation) by releasing a button with a finger movement. The test was
      performed twice, before and immediately after a fatiguing procedure. During the
      endurance task, the participants performed upper trunk repetitive extensions
      against a resistance, with a movement amplitude adjusted between 25 degrees
      flexion and 5 degrees extension, until exhaustion. RESULTS: Patients with chronic
      low back trouble had significantly poorer ability than control subjects on the
      average to sense a change in lumbar position (P = 0.007), which was noticed
      before and after the fatiguing procedure. Lumbar fatigue induced significant
      impairment in the sensation of position change (P < 0.000001). CONCLUSIONS:
      Lumbar fatigue impairs the ability to sense a change in lumbar position. This
      feature was found in patients and control subjects, but patients with low back
      trouble had poorer ability to sense a change in lumbar position than control
      subjects even when they were not fatigued. There seems to be a period after a
      fatiguing task during which the available information on lumbar position and its
      changes is inaccurate.

PMID- 10404575
TI  - Effect of paraspinal muscle vibration on position sense of the lumbosacral spine.
AB  - STUDY DESIGN: A two-group experimental design with repeated measures on one
      factor was used. OBJECTIVES: To investigate the role of the muscle spindles of
      the paraspinal muscles in lumbosacral position sense of healthy individuals.
      SUMMARY OF BACKGROUND DATA: Muscle spindles are recognized to be important
      mediators for position and movement sense in peripheral joints, and they are very
      sensitive to mechanical vibration. However, little is known about their role in
      the control of lumbosacral spine positioning. METHODS: Twenty-five young
      individuals with no low back pain were assigned at random to an experimental or
      control group. Proprioceptive information of the multifidus muscle spindles was
      distorted in half of the trials in 16 individuals by manually applying vibration
      (70 Hz, 0.5 mm amplitude) for approximately 5 seconds. The control group (n = 9)
      only heard the vibrator noise during repositioning of the lumbosacral spine.
      Repositioning accuracy in the sitting position was estimated by calculating the
      mean absolute error, constant error, and variable error among six criteria and
      reproduction sacral tilt angles. RESULTS: Multifidus muscle vibration induced a
      significant muscle lengthening illusion through which the members of the
      experimental group undershot the target position (F(1,15) = 30.77, P < 0.0001).
      The position sense scores of the control group displayed no significant
      differences across trials (F(1,8) = 0.56, P > 0.05). CONCLUSIONS: The findings
      suggest that precise muscle spindle input of the paraspinal muscles is essential
      for accurate positioning of the pelvis and lumbosacral spine in a sitting
      posture.

PMID- 10404576
TI  - Management of nonspecific low back pain by physiotherapists in Britain and
      Ireland. A descriptive questionnaire of current clinical practice.
AB  - STUDY DESIGN: A descriptive questionnaire of chartered physiotherapists.
      OBJECTIVE: To investigate current physiotherapeutic management of low back pain
      throughout Britain and Ireland. SUMMARY OF BACKGROUND DATA: Physiotherapists play
      a key role in low back pain management. Although clinical guidelines for best
      practice have been developed recently, there has been no large-scale attempt to
      describe current physiotherapeutic treatment approaches within Britain or
      Ireland. METHODS: After semi-structured interviews (n = 6) and two pilot studies
      (n = 77) were done, postal questionnaires were distributed to four regional
      cluster samples of the membership of two physiotherapy professional organizations
      (n = 2654). After two mailings, a random sample of 90 nonresponders were followed
      up. Data were analyzed using the Statistical Package for the Social Sciences
      (SPSS Ltd., Woking, Surrey, UK), and precision of the survey estimates was
      assessed by calculation of sampling errors and intraclass correlation
      coefficients for cluster sampling. RESULTS: Results were received from 1548
      therapists (total response rate, 58.3%); of these, 813 reported that they were
      practicing in settings in which they treated patients with low back pain.
      Analysis of the results indicated the overall popularity of the Maitland
      mobilization and McKenzie approaches among physiotherapists. Although exercise
      per se was mentioned frequently by respondents, a marked difference in opinion
      among therapists regarding the optimal type of exercise for low back pain was
      obvious. Little evidence was demonstrated of the use of manipulation, fitness
      programs, or multidisciplinary efforts involving behavioral and physical aspects
      of treatment. Commonly used methods of electrotherapy were interferential
      therapy, ultrasound, pulsed short-wave diathermy, and transcutaneous electrical
      nerve stimulation. CONCLUSIONS: The results of this study emphasize the need to
      evaluate further and improve the dissemination of findings regarding the
      effectiveness of specific physiotherapy approaches for low back pain management.

PMID- 10404577
TI  - Maximal isometric strength of the cervical musculature in 100 healthy volunteers.
AB  - STUDY DESIGN: A descriptive study involving maximal isometric strength
      measurements of the cervical musculature. OBJECTIVES: To determine the maximal
      isometric strength of the flexors and extensors and of the cervical musculature
      in 100 healthy volunteers (50 men and 50 women). SUMMARY OF BACKGROUND DATA: The
      literature contains only a few descriptive studies pertaining to strength levels
      of the cervical musculature. These studies include small subject populations, and
      measurement methods have demonstrated weak reliability. METHODS: Testing was
      carried out using strain-gauge technology on a neck muscle training apparatus.
      RESULTS: A reliability study demonstrated acceptable intraday and day-to-day
      values. Maximal isometric strength was approximately 20% to 25% higher in male
      subjects than female subjects in both flexion and extension from the third to the
      sixth decades. In the seventh decade, the women's strength levels surpassed
      values for men in both flexion and extension. Extension-flexion ratios were
      approximately 1.7 to 1 in both the men and women participants. The men
      demonstrated a significant decrease in maximal isometric strength with increasing
      age in both flexion and extension, whereas the women were able to maintain
      strength values in the ages tested. CONCLUSIONS: Men and women demonstrate
      impressive levels of muscular strength in the flexors and extensors of the
      cervical spine and can maintain these values until the seventh decade of life.
      Successful rehabilitation of the cervical musculature will require considerable
      resistance for sufficient stimulation of the cervical musculature.

PMID- 10404578
TI  - A double-blind study of capacitively coupled electrical stimulation as an adjunct
      to lumbar spinal fusions.
AB  - STUDY DESIGN: A randomized double-blind prospective comparison with a placebo
      control. This report of the results is the first in an ongoing study. OBJECTIVES:
      To evaluate the effect of noninvasive capacitively coupled electrical stimulation
      on the success rate of lumbar spine fusion surgery, and to compare active with
      placebo stimulators as adjuncts to contemporary fusion techniques. SUMMARY OF
      BACKGROUND DATA: Previous studies have established the effectiveness of direct
      current and electromagnetic field stimulation as adjuncts for some forms of
      spinal fusion. None of the previous placebo-controlled studies on external bone
      stimulation included posterolateral fusion techniques, and most were conducted
      with prior generations of internal fixation hardware. METHODS: The investigation
      was conducted by 28 U.S. surgeons. Patients with a primary diagnosis of
      degenerative disc disease with or without other degenerative changes were
      selected. The study protocol defined success as a clinical outcome rated as
      excellent or good and a fusion documented as solid by both the investigator and
      the blinded independent radiologist. Disagreements on radiographic success were
      resolved by a second blinded independent reviewer. RESULTS: For the 179 patients
      who completed treatment and evaluation, the overall protocol success rate (both
      clinical and radiographic results rated as successes) was 84.7% for the active
      patients and 64.9% for the placebo patients. This difference is highly
      significant according to the Yates corrected chi-square test (P = 0.0043). Best
      improvements in patient outcomes (20% or greater success rate) occurred when
      active stimulation was used in conjunction with posterolateral fusion (P = 0.006)
      and when internal fixation also was incorporated (P = 0.013). DISCUSSION: This
      study was consistent in that active stimulation improved results for each
      stratification, although some strata had insufficient numbers of patients for the
      results to have statistical significance. Improved success rates when
      capacitively coupled stimulation is added to internal fixation are hypothesized
      to result from overcoming the biochemical effects of stress shielding.
      CONCLUSIONS: Capacitively coupled stimulation is an effective adjunct to primary
      spine fusion, especially for patients with posterolateral fusion and those with
      internal fixation.

PMID- 10404579
TI  - The efficacy of using an image-guided Kerrison punch in performing an anterior
      cervical foraminotomy. An anatomic analysis.
AB  - STUDY DESIGN: This study comprised two parts: first, a feasibility study to
      determine the efficacy of using an image-guided Kerrison punch while performing a
      foraminotomy during an anterior cervical decompression and, second, an anatomic
      analysis using vector measurement to determine the distance from the entrance of
      the neuroforamen to the medial margin of the vertebral artery in the subaxial
      cervical spine. OBJECTIVE: To assess the feasibility of using an image-guided
      Kerrison punch when performing an anterior foraminotomy and to obtain data
      regarding the distance from the vertebral artery to the entrance of the
      neuroforamen. SUMMARY OF BACKGROUND DATA: The documented incidence of
      catastrophic iatrogenic vertebral artery injury in anterior cervical
      decompression is low. The use of a real-time image-guidance surgical system
      should reduce the risk of this complication. METHODS: Twelve cadaveric cervical
      spines were harvested. Standard anterior cervical discectomies with bilateral
      foraminotomies were performed in the subaxial cervical spine using an image
      guided Kerrison. Surgically significant morphometric data were measured using a
      computer-assisted image-guided surgical system. RESULTS: Successful navigation
      into all neuroforamina in the subaxial cervical spine was attained using the
      image-guided Kerrison punch. The vector measurement from the neuroforamen to the
      vertebral artery averaged 5.8 +/- 1.2 mm at C3-C4, 6.5 +/- 1.6 mm at C4-C5, 7.9
      +/- 1.4 mm at C5-C6, and 9.1 +/- 1.8 mm at C6-C7. Statistically significant
      differences (P < 0.05) were found between all cervical levels except C3-C4 and C4
      C5. CONCLUSION: An image-guided Kerrison punch may be used successfully when
      performing cervical foraminotomies during an anterior cervical discectomy, thus
      eliminating the risk of potential vertebral artery injury. These data confirm
      previous findings by other authors. Knowledge of these data may aid the spine
      surgeon in performing a foraminotomy during anterior cervical decompression.

PMID- 10404580
TI  - Recapping T-saw laminoplasty for spinal cord tumors.
AB  - STUDY DESIGN: A prospective study of patients whose spinal cord tumors were
      managed surgically with a unique posterior method of removing and replacing the
      posterior spinal elements using T-saw ("recapping T-saw laminoplasty").
      OBJECTIVES: To examine the safety and efficacy of the recapping T-saw
      laminoplasty technique for spinal canal surgery. SUMMARY OF BACKGROUND DATA:
      Laminectomy, laminoplasty, and/or laminotomy typically are used to approach
      intraspinal lesions. When removal and replacement of the posterior elements have
      been attempted, the effectiveness of the technique has been limited by the amount
      of bone sacrificed when using burrs or osteotomes. The authors thought to adapt a
      unique "threadwire saw" (T-saw) in these cases, because its use results in
      minimal bone loss. METHODS: Patients underwent recapping T-saw laminoplasty in
      the thoracic or lumbar spine for extirpation of spinal cord tumors. The T-saw was
      used for division of the posterior elements. After resection of the lesion, the
      excised laminae were replaced exactly in situ to their original anatomic
      position. The mean follow-up period was 47 months (range, 31-71 months). Patients
      were observed neurologically and radiologically. RESULTS: One to eight laminae
      were excised and replaced in 24 patients. Findings on computed tomography scans
      confirmed primary bony union in 23 patients by 6 months after surgery, and in one
      patient by 12 months after surgery. No complications such as postoperative spinal
      canal stenosis, facet arthrosis, or kyphosis were observed. CONCLUSIONS:
      Recapping laminoplasty afforded anatomic reconstruction of the vertebral arch
      after excision of spinal cord tumors. This procedure appears to warrant further
      evaluation as an alternative to wide laminectomies for exposure of intraspinal
      tumors.

PMID- 10404581
TI  - Accuracy of blind versus fluoroscopically guided caudal epidural injection.
AB  - STUDY DESIGN: A prospective observational study of a case series of patients with
      low back pain referred for epidural injection of corticosteroid. OBJECTIVES: To
      evaluate the accuracy of caudal epidural injections performed without the use of
      fluoroscopic guidance and to determine the value of specific clinical tests
      performed during the procedure in predicting successful epidural needle
      placement. SUMMARY OF BACKGROUND DATA: Epidural injection of corticosteroid is
      one of many treatments currently used in the nonsurgical management of low back
      pain. The face validity of many studies evaluating the efficacy of epidural
      corticosteroid injections has been criticized for use of a blind technique.
      Although there currently is no consensus in the spine literature as to whether
      epidural injection of corticosteroid (by any technique) is effective, it is
      imperative first to establish the accuracy of the technique being used. METHODS:
      A total of 54 consecutive patients underwent fluoroscopically guided caudal
      epidural injections. Needle insertion was performed blindly (without the use of
      fluoroscopic guidance), and the success of needle placement was predicted
      according to the presence of palpable landmarks, palpation of subcutaneous
      airflow, and the subjective impression that the needle was in a satisfactory
      position. These clinical criteria then were compared with the position of the
      needle as seen under fluoroscopy and the spread of radio-opaque contrast in the
      epidural space after the procedure. RESULTS: Successful injection placement on
      the first attempt occurred in 74.1% of the patients. Results were improved when
      anatomic landmarks were identified easily (87.5%) and no air was palpable
      subcutaneously over the sacrum when injected through the needle (82.9%). The
      combination of these two signs predicted a successful injection in 91.3% of
      attempts. CONCLUSIONS: Caudal epidural injection is performed ideally with
      fluoroscopic guidance as the gold standard for accurate drug placement. If
      fluoroscopic guidance is unavailable, impractical, or contraindicated, the
      presence of readily palpable anatomic landmarks at the sacral hiatus and the
      absence of palpable subcutaneous airflow over the sacrum significantly increase
      the operator's confidence in the likelihood of an accurate injection even before
      any products are administered into the epidural space.

PMID- 10404582
TI  - Multiple gigantic arteriovenous malformations with destruction of lumbar
      vertebral bodies. A case report.
AB  - STUDY DESIGN: This case report describes a patient with massive intramuscular and
      paravertebral arteriovenous malformations with destruction of vertebral bodies.
      OBJECTIVES: To demonstrate successful interbody fusion of the involved vertebral
      bodies after embolization for arteriovenous malformation. SUMMARY OF BACKGROUND
      DATA: Although arteriovenous malformations in the spinal cord are well documented
      in the literature, arteriovenous malformation in the paravertebral and iliopsoas
      muscles with destruction of vertebral bodies is an extremely rare clinical
      condition. METHODS: After careful investigation with angiography, the
      arteriovenous malformations were managed with embolization, and the scoliosis
      caused by the collapsed vertebral bodies was managed surgically by anterior
      spinal fusion with segmental spinal instrumentation. RESULTS: The patient's
      scoliosis caused by vertebral collapse was corrected by surgery, and good
      alignment of the lumbar spine was achieved. The preoperation pain had subsided
      completely by follow-up assessment 1 year and 10 months after fusion. However,
      the arteriovenous malformations still remained. Careful observation should be
      maintained continuously in the coming days. CONCLUSION: In arteriovenous
      malformations with destruction of the vertebral bodies, embolization and spinal
      fusion with segmental instrumentation may be necessary to relieve pain and
      prevent the progression of spinal deformity. Arteriovenous malformation should be
      considered in the diagnostic evaluation of a patient who has experienced
      vertebral collapse with no inflammatory signs.

PMID- 10404584
TI  - The use and interpretation of diagnostic nerve root blocks.

PMID- 10404583
TI  - Hippocrates. The father of spine surgery.
AB  - Hippocrates (5th-4th century B. C.), the founder of scientific medicine, left a
      valuable heritage of knowledge and methodology, which extends to almost all
      branches of modern medicine. Among the many fields of medicine he explored, he
      devoted much of his scientific interest to the study of orthopedics. In fact,
      some of the principles found in the Hippocratic treatises On Fractures and On
      Joints are still valid today. This great physician also was the first to deal
      with the anatomy and the pathology of human spine. In his books, he provides a
      precise description of the segments and the normal curves of the spine, the
      structure of the vertebrae, the tendons attached to them, the blood supply to the
      spine, and even its anatomic relations to adjacent vessels. The Hippocratic list
      of spinal diseases includes tuberculous spondylitis, post-traumatic kyphosis,
      scoliosis, concussion, dislocations of the vertebrae, and fractures of the
      spinous processes. Hippocrates devised two apparatuses, known as the Hippocratic
      ladder and the Hippocratic board, to reduce displaced vertebrae. Those pioneer
      methods are deemed to be the precursors to the sophisticated techniques used in
      spine surgery today. Because of his thorough study of spinal diseases and their
      management, which was the first such study in orthopedics in the history of
      medicine, Hippocrates should be regarded as the father of spine surgery.

PMID- 10404585
TI  - Low back facet joint anesthesia.

PMID- 10404586
TI  - The orientation of the sacroiliac joint portions influence their radiologic
      appearance.

PMID- 10404587
TI  - There's a right way and a wrong way: in vivo and in vitro folding, misfolding and
      subunit assembly of the P22 tailspike.
AB  - The in vivo and in vitro folding, assembly and misfolding of an elongated
      protein, the thermostable tailspike adhesin of phage P22, reveals important
      aspects of the sequence control of chain folding as well as its failure mode,
      inclusion body formation.

PMID- 10404588
TI  - Of barn owls and bankers: a lush variety of alpha/beta hydrolases.
AB  - alpha/beta Hydrolase fold proteins are an important, diverse, widespread group of
      enzymes not yet fully exploited by structural biologists. We describe the current
      state of knowledge of this family, and suggest a smaller definition of the
      required core and some possible future avenues of exploration.

PMID- 10404589
TI  - Protein plasticity to the extreme: changing the topology of a 4-alpha-helical
      bundle with a single amino acid substitution.
AB  - BACKGROUND: Conventional wisdom has it that two proteins sharing 98.4% sequence
      identity have nearly identical three-dimensional structures. Here we provide a
      counter-example to this statement by showing that a single amino acid
      substitution can change the topology of a homodimeric 4-alpha-helical bundle
      protein. RESULTS: We have determined the high-resolution crystal structure of a 4
      alpha-helical protein with a single alanine to proline mutation in the turn
      region, and show that this single amino acid substitution leads to a complete
      reorganisation of the whole molecule. The protein is converted from the canonical
      left-handed all-antiparallel form, to a right-handed mixed parallel and
      antiparallel bundle, which to the best of our knowledge and belief represents a
      novel topological motif for this class of proteins. CONCLUSIONS: The results
      suggest a possible new mechanism for the creation and evolution of topological
      motifs, show the importance of loop regions in determining the allowable folding
      pathways, and illustrate the malleability of protein structures.

PMID- 10404590
TI  - Crystal structure of the Atx1 metallochaperone protein at 1.02 A resolution.
AB  - BACKGROUND: Metallochaperone proteins function in the trafficking and delivery of
      essential, yet potentially toxic, metal ions to distinct locations and particular
      proteins in eukaryotic cells. The Atx1 protein shuttles copper to the transport
      ATPase Ccc2 in yeast cells. Molecular mechanisms for copper delivery by Atx1 and
      similar human chaperones have been proposed, but detailed structural
      characterization is necessary to elucidate how Atx1 binds metal ions and how it
      might interact with Ccc2 to facilitate metal ion transfer. RESULTS: The 1.02 A
      resolution X-ray structure of the Hg(II) form of Atx1 (HgAtx1) reveals the
      overall secondary structure, the location of the metal-binding site, the detailed
      coordination geometry for Hg(II), and specific amino acid residues that may be
      important in interactions with Ccc2. Metal ion transfer experiments establish
      that HgAtx1 is a functional model for the Cu(I) form of Atx1 (CuAtx1). The metal
      binding loop is flexible, changing conformation to form a disulfide bond in the
      oxidized apo form, the structure of which has been solved to 1.20 A resolution.
      CONCLUSIONS: The Atx1 structure represents the first structure of a
      metallochaperone protein, and is one of the largest unknown structures solved by
      direct methods. The structural features of the metal-binding site support the
      proposed Atx1 mechanism in which facile metal ion transfer occurs between metal
      binding sites of the diffusible copper-donor and membrane-tethered copper
      acceptor proteins. The Atx1 structural motif represents a prototypical metal ion
      trafficking unit that is likely to be employed in a variety of organisms for
      different metal ions.

PMID- 10404591
TI  - Crystal structure of human bleomycin hydrolase, a self-compartmentalizing
      cysteine protease.
AB  - BACKGROUND: Bleomycin hydrolase (BH) is a cysteine protease that is found in all
      tissues in mammals as well as in many other eukaryotes and prokaryotes. Although
      its conserved cellular function is as yet unknown, human bleomycin hydrolase
      (hBH) has clinical significance in that it is thought to be the major cause of
      tumor cell resistance to bleomycin chemotherapy. In addition, it has been
      reported that an allelic variant of hBH is genetically linked to Alzheimer's
      disease. RESULTS: We have determined the crystal structures of wild-type hBH and
      of a mutant form of the enzyme. The overall structure is very similar to that of
      the previously determined yeast homolog, however, there is a striking difference
      in the charge distribution. The central channel, which has a strong positive
      electrostatic potential in the yeast protein, is slightly negative in hBH. We
      have determined that hBH does not have the DNA-binding activity of the yeast
      protein and that the enzyme is localized to the cytoplasm. CONCLUSIONS: The
      difference in charge distribution between the yeast and human BH enzymes is most
      likely responsible for the difference in DNA-binding activity. Nevertheless, the
      C-terminal autoprocessing activity and the role of the C terminus as a
      determinant for peptidase activity are conserved between the yeast and human
      forms. The structure of hBH suggests that the putative Alzheimer's disease linked
      variation does not directly alter the intrinsic peptidase activity. Rather, the
      position of the mutation suggests that it could affect interactions with another
      protein, which may modulate peptidase activity through repositioning of the C
      terminus.

PMID- 10404592
TI  - The structure of human 5'-deoxy-5'-methylthioadenosine phosphorylase at 1.7 A
      resolution provides insights into substrate binding and catalysis.
AB  - BACKGROUND: 5'-Deoxy-5'-methylthioadenosine phosphorylase (MTAP) catalyzes the
      reversible phosphorolysis of 5'-deoxy-5'-methylthioadenosine (MTA) to adenine and
      5-methylthio-D-ribose-1-phosphate. MTA is a by-product of polyamine biosynthesis,
      which is essential for cell growth and proliferation. This salvage reaction is
      the principle source of free adenine in human cells. Because of its importance in
      coupling the purine salvage pathway to polyamine biosynthesis MTAP is a potential
      chemotherapeutic target. RESULTS: We have determined the crystal structure of
      MTAP at 1.7 A resolution using multiwavelength anomalous diffraction phasing
      techniques. MTAP is a trimer comprised of three identical subunits. Each subunit
      consists of a single alpha/beta domain containing a central eight-stranded mixed
      beta sheet, a smaller five-stranded mixed beta sheet and six alpha helices. The
      native structure revealed the presence of an adenine molecule in the purine
      binding site. The structure of MTAP with methylthioadenosine and sulfate ion
      soaked into the active site was also determined using diffraction data to 1.7 A
      resolution. CONCLUSIONS: The overall quaternary structure and subunit topology of
      MTAP are similar to mammalian purine nucleoside phosphorylase (PNP). The
      structures of the MTAP-ligand complexes provide a map of the active site and
      suggest possible roles for specific residues in substrate binding and catalysis.
      Residues accounting for the differences in substrate specificity between MTAP and
      PNP are also identified. Detailed information about the structure and chemical
      nature of the MTAP active site will aid in the rational design of inhibitors of
      this potential chemotherapeutic target. The MTAP structure represents the first
      structure of a mammalian PNP that is specific for 6-aminopurines.

PMID- 10404593
TI  - Are predicted structures good enough to preserve functional sites?
AB  - BACKGROUND: A principal goal of structure prediction is the elucidation of
      function. We have studied the ability of computed models to preserve the
      microenvironments of functional sites. In particular, 653 model structures of a
      calcium-binding protein (generated using an ab initio folding protocol) were
      analyzed, and the degree to which calcium-binding sites were recognizable was
      assessed. RESULTS: While some model structures preserve the calcium-binding
      microenvironments, many others, including some with low root mean square
      deviations (rmsds) from the crystal structure of the native protein, do not.
      There is a very weak correlation between the overall rmsd of a structure and the
      preservation of calcium-binding sites. Only when the quality of the model
      structure is high (rmsd less than 2 A for atoms in the 7 A local neighborhood
      around calcium) does the modeling of the binding sites become reliable.
      CONCLUSIONS: Protein structure prediction methods need to be assessed in terms of
      their preservation of functional sites. High-resolution structures are necessary
      for identifying binding sites such as calcium-binding sites.

PMID- 10404594
TI  - Structural analysis of the lymphocyte-specific kinase Lck in complex with non
      selective and Src family selective kinase inhibitors.
AB  - BACKGROUND: The lymphocyte-specific kinase Lck is a member of the Src family of
      non-receptor tyrosine kinases. Lck catalyzes the initial phosphorylation of T
      cell receptor components that is necessary for signal transduction and T-cell
      activation. On the basis of both biochemical and genetic studies, Lck is
      considered an attractive cell-specific target for the design of novel T-cell
      immunosuppressants. To date, the lack of detailed structural information on the
      mode of inhibitor binding to Lck has limited the discovery of novel Lck
      inhibitors. RESULTS: We report here the high-resolution crystal structures of an
      activated Lck kinase domain in complex with three structurally distinct ATP
      competitive inhibitors: AMP-PNP (a non-selective, non-hydrolyzable ATP analog);
      staurosporine (a potent but non-selective protein kinase inhibitor); and PP2 (a
      potent Src family selective protein tyrosine kinase inhibitor). Comparison of
      these structures reveals subtle but important structural changes at the ATP
      binding site. Furthermore, PP2 is found to access a deep, hydrophobic pocket near
      the ATP-binding cleft of the enzyme; this binding pocket is not occupied by
      either AMP-PNP or staurosporine. CONCLUSIONS: The potency of staurosporine
      against Lck derives in part from an induced movement of the glycine-rich loop of
      the enzyme upon binding of this ligand, which maximizes the van der Waals
      interactions present in the complex. In contrast, PP2 binds tightly and
      selectively to Lck and other Src family kinases by making additional contacts in
      a deep, hydrophobic pocket adjacent to the ATP-binding site; the amino acid
      composition of this pocket is unique to Src family kinases. The structures of
      these Lck complexes offer useful structural insights as they demonstrate that
      kinase selectivity can be achieved with small-molecule inhibitors that exploit
      subtle topological differences among protein kinases.

PMID- 10404595
TI  - Soft docking an L and a D peptide to an anticholera toxin antibody using internal
      coordinate mechanics.
AB  - BACKGROUND: The tremendous increase in sequential and structural information is a
      challenge for computer-assisted modelling to predict the binding modes of
      interacting biomolecules. One important area is the structural understanding of
      protein-peptide interactions, information that is increasingly important for the
      design of biologically active compounds. RESULTS: We predicted the three
      dimensional structure of a complex between the monoclonal antibody TE33 and its
      cholera-toxin-derived peptide epitope VPGSQHID. Using the internal coordinate
      mechanics (ICM) method of flexible docking, the bound conformation of the
      initially extended peptide epitope to the antibody crystal or modelled structure
      reproduced the known binding conformation to a root mean square deviation of
      between 1.9 A and 3.1 A. The predicted complexes are in good agreement with
      binding data obtained from substitutional analyses in which each epitope residue
      is replaced by all other amino acids. Furthermore, a de novo prediction of the
      recently discovered TE33-binding D peptide dwGsqhydp (single-letter amino acid
      code where D amino acids are represented by lower-case letters) explains results
      obtained from binding studies with 172 peptide analogues. CONCLUSIONS: Despite
      the difficulties arising from the huge conformational space of a peptide, this
      approach allowed the prediction of the correct binding orientation and the
      majority of essential binding features of a peptide-antibody complex.

PMID- 10404596
TI  - Crystal structure of the ATPase domain of translation initiation factor 4A from
      Saccharomyces cerevisiae--the prototype of the DEAD box protein family.
AB  - BACKGROUND: Translation initiation factor 4A (elF4A) is the prototype of the DEAD
      box family of proteins. DEAD-box proteins are involved in a variety of cellular
      processes including splicing, ribosome biogenesis and RNA degradation. Energy
      from ATP hydrolysis is used to perform RNA unwinding during initiation of mRNA
      translation. The presence of elF4A is required for the 43S preinitiation complex
      to bind to and scan the mRNA. RESULTS: We present here the crystal structure of
      the nucleotide-binding domain of elF4A at 2.0 A and the structures with bound
      adenosinediphosphate and adenosinetriphosphate at 2.2 A and 2.4 A resolution,
      respectively. The structure of the apo form of the enzyme has been determined by
      multiple isomorphous replacement. The ATPase domain contains a central seven
      stranded beta sheet flanked by nine alpha helices. Despite low sequence homology
      to the NTPase domains of RNA and DNA helicases, the three-dimensional fold of
      elF4A is nearly identical to the DNA helicase PcrA of Bacillus stearothermophilus
      and to the RNA helicase NS3 of hepatitis C virus. CONCLUSIONS: We have determined
      the crystal structure of the N-terminal domain of the elF4A from yeast as the
      first structure of a member of the DEAD-box protein family. The complex of the
      protein with bound ADP and ATP offers insight into the mechanism of ATP
      hydrolysis and the transfer of energy to unwind RNA. The identical fold of the
      ATPase domain of the DNA helicase PcrA of B. stearothermophilus and the RNA
      helicase of hepatitis C virus suggests a common fold for all ATPase domains of
      DExx- and DEAD-box proteins.

PMID- 10404597
TI  - NMR structure of the N-terminal domain of E. coli DnaB helicase: implications for
      structure rearrangements in the helicase hexamer.
AB  - BACKGROUND: DnaB is the primary replicative helicase in Escherichia coli. Native
      DnaB is a hexamer of identical subunits, each consisting of a larger C-terminal
      domain and a smaller N-terminal domain. Electron-microscopy data show hexamers
      with C6 or C3 symmetry, indicating large domain movements and reversible pairwise
      association. RESULTS: The three-dimensional structure of the N-terminal domain of
      E. coli DnaB was determined by nuclear magnetic resonance (NMR) spectroscopy.
      Structural similarity was found with the primary dimerisation domain of a
      topoisomerase, the gyrase A subunit from E. coli. A monomer-dimer equilibrium was
      observed for the isolated N-terminal domain of DnaB. A dimer model with C2
      symmetry was derived from intermolecular nuclear Overhauser effects, which is
      consistent with all available NMR data. CONCLUSIONS: The monomer-dimer
      equilibrium observed for the N-terminal domain of DnaB is likely to be of
      functional significance for helicase activity, by participating in the switch
      between C6 and C3 symmetry of the helicase hexamer.

PMID- 10404598
TI  - Crystal structure of the N-terminal domain of the DnaB hexameric helicase.
AB  - BACKGROUND: The hexameric helicase DnaB unwinds the DNA duplex at the Escherichia
      coli chromosome replication fork. Although the mechanism by which DnaB both
      couples ATP hydrolysis to translocation along DNA and denatures the duplex is
      unknown, a change in the quaternary structure of the protein involving
      dimerization of the N-terminal domain has been observed and may occur during the
      enzymatic cycle. This N-terminal domain is required both for interaction with
      other proteins in the primosome and for DnaB helicase activity. Knowledge of the
      structure of this domain may contribute to an understanding of its role in DnaB
      function. RESULTS: We have determined the structure of the N-terminal domain of
      DnaB crystallographically. The structure is globular, highly helical and lacks a
      close structural relative in the database of known protein folds. Conserved
      residues and sites of dominant-negative mutations have structurally significant
      roles. Each asymmetric unit in the crystal contains two independent and identical
      copies of a dimer of the DnaB N-terminal domain. CONCLUSIONS: The large-scale
      domain or subunit reorientation that is seen in DnaB by electron microscopy might
      result from the formation of a true twofold symmetric dimer of N-terminal
      domains, while maintaining a head-to-tail arrangement of C-terminal domains. The
      N-terminal domain of DnaB is the first region of a hexameric DNA replicative
      helicase to be visualized at high resolution. Comparison of this structure to the
      analogous region of the Rho RNA/DNA helicase indicates that the N-terminal
      domains of these hexameric helicases are structurally dissimilar.

PMID- 10404599
TI  - A dimeric ternary complex of FGFR [correction of FGFR1], heparin and FGF-1 leads
      to an 'electrostatic sandwich' model for heparin binding.
AB  - BACKGROUND: Fibroblastic growth factors (FGFs) are a family of cytokines involved
      in regulation of cell growth, differentiation and chemotaxis in a variety of
      tissue types. High-affinity FGF receptors (FGFRs) are transmembrane proteins that
      consist of three extracellular immunoglobulin-like domains, a transmembrane helix
      and an intracellular protein tyrosine kinase signalling domain. FGFRs are
      activated through ligand-dependent dimerization that allows trans
      autophosphorylation of the tyrosine kinase domains. Heparin or heparin-like
      molecules, such as heparan sulphate proteoglycans, bind to both FGFs and FGFRs
      and are required for FGF signal transduction. At present no structure of the
      ternary complex for FGFR, FGF and heparin exists. RESULTS: We have used the type
      1 interleukin-1 receptor-interleukin-1 beta complex crystal structure, in which
      both the ligand and the receptor are homologous to those of the FGF-FGFR pair, to
      identify potential interactions in the FGFR-heparin-FGF ternary complex. A key
      feature of the modelled complex is the 'electrostatic sandwich' that is formed
      between the positively charged surfaces of FGF and the receptor, with the
      negatively charged heparin captured in between. The ternary complex places limits
      on the range of likely modes of receptor dimerization: one of five different
      dimeric receptor complexes built from the ternary complex correlates best with
      the experimental data. CONCLUSIONS: The ternary complex of FGFR, FGF and heparin,
      derived on the basis of the homologous interleukin-1 receptor complex, is in
      agreement with much of the published experimental data, as is the dimeric
      receptor complex (FGFR-heparin-FGF)2. This work suggests that the FGF
      interactions seen in crystal structures, which have previously been used to
      predict the mode of FGF dimerization, might not be relevant to the biologically
      active dimeric FGFR-heparin-FGF complex.

PMID- 10404601
TI  - Belgian food crisis deepens.

PMID- 10404600
TI  - Filamentous phage infection: crystal structure of g3p in complex with its
      coreceptor, the C-terminal domain of TolA.
AB  - BACKGROUND: Infection of male Escherichia coli cells by filamentous Ff
      bacteriophages (M13, fd, and f1) involves interaction of the phage minor coat
      gene 3 protein (g3p) with the bacterial F pilus (primary receptor), and
      subsequently with the integral membrane protein TolA (coreceptor). G3p consists
      of three domains (N1, N2, and CT). The N2 domain interacts with the F pilus,
      whereas the N1 domain--connected to N2 by a flexible glycine-rich linker and
      tightly interacting with it on the phage--forms a complex with the C-terminal
      domain of TolA at later stages of the infection process. RESULTS: The crystal
      structure of the complex between g3p N1 and TolA D3 was obtained by fusing these
      domains with a long flexible linker, which was not visible in the structure,
      indicating its very high disorder and presumably a lack of interference with the
      formation of the complex. The interface between both domains, corresponding to
      approximately 1768 A2 of buried molecular surface, is clearly defined. Despite
      the lack of topological similarity between TolA D3 and g3p N2, both domains
      interact with the same region of the g3p N1 domain. The fold of TolA D3 is not
      similar to any previously known protein motifs. CONCLUSIONS: The structure of the
      fusion protein presented here clearly shows that, during the infection process,
      the g3p N2 domain is displaced by the TolA D3 domain. The folds of g3p N2 and
      TolA D3 are entirely different, leading to distinctive interdomain contacts
      observed in their complexes with g3p N1. We can now also explain how the
      interactions between the g3p N2 domain and the F pilus enable the g3p N1 domain
      to form a complex with TolA.

PMID- 10404602
TI  - Weighing the benefits against the costs: the welfare implications of
      biotechnology.

PMID- 10404603
TI  - Nematode control practices and anthelmintic resistance in dairy calves in the
      south west of England.
AB  - A postal survey of worming practices on West Country dairy farms was undertaken
      and farmers were requested to send faecal samples for nematode egg counts. The
      majority of the farmers who responded had a nematode control policy which was
      based on a mixture of anthelmintics and pasture rotation. Sixty-five per cent
      turned out calves on to the same paddock each year and 57 per cent treated their
      stock with anthelmintics during the second year. Ninety farms submitted samples
      for analysis but only 16 samples contained sufficient eggs to justify repeat egg
      counts and only eight of these produced enough eggs for in vitro tests. The small
      number of positive samples, even into the latter part of the year suggests a
      heavy use of anthelmintics with relatively clean pasture. One Somerset farm had
      larvae which developed in high concentrations of ivermectin, and eggs were still
      being passed after two treatments with ivermectin at the manufacturer's
      recommended dose seven days apart. Of 100 male nematodes isolated from two of the
      calves, 88 were Cooperia species and 12 were Nematodirus species. A controlled
      trial with this isolate in eight Friesian male calves showed a 44 per cent
      reduction in egg counts at day 7 but no significant reduction in worm burden
      postmortem. This is the first reported case of ivermectin-resistant Cooperia
      species in cattle in the United Kingdom.

PMID- 10404604
TI  - Clindamycin hydrochloride and clavulanate-amoxycillin in the treatment of canine
      superficial pyoderma.
AB  - A masked, randomised, controlled clinical trial for the treatment of canine
      superficial pyoderma was undertaken. Dogs with a clinical diagnosis of
      superficial pyoderma, supported by bacterial culture were admitted to the trial
      and randomly assigned to treatment with either clindamycin hydrochloride at 5.5
      mg/kg twice daily or clavulanate-amoxycillin at 12.5 mg/kg twice daily. After 21
      days the animals were re-assessed, and therapy was continued for a further 21
      days in the dogs with persistent lesions if bacterial culture demonstrated
      continued sensitivity. Twenty-nine dogs were treated with clindamycin
      hydrochloride and 27 with clavulanate-amoxycillin. Complete cure was obtained
      after three weeks in 17 (59 per cent) of the clindamycin-treated cases, but in
      only eight (30 per cent) of the clavulanate-amoxycillin treated group.
      Clindamycin was significantly more effective than clavulanate-amoxycillin for the
      treatment of superficial pyoderma in dogs.

PMID- 10404605
TI  - Diagnosis of larval cyathostominosis in horses in Belgium.
AB  - Between October 1996 and May 1997, 94 horses which were suspected of being
      infected with strongyles were examined clinically, and samples of faeces were
      examined for strongyle eggs and cyathostome larvae (L4) and adults. Blood samples
      were monitored for total protein, albumin and beta-globulins. In 28 of the horses
      (30 per cent) cyathostome L4 and adults were detected in the faeces, and were
      significantly associated with the horses' condition, the occurrence of diarrhoea,
      with lower concentrations of total protein and albumin, and with higher
      percentages of beta-globulin. Thirty-four of the horses (36 per cent) were
      excreting strongyle eggs, but in these animals the associations were with high
      concentrations of total protein and albumin, and lower percentages of beta
      globulin. The results showed that during the winter, a horse in poor condition
      which has diarrhoea, an albumin concentration less than 20 g/litre, and a ratio
      of albumin:globulin less than 0.7 is very likely to be infected with L4 and adult
      stages of cyathostomes.

PMID- 10404607
TI  - Absence of serological evidence for human Neospora caninum infection.

PMID- 10404606
TI  - Effect of carprofen on lameness in broiler chickens.
AB  - Lameness is prevalent among broiler chickens and there is concern that it is
      chronically painful. The administration of an analgesic has been frequently used
      to identify pain in lame farm animals. Therefore, in this study the ability of
      lame and normal broiler chickens to traverse an obstacle course was tested after
      treatment with the analgesic, carprofen, a placebo saline injection or a control
      handling procedure. Sound birds traversed the course in approximately 11 seconds,
      irrespective of treatment. Lame birds took approximately 34 seconds to traverse
      the course, unless they received carprofen, which reduced their completion time
      to 18 seconds. Thus, carprofen substantially increased the speed of lame birds,
      providing evidence that birds with moderate lameness suffer pain when they walk.

PMID- 10404608
TI  - Pilot study to investigate the efficacy of a 1 per cent selenium sulphide shampoo
      in the treatment of equine chorioptic mange.

PMID- 10404610
TI  - Rhododendron poisoning in alpacas.

PMID- 10404609
TI  - Diagnosis of a haematoma in the uterine broad ligament associated with a dystocia
      in a cow using ultrasonography.

PMID- 10404611
TI  - In vivo measurement of radius calcium/phosphorus ratio by X-ray absorptiometry.
AB  - We describe a new method for assessing the skeletal Ca/P ratio in vivo using X
      ray absorptiometry. By placing cerium (Ce) and samarium (Sm) filters in the X-ray
      beam from a commercial X-ray source (Norland), mean photon energies of 39 and 89
      keV were obtained. The instrument was designed to take measurements of the
      forearm, at a site located at the distal 1/3 of the radius. The system was
      calibrated with three bone phantoms: Ca10(PO4)6(OH)2, Ca(HPO4)(H2O)2 and
      Ca(HPO4)2(H2O)). The precision for measuring the Ca/P ratio in the human radius
      was 2.3% CV for a skin dose to the forearm ranging from 0.3 to 0.4 mGy, depending
      on the width of the arm. The Ca/P ratio of the radius was significantly lower in
      patients with postmenopausal osteoporosis than in premenopausal controls.

PMID- 10404612
TI  - Radiosynthesis of [18F] N-3-fluoropropyl-2-beta-carbomethoxy-3-beta (4'
      methylphenyl) nortropane (FPCMT).
AB  - A synthetic procedure for the routine preparation of [18F] N-3-fluoropropyl-2
      beta-carbomethoxy-3-beta-(4' methylphenyl) nortropane (18F FPCMT) has been
      developed. The synthesis is based on alkylation of nortropane with 18F labeled
      fluoropropyl tosylate. Purification of the final product was achieved by a
      preparative HPLC procedure using Alltech Econosil column. Separation of the
      desired compound was achieved and the product was clean. The radiochemical yield
      (without decay correction) is 4 to 5%, calculated at the end of the synthesis
      based on the total amount of fluorine recovered from the target. Radiochemical
      purity was in the range of 98 to 99%.

PMID- 10404613
TI  - Determination of 129I in atmospheric samples by accelerator mass spectrometry.
AB  - A method for the radiochemical extraction of 129I from atmospheric charcoal
      filters and its measurement by accelerator mass spectrometry is presented. Either
      the 129I concentration or the 129I/127I atom ratio can be determined in the
      sample. With this method, air filters from Seville, in the Southwest of Spain
      (37.4 degrees N, 6 degrees W) have been analyzed. Sensitivities in the order of
      10(4) atoms/m3 for 129I concentrations and 10(-10) for 129I/127I atom ratios are
      obtained. AMS measurements are performed with the 6 MV tandem accelerator at the
      ETH-Honggerberg in Zurich.

PMID- 10404614
TI  - The spatial variability of Chernobyl-derived 137Cs inventories in a small
      agricultural drainage basin in central Russia.
AB  - Little information currently exists regarding the small-scale spatial variability
      of Chernobyl radiocaesium fallout and associated inventories. This contribution
      reports the results of a study of the variability of 137Cs inventories within the
      2.18-km2 Lapki balka catchment located near Tula in central Russia. The local
      area was characterized by 137Cs inventories in excess of 200 kBq m-2 immediately
      after the Chernobyl accident and pre-existing bomb-derived inventories can be
      ignored in view of their very low magnitude. Field sampling and measurements
      included both collection of soil cores for subsequent laboratory analysis and in
      situ field measurements using a CORAD portable detector. The results obtained
      show evidence of a systematic south-north increase in the reference inventory
      across the basin, which must be taken into account when interpreting subsequent
      radiocaesium redistribution within the basin. Random spatial variability of 137Cs
      inventories of a similar magnitude to that reported for bomb-derived fallout was
      also documented. The extent of random spatial variability varied between
      different geomorphological units. Maximum variability, with coefficients of
      variation up to 20%, was associated with areas of sediment accumulation within
      the balka bottoms. Substantial variability (cv. typically ca. 15%) was found
      within flat cultivated areas and undisturbed areas both on the interfluves and on
      the balka sides, all of which could serve as reference sites. Minimum variability
      (cv. typically ca. 12%) was associated with the cultivated slopes with no
      evidence of sediment accumulation.

PMID- 10404615
TI  - The biology of eukaryotic promoter prediction--a review.
AB  - Computational prediction of eukaryotic promoters from the nucleotide sequence is
      one of the most attractive problems in sequence analysis today, but it is also a
      very difficult one. Thus, current methods predict in the order of one promoter
      per kilobase in human DNA, while the average distance between functional
      promoters has been estimated to be in the range of 30-40 kilobases. Although it
      is conceivable that some of these predicted promoters correspond to cryptic
      initiation sites that are used in vivo, it is likely that most are false
      positives. This suggests that it is important to carefully reconsider the
      biological data that forms the basis of current algorithms, and we here present a
      review of data that may be useful in this regard. The review covers the following
      topics: (1) basal transcription and core promoters, (2) activated transcription
      and transcription factor binding sites, (3) CpG islands and DNA methylation, (4)
      chromosomal structure and nucleosome modification, and (5) chromosomal domains
      and domain boundaries. We discuss the possible lessons that may be learned,
      especially with respect to the wealth of information about epigenetic regulation
      of transcription that has been appearing in recent years.

PMID- 10404616
TI  - Protein-coding region discovery in organisms underrepresented in databases.
AB  - The prediction of coding sequences has received a lot of attention during the
      last decade. We can distinguish two kinds of methods, those that rely on training
      with sets of example and counter-example sequences, and those that exploit the
      intrinsic properties of the DNA sequences to be analyzed. The former are
      generally more powerful but their domains of application are limited by the
      availability of a training set. The latter avoid this drawback but can only be
      applied to sequences that are long enough to allow computation of the statistics.
      Here, we present a method that fills the gap between the two approaches. A
      learning step is applied using a set of sequences that are assumed to contain
      coding and non-coding regions, but with the boundaries of these regions unknown.
      A test step then uses the discriminant function obtained during the learning to
      predict coding regions in sequences from the same organism. The learning relies
      upon a correspondence analysis and prediction is presented on a graphical
      display. The method has been evaluated on a sample of yeast sequences, and the
      analysis of a set of expressed sequence tags from the Eucalyptus globulus
      Pisolithus tinctorius ectomycorrhiza illustrates the relevance of the approach in
      its biological context.

PMID- 10404617
TI  - A multi-agent system simulating human splice site recognition.
AB  - The present paper describes a method detecting splice sites automatically on the
      basis of sequence data and models of site/signal recognition supported by
      experimental evidences. The method is designed to simulate splicing and while
      doing so, track prediction failures, missing information and possibly test
      correcting hypotheses. Correlations between nucleotides in the splice site
      regions and the various elements of the acceptor region are evaluated and
      combined to assess compensating interactions between elements of the splicing
      machinery. A scanning model of the acceptor region and a model of interaction
      between the splicing complexes (exon definition model) are also incorporated in
      the detection process. Subsets of sites presenting deficiencies of several splice
      site elements could be identified. Further examination of these sites helps to
      determine lacking elements and refine models.

PMID- 10404618
TI  - Promoter analysis of co-regulated genes in the yeast genome.
AB  - The use of high density DNA arrays to monitor gene expression at a genome-wide
      scale constitutes a fundamental advance in biology. In particular, the expression
      pattern of all genes in Saccharomyces cerevisiae can be interrogated using
      microarray analysis where cDNAs are hybridized to an array of more than 6000
      genes in the yeast genome. In an effort to build a comprehensive Yeast Promoter
      Database and to develop new computational methods for mapping upstream regulatory
      elements, we started recently in an on going collaboration with experimental
      biologists on analysis of large-scale expression data. It is well known that
      complex gene expression patterns result from dynamic interacting networks of
      genes in the genetic regulatory circuitry. Hierarchical and modular organization
      of regulatory DNA sequence elements are important information for our
      understanding of combinatorial control of gene expression. As a bioinformatics
      attempt in this new direction, we have done some computational exploration of
      various initial experimental data. We will use cell-cycle regulated gene
      expression as a specific example to demonstrate how one may extract promoter
      information computationally from such genome-wide screening. Full report of the
      experiments and of the complete analysis will be published elsewhere when all the
      experiments are to be finished later in this year (Spellman, P.T., et al. 1998.
      Mol. Biol. Cell 9, 3273-3297).

PMID- 10404619
TI  - Sequence complexity and DNA curvature.
AB  - A linguistic complexity measure was applied to the complete genomes of HIV-1,
      Escherichia coli, Bacillus subtilis, Haemophilus influenzae, Mycoplasma
      genitalium, and to long human and yeast genomic fragments. Complexity values
      averaged over entire genomic sequences were compared, as were predicted average
      values of intrinsic DNA curvature. We found that both the most curved and the
      least complex fragments are located preferentially in non-coding parts of the
      genome. Analysis of location of the most curved and the simplest regions in
      bacteria showed that the low-complexity segments are preferentially located in
      close proximity to the highly curved sequences, which are, in turn, placed from
      100 to 200 bases upstream to the start of the nearest coding sequence. We
      conclude that the parallel analysis of sequence complexity and DNA curvature
      might provide important information about sequence-structure-function
      relationship in genomes.

PMID- 10404620
TI  - Zones of low entropy in genomic sequences.
AB  - We consider the problem of detecting regions having low entropy in DNA sequences,
      which is a particular case of searching for dos-DNA zones. The entropy is
      measured in linear time as the number of distinct segments occurring in the
      regions. As a consequence, we are able to determine regions containing a small
      number of repetitions of long segments or a large number of repetitions of short
      segments. The method provides an index on sequences that is applied to compare
      them without any alignment. Comparisons extract regions having similar
      combinatorial features that would not have been found by standard alignment
      methods. The present methodology is applied to Saccharomyces cerevisiae yeast
      chromosomes to show what the approach is able to produce.

PMID- 10404621
TI  - Statistical properties of open reading frames in complete genome sequences.
AB  - Some statistical properties of open reading frames in all currently available
      complete genome sequences are analyzed (seventeen prokatyotic genomes, and 16
      chromosome sequences from the yeast genome). The size distribution of open
      reading frames is characterized by various techniques, such as quantile tables,
      QQ-plots, rank-size plots (Zipf's plots), and spatial densities. The issue of the
      influence of CG% on the size distribution is addressed. When yeast chromosomes
      are compared with archaeal and eubacterial genomes, they tend to have more long
      open reading frames. There is little or no evidence to reject the null hypothesis
      that open reading frames on six different reading frames and two strands
      distribute similarly. A topic of current interest, the base composition asymmetry
      in open reading frames between the two strands, is studied using regression
      analysis. The base composition asymmetry at three codon positions is analyzed
      separately. It was shown in these genome sequences that the first codon position
      is G- and A-rich (i.e. purine-rich); there is a co-existence of A- and T-rich
      branches at the second codon position; and the third codon position is weakly T
      rich.

PMID- 10404622
TI  - Applications of the pyramidal clustering method to biological objects.
AB  - In conventional hierarchical clustering methods, any object can belong to only
      one class or cluster. We present here an application of the pyramidal
      classification method to biological objects, which illustrates the intuitively
      appealing idea that some objects may belong simultaneously to two classes. In a
      first step, we performed an all-by-all comparison of all the open reading frames
      in the genomes from S. cerevisiae, M. jannaschii, E. coli, H. influenzae and
      Synechocystis. In a second step, a series of connex classes was built, each
      connex class containing all those sequences that were linked by a Z-value
      (obtained after 100 sequence shufflings) greater than a given threshold. Finally,
      each connex class was submitted to a pyramidal classification. Three examples of
      such classifications are given, concerning two sets of multi-domains protein
      sequences and a family of aminoacyl-tRNA synthetases. They make it clear that the
      linear order among the classified objects that results from the pyramidal
      classification is useful in deciphering the multiple relationships that can exist
      between the objects under study. A program for calculating and displaying a
      pyramidal classification from a dissimilarity matrix is available from
      http:/(/)genome.genetique.uvsq.fr/Pyramids. The pyramidal classifications of the
      connex classes from the five organisms (intra- and inter-genomic comparisons) are
      available from http:/(/)www.gene-it.com under the family item.

PMID- 10404624
TI  - Two strategies for sequence comparison: profile-preprocessed and secondary
      structure-induced multiple alignment.
AB  - Multiple sequence alignment remains one of the most powerful tools for assessing
      sequence relateness and the identification of structurally and functionally
      important protein regions. In this work, two new techniques are introduced to
      increase the sensitivity of dynamic programming and to enable checks for
      alignment consistency: Profile-preprocessed and secondary structure-induced
      alignments. Both strategies are based upon the hierarchical dynamic programming
      technique and can be applied separately or used in combination. Alignments
      resulting from the strategies are shown in comparison with the multiple alignment
      methods CLUSTALX and MULTAL for distant sequence sets of the flavoxin and
      cupredoxin protein families.

PMID- 10404623
TI  - Whole genome protein domain analysis using a new method for domain clustering.
AB  - We present the outcome of a systematic analysis of protein domain shuffling in 17
      completed microbial genomes. This analysis has been performed using MKDOM Version
      2, a completely new version of the domain clustering program MKDOM based on PSI
      BLAST recursive homology searches. It allows to delineate the most frequent
      protein domain building blocks, which domains are found specifically in Bacteria,
      Archaea or yeast, and which domains are shared between two or all three domains
      of life. The latter are good candidates as the basic protein building blocks
      underlying all forms of cellular life. Statistics of multi-domain proteins
      indicate that some organisms such as Bacillus subtilis or Mycobacterium
      tuberculosis contain an abnormally high number of large multi-domain proteins. We
      also provide examples of highly shuffled or circularly permutated domains. A WWW
      graphical interface has been made available to interactively browse domain
      arrangements of proteins in all 17 genomes, at
      http:@www.toulouse.inra.fr/prodomCG.html.

PMID- 10404625
TI  - Iterated sequence databank search methods.
AB  - Iterated sequence databank search methods were assessed from the viewpoint of
      someone with the sequence of a novel gene product wishing to find distant
      relatives to their protein and, with the specific searches against the PDB, also
      hoping to find a relative of known structure. We examined three methods in
      detail, spanning a range from simple pattern-matching to sophisticated weighted
      profiles. Rather than apply these methods 'blindly' (with default parameters) to
      a large number of test queries, we have concentrated on the globins, so allowing
      a more detailed investigation of each method on different data subsets with
      different parameter settings. Despite their widespread use, regular-expression
      matching proved to be very limited-seldom extending beyond the sub-family from
      which the pattern was derived. To attain any generality, the patterns had to be
      'stripped-down' to include only the most highly conserved parts. The QUEST
      program avoided these problems by introducing a more flexible (weighted)
      matching. On the PDB sequences this was highly effective, missing only a few
      globins with probes based on each sub-family or even a single representative from
      each sub-family. In addition, very few false-positives were encountered, and
      those that did match, often only did so for a few cycles before being lost again.
      On the larger sequence collection, however, QUEST encountered problems with
      maintaining (or achieving) the alignment of the full globin family. psi-BLAST
      also recognised almost all the globins when matching against the PDB sequences,
      typically, missing three or four of the most distantly related sequences while
      picking-up a few false-positives. In contrast to QUEST, psi-BLAST performed very
      well on the larger databank, getting almost a full collection of globins although
      still retaining the same proportion of false-positives. SAM applied to the PDB
      sequences performed reasonably well with the myoglobin and hemoglobin families as
      probes, missing, typically several of the more difficult proteins but performed
      poorly with the leghemoglobin probe. Only with the full family range as a probe
      did it produce results comparable to psi-BLAST and QUEST. With the larger
      databank, SAM produced a good result but, again, this was only achieved using the
      full range of sequence variation with the default regulariser and use of
      Dirichlet mixtures completely failed in this situation.

PMID- 10404626
TI  - A bayesian statistical algorithm for RNA secondary structure prediction.
AB  - A Bayesian approach for predicting RNA secondary structure that addresses the
      following three open issues is described: (1) the need for a representation of
      the full ensemble of probable structures; (2) the need to specify a fixed set of
      energy parameters; (3) the desire to make statistical inferences on all variables
      in the problem. It has recently been shown that Bayesian inference can be
      employed to relax or eliminate the need to specify the parameters of
      bioinformatics recursive algorithms and to give a statistical representation of
      the full ensemble of probable solutions with the incorporation of uncertainty in
      parameter values. In this paper, we make an initial exploration of these
      potential advantages of the Bayesian approach. We present a Bayesian algorithm
      that is based on stacking energy rules but relaxes the need to specify the
      parameters. The algorithm returns the exact posterior distribution of the number
      of destabilizing loops, stacking energy matrices, and secondary structures. The
      algorithm generates statistically representative structures from the full
      ensemble of probable secondary structures in exact proportion to the posterior
      probabilities. Once the forward recursions for the algorithm are completed, the
      backward recursive sampling executes in O(n) time, providing a very efficient
      approach for generating representative structures. We demonstrate the utility of
      the Bayesian approach with several tRNA sequences. The potential of the approach
      for predicting RNA secondary structures and presenting alternative structures is
      illustrated with applications to the Escherichia coli tRNA(Ala) sequence and the
      Xenopus laevis oocyte 5S rRNA sequence.

PMID- 10404627
TI  - Automatic detection of conserved base pairing patterns in RNA virus genomes.
AB  - Almost all RNA molecules--and consequently also almost all subsequences of a
      large RNA molecule-form secondary structures. The presence of secondary structure
      in itself therefore does not indicate any functional significance. In fact, we
      cannot expect a conserved secondary structure for all parts of a viral genome or
      a mRNA, even if there is a significant level of sequence conservation. We present
      a novel method for detecting conserved RNA secondary structures in a family of
      related RNA sequences. The method is based on combining the prediction of base
      pair probability matrices and comparative sequence analysis. It can be applied to
      small sets of long sequences and does not require a prior knowledge of conserved
      sequence or structure motifs. As such it can be used to scan large amounts of
      sequence data for regions that warrant further experimental investigation.
      Applications to complete genomic RNAs of some viruses show that in all cases the
      known secondary structure features are identified. In addition, we predict a
      substantial number of conserved structural elements which have not been described
      so far.

PMID- 10404628
TI  - Findings in fatal cases of poisoning attributed to traditional remedies in South
      Africa.
AB  - An analysis of the Johannesburg forensic database over the years 1991-1995
      revealed 206 cases in which a traditional remedy was either stated to be the
      cause of death or was found to be present in a case of poisoning with an unknown
      substance. The range of toxins detected was wide, with herbal materials being
      found in 43% of cases, and pharmaceutical or agri-chemicals in 20% and 33%
      respectively. Since there are as yet no standard methods for the detection of
      many herbal remedies or their metabolites, careful analysis, using methods such
      as HPLC/MS, are mandatory for the correct identification of the true cause in
      cases of poisoning ascribed to traditional remedies.

PMID- 10404629
TI  - How and why does the platelet count in postmortem blood change during the early
      postmortem interval?
AB  - We examined the changes in the early postmortem platelet count in postmortem
      blood and the reasons for these changes by counting the platelets, by performing
      in vitro hypostatic tests, by estimating the percentage of erythrocytes by volume
      in postmortem blood samples, by immunohistochemistry (anti-CD61, anti
      fibrinogen), and by immunoelectron microscopy (anti-CD62, anti-CD63, anti
      thrombospondin). The apparent initial increase in the platelet count in
      postmortem blood was found to be caused by hypostatic phenomena. The subsequent
      discontinuous decrease in the platelet count despite continuing hypostasis in the
      corpse can be explained in part by postmortem thrombolysis and the development of
      reversible platelet-platelet aggregates. The main point is, that changes in the
      postmortem blood environment cause potentially reversible adhesion of platelets
      to pre-adsorbed fibrinogen on erythrocytes. Thus the decrease in the number of
      platelets in postmortem blood is not attributable to postmortem clotting but to a
      decrease in the number of countable platelets in postmortem blood.

PMID- 10404630
TI  - Population studies of the Y-chromosome specific polymorphisms DYS19, DYS389 I +
      II, DYS390 and DYS393 in a western German population (Bonn area).
AB  - Population studies were carried out on the Y-specific short tandem repeat (STR)
      systems DYS19, DYS389I + II, DYS390 and DYS393 in a Western German population
      sample. Determination of the allele frequencies revealed for all these systems,
      unimodal distribution. The number of observed alleles varied: five for DYS19, six
      for DYS390, three for DYS389I, seven for DYS389II and six for DYS393. In 102
      unrelated male individuals, 56 different haplotypes were found. The haplotype
      diversity values were similar to those of other European populations.

PMID- 10404631
TI  - Italian population data on two new short tandem repeat loci: D6S477 and D19S433.
AB  - A population study on two new short tandem repeat (STR) loci D6S477 and D19S433
      was performed on 214 unrelated Italian Caucasians. The DNA was amplified by PCR
      and separation and detection of the amplified STR fragments were carried out by
      use of a PE/ABD PRISM 377 DNA sequencer 377 automated system (Applied Biosystems
      Division/Perkin Elmer). Both loci meet Hardy-Weinberg expectations. There is no
      evidence for departures from expectations between the two loci. The combined
      probability of discrimination and probability of exclusion for the two STR loci
      are 0.997161 and 0.883183, respectively. The results demonstrate that these loci
      can be useful for human identification in forensic cases in Italy.

PMID- 10404632
TI  - Testing for anabolic steroids in hair from two bodybuilders.
AB  - Two male bodybuilders were recently arrested by the French customs in Strasbourg
      (France) in possession of 2050 tablets and 251 ampoules of various anabolic
      steroids. It was claimed that the steroids were for personal use and not for
      trafficing as suggested by the police. Urine and hair specimens were collected
      from both suspects to clarify the claims. Nandrolone, stanozolol, testosterone
      and their corresponding metabolites were identified in the urine of both
      subjects. After decontamination, the hair was hydrolyzed by sodium hydroxide in
      presence of deuterated internal standards. After extraction with ethyl acetate
      and silylation, the drugs were identified by GC-MS in the electron impact mode.
      Hair from both males were positive for nandrolone (196 and 260 pg/mg),
      testosterone (46 and 71 pg/mg) and stanozolol (135 and 156 pg/mg), clearly
      indicating steroids abuse. Although not yet recognized by the International
      Olympic Committee, hair analysis may be a useful adjunct to conventional drug
      testing in urine from athletes.

PMID- 10404634
TI  - An unusual case of suicide by stabbing with a falling weighted dagger.
AB  - An unusual suicide by self-stabbing is presented. A 42-year-old man committed
      suicide with a dagger weighted with 2.72 kg in total and allowed to fall freely.
      The blade of the dagger fell from a height of 10 cm above the chest, penetrated
      the second left intercostal skin and pierced the upper lobe of the left lung.
      However, the weapon did not penetrate the chest skin from a stationary position
      in our trial at the autopsy. This finding confirms the results of experiments
      with stab wound dynamics which demonstrated that the impact velocity of the
      weapon as well as the sharpness of the tip is important for skin penetration.

PMID- 10404633
TI  - Intra- and perioral shooting fatalities.
AB  - Determination of the manner of death in the case of intra- and perioral firearm
      wounds can be difficult especially if death scene investigation is unclear and
      inadequate. In this study, we investigated some characteristics of these firearm
      wounds which were autopsied in Istanbul. During the 5-year period from 1991
      through 1995, there were 15 intra- and perioral firearm fatalities investigated.
      In all the cases, only one shot was fired into the mouth. They constituted 1% of
      all the firearm fatalities. The mean age of the victims was 27 years and males
      constituted 73.3% of the victims. Most of the wounds were caused by handguns.
      Homicides accounted for 53.3% of these deaths. Three of 15 cases could not be
      identified as intraoral firearm wounds by general practitioners during the scene
      investigations.

PMID- 10404635
TI  - DAP12: a key accessory protein for relaying signals by natural killer cell
      receptors.
AB  - DAP12 is a 12 kDa transmembrane protein recently recognized as a key signal
      transduction receptor element in Natural Killer (NK) cells. It is a disulfide
      linked homodimer that non-covalently associates with several activating receptors
      expressed on NK cells. Activation signals initiated through DAP12 are predicted
      to play strategic roles in triggering NK cell cytotoxicity responses toward
      certain tumor cells and virally infected cells. The cytoplasmic domain of DAP12
      contains an Immunoreceptor Tyrosine-based Activation Motif (ITAM).
      Phosphorylation of ITAM tyrosines mediates associations with protein tyrosine
      kinases, which is a resonant feature of signalling through these motifs in T and
      B cell antigen receptors. In addition, its expression in other tissues, including
      dendritic cells and monocytes, suggests that DAP12 transduces ITAM-mediated
      activation signals for an extended array of receptors in those cells as well.

PMID- 10404636
TI  - EGF receptor.
AB  - The receptor for the epidermal growth factor (EGF) and related ligands (EGFR),
      the prototypal member of the superfamily of receptors with intrinsic tyrosine
      kinase activity, is widely expressed on many cell types, including epithelial and
      mesenchymal lineages. Upon activation by at least five genetically distinct
      ligands (including EGF, transforming growth factor-alpha (TGF alpha) and heparin
      binding EGF (HB-EGF)), the intrinsic kinase is activated and EGFR tyrosyl
      phosphorylates itself and numerous intermediary effector molecules, including
      closely-related c-erbB receptor family members. This initiates myriad signaling
      pathways, some of which attenuate receptor signaling. The integrated biological
      responses to EGFR signaling are pleiotropic including mitogenesis or apoptosis,
      enhanced cell motility, protein secretion, and differentiation or
      dedifferentiation. In addition to being implicated in organ morphogenesis,
      maintenance and repair, upregulated EGFR signaling has been correlated in a wide
      variety of tumors with progression to invasion and metastasis. Thus, EGFR and its
      downstream signaling molecules' are targets for therapeutic interventions in
      wound repair and cancer.

PMID- 10404637
TI  - Human beta-defensin-2.
AB  - Human beta-defensin-2 (HBD-2) is a cysteine-rich cationic low molecular weight
      antimicrobial peptide recently discovered in psoriatic lesional skin. It is
      produced by a number of epithelial cells and exhibits potent antimicrobial
      activity against Gram-negative bacteria and Candida, but not Gram-positive
      Staphylococcus aureus. HBD-2 represents the first human defensin that is produced
      following stimulation of epithelial cells by contact with microorganisms such as
      Pseudomonas aeruginosa or cytokines such as TNF-alpha and IL-1 beta. The HBD-2
      gene and protein are locally expressed in keratinocytes associated with
      inflammatory skin lesions such as psoriasis as well as in the infected lung
      epithelia of patients with cystic fibrosis. It is intriguing to speculate that
      HBD-2 is a dynamic component of the local epithelial defense system of the skin
      and respiratory tract having a role to protect surfaces from infection, and
      providing a possible reason why skin and lung infections with Gram-negative
      bacteria are rather rare.

PMID- 10404638
TI  - The effect of advanced glycation end-product formation upon cell-matrix
      interactions.
AB  - The formation of advanced glycation end-products plays a central role in the
      progressive deterioration of tissues with age, a process that is accelerated in
      diabetes. Collagen in addition to providing structure and tensile strength to
      tissues also provides a dynamic matrix for cells to interact with, and due to its
      long-lived nature is particularly susceptible to modification with age and
      disease. We have recently identified methylglyoxal as a key intermediate in this
      process, reacting predominantly with arginine residues to form imidazolone
      compounds. We therefore postulated that modification of RGD sequences in collagen
      with methylglyoxal would interfere with crucial cell-matrix interactions. To
      investigate this concept we studied the interaction of two cell lines, MG63 and
      HT1080, with collagen modified to varying degrees with respect to arginine.
      Adhesion and subsequent spreading of both cell lines was significantly decreased
      by minimal methylglyoxal modification leading to the conclusion that such
      modification of collagen severely inhibits cell matrix interactions, most likely
      via the loss of specific arginine residues involved in integrin mediated cell
      attachment. This is the first demonstration that methylglyoxal modification of
      collagen can affect cell-matrix interactions and introduces a possible mechanism
      by which some of the deleterious changes in tissues with age and disease are
      occurring.

PMID- 10404640
TI  - Hypoxia induces free radical damage to rat erythrocytes and spleen: analysis of
      the fluorescent end-products of lipid peroxidation.
AB  - Several studies have shown that hypoxia induces alterations in the lipid
      membranes of many cell types. The mechanism of these changes might consist in
      membrane lipid peroxidation. Lipid peroxidation in erythrocytes and spleen is
      easily detected by measurement of the concentration of fluorescent end-products.
      Exposure of rats to hypoxia for various time periods induced formation of
      lipophilic fluorescent products both in erythrocytes and spleen. A new kind of
      fluorophore was found in chloroform extracts from erythrocytes with excitation
      maximum at 270 nm and emission maximum at 310 nm. Additionally, two minor
      fluorophores were observed, emitting at 360 nm and in the region of 415-440 nm.
      Only one type of fluorophore was detected in spleen, emitting at 445 nm after
      excitation at 315 nm. The concentration of fluorophores was dependent on the time
      of hypoxic exposure both in erythrocytes and spleen. In erythrocytes there was a
      decrease of the predominant fluorophore after 3 hours (54%, P < 0.05) and 21 days
      (54%, P < 0.05) of hypoxia in relation to normoxic controls, accompanied by
      changes in spectral patterns of tridimensional fluorescence spectra. There was
      also a significant increase in the concentration of fluorophore in spleen (to
      164%, P < 0.05, after 3 h, and to 240%, P < 0.05, after 21 days). The
      fluorophores, both in erythrocytes and spleen, were resolved into several
      distinct fractions with HPLC. The presented results support the hypothesis of
      hypoxia-induced lipid peroxidation and create a basis for further
      characterization of the fluorescent products.

PMID- 10404639
TI  - Determination of mRNA, and protein levels of p53, MDM2 and protein kinase CK2
      subunits in F9 cells after treatment with the apoptosis-inducing drugs cisplatin
      and carboplatin.
AB  - Protein kinase CK2 is a pleiotropic serine/threonine kinase which has been shown
      to phosphorylate numerous substrates. Evidence is accumulating that CK2 may exist
      complexed to a variety of cellular proteins, e.g. p53, MDM2, and A-Raf. Here, we
      explored the effects of the chemotherapeutic drugs cisplatin and carboplatin on
      the mRNA and protein levels of p53, MDM2 and CK2 in a murine teratocarcinoma cell
      line F9. Northern and Western blot analyses were performed and the CK2 activity
      was determined. The degree of apoptosis after drug treatment was assessed using
      the TUNEL test. Six hours after cisplatin and carboplatin treatment, the RNA
      level of p53 dropped by 59% +/- 9% and 86% +/- 8% respectively, whereas the
      observed level of p53 protein rose to 7 and 10 times over the untreated control,
      respectively. Treatment with 33 microM cisplatin prompted apoptosis as early as 4
      h after drug treatment. More than 50% apoptotic cells were seen after 6 h. We
      conclude that cisplatin and its second generation drug carboplatin act similarly
      i.e. both drugs cause a concomitant decrease in p53 mRNA and an increase in p53
      protein level. After 4 h treatment with either of the two drugs, p53 levels reach
      a threshold which leads to the initiation of apoptosis.

PMID- 10404641
TI  - Molecular cloning and characterization of a cDNA encoding the human leucocyte
      vacuolar protein sorting (h1Vps45).
AB  - We have isolated a novel cDNA clone from human leucocyte cDNA library, encoding a
      Sec1p-like vacuolar protein sorting (h1Vps45) which is believed to be implicated
      in vesicular transportation. Although the deduced amino acid (AA) sequence of
      this cDNA has revealed 97% identity to other known mammalian vacuolar protein
      sorting, there is an extensive variation in nucleotide sequence in comparison to
      that of three previously reported human (hVps45), rat (rVps45) and mouse (mVps45)
      vacuolar protein sorting (Vps45) cDNAs [1-3]. At the nucleotide sequence level
      h1Vps45 demonstrated 90% homology to the hVps45 and rVps45 and 89% identity to
      mVps45 with no significant homology in their noncoding regions. The 2.4 Kb mRNA
      corresponding to the h1Vps45 clone is widely distributed in a variety of human
      tissues expressing highest levels in peripheral blood mononuclear cells (PBMC),
      neutrophils, heart, spleen, and testis. The chromosomal mapping studies have
      demonstrated that the h1Vps45 is localized to long arm of human chromosome 1 at
      q21-q22. Our data indicates that we have isolated, characterized and mapped a
      novel cDNA encoding h1Vps45, which may play an important role in protein
      trafficking as well as have clinical significance in the release of inflammatory
      mediators e.g. histamine, bradykinin and cytokine release.

PMID- 10404642
TI  - Low density lipoprotein-receptor plays a major role in the binding of very low
      density lipoproteins and their remnants on HepG2 cells.
AB  - The binding to HepG2 cells of very low density lipoproteins (VLDL) and their
      remnants (IDL) was alternatively, in the past, attributed to the low density
      lipoprotein receptor (LDLr) or to an apoE-specific receptor. In order to resolve
      this issue, we have compared the binding of those lipoproteins labelled with
      iodine-125 to normal and LDLr deficient HepG2 cells. Those deficient cells were
      obtained by a constitutive antisense strategy and their LDLr level is 14% the
      level of normal HepG2 cells. By saturation curve analysis, we show that VLDL and
      IDL bind to high and low affinity sites on cells. The low affinity binding was
      eliminated by conducting the assay in presence of a 200-fold excess of HDL3
      respective to the concentrations of 125I-labelled VLDL and IDL. For 125I-VLDL
      high affinity binding to normal HepG2 cells, we found a dissociation constant
      (Kd) of 21.2 +/- 3.7 micrograms prot./ml (S.E., N = 5) and a maximal binding
      capacity (Bmax) of 0.0312 +/- 0.0063 microgram prot./mg cell prot, while we have
      measured a Kd of 5.3 +/- 0.8 and a Bmax of 0.0081 +/- 0.0014 with LDLr deficient
      cells. This indicates that LDLr is responsible for 74% of VLDL binding to HepG2
      cells and that the non-LDLr high affinity receptor has a higher affinity for VLDL
      than LDLr. A 53% loss of 125I-IDL binding capacity was measured with LDLr
      deficient cells compared with normal cells (Bmax: 0.028 +/- 0.005 versus 0.059 +/
      0.006), while no significant statistical difference was found between
      affinities. The study shows that the LDLr is almost the only contributor in VLDL
      binding, while it shares IDL binding capacity with another high affinity
      receptor. The physiological importance of LDLr is confirmed by an almost
      equivalent loss of IDL and VLDL degradation in LDLr deficient cells.

PMID- 10404643
TI  - Isolation of a trypsin inhibitor with deletion of N-terminal pentapeptide from
      the seeds of Momordica cochinchinensis, the Chinese drug mubiezhi.
AB  - A trypsin inhibitor, MCCTI-1, with a molecular weight of 3479 Da as determined by
      mass spectrometry, was isolated from Momordica cochinchinensis seeds with a
      procedure involving extraction with 5% acetic acid, ammonium sulfate
      precipitation, ion exchange chromatography on CM-Sepharose and reverse-phase high
      performance liquid chromatography. The sequence of its first 13 N-terminal amino
      acid residues was ILKKCRRDSDCPG which was about 85% identical with the sequence
      of trypsin inhibitor MCTI-1 from Momordica charantia Linn. When compared with the
      sequences of most other squash family trypsin inhibitors, the sequence of MCCTI-1
      was characterized by the deletion of a pentapeptide from the N-terminus. Trypsin
      inhibitors also existed in seeds of some hitherto uninvestigated Cucurbitaceae
      species.

PMID- 10404644
TI  - Feeding is inhibited by sublethal concentrations of toxicants and by heat stress
      in the nematode Caenorhabditis elegans: relationship to the cellular stress
      response.
AB  - We report that the free-living nematode Caenorhabditis elegans can respond to a
      variety of stressors (compounds known to induce the production of cellular stress
      proteins in model biological systems), by ceasing pharyngeal pumping. This
      phenomenon results in both a reduction in intake of the stressor and a cessation
      of feeding. The effect of stressors can therefore be conveniently assayed by
      monitoring the decrease in the density of the bacterial food in liquid cultures
      of nematodes. A great range of stressors induced this response including
      alcohols, heavy metals, sulfhydryl-reactive compounds, salicylate, and heat. For
      several of these stressors, inhibition of pharyngeal pumping occurred at stressor
      concentrations below the threshold required for the induction of the 16-kDa heat
      shock proteins. Salicylate, which did not induce 16-kDa heat shock proteins at
      any concentration, nevertheless inhibited pharyngeal pumping. Heat was also
      inhibitory, at a temperature where 16-kDa heat shock protein production was near
      maximal. Some compounds caused only a partial inhibition of feeding while with
      others the effect was complete. Upon removal of the stressor, the nematodes
      resumed pharyngeal pumping with a residual inhibitory effect that depended on the
      concentration and type of stressor that had been applied. A number of C. elegans
      neurosensory mutant strains also exhibited a cessation of pharyngeal pumping when
      exposed to stressors suggesting that the mechanism underlying this inhibition was
      not entirely neurosensory and may be intrinsic to the pharynx. In C. elegans and
      other invertebrates, stress-induced inhibition of feeding may be an important
      survival mechanism that limits the intake of toxic solutes.

PMID- 10404645
TI  - Elevated plasma osmotic concentration stimulates water absorption response in a
      toad.
AB  - The water-seeking behavior (WR) of toads (Bufo viridis) was investigated. Fully
      hydrated toads that are allowed free choice of wet or dry filter paper
      voluntarily and spontaneously select to sit on water-soaked paper at a regular
      frequency during trials. Dehydration of bladder-emptied toads by 14% elicits WR
      in all animals. Injection of aldosterone or angiotensin-I reduced the dehydration
      threshold to 7% weight loss. WR frequency increased when plasma osmolality was
      elevated by injection of NaCl or other solutes (both ionic and non-ionic). Only
      urea, to which cell membranes are highly permeable, was the exception that did
      not produce this response. The increase in WR frequency induced by elevated
      plasma osmolality was augmented by injection of aldosterone or angiotensin-I. In
      vivo water uptake, measured in a water bath, was increased by an NaCl or oxytocin
      injection, but not by aldosterone. It is concluded that elevated plasma
      osmolality induces an increase in WR frequency that is separate and prior to the
      water uptake process. Different hormones are involved in each step.

PMID- 10404646
TI  - Basolateral regulation of pHi in proximal tubules of avian loopless and long
      looped nephrons in bicarbonate.
AB  - In isolated, nonperfused chicken proximal tubules from both loopless reptilian
      type and long-looped mammalian-type nephrons, resting intracellular pH (pHi),
      measured with pH-sensitive fluorescent dye 2',7'-bis(2-carboxyethyl)-5,6
      carboxyfluorescein (BCECF), was approximately 7.1 under control HCO3- conditions
      [20 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)/5 mM HCO3(-)
      buffered medium with pH 7.4 at 37 degrees C] and was reduced to approximately 6.8
      in response to NH4Cl pulse. The rate of recovery of pHi (dpHi/dt) from this level
      to the resting level in proximal tubules from both nephron types was (1)
      significantly reduced by the removal of Na+ or both Na+ and Cl- from the bath,
      and (2) unaffected by the removal of Cl- from the bath or the presence of a high
      K+ concentration or Ba2+ in the bath. In proximal tubules from long-looped
      mammalian-type, but not loopless reptilian-type, nephrons, dpHi/dt was
      significantly reduced by the addition of either 5-(N-ethyl-N-isopropyl) amiloride
      (EIPA) or 4,4'-diisothiocyanostilbene-2,2'disulfonate (DIDS) to the bath. These
      data suggest that a Na+/H+ exchanger and most likely a Na(+)-dependent Cl-/HCO3-
      exchanger are involved in basolateral regulation of pHi in mammalian-type
      nephrons whereas none of the commonly identified basolateral acid-base
      transporters appear to be involved in regulation of pHi in reptilian-type
      nephrons.

PMID- 10404647
TI  - Nerve-independence of limb regeneration in larval Xenopus laevis is related to
      the presence of mitogenic factors in early limb tissues.
AB  - Early limbs of larval Xenopus laevis can form a regeneration blastema in the
      absence of nerves. The nerve-independence could be due to the synthesis of
      neurotrophic-like factors by the limb bud cells. To test this hypothesis, two
      series of experiments were performed. Series A: the right hindlimbs of stage 57
      larvae (acc. to Nieuwkoop and Faber. 1956. Normal table of Xenopus laevis
      [Daudin]. Amsterdam: North-Holland Pub. Co.), which are nerve-dependent for
      regeneration, were amputated through the tarsalia. The regenerating limbs were
      submitted to: sham denervation; denervation; denervation and implantation of a
      fragment of an early limb, or a late limb, or a spinal cord. Series B: froglets
      were subjected to amputation of both forelimbs. The cone blastemas were
      transplanted into denervated hindlimbs of stage 57 larvae, together with a
      fragment of an early or a late limb. The results in series A showed that the
      implantation of early limb tissue into the denervated blastema maintained cell
      proliferation at levels similar to those observed after the implantation of a
      spinal cord fragment or in sham denervated blastemas. However, the implantation
      of late limb tissues were ineffective. The results of series B showed that the
      implantation of early limb tissue, but not of late limb tissue prevented the
      inhibition of cell proliferation and the regression of denervated limb blastemas
      of juveniles. These results indicate that the nerve-independence is related to
      the synthesis of diffusible mitogenic neurotrophic-like factors in early limb
      tissues, and that nerve-dependence is established when differentiated cells of
      late limb tissues stop producing these factors.

PMID- 10404649
TI  - Environmentally induced limb malformations in mink frogs (Rana septentrionalis).
AB  - In recent years, there has been an increase in the incidence of frog deformities
      throughout many of the northern states of North America. The most readily noticed
      malformations involve the hindlimbs of peri-metamorphic animals. We have analyzed
      skeletal preparations of metamorphosing mink frogs (Rana septentrionalis)
      collected from a site in Minnesota, in order to develop a better understanding of
      the possible causes. In this paper we describe the categories of abnormalities
      found at this site. The spectrum of deformities includes missing limbs, truncated
      limbs, extra limbs (including extra pelvic girdles), and skin webbings. We also
      describe a newly recognized malformation of the proximal-distal limb axis, a bony
      triangle. In this abnormality, the proximal and distal ends of the bone are
      adjacent to one another forming the base of a triangle. The shaft of the bone is
      bent double and protrudes laterally, the midpoint of the bone forming the apex of
      the triangle. In this paper we consider several recently proposed explanations
      for the recent outbreak of amphibian deformities. Based on our analysis, we
      conclude that the spectrum of abnormalities seen in these frogs is remarkably
      similar to the range of abnormalities that has been reported as a result of
      exposure of developing vertebrates to exogenous retinoids. Given the potential
      implications of this possibility for the welfare of humans as well as wildlife,
      further studies are needed to determine whether environmental retinoids are
      responsible for the frog deformities at the site we have examined.

PMID- 10404648
TI  - Sonic hedgehog (shh) expression in developing and regenerating axolotl limbs.
AB  - Sonic hedgehog (shh) expression is detectable in the posterior mesenchyme of many
      developing vertebrate limbs. We have isolated an RT-PCR fragment from the
      axolotl, Ambystoma mexicanum, that has high identity to other vertebrate shh
      genes. We describe the localization of this transcript during development and
      regeneration and in response to tissue grafts and retinoic acid (RA) exposure in
      the axolotl. Even though axolotl digits show a reversed polarity of
      differentiation (anterior [A] to posterior [P]) when compared to other tetrapods
      (P to A), shh is nevertheless expressed on the posterior margin of developing and
      regenerating limb buds. When A cells are grafted adjacent to P cells, an ectopic
      domain of shh is induced. Exposure to retinoic acid (RA), a molecule known to
      alter pattern in all three limb axes in urodeles, results in ectopic expression
      of shh in anterior cells of the regeneration blastema. Prior to this induced
      expression in response to RA, there is an earlier response by the endogenous
      domain of shh, which is downregulated within the first few hours of exposure.

PMID- 10404650
TI  - Purification and characterization of an isoform of crustacean hyperglycemic
      hormone from the eyestalk of Macrobrachium rosenbergii.
AB  - Isolation of the crustacean hyperglycemic hormone (CHH) from the eyestalk of the
      giant freshwater prawn Macrobrachium rosenbergii was performed using 5,000 ground
      eye-stalks extracted in methanol-acetic acid-water (90:1:9). After the extract
      was partially purified using C18 cartridges, it was further purified by eight
      steps of RP-HPLC using four kinds of columns: C18, C8, cyano and phenyl, and
      three solvent systems: acetonitrile (ACN)/trifluoroacetic acid,
      ACN/heptafluoroacetic acid and ACN/triethylammonium acetate. The bioassay of CHH
      during purification was done by injection of eluate fractions into eyestalk
      ablated prawns and determination of the ability of the fractions to elevate
      glucose in the haemolymph. A complete amino acid sequence analysis was performed
      on one isoform of CHH (Mar-CHH-1), consisting of 71 residues. The sequence of Mar
      CHH-1 shows considerable similarity (45-68%) to CHHs reported in other
      crustaceans. It is expected that there might be more than one isoform of CHH in
      M. rosenbergii.

PMID- 10404651
TI  - Inhibitory action of the gonadopeptide inhibin on amphibian (Rana pipiens)
      steroidogenesis and oocyte maturation.
AB  - In view of recent reports on the production of inhibin- and activin-like proteins
      in lower vertebrates and their important role during development, we have
      examined the effects of the gonadopeptide inhibin in the process of oocyte
      maturation using amphibian (Rana pipiens) fully grown preovulatory ovarian
      follicles cultured in vitro. In the presence of frog pituitary homogenate (FPH),
      which stimulates progesterone (P4) levels and the subsequent germinal vesicle
      breakdown (GVBD), purified porcine inhibin (35-50 IU) inhibited both of these
      responses in a dose-dependent manner. Inhibin also blocked GVBD initiated by
      exogenously added P4 in intact as well as denuded oocytes. Thus, inhibin seems to
      act at the follicle (granulosa) cells because it blocked steroidogenesis and at
      the oocyte because it altered the steroid-induced oocyte maturation. The P4
      treated follicles were susceptible to the inhibin action during the first 3 hr of
      steroid stimulation, which indicates that inhibin affects some early events
      during the process of GVBD. Maximum inhibitory effect was observed when P4 and
      inhibin were added simultaneously at the beginning of the incubations. Moreover,
      the inhibitory effect on GVBD caused by the gonadopeptide was dependent on the
      length of exposure of the follicles to inhibin. The continuous presence of
      inhibin in the culture was required to block GVBD efficiently. Data also indicate
      that the inhibitory effect of inhibin was reversible. Taken together, results
      from this study present evidence that inhibin may be a relevant
      paracrine/autocrine regulator of ovarian functions.

PMID- 10404652
TI  - Closing the gap.

PMID- 10404653
TI  - Wardrobe check for terrorist incidents.

PMID- 10404654
TI  - Butyl & Viton hand protection.

PMID- 10404655
TI  - Advances in SMS technology.

PMID- 10404656
TI  - Where the buck stops.

PMID- 10404657
TI  - Group therapy.

PMID- 10404658
TI  - Dealing with drugs.

PMID- 10404659
TI  - Skewering corporate America. Interview by Janet Kalbhen.

PMID- 10404660
TI  - Once upon a culture.

PMID- 10404661
TI  - Wiring up, reaching out.
AB  - Taking another step in our Most Wired project, we conducted cyber-interviews with
      health plans and asked them to tell us just how wired they are. Find out how well
      they connect to members and employers, which HR and educational services they
      offer online, and whether they do business with doctors and hospitals
      electronically. Plus: profiles of major info tech undertakings at six health
      plans. They range from a $78,000 intranet to a $4 million data warehouse. But
      while the six projects differ in cost, they overlap in purpose: putting more
      information into the hands of doctors, hospitals, employers, and consumers. In
      doing that, they show what being wired is all about.

PMID- 10404662
TI  - Marketing nets out. Spending--and expecting--more than ever, hospitals and
      systems take their message to the Web.
AB  - Live on the Web, it's open-heart surgery--a showroom window on sweeping new
      marketing plans. Along with perennial promos like radio and TV ads, health
      systems have tapped the power of the Internet to hard-wire their organizations
      for growth. But marketing must be linked to operations as never before.

PMID- 10404663
TI  - What a day!

PMID- 10404664
TI  - Game, set, & match. Interview by Chris Serb.

PMID- 10404665
TI  - The art of heart.

PMID- 10404667
TI  - Cutting prospects.

PMID- 10404666
TI  - Budget battlers ... profiles.
AB  - If managed care discounts give you a headache, you'll get a migraine figuring
      your losses from the 1997 Balanced Budget Act--they're an 8 on the Richter scale,
      says one hospital policy pro. The savvy aren't waiting to act: Around the
      country, hospitals are fighting the cuts on the national front and battling back
      at home. H&HN profiles five.

PMID- 10404669
TI  - Head games. Hiring trends.
AB  - The times demand executives who can deal well with doctors and handle the chaos
      of rapid change. And that's why your next job interview could include a
      personality test. "I can't supplement efficiencies in those areas with machinery
      or equipment or even training," says one recruiter. "A hospital can give you all
      the tools in the world, but the only one that counts is the one between your
      ears."

PMID- 10404668
TI  - A tale of 5 tests. Insurance coverage.
AB  - They promise precision in detecting cancer cells, bone breakdown, risk of heart
      disease, and other maladies. There's just one problem: Many insurers won't pay
      for these new diagnostic tools, saying they haven't yet proven themselves. "We
      complain, we write letters," says one doctor, who calls a new Pap test a "quantum
      leap" from the existing Pap smear. "I'm just a little physician, crying in the
      woods."

PMID- 10404670
TI  - Burned by the boss.

PMID- 10404671
TI  - The effect of using different culling regimens on genetic response with two
      trait, two-stage selection in a nucleus broiler stock.
AB  - Stochastic simulation was used to study the effect on genetic response and
      inbreeding of various two-stage two-trait culling strategies. Four different
      parameter sets were considered for the two traits, BW and egg number. Selection
      of replacement animals was based on animal model best linear unbiased prediction
      (BLUP) to obtain estimated breeding values (EBV) at the second stage. Culling at
      Stage 1 was based on either animal model BLUP or phenotypes, and information from
      culled animals was either available or not available for calculation of second
      stage EBV. Besides founder individuals, six discrete generations were considered.
      Culling based on BLUP of two traits at Stage 1 produced higher response than
      culling on phenotypic evaluations. It was found that culling based on phenotypic
      evaluation and not carrying information to the second stage reduce rates of
      response by 9 to 17% and produced inbreeding higher than or close to that of BLUP
      selection. This study clearly shows that a double penalty of less response and
      higher inbreeding is generally paid for not using all information. Optimum
      selection schemes will depend on relative costs and benefits of collecting and
      processing the extra information required for full BLUP selection schemes.

PMID- 10404672
TI  - Using recent versus complete pedigree data in genetic evaluation of a closed
      nucleus broiler line.
AB  - Stochastic simulation was used to study the effect of using full data and
      pedigree structure vs more recent data and pedigree structure to obtain best
      linear unbiased predictors (BLUP) of breeding values for single trait selection.
      Simulations used heritabilities of 0.10 and 0.50, with a population structure of
      20 sires each mated to two dams, each producing 10 progeny, with 11 hatches from
      an unselected base population under both discrete and overlapping generations.
      Selection of parents was based on BLUP of breeding values using an animal model.
      The use of the last two generations of data and pedigrees gave the same selection
      response as when using full data and pedigree structure, for both heritabilities.
      Under discrete generations with use of only the last generation data and
      pedigree, which is similar to phenotypic evaluation, response to selection
      decreased by 21 and 3.8% at Generation 10 compared to selection response when
      using the full data and pedigree for heritabilities of 0.10 and 0.50,
      respectively. Corresponding decreases in inbreeding were 72 and 37%. The amount
      of central processing unit time for genetic evaluation when using the last six,
      four, and two generations of data and pedigree was reduced to 70, 40, and 11% of
      that when using the full data set, for a heritability of 0.10 and discrete
      generations. Very similar values were observed for a heritability of 0.50 and
      also under overlapping generations.

PMID- 10404673
TI  - Heterosis and developmental stability of body and organ weights at hatch for
      parental line broiler breeders and specific crosses among them.
AB  - Body, yolk sac, left and right shanks with toes, empty left and right ceca, left
      and right lungs, heart, and bursa of Fabricius weights were obtained at hatch for
      50 chicks from each of five commercial broiler parental lines (three sire and two
      dam) and three F1 crosses involving them. Differences among stocks and between
      sexes were inconsistent among mating combinations. Although correlation
      coefficients between yolk-free chick weight with organ weights were generally
      stock specific, they were high (> 0.75) with shank weight, intermediate with
      heart and lung weights, and low (< 0.25) with ceca and bursa weights. Heart:lung
      ratios of all F1 crosses were greater than those for their respective parental
      lines; however, the degree of heterosis differed among populations. Developmental
      stability, as measured by percentage relative asymmetry, was less in two of the
      sire parental lines than in their respective dam lines and F1 crosses.

PMID- 10404674
TI  - Meal feeding is more effective than early feed restriction at reducing the
      prevalence of leg weakness in broiler chickens.
AB  - Two trials were conducted to investigate whether manipulation of feeding pattern
      or early feed intake affected the prevalence of leg weakness in broiler chickens.
      In Trial 1, the birds were offered two, three, or four meals per day or consumed
      feed ad libitum. In Trial 2, a multifactorial design was used with age at start,
      duration of restriction, and severity of restriction as factors. The start of
      restrictions were at 5, 7, or 9 d, duration of restriction was 5 or 7 d, and feed
      was restricted to achieve 25, 50, and 75% of predicted growth during the
      restriction period. Ad libitum birds served as controls. Leg weakness was
      assessed by gait scoring (GS) and tibial dyschondroplasia (TD) by radiography.
      Foot burn, hock burn, angulation of the hock joint, feed consumption, and body
      weight gain were also assessed. The response of the birds to meal feeding was
      clear. Fewer meals per day was associated with less TD, less hock burn, better
      walking ability, lower body weight, and better feed conversion. The response of
      the birds to feed restriction was also clear. Earlier restriction, longer
      duration, and more severe level of restriction were all associated with lower
      prevalence of TD, better walking ability, lower body weight, and better relative
      growth rates and feed efficiency. However, adjusting the observations for
      differences in body weight removed many of the significant differences; only
      birds that started feed restriction earlier had less TD. From these trials, it
      was concluded that meal feeding can beneficially affect the prevalence of leg
      weakness, and that the major part of this effect is independent of changes in
      body weight. It was also concluded that early feed restriction reduced many
      aspects of leg weakness, but that these effects were mainly a result of reduced
      body weight. Meal feeding and early feed restriction improved feed efficiency.

PMID- 10404675
TI  - The use of poultry litter as co-substrate and source of inorganic nutrients and
      microorganisms for the ex situ biodegradation of petroleum compounds.
AB  - The purpose of this investigation was to determine the feasibility of utilizing
      poultry litter as a source of microorganisms, C co-substrate, N, and P to enhance
      the biodegradation of petroleum compounds in contaminated soil. An initial
      laboratory-scale study utilized soil contaminated with approximately 3,000 mg/kg
      (ppm) total petroleum hydrocarbons (TPHC) as diesel fuel. Biotreatment units,
      each containing 10 L of contaminated soil, were supplemented (0, 1, 10, and 20%,
      total weight basis) with broiler litter containing 3.65% N and 1.89% P. Petroleum
      degrading microorganisms previously enriched from broiler and turkey litter were
      also inoculated into the litter-treated units. A significant first order rate of
      TPHC biodegradation was measured for all treatment units containing broiler
      litter (P < 0.05). Based on these results, a subsequent study was conducted at
      the site of a commercial facility permitted to treat soil (ex situ) contaminated
      with hazardous compounds. Soil treatment plots, each containing approximately 1
      ton of soil contaminated with approximately 1,200 to 1,600 mg/kg diesel fuel were
      established. Each plot was replicated four times and the experiment was conducted
      for 35 d. Treatments were as follows: control, soil only; soil + commercial blend
      of bioremediation nutrients; soil + commercial fertilizer; soil + poultry litter
      (1% by volume); soil + poultry litter (10% by volume); soil + pelleted poultry
      litter (10% by volume). The results showed that the remediation of soil
      contaminated with petroleum compounds is significantly (P < 0.05) enhanced when
      supplemented with poultry litter (pelleted or nonpelleted) in concentrations of
      10% soil volume. These results demonstrate the potential for a specialized market
      for the use of poultry litter.

PMID- 10404676
TI  - Further characterization of M cells in gut-associated lymphoid tissues of the
      chicken.
AB  - M cells are considered to be the most effective cells for the transport of
      antigens from the intestinal lumen into the gut-associated lymphoid tissue. M
      cells are characterized by their ultrastructural appearance, the selective uptake
      of antigens, the binding of lectins, and the presence of underlying lymphocytes.
      Little attention has been paid to the interaction of intra-epithelial leucocytes
      and M cells in chickens; therefore, we have investigated both cell types
      separately and using double immunocytochemical staining in cecal tonsils and
      Meckel's diverticulum. In the follicle-associated epithelium (FAE), cells were
      present that differ from their neighbors by short, irregular microvilli. Ferritin
      was absorbed by these putative M cells, but also by other epithelial cells. The
      lectins of Triticum vulgaris (WGA) and Glycine max (SBA) showed a patchy staining
      of the FAE. The numbers of intra-epithelial leucocytes (IEL) increased rapidly
      after hatch, reaching innumerable at 6 wk of age. Most IEL were T lymphocytes
      expressing CD8 and only about 30% of them were B lymphocytes. Nevertheless,
      double staining of M cells (WGA/SBA) and IEL showed that M cells were much fewer
      than IEL. These results indicate that M cells are not solely induced by the intra
      epithelial localization of leucocytes. Because the phenotype of IEL reflected the
      content of the adjacent underlying lamina propria, IEL immigrate the FAE locally
      and do not migrate along with the epithelial cells from the crypts. In
      conclusion, M cells exist in the chicken, but their phenotype and function are
      less well demarcated from neighbor epithelial cells than is seen in mammals.

PMID- 10404677
TI  - Analysis of MHC class II and class IV restriction fragment length polymorphism in
      chicken lines divergently selected for multitrait immune response.
AB  - In the present study, chickens of four lines divergently selected for high (H)
      and low (L) immunocompetence in replicate were analyzed to investigate
      polymorphisms of MHC class II and MHC class IV on the molecular level associated
      with selection. The long-term selection experiment for multitrait
      immunocompetence was carried out in replicates and allows, therefore, the
      opportunity to distinguish effects of selection from other genetic factors. The
      SacI-digested DNA was hybridized individually with MHC class II and MHC class IV
      gene probes. The MHC class II RFLP analysis revealed four polymorphic bands and
      only one of them showed a significant difference between the selection directions
      H and L pooled between replicates. The small frequency differences of this band
      relative to the long-term selection suggest that this MHC class II fragment may
      contain genetic elements that are only slightly associated with the immune
      response traits used for selection. The hybridization with the MHC class IV probe
      displayed 26 scorable bands, of which 18 were polymorphic. In most instances, the
      differences between the lines were likely caused by the influence of genetic
      factors other than selection for multitrait immunocompetence. Only one band
      displayed a consistency in difference between selection directions in both
      replicates and no frequency difference between replicates. This band was almost
      completely absent in both H sublines, but at a frequency of about 50% in both L
      sublines. The general results of this study did not reveal major differences in
      band frequencies that indicate a close association of MHC class II and MHC class
      IV polymorphic markers to the divergent selection for multitrait immune response.
      Although the MHC makes a crucial contribution in immune response, it may have
      been difficult to detect single-gene associations with the selection criteria of
      this study, because of the myriad of components contributing to general immune
      responses measured in vivo.

PMID- 10404678
TI  - Improving neural network prediction of amino acid levels in feed ingredients.
AB  - Artificial neural networks (ANN) were trained to predict the amino acid (AA)
      profile of feed ingredients. The ANN more effectively identified the complex
      relationship between nutrients and feed ingredients than linear regression (LR).
      Three types of ANN (NeuroShell 2): three-layer backpropagation (BP3), Ward
      Backpropagation (WBP), a general regression neural network (GRNN); and LR (SAS
      Proc GLM) were used to predict the AA level in corn, soybean meal, meat and bone
      meal, fish meal, and wheat based on proximate analysis. In contrast to a past
      study, a variety of alternative ANN training parameters were examined to improve
      ANN performance. Predictive performance was judged on the basis of the maximum R2
      value resulting from all defaults tested. Advanced selection of ANN training
      parameters led to further improvement in performance, especially within the GRNN
      architecture. In 34 of 35 ANN developed, the maximum R2 value for each individual
      AA in each feed ingredient was higher for GRNN than for LR, BP3, or WBP
      prediction methods. For example, the highest R2 value for Met in corn was 0.32
      for LR, 0.40 for 3LBP, 0.51 for WBP, and 0.95 for GRNN analysis. Predictive
      performance was also improved overall as compared to results of a previous study.
      For example, corn maximum R2 values (GRNN) for Met, TSAA, and Trp were: 0.78,
      0.81 and 0.44, previously, and 0.95, 0.96 and 0.88, in the current study. Current
      soybean meal maximum R values (GRNN) were: Met, 0.92; TSAA, 0.94; and Lys, 0.90.
      Current meat and bone mean maximum R2 values (GRNN) were: Met, 0.97; TSAA, 0.97;
      and Lys, 0.97. The ANN computation is a successful alternative to statistical
      regression analysis for predicting AA levels in feed ingredients.

PMID- 10404679
TI  - Dietary fat and protein interactions in the broiler.
AB  - An experiment was conducted to study the interrelationships between dietary fat
      and protein levels in the regulation of lipid metabolism in the broiler chicken.
      Birds were fed diets containing 300, 600, or 1,200 kcal ME from fat (corn oil)
      with either 124 or 190 g CP/kg. Two additional experimental diets contained 234
      or 285 g CP and 300 kcal ME from fat. Regardless of fat level, birds fed the
      diets containing 124 g CP/kg weighed less and were less efficient than birds fed
      diets containing 190 g CP/kg. The diet containing 600 kcal as fat decreased
      lipogenesis and malic enzyme activity (P < 0.05) in birds fed the diet containing
      190 g CP/kg diet, but not in birds fed the diet containing 124 g CP/kg. Birds fed
      the latter level of protein required at least 1,200 kcal as fat to express any
      significant decrease in lipogenesis or malic enzyme activity (P < 0.05). Dietary
      fat did not affect plasma levels of triiodothyronine (T3), thyroxine (T4), or
      insulin-like growth factor-I (IGF-I). Feeding diets containing 124 g CP/kg
      resulted in decreased plasma T4 and IGF-I and elevated T3 (P < 0.05). Increasing
      dietary protein (compared to increasing dietary fat) increased body weights, IGF
      I, T4 and decreased lipogenesis, malic enzyme activity, and T3. Both of these
      regimens involve decreasing dietary carbohydrate at equal rates, but results
      differed. Although replacement of dietary carbohydrates with either fat or
      protein reduce precursors for fat synthesis, both energy sources have additional
      unique effects on metabolism. Dietary protein levels modulate metabolic effects
      of dietary fat.

PMID- 10404680
TI  - Effects of transient treatment with 6-N-propyl-2-thiouracil on testis development
      and function in breeder turkeys.
AB  - Experiments were conducted to address recent reports of precocial testis
      development or testicular hypertrophy induced by the anti-thyroid agent 6-N
      propyl-2-thiouracil (PTU) in domestic fowl and rodents. In three experiments, PTU
      was administered to male turkeys during different stages of development. The PTU
      was given in the feed at a concentration of either 0.1 or 0.5% and effects on
      thyroid hormones were measured. Periods of PTU treatment were 8 to 16 or 10 to 18
      wk of age (Experiment 1); 0 to 8, 0 to 16, and 8 to 16 wk of age (Experiment 2);
      and 8 to 16 and 20 to 35 wk of age (Experiment 3). Data were collected to
      determine the effect of PTU treatment on testicular growth (weight), sexual
      maturation (semen onset and plasma testosterone concentrations), and early adult
      testicular function in terms of semen quantity (semen volume and sperm
      concentration) and quality (sperm viability and fertilizing ability). The 0.1%
      PTU treatment at 8 to 16 wk of age in Experiment 1 resulted in greater testis
      weights and sperm production than those of untreated controls at 24 wk of age.
      The difference was absent by 36 wk of age. Likewise, in Experiment 2, onset of
      semen production was advanced by about 2 wk by the 8 to 16 wk treatment as
      compared to untreated controls (23.3 vs 25.9 wk), although, at 32 and 36 wk of
      age neither the quantity nor quality of semen were significantly affected. Also
      in Experiment 2, 0.1% PTU treatment from 0 to 8 or 0 to 16 wk of age delayed the
      onset of semen production and depressed semen volumes at 32 and 36 wk of age
      without affecting semen quality. In Experiment 3, the mean age at the onset of
      semen was not significantly affected by 0.5% PTU treatment from 8 to 16 or 20 to
      35 wk of age. In addition, semen volume and quality at 32 and 36 wk of age was
      similar to controls. It was concluded that antithyroid treatment with PTU was
      dependent on dose and time of treatment for effects on both sexual development
      and early reproductive performance. Precocial development and associated
      hypertrophy of the testes occurred but was transient. Thereafter, during initial
      reproductive function, semen quantity and quality were normal.

PMID- 10404681
TI  - The effects of in ovo administration of testosterone or an antiandrogen on growth
      of chick embryos and embryonic muscle characteristics.
AB  - Based on earlier studies from our laboratory, we hypothesized that higher levels
      of plasma androgens in male embryos stimulate greater muscle development and are
      responsible for the greater muscle mass of male chickens after hatching. The
      results of these studies show that androgen supplementation by in ovo injection
      of testosterone prior to incubation had no effect on weight of 12-, 16-, or 20-d
      old male chicken embryos or on characteristics of their Pectoralis superficialis
      muscle. In contrast, weight of 12 d-old female embryos was depressed and the
      protein concentration and protein content of the P. superficialis was reduced in
      16-d-old female embryos. Interference with the actions of endogenous androgens by
      preincubation in ovo injection of Flutamide, an antiandrogen, resulted in
      significant linear and quadratic relationships between the dose of Flutamide
      injected and the weight, protein content, and DNA content of the P. superficialis
      of 16-d-old female embryos. Increases over the lower part of the dose range (0 to
      1.74 micromol per egg) were followed by a decrease at the highest dose (2.9
      micromol per egg). The DNA content of the P. superficialis of 16-d-old female
      embryos was similarly affected when Flutamide was injected on Day 8 of
      incubation, whereas the protein content and protein concentration of the muscle
      was increased in 20-d-old female embryos. There were no significant changes in
      the weight, protein content, or DNA content of the P. superficialis of male
      embryos when Flutamide was injected before or on Day 8 of incubation.

PMID- 10404682
TI  - Localization of macrophages in the chicken oviduct: effects of age and gonadal
      steroids.
AB  - The aim of this study was to localize macrophages in the hen oviduct and
      determine the effects of age and gonadal steroids on their population. Cryostat
      sections of oviducal tissues from immature hens (60 d of age), virgin young (175
      d of age), and old (620 d of age) laying hens, and immature hens (84 d of age)
      treated with gonadal steroids were immunostained for macrophages. The population
      of macrophages was analyzed by an image analysis system under a light microscope.
      Macrophages were observed in the stroma and mucosal epithelium of all oviducal
      segments of immature and laying hens. The population of macrophages in the
      oviducal stroma increased with age. Young laying hens had a significantly higher
      population of macrophages than immature hens in the vagina. Old laying hens had a
      significantly higher population than immature hens in the infundibulum, magnum,
      and vagina, and than young laying hens in the magnum. In the immature hens
      treated with gonadal steroids, the macrophage population increased only in the
      stroma of shell gland of the progesterone-treated birds. These results indicate
      that macrophage population in the oviducal stroma increases in association with
      sexual maturation and aging. Their population in the stroma may be partially
      affected by progesterone.

PMID- 10404683
TI  - Gonadal development and growth of chickens and turkeys hatched from eggs injected
      with an aromatase inhibitor.
AB  - It was the purpose of these experiments to describe gonadal development and
      posthatching growth of genetic female chickens and turkeys following in ovo
      injection of the aromatase inhibitor Fadrazole (CGS 16949A) prior to incubation.
      In ovo injection of Fadrazole (CGS 16949A) resulted in the development of testes
      like gonads in the majority of day-old genetic female chickens and turkey poults.
      Ninety-eight to 99% of these birds have masculine-type male genitalia at 1 d of
      age. Microscopic examination of the gonads of day-old genetic female chicks
      hatched from Fadrazole-treated eggs showed the presence of atypical seminiferous
      tubules in 3 of 18 individuals and the presence of ovarian follicles in 3 of 18
      individuals. No germinal elements were seen in 12 individuals. The gonads in the
      majority (8/11) of day-old female poults from treated eggs showed the presence of
      atypical seminiferous tubules. Three of 11 individuals had structures
      characterized as disorganized or degenerate follicles. Between the day of hatch
      and 6 wk, gonads in an increasing proportion of female chickens from Fadrazole
      treated eggs had normal appearing ovarian follicles. A similar trend was seen in
      the female turkeys between hatch and 12 wk of age. There were no differences in
      BW of female chickens hatched from Fadrazole-treated eggs and those from control
      eggs between the day of hatch and 6 wk of age. The pectoral muscle mass and fat
      pad weights of these birds did not differ. In one experiment, the BW of female
      turkeys hatched from Fadrazole-treated eggs was significantly greater than that
      of controls and equal to that of males at 3 and 6 wk of age. Thereafter, both
      types of females were of equal weight and significantly lighter than males.
      Fadrazole treatment did not affect pectoral muscle mass of either sex of turkeys.

PMID- 10404684
TI  - Effects of frequency of semen collection on quantitative and qualitative
      characteristics of semen in turkey breeder males.
AB  - The effects of various frequencies of semen collection on several quantitative
      and qualitative semen characteristics were investigated in adult turkey breeder
      males (30 to 40 wk of age). In Experiment 1, a total of 35 males were first
      trained for semen collection (twice a week for 2 consecutive wk), and then
      divided into five groups (seven males each), each group being collected either
      once every 2 wk, once every week, twice every week, three times every week (each
      for 4 wk) or five to seven times per week (each for 2 wk). Volume, sperm
      concentration, and sperm number per ejaculate were determined for each ejaculate.
      No significant differences between groups were observed for sperm concentration
      (P > 0.05), but males collected once every 2 wk, once per week, or twice per week
      had larger volumes than males collected at higher frequencies (P < 0.05). Thus
      there were significant differences for sperm number per ejaculate between groups
      (P < 0.05). Also, daily semen output (DSO) was markedly increased in males
      collected at the highest frequencies (e.g., DSO = 0.62 x 10(9) and 1.93 x 10(9)
      in males collected once and five times per week). Finally, in euthanatized birds
      (36 wk) no differences between groups were observed for body weight (25.8 +/- 1.7
      kg), testicular weight (51.5 +/- 2.2 g), or total number of elongated spermatids
      per male (14.0 +/- 0.8 x 10(9)). In Experiment 2, 35 males were distributed into
      groups and collected under the same conditions as in Experiment 1. Besides
      quantitative analyses of ejaculates (volume, sperm concentration, and sperm per
      ejaculate), sperm viability between groups was also tested using the Sybr14/PI
      fluorescence test. Our results demonstrated: 1) a favorable effect of high semen
      collection frequencies on sperm viability and, 2) a marked decline in sperm
      viability during the first 2 d following a 2-d resting period in males collected
      five times a week. We concluded that turkey males express their optimal
      reproductive capacity more efficiently when semen collection is undertaken at a
      high rather than a low frequency.

PMID- 10404685
TI  - Intermittent lighting increases egg weight and facilitates early photostimulation
      of turkey breeder hens.
AB  - A major limitation to reducing the age at photostimulation of turkey breeder hens
      has been small egg size, especially at the start of lay. The present study was
      designed to determine whether intermittent lighting (IL) could be used to
      photostimulate hens at an early age (26 wk) and enhance the typical small egg
      size at the start of lay. Control hens were photostimulated with standard [16 h
      light (L):8 h dark (D)] lighting at 26 or 30 wk of age. An additional group of
      hens was photostimulated with IL (2L:12D:2L:8D) from 26 to 32 wk of age and then
      switched to 16L:8D thereafter. Data were collected for BW, onset of lay, egg
      production, and egg weight to 54 wk of age. Although IL delayed onset of lay
      there was no adverse effect on rate of lay because numbers of eggs per hen in 24
      wk of photostimulation (30 to 54 wk of age) were similar to that of controls.
      However, because hens in the IL treatment were photostimulated at 26 wk of age
      they produced about 10 more eggs per hen (P = 0.18) to 54 wk of age than control
      hens photostimulated at 30 wk of age. In addition, IL increased egg weight during
      the first 7 d of lay by about 5% as compared to those of controls also
      photostimulated at 26 wk of age. Interestingly, the increased egg weight in the
      IL treatment persisted to the end of lay, well after IL had been switched to
      16L:8D. Thus, IL lighting facilitated successful early lighting of hens.

PMID- 10404686
TI  - Isolation of sperm storage tubules from the uterovaginal junction mucosa of the
      turkey.
AB  - This study was performed to determine whether intact sperm storage tubules (SST)
      could be successfully isolated from the uterovaginal junction (UVJ) mucosa of the
      turkey. Large White BUTA hens were inseminated and euthanatized 24 to 48 h later.
      Oviducts were excised, UVJ tissue removed, and SST were procured by enzymatic
      digestion. Recovered SST were intact and contained motile sperm. The sperm were
      oriented with their acrosomes pointed towards the distal end of the SST, and
      their long axes in parallel with the long axis of the tubule's lumen. This method
      for the isolation of intact SST can be readily applied for in vitro culture
      studies as well as for the extraction of DNA and RNA from the SST epithelium.

PMID- 10404687
TI  - Monitoring phosphate marinade penetration in tumbled chicken filets using a thin
      slicing, dye-tracing method.
AB  - A simple dye-tracing method was developed to monitor the kinetic process of water
      penetration in chicken filets subjected to rotary tumble marination. A total of
      860 chicken breast filets were tumbled for 0, 5, 15, and 30 min in marinades
      containing 1.6 or 3.2% sodium PP, TPP, or HMP with or without 8% NaCl. Marinade
      penetration was monitored by tracing a dye (FD&C Blue No. 1) migrating into
      different layers of the filets using a spectrophotometric measurement (absorbance
      at 627 nm). Marinades penetrated most rapidly in the initial 5 min, e.g., PP,
      TPP, and HMP at a low level (1.6%) enhancing the rate of penetration of unsalted
      water in the first 5 min by 196, 171, and 138%, respectively. However, the effect
      of phosphates was diminished when their concentration was high (3.2%) or when
      salt was present. Overall, low-level (1.6%) phosphates facilitated water
      penetration deep into the filets, whereas high-level (3.2%) phosphates and salt
      improved water penetration in the surface layers of the filets.

PMID- 10404688
TI  - Time-dependent marinade absorption and retention, cooking yield, and palatability
      of chicken filets marinated in various phosphate solutions.
AB  - The time course of phosphate marinade absorption and its influence on the cooking
      yield and sensory characteristics of chicken filets were investigated. Water
      uptake by the filets was rapid in the initial 5 min, and was substantially slower
      from 15 to 30 min during tumble marination. The rate of marinade absorption
      increased markedly (P < 0.05) by the presence of either high (3.2%) or low (1.6%)
      concentrations of sodium phosphates in the order: pyrophosphate (PP) >
      tripolyphosphate (TPP) > hexametaphosphate (HMP). Salt (8% NaCl) also promoted (P
      < 0.05) moisture absorption but tended to diminish the effects of phosphates.
      Percentage marinade retention after 24 h, which was also influenced by phosphates
      and salt, was well correlated (r2 = 0.93) with marinade absorption. Cooking
      yields increased gradually (P < 0.05) with marination time except for water
      marinated control filets and filets treated with HMP and salt, which had reduced
      cooking yields as the marination time increased. All phosphate solutions, whether
      containing NaCl or not, improved (P < 0.05) cooking yield when compared to the
      water-marination control. Taste panel detected little differences, except for
      saltiness (P < 0.10), between high- and low-level phosphate treatments, and
      considered TPP-treated filets to be similar to PP-treated but higher than HMP
      treated filets in juiciness, saltiness, and overall flavor intensity (P < 0.10).

PMID- 10404690
TI  - The effect of evaporative air chilling and storage temperature on quality and
      shelf life of fresh chicken carcasses.
AB  - The effect of evaporative air chilling on quality of fresh chicken carcasses was
      compared with air chilling as reference method. Cooling efficiency and total heat
      loss were significantly higher for evaporative air chilling. The chilling method
      was of great importance for weight loss. Chicken chilled in cold air lost
      considerably more weight than chicken cooled by evaporative air chilling; the
      difference was 1.8%. The chilling method also affected the skin color and the
      amount of moisture on skin surface. After evaporative air chilling, the chicken
      carcasses had a lighter color and more water on the back and under the wings. The
      moisture content in skin and meat, cooking loss, and pH were not affected by
      chilling method. Odor attributes of raw chicken and odor and flavor attributes of
      cooked chicken did not show any significant differences between the two chilling
      methods. The shelf life of chicken stored at 4 and -1 C were not affected
      significantly by chilling method. Storage time and temperature appeared to be the
      decisive factors for sensory and microbiological quality of fresh chicken
      carcasses.

PMID- 10404689
TI  - Analysis of cholesterol oxides in egg yolk and turkey meat.
AB  - A study was conducted to develop a solvent system that will clean egg yolk
      samples and concentrate cholesterol oxides effectively before analysis.
      Cholesterol oxide standards or lipid samples (0.2 g) loaded onto a silicic column
      were washed with a portion of Solvent I (hexane/diethyl ether, 9:1, vol/vol) and
      then with Solvent II. Four different Solvent II preparations (Solvent IIa,
      hexane:ethyl acetate = 4:1; Solvent IIb, hexane:ethyl acetate = 1:1; Solvent IIc,
      hexane:ethyl acetate:diethyl ether = 2:1:1; Solvent IId, hexane:ethyl
      acetate:diethyl ether = 4:1:2, vol/vol/vol) were prepared and the purification
      efficiencies of Solvent II solutions for neutral lipids, cholesterol, and
      phospholipids in the column were compared. Yield study using cholesterol oxide
      standards showed that one or more of the cholesterol oxide standards were eluted
      by the Solvent IIb and Solvent IIc, but Solvent IIa and Solvent IId did not elute
      any of the cholesterol oxides during washing. Egg samples prepared with Solvent
      IIa showed greater amount of cholesterol oxides than those prepared with Solvent
      IId, probably due to incomplete purifying of phospholipids and interference.
      However, the amounts of cholesterol oxides in cooked meat prepared with the two
      purification solvents were not different. Because egg yolk contains very large
      amounts of phospholipids and cholesterol compared with other foods, at least
      twice as much Solvent IIa as Solvent IId was required to properly clean egg yolk
      samples. It was concluded that purification solvents should be selected by sample
      types, and Solvent IId (hexane:ethyl acetate:diethyl ether = 4:1: 2) was superior
      to Solvent IIa (hexane:ethyl acetate = 4: 1) for egg yolk samples.

PMID- 10404691
TI  - Use of cold-set whey protein gelation to improve poultry meat batters.
AB  - The effect of using preheated whey protein isolate (WPI) to replace part of the
      poultry meat proteins in batters formulated with different salt levels was
      studied. Substitution with 2% preheated whey proteins followed by cold set
      gelation (16 h at 1 C) significantly (P < 0.05) improved binding and water
      holding capacity of the raw batters. In the cooked state, WPI substitution
      reduced cook loss and improved textural parameters, especially at < or = 1.5%
      salt. Unheated whey proteins (i.e., lacking the ability to gel at low
      temperature) did not exhibit a negative effect on the texture of the cooked
      batters, but reduced water holding capacity of the raw batters. Overall, cold
      setting of WPI improved the binding of raw and cooked meat batters, particularly
      at low salt level.

PMID- 10404692
TI  - Retinopathy is independently related to microalbuminuria in type 2 diabetes
      mellitus.
AB  - AIM, SUBJECTS AND METHODS: To evaluate whether microalbuminuria is related to
      retinopathy in type 2 diabetes, we studied a sample of 125 known diabetic
      subjects with a mean disease duration of 11 years (range 5-22 years), aged 46-71
      years, by ophthalmoscopy, fundus photography and fluoresceine angiography.
      Urinary albumin excretion rate (UAER) was measured by nephelometry and the
      fractional clearance of albumin, i.e. in relation to creatinine was calculated
      from spot samples. The subjects were classified into groups based on the UAER/24
      h. RESULTS: Microalbuminuria was present if UAER was 30-300 mg/24 h and overt
      nephropathy when UAER > or = 300 mg/24 h. Background (> or = 2 microaneurysms or
      > or = 2 hemorrhages or > or = 1 more advanced lesions, except proliferative
      changes) and proliferative retinopathies were found in 21% and in 3%,
      respectively. Subjects with microalbuminuria (p = 0.026) and overt nephropathy (p
      = 0.002) had more frequently background retinopathy than their counterparts with
      a normal UAER (chi2-test). A multivariate logistic regression model was obtained
      for background retinopathy (chi2 = 37.5, p = 0.0000039, OR 14.9, correct
      prediction of negative outcome in 97% and of positive outcome in 30.4%) including
      the following variables. The fractional clearance of albumin independently
      explained background retinopathy (OR 3.9, 95% CI 1.3-12, p = 0.028). Insulin
      therapy (p = 0.0017), diabetes duration (p = 0.048), blood glucose at 2 h in
      standard oral glucose tolerance test (p = 0.009) and low fasting serum HDL
      cholesterol (p = 0.023) also independently explained retinopathy. Age, gender,
      BMI, systolic blood pressure, ACE inhibitor therapy, fasting serum total
      cholesterol and triglyceride, blood glucose or insulin, hemoglobin A1c, glucagon
      stimulated C peptide response, glomerular filtration rate or smoking habits did
      not independently explain retinopathy. CONCLUSION: We conclude that
      microalbuminuria is related to background retinopathy in type 2 diabetes.

PMID- 10404693
TI  - Association of angiotensin-converting enzyme gene polymorphism and renal
      pathology in Japanese children with IgA nephropathy.
AB  - Polymorphism of the gene that codes for angiotensin I-converting enzyme (ACE) is
      associated with increased severity of immunoglobulin A (IgA) nephropathy in adult
      patients. We evaluated the relationship between the polymorphism of ACE genotypes
      and the pathological and clinical findings in Japanese children with IgA
      nephropathy. Patients with moderate/diffuse mesangial proliferation, glomerular
      sclerosis and tubulointerstitial damage showed a significant increase of the D/D
      type compared to those who had mild/focal mesangial proliferation, without
      glomerular sclerosis or tubulointerstitial damage (p < 0.05). Proteinuria at the
      first renal biopsy was significantly higher in the former group compared with the
      latter group except glomerular sclerosis (p < 0.01). IgA nephropathy patients
      with tubulointerstitial damage also showed an increased serum creatinine level
      compared to patients without the damage (p < 0.03). We conclude that ACE gene
      polymorphism may be correlated with the prognosis of IgA nephropathy in Japanese
      children.

PMID- 10404694
TI  - Evaluation of measured and calculated creatinine clearances as glomerular
      filtration markers in different stages of liver cirrhosis.
AB  - BACKGROUND: Discrepant results have been published regarding the suitability of
      creatinine clearance (C(Cr)) as a measure of glomerular filtration rate (GFR) in
      cirrhotic patients with normal renal function. SUBJECTS AND METHODS: In this
      study we evaluated the accuracy and precision of measured and calculated C(Cr) as
      indexes of GFR by comparing their values to those of inulin clearance (C(In)) in
      10 healthy subjects and 20 patients with either Child's class A or Child's class
      C liver cirrhosis. RESULTS: The accuracy and precision of GFR estimates obtained
      by measuring C(Cr) were good in all three study groups. The mean values of the
      C(Cr)/C(In) ratio were 1.05, 1.03 and 1.04, respectively, and the corresponding
      coefficients of variations were 2.9, 2.9 and 3.8%. A close correlation between
      C(Cr) and C(In) was also found in each study group (r = 0.98, 0.99 and 0.97,
      respectively, with p < 0.001 in each case). C(Cr) calculated from serum
      creatinine by means of the Cockcroft-Gault formula (predicted GFR) proved to be a
      suitable measure of GFR in normal subjects and patients with Child's class A
      cirrhosis: the predicted-to-true GFR ratios were 0.93 and 0.94, respectively, CV
      was 12% in both cases. Moreover, a significant correlation between predicted and
      true GFR was observed in both groups (r = 0.73, p < 0.02 and r = 0.69, p < 0.025,
      respectively). On the contrary, in Child's class C cirrhotics, calculated C(Cr)
      significantly overestimated GFR (predicted-to-true GFR ratio 1.23, CV 20%) and no
      significant correlation was found between predicted and true GFR (r = 0.58, p >
      0.05). CONCLUSION: In conclusion, this study shows that measured C(Cr) is a
      reliable index of GFR in cirrhotic patients, irrespective of the degree of liver
      dysfunction. Calculated C(Cr) is still an adequate marker of GFR in patients with
      compensated liver cirrhosis, whereas it overestimates GFR in patients with
      decompensated cirrhosis. A lower muscle mass, a reduced ability to convert
      creatine to creatinine, and the presence of ascites are most likely responsible
      for the overestimation of GFR by the Cockcroft-Gault formula in the latter
      patients.

PMID- 10404695
TI  - Two by two hour creatinine clearance--repeatable and valid.
AB  - AIM: The purpose of this study was to determine the repeatability and validity of
      2 x 2 hour creatinine clearance, and the validity of creatinine clearances
      estimated by equations. PATIENTS AND METHODS: In 30 patients two 2 x 2 h and two
      24-h creatinine clearances were performed on consecutive days. In addition,
      creatinine clearances estimated by 4 different equations were calculated. Two by
      two hour creatinine clearance provided a measurement of GFR as valid as 24-h
      creatinine clearance. RESULTS: We found, that 2 x 2 h creatinine clearance was
      well repeatable with a mean difference between 2 repeated measurements of 0.8
      ml/min and low coefficients of repeatability of 14.5 ml/min. The validity of 2 x
      2 h creatinine clearance, assessed by the mean difference between 2 x 2 and 24-h
      creatinine clearances, was 1.2 ml/min with tight 95% limits of agreement with a
      range from -8.1 to 10.5 ml/min. This high degree of repeatability and validity
      was present over the entire range of renal function (6-141 ml/min). As 2 x 2 h
      creatinine clearance is more simple and rapid than 24-h creatinine clearance,
      results are obtained on the same day and easy, but repeatable and valid day-to
      day monitoring of renal function is possible. In addition, the two times two hour
      clearances allow for quality control. In contrast, estimated creatinine
      clearances show only poor validity. CONCLUSION: Because of the high degree of
      repeatability and validity, 2 x 2 h creatinine clearance may replace 24-h
      creatinine clearance as the standard method to determine renal function in
      clinical practice.

PMID- 10404696
TI  - Risk factors of renal failure progression two years prior to dialysis.
AB  - AIM: The respective contribution of sex, type of nephropathy, degree of
      proteinuria, blood pressure, protein and sodium daily intakes, blood lipid
      profile, protidemia, hemoglobinemia, acidosis and CaPO4 product on the rate of
      renal failure progression is debated. PATIENTS AND METHODS: The link between
      these parameters and the decrease of creatinine clearance, deltaCcr (according to
      Cockroft) was assessed in uni- and multivariate analysis in a population of 49
      patients (26 women; age 60+/-15 years, weight 79+/-15 kg) selected out of 173
      presently treated hemodialysis patients on the basis of availability of a
      quarterly follow-up for 2 years before starting dialysis. The patients were
      advised a moderate protein and salt restriction which could be retrospectively
      assessed (on urinary excretion of urea and sodium) at, respectively, 0.82
      g/kg/day and 6.5 g/day. RESULTS: The 2-year deltaCcr was 14+/-14 ml/min. It was
      not different in men and women. This decrease in Ccr was neither significantly
      different in gomerular disease (17+/-8, n = 14), diabetic nephropathy (12+/-6, n
      = 7), nephroangiosclerosis (15+/-8, n = 5), interstitial nephritis (12+/-10, n =
      14), and PKD (11 +/-12, n = 9). Patients with antihypertensive drugs (n = 42) had
      a faster progression than those without drugs (n = 7): deltaCcr = 15+/-14 vs 7+/
      7 ml/min (p < 0.05) in spite of comparable blood pressure but with higher
      proteinuria. Linear regression of deltaCcr with the initial and 2-year averaged
      values of the quantitative parameters showed a significant positive link for both
      values with cholesterol, hemoglobine and proteinuria and a negative one with
      protidemia. A positive link was observed with the initial value of bicarbonate
      and the 2-year mean of diastolic and mean blood pressures. No link at all was
      observed with urea and Na excretion, CaPO4 product and triglycerides. Multiple
      regression disclosed a significant link only for protidemia (negative with both
      initial and 2-year averaged value), diastolic BP (only for the 2-year averaged
      value and hemoglobinemia (for the initial value). When the patients were
      classified according to a threshold value of their protidemia, DBP,
      hemoglobinemia, and cholesterolemia those with the combination of 2 risk factors
      of progression (protidemia > or = 66 g/l, DBP > or = 90 mmHg, hemoglobinemia > 11
      g/dl, proteinuria > or = 3 g/d, CT > 5 mmol/l) had a significantly greater
      decrease of Ccr than those with the 3 other combinations at the exception of the
      association of low protidemia with DBP. CONCLUSION: Diastolic hypertension and
      low protidemia are the 2 most important factors predicting progression of renal
      failure. A predictive synergy was furthermore pointed out between low protidemia
      or diastolic hypertension with proteinuria and cholesterol. On the contrary
      anemia attenuates progression linked to low protidemia, diastolic hypertension,
      proteinuria and high cholesterol.

PMID- 10404698
TI  - Disseminated histoplasmosis 19 years after renal transplantation.
AB  - Infections with fungi like Histoplasma are rarely seen in immunocompromized
      patients. We report the case of a renal transplant recipient who presented with
      fever and was diagnosed to have disseminated histoplasmosis 19 years after
      transplant. The pitfalls in making a diagnosis in non-endemic areas are
      discussed. The literature on renal transplantation recipients with histoplasmosis
      has been reviewed.

PMID- 10404697
TI  - Hematocrit stability following intravenous versus subcutaneous administration of
      epoetin alfa to dialysis patients: a post hoc analysis.
AB  - BACKGROUND, SUBJECTS AND METHODS: A previous study of epoetin alfa dose
      requirements [Paganini et al. 1995] among hemodialysis patients who were switched
      from thrice weekly intravenous (i.v.) to thrice weekly subcutaneous (s.c.)
      administration showed that the weekly epoetin alfa dose requirement decreased by
      18.5% after 13 to 16 weeks s.c. treatment and 26.5% after 21 to 24 weeks, without
      significant change in hematocrit. There was patient-to-patient variation in
      response, however, and 39% of the patients required the same or greater doses of
      epoetin alfa after the change from i.v. to s.c. administration. The present study
      reexamines the database to compare hematocrit stability between the two routes of
      administration. RESULTS: During 4 weeks of i.v. epoetin alfa administration, the
      pooled standard deviation (SD) for the patients' (n = 72) weekly hematocrit
      measurements was 1.40, compared with weeks 13 to 16 of s.c. epoetin alfa
      administration when the SD was 1.66 (p < 0.01). Among 41 patients who completed
      24 weeks of s.c. therapy, the pooled SD for the 4 weeks of i.v. treatment was
      1.37 compared with 2.02 during weeks 21-24 of s.c. treatment (p < 0.01). Sixty
      eight percent of patients had lower hematocrit SD during 4 weeks of i.v. therapy
      than during the 4 weeks of s.c. therapy (p = 0.03). CONCLUSION: These data
      suggest that hematocrits may be more stable when epoetin alfa is administered
      i.v. rather than s.c. to patients on dialysis. These results would be expected
      since 100% of i.v.-administered epoetin alfa reaches the systemic circulation
      compared with 18% to 80% bioavailability of s.c.-administered epoetin alfa.
      Within-patient variation in s.c. epoetin alfa absorption may be related to non
      uniformity of adipose tissue, blood supply, lymphatic drainage, and other factors
      at sequential injection sites, and may explain the variability in hematocrit
      after s.c. administration.

PMID- 10404699
TI  - Lupus nephritis in an anti-nuclear antibody-negative young male. The simultaneous
      presence of class III and class V renal lesions.
AB  - We report about a 27-year-old white male, a known case of class III lupus
      nephritis with a very high anti-nuclear antibody (ANA) titer, who after 10 years
      of complete clinical and serological remission presented with sudden development
      of malar rash, proteinuria and an increase in the serum creatinine. Repeated
      serologic studies were all negative for ANA. A repeat kidney biopsy disclosed the
      presence of focal segmental glomerulosclerosis lupus nephritis (class IIIc)
      superimposed with a new membranous lupus nephritis (class V).

PMID- 10404700
TI  - Therapeutic relowering of the serum sodium in a patient after excessive
      correction of hyponatremia.
AB  - BACKGROUND: Inappropriate correction of chronic hyponatremia could lead to major
      neuropathological sequelae. In man, the risk of brain myelinolysis increases
      strikingly when correction of the serum sodium exceeds 10-15 mEq/l/24 h. No
      treatment is actually available for this iatrogenic brain injury. However, recent
      experimental data showed that rapid reinduction of the hyponatremia greatly
      reduces the incidence of brain damage and death in case of serum sodium
      overshooting. SUBJECTS AND METHODS: We tested this rescue manoeuver in a 71-year
      old woman with nausea, confusion and severe (SNa 106 mEq/l) chronic hyponatremia
      related to thiazides. It was associated with hypokalemia (SK: 3.2 mEq/l).
      RESULTS: Treatment with isotonic saline produced inappropriately high SNa
      correction level of +21 mEq/l after the first 24 h. After initial improvement,
      the neurological status deteriorated after 72 h. Rapid reinduction of the
      hyponatremia was then ordered. Administration of hypotonic fluids (by oral and
      i.v. route) combined with dDAVP induced a prompt decline in the SNa (-16 mEq/l/14
      h) with a final gradient of correction of deltaSNa +9 mEq/l. This manoeuver was
      well tolerated without untoward effects. The natremia then progressively
      normalized and the patient completely recovered without neurological sequelae.
      CONCLUSION: Hypotonic fluids may be safely administered to decrease the natremia
      after excessive correction of hyponatremia for potential prevention of
      myelinolysis.

PMID- 10404701
TI  - Calcaneal bone ultrasonometry in patients with renal failure treated with
      dialysis.

PMID- 10404702
TI  - Glomerular filtration rate and serum creatinine: a reply to Fujita et al.

PMID- 10404704
TI  - Pernicious anemia and IgA nephropathy: a reply to Nunes et al.

PMID- 10404703
TI  - Intravenous single dose of erythropoietin (rHuEPO) does not influence plasma
      leptin concentration in hemodialyzed patients with chronic renal failure (CRF)

PMID- 10404705
TI  - The role of genetic factors in the etiology of seasonal affective disorder and
      seasonality.
AB  - The study of the genetic basis of seasonal affective disorder (SAD), a condition
      where depressions in fall and winter alternate with nondepressed periods in the
      spring and summer, has recently received attention. The data on the genetics of
      seasonal affective disorders are of three types: 1. Familiality: Studies on the
      prevalence of psychiatric disorders among relatives of patients with SAD
      suggested a familial contribution to the development of SAD; 2. Heritability: A
      survey of a cohort of twins showed that genetic effects exert a global influence
      across a variety of behavioral traits and accounted for at least 29% of the
      variance in seasonality in men and women; 3. Molecular genetic research: two
      genetic variants related to serotonergic transmission, the 5-HTTLPR and the 5
      HT2A-1438G/A gene promoter polymorphisms, are associated with SAD; the former but
      not the latter polymorphism is related to seasonality. Future research may
      clarify the role of different genes in the development of SAD.

PMID- 10404706
TI  - Impulsivity: a relevant dimension in depression regarding suicide attempts?
AB  - BACKGROUND: This study focuses on clinical impulsivity in depressed patients,
      regarding suicide attempts. METHODS: Fifty depressed in-patients were assessed
      for impulsivity with the Impulsivity Rating Scale and the Baratt Impulsivity
      Scale, at admission (W0) and after 4 weeks of treatment (W4), with special
      attention to suicide attempts. RESULTS: In the whole sample, impulsivity scores
      decreased significantly between W0 and W4. The scale and the questionnaire
      correlated slightly with each other, suggesting some differences in impulsivity
      assessment between patients and clinicians. The two subgroups of patients,
      suicide attempters (SA) (n = 16) and non-suicide attempters (NSA) (n = 34), were
      different neither in terms of sample characteristics and antidepressant
      treatments nor in terms of depression and general psychopathology assessments.
      However, SA patients scored higher on the impulsivity scale and questionnaire
      than NSA patients, both at W0 and W4. These results suggest first that
      impulsivity may be both a trait and a state in depressed suicide attempters and
      second that it may be relevant in terms of suicide attempts in depression.

PMID- 10404707
TI  - Clinical and quantitative EEG studies of mania.
AB  - BACKGROUND: Earlier EEG studies reported essentially normal findings during acute
      manic episodes but some atypical EEG characteristics and distinctions between
      familial and sporadic cases were described. Recently quantitative EEG (qEEG)
      studies differentiating mania from schizophrenia and depression have been
      published. METHODS: Clinical EEGs were obtained in 202 patients hospitalized for
      acute mania. EEGs were repeated in 75 patients rehospitalized for subsequent
      manic attacks. Quantitative EEGs were recorded in 37 patients who were able to
      cooperate after drug washout and again on completion of randomly assigned
      pharmacotherapy. RESULTS: Normal EEGs were obtained in most patients. Moderately
      abnormal EEGs in 16% were significantly associated with absent family histories
      of affective disorder. Left sided abnormalities were more common than right.
      "Small sharp spikes" and "microsleep" were encountered in 17% and 10%
      respectively of patients who drowsed. EEG findings during subsequent episodes did
      not suggest increasing CNS vulnerability. qEEGs showed significant differences
      between each of the therapeutic agents compared-lithium, carbamazepine, and
      lithium combined with carbamazepine, haloperidol or risperidone. Nonresponders at
      baseline had significantly more diffuse theta activity than responders. During
      pharmacotherapy nonresponders had higher amplitudes in the left temporoparietal
      areas. LIMITATION: Clinical EEG findings confirmed previous reports but did not
      contain original observations. Applications of qEEG were limited by requirements
      for patient cooperation.

PMID- 10404708
TI  - The effect of episodes on recurrence in affective disorder: a case register
      study.
AB  - BACKGROUND: The risk of recurrence has been found to increase with the number of
      episodes in both unipolar and bipolar affective disorder. The present study
      compared the effect of the number of episodes on the risk of recurrence in the
      two disorders. METHOD: A case register study including all hospital admissions
      with primary affective disorder in Denmark during 1971-1993. The effect of the
      number of prior episodes on the rate of recurrence following the first discharge
      after 1984 was estimated. A total of 7925 unipolar patients and 2011 bipolar
      patients were included in the study. RESULTS: The rate of recurrence was, on
      average, 1.6 times greater for bipolar patients than for unipolar patients.
      Nevertheless, the effect of the number of episodes was greatest for unipolar
      patients. Thus, the rate of recurrence increased, on average, 15% with every
      episode for unipolar patients and 9% with every episode for bipolar patients,
      when adjusted for differences in age and gender. CONCLUSION: The risk of
      recurrence increases with every new episode in affective disorder. The effect of
      episodes is greater for unipolar disorder than for bipolar disorder. LIMITATIONS:
      The data relate to re-admissions rather than recurrence. CLINICAL RELEVANCE: The
      study shows that the prognosis worsens more for unipolar than for bipolar
      patients with each new episode and suggests the relevance of earlier and more
      sustained intervention.

PMID- 10404709
TI  - The effect of the first manic episode in affective disorder: a case register
      study of hospitalised episodes.
AB  - BACKGROUND: It is poorly understood how the course of illness in depressive
      patients is affected by a manic episode. METHOD: The course of hospitalised
      episodes was compared for patients with depressive episodes only, patients who
      presented with a manic or circular first episode and patients who presented with
      a depressive first episode and later developed mania. The Danish psychiatric
      central register was used as a study base, including all hospital admissions with
      primary affective disorder in Denmark during 1971-1993. RESULTS: A total of
      17,447 patients presented with a depressive first episode and 2903 patients with
      a manic or circular first episode. Among the 17,447 depressive patients, 762
      patients presented with mania at later episodes (4.4%). Younger age at onset was
      associated with increased risk of developing mania. Patients who had a late first
      manic episode had the same rate of subsequent recurrence as patients with mania
      at first episode and this rate was higher than the rate of recurrence for
      patients who remained having depressive episodes only. Time since first manic
      episode was without importance in relation to the risk of subsequent recurrence.
      CONCLUSION: Patients who present with depression and later develop mania have
      from onset the same risk of recurrence as initially bipolar patients. LIMITATION:
      The data relate to admissions rather than episodes. CLINICAL RELEVANCE: Younger
      patients who present with depression have increased risk of developing bipolar
      disorder.

PMID- 10404710
TI  - Gender differences in the prevalence of depression: a survey in primary care.
AB  - Epidemiological surveys demonstrate that unipolar depression is more common in
      females than in males. Gender-specific cultural and social factors may contribute
      to the female preponderance. This study explores this possibility in a cross
      cultural sample of general-practice patients systematically recruited in the WHO
      study "Psychological Problems in Primary Care" conducted in 14 countries with
      identical sampling and assessment strategies. Although absolute prevalence rates
      are broadly varying between centers proposing that the gender ratio is nearly
      constant with 1:2. The cultural context does not contribute substantially to the
      female preponderance. This study lends some support to previous observations that
      the magnitude of female preponderance is associated with the number of symptoms
      associated with depression requested for caseness and inversely related to the
      degree of social impairment. Matching social role variables (marital status,
      children, occupational status) between females and males reduces the female
      excess by about 50% across all centers. Therefore, we conclude that social
      factors are inducing part of the preponderance of females among depressed cases.

PMID- 10404711
TI  - Temporal evolution of stress in the year prior to the onset of depressive
      disorders.
AB  - BACKGROUND: We investigate how the stress levels in a sample of patients with
      depressive disorders vary in the year prior to the onset of symptoms. DESIGN:
      Observational study of the case/control type. Fifty patients whose first
      depressive episode began in the 6 months prior to the interview METHOD: The LEDS
      was applied to all the subjects. A calculation was made of the evolution week by
      week of stress throughout the year prior to the onset. RESULTS: Notable
      differences were detected in the temporal profile of the stress between the
      depressive patients and control groups. The differences between them were
      especially far-reaching in the 26 weeks prior to the onset of the symptoms, with
      a tendency to increase in the 7 weeks immediately before the onset.

PMID- 10404712
TI  - The effect of naloxone on adrenocorticotropin and cortisol release: evidence for
      a reduced response in depression.
AB  - BACKGROUND: Endogenous opioid peptides inhibit the hypothalamic-pituitary-adrenal
      (HPA) axis by influencing the release of hypothalamic corticotropin releasing
      factors. This study examines whether increased activity of the HPA axis in major
      depression is associated with reduced opioid tone. METHODS: We measured the
      adrenocorticotropin (ACTH) and cortisol responses to an intravenous bolus of
      naloxone 0.125 microg/kg in 13 depressed outpatients and 13 healthy volunteers.
      RESULTS: The mean cortisol response was significantly reduced (P<0.05), and the
      ACTH response was also non-significantly reduced in the depressed subjects.
      CONCLUSIONS: These findings imply that the degree of inhibitory endogenous opioid
      tone is reduced in depression. Various mechanisms for the finding are discussed,
      including possible alteration in the function of alpha-adrenergic pathways.
      CLINICAL IMPLICATIONS: Reduced endogenous opioid tone may explain why some
      depressed individuals self-medicate with opiates, and depression is associated
      with opiate withdrawal. Opioid pathways may have a role in the mechanism of
      action of antidepressant drugs, and may be of relevance in the development of
      novel antidepressants. LIMITATIONS OF THE STUDY: The sample size was small,
      leading to a failure of the difference of the basal cortisol levels and also the
      delta ACTH between the groups to reach statistical significance.

PMID- 10404714
TI  - Clonazepam in the treatment of prolonged depression.
AB  - BACKGROUND: The purpose of this paper was to examine the optimal adjunctive dose
      of clonazepam for the treatment of prolonged depression. METHODS: Sixty nine
      patients with prolonged depression were enrolled in an open trial over a 4 week
      period during which clonazepam was added to their medication. RESULTS: A daily
      dose of 3.0 mg clonazepam as augmentation was significantly more effective than
      doses of 1.5 mg and below. Most of the improved patients showed a rapid onset of
      action within 2 weeks, and side effects were not severe. CONCLUSION: A daily dose
      of at least 3.0 mg clonazepam as augmentation of ongoing antidepressant treatment
      should be considered in prolonged depressive patients with suboptimal
      improvement. LIMITATIONS: The effect on clonazepam alone on prolonged depression
      was not established, and its effect of on severe depression is unknown. High dose
      treatment was not carried out in this study.

PMID- 10404713
TI  - The measurement of premenstrual mood symptoms.
AB  - INTRODUCTION: To aid in the diagnosis and management of premenstrual syndromes,
      dozens of symptom measurement instruments have been created and several methods
      for classifying clinically important change in symptoms have been defined. While
      the diagnosis of premenstrual dysphoric disorder (PMDD) has become standardized
      through the application of research criteria, consensus amongst investigators as
      to the instruments best able to confirm the diagnosis and measure treatment
      effects has yet to be reached. OBJECTIVE: To determine the performance and inter
      correlations of three prospective symptom rating scales used to establish
      severity of premenstrual mood symptoms and measure efficacy during a treatment
      trial for premenstrual dysphoria. METHODS: Single item visual analogue scales
      (VASs) for irritability, tension, depression and mood swings were used in
      combination with the Premenstrual Tension Syndrome Observer (PMTS-O) and Self
      Rating (PMTS-SR) scales to measure the severity of premenstrual mood symptoms at
      baseline and during treatment. RESULTS: Premenstrual mood symptoms as measured by
      VASs significantly correlated with PMTS-0 and PMTS-SR scale scores (range 0.70 to
      0.82, P < 0.001). All scales were sensitive to premenstrual symptom worsening
      (which is a required characteristic of this disorder) and revealed differences in
      effects of treatment on premenstrual mood symptoms (P < 0.001). CONCLUSIONS: VASs
      in combination with the PMTS-O are low in burden to the client, reliable, valid
      and sensitive to change. In light of the current debates regarding instruments
      most appropriate for the classification and measurement of treatment effects in
      women diagnosed with premenstrual dysphoria, further refinement of these scales
      is warranted.

PMID- 10404715
TI  - Olanzapine in the treatment of adolescent acute mania: a report of seven cases.
AB  - BACKGROUND: Clozapine may be effective in adults and adolescents with treatment
      resistant bipolar disorder. Olanzapine has a receptor affinity profile similar to
      that of clozapine. METHODS: The responses of seven consecutive adolescents (ages
      12-17) with DSM-IV bipolar disorder, manic episode, treated with olanzapine were
      evaluated. Response to olanzapine was rated as marked, moderate, minimal, none or
      worse. RESULTS: Five (71%) adolescents showed a marked or moderate response. The
      mean+/-SD olanzapine dose was 0.146+/-0.086 mg/kg/day (11+/-6 mg/day).
      CONCLUSION: Olanzapine may have antimanic effects in some adolescents with acute
      mania. Controlled studies of olanzapine in adolescent bipolar disorder appear to
      be warranted.

PMID- 10404716
TI  - Photocarcinogenesis--models and mechanisms.

PMID- 10404717
TI  - Artificial hardening for polymorphic light eruption: practical points from ten
      years' experience.
AB  - The conservative approach of sunlight avoidance and broad-spectrum sunscreen is
      often disappointing in patients with moderate to severe polymorphic light
      eruption. A springtime course of prophylactic artificial hardening with
      ultraviolet B (UVB) phototherapy or psoralen plus ultraviolet A (PUVA)
      photochemotherapy will often allow patients to tolerate more sunlight and give
      them greater freedom during the summer. In this retrospective study we describe
      ten years' experience of such "desensitization" treatment. Individualized therapy
      with attention to detail will maximize the effectiveness of this treatment.

PMID- 10404718
TI  - Sunbed use in Buenos Aires, Argentina.
AB  - The objectives were to survey tanning salons in a defined geographic area of
      Buenos Aires city and to assess the information offered to consumers regarding
      chronic exposure to ultraviolet radiation, types of radiation used, and safety
      measures employed. A prospective study using a standardized interview with
      limited multiple choice responses for data collection was conducted. Results of
      the interview survey were that 35% of the establishments (tanning salons) said
      they used UVA exclusively, 6% UVB, and 25% both; 35% did not know the type of
      radiation to which their clients were exposed. Sunbeds were promoted as healthy
      in 56% of the tanning salons, whereas potential risks were mentioned in only 15%.
      One to 3 sessions on the same day were allowed by 84%, while 40% allowed
      customers to choose the number of weekly sessions. The use of goggles was
      optional in 65% of the establishments and 21% did not even provide goggles. Use
      of sunscreens was not compulsory, and none of the salons had associated
      physicians. Previous history of skin cancer, sunburn or potential photosensitive
      drug intake were never recorded, and the age of access was not restricted in 71%
      of the establishments. In Argentina there are no guidelines to regulate the
      operation of tanning salon establishments or the equipment they use, and there
      are no specific measures taken to prevent skin and ocular pathologies. Ways to
      reduce the risks of ocular and skin pathologies from artificial tanning in
      Argentina are urgently needed.

PMID- 10404719
TI  - Calculation of erythema dose-response curves using a spreadsheet.
AB  - A method of using an Excel spreadsheet is described which allows dose and
      erythema index values to be entered, a sigmoid curve fitted to the data, and a
      report generated. Summary statistics may be derived from the fitted curve. Data
      and statistics may be saved in a simple database. It is suitable for
      implementation by people who have no previous programming experience, although
      basic familiarity with spreadsheets is assumed.

PMID- 10404720
TI  - Solar ultraviolet radiation exposure of infants and small children.
AB  - Townsville, in Queensland, Australia, experiences very high levels of ambient
      solar ultraviolet radiation (UVR) throughout the year and has a predominantly
      white population which is prone to developing skin cancer. The UVR exposure of 1
      year-old and 2 1/2-year-old children raised in Townsville was measured using UVR
      sensitive polysulphone film badges. In two separate exposure studies undertaken
      for 7 days in October 1995 and 5 days in April 1997, exposure at the chest and
      shoulder for each subject was determined. The chest exposures for the 1-year-olds
      were significantly higher at weekends than on weekdays, whereas for the 2 1/2
      year-old children the shoulder exposures were significantly higher at weekends
      than on weekdays. The median daily total exposure for 1-year-old infants was 0.4
      SED (standard erythemal dose) for the chest and 0.4 SED for the shoulder. The
      median daily total exposure for 2 1/2-year-olds was 0.6 SED for the chest and 0.9
      SED for the shoulder. Although the median daily total exposures were
      comparatively low, the maximum values for the chest and shoulder were 6.5 SED and
      2.4 SED, respectively, for the 1-year-old infants, and 20.6 SED and 8.4 SED,
      respectively, for the 2 1/2-year-olds. While the 2 1/2-year-old children spent
      most of their time outside between 9 am and 4 pm, the 1-year-old infants spent
      more time outside before 9 am and after 4 pm. Exposure increases with age in
      early childhood. Increased mobility and a greater tendency to play outdoors is
      likely to account for the higher exposure levels in 2 1/2-year-old children,
      compared to 1-year-old infants.

PMID- 10404721
TI  - Protection against endogenous and UVB-induced oxidative damage in stratum corneum
      lipids by an antioxidant-containing cosmetic formulation.
AB  - A 16-week human clinical study was carried out to determine the ability of
      antioxidants in a cosmetic vehicle to inhibit the induction of lipid peroxidation
      in stratum corneum lipids. The study consisted of a twice daily application of
      material for 12 weeks followed by a 4-week regression phase. Stratum corneum
      lipids were collected and then exposed to 500 mJ/cm2 of ultraviolet B (UVB)
      radiation in order to avoid excessive erythemal damage to the subjects. Lipid
      peroxides were assayed by a methylene blue derivative assay and expressed per
      unit area of skin. During the treatment period, decreases in the level of lipid
      peroxides were observed on the sites treated with the compositions containing
      antioxidants, as compared to the untreated sites, and expressed as percent
      differences. Decreases were observed in endogenous as well as UV-induced lipid
      peroxides followed by a return to baseline levels. These results demonstrate that
      antioxidants in a topical cosmetic formulation were effective in protecting human
      stratum corneum lipids against endogenous oxidation or if challenged by 500
      mJ/cm2 UVB.

PMID- 10404722
TI  - An extract of Polypodium leucotomos appears to minimize certain photoaging
      changes in a hairless albino mouse animal model. A pilot study.
AB  - Chronic ultraviolet B (UVB) exposure of human or murine skin is known to induce
      cutaneous photoaging and enhanced carcinogenic risk. An extract of Polypodium
      leucotomos (PL), a tropical fern plant, has been known to exhibit interesting
      antioxidant and photoprotective properties against acute exposure to ultraviolet
      radiation. The objective of this preliminary (or pilot) study was to determine
      the photoprotective role of topically applied Polypodium leucotomos extract in
      the prevention or amelioration of cutaneous changes of photoaging in hairless
      mice. PL-treated mice showed significant reduction of skinfold thickness than
      those observed in PL-untreated controls. Additionally, PL-treated mice showed a
      significantly lower degree of histologic parameters of photoaging damage,
      including dermal elastosis, compared with positive control mice. Interestingly,
      PL treatment also showed reduction in the number of mice showing skin tumors at 8
      weeks after the cessation of the UVB exposure protocol. The results of this
      preliminary study illustrate that PL treatment helped to ameliorate and to
      partially inhibit some of the histologic damage associated with photoaging of
      skin and appeared to contribute to a decrease in the prevalence of UVB-induced
      skin tumors in mice.

PMID- 10404723
TI  - Xeroderma pigmentosum variant associated with multiple cancers.
AB  - A 62-year-old Japanese man with xeroderma pigmentosum (XP) variant is reported.
      The patient had developed at least 6 basal cell carcinomas, a squamous cell
      carcinoma, and a malignant melanoma on sun-exposed areas, and an atypical
      carcinoid on the right lung. In vivo phototesting showed a normal response. The
      minimal erythema dose of ultraviolet B (UVB) was not lowered and no delayed
      peaking of the erythema reaction was observed. His skin fibroblasts exhibited
      higher sensitivity to UV irradiation, but a normal level of unscheduled DNA and
      RNA synthesis. Cell fusions with XP group A, C, D, E, F, and G cells after UV
      irradiation were all complemented. Previous reports together with this case
      suggest that older XP variant patients have a high frequency of not only skin
      cancers, but also internal malignancies.

PMID- 10404724
TI  - UV transmission and UV protection factor (UPF) measured on split skin following
      exposure to UVB radiation--correlation with the minimal erythema dose (MED).
AB  - In this study the ultraviolet (UV) transmission of split skin exposed to UVB
      radiation and of non-exposed skin was compared in the 280-390 nm wavelength range
      and quantified. In addition, the correlation between the increase in the minimal
      erythema dose (MED) associated with a defined exposure to UVB and the ultraviolet
      protection factor (UPF) calculated from the transmission data was investigated.
      The study population consisted of 12 patients. Two pieces of split skin of the
      same thickness (0.3 mm) were taken from the right thigh of each patient. One
      specimen was removed from an area of non-exposed healthy skin and the other from
      an area which had been exposed to UVB radiation for a period of 12 days in which
      the initial dose of 1/3 MED was raised by 1/3 MED every 4 days. The split skin
      specimens were stretched over a special frame; subsequently, the UV transmission
      was determined with a spectrophotometer. The mean values obtained for UV
      transmission were all significantly below the initial data for non-exposed split
      skin. In the UV range of 280--390 nm, the transmission measured in the exposed
      specimens was 49.1% of the value measured in the non-exposed split skin (P<0.05).
      The corresponding values for the UVA range (315--390 nm) and the UVB range (280-
      315 nm) were 50.1% and 29.5%, respectively (P<0.05), based on the initial
      transmission data obtained from non-exposed skin. The clinical determination of
      MED after 12 days of exposure to UVB yielded mean values that were 3.2 times the
      initial values. Moreover, the mean UPFs calculated from the transmission data
      measured at the end of the 12-day exposure period were also about three times the
      initial values. The present study has thus established a significant correlation
      between the clinical MED values and the UPFs calculated from the transmission
      data measured following exposure to UVB.

PMID- 10404725
TI  - Persistent solar urticaria. A case report.
AB  - Solar urticaria is an uncommon dermatological disease characterized by wheals
      developing within a few minutes after sun exposure and lasting a few hours. We
      describe a man in whom wheals developed on his trunk and arms more than 30 min
      after sun exposure and lasted more than 24 h. High doses of UVA reproduced
      lesions with histological features typical of urticaria. After 7 years, urticaria
      began to develop even in winter and without sun exposure. Our patient is unusual
      in that his wheals were delayed in onset and longlasting. The later association
      of idiopathic urticaria is an additional unusual feature.

PMID- 10404726
TI  - Assay for hepatitis C virus in peripheral blood mononuclear cells enhances
      sensitivity of diagnosis and monitoring of HCV-associated hepatitis.
AB  - Hepatitis C virus (HCV) is a major etiological factor in chronic hepatitis
      affecting up to 24% of blood donors in Egypt. Since fluctuating levels of HCV RNA
      loads, including undetectable values, have been frequently observed in sera of
      chronic hepatitis patients, this study was designed to assess the sensitivity of
      PCR amplification for the plus- and minus-RNA strands in peripheral blood
      mononuclear cells (PBMC) compared to single serum PCR assay. Since the latter
      test detects viremia in only 79.5% of seropositive cases, the highest sensitivity
      for HCV diagnosis was achieved (93.20% when applying the combined triple test
      including PCR amplification of plus-strand in serum, together with plus-strand in
      PBMC and minus-strand in PBMC. The results of this study indicate that the triple
      test provides significant information on extrahepatic replication of HCV in a
      sizable sample of seropositive subjects (429 cases) and improves the assessment
      of HCV viremia. The cost/effectiveness and speed were upgraded by using
      capillary/air rapid thermal cycler. The use of the triple assay in HCV diagnosis
      and post-therapy monitoring is recommended.

PMID- 10404727
TI  - Sensitivity of electrospray-tandem mass spectrometry using the
      phenylalanine/tyrosine-ratio for differential diagnosis of hyperphenylalaninemia
      in neonates.
AB  - The sensitivity of amino acid analysis by electrospray-tandem mass spectrometry
      (ESI-TMS) in differential diagnosis of the different forms of
      hyperphenylalaniemias (HPA) was studied in a total number of 78 dried blood
      samples from neonates with increased phenylalanine (Phe) concentrations (> 150
      micromol/l). Simultaneous quantitative analysis of Phe and tyrosine (Tyr) were
      performed by ESI-TMS. By means of the Phe/Tyr-ratio it was possible to
      differentiate between phenylketonuria (PKU; n = 23) and nonPKU-HPA patients (n =
      35; P < 0.001) with a sensitivity of 100%. Neonates with transient HPA (n = 9)
      showed a lower Phe/Tyr-ratio compared to the nonPKU-HPA patients (P < 0.001).
      Amino acid analysis by ESI-TMS represents a powerful diagnostic tool in
      differential diagnosis of HPA and is an appropriate technique in the setting of
      neonatal screening based on dried blood spots.

PMID- 10404728
TI  - Thiol and redox reactive agents exert different effects on glutathione metabolism
      in HeLa cell cultures.
AB  - Glutathione protects cells against oxidative damage, free radical damage and
      other types of toxicity. The aim of the present study was to investigate the
      impact on glutathione metabolism exerted by different thiol or redox reactive
      agents. Intracellular concentrations of glutathione in HeLa cell cultures were
      lowered after addition of agents mainly exerting oxidative stress (homocysteine
      and hydrogen peroxide), whereas thiol reactive oxidative agents (mercury ions,
      copper ions and hydroquinone) in concentrations not affecting cell growth seemed
      to stimulate the production of glutathione. Possibly, the thiol reactive agents
      decrease the concentration of glutathione, thereby stimulating further synthesis
      of glutathione, since glutathione synthesis is subject to feedback regulation by
      glutathione on gamma-glutamylcysteine synthase. Redox changes after addition of
      thiol and redox reactive agents were also investigated. Copper ions lowered the
      concentrations of reduced forms of all extracellular thiols and of intracellular
      reduced cysteine in HeLa cell cultures. The addition of mercury ions,
      hydroquinone, homocysteine or hydrogen peroxide did not change the proportions
      between reduced and total thiol concentrations. After addition of buthionine
      sulfoxime, the total concentrations of intra- and extracellular glutathione were
      markedly decreased and the ratio between reduced and total glutathione
      concentrations was lowered. However, both cysteine and homocysteine exhibited
      normal ratios between the concentrations of reduced and total thiols in the
      presence of buthionine sulfoxime. This finding could be due to other cellular
      antioxidants, such as thioredoxin, ascorbic acid or tocopherols, maintaining
      redox status of these thiols.

PMID- 10404729
TI  - Three point mutations of human butyrylcholinesterase in a Japanese family and the
      alterations of three-dimensional structure.
AB  - Three different mutations at codons 330 (TTA to ATA), 365 (GGA to AGA) and 515
      (CGT to TGT) of human butyrylcholinesterase (hBChE) were identified in a Japanese
      family. We correlated alterations in in the patient's hBChE activity with
      possible structural alterations in the three-dimensional structure of hBChE
      caused by the point mutations. This study was performed using the published
      computer-generated three-dimensional structure of hBChE based on the structure of
      acetylcholinesterase. The amino acid substitution at L330I was adjacent to
      hydrophobic residues that form the channel domain of the active center. This side
      chain faced the side opposite the active center. The amino acid substitution at
      G365R was located at the position most remote from the active center, and this
      substitution site was exposed to the surface of the BChE protein. Alpha-helical
      structure was present to the active center, and the guanidyl residue of native
      Arg 515 was hydrogen-bonded to the carboxyl group of Asp 395 in the alpha-helix.
      These point mutations may cause steric effects on the present patient's hBChE
      activity. This is the first report of three-dimensional structural analysis
      performed on the L330I, G365R, and R515C mutations of hBChE.

PMID- 10404730
TI  - Time-course of cardiac troponin I release from isolated perfused rat hearts
      during hypoxia/reoxygenation and ischemia/reperfusion.
AB  - The study was designed to determine the time-course of cardiac troponin I (cTn-I)
      release in isolated and Langendorff-perfused rat hearts during hypoxia and
      reoxygenation (H/Reox), and after various durations of total ischemia and
      subsequent reperfusion (I/R). For this purpose, in H/Reox, cTn-I was measured
      with the conventional Access immunoassay (ng/ml) and a new immunoassay which
      operates at pg/ml, and compared with creatine kinase (CK), lactate dehydrogenase
      (LD) and cardiac troponin T (cTn-T). In I/R, cTn-I was compared with CK and LD.
      The anti-Tn-I mAbs used in cTn-I assays cross-react with cTn-I of the rat. A
      clear difference between time-courses and concentration levels of cTn-I in I/R
      and H/Reox models was found. In I/R, maximum release of cTn-I, CK and LD
      similarly occurred within minutes following reperfusion; however cTn-I did not
      return to baseline values. cTn-I levels were not linked to the duration of
      ischemia. In I/R, we were only able to detect small cTn-I concentrations. In
      H/Reox experiments, cTn-I, CK and LD increased time-dependently. We found higher
      cTn-I maximal peak levels detected with the Access immunoassay than with the new
      assay (median, 0.346 ng/ml per min/g dry wt vs 132 pg/ml per min/g dry wt). cTn-T
      maximal concentrations were lower than maximal cTn-I levels (median, 0.117 ng/ml
      per min/g dry wt). Time-courses of cTn-I release were roughly similar with both
      assays in the H/Reox model (r = 0.90). These data indicate that the cTn-I time
      course is related to experimental model (I/R or H/Reox), but also likely depends
      on the sensitivity of cTn-I assays in such experimental conditions.

PMID- 10404731
TI  - Presenilin-2 mutation and polymorphism in Japanese Alzheimer disease patients.
AB  - The Asn141Ile mutation of the presenilin 2 gene is responsible for familial early
      onset Alzheimer disease found in Volga-German kindreds. However, the genetic
      influence of presenilin 2 gene on sporadic Alzheimer disease remains unknown. In
      this study, the frequency of the mutation and genetic association with the
      presenilin 2 locus were investigated in Japanese sporadic cases. The Asn141Ile
      mutation was not found in 88 cases of sporadic Alzheimer disease or 13 unrelated
      cases of familial Alzheimer disease. Fifty cases of late onset sporadic Alzheimer
      disease and 50 age-matched controls indicated no association with an exon 3
      polymorphism of the presenilin 2 gene. These results indicate that the presenilin
      2 mutation is not a major cause of Alzheimer disease.

PMID- 10404732
TI  - A simple and sensitive high-performance liquid chromatography assay of diltiazem
      and main metabolites in renal transplanted patients.
AB  - A sensitive and specific reversed-phase high-performance liquid chromatographic
      method was developed for determination of the benzothiazepine calcium channel
      blocker diltiazem and three of its main metabolites in human plasma. A solid
      phase extraction method (C18) is described for isolating diltiazem and the
      metabolites N-demethyl-diltiazem (M(A)), deacetyldiltiazem (M1) and N-demethyl
      deacetyl-diltiazem (M2) from human plasma spiked with trans-diltiazem as internal
      standard. Chromatographic analysis of the eluate was accomplished using a
      reversed-phase column (C8) and a mobile phase consisting of acetonitrile,
      potassium dihydrogen phosphate-buffer (pH 2.9), triethylamine and methanol
      (280:598:2:90 v/v/v/v). The limit of detection was 5 ng/ml for diltiazem and 2.5
      ng/ml for the metabolites (UV detection). Recoveries were > 75% for all
      substances. Precision analysis indicated a coefficient of variation below 5% for
      both diltiazem and metabolites at plasma concentrations ranging from 30 to 120
      ng/ml for diltiazem and from 15 to 60 ng/ml for the metabolites. The accuracy was
      < 3% for diltiazem at all concentrations investigated. Metabolites showed an
      accuracy of < 7% at higher concentrations, however at low concentration the
      accuracy was < 16%. A pilot study has been performed in order to study whether
      the method was applicable to patients and volunteers. Plasma samples from renal
      transplanted patients treated with cyclosporin A and healthy volunteers did not
      show any interference by cyclosporin A with the determination of diltiazem and
      metabolites.

PMID- 10404733
TI  - A GC/MS/MS screening method for multiple organic acidemias from urine specimens.
AB  - A gas chromatography tandem mass spectrometry method using an ion trap GC/MS
      system was developed to quickly screen urine samples for 14 organic acids
      associated with multiple organic acidemias. The following organic acids are used
      as diagnostic markers: methylmalonic acid, glutaric acid, 2-ketoisocaproic acid,
      succinylacetone, 3-methylcrotonylglycine, tiglylglycine, isovalerylglycine,
      fumaric acid, butyrylglycine, propionylglycine, hexanoylglycine, adipic acid,
      suberic acid, and sebacic acid. 2-ketocaproic acid is used as an internal
      standard. The samples are prepared using a solid-phase extraction and converted
      to trimethylsilyl derivatives. The extraction efficiency for the 14 compounds is
      between 57 and 106%. A derivatized standard mixture of the 14 markers is run
      prior to the patient samples to determine the accurate absolute and relative
      retention times. The samples are then injected and the product ion spectra
      monitored. For data analysis, one characteristic product ion plot is extracted
      for each of the 14 marker compounds, and the presence of a peak with the expected
      retention time is determined. The areas of the product ion peaks are compared
      with the reference range determined from 30 normal controls. Ten samples of
      patients with known organic acidemias were measured. For all patients, diagnostic
      peaks at the expected retention times of at least five times the upper limit of
      the reference range were detected. The method, with its relatively fast sample
      preparation, short 10.0 min run time and simple data analysis, is suitable for
      use as a quick metabolic screen of very sick patients in whom there is concern
      regarding the possibility of a treatable inborn error.

PMID- 10404734
TI  - Simpler technique for measuring oxidative susceptibility by heparin affinity
      column isolation of lipoproteins.
AB  - Variations in the in vitro oxidative susceptibility or resistance of lipoproteins
      have been used to test the effect of ingested antioxidants and may prove to be a
      marker for coronary artery disease. Here we describe a simple technique for
      isolating and oxidizing beta-lipoproteins that may have utility in the clinical
      laboratory. Electrophoretic profiles showed that beta-lipoproteins were separated
      from alpha-lipoproteins and essentially from most other serum proteins using
      heparin affinity columns. Lipoproteins were normalized in the reaction mixture by
      measuring apo B in the beta-lipoprotein eluate using an automated apo B method,
      which gave good recoveries of 106-112%. Copper mediated oxidation was monitored
      by measurement of conjugated dienes formation at 234 nm for 300 min. When the
      reaction mixture included beta-lipoprotein eluate containing 0.03 g/L of apoB and
      5 micromol/L copper sulfate, conditions were effective for obtaining complete
      oxidation while allowing reproducible measurements, with between day coefficients
      of variation of 2.35%, 14.6%, and 10.5% for lag, propagation and plateau phases,
      respectively. Beta-lipoproteins isolated from serum were more susceptible to
      oxidation than beta-lipoproteins from plasma apparently due to inhibition of
      oxidation by fibrinogen which co-eluted with beta-lipoprotein from plasma. For
      this reason, we recommend using serum preserved with EDTA for this assay.

PMID- 10404735
TI  - Platelet sodium/hydrogen exchanger activity in normotensives and hypertensives.
AB  - Increased activity of sodium/hydrogen exchange provides a potentially important
      mechanism for the development of hypertension. The aims of this study were to
      compare platelet sodium/hydrogen exchanger activity and renal acid-base excretion
      in normotensives and hypertensives of Caucasian origin. Platelet intracellular pH
      (pHi) was measured using the fluorescent dye BCECF to monitor intracellular pH.
      Sodium/hydrogen exchanger activity was estimated from the recovery of pHi clamped
      to 6.25 with nigericin. Normotensives had supine blood pressures of < 140 and <
      90 mmHg; those with essential hypertension had blood pressures > 150/95 mmHg with
      no known secondary cause. Measurements of platelet pHi and sodium/hydrogen
      exchanger activity were made on 26 normotensives (ten female, sixteen male) and
      25 hypertensives (five female, twenty male). All subjects were on their usual
      dietary sodium intake. Statistical analysis was by two-way analysis of variance
      for gender and blood pressure status. Group values are expressed as means+/-SD
      and a P value of < 0.05 was taken as being statistically significant. There were
      no significant differences in platelet pHi between the normotensive (n = 26) and
      the hypertensive (n = 25) group: pHi 7.21+/-0.14 and 7.18+/-0.16, respectively.
      The pHi recovery after acidification was sodium-dependent and inhibited by N
      hexamethylene amiloride. Comparison of kinetic constants showed no significant
      differences between the normotensive and the hypertensive groups: values for rate
      constants and initial velocities were 0.24+/-0.04 s(-1), 0.16+/-0.03 dpHi/s for
      the normotensives and 0.25+/-0.05 s(-1), 0.16+/-0.03 dpHi/s for the
      hypertensives, respectively; there were also no significant differences in proton
      fluxes. The inability to find raised platelet sodium/hydrogen exchanger in the
      hypertensives contrasts with previous observations using other methods for the
      measurement of this exchanger in platelets and this raises important
      methodological issues in the assessment of platelet sodium/hydrogen exchanger
      activity.

PMID- 10404736
TI  - Sex difference in the relationship of calcium and magnesium excretion to
      glycaemic control in type 1 diabetes mellitus.
AB  - In order to assess the variability and possible causes of calcium and magnesium
      losses in diabetes mellitus, urinary calcium and magnesium excretion were
      monitored six monthly over a 3-year period in 108 stable, type 1 diabetic
      patients who were having assessment of their clinical status and glycaemic
      control over the same period. In the patients studied the ranges of excretion of
      both calcium and magnesium were considerably wider than our non-diabetic
      reference ranges but the within subject variation in excretion was high. However,
      using mean values obtained over the study period, a direct relationship was
      observed between the excretion of both calcium and magnesium and HbA1 in female
      patients (P < 0.01) but not in males who had similar HbA1 values. The urinary
      excretion of calcium and magnesium did not relate to any of the other clinical or
      biochemical indices measured, including body mass index, daily insulin dose,
      retinal status or albumin excretion. It is suggested that, in poorly controlled
      patients, females may have a greater risk than males of developing the
      complications associated with chronic calcium and magnesium loss.

PMID- 10404737
TI  - Spectrophotometric determination of trace amounts of hemoglobin using the
      oxidative decomposition reaction of a copper(II)-phthalocyanine complex.
AB  - A catalytic effect of hemoglobin was found in the oxidative decomposition of a
      copper(II)-phthalocyanine complex (Cu-pts) with peroxomonosulfate. Based on this
      finding, a simple, rapid, highly sensitive and high-precision spectrophotometric
      method for hemoglobin was developed. In this indicator system, Cu-pts as the
      indicator and hemoglobin as the catalyst were simultaneously decomposed with
      peroxomonosulfate. Therefore, the slopes of the absorbance-time curve of the
      sample solution become equal to that of the blank solution after 5 min. The
      calibration curve was linear over the range of 12-258 microg/l. Detection limits
      (3sigma) were 8.13 microg/l, and the relative standard deviation was 2.05% (10
      determinations) for 130 microg/l of hemoglobin. The metal ions did not
      significantly produce an interference in this method. The albumin had some
      influence but was permissible up to 6 times the weight of hemoglobin. The
      proposed method was applied to human blood samples with satisfactory results.

PMID- 10404738
TI  - Problems related to determination of trace elements in spent continuous
      ambulatory peritoneal dialysis fluids by electrothermal atomic absorption
      spectrometry.
AB  - Critical parameters which influence the direct determination of trace elements in
      spent continuous ambulatory peritoneal dialysis (CAPD) fluids by electrothermal
      atomic absorption spectrometry (ETAAS) were investigated. Samples were collected
      after CAPD fluid exchange in 5.0 ml polyethylene cups and stored at -20 degrees
      C. Daily spent CAPD fluids were frozen immediately, while nightly spent CAPD
      fluids were frozen 2-3 h after the morning exchange. Before analysis samples were
      equilibrated to room temperature and analysed within 8 h. It was found
      experimentally that some samples which were not frozen immediately leaked out of
      the pyrolytically coated graphite tube before the drying step. In order to keep
      the sample in the graphite tube and to obtain reproducible measurements of
      copper, aluminium and iron, samples were diluted before analysis 1 + 1 with 32%
      v/v nitric acid. The standard addition method was used in the calibration
      procedure. The results of direct ETAAS determinations for copper agreed well (+/
      5-10%) with those obtained after acid digestion of CAPD fluids in Parr bomb. The
      procedure for direct determination of all three elements was validated with
      spiked samples.

PMID- 10404739
TI  - The analysis of peculiar urinary (and other) calculi: an endless source of
      challenge.
AB  - The exact composition of calculi is clinically important, but many specimens are
      not examined, with resultant loss of important information. We describe the
      incidence and nature of false stones, peculiar calculi and crystals growing on
      surprising materials. We studied 3100 calculi (97% urinary, 2% digestive and 1%
      others). Fourier transform infrared spectroscopy was used to identify calculi by
      detailed comparison with libraries of reference spectra. We also used UV-visible
      spectroscopy, nuclear magnetic resonance and gas chromatography-mass spectrometry
      for specific situations. Among 3100 calculi, 154 (5%) had an unusual composition;
      101 specimens (3.3%) were false calculi or artifacts, 31 (1%) contained drugs or
      metabolites and 22 (0.7%) corresponded to crystallizations around other
      materials. The findings contribute to immediate patient management and to
      advances in scientific and medical knowledge. We conclude that the analysis of
      all calculi must be carried out, to determine their composition, and an efficient
      strategy must be used.

PMID- 10404740
TI  - Validity of unbound digoxin measurements by immunoassays in presence of antidote
      (Digibind).
AB  - Measurement of unbound digoxin in presence of Fab fragments may be useful in
      management of overdoses. The analysis can be performed on serum directly or on
      ultrafiltrate of serum. The architecture of the immunoassay may influence the
      validity of results obtained using these two approaches. We tested this
      hypothesis by preparing serum mixtures containing various concentrations of
      digoxin and Digibind and analyzed them by the immunoassays before and after
      ultrafiltration. Four samples collected from Digibind-treated patients were also
      analyzed before and after ultrafiltration. The slopes and the y-intercepts of the
      measured versus the expected values for serum and its ultrafiltrate overlapped
      for the MEIA digoxin assay. For other three immunoassays tested (ACS:180,
      Stratus, and On-Line), either the slope or the intercept for measured versus the
      expected results for serum were significantly different (P < 0.05) than those for
      ultrafiltrate. Following addition of digoxin and Digibind, differences in results
      for serum analyzed directly or after ultrafiltration were < 0.50 ng/ml.
      Comparable samples from digoxin-overdosed patients treated with Digibind had
      differences of > 1.0 ng/ml. Previous claims reporting direct analysis of digoxin
      in presence of antidote but not having used patient samples for validation should
      be revisited. To date, analysis of serum ultrafiltrate by an immunoassay proven
      not to have matrix bias remains the most accurate approach in measuring unbound
      digoxin in presence of antidote.

PMID- 10404741
TI  - Development of enzyme-linked immunosorbent assay for acidic fibroblast growth
      factor and its clinical application.
AB  - We have developed, for the first time, an enzyme-linked immunosorbent assay
      (ELISA) system for the measurement of human acidic fibroblast growth factor
      (aFGF). Anti-bovine aFGF rabbit IgG was conjugated with N-hydroxysuccimidobiotin,
      and the resulting IgG-biotin conjugate was used as the second antibody. This
      assay was highly specific and reproducible, enabling us to detect aFGF at a
      concentration as low as 1 microg/l without any prior processing of samples. With
      this method, it was possible to determine human aFGF up to 833 x 10(3) ng/l, with
      the use of anti-bovine aFGF IgG as the first and second antibody. There was no
      significant cross-reactivity of the antibody with other growth factors, such as
      basic fibroblast growth factor (bFGF) and vascular endothelial growth factor
      (VEGF). The aFGF concentration in pericardial fluid was significantly higher in
      patients with unstable angina than in those with other heart diseases, suggesting
      that the aFGF plays an important role(s) in the course of collateral growth in
      coronary artery disease. Therefore, our ELISA system may be useful in determining
      unknown biological function(s) or pathological role(s) of aFGF in various disease
      entities.

PMID- 10404742
TI  - Semen specific gamma-glutamyltransferase carries ABH antigens: a sandwich ELISA
      for simultaneous semen detection and its ABO blood typing.
AB  - Semen type of gamma-glutamyltransferase (gamma-GTP) is different from the
      membrane bound type of the enzyme in both biochemical and immunological
      properties, and consists of two subunits (150 and 95 kDa). We found that anti-ABH
      antibodies recognize a 150-kDa subunit of seminal gamma-GTP by Western blot and
      immunoprecipitation analyses. Using SG2, one of anti-semen specific gamma-GTP
      monoclonal antibodies which we had produced, and anti-ABH antibodies, we
      established a sandwich ELISA for identifying human seminal gamma-GTP and its ABO
      type simultaneously. This sandwich ELISA allows ABO typing of highly diluted
      semen. The dilutions for ABO typing were 10(5) times for A or O, and 10(4) times
      for B. Furthermore, ABO typing of semen was successfully performed by this ELISA,
      even in the mixed presence of vaginal fluid, saliva and blood. Thus, seminal
      gamma-GTP carries ABH antigens and the sandwich ELISA with SG2 and anti-ABH
      antibodies enables ABO typing of semen. The sandwich ELISA is extremely useful
      for ABO typing originated from semen in the mixture of biological fluids.

PMID- 10404743
TI  - Evaluation of use of singleton measurements of C-peptide by RIA.

PMID- 10404744
TI  - Uracil phosphoribosyltransferase activity in hereditary orotic aciduria.

PMID- 10404745
TI  - Removal of tumours of the orbital apex via a postero-lateral orbitotomy.
AB  - BACKGROUND: The surgical management of pure apical tumours of the orbit may be
      problematic with traditional approaches. A postero-lateral approach, specifically
      designed for apical growths, provides a more favourable angle of vision through a
      relatively small bone opening. METHODS: A series of 103 consecutive cases of
      intraorbital tumours, operated on in a community-based institution, was
      retrospectively reviewed. Out of this series, 8 patients, harbouring lesions
      located in the posterior intraconal space, underwent a postero-lateral
      orbitotomy. This approach, through a small opening on the orbital and temporal
      portions of the greater wing of the sphenoid, with the lesser sphenoidal wing,
      the orbital plate of the frontal bone, the lateral rim of the orbit being
      maintained intact, allowed adequate exposure of the orbital apex and successful
      extirpation of the tumours. In four patients the histological examination
      disclosed a cavernoma; the other patients had, respectively, a dermoid cyst, a
      lymphoma, a hemangiopericytoma and a metastatic melanoma. RESULTS: No recurrences
      were observed in a follow-up period ranging from 1 to 7 years postoperatively
      (the patient with melanoma died 16 months after operation for systemic
      complications of her illness). One patient showed transient weakness of lateral
      rectus muscle due to surgical manipulation, which subsided in few months.
      CONCLUSIONS: The postero-lateral orbitotomy represents a reliable alternative to
      other traditional surgical approaches when dealing with tumours of the orbital
      apex, providing excellent exposure of this region with a low rate of operative
      morbidity.

PMID- 10404747
TI  - Localization accuracy of AC-PC line and functional pallidal target using BRW
      stereotactic implementation system and axial CT scanning. An experimental study.
AB  - BACKGROUND: Ventriculography is still considered an unavoidable step for
      functional target localization, even though this method is invasive and requires
      stereotactic rooms, orthogonal frames, and parallax-free X-ray equipment. In this
      experimental study, the authors investigated the feasibility of performing
      stereotactic lesions using a conventional, widely employed frame, such as the
      Brown-Roberts-Wells (BRW) apparatus, and computerized axial tomography (CAT)
      imaging. METHODS: Five ex vivo models consisting of cadaveric brains enclose in a
      plastic shell were fixed in a BRW frame. A simple BRW implementation was used to
      ensure more symmetrical placement of the basal ring. Two-millimeter plastic balls
      were inserted at the level of the anterior (AC) and posterior commissures (PC)
      and at the target in the pallidus. Their final position was measured on the
      anatomical specimens and compared with Schaltenbrand Atlas maps. RESULTS: The
      error in estimating the length of the intercommissural line ranged from 0.5 mm to
      2.0 mm, with a maximum backward angulation of four degrees in predicting the AC
      PC plane. Upon dissection, in four out of five cases, the balls were found within
      the area of the pallidus defined by Laitinen for posteroventral pallidotomy.
      CONCLUSIONS: The authors conclude that anatomical identification of the AC-PC
      line and the pallidus target, using the BRW stereotactic system and CAT axial
      images alone offers sufficient accuracy. They suggest that functional
      neurosurgery for movement disorders could be safely and successfully carried out
      without ventriculography if neurophysiological monitoring is also employed.

PMID- 10404746
TI  - Carotid Sinus Syndrome: a review of the literature and our experience using
      carotid sinus denervation.
AB  - BACKGROUND: The Carotid Sinus Syndrome (CSS) is a rare condition causing
      spontaneous syncopal attacks or marked dizziness. METHODS: We studied 28 patients
      affected by CSS from January 1991 to October 1996. Eleven patients affected by
      cardioinhibitory type were treated by pace-maker (PM) implant. Seventeen patients
      had mixed type and all, but one who refused any treatment, entered this study.
      Carotid Sinus Denervation (CSD) was first performed in 2 of 10 patients who
      remained symptomatic after PM and in 6 patients as first choice therapy. RESULTS:
      At a mean follow-up of 30 months no patient submitted to CSD had recurrent
      syncopal attacks or dizziness. CONCLUSIONS: CSD is a safe and simple technique to
      abolish either the cardioinhibitory or the vasodepressor response in CSS.

PMID- 10404748
TI  - Myeloradicular damage in traumatic cervical disc herniation.
AB  - BACKGROUND: The literature on pure traumatic disc herniation is now voluminous
      but diversity of opinion exists regarding frequency, pathogenesis and management
      of this type of lesion. As a further contribution to the solution of the question
      it is thus justified to report our series of cervical traumatic disc herniation.
      METHODS: During the period from January 1986 to December 1994, 41 patients (25
      males and 16 females, between the ages of 24 and 51 years) with traumatic
      cervical disc herniations were operated on by anterior approach. Twenty-six
      (63.4%) patients presented with radicular syndrome, 3 (7.3%) with medullary
      symptoms and signs, and 12 (29.3%) with myeloradiculopathy. Disc herniation was
      at the C3/4 level in 4 (9.7%) cases, at the C4/5 level in 7 (17.1%) cases, at the
      C5/6 level in 24 (58.5%) cases, and at the C6/7 level in 8 (19.5%) cases. In 6
      (40%) patients suffering from myelopathy (with or without radiculopathy) an area
      of high MR signal intensity was observed within the cervical cord on T2-weighted
      images; such area corresponded at the level of cord compression by disc and was
      not demonstrated on T1-weighted images. All patients underwent discectomy without
      bone grafting. RESULTS: Among patients with radiculopathy, 27 (71%) experienced
      complete relief of preoperative symptomatology, and 11 (29%) minor pain and/or
      neurological deficits without interference with work activities. The myelopathy
      completely disappeared in 11 (73.3%) cases whereas remained unchanged in 3 (20%);
      1 patient with myelopathy experienced amelioration of preoperative specific
      symptoms and signs. CONCLUSIONS: The results of surgery for cervical
      radiculopathy due to traumatic disc herniation are satisfactory since 92 to 100%
      of the patients postoperatively regain prior activities, an observation we have
      confirmed with our own series. The results in cases of myelopathy are less
      satisfactory: although approximately 73% of our patients with myelopathy reported
      total relief of preoperative symptomatology, published reports indicate that a
      significant postoperative improvement is seen in 33 to 56% of patients.

PMID- 10404749
TI  - Tuberculous spondylitis: a retrospective study on a series of 12 patients
      operated on in a 25-year period.
AB  - BACKGROUND: The incidence of tuberculous spondylitis, which had declined steadily
      for over 40 years in our countries, started increasing again in the eighties,
      paralleling the resurgence of pulmonary tuberculosis. Therefore it has become a
      matter of discussion in contemporary literature, because it can be a diagnostic
      challenge and, in spite of its severe neurological complications, it is a
      potentially curable illness. METHODS: In this retrospective study the authors
      report their experience concerning 12 patients operated on in a 25-year period
      because of serious cord compression from thoracic (9 cases) and cervical (1 case)
      tuberculous spondylitis or from thoracic tubercular epidural lesion (2 cases).
      Surgical techniques were selected on the basis of the cause of cord compression.
      Fusion with autologous bone and metallic osteosynthesis was performed in the
      cervical case (1986); no other patient received spinal instrumentation, and this
      can be explained with the consideration that all but one cases of Pott's
      paraplegia were treated in the years 1968-1977. In all of these cases fusion was
      achieved by means of plaster jackets and prolonged bed rest. Prolonged
      chemotherapy was systematically administered. RESULTS: Follow-up data collected
      in 1995 show good and long-lasting results. CONCLUSIONS: They conclude that
      surgical treatment is required in case of cord compression and results can be
      excellent even in presence of severe neurological impairment; spinal
      instrumentation available in our era should be now considered in order to make
      rehabilitation earlier and morphologic results more satisfactory.

PMID- 10404750
TI  - Growing patterns of cavernous angioma in the fourth ventricle. Case report.
AB  - Cavernous malformations are vascular lesions that occur in all parts of the
      central nervous system but most commonly in the cerebral hemispheres; unusually
      they may be found along the midline (basal ganglia, pineal region or brain stem),
      into the ventricle possibly encroaching upon the fourth and third ventricle. We
      report a case of midline cavernomas of the IV ventricle, that grew to large size
      in-time, demonstrating the capacity for rapid expansion.

PMID- 10404751
TI  - Civilian gunshot wounds to the head with brain stem localization. A case report.
AB  - The authors present a case of a patient wounded to the head and back by civilian
      firearm projectiles. The case peculiarity is that only one bullet reached the
      brain stem level causing significant neurological deficits. The final clinical
      picture is comparable to the "caudal pontine tegmentum syndrome". The authors
      describe both the bullet path and the intracranial localization taking into
      account ballistic details. The problems associated with prognosis, diagnosis, and
      treatment for gunshot wounds are discussed. In addition, the authors explain the
      main intracranial lesions and their mechanisms, the role of investigation, and
      the protocol of medical and surgical treatment. Lastly, a systematic approach for
      treating these types of gunshot wounds is outlined.

PMID- 10404752
TI  - Extradural haematoma complicating lumbar puncture following a craniotomy. A case
      report.
AB  - BACKGROUND: This case report illustrates the development of an intracranial
      extradural haematoma (EDH) as an uncommon complication of a lumbar puncture.
      CLINICAL PRESENTATION: A 10-year-old girl operated for intra-third ventricular
      cysticercosis developed postlumbar puncture headache after a drainage lumbar
      puncture (LP) on the 7th postoperative day. CT scan revealed a right frontal EDH
      away from the operative site. INTERVENTION: The child was managed conservatively
      in view of her preserved sensorium. RESULTS: The child had an uneventful
      recovery. Follow-up CT scans showed resolution of the haematoma. CONCLUSIONS: LP,
      though considered to be a safe procedure, may rarely be associated with a
      potentially lethal intracranial haematoma, which can be managed successfully if
      diagnosed at an early stage.

PMID- 10404753
TI  - Dumbbell lymphoma of the cervical spine in a child. Case report.
AB  - Primary or secondary spinal involvement of lymphoma is a rarely reported entity.
      An eleven-year-old girl with primary cervical dumbbell non-Hodgkin's lymphoma
      (NHL) was presented. We could not found any such growth pattern of primary or
      secondary NHL'S in the literature. For this reason, we reviewed shortly pertinent
      literature and discussed the pathophysiologic, diagnostic and prognostic features
      of the lesion with treatment modalities.

PMID- 10404754
TI  - Spinal malignant melanotic schwannoma. Case report.
AB  - The authors report a rare case of spinal cord compression syndrome due to a
      malignant melanotic schwannoma. Pathogenesis, diagnostic difficulty and
      therapeutical problems are discussed. The authors conclude that such tumours
      should be surgically treated due to the possibility of a benign clinical
      behaviour even in those cases showing malignant histological features.

PMID- 10404755
TI  - A synergistic effect of serotonin transporter gene polymorphism and smoking in
      association with CHD.
AB  - Serotonin induces vasoconstriction in the presence of atherosclerotic lesions.
      Platelets acquire serotonin from the extracellular space by serotonin transporter
      and release it following aggregation. There is a functional polymorphism in the
      serotonin transporter (5-HTT) gene promoter associated with transcriptional
      efficacy and plasma serotonin levels. To examine whether the polymorphism is
      associated with coronary heart disease (CHD) in the Japanese, we analyzed 144
      male CHD patients with an onset age before 65 and 222 apparently healthy men. The
      L allele was observed significantly more frequently in the CHD patients (26%)
      than in the control subjects (19%); the odds ratio was 1.48 (p <0.03). A
      significant interaction between the polymorphism and smoking was observed for CHD
      (p = 0.03), suggesting that the two have a synergistic effect on CHD. Odds ratio
      of the combination of the L allele and smoking was 1.95 (p <0.003). The 5-HTT
      gene promoter polymorphism may play a role in susceptibility to CHD, particularly
      when it is combined with smoking.

PMID- 10404757
TI  - The prothrombin 20210A allele and its association with myocardial infarction.
AB  - The relationship between the prothrombin (PT) 20210A allele and arterial disease
      is controversial. We conducted a case-control study to assess its contribution to
      risk of myocardial infarction (MI). Five hundred and thirty-nine acute MI
      patients and 498 control subjects aged <75 years were studied. Two percent of
      cases carried the PT20210A allele compared to 2.8% of controls. The odds ratio
      for MI was 0.72 (95% CI 0.32-1.60) indicating that the PT20210A allele confers no
      increased risk for MI. Subgroup analysis showed no association between the
      PT20210A allele and either premature MI or MI in females. We conclude the
      PT20210A allele is not a risk factor for MI and suggest that discrepancies in
      studies relating the PT20210A allele to MI may be due to difficulties in
      estimating its low allelic frequency in the general population and thus random
      differences in the observed frequencies in the control populations studied.

PMID- 10404756
TI  - Factor V Q506 (resistance to activated protein C) and prognosis after acute
      coronary syndrome.
AB  - Factor V:Q506 causing resistance to activated protein C (APC-resistance), is a
      risk factor for venous thrombosis. Some studies have indicated an association
      with arterial disease, especially in women. We investigated the prevalence of the
      FV:Q506 allele prospectively in 295 patients with acute coronary syndrome.
      Mortality and myocardial infarction rate were evaluated after 30 days and after 2
      years. The FV:Q506 allele was found in 38 patients. In a Cox proportional hazards
      model, smokers carrying FV:Q506 had a higher risk of infarction or death within
      30 days, compared to non-smokers with a normal genotype (relative risk 2.9 [95%
      CI 1.2-7.0]). The difference remained significant after 2 years (relative risk
      2.8 [95% CI 1.2-6.5]). The effect of the FV:Q506 allele on clinical outcome in
      acute coronary syndrome has not previously been described. Our results
      demonstrate a gene-environment interaction between smoking and the FV:Q506
      allele, with an increased risk of early complications after an acute ischemic
      event.

PMID- 10404758
TI  - Elevated levels of plasmin-alpha2 antiplasmin complexes in unstable angina.
AB  - The evidence of elevated levels of several biochemical markers of prothrombotic
      state in patients with unstable angina suggests that thrombus formation and lysis
      play a pivotal role in acute coronary syndromes. The clinical syndrome of
      unstable angina encompasses a variety of clinical presentations of transient
      episodes of myocardial ischemia. This study was designed to assess plasmin
      generation in different settings of unstable angina. Evidence of plasmin
      generation in patients with unstable angina was measured by circulating plasmin
      alpha2 antiplasmin complexes (PAP). A second objective was to identify whether
      PAP levels had a prognostic value to predict outcome. Eighty-five patients
      admitted to the coronary care unit for unstable angina were classified into three
      groups. Group A included 26 patients with postinfarction angina; group B
      comprised 26 patients with new onset angina; and group C included 33 patients
      with crescendo angina. Mean PAP levels were higher in the three groups compared
      to healthy controls. A significant correlation was found between levels of PAP
      and D-dimer, particularly in postinfarction angina (r = 0.6; p <0.0005). This
      trial adds new insights into the pathophysiology of unstable angina. It
      demonstrates that plasmin is generated in the different settings of unstable
      angina but particularly in postinfarction angina patients where a fibrin-rich
      thrombus is responsible of the symptoms. However, in this series PAP levels do
      not predict an uneventful outcome neither in the acute phase nor at long term (6
      months).

PMID- 10404759
TI  - Free and total platelet glycoprotein IIb/IIIa measurement in whole blood by
      quantitative flow cytometry during and after infusion of c7E3 Fab in patients
      undergoing PTCA.
AB  - A quantitative flow cytometry assay was used to evaluate the ex vivo kinetics of
      c7E3 Fab platelet effect in 16 patients undergoing PTCA treated with abciximab
      and compared with aggregometry assay. Immunolabeling of platelets was directly
      assessed on whole blood, using in parallel two monoclonal antibodies (Mabs)
      raised against GPIIIa, Mab1, the binding of which is inhibited by c7E3 Fab, and
      Mab2, the binding of which is not affected by c7E3 Fab. We found a severe and
      sustained inhibition of both GPIIb/IIIa receptors and platelet functions. The
      inter-individual variation in response to abciximab was low. A significant
      transient increase at H24 and H48 in the binding of Mab2 was found as an
      unexpected result, and confirmed in vitro. Results demonstrate that flow
      cytometry is a reliable method in agreement with aggregation. In addition, our
      results show that it is a standardized tool and a time-saving technique.

PMID- 10404760
TI  - Procedure-dependence and tissue factor-independence of hypercoagulability during
      orthopaedic surgery.
AB  - The increased risk for deep vein thrombosis (DVT) after orthopaedic surgery has
      been well documented as well as hypercoagulable state during both total hip
      arthroplasty (THA) and total knee replacement (TKR). To investigate the influence
      of the surgical procedure [posterolateral (PL) or lateral (L) approach for THA,
      use of tourniquet (TQ) or not use of TQ for TKR] on the hypercoagulability and
      the role of extrinsic pathway activation and endothelial stimulation during
      orthopaedic surgery we have examined 40 patients (20 patients undergoing primary
      THA--10 with PL approach and 10 with L approach--and 20 patients undergoing TKR-
      10 with TQ application and 10 without TQ). Thrombin-antithrombin complexes (TAT),
      tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombomodulin (TM)
      and von Willebrand factor antigen (vWF:Ag) were analyzed before and during the
      orthopaedic surgery. During THA, TAT plasma levels increased more markedly in
      patients assigned to the L than PL approach (p <0.05); during TKR an elevation of
      TAT of higher degree (p <0.05) was observed when TQ was not applicated. Blood
      clotting activation was significantly (p <0.001) more relevant during THA than
      TKR. No changes in TF and vWF:Ag plasma levels were observed in all patients
      undergoing THA and TKR. TFPI plasma levels significantly (p <0.05) decreased 1 h
      after the end of the THA in group PL and group L, whereas they remained
      unaffected in the two groups of patients undergoing TKR. Similarly TM plasma
      levels significantly decreased during THA, but not during TKR. In conclusion,
      these results show that: 1) the site of surgical procedures and the type of
      approach affect the degree of hypercoagulability, 2) the blood clotting
      activation takes place in the early phases of orthopaedic surgery, without signs
      of extrinsic pathway and endothelial activation.

PMID- 10404761
TI  - Prediction of deep vein thrombosis after elective hip replacement surgery by
      preoperative clinical and haemostatic variables: the ECAT DVT Study. European
      Concerted Action on Thrombosis.
AB  - The European Concerted Action on Thrombosis (ECAT) DVT Study was a collaborative
      study of preoperative haemostatic tests in prediction of DVT (diagnosed by
      routine bilateral venography) after elective hip replacement. 480 patients were
      recruited in 11 centres across Europe. Clinical risk factors were assessed, and
      stored citrated plasma aliquots were centrally assayed for 29 haemostatic factors
      according to the ECAT methodology. 120 (32%) of 375 evaluable patients had DVT,
      and 41 (11%) had proximal DVT. Among clinical variables, DVT was significantly
      associated with increased age, obesity, and possibly non-use of stockings. Of the
      29 haemostatic factors, mean preoperative levels were significantly higher in
      patients with subsequent DVT (on univariate analyses) for factor VIII activity,
      prothrombin fragment F1+2, thrombin-antithrombin complexes, and fibrin D-dimer;
      and significantly lower for APTT and APC sensitivity ratio. Factor V Leiden was
      also associated with DVT. Most of these variables were also associated with age,
      while D-dimer was higher in patients with varicose veins. On multivariate
      analyses including clinical variables, only a shorter APTT (locally but not
      centrally performed) and APC resistance showed a statistically significant
      association with DVT. We conclude that (a) DVT is common after elective hip
      replacement despite prophylaxis; (b) the study provides some evidence that DVT is
      associated with a preoperative hypercoaguable state; and (c) preoperative
      haemostatic tests do not add significantly to prediction of DVT from clinical
      variables, with the possible exception of APC resistance.

PMID- 10404762
TI  - Long-term management of homozygous protein C deficiency: replacement therapy with
      subcutaneous purified protein C concentrate.
AB  - We present the case of a full-term newborn in whom purpura fulminans developed
      shortly after birth. A diagnosis of homozygous protein C deficiency was
      established based upon undetectable plasma protein C activity and antigenemia in
      the newborn infant, and was later confirmed by protein C gene analysis. Specific
      replacement therapy with intravenous protein C concentrate was started 9 days
      after birth. This rapidly led to the complete regression of cutaneous lesions and
      consumption coagulopathy. After stabilization, oral anticoagulation was initiated
      in association with prophylactic treatment with intravenous protein C
      concentrate. However, oral anticoagulation was finally abandoned as the patient
      presented several thrombotic and hemorrhagic episodes clearly related to
      difficulties with anticoagulation. Due to the hazards related to prolonged venous
      access, we are currently using subcutaneous infusion of protein C concentrate for
      the long-term management of this condition, with satisfactory results.

PMID- 10404764
TI  - Start of UK confidential haemophilia A database: analysis of 142 patients by
      solid phase fluorescent chemical cleavage of mismatch. Haemophilia Centres.
AB  - A national strategy for optimising genetic services in haemophilia A has been
      initiated in the UK. Solid phase fluorescent chemical cleavage of mismatch is
      used to screen the entire coding region of factor VIII in six segments: four
      amplified from the trace of mRNA in blood lymphocytes and two from genomic DNA
      for the 3.4 kb exon 14 and flanking intron sequences. These segments are analysed
      in two threefold multiplexes so that the genes of 18 patients can be screened in
      a single ABI 377 gel. The promoter and polyadenylation signal region are
      amplified and sequenced directly. We have analysed 142 unrelated patients and
      identified 141 factor VIII mutations and one Normandy type von Willebrand
      homozygote. The former mutations include 89 missense, 10 nonsense, 5 frameshift,
      one 24 bp deletion and one splice signal defect. These comprise 71 different
      changes, of which 39 have not been previously observed.

PMID- 10404763
TI  - Case-control study of the frequency of thrombophilic disorders in couples with
      late foetal loss and no thrombotic antecedent--the Nimes Obstetricians and
      Haematologists Study5 (NOHA5).
AB  - BACKGROUND: Women with familial thrombophilia have an increased risk of still
      birth. We postulated that the presence of asymptomatic risk factors for venous
      thrombosis might be a risk factor for late foetal loss. METHODS: We performed a
      case-control study on the prevalence of heritable thrombophilic defects, of
      antiphospholipid-related markers and of the C677T mutation in the
      methylenetetrahydrofolate reductase (MTHFR) gene in patients with at least one
      episode of late unexplained foetal loss and in control women with successful
      pregnancies. Partners of cases and controls were also studied. Written
      conclusions of the pathological examination of the placentas, when available,
      were also reviewed. RESULTS: We found at least one positive biological risk
      factor for venous thrombosis in 21.1% of the patients and in 3.9% of the controls
      (p < 10(-4)). In women, the crude odds ratio for still birth associated with any
      positive biological risk factor for venous thrombosis was 5.5, 95% confidence
      interval (95%CI) [3.4-9.0]. No difference was found between partners of cases and
      controls (5.2% and 4.7%). Using conditional logistic regression analysis, 4
      adjusted risk factors for still birth remained: protein S deficiency, positive
      anti beta2 glycoprotein I IgG antibodies, positive anticardiolipin IgG antibodies
      and the factor V Leiden mutation. The C677T mutation in the MTHFR gene was not an
      individual risk factor but an homozygous genotype was strongly associated with
      the former 4 risk factors (16.8% of patients vs. 0.9% of controls). In women with
      such associations, still births always occurred in absence of folic acid
      supplementation during pregnancy. Available conclusions of pathological analysis
      of placentas were found to have a very high proportion of "maternal vascular
      disease of the placenta" in patients with at least one positive risk marker for
      thromboembolism, specially in case of association with the C677T MTHFR homozygous
      genotype, compared to patients with negative markers (p <10(-4)). CONCLUSIONS:
      Late foetal loss, through placenta thrombosis, may sometimes be the consequence
      of a maternal multifactorial prothrombotic state associating traditional
      heritable or acquired thrombosis risk factors to conditions predisposing to an
      acute mild hyperhomocysteinaemia (coexistence of a genetic predisposition with
      late pregnancy-related increased folate needs).

PMID- 10404765
TI  - High levels of circulating thrombomodulin in human foetuses and children.
AB  - Thrombomodulin (TM) is an endothelial cell surface proteoglycan with
      anticoagulant functions, also implicated in cell proliferation, cell-cell
      adhesion and differentiation. In this study we determined circulating plasma TM
      (pTM) levels in human foetuses at different stages of pregnancy, at birth and in
      childhood. TM levels increased with gestational age, the median level reaching a
      peak of approximately 165 ng/ml between the 23rd and 26th week, thereafter
      decreasing gradually, reaching a value of 108 ng/ml at birth. pTM continues to
      decrease progressively during childhood, reaching in the 5-15 years group a
      median of 56 ng/ml which approaches the adult value. The pTM peak was
      statistically significant and represents a specific foetal phenomenon as it was
      independent of the corresponding maternal values. As a whole, the pTM pattern
      during foetal maturation appears totally different from that of protein C,
      prothrombin and other coagulation activators and inhibitors and thus, TM may play
      in the foetus another role in addition to its well-known anticoagulant function.

PMID- 10404766
TI  - Age- and sex-related differences of plasma activated factor VII levels in
      children.
AB  - Although the majority of factor VII (FVII) circulates in the zymogen form, low
      levels of activated factor VII (FVIIa) exist in plasma and play an important role
      in the initiation of tissue factor-induced coagulation. It has been reported that
      the concentrations of hemostatic components in children and adults are different.
      Here, we investigated the age- and sex-related differences of FVIIa and FVII
      antigen (FVIIag) levels in children at age of 10 (n = 123; males: n = 62;
      females: n = 61), and 13 (n = 105; males: n = 47: females: n = 58), and compared
      these levels with those of young adults (mean +/- SD of age: 29.6+/-6.0 years).
      In males, there was not a significant difference between the FVIIIa levels of 10
      year-old children and 13-year-old children, but the FVIIa levels in adult
      controls were significantly higher than those in children. In females, the FVIIa
      levels in 13-year-old children were significantly higher than that in 10-year-old
      children, but there was not a significant difference between 13-year-old children
      and adults. Thus, our study showed that plasma FVIIa levels were lower in
      children than in adults, and the increase of FVIIa level was earlier in females
      than in males.

PMID- 10404767
TI  - Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and
      plasma homocysteine.
AB  - We studied hemostatic and inflammatory cardiovascular risk factors (CVRF), and
      total plasma homocysteine (tHcy) in 26 vegetarians (23 lacto- or
      ovolactovegetarians and 3 vegans), matched by age, sex and socioeconomic status
      with omnivorous controls. Vegetarians had significantly lower proportion of
      eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in plasma lipids,
      significantly shortened bleeding time, and increased blood platelet count and in
      vitro platelet function (aggregation and secretion). Plasma levels of all
      coagulation or fibrinolytic factors and natural inhibitors synthesized in the
      liver were lower in vegetarians than in controls. Whereas for some factors this
      decrease was statistically significant (fibrinogen, factor VIIc, antithrombin
      III, protein S, plasminogen) for the remaining (factors VIIIc, Vc, prothrombin,
      protein C) a trend in the same direction was found. For hemostatic proteins of
      predominantly extrahepatic origin (von Willebrand factor. tPA, PAI-1) this
      tendency was not present. No significant differences in inflammatory proteins (C
      reactive protein and alpha1-protease inhibitor) were detected in both groups.
      tHcy was significantly increased in vegetarians, and correlated only with
      cobalamin levels. The increased platelet function and tHcy found in vegetarians
      may counteract the known cardiovascular health benefits of vegetarian diet (VD).

PMID- 10404768
TI  - Activated protein C resistance and the FV:R506Q mutation in a random population
      sample--associations with cardiovascular risk factors and coagulation variables.
AB  - Activated protein C (APC) resistance, defined as a low APC ratio, is associated
      with the factor V mutation R506Q (factor V Leiden). APC ratio may also be
      influenced by other clinical and coagulation variables, which we studied in 460
      men and 495 women aged 25-74 years, from a random population sample (Glasgow
      MONICA Survey). APC ratio correlated positively with APTT; and inversely with
      factor VIIIc, factor IXc, antithrombin activity, prothrombin F1+2 fragment, and
      thrombin-antithrombin complexes; but not with other coagulation variables. APC
      ratio decreased with age, but APTT did not. APC ratio and APTT were significantly
      lower in women versus men, and were significantly lower in users of oral
      contraceptives or hormone replacement therapy. The FV:R506Q mutation (prevalence
      2.5%) was associated with lower APC ratio and protein C and S activities and with
      higher factor VIIIc levels; but not with increases in F1+2 fragment or thrombin
      antithrombin complexes. APC ratio correlated inversely with total cholesterol and
      diastolic blood pressure; and in women with triglycerides, systolic blood
      pressure, and body mass index. Obesity was associated with a significantly lower
      APC ratio. In contrast, smoking markers correlated positively with APC ratio in
      men. These associations of APC ratio may be relevant to the increased risks of
      venous thrombosis with age, female sex, oestrogen use, obesity and high factor
      VIIIc levels. The association of APC resistance with elevated plasma levels of
      coagulation markers suggests that this phenotype represents an in vivo
      hypercoagulable state.

PMID- 10404769
TI  - Increased C-reactive protein levels during short-term hormone replacement therapy
      in healthy postmenopausal women.
AB  - OBJECTIVE: To study the short-term effect of unopposed oestradiol (E2) and
      sequentially combined hormone replacement therapy (E2 + P) on C-reactive protein
      (CRP) in healthy postmenopausal women. DESIGN: Prospective, randomised, placebo
      controlled 12-week study. Sixty healthy. normotensive, non-hysterectomised
      postmenopausal women received either placebo (N = 16) or daily 2 mg micronised
      oestradiol, either unopposed (N = 16, E2 group) or sequentially combined with a
      progestagen on 14 days of each cycle (N = 28, E2+P group). Data were collected at
      baseline and at 4 and 12 weeks. RESULTS: CRP levels increased significantly
      during the 12 weeks in the E2 and the E2+P groups compared to placebo. No
      differences were found between the E2 group and the E2+P group [E2 and E2+P group
      together (N = 44) versus placebo: P = 0.01; E2 versus E2+P: P = 0.75]. To give a
      quantitative estimate of the increase, the median change calculated from baseline
      in both treatment groups together was +87% (P = 0.02) at 4 weeks, and +114% (P =
      0.08) at 12 weeks, as compared to the placebo group. CONCLUSION: In healthy
      postmenopausal women, short-term treatment with E2 or E2+P was associated with a
      rapid rise in CRP concentrations. These observations raise the possibility that
      the increased risk of cardiovascular events is related to an initial increase in
      CRP levels after starting hormone replacement therapy.

PMID- 10404770
TI  - Lupus anticoagulant testing in Europe: an analysis of results from the first
      European Concerted Action on Thrombophilia (ECAT) survey using plasmas spiked
      with monoclonal antibodies against human beta2-glycoprotein I.
AB  - Lupus anticoagulants (LA) are immunoglobulins directed to either prothrombin or
      Beta-2-glycoprotein 1(beta1GPI) bound to phospholipids. Most patients with LA
      have both beta2GPI- and prothrombin-dependent antibodies. Several recent reports
      have shown that LA is more strongly associated with thrombosis than
      anticardiolipin antibodies (aCL). Therefore, an accurate detection of LA is of
      utmost importance in patients suspected of an antiphospholipid syndrome. We
      recently raised a series of murine monoclonal antibodies against human Beta-2
      glycoprotein I (beta2GPI) with LA activity similar to affinity purified human
      beta2GPI-dependent LAs. A normal plasma pool, and the same pool spiked with LA
      positive anti-beta2GPI antibodies at two potency levels, were used as materials
      in an external quality assessment scheme organised by the European Concerted
      Action on Thrombosis (ECAT). Fifty nine laboratories participating in this trial
      were asked to test for the presence of a LA in the 3 samples submitted. The
      majority (82%) of the participants found the high potency LA sample to be
      positive. Only 37% of the laboratories considered the weak potency LA sample to
      be positive. The submission of a normal sample, a weakly positive sample and a
      clearly positive sample enabled us to compare the relative LA responsiveness of
      the different screening assays used. Clotting time ratios varied from 0.81 to
      3.28 for sample B and from 0.66 to 5.32 for sample D. In general, the highest
      clotting time ratios were found with the dilute prothrombin time (dPT), the
      dilute Russell Viper Venom time (dRVVT) and the Kaolin Clotting time. The most
      frequently used screening tests were the aPTT and the dRVVT. With the various
      assay systems, LA responsiveness varied largely according to the reagents used.
      For the beta2GPI-dependent LA used in this study, PTT LA clearly showed the
      highest responsiveness among the aPTT reagents and Innovin among the dPT
      reagents. The present study also shows that many laboratories still rely on
      poorly responsive screening assays for their LA tests. Other laboratories rely on
      sensitive and more specific integrated test systems based on a sensitive
      screening assay with a low phospholipid content and a confirmatory test employing
      high phospholipid concentrations. The most used integrated system was dRVVT
      based. However, also here the LA responsiveness was largely reagent dependent. In
      conclusion, many laboratories still rely on poorly responsive screening assays by
      which weakly positive LA samples are misdiagnosed. LA positive anti-beta2GPI
      moabs have a potential for the unlimited production of LA control specimens, that
      may help hemostasis laboratories choose more LA responsive assay systems and to
      assess intralaboratory precision of their LA testing.

PMID- 10404771
TI  - Correction for lack of coincidence of normal and abnormal calibration slopes in
      ISI determination.
AB  - An underlying assumption of the WHO orthogonal regression model for prothrombin
      time standardisation is that a single line describes the relationship between PT
      of abnormal and normal plasmas. The aim was to evaluate Tomenson's correction for
      lack of coincidence using the model of the ECAA human reagent with lyophilized
      plasma calibrations. Local ISI calibrations using ECAA lyophilized normal and
      abnormal plasmas were performed on coagulometers with the ECAA human
      thromboplastin. They gave a high incidence of non-linearity of the two
      calibration slopes. The mean percentage deviation from assigned values of the
      target coumarin plasmas coagulometer INR at 45 centres before local ISI
      correction was 16.6% and 11.9% respectively in two studies. After local ISI
      calibration. the unsigned deviation was reduced to 5.54% and 6.61% respectively.
      Tomenson's correction for non-linearity further reduced the mean deviation to
      3.08% and 2.96% respectively in the two studies demonstrating the value of the
      procedure.

PMID- 10404772
TI  - A new type of Ser substitution for gamma Arg-275 in fibrinogen Kamogawa I
      characterized by impaired fibrin assembly.
AB  - A new type of substitution, Arg to Ser at gamma275, has been found in a
      heterozygous dysfibrinogen derived from a 23-year-old woman with no major
      bleeding or thrombosis. By sequence analyses of the affected gamma-chain and its
      gene. we found a single amino acid substitution of gamma Arg-275 to Ser in an
      aberrant gamma (274-302) residue peptide isolated from lysyl endopeptidase
      digests of the patient's fibrinogen. In agreement with this amino acid
      substitution, we identified a single nucleotide exchange of A for C at position
      5728 in the gamma-chain gene creating a codon (AGC) encoding Ser instead of the
      codon (CGC) encoding Arg at position gamma 275. Like two other known types of
      mutants with a His or Cys substitution at this position, the functional
      abnormality was characterized by delayed fibrin polymerization, most likely due
      to impaired abutting of two D domains of adjacent fibrin monomers in the same
      strand of fibrin protofibrils. The structural derangement that affects the D:D
      association may not be so severe as compared with those of Cys and His mutants,
      possessing an additional disulfide-linked Cys molecule and an imidazole ring at
      the mutation site, respectively.

PMID- 10404773
TI  - Further studies on the mechanism for the antithrombotic effects of naroparcil, an
      orally active thiozyloside compound.
AB  - The antithrombotic beta-D-xyloside, naroparcil, has previously been shown to
      induce a dose-related increase of circulating glycosaminoglycans (GAGs) together
      with an antithrombin activity (anti-IIa) via heparin cofactor II (HCII) in the
      rabbit. In order to go further in the mechanisms, the relationship between the
      antithrombotic activity, the HCII-mediated anti-IIa activity and the plasma GAG
      content was investigated. We showed that the in vitro specific activity on the
      inhibition of thrombin by HCII of the plasma GAG extract from naroparcil-treated
      rabbits was increased by a factor of 60 when compared to controls. In addition,
      the fractionation of the plasma GAG extract by affinity chromatography on
      immobilized HCII led to a more potent material whereas the low-affinity fraction
      was shown to be inactive in thrombin inhibition by HCII. The qualitative analysis
      of GAGs showed the presence of the deltaDi-4S DS disaccharide, undetectable in
      control, which accounted for 22% in the unfractionated GAG extract and for 60% in
      the high affinity fraction. In vitro experiments using immuno-depleted plasma in
      antithrombin III (ATIII), HCII or both, indicated that the anti-IIa activity of
      the plasma GAG extract from naroparcil-treated rabbits was mainly due to HCII
      potentialisation. The unfractionated GAG extract and the high affinity fraction
      were shown to be antithrombotic in a Wessler-based model in the rat, giving ED80
      values of 610 UA/kg and 56 UA/kg respectively whereas the low-affinity fraction
      was devoid of any antithrombotic activity. These results show that the
      antithrombotic activity of naroparcil is dependent on modification in the plasma
      GAG profile which inactivates thrombin via the HCII.

PMID- 10404774
TI  - Role of the 807 C/T polymorphism of the alpha2 gene in platelet GP Ia collagen
      receptor expression and function--effect in thromboembolic diseases.
AB  - The variability of the platelet GP Ia/IIa density has been associated with the
      807 C/T polymorphism (Phe 224) of the GP Ia gene in American Caucasian
      population. We have investigated the genotype and allelic frequencies of this
      polymorphism in Spanish Caucasians. The T allele was found in 35% of the 284
      blood donors analyzed. We confirmed in 159 healthy subjects a significant
      association between the 807 C/T polymorphism and the platelet GP Ia density. The
      T allele correlated with high number of GP Ia molecules on platelet surface. In
      addition, we observed a similar association of this polymorphism with the
      expression of this protein in other blood cell types. The platelet responsiveness
      to collagen was determined by "in vitro" analysis of the platelet activation and
      aggregation response. We found no significant differences in these functional
      platelet parameters according to the 807 C/T genotype. Finally, results from 3
      case/control studies involving 302 consecutive patients (101 with coronary heart
      disease, 104 with cerebrovascular disease and 97 with deep venous thrombosis)
      determined that the 807 C/T polymorphism of the GP Ia gene does not represent a
      risk factor for arterial or venous thrombosis.

PMID- 10404775
TI  - Effect of clopidogrel on thrombin generation in platelet-rich plasma in the rat.
AB  - Clopidogrel (25 mg/kg, p.o.), a potent and selective inhibitor of ADP-induced
      platelet aggregation, significantly inhibited, in the presence of platelets, ex
      vivo thrombin generation triggered by low concentrations of tissue factor.
      Clopidogrel reduced the area under the curve (23%, p <0.05) and the thrombin peak
      concentration (35%, p <0.05) but did not affect the lag phase of thrombin
      generation. Under the same experimental conditions, heparin (100 microg/ml)
      inhibited thrombin generation mostly by delaying and by reducing the burst of
      thrombin. In a stasis-induced venous thrombosis model in rats under low
      thrombogenic challenge, clopidogrel inhibited thrombus formation (ED50 = 7.9+/
      1.5 mg/kg, p.o. - n = 10), confirming the existence of a close relationship
      between platelet activation and thrombin generation leading to blood coagulation
      and venous thrombosis.

PMID- 10404776
TI  - Endogenous nitric oxide acts as a natural antithrombotic agent in vivo by
      inhibiting platelet aggregation in the pulmonary vasculature.
AB  - Nitric oxide (NO) is a powerful vasodilator and an inhibitor of platelet
      aggregation in vitro. While the ability of NO to modulate vascular tone in vivo
      has been proven, only a few studies have assessed its platelet inhibitory
      activity in vivo. We have employed two complementary animal models of pulmonary
      platelet thromboembolism to assess the antithrombotic activity of endogenous NO
      in vivo. The inhibition of nitric oxide synthase (NOS) by L-NAME significantly
      potentiated while the administration of the NOS substrate L-arginine
      significantly reduced the accumulation of 111In-labelled platelets in the
      pulmonary vasculature of rabbits induced by intravenous collagen plus
      epinephrine. L-NAME or L-arginine did not, however, modify 111In-labelled
      erythrocyte distribution in lungs and phenylephrine had no effect on platelet
      accumulation following collagen + adrenaline, suggesting that the effects of L
      NAME were not due to vasoconstriction but rather to a direct modification of
      platelet function. In mice, L-NAME significantly reduced the dose of collagen +
      adrenaline required to induce thromboembolic mortality, increased the fall in
      circulating platelets and increased the % of pulmonary vessels occluded by
      platelet thrombi. The effects of L-NAME were reversed by L-arginine but not by a
      dose of nicardipine exerting maximal vasodilatation. Phenylephrine did not
      potentiate collagen + adrenaline-induced mortality. In the pulmonary vasculature
      in vivo, endogenous NO inhibits collagen + adrenaline-induced aggregation and
      enhances platelet disaggregation. This natural modulator function of NO is
      exerted via a direct effect on platelets and not as a result of haemodynamic
      changes.

PMID- 10404777
TI  - Thrombin receptor occupancy modulates aggregation efficiency and platelet surface
      expression of vWF and thrombospondin at low thrombin concentrations.
AB  - Previous studies evaluating requirements for occupancy of thrombin receptors in
      normal platelet secretion and aggregation, using the thrombin antagonists hirudin
      and PPACK (D-Phe-Pro-Arg-chloromethylketone), have suggested that at low thrombin
      activating concentrations (0.025-0.13 U/ml), occupancy was required only in the
      first 45-60 s following activation. In our study, we differentiate between
      thrombin receptor occupancy requirements for surface expression of secreted
      adhesive proteins, for activation of GPIIb-IIIa receptors, and for aggregation of
      washed platelets (WP) in laminar shear flow. Platelets activated with 0.05 U/ml
      thrombin for 10 min to allow maximal secretion (hereafter referred to as "pre
      activated platelets"), then sheared, showed a 50-70% decrease in platelet counts
      after 60 s of shear. Treatment of pre-activated platelets with hirudin or PPACK
      produced a 65% reduction of capture efficiencies, alphaG (reflecting
      experimental/theoretical initial rates of aggregation), as well as a 30-40%
      decrease in the surface expression of von Willebrand factor (vWF) and
      thrombospondin (TSP). However, alpha-granule membrane P-selectin expression and
      numbers of activated GPIIb-IIIa receptors were comparable for treated and non
      treated platelets. No significant difference in any of the parameters tested was
      observed when platelets were similarly pre-activated with 0.2 U/ml thrombin, due
      to treatment with thrombin antagonists. Binding of soluble FITC-vWF (GRGDSP
      sensitive) to pre-activated, thrombin antagonist treated platelets, was greatly
      reduced (> or =80%). Soluble Fg was shown to bind to antagonist-treated pre
      activated platelets, but could not significantly enhance platelet aggregation.
      Although occupancy of thrombin receptors by catalytically active thrombin is
      required transiently for secretion and activation of platelets, there is a
      further requirement for thrombin occupancy at low thrombin concentrations, for
      optimizing initial rates of platelet aggregation, surface expression of vWF and
      TSP, and activated GPIIb-IIIa ligand recognition.

PMID- 10404778
TI  - Recombinant vWF type 2A mutants R834Q and R834W show a defect in mediating
      platelet adhesion to collagen, independent of enhanced sensitivity to a plasma
      protease.
AB  - Type 2A von Willebrand Disease (vWD) is characterized by the absence of high
      molecular weight von Willebrand factor (VWF) multimers in plasma which is caused
      by enhanced extracellular proteolysis or defective intracellular transport. We
      identified in vWD type 2A patients two mutations in the A2 domain at position 834
      in which arginine (R) was substituted for glutamine (R834Q) or tryptophan
      (R834W). We reproduced these mutations in vWF cDNA and expressed the recombinant
      proteins in furin cDNA containing baby hamster kidney (fur-BHK) cells. The
      subunit composition and the multimeric structure of both mutants was similar to
      wild-type (WT) vWF. Characterization of mutant R834Q by ristocetin or botrocetin
      induced platelet binding, and by binding to heparin showed no abnormality. R834W
      had normal botrocetin induced platelet binding, but ristocetin induced platelet
      binding and binding to heparin were decreased. Under static conditions R834Q and
      R834W, at 10 microg/ml, bound equally well to collagen type III as WT-vWF. At
      high shear rate conditions both mutants supported platelet adhesion normally when
      coated to a glass surface or preincubated on collagen. When R834Q or R834W was
      added to the perfusate, adhesion to collagen type III was 50% of the WT-vWF
      value, which was not due to a decreased collagen binding under flow. A divalent
      cation dependent protease, purified from plasma, degraded the 2A mutants rapidly
      while WT-vWF was not affected. In conclusion, the mutations present in the A2
      domain of vWF result in an enhanced proteolytic sensitivity to a divalent ion
      dependent protease. When present in the perfusate, R834Q and R834W show a
      decrease in platelet adhesion to collagen type III under flow conditions, which
      is not caused by decreased binding of the mutant vWF to collagen or enhanced
      proteolysis.

PMID- 10404779
TI  - Stimulation of proteinase activated receptor-2 causes endothelial cells to
      promote blood coagulation in vitro.
AB  - Proteolytically activated receptors define a new subclass among the G-protein
      coupled receptors. Proteinase activated receptor-2 (PAR-2), the second member to
      be identified of this growing receptor subclass, can be activated by trypsin and
      trypsin-like serine proteases such as mast cell tryptase. PAR-2 is expressed in
      endothelial cells. Here we have studied if activation of PAR-2 changes the
      coagulation properties of cultured human umbilical vein endothelial cells. We
      show that activation of PAR-2 induces rapid and transient formation of tissue
      factor mRNA with a maximum level 1 hour after receptor stimulation. The increased
      mRNA level was accompanied by an increased tissue factor activity at the
      endothelial cell surface, shortening coagulation time in a standard clotting
      assay. The level of tissue factor activity after PAR-2 activation was comparable
      with the effects of thrombin receptor (PAR-1) activation although neither of the
      two protease receptors were as strong inducers of tissue factor as tumor necrosis
      factor-alpha.

PMID- 10404780
TI  - Factor V Leiden mutation in the Argentinian population.

PMID- 10404781
TI  - Absence of the prothrombin gene variant in Koreans.

PMID- 10404782
TI  - Prothrombin gene mutation (G20210A) in healthy Centenarians.

PMID- 10404783
TI  - Cerebral vein thrombosis not related to use of oral contraceptives in a 7-year
      old child carrier of the prothrombin 20210A allele.

PMID- 10404784
TI  - Evaluation of a new screening assay, protein C pathway (PCP) test, for
      identification of defects in the protein C pathway.

PMID- 10404785
TI  - Which assay is the most suitable to investigate von Willebrand factor functional
      activity?

PMID- 10404786
TI  - Risk factors and thrombosis after airline flight.

PMID- 10404787
TI  - Which DVT patients could be considered the best candidates for home therapy?

PMID- 10404788
TI  - Is leptin a secretion of the brain?

PMID- 10404790
TI  - Therapeutic controversies in primary hyperparathyroidism.
AB  - There is little debate about the primacy of surgery in the management of
      classical PHPT. Rather, the question has been what to do about the many patients
      with nonclassical disease. A 1990 NIH consensus conference (55) clearly
      recommended surgery for patients with significant adverse effects of PHPT, for
      patients with complicating coexistent illnesses, for younger patients, and for
      those in whom consistent long-term follow-up could not be assured. It allowed
      that conscientious surveillance may be justified in patients with minimal
      hypercalcemia and no adverse effects, but it recognized that for many patients,
      the time and expense involved in rigorous follow-up would outweigh the burden of
      surgery. Nine years later, the demonstrated prevalence of nonclassical symptoms
      and their reversibility, the evidence of "asymptomatic" but harmful effects
      reversible by surgery, and the accumulating evidence for surgical reduction of
      increased long-term mortality risk substantially strengthen the argument for
      surgery in such patients. For these reasons, parathyroidectomy should generally
      be recommended for patients with a secure diagnosis of PHPT, even in the absence
      of classical symptoms.

PMID- 10404789
TI  - Leptin is released from the human brain: influence of adiposity and gender.
AB  - Leptin, a 16-kDa circulating protein primarily derived from adipocytes, is an
      important factor in the regulation of appetite and energy expenditure. Using
      simultaneous arterio-venous blood sampling, several organs were assessed with
      regard to their individual roles in leptin metabolism in healthy male and female
      subjects constituting a range of body mass indices. Plasma leptin levels were
      unchanged after passage through the hepatosplanchnic and forearm circulations. In
      contrast, concentrations in the renal vein were consistently lower than those in
      the renal artery (-15%; P<0.005), indicating net extraction, whereas the brain
      was observed to be a net leptin releaser. Concentrations in the internal jugular
      vein were significantly higher than arterial levels in lean females (change,
      3.0+/-1.2 ng/mL; P<0.02) and in obese males (body mass index, >28 kg/m2), but not
      lean (change, 2.3+/-2.3 vs. 0.1+/-0.1 ng/mL, respectively; P<0.05), indicating a
      probable influence of both gender and adiposity on brain leptin release. An
      attempt to grossly localize the site of brain release by using cerebral venous
      scans to distinguish between jugular venous drainage from cortical and
      subcortical brain areas revealed no region-specific secretion. These data raise
      the possibility that the brain is a nonadipose source of leptin. In addition, the
      higher level of brain release observed in females may contribute to the well
      documented gender differences in overall plasma leptin levels.

PMID- 10404791
TI  - Effect of sex hormone replacement on the insulin-like growth factor system and
      bone mineral: a cross-sectional and longitudinal study in 595 perimenopausal
      women participating in the Danish Osteoporosis Prevention Study.
AB  - This study used a cross-sectional design to investigate relationships among serum
      insulin-like growth factor (IGF) parameters (total serum IGF-I, IGF-II, and IGF
      binding protein-3), serum estradiol, and bone mineral density (BMD) stratified
      for potential confounders, and a longitudinal design to investigate the effects
      of hormonal replacement therapy (HRT) on IGFs and BMD. Five hundred and ninety
      five perimenopausal women (median age, 50.0 yr; range, 45-56 yr) participating in
      the Danish Osteoporosis Prevention Study were investigated in a cross-sectional
      study, and a randomly selected subgroup of 110 was followed after 5 yr in a
      longitudinal study for changes in serum IGFs and BMD of lumbar spine, femoral
      neck, and ultradistal forearm during (n = 46) or without HRT (n = 64). In the
      cross-sectional study, serum IGF-I correlated positively to distal forearm BMD
      and spine BMD, but not to femoral neck BMD, after stratification for age, body
      mass index, and other variables. In the follow-up study, HRT decreased IGF-I and
      IGF-II, but did not influence the age-related decline in IGF-binding protein-3
      significantly. Serum alkaline phosphatase and urinary hydroxyproline/creatinine
      ratio both decreased during HRT, whereas BMD increased compared to control
      values. After adjustment for age, body mass index, treatment, and other factors,
      IGF-I correlated positively to changes in forearm and femoral neck BMD, but not
      to changes in spine BMD. We conclude that serum IGF-I was positively associated
      to bone mineral density. Oral HRT decreases IGF-I and IGF-II.

PMID- 10404792
TI  - [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography localizes residual
      thyroid cancer in patients with negative diagnostic (131)I whole body scans and
      elevated serum thyroglobulin levels.
AB  - Progressive dedifferentiation of thyroid cancer cells leads to a loss of iodine
      concentrating ability, with resultant false negative, whole body radioactive
      iodine scans in approximately 20% of all differentiated metastatic thyroid cancer
      lesions. We tested the hypothesis that all metastatic thyroid cancer lesions that
      did not concentrate iodine, but did produce thyroglobulin (Tg), could be
      localized by [18F]2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography
      (PET). We performed FDG-PET on 37 patients with differentiated thyroid cancer
      after surgery and radioiodine ablation who had negative diagnostic 131I whole
      body scans during routine follow-up. Serum Tg, Tg autoantibodies, neck
      ultrasounds, and other clinically indicated imaging procedures were performed to
      detect residual disease. In those with elevated Tg levels, FDG-PET localized
      occult disease in 71%, was false positive in one, and was false negative in five
      patients. The majority of false negative FDG-PET occurred in patients with
      minimal cervical adenopathy. Surgical resections, biopsies, 131 therapy, and
      differentiation therapy were performed based on the PET results. The FDG-PET
      result changed the clinical management in 19 of the 37 patients. In patients with
      elevated Tg levels, FDG-PET had a positive predictive value of 92%. In patients
      with low Tg levels, FDG-PET had a negative predictive value of 93%. No FDG-PET
      scans were positive in stage I patients; however, they were always positive in
      stage IV patients with elevated Tg levels. An elevated TSH level (i.e.
      hypothyroidism) did not increase the ability to detect lesions. FDG-PET is able
      to localize residual thyroid cancer lesions in patients who have negative
      diagnostic 131I whole body scans and elevated Tg levels, although it was not
      sensitive enough to detect minimal residual disease in cervical nodes.

PMID- 10404793
TI  - Blunted growth hormone response to maximal exercise in middle-aged versus young
      subjects and no effect of endurance training.
AB  - The purpose of this study was to evaluate the GH response to exercise and the
      effects of endurance training on this response in early middle-aged men. Seven
      healthy middle-aged [M; 42.0+/-2.4 (+/-SD) yr old] and five young (Y; 21.2+/-1.1
      yr old) competition cyclists were investigated before and after 4 months of
      intensive endurance training. Subjects performed an exhaustive incremental
      exercise test (50 watts for 3 min) with gas exchange measurement, and blood
      samples for lactate, glucose, and GH determinations were drawn before exercise,
      at the end of the exercise, and in the recovery phase (1, 3, 5, 10, 15, 20, and
      30 min). Basal insulin-like growth factor I was also determined. At exhaustion no
      differences were found in relative maximal heart rate or blood lactate and
      glucose peaks. On the contrary, the two groups had markedly different GH
      responses; in fact, the peak GH response to exhaustive exercise was much lower in
      M than in Y (8.1+/-1.3 vs. 57.1+/-15.5 microg/L; P<0.01). The training, similar
      in subjects of the same group, increased progressively from 182 to 300 km/week
      (+64.8%) in M and from 350 to 600 km/week (+71.4%) in Y. After the training, the
      percent increase in maximal oxygen consumption was similar in the two groups (M,
      +15.2%; Y, +17.5%), confirming that the efficiency of the training performed was
      comparable. In neither group did training have any effect on the GH peak response
      to exercise, confirming the blunted GH response in M compared to Y (6.7+/-1.0 vs.
      61.0+/-12.9 microg/L; P<0.01). Similarly, insulin-like growth factor I
      concentrations were not significantly affected by training. In conclusion, active
      middle-aged subjects, compared with the young, showed a blunted GH response to a
      physiological stimulus such as exercise, indicating that the age-related decline
      in GH secretion appears in early middle age. This response was not modified by
      training in either early middle-aged or young subjects.

PMID- 10404794
TI  - Stress echocardiography in hyperthyroidism.
AB  - Exertion symptoms occur frequently in subjects with hyperthyroidism. Using stress
      echocardiography, exercise capacity and global left ventricular function can be
      assessed noninvasively. To evaluate stress-induced changes in cardiovascular
      function, 42 patients with untreated thyrotoxicosis were examined using exercise
      echocardiography. Studies were performed during hyperthyroidism, after treatment
      with propranolol, and after restoration of euthyroidism. Twenty-two healthy
      subjects served as controls. Ergometry was performed with patients in a
      semisupine position using a continuous ramp protocol starting at 20 watts/min. In
      contrast to control and euthyroidism, the change in end-systolic volume index
      from rest to maximal exercise was lower in hyperthyroidism. At rest, the stroke
      volume index, ejection fraction, and cardiac index were significantly increased
      in hyperthyroidism, but exhibited a blunted response to exercise, which
      normalized after restoration of euthyroidism. Propranolol treatment also led to a
      significant increase of delta (delta) stroke volume index. Maximal work load and
      delta heart rate were markedly lower in hyper- vs. euthyroidism. Compared to the
      control value, systemic vascular resistance was lowered by 36% in hyperthyroidism
      at rest, but no further decline was noted at maximal exercise. The delta stroke
      volume index, delta ejection fraction, delta heart rate, and maximal work load
      were significantly reduced in severe hyperthyroidism. Negative correlations
      between free T3 and diastolic blood pressure, maximal work load, delta heart
      rate, and delta ejection fraction were noted. Thus, in hyperthyroidism, stress
      echocardiography revealed impaired chronotropic, contractile, and vasodilatatory
      cardiovascular reserves, which were reversible when euthyroidism was restored.

PMID- 10404795
TI  - Effect of overnight restoration of euglycemia on glucose effectiveness in type 2
      diabetes mellitus.
AB  - The ability of glucose to stimulate its own uptake and suppress its own release
      is impaired in type 2 diabetes. To determine whether glucose effectiveness is
      improved by short term euglycemia, 10 type 2 diabetic subjects were studied on 2
      occasions. Insulin was infused throughout the night to maintain euglycemia
      (approximately 5 mmol/L), or glucose was permitted to remain at ambient
      hyperglycemic levels (approximately 10 mmol/L) until the following morning when
      euglycemia was achieved with a variable insulin infusion. A prandial glucose
      infusion (containing 35 g glucose) was started at 1000 h, and the variable
      insulin infusion was replaced by a constant infusion of insulin (0.25 mU/ kg x
      min), somatostatin (60 ng/kg x min), glucagon (0.65 ng/kg x min), and GH (3 ng/kg
      x min) to maintain hormone concentrations at constant basal levels. Although
      nocturnal glucose concentrations were (by design) higher (P<0.01) on the
      hyperglycemic than on the euglycemic study day (10.1+/-0.2 vs. 5.4+/-0.1 mmol/L),
      glucose concentrations did not differ either before (4.9+/-0.1 vs. 4.9+/-0.1
      mmol/L) or during the prandial glucose infusion (peak, 11.1+/-0.5 vs. 11.3+/-0.5
      mmol/L; incremental area, 1390+/-254 vs. 1409+/-196 mmol/L x 6 h). Furthermore,
      glucose-induced stimulation of glucose disappearance (2068+/-218 vs. 1957+/-244
      micromol/kg x 6 h) and suppression of glucose production (-2253+/-378 vs. -2124+/
      257 micromol/kg x 6 h) did not differ. Thus, restoration of euglycemia by means
      of an overnight insulin infusion does not alter glucose effectiveness in people
      with type 2 diabetes.

PMID- 10404796
TI  - Reduced growth hormone receptor messenger ribonucleic acid in an aged man with
      chronic malnutrition and growth hormone resistance.
AB  - A severely malnourished 87-yr-old man presented with hypoglycemia. Serum GH
      levels were elevated, and serum levels of insulin-like growth factor I (IGF-I),
      IGF-binding protein-3, and GH-binding protein were extremely reduced. The
      patient's GH was biologically active. Administration of GH for 4 consecutive days
      resulted in a slight increment in serum IGF-I levels, but no elevation of serum
      IGF-binding protein-3. The expression of GH receptor messenger ribonucleic acid
      in the liver was greatly reduced. An autopsy revealed a Rathke's cleft cyst
      confined to the sella turcica. Immunohistochemical studies for GH showed that
      there was nothing to suggest a tumor overproducing GH. In addition, TSH levels
      were elevated in the presence of normal thyroid hormone levels, and there was a
      cluster of cells showing strong immunohistochemical staining for the TSH beta
      subunit in the pituitary. In this patient, the decreased expression of GH
      receptor messenger ribonucleic acid in the liver may have been responsible for
      the GH resistance, which was probably caused by malnutrition.

PMID- 10404797
TI  - Changes in free insulin-like growth factor-1 and leptin concentrations during
      acute metabolic decompensation in insulin withdrawn patients with type 1
      diabetes.
AB  - To determine the effect of acute insulin withdrawal and its subsequent
      replacement on components of the insulin-like growth factor (IGF)-1 binding
      protein system and on circulating leptin levels in patients with type 1 diabetes.
      Seventeen patients (age 31 yr +/-10) with type 1 diabetes treated with continuous
      subcutaneous insulin infusion (HbA1c 7.6% +/-1.0) were studied. The protocol
      consisted of two phases: acute insulin withdrawal of up to 8 h followed by a
      further 2-h period of insulin replacement. For the first phase the basal insulin
      infusion was stopped (at 0300 h), and for the second a single dose of either
      regular human or insulin lispro was given subcutaneously (0.2 U/kg). Plasma
      insulin, glucose, growth hormone, glucagon, IGF-1, free IGF-1, IGFBP-1, -2, -3
      and leptin were measured. RESULTS: After interruption of the basal insulin
      infusion, plasma free insulin levels fell from 60+/-12.0 pmol/L to 10.8+/-4.2
      pmol/L, and plasma glucose rose from 5.6+/-0.4 mmol/L to 14.8+/-1.2 mmol/L (P<
      0.01). During insulin withdrawal, IGFBP-1 increased by more than 6-fold (from
      32+/-8 to 205+/-17 ng/mL, P<0.001), IGFBP-3 increased significantly (from 2631+/
      118 to 3053+/-101 ng/mL, P<0.001), and total IGF-1 levels declined modestly (from
      226+/-33 to 182+/-26 ng/mL, P<0.001). In contrast, free IGF-1 concentrations
      (0.72+/-0.22 ng/mL at baseline) were markedly suppressed during insulin
      withdrawal to values below the detection limit of the assay (0.08 ng/mL) in 15 of
      the 17 patients (P<0.001). Circulating plasma leptin declined markedly in females
      from 20+/-3 ng/mL to 11+/-2 ng/mL (P<0.0001) and in males from 10+/-2 ng/mL to
      7+/-2 ng/mL (P<0.02). Within 2 h of insulin replacement, the changes in
      circulating concentrations of IGFBP-1 and IGFBP-3 were partially reversed, and
      free IGF-1 levels rebounded to 0.54+/-0.22 ng/mL (P<0.1 vs. insulin withdrawal).
      Growth hormone, glucagon, and IGFBP-2 levels did not change significantly
      throughout the study. Despite the rapid restoration of plasma insulin and
      substrate levels, circulating leptin levels continued to fall in the 2-h period
      after insulin replacement in both females and males. The marked reduction in
      circulating free IGF-1 after insulin withdrawal and its increase after insulin
      administration suggest that acute changes in IGFBP concentrations induced by
      insulin are important regulators of IGF-1 bioavailability in patients with type 1
      diabetes. In both males and females, the rapid induction of severe insulin
      deficiency is associated with a consistent fall in plasma leptin levels.

PMID- 10404798
TI  - Relationship between generalized and upper body obesity to insulin resistance in
      Asian Indian men.
AB  - It has been proposed that excessive insulin resistance in Asian Indians living in
      urban areas or migrated to western countries is responsible for the higher
      incidence of type 2 diabetes and coronary heart disease observed in this
      population. To evaluate whether Asian Indians are more insulin resistant than
      Caucasians and to define the role of generalized and truncal adiposity, we
      performed hydrodensitometry, skinfold measurements, and euglycemic
      hyperinsulinemic clamps in 21 healthy Asian Indian men and 23 Caucasian men of
      similar age and body fat content. The glucose disposal rate (Rd) was
      significantly lower in the Asian Indians than in the Caucasians (3.7+/-1.3 vs.
      5.3+/-2.0 mg/min x kg lean body mass, respectively; P = 0.003). Despite similar
      total body fat content, Asian Indians had higher truncal adiposity than
      Caucasians (sum of truncal skinfolds, 117+/-37 and 92.4+/-38 mm, respectively).
      In both Asian Indians and Caucasians, the insulin sensitivity index (Rd/plasma
      insulin concentrations) was inversely correlated with both total body fat (r = 
      0.49; P<0.03 and r = -0.67; P<0.001, respectively) and sum of truncal skinfold
      thickness (r = -0.55; P<0.001 and r = -0.61; P<0.002, respectively). After
      adjustment for total body fat and truncal skinfold thickness, Asian Indians still
      had a significantly lower glucose disposal rate (P = 0.04). These results show
      that Asian Indian men are more insulin resistant than Caucasian men independently
      of generalized or truncal adiposity. The excessive insulin resistance in Asian
      Indians is probably a primary metabolic defect and may account for the excessive
      morbidity and mortality from diabetes and coronary heart disease in this
      population.

PMID- 10404800
TI  - Predictive value of human leukocyte antigen class II typing for the development
      of islet autoantibodies and insulin-dependent diabetes postpartum in women with
      gestational diabetes.
AB  - Gestational diabetes mellitus (GDM) is a risk factor for the development of
      insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes
      mellitus postpartum. To evaluate whether there is any association of human
      leukocyte antigen (HLA) class II alleles (DR and DQ) with GDM and the postpartum
      development of IDDM, we analyzed 184 women with GDM from Germany for HLA class II
      alleles, islet autoantibodies [islet cell autoantibodies (ICA), glutamic acid
      decarboxylase autoantibodies (GADA), and protein tyrosine phosphatase IA-2
      autoantibodies (IA-2A), and the postpartum development of diabetes. No elevation
      in the frequency of any HLA class II alleles was observed in GDM patients
      compared to 254 nondiabetic unrelated subjects. DR3 allele frequency was
      significantly increased in 43 women with islet autoantibodies [corrected P value
      (Pc) = 0.02], in particular in those with GADA (Pc = 0.002), or in the 24 women
      who developed IDDM postpartum (Pc = 0.005). In women with GADA, DR4 and DQB1*0302
      were significantly elevated (Pc = 0.009). Twenty-five (59.5%) islet antibody
      positive women and 17 (74%) women who developed IDDM postpartum had a DR3- or DR4
      containing genotype. The cumulative risk to develop IDDM within 2 yr postpartum
      in GDM women with either DR3 or DR4 was 22% compared to 7% in women without those
      alleles (P = 0.02) and rose to 50% in the DR3- or DR4-positive women who had
      required insulin during pregnancy (P = 0.006). Combining the determination of
      susceptible HLA alleles (DR3, DR4) with islet autoantibody measurement increased
      the sensitivity of identifying GDM women developing postpartum IDDM to 92%, but
      did not improve risk assessment above that achieved using GADA measurement alone,
      which was the strongest predictor of IDDM. These results indicate that women with
      GDM who have islet autoantibodies at delivery or develop IDDM postpartum have HLA
      alleles typical of late-onset type 1 diabetes, and that both HLA typing and islet
      antibodies can predict the development of postpartum IDDM.

PMID- 10404799
TI  - Leptin binding activity changes with age: the link between leptin and puberty.
AB  - The timing of the physical transition from child to adult is determined by a
      biological clock that switches off the pituitary gonadal axis during infancy
      until puberty. Body composition (and in particular, fat mass), through leptin,
      are critical signals to this clock. However, no direct relationship between
      leptin and puberty has been demonstrated. Leptin is bound in the circulation by a
      high-affinity binding protein, which has been identified as a soluble leptin
      receptor. We found circulating levels of leptin binding activity (LBA) to be low
      at birth, to be high in the prepubertal years, to fall through puberty, and then
      to remain stable during adult life. LBA correlated with pubertal status in both
      boys and girls. We postulate that the fall in LBA, associated with increasing age
      and puberty, reflects a reduction in expression of truncated leptin receptors,
      and leptin is then available to the full-length receptor, which transmits the
      biological signal for leptin. The high levels of LBA occur during the years when
      the pituitary gonadal axis is quiescent. Thus, the change in LBA could explain
      how leptin regulates puberty.

PMID- 10404801
TI  - Effect of a short-term treatment with alendronate on bone density and bone
      markers in patients with central diabetes insipidus.
AB  - The aim of this open prospective randomized study was to evaluate the effect of a
      6-month treatment with alendronate on the bone mineral density (BMD) at lumbar
      spine in patients with central diabetes insipidus. Eighteen patients with central
      diabetes insipidus and 18 sex- and age-matched healthy subjects entered this
      study. At study entry, all subjects underwent BMD assessment at the lumbar spine
      and measurement of serum osteocalcin (OC) and cross-linked N-telopeptides of type
      I collagen (Ntx). Thereafter, 9 of the 18 patients were randomized to receive
      treatment with alendronate at a dose of 10 mg, orally, once daily for 6 months
      (group 1), whereas the remaining 9 patients did not receive any treatment
      affecting bone status during this period (group 2). After 6 months, bone
      metabolism and bone density study were repeated in all patients. At baseline,
      lumbar BMD values (0.86+/-0.03 vs. 1.01+/-0.02 g/cm2; P<0.001) and serum OC
      levels (4.7+/-0.3 vs. 7.9+/-0.2 microg/L; P<0.001) were significantly lower,
      whereas urinary Ntx levels were significantly higher [72.0+/-1.9 vs. 64.6+/-1.7
      nmol bone collagen equivalents (BCE)/nmol creatinine (Cr); P<0.01] in patients
      than in controls. After randomization, no difference in lumbar BMD, serum OC, or
      urinary Ntx was found between patients of group 1 and group 2. At the 6 month
      follow-up, no difference in serum OC levels was found compared to baseline
      evaluation in patients of both group 1 and group 2. By contrast, a significant
      decrease in urinary Ntx levels was found in patients of group 1 (70.3+/-3.0 vs.
      75.4+/-2.1 nmol BCE/nmol Cr; P<0.05), but not in patients of group 2 (68.8+/-3.3
      vs. 68.5+/-3.0 nmol BCE/nmol Cr; P = NS). A significant increase in lumbar BMD
      values was found in patients of group 1 (0.88+/-0.04 vs. 0.83+/-0.04 g/cm2;
      P<0.05), whereas a significant decrease in lumbar BMD values was found in
      patients of group 2 (0.86+/-0.05 vs. 0.89+/-0.05 g/cm2; P<0.05). Lumbar BMD
      increased 7.0+/-1.5% in patients of group 1 and decreased 4.2+/-1.8% in patients
      of group 2 (P<0.001). In conclusion, this study demonstrated that a 6-month
      treatment with alendronate in patients with central diabetes insipidus was
      effective in significantly improving BMD at the lumbar spine, which was
      significantly worsened in untreated patients. Therefore, alendronate treatment
      could be used in patients with central diabetes insipidus with documented
      osteopenia or osteoporosis.

PMID- 10404802
TI  - Plasma brain natriuretic peptide levels in normotensive noninsulin-dependent
      diabetic patients with microalbuminuria.
AB  - Brain natriuretic peptide (BNP), a member of the natriuretic peptide family, is
      produced and released from cardiac ventricles. BNP regulates the body fluid
      volume, blood pressure, and vascular tones through the A-type guanylate cyclase
      coupled receptor. The presence of renal dysfunction in patients with diabetes
      affects the plasma levels of atrial natriuretic peptide (ANP). In the present
      study, we investigated the plasma levels of BNP and ANP and their relationship in
      normotensive diabetic patients with normoalbuminuria and microalbuminuria. Forty
      seven normotensive lean noninsulin-dependent diabetic patients (31 with
      normoalbuminuria, 16 with microalbuminuria), with normal cardiac function, and 30
      age-matched control subjects were enrolled in this study. The plasma levels of
      BNP in diabetic patients with microalbuminuria were significantly higher than
      those in diabetic patients with normoalbuminuria (16.7+/-2.4 vs. 9.6+/-1.3 pg/mL,
      P<0.01) or normal subjects (16.7+/-2.4 vs. 7.0+/-0.6 pg/mL, P<0.01). There was a
      significant positive correlation between plasma BNP levels and urinary albumin
      excretion rate in all diabetic patients (r = 0.58, P<0.0001). There was also a
      significantly positive correlation between plasma BNP and ANP levels in diabetic
      patients (r = 0.62, P<0.0001). The increased plasma level of BNP in patients with
      microalbuminuria and its significant correlation with urinary albumin excretion
      rate suggest that the elevated circulating levels of BNP are caused by the
      presence of diabetic nephropathy. Down-regulation of A-type guanylate cyclase
      coupled receptor of renal tubules may explain the increased plasma levels of both
      BNP and ANP in normotensive diabetic patients with microalbuminuria.

PMID- 10404803
TI  - Cisapride versus placebo for 8 weeks on glycemic control and gastric emptying in
      insulin-dependent diabetes: a double blind cross-over trial.
AB  - In insulin-dependent diabetes mellitus, slow gastric emptying may make absorption
      unpredictable and foster glycemic instability. Cisapride accelerates emptying,
      but controlled long term studies are scarce, and effects on glycemic control
      unknown. We investigated, in patients with insulin-dependent diabetes mellitus
      and unstable glycemia, the effects of 10 mg cisapride 4 times daily for 8 weeks
      vs. placebo on glycemic control and gastric emptying under random, cross-over,
      double blind conditions. In 14 patients with delayed and 9 with nondelayed
      emptying, blood glucose variability over 28-week treatment periods separated by a
      4-week wash-out and gastric emptying of a semisolid 1168-kJ meal immediately
      after the treatment periods were assessed. Cisapride did not affect glycemic
      control [SD of within-patient mean blood glucose, 4.2 mmol/L +/-0.1 (+/- SEM) vs.
      4.0+/-0.1 mmol/L after placebo; hemoglobin A1c, 8.3+/-0.2% vs. 8.5+/-0.2%].
      Emptying was faster after cisapride than after placebo in 8 of 14 patients with
      delayed vs. 7 of 9 with nondelayed emptying (P = NS) and in 11 of 15 without vs.
      4 of 8 with cardiovascular autonomic neuropathy (P = NS). Autonomic neuropathy
      prevailed in 7 of 14 patients with delayed and 1 of 9 with nondelayed emptying.
      Blood glucose immediately before and during assessment of emptying was unrelated
      to the emptying rate, whereas blood glucose increases over fasting levels were
      greater with faster emptying (P<0.002). In conclusion, cisapride's effects were
      not different from those of placebo on glycemic control and gastric emptying, it
      did not differently affect patients with delayed vs. nondelayed emptying, and it
      slightly accelerated emptying (P = NS) in patients without, but not in those
      with, cardiovascular autonomic neuropathy. Blood glucose levels before and during
      assessment of emptying did not affect emptying, but the glucose rise over fasting
      levels was greater with faster emptying.

PMID- 10404804
TI  - Monitoring of alendronate treatment and prediction of effect on bone mass by
      biochemical markers in the early postmenopausal intervention cohort study.
AB  - To establish whether biochemical markers could be used to monitor alendronate
      (ALN) treatment and predict long-term response in bone mass, we used results from
      an ongoing, randomized trial of ALN treatment for prevention of postmenopausal
      osteoporosis (n = 1202). In women treated with ALN (5 mg), change from baseline
      at month 6 in urine N-telopeptide cross-links of type I collagen (NTX) and
      osteocalcin (OC) correlated with change from baseline at month 24 in spine, hip,
      and total body bone mineral density (BMD) [r = -0.28 to -0.31 (NTX) and r = -0.16
      to -0.25 (OC), P<0.001]. This corresponded to a 4- to 5-fold greater increase at
      month 24 in BMD in the tertiles, with the greatest decrease at month 6 in NTX or
      OC. In women treated with ALN (5 mg) who had a change at month 24 in spine BMD of
      at least 0%, 86% (NTX) and 79% (OC) had a decrease at month 6 of at least 40%
      (NTX) or 20% (OC) (sensitivity). The corresponding specificities were 48% (NTX)
      and 53% (OC). In conclusion, change at month 6 in NTX and OC, in groups of women
      treated with ALN, indicated the numeric long-term response in BMD within these
      groups. In individual women, a decrease at month 6, in NTX or OC below the cut
      point, validly identified women who responded, on ALN treatment, with a
      stabilization or an increase in bone mass. However, lack of decrease below the
      cut-point in NTX or OC could not be used to identify women with a bone loss
      during ALN treatment.

PMID- 10404805
TI  - Screening for mutations of 21-hydroxylase gene in Hungarian patients with
      congenital adrenal hyperplasia.
AB  - Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders,
      causing impaired secretion of cortisol and aldosterone from the adrenal cortex,
      with subsequent overproduction of adrenal androgens. The most common enzyme
      defect causing CAH is steroid 21-hydroxylase deficiency. To determine the
      mutational spectrum in the Hungarian CAH population, the CYP21 active gene was
      analyzed using PCR. A total of 297 Hungarian patients with 21-hydroxylase
      deficiency are registered in the 2nd Department of Pediatrics, Budapest, Hungary,
      and their clinical status was evaluated. Blood samples for CYP21 genotype
      determination could be obtained from 167 patients (representing 306 unrelated
      chromosomes and 56.2% of the total group of patients). Eight of the most common
      mutations were screened [In2 (intron 2 splice mutation), I172N, Del (Del:
      apparents large gene conversion), Q318X, R356W, 1761Tins, ClusterE6, V281L] using
      allele-specific amplification. The most frequent mutation in the Hungarian CAH
      population was found to be In2. Our results have shown a good genotype/phenotype
      correlation in case of most mutations; the In2 mutation is associated mostly with
      the severe form of the disease, whereas I172N was expressed in a wide spectrum of
      phenotypes. 1999)

PMID- 10404806
TI  - Long-term effects of growth hormone (GH) replacement in men with childhood-onset
      GH deficiency.
AB  - Short term GH replacement therapy has been shown to improve body composition and
      exercise capacity. It is not yet known whether GH replacement remains beneficial
      over the long term. We assessed the effects of long term GH replacement on body
      composition, bone mineral density, and cardiac function. Thirty-eight men with
      childhood-onset GH deficiency were studied for a period of 3-5 yr. Measurements
      included anthropometry, computed tomographic scanning of abdomen and upper leg,
      bone densitometry, echo cardiography, and bicycle ergometry. The initial GH dose
      of 1-3 IU/m2 x day (9-27 microg/kg) was gradually tapered to 1.30+/-0.38 IU/m2 x
      day (11 g/kg), aiming at physiological insulin-like growth factor I levels.
      During the study, leg muscle mass progressively increased by 28.7% (P<0.001).
      Subcutaneous and intraabdominal fat decreased by 30.9% and 46.0%, respectively,
      after 1 yr (both P<0.001), but demonstrated a partial regain thereafter. Bone
      mineral density at the lumbar spine, femoral neck, and trochanter gradually
      increased by 9.6%, 11.1%, and 16.2%, respectively (all P<0.001). Left ventricular
      mass exceeded baseline values by 14.1% after 1 yr (P<0.001), but returned to
      pretreatment values thereafter. Stroke volume and cardiac output increased by
      16.3% (P = 0.002) and 33.4% (P<0.001), respectively. Maximal work load increased
      from 189+/-30 to 232+/-41 watts (P<0.001). Thus, long term GH replacement is safe
      and beneficial. It improves cardiac performance without inducing left ventricular
      hypertrophy and progressively increases bone mineral density.

PMID- 10404807
TI  - Altered bone mass and turnover in female patients with adrenal incidentaloma: the
      effect of subclinical hypercortisolism.
AB  - The strategy of treatment for patients with adrenal incidentalomas (AI) may
      depend upon the presence of hormonal hypersecretion. Although alterations of bone
      turnover have been recently reported, data on bone mineral density (BMD) are not
      available in AI patients. We evaluated bone turnover and BMD in 32 female AI
      patients and 64 matched controls. Spinal and femoral BMD were similar in patients
      and controls. Serum bone GLA protein (6.8+/-3.5 vs. 8.8+/-3.2 ng/mL; P<0.005) and
      PTH (48.8+/-15.1 vs. 37.2+/-10.9 pg/mL; P<0.0001) were different in patients and
      controls. Patients were then subdivided into 2 groups: with (n = 8; group A) or
      without (n = 24; group B) subclinical hypercortisolism. PTH was higher (P<0.05)
      in group A than in group B and in both groups than in controls (57.1+/-13.6,
      46.0+/-14.8, and 37.2+/-10.9 pg/mL, respectively), and bone GLA protein was lower
      in group A than in group B and controls (3.8+/-2.3, 7.5+/-3.1, and 8.8+/-3.2
      ng/mL, respectively; P<0.05). Serum type I cross-linked C telopeptide and fasting
      urinary deoxypyridinoline/ creatinine were not different in the three groups. BMD
      at each site was lower (P<0.05) in group A than in group B and controls. Bone
      mass and metabolism are altered in AI patients with subclinical hypercortisolism
      and should be taken into account, therefore, when addressing the treatment of
      choice for these patients.

PMID- 10404808
TI  - Plasma leptin levels after biliopancreatic diversion: dissociation with body mass
      index.
AB  - Human obesity is associated with increased leptin levels, related to body
      composition and fat mass (FM). Insulin has been suggested to be a regulator of in
      vivo leptin secretion. To further investigate the relationships between insulin
      and leptin levels in human obesity, we have studied 10 obese females, aged 26-57
      yr [body mass index (BMI), 42.9+/-6.3], successfully treated by biliopancreatic
      (BPD) diversion, in an early postoperative period (2 months after surgery, post
      BPD I; BMI, 37.2+/-7.5) and a late postoperative period (16-24 months after
      surgery; BMI, 27.6+/-3.96). Fourteen normal female subjects (18-59 yr; BMI,
      27.9+/-1.4 kg/m2) were studied as controls. In pre-BPD obese subjects, leptin
      levels were higher than those in controls (60.5+/-18.8 vs. 28.7+/-4.8 ng/mL;
      P<0.001). BMI and insulin levels were also significantly greater (P<0.0001 and
      P<0.03, respectively). After surgery, the three parameters considered
      significantly decreased (P = 0.0007 for BMI, P<0.0001 for leptin, and P = 0.038
      for insulin, using Friedman's test for repeated data). Concerning the correlation
      between leptin and FM in our patients, control subjects and pre-BPD subjects
      confirmed the correlation found in the general population (r = 0.78; P<0.01). On
      the contrary, post-BPD patients at 2 months lay outside the general correlation
      between FM and leptin; in fact, patients with low leptin levels still had a high
      FM. Moreover, in the post-BPD patients there was no longer a significant
      correlation between FM and leptin. Concerning the correlation between insulin and
      leptin levels, a significant correlation was present in control subjects and pre
      BPD patients (r = 0.46; P<0.05). Using correlation analysis for repeated measures
      in surgically treated obese patients, a significant correlation within the
      subjects was present (r = 0.91; P<0.0001). After operation, BMI and leptin levels
      had a different pattern of decrease; leptin decreased rapidly, without
      correlation with BMI, indicating that body composition is not the only factor
      regulating leptin levels. The consistent correlation with insulin levels suggests
      an important interaction between these two hormones in post-BPD obese subjects.

PMID- 10404809
TI  - Effects of intranasal 17beta-estradiol on bone turnover and serum insulin-like
      growth factor I in postmenopausal women.
AB  - Estrogen therapy, using either oral or transdermal routes, decreases bone
      turnover and prevents postmenopausal bone loss. It has been suggested that oral
      and transdermal 17beta-estradiol (E2) may have different effects on serum insulin
      like growth factor I (IGF-I), a potent bone-forming growth factor. In this study
      we investigated the effects of a new route of administration, the intranasal E2
      spray (S21400), on bone turnover and circulating IGF-I and IGF-binding protein-3
      (IGFBP-3). Four hundred and twenty early postmenopausal women (<5 yr since
      menopause; mean age, 52 yr) were enrolled in a 3-month, double blind, placebo
      controlled study of four doses of intranasal E2 (100, 200, 300, and 400
      microg/day), two doses of oral E2 valerate (1 or 2 mg/day), and placebo. One
      hundred and twelve women were further treated for 12 months with intranasal E2
      (300 microg/day, i.e. the dose that has been shown to be adequate for the
      majority of postmenopausal women). Markers of bone resorption (urinary type I
      collagen C telopeptides) and formation [serum osteocalcin, serum type I collagen
      N-terminal extension propeptide (PINP), and serum bone alkaline phosphatase
      (BAP)] were measured at baseline, 1 month, 3 months, and 15 months. Serum IGF-I
      and IGFBP-3 were measured at baseline, 1 month, and 3 months. Urinary type I
      collagen C telopeptides decreased significantly in all active treatment groups as
      soon as 1 month (P<0.001 vs. placebo) and continued to decrease at 3 months with
      a dose effect for intranasal E2. Serum osteocalcin and PINP did not change at 1
      month for oral E2 (1 and 2 mg), but decreased significantly at 3 months. In
      contrast, formation markers increased significantly at 1 month for the two
      highest doses of intranasal E2 (P<0.01 vs. placebo for osteocalcin and BAP) and
      did not decrease at 3 months. Oral E2 induced a marked decrease in circulating
      IGF-I as early as 1 month, which was amplified at 3 months (-29% and -32% for 1
      and 2 mg, respectively), whereas no significant change from placebo was observed
      for intranasal E2 during the 3-month period. Changes in circulating IGF-I
      correlated significantly (P<0.01) with changes in osteocalcin, PINP, and BAP at 3
      months. Oral and intranasal E2 did not induce any significant change from placebo
      in serum IGFBP-3 at both 1 and 3 months. After 1 yr of treatment with intranasal
      E2 (300 microg/day), both resorption and formation markers decreased, reaching
      the levels in premenopausal women, regardless of the type of treatment during the
      first 3 months. We conclude that E2 administered by this new nasal route
      normalizes bone turnover to premenopausal levels. The delayed decrease in bone
      formation observed with intranasal E2 compared to oral E2 may be related to
      different effects on serum IGF-I levels.

PMID- 10404810
TI  - The development of Graves' disease and the CTLA-4 gene on chromosome 2q33.
AB  - Case-control studies suggest that the CTLA-4 gene may be a susceptibility locus
      for Graves' disease. The previously reported A/G polymorphism at position 49 in
      exon 1 of the CTLA-4 gene was, therefore, investigated in a case-control (n =
      743) and family-based (n = 179) dataset of white Caucasian subjects with Graves'
      disease. The relationship between CTLA-4 genotype and severity of thyroid
      dysfunction at diagnosis was also investigated. An increase in frequency of the G
      (alanine) allele was seen in Graves' patients compared with control subjects (42%
      vs. 31.5%, respectively; corrected P<0.0002; odds ratio = 1.58), and a
      significant difference in the distribution of GG, GA, and AA genotypes was
      observed between the groups (chi2 = 21.7; corrected P<0.00003). Increased
      transmission of the G allele was seen from heterozygous parents to affected
      offspring compared to unaffected offspring (chi2 = 5.7; P = 0.025). Circulating
      free T4 concentrations at diagnosis were significantly associated with CTLA-4
      genotype (F = 3.26; P = 0.04). These results support the hypothesis that CTLA-4
      may play a role in regulating self-tolerance by the immune system and in the
      pathogenesis of autoimmune disorders such as Graves' disease.

PMID- 10404811
TI  - The effect of estradiol and a combined estradiol/progestagen preparation on
      insulin sensitivity in healthy postmenopausal women.
AB  - Abnormalities of carbohydrate metabolism and insulin sensitivity have been
      reported in estrogen deficiency. Estrogen replacement appears to result in an
      improvement in these parameters, although progestagens may antagonize these
      effects. We have examined the effects of transdermal estradiol and oral
      norethisterone on insulin sensitivity using the hyperinsulinemic euglycemic clamp
      method by performing a randomized, double blind, placebo-controlled study in 22
      healthy women after a surgically induced menopause. After baseline measurements,
      subjects were randomized to receive either transdermal 17beta-estradiol (50
      microg) or matching placebo patches for 6 weeks. The subjects were then further
      randomized to receive either estradiol in combination with oral norethisterone (1
      mg) or a matching oral placebo preparation, crossing over after 6 weeks, with
      assessment of insulin sensitivity at the end of each treatment. No significant
      increase in insulin sensitivity was observed after 6 weeks of transdermal 17beta
      estradiol treatment (95% confidence interval, -0.54, 1.86; P = 0.27). Addition of
      norethisterone for a further 6 weeks had no detectable effect on insulin
      sensitivity (95% confidence interval, -1.65, 1.10; P = 0.65). The results of this
      study using transdermal estradiol do not support previous reports that unopposed
      estrogens exert potentially beneficial effects on insulin sensitivity and suggest
      that the addition of an oral progestagen confers no clinically important risk or
      benefit. It is therefore unlikely that effects on insulin sensitivity contribute
      appreciably to the cardioprotective benefits attributed to hormone replacement
      therapy.

PMID- 10404812
TI  - Growth hormone deficiency with ectopic neurohypophysis: anatomical variations and
      relationship between the visibility of the pituitary stalk asserted by magnetic
      resonance imaging and anterior pituitary function.
AB  - In GH-deficient children showing ectopic posterior pituitary hyperintense signal
      (EPP), the anatomical details of the pituitary-hypothalamic region and the
      relationship between the visibility of the pituitary stalk and anterior pituitary
      function were studied by magnetic resonance imaging (MRI). The absence or
      presence of the pituitary stalk was recorded by MRI before and after the
      injection of gadolinium in 25 children with GH deficiency and EPP at the age of
      8.7+/-5.0 yr (16 males and 9 females). Patients were classified into 2 groups
      according to the presence (group 1; n = 14), or the absence (group 2; n = 11) of
      pituitary stalk visibility after gadolinium injection. Most patients in group 1
      (12 of 14) demonstrated isolated GH deficiency, whereas all but 1 patient in
      group 2 showed multiple anterior pituitary hormone deficiency. The prevalence of
      a normally sized adenohypophysis was higher in group 1 than in group 2 (50% vs.
      9%; P<0.05). Although the EPP was found at the median eminence in all group 2
      patients, it was visualized in group 1 at different levels of the pituitary stalk
      in 60% of cases (8 of 14; at the proximal end of the pituitary stalk, n = 4; in
      the middle of the pituitary stalk, n = 2; at the distal end of the pituitary
      stalk, n = 2). This demonstrates that the ectopic posterior pituitary migration
      abnormality may be complete or partial. In conclusion, although the pathogenesis
      of GH deficiency with EPP remains unclear, these results suggest that in cases of
      GH deficiency associated with ectopic posterior pituitary hyperintense signal,
      patients with no visible pituitary stalk on MRI after gadolinium injection
      present a more severe form of the disease in childhood associated with multiple
      anterior pituitary hormone deficiency, whereas visibility of the pituitary stalk
      is related to isolated GH deficiency. Nevertheless, careful follow-up of these
      latter patients is necessary, as the natural history of the disease is not
      established until adulthood.

PMID- 10404813
TI  - 5alpha-reductase activity in women with polycystic ovary syndrome.
AB  - The recent demonstration of high concentrations of 5alpha-androstane-3,17-dione
      in the follicular fluid of polycystic ovaries suggests a potential role for
      5alpha-reduced androgens in the etiology of polycystic ovary syndrome (PCOS). The
      purpose of the present study was to determine whether there is increased 5alpha
      reductase activity or messenger ribonucleic acid (mRNA) expression in polycystic
      ovaries. 5alpha-Reductase 1 and 5alpha-reductase 2 mRNAs were measured in thecal
      (TC) and granulosa (GC) cells from individual follicles of 18 women with PCOS and
      26 regularly cycling control women. Both 5alpha-reductase 1 and 2 mRNA expression
      was higher in GC than in TC, and 5alpha-reductase 2 mRNA levels were
      approximately 3-fold higher than 5alpha-reductase 1 mRNA. 5alpha-Reductase 1 and
      2 mRNA expression were similar in GC from PCOS and control women, but 5alpha
      reductase mRNA was decreased in TC from PCOS follicles. In control women, 5alpha
      reductase 2 mRNA was highest in GC from 3- to 5-mm follicles and decreased to
      undetectable levels in GC from 7-mm follicles. A similar pattern of expression
      was present in GC from PCOS follicles, but detectable levels of 5alpha-reductase
      2 mRNA were present in GC from 7-mm follicles. 5alpha-Reductase activity was
      measured in whole follicles by measuring the conversion of radiolabeled
      testosterone to dihydrotestosterone. Kinetic analysis of total 5alpha-reductase
      activity at physiological pH revealed a Km of 1.46 micromol/L and a maximal
      velocity of 0.31 nmol/min x mg protein, indicating predominantly type 1 activity.
      The total 5alpha-reductase activity was approximately 4-fold higher in PCOS
      follicles than in control follicles. These data demonstrate elevated 5alpha
      reductase activity in polycystic ovaries and support the hypothesis that 5alpha
      reduced androgens may play a role in the pathogenesis of PCOS.

PMID- 10404814
TI  - The relationship between peripheral T cell reactivity to insulin, clinical
      remissions and cytokine production in type 1 (insulin-dependent) diabetes
      mellitus.
AB  - Antigenic proliferative responses of peripheral blood mononuclear cells (PBMC) to
      insulin were studied in 44 type 1 new-onset diabetic subjects. Of them, 14 (32%)
      had a stimulation index (> or =3) above the mean + 3 SD of 39 healthy controls
      and of 7 of 15 (47%) diabetic patients of long duration (P = 0.001). Responses to
      insulin were not dictated by specific major histocompatibility complex class II
      association and were not observed in normal subjects with diabetes-associated
      human leukocyte antigen-DR/DQ alleles. Whereas no relation of PBMC reactivity
      with insulin autoantibodies was found, there was a positive correlation with the
      presence of at least one of the four autoantibodies tested and with IA-2
      antibody. An interesting finding was that the proportion of patients with
      subsequent low insulin requirement, up to 24 months, was significantly higher in
      patients who showed PBMC reactivity to insulin (8 of 8) than in those who did not
      (10 of 24, 42%; P = 0.004). The former had a higher mean stimulation index than
      the latter (3.3+/-2.6 vs. 1.5+/-0.6; P = 0.006). Furthermore, interleukin-4 (IL
      4) production was lower in type 1 diabetic patients who proliferated to insulin
      than in those who did not (23+/-15 vs. 64+/-47 pg/mL; P = 0.04), but interferon
      gamma, IL-2, and IL-10 productions were similar. In conclusion, these results
      suggest that proliferation to insulin may reflect the presence of an higher
      residual beta-cell mass.

PMID- 10404815
TI  - Serum hepatocyte growth factor in patients with peripheral arterial occlusive
      disease.
AB  - Hepatocyte growth factor (HGF) is a multifunctional protein implicated in tissue
      regeneration, wound healing, and angiogenesis. We measured serum HGF
      concentrations in 37 patients with peripheral arterial occlusive disease (PAOD).
      Among them, 36 patients underwent arteriography. Serum HGF concentrations were
      also measured in 40 control subjects who remained free of vascular, liver,
      kidney, or lung disease. Patients with PAOD showed elevated serum HGF
      concentrations compared with control subjects (0.40+/-0.02 vs. 0.19+/-0.01 ng/mL;
      P<0.001). Serum HGF concentrations were significantly higher in smokers compared
      with nonsmokers (0.45+/-0.03 vs. 0.35+/-0.02 ng/mL; P = 0.003). The serum HGF
      concentrations in patients with collaterals tended to be higher than those in
      patients without collaterals (0.43+/-0.03 vs. 0.35+/-0.02 ng/mL; P = 0.06).
      Moreover, in patients who underwent bypass surgery or angioplasty, serum HGF
      concentrations decreased from 0.41+/-0.03 to 0.21+/-0.04 ng/mL after treatment
      (P<0.001). Serum HGF may be an useful marker for the diagnosis of PAOD. HGF may
      play an important role in angiogenesis and collateral vessel growth in PAOD.

PMID- 10404816
TI  - Identification of a three-amino acid deletion in the alpha2B-adrenergic receptor
      that is associated with reduced basal metabolic rate in obese subjects.
AB  - The alpha2-adrenergic receptors mediate part of the actions of the catecholamines
      noradrenaline and adrenaline on the regulation of energy balance. As part of an
      ongoing study on the genetics of obesity, the entire coding sequence of the
      alpha2B-adrenoceptor gene was screened in 58 obese, nondiabetic Finns by PCR
      single stranded conformational analysis (PCR-SSCA). A polymorphism that leads to
      a deletion of 3 glutamic acids from a glutamic acid repeat element (Glu x 12,
      amino acids 297-309) present in the third intracellular loop of the receptor
      protein was identified. This repeat element has previously been shown to be
      important for agonist-dependent receptor desensitization. Of 166 genotyped
      subjects, 47 (28%) had 2 normal (long) alleles (Glu12/Glu12), 90 (54%) were
      heterozygous (Glu12/Glu9), and 29 (17%) were homozygous for the short (Glu9/Glu9)
      form. The basal metabolic rate, determined by indirect calorimetry and adjusted
      for fat-free body mass, fat mass, sex, and age, was 94 Cal/day (5.6%) lower (95%
      confidence interval for difference, 32, 156) in subjects homozygous for the short
      allele than in subjects with two long alleles (F = 4.84; P = 0.009, by ANOVA).
      Thus, a genetic polymorphism of the alpha2B-adrenoceptor subtype can partly
      explain the variation in basal metabolic rate in an obese population and may
      therefore contribute to the pathogenesis of obesity.

PMID- 10404817
TI  - Polymorphisms of amiloride-sensitive sodium channel subunits in five sporadic
      cases of pseudohypoaldosteronism: do they have pathologic potential?
AB  - Pseudohypoaldosteronism (PHA) is characterized by congenital resistance of the
      kidney and/or other mineralocorticoid target tissues to aldosterone, resulting in
      excessive salt wasting. Mineralocorticoid receptor (MR) and postreceptor defects
      in the aldosterone-responsive amiloride-sensitive sodium channel (ENaC) subunits
      have been suggested as potential loci of the defect in this disease, whereas
      recently defects in MR and ENaC subunits were reported in familial PHA cases.
      Here we studied the ENaC subunit alpha, beta, and gamma complementary DNAs
      (cDNAs) in a series of five sporadic cases of PHA, whose MR cDNA contained
      nonconservative homozygous (C944-->T944, Ala241-->Val241) and/or a conservative
      heterozygous substitutions (A760-->G760, Ileu180-->Val180), which, however, were
      also present at high frequencies in a control population with apparently normal
      salt conservation. We found a nonconservative substitution (A2086-->G2086, Thr663
      ->Ala663) in the alphaENaC in all five of our patients, two of whom were
      homozygous and three of whom were heterozygous for this alteration, which was
      also present in the homozygous and heterozygous form in 31% and 64% of control
      subjects, respectively. We also found a nonconservative homozygous substitution
      (C1006-->G1006, Pro336-->Ara336) in the betaENaC and three nonconservative and
      conservative homozygous substitutions (T554-->A554, Trp178-->Arg178; C1526-
      >G1526, Pro501-->Ala501; T1862-->G1862, Ser614-->Ala614) in the gammaENaC of all
      five of our patients and in a substantial proportion of control subjects.
      Interestingly, when the patient group was compared to controls, a significantly
      increased concurrence of the MR and alphaENaC polymorphisms was found in the
      patients (P<0.025). We conclude that the changes identified in the cDNA of the
      three ENaC subunits in the patients with sporadic PHA are polymorphisms, which on
      their own have no apparent pathophysiological significance. We hypothesize,
      however, that these polymorphisms might influence salt conservation negatively if
      they are present concurrently with other genetic defects of the MR or other
      proteins that participate in sodium homeostasis. The latter would be compatible
      with a sporadic presentation and digenic or multigenic expression and heredity in
      PHA.

PMID- 10404818
TI  - Leptin and the perioperative neuroendocrinological stress response.
AB  - The human response to surgical stress is characterized by massive release of
      neuroendocrine hormones, provoking catabolism, thermogenesis, and hyperglycemia.
      Considering the possible adverse outcomes of excessive stress hormones,
      understanding various components of the stress response may improve management of
      postoperative morbidity. Leptin, initially described as an adipocyte-derived
      signaling factor, may also play an important role in regulating the hypothalamo
      pituitary-adrenocortical axis. In phase I, plasma leptin and cortisol were
      measured in women before, during, and after total abdominal hysterectomy. The
      anesthetic technique was strictly controlled, balanced anesthesia. In phase II,
      plasma leptin and cortisol levels were measured in cardiac surgery patients.
      These subjects were anesthetized with a high dose opioid technique that blunts
      the intraoperative surgical stress response. In phase I, mean leptin levels did
      not change over the week before surgery, had a maximal decrease to 49% of
      baseline 2 h after surgery, and increased to just above baseline 24 h
      postoperatively. Cortisol was 176% of the baseline just before surgery, peaked at
      2 h after surgery (383%), and remained elevated 24 h (200%) and 48 h (165%) after
      surgery. During the first 2 h of surgery, the decrease in leptin parallels the
      increase in cortisol. In phase II, high dose fentanyl limited both the cortisol
      increase and the leptin decrease; thus, the ratio of cortisol increase to leptin
      decrease was similar for the cardiac patients and the hysterectomy patients.
      These data indicate that leptin has a role in the surgically induced acute stress
      response in humans. Early in surgery the decrease in leptin parallels the
      increase in cortisol. This suggests a possible relationship between the
      neurobiology of these two systems, which could have important implications for
      regulation of the neuroendocrine response to surgical stress.

PMID- 10404819
TI  - Phytoestrogens alter adrenocortical function: genistein and daidzein suppress
      glucocorticoid and stimulate androgen production by cultured adrenal cortical
      cells.
AB  - Phytoestrogens influence a variety of biological processes. As 17beta-estradiol
      alters adrenocortical cell function, we examined whether the dietary
      phytoestrogens, genistein and daidzein, have related effects. In cultured human
      fetal and postnatal adrenal cortical cells, genistein and daidzein (both 0.4-40
      micromol/L) decreased ACTH-stimulated cortisol production to basal levels (ED50,
      1-4 micromol/L). In the adult adrenocortical cell line, H295, genistein,
      daidzein, and 17beta-estradiol (10 micromol/L) decreased cAMP-stimulated cortisol
      synthesis in a similar fashion. Neither genistein nor daidzein altered basal or
      ACTH-stimulated dehydroepiandosterone sulfate (DHEA-S) production in fetal
      adrenocortical cells, whereas in postnatal adrenocortical cells, DHEA and DHEA-S
      were markedly increased (ED50, 1-4 micromol/L). In H295 cells, basal and cAMP
      stimulated DHEA production were similarly increased by the phytoestrogens and
      17beta-estradiol. Genistein and daidzein did not affect the expression of steroid
      metabolizing enzymes. However, genistein and daidzein specifically inhibited the
      activity of 21-hydroxylase (P450c21); the activities of other steroidogenic
      enzymes were not affected. Thus, phytoestrogens may decrease cortisol synthesis
      by suppressing the activity of P450c21 and, as a consequence, increase DHEA/DHEA
      S synthesis by shunting metabolites away from the glucocorticoid synthetic
      pathway. Therefore, consumption of foods containing phytoestrogens may alter
      adrenocortical function by decreasing cortisol and increasing androgen
      production.

PMID- 10404820
TI  - Restoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship
      to human Na+/I-symporter gene methylation status.
AB  - Disseminated dedifferentiated thyroid epithelial carcinoma, which cannot
      sufficiently concentrate therapeutic radioiodide, is a terminal disease without
      any effective systemic treatment or chemotherapy. This is a likely consequence of
      loss of human sodium-iodide symporter (hNIS) function. We hypothesized that hNIS
      transcriptional failure in thyroid carcinoma could be consequent to methylation
      of DNA in critical regulatory regions and could be reversed with chemical
      demethylation treatment. Analysis of hNIS messenger ribonucleic acid (mRNA)
      expression in 23 tumor samples revealed that although loss of this expression
      corresponded to loss of clinical radioiodide uptake, some thyroid carcinomas with
      hNIS mRNA expression did not concentrate iodide, suggesting additional
      posttranscriptional mechanisms for loss of hNIS function. In addition, analysis
      of DNA methylation in CpG-rich regions of the hNIS promoter extending to the
      first intron failed to define specific methylation patterns associated with
      transcriptional failure in human thyroid tumor samples. In seven human thyroid
      carcinoma cell lines lacking hNIS mRNA, treatment with 5-azacytidine or sodium
      butyrate was able to restore hNIS mRNA expression in four cell lines and iodide
      transport in two cell lines. Investigation of methylation patterns in these cell
      lines revealed that successful restoration of hNIS transcription was associated
      with demethylation of hNIS DNA in the untranslated region within the first exon.
      This was also associated with restoration of expression of thyroid transcription
      factor-1. These results suggest a role for DNA methylation in loss of hNIS
      expression in thyroid carcinomas as well as a potential application for chemical
      demethylation therapy in restoring responsiveness to therapeutic radioiodide.

PMID- 10404821
TI  - Diurnal rhythm of plasma catecholamines in acromegaly.
AB  - We investigated the 24-h profiles of the circulating levels of norepinephrine
      (NE) and epinephrine (E), blood pressure (BP), and heart rate in 14 acromegalic
      patients, before (A) and 3-6 months after transsphenoidal surgery (C-A, cured; A
      A, active), and in 8 age-matched normal subjects (N). In addition, the responses
      of NE, E, PRA, and aldosterone to upright posture were investigated. No
      significant differences in the mean 24-h plasma NE and E levels were observed
      between either group of acromegalics and the N subjects. Analysis of the 24-h
      profiles indicated a statistically significant 24-h rhythm of both NE and E in N
      subjects. No evidence of a 24-h rhythm of plasma NE and E and BP was found in A
      patients. After surgery, a statistically significant 24-h rhythm of NE was
      detected in the patients with acrophase (13.54 and 13.45 h in C-A and A-A
      patients, respectively) and mesor (1019.8+/-45.1 and 1017.8+/-54.7 pmol/L in C-A
      and A-A patients, respectively) similar to those observed in N subjects
      (acrophase, 13.21 h; mesor, 942.3+/-42.5 pmol/L). After surgery, the plasma
      concentration of E clearly fluctuated throughout the 24 h in both C-A and A-A
      patients, even if cosinor analysis failed to reveal a 24-h significant rhythm. A
      statistically significant 24-h rhythm of BP was restored only in C-A patients.
      The mean 24-h heart rate was slightly, but significantly (P<0.05), higher in A
      than in N subjects and decreased after surgery. No significant differences in
      upright-stimulated NE, E, and plasma aldosterone levels were observed between
      each group of acromegalics and N subjects. However, basal and upright-stimulated
      PRA levels were significantly (P<0.001) lower in A patients. In conclusion, our
      study demonstrates the lack of a clear circadian variation in catecholamine
      levels and BP in active acromegaly and the return of a significant 24-h rhythm of
      NE and BP after pituitary surgery, concomitant with the reduction in GH and
      insulin-like growth factor I serum levels.

PMID- 10404822
TI  - Serum antibodies against megalin (GP330) in patients with autoimmune thyroiditis.
AB  - Megalin (gp330) is a multiligand receptor found on the apical surface of selected
      epithelial cells, including thyroid cells. We recently showed that megalin is a
      high-affinity receptor for thyroglobulin. Megalin is capable of inducing
      autoantibodies, as shown in the rat model, Heymann nephritis. Based on this
      consideration and on the knowledge that autoantibodies against several thyroid
      antigens develop in patients with autoimmune thyroid diseases, we searched for
      antimegalin antibodies in 78 patients with autoimmune and nonautoimmune thyroid
      diseases. We developed an assay, based on flow cytometry, to measure binding of
      serum IgGs to L2 cells, a rat carcinoma cell line that expresses abundant
      megalin. After incubation of L2 cells with serum samples and then with
      fluorescein isothiocynate-conjugated antihuman IgG Fc-specific antibody, the mean
      fluorescence intensity (MFI) was determined. Using results obtained in sera from
      32 normal subjects, we established a cutoff value for MFI (50.62), above which,
      tests were considered positive. Significantly elevated values were found in 18
      patients, including 13 of 26 patients with autoimmune thyroiditis (50.0%) and in
      2 of 19 patients with Graves' disease (10.5%). Furthermore, 2 of 19 patients with
      nontoxic goiter (10.5%) and 1 of 14 patients with differentiated thyroid cancer
      (7.14%) had MFI values greater than 50.62, associated with the presence of
      circulating antithyroid autoantibodies. As a control cell line, we used Chinese
      hamster ovary cells, which do not express megalin. We found that, among the 18
      patients with positive tests for binding to L2 cells, only 1 patient with
      nontoxic goiter had significant binding of serum IgGs to Chinese hamster ovary
      cells. Binding of serum IgGs to L2 cells was significantly reduced by
      coincubation with purified megalin in 15 of 18 positive patients (83.33%) and by
      a rabbit antimegalin antibody in 11 patients (61.11%). Further and more
      conclusive evidence that positive tests (MFI >50.62) for binding to L2 cells were
      attributable to serum antimegalin antibodies was demonstrated by
      immunoprecipitation experiments. After incubation of serum samples with L2 cell
      extracts, incubation with antihuman IgG Fc-specific agarose beads resulted in
      immunoprecipitation of megalin in all the 18 positive patients, but not in normal
      subjects, as assessed by Western blotting using a monoclonal antibody against
      megalin. Furthermore, the intensity of the band corresponding to megalin
      precipitated by serum IgGs in the above 18 patients was significantly correlated
      with the L2 binding MFI. This is the first clear-cut demonstration of antibodies
      against megalin in humans. Further studies are needed to determine whether
      antimegalin antibodies have pathogenic significance or diagnostic value in
      autoimmune thyroid diseases.

PMID- 10404823
TI  - Serum hepatocyte growth factor as a possible indicator of vascular lesions.
AB  - To investigate the role of human hepatocyte growth factor (hHGF) in vascular
      lesions associated with endothelial injury, we measured serum hHGF concentrations
      in subjects with retinal arteriosclerosis, coronary atherosclerosis, or
      arteriolitis due to Henoch-Schonlein purpura. Individuals with more advanced
      grades of retinal arteriosclerosis showed higher serum hHGF concentrations [grade
      0, 0.053+/-0.005 ng/mL (n = 68); grade 1, 0.144+/-0.022 ng/mL (n = 21; P<0.01 vs.
      grade 0); grade 2, 0.338+/-0.036 ng/mL (n = 20; P<0.01 vs. grade 0 or 1); grade
      3, 0.526+/-0.051 ng/mL (n = 9; P<0.01 vs. grade 0, 1, or 2)]. Patients with
      active arteriolitis due to Henoch-Schonlein purpura showed higher (P<0.01) serum
      hHGF concentrations (0.347+/-0.038 ng/mL; n = 14) than those in the remission
      phase (0.097+/-0.017 ng/mL; n = 19). Mean serum hHGF concentrations were higher
      in subjects with coronary atherosclerosis than in those without, but a
      significant overlap in serum hHGF concentrations was found between subjects with
      and those without coronary atherosclerosis. Serum hHGF may be an indicator of the
      presence or development of arteriolar lesions.

PMID- 10404824
TI  - Regiospecific esterification of estrogens by lecithin:cholesterol
      acyltransferase.
AB  - Lecithin:cholesterol acyltransferase (LCAT), the enzyme that esterifies
      cholesterol in blood, also esterifies other steroids at the 3beta-hydroxyl. These
      steroids, like cholesterol, are delta5-3beta-hydroxysteroids, such as
      pregnenolone and dehydroepiandrosterone. One unusual LCAT substrate is the
      estrogen, estradiol, which is esterified at the 17beta-hydroxyl. The
      esterification of estradiol by LCAT has been reported to produce a powerful
      antioxidant that protects low density lipoprotein (LDL) from oxidation. We
      investigated the substrate specificity of LCAT, comparing the esterification of
      four different steroids (estradiol, estriol, testosterone, and 5-androstene
      3beta, 17beta-diol) by human LCAT in blood and by acyl-coenzyme A:acyltransferase
      in tissue (placenta and fat). Estradiol was esterified only at the D ring 17beta
      hydroxyl group in both blood and tissue. In contrast, although testosterone has a
      D ring structure identical to that of estradiol, and it was esterified at the
      17beta-hydroxyl by acyl-coenzyme A:acyltransferase in tissue, it was not
      esterified by LCAT. When 5-androstenediol was the substrate in the tissues, both
      the 3beta- and 17beta-esters were synthesized, but the major product was the
      17beta-ester. Conversely, although 5-androstenediol was an excellent substrate
      for LCAT, only the 3beta-hydroxyl was esterified. No 17beta-ester was formed. The
      comparison of the esterification of estriol by acyl-coenzyme A:acyltransferase
      and LCAT was also surprising. In the tissues, estriol is esterified at both D
      ring hydroxyls, and both are esterified about equally. Although estriol is an
      extremely polar estrogen, it is esterified by LCAT, albeit at a very slow rate.
      Although again both D ring hydroxyls were esterified, the LCAT esterification
      site was mainly at the 17beta-hydroxyl. Esterification of estriol at the 17beta
      hydroxyl in preference to the 16alpha-hydroxyl is especially striking, because
      the 17beta-hydroxyl group is sterically shielded by the C-18 methyl group, making
      esterification at this position energetically much more difficult. Furthermore,
      these studies demonstrate that esterification of the 17beta-hydroxyl group by
      LCAT is unique to estrogens. It suggests that this unusual regiospecific
      esterification of C-17 of the estrogens underlies a distinct stereochemical
      requirement for the powerful antioxidant action that has reported for the
      estradiol esters formed by LCAT.

PMID- 10404825
TI  - The growth hormone secretagogue hexarelin stimulates the hypothalamo-pituitary
      adrenal axis via arginine vasopressin.
AB  - GH secretagogues (GHSs) act via specific receptors in the hypothalamus and the
      pituitary gland to release GH. GHSs also stimulate the hypothalamo-pituitary
      adrenal (HPA) axis via central mechanisms probably involving CRH or arginine
      vasopressin (AVP). We studied the effects of hexarelin, CRH, and desmopressin, an
      AVP analog, on the stimulation of the HPA axis in 15 healthy young male
      volunteers. Circulating ACTH, cortisol, GH and PRL concentrations were measured
      for 2 h after the injection of hexarelin, CRH, or desmopressin alone and the
      combination of hexarelin plus CRH or hexarelin plus desmopressin. Symptoms during
      the tests were assessed by visual analog scales. Hexarelin significantly
      increased ACTH and cortisol release (area under the curve, 3,444+/-696 ng/L x 125
      min and 45,844+/-2,925 nmol/L x 125 min, respectively), and this effect was
      augmented by the addition of CRH in a dose that on its own produces maximal
      stimulation (6,580+/-1,572 ng/mL x 125 min and 63,170+/-2,616 nmol/L x 125 min; P
      = 0.01 and 0.001, respectively), but was not influenced by the addition of
      desmopressin (3,540+/-852 ng/mL x 125 min and 35,319+/-3,252 nmol/L x 125 min;
      not significant). CRH on its own caused similar or slightly higher ACTH and
      cortisol release than hexarelin alone. Desmopressin given alone elicited a rapid
      rise in circulating ACTH and cortisol, but its effects were less than those of
      any other treatment and were not augmented by hexarelin. Hexarelin also caused
      significant GH and PRL release, but these effects were not influenced by the
      coadministration of CRH or desmopressin. Visual analog scales showed an acute
      small increment in appetite with hexarelin. Our data suggest that the effect of
      GHSs on the HPA axis involve at least in part the stimulation of AVP release. In
      summary, we have shown that in healthy male volunteers, the effect of hexarelin
      on the HPA axis does not involve CRH, but may occur through the stimulation of
      AVP release.

PMID- 10404826
TI  - Serum inhibin B in combination with serum follicle-stimulating hormone (FSH) is a
      more sensitive marker than serum FSH alone for impaired spermatogenesis in men,
      but cannot predict the presence of sperm in testicular tissue samples.
AB  - The measurement of serum FSH is useful in the diagnostic workup of the infertile
      male, but fails to predict the presence of sperm in testicular tissue. We
      investigated whether inhibin B reflects testicular morphology and the presence of
      sperm more accurately than FSH. Serum inhibin B and gonadotropin levels were
      determined in 91 infertile men undergoing diagnostic bilateral testicular biopsy.
      In 52 of the 91 patients multiple samples were taken for testicular sperm
      extraction (TESE). Inhibin B levels were (mean +/- SEM) 238+/-32 pg/mL in men
      with normal spermatogenesis (n = 9), 102+/-18 pg/mL in men with spermatogenetic
      arrest (n = 15), 98+/-16 pg/mL in hypospermatogenesis (n = 23), 41+/-6 pg/mL in
      focal Sertoli cell-only syndrome (SCO; n = 26), and 27+/-8 pg/mL in complete SCO
      (n = 18). The percentage of SCO tubuli was more strongly correlated to serum
      inhibin B (r = -0.58; P<0.01) than to FSH (r = 0.34; P<0.05). Similarly, the
      percentage of tubules with elongated spermatids was significantly (P<0.05) more
      strongly correlated to serum inhibin B (r = 0.65; P<0.01) than to FSH (r = -0.4;
      P<0.01). Thus, inhibin B is slightly more sensitive than FSH as an index of the
      spermatogenic status. Neither FSH nor inhibin B alone, however, could predict the
      type of spermatogenetic damage exactly. The combination of FSH and inhibin B had
      high diagnostic sensitivity (88%) and specificity (83%) for the presence of
      elongated spermatids in testicular biopsies. Sperm could be retrieved in 34 (65%)
      of the TESE patients. The combination of inhibin B and FSH measurement showed a
      sensitivity of 75% and a specificity of 73% when identifying patients in whom
      sperm could possibly be retrieved by TESE. We conclude that although the
      measurement of serum inhibin B improves the sensitivity of predictive tests for
      the presence of sperm in histology or for TESE, this parameter cannot accurately
      predict TESE outcome.

PMID- 10404827
TI  - A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios
      and associated malformations.
AB  - Permanent primary congenital hypothyroidism (CH) can be caused by abnormal
      thyroid differentiation (athyreosis), migration (ectopy), or function (leading to
      goiter). Goiters follow an autosomal recessive pattern of inheritance, whereas
      ectopy and athyreosis are considered as a single sporadic entity with a female
      preponderance. On the other hand, a high prevalence of extrathyroidal
      malformations has been reported in CH, but without linking specific defects to
      specific types of CH. On the basis of TSH screening, 273 newborns were referred
      to an academic pediatric endocrinology clinic in the province of Quebec between
      1988 and 1997. Of 230 patients with permanent primary CH who had scintigraphy at
      diagnosis, 141 had ectopy (104 girls), 36 had athyreosis (21 girls), 42 had
      goiter (18 girls), 10 (3 girls) had a normal scan, and 1 girl had hemiagenesis.
      Only in the ectopies was the proportion of girls significantly higher than 0.5
      (P<0.001). Isolated cardiac malformations were observed in 7 patients (3.0%), a
      prevalence 5-fold higher than that in the general population; this was largely
      due to atrial and ventricular septal defects, which were only observed in ectopy
      and athyreosis. Our data suggest that the molecular mechanisms that lead to
      complete absence of thyroid differentiation or defective thyroid migration 1) may
      be similar, but are modulated by the genetic makeup of the embryo and/or the
      hormonal milieu of the fetus; and 2) may also be involved in septation of the
      embryonic heart.

PMID- 10404828
TI  - Paracrine regulation of insulin-like growth factor I (IGF-I) an IGF-II on
      prostaglandins F2alpha and E2 synthesis by human corpus luteum in vitro: a
      possible balance of luteotropic and luteolytic effects.
AB  - The existence of a complete intraovarian insulin-like growth factor (IGF) system
      replete with ligands, receptors, and binding proteins has been demonstrated as
      well as the ability of IGF-I to positively affect steroidogenesis in human
      granulosa cells. Furthermore, we recently showed that IGF-I and IGF-II stimulate
      progesterone secretion by human luteal cells. As the PGs, PGE2 and PGF2alpha, are
      classically known to have luteotropic and luteolytic effects, we wanted to
      determine whether the IGFs could affect the human luteal phase by influencing the
      PG system. For this reason, human luteal cells were cultured for different times
      (12, 24, and 48 h) with IGF-I, IGF-II (10-100 ng/mL), and GH (100 ng/mL), and
      both PGs were assayed in the medium culture. We found that both IGF-I and IGF-II
      were able to stimulate PGE2 synthesis in a time- and dose-dependent way, whereas
      they both inhibited PGF2alpha production. GH, too, significantly reduced
      PGF2alpha synthesis; this effect was IGF-I mediated because it was reverted by
      increasing dilutions of an anti-IGF-I antibody. On the contrary, no GH effect was
      observed on PGE2 production. In conclusion, based on these data and on our
      previous results, we speculate that IGFs could influence luteal steroidogenesis
      through PG system.

PMID- 10404829
TI  - Inhibition of sham feeding-stimulated human gastric acid secretion by glucagon
      like peptide-2.
AB  - Glucagon-like peptide (GLP)-2 is formed from proglucagon in the intestinal L
      cells and is secreted postprandially in parallel with the insulinotropic hormone
      GLP-1, the latter of which, in addition, acts to inhibit gastric secretion and
      motility by inhibiting central parasympathetic outflow. We now studied the effect
      of GLP-2 on gastric secretion stimulated by sham feeding to test the hypothesis
      that also GLP-2 acts as an enterogastrone. Eight healthy volunteers were studied
      twice on separate days. They were sham fed with and without GLP-2 infused iv at a
      rate of 0.8 pmol/kg x min. Gastric contents were aspirated continuously by a
      nasogastric tube for determination of acid secretion, volume, and osmolarity.
      Sham feeding increased gastric acid secretion nearly 5-fold. Infusion of GLP-2
      reduced incremental acid secretion by 65+/-6%, compared with saline infusion
      (delta8.75+/-0.37 vs. delta3.04+/-0.47 mmol x 60 min; P<0.01). Plasma
      concentrations of GLP-2 rose from a basal mean of 3.3+/-0.9 to a mean of 115+/-8
      pmol/L (range, 57-149 pmol/L) during infusion of GLP-2 and remained at basal
      level during saline infusion. Plasma concentrations of GLP-1, gastrin,
      cholecystokinin, and secretin remained low and unchanged on both study days. We
      conclude that GLP-2 is a powerful inhibitor of gastric acid secretion in man.
      Further investigations will show to what extent GLP-2 contributes to the
      inhibitory effects on gastric secretion exerted by hormones from the distal small
      intestine, under physiological circumstances.

PMID- 10404830
TI  - Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients.
AB  - Cabergoline is a new long-acting dopamine agonist that is very effective and well
      tolerated in patients with pathological hyperprolactinemia. The aim of this study
      was to examine, in a very large number of hyperprolactinemic patients, the
      ability to normalize PRL levels with cabergoline, to determine the effective dose
      and tolerance, and to assess the effect on clinical symptoms, tumor shrinkage,
      and visual field abnormalities. We also evaluated the effects of cabergoline in a
      large subgroup of patients with bromocriptine intolerance or -resistance. We
      retrospectively reviewed the files of 455 patients (102 males and 353 females)
      with pathological hyperprolactinemia treated with cabergoline in 9 Belgian
      centers. Among these patients, 41% had a microadenoma; 42%, a macroadenoma; 16%,
      idiopathic hyperprolactinemia; and 1%, an empty sella. The median pretreatment
      serum PRL level was 124 microg/L (range, 16-26,250 microg/L). A subgroup of 292
      patients had previously been treated with bromocriptine, of which 140 showed
      bromocriptine intolerance and 58 showed bromocriptine resistance. Treatment with
      cabergoline normalized serum PRL levels in 86% of all patients: in 92% of 244
      patients with idiopathic hyperprolactinemia or a microprolactinoma and in 77% of
      181 macroadenomas. Pretreatment visual field abnormalities normalized in 70% of
      patients, and tumor shrinkage was seen in 67% of cases. Side effects were noted
      in 13% of patients, but only 3.9% discontinued therapy because of side effects.
      The median dose of cabergoline at the start of therapy was 1.0 mg/week but could
      be reduced to 0.5 mg/week once control was achieved. Patients with a
      macroprolactinoma needed a higher median cabergoline dose, compared with those
      with idiopathic hyperprolactinemia or a microprolactinoma: 1.0 mg/week vs. 0.5
      mg/week, although a large overlap existed between these groups. Twenty-seven
      women treated with cabergoline became pregnant, and 25 delivered a healthy child.
      One patient had an intended abortion and another a miscarriage. In the patients
      with bromocriptine intolerance, normalization of PRL was reached in 84% of cases,
      whereas in the bromocriptine-resistant patients, PRL could be normalized in 70%.
      We confirmed, in a large-scale retrospective study, the high efficacy and
      tolerability of cabergoline in the treatment of pathological hyperprolactinemia,
      leaving few patients with unacceptable side effects or inadequate clinical
      response. Patients with idiopathic hyperprolactinemia or a microprolactinoma, on
      average, needed only half the dose of cabergoline as those with
      macroprolactinomas and have a higher chance of obtaining PRL normalization.
      Cabergoline also normalized PRL in the majority of patients with known
      bromocriptine intolerance or -resistance. Once PRL secretion was adequately
      controlled, the dose of cabergoline could often be significantly decreased, which
      further reduced costs of therapy.

PMID- 10404831
TI  - Sources and physiological significance of plasma dopamine sulfate.
AB  - Dopamine in the circulation occurs mainly as dopamine sulfate, the sources and
      physiological significance of which have been obscure. In this study, plasma
      concentrations of dopamine sulfate were measured after a meal, after fasting for
      4 days, and during i.v. L-DOPA, nitroprusside, or trimethaphan infusion in
      volunteers; after dopamine infusion in patients with L-aromatic-amino-acid
      decarboxylase deficiency; in arterial and portal venous plasma of
      gastrointestinal surgery patients; and in patients with sympathetic
      neurocirculatory failure. Meal ingestion increased plasma dopamine sulfate by
      more than 50-fold; however, prolonged fasting decreased plasma dopamine sulfate
      only slightly. L-DOPA infusion produced much larger increments in dopamine
      sulfate than in dopamine; the other drugs were without effect. Patients with L
      aromatic amino acid decarboxylase deficiency had decreased dopamine sulfate
      levels, and patients with sympathetic neurocirculatory failure had normal levels.
      Decarboxylase-deficient patients undergoing dopamine infusion had a dopamine
      sulfate/dopamine ratio about 25 times less than that at baseline in volunteers.
      Surgery patients had large arterial-portal venous increments in plasma
      concentrations of dopamine sulfate, so that mesenteric dopamine sulfate
      production accounted for most of urinary dopamine sulfate excretion, a finding
      consistent with the localization of the dopamine sulfoconjugating enzyme to
      gastrointestinal tissues. The results indicate that plasma dopamine sulfate
      derives mainly from sulfoconjugation of dopamine synthesized from L-DOPA in the
      gastrointestinal tract. Both dietary and endogenous determinants affect plasma
      dopamine sulfate. The findings suggest an enzymatic gut-blood barrier for
      detoxifying exogenous dopamine and delimiting autocrine/paracrine effects of
      endogenous dopamine generated in a "third catecholamine system."

PMID- 10404832
TI  - Thyroxine replacement therapy enhances clearance of chylomicron remnants in
      patients with hypothyroidism.
AB  - To further confirm the benefit of replacement therapy in terms of risk for
      coronary artery disease, we evaluated the effect of T4 on postprandial
      lipoproteins in patients with hypothyroidism. Nine normolipidemic patients (aged
      62.75+/-7.6 yr) with TSH of 32.2+/-13.2 mU/L and free T4 of 0.66+/-0.17 ng/mL
      were treated with T4 (50-100 microg/day) for at least 4 months. The behavior of
      postprandial lipoproteins was assessed before and during treatment by determining
      retinyl palmitate levels in the total plasma, chylomicrons (Sf >1000) and
      chylomicron remnants (Sf <1000) fractions for 8 h after a mixed meal plus vitamin
      A. During T4 treatment, serum levels of TSH and FT4 were 4.4+/-4.9 mU/L and 1.2+/
      0.34 ng/mL (P = 0.001 and P = 0.002), respectively. Fasting low density
      lipoprotein cholesterol decreased from 166+/-35 to 135+/-23 mg/dL (P = 0.035).
      Retinyl palmitate (RP) levels in the chylomicron remnant fraction was reduced
      significantly during therapy from 6948+/-2790 to 5174+/-2401 microg/L x h (area
      under the curve +/-SD; P = 0.014). Total plasma RP and chylomicron RP remained
      unchanged. We conclude that T4 enhances the clearance of chylomicron remnants in
      normolipidemic patients with hypothyroidism.

PMID- 10404833
TI  - A premature stopcodon in thyroglobulin messenger RNA results in familial goiter
      and moderate hypothyroidism.
AB  - Impaired thyroglobulin (Tg) synthesis is one of the putative causes for
      dyshormonogenesis of the thyroid gland. This type of hypothyroidism is
      characterized by intact iodide trapping, normal organification of iodide, and
      usually low serum Tg levels in relation to high TSH, and when untreated the
      patients develop goiter. In thyroid tissue from a 13-yr-old patient suspected of
      a thyroglobulin synthesis defect, the Tg mRNA was studied. The complete coding
      region of 8307 bp was directly sequenced and revealed a homozygous point
      mutation: a C886T transition in exon 7. Upon translation this mutation would
      result in a stopcodon at amino acid position 277, replacing the arginine residue.
      A Tg cDNA construct containing the mutation was expressed in rabbit reticulocyte
      lysate resulting in a truncated protein of 30 kDa. Expression in the presence of
      microsomal membranes resulted in a gel shift of this Tg molecule, indicating
      glycosylation ability. Two other siblings had a clinical presentation like the
      index patient, while their parents were unaffected. Additional restriction
      fragment length polymorphism analysis of the pedigree verified that the
      homozygous nonsense mutation cosegregated with the clinical phenotype.
      Clinically, hypothyroidism was not severe in the affected siblings because the
      truncated Tg glycoprotein was still capable of thyroid hormonogenesis.

PMID- 10404834
TI  - Serum leptin concentrations and expression of leptin transcripts in placental
      trophoblast with advancing baboon pregnancy.
AB  - Leptin is a polypeptide hormone originally thought to be produced exclusively by
      adipocytes. Recently, however, both leptin messenger ribonucleic acid (mRNA) and
      leptin protein were identified in human placental trophoblast cells, suggesting a
      potential role in primate pregnancy. In the present study, venous blood samples
      were collected at 5-day intervals during gestation from baboons (Papio sp), an
      established model for the study of human pregnancy, as well as from nonpregnant
      baboons, and leptin concentrations were determined by RIA. Additionally,
      placental villous tissue was collected upon cesarean delivery at early (days 60
      62; n = 5), mid (days 98-102; n = 5), and late (days 159-167; n = 5) gestation
      (term = approximately 184 days), and leptin mRNA was quantitated by competitive
      RT-PCR. Finally, in situ hybridization was employed to localize transcripts to
      specific placental cell types. Results determined that maternal leptin levels
      (mean +/- SEM), which were dramatically greater (P<0.01) than those in
      nonpregnant cycling baboons (1.4+/-0.1 ng/mL), increased (P<0.005) with
      gestational age from 63.6+/-10.4 ng/mL on day 60 of gestation to 157.8+/-16.1
      near term. Levels declined to those found in cycling baboons by 15 days
      postdelivery. In contrast to maternal leptin concentrations, placental leptin
      mRNA decreased (P<0.02) with advancing pregnancy, as transcript abundance
      declined approximately 8-fold from early to late gestation. Maternal peripheral
      leptin concentrations were positively correlated (r = 0.66; P<0.001) whereas
      placental leptin mRNA levels were negatively correlated (r = -0.64; P<0.01) with
      gestational age. Expression of leptin mRNA transcripts, as evidenced by RT-PCR in
      villous tissue, was localized principally within syncytiotrophoblast by in situ
      hybridization. In summary, changes in maternal peripheral leptin concentrations
      and placental leptin mRNA abundance that occur commensurate with advancing
      gestational age may imply evolving roles for the polypeptide with advancing
      primate pregnancy. In this capacity, localization of leptin transcripts within
      the baboon syncytiotrophoblast suggests the potential for autocrine or paracrine
      interactions within this endocrinologically active tissue. Finally, both the
      similarities in leptin ontogeny in baboon and human pregnancy and the singular
      enhancement of maternal leptin levels inherent throughout baboon gestation
      emphasize the potential of this nonhuman primate model for the study of leptin
      action in the maternal-fetoplacental unit.

PMID- 10404835
TI  - Intrinsic site-specific differences in the expression of leptin in human
      adipocytes and its autocrine effects on glucose uptake.
AB  - Leptin, the ob gene product of adipocytes, regulates body weight by actions on
      the satiety center in the hypothalamus, but it may also have peripheral effects
      on the metabolic actions of insulin. In human mature adipocytes isolated from
      omental (OM) and s.c. tissue, we found that leptin (10 and 100 ng/mL)
      significantly reduced insulin-mediated glucose uptake by 40% (P<0.05). The
      effects were rapid and sustained. A U-shaped dose-response curve was obtained,
      and high leptin concentrations (>100 ng/mL) were without effect. Leptin did not
      affect basal glucose uptake in adipocytes and had no effect on insulin-stimulated
      glucose uptake in human preadipocytes. Because leptin may thus have autocrine
      effects, we examined leptin production from OM and s.c. adipocytes. Western
      blotting of leptin from 96-h conditioned medium showed greater leptin secretion
      from s.c. than OM adipocytes, with a ratio of 3.2 (SE +/-0.3, P<0.01). Long-term
      ceiling cultures were used to examine intrinsic differences in leptin expression
      under closely controlled conditions. Confocal immunofluorescence microscopy of 12
      to 16-day-old ceiling-cultured adipocytes showed that sc adipocytes contained
      3.4-fold more leptin (SE +/-0.5, P<0.01) than OM adipocytes, indicating an
      intrinsic site-specific difference in leptin production. The autocrine effects of
      leptin to inhibit insulin-stimulated glucose uptake and subsequent lipogenesis in
      adipose tissue may, therefore, be less in OM adipocytes and may play a role in
      determining visceral obesity.

PMID- 10404836
TI  - Differentiation of human orbital preadipocyte fibroblasts induces expression of
      functional thyrotropin receptor.
AB  - Although the autoantigen involved in Graves' hyperthyroidism is known to be the
      TSH receptor (TSHr), whether this antigen plays a primary role in the
      pathogenesis of Graves' ophthalmopathy (GO) is unclear. We sought to determine
      whether fibroblasts derived from orbital adipose/connective tissue are capable of
      differentiating into adipocytes that bear immunoreactive and functional TSHr. In
      addition, we assessed relative levels of TSHr gene expression in normal and GO
      orbital adipose/connective tissue specimens. GO and normal orbital preadipocyte
      fibroblasts, cultured under conditions known to stimulate adipocyte
      differentiation, showed evidence of adipogenesis and positive immunostaining for
      TSHr protein. In addition, significantly more cAMP was produced in response to
      TSH stimulation in the differentiated cultures than in undifferentiated cultures
      derived from the same individuals' cells. Other studies demonstrated relatively
      greater TSHr gene expression in GO than in normal orbital tissue specimens. These
      results indicate that orbital preadipocyte fibroblasts increase their TSHr
      expression with differentiation and suggest that these cells play an important
      role in the pathogenesis of GO. Furthermore, our studies support the concept that
      TSHr may be an important target antigen in this condition. Factors that stimulate
      adipocyte differentiation and TSHr expression in the orbit in GO have yet to be
      defined.

PMID- 10404837
TI  - Perivascular interleukin-8 messenger ribonucleic acid expression in human
      endometrium varies across the menstrual cycle and in early pregnancy decidua.
AB  - Human endometrium and decidua contain large numbers of different leukocyte
      populations, the concentration of which fluctuates during the menstrual cycle and
      pregnancy. There is, for example, a large influx of neutrophils into premenstrual
      endometrium associated with an increased expression of interleukin (IL)-8
      protein, which is chemotactic for neutrophils. Our aim in this study was to
      localize IL-8 messenger RNA (mRNA) expression in endometrium and decidua using in
      situ hybridization. In situ hybridization was carried out with a 35S-uridine 5'
      triphosphate-labeled riboprobe using standard procedures. Late secretory
      endometrial and decidual biopsies demonstrated clear perivascular localization of
      IL-8 mRNA, with additional expression colocalized to activated macrophages.
      Midluteal endometrium showed minimal IL-8 expression, whereas endometrium
      obtained from women administered progesterone for 4 days from (LH peak + 8 days),
      to simulate luteal regression, demonstrated significantly increased localization
      of IL-8 mRNA, 48 h after withdrawal of progesterone. In conclusion, IL-8 mRNA
      expression is localized to perivascular cells of late secretory endometrium and
      decidua.

PMID- 10404838
TI  - Coexpression of mineralocorticoid receptors and 11beta-hydroxysteroid
      dehydrogenase 2 in human gastric mucosa.
AB  - The role of mineralocorticoids in human gastrointestinal tract is well
      established. In the stomach, aldosterone is thought to regulate electrolyte
      transport associated with gastric acid secretion. In mineralocorticoid target
      organs, the action of the glucocorticoid inactivating enzyme 11beta
      hydroxysteroid dehydrogenase type 2 (11beta-HSD2) facilitates aldosterone binding
      to a nonselective mineralocorticoid receptor (MR) in the face of high levels of
      circulating glucocorticoids. In the present study, we examined 25 specimens of
      human stomach for the presence of MR and 11beta-HSD2 using a [3H]aldosterone
      binding assay, Northern blot analysis, RT-PCR, and immunohistochemistry. Specific
      [3H]aldosterone binding sites were detected in gastric fundic mucosa, but not in
      the antrum. In fundic mucosa the Kd was 0.72+/-0.05 nmol/L (mean +/- SE), and
      Bmax was 6.0+/-1.4 fmol per milligram of protein. Northern blot analysis
      demonstrated a faint band for MR mRNA at 6.0 kb, although message for 11beta-HSD2
      was undetectable. However, RT-PCR demonstrated specific PCR products for both MR
      and 11beta-HSD2. Immunohistochemistry demonstrated the colocalization of MR and
      11beta-HSD2 only in parietal cells. MR-positive cells were further characterized
      by electron microscopy, confirming the identity of parietal cells. This study
      shows that parietal cells contain both MR and 11beta-HSD2, suggesting that the
      human stomach is a novel target organ for mineralocorticoids. Aldosterone may,
      therefore, regulate biological functions of parietal cells including gastric acid
      secretion.

PMID- 10404839
TI  - Sulfate transport is not impaired in pendred syndrome thyrocytes.
AB  - Pendred syndrome is the most common form of syndromic deafness, characterized by
      dyshormonogenic goiter associated with sensory-neural deafness. The gene
      responsible for the disease (PDS) has been cloned, but its function is as yet
      unknown and the connection between thyroid goiter and sensory-neural deafness
      remains an enigma. PDS codes for a novel protein, pendrin, which is closely
      related to a number of sufate transporters. Mechanisms by which abnormal sulfate
      transport could deleteriously affect iodide organification have been proposed. We
      tested sulfate transport in thyrocytes obtained from Pendred syndrome patients
      and found that it was not defective. This suggests that pendrin in fact may not
      be a sulfate transporter, and emphasizes the importance of functional studies on
      this novel protein.

PMID- 10404840
TI  - Sulfation of thyroid hormone by estrogen sulfotransferase.
AB  - Sulfation is one of the pathways by which thyroid hormone is inactivated.
      Iodothyronine sulfate concentrations are very high in human fetal blood and
      amniotic fluid, suggesting important production of these conjugates in utero.
      Human estrogen sulfotransferase (SULT1E1) is expressed among other tissues in the
      uterus. Here we demonstrate for the first time that SULT1E1 catalyzes the facile
      sulfation of the prohormone T4, the active hormone T3 and the metabolites rT3 and
      3,3'-diiodothyronine (3,3'-T2) with preference for rT3 approximately 3,3'-T2 > T3
      approximately T4. Thus, a single enzyme is capable of sulfating two such
      different hormones as the female sex hormone and thyroid hormone. The potential
      role of SULT1E1 in fetal thyroid hormone metabolism needs to be considered.

PMID- 10404841
TI  - Prop-1 gene expression in human pituitary tumors.
AB  - A novel type of pituitary-specific transcription factor, Prophet of Pit-1 (Prop
      1) gene (PROP1), expresses in just early embryonic stage in mouse and closely
      related as a causative gene in combined pituitary hormone deficiency. We studied
      PROP1 expression to further clarify its correlation with tumorigenesis and
      biological behavior in human pituitary adenomas. Eighteen pituitary adenomas and
      three normal pituitary glands were examined for the expression of PROP1 and
      POU1F1 by using RT-PCR Pituitary adenomas were diagnosed as non-functioning
      adenomas (n = 11), prolactinomas (n=5), GH-producing adenoma (n = 1) and ACTH
      producing adenoma (n = 1). One of non-functioning adenomas was pituitary
      carcinoma with cerebellar metastasis and CSF dissemination. Our results
      demonstrated PROP1 expression in all pituitary tumors examined, in contrast,
      POU1F1 was detected in 14 of pituitary tumors. PROP1 was also expressed in normal
      pituitary gland, however, it was not in normal brain tissue, glioblastomas (cell
      lines and tumor tissues) and meningioma. Our data indicated that PROP1 expression
      was observed constantly both in the pituitary tumors and normal human adult
      pituitary tissues, suggesting that PROP1 is an essential transcriptional factor
      for pituitary specific gene expression in human. Therefore, detection of PROP1
      might be a useful indicator for differentiating pituitary adenomas, regardless of
      their hormonal phenotypes, from other brain tumors.

PMID- 10404842
TI  - Effect of enalaprilat on nitric oxide activity in coronary artery disease.
AB  - Atherosclerosis is associated with vascular endothelial dysfunction and reduced
      nitric oxide (NO) activity. Enhancement of NO activity may have an
      antiatherogenic action. This study was performed to determine whether angiotensin
      converting enzyme (ACE) inhibition improves peripheral vascular NO activity in
      patients with atherosclerosis. In the femoral circulation of 43 patients with
      atherosclerosis and 10 controls, we studied endothelium-dependent vasodilation
      with bradykinin and acetylcholine, and endothelium-independent vasodilation with
      sodium nitroprusside before and after enalaprilat. In 22 patients, we repeated
      these infusions in the presence of L-N(G) monomethyl arginine (L-NMMA). Doppler
      femoral artery flow velocity was measured. Before ACE inhibition, acetylcholine
      responses were depressed in patients with atherosclerosis compared with controls
      (p = 0.03). Enalaprilat did not alter femoral vascular tone at rest or
      vasodilation with sodium nitroprusside, but potentiated bradykinin-mediated
      vasodilation in patients (p<0.001) and controls (p = 0.02). Acetylcholine
      mediated vasodilation was augmented only in patients (p<0.001), but not in
      control subjects. L-NMMA inhibited the potentiation by enalaprilat of
      acetylcholine and bradykinin responses. This study demonstrates that ACE
      inhibition selectively improves endothelial dysfunction in human atherosclerosis
      by enhancing NO activity. The antithrombotic and antiproliferative effects of NO
      may reduce adverse manifestations related to atherosclerosis during long-term
      therapy.

PMID- 10404844
TI  - Usefulness in predicting coronary artery disease by ultrasonic evaluation of the
      carotid arteries in asymptomatic hypercholesterolemic patients with positive
      exercise stress tests.
AB  - A positive exercise electrocardiogram (ECG) is not infrequent occurrence in
      asymptomatic hypercholesterolemic patients, but the number of false-positive
      tests may be relatively high (50%). Therefore, the ability of a positive stress
      ECG to predict coronary artery lesions is low even in populations with > or =1
      cardiovascular risk factors. To increase the diagnostic value of exercise tests
      for screening asymptomatic individuals, we analyzed whether combined clinical
      parameters with carotid echography would accurately predict coronary
      atherosclerotic lesions by coronary angiography in asymptomatic
      hypercholesterolemic patients with a positive exercise ECG. Seventy-six
      asymptomatic patients (between 35 and 65 years of age) with hypercholesterolemia
      (total plasma cholesterol >6.5 mmol/L or 250 mg/dl) and a positive stress ECG
      were referred for carotid B-mode echography and coronary angiography. Carotid
      echography data were divided into 2 categories: (1) absence of any
      atherosclerotic plaque, or (2) presence of > or =1 arterial plaques. Coronary
      stenosis assessed by coronary angiography was considered to correspond to a > or
      =50% reduction of coronary lumen diameter. Forty-three patients (57%) displayed
      coronary lesions; most (38; 88%) had carotid plaque. Multivariate analysis showed
      that the presence of carotid plaque was significantly associated with coronary
      stenosis (odds ratio 15.2; confidence interval 5.0 to 54.5). In subgroups
      characterized by high frequency of false-positive exercise electrocardiographic
      tests (women and patients with a 10-year predicted risk of coronary artery
      disease [CAD] <15%), none of the patients without carotid plaque exhibited
      coronary lesions. Echographic evaluation of carotid plaque (plaque vs no plaque)
      significantly improved the diagnostic specificity of exercise
      electrocardiography. We conclude that the combination of clinical, electrical,
      and echographic data facilitates cost-effective noninvasive detection of CAD in
      asymptomatic hypercholesterolemic patients.

PMID- 10404843
TI  - Safety of low-density lipoprotein cholestrol reduction with atorvastatin versus
      simvastatin in a coronary heart disease population (the TARGET TANGIBLE trial).
AB  - Reduction in plasma lipids has been recognized as one of the primary
      cardiovascular risk reduction strategies in the secondary prevention of coronary
      heart disease (CHD). The primary end points of TARGET TANGIBLE were the safety
      (adverse events and laboratory measurements) and efficacy (responder rates) of
      therapy with atorvastatin versus simvastatin with the aim of achieving low
      density lipoprotein (LDL) cholesterol lowering to < or =100 mg/dl (2.6 mmol/L). A
      total of 3,748 CHD patients with LDL cholesterol levels > or =130 mg/dl (3.4
      mmol/L) entered a run-in diet phase of 6 weeks without any lipid-lowering drug
      therapy. At the end of the diet phase, 2,856 patients met the lipid criteria and
      were randomized to active treatment for 14 weeks. Patients received 10 to 40 mg
      of either drug in an optional titration design at 2:1 randomization for
      atorvastatin versus simvastatin. Adverse event rates were statistically
      equivalent (p<0.01) for simvastatin (35.7%) and for atorvastatin patients
      (36.3%). Both drugs were well tolerated; <5% of patients in both groups were
      withdrawn due to adverse events. In all, 37 atorvastatin patients (2%) and 27
      simvastatin patients (3%) had serious adverse events. Drug-related side effects
      (elevations in creatine kinase, liver enzymes) occurred in both groups at similar
      rates with 10 atorvastatin patients (0.5%) and 5 simvastatin patients (0.5%)
      presenting confirmed transaminase elevations >3 x the upper limit of the normal
      range. Significantly fewer patients in the atorvastatin group (n = 724) required
      titration to 40 mg compared with the simvastatin group (n = 514) (38% vs. 54%,
      respectively; p<0.001). Atorvastatin resulted in a significantly greater number
      of patients reaching the LDL cholesterol goal than those treated with
      simvastatin, with 67% of atorvastatin patients and 53% of simvastatin patients
      reaching the target LDL cholesterol level of < or =100 mg/dl (2.6 mmol/L)
      (p<0.001). Both atorvastatin and simvastatin are safe for use by patients in the
      secondary prevention of CHD, with patients in both drug groups having similar
      adverse event rates. Despite the use of concomitant medications there was no drug
      induced rhabdomyolysis with either atorvastatin or simvastatin.

PMID- 10404845
TI  - Intra-aortic balloon counterpulsation before primary percutaneous transluminal
      coronary angioplasty reduces catheterization laboratory events in high-risk
      patients with acute myocardial infarction.
AB  - The benefit of intra-aortic balloon counterpulsation (IABC) before primary
      percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial
      infarction in high-risk patients has not been well documented. Consecutive
      patients (n = 1,490) with acute myocardial infarction treated with primary PTCA
      from 1984 to 1997 were prospectively enrolled in an ongoing registry.
      Catheterization laboratory events occurred during or after intervention in 88
      patients (5.9%), including ventricular fibrillation in 59 patients (4.0%),
      cardiopulmonary arrest in 46 patients (3.1%), and prolonged hypotension in 33
      patients (2.2%). Cardiogenic shock was the strongest predictor of catheterization
      laboratory events (odds ratio [OR] 2.18, 95% confidence intervals [CI] 1.58 to
      3.02) followed by low ejection fraction (<30%) (OR 1.51, 95% CI 1.06 to 2.15) and
      congestive heart failure (CHF) (OR 1.45, 95% CI 1.01 to 2.07). IABC used before
      intervention was associated with fewer catheterization laboratory events in
      patients with cardiogenic shock (n = 1 19) (14.5% vs. 35.1%, p = 0.009), in
      patients with CHF or low ejection fraction (n = 119) (0% vs. 14.6%, p = 0.10),
      and in all high-risk patients combined (n = 238) (1 1.5% vs. 21.9%, p = 0.05).
      IABC was a significant independent predictor of freedom from catheterization
      laboratory events (OR 0.48, 95% CI 0.29 to 0.79). These data support the use of
      IABC before primary PTCA for acute myocardial infarction in all patients with
      cardiogenic shock, and suggest that prophylactic IABC may also be beneficial in
      patients with CHF or depressed left ventricular function.

PMID- 10404846
TI  - Noninvasive assessment of the infarct-related coronary artery blood flow velocity
      using phase-contrast magnetic resonance imaging after coronary angioplasty.
AB  - This study assesses infarct-related coronary artery blood flow velocity using
      phase-contrast magnetic resonance imaging (MRI) in patients with reperfused acute
      myocardial infarction (AMI) and compares these results with flow measurements
      obtained nonsimultaneously by intracoronary Doppler ultrasound. MRI examination
      was performed in 17 patients with AMI within 1 to 4 days (mean 2.5 days) after
      direct or rescue coronary angioplasty using a 0.014-in Doppler guidewire. MRI was
      performed on a 1.5-T clinical imager. The fast gradient echo segmented k-space
      phase-contrast pulse sequence was employed during breath-hold. The MRI and
      Doppler parameters of average peak velocity and maximum peak velocity were
      measured. Mean phase contrast MRI average peak velocity was 13.3+/-10.7 cm/s, and
      mean phase-contrast MRI maximum peak velocity was 27+/-16.6 cm/s. Mean Doppler
      average peak velocity was 17.1+/-5.1 cm/s, and mean Doppler maximum peak velocity
      was 35.5+/-10.1 cm/s. At the same anatomic levels, phase-contrast MRI average
      peak velocity correlated significantly to Doppler average peak velocity (r =
      0.52; p<0.006) and Doppler maximum peak velocity (r = 0.42; p<0.03). Phase
      contrast MRI velocity measurements were correlated with the same heterogeneity of
      Thrombolysis In Myocardial Infarction 3 flow velocity observed during Doppler
      examination. Thus, by comparing phase-contrast MRI with invasive intracoronary
      Doppler flow measurements, the measured MRI values showed significant correlation
      with Doppler data. Phase-contrast MRI has the potential to noninvasively quantify
      coronary flow velocity and to evaluate quality of reperfusion in patients with
      AMI after reperfused therapy.

PMID- 10404847
TI  - Prediction of coronary heart disease mortality in blacks and whites: pooled data
      from two national cohorts.
AB  - Statistical models used to predict personal risk of death from coronary heart
      disease (CHD) have been based on studies among white populations. We compared the
      predictive functions derived from black and white men and women, using the pooled
      data of 2 national cohorts: the First National Health and Nutrition Examination
      Survey (NHANES I) Epidemiologic Follow-up Study and the Second National Health
      and Nutrition Examination Survey (NHANES II) Mortality Study. The participants
      included 6,937 white men, 940 black men, 9,202 white women, and 1,463 black women
      aged 30 to 74 years who were free of CHD at baseline. The 2 cohorts were followed
      for 20 and 15 years, respectively. There were no significant differences between
      blacks and whites in the magnitude of the Cox coefficients for most of the
      personal risk factors (i.e., age, systolic blood pressure, serum total
      cholesterol, smoking, and diabetes mellitus status) for men and women. The
      receiver operating characteristic (ROC) analyses, with all risk factors
      considered collectively, suggest that the models have similar ability to rank
      personal relative risk among blacks and whites. The areas under the ROC curve
      were 0.77 and 0.76 for white and black men, respectively, and 0.84 and 0.82 for
      white and black women, respectively. However, the equation derived from white men
      overestimated the 15-year cumulative CHD mortality in black men by about 60%.
      Thus, predictive functions derived from 1 demographic group (e.g., whites) can be
      applied to another subgroup (e.g., blacks) to rank personal risk. However,
      prediction of absolute risk is less accurate.

PMID- 10404848
TI  - Intravascular ultrasonic analysis of plaque characteristics associated with
      coronary artery remodeling.
AB  - We sought to determine the patient and plaque characteristics associated with the
      different forms of arterial remodeling as seen by intravascular ultrasound (IVUS)
      before coronary intervention. Remodeling in response to plaque accumulation may
      occur in the form of compensatory enlargement and/or focal vessel contraction.
      Previous studies report variation in the frequency and form of arterial
      remodeling. We performed preintervention IVUS imaging on 169 patients. Vessels
      were categorized as exhibiting compensatory enlargement or focal contraction if
      the arterial area at the lesion was larger or smaller, respectively, than both
      proximal and distal reference arterial areas; otherwise the artery was considered
      not to have undergone significant remodeling. Calcification was assessed and
      noncalcified plaque density was measured by videodensitometry. Sixty-one of 169
      patients (66 narrowings) (46 men and 15 women, age 56+/-11 years) had adequate
      reference segments. Remodeling occurred in 43 of 66 patients (65%): compensatory
      enlargement in 27 of 66 (41%) and focal contraction in 16 of 66 (24%). Lesions
      with focal contraction had significantly smaller arterial area (13.3+/-3.3 vs.
      18.1+/-7.0 mm2, p = 0.02) and plaque area (9.5+/-2.8 vs 13.7+/-5.5 mm2, p<0.01).
      Cross-sectional stenosis was similar (71+/-9% vs. 75+/-10%, p = NS), as was
      plaque density (p = 0.20), eccentricity, and calcium. Patient age, gender, and
      lesion location were not related to the form of remodeling. Similarly, history of
      diabetes, hypercholesterolemia, or hypertension was not predictive. Smoking was
      the only risk factor associated with focal contraction (p<0.01). Thus, whereas
      compensatory enlargement appears to be the most common form of coronary artery
      remodeling, focal contraction occurs more often in smokers.

PMID- 10404849
TI  - Usefulness of three-dimensional transesophageal echocardiographic imaging for
      evaluating narrowing in the coronary arteries.
AB  - Coronary artery (CA) imaging has relied on invasive techniques for diagnosing
      stenotic lesions. Two-dimensional techniques are limited in obtaining optimal
      longitudinal views of all segments of the CA because of their spatial
      orientations. Three-dimensional echocardiography (3DE) may produce any desired
      cross-sectional views and reconstruct 3-dimensional images from a volumetric data
      set. Its role in CA imaging has not been fully explored. The aim of this study
      was to evaluate the potential of 3DE in visualizing CAs and in assessing the
      severity of stenosis. We performed transesophageal 3DE in 46 patients. Images
      were collected sequentially with the transducer rotated through 180 degrees. From
      the 3DE data sets of all 46 patients, cross-sectional views and 3-dimensional
      images of CAs were reconstructed. For segment-by-segment comparison between CA
      angiography and 3DE in semiquantitative analysis of coronary stenosis, 5 segments
      were defined for the proximal CA tree in 20 patients who underwent both
      procedures. The left main, anterior descending, circumflex, and right CAs were
      visualized from 3DE in 100%, 100%, 98%, and 72%. The available lengths of these
      segments from 3DE were 12+/-4 mm (range 4 to 22), 15+/-6 mm (range 6 to 36), 30+/
      12 mm (range 13 to 60), and 18+/-9 mm (range 6 to 36), respectively. Comparison
      between 3DE and CA angiography in semiquantitative estimation of CA stenosis
      resulted in complete agreement in 83% of the segments (kappa value = 0.7). The
      sensitivity and specificity of 3DE in detecting significant stenosis (> or =50%)
      were 84% and 97%. In conclusion, transesophageal 3DE allows imaging of the
      proximal CA, detection of stenotic lesions, and estimation of the severity of
      stenosis.

PMID- 10404850
TI  - A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic
      stable angina pectoris that is responsive to conventional antianginal agents.
      Ranolazine Study Group.
AB  - We assessed efficacy and safety of a new anti-ischemic agent, ranolazine, during
      a randomized, double-blind, placebo-controlled crossover study. In the qualifying
      phase, we withdrew at least 1 antianginal drug from the drug regimen of 312
      patients with chronic stable angina while they took placebo. After exercise time
      had shortened by > or =1.0 minute, we randomly assigned patients to receive
      either immediate-release ranolazine in 3 dosing regimens or placebo during each
      treatment period. After each week of treatment, we measured exercise tolerance
      and ranolazine plasma concentrations at both peak and trough. All exercise
      parameters significantly (p< or =0.02) improved (intention-to-treat analysis)
      with ranolazine (all regimens combined) at mean peak plasma concentrations
      ranging from 1,576 to 2,492 ng/ml compared with placebo without differences in
      double product. Although similar trends persisted at mean trough, plasma
      concentrations (range 275 to 602 ng/ml), only the time to 1.0 mm ST-segment
      depression remained statistically significant. In conclusion, immediate-release
      ranolazine is effective and well tolerated. However, this immediate-release short
      acting formulation with this dosing regimen is not adequate for continuous
      protection. Either larger or more frequent doses or a sustained-release
      formulation would be required for clinical use.

PMID- 10404851
TI  - Relation of minor cardiac troponin I elevation to late cardiac events after
      uncomplicated elective successful percutaneous transluminal coronary angioplasty
      for angina pectoris.
AB  - There is little information about the relation between mild cardiac troponin I
      (cTn-I) increase after coronary interventions and late outcome. We therefore
      focused on the long-term outcome and the clinical, morphologic, and procedural
      correlates of elevation of cTn-I compared with cardiac troponin T, creatine
      kinase (CK), CK-MB activity and mass, and myoglobin in 105 patients with
      successful elective percutaneous transluminal coronary angioplasty (PTCA) for
      stable or unstable angina. Patients with myocardial infarction and those with
      unstable angina who had a detectable increase in serum markers before PTCA were
      excluded. Markers were measured before and after the procedure and for 2 days.
      Patients were followed up to record recurrent angina, myocardial infarction,
      cardiac death, repeat PTCA, or elective coronary artery bypass graft surgery.
      Procedure success was achieved in all cases. Elevation in cTn-I (> or =0.1
      microg/L) was observed in 23 of 105 patients (22%) (median peak: 0.25 microg/L);
      18% had cardiac troponin T (cTn-T) release (> or = 0.1 microg/L, median peak
      0.21); 11.4% CK-MB mass (> or =5 microg/L), and 7.6% myoglobin (> or =90
      microg/L) release. Five and 2 patients had elevated CK and CK-MB activity,
      respectively. Fourteen of 18 patients with cTn-T elevation had a corresponding
      elevation in cTn-I (kappa 0.68; p = 0.001). Patients positive for cTn-I had more
      unstable angina (p = 0.042) and heparin before PTCA (p = 0.046), and had longest
      total time (p = 0.004) and single inflation (p = 0.01). By multivariate logistic
      regression, predictors of postprocedure cTnI elevation were maximum time of each
      inflation (odds ratio 9.2; p = 0.0012), type B lesions (odds ratio 6.6; p =
      0.013), unstable angina (p = 0.041), and age > or =60 years (p = 0.032). Clinical
      follow-up was available in 103 patients (98%) (mean 19+/-10 months). Kaplan-Meier
      survival analysis showed that cTn-I elevation was not an important correlate of
      cardiac events (p = 0.34, by log-rank analysis). The incidence of recurrent
      angina, myocardial infarction, cardiac death, and repeat revascularization after
      12 months was not different in patients positive or negative for cTn-I. We
      conclude that cTn-I elevation after successful PTCA is not associated with
      significantly worse late clinical outcome. Levels of cTn-I allow a much higher
      diagnostic accuracy in detecting minor myocardial injury after PTCA compared with
      other markers, but there is no association with periprocedural myocardial cell
      injury and late outcome when cTn-I and other markers are considered.

PMID- 10404853
TI  - Effect of estrogen on ventricular repolarization in menopausal patients with
      syndrome X and effects of nicorandil.
AB  - Syndrome X may exhibit myocardial ischemia and is associated with estrogen
      deficiency. We sought to assess the possible role of estrogen in modulating the
      characteristics of ventricular repolarization by measurement of QT interval and
      QT dispersion in patients with syndrome X. We prospectively used 12-lead
      electrocardiograms and echocardiograms to study 52 consecutive menopausal
      patients with syndrome X (group subdivided into subgroup 1a, 32 patients who
      received nicorandil, an adenosine triphosphate-sensitive potassium ion channel
      opener; subgroup 1b, 20 patients without dosing nicorandil). For comparisons, a
      control group consisted of age-matched and echocardiographic left ventricular
      mass index-matched 20 healthy menopausal women. Baseline QT intervals and QT
      dispersion were similar between the 2 groups (subgroup 1a and controls). After
      administration of estrogen, there was significant prolongation of maximal QTc
      intervals and reduction in QT or QTc dispersion compared with baseline in
      patients with syndrome X. The changes returned to baseline after nicorandil
      administration. Control subjects had no changes with administration of estrogen.
      Thus, estrogen modulates characteristics of ventricular repolarization, which
      appears to be mediated by blocking adenosine triphosphate-sensitive potassium ion
      channel. The effects of estrogen on QT intervals may be different between
      menopausal women with or without syndrome X.

PMID- 10404852
TI  - Correlation of preoperative myocardial function, perfusion, and metabolism with
      postoperative function at rest and stress after bypass surgery in severe left
      ventricular dysfunction.
AB  - Previous studies of dobutamine echocardiography (DE) and positron emission
      tomography (PET) showed similar accuracy for predicting improvement in resting
      wall motion after revascularization, although limited direct comparative data are
      available. We sought to compare the relative accuracy of detecting contractile
      reserve, ischemia, perfusion, and myocardial metabolism for predicting functional
      recovery after coronary bypass surgery in 94 consecutive patients (aged 63+/-11
      years) with chronic coronary disease and depressed left ventricular function
      (ejection fraction 28+/-5%). PET imaging comprised rest and dipyridamole stress
      myocardial perfusion images, with fluorodeoxyglucose to define metabolism
      perfusion mismatch. A standard dobutamine-atropine stress was used, with
      evaluation of low- and peak-dose echocardiographic responses. Regional function
      was assessed after 13+/-16 weeks at rest in 68 patients who underwent isolated
      coronary bypass operation without evidence of perioperative infarction, and at
      rest and stress in a subgroup of 29 patients. Concordance between methods for
      evaluating abnormal segments (ischemic, viable, and scar) and accuracy of both
      tests for predicting improvement in regional function were identified.
      Concordance between PET and DE for identifying viable or nonviable myocardium was
      63% using a 16-segment model. For predicting improved resting function after
      surgery, the sensitivity of PET (84%) was superior to DE (69%, p<0.001), but DE
      was more specific (78% vs. 37%, p<0.0001) and more accurate (75% vs. 53%,
      p<0.001) in predicting recovery at rest. Analysis of postoperative recovery of
      segmental function during stress also showed the specificity of DE to exceed that
      of PET (89% vs. 32%, p<0.001). The accuracy of DE was enhanced by evaluation of
      function during stress (86%, p<0.001), but this was not altered with PET (52%, p
      = NS). Thus, PET is more sensitive than DE in predicting functional recovery, but
      DE is more specific than PET. Evaluation of left ventricular functional recovery
      during stress may be preferable to assessment at rest.

PMID- 10404854
TI  - Comparison of acebutolol with and without hydrochlorothiazide versus carvedilol
      with and without hydrochlorothiazide in black patients with mild to moderate
      systemic hypertension.
AB  - In the present study, we assessed the antihypertensive efficacy of acebutolol 200
      mg versus carvedilol 25 mg once daily, given as monotherapy for 3 months to 40
      black patients (20 patients in each group, mean age 53+/-10 years, 24 women) with
      mean blood pressure (BP) during the day >90 and <110 mm Hg. Patients in whom
      blood pressure could not be controlled took medication, which was increased at 3
      month intervals as follows: step 2, acebutolol 200 mg or carvedilol 25 mg plus
      hydrochlorothiazide 12.5 mg once daily; step 3, acebutolol 400 mg or carvedilol
      50 mg plus hydrochlorothiazide 25 mg once daily. Overall, significant but modest
      BP reduction was achieved with both beta blockers at 3 months. In the acebutolol
      group, 24-hour BP decreased from 142+/-15/94+/-7 mm Hg to 138+/-16/89+/-8 mm Hg
      (p<0.005 for diastolic BP at 3 months vs baseline). Mean day BP decreased from
      145+/-15/98+/-5 mm Hg to 140+/-14/93+/-7 mm Hg (p<0.05 for systolic BP and
      p<0.0005 for diastolic BP at 3 months vs. baseline). In the carvedilol group, 24
      hour BP decreased from 145+/-11/93+/-6 to 138+/-16/87+/-9 mm Hg (p<0.05 for
      systolic BP and p<0.005 for diastolic BP at 3 months vs baseline). Mean day BP
      decreased from 149+/-10/99+/-5 to 141+/-16/91+/-87 mm Hg (p<0.05 for systolic BP
      and p<0.0005 for diastolic BP at 3 months vs baseline). At 12 months, most
      patients required combination therapy to achieve BP control. The control (mean
      day diastolic BP <90 mm Hg) and response (mean day diastolic BP decrease > or =10
      mm Hg) rates at 12 months were 59% and 82% in the acebutolol and 78% and 78% in
      the carvedilol groups, respectively. In conclusion, acebutolol or carvedilol in
      combination with hydrochlorothiazide, rather than acebutolol or carvedilol alone,
      should be considered as first-line antihypertensive therapy in black patients
      with mild to moderate hypertension.

PMID- 10404855
TI  - Potentials and limitations of the Valsalva maneuver as a method of
      differentiating between normal and pseudonormal left ventricular filling
      patterns.
AB  - Pseudonormalization of the left ventricular (LV) filling pattern complicates the
      Doppler echocardiographic assessment of LV diastolic function in patients with
      heart failure. The Valsalva maneuver is recommended as a method of
      differentiating between normal and pseudonormal LV filling patterns. However,
      neither a standardized Valsalva maneuver nor a healthy control population has
      been studied so far. Therefore, we studied changes in mitral flow velocities in
      response to a standardized Valsolva maneuver in 55 heart failure patients with LV
      systolic dysfunction and 35 control subjects. The study subjects were instructed
      to elevate their intrathoracic airway pressure to 40 mm Hg for 10 seconds.
      Doppler mitral flow velocities were recorded at rest and during the Valsalva
      maneuver. All study subjects had comparable decreases in early mitral flow
      velocity, but mitral flow velocity at atrial contraction increased rather than
      decreased in patients with a restrictive LV filling pattern. This markedly
      abnormal response might be useful in detecting elevated filling pressures and
      pseudonormal filling patterns. Furthermore, in all but 2 patients and all control
      subjects with an E/A ratio between 1 and 2, inversion of the E/A ratio occurred.
      This proves that, in contrast to previous beliefs, inversion of the E/A ratio
      does not differentiate between normal and pseudonormal LV filling patterns.

PMID- 10404857
TI  - Electrocardiographic criteria for predicting the culprit artery in inferior wall
      acute myocardial infarction.
AB  - Two patterns of the QRS complex in the lateral lead aVL on the admission
      electrocardiograms of patients with inferior wall acute myocardial infarction
      (AMI) were correlated with the culprit artery. S/R wave ratio < or =1/3 with ST
      depression < or =1 mm was found to be a sensitive and specific marker for left
      circumflex artery AMI, whereas S/R-wave ratio >1/3 with ST-segment depression >1
      mm was suggestive of right coronary artery AMI.

PMID- 10404856
TI  - Prognostic value of diastolic filling parameters derived using a novel image
      processing technique in patients > or = 70 years of age with congestive heart
      failure.
AB  - Conventional echocardiographic characterization of diastolic function requires
      manual analysis of Doppler E-and A-wave amplitudes, deceleration times,
      isovolumic relaxation times, and pulmonary venous flow patterns. Mathematic
      modeling of the suction pump activity of the heart permits characterization of
      diastolic function through model-based image processing, which relies solely on
      transmitral Doppler images. This automated method uniquely specifies the entire E
      wave contour using 3 parameters (x(o), k, and c) that determine E-wave amplitude,
      width, and rate of decay. Moreover, the index beta = c2 - 4k, reflecting the
      balance between chamber viscosity and stiffness/recoil, represents a novel
      parameter for characterizing diastolic function. We analyzed Doppler E waves from
      39 patients (mean age 79 years, 61% women, mean ejection fraction 47%) using the
      model-based image processing technique. A value of beta <-900 was selected as
      indicative of severe diastolic dysfunction. Of 17 subjects with beta <-900, 8
      (47%) were no longer alive at 1 year. Of 22 subjects with beta >-900, all were
      alive (p = 0.001). The index beta, dichotomized at <-900, had a predictive
      accuracy of 0.769 (30 of 39), a negative predictive value of 1.0 (22 of 22
      alive), and a positive predictive value of 0.471 (8 of 17 deceased) for 1-year
      vital status. Of 14 subjects with deceleration time < or =160 ms, 5 (36%) were
      deceased at 1 year, whereas for deceleration time >160 ms, 22 of 25 patients were
      alive (p = NS). Of 16 subjects with ejection fraction <45%, 6 (38%) were deceased
      at 1 year. Of 23 subjects with ejection fraction >45%, 21 were alive at 1 year (p
      = 0.074). On multivariate analysis, beta dichotomized at -900 was the strongest
      independent predictor of 1-year mortality. We conclude that evaluation of
      diastolic function using model-based image processing provides valuable
      prognostic information in elderly patients with heart failure.

PMID- 10404858
TI  - Effectiveness of coronary stent deployment without predilation.
AB  - The feasibility of coronary stenting without predilation is demonstrated in 240
      patients. In all, 249 stents were placed. Primary implantation was successful in
      93% of cases. In 17 lesions the stents could not be advanced through the stenotic
      lesion. The unexpanded stents were removed through the guiding catheter, and
      stenting was performed after prediction. Minor complications (side branch
      compromise and intimal dissection), which were successfully treated, occurred in
      26 patients (10.6%).

PMID- 10404859
TI  - Effects of troglitazone on frequency of coronary vasospastic-induced angina
      pectoris in patients with diabetes mellitus.
AB  - This study investigates the effects of troglitazone, an insulin sensitizer, on
      the clinical manifestation of coronary vasospastic angina pectoris in patients
      with diabetes mellitus. Troglitazone reduces frequency of angina pectoris and
      improves endothelial function.

PMID- 10404860
TI  - Frequency of lipid-lowering therapy after a coronary event in Helsinki, Finland.
AB  - The results from a survey in Finland suggest an important treatment gap of lipid
      lowering medications. Patients whose coronary artery disease was diagnosed before
      1995 were less likely to be on lipid therapy than patients with a more recent
      diagnosis.

PMID- 10404861
TI  - Coronary artery stent placement in patients with variant angina refractory to
      medical treatment.
AB  - We performed a prospective study to establish the efficacy of coronary stent
      placement in a highly selected group of patients with focal coronary artery spasm
      in whom anginal attacks could not be prevented by full medical therapy. The
      results of this study indicate that intracoronary stent placement may represent
      an alternative and feasible treatment for patients with vasospastic angina
      refractory to aggressive medical therapy.

PMID- 10404862
TI  - Circadian variation of idiopathic ventricular tachycardia originating from right
      ventricular outflow tract.
AB  - We determined circadian variation of isolated ventricular premature complexes
      (VPCs), 2 to 4 consecutive VPCs, and ventricular tachycardia (5 consecutive VPCs)
      originating from the right ventricular outflow tract in patients without apparent
      structural heart diseases. There was apparent circadian variation with 2
      prominent peaks for these ventricular arrhythmias, and blockade abolished
      ventricular tachycardia and attenuated the circadian variation of consecutive
      VPCs.

PMID- 10404863
TI  - Septal Q waves in surface electrocardiographic lead V6 exclude minimal
      ventricular preexcitation.
AB  - Electrocardiograms of 37 consecutive patients with minimal preexcitation (i.e.,
      PR >120 ms, QRS <120 ms) were compared before and after ablation with
      electrocardiograms of 37 age-matched patients with atrioventricular nodal
      reentrant tachycardia. The presence of a septal Q wave could be used to exclude
      minimal preexcitation with a high degree of reliability in both patients and
      controls before and after radiofrequency ablation.

PMID- 10404864
TI  - Effect of intravenous magnesium on heart rate and heart rate variability in
      patients with chronic atrial fibrillation.
AB  - The present double-blind, placebo-controlled study investigated the effects of
      intravenous magnesium on heart rate and rate variability in 30 patients with
      chronic atrial fibrillation. During standardized conditions, intraindividual
      variation in heart rate and rate variability was low in patients with chronic
      atrial fibrillation and magnesium had no effect on heart rate or rate
      variability.

PMID- 10404865
TI  - The potential costs of upcoding for heart failure in the United States.
AB  - Miscoding of hospital discharge diagnoses for heart failure in older adults is
      common, and the direction favors high levels of reimbursement to hospitals. The
      potential costs to Medicare may be as high as $993 million per year.

PMID- 10404866
TI  - Clinical, anatomic, and echocardiographic characteristics of aneurysms of the
      mitral valve.
AB  - This study describes the clinical, anatomic, echocardiographic, and Doppler
      features of 13 patients with mitral valve aneurysms. Eleven patients had
      definitive criteria for infective endocarditis. Transesophageal echocardiography
      was superior to conventional echocardiography in detecting and assessing
      aneurysms. Patients with heart failure required surgery. Echocardiographic
      detection of this lesion should not be, by itself, an immediate surgical
      indication.

PMID- 10404867
TI  - Initial results and clinical follow-up after balloon angioplasty for native
      coarctation.
AB  - This study describes the initial hemodynamic results and early to late clinical
      follow-up, including magnetic resonance imaging and exercise testing, following
      balloon angioplasty for native coarctation of the aorta. We advocate this
      approach as an alternative to surgical intervention in select patients based on
      age, aortic arch anatomy, or in those patients who have coexisting cardiac
      defects that are amenable to transcatheter intervention.

PMID- 10404868
TI  - Acute effects of DDD pacing in patients with pulmonary infundibular stenosis.
AB  - We evaluated acute effects of DDD pacing (right atrium sensed and left ventricle
      paced) in 3 patients with pulmonary infundibular stenosis and found a decrease in
      dynamic right ventricular outflow gradient in all of them. It appears that acute
      temporary DDD pacing may decrease the dynamic obstruction of the right
      ventricular outflow tract in these patients, probably because of asynchronous
      contraction of the right ventricle induced by pacing from the left ventricular
      apex, with contraction of infundibular portion being delayed.

PMID- 10404869
TI  - Benefits and risks due to animal serum used in cell culture production.
AB  - Infection with bovine viral diarrhoea virus (BVDV) and other viruses is frequent
      in the bovine population. In utero infection leads to virus and antibody
      contamination of foetal and other serum used in cell culture production. The use
      of contaminated cells for vaccine production may result in contaminated vaccines,
      which may lead to seroconversion or disease in the vaccinated animal.
      Contaminated serum or cell cultures may also interfere with the diagnosis of
      viral infections. Methods for the detection of BVDV and other viruses in serum,
      cell cultures, seed viruses and vaccines at the CVB-L, and the frequency of
      detection are described. Reasons for continued use of serum in cell culture
      production, and the risks of using serum, are discussed.

PMID- 10404870
TI  - Risks of virus transmission associated with animal sera or substitutes and
      methods of control.

PMID- 10404871
TI  - Why do we still use serum in the production of biopharmaceuticals?
AB  - Eukaryotic cells, in general, require serum for growth in vitro. Serum is a
      complex mixture of a large number of constituents, so the addition of serum
      introduces an ambiguous factor into cell cultivation. However, many commercially
      available sera are of a high uniform quality. Of these, foetal bovine serum is
      the most frequently used and is capable of supporting the growth of a wide
      variety of eukaryotic cells. However, with the identification of essential growth
      factors and nutrients required by different cells, several very effective serum
      free media have been formulated. The use of these serum-free media is limited to
      a very narrow range of cells. Regulatory constraints generally make it
      impractical and uneconomic to alter existing biopharmaceutical production
      processes in which serum is used as a raw material.

PMID- 10404872
TI  - Transmissible spongiform encephalopathy agents and animal sera.

PMID- 10404873
TI  - BSE transmission studies with particular reference to blood.
AB  - Tissue infectivity in BSE has been comprehensively investigated in cattle with
      natural BSE and during the incubation period in an experimental pathogenesis
      study in which cattle were challenged orally with infected cattle brain from
      natural cases. In natural cases of BSE in cattle, infectivity has been found only
      in the CNS, (the brain, the spinal cord and retina). No infectivity has been
      found in about 50 other tissues including bone marrow, clotted blood, buffy coat,
      serum or foetal calf serum. In the pathogenesis study in which clinical disease
      was first detected at 35 months post-infection (39 months of age), infectivity
      has not been found in blood or any assayed component of blood. Experimental
      parenteral challenge of cattle and mice in three separate experiments with (i) a
      pool of five brains, (ii) a pool of five spleens and (iii) a pool of lymph nodes
      from five cattle is incomplete. However, whereas the brain has transmitted
      disease to both species (in cattle even when diluted about one million times)
      neither the spleen pool nor the lymph node pool has transmitted disease to
      either, although the cattle study is incomplete. These experiments have also
      shown that cattle can detect about 1000 times less infectivity/g than can mice.
      No infectivity has ever been detected in the blood or any component of blood in
      natural scrapie of sheep and goats, natural BSE of cattle or experimental BSE of
      cattle.

PMID- 10404874
TI  - Bovine sera used in the manufacture of biologicals: current concerns and policies
      of the U.S. Food and Drug Administration regarding the transmissible spongiform
      encephalopathies.
AB  - Since 1993, consistent with its statutory responsibility to ensure that regulated
      products are safe, pure, and free of << extraneous organisms, >> the United
      States Food and Drug Administration (FDA) has requested that, with certain
      exceptions, bovine-derived materials from animals born in or residing in
      countries where bovine spongiform encephalopathy has occurred, should not be used
      to manufacture products intended for humans. FDA's Center for Biologics
      Evaluation and Research (CBER) has specifically recommended that serum used to
      produce biologicals be obtained from sources << certified to be free from
      contaminants and adventitious agents, such as the agent responsible for the
      production of Bovine Spongiform Encephalopathy. >> The United States Department
      of Agriculture (USDA) has prohibited importation of such serum for use in
      products. FDA staff are aware that bovine blood, including foetal blood, and
      placental tissues and fluids that might contaminate foetal serum have not been
      found to contain the infectious agent of BSE, and that those tissues are
      considered by most authorities to have little risk for transmitting disease to
      humans or animals. However, studies of BSE have been limited in size and
      sensitivity, and several experimental studies of scrapie and CJD in rodents found
      their blood to be infectious. In addition, a recent unpublished study of BSE
      (requiring confirmation) reported finding infectivity in the bone marrow of
      cattle. Possible transmission of BSE from cows to calves, although unlikely to
      constitute a major mode for maintaining the BSE outbreak, has also not been
      rigorously ruled out. Considering the special nature of biological products,
      especially of vaccines intended for widespread use in children, it seems prudent
      for U.S. regulatory authorities to continue current conservative policies that
      discourage or prohibit the use of bovine serum from countries with BSE.

PMID- 10404875
TI  - Bovine polyomavirus, a frequent contaminant of calf sera.

PMID- 10404876
TI  - Detecting viruses in sera: methods used and their merits.

PMID- 10404877
TI  - Quality control of bovine serum used for vaccine production.

PMID- 10404878
TI  - Serum supply: policies and controls operating in New Zealand.
AB  - This paper surveys the legislation and policies governing serum supply in force
      in New Zealand at present, and outlines the regulatory controls, both direct and
      indirect, associated with the production of animal sera. Direct controls are
      concerned with the welfare of the donor animals and the production and processing
      of the product. Controls are also applied to preserve New Zealand's animal health
      status through import controls of animals and animal products. The Animal Health
      Surveillance Programme also monitors the animal health status of New Zealand. The
      level of assurances and integrity represented in this regulatory system has led
      to an increase in recent years in the demand for animal-derived materials that
      are free from major animal diseases.

PMID- 10404879
TI  - Bovine serum: reducing the variables through the use of donor herds.
AB  - Biological materials are variable by their very nature. Serum in particular is a
      complex mix of substances and may contain adventitious agents. Serum for
      pharmaceutical use is controlled on a batch to batch basis given that each batch
      may have differing properties. Control points for slaughterhouse obtained bovine
      and foetal bovine serum exist with the disease status and disease surveillance of
      the country of origin, veterinary inspection for clinical disease, collection
      methods and post collection quality control. With these control points many
      batches of commercially available serum are contaminated with viruses such as
      BVD. The use of donor serum provides a mechanism to extend Good Manufacturing
      Practice principles back to the farm environment giving the manufacturer the
      ability to increase control on production parameters in the donor animal such as
      disease and specific antibody status, genetic type and history, age, diet,
      treatments and origin of feed. As well as providing a secure supply of serum for
      manufacture, donor herds provide added traceability and give the opportunity for
      in vivo manipulation of the serum and specialised selection of the animals for
      specific applications with more consistent reproducibility of performance. The
      BSE crisis of the last 10 years has highlighted the added control that donor
      serum producers can exert: Many producers of donor serum applied ruminant feed
      bans on their animals ahead of nation-wide bans in their own countries. SPF donor
      herds can be set up in several ways and the purchaser should make themselves
      familiar with the methods used. SPF herds with accompanying seronegative status
      allow quality control testing of product free from the interference of specific
      antibodies. Such specific antibody freedom may also allow better growth of
      viruses for vaccine manufacture.

PMID- 10404880
TI  - Virus removal by filtration.
AB  - Advances in membrane technology have allowed the expansion of the size-exclusion
      removal principle to viruses of concern in the processing of pharmaceutical drug
      products derived from biological fluids and cell-culture techniques. Direct flow-
      and cross-flow filters are complementary techniques for virus removal and may be
      used either independently or as an adjunct to other virus clearance methods.
      Representative virus titre reduction data for microfiltration and ultrafiltration
      membranes are presented along with a validation model using bacteriophages as
      challenge viruses. Non-destructive filter integrity tests before and after
      filtration and a stringent process validation regime are applied to enhance
      product safety.

PMID- 10404881
TI  - Gamma irradiation of bovine sera.

PMID- 10404882
TI  - Efficient inactivation of viruses and mycoplasma in animal sera using UVC
      irradiation.
AB  - Transmission of viruses by animal sera represents a considerable risk for humans
      and animals particularly when the serum is used for the production of
      pharmaceutical products such as vaccines. Procedures applicable for inactivating
      large numbers of different viruses, both enveloped and non-enveloped, are
      therefore mandatory. For this purpose we have developed and validated UVC
      irradiation as the virus-inactivation procedure of choice for serum to be used in
      an industrial setting. Spiking experiments in foetal calf serum (FCS) were
      performed by independent contract laboratories and revealed constantly high
      clearance rates for various viruses such as bovine parvovirus, parainfluenza type
      III virus, bovine diarrhoea virus, foot-and-mouth disease virus and different
      forms of mycoplasmas. UVC-treated sera maintained their growth-promoting
      activities for various cell types (MRC-5, Vero, CHO). Conventional growth curves
      generated in the presence of 10% and 1% UVC-treated FCS differed only slightly
      from controls, indicating the lack of significant damage during UVC exposure.
      Experiments using a sensitive photometric-based acid phosphatase assay (APA),
      which correlates well with the more tedious cell counting procedure, confirmed
      these findings even in the presence of minimal serum requirements. UVC treatment
      of animal sera appears advantageous compared to currently recommended
      inactivation procedures, such as Gamma irradiation, for at least three reasons:
      (i) it possesses a high inactivation capacity for parvoviruses, a pathogen that
      cannot be destroyed easily by conventional methods; (ii) it causes no noticeable
      impairment in cell growth and (iii) it can be performed in a controlled manner at
      the production site.

PMID- 10404883
TI  - A universal virus inactivant for decontaminating blood and biopharmaceutical
      products.
AB  - Removal of virus infectivity from blood and biopharmaceutical products prepared
      from blood is an issue of considerable importance. Irrespective of the methods
      that are chosen it is vital that the biological activity of the product is not
      impaired. For blood and unfractionated plasma or serum, the problem is even more
      challenging. Selective inactivation of the genome is the key step in the
      preparation of killed virus vaccines. Imines have been used for more than 30
      years for the preparation of inactivated foot-and-mouth disease virus vaccines
      without any evidence of survival of virus infectivity. Moreover, the
      immunogenicity of the virus is unimpaired. Viruses belonging to all the
      recognised families can be inactivated by imines. The biological properties of
      several proteins, including the cell growth-promoting factors in calf serum, are
      not impaired using conditions which ensure the inactivation of > 10(15)
      infectious units of poliovirus and foot-and-mouth disease virus (FMDV). Moreover,
      both viruses can be inactivated by imines at 4 degrees C, thus providing a method
      for removing infectivity from protein preparations which are unstable at higher
      temperatures. The mechanism by which FMDV is inactivated has been studied. We
      found that the RNA extracted from the virus after inactivation at 4 degrees C was
      not degraded and contained no hidden breaks but nevertheless was non-infectious.
      However, it could be amplified by PCR using primers corresponding to the gene
      coding for a portion of the viral RNA polymerase, but not from that coding for
      VP1, one of the structural proteins, showing that alteration of a base or bases
      had occurred in that region.

PMID- 10404884
TI  - Serum and serum substitutes: virus safety by inactivation or removal.

PMID- 10404885
TI  - Viral validation design of a manufacturing process.
AB  - In many cases, the viral safety evaluation of biological products does not derive
      solely from direct testing for the presence of contaminants, but also from the
      demonstration that the manufacturing process is able to inactivate/eliminate
      them. This is achieved by the voluntary addition of a virus load at various steps
      of the process and the evaluation of viral reduction during the subsequent steps.
      The major difficulty for such viral validation studies is less to calculate a
      reduction factor for each step than to identify clearly and demonstrate the
      contribution of each in-process parameter to the reduction. Consequently, the
      first approach consists of the identification of all the parameter which may
      influence viral reduction. The design of the viral validation needs to take this
      inventory into account and control experiments must be carried out in parallel
      with the main spiking experiment, i.e. mainly to: (i) hold controls with and
      without the biological intermediate product; (ii) control experiments with each
      individual inactivating/partitioning parameter; (iii) control experiment without
      stabilizer if necessary. In addition to these process controls, cytotoxicity and
      interference experiments will allow the use of each in vitro infectivity assay
      for the testing of processed samples to be validated. For a viral inactivation
      step, the kinetics of inactivation will be studied and the data will show: (i) a
      progressive decrease of the viral load over time. If the decrease is too rapid to
      plot the kinetics, the direct relation between the inactivation and the
      inactivating parameter has to be demonstrated in complementary experiments; (ii)
      the reduction obtained when in-process limits are used and (iii) the different
      phases of inactivation when they exist. Moreover, it is pertinent to evaluate for
      each treatment the margin of safety derived from the treatment time on the one
      hand and the strength of the inactivating parameter on the other.

PMID- 10404886
TI  - Elimination of serum from cell culture medium.
AB  - Growth of continuous cell lines for preparing biopharmaceuticals in the absence
      of animal serum has been attempted by many organizations to improve process and
      product quality, prevent exposure to adventitious agents, and reduce costs.
      Literature surveys suggest that substantial academic studies on serum-free medium
      have been pursued for many decades, with varying levels of success for different
      cell types and cell lines in terms of achieving cell growth while retaining cell
      function. Industrial research proceeded for at least three decades. Recent work
      with CHO cells and with some hybridomas has been successful in providing the
      basis for serially propagating cells on a large scale in suspension in the total
      absence of serum, while preserving the ability to prepare biopharmaceuticals. In
      some cases, this can be achieved not only without serum, but also without the use
      of other animal-derived proteins.

PMID- 10404887
TI  - The development, benefits and disadvantages of serum-free media.
AB  - Serum-free culture is used routinely for many cell types, especially if
      transformed, e.g. CHO, hybridoma and recombinant myeloma cell lines. Serum-free
      medium reduces operating costs and process variability, and removes a potential
      source of infectious agents. The removal of the components of serum and the
      elimination of other animal-derived raw materials are proving more challenging.
      Nevertheless, careful risk/benefit analyses to target R&D toward critical
      materials is presenting several solutions in this area. A risk/benefit analysis
      is required for each component replacing serum or serum derivatives. Specific
      serum proteins used in serum-free media can be eliminated. At present large scale
      protein-free processes are not routine.

PMID- 10404888
TI  - Safety issues of animal products used in serum-free media.
AB  - The development of media free of serum and animal or human protein is of utmost
      importance for increasing the safety of biologicals produced for therapy and
      vaccination. The main drawback associated with the use of serum or animal-derived
      substances for animal cell technology is the potential introduction of
      contaminants (adventitious agents) into the process and thus potentially into the
      final product. This fact led to an increased effort to replace serum-containing
      with serum-free media. In most cases, these media are supplemented with purified
      proteins, peptones, or hydrolysates, mainly of animal or human origin. Although
      such serum-free media are more defined than serum-containing media, the risk of
      the introduction of viruses by using animal-derived substances is still present,
      signifying that only a complete replacement of animal-derived substances by non
      animal-derived products leads to a relatively safe serum-free medium. The
      potential replacement of these animal/human-derived substances by those of non
      animal origin (e.g. plant origin) will be discussed. In several examples, the
      potential of serum-free media free of any animal-derived component in supporting
      cell growth and production of biologicals will be presented. In this context, the
      risk of using non-animal-derived substances in serum-free media for animal cell
      technology will be discussed with respect to classically used cell culture media.

PMID- 10404889
TI  - An animal origin perspective of common constituents of serum-free medium
      formulations.
AB  - Serum-free formulations may be << re-engineered >> to eliminate traditional
      protein constituents and replace their biological function with non-protein
      substitutes. Non-protein additives may also be obtained from animal sources.
      Nutrient formulations totally free of exogenous protein and containing no
      materials of animal origin may be designed for high density cell culture and
      biological production. Cell-culture medium production requires (i) strict vendor
      qualification and raw material specifications; (ii) scrupulous maintenance of
      media kitchen facility and equipment; (iii) monitoring of process water; (iv) air
      handling systems and technical personnel; (v) clearly-defined manufacturing
      protocols to ensure correct formulation and dispensing and (vi) validated
      sanitization processes to guard against cross-contamination within a multi-use
      facility.

PMID- 10404890
TI  - Summary and conclusion. Animal sera, animal sera derivatives and substitutes used
      in the manufacture of pharmaceuticals.

PMID- 10404891
TI  - A piece of my mind. Master class.

PMID- 10404892
TI  - "If I work hard(er), I will be loved." Roots of physician stress explored.

PMID- 10404893
TI  - Mentally healthy men at midlife.

PMID- 10404894
TI  - Debate revived on hepatitis B vaccine value.

PMID- 10404895
TI  - Spain leads world in organ donation and transplantation.

PMID- 10404896
TI  - From the Food and Drug Administration.

PMID- 10404897
TI  - From the Centers for Disease Control and Prevention. Cluster of HIV-positive
      young women--New York, 1997-1998.

PMID- 10404898
TI  - From the Centers for Disease Control and Prevention. Blastomycosis acquired
      occupationally during prairie dog relocation--Colorado, 1998.

PMID- 10404899
TI  - The law, the AMA, and partial-birth abortion. American Medical Association.

PMID- 10404900
TI  - The law, the AMA, and partial-birth abortion. American Medical Association.

PMID- 10404901
TI  - The law, the AMA, and partial-birth abortion. American Medical Association.

PMID- 10404902
TI  - The law, the AMA, and partial-birth abortion. American Medical Association.

PMID- 10404903
TI  - The law, the AMA, and partial-birth abortion. American Medical Association.

PMID- 10404904
TI  - The law, the AMA, and partial-birth abortion. American Medical Association.

PMID- 10404905
TI  - The law, the AMA, and partial-birth abortion. American Medical Association.

PMID- 10404906
TI  - Inappropriate secretion of natriuretic peptides in a patient with a cerebral
      tumor.

PMID- 10404907
TI  - Liver enzyme elevations in patients treated with traditional Chinese medicine.

PMID- 10404908
TI  - Zanamivir in the prevention of influenza among healthy adults: a randomized
      controlled trial.
AB  - CONTEXT: The neuraminidase inhibitor zanamivir, a sialic acid analog administered
      directly to the respiratory tract, has been demonstrated in clinical studies to
      be effective in treatment of type A and B influenza. It has also been shown to
      prevent influenza infection and disease in an experimental model. OBJECTIVE: To
      examine the efficacy of zanamivir, administered once daily, in the prevention of
      influenza infection and disease. DESIGN: Double-blind, randomized, placebo
      controlled trial. SETTING: Two midwestern university communities. PARTICIPANTS: A
      total of 1107 healthy adults (mean age [range], 29 [18-69] years) were recruited
      in November 1997, before the influenza season. INTERVENTION: At the start of the
      influenza outbreak, 554 subjects were randomized to receive placebo and 553 to
      receive zanamivir. The drug, 10 mg once per day, or identical placebo was
      administered by oral inhalation for a 4-week period. MAIN OUTCOME MEASURES:
      Illness occurrence was recorded by participants daily and records were evaluated
      weekly. Specimens were collected for viral isolation when symptoms were reported
      within 3 days of illness onset. Infection was also identified by testing paired
      serum samples for rise in antibody titer against the circulating influenza
      viruses. RESULTS: Zanamivir was 67% efficacious (95% confidence interval [CI],
      39%-83%; P<.001) in preventing laboratory-confirmed clinical influenza meeting
      the case definition and 84% efficacious (95% CI, 55%-94%; P=.001) in preventing
      laboratory-confirmed illnesses with fever. All influenza infections occurring
      during the season, with or without symptoms, were prevented with an efficacy of
      31% (95% CI, 4%-50%; P=.03). The nature and incidence of adverse events in the
      zanamivir group did not differ from placebo. Compliance with the once-daily
      dosage was high. CONCLUSIONS: Zanamivir administered once daily is efficacious
      and well tolerated in the prevention of influenza for a 4-week period in healthy
      adults.

PMID- 10404909
TI  - Incidental findings on brain magnetic resonance imaging from 1000 asymptomatic
      volunteers.
AB  - CONTEXT: Previous reports have discussed incidental disease found on brain
      magnetic resonance imaging (MRI) scans that had been requested for an unrelated
      clinical concern or symptom, resulting in a selection bias for disease. However,
      the prevalence of unexpected abnormalities has not been studied in a healthy
      population. OBJECTIVE: To evaluate the prevalence of incidental findings on brain
      MRI scans obtained for a healthy, asymptomatic population without selection bias.
      DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of brain MRI scans
      obtained between May 17, 1996, and July 25, 1997, from 1000 volunteers who
      participated as control subjects for various research protocols at the National
      Institutes of Health. All participants (age range, 3-83 years; 54.6% male) were
      determined to be healthy and asymptomatic by physician examination and
      participant history. MAIN OUTCOME MEASURE: Prevalence of abnormalities on brain
      MRI by category of finding (no referral necessary, routine referral, urgent
      referral [within 1 week of study], and immediate referral [within 1 to several
      days of study]). RESULTS: Eighty-two percent of the MRI results were normal. Of
      the 18% demonstrating incidental abnormal findings, 15.1% required no referral;
      1.8%, routine referral; 1.1%, urgent referral; and 0%, immediate referral. In
      subjects grouped for urgent referral, 2 confirmed primary brain tumors (and a
      possible but unconfirmed third) were found, demonstrating a prevalence of at
      least 0.2%. CONCLUSION: Asymptomatic subjects present with a variety of
      abnormalities, providing valuable information on disease prevalence in a presumed
      healthy population. A small percentage of these findings require urgent medical
      attention and/or additional studies.

PMID- 10404910
TI  - The role of APOE epsilon4 in modulating effects of other risk factors for
      cognitive decline in elderly persons.
AB  - CONTEXT: Cognitive decline in elderly persons is often an early predictor of
      dementia. Subclinical cardiovascular disease (CVD) and diabetes mellitus may
      contribute to substantial decline in cognitive function in the elderly. These
      risks may be modified by gene-environment interactions between apolipoprotein E
      (APOE) genotype and CVD risk factors or subclinical CVD. OBJECTIVES: To examine
      the association between subclinical CVD and decline in cognitive functioning in
      the elderly and to examine effect modification by the APOE genotype of the
      association between subclinical disease and cognitive decline. DESIGN: The
      Cardiovascular Health Study, a population-based, prospective cohort study.
      SETTING AND POPULATION: A total of 5888 randomly selected Medicare-eligible
      participants from Sacramento County, California; Forsyth County, North Carolina;
      Washington County, Maryland; and Pittsburgh, Pa, aged 65 years or older, who were
      recruited in 1989-1990 (n = 5201) and in 1992-1993 (n = 687) and who were
      followed up for 7 and 5 years, respectively. MAIN OUTCOME MEASURES: Change over
      time in scores on the Modified Mini-Mental State Examination and the Digit Symbol
      Substitution Test as a function of APOE genotype, subclinical CVD, and diabetes
      mellitus. RESULTS: Seventy percent of participants had no significant decline on
      the Modified Mini-Mental State Examination. Systolic blood pressure, the ankle
      arm brachial index, atherosclerosis of the internal carotid artery, diabetes
      mellitus, and several diagnoses of prevalent CVD were significantly associated
      with declines in scores on the Modified Mini-Mental State Examination and the
      Digit Symbol Substitution Test. The rate of cognitive decline associated with
      peripheral vascular disease, atherosclerosis of the common and internal carotid
      arteries, or diabetes mellitus was increased by the presence of any APOE epsilon4
      allele. CONCLUSIONS: Most healthy elderly people did not experience cognitive
      decline. Measures of subclinical CVD were modest predictors of cognitive decline.
      Those with any APOE epsilon4 allele in combination with atherosclerosis,
      peripheral vascular disease, or diabetes mellitus were at substantially higher
      risk of cognitive decline than those without the APOE epsilon4 allele or
      subclinical CVD. High levels of atherosclerosis increased cognitive decline
      independently of APOE genotype.

PMID- 10404911
TI  - Health consequences of religious and philosophical exemptions from immunization
      laws: individual and societal risk of measles.
AB  - CONTEXT: All US states require proof of immunization for school entry. Exemptions
      are generally offered for medical, religious, or philosophical reasons, but the
      health consequences of claiming such exemptions are poorly documented.
      OBJECTIVES: To quantify the risk of contracting measles among individuals
      claiming religious and/or philosophical exemptions from immunization (exemptors)
      compared with vaccinated persons, and to examine the risk that exemptors pose to
      the nonexempt population. DESIGN, SETTING, AND PARTICIPANTS: Population-based,
      retrospective cohort study of data from 1985 through 1992, collected by the
      Measles Surveillance System of the Centers for Disease Control and Prevention, as
      well as from annual state immunization program reports on prevalence of exemptors
      and vaccination coverage. The study group was restricted to individuals aged 5 to
      19 years. To empirically determine and quantify community risk, a mathematical
      model was developed that examines the spread of measles through communities with
      varying proportions of exemptors and vaccinated children. MAIN OUTCOME MEASURES:
      Relative risk of contracting measles for exemptors vs vaccinated individuals
      based on cohort study data. Community risk of contracting measles derived from a
      mathematical model. RESULTS: On average, exemptors were 35 times more likely to
      contract measles than were vaccinated persons (95% confidence interval, 34-37).
      Relative risk varied by age and year. Comparing the incidence among exemptors
      with that among vaccinated children and adolescents during the years 1985-1992
      indicated that the 1989-1991 measles resurgence may have occurred 1 year earlier
      among exemptors. Mapping of exemptors by county in California indicated that
      exempt populations tended to be clustered in certain geographic regions.
      Depending on assumptions of the model about the degree of mixing between
      exemptors and nonexemptors, an increase or decrease in the number of exemptors
      would affect the incidence of measles in nonexempt populations. If the number of
      exemptors doubled, the incidence of measles infection in nonexempt individuals
      would increase by 5.5%, 18.6%, and 30.8%, respectively, for intergroup mixing
      ratios of 20%, 40%, and 60%. CONCLUSIONS: These data suggest the need for
      systematic review of vaccine-preventable incidents to examine the effect of
      exemptors, increased surveillance of the number of exemptors and cases among
      them, and research to determine the reasons why individuals claim exemptions.

PMID- 10404912
TI  - Effect of mechanical ventilation on inflammatory mediators in patients with acute
      respiratory distress syndrome: a randomized controlled trial.
AB  - CONTEXT: Studies have shown that an inflammatory response may be elicited by
      mechanical ventilation used for recruitment or derecruitment of collapsed lung
      units or to overdistend alveolar regions, and that a lung-protective strategy may
      reduce this response. OBJECTIVE: To test the hypothesis that mechanical
      ventilation induces a pulmonary and systemic cytokine response that can be
      minimized by limiting recruitment or derecruitment and overdistention. DESIGN AND
      SETTING: Randomized controlled trial in the intensive care units of 2 European
      hospitals from November 1995 to February 1998, with a 28-day follow-up. PATIENTS:
      Forty-four patients (mean [SD] age, 50 [18] years) with acute respiratory
      distress syndrome were enrolled, 7 of whom were withdrawn due to adverse events.
      INTERVENTIONS: After admission, volume-pressure curves were measured and
      bronchoalveolar lavage and blood samples were obtained. Patients were randomized
      to either the control group (n = 19): tidal volume to obtain normal values of
      arterial carbon dioxide tension (35-40 mm Hg) and positive end-expiratory
      pressure (PEEP) producing the greatest improvement in arterial oxygen saturation
      without worsening hemodynamics; or the lung-protective strategy group (n = 18):
      tidal volume and PEEP based on the volume-pressure curve. Measurements were
      repeated 24 to 30 and 36 to 40 hours after randomization. MAIN OUTCOME MEASURES:
      Pulmonary and systemic concentrations of inflammatory mediators approximately 36
      hours after randomization. RESULTS: Physiological characteristics and cytokine
      concentrations were similar in both groups at randomization. There were
      significant differences (mean [SD]) between the control and lung-protective
      strategy groups in tidal volume (11.1 [1.3] vs 7.6 [1.1] mL/kg), end-inspiratory
      plateau pressures (31.0 [4.5] vs 24.6 [2.4] cm H2O), and PEEP (6.5 [1.7] vs 14.8
      [2.7] cm H2O) (P<.001). Patients in the control group had an increase in
      bronchoalveolar lavage concentrations of interleukin (IL) 1beta, IL-6, and IL-1
      receptor agonist and in both bronchoalveolar lavage and plasma concentrations of
      tumor necrosis factor (TNF) alpha, IL-6, and TNF-alpha, receptors over 36 hours
      (P<.05 for all). Patients in the lung-protective strategy group had a reduction
      in bronchoalveolar lavage concentrations of polymorphonuclear cells, TNF-alpha,
      IL-1beta, soluble TNF-alpha receptor 55, and IL-8, and in plasma and
      bronchoalveolar lavage concentrations of IL-6, soluble TNF-alpha receptor 75, and
      IL-1 receptor antagonist (P<.05). The concentration of the inflammatory mediators
      36 hours after randomization was significantly lower in the lung-protective
      strategy group than in the control group (P<.05). CONCLUSIONS: Mechanical
      ventilation can induce a cytokine response that may be attenuated by a strategy
      to minimize overdistention and recruitment/derecruitment of the lung. Whether
      these physiological improvements are associated with improvements in clinical end
      points should be determined in future studies.

PMID- 10404913
TI  - Role of serology in the diagnosis of Lyme disease.
AB  - Numerous concerns regarding the potential for misdiagnosis of Lyme disease using
      commercial assays have been voiced by the US Food and Drug Administration (FDA).
      We attempted to clarify the clinical value of serologic testing for Lyme disease
      using the results of commonly marketed assays for detecting antibody to Borrelia
      burgdorferi, the organism that causes Lyme disease. We reviewed published studies
      on B burgdorferi test performance published through 1998, package insert labeling
      from FDA-cleared test kits for B burgdorferi, and Lyme Disease Survey Set LY-A
      from the College of American Pathologists. We assessed the sensitivity and
      specificity of commercial serologic tests (enzyme-linked immunosorbent assay
      [ELISA], immunofluorescence antibody [IFA], and immunodot) for diagnosis of Lyme
      disease. To reduce this risk of misdiagnosis, it is important that clinicians
      understand the performance characteristics and limitations of these tests. These
      tests, in common use in clinical or commercial laboratories, should be used only
      to support a clinical diagnosis of Lyme disease, not as the primary basis for
      making diagnostic or treatment decisions. Serologic testing is not useful early
      in the course of Lyme disease because of the low sensitivity of tests in early
      disease. Serologic testing may be more useful in later disease, at which time
      sensitivity and specificity of the test are improved. Positive or equivocal
      results on an ELISA, IFA, or immunodot assay requires supplemental testing with a
      Western blot assay. A negative result on the Western blot or ELISA indicates that
      there is no serologic evidence of infection by B burgdorferi at the time the
      sample was drawn.

PMID- 10404914
TI  - Users' Guides to the Medical Literature: XVIII. How to use an article evaluating
      the clinical impact of a computer-based clinical decision support system.

PMID- 10404915
TI  - New options for prevention and control of influenza.

PMID- 10404916
TI  - Progress in understanding ventilator-induced lung injury.

PMID- 10404917
TI  - Lyme disease serology: problems and opportunities.

PMID- 10404918
TI  - JAMA Patient Page: immunizations.

PMID- 10404919
TI  - Chronic care clinics: a randomized controlled trial of a new model of primary
      care for frail older adults.
AB  - OBJECTIVE: To determine whether a new model of primary care, Chronic Care
      Clinics, can improve outcomes of common geriatric syndromes (urinary
      incontinence, falls, depressive symptoms, high risk medications, functional
      impairment) in frail older adults. DESIGN: Randomized controlled trial with 24
      months of follow-up. Physician practices were randomized either to the Chronic
      Care Clinics intervention or to usual care. SETTING: Nine primary care physician
      practices that comprise an ambulatory clinic in a large staff-model HMO in
      western Washington State. PARTICIPANTS: Those patients aged 65 and older in each
      practice with the highest risk for being hospitalized or experiencing functional
      decline. INTERVENTION: Intervention practices (5 physicians, 96 patients) held
      half-day Chronic Care Clinics every 3 to 4 months. These clinics included an
      extended visit with the physician and nurse dedicated to planning chronic disease
      management; a pharmacist visit that emphasized reduction of polypharmacy and high
      risk medications; and a patient self-management/support group. Control practices
      (4 physicians, 73 patients) received usual care. MEASUREMENTS: Changes in self
      reported urinary incontinence, frequency of falls, depressive symptoms, physical
      function, and satisfaction were analyzed using an intention-to-treat analysis
      adjusted for baseline differences, covariates, and practice-level variation.
      Prescriptions for high-risk medications and cost/utilization data obtained from
      administrative data were similarly analyzed. RESULTS: After 24 months, no
      significant improvements in frequency of incontinence, proportion with falls,
      depression scores, physical function scores, or prescriptions for high risk
      medications were demonstrated. Costs of medical care including frequency of
      hospitalization, hospital days, emergency and ambulatory visits, and total costs
      of care were not significantly different between intervention and control groups.
      A higher proportion of intervention patients rated the overall quality of their
      medical care as excellent compared with control patients (40.0% vs 25.3%, P =
      .10). CONCLUSIONS: Although intervention patients expressed high levels of
      satisfaction with Chronic Care Clinics, improved outcomes for selected geriatric
      syndromes were not demonstrated. These findings suggest the need for developing
      greater system-wide support for managing geriatric syndromes in primary care and
      illustrate the challenges of conducting practice improvement research in a
      rapidly changing delivery system.

PMID- 10404920
TI  - A randomized trial of a combined physical activity and environmental intervention
      in nursing home residents: do sleep and agitation improve?
AB  - OBJECTIVES: The purpose of this study was to test whether an intervention
      combining increased daytime physical activity with improvement in the nighttime
      environment improves sleep and decreases agitation in nursing home residents.
      DESIGN: A randomized trial. SETTING: One community nursing home in the Los
      Angeles, California area. PARTICIPANTS: Twenty-nine incontinent residents (mean
      age 88.3 years, 90% female). INTERVENTION: Subjects were randomized to receive
      either (1) an intervention combining increased daytime physical activity (14
      weeks in duration) plus a nighttime program (5 nights in duration) to decrease
      noise and sleep-disruptive nursing care practices (intervention group), or (2)
      the nighttime program alone (control group). MEASUREMENTS: Daytime physical
      activity monitors and structured physical function assessments; nighttime wrist
      activity monitors to estimate nighttime sleep; and timed daytime behavioral
      observations of sleep versus wakefulness, either in or out of bed, and agitation.
      RESULTS: Physical function measures did not change significantly (MANOVA for
      repeated measures, group by time effect). Wrist actigraphy estimation of
      nighttime percent sleep (time asleep over time monitored in bed at night)
      increased in intervention subjects from 51.7% at baseline to 62.5% at follow-up
      compared with 67.0% at baseline to 66.3% at follow-up in controls (MANOVA, group
      by time, F = 4.42, P = .045, df = 27). At follow-up, intervention subjects
      averaged a 32% decrease in the percent of daytime observations in bed compared
      with baseline, with essentially no change in controls (MANOVA, group by time, F =
      5.31, P = .029, df = 27). Seven of 15 intervention subjects had a decrease in
      observed agitation at follow-up, compared with baseline, versus only 1 of 14
      controls with a decrease in observed agitation. CONCLUSIONS: This study provides
      preliminary evidence that an intervention combining increased physical activity
      with improvement in the nighttime nursing home environment improves sleep and
      decreases agitation in nursing home residents.

PMID- 10404921
TI  - Risk factors for falls and for serious injuries on falling among older Japanese
      women in Hawaii.
AB  - OBJECTIVES: To evaluate if similar constellations of factors underlie the risks
      of falls and injuries on falling for Japanese women as reported for predominately
      white populations. DESIGN: A prospective cohort study SETTING: The island of Oahu
      PARTICIPANTS: The older Japanese women who participated in the Hawaii
      Osteoporosis Study (mean age = 74 +/- 5 (SD) years). MEASUREMENTS: As outcomes:
      falls and serious injuries on falling. As predictors: anthropometric
      measurements, measurements of neuromuscular performance, activities of daily
      living (ADLs), past falls, and other suspected risk factors for falls and serious
      injuries. RESULTS: In multivariable models, four subject characteristics were
      positively associated with having a fall (having a fall in the past year (RR =
      2.0 (95% CI, 1.5-2.8)), slow chair stands (RR = 1.4 (95% CI, 1.0-1.9), a short
      height (RR = 1.5 (95% CI, 1.1-2.1)), difficulties with five or more ADLs (RR =
      1.5 (95% CI, 1.1-2.1))). Two subject characteristics were negatively associated
      with having a fall (ability to perform a full tandem balance with eyes closed (RR
      = .7 (95% CI, .5-1.0)) and having a long functional reach (RR = .7 (95% CI, .5
      1.0))). The RRs represent as nearly as possible comparisons of the upper (or
      lower) quartile and the remaining quartiles. In multivariable models, long times
      for chair stands (odds ratio (OR) = 3.0 (95% CI, 1.5-6.1)) and a low BMI (OR =
      3.1 (95% CI, 1.5-6.4)) were positively associated with having a serious injury
      among women who had a fall. Among the same women, taking part in an activity they
      did frequently (OR = .3 (95% CI, .1-.8)) and slow foot reaction times (OR = .3
      (95% CI, .1-.8)) were associated negatively with having a serious injury.
      CONCLUSIONS: The results from this Japanese cohort support the conclusion that
      women at high risk of falling and serious fall injuries can be identified using a
      questionnaire and simple, performance-based tests of neuromuscular function. The
      risk factors for falling overlapped, but were distinct from, those for suffering
      a serious injury once a fall had occurred.

PMID- 10404922
TI  - The relation between cortisol excretion and fractures in healthy older people:
      results from the MacArthur studies-Mac.
AB  - BACKGROUND: In persons with depression, higher urinary cortisol is associated
      with lower bone mineral density. OBJECTIVE: To examine the relation between
      urinary free cortisol (UFC) and fractures. SETTING: Community-based samples from
      Durham, NC, East Boston, MA, and New Haven, CT. PARTICIPANTS: 684 men and women,
      aged 70 to 79 at baseline, who were part of the MacArthur Study of Successful
      Aging. DESIGN: Cohort study. Participants with previous history of fractures at
      baseline were excluded. MEASURES: The primary exposure variable was overnight
      (8:00 p.m. to 8:00 a.m.) UFC (microg/g creatinine) at baseline (1988). Outcomes
      were self-reported hip, arm, spine, wrist, or other fracture during the follow-up
      period (1988-1995). Covariates were baseline age, gender, race, body mass index,
      current physical activity, lower extremity strength, depression subscale of the
      Hopkins Symptom Checklist, and current use of cigarettes and alcohol. ANALYSIS:
      Logistic regression was used to predict the occurrence of incident fractures
      (1988-1995) as a function of quartiles of baseline UFC. Models were adjusted for
      age, gender, and race and were also multiply adjusted for the remaining
      covariates listed above. Gender-stratified models and models that excluded
      corticosteroid users were also run. RESULTS: In multiply adjusted models, higher
      baseline levels of UFC were significantly associated with incident fractures.
      Odds of fracture (95% Confidence Intervals) for increasing quartiles of baseline
      UFC, multiply adjusted, were: 2.28 (.91, 5.77); 3.40 (1.33, 8.69); 5.38 (1.68,
      17.21). Results were not materially influenced by exclusion of persons using
      corticosteroids. CONCLUSIONS: Higher baseline UFC is an independent predictor of
      future fracture.

PMID- 10404923
TI  - Changes in blood pressure and risk factors for cardiovascular disease among older
      Mexican-Americans from 1982-1984 to 1993-1994.
AB  - OBJECTIVE: To determine the 10-year changes in blood pressure and cardiovascular
      risk factors among older Mexican-Americans. DESIGN: Comparative analyses of the
      Hispanic Health and Nutrition Examination Survey (HHANES) and the Hispanic EPESE
      (Established Populations for Epidemiologic Studies of the Elderly). Both of these
      were population-based studies using a multistage stratified probability sampling
      design of noninstitutionalized persons. SETTING: Five US states in the southwest:
      Arizona, California, Colorado, New Mexico, and Texas. PARTICIPANTS: A total of
      216 Mexican-Americans aged 65 to 74 from the 1982-1984 HHANES and 3050 Mexican
      Americans aged 65+ from the 1993-1994 Hispanic EPESE. MEASUREMENTS: Mean systolic
      and diastolic blood pressure; cigarette smoking; high levels of alcohol use; body
      mass index and obesity; self-reported heart attack, stroke, and diabetes;
      hypertension. RESULTS: Among 65- to 74-year-old Mexican-Americans, there was a
      decrease over time in the percent of those who smoked cigarettes from 27.60% to
      13.96% and a decrease in mean systolic blood pressure level. The percent of
      subjects categorized as obese or severely obese increased significantly, as did
      the prevalence of diagnosed diabetes, increasing from 20.06% in 1982-1984 to
      29.82% in 1993-1994. Mean diastolic blood pressure increased from 77.15 mm Hg in
      1982-1984 to 81.21 mm Hg in 1993-1994. CONCLUSIONS: Our findings suggest major
      changes in cardiovascular risk factors between 1982-1984 and 1993-1994 among
      older Mexican-Americans.

PMID- 10404924
TI  - The treatment and prevention of coronary heart disease in Canada: do older
      patients receive efficacious therapies? The Clinical Quality Improvement Network
      (CQIN) Investigators.
AB  - OBJECTIVES: To review the evidence for clinical efficacy and cost-effectiveness
      of proven medications in the treatment and prevention of myocardial infarction
      (MI) in older patients; to summarize Canadian data on treatment patterns and
      clinical outcomes for younger and older patients with coronary heart disease; to
      explore the reasons for gaps between best care, based on the evidence of efficacy
      from trials, and usual care, based on the population effectiveness audits; and to
      explore potential approaches to closing the care gaps. DESIGN: Review of the
      recent clinical trial literature on the management of MI, highlighting results in
      older patients. Review of medication utilization and outcomes data from a series
      of large, consecutively enrolled patient cohorts with acute MI (N = 7070) in a
      variety of cardiac care settings (10 centers in five Canadian provinces,
      including university-based teaching hospitals, community hospitals, cardiologist
      and family physician out-patient clinics) from 1987 to 1996. RESULTS: There is no
      qualitative interaction of cardiac therapies: thrombolytics, beta-blockers,
      acetylsalicylic acid (ASA), and statins are efficacious in all clinically
      relevant patient subgroups, including older people. However, there are consistent
      gaps between usual care and best care, particularly among older patients (in whom
      there is also a concomitantly higher mortality risk). Repeated multivariate
      analyses confirm older age to be an independent contributor to increased risk.
      Use of efficacious medications is, in contrast, consistently associated with
      increased survival. Analysis of temporal trends suggests beneficial changes in
      practice patterns and outcomes are possible to achieve. However, "best care" has
      not been rapidly or completely achieved. Review of strategies to close these care
      gaps suggests that audit and feedback, critical pathways, and multifactorial
      interventions involving patients and other members of the healthcare team as well
      as physicians may be the most efficacious strategies for change. CONCLUSIONS:
      Despite equal or enhanced efficacy, there is consistently less prescription of
      proven drugs among older cardiac patients. These care patterns may contribute to
      their enhanced risk. The causes underlying these practice patterns are complex,
      and their population impact may be undervalued by clinicians and managers.
      Improvement of these patterns is difficult, but ultimately it would be beneficial
      for this presently disadvantaged, readily identified, high risk patient
      population.

PMID- 10404925
TI  - Relationship of age and simulated flight performance.
AB  - OBJECTIVE: To determine the relationship between age and aviator performance on a
      flight simulator. DESIGN: A cross-sectional observational study. PARTICIPANTS:
      The sample consisted of 100 aviators aged 50 to 69 (mean = 58). MAIN OUTCOME
      MEASURES: Pilots were tested on a Frasca 141 flight simulator (Urbana, IL),
      linked to a UNIX-based IRIS 4D computer (Silicon Graphics, Mountain View, CA),
      which both generated graphics of the environment in which the pilots flew and
      collected data concerning the aircraft's flight conditions. RESULTS: We found
      that increased age was significantly associated with decreased aviator
      performance on a flight simulator. CONCLUSIONS: Although there was a significant
      relationship between increased age and decreased aviator performance, age
      explained 22% or less of the variance of performance on different flight tasks;
      hence, other factors are also important in explaining the performance of older
      pilots.

PMID- 10404926
TI  - Treatment for the secondary prevention of stroke in older patients: the influence
      of dementia status.
AB  - OBJECTIVE: To investigate the influence of dementia status on treatment for the
      secondary prevention of stroke in older patients. DESIGN: Based on patient
      examinations and medical record review, we investigated the frequency of aspirin
      and/or warfarin use at hospital discharge for the prevention of recurrent stroke
      in older patients hospitalized with acute ischemic stroke. SETTING: A large
      academic medical center. PARTICIPANTS: A cohort of 272 patients, mean age 72.1 +/
      8.5 years. MEASUREMENTS: We performed neurologic examinations and reviewed
      medical records to investigate the effects of a clinical diagnosis of dementia
      and other potentially relevant factors on treatment with aspirin or warfarin at
      hospital discharge. RESULTS: Thirty-one patients (11.4%) were not prescribed
      aspirin or warfarin at hospital discharge. Logistic regression determined that
      dementia (odds ratio (OR) = 2.57, 95% confidence interval (CI), 1.04-6.30) was a
      significant independent determinant of nontreatment with aspirin or warfarin,
      adjusting for abnormal gait (OR = 2.01, CI, .88-4.59); discharge to a nursing
      home or other institutional residence (OR = 2.55, CI, .83-7.81); cardiac disease
      (OR = .39, CI, .16-.95); cortical infarct location (OR = .45, CI, .18-1.10); male
      sex (OR = .47, CI, .20-1.15); age 80+ (OR = 1.14, CI, .46-2.82) and age 70-79 (OR
      = .96, CI, .32-2.88) versus age 60-69. CONCLUSIONS: Our results suggest that
      dementia is a significant independent determinant of nontreatment with aspirin or
      warfarin when otherwise indicated for the prevention of recurrent stroke. The
      underutilization of aspirin and warfarin in older stroke patients with dementia
      may be a modifiable basis for their increased risk of recurrence and death.

PMID- 10404927
TI  - Identifying patterns of disruptive behavior in long-term care residents.
AB  - OBJECTIVES: To determine the frequency, timing, and pattern of 45 operationalized
      disruptive behaviors (DB) in older people in long-term care units. DESIGN:
      Nursing staff collected prospective descriptive data over 21 consecutive shifts
      for each patient to document prevalence, frequency, and co-occurrences of DBs.
      SETTING: All of the eight long-term care units and one acute/admission unit of a
      large Veterans Administration Medical Center (VAMC). Each 40-bed unit had
      patients with varying levels of cognitive impairment and skilled nursing needs.
      PARTICIPANTS: The sample consisted of 240 hospitalized VA patients with a mean
      age of 72.8 (SD = 8.6) years and mean length of stay of 4.02 (SD = 8.6) years.
      Residents had dementia, a psychiatric diagnosis, or mixed dementia and
      psychiatric diagnoses. MEASUREMENTS: The Disruptive Behavior Scale (DBS), an
      instrument designed for collecting patient-level data on 45 separate DBs.
      RESULTS: In a 24-hour period, the average frequency was 3.6 DBs per subject. We
      found that 41.2% of DB occurred during the day shift, 39.2% during the evening
      shift, and 19.6% during the night shift. In 32% of observed occurrences, only one
      DB occurred within the hour. In the remaining 68% of observations, two or more
      DBs occurred within the same hour. We found two behaviors, Does Not Follow
      Directions and Excessive Motor Activity, to occur with multiple behaviors in
      multiple categories. Several characteristic patterns were noted; e.g., physically
      aggressive behaviors rarely co-occurred with verbal DBs. Physically nonaggressive
      behaviors seemed to occur most frequently with other physically nonaggressive
      behaviors and, to a lesser extent, with verbal DBs. CONCLUSIONS: These findings
      lend support to the existence of patterns of DBs in long-term care patients, a
      useful step toward targeting interventions early in the behavioral sequence.

PMID- 10404928
TI  - Prevalence of combined fecal and urinary incontinence: a community-based study.
AB  - OBJECTIVE: To assess the prevalence of combined fecal and urinary incontinence.
      DESIGN: A cross-sectional, community-based study. SETTING: Olmsted County,
      Minnesota. PARTICIPANTS: Men (n = 778) and women (n = 762), aged 50 years or
      older, selected randomly from the population. MEASUREMENTS: Participants
      completed a previously validated self-administered questionnaire that assessed
      the occurrence of fecal and urinary incontinence in the previous year. RESULTS:
      The age-adjusted prevalence of incontinence was 11.1% (95% Confidence Interval
      (CI), 8.8-13.5) in men and 15.2% (95% CI, 12.5-17.9) in women for fecal
      incontinence; 25.6% (95% CI, 22.5-28.8) in men and 48.4% (95% CI, 44.7-52.2) in
      women for urinary incontinence; and 5.9% (95% CI, 4.1-7.6) in men and 9.4% (95%
      CI, 7.1-11.6) in women for combined urinary and fecal incontinence. The
      prevalence of fecal incontinence increased with age in men but not in women, from
      8.4% among men in their fifties to 18.2% among men in their eighties (P for trend
      = .001). For women, the prevalence increased from 13.1% among 50-year-old women
      to 20.7% among women 80 years or older (P for trend = .5). Among persons with
      fecal incontinence, the prevalence of concurrent urinary incontinence was 51.1%
      among men and 59.6% among women (P = .001 and P = .003, respectively). Cross
      sectionally, the age-adjusted, relative odds of fecal incontinence among persons
      with urinary incontinence was greater in men than in women (Odds Ratio (OR) =
      3.0; 95% CI, 1.9-4.8 in men and OR = 1.8; 95% CI, 1.2-2.7 in women, P = .04).
      CONCLUSIONS: These findings suggest that persons with one form of incontinence
      are likely to have the other form as well. Despite the higher prevalence of
      urinary and fecal incontinence among women, the association between fecal
      incontinence and urinary incontinence was stronger among men than women. This
      finding, and the significant association between fecal incontinence and age
      observed in men but not in women, suggest that the etiologies may be more closely
      linked in men than in women.

PMID- 10404929
TI  - Reporting of dementia on death certificates: a community study.
AB  - OBJECTIVE: To determine the extent to which conditions suggesting dementia are
      reported on death certificates of older adults and to identify the factors
      associated with reporting of dementia. DESIGN: A prospective epidemiological
      study in which community-dwelling subjects with and without dementia were
      identified and followed until death, after which their death certificates were
      examined. POPULATION: A total of 527 individuals who died during 8 years of
      follow-up of a population-based cohort of 1422 persons aged 65 and older at study
      entry. MEASUREMENTS: Demographic; study diagnoses, including Clinical Dementia
      Rating (CDR) Scale stages and diagnoses of Probable and Possible Alzheimer's
      disease (AD) by NINCDS-ADRDA criteria; disorders listed on death certificates as
      immediate, underlying, or contributory causes of death. RESULTS: Of 172 deceased
      subjects with study diagnoses of dementia, 30.2% had CDR = .5 and 69.8% had CDR >
      or = 1. Of 168 subjects in which dementia subtype could be diagnosed, Probable AD
      was diagnosed in 31.0% and Possible AD in 38.7%. On their death certificates,
      conditions indicating or suggesting dementia were reported in 23.8% of dementias
      overall; in 1.9% of those with CDR = .5 and 33.3% of those with CDR > or = 1; in
      36.5% of those with Probable AD and 21.5% of those with Possible AD. In a
      multiple logistic regression model, variables associated independently with the
      reporting of dementia in demented individuals were: higher CDR stage of dementia
      (odds ratio (OR) 22.6; 95% confidence interval (CI), 2.9-174.7); likely etiology
      of dementia, Probable AD (OR = 3.5; CI, 1.1-10.6); and place of death, long-term
      care institution (OR = 3.8; 95% CI, 1.6-9.0). CONCLUSIONS: Although Alzheimer's
      disease is widely regarded as a leading cause of death, dementias are reported on
      the death certificates of only a quarter of demented individuals in the
      population at large. Reporting is more likely in those with more advanced
      dementia, with Probable Alzheimer's disease, and those who die in long-term care
      institutions.

PMID- 10404931
TI  - Alcohol use and functional disability among cognitively impaired adults.
AB  - BACKGROUND: The extent to which alcohol exposure increases risk for functional
      disability among older adults with cognitive impairment has not previously been
      assessed. OBJECTIVE: To examine the potential relationship between alcohol use
      and functional disability among older cognitively impaired adults. DESIGN:
      Retrospective medical record review. SETTING: Hospital-based geriatric assessment
      center. PARTICIPANTS: Two hundred forty-two consecutive participants with Mini
      Mental Status Examination scores of < or = 24. MEASUREMENTS: Proxy-reported
      alcohol intake was classified in categories of never, former, light (< 1
      drink/week), moderate (> or = 1 but < 14 drinks/week), and heavy (> or = 14
      drinks/week) drinkers, and functional status was determined by proxy-reported
      performance in seven basic (BADL) and seven instrumental (IADL) activities of
      daily living (0 = poorest function and 14 = best function). RESULTS: Compared
      with never drinkers, moderate drinkers demonstrated higher mean BADL (12.2 vs
      11.4, P = .033) and IADL scores (6.6 vs 5.6, P = .067), whereas heavy drinkers
      had higher BADL (12.8 vs 11.4, P = .019) but lower IADL scores (4.8 vs 5.6, P =
      .425). Former drinkers demonstrated both lower BADL (10.8 vs 11.4, P = .107) and
      IADL scores (3.9 vs 5.6, P = .011) compared with never drinkers. Evaluation of a
      potential dose-response effect was limited due to low numbers of light and heavy
      drinkers. CONCLUSIONS: Among cognitively impaired adults, moderate and heavy
      drinkers demonstrated better BADL function, whereas former drinkers had poorer
      IADL function, compared with never drinkers. Prospective studies that incorporate
      additional measures of exposure (e.g., cumulative lifetime consumption) and
      function (e.g., performance-based tests) may provide a more comprehensive
      understanding of alcohol's effects among older cognitively impaired adults.

PMID- 10404930
TI  - Psychotropic medication withdrawal and a home-based exercise program to prevent
      falls: a randomized, controlled trial.
AB  - OBJECTIVE: To assess the effectiveness of psychotropic medication withdrawal and
      a home-based exercise program in reducing falls in older people. DESIGN: A
      randomized controlled trial with a two by two factorial design. SETTING:
      Seventeen general practices in Dunedin, New Zealand. PARTICIPANTS: Women and men
      aged 65 years registered with a general practitioner and currently taking
      psychotropic medication (n = 93). INTERVENTIONS: Two interventions: (1) gradual
      withdrawal of psychotropic medication versus continuing to take psychotropic
      medication (double blind) and (2) a home-based exercise program versus no
      exercise program (single blind). MEASUREMENTS: Number of falls and falls risk
      during 44 weeks of follow-up. Analysis was on an intent to treat basis. RESULTS:
      After 44 weeks, the relative hazard for falls in the medication withdrawal group
      compared with the group taking their original medication was .34 (95% CI, .16
      .74). The risk of falling for the exercise program group compared with those not
      receiving the exercise program was not significantly reduced. CONCLUSIONS:
      Withdrawal of psychotropic medication significantly reduced the risk of falling,
      but permanent withdrawal is very difficult to achieve.

PMID- 10404932
TI  - Mortality one-year postdischarge from a Veterans Affairs geriatric evaluation and
      management unit: assessing mortality risks.
AB  - OBJECTIVE: To assess at Geriatric Evaluation and Management Unit (GEM) admission
      factors that affect mortality 12-months postdischarge and to develop a
      preliminary risk scoring protocol to guide targeting of GEM care. SETTING: A 24
      bed-GEM at a Veterans Affairs (VA) Medical Center. DESIGN: Relative risks (RR)
      were assessed using prospective data; a risk protocol from 1988-1989 data was
      tested on 1990-1991 patients. SUBJECTS: A total of 283 male patients, aged 60 to
      102, discharged over 4 years. RESULTS: Age at GEM admission did not correlate
      with death (r = .14; P = .145), but did correlate with risk scores (r = .33, P <
      .001). The risk protocol had a sensitivity of .67 and specificity of 1.00. High
      and low risk patients had mortalities of 51% versus 20%, a Wilcoxon (Gehan)
      statistic of 15.22, df = 1, and P < .001. Differences in mortality ceased about
      100 days postdischarge. Three univariate RR exceeded 1.00 at a 99% Confidence
      Interval (CI): IADL score (RR: 1.12; CI, 1.03-1.21); nursing acuity score (RR:
      1.78; CI: 1.02-3.11); and a primary diagnosis of pneumonia/sepsis (RR: 3.95; CI,
      1.60-9.78). Four RRs exceeded 1.00 at a 90% CI: dementia (RR: 1.78; CI, 1.02
      3.09); transfer into the GEM from a medical service (RR: 1.47; CI, 1.02-2.12);
      deconditioning/functional decline (RR: 1.67; CI, 1.12-2.48); and use of a Foley
      catheter (RR: 2.22; CI, 1.11-4.45). Thirteen other potential risk factors were
      found in a multivariate analysis. CONCLUSIONS: The point estimates of risk
      factors may help clinicians target GEM care, but the development of a useable
      risk protocol requires additional work. Causal models may be needed to assess
      patient conditions related to successful treatment in GEMs.

PMID- 10404933
TI  - Use of physician and acute care services by persons with and without Alzheimer's
      disease: a population-based comparison.
AB  - OBJECTIVE: To estimate differences in use of acute care services between persons
      with and without Alzheimer's disease (AD). STUDY DESIGN: Population-based
      historical cohort study. SETTING/SUBJECTS: All Rochester, Minnesota, residents
      with AD onset between January 1, 1980, and December 31, 1984 (n = 301), plus one
      age- and sex-matched nondemented control per case, were identified with a
      retrospective review of community-based medical records. MEASUREMENTS: Cases and
      controls were followed in their medical records for number of acute care
      encounters in the year before January 1 of the index year (year of onset for AD
      case and their matched control) and in the 4 years following December 31 of the
      index year. Encounters included clinician visits (office or nursing home),
      emergency room (ER) visits, hospitalizations (inpatient and outpatient), and
      inpatient days. Multivariate regression analyses were adjusted for age, sex, pre
      index level of illness, and follow-up time. RESULTS: In the pre-index period,
      cases and controls were similar with respect to level of illness, number of
      office visits, ER visits, and hospitalizations. In the year before AD onset, 17
      cases (7%) had a clinician visit in the nursing home compared with no controls.
      In the 4 years after the index year, mean length of follow-up was 3.4 years for
      both cases and controls. The numbers of ER visits, hospitalizations, and
      inpatient days were similar for cases and controls. Sixty-four percent of AD
      cases had a clinician visit in a nursing home versus 1% of controls. Controls
      experienced more office visits than cases (median = 16 vs 10, P < .001).
      CONCLUSIONS: The onset of AD is not associated with greater use of acute care
      services. However, neither is the high use of nursing home care offset by fewer
      ER or hospital encounters.

PMID- 10404934
TI  - Comparison based on age of baseline electrocardiographic abnormalities in non-Q
      wave myocardial infarction. VANQWISH Trial Research Investigators. Veterans
      Affairs Non-Q-Wave Infarction Strategies In-Hospital.
AB  - OBJECTIVE: To compare the incidence of electrocardiographic abnormalities between
      older (age > or = 70 years) and younger patients presenting with acute non-Q-wave
      myocardial infarction. DESIGN: Retrospective review of qualifying
      electrocardiograms in 918 patients enrolled in the multicenter Veterans Affairs
      Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study. SETTING: Seventeen
      Department of Veterans Affairs medical centers. PARTICIPANTS: A total of 918
      patients (224 > or = 70 years old) with acute non-Q-wave myocardial infarction.
      MEASUREMENTS: Comparison of electrocardiograms in patients aged > or = 70 years
      and younger patients for presence of left ventriculary hypertrophy, widened QRS
      complex, ST and T wave abnormalities, rhythm other than sinus, heart rate > or =
      80 beats/minute, and location of acute non-Q-wave myocardial infarction. RESULTS:
      Left ventricular hypertrophy and ST depression > or = 1 mm were significantly
      more frequent in older than in younger patients. CONCLUSIONS: Older patients
      presenting with non-Q-wave myocardial infarction have a greater incidence of left
      ventricular hypertrophy and ST depression on their electrocardiograms than
      younger patients. Both of these electrocardiographic findings have previously
      been associated with increased risk of death and recurrent myocardial infarction
      and may help account for the worse prognosis of non-Q-wave myocardial infarction
      in older patients.

PMID- 10404935
TI  - Development and testing of a five-item version of the Geriatric Depression Scale.
AB  - OBJECTIVE: To develop and test the effectiveness of a 5-item version of the
      Geriatric Depression Scale (GDS) in screening for depression in a frail community
      dwelling older population. DESIGN: A cross-sectional study. SETTING: A geriatric
      outpatient clinic at the Sepulveda VA Medical Center, Sepulveda, California.
      PARTICIPANTS: A total of 74 frail outpatients (98.6% male, mean age 74.6)
      enrolled in an ongoing trial. MEASUREMENTS: Subjects had a comprehensive
      geriatric assessment that included a structured clinical evaluation for
      depression with geropsychiatric consultation. A 5-item version of the GDS was
      created from the 15-item GDS by selecting the items with the highest Pearson chi2
      correlation with clinical diagnosis of depression. Sensitivity, specificity,
      diagnostic accuracy, and positive and negative predictive values were calculated
      for the 15-item GDS and the new 5-item scale. RESULTS: Subjects had a mean GDS
      score of 6.2 (range 0-15). Clinical evaluation found that 46% of subjects were
      depressed. The depressed and not depressed groups were similar with regard to
      demographics, mental status, educational level, and number of chronic medical
      conditions. Using clinical evaluation as the gold standard for depression, the 5
      item GDS (compared with the 15-item GDS results shown in parentheses) had a
      sensitivity of .97 (.94), specificity of .85 (.83), positive predictive value of
      .85 (.82), negative predictive value of .97 (.94), and accuracy of .90 (.88) for
      predicting depression. Significant agreement was found between depression
      diagnosis and the 5-item GDS (kappa = 0.81). Multiple other short forms were
      tested, and are discussed. The mean administration times for the 5- and 15-item
      GDS were .9 and 2.7 minutes, respectively. CONCLUSIONS: The 5-item GDS was as
      effective as the 15-item GDS for depression screening in this population, with a
      marked reduction in administration time. If validated elsewhere, it may prove to
      be a preferred screening test for depression.

PMID- 10404936
TI  - Factors influencing the proportion of food consumed by nursing home residents
      with dementia.
AB  - BACKGROUND: Assessment of and interventions for promoting eating in persons with
      late-stage dementia have primarily focused on facilitation of safe feeding and
      methods to promote ingestion of nutrients via several routes. Using Social
      Exchange Theory, this study examined how the quality of the interaction between
      care giver and care receiver influenced the proportion of food consumed by
      persons with late-stage dementia. METHODS: Fifty-three dyads composed of nursing
      home residents with late-stage dementia and Certified Nursing Assistants (CNAs)
      were observed during the breakfast meal. The proportion of food consumed by the
      residents was measured by weight. The study included measures of the quality of
      interaction between the resident and the CNA (Interaction Behavior Measure
      Modified (IBM-M) and the IBM), CNA empathy (Interpersonal Reactivity Index), and
      CNA power (Control subscale of the FIRO-B). RESULTS: Specific resident behaviors
      and the CNA's ability to allow another person to control a relationship were most
      predictive of the variance in the proportion of food consumed (R2 = .41; F(3,49)
      = 12.54; P < .001). The quality of the resident-CNA interaction accounted for 32%
      of the variance in the proportion of food consumed. One aspect of power was
      correlated significantly to the proportion of food consumed whereas CNA empathy
      was not. CONCLUSIONS: Because eating is the most social of all ADLs and is
      culturally bound, clinicians need to examine the interactional components of
      meals within the caregiving dyad when a person with late-stage dementia fails to
      ingest adequate nutrients.

PMID- 10404937
TI  - Management of the older person with ventricular arrhythmias.
AB  - OBJECTIVE: To review the prognosis and management of ventricular arrhythmias (VA)
      in persons with and without heart disease, with emphasis on older adults. DATA
      SOURCES: A computer-assisted search of the English language literature (MEDLINE
      database) followed by a manual search of the bibliographies of pertinent
      articles. STUDY SELECTION: Studies on the prognosis and management of VA in
      persons with and without heart disease were screened for review. Studies in older
      persons and recent studies were emphasized. DATA EXTRACTION: Pertinent data were
      extracted from the reviewed articles. Emphasis was placed on studies involving
      older persons. Relevant articles were reviewed in depth. DATA SYNTHESIS:
      Available data on the prognosis and management of VA in persons with and without
      heart disease, with emphasis on studies in older persons, were summarized.
      CONCLUSIONS: Ventricular arrhythmias in older persons without heart disease
      should not be treated with antiarrhythmic drugs, nor should Class I
      antiarrhythmic drugs be used to treat VA in older persons with heart disease.
      Beta-blockers should be used to treat complex VA in older persons with ischemic
      or nonischemic heart disease without contraindications to beta-blockers.
      Amiodarone should be reserved for life-threatening ventricular tachyarrhythmias
      in older persons who cannot tolerate or who do not respond to beta-blockers.
      Angiotensin-converting enzyme inhibitors should be used to treat older persons
      with heart failure, an anterior myocardial infarction, or a left ventricular
      ejection fraction < or = 40%. If older persons have life-threatening recurrent
      ventricular tachycardia (VT) or ventricular fibrillation (VF) resistant to
      antiarrhythmic drugs, invasive intervention should be performed. The automatic
      implantable cardioverter-defibrillator is recommended in older persons who have
      medically refractory sustained VT or VF.

PMID- 10404939
TI  - Incorporating education on palliative care into the long-term care setting.
      National Consensus Conference on Medical Education for Care Near the End of Life.
AB  - Approximately one-third of all Americans will pass through a long-term care
      facility before they die, and many who require palliative care will reside there
      during the final weeks and months of their lives. In order to address this need,
      the unique characteristics of long-term care facilities are outlined, and the
      incentives for all levels of academic institutions to offer education in that
      setting are presented.

PMID- 10404938
TI  - Calorie restriction in primates: will it work and how will we know?
AB  - Dietary caloric restriction is the most robust and reproducible means of slowing
      aging and extending lifespan and healthspan in short-lived mammals and lower
      organisms. Numerous aspects of this paradigm have been investigated in
      laboratories around the world since its inception more than 60 years ago.
      However, two questions about calorie restriction remain unanswered to this day:
      (1) By what mechanism does it work? and (2) Will it work in humans? This review
      will focus on the latter with particular emphasis on evaluation criteria, current
      studies in primate models, available data, and plans for actual human caloric
      restriction interventions.

PMID- 10404940
TI  - Chronic care clinics: why don't they work?

PMID- 10404941
TI  - Function, flying, and the Age-60 rule.

PMID- 10404942
TI  - The Center for Continence: a different concept for an old problem.

PMID- 10404943
TI  - Ethical problems in the use of antidementia drugs.

PMID- 10404944
TI  - Management of pneumonia in the nursing home.

PMID- 10404945
TI  - Assessing effective and balanced twenty-four-hour blood pressure reduction by
      treatment: methodological aspects.

PMID- 10404946
TI  - Effects on blood pressure of drinking green and black tea.
AB  - BACKGROUND: The flavonoid components of tea have been associated in
      epidemiological studies with a decreased risk of cardiovascular disease.
      Flavonoids have been shown to have antioxidant and vasodilator effects in vitro;
      we therefore postulated that drinking green or black tea attenuates the well
      characterized acute pressor response to caffeine and lowers blood pressure during
      regular consumption. OBJECTIVE: To determine whether green and black tea can
      attenuate the transient pressor effect of caffeine, or lower blood pressure
      during regular consumption. METHODS: In the first study, the acute effects of
      four hot drinks - green tea and black tea (at a dose equivalent to four standard
      cups), water matched to the teas for caffeine content ('caffeine') and water -
      were assessed in 20 normotensive men using a Latin-Square designed study. Clinic
      blood pressure was measured before and 30 and 60 min after each drink had been
      ingested. In the second study, the effects on blood pressure of regular green and
      black tea ingestion were examined in 13 subjects with high-normal systolic blood
      pressure and mild systolic hypertension (systolic blood pressure in the range 130
      150 mmHg) using a three-period crossover study. Five cups per day of green tea,
      black tea and caffeine (in hot water and matched to the teas) were consumed for 7
      days each, in random order. Twenty-four hour ambulatory blood pressure was
      measured at the end of each seven-day intervention. Results are presented as
      means and 95% confidence intervals (CI). RESULTS: An acute pressor response to
      caffeine was observed. Relative to caffeine, there were further acute increases
      in systolic and diastolic blood pressure at 30 min among those drinking green tea
      [5.5 mmHg (95%CI -1.4 to 12.4) and 3.1 mmHg (95%CI -0.1 to 6.3), respectively]
      and black tea [10.7 mmHg (95%CI 4.0 to 17.4) and 5.1 mmHg (95%CI 1.8 to 8.4),
      respectively]. The changes in blood pressure at 60 min were not significant The
      effect on 24-h ambulatory systolic and diastolic blood pressure of regular
      drinking of green tea [increases of 1.7 mmHg (95%CI -1.6 to 5.0) and 0.9 mmHg
      (95%CI -1.3 to 3.1), respectively] or black tea [increase of 0.7 mmHg (95%CI -2.6
      to 4.0) and decrease of 0.7 mmHg (95%CI -2.9 to 1.5), respectively] was not
      significant relative to caffeine. CONCLUSIONS: Contrary to our initial
      hypothesis, tea ingestion caused larger acute increases in blood pressure than
      caffeine alone. However, any acute effects of tea on blood pressure did not
      translate into significant alterations in ambulatory blood pressure during
      regular tea consumption.

PMID- 10404947
TI  - Ambulatory blood pressure predicts end-organ damage only in subjects with
      reproducible recordings. HARVEST Study Investigators. Hypertension and Ambulatory
      Recording Venetia Study.
AB  - OBJECTIVE: To determine whether the prediction of target-organ damage varies
      according to the reproducibility of 24 h blood pressure. SETTING: Seventeen
      hypertension clinics in northeast Italy. MAIN OUTCOME MEASURES: Correlations of
      left ventricular mass index and albumin excretion rate with 24 h and office blood
      pressures in relation to tertiles of ambulatory blood pressure reproducibility.
      PATIENTS AND METHODS: In 716 consecutive, stage I, hypertensives enrolled in the
      Hypertension and Ambulatory Recording Venetia Study (HARVEST), ambulatory blood
      pressure monitoring was performed twice, 3 months apart In all subjects, the
      albumin excretion rate was measured by radioimmunoassay, and in 567, the left
      ventricular mass index was assessed by echocardiography. RESULTS: The subjects
      were divided into tertiles of ambulatory blood pressure consistency (between
      monitoring differences, regardless of the sign). In the tertile of subjects with
      good reproducibility, correlation coefficients of systolic and diastolic
      ambulatory blood pressure with left ventricular mass and urinary albumin
      excretion were significant and higher than those of office blood pressure. In
      contrast, in the two tertiles with poorer reproducibility, the coefficients were
      barely or not significant for both pressures. The advantage of ambulatory blood
      pressure over office blood pressure in predicting target-organ damage was no
      longer present for systolic blood pressure differences greater than 3.8 mmHg and
      diastolic blood pressure differences greater than 3.1 mmHg. CONCLUSIONS: These
      data indicate that ambulatory blood pressure is a better predictor of left
      ventricular mass and urinary albumin excretion than office blood pressure, but
      only in subjects with good pressure reproducibility. Therefore, the assessment of
      hypertensive patients should be based on duplicate blood pressure monitorings.
      Recordings with 24 h systolic and diastolic blood pressure differences greater
      than 4 and 3 mmHg, respectively, should be considered with caution.

PMID- 10404948
TI  - Angiotensinogen M235T variant and salt sensitivity in young normotensive
      Caucasians.
AB  - BACKGROUND AND AIMS: A single-nucleotide variant of the angiotensinogen gene (AGT
      235T) has been associated with essential hypertension and increased plasma levels
      of angiotensinogen. This variant may also serve as a genetic marker for the
      increased blood pressure response to dietary salt intake, but the relationship
      between AGT genotype and salt sensitivity has not been studied until now. We
      therefore examined the relationship between the AGT 235T genotype and the blood
      pressure response to short-term dietary salt restriction in young normotensive
      men. SUBJECTS AND METHODS: A total of 187 young normotensive men were
      characterized for family history of hypertension, salt sensitivity, plasma
      parameters of the renin-angiotensin system under high- and low-salt diets, and
      the AGT 235T genotype. RESULTS: While the T allele was significantly associated
      with a positive family history of hypertension (chi2 = 7.0; P< 0.03) and higher
      plasma angiotensinogen levels (P< 0.015) and renin activity (P < 0.037), blood
      pressure under both diets was not significantly affected by the AGT genotype.
      When the subjects were classified into salt-resistant and salt-sensitive groups,
      genotypic distribution was nearly identical between both groups (frequency of T
      allele: 0.45 versus 0.46). CONCLUSION: Our findings demonstrate that the AGT 235T
      allele is significantly associated with a positive family history of
      hypertension, but is not an important determinant of the blood pressure response
      to dietary salt intake in young normotensive subjects. It is therefore unlikely
      that the AGT 235T genotype can serve as an early genetic marker of salt
      sensitivity.

PMID- 10404949
TI  - Biomechanical properties and chemical composition of the aorta in genetic
      hypertensive rats.
AB  - OBJECTIVE: To study the alteration in the biomechanical properties of the
      thoracic aorta and its composition in young normotensive Wistar-Kyoto (WKY) rats,
      spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP). METHODS: The
      in-vitro biomechanical properties of the aorta in 4- and 12-week-old SHRSP were
      determined by means of a tensile testing machine and compared with those of the
      SHR and WKY rats; in addition, a biochemical analysis of collagen, elastin and
      advanced glycation endproducts was performed. RESULTS: The aortic biomechanical
      properties were altered in the 4- and 12-week-old SHRSP, compared with age
      matched WKY rats and SHR. The maximum stress in the 12-week-old SHRSP was reduced
      by 27% compared with the normotensive WKY rats, and by 26% compared with the SHR.
      The maximum strain values in the 4- and 12-week-old SHRSP were lower than those
      in the age-matched WKY rats, by 12 and 9% respectively, whereas this value in the
      12-week-old SHR was significantly increased (by 26%) compared with the age
      matched WKY rats. No differences were observed in the aortic contents of collagen
      and elastin between the SHRSP and SHR. However, the extractability of collagen by
      pepsin digestion in the 12-week-old SHRSP was lower than that in the age-matched
      SHR and WKY rats, and a significantly larger accumulation of advanced glycation
      endproducts was observed in the 12-week-old SHRSP than in the age-matched SHR and
      WKY rats, suggesting a greater formation of collagen-derived cross-links in
      SHRSP. CONCLUSIONS: From these results, we conclude that decreased aortic
      distensibility and mechanical strength values are partly related to the greater
      formation of collagen-derived cross-links in 12-week-old SHRSP, and that the
      mechanical properties in SHRSP may be the result not only of the larger formation
      of collagen-derived cross-links but also of primary defects, since the aortic
      mechanical strength value was decreased even in 4-week-old SHRSP.

PMID- 10404950
TI  - Power spectra of arterial pressure and heart rate in streptozotocin-induced
      diabetes in rats.
AB  - BACKGROUND: Chronic diabetes is associated with alterations in autonomic
      modulation of the cardiovascular system. Although the rat has been used
      extensively in studies of experimental diabetes, there have been no reports on
      the changes in autonomic modulation of the cardiovascular function in chronic
      diabetic rats. OBJECTIVE: To examine chronic diabetic rats to determine the
      autonomic modulation of arterial pressure and heart rate variabilities in the
      time and frequency domain. MATERIALS AND METHODS: Diabetes was induced in rats by
      a single injection of streptozotocin, and 30 min of pulsatile arterial pressure
      was recorded in conscious rats, 5, 10-20 days and 12-18 weeks after the
      streptozotocin injection. Control rats were injected with vehicle. Beat-by-beat
      systolic arterial pressure and heart rate were obtained from pulsatile pressure.
      The spectral density powers of systolic arterial pressure and heart rate were
      calculated using fast Fourier transformation, and integrated in low-(0.015-0.25
      Hz), mid- (0.25-0.75 Hz) and high- (0.75-3.0 Hz) frequency bands. The standard
      deviations of systolic arterial pressure and heart rate were also calculated.
      RESULTS: Basal systolic arterial pressure and heart rate were reduced in diabetic
      animals studied 10-20 days and 12-18 weeks after the streptozotocin injection.
      The standard deviations of systolic arterial pressure and heart rate were also
      reduced in the chronically diabetic animals. Diabetes reduced low- and mid
      frequency variability but not the high-frequency variability of systolic arterial
      pressure. The low-frequency variability, but not the mid-frequency variability,
      of the heart rate was also reduced, while the high-frequency variability of the
      heart rate was reduced in the more chronically diabetic rats. CONCLUSION: Our
      findings that the mid-frequency band variability of arterial pressure was reduced
      in diabetic patients suggest that sympathetic modulation of the cardiovascular
      system is impaired, corroborating other studies in such patients using this and
      other approaches.

PMID- 10404951
TI  - Comparison of cardiovascular responses to intra-hippocampal mu, delta and kappa
      opioid agonists in spontaneously hypertensive rats and isolation-induced
      hypertensive rats.
AB  - OBJECTIVE: To investigate the cardiovascular effects of microinjection into the
      hippocampus of selective mu, delta and kappa opioid receptor agonists in
      anesthetized spontaneously hypertensive rats, isolation-induced hypertensive rats
      and their normotensive Wistar-Kyoto and group-housed Sprague-Dawley controls.
      METHODS AND RESULTS: The microinjection of a selective kappa agonist, spiradoline
      mesylate, (+/-)-(5alpha, 7alpha, 8beta)-3,4-dichloro-N-methyl-N-[7-(1
      pyrrolidinyl)-1-oxaspiro++ +[4.5]dec-8-yl]-benzeneacetamide mesylate) (5 nmol)
      into the dorsal region of hippocampus, where injection of control saline failed
      to affect cardiovascular activities, induced centrally mediated decreases in mean
      blood pressure and heart rate in both hypertensive and normotensive rats. The
      effects were blocked by prior treatment of the hippocampus with nor
      binaltorphimine dihydrochloride, a selective kappa opioid receptor antagonist The
      hypotensive and bradycardic effects were quantitatively similar between
      spontaneously hypertensive rats and Wistar-Kyoto rats and between isolated
      hypertensive rats and normotensive group-housed rats. The sequential
      administration of increasing doses (5, 10, 50 nmol) of the selective mu agonist
      [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin and delta agonists [D-Ala2, D-Leu5]
      enkephalin or [D-Pen2, D-Pen5]-enkephalin into the same areas of the hippocampus
      as used for the kappa agonist had no significant effects on mean blood pressure
      and heart rate in either hypertensive or normotensive rats. CONCLUSION: The
      present results extend our previous findings of a hippocampally mediated
      hypotensive effect of kappa agonists in the spontaneously hypertensive rat to the
      isolated rat model of hypertension and they establish that mu and delta opioid
      receptor agonists similarly applied are ineffective. Hippocampal kappa receptors
      may have a greater role in cardiovascular control than mu and delta receptors.

PMID- 10404952
TI  - Pretreatment with enalaprilat blunts nicardipine-induced sympathetic activation
      in spontaneously hypertensive and Wistar-Kyoto rats.
AB  - OBJECTIVE: We measured changes in heart rate and lumbar sympathetic nerve
      activity in conscious, spontaneously hypertensive and Wistar-Kyoto rats during
      acute blood pressure lowering with nicardipine, enalaprilat and concomitant
      nicardipine/enalaprilat administration. In a second experiment, we determined the
      effect of these drugs on arterial baroreflex control of lumbar sympathetic nerve
      activity. METHODS: Male spontaneously hypertensive and Wistar-Kyoto rats were
      instrumented for continuous heart rate, blood pressure and lumbar sympathetic
      nerve activity recordings. Twenty-four hours later in conscious rats,
      nicardipine, enalaprilat and enalaprilat/nicardipine were infused at sufficient
      doses to reduce mean arterial pressure by 20 mmHg over 30 min. In a second
      experiment with the same drugs, baroreflex curves relating lumbar sympathetic
      nerve activity to mean arterial pressure were analyzed using a logistic curve
      fitting program. RESULTS: Blood pressure reductions induced by the three infusion
      protocols were similar in magnitude and profile. In both spontaneously
      hypertensive and Wistar-Kyoto rats, nicardipine induced greater reflexive
      increases in lumbar sympathetic nerve activity than enalaprilat Pretreatment with
      a reduced dose of enalaprilat blunted subsequent nicardipine-induced sympathetic
      activation. Nicardipine tended to induce greater increases in the heart rate than
      enalaprilat, but overall, the difference was not significant Baroreflex
      sensitivity was similar regardless of drug class. Nicardipine significantly
      increased minimum nerve activity compared with enalaprilat in spontaneously
      hypertensive rats (similar trends were observed in Wistar-Kyoto rats). This
      increase in minimum nerve activity was blunted by enalaprilat CONCLUSIONS: These
      results indicate that pretreatment with an angiotensin converting enzyme
      inhibitor minimizes dihydropyridine-induced increases in sympathetic activity.
      This beneficial effect is attributable to suppression of minimum sympathetic
      activity. These data suggest that co-administration of an angiotensin converting
      enzyme inhibitor may improve the long-term cardiovascular benefit of
      dihydropyridine calcium channel blockers.

PMID- 10404953
TI  - Effect of losartan on heart rate and blood pressure variability during tilt test
      and trinitroglycerine vasodilation.
AB  - OBJECTIVE: To define the changes in variability of heart rate and of blood
      pressure during vasodilation in a group of hypertensive patients treated with an
      angiotensin II type I (AT1) receptor inhibitor. DESIGN: Losartan (50 mg/day at
      0800 h) or placebo were administered for 3 weeks according to a single blind,
      crossover, randomized protocol, to 18 hypertensive patients (16 men and two
      women, mean age 42 + 3.6 years). Continuous ECG recording and beat-to-beat blood
      pressure monitoring were carried out with subjects in the supine position and
      during a head-up tilt test, as well as after sublingual administration of
      trinitroglycerine. The elaboration of ECG traces in the frequency domain, was
      carried out using an autoregressive method and measured using the autoregressive
      moving average technique. RESULTS: Orthostatic stimulus, both during treatment
      with losartan and with placebo, caused a significant decrease in the heart rate
      high frequency power; on the other hand, the low frequency power appeared
      unchanged after placebo and was significantly reduced with losartan. Five minutes
      after the administration of trinitroglycerine, the low frequency power with
      placebo showed a significant increase (817 -+ 221 versus 465 + 101 ms2, P <
      0.03). No change was recorded in total power nor in low frequency or high
      frequency power during losartan therapy. The ratio of low frequency to high
      frequency powers showed a sympathetic prevalence during vasodilation only during
      placebo treatment, whereas a mainly unchanged balance was maintained during
      losartan treatment Blood pressure variability showed a sympathetic prevalence
      after upright and trinitroglycerine stimulation only in placebo-treated subjects.
      CONCLUSIONS: Our study demonstrated that vasodilation is not able to evoke an
      unbalancing of the autonomic modulation in hypertensive patients treated with an
      AT1 receptor inhibitor, but permits the maintenance of a significant vagal
      component, thus highlighting the favorable profile of this drug in the autonomic
      control of circulation.

PMID- 10404954
TI  - Estrogen improves abnormal norepinephrine-induced vasoconstriction in
      postmenopausal women.
AB  - OBJECTIVE: An exaggerated blood pressure response to mental stress in
      postmenopausal women has been reported but the underlying mechanism is not clear.
      In the present study, we examined the role of estrogen in the blood pressure
      response to mental stress. SUBJECTS AND METHODS: Hemodynamic responses to mental
      stress and constrictor responses to norepinephrine were compared in 18
      premenopausal (mean +/- SD age 33 +/- 5 years), 22 postmenopausal women (62 +/- 7
      years) and 13 postmenopausal women with estrogen replacement therapy (58 +/- 8
      years). Premarin was infused in 10 postmenopausal women to determine whether
      estrogen attenuates norepinephrine-induced vasoconstriction. The hemodynamic
      responses to a standard mental arithmetic test were measured. Norepinephrine
      (12.5, 25, 50, 100 ng/min) was infused at 0.5 ml/min for 5 min via the dorsal
      hand vein. Norepinephrine (100 ng/min) combined with premarin (200 microg/min)
      was infused into the dorsal hand vein of postmenopausal women. Changes in venous
      diameter were measured by ultrasonography using a 7.5 MHz transducer. RESULTS:
      All study subjects were healthy, normotensive and had normal lipid profiles. The
      postmenopausal women showed a significantly greater blood pressure response to
      the mental arithmetic test than the premenopausal women or those taking estrogen
      replacement therapy (P < 0.01). Norepinephrine induced significant dose-dependent
      vasoconstriction in all three groups (P < 0.001). The postmenopausal women showed
      significantly greater constriction in response to norepinephrine than the
      premenopausal women and those taking estrogen replacement therapy (P = 0.02).
      Premarin significantly attenuated the norepinephrine-induced vasoconstriction in
      the postmenopausal women (P< 0.001). CONCLUSION: Healthy, normotensive
      postmenopausal women showed an exaggerated blood pressure response to mental
      stress. An increased vasoconstriction in response to norepinephrine and loss of
      estrogen-mediated vasodilation may contribute to the increased blood pressure
      response to stress in postmenopausal women without estrogen replacement therapy.

PMID- 10404955
TI  - Malondialdehyde, lipofuscin and activity of antioxidant enzymes during physical
      exercise in patients with essential hypertension.
AB  - DESIGN: To clarify the role of oxidative damage in essential hypertension, levels
      of lipid peroxidation products (malondialdehyde and lipofuscin) and activity of
      antioxidant enzymes (superoxide dismutase and glutathione peroxidase) were
      examined during a short period of physical exercise. PATIENTS AND METHODS: We
      studied 11 male patients with mild to moderate essential hypertension in World
      Health Organization classes I or II and 10 healthy male controls. Physical
      exercise was performed on a bicycle ergometer at graded intensities of 1.0, 1.5
      and 2.0 W/kg body weight Plasma concentrations of lipofuscin, malondialdehyde,
      epinephrine, norepinephrine, insulin, free fatty acids and glucose were
      determined. Superoxide dismutase activity was analysed in erythrocytes and
      glutathione peroxidase activity in whole blood. RESULTS: Concentrations of
      lipofuscin and malondialdehyde were significantly elevated in hypertensive
      patients. Superoxide dismutase activity was not different between groups, while
      glutathione peroxidase activity was significantly decreased in hypertensive
      subjects. During exercise, the concentration of malondialdehyde and antioxidant
      enzyme activities increased significantly in both groups. No differences were
      found in absolute increases between the normotensive and hypertensive subjects.
      The levels of glucose, insulin and free fatty acids were similar in both groups.
      Basal concentrations of catecholamines and also the exercise-induced increases
      were lower in hypertensive patients. CONCLUSIONS: Our results indicate increased
      oxidative damage in patients with essential hypertension, which might be caused
      by a decrease in the activity of glutathione peroxidase. The ability of
      superoxide dismutase and glutathione peroxidase to respond to increased
      production of reactive oxygen species during a short period of physical exercise
      was not impaired in hypertensive subjects.

PMID- 10404956
TI  - Upregulation of renin-angiotensin system during differentiation of monocytes to
      macrophages.
AB  - BACKGROUND: We have demonstrated that accumulated macrophages in human coronary
      arteries strongly express angiotensin converting enzyme in accordance with the
      development of atheromatous plaques. However, there are few reports on the
      regulation of the renin-angiotensin system in macrophages and in monocytes as
      their source. OBJECTIVE: To examine whether the renin-angiotensin system is
      upregulated during the differentiation of monocytes to macrophages, and whether
      it is further regulated by angiotensin II and cytokines. MATERIALS AND METHODS:
      We used a human leukemia cell line, THP-1, for monocytes. Differentiated THP-1,
      induced by adding phorbol 12-myristate 13-acetate for 24 h, were used as
      macrophages. Expression of messenger RNA of the renin-angiotensin system
      components was measured by quantitative reverse-transcriptase polymerase chain
      reaction. Angiotensin converting enzyme activity and subtype-specific angiotensin
      binding sites of cultured cells, and angiotensin II production in the culture
      medium were measured. RESULTS: Macrophages expressed all components of the renin
      angiotensin system except chymase. Cellular angiotensin converting enzyme
      activity and angiotensin II in the medium were increased 3.2- and 4.5-fold during
      differentiation, respectively. Expression of angiotensin II type 1 (AT1) and type
      2 (AT2) receptors was increased 6.2-and 6.4-fold during differentiation, and was
      sustained for 7 days. Incubation with angiotensin II for 24 h caused
      downregulation of both AT1 and AT2 receptor messenger RNA, but the expression
      levels were still more than threefold higher compared with monocytes. The density
      of binding sites of AT1 and AT2 receptors in macrophages was 0.26 +/- 0.02 and
      0.15 +/- 0.01 fmol/10(6) cells, respectively. CONCLUSION: The renin-angiotensin
      system is markedly activated during monocyte/macrophage differentiation, and may
      participate in the development of atherosclerosis.

PMID- 10404957
TI  - Relative localization of angiotensin-converting enzyme, chymase and angiotensin
      II in human coronary atherosclerotic lesions.
AB  - BACKGROUND: Studies using cell cultures and animal models have indicated an
      important role for angiotensin II in atherosclerosis. In humans, at least two
      major enzymes are involved in the conversion of angiotensin I to angiotensin II:
      so-called angiotensin-converting enzyme (ACE) and chymase. Enhanced activation of
      chymase in atherosclerotic tissue homogenates has been reported in animal models,
      but its contribution to the generation of angiotensin II has not been studied.
      OBJECTIVE: To clarify the localization of chymase and its pathophysiologic role
      in the formation of angiotensin II, using human coronary arteries. DESIGN AND
      METHODS: Twenty-four coronary artery segments obtained from 14 autopsied patients
      were characterized histologically into the following categories: normal coronary
      arteries with diffuse intimal thickening, hypercellular lesions, atheromatous
      plaques and fibrosclerotic plaques. We compared the cellular localization of
      chymase, ACE and angiotensin II expression using immunocytochemical techniques.
      RESULTS: Chymase was expressed only in the cytosole of mast cells in all
      segments. On the basis of the histologic study, the number of chymase-positive
      cells in the intima of atheromatous plaques was significantly higher than that in
      normal coronary arteries with diffuse intimal thickening. The expression of
      angiotensin II in the intima was enhanced in hypercellular lesions and
      atheromatous plaques. Localization of angiotensin II in the intima was associated
      with that of ACE. Immunodouble staining did not show colocalization of
      angiotensin II and chymase. CONCLUSIONS: These results suggest an important role
      for the production of angiotensin II by ACE in the progression of atherosclerosis
      in human coronary arteries. Enhanced expression of chymase appears not to be
      involved in angiotensin II production in the intima.

PMID- 10404958
TI  - Co-expression of renin-angiotensin system genes in human adipose tissue.
AB  - OBJECTIVE: The renin-angiotensin system plays a central role in blood pressure
      regulation, both by affecting renal function and by modulating vascular tone and
      structure. Recent studies in rodents demonstrated the existence of several
      components of this system in adipose tissue. The activity of the renin
      angiotensin system appears to be regulated by food intake, suggesting that it may
      be involved in obesity-associated hypertension. Few data are available on the
      presence of renin-angiotensin system components in human adipose tissue.
      MATERIALS AND METHODS: In order to explore the expression of renin-angiotensin
      system genes in human adipose tissue and adipocytes, total RNA was isolated from
      whole adipose tissue (subcutaneous and omental) or cultured adipocytes (mammary)
      and subjected to reverse-transcriptase polymerase chain reaction with primers
      specific for human angiotensinogen, renin, renin-binding protein, angiotensin
      converting enzyme, chymase and type 1 and type 2 angiotensin receptors. RESULTS:
      Angiotensinogen, angiotensin converting enzyme and type 1 angiotensin receptor
      genes were widely expressed, both in human adipose tissue and in cultured human
      adipocytes. Furthermore, we found expression of the chymase and renin-binding
      protein genes in these samples. CONCLUSIONS: Our findings suggest the presence of
      a local renin -angiotensin system in human adipose tissue, with adipocytes being
      an important part of this system, and prompt speculation that this local renin
      angiotensin system may be involved in obesity-related disorders, including
      hypertension and the metabolic syndrome.

PMID- 10404959
TI  - Pharmacokinetic-pharmacodynamic interactions of candesartan cilexetil and
      losartan.
AB  - BACKGROUND: The variability of the blood pressure response to blockade of the
      angiotensin II type 1 receptor is influenced by renin status and pharmacokinetics
      and pharmacokinetic-pharmacodynamic interactions. OBJECTIVE: To compare the
      pharmacokinetic-pharmacodynamic interactions of two doses of an ester prodrug of
      a noncompetitive angiotensin II type 1 receptor antagonist, candesartan
      cilexetil, at 8 and 16 mg, with those of the reference angiotenisn II type 1
      receptor blocker, losartan, at the standard dose (50 mg), in a human model that
      controls renin status. DESIGN AND METHODS: In a double-blind placebo-controlled
      crossover study, we compared the effects on renin and mean blood pressure over 24
      h of single oral doses of candesartan cilexetil at 8 and 16 mg and losartan at 50
      mg in 16 sodium-depleted normotensive subjects. RESULTS: The area under the curve
      (0-24 h) for plasma active renin did not differ significantly between 8 mg
      candesartan cilexetil and 50 mg losartan, but was significantly higher for 16
      than for 8 mg candesartan cilexetil or for 50 mg losartan. The area under the
      curve (0-24 h) for the fall in mean blood pressure with 16 mg candesartan
      cilexetil (-197 +/- 96 mmHg/h) was significantly greater than that for placebo (
      112 +/- 81 mmHg/h; P< 0.05) but the difference was not statistically significant
      compared with either 8 mg candesartan cilexetil (-158 +/- 95 mmHg/h) or 50 mg
      losartan (-144 +/- 66 mmHg/h). The area under the curve (0-24 h) for the fall in
      mean blood pressure did not significantly differ between 8 mg candesartan
      cilexetil, 50 mg losartan and placebo. The area under the curve (0-24 h) for
      plasma active renin was significantly correlated to that for plasma levels of the
      active metabolite of losartan, EXP 3174 (r = 0.65, n = 16, P< 0.01). No such
      correlation was detected for each single dose of candesartan cilexetil but a dose
      response relationship was present when both doses were combined. CONCLUSIONS: The
      pharmacodynamic effects of a single oral dose of 16 mg candesartan cilexetil are
      greater than those of 50 mg losartan and 8 mg candesartan cilexetil. The
      variability in the pharmacokinetic-pharmacodynamic interaction is less pronounced
      for candesartan than for EXP 3174, which could result in reduced variability of
      the blood pressure effects in patients.

PMID- 10404960
TI  - Left ventricular mass correlates with fat-free mass but not fat mass in adults.
AB  - BACKGROUND: Left ventricular mass is associated with body size, obesity and blood
      pressure. Echocardiography is routinely used to estimate this parameter, which is
      usually indexed to body surface area to allow comparisons to be made between
      individuals and groups of different body size. However, in obese subjects, using
      left ventricular mass indexed to body surface area may inappropriately normalize
      left ventricular mass. OBJECTIVES: The aim of this study was to investigate the
      relationships between left ventricular mass and body composition and to determine
      the best determinants of left ventricular mass. SUBJECTS AND METHODS:
      Echocardiography and dual-energy X-ray absorptiometry were performed in 106
      subjects under primary care. Half were hypertensive subjects and the others were
      normotensive age- and sex-matched control subjects. Univariate correlations were
      studied between left ventricular mass and height, height1.5, height2.7, weight,
      body surface area, body mass index, waist: hip ratio, fat-free mass, bone mineral
      content and fat mass. Stepwise multiple linear regression was performed to
      determine the best determinants of left ventricular mass. RESULTS: Fat-free mass
      was correlated with left ventricular mass (r = 0.53, P = 0.0001) and was the only
      independent predictor of left ventricular mass (R2 = 0.30, P= 0.0001) by
      multivariate analysis. Fat mass did not correlate with left ventricular mass (r= 
      0.005, P= 0.96). Other measures of body size, including body surface area, waist:
      hip ratio, bone mineral content, weight, height, height 1.5, height2.7 and body
      mass index all were correlated with, but were not independent determinants of,
      left ventricular mass. CONCLUSIONS: Left ventricular mass is independently
      determined by fat-free mass but by no other measures of body size or composition.
      Specifically, left ventricular mass was neither correlated with nor determined by
      fat mass. None of the other measures of body size determined left ventricular
      mass. It may be more appropriate to index left ventricular mass to fat-free mass
      rather than to measures of body size which include fat mass.

PMID- 10404962
TI  - Single molecule detection and ultrasensitive analysis in life sciences.
      Proceedings of a workshop. Berlin, Germany, 30 September-2 October 1998.

PMID- 10404961
TI  - Gene expression and synthesis of natriuretic peptides by cultured human
      glomerular cells.
AB  - BACKGROUND: Atrial natriuretic peptide, brain natriuretic peptide and C-type
      natriuretic peptide belong to a family of hormones that have natriuretic and
      vasodepressor activity and may play a pathophysiologic role in hypertension,
      heart failure and renal failure. Whereas immunoreactive human forms of these
      three natriuretic peptides are found in renal tubules, it is not clear whether
      they are derived from the systemic circulation or from local production.
      OBJECTIVE: To examine the gene expression of natriuretic peptides in cultured
      human glomerular cells. MATERIALS AND METHODS: We sought to determine the
      presence of messenger RNA encoding for these natriuretic peptides using
      polymerase chain reaction following reverse transcription. The polymerase chain
      reaction products were confirmed by direct sequencing. Atrial natriuretic
      peptide, brain natriuretic peptide and C-type natriuretic peptide in cell-culture
      supernatants were measured by radioimmunoassays (with detection limits of 2.1,
      2.1 and 0.21 pmol/l, respectively). RESULTS: Atrial natriuretic peptide messenger
      RNA was not found in mesangial or glomerular epithelial cells (despite
      stimulation with tumor necrosis factor-alpha) except when the cells were cultured
      with a high concentration of fetal bovine serum (> 10%). Similarly, this peptide
      was not detected in supernatant unless the cells were cultured with fetal bovine
      serum at concentrations of > 10%. Brain natriuretic peptide messenger RNA was
      readily detected in cultured mesangial and glomerular epithelial cells with a
      lower concentration in the former. Brain natriuretic peptide was not found in the
      supernatant of resting mesangial cells but became detectable when incubated with
      tumor necrosis factor-alpha or fetal bovine serum. C-type natriuretic peptide
      messenger RNA was detected in mesangial and glomerular epithelial cells with a
      higher concentration in the latter. C-type natriuretic peptide was detected in
      the supernatant of resting glomerular epithelial cells and levels rose when
      incubated with increasing concentrations of tumor necrosis factor-alpha or fetal
      bovine serum. However, C-type natriuretic peptide was not detected in the
      supernatant of resting mesangial cells and remained undetectable following
      incubation with tumor necrosis factor-alpha or fetal bovine serum. CONCLUSION:
      Our results suggest differences in the synthesis of natriuretic peptides between
      glomerular mesangial and epithelial cells.

PMID- 10404963
TI  - Single-molecule DNA digestion by lambda-exonuclease.
AB  - We used a bead displacement sensor to determine the enzymatic shortening of
      individual molecules of unstained lambda-DNA attached to optically trapped beads.
      The setup has been described previously (Dapprich and Nicklaus: Bioimaging 6:25
      32, 1998) and works by observing the change in position of a trapped bead
      depending on its viscous drag force during motion. The drag force of a naked bead
      increases with each attached DNA molecule to a characteristic level that depends
      on the length and the number of DNAs per bead. A single undigested DNA molecule
      on a bead will remain stable for extended periods and exhibit a constant drag
      force in flow. If lambda-exonuclease is added, the drag force decreases from the
      level for one strand of DNA on a bead to that of a naked bead in about 45 min.
      This result indicates that the digestion of native lambda-DNA by lambda
      exonuclease occurs at an average rate of approximately 15-20 Hz.

PMID- 10404964
TI  - Fluorescence imaging of single molecules in polymer microspheres.
AB  - We report on far-field fluorescence imaging of single molecules in spherical
      polymer microparticles produced from solution by using microdroplet techniques.
      The fluorescence photobleaching quantum yields of rhodamine 6G in a common water
      soluble polymer (polyvinyl alcohol) are at least five times smaller,
      corresponding to proportionally larger average fluorescence signals, than those
      in ethanolic solvents. This allows for acquisition of multiple images from a
      single molecule on a time scale of several minutes. We also show that fluorescent
      images of single molecules in microspheres can be calculated from semiclassic
      electrodynamics, which may ultimately be useful in retrieving dynamical
      information from experimental images.

PMID- 10404965
TI  - Fluorescence correlation spectroscopy with single-molecule sensitivity on cell
      and model membranes.
AB  - We report on the successful application of fluorescence correlation spectroscopy
      (FCS) to the analysis of single fluorescently labeled lipid analogue molecules
      diffusing laterally in lipid bilayers, as exemplified by time traces of
      fluorescence bursts of individual molecules entering and leaving the excitation
      area. FCS measurements performed on lipid probes in rat basophilic leukemia cell
      membranes showed deviations from two-dimensional Brownian motion with a single
      uniform diffusion constant. Giant unilamellar vesicles were employed as model
      systems to characterize diffusion of fluorescent lipid analogues in both
      homogeneous and mixed lipid phases with diffusion heterogeneity. Comparing the
      results of cell membrane diffusion with the findings on the model systems
      suggests possible explanations for the observations: (a) anomalous subdiffusion
      in which evanescent attractive interactions with disparate mobile molecules
      modifies the diffusion statistics; (b) alternatively, probe molecules are
      localized in microdomains of submicroscopic size, possibly in heterogeneous
      membrane phases.

PMID- 10404966
TI  - Photon-burst analysis in two-photon fluorescence excitation flow cytometry.
AB  - We studied the use of a dramatically reduced testing zone in combination with two
      photon excitation and photon-burst analysis in high-throughput rare-event
      detection simulation using a modified flow cytometer. Two-photon excitation
      measurements were performed with a mode-locked titanium:sapphire laser.
      Fluorescence emission was measured with a photon-counting avalanche photodiode.
      Measured signal was analysed offline by autocorrelation and burst detection
      methods. Test samples were composed of full blood and orange fluorescent
      polystyrene nanospheres mixed in full blood. Results show that two-photon
      fluorescence excitation and time-correlation analysis provide a good signal-to
      noise ratio for rare-event particle detection in a turbid sample environment.

PMID- 10404967
TI  - 3D single-particle tracking and optical trap measurements on adhesion proteins.
AB  - A three-dimensional single-particle tracking system was combined with an optical
      trap to investigate the behavior of transmembrane adhesion proteins. We exploited
      this setup to investigate which part of the cell adhesion protein LFA-1 forms a
      connection to the cytoskeleton after binding to its ligand ICAM-1. LFA-1 is an
      integrin consisting of an alpha and a beta chain. Thus far, only the cytoplasmic
      tail of the beta chain is known to form a connection to the cytoskeleton. We
      investigated cells that express a mutant form of LFA-1 that lacks the complete
      beta cytoplasmic tail and therefore is not thought to bind to the cytoskeleton.
      Interestingly, single-particle tracking measurements using beads coated with the
      ligand ICAM-1 indicate that this mutant form of LFA-1 does not move freely within
      the cell membrane, suggesting that LFA-1 is still connected to the cytoskeleton
      network. This finding is strongly supported by the observation that LFA-1
      exhibits a more diffusive motion when the cytoskeleton network is disrupted and
      confirmed by the optical trap measurements used to force the proteins to move
      through the membrane. Collectively, our findings suggest that the interaction of
      LFA-1 with the cytoskeleton cannot solely be attributed to the cytoplasmic part
      of the beta chain.

PMID- 10404968
TI  - Theoretical investigation of aspects of single-molecule fluorescence detection in
      microcapillaries.
AB  - In the present report, the results of a theoretical investigation of two aspects
      of single-molecule detection by laser-induced fluorescence in microcapillaries
      are presented. The two issues studied are the scattering of the exciting laser
      beam on the microcapillary and the change of the fluorescence lifetime of the
      molecule due to the electrodynamic interaction between its fluorescence emission
      and the confining capillary. Numerical results for experimentally relevant
      conditions are provided.

PMID- 10404969
TI  - Single-molecule manipulation of double-stranded DNA using optical tweezers:
      interaction studies of DNA with RecA and YOYO-1.
AB  - By using optical tweezers and a specially designed flow cell with an integrated
      glass micropipette, we constructed a setup similar to that of Smith et al.
      (Science 271:795-799, 1996) in which an individual double-stranded DNA (dsDNA)
      molecule can be captured between two polystyrene beads. The first bead is
      immobilized by the optical tweezers and the second by the micropipette. Movement
      of the micropipette allows manipulation and stretching of the DNA molecule, and
      the force exerted on it can be monitored simultaneously with the optical
      tweezers. We used this setup to study elongation of dsDNA by RecA protein and
      YOYO-1 dye molecules. We found that the stability of the different DNA-ligand
      complexes and their binding kinetics were quite different. The length of the DNA
      molecule was extended by 45% when RecA protein was added. Interestingly, the
      speed of elongation was dependent on the external force applied to the DNA
      molecule. In experiments in which YOYO-1 was added, a 10-20% extension of the DNA
      molecule length was observed. Moreover, these experiments showed that a change in
      the applied external force results in a time-dependent structural change of the
      DNA-YOYO-1 complex, with a time constant of approximately 35 s (1/e2). Because
      the setup provides an oriented DNA molecule, we determined the orientation of the
      transition dipole moment of YOYO-1 within DNA by using fluorescence polarization.
      The angle of the transition dipole moment with respect to the helical axis of the
      DNA molecule was 69 degrees +/- 3.

PMID- 10404970
TI  - Study of single-molecule dynamics and reactions with classic light microscopy.
AB  - Single-molecule studies in the life sciences often deal with observation or
      spectroscopy. Studies of reactions are rare, and the light microscope has been
      used for such experiments only occasionally. In an experimental environment, for
      example, as is required for most nearfield scanning or electron microscopies, it
      is difficult to study single-molecule reactions of biological relevance.
      Therefore, we have developed techniques to study single-molecule reactions with
      classic (nonscanning) farfield light microscopy. The conversion of nicotinamide
      adenine dinucleotide (NAD+) and lactate to NADH (a reduced form of NAD+),
      pyruvate, and H+ catalyzed by a few LDH-1 enzyme molecules has been studied in
      substrate solutions with different viscosity using the NADH autofluorescence. It
      is even possible to monitor the progress of the reaction by phase-contrast
      microscopy via scattering or absorption by product molecules. As an example for a
      single-molecule reaction with a macromolecule as substrate, the handling and
      enzymatic cutting of fluorescently stained lambda-DNA is studied. In solutions
      containing 10 mM magnesium and 66 mM potassium ions at pH 7.9, an individual DNA
      molecule tends to collapse into a globular structure. When moved through an
      aqueous solution, it becomes stretched by viscosity drag. After stopping the
      motion, the molecule collapses and the dynamics of this process can be
      quantified. When a restriction enzyme is present, sequence-specific cutting can
      be directly observed in the light microscope. The theoretical restriction
      pattern, as predicted from the sequence of the molecule, can be generated
      directly under visual inspection.

PMID- 10404971
TI  - Dynamics of single dye molecules observed by confocal imaging and spectroscopy.
AB  - The fluorescence emission of single rhodamine dye molecules (rhodamine 6G and
      rhodamine 630) at room temperature was analyzed by using scanning confocal laser
      microscopy in conjunction with polarization analysis, fluorescence spectroscopy,
      time-resolved detection (minutes to microseconds), and excitation saturation.
      Results are presented and discussed 1) for samples with dye molecules at the
      glass-air interface and 2) covered with an additional thin protective polymer
      film (polyvinylbutyral). Under the polymer layer, the single-molecule
      fluorescence was more stable than the glass-air interface. This result may be
      explained by fewer spontaneous variations of the fluorescence rate, polarization
      changes, spectral shifts, and longer photochemical lifetimes.

PMID- 10404972
TI  - Single-molecule detection with total internal reflection excitation: comparing
      signal-to-background and total signals in different geometries.
AB  - Excitation of fluorescence with total internal reflection (TIR) excitation yields
      very low background scattered light and good signal-to-background contrast. The
      background and its associated noise can be made low enough to detect single
      fluorescent molecules under ambient conditions. In this paper, different TIR
      geometries were compared for excitation and detection of single rhodamine 6G
      (R6G) molecules at air-silica interfaces and single B-phycoerythrin proteins at
      water-silica interfaces. Through-objective, objective-coverslip, and prism-based
      TIR geometries were investigated. The signal-to-background ratio (SBR) and the
      number of photons detected before photobleaching (Nb) were optimum in different
      geometries. The greatest image contrast was obtained when using prism-TIR (SBR =
      11.5), but the largest number of detected signal photoelectrons was obtained by
      using through-objective TIR for R6G-air-silica (<Nb> = 10(4)). The results were
      discussed in terms of the TIR field enhancements and the modified dipole emission
      pattern near a dielectric interface. The SBR and total detected photons are
      important parameters for designing photon-limited experiments.

PMID- 10404973
TI  - Optical methods for exploring dynamics of single copies of green fluorescent
      protein.
AB  - Single copies of four different phenolate ion mutants of the green fluorescent
      protein (GFP) exhibit a complex blinking and fluctuating behavior, a phenomenon
      that is hidden in measurements on large ensembles. Both total internal reflection
      microscopy and scanning confocal microscopy can be used to study the blinking
      dynamics, and autocorrelation analysis yields histograms of the correlation times
      for many individual molecules. While the total internal reflection method can
      follow several single molecules simultaneously, the confocal method offers higher
      time resolution at the expense of parallelism. We compare and contrast the two
      methods in terms of the ability to follow the complex dynamics of this system.

PMID- 10404974
TI  - Visualising individual green fluorescent proteins with a near field optical
      microscope.
AB  - The use of the green fluorescence protein (GFP) as an individual marker for
      applications in molecular biology requires detailed understanding of its
      photophysical and photodynamical properties. We investigated individual S65T
      mutants of GFP both on a glass surface and embedded in a water-pore gel. An
      aperture-type near field scanning optical microscope (NSOM) with two polarisation
      detection channels was applied to afford high spatial (approximately 70 nm) and
      temporal (0.5 ms) resolution. Shear-force and near field fluorescence imaging
      were performed simultaneously, allowing direct correlation between topographic
      and optical features. Polarisation data showed that the emission dipole moment of
      the proteins is fixed in space within both the barrel structure of the protein
      and the gel matrix used for spatial confinement of the proteins. The
      photophysical behaviour of the S65T-GFP mutants was monitored in time, with 500
      micros real-time resolution and continuous imaging for periods of more than 2 h.
      Our results show the reversible on-off behaviour on a time scale that spans from
      10(-4) to 10(3) s. Even a process generally identified as "bleaching" turns out
      to be reversible if a sufficient long observation time is allowed. As such, the
      photodynamics of individual GFPs appear to be much more complex than the
      properties deduced from ensemble-averaged measurements.

PMID- 10404975
TI  - Analysis of interaction between chaperonin GroEL and its substrate using
      fluorescence correlation spectroscopy.
AB  - Fluorescence correlation spectroscopy (FCS) provides information about
      translational diffusion properties of fluorescent molecules in tiny detection
      volume and allows the analysis of binding processes of biomolecules in
      homogeneous solution. In this study, FCS was used to measure equilibrium binding
      constants of disulfide-reduced apo-alpha-lactalbumin (rLA), denatured pepsin, and
      apo-cytochrome c (apo-cyt c) bound by chaperonin GroEL at different salt
      concentrations. The results indicate that apo-cyt-c has a much stronger affinity
      to GroEL than denatured pepsin and rLA have. Titration experiments of GroEL to
      each substrate with various concentrations of four kinds of salts (K+, Na+, Ca2+,
      and Mg2+) show that the binding constant of denatured pepsin and rLA to GroEL
      depends on the salt concentration. The dependence of denatured pepsin binding to
      GroEL on salt concentration is much stronger than that of rLA. However, the
      interaction of positively charged apo-cyt c with GroEL is not affected by the
      salt concentration. Furthermore, the divalent cation promotes the binding of
      GroEL to denatured pepsin and rLA more strongly than does the monovalent cation.

PMID- 10404976
TI  - Imaging and force-distance analysis of human fibroblasts in vitro by atomic force
      microscopy.
AB  - The structure of human fibroblasts have been characterised in vitro by atomic
      force microscopy (AFM) operated in the imaging or in the force versus distance (F
      d) modes. The choice of cell substrate is important to ensure good adhesion. Of
      greater significance in the context of AFM analysis, is the observation that the
      substrate affects the imaging conditions for in vitro analysis of live cells. For
      instance, very rarely will glass coverslips lead to acceptable outcomes (i.e.,
      resolved cytoskeletal structure). Activated tissue culture dishes, on the other
      hand, promote conditions that routinely result in good quality images. Those
      conditions are then unaffected by adoption of relatively high force loadings
      (more than 10 nN), large fields of view (100 x 100 microm2) and high scan speeds
      (up to ca. 200 microm/sec), all of which exceed values recommended in the
      literature. Plasma membranes are fragile in the context of AFM analysis (F-d
      analysis gives an equivalent Young's Modulus of ca. 5 kPa). However, the present
      work suggests that fragility per se need not be a problem, rather it is the
      adhesive interactions with the tip, which under some circumstances may exceed 20
      nN, that are the source of poor imaging conditions. The present results, being
      supported by a qualitative model, suggest that the activated substrate acts as a
      preferential scavenger of cellular debris thus preventing the tip from
      biofouling, and will therefore promote low adhesion between tip and membrane.
      Good imaging conditions provide non-destructive in vitro information about
      cytoskeletal structure and dynamics, as shown in two examples concerned with
      cytochalasin treatment and with the MTT assay.

PMID- 10404977
TI  - When do strokes cause dementia? Effects of subcortical cerebral infarction on
      cortical glucose metabolism and cognitive function.

PMID- 10404978
TI  - Progenitor cell biology: implications for neural regeneration.
AB  - A few brief years ago, damage to the central nervous system was generally
      perceived to be irreparable, and loss of neurons was largely viewed as an
      irreversible process. However, major advances in the study of neural progenitor
      cells have altered these perceptions, and rational approaches to the repair of
      the damaged nervous system using transplanted progenitor cells now seem feasible.
      This review will discuss the basic biology of neural progenitor cells, the
      mechanisms regulating the generation of neurons and glia from these cells, and
      the techniques that are available for preparing such cells for transplantation
      into the nervous system. The potential uses for these cells in treating
      neurologic disease will then be reviewed, and the theoretical and technical
      problems that may be encountered will be discussed.

PMID- 10404979
TI  - New and emerging therapies for Parkinson disease.
AB  - Few neurological disorders have been more successful in introducing novel
      therapies than Parkinson disease (PD). However, despite enormous progress, many
      challenges remain. Although levodopa is still the most effective drug in the
      symptomatic treatment of PD, adverse effects, particularly motor fluctuations and
      dyskinesias, limit its usefulness. Furthermore, there is a growing concern about
      the escalating cost of PD treatment: the cost-benefit aspect of the novel
      approaches must be balanced against the advantages of long-term experience with
      established treatments.

PMID- 10404980
TI  - Glucocorticoids in central nervous system bacterial infection.
AB  - OBJECTIVE: To evaluate evidence-based data on adjunctive glucocorticoid therapy
      in central nervous system bacterial infections. DESIGN: A literature review of
      studies, particularly controlled trials, that have evaluated dexamethasone
      therapy for acute bacterial meningitis and glucocorticoid therapy for tuberculous
      meningitis. MAIN OUTCOME MEASURES: Clinical outcomes were mortality and morbidity
      rates. Morbidity involved sensorineural hearing loss and other neurologic
      deficits (motor or behavioral disturbances, epilepsy, cranial nerve palsy,
      hydrocephalus, and psychomotor retardation). RESULTS: The evidence-based data
      support adjunctive dexamethasone therapy for children with Haemophilus influenzae
      meningitis. However, the optimal duration of therapy is not defined. Data are
      supportive but not conclusive that dexamethasone benefits meningitis caused by
      other bacterial agents and meningitis in adults. The evidence-based data are
      supportive but not conclusive that adjunctive glucocorticoid therapy benefits
      patients with tuberculous meningitis, particularly those with more severe
      infection. CONCLUSIONS: Although adjunctive glucocorticoid therapy may be
      beneficial in both acute bacterial meningitis and more severe tuberculous
      meningitis, there are conclusive data only for H influenzae meningitis in
      children. For acute bacterial meningitis, further studies are needed to clarify
      the optimal duration of dexamethasone therapy (2 vs 4 days), whether this therapy
      should be used routinely for adults with meningitis, and whether it should be
      used for pathogens other than H influenzae. For tuberculous meningitis, further
      studies are needed to provide conclusive evidence of benefit.

PMID- 10404981
TI  - A new twist for stopping the shakes? Revisiting GABAergic therapy for essential
      tremor.
AB  - Aside from physiological tremor, essential tremor (ET) is by far the most common
      cause of tremor in humans, affecting large numbers of individuals in every human
      population. The crude prevalence of ET has been conservatively estimated to be
      between 0.4% and 3.9%, although some estimates of the prevalence of ET among the
      elderly are higher than 20%. Essential tremor is the most prevalent adult-onset
      movement disorder, and is also regarded as one of the most common neurological
      disorders of adults, with a prevalence that is similar to or greater than that of
      stroke, Alzheimer disease, migraine headache, and lumbosacral pain syndromes.
      Essential tremor is as much as 20 times more prevalent than Parkinson disease.

PMID- 10404982
TI  - Effects of subcortical cerebral infarction on cortical glucose metabolism and
      cognitive function.
AB  - BACKGROUND: The mechanism of dementia in subcortical cerebral infarction is
      incompletely understood. OBJECTIVE: To determine how cognitive function is
      related to cortical metabolism in patients with subcortical infarction and a
      continuum of cognitive impairment. METHODS: We used positron emission tomography
      (PET) and the glucose metabolic tracer fludeoxyglucose F 18 to study 8 patients
      with subcortical stroke and normal cognitive function (S-CN), 5 patients with
      subcortical stroke and cognitive impairment (S-CI) who did not have dementia, 8
      patients with subcortical stroke and dementia (S-D), and 11 controls with no
      cognitive impairment or stroke. A subset of patients had absolute regional
      cerebral metabolic rate of glucose (CMRglc) determined, while in all subjects
      regional tracer uptake normalized to whole brain tracer uptake was calculated.
      PET data were analyzed by constructing volumes of interest using coregistered
      magnetic resonance imaging data and correcting the PET data for atrophy. RESULTS:
      Global CMRglc was significantly lower in the patients with S-D than in the
      control and S-CN groups, with S-CI rates intermediate to those of the S-D and S
      CN groups. Absolute regional CMRs of glucose were similar in the S-D and S-CI
      groups and in the control and S-CN groups. The regional pattern, however, showed
      lower right frontal regional CMRglc ratios in all stroke groups compared with the
      controls. There were modest correlations between performance on the Mini-Mental
      State Examination and whole brain CMRglc when all 4 groups were included.
      CONCLUSIONS: These results demonstrate that subcortical infarction produces
      global cerebral hypometabolism, which is related to the clinical status of the
      patients. In addition, specific frontal lobe hypometabolism also appears to be a
      feature of subcortical infarction. Taken together, both global and regional
      effects on cortical function mediate the production of clinical symptoms in
      patients with subcortical strokes.

PMID- 10404984
TI  - Posterior cerebral artery territory infarcts in the New England Medical Center
      Posterior Circulation Registry.
AB  - BACKGROUND: Infarcts in the territory of the posterior cerebral arteries (PCAs)
      are common. Although associated clinical symptoms and signs are known, the
      mechanisms of stroke and the anatomical distribution of PCA territory lesions
      caused by the various stroke mechanisms are less well defined. Published reports
      have selected only special subgroups of patients. PATIENTS AND METHODS: We
      studied stroke mechanisms, infarct distribution, and clinical findings among 79
      patients in the New England Medical Center Posterior Circulation Registry in whom
      brain imaging scans showed infarcts that involved 1 or more cortical territories
      of the PCA. RESULTS: Forty-eight patients (61%) had infarcts limited to the PCA
      territory (pure PCA), while 31 (39%) also had infarcts in other territories
      (PCA+). Infarcts were in the cortical territory of the PCA in 47 patients (59%)
      and were cortical and deep in 32 (41%). Infarcts that were cortical and deep were
      more common in PCA+ lesions. Stroke mechanisms were embolism of cardiac origin
      (32 [41%]), proximal arterial disease (25[32%]), cryptogenic embolism (8[10%]),
      intrinsic PCA disease (7[9%]), vasoconstriction (4[5%]), and coagulopathy
      (3[4%]). Patients with cardiogenic embolism and intrinsic PCA disease often had
      pure PCA territory infarcts, while patients with proximal arterial disease more
      often had PCA+ infarcts. Visual abnormalities were present in 66 patients (84%).
      Motor weakness, cognitive and behavioral abnormalities, and ataxia were found in
      20 patients (25%); only 12 (15%) had sensory signs. CONCLUSIONS: The great
      majority of pure PCA and PCA+ territory infarcts are caused by cardiac or intra
      arterial embolism. Intrinsic PCA disease, vasoconstriction, and coagulopathy are
      less common causes of infarction.

PMID- 10404983
TI  - Inheritance of frontotemporal dementia.
AB  - BACKGROUND: Previous studies of families with fronto-temporal dementia (FTD)
      support an autosomal dominant inheritance pattern, but most studies have
      described genetic transmission in individual families specifically selected for
      the presence of multiple affected individuals. OBJECTIVE: To investigate the
      familial presentation and inheritance of FTD and related disorders among a large
      group of FTD index cases unselected for family history of dementia. DESIGN AND
      SETTING: We interviewed family members and reviewed medical records and autopsy
      reports at a university hospital and a university-affiliated hospital to
      determine the frequency of familial FTD and the most likely mode of inheritance.
      Characteristic families with the disorder are described, along with the history,
      clinical findings, and neuroimaging results in affected members of these
      families. PATIENTS AND PARTICIPANTS: The 42 index cases of FTD had a mean age of
      onset of 56.1 years (range, 40-69 years). Of these patients, 21 (50%) were women.
      All but one of the patients were white. Participants included male and female
      spouses and children of the index cases. family member with an FTD spectrum
      disorder and were considered familial cases. The majority (17 [89%]) of familial
      FTD cases showed a pattern consistent with dominant inheritance. If depression is
      excluded, familial cases decrease from 19 (45%) to 17 (40%), of which 15 (88%)
      showed a dominant transmission pattern. The initial presentations in the nonindex
      familial cases varied but most frequently consisted of personality and behavioral
      changes that preceded cognitive impairment (19 [43%]), followed by psychiatric
      illness (14 [33%]), dementia without behavioral change (5 [11%]), amyotrophic
      lateral sclerosis (5 [11%]), and parkinsonism (2[5%]). Two of the affected
      nonindex cases had dual presenting diagnoses. The average age of onset was 56.1
      years and did not differ significantly between familial and nonfamilial cases.
      Onset of FTD-related symptoms occurred after the age of 65 years in only 4(10%)
      of 42 index cases and 3 (5%) of 60 affected relatives. CONCLUSIONS: Familial FTD
      is usually inherited in an autosomal dominant pattern. The initial onset is
      insidious, often consisting of mood and behavioral changes occurring in presenile
      years that are often erroneously attributed to other nonneurologic causes.
      Although the precise incidence of FTD in North America is not known, it is one of
      the most common presenile dementias.

PMID- 10404985
TI  - Anatomy of sensory findings in patients with posterior cerebral artery territory
      infarction.
AB  - BACKGROUND: Posterior cerebral arteries (PCAs) supply the ventrolateral thalamic
      sensory nuclei and white matter sensory tracts to the somatosensory parietal
      cortex. Patients with PCA territory strokes often have visual, memory, cognitive,
      and sensory signs. Clinicoanatomic correlation of visual, cognitive, and memory
      functions are well defined but, to our knowledge, no systematic study has
      analyzed the anatomy of sensory abnormalities. OBJECTIVE: To assess the frequency
      and anatomic correlation of sensory symptoms and signs in patients with PCA
      territory infarction. PATIENTS AND METHODS: Sixty patients with hemispheral and
      hemispheral and deep PCA territory infarcts apparent on computed tomographic and
      magnetic resonance imaging scans were studied for the presence of sensory
      findings and location of infarcts. RESULTS: Sensory symptoms or signs were
      present in 15 (25%) of 60 patients. Among patients with sensory findings, 11 of
      15 had infarcts in the ventrolateral thalamus in the territory of the
      thalamogeniculate or lateral posterior choroidal arteries. The other 4 patients
      had no ventrolateral thalamic or white matter infarction but had severe proximal
      vascular occlusive lesions that could have caused temporary thalamic ischemia.
      One of these 4 patients had a medial thalamic infarct and transient hemisensory
      symptoms. Twelve patients had thalamic infarcts and no recorded sensory findings.
      Seven patients with thalamic infarcts (6 medial and 1 ventrolateral) had no
      sensory findings, and sensory findings could not be accurately assessed in 4
      patients with ventrolateral and 1 patient with medial thalamic infarcts.
      CONCLUSIONS: All patients with PCA territory infarcts and sensory findings either
      had thalamic infarcts in thalamogeniculate or lateral posterior choroidal artery
      territory or had thalamic ischemia. Sensory findings in PCA territory infarction
      indicate ventrolateral thalamic ischemia.

PMID- 10404986
TI  - Validity of a performance-based test of function in essential tremor.
AB  - BACKGROUND: The central factor influencing therapeutic decisions in essential
      tremor (ET) is the functional impact of the tremor. Neither the neurological
      examination nor computerized tremor analysis measures function. Questionnaires
      may assess function, but data are highly subjective. Performance-based tests of
      functional impairment provide an alternative means with which to assess the
      functional impact of ET. OBJECTIVE: To determine the internal consistency and
      validity of a performance-based measure of functional impairment in ET. METHODS:
      Subjects with ET from a community in northern Manhattan, NY, and from a clinic
      and control subjects each underwent a 2 1/2-hour evaluation including 12
      screening questions for ET, a 31-item Tremor Disability Questionnaire to assess
      the functional impact of tremor, a 26-item Videotaped Tremor Examination that was
      rated by a neurologist, a 15-item, 10-minute Performance-Based Test, and
      Quantitative Computerized Tremor Analysis. Internal consistency was assessed with
      Cronbach alpha. The correlation between the Performance-Based Test and these
      other measures of tremor was assessed by means of correlation coefficients (r).
      RESULTS: There were 50 ET cases and 51 normal control subjects. The Performance
      Based Test was internally consistent (Cronbach alpha = .92). It also demonstrated
      validity among cases; the total score correlated with the total number of
      screening questions answered yes (r = 0.44; P = .001), the total score on the
      Tremor Disability Questionnaire (r=0.55; P<.001), the total score on the
      Videotaped Tremor Examination (r=0.71; P<.001), and multiple physiological
      measures recorded during Quantitative Computerized Tremor Analysis. CONCLUSIONS:
      A valid performance-based test was developed to objectively assess functional
      capacity in patients with ET. This test would be useful in therapeutic trials,
      where it would provide an objective means to quantify the functional impact of
      tremor.

PMID- 10404988
TI  - Variability in annual Mini-Mental State Examination score in patients with
      probable Alzheimer disease: a clinical perspective of data from the Consortium to
      Establish a Registry for Alzheimer's Disease.
AB  - OBJECTIVE: To determine the variability in annual Mini-Mental State Examination
      scores of patients with Alzheimer disease enrolled in the Consortium to Establish
      a Registry for Alzheimer's Disease (CERAD). PATIENTS: A total of 372 patients
      with probable Alzheimer disease with 1 or more years of follow-up. SETTING:
      Twenty-one CERAD clinical sites throughout the United States. RESULTS: An average
      annual decline of 3.4 points in CERAD patients returning for longitudinal
      reassessments was close to the SD of the measurement error of 2.8 points for the
      Mini-Mental State Examination. There was wide variability in individual rates of
      decline. Even with 4 years of follow-up, 15.8% of the patients had no clinically
      meaningful decline in Mini-Mental State Examination score (defined as a change in
      initial score >3, ie, 1 SD of measurement error). Validity of measurements of the
      rate of change in Mini-Mental State Examination scores improved with longer
      observation intervals and was reliable for most patients when observations were
      separated by 3 or more years. CONCLUSIONS: Although the Mini-Mental State
      Examination is a useful screening instrument to assess level of cognitive
      function, it has limited value in measuring the progression of Alzheimer disease
      in individual patients for periods less than 3 years because of a large
      measurement error and substantial variation in change in annual score.

PMID- 10404987
TI  - Association of cervical artery dissection with recent infection.
AB  - BACKGROUND: Cervical artery dissection (CAD) is an important cause of ischemic
      stroke in younger patients. However, its cause is insufficiently understood.
      OBJECTIVE: To test the hypothesis that CAD is frequently associated with recent
      infection. SUBJECTS AND METHODS: We compared the prevalence of infection during
      the preceding week in 43 consecutive patients with acute CAD and 58 consecutive
      patients younger than 50 years with acute cerebral ischemia from other causes
      (control patients). In subgroups of patients, we correlated infectious status
      with electron microscopic studies of skin biopsy specimens and investigated
      pathways potentially linking infection and CAD. RESULTS: Recent infection was
      more common in patients with CAD (25/43 [58.1%]) than in control patients (19/58
      [32.8%]; P=.01). Respiratory tract infection was preponderant in both groups.
      Recent infection, but not the mechanical factors cough, sneezing, or vomiting,
      was independently associated with CAD in multivariate analysis. Investigation of
      serum antibodies against Chlamydia pneumoniae, smooth muscle cells, endothelial
      cells, collagen types I through IV, and heat shock protein 65 and assessment of
      serum alpha1-antitrypsin and HLA did not contribute to the understanding of the
      pathogenesis of CAD. More patients with pathologic findings in skin biopsy
      specimens tended to have had a recent infection (13/21 [62%]) than patients
      without pathologic findings (2/9 [22%]; P=.11). CONCLUSION: Our results suggest a
      significant association between recent infection and CAD that is not explained by
      mechanical factors occurring during infection.

PMID- 10404989
TI  - Laryngeal electromyographic findings in Charcot-Marie-Tooth disease type II.
AB  - Charcot-Marie-Tooth disease is a hereditary motor and sensory neuropathy that
      exhibits progressive muscular atrophy in the limbs, beginning with the lower
      extremities. It is now understood to be a heterogeneous group of disorders that
      can be differentiated both clinically and genetically. In Charcot-Marie-Tooth
      disease type II C, axonal neuropathy, diaphragm weakness, and vocal cord
      paralysis are described within kindreds. We used laryngeal electromyography to
      study a patient with this disorder. This technique has potential in the diagnosis
      of Charcot-Marie-Tooth disease type II.

PMID- 10404990
TI  - Intracranial hypotension with parkinsonism, ataxia, and bulbar weakness.
AB  - OBJECTIVE: To describe a case of spontaneous intracranial hypotension with a
      previously unreported constellation of presenting features. DESIGN: Case report.
      SETTING: Tertiary care center. MAIN OUTCOME AND RESULTS: We describe a patient
      with intracranial hypotension who presented with a parkinsonian syndrome and
      later development of ataxia and prominent bulbar symptomatology. Headache was not
      a feature of her initial presentation and was only reported after repeated
      questioning during later evaluations. Magnetic resonance imaging of the patient's
      head revealed findings characteristic of intracranial hypotension. An [18F]fluoro
      m-tyrosine positron emission tomographic scan showed normal striatal activity,
      suggesting intact presynaptic nigrostriatal function. Opening pressure on lumbar
      puncture was reduced at 40 mm H2O. A source of cerebrospinal fluid leakage was
      not identified on nuclear cisternography and the patient underwent lumbar
      epidural blood patching, which resulted in complete resolution of her signs and
      symptoms as well as in a marked improvement in her imaging findings. CONCLUSIONS:
      The clinical spectrum of intracranial hypotension can be broadened to include
      parkinsonism, cerebellar ataxia, and prominent bulbar dysfunction. As with more
      common manifestations of the disorder, these features may resolve after
      appropriate treatment.

PMID- 10404992
TI  - Is carotid endarterectomy appropriate for asymptomatic stenosis? No.

PMID- 10404991
TI  - Is carotid endarterectomy appropriate for asymptomatic stenosis? Yes.

PMID- 10404993
TI  - 1914 to 1917: the Great War years.
AB  - In 1914, American and international neurology were already very well developed,
      but like the other scientific and societal forces of the time, they underwent
      numerous changes as a result of World War I. This article reviews the state of
      neurology between 1914 and 1917 as it can be inferred from the journals of the
      time, the main topics they covered, the meetings, and the neurological societies,
      as well as some of the actors on the neurology scene during these years. It
      concludes with a brief survey of the ways in which neurology was changed by the
      Great War. During these years, neurology was there.

PMID- 10404994
TI  - Abnormalities of amyloid beta precursor protein expression in platelets of
      patients with Alzheimer disease: do we understand them well enough?

PMID- 10404995
TI  - Clustering of radiation-produced breaks along chromosomes: modelling the effects
      on chromosome aberrations.
AB  - PURPOSE: For high-LET radiations, and perhaps even for hard X-rays, DNA double
      strand breaks (dsb) are clustered nonrandomly along chromosomes;
      disproportionately, many inter-dsb segments are less than a few Mbp (10(6) base
      pairs). The implications of such dsb clustering for chromosome aberrations are
      analysed. METHODS: Chromosome segments between different dsb within one dsb
      cluster are assumed too small to detect in the aberration assay. Enumeration or
      Monte-Carlo computer simulations are used to compute the relative frequencies of
      many observable aberration patterns: apparently simple or visibly complex. The
      theoretical predictions are compared with X-ray data for human fibroblasts,
      involving painted chromosomes 1, 2, 4, 5, 7 or 13. RESULTS AND CONCLUSIONS:
      Surprisingly, cryptic dsb multiplicity does not affect the frequency ratios
      predicted for aberration patterns by a random breakage-and-rejoining model. The
      model is generally consistent with current data on many different types of
      aberrations, whether or not dsb usually occur in cryptic clusters. For a Revell
      type exchange model, however, the predictions do depend on clustering
      configurations; they gradually approach the predictions of the breakage-and
      rejoining model as average cluster multiplicity increases. The model is
      consistent with the data, for example with the ratio of visibly complex to
      apparently simple aberrations, only if there is considerable dsb clustering even
      at low-LET, with approximately 1.5 or more reactive dsb per cluster on average.

PMID- 10404996
TI  - Exposure temperature, but not donor age, is a confounding factor for in vitro
      translocation production by chronic irradiation.
AB  - PURPOSE: To assess the effects of incubation temperature during irradiation, and
      of donor age, on the in vitro induction of chromosomal translocations in human
      lymphocytes. MATERIAL AND METHODS: Lymphocytes from six human male donors were
      scored, using fluorescence in situ hybridization, for the presence of chromosomal
      translocations involving chromosomes 1 to 6 after in vitro, chronic exposure
      (delivered continuously over 48 h at 37 degrees C or at 20 degrees C) to tritium
      beta-rays or 60Co gamma-rays. RESULTS: No age-related difference in the alpha
      coefficients of the fitted induction curves was observed for gamma-ray-exposed
      lymphocytes obtained from four donors whose ages ranged from 24 to 79 years, or
      for tritium beta-ray-exposed lymphocytes from two donors aged 36 and 62 years.
      Duplicate samples from one donor, irradiated concurrently at 20 degrees C or 37
      degrees C, gave significantly different alpha coefficients: 0.128+/-0.008 and
      0.053+/-0.004, respectively (p<0.0001). The S-ratio (the ratio of induced
      complete to incomplete translocations) was found to be independent of radiation
      dose, donor age and exposure temperature. CONCLUSIONS: For biodosimetry in
      chronic irradiation situations, the use of alpha coefficients derived from the
      dose-response curves of cells chronically irradiated in vitro at body temperature
      is recommended. With respect to induction rates, donor age does not appear to be
      a confounding factor. The S-ratio is independent of radiation doses, exposure
      temperatures, or donor ages.

PMID- 10404997
TI  - Adaptation of human fibroblasts to radiation alters biases in DNA repair at the
      chromosomal level.
AB  - PURPOSE: To determine whether adaptation to ionizing radiation biases repair of
      radiation-induced chromosomal breaks. MATERIALS AND METHODS: Normal human
      fibroblasts were radiation-adapted by exposure to 10 cGy of gamma-radiation. FISH
      probes for chromosomes 2, 4, 7, 18 and 19 were used to determine the chromosomal
      origin of the DNA in micronuclei resulting from a subsequent 4Gy exposure of
      these cells, and corresponding non-adapted cells. RESULTS: Compared with 4 Gy
      exposed but non-adapted cells, the radiation-adapted cells subsequently exposed
      to 4 Gy showed an overall decrease in the frequency of micronuclei. However, the
      micronuclei that did form in the adapted cells had a decreased frequency of DNA
      originating from chromosomes 2 and 18, an increased frequency of DNA from
      chromosome 19 and no change in frequency of DNA from chromosomes 4 and 7.
      CONCLUSIONS: Adaptation to radiation increased the overall cellular repair of
      radiation-induced chromosomal breaks, but also created a repair bias such that
      some chromosomes were preferentially repaired or discriminated against, while the
      repair of others was unbiased.

PMID- 10404998
TI  - Cytogenetic analysis in human lymphocytes after exposure to simulated cosmic
      radiation which reflects the inflight radiation environment.
AB  - PURPOSE: To determine the relative biological effectiveness (RBE) of a mixed
      neutron-gamma-radiation field and its high LET component on the induction of
      chromosome aberrations in human lymphocytes. MATERIALS AND METHODS: Human
      lymphocyte cultures were exposed in vitro to low doses of simulated cosmic
      radiation (2.39-5.81 mGy) at low dose rates (0.04-0.15 mGy/h). Chromosome
      aberrations, micronuclei, and sister chromatid exchanges (SCE) were analysed. The
      RBE for dicentric chromosomes was given in comparison to 60Co gamma-rays.
      RESULTS: For the induction of dicentric chromosomes by simulated cosmic radiation
      the RBE was up to 64, and up to 113 when calculating only the high LET component.
      The investigation of micronuclei and SCE showed no significant differences
      between controls and irradiated samples. CONCLUSIONS: Preliminary data indicate a
      high biological effectiveness of cosmic radiation and its neutron component in
      comparison with 60Co gamma-radiation.

PMID- 10404999
TI  - Inverse dose-rate effect due to pre-mitotic accumulation during continuous low
      dose-rate irradiation of cervix carcinoma cells.
AB  - PURPOSE: To investigate the radiation sensitivity of asynchronous and
      synchronized cancer cervix cells irradiated with low dose rates. MATERIALS AND
      METHODS: Cells were exposed to 60Co gamma-rays at dose rates ranging from 0.33 to
      0.94 Gy/h. Synchronized cells were obtained by collecting detached mitotic cells
      after a shaking procedure. Cell survival was measured as the ability of cells to
      form colonies. Cell-cycle distributions were calculated by computer analysis of a
      DNA histogram recorded by flow cytometry. RESULTS: Irradiation of asynchronous
      cells at either 0.33 or 0.86 Gy/h resulted in exponential dose-survival curves
      with equal alpha-values, i.e. same radiation sensitivity, when dose-survival data
      for irradiation periods less than 20h were considered. However, the radiation
      sensitivity was higher by a factor of two when analysing dose-survival data for
      irradiation periods exceeding 20h. This increase in radiation sensitivity
      occurred when 80% of the cells accumulated in a pre-mitotic stage of the cell
      cycle. Irradiation of synchronized cell populations confirmed that these cells
      were a factor of two more sensitive to radiation in G2 than in G1. CONCLUSIONS:
      An inverse dose-rate effect, i.e. more efficient inactivation of cells at lower
      rather than at higher dose rates, was observed for radiation doses exceeding 7 Gy
      due to pre-mitotic accumulation of cells during low dose-rate irradiation.

PMID- 10405000
TI  - Epstein-Barr virus-transformed lymphoblastoid cell lines of ataxia telangiectasia
      patients are defective in X-ray-induced apoptosis.
AB  - PURPOSE: To investigate and compare the propensity of Epstein-Barr virus (EBV)
      transformed lymphoblastoid cell lines (LCL) obtained from unaffected healthy
      individuals and ataxia telangectasia (A-T) patients to undergo apoptosis after X
      ray exposure. MATERIAL AND METHODS: The LCL were exposed to 1-4 Gy X-rays at a
      dose-rate of 1.36 Gy/min. At various post-irradiation times (0, 24, 48 and 72 h)
      the induction of apoptosis was analysed by: (1) monitoring the formation of high
      molecular weight (HMW) DNA fragments by field inversion pulse gel electrophoresis
      (FIGE); and (2) morphological characterization of apoptotic cells after
      fluorescence staining. In parallel, cell-cycle distribution, monitored by DNA
      flow cytometry, was investigated in these cells. RESULTS: The LCL obtained from
      the A-T homozygotes were resistant to undergoing radiation-induced apoptosis
      during the observation time used. On the contrary, LCL from unaffected healthy
      controls displayed significant radiation-induced chromatin fragmentation seen at
      48 h and 72 h after irradiation. In these cells, radiation-induced G -arrest (24h
      post-irradiation) preceded chromatin cleavage. In A-T LCL, the defective G1
      arrest was not followed by apoptosis. CONCLUSIONS: In spite of a defective cell
      cycle control, EBV-transformed LCL of A-T patients compared with unaffected
      healthy controls do not undergo X-ray-induced apoptosis, at least during their
      first post-irradiation cell cycle.

PMID- 10405001
TI  - Mitotic catastrophe induced by exposure of V79 Chinese hamster cells to low
      energy protons.
AB  - PURPOSE: To determine the yield of mitotic catastrophe induced after low energy
      proton irradiation and to compare this yield with that induced by X-rays.
      MATERIALS: Asynchronous Chinese hamster V79 cells were irradiated with 0.5, 1, 2,
      5 and 10 Gy proton beams and X-rays. Proton LET of 7.7, 11.0 and 30.5 keV microm(
      1), corresponding to energies of 5.01, 3.20 and 0.76 MeV respectively, evaluated
      at the cell mid-plane, were used for experiments. The occurrence and yield of
      mitotic catastrophe was measured as the percentage of cells exhibiting fragmented
      nuclei. RESULTS: Proton irradiation led to an enhanced induction of mitotic
      catastrophe in V79 cells. The onset of nuclear fragmentation, a hallmark of
      mitotic catastrophe, occurred much earlier after cell exposure to proton
      particles than to X-ray irradiation. CONCLUSIONS: Mitotic catastrophe is
      persistent in the subsequent cell generations after proton and X irradiation of
      V79 cells; but protons are more effective than X-rays for the induction of this
      phenomenon. These results are discussed in terms of their importance in space
      exposures and possible acquisition of genomic instability by the progeny of
      irradiated cells.

PMID- 10405002
TI  - Effect of docetaxel (Taxotere) on expression of radiation-induced lethal
      mutations in human cell lines.
AB  - PURPOSE: To investigate if docetaxel, ionizing radiation or a combination of both
      induces delayed cell death in selected human normal or tumour cell lines.
      MATERIALS AND METHODS: The initial and residual surviving fractions were
      determined for two malignant human colon cell lines of widely different
      radiosensitivity (SW 48 and HT29) and for an immortal but non-malignant human
      keratinocyte line (HaCaT). RESULTS: Lethal mutations were observed only after the
      treatment of SW48 and HaCaT cells with radiation alone. No lethal mutations were
      found in the HT29 cell line. No lethal mutations were observed for any cell line
      treated with Docetaxel and the plating efficiency of progeny was actually
      increased above the control level. CONCLUSION: In all cases a combination of
      radiation and docetaxel prevented induction of lethal mutations despite the fact
      that radiation alone induced lethal mutations in the SW48 and HaCaT cell lines.
      This suggests that the effects of pre-treating with Docetaxel are in some way
      blocking or inhibiting the lethal mutation pathway. There appears to be a link
      between the tendency of the cell line to undergo apoptosis and lethal mutation
      expression.

PMID- 10405003
TI  - Radiobiological effects of docetaxel (Taxotere): a potential radiation
      sensitizer.
AB  - PURPOSE: To investigate the ability of docetaxel (Taxotere) to radiosensitize
      human cell lines of differing malignant status, intrinsic radiosensitivity and
      p53 status. MATERIALS AND METHODS: Cell survival following treatment with drug
      and/or radiation was determined by colony-forming assay on two malignant human
      colon cell lines of widely different radiosensitivity (HT29 and SW48). An
      immortal human keratinocyte line (HaCaT), which does not form tumours in nude
      mice, was used to assess the effect on non-malignant human epithelium. RESULTS:
      The experiments indicate that docetaxel had the greatest cytotoxic and
      radiosensitizing effect on the SW48 (p53wt) cell line. The degree of
      radiosensitization was not improved by increasing the drug concentration,
      although the overall cytotoxicity was increased with increasing concentrations of
      the two agents. Both p53mut lines were less sensitive to the drug, irrespective
      of their malignant potential. CONCLUSION: The results support a role for Taxotere
      as a weak radiosensitizer of the three cell lines tested. The p53 status and
      intrinsic radiosensitivity may be relevant to the mechanism.

PMID- 10405005
TI  - Protection against UV-induced systemic immunosuppression in mice by a single
      topical application of the antioxidant vitamins C and E.
AB  - PURPOSE: Reactive oxygen species are involved in UV-induced suppression of the
      immune system. Topical treatment with the antioxidant vitamins C (L-ascorbic
      acid, ASC) and E (D-alpha-tocopherol, TOC) can support the endogenous antioxidant
      defence system and prevent immunosuppression. MATERIALS AND METHODS: Mice were
      topically treated with a single dose of ASC, TOC or a combination and irradiated
      with UVB. Then systemic immunosuppression was measured using a model based on the
      induction of a contact hypersensitivity response to dinitrofluorobenzene. To
      investigate the mechanism of protection, cis-urocanic acid-induced
      immunosuppression was investigated in a different contact hypersensitivity model
      measuring local immunosuppression. The levels of ASC and TOC in the epidermis
      were determined by HPLC. RESULTS: Both ASC and TOC prevented UV-induced
      suppression of the contact hypersensitivity response. TOC was effective at doses
      of 2.5 to 10 nmol/cm2 and ASC at 0.5 to 5 micromol/cm2. At the highest dose, the
      response in the ASC-treated mice was no longer significantly different from that
      in the positive control group. Contrary to expectations, combinations of the two
      compounds did not provide additional protection. The experiments with ASC or TOC
      against immunosuppression by cis-urocanic acid also yielded protection, but this
      was less efficient than against UV. The concentrations of ASC and TOC in the
      epidermis were so low that UVB absorption could be excluded as the cause of the
      protection. CONCLUSIONS: ASC and TOC can be used to prevent systemic UV-induced
      immunosuppression. They are effective at relatively low doses after a single
      topical application prior to the irradiation.

PMID- 10405004
TI  - Interaction between low dose-rate irradiation, mild hyperthermia and low-dose
      caffeine in a human lung cancer cell line.
AB  - PURPOSE: To investigate cell killing by means of low dose-rate irradiation (LDRI)
      combined with concurrent mild hyperthermia and to determine the effect of low
      dose caffeine on this combination treatment. MATERIALS AND METHODS: Human lung
      adenocarcinoma cells, LK87, were treated with LDRI (50 cGy/h) in combination with
      mild hyperthermia at 41 degrees C and low-dose caffeine (1 mM). Cell survival was
      estimated by clonogenic assay. Flow-cytometry was performed with PI staining
      using FACScan. Heat-shock protein (HSP72/73) was measured by the Western blotting
      method. All treatments were simultaneously performed for up to 48 h (24 Gy).
      RESULTS: LDRI cytotoxicities were enhanced by hyperthermia at 41 degrees C. D0
      calculated from the dose-response curve for LDRI combined with 41 degrees C was
      3.46 Gy whereas it was 6.55 Gy for LDRI alone. The survival curve for LDRI +41
      degrees C demonstrated no chronic thermotolerance up to 48 h. For LDRI +
      simultaneous low-dose caffeine, cell killing was also enhanced, where D0 was 3.38
      Gy at 37 degrees C. Radiosensitization caused by caffeine was enhanced by
      combination with simultaneous mild hyperthermia at 41 degrees C, where D0=1.78
      Gy. Cell cycle analysis demonstrated remarkable G2 and mild G1 arrest for LDRI
      alone, but only G1 arrest was observed for LDRI combined with 41 degrees C and
      for LDRI combined with caffeine. Strong and early G1 arrest was observed in the
      treatment with LDRI + caffeine at 41 degrees C. The amount of HSP72/73 in the
      combination of LDRI with caffeine at 41 degrees C was less than that at 41
      degrees C alone. CONCLUSION: LDRI cytotoxicity was enhanced by non-lethal
      hyperthermia. Low dose caffeine produced further cell killing in the combination
      of LDRI with mild hyperthermia.

PMID- 10405006
TI  - Ionizing radiation alters hepatic cholesterol metabolism and plasma lipoproteins
      in Syrian hamster.
AB  - PURPOSE: The investigation of the effects of ionizing radiation on hepatic
      cholesterol metabolism and the concentration and composition of plasma
      lipoproteins in the male Syrian hamster. MATERIALS AND METHODS: After sublethal
      whole-body 60Co gamma-irradiation (8 Gy, 1 Gy/min), plasma lipoproteins were
      separated by density-gradient ultracentrifugation. Activities of
      hydroxymethylglutarylCoA (HMGCoA) reductase and of cholesterol 7alpha-hydroxylase
      were measured in hepatic microsomes and the low-density lipoprotein (LDL)
      receptor mass was determined in hepatic total membranes. Lipid peroxidation in
      LDL was assessed in vitro as the formation of conjugated dienes at 234 nm. A
      group of pair-fed animals served as controls as the food intake was markedly
      decreased with exposure to radiation. RESULTS: Plasma lipid concentrations
      decreased 2 days post-irradiation and then markedly increased by day 6 post
      irradiation; plasma cholesterol was increased by 77% and triglycerides by +207%.
      LDL accumulated in plasma while high-density lipoprotein (HDL) levels decreased.
      HDL contained significant amounts of apo SAA, the acute phase apolipoprotein. The
      activities of hepatic HMGCoA reductase, the rate-limiting enzyme for cholesterol
      synthesis, increased (+125%, p=0.06); hepatic cholesterol 7alpha-hydroxylase, the
      rate-limiting enzyme for bile acid synthesis, decreased (-85%); and the hepatic
      LDL receptor mass also decreased (-44%). The susceptibility of LDL to oxidation
      was also increased when animals were exposed to radiation. CONCLUSIONS:
      Lipoprotein modifications that appeared following radiation exposure may result
      from an induced inflammatory state and may further contribute to vascular damage.

PMID- 10405007
TI  - Changes in peripheral blood lymphocyte subsets in patients undergoing
      radiotherapy.
AB  - PURPOSE: To investigate the changes in peripheral blood lymphocyte subpopulations
      in patients undergoing radiotherapy. MATERIALS AND METHODS: In 8 patients
      undergoing external beam radiotherapy to the pelvis, the different lymphocyte
      subpopulations were followed during treatment. The lymphocyte populations were
      determined using two-colour flow cytometry. The study comprises the T-helper, T
      suppressor/cytotoxic cells, the B-lymphocytes and natural killer (NK) cells.
      RESULTS: The B-cells were characterized by a steep decrease at the beginning of
      the radiotherapy. They reached their lowest level at an equivalent total body
      dose of approximately 1.5 Gy and remained constant during the rest of the therapy
      (10% of the initial level). In T-cells (both T-helper and T-suppressor subsets)
      the steep decrease was less pronounced. T-lymphocytes reached a base level at 2.5
      Gy equivalent total body dose (20% of the initial level). No significant
      differences between the T-helper and the T-suppressor/cytotoxic cells were
      observed. NK cells were characterized by a weak decline during the first weeks of
      therapy, being less pronounced than in the other populations. Near the end of
      therapy, the NK cells reached the level of the T-lymphocytes. CONCLUSION: In
      vivo, NK cells were the most radioresistant and B-cells the most radiosensitive
      lymphocytes. No significant differences between T-helper and T
      suppressor/cytotoxic cells were observed. These data are in agreement with the
      differences in apoptosis induction in peripheral blood lymphocyte subpopulations
      after in vitro gamma-irradiation of whole blood lymphocytes.

PMID- 10405008
TI  - Long-term irradiation of a marine fish, the plaice Pleuronectes platessa: an
      assessment of the effects on size and composition of the testes and of possible
      genotoxic changes in peripheral erythrocytes.
AB  - PURPOSE: Previous investigation showed the very significant effects of chronic
      gamma-radiation on plaice testes at mean absorbed dose rates as low as 1.3 mGy h(
      1) given over a period of 168 days (accumulated dose 4.7 Gy). The present paper
      examines the effects on the testes of exposure to even lower dose rates of gamma
      radiation given over periods of 73 days or 197 days. In addition, the use of
      micronucleus counts and flow-cytometric measurement of nuclear DNA content in
      samples of peripheral blood for monitoring genotoxic effects has been assessed.
      MATERIALS AND METHODS: In Experiment 1, adult male plaice were exposed at mean
      absorbed dose rates of 0.25, 0.5 or 1.2 mGy h(-1) for 73 days (mean accumulated
      doses of 0.43, 0.85 and 2.03 Gy, respectively) and in Experiment 2 to 0.24, 0.5
      or 1.0 mGy h(-1) for 197 days (mean accumulated doses of 1.07, 2.24 and 4.57 Gy,
      respectively). At termination the testes were removed, weighed and sections were
      prepared and examined histometrically. In addition, in Experiment 2, blood
      samples were taken during exposure and at termination. Blood smears were scored
      for micronuclei and samples processed and examined for nuclear DNA content by
      flow cytometry. RESULTS: Significant reductions in testis weight were seen in all
      radiation groups after 197 days of exposure, which were predominantly due to
      decreased amounts of sperm. In plaice killed after 73 days (at an earlier stage
      of spermatogenesis), there were no significant differences in weight compared
      with controls but amounts of spermatogonia were significantly reduced in
      irradiated fish. CONCLUSIONS: Exposure to dose rates as low as 0.24 mGy h(-1) of
      gamma-radiation given over a period of 197 days significantly reduced the weights
      of plaice testes, this being consequent on reductions in the amounts of sperm.
      Although there was some evidence of radiation affecting the numbers of
      spermatogonia it was not possible to determine the primary target for radiation
      damage which eventually caused the sperm reductions. Along with the related work
      described by Greenwood and Knowles (1996) this is the first investigation of a
      marine fish and it indicates that plaice testes are probably more radiosensitive
      than those previously described in tropical fish and of a similar
      radiosensitivity to mammalian testes. Although significant effects were observed
      after the lowest dose rate used of 0.24 mGy h(-1), this is still a factor of
      about 400 times greater than the estimated absorbed dose rate to plaice testes in
      the north-east Irish Sea off Sellafield at the present time. Micronucleus counts
      and flow-cytometric analysis of blood DNA both failed to show any evidence of
      genotoxic damage.

PMID- 10405009
TI  - Neighbourhood characteristics and use of benzodiazepines in The Netherlands.
AB  - This paper analyses the relationship between individual and neighbourhood
      characteristics and the use of benzodiazepines within a Dutch city. It is
      hypothesized that the proportion of users is lower in more socially integrated
      and less deprived neighbourhoods. Hypotheses have been tested by using multi
      level analysis to distinguish between composition and context effects. Age and
      gender have a clear relation to the use of benzodiazepines and neighbourhood
      differences in the proportion of users are partly the effect of population
      composition by age and gender. The proportion of users is higher in
      neighbourhoods with a higher percentage of one-parent families, with a lower
      percentage of social rented housing and with a larger number of rooms per person.
      The strength of the relation between age and use is influenced by neighbourhood
      characteristics. Neighbourhood variation in the amount used only depends on
      population composition.

PMID- 10405010
TI  - Do risk factors and health behaviours contribute to self-ratings of health?
AB  - This study examined the relative importance of five risk factors and health
      behaviours (namely dietary habits, leisure time exercise, smoking, alcohol
      consumption and body mass index) on self-ratings of health among the Swedish
      adult population. The data come from the 1991 Swedish Level of Living Survey, a
      face-to-face survey interview based on a sample representative of the Swedish
      population aged between 18 and 75 years (n = 5306). The analyses were carried out
      using logistic regression analysis. With the exception of the consumption of
      dietary fat, all the risk factors and health behaviours studied were associated
      with self-rated health. When they were adjusted for health problems and
      functional limitations most of the associations weakened or disappeared
      altogether, but smoking and use of vegetables in the diet were still associated
      with self-rated health. Self-ratings of young adults (18-34 years) were found to
      be related to body mass index even when health problems were adjusted for, with
      both obesity and underweight contributing to less than good self-rated health.
      The results indicate that risk factors and health behaviours do not, in general,
      directly contribute to self-ratings of health. Instead, their effect is mediated
      by more specific health problems and their functional consequences. However,
      smoking and not consuming vegetables, as well as obesity and underweight among
      young respondents, were found to have an independent association with self-rated
      health. This may reflect the effects of health problems not captured by our
      indicators of ill health, but may also indicate that risk factors and risky
      behaviours are considered to have an effect on one's perceived health even in the
      absence of health consequences.

PMID- 10405011
TI  - Social support, social selection and self-assessed health status: results from
      the veterans health study in the United States.
AB  - This study provided a comprehensive assessment of the association between social
      support and health using longitudinal data from the Veterans Health Study. Unlike
      previous studies which examined the relationship between one single domain of
      social support with either mental or physical health, the present study assessed
      the effects of three different domains of social support on multiple measures of
      health. The findings of the study indicated that social support tended to mediate
      the deleterious effects of non-military traumatic events; whereas the adverse
      consequences of traumatic events experienced in the military were not affected by
      social support, suggesting that stressors associated with combat had a long
      lasting effect on the health status of veterans. The study results revealed that
      compared with those with better health, respondents with poor health were more
      likely to have lower levels of social support, suggesting that poor health might
      be a barrier to a person's ability to participate and/or maintain social
      relationships. The study also showed that different types of social support had
      varying beneficial effects on different measures of health. While perceived
      support had a strong effect on all the measures of health (except alcoholism)
      included in the study, living arrangement had a significant effect on post
      traumatic stress disorder or physical health and participation in group
      activities had a strong effect only on physical functioning. The results of the
      study highlight the need for future research to determine whether particular
      types of social support affect various aspects of health differently. This
      simultaneous focus on multiple support functions and health outcomes is important
      because it provides insight into the mechanisms linking social support to health.

PMID- 10405012
TI  - The influence of the cardiac surgery patient's sex and age on care-giving
      received.
AB  - Care-giving research has predominantly focused on the care-givers of those with
      long-term illness and the elderly. Little attention has been given to examining
      care-giving from the perspective of the person receiving the care,
      differentiating how the sex or age of the person may influence the care received,
      or examining care-giving in the context of shorter term situations where the
      patient is expected to recover. The purpose of this study was to examine the
      characteristics of the informal care-givers of cardiac surgery patients from
      three hospitals in one Canadian province and the effect of patient
      characteristics (sex, age) on their experience of receiving that care. A
      prospective, non-randomized design, was used to examine the short-term recovery
      from cardiac surgery of 120 subjects (60 men, 60 women). Patients were
      interviewed preoperatively and then at monthly intervals through the third
      postoperative month. The findings from this study suggest that the patterns of
      informal care-giving noted in the chronic care literature are also present in the
      short-term care of post-surgical cardiac patients. The burden of care-giving
      continues to rest predominantly on women. Female patients relied on their spouses
      for help less frequently than did male patients and their care-givers were more
      frequently employed outside the home and in lower status jobs than were the care
      givers of male patients. 30% of care-givers were reported to have a health
      problem of their own to manage while caring for the recovering patient. Patients
      who were male or who were < 65 years of age had higher social support scores than
      did patients who were female or who were > or = 65 years of age. These findings
      suggest that the cardiac patient's sex affects the availability of home-based
      care. In addition, care-givers may themselves be patients in need of care.
      Further research is needed to examine the receipt of home-based care-giving,
      particularly for female patients.

PMID- 10405013
TI  - Disease activity and severity in patients with rheumatoid arthritis: relations to
      socioeconomic inequality.
AB  - The aim of this study was to investigate possible differences in measures on
      disease process, joint damage, health status and self-efficacy between patients
      with rheumatoid arthritis (RA) living in an affluent and in a less affluent area
      in the same city. We analyzed data collected on patients enrolled in a community
      based register of patients with RA in Oslo, Norway. 246 patients were examined by
      questionnaire in 1994 and 133 patients were examined clinically in 1997. Measures
      on disease process, joint damage, health status and self-efficacy were compared
      between patients from two residential areas. There was no significant difference
      regarding joint counts, patients' or investigator's evaluation of disease
      severity, blood test results and number of joint replacements. Significant
      differences were observed for disability and for various dimensions of health
      measured by the arthritis impact measurement scales and the short form-36:
      patients in the less affluent area reported poorer health status. Patients in
      this area also showed significantly lower scores on the arthritis self-efficacy
      scale. Patients with RA in two socioeconomically different areas in Oslo thus
      were found to be equal regarding disease process and joint damage measures.
      However, in the measures reflecting physical and psychosocial health status,
      patients in the less affluent area seemed to be more seriously ill. They also
      showed less confidence in their ability to influence the disease. Even in a
      welfare society with universal access to health care the impact of a well-defined
      chronic disease seems to be closely linked to the patient's socioeconomic
      situation.

PMID- 10405014
TI  - Social inequalities in male mortality amenable to medical intervention in British
      Columbia.
AB  - The objective of this study is to examine the rates of mortality among different
      social classes and socioeconomic groups of British Columbian males from causes of
      death amenable to medical intervention. We examined the rates of avoidable
      mortality from the causes of death published by Charlton, excluding causes of
      death restricted to women as well as perinatal deaths. For the purposes of our
      study, we determined a population at risk using 20% samples of occupational data
      for men from the 1981, 1986 and 1991 censuses conducted by Statistics Canada. For
      the analysis of mortality by social class, individuals were divided into five
      social class levels based on occupation using an adaptation of the UK Registrar
      General's Social Class Scale. In addition, three levels of socioeconomic analysis
      were performed using the Blishen Index classification system. Once individuals
      were assigned to a social class in each classification system, the death rates
      from each amenable cause was calculated and standardized to the total population.
      For almost every cause of death examined, the rate of mortality was higher in
      individuals of lower social and socioeconomic classes than in individuals of the
      upper social and socioeconomic classes. These results were consistent regardless
      of the social class component, education, occupation, or income was being
      measured. The mortality gradient was most notable in deaths due to hypertensive
      heart disease, tuberculosis, asthma and pneumonia and bronchitis. Due to the fact
      that these causes of death were observed to be consistently higher in the lower
      social classes, we feel that specific measures aimed at improving survival from
      these conditions in lower social classes could help to amend the social class
      disparity.

PMID- 10405015
TI  - Explaining differential rates of mortality decline for Swedish men and women: a
      time-series analysis, 1945-1992.
AB  - The aim of this study is to identify social factors that could be related to
      differential rates of mortality decline for men and women in Sweden. The annual
      changes in fifteen indicators and their relationship with changes in absolute
      excess male mortality were analyzed by means of time series analysis for the
      period 1945-1992. Economic growth seems to have been more beneficial for women's
      survival than for that of men. A few labor market indicators (unemployment rate
      and the wage ratio men/women) may have had some influence on changes in excess
      male mortality as well. Consumption factors, such as alcohol consumption and
      cigarette consumption, have been important for changes in excess male mortality.
      Changes in excess male mortality have been particularly pronounced among 65-74
      year olds, due to rapidly improved female survival in these age groups. I discuss
      the finding that there seem to be connections between, on the one hand, changes
      in general social factors such as economic growth and labor market factors, and
      perhaps urbanization and alcohol and cigarette consumption on the other. I
      therefore suggest that gender-specific consumer behavior, seen as an outcome of
      gender-specific norm systems, is one mechanism which links changes in general
      social factors to changes in excess male mortality.

PMID- 10405016
TI  - Ethnicity and attitudes towards life sustaining technology.
AB  - The ethical and legal implications of decisions to withhold and withdraw life
      support have been widely debated. Making end-of-life decisions is never easy, and
      when the cultural background of doctor and patient differ, communication about
      these issues may become even more difficult. In this study, we examined the
      attitudes of people aged 65 and older from different ethnic groups toward
      foregoing life support. To this end, we conducted a survey of 200 respondents
      from each of four ethnic groups: European-American, African-American, Korean
      American and Mexican-American (800 total), followed by in-depth ethnographic
      interviews with 80 respondents. European-Americans were the least likely to both
      accept and want life-support (p < 0.001). Mexican-Americans were generally more
      positive about the use of life-support and were more likely to personally want
      such treatments (p < 0.001). Ethnographic interviews revealed that this was due
      to their belief that life-support would not be suggested if a case was truly
      hopeless. Compared to European-Americans, Korean-Americans were very positive
      regarding life-support (RR = 6.7, p < 0.0001); however, they did not want such
      technology personally (RR = 1.2, p = 0.45). Ethnographic interviews revealed that
      the decision of life support would be made by their family. Compared to European
      Americans, African-Americans felt that it was generally acceptable to withhold or
      withdraw life-support (RR = 1.6, p = 0.06), but were the most likely to want to
      be kept alive on life-support (RR = 2.1, p = 0.002). Ethnographic interviews
      documented a deep distrust towards the health care system and a fear that health
      care was based on one's ability to pay. We concluded that (a) ethnicity is
      strongly related to attitudes toward and personal wishes for the use of life
      support in the event of coma or terminal illness, and (b) this relationship was
      complex and in some cases, contradictory.

PMID- 10405017
TI  - The meanings of pain: an exploration of women's descriptions of symptoms.
AB  - A grounded theory study with repeated semi-structured interviews was conducted to
      explore the meaning of the illness experiences of women patients, impaired by
      biomedically undefined musculoskeletal pain. Twenty female patients were
      recruited at an urban primary health care centre in northern Sweden, where two of
      the researchers work as family physicians. In this paper we focus on
      considerations of patient pain and analyze the findings from aspects linking
      together body, gender, and society. Four categories of symptom description were
      identified: bodily presentations, explanatory models, consequences of pain for
      the patient's activities, and consequences for her self-perception. The bodily
      symptoms signaled loss of control. The explanatory models consisted of physical
      damage and strain injuries, but were also psychological and self-blaming. The
      consequences of pain were described as negative consequences for the women's
      everyday life that challenged their self-perception as women. The participants'
      search and need for legitimization of their illness experiences, and the
      expectations placed on doctors as legitimizing agents was evident. To achieve the
      desired shared understanding in consultations, doctors must be aware of and
      consider not only physical signs and symptoms, but also the patients' gendered
      concerns and psycho-social circumstances.

PMID- 10405019
TI  - The historical roots of high rates of infant death in Aboriginal communities in
      Canada in the early twentieth century: the case of Fisher River, Manitoba.
AB  - Infant mortality is investigated for a period of thirty years at the beginning of
      the 20th century in the Aboriginal Nations community of Fisher River, Manitoba.
      Infant mortality rates were generated from parish records of infant burials from
      the Methodist mission at Fisher River and later archived at the United Church
      Archives in Winnipeg, Man. The average infant mortality rate (IMR) for the total
      period (1910-1939) was 249 per 1000 live births, an exceedingly high rate
      compared to modern IMRs and even higher than those in developing countries today.
      Acute respiratory infections were found to be the cause of death in the majority
      of cases. These infectious diseases and high rates of postneonatal infant
      mortality point to conditions of poverty associated with malnutrition as the
      major precipitating factor in infant death. Fisher River, like other early 20th
      century First Nations communities in Canada, experienced socio-economic
      deprivation because of the decline of the fur trade and the underdevelopment of a
      reserve economy competing for resources with the Canadian government and Euro
      Canadian settlers. These conditions of economic and political marginalization are
      concluded to be the ultimate causes of high rates of infant mortality and are
      incorporated in a disease ecology model.

PMID- 10405018
TI  - The health transition, global modernity and the crisis of traditional medicine:
      the Tibetan case.
AB  - The epidemiologic and demographic consequences of the health transition, coupled
      with worldwide pressures for health care reform according to neoliberal tenets,
      will create new opportunities, and well as new problems, for organized systems of
      indigenous medicine. Spiraling costs of biomedically-based health care, coupled
      with an increasing global burden of chronic, degenerative diseases and mental
      disorder, will produce significant incentives for the expansion of indigenous
      alternatives. Yet this expansion will be accompanied by pressures to rationalize
      and modernize health care services according to the structurally dominant
      scientific paradigm. Without concerted effort to maintain native epistemologies,
      indigenous medical systems face an inevitable slide into narrow herbal traditions
      and a loss of those elements of diagnosis and therapy which may be the most
      valuable and effective. Analyzing the case of Tibetan medicine and other Asian
      medical systems, I show how this process occurs and how it is resisted. I
      conclude by discussing the policy dimensions of this problem.

PMID- 10405020
TI  - Disease and immunity in the pre-Spanish Philippines.
AB  - It is generally asserted that Filipino populations did not suffer the same
      demographic collapse that followed Spanish conquest in the Americas because they
      had previously acquired immunity to Old World diseases through trading contacts
      with Asia. This assertion is examined by trying to establish which diseases were
      present in the islands in pre-Spanish times and whether populations there could
      have acquired immunity to them. This is done through an analysis of the evidence
      for the presence of infections in China and Japan in particular and the existence
      of trading contacts with and between the Philippine islands. The likelihood of
      immunity being acquired is addressed first through a discussion of the physical
      and human geography of the islands and what is known of the epidemiology of
      individual diseases from modern scientific research. Second, it reviews evidence
      from early colonial documents and Filipino dictionaries for the presence and
      impact of Old World diseases in the early colonial period. The study suggests
      that Filipino populations had not acquired significant immunities to acute
      infections in pre-Spanish times, and that their limited demographic impact in the
      colonial period derived more from the particular geography of the islands. It
      suggests that in terms of its disease history, the Philippines had more in common
      with the Pacific islands than mainland Asia, and that the microbiological
      boundary between the Old World and the New is better conceived of as a broad
      zone.

PMID- 10405021
TI  - The health impact of smoking in manual and non-manual social class men and women:
      a test of the Blaxter hypothesis.
AB  - Blaxter has hypothesized that harmful behavioral habits like smoking have a
      greater impact on health in the non-manual than in the manual social classes,
      possibly because other adverse exposures have a more important role in the manual
      social classes. However, the outcome measure used was a composite measure of
      physiological indices of morbidity and the relevance of this to other health
      problems is uncertain. We have therefore investigated the effect of smoking on
      mortality, to test whether the risk of death associated with smoking differs
      between manual and non-manual social classes. Data on 6831 men and 7993 women,
      aged 45-64 when screened in the Renfrew and Paisley study, a large prospective
      observational study in the West of Scotland, have been analyzed. All cause
      mortality rate ratios for smokers compared with never smokers have been
      calculated within manual and non-manual social classes. Although the age adjusted
      rate ratios are slightly higher among the non-manual men and women (2.19 [1.83
      2.61] versus 1.92 [1.71-2.17] for non-manual and manual men respectively, and
      1.75 [1.54-1.99] versus 1.65 [1.50-1.82] for non-manual and manual women), this
      difference between social classes is not statistically significant (p-values for
      test of difference 0.26 and 0.47 for men and women respectively). When
      additionally adjusted for other risk factors, cardiorespiratory symptoms and
      deprivation, this picture remained the same (p-values for test of difference are
      0.41 and 0.50 for men and women respectively). Similar results were found when
      the cohort was divided by deprivation categories rather than social classes or
      when smoking related mortality rather than mortality from all causes was used as
      the outcome measure. We therefore conclude that the health impact of smoking is
      similar in each socio-economic group. The relative health improvement consequent
      on smoking cessation is thus similar in different socio-economic groups.

PMID- 10405022
TI  - Will genetic testing for predisposition for disease result in fatalism? A
      qualitative study of parents responses to neonatal screening for familial
      hypercholesterolaemia.
AB  - OBJECTIVE: to describe parents' perceptions of familial hypercholesterolaemia
      (FH), an inherited predisposition to heart disease, following population-based
      neonatal screening. DESIGN: a qualitative analysis of semi-structured interviews
      with the parents of 24 children who had received a positive screening test result
      informing them that their child was at-risk for having FH. RESULTS: responses to
      screening seemed to vary according to perceptions of the underlying cause of the
      positive screening test result. When parents perceived the test as detecting
      raised cholesterol the condition was perceived as familiar, dietary in origin,
      controllable and less threatening. When the test was seen as detecting a genetic
      problem, the condition was perceived as uncontrollable and, hence, more
      threatening. CONCLUSION: these pilot data raise questions about the extent to
      which assessing disease risks by DNA analysis may result in a sense of fatalism,
      adversely affecting motivation to change behaviour and to reduce risks.

PMID- 10405023
TI  - Rabies virus entry into cultured rat hippocampal neurons.
AB  - Rabies virus entry into cultured hippocampal neurons was investigated by
      immunofluorescence and electron microscopy. Hippocampal neurons were susceptible
      to rabies virus infection and became filled with viral antigen 1 day after
      infection. Infection was inhibited by the lysosomotropic agents chloroquine and
      ammonium chloride. To study entry, neurons were adsorbed with rabies virus at 4
      degrees C and warmed to 37 degrees C for short periods of time prior to fixation
      and localization of viral antigen by immunofluorescence microscopy By 5 min at 37
      degrees C, viral antigen was localized to puncta in the cell body and dendrites
      and in synapses along dendrites. Little viral antigen was present in axons. Cells
      adsorbed with rabies virus were incubated with tracers for early endosomes. The
      endocytic tracers or markers Lucifer Yellow, transferrin receptor, dextran, and
      wheat germ agglutinin co-localized with rabies virus, indicating that rabies
      virus enters an endosome compartment shortly after uptake. Rabies virus also co
      localized with LysoTracker Red, an acidotropic probe, indicating that some of the
      virus-containing endosomes are acidified. Rabies virus also co-localized with
      synapsin I, a synaptic vesicle marker, in nerve terminals but did not co-localize
      with lysosomal glycoprotein. By electron microscopy, after adsorption of virus
      and warming for 10 min, virus particles were present in coated pits, coated
      vesicles, and vacuolar membrane compartments in processes and axon terminals. It
      is concluded that rabies virus enters the somatodendritic domain and axon
      terminals of cultured hippocampal neurons by adsorptive endocytosis and is
      located in endosomes shortly after uptake.

PMID- 10405024
TI  - Induction of beta-family chemokines mRNA in human embryonic astrocytes by
      inflammatory cytokines and measles virus protein.
AB  - The cellular infiltration found during CNS inflammation consists of monocytes and
      activated T cells, suggesting the presence of cell-specific chemotactic signals
      during inflammatory responses. Astrocyte chemokine expression might contribute to
      site-specific leukocyte infiltration within the CNS. To investigate the factors
      that regulate astrocyte chemokine expression, we examined the ability of human
      fetal astrocytes to induce beta-family chemokine mRNA. Astrocyte-derived monocyte
      chemoattractant protein-1 (MCP-1), RANTES, macrophage inflammatory protein-1alpha
      (MIP-1alpha), and MIP-1beta mRNA were easily induced by lipopolysaccharide and/or
      the proinflammatory cytokines (IFN-gamma and/or TNF-alpha), respectively.
      Addition of both IFN-gamma and TNF-alpha together did not lead to an additive
      effect but resulted in the inhibition of MCP-1 and MIP-1beta mRNA expression,
      indicating that interaction between chemokines and cytokines may play a key role
      in regulating the local immune response of resident and infiltrating cells at the
      site of lesion. Interestingly, ultraviolet light-inactivated measles virus, but
      not cytomegalovirus, strongly induced expression of MCP-1, RANTES, MIP-1alpha,
      and MIP-1beta mRNA in human embryonic astrocytes, especially MCP-1 and MIP-1beta.
      An association occurs between the beta-family chemokine expression in astrocytes
      and inflammatory factors/virus, suggesting a possible role for beta-family
      chemokines in the pathogenesis of CNS inflammatory disease.

PMID- 10405025
TI  - Morphological and morphometric studies of the dysmyelinating mutant, the Long
      Evans shaker rat.
AB  - The Long Evans shaker (les) rat is a recently identified CNS myelin mutant with
      an autosomal recessive mode of inheritance. Although scattered myelin sheaths are
      present in some areas of the CNS, most notably the ventral spinal cord in the
      young neonatal rat, this myelin is gradually lost, and 8-12 weeks little myelin
      is present throughout the CNS. Despite this severe myelin deficiency, some
      mutants may live beyond one year of age. Rare, thin myelin sheaths that are
      present early in development lack myelin basic protein (MBP) and on
      ultrastructural examination are poorly compacted and lack a major dense line.
      Many oligodendrocytes develop an accumulation of vesicles and membranous bodies,
      but no abnormal cell death is observed. In the optic nerve, cell kinetic studies
      show an increase in proliferation at early time points in les, while total glial
      cell counts are also increased in les from 2 months of age. In situ hybridization
      studies demonstrate that the numbers of mature oligodendrocytes are similar to
      controls early in life and increase with time compared to controls. There is both
      a progressive astrocyte hypertrophy and microgliosis. While les has a mutation in
      the myelin basic protein (mbp) gene, it is dissimilar in both genotype and
      phenotype to the previously described mbp mouse mutants, shiverer (shi) and
      shiverer(mld). Unlike shi and its allele, where myelin increases with time and
      oligodendrocytes become ultrastructurally normal, les oligodendrocytes are
      permanently disabled, continue to demonstrate cytoplasmic abnormalities, and fail
      to produce myelin beyond the first weeks of life.

PMID- 10405026
TI  - Ultrastructural organization of the optic nerve of the tench (Cyprinidae,
      Teleostei).
AB  - Different parts of the tench optic nerve--the intraocular and intraorbital
      segments, the chiasm, and the post-chiasmatic segment--were studied using light
      and electron microscopy. From the head of the optic nerve, a zone of continuous
      growth constituted by the younger non-myelinated ganglion axons can be
      differentiated from a mature zone where almost all the axons are myelinated. The
      transition from one zone to the other is progressive. The area containing only
      non-myelinated axons is very restricted, and the presence of myelinated and non
      myelinated axons in the same fascicle is frequent. In the head of the optic
      nerve, the growing zone surrounds the central artery. In the intraorbital
      segment, where the optic nerve is organized as a folded ribbon, the growing edge
      is surrounded by other mature folds. In the chiasm and in the post-chiasmatic
      segment of the optic nerve, the organization as a folded ribbon disappears and
      the youngest axons are situated on the periphery. In the growing zones, the
      immature astrocytes predominate; in the transition zones, oligodendrocytes, in
      different stages of maturity, begin to appear. In the mature zone, almost all the
      glial cells are differentiated, although immature cells can be found. The
      microglial cells are not abundant and are of the ramified type. Moreover, in
      contrast to the descriptions of other teleosts, the tench optic nerve is
      profusely supplied with blood vessels throughout its length.

PMID- 10405027
TI  - Ballooning of myelin sheaths in normally aged macaques.
AB  - In aged animal brains, a variety of "holes" are formed in the neuropil. One type
      of hole, here designated as the myelin balloon, is an abnormality of the myelin
      sheath and is found in a number of diverse sites in the brain. Profiles of myelin
      balloons display rather smoothly rounded peripheral contours and typically range
      up to 10 microm in diameter, although exceptionally large examples may be twice
      this size. The balloons are bounded by lamellae of myelin, and to accommodate the
      contents of the balloon, the myelin sheath becomes split at the intraperiod line.
      Since the intraperiod line is formed by the apposition of the outer faces of the
      myelin-forming plasma membrane, the contents of the myelin balloons are, in
      effect, in continuity with the extracellular space, and it is suggested that the
      contents of the balloons are fluid, with the fluid exerting an outward pressure
      on the walls of the balloons to produce their spherical shapes. Myelin balloons
      are not only produced during aging but also occur in a number of genetic strains
      of mice and in a number of human disease states. They thus represent a non
      specific, though distinctive and common, alteration of the myelin sheath and are
      a reflection of the fact that under a variety of conditions, including normal
      aging, oligodendrocytes are unable to maintain the integrity of their sheaths.

PMID- 10405028
TI  - Polyclonal antibodies against NCAM reduce paralysis-induced axonal sprouting.
AB  - The neural cell adhesion molecule (NCAM) is upregulated in paralyzed muscles but
      the functional role of this upregulation is not clear. We have investigated the
      possible involvement of NCAM in botulinum toxin-induced axonal sprouting in mouse
      soleus muscles. Starting 4 days after botulinum toxin-A injection, the paralyzed
      muscles were exposed daily for 6 or 10 days to either rabbit polyclonal NCAM
      antibody or control solutions (preimmune serum or saline) or remained without
      further treatment. By 10 days after botulinum toxin injection, the mean number of
      sprouts and the mean total length of sprouts, respectively, in zinc iodide-osmium
      stained preparations were 2.2 and 212 microm in untreated and control treated
      muscles but 1.0 and 51 microm in anti-NCAM treated muscles. By 14 days, the mean
      number of sprouts rose to 2.9 in untreated muscles but only 1.6 in anti-NCAM
      treated muscles. Macrophages/monocytes, probably originating from neighboring
      tissue damaged by the daily injections, were present in muscles of all groups. No
      T lymphocytes and no signs of muscle fiber damage were found, however, rendering
      antibody-mediated cytotoxic reactions as unlikely. From the blocking effects of
      anti-NCAM, it is concluded that NCAM plays a major role in the growth of
      paralysis-induced axonal sprouts.

PMID- 10405029
TI  - Gordon Memorial Lecture. An egg ist ein ei, es un huevo, est un oeuf.
AB  - 1. Many of the mechanical tests devised to measure shell quality are inadequate
      because they fail to recognise the complex interaction between the organic and
      inorganic aspects of the eggshell. 2. Twelve structural modifications have been
      observed at the level of the mammillary layer and their presence correlated with
      a variety of environmental stress events. Occurring as they do in the basal
      layers of the shell, these morphological variants influence its mechanical
      properties. 3. The organic matrix proteins which complex with the calcium
      carbonate derive from a variety of sites within the oviduct and vary in their
      location within the fully formed shell. In vitro mineralisation reveals the
      significance of these proteins in the crystal growth mechanism. 4. The isolation
      and identification of the protein moiety in well-structured eggshells is an
      essential prerequisite to understanding the abnormalities in crystal growth
      observed in the shells of older birds challenged by disease and other undesirable
      'on farm' events. 5. The eggshell is the daily indicator of the bird's harmony
      with its environment and as such provides a readily accessible and non invasive
      measure of welfare. The integration of these data with those derived from
      behavioural and biochemical testing should provide industry with a reliable
      numerical welfare index.

PMID- 10405030
TI  - Effect of rearing factors on the prevalence of floor eggs, cloacal cannibalism
      and feather pecking in commercial flocks of loose housed laying hens.
AB  - 1. Effects of rearing conditions on behavioural problems were investigated in a
      cohort study of commercial flocks of laying hens housed in 2 different loose
      housing systems. The sample population was 120 385 laying hens from 59 flocks of
      various hybrids at 21 different farms. 2. Logistic regression modelling was used
      to test the effects of selected factors on floor eggs, cloacal cannibalism and
      feather pecking. In addition to early access to perches or litter, models
      included hybrid, stocking density, group size, housing system, age at delivery,
      identical housing system at the rearing farm and at the production farm and, in
      models for floor eggs and cloacal cannibalism, nest area per hen. Odds ratios
      were calculated from the results of the models to allow risk assessment. 3. No
      significant correlations were found between the prevalence of floor eggs, cloacal
      cannibalism and feather pecking. 4. Access to perches from not later than the 4th
      week of age decreased the prevalence of floor eggs during the period from start
      of-lay until 35 weeks of age, odds ratio 0-30 (P<0-001). Furthermore, early
      access to perches decreased the prevalence of cloacal cannibalism during the
      production period, odds ratio 0-46 (P=0.03). 5. No other factor had a significant
      effect in these models. Although it was not significant, early access to litter
      had a non-significant tendency to reduce the prevalence of feather pecking.

PMID- 10405031
TI  - Welfare of food restricted male and female turkeys.
AB  - 1. The welfare of male and female male-line turkeys fed ad libitum or food
      restricted was determined at 4, 8, 12, 16, 20, 24, 28, 36(38) and 46(48) weeks of
      age using behavioural and physiological indices of well-being. Traditional
      turkeys fed ad libitum were kept as a control treatment. Restricted male and
      female male-line turkeys were fed to 0-5 during rearing and subsequently to 0-8
      of sex-specific ad libitum-fed body weight. In another treatment, male-line males
      were fed ad libitum to 18 weeks and 0.8 of ad libitum thereafter. 2. Traditional
      turkeys and restricted male-line turkeys were more active than ad libitum-fed
      birds of both sexes. Restricted turkeys showed a high incidence of wall pecking.
      In the breeding period, about 0.4 of the observations of male-line males were of
      strutting behaviour whereas traditional male turkeys showed no strutting
      behaviour at the end of the breeding period. 3. The heterophil lymphocyte ratio
      (HLR) and the proportion of basophils were not increased in food-restricted
      turkeys. The HLR was relatively low in traditional birds, compared with male-line
      turkeys during the rearing period. 4. Plasma corticosterone concentrations were
      increased by food restriction during the rearing period. Corticosterone
      concentrations were relatively high in traditional turkeys at 4 and 8 weeks of
      age only. 5. Plasma lactate dehydrogenase (LIDH) activity was higher from 12 to
      24 weeks of age in ad libitum-fed male-line turkeys and was consistent with
      mortality from cardiovascular disease in this group of turkeys. The pattern of
      activity of aspartate transaminase was similar, and alkaline phosphatase was
      inversely related to that of LDH. 6. It was concluded that turkeys may be better
      able to adjust physiologically to the demands of food restriction than broiler
      breeders and that there were few deleterious consequences of restricting male
      turkeys after 18 weeks of age. Male-line turkeys were less active than
      traditional turkeys.

PMID- 10405032
TI  - Assessment of pain during locomotion and the welfare of adult male turkeys with
      destructive cartilege loss of the hip joint.
AB  - 1. An assessment was made of the potential pain and stress from musculo-skeletal
      disease at 54 weeks of age in large male-line turkeys fed ad libitum or on
      restricted amounts of food. Males from traditional turkey lines were used as a
      negative control. 2. Traditional turkeys were fed ad libitum and male-line
      turkeys were fed ad libitum or restricted to 0.5 during rearing and subsequently
      to 0.8 of sex-specific ad libitum-fed body weight or fed ad libitum to 18 weeks
      and 0.8 of ad libitum thereafter. 3. Pain was assessed at 54 weeks of age by the
      change in number of steps taken by turkeys with or without musculo-skeletal
      disease after a course of betamethasone, a steroid anti-inflammatory agent with
      analgesic properties. 4. The numbers of steps over 24 h were recorded using a
      pedometer and were similar in all 4 treatments before and after treatment with
      the analgesic. It was concluded that there was no evidence for pain associated
      with musculo-skeletal disease among the turkeys in this experiment. 5. Musculo
      skeletal disease was not associated with raised heterophil-lymphocyte ratio, a
      recognised index of stress.

PMID- 10405033
TI  - Evaluation of stunning/killing methods for quail (Coturnix japonica): bird
      welfare and carcase quality.
AB  - 1. The welfare and carcase quality implications of stunning/killing 7-week-old
      Japanese quail with either an electric current, 90% argon in air or a mixture of
      30% carbon dioxide and 60% argon in air were investigated in 3 separate
      experiments. 2. The results showed that exposure of quail to either argon or the
      carbon dioxide-argon mixture resulted in loss of posture on average at 9 and 8 s
      respectively. In both gas mixtures, convulsions started 6 s after the loss of
      posture and the duration of clonic phase (wing flapping) did not differ
      significantly between the 2 gas mixtures. However, the duration of the tonic
      phase was found to be slightly longer with the carbon dioxide argon mixture than
      with argon alone (P<0.05). 3. The absence of a positive response to toe pinching
      performed soon after the loss of posture indicated that the birds became
      unconscious and insensible to pain before the onset of convulsions. 4. Carcase
      dissection showed that, in comparison with the electrical stunning, gas
      stunning/killing of quail in transport containers eliminated the problem of
      broken bones and significantly reduced haemorrhaging in breast and leg muscles.

PMID- 10405034
TI  - Antibody response to sheep erythrocytes in Indian native vis-a-vis imported
      breeds of chickens.
AB  - 1. A total of 433 birds (7 weeks old) of both sexes belonging to Indian native
      breeds, including, Aseel, Kadakanath, Naked Neck and Frizzle fowl along with the
      imported breeds Dahlem Red, White Leghorn, Synthetic dam line broiler (SDL) and
      Naked Neck broiler were utilised to test the primary antibody response to sheep
      erythrocytes by haemagglutination test. The effect of genotype (breed), sex and
      their interactions on antibody response were also studied. 2. The results
      revealed the presence of natural antibodies in all groups under study. 3. All
      groups except broilers showed the highest HA titre on day 5 post immunisation,
      which gradually declined until the end of the experiment (19th day post
      immunisation). In broilers, the peak HA titre was observed on day 12. 4. Dahlem
      Red showed the highest response throughout. The lowest antibody response was
      recorded for broilers except on day 19 post immunisation when it exceeded the
      White Leghorn value. 5. Amongst the native Indian breeds, the Naked neck had the
      highest titre on day 5 post immunisation but the Aseel titre was highest on days
      12 and 19. 6. Males tended to have higher titres than females in Aseel,
      Kadakanath, Naked Neck, White Leghorn and Naked Neck broilers whereas Frizzle,
      Dahlem Red and SDL broilers showed the converse. 7. Statistical analysis revealed
      significant variation in HA response among the various genetic groups on
      different days post immunisation. The apparent differences between sexes were not
      significant. However, interactions between breed and sex were significant on day
      5 and 19 post immunisation.

PMID- 10405035
TI  - Genetic parameters of growth curve parameters in male and female chickens.
AB  - 1. Individual growth curves of 7143 chickens selected for the form of the growth
      curve were fitted using the Laird form of the Gompertz function, BW4=BW0xe(L/K)(1
      e-Kt) where BWt is the body weight at age t, BW0 the estimated hatching weight, L
      the initial specific growth rate and K the maturation rate. 2. Line and sex
      effects were significant for each parameter of the growth curve. In males, L,
      BW0, age and body weight at inflection (T(I)and BWI) were higher whereas K was
      lower than in females. Lines selected for high adult body weight had higher BW0
      and BW(I) whereas lines selected for high juvenile body weight had larger
      estimates of L and lower estimates of T(I). 3. Data from 38,474 animals were
      included in order to estimate the genetic parameters of growth curve parameters
      in males and females, considering them as sex-limited traits. Genetic parameters
      were estimated with REML (REstricted Maximum Likelihood) and an animal model.
      Maternal genetic effects were also included. 4. Heritabilities of the growth
      curve parameters were moderate to high and ranged between 0.31 and 0.54, L, BW0
      in both sexes and BW(I) in males exhibited significant maternal heritability.
      Heritabilities differed between males and females for BWI and T(I). Genetic
      correlations between sexes differed significantly from one for all parameters. L,
      K and T(I) were highly correlated but correlations involving BW0 and BW(I) were
      low to moderate. 5. Sexual dimorphism of body weight at 8 and 36 weeks and of L,
      K and T(I) was moderately heritable. Selection on growth curve parameters could
      modify the difference between sexes in precocity and thus in body weight at a
      given age.

PMID- 10405036
TI  - Water and air in two poultry processing plants' chilling facilities--a
      bacteriological survey.
AB  - 1. Water, aerosols and air in chilling facilities in 2 poultry abattoirs were
      bacteriologically examined. The different types of samples displayed a variety of
      bacterial loads and genera. 2. The aerobic plate count in water from spray
      nozzles was about log10 2 to 3 in both plants. Flavobacterium, Alcaligenes,
      Acinetobacter and Pseudomonadaceae were predominant in these samples. 3. The
      microbial load in air of the 2 plants was quite different, consisting mainly of
      Micrococcaceae and Gram-positive irregular rods. 4. The aerobic plate count in
      aerosols was extremely high. The flora was the same as was found in the spray
      nozzles samples, plus Enterobacteriaceae, Micrococcaceae and streptococci, which
      presumably came from the air in the system. Cross-contamination may well occur in
      evaporative chilling.

PMID- 10405037
TI  - Effects of alpha-tocopheryl acetate supplementation and salt addition on the
      oxidative stability (TBARS) and warmed-over flavour (WOF) of cooked turkey meat.
AB  - 1. Day-old turkey poults (n = 14) were randomly divided into 2 groups (n = 7) and
      fed diets containing 20 (E20) and 600 (E600) mg all-rac-alpha-tocopheryl
      acetate/kg food for 21 weeks prior to slaughter. Following slaughter, breast and
      leg meat was removed and 4 batches of patties were produced from each. Two of the
      batches were formed from E20 meat (E20) and E20 plus 1% salt (E20S). Two similar
      batches were formed from E600 meat (E600) and E600 plus 1% salt (E600S). 2.
      Patties were fried, cooled and overwrapped with high oxygen-permeable film.
      Overwrapped patties were displayed in a 4 microC cabinet under fluorescent light
      (616 lux). Lipid oxidation (TBARS numbers) was determined on d 0, 2, 4, 6, 8 and
      10, while taste panels to assess warmed-over flavour (WOF) were carried out on d
      0, 2 and 4 of refrigerated (4 degrees C) display. 3. In the case of both leg and
      breast meat, E600 patties were the least susceptible of the 4 treatment batches
      to lipid oxidation. Salt had the effect of promoting lipid oxidation, with E20S
      and E600S patties having higher TBARS numbers than the corresponding patty
      batches where salt was absent. 4. Taste panel results showed that leg and breast
      patties formed from the meat of turkeys given alpha-tocopheryl acetate enriched
      diets developed significantly (P < 0.05) less WOF than those formed from control
      turkey meat on d 2 and 4 of refrigerated (4 degrees C) display. Patties
      containing 1% salt generally exhibited a greater degree of WOF than patties
      without salt. 5. A linear relationship was observed between TBARS numbers and WOF
      percentages for all batches of leg and breast patties.

PMID- 10405038
TI  - Performance and gastro-intestinal response of broiler chickens fed on cereal
      grain-based foods soaked in water.
AB  - 1. Two experiments were carried out to investigate the addition of 1 3 kg water
      per kg air-dry mash diets containing high proportions (600 to 700 g/kg) of ground
      cereal grains (wheat, barley or oats) on broiler performance and the structure
      and function of the gastro-intestinal tract. 2. Chicks at the age of 7 d were fed
      on the wheat-, barley- or oats-based diets in the dry or wet forms for 35 d. Food
      and water intakes were recorded daily while body weight was measured weekly. Two
      birds from each treatment were killed each week to measure gut size and the
      viscosity of gut contents. Tissue samples from various digestive segments were
      histo-morphologically examined to determine the thickness of tissue layers, size
      of tissue glands, villa heights, crypt depths and thickness of tunica muscularis.
      Crypt cell proliferation rate (CCPR) for each segment was also determined using a
      metaphase arrest technique. 3. The results from both experiments showed that
      wetting food significantly (P<0.05) increased food intake, total water intake and
      body weight gain of broiler chickens. The body weight gains of birds were
      proportional to their food intakes so that the efficiency of food utilisation was
      similar for all treatments. Dry matter retention of food tended to increase in
      birds given wet food from 7 to 21 d but not thereafter, compared to the dry-fed
      birds. Although water intake from the water bottle was significantly (P<0.05)
      reduced in birds given wet food, total water intakes from the water bottle plus
      that from food were significantly (P<0.05) higher in the wet-fed birds than in
      the dry-fed birds. The ratio of total water to dry food intake was, however,
      similar in both feeding regimens. 4. The fresh empty weight of the gut was
      increased by wet-feeding while its relative weight to body weight and the length
      of gut was not affected by dietary treatments. Significantly greater development
      of the tissue glands in the proventriculus and gizzard was observed in the birds
      given wet food; this was associated with the reduced thickness of the muscular
      layer of these segments. An increase in villus height was also observed in
      duodenum, small intestine, caeca and colon of birds given wet food, compared to
      those given dry food. CCPR was significantly (P<0.05) reduced by wet-feeding
      throughout the digestive tract. This was associated with a significant decrease
      in the mean viscosity of the gut contents and the concentration of volatile fatty
      acids (VFAs) in the caeca. 5. Wetting diets based on cereal grains caused a
      significant improvement in the performance of broiler chickens. The mechanism of
      the beneficial effects of wet feeding could be attributed to the decreased
      viscosity of gut contents; the greater development of the layer of villi in the
      digestive segments and the reduced CCPR in the crypts of the epithelium.

PMID- 10405039
TI  - Performance of broiler chicks fed on diets containing urea ammoniated neem
      (Azadirachta indica) kernel cake.
AB  - 1. The performance, nutrient utilisation, blood profile, carcase composition,
      gross pathology and sensory evaluation of meat from broiler chicks fed from 3 to
      42 d on diets containing urea ammoniated neem (Azadirachta indica, A.juss) kernel
      cake (NKC) as a protein supplement to replace peanut meal (PNM), were evaluated.
      NKC was ammoniated with urea at 15 (UANKC 1) or 25 g (UANKC 2)/kg and
      incorporated into the test diets to replace either half (134.5 g/kg (L-UANKC 1)
      and 127.5 g/kg (L-UANKC 2), respectively) or all (269, g/kg (H-UANKC 1) and 255.0
      g/kg (H-UANKC 2), respectively) of the nitrogen provided by the PNM. 2. The
      growth, food intake and efficiency of nutrient utilisation of the birds were
      comparable between the reference and L-UANKC 1 and 2 diets but were depressed on
      the other UANKC diets. 3. The retention of dry matter (DM), crude fibre (CF),
      nitrogen-free extract, total carbohydrate, gross energy, acid detergent fibre,
      calcium and phosphorus were similar among groups, except lower DM and higher CF
      and phosphorus retentions were noted in chicks fed on the H-UANKC 1, H-UANKC 2
      and L-UANKC 2 diets. All the chicks were in positive nitrogen balance and
      percentage nitrogen retention did not differ between the reference and test
      diets. 4. Haemoglobin, total erythrocyte count and aspartate amino transferase
      activity were unaffected by diet, but total leucocyte count was higher in chicks
      fed on the H-UANKC 1 and 2 diets and alanine amino transferase activities were
      lower in chicks fed on the test diets. Blood urea increased as the amount of urea
      in the diets increased. 5. Most of the physico-chemical carcase characteristics
      from birds fed on the L-UANKC 2 were comparable to those from birds fed on the
      reference diet. No bitter taste was noticed in cooked meat from any diet by the
      sensory panel. 6. Incorporation of L-UANKC 2 was economical and responses were
      comparable to those observed on the reference diet. 7. It was concluded that NKC
      detoxified with 25 g urea/kg can economically and successfully replace half the
      nitrogen of PNM in broiler diets thereby mitigating the chronic shortage of
      costly oil cakes in developing countries.

PMID- 10405040
TI  - Performance of laying pullets fed on cereal-free diets based on maize offal,
      cassava peel and reject cashew nut meal.
AB  - 1. A 70-d experiment was conducted to determine the response of 26-week-old
      laying pullets to cereal-free diets based on maize offal, cassava peel and full
      fat cashew nut meal (CNM) in comparison with a standard 550 g maize/kg reference
      diet. The 4 test diets all contained 315 g CNM/kg 232.5, 155.0, 77.5 and 0.0 g/kg
      of maize offal in combination with 77.5, 155.0, 232.5 and 315.0 g/kg of cassava
      peel, respectively. 2. Pullets fed on the 4 CNM-based diets consumed (P<0.05)
      less food than those fed on the reference diet; they also had lower (P<0.05)
      rates of lay, produced less (P<0.05) egg mass, had lower (P<0.05) food conversion
      efficiencies and their eggs had a lighter (P<0.05) yolk colour. Pullets fed some
      of the CNM-based diets also gained more (P<0.05) weight, the heaviest (P<0.05)
      being birds reared on the diet containing 315 g/kg cassava peel. Egg weight,
      shell thickness and albumen height from all eggs were similar. Pullets fed on the
      CNM-based diets had inferior (P<0.05) retention of dry matter and protein. 4. It
      was concluded that feeding full-fat CNM allowed for high dietary inclusion rates
      of cassava peel and maize offal and the resultant diets, which contained no
      maize, supported satisfactory performance of laying hens.

PMID- 10405041
TI  - Use of dried papaya skin in the diet of growing pullets.
AB  - 1. The chemical composition of dried papaya (Carica papaya) skin (DPS) was
      determined and the effect of diets containing different concentrations of this
      ingredient (0, 30, 60 and 90 g/kg) was studied using growing pullets as
      experimental animals. 2. Crude protein concentration was determined to be 229
      g/kg and metabolisable energy content was estimated to be 6.4 MJ/kg. 3. Use of
      DPS in the diet up to 90 g/kg did not produce any significant difference in
      weight gain, food intake, food conversion and protein efficiency when compared
      with birds that received the control diet. 4. Survivability of growing pullets
      fed on DPS was 100%, as in the control group. 5. It was concluded that DPS can
      safely be used up to 90 g/kg in the diet of growing pullets.

PMID- 10405042
TI  - Effect of Lactobacillus acidophilus and zinc bacitracin as dietary additives for
      broiler chickens.
AB  - The influence of Lactobacillus acidophilus and zinc bacitracin alone, or in
      combination, on the growth of broiler chickens was monitored over a period of 8
      weeks. 2. The maximum improvement in body weight over the controls was 10.8% with
      both additives in the diet but the use of bacitracin alone induced a 9.1%
      improvement. 3. Food conversion was reduced by zinc bacitracin alone but was
      improved by the use of L. acidophilus and bacitracin in combination. 4. The
      combination treatment increased abdominal fat deposition in the female chickens
      by 31%.

PMID- 10405043
TI  - Higher lipid accumulation in broilers fed on saturated fats than in those fed on
      unsaturated fats.
AB  - 1. Two experiments were conducted to assess the effect of fat sources differing
      in degree of saturation on the performance of and fat deposition in broiler
      chickens fed on isocaloric and isonitrogenous diets. 2. There were no differences
      in initial body weight between sexes but female broilers had lower daily gains
      (P<0.0001), final weights (P<0.0001) and food intakes (P<0.0001) than males.
      Abdominal fat pad weight was lower in male broilers than in female (P<0.001). 3.
      There were no significant differences in intake, weight gain, final body weight
      or food-to-gain ratios between birds fed on diets differing solely in the degree
      of fat saturation. Broilers fed on diets containing an animal fat blend or tallow
      had higher abdominal fat pad weight (P<0.001) and intramuscular lipid content
      (P=0.0085) than those fed on diets containing sunflower oil. 4. It was concluded
      that dietary fat saturation affects fat accumulation in broiler chickens.

PMID- 10405045
TI  - Effect of dietary zinc content and sources on the growth, body zinc deposition
      and retention, zinc excretion and immune response in chickens.
AB  - 1. In areas of intensive animal production heavy metals such as zinc (Zn), which
      is present at high concentrations in poultry excreta in relation to plant
      requirements, may be at the origin of soil phytotoxicity This study was conducted
      in order to determine the effect of decreasing dietary Zn content on growth,
      plasma, tibia and whole body Zn concentrations, immune function, enzyme activity,
      Zn body retention and Zn concentration in excreta in broilers. 2. Two experiments
      were carried out using 160 and 80 1-day-old chicks. Broilers received diets with
      increased Zn contents of 20 to 190 mg/kg. In experiment 1, two sources of zinc
      methionine were compared to zinc sulphate. 3. A dietary Zn concentration of 45
      mg/kg was sufficient to obtain normal broiler performance at 21 d of age. 4.
      Tibia and plasma Zn concentrations increased linearly with Zn dietary content and
      reached a plateau at 75 mg/kg, whereas the whole body Zn was saturated when the
      dietary Zn content was 90 mg/kg. 5. Antibody titres in response to SRBC injection
      and plasma alkaline phosphatase activity were not affected by dietary zinc
      concentration. 6. When the dietary Zn content was decreased from 190 to 65 mg/kg,
      body Zn retention was increased from 8% to 20% and Zn concentration in broiler
      manure was reduced by 75%. 7. Zn sources had no effect on the parameters measured
      in this study. 8. A nutritional approach, that is by lowering dietary Zn
      supplementation may reduce the risks of phytotoxicity in the soil resulting from
      excessive Zn concentration in manure.

PMID- 10405044
TI  - Optimal dietary concentration of vitamin E for alleviating the effect of heat
      stress on egg production in laying hens.
AB  - 1. The effects of different dietary concentrations of vitamin E (alpha-tocopherol
      acetate) were investigated on laying hens exposed to chronic heat stress at 32
      degrees C from 26 to 30 weeks of age. 2. Diets containing 5 dietary
      concentrations of vitamin E (a control diet containing 10 mg alpha-tocopherol/kg
      or this diet supplemented to contain 125, 250, 375 and 500 mg alpha
      tocopherol/kg) were fed to 335 birds. Half of the birds received the supplemented
      diets for only 4 weeks before the heat stress period (short supplementation
      duration, SSD) and were fed on the control diet for a further 12 weeks. The
      remaining birds were fed on the supplemented diets throughout the experiment, 4
      weeks before, 4 weeks during and 8 weeks after the heat stress period (long
      supplementation duration, LSD). 3. Egg production was significantly higher during
      (80-6 vs 68.9%, P<0.02) and after (75.3 vs 62.7%, P<0.02) the period of stress in
      the LSD group fed on the diet containing 250 mg vitamin E/kg compared with the
      group fed on the control diet. LSD birds given 375 and 500 mg vitamin E/kg also
      had higher egg production than control birds during heat stress but the
      differences failed to reach significance (74.6 vs 68.9% and 77.1 vs 68.9%
      respectively). In the SSD groups, mean egg production of the birds given the
      diets supplemented with 125 mg vitamin E/kg or more was significantly different
      from the control group after heat stress (70.3 vs 62.7%, P<0.05). Egg weight and
      food intake were similar in all the groups. 4. Plasma and liver vitamin E
      concentrations were proportional to the vitamin E intake before the stress
      period, dropped during heat stress in the SSD groups but were maintained at
      concentrations closer to those observed before heat stress in the LSD groups. 5.
      It is concluded that a dietary supplement of 250 mg vitamin E/kg provided before,
      during and after heat stress is optimum for alleviating, at least in part, the
      adverse effects of chronic heat stress in laying hens.

PMID- 10405047
TI  - Effect of early-stage thermal conditioning and food restriction on performance
      and thermotolerance of male broiler chickens.
AB  - 1. The effects of early-age thermal conditioning and food restriction on
      performance and thermotolerance were studied in male broiler chickens, in 2
      trials. 2. Chickens were exposed to 36 degrees +/- 1 degree C and 70% to 80%
      relative humidity (RH) for 24 h at the age of 5 d (thermal conditioning, TC), or
      to food restriction (FR) at the age of 7 to 14 d, or to both treatments (TC+FR),
      while a control group was reared under standard conditions. At the age of 42 d,
      chickens were thermally challenged by a heat stress of 350 degrees +/- 1 degree C
      and 20% to 30% RH for 6 h. 3. In both experiments, weight gain of the TC chickens
      between the ages of 7 and 42 d was significantly higher than those of other
      treatments and was associated with higher food intake. 4. Early-age TC
      significantly increased body temperature (Tb). Thermal challenge at the age of 42
      d markedly increased Tb in all groups but that of the TC groups was the lowest.
      5. Mortality during thermal challenge was significantly lower in the treated
      chickens, except for the FR group in trial 2. 6. Plasma triiodothyronine (T3)
      concentration was greatly depressed in all treatment groups during the thermal
      challenge. However, the lowest concentration was observed in the TC group,
      suggesting that these chickens exhibit the lowest rate of heat production under
      such conditions. 7. Thermal conditioning reduced the increase of haematocrit with
      age, whereas food restriction resulted in an increase in haematocrit immediately
      after FR. Thermal challenge resulted in a haematocrit decline in all groups, with
      the lowest values in the TC and TC+FR chickens. 8. It can be concluded that,
      because the TC treatment improved thermotolerance (possibly by reducing heat
      production) and performance, it has advantages over the FR and TC+FR treatments.

PMID- 10405046
TI  - Effect of sodium bentonite on the performance and blood variables of broiler
      chickens intoxicated with aflatoxins.
AB  - 1. This study was conducted to evaluate the protective effect of natural sodium
      bentonite (NaB) in the prevention of toxic effects of aflatoxins. Five hundred
      and twenty-eight 1-d-old Ross male broiler chickens were housed in pens (22
      chickens per pen) for 42 d. There were 3 inclusion rates of NaB (0, 2.5, and 5
      g/kg) and 2 of aflatoxins (0 and 3 mg/kg food). Each treatment had 4 replicates
      of 22 chickens. 2. All chickens treated with aflatoxin and without bentonite were
      adversely affected. NaB treatment at 5.0 g/kg improved body weights at 42 d of
      age by 31.3%, increased food intake by 23.8% and improved productive efficiency
      by 40.1%. Weights of liver, heart, pancreas and crop and biochemical variables
      were not affected by dietary NaB. However, serum phosphorous concentration was
      reduced by 30% compared with chickens that received aflatoxin. 3. NaB caused no
      adverse effects on chickens that did not receive aflatoxin. 4. It is concluded
      that NaB at pH 7.9 partially neutralises the effects of aflatoxins on broiler
      chickens when included at 5.0 g/kg in the diet.

PMID- 10405048
TI  - Effects of thiamine and clenbuterol on body composition, plasma metabolites and
      hepatic oxygen consumption in broiler chicks.
AB  - 1. We examined the effects of thiamine-hydrochloride (10 mg/kg body weight) and a
      beta-agonist, clenbuterol (50 microg/kg body weight), on plasma metabolites and
      hepatic oxygen consumption in female broiler chicks. 2. Clenbuterol, thiamine or
      both, dissolved in saline, were injected into thigh muscle on 2, 4 and 6 d of
      age. At 7 d of age blood samples in each treatment group were obtained and breast
      muscle and liver were weighed; liver slices were used for measurement of oxygen
      consumption. 3. Body weight gain was reduced by clenbuterol. Thiamine increased
      breast muscle weight as a proportion of body weight regardless of clenbuterol
      dose. Clenbuterol increased relative liver weight markedly, especially when
      chicks received thiamine also. 4. Clenbuterol increased plasma free fatty acid
      concentration in chicks treated with thiamine. Thiamine decreased plasma
      triglyceride regardless of clenbuterol dose. Plasma glucose concentration was
      decreased by both thiamine and clenbuterol. 5. The absolute rate of oxygen
      consumption in liver slices was greater in the thiamine-treated chicks;
      clenbuterol did not affect hepatic oxygen consumption. 6. These findings suggest
      that thiamine-induced energy expenditure results not only from thermogenesis in
      the liver, but also from increasing energy utilisation for muscle hypertrophy and
      this vitamin supplementation facilitates the lipolytic effects of the beta
      agonist.

PMID- 10405049
TI  - Effects of phosphate, prostaglandins, arachidonic acid and arginine vasotocin on
      oviposition and pigment secretion from the shell gland in Japanese quail.
AB  - 1. Phosphate solution, prostaglandin F2alpha and E2, arachidonic acid and
      arginine vasotocin were injected intrauterinely or intravenously into laying
      quail hens 6 h before expected oviposition. Following injections, induced
      ovipositions and secretions of pigment from their shell glands were observed. 2.
      The effects of intrauterine injection with prostaglandins, which induced
      oviposition and pigment secretion, were not inhibited by pre-injection of
      indomethacin. 3. Indomethacin completely inhibited the inducing effects on
      oviposition and pigment secretion of intrauterine injections with phosphate
      solution and arachidonic acid. 4. Intravenous injection with arginine vasotocin
      or prostaglandins also induced oviposition and pigment secretion; indomethacin,
      however, only inhibited pigment secretion. 5. It is concluded that the effects of
      prostaglandins on pigment secretion from the shell gland were demonstrated
      experimentally.

PMID- 10405050
TI  - Performance and physiological variables in broiler chicken lines differing in
      susceptibility to the ascites syndrome: 1. Changes in blood gases as a function
      of ambient temperature.
AB  - 1. Male broilers of 5 genetic stocks (A, B, C, D, E) selected in different ways
      for fast growth and low food conversion ratio (FCR) and differing in ascites
      sensitivity were subjected to 2 different ambient temperature step down regimens:
      high temperature (HT: 33 to 20 degrees C over 33 d) and low temperature (LT: 30
      to 15 degrees C over 17 d). 2. Ascites incidence was recorded daily. Food intake
      and body weight gain were measured weekly and FCR was calculated. Heat production
      (Hp) was calculated using the comparative slaughter method. At 28 d venous
      samples were taken for blood gas analysis and haematocrit and relative heart,
      lung and liver weights were recorded. 3. Populations A and C showed the highest
      growth rates combined with a low FCR and a higher ascites incidence. A low FCR in
      these stocks was attributable to low values for Hp. These stocks also had low PO2
      and high pCO2 in venous blood at low ambient temperature compared with other
      stocks. Stock B, which exhibited the slowest growth rate and the highest FCR, was
      not susceptible to ascites and showed higher Hp and PO2 and pCO2 at low ambient
      temperature. Populations D and E were intermediate for almost all variables.
      Heart and lung weights were both increased at LT, while liver weight did not
      differ between temperature regimes. 4. Our results show that a high haematocrit
      is not necessarily linked with an increased susceptibility to ascites.

PMID- 10405051
TI  - Performance and physiological variables in broiler chicken lines differing in
      susceptibility to the ascites syndrome: 2. Effect of ambient temperature on
      partial efficiencies of protein and fat retention and plasma hormone
      concentrations.
AB  - 1. Male broilers of 5 genetic stocks (A, B, C, D and E), selected in different
      ways for fast growth and low food conversion rate (FCR) and differing in
      sensitivity to ascites, were subjected to 2 different ambient temperature (Ta)
      step-down programmes: normal (HT) and low (LT) Ta. 2. Ascites incidence was
      followed daily. Growth and food intake were measured weekly. Heat production
      (Hp), oxygen consumption (Oxc) and energy- metabolism parameters were calculated
      according to the comparative slaughter method. At week 4 blood samples were taken
      for the analysis of plasma T4, T3, growth hormone (GH) and insulin-like growth
      factor-I (IGF-1) concentrations. 3. Within-line changes of GH and IGF-1 point to
      the relative independence of both hormone concentrations. 4. Partial protein
      efficiency was higher in lines with lower GH, especially at LT. 5. The increase
      in plasma T3 concentration at LT was accompanied by a decrease in relative fat
      deposition from the increased energy expenditure. 6. The combination of fast
      growth and low FCR, linked to a low plasma T4 concentration at LT is indicative
      of a thyroid insufficiency which is related to an increased occurrence of ascites
      in these lines.

PMID- 10405052
TI  - Carcase characteristics of emus (Dromaius novaehollandiae).
AB  - 1. Six emus (Dromaius novaehollandiae) were slaughtered at 13 months of age in
      order to determine carcase, by-product and muscle yields. 2. Emus had a lower
      percentage of hot carcase weight (52%) and total fat (28%) to body weight but a
      higher lean meat to carcase weight (69%) than ostriches or rheas. 3. The amount
      of trimming of connective tissue from muscles of the lower leg (Gastrocnemius,
      Fibularis longus) has an influence (P<0.05) on the yields from these muscles.

PMID- 10405053
TI  - Treating Japanese quail with vitamin C does not facilitate their capture by the
      experimenter.
AB  - 1. Vitamin C supplementation reduces fear of novel situations and of people. The
      present study examined its effects on the ease of capture of male Japanese quail
      by the experimenter. 2. At 20 d of age, quail received either vitamin C (ascorbyl
      2-polyphosphate, APP, 1 g L-ascorbic acid/l) solution or untreated drinking water
      (UDW) for 24 h before they were mixed in 2 groups of 40 (20 APP + 20 UDW. All the
      birds in 1 group were caught individually by an unsighted experimenter whereas a
      sighted catcher captured the others. The bird's identity was noted each time.
      This capture/recapture procedure was repeated 6 times for each group (12 capture
      trials per bird) and an overall capture rank across all 12 trials was assigned to
      each bird. 3. Regardless of whether the catcher was sighted or unsighted, the
      mean ranks of neither APP nor UDW quail differed significantly from the value
      expected by chance. Neither were there any linear trends in the effects of
      repeated testing. Thus, prior treatment with vitamin C neither facilitated nor
      hindered capture. 4. Body weights were similar in both treatment groups and there
      were no significant intra-individual correlations between body weight and capture
      rank. 5. Highly significant tendencies were found for individual birds to be
      caught at similar stages of each capture trial regardless of treatment or test
      situation. This finding sounds a cautionary note for all studies involving
      putatively random sampling of a population.

PMID- 10405054
TI  - Correlation of birth weights with cesarean rates.
AB  - OBJECTIVE: To determine whether birth weights correlate with cesarean indications
      and whether a decrease in cesarean rates affects this relationship. MATERIALS AND
      METHODS: During the 1991-1997 period, 14 689 women delivered at Ravenswood
      Hospital Medical Center, Chicago; 2945 by cesarean (20.0%). We studied birth
      weight groups (Group 1, < or = 2500 g; Group 2, 2501-4000 g; and Group 3, > 4000
      g) according to the indication for cesarean delivery. Group 3 was divided into
      two subgroups (3a: 4001-4500 g, and 3b: > 4500 g). As cesarean rates decreased in
      our unit after 1994, we separated the data into two periods: A (1991-1993) and B
      (1994-1997). The differences between proportions were analyzed using the chi2
      tables. A P < 0.05 value was considered significant. RESULTS: Two out of 10 women
      admitted to our unit were delivered by cesarean. Compared to Group 2 (average
      weight), rates for breech and 'other' indications were higher in Groups 1 and 3
      (P < 0.001); the repeat cesarean rate was the lowest in Group 1. Rates for
      dystocia increased with birth weight. In Group 3, one out of four newborns (one
      out of three newborns > 4500 g in Subgroup 3b) had a cesarean birth, more than
      half of them for indications other than dystocia. Compared to Period A, Period B
      shows lower cesarean rates in Group 2 (21.4 vs. 16.4, P < 0.0001) and Subgroup 3b
      (35.4 vs. 26.1, P = 0.041). CONCLUSIONS: Birth weights affect cesarean delivery
      rates. Small and large newborns have more cesarean deliveries than those of
      average weight, whereas cesarean for dystocia increases with birth weights.
      Cesarean rates for non-reassuring fetal status are similar in all groups. A
      decline in repeat and cesareans for dystocia determined the lower total cesarean
      rate during the second period. and snhtetricrr

PMID- 10405056
TI  - The diagnosis of appendicitis during pregnancy and maternal and fetal outcome
      after appendectomy.
AB  - OBJECTIVE: A review of the literature reveals contradictive conclusions regarding
      appendicitis during pregnancy due to the few patients included in previous
      reports. METHODS: From 1980 to 1985, the Danish National Patient Registry
      identified the patients having the WHO codes Y60 (pregnancy), 54000 (acute
      appendicitis) and the operation code 43 000 (appendectomy). Each patient's file
      was reviewed by the authors. RESULTS: The ratio of appendicitis (n = 58) to
      appendectomy (n = 117) was 50%. The appendicitis group was significantly older
      (26.2 years) than the normal appendix group (23.8 years). Second trimester had
      the highest incidence of appendicitis, perforated appendicitis and normal
      appendix. No effect of tocolytic agents could be demonstrated. No maternal
      mortality. Obstetrical complications were few and appeared only in the group
      having a normal appendix and first after discharge. CONCLUSIONS: Pregnant women
      suspected of having appendicitis should be evaluated as non-pregnant women. Use
      of tocolytic agents is a matter of choice. Obstetrical complications are few and
      not related to the surgical trauma.

PMID- 10405055
TI  - Epidural analgesia for labor pain is not associated with a decreased frequency of
      uterine activity.
AB  - STUDY OBJECTIVE: To evaluate the effect of epidural and pethidine analgesia on
      the frequency of uterine contractions during the first stage of labor. DESIGN:
      Retrospective study. SETTING: Delivery ward of a public hospital. PATIENTS: Forty
      consecutive parturients. MEASUREMENTS AND MAIN RESULTS: The mean number of
      contractions in the 30 min before administration of pethidine analgesia was 8.2+/
      1.7 as compared to 8.7+/-1.3 after administration of the analgesia. The mean
      number of contractions in the 30 min before administration of epidural analgesia
      was 8.0+/-1.4 as compared to 8.8+/-1.9 after administration of the analgesia. The
      differences between the two groups and between the number of contractions before
      and after the administration of both types of analgesia were not statistically
      significant. CONCLUSION: Properly and timely administered epidural analgesia
      during the first stage of labor has no effect on frequency of uterine activity.

PMID- 10405057
TI  - Cut-off criteria for second-trimester nuchal skinfold thickness for prenatal
      detection of Down syndrome in a Thai population.
AB  - OBJECTIVE: To evaluate the use of progressive cut-offs for nuchal skinfold
      thickness with advancing gestational age and the commonly applied cut-off method
      (> 6 mm) for prenatal detection of Down syndrome in a Thai population. METHOD: A
      prospective study was performed by experienced perinatologists on 2150 women
      undergoing second-trimester amniocentesis for the indications of advanced
      maternal age and past history of chromosomal abnormality. Reference ranges were
      established for nuchal skinfold thickness from the 16th to the 24th week, using
      either gestational-specific centiles or the parametric method. Assaying different
      cut-off criteria for both centile and the parametric methods were calculated and
      then compared with the commonly applied cut-off level (> or = 6 mm.). RESULTS:
      There were 2114 chromosomally normal pregnancies, 19 fetuses with Down syndrome
      (1:113), and 17 other chromosome abnormalities. In fetuses with normal karyotype
      the nuchal skinfold thickness increased with advancing gestational age [NF (mm) =
      -0.502 + 0.212 GA (week), r = 0.36, P < 0.001]. The sensitivities of an abnormal
      nuchal skinfold thickness using different cut-off criteria for detecting Down
      syndrome were low (5.3-26.3%) with the false positive rates ranging from 2.5 to
      16.5%. CONCLUSIONS: In this study, measurement of second-trimester nuchal
      skinfold thickness was a poor and unreliable screening test for fetal Down
      syndrome in a Thai population.

PMID- 10405058
TI  - Inferior vena cava diameter and the risk of pregnancy-induced hypertension and
      fetal compromise.
AB  - OBJECTIVE: Our objective was to investigate a possible clinical usefulness of the
      measurement of the inferior vena caval diameter (IVCD) during the late second
      trimester in predicting obstetrical complications. METHODS: IVCD was measured in
      the supine and complete left lateral positions in 281 pregnant women at 24-27
      weeks' gestation. RESULTS: In 35 cases who showed the IVCD < or = 10 percentile
      in the complete left lateral position, there were six cases with pregnancy
      induced hypertension and seven cases with a compromized fetus (with fetal
      distress and/or an Apgar score < 7 at 1 min), each incidence being significantly
      higher compared with cases with IVCD > 10 percentile. CONCLUSION: The measurement
      of IVCD in the complete left lateral position may provide a valuable tool in
      predicting pregnancy outcome given its non-invasiveness and easiness.

PMID- 10405059
TI  - Perinatal outcome in hospital and birth center obstetric care.
AB  - OBJECTIVE: Our purpose was to compare birth complications and fetal outcome in
      hospitals and birth centers. METHOD: We retrospectively compared all 801
      deliveries between 1992 and 1994 from two free-standing birth centers against
      3271 hospital deliveries in Berlin. The hospital collective was selected
      according to the same risk criteria of the birth centers. RESULTS: The birth
      center group had significantly fewer medical interventions, with a similar
      cesarean section rate (3.0% vs. 4.6%, P = 0.057) and occurrence of severe
      perineal lesions. The episiotomy rate was significantly higher (P < 0.001) in the
      clinics for first-time and multiple births. The perinatal mortality was not
      significantly different ( < 0.1 per 1000). One-minute Apgar scores less than 7
      were found significantly more often in the birth center group. CONCLUSION: When
      birth centers employ thorough risk selection and significant early referral rates
      to nearby hospitals, there is no evidence of increased maternal or perinatal risk
      compared to hospital deliveries.

PMID- 10405060
TI  - V--Y flap for perineal reconstruction following modified approach to vulvectomy
      in vulvar cancer.
AB  - OBJECTIVE: To evaluate a simple reconstructive procedure used in combination with
      a modified oncological approach to the treatment of invasive vulvar cancer. Local
      and systemic morbidity, length of hospital stay, local recurrence, and mortality
      were evaluated. METHODS: Between September 1995 and January 1997, 19 patients
      underwent radical vulvectomy and inguinal lymphadenectomy with a modified
      oncological approach. The modified approach consisted of a triple incision: two
      inguinal incisions, shorter and following force lines of the groin, and a third
      incision around the vulvar lesion. Vulvectomy included a 2-cm safety margin
      around the tumor, based on clinical examination and anatomical-pathological
      frozen sections of the specimen. This procedure was always followed by perineal
      reconstruction with V-Y flaps by the plastic surgery team. Median follow-up was
      12 months. The complication rate and lengths of hospital stay were evaluated and
      compared with those in a similar group in which radical vulvectomy was performed
      associated with two long longitudinal incisions in the groin. The data were
      statistically analyzed. RESULTS: The perineal and inguinal dehiscence rates in
      group A (traditional approach) were 68.4% and 78.94%, respectively. The same
      rates in group B (modified approach), were 10.5% and 36.84%, respectively. Mean
      hospital stay was 39.5 days in group A (traditional) vs. 14.0 days in group B
      (modified). At 30 months' median follow-up, the rate of local recurrence in group
      A (traditional) was 42.0%; at 12 months' median follow-up, local recurrence in
      group B (modified) was 26.3%. CONCLUSIONS: In this study, the use of V-Y flaps in
      combination with a modified oncological approach significantly reduced local
      complication rates and lengths of hospital stay, while observing oncological
      principles.

PMID- 10405061
TI  - Duration of vaginal retention and potential duration of antiviral activity for
      five nonoxynol-9 containing intravaginal contraceptives.
AB  - OBJECTIVE: The purpose of this study was to determine the vaginal retention of
      five nonoxynol-9 intravaginal contraceptives. METHOD: An open-label crossover
      study in 10 premenopausal volunteers was performed at an outpatient clinical
      research center. The outcomes are described utilizing the median and range.
      RESULT: At 8 h post-instillation, the median amounts of nonoxynol-9 present in
      the vagina were: Delfon 7.68 mg, Conceptrol 5.18 mg, Advantage 24 1.95 mg, VCF
      1.74 mg, and Semicid 1.51 mg respectively. Our calculated theoretical minimal
      amount needed to protect against HIV infection is 2.00 mg. CONCLUSION: The best
      vehicle for retaining nonoxynol-9 in the vagina appears to be foam. Further
      research in the effectiveness of nonoxynol-9 in prevention of the spread of HIV
      infection should be directed toward the use of foam vehicles to deliver nonoxynol
      9 to the vagina.

PMID- 10405062
TI  - Risk factors for human papillomavirus and cervical precancerous lesions, and the
      role of concurrent HIV-1 infection.
AB  - OBJECTIVES: To identify risk factors for human papillomavirus (HPV) infection and
      squamous intraepithelial lesions (SIL) of the cervix, and to measure the impact
      of concurrent HIV-1 infection. METHODS: Women were studied at a family planning
      clinic in Nairobi, Kenya. Demographic and historical information was obtained
      using a semi-structured questionnaire and specimens were collected for sexually
      transmitted diseases (STDs), HPV, cervical cytology, and HIV-1 testing. RESULTS:
      HPV was detected in 87 of 513 women (17%), including 81 (93%) oncogenic types
      (16, 18, 31, 33 and others) and six (7%) non-oncogenic types (6 and 11). HIV-1
      prevalence was 10%. HPV detection was associated with HIV-1 infection [adjusted
      odds ratio (aOR) 3.9, 95% confidence interval (CI), 2.0-7.7], sexual behavior
      indicators including the number of sex partners and inflammatory STDs, as well as
      the number of pregnancies (0 or 1 vs. > or = 3, aOR 0.4; 95% CI, 0.2-0.9). SIL
      was detected in 61 women (11.9%), including 28 (46%) with low-grade lesions
      (LSIL) and 33 (54%) with high-grade lesions (HSIL). HPV infection was strongly
      associated with HSIL (OR 14.9; 95% CI, 6.8-32.8). In a multivariate model
      predictors of HSIL included HIV-1 serpositivity (aOR 4.8; 95% CI, 1.8-12.4), the
      number of lifetime sex partners (0-1 vs. > or = 4; aOR 3.8; 95% CI, 1.1-13.5),
      and older age (< 26 vs. > 30; OR 3.9; 95% CI, 1.1-13.6). An analysis stratified
      by HIV-1 showed a stronger association between HPV and HSIL in HIV-1 negative
      women (OR 17.0; 95% CI, 6.4-46.3) then in HIV-1 positive women (OR 4.5; 95% CI,
      0.8-27.4). CONCLUSION: Our results indicate that HSIL and even invasive cancer
      are highly prevalent in this setting of women on reproductive age considered to
      be at low risk for STDs, suggesting that routine Pap smear screening may save
      lives.

PMID- 10405063
TI  - Conception rates after abortion with methotrexate and misoprostol.
AB  - OBJECTIVE: To evaluate the fertility of a cohort of women within 1 year after
      receiving methotrexate and misoprostol for early abortion. METHODS: Participants
      in a clinical trial of medical abortion were contacted at 1-6 months and
      approximately 12 months after the study abortion to obtain fertility information.
      For both interviews, subjects were asked about sexual activity, contraception
      used since the abortion, and any pregnancies (and their outcomes) since the
      abortion. RESULTS: Ninety-three (81.6%) of 114 subjects were able to be
      contacted. Follow-up intervals ranged from 1 to 19 completed months (median 11
      months) after the study abortion. During the follow-up period, 23 (24.7%) women
      became pregnant; none had been attempting to achieve pregnancy. One patient had a
      normal term delivery, one had a spontaneous abortion and the remainder had
      elective abortions. CONCLUSIONS: Women who have a medical abortion with low-dose
      intramuscular methotrexate and vaginal misoprostol remain at high risk for
      unintended pregnancy.

PMID- 10405064
TI  - First trimester 'retained abortion'--can it be termed 'placenta accreta'?

PMID- 10405065
TI  - Fetal sacrococcygeal teratoma visualized by ultra-fast T2 weighted magnetic
      resonance imaging.
AB  - We report here a fetal sacrococcygeal teratoma found at 26 weeks of gestation. An
      ultra-fast T2 weighted imaging method enables the clear visualization of
      morphological details of the fetus without motion artifacts. Complete surgical
      resection was performed immediately after cesarean birth, and no evidence of
      tumor recurrence was confirmed at 1 year of age.

PMID- 10405066
TI  - Domestic violence and health of Pakistani women.
AB  - OBJECTIVE: Assessment of the prevalence and health consequences of domestic
      violence among women in Karachi, Pakistan. METHODS: Confidential interviews were
      conducted among 150 women randomly selected from health facilities. RESULTS: 34%
      reported ever being physically abused, 15% ever being physically abused whilst
      pregnant and 72% of physically abused women were anxious/depressed. Physical
      abuse was a major predictor of anxiety/depression. CONCLUSIONS: The magnitude,
      physical and mental health consequences of domestic violence represents a serious
      reproductive health concern for Pakistan.

PMID- 10405067
TI  - Use of the partograph among medical personnel in Enugu, Nigeria.

PMID- 10405068
TI  - Idiopathic thrombocytopenic purpura and pregnancy.

PMID- 10405069
TI  - Global climate warming and performance of therapeutic agents in obstetrics and
      gynecology.

PMID- 10405070
TI  - Cervical pregnancy with placenta accreta.

PMID- 10405071
TI  - Patient choice and the maternal-fetal relationship. Number 214, April 1999
      (replaces number 55, October 1987). Committee on Ethics.

PMID- 10405072
TI  - Nonselective embryo reduction: ethical guidance for the obstetrician
      gynecologist. Number 215, April 1999 (replaces number 94, April 1991). Committee
      on Ethics.
AB  - Although physicians may choose not to participate in nonselective embryo
      reduction, they should be knowledgeable about this procedure and be prepared to
      react in a professional and ethical manner to patient requests for information or
      services or both. The first approach to the problem of multiple gestation should
      be prevention. Although embryo reduction will be ethically acceptable to many as
      a response to an unforeseen and unavoidable contingency, in almost all cases it
      is preferable to terminate a cycle or limit the number of embryos to be
      transferred in order to prevent a situation in which the patient and physician
      need to consider an embryo reduction. Counseling for treatment of infertility
      should include the risks of multiple gestation, and the ethical issues
      surrounding embryo reduction should be discussed with patients before the
      initiation of any treatment that could increase the risk of multiembryo
      pregnancy.

PMID- 10405073
TI  - Attention deficit hyperactivity disorder in adults.

PMID- 10405074
TI  - Childhood attention deficit/hyperactivity disorder in adults with anxiety
      disorders.
AB  - BACKGROUND: Previous research has reported co-morbidity between attention deficit
      hyperactivity disorder (ADHD) and anxiety disorders. Interpretation of these
      findings is complicated by symptom overlap in the clinical presentation of the
      disorders. We estimate the prevalence of ADHD in both the current and childhood
      histories of adults with anxiety disorders, while taking symptom overlap into
      account. We also evaluate the utility of the Wender Utah Rating Scale (WURS) for
      retrospective reporting of ADHD. METHODS: Consecutive admissions (N = 149) to an
      anxiety disorders clinic were given a diagnostic and psychometric assessment. The
      WURS was administered to obtain a retrospective diagnosis of childhood ADHD.
      Twenty-nine of the 35 people surpassing the cut-off score on the WURS were given
      a structured interview of adult ADHD symptoms. RESULTS: The WURS contains many
      'internalizing' items that may inflate retrospective accounts of ADHD. After
      taking this into account, there is still a significantly higher prevalence of
      ADHD in the retrospective reports of adults with anxiety disorders (15%) than
      would be expected by chance (4%). Furthermore, of those who meet retrospective
      criteria for ADHD, 45% (13 of 29) continue to meet diagnostic criteria for ADHD
      as adults. CONCLUSIONS: The WURS may require considerable revision for use with
      clinical populations. In spite of these difficulties with retrospective
      assessment, available evidence indicates that ADHD is more prevalent in the
      histories of anxiety disordered patients than would be expected from base rates.

PMID- 10405075
TI  - Executive function and attention deficit hyperactivity disorder: stimulant
      medication and better executive function performance in children.
AB  - BACKGROUND: Executive function deficits have been reported repeatedly in children
      with Attention Deficit Hyperactivity Disorder (ADHD). Stimulant medication has
      been shown to be effective in improving cognitive performance on most executive
      function tasks, but neuropsychological tests of executive function in this
      population have yielded inconsistent results. Methodological limitations may
      explain these inconsistencies. This study aimed to measure executive function in
      medicated and non-medicated children with ADHD by using a computerized battery,
      the Cambridge Neuropsychological Test Automated Battery (CANTAB), which is
      sensitive to executive function deficits in older patients with frontostriatal
      neurological impairments. METHODS: Executive function was assessed in 30 children
      with ADHD: 15 were stimulant medication naive and 15 were treated with stimulant
      medication. These two groups were compared to 15 age, sex and IQ matched
      controls. RESULTS: The unmedicated children with ADHD displayed specific
      cognitive impairments on executive function tasks of spatial short-term memory,
      spatial working memory, set-shifting ability and planning ability. Impairments
      were also seen on spatial recognition memory and delayed matching to sample,
      while pattern recognition memory remained intact. The medicated children with
      ADHD were not impaired on any of the above executive function tasks except for
      deficits in spatial recognition memory. CONCLUSIONS: ADHD is associated with
      deficits in executive function. Stimulant medication is associated with better
      executive function performance. Prospective follow-up studies are required to
      examine these effects.

PMID- 10405077
TI  - Lifetime co-morbidities between social phobia and mood disorders in the US
      National Comorbidity Survey.
AB  - BACKGROUND: General population data were used to study co-morbidities between
      lifetime social phobia and mood disorders. METHODS: Data come from the US
      National Comorbidity Survey (NCS). RESULTS: Strong associations exist between
      lifetime social phobia and major depressive disorder (odds ratio 2.9), dysthymia
      (2.7) and bipolar disorder (5.9). Odds ratios increase in magnitude with number
      of social fears. Reported age of onset is earlier for social phobia than mood
      disorders in the vast majority of co-morbid cases. Temporally-primary social
      phobia predicts subsequent onset of mood disorders, with population attributable
      risk proportions of 10-15%. Social phobia is also associated with severity and
      persistence of co-morbid mood disorders. CONCLUSIONS: Social phobia is a commonly
      occurring, chronic and seriously impairing disorder that is seldom treated unless
      it occurs in conjunction with another co-morbid condition. The adverse
      consequences of social phobia include increased risk of onset, severity and
      course of subsequent mood disorders. Early outreach and treatment of primary
      social phobia might not only reduce the prevalence of this disorder itself, but
      also the subsequent onset of mood disorders.

PMID- 10405078
TI  - Antecedents of the risk of recovery from DSM-III-R social phobia.
AB  - BACKGROUND: This study reports antecedents of recovery from DSM-III-R social
      phobia. METHODS: Retrospective data were obtained from 1116 individuals age 15 to
      64 participating in a large population health survey in the province of Ontario,
      Canada RESULTS: Approximately 50% of the sample recovered from their illness.
      Survival analysis revealed a median length of illness of 25 years with peak
      periods of risk of recovery occurring between 30 and 45 years duration. Using
      discrete time multivariate hazard regression analysis, statistically significant
      predictors of recovery from social phobia included: childhood social contextual
      factors (one or no childhood siblings, a small town childhood place of
      residence), characteristics of the disorder (onset past the age of 7, less than
      three disorder symptoms), an absence of co-morbid health-related conditions and
      psychiatric disorders (chronic health problems and major depression), and the
      occurrence of co-morbid chronic health problems and major depression prior to the
      onset of the disorder. CONCLUSIONS: Our data indicate that social phobia in the
      general population is a chronic and unremittent disorder. Determinants of
      recovery are rooted in distal childhood circumstances, disorder attributes, and
      the physical and mental health status of individuals over the life course.

PMID- 10405076
TI  - Fears and phobias: reliability and heritability.
AB  - BACKGROUND: Familial factors, which are partly genetic, influence risk for
      phobias. Prior family and twin studies, however, were based on a single lifetime
      assessment, which may be only moderately reliable. METHODS: We obtained, 8 years
      apart, two assessments of lifetime history of five unreasonable fears and phobias
      (agoraphobia and social, situational, animal and blood-injury phobia) from face
      to-face and telephone interviews from 1708 individual female twins from a
      population-based registry. We also obtained, 1 month apart, test retest
      reliability on 192 twins. We fitted, using the program Mx, a measurement model
      that estimates the role of genetic and environmental risk factors correcting for
      measurement error. RESULTS: Short-term reliability of the five phobias was modest
      (mean kappa = 0.46), but higher than long-term stability (mean kappa = 0.30).
      Unreliability occurred both for subject recall of unreasonable fears and for
      interviewer assessment of which fears constituted phobias. Examining fears and
      phobias together, in a multiple threshold model, results suggested that twin
      resemblance was due solely to genetic factors, with estimated total
      heritabilities, corrected for unreliability, of: any 43%, agoraphobia 67%, animal
      47%, blood/injury 59%, situational 46% and social 51%. With the exception of
      animal phobia, similar results were obtained analysing phobias alone.
      CONCLUSIONS: Lifetime histories of unreasonable fears and phobias assessed at
      personal interview have substantial unreliability. Correcting for unreliability,
      the liability to fears and their associated phobias is moderately heritable.
      Individual-specific environmental experiences play an important role in the
      development of phobias, while familial-environmental factors appear to be of
      little aetiological significance.

PMID- 10405079
TI  - Consequences of anxiety in older persons: its effect on disability, well-being
      and use of health services.
AB  - BACKGROUND: Although anxiety is quite prevalent in late life, its impact on
      disability, well-being, and health care utilization of older persons has not been
      studied. Older persons are a highly relevant age group for studying the
      consequences of anxiety, since their increasing numbers put an extra strain on
      already limited health care resources. METHODS: Data of a large community-based
      random probability sample (N = 659) of older subjects (55-85 year) in the
      Netherlands were used to select three groups: subjects with a diagnosed anxiety
      disorder, subjects with merely anxiety symptoms and a reference group without
      anxiety. These groups were compared with regard to their functioning, subjective
      well-being, and use of health care services, while controlling for potentially
      confounding variables. RESULTS: Anxiety was associated with increased disability
      and diminished well-being. Older persons with a diagnosed anxiety disorder were
      equally affected in their functioning as those with merely anxiety symptoms.
      Although use of health services was increased in anxiety sufferers, their use of
      appropriate care was generally low. CONCLUSIONS: Anxiety has a clear negative
      impact on the functioning and well-being of older subjects. The similarity of
      participants with an anxiety disorder and those having merely anxiety symptoms
      regarding quality of life variables and health care use was quite striking.
      Finally, in spite of its grave consequences for the quality of life, appropriate
      care for anxiety is seldom received. Efforts to improve recognition, disseminate
      effective treatments in primary care, and referring to specialized care may have
      positive effects on the management of anxiety in late life.

PMID- 10405081
TI  - Factor analysis of symptoms in schizophrenia: differences between White and
      Caribbean patients in Camberwell.
AB  - BACKGROUND: The incidence of schizophrenia among African-Caribbeans living in
      Britain has been frequently reported to be increased. We sought to determine
      whether the symptom profile in schizophrenic patients from this group differed
      from that of their White counterparts. METHODS: Factor analysis was applied to
      symptom data obtained by the Present State Examination (PSE) from a group of
      White (N = 96) and Afro-Caribbean (N = 64) patients who satisfied Research
      Diagnostic Criteria criteria for broad schizophrenia. We identified six symptom
      dimensions: mania, depression, first-rank delusions, other delusions,
      hallucinations and one which comprised both manic and catatonic symptoms.
      RESULTS: The only difference between the two ethnic groups was seen on the mixed
      mania-catatonia dimension with the Afro-Caribbean group being over-represented.
      There were no other significant differences between the groups. Discriminant
      analysis, however, revealed no significant differences between the groups in any
      dimension. CONCLUSIONS: These results indicate that there are no differences
      between White and African-Caribbean patients with schizophrenia in terms of the
      core symptoms of the disorder, however, the African-Caribbean patients may
      present with more symptoms of a mixed affective nature.

PMID- 10405080
TI  - A comparison of the utility of dimensional and categorical representations of
      psychosis. UK700 Group.
AB  - BACKGROUND: The usefulness of any diagnostic scheme is directly related to its
      ability to provide clinically useful information on need for care. In this study,
      the clinical usefulness of dimensional and categorical representations of
      psychotic psychopathology were compared. METHOD: A total of 706 patients aged 16
      65 years with chronic psychosis were recruited. Psychopathology was measured with
      the Comprehensive Psychopathological Rating Scale (CPRS). Lifetime RDC, DSM-III
      R, and ICD-10 diagnoses and ratings of lifetime psychopathology were made using
      OPCRIT. Other clinical measures included: (i) need for care; (ii) quality of
      life; (iii) social disability; (iv) satisfaction with services; (v) abnormal
      movements; (vi) brief neuropsychological screen; and (vii) over the last 2 years-
      illness course, symptom severity, employment, medication use, self-harm, time in
      hospital and living independently. RESULTS: Principal component factor analysis
      of the 65 CPRS items on cross-sectional psychopathology yielded four dimensions
      of positive, negative, depressive and manic symptoms. Regression models comparing
      the relative contributions of dimensional and categorical representations of
      psychopathology with clinical measures consistently indicated strong and
      significant effects of psychopathological dimensions over and above any effect of
      their categorical counterparts, whereas the reverse did not hold. The effect of
      psychopathological dimensions was mostly cumulative: high ratings on more than
      one dimension increased the contribution to the clinical measures in a dose
      response fashion. Similar results were obtained with psychopathological
      dimensions derived from lifetime psychopathology ratings using the OCCPI.
      CONCLUSIONS: A dimensional approach towards classification of psychotic illness
      offers important clinical advantages.

PMID- 10405082
TI  - How do people with schizophrenia explain the behaviour of others? A study of
      theory of mind and its relationship to thought and speech disorganization in
      schizophrenia.
AB  - BACKGROUND: This paper examines the attribution of mental states to others in
      schizophrenia and its links with thought and speech disorganization. METHODS: Two
      groups of schizophrenic subjects (15 with and 10 without thought and speech
      disorganization) were compared with 10 manic subjects and 15 normal controls on
      their pattern of answers to 14 theory of mind comic strips. RESULTS:
      Schizophrenic subjects with disorganization and a more severe general
      psychopathology exhibited more unadaptated interpretations of others' mental
      states than those without disorganization or the manic or normal controls. Their
      explanation of other people's behaviour tended to be influenced by the frequency
      of their actions rather than their mental states. CONCLUSIONS: The
      disorganization pattern in schizophrenia may be associated with a specific
      deficit of the cognitive ability referred to as theory of mind, and this deficit
      could be a state rather than a trait variable. Patients with thought and speech
      disorders may be more likely to understanding other people's mental states in
      unambiguous and common situations.

PMID- 10405083
TI  - Obstetric complications predict treatment response in first-episode
      schizophrenia.
AB  - BACKGROUND: Understanding the role of obstetric complications (OCs) in
      schizophrenia could potentially shed light on the heterogeneity in the aetiology
      and course of schizophrenia. Many investigators have reported an association
      between OCs and schizophrenia, but few have examined the association between OCs
      and treatment outcome. We investigated this question in a sample of patients
      studied during their first episode of schizophrenia, schizoaffective or
      schizophreniform disorder. METHOD: OC histories were obtained for 59 patients
      participating in the Hillside First Episode Study. Cox proportional hazards
      regression analysis was used to estimate the effect of OCs on treatment response
      during the first episode of schizophrenia. RESULTS: Twelve of the 59 patients
      (20%) had positive histories of OCs. This group exhibited lower rates of
      treatment response than those with negative OC histories (hazard ratio
      controlling for sex = 0.28; 95% CI = 0.13, 0.62). The positive OC group also had
      significantly greater lateral ventricle volume, baseline disorganization and
      number of live births. The effect of OC history on treatment response held when
      these three variables were controlled for. CONCLUSION: A history of obstetric
      complications predicted poor response to treatment in the first episode of
      schizophrenia. This large effect was based on a small sample of 59 patients.
      Thus, replication is called for.

PMID- 10405084
TI  - Hippocampal/amygdala volumes in geriatric depression.
AB  - BACKGROUND: The hippocampus, amygdala and related functional circuits have been
      implicated in the regulation of emotional expression and memory processes, which
      are affected in major depression. Several recent investigations have reported
      abnormalities in these structures in adult and elderly depressives. METHODS:
      Elderly DSM-III-R unipolar depressives (N = 40) and normal controls (N = 46)
      participated in a magnetic resonance imaging study (1.0T). Brain images were
      obtained in the coronal plane. Using established anatomical guidelines for
      structure delineation, volumetric measurements of left and right hippocampus and
      anterior hippocampus/amygdala complex were completed under blinded conditions
      using a semi-automated computer mensuration system, with patients and controls in
      random order. RESULTS: Medial temporal volumes did not significantly distinguish
      either elderly depressed and age-similar normal control subjects, or late onset
      and early onset depressed patients (ANCOVA). Major overlap of measured volumes
      existed between patient and control groups. In depressives, hippocampal volumes
      significantly correlated with age, and cognitive and depression ratings, but not
      with number of prior depressive episodes or age-at-onset of first depression.
      CONCLUSIONS: Hippocampal volumes do not discriminate a typical clinical
      population of elderly depressed patients from age-similar normal control
      subjects. If hippocampal dysfunction contributes to a diagnosis of syndromal
      depression in the elderly, such dysfunction does not appear to be regularly
      reflected in structural abnormalities captured by volumetric measurement as
      conducted. On the other hand, relationships between hippocampal volumes and
      clinical phenomena in depressives, but not controls, suggest potentially
      meaningful interactions between hippocampal structure and the expression of major
      depression in the elderly.

PMID- 10405085
TI  - Quantitative proton magnetic resonance spectroscopy of the bilateral frontal
      lobes in patients with bipolar disorder.
AB  - BACKGROUND: Using 31P and 1H magnetic resonance spectroscopy (MRS) we previously
      reported that phosphocreatine was decreased in the left frontal lobe and choline
      containing compounds were increased in the basal ganglia in the depressive state
      in patients with bipolar disorder. We applied quantitative 1H-MRS for further
      characterization of biochemical alteration in the frontal lobes of bipolar
      patients. METHODS: Twenty-three bipolar patients and 20 normal controls were
      examined by 1H-MRS with a 1.5T MR system. All patients were examined in the
      euthymic state, and eight patients were also examined in the depressive state.
      Volumes of interest of 2.5 x 2.5 x 2.5 cm were selected in the left and right
      frontal lobes. Absolute concentrations of N-acetyl-1-aspartate, creatine plus
      phosphocreatine, and choline-containing compounds were calculated from each
      metabolite peak. RESULTS: Creatine concentration in the left frontal lobe in
      bipolar patients in the depressive state was significantly lower than that in the
      euthymic state. Creatine concentration in the right frontal lobe in the male
      patients was significantly higher than that in the female patients and a similar
      trend was also found in the control subjects. CONCLUSIONS: We found a state
      dependent change of creatine metabolism in the left frontal lobe of bipolar
      patients. The present results are compatible with our previous report of
      decreased phosphocreatine measured by 31P-MRS in the left frontal lobe in bipolar
      disorder. We also found an effect of gender on the creatine concentration. There
      may be a gender difference in creatine transport function into the brain.

PMID- 10405086
TI  - Genetic influences on post-natal depressive symptoms: findings from an Australian
      twin sample.
AB  - BACKGROUND: Conflicting evidence exists on causes of vulnerability to post-natal
      depression. We investigated genetic and environmental influences on variation in
      post-natal depressive symptoms (PNDS) following first live birth, and sources of
      covariation with the personality trait Neuroticism and lifetime major depression
      occurring post-natally (DEP-PN) and at other times (DEP-XPN) to test for shared
      genetic influences. METHOD: Retrospective interview and questionnaire data from
      838 parous female twin pairs (539 monozygotic, 299 dizygotic) from the Australian
      National Health and Medical Research Council volunteer adult twin register were
      used for multivariate genetic model-fitting. Data on PNDS were evaluated for
      consistency with diagnostic interview assessment. RESULTS: Genetic factors
      explained 38% of variance in PNDS (95% confidence interval 26-49%) and 25% of the
      variance in interview-assessed DEP-PN. The genetic correlation between PNDS and
      lifetime major depression (DEP-PN and DEP-XPN) was low (r(g) = 0.17, 95%
      confidence interval = 0.09-0.28), suggesting that the questionnaire was measuring
      a construct other than postnatally occurring major depression, possibly post
      natal dysphoria. Associations between PNDS and obstetric factors were very
      modest. CONCLUSIONS: Findings suggest modest genetic influences on major
      depression occurring postnatally. Independent and stronger genetic influences
      identified for post-natal symptomatology or dysphoria (PNDS) justify further
      investigation.

PMID- 10405087
TI  - Prevalence, 20-month incidence and outcome of unipolar depressive disorders in a
      community sample of adolescents.
AB  - BACKGROUND: This article presents prospective longitudinal findings on
      prevalence, incidence, patterns of change and stability of depressive disorders
      in a community sample of 1228 adolescents. METHODS: Data were collected at
      baseline and follow-up (20 months later) in a representative population sample of
      1228 adolescents, aged 14-17 at baseline. Diagnostic assessment was based on the
      Munich Composite International Diagnostic Interview (M-CIDI). RESULTS: The
      overall cumulative lifetime incidence of any depressive condition was 20.0%
      (major depressive disorder (MDD), 12.2%; dysthymia, 3-5%; subthreshold MDD,
      6.3%), of which about one-third were incident depressions in the period between
      baseline and follow-up. Depressive disorders rarely started before the age of 13.
      Females were about twice as likely as males to develop a depressive disorder.
      Overall, the 20-month outcome of baseline depression was unfavourable. Dysthymia
      had the poorest outcome of all, with a complete remission rate of only 33% versus
      43% for MDD and 54% for subthreshold MDD. Dysthymia also had the highest number
      of depressive episodes, and most psychosocial impairment and suicidal behavioural
      during follow-up. Treatment rates were low (8-23%). Subthreshold MDD associated
      with considerable impairment had an almost identical course and outcome as
      threshold MDD. CONCLUSIONS: DSM-IV MDD and dysthymia are rare before the age of
      13, but frequent during adolescence, with an estimated lifetime cumulative
      incidence of 14%. Only a minority of these disorders in adolescence is treated,
      and more than half of them persist or remit only partly.

PMID- 10405088
TI  - The natural history of somatization in primary care.
AB  - BACKGROUND: Somatization is often regarded as a chronic disorder. However,
      empirical studies to support this view and to determine its natural history in
      primary care are lacking. This paper provides data on the incidence and
      persistence of current somatization syndrome in a large cross-national sample
      drawn from 15 sites in 14 countries. METHODS: After screening with the General
      Health Questionnaire, a stratified sample of 5438 primary care patients was
      interviewed with the Composite International Diagnostic Interview and evaluated
      for physical health status, self-rated overall health and for occupational
      disability. Twelve months later, 3204 of the patients completed follow-up
      interviews. RESULTS: Over a 12-month period, an abridged form of somatization
      defined as four current symptoms in males and six in females was persistent in
      45.9% of the patients. Persistence of syndrome was related to age and to
      subjective indices of psychological distress at baseline. Persistence was
      unrelated to depression. The 12-month incidence of the abridged somatization
      syndrome was 7.1% (95% CI, 6.1-8.3%). Individuals with depression at baseline and
      those with poor view of their health were more likely to develop new episodes of
      somatization 12-months later. CONCLUSION: Somatization syndrome showed
      considerable change over time. Persistence and onset of somatization were related
      to both level of psychopathology and health beliefs.

PMID- 10405089
TI  - Typologies of anxiety, depression and somatization symptoms among primary care
      attenders with no formal mental disorder.
AB  - BACKGROUND: Typologies of anxiety, depression and somatization symptoms were
      investigated in individuals with no formal mental disorders, making no a priori
      assumptions about symptom distribution and inter-relationship. METHOD: The
      subjects were 1617 adult primary care attenders from the WHO Collaborative
      Project on Psychological Problems in General Health Care, with at least three
      symptoms of anxiety, depression and/or somatization, but with no formal ICD-10
      disorders. Analyses were based on the grade of membership model, a multivariate
      statistical procedure exploring indistinct boundaries between disease categories
      and preserving the heterogeneity of clinical picture within each category.
      RESULTS: Six prototype categories (or pure types) best described the structure of
      symptoms included in analyses. Pure type I included the full set of somatization
      symptoms. Pure type II was characterized by most anxiety and depression symptoms.
      Pure type III resembled generalized anxiety disorder. Pure type IV consisted of
      individuals reporting sporadic symptoms of anxiety, depression or somatization.
      Pure type V defined individuals with sleep problems. Finally, pure type VI was
      characterized by anxiety symptoms, including panic-like symptoms. CONCLUSIONS:
      These findings provide support to the existence of a mixed anxiety-depression
      category crossing the diagnostic boundaries of current anxiety and depression
      disorders. Moreover, criteria of anxiety and somatization disorders may be re
      examined to assess whether lower diagnostic thresholds can be identified that
      both preserve the symptom profile and clinical features of current diagnostic
      categories and allow for a better characterization of individuals with
      substantial psychopathology though not meeting the high symptom thresholds
      required for a diagnosis of formal mental disorders.

PMID- 10405090
TI  - The general practitioner as the first contacted health professional by patients
      with psychosocial problems: a European study.
AB  - BACKGROUND: There are considerable differences between and within countries in
      the involvement of general practitioners (GPs) in psychosocial care. This study
      aimed to describe the self-perceived role of GPs in 30 European countries as the
      first contacted professional for patients with psychosocial problems. and to
      examine the relationship with characteristics of the health care system, practice
      organization and doctors. METHODS: Data collected in the European Study of GP
      Task Profiles were analysed in relation to the self-perceived involvement of GPs
      in psychosocial care. In 30 countries 7233 GPs answered standardized
      questionnaires in their own languages about seven brief case scenarios. The
      questions focused on care given as the first health care professional contacted,
      and were answered in a scored scale (1-4) ranging from 'never' to 'almost
      always'. Independent variables examined were both on a national level and on an
      individual level, including: listed practice population, referral system,
      employment status of GPs, workload, measures of practice organization, contacts
      with social workers and urbanization of practice area. Data were analysed using
      multi-level techniques. RESULTS: Self-perceived involvement in psychosocial care
      was much higher in Western than in Eastern Europe and also in countries with a
      referral system. Cooperation with social workers, rural practice, keeping medical
      records, presence of an appointment system and high workload were positively
      associated with this perceived involvement. CONCLUSIONS: In countries with self
      employed doctors and a referral system, GPs are in a better position to provide
      psychosocial care. GPs should be encouraged to cooperate with social workers and
      to keep medical records of their patient contacts routinely.

PMID- 10405091
TI  - The unhealthy lifestyle of people with schizophrenia.
AB  - BACKGROUND: Schizophrenia has a high natural mortality of a largely environmental
      aetiology. There is, however, little research about possible risk factors. This
      study measured the diet, cigarette and alcohol use, exercise and obesity of a
      cohort of people with schizophrenia and compared results to general population
      rates. METHODS: Semi-structured interview using validated research instruments on
      102 middle-aged subjects with a diagnosis of schizophrenia, living in the
      community. Results were compared to general population norms using standard
      statistical tests. RESULTS: The subjects ate a diet higher in fat and lower in
      fibre than the general population. They look little exercise but were not
      significantly more obese. They smoked heavily but drank less alcohol. Most
      differences remained significant after controlling for social class. CONCLUSIONS:
      People with schizophrenia have an unhealthy lifestyle, which probably contributes
      to the excess mortality of the disease. They are therefore an appropriate target
      group for health promotion interventions.

PMID- 10405092
TI  - The survey form of SCAN: the feasibility of using experienced lay survey
      interviewers to administer a semi-structured systematic clinical assessment of
      psychotic and non-psychotic disorders.
AB  - BACKGROUND: The success of large scale surveys depends on well designed
      questionnaires and the skills of lay interviewers. Discrepancies in prevalence
      rates between epidemiological surveys and poor agreement between survey
      interviewer and clinician diagnostic interviews are giving rise to increasing
      concern among researchers, public health planners and policy developers. New
      approaches to information collection are called for. The feasibility of training
      experienced survey interviewers in semi-structured, clinical, diagnostic
      interviewing has never been investigated systematically across the range of
      neurotic and psychotic disorders. METHODS: Eight experienced survey interviewers
      from the Office for National Statistics (ONS) were selected and underwent
      extended training in a Survey Form of SCAN (SCAN-SF). Sixty-four adults,
      including a majority of psychiatric in-patients were assessed by ONS interviewers
      and reinterviewed within a week by SCAN-trained clinicians. Feedback was sought
      from interviewers and trainers. RESULTS: Trainers found lay interviewers coped at
      least as well with psychotic as with neurotic symptoms. Concordance for any
      disorder was 0.74 (95% CI: 0.57 to 0.91); for any specific psychotic disorder
      0.63 (0.40 to 0.86); for any specific neurotic disorder 0.63 (0.43 to 0.83).
      Sensitivity ranged from 0.6 to 0.9 and specificity from 0.8 to 0.9. There was no
      evidence of rater bias. CONCLUSIONS: These preliminary findings are very
      promising. However, before the SCAN-SF, administered by carefully trained lay
      interviewers, can be recommended in large scale surveys, further evaluations of
      its feasibility and reliability in the general population are needed.

PMID- 10405093
TI  - Psychosocial adjustment after traumatic brain injury: what are the important
      variables?
AB  - BACKGROUND: The common legacy of severe degrees of traumatic brain injury is
      varying degrees and types of impairments, which impact significantly upon the
      individual's resumption of pre-morbid psychosocial roles. Yet there are few data
      to indicate the relative contribution of these and other non-injury related
      variables. METHODS: Seventy individuals with varying levels of disability after
      severe traumatic brain injury were examined neurologically and
      neuropsychologically, on average at 6 years post-trauma. A range of biographical,
      injury, impairment and psychological variables were examined with multiple
      regression analyses to identify those that contributed to successful psychosocial
      reintegration. RESULTS: Severity of injury and impairments, along with chronicity
      and level of self-esteem were significant predictors of psychosocial adjustment.
      Further analyses revealed that within the neuropsychological domain, the variable
      measuring behavioural regulation of abilities was the most significant.
      Examination of specific domains of psychosocial functioning (occupational
      activities, interpersonal relationships and independent living skills) revealed
      different patterns of significant predictor variables, in addition to indices of
      the severity of initial injury: neurophysical impairments and memory functioning
      predicted successful occupational activities; chronicity, cognitive speed and
      behavioural regulation predicted success in interpersonal relationships; and
      neurophysical impairments, behavioural regulation and memory functioning
      predicted independent living skills. CONCLUSIONS: These results reinforce the
      overriding importance of injury severity and neurological factors (both
      neurophysical as well as neuropsychological) in predicting psychosocial
      adjustment after traumatic brain injury. Support for the contribution of non
      neurological factors was also found.

PMID- 10405094
TI  - Mood, neuropsychological function and cognitions in premenstrual dysphoric
      disorder.
AB  - BACKGROUND: Neuropsychological function and cognitive correlates of depression
      have not previously been examined in a rigorously defined population of patients
      suffering from premenstrual dysphoric disorder (PMDD). METHOD: MOOD,
      neuropsychological function and cognition were measured in 10 PMDD patients and
      10 age-matched controls in both phases of the menstrual cycle in a random order,
      counter-balanced design. RESULTS: The BDI was significantly elevated in the
      luteal phase of PMDD patients only while other cognitive measures showed no
      significant differences. Working memory was impaired in the luteal phase of the
      menstrual cycle with no significant differences between PMDD and control
      subjects. CONCLUSION: Despite the small sample size, these results show that the
      BDI is sensitive to the mood fluctuations of PMDD patients. An impairment in
      working memory was also found although this is a general menstrual cycle effect.

PMID- 10405095
TI  - Neuroticism and polymorphisms in the serotonin transporter gene.
AB  - BACKGROUND: There is evidence for an association between two different
      polymorphisms of the human serotonin transporter gene (5-HTT) and the personality
      trait of neuroticism and affective disorder. METHODS: We studied the association
      between neuroticism and polymorphisms in the 5HTT-linked promoter region and in a
      variable number tandem repeat region (VNTR) of the 5-HTT gene in 204 people aged
      over 60 derived from a random sample of men and women in the general population.
      Approximately half of the subjects were in the top 20% of neuroticism scorers and
      half in the bottom 20%. RESULTS: There were no significant differences in allelic
      or genotypic frequencies between the high and low neuroticism scorers. There was
      highly significant linkage disequilibrium between the two 5-HTT gene
      polymorphisms, and haplotype analysis showed no association between neuroticism
      level and haplotype. CONCLUSIONS: Reports of an association between two 5-HTT
      gene polymorphisms and the personality trait of neuroticism are not supported by
      these results.

PMID- 10405096
TI  - Alteration of the platelet serotonin transporter in romantic love.
AB  - BACKGROUND: The evolutionary consequences of love are so important that there
      must be some long-established biological process regulating it. Recent findings
      suggest that the serotonin (5-HT) transporter might be linked to both neuroticism
      and sexual behaviour as well as to obsessive-compulsive disorder (OCD). The
      similarities between an overvalued idea, such as that typical of subjects in the
      early phase of a love relationship, and obsession, prompted us to explore the
      possibility that the two conditions might share alterations at the level of the 5
      HT transporter. METHODS: Twenty subjects who had recently (within the previous 6
      months) fallen in love, 20 unmedicated OCD patients and 20 normal controls, were
      included in the study. The 5-HT transporter was evaluated with the specific
      binding of 3H-paroxetine (3H-Par) to platelet membranes. RESULTS: The results
      showed that the density of 3H-Par binding sites was significantly lower in
      subjects who had recently fallen in love and in OCD patients than in controls.
      DISCUSSION: The main finding of the present study is that subjects who were in
      the early romantic phase of a love relationship were not different from OCD
      patients in terms of the density of the platelet 5-HT transporter, which proved
      to be significantly lower than in the normal controls. This would suggest common
      neurochemical changes involving the 5-HT system, linked to psychological
      dimensions shared by the two conditions, perhaps at an ideational level.

PMID- 10405097
TI  - Morphometry in schizophrenia revisited: height and its relationship to pre-morbid
      function.

PMID- 10405098
TI  - Gait analysis in the mouse.
AB  - The gait of the adult Swiss (Mike Flack--MF1 subtype) mouse during spontaneous
      walk/trot locomotion at velocities ranging from 14-43 cm s(-1) has been analysed
      using simultaneous video and reaction force analysis. No differences were
      observed between males and females. Velocity adjustments within this range are
      accounted for to a greater extent (>70%) by stride time decreases and to a lesser
      degree (<30%) by stride length increases. Equivalent stride times for fore and
      hindlimbs were, in the former, composed of a shorter stance and a longer swing
      time. Peak vertical reaction force increases with decreasing stance time, with
      that for the forelimb being about 5% greater than that for the hindlimb across
      the whole stance time range studied. The areas under the vertical reaction force
      curves for fore and hindlimbs are, however, not significantly different. The
      results are discussed in the light of in vitro work cycle studies on the
      properties of some of the major hindlimb locomotor mouse muscles, and with
      previously established data in the rat. It is concluded that the mouse shows a
      consistent and quantifiable gait that would allow incorporation of locomotor
      assessment into the evaluation of a number of pathophysiological states.

PMID- 10405099
TI  - Energy consumption of termite colonies of Nasutitermes ephratae (Isoptera:
      Termitidae).
AB  - Measurements of CO2 production of whole termite colonies showed that respiration
      intensity varies slightly during the daily cycle, that the relation between
      standard metabolism and colony size is best described with a negative
      exponential, taking into account the proportion of the various castes. Larger
      colonies were more efficient in their energy use, suggesting that energetic
      considerations may contribute in explaining the maintenance in evolution of
      complex societies.

PMID- 10405100
TI  - Ketaset-Rompun extends the temporal gradient for hypothermia-induced retrograde
      amnesia.
AB  - In studies of experimentally induced retrograde amnesia (RA), as the interval
      between training and the amnestic treatment is lengthened, amnesia decreases (4).
      This temporal gradient for RA has been reported with a wide variety of amnestic
      agents, including RA produced by thermoregulatory disturbances (8). This temporal
      gradient for RA is not unlike certain characteristics of classical conditioning,
      where weaker conditioned responding occurs when the interval between the
      conditioned stimulus (CS) and unconditioned stimulus (US) is lengthened.
      Furthermore, there is evidence that administration of anesthetics can lengthen
      the "effective conditioning" interval between the CS and US, as demonstrated in a
      conditioned taste-aversion (CTA) procedure (10). In that study, little
      conditioning was observed when a 3-h delay (or more) was incorporated between
      presentations of the CS (flavor) and the US (toxin). However, if subjects were
      anesthetized immediately after the CS was delivered and remained anesthetized
      during the CS-US interval, strong conditioning was observed with CS-US intervals
      of up to 9 h. The aim of the present experiment was to determine if the temporal
      gradient for hypothermia-induced RA could also be lengthened. That is, we tested
      whether the interval between training and hypothermia treatment could be
      lengthened by anesthetizing subjects with Ketaset-Rompun. The results indicate
      that the training-to-amnestic agent interval could be lengthened within moderate
      limits. The implications for hypothermia-induced RA is further discussed.

PMID- 10405101
TI  - The generalizability of capsaicin sensitization and desensitization.
AB  - Studies using capsaicin-saturated filter papers have shown that the intensity of
      oral irritation tends to grow over successive samples, a phenomenon known as
      sensitization. If a hiatus of 5-15 min is then introduced, the intensity of
      irritation produced by a subsequent capsaicin stimulus is much reduced, and
      desensitization is said to have occurred. The use of other methodologies such as
      whole-mouth rinses, either with capsaicin or the irritants menthol or zingerone,
      have not consistently shown this response pattern, casting doubt on the extent to
      which sensitization and desensitization are general phenomena. Experiment 1
      addressed this issue by comparing responses to whole-mouth rinses of 0.6 and 3
      ppm capsaicin with those to 3 ppm capsaicin filter papers. Over an initial series
      of 10 samples, sensitization was evident but only for the 3 ppm capsaicin
      stimuli. Following a 10-min hiatus, desensitization was observed for all stimulus
      types. An examination of the data of individual subjects revealed considerable
      variability in response patterns over the initial 10 samples between subjects
      and, within subjects, between the filter paper and rinse stimuli, and between the
      test replications. Desensitization to the posthiatus stimuli was more consistent.
      A second experiment examined whether the capsaicin sensitization and
      desensitization shown by stimulation with filter papers or solutions also
      occurred in the context of the consumption of foods containing capsaicin. Two
      foods--soup and chili con carne--were consumed under conditions in which the rate
      of consumption was timed, as in Experiment 1, or was self-paced. In neither of
      the two conditions or foods was there strong evidence of sensitization, although,
      again, desensitization following a hiatus was evident. Substantial individual
      variability in response patterns was again apparent. There is thus no evidence
      for sensitization occurring during normal food consumption.

PMID- 10405102
TI  - Do long-term glucocorticoid treatments induce behavioral rhythm disturbances in
      rats?
AB  - To examine the influences of a long-term glucocorticoid treatment on behavioral
      rhythm in rats, I measured motor activity, feeding and drinking, and body
      temperature in rats that had been treated with corticosterone over a long term,
      by means of an automatic behavioral measurement system combined with a telemetry
      system. Either a cholesterol (100 mg, as a control) or corticosterone (100 mg)
      bead was implanted subcutaneously in rats for 3 months, and the effects of the
      treatments on behavioral parameters were evaluated 2 to 4 months after the
      termination of the treatments. Corticosterone did not significantly change daily
      rhythms of all four parameters and mean values of them. However, three out of six
      corticosterone-treated rats appeared to show higher the mesor of motor activity
      compared with the control group. The present study demonstrates that a long-term
      glucocorticoid treatment does not impair behavioral daily rhythm, then suggests
      that a long-term glucocorticoid exposures could not damage the endogenous clock
      of the brain, that is, the suprachiasmatic nucleus.

PMID- 10405103
TI  - Septal vasopressin modulates motility and passive avoidance in pinealectomized
      rats.
AB  - Experiments were performed to investigate the role of central arginine
      vasopressin (AVP) in an interrelationship with the pineal gland on motility and
      passive avoidance response in rats. The involvement of the pineal gland in
      behavioral paradigms was examined using pinealectomized (PE) and pineal-intact
      (sham-operated and nonoperated) animals. Central administration of 200 pg AVP or
      40 ng of the AVP receptor antagonist, d(CH2)sThyr(Et)VAVP (AAVP) was performed
      into the mediolateral septum by means of microdialysis probes. The blockade of
      vasopressinergic neurotransmission or neuromodulation into the septal area by
      AAVP decreased the motility in both pineal-intact groups, whereas AVP was without
      effect. In PE rats during AVP administration an increased motility was found, but
      AAVP was without effect. In pineal-intact rats the avoidance latency of passive
      avoidance retrieval was not influenced after application of both AVP and AAVP.
      However, an increase in avoidance latency was found both immediately and 24 h
      after AVP or AAVP administration into the septum of PE rats. The results support
      the hypothesis that septal AVP modulate motility and passive avoidance behavior
      and this modulation is influenced by the pineal gland.

PMID- 10405104
TI  - Effects of naloxone on the acquisition and expression of appetitive and
      consummatory sexual behavior in male Japanese quail.
AB  - Previous studies in Japanese quail indicate that central administration of the
      opioid antagonist naloxone enhances consummatory sexual behavior (CSB). This
      effect could be related either to a decrease in sexual satiety or to previously
      documented stimulatory effects of naloxone on GnRH. The present studies were
      performed to investigate these two possibilities and to explore for the first
      time opioid involvement in the expression and acquisition of appetitive aspects
      of sexual behavior (ASB) in castrated, testosterone-treated Japanese quail.
      Although no effects on either ASB or CSB were observed in response to peripheral
      naloxone injections, a significant increase in CSB was observed in males
      receiving central injections of naloxone. Central injections of naloxone had no
      effect on the acquisition of a social proximity response used to measure ASB.
      However, compared to controls a greater number of naloxone-treated birds
      copulated in the test arena on the first day. Overall, these results indicate an
      inhibitory role for opioids in CSB, and suggest that opioids are differentially
      involved in different aspects of sexual behavior.

PMID- 10405105
TI  - Temporal differences in the responses of the pituitary adrenocortical axis, the
      sympathoadrenomedullar axis, heart rate, and behaviour to a daily repeated
      stressor in domestic pigs.
AB  - In this study we examined responses of domestic pigs (Sus scrofa domestica) to a
      daily repeated stressor. In particular, we focused on differences in temporal
      changes across treatment repetition between the pituitary adrenocortical axis,
      the sympathoadrenomedullar axis, heart rate, and behaviour. To induce a stress
      response, we separated eight castrated male pigs from their group mates visually
      and auditorily for 1 h on 10 successive days. Overall, enhanced plasma levels of
      cortisol, ACTH, and adrenaline indicated a clear stress response. Levels of
      cortisol and ACTH decreased continuously with repetition of exposures to the
      stressor. In contrast, levels of adrenaline, behavioural activity, and heart rate
      did not change consistently across repetition of exposures. Interestingly,
      therefore, hormones of the pituitary adrenocortical axis showed a process of
      adaptation whereas subjects did not adapt to the stressor with respect to titres
      of adrenaline, heart rate, and particular behaviours (e.g., grid pressing,
      vocalisation, locomotion). Instead, they continued to react actively towards the
      social separation. Our results suggest that different stress systems can differ
      in temporal pattern of their response towards a repeated stressor. Such temporal
      differences should be considered when studying the effects of repeated stress.

PMID- 10405106
TI  - A therapeutic role for melatonin antagonism in experimental models of Parkinson's
      disease.
AB  - To determine the effects of endogenous and exogenous melatonin on experimental
      models of Parkinson's disease (PD), Sprague-Dawley rats were exposed to
      intracerebroventricular implants of slow release melatonin, pinealectomy (PX), or
      constant light (LL) and then injected with central 6-hydroxydopamine (6-OHDA) or
      i.p. 1-methyl-4-phenyl,1-1,2,3,6-tetrahydropyridine (MPTP). The resulting
      impairment of motor function and related behavioural impairment were exacerbated
      by melatonin implantation, while PX and exposure to LL significantly reduced the
      severity of experimental PD. These results are consistent with previous work
      highlighting the importance of aberrant amine production in neurological disease
      and demonstrate that treatments that reduce endogenous melatonin bioavailability
      can ameliorate experimental PD. Furthermore, these findings illustrate that
      melatonin is not the universal remedy that it is currently claimed to be, and may
      pose considerable problems in neurological diseases characterised by dopamine
      degeneration.

PMID- 10405107
TI  - Further experiments on the relationship between the period of circadian rhythms
      and locomotor activity levels in hamsters.
AB  - A number of experiments in the past have demonstrated that rats and mice have
      shorter free-running circadian rhythms when they have access to a running wheel
      in their cage. Moreover, within groups of rats and hamsters, individuals making
      most use of their running wheels tend to have shorter circadian rhythms. However,
      these effects are not always evident. This article analyzes the results of four
      additional experiments on hamsters, some showing correlations between high
      activity and fast rhythms, and others not. It is suggested that failure to find
      this relationship occurs when there is an insufficient range of activity levels
      within a group. When present, correlations between locomotor activity and
      periodicity reflect causal links because shorter rhythms can be produced by
      providing a type of running wheel on which hamsters run more. The effects of
      possible changes in activity on circadian period should be considered when
      interpreting experiments on physiological manipulations of the circadian period.

PMID- 10405108
TI  - VMH lesions reduce excessive running under the activity-stress paradigm in the
      rat.
AB  - We have previously shown that excitation of certain neurons in the ventromedial
      nucleus of the hypothalamus (VMH) of rats induces hyperrunning activity. The
      present study investigated the involvement of these VMH neurons in inducing
      excessive running under the activity-stress paradigm. The VMH of 6-week-old male
      rats was bilaterally lesioned by administration of kainic acid. Control animals
      received saline in the VMH. They were housed in running-wheel activity cages with
      free access to food for 6 days of the recovering period, and then fed 1 h each
      day for 6 days. Control animals exhibited marked increases in both running
      activity and its light/dark ratio, and developed stomach ulcers. In contrast,
      animals with bilateral VMH lesions showed a significantly attenuated increase in
      running activity and no change in light/dark ratio. VMH lesions also suppressed
      stomach ulceration. These results suggest that VMH neurons play a crucial role in
      inducing excessive running and stomach ulceration during exposure to the activity
      stress paradigm.

PMID- 10405109
TI  - Latency to traverse a T-maze at 2 days of age and later adrenocortical responses
      to an acute stressor in domestic chicks.
AB  - Latencies to escape from a T-maze, and thereby reinstate visual contact with
      conspecifics, were measured in broiler chicks at 2 days of age. Chicks were
      assigned to high- (HP) or low- (LP) performance categories if their escape
      latencies fell below 25 s or above 75 s, respectively. These chicks were then
      housed socially in 10 same-category groups (5 HP, 5 LP), each comprising eight
      birds. At 15 days of age, one chick was taken from each of two randomly selected
      cages (1 HP, 1 LP) and immediately bled (undisturbed controls). At the same time,
      another chick was taken from each of these boxes and immersed up to its neck in
      warm water (partial water immersion, PWI) for 15 min before blood was collected.
      All chicks were sexed after bleeding. There were no differences between the
      plasma corticosterone (CS) levels of undisturbed (control) HP and LP chicks.
      Exposure to PWI significantly increased circulating CS levels, and this elevation
      was more pronounced in LP than in HP chicks. Male chicks also showed higher
      stress-induced adrenocortical responses than did females. The present findings
      suggest that the T-maze responses of young chicks might predict their later
      adrenocortical responses to a known stressor. This relationship is discussed in
      terms of individual differences in fearfulness, ability to cope with challenge,
      and/or stress susceptibility.

PMID- 10405110
TI  - Fluoxetine-maintained obese humans: effect on food intake and body weight.
AB  - The effects of fluoxetine on food intake, body weight, and mood of obese
      individuals was examined in a 16-week inpatient/outpatient study. Six male and
      eight female obese volunteers began the study (four male and five females
      completed all phases of the study). They lived in a residential laboratory during
      three one-week inpatient periods separated by a 5-week and an 8-week outpatient
      period. Following an initial 4-day placebo baseline, participants were maintained
      on fluoxetine (60 mg/day) for the remainder of the study. Food intake parameters
      (total daily energy intake, macronutrient intake, mean number of eating bouts,
      interbout interval), body weight, subjective effects, and task performance were
      measured several times during the day during inpatient periods; food intake
      questionnaires were completed daily during the outpatient periods. Fluoxetine
      significantly reduced daily energy intake derived from fat, carbohydrate, and
      protein by decreasing the mean number of eating bouts per day throughout the
      study. No other food intake parameter was affected. Body weight was significantly
      reduced after 7 weeks, but not after 16 weeks of daily fluoxetine administration.
      These results indicate that fluoxetine reduced food intake for at least 16 weeks
      in nondepressed obese individuals without specifically affecting carbohydrate
      intake. Weight that was lost during the first few weeks of daily fluoxetine
      administration was subsequently regained even though food intake remained
      reduced. Therefore, fluoxetine maintenance does not appear promising as a sole
      long-term therapy for obesity.

PMID- 10405111
TI  - Persistent neonatal Borna disease virus (BDV) infection of the brain causes
      chronic emotional abnormalities in adult rats.
AB  - Neonatal Borna disease virus (BDV) brain infection results in selective
      developmental damage to the hippocampal dentate gyrus and the cerebellum. When
      mature, neonatally BDV-infected rats show extreme locomotor hyperactivity and
      reduced freezing behavior in novel environments. Traditional interpretation of
      both of these behavioral abnormalities would suggest decreased anxiety in
      infected rats compared to normal animals. However, it also possible that the
      locomotor hyperactivity in infected rats reflects higher rather than reduced
      anxiety, and is the result of increased escape responses to aversive stimuli. The
      present experiments were undertaken to test a hypothesis about elevated anxiety
      in neonatally BDV-infected adult Lewis rats by studying their species-specific
      fear-related responses. Compared to normal subjects, BDV-infected rats exhibited
      locomotor hyperactivity and elevated defecation in a highly aversive, brightly
      lit open field. As expected, in a less aversive, dimly lit open field, uninfected
      controls increased ambulation, whereas infected rats significantly decreased
      locomotor activity and defecation. Unlike uninfected rats, BDV-infected rats
      exhibited an attenuated freezing response immediately after loud auditory
      stimuli. On the contrary, immediate freezing responses following footshock were
      comparable in the two groups of animals indicating an intact ability to freeze in
      BDV-infected rats. Despite a decreased baseline startle responsiveness, BDV
      infected rats demonstrated increased sensitization of the startle response by
      preceding footshocks, suggesting a tendency toward elevated escape responses.
      Compared to normal subjects, BDV-infected rats showed decreased conditional
      freezing and elevated conditional defecation response in the context previously
      paired with aversive stimulation indicating sparing of an autonomic component of
      fear conditioning. The findings indicate that neonatally BDV-infected adult rats
      are hyperreactive to aversive stimuli, possibly as a result of chronic emotional
      abnormalities.

PMID- 10405112
TI  - An imbalance of dietary essential fatty acids retards behavioral development in
      mice.
AB  - This study investigated the effects of an imbalance of dietary essential fatty
      acids on behavioral development. Pregnant and lactating mice were fed a diet with
      a very low (n-6):(n-3) ratio, in which the (n-6) and (n-3) fatty acids were
      provided solely as linoleic acid [LA, 18:2 (n-6)] and very high levels of
      docosahexaenoic acid [DHA, 22:6 (n-3)], respectively. The development of the pups
      was compared with that of pups of similar age and body weight that had been
      undernourished by rearing in large litters. On the day of conception (Day 0),
      pregnant B6D2F1 mice were assigned randomly to one of four dietary groups. Two of
      these groups were fed lab chow, and after birth varied in terms of the number of
      pups per litter, large (LgLIT) = 12, and normal (NmLIT) = 6. The remaining two
      groups both had six pups per litter, but varied in dietary (n-6):(n-3) ratio, low
      (LoRAT = 0.32) and normal (NmRAT = 4.0). On Day 32 postconception both the LgLIT
      and the LoRAT groups had lower body weights and were behaviorally retarded
      relative to their respective NmLIT and NmRAT controls. Nonetheless, there was
      some sparing of function in both these groups, as they were behaviorally advanced
      relative to younger animals of a similar body weight. These findings show that
      the growth retardation seen in the offspring of dams fed a diet with a low (n
      6):(n-3) ratio and very high levels of DHA is accompanied by behavioral
      retardation of a similar degree to that seen in malnourished pups.

PMID- 10405113
TI  - Absolute and relative rewarding properties of fructose, glucose, and saccharin
      mixtures as reflected in anticipatory contrast.
AB  - Rats preferred 2% fructose (F) to 2% glucose (G) in daily 5-min two-bottle
      preference tests, but preferred 8% G to 8% F with the same testing procedure. In
      four subsequent experiments brief (3 min) once-per-day sequential presentations
      of two F or two G solutions showed the following results. Anticipatory negative
      contrast (suppressed intake of the initial solution) was greater with
      quantitative variations in fructose (2% F followed by either 8, 16, or 32% F)
      than was the case when the same concentrations of G were paired. No contrast
      occurred with qualitative pairings of the two sugars--instead G enhanced the
      intake of F whether it was presented before or after F. A solution of 0.15%
      saccharin produced more suppression (contrast) of 2% glucose than of 2% fructose.
      Also, mixtures of 0.15% saccharin with either sugar (2 or 8% F or G) enhanced
      absolute intake of the sugars but did not substantially increase their contrast
      producing properties--suggesting a distinction between absolute and relative
      rewarding properties of sugar/saccharin mixtures. In summary, anticipatory
      negative contrast can be produced by either taste or postingestive factors but
      the relationship between two-bottle preference, absolute reward value (as
      reflected in consumption in noncontrast conditions), and relative reward value
      (measured by the capacity to produce contrast) is complex.

PMID- 10405114
TI  - Physiological suppression of sexual function of subordinate males: a subtle form
      of intrasexual competition among male sifakas (Propithecus verreauxi)?
AB  - In contrast to most anthropoid primates, sifakas (Propithecus verreauxi), like
      many group-living lemurs, exhibit a number of features that deviate from
      predictions of sexual selection theory. Despite a promiscuous mating system, they
      lack sexual dimorphism, suggesting that physical combat plays only a minor role
      in intrasexual competition for receptive females. In this study, we investigated
      the hypothesis that socioendocrinological mechanisms contribute to suppression of
      reproductive function of subordinate males. For that purpose, 10 male sifakas
      from five social groups were observed for 669 focal animal hours for 4 months,
      including the mating season, in Western Madagascar. Concomitantly 315 fecal
      samples of these animals were collected and the concentration of immunoreactive
      testosterone was quantified hy enzymeimmunoassay procedures. Clear dominance
      relationships existed among coresident males. Testosterone levels of dominant
      males were significantly higher than those of subordinates during, as well as
      outside, the mating season. Additionally, the increase in testosterone levels
      prior to the mating season was more pronounced for dominant than for subordinate
      males. These findings are in accordance with the hypothesis of suppression of
      sexual function of subordinate males, probably providing dominant males with ani
      advantage in sperm competition. If reproductive success is mainly determined by
      this nonagonistic form of intrasexual competition, the results of this study
      contribute an important piece to the puzzle of lacking sexual dimorphism in P.
      verreauxi.

PMID- 10405116
TI  - Impaired learning and memory in OLETF rats without cholecystokinin (CCK)-A
      receptor.
AB  - Cholecystokinin (CCK) is one of the most abundant neurotransmitter peptides in
      the brain. As OLETF rats lack CCK-A receptor because of a genetic abnormality, we
      examined whether learning and memory were impaired in these animals using an
      elevated eight-arm radial maze. After the completion of a radial maze study, the
      animals were sacrificed for histological examination of the brain. In some
      animals, long-term potentiation (LTP) in the hippocampus was measured. In the
      radial maze, the level of activity (seconds/entry) and the time remaining in the
      arms were significantly longer in OLETF rats. The number of errors was also
      significantly higher, and that of the correct choices was significantly lower in
      OLETF rats compared to the controls (LETO rats). The LTP of the population spike
      was significantly lower in the OLETF than in the LETO rats. No histological
      abnormalities were observed. From these observations, we concluded that learning
      and memory functions were impaired in the OLETF rats.

PMID- 10405117
TI  - Sodium intake and reproduction in BALB/C mice.
AB  - The effect of sodium intake on the reproductive performance of BALB/C mice was
      assessed in four groups of 11 or 12 mice that received ad lib access to low or
      higher sodium food (LSF 4-5, HSF 120-143 mmol Na+/kg). The two groups that
      received HSF had (mean values) 100% matings, 83 and 91% litters, 5.9 pups/litter,
      pups weighing 2.05 and 2.22 g (3 days after birth) and 10.47 and 10.96 g at
      weaning (19 days). One of the HSF groups that also had 300 mM NaCl to drink did
      not show any benefit. Two groups received LSF, and one of them also received 30
      mM NaCl. The group given LSF only had 83% matings, 20% litters, 1.5 pups/litter,
      and pups that were significantly smaller at birth and at weaning. However, the
      LSF group given 30 mM NaCl to drink performed almost as well as the two HSF
      groups. The results show that (a) the daily sodium requirement for optimal
      reproduction was > or = 400 (micromol/day, based on voluntary sodium intake late
      in gestation and lactation; (b) sodium deficiency was the cause of reproductive
      deficiency in mice on LSF; (c) severe sodium deficiency suppressed reproduction
      primarily at the gestation step; (d) this deficiency could be prevented by the
      voluntary sodium intake of mothers with access to salt solution; and (e) pups on
      the LSF showed an avid innate salt appetite when offered salt solution at 12 days
      of age.

PMID- 10405115
TI  - Hyperresponsiveness to palatable and aversive taste stimuli in genetically obese
      (bombesin receptor subtype-3-deficient) mice.
AB  - Taste preference in obese mice was examined using genetically obese (bombesin
      receptor subtype-3: BRS-3 deficient) animals. Preference for either sodium
      saccharin (0.2%). sodium chloride (0.9%), citric acid (0.1%), or quinine sulfate
      (0.002%) solution was examined using a two-bottle test situation, and BRS-3
      deficient mice not only showed a stronger preference for saccharin solution, but
      also a stronger aversive response to quinine solution, relative to wild-type
      littermates. Furthermore, a conditioned taste-aversion test measured the
      consumption of sodium saccharin (0.2%) and sodium chloride (0.9%) solutions after
      intraperitoneal injection of LiCl (0.3 M, 1 mg/kg), and BRS-3-deficient mice
      exhibited stronger aversion to both solutions than did control animals. In situ
      hybridization demonstrated that the BRS-3 gene is expressed in the parabrachial
      nucleus, the medial and central nuclei of the amygdala, and the hypothalamic
      nuclei such as paraventricular nucleus, all of which are known to be involved in
      taste perception. These results suggest that expression of the BRS-3 gene in
      these nuclei is important for the modulation of taste preference, as well as the
      development of obesity.

PMID- 10405118
TI  - Feeding response to neuropeptide Y-related compounds in rats treated with Y5
      receptor antisense or sense phosphothio-oligodeoxynucleotide.
AB  - Neuropeptide Y (NPY), NPY 3-36 and pancreatic polypeptide (PP) increase short
      term (2-h) food intake to varying degrees when given intracerebroventricularly
      (i.c.v.). Various Y receptor subtypes are proposed to participate in Y receptor
      ligand-induced stimulation of food intake. Here, we used an antisense phosphothio
      oligodeoxynucleotide sequence (-5 relative to the initiating ATG) to the Y5
      receptor subtype, which has been suggested to mediate NPY-induced feeding. Rats
      were treated with i.c.v. antisense or sense phosphothio-oligodeoxynucleotide for
      3.5 days before NPY, NPY 3-36, or PP i.c.v. administration. The results show that
      antisense to the Y5 receptor had no effect on either spontaneous 2-h or NPY-, NPY
      3-36-, or PP-stimulated 2-h food intake. However, there was a significant
      decrease relative to the sense control group in 10-h food intake following the
      initial 2-h feeding response to NPY (n = 10, p < 0.0001) or NPY 3-36 (n = 10, p <
      0.05). The data suggest that the Y5 receptor has a modulatory role in the
      maintenance of feeding, but not as the critical receptor to confer for NPY and
      NPY 3-36 action on food intake.

PMID- 10405119
TI  - Brain norepinephrine changes with simulated weightlessness and relation to
      exercise training.
AB  - Maintenance of nervous system function during periods of a deconditioning
      syndrome is important to prevent diminished psychological/behavioral, and
      physiological function observed during periods of bed rest, physical inactivity,
      and weightlessness. A main neurotransmitter is norepinephrine (NE), and its
      regulation yields insight into nervous system function. This research tested the
      hypotheses that, 1) deconditioning syndrome induced by simulated weightlessness
      of 9 days via the head-down tilt (HDT) model results in a blunted noradrenergic
      turnover rate in selected brain tissue and, 2) that exercise training acts as a
      countermeasure for these changes in noradrenergic activity. Male Sprague-Dawley
      rats (3 months, n = 60) were divided into either a HDT (HDT, n = 20), cage
      control (CAGE-CN, n = 20) or an exercise trained HDT (HDT-EX, n = 20) group. Each
      group was further subdivided into a saline (n = 10) or alpha-methyl-tyrosine (AM,
      n = 10) (200 mg/kg) injected subgroup. Animals in the HDT groups were tail
      suspended in a 30 degrees head-down tilt position for 9 days. Norepinephrine
      turnover was determined 3 h following administration of saline or alpha-methyl
      para-tyrosine. The NE turnover rate (ng gm(-1) x h(-1)) for the CN, HDT, and HDT
      EX groups, respectively, were as follows: locus coeruleus, 63 +/- 33, *134 +/-
      65, 85 +/- 61; hypothalamus, 195 +/- 50, *47 +/- 47; *93 +/- 34; cerebellum, 10
      +/- 18, *65 +/- 15, *53 +/- 19; cerebral cortex, 6 +/- 20, *28 +/- 15, *68 +/-
      22. (*Denotes significant difference from the control group at the p < or = 0.05
      level of significance; +denotes significant difference from the HDT group at the
      p < or = 0.05 level of significance.) These findings suggest that: 1)
      norepinephrine turnover rate adapts in a tissue-specific manner following a 9-day
      tail suspension, 2) increased norepinephrine turnover rates and norepinephrine
      tissue content in the HDT group are consistent with neural adaptation to a
      chronic stress response.

PMID- 10405120
TI  - Food restriction neither improves nor exacerbates reproduction in obese female
      Zucker rats.
AB  - Obese female Zucker rats have several reproductive abnormalities, including
      delayed puberty, abnormal estrous cyclicity, and behavioral hyporesponsiveness to
      ovarian steroid hormones. To ascertain whether excessive body weight per se
      causes these reproductive abnormalities, obese Zucker female rats were fed ad lib
      or were food restricted to match their body weights to those of lean
      counterparts. Food restriction neither accelerated vaginal opening nor normalized
      estrous cyclicity in obese female rats. Following ovariectomy, an injection of
      estradiol benzoate (EB, 15 microg/kg, s.c.) induced extremely low sexual
      receptivity in all rats, and proceptive behaviors were never observed. After
      treatment with EB plus progesterone (P, 2 mg/kg, s.c.), lean rats were very
      receptive (lordosis quotient, LQ = 94 +/- 2%) and proceptive (PRO = 12.5 +/- 2
      events/min) while both ad lib-fed and food-restricted obese rats were only
      marginally receptive and proceptive (LQ= 19 +/- 9%, PRO = 1.8 +/- 0.7 events/min;
      LQ = 31 +/- 15%, PRO = 4.7 +/- 3 events/min, respectively). A higher progesterone
      dose (20 mg/kg) elicited vigorous sexual receptivity (LQ = 88-99%) and
      proceptivity (PRO = 16.5-20.4 events/min) in all EB-treated rats. Adiposity was
      significantly lower in food-restricted obese rats as compared to ad lib-fed obese
      rats (36.5 +/- 1.7% vs. 69.4 +/- 2.7%), but greater than that observed in lean
      rats (24.4 +/- 1.1%). These data suggest that excessive body weight per se does
      not underlie reproductive abnormalities in obese Zucker rats, but do not rule out
      the possibility that excessive adiposity may contribute to their infertility.

PMID- 10405121
TI  - Nuclear medicine in the 21st century: integration with other specialties.

PMID- 10405122
TI  - Pharmaceutical discovery and development: nuclear and molecular imaging
      technologies recognized.

PMID- 10405123
TI  - The barium enigma.

PMID- 10405124
TI  - Hyperacute changes in glucose metabolism of brain tumors after stereotactic
      radiosurgery: a PET study.
AB  - Cultured tumor cells show a marked increase in deoxyglucose uptake as early as 3
      h after single high-dose irradiation, reflecting hyperacute response of the cells
      to noxious intervention. To evaluate the hyperacute effect of high-dose
      irradiation on tumor glucose metabolism in vivo, we measured 2-[18F]fluoro-2
      deoxy-D-glucose (FDG) tumor uptake before and immediately after stereotactic
      radiosurgery. METHODS: A total of 19 brain tumors (17 metastatic and 2 primary, a
      meningioma and a central neurocytoma) in eight patients were treated with
      stereotactic radiosurgery. The received dose was between 24 and 32 Gy delivered
      to the central target point in the tumor. FDG PET was performed within 1 wk
      before radiosurgery and again 4 h after treatment. The net influx constant (Ki)
      was calculated on a pixel-by-pixel basis using graphical analysis, and the Ki
      ratio of tumor to ipsilateral cerebellum was used as an index of FDG uptake of
      the tumor. RESULTS: Eighteen of 19 irradiated tumors, all metastatic tumors and
      the meningioma, showed a 29.7% +/- 14.0% increase in the Ki ratio, which was
      significantly higher than that of nonirradiated tumors (4.1% +/- 3.6%, n = 8, P <
      0.0001, analysis of variance). In metastatic tumors, an increase in the Ki ratio
      was significantly correlated with a decrease in the size of the irradiated
      tumors, as revealed by follow-up with CT or MRI (r = 0.61, P = 0.012, simple
      regression). The meningioma did not show a significant decrease in size, probably
      due to the short follow-up period. The central neurocytoma did not show any
      change in the Ki ratio or in tumor size. CONCLUSION: Serial FDG PET could be a
      potential tool for predicting the outcome of radiosurgery for brain tumors by
      detecting hyperacute changes in tumor glucose metabolism.

PMID- 10405126
TI  - Quantitative and clinical analysis of SPECT image registration for epilepsy
      studies.
AB  - This study reports quantitative measurements of the accuracy of two popular voxel
      based registration algorithms--Woods' automated image registration algorithm and
      mutual information correlation--and compares these with conventional surface
      matching (SM) registration. METHODS: The registration algorithms were compared
      (15 different matches each) for (a) three-dimensional brain phantom images, (b)
      an ictal SPECT image from a patient with partial epilepsy matched to itself after
      modification to simulate changes in the cerebral blood flow pattern and (c)
      ictal/interictal SPECT images from 15 patients with partial epilepsy. Blinded
      visual ranking and localization of the subtraction images derived from the
      patient images were also performed. RESULTS: Both voxel-based registration
      methods were more accurate than SM registration (P < 0.0005). Automated image
      registration algorithm was more accurate than mutual information correlation for
      the computer-simulated ictal/interictal images and the patient ictal/interictal
      studies (P < 0.05). The subtraction SPECTs from SM were poorer in visual ranking
      more often than the voxel-based methods (P < 0.05). CONCLUSION: Voxel intensity
      based registration algorithms provide significant improvement in ictal/interictal
      SPECT registration accuracy and result in a clinically detectable improvement in
      the subtraction SPECT images.

PMID- 10405125
TI  - Quantification and visualization of defects of the functional dopaminergic system
      using an automatic algorithm.
AB  - In SPECT, the binding of radiotracers in brain areas is usually assessed by
      manual positioning of regions of interest (ROIs). The disadvantages of this
      method are that it is an observer-dependent procedure and that it may not be
      sensitive for assessing defects significantly smaller than the ROI. To circumvent
      these limitations, we developed a fully automatic three-dimensional technique
      that quantifies neuronal radiotracer binding on a voxel-by-voxel basis. METHODS:
      To build a model of normal 123I-labeled N-omega-fluoropropyl-2beta-carbomethoxy
      3beta-(4-iodophenyl) nortropane (FPCIT) binding, 17 studies of healthy volunteers
      were registered to the same orientation. After registration, the specific-to
      nonspecific binding ratio was calculated for each voxel of the striatal volumes
      of interest (VOIs). The mean and SD of that binding ratio were then calculated on
      a voxel-by-voxel basis. For the analysis of 10 healthy volunteer studies (control
      group) and 21 studies of drug-naive patients with Parkinson's disease, the
      registration and calculation of the specific-to-nonspecific [123I]FPCIT binding
      ratio were performed by the same method. Subsequently, a voxel of the striata was
      classified as a diminished [123I]FPCIT binding ratio if its value was lower than
      the mean -2 x SD. For each subject, the defect size, the relative number of
      voxels with a diminished binding ratio and the binding ratio of the whole
      striatal VOIs were calculated and compared with the binding ratio as assessed by
      the traditional ROI method. RESULTS: The results of the automatic method
      correlated significantly with the results of the traditional ROI method.
      Furthermore, for the ipsilateral side, the automatically calculated defect size
      had less overlap between the patient and the control group than the traditionally
      calculated binding ratio. CONCLUSION: The method presented quantifies [123I]FPCIT
      binding ratio automatically on a voxel-by-voxel basis, by comparison with a model
      of healthy volunteers. We have shown that it is appropriate to use the automatic
      method as a replacement for the traditional manual method, which enables us to
      study the localized dopaminergic degeneration process in Parkinson's disease more
      precisely and without any inter- or intraobserver variability.

PMID- 10405127
TI  - Gastric emptying rate assessment based on the proportion of intra-abdominal
      radioactivity in the stomach.
AB  - Using scintigraphic techniques, the rate of gastric emptying is calculated by
      quantifying the absolute radioactivity within a gastric region of interest
      (intragastric method) with the time of meal completion considered 100% retention.
      However, this technique has significant limitations arising from subject movement
      and radionuclide gamma-ray attenuation, which may render curve fitting difficult,
      particularly in patients with gastroparesis. In an attempt to minimize these
      limitations, we have expressed the intragastric content as a percentage of the
      total abdominal radioactivity (abdominal method) and compared these two methods.
      METHODS: Forty-five subjects in a sitting position consumed a meal consisting of
      two fried eggs labeled with 99mTc, two slices of toast and 300 mL 5% glucose
      water (412 kcal). Data were acquired at a rate of one frame every 5 min from the
      left anterior oblique view. Using the two methods, the intragastric retention
      ratios at 30, 60, 90, 120 and 240 min and the 50% emptying time (T50) were
      obtained from both observation and calculation by power exponential fit. R2,
      representing goodness of fit of the nonlinear curve fitting, was calculated.
      RESULTS: There were no differences in the calculated values of T50 between the
      two methods. Quantitative estimates of T50 by extrapolation of a power
      exponential fit were feasible in 42 of the 45 subjects when the abdominal method
      was used, compared with only 29 of the 45 subjects when the intragastric method
      was used. In the 23 subjects with delayed emptying, quantitative estimates of T50
      were feasible in 20 subjects when the abdominal method was used, compared with 7
      subjects when the intragastric method was used. Using the abdominal method as
      opposed to the intragastric method also significantly improved R2. The difference
      between observed values and estimated values of T50 and intragastric retention
      ratios at 30, 90 and 120 min was smaller using the abdominal method. CONCLUSION:
      Scintigraphic measurement of gastric emptying calculated using the proportion of
      the abdominal radioactivity in the stomach offers substantial advantages over
      conventional methods, particularly in patients with gastroparesis.

PMID- 10405128
TI  - Quantitative SPECT of 99mTc-DMSA uptake in kidneys of infants with unilateral
      ureteropelvic junction obstruction: assessment of structural and functional
      abnormalities.
AB  - We evaluated individual renal function using quantitative SPECT of
      dimercaptosuccinic acid (DMSA) uptake by the kidneys (QDMSA) in infants with
      unilateral ureteropelvic junction (UPJ) obstruction and compared our findings
      with infants without obstruction. METHODS: QDMSA was performed on 13 infants
      (mean age of 2.8 +/- 2.8 mo) with unilateral UPJ obstruction and on 15 age
      matched controls without obstruction. RESULTS: Control kidneys (n = 30) had a
      volume of 43.5 +/- 8.8 mL, a percentage injected dose (%ID)/mL 0.62 +/- 0.12 and
      uptake of 26.1% +/- 3.9%. Kidneys with UPJ obstruction (n = 13) had a volume of
      61.2 +/- 19.3 mL, a %ID/mL of 0.42 +/- 0.11 and uptake of 25.4% +/- 8.2%.
      Contralateral kidneys (n = 13) had a volume of 44.0 +/- 11.9 mL, a %ID/mL of 0.57
      +/- 0.16 and uptake of 24.2% +/- 4.6%. The uptake in obstructed kidneys was
      similar to that observed in contralateral and control kidneys (t = -0.77, P =
      0.45; t = -0.37, P = 0.71; respectively). UPJ kidneys had a statistically
      significant increased volume and decreased %ID/mL, compared with contralateral
      kidneys (t = 3.35, P < 0.006 and t = 3.75, P < 0.003, respectively) and control
      kidneys (t = -4.2, P < 0.001 and t = 4.7, P < 0.001, respectively). There was no
      significant difference between contralateral kidneys and control kidneys
      regarding volume (t = -0.16, P = 0.87), %ID/mL (t = 0.98, P = 0.33) and uptake (t
      = -1.41, P = 0.16). Of 13 infants, 11 (85%) showed large kidneys with thinning of
      the renal cortex. In 1 infant, there was no difference between the obstructed and
      contralateral kidneys regarding volume, %ID/mL and uptake, and 1 infant showed
      significant decreased uptake in the UPJ kidney compared with the contralateral
      kidney. CONCLUSION: Although the overall renal function of the obstructed kidneys
      remained unchanged, there was a statistically significant decrease in the %ID/mL
      of renal tissue in UPJ kidneys, which may represent renal dysfunction. Increased
      functional volume with a thin cortex may represent a compensatory mechanism of
      the obstructed kidney. Such changes may contribute to the understanding of
      pathophysiologic mechanisms and may be an early sign of obstruction in infants
      with hydronephrosis. Further longitudinal studies with an extended number of
      infants and serial measurements of kidney volumes and %ID/mL are warranted to
      assess the significance of QDMSA in the management of infants with asymptomatic
      unilateral renal pelvic dilatation.

PMID- 10405129
TI  - Insulin action on heart and skeletal muscle FDG uptake in patients with
      hypertriglyceridemia.
AB  - Abnormal heart and skeletal muscle 18F-fluorodeoxyglucose (FDG) uptake in
      patients with insulin resistance has been demonstrated. Although the existence of
      whole-body insulin resistance has been reported in hypertriglyceridemics, its
      specific role in heart and skeletal muscle FDG uptake in hypertriglyceridemics
      has not been clarified. METHODS: We compared heart and skeletal muscle FDG uptake
      using PET and the whole-body glucose disposal rate (GDR) during insulin clamping
      in 17 hypertriglyceridemics and 12 age-matched control subjects to increase our
      knowledge of whole-body insulin resistance and its relationship to heart and
      skeletal muscle FDG uptake in hypertriglyceridemics. RESULTS: GDR was
      significantly reduced in hypertriglyceridemics compared with control subjects
      (4.50 +/- 1.37 mg/min/kg versus 10.0 +/- 2.97 mg/min/kg, P = 0.00001), as were
      the skeletal muscle FDG Ki = (k1 x k3)/(k2 + k3) (SFKi: 0.007 +/- 0.003 mL/min/g
      versus 0.018 +/- 0.01 mL/min/g, P = 0.0001) and skeletal muscle FDG uptake
      ([SMFU] 0.725 +/- 0.282 mg/min/100 g versus 1.86 +/- 1.06 mg/min/100 g, P =
      0.00023). However, myocardial FDG Ki (MFKi) tended to be reduced in
      hypertriglyceridemics compared with that in control subjects (0.062 +/- 0.017
      mL/min/g versus 0.068 +/- 0.015 mL/min/g), but the difference was statistically
      insignificant (P = 0.3532). Moreover, myocardial FDG uptake (MFU) in
      hypertriglyceridemics (6.47 +/- 1.72 mg/min/100 g) tended to be reduced compared
      with that in control subjects (6.97 +/- 1.73 mg/min/100 g), but the difference
      was statistically insignificant (P = 0.4485). GDR was significantly correlated
      with SFKi (r = 0.69, P = 0.0022), SMFU (r = 0.612, P = 0.009), MFKi (r = 0.57, P
      = 0.0174) and MFU (r = 0.505, P = 0.0385) in hypertriglyceridemics. CONCLUSION:
      Both heart and skeletal muscle glucose utilization were related to insulin
      resistance in hypertriglyceridemics. However, the less severe reduction in MFU
      (compared with SMFU) suggests that myocardium may have a mechanism to oppose
      insulin resistance in hypertriglyceridemics.

PMID- 10405130
TI  - Reproducibility of single-sample clearance of 99mTc-mercaptoacetyltriglycine and
      131I-orthoiodohippurate.
AB  - Recent literature has questioned whether 99mTc-mercaptoacetyltriglycine (MAG3)
      clearance measurements are reproducible enough for routine clinical monitoring of
      renal function. For many years, we have routinely followed the renal function of
      patients with spinal cord injuries using a combination of radionuclide imaging
      and clearance measurement. METHODS: In this study, we retrospectively review 1626
      effective renal plasma flow (ERPF) measurements in 197 patients with paraplegia
      or quadriplegia performed over a 21-y period, using 131I-orthoiodohippurate (OIH)
      through 1990 and MAG3 since 1991. MAG3 clearance was divided by 0.53 to convert
      it to ERPF. Reproducibility was measured as pooled SD from the single-patient
      linear regression lines of ERPF versus time. RESULTS AND CONCLUSION: There was no
      significant difference between MAG3 (SD = 46 mL/min, n = 907) and OIH (SD = 52
      mL/min, n = 719). The data were therefore combined to obtain the SD for a single
      ERPF measurement, which was 49 mL/min. The corresponding coefficient of variation
      was 8.5% of the mean value of 581 mL/min. In our experience, this is adequate for
      monitoring the renal function of these patients.

PMID- 10405131
TI  - Evaluation of FDG PET in patients with cervical cancer.
AB  - Although many human cancers can be imaged by 2-[18F]-fluoro-2-deoxy-D-glucose
      (FDG) and PET, there is little clinical experience with FDG PET in cervical
      cancer. The purpose of this study was to evaluate the feasibility of FDG PET
      scans on patients with cervical cancer. METHODS: FDG PET scans were performed on
      21 patients with histologically proven uterine cervical cancer (17 newly
      diagnosed, 4 recurrence). After two levels of transmission scanning,
      approximately 370 MBq FDG were injected, and dynamic scans over 60 min were
      obtained at the level of suspected tumors, followed by static scans. Postvoid
      scans were also obtained in 11 patients to minimize FDG activity in the urinary
      bladder. FDG uptake was interpreted visually and classified into 4 grades (0 =
      normal, 1 = probably normal, 2 = probably abnormal and 3 = definitely abnormal).
      For a semiquantitative index of FDG uptake in tumors, the standardized uptake
      value (SUV) corrected by predicted lean body mass (SUL) was calculated and
      compared. The detectability of lymph node metastases by PET was compared with
      that by CT. RESULTS: Of the 21 newly diagnosed or recurrent cancers, 16 (76%)
      were detected by FDG PET without use of postvoid imaging (i.e., interpreted as
      grade 2 or 3). The SULs of tumors ranged from 2.74-13.03, with a mean of 8.15 +/-
      3.00 (SUV range 3.68-14.94, mean 10.31 +/- 3.19). There was no significant
      relationship between the SUL of cervical cancer and the clinical stage. Postvoid
      FDG PET images substantially reduced the tracer activity in the urinary bladder
      and improved the visualization of cervical cancers, with three additional cases
      detected using the postvoid images. In the 11 patients with postvoid imaging, all
      11 cancers (100%) were detected. FDG PET detected lymph node metastases in 6
      (86%) of 7 patients with known metastases, whereas CT was positive in 4 patients
      (57%), equivocal in 2 patients (29%) and negative in 1 patient (14%). All PET and
      CT scans were true-negative in the patients with no lymph node metastases
      (interpreted as grade 0 or 1 by PET, and as negative by CT). CONCLUSION: These
      preliminary data demonstrate the feasibility of FDG PET imaging in patients with
      cervical cancer. FDG PET appears to be promising for detecting untreated or
      recurrent cervical cancers and lymph node metastases, although the excreted FDG
      in the urine remains problematic in some cases.

PMID- 10405132
TI  - FDG PET to evaluate combined intra-arterial chemotherapy and radiotherapy of head
      and neck neoplasms.
AB  - We evaluated the effectiveness of combined intra-arterial chemotherapy and
      radiotherapy on head and neck squamous cell carcinomas using fluorodeoxyglucose
      (FDG) PET. METHODS: Fifteen patients with squamous cell carcinoma of the head and
      neck were included in the study. Fourteen patients completed the treatment
      regimen and underwent FDG PET before and 4 wk after chemoradiotherapy. One
      patient underwent pretreatment FDG PET only. The pretreatment and post-treatment
      PET images were compared with clinical and histopathologic evaluations of the
      effects of chemoradiotherapy. For the quantitative evaluation of regional
      radioactivity, standardized uptake values (SUVs) with an uptake period of 50 min
      were used. RESULTS: Before treatment, FDG PET detected neoplasms in all 15
      patients. The overall clinical response rate to chemoradiotherapy in the 14
      patients who were imaged before and after treatment was 100%. Before treatment,
      the neoplastic lesions showed high SUVs (mean 7.77 mg/mL), which significantly
      decreased after therapy (3.62 mg/mL, P < 0.01). Lesions with higher pretreatment
      SUVs (> 7 mg/mL) showed residual viable tumor cells after the treatment in 3 of 8
      patients, whereas those with lower SUVs (< 7 mg/mL, 6 patients) were successfully
      treated. Three of seven tumors with post-treatment SUVs > 4 mg/mL had viable
      tumor cells, whereas all tumors (7/7) with post-treatment SUVs < 4 mg/mL showed
      no viable cells. With concomitant chemoradiotherapy monitored by FDG PET, 5
      patients avoided surgery entirely, and the remaining 9 patients underwent a
      reduced form of surgery. CONCLUSION: FDG PET is useful in evaluating the effects
      of combined chemotherapy and radiotherapy in patients with head and neck
      carcinoma. Pretreatment FDG PET is useful in predicting the response to
      treatment, and post-treatment FDG PET can evaluate residual viable cells. Hence,
      FDG PET is a valuable tool in the treatment of head and neck tumors.

PMID- 10405133
TI  - Multiple myeloma evaluated with 201Tl scintigraphy compared with bone
      scintigraphy.
AB  - The purpose of this study was to investigate the clinical usefulness of 201Tl
      chloride scintigraphy in the diagnostic evaluation of 20 patients with multiple
      myeloma (19/20 patients) or extramedullary plasmacytoma (1/20 patients) in
      comparison with bone scintigraphy. METHODS: Both 201Tl and bone scintigraphy were
      performed to obtain planar images on the same instrument. RESULTS: 201Tl
      scintigraphy showed increased uptake in 15 of 20 patients (75%) and was negative
      in 5 of 20 patients (25%). In addition, 201Tl scintigraphy of multiple myeloma
      was more useful in detecting the lesions in 11 of 17 patients and less useful in
      6 of 17 patients than bone scintigraphy. CONCLUSION: The combination of 201Tl and
      bone scintigraphy, compared with bone scintigraphy alone, shows promise in more
      accurately diagnosing multiple myeloma.

PMID- 10405134
TI  - 99mTc-human serum albumin: an effective radiotracer for identifying sentinel
      lymph nodes in melanoma.
AB  - Sentinel lymph node (SLN) biopsy has emerged as a novel approach for identifying
      patients with melanoma and regional nodal micrometastasis who may benefit from
      full nodal basin resection. To identify the pattern of tumor lymphatic drainage
      and the SLN, lymphoscintigraphy has been performed using primarily 99mTc-sulfur
      colloid (SC). In this study, we compare the efficacy of SLN biopsy using 99mTc
      human serum albumin (HSA) with SLN biopsy after SC-based lymphoscintigraphy.
      METHODS: One hundred and six patients with localized cutaneous melanoma were
      studied. Lymphoscintigraphy was performed after intradermal injection of HSA in
      85 patients and SC in 21 patients. Four patients underwent lymphoscintigraphy
      twice, once with SC and once with HSA. Dynamic images were acquired for up to 1
      h, followed by high-count images of the SLN in various projections so that the
      most likely site was marked on the skin for biopsy. Intraoperatively, blue dye
      was injected around the primary site. Twenty-four patients underwent SLN
      dissection directed by preoperative lymphoscintigraphy and vital blue dye
      mapping; in the remaining 80 patients, a gamma probe was added intraoperatively
      to the localization procedure. Two patients underwent mapping with gamma probe
      alone. RESULTS: Draining lymphatic basins and nodes were identified by
      lymphoscintigraphy in all patients. The SLN was identified in 95% of patients
      when both blue dye and intraoperative gamma probe were used. When 99mTc-HSA was
      used for imaging, 98% of the SLNs ultimately identified were radiolabeled, and
      82% were both hot and blue. Of the SLN recovered with SC, all the nodes were
      radiolabeled; however, there was only 58% hot and blue concordance. Greater
      numbers of SLNs were removed in the SC group (median 2.0 versus 1.0, P = 0.02);
      however, the incidence of micrometastasis was statistically similar in both HSA
      and SC cohorts. In the 4 patients examined with both tracers, SLN mapping was
      similar. CONCLUSION: Although SC has been the radiotracer of choice for SLN
      mapping in melanoma, HSA appears to be a suitable alternative, with identical
      success rates. In fact, the higher concordance between hot and blue nodes using
      HSA suggests superiority of this tracer for this purpose.

PMID- 10405135
TI  - Blue dye and 99mTc-labeled human serum albumin: sentinel node detection by magic
      bullets?

PMID- 10405136
TI  - A radionuclide therapy treatment planning and dose estimation system.
AB  - An object-oriented software system is described for estimating internal emitter
      absorbed doses using a set of computer modules operating within a personal
      computer environment. The system is called the Radionuclide Treatment Planning
      and Absorbed Dose Estimation System (RTDS). It is intended for radioimmunotherapy
      applications, although other forms of internal emitter therapy may also be
      considered. METHODS: Four software modules interact through a database backend.
      Clinical, demographic and image data are directly entered into the database.
      Modules include those devoted to clinical imaging (nuclear, CT and MR), activity
      determination, organ compartmental modeling and absorbed dose estimation.
      RESULTS: Both standard phantom (Medical Internal Radiation Dose [MIRD]) and
      patient-specific absorbed doses are estimated. All modules interact with the
      database backend so that changes in one process do not influence other
      operations. Results of the modular operations are written to the database as
      computations are completed. Dose-volume histograms are an intrinsic part of the
      output for patient-specific absorbed dose estimates. A sample dose estimate for a
      potential 90Y monoclonal antibody is described. CONCLUSION: A four-module
      software system has been implemented to estimate MIRD phantom and patient
      specific absorbed doses. Computations of the doses and their statistical
      distribution for a pure beta emitter such as 90Y take approximately 1 min on a
      300 MHz personal computer.

PMID- 10405137
TI  - PET and drug research and development.
AB  - The use of PET to examine the behavioral, therapeutic and toxic properties of
      drugs and substances of abuse is emerging as a powerful new scientific tool. PET
      provides a new perspective on drug research by virtue of its ability to directly
      assess both pharmacokinetic and pharmacodynamic events in humans and in animals.
      These parameters can be assessed directly in the human body both in healthy
      volunteers and in patients. Moreover, the new generation of high-resolution,
      small-animal cameras hold the promise of introducing imaging in the early stages
      of drug development and make it possible to carry out longitudinal studies in
      animals and to study genetically altered animals. This places PET in a unique
      position to contribute significantly to the process of drug development through
      understanding the molecular mechanisms underlying drug action while addressing
      some very practical questions such as determining effective drug doses for
      clinical trials for new drugs, determining the duration of drug action and
      examining potential drug interactions.

PMID- 10405139
TI  - Small-animal PET: advent of a new era of PET research.

PMID- 10405138
TI  - Performance evaluation of microPET: a high-resolution lutetium oxyorthosilicate
      PET scanner for animal imaging.
AB  - A new dedicated PET scanner, microPET, was designed and developed at the
      University of California, Los Angeles, for imaging small laboratory animals. The
      goal was to provide a compact system with superior spatial resolution at a
      fraction of the cost of a clinical PET scanner. METHODS: The system uses
      fiberoptic readout of individually cut lutetium oxyorthosilicate (LSO) crystals
      to achieve high spatial resolution. Each microPET detector consists of an 8 x 8
      array of 2 x 2 x 10-mm LSO scintillation crystals that are coupled to a 64
      channel photomultiplier tube by optical fibers. The tomograph consists of 30
      detectors in a continuous ring with a 17.2-cm diameter and fields of view (FOVs)
      of 11.25 cm in the transaxial direction and 1.8 cm in the axial direction. The
      system has eight crystal rings and no interplane septa. It operates exclusively
      in the three-dimensional mode and has an electronically controlled bed that is
      capable of wobbling with a radius of 300 microm. We describe the performance of
      the tomograph in terms of its spatial, energy and timing resolution, as well as
      its sensitivity and counting-rate performance. We also illustrate its overall
      imaging performance with phantom and animal studies that demonstrate the
      potential applications of this device to biomedical research. RESULTS: Images
      reconstructed with three-dimensional filtered backprojection show a spatial
      resolution of 1.8 mm at the center of the FOV (CFOV), which remains <2.5 mm for
      the central 5 cm of the transaxial FOV. The resulting volumetric resolution of
      the system is <8 microL. The absolute system sensitivity measured with a 0.74 MBq
      (20 microCi) 68Ge point source at the CFOV is 5.62 Hz/kBq. The maximum noise
      equivalent counting rate obtained with a 6.4-cm diameter cylinder spanning the
      central 56% of the FOV is 10 kcps, whereas the scatter fraction is 37% at the
      CFOV for an energy window of 250-650 keV and the same diameter cylinder.
      CONCLUSION: This is the first PET scanner to use the new scintillator LSO and
      uses a novel detector design to achieve high volumetric spatial resolution. The
      combination of imaging characteristics of this prototype system (resolution,
      sensitivity, counting-rate performance and scatter fraction) opens up new
      possibilities in the study of animal models with PET.

PMID- 10405140
TI  - Enhanced uptake of [11C]TPMP in canine brain tumor: a PET study.
AB  - In vitro studies have demonstrated the membrane potential-dependent enhanced
      uptake of phosphonium salts, including [3H]triphenylmethylphosphonium (TPMP),
      into mitochondria of carcinoma and glioma-derived tumor cells, suggesting the
      potential use of phosphonium salts as tracers for tumor imaging. This study
      characterizes the in vivo uptake of [11C]TPMP in canine brain glioma using PET.
      METHODS: Dynamic paired PET studies of [11C]TPMP followed by
      [68Ga]ethylenediaminetetraacetic acid (EDTA) were performed 4 d before and 9 d
      after tumor cell inoculation. Graphical analysis was used to evaluate [11C]TPMP
      retention in tumor tissue. Distribution of tracer uptake was compared with tumor
      histological sections. RESULTS: [11C]TPMP exhibited enhanced uptake and prolonged
      retention in tumor cells. Patlak plot was linear over the 20- to 95-min
      postinjection period (r = 0.97 +/- 0.1). [68Ga]EDTA exhibited a gradual washout
      from the tumor tissue. The tumor-to-normal brain uptake ratio at 55 to 95 min
      postinjection was 47.5 for [11C]TPMP and 8.1 for [68Ga]EDTA. Qualitative
      comparison with histological sections indicated that [11C]TPMP enhanced uptake
      was restricted to the tumor area. CONCLUSION: The enhanced uptake and prolonged
      retention in tumor suggest [11C]TPMP as a promising means for imaging of gliomas
      in dogs. The need for studies in humans is indicated.

PMID- 10405141
TI  - Myocardial glucose uptake measured with fluorodeoxyglucose: a proposed method to
      account for variable lumped constants.
AB  - Quantitative assessment of myocardial glucose uptake by the glucose tracer analog
      2-deoxy-2-[18F]fluoro-D-glucose (FDG) depends on a correction factor (lumped
      constant [LC]), which may vary. We propose that this variability is caused by
      different affinities of FDG and glucose for membrane transport and
      phosphorylation and can be predicted from the time course of FDG retention. We
      therefore measured the LC under steady-state metabolic conditions and compared
      the results with values predicted from the tracer retention alone. METHODS: We
      measured rates of myocardial glucose uptake by tracer ([2-3H]glucose) and tracer
      analog methods (FDG) in isolated working Sprague-Dawley rat hearts perfused with
      Krebs buffer and glucose, or glucose plus insulin or beta-hydroxybutyrate. In
      separate experiments, we established the theoretical upper and lower limits for
      the LC (Rt and Rp), which are determined by the relative rates of FDG and glucose
      membrane transport (Rt, 1.73 +/- 0.22) and the relative rates of FDG and glucose
      phosphorylation (Rp, 0.15 +/- 0.04). RESULTS: The LC was decreased in the
      presence of insulin or beta-hydroxybutyrate or both (from 1.14 +/- 0.3 to 0.58 +/
      0.16 [insulin], to 0.75 +/- 0.17 [beta-hydroxybutyrate] or to 0.53 +/- 0.17
      [both], P < 0.05). The time-activity curves of FDG retention reflected these
      changes. Combining the upper and lower limits for the LC with the ratio between
      unidirectional and steady-state FDG uptake rates allowed the prediction of
      individual LCs, which agreed well with the actually measured values (r = 0.96, P
      < 0.001). CONCLUSION: The LC is not a constant but is a predictable quotient. As
      a result of the fixed relation between tracer and tracee for both membrane
      transport and phosphorylation, the quotient can be determined from the FDG time
      activity curve and true rates of myocardial glucose uptake can be measured.

PMID- 10405142
TI  - 211At- and 131I-labeled bisphosphonates with high in vivo stability and bone
      accumulation.
AB  - Bisphosphonates were synthesized for use as carriers for astatine and iodine
      radioisotopes to target bone neoplasms. METHODS: Radiohalogenated activated
      esters were coupled to the amino group in the side chain of the bisphosphonate.
      The bisphosphonate 3-amino-1-hydroxypropylidene bisphosphonate was combined with
      four different acylation agents: N-succinimidyl 3-[211At]astatobenzoate, N
      succinimidyl 3-[131I]iodobenzoate, N-succinimidyl-5-[211At]astato-3
      pyridinecarboxylate and N-succinimidyl-5-[131I]iodo-5-pyridinecarboxylate. The
      products, 3-[131I]iodobenzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (IBPB),
      3-[211At]astato-benzamide-N-3-hydroxypropylidene-3,3-bisphosphonat e (ABPB), 5
      [131I]iodopyridine-3-amide-N-3-hydroxypropylidene-3,3-bisphospho nate (IPPB) and
      5-[211At]astatopyridine-3-amide-N-3-hydroxypropylidene-3,3-bisphos phonate
      (APPB), were injected intravenously into Balb/c mice. MIRD and Monte Carlo
      methods were used on the basis of cumulated activity calculated from
      biodistribution data to estimate dose to organs and bone segments. RESULTS: All
      131I- and 211At-labeled analogs were strongly incorporated into osseous tissue
      and retained there at stable levels, while a rapid clearance from blood was
      observed. The bone uptake was found to be similar for 211At- and 131I-labeled
      bisphosphonate when compared in paired label experiments. Bone uptake and bone-to
      tissue ratios were better for IBPB compared with IPPB, and ABPB compared with
      APPB. All four compounds appeared to be highly resistant to in vivo
      dehalogenation as indicated by low uptake of 131I/211At in the thyroid gland and
      stomach. According to dosimetric estimates, the bone surface-to-bone marrow ratio
      was three times higher with 211At than with 131I. CONCLUSION: Both the beta
      particle- and alpha-particle-emitting compounds showed high in vivo stability and
      excellent affinity for osseous tissue. Further preclinical evaluation is
      therefore warranted.

PMID- 10405143
TI  - Metabolism of radioiodinated fatty acid analogs in ischemic and hypoxic canine
      myocardium.
AB  - Myocardial metabolism of 17-[123I]-iodoheptadecanoic acid (IHDA), 15-(p-[131I]
      iodophenyl)pentadecanoic acid (pIPPA) and 15-(p-[125I]-iodophenyl)-3,3
      dimethylpentadecanoic acid (DMIPP) was assessed during ischemia and hypoxia. The
      simultaneous investigation allowed us to evaluate differences in metabolic
      handling of these three fatty acids. METHODS: In 17 open-chest dogs, the left
      ascending coronary artery was cannulated and extracorporeal bypass (ECB)
      perfused. In 3 dogs, ECB flow was kept normal, and these control experiments
      showed that kinetics of the radioiodinated fatty acids were not affected by the
      ECB technique itself. In 9 dogs, ECB flow was reduced to one third (ischemia),
      and in 5 dogs, the ECB area was perfused with venous blood and was kept at
      control values (hypoxia). After simultaneous intravenous injection of IHDA, pIPPA
      and DMIPP, seven paired biopsy specimens from the native and ECB-perfused
      myocardium were taken over an assay period of 35 min. Total activity and the
      distribution in the aqueous phase and lipid fractions were determined, and time
      activity curves were constructed. RESULTS: In ischemic (Is) but not in hypoxic
      (Hy) myocardium, peak total activity of IHDA, pIPPA and DMIPP decreased
      significantly versus normal (N) myocardium (IHDA: N = 700 +/- 267 versus Is = 335
      +/- 158 dpm/mg/mCi; pIPPA: N = 988 +/- 318 versus Is = 438 +/- 180 dpm/mg/mCi;
      DMIPP: N = 352 +/- 146 versus Is = 179 +/- 82 dpm/mg/mCi; all P values < 0.001).
      The relative decrease was similar for IHDA, pIPPA or DMIPP. Half-time values of
      total activity were prolonged for IHDA and pIPPA but were shortened for DMIPP in
      ischemic and hypoxic myocardium (IHDA: N = 22, Is = 44 and Hy = 50 min; pIPPA: N
      = 24, Is = 95 and Hy = 169 min; DMIPP: N = 528, Is = 409 and Hy = 115 min). The
      aqueous phase activity for IHDA, pIPPA and DMIPP decreased significantly versus
      normal myocardium in both ischemic (IHDA: N = 71% +/- 9% versus Is = 36% +/- 9%,
      P < 0.001; pIPPA: N = 62% +/- 10% versus Is = 25% +/- 8%, P < 0.001; DMIPP: N =
      26% +/- 11% versus Is = 18% +/- 3%, P < 0.05) and hypoxic (IHDA: N = 76% +/- 8%
      versus Hy = 62% +/- 8%, P < 0.05; pIPPA: N = 66% +/- 8% versus Hy = 46% +/- 10%,
      P < 0.05; DMIPP: N = 32% +/- 6% versus Hy = 24% +/- 4%, P < 0.05) myocardium. The
      relative decrease was significantly highest for pIPPA and lowest for DMIPP.
      Incorporation into triacylglycerols increased significantly for IHDA, pIPPA and
      DMIPP in both ischemic and hypoxic myocardium. In normal myocardium, DMIPP was
      already mainly incorporated into triacylglycerols. Activity of IHDA and pIPPA in
      acylcarnitine increased significantly in ischemic and hypoxic myocardium.
      CONCLUSION: Kinetics of the radioiodinated fatty acid analogs in myocardium are
      altered during oxygen deprivation in a similar fashion as documented in
      literature for natural fatty acids. However, the changes were different between
      IHDA, pIPPA and DMIPP, suggesting different metabolic handling and thus
      reflecting different aspects of myocardial fatty acid metabolism.

PMID- 10405144
TI  - Two-step targeting and dosimetry for small cell lung cancer xenograft with anti
      NCAM/antihistamine bispecific antibody and radioiodinated bivalent hapten.
AB  - The "affinity enhancement system," a two-step targeting technique using
      bispecific antibody and radiolabeled bivalent hapten, has been reported to be
      useful for carcinoembryonic antigen-expressing tumors. The purpose of this study
      was to evaluate the efficacy of this method for targeting human small cell lung
      cancer using an antineural cell adhesion molecule antibody. METHODS: Antineural
      cell adhesion molecule/antihistamine bispecific antibody NK1NBL1-679 was prepared
      by coupling an equimolecular quantity of a Fab' fragment of NK1NBL1 to a Fab
      fragment of antihistamine 679. Athymic mice inoculated with NCI-H69 small cell
      lung cancer cells expressing neural cell adhesion molecule were administered
      bispecific antibody and then 48 h later 125I-labeled bivalent histamine hapten.
      125I-labeled intact NK1NBL1 was injected into other groups of mice.
      Biodistributions were examined as a function of time. RESULTS: In mice of the two
      step targeting, tumor uptake was 2.5 +/- 0.2, 3.2 +/- 0.4, 6.4 +/- 2.0, 7.2 +/-
      2.7, 6.1 +/- 2.1 and 2.2 +/- 0.4 %ID/g at 5, 30 min, 5, 24, 48 and 96 h, and
      tumor-to-blood, tumor-to-liver and tumor-to-kidney ratios were 1.4 +/- 1.1, 10.8
      +/- 13.2 and 4.6 +/- 4.7, respectively, at 5 h, whereas 125I-labeled NK1NBL1
      showed a tumor uptake of 5.7 +/- 0.4 %ID/g and tumor-to-blood, tumor-to-liver and
      tumor-to-kidney ratios of 0.3 +/- 0.1, 1.1 +/- 0.2 and 0.9 +/- 0.1, respectively,
      at 5 h. These results were confirmed by autoradiographic studies, which
      demonstrated clear tumor-to-normal tissue contrast. Dosimetry showed that the
      affinity enhancement system could enhance the therapeutic potential of the
      antineural cell adhesion molecule antibody NK1NBL1. CONCLUSION: This two-step
      targeting method seems promising for the diagnosis and therapy of small cell lung
      cancer.

PMID- 10405145
TI  - 111In-labeled antimyosin scintigraphy for detection of cardiac and skeletal
      muscular involvement in hereditary muscular dystrophy.

PMID- 10405146
TI  - Chest pain in women: dobutamine stress echocardiography or myocardial perfusion
      scintigraphy?

PMID- 10405147
TI  - Inverse correlation between 99mTc-tetrofosmin uptake and P-glycoprotein in non
      small cell lung cancer.

PMID- 10405148
TI  - On effect of coronary artery bypass surgery on brain perfusion.

PMID- 10405149
TI  - Procedure guideline for gastrointestinal bleeding and Meckel's diverticulum
      scintigraphy. Society of Nuclear Medicine.

PMID- 10405150
TI  - Procedure guideline for breast scintigraphy. Society of Nuclear Medicine.

PMID- 10405151
TI  - Procedure guideline for gastric emptying and motility. Society of Nuclear
      Medicine.

PMID- 10405152
TI  - Human hepatitis B virus mutants: significance of molecular changes.
AB  - Human hepatitis B virus, the leading pathogen for hepatitis B, is a compact DNA
      virus with viral genes that largely overlap. An increasing number of mutations
      have emerged following human interventions such as vaccination and anti-viral
      therapy. While vaccine escape mutants are characterized by mutations on the
      antigenic hepatitis B surface antigen, those carrying mutations in other viral
      proteins are either resistant to anti-viral therapy or implicated in acute liver
      diseases. Molecular identification of these various mutants should shed new
      lights on the underlying mechanism of hepatitis B virus viral escape and
      resistance and provide helpful information on their effective eradication.

PMID- 10405153
TI  - Differential expression of gap-junction gene connexin 31 in seminiferous
      epithelium of rat testes.
AB  - Spermatogenesis, a tightly regulated developmental process of male germ cells in
      testis, is associated with temporal and spatial expression of certain gap
      junction connexins. Our findings by RT-PCR indicate that the Cx31 gene is
      expressed in testis tissue of adult and postnatal rats. During the postnatal
      spermatogenic process, the Cx31-specific signal became detectable at 15 dpp and
      onward by in situ hybridization, and apparently localized in the basal
      compartment of seminiferous epithelium where active spermatogonia and early
      primary spermatocytes reside. No signal was found in the luminal region. In adult
      testes, spermatids of elongation phase were also Cx31 positive.
      Immunohistochemical analysis with mouse anti-Cx31 antibody gave a similar
      staining pattern, providing further evidence that the gap-junction protein is
      abundant in the basal seminiferous epithelium, in accordance with the cellular
      distribution of Cx31 mRNA. These results represent the first demonstration of
      Cx31 expression at both transcriptional and protein levels in the seminiferous
      epithelium of rat testes. Thus, Cx31 may play a role in cell-cell communication
      during spermatogenesis.

PMID- 10405154
TI  - Protein kinase C-theta is specifically activated in murine erythroleukaemia cells
      during mitosis.
AB  - Protein kinase C-theta is a member of the n-protein kinase C subfamily that in
      mitotic cells translocates to centrosomes and kinetochores. Although this kinase
      is expressed in comparable amounts in murine erythroleukaemia cells during the
      interphase or metaphase, when localized in the mitotic structures, it selectively
      phosphorylates a 66 kDa protein, also associated to chromosomes. Moreover,
      protein kinase C-theta immunoprecipitated from cells at the metaphase results
      four times more active in the absence of lipid cofactors as compared with the
      kinase obtained from cells in the interphase. This activation is accomplished by
      interaction of protein kinase C-theta with a protein factor which also promotes
      an increased autophosphorylation of the kinase. These findings indicate that in
      the mitotic phase of the cell cycle, protein kinase C-theta recognizes a protein
      factor which operates as a positive modulator of the kinase activity in the
      absence lipids.

PMID- 10405155
TI  - cAPK-phosphorylation controls the interaction of the regulatory domain of cardiac
      myosin binding protein C with myosin-S2 in an on-off fashion.
AB  - Myosin binding protein C is a protein of the myosin filaments of striated muscle
      which is expressed in isoforms specific for cardiac and skeletal muscle. The
      cardiac isoform is phosphorylated rapidly upon adrenergic stimulation of
      myocardium by cAMP-dependent protein kinase, and together with the
      phosphorylation of troponin-I and phospholamban contributes to the positive
      inotropy that results from adrenergic stimulation of the heart. Cardiac myosin
      binding protein C is phosphorylated by cAMP-dependent protein kinase on three
      sites in a myosin binding protein C specific N-terminal domain which binds to
      myosin-S2. This interaction with myosin close to the motor domain is likely to
      mediate the regulatory function of the protein. Cardiac myosin binding protein C
      is a common target gene of familial hypertrophic cardiomyopathy and most
      mutations encode N-terminal subfragments of myosin binding protein C. The
      understanding of the signalling interactions of the N-terminal region is
      therefore important for understanding the pathophysiology of myosin binding
      protein C associated cardiomyopathy. We demonstrate here by cosedimentation
      assays and isothermal titration calorimetry that the myosin-S2 binding properties
      of the myosin binding protein C motif are abolished by cAMP-dependent protein
      kinase-mediated tris-phosphorylation, decreasing the S2 affinity from a Kd of
      approximately 5 microM to undetectable levels. We show that the slow and fast
      skeletal muscle isoforms are no cAMP-dependent protein kinase substrates and that
      the S2 interaction of these myosin binding protein C isoforms is therefore
      constitutively on. The regulation of cardiac contractility by myosin binding
      protein C therefore appears to be a 'brake-off' mechanism that will free a
      specific subset of myosin heads from sterical constraints imposed by the binding
      to the myosin binding protein C motif.

PMID- 10405156
TI  - Lithium protects cultured neurons against beta-amyloid-induced neurodegeneration.
AB  - The deposition of beta-amyloid peptide (A beta), the hyperphosphorylation of tau
      protein and the death of neurons in certain brain regions are characteristic
      features of Alzheimer's disease. It has been proposed that the accumulation of
      aggregates of A beta is the trigger of neurodegeneration in this disease. In
      support of this view, several studies have demonstrated that the treatment of
      cultured neurons with A beta leads to the hyperphosphorylation of tau protein and
      neuronal cell death. Here we report that lithium prevents the enhanced
      phosphorylation of tau protein at the sites recognized by antibodies Tau-1 and
      PHF-1 which occurs when cultured rat cortical neurons are incubated with A beta.
      Interestingly, lithium also significantly protects cultured neurons from A beta
      induced cell death. These results raise the possibility of using chronic lithium
      treatment for the therapy of Alzheimer's disease.

PMID- 10405157
TI  - Production of singlet oxygen by eosinophils activated in vitro by C5a and
      leukotriene B4.
AB  - Using the trans-methoxyvinylpyrene analogues of benzo[a]pyrene-7,8-dihydrodiol
      (MVP) as a singlet oxygen ((1)O2) chemiluminescence probe, we have demonstrated
      that guinea pig eosinophils release (1)O2 when activated with the physiological
      agonists C5a and leukotriene B4. This release, which occurs at agonist
      concentrations as low as 10(-7) M, occurs more rapidly than activation with
      phorbol ester (10(-6) M), is similar in level, but is more transitory. In
      addition, the release of (1)O2 occurs in the absence of added bromide ions and
      represents, we propose, an important feature of eosinophil-mediated inflammatory
      damage.

PMID- 10405158
TI  - N-acetyl-sphingenine-1-phosphate is a potent calcium mobilizing agent.
AB  - Calcium mobilization induced by phosphorylated sphingoid bases was analyzed in
      calf pulmonary artery endothelial cells by confocal microscopy. A sphingenine-1
      phosphate (SeP) analogue, N-acetyl-sphingenine-1-phosphate (N-C2-SeP),
      exogenously added to these cells, caused a fast and transient intracellular rise
      in calcium and was as potent as SeP. A minimal concentration of 0.6 nM for N-C2
      SeP versus 1 nM for SeP was determined. The N-C2-SeP-induced Ca2+-signaling, like
      the response to SeP, was due to a release from thapsigargin-sensitive, ryanodine
      insensitive, intracellular Ca2+-stores and not to a Ca2+-influx. N-C2-SeP can be
      considered as a truncated ceramide-phosphate, a lipid already reported to be
      mitogenic (Gomez-Munoz, A., Duffy, P.A., Martin, A., O'Brien, L., Byun, H.S.,
      Bittman, R. and Brindley, D.N. (1995) Mol. Pharmacol. 47, 833-839), an effect
      that might be secondary to Ca2+-mobilization.

PMID- 10405159
TI  - The RNA polymerase II core subunit 11 interacts with keratin 19, a component of
      the intermediate filament proteins.
AB  - We have previously cloned the human RNA polymerase II subunit 11, as a
      doxorubicin sensitive gene product. We suggested multiple tasks for this subunit,
      including structural and regulatory roles. With the aim to clarify the human RNA
      polymerase II subunit 11 function, we have identified its interacting protein
      partners using the yeast two-hybrid system. Here, we show that human RNA
      polymerase II subunit 11 specifically binds keratin 19, a component of the
      intermediate filament protein family, which is expressed in a tissue and
      differentiation-specific manner. In particular, keratin 19 is a part of the
      nuclear matrix intermediate filaments. We provide evidence that human RNA
      polymerase II subunit 11 interacts with keratin 19 via its N-terminal alpha
      motif, the same motif necessary for its interaction with the human RNA polymerase
      II core subunit 3. We found that keratin 19 contains two putative leucine zipper
      domains sharing peculiar homology with the alpha motif of human RNA polymerase II
      subunit 3. Finally, we demonstrate that keratin 19 can compete for binding human
      RNA polymerase II subunit 11/human RNA polymerase II subunit 3 in vitro,
      suggesting a possible regulatory role for this molecule in RNA polymerase II
      assembly/activity.

PMID- 10405160
TI  - Ratio-fluorescence microscopy of lipid oxidation in living cells using C11
      BODIPY(581/591).
AB  - A ratio-fluorescence assay was developed for on-line localization and
      quantification of lipid oxidation in living cells. The assay explores the
      oxidative sensitivity of C11-BODIPY(581/591). Upon oxidation, the fluorescence of
      this fluorophore shifts from red to green. The probe incorporates readily into
      cellular membranes and is about twice as sensitive to oxidation as arachidonic
      acid. Using confocal microscopy, the cumene hydroperoxide-induced oxidation of
      C11-BODIPY(581/591) was visualized at the sub-cellular level in rat-1
      fibroblasts. Preloading of the cells with tocopherol retarded this oxidation. The
      data demonstrate that C11-BODIPY(581/591) is a valuable tool to quantify lipid
      oxidation and anti-oxidant efficacy in single cells.

PMID- 10405161
TI  - High molecular weight hyaluronic acid inhibits advanced glycation endproduct
      induced NF-kappaB activation and cytokine expression.
AB  - Advanced glycation endproducts (AGEs), which accumulate on long-lived proteins
      and protein deposits (amyloids), induce the expression of proinflammatory
      cytokines through NF-kappaB-dependent pathways. Hyaluronic acid with a molecular
      weight above 1.2 MDa (HMW-HA) inhibits the AGE-induced activation of the
      transcription factor NF-kappaB and the NF-kappaB-regulated cytokines interleukin
      1alpha, interleukin-6 and tumor necrosis factor-alpha. Since the molecular weight
      of hyaluronic acid in humans decreases with age and under conditions of oxidative
      stress, it is likely that the protective effect of HMW-HA against AGE-induced
      cellular activation is lost at sites of chronic inflammation and in older age.

PMID- 10405162
TI  - A novel substrate for analyzing Alzheimer's disease gamma-secretase.
AB  - Proteolytic processing of Alzheimer's disease amyloid precursor protein (APP) by
      beta-secretase leads to A4CT (C99), which is further cleaved by the as yet
      unknown protease called gamma-secretase. To study the enzymatic properties of
      gamma-secretase independently of beta-secretase, A4CT together with an N-terminal
      signal peptide (SPA4CT) may be expressed in eukaryotic cells. However, in all
      existing SPA4CT proteins the signal peptide is not correctly cleaved upon
      membrane insertion. Here, we report the generation of a mutated SPA4CT protein
      that is correctly cleaved by signal peptidase and, thus, identical to the APP
      derived A4CT. This novel SPA4CT protein is processed by gamma-secretase in the
      same manner as APP-derived A4CT and might be valuable for the generation of
      transgenic animals showing amyloid pathology.

PMID- 10405163
TI  - Oyster IKK-like protein shares structural and functional properties with its
      mammalian homologues.
AB  - In our search for genes involved in oyster immunity we isolated a cDNA encoding a
      polypeptide closely related to the mammalian IkappaB kinase (IKK) family. IKK
      proteins play a central role in cell signaling by regulating nuclear factor
      kappaB (NF-kappaB) activation. We report here the cloning of an oyster IKK-like
      protein (oIKK) which possesses the characteristic organization of the mammalian
      IKK proteins, namely an amino-terminal kinase domain followed by a leucine zipper
      region and a carboxyl-terminal helix-loop-helix motif. When transfected into
      human cell lines, oIKK activated the expression of NF-kappaB-controlled reporter
      gene, whereas transfections with mutants of oIKK deleted within the kinase domain
      or within the helix-loop-helix motif respectively abolished and greatly reduced
      reporter gene activation. These results indicate that oIKK can replace the hIKK
      alpha in catalyzing NF-kappaB nuclear translocation, and in triggering gene
      expression. Our results sustain the concept of an evolutionarily conserved
      signaling machinery in which IKK plays a major role.

PMID- 10405164
TI  - Analysis of the in vivo interaction between a basic repressor and an acidic
      activator.
AB  - The artificial basic repressor SSB24 represses transcription of a reporter
      construct activated by GCN4. We show that the positively charged SSB24 and the
      negatively charged acidic activator GCN4 interact in vitro and in vivo. However,
      deleting the interaction domain from the GCN4 activator does not result in loss
      of repression by SSB24. Similarly, transcription activated by the holoenzyme
      component SRB2 is repressed, although SSB24 and SRB2 do not interact. Repression
      by SSB24 therefore does not depend on the observed protein-protein interaction
      between SSB24 and GCN4.

PMID- 10405165
TI  - Design of generic biosensors based on green fluorescent proteins with allosteric
      sites by directed evolution.
AB  - Protein-engineering techniques have been adapted for the molecular design of
      biosensors that combine a molecular-recognition site with a signal-transduction
      function. The optical signal-transduction mechanism of green fluorescent protein
      (GFP) is most attractive, but hard to combine with a ligand-binding site. Here we
      describe a general method of creating entirely new molecular-recognition sites on
      GFPs. At the first step, a protein domain containing a desired molecular-binding
      site is inserted into a surface loop of GFP. Next, the insertional fusion protein
      is randomly mutated, and new allosteric proteins that undergo changes in
      fluorescence upon binding of target molecules are selected from the random
      library. We have tested this methodology by using TEM1 beta-lactamase and its
      inhibitory protein as our model protein-ligand system. 'Allosteric GFP
      biosensors' constructed by this method may be used in a wide range of
      applications including biochemistry and cell biology.

PMID- 10405166
TI  - Induction of p53 dependent apoptosis upon overexpression of a nuclear protein
      tyrosine phosphatase.
AB  - Two ubiquitously expressed protein tyrosine phosphatases, PTP-S2 and PTP-S4 (also
      known as TC45 and TC48, respectively), are alternately spliced products of the
      same gene. Overexpression of PTP-S2 by transient transfection induced chromatin
      condensation and nuclear fragmentation, typical of apoptosis. Expression of PTP
      S4 resulted in a much lower number of cells with apoptotic phenotype. PTP-S2
      induced apoptosis in MCF7 and A549 human tumor cell lines which are p53 positive
      but not in HeLa and SW620 cells which are p53 negative. Apoptosis induced by PTP
      S2 in MCF7 cells was inhibited by cotransfection with mutant p53 (Arg-273 -->
      His) but not by wild type p53. PTP-S2 induced apoptosis was inhibited by
      antiapoptotic protein Bcl2 and certain inhibitors of caspases. These results
      suggest that the nuclear tyrosine phosphatase PTP-S2 induces p53 dependent, serum
      starvation independent and caspase mediated apoptosis.

PMID- 10405167
TI  - A RNA polymerase with transcriptional activity at 0 degrees C from the Antarctic
      bacterium Pseudomonas syringae.
AB  - A DNA-dependent RNA polymerase was purified from the Antarctic psychrotrophic
      bacterium Pseudomonas syringae. The RNA polymerase showed a typical eubacterial
      subunit composition with beta, beta', alpha2 and sigma subunits. The subunits
      cross-reacted with antibodies raised against holoenzyme and the individual
      subunits of the RNA polymerase of Escherichia coli. However, the enzyme was
      considered unique, since unlike the RNA polymerase of mesophilic E. coli it
      exhibited significant and consistent transcriptional activity (10-15%) even at 0
      degrees C. But, similar to the enzyme from the mesophilic bacterium, the RNA
      polymerase from P. syringae exhibited optimum activity at 37 degrees C. The study
      also demonstrates that the RNA polymerase of P. syringae could preferentially
      transcribe the cold-inducible gene cspA of E. coli only at lower temperatures (0
      22 degrees C). The polymerase was also observed to be relatively more rifampicin
      resistant during transcription at lower temperature.

PMID- 10405168
TI  - The structural flexibility of the preferredoxin transit peptide.
AB  - In order to obtain insight into the structural flexibility of chloroplast
      targeting sequences, the Silene pratensis preferredoxin transit peptide was
      studied by circular dichroism and nuclear magnetic resonance spectroscopy. In
      water, the peptide is unstructured, with a minor propensity towards helix
      formation from Val-9 to Ser-12 and from Gly-30 to Ser-40. In 50% (v/v)
      trifluoroethanol, structurally independent N- and C-terminal helices are
      stabilized. The N-terminal helix appears to be amphipathic, with hydrophobic and
      hydroxylated amino acids on opposite sides. The C-terminal helix comprises amino
      acids Met-29-Gly-50 and is destabilized at Gly-39. No ordered tertiary structure
      was observed. The results are discussed in terms of protein import into
      chloroplasts, in which the possible interactions between the transit peptide and
      lipids are emphasized.

PMID- 10405169
TI  - Immunochemical detection of oxalate monoalkylamide, an ascorbate-derived Maillard
      reaction product in the human lens.
AB  - Carbohydrates with reactive aldehyde and ketone groups can undergo Maillard
      reactions with proteins to form advanced glycation end products. Oxalate
      monoalkylamide was identified as one of the advanced glycation end products
      formed from the Maillard reaction of ascorbate with proteins. In these
      experiments, we have analyzed human lens proteins immunochemically for the
      presence of oxalate monoalkylamide. Oxalate monoalkylamide was absent in most of
      the very young lenses but was present in old and cataractous lenses. The highest
      levels were found in senile brunescent lenses. Incubation experiments using
      bovine lens proteins revealed that oxalate monoalkylamide could form from the
      ascorbate degradation products, 2,3-diketogulonate and L-threose. These data
      provide the first evidence for oxalate monoalkylamide in vivo and suggest that
      ascorbate degradation and its binding to proteins are enhanced during lens aging
      and cataract formation.

PMID- 10405170
TI  - Studies of a putative ice-binding motif in winter flounder skin-type anti-freeze
      polypeptide.
AB  - Winter flounder contains two distinct anti-freeze protein isoforms, which are the
      liver-type extracellular anti-freeze proteins and the skin-type intracellular
      anti-freeze protein. The skin-type anti-freeze proteins exhibit lower anti-freeze
      activities than the liver-type isoforms and this might be due to their lacking
      complete ice-binding motifs. One of the skin-type anti-freeze proteins, skin-type
      anti-freeze protein-3, does contain putative overlapping ice-binding motifs with
      the sequences '-K-DT-' and '-DT-K-'. Synthetic anti-freezes containing 0-3
      repeats of the '-DT-K-' motif were tested for stability and activity. Loss of the
      single '-DT-K-' of skin-type anti-freeze protein-3 increases the anti-freeze
      activity and increasing the number of motifs to two or three lowers the activity.
      The decrease in activity with an increasing frequency of the motif correlates
      with a decrease in the helical content of these peptides at 0 degrees C.

PMID- 10405171
TI  - The cDNA cloning of human placental ecto-ATP diphosphohydrolases I and II.
AB  - The cDNA clones of two isoforms (enzymes I and II) of human placental ecto-ATP
      diphosphohydrolases have been isolated based on the N-terminal amino acid (aa)
      sequence of the immunopurified 82 kDa protein and characterized. The cDNA clone
      encoding enzyme I consists of 2081 nucleotides and the predicted enzyme I
      consists of 517 aa residues. Enzyme I has a 5'-UTR and an N-terminal 11 aa
      sequence that differ from CD39, but the rest of the sequence is the same as CD39.
      The hydropathy plot indicated that enzyme I has two hydrophobic regions near the
      N- and C-termini of the molecule. In contrast, enzyme II consists of 1814
      nucleotides and the predicted protein consists of 306 aa residues. The sequence
      of 1-1018 nucleotides of enzyme II is identical to that of enzyme I, but the 1019
      1814 nucleotide sequence is different from both enzyme I and CD39. The hydropathy
      plot indicated that enzyme II has one hydrophobic region near the N-terminus,
      suggesting that enzyme II is also anchored to the cell membrane. It is, however,
      likely that some of enzyme II exists as a soluble form in plasma, possibly after
      proteolytic processing.

PMID- 10405172
TI  - Plant cell growth and differentiation may involve GAP regulation of Rac activity.
AB  - Two Rac GTPase cDNAs, LjRac1 and LjRac2, were identified in the legume Lotus
      japonicus. Two-hybrid screening with dominant-constitutive mutations in the two
      Rac GTPases target three plant cDNAs, LjRacGAP1, LjRacGAP2 and LjRacGAP3, that
      encode putative GTPase activating proteins of Rho-GTPase subfamily members.
      Employing Rac antiserum, purified recombinant LjRac GTPases and recombinant
      LjRacGAP1, for ligand overlay assays, in vitro GAP affinity assays and GTPase
      activation, we confirmed that eukaryote Rac/RacGAP interplay is conserved in
      plants. In this investigation we have developed some tools that can be used to
      characterize the role of enhanced LjRac2 expression in developing root nodules.

PMID- 10405173
TI  - Multiple TGF-beta receptor related genes in sponge and ancient gene duplications
      before the parazoan-eumetazoan split.
AB  - Members of the transforming growth factor beta (TGF-beta) family mediate key
      events in cell growth and development. Various receptors for diverse members of
      the TGF-beta family have recently been isolated and sequenced. These receptors
      form a family (TbetaR family) with a Ser/Thr kinase domain in common. To
      understand the divergence pattern of the TbetaR family during animal evolution,
      we have conducted cloning of cDNAs encoding the TbetaR family members from
      Ephydatia fluviatilis, a freshwater sponge. We obtained seven cDNAs (sALK-1-sALK
      7) which are closely related in structure to known family members. Including
      these sponge sequences, a phylogenetic tree of the family members was inferred by
      a maximum likelihood method. The phylogenetic tree suggests that the sponge
      receptors sALK-1-sALK-3, which are closely related to each other, are sponge
      homologs of vertebrate activin type I receptor (ActR-I). sALK-5 is likely to be a
      homolog of TGF-beta type II receptor. sALK-4 and sALK-6 might be ancestral
      precursors of type I and type II receptors, respectively, and sALK-7 is possibly
      an ancestral precursor of both types. The tree revealed that most, if not all, of
      the gene duplications that gave rise to known subtypes with distinct ligand
      specificities antedate the divergence of parazoans and eumetazoans, the earliest
      divergence of extant animal phyla.

PMID- 10405174
TI  - Specific sequence-directed anti-bilitranslocase antibodies as a tool to detect
      potentially bilirubin-binding proteins in different tissues of the rat.
AB  - The hypothesis that the uneven distribution of bilirubin in the organism, which
      occurs in hyperbilirubinemia, could reflect an uneven distribution of bilirubin
      binding proteins was tested by searching for peptides containing the bilirubin
      binding motif identified in bilitranslocase (Battiston et al., 1998). In the rat,
      positive proteins bands were found to be present only in the liver, gastric
      mucosa and central nervous system. The electrophoretic mobilities of the positive
      compounds in the liver and stomach were identical to that of purified
      bilitranslocase (38 kDa). In the brain, on the contrary, two peptides were found
      with molecular masses of 79 and 34 kDa, respectively. Their distribution pattern
      in the central nervous system was different for each of them.

PMID- 10405175
TI  - Imaging of caspase-3 activation in HeLa cells stimulated with etoposide using a
      novel fluorescent probe.
AB  - Microscopic visualization of intracellular enzyme activity can provide
      information about the physiological role of the enzyme. Caspases are cysteine
      proteases that have critical roles in the execution of apoptosis. General
      fluorometric substrates of caspase-3, such as DEVD-MCA, are unsuitable for
      imaging because they are excited at short wavelength, so we designed and
      synthesized novel fluorescent probes that are excited at suitable wavelengths for
      detecting caspase-3 activity in living cells. Using one of these probes, we
      succeeded in microscopic visualization of caspase-3-like activity within HeLa
      cells treated with etoposide. The caspase-3-like activity was increased in the
      cytosol at first, then expanded to the whole cell.

PMID- 10405176
TI  - Activation of caspase-3 in axotomized rat retinal ganglion cells in vivo.
AB  - Recently, we have shown that inhibition of caspase-3-like caspases is the most
      effective treatment strategy to protect adult rat retinal ganglion cells from
      secondary death following optic nerve transection. In the present study, we
      localized active caspase-3 in axotomized retinal ganglion cells in vivo and
      demonstrated a co-localization of the active p20 fragment and TUNEL-staining in
      some of these cells. In line with this, we detected an enhanced cleavage and
      activity of caspase-3 protein in retinal tissue after lesion, while caspase-3
      mRNA expression remained unchanged. These data suggest caspase-3 as an important
      mediator of secondary retinal ganglion cell death following axotomy in vivo.

PMID- 10405177
TI  - Site-specific DNA damage at GGG sequence by oxidative stress may accelerate
      telomere shortening.
AB  - Telomere shortening during human aging has been reported to be accelerated by
      oxidative stress. We investigated the mechanism of telomere shortening by
      oxidative stress. H2O2 plus Cu(II) caused predominant DNA damage at the 5' site
      of 5'-GGG-3' in the telomere sequence. Furthermore, H2O2 plus Cu(II) induced 8
      oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation in telomere sequences more
      efficiently than that in non-telomere sequences. NO plus O2- efficiently caused
      base alteration at the 5' site of 5'-GGG-3' in the telomere sequence. It is
      concluded that the site-specific DNA damage at the GGG sequence by oxidative
      stress may play an important role in increasing the rate of telomere shortening
      with aging.

PMID- 10405178
TI  - Identification of human GC-box-binding zinc finger protein, a new Kruppel-like
      zinc finger protein, by the yeast one-hybrid screening with a GC-rich target
      sequence.
AB  - A new human zinc finger DNA-binding protein was identified by using a yeast one
      hybrid selection system. Two versions of the cDNA, encoding the same protein,
      were detected that differ for a 584 bp extension at the 5' region. Sequence
      analysis showed that the longer clone is a full length version containing part of
      the 5' untranslated region. The smaller version was fused in frame with the yeast
      GAL4 activation domain whereas the 5' region of the longer clone displayed a stop
      codon interrupting the fusion with the GAL4 domain. Nevertheless, this clone
      activated the yeast HIS3 reporter gene with the same efficiency as the smaller
      version. Sequence comparison of the derived protein with the database showed that
      it belongs to a family of zinc finger DNA-binding proteins which regulate the
      expression of genes involved in cell proliferation. Expression of the protein in
      an in vitro system, DNA-binding studies and genetic experiments identify this
      factor as a new zinc finger DNA-binding protein which binds GC-rich sequences and
      contains a domain probably functioning as a transcriptional activator. The new
      human protein identified in this study was therefore named GC-box-binding zinc
      finger protein).

PMID- 10405179
TI  - Structural analysis of a plant sucrose carrier using monoclonal antibodies and
      bacteriophage lambda surface display.
AB  - Monoclonal antibodies were raised and selected against recombinant Plantago major
      PmSUC2 sucrose carrier protein. Epitopes of two monoclonal antibodies (PS2-1A2
      and PS2-4D4) were mapped using N-terminally truncated PmSUC2 proteins and a
      lambda library displaying random PmSUC2 peptides. PS2-1A2 recognizes an
      octapeptide close to the N-terminus of PmSUC2, PS2-4D4 binds to a decapeptide at
      the very C-terminus. Analyses of antibody binding to yeast protoplasts with
      functionally active, tagged PmSUC2 protein revealed that both epitopes are
      located in cytoplasmic domains of PmSUC2. These results support a model for plant
      sucrose transporters containing 12 transmembrane helices with the N-terminus and
      the C-terminus on the cytoplasmic side of the plasma membrane.

PMID- 10405180
TI  - Crystallization of the immunodominant outer membrane protein OmpC; the first
      protein crystals from Salmonella typhi, a human pathogen.
AB  - OmpC, a surface antigen of Salmonella typhi was crystallized after several
      attempts, using PEG 3350. Well shaped hexagonal crystals were grown from vapor
      diffusion method using octyl glucoside and C12E9 as detergents. Crystals are
      sensitive to X-ray and diffract weakly up to 7 A. Porin isoforms, due to the
      bound lipopolysaccharides, could be the cause for poor diffraction. Crystal
      quality depends largely on the purification method, and in case of LPS
      contamination, the genetic background of the bacteria. Crystallization and
      initial data collection suggest optimum conditions and the method of choice for
      OmpC crystallization.

PMID- 10405182
TI  - Mutational analysis of sites in the translational regulator, PHAS-I, that are
      selectively phosphorylated by mTOR.
AB  - Results obtained with PHAS-I proteins having Ser to Ala mutations in the five
      known phosphorylation sites indicate that mTOR preferentially phosphorylates
      Thr36 and Thr45. The effects of phosphorylating these sites on eIF4E binding were
      assessed in a far-Western analysis with a labeled eIF4E probe. Phosphorylation of
      Thr36 only slightly attenuated binding of PHAS-I to eIF4E, while phosphorylation
      of Thr45 markedly inhibited binding. Phosphorylation of neither site affected the
      electrophoretic mobility of the protein, indicating that results of studies that
      rely solely on a gel-shift assay to assess changes in PHAS-I phosphorylation must
      be interpreted with caution.

PMID- 10405181
TI  - Molecular architecture of Manduca sexta midgut V1 ATPase visualized by electron
      microscopy.
AB  - The structure of the V1 ATPase from the tobacco hornworm Manduca sexta has been
      determined from electron micrographs of isolated, negatively stained specimens.
      The resulting images clearly show a pseudohexagonal arrangement of six equal
      sized protein densities, presumably representing the three copies each of
      subunits A and B, which comprise the headpiece of the enzyme. A seventh density
      could be observed either centrally or asymmetrically to the hexamer. The maximum
      diameter of the V1 complex in the hexagonal projection is 13 nm with each of the
      six peripheral densities being 3-4 nm in diameter.

PMID- 10405183
TI  - N-glycans are not a universal signal for apical sorting of secretory proteins.
AB  - In MDCK cells, N-glycans have been shown to determine the sorting of secretory
      proteins and membrane proteins to the apical domain in the absence of a dominant
      basolateral targeting signal. We have examined the sorting of endogenous proteins
      in ECV304 cells in the presence and absence of tunicamycin, an inhibitor of N
      linked glycosylation. A prominent apically secreted protein of 71 kDa was not N
      glycosylated and continued to be secreted apically in the presence of
      tunicamycin. In contrast, other endogenous proteins that were N-glycosylated were
      secreted preferentially into the basolateral medium or without polarity. When rat
      growth hormone was expressed in MDCK and ECV304 cells, we observed 65 and 94% of
      the secretion to the basolateral medium, respectively. Introduction of a single N
      glycan caused 83% of the growth hormone to be secreted at the apical surface in
      MDCK cells but had no significant effect on the polarity of secretion of growth
      hormone in ECV304 cells. These results indicate that not all cell lines recognise
      N-glycans as a signal for apical sorting and raises the possibility of using
      ECV304 cells as a model system for analysis of apical sorting molecules.

PMID- 10405184
TI  - Heparin binding to cobra basic phospholipase A2 depends on heparin chain length
      and amino acid specificity.
AB  - Heparin is shown to bind specifically to the carboxy-terminal region of toxic
      type I phospholipase A2 from Naja nigricollis (N-PLA2) by competition assay using
      synthetic polypeptides and heparin affinity chromatography. The binding strength
      is seen to depend on heparin chain length and the presence of N-sulfate groups of
      heparin. It is observed that both electrostatic and non-electrostatic
      interactions are involved in the specific binding of heparin to the carboxy
      terminus. When heparin's size is at least a decasaccharide, about two molecules
      of N-PLA2 bind to one molecule of heparin, as evidenced by the chemical estimate
      of protein to carbohydrate ratio in such N-PLA2/heparin complexes. Based on such
      a stoichiometric measurement and computer modeling of the N-PLA2/heparin complex,
      it is suggested that the binding sites of the two N-PLA2 molecules on one heparin
      molecule lie on the opposite sides of the heparin chain.

PMID- 10405185
TI  - Reversal of mitochondrial Na/Ca exchange during metabolic inhibition in rat
      cardiomyocytes.
AB  - During hypoxia of isolated cardiomyocytes, Ca2+ entry into mitochondria may occur
      via the Na/Ca exchanger, the normal efflux pathway, and not the Ca-uniporter, the
      normal influx route. If this is the case, then depletion of myocyte Na+ should
      inhibit Ca2+ uptake, and collapse of the mitochondrial membrane potential (delta
      psi(m)) would inhibit the uniporter. To test these hypotheses, isolated rat
      myocytes were exposed to metabolic inhibition, to mimic hypoxia, and [Ca2+]m and
      [Ca2+]c determined by selective loading of indo-1 into these compartments. Delta
      psi(m) was determined using rhodamine 123. Following metabolic inhibition,
      [Ca2+]m was significantly lower in Na-depleted cells than controls (P<0.001),
      [Ca2+]c was approximately the same in both groups, and mitochondria depolarised
      completely. Thus Na-depletion inhibited mitochondrial Ca2+ uptake, suggesting
      that Ca2+ entry occurred via Na/Ca exchange, and the collapse of delta psi(m)
      during metabolic inhibition is consistent with inactivity of the Ca-uniporter.

PMID- 10405186
TI  - Comparison of neurotoxic effects and potential risks from oral administration or
      ingestion of tricresyl phosphate and jet engine oil containing tricresyl
      phosphate.
AB  - Neurotoxicity of tricresyl phosphates (TCPs) and jet engine oil (JEO) containing
      TCPs were evaluated in studies conducted in both rat and hen. Results for
      currently produced samples ("conventional" and "low-toxicity") were compared with
      published findings on older samples to identify compositional changes and relate
      those changes to neurotoxic potential. Finally, a human risk assessment for
      exposure by oral ingestion of currently produced TCPs in JEO at 3% (JEO + 3%) was
      conducted. TCPs and certain other triaryl phosphates administered as single doses
      inhibited brain neuropathy target esterase (B-NTE; neurotoxic esterase) in the
      rat and the hen (hen 3.25 times as sensitive), and both species were deemed
      acceptable for initial screening purposes. Neither rat nor hen was sensitive
      enough to detect statistically significant inhibition of B-NTE after single doses
      of IEO + 3% "conventional" TCP. Subacute administration of 2 g/kg/d of JEO + 3%
      "conventional" TCP to the hen produced B-NTE inhibition (32%), which did not
      result in organophosphorus-induced delayed neurotoxicity (OPIDN). Subchronic
      administration of JEO + 3% TCP but not JEO + 1% TCP at 2 g/kg/d produced OPIDN.
      Thus, the threshold for OPIDN was between 20 and 60 mg "conventional" TCP/kg/d in
      JEO for 10 wk. The current "conventional" TCPs used in JEO and new "low-toxicity"
      TCPs now used in some JEO are synthesized from phenolic mixtures having reduced
      levels of ortho-cresol and ortho-xylenols resulting in TCPs of very high content
      of meta- and para-substituted phenyl moieties; this change in composition results
      in lower toxicity. The "conventional" TCPs still retain enough inhibitory
      activity to produce OPIDN, largely because of the presence of ortho-xylyl
      moieties; the "low-toxicity" TCPs are largely devoid of ortho substituents and
      have extremely low potential to cause OPIDN. The TCPs produced in the 1940s and
      1950s were more than 400 times as toxic as the "low-toxicity" TCPs produced
      today. Analysis of the doses required to produce OPIDN in a subchronic hen study
      suggests that the minimum toxic dose of "conventional" TCP for producing OPIDN in
      a 70-kg person would be 280 mg/d, and for JEO containing 3% TCP, 9.4 g/d. Food
      products could be inadvertently contaminated with neat "conventional" TCP but it
      is unlikely that food such as cooking oil would be contaminated with enough JEO +
      3% TCP to cause toxicity. Further, at the dosage required for neurotoxicity, it
      would be virtually impossible for a person to receive enough JEO + 3% TCP in the
      normal workplace (or in an aircraft) to cause such toxicity. There is no record
      of a JEO formulated with the modern "conventional" TCP causing human
      neurotoxicity.

PMID- 10405187
TI  - Alteration of epithelial integrity, alkaline phosphatase activity, and
      fibronectin expression in lungs of rats exposed to ozone.
AB  - The deleterious effects of ozone (O3), an oxidant air pollutant, in the lung are
      dependent on dose and exposure duration and generally evolve with time
      postexposure. This study characterized the time sequence of epithelial injury and
      fibronectin expression in the lungs of rats exposed to O3. Bronchoalveolar lavage
      (BAL) fluid was analyzed for alkaline phosphatase and total protein as markers of
      epithelial injury and increased permeability, and fibronectin for its role in
      inflammation and lung injury. The results revealed a time-related increase in
      total protein in the BAL fluid following a 3-h exposure of rats to 1 ppm O3. The
      increased protein concentrations peaked at 12 h and then declined, but remained
      significantly higher than control at 24 h postexposure. A similar time-related
      significant increase also occurred for BAL fibronectin and alkaline phosphatase
      activity. However, the return of alkaline phosphatase levels to baseline prior to
      a comparable reduction in protein levels suggests repair of injured cells, but a
      delay in the formation of epithelial junctions that limit the transfer of serum
      proteins to air spaces. By cytochemistry, alkaline phosphatase activity was
      detected in association with lung type II epithelial cells and in BAL
      polymorphonuclear leukocytes (PMNs), but not in macrophages. While a significant
      increase in cytochemically detectable alkaline phosphatase resulted from the
      increase in PMN number following O3 exposure, mononuclear cells constituted the
      primary cell type responsible for fibronectin mRNA upregulation. While the
      cytochemical observations support the role of inflammatory cells in the injury
      process, the comparability of temporal changes in BAL protein, fibronectin, and
      alkaline phosphatase suggests a mechanistic role for fibronectin in lung injury.

PMID- 10405188
TI  - Uptake, tissue distribution, and excretion of brevetoxin 3 administered to rats
      by intratracheal instillation.
AB  - Brevetoxins are cyclic polyether neurotoxins produced by the marine
      dinoflagellate Ptychodiscus brevis. Blooms of P. brevis (red tides) are toxic to
      fish, marine mammals, and humans. Humans exposed to seaspray aerosols containing
      brevetoxins may experience respiratory tract irritation. Because a major route of
      human exposure to brevetoxins is via the respiratory tract, the objective of this
      study was to examine the toxicokinetics of brevetoxin 3 (PbTx-3) administered to
      the lung by intratracheal instillation. Twenty-one male F344/Crl BR rats, 12 wk
      of age, were administered 3H-PbTx-3 (1 microCi, 6.6 microg PbTx-3/kg) by
      intratracheal instillation. Groups of 3 rats were sacrificed at 0.5, 3, 6, 24,
      48, and 96 h after exposure, and tissues were collected. Three additional rats
      were placed in glass metabolism cages for collection of urine and feces over a 7
      d period. PbTx-3-associated activity was cleared rapidly from the lung and
      distributed throughout the body, chiefly to the carcass, intestines, and liver.
      Blood, brain, and fat contained the lowest percentages of the administered dose.
      Although a majority of the PbTx-3 was cleared rapidly from lung, liver, and
      kidneys, approximately 20% of the initial concentration present in each organ was
      retained for 7 d. Concentrations of PbTx-3 in brain and fat were low, but
      remained relatively constant over time. Approximately twice as much PbTx-3
      associated activity was excreted in feces than in urine, with the majority of
      excretion occurring within 48 h after instillation. The results of this study
      indicate that over 80% of the PbTx-3 is rapidly absorbed from the lung to the
      blood and distributed to all tissues. The tissues containing the greatest amount
      of PbTx-3-associated activity reflect the compound's site of deposition, storage
      compartment, and major route of metabolism and excretion. These results
      illustrate that brevetoxin exposure by the respiratory route results in systemic
      distribution of brevetoxin and suggest that the initial respiratory irritation
      and bronchoconstriction may only be a part of the overall toxicological
      consequences associated with brevetoxin inhalation.

PMID- 10405189
TI  - Effect of enterohepatic circulation on the pharmacokinetics of chloral hydrate
      and its metabolites in F344 rats.
AB  - Chloral hydrate (CH) is a commonly found disinfection by-product in water
      purification, a metabolite of trichloroethylene, and a sedative/hypnotic drug. CH
      and two of its reported metabolites, trichloroacetic acid (TCA) and
      dichloroacetic acid (DCA), are hepatocarcinogenic in mice. Another metabolite of
      CH, trichloroethanol (TCE), is also metabolized into TCA, and the enterohepatic
      circulation (EHC) of TCE maintains a pool of metabolite for the eventual
      production of TCA. To gain insight on the effects of EHC on the kinetics of CH
      and on the formation of TCA and DCA, dual cannulated F344 rats were infused with
      12, 48, or 192 mg/kg of CH and the blood, bile, urine, and feces were collected
      over a 48-h period. CH was cleared rapidly (>3000 ml/h/kg) and displayed biphasic
      elimination kinetics, with the first phase being elimination of the dose and the
      second phase exhibiting formation rate-limited kinetics relative to its TCE
      metabolite. The effects of EHC on metabolite kinetics were only significant at
      the highest dose, resulting in a 44% and 17% decrease in the area under the curve
      (AUC) of TCA and TCE, respectively. The renal clearance of CH, free TCE (f-TCE),
      and TCA of 2, 2.7, and 38 ml/h/kg, respectively, indicates an efficient
      reabsorption mechanism for all of these small chlorinated compounds. DCA was
      detected at only trace levels (<2 microM) as a metabolite of CH, TCA, or TCE.

PMID- 10405191
TI  - Bacterial meningitis in the newborn: a prospective study of mortality and
      morbidity.
AB  - Neonatal bacterial meningitis is a serious disease around the world, with the
      incidence changing little in the past 30 years. Group B streptococci, Escherichia
      coli, and Klebsiella pneumoniae are common causative organisms and lumbar
      puncture remains the definitive method of diagnosis. The mortality rate has
      declined in industrialized countries over the years, from almost 50% in the 1970s
      to less than 10% in 1997. However, neurological sequelae are still frequently
      observed despite major changes in treatment. Preliminary analysis of our own data
      from a prospective study of cases in the United Kingdom suggests that treatment
      with third generation cephalosporins is related to a decrease in mortality but
      not morbidity.

PMID- 10405190
TI  - Early-onset intraventricular hemorrhage in preterm neonates: incidence of
      neurodevelopmental handicap.
AB  - The neurodevelopmental outcome of very low birth weight infants experiencing
      early-onset intraventricular hemorrhage (IVH) occurring within the first 6
      postnatal hours was compared with that of their peers without early-onset IVH at
      3 years corrected age. The 440 surviving preterm infants (birth weight 600 to
      1,250 g) who had been enrolled in a multicenter, prospectively randomized,
      controlled trial evaluating the efficacy of postnatal indomethacin to prevent IVH
      were evaluated with the Stanford-Binet Intelligence Scale and neurological
      examinations at 3 years corrected age. All study infants had echoencephalography
      between 5 and 11 hours of life, and testing is reported for all children residing
      in English monolingual households at 3 years corrected age (i.e., from the
      obstetric due date). Fifty five of the 73 (75%) infants with IVH within the first
      5 to 11 hours survived to 3 years of age, compared with 385 of the 432 (89%)
      children without early-onset hemorrhage who were alive at 3 years corrected age
      (P<.001). Eleven of the 29 (38%) English monolingual children with early-onset
      IVH had Stanford-Binet intelligence quotient scores of less than 70, compared
      with 47 of the 249 (19%) children without early IVH (P = .03). Similarly, 7 of 28
      (25%) early IVH children were found to have cerebral palsy, compared with 20 of
      241 (8%) children without early IVH (P = .01). These data suggest that infants
      who experience the early onset of IVH are at high risk for both cognitive and
      motor handicaps at 3 years corrected age.

PMID- 10405192
TI  - An international network for evaluating neuroprotective therapy after severe
      birth asphyxia.
AB  - Animal studies have shown great promise in their applicability to potentially
      neuroprotective therapies for severe birth asphyxia in human babies. It is now
      necessary to consider a strategy to evaluate some or all of these techniques
      within the context of human neonatal randomized control trials (RCT). We have set
      up a pilot study for an international RCT of mature babies with severe asphyxia
      (defined by an Apgar score of 5 or less at 10 minutes) and have shown that we can
      recruit from 120 centers in 17 countries an average of three babies a week, which
      is the required number to undertake a study over a 2-year period with sufficient
      power to show a significant improvement in outcome. Particular attention must be
      given in future studies to the size of improvement in outcome required,
      generalizability of entry criteria, and the appropriate measure of functional
      outcome in treated babies.

PMID- 10405193
TI  - End-of-life decisions in neonates.
AB  - In a large percentage of the infants who die in the neonatal intensive care
      setting, an end-of-life decision was made before death, usually a decision to
      forego life-sustaining treatment. This was confirmed in a recent study in The
      Netherlands that showed also that a minority of cases include the administration
      of drugs to hasten death, usually in patients with severe congenital multiple or
      central nervous system anomalies. Over 80% of Dutch pediatricians support this
      option under certain conditions. Almost all pediatricians are of the opinion that
      these cases have to be subject to public review, but they favor review by a
      committee of independent medical, judicial, and ethical professionals rather than
      by the public prosecutor. A discussion group on this subject recently made a
      proposal for such a reviewing procedure to the Dutch governmental authorities and
      described the requirements concerning end-of-life decisions in neonatal medicine.
      Proper handling of ethical aspects of medical treatment including review and
      feedback after end-of-life decisions can contribute to high standards of quality
      of care.

PMID- 10405194
TI  - Protective function of human milk: the milk fat globule.
AB  - Human milk contains many components that protect the newborn against infection at
      a time when the infant's own defense mechanisms are poorly developed. Fat is one
      of the major nutrients in human milk. The fat is contained within milk fat
      globules composed of a core of triglyceride and a membrane consisting of
      phospholipids, cholesterol, proteins, and glycoproteins. Both the membrane and
      the core components can provide protection against microorganisms. The major
      protective membrane glycoproteins, mucin, and lactadherin are resistant to
      conditions in the newborn's stomach and maintain their structure and function
      even at low pH and in the presence of the proteolytic enzyme pepsin. The core
      triglycerides upon hydrolysis by digestive lipases (especially gastric lipase,
      which is well developed in the newborn) produce free fatty acids and
      monoglycerides, amphiphylic substances able to lyse enveloped viruses, bacteria,
      and protozoa. Therefore, in addition to its nutritional value, the fat in human
      milk has a major protective function.

PMID- 10405195
TI  - Deregulation of cyclooxygenase and nitric oxide synthase gene expression in the
      inflammatory cascade triggered by experimental group B streptococcal meningitis
      in the newborn brain and cerebral microvessels.
AB  - Group B Streptococcus (GBS) is the most common cause of neonatal sepsis and
      meningitis. Despite antibiotics, GBS in the newborn initiates a cascade of
      molecular and biological events leading to altered cerebral perfusion, blood
      brain barrier disruption, cerebral edema, intracranial hypertension, neurological
      damage, and even death. Having previously shown that GBS infection impairs
      cerebral blood flow autoregulation and increases prostaglandin (PG) levels, we
      examined the regulation of some crucial inflammatory mediators (PGs, nitric oxide
      (NO), tumor necrosis factor-a) in the brain and cerebral microvessels (MVs) from
      newborn piglets. Cyclooxygenase (COX), the key enzyme in PG biosynthesis, exists
      in two isoforms, COX-1 and COX-2. Both may be directly induced by NO in a model
      of renal inflammation. Besides its neurotransmitter role, NO is a potent
      vasorelaxant whose production is catalyzed by at least three distinct nitric
      oxide synthases (NOS) (bNOS, ecNOS, iNOS). Western blot analyses showed that the
      newborn (4 day old) brain expressed lower levels of COX-1 (8-fold), COX-2 (20
      fold), bNOS (12-fold), and ecNOS (5-fold) than in the 1 day old. MV showed
      approximately equal levels of COX-2, lower levels of COX-1 (4-fold), bNOS (5
      fold), and higher levels of ecNOS (20-fold) in comparison to 4-day-old cerebral
      MV. A 4-day-old brain expressed lower levels of bNOS (5-fold), ecNOS (10-fold),
      and COX-1 (2-fold) than the 6-week-old pig. COX-2 protein was undetected in a 4
      day-old pig brain, but present in great excess in MV. Purified MV showed lower
      ecNOS (14-fold), COX-1 (2-fold), and about equal levels of bNOS and COX-2 in
      comparison with MV from 6-week-old pigs. Reverse transcription polymerase chain
      reaction analyses confirmed these results. Treatment with noo-nitro-L-arginine
      (LNA), a NOS inhibitor, downregulated COX-1 expression in the newborn brain and
      both COX-1 and COX-2 cerebral MV expression. GBS infection (10(9) colony-forming
      units, 0.5 mL intracerebroventricular) of sedated newborn piglets induced the
      expression of tumor necrosis factor-alpha in the cerebrospinal fluid after 2
      hours, upregulated bNOS expression in both brain and MVs, upregulated ecNOS in
      MVs, and downregulated COX-1, COX-2, and ecNOS in the brain. GBS did not trigger
      the expression of iNOS. Our data suggest that there is a net deficiency of NOS
      isoforms in the immature brain and microvasculature of the 4-day-old piglet and
      that the differences in expression lead to the immature control of NO and PG
      production, rendering newborns particularly susceptible to neurological damage
      because of the undeveloped nature of their response mechanisms. Moreover, the GBS
      induced cascade deregulates the gene expression of interacting inflammatory
      mediators and may cause a net vasoconstrictor/vasodilator imbalance, leading to
      cerebral hypertension and edema in the early stages of infection. Pharmacological
      manipulations of the inflammatory cascade could lead to novel therapeutic
      approaches for the treatment of GBS meningitis.

PMID- 10405196
TI  - Distribution of the sodium/phosphate transporter during postnatal ontogeny of the
      rat kidney.
AB  - Renal phosphate reabsorption via the type II sodium/ phosphate cotransporter
      (NaPi-2) in the brush border membrane (BBM) of proximal tubules underlies
      alterations during aging. The ontogeny of NaPi-2 in kidneys from newborn to 6-wk
      old rats was investigated. NaPi-2 protein distribution in the kidneys of
      neonatal, 13-d-old, 22-d-old, and 6-wk-old rats was immunohistochemically
      analyzed, and NaPi-2 mRNA distribution in neonatal and 6-wk-old rats was analyzed
      by in situ hybridization. In kidneys of newborn rats, the appearance of NaPi-2
      protein and mRNA coincided with the development of the brush border (assessed by
      actin staining) on proximal tubular cells. NaPi-2 was not detectable in the
      nephrogenic zone or in the outgrowing straight sections of proximal tubules,
      which lack a brush border. In 13-d-old suckling rats, strong NaPi-2 staining was
      seen in the BBM of convoluted proximal tubules of all nephron generations. In
      contrast, in 22-d-old weaned rats, NaPi-2 staining in the BBM of superficial
      nephrons was weaker than that in the BBM of juxtamedullary nephrons. Western
      blotting demonstrated that the overall abundance of NaPi-2 protein in the BBM of
      22-d-old rats was decreased to approximately 70% of that in 13-d-old rats. In
      kidneys of 6-wk-old rats, the internephron gradient for NaPi-2 abundance in the
      BBM corresponded to that in adult rats. The data suggest that the NaPi-2 system
      in the kidney is fully functional and possesses the capacity for regulation as
      soon as nephrogenesis is completed. The manifestation of NaPi-2 internephron
      heterogeneity immediately after weaning might be related to the change in dietary
      inorganic phosphate content.

PMID- 10405197
TI  - Urinary excretion of aquaporin-2 in rat is mediated by a vasopressin-dependent
      apical pathway.
AB  - Clinical studies have shown that aquaporin-2 (AQP2), the vasopressin-regulated
      water channel, is excreted in the urine, and that the excretion increases in
      response to vasopressin. However, the cellular mechanisms involved in AQP2
      excretion are unknown, and it is unknown whether the excretion correlates with
      AQP2 levels in kidney or levels in the apical plasma membrane. The present study
      was undertaken to clarify these issues. Immunoblotting of rat urine samples
      revealed significant excretion of AQP2, whereas AQP3, being a basolateral
      aquaporin in the same cells, was undetectable. Thus, there was a nonproportional
      excretion of AQP2 and AQP3 (compared with kidney levels), indicating that AQP2 is
      excreted predominantly via a selective apical pathway and not by whole cell
      shedding. Urinary AQP2 was associated with small vesicles, membrane fragments,
      and multivesicular bodies as determined by immunoelectron microscopy and negative
      staining techniques. In rats with normal water supply, daily urinary excretion of
      AQP2 was 3.9+/-0.9% (n = 6) of total kidney expression. Treatment with
      desmopressin acetate subcutaneously caused a fourfold increase in urinary
      excretion of AQP2 during 8 h. Forty-eight hours of thirsting, known to increase
      endogenous vasopressin secretion, resulted in a three-fold increase in kidney
      AQP2 levels but urinary excretion increased ninefold to 15+/-3% (n = 6) of AQP2
      in kidney of thirsted rats. Moreover, rats that were thirsted for 48 h and
      subsequently allowed free access to water for 24 h produced a decrease in urinary
      AQP2 excretion to 38+/-15% (n = 6) of that during thirsting. In Brattleboro rats
      or lithium-treated normal rats completely lacking vasopressin action, and hence
      having extremely low levels of AQP2 in the apical plasma membrane, AQP2 was
      undetectable in urine. Thus, conditions with known altered vasopressin levels and
      altered levels of AQP2 in the apical plasma membrane were associated with
      corresponding major changes in AQP2 urine excretion. In contrast, in such
      conditions, kidney AQP2 levels and urinary AQP2 excretion did not show a
      proportional relationship.

PMID- 10405198
TI  - Chronic effects of lovastatin and bezafibrate on cortical and medullary
      hemodynamics in deoxycorticosterone acetate-salt hypertensive mice.
AB  - Cholesterol synthesis inhibitors and fibrates both exercise effects that could
      influence BP and renal function in hypertension. To test this issue, transit-time
      ultrasound flow probes, implanted optical fibers, and laser-Doppler flowmetry
      were used for measurements of total and regional renal blood flows in lovastatin
      (40 mg/kg body wt) and bezafibrate (50 mg/kg body wt) chronically treated
      deoxycorticosterone acetate (DOCA)-salt hypertensive mice. Total renal blood flow
      was well autoregulated between 70 and 150 mmHg (approximately 3.5 ml/min per g
      kidney weight in DOCA-salt mice). Both lovastatin and bezafibrate increased renal
      blood flow to a range between 4.7 and 5.5 ml/min per g kidney weight. In the
      renal perfusion pressure ranges investigated, renal vascular resistance increased
      in lovastin- and bezafibrate-treated DOCA-salt mice, but not as steeply as in
      vehicle-treated DOCA-salt mice. During a stepwise increase in renal perfusion
      pressure in lovastatin-treated DOCA-salt mice, medullary blood flow increased up
      to 130% of baseline values, which was not seen in vehicle- or bezafibrate-treated
      mice. After extracellular volume expansion with 1% saline, 1 ml over 1 min, total
      renal blood flow was also higher in lovastatin- or bezafibrate-treated DOCA-salt
      mice, whereas medullary blood flow increased more steeply in lovastatin-,
      compared with bezafibrate- or vehicle-treated mice. Systemic BP was significantly
      decreased in lovastatin-treated DOCA-salt mice compared with vehicle-treated
      mice. Lovastatin prevented histologic evidence for hemostasis in the medullary
      circulation of DOCA-salt mice. The results suggest that both lovastatin and
      bezafibrate diminished DOCA-salt-induced reductions in total renal blood flow.
      Lovastatin also abolished the perturbed medullary blood flow reactions to
      increased perfusion pressure or to volume expansion. Finally, lovastatin
      decreased systemic BP in DOCA-salt mice. These data suggest that cholesterol
      synthesis inhibition or fibrate treatment improve disturbed renal function in a
      mouse model of salt-dependent hypertension.

PMID- 10405199
TI  - Differential effects of endothelin-1 antagonists on erythropoietin-induced
      hypertension in renal failure.
AB  - Recently, it was reported that blood vessel immunoreactive endothelin-1 (irET-1)
      content is increased in hypertensive uremic rats treated with recombinant human
      erythropoietin (rhEPO). The present study was designed to evaluate whether ET-1
      receptor blockade can prevent the progression of hypertension in renal failure
      rats receiving rhEPO and, if so, whether selective ET(A) and nonselective
      ET(A)/ET(B) receptor antagonists are equally effective. Renal failure was induced
      by a two-stage 5/6 nephrectomy; the animals developed uremia, anemia, and
      hypertension. After a 4-wk stabilization period, the animals received either
      rhEPO (100 U/kg, subcutaneously, three times per week) or the vehicle for 4 wk.
      In protocol A, half of the rats in each group were simultaneously treated with
      the ET(A)/ET(B) receptor antagonist bosentan (100 mg/kg per d). In protocol B,
      half of the rats in each group received the selective ET(A) receptor antagonist
      LU 135252 (50 mg/kg per d). Systolic BP was recorded before and at 2 and 4 wk
      after the onset of treatment. Serum creatinine levels and hematocrit were
      measured before treatment and at the end of the study. Creatinine clearance rates
      and plasma irET-1 concentrations were determined at the end of the study. rhEPO
      corrected the anemia, but aggravated the hypertension. There was a slight and
      similar increase in serum creatinine throughout the treatment period in all
      groups of rats. Both ET-1 receptor antagonists bosentan and LU135252 were
      effective in attenuating the progression of hypertension in uremic rats receiving
      the vehicle (P < 0.05). Treatment with LU135252 corrected the increase in BP in
      rhEPO-treated rats (160+/-7 mmHg versus 187+/-9 mmHg, P < 0.05). In contrast,
      bosentan did not attenuate the progression of hypertension in rhEPO-treated rats
      (172+/-10 mmHg versus 168+/-9 mmHg, NS). In summary, selective ET(A) but not
      ET(A)/ET(B) receptor blockade can prevent the aggravation of hypertension in
      renal failure rats treated with rhEPO. These results suggest that the endothelin
      system may be involved in the pathogenesis of rhEPO-induced hypertension in
      uremic rats with a differential role for ET(A) and ET(B) receptors.

PMID- 10405200
TI  - Converting enzyme inhibition and the glomerular hemodynamic response to glycine
      in diabetic rats.
AB  - GFR normally increases during glycine infusion. This response is absent in humans
      and rats with established diabetes mellitus. In diabetic patients, angiotensin
      converting enzyme inhibition (ACEI) restores the effect of glycine on GFR. To
      ascertain the glomerular hemodynamic basis for this effect of ACEI, micropuncture
      studies were performed in male Wistar-Froemter rats after 5 to 6 wk of insulin
      treated streptozotocin diabetes. The determinants of single-nephron GFR (SNGFR)
      were assessed in each rat before and during glycine infusion. Studies were
      performed in diabetics, diabetics after 5 d of ACEI (enalapril in the drinking
      water), and weight-matched controls. Diabetic rats manifest renal hypertrophy and
      glomerular hyperfiltration but not glomerular capillary hypertension. ACEI
      reduced glomerular capillary pressure, increased glomerular ultrafiltration
      coefficient, and did not mitigate hyperfiltration. In controls, glycine increased
      SNGFR by 30% due to increased nephron plasma flow. In diabetics, glycine had no
      effect on any determinant of SNGFR. In ACEI-treated diabetics, the SNGFR response
      to glycine was indistinguishable from nondiabetics, but the effect of glycine was
      mediated by greater ultrafiltration pressure rather than by greater plasma flow.
      These findings demonstrate that: (1) The absent response to glycine in
      established diabetes does not indicate that renal functional reserve is exhausted
      by hyperfiltration; and (2) ACEI restores the GFR response to glycine in
      established diabetes, but this response is mediated by increased ultrafiltration
      pressure rather than by increased nephron plasma flow.

PMID- 10405201
TI  - Noninvasive evaluation of a novel swine model of renal artery stenosis.
AB  - Intrarenal hemodynamics and excretory function distal to renal artery stenosis
      are difficult to quantify noninvasively. In this study, a swine model of chronic
      unilateral renal artery stenosis, achieved by implantation of an intravascular
      device that leads to a gradual and progressive luminal area narrowing, was
      developed and evaluated. Bilateral cortical and medullary volumes, blood flows,
      and segmental tubular dynamics were assessed in the intact kidneys of seven pigs
      using electron-beam computerized tomography before and 1 mo after implantation of
      the device. Within 1 mo, a 66% angiographic stenosis was significantly correlated
      with a 25% increase in BP. The volume and blood flow were markedly lower in the
      stenotic compared with the contralateral kidney and cortex, while the medulla
      exhibited minimal changes. In the stenotic kidney, intratubular contrast content
      has decreased in all nephron segments, especially in the distal tubule, where it
      correlated with an increase in serum creatinine and stenosis severity. In the
      contralateral kidney, dilution of proximal tubular fluid correlated with the
      increase in BP, likely due to pressure-natriuresis. In conclusion, the swine
      model closely resembles human renovascular hypertension. In the stenotic kidney,
      the hemodynamic impairment of the cortex is dissociated from the relatively
      preserved renal medulla, and the earliest effect on excretory function is
      observed in the distal nephron, where the fall in the amount of fluid reaching
      that segment is directly proportional to the renal arterial compromise. Electron
      beam computerized tomography shows promise to noninvasively quantify, follow-up,
      and study changes in concurrent, in vivo intrarenal hemodynamics and segmental
      tubular function in renovascular hypertension.

PMID- 10405203
TI  - Effects of advanced glycation end products on cytosolic Ca2+ signaling of
      cultured human mesangial cells.
AB  - Advanced glycation end product (AGE) accumulation in a high glucose (HG)
      environment is thought to mediate some of the vascular complications of diabetes.
      Transmembrane signaling of contractile cells is generally inhibited by HG, with
      implications for systemic and target organ hemodynamics. In the kidney,
      glomerular mesangial cells grown in HG media are hyporesponsive to the effects of
      vasoconstrictor agents, possibly explaining the hyperfiltration and increased
      capillary pressure that eventually lead to diabetic glomerulopathy. To verify
      whether AGE binding to specific mesangial receptors could mediate these effects
      of HG, cultured human mesangial cells (HMC) were exposed to in vitro glycated
      bovine serum albumin (BSA) for 60 min at 37 degrees C before measurement of
      cytosolic Ca2+ ([Ca2+]i) by microfluorometric techniques in monolayers or single
      cells. AGE-BSA (2 mg/ml) reduced Ca2+ release from intracellular stores by 1
      microM angiotensin II from peak [Ca2+]i levels of 843+/-117 to 390+/-50 nM in
      monolayers and from 689+/-68 to 291+/-36 nM in individual cells (P < 0.05).
      Nonglycated BSA and BSA exposed to 250 mM glucose-6-phosphate for 30 d in the
      presence of 250 mM aminoguanidine (AMGD), an inhibitor of nonenzymatic glycation,
      had no effect on the angiotensin II-induced [Ca2+]i spike (peak 766+/-104 and
      647+/-87 nM, monolayers/ single cells, respectively, P = NS). AGE also inhibited
      store-operated Ca2+ influx through plasma membrane channels, assessed by addition
      of 1 to 10 mM extracellular Ca2+ to cells previously held in Ca2(+)-free media
      (control 339+/- 46/593 +/- 51, +AGE-BSA 236 +/- 25/390 +/- 56, +AMGD 483+/-55/
      374+/-64 nM [Ca2+]i, monolayers/single cells at 10 mM Ca2+, respectively; +AGE
      BSA, P < 0.05 versus control). Contrary to HG, AGE-BSA did not translocate
      protein kinase C isoforms alpha, zeta, and delta to the plasma membrane. Culture
      of HMC in HG supplemented with 1 mM AMGD prevented downregulation of [Ca2+]i
      signaling. These data suggest that glycated macromolecules or matrix components
      may inhibit transmembrane Ca2+ signaling of glomerular cells through binding to a
      specific AGE receptor, thus mediating some of the known functional effects of HG
      on the kidney.

PMID- 10405202
TI  - Transcriptional regulation of the interleukin-6 gene in mesangial cells.
AB  - Cytokine secretion by mesangial cells (MC) plays a major role in the pathogenesis
      of glomerulonephritis. To define signaling events that occur during the
      activation of MC, the cell-specific transcriptional regulation of the interleukin
      6 (IL-6) gene was studied. Stimulation with lipopolysaccharide and IL-1beta
      resulted in the full induction of IL-6 expression only if the cells were
      coincubated with cAMP agonists; this effect was attenuated by protein kinase A
      inhibitors. In reporter gene experiments, the IL-6 promoter showed a stimulation
      pattern comparable to that of the endogenous gene. Elimination of individual
      transcription factor binding sites provided evidence for functional roles for
      four cis-acting elements, i.e., activator protein-1, cAMP response element
      binding protein (CREB), nuclear factor for IL-6 expression (NF-IL6), and nuclear
      factor-kappaB (NF-kappaB). Electrophoretic mobility shift assays using nuclear
      extracts from MC revealed that the DNA-binding activities of activator protein-1
      and NF-KB were inducible, whereas no change could be observed for CREB and NF
      IL6. The presence of several transcription factor proteins, including JunB, JunD,
      c-Fos, Fra-1, CREB-1, activating transcription factor-2, NF-KB p50, p52, and p65,
      and CAAT/enhancer-binding protein-delta, was demonstrated by supershift analysis.
      Of particular interest was the novel finding of the participation of NF-kappaB
      p65 in the NF-IL6 complex. In summary, a signal transduction pathway in MC that
      requires protein kinase A activation in addition to a second signal provided by
      lipopolysaccharide or IL-1beta was identified.

PMID- 10405204
TI  - Activation of mitogenic pathways by albumin in kidney proximal tubule epithelial
      cells: implications for the pathophysiology of proteinuric states.
AB  - Albumin is filtered into the proximal tubule in large quantities in nephrotic
      states. It has been proposed that this protein may have a toxic effect on tubular
      epithelial cells and may be responsible for the initiation of interstitial
      inflammation and scarring. The mitogenic effect of recombinant human albumin in
      wild-type opossum kidney cells and in similar cells transfected with a dominant
      negative p85 subunit (deltap85) of phopshatidylinositide 3-kinase (PI 3-kinase)
      has been studied. This study demonstrates that recombinant human albumin
      stimulates proliferation of opossum kidney cells in culture. This effect is
      mediated via PI 3-kinase, and is inhibited by wortmannin and deltap85 expression.
      Albumin stimulates PI 3-kinase activity in opossum kidney cells as determined by
      three different experimental procedures. Recombinant albumin also stimulates
      pp70(s6) kinase activity in a kinase cascade downstream of PI 3-kinase. Activity
      of pp70(s6) kinase is essential for albumin-induced proliferation of opossum
      kidney cells. It is proposed that this mitogenic pathway may have a critical role
      in proximal tubular homeostasis and pathophysiology of proteinuric states.

PMID- 10405205
TI  - Mast cells in rapidly progressive glomerulonephritis.
AB  - The role of mast cells (MC) in tubulointerstitial damage in glomerulonephritis
      (GN) is not fully understood. The distribution of MC was compared in renal
      biopsies from 50 patients with different stages of rapidly progressive GN (RPGN)
      and in 20 control samples. The immunoreactivity of renal MC with anti-tryptase
      and anti-chymase antibodies was studied. Interstitial myofibroblasts were stained
      with anti-alpha-smooth muscle actin (alpha-SMA) antibody, and inflammatory cells
      were identified by anti-CD3, -CD20, and -CD68 monoclonal antibodies. Positively
      stained cells were counted, and the relative interstitial and fractional areas of
      anti-alpha-SMA-stained cells were measured. MC were rarely found in control
      samples. In contrast, samples showing crescentic GN contained numerous tryptase
      positive MC (MC(T)) (43.7+/-4.65 versus 7.14+/-1.3/mm2) and fewer tryptase- and
      chymase-positive MC (MC(TC)) (13.8+/-1.86 versus 1.89+/-0.86/mm2) in the renal
      interstitium but never in the glomerulus. Double immunostaining demonstrated the
      presence of both phenotypes of MC. Accumulation of MC was significantly
      correlated with the numbers of T lymphocytes (MC(T), r = 0.67) and interstitial
      macrophages (MC(T), r = 0.455). There was also a significant correlation between
      the number of MC(T) and the relative interstitial area. The number of MC(TC) was
      well correlated with the fractional area of alpha-SMA-positive interstitium (r =
      0.749) and the percentage of the interstitial fibrotic area (r = 0.598). There
      was also a significant negative correlation between interstitial MC(TC)
      accumulation and creatinine clearance (r = 0.661). The density of MC(TC) was
      higher (1.4-fold) in advanced forms of GN associated with fibrocellular crescents
      and interstitial fibrosis. These results show the potential involvement of MC in
      the fibroproliferative process in the renal interstitium of patients with RPGN.
      The results indicate that these cells constitute part of the overall inflammatory
      cell accumulation in RPGN.

PMID- 10405207
TI  - Thrombin stimulates synthesis of type IV collagen and tissue inhibitor of
      metalloproteinases-1 by cultured human mesangial cells.
AB  - Glomerular accumulation of extracellular matrix (ECM) is the common pathologic
      feature following glomerular injury, and the alteration in the synthesis and
      degradation of ECM may be involved in the glomerular accumulation of ECM.
      Glomerular fibrin formation occurs in various forms of human and experimental
      glomerulonephritis, and it may play an important role in progressive glomerular
      injury. Thrombin, a multifunctional serine proteinase that is generated at the
      site of vascular injury, has central functions in hemostasis and it also shows
      various biologic effects. In this study, it is hypothesized that thrombin may
      alter the production and the degradation of type IV collagen, which is an
      important component of ECM in the glomeruli. Human mesangial cells (HMC) were
      cultured, and the levels of type IV collagen, tissue inhibitor of
      metalloproteinase-1 (TIMP-1), and matrix metalloproteinase-2 (MMP-2) in the
      culture supernatants were measured by enzyme immunoassay using specific
      antibodies. MMP-2 activity was also evaluated by zymography using polyacrylamide/
      sodium dodecyl sulfate gel-containing gelatin. Thrombin increased the production
      of type IV collagen and TIMP-1 in a dose-and time-dependent manner, but it did
      not increase MMP-2. Thrombin also stimulated the gene expressions of the type IV
      collagen and TIMP-1 in HMC in a dose- and time-dependent manner. Thrombin treated
      with diisopropylfluorophosphate, a serine proteinase inhibitor, did not show any
      of these effects. Hirudin, a natural thrombin inhibitor, and anti-transforming
      growth factor-beta-neutralizing antibody inhibited the stimulating effect of
      thrombin. These findings suggest that thrombin may contribute to the excessive
      accumulation of ECM and progression of glomerulosclerosis through an increase of
      type IV collagen production and a decreased matrix degradation presumably via a
      transforming growth factor-beta-dependent mechanism.

PMID- 10405206
TI  - In vitro neutrophil activation by antibodies to proteinase 3 and myeloperoxidase
      from patients with crescentic glomerulonephritis.
AB  - Previously, it was found that patients with necrotizing crescentic
      glomerulonephritis (NCGN) and anti-neutrophil cytoplasmic autoantibodies (ANCA)
      directed against proteinase 3 (anti-PR3) had a faster deterioration of renal
      function and more active renal vasculitic lesions than patients with ANCA
      directed against myeloperoxidase (anti-MPO). Because ANCA-mediated neutrophil
      activation is thought to play an important role in the pathophysiology of this
      form of glomerulonephritis, this study was conducted to determine whether anti
      PR3 are capable of inducing a more pronounced activation of neutrophils in vitro
      than anti-MPO. To test this hypothesis, the release of reactive oxygen radicals,
      as assessed by ferricytochrome c reduction and by dihydrorhodamine 123 oxidation,
      and the release of granule constituents from healthy donor neutrophils upon
      stimulation with IgG fractions were measured from 17 anti-PR3- and 14 anti-MPO
      positive patients with active NCGN. Patients with anti-PR3 had a higher renal
      activity index (P < 0.05) compared with patients with anti-MPO. IgG fractions
      from anti-PR3-positive patients induced more oxygen radical release from tumor
      necrosis factor-alpha-primed neutrophils compared with IgG fractions from anti
      MPO-positive patients, as assessed by ferricytochrome c reduction (P < 0.05) and
      dihydrorhodamine 123 oxidation (P < 0.01). In addition, IgG fractions from anti
      PR3-positive patients generated more neutrophil degranulation of beta
      glucuronidase (P < 0.01) than IgG fractions from anti-MPO-positive patients. In
      conclusion, IgG fractions from anti-PR3-positive patients with NCGN are more
      potent activators of the respiratory burst and degranulation in vitro than IgG
      fractions from anti-MPO-positive patients. These observations may be relevant in
      view of the clinical differences between anti-PR3- and anti-MPO-positive patients
      with NCGN.

PMID- 10405208
TI  - Somatic PKD2 mutations in individual kidney and liver cysts support a "two-hit"
      model of cystogenesis in type 2 autosomal dominant polycystic kidney disease.
AB  - An intriguing feature of autosomal dominant polycystic kidney disease (ADPKD) is
      the focal and sporadic formation of renal and extrarenal cysts. Recent
      documentation of somatic PKD1 mutations in cystic epithelia of patients with germ
      line PKD1 mutations suggests a "two-hit" model for cystogenesis in type 1 ADPKD.
      This study tests whether the same mechanism for cystogenesis might also occur in
      type 2 ADPKD. Genomic DNA was obtained from 54 kidney and liver cysts from three
      patients with known germ-line PKD2 mutations, using procedures that minimize
      contamination of cells from noncystic tissue. Using intragenic and microsatellite
      markers, these cyst samples were screened for loss of heterozygosity. The same
      samples were also screened for somatic mutations in five of the 15 exons in PKD2
      by single-stranded conformational polymorphism analysis. Loss of heterozygosity
      was found in five cysts, and unique intragenic mutations were found in seven
      other cysts. In 11 of these 12 cysts, it was also determined that the somatic
      mutation occurred nonrandomly in the copy of PKD2 inherited from the unaffected
      parent. These findings support the "two-hit" model as a unified mechanism for
      cystogenesis in ADPKD. In this model, the requirement of a somatic mutation as
      the rate-limiting step for individual cyst formation has potential therapeutic
      implications.

PMID- 10405209
TI  - Pronatriodilatin gene polymorphisms, microvascular permeability, and diabetic
      nephropathy in type 1 diabetes mellitus.
AB  - Approximately 30% of diabetic patients develop nephropathy, the appearance of
      which is partially under genetic control. Atrial natriuretic peptide (ANP) has
      associated physiologic effects on the kidney. This study was conducted to examine
      the relationship between a newly identified and known polymorphism at the
      pronatriodilatin (PND) gene locus and renal involvement in type 1 diabetic
      subjects. Of 454 type 1 diabetic patients (219 men, 235 women), 323 showed no
      sign of nephropathy, 79 had incipient renal involvement, and 52 established
      nephropathy; 58 healthy control subjects were examined for comparison. Allele
      frequencies (C708 versus T708) were: 0.95 and 0.05 in normoalbuminuric patients,
      respectively; 0.88 and 0.12 in microalbuminuric patients; 0.96 and 0.04 both in
      those with overt nephropathy and in healthy control subjects (P = 0.011).
      Patients with incipient nephropathy were in disequilibrium compared with the
      total diabetic cohort (P = 0.02). In the same populations, an additional genotype
      for ScaI polymorphism of the PND gene was tested. The A1 and A2 allele
      frequencies were: 0.21 and 0.79 in normoalbuminuric patients; 0. 13 and 0.87 in
      microalbuminuric patients; 0.06 and 0.94 in type 1 diabetic subjects with overt
      nephropathy; and 0.20 and 0.80 in healthy control subjects, respectively (P <
      0.0001). A subset of 55 normotensive patients with type 1 diabetes, well matched
      for clinical features, plasma ANP levels, and microvascular permeability to
      macromolecules, was investigated on the basis of the C708/T and A2/A1
      polymorphisms. Both transcapillary escape rate of albumin (TERalb) and plasma ANP
      levels were significantly lower in patients with the T708 than with C708 allele,
      as well as in the A1 than in A2 allele (TERalb: T708 versus C708: 5.5+/-1.7
      versus 7.8+/-2.0%/h, P = 0.0001; plasma ANP levels: 8.3+/-3.9 versus 15.3+/-7.7
      pg/ml, P = 0.0003; A1 versus A2: 6.05+/-2.2 versus 7.3+/-2.1%/h, P = 0.044;
      8.53+/-4.6 versus 14.5+/-7.4 pg/ml, P = 0.0024, respectively). Thus, in a large
      ethnically homogeneous cohort of diabetic subjects, our data show: (1) a
      significant association of C708/T polymorphism with microalbuminuria in long-term
      diabetes and with both lower plasma ANP levels and widespread albumin leakage;
      and (2) a strong association between ScaI polymorphism and both diabetic
      nephropathy and plasma ANP concentrations. These results suggest a possible role
      of PND gene in conferring protection from nephropathy and microvascular damage in
      type 1 diabetes.

PMID- 10405210
TI  - Combining an antiproteinuric approach with mycophenolate mofetil fully suppresses
      progressive nephropathy of experimental animals.
AB  - Chronic renal diseases progress to organ insufficiency, which may require
      replacement therapy within one to three decades even independently of the type of
      initial insults. In the majority of cases, the degrees of proteinuria and
      interstitial leukocyte infiltration and scarring are strictly correlated with the
      rate of disease progression. This study tests the hypothesis that excess
      intrarenal protein traffic may cause lymphocyte-dependent interstitial injury
      that, while not fully controlled by antiproteinuric therapy, can be further
      inhibited by concomitant immunosuppression. A primarily nonimmune model was used
      to reproduce progressive renal disease due to a critical loss of nephron mass.
      Angiotensin-converting enzyme (ACE) inhibitor limited proteinuria, interstitial
      inflammation, MHC class II antigen expression, and severe lesions. Combined
      treatment with ACE inhibitor and a specific antilymphocyte agent, mycophenolate
      mofetil, dramatically attenuated macrophage and T cell infiltration, MHC-class II
      overexpression, dendritic cells, and all manifestations of the disease. Evidence
      of lymphocyte-mediated renal injury in the setting of excess protein traffic
      provides the basis for combining ACE inhibition and immunosuppression to halt
      progression of proteinuric kidney disease and minimize the need for dialysis or
      transplantation.

PMID- 10405211
TI  - Postnatal time frame for renal vulnerability to enalapril in rats.
AB  - Angiotensin-converting enzyme inhibition or angiotensin II type 1 receptor
      blockade in neonatal, but not in weaned, rats induces irreversible renal
      histologic abnormalities and an impaired urinary concentrating ability. The aim
      of the present study was to define the postnatal time frame when the rat kidney
      is vulnerable to an interruption of the renin-angiotensin system. Male Wistar
      rats received daily injections of enalapril (10 mg/kg, intraperitoneally) during
      different age intervals within 3 to 24 d,of age. Fluid handling and urinary
      concentrating ability, renal function under pentobarbital anesthesia, and kidney
      histology using stereologic techniques were evaluated in adult rats. Enalapril
      treatment within 3 to 13 d after birth induced abnormalities in renal function
      and morphology long-term, whereas treatment initiated at 14 d of age did not. The
      main histologic alterations were papillary atrophy, and a reduction in the volume
      of tubular epithelial cells in association with an increase in the proportion of
      interstitium, throughout the cortex and outer medulla. Functionally, the
      predominant defect was an impairment in urinary concentrating ability, which
      correlated with the degree of papillary atrophy. In conclusion, the vulnerable
      age interval for the induction of irreversible renal abnormalities by enalapril
      was the first 13 d after birth in the rat. This postnatal time span coincides
      with the completion of nephrogenesis and a period of marked tubular growth and
      differentiation, suggesting a pivotal role for angiotensin II in these processes.

PMID- 10405212
TI  - The dynamics of glomerular filtration after Caesarean section.
AB  - The objective of this study was to determine whether the glomerular
      hyperfiltration of pregnancy is maintained even after Caesarean section and, if
      so, to define the responsible hemodynamics. The dynamics of glomerular filtration
      were evaluated in 12 healthy women who had just completed an uncomplicated
      pregnancy and were delivered by Caesarean section. Age-matched but non-gravid
      female volunteers (n = 22) served as control subjects. GFR in postpartum women
      was elevated above control values by 41%; 149+/-10 versus 106+/-3 ml/min per 1.73
      m2, respectively (P < 0.001). In contrast, corresponding renal plasma flow was
      the same in the two groups, such that the postpartum filtration fraction was
      significantly elevated by 20%. Computation of glomerular intracapillary oncotic
      pressure (piGC) from knowledge of plasma oncotic pressure and the filtration
      fraction revealed this quantity to be significantly reduced in postpartum women,
      20.6+/-1.7 versus 26.1+/-2.0 mmHg in control subjects (P < 0.001). A theoretical
      analysis of glomerular ultrafiltration suggests that depression of piGC, the
      force opposing the formation of filtrate, is predominantly or uniquely
      responsible for the observed postpartum hyperfiltration.

PMID- 10405213
TI  - Hepatitis C virus-associated glomerular disease in patients with human
      immunodeficiency virus coinfection.
AB  - Chronic infection with hepatitis C virus (HCV) has been linked to the development
      of glomerular disease. HCV infection is highly prevalent among intravenous drug
      users, a population that is also at risk for HIV coinfection. This study reports
      the clinical-pathologic features and outcome of HCV-associated glomerular disease
      (HCV-GD) in 14 patients with HIV coinfection. All were intravenous drug users and
      all but one were African-Americans. Renal presentations included renal
      insufficiency, microscopic hematuria with active urine sediment, hypertension,
      and nephrotic syndrome or nephrotic-range proteinuria without
      hypercholesterolemia. Hypocomplementemia and cryoglobulinemia were present in 46
      and 33% of patients, respectively. The predominant renal biopsy findings were
      membranoproliferative glomerulonephritis type 1 or type 3 (Burkholder subtype) in
      79% of patients and membranous glomerulopathy with atypical features in 21%
      (including overlap with collapsing glomerulopathy in one patient). The clinical
      course was characterized by rapid progression to renal failure requiring
      dialysis. The overall morbidity and mortality were high with median time of 5.8
      mo to dialysis or death. Although most patients died in renal failure, cause of
      death was primarily attributable to long-term immunosuppression and advanced
      AIDS. Patients with AIDS had shorter survival than those without (median survival
      time of 6.1 mo versus 45.9 mo, log-rank test P = 0.02). Only two patients were
      alive with stable renal function at follow-up of 28.5 mo. In patients with HCV
      GD, coinfection with HIV leads to an aggressive form of renal disease that can be
      easily confused with HIV-associated nephropathy. Although hypocomplementemia,
      cryoglobulinemia, and more prominent hypertension and microscopic hematuria may
      provide clues to the presence of HCV-GD, renal biopsy is essential to
      differentiate HCV-GD from HIV-associated nephropathy.

PMID- 10405214
TI  - The relation between body size and normalized small solute clearances in
      continuous ambulatory peritoneal dialysis.
AB  - The normalized peritoneal clearances of small solutes depend on the ratio of
      their concentration in dialysate and plasma (D/P) and the drain volume (Dv)
      corrected for some measure of body size such as body water (V) or body surface
      area (BSA). The clearance formulas (D/P) x (Dv/V) and (D/ P) x (Dv/BSA) can be
      used to examine why large individuals tend to be underdialyzed. Large people have
      low normalized drain volumes (Dv/V, Dv/BSA). It is not known whether size affects
      the D/P ratios. The purpose of this study was to examine the relationship between
      normalized peritoneal clearances (Kt/Vurea, CCr per 1.73 m2 BSA) and four size
      indicators (weight, height, V, BSA) in 301 patients on continuous ambulatory
      peritoneal dialysis (four daily exchanges with 2-L exchange volume) who underwent
      613 clearance studies. Highly significant (P < 0.001) nonlinear relationships
      were found between Kt/Vurea and weight (r2 = 0.371), height (r2 = 0.289), BSA (r2
      = 0.436), and V (r2 = 0.527); and between CCr and weight (r2 = 0.178), height (r2
      = 0.115), BSA (r2 = 0.199), and V (r2 = 0.151). There were also significant
      negative correlations between the normalized drain volumes (Dv/V and Dv/BSA) and
      all four indicators of body size. Raw (not normalized) peritoneal clearances and
      drain volumes correlated positively with size. However, D/P(urea) or
      D/P(creatinine) did not vary with any size indicator except for a weak
      association between D/P(creatinine) and V (r = 0.089, P = 0.028). This
      association was not confirmed when V was used to stratify subjects into
      quartiles, and group differences for D/P(creatinine were tested by one-way ANOVA.
      This study shows that the exclusive cause of the low normalized peritoneal
      clearances in large subjects on continuous ambulatory peritoneal dialysis is a
      low normalized drain volume. No evidence was found to indicate that body size
      influences the D/P ratio of small solutes. The portion of the variance in
      normalized clearance explained by size varies by size indicator and solute (urea
      versus creatinine).

PMID- 10405215
TI  - Clinical rejection is distinguished from subclinical rejection by increased
      infiltration by a population of activated macrophages.
AB  - It has been reported previously that one-third of protocol renal biopsies in
      asymptomatic, biochemically stable renal transplant recipients in the first 6 mo
      show unsuspected subclinical graft rejection (both infiltrate and tubulitis) and
      that subclinical rejection is a risk factor for chronic renal dysfunction. This
      study was performed to determine whether differences in phenotype or activation
      status of graft-infiltrating cells underlie these different manifestations of
      acute rejection. Biopsies with normal histology (n = 10), subclinical rejection
      (n = 13), and clinical rejection (n = 9) were studied using immunohistochemistry
      and computerized image analysis. Subclinical and clinical rejections had similar
      histologic Banff scores. Univariate analysis showed a trend for a higher
      infiltration with CD8+ (P = 0.053) and CD68+(P = 0.06) cells in clinical
      rejection. Of the activation markers studied (CD25, perforin, tumor necrosis
      factor-alpha), only allograft inflammatory factor-1+-activated macrophages were
      significantly (P = 0.014) increased in the infiltrate of clinical rejection
      biopsies. These data suggest that activated macrophages or their products are
      responsible for acute renal dysfunction associated with clinical rejection
      episodes.

PMID- 10405216
TI  - Apolipoprotein E2/E5 variants in lipoprotein glomerulopathy recurred in
      transplanted kidney.
AB  - Lipid abnormalities are associated with various disorders ranging from
      generalized atherosclerosis to renal diseases, including lipoprotein
      glomerulopathy that is characterized by glomerular lipoprotein thrombi and causes
      type III hyperlipoproteinemia, proteinuria, and renal failure. This study
      examines lipoprotein glomerulopathy, which recurred in a transplanted kidney.
      Molecular biologic analysis of the patient's apolipoprotein (apo) E gene
      demonstrated E2/E5 type variants. Immunohistochemical analysis of the diseased
      kidney demonstrated various lipid peroxidation-specific protein adducts,
      suggesting a potential role of oxidative stress in this disorder. Recurrence in
      the transplanted kidney suggested a pathogenic role of extraglomerular humoral
      component(s) resulting from abnormal lipoprotein metabolism, presumably linked to
      apo E and other genetic or acquired factor(s). Furthermore, the finding that the
      patient showed pathologic abnormalities in the transplanted kidney with no
      clinical signs or symptoms of renal disease indicated that lipoprotein glomerular
      damage progresses early before any clinical manifestations.

PMID- 10405218
TI  - The clinical epidemiology of cardiac disease in chronic renal failure.

PMID- 10405217
TI  - Gene targeting approaches to analyzing hypertension.
AB  - Essential hypertension probably results from combinations of small genetic
      variations that are partly normal variations and may not be appreciably harmful
      individually. Strategies to identify genes contributing to hypertension are
      discussed in this review. Gene targeting approaches, especially gene titration,
      have been used in these studies of hypertension. Gene titration experiments vary
      the expression of a chosen gene product by generating animals having different
      numbers of copies of the gene coding for the product. Gene titration is powerful
      for analyzing quantitative variations seen in common polygenic disorders, such as
      kidney diseases, diabetes mellitus, and atherosclerosis, as well as hypertension,
      because it allows tests of causation by determining the effects on a phenotype by
      changes in expression of the altered gene and because it matches normal
      quantitative variations more closely than is possible with classic transgenic
      mice. The use of zero-copy (gene "knockout") animals generated by gene disruption
      for studies of qualitative gene effects is also discussed. These various gene
      targeting experiments help identify genes regulating BP, promote a better
      understanding of the pathophysiology of the condition, and help identify
      potential targets for therapies.

PMID- 10405219
TI  - Hypomagnesemia.

PMID- 10405220
TI  - The similarity of effects of vasopressin, adenosine-3',5'-phosphate (cyclic AMP)
      and theophylline on the toad bladder. 1962.

PMID- 10405222
TI  - Endoscopic resection for early gastric cancer: possibilities and limitations.

PMID- 10405221
TI  - Epstein-Barr virus: a possible accomplice in gastric oncogenesis.

PMID- 10405223
TI  - Paraesophageal hernias: current concepts.

PMID- 10405224
TI  - Current concepts in the management of paraesophageal hiatal hernia.
AB  - Herniation of a portion of the stomach through the esophageal hiatus into the
      posterior mediastinum is a common affliction of humans. The incidence of hiatal
      hernia is difficult to determine because of the absence of symptoms in a large
      number of patients. Upper gastrointestinal barium examinations in symptomatic
      patients identify some type of hiatal hernia in as many as 15% of patients.

PMID- 10405225
TI  - Tumors of the gallbladder and bile ducts.
AB  - Gallbladder cancer is the fifth most common gastrointestinal cancer in the US
      (5,000 new cases each year). Primary bile duct cancer (cholangiocarcinoma) is
      seen most often in patients with risk factors including primary sclerosing
      cholangitis (PSC), bile duct stones, and fluke infestation. Both cancers have a
      poor prognosis, in part because they present late. Malignant tumors of the
      gallbladder and bile ducts are rarely curable by surgery. Benign tumors of the
      biliary tree are rare, and with the exception of biliary papillomatosis and
      carcinoids, are not considered premalignant.

PMID- 10405226
TI  - Wilson's disease: copper unfettered.
AB  - Wilson's disease is a rare autosomal recessive inherited disorder of copper
      metabolism. Hepatic excretion of copper is impaired due to mutation of the gene
      for a copper-transporting adenosine triphosphatase, ATP7B. Copper accumulation in
      liver, brain, and other tissues may cause a wide spectrum of hepatic,
      neuropsychiatric, and other clinical manifestations. The diagnosis may be
      supported by measurement of serum ceruloplasmin, urinary copper excretion, and
      hepatic copper content as well as by detection of Kayser-Fleischer rings. Several
      treatments are available to increase urinary excretion and decrease intestinal
      absorption of copper.

PMID- 10405227
TI  - NSAIDs, aspirin, and esophageal strictures: are over-the-counter medications
      harmful to the esophagus?
AB  - There are several studies that suggest that aspirin (acetylsalicylic acid [ASA])
      and nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with esophagitis
      or esophageal stricture formation. There are limited data on the potential of low
      dose ASA and over-the-counter (OTC) NSAIDs to cause esophageal injury. The goal
      of this study was to determine whether there is an association between esophageal
      strictures and ASA/NSAID use, including low-dose ASA and OTC NSAIDs. A total of
      79 consecutive patients (mean age, 52.8 years; 38 men, 41 women) referred for
      endoscopy from 4/1/96 to 11/15/96 for chronic gastroesophageal reflux disease
      symptoms were evaluated. Data collected include gender, race, and age, NSAID or
      ASA use, as well as an assessment of dysphagia, heartburn duration, and heartburn
      frequency. Patients taking NSAIDs or ASA at least twice a week were considered
      ASA/NSAID users. There were 46 patients without strictures and 33 patients with
      peptic strictures. Patients with strictures were older than patients without
      strictures (mean age, 58.7 versus 48.6 years; p < 0.01), had longer duration of
      heartburn symptoms (8.6 versus 6.4 years, p < 0.05), and were more likely to have
      mucosal injury (50% versus 26.1%). Stricture patients were more likely to use
      ASA/NSAIDs (63.6% versus 26.1%; p < 0.01). In particular, stricture patients were
      more likely to use low-dose ASA than patients without strictures (30.3% versus
      2.2%; p < 0.01). Otherwise, there were no significant differences with regard to
      gender, race, or heartburn duration or frequency. Linear regression analysis
      showed that ASA/NSAID use had a greater influence on the incidence of peptic
      strictures than age. There is an association between esophageal stricture and
      ASA/NSAID use, which includes OTC NSAIDs and low-dose ASA.

PMID- 10405228
TI  - Clinicopathologic study of esophageal squamous cell carcinoma confined to the
      mucosa.
AB  - The authors studied patients with esophageal squamous cell carcinoma confined to
      the mucosa (ESCM) with respect to various clinicopathologic factors to
      investigate the course of invasion of very early-stage esophageal cancers. A
      total of 74 patients with ESCM were studied. Fifty of these patients had tumor
      invasion of the basement membrane confined to the lamina propria mucosae (m2
      cancer), and 24 patients had tumor invasion of the muscularis mucosa (m3 cancer).
      All lesions were investigated with regard to clinicopathologic factors such as
      tumor differentiation, pattern of invasion, endoscopic morphology, and
      inflammatory response. The patients were divided into groups of 8 patients with
      positive lymphatic invasion, lymph node involvement, or both (Inv[+] group), and
      a group of 66 patients with no lymphatic invasion or lymph node involvement (Inv[
      ] group). The inflammatory response was evaluated on the basis of lymphocyte
      infiltration at the tumor invasion front and lymphocytic follicles beneath the
      tumor invasion front. Mean lesion size was significantly greater in the Inv(+)
      group than in the Inv(-) group (p < 0.05). However, there was no significant
      difference in the mean area of invasion of the lamina propria mucosae or deeper
      between the Inv(+) group and Inv(-) group. Patients with m2 cancer had a
      significantly higher rate of high-degree lymphocytic follicles than those with m3
      cancer (p < 0.01). In patients with m2 cancer, the mean area of invasion of the
      lamina propria mucosae in patients with high-degree lymphocytic follicles was
      significantly greater than that in patients with low-degree lymphocytic follicles
      (p < 0.05), whereas there was no significant difference in mean lesion size
      between patients with high-degree and low-degree lymphocytic follicles. In
      patients with ESCM, lesion size was an important risk factor for lymphatic
      invasion and nodal involvement, lymphocytic follicles were prominent beneath the
      front of relatively broad cancer invasion, and lymphocytic follicles were less
      common with deeper cancer invasion.

PMID- 10405229
TI  - Epstein-Barr virus-associated gastric carcinoma and atrophic gastritis.
AB  - Although Epstein-Barr virus (EBV) has been reported to be present in some 7% of
      gastric carcinomas, the nature of the background gastric mucosa of carcinoma has
      not been elucidated. The authors evaluated the degree of gastritis in the
      background gastric mucosa of EBV-associated gastric carcinoma. EBV was detected
      using in situ hybridization for EBV-encoded small ribonucleic acid 1 (EBER-1) in
      carcinoma cells. The authors compared gastritis in surgically resected stomachs
      with 8 EBER-1-positive and 16 EBER-1-negative gastric carcinomas of a similar
      histologic type using histologic variables of the Updated Sydney System. All
      eight lesions of EBER-1-positive gastric carcinomas had intestinal metaplasia in
      the background. Mild to moderate glandular atrophy was common in both groups.
      Many of the tested lesions, 87.5% of EBER-1-positive and 62.5% of EBER-1-negative
      lesions, were located near the mucosal atrophic border. The background gastric
      mucosa for EBV-associated gastric carcinomas is rich in atrophic changes. EBV
      associated gastric carcinomas are located near the mucosal atrophic border.

PMID- 10405230
TI  - Predictive factors for metachronous recurrence of early gastric cancer after
      endoscopic treatment.
AB  - Since endoscopic treatment has been evaluated and become established as treatment
      for early gastric cancer, metachronous recurrence has become a major problem. In
      this report, predictive factors for recurrence were studied using the Kaplan
      Meier method and Cox's proportional hazards regression model in 76 patients who
      received endoscopic treatment. There were 48 men and 28 women age 69.6 +/- 8.3
      years (mean +/- standard deviation), 5 of whom had synchronous multiple lesions
      and 71 who had a single lesion found during the initial endoscopic treatment. In
      all patients, periodic follow-ups were performed by endoscopy for more than 2
      years after treatment. Helicobacter pylori infection was assessed in 55 of the 76
      patients, and proved positive in 43 and negative in 12. Metachronous recurrence
      was detected significantly more frequently in patients whose synchronous multiple
      lesions were found during the initial treatment. In addition, age affected the
      recurrence positively. However, gender and H. pylori infection had no significant
      relationship with metachronous recurrence.

PMID- 10405231
TI  - Upper gastrointestinal bleeding due to gastric ulcers in children with
      gastrostomy tubes.
AB  - The authors describe four children with gastrostomy tubes (G-tubes) presenting
      with upper gastrointestinal bleeding due to gastric ulcers years after G-tube
      insertion. They review the literature and discuss the possible mechanisms of
      gastric ulcer formation in these patients.

PMID- 10405233
TI  - Pharmacokinetic interaction between acetaminophen and lansoprazole.
AB  - Because of its minimal gastric toxicity, acetaminophen is the analgesic of choice
      for patients with gastric acid-related disorders. Because proton pump inhibitors
      are widely used, concomitant prescription of acetaminophen and lansoprazole would
      be prevalent. This crossover study was conducted to investigate an acetaminophen
      lansoprazole interaction. On one occasion, each of six healthy, fasted, male
      volunteers ingested 1.0 g acetaminophen dissolved in 200 mL water. On another
      occasion, at least 1 week apart, 30 mg lansoprazole was administered orally,
      simultaneously with acetaminophen, after pretreatment with the same dose of
      lansoprazole once daily for 2 days. Plasma acetaminophen concentrations were
      measured at 0, 0.25, 0.5, 0.75, 1, 2, 3, 5, and 8 hours after dosing. The peak
      plasma concentration of acetaminophen and the time to its occurrence were
      significantly higher and shorter, respectively, during the lansoprazole session
      than during the control session. Neither the elimination half-life nor the area
      under the curve was significantly different between the two sessions.
      Lansoprazole hastens the absorption of acetaminophen solution, but little
      modifies its elimination rate and bioavailability.

PMID- 10405232
TI  - Eradication of Helicobacter pylori infection with proton pump-based triple
      therapy in patients in whom bismuth-based triple therapy failed.
AB  - To study the effects of treatment of Helicobacter pylori infection in a
      hyperendemic population, 143 infected patients from the region of Narino,
      Colombia, were treated for 2 weeks with clarithromycin (500 mg twice a day),
      amoxicillin (1 g twice a day), and either lansoprazole (30 mg twice a day) or
      omeprazole (30 mg twice a day). All patients belong to a low socioeconomic
      strata, had multifocal atrophic gastritis documented by gastric biopsies, and had
      been treated previously and unsuccessfully for 2 weeks with bismuth subsalicylate
      (262 mg four times a day), amoxicillin (500 mg three times a day), and
      metronidazole (400 mg three times a day). 13C-urea breath tests were performed 6,
      12, 24, and 60 weeks after completing therapy. The 13C-urea breath test was
      negative in 79.7% of patients 1 month after finishing therapy, and in 69.2% of
      patients 1 year after finishing treatment. There were no differences in
      eradication rates between patients treated with omeprazole versus lansoprazole.
      Dyspepsia symptoms decreased from 74% in patients at baseline to 19% at the time
      of finishing treatment. In low-socioeconomic status populations with hyperendemic
      infection, triple therapy using omeprazole or lansoprazole plus clarithromycin
      and amoxicillin is an effective alternative when previous standard bismuth-based
      triple therapy has failed.

PMID- 10405234
TI  - Sulpiride versus metoclopramide in nononcologic patients with vomiting or nausea.
AB  - Metoclopramide, a benzamide substitute, is used frequently as an antiemetic drug.
      Sulpiride, another benzamide substitute, was investigated and found to be safe
      and effective in a handful of studies involving only oncologic or other severely
      symptomatic patients. In this investigation the authors compared prospectively
      the antiemetic efficacy of sulpiride versus metoclopramide in a double-blind,
      randomized study involving 36 nononcologic patients with transient vomiting or
      nausea of various etiologies. Each group of 18 patients received oral
      metoclopramide or sulpiride (10 mg or 50 mg respectively) every 8 hours for a
      total of three doses each (24 hours of treatment). A 5-point score was used to
      evaluate symptomatic relief. Efficacy of the two drugs proved similar, and at the
      end of the study, 14 and 13 of 18 patients on sulpiride or metoclopramide
      respectively were asymptomatic. Only transient, minor side effects were reported
      in one patient in each group. The authors conclude that sulpiride is an effective
      and safe antiemetic drug that can be adopted legitimately in such cases as a
      first choice, or serve as an equipotent alternative to metoclopramide in patients
      sensitive to the latter.

PMID- 10405235
TI  - Expression of tetraspans transmembrane family in the epithelium of the
      gastrointestinal tract.
AB  - Tetraspans transmembrane family (TSTF) members, also known as tetraspanin
      superfamily, have various effects on cell proliferation, motility, and adhesion
      not only in hematopoietic cells, but also in other type of cells. However, little
      is known about their expression in the human gastrointestinal (GI) tract. The
      authors characterized immunohistologically the localization of six members of
      TSTF (CD9, CD37, CD53, CD63, CD81, and CD82) in the normal epithelium from
      esophagus to colon. CD9 and CD82 molecules were strongly expressed in all
      epithelial surface membranes, from esophagus to colon, and their staining pattern
      was quite similar. Expression of CD37 was not detectable throughout the GI tract.
      Expression of CD53 was barely detectable. Expression of CD63 was clearly detected
      distal to the stomach, including the duodenum, small intestine, and colon. On the
      contrary, expression of CD81 was detected only in the esophagus--confined to a
      few layers from the basal layer. From these data it seems likely that the
      expression of TSTF molecules might be regulated differentially depending on the
      site of the GI tract.

PMID- 10405236
TI  - Is routine cholangiography useful in men with suspected primary biliary
      cirrhosis?
AB  - The aim of this study was to assess the diagnostic value of cholangiography in
      men with chronic cholestasis and positive antimitochondrial antibody (AMA) titers
      who were suspected of having primary biliary cirrhosis (PBC). The authors
      reviewed retrospectively the records of men who had positive AMA titers over a 16
      month period to determine the results of cholangiography. They also reviewed the
      records of 102 patients with primary sclerosing cholangitis (PSC) from 1989 to
      1995 who had undergone cholangiography and testing for AMA. Of 35 men with
      positive tests for serum AMA, 12 of these patients were referred for
      cholangiography (11 endoscopic and 1 transhepatic). All completed cholangiograms
      were normal. A diagnosis of PBC was made in nine patients and atypical autoimmune
      hepatitis in one. Conversely, only two PSC patients had positive AMA titers (1:20
      and 1:80). Both of these patients had coexisting inflammatory bowel disease and
      cholangiograms diagnostic of PSC. Cholangiography was negative in the male
      patients with positive AMA titers who were suspected of having PBC. In men with
      cholestatic liver biochemistries and strongly positive AMA titers, especially in
      the absence of associated inflammatory bowel disease, routine cholangiography
      does not add to the diagnostic evaluation.

PMID- 10405237
TI  - Significance of repeatedly normal aminotransferase activities in HCV-infected
      patients.
AB  - The significance of repeatedly normal serum aminotransferase activities in
      antihepatitis C virus (anti-HCV)-positive patients is not clear. To address this
      issue, the authors analyzed clinical, virologic, histopathologic, and biological
      characteristics of such subjects. Among their active file of 1,200 anti-HCV
      positive immunocompetent patients, they identified 36 subjects (3%) with
      repeatedly normal aminotransferase activities, as defined by at least four normal
      values of aminotransferase over a minimum period of 6 months without any abnormal
      value (mean of this period, 31 +/- 21 months). The 36 patients included 11 men
      and 25 women with a mean age of 45 +/- 15 years. Twenty-three of these 36
      subjects (64%) had detectable HCV viremia by polymerase chain reaction. Their
      genotype distribution was as follows: genotype 1a or 1b, 57%; genotype 2, 26%;
      and genotype 3, 17%. Of the HCV ribonucleic acid (RNA)-positive and HCV RNA
      negative subjects, 17 and 5 had a liver biopsy respectively. In the former, the
      mean Knodell score was 5.6 +/- 3.5 (range, 1 to 14), and was < 5 in 9 patients
      (53%) and > or = 5 in 8 (47%), including extensive fibrosis (n = 2) or cirrhosis
      (n = 2). In the HCV RNA-negative subjects, one patient had a Knodell score > or =
      5. Comparing the 23 immunocompetent viremic subjects with repeatedly normal serum
      aminotransferase activities with our group (n = 564) of immunocompetent viremic
      patients with abnormal aminotransferase activities, there was a significant
      predominance of women (70% versus 44%, p < 0.05) and of genotype 2 in the former
      (26% versus 7%, p < 0.05), but no differences according to quantitative viremia,
      alcohol consumption, or distribution of risk factor were observed. Most of
      viremic HCV-infected patients with long-term and repeatedly normal
      aminotransferase values have indeed chronic active hepatitis, including extensive
      fibrosis or cirrhosis in as many as 20% of patients. This emphasizes the need for
      serum HCV RNA determination in anti-HCV-positive patients with normal
      aminotransferase activities. In these patients liver biopsy may be necessary and
      should be discussed.

PMID- 10405238
TI  - Unplanned work absence following outpatient colonoscopy.
AB  - The authors investigated the incidence of unplanned work absence the day
      following outpatient colonoscopy and examined factors associated with missing
      work. A total of 250 patients were studied. Patient demographic information, the
      length of the procedure, time of day the exam was performed, and the amount and
      type of sedation medication used was obtained at the time of the procedure. The
      incidence and reasons for missing work were elicited via a phone survey 7 days
      postprocedure. Ten patients (4%) had an unplanned work absence the day after
      their colonoscopy. No complications were noted. Feeling sleepy and weak or
      abdominal pain and bloating were the most common reasons for missing work. In
      univariate analyses, patients with an unplanned work absence were more likely to
      be younger (p = 0.009), and female (p = 0.02) compared with patients who returned
      to work. No statistically significant differences were found with regard to the
      amount of sedation medication used, the length of the procedure, or whether the
      procedure was performed in the morning or afternoon. Unplanned work absence is
      low following outpatient colonoscopy in a community-based practice. Female gender
      and younger age are associated with a higher likelihood of missing work.
      Postprocedure work absence may have a greater economic impact than procedure
      related complications.

PMID- 10405239
TI  - Normal esophageal function after myotomy in a patient with idiopathic diffuse
      esophageal spasm.
AB  - A 52-year-old man with idiopathic diffuse esophageal spasm and hypertensive lower
      esophageal sphincter presented with dysphagia for several years. After
      unsuccessful therapy with forceful pneumatic dilation of the cardia, a myotomy of
      the cardia and distal esophagus was performed. The patient became asymptomatic,
      lower esophageal sphincter pressure diminished to less than 10 mm Hg, and
      esophageal body motor activity was normalized. This situation remains unchanged 6
      years after the operation.

PMID- 10405240
TI  - CEA-producing mucin-negative gastric signet-ring cell carcinoma with
      neuroendocrine markers: a case report.
AB  - Biopsy and autopsy materials excised from a 69-year-old woman were investigated.
      Serum carcinoembryonic antigen (CEA) showed a high value of 955 ng/mL. A
      plateaulike tumor was located in the gastric cardia and fundus to the entire
      gastric body. It showed severe proliferation and infiltration from the mucosa to
      the serosa. The tumor was comprised of signet-ring cells and poorly
      differentiated adenocarcinoma cells, which spread into the submucosa of the
      pylorus, duodenum, and jejunum. Signet-ring cells had a large, eccentric
      vesicular nucleus and a pale cytoplasmic inclusion. Poorly differentiated
      adenocarcinoma cells had a pleomorphic nucleus, small eosinophilic nucleolus, and
      abundant eosinophilic cytoplasm. Both neoplastic cells were positive for CEA,
      epithelial membrane antigen, Leu-7 (CD57), and neuron-specific enolase, and were
      negative for cytokeratin, vimentin, and periodic acid-Schiff, Alcian blue, and
      mucicarmine stains. Electron microscopy showed endocrine granules with a limiting
      membrane measuring approximately 238 nm in diameter in the cytoplasm. The authors
      diagnosed this patient as having mucin-negative gastric signet-ring cell
      carcinoma with neuroendocrine markers, which is suggested to exist among poorly
      differentiated adenocarcinoma, undifferentiated carcinoma, and signet-ring cell
      carcinoma.

PMID- 10405241
TI  - Recurrent gastrointestinal Henoch-Schonlein purpura.
AB  - A 7-year-old boy was seen for severe abdominal pain, vomiting, and a 2.0-kg
      weight loss of 2 weeks duration. Stools were Hemoccult positive. Upper
      gastrointestinal (UGI) endoscopy showed multiple, raised red lesions in the
      duodenal bulb and descending duodenum. Although the patient did not have the
      typical cutaneous eruption, other findings such as acute onset of abdominal pain
      in a previously healthy boy, absence of infectious or surgical lesions, and more
      importantly endoscopic changes seen typically in the descending duodenum, led to
      the likely diagnosis of Henoch-Schonlein purpura (HSP). The patient was treated
      with prednisone and the duodenal lesions resolved. The diagnosis of HSP was
      confirmed 24 weeks after the initial symptom when he developed a palpable
      purpuric rash over both legs. Thirteen months following the initial symptoms and
      6 months after the onset of rash, severe abdominal pain with epigastric
      tenderness recurred and stools were Hemoccult positive. UGI endoscopy showed
      multiple, raised red lesions in the descending duodenum as seen earlier. The
      patient was diagnosed with recurrent HSP. This presentation is atypical because
      of the abnormally long interval between the onset of abdominal pain and the
      appearance of the skin rash, and unique because of the endoscopically
      demonstrated recurrent gastrointestinal lesions.

PMID- 10405242
TI  - Oral contraceptive-induced mesenteric venous thrombosis with resultant intestinal
      ischemia.
AB  - The author reports a case of oral contraceptive-induced mesenteric venous
      thrombosis with resultant intestinal ischemia in a young woman. The relationship
      between mesenteric venous thrombosis and oral contraceptives is discussed. Twenty
      six other cases of oral contraceptive-related mesenteric venous thrombosis
      reported in the English literature are reviewed.

PMID- 10405243
TI  - Primary splenic tuberculosis in a patient with nasal angiocentric lymphoma:
      mimicking metastatic tumor on abdominal CT.
AB  - Tuberculosis may be difficult to diagnose when it presents in an uncommon
      extrapulmonary site. The authors report a case of splenic tuberculosis mimicking
      metastatic tumor on computed tomography in a 60-year-old woman who had been
      treated with combination chemotherapy for nasal angiocentric lymphoma. Diagnostic
      splenectomy revealed multiple necrotic masses in the spleen, which were
      consistent with caseating granulomas microscopically. Diagnosis was confirmed by
      positive cultures in Lowenstein medium, which grew typical Mycobacterium
      tuberculosis organisms. Following splenectomy, the patient was also treated with
      a triple-drug antituberculosis regimen with no recurrence of her symptoms.

PMID- 10405244
TI  - Anaplastic and sarcomatoid carcinoma of the small intestine: an unusual tumor.
AB  - Primary malignant tumors of the small intestine are rare, and sarcomatoid
      carcinomas have rarely been reported at this site. Anaplastic and sarcomatoid
      carcinomas are well described in the upper aerodigestive tract, particularly in
      the esophagus and the larynx. The authors report a case of anaplastic and
      sarcomatoid carcinoma of the ileum presenting as gastrointestinal bleeding. Their
      patient and the literature suggest that these tumors are much more aggressive
      than other small intestinal tumors. The importance of a systematic diagnostic
      approach in diagnosing these tumors is also discussed.

PMID- 10405245
TI  - Bizarre early and late complications of percutaneous endoscopic gastrostomy.

PMID- 10405246
TI  - Iatrogenic entrapped nasogastric tube with endoscopic removal.

PMID- 10405247
TI  - Inflammatory myoglandular polyp.

PMID- 10405248
TI  - Three photoconvertible forms of green fluorescent protein identified by spectral
      hole-burning.

PMID- 10405249
TI  - Fragrances and health.

PMID- 10405250
TI  - Animal and human carcinogens.

PMID- 10405286
TI  - Comparison of fluorescence, (31)P NMR, and (7)Li NMR spectroscopic methods for
      investigating Li(+)/Mg(2+) competition for biomolecules.
AB  - The biochemical action of lithium in the treatment of manic-depressive illness is
      still unknown. One hypothesis is that Li(+) competes for Mg(2+)-binding sites in
      biomolecules. We report here our studies on metal ion competition by three
      distinct methods: fluorescence, (31)P NMR, and (7)Li NMR spectroscopy, using ATP
      as a model ligand. By fluorescence spectroscopy, we used the dye, furaptra, by
      measuring the increases in Mg(2+) levels in an ATP solution as Li(+) levels were
      increased in the solution. This increase in Mg(2+) levels was indicated by
      increases in the fluorescence intensity ratio (335/370) of furaptra. By (31)P NMR
      spectroscopy, this competition was demonstrated by changes in the (31)P NMR
      spectrum of ATP. The Li(+)/Mg(2+) competition was indicated by predictable
      changes in the separation between the alpha and beta resonances of the phosphates
      of ATP. For (7)Li NMR spectroscopy, spin-lattice relaxation measurements were
      used, which provided free Li(+) concentrations that could be used for determining
      the free Mg(2+) values in ATP solutions. The values of the free Mg(2+)
      concentrations obtained by all three methods were in good agreement. The
      fluorescence and (7)Li NMR methods, however, proved to be more sensitive to low
      concentrations of Li(+) than the (31)P NMR method.

PMID- 10405287
TI  - Assessing the relative stabilities of engineered hemoglobins using electrospray
      mass spectrometry.
AB  - An ion trap mass spectrometer equipped with an electrospray source was used to
      examine the relative thermodynamic stabilities of various hemoglobins with
      respect to both tetramer dissociation and hemin dissociation. The results
      demonstrated that the stability of hemoglobin molecules can be differentiated by
      the amount of applied collision-induced dissociation (CID) energy necessary to
      break up the intact tetramer into its constituent globins. The stability of the
      intact tetramer was affected by single mutations in the beta-globins. The
      stabilities of the constituent hologlobins were assessed via trap CID of selected
      ions. The results demonstrated the importance of the contributions of the
      hologlobin components to the stability of the intact tetramer. Genetic fusion of
      two alpha-globins, through the introduction of a single glycine residue between
      the C-terminus of one alpha-chain and the N-terminus of the second, significantly
      increased the stability of the hemoglobin pseudo-tetramer. Chemical crosslinking
      of the beta-globins in addition to genetic fusion of alpha-globins further
      stabilized the hemoglobin molecule. A dihemoglobin molecule produced by the
      genetic fusion of two di-alpha-globins with a flexible linker demonstrated a
      decreased stability relative to the corresponding monohemoglobin.

PMID- 10405288
TI  - Matrix-assisted laser desorption ionization mass spectrometry: a new tool for
      probing interactions between proteins and metal surfaces. Use in dental
      implantology.
AB  - The fixation in the bone of an artificial titanium tooth root is believed to be
      initiated by the rapid adsorption of the proteins present in the surgical cavity
      on the titanium surface. The study of this adsorption should make it possible to
      predict the osseointegration capacities of new implant surface treatments. We
      describe here a new method, based on matrix-assisted laser desorption ionization
      mass spectrometry (MALDI-MS), for quantifying proteins adsorbed on titanium
      surfaces fully identical to these designed for implantology. The key step of this
      method is a new MALDI-MS sample preparation allowing the adsorbed proteins to be
      removed from the surface and to be homogeneously dispersed in the matrix
      crystals. The adsorption of a model protein (lysozyme) on two titanium surfaces
      (polished and sandblasted) was studied in order to evaluate the method. The
      absolute MALDI-MS intensity was shown to vary linearly with the amount of
      adsorbed lysozyme. After dipping the titanium surfaces for different times in
      lysozyme solutions at different concentrations, the maximum amount of adsorbed
      lysozyme was measured by MALDI-MS and was shown to correspond to a lysozyme
      monolayer, which is consistent with results described in the literature.

PMID- 10405289
TI  - Electrospray ionization-mass spectrometry study of the interaction of cisplatin
      adducted oligonucleotides with human XPA minimal binding domain protein.
AB  - Nucleotide excision repair (NER) is the process responsible for eliminating most
      ultraviolet (UV) radiation damage from DNA, as well as base alterations caused by
      a variety of mutagens. The xeroderma pigmentosum group A complementing protein
      (XPA) is believed to be involved in the early step of NER by recognizing and
      binding damaged DNA. Recent work has suggested that electrospray ionization-mass
      spectrometry (ESI-MS) can be an effective tool for the study of protein-DNA
      complexes. We have used ESI-Fourier transform ion cyclotron resonance (FTICR)
      mass spectrometry to examine the cisplatin-adducted oligonucleotide and its
      interaction with the human XPA minimal binding domain (XPA-MBD). High-resolution
      FTICR experiments of the binding products showed that both double-stranded
      damaged 20-mer and double-stranded undamaged 20-mer formed 1:1 noncovalent
      complexes with XPA-MBD. A 2:1 binding stoichiometry complex was also observed
      between XPA-MBD and double-stranded damaged 20-mer. Competitive binding
      experiments indicated only slightly preferential binding of XPA-MBD with the
      double-stranded damaged 20-mer compared to the undamaged 20-mer. The results
      demonstrate that ESI-FTICR mass spectrometry provides a fast and efficient
      approach for characterizing weak protein-DNA interactions such as the binding
      between XPA-MBD and a 20-mer oligonucleotide system.

PMID- 10405290
TI  - An automated aequorin luminescence-based functional calcium assay for G-protein
      coupled receptors.
AB  - We describe in detail an automated and highly sensitive functional assay for
      calcium-coupled receptors (those receptors whose activation results in an
      increase in intracellular calcium levels) utilizing coelenterazine-charged
      aequorin as a probe for intracellular calcium levels ([Ca(2+)](i)). The assay was
      originally established to investigate Galpha(q)-coupled prostanoid receptors,
      which are members of the G-protein-coupled receptor (GPCR) superfamily, signaling
      through elevation of [Ca(2+)](i), initially focusing on the human EP(1)
      prostanoid receptor (hEP(1)). The parental human embryonic kidney cell line 293
      AEQ17, developed by Button and Brownstein (Cell Calcium 14, 663-671, 1993),
      constitutively expresses apoaequorin and was used to develop a clonal cell line
      which stably coexpresses hEP(1). This cell line was used to optimize assay
      parameters in order to maximize accuracy and throughput in an automated 96-well
      format with the result that each 96-well plate can be completed in 70 min. Use of
      this flexible system will greatly simplify the functional analysis of GPCRs and
      other receptors which when activated result in increases in [Ca(2+)](i).

PMID- 10405291
TI  - A method of fast separation of lignin peroxidases using convective interaction
      media disks.
AB  - The HPLC separation of lignin peroxidase isoenzymes using Convective Interaction
      Media disks containing quaternary amine and diethylaminoethyl ion-exchange active
      groups is proposed. In contrast to standard HPLC procedures the separation can be
      performed within a few minutes without considerably affecting the separation
      resolution. The method is reproducible and gives a linear response of integrated
      peak area to protein concentration for all measured isoenzymes. The separation
      resolution is retained unchanged by applying crude culture filtrate instead of a
      sample previously frozen and dialyzed. The optimized method might therefore be
      used for on-line monitoring of lignin peroxidase isoenzyme composition during
      fermentation. On the other hand, the proposed method is comparable in time to the
      original method of lignin peroxidase activity measurement (proposed by Tien and
      Kirk), providing additionally the isoenzyme composition.

PMID- 10405292
TI  - Quantification of N-(glucitol)ethanolamine and N-(carboxymethyl)serine: two
      products of nonenzymatic modification of aminophospholipids formed in vivo.
AB  - Chemical, nonenzymatic modification of protein and lipids by reducing sugars,
      such as glucose, is thought to contribute to age-related deterioration in tissue
      protein and cellular membranes and to the pathogenesis of diabetic complications.
      This report describes the synthesis and quantification of N
      (glucitol)ethanolamine (GE) and N-(carboxymethyl)serine (CMS), two products of
      nonenzymatic modification of aminophospholipids. GE is the product of reduction
      and hydrolysis of glycated phosphatidylethanolamine (PE), while CMS is formed
      through reaction of phosphatidylserine (PS) with products of oxidation of either
      carbohydrate (glycoxidation) or lipids (lipoxidation). Gas chromatography/mass
      spectrometry procedures for quantification of the N,O-acetyl methyl ester
      derivatives of the modified head groups were developed. GE and CMS were
      quantified in samples of PE and PS, respectively, following incubation with
      glucose in vitro; CMS formation was dependent on the presence of oxygen during
      the incubation. Both GE and CMS were detected and quantified in lipid extracts of
      human red blood cell membranes. The content of GE, but not CMS, was increased in
      the lipids from diabetic compared to nondiabetic subjects. Measurement of these
      modified lipids should prove useful for assessing the role of carbonyl-amine
      reactions of aminophospholipids in aging and age-related diseases.

PMID- 10405293
TI  - Kinetic microplate-based assays for inhibitors of mitochondrial NADH:ubiquinone
      oxidoreductase (complex I) and succinate:cytochrome c oxidoreductase.
AB  - Kinetic microplate-based assays for both mitochondrial NADH:ubiquinone
      oxidoreductase (complex I) and succinate:cytochrome c oxidoreductase using insect
      submitochondrial particles as the source of the enzyme activities have been
      developed. These assays have been used to design high-throughput screens for
      inhibitors of these mitochondrial electron transfer activities to assess their
      intrinsic in vitro efficacies as potential pesticides. These methods can be used
      to test up to 60 compounds per day without the use of automated sample handling
      and diluting technology. The accuracy, specificity, and reproducibility of the
      microplate methods compared well with conventional spectrophotometer-based
      assays.

PMID- 10405294
TI  - Acetylated prothrombin as a substrate in the measurement of the procoagulant
      activity of platelets: elimination of the feedback activation of platelets by
      thrombin.
AB  - Human prothrombin was acetylated to produce a modified prothrombin that upon
      activation by platelet-bound prothrombinase generates a form of thrombin that
      does not activate platelets but retains its amidolytic activity on a chromogenic
      peptide substrate. If normal prothrombin is used in such an assay, the thrombin
      that is generated activates the platelets in a feedback manner, accelerating the
      rate of thrombin generation and thereby preventing accurate measurement of the
      initial platelet procoagulant activity. Acetylation of prothrombin was carried
      out over a range of concentrations of sulfo-N-succinimidyl acetate (SNSA).
      Acetylation by 3 mM SNSA at room temperature for 30 min at pH 8.2 in the absence
      of metal ions produced a modified prothrombin that has <0.1% clotting activity
      (by specific prothrombin clotting assay), but it is activated by factor Xa (in
      the presence of either activated platelets or factor Va + anionic phospholipid)
      to produce thrombin activity that is measurable with a chromogenic substrate.
      Because the feedback action on the platelets is blocked, thrombin generation is
      linear, allowing quantitative measurement of the initial platelet activation
      state.

PMID- 10405295
TI  - Identification and quantitation of phosphorus metabolites in yeast neutral pH
      extracts by nuclear magnetic resonance spectroscopy.
AB  - (31)P NMR spectroscopy offers a possibility to obtain a survey of all low
      molecular-weight phosphorylated compounds in yeast. The yeast cells have been
      extracted using chloroform into a neutral aqueous phase. The use of high fields
      and the neutral pH extracts, which are suitable for NMR analysis, results in well
      resolved (31)P NMR spectra. Two-dimensional NMR experiments, such as proton
      detected heteronuclear single quantum ((1)H-(31)P HSQC) and (31)P correlation
      spectroscopy ((31)P COSY), have been used to assign the resonances. In the
      phosphomonoester region many of the signals could be assigned to known
      metabolites in the glycolytic and pentose phosphate pathways, although some
      signals remain unidentified. Accumulation of ribulose 5-phosphate, xylulose 5
      phosphate, and ribose 5-phosphate was observed in a strain lacking transketolase
      activity when grown in synthetic complete medium. No such accumulation occurred
      when the cells were grown in yeast-peptone-dextrose medium. Trimetaphosphate
      (intracellular concentration about 0.2 mM) was detected in both cold methanol
      chloroform and perchloric acid extracts.

PMID- 10405296
TI  - Enzymatic measurement of sphingosine 1-phosphate.
AB  - Sphingosine 1-phosphate (SPP) is a sphingolipid metabolite which has novel dual
      actions acting as both an intracellular second messenger and a ligand for a
      family of G protein-coupled receptors. This paper describes a rapid enzymatic
      method to quantify mass levels of SPP in serum, mammalian tissues, and cultured
      cells. The assay utilizes an alkaline lipid extraction to selectively separate
      SPP from other phospholipids and sphingolipids, including sphingosine. Extracted
      SPP is efficiently converted to sphingosine by alkaline phosphatase treatment.
      Sphingosine thus formed is then quantitatively phosphorylated to [(32)P]SPP using
      recombinant sphingosine kinase and [gamma-(32)P]ATP. With this procedure we were
      able to obtain reproducible measurements of SPP over a broad range from 0.25 pmol
      to 2.5 nmol. In various rat tissues, levels of SPP varied between 0. 5 and 6
      pmol/mg wet wt. The lowest levels were found in heart and testes, while brain
      contained the highest levels. The method was adapted easily to measure minute
      amounts of SPP present in various cultured cell types. The amount of SPP in cell
      extracts was proportional to the cell number and varied between 0.04 and 2
      pmol/10(6) cells. Concurrent measurements of sphingosine levels revealed that its
      concentration was significantly higher than SPP in most cells and tissues.
      Furthermore, with this assay we were able to measure increases in intracellular
      SPP levels in rat pheochromocytoma PC12 cells after treatment with exogenous
      sphingosine or with nerve growth factor which stimulates sphingosine kinase
      activity.

PMID- 10405297
TI  - Sensing of carbon dioxide by a decrease in photoinduced electron transfer
      quenching.
AB  - We described a new approach to sensing of carbon dioxide based on photoinduced
      electron transfer (PET) quenching. Fluorophores like naphthalene and anthracene
      are known to be quenched by unprotonated amines by the PET mechanism. We examined
      the fluorescence spectral properties of two amine-containing fluorophores, 1
      naphthylmetylamine (NMA) and 9-ethanolaminomethylanthracene (EAA). When dissolved
      in an organic solvent, both fluorophores displayed increased intensity when
      equilibrated with gaseous carbon dioxide. In the case of NMA, we found that the
      mean lifetime increased with increasing partial pressures of CO(2). The intensity
      and lifetime changes of NMA are completely reversible when CO(2) is removed by
      purging with argon. Our results are consistent with decreased quenching by the
      covalently linked amino groups when CO(2) is dissolved in the solution. At
      present, we are not certain whether the increased intensity is due to protonation
      of the amino groups or to carbamate formation. In either event, these results
      suggest that CO(2) can be detected directly using amine-containing fluorophores
      without the use of bicarbonate and a pH-sensitive fluorophore.

PMID- 10405298
TI  - Continuous assay for VanX, the D-alanyl-D-alanine dipeptidase required for high
      level vancomycin resistance.
AB  - The reaction of L-alanine-p-nitroanilide with VanX was studied in an effort to
      develop a continuous assay for VanX activity for future kinetic and inhibition
      studies. VanX, containing Zn(II), Co(II), Fe(II), or Ni(II), catalyzes the
      hydrolysis of L-alanine-p-nitroanilide producing L-alanine and p-nitroaniline as
      products; the formation of the latter product (epsilon(404nm) = 10, 700 M(-1) cm(
      1)) can be continuously monitored using UV-VIS spectrophotometry. Zn(II)-, Co(II)
      , Fe(II)-, and Ni(II)-containing VanX exhibit saturation kinetics when L-alanine
      p-nitroanilide is used as the substrate with K(m) and k(cat) values ranging from
      300 to 700 microM and 0.028 to 0.080 s(-1), respectively. Inhibition studies
      using O-[(1S)-aminoethylhydroxyphosphinyl]-D-lactic acid as the inhibitor and L
      alanine-p-nitroanilide as the substrate yielded a K(i) of 400 +/- 8 microM at pH
      7.0. These studies reveal a continuous assay of VanX activity which could be used
      to further study the kinetic mechanism of VanX and to allow for the development
      of high-throughput screening for inhibitors of VanX.

PMID- 10405299
TI  - Purification and recovery of bulky hydrophobic DNA adducts.
AB  - For many years (32)P postlabeling has detected DNA adducts at very low levels and
      yet has not been able to identify unknown adducts. Mass spectrometry offers
      substantially improved identification powers, albeit at some loss in detection
      limits. With this ultimate utilization of mass spectrometry in mind, the current
      research presents a new method to quantitatively purify bulky hydrophobic DNA
      adducts at levels that are pertinent to ongoing DNA adduct research in human
      health and environmental fields. This method was demonstrated with benzo[a]pyrene
      adducts. Purification was accomplished with the use of small columns (7.5-mm
      frits) with an 11 mg bed of polystyrene-divinlybenzene beads which retained the
      adducts while permitting the nonadducted nucleotides to be washed out with water.
      Subsequently, the adducts were eluted with 50% MeOH and the sample was reduced in
      volume in an evacuated centrifuge. Purification was demonstrated at adduct levels
      ranging from 4 adducts in 10(6) nonadducted nucleotides to 4 in 10(8). For these
      levels, analyses by capillary electrophoresis with sample stacking and UV
      detection determined that recoveries ranged from 91 to 54%, respectively. The
      adduct quantities isolated should be sufficient to allow the use of current MS
      capabilities that are linked on-line to separation methodologies such as
      capillary electrophoresis, capillary electrochromatography, and high-pressure
      liquid chromatography.

PMID- 10405300
TI  - An improved monobromobimane assay for glutathione utilizing tris- (2
      carboxyethyl)phosphine as the reductant.

PMID- 10405301
TI  - Extraction of superior-quality plasmid DNA by a combination of modified alkaline
      lysis and silica matrix.

PMID- 10405303
TI  - Pathogenesis of African horse sickness: ultrastructural study of the capillaries
      in experimental infection.
AB  - African horse sickness (AHS) was induced in five horses by inoculation, to
      determine the ultrastructural changes in endothelial cells of capillaries in the
      myocardium, lung, spleen and liver. The animals developed cardiac and mixed forms
      of the disease. Alterations detected in the endothelial cells of the vessels of
      infected animals included: the presence of structures associated with viral
      infection, hypertrophy, degenerative changes, appearance of cytoplasmic
      projections, changes in permeability, alteration of intercellular junctions, loss
      of endothelium, subendothelial deposition of cell debris and fibrin, and vascular
      repair. In association with these changes, oedema, haemorrhages and
      microthromboses were detected, particularly in the myocardium and lung. This
      study showed that infection of, and changes to, the capillary endothelial cells
      of the organs under study was independent of the form in which the disease
      manifested itself but was dependent on the organ and blood vessel type. Thus,
      different levels of viral tropism were observed for the endothelial cells of the
      vessels in different organs. Viral infection was commonest in the endothelial
      cells of myocardial vessels, followed by those in the lung, whereas in the spleen
      and liver, endothelial cell infection was rare and, in the case of the liver,
      limited to the interstitial capillaries.

PMID- 10405302
TI  - pUCP-Nco and pUCP-Nde: Escherichia-Pseudomonas shuttle vectors for recombinant
      protein expression in Pseudomonas.

PMID- 10405304
TI  - Repeated oral dosing with Listeria monocytogenes in mice as a model of central
      nervous system listeriosis in man.
AB  - Human listeriosis is a food-borne disease of immunosuppressed or previously
      healthy adults. The repeated oral administration of a sublethal dose
      (5x10(9)colony-forming units) of Listeria monocytogenes for 7 or 10 consecutive
      days led to the development of severe central nervous system (CNS) lesions in 25%
      of experimental mice. Histopathological examination of the brain revealed
      rhombencephalitis and ventriculitis as two distinct inflammatory patterns,
      resembling those seen in human listeriosis. This model would seem to be
      potentially useful for research on pathogenesis, predisposing factors and therapy
      in CNS listeriosis in man. 1999 W.B. Saunders and Company Ltd.

PMID- 10405305
TI  - Comparison of the effects of Clostridium perfringens type D culture supernates in
      ligated intestinal loops of goats and sheep.
AB  - The effects of Clostridium perfringens type D culture supernates were compared in
      ligated loops of the small intestine (ileum) and colon of four goat kids and four
      lambs, the loops being examined histopathologically and electron microscopically
      7 h after inoculation. No lesions were observed in the small intestine of any
      animal, or in control colonic loops. In the caprine and ovine colonic loops
      treated with culture supernates, most goblet cells were empty and the lumina
      contained a layer of mucus, polymorphonuclear leucocytes, bacteria and sloughed
      epithelial cells. The apical cytoplasm of the superficial epithelial cells was
      lost. Moderate oedema was observed in the submucosa and muscular layer. The
      colonic lesions were more severe in kids than in lambs. No changes were seen in
      vascular endothelial cells in any loop. 1999 W.B. Saunders and Company Ltd.

PMID- 10405306
TI  - Experimental inoculation of conventional pigs with tissue homogenates from pigs
      with post-weaning multisystemic wasting syndrome.
AB  - This report describes the experimental inoculation of conventional pigs with a
      tissue homogenate obtained from two pigs affected with postweaning multisystemic
      wasting syndrome (PMWS). Eight 2-month-old pigs were inoculated by the intranasal
      route, and two pigs were left as uninfected controls. Clinical signs, rectal
      temperatures and body weights were recorded. Pigs were necropsied at days 14 or
      21 post-inoculation, and tissue samples were taken for histopathology and porcine
      circovirus (PCV) in-situ hybridization. Although only mild clinical signs of
      disease were observed, lesions of PMWS were seen, and PCV was shown to have been
      successfully transmitted to six of the eight pigs. Seroconversion of all
      inoculated pigs to PCV-2, but not to PCV-1, was also detected, suggesting that
      the PCV nucleic acid detected by in-situ hybridization in inoculated pigs
      corresponded to PCV-2. In conclusion, this report shows that PCV-2 is
      transmissible to pigs, and the inoculation of tissue homogenates containing the
      virus results in the development of PMWS-like lesions.

PMID- 10405307
TI  - Immunohistochemical demonstration of bovine viral diarrhoea virus antigen in the
      pancreatic islet cells of cattle with insulin-dependent diabetes mellitus.
AB  - The pancreatic islets were studied in seven cattle with insulin-dependent
      diabetes mellitus (IDDM) associated with persistent bovine viral diarrhoea virus
      (BVDV) infection. BVDV antigen was detected immunohistochemically in the
      pancreatic islet cells. There was a decrease in the size and number of islets,
      vacuolar degeneration of residual islet cells, and lymphocytic insulitis. The
      atrophied islets were composed of small uniform cells with limited amounts of
      cytoplasm, containing a small number of insulin- and chromogranin-positive
      granules. Enlarged islets consisting of islet cells with vacuolated cytoplasm
      were also frequently observed. Many of the vacuolated islet cells differed from
      the cells of normal islets in containing fewer cytoplasmic insulin- and
      chromogranin-positive granules. Mild lymphocytic insulitis was observed
      frequently in enlarged islets but rarely in atrophied islets. Immunoreactivity
      with BVDV antibody was found in the acinar cells of the pars exocrina in all
      seven cattle and in the residual cells of the islets of Langerhans of four
      cattle. BVDV antigen-positive cells were seen more frequently in the enlarged
      islets than in the atrophied islets. Some islets with lymphocytic infiltrates
      showed a small number of antigen-positive cells. These findings suggest that
      autoimmune IDDM was induced by persistent BVDV infection, resulting in gradual
      destruction of the islet beta cells.

PMID- 10405308
TI  - Clusterin in bovine spongiform encephalopathy (BSE).
AB  - Clusterin mRNA, detected in increased quantities in the cervical spinal cord of
      cattle with bovine spongiform encephalopathy (BSE), was localized mainly in the
      neuroglia (including astrocytes) of the lateral and ventral areas of white
      matter. Axonal degeneration was also observed in these areas. The dorsal horns of
      the spinal cord in which BSE prion protein (PrP(BSE)) was deposited did not
      exhibit strong clusterin "up-regulation" but showed increased clusterin
      immunolabelling with a punctate distribution in the neuropil. Labelling of
      adjacent sections of the grey matter in BSE-affected spinal cord and thalamus
      demonstrated that the clusterin was deposited in association with extracellular
      PrP(BSE).

PMID- 10405309
TI  - The presence of transforming growth factor e in bovine mammary gland.
AB  - Transforming growth factor e (TGFe) was demonstrated immunohistochemically in the
      bovine mammary gland, mainly in the glandular and ductal epithelium. In the teat,
      its expression was largely limited to the skin keratinocytes, ductal epithelium
      and ductal glands. It is suggested that this growth factor plays a role in
      lactation.

PMID- 10405310
TI  - Fatal visceral and neural sarcocystosis in dogs.
AB  - This paper describes acute visceral and neural sarcocystosis in four dogs. One
      animal was simultaneously infected with distemper virus, and another with
      Blastomyces dermatitidis. Schizonts and merozoites of Sarcocystis canis were
      found in the lesions. 1999 W.B. Saunders and Company Ltd.

PMID- 10405311
TI  - Necrotizing pneumonia in a cat caused by an orthopox virus.
AB  - A necrotizing pneumonia was observed in a domestic cat which had a clinical
      history of severe respiratory distress. Histology, immunohistology and
      electronmicroscopy revealed poxvirus as the causative agent. By the polymerase
      chain reaction and gene sequencing, an orthopox virus with 93% homology to cowpox
      virus was identified.

PMID- 10405312
TI  - Malignant rhabdoid tumour in the orbit of a horse.
AB  - A malignant rhabdoid tumour was diagnosed in the orbit of a 2-year-old
      Thoroughbred filly. The neoplasm, which was very aggressive, was present in
      nearly every part of the ocular and periocular structures and had spread to the
      lymph nodes of the head and neck, the salivary glands and the subcutaneous
      tissues around the eye. The neoplasm was composed of polygonal cells with
      abundant eosinophilic cytoplasm. Many cells had a large, vesiculate, indented
      nucleus and contained a paranuclear globular inclusion. Ultrastructurally, the
      inclusions were seen to consist of whorls of intermediate filaments. The
      neoplastic cells were immunoreactive to vimentin and cytokeratin antisera, but
      were negative for desmin and actin.

PMID- 10405313
TI  - Distinct effects on the conformation of estrogen receptor alpha and beta by both
      the antiestrogens ICI 164,384 and ICI 182,780 leading to opposite effects on
      receptor stability.
AB  - Tissue-specific effects of 17beta-estradiol (E(2)) and synthetic estrogen
      receptor (ER) ligands on target gene regulation might, at least partly, be
      explained by a selective ligand-induced conformational change of their receptors
      (ERalpha and ERbeta). In this study, the effects of E(2) and the synthetic ER
      ligands tamoxifen (TAM), ICI 164,384, and ICI 182,780 on the conformation of
      ERalpha and ERbeta were examined using limited proteolytic digestion analysis. We
      found that E(2) induced a conformational change of ERalpha resulting in the
      protection of a 30-kDa product, whereas TAM protected a 28-kDa fragment.
      Strikingly, the ERalpha conformational change induced by both ICI 164,384 and ICI
      182,780 did not result in protection but rather seems to induce a ligand
      concentration-dependent increase in proteolytic degradation of the 30- and 28-kDa
      products. Incubation of ERbeta with E(2) resulted in an increased protection of a
      30-kDa fragment, whereas with TAM protection of a 29-kDa fragment was observed.
      In contrast to the situation with ERalpha, ICI 164,384 and ICI 182,780 incubation
      induced the protection in a manner similar to 30-kDa fragment E(2). In addition,
      the ICI compounds also induced in a dose-dependent manner the preservation of a
      32-kDa fragment. Our observations demonstrate that ICI 164,384 and ICI 182,780
      have distinct effects on the conformation of ERalpha and ERbeta, resulting in
      receptor subtype-selective opposite effects on receptor stability in vitro.

PMID- 10405314
TI  - Flow stimulates nitric oxide release in guinea pig heart: role of stretch
      activated ion channels.
AB  - Blood flow regulates vessel tone triggering the release of nitric oxide; however,
      the mechanism involved in this phenomenon is unknown. We investigated whether
      coronary flow induces nitric oxide release in the isolated perfused guinea pig
      heart and the role of the stretch-activated ion channels in the effect of flow.
      We used gadolinium (3 microM) in order to block these channels, and estimated
      nitric oxide release by an oxyhemoglobin method. The results have shown a flow
      dependent stimulation of nitric oxide release (fivefold increase at perfusion
      flow of 25 ml/min). Gadolinium inhibited this effect in a dose-dependent fashion.
      Acetylcholine was able to stimulate nitric oxide release in presence of
      gadolinium. We concluded that coronary flow stimulates nitric oxide release in
      the guinea pig heart. Stretch-activated ion channels mediate this effect.
      Acetylcholine and flow stimulate nitric oxide release by different mechanisms of
      action.

PMID- 10405315
TI  - Arginine deiminase inhibits cell proliferation by arresting cell cycle and
      inducing apoptosis.
AB  - We have previously demonstrated that arginine deiminase inhibits the
      proliferation of vascular endothelial cells, but the mechanisms leading to growth
      inhibition have remained unclear. We report here that low concentrations of
      arginine deiminase purified from Mycoplasma arginini inhibit proliferation of
      various cultured cells by arresting the cell cycle in G(1) and/or S phase with
      higher arginine deiminase concentrations leading to subsequent apoptosis. Our
      results demonstrate that arginine deiminase inhibits cell proliferation not only
      by depletion of arginine, but also by mechanisms involving the cell cycle and
      death signals.

PMID- 10405316
TI  - Gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide:
      down-regulation of nitric oxide synthase-2 and caspase-3 by sulglycotide.
AB  - We applied the animal model of H. pylori lipopolysaccharide-induced gastritis to
      assess the effect of antiulcer agent, sulglycotide, on the mucosal inflammatory
      responses by analyzing the interplay between the activity of a key apoptotic
      caspase, caspase-3, epithelial cell apoptosis, and the expression of constitutive
      (cNOS) and inducible (NOS-2) nitric oxide synthase. H. pylori lipopolysaccharide
      applied intragastrically elicited within 4 days a pattern of mucosal responses
      resembling that of acute gastritis. 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 2.2-fold decline in cNOS, and a 5.4-fold increase in caspase-3 activity.
      Treatment with sulglycotide led to a 56.7% reduction in the extent of mucosal
      inflammatory changes elicited by H. pylori lipopolysaccharide and an 88.3%
      decrease in the epithelial cells apoptosis. Furthermore, this effect of
      sulglycotide was associated with a 51% decrease in mucosal expression of caspase
      3 activity, a 73.7% decline in NOS-2, and a 64.1% increase in cNOS. The findings
      suggest that sulglycotide suppresses the H. pylori-induced mucosal inflammatory
      responses by up-regulating cNOS and interfering with the events propagated by NOS
      2 and caspase-3.

PMID- 10405317
TI  - Cloning, expression, and chromosomal mapping of a human ganglioside sialidase.
AB  - Here we report the cDNA sequence of a human ganglioside sialidase. The cDNA was
      isolated from a human brain cDNA library by screening with a 240 bp probe
      generated by polymerase chain reaction using primers based on the sequences of
      rat cytosolic and bovine membrane sialidases which we previously cloned. The 3.0
      kb cDNA encodes an open reading frame of 436 amino acids containing a putative
      transmenbrane domain and an Arg-Ile-Pro and three Asp-box sequences
      characteristic of sialidases and showing overall 83% and 39% identities to the
      bovine and rat enzymes, respectively. Northern blot analysis revealed high
      expression in skeletal muscle and testis, but low level in kidney, placenta,
      lung, and digestive organs. Transient expression of the cDNA in COS-1 cells
      resulted in a 130-fold increase in sialidase activity compared to the control
      level, and the activity was found to be almost specific for gangliosides.
      Fluorescent in situ hybridization allowed the human sialidase gene localized to
      chromosome 11 at q 13.5.

PMID- 10405319
TI  - Cloning of differentially expressed genes in highly and low metastatic rat
      osteosarcomas by a modified cDNA-AFLP method.
AB  - To identify differentially expressed genes between highly and low metastatic rat
      transplantable osteosarcomas, we applied a modified AFLP (amplified fragment
      length polymorphisms) method for cDNA subtraction. The specific point of our
      modification is selective amplification using suppression PCR technique after
      restriction enzyme cutting. Our cDNA-AFLP gave high reproducibility (about 95%)
      in mRNA patterns and enabled us to clone four dominantly expressed genes in a
      highly metastatic tumor line. Three showed homology with known genes, encoding Ki
      67, a proliferation-associated effective marker of malignancy, type IV collagen
      alpha-3, a major component of basement membrane, and KIAA77 for which the
      function is unknown. Although one fragment showed no database homology, we
      revealed a derivation from the rat homologue of the Drosophila melanogaster
      diaphanous gene (Dia) by cloning of longer cDNA. Dia genes, known to affect actin
      filament formation, are downstream effectors of Rho small GTPase. The results
      suggest that alterations in the expression of cytoskeletal protein, basement
      membrane elements, and proliferative markers may be important for metastasis of
      osteosarcomas.

PMID- 10405318
TI  - The antioxidant defense protein ferritin is a novel and specific target for
      pentaerithrityl tetranitrate in endothelial cells.
AB  - The organic nitrate pentaerithrityl tetranitrate (PETN) is known to exert long
      term antioxidant and antiatherogenic effects by as yet unidentified mechanisms.
      In porcine aortic endothelial cells, a 24 h incubation with PETN (1-100 microM)
      or its metabolite pentaerithrityl trinitrate (PETriN) increased levels of the
      antioxidant protein ferritin up to three-fold over basal, whereas isosorbide
      dinitrate and isosorbide-5-mononitrate were without significant effect under
      these conditions. PETriN-induced ferritin expression was blocked by the NO
      scavenger PTIO but remained unaltered in the presence of ODQ, an inhibitor of
      soluble guanylyl cyclase. 8-Bromo cyclic GMP and dibutyryl cyclic GMP did not
      influence basal ferritin synthesis. The iron chelator desferrioxamine abolished
      ferritin induction by PETriN. Our results show that PETN or its active metabolite
      PETriN induce ferritin synthesis through NO- and iron-dependent but cyclic GMP
      independent pathways. Increased activity of ferritin may contribute to, and at
      least in part explain, the specific antiatherogenic and antioxidant action of
      PETN.

PMID- 10405320
TI  - Retinol, a probe of conformational changes in protein disulfide isomerase.
AB  - Nanosecond and steady fluorescence techniques have been employed to study the
      interaction of retinol with protein disulfide isomerase (PDI). Retinol binds
      tightly to PDI; and the rotational correlation time (&theta; = 36 ns) corresponds
      to a monomeric subunit of 55 kDa. The enzyme does not undergo aggregation in the
      presence of low molecular weight peptides. Under denaturing conditions; presence
      of 0.75 M Gnd HCl, the fluorescence yield of bound retinol is enhanced,
      suggesting stronger interactions of exposed hydrophobic groups of the protein
      with retinol. Based on far UV CD and fluorescence measurements of the protein in
      the presence of Gnd HCl, it is proposed the existence of molten globule
      intermediates during the unfolding of PDI.

PMID- 10405321
TI  - Molecular analyses of five new chimpanzee MHC class I alleles: implications for
      differences between evolutional mechanisms of HLA-A, -B, and -C loci.
AB  - In order to study the origin of the polymorphism of MHC class I molecules, we
      have cloned and sequenced five new Patr-A, -B, and -C loci alleles from two
      chimpanzees. Previous studies of sequence comparison between Patr and HLA class I
      alleles revealed that many of the sequence motifs were shared and the origin of
      class I molecules predated the divergence of chimpanzees and humans. These
      findings are confirmed by our current study. Additionally, our data suggest
      significant differences between mechanisms of evolution of the A, B, and C loci:
      (1) The B locus is characterized by frequent nucleotide substitutions, whereas
      the A and C loci are relatively more conserved; (2) However, unlike the A locus,
      the alpha2 domains of the C locus sequenced appear to produce MHC polymorphism
      between these species. These differences might imply the distinctive
      contributions of each locus during the evolutionary history.

PMID- 10405322
TI  - Identification of the region of mi transcription factor which is responsible for
      the synergy with PEBP2/CBF.
AB  - The mi locus encodes the mi transcription factor (MITF), a member of the basic
      helix-loop-helix-leucine zipper protein family of transcription factors. MITF
      binds the alphaB1/AML1 subtype of the alpha subunit of the polyomavirus enhancer
      binding protein 2 (PEBP2). These two transcription factors synergistically
      transactivate the mouse mast cell protease 6 (MMCP-6) gene. The interaction of
      PEBP2 with MITF is mediated through the region carboxy-terminal to the DNA
      binding Runt domain. In the present study, we examined the region of MITF that is
      responsible for the interaction with PEBP2. The MITF mutant that lacked the
      region aa 67-152 did not bind PEBP2, and the mutant that lacked the region aa 1
      152 lost the synergistic function in the transactivation of the MMCP-6 promoter.
      We conclude that the region amino-terminal to the basic region of MITF is
      required for physical and functional interactions with PEBP2.

PMID- 10405323
TI  - Thrombopoietin potentiates agonist-stimulated activation of p38 mitogen-activated
      protein kinase in human platelets.
AB  - Thrombopoietin (TPO) plays a crucial role in megakaryocyte differentiation and
      platelet production. c-Mpl, a receptor for TPO, is also expressed in terminally
      differentiated platelets. We investigated the effects of TPO on activation of p38
      mitogen-activated protein kinase in human platelets. Thrombin, a thrombin
      receptor agonist peptide, a thromboxane A(2) analogue, collagen, crosslinking the
      glycoprotein VI, ADP, and epinephrine, but not phorbol 12, 13-dibutyrate
      activated p38. TPO did not activate p38 by itself, whereas TPO pretreatment
      potentiated the agonist-induced activation of p38. TPO did not promote
      phosphorylation of Hsp27 and cytosolic phospholipase A(2) by itself, but enhanced
      thrombin-induced phosphorylation of them. The specific p38 inhibitor SB203580
      strongly inhibited such phosphorylation. Thus, TPO possesses the priming effect
      on p38 activation in human platelets and could affect platelet functions through
      the p38 pathway.

PMID- 10405324
TI  - A novel human gene encoding an F-box/WD40 containing protein maps in the SHFM3
      critical region on 10q24.
AB  - We report the cloning and characterization of a new human gene, Dactylin,
      encoding a novel member of the F-box/WD40 protein family. The Dactylin gene
      comprises nine exons distributed in more than 85 kb of genomic DNA and encoding a
      protein with four WD40 repeats and an F-box motif. Northern blot analysis
      demonstrates a single 2.8 kb transcript in brain, kidney, lung and liver. FISH
      hybridization localized Dactylin to 10q24.3. Using an Msc I SNP identified in the
      first exon of the gene, we were able to assign Dactylin within the critical
      region for Split Hand Split Foot malformation (SHFM3) that has been mapped to
      10q24. The SHFM3 phenotype includes absence or hypoplasia of the central digital
      rays, a deep median cleft and syndactyly of the remaining digits. Recent studies
      have demonstrated the importance of F-box/WD40 proteins in the regulation of
      developmental processes, by a mechanism of specific ubiquitinization and
      subsequent proteolysis of target proteins belonging to the Wnt, Hh and NF-kappaB
      signaling pathways. The chromosomal location of Dactylin and its putative
      function as an F-box/WD40 repeat protein, likely to be involved in key signaling
      pathways crucial for normal limb development, make it a promising candidate gene
      for SHFM3.

PMID- 10405325
TI  - Cytochrome c is dispensable for fas-induced caspase activation and apoptosis.
AB  - Cytochrome c is thought to play an important role in the initiation of apoptosis
      following its release from mitochondria. It is controversial whether such release
      is also involved in caspase activation and apoptotic cell death after ligation of
      the cell surface molecule Fas. We addressed this issue by investigating cells
      from the human cell lines Jurkat and SKW6 which had been treated with the
      inhibitor of the mitochondrial F0/F1-ATPase, oligomycin. Oligomycin-treatment
      led, over a wide range of concentrations, to ATP-depletion and, at similar
      concentrations, abrogated the appearance of caspase-3-like activity caused by
      stauroporine. Electroporation of cytochrome c protein into intact cells induced
      caspase activation in both cell lines and significant nuclear apoptosis in Jurkat
      cells. In ATP-depleted cells, electroporation of cytochrome c induced neither
      caspase activation nor nuclear fragmentation. Fas-induced caspase activation and
      nuclear apoptosis, however, were unaffected by the depletion of ATP. Thus,
      cytochrome c is unlikely to be an important factor in Fas-induced cell death.

PMID- 10405326
TI  - Functional consequences of a carboxyl terminal missense mutation Arg278Cys in
      human cardiac troponin T.
AB  - A carboxyl terminal missense mutant Arg278Cys of human cardiac troponin T that
      causes familial hypertrophic cardiomyopathy was expressed in Escherichia coli,
      purified, and exchanged into rabbit cardiac skinned muscle fibers using a
      troponin exchange technique. Compared to the fibers exchanged with human cardiac
      wild-type troponin T, the fibers exchanged with the mutant Arg278Cys developed
      less maximum force with a decreased cooperativity and a slightly increased Ca(2+)
      sensitivity, resulting in a significant elevation of sub-half-maximal force.
      Since intact cardiac muscle is thought to never be activated beyond the half
      maximum level, the results suggest that an enhanced myofilament response to
      Ca(2+) may be responsible for the pathogenesis of hypertrophic cardiomyopathy
      associated with this mutation. The results also provide the first evidence that
      the carboxyl terminal region of cardiac troponin T plays an important role
      probably through its interaction with tropomyosin in allowing troponin complex to
      inhibit the muscle contraction at low Ca(2+), in agreement with the hypothesis
      deduced from the previous studies on fast skeletal troponin T.

PMID- 10405327
TI  - The MUC3 gene encodes a transmembrane mucin and is alternatively spliced.
AB  - Epithelial mucins are a family of secreted and cell surface glycoproteins
      expressed by epithelial tissues and implicated in epithelial cell protection,
      adhesion modulation and signaling. The gene encoding human MUC3 (hMUC3),
      localised to chromosome 7q22, is most highly expressed in the small intestine. It
      has previously been reported to be a non-transmembrane mucin with minimal
      homology to its suggested orthologues from rat (rMuc3) and mouse (mMuc3). RT-PCR
      was performed to investigate the carboxyl terminus of the published sequence of
      hMUC3 from normal colon and small intestine tissues and also from a series of 10
      colorectal cancer cell lines. Two distinct PCR products were identified. In
      contrast to the previously published hMUC3 sequence, which terminates shortly
      after a single cysteine-rich EGF-like domain, conceptual protein translation of
      the dominant and largest PCR product identified two extracellular cysteine-rich
      EGF-like domains separated by an N-glycosylation-rich domain and a potential
      coiled-coil region, followed by a putative transmembrane region and a 75 amino
      acid cytoplasmic tail. The smaller of the two PCR products was found to be an
      alternative splice variant of MUC3 including the first EGF-like domain but
      lacking part of the second EGF-like domain and the transmembrane region. Nine out
      of 10 colorectal cancer cell lines were found to express MUC3. Interestingly, one
      of the cell lines, LoVo, expressed predominantly the alternative splice form
      lacking a transmembrane domain. Structural homology of the new protein sequence
      of hMUC3 with rMuc3 and mMuc3 indicates it is closely related to the rodent
      proteins and is likely to be involved in ligand-binding and intracellular
      signaling. The new finding that MUC3 encodes a transmembrane molecule presents a
      new paradigm for the structure of this mucin and the manner in which it may
      function.

PMID- 10405328
TI  - HIV-1 Tat protein is poly(ADP-ribosyl)ated in vitro.
AB  - Purified recombinant HIV-1 Tat protein stimulated acceptor-dependent reaction of
      poly(ADP-ribose) polymerase in a dose-dependent manner. Analysis of the reaction
      products by SDS-polyacrylamide gel electrophoresis followed by immunoblotting
      with anti-poly(ADP-ribose) antibody revealed that recombinant Tat proteins were
      covalently modified with poly(ADP-ribose) in the enzyme reaction. Eventhough no
      significant effect of the modification was detected in the activity of Tat to
      form a specific complex with TAR (a viral transactivation response element) RNA,
      the present results raise the possibility that poly(ADP-ribose) polymerase is
      involved in the regulation of HIV-1 through the modification of a virus-encoded
      transactivator, Tat protein.

PMID- 10405329
TI  - Inhibitory effect of phosphorylated myosin light chain kinase on the ATP
      dependent actin-myosin interaction.
AB  - Myosin light chain kinase (MLCK) phosphorylates the regulatory light chain of
      myosin in the presence of Ca(2+) and calmodulin (Ca(2+)-CaM) so that myosin can
      interact with actin filaments. MLCK has another activity that is not attributable
      to this kinase activity, i.e., it inhibits the ATP-dependent movement of actin
      filaments on a myosin-coated glass surface. MLCK itself can be phosphorylated at
      site A and site B with a few kinases. The phosphorylation at site A reduces
      kinase activity. However, we have no knowledge as to how phosphorylation of MLCK
      affects the inhibitory activity of MLCK. When MLCK was phosphorylated at site B,
      it exerted an inhibitory effect on the movement in much lower concentrations.
      When Ca(2+)-CaM or ML-9 was present, the inhibition was reduced. The reduction
      was less when the movement was arrested by the MLCK phosphorylated at site B.
      This observation was explained by the increase in the affinity of MLCK to myosin
      upon the phosphorylation at site B.

PMID- 10405330
TI  - Expression and localization of human alcohol and aldehyde dehydrogenase enzymes
      in skin.
AB  - Alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase (ALDH; EC
      1.2.1.3.) are important enzymes involved in the biotransformation of both
      alcohols and aldehydes. Today, six classes of ADH and twelve classes of ALDH have
      been defined in mammals. Here we report the detection and localisation of three
      classes of ADH and two classes of ALDH in human skin, using Western blot analysis
      and immunohistochemistry with class-specific antisera. Western blot analysis of
      human skin cytosol revealed that class I-III ADH and class 1 and class 3 ALDH
      enzymes are expressed, constitutively, in three different anatomical regions of
      human skin (foreskin, breast, abdomen). Densitometric analysis of the
      immunoreactive bands revealed differential constitutive expression of these
      enzymes in foreskin, breast, and abdomen skin. Immunohistochemistry showed the
      presence of class I ADH and class III ADH enzymes, predominantly in the epidermis
      with some localised expression in the dermal appendages of human skin. In
      comparison, staining for class II ADH was more faint in the epidermis with very
      little dermal expression. Class 1 ALDH and class 3 ALDH were predominantly
      localised to the epidermis with minimal, highly localised dermal appendageal
      expression. These cutaneous ADH and ALDH enzymes may play significant roles in
      the metabolism of endogenous or xenobiotic alcohols and aldehydes.

PMID- 10405331
TI  - Glial cell line-derived neurotrophic factor induces barrier function of
      endothelial cells forming the blood-brain barrier.
AB  - Since a deep involvement of astrocytes, a kind of glial cells, in differentiation
      of the blood-brain barrier (BBB) has been suggested, we examined the relation of
      glial cell line-derived neurotrophic factor (GDNF) to the BBB. First,
      immunohistochemical examination of the cerebral cortex of rats revealed that
      glial cell line-derived neurotrophic factor receptor (GFRalpha1) was
      preferentially expressed on the cell membranes of capillary endothelial cells.
      Second, to elucidate the effects of GDNF on the BBB, capillary endothelial cells
      isolated from the porcine cerebral cortex were cultured and then changes in tight
      junction function of the endothelial cells were examined after addition of GDNF,
      in terms of transendothelial electrical resistance (TER) and permeability. GDNF
      at concentrations of 0.1 and 1 ng/ml significantly activated the barrier function
      of the endothelial cells in the presence of cAMP. Since GDNF is secreted from
      astrocytes sheathing capillary endothelial cells in the brain cortex, our results
      strongly suggest that GDNF enhances the barrier function of tight junctions of
      the BBB on the one hand, and also supports the survival of neurons on the other
      hand.

PMID- 10405332
TI  - High mobility group-like protein in bovine milk stimulates the proliferation of
      osteoblastic MC3T3-E1 cells.
AB  - The active component in bovine milk on the proliferation of osteoblastic MC3T3-E1
      cells was purified and identified. Growth-promoting activity was measured by
      [(3)H]thymidine incorporation on the cell. The molecular weight of the purified
      protein was 10 kDa. The amino-terminal sequence of this 10-kDa protein was
      identical to bovine high mobility group protein (HMG) 1. This 10-kDa protein is
      suggested to be a basic protein and to have an HMG box, a consensus sequence
      motif among the HMG family. From these results, we named this protein HMG-like
      protein. HMG is a ubiquitous nonhistone component of chromatin and considered to
      be implicated in DNA replication. We found this protein in milk, and it showed a
      growth-promoting activity. We propose the possibility that HMG-like protein
      existed in milk and plays an important role for neonate in bone formation by
      activating osteoblasts.

PMID- 10405333
TI  - cAMP-dependent positive control of cyclin A2 expression during G1/S transition in
      primary hepatocytes.
AB  - cAMP positively and negatively regulates hepatocyte proliferation but its
      molecular targets are still unknown. Cyclin A2 is a major regulator of the cell
      cycle progression and its synthesis is required for progression to S phase. We
      have investigated whether cyclin A2 and cyclin A2-associated kinase might be one
      of the targets for the cAMP transduction pathway during progression of
      hepatocytes through G1 and G1/S. We show that stimulation of primary cultured
      hepatocytes by glucagon differentially modulated the expression of G1/S cyclins.
      Glucagon indeed upregulated cyclin A2 and cyclin A2-associated kinase while
      cyclin E-associated kinase was unmodified. In conclusion, our study identifies
      cyclin A2 as an important effector of the cAMP transduction network during
      hepatocyte proliferation.

PMID- 10405334
TI  - Reduced mitochondrial membrane potential and altered responsiveness of a
      mitochondrial membrane megachannel in p53-induced senescence.
AB  - There is accumulating evidence that mitochondrial membrane potential
      (DeltaPsi(M)) is reduced in aged cells. In addition, a decrease of DeltaPsi(M)
      has been shown to be an early event in many forms of apoptosis. Here we use a
      mitochondrial potentiometric dye with in situ laser scanning confocal microscopic
      (LSCM) imaging to demonstrate that DeltaPsi(M) is dramatically decreased in both
      the p53-overexpressing, senescent EJ tumor cells and in pre-apoptotic PC12 cells
      compared to controls. Treatment with cyclosporin A (CSA), which facilitates
      closure of the mitochondrial permeability transition pore (PTP), was able to
      reverse the decrease in DeltaPsi(M) in pre-apoptotic PC12 cells but not in the
      senescent EJ-p53 cells. The capacity to prevent dissipation of DeltaPsi(M) in
      response to agents that facilitate PTP closure may differentiate cells entering
      apoptosis from those participating in senescence. Therefore, regulation of the
      closure of the mitochondrial PTP in the presence of decreased DeltaPsi(M) may be
      a decisional checkpoint in distinguishing between growth arrest pathways.

PMID- 10405335
TI  - TAK-778, a novel synthetic 3-benzothiepin derivative, promotes chondrogenesis in
      vitro and in vivo.
AB  - TAK-778, a novel synthetic 3-benzothiepin derivative, stimulates the formation of
      cartilaginous nodules in mouse chondroprogenitor-like ATDC5 cells in vitro in
      association with upregulation of the gene expression of transforming growth
      factor-beta(2), but not bone morphogenetic protein-4 and insulin-like growth
      factor-I. One-shot injection of the TAK-778-containing sustained-release
      microcapsules accelerated the repair process of the full thickness defects of
      articular cartilage in rabbit knees. Our in vitro and in vivo results indicate
      that TAK-778 may be a therapeutically useful synthetic agent for articular
      cartilage repair.

PMID- 10405336
TI  - Induction of manganese-superoxide dismutase in MRC-5 cells persistently infected
      with an alphavirus, sindbis.
AB  - Sindbis virus (SV), a single-stranded positive-sense RNA virus, multiplies in a
      variety of cells and causes various outcomes of infection. As we described acute
      infection of SV induces stress response of small heat shock protein HSP27 and
      activation of mitogen-activated protein kinase (MAP) signaling pathway (Nakatsue,
      T., et al., Biochem. Biophys. Res. Commun. 253, 59-64, 1998). In contrast to
      lytic infection in Vero cells, MRC-5 cells, a human fetus lung cell line,
      resulted in persistent infection by SV. Here we investigated a cellular factor
      involved in persistent infection of MRC-5 cells infected with SV. Partial
      sequence analysis of a 25 kilodalton (kDa) protein, accumulated in large amounts
      in the cells, showed that manganese-superoxide dismutase (Mn-SOD) was induced
      during the infections. When Mn-SOD was overexpressed in Vero cells, 20% of the
      cells survived more than one month, in contrast with the death of 99% of the
      vehicle-transfected Vero cells at 48 h after infection with SV. These data
      strongly suggest that a cellular factor which regulates the oxidative pathway
      modulates the outcome of SV infection.

PMID- 10405337
TI  - High extracellular calcium inhibits osteoclast-like cell formation by directly
      acting on the calcium-sensing receptor existing in osteoclast precursor cells.
AB  - Although it has recently been suggested that high extracellular calcium
      ([Ca(2+)](e)) inhibits osteoclast function via a calcium-sensing receptor (CaSR)
      in mature osteoclasts, the role of CaSR in the regulation of osteoclast formation
      remains unknown. The present study was performed to investigate whether
      osteoclast precursor cells possess CaSR and to clarify the possible role of CaSR
      in the regulation of osteoclast formation. Immunocytochemistry detected CaSR in
      osteoclast precursor cells derived from spleen cells as well as in osteoblastic
      MC3T3-E1 cells. The use of reverse-transcription polymerase chain reaction (RT
      PCR) with CaSR-specific primers, followed by nucleotide sequencing of the
      amplified products, also identified CaSR transcripts in osteoclast precursor
      cells derived from spleen cells as well as in MC3T3-E1 cells. High [Ca(2+)](e) (3
      to 5 mM) concentration dependently inhibited 1,25(OH)2D3- or human parathyroid
      hormone (hPTH) (1-34)-induced osteoclast-like cell (Ocl) formation from
      osteoclast precursor cells derived from spleen cells. Further, the CaSR agonist
      neomycin also concentration dependently inhibited 1,25(OH)2D3- or hPTH(1-34)
      induced Ocl formation. Moreover, a calcimimetic which mimics or potentiates the
      effects of [Ca(2+)](e) at the CaSR NPS R-467 (1-100 microM) concentration
      dependently inhibited Ocl formation stimulated by 1,25(OH)2D3 or hPTH(1-34).
      These findings first demonstrated that osteoclast precursor cells possess CaSR
      very similar, if not identical, to those in the parathyroid and kidney.
      Furthermore, the CaSR in osteoclast precursor cells could play a key role in
      regulating Ocl formation by sensing local changes in [Ca(2+)](e) at the
      resorptive sites.

PMID- 10405338
TI  - Endothelin converting enzyme activity in primary rat astrocytes is modulated by
      endothelin B receptors.
AB  - Astrocytes express endothelin-1 (ET-1), ET-3, and their receptors, ET(A) and
      ET(B). We report here that activated astrocytes in vivo also express endothelin
      converting enzyme-1 (ECE-1). Higher basal ET-1 concentrations in astrocyte media
      from ET(B)-deficient (sl/sl) versus wildtype (+/+) rats suggested that altered
      ECE activity may be related to the absence of ET(B) receptors. Quantification of
      ECE activity in membranes from sl/sl astrocytes yielded a 50% higher conversion
      compared to +/+ astrocytes, with indistinguishable ECE-1 mRNA and protein levels.
      Kinetic analysis of ECE activity revealed similar V(max) values in sl/sl and +/+
      astrocytes. Enzyme activity was competitively inhibited by phosphoramidon with
      K(i) values of 0. 6 and 0.3 microM, respectively. The K(m) value of ECE was 0.5
      microM in +/+ and 0.2 microM in sl/sl astrocytes. Two-dimensional focussing of
      astrocytic ECE-1 uncovered heterogeneity of charge and molecular weight. ECE-1
      from sl/sl revealed a glycosylation pattern different from +/+ astrocytes. In
      conclusion, the ET(B) receptor may, via ECE-1 glycosylation, exert a negative
      feedback on ECE activity in the astrocytic endothelin system.

PMID- 10405339
TI  - Cloning and functional characterization of CYP94A2, a medium chain fatty acid
      hydroxylase from Vicia sativa.
AB  - A full length cDNA encoding a new cytochrome P450-dependent fatty acid
      hydroxylase (CYP94A2) was isolated from a Vicia sativa library. CYP94A2 displays
      58% sequence identity with CYP94A1, a fatty acid omega-hydroxylase isolated from
      the same material. Heterologous expression of CYP94A2 in Saccharomyces cerevisiae
      yeast strain WAT11 shows that it catalyses the hydroxylation of myristic (C14)
      acid with a K(m(app)) of 4.0 microM and a turnover rate number of 80 min(-1). In
      addition, lauric (C12) and palmitic (C16) acids were hydroxylated at a ten-fold
      lower rate, while C18 fatty acids were not oxidized. Remarkably, the
      regiospecificity of hydroxylation is different for the C12, C14, and C16 fatty
      acids and appears to be correlated with the length of the carbon chain. Northern
      blot analysis showed a low level of constitutive expression of CYP94A2 in V.
      sativa seedlings. In contrast to CYP94A1, transcript accumulation of CYP94A2 was
      only weakly enhanced in seedlings treated with clofibrate or methyl jasmonate,
      indicating that both substrate range and gene regulation of the two fatty acid
      hydroxylases are different.

PMID- 10405340
TI  - Identification and localization of MEP1A-like sequences (MEP1AL1-4) in the human
      genome.
AB  - The human MEP1A gene encodes the meprin alpha subunit that consists of a protease
      domain conserved in the astacin family of metalloendopeptidases and several C
      terminal interaction domains present in other proteins. Using the alpha subunit
      cDNA, we identified two clones from a human P1-derived artificial chromosome
      (PAC) library. Fluorescence in situ hybridization (FISH) mapped both PACs (1e12,
      65a14) to chromosome 6p21, confirming the MEP1A location. FISH also mapped PAC
      65a14 to chromosome 13cen, and to chromosome 9 in three different regions, 9p12
      13, 9q21, and 9q22. Southern blot analysis showed that sequences of PAC 65a14 and
      MEP1A were similar in the 3' end but different in the 5' end, revealing for the
      first time that the human genome may encode multiple interaction domains highly
      similar to those of the meprin alpha subunit. The symbols of MEP1AL1, MEP1AL2,
      MEP1AL3, and MEP1AL4 have been designated for MEP1A-like sequences on 9p12-13,
      9q21, 9q22, and 13cen, respectively.

PMID- 10405341
TI  - Gene expression of a novel cytochrome P450 of the CYP4F subfamily in human
      seminal vesicles.
AB  - 19R-Hydroxyprostaglandins are major components of human seminal fluid. They are
      apparently formed in the seminal vesicles by NADPH-dependent omega2
      hydroxylation. The hydroxylase is likely a cytochrome P450 (CYP), which has not
      been identified. To address this issue we studied gene expression of CYPs in
      human seminal vesicles (n = 4) with reverse-transcription polymerase chain
      reaction (RT-PCR). CYP1B1, CYP2E1, CYP2J2, CYP3A5, CYP4B1, and CYP4B1 with
      insertion of three nucleotides (Ser207) were detected in all subjects. RT-PCR
      with degenerate primers for the CYP4 family yielded a novel cDNA sequence, which
      was derived from a previously reported genomic sequence on chromosome 19p13.1 and
      present in all subjects. cDNA cloning showed that the deduced amino acid sequence
      consisted of 520 amino acids. Northern blot analysis demonstrated mRNA
      transcripts of approximately 2.1 and approximately 2.3 kb. The deduced protein
      showed 81.2 and 76.7% amino acid identity with the human enzymes CYP4F2 and
      CYP4F3. The novel CYP was designated CYP4F8.

PMID- 10405342
TI  - Experimental induction of AGEs in fetal L132 lung cells changes the level of
      intracellular cathepsin D.
AB  - The effect of the carbonyl compound glyoxal on the induction of advanced
      glycation end products (AGEs) in the fetal epithelial lung cells L132 was
      investigated using immunohistochemical, immunoelectron microscopic, and
      biochemical methods. It was found that glyoxal treatment resulted in
      morphological changes of the cells and in the membranous and cytosolic
      localization of AGEs such as methyl-glyoxal-derived compounds, N
      (carboxymethyllysine) (CML) and imidazolone. The formation of AGEs was
      accompanied with a change in the intracellular expression of cathepsin D and a
      loss of enzymatic activity.

PMID- 10405343
TI  - Cloning and functional expression of a human heparanase gene.
AB  - We have cloned a gene (HSE1) from a human placental cDNA library that encodes a
      novel protein exhibiting heparanase activity. The cDNA was identified through
      peptide sequences derived from purified heparanase isolated from human SK-HEP-1
      hepatoma cells. HSE1 contains an open reading frame encoding a predicted
      polypeptide of 543 amino acids and possesses a putative signal sequence at its
      amino terminus. Northern blot analysis suggested strong expression of HSE1 in
      placenta and spleen. Transient transfection of HSE1 in COS7 cells resulted in the
      expression of a protein with an apparent molecular mass of 67-72 kDa. HSE1
      protein was detectable in conditioned media but was also associated with the
      membrane fraction following cell lysis. The HSE1 gene product was shown to
      exhibit heparanase activity by specifically cleaving a labeled heparan sulfate
      substrate in a similar manner as purified native protein.

PMID- 10405344
TI  - Pharbin, a novel inositol polyphosphate 5-phosphatase, induces dendritic
      appearances in fibroblasts.
AB  - We have cloned a cDNA encoding a novel protein pharbin with a homology to
      inositol polyphosphate 5-phosphatases. Pharbin contains relatively well-conserved
      catalytic motifs for 5-phosphatase, a proline-rich sequence corresponding to the
      SH3-binding motif, and a sequence consistent with the CaaX motif at the C
      terminus. COS-7 cells transfected with pharbin exhibited elevated hydrolytic
      activity on the 5-phosphate group of inositol 1,4,5-trisphosphate, inositol
      1,3,4,5-tetrakisphosphate, and phosphatidylinositol 4, 5-bisphosphate. Thus,
      pharbin indeed serves as an inositol polyphosphate 5-phosphatase. When pharbin
      was transfected to C3H/10T1/2 fibroblasts, it was located to the plasma membrane
      associated structures including membrane ruffles. The cells were converted to
      dendritic forms within 24 h. The protein with deleted or point-mutated CaaX motif
      hardly induced the dendritic forms but remained associated with the membranes.
      These results imply that the CaaX motif is required for the morphological
      alteration but that some other structural element is likely to also be
      responsible for the membrane localization.

PMID- 10405345
TI  - A convenient microscale colorimetric method for terminal galactose on
      immunoglobulins.
AB  - A new approach for quantitative determination of terminal galactose (Gal)
      residues of immunoglobulins was developed by combining exoglycosidase digestion
      with the classical colorimetric estimation of reducing sugars. The ferricyanide
      colorimetric method was modified to increase the stability of the chromophore
      (Prussian blue) and adapted to determine the amount of terminal Gal residues
      present in immunoglobulins. The method involves the release of covalently bound
      Gal from immunoglobulins by Diplococcus pneumoniae beta-D-galactosidase (specific
      for beta(1,4) linked galactose), removal of the glycoprotein and enzyme from the
      reaction mixture by heat denaturation or ethanol precipitation, followed by
      colorimetric measurement of the released sugar using the ferricyanide assay. The
      ferricyanide method was modified to enhance the solubility and stability of the
      chromophore by increasing the concentration of aqueous sulfuric acid and sodium
      dodecyl sulfate (SDS). The linear range of the modified method was from
      approximately 11 to 111 microM Gal. Typical variation in assay results was on the
      order of 5%. Using the modified method, the terminal Gal content of a recombinant
      chimeric monoclonal antibody (anti-CD20, rIgG) expressed in Chinese hamster ovary
      (CHO) cells was determined and evaluated for batch-to-batch consistency. The
      method was used to optimize pH, time, temperature, and enzyme concentration for
      beta-galactosidase digestion for maximal release of terminal Gal residues from
      rIgG.

PMID- 10405346
TI  - Hypertension augments ethanol-induced depression of cell shortening and
      intracellular Ca(2+) transients in adult rat ventricular myocytes.
AB  - Ethanol, a risk factor for myocardial dysfunction, depresses myocardial
      contraction. This study was to determine whether ethanol-induced myocardial
      depression is affected by hypertension. Mechanical properties of ventricular
      myocytes isolated from both normotensive Wistar-Kyoto (WKY) and spontaneously
      hypertensive (SHR) rats were evaluated using a video edge-detection system.
      Myocytes were electrically stimulated to contract at 0.5 Hz. Contractile
      properties analyzed include peak twitch amplitude (PTA), time-to-PTA (TPS), time
      to-90% relengthening (TR(90)), and maximal velocities of shortening/relengthening
      (+/-dL/dt). Intracellular Ca(2+) transients were measured as fura-2 fluorescence
      intensity (DeltaFFI) changes. Acute ethanol exposure (80-640 mg/dl) caused a
      concentration-dependent inhibition of PTA and DeltaFFI in both WKY and SHR
      myocytes. The extent of maximal inhibition of PTA and FFI was significantly
      greater in SHRs (53.7 and 38.9%) compared to the WKY group (21.0 and 25.4%).
      Ethanol did not affect TPS but shortened TR(90) and slowed +/-dL/dt at high
      concentration ranges. Interestingly, the augmented ethanol-induced inhibition of
      cell shortening in hypertension was greatly attenuated by Ca(2+) channel opener
      BayK 8644 (1 microM). These results suggest that ethanol-induced myocardial
      depression may be augmented in hypertension, possibly due to mechanism(s)
      involving sarcolemmal Ca(2+) channels.

PMID- 10405347
TI  - Analogs of MTII, lactam derivatives of alpha-melanotropin, modified at the N
      terminus, and their selectivity at human melanocortin receptors 3, 4, and 5.
AB  - In search for selective agonists at human melanocortin-4 receptor, proline
      substituted analogs of MTII, a potent nonselective agonist at melanocortin
      receptors, were prepared by solid-phase syntheses and evaluated for their ability
      to bind and activate human MC-3, MC-4, and MC-5 receptors. Replacement of Nle(4)
      with Pro resulted in [Pro(4)]MTII with affinity to and agonist potency at hMC-4R
      similar to MTII, but with about 400-fold lower potency at hMC-5R and about 20
      fold lower potency at hMC-3R. The substantial increase in selectivity of
      [Pro(4)]MTII with respect to hMC-5R prompted us to investigate additional analogs
      of MTII with modified N-termini. The Ac-Nle(4) segment, not encompassed in the
      lactam ring, was substituted with flexible, hydrophobic, or hydrophilic
      substituents, and also, with residues resembling proline. The similar agonist
      potency of these peptides to that of MTII at hMC-4R but significantly lower
      activity of these compounds at hMC-5R demonstrated that the N-terminal fragment
      of MTII has virtually no effect on the binding affinity and activation at hMC-4R,
      but it is essential for full potency at hMC-5R.

PMID- 10405348
TI  - Inhibition of tumor necrosis factor alpha-stimulated aromatase activity by
      microtubule-stabilizing agents, paclitaxel and 2-methoxyestradiol.
AB  - The aromatase enzyme, which converts androstenedione to oestrone, regulates the
      availability of oestrogen to support the growth of hormone-dependent breast
      tumours. Cytokines, such as interleukin 6 (IL-6) and tumour necrosis factor alpha
      (TNFalpha) or prostaglandin E(2) (PGE(2)), can stimulate aromatase activity.
      These factors may originate from cells of the immune system that infiltrate
      breast tumours. Paclitaxel, which is used in the treatment of breast cancer,
      stabilizes microtubules and has previously been shown to rapidly down-regulate
      TNF-receptors on human macrophages. The endogenous oestrogen metabolite, 2
      methoxyestradiol (2-meOE2), also acts to stabilize microtubules. In this study,
      we have examined the ability of paclitaxel or 2-meOE2 to antagonise TNFalpha
      stimulated aromatase activity in stromal fibroblasts derived from normal or
      malignant breast tissues. Paclitaxel inhibited basal and TNFalpha-stimulated
      aromatase activities by 88% and 91% respectively. 2-MeOE2 also reduced basal and
      TNFalpha-stimulated aromatase activities by 46% and 56% respectively. Both
      paclitaxel and 2-meOE2 also inhibited stimulation of aromatase activity by IL-6
      plus its soluble receptor and PGE(2). The 16alpha-hydroxylated derivative of 2
      meoE2 and 2-meOE3, which does not bind to microtubules, was less effective at
      inhibiting TNFalpha-stimulated aromatase activity. Increased 2-hydroxylation of
      oestrogens, and subsequent formation of their 2-methoxy derivatives, may be
      associated with a reduced risk of breast cancer. It is possible that the pathway
      of oestrogen metabolism may influence the ability of stromal cells to respond to
      cytokine stimulation.

PMID- 10405349
TI  - Lipoxygenase inhibitors abolish proliferation of 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, but their role in pancreatic
      cancer growth is unknown. The expression of 5-LOX and 12-LOX as well as their
      effects on cell proliferation was investigated in four human pancreatic cancer
      cell lines (PANC-1, MiaPaca2, Capan2, and ASPC-1). Expression of 5-LOX and 12-LOX
      mRNA was measured by nested RT-PCR. Effects of LOX inhibitors and specific LOX
      antisense oligonucleotides on pancreatic cancer cell proliferation were measured
      by (3)H-thymidine incorporation. Our results showed that (1) 5-LOX and 12-LOX
      were expressed in all pancreatic cancer cell lines tested, while they were not
      detectable in normal human pancreatic ductal cells; (2) both LOX inhibitors and
      LOX antisense markedly inhibited cell proliferation in a concentration-dependent
      and time-dependent manner; (3) the 5-LOX and 12-LOX metabolites 5-HETE and 12
      HETE as well as arachidonic and linoleic acids directly stimulated pancreatic
      cancer cell proliferation; (4) LOX inhibitor-induced growth inhibition was
      reversed by 5-HETE and 12-HETE. The current studies indicate that both 5-LOX and
      12-LOX expression is upregulated in human pancreatic cancer cells and LOX plays a
      critical role in pancreatic cancer cell proliferation. LOX inhibitors may be
      valuable for the treatment of pancreatic cancer.

PMID- 10405350
TI  - Molecular cloning and characterization of MSRV-related sequences associated with
      retrovirus-like particles.
AB  - New sequences have been obtained by successive overlapping RT-PCR extensions from
      the pol region of a retroviral RNA (multiple sclerosis-associated retroviral
      element, MSRV) amplified in retrovirus-like particles from patients with multiple
      sclerosis. gag and pol sequences are related to type C oncoviruses, whereas the
      env sequence is closer to type D. A tryptophan-like (W) tRNA primer-binding site
      was identified downstream of the RU5 region in the 5'LTR, and the U3R region
      cloned in the 3'LTR exhibited potent promoter activity. MSRV clones define a
      novel family of endogenous elements, HERV-W. From our data, HERV-W RNAs are
      copackaged in extracellular particles which might be produced by replication
      competent or transcomplemented HERV-W copies or by an exogenous member of the
      HERV-W family.

PMID- 10405351
TI  - Three-dimensional visualization of tegument/capsid interactions in the intact
      human cytomegalovirus.
AB  - The three-dimensional structure of the intact human cytomegalovirus (HCMV) was
      determined to 18-A resolution by electron cryomicroscopy and computer
      reconstruction. Its capsid shell is composed of pentons, hexons, and triplexes
      arranged on a T = 16 icosahedral lattice and is identical to that of the B-capsid
      isolated from host cell nuclei. An icosahedrally ordered tegument layer formed by
      960 copies of filamentous density is also visualized, which interacts with the
      pentons, hexons, and triplexes of the underlying capsid. The observed structural
      similarities and differences of HCMV with those of herpes simplex virus offer
      insights into the significance of the different tegument components for their
      infection processes while maintaining similar capsids.

PMID- 10405352
TI  - Complete circular DNA genome of a TT virus variant (isolate name SANBAN) and 44
      partial ORF2 sequences implicating a great degree of diversity beyond genotypes.
AB  - Information on the entire genome of TT virus (TTV) has been scarce. The circular
      ssDNA genome of a variant (isolate name SANBAN) that we sequenced was only 56.7%
      homologous to the prototype isolate (TA278), with even lower homology at the
      amino acid level: 34.2% for ORF1 and 39.7% for ORF2. Regarding the ORF1, SANBAN
      was only very distantly related to the six major TTV genotypes reported to date.
      In partial ORF2 sequences determined on 44 isolates taken together, TTV has a
      broad range of genetic diversity and the SANBAN isolate may represent a new TTV
      like viral species or genus and not merely a genotype of TTV.

PMID- 10405353
TI  - Localization of actin in Moloney murine leukemia virus by immunoelectron
      microscopy.
AB  - Immunoelectron microscopy was used to detect actin in wild-type (wt) Moloney
      murine leukemia virus (MoMuLV) and in virus-like particles (VLP) produced by
      recombinant Semliki Forest virus expressing only the MoMuLV gag polyprotein. Gold
      immunolabeling revealed the presence of actin on the surface of delipidized VLP
      and delipidized wt virus particles. Statistical evaluation of the number of
      colloidal gold particles per VLP revealed a large range of values and a
      prevalence of VLP with small numbers of gold particles. Labeling for actin was
      lost after prolonged treatment of VLP with 1% Nonidet-P40, high-pH buffer, or
      gelsolin. Gold immunolabeling with antibodies to gag proteins p15 (MA) and p12
      and p30 (CA) was abundant and was not affected by treatment of VLP or wt virus
      with 1% Nonidet or gelsolin. VLP treated with a mixture of detergent and aldehyde
      fixatives showed more uniform and consistent labeling for actin than without
      fixatives. Negative staining or heavy metal shadowing revealed a globular surface
      of delipidized VLP. Stereomicrographs of gold-immunolabeled VLP showed that
      p15gag and p12gag were associated with the globular projections. Delipidized VLP
      were also well labeled with antibody to p30gag, which indicated that the gag
      shell permitted access of antibodies to p30gag and was therefore not a closely
      packed structure. Labeling for actin-binding proteins moesin and ezrin was
      negative in both the wt virus and the VLP. The absence of Gaussian distribution
      of actin in the sample of VLP suggests that actin is not a structural protein and
      its presence in MuLV virus particles may be fortuitous. This, however, does not
      rule out any possible role of actin in transport, assembly, budding, or release
      of virus particles, events which take place in the cytoplasm or at the plasma
      membrane. The site of actin in VLP is discussed in relation to the present
      knowledge of the molecular organization of the MuLV gag shell.

PMID- 10405354
TI  - Immune responses and protection induced by DNA vaccines encoding bovine
      parainfluenza virus type 3 glycoproteins.
AB  - This study was designed to assess the parameters influencing the magnitude and
      type of immune responses generated to plasmids encoding the
      hemagglutinin/neuraminidase (HN) and fusion (F) proteins of bovine
      parainfluenzavirus type 3 (BPIV3). Mice immunized with plasmids expressing HN or
      F under control of the Rous sarcoma virus long terminal repeat promoter were
      primed, but they did not develop measurable immune responses. In contrast, strong
      humoral and cellular immune responses were induced with constructs containing the
      human cytomegalovirus immediate-early promoter and intron A. After immunization
      with both HN- and F-encoding plasmids, enhanced responses were observed. Analysis
      of in vitro protein synthesis confirmed that the presence of the intron is
      crucial for the expression of the BPIV3 HN gene. Plasmid encoding HN induced
      significantly higher serum antibody titers by intradermal injection than by
      intramuscular delivery, whereas antigen-specific T cell proliferation was
      stronger in intramuscularly injected mice. Both the isotype ratios and the
      cytokine profiles indicated a Th1-type response after intramuscular immunization
      and a mixed to Th2-type response in intradermally immunized mice. A plasmid
      encoding a truncated, secreted form of HN induced a Th2-type immune response,
      regardless of the route of delivery. In cotton rats, HN- and F-encoding plasmids
      conferred protection from BPIV3 challenge.

PMID- 10405355
TI  - Comparison of the immunoglobulin-G-specific seroreactivity of different
      recombinant antigens of the human herpesvirus 8.
AB  - The open reading frames ORF 52, ORF 65, K12, and K8.1 of the human herpesvirus 8
      (HHV8) were expressed as glutathione-S-transferase (GST) fusion proteins and
      analysed by Western blotting (WB) and enzyme-linked immunosorbent assay (ELISA).
      The open reading frame (ORF) 65 and K8.1 antigens gave the highest reactivity
      (71%) in sera from HIV-dependent Kaposi's sarcoma (KS) patients. Therefore both
      antigens appear to be essential for HHV8 diagnostics, whereas ORF K12 and ORF 52
      were of minor importance. Using polymerase chain reaction (PCR) out of the
      peripheral blood of these KS patients, 48% were detected as positive. By testing
      an N-terminal-deleted construct (amino acid 80-171) of ORF 65, we could show that
      the N-terminal region of this protein is essential to mediate full immunogenic
      reactivity. By analysing different deletion mutants of ORF K8.1, the major
      epitope was found to be located between aa 29 and 101. The prevalence of
      antibodies directed against the different antigens was determined for healthy
      blood donors to be 3-6%. The different antibody patterns obtained in HIV-patients
      with and without KS support the hypothesis that different antibody profiles
      develop during the course of KS.

PMID- 10405356
TI  - Evidence for two nonoverlapping functional domains in the potato virus X 25K
      movement protein.
AB  - To study subdomain organization of the potato virus X (PVX) movement protein (MP)
      encoded by the first gene in the triple gene block (TGB), we mutated the 25-kDa
      TGBp1 protein. The N-terminal deletion of the helicase motifs I, IA, and II
      resulted in loss of the ATPase activity and RNA binding. A frameshift mutation
      truncating the C-terminal motifs V and VI gave rise to increase of the TGBp1
      ATPase activity and had little effect on RNA binding in vitro. Fusions of the
      green fluorescent protein with 25-kDa MP and its derivative lacking motifs V-VI
      exhibited similar fluorescence patterns in epidermal cells of Nicotiana
      benthamiana leaves. Cell-to-cell movement of the 25K-deficient PVX genome was not
      complemented by the TGBp1 of Plantago asiatica mosaic potexvirus (PlAMV) but was
      efficiently complemented by a chimeric TGBp1 consisting of the N-terminal part of
      PlAMV protein (motifs I-IV) and the PVX-specific C-terminal part (motifs V-VI).
      These results suggest that NTP hydrolysis, RNA binding, and targeting to the
      specific cellular compartment(s) are associated with the N-terminal domain of the
      TGBp1 including the helicase motifs I-IV and that the C-terminal domain is
      involved in specific interactions with other virus proteins.

PMID- 10405357
TI  - Comparison of the assembly of the bacteriophage T4 clamp loader complex (gp44/62)
      expressed in a cis versus trans genomic configuration.
AB  - Proper formation of the bacteriophage T4 DNA polymerase holoenzyme requires a
      wide spectrum of protein-protein and protein-DNA interactions among the DNA
      polymerase gp43, the sliding clamp gp45, and gp44/62, the clamp loader complex
      (CLC). The 44 and 62 proteins associate to form a tight complex maintained in a
      4:1 ratio. The 44 and 62 genes are adjacent to each other on the T4 genome, are
      cotranscribed, and are translationally coupled. It has been suggested that
      translational coupling may play a role in the formation of the clamp loader
      complex and may control its stoichiometry. To examine the effect of coupling on
      the assembly of the complex, expression in trans of genes 44 and 62 was
      accomplished by cotransforming Escherichia coli with compatible, inducible
      plasmid vectors. A gp44/62 complex could be purified from such cells. The complex
      assembled in trans exhibited stoichiometry and ATPase activity identical to
      native complex. Burst sizes were determined to gauge the efficiency of clamp
      loader complex formation. When gp44 was supplied by a plasmid and gp62 was
      supplied by the T4 genome, complex formation was as efficient as in wild-type
      virus. However, when gp62 was supplied by plasmid and gp44 was supplied by the T4
      genome, efficiency of complex formation was decreased. This decrease in the
      efficiency of complex formation was temperature dependent, being more pronounced
      at higher temperatures. At higher temperatures, a larger proportion of gp62
      expressed from the plasmid was found to be present in an insoluble form. The
      decrease in efficiency of complex formation correlated to a decrease in
      solubility of the gene 62 protein.

PMID- 10405358
TI  - Muscle-specific expression of hepatitis B surface antigen: no effect on DNA
      raised immune responses.
AB  - The injection of plasmid DNA encoding hepatitis B virus (HBV) envelope proteins
      in mouse muscle leads to the induction of specific humoral and cellular immune
      responses. Most studies on DNA-based immunization have used viral promoters to
      drive antigen expression. In this study, we compared the efficiency of a muscle
      specific promoter, the human desmin gene promoter, with the commonly used
      cytomegalovirus (CMV) early gene promoter. We showed that increased in vitro
      expression of HBV envelope proteins from the human desmin gene promoter has no
      effect on the in vivo immune response even after the injection of as little as 10
      micrograms of DNA. The injection of vectors encoding HBV envelope proteins under
      the control of either the human desmin gene promoter or the CMV promoter induced
      humoral and cytotoxic immune responses at comparable levels and of the same
      duration. The recruitment of antigen-presenting cells to the DNA injection site
      by pretreatment of muscle with a necrotizing agent increases the precocity and
      the intensity of the responses, particularly when the nonspecific CMV vector was
      used.

PMID- 10405359
TI  - Influence of the human high-affinity IgG receptor FcgammaRI (CD64) on residual
      infectivity of neutralized dengue virus.
AB  - We examined dengue virus immune complex-phagocyte interaction with respect to a
      single Fc receptor class using a transient expression system involving the high
      affinity human macrophage receptor, FcgammaRI. We found that New Guinea C strain
      dengue 2 virus formed well-defined plaques in normal and transfected COS cells
      and we analyzed the structural determinants of FcgammaRI-mediated binding and
      internalization of dengue 2 virus immune complexes by expressing native or
      truncated forms of the receptor in COS cells, alone or with its accessory gamma
      chain signaling unit, which bears an immunoreceptor tyrosine-based activation
      motif (ITAM). The residual infectivity of dengue 2 virus treated with
      neutralizing human antiserum was strikingly higher in FcgammaRI-bearing COS cells
      than in controls. Compatible with the IgG subclass specificity of FcgammaRI, this
      difference was abrogated quantitatively by treatment of FcgammaRI-transfected
      cells with human IgG1 but not IgG2 myeloma protein. The magnitude of receptor
      mediated plaque formation after cotransfection with gamma chain was also
      significantly higher than in controls but was less than that observed with
      FcgammaRI transfection only, a difference probably explained by reduced levels of
      FcgammaRI expression in gamma chain cotransfectants. Deletion of the FcgammaRI
      cytoplasmic domain had no effect on receptor-mediated immune complex infectivity.
      We conclude that the FcgammaRI extracellular domain is sufficient for
      internalization of infectious dengue virus immune complexes through a mechanism
      that does not involve classical ITAM-dependent signaling.

PMID- 10405360
TI  - Major product pp43 of human cytomegalovirus U(L)112-113 gene is a transcriptional
      coactivator with two functionally distinct domains.
AB  - Human cytomegalovirus U(L)112-113 encodes four phosphoproteins, pp84, pp50, pp43,
      and pp34, with common amino-termini. A previous report by Kerry et al. (J. Virol.
      70, 373-382, 1996) demonstrated that U(L)112-113 products activate U(L)54
      promoter in cooperation with immediate-early (IE) proteins. In this study, we
      identified a domain required for transcriptional activation in the pp43 protein,
      which consisted of two distinct regions: domain I (amino acids 272-296) and
      domain II (amino acids 297-306). Domain I contained two long glycine stretches,
      and domain II was a short proline-containing region. Both of domains were
      required for IE2-dependent transcriptional activation. The pp43 mutant that had
      domain I but lacked domain II acted as a dominant negative mutant and suppressed
      most of the IE2-dependent activation, indicating the importance of coactivation
      by pp43 in this transcriptional activation. The major protein pp43 also weakly
      activated the promoter through IR1 element in a manner independent of IE2. Only
      domain I was required for this IE2-independent activation. These domains were
      common in pp84, pp50, and pp43 but did not exist in pp34, which did not activate
      transcription alone. These results suggest that the major product, pp43, of
      U(L)112-113 has two functionally distinct domains and plays an important role in
      mediating IE2-dependent transcriptional activation.

PMID- 10405361
TI  - Host-specific cell-to-cell and long-distance movements of cucumber mosaic virus
      are facilitated by the movement protein of groundnut rosette virus.
AB  - The cucumovirus, cucumber mosaic virus (CMV), requires both the 3a movement
      protein (MP) and the capsid protein (CP) for cell-to-cell movement. Replacement
      of the MP of CMV with the MP of the umbravirus, groundnut rosette virus (GRV),
      which does not encode a CP, resulted in a hybrid virus, CMV(ORF4), which could
      move cell to cell in Nicotiana tabacum and long distance in N. benthamiana. After
      replacement of the CMV CP in CMV(ORF4) with the gene encoding the green
      fluorescent protein (GFP), the hybrid virus, CMV(ORF4.GFP), expressing both the
      GRV MP and the GFP, could move cell to cell but not systemically in either
      Nicotiana species. Immunoelectron microscopic analysis of cells infected by the
      hybrid viruses showed different cellular barriers in the vasculature preventing
      long-distance movement of CMV(ORF4) in N. tabacum and CMV(ORF4.GFP) in N.
      benthamiana. Thus the GRV MP, which shows limited sequence similarity to the CMV
      MP, was able to support CP-independent cell-to-cell movement of the hybrid virus,
      but CP was still required for long-distance movement and entry of particular
      vascular cells required functions encoded by different proteins.

PMID- 10405362
TI  - Dose-dependent transduction of vesicular stomatitis virus G protein-pseudotyped
      retrovirus vector into human solid tumor cell lines and murine fibroblasts.
AB  - We examined the transduction efficiency of a VSV-G (vesicular stomatitis virus G
      protein)-pseudotyped vector encoding beta-galactosidase (lacZ) into human solid
      tumor cell lines and murine fibroblasts, compared with that of an amphotropic
      vector carrying the same RNA sequence. The ratio of cells transduced with the VSV
      G-pseudotyped vector corresponded closely to 1 - e(-m.o.i.), as predicted from a
      Poisson distribution of transduction to the entire cellular population, while
      this was not the case for the amphotropic vector. Here m.o.i. (multiplicity of
      infection) is defined as the ratio of input infectious units (titrated on the
      corresponding cell line) to the number of cells used for the transduction. At
      high m.o.i.s (values greater than 3), the VSV-G-pseudotyped vector transduced
      approximately 95% of the culture population of all cell lines examined. The
      transduction efficiency of the amphotropic vector, however, was not dose
      dependent and reached a plateau or even decreased, especially at high m.o.i.;
      this may be attributable at least in part to the presence of envelope protein and
      noninfectious particles that compete for the receptor of infectious amphotropic
      virus. The copy number of integrated vector proviral DNA and the expression level
      of lacZ increased almost linearly with the dose of the VSV-G-pseudotyed vector,
      which could readily achieve multiple transduction of more than 10 copies per cell
      and afforded about 100-fold more transgene product than could be achieved with
      the amphotropic vector. These features of both the VSV-G-pseudotyped vector and
      the amphotropic vector were essentially unaffected by purification using
      centrifugation. These properties of the vector should be highly advantageous for
      gene transfer into entire populations of human tumor cell lines at a designed
      dosage.

PMID- 10405363
TI  - Isolation and partial characterization of a lentivirus from talapoin monkeys
      (Myopithecus talapoin).
AB  - We have identified a novel lentivirus prevalent in talapoin monkeys (Myopithecus
      talapoin), extending previous observations of human immunodeficiency virus-1
      cross-reactive antibodies in the serum of these monkeys. We obtained a virus
      isolate from one of three seropositive monkeys initially available to us. The
      virus was tentatively named simian immunodeficiency virus from talapoin monkeys
      (SIVtal). Despite the difficulty of isolating this virus, it was readily passed
      between monkeys in captivity through unknown routes of transmission. The virus
      could be propagated for short terms in peripheral blood mononuclear cells of
      talapoin monkeys but not in human peripheral blood mononuclear cells or human T
      cell lines. The propagated virus was used to infect a naive talapoin monkey, four
      rhesus macaques (M. mulatta), and two cynomolgus macaques (M. fascicularis). All
      animals seroconverted and virus could be reisolated during a short period after
      experimental infection. A survey of SIVtal-infected captive talapoin monkeys
      revealed a relative decrease in CD4(+) cell numbers in chronically (>2 years)
      infected animals. No other signs of immunodeficiency were observed in any of the
      infected animals. PCR amplification followed by DNA sequencing of two fragments
      of the polymerase gene revealed that SIVtal is different from the presently known
      lentiviruses and perhaps most related to the SIV from Sykes monkeys.

PMID- 10405364
TI  - Attenuation of the recombinant human parainfluenza virus type 3 cp45 candidate
      vaccine virus is augmented by importation of the respiratory syncytial virus
      cpts530 L polymerase mutation.
AB  - A phenylalanine to leucine mutation at position 521 in the L polymerase of
      cpts530, a live-attenuated respiratory syncytial virus (RSV) cold-passaged (cp),
      temperature-sensitive (ts) candidate vaccine, specifies the ts and attenuation
      (att) phenotypes. Sequence alignment of this region in the L proteins of several
      distantly related paramyxoviruses revealed that this phenylalanine is conserved.
      Using reverse genetics, the analogous phenylalanine at position 456 in the L
      protein of wild-type PIV3 was mutagenized to leucine (F456L). The resulting
      virus, designated r456(L), was ts (40 degrees C shut-off temperature of plaque
      formation), and its replication in the upper, but not the lower, respiratory
      tract of hamsters was 10-fold reduced compared with that of the recombinant wild
      type PIV3 (rwt). Thus the phenylalanine to leucine mutation specified a similar
      level of temperature sensitivity and attenuation in two distantly related
      paramyxoviruses. We next sought to determine whether the addition of this
      mutation to the L protein of two rPIV3 candidate vaccine viruses, one bearing the
      three cp45 ts missense mutations in the L protein (rcp45(L)) and the other
      bearing all 15 cp45 mutations (rcp45), would further attenuate the viruses in
      vivo. Each rcp45 derivative to which the F456L mutation was added exhibited an
      increased level of temperature sensitivity. Furthermore rcp45(L)-456 and rcp45
      456 were 100- to 1000-fold more restricted in replication in hamsters than their
      rcp45(L) and rcp45 parents. Despite the high level of restriction of replication
      in hamsters, immunization with rcp45-456 induced a moderate level of resistance
      to replication of PIV3 challenge virus. In contrast to the highly restricted
      replication observed in hamsters, rcp45-456 was only fivefold more restricted in
      the respiratory tract of chimpanzees than rcp45 and induced a comparable,
      moderate to high level of PIV3-specific serum antibodies. rcp45 and rcp45-456
      viruses isolated from chimpanzees throughout the 2-week course of replication
      maintained the level of temperature sensitivity of their respective input
      viruses, illustrating their phenotypic stability. Thus the acquisition of the
      F456L mutation by the cp45 virus resulted in a small, incremental increase in its
      level of attenuation, indicating its possible usefulness in the fine tuning of
      the level of attenuation of the cp45 vaccine candidate. The ability to transfer
      mutations identified in heterologous paramyxoviruses, which in this case
      represent different subfamilies, greatly enhances our ability to rapidly develop
      novel parainfluenza virus candidate vaccines.

PMID- 10405366
TI  - Quantification of endogenous viral polymerase, 3D(pol), in preparations of Mengo
      and encephalomyocarditis viruses.
AB  - Measurement of an antigenic response to the aphthovirus infection-associated
      antigen (VIA), the viral RNA polymerase 3D(pol), is frequently used as a
      discriminating assay for the extent of viral replication in animals. In practice,
      animals seropositive for VIA are assumed to have been exposed to live virus,
      although in fact it is suspected that endogenous 3D(pol) in commercial
      inactivated vaccines may occasionally stimulate analogous responses and result in
      false-positive tests for virus exposure. Cardiovirus infections in mice produce
      similar anti-VIA antibodies, and in view of recently developed attenuated Mengo
      vaccines and live Mengo vectors, these VIA responses are also under investigation
      as potential correlates of vaccine efficacy. We have purified recombinant Mengo
      3D(pol), developed monoclonal antibodies to the protein, and used these reagents
      in highly sensitive Western blot assays to quantify the levels of endogenous
      3D(pol) in Mengo and encephalomyocarditis virus (EMCV) preparations. The presence
      of 3D(pol) was detected at all stages of standard vaccine purification
      procedures, including materials purified by CsCl. Clarified suspensions of Mengo-
      or encephalomyocarditis virus-infected HeLa cells were found to contain very high
      quantities of 3D(pol), averaging approximately 1.2-1.5 micrograms of
      protein/micrograms of virus. Pelleting through 30% sucrose or purification by
      CsCl removed much of this material, but even these samples retained approximately
      0.2-0.4 ng of 3D(pol)/micrograms virus. These ratios represent approximately 1
      3D(pol) molecule/20 virus particles in the most highly purified materials and
      probably indicate that 3D(pol) is a contaminant on the particle surface rather
      than an intrinsically packaged molecule. In clarified cell lysates, which are
      commonly used as vaccine inocula, the protein to virus ratio was approximately
      210:1, a level that could represent serious contamination problems for future VIA
      detection if such inocula are used without further purification.

PMID- 10405365
TI  - Lymphotoxin-beta-deficient mice show defective antiviral immunity.
AB  - Lymphotoxin beta (LTbeta), a member of the tumor necrosis factor family, plays an
      important role in lymphoid organogenesis. In order to determine whether LTbeta is
      involved in cellular immunity, we investigated the antiviral immune response of
      LTbeta-deficient (LTbeta -/-) mice to lymphocytic choriomeningitis virus (LCMV).
      Cytotoxic T lymphocyte (CTL) responses to LCMV were severely diminished, leading
      to viral persistence in brain and kidney. However, major functions of LTbeta
      deficient T lymphocytes and dendritic cells were intact. Reconstitution of
      irradiated LTbeta +/+ mice with LTbeta -/- bone marrow induced a disorganized
      splenic structure, accompanied by impairment of the LCMV-specific CTL response.
      These data indicate that the absence of LTbeta does not affect the intrinsic
      function of T lymphocytes or of dendritic cells but that the structural integrity
      of the spleen is strongly associated with generation of antiviral immunity.

PMID- 10405367
TI  - Transcriptional analysis of the murine cytomegalovirus HindIII-I region:
      identification of a novel immediate-early gene region.
AB  - Cytomegaloviruses likely encode numerous gene products involved in regulating
      virus-host cell interactions and pathogenesis. We previously identified a region
      of murine cytomegalovirus (MCMV) within HindIII-J and -I that regulates
      pathogenesis of the virus [open reading frames (ORFs) M139-M141] or is likely
      required for MCMV replication (ORFs m142 and m143). As a prerequisite for further
      studies on the structure and function of this gene region, we mapped the
      transcripts encoded within MCMV HindIII-I. Probes for ORFs M140 and M141
      hybridized to 5.4- and 7.0-kb RNA, respectively, which were transcribed with
      early kinetics and were 3' coterminal with HindIII-J ORF M139. Probes
      representing ORFs m142, m143, or m144 hybridized to 3' coterminal transcripts of
      1.8, 3.8, and 5.1 kb, respectively. ORFs m142 and m143 were transcribed with
      immediate-early kinetics but were most abundantly expressed at early times.
      Probes for the rightmost end of HindIII-I hybridized to a 5. 1-kb early/late RNA
      corresponding to m144 and to a 1.8-kb early RNA transcribed from m145. All of the
      major transcripts were polyadenylated and therefore are likely coding. Additional
      minor transcripts of intermediate sizes were also detected. ORFs M139-m143 showed
      homology to the betaherpesvirus-specific HCMV US22 gene family. Because deletion
      of these viral genes results in attenuated or helper-dependent phenotypes, this
      conserved region of US22 family genes may have a role in virus replication as
      well as in the pathogenesis of betaherpesviruses in their natural hosts.

PMID- 10405369
TI  - Subcellular localization of the HSP70-homolog encoded by beet yellows
      closterovirus.
AB  - Closteroviridae is the only viral family coding for a homolog of HSP70 (HSP70h).
      Polyclonal antiserum to recombinant beet yellows closterovirus (BYV) HSP70h was
      generated and used for immunogold labeling of the leaf samples derived from the
      infected Nicotiana benthamiana plants. Ultrastructural analysis revealed the
      preferential accumulation of BYV in phloem, although occasional infection of the
      leaf mesophyll cells was also observed. The strongest HSP70h-specific labeling
      was associated with virion aggregates and vesicles harboring scattered virions.
      HSP70h was also observed in close proximity of plasmodesmata and inside the
      plasmodesmatal channels. The possible role of the BYV HSP70h in RNA encapsidation
      was tested in tobacco protoplasts. A BYV mutant possessing an inactivated HSP70h
      gene exhibited no detectable encapsidation defects. Collectively, the obtained
      results suggested that closteroviral HSP70h escorts the virions to their
      destinations inside the infected cells and possibly participates in the
      intercellular translocation of BYV.

PMID- 10405368
TI  - Nucleotide sequence and characterization of human papillomavirus type 83, a novel
      genital papillomavirus.
AB  - Studies of human papillomaviruses (HPV) are hampered by the lack of a
      conventional culture system, because HPV completes its life cycle only in fully
      differentiated human tissue. To overcome this obstacle, the athymic mouse
      xenograft system has been used to study the pathogenesis of a limited number of
      HPV types. We recently reported the propagation of a novel HPV type in the mouse
      xenograft system and the cloning of its genome. Consensus primer PCR had
      previously identified this virus as MM7, LVX82, or PAP291. Here we report the
      nucleotide sequence of the 8104-bp genome of this virus, now called HPV 83. HPV
      83 is most closely related to HPV 61 and HPV 72, placing it in the papillomavirus
      genome homology group A3. Based on limited epidemiological data, the histological
      appearance of infected human foreskin implants, and the structure of the
      predicted HPV 83 E7 protein, this virus is probably of at least intermediate
      cancer risk. Like other papillomaviruses, HPV 83 produces an E1 E4, E5
      transcript, but the position of the splice acceptor differs from that of other
      HPVs. The presence of an E5 open reading frame in the HPV 83 genome is uncertain;
      the most likely candidate to be the HPV 83 E5 protein has some structural
      similarity to the bovine papillomavirus 1 E5 oncoprotein, and is unlike most
      other HPV E5 proteins. HPV 83 is a relatively prevalent genital papillomavirus
      that has the largest genome of any characterized HPV and several other novel
      structural features that merit further study.

PMID- 10405370
TI  - Effect of C-terminal mutations of alfalfa mosaic virus coat protein on dimer
      formation and assembly in vitro.
AB  - The coat protein (CP) of alfalfa mosaic virus (AMV) strain 425 assembles to
      bacilliform or rod-shaped particles in the presence of nucleic acids or to T = 1
      empty icosahedral particles in the absence of nucleic acids. To study the
      determinants of CP assembly, recombinant CPs (rCPs) that contained a (His)(6)
      region were expressed in Escherichia coli. Wt rCP and a mutant rCP, which lacked
      the last nine amino acids of the C terminus (amino acids 213-221), assembled to
      particles that were identical in electron micrographs. However, a mutant rCP,
      which lacked the last 18 amino acids of the C terminus (amino acids 204-221), did
      not assemble. Likewise, a mutant with alanine substitutions at W(191), F(197),
      and P(198) did not assemble. Furthermore rCP with a single alanine substitution
      at W(191) did not assemble, whereas the rCP, which had an arginine and an alanine
      substitution at A(196) and F(197), respectively, formed rod-shaped particles. The
      mutations that prevented assembly prevented dimer formation, which indicates that
      dimers are the minimal building blocks of particles. Our results indicate that
      two separate regions in the C terminus of AMV CP are critical for dimer formation
      and assembly and that changes in key amino acids in one of the regions affect
      both assembly and particle morphology.

PMID- 10405371
TI  - Oligomerization of the influenza virus nucleoprotein: identification of positive
      and negative sequence elements.
AB  - The RNA genome of influenza virus is encapsidated by the virus nucleoprotein (NP)
      to form ribonucleoprotein (RNP) structures of defined morphology. These
      structures result from the ability of NP to oligomerise and to bind single-strand
      RNA. To characterise NP oligomerization, we developed a binding assay using
      immobilised NP fusion proteins and in vitro translated NP. This system was used
      to estimate a dissociation constant for NP-NP contacts of 2 x 10 (-7)M. Analysis
      of NP deletion mutants identified three sequence elements important for
      oligomerization. Two regions corresponding to the middle and C-terminal thirds of
      the polypeptide were identified as the minimal sequences capable of promoting NP
      NP contacts. However, the C-terminal 23 amino-acids of NP inhibited
      oligomerization, as their removal increased self-association 10-fold. Single
      codon changes identified amino acids important for the function of these regions.
      Alanine substitution of R199 decreased binding affinity threefold, whereas
      alteration of R416 had a more drastic effect, reducing binding >10-fold. In
      contrast, mutation of F479 increased self-association fivefold. Mutations
      altering NP oligomerization affected the ability of the polypeptides to support
      influenza virus gene expression in an in vivo assay. Decreased oligomerization
      activity correlated with decreased transcriptional function. However, mutations
      that increased self-association also decreased transcription competence. This
      indicates that NP contains both positive and negative sequence elements involved
      in oligomerization and is consistent with the importance of NP-NP contacts for
      the formation of a transcriptionally active RNP.

PMID- 10405372
TI  - Equine arteritis virus derived from an infectious cDNA clone is attenuated and
      genetically stable in infected stallions.
AB  - Virus derived from an infectious cDNA clone of equine arteritis virus (EAV030H)
      was intranasally inoculated into two stallions, neither of which subsequently
      developed clinical manifestations of equine viral arteritis (EVA). Virus was
      isolated from nasal swabs and mononuclear cells collected from both stallions
      </=14 days p.i. and from the semen of one stallion only at 7 days p.i. Similarly,
      viral RNA was detected by RT nested-PCR in nasal swabs and mononuclear cells for
      </=14 days p.i. and at 7 days p.i. in the semen of the one stallion. Both
      stallions seroconverted to EAV by 10 days p.i. and maintained high neutralizing
      antibody titers thereafter. Sequence and restriction digestion analysis
      demonstrated that the recombinant virus present in nasal swabs, mononuclear
      cells, and semen from the two stallions was identical to the infectious clone
      derived virus that was used to inoculate them. Furthermore analysis of multiple
      clones derived by RT nested-PCR amplification from several samples indicated that
      the recombinant EAV030H virus was stable during replication in horses. These
      studies document for the first time that a recombinant virus derived from an
      infectious cDNA clone of a member of the order Nidovirales is replication
      competent in animals, and the genetic stability of the recombinant virus during
      in vivo replication indicates that it will be useful for the characterization of
      genetic determinants of virulence and persistence of EAV. The genetic
      conservation of the cloned recombinant virus during in vivo infection is similar
      to that which occurs during natural horizontal and vertical transmission of EAV
      in horses and contrasts with the heterogeneous virus population (quasispecies)
      that occurs in the semen of carrier stallions.

PMID- 10405373
TI  - Genetic basis for immunological aberrations in poliovirus Sabin serotype 3
      strains imported in the netherlands.
AB  - During the characterization of poliovirus type 3 strains imported in The
      Netherlands, Sabin serotype 3 strains that reacted with both specific antisera
      against Sabin-like (vaccine) and non-Sabin-like (wild-type) strains by the
      intratypic strain differentiation assay have been found. The present study was
      done to determine the pathogenic potential of these virus strains for humans.
      Characterization of these so-called double-reactive strains with neutralizing
      monoclonal antibodies (MAbs) against the major antigenic sites of serotype 3
      Sabin virus led to the identification of two groups with different antigenic
      properties. Six of the seven strains were resistant to neutralization with MAbs
      against sites 2B and 3B and one strain was neutralized by all the MAbs in a
      manner similar to that for the Sabin serotype 3 virus. Partial sequencing of the
      coding regions confirmed the antigenic changes for all six antigenically distinct
      strains. By inoculation of these viruses into transgenic mice which express the
      human poliovirus receptor, one strain was identified as highly neurovirulent,
      three were identified as intermediate, and three were identified as attenuated.
      Sera from vaccinated persons efficiently neutralized the mutants. Our data
      suggest that some double-reactive strains are a potential risk to the
      unvaccinated community but not to the vaccinated population.

PMID- 10405374
TI  - Prototypal diarrheagenic strains of Hafnia alvei are actually members of the
      genus Escherichia.
AB  - We analyzed five bacterial strains, designated 19982, 9194, 10457, 10790, and
      12502, that were isolated from stool specimens of individuals with diarrheal
      illness by the International Centre for Diarrhoeal Disease Research in Dhaka,
      Bangladesh (M. J. Albert, S. M. Faruque, M. Ansaruzzaman, M. M. Islam, K. Haider,
      K. Alam, I. Kabir, and R. Robins-Browne, J. Med. Microbiol. 37:310-314, 1992).
      The strains were initially identified as Hafnia alvei with a commercial
      identification system and were reported to contain the eae gene of
      enteropathogenic Escherichia coli. Results of conventional biochemical analyses,
      testing of susceptibility to cephalothin, lysis by a Hafnia-specific phage, and
      amplification of the outer membrane protein gene phoE with species-specific
      primers support the identification of these strains as members of the genus
      Escherichia rather than Hafnia alvei. These strains varied from typical E. coli
      strains by their inability to produce acid from lactose or D-sorbitol and failure
      to elaborate the enzyme beta-D-glucuronidase. PCR analysis confirmed previous
      findings that the strains were positive for the eae gene and negative for other
      virulence markers present among recognized categories of diarrheagenic E. coli.
      Our findings support the hypothesis that these strains are a new category of
      diarrheagenic isolates belonging to the genus Escherichia and illustrate the
      importance of using multiple methodologies when identifying new bacterial agents
      of diarrheal disease.

PMID- 10405375
TI  - Cleavase fragment length polymorphism analysis of Neisseria meningitidis basic
      metabolic genes.
AB  - Cleavase fragment length polymorphism (CFLP) is a subtyping system based on the
      property of the enzyme cleavase to recognize junctions between single- and double
      stranded regions of DNA formed after denaturation and cooling. To assess the
      capacity of CFLP for discriminating Neisseria meningitidis serogroup B strains
      belonging to the electrophoretic type (ET) 5 (ET-5) complex from other serogroup
      B strains, 30 serogroup B N. meningitidis isolates were subtyped by CFLP with
      internal fragments of five housekeeping genes, adk, aspC, carA, dhp, and glnA.
      Two genes (glnA and carA) which demonstrated a high degree of diversity for the
      serogroup B isolates were then used to further evaluate the suitability of CFLP
      for screening 50 serogroup C N. meningitidis outbreak-associated and sporadic
      case isolates with a single metabolic gene. The results were compared to those
      from multilocus enzyme electrophoresis (MEE), the current standard subtyping
      method. CFLP was able to distinguish the ET-5 complex isolates from other
      serogroup B isolates as efficiently as MEE. Furthermore, CFLP analysis of a
      single gene was sufficient to identify and cluster the serogroup C isolates
      belonging to the ET-37 complex from other, unrelated serogroup C isolates but was
      not capable of differentiating between the isolates of the major individual ETs
      of this complex (ET-17 and ET-24) causing most serogroup C meningococcal disease
      outbreaks in the United States. CFLP based on a single gene with a high degree of
      diversity but not under selective pressure can be applied to the rapid screening
      of a large number of isolates related to the recognized epidemic complex ET-5 or
      ET-37. Additionally, CFLP can be used as an initial screening tool to survey the
      amount of diversity in genes that might be used to develop a DNA sequence-based
      subtyping system.

PMID- 10405376
TI  - Utility of multiple-stool-specimen ova and parasite examinations in a high
      prevalence setting.
AB  - A retrospective analysis of the results of 2,704 ova and parasite (O & P)
      examinations performed on stool specimens collected from 1,374 patients between
      October 1996 and September 1997 was performed to evaluate the utility of
      performing O & P examinations on multiple, independently collected stool
      specimens in a high-prevalence setting. A total of 995 specimens (36.8%) examined
      during the study contained parasites; 546 (20.2%) contained pathogenic organisms.
      The positivity rate (54.5%) for the patients from whom three specimens were
      examined was significantly higher than for the patients from whom either two
      specimens (33.3%) or a single specimen (19.8%) was submitted for examination. For
      the group of patients from whom at least 3 specimens were submitted for O & P
      examination, 373 independent opportunities for diagnosing infection with
      intestinal parasites could be analyzed. The first stool specimen collected proved
      to be adequate in only 75.9% (283 of 373) of evaluated cases; however,
      examination of two specimens increased the sensitivity of O & P detection to 92%
      (343 of 373). The third specimen collected provided additional information on
      only 30 of 373 occasions (8%). These data indicate that in populations with a
      high prevalence of intestinal parasitic infections, two independently collected
      stool specimens should be subjected to O & P examination to ensure adequate
      diagnostic sensitivity.

PMID- 10405377
TI  - Field evaluation of the ICT malaria P.f/P.v immunochromatographic test for
      detection of Plasmodium falciparum and Plasmodium vivax in patients with a
      presumptive clinical diagnosis of malaria in eastern Indonesia.
AB  - In areas such as eastern Indonesia where both Plasmodium falciparum and
      Plasmodium vivax occur, rapid antigen detection tests for malaria need to be able
      to detect both species. We evaluated the new combined P. falciparum-P. vivax
      immunochromatographic test (ICT Malaria P.f/P.v.) in Radamata Primary Health
      Centre, Sumba, Indonesia, from February to May 1998 with 560 symptomatic adults
      and children with a presumptive clinical diagnosis of malaria. Blinded microscopy
      was used as the "gold standard," with all discordant and 20% of concordant
      results cross-checked blindly. Only 50% of those with a presumptive clinical
      diagnosis of malaria were parasitemic. The ICT Malaria P.f/P.v
      immunochromatographic test was sensitive (95. 5%) and specific (89.8%) for the
      diagnosis of falciparum malaria, with a positive predictive value (PPV) and a
      negative predictive value (NPV) of 88.1 and 96.2%, respectively. HRP2 and
      panmalarial antigen line intensities were associated with parasitemia density for
      both species. Although the specificity and NPV for the diagnosis of vivax malaria
      were 94.8 and 98.2%, respectively, the overall sensitivity (75%) and PPV (50%)
      for the diagnosis of vivax malaria were less than the desirable levels. The
      sensitivity for the diagnosis of P. vivax malaria was 96% with parasitemias of
      >500/microl but only 29% with parasitemias of <500/microl. Nevertheless, compared
      with the test with HRP2 alone, use of the combined antigen detection test would
      reduce the rate of undertreatment from 14.7 to 3.6% for microscopy-positive
      patients, and this would be at the expense of only a modest increase in the rate
      of overtreatment of microscopy-negative patients from 7.1 to 15. 4%. Cost remains
      a major obstacle to widespread use in areas of endemicity.

PMID- 10405378
TI  - Salmonella enterica serotype Dublin infection: an emerging infectious disease for
      the northeastern United States.
AB  - Salmonella enterica subspecies enterica serotype Dublin (S. enterica Dublin)
      emerged for the first time in New York, Pennsylvania, and Ohio in 1988. Since
      that time this host-adapted serotype has spread throughout the veal- and dairy
      beef-raising operations in the region; very few dairy farms have experienced
      clinical S. enterica Dublin infections. This study details the epidemiology of
      the outbreaks in cattle. During the period 1988 through 1995, nine New York and
      four Pennsylvania counties have been affected; 13 different locations were
      involved in New York, and 10 were involved in Pennsylvania. The morbidity and
      mortality and seasonal distribution of outbreaks, which totaled 35, is described.
      The antimicrobial susceptibility pattern of isolates revealed that many of the
      strains were resistant to a number of commonly used drugs. Clinical case details
      and pathology information are provided, with a caution to clinicians and
      microbiologists presented with suspect animals, i.e., most cases occurred in
      older calves, which is atypical for salmonellosis for this region (calves were 8
      or more weeks old) and presented as pneumonia and septicemia rather than the
      primarily diarrheal syndrome that is more typically recognized for the region.
      The epidemiology of cases is analyzed through cluster analysis of bacterial
      isolates and their fatty acid methyl ester profiles; at least six clones appeared
      in the region during the study period. Results of the epidemiology analysis are
      used to support a hypothesis regarding the source of S. enterica Dublin for the
      region and its manner of dissemination.

PMID- 10405380
TI  - Specific detection of fusarium species in blood and tissues by a PCR technique.
AB  - Fusarium species are opportunistic nosocomial pathogens that often cause fatal
      invasive mycoses. We designed a primer pair that amplifies by PCR a fragment of a
      gene coding for the rRNA of Fusarium species. The DNAs of the main Fusarium
      species and Neocosmospora vasinfecta but not the DNAs from 11 medically important
      fungi were amplified by these primers. The lower limit of detection of the PCR
      system was 10 fg of Fusarium solani DNA by ethidium bromide staining. To test the
      ability of this PCR system to detect Fusarium DNA in tissues, we developed a
      mouse model of disseminated fusariosis. Using the PCR, we detected Fusarium DNA
      in mouse tissues and in spiked human blood. Furthermore, F. solani, Fusarium
      moniliforme, and Fusarium oxysporum were testing by random amplified polymorphic
      DNA (RAPD) analysis. The bands produced by RAPD analysis were purified, cloned,
      and sequenced. The information was used to design primer pairs that selectively
      amplified one or several Fusarium species. The method developed may be useful for
      the rapid detection and identification of Fusarium species both from culture and
      from clinical samples.

PMID- 10405379
TI  - Effects of anticoagulant, processing delay, and assay method (branched DNA versus
      reverse transcriptase PCR) on measurement of human immunodeficiency virus type 1
      RNA levels in plasma.
AB  - We conducted two studies to determine the potential influence of delays in blood
      processing, type of anticoagulant, and assay method on human immunodeficiency
      virus type 1 (HIV-1) RNA levels in plasma. The first was an experimental study in
      which heparin- and EDTA-anticoagulated blood samples were collected from 101 HIV
      positive individuals and processed to plasma after delays of 2, 6, and 18 h. HIV
      1 RNA levels in each sample were then measured by both branched-DNA (bDNA) and
      reverse transcriptase PCR (RT-PCR) assays. Compared to samples processed within 2
      h, the loss (decay) of HIV-1 RNA in heparinized blood was significant (P < 0.05)
      but small after 6 h (bDNA assay, -0.12 log(10) copies/ml; RT-PCR, -0.05 log(10)
      copies/ml) and after 18 h (bDNA assay, -0.27 log(10) copies/ml; RT-PCR, -0.15
      log(10) copies/ml). Decay in EDTA-anticoagulated blood was not significant after
      6 h (bDNA assay, -0.002 log(10) copies/ml; RT-PCR, -0.02 log(10) copies/ml), but
      it was after 18 h (bDNA assay, -0.09 log(10) copies/ml; RT-PCR, -0.09 log(10)
      copies/ml). Only 4% of samples processed after 6 h lost more than 50% (>/=0.3
      log(10) copies/ml) of the HIV-1 RNA, regardless of the anticoagulant or the assay
      that was used. The second study compared HIV-1 RNA levels in samples from the
      Multicenter AIDS Cohort Study (MACS; samples were collected in heparin-containing
      tubes in 1985, had a 6-h average processing delay, and were assayed by bDNA
      assay) and the British Columbia Drug Treatment Program (BCDTP) (collected in EDTA
      or acid citrate dextrose-containing tubes in 1996 and 1997, had a 2-h maximum
      processing delay, and were assayed by RT-PCR). HIV-1 RNA levels in samples from
      the two cohorts were not significantly different after adjusting for CD4(+)-cell
      count and converting bDNA assay values to those corresponding to the RT-PCR
      results. In summary, the decay of HIV-1 RNA measured in heparinized blood after 6
      h was small (-0.05 to -0.12 log(10) copies/ml), and the minor impact of this
      decay on HIV-1 RNA concentrations in archived plasma samples of the MACS was
      confirmed by the similarity of CD4(+)-cell counts and assay-adjusted HIV-1 RNA
      concentrations in the MACS and BCDTP.

PMID- 10405381
TI  - Recurrent bacteremia caused by a "Flexispira"-like organism in a patient with X
      linked (Bruton's) agammaglobulinemia.
AB  - Helicobacter spp., except for Helicobacter cinaedi, have only rarely been
      reported in cases of septicemia. A patient with X-linked (Bruton's)
      agammaglobulinemia was found to have persistent sepsis with a Helicobacter-like
      organism despite multiple courses of antibiotics. His periods of sepsis were
      associated with leg swelling thought to be consistent with cellulitis. The
      organism was fastidious and required a microaerophilic environment containing
      H(2) for growth. Optimal growth was observed at 35 to 37 degrees C on sheep
      blood, CDC anaerobe, and Bordet-Gengou agars. Serial subcultures every 4 to 5
      days were required to maintain viability. The organism was strongly urease
      positive and showed highest relatedness to Helicobacter-like organisms with the
      vernacular name "Flexispira rappini" by 16S rRNA gene sequence analysis. Genomic
      DNA hybridization studies, however, found 24 to 37% relatedness to "F. rappini"
      and even less to other Helicobacter spp. Although the organism phenotypically
      resembles "Flexispira" and Helicobacter, it is thought to represent a new taxon.
      The patient's infection was eventually cleared with a prolonged (5-month) course
      of intravenous imipenem and gentamicin.

PMID- 10405382
TI  - Involvement of enterotoxins G and I in staphylococcal toxic shock syndrome and
      staphylococcal scarlet fever.
AB  - We investigated the involvement of the recently described staphylococcal
      enterotoxins G and I in toxic shock syndrome. We reexamined Staphylococcus aureus
      strains isolated from patients with menstrual and nonmenstrual toxic shock
      syndrome (nine cases) or staphylococcal scarlet fever (three cases). These
      strains were selected because they produced none of the toxins known to be
      involved in these syndromes (toxic shock syndrome toxin 1 and enterotoxins A, B,
      C, and D), enterotoxin E or H, or exfoliative toxin A or B, despite the fact that
      superantigenic toxins were detected in a CD69-specific flow cytometry assay
      measuring T-cell activation. Sets of primers specific to the enterotoxin G and I
      genes (seg and sei, respectively) were designed and used for PCR amplification.
      All of the strains were positive for seg and sei. Sequence analysis confirmed
      that the PCR products, corresponded to the target genes. We suggest that
      staphylococcal enterotoxins G and I may be capable of causing human
      staphylococcal toxic shock syndrome and staphylococcal scarlet fever.

PMID- 10405383
TI  - Molecular analysis of Mycobacterium avium isolates by using pulsed-field gel
      electrophoresis and PCR.
AB  - Genetic relationships among 46 isolates of Mycobacterium avium recovered from 37
      patients in a 2,500-bed hospital from 1993 to 1998 were assessed by pulsed-field
      gel electrophoresis (PFGE) and PCR amplification of genomic sequences located
      between the repetitive elements IS1245 and IS1311. Each technique enabled the
      identification of 27 to 32 different patterns among the 46 isolates, confirming
      that the genetic heterogeneity of M. avium strains is high in a given community.
      Furthermore, this retrospective analysis of sporadic isolates allowed us (i) to
      suggest the existence of two remanent strains in our region, (ii) to raise the
      question of the possibility of nosocomial acquisition of M. avium strains, and
      (iii) to document laboratory contamination. The methods applied in the present
      study were found to be useful for the typing of M. avium isolates. In general,
      both methods yielded similar results for both related and unrelated isolates.
      However, the isolates in five of the six PCR clusters were distributed among two
      to three PFGE patterns, suggesting that this PCR-based method may have
      limitations for the analysis of strains with low insertion sequence copy numbers
      or for resolution of extended epidemiologic relationships.

PMID- 10405385
TI  - Comparison of the second-generation digene hybrid capture assay with the branched
      DNA assay for measurement of hepatitis B virus DNA in serum.
AB  - The optimal hepatitis B virus (HBV) DNA quantitative assay for clinical use
      remains to be determined. We examined the sensitivity, linearity, and variability
      of a novel second-generation antibody capture solution hybridization assay, the
      Digene Hybrid Capture II assay (HCII), and compared it with another widely used
      solution hybridization assay, the branched-DNA (bDNA) assay (Quantiplex; Chiron
      Corp.). Our results showed similar and satisfactory assay linearity values, as
      well as interassay and intra-assay variability values, for both HCII and bDNA
      assays across different ranges of HBV DNA. Ninety-one percent of 102 serum
      samples from hepatitis B surface antigen-positive patients showed concordant
      results with the two assays. The HCII assay was more sensitive than the bDNA
      assay by 1 dilution, with the lowest reading being 0.9 pg/ml (3.8 pg/ml by bDNA
      assay). The HBV DNA seropositivity rates for the 102 samples were 58, 67, and 97%
      by bDNA, HCII, and nested PCR, respectively. While the relationship between
      results obtained with the bDNA assay and those with the HCII assay was nonlinear,
      with the bDNA assay yielding values 2.83 +/- 0.92-fold higher than those of the
      HCII assay, especially at high HBV DNA levels, a linear relationship was observed
      between the two sets of data after logarithmic conversion. The formula for
      interassay conversion of results was derived as follows: HBV DNA by HCII
      (picograms per milliliter) = 3.19 x [HBV DNA by bDNA (megaequivalents per
      milliliter)](0.866). The HCII assay was technically less complex and required a
      shorter assay time (4 h) than the bDNA assay (24 h). We conclude that the HCII
      assay compares favorably with the bDNA assay and offers the additional advantages
      of increased sensitivity and shorter assay time. The increased sensitivity should
      be particularly useful in monitoring the efficacy of antiviral therapies and
      detecting the emergence of drug-resistant HBV mutants.

PMID- 10405384
TI  - Helicobacter pylori infection in indigenous families of Central America:
      serostatus and oral and fingernail carriage.
AB  - Helicobacter pylori infection remains one of the most common in humans, but the
      route of transmission of the bacterium is still uncertain. This study was
      designed to elucidate possible sources of infection in an isolated, rural
      population in Guatemala. A total of 242 subjects in family units participated in
      the study. A medical history, including a history of dyspepsia, was taken by a
      physician and immunoglobulin G antibodies to H. pylori were detected with the
      QuickVue (Quidel, San Diego, Calif.) onsite serology test. Overall, 58% of
      subjects were seropositive, with a positive relationship between mother and child
      (P = 0.02) and a positive correlation between the serostatuses of siblings
      (intraclass correlation coefficient = 0.63). There was no association between
      serostatus and gastric symptoms. Oral H. pylori was detected from periodontal
      pockets of various depths and the dorsum of the tongue by nested PCR. Eighty
      seven percent of subjects had at least one oral site positive for H. pylori, with
      the majority of subjects having multiple positive sites. There was no association
      between periodontal pocket depth and the detection of H. pylori. Nested PCR was
      also used to detect H. pylori from beneath the nail of the index finger of each
      subject's dominant hand. Overall, 58% of subjects had a positive fingernail
      result, with a significant positive relationship between fingernail and tongue
      positivity (P = 0.002). In conclusion, the results of this study suggest that
      oral carriage of H. pylori may play a role in the transmission of infection and
      that the hand may be instrumental in transmission.

PMID- 10405386
TI  - Molecular typing of multiple-antibiotic-resistant Salmonella enterica serovar
      Typhi from Vietnam: application to acute and relapse cases of typhoid fever.
AB  - The rate of multiple-antibiotic resistance is increasing among Salmonella
      enterica serovar Typhi strains in Southeast Asia. Pulsed-field gel
      electrophoresis (PFGE) and other typing methods were used to analyze drug
      resistant and -susceptible organisms isolated from patients with typhoid fever in
      several districts in southern Vietnam. Multiple PFGE and phage typing patterns
      were detected, although individual patients were infected with strains of a
      single type. The PFGE patterns were stable when the S. enterica serovar Typhi
      strains were passaged many times in vitro on laboratory medium. Paired S.
      enterica serovar Typhi isolates recovered from the blood and bone marrow of
      individual patients exhibited similar PFGE patterns. Typing of S. enterica
      serovar Typhi isolates from patients with relapses of typhoid indicated that the
      majority of relapses were caused by the same S. enterica serovar Typhi strain
      that was isolated during the initial infection. However, some individuals were
      infected with distinct and presumably newly acquired S. enterica serovar Typhi
      isolates.

PMID- 10405387
TI  - Comparison of molecular methods for typing Vibrio parahaemolyticus.
AB  - An outbreak of Vibrio parahaemolyticus gastroenteritis on Canada's west coast in
      1997 emphasized the need to develop molecular methods for differentiation and
      typing of these organisms. Isolates were analyzed by enterobacterial repetitive
      intergenic consensus sequence (ERIC) PCR, detection of restriction fragment
      length polymorphisms (RFLP) in rRNA genes (ribotyping), pulsed-field gel
      electrophoresis (PFGE), and RFLP analysis of the genetic locus encoding the polar
      flagellum (Fla locus RFLP analysis). ERIC PCR and ribotyping were the most
      informative typing methods, especially when used together, while Fla locus RFLP
      analysis was the least discriminatory. PFGE exhibited good discrimination but
      suffered from a high incidence of DNA degradation. ERIC PCR and ribotyping will
      be useful for the evaluation of genetic and epidemiological relationships among
      V. parahaemolyticus strains.

PMID- 10405388
TI  - PCR and blood culture for detection of Escherichia coli bacteremia in rats.
AB  - Critically ill patients often develop symptoms of sepsis and therefore require
      microbiological tests for bacteremia that use conventional blood culture (BC)
      techniques. However, since these patients frequently receive early empirical
      antibiotic therapy before diagnostic procedures are completed, examination by BC
      can return false-negative results. We therefore hypothesized that PCR could
      improve the rate of detection of microbial pathogens over that of BC. To test
      this hypothesis, male Wistar rats were challenged intravenously with 10(6) CFU of
      Escherichia coli. Blood was then taken at several time points for detection of E.
      coli by BC and by PCR with E. coli-specific primers derived from the uidA gene,
      encoding beta-glucuronidase. In further experiments, cefotaxime (100 or 50 mg/kg
      of body weight) was administered intravenously to rats 10 min after E. coli
      challenge. Without this chemotherapy, the E. coli detection rate decreased at 15
      min and at 210 min after challenge from 100% to 62% of the animals with PCR and
      from 100% to 54% of the animals with BC (P, >0.05). Chemotherapy decreased the E.
      coli detection rate at 25 min and at 55 min after challenge from 100% to 50% with
      PCR and from 100% to 0% with BC (P, <0.05). Thus, at clinically relevant serum
      antibiotic levels, PCR affords a significantly higher detection rate than BC in
      this rat model. The results suggest that PCR could be a useful adjunct tool
      supplementing conventional BC techniques in diagnosing bacteremia.

PMID- 10405389
TI  - Novel human erythrovirus associated with transient aplastic anemia.
AB  - Erythrovirus (formerly parvovirus) B19 causes a wide range of diseases in humans,
      including anemia due to aplastic crisis. Diagnosis of B19 infection relies on
      serology and the detection of viral DNA by PCR. These techniques are usually
      thought to detect all erythrovirus field isolates, since the B19 genome is known
      to undergo few genetic variations. We have detected an erythrovirus (V9) markedly
      different from B19 in the serum and bone marrow of a child with transient
      aplastic anemia. The B19 PCR assay yielded a product that hybridized only very
      weakly to the B19-specific probe and whose sequence diverged more from those of
      24 B19 viruses (11 to 14%) than the divergence found within the B19 group
      (</=6.65%). Restriction enzyme analysis of the V9 genome revealed that this
      genetic divergence extended beyond the amplified region. Interestingly,
      serological tests failed to demonstrate a response characteristic of acute B19
      infection. V9 could be a new erythrovirus, and new diagnostic tests are needed
      for its detection.

PMID- 10405390
TI  - Value of enterobacterial repetitive intergenic consensus PCR for study of
      Pasteurella multocida strains isolated from mouths of dogs.
AB  - Fifty-six Pasteurella multocida strains (40 P. multocida subsp. septica and 16 P.
      multocida subsp. multocida strains) isolated from the mouths of 56 dogs among the
      134 living in a French canine military training center (132e Groupe Cynophile de
      l'Armee de Terre, Suippes, France) were studied by use of enterobacterial
      repetitive intergenic consensus-PCR (ERIC-PCR) and restriction fragment length
      polymorphism (RFLP) techniques. Both techniques showed genomic heterogeneity of
      the strains studied. However, RFLP was more discriminatory than ERIC-PCR for
      differentiating P. multocida strains. All but three pairs of strains were
      discriminated by RFLP, suggesting a limited circulation of strains between these
      dogs living in proximity. Although ERIC-PCR is easier and faster to perform, it
      cannot be recommended for epidemiological studies of P. multocida strains.

PMID- 10405391
TI  - Phialemonium fungemia: two documented nosocomial cases.
AB  - Two fungal isolates recovered from the blood of two immunosuppressed patients are
      described as Phialemonium curvatum. One patient died, while the other, who was
      infected with Exophiala jeanselmei at the same time, survived after successful
      treatment with itraconazole. Analysis of internal transcribed spacer sequences
      demonstrated that the isolates belonged to the same strain and that the source of
      infection was probably a catheter. The taxonomic position of P. curvatum is
      discussed, and Phialemonium dimorphosporum is considered a synonym. The in vitro
      inhibitory activities of six antifungal agents (amphotericin B, itraconazole,
      ketaconazole, miconazole, flucytosine, and fluconazole) were determined against
      seven isolates of Phialemonium. Except for flucytosine, all of them were
      remarkably effective. Phialemonium should be added to the list of potential
      causes of nosocomial fungemia in cancer patients.

PMID- 10405392
TI  - Detection of bovine herpesvirus type 1 in blood from naturally infected cattle by
      using a sensitive PCR that discriminates between wild-type virus and virus
      lacking glycoprotein E.
AB  - In the present study, we report for the first time on the detection of bovine
      herpesvirus type 1 (BHV-1) in whole-blood samples derived from naturally infected
      cattle. Sensitive PCR assays specific for glycoprotein B (gB), gC, and gE of BHV
      1 allow the detection of one BHV-1 DNA copy in 10(5) to 10(7) peripheral blood
      leukocytes (PBLs). The incidence of BHV-1-positive PBLs in naturally infected
      cattle appears to be quite high (92.2% positive PBLs among all samples tested),
      although in most cases only between 10(-5) and 10(-7) positive leukocytes were
      present. The results demonstrate that the viral DNA is detectable not only in the
      peripheral blood of acutely infected animals but, more importantly, also in the
      peripheral blood of subclinically infected cattle. The gE-specific PCR described
      in the report allows discrimination between wild-type (WT) virus-infected and
      vaccinated animals, which is of importance for control programs that use the
      recently introduced vaccination strategy with a gE-negative virus. The results
      further show that doubtful serological results can be verified or falsified and
      that individual animals can be monitored for the presence or absence of WT BHV-1
      or gE-negative virus in cattle herds. The PCR protocols allow the detection of
      BHV-1 prior to seroconversion or in BHV-1-seronegative cattle. Finally, the
      results indicate the simultaneous presence of WT and gE-negative vaccine virus in
      the PBLs of several cattle. Therefore, investigations of viremia in naturally and
      experimentally infected cattle and on the identification of infected cell types
      of bovine PBLs can be now performed.

PMID- 10405393
TI  - Development and clinical evaluation of a highly sensitive PCR-reverse
      hybridization line probe assay for detection and identification of anogenital
      human papillomavirus.
AB  - Human papillomavirus (HPV) can be detected by amplification of viral DNA. A novel
      PCR primer set generating a short PCR fragment (SPF PCR) was used for
      amplification of a fragment of only 65 bp from the L1 region and permitted
      ultrasensitive detection of a broad spectrum of HPV genotypes. The intra- and
      intertypic sequence variations of the 22-bp interprimer region of this amplimer
      were studied. Among 238 HPV sequences from GenBank and clinical specimens, HPV
      genotypes were correctly identified based on the 22-bp sequence in 232 cases
      (97.2%). Genotype-specific probes for HPV genotypes 6, 11, 16, 18, 31, 33 to 35,
      39, 40, 42 to 45, 51 to 54, 56, 58, 59, 66, 68, 70, and 74 were selected, and a
      reverse hybridization line probe assay (LiPA) (the INNO-LiPA HPV prototype
      research assay) was developed. This LiPA permits the use of amplimers generated
      by the SPF as well as the MY 09/11 primers. The assay was evaluated with a total
      of 1, 354 clinical specimens, comprising cervical scrapes (classifications
      ranging from normal cytology to severe dyskaryosis) and formalin-fixed, paraffin
      embedded cervical carcinoma samples. LiPA results were highly concordant with
      sequence analysis of the SPF amplimer, genotype-specific PCR, and sequence
      analysis of amplimers generated by MY 09/11 primers. The sensitivity of the SPF
      primers was higher than that of the GP5(+)/6(+) primers over a broad range of HPV
      types, especially when multiple HPV genotypes were present. In conclusion, the
      SPF LiPA method allows extremely sensitive detection of HPV DNA as well as
      reliable identification of HPV genotypes in both cervical smears and paraffin
      embedded materials.

PMID- 10405395
TI  - Genotype dependence of hepatitis C virus load measurement in commercially
      available quantitative assays.
AB  - Standardization and genotype independence of methods used to quantify hepatitis C
      virus (HCV) RNA in clinical specimens are necessary for accurate assessment of
      the role of HCV quantitation as a prognostic marker for HCV infection and
      monitoring of the response to antiviral treatment. Commercially available methods
      used to measure HCV loads include PCR-based (Roche Monitor) and hybridization
      based (Quantiplex bDNA-2) methods. Recently, a new version of the Roche Monitor
      assay (version 2.0) has become available; it has been modified to achieve more
      equal quantitation of different HCV genotypes. Consistent with previous reports,
      Roche Monitor version 1.0 substantially underestimated concentrations of RNA
      transcripts of types 2b, 3a, 4a, 5a, and 6a and virus loads in individuals
      infected with genotypes 2 to 6 relative to reference tests. However, version 2.0
      achieved equivalent quantitation of each genotype over a narrow quantitative
      range (10(3) to 5 x 10(5) copies of RNA/ml) but significantly underestimated RNA
      concentrations above this range. The assay showed an equivalent inability to
      quantify high levels of HCV RNA in plasma samples, and this was responsible for
      the falsely narrow range of virus loads detected in HCV-infected individuals. In
      contrast, the Chiron bDNA-2 assay could only measure RNA concentrations in the
      upper quantitative range (2 x 10(5) to 5 x 10(7) copies of RNA/ml) but showed
      equivalent sensitivity for genotypes 1 to 5; however, concentrations of type 6a
      RNA transcripts and virus loads in clinical specimens from individuals infected
      with type 6a were underestimated by a factor of 2 to 4. Differences were observed
      between PCR- and hybridization-based assays in their relative quantitation of HCV
      RNA transcripts and HCV genomic RNA, which may cause problems with the use of
      transcripts for interassay calibration.

PMID- 10405394
TI  - Invasion and intracellular development of the human granulocytic ehrlichiosis
      agent in tick cell culture.
AB  - Human granulocytotropic ehrlichias are tick-borne bacterial pathogens that cause
      an acute, life-threatening illness, human granulocytic ehrlichiosis (HGE).
      Ehrlichias within neutrophil granulocytes that invade tick bite sites are likely
      ingested by the vector, to be transmitted to another mammalian host during the
      tick's next blood meal. Thus, the cycle of replication and development in the
      vector is prerequisite to mammalian infection, and yet these events have not been
      described. We report tick cell culture isolation of two strains of the HGE agent
      directly from an infected horse and a dog and have also established a human
      isolate from HL60 culture in tick cells, proving that the blood stages of the HGE
      agent are infectious for tick cells, as are those replicating in the human cell
      line HL60. This required changes to the culture system, including a new tick cell
      line. In tick cell layers, the HGE agent induced foci of infection that caused
      necrotic plaques and eventual destruction of the culture. Using the human isolate
      and electron microscopy, we monitored adhesion, internalization, and replication
      in vector tick cells. Both electron-lucent and -dense forms adhered to and
      entered cells by a mechanism reminiscent of phagocytosis. Ehrlichial cell
      division was initiated soon after, resulting in endosomes filled with numerous
      ehrlichias. During early development, pale ehrlichias with a tight cell wall
      dominated, but by day 2, individual bacteria condensed into dark forms with a
      rippled membrane. These may become compacted into clumps where individual
      organisms are barely discernible. Whether these are part of an ehrlichia life
      cycle or are degenerating is unknown.

PMID- 10405396
TI  - Performance of the Affymetrix GeneChip HIV PRT 440 platform for antiretroviral
      drug resistance genotyping of human immunodeficiency virus type 1 clades and
      viral isolates with length polymorphisms.
AB  - The performance of a silica chip-based resequencing method, the Affymetrix HIV
      PRT 440 assay (hereafter referred to as the Affymetrix assay), was evaluated on a
      panel of well-characterized nonclade B viral isolates and on isolates exhibiting
      length polymorphisms. Sequencing of human immunodeficiency virus type 1 (HIV-1)
      pol cDNAs from clades A, C, D, E, and F resulted in clade-specific regions of
      base-calling ambiguities in regions not known to be associated with resistance
      polymorphisms, as well as a small number of spurious resistance polymorphisms.
      The Affymetrix assay failed to detect the presence of additional serine codons
      distal to reverse transcriptase (RT) codon 68 that are associated with
      multinucleoside RT inhibitor resistance. The increasing prevalence of non-clade B
      HIV-1 strains in the United States and Europe and the identification of
      clinically relevant pol gene length polymorphisms will impact the
      generalizability of the Affymetrix assay, emphasizing the need to accommodate
      this expanding pool of pol genotypes in future assay versions.

PMID- 10405397
TI  - TT virus infection in French hemodialysis patients: study of prevalence and risk
      factors.
AB  - The TT virus (TTV) is a recently discovered DNA virus which was first identified
      in patients with non-A to -G hepatitis following blood transfusion. In this
      study, we tested 150 attendees of two hemodialysis (HD) units of the public
      hospitals of Marseilles, France, for the presence of TTV genome by using a PCR
      based methodology. The overall prevalence of TTV viremia was 28% (compared to
      5.3% in blood donors from the same region). We demonstrated the existence of
      chronic infections and superinfections by strains belonging to different
      genotypes. The prevalence of infection was higher in patients originating from
      Africa, in patients with previous blood transfusion or organ transplantation, in
      patients with antibody to hepatitis B core antigen, and in those with diabetes
      mellitus. A high prevalence of TTV infection (50%) was also observed in a
      population of patients with diabetes mellitus but without renal disease. No
      significant relationship was found between TTV viremia and hepatitis C virus or
      GB virus C, transaminases, age, sex, and duration of HD treatment. The PCR
      amplification products (located in open reading frame 1 of the TTV genome) were
      sequenced. These genomic sequences were submitted to phylogenetic analysis by
      using the Jukes-Cantor algorithm for distance determination and the neighbor
      joining method for tree building. In several instances, sequences from viruses
      isolated in a HD unit were grouped in the same phylogenetic cluster. These
      results together with the different distribution of cases in the two HD units
      suggest there is viral transmission within each.

PMID- 10405398
TI  - Detection of dengue virus RNA in patients after primary or secondary dengue
      infection by using the TaqMan automated amplification system.
AB  - In consecutive serum samples from 25 tourists with acute dengue fever, virus
      specific RNA was detected by using fully automated TaqMan reverse transcriptase
      PCR. For this amplification technique new primers and special fluorochrome
      labeled probes had to be synthesized. During amplification the increasing amount
      of viral DNA could simultaneously be measured in the tightly sealed tubes. Dengue
      virus RNA was found in almost all patients (17 of 18), if the samples had been
      taken soon after the onset of symptoms and before anti-dengue virus antibody had
      been produced. RNA was detectable in only one of five persons who had anti-dengue
      virus immunoglobulin M (IgM) antibodies but not yet IgG antibodies. In 30 late
      samples with both IgG and IgM antibodies viral RNA was no longer demonstrable. In
      two early samples from two frequent travelers obtained 1 and 2 days after the
      onset of symptoms significant IgG antibody titers were present but there were no
      anti-dengue virus IgM antibodies. In these samples a viral load of >5 x 10(6)
      dengue virus RNA copies (dengue types 1 and 2) was detectable. These findings of
      a high viral load in the presence of anti-dengue virus IgG antibody are
      suggestive of a secondary dengue virus infection. In the 20 tourists (17 plus 1
      plus 2) in whom viral RNA was found, the dengue virus serotype could be related
      to the area where the infection had taken place. Most of our patients came from
      southeast Asia and most frequently had dengue virus type 1 infections (8 of 20).

PMID- 10405399
TI  - Molecular epidemiological study of Haemophilus influenzae serotype b strains
      obtained from children with meningitis in Japan.
AB  - We report an epidemiological study of 30 Haemophilus influenzae serotype b (Hib)
      strains derived from the cerebrospinal fluid of children with meningitis. The Hib
      strains were biotyped, tested for beta-lactamase production, and genotyped by
      long PCR-ribotyping, random amplified polymorphic DNA (RAPD) analysis, and
      genomic DNA restriction fragment length polymorphism (RFLP) analysis by pulsed
      field gel electrophoresis (PFGE). The phenotypic study characterized 22 of the
      strains (73%) as biotype I. A genotypic study using long PCR-ribotyping with
      HaeIII restriction digestion showed no polymorphisms among these 30 Hib strains,
      but RAPD analysis with two sets of primers demonstrated two distinctive subtypes:
      one typical of the strains of biotype group II and the second characteristic of
      the strains of biotype groups I and IV. Each RAPD group was subtyped into several
      genotypic groups by PFGE-RFLP with SmaI digestion. The genotyping of clinically
      isolated Hib strains may help to elucidate transmission routes in community
      infections, endemicity, and the reasons for vaccine failure.

PMID- 10405400
TI  - Abiotrophia elegans strains comprise 8% of the nutritionally variant streptococci
      isolated from the human mouth.
AB  - Ninety-one isolates of nutritionally variant streptococci (NVS) that were
      previously isolated from the human mouth were regarded as consisting of 7
      Streptococcus defectivus isolates, 78 Streptococcus adjacens isolates, and 6
      Gemella morbillorum isolates. However, recent references to the taxonomic
      reclassification of NVS, from S. defectivus to Abiotrophia defectiva and from S.
      adjacens to Abiotrophia adiacens, and the newly introduced species Abiotrophia
      elegans as a third Abiotrophia species, emphasize the need for genetic analyses
      for identification of NVS. When PCR-restriction fragment length polymorphism
      (RFLP) and phylogenetic distances were examined based on 16S rRNA gene sequences,
      the results indicated that 7 of the 91 NVS isolates were closely related to A.
      elegans. These seven isolates consisted of four isolates previously identified as
      G. morbillorum and three isolates previously identified as S. adjacens. Two
      isolates previously identified as G. morbillorum were related to A. adiacens. In
      biochemical tests, A. elegans and the seven isolates related to it possessed
      arginine dihydrolase (ADH) activity but the other Abiotrophia species did not. As
      a result, A. elegans strains comprised 8% of the 91 NVS isolates. Our findings
      suggest that A. elegans, A. adiacens, and A. defectiva exist in the human mouth
      in proportions of about 1:11:1 and that A. elegans can be genetically
      distinguished from the other two Abiotrophia species by PCR-RFLP analysis of 16S
      rRNA gene sequences and can be biochemically distinguished by ADH activity.

PMID- 10405402
TI  - Inhibition enzyme-linked immunosorbent assay for serotyping of group B
      streptococcal isolates.
AB  - Group B Streptococcus (GBS) is one of the most common organisms causing neonatal
      sepsis as well as serious infections in adults. Serotyping the organism is
      important in studying the epidemiology of the disease as well as deciding a
      course of treatment. There are several methods available for serotyping. Most of
      them need high-titered sera and are not quantitative. We are reporting a new
      inhibition enzyme-linked immunosorbent assay (ELISA) for serotyping which is
      sensitive and specific compared to the conventional methods but does not need
      high-titered serotype-specific antisera, as the specificity is controlled by the
      polysaccharide coating on the ELISA plates. The method can also be quantitative,
      and we have measured polysaccharide elaborated by different serotype V strains.
      Thus, the inhibition ELISA method will be useful in serotyping for
      epidemiological studies, assessing virulence, and performing strain selection for
      vaccine production.

PMID- 10405401
TI  - Development of calibrated viral load standards for group M subtypes of human
      immunodeficiency virus type 1 and performance of an improved AMPLICOR HIV-1
      MONITOR test with isolates of diverse subtypes.
AB  - Accurate determination of plasma human immunodeficiency virus type 1 (HIV-1) RNA
      levels is critical for the effective management of HIV-1 disease. The AMPLICOR
      HIV-1 MONITOR Test, a reverse transcription-PCR-based test for quantification of
      HIV-1 RNA in plasma, was developed when little sequence information on HIV-1
      isolates from outside North America was available. It has since become apparent
      that many non-subtype B isolates, particularly subtypes A and E, are detected
      inefficiently by the test. We describe here the AMPLICOR HIV-1 MONITOR Test,
      version 1.5, an upgraded test developed to minimize subtype-related variation. We
      also developed a panel of HIV-1 standards containing 30 HIV-1 isolates of
      subtypes A through G. The virus particle concentration of each cultured viral
      stock was standardized by electron microscopic virus particle counting. We used
      this panel to determine the performance of the original AMPLICOR HIV-1 MONITOR
      Test and version 1.5 of the test with HIV-1 subtypes A through G. The original
      test underestimated the concentration of HIV-1 subtype A, E, F, and G RNA by 10
      fold or more, whereas version of the 1.5 test yielded equivalent quantification
      of HIV-1 RNA regardless of the subtype. In light of the increasing intermixing of
      HIV-1 subtypes worldwide, standardization of PCR-based tests against well
      characterized viral isolates representing the full range of HIV-1 diversity will
      be essential for the continued utility of these important clinical management
      tools.

PMID- 10405403
TI  - Comparison of Ehrlichia chaffeensis recombinant proteins for serologic diagnosis
      of human monocytotropic ehrlichiosis.
AB  - Diagnosis of human monocytotropic ehrlichiosis (HME) generally depends on
      serology that detects the antibody response to immunodominant proteins of
      Ehrlichia chaffeensis. Protein immunoblotting was used to evaluate the reaction
      of the antibodies in patients' sera with the recombinant E. chaffeensis 120- and
      28-kDa proteins as well as the 106- and the 37-kDa proteins. The cloning of the
      genes encoding the latter two proteins is described in this report.
      Immunoelectron microscopy demonstrated that the 106-kDa protein is located at the
      surfaces of ehrlichiae and on the intramorular fibrillar structures associated
      with E. chaffeensis. The 37-kDa protein is homologous to the iron-binding protein
      of gram-negative bacteria. Forty-two serum samples from patients who were
      suspected to have HME were tested by immunofluorescence (IFA) using E.
      chaffeensis antigen and by protein immunoblotting using recombinant E.
      chaffeensis proteins expressed in Escherichia coli. Thirty-two serum samples
      contained IFA antibodies at a titer of 1:64 or greater. The correlation of IFA
      and recombinant protein immunoblotting was 100% for the 120-kDa protein, 41% for
      the 28-kDa protein, 9.4% for the 106-kDa protein, and 0% for the 37-kDa protein.
      None of the recombinant antigens yielded false-positive results. All the sera
      reactive with the recombinant 28- or the 106-kDa proteins also reacted with the
      recombinant 120-kDa protein.

PMID- 10405405
TI  - Detection of phylogenetically diverse human immunodeficiency virus type 1 groups
      M and O from plasma by using highly sensitive and specific generic primers.
AB  - The high degree of genetic diversity within human immunodeficiency virus type 1
      (HIV-1), which includes two major groups, M (major) and O (outlier), and various
      env subtypes within group M (subtypes A to J), has made designing assays that
      will detect all known HIV-1 strains difficult. We have developed a generic primer
      set based on the conserved immunodominant region of transmembrane protein gp41
      that can reliably amplify as few as 10 copies/PCR of viral DNA from near-full
      length clones representing group M subtypes A to H (subtypes I and J were not
      available). The assay is highly sensitive in detecting plasma viral RNA from HIV
      1 strains of diverse geographic origins representing different subtypes of HIV-1
      group M as well as HIV-1 group O. Of the 253 group M plasma specimens (subtypes
      A, 68 specimens; B, 71; C, 19; D, 27; E, 23; F, 33; and G, 12), 250 (98.8%) were
      amplified by using the gp41 M/O primer set. More importantly, all 32 (100%) group
      O plasma samples were also amplified with these primers. In vitro spiking
      experiments further revealed that the assay could reliably detect as few as 25
      copies/ml of viral RNA and gave positive signals in HIV-1-seropositive specimens
      with plasma copy numbers below the limits of detection by all commercially
      available viral load assays. In addition, analysis of five seroconversion panels
      indicated that the assay is highly sensitive for early detection of plasma
      viremia during the "window period." Thus, the highly sensitive assay will be
      useful for early detection of HIV-1 in clinical specimens from all known HIV-1
      infections, regardless of their genotypes and geographic origins.

PMID- 10405404
TI  - Serological determination of hepatitis C virus subtypes 1a, 1b, 2a, 2b, 3a, and
      4a by a recombinant immunoblot assay.
AB  - Serological determination of hepatitis C virus (HCV) subtypes has been hampered
      by the lack of suitable assays. Therefore, a recombinant immunoblot assay has
      been established for serological differentiation of HCV subtypes 1a, 1b, 2a, 2b,
      3a, and 4a. It consists of recombinant HCV proteins from the NS-4 region
      propagated in Escherichia coli. To confirm the serotyping assay results, the
      results were compared with those obtained by nucleotide sequencing of the NS-5
      region. Sera from 157 patients with chronic HCV infection were examined by this
      assay, and specific antibodies could be detected in 86% (n = 135) of them. The
      HCV genotype was determined correctly in all but one sample, and the subtypes
      determined by the serotyping assay corresponded to the HCV subtypes detected by
      nucleotide sequencing for 95% (n = 128) of the samples. These data indicate that
      HCV subtypes can be distinguished serologically. The assay that is described
      provides an easier means of identification of infection with different HCV
      subtypes for wider clinical and epidemiological applications.

PMID- 10405406
TI  - Evaluation of the PrimeCapture CMV DNA detection plate system for detection of
      cytomegalovirus in clinical specimens.
AB  - With the availability of anticytomegalovirus (CMV) therapeutic agents, rapid
      detection of CMV is important in the care and management of the immunosuppressed
      patient. The PrimeCapture CMV DNA Detection Plate System (PC-PCR) was evaluated
      for the detection of CMV in blood and cerebrospinal fluid (CSF). The resolution
      of discordant results was performed by consensus testing utilizing a combination
      of conventional cell culture (TC-CPE), the CMV-antigenemia (CMV-Ag) assay, one or
      more in-house CMV nested PCR assays, and/or patient evaluation and follow-up. Of
      51 blood specimens from 34 patients, 23 (45%) were identified as true positives.
      PC-PCR was significantly more sensitive than the CMV-Ag assay, TC-CPE, or a
      combination of both tests. The sensitivities, specificities, positive predictive
      values (PPV), and negative predictive values (NPV) for PC-PCR, the CMV-Ag assay,
      TC-CPE, and a combination of CMV-Ag and TC-CPE were 78, 75, 72, 81%; 46, 100,
      100, 70%; 39, 100, 100, 67%; and 58, 100, 100, 73%, respectively. CMV was not
      detected or isolated in CSF, resulting in a combined PC-PCR sensitivity,
      specificity, PPV, and NPV of 77, 90, 68, and 93%, respectively. Among those
      laboratorians considering the incorporation of molecular CMV diagnostics into
      their clinical microbiology or virology laboratories, the CMV PC-PCR offers a
      relatively simple-to-perform and sensitive assay system.

PMID- 10405407
TI  - Identification of two novel Mycobacterium avium allelic variants in pig and human
      isolates from Brazil by PCR-restriction enzyme analysis.
AB  - Mycobacterium avium complex (MAC) is composed of environmental mycobacteria found
      widely in soil, water, and aerosols that can cause disease in animals and humans,
      especially disseminated infections in AIDS patients. MAC consists of two closely
      related species, M. avium and M. intracellulare, and may also include other, less
      defined groups. The precise differentiation of MAC species is a fundamental step
      in epidemiological studies and for the evaluation of possible reservoirs for MAC
      infection in humans and animals. In this study, which included 111 pig and 26
      clinical MAC isolates, two novel allelic M. avium PCR-restriction enzyme analysis
      (PRA) variants were identified, differing from the M. avium PRA prototype in the
      HaeIII digestion pattern. Mutations in HaeIII sites were confirmed by DNA
      sequencing. Identification of these isolates as M. avium was confirmed by PCR
      with DT1-DT6 and IS1245 primers, nucleic acid hybridization with the AccuProbe
      system, 16S ribosomal DNA sequencing, and biochemical tests. The characterization
      of M. avium PRA variants can be useful in the elucidation of factors involved in
      mycobacterial virulence and routes of infection and also has diagnostic
      significance, since they can be misidentified as M. simiae II and M. kansasii I
      if the PRA method is used in the clinical laboratory for identification of
      mycobacteria.

PMID- 10405408
TI  - Isolation of a new subspecies, Bartonella vinsonii subsp. arupensis, from a
      cattle rancher: identity with isolates found in conjunction with Borrelia
      burgdorferi and Babesia microti among naturally infected mice.
AB  - Bacteremia with fever due to a novel subspecies of Bartonella vinsonii was found
      in a cattle rancher. The subspecies shared major characteristics of the genus
      Bartonella in terms of most biochemical features and cellular fatty acid profile,
      but it was distinguishable from other subspecies of B. vinsonii by good growth on
      heart infusion agar supplemented with X factor and by its pattern of enzymatic
      hydrolysis of peptide substrates. DNA relatedness studies verified that the
      isolate belonged to the genus Bartonella and that it was genotypically related to
      B. vinsonii. The highest level of relatedness was observed with recently
      characterized strains from naturally infected mice that were coinfected with
      Borrelia burgdorferi and Babesia microti. We propose the name Bartonella vinsonii
      subsp. arupensis subsp. nov. as the new subspecies to accommodate these human and
      murine isolates.

PMID- 10405409
TI  - Usefulness of spoligotyping To discriminate IS6110 low-copy-number Mycobacterium
      tuberculosis complex strains cultured in Denmark.
AB  - Mycobacterium tuberculosis complex strains cultured in Denmark have been analyzed
      by IS6110 restriction fragment length polymorphism (RFLP) on a routine basis from
      1992 and onwards. Due to the influx of immigrants with tuberculosis, the number
      of strains harboring only one to five copies of IS6110 has increased steadily.
      Since the discriminatory power of IS6110 fingerprinting for such strains is poor,
      we have performed additional genotyping of all low-copy-number strains by the
      recently described PCR-based method known as spoligotyping. A total of 311
      clinical strains were typed: 14 Mycobacterium bovis BCG, 48 M. bovis, and 249 M.
      tuberculosis strains. Spoligotyping correctly differentiated M. bovis and M.
      bovis BCG from M. tuberculosis strains, but it did not differentiate M. bovis
      from M. bovis BCG. All M. bovis BCG strains exhibited identical spoligotype
      patterns. The discriminatory power of spoligotyping of low-copy-number M.
      tuberculosis strains was higher than that of IS6110 fingerprinting. Based on RFLP
      typing solely, 83% of the low-copy-number M. tuberculosis strains were found to
      form part of a cluster, and 75% were found to form a cluster on the basis of
      spoligotyping. When the two techniques were combined, the amount of clustering
      decreased to 55%. The combination of these two techniques might be valuable in
      studying the epidemiology of M. tuberculosis strains harboring few copies of the
      IS6110 element.

PMID- 10405411
TI  - Biochemical identification of Citrobacter species defined by DNA hybridization
      and description of Citrobacter gillenii sp. nov. (formerly Citrobacter
      genomospecies 10) and Citrobacter murliniae sp. nov. (formerly Citrobacter
      genomospecies 11).
AB  - Recent work describing six named species and two unnamed genomospecies within
      Citrobacter has enlarged the genus to 11 species. DNA relatedness and phenotypic
      tests were used to determine how well these species can be identified. One
      hundred thirty-six strains were identified to species level by DNA relatedness
      and then identified phenotypically in a blinded fashion. By using conventional
      tests, 119 of the 136 strains (88%) were correctly identified to species level.
      Three additional strains (2%) were identified as citrobacteria but were not
      identified to species level, and 14 strains (10%) were misidentified as other
      Citrobacter species. Carbon source utilization tests were used to identify 86 of
      the strains. Eighty-four strains (98%) were correctly identified, and two strains
      (2%) were misidentified as other Citrobacter species. Additional strains of
      Citrobacter genomospecies 10 and Citrobacter genomospecies 11 were identified,
      allowing these species to be formally named as Citrobacter gillenii sp. nov. and
      Citrobacter murliniae sp. nov., respectively.

PMID- 10405410
TI  - Comparison of methods based on different molecular epidemiological markers for
      typing of Mycobacterium tuberculosis complex strains: interlaboratory study of
      discriminatory power and reproducibility.
AB  - In this study, the currently known typing methods for Mycobacterium tuberculosis
      isolates were evaluated with regard to reproducibility, discrimination, and
      specificity. Therefore, 90 M. tuberculosis complex strains, originating from 38
      countries, were tested in five restriction fragment length polymorphism (RFLP)
      typing methods and in seven PCR-based assays. In all methods, one or more
      repetitive DNA elements were targeted. The strain typing and the DNA fingerprint
      analysis were performed in the laboratory most experienced in the respective
      method. To examine intralaboratory reproducibility, blinded duplicate samples
      were included. The specificities of the various methods were tested by inclusion
      of 10 non-M. tuberculosis complex strains. All five RFLP typing methods were
      highly reproducible. The reliability of the PCR-based methods was highest for the
      mixed-linker PCR, followed by variable numbers of tandem repeat (VNTR) typing and
      spoligotyping. In contrast, the double repetitive element PCR (DRE-PCR), IS6110
      inverse PCR, IS6110 ampliprinting, and arbitrarily primed PCR (APPCR) typing were
      found to be poorly reproducible. The 90 strains were best discriminated by IS6110
      RFLP typing, yielding 84 different banding patterns, followed by mixed-linker PCR
      (81 patterns), APPCR (71 patterns), RFLP using the polymorphic GC-rich sequence
      as a probe (70 patterns), DRE-PCR (63 patterns), spoligotyping (61 patterns), and
      VNTR typing (56 patterns). We conclude that for epidemiological investigations,
      strain differentiation by IS6110 RFLP or mixed-linker PCR are the methods of
      choice. A strong association was found between the results of different genetic
      markers, indicating a clonal population structure of M. tuberculosis strains.
      Several separate genotype families within the M. tuberculosis complex could be
      recognized on the basis of the genetic markers used.

PMID- 10405412
TI  - Determination of hepatitis C virus genotype by direct sequence analysis of
      products generated with the Amplicor HCV test.
AB  - Consistent with other members of the family Flaviviridae, hepatitis C virus (HCV)
      demonstrates a high degree of sequence variation throughout the coding regions of
      its genome. However, there is a high degree of sequence conservation found within
      the 5' untranslated region (UTR) of the genome, making this region a target of
      choice for most nucleic acid amplification-based detection assays. In this study,
      the Amplicor HCV test, a commercially available assay which detects the 5'UTR,
      was used for the detection of HCV RNA in 669 serum samples obtained from a cohort
      of liver transplantation patients. Amplification products obtained from the HCV
      positive cases were subjected to direct sequencing and genotyping based upon
      seven phylogenetically informative regions within the 5'UTR. Of the 669
      specimens, 416 (62.2%) tested positive for the presence of HCV RNA. Of these, 372
      (89.4%) specimens were successfully classified into 11 HCV genotypes and subtypes
      after computer-assisted analysis of the sequence data. Forty-four (10.6%) of the
      HCV RNA-positive specimens were not classifiable, the majority corresponding to
      low-titer specimens as determined by the Chiron Quantiplex HCV RNA 2. 0 assay.
      Additional comparative studies targeting the NS-5 region of the viral genome
      generally confirmed the accuracy and sensitivity of the 5'UTR-based
      classifications, with the exception of the misclassification of a small number of
      type 1a cases as type 1b. We conclude that although the high sequence
      conservation within the 5'UTR results in the misclassification of a small number
      of HCV subtypes, the overall gains of efficiency, the shorter turnaround time,
      the inclusion of contamination control measures, and the low rate of test failure
      compared to that of methods based on the NS-5 gene together constitute
      significant advantages over other techniques.

PMID- 10405413
TI  - Coinfection with multiple tick-borne pathogens in a Walker Hound kennel in North
      Carolina.
AB  - Both dogs and humans can be coinfected with various Ehrlichia, Bartonella,
      Rickettsia, and Babesia species. We investigated a kennel of sick Walker Hounds
      and their owners in southeastern North Carolina for evidence of tick-borne
      infections and associated risk factors. A high degree of coinfection was
      documented in the dog population. Of the 27 dogs, 26 were seroreactive to an
      Ehrlichia sp., 16 to Babesia canis, and 25 to Bartonella vinsonii, and 22
      seroconverted to Rickettsia rickettsii antigens. According to PCR results, 15
      dogs were infected with Ehrlichia canis, 9 with Ehrlichia chaffeensis, 8 with
      Ehrlichia ewingii, 3 with Ehrlichia equi, 9 with Ehrlichia platys, 20 with a
      Rickettsia species, 16 with a Bartonella species, and 7 with B. canis. The
      detection of DNA from any Ehrlichia species was associated with clinical illness
      and with concurrent B. canis infection (by PCR). Both E. canis and an
      uncharacterized Rickettsia species appeared to result in chronic or recurrent
      infection. Death in the dog population was associated with living in a dirt lot
      rather than the concrete kennel. Of 23 people on whom serologic testing was
      conducted, eight were seroreactive to Bartonella henselae, one to E. chaffeensis,
      and one to R. rickettsii antigen; however, none had clinical or hematologic
      abnormalities consistent with illness caused by these organisms. We conclude that
      kennel dogs with heavy tick exposure can be infected at a high rate with
      multiple, potentially zoonotic, tick-borne pathogens. In addition, our findings
      further illustrate the utility of PCR for documenting coinfection with tick
      transmitted pathogens.

PMID- 10405414
TI  - Improved detection of hepatitis B virus surface antigen by a new rapid automated
      assay.
AB  - The performance of hepatitis B virus (HBV) surface antigen (HBsAg) screening
      assays is continuously improved in order to reduce the residual risk of
      transfusion-associated hepatitis B. In a multicenter study, a new automated rapid
      screening assay, Elecsys HBsAg (Roche Diagnostics), was compared to well
      established tests (Auszyme Monoclonal [overnight incubation] version B and IMx
      HBsAg [Abbott]). Included in the evaluation were 23 seroconversion panels; sera
      from the acute and chronic phases of infection; dilution series of various HBsAg
      standards, HBV subtypes, and S gene mutants; and isolated anti-HBV core antigen
      positive samples. To challenge the specificity of the new assay, sera from HBsAg
      negative blood donors, pregnant women, and dialysis and hospitalized patients and
      potentially cross-reactive samples were investigated. Elecsys HBsAg showed a
      higher sensitivity for HBsAg subtypes ad, ay, adw2, adw4, ayw1, ayw2, ayw4, and
      adr detection in dilution series of different standards or sera than Auszyme
      Monoclonal version B and/or IMx HBsAg. Acute hepatitis B was detected in 11 to 16
      of 23 seroconversion panels between 2 and 16 days earlier with Elecsys HBsAg than
      with the alternative assays. Elecsys HBsAg and Auszyme Monoclonal version B
      detected HBsAg surface mutants with equal sensitivity. The sensitivity and
      specificity of Elecsys HBsAg were 100%. Auszyme Monoclonal version B had a 99.9%
      specificity, and its sensitivity was 96.6%. IMx HBsAg showed a poorer sensitivity
      and specificity than the other assays. In conclusion, Elecsys HBsAg permits
      earlier detection of acute hepatitis B and different HBV subtypes than the
      alternative assays. By using highly sensitive HBsAg screening assays, low-level
      HBsAg carriers among isolated anti-HBV core antigen-positive individuals can be
      detected.

PMID- 10405415
TI  - Evaluation of the Granada agar plate for detection of vaginal and rectal group B
      streptococci in pregnant women.
AB  - Granada medium was evaluated for the detection of group B streptococci (GBS) in
      vaginal and rectal swabs compared with selective Columbia blood agar and
      selective Lim broth. From May 1996 to March 1998, 702 pregnant women (35 to 37
      weeks of gestation) participated in this three-phase study; 103 (14.7%) of these
      women carried GBS. In the first phase of the experiment (n = 273 women),
      vaginorectal specimens were collected on the same swab; the sensitivities of
      Granada tube, selective Columbia blood agar, and Lim broth were 31.4, 94.3, and
      74.3%, respectively. In the second and third phases (n = 429 women), vaginal and
      rectal specimens were collected separately; the sensitivities of Granada plate,
      selective Columbia blood agar, and Lim broth (subcultured at 4 h on selective
      Columbia agar in the second phase and at 18 to 24 h in Granada plate in the third
      phase) were 91.1, 83.9, and 75%, respectively, in the second phase and 88.5,
      90.4, and 63.5%, respectively, in the third phase. There were no statistically
      significant differences in GBS recovery between the Granada agar plate and
      selective Columbia blood agar, but the Granada plate provided a clear advantage;
      the characteristic red-orange colonies produced overnight by GBS can be
      identified by the naked eye and is so specific that further identification is
      unnecessary. The use of the Granada tube and Lim broth did not result in
      increased isolation of GBS. In conclusion, the Granada agar plate is highly
      sensitive for detecting GBS in vaginal and rectal swabs from pregnant women and
      can provide results in 18 to 24 h.

PMID- 10405416
TI  - Single clonal origin of a high proportion of Legionella pneumophila serogroup 1
      isolates from patients and the environment in the area of Paris, France, over a
      10-year period.
AB  - Arbitrarily primed PCR with three primers and pulsed-field gel electrophoresis
      were used to characterize a set of 75 clinical Legionella pneumophila serogroup 1
      isolates, with no apparent epidemiological link, obtained from 24 hospitals in
      Paris, France, from 1987 to 1997. Unexpectedly, 25 clinical isolates from 15
      hospitals had an identical profile (termed type A) by both methods. The same
      profile was subsequently found in 16 of 64 randomly selected environmental L.
      pneumophila serogroup 1 isolates from 15 different sites in the Paris area. There
      was no evidence of geographic clustering or a peak incidence of type A isolation.
      Type A has not been found in France outside the Paris area, suggesting that a
      particular type of L. pneumophila serogroup 1 is specifically present in the
      Paris water distribution network.

PMID- 10405417
TI  - Disseminated zygomycosis due to Rhizopus schipperae after heatstroke.
AB  - A 21-year-old woman suffered heatstroke and developed diarrhea while trekking
      across south Texas. The heatstroke was complicated by seizures, rhabdomyolysis,
      pneumonia, renal failure, and disseminated intravascular coagulation. The
      patient's stool and blood cultures grew Campylobacter jejuni. The patient
      subsequently developed paranasal and gastrointestinal zygomycosis and required
      surgical debridement and a prolonged course of amphotericin B. The zygomycete
      cultured was Rhizopus schipperae. This is only the second isolate of R.
      schipperae that has been described. R. schipperae is characterized by the
      production of clusters of up to 10 sporangiophores arising from simple but well
      developed rhizoids. These asexual reproductive propagules are produced on Czapek
      Dox agar but are absent on routine mycology media, where only chlamydospores are
      observed. Despite multiorgan failure, bacteremia, and disseminated zygomycosis,
      the patient survived and had a good neurological outcome. Heatstroke has not been
      previously described as a risk factor for the development of disseminated
      zygomycosis.

PMID- 10405418
TI  - Mutations in the rpoB gene of rifampin-resistant Mycobacterium tuberculosis
      strains isolated mostly in Asian countries and their rapid detection by line
      probe assay.
AB  - Mutations in the rpoB gene of 90 rifampin-resistant Mycobacterium tuberculosis
      isolates mostly from Asian countries were analyzed. Ten distinct single
      nucleotide substitutions were found among the isolates by automated sequencing. A
      3-nucleotide insertion was found in two isolates, and no mutation was found in
      five isolates (5.6%). A reverse hybridization-based line probe assay (INNO-LiPA
      Rif TB) for rapid detection of the mutations was evaluated with these isolates.
      Concordance rates with sequencing results for five wild-type probes (S probes)
      and four probes for specific mutations (R probes) were 96.7 and 100%,
      respectively. The overall concordance rate with the in vitro susceptibility
      testing results was 92.2% (83 of 90 isolates). These results indicate that a
      commercial line probe assay kit may be useful for rapid diagnosis of rifampin
      resistant tuberculosis.

PMID- 10405420
TI  - Use of Granada medium to detect group B streptococcal colonization in pregnant
      women.
AB  - Direct inoculation onto Granada medium (GM) in plates and tubes was compared to
      inoculation into a selective Todd-Hewitt broth (with 8 microg of gentamicin per
      ml and 15 microg of nalidixic acid per ml) for detection of group B streptococci
      (GBS) in pregnant women with 800 vaginal and 450 vaginoanorectal samples.
      Comparatively, GM was found to be as sensitive as the selective broth for the
      detection of GBS in vaginal specimens and more sensitive than selective broth for
      the detection of GBS in vaginoanorectal samples (96 versus 82%). The use of GM
      improved the time to reporting of a GBS-positive result by at least 24 h and
      reduced the direct cost of screening. We have also found that the inconvenience
      of anaerobic incubation of GM plates can be avoided when a cover slide is placed
      upon the inoculum, because aerobic incubation in GM plates with cover slides
      causes GBS to develop the same pigmentation that it develops with incubation
      under anaerobic conditions. These data support the routine use of GM plates or
      tubes as a more accurate, easier, and cheaper method of identification of GBS
      colonized women compared to the enrichment broth technique.

PMID- 10405421
TI  - Sensitive assays for isolation and detection of simian foamy retroviruses.
AB  - Simian foamy viruses (SFVs) are highly prevalent in a variety of nonhuman primate
      species ranging from prosimians to apes. SFVs possess a broad host range, and
      human infections can occur by cross-species transfer (W. Heneine et al., Nat.
      Med. 4:403-407, 1998). Retrovirus screening of potential sources of infection,
      such as laboratory research animals and simian-derived biological products, could
      minimize human exposure to SFVs by reducing the risk of potential retrovirus
      infection in humans. We describe a variety of sensitive assays for SFV isolation
      and detection which were developed with a prototype strain of SFV serotype 2. The
      Mus dunni cell line (M. R. Lander and S. K. Chattopadhyay, J. Virol. 52:695-698,
      1984) was found to be highly sensitive for SFV production on the basis of various
      general and specific retrovirus detection assays such as reverse transcriptase
      assay, transmission electron microscopy, immunofluorescence assay, and Western
      blotting. A highly sensitive PCR assay was developed on the basis of the
      sequences in primary SFV isolates obtained from pig-tailed macaques (Macaca
      nemestrina) and rhesus macaques (Macaca mulatta). Analysis of naturally occurring
      SFV infection in macaques indicated that analysis by a combination of assays,
      including both highly sensitive, specific assays and less sensitive, broadly
      reactive assays, is important for evaluation of retrovirus infection.

PMID- 10405419
TI  - Detection of Staphylococcus aureus and Staphylococcus epidermidis in clinical
      samples by 16S rRNA-directed in situ hybridization.
AB  - Staphylococcus epidermidis and Staphylococcus aureus are the most common causes
      of medical device-associated infections, including septicemic loosenings of
      orthopedic implants. Frequently, the microbiological diagnosis of these
      infections remains ambiguous, since at least some staphylococci have the capacity
      to reduce their growth rate considerably. These strains exhibit a small-colony
      phenotype, and often they are not detectable by conventional microbiological
      techniques. Moreover, clinical isolates of S. aureus and S. epidermidis adhere to
      polymer and metal surfaces by the generation of thick, multilayered biofilms
      consisting of bacteria and extracellular polysaccharides. This study reports
      improved detection and identification of S. aureus and S. epidermidis by an in
      situ hybridization method with fluorescence-labeled oligonucleotide probes
      specific for staphylococcal 16S rRNA. The technique has proven to be suitable for
      the in situ detection of staphylococci, which is illustrated by the
      identification of S. epidermidis in a connective tissue sample obtained from a
      patient with septicemic loosening of a hip arthroplasty. We also show that this
      technique allows the detection of intracellularly persisting bacteria, including
      small-colony variants of S. aureus, and the differentiation of S. epidermidis
      from other clinically relevant staphylococci even when they are embedded in
      biofilms. These results suggest that the 16S rRNA in situ hybridization technique
      could represent a powerful diagnostic tool for the detection and differentiation
      of many other fastidious microorganisms.

PMID- 10405423
TI  - Versatile fluorescent staining of fungi in clinical specimens by using the
      optical brightener Blankophor.
AB  - Fluorescent staining of fungi in clinical specimens with the optical brightener
      Blankophor can be performed concomitantly with maceration of surrounding tissue
      and may be accelerated by heating. The procedure is suitable for disclosing fungi
      in gram-stained microscopical mounts and can be used for screening of tissue
      sections prior to immunofluorescence.

PMID- 10405422
TI  - Fluorescent oligonucleotide probes for clinical and environmental detection of
      Acanthamoeba and the T4 18S rRNA gene sequence type.
AB  - The first genus- and subgenus-specific fluorescent oligonucleotide probes for in
      situ staining of Acanthamoeba are described. Sequences of these phylogeny-based
      probes complement the 18S rRNA and the gene encoding it (18S rDNA). The genus
      specific probe (GSP) is a fluorescein-labeled 22-mer specific for Acanthamoeba as
      shown here by its hybridization to growing trophozoites of all 12 known
      Acanthamoeba 18S rDNA sequence types and by its failure to hybridize with amoebae
      of two other genera (Hartmannella vermiformis and Balamuthia mandrillaris), two
      human cell lines, and two bacteria (Pseudomonas aeruginosa and Escherichia coli).
      The sequence type T4-specific probe (ST4P) is a rhodamine-labeled 30-mer specific
      for Acanthamoeba 18S rDNA sequence type T4, as shown here in hybridization tests
      with trophozoites of all 12 sequence types. T4 is the subgenus group associated
      most closely with Acanthamoeba keratitis (AK). GSP also was tested with corneal
      scrapings from 17 patients with a high index of clinical suspicion of AK plus 5
      patient controls. GSP stained both trophozoites and cysts, although nonspecific
      cyst wall autofluorescence also was observed. Results could be obtained with GSP
      in 1 to 2 days, and based on results from cell culture tests, the probe correctly
      detected the presence or absence of Acanthamoeba in 21 of 24 specimens from the
      22 patients. The use of GSP with cultured trophozoites and cysts from corneal
      scrapings has illustrated the suitability of using fluorescent oligonucleotide
      probes for identification of the genus Acanthamoeba in both environmental and
      clinical samples. In addition, the use of ST4P with cultured amoebae has
      indicated the potential of oligonucleotide probes for use in subgenus
      classification.

PMID- 10405424
TI  - Comparative performance of the RapID Yeast Plus System and the API 20C AUX
      Clinical Yeast System.
AB  - The performance of the RapID Yeast Plus System (Innovative Diagnostic Systems,
      Norcross, Ga.), a 4-h micropanel using single-substrate enzymatic test reactions,
      was compared with that of the API 20C AUX Clinical Yeast System (bioMerieux
      Vitek, Hazelwood, Mo.), a 48- to 72-h carbohydrate assimilation panel. Two
      hundred twenty-five yeasts, yeast-like fungi, and algae, comprising 28 species
      and including 30 isolates of Cryptococcus neoformans, an important pathogen not
      tested in appreciable numbers in other comparisons, were tested by both methods.
      On initial testing, 196 (87.1%) and 215 (95.6%) isolates were correctly
      identified by the RapID and API systems, respectively. Upon repeat testing, the
      number of correctly identified isolates increased to 220 (97.8%) for the RapID
      system and 223 (99.1%) for the API system. Reducing the turbidity of the test
      inoculum to that of a no. 3 McFarland turbidity standard, which is below that
      recommended by the manufacturer, resulted in the correct identification of most
      of the isolates initially misidentified by the RapID system, including 10 of 30
      C. neoformans isolates. Concordance between the RapID and API results after
      repeat testing was 97.3%.

PMID- 10405426
TI  - TT virus infection is widespread in the general populations from different
      geographic regions.
AB  - By PCR screening, we found an extremely high prevalence of TT virus (TTV) in the
      general populations from different geographic regions. This suggests that TTV may
      be a common DNA virus with no clear disease association in humans. TTV genotyping
      by phylogenetic analysis was also performed.

PMID- 10405427
TI  - Identification of human rotavirus strains with the P[14] genotype by PCR.
AB  - A seminested PCR typing assay has been extended to identify rotavirus strains
      with the P[14] genotype. The specificity of the method was confirmed by Southern
      hybridization and by restriction analysis with the enzyme AluI. One out of four
      human rotavirus (HRV) strains with unusual subgroup-electropherotype linkage but
      none out of 50 HRV strains with usual linkage was typed as P[14].

PMID- 10405425
TI  - Indigenous disseminated Penicillium marneffei infection in the state of Manipur,
      India: report of four autochthonous cases.
AB  - We describe four cases of disseminated infection caused by endemic Penicillium
      marneffei in human immunodeficiency virus (HIV)-infected patients from the
      Manipur state of India. The most common clinical features observed were fever,
      anorexia, weight loss, hepatosplenomegaly, and, more importantly, skin lesions
      resembling molluscum contagiosum. The diagnosis in each of the four cases was
      achieved by direct examination of smears, observance of intracellular yeast-like
      cells multiplying by fission in biopsied tissue from skin lesions, and isolation
      of the dimorphic P. marneffei in pure culture in each case. In one case,
      fluorescent antibody studies allowed specific diagnosis. This report documents a
      new area in which P. marneffei is endemic, located in eastern India, and
      describes the first occurrence in India of P. marneffei in HIV-infected patients
      as well as the extension of the areas of P. marneffei endemicity westward to the
      northeastern state of Manipur.

PMID- 10405428
TI  - Novel immunoblot assay using four recombinant antigens for diagnosis of Epstein
      Barr virus primary infection and reactivation.
AB  - A new immunoblot assay, composed of four Epstein-Barr virus (EBV)-encoded
      recombinant proteins (virus capsid antigen [VCA] p23, early antigen [EA] p138, EA
      p54, and EBNA-1 p72), was compared with an immunofluorescence assay on a total of
      291 sera. The test was accurate in 94.5% of cases of primary EBV infection, while
      an immunoglobulin G anti-VCA p23 band with strong intensity correlated with
      reactivation.

PMID- 10405429
TI  - A multidrug-resistant tuberculosis microepidemic caused by genetically closely
      related Mycobacterium tuberculosis strains.
AB  - IS6110 DNA fingerprinting was used to characterize an outbreak of multidrug
      resistant tuberculosis in 21 individuals (17 males and 4 females) living in or
      roaming among four distantly separated areas in the Czech Republic. The
      restriction fragment length polymorphism (RFLP) analysis separated the collected
      Mycobacterium tuberculosis strains into group A, including 14 patients with six
      IS6110 copies, and group B, with 7 patients displaying highly similar RFLP
      patterns but with two additional IS6110 bands. A switch from pattern A to pattern
      B was observed in one patient, and the subsequent detection of subclone B in
      seven more individuals has been explained by the instability of DNA genotypes
      caused by transposition of IS6110 elements.

PMID- 10405430
TI  - Typing of clinical herpes simplex virus type 1 and type 2 isolates with
      monoclonal antibodies.
AB  - The purpose of this study was to evaluate the performance of a herpes simplex
      virus (HSV) type 1-specific anti-glycoprotein C-1 monoclonal antibody (MAb) and a
      type 2-specific anti-glycoprotein G-2 MAb for typing of 2,400 clinical HSV-1
      isolates and 2,400 clinical HSV-2 isolates, respectively, using an enzyme
      immunoassay. The anti-HSV-1 MAb showed sensitivity and specificity of 100%, and
      the anti-HSV-2 MAb showed a sensitivity of 99.46% and 100% specificity,
      indicating that these MAbs are suitable for typing of clinical HSV isolates.

PMID- 10405431
TI  - Molecular detection and identification of intimin alleles in pathogenic
      Escherichia coli by multiplex PCR.
AB  - A multiplex PCR was designed to detect the eae gene and simultaneously identify
      specific alleles in pathogenic Escherichia coli. The method was tested on 87
      strains representing the diarrheagenic E. coli clones. The results show that the
      PCR assay accurately detects eae and resolves alleles encoding the alpha, beta,
      and gamma intimin variants.

PMID- 10405432
TI  - Sequencing of the ribosomal intergenic spacer region for strain identification of
      Porphyromonas gingivalis.
AB  - The ribosomal intergenic spacer regions (ISRs) of 19 laboratory strains and 30
      clinical samples of Porphyromonas gingivalis were amplified by PCR and sequenced
      to provide a strain identifier. The ISR is a variable region of DNA located
      between the conserved 16S and 23S rRNA genes. This makes it an ideal locus for
      differentiation of strains within a species: primers specific for the conserved
      flanking genes were used to amplify the ISR, which was then sequenced to identify
      the strain. We have constructed a P. gingivalis ISR sequence database to
      facilitate strain identification. ISR sequence analysis provides a strain
      identifier that can be easily reproduced among laboratories and catalogued for
      unambiguous comparison.

PMID- 10405433
TI  - Diagnostic value of anti-hepatitis C virus (HCV) core immunoglobulin M in
      recurrence of HCV infection after orthotopic liver transplantation.
AB  - The significance of anti-hepatitis C virus (HCV) core immunoglobulin M (IgM) and
      its relationship with genotypes, alanine aminotransferase abnormality, and
      histological data were studied for 18 patients who had undergone orthotopic liver
      transplantation due to HCV-related end-stage disease. During follow-up, IgM
      response seemed to be associated with the recurrence of HCV infection but did not
      correlate with abnormal alanine aminotransferase levels and histological data. In
      addition, the results of this study indicated that the detection of HCV RNA is
      critical for diagnosis of reinfection in liver transplantation.

PMID- 10405434
TI  - An uncommon Helicobacter isolate from blood: evidence of a group of Helicobacter
      spp. pathogenic in AIDS patients.
AB  - An unusual Helicobacter sp. was isolated from the blood of a human
      immunodeficiency virus (HIV)-infected patient. This organism had spiral
      morphology, with single amphitrichous flagella, and was negative for hippurate
      hydrolysis, production of urease, and reduction of nitrate. 16S rRNA gene
      sequence analysis verified that the isolate was a species of Helicobacter, most
      closely related to an undescribed Helicobacter-like isolate from Vancouver,
      British Columbia, Canada, and to Helicobacter westmeadii, a recently described
      species from Australia. Both organisms had also been isolated from the blood of
      HIV-infected patients. These blood isolates, along with Helicobacter cinaedi,
      form a cluster of closely related Helicobacter spp. that may represent an
      emerging group of pathogens in immunocompromised patients.

PMID- 10405435
TI  - Detection of porcine rotavirus type G9 and of a mixture of types G1 and G5
      associated with Wa-like VP4 specificity: evidence for natural human-porcine
      genetic reassortment.
AB  - Rotavirus type G5 is a primarily porcine pathogen that has caused frequent and
      widespread diarrhea in children in Brazil and in piglets elsewhere. Initial
      results on the rotavirus types circulating in diarrheic piglets in Brazil
      disclosed a high diversity of strains with distinct G types including G1, G4, G5,
      and G9 and the novelty of P[8], the predominant human P specificity type. Those
      results add strong evidence for the emergence of new strains through natural
      reassortment between rotaviruses of human and porcine origins.

PMID- 10405436
TI  - Destructive knee joint infection caused by Peptostreptococcus micros: importance
      of early microbiological diagnosis.
AB  - Peptostreptococcus micros is a commensal of the oral cavity and the genitourinary
      tract that rarely causes serious infections. A case of a destructive knee joint
      infection with rapid progress caused by P. micros is presented. The significance
      of the microbiological findings was initially not acknowledged, which contributed
      to a nonsuccessful clinical outcome.

PMID- 10405437
TI  - Stable and unstable amoxicillin resistance in Helicobacter pylori: should
      antibiotic resistance testing be performed prior to eradication therapy?

PMID- 10405438
TI  - Symmetric replication of an unstable isodicentric Xq chromosome derived from
      isolocal maternal sister chromatid recombination.
AB  - An amniocyte culture was found to be mosaic for 45,X/46,X, idic(X)(p11.2)/ 47,X,
      idic(X)(p11.2),idic(X)(p11.2) cell lines, reflecting mitotic nondisjunction of
      the idic(X)(p11.2) chromosome. Upon learning of abnormal karyotype and ultrasound
      findings, the parents decided to discontinue the pregnancy. Subsequent cultures
      of fetal skin, kidney, and lung were mosaic 45,X/46,X,idic(X)(p11.2) reflecting
      mitotic loss of the unstable idic(X)(p11.2) chromosome. C-banding and in situ
      hybridization of X chromosome-specific alpha-satellite probe to metaphase fetal
      cells confirmed two centromeres on the idic(X)(p11.2) chromosome with both
      centromeres appearing to be active in two-thirds of cells. This result was
      confirmed by centromere protein-E (CENP-E) antibody staining which delineated 80%
      of scored cells with two active centromeres and 20% with 1 active centromere.
      Bromodeoxyuridine (BrdU) incorporation and acridine orange staining characterized
      the DNA replication pattern of the idic(X)(p11.2) chromosome as late and
      symmetrically replicating. Polymerase chain reaction analysis of highly
      polymorphic loci determined that the normal X chromosome carried paternal alleles
      and the idic(X)(p11.2) chromosome carried maternal alleles from only one
      grandparental chromosome. Overall, the results suggest that recombination
      occurred between two maternal sister chromatids both in the same chromosome band
      Xp11.2 (isolocal) prior to maternal meiosis II anaphase to generate an unstable
      maternal idic(X)(p11.2) chromosome. Additional factors that could contribute to
      i(Xq) and idic(X) formation and instability are discussed along with a mechanism
      to explain the high frequency of intrauterine loss in 45,X pregnancies.

PMID- 10405439
TI  - Severe end of Opitz trigonocephaly (C) syndrome or new syndrome?
AB  - We report on four unrelated cases of an Opitz trigonocephaly (C)-like syndrome
      with a highly characteristic combination of facial anomalies including prominent
      metopic suture, exophthalmos, hypertelorism, cleft lip and palate, flexion
      deformities of the upper limbs and multiple other anomalies. We also review two
      very similar published cases formerly considered to have the C syndrome. Although
      there is overlap, a clinical distinction from the Opitz trigonocephaly and other
      syndromes seems possible, and thus a specific causal entity may be postulated.

PMID- 10405441
TI  - Maternal gonadal mosaicism causing ornithine transcarbamylase deficiency.
AB  - Ornithine transcarbamylase (OTC) deficiency (McKusick 311250), an X-linked
      inherited disorder, often presents in males with severe neonatal onset of
      hyperammonemia. Maternal gonadal mosaicism in OTC deficiency was postulated
      previously, but no cases have been reported. We report on a family in which two
      consecutive males were affected with OTC deficiency, which was proven
      biochemically with characteristic metabolites and absent enzyme activity in
      liver. OTC genotyping in both brothers showed a new mutation in exon 6
      (Met206Arg: ATG-->AGG), which encodes part of the equatorial H6 alpha-helix.
      Biochemical investigations confirmed normal results in the mother and grandmother
      and the absence of OTC activity in the affected males. Genotyping of the mother
      and grandmother was performed on peripheral blood leukocytes and skin fibroblasts
      and showed no mutation in the somatic cells. The recurrence of OTC deficiency in
      offsprings of a woman with normal genotype strongly suggests gonadal mosaicism.
      Gonadal mosaicism needs to be considered when counseling couples in which the
      mother has had a previously affected child with OTC deficiency but apparently is
      not a carrier.

PMID- 10405440
TI  - De novo complete trisomy 5p: clinical report and FISH studies.
AB  - We describe a de novo trisomy 5p in a 1-year-old severely retarded boy. The
      complete short arm of chromosome 5 segregated as an additional marker chromosome
      in all metaphases. The marker was identified as 5p by conventional cytogenetic
      techniques (GTG, GBG, CBG) and molecular cytogenetic techniques (whole chromosome
      painting probe, probes for the cri-du-chat region and the centromere, and
      additionally high-resolution multicolor banding using a chromosome 5-specific DNA
      probe cocktail). The clinical findings were similar to the established trisomy 5p
      phenotype including macrocephaly, facial abnormalities, tracheobronchial defects
      with subsequent respiratory infections, hypotonia, and psychomotor retardation.
      To the best of our knowledge this is the first description of an isolated
      complete 5p trisomy without involvement of the aberrant chromosome in any
      structural chromosomal rearrangements.

PMID- 10405442
TI  - Congenital anomalies and anthropometry of 42 individuals with deletions of
      chromosome 18q.
AB  - Deletions of chromosome 18q are among the most common segmental aneusomies
      compatible with life. The estimated frequency is approximately 1/40,000 live
      births [Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, Kaye CI, Leach RJ.
      1997. Am. J. Med. Genet. 69:280-286]. Most deletions are terminal encompassing as
      much as 36 Mb, but interstitial deletions have also been reported. We have
      evaluated 42 subjects with deletions of 18q at our institution. This is the
      largest number of individuals with this chromosome abnormality studied by one
      group of investigators. Here we report the physical findings in these
      individuals. We have compared our findings with those of previously reported
      cases and have found a significantly different incidence of several minor
      anomalies in our subjects. We also describe here several anomalies not previously
      reported in individuals with deletions of 18q, including short frenulum, short
      palpebral fissures, disproportionate short stature, overlap of second and third
      toes, and a prominent abdominal venous pattern. Characteristics found in subjects
      were analyzed for correlation with cytogenetic breakpoints. Several traits were
      found to correlate with the extent of the deletion. Large deletions were
      associated with significantly decreased head circumference and ear length as well
      as the presence of proximally placed and/or anomalous thumbs. Individuals with
      the smallest deletions were more likely to have metatarsus adductus. Although
      relatively few genotype/phenotype correlations were apparent, these data
      demonstrate that correlations with breakpoint are possible. This implies that
      more correlations will become evident when the more precise molecularly based
      genotyping is completed. These correlations will identify critical regions on the
      chromosome in which genes responsible for specific abnormal phenotypes are
      located.

PMID- 10405443
TI  - Duplications and de novo deletions of the SMNt gene demonstrated by fluorescence
      based carrier testing for spinal muscular atrophy.
AB  - Approximately 95% of individuals with spinal muscular atrophy (SMA) lack both
      copies of the SMNt gene at 5q13. The presence of a nearly identical centromeric
      homolog of the SMNt gene, SMNc, necessitates a quantitative polymerase chain
      reaction approach to direct carrier testing. Adapting a radioactivity-based
      method described previously, multiplex polymerase chain reaction was performed
      using fluorescently labeled primers followed by analysis on an ABI 373a DNA
      sequencer. The SMNt copy number was calculated from ratios of peak areas using
      both internal and genomic standards. Samples from 60 presumed carriers (50
      parents of affected individuals and 10 relatives implicated by linkage analysis)
      and 40 normal control individuals were tested. Normalized results (to the mean of
      five or more control samples harboring two copies of the SMNt gene) were
      consistently within the ranges of 0.4 to 0.6 for carriers (one copy) and 0.8 to
      1.2 for normal controls (two copies), without overlap. Combining linkage analyses
      with direct carrier test results demonstrated de novo deletions associated with
      crossovers, unaffected individuals carrying two SMNt gene copies on one
      chromosome and zero SMNt gene copies on the other chromosome, and unaffected
      individuals with three copies of the SMNt gene. This report demonstrates that
      fluorescence-based carrier testing for SMA is accurate, reproducible, and useful
      for genetic risk assessment, and that carrier testing may need to be combined
      with linkage analysis in certain circumstances.

PMID- 10405444
TI  - Clinical and behavioral characteristics in FG syndrome.
AB  - FG syndrome is a rare X-linked recessive form of mental retardation, first
      described by Opitz and Kaveggia in 1974. Based on over 50 reported cases, FG
      syndrome is associated with agenesis of the corpus callosum, minor facial
      anomalies (high, broad forehead with frontal cowlick, ocular hypertelorism, down
      slanted palpebral fissures, and small cupped auricles), relative macrocephaly,
      broad thumbs and halluces, and prominent fetal fingertip pads. Affected
      individuals manifest neonatal hypotonia and severe constipation, which usually
      resolves during mid-childhood. The hypotonia with joint hyperlaxity evolves into
      spasticity with joint contractures in later life. Affability, hyperactivity, and
      excessive talkativeness are noted frequently in patients with FG syndrome.
      Recently, we described three additional families (six additional patients) with
      FG syndrome who support the localization of a gene for the FG syndrome in
      chromosome region Xq12-q21 [Graham JM Jr, Tackels D, Dibbern K, Superneau D,
      Rodgers C, Corning K, Schwartz CE. 1998. Am J Med Genet 80:145-156.]. Using these
      same families and one additional sporadic case of FG syndrome, we compared
      behavioral and personality characteristics of 6 FG boys with other boys with
      syndromic and nonsyndromic mental retardation: eight with Down syndrome, seven
      with Prader-Willi syndrome, eight with nonspecific mental retardation, and 13
      with Williams syndrome. Using the Vineland Adaptive Behavior Scales, the Reiss
      Personality Profiles, and the Achenbach Child Behavior Checklist, parents were
      asked to characterize the behavior and personality of their boys from ages 4 to
      10 years. When compared with Williams syndrome, the FG boys had fewer
      internalizing behaviors and were significantly less anxious and withdrawn but had
      similar socially oriented, attention-seeking behaviors. On the Reiss Profile, FG
      boys were also quite similar to Williams syndrome boys. On the Vineland Scales,
      FG boys demonstrated significant relative strengths in their socialization
      skills, consistent with their personality, tending to confirm previous
      descriptions of their personalities.

PMID- 10405445
TI  - Prenatal evaluation of a de novo X;9 translocation.
AB  - A case of X-autosome translocation was diagnosed prenatally [46,X, t(X;9)(p21.3
      approximately 22.1;q22]. We describe the use of fluorescence in situ
      hybridization (FISH) to estimate the integrity of the Duchenne muscular dystrophy
      (DMD) gene. X-inactivation studies were used as well to assess the probability of
      phenotypic abnormalities associated with functional partial disomy X and monosomy
      9.

PMID- 10405446
TI  - Albinism and agenesis of the corpus callosum with profound developmental delay:
      Vici syndrome, evidence for autosomal recessive inheritance.
AB  - We report on two sibs and two other unrelated patients with agenesis of corpus
      callosum, oculocutaneous albinism, repeated infections, and cardiomyopathy. All
      manifested postnatal growth retardation, microcephaly, and profound developmental
      delay. Additional central nervous system anomalies present in at least one
      patient included hypoplasia of the cerebellar vermis, white matter neuronal
      heterotopia, or bilateral schizencephaly. Repeated viral, bacterial, and fungal
      infections were consistent with a primary immunodeficiency. However,
      immunological studies showed variable, nonspecific findings. Cardiomyopathy with
      progressive heart failure or infection led to death before age 2 years in three
      of the patients. This syndrome was first described by Vici et al. [1988: Am. J.
      Med. Genet. 29:1-8]. The four patients reported herein confirm this unique
      disorder. Affected sibs of both sexes born to unaffected parents provide evidence
      for autosomal recessive inheritance.

PMID- 10405448
TI  - Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams
      syndrome.
AB  - A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH)
      levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent
      antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed
      hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to
      thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was
      exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological
      activity of circulating TSH was slightly below the normal range [TSH bioactivity
      (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2]. These
      abnormalities are similar to those seen in patients with hypothalamic
      hypothyroidism. Thyroid function is not a recognized manifestation of WS and is
      not routinely investigated. However, abnormalities of the hypothalamic-pituitary
      thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases.
      Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS
      patients, may be involved in the development of the thyroid gland, contributing
      to the complex phenotype of WS.

PMID- 10405447
TI  - Identification of nine novel mutations in cartilage oligomeric matrix protein in
      patients with pseudoachondroplasia and multiple epiphyseal dysplasia.
AB  - Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1) are allelic
      disorders caused by mutations in the gene encoding cartilage oligomeric matrix
      protein (COMP). PSACH is a dominant condition characterized by disproportionate
      short stature, joint laxity, and early-onset osteoarthritis. EDM1 is a less
      severe skeletal dysplasia associated with average to mild short stature, joint
      pain, and early-onset osteoarthritis. COMP is an extracellular matrix protein
      present in cartilage, ligament, and tendon tissues. Here, we report on nine novel
      mutations in COMP causing PSACH and EDM1. Four of these mutations are in exons
      13C and 14 where no previous mutations had been reported. One of those mutations
      was identified in two separate EDM1 families. In addition, we have identified the
      first case of PSACH resulting from an expansion of the five aspartates in exon
      17B. We are also reporting a mutation in a third PSACH family with
      somatic/germline mosaicism. Therefore, this report increases the range of
      mutations that cause PSACH and EDM1 and provides additional regions to target for
      mutational analysis.

PMID- 10405449
TI  - Sporadic case of trichorhinophalangeal syndrome type III in a European patient.
AB  - Trichorhinophalangeal syndrome type III (TRP III) shares common traits with TRP I
      and II, including sparse hair, a "pear-shaped" nose, osteodysplasia with cone
      shaped epiphyses, and autosomal dominant inheritance, but is distinguished by the
      presence of severe brachydactyly. TRP III was first described in 1984 in Japanese
      patients, one sporadic case [Sugio and Kajii, 1984: Am. J. Med. Genet. 19:741
      753,1984] and two families [Niikawa and Kamei, 1986: Am. J. Med. Genet. 24:759
      760; Nagai et al., 1994: Am. J. Med. Genet. 49:278-280], and more recently in a
      Turkish family [Itin et al., 1996: Dermatology 193:349-352]. We report an
      additional observation in a patient of European descent, who presented with short
      stature, cone-shaped epiphyses, sparse hair, a pear-shaped nose, normal
      intelligence and severe brachydactyly. Neither parent had manifestations of TRP
      and there was no other reported case in the family, indicating a presumably fresh
      mutation. Our observation refines the clinical spectrum of TRP III in another
      ethnic background and may be of help in identifying the gene or genes for TRP
      syndromes.

PMID- 10405450
TI  - Nonrandom tissue distribution of mutant mtDNA.
AB  - Heteroplasmic mitochondrial DNA (mtDNA) defects are an important cause of
      inherited human disease. On a cellular level, the percentage of mutant mtDNA is
      the principal factor behind the expression of the genetic defect. Marked
      variation in the level of mutant mtDNA among tissues is thought to be responsible
      for the diverse clinical phenotypes associated with the same pathogenic mtDNA
      mutation. This study was designed to determine whether the percentage level of a
      pathogenic mtDNA molecule is determined by a purely random process. The tissue
      distribution of the A3243G MELAS point mutation was analyzed in five individuals
      who were members of a family with maternally inherited diabetes and deafness. The
      level of mutant mtDNA was measured in four tissues in three individuals and three
      tissues in two individuals. The highest level of mutant mtDNA occurred in
      skeletal muscle, followed by hair follicles, and then buccal mucosa, with the
      lowest levels in blood (leucocyte/platelet fraction). The probability of
      observing any strict hierarchy in family is 4.82 x 10(-5). These results indicate
      that the distribution of the A3243G mutation is not solely determined by random
      processes.

PMID- 10405451
TI  - Peroxisomal disorders: clinical and biochemical studies in 15 children and
      prenatal diagnosis in 7 families.
AB  - We describe the main clinical and biochemical findings in 15 patients with
      peroxisomal disorders, together with the results of 11 prenatal investigations
      for Zellweger syndrome. The initial laboratory diagnosis depended in most cases
      on demonstration of elevated very long chain fatty acids in plasma, but follow-up
      studies using cultured fibroblasts were essential for complete classification.
      The patient group comprises nine cases of Zellweger syndrome, one of neonatal
      adrenoleucodystrophy, two of infantile Refsum disease, one of bifunctional
      protein deficiency, and two of rhizomelic chondrodysplasia punctata. The study
      illustrates the clinical and biochemical variability of this group of patients
      and the detailed studies that are required for classification.

PMID- 10405452
TI  - Holoprosencephaly in a Klinefelter fetus.

PMID- 10405453
TI  - Low frequency of inherited deletions of 22q11.

PMID- 10405454
TI  - International Federation of Human Genetics Societies.

PMID- 10405456
TI  - A family history study of male sexual orientation using three independent
      samples.
AB  - Available evidence suggests that male homosexuality is both familial and somewhat
      heritable and that some cases may be caused by an X-linked gene. However, most
      studies have recruited subjects in a relatively unsystematic manner, typically
      via advertisements, and hence suffer from the potential methodological flaw of
      ascertainment bias due to volunteer self-selection. In the present study we
      assessed the familiality of male homosexuality using two carefully ascertained
      samples and attempted to replicate findings consistent with X-linkage in three
      samples. The percentage of siblings of the probands rated as either homosexual or
      bisexual, with a high degree of certainty, ranged from 7 to 10% for brothers and
      3 to 4% for sisters. These estimates are higher than recent comparable population
      based estimates of homosexuality, supporting the importance of familial factors
      for male homosexuality. Estimates of lambda s for male homosexuality ranged from
      3.0 to 4.0. None of the samples showed a significantly greater proportion of
      maternal than paternal homosexual uncles or homosexual male maternal first
      cousins. Although our results differed significantly with those of some prior
      studies, they do not exclude the possibility of moderate X-linkage for male
      sexual orientation.

PMID- 10405455
TI  - Biochemical variants of Smith-Lemli-Opitz syndrome.
AB  - Smith-Lemli-Opitz (SLO or RSH) syndrome is characterized by multiple congenital
      anomalies, mental retardation, and defective growth; it results from an inherited
      defect in the biosynthesis of cholesterol. Patients have elevated plasma
      concentrations of 7-dehydrocholesterol, the immediate biosynthetic precursor of
      cholesterol and most also have low circulating levels of cholesterol. To
      understand better the biochemical basis of clinical variability, we evaluated
      cholesterol biosynthesis in lymphoblasts from 3 unrelated SLOS patients with
      distinct phenotypes. One patient has "type I SLOS", the second has the more
      severe "type II SLOS" and the third is classified as atypical and had been
      postulated to have a defect in sterol transport. The lymphoblasts of each patient
      show normal subcellular localization of cholesterol and 7-dehydrocholesterol by
      gradient fractionation. Biochemical differences in the ability of the
      lymphoblasts to convert 7-dehydrocholesterol to cholesterol are described and
      correspond to the severity of disease (type II > type I > atypical). Recently,
      the gene responsible for most SLOS cases (DHCR7) was mapped to chromosome 11 and
      mutations in DHCR7 were found in each of these patients. The biochemical
      differences described here likely result from the different mutations observed in
      DHCR7.

PMID- 10405457
TI  - Effects of chorion type on neonatal temperament differences in monozygotic twin
      pairs.
AB  - Monozygotic (MZ) twins with a known chorion type were assessed in the neonatal
      period to determine if placentation was related to twin similarity in early
      temperament development. The sample included 48 pairs with monochorionic
      placentas and 29 pairs with dichorionic placentas. The assessment focused on
      irritability, resistance to soothing, activity while awake, activity during
      sleep, reactivity, and reinforcement value. There were no differences between the
      monochorionic and the dichorionic twins in any of the temperament ratings.
      Chorion type was not related to cotwin similarity on any of the temperament
      ratings. It was concluded that differences in prenatal environment reflected in
      placentation type did not affect early temperament for MZ twins.

PMID- 10405458
TI  - Genetic influences on human conditionability: a twin study of the conditioned
      eyeblink response.
AB  - Acquisition of the classically conditioned eyeblink response is generally
      regarded as one of the most basic forms of associative learning. A great deal is
      known about how the brain encodes this simple form of learning, so that
      performance of this task may be an indirect indicator of brain functioning.
      Individual differences in response acquisition have been revealed, but largely
      ignored, in the research literature. We tested the temporal stability and
      familial origins of these individual differences using a classic twin study
      design. Results reveal substantial individual differences in acquisition of the
      conditioned eyeblink response. These differences are stable across brief retest,
      and differences in response acquisition exhibit familial aggregation, apparently
      due, in part, to genetic resemblance.

PMID- 10405459
TI  - Left-handedness as a function of sex, maternal versus paternal inheritance, and
      report bias.
AB  - The right-shift (RS) theory suggests that sex differences for handedness are due
      to the displacement of a chance distribution of asymmetry farther to the right in
      females than males by about 20%. An analysis of studies in the literature shows
      that when handedness is assessed by self-report, paired samples of males and
      females differ for incidence of left-handedness as predicted, but for parents
      assessed by indirect-report, there are fewer left-handed mothers than expected.
      When handedness is assessed by self-report in both generations, the RS genetic
      model successfully predicts the distribution in families. It is also successful
      at different levels of criterion from left-writing to non-right-handedness. The
      RS predictions are not always consistent with the findings of studies that
      depended on indirect report of parental handedness. When parental incidences are
      low the proportion of left-handed children in the families of left-handed mothers
      is higher than expected. When parental incidences are high, predictions for the
      families of left-handed mothers are excellent, but the percentage of left-handed
      children in the families of left-handed fathers is lower than expected. Data for
      all indirect-report studies are combined to test the idea that the chief cause of
      poor fit is underreporting of left-handed mothers by right-handed children.
      Transfer of right-handed children from R x R to R x L families, thereby raising
      the percentage of left-handed mothers by about 1%, is sufficient to give good
      fits to RS predictions for both sexes.

PMID- 10405460
TI  - Diagnosis of zygosity by questionnaire and polymarker polymerase chain reaction
      in young twins.
AB  - We developed a zygosity questionnaire for use in young twins and assessed its
      validity using the results of DNA diagnosis. The participants were divided into
      two groups: 105 pairs of adolescent twins (12-16 years old), 47 pairs of child
      twins (2-12 years old), and their respective parents. The DNA diagnosis of
      zygosity was made with polymarker polymerase chain reaction (PCR) amplification
      of five loci, using the AmpliType PM PCR Amplification and Typing Kit; this
      method has an accuracy rate of 99.0%. A parsimonious model for each sample was
      established using stepwise logistic regression analysis of the 20 items of the
      questionnaire. The total accuracy rate of the model was satisfactory for both
      parental reports (three items) and self-reports (three items) of adolescent twins
      (97.4 and 95.6%, respectively), while that for parental reports on child twins
      (two items) was less satisfactory (92.5%). For adolescent twins, if DNA
      diagnostic workups were limited to those with discordant reports either from
      themselves or from their parents, the accuracy rate increased to 100% for
      parental reports and 98% for self-reports.

PMID- 10405461
TI  - Audiogenic seizure sensitivity in mouse lines genetically selected for high
      versus low blood magnesium levels.
AB  - The MGH and MGL mouse lines, genetically selected for high and low blood
      magnesium (Mg) levels, respectively, exhibit marked differences for
      characteristics expected to be related to blood Mg levels, such as increased
      stress sensitivity and stress-induced aggressivity in MGL mice. However, although
      Mg deficiency experimentally induced by low oral Mg intake has been shown
      previously to increase susceptibility to audiogenic seizures, MGL were less
      sensitive to audiogenic seizures than MGH mice. The MGH-MGL lines may, therefore,
      provide a beneficial and complementary model for the study of the relationships
      between audiogenic seizures and blood Mg levels.

PMID- 10405462
TI  - Genetic correlation between steroid sulfatase concentration and initiation of
      attack behavior in mice.
AB  - The pairing region of the X-Y chromosomes recombines at male meiosis. We
      previously found that offense behavior in male mice, measured by initiation of
      attack against a conspecific male, was linked to this region. Only one functional
      gene (coding for steroid sulfatase or Sts) is mapped on this region as of yet,
      suggesting that it could be a candidate for offense behavior. We estimated the
      genetic correlation between the concentration of STS protein in the liver and the
      initiation of attack behavior in 11 strains of inbred mice. The high correlation
      (close to reliability) coefficient of the behavioral phenotype indicates the
      implication of STS in offense behavior. Recent investigations have demonstrated
      the involvement of STS in neurosteroid biochemical pathways, and several lines of
      evidence indicate that neurosteroids interact with neurotransmitters. These
      conclusions and our present results support the hypothesis that sulfatation of
      steroids may be the prime mover of a complex network, including genes shown to be
      implicated in aggression by mutagenesis.

PMID- 10405463
TI  - Plasma ACTH levels during early, two-way avoidance acquisition in high- and low
      avoidance rats (Hatano strains).
AB  - Having successfully bred for high- and low-avoidance rats (HAA and LAA,
      respectively) on a shuttlebox task, we performed three experiments designed to
      identify factors which might be related to the phenotypic differences seen in
      avoidance behavior. In experiment 1, shuttlebox behavior was measured to
      determine whether the phenotypic difference was activity related. In terms of
      intertrial responses, there was no difference between HAA and LAA rats in
      locomotor activity during the conditioning process. Experiment 2 compared adrenal
      weights of HAA and LAA rats at 11 weeks of age. The observation that the adrenal
      glands were heavier in HAA than in LAA rats suggested that these strains might
      differ in aspects of endocrine response. In experiment 3, plasma levels of ACTH
      and corticosterone were determined during early escape/avoidance acquisition in
      the shuttlebox. Plasma levels of ACTH after the shuttlebox testing were higher in
      HAA than in LAA rats. There was no difference between the two strains in plasma
      levels of corticosterone after testing, possibly due to a ceiling effect. These
      results suggest that the phenotypic differences in the acquisition of avoidance
      behavior of HAA and LAA rats may be related to different endocrine responses,
      rather than to locomotor activity.

PMID- 10405464
TI  - Fast track consult.

PMID- 10405465
TI  - Statutory registration for dental nurses.

PMID- 10405466
TI  - Measuring nursing competence.

PMID- 10405467
TI  - Training for nurses in oral care.

PMID- 10405468
TI  - Amalgam bonding.

PMID- 10405469
TI  - Reflections on professional and lay perspectives of the dentist-patient
      interaction.

PMID- 10405470
TI  - Tooth surface loss. 9. Treatment planning.

PMID- 10405471
TI  - Barriers to improving endodontic care: the views of NHS practitioners.
AB  - AIMS: Concerns have been expressed about the technical quality of NHS endodontic
      treatment. Bringing performance into line with guidelines for good practice needs
      to be underpinned by an understanding of barriers to compliance. To this end, our
      research involved an exploratory investigation of the factors influencing the
      behaviour of general dental practitioners in their practice of endodontics.
      MATERIALS AND METHODS: Subjects 12 dental practitioners, representative of
      varying levels of professional experience and status, and of compliance with good
      practice guidelines. Data collection In-depth interviews, following a topic
      guide. Analysis Identification, abstraction and charting of major themes.
      FINDINGS: Informants' responses suggested that general dental practitioners'
      endodontic practice is influenced by a complex web of factors. A key barrier to
      high quality treatment is the NHS remuneration scheme. Undergraduate and
      postgraduate education and training are also highly influential on practice.
      Dentists reported employing a range of strategies to manage the time-cost
      tensions imposed by the remuneration system. Perceived deficiencies in the
      content and delivery of postgraduate training were highlighted by our informants.
      CONCLUSIONS: There was a perception among our informants that the NHS fee
      structure needs to be revised. Their views suggest that a system which rewards
      quality rather than volume may be more appropriate, but, we believe, such a
      system would need to take into account efficiency as well as effectiveness.
      Modification of the current system of postgraduate training in endodontics is
      also indicated by the views expressed in the interviews. From the diversity of
      views and from a critical review of the literature, we conclude that flexibility
      is the key note in changing practice, with no single strategy likely to be
      universally appropriate.

PMID- 10405473
TI  - A review of teaching of behavioural sciences in the United Kingdom dental
      undergraduate curriculum.
AB  - In 1990, the GDC published its recommendations on the teaching of behavioural
      sciences. A study of sociological and psychological teaching in the dental
      undergraduate curriculum has shown a great deal of variation between the 14
      dental schools in the United Kingdom. Most of this teaching was also theoretical
      and at a pre-clinical level. Should skills and applied psychology be given an
      increased emphasis in the core clinical content of the undergraduate curriculum?

PMID- 10405472
TI  - An evaluation of sealant restorations after 2 years.
AB  - AIM: To obtain evidence of the efficacy of sealant restoration used in the
      management of fissure caries. DESIGN: A controlled study in a UK dental hospital
      environment. METHODS: Suspect fissure lesions were investigated in 164 young
      adult patients attending for routine dental care. Only one test tooth per subject
      was included in the study. Patients were recalled after 6, 12 and 24 months at
      which time the fissure sealant retention and the performance of the restorative
      materials were noted. RESULTS: Successful recall was achieved with 91.5% of
      patients. Most teeth treated (92%) involved the preparation of an investigative
      cavity. The mean age of patients treated was 23.9 years and second permanent
      molar teeth were the most commonly affected teeth requiring treatment in this age
      group. The presence of small composite restorations did not adversely affect
      fissure sealant retention but after 2 years, significantly more sealant was lost
      from the surface of light cured glass-ionomer cement and larger composite
      restorations. CONCLUSIONS: Sealant restorations provide an effective method of
      management of fissure caries in young adult patients.

PMID- 10405474
TI  - Influenza on a cruise ship in the Mediterranean.

PMID- 10405475
TI  - WHO intensifies drive for global eradication of polio.

PMID- 10405476
TI  - Evaluation of thyroid function in north Indians with alopecia areata: response to
      intravenous injection of 100 micrograms thyrotropin releasing hormone (TRH).
AB  - There is a lack of agreement on the overall prevalence of thyroid disease and
      thyroid function abnormalities in alopecia areata. Only one study is available
      from the Indian subcontinent. All patients with alopecia areata attending a
      dermatology outpatient clinic between 1983 and 1997 were screened for the
      presence of clinical thyroid disease. Sixty-two consecutive patients during the
      year 1994 were evaluated in detail for thyroid functions by measuring T3, T4, TSH
      levels and testing for antithyroid and antimicrosomal antibodies. Twenty-two
      patients randomly selected from the above-mentioned sixty two were studied for
      TSH response to intravenous injection of 100 micrograms TRH at -20, 0 and 20, 60,
      and 120 minutes after TRH injection. Thyroid disease was clinically evident in 16
      (0.85%) of the 1700 patients with alopecia areata seen over the last fifteen
      years. All sixty-two patients evaluated for thyroid functions were clinically
      euthyroid. Seven (11.3%) out of these 62 patients had abnormal thyroid hormone
      levels. Antithyroid and antimicrosomal antibodies were found in five patients;
      all five had abnormalities in thyroid function. TSH response to TRH was
      suggestive of hypothyroidism in 4 (18%) of the 22 patients studied. Manifest
      thyroid disease is infrequently associated with alopecia areata. Abnormalities in
      thyroid functional status were more frequent; they were found in 7 (11.3%) out of
      62 patients. TSH response to intravenous TRH was abnormal in an even higher
      proportion [4 (18%) out of 22 patients]. There was no apparent correlation with
      duration or type of alopecia areata.

PMID- 10405477
TI  - Postoperative alveolar hydatid disease with cutaneous-subcutaneous involvement.
AB  - The first Japanese case of alveolar hydatid disease with cutaneous-subcutaneous
      lesions is reported. The patient, a 58-year-old man who developed an indurated
      subcutaneous tumor on the right side of the abdomen, had had partial hepatectomy
      of the right lobe for echinococcosis thirteen years earlier. Clinically, the
      tumor was adherent with a fistulosis communication to deeper structures.
      Histopathologically, multiple PAS-positive cuticular layers with foreign body
      granulomas and fibrosis were observed between the dermis and subcutaneous fatty
      tissue. Surgical excision of the swelling provided the patient with temporary
      relief. To our knowledge, only eight cases of subcutaneous alveolar hydatid
      disease have been reported throughout the world. Ours, the ninth case, highlights
      the importance and difficulty of treating of alveolar hydatid disease.

PMID- 10405478
TI  - Unilateral Schamberg disease in a 14-year-old Japanese boy.
AB  - We report a 14-year-old Japanese boy who has had asymptomatic, multiple, reddish
      brown macules and petechiae distributed segmentally only in the right lower
      extremity for the last 6 months. Histological examination showed a perivascular
      lymphohistiocytic infiltrate in the papillary dermis, extravasation of red blood
      cells, and hemosiderin deposition. Treatment with tranilast and topical
      corticosteroid was dramatically effective. Although the histological findings
      were compatible with those of Schamberg disease, this case was unusual because
      the patient was very young and only one extremity was affected.

PMID- 10405479
TI  - Paraneoplastic syndromes of leukocytosis, thrombocytosis, and hypercalcemia
      associated with squamous cell carcinoma.
AB  - Paraneoplastic syndromes including leukocytosis, thrombocytosis and hypercalcemia
      are occasionally seen in patients suffering from progressive malignant disorders.
      Recent studies have revealed the production of several humoral factors by tumor
      cells and normal splenic cells of tumor-bearing patients to be the major cause of
      these reactions. Granulocyte-macrophage colony-stimulating factor (GM-CSF),
      granulocyte-colony stimulating factor (G-CSF), parathyroid hormone-related
      peptide, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) have been
      implicated. We describe a 58-year-old Japanese man with squamous cell carcinoma
      (SCC) on the left sole, which developed in a deep linear scar after a train
      crash. He developed pulmonary and lymph node metastases, then leukocytosis
      (57,110/mm3 with 95% neutrophilia), thrombocytosis (86.3 x 10(4)/mm3), and
      hypercalcemia (7.0 mEq/1), and finally cachexia, followed by death. Serum G-CSF,
      IL-1 alpha, IL-1 beta, and TNF-beta were determined; revealing G-CSF and IL-1
      beta levels were above the upper limits of their normal ranges at 39.2 pg/ml and
      4.63 pg/ml, respectively. It is probable that these humoral factors were
      partially responsible for the paraneoplastic syndromes induced by the cutaneous
      SCC with metastasis in the present case.

PMID- 10405480
TI  - Acute generalized exanthematous pustulosis induced by salazosulfapyridine in a
      patient with ulcerative colitis.
AB  - We report a case of acute generalized exanthematous pustulosis (AGEP) induced by
      salazosulfapyridine in a patient with ulcerative colitis. A 26-year-old Japanese
      man, who had been receiving medical attention for ulcerative colitis for one
      year, presented with diffuse erythema and pustules on his face and trunk,
      malaise, and fever up to 39 degrees C one day after the administration of
      salazosulfapyridine. A skin biopsy specimen disclosed intracorneal pustule
      composed of neutrophils and lymphohistiocytic infiltrate in the dermis. A drug
      lymphocyte stimulation test for salazoslufapyridine was positive, but the patch
      test was negative. Immunological mechanisms are suggested in the pathogenesis of
      psoriasis and ulcerative colitis. We suspect that a similar immunological pathway
      played a role in the pathogenesis of AGEP appearing in psoriasis and ulcerative
      colitis.

PMID- 10405481
TI  - Cellular neurothekeoma with possible neuroendocrine differentiation.
AB  - We report a case of cellular neurothekeoma showing unusual immunohistochemical
      findings and occurring on the left upper arm of a healthy 48-year-old woman. She
      presented with a 1 cm, red, asymptomatic, dermal nodule of 1 year duration. A
      biopsy showed dermal proliferation of plexiform fascicles of spindle-shaped or
      polygonal cells with plentiful eosinophilic cytoplasms. The immunohistochemical
      profile included negative stains for S-100, CD34, factor XIIIa, CD68, HMB45,
      cytokeratins, and EMA, strongly positive stains for neuron specific enolase
      (NSE), synaptophysin, and chromogranin A, and focally positive ones for NKI/C3
      and alpha-smooth muscle actin. Ultrastructural analysis showed undifferentiated
      mesenchymal cells with cytoplasmic projections and abundant RER. Although we
      couldn't find any confirmative cell type in this cellular tumor, we believe that
      cellular neurothekeoma is predominantly composed of undifferentiated cells that
      can exhibit features of neuroendocrine cells in addition to fibroblastic or
      myofibroblastic ones, suggesting a divergent cell origin.

PMID- 10405482
TI  - Pentazocine induced widespread cutaneous and myo-fibrosis.
AB  - We report a case of extensive subcutaneous and muscle fibrosis in a 26-year-old
      Indian woman caused by repeated intramuscular pentazocine injections over five
      years to highlight the extent and sequelae of this avoidable condition.

PMID- 10405483
TI  - Two cases of gigantic dystrophic calcinosis cutis caused by subcutaneous and/or
      intramuscular injections.
AB  - We describe two female patients with gigantic dystrophic calcinosis cutis caused
      by a large number of subcutaneous and/or intramuscular injections which they
      received when they were much younger. Laboratory data and physical examinations
      were generally within normal limits, and we detected no disease which might
      induce cutaneous calcification. There are many reports of dystrophic calcinosis
      cutis caused by injection of several kinds of drugs. However, we found no
      previous report describing a patient with calcinosis cutis induced by local
      tissue injury from a large number of injections and with extraordinarily
      widespread calcification at the injection sites. Because we do not know the exact
      drugs injected, it is difficult to say if a specific ingredient in the injections
      was related to this condition. We do know that a large number of subcutaneous or
      intramuscular injections were frequently administered to patients who had
      difficulty in maintaining venous infusions in the past, so there may be similar
      cases of dystrophic calcinosis cutis which have not been reported.

PMID- 10405484
TI  - Kaposi's varicelliform eruptions during the course of steroid withdrawal in a
      senile erythroderma patient: cure of regional erythrodermic lesions following
      infection.
AB  - The author encountered a case of Kaposi's varicelliform eruptions on both axillar
      regions during the course of steroid withdrawal in a 68-year-old male with
      eythroderma following eczema. Immnohistochemical study gave positive indication
      of herpes simplex virus type I in epidermal keratinocytes in lesional vesicles.
      Following cure of the varicelliform eruptions, erythrodermic lesions in the
      axillar regions cleared up completely. For those at other sites, considerably
      more time was required for cure, with steroid withdrawal being a factor of this
      period.

PMID- 10405485
TI  - A case of cutaneous extramedullary hematopoiesis in myelofibrosis with a
      preponderance of eosinophilic precursor cells.
AB  - A 48-year-old Korean man with myelofibrosis had erythematous papules and nodules
      on his scalp, anterior chest, back, lower abdomen, and both thighs. Skin biopsy
      showed cellular infiltration on the perivascular dermis and subcutaneous fat.
      Infiltrates were composed mainly of myeloid cells, especially of eosinophilic
      precursor cells. Erythroid and a few megakaryocytic precursors were also found.
      We diagnosed cutaneous extramedullary hematopoiesis with an interesting
      preponderance of eosinophilic precursor cells.

PMID- 10405486
TI  - Histiocytic necrotizing lymphadenitis (Kikuchi's disease): the necrotic
      appearance of the lymph node cells is caused by apoptosis.
AB  - We report a case of histiocytic necrotizing lymphadenitis in a 28-year-old woman.
      The biopsy specimen of the enlarged lymph node showed lymphocytes, histiocytes,
      and a large amount of nuclear debris as well as marked eosinophilic deposits. We
      found DNA fragments by means of the modified TUNEL method, especially in the
      transitional area between intact cells and the foci of eosinophilic deposits and
      the cells positive for anti-Fas antibody in the biopsied lymph node. Therefore,
      the necrotic appearance of the lymph node was thought to be caused by apoptosis
      induced by the Fas-Fas ligand system. We hypothesize that the apoptosis was
      strongly related to the pathogenesis of this disease.

PMID- 10405488
TI  - Elephantiasis neuromatosa and Becker's melanosis.
AB  - The most characteristic lesions of neurofibromatosis are the extremely large
      plexiform neurofibromas involving an entire extremity, which give rise to the
      condition known as elephantiasis neuromatosa. In this article, we present a
      patient who was diagnosed as elephantiasis neuromatosa with Becker's melanosis
      clinically and review the literature briefly.

PMID- 10405487
TI  - Adenocarcinoma with signet ring cells of the axilla: two case reports and review
      of the literature.
AB  - Adenocarcinoma with signet ring cells (ASRC) is a rare skin neoplasm whose
      histology shows a solid tumor intermingled with signet ring cells in variable
      numbers. There have been only ten reported cases. All were elderly males affected
      on the eyelids except for a single case in the axilla. Two new patients with ASRC
      of the axilla are described. In both of them, immunohistochemical studies
      revealed neoplastic cells that had differentiated toward apocrine glands. These
      are the second and third reported cases of ASRC in the axilla, one of them is the
      first ASRC case in a female. It seemed that the apocrine sweat gland or aberrant
      breast tissue in the axilla were possible origins of these tumors.

PMID- 10405489
TI  - Confluent ecchymoses on the lower extremities of a malnourished patient.
AB  - Nutritional deficiencies result in many distinctive cutaneous manifestations.
      Vitamin C deficiency, or scurvy, produces follicular hyperkeratosis,
      perifollicular hemorrhages, gingival hypertrophy, and bleeding (1). We report
      here a case of malnutrition who suddenly developed extensive eccymoses on the
      lower extremities sharing morphological similarities with purpura fulminans.
      Although the patient did not have the characteristic dermatological features of
      scurvy, serum levels of vitamins C, K, B12, and E were decreased.

PMID- 10405491
TI  - Disseminated superficial porokeratosis with dermal amyloid deposition.

PMID- 10405490
TI  - Eruptive vellus hair cyst in a patient with pachyonychia congenita.
AB  - Pachyonychia congenita is characterized by symmetrical nail dystrophy,
      palmoplantar keratoderma, oral leukokeratosis, and follicular hyperkeratosis. In
      addition to these features, multiple cutaneous cysts of various kinds have been
      described. We report a case of pachyonychia congenita associated with eruptive
      vellus hair cyst.

PMID- 10405492
TI  - Carbamazepine for Kleine-Levin syndrome.

PMID- 10405493
TI  - Appetite and weight in children treated for ADHD.

PMID- 10405494
TI  - Dystonia as a side effect of nonneuroleptics.

PMID- 10405495
TI  - Secretin and autism: the role of cysteine.

PMID- 10405496
TI  - Are stimulants overprescribed? Treatment of ADHD in four U.S. communities.
AB  - OBJECTIVE: To address rising concerns about the possible overdiagnosis of
      attention-deficit hyperactivity disorder (ADHD) and overtreatment with
      stimulants. To date, almost no studies have examined ADHD in unbiased community
      based studies, ascertaining both the prevalence of the diagnosis within
      nonreferred populations and the extent to which various treatments (i.e.,
      stimulant medication, mental health treatments, and educational interventions)
      are used. METHOD: As a part of the Methods for the Epidemiology of Child and
      Adolescent Mental Disorders (MECA) Study, the authors examined epidemiological
      survey data obtained from 1,285 children and their parents across 4 U.S.
      communities. Analyses examined the frequency of children's ADHD diagnosis, the
      extent to which medications were prescribed, as well as the provision of other
      services (e.g., psychosocial treatments, school-based educational interventions).
      RESULTS: Findings indicated that 5.1% of children met full DSM-III-RADHD criteria
      across the pooled sample. Only 12.5% of children meeting ADHD criteria had been
      treated with stimulants during the previous 12 months. Some children who had been
      prescribed stimulants did not meet full ADHD diagnostic criteria, but these
      children manifested high levels of ADHD symptoms, suggesting that the medication
      had been appropriately prescribed. Children with ADHD were generally more likely
      to receive mental health counseling and/or school-based interventions than
      medication. CONCLUSIONS: Medication treatments are often not used in treating
      ADHD children identified in the community, suggesting the need for better
      education of parents, physicians, and mental health professionals about the
      effectiveness of these treatments. On the basis of these data it cannot be
      concluded that substantial "overtreatment" with stimulants is occurring across
      communities in general.

PMID- 10405497
TI  - Efficacy of methylphenidate among preschool children with developmental
      disabilities and ADHD.
AB  - OBJECTIVE: This was a double-blind, placebo-controlled, crossover design study of
      the safety and efficacy of methylphenidate (MPH) in 11 preschool children (aged
      4.0-5.11 years) with developmental disabilities and attention-deficit
      hyperactivity disorder (ADHD). METHOD: MPH doses of 0.3 and 0.6 mg/kg per dose
      and a placebo were given. Drug response was evaluated via teacher-completed
      behavior checklists and clinic-based observations of activity level, attention,
      and compliance to adult requests. A side effects checklist was also completed by
      teachers and parents. RESULTS: Significant improvement on teacher ratings of
      hyperactivity and inattention as well as clinic-based observations of activity
      level and compliance were associated with MPH. Eight of 11 preschool children
      were medication responders (based on a minimum 40% decrease between placebo and
      one drug condition on either the teacher-rated Conners Hyperactivity Index or the
      Hyperactive-Distractible subscale of the Preschool Behavior Questionnaire). Five
      children exhibited significant adverse drug side effects such as severe social
      withdrawal, increased crying, and irritability, especially at the higher dose
      (0.6 mg/kg). CONCLUSIONS: Results suggest that preschool children with
      developmental disabilities and ADHD respond to MPH at rates similar to those of
      school-age children with mental retardation and ADHD. However, this population
      appears to be especially susceptible to adverse drug side effects.

PMID- 10405498
TI  - Differential effectiveness of methylphenidate and Adderall in school-age youths
      with attention-deficit/hyperactivity disorder.
AB  - OBJECTIVE: To compare the effectiveness of a single dose of Adderall (q.d.) with
      that of 2 daily doses of methylphenidate (b.i.d.; MPH) as a treatment for
      attention-deficit/hyperactivity disorder (ADHD) in youths ranging in age from 5
      to 17 years. Forty-two youths treated with MPH were compared with 42 youths
      treated with Adderall. Subjects were matched for age, sex, and DSM-IV diagnostic
      subtype. METHOD: Youths were assigned to the Adderall or MPH condition by their
      prescribing physician. All youths were evaluated under 5 conditions, including
      baseline, placebo, 5 mg, 10 mg, and 15 mg. The best dose was assigned prior to
      breaking the medication blind and was assigned by the consensus of the
      psychologist and psychiatrist. Subjective ratings by both teachers and parents
      were examined for dosage level effects and medication type effects. RESULTS: Best
      dose was always superior to baseline and placebo conditions. No differences
      between MPH and Adderall were observed on either teacher or parent ratings of
      behavior. CONCLUSIONS: Both MPH and Adderall have been shown to be effective
      treatments for children with ADHD. Both medications appear to improve teachers'
      and parents' ratings of behavior. Single-dose treatments of Adderall appear to be
      as effective as 2 daily doses of MPH and therefore increase the possibility of
      managing treatment without involving the school in medication administration. In
      addition, youths who have previously been unsuccessfully treated with MPH because
      of adverse side effects or poor response may be successfully treated with
      Adderall.

PMID- 10405499
TI  - Developmental coordination disorder in Swedish 7-year-old children.
AB  - OBJECTIVE: To estimate the prevalence, comorbidity, and outcome in developmental
      coordination disorder (DCD). METHOD: In this population study of 7-year-olds
      undergoing individual examination plus teacher and parent interviews, children
      were followed up at ages 8, 9, and 10 years. RESULTS: Severe DCD occurred in 4.9%
      and moderate DCD in another 8.6%. Boy-girl ratios ranged from 4:1 to 7:1.
      Children with severe and moderate DCD did not differ from each other on any
      measure, but both groups were clearly separated from children without DCD with
      respect to associated attention deficit symptoms. Asperger's disorder symptoms,
      school dysfunction scores, and outcome. Approximately half of all children with
      DCD had moderate to severe symptoms of attention-deficit/hyperactivity disorder
      (ADHD). CONCLUSIONS: DCD is a common problem, and it is strongly associated with
      ADHD symptoms. A diagnosis of DCD at age 7 years predicts DCD at age 8 years and
      restricted reading comprehension at age 10 years. Clinicians need to acquaint
      themselves with DCD and its comorbidity so that they can provide better services
      to affected children.

PMID- 10405500
TI  - Recovery and relapse in anorexia and bulimia nervosa: a 7.5-year follow-up study.
AB  - OBJECTIVE: To assess the course and outcome of anorexia nervosa (AN) and bulimia
      nervosa (BN) at a median of 90 months of follow-up in a large cohort of women
      with eating disorders. METHOD: A prospective, naturalistic, longitudinal design
      was used to map the course of AN and BN in 246 women. Follow-up data are
      presented in terms of full and partial recovery, predictors of time to recovery,
      and rates and predictors of relapse. RESULTS: The full recovery rate of women
      with BN was significantly higher than that of women with AN, with 74% of those
      with BN and 33% of those with AN achieving full recovery by a median of 90 months
      of follow-up. Intake diagnosis of AN was the strongest predictor of worse
      outcome. No predictors of recovery emerged among bulimic subjects. Eighty-three
      percent of women with AN and 99% of those with BN achieved partial recovery.
      Approximately one third of both women with AN and women with BN relapsed after
      full recovery. No predictors of relapse emerged. CONCLUSIONS: The findings
      suggest that the course of AN is characterized by high rates of partial recovery
      and low rates of full recovery, while the course of BN is characterized by higher
      rates of both partial and full recovery.

PMID- 10405501
TI  - Preschool boys with oppositional defiant disorder: clinical presentation and
      diagnostic change.
AB  - OBJECTIVE: Little is known about the clinical presentation and course of
      oppositional defiant disorder (ODD) when first diagnosed in the preschool years.
      Patterns of ODD symptomatology, comorbidity, persistence of disorder, and
      predictors of diagnostic outcome were examined in clinic-referred preschool boys.
      METHOD: Boys (aged 4-5.5 years) with a DSM-III-R diagnosis of ODD were
      prospectively followed over a 2-year period. Multiple assessment procedures were
      used, including a modified version of the Diagnostic Interview Schedule for
      Children and parent and teacher ratings. RESULTS: Ninety-two boys (mean age 56.9
      months) with ODD were followed; 42 had comorbid attention-deficit hyperactivity
      disorder (ADHD). Among 79 boys assessed 2 years later, 76% had ODD, ADHD, or
      both. Of those, 25% had other diagnoses as well, primarily anxiety and/or mood
      disorders. Conduct disorder was rare. Subjects with comorbid ODD/ADHD at intake
      were significantly more likely to have a psychiatric disorder at follow-up,
      especially ADHD alone. CONCLUSIONS: The findings suggest that ODD in the
      preschool period is a clear indicator of high risk, especially when co-occurring
      with ADHD. Further investigation of individual patterns of ODD symptom expression
      is recommended.

PMID- 10405502
TI  - Suicide in adolescents with disruptive disorders.
AB  - OBJECTIVE: To determine the psychiatric risk factors for suicide in adolescents
      with disruptive disorders. METHOD: Fifty-nine adolescent suicide completers and
      18 community controls, both having a probable or definite current DSM-III
      diagnosis of disruptive disorders, were compared. RESULTS: Adolescents with
      disruptive disorders who committed suicide had higher rates of current substance
      abuse, past suicide attempt, family history of substance abuse, and family
      history of mood disorder than disruptive community controls. CONCLUSIONS:
      Disruptive adolescents appear to be at risk for completed suicide when comorbid
      substance abuse and past history of suicide attempt are present. The risk
      increases if the adolescents have a past history of physical abuse and if they
      have parents with substance abuse and mood disorders. Clinicians should be aware
      of these risk factors and implement active interventions to prevent suicide.
      Treatment should focus on treating not only the adolescents, but also their
      family members. The findings of this study also highlight the need for future
      research in the prevention of suicide in adolescents with disruptive disorders
      and comorbid substance abuse.

PMID- 10405504
TI  - Case study: missed diagnosis and mistreatment of unrecognized comorbid Graves
      disease.
AB  - Comorbid medical conditions are known to complicate the course and treatment of
      psychiatric disorders. This case study provides the first published report of
      Graves disease exacerbating the symptoms of Tourette's disorder and attention
      deficit hyperactivity disorder (ADHD). The lack of diagnosis of the Graves
      disease compromised the efficacy of the treatment of Tourette's disorder and
      ADHD. This case study supports the need to the consider increased risk of a
      second immunoendocrinological disorder in the presence of diabetes mellitus type
      I, one of the several disorders that comprise the syndrome of polyglandular
      autoimmune endocrinopathy type II.

PMID- 10405503
TI  - Somatic complaints and psychopathology in children and adolescents: stomach
      aches, musculoskeletal pains, and headaches.
AB  - OBJECTIVE: To examine the associations of somatic complaints with DSM-III-R
      defined depression, anxiety disorders, conduct disorder, oppositional defiant
      disorder, and attention-deficit hyperactivity disorder in a population-based
      sample of children and adolescents. METHODS: Data from 4 annual waves of
      interviews with 9- to 16-year-olds from the Great Smoky Mountains Study were
      analyzed. RESULTS: Overall, somatic complaints were strongly associated with
      emotional disorders in girls and with disruptive behavior disorders in boys. For
      girls, stomach aches and headaches together and musculoskeletal pains alone were
      associated with anxiety disorders. For boys, stomach aches were associated with
      oppositional defiant disorder and attention-deficit hyperactivity disorder.
      Musculoskeletal pains were associated with depression in both girls and boys.
      CONCLUSIONS: There were gender-, illness- and complaint-specific associations
      between somatic complaints and psychopathology. It appears likely that there are
      differences in the psychobiological processes underlying these associations in
      boys and girls. Clinical recommendations include screening children and
      adolescents with persistent complaints of headaches, stomach aches, or
      musculoskeletal pains for psychiatric disorders with an awareness that gender may
      affect the type of psychopathology associated with the somatic complaints.

PMID- 10405505
TI  - Psychosexual dysfunction in males with genital anomalies: late adolescence,
      Tanner stages IV to VI.
AB  - OBJECTIVE: To assess psychosexual function in adolescent males with genital
      anomalies. METHOD: Fourteen consecutive males with bladder exstrophy-epispadias,
      14 to 19 years old, Tanner stages IV to VI, were assessed along with their
      parents, using a developmental questionnaire, Hollingshead socioeconomic status
      rating, Child Behavior Checklist, Youth Self-Report, semistructured psychiatric
      interview, detailed sexual history, and 5 written, open-ended questions. RESULTS:
      All subjects showed psychosexual dysfunction in terms of genital satisfaction and
      genital touching; only 2 had ever undressed in front of anyone; only 2 had ever
      masturbated and only after age 16; 8 had few friends and only 5 considered any
      girls as friends; all expressed heterosexuality but only 4 had dated, 1 at age 17
      and 2 after age 18; only the two 19-year-olds had experienced sexual intercourse,
      at the age of 19. All had an anxiety disorder. Half had experienced a major
      depressive disorder. CONCLUSIONS: Psychosexual dysfunction and anxiety were
      universal and chronic in these males with genital anomalies, leading to social
      and sexual developmental impairment. Half had a mood disorder. Implications for
      adulthood as well as for children with other genital anomalies are unclear but
      deserve further study. Males with genital anomalies should be evaluated for
      psychosexual developmental impairment.

PMID- 10405506
TI  - Imipramine treatment in pediatric burn patients with symptoms of acute stress
      disorder: a pilot study.
AB  - OBJECTIVE: Pediatric burn patients often exhibit acute stress disorder (ASD)
      symptoms. Information on psychopharmacological treatment of ASD symptoms in
      children is scarce. This pilot study used a prospective, randomized, double-blind
      design to test whether thermally injured children suffering ASD symptoms benefit
      from imipramine. METHOD: Twenty-five children, aged 2 to 19 years, received
      either imipramine or chloral hydrate for 7 days. A structured interview
      (clinically useful, but validity and reliability not yet established) was used to
      assess the presence and frequency of ASD symptoms both before treatment and 3
      times during the treatment period. RESULTS: Eleven females and 14 males
      participated, with a mean total burn surface area of 45% (SD = 23%) and mean age
      of 8 years (SD = 6). Imipramine was more effective than chloral hydrate in
      treating ASD symptoms (chi 2 [1, N = 25] = 5.24, p < .02). Five of 13 were
      positive responders to chloral hydrate (38%). Ten of 12 were positive responders
      to low-dose imipramine (83%). CONCLUSIONS: This pilot study suggests a place for
      cautious initial use of imipramine to reduce ASD symptoms in burned children.
      Care must be taken to minimize cardiovascular risks in an off-label application
      of imipramine in children, especially those receiving additional medications.

PMID- 10405507
TI  - Psychopathology and achievement in children at high risk for developing
      alcoholism.
AB  - OBJECTIVE: To compare rates of psychopathology and academic achievement in
      children who were either at high or low risk for developing alcoholism and to
      determine whether academic deficits would predict prospectively the presence of
      psychopathology occurring within the next year. METHOD: Children and adolescents,
      aged 8 to 18 years, were evaluated as part of a longitudinal follow-up. Diagnoses
      obtained by using the Schedule for Affective Disorders and Schizophrenia for
      School-Age Children and grade-equivalent scores from the reading, spelling, and
      arithmetic sections of the Wide Range Achievement Test were determined at yearly
      intervals. RESULTS: High-risk offspring were more likely to have a diagnosable
      disorder. In addition, analyses using the mother's and father's diagnosis of
      alcoholism as a covariate showed higher hazard ratios for selected disorders
      (depression, affective disorder, attention-deficit/hyperactivity disorder, and
      conduct disorder), some of which were gender-dependent. Logistic regression
      analysis of achievement test scores demonstrated that reading and math scores
      predicted the presence of childhood psychopathology at the following annual
      evaluation. CONCLUSIONS: Children from pedigrees with a high density of
      alcoholism are at greater risk for developing psychopathology. Furthermore,
      observed deficits in academic performance may be considered an indicator of a
      developing diagnosable illness.

PMID- 10405508
TI  - Maternal smoking during pregnancy and psychopathology in offspring followed to
      adulthood.
AB  - OBJECTIVE: To extend findings from several independent reports of an association
      between maternal smoking during pregnancy and attention-deficit hyperactivity
      disorder, conduct disorder, and substance abuse in the offspring. METHOD: This is
      a 10-year longitudinal study of offspring assessed at 3 points in time into
      adulthood. Fifty offspring of mothers who reported smoking at least 10 cigarettes
      almost daily during pregnancy and 97 offspring of mothers who reported never
      smoking during pregnancy were studied. Psychiatric diagnosis in offspring was
      assessed blind to parental diagnosis. RESULTS: There was a greater than 4-fold
      increased risk of prepubertal-onset conduct disorder in boys and a greater than 5
      fold increased risk of adolescent-onset drug dependence in girls whose mothers
      smoked 10 or more cigarettes almost daily during pregnancy. These findings could
      not be explained by maternal substance abuse during pregnancy, parental
      psychiatric diagnosis, family risk factors, prenatal and early developmental
      history of offspring, postnatal maternal smoking, or smoking in the offspring.
      CONCLUSIONS: Maternal smoking during pregnancy may have a long-term effect on
      specific psychopathology in offspring. The underlying pathophysiology of nicotine
      on the fetus requires study. The findings suggest the importance of programs
      aimed at smoking prevention and cessation in women during pregnancy.

PMID- 10405509
TI  - Problem drug and alcohol use in a community sample of adolescents.
AB  - OBJECTIVE: Epidemiological studies of illegal drug use in adolescents have
      examined frequency of drug use; a few have examined diagnoses or symptoms of drug
      abuse or dependence. This study examined problem use of illegal drugs, about
      which very little is known. METHOD: Adolescents (879 boys and 929 girls), mean
      age of 15.7 years, representative of the province of Quebec, Canada, were asked
      about problem use of alcohol and illegal drugs. RESULTS: Almost one third had
      used illegal drugs more than 5 times. Of this group, more than 70% reported going
      to school high on drugs, and the majority reported playing sports while high and
      using drugs in the morning. In these drugs users, 94% of the boys and 85% of the
      girls reported at least 1 problem and two thirds of the boys and more than half
      of the girls reported 3 or more problems from illegal drugs. Marijuana was used
      by almost all subjects at the time of maximal drug use; hallucinogens were the
      second most commonly used drug. Alcohol was used more frequently than illegal
      drugs, but problem use was less common. CONCLUSIONS: Problem drug use is the norm
      among the large minority who use illegal drugs more than a few times, and drug
      use is commonly incorporated into 2 major routine activities of teenagers--school
      and sports.

PMID- 10405510
TI  - Continuity of depression during the transition to adulthood: a 5-year
      longitudinal study of young women.
AB  - OBJECTIVE: To characterize the clinical course and psychosocial correlates of
      unipolar depression in late adolescent women and to examine the continuity in
      affective disturbance from adolescence to early adulthood during the post-high
      school transition. METHOD: One hundred fifty-five women aged 17 or 18 years were
      recruited from 3 local public high schools and were followed at yearly intervals
      for 5 years for clinical and psychosocial outcomes. RESULTS: The 5-year incidence
      of first major depressive episode was 36.9%, and overall, 47% of the women had
      one or more episodes of major depression. Risk for recurrence was substantial,
      and those with onsets prior to the study were more likely to have depressive
      episodes during the post-high school period. The presence of nonaffective
      disorder also increased the risk for depression. Young women with major
      depression during the post-high school transition had more negative functional
      outcomes in school and intimate romantic relationships. CONCLUSIONS: These
      results suggest that there is substantial continuity in affective disturbance
      from adolescence to adulthood. The risk for both new onset of depression and
      recurrence is remarkably high during late adolescence, and the risk continues
      throughout early adult years, accompanied by notable interpersonal dysfunction.

PMID- 10405511
TI  - Anxiety and depressive disorders in fathers and mothers of anxious school
      refusing children.
AB  - OBJECTIVE: To examine anxiety and depressive disorders in the mothers and fathers
      of children with anxious school refusal and to test for the existence of
      differences in familial aggregation between children suffering from school
      refusal related to separation anxiety disorder and those suffering from phobic
      disorder-based school refusal. METHOD: Using a blind standardized diagnostic
      evaluation (Schedule for Affective Disorders and Schizophrenia-Lifetime version,
      modified for the study of anxiety disorders; Diagnostic Interview for Genetic
      Studies; and Schedule for Affective Disorders and Schizophrenia for School-Age
      Children), the authors compared parental lifetime psychiatric illness for the 2
      groups of anxious school refusers. RESULTS: Relationships between specific
      anxiety disorders in children and their parents revealed increased prevalence of
      simple phobia and simple and/or social phobia among the fathers and mothers of
      phobic school refusers, and increased prevalence of panic disorder and panic
      disorder and/or agoraphobia among the fathers and mothers of school refusers with
      separation anxiety disorder. Simple and/or social phobia in the father, simple
      phobia in the mother, and age of the father were associated with the group of
      phobic school refusers. CONCLUSIONS: The data show the high prevalence of both
      anxiety and depressive disorders in fathers and mothers of anxious school
      refusers. Significant differences were observed in familial aggregation
      considering the subgroups of anxious school-refusing children.

PMID- 10405512
TI  - Higher-functioning pervasive developmental disorders: rates and patterns of
      psychotropic drug use.
AB  - OBJECTIVE: To explore the frequency, characteristics, and associated target
      symptoms of psychotropic drug use among subjects with higher-functioning
      pervasive developmental disorders (HFPDDs). METHOD: A total of 109 children,
      adolescents, and adults (mean age = 13.9 years, SD = 6.9) consecutively seeking
      enrollment into the Yale Child Study Center's Project on Social Learning
      Disabilities were included in the study. Individuals in whom Asperger's disorder,
      autism, or pervasive developmental disorder-not otherwise specified had been
      previously diagnosed and who had a documented Full Scale IQ > or = 70 completed
      surveys on demographic, clinical, and medication history information. To
      naturalistically evaluate medication use patterns in this population, each drug
      class was analyzed with respect to demographic and clinical variables. RESULTS:
      In all, 55% of subjects were taking psychotropics, with 29.3% taking 2 or more
      medications simultaneously. Antidepressants were the most commonly used agents
      (32.1%), followed by stimulants (20.2%) and neuroleptics (16.5%). The clinical
      presentation of subjects taking psychotropic agents was heterogeneous, and most
      consistently included anxiety-related target symptoms (in 65% of medicated
      individuals). CONCLUSIONS: Psychotropic medication use appears to be common among
      subjects with HFPDDs, yet not generally based on the results of empirical
      research. Clinical heterogeneity among treated subjects suggests that psychiatric
      comorbidity may be overlooked in this population.

PMID- 10405513
TI  - Genetics of childhood disorders: IV. Linkage analysis.

PMID- 10405514
TI  - Novel therapeutic options bring hope to patients with rheumatic conditions--and
      to the physicians who treat them.

PMID- 10405515
TI  - Appropriate use of gastrointestinal-protective agents in elderly needs
      clarification.

PMID- 10405517
TI  - Hybrid casts: a comparison of different casting materials.
AB  - Casting and splinting materials used in orthopedics have historically consisted
      of plaster of Paris and, more recently, fiberglass. Plaster is cost-effective and
      malleable enough to help to hold reductions. Fiberglass is stronger and lighter,
      but more expensive. The hybrid cast of plaster and fiberglass optimizes the
      advantages of both materials in fracture management; it is sufficiently strong,
      yet still cost-effective.

PMID- 10405516
TI  - Gastropathy induced by nonsteroidal anti-inflammatory drugs: prescribing patterns
      among geriatric practitioners.
AB  - The objective of this study was to determine patterns among geriatric
      practitioners in prescribing agents that protect the gastrointestinal tract when
      nonsteroidal anti-inflammatory drug (NSAID) treatment is started for elderly
      patients. A questionnaire describing five scenarios of elderly patients requiring
      NSAID therapy asked respondents to choose gastrointestinal-protective agents for
      each scenario. Respondents were then asked to what extent four established risk
      factors for NSAID gastropathy (age, previous peptic ulcer, previous
      gastrointestinal bleeding, and heart disease) affected their choices. The choice
      of gastrointestinal-protective agent was compared with the training and
      experience of the respondents. This self-administered survey was provided to 821
      randomly selected physicians from the membership of the American Geriatrics
      Society throughout the United States and Puerto Rico. Statistical Package for the
      Social Sciences (SPSS), version 6.1.4, was used to obtain frequencies. Of 821
      surveys, 229 (28%) were returned. It was found that well elderly patients and
      nursing home residents were not treated with any gastrointestinal-protective
      agent by 64% (well elderly patients) and 32% (nursing home residents) of
      respondents. Among respondents who would prescribe, about half would choose
      misoprostol for a well elderly patient or a nursing home resident, whereas half
      or more preferred histamine H2-receptor antagonists. Twenty-three percent would
      not prescribe misoprostol when NSAID therapy was resumed after an active ulcer
      had healed, and 68% preferred H2 antagonists in that setting. The difference in
      response attributable to training/experience was less than 9%. Factors that did
      not affect prescribing patterns included the patient's age (15% to 62%) and heart
      disease (44% to 50%). The study concluded that age and heart disease are risk
      factors to which physicians give less consideration when choosing
      gastrointestinal-protective agents. Although misoprostol is the only agent
      approved by the Food and Drug Administration for prophylaxis against NSAID
      gastropathy, 23% of respondents chose not to prescribe misoprostol when NSAID
      therapy was resumed after an active ulcer had healed. Histamine H2-receptor
      antagonists were preferred over misoprostol for well elderly patients and nursing
      home residents. Training and experience were not responsible for differences
      among respondents' prescribing patterns.

PMID- 10405518
TI  - Rheumatoid arthritis and primary care: the case for early diagnosis and
      treatment.
AB  - Rheumatoid arthritis is a chronic inflammatory disease that can cause severe pain
      and disability. Disease management historically was based on a "therapeutic
      pyramid" in which treatment escalated as symptoms worsened. However, the
      demonstration of early joint damage in patients with rheumatoid arthritis has
      emphasized the importance of early identification and treatment. Key features in
      establishing a diagnosis include joint examinations, assessments of extra
      articular manifestations, laboratory tests, and radiologic examinations. Care
      must be taken to rule out other disorders with symptoms that overlap those of
      rheumatoid arthritis. Treatment of rheumatoid arthritis typically involves
      disease-modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and
      low-dose corticosteroids--often used in combination. A new class of therapeutic
      agents designed to neutralize inflammatory cytokines has added a new dimension to
      the therapeutic armamentarium against rheumatoid arthritis. Etanercept, a
      bioengineered soluble receptor fusion protein that blocks tumor necrosis factor
      activity, is the first compound in this class to be approved for treatment of
      patients with refractory rheumatoid arthritis. Therapeutic trials indicate that
      etanercept can reduce disease activity with relatively few drug-related adverse
      effects, thus helping persons with rheumatoid arthritis return to more normal,
      healthy lives.

PMID- 10405520
TI  - Diagnosis and treatment of severe dysplastic spondylolisthesis.
AB  - Spondylolisthesis, the anterior or posterior displacement of one vertebra on
      another, usually affects the lumbar region. Five percent of the population has
      one of the five classes of spondylolisthesis, which include dysplastic, isthmic,
      degenerative, traumatic, and pathologic spondylolisthesis. This article focuses
      on the dysplastic type, which makes up 14% to 21% of all spondylolisthesis.
      Dysplastic spondylolisthesis usually causes no symptoms in children; pain usually
      begins in adolescence. The key to diagnosis is the appropriate use of radiography
      in the evaluation of low back pain. This report describes a case involving a 21
      year-old woman presenting with back pain to the family physician. Also, it
      details how the diagnosis was achieved and evaluates conservative and aggressive
      treatment options.

PMID- 10405519
TI  - Specific cyclooxygenase-2 (COX-2) inhibitors.
AB  - Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently among the most widely
      prescribed drugs worldwide. Their therapeutic benefits and their side effects in
      the gastrointestinal tract and kidney, as well as in hemostasis, are of great
      importance in modern medicine. Within the past decade, new insights into how
      NSAIDs produce both their therapeutic benefits and their serious side effects
      have been discovered. It is now known that there are two froms of the
      cyclooxygenase (COX) enzyme that metabolize arachidonic acid into prostaglandins.
      Drugs that specifically inhibit the COX-2 enzyme were formulated and put into
      clinical trials during the past 5 years. These drugs are now available to treat
      patients in the United States. Specific COX-2 inhibitors offer the benefit of
      being able to treat the pain and inflammation of arthritis with potentially
      little risk of serious gastrointestinal injury.

PMID- 10405521
TI  - Barrier function of gastric mucus.
AB  - A viscoelastic mucus gel layer covers the gastric mucosa in a continuous sheet.
      The functions of the mucus gel have been one of the least studied aspects of
      gastric barrier function. Although the role of gastric mucus in providing
      physical protection against ingested particles, and preventing contact between
      digestive enzymes such as pepsin and the underlying mucosa is generally accepted,
      the barrier role function of gastric mucus with regard to luminal acid is still
      conjectural. The modest proton diffusion barrier that mucus provides is
      negligible in relation to the overall barrier properties of the gastric mucosa;
      nevertheless, stabilization of unstirred layers and damping of rapid shifts in
      luminal pH are potentially important functions. Associative studies have
      suggested a possible role of a hydrophobic barrier in strengthening the barrier
      functions of mucus. One of the most actively investigated areas of mucus function
      in recent times has been the mechanism by which secreted acid traverses the gel.
      Although compelling and complementary data obtained in vivo and in vitro have
      been consistent with secretion of acid under pressure, creating temporary viscous
      fingers through the gel, recent evidence obtained with in vivo confocal
      microscopy suggests that secreted acid diffuses through the gel. Since
      Helicobacter pylori exists solely in the juxtamucosal portion of the gastric
      mucus gel, detailed knowledge concerning the pH microenvironment in which the
      organism thrives is important in understanding the pathophysiology of peptic
      ulcer disease and related conditions.

PMID- 10405522
TI  - Protein metabolism in critical illness: methodologies and their problems
      underlying in kinetic studies using isotope tracers in vivo.
AB  - The response to critical illness involves alterations in all aspects of metabolic
      control, favoring catabolism of body protein. In particular, as the result of the
      alteration of protein metabolism, body protein loss occurs, which has been
      reported to be inversely correlated with the survival of critically ill patients.
      Despite the availability of various therapeutic modalities aiming to prevent loss
      of body protein pool such as total parenteral nutrition, and enteral nutrition
      that has made to provide excessive calories as a form of energy substrate and
      protein itself, the loss of body protein could not be prevented. Loss of body
      protein store occurs as a consequence of the alteration of intermediate
      metabolism that works for the production of energy substrate. This alteration of
      substrate metabolism may link to the alteration of protein metabolism. However,
      no specific factors regulating protein metabolism have been identified. Thus,
      further investigations evaluating amino acid and protein metabolism are required
      to obtain a better understanding of the metabolic regulation in the body, which
      may lead to the development of novel and more effective therapeutic modalities
      for nutrition in the future.

PMID- 10405523
TI  - Current trends in cognitive rehabilitation for memory disorders.
AB  - Progress in the neuropsychology of memory disorders has provided a foundation for
      development of cognitive rehabilitation for amnesic patients. Accumulating
      evidence in the past two decades suggested that certain training techniques could
      be beneficial to many amnesic patients, such as teaching and acquisition of
      domain-specific knowledge, motor coding, reality orientation, and meta-cognition
      improvement. In this article we review and discuss the current trends in
      cognitive rehabilitation of memory disorders and provide a future direction in
      this emerging field. In addition, our experience in the successful rehabilitation
      of Korsakoff syndrome patients is also introduced.

PMID- 10405524
TI  - Differential induction of the androgen receptor transcriptional activity by
      selective androgen receptor coactivators.
AB  - Several new androgen receptor (AR) cofactors, associated to the ligand binding
      domain of AR, have been identified by our group and named AR associated protein
      (ARA)70, ARA55, and ARA54. Our previous reports have suggested that the cofactor
      ARA70 can confer the androgenic effect from 17 beta-estradiol (E2) and
      antiandrogen to AR. It is of interest for us to compare and determine if the
      specificity of sex hormones and antiandrogens could be modulated by different
      coactivators. Our results indicate that ARA70 is the best coactivator to confer
      the androgenic activity on E2. Only ARA70 and ARA55 could increase significantly
      the androgenic activity of hydroxyflutamide, a widely used antiandrogen for the
      treatment of prostate cancer. Furthermore, as compared to the relative
      specificity of these coactivators to AR in the prostate cancer DU145 cells, our
      results suggest that ARA70 has a relatively higher specificity. Together, our
      data suggest that the specificity of sex hormones and antiandrogens can be
      modulated by some selective AR coactivators. These findings may not only help us
      to better understand the specificity of the sex hormones and antiandrogens, but
      also to facilitate the development of better antiandrogens or androgens to fight
      the androgen-related diseases, such as prostate cancer.

PMID- 10405525
TI  - In vivo and in vitro positive interference by cefpirome in measurement of serum
      creatinine by the Jaffe method.
AB  - We report the case of an 81-year-old female patient with diverticulitis of the
      colon, whose symptoms were relieved by intravenous administration of cefpirome.
      However, her serum creatinine levels were falsely increased by the Jaffe method
      when serum samples were drawn after intravenous administration of cefpirome. The
      serum creatinine level in the same sample was within the normal range by the
      enzymatic method in the automated analyzer. In vitro experiment demonstrated dose
      dependent positive interference of the creatinine level with cefpirome. These
      results indicate that we should be aware of the positive interfering effect of
      cefpirome when we measure serum creatinine by the Jaffe method, and that the
      enzymatic method should be widely used to measure serum creatinine levels to
      eliminate false reactions due to certain chemicals.

PMID- 10405526
TI  - [It was called shy before--today it's social phobia we are talking about. Drugs
      and cognitive behavior therapy can reduce the problems].

PMID- 10405527
TI  - [Breasts and femininity, a given correlation?].

PMID- 10405528
TI  - [Wonder at the priority committee and its survey].

PMID- 10405529
TI  - [Hearing tests of newborn infants will hopefully be introduced in the whole
      country!].

PMID- 10405530
TI  - [Male depression--a condition or a process?].

PMID- 10405531
TI  - [Increased travelling--increased risk of imported viruses. A review of the
      diagnostic capacity of the Swedish Institute for Infectious Disease Control].
AB  - The increase in global travel, especially by air, has facilitated the spread of
      infectious agents from one part of the world to another. Returning travellers are
      often vectors for viral disease import to Sweden. While dengue fever has been
      quite frequently diagnosed during the past five years, especially in travellers
      returning from Thailand, only isolated cases of sandfly fever, Japanese
      encephalitis and Ross River fever have been seen. Dobrava virus was recently
      shown to have caused a severe form of haemorrhagic fever with renal syndrome in
      several European countries, and thus constitutes a risk for travellers to areas
      where it is endemic.

PMID- 10405532
TI  - [Centrally disturbed pain modulation explains prolonged pain. New knowledge
      changes the view on the problematic patient].

PMID- 10405533
TI  - [Serotonin both stimulates and inhibits sexual behavior of rats. New
      possibilities to understand the effects and side-effects of serotonergic drugs].

PMID- 10405534
TI  - [Cost-effectiveness analysis of cardiovascular disease prevention: a graded list
      as aid to the rational distribution of resources].
AB  - In a study designed to compare the cost-effectiveness of three cardiovascular
      disease prevention programmes, subject to a defined budget, a population was
      subgrouped according to risk levels. Cost per year of life saved and annual
      budget expenditure were calculated for each subgroup. Budget expenditure was
      defined in terms of current direct costs. A ranked list was constructed, and the
      cut-off level of 'acceptable' cost-effectiveness elicited.

PMID- 10405535
TI  - [Non-profit networks for suicide prevention].
AB  - Survival groups and suicide clusters constitute new challenges for suicide
      prevention. Emergency ward and intensive care personnel and psychologists working
      in close co-operation with general practitioners are strategically important in
      such preventive endeavours. Scientists and health care personnel need to develop
      joint strategies for the purpose. Politicians and administrators are important
      target groups for information on suicide prevention. The foregoing are important
      findings in the first year's experience of the West Swedish Network for Suicide
      Prevention.

PMID- 10405536
TI  - [Decreased quality of clinical chemistry education for physicians].

PMID- 10405537
TI  - [Report from the medical tent at three rock festivals. Lots of music, great fun
      and very little drunkeness].
AB  - Rock festivals are popular summer attractions in Scandinavia, and each of the
      largest festivals has its own voluntary medical crew of doctors, nurses and
      nursing auxiliaries. The medical crew is an important part of the festival safety
      facilities, providing free acute health care to festival visitors, and thus
      relieving pressure on local primary health centres and hospitals. In 1998, 797 of
      the 25,000 visitors to the three-day Hultsfred Festival were treated at the
      medical tent, 465 of them by a doctor; and 305 of the 17,000 people attending the
      two-day Fanclub88 event were treated at the medical tent, 132 by a doctor. No
      figures are available for the 1998 Roskilde Festival in Denmark, but at the 1997
      festival, 3,369 of the 95,000 visitors were treated at the medical tent.

PMID- 10405538
TI  - [Gunnar Inghe--advocate of the poor. The first specialist in social medicine in
      Sweden an inspiring teacher].

PMID- 10405540
TI  - Childhood leprosy in an endemic area.
AB  - A study was done on 794 new cases of leprosy among children (aged 0-14 years)
      detected and treated with MDT during 1990-1995 in Gudiyatham Taluk, South India.
      Incidence rates of leprosy and proportion of multibacillary cases increased with
      age, while bacillary + tuberculoid was most common. Over 80% had a single patch
      and most children were detected through surveys. Nearly 30% had history of
      household contacts with leprosy, mostly parents or grandparents. Reactions and
      relapses were not uncommon. The findings emphasize the need for more careful
      surveys for case detection and better follow-up in case management.

PMID- 10405539
TI  - Clinical and electrophysiological evaluation of nerve function impairment
      following cessation of multidrug therapy in leprosy.
AB  - Seventeen multibacillary (MB) and 15 paucibacillary (PB) cases of leprosy who had
      had regular and adequate multidrug therapy (MDT) were examined clinically and
      electrophysiologically at periodic intervals for 1 year following cessation of
      MDT. All the major nerves were assessed for nerve function impairment (NFI).
      Overall, two MB (13.3%) and three PB (20%) cases showed signs of deterioration
      clinically and/or electrophysiologically. The nerve conduction (NC) follow-up
      studies revealed no significant improvement in the sensory conduction in both the
      MB and PB groups of nerves, whilst motor conduction showed a significant
      improvement at the first 6-monthly follow-up among the MB group of nerves. At the
      study onset, sensory impairment (MB = 62%, PB = 25%) predominated over motor in
      terms of both severity and frequency. The lower extremity was more frequently and
      severely affected than the upper in both groups of patients. As an individual
      test, NC measurement proved to be more sensitive in detecting NFI, but the
      combination of physical palpatation for nerve thickening and graded nylon test
      (GNT) was closely comparable to measurement of nerve conduction.

PMID- 10405541
TI  - Is knowledge of leprosy adequate among teachers? A comparative study.
AB  - A cross-sectional comparative study on the levels of knowledge and attitude on
      leprosy among teachers and students was carried out in a rural area of Vellore
      district in Tamil Nadu, India. A total of 30 teachers and 120 students
      participated in the study. It was found that knowledge about leprosy among
      teachers was inadequate. Only 23.4% of teachers stated that germs caused leprosy,
      while 23.4% mentioned immoral conduct, 20.0% marrying a leprosy patient, 6.6%
      insects and 26.6% did not know the causes of leprosy. While 80.0% of teachers
      knew that anaesthetic hypopigmented patches were a sign of leprosy, enlarged
      painful nerves were not mentioned by a single teacher, although this sign was
      identified by 17.5% of students. Teachers had a more positive attitude towards
      leprosy than students and this was statistically significant (p < 0.001). This
      paper discusses the need for continuous education, especially for teachers and
      through them the students, using different media so as to ensure sustained
      knowledge for behavioural change in the community.

PMID- 10405542
TI  - Knowledge, attitude and practice regarding leprosy and tuberculosis in
      Bangladesh.
AB  - A small survey was carried out in two areas of northern Bangladesh to assess and
      compare the level of knowledge, attitude and practice towards leprosy and
      tuberculosis (TB) among two communities that differed widely in the amount of
      health education received about these diseases. The results indicate that without
      a health education programme, levels of knowledge about the cause and
      treatability of the diseases are poor, worse for leprosy than TB, with
      correspondingly negative attitudes. Only 16% of the respondents in the
      'uninformed' area mentioned 'skin patch' in a question about what they knew about
      leprosy; and only 44% mentioned 'cough' as a symptom of TB. In the area that had
      received health education, 90% mentioned, respectively, 'skin patch' and 'cough'.
      Seventy-eight percent of the respondents would not buy goods from a shopkeeper
      known to have leprosy, 76% if he had TB in the uninformed area; but in the
      community who had received health education the proportions were reversed, with
      three-quarters agreeing to purchase from a diseased shopkeeper. The implications
      of these findings for the DBLM and National Health Education programmes are
      discussed.

PMID- 10405543
TI  - Viability and drug sensitivity of M. leprae isolated from long-term WHO/MDT
      treated multibacillary leprosy patients.

PMID- 10405544
TI  - An assessment of the value of midfinger smears in multibacillary leprosy
      patients.
AB  - In view of the different opinions on fingers as sites for persisting bacilli in
      multibacillary leprosy patients, it was decided to examine the midfingers for the
      presence of acid-fast bacilli (AFB) and establish its usefulness. Sixty-nine
      multibacillary leprosy patients, [lepromatous (LL) and borderline lepromatous
      (BL)] treated with multidrug therapy for fixed duration (2 years) were analysed.
      The bacillary load in the midfinger sites was lower when compared to that in the
      'compulsory' (both earlobes) and 'optional' (four active lesions) sites. The
      midfinger bacterial index (BI) was higher among LL patients when compared to BL
      patients (p < 0.001). However, the difference in mean BI in 'optional' and
      'compulsory sites' was not significant. The overall fall in BI was gradual and on
      expected lines for all sites, including midfingers, during treatment and follow
      up period. Except in one case, at no time were the smears from midfinger sites
      positive when all other sites were negative, and their inclusion did not
      contribute to the early detection of relapse. Furthermore, the collection of
      blood-free smears from this site is technically difficult and often painful for
      the patient. The inclusion of midfinger smears in this study in patients in South
      India did not contribute useful information to that which is routinely available
      from smears of earlobes and other active sites.

PMID- 10405545
TI  - Results of a 1 year Special Action Project for the Elimination of Leprosy (SAPEL)
      in poorly accessible areas of Akwa Ibom State, Nigeria.
AB  - This article reports the outcome of a Special Action Project for the Elimination
      of Leprosy (SAPEL), including the implementation of multidrug therapy (MDT) in
      difficult situations in Akwa Ibom State in Nigeria. Twenty-two fishing villages
      and five communities in areas of gully erosion participated in the project from
      August 1996 to September 1997. Seven new cases were detected and treated with
      MDT. Twenty-one out of 22 defaulters examined resided in the mainland part of the
      project area and not in the fishing villages. Considerable difficulties were
      encountered with regard to the exorbitant cost of transport, physical attacks on
      the teams and the lack of reliable information on population figures for the
      project area. The discussion includes attention to the cost-effectiveness of the
      SAPEL approach under the conditions described and the need to develop better
      monitoring of treatment and community participation in poorly accessible areas.

PMID- 10405546
TI  - Management of plantar ulcers in leprosy.

PMID- 10405547
TI  - Multidrug therapy.

PMID- 10405548
TI  - Proposal regarding MB MDT.

PMID- 10405549
TI  - Leprosy before and after the year 2000: pre- and post-elimination controversies
      need clarifications.

PMID- 10405550
TI  - Intraocular lens implantation for cataract following leprosy.

PMID- 10405551
TI  - Disease and disease control. International Leprosy Congress, Beijing, 7-12
      September 1998. Workshop report.
AB  - Four workshops were conducted during the congress under the disease control
      theme. The workshops were on the issues of defining disease and antibacterial
      therapy, early case detection, sustaining leprosy control in low endemic
      situations, and the prevention of disability. These workshops spanned the
      spectrum of disease and its consequences through from early detection, the
      definition of disease to the prevention of disability. All of these topics being
      important contemporary issues challenging leprosy control programmes world wide.
      Despite the broad spectrum of the topics it was interesting to see that a number
      of important themes emerged which were common to all topics. It is possible to
      identify five major themes arising from the output of the workshops which are now
      described below. Each of the workshops adopted broad and comprehensive approaches
      to their topic. In the past, there has been narrowness in defining disease in
      terms of the need for chemotherapy. The approach taken in the workshop now is for
      a much more comprehensive approach looking at all the consequences of the disease
      process rather than the requirement for antibacterial chemotherapy. Similarly
      broad approaches were taken to low endemic situations, considering comprehensive
      approaches which are inclusive rather than exclusive. Disability prevention also
      continues this same theme of comprehensive approaches based on multidisciplinary
      involvement in prevention of the consequences of the disease process. The second
      major theme to be identified in the output of the workshops was the importance of
      relevance to patients and people affected by leprosy. It is no longer adequate to
      view programmes in terms of their acceptance to those running the programmes.
      Control programmes must be acceptable to the people they are designed to benefit.
      This even impacts on definitions of disease in terms of what matters to patients
      rather than only restricting this to disease pathology. Similarly, approaches to
      disability prevention are not merely about measurement of impairments due to
      nerve function deficit but rather consider the abilities and functions which are
      most important to the individuals affected. The third theme which spans all of
      the workshops is the need to develop partnerships with others in addressing the
      challenges of leprosy today. Each workshop identified important groups with which
      partnerships need to be developed included local patient groups, voluntary
      associations and primary health care services. All of these have a role to play,
      from early case detection right through to the prevention of disability and the
      sustaining of control under low endemic situations. The fourth important theme is
      sustainability of programmes which need to be developed for the long term benefit
      of those affected by disease rather than short term goals. Again, this impacts an
      area such as case detection methods which need to be sustained in the long term.
      Approaches such as intensive case detection through mass survey are not
      sustainable given changes to the patterns of disease, whereas involvement of
      communities and community participation in the process of early case detection is
      a much more sustainable approach. This is important, as programmes attain low
      endemic status and is also important in preventing disabilities where the
      progressive nature of secondary impairments following primary impairments may be
      lifelong. The final theme is that of the importance of training, as each area is
      recommending new approaches to be taken and for new people to be involved in
      leprosy programmes. The implications are that those to be involved need to be
      trained and that the training requirements will be different from those of the
      last ten years. Training programmes will need to adapt to a wider range of
      individuals and groups being involved in programmes and to much more
      comprehensive approaches. These implications for training are profound and
      training centres and training programmes rapidly

PMID- 10405552
TI  - Social aspects and rehabilitation. International Leprosy Congress, Beijing, 7-12
      September 1998. Workshop report.
AB  - 1. Equal rights and opportunities for people affected with leprosy to develop
      their full potentials is a matter of human rights. 2. Leprosy and its
      consequences are a complex human problem leading to discriminations, stigma and
      prejudices. 3. There is lack of complete understanding about global needs for
      rehabilitation. 4. Concentration on medical care of people affected with leprosy
      (MDT, surgery, etc.), though vastly beneficial, has led to highly inadequate
      psycho-socio-economic rehabilitation in a holistic manner resulting in poor
      quality of life. 5. People affected with leprosy have not been full partners and
      decision makers for their own development and lack self-confidence and
      opportunities for self-expression. 6. Community and health providers lack the
      right attitude and sensitivity, thus failing to assist in the empowerment of
      people affected with leprosy in an integrated manner. 8. There is insufficient
      coordination at international/NGOs/government levels to utilize scarce resources
      to allow full development of people affected with leprosy.

PMID- 10405553
TI  - Causative organism and host response. International Leprosy Congress, Beijing, 7
      12 September 1998. Workshop report.
AB  - Whether or not the leprosy elimination target is met in all endemic countries by
      the year 2000, the MDT programme will have greatly reduced worldwide prevalence.
      However, our workshop chairmen were asked to ignore the prevalence-based leprosy
      'elimination' programme and focus on recommendations for a long term, incidence
      based eradication target where transmission is blocked. They were asked to be
      concerned with basic leprosy research goals in the post 2000 era. The members of
      our workshops are actively productive workers, committed to their special
      interests. They are fully cognizant of the obstacles faced daily in working with
      leprosy and M. leprae, the requirement for clever experimental design even with
      the availability of the powerful tools of molecular biology which can now be
      brought to bear on some of the research obstacles. They are also aware of our
      lack of understanding about leprosy and M. leprae. How do you block transmission
      if you don't know how infection is transmitted? Can infection be detected,
      diagnosis made earlier? Is there a non-human reservoir host, a carrier state, an
      environmental source? What is the basis of M. leprae's predilection for nerves,
      the mechanisms underlying reactions? What needs to be targeted to treat
      reactions? Can a vaccine play a role? There is nothing startling in the
      workshops' recommendations. Other individuals and groups of experts have made the
      same suggestions, with slightly varying priorities. What one can read between the
      lines of these reports, is a sense of urgency to get as much done as soon as
      possible. Worldwide interest in leprosy will soon be diminished, not by design
      but as a consequence of the laudable success of the MDT programme. The experiment
      is still underway, but chemotherapy alone, killing bacilli in the detectable
      human host, does not appear to be the answer to blocking transmission. A number
      of goals must be addressed while there are still intact national and
      international leprosy programmes, while there are still leprosy treatment and
      research centres that can co-ordinate and facilitate the necessary trials for
      early diagnosis, early detection of reactions, evaluation of immunosuppressive
      regimens for reactions. A key recommendation is concerned with the means of
      measuring progress. A clear and explicit means of reporting incidence, prevalence
      and 'case detection' should be implemented to avoid a distorted picture of
      worldwide leprosy. These recommendations are non-controversial. What should be
      done is clear. The uncertainty is in determining who will do the work. Who will
      fund the laboratories engaged in this work? Look around you. There are fewer
      scientists attending this Congress but browsing the abstracts and attending our
      sessions and posters clearly revealed to me that fewer of us are doing far better
      work than in the past. Alternative sources of funding will help. Tuberculosis
      research is enticing researchers away from leprosy in the developed countries but
      is visibly sustaining leprosy research in many centres in developing countries.
      Formation of alliances was a key goal of this Congress. I asked my colleagues
      from Carville to identify in their own discipline, dedicated people, committed
      laboratories that will sustain their leprosy research efforts over the next 5, 10
      or more years. These are the people with whom we wish to collaborate, form
      alliances, share resources and expertise, address the future of worldwide
      leprosy.

PMID- 10405554
TI  - Should nurses offer discharge formula samples to women who plan to breastfeed?

PMID- 10405555
TI  - Responsibilities, roles & staffing patterns of nurse practitioners in the
      neonatal intensive care unit.
AB  - PURPOSE: To describe the unique contribution of the NP in caring for critically
      ill infants through the study of NP responsibilities, roles, staffing patterns,
      and patient profiles. DESIGN: This prospective descriptive study was conducted in
      conjunction with a regional multi-site outcomes study. METHODS: Data were
      collected at five regional level II/III NICUs in Massachusetts and Rhode Island.
      Twenty-two NPs were surveyed. Existing data on outcomes of 2,146 very low birth
      weight infants were used to describe patient profiles. NP care was defined as
      assignment to an NP at admission. Illness severity was measured using the Score
      of Neonatal Acute Physiology (SNAP). RESULTS: NP roles included all levels of
      NICU care as well as antepartal consultation, delivery room management,
      transport, and outpatient follow-up. NPs were equally involved with patients of
      all degrees of complexity and birthweights. Patient assignments were most often
      made by a rotational system with the resident/fellow or by complexity of infant
      with the NP in some NICUs caring for sicker smaller babies. CLINICAL
      IMPLICATIONS: This study documents a blended model of NP MD care in the NICU with
      each provider bringing unique strengths to the team. Nurse practitioners working
      in the NICU provide an invaluable contribution in terms of parent support and
      teaching, post NICU follow-up care, and professional education and research. The
      NP role in the NICU should not be viewed as a substitution for resident
      physicians.

PMID- 10405556
TI  - The essential forces of labor revisited: 13 Ps reported in womens' stories.
AB  - PURPOSE: The purpose of this study was to analyze women's birth stories. Women's
      perspectives were used to expand the current model of the essential forces of
      labor (the three Ps: powers, passenger, and passageway). DESIGN: This was a
      qualitative descriptive study analyzing women's birth narratives. METHODS:
      Narratives consisted of women's spontaneous responses to the request to tell
      their birth stories in any way they wished. Fifteen Midwestern women (eight
      primiparas and seven multiparas) were interviewed, resulting in a total of 33
      birth stories. Content and thematic analyses of verbatim transcripts of the birth
      narratives were done to elicit women's personal meanings of control during labor.
      RESULTS: Women identified many essential forces of labor that exerted control or
      direction over their labors. Some of the forces were internal to the women, such
      as maternal psyche and position, as well as the classic three Ps (powers,
      passenger, and passageway). Others were external forces such as professional
      providers and procedures. An expanded model is proposed to demonstrate the
      complexity of labor and the multiple interacting forces. CLINICAL IMPLICATIONS:
      The educational model, consisting of three essential forces that currently
      appears in textbooks, is inadequate. Maternity nursing practice can be improved
      by including a broader array of the essential forces of labor, thus attending
      more adequately to the complexity of caring holistically and contextually for
      laboring women. Women indicated that nurses have a profound impact during labor.
      Nurses are in a position to make positive change by working with women to share
      control.

PMID- 10405557
TI  - Development of a family liaison model during operative procedures.
AB  - The essence of family-centered care is the provision, by all health
      professionals, of psychosocially supportive care that fosters family integrity
      and functioning. Data from a hospital-based satisfaction survey at The Children's
      Hospital of Philadelphia (CHOP) indicated that the primary reason for parents
      being "less than completely satisfied" was lack of communication. A search of
      recent literature suggests also that breakdown in family-centered care in
      intensive care units is neither new nor unique. The purpose of this article is to
      describe how efforts to improve communication with parents and families led to
      the development of a family liaison program and an expanded role for staff nurses
      in the Cardiac Intensive Care Unit (CICU). The goals of this family liaison
      program were three-fold: to facilitate establishment of a relationship between
      CICU nursing staff, parents, and families at the earliest possible point in time;
      to ensure communication with parents and families at regular intervals during
      their child's surgery; and to promote practice that incorporates principles of
      family-centered care within the CICU. The design and implementation of such a
      program presented nurses in the CICU with both a challenge and an opportunity to
      take an innovative approach to meeting the fundamental need for information
      reported by parents and families, and echoed throughout nursing literature. This
      family liaison program serves to educate parents and families, communicate
      updates, provide physical and emotional support, and establish continuity of care
      for the patient and family. Additionally, nurses involved in the program have
      given positive feedback regarding their expanded role in this family-centered
      care model.

PMID- 10405558
TI  - Using kangaroo care in a clinical setting with fullterm infants having
      breastfeeding difficulties.
AB  - Usually Kangaroo Care (KC) or skin-to-skin holding care is done with preterm
      infants. This article, however, documents clinical experiences with three mothers
      and their fullterm infants who were having latching/breastfeeding difficulties.
      In each case the nurse placed the fullterm infant in KC for approximately 1 hour
      prior to and continuing into the next breastfeeding session. Although no
      recommendations can be made based on case studies, these clinical experiences
      suggest that KC is a worthwhile intervention to try when a mother and her
      fullterm infant are struggling to achieve successful breastfeeding.

PMID- 10405559
TI  - Current concepts in preeclampsia.
AB  - The purpose of this article is to review recent epidemiologic and
      pathophysiologic findings that advance the understanding of preeclampsia for the
      nurse in perinatal practice. Preeclampsia is different from other hypertensive
      disorders of pregnancy. Risk factors for preeclampsia and recent findings
      regarding normal and aberrant implantation are presented. Abnormal implantation
      and resulting poor placental perfusion may be the impetus for endothelial changes
      evidenced in preeclampsia; pathophysiology is described in relation to this
      event. The interaction of maternal factors, reduced placental perfusion, and
      endothelial cell dysfunction provides an explanation for the occurrence of
      preeclampsia and provides a basis for nursing practice and research. Implications
      for nursing care for women of childbearing age before, during, or after pregnancy
      may include (a) preconception or post-delivery counseling to reduce modifiable
      risk factors such as obesity, sedentary lifestyle, or high fat intake, (b)
      assessment of risk factors and increased surveillance when risk factors are
      present, and (c) surveillance of blood pressure changes of > 30 mmHg systolic or
      > 15 mmHg diastolic in advance of the third trimester of pregnancy.

PMID- 10405560
TI  - Living with postpartum depression: the father's experience.
AB  - PURPOSE: To derive a deeper understanding of postpartum depression (PPD) and its
      impact on the family through the experiences of fathers whose spouses suffered
      from this disorder. DESIGN: Phenomenology. METHODS: Eight men were interviewed.
      Interviews were recorded on audio tape and transcribed verbatim. Thematic
      analysis conducted within an interdisciplinary phenomenological research group
      led to a description of the experiences and emotions involved. RESULTS:
      Respondents in this study revealed a major disruption in their lives and in their
      relationship with their wives as a result of PPD. The men experienced fear,
      confusion, and much concern for their spouses, and felt unable to help them in
      overcoming PPD. The inability to "fix the problem" created frustration and anger.
      The majority of the respondents reported that they made many sacrifices to hold
      the relationship and the family together. Even though the PPD improved over time,
      fathers were left to face an uncertain future with a spouse who seemed to be very
      different from the person they had previously known. CLINICAL IMPLICATIONS:
      Health care professionals need to design interventions that are more supportive
      of men, for men also suffer when their spouses experience PPD.

PMID- 10405561
TI  - Acute interstitial nephritis following amoxicillin overdose.
AB  - Antibiotics are commonly prescribed medications for pediatric infections. Acute
      interstitial nephritis has been reported with B-lactam antibiotics. We report the
      case of a 4-year-old boy who ingested 240 mg/kg of amoxicillin and developed
      acute oliguric renal failure with hematuria and crystalluria. The patient was
      hospitalized for serial renal function and electrolyte evaluation. Although he
      developed hyperkalemia, full recovery was obtained with conservative management.
      This case emphasizes that medications considered to be non-toxic even with
      overdose can have serious adverse effects which may require therapeutic
      intervention.

PMID- 10405562
TI  - [Acute mountain sickness].

PMID- 10405564
TI  - [Studies of arrhythmia incidence and heart rate variability in patients suffering
      from cerebral stroke].
AB  - Patients with cerebral stroke develop electrocardiographic changes concerning the
      period of ventricular muscle repolarization and cardiac arrhythmias, which may
      results in the possibility of acute circulatory arrest. ECG monitoring by means
      of Holter method provides not only information concerning arrhythmias, episodes
      of ischaemia of the cardiac muscle, but it is also a recognised and generally
      accepted method of investigation of the autonomic system. The aim of the study
      was to assess the incidence of arrhythmias and heart rate variability in patients
      suffering from recent cerebral stroke. The studies involved 36 patients, in that
      22 women (mean age 67.7 +/- 7.2 years) and 14 men (mean age 66.5 +/- 11.3 years)
      within first 24 hours after cerebral stroke confirmed by computerised tomography
      (CT). One the basis of CT scan haemorrhagic stroke was diagnosed in 7 patients
      and ischaemic stroke, after ruling out haemorrhagic stroke and neurological
      consultations, in 29 patients. Moreover, all patients revealed hypertension, 12
      of them mild degree (1 degree), and 21 of moderate degree (2 degrees), and 3 of
      severe degree (3 degrees). The control group comprised 65 patients suffering from
      primary hypertension without concomitant cerebral stroke, matching the study
      group as to sex and age as well as the degree of hypertension. All of them were
      submitted to 24-hour Holter monitoring on tape by means of 3-channel registrator
      MR45, analysis of ECG tracings was carried out according to Optima Jet system
      manufactured by Oxford. In order to facilitate further analysis, the automatic
      recording was verified visually and next heart rate variability (HRV) was
      estimated within 24 hours and separately for day hours 6:00-22:00 and night hours
      22:00-6:00. In comparison to patients with hypertension, but without stroke,
      subjects with hypertension and accompanying cerebral stroke more often reveal
      premature supraventricular beats, pairs of ventricular beats as well as episodes
      of nonsustained ventricular tachycardia; they also reveal lower 24-hours heart
      rate variability.

PMID- 10405563
TI  - [Evaluation of nitrogen balance in patients treated with continuous ambulatory
      peritoneal dialysis].
AB  - The aim of the study was an estimation of nitrogen balance (NB) in patients
      treated with continuous ambulatory peritoneal dialysis (CAPD) and an evaluation
      of relationship between NB and CAPD adequacy parameters, dietary intake and
      nutritional status of CAPD patients. Examinations, preformed every 3 months
      through 2 years, included the group of 44 patients in the age of 45 +/- 12 years,
      treated with CAPD through 17 +/- 10 months. NB was calculated as a difference
      between nitrogen intake (value obtained using dietary protein intake taken from
      computer analysis of diet histories--Method I or using protein catabolic rate
      calculated according to Randerson et al.--Method II) and amount of nitrogen
      excreted with dialysate and urine, estimated with modified Kjeldahl method.
      Results of NB I and NB II were normalized using actual total, standard, ideal or
      lean body mass (TBM, SBM, IBM and LBM, respectively). LBM was estimated with 3
      methods: from creatinine kinetics (LBMcr), anthropometric measurements (LBManthr)
      and as 1/0.73 of total body water (LBMTBW/0.73). Mean values of NB were positive
      during the entire period of CAPD treatment. Results of NB I exceeded that of NB
      II (6.31 +/- 3.26 v. 4.80 +/- 2.94 g/day with daily protein and energy intake of
      1.0 g/kg IBM and 37 kcal/kg IBM, respectively). Mean values of NB I or NB II,
      normalized using total body mass, were the highest when IBM was used, and the
      lowest--when TBM was applied. When normalization of NB was done with LBM, the
      highest values were expressed in g/kg LBMcr, the lowest--in g/kg LBManthr.
      Significant positive correlation was shown between NB I and plasma concentration
      of total protein and albumin, clinical-laboratory scores (Missouri system),
      dietary intake of fat, fatty acids, carbohydrates, sodium, potassium, calcium,
      ferrum, leucin, alanin, glycin and energy (without and with energy of glucose
      absorbed from the peritoneal cavity). Negative correlation was shown between NB I
      and dialysis duration. The highest correlation coefficients occurred when NB I
      was expressed in g/day, the lowest--when NB I was normalized with LBMcr. Values
      of NB II showed positive correlation with plasma albumin concentration, negative
      one--with CAPD efficacy number and creatinine D/P ratio in the peritoneal
      equilibration test. The highest correlation coefficients were obtained for NB II
      in g/kg LBManthr/day, the lowest--when NB II was expressed in g/day. Values of NB
      and their relationships with other parameters dependent on methods of NB
      estimation: when in calculations diet histories were applied, an influence of NB
      on plasma protein concentration and clinical-laboratory scores as well as
      relationship between NB and dietary intake and dialysis duration were shown; the
      use of protein catabolic rate for NB calculation revealed correlation between NB
      and plasma albumin concentration, peritoneal membrane permeability and CAPD
      adequacy. Patients, in whom nightly exchange of standard dialysis solution was
      replaced with amino acid containing dialysis solution, showed significantly
      higher NB II as compared to that of patients treated exclusively with standard
      solutions.

PMID- 10405565
TI  - [T lymphocyte subpopulations in B-cell chronic lymphocytic leukemia patients with
      a different percentage of CD4+ helper T cells in bone marrow].
AB  - Heterogeneity of B-cell chronic lymphocytic leukemia (B-CLL) may by partial an
      explanation of the ability of CLL cells to interact with the environment and it
      seems to be not related exclusively to cytogenetic abnormalities. For this reason
      T cell subpopulations were analysed in bone marrow and peripheral blood in two
      selected groups of B-CLL patients. These groups differed significantly in
      percentages of CD4+ helper T cells in bone marrow. In the first group (11
      patients) percentage of CD4+ cells was higher than 9 p.c., in the second (10
      patients) this percentage was equal, or lower than 2 p.c. Moreover these groups
      differed also in total tumor mass score (TTM-score) according to the criteria of
      Jaksic and Vitale. TTM-score in the first group was 9.7 in the second--22.9. In
      the first group CD4- cells predominated over CD8+ cytotoxic suppressor cells, as
      well as CD4+ CD45RO+ helper-inducer cells predominated over CD4+ CD45RA+
      suppressor-inducer cells. In the second group we observed some superiority of
      CD8+ and CD4+ CD45RA+ cells. We can speculate that the predominance of CD4+ and
      CD4+ CD45RO+ cells over CD8+ and CD4+ CD45RA+ cells in bone marrow facilitate the
      proliferation or inhibits the apoptosis of CLL cells when the TTM-score is small.
      On the contrary when the TTM-score is larger, than the leukemic cells expanded in
      bone marrow without concomitant helper cells.

PMID- 10405566
TI  - [Sodium efflux through lymphocytic cell membranes in patients with chronic
      respiratory insufficiency].
AB  - Disturbances of Na(+)-K(+)-ATPase activity in patients with respiratory
      insufficiency may cause the hypertonia of non-striated muscles, which leads to
      increased peripheral resistance or bronchoconstriction, and also may inhibit the
      uptake of catecholamines and therefore may intensify their action on the
      respiratory and circulatory systems. All this is very harmful in respiratory
      insufficiency. The aim of the study was the examination if there are any changes
      in sodium efflux through lymphocytic cell membrane in patients with chronic
      respiratory insufficiency and if retraction of insufficiency can influence the
      activity of Na(+)-K(+)-ATPase. The study was performed in 40 patients with
      chronic respiratory insufficiency, of these 11 were women aged from 58 to 72
      years and 29 were men aged from 62 to 77 years. Control group consisted of 31
      healthy persons, of these 9 were women aged from 37 to 55 and 22 years were men
      aged from 21 to 60 years. In the study we included patients with exacerbation of
      chronic obstructive pulmonary disease (COPD). Blood samples were obtained during
      the exacerbation of COPD and after partial improvement. We determined arterial
      blood gases and rates of total, ouabain-sensitive and furosemide-sensitive sodium
      efflux through lymphocytic cell membrane in venous blood. The rates of sodium
      efflux were estimated with the method described by Haegerty et al. In the study
      we showed that in patients with exacerbation of COPD rates of total and ouabain
      sensitive sodium efflux through lymphocytic cell membrane were decreased, but
      after improvement of the disease these rates normalized. In patients with
      exacerbation of COPD rates of furosemide-sensitive sodium efflux were normal.
      Disturbances of activity of Na(+)-K(+)-ATPase in patients with exacerbation of
      chronic pulmonary insufficiency are due to hypoxia.

PMID- 10405567
TI  - [Sodium efflux through lymphocytic cell membranes in patients with acute
      myocardial infarction].
AB  - One of the reasons of ventricular arrhythmias and coronary artery spasms in
      patients with acute myocardial infarction (AMI) may be the lower Na(+)-K(+)
      ATPase activity, which causes decrease of potassium intracellular concentration
      and increase of calcium intracellular concentration. The aim of the study was the
      examination of the rate of sodium efflux through the lymphocytic cell membrane in
      patients with AMI after thrombolytic therapy. The survey was made in 50 patients
      with AMI after thrombolytic therapy: 30 of them with reperfusion (group I) and 20
      without reperfusion (group II). The control group consisted of 31 healthy
      persons. Rates of total, ouabain-sensitive and furosemide-sensitive sodium efflux
      through the lymphocytic cell membrane were measured before thrombolysis, then 3
      and 5 days after, using the method elaborated by Haegerty et al. All patients
      were treated with aspirin, glyceryl trinitrate and thrombolysis therapy with
      alteplase (r-TPA). In all patients with AMI rates of total and ouabaine-sensitive
      sodium efflux through the lymphocytic cell membrane were decreased, but rates of
      furosemide-sensitive sodium efflux were normal. In patients after thrombolytic
      therapy with reperfusion, 3 and 5 days after thrombolysis the decreased rates
      were normal, but they were still decreased in patients without reperfusion.

PMID- 10405568
TI  - [Radiofrequency catheter ablation of two accessory pathways in patients with WPW
      Syndrome].
AB  - In 10-30% patients with WPW syndrome more than one accessory pathway in
      electrophysiology study is observed. These patients make a group of higher atrial
      fibrillation and coming next ventricle fibrillation risk. We present the 39 years
      old patient with symptomatic WPW syndrome, without preexcitation signs in ECG at
      rest. In medical history--palpitations was observed from childhood with one
      episode of atrial fibrillation with high ventricle response required
      cardioversion. Electrophysiology study: without preexcitation signs at rest, two
      ortodromic AV reentrant tachycardias were induced--200 and 166/min. Two accessory
      pathways were diagnosed, left lateral and left midseptal. Radiofrequency catheter
      ablation of both accessory pathways was made during tachycardia, first lateral,
      next septal. In six month follow-up the patient was asymptomatic.

PMID- 10405569
TI  - [Three episodes of acute multiorgan failure in a woman with secondary
      antiphospholipid syndrome].
AB  - We report the case of a 43-year-old woman with systemic lupus erythematosus who
      survived three episodes of catastrophic antiphospholipid syndrome. During the
      first episode symptoms involved predominantly the central nervous system, whilst
      during the second episode of multiorgan failure, the cardiovascular system, lungs
      and kidneys were particularly affected. Twenty months later, the patient
      experienced an acute exacerbation of chronic renal failure and later, died of
      massive pulmonary embolism. The characteristic findings of antiphospholipid
      syndrome included persistently high titers of IgG anticardiolipin antibodies,
      positive lupus anticoagulant, and microcytic anaemia with a distinct haemolytic
      component.

PMID- 10405571
TI  - [The role of cell adhesion molecules in the pathogenesis of type 1 diabetes].

PMID- 10405570
TI  - [Clinical pharmacology of hypotensive drugs acting on central imidazoline
      receptors].

PMID- 10405572
TI  - [The new generation of macrolide antibiotics].

PMID- 10405574
TI  - [Professor Maximillian Kocijancic awarded with the Medal of the Polish Society of
      Internal Medicine].

PMID- 10405575
TI  - [Forensic medicine in the next millenium].

PMID- 10405573
TI  - [Use of serum troponin level measurement in clinical practice].

PMID- 10405577
TI  - [Why do we age so differently?].
AB  - One of the most intriguing aspects of ageing is how different the ageing process
      is from person to person: some maintain their physical and cognitive abilities
      throughout a long life while others lose these abilities rather early in adult
      life. The basis for this variation is largely an enigma. In this review some of
      the most prominent ageing theories are described and compared with results from
      Danish genetic-epidemiological aging research.

PMID- 10405576
TI  - [New discoveries in forensic medicine. Hair analysis].
AB  - A review of forensic chemical drug testing in hair is given. Applications for
      analysis of hair are described. The special problems linked to the determination
      of drugs in hair such as contamination, differences in sex and ethnic groups and
      cosmetic pretreatment of the hair are outlined. It is concluded that greater
      knowledge of hair analysis is needed before the results can be used for
      toxicological evaluation at the same level as blood. On the other hand, a
      chemical hair analysis might expose a (mis)use of drugs and follow it step by
      step up to half a year back in time. In this way, it may supplement a systematic
      toxicological analysis (STA) for 'a general unknown' for use by police and
      forensic pathologists.

PMID- 10405578
TI  - [Results after surgical treatment of unstable thoracolumbar fractures].
AB  - Seventy-eight patients with unstable, one-level fracture of the thoracolumbar
      spine and no neurological impairment were treated with short segment fixation,
      transpedicular autologous bone transplantation and posterolateral fusion.
      Kyphotic deformity and anterior column height improved significantly.
      Complications consisted of one case of late deep infection, three cases of
      seroma, four cases with 5 mm schantz screw breakage and two cases with screw
      loosening. Mild to moderate pain was present in 79% of the patients at follow-up,
      median 32 (13-72) months. Sixty-seven percent of the patients had returned to
      previous activity levels of employment. Short posterior internal fixation,
      transpedicular transplantation and posterolateral fusion allowed neurologically
      intact patients to be mobilized early, to spend median 12 days in hospital, and
      carried no risk of deterioration in neurological function.

PMID- 10405579
TI  - [Deaths at the neonatal department. Withholding or interruption of life-support
      treatment].
AB  - The circumstances of 88 deaths in the Neonatal Department, Rigshospitalet
      Copenhagen, were reviewed with special emphasis on the clinical background for,
      and parental attitude to withholding life-sustaining treatment. We recorded
      whether these considerations appeared in the patient's medical record, the type
      of treatment withheld and the use of opioids. No infant died under ongoing
      maximal treatment. Fourteen infants were judged to have died with "almost
      certainty" (gr A), 48 infants were judged to have died with great probability (gr
      B) and 26 infants were judged to have had a considerable chance of survival (gr
      C). Opioids were used more often in the terminal course of treatment in group C
      as opposed to group B. Parental attitudes and clinical background were not fully
      described in the medical record for many patients. The decision to withhold life
      sustaining treatment in the severely ill neonate was made to avoid prolonged
      futile suffering, or survival with very severe handicaps.

PMID- 10405580
TI  - [The effect of pedicle screw instrumentation on posterolateral spinal fusion. A
      prospective, randomized study with a two-year follow-up].
AB  - The aim was to evaluate the effect of supplementary pedicle screw fixation
      (Cotrel-Dubousset [CD]) in posterolateral lumbar spinal fusion. The study
      comprises 130 patients undergoing lumbar or lumbosacral fusion for
      spondyloisthesis grades I-II or degenerative segmental instability conditions.
      The patients were randomly allocated for no instrumentation (n = 66) or CD
      instrumentation (n = 64) in posterolateral lumbar fusion. A 97.7% follow-up was
      achieved. There were no significant differences between the two groups concerning
      fusion rates assessed by X-ray or functional outcomes assessed by Dallas Pain
      Questionnaire. The global patient satisfaction was 82% in the instrumented group
      versus 74% in the noninstrumented group. Instrumentation increased both operation
      time, blood loss, and early re-operation rates significantly. A high patient
      satisfaction was found in both groups. However, the results from this study do
      not justify the general use of pedicle screw fixation alone as an adjunct to
      posterolateral lumbar fusion.

PMID- 10405581
TI  - [Back problems during military service--significance for later back problems. A
      12-year follow-up study].
AB  - One thousand and fifty-eight conscripts participating in an investigation of back
      problems among conscripts in 1979-80 were re-examined 12 years later with an
      identical questionnaire concerning back problems. The questionnaire was answered
      by seven hundred and eighty-four persons (74%). The lifetime prevalence for low
      back trouble was 73%, the one-year prevalence 53% and the point prevalence 26%.
      At the time of follow-up the incidence of low-back trouble depended on ever
      having had back pains and on having an X-ray made because of back problems. The
      probability for sick leave from work caused by lowback trouble was increased when
      back troubles had been reported at the time of the initial investigation. A
      significant amount of the conscripts that had been rejected due to back problems
      (60%) had been unfit for work because of low-back trouble in the follow-up
      period, and 95% of them had had low-back trouble in the year before follow-up,
      compared to 51% of the other conscripts. Previous back trouble increases the risk
      of getting back trouble once again. The risk of sick leave from work caused by
      low-back trouble increases with the incidence of back trouble up to the
      investigation in 1979-80. Rejection from service due to back problems increases
      the risk of later low-back trouble and sick leave from work caused by low-back
      troubles.

PMID- 10405582
TI  - [Stridor caused by laryngeal rheumatoid arthritis].
AB  - A 71-year old man who had had severe rheumatoid arthritis for many years
      involving all the joints suddenly developed stridor caused by immobilisation of
      both the vocal cords. Arthritis of the cricoarytenoid joints of the larynx was
      suspected, and the patient was successfully treated with prednisolone.

PMID- 10405583
TI  - [Non-ulcus dyspepsia--eradication of Helicobacter pylori].

PMID- 10405585
TI  - [Depression--a public disease which should be treated?].

PMID- 10405584
TI  - [Picture of the month. Iatrogenic hernia].

PMID- 10405586
TI  - [Infection hospitals--a continuous need?].

PMID- 10405587
TI  - [Headache is a question of feelings].

PMID- 10405588
TI  - [Back pain--one more comment].

PMID- 10405589
TI  - [Surgical treatment of obstructive sleep apnea syndrome].

PMID- 10405590
TI  - New approach to assessing clinical quality of care for women: the QA Tool system.

PMID- 10405591
TI  - Ethical considerations in research involving pregnant women. The American College
      of Obstetricians and Gynecologists.

PMID- 10405593
TI  - Postmenopausal women take steps to reduce their osteoporosis risk.

PMID- 10405592
TI  - Two challenges for research ethics: innovative treatment and fetal therapy.

PMID- 10405594
TI  - Congestive heart failure with preserved systolic function: is it a woman's
      disease?
AB  - Congestive heart failure with preserved systolic function is increased in
      prevalence with advancing age, especially in women, indicating the strong impact
      of gender on this common disease.

PMID- 10405595
TI  - Investigation of solid-phase peptide synthesis by the near-infrared multispectral
      imaging technique: a detection method for combinatorial chemistry.
AB  - A near-infrared (NIR) multispectral imaging spectrometer was used to monitor
      solid-phase peptide synthesis. This imaging spectrometer has fast scanning
      ability and high sensitivity because it is based on an acousto-optic tunable
      filter and a NIR InGaAs focal plane array camera. This NIR imaging instrument
      possesses all the advantages of conventional NIR spectrometers; namely, it can be
      used for noninvasive monitoring of the reactions and identification of the
      products during the solid-phase peptide synthesis of glycine, alanine, and valine
      mediated by aminomethylstyrene resin beads. The reaction was determined by
      monitoring either the decrease of the band at 1529 nm, which is due to the amine
      group on the beads, or the increase of the amide band generated at 1483 nm. The
      amine band at 1529 nm was also used to determine the presence of the Fmoc
      protecting groups and the efficiency of its removal. More importantly, this NIR
      imaging spectrometer has additional features that conventional NIR spectrometers
      cannot offer; namely, its ability to measure spectra at different positions
      within a sample. This feature was utilized for the first demonstration in which
      reactions of three different solid-phase peptide syntheses (in a three
      compartment cell) were simultaneously monitored. As expected, the kinetics
      obtained for three reactions are similar to those obtained when the each of the
      reactions was individually determined. In this study, data recorded by 16 x 16
      pixels were used to calculate a spectrum for each sample. However, a relatively
      good spectrum can be obtained by using data recorded by a single pixel. Since the
      NIR camera used in this camera is equipped with 240 x 320 pixels, this NIR
      mutispectral imaging technique is not limited to the three-compartment cell used
      in this study but rather can be used as the detection method for the solid-phase
      peptide synthesis in combinatorial chemistry.

PMID- 10405596
TI  - Chemical cleavage sequencing of DNA using matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry.
AB  - In this paper, we report for the first time use of laser desorption mass
      spectrometry for measurement of chemical cleavage sequencing products of DNA. In
      this method, the target DNA was labeled with biotin and subjected to chemical
      modification and cleavage according to the Maxam-Gilbert sequencing protocol. The
      biotin-containing fragments were captured by streptavidin-coated magnetic beads
      and separated from the other fragments. The captured fragments were released by
      hot ammonia treatment, and the released fragments were analyzed by mass
      spectrometry. Potential applications of this method in resolving sequence
      ambiguities and sequencing repeat sequences as well as in the analysis of DNA
      protein interactions are discussed.

PMID- 10405597
TI  - Identification of proteins in complexes by solid-phase microextraction/multistep
      elution/capillary electrophoresis/tandem mass spectrometry.
AB  - A method to directly identify proteins in complex mixtures by solid-phase
      microextraction (micro-SPE)/multistep elution/capillary electrophoresis
      (CE)/tandem mass spectrometry (MS/MS) is described. A sheathless liquid-metal
      junction interface is used to interface CE and electrospray ionization MS/MS. A
      subfemtomole detection limit is achieved for protein identification through
      database searching using MS/MS data. The SPE serves as a semiseparation dimension
      using an organic-phase step-elution gradient in combination with the second
      separation dimension for increased resolving power of complex peptide mixtures.
      This approach improves the concentration detection limit for CE and allows more
      proteins in complex mixtures to be identified. A 75-protein complex from yeast
      ribosome is analyzed using this method and 80-90% of the proteins in the complex
      can be identified by searching the database using the MS/MS data from a complete
      analysis. This multidimensional CE/MS/MS methodology provides an alternative to
      multidimensional liquid chromatography/MS/MS for direct identification of small
      amounts of protein in mixtures.

PMID- 10405598
TI  - Data-dependent modulation of solid-phase extraction capillary electrophoresis for
      the analysis of complex peptide and phosphopeptide mixtures by tandem mass
      spectrometry: application to endothelial nitric oxide synthase.
AB  - Electrospray ionization (ESI) tandem mass spectrometry (MS/MS) of peptides in
      conjunction with automated sequence database searching of the resulting collision
      induced dissociation (CID) spectra has become a powerful method for the
      identification of purified proteins or the components of protein mixtures. The
      success of the method is critically dependent on the manner by which the peptides
      are introduced into the mass spectrometer. In this report, we describe a
      capillary electrophoresis-based system for the automated, sensitive analysis of
      complex peptide mixtures. The system consists of an ESI-MS/MS instrument, a solid
      phase extraction (SPE)-capillary zone electrophoresis (CZE) device for peptide
      concentration and separation, and an algorithm written in Instrument Control
      Language (ICL) which modulates the electrophoretic conditions in a data-dependent
      manner to optimize available time for the generation of high-quality CID spectra
      of peptides in complex samples. We demonstrate that the data-dependent modulation
      of the electric field significantly expands the analytical window for each
      peptide analyzed and that the sensitivity of the SPE-CZE technique is not
      noticeably altered by the procedure. By applying the technique to the analysis of
      in vivo phosphorylation sites of endothelial nitric oxide synthase (eNOS), we
      demonstrate the power of this system for the MS/MS analysis of minor peptide
      species in complex samples such as phosphopeptides generated by the proteolytic
      digestion of a large protein, eNOS, phosphorylated at low stoichiometry.

PMID- 10405599
TI  - High-throughput bioanalytical LC/MS/MS determination of benzodiazepines in human
      urine: 1000 samples per 12 hours.
AB  - The analytical capabilities of liquid chromatography tandem mass spectrometry for
      sensitive and highly selective determination of target compounds in complex
      biological samples makes it well suited for high-throughput analysis. We report
      the fast separation of six benzodiazepines isolated from human urine via selected
      reaction monitoring liquid chromatography/mass spectrometry using short dwell
      times to accommodate fast-eluting chromatographic peaks. The analytes were
      extracted from human urine samples along with their deuterium-labeled internal
      standards by a simple liquid-liquid extraction in 96-well plates. Using four
      autosamplers coupled to one chromatographic column and one tandem mass
      spectrometer operated in the turbo ion spray mode with positive ion detection,
      1152 samples (12 96-well plates) were analyzed in less than 12 h. Through an
      electronic switching box designed and constructed in-house, the autosamplers were
      synchronized with the mass spectrometer so that injections were made as soon as
      the mass spectrometer was ready to collect data. Each run required 30 s to
      complete with another 7-8 s for the data system to load the next data file to be
      collected. Chromatographic integrity and ion current response remained relatively
      constant for the duration of the analyses. The results show acceptable precision
      and accuracy and demonstrate the feasibility of using fast separations with
      tandem mass spectrometry for high-throughout analysis of biological samples
      containing multiple analytes.

PMID- 10405600
TI  - Analysis of VX on soil particles using ion trap secondary ion mass spectrometry.
AB  - The direct detection of the nerve agent VX (methylphosphonothioic acid, S-[2
      [bis(1-methylethyl)amino]ethyl] O-ethyl ester) on milligram quantities of soil
      particles has been achieved using ion trap secondary ion mass spectrometry (IT
      SIMS). VX is highly adsorptive toward a wide variety of surfaces; this attribute
      makes detection using gas-phase approaches difficult but renders the compound
      very amenable to surface detection. An ion trap mass spectrometer, modified to
      perform SIMS, was employed in the present study. A primary ion beam (ReO4-) was
      fired on axis through the ion trap, where it impacted the soil particle samples.
      [VX + H]+, [VX + H]+ fragment ions, and ions from the chemical background were
      sputtered into the gas-phase environment of the ion trap, where they were either
      scanned out or isolated and fragmented (MS2). At a surface concentration of 0.4
      monolayer, intact [VX + H]+, and its fragment ions, were readily observable above
      background. However, at lower concentrations, the secondary ion signal from VX
      became obscured by ions derived from the chemical background on the surface of
      the soil particles. MS2 analysis using the ion trap was employed to improve
      detection of lower concentrations of VX: detection of the 34S isotopic ion of [VX
      + H]+, present at a surface concentration of approximately 0.002 monolayer, was
      accomplished. The study afforded the opportunity to investigate the fragmentation
      chemistry of VX. Semiempirical calculations suggest strongly that the molecule is
      protonated at the N atom. Deuterium labeling showed that formation of the base
      peak ion (C2H4)N(i-C3H7)2+ involves transfer of the amino proton to the
      phosphonothioate moiety prior to, or concurrent with, C-S bond cleavage. To
      manage the risk associated with working with the compound, the vacuum unit of the
      IT-SIMS was located in a hood, connected by cables to the externally located
      electronics and computer.

PMID- 10405601
TI  - Detection of double-stranded DNA by IR- and UV-MALDI mass spectrometry.
AB  - Double-stranded DNA ranging from 9 kDa to over 500 kDa were desorbed and analyzed
      by MALDI TOF mass spectrometry. IR-MALDI with glycerol as matrix yielded
      excellent results for larger double-stranded DNA by adjustment of the ionic
      strength through the addition of salts. Very little fragmentation and a routine
      sensitivity in the subpicomole range were observed in IR-MALDI when double
      stranded analytes harboring 70 base pairs or more were probed. In the lower mass
      range (up to approximately 70 base pairs), UV-MALDI with 6-aza-2-thiothymine as
      matrix was the ionization method of choice because it allowed specific double
      stranded complexes containing relatively few base pairs to be desorbed intactly.
      In this mode, an essentially quantitative detection of the double-stranded form
      was observed for a 70-mer. The UV-MALDI was accompanied by a significant
      fragmentation and a resulting reduced sensitivity and mass resolution. The
      methods described open MALDI-MS for the analysis of large DNA-DNA and DNA-protein
      complexes.

PMID- 10405602
TI  - Liquid-liquid extraction in the 96-well plate format with SRM LC/MS quantitative
      determination of methotrexate and its major metabolite in human plasma.
AB  - A method involving the semirobotic liquid-liquid extraction (LLE) in deep-well 96
      well plates was developed for the quantitation of the anti
      cancer/antiinflammatory drug methotrexate (MTX) and its major metabolite, 7
      hydroxymethotrexate (7OH-MTX) in human plasma. The extraction time for the sample
      preparation was relatively short with four 96-well plates (384 samples) prepared
      in approximately 90 min by one person. The sample extracts were each analyzed
      within 1.2 min using a positive ion turbo-ionspray selected reaction monitoring
      liquid chromatography/mass spectrometric (SRM LC/MS) method in which 768 samples
      were easily analyzed within 22 h (maximum of 820 samples in 24 h). Deuterated
      internal standards, MTX-d3 and 7OH-MTX-d3, were used. The calibration curves for
      MTX and 7OH-MTX were linear (R2 > 0.997) and ranged from 0.5 to 250 and 0.75 to
      100 ng/mL, respectively. The limit of quantitation (LOQ) for MTX and 7OH-MTX was
      0.5 and 0.75 ng/mL, respectively; persistent carryover from the autosampler
      limited the LOQ achievable. The limit of detection (LOD) was 0.05 ng/mL for MTX
      and 0.1 ng/mL for 7OH-MTX. The intra- and inter-assay precision and accuracy did
      not exceed 15% for both MTX and 7OH-MTX. The recoveries were 61% for MTX and 47%
      for 7OH-MTX. The method was validated and demonstrated to be robust with high
      precision and accuracy.

PMID- 10405603
TI  - Nanoelectrospray mass spectrometry and precursor ion monitoring for quantitative
      steroid analysis and attomole sensitivity.
AB  - Nanoelectrospray ionization (nanoESI) mass spectrometry was performed on
      naturally occurring steroid sulfates and unconjugated steroids derivatized to
      their sulfate esters using precursor ion monitoring. Initially, an extraction
      method was developed based on a combinatorial approach employed to obtain the
      most efficient liquid/liquid extraction protocol. The new method allowed
      unconjugated steroids and their sulfated analogues to be isolated separately in a
      two-step procedure using diethyl ether/hexane (90:10, v/v) in the first step to
      extract the unconjugated steroids and chloroform/2-butanol (50:50, v/v) in the
      second step to extract steroid sulfates. Precursor ion scanning performed with a
      triple-quadrupole mass spectrometer was used to examine quantitatively the
      extracted unconjugated and sulfated steroids, where the recovery efficiency
      averaged 70 and 87%, respectively. In addition, some steroids could be
      structurally elucidated by employing tandem mass spectrometry. The limit of
      detection for steroid sulfates from the biological matrix was 200 amol/microL
      (approximately 80 fg/microL) with only 1 microL of sample being injected.
      Endogenous levels of the unconjugated and sulfated steroids were detected and
      quantified from physiological samples including urine and blood. Internal
      standards, pregnenolone-d4 sulfate and dehydroepiandrosterone-d2 (DHEA), were
      used for quantitation. Extraction and nanoESI analyses were also performed on
      cerebrospinal fluid where the neurosteroid DHEA sulfate was detected. The small
      amount of material consumed (typically less than 20% of the injection volume)
      suggests that nanoESI has even greater potential for high sensitivity when
      combined with nanoLC approaches, especially for monitoring reproductive and
      adrenal steroids, as well as for the analysis of the less abundant neurosteroids.

PMID- 10405604
TI  - Sequencing of argentinated peptides by means of electrospray tandem mass
      spectrometry.
AB  - A strategy for semiautomatic sequencing of argentinated (silver-containing)
      oligopeptides has been developed. Sequencing is based on a search algorithm that
      identifies a triplet peak relationship in a product ion spectrum of the [M + Ag]+
      ion of an oligopeptide. The ions that constitute a triplet are [bn + OH + Ag]+,
      [bn - H + Ag]+, and [a(n) - H + Ag]+, which are separated by 18 and 28 m/z units,
      respectively. The difference in the m/z values of adjacent triplets identifies
      the residue that is "cleaved". Observation of the [yn + H + Ag]+ ion containing
      the cleaved residue confirms the assignment. Sequencing of argentinated tryptic
      peptides may prove useful for automated proteome analysis via the sequence tag
      method.

PMID- 10405605
TI  - Assessment of alginic acid molecular weight and chemical composition through
      capillary electrophoresis.
AB  - The polydispersity of alginic acids regarding distributions in molecular weight
      and chemical composition is analyzed by capillary electrophoresis. Low
      concentrations of linear polyacrylamide in the electrolyte provide the means for
      separation of alginate fractions into the megadalton range, while high-resolution
      polysaccharide mapping of structural variants could be achieved at higher LPAA
      concentrations. The fraction and block length of the structurally important
      guluronic acid constituent is determined through the selective complexation with
      calcium ions. The methodology presented here might serve as a general approach
      for the assessment of alginate composition and size and the relation to technical
      properties desired in medical and pharmaceutical applications.

PMID- 10405606
TI  - Rapid determination of aspartate enantiomers in tissue samples by microdialysis
      coupled on-line with capillary electrophoresis.
AB  - Microdialysis was coupled on-line with derivatization by o-phthalaldehyde and
      beta-mercaptoethanol and optically gated capillary electrophoresis to determine D
      and L-aspartate in tissue samples obtained from rats. The microdialysis probe
      was inserted into a homogenized tissue sample which allowed generation of a
      continuous sample stream that was filtered and deproteinated. With 7.5 mM beta
      cyclodextrin (CD) in the electrophoresis buffer, the enantiomers of interest
      could be resolved in 3 s with an electric field of 2500 V/cm over a separation
      length of 15 mm. Values of D- and L-aspartate in different tissues agreed well
      with those obtained by an HPLC procedure that required protein precipitation,
      centrifugation, and extraction. The speed and compatibility with automation of
      the microdialysis/CE method may make it a general approach for a variety of
      applications involving high-throughput analysis or sensorlike operation.

PMID- 10405607
TI  - Capillary electrophoresis sodium dodecyl sulfate nongel sieving analysis of a
      therapeutic recombinant monoclonal antibody: a biotechnology perspective.
AB  - With the increasing interest in the therapeutic use of recombinant monoclonal
      antibodies (rMAbs), a generic analytical approach for the analysis of size-based
      rMAb variants is desired. Such a method using capillary electrophoresis (CE) with
      laser-induced fluorescence detection is described. The assay was developed as a
      replacement for silver-stained SDS-PAGE and was validated according to the
      guidelines of the International Committee on Harmonization for use in routine lot
      release testing of a rMAb pharmaceutical. In this assay, the rMAb solution is
      first derivatized with a neutral fluorophore, e.g., 5-carboxytetramethylrhodamine
      succinimidyl ester. The labeled sample is then incubated with SDS, and the SDS
      protein complexes are then separated by CE using a hydrophilic polymer as a
      sieving matrix. The precolumn labeling conditions described in this study allowed
      the detection of rMAb at a low-nanomolar concentration (9 ng/mL), with no
      apparent loss in resolution or changes to the distribution of rMAb analyte
      species, when compared to an unlabeled sample. In addition, the traditional
      practice of heating proteins at elevated temperatures in the presence of SDS to
      facilitate SDS-protein binding resulted in the generation of significant levels
      of rMAb fragmentation, and alternative conditions to minimize this artifact are
      discussed. Illustrations of the uses of this assay in monitoring consistency of
      bulk manufacture of a protein pharmaceutical, and in providing a size-based
      separation of product-related variants, as well as nonproduct impurities are
      shown. In brief, the assay described in this paper demonstrated comparable
      resolution and sensitivity to silver-stained SDS-PAGE but offered the advantages
      of enhanced precision and robustness, speed, ease of use, and on-line detection.

PMID- 10405608
TI  - Pharmaceutical fingerprinting in phase space. 1. Construction of phase
      fingerprints.
AB  - The present study proposes a general method for constructing pharmaceutical
      fingerprints in the analysis of HPLC trace organic impurity patterns. The
      approach considers signals in phase space and accounts for two different types of
      noise: additive and perturbative. The first type, additive noise, contributes to
      distortion of the absolute values of signal peaks. The second type, perturbative
      noise, contributes to variations of the retention times of signal peaks and
      distorts the time scale of the trace organic impurity patterns. The ability of
      the proposed approach to consider both types of noise significantly distinguishes
      it from existing methods of data analysis that are usually designed to treat only
      the additive noise. Analysis of the HPLC signals in phase space eliminates the
      problem of perturbation noise and enables detection and comparison of similar
      signal segments recorded at different retention times. The current study analyzes
      the chromatographic trace organic impurity patterns collected from six different
      manufacturers of L-tryptophan using three HPLC columns. For five manufacturers
      the variability of data recorded with the same column are in perfect agreement
      with the proposed model. A significant variance of parameters is detected for one
      manufacturer, thus indicating a possible change in its product consistency. The
      analysis in phase space is also used to explain the previously detected
      variability of HPLC signals across columns. The accompanying paper reports an
      application of the proposed approach for the pattern recognition of HPLC data.

PMID- 10405609
TI  - Pharmaceutical fingerprinting in phase space. 2. Pattern recognition.
AB  - The current study introduces an approach for pattern recognition of drug
      manufacturers according to their HPLC trace impurity data. This method considers
      signals in phase space and accounts for two different types of noise: additive
      and perturbative. The pharmaceutical fingerprints are estimated as mean
      trajectories of HPLC trace impurity data and are used as reference models for
      recognition of new data by the minimal length classifier. The chromatographic
      trace organic impurity patterns collected from six different manufacturers of L
      tryptophan are analyzed as an example. The prediction ability of the new method
      tested using three different cross-validation procedures remains about 95% even
      if the number of available data in the training sets decreases by 5 times. The
      accuracy of prediction in phase space is superior compared to results calculated
      using a Window Preprocessing method and artificial neural networks. The
      difference in performance between new and previous methods becomes more
      significant under particular conditions that are more adequate for practical
      application of the method. In addition, the current approach enables simple and
      comprehensive interpretation of the calculated results.

PMID- 10405610
TI  - Probing the binding behavior and conformational states of globular proteins in
      reversed-phase high-performance liquid chromatography.
AB  - Reversed-phase high-performance liquid chromatography (RP-HPLC) is a widely used
      technique for the separation of proteins under low pH aquo-organic solvent
      gradient elution conditions, typically carried out at ambient temperatures. These
      conditions can however induce conformational effects with proteins as evident
      from changes in their biological or immunological activities. By monitoring the
      influence of temperature on the retention and band-broadening characteristics of
      proteins, the role of conformational processes in these lipophilic environments
      can be examined. These processes can then be interpreted in terms of a two-state
      model involving a native (N) and a fully unfolded species (U) or more complex
      folding/unfolding models. In the present study, the gradient elution RP-HPLC
      behavior of sperm whale myoglobin (SWMYO) and hen egg white lysozyme (HEWL) has
      been investigated at temperatures between 5 and 85 degrees C with n-octadecyl
      (C18)- and n-butyl (C4)-silica reversed-phase sorbents. The interaction of these
      proteins with these reversed-phase sorbents has also been examined in terms of
      the contributions that the heme prosthetic group of SWMYO and the disulfide bonds
      in HEWL make to the stabilization of the native conformation of these proteins in
      these hydrophobic environments. The observed interconversions of multiple peak
      zones of SWMYO and HEWL in the presence of C18 and C4 ligands have been
      subsequently analyzed in terms of the unfolding processes that these proteins can
      undergo at low pH and at elevated temperatures. The ability of hydrocarbonaceous
      ligands to trap ensemblies of partially unfolded conformational intermediates of
      proteins in these perturbing environments has been examined. Pseudo-first-order
      rate constants have been derived for these processes from analysis of the
      dependencies on time of the concentration of the different protein species at
      specified temperatures. The relationship of these processes to the conformational
      transitions that these proteins can undergo via molten globule-like intermediates
      (i.e., compact denatured states with a significant amount of residual secondary
      structure) in solution has also been examined. This study thus further documents
      an experimental strategy to assess the folding/unfolding behavior of globular
      proteins in the presence of hydrophobic surfaces and aquo-organic solvents,
      whereby the system parameters can potentially affect the preservation of native
      conformations, and thus the function, of the protein under these conditions.

PMID- 10405611
TI  - Identification and optimization of regeneration conditions for affinity-based
      biosensor assays. A multivariate cocktail approach.
AB  - A general regeneration, identification, and optimization (RO) protocol for
      Biacore systems was developed. The RO protocol uses six multi-ingredient stock
      solutions that represent the six most common chemical properties employed as
      regeneration agents. The regeneration effect of different regeneration cocktails
      of these six stock solutions were tested iteratively until a satisfactory result
      was obtained. The RO protocol was designed with an ease-of-use and multivariate
      approach. The RO protocol was tested on 13 different antibody-antigen systems.
      For 10 of these, only the first screening session was tested. For 9 of the 13
      systems, the RO-protocol screening session identified cocktails that removed more
      than 90% of the bound analyte in a 30 s pulse. For 5 systems, the RO protocol
      identified cocktails that regenerated the surface completely and that were more
      gentle than previously used regeneration conditions. Furthermore, the
      regeneration optimization results can be interpreted as a characterization of the
      interacting molecules. The relevance of testing cocktails was justified by the
      fact that at least one cocktail was significantly better than all diluted stock
      solutions for all tested model systems. By using the multivariate approach, the
      risk of missing relevant combinations of stock solutions was minimized. This
      resulted in an unexpected discovery of excellent properties of EDTA as an
      additive in regeneration cocktails containing chaotropic agents and ions in high
      concentration.

PMID- 10405612
TI  - Processible polyaniline as an advanced potentiometric pH transducer. Application
      to biosensors.
AB  - An advanced potentiometric pH transducer based on processible polyaniline (PCPAn)
      is reported on. Both glassy carbon and screen-printed carbon electrodes modified
      with PCPAn by dip-coating exhibited a fully reversible potentiometric response of
      approximately 90 mV/pH unit over the range from pH 3 to 9. Such a significantly
      higher potentiometric response of PCPAn-modified electrodes as compared with
      those of existing devices is explained on the basis of the thermodynamics of
      polyaniline redox reactions. The PCPAn-based pH transducers exhibit both good
      operational stability and prolonged shelf life and display a negligible response
      toward singly charged cations. The new thick-film pH transducer was employed for
      designing a potentiometric biosensor for urea. In the model solution which mimics
      blood serum, the urea-sensitive electrode has a detection limit of 10(-5) M urea
      and a maximum response of approximately 120 mV. The attractive performance
      characteristics are advantageous over those of existing pH sensors and offer
      great promise for sensing and biosensing applications.

PMID- 10405613
TI  - Automated flow injection gradient technique for binding studies of micromolecules
      to proteins using potentiometric sensors: application to bovine serum albumin
      with anilinonaphthalenesulfonate probe and drugs.
AB  - An automated flow injection (FI) gradient technique is described for the binding
      study of the potentiometric probe 1-anilino-8-naphthalenesulfonate (ANS) to
      bovine serum albumin (BSA). Using a single-channel FI system with a mixing
      chamber and a flow ANS electrode, the binding parameters (binding constant and
      number of binding sites) were calculated using the Scatchard model. The
      concentration gradient was calibrated by injecting ANS in the stream, and the
      binding experiment was performed by injecting ANS-BSA solution in the carrier
      solution of equal albumin concentration. The equations describing the
      concentration gradient and the corresponding electrode potential curve are
      presented. A systematic study of the factors affecting the complexation
      equilibrium and the electrode response was performed. For the ANS binding to BSA,
      two binding classes were determined with binding constants of (2.1 +/- 0.3) x
      10(5) and (3.3 +/- 0.8) x 10(3) M-1 and 3.8 +/- 0.6 and 10 +/- 2 binding sites
      per class, respectively, at 27 +/- 1 degrees C, in 0.10 M phosphate pH 7.4.
      Competitive binding experiments of sulfamethoxazole, salicylate, azapropazone,
      ketoprofen, and tolmetin to albumin were also performed by monitoring ANS binding
      inhibition (decrease of apparent binding constant). This technique takes
      advantage of FI gradients and direct potentiometry and utilizes the total
      information contained in FI peaks, providing fast and accurate binding
      information in a wide range of concentration ratios.

PMID- 10405614
TI  - Micrometer dimension derivatization of biosensor surfaces using confocal dynamic
      patterning.
AB  - Using laser scanning confocal optics in conjunction with avidin/biotin
      technology, micrometer-sized patterns of biomolecules were fabricated on glassy
      carbon and fused-silica surfaces. Photoactive biotin was immobilized using the
      325-nm line of a Helium-Cadmium laser, which was focused through a 25x or 100x
      quartz microscope objective. A three-dimensional piezoelectric micromanipulator
      was used to position the sample surface in the focal plane of the microscope
      objective and to create patterns on the focused surface. Biotin patterns with
      line widths of 5-20 microns were produced by varying the scan speed of the
      micromanipulator while exposing the surface to the laser. The integrity of the
      immobilized biotin was confirmed by subsequent derivatization with fluorescently
      labeled avidin. Fluorescence microscopy with a cooled charge coupled device (CCD)
      imaging system was used to visualize the distribution of biotin and fluorescent
      avidin within the patterns created by the laser.

PMID- 10405615
TI  - An immunomagnetic electrochemical sensor based on a perfluorosulfonate-coated
      screen-printed electrode for the determination of 2,4-dichlorophenoxyacetic acid.
AB  - A disposable immunomagnetic electrochemical sensor involving a magnetic particle
      based solid phase and a Nafion film-coated screen-printed electrode (Nafion-SPE)
      stuck at the bottom of a polystyrene cylinder (microwell of 300 microL) was
      developed and evaluated in a competitive immunoassay of the widely used herbicide
      2,4-dichlorophenoxyacetic acid (2,4-D). The competitive binding of 2,4-D and 2,4
      D labled with alkaline phosphatase (AP) for a limited amount of polyclonal anti
      2,4-D antibody-coated magnetic beads was monitored electrochemically by measuring
      the AP labled++ activity bound to the beads. The phosphoric acid ester of [[(4
      hydroxyphenyl)amino]-carbonyl]cobaltocenium hexafluorophosphate was used as the
      AP substrate. This anionic substrate (S-) is enzymatically transformed at pH 9.0
      into a cationic phenol derivative (P+) which can be easily accumulated in the
      polyanionic Nafion coating and determined by cyclic voltammetry. During the
      enzyme reaction, the AP-associated beads were localized on the surface of the
      Nafion-SPE with the aid of a magnet, thus effectively increasing the
      concentration of P+ in the Nafion-modified electrode vicinity. The enzyme
      generation of P+ close to the electrode surface, and thereby to the Nafion film,
      resulted in a high amplification of the response. A detection limit of 0.01
      microgram L-1 2,4-D was thus achieved. The performance of the sensor was
      successfully evaluated on river water samples spiked with 2,4-D, indicating that
      this convenient and sensitive technique offers great promise for decentralized
      environmental applications.

PMID- 10405616
TI  - Self-reports of short- and long-term effects of bullying on children who stammer.
AB  - BACKGROUND: Victimisation at school may result in long-term social, emotional and
      psychological effects (Parker & Asher, 1987; Sharp, 1995), particularly for
      children with special educational needs (Whitney et al., 1994). Children who
      stammer may be at risk of being bullied due to their peer-relationship and verbal
      difficulties. AIM: This study aimed to explore the nature, frequency and causes
      of bullying amongst children who stammer as well as the short- and long-term
      effects of their victimisation. SAMPLE: The sample consisted of 276 respondents
      from the British Stammering Association, a national association for dysfluent
      people. METHOD: A retrospective analysis of school experiences related to
      bullying, and its effects, was conducted through both semi-structured interviews
      and postal questionnaires. RESULTS: A majority of respondents had experienced
      bullying at school, and the likelihood of being bullied was related to the
      reported difficulties in friendship-making. Nearly one-half of teachers and
      families were reported as not being aware of this bullying. A majority reported
      immediate negative personal effects of this bullying, and 46% reported some long
      term effects. CONCLUSION: Logistic regression analyses suggested that the
      severity of bullying, together with other factors such as difficulty with
      friendships, predicted these effects. COMMENT: In response to the high incidence
      of bullying experienced by children who stammer, a pack has been developed which
      aims to create a more empathetic school climate where differences are tolerated
      rather than assaulted.

PMID- 10405617
TI  - The relationship between personality and attainment in 16-19-year-old students in
      a sixth form college. I: Construction of the Student Self-Perception Scale.
AB  - BACKGROUND: Of the research that has been undertaken into the relationship
      between personality and attainment, relatively little exists relating to the 16
      19 age range. In a substantive study examining the relationship between academic
      self-concept, attainment and personality in sixth form students, a first
      requirement was to design a self-perception instrument. AIMS: The psychometric
      element of the study aimed to construct a Student Self-Perception Scale (SSPS)
      that would be effective for students in the FE (further education) context.
      SAMPLES: The samples comprised a pilot sample of 152 students (aged 16-17 years
      from two sixth from colleges) and a main sample of 364 students (mean age, 16yrs
      10mths, range 16:0 to 18:6 years, from one sixth form college). The main sample
      included similar numbers of male and female students (46% male, 54% female) and
      ethnic minority students comprised 14% of this sample. METHOD: An initial item
      pool of 88 four-point Likert type statements was compiled from comparable
      existing scales and from responses to a Student Induction Questionnaire. Item
      analysis was based on oblique factor analysis of the pilot sample responses,
      followed by cross-validation on the main sample to refine the scale structures.
      Construct validity was established from the substantive study, especially the
      Nowicki & Strickland (1973) locus of control results. RESULTS: Exploration of the
      four- and five-factor structures led to a final specification based on 52 items
      from five oblique factors. The constituent scales were Passivity (12 items, alpha
      = .81). Mastery (15 items, alpha = .79), Work Related Inadequacy (11 items, alpha
      = .72), Extraversion (4 items, alpha = .70) and Social Dependence (10 items,
      alpha = .66), all statistics compiled from the cross-validation sample.
      Correlations with Locus of Control ranged from 0.52 for Mastery to -.34 for Work
      Related Inadequacy. Distribution statistics for Locus of Control matched a
      comparable American sample. CONCLUSIONS: The five-scale structure exhibits good
      cross-validation characteristics and supports revealing analyses of relationships
      within the substantive study. Its 52-item format is suitable for research or
      exploratory use within its intended FE context.

PMID- 10405618
TI  - The relationship between personality and attainment in 16-19-year-old students in
      a sixth form college: II: Self-perception, gender and attainment.
AB  - BACKGROUND: A related paper (Summerfield & Youngman, 1999) has described the
      development of a scale, the Student Self-Perception Scale (SSPS) designed to
      explore the relationship between academic self-concept, attainment and
      personality in sixth form college students. AIMS: The study aimed to identify
      groups of students exhibiting varying patterns of relationship using a range of
      measures including the SSPS. Issues of gender and also examined. SAMPLES: The
      samples comprised a pilot sample of 152 students (aged 16-17 years from two sixth
      form colleges) and a main sample of 364 students (mean age, 16 yrs 10 mths range
      16:0 to 18:6 years, from one sixth form college). The main sample included
      similar numbers of male and female students (46% male, 54% female) and ethnic
      minority students comprised 14% of this sample. METHOD: Data comprised responses
      to two personality measures (the SSPS, Summerfield, 1995, and the Nowicki
      Strickland Locus of Control Scale, Nowicki & Strickland, 1973), various student
      and tutor estimates of success, and performance data from college records.
      Students were classified using relocation cluster analysis and cluster
      differences verified using discriminant function analysis. Thirty outcome models
      were tested using covariance regression analysis. RESULTS: Eight distinct and
      interpretable groups, consistent with other research, were identified but the
      hypothesis of a positive, linear relationship between mastery and academic
      attainment was not sustained without qualification. Previous attainment was the
      major determinant of final performance. Gender variations were detected on the
      personality measures, particularly Confidence of outcomes, Prediction
      discrepancy, Passivity, Mastery, Dependency and Locus of control, and these were
      implicated in the cluster characteristics. CONCLUSIONS: The results suggest that
      a non-linear methodology may be required to isolate relationships between self
      concept, personality and attainment, especially where gender effects may exist.

PMID- 10405619
TI  - Experimental appraisal of personal beliefs in science: constraints on performance
      in the 9 to 14 age group.
AB  - BACKGROUND: Recent curricula initiatives have promoted experimentation as a means
      by which relatively young children can appraise their personal beliefs and
      thereby modify these beliefs towards received scientific ideas. However, key
      psychological theories signal problems, and the enterprise is not in any event
      securely grounded in empirical research. AIMS: As a consequence, the study
      reported here aimed to provide comprehensive information about children's
      abilities to use experimentation to appraise their beliefs, while allowing full
      exploration of theorized constraints. SAMPLES: The study involved 24 children at
      each of three age levels within the 9 to 14 range. METHODS: The children were
      first interviewed to establish their beliefs about influences on outcome in four
      educationally significant topic areas: flotation, pressure, motion and shadows.
      Subsequently, they were asked to conduct investigations to determine whether
      selected beliefs were correct. RESULTS: The results showed that, regardless of
      age or topic, very few children appreciated that to explore whether some variable
      is influencing outcome it is necessary to manipulate that variable experimentally
      and that variable only. There was a strong tendency to manipulate other
      variables, a tendency attributed to the intrusion of everyday reasoning practices
      into the experimental context. Once extraneous variables had been introduced, the
      children experienced great difficulties with subsequent stages in the
      experimental process, e.g., predicting, observing and drawing conclusions.
      CONCLUSIONS: It is concluded that experimentation as a means of appraising
      beliefs is not straightforward in the 9 to 14 age group, and that the pattern of
      difficulties has psychological significance given the background theories.
      Nevertheless, while not straightforward, experimental appraisal remains possible
      given appropriate teacher support, and proposals are made as to the form which
      the support should take.

PMID- 10405621
TI  - Minding the Brain in the 21st Century. 34th Congress of the Royal Australian and
      New Zealand College of Psychiatrists. Perth, Western Australia, 11-15 April 1999.
      Abstracts.

PMID- 10405620
TI  - Society for Academic Emergency Medicine 1999 annual meeting. Boston,
      Massachusetts, USA. May 20-23, 1999. Abstracts.

PMID- 10405622
TI  - 11th Biotechnocenter Colloquium. Seillac, France, 6-7 November 1998. Abstracts.

PMID- 10405624
TI  - 18th Southern Biomedical Engineering Conference and 2nd International Conference
      on Ethical Issues in Biomedical Engineering. Abstracts.

PMID- 10405625
TI  - British Diabetic Association annual professional conference. Glasgow, United
      Kingdom, 28-30 April 1999. Abstracts.

PMID- 10405623
TI  - 8th International Symposium on Cardiovascular Pharmacotherapy. Amsterdam, The
      Netherlands. March 28 April 1, 1999. Abstracts.

PMID- 10405626
TI  - 4th European College of Neuropsychopharmacology (ECNP) regional meeting. Krakow,
      Poland, April 17-19, 1999. Abstracts.

PMID- 10405627
TI  - 34th Congress of the European Society for Surgical Research (ESSR). Bern,
      Switzerland, April 22-24, 1999. Abstracts.

PMID- 10405628
TI  - Swiss Academy of Medical Sciences. Annual report 1997.

PMID- 10405629
TI  - The Physiological Society proceedings of the scientific meetings held at Harlow 2
      3 November 1998 and Cardiff University 14-18 December 1998.

PMID- 10405630
TI  - American Society for Laser Medicine and Surgery 19th annual meeting. Lake Buena
      Vista, Florida, USA. April 16-18, 1999. Abstracts.

PMID- 10405631
TI  - Proceedings of SCANNING 99. Chicago, Illinois, USA. April 1999.

PMID- 10405632
TI  - [50th Anniversary of the Pomoranian Academy 1948-1998. 10 years of the Pomoranian
      Medical Academy in Szczecin 1988-1998].

PMID- 10405633
TI  - [Membership list].

PMID- 10405634
TI  - [XX Portuguese Congress of Cardiology. Vilamoura, Portugal, 11-14 April 1999.
      Abstracts].

PMID- 10405635
TI  - Structural and functional analysis of the control region of the human DNA
      topoisomerase II alpha gene in drug-resistant cells.
AB  - We have previously shown that the DNA topoisomerase II alpha (topo II alpha) gene
      is down-regulated in VP16/VM26-resistant cells at the transcriptional level. To
      determine the DNA elements responsible for down-regulation, the transcriptional
      activities of luciferase reporter constructs containing various lengths of the
      promoter sequences were investigated by transient transfection of two resistant
      cell lines, KB/VP2 and KB/VM4. The transcriptional activities of the full-length
      promoter (-295 to +85) and of three deletion constructs (-197, -154 and -74 to
      +85) were significantly down-regulated in resistant cells. In contrast, the
      transcriptional activity of the minimal promoter (-20 to +85) in resistant cells
      was similar to that in parental KB cells. Furthermore, introduction of a mutation
      in ICE1 abolished the down-regulation of the topo II alpha promoter activity in
      drug-resistant cells. In vivo footprinting analysis of topo II alpha gene
      promoter revealed several specific protein-binding sites, a GC box, ICE1, ICE2
      and ICE3. In vivo footprinting analysis also identified a cluster of
      hypersensitive sites. However, there was no marked difference in protein-binding
      sites between parental and resistant cells. To confirm our previous results, we
      have established the VP16-resistant cell lines T12-VP1 and T12-VP2 from T12 cells
      derived from human bladder cancer T24 cells stably transfected with the
      chloramphenicol acetyltransferase reporter gene driven by the topo II alpha gene
      promoter. The expression to topo II alpha was down-regulated in both cell lines.
      We also found that CAT gene expression was significantly decreased to one-fifth
      of that in T12 parental cells. These results suggest that the expression of the
      topo II alpha gene requires the binding of multiple factors to the core promoter
      and is down-regulated at the transcriptional level, probably through binding of a
      negative factor to ICE1 in drug-resistant cells.

PMID- 10405636
TI  - Application of the ADEPT strategy to the MDR resistance in cancer chemotherapy.
AB  - New prodrugs consisting of a beta-D-glucuronic acid linked to a MDR reversal
      agent (verapamil, quinine or dipyridamole) through a self-immolative spacer were
      synthesized. Four of them were selected for their reduced cytoxicity and beta
      glucuronidase enzymatic efficient hydrolysis. Combined use of these prodrugs with
      a beta-D-glucuronyl-spacer-doxorubicin (HMR1826) according to an ADEPT strategy
      restored in vitro the sensibility of a MDR resistant strain.

PMID- 10405637
TI  - Influence of p53 mutation on pathological grade, but not prognosis of non
      Hodgkin's lymphoma.
AB  - Mutations in the p53 gene were detected in 27 of the 107 (25%) cases of non
      Hodgkin's lymphoma (NHL), examined by assaying the transcriptional activity of
      p53 in yeast. A relatively high mutation rate of p53 was observed in B-cell
      intermediate-grade NHL and in T-cell high-grade immunoblastic NHL, in contrast to
      the relatively low mutation rate observed in other pathological classifications.
      However, retrospective analyses of all 76 cases revealed that the survival
      profile and therapeutic responses were very similar in NHL patients bearing
      lymphomas with a mutant p53 or with the wild-type p53 even within the subclasses
      characterized by frequent p53 mutation. In patients with high-intermediate grade
      tumors, the median survival period was 24 months in mutated p53 cases and 14
      months in wild-type cases. Complete remission (CR) was observed in 9 of the 17
      patients (53%) with mutated forms of p53 and 18 of the 35 patients (51%) with
      wild-type p53 genes. Our analyses of NHL patients revealed that the presence of
      p53 mutations may influence pathological grades of NHL, but did not strongly
      correlate with poor prognosis or reduced chemo/radiosensitivity in NHL. Hence,
      mutations of p53 do not serve as a prognostic, or chemo/radiosensitivity marker
      in NHL.

PMID- 10405638
TI  - Recent progress in P-glycoprotein research.
AB  - P-glycoprotein can extrude a variety of structurally diverse, toxic xenobiotic
      compounds from cells. It is believed to be one of key molecules which can cause
      multidrug resistance in cancer. This paper deals with recent progress in P
      glycoprotein research, especially in its structure, mechanisms for substrate
      recognition and transport. The review also discusses specific modulators of
      multidrug resistance in cancer and gene therapy using the MDR1 gene.

PMID- 10405639
TI  - Multidrug resistance-associated protein subfamily transporters and drug
      resistance.
AB  - Multidrug resistance-associated protein gene MRP/MRP1, and its family genes,
      including MRP2/cMOAT, have been isolated and characterized. These ATP-binding
      cassette (ABC) superfamily transporter genes are differentially expressed in
      various normal tissues and multidrug-resistant cell lines. Transfection of
      MRP/MRP1 and MRP2/cMOAT cDNA confers drug resistance on different spectra of
      anticancer agents from that of MDR1 coding P-glycoprotein. Although it remains
      unclear how MRP/MRP1 and related family genes are specifically involved in drug
      resistance in clinical cancers, current knowledge of the MRP subfamily suggests
      the importance of this class of transporters as a molecular target for drug
      sensitivity to anticancer agents.

PMID- 10405640
TI  - Cytoskeletons and antimitotic agents developed in Japan.
AB  - Resistance to antimitotic agents is caused by decreased accumulation, altered
      tubulin, altered microtubule-associated proteins and increased metabolism. Vinca
      alkaloids, paclitaxel and docetaxel are actively effluxed by P-glycoprotein
      and/or the MRP1. Decreased intracellular accumulation is one of the major
      determinants of resistance to antimitotic agents. Increased tubulin levels and a
      decreased polymerization ratio were observed in resistant cells. Increased
      acetylation of tubulin and altered intracellular distribution of tubulin were
      also observed in resistant cells; however, the relationship between the function
      of tubulin and resistance remains unclear. The expression of each beta-tubulin
      isotype (beta 1-beta 6) is altered in resistant cells, but the functional
      differences among the isotypes have not been clarified. Recent evidence has
      demonstrated the alteration of binding properties of antimitotic agents in
      resistant cells. Therefore, the altered expressions of tubulin isotypes and
      related molecules might influence the antimitotic action and adverse events by
      antimitotic agents. Taxanes are metabolized and inactivated by p450 isozymes, and
      this is related to drug-resistant to taxanes.

PMID- 10405641
TI  - Resistance to cisplatin.
AB  - Resistance to cis-diamminedichloroplatinum(II) (cisplatin), a DNA damaging agent,
      is a major obstacle for its clinical effectiveness. Multiple mechanisms may be
      involved in cisplatin resistance. Frequently cited mechanisms include reduced
      accumulation, elevated levels of glutathione (GSH) and metallothionein, and
      enhanced DNA repair. Alterations in oncogene expression and in signal
      transduction pathways involved in apoptosis have been associated with cisplatin
      resistance. Of these mechanisms, decreased accumulation of cisplatin is the most
      common finding. Efflux of cisplatin by an organic anion transporter has been
      proposed, and one of the organic anion transporters, canalicular multispecific
      organic anion transporter, is associated with cisplatin resistance. Sensitivity
      to cisplatin has been increased by inhibitors of DNA repair, agents that increase
      accumulation of cisplatin and depletion of GSH. None of the agents tested that
      modulate cisplatin sensitivity completely reverses cisplatin resistance. These
      observations indicate that multiple mechanisms of resistance arise in the same
      cell line when cells are selected in vitro.

PMID- 10405642
TI  - Adhesion-dependent multicellular drug resistance.
AB  - Herein we review studies demonstrating resistance manifested at the multicellular
      level, a phenomenon referred to as intrinsic or acquired multicellular resistance
      (MR). In addition, due to the fact that such resistance can be recapitulated in
      vitro only when cells are adhered to one another in a three-dimensional culture
      context, we examine the roles of cell adhesion molecules and how they may
      contribute directly or indirectly to MR. Finally, we suggest an experimental
      approach to circumvent MR in the treatment of advanced, aggressive ascites
      tumors.

PMID- 10405643
TI  - Drug resistance mediated by cellular stress response to the microenvironment of
      solid tumors.
AB  - Most solid tumors show resistance to current chemotherapy. This drug resistance
      can be associated with the unique physiology of solid tumors. Solid tumors
      generally have regions of low oxygen (hypoxia), low pH and low levels of glucose,
      which are not observed in normal tissues. These tumor-specific conditions
      commonly cause the glucose-regulated stress response of cancer cells.
      Accumulating evidence shows that the stress response leads to induction of
      resistance to multiple drugs, such as etoposide, doxorubicin, camptothecin and
      vincristine. This type of drug resistance is reversible and decays rapidly when
      stress conditions are removed. The induction of drug resistance can be partly
      explained by cell cycle arrest at the G1 phase in stressed cells because most
      anticancer drugs are primarily effective against rapidly dividing cells. Specific
      mechanisms, such as the decreased expression of DNA topoisomerase (topo) II alpha
      for the resistance to topo II poisons, are also involved in the drug resistance.
      Stressed cells, however, become hypersensitive to cisplatin, one of the most
      effective drugs against solid tumors, suggesting that preferential cytotoxicity
      to stressed cells may be important for the clinical efficacy against solid
      tumors. Further characterization of stressed cells will provide a unique target
      to circumvent the drug resistance of solid tumors.

PMID- 10405644
TI  - The development of radiology guidelines in Canada, Part 2.
AB  - In the second part of a two-part article on the development of Canadian clinical
      practice guidelines in radiology, the author discusses the implementation of
      guidelines. The aim is to translate guidelines into practice policies, but nation
      wide implementation is difficult because of the regional circumstances and
      constraints in Canadian health care. One approach to making guidelines more
      effective tools and preventing conflict is to distinguish between effectiveness
      (benefit of an intervention under average conditions of use) and efficiency
      (value of an intervention compared with other things that could be done with the
      same resources). Clinical practice guidelines are based on effectiveness criteria
      alone, whereas practice policies can be based on efficiency criteria and are made
      by those responsible for allocating resources. From an ethical point of view,
      guidelines have an important feature in common with applied ethics: neither can
      give the right answer in a situation, but both can indicate the right decision
      making process, including who should decide, on what basis, using which process
      and for what purpose. From a legal standpoint, if the medical community views
      guidelines as constituting reasonable medical care and jurists see them as a
      medical and legal norm, they can have significant influence in malpractice
      litigation. At the last annual meeting of the CAR, the executive committee
      decided that an integrated national approach to guidelines is needed because of
      the considerable confusion in this field. It supports the National Framework
      Development Committee's efforts to set national principles and operating rules
      for development and implementation. This necessitates an organizational structure
      consisting of a coordinating group representing consumers, service providers,
      regulators and funding agencies; multidisciplinary guidelines-development groups;
      and methodology resource groups.

PMID- 10405645
TI  - Palliation of primary and recurrent gastric carcinoma with expandable metallic
      stents: 2 case reports.

PMID- 10405646
TI  - Jejunal perforation mimicking acute pancreatitis in a patient with systemic lupus
      erythematosus: case report.

PMID- 10405647
TI  - Magnetic resonance imaging findings of hepatic adenomas in von Gierke (type I)
      glycogen storage disease: case report.

PMID- 10405648
TI  - Gastrointestinal manifestations of cystic fibrosis in adults: pictorial essay.

PMID- 10405649
TI  - Small bowel intussusception secondary to osteogenic sarcoma metastasis: case
      report.

PMID- 10405650
TI  - Transrectal ultrasound-guided biopsy of the prostate: relation between ASA use
      and bleeding complications.
AB  - OBJECTIVE: To determine the relation between ASA ingestion and the incidence of
      bleeding complications after transrectal ultrasound (TRUS)-guided biopsy of the
      prostate. METHODS: Overall, 1810 patients with suspected prostate disease were
      followed after biopsy. ASA use was determined before the procedure. A TRUS-guided
      sextant biopsy was performed and patients were contacted immediately and by
      follow-up telephone call to determine whether there were any immediate or delayed
      bleeding complications. RESULTS: Overall, 46 subjects (2.5%) had bleeding
      complications. Of the 54 subjects reporting current use of ASA, 2 (3.7%) had such
      complications. This difference was not significant. CONCLUSION: There was no
      evidence of an association between the use of ASA and postbiopsy bleeding
      complications.

PMID- 10405651
TI  - Apheresis: another indication for radiologically placed central venous catheters.
AB  - OBJECTIVE: Apheresis is an important technique, used increasingly for a variety
      of conditions. It is sometimes performed via peripheral access because of concern
      over major complications associated with central venous catheter (CVC) placement.
      This study was to determine the safety and success of radiologic placement of
      CVCs for apheresis. METHODS: Data were collected prospectively for 278 CVCs
      placed under real-time sonographic or fluoroscopic guidance in the radiology
      department. Complications were noted in all cases; the number of passes required
      for venipuncture and whether this was achieved with a single wall puncture were
      noted in 265 cases; duration of catheterization and reason for removal of the
      catheter were recorded in all cases. The study group included 83 donors providing
      peripheral blood stem cells for allogeneic transplant. RESULTS: CVCs were
      successfully placed in all patients, 269 in the internal jugular and 9 in the
      femoral vein. In 87% of cases, only a single pass was required, and in 80% of
      cases venipuncture was achieved with a single anterior wall puncture. There was
      inadvertent but clinically insignificant arterial puncture in 6 cases (2%). In no
      case did this prevent CVC placement. Most catheters (211/274, 77%) were removed
      the same day. Only 3 catheters were removed prematurely (1%), 1 because of
      infection and 2 because of clotting. There was 1 case of venous bleeding.
      CONCLUSION: CVCs are safe for apheresis if real-time sonographic guidance is used
      for the puncture, guide wire and catheter placement are confirmed
      fluoroscopically, and the duration of catheterization is short.

PMID- 10405652
TI  - Ultrasound-guided percutaneous thrombin injection for treatment of femoral
      pseudoaneurysms: technical note.

PMID- 10405653
TI  - Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric
      dysplasia: review and update.
AB  - The authors summarize the clinical, genetic and histopathologic features, as well
      as the complications, and radiological diagnosis of 3 related generalized short
      limb skeletal dysplasias: achondroplasia, hypochondroplasia and thanatophoric
      dysplasia. In all of these dysplasias, there is abnormal endochondral
      ossification, but periosteal ossification is not affected. These 3 relatively
      common entities are known to be allelic to the same gene: the fibroblast growth
      factor receptor 3 gene on chromosome 4p. Heterozygous achondroplasia is the most
      common nonlethal skeletal dysplasia. The distinctive clinical and radiological
      features allow a precise diagnosis, as there is little variability in the
      appearance of affected patients. There is also a very evident molecular
      homogeneity. On histopathology of the growth plate, there is a quantitative
      decrease in endochondral ossification. Precise prenatal ultrasonographic
      diagnosis is possible in the third trimester, and sometimes even in the second.
      Hypochondroplasia is a relatively common, milder form of achondroplasia, which
      varies within and between families and lacks the neurological complications often
      seen in achondroplasia of this group. An accurate prenatal ultrasonographic
      diagnosis is rare. There are milder changes on histology of the growth plate.
      Thanatophoric dysplasia is the lethal and most severe dysplasia. It has distinct
      features--mainly short tubular bones and short ribs with platyspondyly--allowing
      a precise radiologic and prenatal ultrasonographic diagnosis. On histopathology
      of the growth plate, there is disruption of endochondral ossification.

PMID- 10405654
TI  - Computed tomographic demonstration of very-low-density pulmonary nodules in
      metastatic gastric carcinoma: case report.

PMID- 10405655
TI  - Answer to case of the month #61. Situs inversus abdominis with duodenal diaphragm
      and intestinal malrotation.

PMID- 10405656
TI  - Measuring carotid stenosis.

PMID- 10405657
TI  - Conceptualizing risk.

PMID- 10405658
TI  - Prostate cancer from a patient's perspective.

PMID- 10405659
TI  - The more the better?

PMID- 10405660
TI  - Understanding obesity.

PMID- 10405661
TI  - Understanding obesity.

PMID- 10405663
TI  - Galloping to the defence of other species.

PMID- 10405662
TI  - Proud of Premarin.

PMID- 10405664
TI  - Transfusion medicine in another era.

PMID- 10405665
TI  - Bone densitometry: does the emperor have clothes?

PMID- 10405666
TI  - Prevalence of asthma, rhinitis and eczema among children in 2 Canadian cities:
      the International Study of Asthma and Allergies in Childhood.
AB  - BACKGROUND: Wide variations in the prevalence of asthma, rhinitis and eczema have
      been reported between regions within Canada and between different countries. The
      International Study of Asthma and Allergies in Childhood (ISAAC) was developed to
      provide a standardized tool and methodology to ascertain the prevalence of asthma
      and allergies in different regions. Comparisons of prevalence rates across
      geographic regions and at different times may help to identify factors that
      contribute to the development of these conditions in individuals. METHODS: Two
      Canadian centres, Hamilton and Saskatoon, participated in the ISAAC. A standard
      questionnaire was distributed through schools and completed by 13- and 14-year
      old children and by the parents of 6- and 7-year-old children. Prevalence rates
      and 95% confidence intervals were calculated for asthma, wheezing, rhinitis and
      eczema. RESULTS: The overall response rates were 75.1% among the children 6 and 7
      years old and 68.6% among those 13 and 14 years old. Among the younger children,
      the lifetime prevalence of asthma was 17.2% in Hamilton and 11.2% in Saskatoon;
      the corresponding rates among the older children were 19.2% and 12.2%
      respectively. The prevalence of wheezing in the 12 months before the survey in
      the younger group was 20.1% in Hamilton and 14.1% in Saskatoon; in the older
      group it was 30.6% and 24.0% respectively. The prevalence of rhinitis in the 12
      months before the survey was 28.6% in Hamilton and 22.6% in Saskatoon in the
      younger group and 45.8% and 33.8% respectively in the older group. The prevalence
      of eczema was slightly higher in Saskatoon in both age groups. INTERPRETATION:
      High prevalence rates of asthma, rhinitis and eczema exist among school children
      in Hamilton and Saskatoon, similar to rates in other Western countries. Further
      studies are required to determine the factors associated with the high rates in
      the 2 regions and possible reasons for the higher rates in Hamilton.

PMID- 10405668
TI  - Incidence of tuberculosis among reported AIDS cases in Quebec from 1979 to 1996.
AB  - BACKGROUND: The impact of HIV infection on tuberculosis (TB) rates in Quebec has
      not been fully established. Because concurrent HIV infection is the single most
      important factor in TB reactivation, the authors used Quebec AIDS surveillance
      data to quantify the extent of TB among reported AIDS cases and to identify the
      characteristics of AIDS patients with TB. METHODS: The study population comprised
      people aged 15 years and over with AIDS diagnosed between Jan. 1, 1979, and Dec.
      31, 1996, and reported by Mar. 13, 1997. Patients with TB (all forms) and those
      without TB were compared. Multivariate logistic regression analysis was used to
      examine the independent effect of each variable on the AIDS-TB cases. The authors
      also compared the number of AIDS-TB cases with the number of TB cases to estimate
      the effect of HIV infection on TB incidence. RESULTS: Of the 4684 people with
      AIDS reported in Quebec, 242 (5.2%) had active TB at some point during the course
      of their illness. During 1992-1995, 9.6% of the people with TB in Montreal, and
      5.8% in the province of Quebec, also had HIV infection. Those with AIDS and TB
      were predominantly male (75.2%), manual workers (40.1%) and residents of Montreal
      (86.4%) and were born in an HIV-endemic country (63.8%). The multivariate
      analysis indicated that AIDS patients who were born in HIV-endemic countries in
      the Caribbean, sub-Saharan Africa or other developing regions were 21.8 times
      (95% confidence interval [CI] 19.5-28.5), 17.9 times (95% CI 12.7-27.1) and 4.9
      times (95% CI 3.5-7.0) more likely to have TB than those born in Canada; manual
      workers and unemployed people with AIDS were 1.6 times (95% CI 1.3-2.0) and 2.0
      times (95% CI 1.5-2.6) more likely to have TB than professional workers; and
      people who acquired HIV infection through heterosexual contact were 2.1 times
      (95% CI 1.6-3.1) more likely to have TB than men who acquired it through sexual
      contact with other men. INTERPRETATION: AIDS seems to contribute significantly to
      the number of TB cases. The results of this study reinforce the importance of
      offering HIV testing to people in high-risk groups, such as those born in a
      country where HIV and TB is endemic.

PMID- 10405667
TI  - Do physicians assess lifestyle health risks during general medical examinations?
      A survey of general practitioners and obstetrician-gynecologists in Quebec.
AB  - BACKGROUND: In Canada several guidelines have been published for the screening of
      lifestyle health risks during general medical examinations. The authors sought to
      examine the extent to which such screening practices have been integrated into
      medical practice, to measure physicians' perceived level of difficulty in
      assessing these risks and to document physicians' evaluation of their formal
      medical training in lifestyle risk assessment. METHODS: An anonymous mail survey
      was conducted in 1995 in Quebec with a stratified random sample of 1086 general
      practitioners (GPs) and with all 241 obstetrician-gynecologists (Ob-Gyns). The
      authors evaluated the proportion of physicians who reported routine assessment
      (with 90% or more of their patients) of substance use, family violence and sexual
      history during general medical examinations of adult and adolescent patients; the
      proportion of those who find inquiring about these issues difficult; and the
      proportion of those who evaluated their medical training in lifestyle risk
      assessment as adequate or excellent. RESULTS: The overall response rate was
      72.6%. Among adult patients, 82.2% of the GPs reported routinely assessing
      tobacco use, 67.2% alcohol consumption, 34.2% illicit drug use and 3.2% family
      violence; the corresponding proportions for assessment among adolescent patients
      were 77.1%, 61.8%, 52.9% and 5.6%. Comparatively fewer Ob-Gyns reported routinely
      assessing these issues (56.1%, 28.6%, 20.4% and 1.3% respectively among adults
      and 62.7%, 35.2%, 26.8% and 2.8% respectively among adolescents). In the area of
      sexual history, condom use was routinely assessed by more Ob-Gyns than GPs (47.0%
      v. 28.2%); however, the proportion of Ob-Gyns and GPs was equally low for
      assessing number of partners (24.8% and 23.1%), sexual orientation (18.8% and
      16.9%) and STD risk (26.2% and 21.2%). The vast majority of GPs and Ob-Gyns
      reported finding it difficult to assess family violence (86.5% and 93.0%) and
      sexual abuse (92.7% and 92.4% respectively). Over 80% of the physicians felt that
      they had had adequate or excellent medical training in assessing risk behaviours
      for heart disease and STD risk. The proportion who felt this way about their
      training in screening for illicit drug use, family violence and sexual abuse
      ranged between 12.7% and 31.6%. INTERPRETATION: Although morbidity and mortality
      associated with smoking, alcohol consumption, illicit drug use, unsafe sexual
      practices, family violence and sexual abuse have been well documented, routine
      screening for these risk factors during general medical examinations has yet to
      be integrated into medical practice.

PMID- 10405670
TI  - Should physicians assess lifestyle risk factors routinely?

PMID- 10405669
TI  - Fatal work-related farm injuries in Canada, 1991-1995. Canadian Agricultural
      Injury Surveillance Program.
AB  - BACKGROUND: Studies from other developed countries have shown that agriculture is
      among the most dangerous occupational sectors in terms of work-related deaths.
      The authors describe the occurrence of fatal work-related farm injuries in Canada
      and compare these rates with those in other Canadian industries. METHODS: The
      authors present a descriptive, epidemiological analysis of data from the recently
      established Canadian Agricultural Injury Surveillance Program. The study
      population comprised Canadians who died from work-related farm injuries between
      1991 and 1995. Crude, age-standardized, age-specific and provincial rates of such
      injuries are presented, as are overall death rates in other Canadian industries.
      Other factors examined were the people involved, the mechanism of injury, and the
      place and time of injury. RESULTS: There were 503 deaths from work-related farm
      injuries during the study period, for an overall annual rate of 11.6 deaths per
      100,000 farm population. Modest excesses in this rate were observed in Ontario,
      Quebec and the Atlantic provinces. High rates were observed among men of all ages
      and among elderly people. Among the cases that listed the person involved, farm
      owner-operators accounted for 60.2% of the people killed. There was no
      substantial increase or decrease in the annual number of deaths over the 5 years
      of study. The leading mechanisms of fatal injury included tractor rollovers,
      blind runovers (person not visible by driver), extra-rider runovers, and
      entanglements in machinery. Compared with other industries, agriculture appears
      to be the fourth most dangerous in Canada in terms of fatal injury, behind
      mining, logging and forestry, and construction. INTERPRETATION: Canada now has a
      national registry for the surveillance of fatal farm injuries. Farming clearly is
      among the most dangerous occupations in Canada in terms of fatal work-related
      injuries. Secondary analyses of data from this registry suggest priorities for
      prevention, continued surveillance and in-depth research.

PMID- 10405672
TI  - Nutrition education needs an appropriate setting.

PMID- 10405671
TI  - Two tick-borne diseases in one: a case report of concurrent babesiosis and Lyme
      disease in Ontario.

PMID- 10405674
TI  - The Medicare Medical Nutrition Therapy Act of 1999: effort to secure MNT coverage
      still popular with lawmakers.

PMID- 10405673
TI  - Latex-diet syndrome.

PMID- 10405675
TI  - From aspartame to Xenical. A look at the FDA review process.

PMID- 10405676
TI  - Broadening career opportunities in dietetics: employment in independent research.
AB  - Independent research organizations provide opportunities for dietetics
      professionals, along with the interdisciplinary research team, to make an optimal
      contribution to health care. They also offer a wide variety of career options
      from principal investigators to study managers. Further, opportunities in
      progressive independent research organizations often focus on linking research
      and practical nutritional applications to enhance the dietetics profession. With
      the shrinking traditional employment market for dietitians, new options must be
      pursued. Dietitians should consider independent research organizations for an
      exciting and rewarding career opportunity.

PMID- 10405677
TI  - Economic implications of an early postoperative enteral feeding protocol.
AB  - OBJECTIVE: To study the cost-effectiveness of an early postoperative feeding
      protocol for patients undergoing bowel resections. DESIGN: A nonrandomized,
      prospective, clinical trial. Surgeons elected to participate in the treatment arm
      before the study's outset. SUBJECTS/SETTING: Treatment (n = 66) and control (n =
      159) patients were admitted to a nonprofit general teaching hospital in the Texas
      Medical Center for similar diagnoses and subsequent bowel resections during an 18
      month period. INTERVENTION: Treatment patients who met specific inclusion
      criteria had a jejunal feeding tube placed during surgery. Tube feedings were
      initiated within 12 hours after surgery. Control patients who met the same
      inclusion criteria received usual care. OUTCOMES: A successful outcome was
      defined as a patient developing no postoperative infection. The average cost of a
      nosocomial infection is presented. Variable direct and total costs (fixed plus
      variable) are compared between patient groups. STATISTICAL ANALYSIS: Mean cost
      was adjusted for rate of success in each patient group according to an analytic
      model. The mean cost difference between groups was analyzed by independent
      samples t tests. Nonparametric Mann-Whitney rank sum tests were used to determine
      the cost significance of a nosocomial infection. RESULTS: The average variable
      direct cost savings per successful treatment patient was $1,531, which required
      an additional variable cost of $108.30 for the dietitian's time. The protocol
      resulted in a total cost savings of $4,450 per success in the treatment group.
      CONCLUSION: An early postoperative enteral feeding protocol as part of an
      outcomes management program for patients undergoing bowel resection is cost
      effective.

PMID- 10405678
TI  - Self-perceived competence of advanced public health nutritionists in the United
      States.
AB  - OBJECTIVE: To describe the development and use of a self-assessment tool designed
      to evaluate competencies in skill areas, including management and leadership,
      among advanced public health nutritionists. DESIGN: Subjects were identified by
      state and territorial nutrition directors who provided lists of nutrition
      personnel in official, state, public health agencies. The 519 nutritionists
      identified were mailed a 137-item self-assessment tool developed for advanced
      public health nutritionists. SUBJECTS: A self-selected sample of 281 state public
      health nutritionists responded. STATISTICAL ANALYSES PERFORMED: Means and
      standard deviations were calculated for descriptive variables. Factor analysis
      was conducted to examine associations of items within the assessment tool
      measured by Spearman correlation. The Cronbach alpha coefficient statistic was
      used to examine reliability. RESULTS: Factor analysis produced a 48-item, 3
      factor tool comprising items with a correlation of 0.6 or greater; the 3 factors
      were management, public health nutrition, and communication. Mean scores on the
      assessment tool indicated that respondents scored competent in 50% of items and
      adequate in 50% of items. CONCLUSIONS: Ongoing self-assessment by public health
      nutrition professionals can guide the selection of continuing education and
      higher education degree programs. Although this self-assessment tool was tested
      in the public health arena, it can be applied to all nutritionists and dietitians
      with management responsibilities.

PMID- 10405679
TI  - Estimates of animal and plant protein intake in US adults: results from the Third
      National Health and Nutrition Examination Survey, 1988-1991.
AB  - OBJECTIVE: To describe the sources of protein intake in a sample of the US adult
      population and among subgroups defined by race-ethnicity, age, and gender.
      DESIGN: The Third National Health and Nutrition Examination Survey, 1988-1991, is
      a stratified random sample of the total civilian noninstitutionalized population,
      drawn from the 50 United States and the District of Columbia. For all foods
      consumed by the participants, based on a 24-hour dietary recall, protein sources
      and the contribution of each protein type to the total protein intake were
      determined. SUBJECTS: Adult participants in the third National Health and
      Nutrition Examination Survey (n = 7,924). STATISTICAL ANALYSES: Weighted total,
      age-specific, and age-adjusted mean protein intakes were calculated using SAS and
      WesVarPC. Statistical differences were determined by 2-tailed t tests. RESULTS:
      The main protein source in the American diet is animal protein (69%). Meat, fish,
      and poultry protein combined contributed the most to animal protein (42%),
      followed by dairy protein (20%). Grains (18%) contributed the most to plant
      protein consumption. Women consumed a lower percentage of beef (14%) and pork
      (7%) protein than did men (18% and 9%, respectively). Women also consumed a
      higher percentage of poultry (13%), dairy (22%), and fruit and vegetable (11%)
      protein than did men (11%, 19%, and 9%, respectively). Blacks reported eating a
      higher percentage of poultry (18%) and pork (11%) protein and a lower percent of
      dairy protein (14%) than did whites (12%, 7%, and 22%, respectively) and Mexican
      Americans (11%, 8%, and 17%, respectively). Mexican-Americans consumed a higher
      percentage of legume (7%) and egg (7%) protein than did whites (4% and 4%,
      respectively) and blacks (4% and 5%, respectively). Whites consumed a higher
      percentage of grain protein (19%) than did blacks (16%) and Mexican-Americans
      (15%). CONCLUSIONS: These results show that, although the percentage of total
      energy from protein may be similar among race-ethnicities and between men and
      women, their sources of protein are different. These differences should be taken
      into account when providing nutrition education for specific populations.

PMID- 10405680
TI  - Predictors of milk consumption in a population of 17- to 35-year-old military
      personnel.
AB  - OBJECTIVE: The purpose of this investigation was to survey an entire population
      of Air Force recruits (N = 32,144) regarding milk consumption and demographic and
      health-related factors that may predict milk consumption. DESIGN: All subjects
      were required to fill out a 53-item health survey at the start of basic military
      training. SUBJECTS/SETTING: All recruits who entered the US Air Force from August
      1995 to August 1996 participated in this study (N = 32,144). STATISTICAL ANALYSES
      PERFORMED: Potential correlates of milk intake were analyzed using Spearman rank
      order correlations and multiple linear regression. Variables were removed if they
      did not make a meaningful contribution to variance in milk intake. Because of
      skewed distributions, several variables were dichotomized (e.g., age: 17 to 24 vs
      25 to 35 years). RESULTS: In terms of milk consumption, 51.7% of the respondents
      reported intake of fewer than 1 serving per day; only 17.9% reported intake of 3
      servings or more per day. Milk intake was positively associated with body weight
      and fruit/vegetable intake and negatively associated with age, education level,
      reported milk-related gastric distress, physical activity level, dieting
      frequency, and concern about weight. Gender (women reported lower intake) and
      ethnicity (minorities reported lower intake) were independently related to milk
      consumption. Of all respondents, 16.1% reported themselves to have milk-related
      gastric distress, but rates varied depending on age, gender, and ethnicity
      (ranging from 10.2% for younger non-Hispanic white men to 60.4% for older Asian
      men). APPLICATIONS/CONCLUSIONS: Despite the efforts of large, costly campaigns
      designed to increase milk consumption, self-reported milk consumption in young
      adults is extremely low. Given the importance of dairy products as a major source
      of calcium in the American diet, dietetics practitioners should assess milk
      consumption among young adults to ensure sufficient calcium intake to maximize
      peak bone mass in this group.

PMID- 10405681
TI  - Diet and physical activity patterns of Lakota Indian adults.
AB  - OBJECTIVES: This study assessed specific dietary practices and overall physical
      activity patterns of Lakota adults residing on Indian reservations in South
      Dakota. Perceived barriers to changing dietary and physical activity behaviors
      were also examined. DESIGN: A convenience sample of Lakota adults was surveyed.
      Data on consumption of higher-fat foods, fruit and vegetable intake, use of sugar
      sweetened beverages, physical activity patterns, and barriers to change in diet
      and physical activity were collected via in-person interviews. SUBJECTS/SETTING:
      A total of 219 adults from 2 adjacent reservations in South Dakota participated.
      RESULTS: Higher-fat foods consumed most frequently included margarine and butter
      (32.0% > or = 5 times per week); eggs (30.1% > or = 5 times per week); whole milk
      (25.7% > or = 5 times per week); potato chips, corn chips, and popcorn (15.1% >
      or = 5 times per week); and bacon and sausage (13.3% > or = 5 times per week).
      Few subjects reported consuming fruit on a daily basis. Vegetables were consumed
      somewhat more frequently. Most subjects reported engaging in mild or moderate
      physical activities 3 or more times per week, although women were found to engage
      in moderate and strenuous physical activities less frequently than men. Major
      barriers to fruit intake included expense (16.4%), quality (14.2%), and
      availability (13.2%). Barriers to vegetable intake mentioned most frequently
      included availability (11.4%), cost (10.4%), and quality (9.1%). Taste was the
      most frequently mentioned barrier to cutting intake of high-fat foods (27.9%).
      Lack of child care (15.8%), lack of time (14.7%), and safety concerns (14.6%)
      were the most salient barriers to regular exercise. APPLICATIONS/CONCLUSIONS:
      Nutrition interventions are needed that address the major barriers to diet change
      reported by Lakota adults. Efforts to increase physical activity should focus on
      Lakota women and should address the identified barriers to regular exercise.

PMID- 10405682
TI  - The diverse role of selenium within selenoproteins: a review.
AB  - Selenium functions within mammalian systems primarily in the form of
      selenoproteins. Selenoproteins contain selenium as selenocysteine and perform a
      variety of physiological roles. Eleven selenoproteins have been identified:
      cellular or classical glutathione peroxidase; plasma (or extracellular)
      glutathione peroxidase; phospholipid hydroperoxide glutathione peroxidase;
      gastrointestinal glutathione peroxidase; selenoprotein P; types 1, 2, and 3
      iodothyronine deiodinase; selenoprotein W; thioredoxin reductase; and
      selenophosphate synthetase. Of these, cellular and plasma glutathione peroxidase
      are the functional parameters used for the assessment of selenium status.
      Glutathione peroxidases catalyze the reduction of peroxides that can cause
      cellular damage. Thioredoxin reductase provides reducing power for several
      biochemical processes and defends against oxidative stress. Selenoprotein P
      appears to play a role in oxidant defense. Selenoprotein W may play a role in
      oxidant defense and be involved with muscle metabolism. Thyroid deiodinases
      function in the formation and regulation of active thyroid hormone.
      Selenophosphate synthetase is an enzyme required for the incorporation of
      selenocysteine into selenoproteins. In addition, a protein in the sperm
      mitochondrial capsule, which is vital to the integrity of sperm flagella, may be
      a unique selenoprotein. Recommended intakes, food sources, and status assessment
      of selenium, as well as selenium's role in health and disease processes, are
      reviewed.

PMID- 10405683
TI  - Comparison of energy estimation equations with measured energy expenditure in
      obese adolescent patients with cancer.
AB  - Obesity is increasing in the US adolescent population. As the number of obese
      adolescents increases, obesity is becoming a more frequent problem in the
      hospital setting, sometimes causing patients to have complicated and prolonged
      hospital stays. Calculation of the energy requirements of obese adolescent
      patients with chronic diseases such as cancer is complicated by increased energy
      requirements as a result of disease state and growth. This study examined the
      accuracy of the commonly used equations for calculating energy requirements.
      Estimated energy expenditure was compared with measured energy expenditure
      determined by indirect calorimetry. All energy estimation equations were
      inaccurate, which indicates the need for a specific equation for determination of
      energy needs in this special patient population. Until further research is done,
      indirect calorimetry is recommended for all obese adolescent patients with cancer
      who require nutrition support.

PMID- 10405685
TI  - Motivations for using vitamin and mineral supplements.

PMID- 10405684
TI  - Behavioral or epidemiologic coding of fruit and vegetable consumption from 24
      hour dietary recalls: research question guides choice.

PMID- 10405686
TI  - People with marginal vitamin C status are at high risk of developing vitamin C
      deficiency.

PMID- 10405687
TI  - Factors affecting selection of restaurants by Anglo- and Mexican-American
      families.

PMID- 10405688
TI  - Thiamin, riboflavin, and niacin contents of the gluten-free diet: is there cause
      for concern?

PMID- 10405689
TI  - The Gerontological Nutritionists Standards of Professional Practice for dietetics
      professionals working with older adults. American Dietetic Association.

PMID- 10405690
TI  - Your input counts: results of the Commission on Dietetic Registration Customer
      Satisfaction and Needs Assessment Survey.

PMID- 10405691
TI  - Dr John S. Lundy and the 75th anniversary of anesthesiology at Mayo.

PMID- 10405692
TI  - Trends in heart disease deaths in Olmsted County, Minnesota, 1979-1994.
AB  - BACKGROUND: Although age-adjusted heart disease mortality has declined since the
      1960s, this decline may not have applied equally to all subgroups. OBJECTIVE: To
      examine recent trends in heart disease mortality, specifically in women and in
      the elderly. METHODS: Age- and sex-specific heart disease mortality
      (International Classification of Diseases, Ninth Edition, Clinical Modification
      [ICD-9-CM] codes 390-398, 402, 404-429) in Olmsted County, Minnesota, between
      1979 and 1994 were studied. RESULTS: The total number of heart disease deaths was
      3095; 1578 (51%) occurred in women and 1984 (64%) in persons aged 75 years or
      older. Most heart disease deaths (77%) were coronary disease deaths (ICD-9-CM
      codes 410-414). Age-adjusted heart disease mortality rates declined from 123 per
      100,000 (95% confidence interval [CI], 102-144/100,000) in 1979 to 81 per 100,000
      (95% CI, 67-95/100,000) in 1994. Poisson regression analyses indicated that the
      trends differed according to sex and age. For women, the relative risk (RR) of
      heart disease death in 1994 compared with 1979 was 0.69 vs 0.53 for men (P =
      .06). This equates to a decline in heart disease mortality of 2.5% per year in
      women or 32% over the period and 4.2% per year in men or 47% over the period. The
      decline was less pronounced as age increased (P < .001). For 60-year-old women,
      the RR for 1994 compared with 1979 was 0.59, whereas for 80-year-old women, the
      RR for 1994 compared with 1979 was 0.76. For men, the RR for 1994 compared with
      1979 was 0.60 for 80-year-old men vs 0.46 for 60-year-old men. CONCLUSIONS:
      Between 1979 and 1994, in Olmsted County, the decline in heart disease mortality
      was of lesser magnitude in women and in the elderly, emphasizing the importance
      of age- and sex-specific trends to characterize time patterns in heart disease
      deaths to target preventive measures.

PMID- 10405693
TI  - Dermatologic manifestations in HIV-infected patients: a primary care perspective.
AB  - OBJECTIVE: To document the prevalence of dermatologic manifestations in patients
      infected with the human immunodeficiency virus (HIV) on presentation to primary
      medical care. DESIGN: Prospective consecutive case series evaluated between June
      and November 1995. SETTING: The HIV intake clinic at an urban hospital. SUBJECTS
      AND METHODS: Ninety-five individuals initiating HIV-related primary care.
      RESULTS: Dermatologic manifestations were found in 82 patients (86%). The most
      common conditions were dermatophytosis in 32 patients (34%), oral hairy
      leukoplakia in 22 (23%), and folliculitis in 18 (19%). Well-described HIV
      associated dermatologic manifestations such as Kaposi sarcoma, herpes zoster, and
      psoriasis were uncommon. CONCLUSIONS: The high prevalence of treatable skin
      disorders found in HIV-infected patients underscores the importance of careful
      and complete skin examination as a fundamental aspect of the initial clinical
      evaluation in this population.

PMID- 10405694
TI  - Preliminary comparison of the endoscopic transnasal vs the sublabial transseptal
      approach for clinically nonfunctioning pituitary macroadenomas.
AB  - OBJECTIVE: To assess the advantages and disadvantages of an endoscopic transnasal
      approach to pituitary surgery for a select group of clinically nonfunctioning
      macroadenomas and to compare results of this approach with the sublabial
      transseptal approach at a single institution. PATIENTS AND METHODS: We
      retrospectively reviewed the records of 26 patients with clinically
      nonfunctioning pituitary macroadenomas approached endoscopically and 44 matched
      control patients with the same tumors approached sublabially between January 1,
      1995, and October 31, 1997. RESULTS: At baseline, the groups were not
      significantly different for age, sex distribution, number of comorbid conditions,
      visual field defects, degree of anterior pituitary insufficiency, or preoperative
      assessment of tumor volume or invasiveness. Mean (SD) operative times were
      significantly reduced in the endoscopic group vs the sublabial group: 2.7 (0.7)
      hours vs 3.4 (0.9) hours (P < .001). Postoperative assessment of surgical
      resection and postoperative alterations of anterior pituitary function or visual
      fields were not significantly different between groups, and complication rates
      were similar in both groups. CONCLUSION: This endoscopic transnasal approach to
      pituitary resection results in significantly shorter operative time without
      compromising the extent of tumor resection. The distinct disadvantage of this
      approach is an off-center view of the sella and a diminished working channel to
      the sella turcica. For these reasons, the endoscopic approach or its variation is
      an alternative to the sublabial approach but should be considered only by
      experienced pituitary neurosurgeons.

PMID- 10405695
TI  - Pulmonary arteriovenous fistulas: Mayo Clinic experience, 1982-1997.
AB  - OBJECTIVE: To describe the results of analysis of clinical, physiologic,
      diagnostic, and therapeutic aspects and complications in patients with pulmonary
      arteriovenous fistulas (PAVFs). PATIENTS AND METHODS: Retrospective review of
      medical records of all patients with the diagnosis of PAVF evaluated at Mayo
      Clinic Rochester from 1982 through 1997. Demographic characteristics, presence or
      absence of hereditary hemorrhagic telangiectasia, clinical features, and results
      of imaging studies and blood gas analyses, treatments, and complications related
      to PAVFs were reviewed. RESULTS: Among the 93 patients, 44 were male and 49
      female. The mean age at the time of evaluation was 40 years (range, 5-83 years).
      Fifteen patients (16%) were asymptomatic. History of hereditary hemorrhagic
      telangiectasia was present in 52 patients (56%). Notable clinical findings
      included epistaxis in 46 (49%), hemoptysis in 14 (15%), cyanosis in 27 (29%),
      clubbing in 18 (19%), dyspnea in 53 (57%), and pulmonary bruits/murmurs in 32
      (34%). Chest x-ray films with or without tomograms showed abnormal findings in 87
      (94%), of which 68 (73%) suggested PAVF. Polycythemia was detected in 12 (13%).
      Pretherapy arterial PO2 measured on room air averaged 56 mm Hg (range, 32-95 mm
      Hg), and the posttherapy PO2 averaged 77 mm Hg (range, 46-110 mm Hg).
      Echocardiography with indocyanine green dye was diagnostic of extracardiac right
      to-left shunt in 26 (90%) of 29 patients tested. Diagnostic studies revealed
      single lesions in 32 patients (34%) and multiple lesions in 61 (66%). The most
      prominent complications of the disease were neurologic events in 34 patients
      (37%). These complications included transient ischemic attacks, hemiplegia, brain
      abscesses, and seizures. Surgical resection alone was carried out in 18 patients
      (19%), embolization therapy alone in 41 (44%), and both therapies in 7 (8%). The
      48 patients treated with embolization required 78 embolization sessions with more
      than 200 lesions occluded. Complications of treatment included postembolization
      hemothorax in 1 patient and right-sided hemiparesis in another patient. Follow-up
      disclosed that 1 patient died from PAVF-related complications. CONCLUSIONS: Among
      our patients with PAVFs, hereditary hemorrhagic telangiectasia was observed in
      more than half and neurologic complications in more than one third. Because of
      the considerable risk of neurologic and other complications, definitive treatment
      should be considered in patients with PAVFs. Embolization is currently the
      preferred treatment in most patients. Frequent follow-up of treated patients is
      necessary because PAVFs tend to increase both in number and in size over time.

PMID- 10405696
TI  - Detection of preclinical Parkinson disease in at-risk family members with use of
      [123I]beta-CIT and SPECT: an exploratory study.
AB  - OBJECTIVE: To explore whether the radioligand 2 beta-carboxymethoxy-3 beta-(4
      [123I] iodophenyl) tropane ([123I]beta-CIT) and single-photon emission computed
      tomography (SPECT) can detect decreased striatal uptake in at-risk relatives of
      patients with Parkinson disease (PD). PATIENTS AND METHODS: Ten PD patients, 10
      at-risk first-degree relatives of PD patients, and 10 controls underwent
      [123I]beta-CIT and SPECT brain imaging. Their striatal uptake ratios were
      compared. RESULTS: Age-adjusted specific to nonspecific striatal uptake ratios
      were lower in patients compared with controls and with relatives; however, ratios
      were similar in relatives and controls. Among relatives, ratios were consistently
      lower in subgroups postulated to be at higher risk for preclinical PD.
      CONCLUSION: Our findings provide preliminary support that [123I]beta-CIT and
      SPECT may detect decreased striatal uptake in relatives of PD patients postulated
      to be at higher risk for PD.

PMID- 10405697
TI  - British physician suggests cure for scurvy.

PMID- 10405698
TI  - Tumor imaging via indium 111-labeled DTPA-adenosylcobalamin.
AB  - Vitamin B12 is essential for life. Lack of it results in pernicious anemia and
      death. Conversely, the demand for vitamin B12 increases in rapidly dividing
      tumors. This is secondary to the direct involvement of vitamin B12 in
      mitochondrial metabolism as well as its indirect role in the production of
      thymidylate and S-adenosylmethionine. The latter 2 substances are needed for DNA
      synthesis and cellular methylation reactions, respectively. Novel radiolabeling
      of adenosylcobalamin has proven to be useful in the imaging of transplanted and
      spontaneous tumors in animals. Herein, we describe what we believe to be the
      first human to have imaging with conventional gamma cameras of vitamin B12
      metabolism in a breast tumor.

PMID- 10405699
TI  - Acute hepatitis due to fluoxetine therapy.
AB  - Fluoxetine-induced hepatotoxicity is generally considered of minimal clinical
      importance and is not well recognized. Asymptomatic increases in liver enzyme
      values have been observed in 0.5% of patients who take long-term fluoxetine
      therapy. This report details 2 cases of acute hepatitis believed to be caused by
      fluoxetine. Three cases of acute hepatitis caused by fluoxetine have been
      reported previously. The mechanism of fluoxetine-induced hepatotoxicity is
      unknown. Although routine monitoring of liver function may not be cost-effective,
      physicians should be alert to the possibility of fluoxetine-associated hepatitis
      and consider early discontinuation of the drug if this condition is suspected.

PMID- 10405700
TI  - Autonomic failure and proximal skeletal myopathy in a patient with primary
      Sjogren syndrome.
AB  - Autonomic failure and proximal skeletal myopathy are rare features of the Sjogren
      syndrome (SS). We describe a 51-year-old woman with primary SS who had
      development of esophageal dysmotility, urinary retention, severe orthostatism,
      and skeletal myopathy during a 3-month period after the diagnosis of SS. Her
      symptoms and signs responded well to corticosteroid therapy. Although dysfunction
      of the peripheral nervous system has a prevalence rate of 20% in patients with
      SS, most commonly the nerve dysfunction is a sensory deficit, and autonomic
      neuropathy is less frequent. Autonomic neuropathy due to SS may be underreported.
      The cause of our patient's myopathy remains undetermined. We speculate that the
      myopathy was due to either a form of polymyositis or an immune-mediated
      neuropathy with muscle involvement.

PMID- 10405701
TI  - Bronchial mucormycosis with progressive air trapping.
AB  - A previously healthy 70-year-old woman developed fever, cough, and exertional
      dyspnea. Her symptoms progressed over a 2-month period despite treatment by her
      primary care physician with 2 courses of oral antibiotics and the addition of
      prednisone. Hypoxemia and the finding of hyperglycemia with mild ketoacidosis led
      to hospital admission. Serial chest radiographs demonstrated diffuse
      heterogeneous pulmonary opacities and progressive air trapping in the right lower
      lobe. Fiberoptic bronchoscopy revealed a deep penetrating ulcer with exposed
      bronchial cartilage of the bronchus intermedius and dynamic airway obstruction
      with complete closure during expiration. Biopsy of the ulcer revealed Rhizopus
      arrhizus. Respiratory failure stabilized with the patient on conventional
      mechanical ventilation and receiving amphotericin B. Before surgery could be
      performed, Pseudomonas aeruginosa pneumonia and septic shock developed, and the
      patient died.

PMID- 10405702
TI  - Treatment of migraine headaches.
AB  - Migraine headaches are common and costly. Patients with migraine frequently seek
      medical attention from primary care physicians. Although effective therapy is
      available, migraine is underdiagnosed and undertreated. The 3 main forms of
      management are avoidance of migraine triggers, treatment of the acute attack with
      medications, and regular use of preventive medications. Although changes in
      lifestyle can help to prevent some migraine attacks, the mainstay of treatment is
      the use of medications taken early during the attack. A wide variety of single
      ingredient and combination over-the-counter and prescription medications are now
      available. Especially effective are the new selective serotonin (5
      hydroxytryptamine1 receptor) agonists such as sumatriptan. For patients who have
      frequent and severe migraine headaches despite the use of acute treatment,
      preventive medications, including beta-adrenergic blockers, calcium channel
      blockers, tricyclic antidepressants, and one anticonvulsant, should be
      considered. The vast majority of patients with migraine can be helped.

PMID- 10405703
TI  - Pharmacotherapeutic advances in the treatment of erectile dysfunction.
AB  - An estimated 20 million to 30 million American men have erectile dysfunction
      (ED). The past 2 decades of research defining erectile physiology and
      investigating the pathogenesis of ED have led to the recognition of a
      predominantly vascular basis for organic male sexual dysfunction. These
      scientific advances have laid the foundation for the advent of pharmacotherapies.
      The Food and Drug Administration approval of intracavernosal, intraurethral, and
      oral pharmacotherapeutics for ED has revolutionized non-surgical management of
      this condition. The primary care physician is faced with the challenges of
      diagnosis and treatment of ED, as well as referral of patients to urologists. In
      this article, erectile physiology and pathophysiology are reviewed, and
      pharmacotherapeutics are classified and discussed by their mechanisms of action
      and the means of administration. A thorough understanding of these new
      therapeutic options is key to the accurate diagnosis and successful treatment of
      ED and maximal patient satisfaction and care.

PMID- 10405704
TI  - 72-year-old man with exertional chest discomfort.

PMID- 10405705
TI  - The tetracyclines.
AB  - The tetracyclines, among the first of the antibiotics to become available 50
      years ago, remain widely used. Tetracyclines have bacteriostatic activity against
      a wide variety of pathogens that are responsible for many common and some exotic
      infections. They are particularly valuable in the treatment of atypical pneumonia
      syndromes, chlamydial genital infections, rickettsial infection (Rocky Mountain
      spotted fever, typhus, Q fever), Lyme disease, and ehrlichiosis. On the basis of
      pharmacokinetic considerations, doxycycline is the preferred agent among the
      tetracycline congeners. Minocycline may have a limited role in the treatment of
      methicillin-resistant staphylococcal disease in situations in which an oral
      antimicrobial agent may be appropriate. The tetracyclines are generally
      contraindicated during pregnancy and childhood because of their association with
      dental staining and interference with bone growth. Photosensitivity may occur
      with some tetracyclines, and several drug and food interactions may limit
      gastrointestinal absorption.

PMID- 10405706
TI  - Trimethoprim-sulfamethoxazole.
AB  - After 25 years of use in the United States, trimethoprim-sulfamethoxazole (TMP
      SMX) is widely prescribed for various indications. By virtue of sequential
      blockade of microbial folic acid synthesis, the antimicrobial combination has
      excellent in vitro inhibitory activity against many common respiratory and
      urinary tract pathogens, as well as many nosocomial infecting strains. In
      patients infected with the human immunodeficiency virus, TMP-SMX provides
      prophylactic and therapeutic potency against Pneumocystis carinii but at the risk
      of frequent side effects. TMP-SMX is also used for treatment of pulmonary and
      disseminated nocardiosis and some forms of Wegener's granulomatosis, as well as
      for prophylaxis of spontaneous bacterial peritonitis. Increasing bacterial
      resistance and concern about occasional severe adverse effects suggest that the
      usefulness of TMP-SMX may diminish in the future.

PMID- 10405707
TI  - Dr Dickinson Ober Wheelock--a case of sporadic insulinoma or multiple endocrine
      neoplasia type 1?

PMID- 10405708
TI  - Determination of the cause of death: its relationship to cardiac disease and
      autopsy findings.

PMID- 10405709
TI  - Hypereosinophilic syndrome or chronic eosinophilic leukemia?

PMID- 10405710
TI  - Medically induced gingival hyperplasia.

PMID- 10405711
TI  - Radiation-induced pneumonitis outside the radiation field.

PMID- 10405712
TI  - Mycobacterial lung infections.

PMID- 10405713
TI  - Pulmonary emphysema: imaging assessment of lung volume reduction surgery.

PMID- 10405714
TI  - Tissue characterization in the female pelvis by means of MR imaging.
AB  - Pelvic imaging techniques such as computed tomography and ultrasonography provide
      a limited capability for tissue characterization. Fat, fluid, and calcification,
      for example, can be identified on the basis of parameters such as x-ray
      attenuation, echogenicity, and sound attenuation. Because of the many tissue
      parameters, such as T1, T2, magnetic susceptibility, and chemical shift, that
      contribute to signal intensity, magnetic resonance (MR) imaging may afford an
      ability to identify a wider array of specific tissues. The purpose of this
      article is to review the ability of MR imaging to help identify various types of
      soft tissue and to provide an approach to interpretation of MR images of the
      female pelvis through tissue characterization. Lipid, fluid, hemorrhage, smooth
      muscle, fibrosis, solid malignant tissue, and hydrated soft tissue (including
      edema, mucin, and myxomatous tissue) have typical MR imaging properties, and
      their presence in a mass can often be established on MR images. Consideration of
      the tissue composition of various pathologic processes in the pelvis can result
      in more systematic approaches to image interpretation and thus narrow the
      differential diagnosis.

PMID- 10405715
TI  - Diagnosis and staging of ovarian cancer: comparative values of Doppler and
      conventional US, CT, and MR imaging correlated with surgery and histopathologic
      analysis--report of the Radiology Diagnostic Oncology Group.
AB  - PURPOSE: To determine the optimal imaging modality for diagnosis and staging of
      ovarian cancer. MATERIALS AND METHODS: Two hundred eighty women suspected to have
      ovarian cancer were enrolled in a prospective study before surgery. Doppler
      ultrasonography (US), computed tomography (CT), and magnetic resonance (MR)
      imaging were used to evaluate the mass; conventional US, CT, and MR imaging were
      used to stage spread. RESULTS: All three modalities had high accuracy (0.91) for
      the overall diagnosis of malignancy. In the ovaries, the accuracy of MR imaging
      (0.91) was higher than that of CT and significantly higher than that of Doppler
      US (0.78). In the extraovarian pelvis and in the abdomen, conventional US, CT,
      and MR imaging had similar accuracies (0.87-0.95). In differentiation of disease
      confined to the pelvis from abdominal spread, the specificity of conventional US
      (96%) was higher than that of CT and significantly higher than that of MR imaging
      (88%), whereas the sensitivities of MR imaging (98%) and CT (92%) were
      significantly higher than that of conventional US (75%). CONCLUSION: MR imaging
      is superior to Doppler US and CT in diagnosis of malignant ovarian masses. There
      is little variation among conventional US, CT, and MR imaging as regards staging.

PMID- 10405716
TI  - Renal neoplasms amenable to partial nephrectomy: MR imaging.
AB  - PURPOSE: To determine the magnetic resonance (MR) imaging characteristics of
      renal lesions in patients who undergo technically successful partial nephrectomy.
      MATERIALS AND METHODS: Between February 1991 and September 1997, 38 patients (41
      lesions) who underwent partial nephrectomy at a single institution were
      preoperatively evaluated with contrast material-enhanced, multiplanar, surface
      coil MR imaging. Imaging findings that could affect the decision to perform
      partial nephrectomy were retrospectively evaluated: tumor size; tumor location;
      presence of pseudocapsule; suspected tumor invasion of renal sinus fat, renal
      collecting system, renal vein, or perinephric fat; and morphologic and
      physiologic status of the contralateral kidney. Correlation was made with
      surgical and pathologic findings. RESULTS: Thirty-three of 41 lesions (80%) were
      renal cell carcinomas, five were oncocytic neoplasms (12%), two were hemorrhagic
      cysts (5%), and one was an angiomyolipoma (2%). Twenty-four of 41 (59%) lesions
      had pseudocapsules. In most cases, the perinephric fat (n = 38 [93%]), the renal
      sinus fat (n = 31 [76%]), and the renal collecting system (n = 39 [95%]) were
      correctly interpreted as being uninvolved by tumor. CONCLUSION: Renal neoplasms
      amenable to partial nephrectomy can be identified and characterized with contrast
      enhanced, multiplanar, surface-coil MR imaging.

PMID- 10405717
TI  - Pheochromocytomas: imaging with 2-[fluorine-18]fluoro-2-deoxy-D-glucose PET.
AB  - PURPOSE: To assess the sensitivity of positron emission tomography (PET) with 2
      [fluorine-18]fluoro-2-deoxy-D-glucose (FDG) in pheochromocytomas and,
      secondarily, to compare images obtained with FDG PET to those obtained with
      metaiodobenzylguanidine (MIBG) scintigraphy. MATERIALS AND METHODS: Twenty-nine
      patients with one or more known or subsequently proved pheochromocytomas
      underwent FDG PET (35 scans) and MIBG scintigraphy (35 scans). Tumor uptake of
      FDG was quantified on positive PET scans. RESULTS: Tumor uptake of FDG was
      detected in 22 of 29 patients. Most benign (seven of 12 patients) and most
      malignant (15 of 17 patients) pheochromocytomas and their metastases avidly
      concentrated FDG. In four patients whose pheochromocytomas failed to accumulate
      MIBG, uptake of FDG in the tumors was intense. For the majority of the 16
      patients whose tumors concentrated both agents, however, ratings for MIBG images
      compared to FDG PET images for delineation of the tumor in comparison to
      background and normal organ accumulation were superior for nine patients (56%)
      and as good or better for 14 (88%). CONCLUSION: Most pheochromocytomas accumulate
      FDG. Uptake is found in a greater percentage of malignant than benign
      pheochromocytomas. FDG PET is especially useful in defining the distribution of
      those pheochromocytomas that fail to concentrate MIBG.

PMID- 10405718
TI  - Congenital chest lesions: diagnosis and characterization with prenatal MR
      imaging.
AB  - PURPOSE: To evaluate prenatal magnetic resonance (MR) imaging for diagnosis of
      fetal chest masses and to determine if MR imaging provides information in
      addition to that of ultrasonography (US). MATERIALS AND METHODS: Eighteen
      pregnant women were referred for MR imaging of possible fetal chest tumors seen
      at US (16 congenital cystic adenomatoid malformation [CCAM], two bronchopulmonary
      sequestration [BPS]). The presence, position, size, and characteristics of masses
      were determined and correlated with postnatal results. RESULTS: The MR imaging
      diagnoses were three cases of congenital diaphragmatic hernia, nine of CCAM, two
      of BPS, and one each of foregut cyst, lung atresia, tracheal atresia, and
      bronchial stenosis. MR imaging results were in agreement with US results in nine
      fetuses and in disagreement in nine. MR imaging diagnoses were confirmed at
      surgery or autopsy in 17 fetuses. MR imaging results led to an error in diagnosis
      in one fetus with BPS. CONCLUSION: Fetal chest masses had characteristic MR
      imaging appearances. MR imaging was accurate for distinguishing congenital
      diaphragmatic hernia from CCAM and was useful for less common diagnoses and
      determination of the origin of very large chest tumors. Prenatal diagnosis was
      changed in some patients owing to MR results and affected treatment and
      counseling of parents. MR imaging is a valuable adjunct to US for prenatal
      diagnosis of fetal chest masses.

PMID- 10405719
TI  - Advanced emphysema: preoperative chest radiographic findings as predictors of
      outcome following lung volume reduction surgery.
AB  - PURPOSE: To determine whether preoperative chest radiographic findings alone can
      reliably predict which patients will achieve the best functional outcome of lung
      volume reduction surgery. MATERIALS AND METHODS: The preoperative chest
      radiographs obtained in 57 patients who had undergone lung volume reduction
      surgery were retrospectively scored by five blinded readers for severity and
      distribution of emphysema, evidence of lung compression, disease heterogeneity,
      and other features. Comparisons were made with the 3-6-month postoperative
      functional outcome for each patient. RESULTS: High disease heterogeneity (score >
      2) and unequivocal lung compression (score 1) both were 100% predictive of a
      favorable outcome (FEV1 increase, > or = 30%). Low heterogeneity (score < 1) was
      94% predictive of an unfavorable outcome (FEV1 increase < 30%), as was a lack of
      lung compression, which was 92% predictive of an unfavorable outcome. These two
      features also correlated with an improved 6-minute walk test result, although
      this correlation was weaker. CONCLUSION: Chest radiography alone may be
      sufficient for initial screening. High disease heterogeneity and lung compression
      on chest radiographs are highly predictive of a favorable functional outcome.

PMID- 10405720
TI  - Lung cancer staging and management: comparison of contrast-enhanced and
      nonenhanced helical CT of the thorax.
AB  - PURPOSE: To determine whether contrast material-enhanced helical computed
      tomography (CT) of the thorax and upper abdomen changes the tumor stage and
      management compared with nonenhanced helical CT in patients with newly diagnosed
      lung cancer. MATERIALS AND METHODS: During 15 months, any patient in whom lung
      cancer was strongly suspected or newly diagnosed and who was scheduled for
      thoracic CT was considered eligible for the study. All patients underwent
      nonenhanced thoracic helical CT from the lung apices through the adrenal glands
      and then contrast-enhanced thoracic helical CT from the lung apices through the
      entire liver. Each study was read independently, and the thoracic radiologic
      stage was determined. Tissue sampling was performed and the final pathologic
      stage assigned. RESULTS: Ninety-six patients had a final pathologic diagnosis of
      lung cancer. There was agreement in stage between the nonenhanced and contrast
      enhanced examinations in 92 of the 96 patients. In three patients, the tumor
      stage at nonehanced CT increased at contrast-enhanced CT, from IA to IIA (n = 1),
      IIB to IV (n = 1), and IIIB to IV (n = 1). In one patient, the tumor stage
      decreased from IIIB to IIB. There was no substantial change in management of any
      patient. CONCLUSION: The results suggest that contrast-enhanced thoracic CT
      through the liver for staging lung cancer rarely changes the tumor stage
      determined with nonenhanced CT through the adrenal glands and does not
      substantially influence management decisions.

PMID- 10405721
TI  - Detection failures in spiral CT screening for lung cancer: analysis of CT
      findings.
AB  - PURPOSE: To clarify the computed tomographic (CT) findings and the progression of
      minute lung cancers that were missed at initial spiral CT screening but were
      later detected. MATERIALS AND METHODS: The findings from seven patients with lung
      cancer that was missed at the initial spiral CT screening were reviewed.
      Retrospective CT findings, time to detection, cell type, and pathologic stage
      were evaluated. RESULTS: Minute lung cancers missed at early spiral CT included a
      nodule among the shadows of old tuberculosis (n = 2), a faint nodule with high
      attenuation in the center of the nodule (n = 1), an increase in attenuation just
      adjacent to an axial peripheral pulmonary vessel (n = 1) and adjacent to a
      craniocaudal peripheral pulmonary vessel (n = 1), and a minute faint nodule (n =
      2). The time to detection ranged from 6 to 18 months. At pathologic examination,
      six cancers were stage I, and one was stage II. CONCLUSION: Minute nodules of
      lung cancer that are near the threshold of detectability may be missed at spiral
      CT screening. It is important to examine noncalcified nodules with thin-section
      CT even when lesions from prior disease, such as those from old tuberculosis,
      exist and to evaluate the shadows of pulmonary vessels carefully. A follow-up
      examination is highly recommended.

PMID- 10405722
TI  - The signet ring sign.

PMID- 10405723
TI  - Pericardial sinuses and recesses: findings at electrocardiographically triggered
      electron-beam CT.
AB  - PURPOSE: To evaluate the appearance of the pericardial sinuses and recesses at
      electrocardiographically triggered electron-beam computed tomography (CT).
      MATERIALS AND METHODS: Findings in 100 patients without known pericardial disease
      were reviewed. The patients underwent electron-beam CT of the heart because of
      suspected coronary arterial disease. Incremental electrocardiographically
      triggered images were obtained with a 100-msec exposure time and 1.5-mm section
      thickness after intravenous administration of contrast material. The appearance
      of the pericardial sinuses and recesses was determined. RESULTS: In each patient,
      at least one of the sinuses was visible at CT. The transverse and oblique sinuses
      (or one of their recesses) were depicted in 95 and 89 patients, respectively. The
      left pulmonic recess was depicted in 81 patients; inferior aortic recess, 80
      patients; posterior pericardial recess, 67 patients; left pulmonic vein recess,
      60 patients; right pulmonic recess, 51 patients; superior aortic recess, 47
      patients; right pulmonic vein recess, 29 patients; and postcaval recess, 23
      patients. CONCLUSION: Pericardial sinuses and recesses are frequently depicted on
      electrocardiographically triggered electron-beam CT images. Knowledge of their
      locations is helpful in the differentiation of normal pericardium from
      pericardial effusions and mediastinal processes such as lymph nodes.

PMID- 10405724
TI  - Clinically suspected pulmonary embolism: use of bilateral lower extremity US as
      the initial examination--a prospective study.
AB  - PURPOSE: To determine the prevalence of deep venous thrombosis (DVT) and evaluate
      the use of symptoms and risk factors as selection criteria in the patient
      population undergoing lower extremity ultrasonography (US) as an initial
      examination for suspected pulmonary embolism (PE). MATERIALS AND METHODS: One
      hundred eighty-two consecutive patients referred for bilateral lower extremity US
      as the first examination for suspected PE were evaluated prospectively for
      predisposing factors and symptoms of DVT. Patients were placed into four groups:
      group 1, no symptoms or risk factors; group 2, both symptoms and risk factors;
      group 3, only risk factors; group 4, only symptoms. The prevalence of DVT
      detected at lower extremity US in each group was determined. RESULTS: There were
      89 patients in group 1, 12 in group 2, 43 in group 3, and 38 in group 4, with a
      DVT prevalence of 0%, 25%, 14%, and 24%, respectively. There was no significant
      difference in DVT prevalence between groups with symptoms or risk factors but a
      significant difference between these groups and the group lacking both symptoms
      and risk factors. CONCLUSION: Lower extremity US as the initial examination in
      patients suspected of having PE should be used only in those patients who have
      symptoms or risk factors for DVT. This would substantially decrease the number of
      examinations performed without a decline in DVT detection.

PMID- 10405725
TI  - Stenosis of the main artery supplying an organ: effect of end-organ vascular
      resistance on the poststenotic peak systolic velocity in an in vitro hydraulic
      model at Doppler US.
AB  - PURPOSE: To test the hypothesis that increased end-organ vascular resistance
      reduces blood flow to the kidney, thus reducing the mean velocity in the renal
      artery and secondarily lowering the peak systolic velocity (PSV). MATERIALS AND
      METHODS: An in vitro hydraulic model with a pulsatile pump, blood-mimicking
      fluid, interchangeable stenoses, and variable compliance and resistance was used
      to investigate the relationship between end-organ vascular resistance and
      poststenotic PSV. RESULTS: Poststenotic PSV was mildly dependent on end-organ
      vascular resistance and decreased with increasing resistance. CONCLUSION: The
      results help explain some of the reported variability from using poststenotic PSV
      to detect hemodynamically significant renal arterial stenoses, but the effect is
      not great enough to completely explain the variability. Other factors not
      investigated in this study must be at work as well.

PMID- 10405726
TI  - Shark liver oil-induced lipoid pneumonia in pigs: correlation of thin-section CT
      and histopathologic findings.
AB  - PURPOSE: To evaluate sequential changes in thin-section computed tomographic (CT)
      findings after inducement of lipoid pneumonia and provide the histopathologic
      bases of these findings. MATERIALS AND METHODS: Shark liver oil was administered
      to 12 sites in seven pigs. Thin-section CT scans were obtained within 1 hour and
      at 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 16 weeks after oil
      administration. Scans were assessed for opacity, distribution, location at the
      lobular level, extent, and volume of the lesions. The CT number in consolidation
      areas also was measured. Findings at CT were correlated with those in the
      histopathologic specimens. RESULTS: Diffuse ground-glass opacity was noted on all
      immediately obtained scans. The opacity of the lesions was highest at 1 week;
      then it decreased gradually to an area of ground-glass opacity. The extent and
      volume of the lesions decreased at follow-up CT. Histopathologically, the lesions
      showed a lobular distribution sharply demarcated from the normal lungs. The
      lobules of decreased volume showed residual thickening of the alveolar walls with
      bronchiolectasis and mild collagen deposition of the interlobular septa.
      Pathologic examination of the low-attenuating consolidation area at CT revealed
      evidence of partial aeration. CONCLUSION: Thin-section CT findings of lipoid
      pneumonia include ground-glass opacity and airspace consolidation, followed by
      complete or incomplete resolution with volume loss and septal thickening. Low
      attenuating consolidation at CT does not always indicate the presence of fat.

PMID- 10405727
TI  - Contrast medium-induced pulmonary edema is aggravated by silicone contamination
      in rats.
AB  - PURPOSE: To examine the effect of silicone contamination, which occurs in
      clinical settings during vial preparation with disposable syringes, on contrast
      medium-induced pulmonary edema in rats. MATERIALS AND METHODS: Ioxaglate,
      ioversol, and iohexol, silicone-containing physiologic saline solutions, and
      three silicone-containing contrast media were separately, intravenously injected
      at 1.5 mL/min in rats. Pulmonary edema was evaluated as changes in the relative
      lung weight and in the water, sodium, and potassium contents of the lung.
      RESULTS: Intravenous injection of ioxaglate induced marked pulmonary edema, even
      with a dose of only 4 g of iodine per kilogram of body weight. In contrast,
      ioversol and iohexol induced significant pulmonary edema only after the injection
      of large doses (6 g of iodine per kilogram; P < .05). The injection of 4
      microL/mL silicone-containing physiologic saline at a dose of 18.75 mL/kg also
      produced marked pulmonary edema, whereas doses of 6.25 and 12.5 mL/kg showed no
      significant influence. The addition of an ineffective dose (12.5 mL of
      physiologic saline per kilogram of body weight) of silicone in contrast medium
      substantially aggravated the pulmonary edema induced by the contrast medium
      alone; this phenomenon was also confirmed with morphologic observation.
      CONCLUSION: Ionic contrast media are more toxic to the endothelial cells than are
      nonionic contrast media. Silicone contamination might be one of the causes of
      pulmonary edema after intravenous injection. However, caution must be exercised
      in extrapolating these results to humans.

PMID- 10405728
TI  - Iliotibial band friction syndrome: MR imaging findings in 16 patients and MR
      arthrographic study of six cadaveric knees.
AB  - PURPOSE: To define magnetic resonance (MR) imaging findings in patients with the
      iliotibial band friction syndrome (ITBFS) and to correlate these findings with
      anatomic features defined at magnetic resonance (MR) arthrography in cadavers.
      MATERIALS AND METHODS: The anatomic relationship of the iliotibial tract (ITT) to
      the lateral recesses of the knee joint and the lateral femoral epicondyle was
      investigated with MR arthrography at full extension and at 30 degrees and 60
      degrees of knee flexion in six cadaveric knees. Seventeen MR imaging studies in
      16 patients with ITBFS were evaluated. RESULTS: In the cadaveric study, no
      interference of the lateral synovial recess with the lateral femoral epicondyle
      at full extension and at 30 degrees and 60 degrees of knee flexion was observed.
      In all specimens, correlation of MR images with macroscopic and microscopic
      sections revealed no primary bursa between the lateral femoral epicondyle and the
      ITT. In clinical studies, MR imaging findings of poorly defined signal intensity
      abnormalities or circumscribed fluid collections were located in a
      compartmentlike space confined laterally by the ITT and medially by the
      meniscocapsular junction, the lateral collateral ligament, and the lateral
      femoral epicondyle. CONCLUSION: MR imaging accurately depicts the compartmentlike
      distribution of signal intensity abnormalities in patients with ITBFS.

PMID- 10405729
TI  - Bicipitoradial bursitis: MR imaging findings in eight patients and anatomic data
      from contrast material opacification of bursae followed by routine radiography
      and MR imaging in cadavers.
AB  - PURPOSE: To use radiography and magnetic resonance (MR) imaging after contrast
      material opacification of the bursae in cadaveric specimens to demonstrate the
      anatomy of the bicipitoradial bursa and to report MR imaging findings in patients
      with bicipitoradial bursitis. MATERIALS AND METHODS: Bicipitoradial bursa in
      eight cadaveric elbows were injected with a solution containing gadodiamide,
      iodinated contrast agent, and gelatin. Radiographs and MR images were obtained in
      each specimen, with both supination and pronation of the forearm. The morphology
      and relationships of the bursa were studied. Anatomic sections subsequently were
      obtained. MR imaging studies in eight patients with bicipitoradial bursitis were
      also evaluated. RESULTS: The bicipitoradial bursa revealed a smooth outline and a
      wide base along the superficial aspect of the radius. The mean volume of contrast
      material that could be injected before extravasation was 4 mL. The mean size of
      the bursa was 1.8 x 2.5 cm. The bicipitoradial bursa enveloped the biceps tendon,
      with internal septation seen in two cases. Displacement of the superficial branch
      of the radial nerve by the bursa was found in two specimens. Communication
      between the bicipitoradial bursa and elbow joint was not observed. In patients,
      MR imaging demonstrated fluid collections in the bicipitoradial bursa in all
      cases, with compression of branches of the radial nerve in two cases. CONCLUSION:
      The anatomy of the bicipitoradial bursa is demonstrated with radiography and MR
      imaging of bursae. MR imaging allows accurate diagnosis of bicipitoradial
      bursitis and its effects on adjacent structures.

PMID- 10405730
TI  - Cervical spine screening with CT in trauma patients: a cost-effectiveness
      analysis.
AB  - PURPOSE: To investigate the cost-effectiveness of computed tomography (CT)
      relative to radiography for cervical spine screening in trauma patients.
      MATERIALS AND METHODS: A decision analysis model was constructed to compare the
      incremental cost-effectiveness of radiography and CT as primary cervical spine
      screening modalities in trauma patients. Analyses were performed from a societal
      perspective, and probability and cost estimates from the literature and
      institutional experience were used. In separate cost-effectiveness analyses,
      hypothetical cohorts of trauma patients from three defined clinical scenarios
      were considered: high, moderate, and low risk for cervical spine fracture.
      Outcome measures included cases of paralysis prevented, total cost of screening
      strategies, and incremental cost-effectiveness ratios. RESULTS: In high-risk
      patients, screening with CT is a dominant strategy that prevents cases of
      paralysis and saves money for society. In moderate-risk patients, screening with
      CT is cost-effective with reference-case assumptions and within the range of most
      sensitivity analyses. In the low-risk group, CT screening helps prevent cases of
      paralysis, but the incremental cost-effectiveness ratio is high (> $80,000 per
      quality-adjusted life year). CONCLUSION: CT is the preferred cervical spine
      screening modality in trauma patients at high and moderate risk for cervical
      spine fracture.

PMID- 10405731
TI  - Diagnosis please. Case 12: Mazabraud syndrome.

PMID- 10405732
TI  - Central nervous pathway for acupuncture stimulation: localization of processing
      with functional MR imaging of the brain--preliminary experience.
AB  - PURPOSE: To characterize the central nervous system (CNS) pathway for acupuncture
      stimulation in the human brain by using functional magnetic resonance (MR)
      imaging. MATERIALS AND METHODS: Functional MR imaging of the whole brain was
      performed in two groups of nine healthy subjects during four stimulation
      paradigms: real acupuncture at acupoints ST.36 (on the leg) and LI.4 (on the
      hand) and control stimulations (minimal acupuncture and superficial pricking on
      the leg). Stimulations were performed in semirandomized, balanced order nested
      within two experiments. Psychophysical responses (pain, De-Qi effect
      [characteristic acupuncture effect of needle-manipulation sensation], anxiety,
      and unpleasantness) and autonomic responses were assessed. Talairach coordinates
      transformed imaging data were averaged for a group analysis. RESULTS: Acupuncture
      at LI.4 and ST.36 resulted in significantly higher scores for De-Qi and in
      substantial bradycardia. Acupuncture at both acupoints resulted in activation of
      the hypothalamus and nucleus accumbens and deactivation of the rostral part of
      the anterior cingulate cortex, amygdala formation, and hippocampal complex;
      control stimulations did not result in such activations and deactivations.
      CONCLUSION: Functional MR imaging can demonstrate the CNS pathway for acupuncture
      stimulation. Acupuncture at ST.36 and LI.4 activates structures of descending
      antinociceptive pathway and deactivates multiple limbic areas subserving pain
      association. These findings may shed light on the CNS mechanism of acupuncture
      analgesia and form a basis for future investigations of endogenous pain
      modulation circuits in the human brain.

PMID- 10405733
TI  - Stereotactic radiosurgical pallidotomy and thalamotomy with the gamma knife: MR
      imaging findings with clinical correlation--preliminary experience.
AB  - PURPOSE: To evaluate the temporal evolution and appearance of a radiosurgical
      lesion at magnetic resonance (MR) imaging and the clinical response in patients
      undergoing stereotactic radiosurgical pallidotomy or thalamotomy with the gamma
      knife. MATERIALS AND METHODS: Seventeen patients with medically refractory
      movement disorders underwent stereotactic radiosurgical pallidotomy (n = 2) or
      thalamotomy (n = 15). A single dose of 120-140 Gy was administered to a target in
      the globus pallidus interna or ventralis intermedius thalamic nucleus.
      Postprocedure gadolinium-enhanced MR imaging and clinical assessment were
      performed at 1 month and 3 months. RESULTS: At 3 months, the radiosurgical lesion
      most commonly (n = 11) appeared as a ring-enhancing focus 5 mm or less in
      diameter surrounded by vasogenic edema that extended less than 7 mm in radius
      beyond the target. Five patients had ring-enhancing lesions 7 mm or more in
      diameter; four of these developed symptomatic perilesional edema at 3 (n = 2) or
      8 (n = 2) months after the procedure. Onset of therapeutic effect began
      approximately 4 weeks after treatment. In the 15 patients with tremor, there was
      a mean decline of 2.1 on the Tremor Rating Scale. CONCLUSION: Findings in this
      pilot study suggest that radiosurgical thalamotomy is a promising treatment for
      medically refractory tremor. Three-month follow-up MR studies show a ring
      enhancing lesion surrounded by a variable amount of vasogenic edema.
      Visualization of the radiosurgical lesion and the clinical response are delayed
      compared to that with radio-frequency procedures.

PMID- 10405734
TI  - MR imaging of intraventricular silicone: case report.
AB  - A 42-year-old man with human immunodeficiency viral infection developed
      cytomegaloviral retinitis that was complicated by retinal detachment and was
      treated with an intravitreous injection of silicone. Fifteen months later,
      magnetic resonance imaging revealed intraocular and intraventricular silicone.
      Signal intensity characteristics and chemical shifts of silicone in the two
      locations were identical.

PMID- 10405735
TI  - Localization of the apex of the vagina: implications for radiation therapy
      planning.
AB  - PURPOSE: To evaluate (a) the displacement of the vaginal apex by a rod during
      radiation therapy simulation for gynecologic malignancy and (b) apical
      localization with implanted radiopaque markers. MATERIALS AND METHODS: Metallic
      markers were implanted in the cervix or vaginal cuff in nine patients with
      cervical or endometrial carcinoma who underwent irradiation. In all but one
      patient, radiographs were obtained with and then without the vaginal rod.
      Displacement of the markers relative to bone landmarks was measured. The total
      displacement was the square root of the sum of the squares of displacement in
      each axial direction. RESULTS: All patients showed displacement of the cervical
      markers by the vaginal rod (mean total displacement, 1.9 cm; range, 0.6-3.6 cm).
      The greatest displacement was cephalic (mean, 1.5 cm; range, 0.5-2.4 cm).
      Anteroposterior displacement occurred in all patients but was not as predictable
      as cephalic displacement. Displacement was anterior in five of the eight
      patients, posterior in three patients, and lateral in four patients. CONCLUSION:
      Displacement of the vaginal apex and/or cervix with placement of the vaginal rod
      during simulation was marked in all patients. Use of implanted cervical markers
      to localize the vaginal apex or the cervix during simulation is more accurate
      than use of a vaginal rod.

PMID- 10405736
TI  - Transrectal versus transvaginal abscess drainage: survey of patient tolerance and
      effect on activities of daily living.
AB  - PURPOSE: To evaluate patient perception of pain related to transrectal and
      transvaginal drainage and the catheter's effect on activities of daily living.
      MATERIALS AND METHODS: From July 1993 to August 1997, 22 male and 40 female
      patients (mean age, 41 years; age range, 4-80 years) underwent transrectal or
      transvaginal aspiration or drainage. Fifty-seven drainages were performed. In a
      follow-up survey, patients were asked to score pain experienced during the
      procedure and afterward on a scale of 1-10 and to rate the effect of the catheter
      on their activities of daily living. RESULTS: Twenty-two patients participated in
      the telephone survey. For those able to recall the insertion procedure, the mean
      pain score was 3.2 for transrectal and 5.9 for transvaginal drainage. Mean
      indwelling catheter pain was 1.6 for transrectal and 4.8 for transvaginal
      drainage. Pain after removal was 1.4 for transrectal and 2.3 for transvaginal
      drainage. Only one patient with a transrectal catheter reported severe limitation
      (bowel movement), with no reports of any serious effect on urinating, bathing,
      sitting, or walking. Transvaginally placed catheters caused marked limitation in
      all categories and were more painful than transrectal catheters (P < .05).
      CONCLUSION: Of the transrectal and transvaginal approaches, transrectal is better
      tolerated.

PMID- 10405737
TI  - Transthoracic needle aspiration biopsy: variables that affect risk of
      pneumothorax.
AB  - PURPOSE: To analyze the influence of multiple variables on the rate of
      pneumothorax and chest tube placement associated with transthoracic needle
      aspiration biopsy of the lung. MATERIALS AND METHODS: In 346 patients, 331
      computed tomographically (CT) guided and 24 fluoroscopically guided lung biopsies
      were performed. Variables analyzed were lesion size, depth, and location; number
      of pleural passes; needle size; presence of emphysema; and training level of the
      person who performed the biopsy. RESULTS: Pneumothorax occurred at 144 (40.4%) of
      356 biopsies, including 139 (42.0%) CT-guided and five (21%) fluoroscopically
      guided biopsies. Chest tube placement was needed in 25 (17.4%) of 144 cases of
      pneumothorax (7% of all biopsies). An increased rate of pneumothorax was
      correlated with smaller lesion size (P = .001) and presence of emphysema (P =
      .01). Patients with emphysema were three times as likely to require chest tube
      placement. The pneumothorax rate was 15% (16 of 105) if no aerated lung was
      traversed and approximately 50% if aerated lung was penetrated. Lesion location,
      needle size, number of pleural passes, and level of training were not correlated
      with pneumothorax rate. CONCLUSION: Smaller lesion size and emphysema are
      strongly correlated with occurrence of pneumothorax. Pneumothorax was more than
      three times less frequent if no aerated lung was traversed. After pneumothorax,
      chest tube placements were related to the presence of emphysema.

PMID- 10405738
TI  - Descending thoracic aortic aneurysm: thoracic CT findings after endovascular
      stent-graft placement.
AB  - PURPOSE: To evaluate the usefulness of thoracic computed tomography (CT) after
      placement of an endovascular stent-graft for the treatment of descending thoracic
      aortic aneurysm. MATERIALS AND METHODS: From 1992 to 1996, 85 patients with
      thoracic aortic aneurysm underwent stent-graft placement. In 63 patients,
      thoracic CT scans were obtained both before and within 10 days after placement.
      The CT findings were retrospectively studied, and their clinical effect analyzed.
      In 20 of 63 patients, long-term follow-up CT findings were also evaluated.
      RESULTS: After stent-graft placement in the 63 patients, CT demonstrated an
      increase in pleural effusion in 46 (73%), periaortic changes in 21 (33%),
      perigraft leak in 13 (21%), atelectasis in six (10%), mural thrombus within the
      stent-graft in two (3%), and new aortic dissection in one (2%). The mean maximum
      diameter of the aneurysm was 58.8 mm before and 60.0 mm after stent-graft
      insertion. Sixty-two (98%) patients were successfully treated until discharge.
      Interventional procedures were performed to eliminate the leakage into the
      aneurysm sac in 10 patients with perigraft flow depicted at CT. Other
      complications were managed conservatively. CONCLUSION: Thoracic CT is useful in
      the treatment of patients after stent-graft insertion for the management of
      descending thoracic aortic aneurysm.

PMID- 10405739
TI  - Treatment of hemodialysis-related central venous stenosis or occlusion: results
      of primary Wallstent placement and follow-up in 50 patients.
AB  - PURPOSE: To analyze the effectiveness of stent placement as the primary treatment
      for central venous obstruction in patients undergoing hemodialysis. MATERIAL AND
      METHODS: Fifty-seven Wallstents were placed in 50 patients with symptomatic shunt
      dysfunction and arm swelling due to central venous obstruction. Technical
      success, complication, and patency rates were evaluated. RESULTS: Stent
      deployment was successful in all patients, and early rethrombosis (within 1 week)
      was noted in one patient (2%). Seventy-three episodes of reobstruction occurred
      and were treated percutaneously with angioplasty alone in 54 cases (74%).
      Nineteen cases (26%) necessitated additional stent placement. The 3-, 6-, 12-,
      and 24-month primary patency rates were 92%, 84%, 56%, and 28%, respectively.
      Cumulative overall stent patency was 97% after 6 and 12 months, 89% after 24
      months, and 81% after 36 and 48 months. CONCLUSION: In the treatment of
      brachiocephalic and subclavian venous obstruction, stent placement shows
      excellent technical results and helps preserve vascular access for a substantial
      period. Multiple repeat interventions are, however, frequently required to
      maintain patency.

PMID- 10405741
TI  - Follow-up of breast lesions diagnosed as benign with stereotactic core-needle
      biopsy: frequency of mammographic change and false-negative rate.
AB  - PURPOSE: To determine how often lesions diagnosed as benign with stereotactic
      core-needle biopsy (SCNB) change at follow-up mammography and to determine the
      optimal follow-up strategy and the delayed false-negative rate. MATERIALS AND
      METHODS: From July 1992 through December 1995, 355 of 540 cases (66%) in which
      SCNB yielded benign results were managed with follow-up mammography. Mammographic
      follow-up was available for 298 of these cases (84%). Follow-up mammography
      reports were reviewed. When a change was reported, pre- and postbiopsy
      mammograms, pathology reports, and results of subsequent mammographic follow-up
      were reviewed. RESULTS: Mammographic change occurred in 21 of 298 cases (7%) at
      intervals of 6-55 months (mean, 20 months). Change occurred after initial
      mammographic stability in 10 of 21 cases. Repeat biopsy was performed in 18 of 21
      cases. Malignancy was diagnosed in two cases: one mass that changed at 6 months
      and one case of microcalcifications that changed at 24 months. This represented a
      delayed false-negative rate of 2% (two of 105 malignancies among 540 biopsies).
      CONCLUSION: A small percentage of cases diagnosed as benign with SCNB will change
      on follow-up mammograms, which may necessitate repeat biopsy. These results
      suggest that 6-month follow-up for cases that yield nonspecific benign results at
      SCNB and yearly screening mammography for cases with specific benign results is a
      reasonable management strategy.

PMID- 10405740
TI  - Core-needle and surgical breast biopsy: comparison of three methods of assessing
      cost.
AB  - PURPOSE: To compare and evaluate the measures of costs for core-needle and
      surgical breast biopsies. MATERIALS AND METHODS: Three measures of costs were
      evaluated: (a) input resources, (b) actual payments, and (c) billed charges. A
      combination of methods were used for data collection from 10 sites enrolled in a
      large-scale, multiinstitutional, randomized controlled clinical trial. RESULTS:
      Input resource cost data (42 core-needle and eight surgical biopsies) were the
      most difficult to obtain. Actual payments and billed charges data collection (32
      core-needle and 44 surgical biopsies) was hampered by the difficulty of obtaining
      data from all providers involved in the procedures. Average direct input resource
      costs for surgical biopsy (including needle localization) were almost three times
      as high as those for core-needle biopsy ($698 vs $243). Actual payments ($2,398
      vs $799) and billed charges ($3,764 vs $1,496) for surgical biopsy averaged two
      and a half to three times higher than those for core biopsy (P < .001).
      CONCLUSION: There was remarkable consistency in relative costs. Input resource
      costs were much more difficult to obtain than were either actual payments or
      billed charges. However, input resource costs present a more reliable indication
      of the actual costs of a procedure than do the other measures. Given the
      difficulty in obtaining input resource costs, analyses by using actual payments
      may be preferred.

PMID- 10405742
TI  - Display modes for CT colonography. Part I. Synthesis and insertion of polyps into
      patient CT data.
AB  - PURPOSE: To develop and validate a method for the insertion of digitally
      synthesized polyps into computed tomographic (CT) images of the human colon for
      use as ground truth for evaluation of virtual colonoscopy. MATERIALS AND METHODS:
      Spiral CT simulator software was used to generate 10 synthetic polyps in various
      configurations. Additional software was developed to insert these polyps into
      volume CT scans. Ten polyps in eight patients were selected for comparison. Three
      radiologists evaluated whether two-dimensional (2D) CT images and three
      dimensional (3D) volume-rendered CT images showed synthetic or real polyps.
      RESULTS: Edge-response profiles and noise of simulated polyps matched those of
      native polyps. Frequency distributions of reviewers' responses were not
      significantly different for synthetic versus real polyps in either 3D or 2D
      images. Responses were clustered around the response of "unsure" if lesions were
      real or synthetic. Receiver operating characteristic curves had areas of 0.54
      (95% CI = 0.39, 0.68) for 3D and 0.39 (95% CI = 0.25, 0.53) for 2D images, which
      were not significantly different from random guessing (P = .70 and .28 for 3D and
      2D images, respectively). CONCLUSION: Synthetic polyps were indistinguishable
      from real polyps. This method can be used to generate ground truth experimental
      data for comparison of CT colonographic display and detection methods.

PMID- 10405744
TI  - Pancreatic carcinoma versus chronic pancreatitis: dynamic MR imaging.
AB  - PURPOSE: To determine if dynamic gadolinium-enhanced magnetic resonance (MR)
      imaging can distinguish chronic pancreatitis from pancreatic carcinoma. MATERIALS
      AND METHODS: A retrospective review of MR and pathology examination findings was
      performed for 24 patients with pancreatic ductal adenocarcinoma and seven with
      chronic pancreatitis who underwent dynamic gadolinium-enhanced breath-hold
      spoiled gradient-echo imaging. Arterial, portal, and delayed phase images were
      obtained after injection of gadopentatate dimeglumine. The MR images of 14
      patients without clinical evidence of pancreatic disease were also reviewed as
      controls. Signal intensity (SI) was measured on the precontrast (pre) and
      gadolinium-enhanced (post) images of the area of the pancreas sampled at biopsy
      and of the nontumorous pancreas. Percentage enhancement was defined as
      SIpre/SIpost x 100. RESULTS: Normal pancreas showed rapid enhancement that peaked
      in the arterial or portal phase. For both diseases, T1-weighted images showed
      hypointense masses with progressive enhancement (differences were significant [P
      < .05] on only delayed fat-saturated images). Differences in enhancement between
      either disease state and normal pancreas were significant for at least one phase.
      Nontumorous pancreas in patients with carcinoma showed gradual enhancement that
      was significantly different from that of normal pancreas. CONCLUSION: Chronic
      pancreatitis and pancreatic carcinoma show abnormal pancreatic enhancement, but
      the two were not distinguished on the basis of degree and time of enhancement.

PMID- 10405743
TI  - Display modes for CT colonography. Part II. Blinded comparison of axial CT and
      virtual endoscopic and panoramic endoscopic volume-rendered studies.
AB  - PURPOSE: To determine the sensitivity of radiologist observers for detecting
      colonic polyps by using three different data review (display) modes for computed
      tomographic (CT) colonography, or "virtual colonoscopy." MATERIALS AND METHODS:
      CT colonographic data in a patient with a normal colon were used as base data for
      insertion of digitally synthesized polyps. Forty such polyps (3.5, 5, 7, and 10
      mm in diameter) were randomly inserted in four copies of the base data. Axial CT
      studies, volume-rendered virtual endoscopic movies, and studies from a three
      dimensional mode termed "panoramic endoscopy" were reviewed blindly and
      independently by two radiologists. RESULTS: Detection improved with increasing
      polyp size. Trends in sensitivity were dependent on whether all inserted lesions
      or only visible lesions were considered, because modes differed in how completely
      the colonic surface was depicted. For both reviewers and all polyps 7 mm or
      larger, panoramic endoscopy resulted in significantly greater sensitivity (90%)
      than did virtual endoscopy (68%, P = .014). For visible lesions only, the
      sensitivities were 85%, 81%, and 60% for one reader and 65%, 62%, and 28% for the
      other for virtual endoscopy, panoramic endoscopy, and axial CT, respectively.
      Three-dimensional displays were more sensitive than two-dimensional displays (P <
      .05). CONCLUSION: The sensitivity of panoramic endoscopy is higher than that of
      virtual endoscopy, because the former displays more of the colonic surface.
      Higher sensitivities for three-dimensional displays may justify the additional
      computation and review time.

PMID- 10405745
TI  - Pancreatic CT imaging: effects of different injection rates and doses of contrast
      material.
AB  - PURPOSE: To assess the effects of the intravenous injection rate and dose of
      contrast material on pancreatic computed tomography (CT). MATERIALS AND METHODS:
      A total of 126 patients were divided at random into four groups with different
      injection rates and doses. Groups 1 and 2 underwent injection of 2 mL per
      kilogram of body weight of 300 mg of iodine per milliliter of contrast material,
      and groups 3 and 4 underwent injection of 1.5 mL/kg. The injection rate was 5
      mL/sec for groups 1 and 3 and 3 mL/sec for groups 2 and 4. Single-level serial CT
      scanning was performed at the level of the pancreatic head, and the pancreatic
      enhancement value was calculated. RESULTS: The maximum pancreatic enhancement
      value was 99 HU +/- 18 (mean +/- SD) for group 1, 90 HU +/- 18 for group 2, 86 HU
      +/- 15 for group 3, and 74 HU +/- 13 for group 4. There were significant
      differences in the maximum pancreatic enhancement value between groups 1 and 2 (P
      = .045), between groups 3 and 4 (P = .001), between groups 1 and 3 (P = .016),
      and between groups 2 and 4 (P = .001). CONCLUSION: Both a higher dose and a
      faster injection rate increased the maximum pancreatic enhancement value.

PMID- 10405746
TI  - Hepatic iron concentration: noninvasive estimation by means of MR imaging
      techniques.
AB  - PURPOSE: To identify a magnetic resonance (MR) imaging method sufficiently
      sensitive and specific in the estimation of hepatic iron content to obviate liver
      biopsy. MATERIALS AND METHODS: Thirty-eight patients underwent percutaneous
      needle biopsy of the liver with chemical measurement of the hepatic iron
      concentration and hepatic MR imaging with several spin-echo and gradient-recalled
      echo (GRE) techniques. Correlations between MR imaging parameters and the hepatic
      iron concentration were determined. RESULTS: Inverse curvilinear relationships
      were noted between several MR parameters and hepatic iron concentrations. GRE
      sequences with short repetition and echo times were more accurate and precise
      than spin-echo sequences for the estimation of hepatic iron concentration. A GRE
      sequence with a repetition time of 18 msec, an echo time of 5 msec, and a flip
      angle of 10 degrees showed close correlation between the hepatic iron
      concentration and the natural logarithm of the ratio of the signal intensity of
      liver to the SD of background noise (r = -0.94) and low coefficient of variation
      (12%). CONCLUSION: MR imaging with these parameters is a rapid, noninvasive, and
      accurate modality for estimation of hepatic iron concentration; it is
      sufficiently accurate and precise to obviate liver biopsy for the purpose of
      measuring hepatic iron concentration.

PMID- 10405747
TI  - Hepatocellular carcinoma: association with increased iron deposition in the
      cirrhotic liver at MR imaging.
AB  - PURPOSE: To determine whether the frequency of hepatocellular carcinoma (HCC) in
      patients with cirrhosis is affected by hepatic iron deposition as detected with
      magnetic resonance (MR) imaging. MATERIALS AND METHODS: In a retrospective search
      of MR imaging and histopathology records, 196 patients with histopathologically
      proved cirrhosis and with (n = 80) or without (n = 116) HCC who underwent T2
      weighted conventional or fast spin-echo and gradient-echo (GRE) (echo time > or =
      6.0 msec) imaging were identified. MR images were qualitatively and
      quantitatively evaluated for diffuse hepatic iron deposition and siderotic
      regenerative nodules to assess their correlation with the presence of HCC.
      RESULTS: Hepatic parenchymal iron deposition was seen in 79 (40%) patients, and
      iron deposition in regenerative nodules was seen in 71 (36%) at MR imaging. The
      mean signal intensity ratio of GRE images in patients with hepatic iron
      deposition was significantly lower than that in patients without it (P < .001).
      The frequency of HCC in patients with iron deposition in regenerative nodules
      (52% [37 of 71 patients]) was significantly higher (P = .015) than that in
      patients without iron in regenerative nodules (34% [43 of 125 patients]).
      CONCLUSION: The occurrence of HCC may be associated causally with iron deposition
      in regenerative nodules in patients with cirrhosis. MR imaging can enable
      detection of iron deposition in regenerative nodules as a possible risk factor
      for the development of HCC.

PMID- 10405748
TI  - Low-grade gastric mucosa-associated lymphoid tissue lymphoma: correlation of
      radiographic and pathologic findings.
AB  - PURPOSE: To describe upper gastrointestinal (Gl) examination findings of low
      grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma and to correlate
      them with pathologic examination findings. MATERIALS AND METHODS: A retrospective
      review of upper Gl examinations was performed in 25 patients with proved low
      grade gastric MALT lymphomas. Upper Gl examinations were reviewed for common
      findings and most probable diagnosis, and these findings were correlated with
      pathologic findings in resected specimens in 15 patients. RESULTS: The common
      findings at upper Gl examination included mucosal nodularity (n = 13), ulcer (n =
      12), rugal thickening (n = 6), mass (n = 4), and enlarged areae gastricae (n =
      2). The most probable diagnoses were early gastric carcinoma (n = 7), advanced
      gastric carcinoma (n = 6), gastritis (n = 9), and lymphoma (n = 3). Of 17 lesions
      found on resected specimens, six ulcers and two masses were not depicted at
      barium study. Disorganized convergent rugae projecting to multiple points and
      vague ulcer margins were present in four and seven lesions, respectively.
      Multiple ulcers were seen in two patients. CONCLUSION: Although the common
      radiographic and pathologic findings observed in low-grade gastric MALT lymphomas
      were similar to those of gastric carcinomas or gastritis, disorganized convergent
      rugae, vague ulcer margins, and multiplicity of lesions may be helpful in
      differentiating them from gastric carcinomas or gastritis.

PMID- 10405749
TI  - MR cholangiography in the evaluation of neonatal cholestasis.
AB  - PURPOSE: To evaluate the usefulness of magnetic resonance (MR) cholangiography in
      excluding biliary atresia as the cause of neonatal cholestasis. MATERIALS AND
      METHODS: MR cholangiography was performed on 10 control and 16 jaundiced neonates
      and infants aged 3 days to 5 months. Diagnosis of biliary atresia (n = 6) was
      confirmed with surgery and liver biopsy, with or without surgical
      cholangiography. Diagnosis of neonatal hepatitis (n = 9) was confirmed with
      clinical follow-up until jaundice resolved. In one infant, paucity of
      intrahepatic ducts was diagnosed at liver biopsy. MR cholangiography was
      performed with respiratory-triggered, heavily T2-weighted turbo spin-echo and
      optional inversion-recovery turbo spin-echo sequences. Diagnosis of biliary
      atresia was based on nonvisualization of either the common bile duct or common
      hepatic duct. Cholescintigraphy with technetium 99m disofenin was performed in
      all 16 jaundiced patients. RESULTS: In the 10 controls, the nine patients with
      neonatal hepatitis, and the one infant with paucity of intrahepatic ducts, MR
      cholangiography clearly depicted the gallbladder and common hepatic and common
      bile ducts. MR cholangiography was 100% accurate in excluding biliary atresia as
      the cause of neonatal cholestasis, while 99mTc disofenin cholescintigraphic
      findings were false-positive in four of 10 patients with nonobstructive
      cholestasis. CONCLUSION: MR cholangiography can be used to depict the major
      biliary structures of neonates and small infants and to exclude biliary atresia
      as the cause of neonatal cholestasis by allowing visualization of the biliary
      tract.

PMID- 10405751
TI  - MR colonography: optimized enema composition.
AB  - Manganese chloride, iron glycerophosphate, and cellulose additive were assessed
      as base materials for use in a T1-shortening single contrast enema for magnetic
      resonance (MR) colonography. Contrast-to-noise ratios (CNRs) were compared to
      those with the standard 10 mmol/L gadolinium-based enema. On T1-weighted three
      dimensional gradient-recalled-echo images, CNRs with the iron glycerophosphate
      enema exceeded those with the manganese- and gadolinium-based enemas. Use of an
      additive of 0.8% wt/wt cellulose was found to be practicable as it increased
      viscosity sufficiently without altering CNR. The gadolinium-based enema can be
      replaced with an iron glycerophosphate enema to render MR colonography less
      costly.

PMID- 10405750
TI  - Autoimmune lymphoproliferative syndrome: a syndrome associated with inherited
      genetic defects that impair lymphocytic apoptosis--CT and US features.
AB  - PURPOSE: To describe the imaging findings in patients with autoimmune
      lymphoproliferative syndrome (ALPS) and to relate the findings to the clinical
      and genetic features of this recently recognized syndrome. MATERIALS AND METHODS:
      Retrospective or prospective reviews of the computed tomographic (CT) and
      ultrasonographic (US) studies and the clinical features in 19 consecutive
      patients with ALPS were performed. RESULTS: Most patients presented in the 1st
      year of life with symptoms of adenopathy and hepatosplenomegaly. At the time of
      presentation to the institution, 12 patients had already undergone splenectomy,
      and 14 patients had developed autoimmune disorders. All patients had multifocal
      adenopathy, which was massive in some patients; 14 of 15 patients who underwent
      CT of the chest had an enlarged thymus, and all six patients who retained their
      spleens and who underwent imaging had splenomegaly. Ten of 18 patients who
      underwent liver imaging had hepatomegaly. The adenopathy at US was hyper- and/or
      isoechoic relative to the liver and thyroid and was enhanced at CT in some
      patients. All patients had defective lymphocytic apoptosis, or programmed cell
      death, which was due to specific Fas (APT1 [TNFRSF6]) mutations in 15 patients.
      CONCLUSION: Patients with ALPS demonstrate nonspecific but often dramatic imaging
      findings of lymphoproliferative disorders, such as adenopathy, splenomegaly,
      thymic enlargement, and hepatomegaly. The stability of the clinical findings over
      months to years and the pattern of lymph node echogenicity may suggest the
      diagnosis of ALPS.

PMID- 10405752
TI  - Volumetric imaging with ultrasonic spiral CT.
AB  - To examine the feasibility of implementing spiral computed tomography (CT) in
      ultrasonic imaging as a potential method for breast screening, an algorithm for x
      ray spiral CT was applied to ultrasonic waves on a specially built ultrasonic
      tomographic system. Three-dimensional reconstructions of various phantoms were
      obtained. Spiral ultrasonic CT is feasible, and it may have clinical merit as a
      breast imaging method.

PMID- 10405753
TI  - Virtual CT intravascular endoscopy of the aorta: pierced surface and floating
      shape thresholding artifacts.
AB  - Two types of artifacts may appear in virtual computed tomographic endoscopic
      views of the aorta rendered at different threshold levels: pierced surface and
      floating shape artifacts. A positive correlation was found between mean
      attenuation of the aorta and the threshold levels at which these artifacts
      appeared. The correlation was statistically significant (0.71 < or = r < or =
      0.86) for floating shape. An artifact-free threshold range can be predicted on
      the basis of aortic enhancement.

PMID- 10405754
TI  - Gadolinium-based contrast agents as an alternative at vena cavography in patients
      with renal insufficiency--early experience.
AB  - The authors reviewed results of digital subtraction vena cavography with a
      gadolinium-based contrast agent in 14 patients with serum creatinine levels
      greater than or equal to 1.5 mg/dL (133 mumol/L). All cavograms were diagnostic.
      In 11 patients, there was no impairment of renal function. In three patients, a
      rise in serum creatinine level of greater than or equal to 0.5 mg/dL (44 mumol/L)
      was attributable to concurrent medical problems. Gadolinium-based contrast agents
      may be suitable for digital subtraction vena cavography in patients with renal
      insufficiency.

PMID- 10405755
TI  - Head and neck cancer: detection of recurrence with three-dimensional principal
      components analysis at dynamic FDG PET.
AB  - Fully automated principal components analysis (PCA) was applied to dynamic 2
      [fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomographic (PET)
      images obtained in 15 patients with previously treated head and neck cancer. PCA
      with time-activity curves incorporated kinetic information about FDG uptake,
      which improved tissue characterization on FDG PET images. The combination of
      standardized uptake value and PCA image sets likely will improve the reliability
      of tumor detection in head and neck cancers.

PMID- 10405756
TI  - Can inversion-recovery gradient- and spin-echo T2-weighted MR imaging be an
      alternative to fast spin-echo imaging with fat suppression?

PMID- 10405757
TI  - Crosstalk between protein kinase A and growth factor receptor signaling pathways
      in arterial smooth muscle.
AB  - Crosstalk between the cyclic AMP-dependent protein kinase (PKA) and growth factor
      receptor signaling is one of many emerging concepts of crosstalk in signal
      transduction. Understanding of PKA crosstalk may have important implications for
      studies of crosstalk between other, less well known, signaling pathways. This
      review focuses on PKA crosstalk in arterial smooth muscle. Proliferation and
      migration of arterial smooth muscle cells (SMCs) contribute to the thickening of
      the blood vessel wall that occurs in many types of cardiovascular disease. PKA
      potently inhibits SMC proliferation by antagonizing the major mitogenic signaling
      pathways induced by growth factors in SMCs. PKA also inhibits growth factor
      induced SMC migration. An intricate crosstalk between PKA and the mitogen
      activated protein kinase (MAPK/ERK) pathway, the p70 S6 kinase pathway and cyclin
      dependent kinases has been described. Further, PKA regulates expression of growth
      regulatory molecules. The result of PKA activation in SMCs is the potent
      inhibition of cell cycle traverse and SMC migration. In this review, we discuss
      recent advances in our understanding of the crosstalk between PKA and signaling
      pathways induced by growth factor receptors in SMCs, and where relevant, in other
      cell types in which interesting examples of PKA crosstalk have been described.

PMID- 10405758
TI  - Dual activity of pyrrolidine dithiocarbamate on kappa B-dependent gene expression
      in U937 cells: I. Regulation by the phorbol ester TPA.
AB  - Pyrrolidine dithiocarbamate (PDTC) has been widely used as an inhibitor of the
      nuclear factor-kappa B, (NF-kappa B) signalling pathway. Here, we show that kappa
      B-dependent reporter gene expression induced by low concentrations of 12-O
      tetradecanoylphorbol-13-acetate (TPA) is potentiated by PDTC in the human pro
      monocytic U937 cell line. The stimulatory effect of PDTC on kappa B-dependent
      gene expression was shown with a 4 x kappa B chloramphenicol acetyltransferase
      construct and required an intact kappa B element in the human immunodeficiency
      virus long terminal repeat (HIV-1 LTR). Unexpectedly, an HIV-1 LTR construct with
      a mutation of the activator protein 2 (AP-2) binding site located between the two
      kappa B elements was unresponsive to the stimulatory effect of PDTC with TPA. The
      stimulation or inhibition of kappa B-dependent gene expression was dependent on
      PDTC pre-treatment and the concentration of TPA. No stimulatory effect on HIV-1
      LTR activity was observed with the metal chelator dipyridyl or the anti-oxidant N
      acetyl-L-cysteine. These results are consistent with the hypothesis that PDTC
      treatment potentiated kappa B-dependent gene expression in a manner dependent on
      the concentration of TPA.

PMID- 10405759
TI  - Involvement of mitogen-activated protein kinase homologues in the regulation of
      lipopolysaccharide-mediated induction of cyclo-oxygenase-2 but not nitric oxide
      synthase in RAW 264.7 macrophages.
AB  - In RAW 264.7 macrophages lipopolysaccharide (LPS) stimulated the activation of
      p42 and p44 MAP kinases and their upstream activator mitogen-activated protein
      (MAP) kinase kinase (MAPKK), and induced the 69-kDa isoform of cyclo-oxygenase-2
      (COX-2) and the 130-kDa isoform of nitric oxide synthase (iNOS). PD 098059, a
      specific inhibitor of the activation of MAPKK, prevented LPS-mediated activation
      of MAPKK (IC50 = 3.0 +/- 0.1 microM, n = 3) and p42/44 MAP kinases and
      substantially reduced the induction of COX-2 by approximately 40%-70%, but was
      without effect upon the induction of iNOS. In parallel, LPS also stimulated the
      activation of p38 MAP kinase and the MAPKAP kinase-2, a downstream target of p38
      MAP kinase. SB 203580, a specific inhibitor of p38 MAP kinase prevented the
      activation of p38 MAP kinase (IC50 = 3.3 +/- 1.4 microM, n = 3) and MAPKAP kinase
      2 by LPS and reduced the induction of COX-2 by approximately 50-90%, with no
      significant effect upon iNOS expression. These studies indicate the involvement
      of both the classical p42/44 MAP kinases and p38 MAP kinase in the regulation of
      COX-2 but not iNOS induction following exposure to LPS.

PMID- 10405760
TI  - Identification of distinct signalling pathways for somatostatin receptors SSTR1
      and SSTR2 as revealed by microphysiometry.
AB  - Somatostatin receptors (SSTRs) are known to mediate diverse cellular responses.
      Most target cell express more than one SSTR isoform, making it difficult to
      define the signalling pathway used by individual receptor subtypes. Thus, we have
      expressed SSTR1 or SSTR2 in rat pituitary F4C1 cells which lack endogenous SSTRs.
      Using a silicon-based biosensor system, the Cytosensor microphysiometer, which
      measures the extracellular acidification rate (ECAR) in real time, we have
      studied the responses to SS mediated by either SSTR1 or SSTR2. In control F4C1
      cells, SS had no effect on the basal ECAR. In transfected cells expressing only
      SSTR1, SS caused a unique decrease in ECAR in a concentration-dependent manner.
      Receptor-mediated decreases in ECAR have not been reported previously. In F4C1
      cells expressing only SSTR2, SS induced a bidirectional ECAR response, a rapid
      increase followed by a decrease below basal. Two SS analogues, MK678 and CH275,
      induced characteristic ECAR responses with the expected receptor selectivities
      for SSTR1 or SSTR2. Pretreatment of F4C1 cells with pertussis toxin abolished the
      decreases in ECAR mediated by both SSTR1 and SSTR2, but only partially reduced
      the increase in ECAR mediated by SSTR2. The decrease in ECAR did not depend on a
      decrease in intracellular cAMP. The ECAR responses to SS were modestly attenuated
      by methylisobutylamiloride (MIA), an inhibitor of the ubiquitous Na(+)-H+
      exchanger NHE1. Removal of extracellular Na+ greatly inhibited the ECAR responses
      to SS, demonstrating a role for both amiloride-sensitive and -insensitive Na(+)
      dependent acid transport mechanisms in SS-induced extracellular acidification. In
      conclusion, we have identified and characterized different signalling pathways
      for SSTR1 and SSTR2 in pituitary cells as measured by microphysiometry.

PMID- 10405761
TI  - Tyrosine phosphorylation enhances the SH2 domain-binding activity of Bcr and
      inhibits Bcr interaction with 14-3-3 proteins.
AB  - The cellular Bcr protein consists of an N-terminal serine/threonine kinase
      domain, a central guanine nucleotide exchange factor homology region and a C
      terminal GTPase-activating protein domain. Previous work in our laboratory
      established that Bcr is a major transformation-related substrate for the v-Fps
      tyrosine kinase, and tyrosine phosphorylation of Bcr induces Bcr-Grb-2/SOS
      association in vivo through the Src homology 2 (SH2) domain of Grb-2. In the
      present study, we mapped the region of Bcr tyrosine phosphorylation by c-Fes, the
      human homologue of v-Fps, to Bcr N-terminal amino acids 162-413 by using a
      baculovirus/Sf-9 cell co-expression system. Tyrosine phosphorylation of Bcr by
      Fes greatly enhanced the binding of Bcr to the SH2 domains of multiple signalling
      molecules in vitro, including Grb-2, Ras GTPase activating protein, phospholipase
      C-gamma, the 85,000 M(r) subunit of phosphatidylinositol 3'-kinase, and the Abl
      tyrosine kinase. In contrast with SH2 binding, tyrosine phosphorylation of Bcr
      reduced its ability to associate with the 14-3-3 protein Bap-1 (Bcr-associated
      protein-1), a Bcr substrate and member of a family of phosphoserine-binding
      adaptor proteins. These experiments provide in vitro evidence that tyrosine
      phosphorylation may modulate the interaction of Bcr with multiple growth
      regulatory signalling pathways.

PMID- 10405762
TI  - Molecular cloning of magnesium-independent type 2 phosphatidic acid phosphatases
      from airway smooth muscle.
AB  - Members of the type 2 phosphatidic acid phosphatase (PAP2) family catalyse the
      dephosphorylation of phosphatidic acid (PA), lysophosphatidate and sphingosine 1
      phosphate. Here, we demonstrate the presence of a Mg(2+)-independent and N
      ethymaleimide-insensitive PAP2 activity in cultured guinea-pig airway smooth
      muscle (ASM) cells. Two PAP2 cDNAs of 923 and 926 base pairs were identified and
      subsequently cloned from these cells. The ORF of the 923 base pair cDNA encoded a
      protein of 285 amino acids (Mr = 32.1 kDa), which had 94% homology with human
      PAP2a (hPAP2a) and which probably represents a guinea-pig specific PAP2a
      (gpPAP2a1). The ORF of the 926 base pair cDNA encoded a protein of 286 amino
      acids (Mr = 32.1 kDa) which had 84% and 91% homology with hPAP2a and gpPAP2a1,
      respectively. This protein, termed gpPAP2a2, has two regions (aa 21-33 and 51-74)
      of marked divergence and altered hydrophobicity compared with hPAP2a and
      gpPAP2a1. This occurs in the predicted first and second transmembrane domains and
      at the extremes of the first outer loop. Other significant differences between
      gpPAP2a1/2 and hPAP2a, hPAP2b and hPAP2c occur at the cytoplasmic C-terminal.
      Transient expression of gpPAP2a2 in Cos-7 cells resulted in an approx. 4-fold
      increase in Mg(2+)-independent PAP activity, thereby confirming that gpPAP2a2 is
      another catalytically active member of an extended PAP2 family.

PMID- 10405763
TI  - Stable association of G proteins with beta 2AR is independent of the state of
      receptor activation.
AB  - beta 2-Adrenergic receptors expressed in Sf9 cells activate endogenous Gs and
      adenylyl cyclase [Mouillac B., Caron M., Bonin H., Dennis M. and Bouvier M.
      (1992) J. Biol. Chem. 267, 21733-21737]. However, high affinity agonist binding
      is not detectable under these conditions suggesting an improper stoichiometry
      between the receptor and the G protein and possibly the effector molecule as
      well. In this study we demonstrate that when beta 2-adrenergic receptors were co
      expressed with various mammalian G protein subunits in Sf9 cells using
      recombinant baculoviruses signalling properties found in native receptor systems
      were reconstituted. For example, when beta 2AR was co-expressed with the Gs alpha
      subunit, maximal receptor-mediated adenylyl cyclase stimulation was greatly
      enhanced (60 +/- 9.0 versus 150 +/- 52 pmol cAMP/min/mg protein) and high
      affinity, GppNHp-sensitive, agonist binding was detected. When G beta gamma
      subunits were co-expressed with Gs alpha and the beta 2AR, receptor-stimulated
      GTPase activity was also demonstrated, in contrast to when the receptor was
      expressed alone, and this activity was higher than when beta 2AR was co-expressed
      with Gs alpha alone. Other properties of the receptor, including receptor
      desensitization and response to inverse agonists were unaltered. Using antisera
      against an epitope-tagged beta 2AR, both Gs alpha and beta gamma subunits could
      be co-immunoprecipitated with the beta 2AR under conditions where subunit
      dissociation would be expected given current models of G protein function. A
      desensitization-defective beta 2AR (S261, 262, 345, 346A) and a mutant which is
      constitutively desensitized (C341G) could also co-immunoprecipitate G protein
      subunits. These results will be discussed in terms of a revised view of G protein
      mediated signalling which may help address issues of specificity in receptor/G
      protein coupling.

PMID- 10405764
TI  - Isolation, expression and analysis of splice variants of a human Ca2+/calmodulin
      stimulated phosphodiesterase (PDE1A).
AB  - The PDE1A gene encodes a Ca2+/calmodulin-stimulated 3',5'-cyclic nucleotide
      phosphodiesterase (PDE). We have performed 5' and 3' RACE and identified two
      additional 5'-splice variants and one additional 3'-splice variant of the human
      PDE1A gene. The three known 5'-splice variants and the two known 3'-splice
      variants combine to generate six different PDE1A mRNAs. However, one of the 5'
      splice variants exhibits alternate splicing in the 5' untranslated region. Thus
      the six mRNAs encode four different PDE1A proteins. Recombinant forms of the
      different human PDE1A isoforms were expressed in Sf9 cells. The kinetic
      properties and inhibitor sensitivities of the four PDE1A isoforms are very
      similar to one another.

PMID- 10405765
TI  - The effect of sound direction on frequency tuning in mouse inferior collicular
      neurons.
AB  - This study examined the effect of sound direction on frequency tuning of inferior
      collicular (IC) neurons of mice under free field stimulation conditions. Fewer
      than 20% of IC neurons studied were spontaneously active. Discharge patterns can
      be described as phasic on responders, phasic on-off responders, off responders,
      choppers and tonic responders. The frequency tuning curves (FTCs) of IC neurons
      can be described as narrow, intermediate or broad. Although sound direction
      typically had little effect on most best frequencies (BFs), sharpness of FTCs
      increased as sound direction changed from contralateral angles to ipsilateral
      angles. Sound delivered from the upper and lower portions of the frontal auditory
      space also appeared to produce sharper frequency tuning than from the front.
      Possible mechanisms underlying this direction dependent frequency tuning are
      discussed.

PMID- 10405766
TI  - Role for nitric oxide but not prostaglandins in acetylcholine-induced relaxation
      of rat cremaster third-order arterioles in 5-hour ischemia-reperfusion control
      rats.
AB  - Intravital videomicroscopy was used for 1 hr in anesthetized 4- to 5-week-old
      rats, while mean femoral arterial blood pressure and suffusate Po2 were
      continuously monitored. The total duration for experimentation was 5 hr in order
      to mimic the controls used previously for a 4-hr ischemia and 1-hr reperfusion
      model. The specific aim was to examine further the efficacy of this model by (a)
      assessing the potential role(s) of nitric oxide (NO) and/or prostaglandins (PG)
      in acetylcholine (ACh)-induced relaxation, and (b) determining if inherently low
      vasomotor tone (VT) and wall shear stress (WSS) mask latent NO- and/or PG
      mediated responses to ACh. Reactivity to 10(-4) M ACh or 10(-6) M sodium
      nitroprusside (NP) were determined in resting third-order arterioles (3A) or in
      those preconstricted with norepinephrine (10(-6) M NE) at physiological suffusate
      Po2 (25-30 mm Hg). Repeated and randomized topical administrations of ACh, NP,
      arachidonic acid (10(-5) M AA), NE, or 10(-5) M atropine (ATR), NG-nitro-L
      arginine methyl ester (L-NAME), or ibuprofen (Ib) alone or in combination to the
      surface of exteriorized cremaster flaps, provoked no alteration in mean systemic
      arterial blood pressure. ACh and NP were equipotent evoking relaxations on the
      same order of magnitude and duration as reported previously for arterioles with
      spontaneous or NE-enhanced VT. ATR or L-NAME decreased resting internal diameter
      by 12 to 14% and reversed relaxation of resting or preconstricted arterioles to
      ACh but not to NP. Ib failed to elicit blockade. However, administration of AA
      demonstrated Ib-inhibitable increases of 20 and 52% in resting and NE
      preconstricted arterioles, respectively, implicating NO but not PG in the
      regulation of resting (relaxant) tone and in ACh-induced dilation following
      activation of 3A muscarinic receptors. The absence of PG-mediated responses
      appears unrelated to low initial WSS at physiologic suffusate Po2, since NE
      induced elevations of VT and centerline cell velocity also did not cause Ib
      inhibitable relaxation. These and our previous findings suggest that the impaired
      relaxant function of 3A arterioles is caused in part by a paucity in spontaneous
      tone inherent to this model and by depressed vasoreactivity arising from
      disruption of NO biosynthesis.

PMID- 10405767
TI  - Erythrophagocytosis and iron deposition in atherosclerotic lesions.
AB  - Iron deposition has been shown to be prominent in atherosclerotic lesions.
      However, the source of iron accumulated in arterial walls is unclear. In present
      report, we provide the histological evidence to demonstrate the localization of
      erythrocytes in atherosclerotic lesions from experimental animals. As revealed by
      scanning and transmission electron microscopy, the circulating erythrocytes were
      found to be present in intima of atherosclerotic aortas from apoE-deficient mice.
      These erythrocytes appeared to be readily phagocytosed by macrophages in lesions.
      The erythrophagocytosis was also evident in lesions from cholesterol-fed rabbits.
      Furthermore, the iron deposition was detectable in the region with erythrocytes.
      When the aortic sections of humans and apoE-deficient mice were immunostained
      with specific antibody to hemoglobin, it was clearly shown that the positive
      stain was detectable in macrophage-derived foam cells. Immunostaining of serial
      sections with specific antibodies to heme oxygenase-1 (HO-1) and ferritin further
      demonstrated the colocalization of HO-1 and ferritin in area with positive
      immunoreactivity for hemoglobin. Likewise, Perls' reaction revealed the positive
      iron stain in the same region. Collectively, these results suggest that
      hemoglobin/heme released from the phagocytosed erythrocytes may contribute to at
      least part of iron deposited in atherosclerotic lesions.

PMID- 10405768
TI  - Fractal geometry in urodynamics of lower urinary tract.
AB  - The physiological signals are usually extremely complicated and difficult to
      analyze. Recently, investigators have tried the fractal dimension that can
      characterize roughness and self-similarity of them. It turns out that it is also
      suitable for obtaining the modalities of lower urinary tract during normal
      micturition. In this investigation, the external urethral sphincter
      electromyogram (EUS EMG) and the cystometrogram (CMG) of the Wistar rats under
      both room temperature and cold water stimulation of the bladder are studied. The
      modified relative differential box-counting (RDBC) method is used to calculate
      the fractal dimensions of EMG and CMG time series. According to the experimental
      results, the modalities of micturition for the Wistar rats can be characterized
      as normal if both the fractal dimensions of EMG and CMG are of low values during
      voiding. Furthermore, the technique is validated in identifying the dyssynergia
      of the bladder and EUS under cold water stimulation.

PMID- 10405769
TI  - A further investigation of ATP-induced calcium mobilization in MDCK cells.
AB  - We have previously reported that La3+ inhibited the ATP-induced rise in
      intracellular Ca2+ levels ([Ca2+]i) measured by fura-2 fluorimetry in Madin Darby
      canine kidney (MDCK) cells. Here we further investigated the ATP-induced Ca2+
      signal. ATP caused a rise in [Ca2+]i dose-dependently between 1 microM-1 mM. The
      rises induced by 10 microM-1 mM ATP were inhibited by Ca2+ removal. The pleateau
      phase of the ATP response was primarily maintained by Ca2+ influx because it was
      reduced or eliminated by Ca2+ removal. ATP failed to elevate [Ca2+]i after the
      endoplasmic reticulum Ca2+ store had been depleted by 2,5-di-tert
      butylhydroquinone or cyclopiazonic acid, suggesting that the ATP-induced Ca2+
      influx was capacitative Ca2+ entry. Capacitative Ca2+ entry was directly measured
      by addition of 5 mM CaCl2 to cells pretreated with ATP (0.1 mM) in Ca(2+)-free
      medium. This capacitative Ca2+ entry was inhibited by econazole (25 microM) or
      SKF96365 (50 microM). The ATP response was significantly enhanced by
      extracellular alkalization to pH 8 or pretreatment with gly-phe-beta
      naphthylamide. Pretreatment with carbonylcyanide m-chlorophenylhydrazone (CCCP)
      or extracellular Na+ removal had no enhancement, implicating that efflux via
      plasmalemmal Ca2+ pumps (but not Na+/Ca2+ exchange) and buffering by lysosomes
      (but not mitochondria) might be involved in the decay of the ATP response.

PMID- 10405770
TI  - Variation of capsaicin-sensitive motor activities along the rat gastrointestinal
      tract.
AB  - Variation in motility may be a character to move gut contents. The aim of present
      study was to assess whether the rat upper gastrointestinal motilities were
      variable according to the segments or studied periods under systemic capsaicin
      treatment. Sedated rats were intubated with a catheter to feed a suspension
      containing both charcoal and radiochromium motility markers. Capsaicin in the
      doses of 0.5 mg kg-1, 1 mg kg-1, 5 mg kg-1 or vehicle were simultaneously
      injected via intraperitoneal route. They were sacrificed at 5 min or 30 min later
      and the whole gut was removed. Charcoal transit in the small intestine was
      computed while the radioactivities of stomach and ten equally divided small
      intestinal segments were counted to obtain the gastric emptying and geometric
      center of intestinal transit, respectively. Large dose treatment inhibited early
      gastric emptying (p < 0.05), whereas late gastric emptying remained unchanged.
      Larger dose treatment inhibited charcoal represented transit in the early (p <
      0.05) and late periods (p < 0.01). The intestinal transits seen with geometric
      center were almost similar to these of charcoal representation (p < 0.01). In
      conclusion, capsaicin-sensitive gastric emptying changes with studied periods
      while intestinal transit is always inhibited at any period. We confirm the notion
      of variation in capsaicin-sensitive motor responses along the rat upper digestive
      organ.

PMID- 10405771
TI  - Endothelium dependent and independent relaxations induced by ceramide in vascular
      smooth muscles.
AB  - The second messenger of sphingomyelin signaling, ceramide, acts as an
      intracellular signal via phosphatase activation and protein kinase C (PKC)
      inhibition. We tested the hypothesis that ceramide may have an regulatory role in
      determining vascular tone. Natural ceramide was applied to phenylephrine
      precontracted aortic rings from Sprague-Dawley rats in an organ bath. In
      endothelium-intact aortic rings, concentrations of ceramide at 10(-6) and 10(-5)
      mole/L induced 24 +/- 6 and 52 +/- 7% relaxation, respectively. Removal of the
      endothelium significantly inhibited ceramide-induced relaxation to 13 +/- 5% (10(
      6) mole/L) and 29 +/- 5% (10(-5) mole/L). Similar inhibition was observed in
      endothelium-intact aortic rings pretreated with N omega-nitro-L-arginine (10(-4)
      mole/L) or methylene blue (10(-5) mole/L), suggesting that endothelium-derived
      nitric oxide is involved in ceramide-induced relaxation. N-acetylsphingosine (C2
      ceramide), N-hexanoylsphingosine (C6-ceramide), N-palmitoylsphingosine (C16
      ceramide) and D-sphingosine all demonstrated dose-dependent relaxation responses
      in endothelium-intact vessels. Sphingomyelin signaling through the nitric oxide
      dependent mechanism may have an important role in regulating vascular tone.

PMID- 10405772
TI  - Opioid receptor signalling mechanisms.
AB  - 1. Three pharmacological types of opioid receptors, mu, delta and kappa, and
      their corresponding genes have been identified. Although other types of opioid
      receptors have been suggested, their existence has not been established
      unequivocally. A fourth opioid receptor, ORL1, which is genetically closely
      related to the others, has also been isolated. ORL1 responds to the endogenous
      agonist nociceptin (orphanin FQ) and displays a pharmacological profile that
      differs greatly from mu, delta and kappa receptors. 2. All opioid receptors
      mediate many of their cellular effects via activation of heterotrimeric G
      proteins. The mu, delta and kappa receptors are all capable of interacting with
      the pertussis toxin-sensitive G-protein alpha-subunits Gi1, Gi2, Gi3, Go1, Go2
      and the pertussis toxin-insensitive Gz and G16. None of the opioid receptors
      interacts substantially with Gs and mu receptors do not activate Gq, G11, G12,
      G13, or G14. 3. Differential coupling of different opioid receptors to most types
      of G-proteins is marginal. The mu, delta and kappa receptors appear to
      preferentially activate Go and Gi2 over other pertussis toxin-sensitive G
      proteins, although there is evidence that mu receptors show some preference for
      Gi3. delta Receptors couple more efficiently to G16 than do mu or kappa
      receptors. 4. There is some evidence that opioid receptors, particularly mu and
      ORL1 receptors, can also couple to cellular effectors in a G-protein-independent
      manner. 5. In general, the consequences of activation of any of the opioid
      receptors in a given cell type depend more on the profile (stoichiometry) of the
      G-proteins and effectors expressed than on the type of opioid receptor present in
      the cell. Notions that different types of opioid receptors intrinsically couple
      preferentially to one type of effector rather than another should, therefore, be
      discarded.

PMID- 10405773
TI  - Amlodipine, a long-acting calcium channel blocker, attenuates morning blood
      pressure rise in hypertensive patients.
AB  - 1. The effects of once-daily calcium channel blockers with different plasma half
      lives on diurnal blood pressure changes were examined in hypertensive patients.
      2. Patients with essential hypertension, nine men and 13 women aged 61 +/- 2
      years, were treated with amlodipine or nitrendipine in a random cross-over design
      for 12-16 weeks each. The study drugs were given once daily as monotherapy (n =
      8) or in combination with other classes of antihypertensive drugs (n = 14). The
      plasma half-life of amlodipine is as long as 36 h, while that of nitrendipine is
      10 h. At the end of each treatment period, 24 h ambulatory blood pressure and
      pulse rate were monitored. 3. Average office blood pressure was comparably
      controlled below 140/90 mmHg by either amlodipine or nitrendipine, both in the
      monotherapy and the combination therapy groups; however, pulse rate was greater
      in nitrendipine than in amlodipine either in the monotherapy (by 6 b.p.m., P <
      0.05) or in the combination therapy (by 5 b.p.m., P < 0.01). 4. In 24 h blood
      pressure monitoring, morning (05.30-09.00 h) blood pressure was higher in
      nitrendipine than in amlodipine by 6/4 mmHg in the monotherapy (P < 0.05) and by
      7/5 mmHg in the combination therapy (P < 0.03), although the blood pressure in
      the remainder of the 24 h did not differ between the two treatment periods. In
      addition, pulse rate in the daytime (09.30-18.00 h) was greater in nitrendipine
      than in amlodipine by 6 b.p.m. in the monotherapy (P < 0.01) and by 7 b.p.m. in
      the combination therapy (P < 0.02). 5. These results suggest slow
      pharmacokinetics of amlodipine provides an advantage in controlling morning blood
      pressure and mitigating reflex activation of the sympathetic nervous system.

PMID- 10405774
TI  - Diurnal variations in insulin secretion and K+ permeability in isolated rat
      islets.
AB  - 1. The effects of glucose on insulin secretion and 86Rb efflux from isolated rat
      islets were studied at six different times during a 24-h period (00.00, 04.00,
      08.00, 12.00, 16.00 and 20.00 h). 2. In the absence of glucose and in the
      presence of substimulatory concentrations (2.8 mmol/L) of the sugar, insulin
      secretion did not vary with the time of day. At a glucose concentration of 5.6
      mmol/L the stimulated insulin secretion was greater than basal levels only at
      20.00 h. 3. At a higher sugar concentration (8.3 mmol/L) the increase in insulin
      secretion and the reduction in 86Rb efflux rate were more marked during the dark
      period. No effect of the time of day on insulin secretion was observed at glucose
      concentrations above 8.3 mmol/L (except in 27.7 mmol/L). 4. The time of day
      appears to affect insulin secretion mainly at glucose concentrations close to
      physiological values (5.6-8.3 mmol/L). 5. This result agrees with the ability of
      physiological amounts of glucose to alter the 86Rb-permeability of pancreatic B
      cells at the same time intervals.

PMID- 10405775
TI  - Inhibition of human cardiac fibroblast mitogenesis by blockade of mitogen
      activated protein kinase and phosphatidylinositol 3-kinase.
AB  - 1. Interstitial fibroblast proliferation is an elemental feature in the
      development of cardiac fibrosis. The effects of inhibitors of the intracellular
      signalling proteins, MEK, a kinase involved in the mitogen-activated protein
      kinase (MAPK) pathway and phosphatidylinositol 3-kinase (PI3-K), were tested on
      growth of cultured human cardiac fibroblasts. 2. Cardiac fibroblasts were
      isolated from transplant recipient myocardium and made quiescent by serum
      deprivation for 48 h. Cells were incubated for 24 h with the inhibitors PD 098059
      (0.3-30 mumol/L) and LY294002 (1-25 mumol/L) in the presence and absence of
      platelet-derived growth factor-AB (PDGF-AB, 10 ng/mL). DNA synthesis was measured
      by [3H]-thymidine incorporation assay (20-24 h). 3. Both compounds markedly
      inhibited both basal and PDGF-stimulated increases in DNA synthesis in a
      concentration-dependent manner. Cardiac fibroblast DNA synthesis was reduced to
      near control levels by PD 098059, while it was inhibited completely by LY294002.
      4. These results implicate the importance of MAPK and PI3-K activation in the
      signal transduction pathways necessary for cardiac fibroblast replication.

PMID- 10405776
TI  - Left ventricular mass and microalbuminuria: relation to ambulatory blood
      pressure. Hypertension Diagnostic Service Investigators.
AB  - 1. Both microalbuminuria and left ventricular hypertrophy may reflect target
      organ damage in essential hypertension. Both are related to the prevailing level
      of blood pressure and both are associated with an increase in morbidity and
      mortality. 2. The database of the Hypertension Diagnostic Service, a multicentre
      secondary referral clinic for patients with essential hypertension, was analysed
      in order to clarify the level of association between microalbuminuria and left
      ventricular hypertrophy, which might explain the observed increase in morbidity
      and mortality in patients with microalbuminuria. Microalbuminuria was measured
      semiquantitatively by urine dip-stix. After the exclusion of patients with
      potential secondary hypertension, renal disease and diabetes mellitus, patients
      with complete data for microalbuminuria, left ventricular mass (LVM) and 24 h
      blood pressure monitoring were selected. 3. Data were complete for 704 patients
      (47% male, age 51 +/- 12 years) and 42% tested positive for microalbuminuria.
      Microalbuminuria was positively related to 24 h systolic blood pressure and
      weight and was negatively related to age. Left ventricular mass was higher in
      patients with microalbuminuria (men, 265 +/- 69 g; women, 207 +/- 61 g) than in
      those without (men, 250 +/- 64 g, P < 0.05; women, 185 +/- 50 g, P < 0.001).
      After correction for the effects of gender, body mass index and 24 h systolic
      blood pressure, the presence of microalbuminuria was associated with an increase
      in LVM of 10 g (P < 0.05, 95% confidence interval, 2-19 g).

PMID- 10405777
TI  - Interaction between endothelin and angiotensin II.
AB  - 1. Angiotensin II (AngII) and endothelin (ET) stimulate cardiac hypertrophy in
      vitro and in vivo. Also AngII stimulates ET production. 2. In order to
      investigate whether AngII produces its cardiac hypertrophic effects through
      stimulating ET production which acts on the ETA receptor, male Sprague-Dawley
      rats (6-8 weeks of age) received an intravenous infusion of AngII at 0, 100 or
      200 ng/kg per min via Alzet osmotic minipumps and jugular venous catheters for 7
      days (n = 12 per dose). Half of the rats in each group received the selective ETA
      receptor antagonist BMS 193884 25 mg/kg per orally and the other half received
      the vehicle daily. 3. Telemetrically measured mean arterial pressure (MAP) rose
      with the 200 ng/kg per min dose of AngII (P = 0.0001). The ETA receptor blockade
      lowered MAP in all groups (P = 0.011). Left ventricular weights increased only in
      the 200 ng/kg per min AngII infusion rats (P = 0.04). There was no effect of ETA
      receptor blockade on left ventricular weights. 4. These results suggest that
      AngII causes left ventricular hypertrophy not only in association with a pressor
      response but also when MAP was lowered with ETA blockade to control levels,
      suggesting a non-pressor effect of AngII on cardiac hypertrophy. Also, ET, acting
      via ETA receptors, does not mediate the hypertrophic effect of AngII in this
      model.

PMID- 10405778
TI  - Hyperglycaemia abolishes the antihypertrophic efficacy of bradykinin in rat
      ventricular myocytes.
AB  - 1. Bradykinin inhibits hypertrophy of rat ventricular myocytes, but only in the
      presence of endothelial cells. 2. The influence of hyperglycaemia on the ability
      of bradykinin to prevent hypertrophy was investigated in adult rat ventricular
      myocytes cocultured with bovine aortic endothelial cells (BAEC). 3. In myocytes
      cocultured with normal BAEC, angiotensin II (AngII; 1 mumol/L) significantly
      increased [3H]-phenylalanine incorporation (an in vitro marker of hypertrophy) by
      32 +/- 2%. This was abolished by bradykinin (10 mumol/L). 4. Pretreatment of BAEC
      with high glucose (25 mmol/L for 24 h) prior to coculture with myocytes reduced
      the antihypertrophic effect of bradykinin, but did not modulate the hypertrophic
      effect of AngII. 5. Pretreatment of BAEC with hyperglycaemia abolishes the
      antihypertrophic efficacy of bradykinin in rat ventricular myocytes cocultured
      with BAEC. This has implications for the action of angiotensin-converting enzyme
      inhibitors.

PMID- 10405779
TI  - Lipocortin-1 preserves myocardial responsiveness to beta-adrenergic stimulation
      in rat papillary muscle.
AB  - 1. During septic shock, myocardial contractile dysfunction is accompanied by the
      release of cytokines and enhanced production of nitric oxide, and the contractile
      dysfunction is prevented by glucocorticoids. 2. Myocardial dysfunction was
      induced in vitro by incubation of rat papillary muscle for 15 h with endotoxin
      (lipopolysaccharide, LPS) and interferon-gamma (IFN-gamma). 3. Both baseline
      contractile function and inotropic responsiveness to isoprenaline were markedly
      reduced by the combination of LPS plus IFN-gamma. 4. Lipocortin-1 (LC-1) is
      induced by glucocorticoids, and LC-1(2-26), its N-terminal fragment, protected
      the papillary muscle inotropic responsiveness to isoprenaline, but did not affect
      the decline in baseline contractile function induced by LPS plus IFN-gamma. 5.
      The mechanisms of this protective action need to be explored further, but LC-1
      may prove to be a novel cardioprotective agent for the management of septic
      shock.

PMID- 10405780
TI  - The A1166C mutation in the angiotensin II type I receptor and hypertension in the
      elderly.
AB  - 1. Using a nested case-control study of 661 non-institutionalized elderly (> or =
      60 years) residents of Dubbo, New South Wales, Australia, the aim of this study
      is to determine whether the A1166C polymorphism of the angiotensin II type I
      (AT1) receptor gene is associated with hypertension in the elderly. 2.
      Individuals were classified as isolated systolic hypertension (ISH, n = 146),
      systolic diastolic hypertension (SDH, n = 188), or normotensive, age- and sex
      matched controls (n = 327). AA, CC and AC genotypes were determined using
      restriction fragment length polymorphism analysis of DNA generated by nested
      polymerase chain reaction. 3. A univariate analysis (chi 2) was complemented by a
      logistic regression analysis, facilitating adjustment for potential confounders.
      The unadjusted genotype and allele frequencies in ISH or SDH subjects did not
      differ significantly from the control subjects (chi 2 = 3.0, P = 0.55, 4 d.f.;
      chi 2 = 3.0, P = 0.23, 2 d.f., respectively). After adjustment for potential
      confounders neither genotype nor allele predicted ISH or SDH in this cohort. 4.
      From this study we conclude that the A1166C polymorphism of the AT1 receptor gene
      is not a marker for ISH nor for SDH in this large, elderly community sample.

PMID- 10405782
TI  - Analysis in spontaneously hypertensive rats.
AB  - 1. Linkage analysis is performed between basal or salt-sensitive high blood
      pressure and several loci on chromosomes in F2 progenies obtained from crossing
      stroke-prone spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto
      rats. 2. Basal hypertensive genes are mapped to a region near the D1Mit2 locus on
      chromosome 1 and near the D3Mgh8 locus on chromosome 3 in the male and female F2
      progenies. 3. Salt-sensitive hypertensive gene is mapped to a region near RR1023
      locus on chromosome 10 in the male F2 progenies. 4. Salt-sensitive hypertensive
      gene is mapped to a region near D3Mgh12 locus on chromosome 3 in the female F2
      progenies.

PMID- 10405781
TI  - Physiological genetics: application to hypertension research.
AB  - 1. The rapid advancement of the human genome within the next 5-7 years begins a
      new era for biological research. The structure of all approximately 100,000 genes
      will be known, but the function of the majority of these genes will remain
      unknown. This paper outlines a 'physiological genetics' strategy for determining
      the genetic basis of hypertension by combining a variety of techniques (e.g.
      genetics, molecular biology, bioinformatics and physiology), to help identify
      gene function and the pathways involved in the development of hypertension in the
      rat. 2. Using comparative gene mapping, these regions can be used to implicate
      susceptibility loci for hypertension in humans, resulting in rapid conversion of
      basic research in animal models to relevant clinical assessment. The present
      study outlines some new strategies (i.e. whole-animal physiological genetics) as
      a means to study disease aetiology in polygenic disorders and to facilitate gene
      identification in the ascent of functional genomics.

PMID- 10405784
TI  - From animal models to humans.
AB  - 1. Essential hypertension is a mixture of several 'hypertensions' with different
      aetiologies. Analyses of inbred rat models of hypertension have so far provided
      several candidate loci and genes that may be responsible for hypertension. Among
      them, SA and alpha-adducin were evaluated in humans both by linkage and
      association analyses. However, the results are still controversial. Two major
      reasons may account for these discrepancies. 2. Heterogeneity of human essential
      hypertension still keeps us from comprehensive conclusions. Comparative analysis
      of more than one homogeneous population may be necessary to overcome this
      problem. 3. As in the case of SA, a lack of information on the physiological or
      pathophysiological roles of candidate genes makes it difficult to evaluate them
      in human hypertension. Efforts to find good intermediate phenotypes regulated
      directly by putative hypertension genes are essential to dissect a heterogeneous
      mixture of 'hypertensions'. In this context, physiological studies on congenic
      strains as well as conventional rat models will become important.

PMID- 10405783
TI  - Genetic analysis in Dahl salt-sensitive rats.
AB  - 1. To investigate predisposition to hypertension in Dahl salt-sensitive rats,
      genome-wide screens were performed in F2 populations. 2. Several quantitative
      trait loci (QTL) for blood pressure were detected, of which some were shown to
      confer susceptibility genes by the construction of congenic animals carrying
      relevant chromosome fragments. 3. Chromosome regions homologous to one QTL (on
      rat chromosome 10) were recently shown to be linked to hypertension in humans.
      Thus, there is a possibility that a 'common' susceptibility gene causes
      hypertension in both species.

PMID- 10405785
TI  - Angiotensin receptors: molecular biology and signalling.
AB  - 1. The active peptide hormone angiotensin II (AngII) is formed from its
      prohormone angiotensinogen by way of inactive angiotensin I. The highly specific
      protease, renin, responsible for the initiation of this system was elusive and
      considered unstable. We isolated it in a pure and stable form from the kidney of
      the pig, human, rat, and land submandibular glands of the mouse. It was shown
      that there is only one type of renin with highly stringent substrate specificity,
      except certain strains of the mouse which have two gene products. 2. The well
      known diversity of action of AngII can be attributed to the presence of more than
      two subtypes, AT1 and AT2, as well as multiple signalling pathways for both of
      them. 3. The first subtype AT1 was shown to mediate most of the traditionally
      recognized AngII functions such as vasoconstriction, electrolyte homeostasis etc.
      4. Although the identification of the signalling modes of the second subtype AT2
      still remains elusive, we and others have shown evidence that its action is
      generally antagonistic to that of AT1. AT2 inhibits AT1 (growth factor-stimulated
      cell growth), AT2 attenuates the vasoconstriction induced by AT1. Since AT2 seems
      to mediate nitric oxide formation in the renal cells, it may initiate a
      natriuretic pathway in contrast to the sodium-retaining action of AT1-mediated
      AngII action. 5. Newer mechanisms and functions of these and other receptors will
      be clarified by the combination of molecular, cellular and integrated
      physiological studies.

PMID- 10405786
TI  - Effect of steroid hormones on blood pressure.
AB  - 1. There is considerable evidence to support the idea that steroid hormones have
      the potential to increase blood pressure that may not always be via 'classical'
      mineralocorticoid or glucocorticoid action. 2. Epidemiological studies, together
      with the evidence from studies in animals, proposed the link between an adverse
      intra-uterine environment (i.e. undernutrition or excess exposure to
      glucocorticoids) and the early onset of cardiovascular and metabolic diseases
      later in life. 3. We tested this by treating pregnant ewes (and foetuses) with
      excess steroid early in pregnancy. The mean ages at which the prenatal exposure
      to glucocorticoid (dexamethasone 0.48 mg/h for 48 h) occurred were 22 +/- 0.4 to
      29 +/- 0.4 days (prenatal treatment group 1; PTG1) and 59 +/- 2 to 66 +/- 2 days
      (PTG2), respectively. Basal blood pressures and hormones and the vascular
      responsiveness to graded doses of angiotensin II and noradrenaline, or to a 5-day
      adrenocorticotropin hormone treatment (ACTH), in lambs at 4, 10 and 19 months of
      age were studied. 4. Basal mean arterial pressure in PTG1 group (80 +/- 1 mmHg at
      4 months; 83 +/- 1 mmHg at 10 months; and 89 +/- 1 mmHg at 19 months; n = 6) was
      significantly different (P < 0.05 in all groups) from that in the control group
      of lambs (74 +/- 2 mmHg at 4 months; 76 +/- 1 mmHg at 10 months; and 81 +/- 1
      mmHg at 19 months; n = 7). Prenatal glucocorticoid exposure did not alter
      vascular responsiveness to noradrenaline, angiotensin II and ACTH in these sheep
      at any of the ages studied. 5. These results suggest that foetal exposure to
      maternal dexamethasone during defined developmental stage or 'window' programmes
      elevated blood pressure, which persists later in life.

PMID- 10405787
TI  - Sarcoplasmic reticulum in vascular cells in hypertension and during
      proliferation.
AB  - 1. Multiple sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) and two types of
      sarcoplasmic reticulum Ca2+ channels, the ryanodine receptor and the inositol
      1,4,5 triphosphate (IP3) receptor are expressed. The heterogeneity of the Ca2+
      pumps and Ca2+ channels in vascular cells will be discussed. 2. An age-related
      change in expression of the SERCA isoforms is observed in smooth muscle cells. 3.
      The sarcoplasmic reticulum Ca(2+)-uptake rate and the level of SERCA 2 mRNA are
      different in thoracic than in abdominal aortas and in aortas from spontaneously
      hypertensive rats than from normotensive rats. 4. Proliferation of vascular
      smooth muscle cells is associated with major changes in intracellular Ca(2+)
      handling mechanisms.

PMID- 10405788
TI  - Hypertension and insulin resistance: role of peroxisome proliferator-activated
      receptor gamma.
AB  - 1. Insulin resistance has been highlighted as a common causal factor for
      hypertension, hyperlipidaemia, diabetes mellitus and obesity, all of which are
      recognized to occur simultaneously, and a distinct clinical entity is defined as
      'multiple risk factor syndrome'. 2. Recently, a new class of antidiabetic agents,
      thiazolidinediones (TZD) has been developed and has been shown to improve insulin
      resistance by binding and activating a nuclear receptor, peroxisome proliferator
      activated receptor (PPAR) gamma. 3. cDNA of rat PPAR gamma 1 and gamma 2 were
      cloned and gene regulation of PPAR gamma in rat mature adipocytes was examined.
      Hydrogen peroxide, an oxygen radical, which is recognized to be the common
      intracellular signal for multiple risk factors, potently down-regulated PPAR
      gamma mRNA expression in rat mature adipocytes. 4. Tumour necrosis factor (TNF)
      alpha, which is considered to play a role in obesity-induced non-insulin
      dependent diabetes mellitus and to augment oxidative stress, also suppressed PPAR
      gamma expression. 5. Thiazolidinediones dose-dependently recovered TNF-alpha
      induced down-regulation of PPAR gamma mRNA expression. 6. The modulation of PPAR
      gamma expression by TZD can be one mechanism for the improvement of insulin
      resistance by TZD. 7. Vascular tone and remodelling are controlled by several
      vasoactive autocrine/paracrine factors produced by endothelial cells in response
      to several vascular injury stimuli, including hypertension. The PPAR gamma gene
      transcript was detected in cultured endothelial cells. 8. The administration of
      TZD stimulated the endothelial secretion of type-C natriuretic peptide, which is
      one of the natriuretic peptide family and is demonstrated by us to act as a novel
      endothelium-derived relaxing peptide. 9. Concomitantly, TZD significantly
      suppressed the secretion of endothelin, a potent endothelium-derived
      vasoconstricting peptide. 10. Thiazolidinediones can affect vascular tone and
      growth by modulating the production of endothelium-derived vasoactive substances
      to influence occurrence and progression of hypertension and atherosclerosis.

PMID- 10405789
TI  - New members of uncoupling protein family implicated in energy metabolism.
AB  - 1. The regulation of energy metabolism involves food intake and energy
      expenditure. Mitochondrial uncoupling proteins (UCP) are implicated in energy
      expenditure. 2. cDNA of a homologue of UCP highly expressed in rat skeletal
      muscle, UCP-3, is isolated and sequenced. Rat UCP-2 cDNA is also isolated and
      sequenced. 3. Rat UCP-3 cDNA probe hybridized two bands, a major band at 2.5 kb
      and a minor band at 2.8 kb in rat tissues. The mRNA was expressed at the highest
      level in the skeletal muscle, and moderately in the interscapular brown adipose
      tissue (BAT). Only weak signals were detected in the epididymal white adipose
      tissue (WAT) and the heart. Rat UCP-2 cDNA probe hybridized a 1.7 kb band
      detected widely in the whole body, especially abundant in the lung and the
      spleen. In contrast to the UCP-3 gene expression, the UCP-2 gene expression was
      expressed at substantial levels in the WAT and only at slight levels in the
      skeletal muscle and BAT. 4. The UCP-3 gene expression is augmented two-fold in
      the gastrocnemius muscle from rats fed a high-fat diet (P < 0.05). The UCP-3 mRNA
      levels remained unchanged in the interscapular BAT, and epididymal WAT. The
      levels of the UCP-2 gene expression are augmented significantly in the epididymal
      WAT (1.6-fold; P < 0.05), while no significant increase is observed in the
      gastrocnemius muscle and interscapular BAT.

PMID- 10405790
TI  - Hypertension mechanisms causing stroke.
AB  - 1. Although it is well established that hypertension is the main risk factor for
      stroke, the complexity of cerebrovascular problems related to hypertension is not
      generally appreciated. 2. Hypertension can cause stroke through many mechanisms.
      A high intraluminal pressure will lead to extensive alteration in endothelium and
      smooth muscle function in intracerebral arteries. The increased stress on the
      endothelium can increase permeability over the blood-brain barrier and local or
      multifocal brain oedema. Endothelial damage and altered blood cell-endothelium
      interaction can lead to local thrombi formation and ischaemic lesions. Fibrinoid
      necrosis can cause lacunar infarcts through focal stenosis and occlusions.
      Degenerative changes in smooth muscle cells and endothelium predisposes for
      intracerebral haemorrhages. Furthermore, hypertension accelerates the
      arteriosclerotic process, thus increasing the likelihood for cerebral lesions
      related to stenosis and embolism originating from large extracranial vessels, the
      aortic arch and from the heart. 3. Adaptive structural changes in the resistance
      vessels, while having the positive effect of reducing the vessel wall tension,
      have the negative consequence of increased peripheral vascular resistance that
      may compromise the collateral circulation and enhance the risk for ischaemic
      events in connection with episodes of hypotension or distal to a stenosis. 4.
      Hypertension is clearly a risk factor for vascular dementia. All the mechanisms
      referred to above may be important.

PMID- 10405791
TI  - Gene related to stroke in stroke-prone spontaneously hypertensive rats.
AB  - 1. In order to study genes related to stroke in stroke-prone spontaneously
      hypertensive rats (SHRSP), linkage analysis was performed using F2 rats
      (SHRSP/Izm x WKY/Izm). The brainweight that reflected cerebral stroke in F2 rats
      showed cosegregation with three genetic markers, D4Mit19 (P < 0.0015), D4Mgh7 (P
      < 0.0014) and D4Mgh8 (P < 0.004) on chromosome 4, but not blood pressure. 2.
      These results suggest that a chromosomal region other than the region responsible
      for hypertension contributes to the development of stroke in SHRSP.

PMID- 10405792
TI  - Implication of hypertensive rat models for primordial nutritional prevention of
      cardiovascular diseases.
AB  - 1. Various substrains maintained during selective sib-mating contributed to the
      establishment of spontaneously hypertensive rats (SHR) with a variety of clinical
      features. 2. Stroke-prone SHR (SHRSP), developing haemorrhagic and/or ischaemic
      stroke spontaneously, are regarded as a model for osteoporosis. 3. The genetic
      mechanisms of spontaneous hypertension have been attributed pathophysiologically
      to neural and structural vascular alterations. 4. The mechanisms of stroke are
      ascribed to the limited regional oxygen and nutrient supplies to the brain areas
      fed by perforating arteries. 5. The genome-wide linkage analysis on the F2
      obtained by crosses of SHRSP with normotensive strains has demonstrated different
      gene loci contributing to the development and maintenance of hypertension during
      the ageing process and also genes influencing the susceptibility to stroke
      without any effect on blood pressure. 6. Experimental studies in SHRSP revealed
      that stroke could be prevented by protein, Ca- or Mg-supplemented diets,
      particularly if given in the early stage, indicating the importance of primordial
      nutritional prevention of cardiovascular diseases (CVD). 7. Experimental findings
      in SHRSP as well as epidemiological studies on nutrition and CVD indicate the
      future avenue towards 'predictive-preventive medicine' for CVD.

PMID- 10405793
TI  - Preventive nutritional factors in epidemiology: interaction between sodium and
      calcium.
AB  - 1. It is generally believed, though difficult to prove, that diet plays a role in
      the risk of various diseases. Components of difficulties include several issues
      such as dietary assessment method, regression dilution bias, multicolinearity and
      interaction among nutrients. 2. The present study focuses on colinearity and
      interaction between sodium and calcium, which should be cautiously examined in
      nutritional epidemiological studies in relation to blood pressure and bone
      mineral density. 3. The World Health Organization's International Cooperative
      Cardiovascular Diseases and Alimentary Comparison study showed significant
      multicolinearity among urinary sodium, calcium and urea nitrogen as well as
      urinary calcium and magnesium. Urinary sodium and calcium had significant
      correlation (r = 0.438, P < 0.05, n = 48) by cross-centre analysis. 4.
      Interaction between sodium and calcium on bone mineral density is studied using
      the data set from bone mineral density screening for 1658 females, aged 20-40
      years, in Yokohama, Japan. Among those who have lower calcium intake (< 600
      mg/day), higher calcium intake (%) from small fish, which is likely to be
      associated with a high salt diet, related to significantly lower mineral bone
      density. 5. Interaction between sodium and calcium on bone mineral density among
      young Japanese females is suggested. Moderate sodium restriction is needed for
      prevention of not only cardiovascular diseases but also osteoporosis.

PMID- 10405794
TI  - Bad genes, good people, association, linkage, longevity and the prevention of
      cardiovascular disease.
AB  - 1. Cardiovascular disease, the most common cause of death, is the product of risk
      factors such as hypertension, lipid disturbances, diabetes mellitus, left
      ventricular hypertrophy and nicotine smoking, all of which are influenced by
      genetic variance. Thus, genes that influence these factors have a considerable
      bearing on longevity. 2. Although mortality rates increase exponentially with
      increasing age, an interesting tendency towards a plateau occurs, suggesting that
      old individuals are somewhat protected from the propensity to die. This
      phenomenon is difficult to explain. 3. One possibility is a model of repair, in
      which certain alleles exert a beneficial influence at an advanced age. 4. An
      alternative explanation might be a mutation that exerts both negative and
      positive effects. 5. The insertion/deletion (I/D) polymorphism in the angiotensin
      converting enzyme (ACE) gene exerts was observed to have an effect on heart size.
      The D allele was linked to a greater heart size, compared with the I allele in a
      modified sibpair model. This potentially deleterious effect was counter-balanced
      by linkage of the D allele to increased heart rate variability, which is
      potentially a beneficial attribute. Furthermore, in a cohort of the German
      population over age 80 years, it was observed that the D allele occurred at a
      frequency higher than would be expected. 6. The present study discusses the
      hypothesis that the ACE gene I/D polymorphism may be a genetic variant with both
      negative and positive effects.

PMID- 10405795
TI  - Degradation of pesticides by actinomycetes.
AB  - Actinomycetes have considerable potential for the biotransformation and
      biodegradation of pesticides. Members of this group of Gram-positive bacteria
      have been found to degrade pesticides with widely different chemical structures,
      including organochlorines, s-triazines, triazinones, carbamates,
      organophosphates, organophosphonates, acetanilides, and sulfonylureas. A limited
      number of these xenobiotic pesticides can be mineralized by single isolates, but
      often consortia of bacteria are required for complete degradation. Cometabolism
      of pesticides is frequently observed within this group of bacteria. When compared
      with pesticide degradation by Gram-negative bacteria, much less information about
      molecular mechanisms involved in biotransformations of pesticides by
      actinomycetes is available. Progress in this area has been seriously hampered by
      a lack of suitable molecular genetic tools for most representatives of this major
      group of soil bacteria. Overcoming this constraint would enable a better
      exploitation of the biodegradation and biotransformation abilities of
      actinomycetes for applications such as bioremediation and construction of
      transgenic herbicide-resistant crops.

PMID- 10405796
TI  - From field barley to malt: detection and specification of microbial activity for
      quality aspects.
AB  - Barley grain carries a numerous, variable, and complex microbial population that
      mainly consists of bacteria, yeasts, and filamentous fungi and that can partly be
      detected and quantified using plating methods and microscopic and molecular
      techniques. The extent and the activity of this microflora are determined by the
      altering state of the grain and the environmental conditions in the malt
      production chain. Three ecological systems can be distinguished: the growing
      cereal in the field, the dry barley grain under storage, and the germinating
      barley kernel during actual malting. Microorganisms interact with the malting
      process both by their presence and by their metabolic activity. In this respect,
      interference with the oxygen uptake by the barley grain and secretion of enzymes,
      hormones, toxins, and acids that may affect the plant physiological processes
      have been studied. As a result of the interaction, microorganisms can cause
      important losses and influence malt quality as measured by brewhouse performance
      and beer quality. Of particular concern is the occurrence of mycotoxins that may
      affect the safety of malt. The development of the microflora during malt
      production can to a certain extent be controlled by the selection of appropriate
      process conditions. Physical and chemical treatments to inactivate the microbial
      population on the barley grain are suggested. Recent developments, however, aim
      to control the microbial activity during malt production by promoting the growth
      of desirable microbial cultures, selected either as biocontrol agents inhibiting
      mycotoxin-producing molds or as starter cultures actively contributing to malt
      modification. Such techniques may offer natural opportunities to improve the
      quality and safety of malt.

PMID- 10405797
TI  - The Papanicolaou smear and the obstetric patient: a simple test with great
      benefits.

PMID- 10405798
TI  - Pap smear follow-up of possible role of mucopurulent exudate as a prognosticator
      of a negative pregnancy outcome.
AB  - Our objective was to study a cohort of women by various means to detect sexually
      transmitted diseases (STD) and to correlate the presence of mucopurulent exudate
      (PEX) on Papanicolaou (Pap) smears with pregnancy outcome. Bacteriologic cultures
      taken from swabs for chlamydia and gonorrhea were correlated with Gen-Probe
      results. Smears were examined for trichomonas, yeast, HPV, obscuring mucopurulent
      exudate, and squamous intraepithelial abnormalities. There was no positive
      correlation between STD and negative pregnancy outcome. Mucopurulent exudate on
      Pap smears was very high in this population. Continuing study of this population
      of women is needed to see if larger cohorts will demonstrate any positive
      correlations between PEX and pregnancy outcome. Placing women with obscuring
      mucopurulent exudate in a "high-risk" category for complications may prevent
      adverse side effects to the birth product. The Pap smear works as well as the
      Gram stain for detection of bacterial vaginosis and cervicitis. Eliminating the
      Gram stain from routine pelvic exam results in cost savings.

PMID- 10405799
TI  - Association between a shift in vaginal flora on Papanicolaou smear and acute
      chorioamnionitis and preterm delivery.
AB  - Bacterial vaginosis has been implicated as a cause of acute chorioamnionitis and
      preterm delivery. This study was designed to determine any association between
      the detection of bacterial vaginosis on a prenatal Papanicolaou (Pap) smear,
      defined as a shift in vaginal flora, and the subsequent occurrence of acute
      chorioamnionitis or preterm labor. A 47-mo retrospective case-control analysis
      comparing 186 patients with histologically-proven acute chorioamnionitis (cases)
      and 186 controls was performed. Initial prenatal Pap smears were evaluated for
      the presence of altered vaginal flora. Pap smears from women with acute
      chorioamnionitis were more likely to have altered vaginal flora than those
      without chorioamnionitis (P < 0.01). Preterm delivery was also more common among
      women with a shift in vaginal flora (P < 0.01). In conclusion, women at risk for
      chorioamnionitis and/or preterm delivery may be able to be identified by the
      results of their prenatal Pap smear.

PMID- 10405800
TI  - Routine Pap smears for the diagnosis of bacterial vaginosis.
AB  - This study investigated the role of Papanicolaou (Pap) smears in determining the
      presence of bacterial vaginosis (BV). Pap results, vaginal Gram stains, signs,
      symptoms, and wet mounts were evaluated. Vaginal smears for Gram stain and
      routine Pap smears were collected from 420 consecutive patients. Ninety-three
      percent of patients with Pap smears showing only coccobacilli had a corresponding
      BV-positive Gram stain. Pap smears with mixed bacterial patterns had 22-71%
      positive Gram stains depending on the types of bacteria present. Only 10 of 70
      symptomatic patients and 13 of 132 with cervicitis or discharge had a positive
      Gram stain and/or an altered bacterial pattern. All positive wet mounts had
      positive Gram stains and coccobacilli only on Pap smears. The most specific
      diagnosis of BV with Pap smears requires coccobacilli only. This reiterates the
      Bethesda system criteria. Clinical signs, physical symptoms, and wet-mount
      examinations were noncontributory in this study.

PMID- 10405801
TI  - Clinical significance of identifying candida on cervicovaginal (Pap) smears.
AB  - This study was undertaken to determine the clinical significance of detecting
      candida on Pap smear. Clinical information was obtained from a questionnaire sent
      to the health care provider whenever candida was identified during the study
      period. Candida was identified in 309 (3.0%) of the 10,370 Pap smears examined.
      Completed questionnaires were returned on 137 (44.3%) patients. All 137 smears
      were reviewed. Ninety-nine (72%) patients were asymptomatic, 29 (21%) had
      symptoms typical of candida infection, and nine (7%) had nonspecific symptoms.
      Forty-four (32%) patients had been treated for candida during the original clinic
      visit. After the Pap smear reported candida, 19 (20%) of the 93 nontreated
      patients were contacted and treated, while 10 (11%) were scheduled for further
      evaluation. No action was taken on the remaining 64 (69%) patients. There was a
      significant association between having initial symptoms and receiving immediate
      treatment (P < 0.001) and undergoing subsequent treatment or further evaluation
      after the Pap smear report (P < 0.001). Marked inflammation was statistically
      associated with symptoms (P = 0.014), but the form or number of candida organisms
      was not. In conclusion, the identification of Candida on Pap smear does not
      necessarily indicate a symptomatic infection, although the Pap smear results had
      a direct impact on the treatment of 21% of patients in this study and served as a
      confirmation for clinical treatment in another 32% who had received such
      treatment at the time of the original visit.

PMID- 10405802
TI  - Immunohistochemical detection of cytotoxic lymphocytes in malignant serous
      effusions.
AB  - The use of ancillary techniques to aid in the diagnosis of metastatic carcinoma
      in serous effusions has been the subject of numerous studies. In this article, we
      study 35 cases of malignant effusions (metastatic adenocarcinoma) and 20 benign
      effusions using a panel of immunohistochemical markers to determine whether
      changes in the subpopulations of accompanying lymphoid cells can be detected with
      this technique and whether such changes are associated with the presence of
      malignancy. We noted a significant increase in cytotoxic lymphocytes, defined as
      the percentage of all lymphoid cells staining with an antibody to TIA-1 (an
      antigen localized to the cytotoxic granule membranes of cytotoxic T cells and
      natural killer cells) in malignant compared with benign effusions (23% vs. 12%; P
      < 0.05). In addition, nearly all cases in which cytotoxic lymphocytes composed >
      20% of the lymphoid cell population contained metastatic tumor. Thus,
      immunohistochemical staining for TIA-1 can reliably detect cytotoxic lymphocytes
      in cell blocks of serous effusions; in addition, a relative increase in their
      number is associated with the presence of malignancy.

PMID- 10405803
TI  - Fine-needle aspiration findings in idiopathic retroperitoneal fibrosis.
AB  - Idiopathic retroperitoneal fibrosis (IRF) is an inflammatory and fibrosing
      process that can be complicated by periureteral encasement, ureteral obstruction,
      and subsequent renal failure if left untreated. Unfortunately, treatment is often
      delayed due to the nonspecific nature of the presenting signs and symptoms.
      Clinical, radiologic, and microscopic findings in IRF, if examined independently,
      are all nonspecific for its diagnosis. Rendering a diagnosis of IRF by fine
      needle aspiration (FNA) requires supportive clinical and radiologic data and
      systematic evaluation of entities in the differential diagnosis. Herein we report
      2 cases of IRF diagnosed by FNA with subsequent histologic confirmation. Smears
      prepared from the aspirates revealed a combination of inflammatory cells and
      fibrous tissue. The inflammatory component was comprised of a mixture of
      lymphocytes, plasma cells, and rare eosinophils and mast cells. These 2 cases
      represent, to our knowledge, only the second report of IRF diagnosed by FNA.

PMID- 10405804
TI  - Utility of the BTA stat test kit for bladder cancer screening.
AB  - Our study evaluated the BTA (bladder tumor antigen) stat test kit as a primary
      screening device for the detection of transitional-cell carcinoma (TCC) of the
      bladder, with direct comparison by voided urine cytology (VUC) on the same
      specimens. The unfixed voided urine of 100 patients with no history of bladder
      cancer who had signs and symptoms of dysuria, incontinence, and gross hematuria
      and microhematuria were tested using the one-step BTA stat test kit before
      processing via the cytospin technique for fluid cytological evaluation. The
      patients in the study were followed for up to 12 mo with repeated urine
      cytological testing, cystoscopy, and bladder biopsy when clinically indicated.
      Nineteen cases tested positive, and 81 cases tested negative on the BTA stat
      test. VUC diagnosed three cases as unequivocally positive for TCC, 93 cases as
      negative, and four cases in which unqualified atypical urothelial cells were
      noted. TCC was confirmed by cystoscopy and bladder biopsy in three of three cases
      diagnosed by VUC and in three of 19 cases that tested positive by the BTA stat
      test. These findings resulted in an 84% false-positive rate for the BTA stat test
      and no false-positive cases for VUC during the 12-mo follow-up period. The
      results indicate that the sensitivity and specificity of BTA stat test are
      comparable to those of VUC; however, owing to a relatively high false-positive
      rate, it can at best act as an adjunct to urine cytological study for bladder
      cancer screening.

PMID- 10405805
TI  - Comparative cytologic and histologic study of fifteen salivary basal-cell tumors:
      differential diagnostic considerations.
AB  - Cytologic results of preoperative fine-needle sampling (FNS) of 15 salivary basal
      cell tumors are presented, described, and compared with histologic results.
      Eleven of the FNAS showed individual and clusters of homogeneous basaloid cells
      with scanty cytoplasm, occasional peripheral palisading, and naked nuclei and
      were diagnosed as basal-cell adenoma. Four samples showed, in addition, three
      dimensional cell clusters with mild cytonuclear atypia, occasional mitosis,
      and/or focal necrosis and were diagnosed as basal-cell adenocarcinoma. Basal-cell
      tumors must be diagnostically differentiated from adenoid cystic carcinoma and
      metastatic basal-cell carcinoma. Although the adenomas diagnosed by cytologic
      examination and four suspected carcinomas in our series were verified by
      histologic testing, the bland cytologic features of basal-cell adenocarcinoma may
      not always allow diagnosis on cytologic examination.

PMID- 10405806
TI  - Utilization of fine-needle aspiration in the diagnosis of metastatic tumors to
      the kidney.
AB  - Renal masses secondary to metastases are not common. Few comprehensive reviews
      exist, which consist primarily of autopsy and radiologic reports. The purpose of
      this study was to review the types and incidences of various neoplasms which
      metastasize to the kidney and to determine the usefulness of fine-needle
      aspiration (FNA) in diagnosing them. Two hundred and sixty-one radiologically
      guided FNAs of renal lesions over a 9-yr period were reviewed. The diagnoses of
      the 261 renal FNAs were as follows: 136 (52%) were malignant, 111 (43%) were
      benign, and 14 (5%) were unsatisfactory. Of the 136 positive FNAs, 28 (21%)
      revealed metastatic tumors. The overall incidence of renal FNAs displaying
      metastatic tumors was 11%. Among the 28 patients with metastases to the kidney,
      23 patients were men and 5 were women, with the mean age being 58 yr. Twenty-five
      patients (89%) had prior history of a primary malignancy, including lung
      carcinoma (11 cases, 39%), lymphoma (8 cases, 29%), hepatocellular carcinoma (3
      cases, 11%), and one case each of breast, pancreatic, and cervical cancer. In the
      remaining 3 patients (11%), with metastatic adenocarcinoma (2 cases) and squamous
      cell carcinoma (1 case), the primary tumor site remained unknown despite an
      extensive clinical workup. Overall survival after FNA was poor, with a mean of
      9.8 mo. FNA is useful in the diagnosis of masses in the kidney secondary to
      metastatic disease. This information is of clinical importance, principally in
      the exclusion of a primary malignancy, but also to avoid unnecessary surgery and
      to plan for subsequent patient care.

PMID- 10405807
TI  - Correlation of CT-guided fine-needle aspiration biopsy of the liver with fluoride
      18 fluorodeoxyglucose positron emission tomography in the assessment of
      metastatic hepatic abnormalities.
AB  - Imaging studies using the fluoride-18 fluorodeoxyglucose positron emission
      tomography (FDG-PET) scan have recently become available for patient neoplasia
      evaluation. Fine-needle aspiration (FNA) biopsy is a well-described diagnostic
      method for hepatic lesion evaluation. Correlation of these testing modalities in
      hepatic abnormalities has not been previously reported. Pathology files of Saint
      Louis University Hospital were retrospectively searched for patients with FNA
      biopsy of the liver. Thirty-one patients with a total of 32 FNA biopsies of the
      liver with corresponding FDG-PET scans were identified. Twenty-five patients had
      25 cases of metastatic malignant neoplasia diagnosed by FNA biopsy. Of these
      cases, all but one had an FDG-PET scan positive for malignancy, yielding a
      sensitivity of 96% (24/25) for the FDG-PET scan. Combined positivity of the two
      testing modalities yielded a sensitivity of 100% (24/24). Seven patients did not
      demonstrate neoplasia by FNA biopsy, and the FDG-PET scan was negative in 6 of
      these 7 cases. The FDG-PET scan is an important imaging technique and, combined
      with FNA biopsy, can provide reliable diagnostic results and assist in the
      guidance of oncologic patient management.

PMID- 10405808
TI  - Hepatic metastases from medullary thyroid carcinoma appearing twelve years after
      the eradication of primitive tumor: cytological and radiological aspects.
AB  - We report on radiological and cytological findings from a case of medullary
      thyroid carcinoma (MTC) metastatizing to the liver 12 yr after the eradication of
      the primary neoplasm. This behavior has never before been described in a sporadic
      form of MTC.

PMID- 10405810
TI  - Multicentric oncocytoma of the lung diagnosed by fine-needle aspiration.
AB  - A 50-yr-old man presented with dyspnea. On chest X-ray, multiple pulmonary
      nodules were observed. Fine-needle aspiration biopsy (FNAB) showed tridimensional
      aggregates of atypical round epithelial cells, containing numerous cytoplasmic
      granules. The tissue fragment confirmed the presence of an epithelial tumor
      composed of trabecular sheets of clear cells, with numerous cytoplasmic granules
      which stained with phosphotungstic acid hematoxylin (PTAH).
      Immunohistochemically, the tumor cells were positive for cytokeratins and
      antimitochondrial antigen, whereas chromogranin, synaptophysin, S-100 protein,
      and HMB-45 were negative. Clinical and tomographic studies ruled out any tumor
      mass elsewhere. The rarity of this lesion in the lung and the potential
      difficulties for its diagnosis prompted us to report the clinical, cytological,
      and immunohistochemical findings in this case.

PMID- 10405809
TI  - Salivary gland neoplasms with basaloid cell features: report of two cases
      diagnosed by fine-needle aspiration cytology.
AB  - Basal-cell adenoma and basal-cell adenocarcinoma of the salivary gland are rare
      tumors. Fine-needle aspiration cytology of these tumors, particularly those of
      basal-cell adenocarcinoma, has rarely been described in the literature. In this
      report, we describe the clinical, cytomorphologic, histopathologic, and
      immunohistochemical features of basal-cell adenoma and its malignant counterpart,
      basal-cell adenocarcinoma, in 2 patients. Fine-needle aspiration specimens from
      both tumors contained abundant cohesive groups of neoplastic cells. Basaloid
      cells were prominent in both tumors; however, there were significant cytologic
      atypia, hyperchromasia, and increased nuclear-to-cytoplasmic ratio in basal-cell
      adenocarcinoma. Review of the literature and cytomorphologic distinction between
      both tumors and others are discussed.

PMID- 10405811
TI  - Interesting morphologic finding in T-cell acute lymphoblastic leukemia.
AB  - There is no specific morphologic finding that is representative of different
      phenotypic patterns of acute lymphoblastic leukemia (ALL). In 15 cases of T-cell
      ALL, there were ruptured white blood cells among the lymphoblasts, as seen in
      chronic lymphocytic leukemia. These 15 cases are presented in this report.

PMID- 10405813
TI  - Guidelines of the Papanicolaou Society of Cytopathology for the examination of
      cytologic specimens obtained from the respiratory tract. Papanicolaou Society of
      Cytopathology Task Force on Standards of Practice.

PMID- 10405812
TI  - Fine-needle aspiration findings in Castleman's disease.
AB  - Castleman's disease of the hyaline vascular subtype is an uncommon lesion;
      experience with fine-needle aspiration (FNA) of this tumor is limited to rare
      case reports. We describe the cytologic, flow cytometric, and immunohistochemical
      findings in two cases initially sampled by FNA. Two females, aged 40 and 26 yr,
      were found incidentally to have an oropharyngeal and a mediastinal mass,
      respectively. Neither complained of systemic symptoms, and both had a normal
      routine laboratory workup. FNA followed by surgical excision in both cases was
      consistent with Castleman's disease of the hyaline vascular type. In the
      appropriate clinical context, a mature small lymphoid population associated with
      larger atypical cells, which are consistent with follicular dendritic cells, can
      be suggestive of Castleman's disease. Confirmation of a polytypic B-cell
      population by flow cytometry, supported by immunohistochemistry, is very helpful.
      However, definitive distinction from Hodgkin's lymphoma on FNA is probably not
      possible.

PMID- 10405814
TI  - Metastatic inflammatory breast carcinoma.

PMID- 10405815
TI  - Metastatic hepatocellular carcinoma (HCC) in adrenal fine-needle aspirate.
      Cytopathologic findings in an unusual case.

PMID- 10405816
TI  - Dipeptidyl aminopeptidase IV (CD26) expression in thyroid tissues.

PMID- 10405817
TI  - Extrapineal melatonin: location and role within diffuse neuroendocrine system.
AB  - During the last decade, much attention has centred on melatonin, one of the
      hormones of the diffuse neuroendocrine system. For many years it was considered
      to be only a hormone of the pineal gland. As soon as highly sensitive antibodies
      to indolealkylamines became available, melatonin was identified not only in
      pineal gland, but also in extrapineal tissues. These included the retina,
      Harderian gland, gut mucosa, cerebellum, airway epithelium, liver, kidney,
      adrenals, thymus, thyroid, pancreas, ovary, carotid body, placenta and
      endometrium. It has also been localized in non-neuroendocrine cells such as mast
      cells, natural killer cells, eosinophilic leukocytes, platelets and endothelial
      cells. This list of cells indicates that melatonin has a unique position among
      the hormones of the diffuse neuroendocrine system. It is found in practically all
      organ systems. Functionally, melatonin-producing cells are part and parcel of the
      diffuse neuroendocrine system as a universal system of response, control and
      organism protection. Taking into account the large number of such melatonin
      producing cells in many organs, the wide spectrum of biological activities of
      melatonin and especially its main property as a universal regulator of biological
      rhythms, it is now possible to consider extrapineal melatonin as a key paracrine
      signal molecule for the local co-ordination of intercellular relationships.

PMID- 10405819
TI  - An unusual sexually dimorphic mosaic distribution of a subset of kallikreins in
      the granular convoluted tubule of the mouse submandibular gland detected by an
      antibody with restricted immunoreactivity.
AB  - The granular convoluted tubule of the mouse submandibular gland contains a wide
      variety of biologically active proteins, including several kallikreins. The
      tubule is under multihormonal regulation, and is sexually dimorphic, being larger
      in males than in females. Correspondingly, levels of its various protein
      secretory products are more abundant in males than in females. However,
      isoelectric focussing studies show that the true tissue kallikrein, mK1, is more
      abundant in the female than in the male submandibular gland. In this study, an
      antiserum was prepared with restricted immunoreactivity for mouse mK1, and
      possibly other kallikrein family members of low abundance in the mouse
      submandibular gland, and used for the immunocytochemical staining of the granular
      convoluted tubule cells in the submandibular gland of adult male and female mice,
      by indirect enzyme-labeled and immunogold-labeled antibody methods for light and
      electron microscopy, respectively. The distribution of immunoreactive tubule
      cells showed an unusual sexual dimorphism. In males only a few scattered slender
      tubule cells were strongly stained, while the more typical large tubule cells
      were only occasionally weakly positive, and many of them were not stained. By
      contrast, in females slender tubule cells were not seen, and about two thirds of
      the more typical tubule cells showed moderate to strong immunostaining.
      Immunoelectron microscopy revealed that immunostaining was confined to the
      secretion granules in granular convoluted tubule cells in both sexes. The slender
      tubule cells of males had many strongly stained small apical secretion granules
      and occasional basal infoldings; in the weakly positive larger more typical
      tubule cells not all secretion granules were positive, and there was
      intergranular variation in the intensity of staining of positive granules. In
      females, although more tubule cells were stained, intergranular variations in
      staining intensity were also noted. In both sexes, many tubule cells did not
      contain any secretion granules that showed immunogold labeling for kallikreins.
      These findings establish that, in contrast to the situation for the majority of
      granular convoluted tubules proteins, mK1 and possibly other minor kallikrein
      family members are more abundant in the granular convoluted tubules of female
      mice, and that there is considerable variation in the content of these
      kallikreins not only between different tubule cells, but also in individual
      secretion granules in any given tubule cell in either sex.

PMID- 10405818
TI  - Expression of transglutaminase K in normal cervix tissue and cervix carcinomas.
AB  - The localization and expression of transglutaminase K has been investigated
      immunohistochemically in normal cervix tissue (n = 15) and in cervix carcinomas
      (n = 23). The distribution of the transglutaminase K was compared with the
      staining patterns of cytokeratin 10, Ki-67, p53, and oestrogen and progesterone
      receptors in these tumours. Weak to strong membrane-bound immunoreactivity for
      transglutaminase K was detected in almost all cervix carcinomas analyzed. The
      immunostaining was heterogeneous, with visual differences between individual
      tumour cells. 66.7% of normal cervix tissues revealed no immunoreactivity for the
      transglutaminase K. In normal cervix tissue, the immunoreactivity was confined to
      upper cervix layers, predominantly to the superficial and intermediate cell
      layers. The intensity of both the immunostaining and the number of
      transglutaminase K-positive cells were upregulated in cervix carcinomas as
      compared to normal cervix tissue. When the coexpressions of transglutaminase K
      with markers of proliferation and differentiation were analyzed, no statistically
      significant correlation was found. Our findings indicate that (1)
      transglutaminase K is upregulated at the protein level in cervix carcinomas as
      compared to normal cervix tissue; (2) upregulation of the transglutaminase K in
      cervix carcinoma is not exclusively induced by alterations of epithelial
      differentiation or proliferation, but by different, unknown mechanisms; and (3)
      upregulation of transglutaminase K in cervix carcinomas may play an important
      role for the regulation of tumour invasive properties by modulating cell-cell
      interactions.

PMID- 10405820
TI  - Cytochemical and western blot analysis of the subcompartmentalization of the
      acrosome in rodents using soybean lectin.
AB  - In the present study, the formation and development of the acrosome during
      spermiogenesis in four different rodent species (rat, mouse, hamster and guinea
      pig) was compared by means of cytochemical and blotting techniques using a lectin
      from soybean (SBA). This lectin recognizes specifically the acrosome of the four
      species at all steps of formation. At the ultrastructural level, SBA-binding
      pattern was similar in the acrosome of the rat, mouse and hamster. SBA
      preferentially labelled the electron-lucent area of the acrosome in early
      spermatids (Golgi and cap phases) and the outer region of the acrosome in mature
      spermatids (acrosome and maturation phase). The lectin binding pattern was more
      complex in the guinea pig acrosome. Three different subdomains can be established
      in the early acrosome of the guinea pig. The lectin bound the three subdomains
      but mainly a thin fold which spreads over the nucleus during the cap phase. In
      the acrosome phase, SBA strongly reacted with the principal segment. In contrast,
      no reactivity was observed in most of this segment in maturation phase
      spermatids. In this phase, SBA bound preferentially a thin area covering the
      dorsal region of the apical segment. Lectin blots of detergent-extracted testes
      indicated that SBA only recognizes proteins of high molecular weight (> 100 kD)
      in the four species studied. The results obtained in the present study suggest
      that the development of acrosomal subdomains is very similar in the mouse, rat
      and hamster but shows a more complex pattern in the guinea pig.

PMID- 10405821
TI  - Expression of an antigen associated with basal bodies of human ciliated
      epithelial cells.
AB  - The process and regulation of ciliogenesis in human epithelia is little
      understood and many components of the cilium and associated structures have not
      been characterised. We have identified a monoclonal antibody, LhS28, which
      recognises a 44,000-45,000 M(r) protein specifically associated with human
      ciliated epithelial cells. Immunoperoxidase labelling of formalin-fixed paraffin
      wax-embedded human tissues showed that LhS28 was expressed in the sub-apical zone
      of ciliated epithelial cells of the Fallopian tube and upper respiratory tract,
      but not ciliated ependyma, non-ciliated epithelia or testis containing developing
      spermatozoa. Immunoelectron microscopy demonstrated that the antigen recognised
      by LhS28 was associated with the basal body structure of the cilium and
      specifically with the 9 + 0 microtubule arrays. LhS28 should be a useful tool in
      the identification of ciliated cells in pathological specimens and for
      investigating mechanisms of ciliogenesis.

PMID- 10405822
TI  - Time-resolved fluorescence in immunocytochemical detection of prostate-specific
      antigen in prostatic tissue sections.
AB  - Chelates with fluorescent lanthanides such as europium and terbium are widely
      used in immunofluorometric assays, e.g. for the measurement of different
      molecular forms of prostate-specific antigen (PSA) in serum for detection and
      monitoring of prostate cancer. These chelates have also been introduced as non
      radioactive labels in immunocytochemistry and in situ hybridization. In the
      present study, sections of non-malignant prostate were investigated using
      monoclonal IgGs against PSA. Detection of specific immunostaining employing time
      resolved fluorescence with europium-labeled streptavidin was compared with
      conventional detection by streptavidin conjugated to horse-radish peroxidase. The
      high PSA concentration in the tissue produced high intensity, specific time
      resolved fluorescence signals in the epithelial cells of the prostate gland
      without disturbance from non-specific tissue autofluorescense. This allowed short
      exposure times to be used which resulted in insignificant photobleaching. Two of
      the three europium-chelates evaluated yielded high signal intensities.
      Counterstaining was found to be optimal with Gill No. 1-Haematoxylin solution and
      Merckoglas was the best mounting medium for the europium chelates tested. In
      conclusion, time-resolved fluorescence imaging is an attractive alternative to
      conventional detection of streptavidin conjugated to horse-radish peroxidase, as
      it provides linear, high intensity, specific signals subsequent to the decay of
      non-specific tissue autofluorescence.

PMID- 10405823
TI  - Association of matrix acid and alkaline phosphatases with mineralization of
      cartilage and endochondral bone.
AB  - The activities of acid and alkaline phosphatases were localized by enzyme
      histochemistry in the chondroepiphyses of 5 week old rabbits. Using
      paraformaldehyde-lysine-periodate as fixative, the activity of acid phosphatase
      was particularly well preserved and could be demonstrated not only in
      osteoclasts, but also in chondrocytes as well as in the cartilage and early
      endochondral matrices. The acid phosphatase in the chondrocytes and the matrix
      was tartrate-resistant, but inhibited by 2 mM sodium fluoride, whereas for
      osteoclasts 50-100 mM sodium fluoride were required for inhibition. Simultaneous
      localisation of both acid and alkaline phosphatase activities was possible in
      tissue that had been fixed in 85% ethanol and processed immediately. In the
      growth plates of the secondary ossification centre and the physis, there was a
      sequential localisation of the two phosphatases associated with chondrocyte
      maturation. The matrix surrounding immature epiphyseal chondrocytes or
      resting/proliferating growth plate chondrocytes contained weak acid phosphatase
      activity. Maturing chondrocytes were positive for alkaline phosphatase which
      spread to the matrix in the pre-mineralizing zone, in a pattern that was
      consistent with the known location of matrix vesicles. The region of strong
      alkaline phosphatase activity was the precise region where acid phosphatase
      activity was reduced. With the onset of cartilage calcification, alkaline
      phosphatase activity disappeared, but strong acid phosphatase activity was found
      in close association with the early mineral deposition. Acid phosphatase activity
      was also present in the matrix of the endochondral bone, but was only found in
      early spicules which had recently mineralised. The results suggest that alkaline
      phosphatase activity is required in preparation of mineralization, whereas acid
      phosphatase activity might have a contributory role during the early progression
      of mineral formation.

PMID- 10405825
TI  - Tannic acid and thiocarbohydrazide as structural reinforcement agents in the
      preparation of rabbit knee articular cartilage for the scanning electron
      microscope.
AB  - Samples from seven sectors of the rabbit knee articular cartilage were shaved and
      prepared for the scanning electron microscope using either tannic acid,
      thiocarbohydrazide or nothing (control). Surface morphology was found to be more
      typical to a given sector and less so to a specific preparation procedure. Rough
      areas were recorded from load-bearing sectors, while smooth areas appeared on
      load-free ones. However, fibrillations were discerned on control load-bearing
      sectors only, and pits and humps were never detected. Tannic acid and
      thiocarbohydrazide may have exerted their structural reinforcing effect on the
      tissue preservation by enhancing the binding of osmium tetroxide to it, possibly
      along with that of other soluble tissue constituents.

PMID- 10405824
TI  - Chromatin texture analysis in living cells.
AB  - In recent years, there has been an increasing interest in applications of
      fluorescence measurements to studies on many physiological mechanisms in living
      cells. However, few studies have taken advantage of DNA quantification by
      fluorometry for dynamic assessment of chromatin organization. This type of
      approach involves both optimal conditions for DNA staining and the use of image
      cytometry. In this context, this report describes the application of an internal
      grey-level segmentation method for the assessment of real time modifications of
      chromatin organization in living cells. These developments are based on a
      specific, stoichiometric method for nuclear DNA content measurement. Preliminary
      data obtained from Hela cells suggests the possibility of following variations of
      nuclear texture (heterogeneity, granularity, condensation, radial distribution)
      related to the cell cycle progression of cells that are maintained alive.

PMID- 10405826
TI  - Immunohistochemical detection of induced expression of wild-type p53 tumor
      suppressor protein in the livers of rats treated with diethylnitrosamine.
AB  - Paraffin sections of formalin-perfused rat livers were stained
      immunohistochemically for p53. In livers from untreated rats, no p53 expression
      was observed. p53 expression was induced in a response to treatment with
      diethylnitrosamine 24 h prior to sacrifice. Staining for p53 was localized in the
      nucleus of perivenous hepatocytes. In serial sections p53-immunopositive areas
      were found to co-localize with increased expression of TUNEL-positive cells.
      Without formalin perfusion, the staining for p53 was uneven and often barely
      detectable. Perfusion with saline prior to formalin resulted in a rapid decrease
      in the detectability of p53, indicating rapid degradation of this protein under
      these conditions. We conclude that rapid fixation by formalin perfusion increases
      the detectability of p53 by immunohistochemical staining. This provides a
      convenient procedure for studying the response of wild-type p53 in rodent liver.
      This procedure is also suitable for in situ investigations on the degradation of
      p53 protein stabilized by DNA damage.

PMID- 10405827
TI  - LR White embedding for immunoelectron microscopy.

PMID- 10405828
TI  - Establishment of a human fusion partner for making human T-T hybridomas which can
      grow in serum free medium.
AB  - A new human fusion partner, ICLU-T was established for making human T-T
      hybridomas. Some 6-thioguanine resistant (6-TGr) clones were separated from human
      T cell acute lymphocytic leukemia, PEER. The fastest growing clone of the 6-TGr
      cells was scaled up and was cultured in serum free medium. The clone that
      proliferated most quickly in the serum free medium was separated and named ICLU
      T. When ICLU-T was fused with human peripheral blood lymphocytes by using only
      polyethylene glycol, the viability of fused cells was below 20% just after fusion
      and the fusion efficiency was 0.01-0.02 per 10(5) parent cells. Whereas, the
      combined use of 1% lecithin with polyethylene glycol increased the viability over
      50% and the fusion efficiencies over 0.2 per 10(5) parent cells on the average.
      In a total of 34 clones of obtained hybridomas, there were 25 CD2 positive
      clones. CD4 positive or CD8 positive clones of the CD2 positive clones were 12
      and 5 clones, respectively. Further, 4 clones of all hybridomas were CD19
      positive, and one clone of these hybridomas was an Ig producer. These obtained
      hybridomas could proliferate in serum free medium.

PMID- 10405829
TI  - New human fusion partners, ICLU-B, -T, -E for making human hybridomas derived
      from various immunological cells.
AB  - To investigate human immune responses, it is useful to use cultured human
      immunological cell lines. Cell fusion is one method to immortalize desired cells.
      Therefore, we established HAT sensitive human fusion partners, ICLU-B derived
      from human burkitt lymphoma, ICLU-T from human T cell acute lymphocytic leukemia,
      ICLU-E from human eosinophilic leukemia, for efficiently making various human
      immunological hybridomas. When each fusion partner was fused with human
      peripheral blood lymphocytes or cord blood lymphocytes, their fusion efficiencies
      were about 1.3, 0.3 and 0.4 clones per 10(5) fusion partners. Approximately 70%
      of hybridomas derived from ICLU-B were CD19 positive hybridomas, and
      approximately 80% of those derived from ICLU-T were CD2 positive hybridomas. The
      CD4 positive or CD8 positive hybridomas of the CD2 positive were approximately
      35% and 15%, respectively. Though approximately 80% of hybridomas derived from
      ICLU-E were CD2 or CD19 positive hybridomas, phagocytosis was observed in the
      remaining hybridomas which were both CD2 and CD19 negative. Most obtained
      hybridomas could proliferate in serum free medium as well as the fusion partners.
      These results suggested that ICLU-B, -T, -E were useful for making human
      hybridomas derived from various immunological cells.

PMID- 10405830
TI  - A human monoclonal antibody encoded by the V4-34 gene segment recognises melanoma
      associated ganglioside via CDR3 and FWR1.
AB  - A heterohybridoma cell line producing the human monoclonal antibody (MoAb) MDT.1
      has been established. The heavy chain of MoAb MDT.1 is encoded by the VH gene
      segment V4-34 (previously designated VH4-21), and the light chain is encoded by
      the V kappa 1-L12a gene segment, both in germline configuration. MDT.1 has
      reactivity against lipid A, double- and single-stranded DNA, red blood cell
      associated i antigen, and ganglioside antigens. In a panel of tumour cell lines,
      MDT.1 reacted specifically with melanoma cells and other tumour cells of
      neuroectodermal origin. Cellular recognition appears to be via tumour-associated
      ganglioside antigens, and may involve the minimal essential epitope NeuNac alpha
      2-->3Gal beta 1-->-4Glc-. Binding to ganglioside antigen is inhibited by the
      monoclonal anti-idiotypic antibody 9G4. Since the 9G4 idiotope is located in
      framework region 1 (FWR1) of V4-34-encoded antibodies, this region is likely to
      be involved, either directly or indirectly, in ganglioside binding. The
      complementarity-determining region 3 (CDR3) of MDT.1 is arginine rich, with five
      out of 12 residues being arginine and these residues are candidates for
      interaction with the negatively charged ganglioside. The ability of MoAb MDT.1 to
      recognise ganglioside antigens is associated with potentially useful anti-tumour
      activity.

PMID- 10405831
TI  - Human monoclonal antibodies to MN-24 peptide of gp 120 HIV-1.
AB  - Human monoclonal IgM antibodies to synthetic peptide MN-24 corresponding to 303
      325 residues of gp 120 HIV were obtained. Antibodies are made synthetic by CD5+B
      lymphocytes and are polyspecific: they react not only with different short
      peptides but with some macromolecular antigens as well. Anti-MN-24 antibodies
      possess antigen-binding activity but do not possess virus neutralizing activity.
      It is suggested that anti-MN-24 antibodies belong to the natural antibodies.

PMID- 10405832
TI  - Recombinant light chain of human monoclonal antibody HB4C5 as a potentially
      useful lung cancer-targeting vehicle.
AB  - Recombinant lambda light chain of lung cancer-reacting human monoclonal antibody
      HB4C5 was expressed in Escherichia coli. Expression in bacteria ensured the
      generation of homogeneous light chain species devoid of activity-hampering N
      linked glycosylation usually found in the light chain CDR-1 of HB4C5. Molecular
      engineering was also employed to eliminate the C-terminal two amino acid
      residues, i.e., Cys and Ser, to prevent the formation of lambda light chain
      dimers which are less reactive than the monomeric form. The lambda light chain
      was overexpressed in E. coli as inclusion bodies, which were solubilized,
      refolded, and treated with Aeromonas proteolytica aminopeptidase to remove the N
      terminal Met with subsequent natural cyclization of the penultimate Gln residue
      to pyroglutamate, the same N-terminal end as that of naturally occurring lambda
      light chain in HB4C5. Monomeric recombinant lambda light chains, both before and
      after removal of the N-terminal Met residue, were 40 times more immunoreactive
      than the parent HB4C5. The immunostaining of lung cancer tissue sections with the
      recombinant lambda light chain indicated cancer-specific reactions to all
      specimens of adenocarcinoma, squamous cell carcinoma and large cell carcinoma
      histologies, but did not react with small cell carcinoma. Tumor
      radioimmunoimaging experiments in LC6 (lung squamous cell carcinoma line)-
      xenografted nude mice by the i.p. injection of 125I-labeled recombinant lambda
      light chain and 125I-labeled human lambda light chain control gave tumor-specific
      and recombinant lambda light chain-dependent images on day 5 postinjection, and
      images were also detectable on day 3. Biodistribution studies with 125I-labeled
      recombinant lambda light chain demonstrated that the lambda light chain could
      penetrate better into the tumor sites, both at the necrotic and solid parts of
      the xenograft, as compared to our previous results with 125I-labeled HB4C5 which
      could localize to the necrotic part only. These results suggest that the
      recombinant lambda light chain is potentially useful as a lung cancer-targeting
      vehicle, for such as radioimmunoimaging and radioimmunotherapy, with least
      possible adverse immunogenic effects.

PMID- 10405833
TI  - Anti-cardiolipin, anti-endothelial-cell and anti-malondialdehyde-LDL antibodies
      in uremic patients undergoing hemodialysis: relationship with vascular access
      thrombosis and thromboembolic events.
AB  - Patients with chronic renal failure requiring regular hemodialysis are known to
      be prone to thromboembolic events due to a hypercoagulable state. Vascular access
      thrombosis (VAT; including thrombosis of the vascular shunt or graft) represents
      a serious complication and jeopardizes life in these patients. In the current
      study, conducted on 81 consecutive patients from the Hemodialysis Unit, we have
      employed ELISA for the estimation of various autoantibody levels (anti
      endothelial cell antibodies, anti-cardiolipin, anti-beta 2GPI and anti-modified
      LDL antibodies) and correlated them with the occurrence of thromboembolic events
      in general, and VAT in particular. We have found that the levels of antibodies
      reactive with human umbilical vein endothelial cells (HUVEC) but not with other
      EC lines (microvascular or EaHy 929) were significantly higher in hemodialysed
      patients with VAT in comparison with patients with no VAT (p = 0.001). A weaker
      but yet positive correlation was observed between the levels of anti-HUVEC and
      anti-cardiolipin antibodies and the occurrence of thromboembolic events including
      deep vein thrombosis, pulmonary infarction, cerbrovascular events and VAT (both p
      values equal 0.02). Anticardiolipin antibodies (aCL) were not cross reactive with
      beta 2GPI or with HUVEC. Antibodies to modified LDL, although higher in
      hemodialyzed patients, did not correlate with thromboembolic events. The results
      of this study suggest that antibodies to HUVEC may prove as a fairly good marker
      of VAT in hemodialysis. High levels of aCL are weakly associated with
      thromboembolic events and antibodies to modified LDL do not correlate with a
      prothrombotic state.

PMID- 10405834
TI  - The significance of immune disorder in tropical spastic paraparesis.
AB  - The reports of the occurrence of HTLV-1 infection and/or HTLV-1 associated
      myelopathy (HAM/tropical spastic paraparesis (TSP) in patients with certain organ
      specific and nonorgan-specific autoimmune diseases prompted us to assess the
      relationship between TSP and humoral autoimmunity. Blood samples from 76 TSP
      patients, 60 asymptomatic HTLV-1 carriers and 100 HTLV-1 seronegative blood
      donors were examined for the presence of organ-specific and nonorgan-specific
      autoantibodies, reactive serological tests for syphilis, immunoglobulin and
      complement concentrations as well as immunecomplexes. High prevalences of
      autoantibodies (39/76, 51%), reactive serological tests for syphilis (23/76;
      30%), hypergammaglobulinaemia (69/76, 90%) and complement fixing immune complexes
      (44/76, 58%) were found in the TSP patients. These indicators of immunological
      disorder were found in statistically significantly lower prevalences in
      asymptomatic HTLV-1 carriers (12/60, 20%; p < 0.001; 6/60, 10%; p < 0.05; 32/60,
      53%; p < 0.001 and 8/60, 13%; p < 0.001, respectively) and HTLV-1 seronegative
      blood donors (8/100, 8%; p < 0.001; 3/100, 3%; p < 0.001; 15/100, 15%; p < 0.001
      and 5/100, 5%; p < 0.001, respectively). The profiles of autoimmune phenomena
      observed in the patient and control groups revealed that they were associated
      with TSP rather than mere HTLV-1 infection and consequently pathogenetic
      significance. The array of immunological features present in TSP was suggestive
      of autoimmune disease resulting from immune dysfunction. Studies which explore
      the possible existence of HTLV-1 induced autoantibodies with specificity for
      antigens of the spinal cord in TSP might be useful in elucidating its
      pathogenesis.

PMID- 10405835
TI  - Geographical differences of cancer incidence in Costa Rica in relation to
      environmental and occupational pesticide exposure.
AB  - BACKGROUND: This study describes geographical differences in cancer incidence in
      Costa Rica, and investigates if some of these differences may be related to
      pesticides. METHODS: Data were combined from the cancer registry (1981-1993), the
      1984 population census, the 1984 agricultural census, and a national pesticide
      data set. The 81 counties of Costa Rica were the units for the ecological
      analyses. Adjacent counties were grouped into 14 regions (3 urban and 11 rural)
      with relatively similar socioeconomic characteristics. County indices for
      population density and agricultural variables were constructed and categorized.
      Differences across regions and categories were assessed by comparing observed
      numbers of incident cases to expected values derived from national rates. Within
      the tertile of most rural counties, rate ratios between categories of high and
      low pesticide use were calculated. RESULTS: In urban regions, excesses were
      observed for lung, colorectal, breast, uterus, ovary, prostate, testis, kidney,
      and bladder cancers; and in rural regions for gastric, cervical, penile, and skin
      cancers. Skin cancers (lip, melanoma, non-melanocytic skin and penile cancer)
      occurred in excess in coffee growing areas with extensive use of paraquat and
      lead arsenate. In the most rural subset, heavy pesticide use was associated with
      an increase of cancer incidence overall and at a considerable number of specific
      sites, including lung cancer (relative risk [RR] 2.0 for men and 2.6 for women)
      and all female hormone-related cancers (RR between 1.3 and 1.8). CONCLUSIONS:
      Regions and populations at high risk for specific cancers were identified.
      Several hypotheses for associations between pesticides and cancer emerged. The
      findings call for studies at the individual level.

PMID- 10405836
TI  - Barbiturates and lung cancer: a re-evaluation.
AB  - BACKGROUND: Barbiturates, particularly phenobarbital, have been shown to be a
      tumour promoter in animal experiments and were found to be associated with
      increased risk of lung cancer in our cohort follow-up study to screen
      pharmaceuticals for possible carcinogenic effects. Sixteen more years of follow
      up have accumulated permitting a more detailed evaluation of this association.
      METHODS: In all, 10,213 subscribers of the Kaiser Permanente Medical Care Program
      who received barbiturates between 1969 and 1973 from its San Francisco pharmacy
      were followed up through 1992 and their incidence of lung cancer at biennial
      intervals was compared with what was expected based on the experience of the
      entire pharmacy cohort (143,594). Smoking-habit data were available on about half
      of the barbiturate users and were used to adjust for cigarette smoking in both
      the observed/expected analysis and in Cox proportional hazards analysis. RESULTS:
      The initially elevated standard morbidity ratio of 1.55 (95% CI: 1.25-1.91) with
      3-7 years of follow-up gradually decreased and stabilized at about 1.3 after 11
      15 years of follow-up. This trend for diminishing relative risk over time was
      more pronounced among the never smokers but their initial excess risk was not
      statistically significant due to small numbers. A dose-response trend was
      observed, based on the number of prescriptions dispensed. Analytical control for
      cigarette smoking reduced but did not eliminate either the association or the
      dose-response trend. Most of the barbiturate-associated cases in never smokers
      were women and the predominant histological type was adenocarcinoma. CONCLUSIONS:
      These findings from up to 23 years of follow-up are not conclusive because of the
      continuing small number of never smokers who developed lung cancer. However, they
      strengthen and refine previous observations of a barbiturate-lung cancer
      association, which is probably not fully explained by confounding by cigarette
      smoking. The diminution of excess risk over time is consistent with a tumour
      promoter effect. Findings among the never smokers suggest that this possible
      effect may be greatest on adenocarcinomas in women.

PMID- 10405837
TI  - Education, socioeconomic status and risk of cancer of the colon and rectum.
AB  - BACKGROUND: Socioeconomic correlates of cancer of the large bowel differ in
      various countries and calendar periods and may differ for the colon and rectum.
      Thus, the relationship between education and social class and risk of cancers of
      the colon and rectum was considered. METHODS: Combination of two hospital-based
      case-control studies conducted in six Italian centres between 1985 and 1996.
      Cases were 3533 patients aged < 79, with histologically confirmed cancer of the
      colon (n = 2180) or rectum (n = 1353), and controls were 7062 patients admitted
      to hospital for a wide spectrum of acute, non-neoplastic, non-digestive tract
      diseases. RESULTS: Compared to individuals with < 7 years of education the
      multivariate odds ratios (OR) of colon cancer for those with > or = 16 years were
      2.45 (95% confidence interval [CI]: 1.87-3.23) in men and 1.29 (95% CI: 0.88
      1.90) in women, with significant trends in risk. No significant association
      emerged between education and risk of rectal cancer, with OR of 1.18 (95% CI:
      0.83-1.70) and 1.01 (95% CI: 0.61-1.67) respectively for men and women in the
      highest educational category compared to the lowest. Social class was also
      related to colon cancer risk: the OR were 2.30 (95% CI: 1.82-2.90) in men and
      1.33 (95% CI: 1.03-1.73) in women in the highest versus the lowest social class.
      No association was found between social class and rectal cancer risk, with OR of
      1.18 for either men or women in the highest as compared to the lowest social
      class. No significant heterogeneity was found for the association between
      education and colon cancer risk in either sex across strata of age at diagnosis,
      coffee, alcohol and vegetable intake, family history of the disease, and in
      anatomical subsites within the colon. CONCLUSION: This study, based on a uniquely
      large dataset, indicates that there are different social class correlates for
      colon and rectal cancer. Consequently the two sites should not be combined in
      studies considering lifestyle factors in the aetiology of these neoplasms.

PMID- 10405839
TI  - Mortality trend from cancer of the gastric cardia in The Netherlands, 1969-1994.
AB  - BACKGROUND: Time trends of cancer of the gastric cardia differ between
      populations and the reasons are not fully understood. The object of this study
      was to investigate the occurrence of cancer of the gastric cardia in descriptive
      relation to age at death, calendar period, birth cohort and gender in the
      Netherlands between 1969 and 1994. METHODS: Data on the number of people with
      cancer of the gastric cardia as the underlying cause of death from 1969 to 1994
      were obtained from annual publications by the National Causes of Death Registry
      of Statistics Netherlands. To estimate the separate effects of age, calendar
      period and birth cohort on the trend in mortality, a simultaneous analysis of
      these factors was performed using a log-linear Poisson model. RESULTS: In 1969,
      the mortality rates from cancer of the gastric cardia for males and females per
      100,000 people were 2.1 and 1.1; in 1994 the mortality rates were 1.5 and 0.7,
      respectively. Examination of the time trend suggested that mortality for cancer
      of the gastric cardia may reflect a period phenomenon, although a cohort effect
      may have also contributed to the observed time trend. Furthermore, more males
      than females died from cancer of the gastric cardia. The difference was most
      striking in the younger age categories. CONCLUSION: In this Dutch population, the
      age-period-cohort-gender analysis indicated that the mortality rates decreased
      after the period 1975-1979 which might be explained by a decrease in exposure to
      risk factor(s) or an increase in exposure to protective factor(s).

PMID- 10405838
TI  - Interval cancers in a randomized controlled trial of screening for colorectal
      cancer using a faecal occult blood test.
AB  - BACKGROUND: The sensitivity of unhydrated Haemoccult II has been examined in the
      context of a randomized controlled trial of faecal occult blood screening for
      colorectal cancer in Nottingham, UK. METHOD: Both traditional and proportional
      incidence methods were used to calculate sensitivity separately for both sexes,
      for two age groups at entry to the trial, for first screen and repeat screens and
      for three subsites within the large bowel. RESULTS: The traditional method of
      estimation yielded a sensitivity of 59% whereas the corresponding figure obtained
      using the proportional incidence method was 54%. The difference between the
      estimates using the two methods was greatest in subjects aged > or = 65 at entry
      to the trial and in cancers of the distal colon. CONCLUSIONS: The results suggest
      that there may be a higher proportion of slower growing tumours in subjects aged
      > or = 65 and that cancers occurring in the distal colon may have a longer mean
      sojourn time than cancers proximal to the sigmoid colon.

PMID- 10405840
TI  - Lactation and breast cancer risk.
AB  - BACKGROUND: Data from the Carolina Breast Cancer Study, a population-based, case
      control study of breast cancer in African-American and white women residents of
      North Carolina, were evaluated to determine whether specific aspects of lactation
      are associated with a reduction in the risk of breast cancer. METHODS: Analyses
      included 751 parous cases and 742 parous controls frequency-matched on age and
      race. Information on lactation, reproductive history, lifestyle characteristics
      and family history were obtained through a personal interview. RESULTS: When
      women who breastfed were compared to those who never breastfed, odds ratios and
      95% confidence intervals of 0.8 (0.5-1.1) and 0.7 (0.5-0.9) were found for women
      20-49 years and 50-74 years, respectively. Similar inverse associations were
      observed for each of three categories of lifetime duration (1-3, 4-12, 13+
      months). The inverse associations persisted and did not vary when number of
      children breastfed, ages at first and last lactation and lactational amenorrhoea
      were examined. CONCLUSIONS: Our findings suggest that any lactation, regardless
      of duration or timing, is associated with a slight reduction in the risk of
      breast cancer among younger and older parous women.

PMID- 10405841
TI  - Increased risk of fatal prostate cancer may explain the rise in mortality in The
      Netherlands.
AB  - BACKGROUND: Several lines of evidence suggest that, as a result of improved
      diagnostic techniques, the increase in incidence of prostate cancer is due
      largely to increased detection of subclinical cases. Between 1971 and 1989, a
      considerable increase in incidence was found in Southeastern Netherlands among
      men aged under 60 years without an improvement in prognosis. We hypothesized that
      in addition to the increase due to increased detection, a genuine increase in
      incidence has occurred in the last two decades and that this should be reflected
      in national mortality rates. METHODS: Age-specific and age-adjusted mortality
      rates were calculated to determine whether mortality due to prostate cancer
      continued to increase after 1990. Using log-linear Poisson modelling according to
      Clayton and Schifflers, we estimated the contribution of period and cohort
      effects to prostate cancer mortality between 1955 and 1994. RESULTS: The age
      adjusted mortality increased from 22 in 1955-1959 to 33 per 10(5) in 1990-1994
      (European standardized rate). For men under 65, the rates stabilized after 1989.
      The age-cohort model fitted the data better than the age-period model. Therefore,
      the increase in mortality can be explained largely by the increasing risk for
      successive birth cohorts for men born until 1930. However, more frequent
      reporting of prostate cancer as the underlying cause of death (partly
      attributable to a decline in competing causes of death) may have occurred as
      well. CONCLUSIONS: Our findings suggest an increased risk of fatal prostate
      cancer in The Netherlands between 1955 and 1994.

PMID- 10405842
TI  - Comparison of self-report data and medical records data: results from a case
      control study on prostate cancer.
AB  - BACKGROUND: Self-report and review of medical records are the most common methods
      for the assessment of past exposures. However, information obtained from self
      reports and medical records may not be consistent. This study compared
      information provided in a self-administered questionnaire with medical records
      data. METHODS: Self-report and medical records data came from a case-control
      study on prostate cancer. Cases were 181 patients with primary prostate cancer
      and controls were 297 men without the disease, enrolled in Group Health
      Cooperative (GHC) in Seattle. The consistencies between the two data sources were
      examined. RESULTS: In general, agreement between the two data sources was almost
      perfect for demographic and anthropometric variables, substantial for the history
      of inguinal hernia and kidney stones, and moderate for vasectomy, family history
      of prostate cancer, smoking and alcohol consumption. However, the two data
      sources generally were poorly concordant for prior genitourinary diseases that
      have less explicit diagnostic criteria such as benign prostatic hyperplasia and
      prostatitis. Analyses of discordant data showed that men were more likely to
      report an exposure or medical condition that could not be verified from medical
      records. No discernible patterns in the difference of agreement were found
      according to age, GHC membership length or case-control status. CONCLUSIONS: This
      study suggests that agreement between self-reported data and medical records data
      varies depending upon the study variables. While both data sources are subject to
      some problems, self-report may provide more complete and comparable information,
      at least for variables unrelated to diagnosis.

PMID- 10405843
TI  - Association of cutaneous malignant melanoma with intermittent exposure to
      ultraviolet radiation: results of a case-control study in Ontario, Canada.
AB  - BACKGROUND: Although solar radiation is well established as a risk factor for
      melanoma, it is less clear how the pattern and timing of exposure to ultraviolet
      (UV) radiation might be important. The particular objective of this study was to
      evaluate the association of melanoma risk with various measures of intermittent
      and chronic exposures to UV radiation, and to assess how these exposures interact
      with other risk factors such as skin type. METHODS: Data were analysed from a
      large case-control study (583 cases, 608 controls) of malignant melanoma, carried
      out in southern Ontario, Canada. RESULTS: Significant risk increases were
      identified with several measures of intermittent exposure, including beach
      vacations in adolescence and in the past 5 years, previous sunburn, and use of
      sunbeds and sunlamps. Chronic exposure, indicated by days of outdoor activity
      during adolescence and by occupation in recent adult life, was associated with
      significantly reduced risk. Subgroup analyses showed: no major risk differences
      by body site of melanoma; stronger association of lentigo maligna melanoma with
      intermittent exposure; more pronounced effects of beach vacations and sunburn in
      younger subjects; and consistently higher risks for intermittent exposures among
      subjects with skin more susceptible to burning. CONCLUSIONS: The data lend
      limited support to the hypothesis of increased risk associated with intermittent
      UV exposure. The findings suggest that future studies should take age at
      diagnosis, host susceptibility and histological subtype into account.

PMID- 10405844
TI  - Greater sensitivity to ionizing radiation at older age: follow-up of workers at
      Oak Ridge National Laboratory through 1990.
AB  - BACKGROUND: Workers at Oak Ridge National Laboratory (ORNL) were individually
      monitored for whole body exposure to ionizing radiation. Studies of these workers
      may provide valuable information about the long-term effects of occupational
      exposure to ionizing radiation. Since biological changes occur as adults age, a
      potentially important question in these investigations is whether sensitivity to
      the carcinogenic effects of ionizing radiation changes with age at exposure.
      METHODS: Vital status and cause of death were ascertained through 1990 for 8307
      white males hired at ORNL from 1943 through 1972. Associations between whole body
      ionizing radiation dose and all-cancer mortality were quantified using life table
      regression methods for time dependent exposures. Analyses focused of differences
      in radiation-cancer associations with age at exposure. Length of follow-up,
      period of hire, and age at risk were considered as alternative explanations for
      effects of age at exposure. RESULTS: Cumulative radiation dose was associated
      with a 1.8% (SE = 0.9) increase in all-cancer mortality per 10 mSv, assuming a 10
      year lag between exposure and mortality. However, radiation doses received at
      older ages exhibited larger associations with cancer mortality than doses
      received at younger ages. Doses received after age 45 were associated with a 5.9%
      (SE = 1.7) increase in cancer mortality per 10 mSv, adjusted for doses received
      before age 45. Dose-response associations between cancer mortality and doses
      received after age 45 appeared consistent across periods of follow-up, periods of
      hire, and ages at risk. CONCLUSIONS: Findings suggest that sensitivity to the
      carcinogenic effects of ionizing radiation may increase with older ages at
      exposure. More attention should be given to the role of age at exposure in
      studies of the health effects of low-level exposure to ionizing radiation, and to
      efforts to limit exposure to ionizing radiation.

PMID- 10405846
TI  - The association of body mass index with social and economic disadvantage in women
      and men.
AB  - BACKGROUND: Although an inverse relationship between socioeconomic status and
      body mass index (BMI) is well documented, broad population studies focusing on
      the association between BMI and various forms of disadvantage such as
      unemployment, low income or social isolation are rare. METHODS: A nationwide,
      representative sample of 25-64-year-old Finnish subjects (n = 6016) was
      classified according to their BMI into four groups: 'thin' (BMI < 20), 'normal'
      (BMI 20-24.9), 'overweight' (BMI 25-29.9) and 'obese' (BMI > or = 30).
      Multivariable analyses using logistic regression were conducted with this BMI
      grouping as an independent variable to predict social and economic disadvantage,
      controlling simultaneously for age, educational attainment, region of residence,
      and limiting long-standing illness. RESULTS: In women, overweight was associated
      with current unemployment and obesity with long-term unemployment as well as
      absence of close friends outside the family circle. Both overweight and obesity
      were associated with low individual earnings. Obese women were also most likely
      to have low household disposable and individual incomes; a similar pattern was
      seen among thin women. A small subgroup of thin men were socially and
      economically disadvantaged with all our indicators whereas excess body weight was
      not problematic for men. CONCLUSIONS: Deviant body weight is associated with
      social and economic disadvantage in a gender-specific and partly curvilinear way.
      In particular, obese women face multiple social and economic disadvantage.

PMID- 10405845
TI  - An ecological study of determinants of coronary heart disease rates: a comparison
      of Czech, Bavarian and Israeli men.
AB  - BACKGROUND: The large differences in cardiovascular disease rates between Eastern
      and Western Europe have largely developed over the last few decades, and are only
      partly explained by classical risk factors. This study was set up to identify
      other potential determinants of these differences. METHODS: This was an
      ecological study comparing random samples of men aged 45-64 years selected from
      three cities representing populations with different rates of cardiovascular
      mortality: Pardubice (Czech Republic), Augsburg (Bavaria, Germany), and Jerusalem
      (Israel). In total, 191 (response rate 70%), 153 (70%) and 162 (62%) men,
      respectively, participated. All centres followed the same study protocol.
      Lifestyle, anthropometry and biochemical risk factors were assessed by identical
      questionnaires, standardized medical examination, and central analyses of fasting
      blood samples. RESULTS: The mortality rates in the study populations, as well as
      the prevalence of coronary heart disease in study samples, were highest in Czech,
      intermediate in Bavarian and low in Israeli men. This pattern was replicated
      across the three samples by mean blood pressure (P < 0.001), cigarette smoking
      (not significant), triglycerides (P < 0.05), fibrinogen or D-dimer levels (P <
      0.05). On the other hand, the prevalence of diabetes and obesity were similar;
      total and high density lipoprotein (HDL)-cholesterol, apolipoprotein B,
      lipoprotein (Lp(a)) and glucose did not differ between Czech and Bavarian men;
      and Czechs had particularly low levels of serum insulin and factor VIIc. Israelis
      had low fasting glucose and total cholesterol, as well as HDL-cholesterol levels
      and a high Lp(a) (each P < 0.001) compared with the two other samples. Striking
      differences were found for plasma homocysteine (10.5 in Czechs versus 8.9 mumol/l
      in Bavarians, P < 0.001) and for alpha-carotene (geometric mean in Czechs 16,
      Bavarians 21 and Israelis 30 micrograms/l), beta-carotene (60, 110 and 102
      micrograms/l), and lycopene (84, 177 and 223 micrograms/l), respectively; all P
      values < 0.001). Adjustment for obesity or smoking did not change these
      estimates. There were no differences in the levels of tocopherol and retinol.
      CONCLUSIONS: Czech men had high levels of blood pressure, triglycerides,
      fibrinogen and D-dimer but many other traditional risk factors, as well as
      indicators of metabolic disorders and vitamins A and E, did not differ between
      the study samples. The low levels of carotenoids and high concentrations of
      homocysteine in Czech men seem to reflect their low dietary intakes of fruit and
      vegetables. The results provide indirect support for the importance of dietary
      factors in the East-West morbidity and mortality divide.

PMID- 10405847
TI  - Plasma vitamin C levels in men and women from different ethnic backgrounds living
      in England.
AB  - BACKGROUND: People of South Asian origin living in the UK have higher death rates
      due to coronary heart disease than whites. The reasons for these differences are
      not fully understood. Previous attempts to relate diet to cardiovascular risk in
      South Asians have been inconclusive. METHODS: We compared the levels of plasma
      vitamin C in a cross-sectional population-based study of 1018 men and women aged
      40-59 (455 men, 563 women, 328 South Asians, 355 of African descent, 335 whites)
      co-resident in a geographically defined area of South London, when allowing for
      potential confounders. RESULTS: Fasting plasma vitamin C levels were
      significantly higher in women, vegetarians, supplement takers and non-smokers.
      After adjustment for age, body mass index, current smoking, supplement use and
      vegetarianism the mean plasma vitamin C levels were 38.8 (SE 1.6) mumol/l in
      white men, 36.5 (1.6) mumol/l in men of African descent and 32.9 (1.5) mumol/l in
      South Asian men (P = 0.033 by analysis of co-variance). In women the adjusted
      mean plasma vitamin C levels were 52.4 (1.6) mumol/l in whites, 46.0 (1.4)
      mumol/l in women of African descent and 37.3 (1.8) mumol/l in South Asians (P <
      0.0001 by analysis of covariance). South Asians had lower levels than whites in
      both men (difference 6.4 [95% CI: 1.5, 11.3] mumol/l) and women (16.8 [95% CI:
      11.5, 22.1] mumol/l). South Asian women, but not men, also had lower levels than
      those of African descent (8.8 [95% CI: 4.5, 13.1] mumol/l). African women, but
      not men, had lower levels than white women (6.6 [95% CI: 2.3, 10.9] mumol/l). No
      significant differences were seen between Caribbeans and West Africans or between
      South Asian Hindus and Muslims. CONCLUSIONS: These data suggest that important
      dietary differences in vitamin C exist between different ethnic groups living in
      England. The larger differences in South Asians may contribute to their increased
      coronary risk.

PMID- 10405848
TI  - Mortality and causes of death among Danish medical doctors 1973-1992.
AB  - BACKGROUND: To examine the mortality pattern of Danish doctors for the period
      1973-1992. METHODS: A historical prospective cohort study based on the membership
      register of the Danish Medical Association. The study population consisted of
      21,943 medical doctors, 6012 of whom were women. The doctors' cause-specific
      mortality was compared with that of the general population. RESULTS: The study
      covered about 277,000 person-years. A total of 2387 deaths occurred from 1
      January 1973 to 31 December 1992. The doctors' mortality was lower than that of
      the general population. Both sexes showed a standardized mortality ratio (SMR)
      below one for cancer, circulatory diseases and other natural causes. Mortality
      due to lung cancer was particularly low. The SMR for suicide was significantly
      increased, 1.6 for males (95% CI: 1.4-1.9) and 1.7 for females (95% CI: 1.1-2.5).
      The suicide rate was increased, in particular because of an increased number of
      suicides by poisoning. In addition female doctors displayed a relatively high
      mortality due to accidents and other types of violent death. CONCLUSIONS:
      Compared with the general population the doctors' mortality was low, but the
      mortality from external causes was increased, mainly due to an excess number of
      suicides.

PMID- 10405849
TI  - Anaemia during pregnancy as a risk factor for iron-deficiency anaemia in infancy:
      a case-control study in Jordan.
AB  - BACKGROUND: A high prevalence of 50-65% iron-deficiency anaemia in mothers and
      infants in Jordan was reported by the United Nations Relief and Works Agency
      (UNRWA) in 1990. Iron-deficiency in infancy has been shown to delay cognitive and
      psychomotor development with long-term consequences. While socioeconomic
      deprivation and inadequate nutrition are known underlying factors, it is unclear
      whether iron endowment at birth is compromised when mothers are anaemic, further
      jeopardizing iron status during infancy. A prospective case-control study of
      infants from birth to one year was conducted in a lower middle-class urban
      setting in Amman, Jordan. The study objective was to examine the relationship
      between maternal anaemia and iron-deficiency anaemia during infancy. METHOD: A
      sample of 107 anaemic (Hb < 11 g/dl) and 125 non-anaemic mothers was selected at
      37 weeks' gestation and matched for age and parity, and infant data at birth
      obtained. The infants were reviewed at 3, 6, 9 and 12 months, to assess growth,
      current nutrition, infection rates and iron status. The main outcome measure was
      the incidence of iron-deficiency anaemia in the two groups of infants, defined in
      the study as Hb < 11 g/dl and either plasma ferritin < 12 mcg/l or zinc
      protoporphyrin > 35 mcg/dl. RESULTS: Iron endowment in cord blood samples
      appeared similar between the two groups. The incidence of iron-deficiency anaemia
      was very high in these infants, at 72% by research criteria, (51% if Hb < 10.5
      g/dl), but significantly higher in the infants born to anaemic mothers at all
      stages of the year, with overall incidence of 81% (n = 91), compared to 65% in
      controls (n = 112). This was not explained by differences in environmental risk
      factors. Anaemic mothers had not recovered adequate iron status at 6 months'
      postpartum, with implications for future pregnancy iron demands. CONCLUSIONS:
      Anaemia during pregnancy compromises the health of mothers in traditional
      cultures, where women tend to have several children close together after
      marriage, with an inadequate interval to replenish nutritional stores. Their
      infants also appear to be at increased risk of developing iron-deficiency
      anaemia, undetected at birth.

PMID- 10405850
TI  - Influence of heavy agricultural work during pregnancy on birthweight in northeast
      Brazil.
AB  - BACKGROUND: Women in developing countries often continue their agricultural work
      during late pregnancy. Whether this adversely affects birthweight is not clear
      from previous studies as few controlled for confounding factors. This study seeks
      to clarify this issue. METHODS: This retrospective cohort study investigated 958
      low-income women and their singleton newborn babies residing in a region of
      Northeast Brazil dependent on sugar-cane production. Women were recruited at
      maternity centres, when attending for delivery, and were allocated to one of two
      groups according to their exposure to heavy agricultural labour for at least 3
      months during the second and third trimesters of pregnancy (n = 250), or to
      household activities only (n = 708). RESULTS: The mean birthweight of infants
      born to women who worked in agriculture during 9 months of pregnancy was 190 g
      lower than that of the non-exposed group (P = 0.02). After controlling for
      confounding factors, the adjusted effect was 117 g (P = 0.05). Heavy agricultural
      work for 6, 7 or 8 months had no significant effect. CONCLUSIONS: These findings
      suggest that working throughout pregnancy significantly reduces birthweight in
      this low-income population.

PMID- 10405852
TI  - The effect of dietary calcium intake on bone mineral density in healthy
      adolescent girls and young women in southern Italy.
AB  - BACKGROUND: The association between forearm bone mineral areal density (BMD) and
      dietary calcium, anthropometric characteristics, puberty, and physical activity
      was studied for the first time in 200 girls (aged 11-15 years) and 100 women
      (aged 20-23 years) living in Southern Italy. METHODS: The BMD was assessed by
      dual energy x-ray absorptiometry at ultradistal (ud) and proximal (pr) radial
      sites and dietary calcium was evaluated using Food Frequency Questionnaires and
      detailed 3-day food records. RESULTS: For population samples grouped according to
      low and high calcium intake levels, forearm densities were quite similar among
      both girls and women. Independently of calcium intake, girls displayed strong
      correlations between ud/pr-BMD and age, bone age, weight, height and BMI.
      Furthermore, in girls of similar age and BMI, radial densities were substantially
      increased following menarche. Positive relationships between weight, BMI and both
      ud/pr-BMD were only evident in women with high calcium intake. CONCLUSIONS: This
      study showed that different calcium intake values do not appear to affect forearm
      mineral densities at the ages investigated, however puberty represents the major
      event in radial bone mass acquisition during adolescence.

PMID- 10405851
TI  - Maternal predictors of perinatal mortality: the role of birthweight.
AB  - BACKGROUND: Many maternal characteristics increase the risk for perinatal death.
      To locate potential sites for intervention, it is important to identify these
      risk factors and examine how much of the excess mortality is explained by
      infants' low birthweight. METHODS: Data on all newborns in Finland born between
      1991 and 1993 (N = 199,291, of which 1461 were perinatal deaths) were obtained
      from the Medical Birth Register. Logistic regression analysis was used to adjust
      for background variables, both including and excluding infants' birthweight. The
      percentage reduction in odds ratios after adjustment for infants' birthweight was
      used to estimate the contribution of infants' low birthweight to the excess
      mortality. RESULTS: After adjusting confounding factors, increased risk for
      perinatal death was found for eight maternal characteristics. In the following
      the increased risk is given as odds ratios and the proportions of the excess
      mortality explained by infants' low birthweight are in parentheses: in-vitro
      fertilization 4.12 (> 100%); earlier stillbirth 3.43 (87%); higher maternal age,
      from 1.21 to 3.08 (38-99%); maternal diabetes 2.87 (50%); lower socioeconomic
      status, from 1.30 to 1.70 (27-44%); smoking during pregnancy 1.45 (> 100%);
      single mother 1.44 (50%); first birth 1.36 (75%). CONCLUSIONS: Excess mortality
      due to maternal risk factors occurred mainly through their tendency to cause low
      birthweight. However, the excess mortality associated with low socioeconomic
      status, single motherhood, and diabetes was mediated by other mechanisms in
      addition to low birthweight.

PMID- 10405853
TI  - Age and gender variation in the impact of household structure on elderly
      mortality.
AB  - BACKGROUND: There is little information about the impact of household structure
      and composition on elderly mortality in developing countries. This study examines
      the impact of relationship to head of household, and the presence of co-resident
      spouses and sons on elderly mortality in rural Bangladesh with a particular focus
      on age and gender differences. METHODS: A total of 9365 individuals aged > or =
      60 at baseline (5128 males and 4237 females) in the Matlab Surveillance area in
      rural Bangladesh were followed for a period of 8 years (1974-1982) with all
      predictors (the presence of a spouse, one or more co-resident adult sons,
      relationship to head of household, household economic status, age and disability
      status) being measured at the beginning of follow-up. Cox proportional hazard
      models were used in the analysis. RESULTS: Being the head of household had a
      significant impact on reducing elderly mortality for both men and women. The
      presence of a spouse reduced mortality for all elderly men but had a significant
      beneficial impact only on women whose husbands were heads of households. Finally
      the presence of one or more co-resident adult sons reduced mortality for elderly
      women but not for elderly men. For all three of the above predictors there was a
      decline in effect with the age of the elderly. CONCLUSIONS: Relationship to head
      of household and the presence of spouses and sons have powerful impacts on
      reducing mortality for elderly men and women in rural Bangladesh with the effects
      varying significantly by gender and age. Furthermore, individual rather than
      joint access to material resources is an important determinant of elderly
      mortality.

PMID- 10405854
TI  - Education and incident Alzheimer's disease: a biased association due to selective
      attrition and use of a two-step diagnostic procedure?
AB  - BACKGROUND: It is still not clear whether a low level of education increases the
      risk of developing Alzheimer's disease (AD). Two common problems in cohort
      studies involving an elderly population and a two-step diagnostic procedure are
      the loss to follow-up without data on the presence of AD, and the fact that, in
      general, people with higher levels of education perform better on traditional
      cognitive tests, such as the Mini-Mental State Examination (MMSE). Both phenomena
      may lead to misclassification, resulting in a biased association between level of
      education and AD. This study investigated to what extent these selection
      mechanisms may influence this association. METHODS: In the community-based
      Amsterdam Study of the Elderly (AMSTEL) a cohort at risk for AD was selected of
      3778 people aged 65-84 years. Level of education was expressed in two categories:
      low (primary education or less) versus high (partial secondary education to
      completed university education). At follow-up, a subsample of elderly people was
      selected for further diagnostic evaluation, using a memory test in addition to
      the MMSE. Clinical diagnoses of AD were made according to DSM-IV (Diagnostic and
      Statistical Manual of Mental Disorders) criteria. To examine the extent to which
      loss to follow-up may have affected the results, a sensitivity analysis was
      performed comparing two extreme possibilities. Furthermore, to examine to what
      extent use of the MMSE only may have affected the results, the observed odds
      ratio (OR) was compared with the OR based on only those AD patients who were
      selected for diagnostics with the MMSE alone. RESULTS: After an average of 3.2
      years, 77 people had developed AD. Multivariate logistic regression analyses
      indicated that a low level of education was associated with incident AD (OR
      adjusted for age and sex 2.09; 95% CI: 1.29-3.38). The results of the sensitivity
      analysis still indicated that a low level of education was associated with
      incident AD. Screening with only the MMSE led to a higher OR than the one
      observed. CONCLUSION: Selective attrition and use of cognitive screening tests
      that are associated with educational level may influence the strength of the
      association between a low level of education and incident AD; however, it appears
      that these influences cannot completely explain this association.

PMID- 10405855
TI  - Evaluating the reported prevalence of type 2 diabetes mellitus by the Oguni
      diabetes registry using a two-sample method of capture-recapture.
AB  - BACKGROUND: Capture-recapture methods have been widely employed in the study of
      wildlife populations and have recently been applied to count various human
      diseases and conditions. We have estimated the prevalence of type 2 diabetes
      mellitus by adjusting for the degree of undercount using a two-sample model of
      capture-recapture among men and women aged 50-69 in Oguni town, Japan. METHODS:
      Oguni town diabetes registry data were utilized as the first source. In the
      registry, only those who had experienced fasting plasma glucose of > or = 7.8
      mmol/l (140 mg/dl) or 2 h plasma glucose after a 75 g oral glucose tolerance test
      (OGTT) of > or = 11.1 mmol/l (200 mg/dl) were counted as having diabetes. A
      second source was a sample study selecting 200 men and 200 women aged 50-69
      randomly, which was conducted in August 1991. A 75 g OGTT was done in the
      morning. The 1985 World Health Organization criteria were used to classify the
      diabetes status of the participants. A two-sample model of capture-recapture
      methods was employed to estimate the total number of cases of diabetes and
      determine the ascertainment rates of the registry. RESULTS: The prevalence
      estimated by the diabetes registry was 7.1%. The prevalence from the sample study
      was 8.8% with a participation rate of 74%. Estimated prevalence employing the
      capture-recapture method was 13.1%. The ascertainment rate of the registry was
      53.8%. CONCLUSIONS: Little is known about the prevalence of type 2 diabetes in
      local areas in Japan, the US and the world. Capture-recapture methods are likely
      to provide a means to accurately assess the prevalence of diabetes.

PMID- 10405856
TI  - Community-based injury prevention: effects on health care utilization.
AB  - BACKGROUND: Worldwide, an estimated 78 million people are disabled each year
      because of unintentional injuries and about 3 million die. The WHO Safe Community
      model is a framework for community-based injury prevention programmes. The aim of
      this study is to evaluate the outcome on health care utilization of a Safe
      Community programme. METHODS: The incidence of injuries treated at health care
      facilities in an intervention municipality (pop. 41,000) was compared to the
      injury incidence in a control municipality (pop. 26,000). The incidence was
      recorded immediately before and one year after programme implementation from
      registrations made during all first-contact health care visits and from
      examination of hospital discharge registers. RESULTS: The incidence of health
      care treated injuries in the intervention area had decreased by 13% (95% CI: 9
      16%) from 119 (95% CI: 115-122) per 1000 population-years to 104 (95% CI: 101
      107). In the control area, the corresponding injury incidences were 104 (95% CI:
      100-108) and 106 (95% CI: 102-109). The hospital-treated injuries in the
      intervention area decreased by 15% (95% CI: 7-24%) from 19 (95% CI: 17-20) per
      1000 population-years to 16 (95% CI: 15-17), while in the control area, the
      incidences remained at 13 (95% CI: 11-14) per 1000 population-years. Utilization
      of acute care in the intervention area for reasons other than injuries increased
      by 8% (95% CI: 6-10%), while in the control area, the number of visits did not
      show significant change. CONCLUSION: This first controlled evaluation showed that
      an injury prevention programme based on local action groups can significantly
      reduce injuries requiring health care in a community. Local prevention can
      provide a complement to national level campaigns.

PMID- 10405857
TI  - Prevalence and correlates of anergy among drug users in Puerto Rico.
AB  - OBJECTIVES: This study assessed prevalence and correlates of anergy among a
      cohort of drug users in communities in the San Juan metropolitan area. METHODS:
      In all, 719 drug injectors and crack users were recruited in neighbourhoods in
      the San Juan metropolitan area following a stratified cluster design of 30
      copping areas (places where drugs are sold). RESULTS: Slightly more than one
      third of the total proportion of participants, 34.2%, were HIV positive and 30.3%
      anergic. Subjects with a history of incarceration, the HIV positive, and those
      reporting chronic illness were more likely to be anergic than those subjects
      without these characteristics. CONCLUSIONS: Most studies addressing drug users'
      immune system dysfunction are related to HIV infection. Additional studies are
      needed to provide a more comprehensive understanding of drug users' immune
      systems.

PMID- 10405858
TI  - The validity of drug users' self-reports in a non-treatment setting: prevalence
      and predictors of incorrect reporting methadone treatment modalities.
AB  - BACKGROUND: Epidemiological studies among drug users are often based on
      retrospective self-reports. However, among others, memory failure, being under
      the influence of drugs, psychopathology, misunderstanding of questions and
      socially desirable answering may generate inaccurate reporting. METHODS: This
      study validated self-reported current (methadone dosage) and medium-term (main
      location of methadone dispensing and frequency of methadone programme attendance
      over the previous 4-6 months) aspects of methadone treatment in the Amsterdam
      AIDS cohort study among drug users, using data of the Central Methadone Register.
      In addition to descriptive measures, logistic regression analysis was used
      (adjusted for intra-individual correlation) to identify subgroups with incorrect
      reporting. Data collected at 4406 visits of 505 cohort participants were
      analysed. RESULTS: Current methadone dosage was accurately reported (unweighted
      kappa [kappa]: 0.94, weighted kappa [kappa W]: 0.97). A low methadone dosage,
      short duration of school education and depressive or euphoric mood during the
      interview were significant and independent predictors of incorrect reporting of
      methadone dosage. For main location of dispensing kappa was 0.82, for frequency
      of programme attendance kappa was 0.53 and kappa W 0.87. There was a tendency to
      reporting the extreme answering categories. Infrequent programme attendance was
      the only significant predictor of incorrectly reporting frequency of programme
      attendance. CONCLUSIONS: Drug users are able to give valid self-reports in a
      setting where social desirability does not play an important role. The main
      reasons of incorrect reporting were impaired cognitive functioning, memory
      failure and misunderstanding of questions.

PMID- 10405859
TI  - Selecting diagnostic tests for ruling out or ruling in disease: the use of the
      Kullback-Leibler distance.
AB  - BACKGROUND: To select a proper diagnostic test, it is recommended that the most
      specific test be used to confirm (rule in) a diagnosis, and the most sensitive
      test be used to establish that a disease is unlikely (rule out). These rule-in
      and rule-out concepts can also be characterized by the likelihood ratio (LR).
      However, previous papers discussed only the case of binary tests and assumed test
      results already known. METHODS: The author proposes using the 'Kullback-Leibler
      distance' as a new measure of rule-in/out potential. The Kullback-Leibler
      distance is an abstract concept arising from statistics and information theory.
      The author shows that it integrates in a proper way two sources of information-
      the distribution of test outcomes and the LR function. The index predicts the
      fate of an average subject before testing. RESULTS: Analysis of real and
      hypothetical data demonstrates its applications beyond binary tests. It works
      even when the conventional methods of dichotomization and ROC curve analysis
      fail. CONCLUSIONS: The Kullback-Leibler distance nicely characterizes the before
      test rule-in/out potentials. It offers a new perspective from which to evaluate a
      diagnostic test.

PMID- 10405860
TI  - When did bovine spongiform encephalopathy (BSE) start? Implications on the
      prediction of a new variant of Creutzfeldt-Jakob disease (nvCJD) epidemic.
AB  - BACKGROUND: Knowing the starting date of the BSE epidemic and its size at the
      very beginning is crucial to interpret the timing of the nvCJD cases and to
      forecast the nvCJD epidemic. The first cases occurred in 1985. The models devised
      by Anderson (back-calculation) and Dealler (age-period-cohort) led to an estimate
      of less than 50 cases in 1983, and none earlier. Here, we applied age-cohort
      models to the BSE data in order to estimate the earliest possible date of the
      first unrecognized BSE cases. METHODS: The numbers of confirmed BSE cases in the
      UK, by age group and by calendar year from 1988 to 1996, were analysed by Poisson
      regression. The cases' age distribution was considered as constant between the
      different birth cohorts. The herd's age structure was taken into account.
      RESULTS: According to the models, BSE cases may have occurred as early as 1980.
      The expected number of cases before 1990 is almost twice the number of confirmed
      cases and exceeds by more than 20% the expected value of Anderson's model. The
      scenario of first human exposure in 1980 leads to fewer future nvCJD cases than
      predicted by Cousens with exposure patterns starting in 1983 or 1985. CONCLUSION:
      The first birth cohort available, consisting of two cases older than 10 in 1988,
      does not allow any projections before 1980. Moreover, confidence intervals are
      wide and the power of the study is limited by the great dispersion of the data;
      the precision of the estimations would be improved by considering geographical
      incidence. Nevertheless, our projections are consistent with Wilesmith's survey
      of rendering plants relating the emergence of BSE to the dramatic fall in the
      proportion of meat and bone meal following solvent extraction, initiated in the
      late 1970s (65% in 1977 to 10% in 1983).

PMID- 10405861
TI  - Growth of children according to maternal and child HIV, immunological and disease
      characteristics: a prospective cohort study in Kinshasa, Democratic Republic of
      Congo.
AB  - BACKGROUND: Most HIV-infection in children occurs in sub-Saharan Africa where
      antiretroviral therapy is seldom available. This study compares the growth
      progression and retardation of HIV-infected and uninfected children in the
      Democratic Republic of Congo (formerly Zaire). It estimates the risk for child
      growth retardation according to child and maternal immunological factors,
      severity of maternal and child illness, and maternal socioeconomic and marital
      status. METHODS: In a prospective cohort study of 258 children born to HIV
      seropositive mothers and 256 children of seronegative mothers in Kinshasa, Congo,
      the growth in length, weight, and weight-for-length of infected children (n =
      68), uninfected children born to seropositive mothers (n = 190), and uninfected
      children born to uninfected mothers (n = 256) was compared. Serological,
      anthropometric and other clinical measures were collected monthly from 3-12
      months and bi-monthly during the second year of life. Polymerase chain reaction
      for HIV was performed on bloods drawn at 2 days and 3 months post partum. Length
      for-age, weight-for-age, and weight-for-length mean z-scores against National
      Center for Health Statistics (NCHS) reference data were calculated, and Cox
      proportional hazards models were used to estimate the risk of falling below -2.00
      z-scores as a function of child and maternal immunological, clinical and
      sociodemographic variables. RESULTS: There was no difference in mean length-for
      age at birth between HIV-infected (Group 1) children, uninfected children of
      infected mothers (Group 2) or Control children, but by 3 months old, HIV-infected
      children were shorter than both Group 2 and Controls. In weight-for-age and
      weight-for-length, Group 1 infants were lighter and more wasted at birth and
      onwards. Group 2 newborns were lighter than Controls at birth, but by three
      months they had caught up to Controls in both length and weight and remained the
      same as Controls thereafter. The odds of falling below -2.00 z-scores by 20
      months for length, weight, and weight-for-length for HIV-infected children
      compared to uninfected children were 2.10, 2.84, and 2.56 respectively. Both HIV
      infection and associated illnesses were factors associated with child stunting,
      underweight and wasting. The mother's age, socioeconomic status, presence of
      father, stage of illness and immune status had no detectable effect on the
      child's growth in the first two years of life. CONCLUSION: The HIV-infected
      children in Congo with no access to antiretroviral therapy were stunted,
      underweight, and wasted compared to same age uninfected children. Both HIV
      infection and HIV-associated signs and symptoms, not maternal immunological or
      socioeconomic circumstances, placed children at risk for growth retardation.

PMID- 10405863
TI  - Fuzzy logic and measles vaccination: designing a control strategy.
AB  - BACKGROUND: The State of Sao Paulo, the most populous in Brazil, was virtually
      free of measles from 1987 until the end of 1996 when the number of cases started
      to rise. It reached alarming numbers in the middle of 1997 and local health
      authorities decided to implement a mass vaccination campaign. METHODS: Fuzzy
      Decision Making techniques are applied to the design of the vaccination campaign.
      RESULTS: The mass vaccination strategy chosen changed the natural course of the
      epidemic. It had a significant impact on the epidemic in the metropolitan area of
      Sao Paulo city, but a second epidemic in the State's interior forced the public
      health authorities to implement a second mass vaccination campaign 2 months after
      the first. CONCLUSIONS: Fuzzy Logic techniques are a powerful tool for the design
      of control strategies against epidemics of infectious diseases.

PMID- 10405862
TI  - Geographical variation in disease progression in HIV-1 seroconverted injecting
      drug users in Europe?
AB  - BACKGROUND: Human immunodeficiency virus (HIV) disease progression might vary by
      geographical region due to differences in the spectrum of HIV-related illnesses
      and (access to) health care. Therefore, the effect of geographical region, next
      to the effect of other potential cofactors, on disease progression in 664
      injecting drug users (IDU) with documented HIV seroconversion from eight cohorts
      in Europe was studied. METHODS: Kaplan-Meier methods and Cox proportional hazards
      analysis were performed to assess the effect of geographical region, other
      sociodemographics, drug use and repeated HIV exposure on progression from HIV
      seroconversion to immunosuppression, AIDS and death with AIDS. We considered the
      confounding effect of study-design related factors (e.g. setting of follow-up),
      and accounted for pre-AIDS death from natural causes by imputing when each
      endpoint would have occurred, had they not died without AIDS. RESULTS: Estimates
      of progression to AIDS and death with AIDS were substantially faster after taking
      pre-AIDS mortality into account. Median incubation time from seroconversion to
      the first CD4 count < 200 cells/microliter was 7.7 years (95% CI: 7.1-8.3) and to
      AIDS 10.4 years (95% CI: 9.8-infinity). The 10-year survival was 70.3% (95% CI:
      62.8-76.6). The relative hazards (RH) of AIDS for IDU from central and southern
      Europe compared with IDU from northern Europe was 1.9 (95% CI: 1.2-3.0) and 1.2
      (95% CI: 0.6-2.3), respectively, before, and 1.5 (95% CI: 0.7-3.2) and 1.1 (95%
      CI: 0.6-2.3) after taking differences in study-design related factors into
      account. Accounting for these factors, the RH of death with AIDS was 0.9 (95% CI:
      0.3-2.5) for central and 1.2 (95% CI: 0.4-3.4) for southern Europe compared with
      northern Europe. For the first CD4 count < 200 cells/microliter these figures
      were 0.8 (95% CI: 0.5-1.4) and 0.8 (95% CI: 0.5-1.4). Age at seroconversion was
      the strongest predictor of disease progression. No statistically significant
      differences in disease progression were found by gender, foreign nationality,
      drug use and potential repeated HIV exposure. CONCLUSIONS: We found no evidence
      for regional variability in HIV disease progression among European IDU. Future
      studies evaluating geographical differences should consider the confounding
      effect of study-design related factors and differential non-AIDS mortality. As
      age is an important determinant of disease progression, it should be considered
      in recommending treatment.

PMID- 10405864
TI  - Measles epidemiology in Catalonia (Spain): implications for a regional
      vaccination programme.
AB  - BACKGROUND: To analyse progress in measles control it is recommended that
      immunization programmes be evaluated by means of specific epidemiological disease
      surveillance. The aim of the study was to analyse a series of measles cases in
      Catalonia in the light of vaccination records. METHODS: Cases were detected by
      means of the epidemiological surveillance system and then surveyed for
      information on: age, sex, clinical symptoms, laboratory confirmation, record of
      vaccination, place of infection and possible outbreak-related links. The
      relationship between 'record of vaccination' and the remaining variables was
      determined using the adjusted odds ratio (OR) and its 95% confidence interval
      (CI). RESULTS: The epidemiological survey confirmed that 82.2% of patients
      (171/208) fulfilled the case criteria. In the multivariate analysis, lack of
      record of vaccination was associated with age groups < 5 years (OR = 4.0; 95% CI:
      1.4-11.8) and > 14 years (OR = 19.2; 95% CI: 5.1-220.5). CONCLUSIONS: Improvement
      in vaccination coverage at 15 months and the introduction of vaccination-status
      monitoring at school-entry age and among those aged > 14 years on entry into the
      job market, university or military service could contribute to the elimination of
      measles.

PMID- 10405865
TI  - Cost-effectiveness of screening compared to case-finding approaches to
      tuberculosis in long-term care facilities for the elderly.
AB  - BACKGROUND: To determine if the more interventionist approach of screening with
      the tuberculin test and chemoprophylaxis for high-risk positive reactors to
      control tuberculosis in long-term care facilities is cost-effective when compared
      to the case-finding and treatment approach. METHOD: A decision-analysis model was
      designed wherein systematic screening with the tuberculin skin test of all
      elderly patients newly admitted to facilities was compared to public health
      interventions restricted to investigation of cases and contacts with symptoms of
      tuberculosis after suspected exposure. Differences in life-years (LY), quality
      adjusted life-years (QALY), cost per QALY and LY gained, annual cost per 1000
      institutional patients were calculated in a health-care system perspective.
      RESULTS: In every situation analysed, screening and chemoprophylaxis were more
      effective. The cost per LY gained was within an acceptable range: $3437 per LY
      with a 0.6% nosocomial transmission rate and $7552 per LY when no nosocomial
      transmission was postulated. CONCLUSION: Screening plus chemoprophylaxis for high
      risk reactors is more cost-effective than case-finding. This holds even when
      nosocomial transmission is assumed not to occur in facilities.

PMID- 10405866
TI  - Analysis of herpes simplex virus 1 and 2 infection in women with high risk sexual
      behaviour in Mexico.
AB  - BACKGROUND: This paper describes the seroprevalence and risk factors of Herpes
      simplex virus (HSV) infection in a group of female prostitutes from Mexico City.
      METHODS: Women who consented to participate in the study voluntarily attended a
      sexually transmitted disease (STD) clinic during 1992. A standardized
      questionnaire was administered and a blood sample was obtained from each
      participant. Type-specific Western blot serology was performed to determine the
      serostatus of HSV-1 and HSV-2 for participants. Bivariate and multivariate
      analyses were applied to identify variables associated with an increased risk for
      HSV infection. RESULTS: Prevalences of infection among the 997 prostitutes
      studied were 93.9% for HSV-1 and 60.8% for HSV-2. Only 1.8% of the women were
      seronegative for both viruses. The only variable associated with HSV-1
      seropositivity was crowding index. The following variables were associated with
      an increased risk for infection with HSV-2: age, level of education, working
      site, born outside Mexico City and increasing time as a prostitute. CONCLUSIONS:
      This is the first assessment of HSV infection in Mexico and may be useful for the
      development and application of control and preventive measures among the
      prostitute population at risk of acquiring and transmitting human
      immunodeficiency virus (HIV) and other STD.

PMID- 10405867
TI  - Helicobacter pylori infection and atrophic gastritis in middle-aged Japanese
      residents of Sao Paulo and Lima.
AB  - BACKGROUND: Helicobacter pylori infection and atrophic gastritis (AG) are
      markedly more prevalent in Japan than in other industrialized countries, however,
      the reasons for such a high prevalence are not fully understood. To add to
      information on H. pylori infection and its association with AG, the authors
      studied Japanese living in less developed countries. METHODS: Cross-sectional
      surveys were conducted of randomly selected Japanese residents aged 40-59 years
      in Sao Paulo, Brazil and Lima, Peru. Serum IgG antibody to H. pylori and
      pepsinogen I (PGI) and II (PGII) were measured as markers of AG. RESULTS: The
      prevalence of H. pylori infection was similar in both populations, 77% (95% CI:
      70-83) in Sao Paulo and 75% (95% CI: 65-82) in Lima, and was within the range of
      five populations in Japan from our previous study. However, the prevalence of AG,
      defined by PGI < 70 ng/ml and PGI/PGII < 3.0 was more prevalent among Japanese in
      Sao Paulo (39% [95% CI: 32-47]), than Japanese in Lima (18% [95% CI: 12-27]).
      This difference was not explained by sex, age, generation or H. pylori infection.
      CONCLUSIONS: Helicobacter pylori infection among Japanese in less developed
      countries was similar to Japanese in Japan, although prevalence of AG varied.
      Factors other than H. pylori infection are important in the development of AG
      among Japanese.

PMID- 10405868
TI  - Factors associated with clinical leptospirosis: a population-based case-control
      study in the Seychelles (Indian Ocean).
AB  - BACKGROUND: In Western countries, leptospirosis is uncommon and mainly occurs in
      farmers and individuals indulging in water-related activities. In tropical
      countries, leptospirosis can be up to 1000 times more frequent and risk factors
      for this often severe disease may differ. METHODS: We conducted a one-year
      population-based matched case-control study to investigate the frequency and
      associated factors of leptospirosis in the entire population of Seychelles.
      RESULTS: A total of 75 patients had definite acute leptospirosis based on
      microagglutination test (MAT) and polymerase chain reaction (PCR) assay
      (incidence: 101 per 100,000 per year; 95% confidence interval [CI]: 79-126).
      Among the controls, MAT was positive in 37% (past infection) and PCR assay in 9%
      (subclinical infection) of men aged 25-64 with manual occupation. Comparing cases
      and controls with negative MAT and PCR, leptospirosis was associated positively
      with walking barefoot around the home, washing in streams, gardening, activities
      in forests, alcohol consumption, rainfall, wet soil around the home, refuse
      around the home, rats visible around the home during day time, cats in the home,
      skin wounds and inversely with indoor occupation. The considered factors
      accounted for as much as 57% of the variance in predicting the disease.
      CONCLUSION: These data indicate a high incidence of leptospirosis in Seychelles.
      This suggests that leptospires are likely to be ubiquitous and that effective
      leptospirosis control in tropical countries needs a multifactorial approach
      including major behaviour change by large segments of the general public.

PMID- 10405869
TI  - A controlled evaluation of two school-based anthelminthic chemotherapy regimens
      on intensity of intestinal helminth infections.
AB  - BACKGROUND: School-based deworming programmes have been promoted as a cost
      effective strategy for control of nematode infection in developing countries.
      While numerous efficacy studies have been conducted, there is little information
      on actual programme effectiveness in areas of intense transmission. METHODS: A
      randomized trial of a school-based deworming programme was conducted in 12
      primary schools on Pemba Island, Zanzibar. Four schools each were randomized to
      control, twice a year deworming with single dose mebendazole or three times a
      year deworming. Baseline and 12-month follow-up data on helminth infection using
      the Kato-Katz technique, demographic information and nutritional status were
      collected on 3028 children from March 1994 to May 1995. RESULTS: Intensity of
      infection measured as eggs per gram of faeces (epg) declined significantly for
      Ascaris lumbricoides, Trichuris trichiura and hookworm infections in both
      treatment groups. A. lumbricoides infection intensity declined 63.1% and 96.7% in
      the twice and three times per year treatment groups compared to the controls. T.
      trichiura infection intensity declined 40.4% and 75.9% respectively and hookworm
      intensity declined 35.3% and 57.2% respectively compared to control schools.
      CONCLUSIONS: These results suggest that school-based programmes can be a cost
      effective approach for controlling the intensity of intestinal helminth infection
      even in environments where transmission is high.

PMID- 10405870
TI  - Reduced ratio of male to female births in Japan.

PMID- 10405871
TI  - Haybittle, use of Gompertz function.

PMID- 10405872
TI  - The ketolide antimicrobial agent HMR-3004 inhibits neutrophil superoxide
      production by a membrane-stabilizing mechanism.
AB  - We have investigated the membrane-stabilizing potential of the prototype ketolide
      antimicrobial agent, HMR-3004 (3.75-125 microM), as well as the effects of this
      agent on the production of superoxide by human neutrophils activated with FMLP,
      the calcium ionophore A23187, phorbol 12-myristate 13-acetate (PMA) or opsonized
      zymosan (OZ), each of which uses different transductional mechanisms to activate
      NADPH-oxidase. Membrane-stabilizing activity was investigated using a hemolytic
      procedure, while superoxide production was assayed by lucigenin-enhanced
      chemiluminescence. At concentrations of 3.75 microM and greater, HMR-3004 caused
      dose-related inhibition of superoxide production by neutrophils activated by all
      four stimuli of membrane-associated oxidative metabolism, which was not
      associated with cytotoxicity or superoxide-scavenging activity. At the same
      concentrations, HMR-3004 antagonized the hemolytic actions of the membrane
      disruptive bioactive phospholipids, lysophosphatidylcholine (LPC), platelet
      activating factor (PAF) and lyso-PAF. A mechanistic relationship between the
      membrane-stabilizing and the anti-oxidative properties of HMR-3004 was suggested
      by the observation that treatment of neutrophils with non-cytolytic
      concentrations of LPC antagonized the inhibitory effects of the ketolide on
      superoxide production by these cells. These membrane-stabilizing, anti-oxidative
      activities of HMR-3004 suggest that in addition to its antimicrobial properties,
      this agent possesses anti-inflammatory properties which are superior to those of
      the presently available macrolide and azalide agents.

PMID- 10405873
TI  - Differential effect of flavonoids on inhibition of secretion and accumulation of
      secretory granules in rat basophilic leukemia cells.
AB  - Rat basophilic leukemia (RBL) cells resemble mucosal mast cells (MMC) and develop
      few secretory granules under normal culture conditions. RBL cells have been used
      for the study of secretion and for the possible involvement of MMC in food
      allergies and irritable bowel syndrome (IBS). The flavonoid quercetin is one of
      very few molecules that inhibit RBL cell proliferation and constitutive histamine
      release; it also induces synthesis of rat mast cell protease (RMCP) II and
      accumulation of secretory granules. Even though quercetin is available as a food
      supplement over the counter, some early studies had indicated it may be
      carcinogenic. We, therefore, compared the effect of quercetin to that of other
      flavonoids with similar structure. Flavone, kaempferol, myricetin and morin were
      investigated for their action on RBL cell secretion of beta-hexosaminidase
      stimulated by anti-DNP serum and DNP-BSA, as well as on secretory granule
      development. Quercetin, myricetin and kaempferol inhibited RBL cell secretion
      significantly only at 10(-4) M. Flavone inhibited secretion at 10(-4), 10(-5) and
      10(-6) M; it also maximally induced secretory granule accumulation as evidenced
      by light and electron microscopy. In contrast, morin which differs structurally
      only by one extra hydroxyl group had minimal effect. These results indicate that
      flavone is capable of inhibiting stimulated secretion and inducing secretory
      granule development at reasonable concentrations.

PMID- 10405874
TI  - Pharmacology of the biological response modifier bropirimine (PNU-54461) on
      experimental autoimmune encephalomyelitis (EAE) in mice.
AB  - In murine severe experimental autoimmune encephalomyelitis (EAE), an animal model
      for the human disease multiple sclerosis (MS), we tested the efficacy of a 5-halo
      6-phenyl pyrimidinone compound, bropirimine (PNU-54461). We observed that the
      compound is active in suppressing EAE when administered orally, a significant
      pharmacological advantage compared to some current therapies for the treatment of
      MS. Furthermore, bropirimine was most efficacious when dosing was begun 5-10 days
      after injection of myelin basic protein, the protein isolated from the central
      nervous system and used for inducing EAE in our model. This is a period of time
      following the initial immunological events leading to the disease, when large
      scale leukocyte infiltration into the central nervous system begins. Following
      oral dosing, bropirimine peaked in the blood within 3 h and was cleared to
      undetectable concentrations within 16-18 h. Despite the pharmacokinetics in the
      blood, bropirimine was fully efficacious when dosed orally every two or three
      days. Surprisingly, bropirimine treatment did not result in a statistically
      significant decrease in leukocyte infiltration into the lower spinal cord, unless
      the compound was dosed daily at a high concentration. We also observed the
      concentration and time course of alpha-interferon in blood following oral dosing
      of bropirimine. The kinetics of interferon in the blood are similar to, but
      clearly distinguishable from, the pharmacokinetics of bropirimine in the blood.
      It is not clear whether or not the induction of interferon plays a key role in
      the efficacy of bropirimine. Nevertheless, the results using bropirimine in EAE
      suggest that the compound may be useful for the treatment of multiple sclerosis.

PMID- 10405875
TI  - Neutropenia as a complication of intravenous immunoglobulin (IVIG) therapy in
      children with immune thrombocytopenic purpura: common and non-alarming.
AB  - Following reports on adult patients with neutropenia as a result of
      administration of intravenous immunoglobulin (IVIG) we have investigated the
      incidence and consequences of neutropenia following IVIG treatment in children
      with immune thrombocytopenic purpura (ITP). The medical records of 14 children
      with ITP who received IVIG as inpatients were reviewed. Past and present history,
      age, previous medications, complete blood count and differential before and after
      treatment with IVIG were recorded for each patient. The patients, aged 5.5 +/-
      3.5 (0.5-11.5) years [mean +/- SD; range] received one or more courses of IVIG.
      Neutropenia (total neutrophils < 2000/mm3) was observed within 24 h after the
      first course of IVIG in five children (36%). The pretreatment neutrophil count in
      this group was not significantly different from that observed in the patients
      without IVIG-induced neutropenia (p = 0.98). The condition resolved spontaneously
      and without complications in all patients within 48 h. In a preliminary
      experiment in which bone marrow derived mononuclear cells were assayed for the
      clonogenicity in methylcellulose, there was no suppressive effect of IVIG on the
      number of CFU-GM colonies. CONCLUSIONS: Since IVIG is currently administered in a
      vast number of medical indications, neutropenia following IVIG administration may
      not be an uncommon finding. It seems to be transient and self limited.

PMID- 10405876
TI  - Happy birthday DIOGENE: a hospital information system born 20 years ago.
AB  - Since its birth in 1978, DIOGENE, the hospital information system of Geneva
      University Hospital has been constantly evolving, with a major change in 1995,
      when migrating from a centralized to an open distributed architecture. For a few
      years, the hospital had to face health policy revolution with both economical
      constraints and opening of the healthcare network. The hospital information
      system DIOGENE plays a significant role by integrating four axes of knowledge:
      medico-economical context for better understanding and influencing resources
      consumption; the whole set of patient reports and documents (reports, encoded
      summaries, clinical findings, images, lab data, etc.), patient-dependent
      knowledge, in a vision integrating time and space; external knowledge bases such
      as Medline (patient-independent knowledge); integration of these patient
      dependent and independent knowledge in a case-based reasoning format, providing
      on the physician desktop all relevant information for helping him to take the
      most appropriate adequate decision.

PMID- 10405877
TI  - The HELP hospital information system: update 1998.
AB  - The HELP hospital information system has been operational at LDS Hospital since
      1967. The system initially supported a heart catheterization laboratory and a
      post open heart Intensive Care Unit. Since the initial installation the system
      has been expanded to become an integrated hospital information system providing
      services with sophisticated clinical decision-support capabilities to a wide
      variety of clinical areas such as laboratory, nurse charting, radiology,
      pharmacy, etc. The HELP system is currently operational in multiple hospitals of
      LDS Hospital's parent health care enterprise--Intermountain Health Care (IHC).
      The HELP system has also been integrated into the daily operations of several
      other hospitals in addition to those at IHC. Evaluations of the system have
      shown: (1) it to be widely accepted by clinical staff; (2) computerized clinical
      decision-support is feasible; (3) the system provides improvements in patient
      care; and (4) the system has aided in providing more cost-effective patient care.
      Plans for making the transition from the 'function rich' HELP system to more
      modern hardware and software platforms are also discussed.

PMID- 10405879
TI  - The Brigham integrated computing system (BICS): advanced clinical systems in an
      academic hospital environment.
AB  - The Brigham integrated computing system (BICS) provides nearly all clinical,
      administrative, and financial computing services to Brigham and Women's Hospital,
      an academic tertiary-care hospital in Boston. The BICS clinical information
      system includes a very wide range of data and applications, including results
      review, longitudinal medical records, provider order entry, critical pathway
      management, operating-room dynamic scheduling, critical-event detection and
      altering, dynamic coverage lists, automated inpatient summaries, and an online
      reference library. BICS design emphasizes direct physician interaction and
      extensive clinical decision support. Impact studies have demonstrated significant
      value of the system in preventing adverse events and in saving costs,
      particularly for medications.

PMID- 10405878
TI  - The CCC system in two teaching hospitals: a progress report.
AB  - Computing systems developed by the Center for Clinical Computing (CCC) have been
      in operation in Beth Israel and Brigham and Women's hospitals for over 10 years.
      Designed to be of direct benefit to doctors, nurses, and other clinicians in the
      care of their patients, the CCC systems give the results of diagnostic studies
      immediately upon request; offer access to the medical literature: give advice,
      consultation, alerts, and reminders; assist in the day-to-day practice to
      medicine, and participate directly in the education of medical students and house
      officers. The CCC systems are extensively used, even by physicians who are under
      no obligation to use them. Studies have shown that the systems are well received
      and that they help clinicians improve the quality of patient care. In addition,
      the CCC systems have had a beneficial impact on the finances of the two
      hospitals, and they have cost less than what many hospitals spend for financial
      computing alone.

PMID- 10405880
TI  - Evolution of an integrated HIS in The Netherlands.
AB  - This article considers the 26 years history of an integrated hospital information
      system (HIS). The system emerged from an experimental government sponsored
      project in the Leiden University Hospital and is now the leading HIS in The
      Netherlands. The evolution during these 26 years is presented and discussed in
      this article with an emphasis on the organisational setting and financing besides
      the aspects functionality, technology/architecture and evaluation aspects.
      Recently HISCOM was acquired by the BAAN-group completing the evolution and
      bringing the HIS to the international health care IT market.

PMID- 10405881
TI  - The Regenstrief Medical Record System: a quarter century experience.
AB  - Entrusted with the records for more than 1.5 million patients, the Regenstrief
      Medical Record System (RMRS) has evolved into a fast and comprehensive data
      repository used extensively at three hospitals on the Indiana University Medical
      Center campus and more than 30 Indianapolis clinics. The RMRS routinely captures
      laboratory results, narrative reports, orders, medications, radiology reports,
      registration information, nursing assessments, vital signs, EKGs and other
      clinical data. In this paper, we describe the RMRS data model, file structures
      and architecture, as well as recent necessary changes to these as we coordinate a
      collaborative effort among all major Indianapolis hospital systems, improving
      patient care by capturing city-wide laboratory and encounter data. We believe
      that our success represents persistent efforts to build interfaces directly to
      multiple independent instruments and other data collection systems, using medical
      standards such as HL7, LOINC, and DICOM. Inpatient and outpatient order entry
      systems, instruments for visit notes and on-line questionnaires that replace
      hardcopy forms, and intelligent use of coded data entry supplement the RMRS.
      Physicians happily enter orders, problems, allergies, visit notes, and discharge
      summaries into our locally developed Gopher order entry system, as we provide
      them with convenient output forms, choice lists, defaults, templates, reminders,
      drug interaction information, charge information, and on-line articles and
      textbooks. To prepare for the future, we have begun wrapping our system in Web
      browser technology, testing voice dictation and understanding, and employing
      wireless technology.

PMID- 10405882
TI  - The 1998 Biomaterials Access Assurance Act.

PMID- 10405883
TI  - A review of improvements in acrylic bone cements.

PMID- 10405884
TI  - The antithrombotic versus calcium antagonistic effects of polyethylene glycol
      grafted bovine pericardium.
AB  - Cardiovascular calcification, the formation of calcium phosphate deposits in
      cardiovascular tissue, is a common end stage phenomenon affecting a wide variety
      of bioprosthesis. This study proposes a novel approach of reducing pericardial
      calcification and thrombosis via coupling polyethylene glycols (PEG) to
      glutaraldehyde treated bovine pericardium via acetal linkages. The calcification
      of the PEG modified tissue and the control pericardium (extracted and
      glutaraldehyde treated) was investigated by in vivo rat subcutaneous implantation
      models and by in vitro meta stable calcium phosphate solutions. Scanning electron
      microscopy showed that calcification primarily involved the surface of collagen
      fibrils and the intrafibrillar spaces. However, the grafting of pericardium with
      PEG-20,000 had dramatically modified the surface and subsequently inhibited the
      deposits of calcium. Further, the modified tissue had also reduced the platelet
      surface attachment. Such a reduced calcification of PEG modified tissues can be
      explained by decrease of free aldehyde groups, a space filling effect and
      therefore improved biostability and synergistic blood compatible effects of PEG
      after coupling to the tissues. This simple method can be a useful
      anticalcification treatment for implantable tissue valves.

PMID- 10405885
TI  - Biomedical applications of polyurethanes: a review of past promises, present
      realities, and a vibrant future.
AB  - Polyurethanes, having extensive structure/property diversity, are one of the most
      bio- and blood-compatible materials known today. These materials played a major
      role in the development of many medical devices ranging from catheters to total
      artificial heart. Properties such as durability, elasticity, elastomer-like
      character, fatigue resistance, compliance, and acceptance or tolerance in the
      body during the healing, became often associated with polyurethanes. Furthermore,
      propensity for bulk and surface modification via hydrophilic/hydrophobic balance
      or by attachments of biologically active species such as anticoagulants or
      biorecognizable groups are possible via chemical groups typical for polyurethane
      structure. These modifications are designed to mediate and enhance the acceptance
      and healing of the device or implant. Many innovative processing technologies are
      used to fabricate functional devices, feeling and often behaving like natural
      tissue. The hydrolytically unstable polyester polyurethanes were replaced by more
      resistant but oxidation-sensitive polyether polyols based polyurethanes and their
      clones containing silicone and other modifying polymeric intermediates. Chronic
      in vivo instability, however, observed on prolonged implantation, became a major
      roadblock for many applications. Presently, utilization of more oxidation
      resistant polycarbonate polyols as soft segments, in combination with
      antioxidants such as Vitamin E, offer materials which can endure in the body for
      several years. The applications cover cardiovascular devices, artificial organs,
      tissue replacement and augmentation, performance enhancing coatings and many
      others. In situ polymerized, cross-linked systems could extend this biodurability
      even further. The future will expand this field by revisiting chemically
      controlled biodegradation, in combination with a mini-version of RIM technology
      and minimally invasive surgical procedures, to form, in vivo, a scaffold, by
      delivery of reacting materials to the specific site in the body and polymerizing
      the mass in situ. This scaffold will provide anchor for tissue regeneration via
      cell attachment, proliferation, control of inflammation, and healing.

PMID- 10405886
TI  - Enhancing the response to interferon-alpha.
AB  - BACKGROUND: Though initially recognized as antiviral agents, it was soon
      demonstrated that certain neoplasms were particularly sensitive to interferon
      alpha (IFN-alpha). Indeed, the initial success of systemic IFN-alpha treatment in
      AIDS-associated Kaposi's sarcoma (AIDS-KS) occurred before identification of the
      human immunodeficiency virus (HIV) and in the absence of any coherent view of KS
      pathogenesis. With a more comprehensive understanding how KS develops and which
      circumstances provide an increased virulence of this neoplasm in HIV-infected
      persons, a more subtle rationale for IFN-alpha treatment arose regarding the
      disorder of the endogenous IFN-system in HIV-positive individuals. Until recently
      IFN-alpha was the only therapy available for patients with chronic hepatitis C
      (CHC). However, no more than 30% of these patients show a sustained virological
      response. Initial therapy with a combination therapy of IFN-alpha and ribavirin
      turned out to be more effective than treatment with IFN-alpha alone. To
      ameliorate response rates in antiviral IFN-therapy a profound understanding of
      viral dynamics, as well as immunological conditions associated with viral
      persistence, seems to be essential. Within a conference of the European Society
      of Clinical Virology (ESCV), which took place in Hamburg from August 30 to
      September 2, 1998, and was entitled 'Progress in Clinical Virology IV', a
      satellite symposium was organized to evaluate the clinical results of special
      antiviral treatment options with IFN-alpha, to analyze treatment failures with
      this cytokine and to ameliorate future strategies of IFN-alpha therapy. It
      focussed on HIV-related complications as coinfection with hepatitis C virus (HCV)
      and AIDS-KS, respectively. METHODS: A kinetic model of HCV infection based on
      principles established in studying HIV-1 infection was presented which is
      predictive for the outcome of IFN-alpha treatment. It involves different rates of
      velocity and compares the rates of acute clearance after different dosages of IFN
      alpha application. Using the hypothesis to fit the changes in serum HCV RNA
      measured in a set of patients, it was found that 5 mIU daily dosing on average
      blocks 81% of HCV production/release, whereas 10 or 15 mIU blocks about 95% of
      HCV production/release. RESULTS: Only recently clinical data revealed a greater
      benefit of combination therapy with IFN-alpha and ribavirin compared to IFN-alpha
      alone in patients with chronic hepatitis C. In 345 CHC patients relapsing after
      pretreatment with IFN-alpha monotherapy, sustained response was achieved in a 10
      fold higher degree with a combination of IFN and ribavirin compared to patients
      retreated with IFN alone. In 1775 treatment-naive patients with CHC, response
      rates to the combination therapy was significantly higher in all patient groups
      with more than 60% of sustained virological response in patients with genotype 2
      and 3, while patients with genotype 1 (poorer prognosis) benefit from extended
      combination treatment duration from 24 to 48 weeks (17 versus 29% of sustained
      virological response), respectively. CONCLUSIONS: As viral dynamics on one side
      and host immune response on the other feature as two landmarks on which the
      manifestation of viral persistence and chronic viral infections is established,
      some similarities of HCV and HIV disease are striking. An unusual endogenous IFN
      alpha system is associated with both infections and is a negative prognostic
      factor to response to treatment with IFN-alpha in CHC as well as AIDS-KS. The
      consequences for treatment options with IFN are a combination with ribavirin in
      CHC and a graduated systemic treatment schedule in AIDS-KS starting with IFN
      treatment in early disease followed by chemotherapy in advanced stages of KS.

PMID- 10405887
TI  - Rotaviruses detected by reverse transcription polymerase chain reaction in acute
      gastroenteritis during a trial of rhesus-human reassortant rotavirus tetravalent
      vaccine: implications for vaccine efficacy analysis.
AB  - BACKGROUND: Rotaviruses are routinely diagnosed by detection of rotavirus antigen
      in stools using an enzyme immunoassay (EIA). A sensitive method, like reverse
      transcription polymerase chain reaction (RT-PCR), may reveal more rotaviruses,
      but the clinical significance of such findings is not well established.
      OBJECTIVES: To study whether RT-PCR can detect more episodes of rotavirus
      associated gastroenteritis than EIA and to determine how rotavirus RT-PCR
      findings might change efficacy analysis of a rotavirus vaccine trial, in which
      the outcome measure was rotavirus gastroenteritis diagnosis with EIA. STUDY
      DESIGN: We applied RT-PCR for detection of rotaviruses in gastroenteritis
      episodes encountered in an efficacy trial of rhesus-human reassortant rotavirus
      tetravalent (RRV-TV) vaccine, in a total of 2398 infants. During a follow-up,
      covering two rotavirus epidemic seasons, 256 cases of rotavirus associated
      gastroenteritis were detected by EIA; 226 were in the primary efficacy analysis
      period that included children who had received three doses of vaccine or placebo.
      RESULTS: With RT-PCR, 84 (33%) more cases of rotavirus gastroenteritis were
      diagnosed than with EIA, 65 of these were in the primary efficacy analysis
      period. Clinically, cases of rotavirus gastroenteritis diagnosed by RT-PCR were
      much milder (median severity score 6 on a 20-point scale) than those diagnosed by
      EIA (median score 11), P < 0.0001. RT-PCR revealed proportionally more G2 and G4
      rotaviruses than EIA. G1 rotaviruses detected by RT-PCR were almost equally
      divided between RRV-TV (25) vaccine and placebo (28) groups, whereas an apparent
      vaccine protective effect was seen in the distribution of G2 (one in the RRV-TV
      and eight in the placebo group) and G4 rotaviruses (six in the RRV-TV and 14 in
      the placebo group). CONCLUSION: RT-PCR is a useful tool in the diagnosis of
      rotavirus gastroenteritis, particularly for cases associated with other than the
      epidemiologically dominant G-type. Application of RT-PCR contributes to the
      overall appraisal of performance of rotavirus vaccine.

PMID- 10405888
TI  - Enhanced protection against viral infection by co-administration of plasmid DNA
      coding for viral antigen and cytokines in mice.
AB  - BACKGROUND: DNA vaccines have been shown to induce protective immunity against
      viral infections in different animal models. We have recently demonstrated that
      DNA vaccine induced protective immunity against influenza A virus and La Crosse
      virus (LACV) is primarily mediated by humoral immune response. OBJECTIVE: The
      goal of this study was to investigate whether administration of DNA coding for
      cytokines such as interleukin 12 (IL-12) and granulocyte-macrophage colony
      stimulating factor (GM-CSF) could increase the protective immune response induced
      by vaccination with DNA coding for viral antigens. STUDY DESIGN: For the
      influenza A virus or LACV model, C57BL/6 or interferon-alpha/beta receptor (IFNAR
      1)-deficient mice, respectively, were vaccinated once or twice with 100
      micrograms of DNA encoding viral antigens. At the same time plasmid DNAs (100
      micrograms) coding either for mouse GM-CSF or mouse IL-12 were administered. The
      mice were subsequently challenged with a lethal dose of influenza A virus or LACV
      and monitored for clinical symptoms (weight loss) and survival. RESULTS: To
      achieve a high degree of protection (70% survival) two injections of DNA encoding
      the influenza A virus surface protein hemagglutinin (HA) were required.
      Intriguingly, administration of DNA coding for IL-12 alone also led to a
      pronounced protective effect against virus challenge. Co-administration of DNAs
      encoding IL-12 and HA significantly increased the protective immunity against
      influenza A virus, while IL-12 expression did not improve protection upon
      vaccination with DNA coding for the internal nucleocapsid protein N of LACV. Co
      injection of DNA coding for mouse GM-CSF and HA also showed an adjuvant effect.
      CONCLUSIONS: The data clearly indicate that co-administration of DNA encoding
      cytokines such as IL-12 and GM-CSF with DNA coding for viral antigens has
      adjuvant effects on the protective immune response against different viral
      pathogens.

PMID- 10405889
TI  - A new variant of echovirus 4 associated with a large outbreak of aseptic
      meningitis.
AB  - BACKGROUND: A large outbreak of aseptic meningitis which began in April 1997
      involved hundreds of cases in all geographical regions of Israel and the
      Palestinian Authority, peaked between June and September, and lasted until
      December. OBJECTIVES: We have investigated the virus associated with the outbreak
      to determine its serotype and molecular type and to establish epidemiological
      links. DESIGN: Virus strains isolated from 210 clinical samples were serotyped by
      neutralization using LBM and WHO antiserum pools and two echovirus 4 (EV4)
      specific antisera, and by immunofluorescence using a monoclonal antibody. RNA was
      extracted and a 435 base long fragment derived from the 5'UTR of the genome was
      amplified by RT-PCR using common primers, and sequenced. Sequences were compared
      to echoviruses 4, 6 and 7 prototypes from ATCC, and to other echoviruses
      sequences from the EMBL/Genbank data base. RESULTS: The outbreak isolates were
      identified by the EV4 type-specific antisera and the monoclonal antibody but not
      with the WHO pools. Very few isolates could be typed by the LBM pools. The EV4
      isolates accounted for 68% of all enterovirus isolates in our laboratory in 1997.
      The age distribution of the patients was: 0-11 month, 11.2%; 1-4 years, 16.1%; 5
      9 years, 31.8%; 10-14 years, 9.9%; 15-20 years, 9.5%; 21-44 years, 21.5%; and >
      45 years, 0%. Males between 1 and 14 years of age were affected more frequently
      than females of the same age. The sequences of 25 of 28 EV4 isolates analyzed
      were closely related to each other (> 95% homology) and the remaining three
      isolates had < 95% homology to the others and to each other. Interestingly, the
      outbreak strains were less closely related to the EV4 prototype, than to several
      other echoviruses. Three closely related subgroups were identified which
      correlated with geographical distribution but the temporal distribution did not
      reveal links leading to the source of the outbreak. CONCLUSION: The outbreak was
      caused by a variant of EV4 which apparently did not circulate in the area before
      and thus was capable of causing a widespread infection.

PMID- 10405890
TI  - Parvovirus B19 infection in thoracic organ transplant recipients.
AB  - BACKGROUND: Clinical manifestations of parvovirus B19 infection in
      immunocompromised patients are mostly reported as acute or chronic hematologic
      disorders. More recently, respiratory or renal involvement has been described.
      OBJECTIVE: We started in 1994 a prospective study of parvovirus B19 infection in
      a group of lung (LTP) and heart-lung (HLTP) transplanted patients, including
      occasionally heart transplanted (HTP) patients. STUDY DESIGN: 62 patients (49
      LTP, 11 HLTP, 2 HTP) were included in a serological survey and DNA detection by
      PCR was performed on each serum sample of the first 29 patients; later we
      performed it only when serology could suggest an acute episode, or when
      parvovirus infection could be suspected on clinical or biological observations. A
      total of 1655 sera were examined by serological tests and DNA detection was done
      in 500 samples. Specific IgM, seroconversion, significant increase of specific
      IgG levels, and/or parvovirus B19 DNA detection, were considered as markers of
      viral infection. RESULTS: We observed the presence of both markers of infection
      in 24 patients (39%), with an individual combination of positive antibody and PCR
      results. Acute or chronic anaemia, neutropenia were associated to these
      laboratory findings in 19 patients, but in five cases, an asymptomatic clinical
      infection suggested viral persistence. CONCLUSIONS: We report parvovirus
      associated acute or chronic anaemia and pancytopenia in a group of LTP, HLTP and
      HTP patients, as well as asymptomatic cases of infection. In the hypothesis of a
      parvoviral persistent or latent infection, current diagnosis methods may be
      unreliable to identify any other clinical manifestations.

PMID- 10405891
TI  - High rate of chronicity in HCV infection determined by antibody confirmatory
      assay and PCR in 4110 patients during long-term follow-up.
AB  - BACKGROUND: It is still unclear how many patients with hepatitis C virus (HCV)
      antibodies have viremia and hence are infectious. OBJECTIVES: To determine the
      chronicity of HCV infection by correlation of HCV antibodies with presence of
      viremia in long-term follow-up. STUDY DESIGN: In a longitudinal study sera of
      4110 patients were analyzed with second generation HCV-enzyme immunoassay (EIA)
      and polymerase chain reaction (PCR). Only those patients were included in this
      study in whom sequential serum samples over a period of 2 years were available.
      To avoid preanalytical and analytical failures, we used a transport solution to
      prevent RNA degradation and a four-antigen recombinant immunoblot assay,
      established in our laboratory, for confirmation of antibody reactivity. RESULTS:
      Of 2815 patients with confirmed HCV antibodies 2784 (98.9%) were also positive in
      HCV-PCR assay. False reactive EIA results were detected in 177 (13.7%)
      individuals as shown by confirmatory assay and PCR. Only one patient (0.04%)
      spontaneously lost detectable HCV viremia and subsequently HCV-specific
      antibodies. CONCLUSIONS: Our study clearly demonstrates that presence of
      confirmed HCV-specific antibodies correlates significantly (98.9%; P < 0.001)
      with HCV viremia, and that spontaneous loss of viremia is a very rare event in
      HCV infection. We also found that elimination of HCV infection is not
      sufficiently predicted by the loss of detectable viremia in PCR, but can be
      concluded from the disappearance of virus-specific antibodies.

PMID- 10405892
TI  - Rapid detection by reverse hybridization of mutations in the UL97 gene of human
      cytomegalovirus conferring resistance to ganciclovir.
AB  - BACKGROUND OF STUDY: Diseases due to human cytomegalovirus (HCMV) infection
      constitute a major threat in marrow and solid organ transplant recipients.
      Ganciclovir (GCV) is widely used in prophylaxis and pre-emptive therapy of active
      HCMV infection. Resistance to ganciclovir (GCV) may arise at variable frequency
      under GCV therapy and is conferred by mutations (i) in the UL97 gene (codons 460,
      520, and 591-607) encoding a phosphotransferase which is essential for
      monophosphorylation of GCV and, to a lesser extent, (ii) in the UL54 gene coding
      for the DNA polymerase of HCMV. OBJECTIVE: The purpose was to develop a rapid
      assay to screen for emerging GCV resistance mutations in the UL97 gene of HCMV
      whereby avoiding virus isolation and nucleotide sequencing procedures. STUDY
      DESIGN: A nested PCR (nPCR) amplifying UL97 codons 450-672 was developed. Nested
      amplicons were subsequently sequenced directly. Oligonucleotides for use in a
      reverse hybridization assay were designed to detect relevant non-synonymous
      mutations at codons UL97 460, 520, 603 and 607. Strain AD169 served as a wild
      type control. RESULTS: UL97-specific nPCR amplicons were obtained from 18 EDTA
      blood samples of ten transplant recipients receiving GCV for more than 30 days.
      In three consecutive samples from a single patient a GCV resistance mutation at
      codon 603 (C-->W) was detected. In addition, two out of four cell culture-adapted
      HCMV isolates known to exhibit GCV resistance in vitro revealed mutations at
      codons 460 (M-->V) and 607 (C-->Y), respectively. By reverse hybridization a
      discrimination of single nucleotide changes at codons 460, 520, 603 and 607 was
      possible whereby matching exactly the results of the nucleotide sequence analysis
      for all 23 amplicons examined. CONCLUSIONS: Reverse hybridization appeared to be
      a rapid and convenient alternative to nucleotide sequencing when screening the
      UL97 gene of HCMV for selected markers of GCV resistance.

PMID- 10405893
TI  - Identification and characterization of a histone binding site of the non
      structural protein 3 of hepatitis C virus.
AB  - BACKGROUND: Chronic hepatitis resulting from the hepatitis C virus (HCV)
      infection leads to cirrhosis in at least half the infected patients and increases
      the risk of hepatocellular carcinoma. There are indications that this pathogenic
      effect may result from the disturbance of intracellular signal cascades caused by
      the interaction with viral antigens. Although a great amount of data has been
      accumulated about functional regions in HCV proteins, relatively little is known
      about their intracellular targets. Previously, we have demonstrated that the full
      length non-structural protein 3 of HCV (NS3) (Borowski P, Heiland M, Feucht H,
      Laufs R. Characterisation of non-structural protein 3 of hepatitis C virus as
      modulator of protein phosphorylation mediated by PKA and PKC. Evidences for
      action on the level of substrate and enzyme. Arch Virol 1999a; 144) and its NH2-
      and COOH-terminal truncated form (Borowski P, Heiland M, Oehlmann K, Becker B,
      Kornetzky L, Feucht HH, Laufs R. Non-structural protein 3 of hepatitis C virus
      inhibits phosphorylation mediated by cAMP-dependent protein kinase. Eur J Biochem
      1996;237:611-618) associate to stable complexes with core histones H2B and H4.
      The changes of the properties of histones as substrate for cAMP-dependent protein
      kinase (PKA) and protein kinase C (PKC) were found as a direct consequence of the
      interaction. OBJECTIVE: In the present study we further these observations,
      localize the histone binding domain of NS3 and investigate the mechanisms by
      which NS3 affects the functions of the histones in vitro. STUDY DESIGN: HCV
      protein exhibiting the mentioned histone binding activity was produced in a
      bacterial expression system, purified and binding to histones was biochemically
      characterized. The region of NS3 involved in the interaction with histones was
      defined by proteolytic fragmentation, microsequencing and a specific histone
      binding assay. Furthermore, a functional test to quantify the interaction of
      histones with DNA was established and the binding of DNA to histone as a function
      of NS3 concentration was analysed by means of graphical methods. RESULTS: The
      investigated fragment of HCV polyprotein consisting of amino acid residues 1189
      1525 (HCV-polyprotein-(1189-1525)) displayed significant histone binding
      activity. The binding occurred at a molar ratio 1:1 of histone to HCV-polyprotein
      (1189-1525) and was mediated by a linear stretch of amino acids located between
      the residues 1343 and 1379 of the HCV polyprotein. To demonstrate that HCV
      polyprotein-(1189-1525) affects the binding of DNA to histones we used two
      independent methods: overlay assay and binding assay on Sepharose beads. Graphic
      analysis of the binding kinetics revealed an uncompetitive type of inhibition.
      CONCLUSIONS: Our results provide the first evidence that NS3 binds and affects
      the functions of core histones. The mechanism by which the NS3 interferes with
      the histone functions involves conformational changes of histone molecule.

PMID- 10405894
TI  - Rapid, phenotypic HIV-1 drug sensitivity assay for protease and reverse
      transcriptase inhibitors.
AB  - BACKGROUND: Development of drug resistance is one of the major reasons for the
      failure of antiretroviral therapy of HIV-1 infection. Knowing the drug
      sensitivity-resistance profile of viruses present in a patient prior to treatment
      or change in treatment could help to optimize therapy. OBJECTIVE: Development of
      a rapid standardized phenotypic HIV-1 drug sensitivity assay for protease (PR)
      and reverse transcriptase (RT) inhibitors. DESIGN: The PR gene (codons 1-99) and
      the 5' part of the RT gene (codons 1-300) of HIV-1 is amplified from the plasma
      of infected individuals by RT-PCR and ligated into a proviral clone of HIV-1
      containing a deletion of the PR gene and the 5' part of the RT gene. Bacteria are
      transformed with the ligation product and plasmid DNA is prepared from a library
      of transformed bacteria. The plasmid DNA is transfected into 293 T cells and
      recombinant virus is harvested from the supernatant of the transfected cells 2
      days after transfection. The sensitivity of the recombinant virus is determined
      with the help of a sensitive indicator cell line. RESULTS: Recombinant viruses
      were generated with high efficiency. Determination of the drug sensitivity of the
      recombinant viruses with an indicator cell line was highly reproducible. The
      recombinant viruses accurately reflected the sensitivity-resistance profile of
      the parental viruses. The phenotypic drug sensitivity determined by this assay
      correlated well with the treatment history of patients. CONCLUSION: This assay
      system should allow rapid, high-throughput analyses of phenotypic HIV-1 drug
      sensitivity for PR and RT inhibitors. Due to the efficient generation of
      recombinant viruses, propagation of the recombinant viruses in cell culture is
      not required prior to the determination of the sensitivity of the recombinant
      viruses. The risk of selecting fitter non-resistant viruses due to culture
      conditions is minimized.

PMID- 10405895
TI  - Evaluation of the AmpliSensor PCR and the SHARP signal detection system for the
      early prediction of symptomatic CMV infection in solid transplant recipients.
AB  - BACKGROUND: Cytomegalovirus (CMV) is associated with high morbidity and mortality
      in transplant patients. Specific antiviral treatment at an early stage of CMV
      infection may effectively ameliorate, but not eliminate CMV disease in these
      patients. Presently, the pp65 antigenemia test on peripheral leukocytes is the
      method most widely used for predicting and monitoring transplant patients for
      active CMV infection. Nucleic acid amplification methods are less well defined
      since they lack standardisation. OBJECTIVE: A seminested fluorometric PCR assay
      (AmpliSensor-CMV, BAG, Germany) and a one-step PCR with a signal-amplification
      step (SHARP, Abbott, Germany) specific for the fragments of the CMV UL 122 and UL
      123 genes, respectively, were evaluated for the early diagnosis of CMV infection.
      DESIGN: A total of 26 recipients of heterogeneous solid organs were monitored
      prospectively for a median of 99 days after transplantation. By testing 371
      clinical samples parallel with the pp65-antigen assay and IgM and IgG EIA assays
      the sensitivity, specificity, correlation and quantitation potential of both PCRs
      was evaluated. RESULTS: Eight out of 26 patients developed active CMV infection.
      A total of 48 samples of these patients exceeded a CMV-DNA load threshold of 15
      genome equivalents/10(5) leukocytes (AmpliSensor-CMV) and 41 samples exceeded the
      critical cut-off for the SHARP system. The AmpliSensor PCR exceeded its threshold
      consistently before the clinical onset of CMV disease (median 8 days). There was
      very good agreement between symptomatic CMV infection in patients and AmpliSensor
      PCR, SHARP PCR, and pp65-antigen results (kappa-coefficient > 0.900). IgM and IgG
      EIA showed moderate agreement (kappa-coefficient = 0.591 and 0.552,
      respectively). CONCLUSION: Both PCRs and pp65 antigen assay correlated
      significantly better with CMV disease than serodiagnosis. The AmpliSensor PCR
      allowed more precisely than the SHARP system a quantitative determination of
      viral load and an early and reliable prediction of active CMV infection. The use
      of AmpliSensor PCR may improve the diagnosis and management of active CMV
      infection in organ transplant recipients.

PMID- 10405896
TI  - High-throughput extraction, amplification, and detection (HEAD) of HCV-RNA in
      individual blood donations.
AB  - BACKGROUND: High-throughput nucleic acid amplification techniques (NATs) are
      required for the detection of viral genomes in individual blood donations and
      might be helpful in any virological laboratory. OBJECTIVE: To develop and
      automate a method for the detection of hepatitis C virus RNA in individual blood
      donations, compatible with the time schedule of routine blood bank screening an
      product release. STUDY DESIGN: The viral RNA was isolated with the use of target
      specific capture oligonucleotides and magnetic beads. This extraction method was
      combined with reverse transcription/amplification (RT/PCR) and fluorescence
      detection. We adapted our method on a pipetting robot and pipetted all steps in a
      single room. When the pipetting was completed, microtiter plates were heat-sealed
      with foils and placed into a thermocycler. Positive reactions were detected with
      a fluorescent dye in a second room. Aerosols were avoided with programmed slow
      pipetting steps and with a special device constructed for the removal of the used
      disposable tips. During a 7 month period, we used this method in routine testing
      of individual donations prior to the release of all blood components. RESULTS:
      The total number of 11,700 individual donations including platelet concentrates
      were analysed. We tested up to 192 specimens in one run within 7 h. The frequency
      of cross-contamination using the automated procedure was 0.1%. Five specimens
      have been found repeatedly reactive for HCV-RNA, four of these were anti-HCV
      positive, one sample from a repeat donor was negative in anti-HCV assays. A
      seroconversion was detectable at his next presentation, 6 months later.
      CONCLUSION: In this pilot study, we demonstrate that automated HCV-RT-PCR testing
      is practicable for individual donations in high-throughput. Additionally, the
      described PCR approach could easily be adapted to the detection of other viral
      genomes by the use of specific primers.

PMID- 10405897
TI  - Diagnostic electron microscopy is still a timely and rewarding method.
AB  - BACKGROUND: Parallel to its technical development starting in the 1930s, electron
      microscopy (EM) became an important tool in basic and clinical virology. First
      utilized in the rapid diagnosis of smallpox, it developed to a diagnostic routine
      in the early 1960s using the negative staining technique. EM was applied to
      infected cell-cultures and also to 'dirty' specimens including urine, feces,
      vesicle fluid, liquor. With the implementation of molecular biological and
      genetic techniques, the use of diagnostic EM decreased. OBJECTIVES: (1) To give a
      perspective on future indications and possible uses by discussing the past and
      the present of diagnostic EM, (2) To describe the system of External Quality
      Assessment on EM virus diagnosis (EQA-EMV) established in 1994 by our laboratory
      and its achievements. STUDY DESIGN: EQA-EMV is run to evaluate, to confirm and to
      improve the quality of diagnostic EM. Two different types of specimen are sent
      out: (1) prepared grids to assess and train the diagnostic skills of the
      participants, (2) stabilized virus particle suspensions to assess preparation
      efficiency. RESULTS: Diagnostic EM differs from other diagnostic tests in its
      rapidity and its undirected 'open view'. To emphasize these advantages, the
      indications for diagnostic EM are discussed, fundamental for a continuing future
      adaptation. Besides appropriate techniques, quality control measures are required
      to achieve and keep high diagnostic standards. The results from 6 years of EQA
      EMV are presented. CONCLUSIONS: In the history of diagnostic EM in virology, a
      change in use has been seen. Starting in the 1990s and coincident with the broad
      introduction of 'modern' diagnostic techniques, the number of EM diagnostic labs
      has decreased considerably--in spite of the obvious advantages of this technique.
      To guarantee the continuing performance of diagnostic EM in the future. EQA runs
      have to be performed as with other techniques in the diagnostic armament. The
      growing number of participants and participating countries indicates an interest
      in as well as a need for this program.

PMID- 10405898
TI  - Laparoscopic renal cryoablation: acute and long-term clinical, radiographic, and
      pathologic effects in an animal model and application in a clinical trial.
AB  - OBJECTIVES: To evaluate renal cryosurgery by studying the feasibility of
      laparoscopic delivery and the radiographic characteristics and histopathologic
      effects in a porcine model using different freeze cycles. On the basis of the
      results, a clinical trial of laparoscopic cryosurgical ablation in select
      patients with clinical stage T1 renal tumors was started. MATERIALS AND METHODS:
      Twelve kidneys from six farm pigs underwent cryosurgery. Each kidney was treated
      with two freeze cycles to -180 degrees C. Six kidneys were retroperitonealized,
      and six were not. An abdominal CT scan was performed at various times to evaluate
      for the presence of urinoma or hematoma and to monitor lesion changes. Organs
      were harvested at times ranging from 24 hours to 13 weeks. Radiographic and
      histopathologic changes were recorded for each time period. Eight patients with
      small (average 2-cm) exophytic renal masses underwent laparoscopic biopsy and
      cryosurgical ablation using a 3- or 4.8-mm probe (Cryomedical Sciences Inc.,
      Rockville, MD) for one 15-minute or two 5-minute freeze cycles to a temperature
      of -180 degrees C to extend the ice ball at least 7 mm beyond the tumor margin.
      RESULTS: Dense adhesions between the bowel and cryoablated renal tissue were
      encountered in all non-retroperitonealized kidneys, but no fistula formation was
      present. The retroperitonealized kidneys had minimal adhesion formation. None of
      the animals developed a urinary fistula. At 24 hours and 1 week, CT scanning
      demonstrated an enhancement defect corresponding to the region of the ice ball
      with no urinoma or hematoma. At 13 weeks, only a nonenhancing cortical defect was
      seen. At immediate harvest, hemorrhage was noted in the area of the ice ball with
      a sharp demarcation at the edge of the freeze zone. At 1 week, four distinct
      zones were seen: central necrosis, inflammatory infiltrate, hemorrhage, and
      fibrosis with regeneration. At 13 weeks, the necrotic tissue had been replaced
      with a circumscribed area of fibrosis. There were no intraoperative or
      postoperative complications in the eight patients. The estimated blood loss was
      140 mL, and the mean hospital stay was 3.5 days. At a mean clinical follow-up of
      7.7 (range 1-18) months and radiographic follow-up of 5 months; there have been
      no tumor recurrences or significant changes in the serum creatinine
      concentration. At 24 hours, there was an enhancement defect in the area of the
      ice ball. The CT images at 13 weeks showed a nonenhancing cortical defect in the
      area of the ice ball. CONCLUSIONS: Cryosurgery can be readily delivered
      laparoscopically, creating a discrete lesion at the time of treatment that
      appears to be consistent over time. In the animal studies, complete tissue
      necrosis developed in the freeze zone, followed by reabsorption, and by 13 weeks,
      fibrous tissue had replaced the defect. In the animal and human trials, there
      were no operative complications, urinomas, hematomas, or bowel or urinary
      fistulas. Follow-up imaging in human trials revealed a persistent nonenhancing
      defect in the area of the freeze zone. Long-term clinical follow-up will be
      necessary to determine the cancer-free survival rate.

PMID- 10405899
TI  - Laparoscopic replacement of urinary tract segments using biodegradable materials
      in a large-animal model.
AB  - OBJECTIVE: We elected to evaluate laparoscopic segmental bladder and ureteral
      replacement with free biodegradable graft materials in a large-animal model.
      MATERIALS AND METHODS: In 18 Yucatan minipigs, a 1.5- to 2.8-cm segment of the
      upper ureter was excised. In 15 study animals, the ureter was laparoscopically
      replaced: by a stinted (6F double-J stent) tube graft made of acellular matrix
      (AMX) prepared from minipig ureters (MUMX) in 6 animals, acellular matrix
      prepared from domestic pig ureters (DUMX) in 3, and small-intestinal submucosa
      (SIS) in 6. In 3 control animals, the ureteral gap was bridged only by an
      indwelling stent. The stent was removed at 6 weeks, and retrograde
      ureteropyelography was performed preoperatively and at 8 and 12 weeks
      postoperatively, when animals were sacrificed. In 18 Yucatan minipigs, 3 x 3-cm
      bladder dome segments were laparoscopically replaced: by acellular matrix
      prepared from minipig small bowel (MBMX) in 6 animals, and SIS in 6 animals. The
      bladder was closed primarily in 6 control animals. Bladder capacity was assessed
      preoperatively and at 6 and at 12 weeks, when the animals were sacrificed.
      RESULTS: The average operating time for ureteral replacement was 187 (range 105
      360) minutes. At 12 weeks, all animals had complete obstruction at the level of
      the replacement, with fibrosis +/- bone formation at the level of the stricture.
      For the bladder replacement groups, the average operating time was 147 (range 85
      200) minutes. At 12 weeks, the bladder capacity was 60% of the preoperative
      capacity in the control group, 118% in the MBMX group, and 142% in the SIS group.
      Histologic examination showed regeneration of urothelium and some muscle with
      both MBMX and SIS. CONCLUSIONS: We were able to develop a reliable laparoscopic
      technique for both segmental ureteral and partial bladder replacement in a
      porcine model. With AMX and SIS replacement, regeneration of urothelium occurred
      in both ureter and bladder. However, functional replacement was successful only
      in the bladder.

PMID- 10405900
TI  - Acute ureteral elongation in two animal models using a balloon expander.
AB  - BACKGROUND AND OBJECTIVE: Repair of ureteral injuries and strictures often
      necessitates a major reconstructive procedure such as a psoas hitch, Boari flap,
      renal mobilization, ileal interposition, or autotransplantation. Tissue expanders
      have been used to elongate nerves and arteries. We examined the effects of acute
      ureteral elongation in two animal models. MATERIALS AND METHODS: In eight female
      rabbits, we exposed the left ureter through a midline incision and placed a Ruiz
      Cohen balloon beneath the undermined portion. The expander was then inflated
      until the ureter was tightly stretched across it. After deflation, the expanded
      segment was measured in situ and compared with its original length. Follow-up
      urography was performed, and the tissue was harvested and examined by a
      pathologist. The same procedure was performed in five pigs; however, in these
      animals, a segment of ureter was excised, and a ureteroureterostomy was
      performed, after the acute expansion. RESULTS: We were able to achieve acute
      elongation of the expanded ureteral segment. The mean elongation was 31.3% in the
      rabbits and 32.0% in the pigs. An intravenous urogram (IVU) 6 weeks after the
      elongation showed a functioning kidney and a patent ureter. Histologic
      examination of the ureter within 24 hours after the expansion revealed that all
      segments were viable, the luminal epithelium was intact, and the muscular layers
      appeared normal. At 6 weeks, the expanded segment showed mild inflammatory
      changes, but the overall morphology, size, and cytology findings were similar to
      those of a normal control. CONCLUSIONS: Acute ureteral elongation using a tissue
      expander is a new method of increasing ureteral length. It may be useful to cover
      defects that would need major operations with greater morbidity.

PMID- 10405901
TI  - Advances in digital imaging during endoscopic surgery.
AB  - BACKGROUND AND OBJECTIVE: Digital imaging capabilities have recently been
      incorporated into a number of video systems. Contrast enhancement when using a
      rigid or semirigid endoscope improves image definition by seeking out existing
      transitions in detail. Only the areas of transition are accentuated, whereas
      areas without detail are unaffected. During flexible endoscopy, fiberoptic
      bundles create a classic honeycomb appearance. The use of "fiberscope" filters
      minimizes this appearance by expanding the image of each fiberoptic fiber. We
      therefore assessed whether new developments in digital video image processing
      have improved image quality for endoscopic surgery. MATERIALS AND METHODS: Fifty
      urologists reviewed a video playback of various endourologic procedures. The type
      of endoscope was identified, but the urologic surgeon was blinded to the level of
      enhancement (high or low) or fiberscope filter (A or B) used. Each video clip was
      scored from 1 to 5 for the following image variables: identification of
      structure, detail of image, and background noise or interference. All results
      were averaged and compared using Student's paired t-test. RESULTS: During rigid
      endoscopy, the high and low digital enhancement settings were both superior to no
      enhancement (P < 0.001), and high enhancement was better than low (P < 0.001).
      With semirigid endoscopic procedures, high and low digital enhancement were
      comparable but were superior to no enhancement (P < 0.001). Filters A and B were
      no better than no enhancement. There was a significant improvement noted with the
      use of filter A or B during flexible ureteroscopy over no enhancement (P <
      0.001). In addition, filter A was better than filter B (P < 0.001). CONCLUSIONS:
      Digital enhancement settings during video endoscopy significantly improve images
      from rigid and semirigid endoscopes. The digital fiberscope filter significantly
      improves images obtained during flexible ureteroscopy. Digital image enhancement
      capabilities should be strongly considered when upgrading video systems. Digital
      technology must be further studied to improve clinical video imaging during
      endoscopic surgery.

PMID- 10405902
TI  - The effect of patient position on intrarenal anatomy.
AB  - BACKGROUND AND OBJECTIVE: Although flexible ureteroscopes are designed with
      mechanisms for active and passive tip deflection, one of the major problems is
      the not infrequent inability to enter the lower pole calices. Accordingly, we
      measured the change in the lower pole infundibulopelvic (LIP) angle when the
      patient's position was varied (i.e., prone, supine, head down) during intravenous
      urography (IVU). PATIENTS AND METHODS: The LIP angle was measured in 20 right and
      26 left adult kidneys during an IVU with the patient in six different positions:
      supine level, supine 20 degrees head down, supine 45 degrees head up, prone
      level, prone 20 degrees head down, and prone 45 degrees head up. None of the
      patients had a history of renal surgery. RESULTS: In all cases, the broadest
      angle of entry to the lower pole infundibulum was obtained with the patient in a
      prone position and 20 degrees head down. CONCLUSIONS: The LIP angle broadens when
      the patient lies in a prone 20 degrees head down position. This maneuver could
      improve the surgeon's ability to access the lower pole calices when performing
      flexible ureteronephroscopy.

PMID- 10405903
TI  - Optimizing results of lithotripsy using robust electromagnetic probe.
AB  - BACKGROUND AND OBJECTIVE: A significant impediment to the measurement of the
      pressures and forces created by lithotripter shockwaves has been their
      destructive properties, which have rendered most measuring devices impractical.
      We have developed and tested a robust electromagnetic probe to measure
      cavitational forces in vitro in the focal zones of extracorporeal lithotripters.
      The probe responds to the pressure gradient generated by the radial motion of
      cavitation bubbles. MATERIALS AND METHODS: The effects of shockwaves from the
      Dornier MPL 9000 electrohydraulic lithotripter were measured over the lifetime of
      multiple electrodes. RESULTS: The pulse energy from the electrodes dropped off
      rapidly after approximately 50% of the lifetime quoted by the manufacturer. The
      electrodes were more efficient at higher power settings. As a result, we altered
      our protocol for the treatment of ureteral stones to use a higher kilovoltage and
      a second electrode whenever necessary. Stone-free rates after shockwave
      lithotripsy (SWL) in situ for stones < 11 mm have increased from 68.2% to 83.3%,
      and the retreatment rate has dropped from 23% to 15%. Despite significantly
      higher power settings (23.7 kV v 18.7 kV; P < 0.0001), the need for sedoanalgesia
      has remained relatively constant (26% v 31%). CONCLUSIONS: Measurement of
      cavitational forces from lithotripters using a robust electromagnetic probe is
      useful in planning treatment strategy. We have demonstrated a clinically
      measurable improvement since implementing our new treatment protocol. Because the
      probe responds directly to cavitational forces, it should also prove useful for
      the objective comparison of different SWL machines.

PMID- 10405904
TI  - Mechanism of ureteral stent flow: a comparative in vivo study.
AB  - BACKGROUND AND OBJECTIVES: The flow characteristics of ureteral stents have yet
      to be clearly defined. In this study, flow mechanics were studied in several
      silicone-based stents including 4.8F, 7F, and 10.3F pigtail; 7F Tower; and a
      prototype mesh stent. MATERIALS AND METHODS: Forty-five female Yucatan minipigs
      underwent bilateral laparoscopic occlusion of their renal vessels to stop urine
      production. A nephrostomy tract was established by retrograde puncture. A stent
      was placed in the ureter, and three measurements were taken with flow from a bag
      of irrigant 20 cm above the kidney: stent occluded with a guidewire (extraluminal
      flow), stent unobstructed (total flow), and laparoscopically placed extraureteral
      ligature (luminal flow). RESULTS: Luminal flow and, to a lesser extent, total
      flow appeared to increase as the internal and external diameters of the stent
      increased. The Tower stent, which had no sideholes, had much lower flow rates in
      all categories, while the prototype mesh stent showed greater total flow compared
      with the other stents. Extraluminal flow did not increase with stent size greater
      than 7F. CONCLUSIONS: Luminal flow, but not extraluminal flow, increased with an
      increase in the internal diameter of the stent. In general, the least favorable
      flow occurred with a Tower stent, which had the smallest internal diameter. The
      greatest flow was seen with the prototype mesh stent.

PMID- 10405905
TI  - Escherichia coli promotes macrophage apoptosis.
AB  - BACKGROUND: Escherichia coli is the bacterium most commonly isolated from the
      urine of patients with urinary tract infection (UTI). Recurrent episodes of UTI
      lead to renal interstitial scarring. In interstitial fibrosis and scarring,
      infiltration of mononuclear cells has been reported to play a key role. MATERIALS
      AND METHODS: We evaluated the effect of two strains of E. coli--the pathogenic BH
      5 and the plasmidless, nonfimbriated HB-101-on human monocyte and murine
      macrophage apoptosis. RESULTS: E. coli BH-5 enhanced apoptosis in a time- and
      dose-dependent manner. It also promoted necrosis in a time- and dose-dependent
      manner. Strain HB-101 promoted monocyte apoptosis in a dose-dependent manner.
      However, the magnitude of HB-101-induced monocyte apoptosis was lower than BH-5
      induced macrophage apoptosis. CONCLUSION: The ability of E. coli to induce
      apoptosis may contribute to its virulence and play a role in renal interstitial
      scarring.

PMID- 10405906
TI  - Chronic effect of pneumoperitoneum on renal histology.
AB  - BACKGROUND AND OBJECTIVE: Transient intraoperative oliguria is a constant
      phenomenon during laparoscopic procedures. Laboratory studies have demonstrated
      that this effect is secondary to a decrease in renal blood flow caused by the
      pneumoperitoneum. With the advent of laparoscopic harvest of the kidney for renal
      transplantation, a concern is that increased intra-abdominal pressure may
      compound the effect of acute cold and warm renal ischemia during transplantation.
      Acute transient renal ischemia can produce chronic sclerosing histopathologic
      changes in native kidneys which are similar to those seen in chronic allograft
      rejection. The effect of positive-pressure abdominal pneumoperitoneum (15 mm Hg)
      on native kidneys was examined using a rodent model. The effects on renal
      function and histologic features were also studied. MATERIALS AND METHODS: Twenty
      four Harlan Wistar-Furth rats were divided into four groups: controls, 1-hour
      pneumoperitoneum-91-day survival, 5-hour pneumoperitoneum-91-day survival, and 5
      hour pneumoperitoneum-7-day survival. Control animals underwent placement of the
      Veress needle and anesthesia but no induction of pneumoperitoneum. At the time of
      sacrifice, blood was sampled for serum creatinine measurement. Both kidneys were
      harvested for frozen and permanent section and stained using hematoxylin and
      eosin. Specimens were graded for inflammatory and ischemic/sclerotic changes in
      the interstitium, tubules, glomeruli, and vasculature by a renal pathologist
      using a histologic score (0-3). RESULTS: In all groups, at a sacrifice interval
      of either 1 week or 3 months, there were no statistical differences in the
      histologic score, serum creatinine concentration, or renal weight. CONCLUSIONS:
      In a rodent model, no signs of chronic ischemic histologic changes were detected
      for a period of 3 months after up to 5 hours of pneumoperitoneum. As well, there
      was no change in the serum creatinine concentration.

PMID- 10405907
TI  - Antifibrinolytic additives to fibrin glue for laparoscopic wound closure in
      urinary tract.
AB  - BACKGROUND AND OBJECTIVES: Fibrinolytic activity of urine may rapidly degrade
      fibrin glue used in the urinary tract, thereby limiting tissue adhesion. The
      goals of this study were to verify the ability of antifibrinolytic agents to
      delay the degradation of fibrin glue in the urinary tract and to assess the
      results of this delay on subsequent wound healing. MATERIALS AND METHODS: In 25
      domestic pigs, a 3.5-cm incision in the urinary bladder was left open (N = 6) or
      closed laparoscopically with fibrin glue alone (N = 6), fibrin glue containing
      aprotinin 5000 KIU/mL (N = 6), or fibrin glue containing aprotinin 2500 KIU/mL
      with (N = 4) or without (N = 3) aminocaproic acid 12.5 mg/mL. At harvest 7 days
      later, the bladder was tested for leakage. Histologic features were scored by a
      pathologist blinded to the closure method. RESULTS: There were no significant
      differences among the groups in the amount of leakage at harvest. Significant
      fibrin glue material in the wound was noted more often in the pigs treated with
      fibrin glue plus aprotinin (7 of 13) than in the fibrin glue-only group (0 of 6;
      P = 0.04). The presence of significant fibrin material in the wound correlated
      well with absence of granulation tissue (P < 0.001), such that granulation tissue
      bridging the wound edges was found more often in the fibrin glue-only group (6 of
      6) than in the groups treated with fibrin glue plus aprotinin (4 of 13; P =
      0.01). CONCLUSIONS: Although aprotinin +/- aminocaproic acid did delay the
      degradation of fibrin glue used to close a bladder wound, it was associated with
      inhibition of granulation tissue in the glued wound. These findings suggest that
      aprotinin alone and aprotinin plus aminocaproic acid are not useful additives to
      fibrin glue used for wound closure in the urinary tract.

PMID- 10405908
TI  - 13-year survival comparison of percutaneous and open nephroureterectomy
      approaches for management of transitional cell carcinoma of renal collecting
      system: equivalent outcomes.
AB  - BACKGROUND AND OBJECTIVE: Transitional cell carcinoma (TCC) of the renal
      collecting system traditionally has been managed by open nephroureterectomy with
      en bloc resection of a bladder cuff. However, for a select patient population
      with a solitary kidney or bilateral disease, the morbidity and mortality
      associated with chronic renal insufficiency and dialysis is deterring. In these
      situations, a more conservative approach such as antegrade percutaneous resection
      should be considered. The long-term disease-free outcome of percutaneous
      management in comparison with open nephroureterectomy has not been previously
      reported. We evaluated our experience with two surgical approaches to treat upper
      tract TCC: percutaneous resection and nephroureterectomy/nephrectomy to assess
      the clinical efficacy of these surgical modalities. PATIENTS AND METHODS: We
      retrospectively identified 162 patients who had clinically localized TCC of the
      upper urinary tract. Records were reviewed to identify those with 13-year follow
      up (N = 110) in respect to tumor grade, stage, disease-free status, length of
      cancer-specific survival, and overall survival. Statistical analysis of the
      results of open nephroureterectomy/nephrectomy (N = 60) and percutaneous
      resection (N = 50) was performed using Kaplan-Meier survival curves and Student's
      t-test. RESULTS: All patients had disease in clinical stage Ta through T3. During
      a mean follow-up of 46.6 (range 6-150) months, grade 1 disease demonstrated
      little invasive potential. Of the disease-specific deaths, 60% (17/26) were of
      patients with grade 3 lesions, with a mean cancer survival period of 15.2 months
      after the initial procedure. Disease-specific survival rates after open and
      percutaneous approaches for grade 2 disease were 53.8 and 53.3 months,
      respectively (P > 0.05). CONCLUSIONS: Tumor grade appeared to be the most
      important prognostic indicator in patients with renal TCC regardless of the
      surgical approach. Grade 3 tumors were more aggressive, presenting in an advanced
      stage with invasion, and recurrences were usually associated with metastasis. In
      this population, nephroureterectomy is warranted if the patient is a surgical
      candidate. The percutaneous option for grade 1 or 2 disease may be extended
      beyond the population with solitary kidneys and a risk of chronic renal failure
      to be offered to healthy individuals with normal contralateral kidneys who are
      willing to abide by a strict and lengthy follow-up.

PMID- 10405909
TI  - Failed endopyelotomy: low expression of TGF beta regardless of the presence or
      absence of crossing vessels.
AB  - BACKGROUND AND OBJECTIVE: Endopyelotomy relies on Davis' intubated ureterotomy
      principle of healing by secondary intention and smooth-muscle regeneration.
      Approximately 15% of endopyelotomies fail, and the restrictured segment almost
      always shows evidence of reactive fibrosis with little smooth-muscle
      regeneration. Previous data suggests that an elevation of TGF beta in obstructed
      ureteropelvic junctures may be necessary for successful tissue repair following
      endopyelotomy. The role of crossing vessels in endopyelotomy failure is very
      controversial. To better understand the pathophysiology of endopyelotomy failure,
      the expression of transforming growth factor-beta (TBG beta) in patients with a
      failed endopyelotomy and crossing vessels was compared with that in patients
      without crossing vessels, as well as those having primary pyeloplasty or a normal
      ureteropelvic junction (UPJ). MATERIALS AND METHODS: The expression of TGF beta
      was detected immunohistochemically in slide-mounted thin sections (4 microns) cut
      from paraffin-blocked adult UPJ segments obtained during primary pyeloplasty (N =
      11), secondary pyeloplasty after failed endopyelotomy with documented crossing
      vessels (N = 10), secondary pyeloplasty after failed endopyelotomy without
      crossing vessels (N = 11), and normal UPJs removed during nephrectomy for
      purposes unrelated to obstruction (N = 11). Expression was graded on a scale of 0
      to 4. RESULTS: The combined failed endopyelotomy group had a significantly (P <
      0.05) lower level of TGF beta (1.9 +/- 0.7) than did primary obstructed UPJs (2.6
      +/- 0.7). The TGF beta level in the crossing vessels group (1.9 +/- 0.7) did not
      differ from that in the group without crossing vessels (1.8 +/- 0.7), nor did it
      differ from that in the group with normal UPJs (1.6 +/- 0.7). As expected,
      primary obstructed UPJs had a significantly higher level of TGF beta than normal
      ones (P < 0.02). CONCLUSIONS: Obstructed UPJs that had failed endopyelotomy had a
      similarly reduced level of TGF beta whether or not crossing vessels were present.
      These data suggest that an elevation of TGF beta in obstructed UPJs may be
      necessary for successful tissue repair after endopyelotomy and that the presence
      of crossing vessels is probably not relevant.

PMID- 10405910
TI  - Acute and chronic interstitial cryotherapy of the adrenal gland as a treatment
      modality.
AB  - BACKGROUND AND OBJECTIVES: Adrenalectomy is indicated for patients with large
      adrenal lesions or functional tumors. Cryoablation is currently used as a
      surgical alternative for the treatment of prostate, lung, brain, pharynx, and
      liver tumors. The purpose of this study was to determine if cryosurgery could be
      delivered to small areas in the adrenal gland in a controllable and reproducible
      manner, so that tissue could heal in a nonpathological way. MATERIALS AND
      METHODS: Fourteen female mongrel dogs underwent acute (N = 8) or chronic (4
      weeks) (N = 6) cryoablation using the Cryounit. In the acute study, using an open
      transabdominal approach, a 2-mm cryoprobe was placed interstitially into the
      adrenal tissue, while 0.032-inch thermocouples were cannulated into the
      ipsilateral adrenal artery and vein. Adrenal parenchymal temperature changes were
      measured using thermocouples placed at 0.4- and 0.8-cm intervals from the
      cryoprobe. In the chronic study, cryoablation was achieved by transperitoneal
      laparoscopic access using standard laparoscopic technique. RESULTS: Interstitial
      cryoprobe temperatures decreased from 33.1 +/- 1.9 degrees C to -148 +/- 1.2
      degrees C following 15 minutes of freezing in the acute study. Cryoablation of
      adrenal tissue achieved temperatures of -41.8 +/- 5.7 degrees C and -21.8 +/- 1
      degrees C at distances of 0.4 and 0.8 cm from the cryoprobe, respectively. There
      were no significant changes in adrenal artery or vein temperatures during
      cryoablation. Histologically, there was a clear demarcation between viable and
      nonviable tissue, the latter being characterized by areas of multifocal
      hemorrhage and pyknosis. After 4 weeks of healing, there was a well-defined line
      between necrotic and viable tissue. CONCLUSION: Cryoablation of the adrenal gland
      can be obtained in an effective, controllable, and reproducible manner. This
      controllable energy form may provide new modality for tissue destruction where
      adrenal gland preservation is necessary and can be delivered by the laparoscopic
      approach. Understanding the effect of adrenal cryoablation may allow us to treat
      selected patients with small tumors in whom organ preservation is necessary.

PMID- 10405911
TI  - Retrieval capabilities of different stone basket designs in vitro.
AB  - BACKGROUND AND OBJECTIVE: Several designs of endoscopic stone retrieval baskets
      are available. Each instrument has special characteristics which can be employed
      in different locations with different techniques and various effects. In this
      study, we compared the retrieval capability of five basket designs in two in
      vitro models. MATERIALS AND METHODS: The five baskets were a flat wire (Segura),
      Parachute, N-0-tip, and two helical designs. The ability of the baskets to
      retrieve beads of 4, 6, and 8 mm was compared in two models. Each size was used
      individually, and four beads of the 4-mm size were also studied. In the first
      model, single and multiple beads were placed in a cylindrical plastic tube to
      mimic removal of the stone from the ureter. In single-bead retrieval trials, the
      basket was opened beyond the bead and withdrawn, whereas with multiple beads, the
      basket was opened beyond, withdrawn, and closed. Bead engagement and removal was
      considered a successful retrieval. Three repetitions were performed for each
      basket and each bead size. In the second model, similar beads were placed in a
      round-bottom test tube to simulate a stone within a calix. The basket was opened
      at the base of the tube and closed. The number of beads removed was noted for
      three repetitions for each basket. RESULTS: All baskets were able to retrieve the
      4-, 6-, and 8-mm beads from the cylinder, with the exception of the four-wire
      helical basket, which failed in two of the three retrieval attempts for the 4-
      and 6-mm beads, and the double-helical basket, which failed in two of the three
      retrieval attempts for the 4-mm bead. When four beads 4 mm in size were used, the
      Parachute and double-helical baskets retrieved all of them within two trials and
      the N-0-tip and four-wire helical baskets within three trials. The Segura basket
      failed all trials. In the test tube model, all baskets failed to remove any beads
      with the exception of the N-0-tip, which was successful in removing a single bead
      with each positioning. CONCLUSIONS: In these in vitro models, it was apparent
      that the design of the basket affects its ability to retrieve calculi in
      different situations.

PMID- 10405912
TI  - Urolithiasis associated with protease inhibitors.
AB  - OBJECTIVE: We evaluated the radiographic characteristics as well as the clinical
      management of urolithiasis induced by systemic therapy with indinavir sulfate, a
      protease inhibitor utilized in the treatment of HIV infection. PATIENTS AND
      METHODS: Fifteen consecutive HIV-positive male patients (average age 41.3 years)
      who presented with urolithiasis while being treated with indinavir sulfate
      (average time 11.1 months) were studied. RESULTS: All patients presented with
      flank pain, and eight had gross hematuria. All but one patient had microscopic
      hematuria. The location of the stones was the kidney in three, the proximal
      ureter in four, and the distal ureter in nine. One patient had both a renal and a
      proximal ureteral stone. The stones were radiolucent on CT imaging in five
      patients and could not be seen in five. In the five cases in which a stone was
      not definitely identified, a diagnosis of urolithiasis was established on the
      basis of ureteral obstruction and periureteral/renal streaking noted on CT.
      Treatment included observation with hydration in eight patients, ureteral stent
      placement in two patients, ureteroscopy in three patients, and extracorporeal
      shockwave lithotripsy in two patients. Stones were analyzed in five patients and
      proved to be 100% indinavir in three and a mixture of indinavir, calcium oxalate
      monohydrate, and calcium oxalate dihydrate in two. CONCLUSIONS: Urolithiasis is a
      recognized complication of treatment with indinavir sulfate. Pure indinavir
      stones cannot be seen on CT unless intravenous contrast medium is utilized. Mixed
      calcium and indinavir stones can occur and may be radiopaque. The majority of HIV
      positive patients with symptomatic urolithiasis can be treated conservatively
      with hydration. Metabolic evaluation of these patients with identification and
      correction of factors predisposing to stone formation may minimize future
      recurrences. Administration of this effective medication thus can continue
      uninterrupted.

PMID- 10405914
TI  - Transrectal ultrasound parameters: presumed circle area ratio and transitional
      zone area in the evaluation of patients with lower urinary tract symptoms.
AB  - BACKGROUND AND OBJECTIVES: Benign prostatic hyperplasia (BPH) is not the only
      cause of lower urinary tract symptoms (LUTS) in elderly men. Thus, routine use of
      invasive measures to debulk the prostate will produce suboptimal treatment
      outcomes in many patients. We attempted to determine whether two parameters based
      on transrectal ultrasonography could accurately determine the presence of
      obstruction and predict the response to therapy. PATIENTS AND METHODS: In the
      first part of the study, the presumed circle area ratio (PCAR) and transitional
      zone area ratio (TZAR) were determined in 86 men aged 50 years or greater and
      correlated with the patient's age, International Prostate Symptom Score (IPSS),
      and peak flow rate Qmax. The ability of cut-off values of PCAR = 0.75 and TZAR =
      0.5 to stratify patients for the presence of obstruction was determined. In the
      second part of the study, PCAR and TZAR were determined in 25 men in urinary
      retention, who were further classified as having high voiding pressure (Group A)
      or an underactive detrusor muscle (Group B). Obstruction was reassessed
      immediately and 1 month after transurethral resection (TURP), and the ability of
      PCAR and TZAR to predict treatment outcome was assessed. RESULTS: Both PCAR and
      TZAR showed weak correlations with IPSS and a moderate inverse correlation with
      Qmax. The cut-off values were able to separate patients according to Qmax and
      overall obstructive states. A PCAR of > or = 0.75 or a TZAR of > or = 0.5 would
      have predicted obstruction in 34 of 36 obstructed patients, and lower values
      would have correctly predicted the absence of obstruction in 33 of 37 patients.
      In patients with high voiding pressure, all those with PCAR and TZAR values above
      the cut-off showed good to average improvement after TURP. In patients with an
      underactive detrusor, both PCAR and TZAR were extremely useful in predicting the
      response to TURP. CONCLUSION: In view of the morbidity and mortality of invasive
      treatments for BPH, subjecting patients with LUTS to these treatments in the
      absence of obstruction is irrational. We recommend the use of transrectal
      ultrasonography measures in the routine evaluation of BPH and reserve the more
      invasive urodynamic studies for patients with discrepant findings. Further
      studies in a larger group of patients are needed.

PMID- 10405913
TI  - Familial calcium stone disease: TaqI polymorphism and the vitamin D receptor.
AB  - BACKGROUND AND OBJECTIVE: Calcium nephrolithiasis has a strong familial
      component. However, to date, no specific genetic abnormality has been identified.
      Allelic variation in the vitamin D receptor (VDR) gene has been suggested as a
      partial explanation of differential calcium absorption or excretion in these
      patients. Polymorphism of this gene has been associated with altered vitamin D
      activity and has been implicated in osteoporosis and prostate cancer. We propose
      that a similar association may be found between familial hypercalciuric stone
      disease and the VDR. SUBJECTS AND METHODS: Genomic DNA was isolated from 37
      controls and 19 patients with hypercalciuria (> 250 mg/24 hours) and a family
      history of nephrolithiasis. A 740-basepair segment of the VDR gene was amplified
      by polymerase chain reaction, digested with TaqI endonuclease, and resolved by
      gel electrophoresis. Alleles were classified as "T" if only one TaqI site was
      present and "t" if two were present. A simplified strength of family history
      score (FHS) was computed by adding 2 and 1 points, respectively, for each first-
      and second-degree relative affected by stone disease. RESULTS: No difference in
      allelic or genotypic frequencies between the study and control groups was
      present. In the stone group, a significant association was found between the
      strength of the family history and the TT genotype. Patients with this genotype
      had an average FHS of 4.0, whereas the mean FHS for the Tt and tt genotypes was
      2.0 and 1.8, respectively (P < 0.05). Nonsignificant trends of the TT genotype
      toward a higher number of stone episodes (19 v 13 and 3) and higher 24-hour urine
      calcium excretion (408 v 297 and 353 mg) were also noted in the study group.
      CONCLUSION: The results suggest that the TT genotype is associated with more
      aggressive stone disease, both within families and with respect to recurrence.
      Quantifying the risk of calcium stone disease through DNA markers has potential
      application in determining the risk of a patient's family members for
      nephrolithiasis or a patient's risk of recurrence. This information may have
      therapeutic implications with regard to the rigor of medical therapy and
      frequency of follow-up.

PMID- 10405915
TI  - Strengthening domestic violence theories: intersections of race, class, sexual
      orientation, and gender.
AB  - Current family therapy theories and practices of domestic violence place an
      important emphasis on gender. Employing the notion of intersectionality, this
      article demonstrates how the relevance and applicability of contemporary theories
      and practices may be enhanced through the inclusion of primary dimensions of
      social life, including but not limited to race, class, and sexual orientation.
      Theoretical in nature, this article suggests future directions for theory
      construction and clinical practice, drawing on literature not easily accessible
      to most marital and family therapists.

PMID- 10405916
TI  - Battering and couples therapy: universal screening and selection of treatment
      modality.
AB  - As family therapists begin to experiment with couples treatment models for
      batterers and their partners, a basic question is: Which couples can be safely
      treated with conjoint therapy? Following a definition of battering and a review
      of rationales for considering couples therapy in cases of domestic violence, a
      framework for assessment of domestic violence is outlined, including sample
      questions, criteria for excluding couples from conjoint therapy, how to conduct a
      lethality assessment, and how to conceptualize postassessment treatment
      recommendations. This article also introduces family and couples therapists to
      domestic violence literature that is often not well integrated in family therapy
      theory and practice.

PMID- 10405917
TI  - The cultural context model: therapy for couples with domestic violence.
AB  - This article offers a brief analysis of heterosexual dominance within various
      cultures toward a larger understanding of domestic violence. It then describes
      the Cultural Context Model, developed over 15 years of experience treating
      domestic violence in its broader context, utilizing separate "culture circles"
      for men and women before and during couple therapy. It then identifies guidelines
      for assessment and intervention with a discussion of the special issues raised
      when substance abuse is involved.

PMID- 10405918
TI  - Morality and multiplicity: perspectives on the treatment of violence in intimate
      life.

PMID- 10405919
TI  - Demand/withdraw interaction patterns between different types of batterers and
      their spouses.
AB  - The investigation of subtypes of violent men could provide invaluable information
      to researchers and clinicians. In earlier studies, investigators examined whether
      subtypes of male batterers could be identified based on physiological markers in
      combination with observational and self-report perspectives. In a sample of
      batterers and their wives, they found a physiological marker that discriminated
      between two groups of violent men on several interesting dimensions. To highlight
      the importance of studying batterer typologies, the present study examined
      differences in marital interaction patterns across the two groups of batterers.
      Analyses revealed clinically relevant patterns of interaction in the two groups,
      and effect sizes indicating the possibility of differences between the two types
      of batterers. Implications for future research as well as therapy are discussed.

PMID- 10405920
TI  - Intimate justice. II: Fostering mutuality, reciprocity, and accommodation in
      therapy for psychological abuse.
AB  - This article presents part of the findings of a study of psychological abuse and
      physical violence in couples who voluntarily entered therapy. The study found
      that most of the men exhibited patterns of deception, devaluation, and
      dictatorial attitudes with their women partners and that these patterns were a
      considerable barrier to mutuality, reciprocity, and accommodation in the
      partnership. The researchers developed four interventions to challenge the men to
      change these patterns: true intentions, no free rides, the perception paradox,
      and the infallibility fallacy. The study was based on intimate justice theory, a
      developing clinical approach to therapy based on ethical theory.

PMID- 10405921
TI  - Toward a theory of constraints.
AB  - Grounded in the cybernetic concept of negative explanation, the theory of
      constraints examines how human systems are kept from solving problems. To
      identify constraints, therapists must know where to look for them and what to
      look for. The theory proposes that constraints exist among the levels of a
      biopsychosocial system, which include biology, person, relationship, family,
      community, and society. The six metaframeworks of organization, sequences, mind,
      development, gender, and culture assist constraint identification. Combining the
      levels and metaframeworks creates a web of constraints, the complexity of which
      determines how difficult it will be to solve a given problem. The theory of
      constraint offers an integrative and pragmatic approach to therapy while
      simultaneously honoring the complexity of human systems.

PMID- 10405922
TI  - The role of marital status in health services expenditures for psychiatric
      outpatients.
AB  - This study tested the hypothesis that married psychiatric outpatients would have
      lower total health services expenditures than divorced or separated patients.
      Chart review of the 471 individuals attending an academic medical center
      outpatient psychiatric clinic during 1994 identified 131 married, 40 separated,
      and 93 divorced patients. Separated men had significantly higher average total
      charges ($16,890) than married ($5,279) or divorced ($5,539) men by one-way ANOVA
      (p < .05). The nonparametric Mann-Whitney test also showed that separated men had
      higher charges than married or divorced men. There were no differences between
      marital status groups for women.

PMID- 10405923
TI  - Depression in mature marriages: impact and implications for marital therapy.
AB  - Recent reviews of MFT literature have shown a failure to address mental health
      issues of the aging. Chief among these issues is depression, one of the most
      common psychological disorders found in older people. Although the relationship
      between depression and aging is a well-researched topic, few studies approach
      this common problem from a systemic perspective. Using data from a national
      survey of preretirement- and retirement-aged couples, this paper discusses the
      association between depression and marital quality in mature marriages as well
      the possibility of mediating variables such as the personality construct
      hardiness. Implications for marital therapy with older couples experiencing
      depression and future research are discussed.

PMID- 10405924
TI  - Risk factors and current NSAID use.

PMID- 10405925
TI  - Assessment of quality of life in children with rheumatic disease.

PMID- 10405926
TI  - IgG 1 subclass specificity for IgG rheumatoid factors in patients with rheumatoid
      arthritis.
AB  - OBJECTIVE: To investigate the significance of IgG rheumatoid factors (IgG RF) in
      the pathogenesis of rheumatoid arthritis (RA), and to determine the specificity
      of IgG subclasses binding with IgG RF in RA (RA IgG RF) compared to IgG RF in
      normal subjects (NS IgG RF). METHODS: The reactivities of RA IgG RF and NS IgG RF
      for various IgG subclasses were studied by ELISA and inhibition assay, using
      purified IgG heavy chains of different IgG subclasses. RESULTS: In ELISA, the
      optical density (OD) value of the reaction of RA IgG RF with IgG 1 was
      significantly higher than with IgG 2, 3, or 4 (p < 0.01). Similarly, the OD value
      of the reaction of NS IgG RF with IgG 1 was significantly higher than with IgG 2
      or 4 (p < 0.05). In the inhibition assay, the OD value of the reaction of RA IgG
      RF was decreased by IgG 1, 2, and 3 (p < 0.01), but not by IgG 4. The extent of
      inhibition by IgG 1 was significantly greater than that by IgG 2, 3, or 4 (p <
      0.05). In contrast, the OD value of the reaction of NS IgG RF was not
      significantly inhibited by any of the IgG subclasses. CONCLUSION: RA IgG RF and
      NS IgG RF reacted most strongly with IgG 1. From the differences in reactivities
      between RA IgG RF and NS IgG RF in the inhibition assay, it can be inferred that
      RA IgG RF exhibits higher affinity for IgG than NS IgG RF.

PMID- 10405928
TI  - HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and
      severity in patients from eastern France with rheumatoid arthritis.
AB  - OBJECTIVE: To examine the effects of HLA-DRB1 alleles and amino acid sequences
      that carry the shared epitope (SE) upon rheumatoid arthritis (RA) susceptibility
      and disease severity in patients from Eastern France. METHODS: HLA-DRB1 alleles
      were determined in 120 patients and 104 healthy controls by polymerase chain
      reaction/sequence specific oligonucleotide probes. Subtyping of DRB1*01 and *04
      were performed using sequence specific primers. Patients were retrospectively
      evaluated for disease duration, age at disease onset, presence of rheumatoid
      factors, subcutaneous nodules, vasculitis and other extraarticular diseases, for
      the need for arthroplasty and immunosuppressive/immunoregulatory agents, and for
      radiographic damage. RESULTS: The prevalence of HLA-DRB1*04 was significantly
      higher in patients (46.6%) than in controls (17.3%) (Pcorr = 0.000003). HLA
      DRB1*0101 and *0401 were the most prominently associated subtypes in patients
      with RA (33.3%, Pcorr = 0.011, and 28.3%, Pcorr = 0.00008, respectively). A
      significant fraction of patients (72.5%) expressed one or 2 copies of the SE (p <
      0.0000001; OR 4.77, CI 2.61-8.78). The presence of double SE was associated with
      a higher risk of developing RA (OR 4.83, CI 1.91-12.71; p = 0.0001). No
      significant differences in the clinical records among patients expressing no RA
      linked alleles, one and 2 copies of the SE, were observed. However, analyzing the
      specific effect of each amino acid sequence, we observed a significant
      association of the QKRAA motif with vasculitis (p = 0.03) and history of joint
      replacement surgery (p = 0.05), suggesting a role for lysine in position 71 of
      the shared sequence. CONCLUSION: These findings differ from those of previous HLA
      DRB1 allele studies in patients with RA from other regions of France. Thus, the
      heterogeneity in both the expression of DRB1 alleles and the association of these
      alleles with disease severity could be relevant within a country such as France.

PMID- 10405927
TI  - Isolation of an IgG monoclonal anti-dnaJ antibody from an immunoglobulin
      combinatorial library from a patient with rheumatoid arthritis.
AB  - OBJECTIVE: Previously, we showed that rheumatoid arthritis (RA) had both
      antibodies and T cells specific for the QKRAA-encompassing Escherichia coli dnaJ
      protein. These findings suggest that the bacteria induced anti-dnaJ responses may
      cross react with the human homolog of bacterial dnaJ in the joint, resulting in
      tissue damage. METHODS: We used the combinatorial library technique to isolate
      and characterize an IgG monoclonal anti-dnaJ antibody (designated CG1) from the
      blood of a patient with RA. RESULTS: Sequence analysis of CG1 revealed that its
      heavy and light chain V regions were respectively most homologous to the 3d279d
      VH4 and the O18 Vk1 genes. Interestingly, 3d279d is frequently expressed by B
      cells stimulated with staphylococcal enterotoxin; and O18 is the main gene
      employed by the Vk1 IgG antibodies against Haemophilus influenzae. CONCLUSION:
      The combinatorial immunoglobulin library method represents an interesting model
      of how to approach the isolation and characterization of antibody-like reagents
      in the elucidation of autoantigens in RA.

PMID- 10405929
TI  - Cytomegalovirus seropositivity is associated with the expansion of CD4+CD28- and
      CD8+CD28- T cells in rheumatoid arthritis.
AB  - OBJECTIVE: Previous researchers have found expansion of CD4+CD28- T cells in
      patients with rheumatoid arthritis (RA) compared to age matched controls, and
      have identified expanded clones of autoreactive cells within this population. We
      examine the association of prior cytomegalovirus (CMV) infection (positive serum
      anti-CMV IgG) with the percentage of CD4+CD28- T cells and CD8+CD28- T cells in
      patients with RA. METHODS: A total of 45 patients (36 women, 9 men), mean age of
      59 years, with definite RA were studied. RESULTS: In this group 28 patients were
      seropositive for CMV and 17 seronegative. Seropositive and seronegative subjects
      did not differ significantly in age, sex, medication use, or severity of disease.
      Joint count, Health Assessment Questionnaire, pain score, patient global
      assessment, physician global assessment, and presence of extraarticular disease
      served to assess disease severity. Expression of CD4/CD28/CD57 and CD8/CD28/CD57
      on lymphocytes was determined by 3 color flow cytometry. (CD28 and CD57 are
      reciprocally related.) CD4+CD28-CD57+ T cells were expanded only in CMV
      seropositive patients. CONCLUSION: The "carrier" phenotype that has been
      hypothesized based on a 2 population model for the distribution of CD4+CD28- T
      cells in RA can be explained by prior infection with CMV.

PMID- 10405930
TI  - Gallstones in patients with rheumatoid arthritis.
AB  - OBJECTIVE: We performed abdominal ultrasonography (US) on patients with
      rheumatoid arthritis (RA) to investigate the frequency and characteristics of
      gallstones (GS). METHODS: Patients with RA (n = 224; 42 male and 182 female)
      underwent abdominal US. RESULTS: The incidence of GS (including post
      chorecystectomy patients) was significantly higher in female patients with RA
      (15.4%) than in female controls (5.2%, p < 0.01). There was no significant
      difference in GS incidence between male patients with RA (9.5%) and male controls
      (3.8%). The percentage of cholesterol stones was 100% in patients with RA with GS
      but only 66.7% in controls with GS (p < 0.01). Compared to patients with RA
      without GS, patients with RA with GS were older and had lower C-reactive protein
      levels, a decreased creatinine clearance and urinary calcium excretion, and an
      increased incidence of hypercholesterolemia. CONCLUSION: We observed a high
      incidence of GS in female patients with RA. With our previous observation of a
      high incidence of renal stones in patients with RA, these results suggest the
      importance of US as a diagnostic tool in the management of RA.

PMID- 10405931
TI  - Patterns of disease progression in the rheumatoid wrist: a long-term followup.
AB  - OBJECTIVE: To identify different patterns of disease manifestation and changes in
      the rate of progression of rheumatoid arthritis (RA) in the wrist. METHODS: Forty
      wrists, with normal baseline radiographs, of 20 patients with RA were evaluated
      by means of a retrospective radiographic review for a period of at least 15
      years. RESULTS: Radiographical scores for damage (Larsen method) and malalignment
      (carpal collapse and ulnar translocation index; radial deviation of the wrist and
      ulnar shift of the fingers) showed progression with increasing disease duration
      for all patients. Women had higher Larsen scores than men (p < 0.05) and
      rheumatoid factor positive patients had higher Larsen scores than rheumatoid
      factor negative patients. For all 3 left-handed patients the dominant scores were
      somewhat higher than the right-handed scores, but the difference was not
      significant. For the 17 right-handed patients no differences were found between
      the dominant and the left hand. Early in the course of the disease 4 types of
      wrist involvement can be identified on the basis of the first localization of
      damage in the wrist (central, radial, ulnar, and diffuse type). Radial deviation
      of the wrist was increased in wrists with "central" involvement compared to
      wrists with "diffuse" involvement (p < 0.05). Furthermore, radial deviation of
      the wrist was positively correlated with ulnar drift of the fingers (p < 0.01).
      CONCLUSION: Wrist involvement was found to play an important role in the typical
      rheumatoid deformity of the hand. Early treatment of the wrist is proposed to
      prevent this deformity.

PMID- 10405932
TI  - The responsiveness of health status measures in patients with rheumatoid
      arthritis: comparison of disease-specific and generic instruments.
AB  - OBJECTIVE: To compare the responsiveness of 2 disease-specific questionnaires,
      the Modified Health Assessment Questionnaire (MHAQ) and the Arthritis Impact
      Measurement Scale (AIMS2) with corresponding dimensions (physical function,
      mental health, pain, and fatigue) in a generic health status measure [the MOS
      Short Form-36)] in patients with rheumatoid arthritis (RA). METHODS: Within the
      framework of an observational study, a prospective cohort of 595 patients with RA
      from a community based patient register responded to a questionnaire at baseline
      and after 2 years' followup. Changes in patient global disease activity assessed
      on a categorical verbal rating scale (range 1-5) were used as external indicator
      of improvement or deterioration. Responsiveness was evaluated with standardized
      response means (SRM), calculated as mean change score divided by the standard
      deviation of the mean change score. RESULTS: Changes in patient global disease
      activity were classified as much better (n = 33), slightly better (n = 108), no
      change (n = 291), slightly worse (n = 108), and much worse (n = 20). There were
      no significant differences in responsiveness between SF-36 and the disease
      specific measures within the same dimensions of health. The SRM of the tools
      within the dimension of pain (AIMS2 and SF-36) were moderate (0.5-0.8) to large
      (> 0.8) consistently in both directions (improvement and deterioration). The
      physical function subscales detected the same pattern, but the magnitude of the
      gradients was smaller. The fatigue and mental health subscales did not show any
      clear and consistent pattern of change. CONCLUSION: In patients with RA, there
      was no difference in responsiveness of subscales from SF-36 and disease-specific
      instruments when using changes in patient assessed global disease activity as an
      external indicator of change in health status. The dimension of pain was most
      sensitive to changes in patient assessed global disease activity followed by
      physical function, fatigue, and mental health.

PMID- 10405933
TI  - Anterior arthroscopic synovectomy plus capsuloplasty with a pedicle graft for the
      treatment of rheumatoid popliteal cysts.
AB  - OBJECTIVE: To assess the value of arthroscopic synovectomy plus capsuloplasty
      with a pedicle graft in patients with rheumatoid cysts of the knee. METHODS: We
      examined 31 rheumatoid knees in 9 men and 22 women with an average age of 52.5
      years at time of operation. Postoperative clinical symptoms were investigated in
      comparison with each factor examined before the operation. RESULTS: Postoperative
      results showed that 74% of the patients were grade 0 (no swelling or pain), 23%
      were grade 1 (swelling and slight discomfort after strenuous work or sports), and
      3% were grade 2 (swelling and tenderness after normal activities). The
      improvement rate of the patients with arthroscopic synovectomy plus pedicle graft
      capsuloplasty was significantly higher than that of the untreated controls or
      patients with arthroscopic synovectomy or pedicle graft capsuloplasty. The
      preoperative degree of joint effusion, acceleration in the erythrocyte
      sedimentation rate, radiographic grades, and histological activity in the knee
      joint at the time of operation were correlated with the final clinical symptoms.
      CONCLUSION: Our method may be useful for preventing recurrence of rheumatoid
      popliteal cysts.

PMID- 10405934
TI  - Frequency of the Fc gamma RIIIA-158F allele in African American patients with
      systemic lupus erythematosus.
AB  - OBJECTIVE: Defects in genes involved in immune complex clearance constitute one
      of the most common gene defects identified in patients with systemic lupus
      erythematosus (SLE). Defects in early complement components, complement
      receptors, and Fc receptors have all been implicated in the susceptibility to
      SLE. Recently, the role of functionally relevant Fc receptor polymorphisms in the
      etiology of SLE has been investigated. Specifically, a polymorphism of FC gamma
      RIII, termed Fc gamma RIIIA-158F, has been found to be associated with SLE in 2
      largely Caucasian populations and appeared to constitute a risk factor for
      nephritis. We investigated the association of the Fc gamma RIIIA-158F and Fc
      gamma RIIIA-131R polymorphisms with SLE in an African American study population.
      METHODS: Nested polymerase chain reaction (PCR) and allele-specific PCR was used
      to genotype patients with SLE and controls. RESULTS: There was no difference in
      Fc gamma RIIIA-158F or Fc gamma RIIA-131R gene frequencies in the SLE populations
      compared to controls. There was no significant association between Fc gamma RIIIA
      158F or Fc gamma RIIA-131R and any specific clinical or laboratory variable.
      CONCLUSION: In our African American study population, there did not appear to be
      any association of Fc gamma RIIA-158F or Fc gamma RIIA-131R with SLE.

PMID- 10405935
TI  - Extrarenal disease activity in systemic lupus erythematosus is not suppressed by
      chronic renal insufficiency or renal replacement therapy.
AB  - OBJECTIVE: To assess whether chronic renal impairment (CRI) and/or renal
      replacement therapy (RRT) in systemic lupus erythematosus (SLE) are associated
      with reduced extrarenal SLE activity. METHODS: This was a retrospective cohort
      analysis of patients with SLE who are followed at the University of Toronto Lupus
      Clinic. Patients with SLE were studied in 2 stages; chronic renal insufficiency
      (defined as a serum creatinine > 200 mumol/1 for > 6 months) and following the
      institution of dialysis therapy. Controls consisted of the next 2 age and sex
      matched patients in the clinic with a history of lupus nephritis who had not
      developed renal insufficiency. We assessed the flare rate (an increase in
      nonrenal SLEDAI > or = 1.0) for patients and controls in the first 12 months of
      followup at the clinic in each stage. RESULTS: Twenty-one patients, 17 female and
      4 male, were followed through 25 episodes of CRI or RRT as were 50 controls. In
      the CRI stage (n = 12), flares occurred in 8 (67%) within one year compared to 14
      (58%) of 24 controls (p = NS). In the RRT stage (n = 13), flares occurred in 7
      (54%) compared to 16 (62%) of 26 controls (p = NS). The magnitude as well as the
      characteristics of the flares did not differ between patients and controls in
      either stage. CONCLUSION: Patients with SLE who develop CRI, or who receive RRT,
      continue to display evidence of ongoing extrarenal disease activity. Such
      patients require careful longterm followup for management of their extrarenal
      disease.

PMID- 10405936
TI  - Familial aggregation of lupus and autoimmunity in an unusual multiplex pedigree.
AB  - OBJECTIVE: To evaluate an unusual pedigree with 8 members diagnosed with systemic
      lupus erythematosus (SLE) METHODS: Pedigree members were evaluated through
      questionnaires, interviews, and medical records. Sixty members contributed serum
      samples for autoantibody analysis. RESULTS: The 8 affected females shared several
      disease features, including arthritis (8/8), antinuclear antibodies (ANA) (8/8),
      pleuritis (6/8), malar rash (6/8), photosensitivity (5/8), and nephritis (4/8). A
      total of 15 of 51 (29%) blood relatives had autoantibodies; 9 had autoimmune
      disease, including 7 with SLE, one with psoriasis, and one with Sjogren's
      syndrome. Five of 11 (45%) nonconsanguineous spouses also had autoantibodies; one
      spouse had SLE, and 2 others had thyroid disease. Among 68 spouses of patients
      with SLE in other pedigrees, only 9 (13%) had autoantibodies, and none were
      symptomatic (p = 0.02). CONCLUSION: The high rate of autoimmunity among both
      blood relatives and nonconsanguineous mates in this unusual pedigree suggests a
      complex interaction of genetic and environmental factors contributing to disease.

PMID- 10405937
TI  - An international perspective on the well being and health care costs for patients
      with systemic lupus erythematosus. Tri-Nation Study Group.
AB  - OBJECTIVE: To compare health care expenditure and health status for patients with
      systemic lupus erythematosus (SLE) between nations with distinct mechanisms for
      funding and delivering health care services. METHODS: Seven hundred eight
      patients with SLE from 2 centers in each of 3 countries (Canada 229, United
      States 268, United Kingdom 211) underwent physician assessment of disease
      activity and damage and reported on physical and psychosocial well being,
      satisfaction, social support, and health resource utilization. To compare overall
      utilization, constant prices (1997 Canadian dollars) were applied across
      countries for each service, enabling diverse resources to be collapsed into a
      single expression. RESULTS: After adjusting for important patient covariates,
      Canadian, compared to American and British patients, reported significantly
      superior health status in 3 of 8 Medical Outcome Survey Short Form-36 (SF-36)
      subscales, the SF-36 physical component summary score, and the visual analog
      scale of general health status. There was no consistent trend in patient
      satisfaction. Overall annual resource utilization did not vary significantly,
      with mean annual per patient expenditures (adjusted for demographics, disease
      duration, activity, damage, social support, health status, patient satisfaction,
      and age and sex adjusted country-specific SF-36 general population norms)
      totalling $4853, $5285, and $4760 for Canada, US, and the UK, respectively.
      However, within each resource category, differences were observed. Canadians saw
      more specialists than the British, the British more generalists. Canadians and
      Americans were more frequent users of the emergency room; Americans of
      laboratory/imaging procedures. Canadians had higher hospital costs than
      Americans. CONCLUSION: After adjustment, Canadian patients reported better well
      being than their counterparts. Despite considerable differences in the mechanisms
      of health care funding and service mixture, overall resource utilization did not
      vary significantly between the countries, although there was a trend towards more
      intense use of inpatient services in Canada and outpatient services in the United
      States.

PMID- 10405938
TI  - The Rheumatology Attitudes Index and its helplessness subscale are valid and
      reliable measures of learned helplessness in Asian patients with systemic lupus
      erythematosus.
AB  - OBJECTIVE: To assess the internal consistency, reliability, and construct
      validity of the Rheumatology Attitudes Index (RAI) and its subscales in a cohort
      of Asian patients with systemic lupus erythematosus (SLE). METHODS: English
      speaking ethnic Chinese, Malay, or Indian patients with SLE (n = 120) seen at a
      rheumatology unit completed a questionnaire containing the RAI twice within a 2
      week period. Lupus activity was assessed using the British Isles Lupus Activity
      Group (BILAG) score, disease related damage using the Systemic Lupus
      International Collaborating Clinics/American College of Rheumatology (SLICC/ACR)
      damage index, and quality of life using the Medical Outcome Survey Short Form 36
      Health Survey (SF-36). Factor analysis and Cronbach's alpha were used to study
      the psychometric properties of the RAI. The magnitude of test-retest differences
      was assessed using the method of Bland and Altman. Relationships between the RAI,
      its helplessness (HS) and internality (IS) subscales, and BILAG, SLICC/ACR damage
      index and SF-36 scores were studied using Spearman's rank correlation. RESULTS:
      Factor analysis (n = 105) identified 2 factors corresponding to the HS and IS
      subscales of the RAI. All scales showed acceptable internal consistency, with
      Cronbach's alpha of 0.64 for the HS, 0.77 for the IS, and 0.74 for the RAI. Mean
      (SD) test-retest differences were 0.85 (3.96) points for the HS (n = 86), 0.81
      (4.44) points for the IS (n = 85), and 1.46 (7.88) points for the RAI (n = 74).
      Six of 10 hypotheses relating the RAI and HS to demographic, disease, and quality
      of life variables were confirmed, supporting the construct validity of these
      scales. CONCLUSION: The RAI and its helplessness subscale are valid and reliable
      measures of learned helplessness in a multiethnic cohort of Asian patients with
      SLE in Singapore.

PMID- 10405939
TI  - Defective proliferative response of T lymphocytes from patients with inactive
      systemic lupus erythematosus.
AB  - OBJECTIVE: To further define the pattern of alterations in the activation and
      apoptosis of T lymphocytes in patients with inactive systemic lupus erythematosus
      (SLE) through analysis of a large series of individuals. METHODS: We isolated
      CD2+ peripheral blood lymphocytes (PBL) from 41 patients with inactive SLE and
      analyzed their proliferative and apoptotic responses to polyclonal activation.
      RESULTS: In 19 of 41 (47%) patients, a low proliferative response to polyclonal
      mitogens was found. This defective response was inversely associated with an
      increased apoptotic response and increased expression of CD95 and CD45RO
      antigens. CONCLUSION: We found that 2 groups of patients with inactive disease
      can be defined according to the functional behavior of their T lymphocytes, as
      defined by the proliferative and apoptotic responses to mitogenic signals.

PMID- 10405940
TI  - Corticosteroid resistant interstitial pneumonitis in
      dermatomyositis/polymyositis: prediction and treatment with cyclosporine.
AB  - OBJECTIVE: To determine the characteristics of corticosteroid resistant
      interstitial pneumonitis (IP) in dermatomyositis (DM) and polymyositis (PM), and
      to evaluate the effect of cyclosporine on corticosteroid resistant IP in DM/PM.
      METHODS: We analyzed retrospectively the incidence, clinical features, and
      corticosteroid responses of IP in 111 patients with DM (56) or PM (55). All
      patients with DM/PM were treated with prednisolone, and corticosteroid resistant
      IP was defined as a progression of IP despite administration of 1 mg/kg/day
      prednisolone for more than 4 weeks. We also evaluated the effect of cyclosporine
      on corticosteroid resistant IP in patients with DM/PM. RESULTS: IP occurred in 24
      of 56 DM and 12 of 55 PM patients. We then classified IP in DM/PM according to
      serum CPK levels at the onset of IP; IP associated with high CPK levels (type I)
      (19) and IP associated with normal CPK levels (type II) (17). Only 2 of 19 (11%)
      type I IP were resistant to prednisolone therapy, while 14 of 17 (82%) type II IP
      were resistant to prednisolone therapy. Thus, patients with type II IP showed
      poorer prognosis than those with type I IP (one year survival rate: type I 89% vs
      type II 31%). Cyclosporine was effective in all 5 cases with corticosteroid
      resistant IP in DM/PM (one year survival rate 80%). CONCLUSION: (1)
      Corticosteroid resistant IP develops mostly in patients with DM/PM without CPK
      elevation at the onset of IP (type II IP), and (2) cyclosporine is effective for
      the corticosteroid resistant IP in DM/PM and significantly prolongs survival of
      patients.

PMID- 10405942
TI  - Spondyloarthropathy in the community: clinical syndromes and disease
      manifestations in Alaskan Eskimo populations.
AB  - OBJECTIVE: To define the clinical spectrum and disease manifestations of
      spondyloarthropathy (SpA) as seen in a community, rather than a referral setting.
      METHODS: Eighty percent (83/104) of all individuals identified as having SpA in a
      community wide epidemiologic study of Alaskan Eskimos and 83 age and sex matched
      controls from the same regions participated in a 5 year clinical study. The study
      included baseline and followup interviews, physical, radiographic, and
      electrocardiographic examinations, record reviews, and functional assessment. The
      medical records of an additional 83 age and sex matched controls were reviewed
      and followed over the same 5 year period. RESULTS: The spectrum of disease varied
      from very mild undifferentiated SpA (USpA) to incapacitating ankylosing
      spondylitis (AS). Most cases were mild. Overlapping clinical features were common
      in the different syndromes; 10% of the cases met more than 1 set of disease
      criteria. Axial signs and symptoms were more frequent in patients with AS, but
      occurred in over half of the patients with USpA and reactive arthritis (ReA)
      also. Peripheral joint involvement was noted in 85% of the AS cases, usually
      early in the course of disease. The patterns of joint involvement and
      enthesopathy were similar in SpA subjects with different syndromes and
      significantly different from those in control subjects. Patients with AS had a
      higher frequency of uveitis and of aortic root disease than patients with other
      syndromes. CONCLUSION: The results illustrate the extent of shared clinical
      features in the different SpA syndromes, and describe the frequency of different
      features associated with SpA in patients and matched controls in a community
      setting. ReA and USpA were more prevalent and less severe than AS in these
      populations.

PMID- 10405941
TI  - Evidence that HLA-B*2706 is not protective against spondyloarthropathy.
AB  - OBJECTIVE: Studies in Southeast Asia showed that HLA-B*2704 is positively
      associated with spondyloarthropathy (SpA), while B*2706 does not occur in such
      patients. In view of the absence of an association between B*2706 and SpA it was
      suggested that B*2706 protects against the disease, while it is supposed that
      B*2704 presents pathogenetic peptides. We studied families in which both B*2704
      and B*2706 occurred to see whether in B*2704/B*2706 heterozygotes the effect of
      one of the subtypes shows a preponderance over the other. METHODS: Two families
      of mixed Chinese/Indonesian origin were studied. HLA-B27 subtyping was performed
      by polymerase chain reaction in combination with sequence specific
      oligonucleotide probes. RESULTS: In one family, members with B*2704, B*2706, or
      both occurred. In the other family B*2704, B*2706, and B*2708 were present. In
      both families SpA was seen only in B*2704 positive members, while the B*2706 and
      B*2708 positive members were healthy, except some B*2704/B*2706 or B*2704/B2708
      heterozygotes. CONCLUSION: The pathogenic influence of B*2704 is thus dominant
      over the supposed protective influence of B*2706. It is probable that B*2704 can
      present pathogenetic peptides, while a protective influence of B*2706 does not
      exist. B*2708, which was until now described in only a few cases, behaved in this
      study as B*2706 and is probably not associated with SpA.

PMID- 10405943
TI  - 36 month intermittent cyclical etidronate treatment in patients with established
      corticosteroid induced osteoporosis.
AB  - OBJECTIVE: To determine the longterm safety and efficacy of etidronate therapy in
      patients in whom corticosteroid induced bone loss has already occurred. METHODS:
      We performed a 36 month observational cohort study in which all data were
      obtained from Canadian Database of Osteoporosis and Osteopenia (CANDOO) patients.
      The etidronate group consisted of 24 patients who received 400 mg of etidronate
      disodium for 14 days, followed by 76 days of calcium carbonate (500 mg of
      elemental calcium), repeated every 3 mo; the control group included 37 patients
      who received calcium carbonate 500 to 1000 mg daily. Outcome measurements
      included changes within groups from baseline and differences between groups in
      the bone mineral density (BMD) of the lumbar spine, femoral neck, and trochanter
      at 12, 24, and 36 months. The incidence of vertebral fractures was also
      determined. RESULTS: Etidronate therapy resulted in a meaningful percentage
      increase from baseline in lumbar spine BMD, primarily during the first 24 months
      of treatment, and this increase was sustained for the remainder of the 36 month
      study period (5.2%; p = 0.016). Analysis of covariance revealed a significant
      percentage difference (SD) between groups in lumbar spine BMD at 12 [5.5 (13.5)
      percent; p = 0.003] and 24 months [6.0 (17.4) percent; p = 0.011] in favor of the
      etidronate group. After 3 years of therapy, one patient (4%) experienced one
      vertebral fracture in the etidronate group, whereas 3 patients (8%) experienced 5
      vertebral fractures in the control group. CONCLUSION: Etidronate treatment
      administered for 36 months reversed lumbar spine bone loss, and appeared to be
      safe in patients with established corticosteroid induced osteoporosis.

PMID- 10405944
TI  - Scintigraphic hand osteoarthritis (OA)--prevalence, joint distribution, and
      association with OA at other sites.
AB  - OBJECTIVE: To assess the information available from routine bone scans on
      prevalence and joint distribution of osteoarthritis (OA), particularly of the
      hand. METHODS: Consecutive whole body bone scans of 414 patients, including a
      special hand projection, were analyzed for evidence of OA related uptake. After
      exclusions for various reasons, 297 scans were considered "representative" with
      regard to hand OA (108 male and 189 female patients). Kappa values for
      interreader agreement ranged from 0.61 to 0.82 for hand joints and was slightly
      lower for other joints. RESULTS: The prevalence of positive hand joints was low
      before the age of 40, but increased rapidly in the 5th and 6th decade to reach a
      plateau. Women had a higher prevalence of uptake than men in the carpometacarpal
      1 (CMC1) joint and patella. Uptake was similar on the dominant and non-dominant
      sides in all joints with the exception of the shoulder. Subchondral knee uptake
      prevalence tended to decrease in the oldest age groups, but other joint sites
      showed a steadily increasing prevalence throughout life. Hand symptoms were
      related to distal interphalangeal (DIP) and CMC1 uptake, thumb symptoms with
      first metacarpophalangeal joint (MCP1) CMC1 uptake, and knee symptoms with the
      subchondral knee uptake pattern. Affected hand joint distribution was
      characterized by a strong bilateral concordance within rows, and an association
      was seen between subchondral knee uptake and hand involvement, particularly in
      the DIP joints, but to a lesser degree also with CMC1 and proximal
      interphalangeal (PIP) uptake. Association between spinal sites and between the
      forefoot and the knee was also observed. CONCLUSION: Bone scintigraphy is
      valuable method in epidemiological studies of OA, with acceptable interreader
      reproducibility and relation to joint symptoms. Although much of the current
      findings seem comparable with previous radiologic studies, they provide new ideas
      about age related patterns and joint subsets, possibly indicating a difference in
      pathogenetic mechanisms among joints in OA.

PMID- 10405945
TI  - Complications of nonsteroidal antiiflammatory drug gastropathy and use of gastric
      cytoprotection: experience at a tertiary care health center.
AB  - OBJECTIVE: To determine what proportion of patients admitted to an academic
      medical center with complications of nonsteroidal antiinflammatory drug (NSAID)
      gastropathy had true indications for NSAID use, and whether patients with risk
      factors for NSAID gastropathy were receiving appropriate cytoprotection. METHODS:
      A retrospective chart review was carried out of all patients admitted with upper
      gastrointestinal (GI) bleeding, ulcer perforation, or gastric outlet obstruction
      during 1990-91 and 1995-96. NSAID or acetylsalicylic acid (ASA) use and medical
      indications were determined. Risk factors for NSAID gastropathy were documented
      and included concomitant steroid use, history of peptic ulcer disease or GI
      bleeding, history of cardiovascular disease, age > 60 years, and use of more than
      one NSAID. GI medication coprescription for patients with risk factors for
      gastropathy was evaluated. RESULTS: A total of 296 cases were identified. Use of
      NSAID was a contributing factor in 24% of patients admitted with upper GI
      bleeding, ulcer perforation, or gastric outlet obstruction. Use of ASA was a
      contributing factor in 25%. A true indication for NSAID/ASA use was identified in
      only 55% of cases. Fifty-nine patients had a single risk factor for NSAID
      gastropathy. Of these, 24% were receiving a coprescription for any GI medication
      at the time of admission to hospital and 8% were receiving misoprostol. In the 64
      patients with 2 or more risk factors for NSAID gastropathy, 23% were concurrently
      receiving and GI medication and 2% were receiving misoprostol. In the 46 patients
      identified with a history of peptic ulcer disease or GI bleeding 28% were
      coprescribed a GI medication and 2% were taking misoprostol. There were no
      significant differences in the proportion of patients in any of the high risk
      groups who were receiving GI medications between 1990-91 and 1995-96. CONCLUSION:
      Inappropriate use of NSAID/ASA and failure to adequately cytoprotect patients at
      risk of NSAID gastropathy may account for a significant proportion of patients
      who develop life threatening complications.

PMID- 10405946
TI  - Increased concentrations of nerve growth factor in cerebrospinal fluid of
      patients with fibromyalgia.
AB  - OBJECTIVE: To determine whether there is a difference in the concentration of
      nerve growth factor (NGF) in the cerebrospinal fluid (CSF) from patients
      diagnosed with primary fibromyalgia syndrome (FM), fibromyalgia associated with
      other secondary conditions (SFM), patients with other painful conditions but
      lacking fibromyalgia (OTHER), and healthy controls. METHODS: The clinical
      measures of pain threshold included the tender point index, a measure of pain
      threshold intensity measured by digital pressure, and the average pain threshold
      measured by dolorimetry. Concentrations of NGF in the CSF were measured using a 2
      site enzyme immunoassay. RESULTS: The mean (+/- SEM) concentration of NGF
      measured in patients with FM was significantly increased (41.8 +/- 12.7 pg/ml)
      compared to controls (9.1 +/- 4.1 pg/ml), but with large variability.
      Concentrations of NGF is SFM (8.9 +/- 4.4 pg/ml) and OTHER (16.2 +/- 8.4 pg/ml)
      were not elevated compared to controls. CONCLUSION: The findings of increased
      concentrations of NGF in patients with FM suggest a central mechanism, involving
      abnormalities in neuropeptides such as NGF, may be a factor in the pathogenesis
      of FM.

PMID- 10405947
TI  - The London Fibromyalgia Epidemiology Study: the prevalence of fibromyalgia
      syndrome in London, Ontario.
AB  - OBJECTIVE: To estimate the point prevalence of fibromyalgia syndrome (FM) among
      noninstitutionalized Canadian adults; and to assess the effect of demographic
      variables on the odds of having FM. METHODS: A screening questionnaire was
      administered via telephone to a random community sample of 3395
      noninstitutionalized adults residing in London, Ontario. Individuals screening
      positive were invited to be examined by a rheumatologist to confirm or exclude FM
      using the 1990 American College of Rheumatology classification criteria. RESULTS:
      One hundred confirmed cases of FM were identified, of whom 86 were women. Mean
      age among FM cases was 49.2 years among women, 39.3 years among men (p < 0.02).
      FM affects an estimated 4.9% (95% CI 4.7%, 5.1%) of adult women and 1.6% (1.3%,
      1.9%) of adult men in London, for a female to male ratio of roughly 3 to one. In
      women, prevalence rises steadily with age from < 1% in women aged 18-30 to almost
      8% in women 55-64. Thereafter, it declines. The peak prevalence in men also
      appears to be in middle age (2.5%; 1.1%, 5.7%). FM affects 3.3% (3.2%, 3.4%) of
      noninstitutionalized adults in London. Female sex, middle age, less education,
      lower household income, being divorced, and being disabled are associated with
      increased odds of having FM. CONCLUSION: FM is a common musculoskeletal disorder
      among Canadian adults, especially among women and persons of lower socioeconomic
      status.

PMID- 10405948
TI  - The London Fibromyalgia Epidemiology Study: comparing the demographic and
      clinical characteristics in 100 random community cases of fibromyalgia versus
      controls.
AB  - OBJECTIVE: To identify demographic and clinical features that distinguish
      fibromyalgia (FM) from other chronic widespread pain. METHODS: We identified 100
      confirmed FM cases, 76 widespread pain controls, and 135 general controls in a
      random community survey of 3395 noninstitutionalized adults living in London,
      Ontario. FM cases were distinguished from pain controls using the 1990 American
      College of Rheumatology (ACR) classification criteria for FM. RESULTS: The mean
      age of FM cases was 47.8 years (range 19 to 86), the same as for pain controls;
      86% of FM cases were female versus 67.1% of pain controls (p < 0.01). FM cases
      were less educated than general controls (p = 0.03). Male and female FM cases
      were similar, except females were older and reported more major symptoms (both p
      = 0.02). FM cases reported more severe pain and fatigue, more symptoms, more
      major symptoms, and worse overall health than pain controls or general controls.
      The most commonly reported major symptoms among FM cases were musculoskeletal
      pain (77.3%), fatigue (77.3%), severe fatigue lasting 24 h after minimal activity
      (77.0%), nonrestorative sleep (65.7%), and insomnia (56.0%). Subjects with 11-14
      tender points were more similar to those with 15-18 tender points than to those
      with 7-10 points in 11 of 14 clinical variables. On multivariate analysis, 4
      symptoms distinguished FM cases from pain controls: pain severity (p = 0.004),
      severe fatigue lasting 24 h after minimal activity (p = 0.006), weakness (p =
      0.008), and self-reported swelling of neck glands (p = 0.01). CONCLUSION: In the
      general population, adults who meet the ACR definition of FM appear to have
      distinct features compared to those with chronic widespread pain who do not meet
      criteria.

PMID- 10405949
TI  - Effects of selective slow wave sleep disruption on musculoskeletal pain and
      fatigue in middle aged women.
AB  - OBJECTIVE: To determine whether disrupted slow wave sleep (SWS) would evoke
      musculoskeletal pain, fatigue, and an alpha electroencephalograph (EEG) sleep
      pattern. We selectively deprived 12 healthy, middle aged, sedentary women without
      muscle discomfort of SWS for 3 consecutive nights. Effects were assessed for the
      following measures: polysomnographic sleep, musculoskeletal tender point pain
      threshold, skinfold tenderness, reactive hyperemia (inflammatory flare response),
      somatic symptoms, and mood state. METHODS: Sleep was recorded and scored using
      standard methods. On selective SWS deprivation (SWSD) nights, when delta waves
      (indicative of SWS) were detected on EEG, a computer generated tone (maximum 85
      decibels) was delivered until delta waves disappeared. Musculoskeletal tender
      points were measured by dolorimetry; skinfold tenderness was assessed by skin
      roll procedure; and reactive hyperemia was assessed with a cotton swab test.
      Subjects completed questionnaires on bodily feelings, symptoms, and mood.
      RESULTS: On each SWSD night, SWS was decreased significantly with minimal
      alterations in total sleep time, sleep efficiency, and other sleep stages.
      Subjects showed a 24% decrease in musculoskeletal pain threshold after the third
      SWSD night. They also reported increased discomfort, tiredness, fatigue, and
      reduced vigor. The flare response (area of vasodilatation) in skin was greater
      than baseline after the first, and again, after the third SWSD night. However,
      the automated program for SWSD did not evoke an alpha EEG sleep pattern.
      CONCLUSION: Disrupting SWS, without reducing total sleep or sleep efficiency, for
      several consecutive nights is associated with decreased pain threshold, increased
      discomfort, fatigue, and the inflammatory flare response in skin. These results
      suggest that disrupted sleep is probably an important factor in the
      pathophysiology of symptoms in fibromyalgia.

PMID- 10405950
TI  - A survey of outcome measurement procedures in routine rheumatology outpatient
      practice in Australia.
AB  - OBJECTIVE: To assess the extent to which quantitative clinical measurement is
      performed by rheumatologists in the longitudinal followup of patients with
      rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis (AS), and
      fibromyalgia (FM) in routine outpatient practice in Australia. METHODS: A cross
      sectional postal survey was conducted using an 18-item self-administered
      questionnaire sent to Australian Rheumatology Association (ARA) members. RESULTS:
      Rheumatologists (response rate = 76%, completion rate = 72%) were more likely to
      longitudinally follow patients with RA and AS than those with OA or FM. There was
      a high degree of variability in the methods used to monitor patients
      longitudinally. Many measures used in clinical research were used infrequently in
      routine clinical practice. In general, the major health status measures surveyed
      were not used in clinical monitoring. There was a high level of agreement (> 80%)
      that the characteristics required of an outcome measure for use in clinical
      practice should include simplicity, brevity, ease of scoring, reliability,
      validity, and sensitivity to change. CONCLUSION: The majority of Australian
      rheumatologists perform outcome measurement during the longitudinal followup of
      their outpatients with RA, AS, OA, and FM. However, the process lacks
      standardization. High performance health status measures developed for clinical
      research have not been widely adopted in rheumatology practices. There is
      agreement on the characteristics required by Australian rheumatologists for
      measurement procedures used in routine clinical care. Quantitative measurement in
      clinical practice using standardized procedures is an attainable, but as yet,
      unrealized opportunity.

PMID- 10405951
TI  - Epidemiology of juvenile chronic arthritis: risk dependent on sibship, parental
      income, and housing.
AB  - OBJECTIVE: We studied the socioeconomic background of children with juvenile
      chronic arthritis (JCA) diagnosed during the years 1988-91 in Denmark. The
      working hypothesis is that JCA may be triggered by one or several different
      infectious agents and that the amount of exposure to infectious agents in infancy
      and childhood affects the risk of JCA. METHODS: In this case-control study, we
      investigated socioeconomic variables prior to disease onset from national
      registers, primarily the Fertility Database of Statistics Denmark, in a national
      cohort of all 220 known cases of JCA fulfilling the EULAR criteria incident
      during the years 1988-91, identified from national and local diagnosis registers.
      There were 4 controls per case, matched for sex, age, and county of residence.
      Socioeconomic variables as risk factors were quantified by odds ratios, which are
      equivalent to relative risks of contracting JCA if exposed to a risk factor.
      RESULTS: Three socioeconomic variables were significantly and mutually
      independently associated with the risk of developing JCA during the following
      year. An only child had a risk of JCA 1.6 times that of a child with siblings.
      Children whose parents had a high income had a relative risk of 1.9. Children
      living in an urban flat had a risk 2.7 times that of children living on a farm.
      We found no space-time clustering of cases and no cyclical variations of
      incidence rates. CONCLUSION: The absence of clustering and of seasonal variation
      does not support a theory of triggering by infection. The hitherto unreported
      effects of the socioeconomic variables on the risk of JCA are of the same order
      of magnitude as reported for certain HLA alleles. Our findings do not lend full
      support to either of the 2 mechanisms, that growing up under either hygienic or
      unhygienic conditions increases the risk of JCA, and lack an obvious biological
      explanation.

PMID- 10405952
TI  - Remission of juvenile rheumatoid arthritis with varicella infection.
AB  - This report describes 2 children with juvenile rheumatoid arthritis (JRA) poorly
      responsive to therapy. Both patients experienced dramatic improvement in their
      arthritis coincident with acute, uncomplicated varicella infection. Although
      remission of JRA has been associated with other viral infections, this phenomenon
      has not been previously reported with varicella infection.

PMID- 10405953
TI  - Progressive multifocal leukoencephalopathy in a patient with systemic lupus
      erythematosus.
AB  - We describe a patient with longstanding systemic lupus erythematosus (SLE) in
      remission who presented with recent onset neurological symptoms. Magnetic
      resonance imaging, followed by a brain biopsy and in situ hybridization,
      confirmed the diagnosis of progressive multifocal leukoencephalopathy (PML). The
      clinical findings in this patient emphasize the importance of considering PML in
      an individual with SLE and neurological abnormalities.

PMID- 10405954
TI  - Thrombotic thrombocytopenic purpura as an initial presentation of limited
      systemic sclerosis.
AB  - Thrombotic thrombocytopenic purpura (TTP) is a rare complication of scleroderma
      (systemic sclerosis, SSc). In the 5 reports documenting the association of TTP
      and SSc, the TTP syndrome developed on a background of well established SSc. We
      describe a 51-year-old woman with a 5 month history of an evolving connective
      tissue disease syndrome who presented initially with TTP, followed 4 months later
      by limited cutaneous SSc and Raynaud's phenomenon.

PMID- 10405955
TI  - Pulmonary manifestations of ulcerative colitis mimicking Wegener's
      granulomatosis.
AB  - We describe 2 patients with quiescent ulcerative colitis who developed clinical
      syndromes suggesting Wegener's granulomatosis. Both patients had features of
      systemic illnesses, nodular lung lesions, and antineutrophil cytoplasmic
      antibodies. Although the inflammatory bowel disease of both patients was
      quiescent at the time of their pulmonary presentations, lung biopsy results were
      consistent with pulmonary complications of ulcerative colitis, an unusual
      manifestation of that disorder. These cases illustrate that pathological
      confirmation of the diagnosis is essential in cases of suspected vasculitis. The
      patients' pulmonary lesions resolved promptly after treatment with
      corticosteroids.

PMID- 10405956
TI  - Giant geode as the differential diagnosis of a large lobular radiolucency in the
      distal femur of a patient with rheumatoid arthritis.

PMID- 10405957
TI  - Rheumatoid epitopes and CD4+ immunodominant regions of recombinant hepatitis B
      surface antigen.

PMID- 10405958
TI  - Polymyalgia rheumatica, aging and mitochondria.

PMID- 10405959
TI  - Bacillus Calmette-Guerin induced reactive arthritis.

PMID- 10405960
TI  - Prevalence of juvenile chronic arthritis and familial Mediterranean fever in
      Turkey: a field study.

PMID- 10405962
TI  - Recognition of hypertrophic osteoarthropathy in skeletal remains.

PMID- 10405961
TI  - Anterior atlantoaxial subluxation in a patient with DISH.

PMID- 10405963
TI  - Seasonal variations in the frequency and synovial fluid inflammation in acute
      gout and pseudogout.

PMID- 10405964
TI  - Intraarticular rupture of digital tenosynovial calcification: an unusual case of
      acute arthritis of the finger.

PMID- 10405966
TI  - High-fat dairy product consumption increases delta 9c,11t-18:2 (rumenic acid) and
      total lipid concentrations of human milk.
AB  - Conjugated octadecadienoic acids (18:2, conjugated linoleic acids) have been
      shown to be anticarcinogenic and may influence growth and nutrient partitioning.
      The delta 9c,11t-18:2 isomer (rumenic acid, RA) is most common in both food
      sources and human tissues. To determine if maternal diet can influence milk RA
      concentration, breastfeeding women (n = 16) were enrolled in a 3-wk crossover
      study. Women initially consumed minimal amounts of food containing RA during week
      1, then were assigned randomly to consume diets rich in high-fat dairy foods (and
      thus RA) during week 2 or 3. Milk was collected by complete breast expression
      twice during each experimental week. Current and chronic RA intakes were
      estimated by 3-d dietary records and food frequency questionnaires, respectively.
      Estimated chronic RA intakes ranged from 49 to 659 mg/d. Dietary RA intake was
      greater during the high compared to the low dairy period (291 +/- 75 vs. 15 +/-
      24 mg/d, respectively; P < 0.0001). Milk contained more RA during the high than
      the low dairy period (13.5 +/- 0.1 vs. 8.2 +/- 0.4 mumol/g lipid, respectively; P
      < 0.0001). Milk lipid concentration was influenced by diet, such that lipid
      concentration was greater during the high than the low dairy period (46.6 +/- 5.0
      vs. 38.3 +/- 1.6 mg/g milk, respectively; P < 0.05). Additionally, multiple
      regression analyses suggested that body mass index was the primary predictor of
      milk RA and lipid concentrations. In summary, these data indicate that both lipid
      and RA concentrations of human milk can be influenced by diet.

PMID- 10405965
TI  - Metabolism of individual fatty acids during infusion of a triacylglycerol
      emulsion.
AB  - The triacylglycerol emulsion Intralipid was infused into six normal subjects to
      investigate the metabolism of individual fatty acids in subcutaneous adipose
      tissue and forearm muscle, by measurement of arteriovenous differences. The
      composition of plasma nonesterified fatty acids changed steadily after passage
      through adipose tissue and became similar to that of the emulsion, reflecting
      hydrolysis of the Intralipidtriacylglycerol by lipoprotein lipase, since
      endogenous lipolysis (hormone-sensitive lipase activity plus lipoprotein lipase
      hydrolysis of very low density lipoprotein triacylglycerol) was decreased. There
      was no significant net release of total or individual fatty acids from forearm
      muscle although there was a tendency for the composition of the fatty acids in
      forearm venous plasma to change during passage through the tissue to reflect the
      composition of the emulsion. This may reflect hydrolysis of emulsion particles by
      lipoprotein lipase situated in capillaries which drain into the forearm vein. The
      behavior of stearic acid in the plasma nonesterified fatty acid pool was
      consistently aberrant, with arterialized concentrations considerably higher than
      predicted from adipose tissue release, both before and during Intralipid
      infusion. We conclude that there are no significant differences in the metabolism
      of specific fatty acids, with the exception of stearic acid.

PMID- 10405967
TI  - Elevated plasma levels of F2 alpha isoprostane in cystic fibrosis.
AB  - Cystic fibrosis (CF) is associated with chronic lung infection, inflammation, and
      elevated indices of oxidative stress. Recently, isoprostanes were shown to be a
      reliable in vivo marker of oxidant injury with 8-iso-PGF2 alpha, shown to cause
      airflow obstruction and plasma exudation in guinea pig lung. The present study
      was designed to examine the relationship between 8-iso-PGF2 alpha levels, plasma
      antioxidants, and clinical status in CF. We hypothesized that plasma 8-iso-PGF2
      alpha levels would be higher in subjects with CF compared to healthy controls.
      Plasma 8-iso-PGF2 alpha levels were prospectively measured in 22 subjects with CF
      and nine healthy controls using an 8-isoprostane enzyme immunoassay kit along
      with plasma vitamins A, E, and beta-carotene. Plasma 8-iso-PGF2 alpha levels were
      shown to be significantly elevated in the CF subjects compared to controls (319.6
      +/- 52.6 vs. 145.0 +/- 21.0 pg/mL, P = 0.005). Plasma levels of antioxidants were
      significantly lower for the CF subjects compared to the controls (vitamin A, P <
      0.003; vitamin E, P < 0.001; and beta-carotene, P < 0.01). This study confirms
      significantly elevated lipid peroxidation in CF using 8-iso-PGF2 alpha levels.

PMID- 10405968
TI  - Cholesterol-derived hydroperoxides in alcoholic liver disease.
AB  - Human liver samples from 33 patients were collected at autopsy (controls, n = 9;
      fatty liver, n = 12; liver cirrhosis, n = 12), and samples homogenized. Lipids
      extracted with chloroform and methanol were injected into the octyl column of a
      high-performance liquid chromatograph with post-column chemiluminescence. Liquid
      chromatography-mass spectrometry was developed to identify 7-hydroperoxycholest-5
      en-3 beta-ol (7-OOH). We found that two cholesterol-derived hydroperoxides, 7
      alpha-hydroperoxycholest-5-en-3 beta-ol (7 alpha-OOH) and 7 beta
      hydroperoxycholest-5-en-3 beta-ol (7 beta-OOH), are present in significantly
      elevated amounts (12.4 and 25.0 nmol/g tissue, respectively) in lipid extracts
      from alcoholic fatty liver, but not in extracts from alcoholic cirrhotic liver. 7
      alpha-OOH and 7 beta-OOH are early intermediates produced during free radical
      mediated cholesterol oxidation and can serve as molecular indicators of chain
      peroxidative damage in cell membranes. This is the first demonstration of 7 alpha
      OOH and 7 beta-OOH accumulations in human liver, and it is presumed to reflect
      greater oxidative stress pathology in alcoholic fatty liver.

PMID- 10405969
TI  - Lymphatic absorption of phytosterol oxides in rats.
AB  - Two of the main classes of oxyphytosterols (7-keto and epoxides) were synthesized
      from sitosterol and campesterol and given to mesenteric duct-cannulated adult
      male rats. Lymph was collected during 24 h and was analyzed for oxysterols. The
      results showed that the lymphatic recovery of the phytosterol oxides was low:
      4.7% of the given dose for epoxy derivatives and 1.5% for 7-keto compounds. The
      campesterol oxides presented a better absorption than the sitosterol oxides.
      During the process of absorption, the epoxyphytostanols were also partly
      transformed in campestanetriol and stigmastanetriol.

PMID- 10405971
TI  - The metabolism of native and randomized butterfat chylomicrons in the rat is
      similar.
AB  - Reportedly, randomly rearranging the position of fatty acids (FA) in butterfat
      triacylglycerol (TAG) by interesterification, thereby lowering the proportion of
      saturated FA in the sn-2 position, reduces its hypercholesterolemic and
      hypertriglyceridemic properties when fed to humans. The aim of this work was to
      determine if these reductions in plasma cholesterol and TAG could be explained by
      an improved rate of clearance from the plasma of chylomicrons composed of
      randomized butterfat, using a rat model. Acute chylomicron clearance studies
      demonstrated no differences in fractional clearance rates of cholesteryl esters
      and TAG from the plasma of rats infused with chylomicrons produced from gastric
      feeding of either native (NBF) or randomized (RBF) butterfat. Although there was
      a 14% decrease in the level of saturated FA occupying the sn-2 position of TAG in
      RBF compared with NBF, this difference became negligible (approximately 5%),
      following digestion of the fat and subsequent repackaging of TAG into
      chylomicrons. These observations suggest that the previously observed reduction
      in hypercholesterolemic properties of randomized butterfat in rat is unlikely to
      be explained by improved clearance of chylomicron TAG.

PMID- 10405970
TI  - The incorporation of fatty acids of different chain length into liver and biliary
      lipids in the perfused rat liver.
AB  - In an attempt to correlate the incorporation of fatty acids (FA) of different
      chain length into liver and biliary lipids, isolated rat livers were perfused for
      2 h with Krebs-Ringer bicarbonate containing 1% albumin and 10 mumol of [1-14C]
      labeled FA: C2, C8, C10, C12, C16, and C18:1. One to 1.36 mumol of medium-chain
      fatty acids (MCFA, C8, C10, and C12) and 6.6 mumol of long-chain FA (LCFA) were
      incorporated into liver lipids, 40% of the latter into phosphatidylcholine (PC).
      14C-acetate (13 nmol) was incorporated into biliary cholesterol; 14C-MCFA
      contributed only 3.2-5 nmol; LCFA did not lead to newly synthesized cholesterol.
      Newly synthesized liver PC (2.75 to 3.25%) and newly synthesized liver
      cholesterol (6.5 to 10%) were secreted into bile. The specific radioactivity of
      biliary PC after infusion of all-saturated FA was 3.8-6.8 times higher than that
      of liver PC; for C18:1 it was only 1.7-fold. The specific radioactivity of
      biliary cholesterol, as compared to liver cholesterol, was 12 times higher for C2
      and five times higher for MCFA. This indicates that a considerable proportion of
      the newly synthesized lipids was secreted into bile prior to significant mixing
      with preexisting liver PC and cholesterol pools. Liver PC contained 8% of
      unchanged 14C-C12; while 14C-C10 was not detected. Biliary PC, in contrast,
      contained 18% of unchanged 14C-C12 and 3% 14C-C10. These results suggest that
      after prolonged infusion of medium-chain triacylglycerols/long-chain
      triacylglycerols to patients, biliary PC may become enriched with MCTA. In
      addition, the oxidation of these FA may provide C-2 units which increase
      cholesterol synthesis.

PMID- 10405972
TI  - Cholesterol synthesis and degradation in normal rats fed a cholesterol-free diet
      with excess cystine.
AB  - Feeding a diet with excess cystine to rats resulted in hypercholesterolemia. To
      understand the mechanism of the hypercholesterolemia, cholesterol synthesis and
      degradation, bile acid content of bile, and fecal steroids were determined. The
      in vivo incorporation of tritiated water into hepatic cholesterol, and activity
      of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase in rats fed a high-cystine
      diet were significantly higher than those in rats fed a control diet. The
      activity of hepatic cholesterol 7 alpha-hydroxylase was similar between two
      groups. Little effect of cystine supplementation was found on fecal sterol
      excretion although there were some changes in biliary excretion of cholic acid
      derivatives. These results indicate that hypercholesterolemia caused by feeding
      of a high-cystine diet may be due to the stimulation of hepatic cholesterol
      synthesis.

PMID- 10405973
TI  - Regulation of HepG2 cell apolipoprotein B metabolism by the citrus flavanones
      hesperetin and naringenin.
AB  - Our previous studies showed that replacing the drinking water of rabbits fed a
      casein-containing diet with either orange juice or grapefruit juice reduced serum
      low density lipoprotein cholesterol and hepatic cholesteryl ester concentrations.
      To determine whether the changes observed in rabbits were due to flavonoids
      present in the juices acting directly on the liver, the effects of hesperetin and
      naringenin on net apolipoprotein B (apoB) secretion by HepG2 cells were
      investigated. These flavanones dose-dependently reduced net apoB secretion by up
      to 81% after a 24 h incubation, while doses of 60 micrograms/mL reduced net apoB
      secretion by 50% after 4 h. Coincubation with the proteasome inhibitor, MG-132,
      did not alter the ability of the flavonoids to reduce net apoB secretion over 4
      h, suggesting that the flavonoid-induced changes in apoB metabolism were not due
      to a direct increase in proteasomal activity. However, the flavonoids were unable
      to reduce net apoB secretion after 4 h in the presence of oleate, suggesting that
      these compounds may interfere with the availability of neutral lipids for
      lipoprotein assembly. Furthermore, our 14C-acetate-labeling studies showed a 50%
      reduction in cholesteryl ester synthesis in the presence of either flavonoid,
      which could account for the reduction in net apoB secretion caused by incubation
      with these compounds. These in vitro studies suggest that hesperetin and
      naringenin may, in part, reduce net apoB secretion by HepG2 cells by inhibiting
      cholesteryl ester synthesis and that these compounds are good candidates for
      further in vivo studies to determine whether they are responsible for the
      cholesterol-lowering properties of dietary citrus juices.

PMID- 10405975
TI  - Enhancement of sterol synthesis by the monoterpene perillyl alcohol is unaffected
      by competitive 3-hydroxy-3-methylglutaryl-CoA reductase inhibition.
AB  - Monoterpenes such as limonene and perillyl alcohol (PA) are currently under
      investigation for their chemotherapeutic properties which have been tied to their
      ability to affect protein isoprenylation. Because PA affects the synthesis of
      isoprenoids, such as ubiquinone, and cholesterol is the end product of the
      synthetic pathway from which this isoprenoid pathway branches, we investigated
      the effects of this compound upon cholesterol metabolism in the colonic
      adenocarcinoma cell line SW480. PA (1 mM) inhibited incorporation of 14C
      mevalonate into 21-26 kDa proteins by 25% in SW480 cells. Cholesterol (CH)
      biosynthesis was assessed by measuring the incorporation of 14C-acetate and 14C
      mevalonate into 27-carbon-sterols. Cells treated with PA (1 mM) exhibited a
      fourfold increase in the incorporation of 14C-acetate but not 14C-mevalonate into
      cholesterol. Mevinolin (lovastatin), an inhibitor of 3-hydroxy-3-methylglutaryl
      CoA(HMG-CoA) reductase, at 2 microM concentration, inhibited CH synthesis from
      14C-acetate by 80%. Surprisingly, concurrent addition of mevinolin and PA did not
      significantly alter the stimulatory effects of PA. As observed differences in 14C
      acetate and 14C-mevalonate precursor labeling could indicate PA affects early
      pathway events, the effects of this monoterpene on HMG-CoA reductase activity
      were evaluated. Unexpectedly, 1 mM PA did not stimulate activity of this enzyme.
      Consistent with its action as a reversibly bound inhibitor, in washed microsomes,
      2 microM mevinolin pretreatment increased reductase protein expression causing a
      12.7 (+/- 2.4)-fold compensatory HMG-CoA reductase activity increase; concurrent
      treatment with 1 mM PA attenuated this to a 5.3 (+/- 0.03)-fold increase. Gas
      chromatographic analysis confirmed CH was the major lipid present in the measured
      thin-layer chromatography spot. Since 14C-acetate incorporation into free fatty
      acid and phospholipid pools was not significantly affected by PA treatment,
      nonspecific changes in whole acetate pool sizes were not indicated. Because
      increases in endogenous CH synthesis should result in compensatory changes in
      exogenous sterol utilization, the effects of PA upon low density lipoprotein
      (LDL) receptor activity were evaluated. Consistent with the observed increases in
      CH synthesis, 1 mM PA decreased 125I-LDL internalization to 50% of the fetal
      bovine serum control; concurrent addition of 2 microM mevinolin attenuated this
      effect to a reduction of 80% of the control value. Data suggest that in certain
      colonic tumor cells PA strongly affects cholesterol metabolism via a mechanism of
      action that is insensitive to the HMG-CoA reductase inhibitor mevinolin.

PMID- 10405976
TI  - Biosynthesis of R-(+)-octane-1,3-diol. Crucial role of beta-oxidation in the
      enantioselective generation of 1,3-diols in stored apples.
AB  - The biosynthesis of R-octane-1,3-diol and R-5(Z)-octene-1,3-diol, two natural
      antimicrobial agents in apples and pears, was investigated in stored apples after
      application of [9,10,12,13-3H]linoleic acid, [9,10,12,13,15,16-3H]linolenic acid,
      [1-14C]linoleic acid, [U-14C]oleic acid, lipoxygenase-derived metabolites of
      [9,10,12,13-3H]linoleic acid, 13C18-labeled linoleic acid hydroperoxides, and 2H
      labeled octanol derivatives. Analysis of the products and quantification of
      incorporation and labeling pattern were achieved by high-performance liquid
      chromatography-radiodetection, capillary gas chromatography (GC)-isotope ratio
      mass spectrometry, and GC-mass spectrometry analysis. Almost all the applied
      precursors were partly transformed into R-octane-1,3-diol. Linoleic acid
      derivatives, still containing the 12,13 cis double bond, and octanol derivatives
      oxy-functionalized at carbon 3 were the most efficient precursors of the 1,3
      diol. The data imply that R-octane-1,3-diol is generated in stored apples in the
      course of the beta-oxidation from R-3-hydroxy-octanoyl-SCoA originating from 2
      cis-octenoyl-SCoA by enoyl-CoA hydratase. In an analogous fashion, R-5(Z)-octene
      1,3-diol is formed from the unsaturated intermediate.

PMID- 10405974
TI  - Cell proliferation, differentiation, and apoptosis are modified by n-3
      polyunsaturated fatty acids in normal colonic mucosa.
AB  - Supplementation with low doses of eicosapentaenoic (EPA) or docosahexaenoic (DHA)
      acid was used here to investigate changes in epithelial proliferation,
      differentiation, and apoptosis in normal rat colonic mucosa. ACI/T rats received
      by oral administration low doses of purified EPA or DHA ethyl esters (1 g/kg body
      weight) and colonic mucosa was analyzed for cell proliferation, differentiation,
      and apoptosis. n-3 Polyunsaturated fatty acid incorporation into membrane
      phospholipids was investigated as reflections of fatty acid metabolism. Both EPA
      and DHA suppressed colonocyte proliferation and increased the numbers of
      differentiating and apoptotic cells without modification of the crypt morphology
      and the number of cells per crypt columns. A significant incorporation of the
      supplemented fatty acids into total phospholipids was observed. This enrichment
      was accompanied by a decreased content in arachidonic acid. The observation that
      EPA and DHA do not alter crypt morphology although they modify cell turnover in
      normal colonic mucosa suggests a possible use of these fatty acids as dietary
      chemopreventive agents.

PMID- 10405977
TI  - Excess vitamin E decreases canthaxanthin absorption in the rat.
AB  - The recent attention given to the possible role of alpha-tocopherol (alpha-Toc)
      and carotenoids in the prevention and treatment of a variety of illnesses
      resulted in segments of the population increasing their consumption of these
      nutrient/antioxidants. Once consumed, alpha-Toc and carotenoids are thought to
      follow the same absorptive pathway and may influence each other's absorption,
      particularly when taken in large doses. The purpose of this study was to
      determine if alpha-Toc and the carotenoid, canthaxanthin (CTX), interact during
      absorption. Rats were intraduodenally infused with corn oil emulsions containing
      combinations of alpha-Toc (0 or 300 mumol/L) and CTX (5, 10, 15, 20 mumol/L) in a
      2 x 4 factorial arrangement. Absorption was determined by measuring recovery of
      CTX and alpha-Toc in the mesenteric lymph. The amount of CTX in the lymph
      increased significantly with the amount infused into the duodenum. The overall
      efficiency of CTX absorption from emulsions without alpha-Toc averaged 12% with
      individual animals having a range of 8 to 18%. Efficiency of absorption was not
      related to concentration of CTX infused. When alpha-Toc (300 mumol/L) was added
      to the oil emulsion, the absorption of CTX was decreased by at least 50%.
      Recovery of alpha-Toc in the lymph averaged ca. 10% and was not affected by CTX.
      These results suggest that concurrent consumption of a large dose of alpha-Toc
      may influence carotenoid bioavailability.

PMID- 10405979
TI  - Seasonal variation in the fatty acid composition and quality of sardine oil from
      Sardinops sagax caeruleus of the Gulf of California.
AB  - One of the few sources of long-chain n-3 polyunsaturated fatty acids is fish oil,
      but considerable variation may exist according to species and season. In this
      study, the fatty acid profiles of sardine oils from Sardinops sagax caeruleus of
      the Gulf of California, Mexico, were evaluated in three seasonal catch periods.
      Oil quality was also evaluated by peroxide and free acid values. The most
      abundant fatty acids found in the oils were palmitic acid (19.3%), oleic acid
      (14.3%), eicosapentaenoic acid (EPA, 20.4%), and docosahexaenoic acid (DHA,
      12.2%). There was no significant difference in the composition and quality among
      the six reduction plants where the samples were obtained. However, a significant
      difference in the proportion of EPA and DHA in one of the catch seasons analyzed
      was observed.

PMID- 10405978
TI  - The metabolism and distribution of sesame lignans (sesamin and episesamin) in
      rats.
AB  - In this study, we examined the distribution and metabolism of refined sesame oil
      lignans (sesamin and episesamin) in rat. For 8 wk rats were fed the diet
      including 0.5% (w/w) sesame lignans (sesamin and episesamin) with 5% (w/w) corn
      oil or eicosapentaenoic acid (EPA)-rich oil. The concentrations of sesamin and
      episesamin in rat liver after their administration for 8 wk were very low; both
      of them were less than 0.5 microgram/g liver. These were observed in both oil
      groups although the fatty acid compositions of dietary oils were completely
      different. No significant difference existed in lymphatic absorption between
      sesamin and episesamin. To investigate the distribution of sesamin and episesamin
      in rats, the concentrations of sesamin and episesamin were determined in tissues
      and serum within 24 h after administration to rats. Sesamin and episesamin may
      be, at first, incorporated into the liver and then transported to the other
      tissues (lung, heart, kidney, and brain). They are lost from the body within 24 h
      after administration. There was no significant difference in lymphatic absorption
      between sesamin and episesamin, but the amount of sesamin was significantly lower
      than that of episesamin in all tissues and serum. These results suggest that
      sesamin is absorbed in lymph the same as episesamin, but that sesamin is
      subsequently metabolized faster by the liver.

PMID- 10405980
TI  - Aging and T-cell-mediated immunity.
AB  - Changes in the T-lymphocyte compartment represent the most critical component of
      immunological aging. Recent studies have demonstrated that the age-related
      decline in T-cell-mediated immunity is a multifactorial phenomenon affecting T
      cell subset composition as well as several proximal events such as protein
      tyrosine phosphorylation, generation of second messengers, calcium mobilization
      and translocation of protein kinase C, and distal events such as lymphocyte
      proliferation and cytokine production of the T-cell activation pathway. Age
      related T-cell immune deficiency is preceded by thymic involution and is
      influenced by several intrinsic as well as extrinsic factors. Further, the role
      of monocytes and macrophages in T-cell activation changes with advancing age.
      This brief review will summarize the current knowledge of the cellular as well as
      molecular aspects of immunodeficiency of T cells due to aging, some of the
      paradoxes of aging as related to T-cell-mediated immunity, and possible factors
      which contribute to this paradox. Finally, experimental approaches will be
      suggested that might resolve these controversies and that might provide insights
      into the diverse and complex mechanisms that contribute to immunodeficiency of T
      cells. Ultimately these studies may suggest possible therapeutic interventions to
      enhance immune function in the elderly.

PMID- 10405981
TI  - Myocardial and skeletal muscle aging and changes in oxidative stress in
      relationship to rigorous exercise training.
AB  - Cardiac and skeletal muscle are very different functional tissues, and we would
      expect a variation in the ROS generation, in ageing and rigorous exercise-related
      in both tissues. We determined TBARS, total SOD, Cu, ZnSOD and MnSOD activities,
      and the patterns of SOD isoenzymes in skeletal muscle and heart of male Wistar
      rats, young and old, in rest and after rigorous exercise. There were no
      differences in the levels of lipoperoxidation in aged rest animals in both
      tissues, but the level was increased after exhaustion. The level of SOD
      activities was bigger in the heart than in skeletal muscle. Total SOD and Cu,
      ZnSOD activities were higher in old rest animals in the skeletal muscle than in
      young rest rats. This change did not occur in the heart. After rigorous exercise,
      the level of SOD activities was increased in young rats in both tissues. However,
      in old exhausted rats, the activities were only elevated in the heart. Different
      Cu, ZnSOD isoenzyme patterns showed in relation to tissues. In the skeletal
      muscle in old animals, the Cu, ZnSOD isoenzyme pattern was modified. The rigorous
      exercise did not change this pattern. The pattern of MnSOD isoenzyme was not
      varied in either tissue, age nor and exercise.

PMID- 10405982
TI  - Human rectal endocrine cells and aging.
AB  - Endocrine cells of the human rectum were investigated by immunocytochemistry and
      quantified by computerized image analysis in three different age groups. The age
      intervals were 20-29, 40-49 and 60-69 years. No statistically significant
      differences were found between the age groups, regarding the numbers of all
      endocrine cell types investigated, namely peptide YY (PYY)-, pancreatic
      polypeptide (PP)-, enteroglucagon-, somatostatin- and serotonin-immunoreactive
      cells. Nor was there any difference regarding the cell secretory index. Nuclear
      volume was significantly greater in the 40-49 year olds than the other age
      groups. There was no statistically significant difference between females and
      males regarding numbers of the endocrine cell types investigated. It is concluded
      that age does not affect the endocrine cells of the human large intestine as it
      was earlier found in animal models of aging. It is imperative that caution should
      be taken when applying results obtained in animal models of aging in humans.

PMID- 10405983
TI  - Aberrations of cell cycle and cell death in normal development of the chick
      embryo growth plate.
AB  - The epiphyses of femurs from 7.5-15 day chicken embryos were studied by electron
      microscopy. Several forms of aberrant cell cycles were present: (1) in the
      perichondrium, polyploid metaphases, segmentating large (giant) cells, and
      mitotic catastrophe (midway between mitosis and apoptosis) were observed; (2) in
      the resting zone, premature chromosome condensation was found; (3) in the
      proliferative zone, approximately 5% of divisions were aberrant, representing
      most often mitosis restitution from metaphase and more seldom from the anaphase;
      (4) in all layers, 'dark chondrocytes' representing a premortal form of
      hypersecretory cells undergoing often a-mitotic nuclear segmentation were
      present. Many of the aberrations of cell cycle were combined with cell death.
      These deviations omitting or adapting the cell cycle check-points represent
      evidently the normal epigenetic mechanisms of development and repair. At the same
      time, by origin and appearances they seem very close to the loss of the growth
      control displayed by malignant tumours. This connection is briefly analysed in
      view of some current concepts of carcinogenesis.

PMID- 10405984
TI  - Advanced glycation in D-galactose induced mouse aging model.
AB  - It was first reported in China that injection of a low dose of D-galactose into
      mice could induce changes which resembled accelerated aging. The aging model
      shows neurological impairment, decreased activity of anti-oxidant enzymes, and
      poor immune responses. However, the underlining mechanism remains largely
      unknown. D-galactose is a reducing sugar that can form advanced glycation
      endproducts (AGE) in vivo. To investigate the role of AGE in this aging model, a
      group of 5-month-old C57 mice were injected daily with D-galactose, D-galactose
      modified AGE-lysine (AGE-lysine), L-glucose, L-lysine, or control buffer for 8
      weeks. Two additional groups were treated with the AGE formation inhibitor,
      aminoguanidine. The results show that D-galactose, L-glucose, and AGE-lysine
      treated mice had a significant increase in serum AGE levels, memory latency time
      and error rate, and skin hydroxyproline content. Similar to aged controls, these
      mice also had a significant decrease in motor activity, lymphocyte mitogenesis,
      interleukin-2 (IL-2) production, and superoxide dismutase (SOD) enzyme activity.
      The aminoguanidine treated D-galactose-injected mice, however, showed no
      significant changes in these parameters in comparison with young controls. These
      data indicate that D-galactose and L-glucose form AGEs in vivo and that elevated
      AGEs may accelerate the aging process. The fact that both D-galactose and AGE
      treated mice resemble aged mice suggests that advanced glycation, at least
      partially, accounts for the mechanism of this aging model.

PMID- 10405985
TI  - Effects of 6 months of moderate aerobic exercise training on immune function in
      the elderly.
AB  - The purpose of this study was to determine the effects of 6 months of moderate
      aerobic exercise on age-dysregulated measures of T lymphocyte and natural killer
      (NK) cell number and function. Previously sedentary elderly (age = 65 +/- 0.8
      years) subjects were randomly assigned to supervised 3 time/week exercise
      intervention group (EXC, n = 14) or flexibility/toning control group (FT-CON, n =
      15). Fasting resting blood samples were drawn prior to and after the 6 month
      intervention. The EXC group exhibited a significant (P < 0.05) 20% increase in
      VO2 max, whereas the FT-CON group had a smaller non-significant (P = 0.07)
      increase (9%). Immune results revealed that, in general, changes in immune
      function in response to 6 months of exercise training at an average intensity of
      52% heart rate reserve (HRR) were similar when compared to FT-CON who exercised
      at approximately 21% HRR. There were no intervention-induced changes in total
      white blood cell, neutrophil, lymphocyte, monocyte, eosinophil, or basophil blood
      counts. Furthermore, the percentage and number of CD3+, CD4+ and CD8+ T cells in
      the blood remained unchanged. There was a tendency for the percentage and number
      of CD4+ and CD8+ naive cells (CD45RA+) to increase and for CD4+ memory cells
      (CD45RO+) to decrease post-intervention, especially in FT-CON. Both groups
      exhibited a small intervention-induced increase in the T-cell proliferative
      response to mitogenic stimulation: the percentage change of which was higher in
      the EXC group at several doses of Con A. Unstimulated NK cell cytolysis versus
      K562 cells tended to increase (P < 0.1) in the EXC group with little change in FT
      CON. We conclude that 6 months of supervised exercise training can lead to
      nominal increases in some measures of immune function, while not affecting
      others, in previously sedentary elderly.

PMID- 10405986
TI  - Influence of physical activity on plasma insulin-like growth factor-1 and insulin
      like growth factor binding proteins in healthy older women.
AB  - It was examined whether physical activity could alter the bioavailability of
      insulin-like growth factor-1 (IGF-1) which is dependent upon plasma IGF-1 and
      insulin-like growth factor binding protein (IGFBPs) levels. The potential role
      that growth hormone (GH) and insulin play in this process was also examined.
      Seven healthy 62-69-year-old women performed four bouts of physical activity on
      separate occasions at either a low (L; heart rate = 100 bpm) or moderate
      intensity (M; heart rate = 120 bpm) for either 25 (S) or 50 (L) min (LS, low
      intensity/short duration; LL, low intensity/long duration; MS, moderate
      intensity/short duration; ML, moderate intensity/long duration). GH levels were
      elevated immediately following the physical activity from 1.3 to 2.6-fold (P <
      0.05) whereas IGF-1 levels were not affected by any activity condition. Plasma
      insulin levels decreased about 35% under all activity conditions (P < 0.05).
      Plasma levels of IGFBP-1 (BP-1) were decreased immediately following the ML (
      47%; P < 0.05) and the LL (-21%) activity bouts and remained lower than initial
      values 1 h after these activity bouts (-25 and 34%, respectively, P < 0.05). The
      ML exercise bout resulted in significant (P < 0.05) increases in IGFBP-2 (BP-2)
      and IGFBP-3 (BP-3) immediately following activity (+31, and +30%, respectively)
      and these binding proteins remained elevated following the activity (+28, and
      +48%, respectively). No relationship was found between any changes in plasma GH
      or insulin, and changes in plasma IGFBPs. Thus, moderate intensity physical
      activity of long duration may modulate the bioavailability of IGF-1 in the
      elderly via alterations in BP-1, -2 and -3. However, changes in circulating
      levels of GH, insulin or IGF-1 do not appear to be regulating IGF-1
      bioavailability in response to physical activity.

PMID- 10405987
TI  - Effect of enzyme imprinting of liver microsomal monooxygenases upon lifespan of
      rats.
AB  - Effect of the enzyme imprinting by phenobarbital upon alterations of hepatic
      microsomal monooxygenase activities and lifespan of Wistar rats has been studied.
      Phenobarbital-sodium (3.5 mg/100 g body weight per day, i.p.) was injected during
      1-3 days after birth. This resulted in the enzyme imprinting of the liver
      microsomal monooxygenases, however, this effect being observed in female but not
      male rats. In the phenobarbital treated female rats of different age the duration
      of sleeping time was significantly lower than that in control animals, whereas it
      did not differ substantially in male rats. The cytochrome P-450 content increased
      by 34.5% in phenobarbital treated female rats in the age of 12 months in
      comparison with control animals. A mean lifespan of experimental female rats
      increased by 17.5% compared to the level of control animals and did not change in
      male rats. The analysis of survival of animals in Gompertz equation coordinates
      showed that enzyme imprinting by phenobarbital caused changes in the mortality
      patterns at different stages of ontogenesis in experimental female but not male
      rats. An inverse correlation was found between the duration of pentobarbital
      sleeping time and lifespan of female and male rats.

PMID- 10405988
TI  - Human longevity: an evolutionary approach.
AB  - Humans are unique in having a considerably longer life span post female
      reproductive age as compared to other primates. It is proposed that transmission
      of knowledge from grandparents to progeny served as a driving force for extending
      human longevity. It is suggested that grandparents and grandchildren have evolved
      adaptive complementary behaviors that fit the educator/pupil roles. Older
      individuals specifically retain the ability to preserve their knowledge base that
      allows them to focus on transmitting to children knowledge accumulated over
      generations. A repair management model of aging is proposed, according to which
      inhibition of repair in older individuals at times of stress allows to focus
      resources on the task at hand. Such an adaptation will inevitably accelerate the
      rate of aging in animals and in humans and will appear as 'programmed aging'. It
      is further suggested that in humans, older individuals in early societies who are
      no longer useful could increase their reproductive success by activating this
      programmed aging mechanism, which would result in channeling resources to
      progeny. Decreased emotional support and mastery are mortality risk factors in
      the elderly, supporting this hypothesis of programmed death in humans, and
      providing a rationale for increasing longevity.

PMID- 10405989
TI  - Resistance to stress as a function of age in Drosophila melanogaster living in
      hypergravity.
AB  - Male and female fruitflies (Drosophila melanogaster) living at different gravity
      levels [1g: terrestrial gravity; 3 and 5g: hypergravity (HG)] were used to
      investigate the age-specific (young: 7 days; middle-aged: 28 days; and old: 49
      days) resistance to various stresses (starvation, desiccation, and cold). The
      experiment showed that the resistance of the flies to the studied stresses
      decreased with age, except in the case of females submitted to starvation which
      was increased. These variations were explained by the amount of lipid. Variation
      in desiccation resistance was not explained by the amount of water. As a function
      of gravity, no or slight differences were observed for the studied stresses. The
      resistance to heat of young flies increased with the gravity level. This
      resistance was not explained by a decreased locomotor activity of HG-living flies
      during heat stress, nor by the water and lipid contents.

PMID- 10405990
TI  - HSP70 induction may explain the long-lasting resistance to heat of Drosophila
      melanogaster having lived in hypergravity.
AB  - In this study, we showed that in flies kept for 2 weeks at 1 (terrestrial
      gravity), 3 or 5 x g (hypergravity, HG) before transfer to 1 x g, resistance to
      heat remained higher in HG flies for several weeks after the transfer. The
      measurement of heat shock protein 70 (hsp70) indicated no induction of the
      protein in HG, but the study revealed that flies living in HG expressed more
      hsp70 only after being submitted to severe stress. The higher induction of hsp70
      may explain the higher thermotolerance of these HG-treated young flies. Finally,
      an unknown protein was observed only in females. This protein may belong to a
      class of higher molecular weight hsp (hsp110), which have not previously been
      observed in Drosophila.

PMID- 10405991
TI  - Overview of the effects of alcohol on the cerebral nervous system.

PMID- 10405992
TI  - Regulation of neuronal voltage-gated calcium channels by ethanol.
AB  - Voltage-gated calcium channels are key regulators of neuronal excitability.
      Several studies indicate that intoxicating concentrations of ethanol inhibit L
      type, N-type and possibly T-type channels. The effects of ethanol on other
      channel subtypes are not yet clear. Chronic exposure to ethanol is associated
      with increases in functional L-type channels and this may contribute to signs of
      ethanol withdrawal. Preclinical studies in animals suggest that L-type calcium
      channel antagonists decrease ethanol consumption and signs of alcohol withdrawal.
      Although L-type channel antagonists do not appear to alter the performance
      impairing or psychological effects of acute ethanol administration, clinical
      trials will be needed to determine if L-type channel antagonists reduce ethanol
      consumption in humans.

PMID- 10405993
TI  - Alcohol modulation of calcium-activated potassium channels.

PMID- 10405994
TI  - Ionotropic glutamate receptors as sites of action for ethanol in the brain.

PMID- 10405995
TI  - Acute effects of ethanol on GABAA and glycine receptor function.

PMID- 10405996
TI  - 5-HT3 receptors and the neural actions of alcohols: an increasingly exciting
      topic.
AB  - The 5-HT3 receptor is a ligand-gated ion channel activated by the
      neurotransmitter serotonin. Receptors of this subtype have been localized to
      several regions of the brain, and appear to be involved in many neuronal
      functions including responses to alcohol and other drugs of abuse. There is an
      extensive and growing literature indicating that 5-HT3 receptors are involved in
      several facets of alcohol seeking behavior, alcohol intoxication and addiction.
      In addition, there is strong evidence that alcohols, including ethanol, alter the
      function of the 5-HT3 receptor, possibly through actions on the receptor protein
      itself. In this article, our current understanding of the role of the 5-HT3
      receptor in alcohol abuse and alcoholism will be reviewed. In addition, an
      overview of current understanding of the mechanism of alcohol actions of the
      receptor is provided.

PMID- 10405997
TI  - Neuronal nicotinic acetylcholine receptors: a new target site of ethanol.
AB  - Whereas a variety of neuroreceptors and ion channels have been demonstrated to be
      affected by ethanol including GABAA receptors, NMDA receptors, non-NMDA glutamate
      receptors, 5-HT3 receptors and voltage-gated calcium channels, neuronal nicotinic
      acetylcholine receptors (nnAChRs) have recently emerged as a new target site of
      ethanol. The nnAChRs are different from the muscle type nicotinic AChRs with
      respect to their molecular architecture and pharmacology. This article briefly
      reviews the structure, distribution and function of nnAChRs for which a
      considerable amount of information has been rapidly accumulated during the past 5
      10 years. The potent and unique action of ethanol on nnAChRs has been unveiled
      only during the past few years. Most recent developments along this line of
      ethanol action are discussed in this paper.

PMID- 10405998
TI  - Alcohol action on membrane ion channels gated by extracellular ATP (P2X
      receptors).
AB  - Extracellular adenosine 5'-triphosphate (ATP) has been reported to produce
      excitatory actions in the nervous system, such as excitatory postsynaptic
      potentials or currents in both central and peripheral neurons, via activation of
      a class of ATP-gated membrane ion channels designated P2X receptors. This article
      reviews studies of alcohol effects on these receptor-channels. Ethanol has been
      found to inhibit ATP-gated ion channel function by shifting the agonist
      concentration-response curve to the right in a parallel manner, increasing the
      EC50 without affecting Emax of this curve. To distinguish whether this inhibition
      involves competitive antagonism of agonist action or a decrease in the affinity
      of the agonist binding site, the kinetics of activation and deactivation of
      agonist-activated current were studied. Ethanol was found to decrease the time
      constant of deactivation of ATP-gated ion channels without affecting the time
      constant of activation, indicating that ethanol inhibits the function of these
      receptors by an allosteric decrease in the affinity of the agonist binding site.
      The inhibition of ATP-gated ion channel function by a number of alcohols was
      found to exhibit a distinct cutoff effect that appeared to be related to the
      molecular volume of the alcohols. For alcohols with a molecular volume of < or =
      42.2 ml/mol, potency for inhibiting ATP-activated current was correlated with
      lipid solubility (order of potency: 1-propanol = trifluoroethanol >
      monochloroethanol > ethanol > methanol). However, despite increased lipid
      solubility, alcohols with a molecular volume of > or = 46.1 ml/mol (1-butanol, 1
      pentanol, trichloroethanol, and dichloroethanol) were without effect on the ATP
      activated current. This cutoff effect has been interpreted as evidence that
      alcohols inhibit the function of ATP-gated ion channels by interacting with a
      hydrophobic pocket of circumscribed dimensions on the receptor protein. To
      evaluate the localization of this presumed alcohol binding site, the effect of
      the intracellular application of ethanol was studied on the inhibition of ATP
      activated current by extracellularly applied ethanol. The intracellular
      application of 100 mM ethanol did not affect the inhibition of current by 100 mM
      extracellular ethanol, suggesting that the alcohol inhibition of ATP-gated ion
      channel function involves the extracellular domain of the receptor. Finally,
      recent studies suggest that the alcohol sensitivity of ATP-gated channels may be
      regulated by physiological mechanisms.

PMID- 10405999
TI  - Ethanol-induced inhibition of NMDA receptor channels.
AB  - Ethanol is a potent inhibitor of the N-methyl-D-aspartate (NMDA)-receptor subtype
      of glutamate receptor in a number of brain areas. The mechanism of ethanol action
      has been investigated by means of patch-clamp recording of ionic currents and
      fura-2 measurement of intracellular Ca2+ concentration in cell culture systems;
      the subunit composition of NMDA receptors and their influence on the effect of
      ethanol was determined by molecular biology methods. Ethanol does not appear to
      interact with NMDA either at the glutamate recognition site of the receptor, or
      at any of the hitherto known multiple modulatory sites, such as the glycine or
      polyamine site. Moreover, ethanol does not cause an open channel block by itself
      and fails to interact with Mg2+ at the site where it causes open channel block.
      The ability of ethanol to inhibit responses to NMDA is dependent on the subunit
      combination of NMDA receptors. The NR1/NR2A and NR1/NR2B combinations are
      preferentially sensitive to ethanol inhibition. Chronic treatment with ethanol
      leads to an increase of the NMDA receptor number at the transcriptional and
      posttranscriptional level; the receptor function is also facilitated. This causes
      withdrawal-type seizures after termination of chronic treatment with ethanol. The
      inhibition of NMDA receptors by ethanol leads to the depression of excitatory
      synaptic potentials mediated by this type of excitatory amino acid receptor.
      Ethanol-induced disturbances in certain regions of the brain, i.e. hippocampus,
      nucleus accumbens or locus coeruleus may lead to cognitive disorders or drug
      dependence. Brain slices containing the locus coeruleus may be used as an in
      vitro test system to investigate the addictive properties of ethanol.

PMID- 10406000
TI  - Chronic ethanol exposure enhances AMPA-elicited Ca2+ signals in the somatic and
      dendritic regions of cerebellar Purkinje neurons.
AB  - Intracellular Ca2+ signals produced by the glutamate receptor agonist alpha-amino
      3-hydroxy-5-methyl-4-isoxazole propionate (AMPA; 5 microM) were measured in the
      somatic and dendritic regions of cerebellar Purkinje neurons in mature cerebellar
      control cultures (> or = 20 days in vitro) and cultures chronically treated with
      32 mM ethanol (146 mg%; 8-11 days). Recordings were made in physiological saline
      without ethanol. The mean peak amplitude of the Ca2+ signal elicited by AMPA
      (applied by brief 1-s microperfusion) in the somatic region was enhanced 38% in
      chronic ethanol-treated Purkinje neurons compared with control neurons. In
      contrast, Ca2+ signals evoked by AMPA in the dendritic region were similar in
      magnitude between control and chronic ethanol-treated Purkinje neurons. When
      tetrodotoxin (TTX; 500 nM) was included in the bath saline to block spike
      activity and synaptically-generated events, the mean peak amplitude of the Ca2+
      signal elicited by AMPA was enhanced 60% in both the somatic and dendritic
      regions of chronic ethanol-treated Purkinje neurons compared with control
      neurons. Thus, TTX-sensitive mechanisms (i.e., spike or synaptic activity) appear
      to play a role in normalizing neuronal functions involved in Ca2+ signaling in
      the chronic ethanol-treated neurons. In parallel current clamp experiments, the
      resting membrane potential of chronic ethanol-treated neurons was slightly
      depolarized compared with control neurons. However, no differences were found
      between control and chronic ethanol-treated Purkinje neurons in input resistance
      or the peak amplitude or duration of the depolarizations or hyperpolarizations
      elicited by AMPA. AMPA receptors mediate fast excitatory neurotransmission in the
      majority of neurons in the central nervous system (CNS) and Ca2+ signals in
      response to AMPA receptor activation contribute to synaptic function. Thus, our
      results suggest that modulation of Ca2+ signals to AMPA receptor activation (or
      other cellular inputs) may provide an important mechanism contributing to the
      actions of prolonged ethanol exposure in the CNS.

PMID- 10406001
TI  - Ethanol modulates AMPA-induced current responses of primary somatosensory
      cortical neurons.
AB  - This study examined the effect of ethanol on responses of primary somatosensory
      cortical neurons to AMPA. Thin (200-250 microns) brain slices were sectioned to
      include the primary somatosensory cortex of rats 6-15 days after birth. Visually
      identified neurons were selected for whole-cell patch clamp recording and an
      eight-barrel drug pipet assembly was used to deliver test agents. Ethanol (5-100
      mM) either positively or negatively modulated AMPA (100 microM)-induced current
      to varying degrees in approximately 70% of primary somatosensory cortical
      neurons. As revealed in layer V large pyramidal neurons, the outcome of an
      ethanol-induced modulation appeared to be age-dependent, the trend being one of
      potentiation in slices derived from younger rats (postnatal days 6-9) but one of
      attenuation in those derived from older animals (postnatal days 13-15). These
      findings indicate that ethanol at physiologically relevant concentrations
      modulates non-NMDA receptor-mediated responses of neurons in the rat primary
      somatosensory cortex.

PMID- 10406002
TI  - Action of ethanol on responses to nicotine from cerebellar Purkinje neurons:
      relationship to methyllycaconitine (MLA) inhibition of nicotine responses.
AB  - The effect of ethanol on responses to nicotine from rat cerebellar Purkinje
      neurons was investigated using extracellular single-unit recording. Systemic
      administration of ethanol initially enhanced the nicotine-induced inhibition from
      50% of the Purkinje neurons. However, irrespective of whether there was an
      initial enhancement, systemic administration of ethanol antagonized the response
      to nicotine from the majority of Purkinje neurons. When varying ethanol
      concentrations were electro-osmotically applied to this neuronal cell type, the
      responses to nicotine (6/8) were enhanced when a low concentration of ethanol (40
      mM) was in the pipette, whereas the majority of nicotine responses (10/11) were
      antagonized when a higher concentration of ethanol (160 mM) was applied to
      Purkinje neurons. Thus, the concentration of ethanol presented to the neuron
      seemed to explain the biphasic consequence of systemically administered ethanol
      on responses to nicotine. In order to determine whether ethanol affected a
      specific nACh receptor subtype containing the alpha-7 subunit, it was initially
      established that the nicotinic antagonists, alpha-bungarotoxin (alpha-BTX) and
      methyllycaconitine (MLA), which are associated with this subunit, had identical
      actions on responses to nicotine from Purkinje neurons. When MLA was tested
      against responses to nicotine from this cell type, MLA antagonized the response
      to nicotine from 45% (9/20) of the neurons tested. In a direct comparison of the
      action of ethanol to inhibit responses to nicotine with the action of MLA on the
      same Purkinje neuron, ethanol inhibited responses to nicotine on all neurons
      sensitive to MLA. However, ethanol also affected nicotine-induced neural changes
      from some Purkinje neurons not sensitive to MLA antagonism of nicotine. These
      data support the supposition that ethanol affects a nACh receptor subtype which
      has an alpha-7 subunit as well as other nACh receptor subtypes without this
      specific subunit.

PMID- 10406003
TI  - Clinical trials in head injury.
AB  - Secondary brain damage, following severe head injury is considered to be a major
      cause for bad outcome. Impressive reductions of the extent of brain damage in
      experimental studies have raised high expectations for cerebral neuroprotective
      treatment, in the clinic. Therefore multiple compounds were and are being
      evaluated in trials. In this review we discuss the pathomechanisms of traumatic
      brain damage, based upon their clinical importance. The role of hypothermia,
      mannitol, barbiturates, steroids, free radical scavengers, arachidonic acid
      inhibitors, calcium channel blockers, N-methyl-D-aspartate (NMDA) antagonists,
      and potassium channel blockers, will be discussed. The importance of a uniform
      strategic approach for evaluation of potentially interesting new compounds in
      clinical trials, to ameliorate outcome in patients with severe head injury, is
      proposed. To achieve this goal, two nonprofit organizations were founded: the
      European Brain Injury Consortium (EBIC) and the American Brain Injury Consortium
      (ABIC). Their aim lies in conducting better clinical trials, which incorporate
      lessons learned from previous trials, such that the succession of negative, or
      incomplete studies, as performed in previous years, will cease.

PMID- 10406004
TI  - Immunohistochemical study of insulin-like growth factor II (IGF-II) and insulin
      like growth factor binding protein-2 (IGFBP-2) in choroid plexus papilloma.
AB  - Insulin-like growth factor-II (IGF-II), a mitogen for various kinds of cells, has
      been shown to be secreted from the choroid plexus in animals. Insulin-like growth
      factor binding protein-2 (IGFBP-2), one of the six carrier proteins for IGFs, is
      also thought to be released from the choroid plexus, bind to IGF-II in the
      cerebrospinal fluid (CSF) and modulate the action of this growth factor. Little
      is known about the expression and localization of these substances in human
      choroid plexus and choroid plexus papillomas. The present immunohistochemical
      study demonstrated all six choroid plexus papillomas were positive for IGF-II,
      whereas normal choroid plexuses were negative for IGF-II. On the other hand,
      IGFBP-2 was positive in the endothelium and vascular media in the normal choroid
      plexus, while it was weakly positive in four and negative in two out of six
      choroid plexus papillomas. These results suggest that the alterations in the IGF
      II/IGFBP-2 axis might be involved in the tumorigenesis of choroid plexus
      papilloma.

PMID- 10406005
TI  - The protective effect of K+ channel openers on beta-amyloid induced
      cerebrovascular endothelial dysfunction.
AB  - Amyloid angiopathy is characterized by amyloid beta-peptide (A beta) deposition
      and may contribute to the cerebrovascular abnormalities that precede the onset of
      Alzheimer's Disease (AD). That aberrant potassium (K+) channel function occurs in
      AD patients is supported by deleterious effects of A beta on normal fibroblast K+
      channels and prevention of A beta-induced toxicity by potassium channel openers
      (KCOs) in neuronal cell culture. We report here that KCOs protect cerebral and
      peripheral vessels against the endothelial damage induced by A beta. Pressurized
      posterior cerebral artery and aortic ring segments from the rat were constricted
      and then relaxed with the endothelium-dependent vasodilator acetylcholine before
      and after incubation with A beta (10(-6) M), or pre-treatment with KCOs before
      the addition of beta-amyloid. Vessels treated with A beta exhibited features of
      endothelial dysfunction: enhanced vasoconstriction and diminished endothelium
      dependent vasodilation. Pre-treatment with KCOs significantly antagonized the A
      beta effect in both cerebral and aortic vessel segments. This protection was
      provided by both KCa and KATP channel openers. Endothelial damage by A beta and
      protection by KCOs was verified by electron microscopy. The K+ channel blocker,
      TEA, reversed the protective effect of KCO. The results suggest that potassium
      channel openers protect against A beta induced endothelial dysfunction and that
      KCOs may have a role in the treatment of degenerative cerebrovascular disease as
      seen in stroke, AD and aging.

PMID- 10406006
TI  - Monitoring of brain metabolism during aneurysm surgery using microdialysis and
      brain multiparameter sensors.
AB  - The aim of the study was to monitor brain metabolism during aneurysm clipping
      using microdialysis and multiparameter sensors, particularly to investigate the
      effects of temporary clipping of vessels. Microdialysis catheters (n = 10) and
      Paratrend brain multiparameter (O2, CO2, pH and temperature) sensors (n = 15)
      were inserted into the cerebral cortex via a specially designed triple bolt prior
      to craniotomy. Baseline brain O2 levels ranging from 15-45 mmHg (2.0-6.0 kPa) and
      glucose levels from 0.5-3 mmol l-1 were stable during uneventful periods. The
      mean lactate/pyruvate (L/P) ratio ranged from 32 to 65 (normal < 30), indicating
      a tendency towards anerobic metabolism in all patients. Overall, short periods of
      temporary clipping (< 3 min; n = 6) were well tolerated producing no significant
      reduction in brain O2 (pre-clip mean 23 mmHg (3.0 kPa) vs. post-clip mean 20 mmHg
      (2.6 kPa)) or elevation of the L/P ratio (pre-clip mean 42 vs. post-clip mean
      43). Two patients with prolonged temporary clipping showed derangements in the
      Paratrend parameters associated with increases in the L/P ratio. The results
      demonstrated that the monitored variables remained stable during uneventful
      procedures, including transient temporary clipping, but adverse events such as
      prolonged temporary clipping resulted in pronounced changes in brain metabolism.
      Monitoring of metabolism during aneurysm surgery may be of benefit in selected
      patients.

PMID- 10406007
TI  - Monitoring spinal cord motor and somatosensory evoked potentials in anesthetized
      primates.
AB  - Monitoring Motor Evoked Potential (MEP) to Transcranial Stimulation (TMS)
      monitoring (MEP) is a growing technique to assess motor function under
      anesthesia. The following primate study was conducted to analyze the non-myogenic
      spinal motor and sensory volleys and to examine their reproducibility under
      nitrous oxide-methohexidone anesthesia. The traveling periodic spinal descending
      MEP to TMS and ascending somatosensory (SEP) to posterior tibial nerve
      stimulation across the thoracic cord were recorded in 12 cynomolgus monkeys.
      Through a small T11-T12 laminotomy, an insulated stainless steel electrode was
      inserted into the epidural thoracic space. The potentials were analyzed under 50
      vol% NO in O2 with methohexital (0.1-0.2 mg kg-1 min-1). A well-defined periodic
      TMS-MEPs and PTN-SEPs were recorded with high reproducibility and consistency in
      repeated trials under N2O-methohexital anesthesia. MEP tracing consisted of an
      initial peak (direct (D) wave), occurring at 2.43 (+/- 0.28) msec followed by
      subsequent five positive (indirect (I) waves). Spinal SEPs-MEPs were clearly
      defined, morphologically stable, and consistent over time under N2O-methohexitone
      anesthesia. The present primate study may set a model to monitor both modalities
      in anesthetized neurosurgical patients.

PMID- 10406008
TI  - Analysis of phospholipase C gene in patients with subarachnoid hemorrhage due to
      ruptured intracranial saccular aneurysm.
AB  - This study is designed to determine whether patients with aneurysmal subarachnoid
      hemorrhage have mutations in the phospholipase C-delta 1 (PLC-delta 1) gene,
      which was identified as a gene responsible for hypertension in spontaneously
      hypertensive rats. Seventy-two cases (31 male and 41 female) with intracranial
      saccular aneurysms were analyzed. The mean age was 60.1 +/- 11.5 years (mean +/-
      SD) (range 24-85 years). There were 35 patients (48.6%) with hypertension, 5
      (6.9%) with diabetes mellitus, 12 (16.7%) with hyperlipidemia, 8 (11.1%) with
      ischemic heart disease, and 25 (34.7%) who were active smokers. The location of
      aneurysm was distributed as follows: 33 (33%) were at anterior cerebral artery,
      23 (23%) were at middle cerebral artery, 28 (28%) were at internal carotid
      artery, and 16 (16%) were at vertebro-basilar artery. Six patients (8.3%) had a
      family history of intracranial aneurysms. There were 20 patients (27.8%) with
      multiple aneurysms, and 8 patients (11.1%) with a large or giant aneurysm. The
      four regions of PLC-delta 1 gene (bases 1099-1271, 1254-1401, 1343-1481, and 1882
      2023) where genetic mutations were found in spontaneously hypertensive rats, were
      screened by PCR-SSCP analysis and their nucleotide sequences of all patients were
      determined. However, no mutations were detected in all patients. These results
      suggest that mutations of PLC-delta 1 gene previously implicated in hypertensive
      factor in rats may not be the case with human patients and therefore may be
      poorly related with aneurysmal subarachnoid hemorrhage.

PMID- 10406009
TI  - Ultrasound-monitored effects of acupuncture on brain and eye.
AB  - A new transcranial Doppler sonography arrangement was used to monitor blood flow
      profiles in the supratrochlear and middle cerebral arteries simultaneously and
      continuously. The technique selectively demonstrated the specific effect of
      acupuncture on the cranial arteries, in a 25-year-old female with pigmentary
      retinopathy. Stimulation of points Zanzhu and Yuyao led to a marked increase of
      blood flow velocity in the supratrochlear artery and to a decrease of flow
      velocity, in the middle cerebral artery. These acupuncture-induced effects were
      reproducible even though both arteries originate from the same major vessel.

PMID- 10406011
TI  - Metalloproteases and intracranial vascular lesions.
AB  - Recent studies have suggested that metalloproteinases (MMP) might be involved in
      the pathogenesis of cerebral aneurysm formation and rupture and that elevated
      serum levels of MMP may effectively be considered as possible markers of
      cerebrovascular malformations. The present study was planned in order to verify
      if serum levels of MMPs may be the mirror of the MMP activity in the wall of
      intracranial aneurysms, reflecting the predisposition to aneurysm development
      and/or rupture. A series of 84 patients operated for intracranial cerebrovascular
      lesions (63 aneurysms and 21 arterovenous malformations (AVM)) and 20 controls
      entered the study. Among the 63 cases of intracranial aneurysms, nine were
      discovered before rupture, while 54 patients were included after subarachnoid
      hemorrhage (SAH). Using radioimmunoassay, plasma elastase levels were measured in
      all cases, while in 25 cases, when aneurysmectomy was possible, the activity of
      elastase and collagenase were measured in aneurysm samples. Mean plasma elastase
      level in patients bearing both an intracranial aneurysm or an intracranial AVM
      was significantly higher than in controls, while there was no significant
      difference between plasmatic level of elastase in patients with aneurysms when
      compared with patients bearing an intracranial AVM; there was no significant
      difference between mean elastase level in patients who suffered SAH and patients
      bearing an intracranial unruptured aneurysm. The activity of elastase and
      collagenase measured in the aneurysm wall were significantly higher in cases of
      ruptured than in unruptured aneurysms. The present results show that plasmatic
      level of elastase does not reflect the activity of MMP as measured in the
      aneurysm wall and that the patterns of MMP activities measured in the aneurysm
      wall differ considerably at different stages of SAH. This suggests that local
      rather than systemic changes in metalloproteases activity might be involved in
      cerebral aneurysm formation and rupture.

PMID- 10406010
TI  - Nitric oxide synthase inhibitor augments post-ischemic leukocyte adhesion in the
      cerebral microcirculation in vivo.
AB  - The objective was to examine the effect of the nitric oxide synthase inhibitor, N
      omega-nitro-L-arginine methyl ester (L-NAME) on leukocyte adhesion in the
      cerebral microcirculation during reperfusion following partial forebrain ischemia
      in the rat. Intravital fluorescence video-microscopy through a closed cranial
      window was used to visualize leukocyte-endothelium interaction in small pial
      veins of 15-100 microns diameter. Forebrain ischemia was produced by the ligation
      of both common carotid arteries plus elevation of the intracranial pressure to 20
      mmHg for 60 min. The number of leukocytes adhering to the endothelium for longer
      than 3 sec was determined during ischemia (5 min and 60 min) and during
      reperfusion (5 min and 60 min). Two experimental groups were treated with either
      L-NAME or its inactive enantiomer D-NAME (20 mg kg-1 i.v.) 30 min prior to
      reperfusion. In a third group, also treated with D-NAME, post-ischemic hyperemia
      was prevented by lowering the ICP without removing the occlusion of common
      carotid arteries (partial reperfusion). The velocity of flow adjacent to the
      endothelial surface of pial veins was measured by tracking the movement of
      fluorescently labeled red blood cells as flow markers before and after ischemia.
      During ischemia, the number of adhering leukocytes increased approximately two
      fold at 5 min, and three-fold at 60 min. In the D-NAME-treated group with
      complete reperfusion, leukocyte adhesion returned to the baseline level by 60 min
      of reperfusion. However, in the L-NAME-treated group, leukocyte adhesion remained
      elevated at 60 min of reperfusion. Post-ischemic flow velocity was significantly
      decreased (-66%) from control after L-NAME treatment whereas it was increased
      (+53%) in the D-NAME-treated group. In the partial reperfusion group, leukocyte
      adhesion continued to increase after the first hour of ischemia and reached a
      level 2.7-fold over baseline at 60 min reperfusion. Flow velocity remained below
      control (-26%) at 60 min reperfusion. Leukocyte adhesion was absent in pial
      arteries and no plugging by leukocytes was observed in cortical capillaries. The
      results suggest that leukocyte adhesion in small pial veins increases during 1 h
      forebrain ischemia and continues to increase during reperfusion if the velocity
      of flow or shear rate is low. The increase in leukocyte adhesion is reversible if
      flow velocity is elevated during reperfusion. L-NAME prevents post-ischemic
      hyperemia and augments leukocyte adhesion principally via a decrease in velocity
      or shear rate.

PMID- 10406013
TI  - Neuropathology of limbic status epilepticus induced by electrical stimulation of
      naive rats.
AB  - Neuronal damage in relation to the duration of seizure was studied in limbic
      status epilepticus (SE) induced by electric stimulation of naive rats. Adult
      Sprague-Dawley rats were stimulated at the right amygdala to induce SE. To stop
      the seizures, diazepam was given to different groups of rats at 0.5 h (n = 4), 1
      h (n = 6), 2 h (n = 6), and 3-4 h (n = 8) of SE. Eighteen hours after the end of
      SE, the rats were perfusion fixed. Naive (n = 6) and sham-operated (n = 4) rats
      served as controls. Horizontal paraffin sections were stained with acid fuchsin
      and cresyl violet. Neuronal damage was absent after 30 min of SE. Status
      epilepticus of 1 h or longer duration regularly caused neuronal damage to the
      cerebral cortex, thalamus, hippocampus, amygdala, and pars reticulata of the
      substantia nigra. Damage in the cerebral cortex predominated in the entorhinal,
      temporal, and pyriform regions. In the hippocampus, the dentate hilus was most
      severely affected, followed by CA3 and CA1. Damage to the dentate granule layer
      was mild. Further studies of the pathophysiology of excitotoxicity may help to
      protect patients from sequels of status epilepticus such as neuronal damage and
      epilepsy.

PMID- 10406012
TI  - Effects of microbial invasion on cerebral hemodynamics and oxygenation monitored
      by near infrared spectroscopy in experimental Escherichia coli meningitis in the
      newborn piglet.
AB  - This study was carried out to elucidate the pathophysiologic mechanism of
      cerebral hyperemia observed during the early phase of bacterial meningitis. We
      tested the hypothesis that microbial invasion through the blood-brain barrier is
      responsible for cerebral vasodilation and hyperemia in meningitis. Escherichia
      coli was given either intravenously (i.v.) or intracisternally (i.c.) to closely
      mimic the primary or secondary bacterial invasion occurring in meningitis and
      newborn piglets were grouped according to their invasion results (+ or -); 12 in
      the i.v. (+) group, 14 in the i.v. (-) group, 13 in the i.c. (+) group, 15 in the
      i.c. (-) group. The results were compared with eight animals in the control
      group. Near infrared spectroscopy (NIRS) was employed to monitor changes in total
      hemoglobin (HbT), oxygenated hemoglobin (HbO), deoxygenated hemoglobin (Hb),
      deduced hemoglobin (HbD), and oxidized cytochrome aa3 (Cyt aa3). HbT, as an index
      of cerebral blood volume, increased progressively in both i.v. (+) and i.v. (-)
      groups and became significantly different from control and baseline values at 2
      h. Hb significantly increased only in i.v. (+) group. HbD, as an index of
      cerebral blood flow, decreased significantly in i.v. (+), i.v.(-) and i.c. (-)
      groups and this change was mitigated in i.c. (+) group, HbO was reduced in i.c. (
      ) group and this decrease was attenuated in i.c. (+) group. Increased Cyt aa3 was
      observed in all experimental groups after bacterial inoculation. Changes in ICP,
      blood pressure, cerebral perfusion pressure, blood or CSF glucose or lactate, CSF
      TNF-alpha level, or CSF leukocytes number were not associated with changes in
      NIRS findings. These findings suggest that primary or secondary bacterial
      invasion across the blood-brain barrier is primarily responsible for cerebral
      vasodilation and hyperemia observed during the early phase of bacterial
      meningitis.

PMID- 10406014
TI  - Subarachnoid blood infusion versus raised intracranial pressure: effects on the
      amino acid pattern in the extracellular fluid of the rabbit hippocampus.
AB  - In order to evaluate the role of a hemorrhage versus that of a transient increase
      in intracranial pressure in subarachnoid hemorrhage, the two components were
      induced separately in rabbits. Extracellular glutamate, sampled from the
      hippocampus with microdialysis, was used to evaluate the degree of CNS tissue
      damage. In four rabbits, autologous arterial blood was infused in the cisterna
      magna in a volume that would not affect the intracranial pressure. The other
      group of animals was infused with saline to elevate the intracranial pressure
      from 10 to > 100 mmHg. The increase of intracranial pressure per se did not
      induce significant changes in extracellular glutamate. However, 20-60 min after
      infusion of blood, a significant glutamate increase was recorded. Furthermore,
      aspartate, alanine, glycine and serine were also raised. The results indicate
      that blood in the subarachnoid space damages the brain primarily by inducing
      ischemia. Furthermore, the parameters employed gave no indication that an
      increase in intracranial pressure had a deleterious effect on CNS tissue.

PMID- 10406015
TI  - Apoptosis-inducing activity and growth suppression by vesnarinone on human glioma
      transplanted in nude mice.
AB  - The growth and morphological change of human glioma transplanted subcutaneously
      and intracerebrally to nude mice with orally administered vesnarinone, 3,4
      dihydro-6-[4-(3,4-dimethoxy-benzoyl)-1-piperazinyl]-2(1H)-quinolinon e, were
      examined. The tumor volume of human glioma xenograft, GL-9, subcutaneously
      transplanted to nude mice, was significantly decreased by orally administered
      vesnarinone at a dose of 500 mg kg-1. Vesnarinone also significantly prolonged
      the survival of nude mice transplanted intracerebrally with GL-9. Apoptosis was
      observed in paraffin sections of both subcutaneous and intracerebral GL-9 by the
      method of direct immunoperoxidase detection of digoxigenin-dUTP-labeled nick ends
      introduced by terminal deoxynucleotidyl transferase. These findings suggest that
      vesnarinone suppresses the growth and induces apoptosis of glioma cells in vivo.

PMID- 10406016
TI  - Effect of fucoidan treatment on collagenase-induced intracerebral hemorrhage in
      rats.
AB  - Inflammatory cells are postulated to mediate some of the brain damage following
      ischemic stroke. Intracerebral hemorrhage is associated with more inflammation
      than ischemic stroke. We tested the sulfated polysaccharide fucoidan, which has
      been reported to reduce inflammatory brain damage, in a rat model of
      intracerebral hemorrhage induced by injection of bacterial collagenase into the
      caudate nucleus. Rats were treated with seven day intravenous infusion of
      fucoidan (30 micrograms h-1) or vehicle. The hematoma was assessed in vivo by
      magnetic resonance imaging. Motor behavior, passive avoidance, and skilled
      forelimb function were tested repeatedly for six weeks. Fucoidan-treated rats
      exhibited evidence of impaired blood clotting and hemodilution, had larger
      hematomas, and tended to have less inflammation in the vicinity of the hematoma
      after three days. They showed significantly more rapid improvement of motor
      function in the first week following hemorrhage and better memory retention in
      the passive avoidance test. Acute white matter edema and eventual neuronal loss
      in the striatum adjacent to the hematoma did not differ between the two groups.
      Investigation of more specific anti-inflammatory agents and hemodiluting agents
      are warranted in intracerebral hemorrhage.

PMID- 10406017
TI  - Technical considerations regarding accuracy of the MKM navigation system. An
      experimental study on impact factors.
AB  - The purpose of this study was to investigate experimentally, factors determining
      the navigation accuracy of the MKM navigation system by Zeiss. The MKM consists
      of an operating microscope mounted to a six-axis motor-driven robot arm and an
      alpha-workstation. The image-guided surgery device provides navigation
      information based on calculation of the cartesian coordinates of the robot arm,
      and coordinates of the focus point assessed by laser assisted measurement.
      Navigation information (current position, direction and distance to a previously
      selected target) is optically projected into the microscopic field. Following
      factors were examined in an experimental setting for their impact on accuracy of
      the MKM: optical system, mechanical precision of the robot arm, and registration
      procedure. The robot arm and the optical system of the microscope allow high
      precision measurements of any focus point (error < 2 mm if the following aspects
      are considered: the use of auto-focus function instead of manual focusing,
      positioning of the registration points as a square or a triangle focus point
      should be selected on a surface that is perpendicular to the optical axis.

PMID- 10406018
TI  - Neuropeptide Y suppresses epileptiform activity in rat frontal cortex and
      hippocampus in vitro via different NPY receptor subtypes.
AB  - Neuropeptide Y (NPY) and different NPY receptor (Y) subtype-selective agonists
      were tested for their effects on spontaneous epileptiform discharges which
      developed in rat cortical and hippocampal slices in Mg(2+)-free medium.
      Epileptiform activity, recorded extracellularly, was attenuated by NPY (0.5-1
      microM) in both the frontal cortex and hippocampal CA3/CA1 pyramidal cell layers.
      In the cortex the Y1/5 selective agonist [Leu31 Pro34] NPY was more effective
      than the Y2 preferring agonist NPY13-36 and the Y2/5 preferring agonist NPY3-36.
      The suppression of epileptiform discharges induced by NPY in cortical slices was
      blocked by the selective Y1 receptor antagonist (R)-N2-(diphenylacetyl)-N-((4
      hydroxyphenyl)methyl] argininamide (BIBP 3226). In the hippocampus, NPY13-36 and
      NPY3-36 were more effective than [Leu31 Pro34] NPY. In conclusion, the
      antiepileptic activity of NPY is mediated predominantly by the Y1 receptor
      subtype in the frontal cortex and by Y2 and probably Y5 receptors in the
      hippocampal CA3/CA1 areas.

PMID- 10406019
TI  - Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion
      size after permanent middle cerebral artery occlusion in mice.
AB  - Protective effects after focal cerebral ischemia were assessed in transgenic mice
      that overexpress in a neuron-specific fashion mouse Bcl-XL or human Bcl-2. Both
      Bcl genes were under the control of the same mouse Thy-1 regulatory sequences
      resulting in very similar expression patterns in cortical neurons. Furthermore,
      these sequences direct lateonset (i.e. around birth) expression in brain, thus
      minimizing effects of transgene expression during brain development. Effects on
      infarct volume were measured using MRI after permanent occlusion of the middle
      cerebral artery (MCA). When compared to their non-transgenic littermates,
      Thy1mbcl-XL mice showed a significant 21% reduction in infarct size whereas
      Thy1hbcl-2 mice did not reveal any reduction. These findings suggest a selective
      protective advantage of Bcl-XL as compared with Bcl-2 in this mouse model for
      human stroke.

PMID- 10406020
TI  - Clinical relevance of age-dependent EEG signatures in the detection of neonates
      at high risk for apnea.
AB  - Age dependent EEG signatures were detected in the EEG of 71 neonates of 28-100
      weeks of conceptional age (CA). Using the new method presented, neonates were
      automatically classified in three age groups (28-35 weeks CA), (36-40 weeks CA)
      and (41-100 weeks CA). Analysis was performed employing relative distance
      functions for the complete frequency spectra of the EEG registered by electrodes
      in C3 and C4 positions. The analysis was successful in automatic identification
      of individuals showing EEG anomalies. Polysomnographic analysis demonstrated
      these to be apnea risk patients. Accordingly, a purely EEG based detection of
      neonates that are medically at risk becomes feasible.

PMID- 10406021
TI  - A role for AMPA/kainate receptors in conditioned place preference induced by
      diazepam in the rat.
AB  - There is increasing evidence for a role of glutamate receptors in the reinforcing
      properties of dependence producing drugs such as the psychostimulants and
      opiates. Activation of AMPA/kainate receptors are implicated in the acquisition
      of amphetamine-induced reinforcement but a role for this receptor in
      benzodiazepine-induced reinforcement has not been examined. In the present study
      the ability of the orally active AMPA/kainate antagonist GYKI 52466 was assessed
      for its ability to block the reinforcing properties of diazepam in a conditioned
      place preference paradigm. Diazepam (2.5 and 5.0 mg/kg, i.p.) produced a robust
      place preference and GYKI 52466 inhibited the acquisition of place preference
      conditioning-induced by diazepam. These results suggest that glutamatergic
      pathways are an important component of the circuitry involved in the acquisition
      of a benzodiazepine induced place preference.

PMID- 10406022
TI  - Gene expression of oligodendrocyte markers in human amniotic epithelial cells
      using neural cell-type-specific expression system.
AB  - We have previously reported that human amniotic epithelial (HAE) cells expressed
      neuronal and glial cell markers using immunostaining and western blotting. To
      study the expression system of these cell markers in HAE cells, we investigated
      the expression of mRNA for oligodendrocyte markers in HAE cells by reverse
      transcriptase-polymerase chain reaction (RT-PCR) and northern blotting. Neural
      cell-specific expression system was used to examine the transcriptional activity
      of myelin basic protein (MBP). Oligodendrocyte markers were expressed such as
      CNPase, MBP and proteolipid protein (PLP and DM-20). PLP gene transcripts in the
      cells were in a lower level than DM-20, compared with those of human brain.
      Neural cell-type-specific expression system disclosed HAE cells were about 20%
      positive for beta-Gal using AdexMBP-NL-LacZ. This strongly indicates that HAE
      cells have MBP-specific gene expressing cells.

PMID- 10406023
TI  - Up-regulation of somatostatin after lesions in the cerebellum of the teleost fish
      Apteronotus leptorhynchus.
AB  - Following application of mechanical lesions to the corpus cerebelli, a cerebellar
      subdivision, in adult individuals of the teleost fish Apteronotus leptorhynchus,
      the pattern of expression of the neuropeptide somatostatin was examined by
      employing immunohistochemical techniques. In the intact corpus cerebelli, only a
      very few cells displayed somatostatin-like immunoreactivity. This number
      dramatically increased in the area of the lesion within the granule cell layer 1
      day following the injury and peaked after 2 days, when the normalized total
      number of somatostatin-positive cells was approximately 50 times higher than the
      mean number of labeled cells found after 3, 6, and 12 h of survival. Between 5
      and 10 days of post-lesioning survival time, this number abruptly declined and
      returned to background levels at 17 and 25 days. Confocal microscopy revealed
      three cell types, presumably corresponding to granule cell neurons, astrocytes
      and microglia, which all displayed a similar temporal pattern of somatostatin
      expression. It is hypothesized that somatostatin is involved in regulation of the
      genesis and/or development of new neurons which are produced in response to
      injuries and which replace damaged cells at the site of the lesion.

PMID- 10406024
TI  - Alzheimer's disease-related gene expression in the brain of senescence
      accelerated mouse.
AB  - The levels of Alzheimer's disease (AD)-related genes, including beta-amyloid
      precursor protein(APP), presenilin-1 (PS-1), PS-2, apoE, tau, c-fos, neural cell
      adhesion molecular 180 (NCAM-180), TGF-beta 1, IL-1 alpha/beta, IL-6, TNF
      alpha/beta, alpha-2-Macroglobulin (alpha 2M), class II major histocompatibility
      antigen la (MHCII la), bcl-2 alpha, glucocorticoid receptor-alpha (GR alpha) and
      mineralocorticoid receptor (MR) mRNAs were determined by reverse transcription
      polymerase chain reaction (RT-PCR) in the hippocampus and cerebral cortex of
      senescence accelerated mouse (SAM). The levels of TGF-beta 1, IL-1 alpha, TNF
      beta, c-fos, NCAM-180, PS-1 and APP mRNAs were normally expressed in SAMP8
      compared with age-matched other subline that is resistant (SAMR1). The levels of
      apoE, GR alpha and MR mRNAs in the hippocampus of SAMP8, especially GR alpha,
      were evidently lower than those in the hippocampus of SAMR1. While bcl-2 alpha,
      PS-2 and tau mRNA levels of SAMP8 were significantly higher than those of SAMR1.
      Inflammatory cytokines (IL-1 beta, IL-6, TNF-alpha), alpha 2M and MHCII la
      antigen mRNAs were not detected in the brain of SAM. The differences of gene
      expression in the cerebral cortex were less evident than in the hippocampus. The
      results indicated that some genes abnormally expressed in the AD brain were also
      found in the brain of SAMP8, which may contribute to its age-related
      deterioration of learning and memory. Our results also suggested that functional
      and pathological changes which occurred in the brain of SAMP8 possessed some
      different aspects in comparison with the AD in consideration of the differences
      in gene expression.

PMID- 10406025
TI  - Antisense oligonucleotides to C-fos reduce postictal seizure susceptibility
      following fully kindled seizures in rats.
AB  - In a previous study we demonstrated that increased FOS expression in the amygdala
      induced by partial kindling seizures could be attenuated by administering c-Fos
      specific antisense oligonucleotides. In addition, we found that the
      administration of c-Fos antisense oligonucleotides at the beginning of the
      amygdala kindling process facilitated the appearance of stage V kindled seizures.
      In the present study, we evaluated the effect of the suppression of FOS on the
      expression and severity of the generalized fully kindled seizures as well as on
      the susceptibility to additional ictal events during the postictal and interictal
      periods. We observed that the administration of c-Fos antisense oligonucleotides
      did not modify the behavioral and electrographic manifestations of generalized
      stage V kindled seizures. However, c-Fos antisense oligonucleotides significantly
      reduced the susceptibility to additional ictal events during the postictal
      refractory period. Hence, the increased FOS protein induced by generalized tonic
      clonic seizures may participate in postictal mechanisms.

PMID- 10406026
TI  - Transient vasodilatory effects of adrenomedullin on cerebral parenchymal
      microvessels in cats.
AB  - We studied the effects of adrenomedullin, structural homology of calcitonin gene
      related peptide (CGRP), on the cerebral parenchymal microvessels in cats by our
      photoelectric method. Adrenomedullin significantly increased cerebral blood
      volume (CBV) at 0.5 and 1 min after intracarotid injection (0.01-1 nmol/kg,
      maximum; +0.71 vol% for 0.1 nmol/kg adrenomedullin). Adrenomedullin antagonist,
      adrenomedullin22-62 (0.01-10 nmol/kg), caused no significant changes in CBV and
      mean arterial blood pressure. Preinjection of 10 nmol/kg adrenomedullin22-52
      blocked the vasodilatory effect of 0.01 nmol/kg adrenomedullin (P < 0.05).
      Pretreatment of 1 nmol/kg CGRP8-37, which has antagonistic activity against CGRP,
      also inhibited the vasodilatation of adrenomedullin. The degree of CBV reduction
      after adrenomedullin22-52 injection was greater than that after CGRP8-37
      injection. Adrenomedullin has no major role in the maintenance of resting tone of
      intracerebral parenchymal vessels. Intravascularly administered adrenomedullin
      dilates cortical microvessels mainly through the specific adrenomedullin
      receptor.

PMID- 10406027
TI  - N-methyl-D-aspartate-evoked changes in the striatal extracellular levels of
      dopamine and its metabolites in vivo in rats with acute hepatic encephalopathy.
AB  - Acute hepatic encephalopathy (HE) is associated with disturbances in motor
      functions, but the underlying mechanisms remain obscure. Considerable
      experimental evidence suggests that motor activity is modulated by striatal
      dopamine neurons whose discharge is under glutamatergic control, mostly through
      activation of N-methyl-D-aspartate (NMDA) receptors. In this study we used
      intrastriatal microdialysis to compare the effects of infusion of 10 mM NMDA or
      50 mM KCl as a general release stimulus, on the extracellular levels of
      endogenous dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC)
      and homovanillic acid (HVA) in control rats and in rats with acute HE induced by
      repeated administration of thioacetamide. The basal levels of DA and DOPAC were
      not significantly altered by HE, while the HVA level was reduced. HE did not
      significantly affect the NMDA- or KCl-evoked increase in extracellular DA.
      Infusion of NMDA or KCl led to a decrease in extracellular DOPAC, and HE did not
      modulate these effects. However, HE attenuated the NMDA- but not the KCl-induced
      reduction in extracellular HVA. The results point to the impairment of modulation
      of striatal DA discharge and metabolism by glutamate acting at NMDA receptors,
      contributing to the motor disturbances in HE.

PMID- 10406028
TI  - Kindling induces an asymmetric enhancement of N-type Ca2+ channel density in the
      dendritic fields of the rat hippocampus.
AB  - The mechanisms underlying epilepsy are largely unknown. Recent genetic,
      pharmacological and electrophysiological data indicate a significant, but poorly
      understood, role for voltage-dependent calcium channels (VDCCs). Since the
      contribution of ion channels to nerve function depends on their cell surface
      distribution, we hypothesized that epilepsy might alter VDCC surface densities.
      To test this idea we mapped the expression and distribution of fluorescent
      labeled hippocampal N-type VDCCs (N-VDCCs) in an animal model of epilepsy,
      amygdala kindling. Image analysis demonstrated that kindling induced a 21-40%
      increase in N-VDCC expression in CA1 but not CA3. This increase occurred in the
      stratum radiatum and was twice as high in tissues contra- versus ipsi-lateral to
      the stimulating electrode. These data rationalize recent electrophysiology and
      argue that a persistent alteration in N-VDCC trafficking in dendrites or nerve
      termini may contribute to seizure-induced synaptic plasticity.

PMID- 10406029
TI  - Optical monitoring of the neural activity evoked by mechanical stimulation in the
      earthworm nervous system with a fluorescent dye, FM1-43.
AB  - In the central nervous system of the earthworm, sensory and motor neurons have
      direct synapses on three giant fibers. To determine the locations of synapses and
      neural network activated by mechanical stimuli, we optically monitored the
      activity-dependent staining in the earthworm ventral nerve cord with a styryl
      dye, N-(3-triethylammoniumpropyl)-4- (4-(dibutylamino)styryl)pyridinium dibromide
      (FM1-43), and a confocal laser scanning microscope. When scratch stimulus was
      applied to the body wall of the earthworm, bright fluorescent spots with 3-10
      microns in diameter localized only in the stimulated segmental ganglion of the
      ventral nerve cord. The fluorescent intensity of these spots decreased during dye
      free high K+ saline incubation. These results suggest that FM1-43 is useful for
      activity-dependent staining of invertebrate neurons and their synaptic regions as
      well as vertebrate nervous system.

PMID- 10406030
TI  - Epileptiform discharges induced by combined application of bicuculline and 4
      aminopyridine are resistant to standard anticonvulsants in slices of rats.
AB  - Application of 4-aminopyridine (4AP) has previously been reported to produce
      different patterns of epileptiform discharges in entorhinal cortex-hippocampal
      slices. Here we describe that 4-AP induced epileptiform activity in the EC
      becomes insensitive to anticonvulsant drugs (phenytoin, carbamazepine, valproic
      acid, phenobarbital) when GABAergic transmission is blocked by bicuculline. We
      propose that the activities induced by 4-aminopyridine and bicuculline may
      provide an in vitro model for the development of new drugs against difficult-to
      treat focal epilepsy.

PMID- 10406031
TI  - PCR-based DNA fingerprinting of Giardia duodenalis isolates using the intergenic
      rDNA spacer.
AB  - The potential for the non-coding intergenic rDNA spacer (IGS) to DNA fingerprint
      Giardia duodenalis isolates was investigated. Conserved PCR primers, specific for
      the flanking large and small rDNA genes, were used to amplify the IGS from 52 in
      vitro-cultured Giardia isolates. Four distinct IGS-PCR size groups (1.35-1.6 kb)
      were observed, which correlated closely with the major genetic assemblages
      established previously for the same isolates using isoenzyme analysis. IGS-PCR
      size groups A (1.42 kb) C (1.4 kb) and D (1.35 kb) corresponded to isoenzyme
      assemblage A, and IGS-PCR group B (1.6 kb) to isoenzyme assemblage B. Amplified
      products from IGS-PCR size groups A and B, which contained 50/52 isolates, were
      subsequently digested with 8 different restriction enzymes and their profiles
      compared. Analysis separated isolates within each IGS-PCR size group into 2
      distinct clusters which correlated almost exactly with the same genetic groups
      established previously using isoenzyme electrophoresis. Within each cluster, both
      methods exhibited a similar capacity to distinguish between Giardia genotypes
      although they established different genetic relationships between individual
      isolates. Much of the variability associated with the IGS was attributed to
      isolates harbouring multiple IGS-sequence types. Restriction analysis of IGS-PCR
      products amplified from cloned and parent lines of a human isolate BAH 39, which
      contains multiple IGS variants, showed that trophozoite populations are
      homogeneous with respect to the types of IGS-variants they maintain. Furthermore,
      in vitro culture of the cloned isolate BAH39c9 over a 6-year period also failed
      to reveal variation in IGS-PCR digestion profiles. These results suggest that IGS
      PCR RFLP profiles are inherently stable. IGS-PCR analysis was successfully
      applied to 11 Giardia cyst samples highlighting the potential for this approach
      to genotype Giardia isolates without the need for in vitro culture.

PMID- 10406032
TI  - Theileria parva ribosomal internal transcribed spacer sequences exhibit extensive
      polymorphism and mosaic evolution: application to the characterization of
      parasites from cattle and buffalo.
AB  - We sequenced the rRNA genes and internal transcribed spacers (ITS) of several
      Theileria parva isolates in an attempt to distinguish between the causative
      agents of East coast fever and Corridor disease. The small subunit (SSU) and
      large subunit (LSU) rRNA genes from a cloned T. p. lawrencei parasite were
      sequenced; the former was identical to that of T. p. parva Muguga, and there were
      minor heterogeneities in the latter. The 5.8S gene sequences of 11 T. parva
      isolates were identical, but major differences were found in the ITS. Six
      characterization oligonucleotides were designed to hybridize within the variable
      ITS1 region; 93.5% of T. p. parva isolates examined were detected by probe TPP1
      and 81.8% of T. p. lawrencei isolates were detected by TPL2 and/or TPL3a. There
      was no absolute distinction between T. p. parva and T. p. lawrencei and the
      former hybridized with fewer of the probes than did the latter. It therefore
      seems that a relatively homogenous subpopulation of T. parva has been selected in
      cattle from a more diverse gene pool in buffalo. The ITSs of both T. p. parva and
      T. p. lawrencei contained different combinations of identifiable sequence
      segments, resulting in a mosaic of segments in any one isolate, suggesting that
      the two populations undergo genetic recombination and that their gene pools are
      not completely separate.

PMID- 10406033
TI  - Small subunit rDNA phylogeny of Bacillidium sp. (Microspora, Mrazekiidae)
      infecting oligochaets.
AB  - Small subunit (SSU) rDNA has been sequenced from a microsporidium, identified as
      a member of the genus Bacillidium obtained from an oligochaete. The length of the
      amplified PCR product was 1386 bp which is currently the longest microsporidium
      SSU sequence known. Phylogenetic analysis using 28 microsporidia SSU sequences,
      using 3 different tree-building methods indicated that Bacillidium sp. may be one
      of the earliest branches on the microsporidia tree. However, bootstrapping failed
      to give a high score (more than 50%) for the position of Bacillidium sp. The
      branch leading to Bacillidium sp. was long, indicating that this species is not
      closely related to any of the other microsporidia so far studied by means of
      rDNA.

PMID- 10406034
TI  - Glutathione protects macrophages and Leishmania major against nitric oxide
      mediated cytotoxicity.
AB  - The aim of this investigation was to examine whether macrophage and Leishmania
      major glutathione were involved in either host or parasite protection against NO
      cytotoxicity. Buthionine sulfoximine (BSO), an inhibitor of gamma
      glutamylcysteine synthase, caused a complete and irreversible depletion of
      macrophage glutathione, but only a 20% and reversible decrease in L. major
      glutathione. Glutathione-depleted macrophages, when activated with IFN-gamma/LPS,
      released less than 60% of the NO produced by untreated macrophages, resulting in
      a corresponding decrease in their leishmanicidal activity. BSO-treated
      macrophages were more susceptible to the cytotoxic effects of the NO donor SNAP.
      Treatment of macrophages with 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), an
      inhibitor of glutathione reductase and trypanothione reductase or with Br-Octane,
      a glutathione-S-transferase substrate, resulted in a transient decrease in
      glutathione levels and did not increase the susceptibility of the macrophages to
      SNAP. Treatment of the promastigote forms of L. major with BCNU resulted in an
      80% decrease in total glutathione concentration with no concomitant change in
      viability. However, this treatment rendered the parasites more susceptible to
      SNAP. Finally, macrophage glutathione protected the internalized L. major from
      SNAP. Overall, these results demonstrate that glutathione is an essential
      protective component against NO cytotoxicity on both macrophages and parasites.

PMID- 10406035
TI  - Ca2+ and calmodulin-dependent protein phosphatase from Leishmania donovani.
AB  - A protein phosphatase exclusively dependent upon micromolar amounts of Ca2+ and
      calmodulin has been identified and partially purified from Leishmania spp.
      Complete obliteration of its activity is observed in the presence of calmodulin
      antagonists such as trifluoperazine, fluphenazine and calmidazolium. Relative
      insensitivity to okadaic acid and lack of activation in the absence of Ca2+ and
      calmodulin distinguishes this enzyme from PP1, PP2A and PP2C-type protein
      phosphatases. Cross-reactivity of the enzyme was observed with antibodies that
      recognize both the A and B chains of calcineurin, a PP2B type Ca2+ and calmodulin
      dependent phosphatase from brain. FK506, an immunosuppresive drug that inhibits
      the enzyme from other sources inhibited the enzyme only in the presence of
      exogenous FK binding protein, whereas Cyclosporin A inhibited the enzyme in crude
      preparations. Taken together these results reveal the presence of a Ca2+ and
      calmodulin-dependent phosphatase from Leishmania. This is the first report of the
      presence of a PP2B-type protein phosphatase from a pathogenic protozoa.

PMID- 10406036
TI  - The anti-leishmanial effect of Kalanchoe is mediated by nitric oxide
      intermediates.
AB  - We have previously shown that oral treatment with the leaf extract of the plant
      Kalanchoe pinnata (Kp) significantly decreases the lesion size and the parasite
      load in BALB/c mice infected with Leishmania amazonensis. Here we report on the
      mode of action of Kp, particularly on the induction of nitric oxide (NO)
      production by macrophages. We observed that Kp has no direct inhibitory activity
      on extracellular promastigotes, but effectively decreases the intracellular
      amastigote growth in a dose-related fashion. A 58% reduction in amastigote growth
      induced by 500 micrograms/ml Kp was associated with a 6-fold increase in the
      production of NO by the macrophages. IFN-gamma synergistically enhanced the NO
      stimulating effect of Kp in culture. Co-treatment with the inducible NO synthase
      enzyme inhibitor L-NG-monomethyl-arginine abolished the antileishmanial effect of
      Kp in vitro and in L. amazonensis-infected BALB/c mice. These results indicate
      that the protective effect of Kp in leishmaniasis may not be due to a direct
      effect on the parasite itself but rather to activation of the reactive nitrogen
      intermediates pathway of macrophages.

PMID- 10406037
TI  - Characterization, cloning and immunogenicity of antigens released by lung-stage
      larvae of Schistosoma mansoni.
AB  - Lung-stage schistosomula are the target of protective immunity in mice vaccinated
      with attenuated cercariae of Schistosoma mansoni. Therefore, proteins present at
      this developmental stage, and in particular those which are secreted, are a
      potential source of novel vaccine candidates. However, little information is
      available about such molecules. Here we describe the cDNA clones identified by
      screening expression libraries with serum raised against proteins released by
      lung-stage schistosomula. In total, 11 different cDNA species were identified, 6
      of which have been described previously in S. mansoni; these included fructose
      1,6-bisphosphate aldolase and Sm21.7 which together accounted for two-thirds of
      all positive clones. Of the 5 newly described schistosome genes, 1 cDNA had a
      high degree of homology to the s5a subunit of 26S proteasomes, most significant
      being with the human protein. The remaining 4 clones showed no significant
      homologies to any genes sequenced previously. Fructose 1,6-bisphosphate aldolase,
      Sm21.7, the proteasome homologue and 1 unknown clone (A26) have been expressed in
      a bacterial expression system and serum produced against each recombinant
      protein. Immunolocalization showed fructose 1,6-bisphosphate aldolase, Sm21.7 and
      the proteasome homologue to be most abundant in muscle cells whilst clone A26 was
      distributed throughout many tissues, but was most abundant in the tegument.
      Analysis of the cellular immune responses of vaccinated mice showed 3 of the 4
      expressed clones to be highly immunogenic, inducing the secretion of large
      quantities of the Th1-type cytokine interferon gamma.

PMID- 10406038
TI  - Compatibility of Schistosoma mansoni and Biomphalaria pfeifferi in northern
      Senegal.
AB  - The construction of the Diama dam on the Senegal River and the ensuing ecological
      changes have led to a massive outbreak of Schistosoma mansoni infection in
      Northern Senegal, associated with very high intensity of infections, due to
      extremely intense transmission. The vectorial capacity of Biomphalaria pfeifferi
      from Ndombo, near Richard-Toll was investigated in order to assess the role of
      the snail-parasite relationship in this particular epidemiological situation. The
      results revealed an unusually high compatibility between the Senegalese S.
      mansoni strain and its local snail intermediate host, B. pfeifferi. The snail
      infection rate after exposure to a single miracidium per snail was 87%. The
      cercarial production of infected snails was very high, with a mean total
      production of 50,456 cercariae per snail. No significant difference was found in
      the total cercarial output between snails exposed to 1 miracidium and those
      exposed to 5 miracidia. The increase in the rate of cercarial output was
      significantly greater in snails exposed to 5 miracidia, but there was a higher
      mortality in this group. The chronobiological cercarial production pattern showed
      a peak around mid-day. The implications of these findings on the epidemiology of
      schistosomiasis in Northern Senegal are discussed.

PMID- 10406039
TI  - Shock response induced in rat brain and spleen during primary infection with
      Trichinella spiralis larvae.
AB  - An infection approach was adopted for examining consequential heat shock (HS) or
      stress response in brain and spleen tissues from Wistar rats. Stress in this
      system was due to interactions with the infecting helminth, Trichinella spiralis,
      or its body-dwelling larval stages, or products thereof. It was argued that in
      the infection model used, elements effecting stress in the brain would differ
      from those in the spleen. HS responses were measured by quantitation of 4 levels
      of HS proteins (HSP25, HSP60, HSP70 and HSP90) with time, in infected and
      uninfected rat tissues using an assay depending on immunoblotting specifically to
      detect the separate HSPs and image analysis to measure HSP content. In brain and
      spleen tissue from uninfected rats, a continuous expression of the above HSPs was
      observed at levels which hardly varied throughout the experiment. In contrast,
      HSP25, HSP60 and HSP70 levels in infected rat tissues varied and apparently
      depended on 'infection cycle'-related events. Thus, an enhanced expression of
      HSP25 and HSP60 and of these plus HSP70 was observed at certain, yet different,
      time-points during infection in rat spleen and rat brain, respectively.
      Interestingly, HSP90 expression in spleen tissue from infected rats versus
      controls, was significantly reduced throughout the experiment suggesting some
      important (as yet undefined) role for HSP90 in the infection cycle. These studies
      seem to have provided evidence for the occurrence of soluble factors causing
      altered HSP expression at both sides of the blood-brain barrier in rats with a
      primary T. spiralis infection.

PMID- 10406040
TI  - A panel of antigens of muscle larvae of Trichinella spiralis and T.
      pseudospiralis as revealed by two-dimensional western blot and immunoelectron
      microscopy.
AB  - This study characterized antigens of Trichinella spiralis and T. pseudospiralis
      muscle larvae recognized by mice infected with the worms. Two-dimensional (2-D)
      Western blot analysis revealed some profile of antigenic peptides including: (1)
      molecular weight (MW); (2) isoelectric points (pI), (3) reactivity to well
      defined monoclonal antibodies (mAb) and (4) cross-reactivity between the 2
      species. Antigenic peptides of T. spiralis consisted of about 100 spots. The MW
      ranged from 22 to 80 kDa, and pI ranged from 4 to 7. The mAb against TSL-1
      stained most of the T. spiralis excretory-secretory (E-S) peptides migrating at
      40, 45 and 50 kDa, and the mAb against TSL-4 stained non-E-S peptides. Antigenic
      peptides of T. pseudospiralis consisted of about 20 to 30 peptide spots. The MW
      ranged from 25 to 80 kDa, and pI ranged from 4 to 7. The mAb against TSL-1
      stained most of the T. pseudospiralis E-S peptides migrating at 35 and 45 kDa,
      and the mAb against TSL-4 stained non-E-S peptides. Two-dimensional Western blots
      showed that the E-S products of T. spiralis and T. pseudospiralis were highly
      cross-reactive with each other. The non-E-S peptides were, however, not
      recognized by T. pseudospiralis-infected sera but were recognized by T. spiralis
      infected sera. An immunoelectron microscopical study showed the similar result
      that stichocyte granules and cuticle surface (known to contain E-S antigen) had
      cross-reactive antigens between the two species. T. pseudospiralis-infected sera
      stained very weakly the cuticle inner layers and haemolymph (known to contain non
      E-S antigen). This evidence implies that mice infected with T. pseudospiralis do
      not evoke antibodies against non-E-S antigen at the detectable level.

PMID- 10406041
TI  - The systemic immune response of BALB/c mice infected with larval Taenia
      crassiceps is a mixed Th1/Th2-type response.
AB  - The subsets of lymphocytes and cytokines regulating the site-specific immune
      response in experimental cysticercosis (Taenia crassiceps) are not known. This
      study investigated the cells present at the site of infection (PECs) using flow
      cytometry and measured the cytokines produced by these cells through 50 days of
      infection. The results showed an expansion of B220+CD5+, B220+CD5-, alpha beta
      TCR+CD4+ and CD8+ cells coincident with a transient increase in IL-10 production.
      After the initial increase, the percentage of B220+CD5- and helper T cells
      decreased with a concomitant decrease in IL-10 production. CD8+ T cells continued
      to increase throughout infection and gamma delta TCR+ cells increased after 10
      days of infection. PECs demonstrated an increased IFN-gamma and IL-4 production
      throughout infection when stimulated with larval antigens. Because a Th2-type
      polarization has been shown for spleen cells from infected BALB/c mice, cytokine
      profiles of spleen cells and PECs in response to ConA and larval antigens were
      compared. ConA and antigen-specific stimulation of spleen cells from 50-day
      infected mice produced increased amounts of IL-10 while PECs showed a decreased
      IL-10 production suggesting that anatomically distinct lymphoid populations
      produce different cytokines and promote different types of responses.
      Surprisingly, late in infection the levels of IL-4 and IFN-gamma in serum
      increased substantially (460-fold and 100-fold, respectively). The systemic
      immune response of BALB/c mice during experimental cysticercosis, therefore, is a
      mixed Th1/Th2-type response.

PMID- 10406042
TI  - Antibody response of carp, Cyprinus carpio to the cestode, Bothriocephalus
      acheilognathi.
AB  - The humoral antibody response and the number of pronephric antibody-secreting
      cells were examined in naturally Bothriocephalus acheilognathi-infected carp.
      Cyprinus carpio, and in those injected intraperitoneally with an extract of the
      cestode. In the extract-injected fish, specific antibody was detected 3 weeks
      after a second injection given 2 weeks after the primary injection, and antibody
      levels persisted for more than 200 days. A third injection also enhanced the
      antibody level in the extract-injected carp. The numbers of antibody-secreting
      cells were significantly higher in carp injected 3 times with the extract than in
      the control. In naturally-infected fish, the serum antibody levels and the number
      of pronephric antibody-secreting cells were higher in infected fish than in
      uninfected individuals although this difference was not statistically
      significant. The relevance of these results to immune protection against
      infection is discussed.

PMID- 10406043
TI  - All that coughs is not asthma.

PMID- 10406044
TI  - Inhaled nitric oxide, oxygen, and alkalosis: dose-response interactions in a lamb
      model of pulmonary hypertension.
AB  - Inhaled nitric oxide (NO) is currently used as an adjuvant therapy for a variety
      of pulmonary hypertensive disorders. In both animal and human studies, inhaled NO
      induces selective, dose-dependent pulmonary vasodilation. However, its potential
      interactions with other simultaneously used pulmonary vasodilator therapies have
      not been studied. Therefore, the objective of this study was to determine the
      potential dose-response interactions of inhaled NO, oxygen, and alkalosis
      therapies. Fourteen newborn lambs (age 1-6 days) were instrumented to measure
      vascular pressures and left pulmonary artery blood flow. After recovery, the
      lambs were sedated and mechanically ventilated. During steady-state pulmonary
      hypertension induced by U46619 (a thromboxane A2 mimic), the lambs were exposed
      to the following conditions: Protocol A, inhaled NO (0, 5, 40, and 80 ppm) and
      inspired oxygen concentrations (FiO2) of 0.21, 0.50, and 1.00; and Protocol B,
      inhaled NO (0, 5, 40, and 80 ppm) and arterial pH levels of 7.30, 7.40, 7.50, and
      7.60. Each condition (in randomly chosen order) was maintained for 10 min, and
      all variables were allowed to return to baseline between conditions. Inhaled NO,
      oxygen, and alkalosis produced dose-dependent decreases in mean pulmonary
      arterial pressures (P < 0.05). Systemic arterial pressure remained unchanged. At
      5 ppm of inhaled NO, alkalosis and oxygen induced further dose-dependent
      decreases in mean pulmonary arterial pressures (P < 0.05). At inhaled NO doses >
      5 ppm, alkalosis induced further dose-independent decreases in mean pulmonary
      arterial pressure, while oxygen did not. We conclude that in this animal model,
      oxygen, alkalosis, and inhaled NO induced selective, dose-dependent pulmonary
      vasodilation. However, when combined, a systemic arterial pH > 7.40 augmented
      inhaled NO-induced pulmonary vasodilation, while an FiO2 > 0.5 did not.
      Therefore, weaning high FiO2 during inhaled NO therapy should be considered,
      since it may not diminish the pulmonary vasodilating effects. Further studies are
      warranted to guide the clinical weaning strategies of these pulmonary vasodilator
      therapies.

PMID- 10406045
TI  - PEEP-induced pulmonary vasoconstriction in neonatal piglets: analysis by pressure
      flow curves.
AB  - We analyzed the effect of two levels of positive end-expiratory pressure (PEEP:
      10 and 15 cm H2O) on pulmonary hemodynamics in neonatal piglet lungs isolated in
      situ and perfused extracorporeally using pulmonary artery pressure-flow (Pa/Q)
      relationships. Pulmonary artery pressure (Pa) was measured at flow rates of 50,
      75, 100, 125, and 150 mL/kg/min. Pa/Q relationship was evaluated by the slope of
      the Pa/Q plot and the zero-flow intercept pressure (Pi). Pa/Q relationship with
      PEEP was studied before and after verapamil. Both levels of PEEP increased the
      slope of the Pa/Q plot and Pi. PEEP of 15 cm H2O resulted in a steeper slope and
      a higher Pi compared to 10 cm H2O of PEEP (P < 0.05). Verapamil abolished the
      increase in slope of the pulmonary artery Pa/Q plot but did not affect the
      increase in Pi with PEEP. The increase in Pi was equal to the increase in mean
      airway pressure. Verapamil did not affect changes in ventilatory parameters. PEEP
      increased pulmonary vascular resistance (PVR) both by increasing the Pi, which
      reflects the weighted average of the critical closing pressure, and represents a
      "Starling resistor" phenomenon, and an increase in the slope of the P-Q plot,
      reflecting an increase in pulmonary vascular tone. This response may be unique to
      the neonatal pulmonary circulation.

PMID- 10406046
TI  - Treatment of meconium aspiration syndrome with surfactant lavage in an
      experimental rabbit model.
AB  - Meconium aspiration syndrome (MAS) is a frequent cause of respiratory distress in
      term infants. Recent reports suggested that surfactant dysfunction contributes to
      the pathophysiology of MAS. In the present study, we assessed the effect of three
      different concentrations of surfactant suspensions in the lavage fluid of a
      rabbit model of MAS. Young animals were given 5 mL/kg of a 20% slurry of human
      meconium into the endotracheal tube and were then mechanically ventilated. The
      animals were divided into four groups receiving lavage fluids with either saline
      or surfactant suspensions (2.5 mg/mL, 5 mg/mL, and 10 mg/mL). Lavage was
      performed an hour after meconium instillation with one of the four solutions at
      10 mL/kg in three divided doses. After lavage, the total amount of meconium
      recovered was measured. The 10 mg/mL surfactant lavage group had the best
      improvement in gas exchange, whereas the saline group had no improvement. The
      amount of meconium recovered was the best in the 10 mg/mL surfactant group among
      the four groups studied. On histologic examination, alveolar inflammation was
      less evident in the surfactant lavage groups than in the saline lavage group. It
      was concluded that lavage with surfactant solution at a concentration of 10 mg/mL
      washed out meconium most effectively, and improved gas exchange and lung
      histology in the rabbit model of MAS more than saline lavage.

PMID- 10406047
TI  - Infant lung function after inhaled nitric oxide therapy for persistent pulmonary
      hypertension of the newborn.
AB  - Our objectives were to determine whether the use of inhaled nitric oxide (iNO)
      for severe persistent pulmonary hypertension of the newborn (PPHN) causes
      impaired lung function during infancy. We therefore performed a prospective study
      of lung function in 22 infants after neonatal intensive care unit (NICU)
      discharge who had been treated for severe persistent pulmonary hypertension of
      the newborn (PPHN) with (n = 15) or without (n = 7) iNO, and compared these
      findings in lung function to those of healthy control infants (n = 18). Five
      infants with interstitial lung disease (ILD) were included to assure that the
      pulmonary function tests (PFT) were sensitive enough to detect abnormalities of
      lung function in this age group. We measured passive respiratory mechanics and
      functional residual capacity (FRC) using a commercially available system. All
      data were expressed as means and standard deviation. Statistical analysis was
      performed by analysis of variance (ANOVA). A Bonferroni multiple comparisons test
      was used for variables that showed overall group differences. Twenty-two infants
      were studied during follow-up 4-12 months after NICU discharge. None of the
      infants were actuely ill, and only one infant was on 0.25 L of oxygen per minute
      at the time of study. We found no differences in lung function between the
      treatment groups (iNO + mechanical ventilation (MV), or MV alone), or between
      either treatment group and healthy control infants of the same age. We were able
      to detect significant differences in functional residual capacity adjusted for
      weight or height, and compliance of the respiratory system adjusted for weight or
      lung volume in the ILD infants compared to the healthy controls or infants who
      had PPHN, indicating that these PFTs were sensitive enough to determine abnormal
      lung function in this age group. We conclude that inhaled nitric oxide therapy
      for the treatment of severe PPHN does not alter lung function as determined by
      lung volume and passive respiratory mechanics measurements during early infancy.

PMID- 10406049
TI  - Outpatient exercise training in children with cystic fibrosis: physiological
      effects, perceived competence, and acceptability.
AB  - Exercise training is currently advocated as part of the treatment of patients
      with cystic fibrosis (CF). However, data are few that document physiologic
      benefits or changes in patients' perceptions of long-term training programs in
      children with CF. The aim of this study was to investigate the effects and
      acceptability of a home cycling program in children with CF. Fourteen patients (9
      boys, 5 girls) with CF, mean (SD) age 14.1 (2.0) years, with mild to moderate
      impairment of lung function (forced expiratory volume in 1 s, mean (SD) 58.3
      (16.3)% of predicted) were studied for 1 year. The first half of the study year
      was used to obtain baseline values at 0 and 6 months. During the second half of
      the year, a cycle program was carried out 5 times a week, for 20 min each day at
      a level of work that resulted in a heart rate of 140-160 beats/min. Once a week
      the cycle program was supervised by a physiotherapist. Measurements were repeated
      at 12 months. Effects of the exercise program were measured in terms of lung
      function, nutritional status, growth, muscle strength, exercise performance,
      perceived competence, and attitude towards the training program. Differences
      between the changes during the 6-month training period as compared to the 6-month
      control period were analyzed by multivariate statistics and nonparametric tests.
      Statistically significant differences (P < 0.05) between the two periods were
      found with respect to muscle strength of knee extensors and ankle dorsiflexors,
      and with respect to maximal oxygen consumption per kg body weight as well as per
      kg fat free mass. All changes were positive. No adverse effects were found.
      Perceived competence showed significant positive changes in feelings about
      physical appearance, general self-worth, and Total Perceived Competence Score.
      Scores concerning perceived acceptability of the program were significantly lower
      at the end of the training period; however, patients reported that they did want
      to continue with other sorts of training. We conclude that an exercise training
      program in the home can produce beneficial effects on oxygen consumption, muscle
      force, and perceived competence in children with CF. However, acceptability of
      the program was low, suggesting that long-term adherence would be poor, and
      hence, other sorts of training need to be identified.

PMID- 10406048
TI  - Respiratory function in children undergoing bone marrow transplantation.
AB  - We conducted a prospective study of respiratory function in children undergoing
      bone marrow transplantation (BMT) for onco-hematological disorders. Each child
      was evaluated before and 100 days after BMT. The investigations included clinical
      examination, chest X-ray, and pulmonary function tests (PFT) to determine: slow
      vital capacity (VC), functional residual capacity (FRC), total lung capacity
      (TLC), forced expiratory volume in 1 s (FEV1), carbon monoxide diffusing capacity
      (DLCO), ratio of residual volume (RV) to TLC, and FEV1/VC. The values obtained
      before and after BMT were compared to predicted values, and the post-BMT values
      were compared to the pre-BMT values (Student's t-test). From 1986 to 1995, 77
      children underwent BMT, of whom 39 were available for testing. The pre-BMT VC (P
      = 0.0234) and DLCO (P < 0.0001) were lower and FRC higher (P < 0.0001) than
      predicted values. After BMT, the VC (P = 0.004), TLC (P = 0.044), and FEV1 (P =
      0.012) were lower, and the RV/TLC ratio was higher (P = 0.043), compared with pre
      BMT data. The observed respiratory abnormalities were not clinically relevant.
      The only identifiable risk factor for a decrease in lung function was age at BMT.
      This study shows that some lung dysfunction may be present before BMT and be
      further altered by BMT. This stresses the need for longitudinal respiratory
      monitoring and follow up to detect such dysfunctions and to insure an optimal
      treatment program for these children.

PMID- 10406050
TI  - Outcome of idiopathic apparent life-threatening events: infant and mother
      perspectives.
AB  - The objective of this study was to determine the neurodevelopmental and
      temperamental outcome of infants who suffered an idiopathic apparent life
      threatening event (IALTE) and their mothers' perceptions of such an event, and to
      compare such infants with a matched group of babies hospitalized for
      nonthreatening events. Infants (N = 19) who were hospitalized at a mean age of
      2.8 months for an IALTE with no underlying disease and matched controls
      hospitalized for an acute nonthreatening illness were sequentially recruited to
      the study at a mean age of 24 months (SD, 14 months). Physical, neurological,
      developmental, and temperamental status were assessed. Mothers' stress was
      assessed by their salivary cortisol response to the physical examination of their
      infants and completion of appropriate questionnaires assessing their infants'
      temperament. The investigators were not blinded to the assignment of the infants
      to each of the study groups. Infants' perceived "difficultness" was positively
      correlated with the time interval following the event (r = 0.5, P = 0.001),
      mothers' stress as related to their child (r = 0.4, P = 0.004), and mothers'
      cortisol response (r = 0.5, P = 0.01) among the study group mothers only. IALTE
      during early infancy was associated with developmentally and neurologically
      normal outcome in infancy. We conclude that mothers of infants with IALTE
      differed in the way they perceived their infants' temperament over time, and in
      their stress response compared to mothers of a control group of hospitalized
      children who had not experienced an IALTE.

PMID- 10406051
TI  - Effect of a Soft Boston Orthosis on pulmonary mechanics in severe cerebral palsy.
AB  - Spinal braces such as the Soft Boston Orthosis (SBO) help stabilize scoliosis and
      improve sitting, positioning, and head control in individuals with cerebral
      palsy. However, their impact on pulmonary mechanics in this population has not
      been studied. We examined the effect of a Soft Boston Orthosis on the pulmonary
      mechanics and gas exchange in 12 children and young adults (5-23 years of age)
      with severe cerebral palsy. Pulmonary resistance, compliance, tidal volume,
      minute ventilation, work of breathing, oxygen saturation, and end-tidal CO2
      tension were measured with the subjects seated both with and without the orthosis
      and in the supine position without the orthosis. There were no significant
      differences in the measured parameters when comparing subjects with and without
      their orthoses in the sitting or in the supine position. As would be expected in
      individuals with severe cerebral palsy, pulmonary resistance was increased (7.33
      cm H2O/L/s) and compliance was decreased (0.12 L/cm H2O) compared to reported
      normal values. Work of breathing was greatest in the sitting position without the
      orthosis (1.2 dynes/cm), suggesting that the improved positioning achieved with
      the orthosis may decrease the work of breathing. We conclude that the application
      of a Soft Boston Orthosis does not impact negatively on pulmonary mechanics and
      gas exchange in young people with severe cerebral palsy.

PMID- 10406052
TI  - Cough, cough receptors, and asthma in children.
AB  - This review discusses current general concepts on cough and the relationship
      between cough, cough receptor sensitivity, and asthma in children. It presents
      models of the relationship between cough and bronchoconstriction, and proposes a
      new model outlining the relationship between cough receptor sensitivity, airway
      hyperresponsiveness, and the clinical issues of cough, wheeze, and dyspnea in
      children with and without asthma. Cough is very common in children, with a
      prevalence of 15-20%. Those with non-specific cough (dry cough in the absence of
      identifiable respiratory illness) are often treated with a variety of drugs, in
      particular, medications for asthma and gastroesophageal reflux. However, there is
      little evidence to use these medications for the sole symptom of cough in
      children. Clinical studies on cough need to be interpreted in light of inherent
      methodological problems in studying cough. These methodological problems include
      the nonrepeatable nature of questions on cough, the unreliability of subjective
      measurements of cough, the lack of objective measurements to quantify cough
      severity, and the period effect (spontaneous resolution of cough). Although cough
      can be troublesome, cough serves as an important function for maintaining normal
      health of the respiratory system. The importance of cough in maintaining
      respiratory health is reflected in the development of lung atelactasis/collapse
      from retained secretions and recurrent pneumonia in clinical situations where the
      cough reflex is ineffective. The cough reflex is complex and still poorly
      understood. In this article the simplified cough pathway is presented and
      involves cough receptors, mediators of sensory nerves and the afferent pathway,
      the vagus nerve, the cough centre, efferent pathway, and cough effectors.

PMID- 10406053
TI  - Third International Consensus statement on the management of childhood asthma.

PMID- 10406054
TI  - Molecular markers as prognostic factors for local recurrence and radioresistance
      in head and neck squamous cell carcinoma.
AB  - Squamous cell carcinoma of the head and neck affects more than 500,000 people
      worldwide each year. Local-regional recurrence of disease is a common and
      challenging oncological problem in patients affected by this disease.
      Identification of risk factors for local relapse after appropriate local therapy
      with surgery, radiation, or combination therapy remains an active area of
      clinical research. The recent development of novel molecular markers has resulted
      in numerous studies evaluating the prognostic significance and potential clinical
      utility of these markers in identifying patients at risk for local-regional
      relapse. This article reviews recent studies evaluating molecular markers,
      including p53, angiogenesis-related markers, cyclin D1, epidermal growth factor
      receptor, loss of heterozygosity, DNA ploidy, and cell kinetic markers. The
      potential clinical utility of these markers and future directions along this
      avenue of investigation are discussed.

PMID- 10406055
TI  - NF kappa B activity and target gene expression in the rat brain after one and two
      exposures to ionizing radiation.
AB  - The central nervous system injury that can result after radiotherapy has been
      suggested to involve induced gene expression and cytokine production. We have
      previously shown that irradiation of primary cultures of rat astrocytes results
      in the activation of NF kappa B. To determine whether such an effect also occurs
      in vivo, NF kappa B activity was analyzed in the cerebral cortex of the rat brain
      after whole body irradiation. After a single dose of 15 Gy, NF kappa B activity
      was increased by 2 h postirradiation, returning to unirradiated levels by 8
      hours. The increase was dose-dependent beginning at 2 Gy and continuing to at
      least 22.5 Gy. NF kappa B activity in the irradiated cortex was not accompanied
      by I kappa B alpha degradation. When 7.5 Gy was delivered 24 h before the 15 Gy,
      the increase in NF kappa B activity after 15 Gy was significantly reduced. These
      results suggest that an initial exposure to radiation induced a refractory period
      in the brain during which the susceptibility of NF kappa B to activation by
      subsequent irradiation was significantly reduced. This period of reduced
      sensitivity to radiation was also apparent for the induction of the NF kappa B
      regulated cytokines IL-1 beta, IL-6, and TNF alpha.

PMID- 10406056
TI  - Evaluation of cross-resistance between responses to cisplatin, hyperthermia, and
      radiation in human glioma cells and eight clones selected for cisplatin
      resistance.
AB  - Human glioma cells were exposed to stepwise increasing concentrations of
      cisplatin and given a final, acute, high concentration treatment of cisplatin.
      From the surviving cells, eight cisplatin resistant clones were selected. These
      clones demonstrated a range of cisplatin sensitivities that were retained in the
      absence of cisplatin when cells were continually passaged. These cells were
      tested for cross-resistance to radiation and hyperthermia at 42 and 45 degrees C.
      The data showed that seven of the eight clones were also more radioresistant than
      the parental line, while one was more radiosensitive. The degree of cisplatin
      resistance was not related to the degree of radiation resistance. For
      hyperthermia at 42 and 45 degrees C, some of the clones were slightly more
      resistant than the parental line, while one clone was much more sensitive. This
      was not the same clone that was radiosensitive. In conclusion, there was no
      direct correlation between cisplatin resistance, radiation resistance, and
      hyperthermia response, although some of the clones were resistant to all three
      treatments.

PMID- 10406057
TI  - Radiobiological characterization of two human chemotherapy-resistant intermediate
      grade non-Hodgkin's lymphoma cell lines.
AB  - Intermediate grade non-Hodgkin's lymphoma (IGNHL) is generally considered a
      radiosensitive tumor that can be controlled with moderate radiation doses. Cell
      survival curves of cell lines derived from IGNHL have been typically described to
      exhibit small or no shoulder, implying inability to accumulate or repair
      sublethal radiation damage. We characterize in this report the clonogenic
      radiation survival curves of two human IGNHL cell lines, WSU-DLCL2 and SK-DHL2B,
      established from patients who expired after having exhibited chemotherapy
      resistance of their tumors. The cells were irradiated with 60Co radiation at a
      dose rate of 85-100 cGy/min and cell survival data were analyzed according to the
      linear quadratic model. The alpha/beta values for WSU-DLCL2 and SK-DHL2B cells
      are 2 and 8.6, respectively. The corresponding SF2 are 0.42 and 0.35,
      respectively. Both cell lines are able to repair radiation-induced sublethal
      damage. These data indicate that these cells are only moderately radiosensitive.

PMID- 10406058
TI  - Comparison of the effectiveness of tirapazamine and carbogen with nicotinamide in
      enhancing the response of a human tumor xenograft to fractionated irradiation.
AB  - The goal of this study was to compare, with a human tumor xenograft, two
      different strategies for increasing tumor response to fractionated irradiation,
      namely, oxygenating the hypoxic tumor cells with carbogen and nicotinamide, or
      killing these cells with the hypoxic cytotoxin, tirapazamine (TPZ). We used the
      human hypopharyngeal squamous cell carcinoma cell line FaDu implanted in immune
      deficient SCID mice and assessed its response to radiation by cell survival and
      by growth delay. The tumors were irradiated either once or twice daily with 2 or
      2.5 Gy/fraction with either TPZ (0.08 mmol/kg) or nicotinamide (1,000 mg/kg) with
      carbogen breathing. We also tested the effect of giving TPZ on alternate days, or
      daily during the first half of the course, the second half, or for the whole
      course of radiation. We found that adding TPZ or nicotinamide with carbogen to
      the fractionated radiation regimen enhanced the response of the human xenograft.
      The enhancement was somewhat greater (though not significantly so) for TPZ,
      especially when given with each radiation dose. In conclusion, adding TPZ, or
      nicotinamide plus carbogen, to fractionated irradiation enhanced the response of
      this human tumor xenograft to fractionated irradiation. Consistent with
      theoretical modeling, there was a greater enhancement of the radiation response
      of the tumor when TPZ was given with each radiation dose than when given with
      only half of the radiation doses.

PMID- 10406059
TI  - Clinical efficacy of applying four-field portals to paraaortic irradiation in the
      treatment of cervical carcinoma.
AB  - Paraaortic nodal irradiation (PAI) was thought to be useful in the treatment of
      cervical cancer, but its clinical application has been limited by a relatively
      high morbidity. To reduce this morbidity, we routinely applied the four-field
      technique in PAI. To clarify its efficacy, clinical data were retrospectively
      analyzed. Ninety-seven patients with cervical cancer, who received a minimum 40
      Gy of paraaortic irradiation between 1976 and 1994, were enrolled in the
      analysis. The patients were prescribed PAI using four-field portals with 10 MV
      photons (mean 50.4 Gy, range 40-70 Gy). The 5-year cause-specific survival rate
      was 32.2%. As for sequelae determined using the French-Italian glossary, G1a/G2a
      of stomach and duodenum developed in 26.8/1.0%, G2b of small bowel in 3.1%, G1b
      of nonspecific abdominal symptoms and/or signs in 12.4%, and G2 of bone in 3.1%.
      The operative history group had a slightly larger incidence of gastrointestinal
      complications than those without operative history, but the difference was not
      statistically significant. Application of four-field portals in PAI was useful,
      with acceptably low toxicity and successful compliance for moderate-to-high dose
      irradiation. This suggests that PAI may greatly contribute to the improvement of
      the therapeutic outcome of cervical carcinoma.

PMID- 10406060
TI  - Prospective study of fatigue in localized prostate cancer patients undergoing
      radiotherapy.
AB  - The objectives were to (1) prospectively evaluate fatigue utilizing validated
      instruments in patients with localized prostate cancer, and (2) examine the
      relationships between fatigue, depression, quality of life, and sleep
      disturbance. The instruments used included: Piper Fatigue Scale, Beck Depression
      Inventory, Epworth Sleepiness Scale, and Functional Assessment of Cancer Therapy
      for Prostate Scale. Data on cancer stage, prostate specific antigen levels,
      hematocrit, patient's body weight and radiation dosage were recorded. Patients
      were evaluated preradiotherapy, middle of radiotherapy, completion of
      radiotherapy, and at 4-5 weeks follow-up. Thirty-six veterans with localized
      prostate cancer were studied. Mean age was 66.9 years (range 55-79). Duration of
      treatment was 7-8 weeks. Univariate procedure and Wilcoxon Signed Rank-test were
      used to examine changes in pretreatment scores for each of the three subsequent
      study periods. To adjust for multiple comparisons Bonferroni test was used.
      Spearman Correlations were calculated among parameters. No significant changes
      were noted in mean scores of hematocrit and body weight during the study period.
      On the Piper Fatigue Scale, adjusted for multiple comparisons, the median scores
      were significantly higher at completion of radiotherapy as compared with
      preradiotherapy values. Three patients (8%) were experienced fatigue according to
      Piper Fatigue Scale before treatment as compared to nine patients (25%) at
      completion of radiotherapy. On Prostate Cancer Specific and Physical Well Being
      subscales of the Functional Assessment for Prostate Cancer Therapy, the scores
      were significantly lower at middle and completion of radiotherapy than at
      pretreatment. At preradiotherapy, middle of radiotherapy, completion of
      radiotherapy and follow-up evaluation, patients scoring higher on the Piper
      Fatigue Scale were more likely to report a poorer quality of Physical Well Being
      on Functional Assessment of Cancer Therapy for Prostates. No significant changes
      were noted in the Beck Depression Inventory and Epworth Sleepiness Scale scores
      during treatment. Eight patients scored 10 or more on the Beck Depression
      Inventory before starting radiotherapy, suggesting depressive symptomatology. Of
      these, only seven patients scored 10 or more at completion of treatment. The
      incidence of fatigue is lower in our study than in previously published data. A
      relationship exists between fatigue scores and physical well being subscale
      scores. Higher scores on the Piper Fatigue Scale at the completion of
      radiotherapy, as well as no changes on depression and sleepiness scales, suggest
      that fatigue may not be the result of depression or sleep disturbance. Based upon
      our previous work, we propose that the physical expression of fatigue may be
      secondary to a decline in neuromuscular efficiency and enhanced muscle fatigue.

PMID- 10406061
TI  - Value of radiation therapy in the management of chemoresistant intermediate grade
      non-Hodgkin's lymphoma.
AB  - The purpose of this study was to evaluate the probability and extent of response
      to radiation therapy in patients with chemotherapy-resistant intermediate grade
      non-Hodgkin's lymphoma. Thirty-five patients with chemotherapy-resistant non
      Hodgkin's lymphoma received local radiation therapy after initial treatment with
      at least six cycles of systemic chemotherapy. There were 17 men and 18 women in
      our study. Ages ranged from 15 to 68 years, median age was 42 years. Chemotherapy
      resistance was defined as relapse after initial chemotherapy (11 patients) or
      failure to achieve complete remission (partial response in 18 patients, stable
      disease in 1 patient, and disease progression in 5 patients). Radiation doses
      were between 1,980-5,040 cGy (median dose of 3,200 cGy). Treatment outcome was
      evaluated with respect to any subsequent relapse either within or outside the
      irradiated region. The 2-year actuarial survival was 65%. The cumulative
      incidence of isolated local failure and any local failure at 2 years were 33% and
      54%, respectively. Tumors that responded to initial chemotherapy had a better
      local control probability than tumors that did not respond. The 2-year actuarial
      local failure rates for these two groups were 51% and 83%, respectively (P =
      0.01). There was a trend for improved local control with radiation doses > or =
      3,960 cGy, suggesting the presence of a dose-control relationship. The rate of
      disease progression within an irradiated region in patients with intermediate
      grade non-Hodgkin's lymphoma that relapsed after or failed to respond completely
      to full course chemotherapy was substantially higher than the historical in-field
      failure rates when radiation therapy was used as the sole modality of treatment.
      Prior response to initial chemotherapy was a predicting factor for local control
      following radiation therapy.

PMID- 10406062
TI  - The history of angioplasty therapy for acute myocardial infarction: buried alive
      but still kicking?
AB  - Angioplasty therapy for acute myocardial infarction (direct or primary coronary
      angioplasty) has been a hot issue of the medical literature since 1982. It was
      first presented as a rescue therapy in the case of failed intracoronary
      thrombolysis. Later it was described as a useful complement to thrombolysis
      before it emerged as a formidable alternative. For a number of years in the late
      1980s, the advent of clot-specific intravenous thrombolysis swayed the spotlight
      from direct angioplasty on to the non-invasive active drug treatment. This was
      reversed by the appearance of several randomized studies demonstrating
      superiority of angioplasty in 1992. Later studies have put this advantage of
      angioplasty over thrombolysis in perspective again. It was found that the
      superior results of the randomized studies on selected patients could not be
      reproduced in everyday cases. Nonetheless, a small but significant advantage of
      primary angioplasty remains when all available literature is scrutinized
      carefully. Even if the results in terms of mortality and acute events during the
      initial hospital stay are quite comparable for thrombolysis and primary
      angioplasty, the latter removes the culprit clot, treats the underlying lesion,
      and informs about the general state of the coronary vasculature and the
      myocardium with unsurpassed details. Moreover, most patients with intravenous
      thrombolysis will undergo cardiac catheterization within the first year after
      their infarction. Thus, the facts that the initial savings of foregoing cardiac
      catheterization is lost and the cost of the thrombolytic drug can be spared with
      primary angioplasty may tilt the scale in favour of primary catheter
      intervention. As direct angioplasty establishes patency earlier and more
      completely than thrombolysis, a slightly better hospital course and markedly
      better long-term course with improved longevity, myocardial function, and fewer
      cardiac events can be achieved. This is not necessarily associated with a higher
      investment, because the initial surplus in cost of primary angioplasty tends to
      revert into savings over time. All patients amenable to direct angioplasty within
      30-60 min after initial diagnosis should be offered the procedure. In the
      remaining cases, thrombolysis is the preferred treatment. The role of primary
      angioplasty is the more important the larger the infarction. However, in small
      infarctions but also in protracted cardiogenic shock it may be wasted, but so is
      any other aggressive treatment.

PMID- 10406063
TI  - What an interventional cardiologist should know about the pathophysiology of
      acute myocardial infarction.
AB  - Basic knowledge of the sequence of cellular events that change the relative
      benign disease coronary atherosclerosis into a life-threatening acute coronary
      syndrome is of great importance for the interventional cardiologist in order to
      understand and choose the correct pharmacological and interventional management
      in patients with acute myocardial infarction. Plaque disruption, or fissuring,
      with superimposed thrombosis frequently complicates the course of coronary
      atherosclerosis. Small ruptures often remain clinically silent, whereas more
      extensive plaque rupture may lead to the development of unstable angina, acute
      myocardial infarction, and sudden cardiac death. The risk of plaque disruption
      depends more on plaque composition than on plaque size and stenosis severity.
      Major determinants of a plaque's vulnerability to rupture are: the size and
      consistency of the lipid-rich atheromatous core, the thickness of the fibrous cap
      covering the core, and inflammation and repair within the cap. The elevation of
      fibrinogen and C-reactive protein in patients with unstable angina may be markers
      of ongoing plaque inflammation. Both plaque vulnerability and rupture triggers
      are important for plaque disruption. The resultant thrombotic response, which is
      important for the clinical presentation and outcome, is in part determined by the
      reactivity of the circulating platelets and the balance between the fibrinolytic
      and coagulation systems. New ways of identification and treatment of the
      dangerous vulnerable plaques responsible for infarction and death and
      optimization of anti-thrombotic treatment are highly warranted in order to
      prevent and treat life-threatening coronary thrombosis.

PMID- 10406064
TI  - What an interventional cardiologist should know about the pharmacological
      treatment of acute myocardial infarction.
AB  - The treatment of acute myocardial infarction consists of pain and anxiety relief,
      anti-ischaemic treatment and antithrombotic therapy. Due to its bleeding
      complications and, in some cases, procoagulant effects, antithrombotic therapy
      has consequences for coronary procedures in the setting of acute myocardial
      infarction. Antiplatelet therapy has no procoagulant effects, and its bleeding
      complications can easily be managed. Antithrombin therapy has rebound effects,
      for which no clear solution is available. Thrombolytic therapy has also
      procoagulant effects, which may interfere with coronary procedures in the early
      hours of acute myocardial infarction. Heparin may counteract the thrombolysis
      induced thrombin generation, but has an unpredictable effect. Postprocedural
      therapy after angioplasty in the setting of acute myocardial infarction should
      consist of antiplatelet therapy.

PMID- 10406065
TI  - Primary mechanical reperfusion in acute myocardial infarction: the United States
      experience.
AB  - Achievement of infarct-related artery (IRA) patency with thrombolytic agents has
      improved the clinical outcome of patients with acute myocardial infarction (MI).
      Primary angioplasty (PTCA) for direct IRA reperfusion may further improve patient
      outcome by overcoming several limitations of thrombolytic therapy, e.g. by
      decreasing the risk of haemorrhagic stroke, increasing the achievement of brisk
      antegrade flow, decreasing the risk of IRA reocclusion, and allowing early
      identification of patients who need surgical revascularization. In the PAMI-1
      randomized trial, primary PTCA was superior to thrombolytic therapy. The GUSTO
      IIb angioplasty substudy supported the same conclusion but with a narrower margin
      of benefit from PTCA. In order to further improve the outcome of primary
      mechanical reperfusion, routine intra-aortic balloon pump (IABP) insertion in
      high-risk MI patients and primary stenting have been evaluated. In PAMI-2, there
      was no major clinical benefit in routine IABP insertion during primary PTCA in
      high-risk patients. In contrast, primary stenting appears to offer significant
      advantages over PTCA, especially by decreasing the need for subsequent IRA
      revascularization procedures as shown in the recent PAMI Stent Randomized Trial.
      Adjunctive pharmacotherapy with potent antiplatelet agents in acute MI is being
      evaluated both in combination with thrombolytic therapy, and with primary PTCA
      and stenting. Finally, meaningful consideration of cost-effectiveness and health
      policy guidelines is warranted to optimize the appropriate management of MI
      patients in the current era, given the increasingly complex and expensive
      therapeutic strategies available.

PMID- 10406066
TI  - The emerging role of stenting for acute myocardial infarction.
AB  - Although the benefits of primary angioplasty for acute myocardial infarction have
      been demonstrated, several areas for improvement remain. The initial results of
      randomized trials have shown that primary stenting for acute myocardial
      infarction is feasible and effective with a low complication rate. Primary
      stenting results in a reduction in recurrent infarction and in the need for
      subsequent re-intervention, when compared to balloon angioplasty. Whether long
      term clinical and angiographic outcome is also favourable has yet to be confirmed
      in large-scale multicentre trials, before primary stenting can be adopted as
      routine approach for acute myocardial infarction.

PMID- 10406067
TI  - The German experience with primary angioplasty.
AB  - From July 1994 to October 1998, 4280 primary PTCA procedures were entered into
      the registry of the Arbeitsgemeinschaft Leitender Kardiologischer
      Krankenhausarzte. The success rate of PTCA, as defined by TIMI-3 perfusion of the
      infarct-related artery was 87.1%, in-hospital mortality was 10.2% and 2.6% had
      reinfarction. The most powerful predictors of death were cardiogenic shock
      present in 14.6% of whom 47% died, and failed PTCA with a mortality of 32%.
      Stents were used in 4.1% in 1994 increasing to 64.5% in 1998 without significant
      changes in success rates, but associated with a slight decrease in mortality and
      reinfarction rates.

PMID- 10406068
TI  - Experiences with primary angioplasty without on site-cardiac surgery.
AB  - Growing evidence suggests that primary angioplasty is superior to thrombolysis
      for the treatment of acute myocardial infarction, in particular in some high-risk
      subsets. The performance of primary angioplasty in centres without on-site
      cardiac surgery may extend the availability of this effective reperfusion
      therapy. This will benefit in particular those patients who would not be treated
      otherwise. Optimal primary angioplasty requires a high level of logistic
      organization, operator expertise, and commitment of the whole team. The outcome
      does not depend on the presence or absence of surgeons on site. In fact,
      feasibility, safety and efficacy of primary angioplasty are similar in both types
      of centres when high standards of care are guaranteed.

PMID- 10406069
TI  - Primary angioplasty for acute myocardial infarction: the Zwolle approach.
AB  - Timely restoration of antegrade coronary blood flow by primary angioplasty of the
      infarct-related vessel of a patient with an acute myocardial infarction results
      in myocardial salvage and improved survival. The main issues pertinent to the
      delivery of primary angioplasty therapy are discussed, and the 'Zwolle approach'
      is described with regard to the prehospital phase, the first 15 min in-hospital,
      pharmacological therapy, angiography and angioplasty, risk stratification,
      rehabilitation and secondary prevention.

PMID- 10406070
TI  - Implications of decidualization-associated protease expression in implantation
      and menstruation.
AB  - During progesterone-induced decidualization of estradiol (E2)-primed human
      endometrial stromal cells (HESCs), the interstitial-type extracellular matrix
      (ECM) of the follicular phase endometrium is transformed in the luteal phase to a
      mixture of residual interstitial- and new basal laminar-type components. This
      transformation is accelerated by reduced proteolytic activity of HESCs undergoing
      decidualization (DZ). In cultured HESCs, progestins, but not E2, induce the
      expression of several DZ markers, and E2 enhances these effects despite the lack
      of response to E2 alone. Using this well-characterized in vitro DZ model we
      evaluated the expression of plasminogen activators (PAs), which degrade ECM
      components that undergo rapid turnover, and matrix metalloproteinases (MMPs),
      which degrade the bulk of ECM components. Medroxyprogesterone acetate (MPA)
      inhibited the catalytic activity of urokinase-type PA (uPA) and tissue-type PA
      (tPA) as well as the expression of such MMPs as interstitial collagenase (MMP-1)
      and stromelysin-1 (MMP-3). Moreover, E2 + MPA elicited greater inhibitory effects
      on the expression of all of these proteases. Progestin inhibition of PA
      activities reflected reciprocal upregulation in the output of the PA inhibitor
      PAI-1, which produced large molar excesses of PAI-1 compared with the PAs in HESC
      conditioned medium. By contrast, the tissue inhibitor of the MMPs, TIMP1, as well
      as gelatinase A (MMP-2), was constitutively expressed by the HESCs. In the
      absence of implantation, menstruation-associated degradation of the functional
      endometrial ECM is triggered by withdrawal of circulating ovarian steroids. This
      process was evaluated in cultured HESCs that were first decidualized during 10
      days of exposure to E2 + MPA, and then withdrawn to steroid-free medium with and
      without the antiprogestin RU 486. As expected, steroid withdrawal reversed
      progestin-inhibited PA activity as well as the expression of MMP-1 and MMP-3 and
      progestin-enhanced PAI-1; much greater reversal was observed in medium
      supplemented with RU 486. Unlike the changes in PAI-1, neither TIMP1, nor MMP-2
      expression was affected by withdrawal to steroid-free or to RU 486-medium. By
      altering the composition of the ECM of the luteal phase endometrium, progestin
      elicited inhibition of the PAs, uPA and tPA, as well as that of the MMPs, MMP-1
      and MMP-3, modulates trophoblast adhesion, migration and differentiation.
      Conversely, steroid withdrawal elicited increases in uPA, MMP-1 and MMP-3
      activities would promote endometrial sloughing by degrading the mixture of
      decidual cell-derived basement membrane-like proteins and interstitial components
      that comprise the stromal ECM of the perimenstrual endometrium.

PMID- 10406071
TI  - Roles of the insulinlike growth factor family in nonpregnant human endometrium
      and at the decidual: trophoblast interface.
AB  - The insulinlike growth factor (IGF) family is believed to be important in
      endometrial development during the menstrual cycle and in the process of
      implantation. The mitogenic, differentiative, and antiapoptotic properties of the
      IGFs and their binding proteins, as well as their spatial and temporal expression
      in cycling endometrium, suggest that they may participate in endometrial growth,
      differentiation, apoptosis, and perhaps angiogenesis. IGFBP proteases, which
      increase IGF bioavailability, have been localized to endometrial stromal cells
      and to the human cytotrophoblast and likely play important roles in endometrial,
      decidual, and trophoblast physiology. IGFBP-1 is a major protein product of
      nonpregnant endometrium during the mid-late secretory phase and occurs in
      abundance in decidua. Its roles as an IGF-binding protein and as a trophoblast
      integrin ligand suggest that it may have multiple roles in endometrial
      development and in interactions between the decidua and the invading trophoblast.
      Recent evidence suggests that it may have a role in the process of shallow
      implantation in the clinical disorder of preclampsia. In contrast to knowledge
      about the roles of IGF peptides, IGFBP proteases, and IGFBPs in normal
      endometrial development and early human pregnancy, little information is
      available regarding this family in abnormal endometrial development, in occult
      endometrial defects, and in uterine receptivity and nonreceptivity.

PMID- 10406072
TI  - Prolactin and its receptor in human endometrium.
AB  - Synthesis of prolactin (PRL) in human endometrium extends from the late luteal
      phase of the menstrual cycle throughout the pregnancy. We have studied the
      hormonal requirements for the sustained production of PRL and its receptor (PRL
      R) in a long-term primary cell culture system. Progestin stimulates the
      production PRL and its receptor when stromal cells transform into decidual cells.
      The rise in PRL production rate correlates with an increase in steady-state PRL
      mRNA levels which are caused by increased transcription rate gene. Replacing
      progestin by the antiprogestin, RU 486, causes a transient superinduction of PRL
      production followed by reduction to basal level of expression. On the other hand,
      RU 486 exerts immediate inhibition of PRL-receptor mRNA expression. In addition,
      relaxin (RLX) enhances PRL synthesis. The transcription of the PRL gene in
      endometrium is dependent upon the promotor 6-kb upstream of the transcription
      start site in the pituitary. That biological functions of PRL and its receptor
      are critical to implantation and the maintenance of pregnancy is suggested by the
      impaired fertility of PRL and PRL-R knockout mice. PRL enhances endometrial cell
      growth at low concentrations and inhibits it at high concentrations. This dual
      action indicates an autocrine action of PRL-R-mediated signaling transduction
      pathways during reproductive cycles and pregnancy. During gestation, decidual
      derived prolactin regulates the volume of amniotic and fetal extracellular fluid
      and electrolytes.

PMID- 10406073
TI  - Paracrinology of endometrial neuropeptides: corticotropin-releasing hormone and
      opioids.
AB  - Human endometrium possesses remarkable secretory properties and the
      characteristics of a neuroendocrine organ. Epithelial cells of human endometrium
      express the corticotropin-releasing hormone (CRH) and opioid peptide precursors
      genes (i.e., proopiomelanocortin, proenkephalin, and prodynorphin) and their end
      products. Endometrial neuropeptides are under the control of ovarian steroid
      hormones and locally produced prostanoids and cytokines. Additionally,
      neuropeptides participate in local paracrine regulatory loops, facilitating
      communication between endometrial epithelial and stromal cells as well as the
      interaction between endometrial and myometrial cells. In view of the
      proinflammatory cytokine properties of CRH, we postulate that endometrial CRH may
      participate in intrauterine inflammatory and vascular processes associated with
      stromal cell decidualization and blastocyst implantation. Additionally, given the
      myorelaxant actions of opioids these endometrial neuropeptides may participate in
      the control of myometrial contractility.

PMID- 10406074
TI  - The role of placental Fas ligand in maintaining immune privilege at maternal
      fetal interfaces.
AB  - It is now recognized that immunosuppressive factors synthesized by placenta may
      play a critical role in the maintenance of pregnancy. Over the last several years
      our group and others have formulated a hypothesis that trophoblast Fas ligand
      (FasL) plays an important role in maintaining fetal immune privilege in human
      pregnancy by actively promoting apoptosis (programmed cell death) of activated
      maternal lymphocytes bearing Fas (i.e., the FasL receptor). This review initially
      provides background information and updates aspects of the Fas/FasL signaling
      system, including the role of caspases and molecules recruited to the Fasl/Fas
      signaling complex and the revised functions ascribed to membrane and soluble
      forms of FasL. Information is then presented concerning the role of FasL at
      immune-privileged sites including the eye and testis. Pathways through which the
      placenta and tumors avoid may avoid immune clearance vis-a-vis the FasL/Fas
      signaling cascade are described. A model is then presented through which FasL
      production by human syncytiotrophoblasts and extravillous trophoblasts may
      protect the fetus against the cytolytic actions of activated Fas-bearing maternal
      lymphocytes in the intervillous space and in the placental bed, respectively. We
      conclude with a review of studies in support this model that specifically
      demonstrate trophoblast expression of FasL and identify potential lymphocyte
      targets (i.e., Fas-expressing maternal immune cells) of trophoblast FasL.

PMID- 10406075
TI  - The decidua regulates hemostasis in human endometrium.
AB  - Survival of the implanting human blastocyst requires that trophoblasts gain
      access to the maternal circulation. This is initially achieved when
      syncytiotrophoblasts breach endometrial capillarlies and venules. Subsequently,
      extravillous cytotrophoblasts penetrate the spiral arteries to induce their
      morphological transformation into high-flow, low-resistance vessels. This process
      provides the embryo with a requisite source of oxygen and nutrients, but risks
      decidual hemorrhage leading to abortion and abruption. Endovascular trophoblast
      invasion occurs within a matrix of decidualizing endometrial stromal cells. These
      decidual cells are temporally and spatially positioned to create a local
      hemostatic milieu which can counteract the threat of hemorrhage. Prior studies
      from our laboratory have established that decidual cells of luteal phase and
      pregnant endometrium express two crucial modulators of hemostasis: 1) tissue
      factor (TF), the primary initiator of hemostasis via factor Xa activation; and 2)
      plasminogen activator inhibitor type 1 (PAI-1), the fast inhibitor of the primary
      fibrinolytic agent, tissue type plasminogen activator. This coordinate increase
      in TF and PAI-1 expression provides a mechanism by which decidual cells control
      local hemostasis during endovascular trophoblast invasion. Cultures of human
      endometrial stromal cells and decidual cells isolated from first trimester
      endometrium demonstrate that progestins enhance TF and PAI-1 protein and mRNA
      expression via the induction of crucial intermediate transcription factors.
      Integration of these in vivo observations and in vitro studies suggest a model by
      which decidua acts to maintain hemostasis during implantation and placentation.

PMID- 10406076
TI  - Expression of 11 beta-hydroxysteroid dehydrogenase in early pregnancy:
      implications in human trophoblast-endometrial interactions.
AB  - Glucocorticoid hormone action in target tissues is modulated by 11 beta
      hydroxysteroid dehydrogenase (11 beta-HSD), which interconverts active cortisol
      and corticosterone and their inert 11-keto metabolites, cortisone and 11
      dehydrocorticosterone. Two different 11 beta-HSD isoforms exist: a low-affinity
      NADP-dependent dehydrogenase/oxoreductase (11 beta-HSD1) and a high-affinity NAD
      dependent dehydrogenase (11 beta-HSD2). This brief review describes the
      expression and distribution of 11 beta-HSD isoforms in human placenta. In
      particular, it discusses the results of studies dealing with the expression of 11
      beta-HSD activity in experimental models representative of the fetomaternal
      interface in the early gestation. The findings have implications in terms of
      protection of the fetus against corticosteroid toxicity and modulation of active
      glucocorticoid levels and their biological effects in early pregnancy.

PMID- 10406077
TI  - Decidual and vascular pathophysiology in pregnancy compromise.

PMID- 10406078
TI  - Loss of growth regulation by transforming growth factor-beta (TGF-beta) in human
      cancers: studies on endometrial carcinoma.
AB  - Members of the Transforming Growth Factor-beta (TGF-beta) family are one of the
      few endogenous inhibitors of cell growth. As uncontrolled cellular proliferation
      is a hallmark of cancer, an important question to address is how cancer cells
      escape normal growth regulatory mechanisms to become malignant. In this context,
      components of the TGF-beta growth response pathway are considered to be tumor
      suppressor genes, as absence of one or more of TGF-beta receptor and signaling
      proteins cause loss of cell growth regulation through an inability to regulate
      proteins that directly block cells in G1 phase of the cell cycle. Endometrial
      carcinoma (ECA) provides an excellent paradigm to study the changes that
      accompany loss of TGF-beta-mediated growth, control as a function of neoplastic
      development, since it is generally preceded by complex hyperplasia. Type 1 ECA is
      characterized as an estrogen-induced cancer, which responds well to progestin
      therapy. Since it has become increasingly evident that steroids can regulate
      growth through growth factors, ECA is also an ideal model for investigating the
      role for gonadal steroids in the loss of TGF-beta growth regulation in the
      etiopathogenesis of ECA. Thus, hormonal carcinogenesis adds another level of
      complexity in studying loss of growth regulation in human cancers. The purpose of
      this review is to 1) provide the most current background information on how TGF
      beta functions including its activation, receptors, signal transduction
      mechanisms, and control of the cell cycle. 2) present recent information that
      shows how malignant cells subvert the growth inhibitory effects of TGF-beta by
      incurring defects in every aspect of the pathway that mediates the TGF-beta
      growth inhibitory response, and 3) describe the putative role for TGF-beta in the
      oncogenesis of ECA, provided primarily by the results from our laboratory.
      Understanding the molecular events involved in TGF-beta function in normal cells
      and its lack of function in tumor cells should identify novel therapeutic targets
      in human cancers.

PMID- 10406079
TI  - Structure and function of cultured endometrial epithelial cells.
AB  - Uterine endometrial epithelial cells undergo profound changes in structure and
      function in preparation for blastocyst implantation. The dynamics of this process
      for human endometrium can be studied only in cell culture. Primary cell cultures
      started from tissue removed at varying times during the cycle retain some aspects
      of differentiation as manifest in regulated protein synthesis. Differentiation of
      endometrial, epithelial cell lines will occur when culture conditions are varied.
      Domes, gland-like structures, polarized sheets and spheroids can be produced.
      Studying the process of differentiation in vitro should provide information about
      differentiation in vivo, particularly about how changing protein synthesis
      accompanies changing cell structure. Endometrial epithelial cells in culture can
      also be manipulated to allow study of steroid agonism and antagonism, cancer,
      menses and regeneration and endometriosis.

PMID- 10406080
TI  - Models for the study of uterine receptivity for blastocyst implantation.
AB  - A variety of models have been developed to study endometrial receptivity which
      involves normal, appropriately timed endometrial development and remodeling for
      blastocyst attachment and trophoblast invasion during the luteal phase of the
      menstrual cycle. Due to species differences, the human is by far the best model
      per se by which to study human endometrial receptivity. Techniques have evolved
      to obtain in vivo data on endometrial receptivity using hysteroscopy,
      ultrasonography or magnetic resonance imaging. Despite species differences,
      comparative studies of mammalian models and tissue- and cell culture models using
      endometrial tissue or cells harvested at particular phases of the reproductive
      cycle, or following experimental manipulation, have been used productively to
      study endometrial function. Differences as well as similarities have proven to be
      instructive. Such models have been used to study a variety of entities, such as
      homotypic and heterotypic cell-cell interaction, the role of steroids, cytokines,
      growth factors, immunomodulatory agents and pharmacological substances. These
      models have also been used to study cellular, biochemical and molecular
      mechanisms involved with uterine receptivity. This chapter was designed to
      provide a critical review of contemporary literature relating to in vivo models
      and laboratory strategies and paradigms for the study of uterine receptivity for
      blastocyst implantation.

PMID- 10406081
TI  - Effects of prolonged iron loading in the rat using both parenteral and dietary
      routes.
AB  - Female Porton rats have been treated with either parenteral iron (intraperitoneal
      red cells) or dietary iron (carbonyl iron) for up to 12 months or 22 months
      respectively. In the parenteral iron loaded animals, the liver iron concentration
      rose from approximately 2 mg g-1 dry wt at 2 months to 21 mg g-1 dry wt at 12
      months, while for the dietary iron loaded animals, this value rose from 14 to 48
      mg g-1 dry wt at 12 months to over 60 mg g-1 dry wt after 22 months. In contrast,
      splenic iron concentrations rose more in the parenterally loaded animals (up to
      66 mg g-1 dry wt after 12 months) than in the dietary loaded animals (approx. 34
      mg g-1 dry wt after 24 months). This study yielded hepatic iron concentrations
      comparable to those seen in human thalassaemia patients with comparative low
      hepatotoxicity. Splenic iron concentrations in the parenteral iron loaded group
      generally exceeded those reported in thalassaemia. Iron concentrations derived
      from computer assisted morphometry of liver iron deposits correlated well (r =
      0.88, p < 0.001) with chemical analysis data. The fraction of iron in the non
      parenchymal cells correlated positively with the duration of iron loading (r =
      0.86, p < 0.001).

PMID- 10406082
TI  - Apoptosis and p53 gene expression in male reproductive tissues of cadmium exposed
      rats.
AB  - Reverse transcription (RT) PCR technique was used to investigate the mechanism of
      apoptosis induced by Cd and the change of its related genes in testes and
      prostate of rats. Adult male rats were given a single (s.c.) injection of CdCl2
      0, 2.5, 5.0, 10 mumol/kg. 48 h and 72 h after administration of Cd, animals were
      sacrificed. The results indicated that Cd can induce apoptosis in testes via p53
      independent pathway. No apoptosis occurred in prostate in any of the Cd-exposed
      groups. There was a clearly negative relationship in testes between p53 gene
      expression and Cd exposure and this dose-response relationship was observed both
      at 48 h and 72 h. There was a very small increase of this gene expression in the
      dorsolateral lobe of the prostate in Cd exposed groups. The other apoptosis
      related gene, bcl-x, was not detectable in either control or Cd-exposed group in
      testes and dorsal prostate. Although the MT-I gene was expressed in testes or
      dorsal prostate both in control and exposed groups, no overexpression of MT-I
      gene was found after administration of Cd. The expression of MT-I in the ventral
      prostate was not detected in the control group, but a weak expression was found
      after Cd exposure. Since p53 is a tumor suppressor gene which can inhibit
      tumorigenesis, the consequence of a Cd-induced decrease of p53 in testes may have
      a relation to the known risk of Cd tumorigenesis in this tissue.

PMID- 10406083
TI  - Oxidation of arsenite to arsenate by a bacterium isolated from an aquatic
      environment.
AB  - Arsenic is ubiquitous in the biosphere and frequently reported to be an
      environmental pollutant. Global cycling of arsenic is affected by microorganisms.
      This paper describes a new bacterial strain which is able to efficiently oxidize
      arsenite (As[III]) into arsenate (As[V]) in liquid medium. The rate of the
      transformation depends on the cell density. Arsenic species were separated by
      high performance liquid chromatography (HPLC) and quantified by inductively
      coupled plasma-atomic emission spectrometry (ICP-AES). The strain also exhibits
      high minimum inhibitory concentrations (MICs) for As[III] (6.65 mM (500 mg L-1))
      and other heavy metals, such as cadmium (1.42 mM (160 mg L-1)) or lead (1.20 mM
      (250 mg L-1)). Partial identification of the strain revealed a
      chemoorganotrophic, Gram-negative and motile rod. The results presented here
      demonstrate that this strain could represent a good candidate for arsenic
      remediation in heavily polluted sites.

PMID- 10406084
TI  - Synthesis and activity of p-azidobenzoyloxyferricrocin, a photoactivatable analog
      of ferrichrome.
AB  - p-azidobenzoyloxy desferriferricrocin (AF) 2, a photoactivatable analog of
      ferrichrome, was prepared by selective acylation of the serine group of
      ferricrocin 1 in two steps: transesterification of ferricrocin followed by
      demetallation. A model compound, (L) 2-benzyloxycarbonylamino-3-p-azidobenzoyloxy
      N-isopropyl propionamide 8, was separately synthesized in order to set up optimal
      transesterification conditions to avoid alpha, beta-elimination or epimerization
      of serine. Binding of iron-loaded AF (FeAF) to the FhuA outer membrane receptor
      protein of Escherichia coli AB2847 was demonstrated by inhibition of ferrichrome
      transport, interference with the infection by the bacteriophage phi 80 and with
      killing of cells by albomycin and colicin M. FeAF transported iron only weakly
      which indicates that the photoaffinity moiety is incompatible with transport or
      intracellular iron release from the siderophore.

PMID- 10406085
TI  - Lack of acute zinc effects in glucose metabolism in healthy and insulin-dependent
      diabetes mellitus patients.
AB  - Acute or chronic zinc administration may cause hyperglycemia in experimental
      animals. These findings are attributed to permissive actions of glucocorticoids
      and glucagon upon hepatic gluconeogenesis and glycogenolysis. The effect of
      Zn(+)+ on plasma glucose, C-peptide, glucagon, and cortisol was investigated in
      healthy and insulin-dependent diabetes mellitus (IDDM) patients. Ten normal
      individuals (5 of each sex, aged 24.10 +/- 1.96) and 10 IDDM (5 of each sex, aged
      25.20 +/- 8.10) were tested at 7:00 AM after 12-h fast. Twenty-five mg of Zn(+)+
      were administered intravenously during 1 min, and blood samples were collected
      from the contralateral arm at 0, 3, 30, 60, 90 and 120 min after Zn(+)+
      injection. The plasma levels of glucose, C-peptide, and glucagon remained
      constant throughout the experimental period in both groups studied. Plasma
      cortisol levels decreased significantly, which is consistent with our previous
      findings. These results suggest that, in contrast to experimental animals, acute
      Zn(+)+ administration, despite decreasing cortisol levels, does not change
      carbohydrate metabolism in human beings.

PMID- 10406086
TI  - Subcellular distribution of metallothionein and cadmium in the liver and kidneys
      of bank voles (Clethrionomys glareolus) exposed to dietary cadmium.
AB  - Metallothionein (MT) and cadmium (Cd) contents were determined in the subcellular
      fractions of the liver and kidneys of bank voles exposed for 6 weeks to elevated
      levels of dietary Cd-40 and 80 micrograms g-1 dry weight. Hepatic and renal MT
      was detected exclusively in the cytosol, while Cd was found in the cytosol (73
      79% of the total content), nuclei (14-18%) and particulates (4-9%). The
      concentration of MT in the cytosol as well as Cd content in the particular
      subcellular fractions appeared to be a dose-dependent. The absence of MT in the
      nuclear and particulate fractions implied that Cd present in these compartments
      was not bound to the protein that is considered to provide protection against the
      toxic metal. Therefore, it is assumed that this component of intracellular Cd
      could be responsible for the histopathological changes that occurred in the liver
      (granuloma and focal hepatocyte swelling) and kidneys (focal degeneration of
      proximal tubules) of bank voles exposed to the higher level of dietary Cd.

PMID- 10406087
TI  - Intestinal absorption of copper from drinking water containing fulvic acids and
      an infant formula mixture studied in a suckling rat model.
AB  - The purpose of this study was to investigate if the intestinal absorption of
      copper in drinking water is altered in the presence of complexing agents from a
      fulvic acid mixture and an infant formula powder. Ten to twelve day old rat pups
      were given a single oral dose of radio-labeled Cu in deionized water (0.93 mg
      Cu/l), in water containing fulvic acids (10 mg/l), in infant formula mixed with
      deionized water, or in infant formula mixed with water containing fulvic acids.
      Six hours after dosage, radioactive Cu was analyzed in the mucosa of the small
      intestine, the liver and the remaining carcass (excluding the liver and
      gastrointestinal tract) by gamma counting. Dialysis and centrifugation
      experiments showed that Cu was complexed by components in the fulvic acid and
      formula mixtures, although the presence of fulvic acids in the water did not
      alter the Cu fractionation in the formula. The fractional Cu uptake (% of dose)
      from the intestinal lumen to the mucosa was not markedly changed by the presence
      of the chelating agents. However, the retention of Cu in the intestinal mucosa
      was increased by both fulvic acids and formula. Concomitantly, the absorption
      rate of Cd to the circulatory system was decreased. No interactive effect between
      fulvic acids and formula was found on the Cu absorption. These findings indicate
      that the water quality may be an important determinant of the rate of intestinal
      Cu absorption from drinking water. Moreover, in the future risk assessment of
      copper in drinking water, the possibility of alterations in absorption of
      drinking-water Cu has to be considered when the drinking water is used for
      cooking.

PMID- 10406088
TI  - The molecular biology of Schwanniomyces occidentalis klocker.
AB  - This review describes the molecular studies of Schwanniomyces occidentalis
      (Debaryomyces occidentalis) concerning transformation, genome, gene cloning, gene
      structure, gene expression and its characteristics to application. Schw.
      occidentalis appears to have at least five or seven chromosomes and no native
      plasmid from the yeast has been reported. Four transformation systems based on
      complement of Schw. occidentalis auxotrophic mutants were established. Vectors
      with the replicon of 2-micron plasmid and autonomous replication sequences (ARS)
      of Saccharomyces cerevisiae and Schw. occidentalis ARS replicated
      extrachromosomally in Schw. occidentalis transformants, without modification of
      the transformed vector DNA. So far, at least 21 Schw. occidentalis genes encoding
      14 different proteins have been cloned. Most of the Schw. occidentalis genes have
      shown homologies (45 to 91%) with the corresponding genes of other organisms,
      especially of S. cerevisiae. However, some Schw. occidentalis genes possess other
      unique structures for their operators, promoters, transcription initiation sites,
      and terminators. Some foreign genes were expressed in Schw. occidentalis, while
      Schw. occidentalis genes functioned in other yeasts and bacteria, Escherichia
      coli, and Streptomyces lividans. Due to a strong ability of secretion and low
      level of glycosylation, Schw. occidentalis might be a promising host to produce
      heterologous proteins.

PMID- 10406089
TI  - Insect pheromones--an overview of biosynthesis and endocrine regulation.
AB  - This overview describes, compares, and attempts to unify major themes related to
      the biosynthetic pathways and endocrine regulation of insect pheromone
      production. Rather than developing and dedicating an entirely unique set of
      enzymes for pheromone biosynthesis, insects appear to have evolved to add one or
      a few tissue-specific auxiliary or modified enzymes that transform the products
      of "normal" metabolism to pheromone compounds of high stereochemical and
      quantitative specificity. This general understanding is derived from research on
      model species from one exopterygote insect order (Blattodea) and three
      endopterygote insect orders (Coleoptera, Diptera, and Lepidoptera). For instance,
      the ketone hydrocarbon contact sex pheromone of the female German cockroach,
      Blattella germanica, derives its origins from fatty acid biosynthesis, arising
      from elongation of a methyl-branched fatty acyl-CoA moiety followed by
      decarboxylation, hydroxylation, and oxidation. Coleopteran sex and aggregation
      pheromones also arise from modifications of fatty acid biosynthesis or other
      biosynthetic pathways, such as the isoprenoid pathway (e.g. Cucujidae,
      Curculionidae, and Scolytidae), or from simple transformations of amino acids or
      other highly elaborated host precursors (e.g. Scarabaeidae and Scolytidae). Like
      the sex pheromone of B. germanica, female-produced dipteran (e.g. Drosophilidae
      and Muscidae) sex pheromone components originate from elongation of fatty acyl
      CoA moieties followed by loss of the carbonyl carbon and the formation of the
      corresponding hydrocarbon. Female-produced lepidopteran sex pheromones are also
      derived from fatty acids, but many moths utilize a species-specific combination
      of desaturation and chain-shortening reactions followed by reductive modification
      of the carbonyl carbon. Carbon skeletons derived from amino acids can also be
      used as chain initiating units and elongated to lepidopteran pheromones by this
      pathway (e.g. Arctiidae and Noctuidae). Insects utilize at least three hormonal
      messengers to regulate pheromone biosynthesis. Blattodean and coleopteran
      pheromone production is induced by juvenile hormone III (JH III). In the female
      common house fly, Musca domestica, and possibly other species of Diptera, it
      appears that during hydrocarbon sex pheromone biosynthesis, ovarian-produced
      ecdysteroids regulate synthesis by affecting the activities of one or more fatty
      acyl-CoA elongation enzyme(s) (elongases). Lepidopteran sex pheromone
      biosynthesis is often mediated by a 33 or 34 amino acid pheromone biosynthesis
      activating neuropeptide (PBAN) through alteration of enzyme activities at one or
      more steps prior to or during fatty acid synthesis or during modification of the
      carbonyl group. Although a molecular level understanding of the regulation of
      insect pheromone biosynthesis is in its infancy, in the male California
      fivespined ips, Ips paraconfusus (Coleoptera: Scolytidae), JH III acts at the
      transcriptional level by increasing the abundance of mRNA for 3-hydroxy-3
      methylglutaryl-CoA reductase, a key enzyme in de novo isoprenoid aggregation
      pheromone biosynthesis.

PMID- 10406090
TI  - Identification of surface molecules on salivary glands of the mosquito, Aedes
      aegypti, by a panel of monoclonal antibodies.
AB  - Malaria transmission by the mosquito vector requires sporozoite invasion into
      mosquito salivary glands. Parasites probably enter the glands by specific
      receptor-ligand interactions with molecules on the surface of the glands. We have
      undertaken the characterization of salivary gland surface molecules of Aedes
      aegypti to identify candidate receptors for Plasmodium gallinaceum sporozoite
      invasion. Monoclonal antibodies (mAbs) were generated against antigen enriched
      for salivary gland membranes and basal lamina. A panel of 44 mAbs were generated
      that bound to surface molecules of mosquito tissues. Twenty-four mAbs bound
      exclusively to salivary glands, six bound to salivary glands and ovaries, one
      bound to salivary gland and midgut, and 13 bound to all tissues tested. We
      present data on the immunolocalization and biochemical characteristics of the
      antigens. Many of the salivary gland-specific mAbs bound preferentially to the
      median and distal lateral lobes of the salivary glands, indicating that there are
      anatomical region-specific biochemical differences on the gland surface. These
      lobes of the salivary glands are the preferential sites of malaria sporozoite
      invasion. Therefore, antigens specific for these regions are promising candidate
      receptors for sporozoite invasion. The present identification of surface
      molecules of mosquito salivary glands by means of monoclonal antibodies
      represents the first description of individual molecules on the mosquito salivary
      gland surface. This work lays the basis for further studies on the molecular
      mechanisms involved in malaria sporozoite invasion of mosquito salivary glands.

PMID- 10406091
TI  - Cloning and complete sequence characterization of two gypsy moth aminopeptidase-N
      cDNAs, including the receptor for Bacillus thuringiensis Cry1Ac toxin.
AB  - The complete cDNAs corresponding to two distinct gypsy moth (Lymantria dispar)
      larval gut aminopeptidases, APN1 and lambda APN2, were cloned and sequenced. The
      3.4 kilobasepair cDNA of APN1 which encodes a 1017 amino acid prepro-protein
      corresponds to the previously-identified gypsy moth APN (APN-1) that specifically
      binds the Cry1Ac delta-endotoxin of Bacillus thuringiensis. Analysis of the
      primary structure of APN1 revealed a cluster of five potential N-linked
      glycosylation sites near the N-terminus and a C-terminal sequence characteristic
      of a putative glycosylphosphatidyl-inositol (GPI) anchor signal sequence. The
      cDNA of APN1 encodes the N-terminal peptide sequence and nine internal sequences
      obtained from the purified brush border membrane vesicle Cry1Ac receptor by
      protein sequencing. The lambda APN2 cDNA encodes a shorter protein with 51%
      similarity to APN1 that also appears to have a GPI anchor signal sequence.
      Expression of the APN1 cDNA in a baculovirus vector was confirmed by
      immunoblotting.

PMID- 10406093
TI  - Can the insect nervous system synthesize ecdysteroids?
AB  - The term "neurosteroid" refers to both classic and unique steroid molecules that
      are synthesized from cholesterol (C) by the central and peripheral nervous
      systems of higher vertebrates. Therein, they accumulate and modulate nervous
      activity by a variety of mechanisms other than the classic steroid receptor
      mediated modulation of genomic activity, although such may also be involved.
      Since the insect nervous system expresses ecdysteroid receptors and responds both
      directly and developmentally to ecdysteroids, the possibility of
      ecdysteroidogenesis in the pupal and adult central and peripheral nervous system
      of Manduca sexta and the nervous system of Drosophila melanogaster larvae was
      investigated. The endogenous concentrations of the critical, dietary-derived
      delta 5,7-sterols ergosterol and 7-dehydrocholesterol (7dC) remained 10 to 20
      fold higher in the Manduca pupal and adult nervous tissues than was found in the
      larval hemolymph at the cessation of feeding. In addition, it was determined that
      the Manduca pupal nervous system, but not that of the adult, could synthesize
      3H/14C-7dC or 3H-7-dehydro-25-hydroxycholesterol (3H-7d25C) from 3H/14C
      cholesterol (3H/14C-C) or the polar sterol substrate 3H-25-hydroxycholesterol (3H
      25C), respectively. However, none of the nervous system samples from the two
      species and the several stages analyzed, a small window of neural development in
      these insects, were capable of incorporating any of the above tracer precursor
      sterols into a radiolabelled ecdysteroid, i.e. less than 0.0005%. Thus, the
      absence of neurosteroidogenesis by the insect nervous system stands in sharp
      contrast to previously described nervous system steroid hormone biosynthesis by
      the mammalian nervous system.

PMID- 10406092
TI  - Molecular cloning of a gut-specific chitinase cDNA from the beetle Phaedon
      cochleariae.
AB  - A cDNA encoding a chitinase of Pheadon cochleariae was isolated from a larval gut
      library. The cDNA encodes a preenzyme with a putative 20 amino-acid signal
      peptide and a 385 amino-acid mature enzyme of calculated mass of 42.7 kDa. Amino
      acid alignment shows 24-33% identity to other insect and crustacea chitinases.
      The sequence lacks C-terminus domains but active site residues are conserved.
      Northern analysis localizes the mRNA to guts of feeding larvae. Southern blot
      analysis, with a complete cDNA probe, suggests that the P. cochleariae genome may
      contain several chitinase genes. Activity gels show that two groups of chitinases
      are expressed in the insect. One group comprises chitinases of 30-40 kDa that are
      active at pH 5.0 and detected in guts of feeding larvae and adults, as well as in
      pre-pupae and pupae. The other group comprises chitinases of 40-70 kDa that are
      more active at pH 7.0 and are mainly expressed in pre-pupae and pupae. The
      biological significance of both groups of chitinases is discussed.

PMID- 10406094
TI  - A bacterial single-chain Fv antibody fragment that inhibits binding of its
      parental anti-E-selectin monoclonal antibody to activated human endothelial
      cells.
AB  - Using the polymerase chain reaction, we cloned, modified, and linked antibody
      variable (V) region coding genes from a mouse hybridoma, and produced a bacterial
      single-chain Fv (scFv) antibody fragment specific for E-Selectin. A vector of
      pBR322 origin, bearing the tryptophan promoter and the ompA bacterial signal
      peptide, was used to direct scFv expression to periplasm. The vector included a
      six-histidine coding sequence 5' to the scFv for the purification of the
      expressed protein using immobilized metal affinity chromatography (IMAC). We
      found that the VH-Linker-VL 32-33 kDa scFv remained insoluble after cellular
      fractionation, and transmission electron microscopy showed the new protein to be
      present in the periplasm as inclusion bodies. The scFv was solubilized using
      urea, purified using IMAC, and renatured to its active form. In a competitive
      enzyme-linked immunosorbent assay with activated human vein endothelial cells in
      the solid phase, the scFv competed for binding with the original monoclonal
      antibody.

PMID- 10406095
TI  - High cytoplasmic expression in E. coli, purification, and in vitro refolding of a
      single chain Fv antibody fragment against the hepatitis B surface antigen.
AB  - A single-chain Fv (scFv) antibody fragment against the hepatitis B surface
      antigen (HBsAg) was expressed in Escherichia coli in the form of two independent
      fusion proteins, with either 60 ('long') or 27 ('short') amino acid N-terminal
      encoding sequences related to human interleukin-2. Both fusion proteins were
      expressed insolubly and at high levels in the bacterial cytoplasm (approximately
      30% of total bacterial protein in MM294 cells at a laboratory scale). When
      recombinant cells were cultured in 5-1 fermentors, expression and optical density
      increased 2- and 4-fold, respectively, compared to a previous periplasmic
      insoluble version of the same anti HBsAg scFv. After extraction and
      solubilization in urea, the cytoplasmic scFvs were purified using immobilized
      metal ion affinity chromatography, followed by DTT treatment, and refolding by
      dialysis against a basic pH buffer containing EDTA. The refolded scFvs recognized
      the recombinant HBsAg in ELISA. Results of an ELISA where antigen affinity
      chromatography repurified scFvs were used as standards, indicated that refolding
      efficiencies were high: 56.2% for the 'short' fusion scFv, and 50.6% for the
      'long' fusion scFv. Corrected final yields of active scFv were 30.3 and 27.3 mg l
      1, respectively, for the aforementioned fusion proteins, 5-6 times better than
      those reported for the periplasmic scFv variant.

PMID- 10406097
TI  - Production of O-acetylated and sulfated chitooligosaccharides by recombinant
      Escherichia coli strains harboring different combinations of nod genes.
AB  - High cell density cultivation of recombinant Escherichia coli strains harboring
      the nodBC genes (encoding chitooligosaccharide synthase and chitooligosaccharide
      N-deacetylase, respectively) from Azorhizobium caulinodans has been previously
      described as a practical method for the preparation of gram-scale quantities of
      penta-N-acetyl-chitopentaose and tetra-N-acetylchitopentaose (Samain, E.,
      Drouillard, S., Heyraud, A., Driguez, H., Geremia, R.A., 1997. Carbohydr. Res.
      30, 235-242). We have now extended this method to the production of sulfated and
      O-acetylated derivatives of these two compounds by coexpressing nodC or nodBC
      with nodH and/or nodL that encode chitooligosaccharide sulfotransferase and
      chitooligosaccharide O-acetyltransferase, respectively. In addition, these
      substituted chitooligosaccharides were also obtained as tetramers by using nodC
      from Rhizobium meliloti instead of nodC from A. caulinodans. These compounds
      should be useful precursors for the preparation of Nod factor analogues by
      chemical modification.

PMID- 10406098
TI  - Expression and characterization of chimeric hepatitis B surface antigen particles
      carrying preS epitopes.
AB  - Many studies have provided evidence that hepatitis B surface antigen (HBsAg)
      including preS1 and preS2 sequences could be an ideal candidate for a new
      hepatitis B virus (HBV) vaccine with higher efficacy. However, the large (L)
      protein containing the entire preS region expressed in mammalian cells is not
      efficiently assembled into particles and secreted. Here we report an alternative
      approach to include the dominant epitopes of preS1 and preS2 to the small (S)
      protein as fusion proteins by the recombinant DNA technology. Three fusion
      proteins containing preS2(120-146) and preS1(21-47) at the N-terminus and/or
      truncated C-terminus of S protein were expressed using the recombinant vaccinia
      virus system. All these fusion proteins were efficiently secreted in the
      particulate form, and displayed S, preS1 and/or preS2 antigenicity. Further
      analysis showed that these chimeric HBsAg particles elicited strong antibody
      responses against S, preS1 and preS2 antigens in BALB/c mice, suggesting that
      they could be promising candidates for a new recombinant vaccine to induce
      broader antibody response required for protection against hepatitis B viral
      infection.

PMID- 10406099
TI  - A novel gene encoding a sulfur-regulated outer membrane protein in Thiobacillus
      ferrooxidans.
AB  - Thiobacillus ferrooxidans is a Gram-negative chemolithotrophic bacterium able to
      oxidize ferrous iron, elemental sulfur and inorganic sulfur compounds. The
      oxidation of sulfur by T. ferrooxidans resulted in an expression of some outer
      membrane proteins (OMPs) at a level higher than that observed during ferrous iron
      oxidation. Among these OMPs, a protein with a molecular mass of 54 kDa was
      purified and 18 amino acids of the N-terminal sequence determined. Using a 54 bp
      PCR generated DNA product as a probe for the protein, we isolated a 4.5 kb Pst I
      DNA chromosomal fragment containing the corresponding gene. Sequencing 2169 bp of
      this fragment revealed the open reading frame codifying for the protein,
      consisting of 467 amino acids and a molecular mass of 49,674 Da. The mature
      protein was produced by the removal of a 32 amino acid signal peptide-like
      sequence from the N-terminus of a 499 amino acid peptide. Although no significant
      homology with any known protein has been found and its physiological role remains
      unclear, its high expression on sulfur substrates suggests a role in sulfide
      mineral oxidation.

PMID- 10406100
TI  - Bacterial xylanase expression in mammalian cells and transgenic mice.
AB  - The energy which simple-stomached livestock can derive from dietary plant
      material is limited by the lack of plant polysaccharide degrading enzymes in
      their gastro-intestinal (GI) tract and the inefficient microbial fermentation of
      such material in their hind-gut. In poultry the non-starch polysaccharides found
      in cereal grains can also impair normal digestive function as they form viscous
      gels in the GI tract inhibiting the breakdown and absorption of nutrients. The
      nutrition of such livestock could, therefore, be improved by the introduction of
      enzymes able to degrade plant polysaccharides in the small intestine. We describe
      the expression of a xylanase, XYLY', from the bacterium Clostridium thermocellum
      in mammalian cells and the exocrine pancreas of transgenic mice. The enzyme is
      synthesised, secreted and functionally active in the eukaryote system. This work
      demonstrates the feasibility of generating animals with the endogenous capacity
      to depolymerise the xylan component of hemi-cellulose.

PMID- 10406101
TI  - Cloning and expression of the gene encoding phospholipase A1 from Serratia sp.
      MK1 in Escherichia coli.
AB  - The gene encoding extracellular phospholipase A1 of Serratia sp. MK1 was cloned
      from a genomic DNA library. Formation of transparent halos on the PCY agar plates
      was used to identify E. coli carrying the phospholipase A1 gene. A 4.2 kb EcoRI
      fragment was isolated and sequenced. From nucleotide sequences and expression of
      various plasmids, two open reading frames (plaA and plaS) involved in efficient
      expression of phospholipase A1 in natural and recombinant host were identified.
      Extracellular phospholipase A1 activity was identified as the gene product of
      plaA encoding 321 amino acids with a predicted MW of 33,400. Analysis of the
      amino acid sequence revealed significant homology (around 70%) to phospholipase
      A1 of Serratia liquefaciens and Yersinia enterocolitica. The sequence, -Gly-X1
      Ser-X2-Gly-, known as a lipase-specific consensus sequence was also found in the
      bacterial phospholipase A1. PlaS encoding a protein of 224 amino acids showed no
      enzymatic activity, but might be necessary for the efficient expression of
      phospholipase A1 in E. coli. To further improve the production of phospholipase
      A1 as a soluble and active form in E. coli, the effect of some parameters was
      examined. Surprisingly, a higher yield of soluble and active phospholipase A1
      could be obtained under the combined conditions of a lower temperature, an
      enriched medium, and a lower-strength promoter.

PMID- 10406102
TI  - Protection of immunoreactivity of dry immobilized proteins on microtitration
      plates in ELISA: application for detection of autoantibodies in myasthenia
      gravis.
AB  - We show the ability of the BSA-trehalose film to convert normally fragile
      proteins such as mouse monoclonal antibody to the Alzheimer precursor protein A4
      (APP695) and cell line TE671 acetylcholine receptor (AChRTE671) into a stable
      reagent, after its immobilization on microtitration plates. The remarkable
      property of the dry immobilized proteins are their stability under prolonged
      exposure to temperatures as high as 50 degrees C. Using the AChRTE671, the
      proposed method was applied for the measurement of anti-AChR autoantibodies in
      Myasthenia gravis by means of an enzyme-linked immunosorbent assay (ELISA). The
      test was shown to be specific and able to detect anti-AChR autoantibodies at
      concentrations as low as 3 nM. Using the same AchRTE671 as antigen, the results
      of examination of 34 serum samples for detection of anti-AChR autoantibodies by
      ELISA were compared with those of the conventional radioimmunoprecipitation assay
      (RIA). It was concluded that ELISA is another useful method for the diagnosis of
      M. gravis. The ELISA method offers a rapid, simple, safe and inexpensive means
      for mass screening of M. gravis.

PMID- 10406103
TI  - Predictors of crossword puzzle proficiency and moderators of age-cognition
      relations.
AB  - Four studies, each with approximately 200 adults between the ages of 18 and 80,
      were conducted to address two major goals. The first goal was to examine the
      relative contributions of different factors to the successful solution of
      crossword puzzles. Correlations and structural equation analyses revealed that
      general knowledge is the strongest predictor of crossword puzzle proficiency.
      Surprisingly, abstract reasoning ability, as measured by several different tests,
      had no direct relation to puzzle proficiency. The second goal of the project was
      to examine moderators of the relations between age and measures of both fluid and
      crystallized cognition. The results provide no evidence to suggest that amount of
      crossword puzzle experience reduces age-related decreases in fluid cognition or
      enhances age-related increases in crystallized cognition.

PMID- 10406104
TI  - On the discovery of novel wordlike units from utterances: an artificial-language
      study with implications for native-language acquisition.
AB  - In 4 experiments, adults were familiarized with utterances from an artificial
      language. Short utterances occurred both in isolation and as part of a longer
      utterance, either at the edge or in the middle of the longer utterance. After
      familiarization, participants' recognition memory for fragments of the long
      utterance was tested. Recognition was greatest for the remainder of the longer
      utterance after extraction of the short utterance, but only when the short
      utterance was located at the edge of the long utterance. These results support
      the incremental distributional regularity optimization (INCDROP) model of speech
      segmentation and word discovery, which asserts that people segment utterances
      into familiar and new wordlike units in such a way as to minimize the burden of
      processing new units. INCDROP suggests that segmentation and word discovery
      during native-language acquisition may be driven by recognition of familiar units
      from the start, with no need for transient bootstrapping mechanisms.

PMID- 10406105
TI  - The fan effect: a tale of two theories.
AB  - This article addresses J. R. Anderson and L. M. Reder's (1999) account of the
      differential fan effect reported by G. A. Radvansky, D. H. Spieler, and R. T.
      Zacks (1993). The differential fan effect is the finding of greater interference
      with an increased number of associations under some conditions, but not others,
      in a within-subjects mixed-list recognition test. Anderson and Reder concluded
      that the differential fan effects can be adequately explained by assuming
      differences in the weights given to concepts in long-term memory. When a broader
      range of data is considered, this account is less well supported. Instead, it is
      better to assume that the organization of information into referential
      representations, such as situation models, has a meaningful influence on long
      term memory retrieval.

PMID- 10406106
TI  - Process, not representation: reply to Radvansky (1999).
AB  - The size of fan effects is determined by processes at retrieval, not by whether
      or not information is represented as situations. Evidence contradicts G. A.
      Radvansky's (1999) claim that time to retrieve information from a situation does
      not depend on the number of elements in the situation. Moreover, Radvansky's
      principles for ascribing situational models to experiments appear to be post hoc
      ways of redescribing the data. On the other hand, the evidence does support the
      Adaptive Control of Thought--Rational (ACT-R) assumption that participants can
      adjust their attentional weightings and so produce differential fan effects.
      Moreover, the ACT-R theory of the fan effect is consistent with many other
      findings.

PMID- 10406107
TI  - Metallothioneins in antarctic fish: evidence for independent duplication and gene
      conversion.
AB  - In the present paper, we examine eight species of Antarctic fish belonging to the
      suborder Notothenioidei, using reverse-transcriptase polymerase chain reaction,
      to investigate the presence of mRNAs encoding metallothionein (MT) isoforms. A
      total of 168 bp from the coding region and the complete (133-165 bp) 3'
      untranslated region (UTR) was obtained for all species (for three of them, we
      also sequenced the full-length cDNA, including the 5' UTR). Phylogenetic analyses
      carried out on the MT-coding region suggest monophyly for Antarctic fish MTs with
      respect to other teleost MT genes. Analyses also revealed that notothenioid MTs
      can be divided into at least two groups of paralogy, MT-1 and MT-2. These results
      indicate that notothenioid MT isoforms arose from at least one gene duplication
      event occurring in the ancestral lineage of the Notothenioidei. This duplication
      occurred independent of the one which gave origin to two metallothionein isoforms
      in the rainbow trout. In addition, an instance of gene conversion was observed
      between MT-1 and MT-2 genes in Notothenia coriiceps. Analyses of the 5' UTR,
      combined with quantitative assay of differential expression of MT-1 and MT-2,
      indicate that only the 3' UTR underwent a gene conversion event in the mentioned
      species. These findings, together with the observation of a differential pattern
      of expression for the two MT isoforms, disclose an unexpected complexity in the
      evolution and function of notothenioid MTs; as in most teleost species examined
      (apart from the rainbow trout), a single MT form is present.

PMID- 10406108
TI  - The retrotransposon Osvaldo from Drosophila buzzatii displays all structural
      features of a functional retrovirus.
AB  - The Osvaldo retrotransposon has shown a high transposition rate in some strains
      of Drosophila buzzatii and in hybrids between D. buzzatii and its sibling D.
      koepferae. In order to understand the molecular basis of this phenomenon, we
      developed a procedure to clone a recently transposed copy with the aim of
      characterizing an active, full- length Osvaldo element. The complete nucleotide
      sequence of Osvaldo, obtained from a recent insertion site, was determined.
      Osvaldo is 9,045 bp long and is composed of a central coding region flanked by
      identical long terminal repeats (LTRs) of 1,196 bp each. Sequences homologous to
      the polypurine tract and tRNA-primer-binding site of retroviruses are located
      adjacent to the 3' and 5' LTRs, respectively. The internal region of Osvaldo
      contains three long open reading frames (ORFs 1, 2, and 3), comparable in size
      and location to gag, pol, and env retroviral genes. The conceptual translation of
      Osvaldo ORF1 exhibits sequence homology to HIV1 and SIV capsid (p24) and
      nucleocapsid (p7) mature proteins. ORF2 encodes the putative protease (PR),
      reverse transcriptase/ribonuclease H (RT/RH), integrase (IN), and a significant
      portion of the surface envelope (ENV) protein that is interrupted by a putative
      intron. A third ORF encodes the remaining part of the ENV protein. The predicted
      62-kDa ENV protein shares several general features with membrane glycoproteins,
      including a potential signal peptide, a transmembrane domain near the C-terminus
      that could function as a membrane anchor, four consensus N-linked glycosylation
      motifs, and, finally, a potential protease cleavage site. The phylogenetic
      relationships of Osvaldo are explored, and they suggest that Osvaldo may
      constitute a new family of retroviruses in insects, distantly related to the
      previously described group of gypsy retroviruses.

PMID- 10406109
TI  - DNA bend sites in the human beta-globin locus: evidence for a basic and universal
      structural component of genomic DNA.
AB  - Here we summarize the DNA bend sites in a 66-kb region of the human beta-globin
      locus. A total of 98 sites were mapped by circular permutation assay along the
      locus with an average interval of 679.2 +/- 229.6 bp between them. The
      distribution of the bend sites indicated that although the most frequent distance
      was about 650-700 bp, there appeared to be preferences at 300-400, 500-550, 800
      850, 1,000-1,050, and 1,150-1,200 bp, indicating that these distances are
      multimers of a 170-bp basic unit. DNA bend sites in the globin-encoding regions
      indicated that most of their locations relative to the cap sites were conserved
      during evolution. Insertion of Alu and L1 sequences that occurred at various
      times and changed the distances of the sites was corrected for the epsilon-, psi
      beta-, and delta-globin genes. The only exception of the conservation was
      observed at the duplication junctions of the two gamma-globin genes, which
      occurred 25-35 MYA. Among the 75 A/A/A (A2N8A2N8A2) sequences found in the 51
      bend sites, 59 sequences from 47 sites showed bending profiles by oligonucleotide
      based assay. All of these sites were included in the sites predicted by computer
      analysis based on the distribution of AA and TT dinucleotides. These lines of
      evidence suggest that these DNA bend sites are one of the basic structural
      components universally present in genomic DNA.

PMID- 10406110
TI  - Interspecific hybridization increases transposition rates of Osvaldo.
AB  - Several authors have postulated that genetic divergence between populations could
      result in genomic incompatibilities that would cause an increase in transposition
      in their hybrids, producing secondary effects such as sterility and therefore
      starting a speciation process. It has been demonstrated that transposition
      largely depends on intraspecific hybridization for P, hobo, and I elements in
      Drosophila melanogaster and for several elements, including long terminal repeat
      (LTR) and non-LTR retrotransposons, in D. virilis. However, in order to
      demonstrate the putative effect of transposable elements on speciation, high
      levels of transposition should also be induced in hybrids between species that
      could have been originated by this process and that are still able to interbreed.
      To test this hypothesis, we studied the transposition of the LTR retrotransposon
      Osvaldo in Drosophila buzzatii-Drosophila koepferae hybrids. We used a simple and
      robust experimental design, analyzing large samples of single-pair mate
      offspring, which allowed us to detect new insertions by in situ hybridization to
      polytene chromosomes. In order to compare transposition rates, we also used a
      stock recently obtained from the field and a highly inbred D. buzzatii strain.
      Our results show that the transposition rate of Osvaldo is 10(-3) transpositions
      per element per generation in all nonhybrid samples, very high when compared with
      those of other transposable elements. In hybrids, the transposition rate was
      always 10(-2), significantly higher than in nonhybrids. We show that inbreeding
      has no effect on transposition in the strains used, concluding that hybridization
      significantly increases the Osvaldo transposition rate.

PMID- 10406111
TI  - Evolution of sea urchin retroviral-like (SURL) elements: evidence from 40
      echinoid species.
AB  - We conducted a phylogenetic survey of sea urchin retroviral-like (SURL)
      retrotransposable elements in 33 species of the class Echinoidea (sea urchins,
      sand dollars, and heart urchins). A 263-bp fragment from the coding region of the
      reverse transcriptase (RT) gene was amplified, cloned, and sequenced.
      Phylogenetic relationships of the elements isolated from independent clones,
      along with those from seven additional echinoid species obtained earlier by
      Springer et al., were compared with host phylogeny. Vertical transmission and the
      presence of paralogous sequences that diverged prior to host speciation can
      explain most of the phylogenetic relationships among SURL elements. Rates of
      evolution were estimated from cases in which SURL and host phylogenies were
      concordant. In agreement with conclusions reached previously by Springer et al.,
      average rates of synonymous substitution were comparable with those of single
      copy sea urchin DNA. High ratios of synonymous to nonsynonymous substitution
      suggest that the RT of the elements is under strong purifying selection. However,
      a high proportion (approximately 15%) of elements with deleterious frameshifts
      and stop codons and an increase of the ratio of synonymous to nonsynonymous
      substitutions with divergence time show that in the short term this selection is
      relaxed. Despite the predominance of vertical transmission, sequence similarity
      of 83%-94% for SURL elements from hosts that have been separated for 200 Myr
      suggests four cases of apparent horizontal transfer between the ancestors of the
      extant echinoid species. In three additional cases, elements with identical RT
      sequences were found in sea urchin species separated for a minimum of 3 Myr.
      Thus, horizontal transfer plays a role in the evolution of this retrotransposon
      family.

PMID- 10406112
TI  - The mid-depth method and HIV-1: a practical approach for testing hypotheses of
      viral epidemic history.
AB  - We introduce the mid-depth method, a practical approach for testing hypotheses of
      demographic history using genealogies reconstructed from sequence data. The
      relative positions of internal nodes within a genealogy contain information about
      past population dynamics. We explain how this information can be used to (1) test
      the null hypothesis of constant population size and (2) estimate the growth rate
      and current population size of an exponentially growing population. Simulation
      tests indicate that, as expected, estimates of exponential growth rates are
      sometimes biased. The mid-depth method is computationally rapid and does not
      require knowledge of the sample's mutation rate. However, it does assume that the
      reconstructed genealogy is correct and is therefore best suited to the analysis
      of variation-rich viral data sets. When applied to HIV-1 sequence data, the mid
      depth method provides phylogenetic evidence of different exponential growth rates
      for subtypes A and B. We posit that this difference in growth rate reflects the
      different transmission routes and epidemiological histories of the two subtypes.

PMID- 10406113
TI  - Mitochondrial DNA reveals cryptic oligochaete species differing in cadmium
      resistance.
AB  - Species of the family Tubificidae represent a major faunal element in benthic
      freshwater communities throughout the world. Some of them are considered
      particularly tolerant of the influence of toxicants such as cadmium. One of the
      most abundant species, "Tubifex tubifex," is frequently used as an indicator of
      environmental pollution, despite considerable taxonomic problems caused by
      phenotypic plasticity and genetic heterogeneity. Our study provides a phylogeny
      of "T. tubifex" based on a segment of the mitochondrial 16S rDNA and presents a
      rapid PCR-based method of genotype screening which was then applied in cadmium
      toxicity studies on natural populations. Phylogenetic analysis identified five
      major mitochondrial lineages, some of them separated by large genetic distances
      (up to 13%) but morphologically indistinguishable, thus highly suggestive of the
      existence of cryptic species. All lineages were present at different frequencies
      in the European river populations studied, with a tendency of the more resistant
      lineages to occur at higher frequencies in the more tolerant populations. In
      fact, lineage-specific toxicity experiments showed that individuals of different
      mitochondrial lineages consistently varied in cadmium resistance, suggesting that
      in benthic oligochaetes, evolution seems to proceed predominantly through natural
      selection acting on physiological, rather than morphological, characters. In
      consequence, toxicological studies involving "T. tubifex" as a monitoring or test
      organism should allow for the possibility of genetic inhomogeneity of this
      mudworm group by combining both toxicological and genetic methods.

PMID- 10406114
TI  - The divergence-homogenization duality in the evolution of the b1 mating type gene
      of Coprinus cinereus.
AB  - The A mating type locus of the fungus Coprinus cinereus is a complex, multigenic
      locus which regulates compatibility and subsequent sexual development. Genes
      within the A locus such as the b1 gene studied here exhibit extreme sequence
      variation. In this work, we asked how b1 alleles have evolved high levels of
      variation and, at the same time, conserved function. We compared sequence
      variation in 17 alleles characterized as belonging to seven different
      compatibility classes. Comparison of sequence variation between representatives
      of these seven classes shows that different regions of the b1 gene have been
      subject to varying levels of substitution, recombination, and
      structural/functional constraints. The N-terminal region of the encoded protein,
      which has been previously demonstrated to govern self/nonself recognition,
      exhibited hypervariability with levels of amino acid identity as low as 41%. We
      used a novel analysis of neutral mutations accumulating in this gene to rule out
      the possibility that the N-terminal region is hypermutable. In contrast, the C
      terminal region displayed heterogeneous levels of variation, with functional
      motifs being better conserved. In fact, there is a duality in the b1 gene between
      variability and conservation; recombination events have homogenized the C
      terminal region, while recombination events are undetectable in the N-terminal
      region. The ability to regulate sexual development is maintained in all of the
      mating compatibility alleles studied, and these data suggest that some functional
      motifs may tolerate high levels of substitution.

PMID- 10406115
TI  - Molecular phylogeny and rearrangement of rRNA genes in Rickettsia species.
AB  - It has previously been observed that Rickettsia prowazekii has an unusual
      arrangement of the rRNA genes. In this species, the three rRNA genes, 16S (rrs),
      23S (rrl), and 5S (rrf), are not linked in the typical arrangements for bacteria.
      Rather, the 16S rRNA gene has been separated from the 23S and 5S rRNA gene
      cluster, and the 23S rRNA gene is preceded by a gene which codes for methionyl
      tRNAf(Met) formyltransferase (fmt). In this study, we screened the genus
      Rickettsia for the fmt-rrl motif in order to examine the phylogenetic depth of
      this unusual rRNA gene organization. A rearranged operon structure was observed
      in Rickettsia conorii, Rickettsia parkeri, Rickettsia sibirica, Rickettsia
      rickettsii, Rickettsia amblyomii, Rickettsia montana, Rickettsia rhipicephali,
      Rickettsia australis, Rickettsia akari, Rickettsia felis, Rickettsia canada, and
      Rickettsia typhi. There is also evidence for a divided operon in Rickettsia
      belli, but in this species, the fmt gene could not be identified upstream of the
      23S rRNA gene. In order to place the rearrangement event in the evolutionary
      history of the Rickettsia, phylogenetic analyses were performed based on the fmt
      rrl spacer regions and the 23S rRNA genes. Based on these phylogenies, we suggest
      that the genomic rearrangement of the rRNA genes preceded the divergence of the
      typhus group and the spotted fever group Rickettsia. The unique organization of
      the 23S rRNA genes provides a simple diagnostic tool for identification of
      Rickettsia species.

PMID- 10406116
TI  - Substitution rates of organelle and nuclear genes in sharks: implicating
      metabolic rate (again).
AB  - Rates of nucleotide substitution for nuclear genes are thought to be governed
      primarily by the number of germ line replication events (the so-called
      "generation time" hypothesis). In contrast, rates of mitochondrial DNA evolution
      appear to be set primarily by DNA damage pathways of mutation mediated by
      mutagenic by-products of oxidative phosphorylation (the so-called "metabolic
      rate" hypothesis). Comparison of synonymous substitution rates estimated for the
      mitochondrial cytochrome b gene and nuclear-encoded dlx, hsp70, and RAG-1 genes
      in mammals and sharks shows that rates of molecular evolution for sharks are
      approximately an order of magnitude slower than those for mammals for both
      nuclear and mitochondrial genes. In addition, there is significant positive
      covariation of substitution rate for mitochondrial and nuclear genes within
      sharks. These results, interpreted in light of the pervasiveness of DNA damage by
      mutagenic by-products of oxygen metabolism to both nuclear and mitochondrial
      genes and coupled with increasing evidence for cross-genome activity of DNA
      repair enzymes, suggest that molecular clocks for mitochondrial and nuclear genes
      may be set primarily by common mutational mechanisms.

PMID- 10406117
TI  - A human population bottleneck can account for the discordance between patterns of
      mitochondrial versus nuclear DNA variation.

PMID- 10406119
TI  - The expression of tobacco knotted1-type class 1 homeobox genes correspond to
      regions predicted by the cytohistological zonation model.
AB  - We have isolated and characterized four tobacco homeobox genes, NTH1, NTH9,
      NTH20, NTH22 (Nicotiana tabacum homeobox) which belong to the class 1 knotted1
      type family of homeobox genes. Comparison of the inferred amino acid sequences of
      the ELK homeodomains of these genes and previously reported kn1-type class 1
      proteins has revealed that the four new tobacco genes belong to distinct
      subclasses, suggesting that each NTH gene may have distinct functions. Using in
      situ hybridization and by analysing the distribution of GUS activity in tobacco
      plants transformed with NTH promoter::GUS constructs, localized expression of the
      three NTH genes was observed in the shoot apical meristem (SAM). In the
      vegetative SAM, NTH1 and NTH15 showed overlapping expression in the corpus, NTH20
      was expressed in the peripheral zone, and NTH9 was predominantly expressed in the
      rib zone. The expression patterns of the different NTH genes correspond to
      regions predicted by the cytohistological zonation model, suggesting that each
      NTH gene specifies the function of the SAM zone with which it is associated.

PMID- 10406120
TI  - Distribution of fungal endophyte genotypes in doubly infected host grasses.
AB  - Fungal endophytes of the genus Epichloe live intercellulary in above ground plant
      parts of many pooid 'grasses of the temperate regions. The associations are
      characterized by single genotype entities since a given host individual normally
      contains a single endophyte genotype. They can persist over the life span of the
      hosts. This study examines whether two fungal genotypes can co-exist within a
      host plant, and how fungal genotypes are distributed within a host in the case of
      double infections. We selected four Epichloe bromicola strains that we identified
      as unique genotypes through RAPD' analysis. Young Bromus erectus plants, derived
      from callus cultures, were artificially inoculated with all possible double
      strain mixtures of these fungal genotypes. For identification of fungal genotypes
      in planta, we designed genotype-specific primer pairs that flanked size-variable
      loci in the fungal genomes. Diagnostic PCR revealed that only one fungal genotype
      was present in most inoculated plants, but double infections were also observed
      with a frequency of 8% of all infected plants. Subsequent analyses of individual
      tillers of doubly infected plants revealed that, in a given tiller, both the leaf
      blade and the leaf-sheath were colonized with only one endophyte genotype.
      Tillers without any detectable fungal DNA were also observed. Thus, co-existence
      of multiple endophyte genotypes within a single host plant is governed by mutual
      exclusion at the tiller level.

PMID- 10406121
TI  - In vitro activities of four xyloglucan endotransglycosylases from Arabidopsis.
AB  - Xyloglucan endotransglycosylases (XETs) are encoded by a gene family in
      Arabidopsis thaliana. These enzymes modify a major structural component of the
      plant cell wall, xyloglucan, and therefore may influence plant growth and
      development. We have produced four Arabidopsis XETs (TCH4, Meri-5, EXGT and XTR9)
      using the baculovirus/insect cell system and compared their biochemical
      activities. TCH4, as previously demonstrated, and the other three proteins are
      capable of carrying out transglycosylation of xyloglucans. The K(m) for XLLGol
      acceptor oligosaccharide is in the range of 20-40 microM for all the XETs except
      XTR9, which has a Km of 5 microM and is significantly inhibited by high levels of
      XLLGol. All four enzymes are most active between pH 6.0 and 6.5. TCH4 and XTR9
      have temperature optima of 18 degrees C, whereas Meri-5 and EXGT are most active
      at 28 and 37 degrees C, respectively. Although the activity levels of three of
      the XETs are not influenced by the presence of fucose on the xyloglucan polymer,
      XTR9 has a clear preference for non-fucosylated xyloglucan polymer. The four XETs
      show a marked preference for XLLGol over either XXFGol or XXXGol as acceptor
      oligosaccharide. All four XETs are glycosylated; however, only the activities of
      TCH4 and Meri-5 are affected by the removal of the N-glycan with PNGase F. These
      four enzymes most likely function solely as transglycosylases because xyloglucan
      endoglucanase activity was not apparent. Subtle differences in biochemical
      activities may influence the physiological functions of the distinct XETs in
      vivo.

PMID- 10406122
TI  - A 13-bp cis-regulatory element in the LTR promoter of the tobacco retrotransposon
      Tto1 is involved in responsiveness to tissue culture, wounding, methyl jasmonate
      and fungal elicitors.
AB  - The tobacco Tto1 is one of the few active LTR-retrotransposons of plants, and its
      transposition is activated by tissue culture and is primarily regulated at the
      transcriptional level. The expression of Tto1 RNA can also be activated by
      various stresses, including viral infection, wounding, and treatment with
      jasmonate, a signal molecule of plant defence responses. It is shown here that
      the Tto1 LTR promoter is responsible for a high level of expression in cultured
      tissues of transgenic tobacco plants. We demonstrate that a 13-bp repeated motif
      (TGGTAGGTGAGAT) in the LTR functions as a cis-regulatory element, which confers
      the responsiveness to tissue culture, wounding and methyl jasmonate. Fungal
      elicitors also activate the promoter containing multiple copies of the 13-bp
      motif. Expression mediated by the 13-bp motif is activated markedly by okadaic
      acid and moderately by K252a, so that both phosphorylation and dephosphorylation
      of proteins are possibly involved in the signalling pathways. Interestingly, the
      13-bp motif contains a conserved motif, Box L (also called AC-I or H-box like
      sequence) which has been shown to be involved in the expression of
      phenylpropanoid synthetic genes. Moreover, extended homologies are found between
      promoters of Tto1 and an asparagus defence gene, AoPR1, suggesting a possibility
      that the ancient insertion of an ancestral Tto1-related retrotransposon has
      provided some of the promoter/regulatory sequences, including the 13-bp motif
      related sequence, of the AoPR1 gene. Based on the structural and functional
      similarity between the two promoters, a possible evolutionary role of the
      regulatory sequences of LTR-retrotransposons is discussed.

PMID- 10406123
TI  - FPF1 modulates the competence to flowering in Arabidopsis.
AB  - During the transition to flowing the FPF1 gene is expressed in the peripheral
      zone of apical meristems and in floral meristems of Arabidopsis. Constitutive
      expression of FPF1 causes early flowering in Arabidopsis under both long-day and
      short-day conditions and leads to a shortened juvenile phase as measured by the
      trichome distribution on the abaxial leaf surface. In the classical late
      flowering mutants, overexpression of FPF1 compensates partially for the late
      flowering phenotype, indicating that FPF1 acts downstream or in a parallel
      pathway to the mutated genes. The co-overexpression of 35S::AP1 with 35S::FPF1
      leads to a synergistic effect on the shortening of the time to flowering under
      short-day conditions. The co-overexpression of 35S::FPF1 and 35S::LFY, however,
      shows only an additive reduction of flowering time and the conversion of nearly
      every shoot meristem, except the inflorescence meristem, to a floral meristem
      under the same light conditions. In addition, the constitutive expression of FPF1
      attenuates the severe lfy-1 phenotype under short days and phenocopies to a great
      extent the lfy-1 mutant grown under long-day conditions. Thus, we assume that
      FPF1 modulates the competence to flowering of apical meristems.

PMID- 10406124
TI  - Developmental stage-specific multi-subunit plastid RNA polymerases (PEP) in
      wheat.
AB  - Most photosystem I and II plastid genes are transcribed by a plastid encoded
      Escherichia coli-like RNA polymerase (PEP). In this study, we show that both
      promoter selectivity and light-dependency of PEP change dramatically during
      development in wheat leaves. In the leaf tip, psbA and psbD promoter activities
      are light induced, whilst psbC, psbE and 16S rRNA promoters do not function
      efficiently irrespective of light conditions. In contrast to the leaf tip, in the
      basal portion all PEP promoters studied function in the dark as well as the
      light, except for psbD. Using in vitro transcription, we found that PEP in the
      illuminated leaf tip can initiate transcription from the -35 destructed psbA
      promoter, but the -35 element is essential for transcription in the basal
      portion. There is an extended -10 element in the psbA promoter, recognized by the
      PEP in the illuminated leaf tip or purified sigma 70-type Escherichia coli RNA
      polymerase but not by the PEP in the leaf base. These results suggest that during
      wheat leaf development, PEP in the leaf base that is functional for most PEP
      promoters even in the dark is replaced by the light-dependent PEP selectively
      transcribing the psbA and psbD promoters.

PMID- 10406125
TI  - Two MAR DNA-binding proteins of the pea nuclear matrix identify a new class of
      DNA-binding proteins.
AB  - Four MAR-binding proteins of 60, 65, 70 and 72 kDa have been detected by South
      Western blotting and isolated from pea nuclear matrices. Two cDNAs encoding the
      60 and 65 kDa proteins (MARBP-1 and MARBP-2) were isolated from a pea leaf cDNA
      library by screening with a PCR product obtained using degenerate primers based
      on an amino acid sequence from the 60 kDa protein. The proteins of 560 and 550
      amino acids are 86% identical and contain several KKD/E repeats near the C
      terminus. Escherichia coli-expressed MARBP-1 specifically binds A/T-rich MAR DNA.
      The interaction of MARBP-1/MARBP-2 with MAR DNA involves novel DNA-binding
      motifs. The MARBP-1 and MARBP-2 genes are expressed in a range of pea tissues and
      are encoded by genes at different loci. MARBP-1 and MARBP-2 are homologous to
      yeast nucleolar proteins Nop56p and Nop58p, which are involved in ribosome
      biogenesis, and to similar highly conserved proteins in other eukaryotes and in
      archaebacteria. MARBP-1 and MARBP-2 may have multifunctional roles in chromatin
      organisation and ribosome biogenesis.

PMID- 10406126
TI  - Bigfoot. a new family of MITE elements characterized from the Medicago genus.
AB  - We have characterized from the legume plant Medicago a new family of miniature
      inverted-repeat transposable elements (MITE), called the Bigfoot transposable
      elements. Two of these insertion elements are present only in a single allele of
      two different M. sativa genes. Using a PCR strategy we have isolated 19 other
      Bigfoot elements from the M. sativa and M. truncatula genomes. They differ from
      the previously characterized MITEs by their sequence, a target site of 9 bp and a
      partially clustered genomic distribution. In addition, we show that they exhibit
      a significantly stable secondary structure. These elements may represent up to
      0.1% of the genome of the outcrossing Medicago sativa but are present at a
      reduced copy number in the genome of the autogamous M. truncatula plant,
      revealing major differences in the genome organization of these two plants.

PMID- 10406127
TI  - Non-invasive quantitative detection and applications of non-toxic, S65T-type
      green fluorescent protein in living plants.
AB  - Green fluorescent protein (GFP) has emerged as a powerful new tool in a variety
      of organisms. An engineered sGFP(S65T) sequence containing optimized codons of
      highly expressed eukaryotic proteins has provided up to 100-fold brighter
      fluorescence signals than the original jellyfish GFP sequence in plant and
      mammalian cells. It would be useful to establish a non-invasive, quantitative
      detection system which is optimized for S65T-type GFP, one of the brightest
      chromophore mutants among the various GFPs. We demonstrate here that highly
      fluorescent transgenic Arabidopsis can be generated, and the fluorescence
      intensity of whole plants can be measured under non-disruptive, sterile
      conditions using a quantitative fluorescent imaging system with blue laser
      excitation. Homozygous plants can be distinguished from heterozygous plants and
      fully fertile progenies can be obtained from the analyzed plants. In the case of
      cultured tobacco cells, GFP-positive cells can be quantitatively distinguished
      from non-transformed cells under non-selective conditions. This system will be
      useful in applications such as mutant screening, analysis of whole-body
      phenomena, including gene silencing and quantitative assessments of colonies from
      microorganisms to cultured eukaryotic cells. To facilitate the elucidation of
      protein targeting and organelle biogenesis in planta, we also generated
      transgenic Arabidopsis that stably express the plastid- or mitochondria-targeted
      sGFP(S65T). Etioplasts in dark-grown cotyledons and mitochondria in dry seed
      embryos could be visualized for the first time in transgenic Arabidopsis plants
      under normal growing conditions.

PMID- 10406128
TI  - The rise and fall of the Aldabran giant tortoise population.
AB  - At the end of the 19th century, after prolonged and extensive harvesting,
      indigenous giant tortoises had been eliminated from all islands in the Indian
      Ocean, except Aldabra atoll, where only a few survived. With greatly reduced
      levels of exploitation during the 20th century, the population recovered to a
      revised estimated total of 129,000 in 1973-1974, when the first sample census was
      conducted. A repeat census in 1997 revealed a highly significant reduction in
      numbers over the past 24 years to an estimated total of 100,000. The great
      majority of tortoises are still found at relatively high density in south-eastern
      Grande Terre, where the number of animals has declined by more than one-third. In
      contrast, low-density subpopulations on Malabar and Picard have almost doubled in
      size, but they represent less than 5% of the total population. Corroborative
      evidence for the crash in the Grande Terre subpopulation comes from two
      independent observations: a significant increase in tortoise mortality; and a
      significant decline in tortoise counts on long-term population monitoring
      transects. These population changes are attributed to natural population
      regulatory mechanisms, exacerbated by low rainfall years in the period 1980-1997,
      including two consecutive years of below average rainfall in 1995-1996 and 1996
      1997.

PMID- 10406130
TI  - Lunar cycles in diel prey migrations exert a stronger effect on the diving of
      juveniles than adult Galapagos fur seals.
AB  - In our study of the development of diving in Galapagos fur seals, we analysed
      changes in diving activity and body mass trends over the lunar cycle. Based on
      previously observed lunar cycles in colony attendance patterns, we hypothesized a
      greater impact of prey migrations of deep scattering layer organisms on younger
      fur seals. Using electronic dive recorders, we determined that seals dived less
      and deeper on moonlit nights than at new moon, and incurred body mass losses.
      These changes in foraging over the lunar cycle correlate with the suppression of
      the vertical migration of prey by lunar light. All effects were more pronounced
      in juveniles than adult females, with greater relative mass loss during full
      moon, which must (i) negatively affect long-term juvenile growth rates, (ii)
      lengthen periods of maternal dependence, and (iii) contribute to the lowest
      reproductive rate reported for seals. This underlines the importance of studying
      ontogeny in order to understand life histories, and for determining the
      susceptibility of animal populations to fluctuations in food availability.

PMID- 10406129
TI  - Carotenoids, sexual signals and immune function in barn swallows from Chernobyl.
AB  - Carotenoids have been hypothesized to facilitate immune function and act as free
      radical scavengers, thereby minimizing the frequency of mutations. Populations of
      animals exposed to higher levels of free radicals are thus expected to
      demonstrate reduced sexual coloration if use of carotenoids for free-radical
      scavenging is traded against use for sexual signals. The intensity of carotenoid
      based sexual coloration was compared among three populations of barn swallows
      Hirundo rustica differing in exposure to radioactive contamination. Lymphocyte
      and immunoglobulin concentrations were depressed, whereas the
      heterophil:lymphocyte ratio, an index of stress, was enhanced in Chernobyl
      swallows compared to controls. Spleen size was reduced in Chernobyl compared to
      that of two control populations. Sexual coloration varied significantly among
      populations, with the size of a secondary sexual character (the length of the
      outermost tail feathers) being positively related to coloration in the two
      control populations, but not in the Chernobyl population. Thus the positive
      covariation between coloration and sexual signalling disappeared in the
      population subject to intense radioactive contamination. These findings suggest
      that the reliable signalling function of secondary sexual characters breaks down
      under extreme environmental conditions, no longer providing reliable information
      about the health status of males.

PMID- 10406131
TI  - Intracommunity relationships, dispersal pattern and paternity success in a wild
      living community of Bonobos (Pan paniscus) determined from DNA analysis of faecal
      samples.
AB  - Differences in social relationships among community members are often explained
      by differences in genetic relationships. The current techniques of DNA analysis
      allow explicit testing of such a hypothesis. Here, we have analysed the genetic
      relationships for a community of wild bonobos (Pan paniscus) using nuclear and
      mitochondrial DNA markers extracted from faecal samples. Bonobos show an
      opportunistic and promiscuous mating behaviour, even with mates from outside the
      community. Nonetheless, we find that most infants were sired by resident males
      and that two dominant males together attained the highest paternity success.
      Intriguingly, the latter males are the sons of high-ranking females, suggesting
      an important influence of mothers on the paternity success of their sons. The
      molecular data support previous inferences on female dispersal and male
      philopatry. We find a total of five different mitochondrial haplotypes among 15
      adult females, suggesting a frequent migration of females. Moreover, for most
      adult and subadult males in the group we find a matching mother, while this is
      not the case for most females, indicating that these leave the community during
      adolescence. Our study demonstrates that faecal samples can be a useful source
      for the determination of kinship in a whole community.

PMID- 10406132
TI  - Leginon: a system for fully automated acquisition of 1000 electron micrographs a
      day.
AB  - We have developed a system to automatically acquire large numbers of acceptable
      quality images from specimens of negatively stained catalase, a biological
      protein which forms crystals. In this paper we will describe the details of the
      system architecture and analyze the performance of the system as compared to a
      human operator. The ultimate goal of the system if to automate the process of
      acquiring cryo-electron micrographs.

PMID- 10406133
TI  - A predictive reinforcement model of dopamine neurons for learning approach
      behavior.
AB  - A neural network model of how dopamine and prefrontal cortex activity guides
      short- and long-term information processing within the cortico-striatal circuits
      during reward-related learning of approach behavior is proposed. The model
      predicts two types of reward-related neuronal responses generated during
      learning: (1) cell activity signaling errors in the prediction of the expected
      time of reward delivery and (2) neural activations coding for errors in the
      prediction of the amount and type of reward or stimulus expectancies. The former
      type of signal is consistent with the responses of dopaminergic neurons, while
      the latter signal is consistent with reward expectancy responses reported in the
      prefrontal cortex. It is shown that a neural network architecture that satisfies
      the design principles of the adaptive resonance theory of Carpenter and Grossberg
      (1987) can account for the dopamine responses to novelty, generalization, and
      discrimination of appetitive and aversive stimuli. These hypotheses are
      scrutinized via simulations of the model in relation to the delivery of free food
      outside a task, the timed contingent delivery of appetitive and aversive stimuli,
      and an asymmetric, instructed delay response task.

PMID- 10406135
TI  - Resonantlike synchronization and bursting in a model of pulse-coupled neurons
      with active dendrites.
AB  - We analyze the dynamical effects of active, linearized dendritic membranes on the
      synchronization properties of neuronal interactions. We show that a pair of pulse
      coupled integrate-and-fire neurons interacting via active dendritic cables can
      exhibit resonantlike synchronization when the frequency of the oscillators is
      approximately matched to the resonant frequency of the membrane impedance. For
      weak coupling the neurons are phase-locked with constant interspike intervals
      whereas for strong coupling periodic bursting patterns are observed. This
      bursting behavior is reflected by the occurrence of a Hopf bifurcation in the
      firing rates of a corresponding rate-coded model.

PMID- 10406136
TI  - A functional hypothesis for LGN-V1-TRN connectivities suggested by computer
      simulation.
AB  - We employ computer simulation to investigate the function of neural circuitries
      between thalamic sensory relay nuclei, primary sensory cortices, and the thalamic
      reticular nucleus (TRN). Computational similarities exist between these circuits
      and the architecture of a simple artificial neural network. We impose processing
      parameters on this network architecture in keeping with anatomical and
      physiological details of the mammalian geniculo-cortical visual pathway, and then
      run the simulation on a task involving multiple simultaneous inputs from the
      simulated visual field. After two to three loops through the simulation, activity
      in cortical and thalamic units whose receptive fields include the stronger
      stimulus remains constant, while activity in other cortical and thalamic units
      activated by weaker stimuli declines toward resting values. These results suggest
      that the modeled neural circuitry functions to "prime" selective attentional
      mechanisms further up the visual streams toward specific portions of the total
      visual stimulus. Besides extending existing models and evidence about the
      function of these neural circuits, our results also provide physiologists with
      predicted activity profiles of thalamic and cortical elements of the modeled
      neural system for a task not yet studied experimentally.

PMID- 10406134
TI  - Role of multiple calcium and calcium-dependent conductances in regulation of
      hippocampal dentate granule cell excitability.
AB  - We have constructed a detailed model of a hippocampal dentate granule (DG) cell
      that includes nine different channel types. Channel densities and distributions
      were chosen to reproduce reported physiological responses observed in normal
      solution and when blockers were applied. The model was used to explore the
      contribution of each channel type to spiking behavior with particular emphasis on
      the mechanisms underlying postspike events. T-type calcium current in more distal
      dendrites contributed prominently to the appearance of the depolarizing after
      potential, and its effect was controlled by activation of BK-type calcium
      dependent potassium channels. Coactivation and interaction of N-, and/or L-type
      calcium and AHP currents present in somatic and proximal dendritic regions
      contributed to the adaptive properties of the model DG cell in response to long
      lasting current injection. The model was used to predict changes in channel
      densities that could lead to epileptogenic burst discharges and to predict the
      effect of altered buffering capacity on firing behavior. We conclude that the
      clustered spatial distributions of calcium related channels, the presence of slow
      delayed rectifier potassium currents in dendrites, and calcium buffering
      properties, together, might explain the resistance of DG cells to the development
      of epileptogenic burst discharges.

PMID- 10406137
TI  - Computational rules for chemotaxis in the nematode C. elegans.
AB  - We derive a linear neural network model of the chemotaxis control circuit in the
      nematode Caenorhabditis elegans and demonstrate that this model is capable of
      producing nematodelike chemotaxis. By expanding the analytic solution for the
      network output in time-derivatives of the network input, we extract simple
      computational rules that reveal how the model network controls chemotaxis. Based
      on these rules we find that optimized linear networks typically control
      chemotaxis by computing the first time-derivative of the chemical concentration
      and modulating the body turning rate in response to this derivative. We argue
      that this is consistent with behavioral studies and a plausible mechanism for at
      least one component of chemotaxis in real nematodes.

PMID- 10406138
TI  - Neural coding of finger and wrist movements.
AB  - Previous work (Schieber and Hibbard, 1993) has shown that single motor cortical
      neurons do not discharge specifically for a particular flexion-extension finger
      movement but instead are active with movements of different fingers. In addition,
      neuronal populations active with movements of different fingers overlap
      extensively in their spatial locations in the motor cortex. These data suggested
      that control of any finger movement utilizes a distributed population of neurons.
      In this study we applied the neuronal population vector analysis (Georgopoulos et
      al., 1983) to these same data to determine (1) whether single cells are tuned in
      an abstract, three-dimensional (3D) instructed finger and wrist movement space
      with hand-like geometry and (2) whether the neuronal population encodes specific
      finger movements. We found that the activity of 132/176 (75%) motor cortical
      neurons related to finger movements was indeed tuned in this space. Moreover, the
      population vector computed in this space predicted well the instructed finger
      movement. Thus, although single neurons may be related to several disparate
      finger movements, and neurons related to different finger movements are
      intermingled throughout the hand area of the motor cortex, the neuronal
      population activity does specify particular finger movements.

PMID- 10406139
TI  - Emergent oscillations in a realistic network: the role of inhibition and the
      effect of the spatiotemporal distribution of the input.
AB  - We have simulated a network of 10,000 two-compartment cells, spatially
      distributed on a two-dimensional sheet; 15% of the cells were inhibitory. The
      input to the network was spatially delimited. Global oscillations frequently were
      achieved with a simple set of connectivity rules. The inhibitory neurons paced
      the network, whereas the excitatory neurons amplified the input, permitting
      oscillations at low-input intensities. Inhibitory neurons were active over a
      greater area than excitatory ones, forming a ring of inhibition. The oscillation
      frequency was modulated to some extent by the input intensity, as has been shown
      experimentally in the striate cortex, but predominantly by the properties of the
      inhibitory neurons and their connections: the membrane and synaptic time
      constants and the distribution of delays. In networks that showed oscillations
      and in those that did not, widely distributed inputs could lead to the specific
      recruitment of the inhibitory neurons and to near zero activity of the excitatory
      cells. Hence the spatial distribution of excitatory inputs could provide a means
      of selectively exciting or inhibiting a target network. Finally, neither the
      presence of oscillations nor the global spike activity provided any reliable
      indication of the level of excitatory output from the network.

PMID- 10406140
TI  - Long-term outcome of RPE allografts to the subretinal space of rabbits.
AB  - PURPOSE: To determine the long-term RPE allograft survival in the subretinal
      space using suspensions of RPE cells and atraumatic transplantation surgery.
      METHODS: Nineteen albino rabbits were transplanted with suspensions of pigmented
      RPE cells from brown rabbits. Following pars plana vitrectomy, the RPE cell
      suspension was injected through a small retinotomy using a glass micropipette
      into the subretinal space under microscopic control. No immunosuppression was
      used. The eyes were monitored by biomicroscopy, color fundus photography, and
      fluorescein angiography. Rabbits were sacrificed at 1, 3 and 6 months,
      respectively, and the eyes processed for light and electron microscopy, using
      monoclonal antibodies for identifying macrophages. RESULTS: Transplanted RPE
      cells were present in the subretinal space in all eyes at 6 months. There was no
      fluorescein leakage. Generally, the RPE allograft formed a monolayer, but focal
      fragmentation and disruption with dispersion of melanin pigment occurred. Foci of
      multilayers of cells in the subretinal space, containing large macrophages, were
      associated with adjacent photoreceptor damage. There was no infiltration of
      lymphocytes but macrophages and glial cells were contiguous to the transplant.
      Cells harboring intracytoplasmatic melanin pigment were observed in the neural
      retina. CONCLUSION: Transplantation of RPE cell suspensions to the subretinal
      space generally forms a monolayer that persists at 6 months. However, in areas of
      multilayers of RPE cells and macrophages, graft failure occurs in combination
      with adjacent photoreceptor damage. Graft failure is not associated with the
      infiltration of lymphocytes, but other mechanisms seem to occur.

PMID- 10406141
TI  - Expression of GABA transporter subtypes (GAT1, GAT3) in the adult rabbit retina.
AB  - PURPOSE: GABA transporters (GATs) are of importance for GABA signal systems. They
      have previously not been examined in rabbit retina, nor has their correlation
      with neurotransmitter GABA and GABA receptors been examined in the retina of any
      species. METHODS: The distribution of GATs, GABA and GABA receptors was examined
      with immunohistochemical methods. RESULTS: Both GAT1 and GAT3 immunoreactivities
      were found in the inner plexiform layer and in amacrine cells. GAT3 was also
      present in Muller cells. GAT1 appeared in amacrine cells that also had a high
      GABA concentration, but not in cells with moderate to low GABA concentration.
      GAT1 was also present in amacrine cells that did not show GABA immunoreactivity,
      possibly indicating a postsynaptic GABA uptake system. CONCLUSION: GAT3 is
      probably involved in both neuronal and glial GABA uptake whereas GAT1 is involved
      in predominantly neuronal uptake, and possibly also into non-GABA-ergic amacrine
      cells. Further, there may be at least two populations of GABA containing neurons.

PMID- 10406142
TI  - Expression of GABA transporter subtypes (GAT1, GAT3) in the developing rabbit
      retina.
AB  - PURPOSE: Little is known about the expression of GABA transporters (GATs) in the
      developing retina. We have therefore examined the expression of GABA transporters
      (GAT1 and GAT3) in the developing rabbit retina. METHODS: The distribution of
      GATs was examined with immunohistochemical methods. RESULTS: GAT3
      immunoreactivity appeared at PN0, whereas GAT1 immunoreactivity appeared first at
      PN3, both in the inner plexiform layer. From PN5 and onwards, both GAT1 and GAT3
      immunoreactivity gradually appeared in numerous amacrine cell somas. At PN10, the
      immunostaining patterns and the distribution of both GAT1 and GAT3 were similar
      to that found in the adult rabbit retina. Full staining intensity was reached at
      PN20. CONCLUSION: GABA neurotransmission starts to develop already the first one
      to three days after birth, reaches the mature neuron pattern at about PN9 to PN10
      but is not fully developed until about PN20. Neither GAT1 nor GAT3 appears to be
      involved in trophic actions by GABA in the prenatal retina.

PMID- 10406143
TI  - Metabolic changes of the human donor cornea during organ-culture.
AB  - PURPOSE: To study metabolic changes of the human cornea during organ-culture.
      Morphological changes have been extensively studied, whereas changes in human
      corneal metabolism have not been investigated yet. MATERIAL AND METHODS: 106
      human corneas were stored for 1, 7, 15, 18, 21 and 28 days in a closed-system
      under standard eyebank conditions. After storage, glucose, lactate, ATP, ADP and
      AMP concentrations were determined in each cornea. RESULTS: Glucose concentration
      decreased during the first two weeks with a minimum on day 15. ATP and ADP
      concentrations increased during the same period of time, but had their minimum
      later, on day 18. Lactate increased during the culture period up to day 21 and
      decreased thereafter. CONCLUSION: From these data we conclude that the human
      cornea recovers during organ-culture, especially during the first two weeks. The
      changes occurring after a fortnight might be related to the artificial culture
      conditions. Nevertheless, the metabolic status is better than in post-mortem
      corneas. The changes may be partly avoided by changing the medium after at least
      two weeks of organ-culture.

PMID- 10406144
TI  - Follow-up study of human corneal endothelial cells, photographed in vivo before
      enucleation and 20 years later in grafts.
AB  - PURPOSE: To evaluate the long-term (20-year) survival of transplanted human
      corneal endothelial cells. METHODS: The donor endothelium had been photographed
      20 years ago with a specular microscope both before enucleation in the
      melanomatous eye and in situ after keratoplasty. The same donor endothelial cells
      were now photographed again 20 years later with a modern specular microscope to
      ascertain the morphology and cell density of the grafts. RESULTS: In the earlier
      study the mean postoperative endothelial cell density was 1357+/-543 cells/mm2,
      the average cell loss 11 months postoperatively being 48.2%; 20.5 years
      postoperatively the cell loss was 62.9% of the preoperative cell count. In our
      well-documented patient population the endothelial cell loss during the last 19
      years had been only 14.7%, which amounts to a cell loss of less than 1% per year.
      CONCLUSION: In transplanted corneas, the main endothelial cell loss seems to take
      place during the first 1-2 postoperative years.

PMID- 10406145
TI  - Corneal transplantation with donor tissue kept in organ culture for 7 weeks.
AB  - PURPOSE: To study the fate of corneal grafts after extended organ culture (7
      weeks). METHODS: Six patients with symmetrical eye diseases were grafted
      bilaterally, in one eye with a cornea prepared by routine organ culture (mean 16
      days), in the other eye with a donor cornea kept for 7 weeks (mean 49 days) in
      organ culture. The outcome was evaluated by biomicroscopy, graft thickness,
      endothelial cell density and visual performance after an observation time of at
      least 1 year. RESULTS: Penetrating 7-8 mm grafting was uncomplicated in all
      cases. The endothelial densities were in both groups in the range 1000-2000
      cells/mm2, and visual acuity 0.2-0.9 in cases with no other ocular pathology.
      Postoperative graft thickness and deswelling did not differ between 2- and 7-week
      cultured corneas. At final examination the thicknesses were 0.50 mm and 0.49 mm
      for 2- and 7-weeks cultured corneas. CONCLUSION: Seven-week cultured corneas give
      clinical results comparable to those obtained using shorter culture periods. An
      extended culture period may be used to improve other qualities of the graft
      (compatibility, cell number, cell metabolism) and microbiological control.

PMID- 10406146
TI  - Scleral and episcleral histological changes related to encircling explants in 20
      eyes.
AB  - PURPOSE: To investigate scleral and episcleral histological alterations induced
      by encircling explants used in scleral buckling procedures. METHODS: We performed
      a histopathological study of 20 enucleated eyes after failure of retinal
      detachment surgery including encircling scleral buckle. RESULTS: Nonabsorbable
      materials were encapsulated and often gave rise to a limited scleral
      invagination. The inner capsular surface was regular in 10 silicone explants, it
      was partially covered with hydrogel fragments and a granulomatous foreign body
      giant cell reaction in 8 hydrogel explants. One Arruga thread was encased in
      fibrosis and a catgut circle showed no encapsulation. Other changes were mostly
      related to the long-standing retinal detachment: peripheral anterior synechiae,
      anterior uveal effusion, persistent retinal detachment, retinal gliosis, retinal
      atrophy, retinal breaks, and silicone oil droplets. CONCLUSION: All nonabsorbable
      explants underwent encapsulation and prompted scleral invagination. A
      granulomatous reaction accompanied hydrogel fragmentation. The long term
      fragmentation impact on implanted eyes remains unknown.

PMID- 10406147
TI  - Longitudinal changes in visual acuity and visual ability in a cohort followed
      from the age of 70 to 88 years.
AB  - PURPOSE: To assess the change in visual acuity (VA) for distance and near and to
      correlate VA to changes in visual ability in a longitudinal study group followed
      from 70 to 88 years. METHODS: In the population-based study H70 in Gothenburg,
      Sweden, 958 subjects from the original cohort were eye examined at age 70 and the
      surviving subjects were reexamined at age 82 (n=203) and at 88 years (n=129).
      Evaluation of change in visual function between age 82 and 88 was made in 66
      subjects who took part in all three eye examinations. RESULTS: The VA in the
      subsample (n=66) showed minimal difference compared to the cross-sectional
      groups. At age 70 nearly 100% of both sexes had VA> or =0.8. At age 82 about 50%
      and at age 88 about 25% had this VA level. Males retained a slightly better
      visual acuity compared to women. VA< or =0.3 was found in about 10% at age 82 and
      in >20% at age 88. Reading ability remained high, but at 82 years 1.6% and at 88
      years 10.5% could benefit from adjustment of their near glasses. Visual ability
      corresponded well to VA at age 82, but not at 88 years. Women lost the ability
      for most tasks, whereas men showed small changes. CONCLUSIONS: The majority of
      old people had good distance and near vision. A deterioration in visual acuity
      did not necessarily mean a negative change in visual ability. This emphasizes the
      importance of relating objective and subjective findings regarding VA and visual
      impairment to functional ability of the oldest of the elderly.

PMID- 10406148
TI  - Ultrasound biomicroscopy. III. Accuracy and agreement of measurements.
AB  - PURPOSE: To estimate the accuracy of measurements by the 50 MHz Humphrey
      Ultrasound Biomicroscope and evaluate the agreement of measurements by ultrasound
      biomicroscopy and optical pachometry. METHODS: The accuracy was estimated by
      comparing measurements by ultrasound biomicroscopy with more exact mechanical
      methods. Forty-seven PMMA intraocular lenses and 52 distances between horizontal
      separated sutures were measured. The agreement between ultrasound biomicroscopy
      and optical pachometry was evaluated by comparing measurements of central cornea
      thickness and anterior chamber depth of 46 eyes. RESULTS: The axial measurements
      by ultrasound biomicroscopy was on average 10 microm higher than the reference
      method (SEM 3 microm). The lateral measurements was without systematic difference
      from the reference method (SEM 5 microm). The mean central corneal thickness was
      considerably higher by optical pachometry, 557+/-5 microm (SEM), than by
      ultrasound biomicroscopy, 533+/-5 microm. Similarly for anterior chamber depth
      where mean measurements were 2955+/-66 microm and 2897+/-63 microm, respectively.
      CONCLUSIONS: The axial and lateral accuracy of ultrasound biomicroscopic
      measurements was good. The agreement between measurements obtained by ultrasound
      biomicroscopy and optical pachometry was poor in this investigation. Several
      circumstances could be accountable for this.

PMID- 10406149
TI  - An experimental study on damage of retina function due to toxicity of carbon
      disulfide and lipid peroxidation.
AB  - PURPOSE: To study the relation between the changes in the electroretinogram and
      the lipid peroxidation of the retina during the period of retinal damage due to
      carbon disulfide (CS2). METHODS: To examine the amplitude and latency of a, b
      waves of the electroretinogram (ERG) and to assay the activities of total
      superoxide dismutases (TSOD), (EC no. 1.15.1.1), glutathione peroxidase (GSH-Px)
      (EC no.1.11.1.9) and malondialdehyed (MDA) in the retina of animals with
      experimental CS2 toxic retinopathy. RESULTS: The b wave amplitude (161+/-51
      microv) of the animals exposed to CS2 for 3 weeks was significantly lower than
      that of the controls (310+/-93 microv) (p<0.05). TSOD (30+/-5 Nu/mg)in the
      retinal tissues exposed was lower than that (38+/-8 Nu/mg) (p<0.05) in the
      controls and MDA (7+/-2 nmol/mg) in the exposed was higher than that (4+/-1
      nmol/mg) (p<0.05) in the controls at a concentration of CS2 1000 mg/m3. Analyzed
      with the correlation coefficient, there was a significant positive correlation
      between the amplitude changes of ERG b wave and TSOD (p<0.001) and a remarkable
      negative correlation between the amplitude changes of ERG b wave and MDA (p<0.05)
      in the animals' exposed retinal tissues. CONCLUSION: The present studies
      indicated that the damaged function of early CS2 toxic retinopathy was possibly
      associated with lipid peroxidation.

PMID- 10406150
TI  - Refractive changes among Norwegian university students--a three-year longitudinal
      study.
AB  - PURPOSE: The aim of this study was to investigate the changes in refractive error
      during a three-year period among university students exposed to high educational
      demands. METHODS: A three-year longitudinal cohort study was performed among 224
      Norwegian engineering students (mean age 20.6 years, 117 females and 107 males)
      measuring their refraction at the beginning and the end of the period. The
      examinations included automated and clinical refraction in cycloplegia. A total
      of 192 students (100 females and 92 males) completed the study. RESULTS: In the
      student population under study the prevalence of myopia increased significantly
      from 48% to 65% (p<0.001, right eye) and the mean refractive error increased
      significantly from -0.64+/-2.18 D (n=224) to -1.21+/-2.30 D (n=192) (p<0.001,
      right eye) during the period. Of eyes emmetropic at the start of the study (n=49,
      right eye), 59% became myopic. Among the eyes initially myopic (n=92, right eye),
      73% progressed further into myopia, with at least -0.37 D during the three-year
      period. Of eyes initially hyperopic (n=51, right eye), 8% became myopic, while
      14% became emmetropic. CONCLUSIONS: A shift in refraction towards myopia is
      frequent among university students during their study period.

PMID- 10406151
TI  - Prevalence of myopia in school children in the Sultanate of Oman: a nation-wide
      study of 6292 randomly selected children.
AB  - PURPOSE: Between 1992 to 1994 in the Sultanate of Oman, 6292 randomly selected
      school children from Grade 1 (6-year-olds) and Grade 6 (12-year-olds) were
      examined for visual acuity. The purpose of this paper is to present results that
      relate to the prevalence of myopia in this population. METHODS: All children with
      uncorrected visual acuity below 0.5 in one or both eyes received a thorough eye
      examination including cycloplegic retinoscopy. RESULTS: In the 6-year-olds there
      was an overall myopia (> or =-1.0 D) of 0.56% and in the 12-year-olds there was
      5.16%. In rural, remote areas there was statistically significantly less myopia
      in the older group when compared with the rest of the country. In the town of
      Nizwa in the region of Dakhlia, the value for high myopia (> or =-7.0 diopters)
      in 12-year-old girls was 2.82% compared to an average prevalence 0.13%.
      CONCLUSION: In the Sultanate of Oman the prevalence of myopia showed consistency
      with findings in Europe and North America. There was significantly less myopia in
      remote areas. An increased prevalence of high myopia was seen in one of Oman's
      major cities.

PMID- 10406152
TI  - Results of school eye screening of 5.4 million children in India--a five-year
      follow-up study.
AB  - PURPOSE: To assess results of a vision screening programme in schools in India, 5
      years after its introduction. MATERIAL: Questionnaires on school eye screening
      activities were sent to 200 randomly selected districts. METHODS: Data from 61
      districts were analysed, using process indicators to assess performance at
      different stages of the screening procedure. RESULTS: Teachers screened 5.39
      million children in 61 districts. Refraction was done on 205,082 children (3.8%)
      and 43,922 children (0.8%) were provided with spectacles. Children of 10-15 years
      have more refractive errors. Different stages in the procedure are evaluated.
      CONCLUSION: Vision screening in schools has been taken up successfully in many
      districts in India. This has reduced the workload of eye care staff and increased
      the coverage. The simplicity of the procedure facilitates widespread application.
      Many parents take their children to the private sector for services. Monitoring
      and reporting needs to be improved.

PMID- 10406153
TI  - Treatment of nonproliferative diabetic retinopathy with Defibrotide in noninsulin
      dependent diabetes mellitus: a pilot study.
AB  - PURPOSE: Microvascular alterations, impairment of coagulation, ischemia and
      diffuse endothelial damage are related to the progression of diabetic
      retinopathy. Defibrotide has been demonstrated to produce profibrinolytic,
      cytoprotective and vasofacilatory activities. The aim of the present study was to
      evaluate the therapeutic effect of Defibrotide in the treatment of
      nonproliferative diabetic retinopathy. METHODS: Two randomized age- and sex
      matched groups (cases and controls) of 35 NIDDM patients presenting non
      proliferative diabetic retinopathy were included in this study: cases were
      treated with Defibrotide (800-1600 mg daily) for two years. RESULTS: All tested
      parameters (ETDRS visual acuity; computerized perimetry; retinography;
      fluorescein angiography), improved significantly (p<0.001) in Defibrotide-treated
      patients compared to controls. In our opinion, Defibrotide's manifold effects on
      vascular endothelia may account for this improvement by stimulation of tPA, PGI2,
      PGE2, thrombomodulin and modulation of endothelin-1 release. CONCLUSIONS: Our
      preliminary data seem to suggest that Defibrotide could be proposed for medical
      treatment of nonproliferative diabetic retinopathy.

PMID- 10406154
TI  - Intraocular foreign bodies. Factors influencing final visual outcome.
AB  - PURPOSE: To identify the prognostic factors of poor visual outcome (visual acuity
      < or =6/240) in eyes with intraocular foreign bodies. METHODS: The records of 95
      consecutive patients were retrospectively reviewed for 6 years (1990-1995). All
      eyes underwent a primary surgical repair and foreign-body removal (electromagnet
      or vitrectomy). The mean follow-up period was 25 months (6-72 months). Single
      analysis and multiple logistic stepwise regression analysis were performed to
      determine predictors of poor vision. RESULTS: Thirty patients (31.6%) showed
      6/240 or worse vision at the end of their follow-up period. Three significant
      predictive factors had independent and combined effects on post-operative visual
      outcome: a corneo-scleral entry wound (odds ratio (OR)=14.5, p=0.001), largest
      diameter of IOFB (OR=1.21, p=0.01) and the presence of secondary retinal
      detachment (OR=9.48, p=0.0002). Post-operative complications included traumatic
      cataracts (51%), retinal detachments (28%) and phthisis bulbi (8%). CONCLUSION:
      Using multivariate analysis, corneo-scleral entry wound, largest diameter of
      foreign body and secondary retinal detachment were found to be predictors of poor
      visual outcome after intraocular foreign body removal. Our results suggest that
      patients with high-risk intraocular foreign body trauma should be candidates for
      pars plana vitrectomy rather than electromagnet procedure.

PMID- 10406155
TI  - Survival after malignant tumors of the orbit and periorbit treated by
      exenteration.
AB  - PURPOSE: In order to further assess the survival value of orbital exenteration in
      malignant orbital and periorbital tumors. METHODS: The charts of 44 patients
      exenterated for a neoplasm of the orbit or periorbit were reviewed in a
      retrospective study. RESULTS: The overall 4-year survival was 45%. 26 patients
      had free margins on histological examination and 24 patients had developed local
      recurrence or metastasis. Local recurrence or metastasis were significantly more
      common in the group with transected margins than in the group with free-margins
      (p= 0.01). Survival between the group of patients with local recurrence or
      metastasis and the group without local recurrence or metastasis showed
      statistically significant difference (p=0.0025). In contrast, survival between
      the group of patients with free margins and the group with transected margins did
      not show statistically significant difference (p=0.13). CONCLUSION: Surgical free
      margins section is a key element in successful cancer surgery but seems not the
      only prognosis variable.

PMID- 10406156
TI  - Review of 1028 bulbar eviscerations and enucleations. Changes in aetiology and
      frequency over a 20-year period.
AB  - PURPOSE: To evaluate possible changes in aetiology and frequency of bulbar
      eviscerations and enucleations. METHODS: A total of 1028 cases from three two
      year periods: 1975-76, 1985-86 and 1995-96 collected by the Eye Pathology
      Institute were reviewed. RESULTS: A significant decrease (p<0.001) in number of
      enucleations was observed from 358 in 1975-76 to 214 in 1995-96, corresponding to
      an almost equivalent increase in number of eviscerations from 5 in 1975-76 to 83
      in 1995-96. The total number of eye removals decreased significantly (p<0.01)
      over the last two periods from 368 in 1985-86 to 296 in 1995-96. This was
      primarily caused by a decrease in the number of glaucoma-related enucleations
      from 32.7% in 1975-76 to 15.0% in 1995-96. The reduction in number was not fully
      balanced by the increase in glaucoma-related eviscerations. CONCLUSION: Over the
      last 20 years there has been a change in choice of operation from enucleation to
      evisceration.

PMID- 10406157
TI  - Clinical experience with latanoprost: a retrospective study of 153 patients.
AB  - PURPOSE: To evaluate the pressure-reducing effect of latanoprost in a clinical
      setting. PATIENTS AND METHODS: Data from 153 consecutive patients with open angle
      glaucoma receiving latanoprost were recorded at baseline (n=153), 2 weeks (n=151)
      and 8 to 12 months (n=89) after starting latanoprost treatment. In 82 patients
      (54%) latanoprost was added to ongoing treatment. Two patients terminated
      treatment because of side effects before the first follow-up examination.
      RESULTS: 56% (84/151) of the patients showed an intraocular pressure reduction of
      20% or more after 2 weeks, regardless of baseline therapy. The difference between
      intraocular pressure before (24.4+/-5.8 mm Hg) and after 2 weeks of latanoprost
      treatment (19.9+/-6.9 mm Hg) in the total group (n=151) was highly significant
      (p<0.0001). The pressure reduction was significantly correlated with the
      pretreatment intraocular pressure level (r=0.48, p<0.0001). In the 89 patients
      who could be followed for 8 to 12 months no significant upward drift in mean
      intraocular pressure was observed, but in fourteen patients intraocular pressure
      increased with 5 mm Hg or more. Thirteen patients reported side effects, five of
      these discontinued the treatment. CONCLUSION: Latanoprost is obviously an
      efficient pressure reducing drug which can be used in glaucoma patients as an
      adjunct to any ongoing therapy with the expectation of clinically relevant
      intraocular pressure reduction in 45-71% of the patients.

PMID- 10406158
TI  - Management of traumatic luxation of the globe. A case report.
AB  - PURPOSE: To report the management of a patient who had LeFort type III fractures
      and traumatic luxation of the globe with avulsion of the optic nerve and all
      extraocular muscles except for the medial rectus. METHODS: Eight hours after the
      trauma, the detached and retracted superior and lateral recti muscles could be
      found and sutured to their original insertions. The inferior rectus could not be
      retrieved. RESULTS: Although the left eye had no light perception, most of its
      motility was restored resulting in an unblemished cosmesis. CONCLUSION: Avoiding
      primary enucleation helped to alleviate the psychological burden of the trauma on
      the patient. In case of the eventual development of phthisis bulbi, the patient
      will have a chance to be fitted with a prosthesis over his own eye with a
      resulting better motility.

PMID- 10406159
TI  - Phakomatous choristoma may be located in the eyelid or orbit or both.
AB  - PURPOSE: Phakomatous choristoma is a rare congenital tumour of lenticular origin.
      The exact location at clinical presentation is controversial, but herein we
      provide evidence that phakomatous choristoma may be located in the lower eyelid
      or orbit or both. METHODS: Case report of an infant presenting with a mass in the
      lower eyelid at birth, a systematic review of previous cases of phakomatous
      choristoma and an outline of the histopathological features in normal mid-facial
      embryonic development at different gestational ages. RESULTS: The
      histopathological features of the present case were consistent with those of a
      phakomatous choristoma. The preoperative imaging studies and clinical findings at
      surgery suggested that the tumour occupied parts of both the lower eyelid and
      anterior orbit. Histopathological sections of a normal human embryo showed that
      at the 26-mm stage of development the embryonic lens is formed but the bony walls
      defining the orbit are not yet present. CONCLUSION: Phakomatous choristoma arises
      in a setting of undifferentiated mesenchymal tissue which later may develop into
      the lower eyelid or orbit depending on the choristomatous elements being
      deposited superficial or deep to the embryonic surface.

PMID- 10406160
TI  - Severe Acanthamoeba sclerokeratitis in a non-contact lens wearer.
AB  - PURPOSE: To report a case of severe Acanthamoeba sclerokeratitis. METHODS: A 70
      year-old male non-contact lens wearer was examined for severe pain in the left
      eye which began about 40 days after cataract surgery. In spite of a careful
      search, it required 6 weeks to detect Acanthamoeba. Systemic and topical
      fluconazol and miconazol did not help and the keratitis progressed into necrotic
      sclerokeratitis with protrusion of uveal tissue through the thin sclera. RESULTS:
      Those findings slowly got worse before the Acanthamoeba sclerokeratitis resolved
      6 months later with scar formation. CONCLUSION: We describe the terminal and
      cicatricial stages of Acanthamoeba keratitis, and report that the healing process
      can follow the terminal stage and the eye does not need to be enucleated.

PMID- 10406162
TI  - Primary laser photocoagulation of "small" choroidal melanomas.
AB  - PURPOSE: To evaluate primary laser photocoagulation of "small" posterior
      choroidal melanomas in eyes with good vision. METHOD: This study includes a case
      series comprising six patients treated with standard laser techniques for
      melanoma, which had a mean thickness of 3.1 mm (range 2.9-3.9 mm), largest basal
      diameter of 8.6 mm (mean, range 7.0-10.0 mm), and located 0.5-2 disk diameters
      from the fovea or 0.3-3 disk diameters from the optic nerve head. RESULTS: No
      metastatic death was observed in the follow-up period (range 3 1/2-7 1/2 years).
      Two local recurrences appeared, both were treated with plaques, one eye was later
      enucleated. Two additional cases were also treated with plaques. Only two of the
      irradiated eyes retained reading vision. CONCLUSION: Primary photocoagulation of
      "small" posterior choroidal melanomas with argon laser is not recommended.

PMID- 10406161
TI  - Anterior uveitis associated with Mycoplasma pneumoniae pneumonia: a case report.
AB  - The authors report a case of bilateral uveitis following Mycoplasma pneumoniae
      pneumonia verified by IgM and rising IgG antibodies against the organism. Uveitis
      is a rare manifestation of Mycoplasma pneumoniae pneumonia and since it is a
      common pathogen, it should be considered in the differential diagnosis, even in
      the absence of respiratory symptoms or neurological findings. Immunobiological
      hypotheses are briefly discussed.

PMID- 10406163
TI  - A new device for ocular massage after trabeculectomy.

PMID- 10406164
TI  - Bilateral dacryoadenitis associated with brucellosis.

PMID- 10406165
TI  - Classification and desirable result in intermittent exotropia.

PMID- 10406166
TI  - Unilateral atypical fundus lesions with slow progression.

PMID- 10406167
TI  - Biomechanical measurements of the lens capsule.

PMID- 10406168
TI  - Blue-on-yellow perimetry in the diagnosis of glaucoma.

PMID- 10406169
TI  - Visual dysfunction and ocular signs associated with periventricular leukomalacia
      in children born preterm.

PMID- 10406170
TI  - Corneal keratocyte density: aspects of methodology, physiology and
      pathophysiology.

PMID- 10406171
TI  - The role of HBV DNA quantitative PCR in monitoring the response to interferon
      treatment in chronic hepatitis B virus infection.
AB  - BACKGROUND/AIMS: To investigate whether the measurement of HBV DNA by
      quantitative polymerase chain reaction (PCR) is helpful in monitoring response to
      interferon treatment in chronic hepatitis B virus infection, we have determined
      sequentially serum levels of HBV DNA during and up to 18 months after treatment,
      in 10 patients with a sustained response (all anti-HBe positive, five also HBsAg
      negative and anti-HBs positive) and, as controls, in 12 non-responders. METHODS:
      Serum HBV DNA was measured by standard hybrisation assay (Genostics, Abbott) and
      by quantitative PCR (Amplicor HBV Monitor test, Roche Diagnostic Systems).
      RESULTS: A clear difference in HBV viral load between responders and non
      responders was observed from the fourth week of treatment and was maintained
      throughout the study period. At the last follow up 16-26 (median 21) months after
      starting treatment, all the 10 responders were HBV DNA negative by hybridisation.
      By PCR, however, five (one anti-HBs and four anti-HBe positive) were still HBV
      DNA positive. In addition, one anti-HBs positive patient HBV DNA negative by PCR
      at last follow up, had fluctuating levels of HBV DNA by PCR during the
      observation period, only intermittently falling below the threshold of the assay.
      CONCLUSIONS: The measurement of HBV DNA by quantitative PCR provides early
      prediction of response to interferon, allowing prompt modification of treatment.
      With this technique, HBV DNA is detected in a high proportion of sustained
      responders, suggesting that HBV may never be completely eliminated by interferon
      treatment, even after anti-HBs seroconversion.

PMID- 10406172
TI  - Mother-to-infant transmission of hepatitis C virus: molecular evidence of
      superinfection by homologous virus in children.
AB  - BACKGROUND/AIM: Vertical transmission of hepatitis C virus (HCV) is well
      established but its incidence is low. To assess the molecular evidence of mother
      to-infant transmission or intrafamilial transmission of HCV, the NS5 B region and
      the hypervariable region 1 (HVR1) of the E2/NS1 region of the HCV genome from
      each member of a family were investigated. METHODS: A 35-year-old mother with
      chronic hepatitis C virus infection and her four infected boys were studied. The
      same HCV 1a genotype was found in all five. Phylogenetic analysis was done by the
      neighbor-joining, the maximum likelihood, and the maximum parsimony methods.
      RESULTS: Comparison of the phylogenetic trees in the NS5B and HVR1 regions showed
      that the sequences in the children were more closely related to the population of
      variants of their own mother than to any genotype la sequence available in the
      databases. However, four HVR1 clones from two brothers (E2 and E3) had a strong
      homology, but were significantly divergent from the variants of the mother.
      CONCLUSIONS: These results suggest that a cluster of HCV strains exists in the
      family and that E3 could have been superinfected by E2 HCV strains and
      reciprocally. In conclusion, phylogenetic analysis through variable regions of
      the genome suggests that at least two modes of transmission are involved in this
      family: perinatal and horizontal.

PMID- 10406173
TI  - Association of the HLA-DRB1*01 allele with spontaneous viral clearance in an
      Irish cohort infected with hepatitis C virus via contaminated anti-D
      immunoglobulin.
AB  - BACKGROUND/AIMS: The host's immune response may influence the course of hepatitis
      C virus (HCV) infection. The aim of this study was to examine the distribution of
      HLA Class II DRB1* alleles in a homogeneous cohort of individuals who were
      infected with HCV-contaminated anti-D immunoglobulin, and to compare frequencies
      of alleles in individuals with spontaneous viral clearance to those with chronic
      HCV infection. METHODS: HLA DRB1* typing was performed on whole blood or serum
      from 157 females. Of these, 73 had spontaneously recovered from infection
      (persistently HCV RNA negative), while 84 had chronic HCV infection (persistently
      HCV RNA positive). A group of 5000 healthy bone marrow donors served as a control
      population. RESULTS: No significant differences were observed between individuals
      with spontaneous viral clearance or chronic HCV infection for age, sex, alcohol
      consumption, source or duration of infection. The DRB1*01 allele was found
      significantly more frequently in individuals with viral clearance compared to
      those with chronic infection (27.4% vs. 7.1% p = 0.001, odds ratio OR = 4.9, pc =
      0.01). No significant association was shown between severity of liver disease and
      DRB1* alleles. CONCLUSIONS: DRB1*01 is associated with spontaneous viral
      clearance in an Irish cohort infected with HCV via contaminated anti-D
      immunoglobulin. HLA-DRB1* genes do not appear to influence severity of liver
      disease. These results suggest that host HLA-DRB1* alleles are important
      contributors to disease outcome.

PMID- 10406175
TI  - Ethnic difference in the prevalence of monoclonal B-cell proliferation in
      patients affected by hepatitis C virus chronic liver disease.
AB  - BACKGROUND/AIM: In previous studies we demonstrated that all patients affected by
      HCV-positive type II mixed cryoglobulinaemia have a monoclonal B-cell population
      in peripheral blood mononuclear cells, and that a large fraction of HCV-infected
      patients develop a monoclonal B-cell expansion, even in the absence of dosable
      serum cryoglobulins. However, the prevalence of Type II mixed cryoglobulinaemia
      in HCV-infected individuals seems to be high in Italy, whereas it is very low in
      Japan. This study was performed to investigate whether there are ethnic
      differences in the prevalence of asymptomatic HCV-associated monoclonal B-cell
      expansions. METHODS: Forty-four Japanese patients affected by HCV-positive
      chronic liver disease (two healthy carriers, 31 chronic hepatitis and 11
      cirrhosis) were compared with a group of 60 Italian patients (one healthy
      carrier, 49 chronic hepatitis, and 10 cirrhosis) without dosable levels of
      cryoglobulins. The monoclonality of peripheral blood mononuclear cells was
      investigated by RT/PCR analysis of Immunoglobulin gene rearrangements. Liver
      function tests, rheumatoid factor, cryocrit level, anti-HCV antibodies, HCV-RNA,
      and HCV genotype were performed according to standard methodology. RESULTS: A B
      cell monoclonal population was found in 26% of Italian patients, whereas all
      Japanese patients were negative. No correlation was found between B-cell
      monoclonality and severity of liver disease, length or source of the infection,
      HCV genotype, sex, clinical and biochemical parameters. CONCLUSIONS: This study
      indicates that a monoclonal B-cell proliferation in peripheral blood mononuclear
      cells is common in HCV infection, but only in Italy, whereas it is absent in
      Japan. This explains the very low prevalence of Type II mixed cryoglobulinaemia
      in HCV-positive Japanese subjects, and suggests that HCV is able to determine a B
      cell expansion only in the presence of, presently undetermined, host factors.

PMID- 10406174
TI  - HLA class II favors clearance of HCV infection and progression of the chronic
      liver damage.
AB  - BACKGROUND/AIMS: This study was aimed to determine whether host-dependent genetic
      factors modulate the outcome of HCV infection. METHODS: HLA class II DRB and DQB
      typing was performed in 184 infected patients and 200 healthy volunteers. Among
      the patients, 149 subjects had persistent HCV viremia (Group 1) and 35 subjects
      underwent spontaneous viral clearance (Group 2). Group 1 included cirrhotic
      patients with transfusion-acquired infections (n = 79), asymptomatic HCV carriers
      (n = 42), and patients with chronic hepatitis C responsive to interferon therapy
      (n = 28). RESULTS: Spontaneous viral clearance was associated with HLA DRB1*1104
      (pc = 0.054, OR = 4.51, 95% C.I. 2.02-10.1) and HLA DQB1*0301 (pc = 0.0039, OR =
      4.52, 95% C.I. 2.15-9.51). In Group 1 the haplotype DRB1*1104/DQB1*0301 was less
      frequent (4.8%) than in Group 2 (18.3%) (pc = 0.009, OR = 7.38, 95% C.I. 2.58
      21.59). At the HLA level, cirrhotic patients were not different from asymptomatic
      HCV carriers and patients with interferon-induced viral clearance. In cirrhotic
      patients infected with genotype 1b, the DQB1*0502 allele was more frequently
      found in those with rapidly progressive liver damage (OR = 8.15, 95% C.I. 1.49
      44.44), but the corrected p-value was not significant (pc = 0.09). CONCLUSIONS:
      The HLA haplotype DRB1*1104/DQB1*0301 appears to contribute to the spontaneous
      clearance of HCV infection. The predominance of the DQB1*0502 allele in cirrhotic
      patients with a rapidly progressive disease possibly reflects an influence of
      this allele on the progression of the HCV-related liver disease.

PMID- 10406176
TI  - Immunohistochemical analysis of hepatic interferon alpha-beta receptor level:
      relationship between receptor expression and response to interferon therapy in
      patients with chronic hepatitis C.
AB  - BACKGROUND/AIMS: This study aimed to determine the expression level of interferon
      alpha/beta (IFN-alpha/beta) receptor in the liver immunohistochemically and
      evaluate its usefulness in predicting the outcome to IFN therapy in patients with
      chronic hepatitis C. METHODS: The level of IFN-alpha/beta receptor expression was
      determined in immunoperoxidase-stained pretreatment sections of 55 chronic
      hepatitis C patients later treated with IFN. We used liver biopsy specimens and
      mouse monoclonal anti-human IFN-alpha/beta receptor antibody. Quantitative
      analysis of immunostaining was performed by image analysis software. The level of
      IFN-alpha/beta receptor was expressed as Unit (U). Sustained responders were
      patients who showed persistent disappearance of serum HCV-RNA during the 6-month
      period after treatment, while non-responders showed persistence of viremia after
      therapy. RESULTS: Positive immunostaining was observed in the cytoplasm of
      hepatocytes. The mean expression level of hepatic IFN-alpha/beta receptor in
      sustained responders (2.65+/-1.11 U, n = 15) was significantly (p<0.001) higher
      than in non-responders (1.61+/-1.05 U, n = 40). A significant decrease in IFN
      alpha/beta receptor expression level was observed in patients with advanced liver
      fibrosis. In patients with low level viremia (pretreatment serum HCV-RNA <1
      Meq/ml, n = 18), the level of IFN-alpha/beta receptor in sustained responders
      (2.89+/-1.12 U, n = 11) was significantly (p<0.01) higher than in non-responders
      (0.93+/-0.33 U, n = 7). CONCLUSIONS: Our results suggest that measurement of the
      level of hepatic IFN-alpha/beta receptor in patients with chronic hepatitis C
      might be useful for predicting the response to IFN therapy. Resistance to IFN
      therapy in patients with chronic hepatitis C might be due to low levels of
      hepatic IFN-alpha/beta receptor.

PMID- 10406177
TI  - Improved correlation between multiple mutations within the NS5A region and
      virological response in European patients chronically infected with hepatitis C
      virus type 1b undergoing combination therapy.
AB  - BACKGROUND/AIMS: Studies from Japan showed that HCV-1b isolates with at least
      four amino acid changes within NS5A2209-2248 compared with the prototype sequence
      HCV-J are more sensitive to interferon than isolates with a prototype sequence.
      However, the data were not unequivocally confirmed in studies from other
      geographical areas. These discrepancies may be explained by differences in the
      prevalence of multiple mutations within the NS5A2209-2248 and/or the treatment
      efficacy. METHODS: In the present study, we therefore investigated the
      correlation between NS5A2209-2248 sequences of HCV-1b isolates and sustained
      virological response in 72 European patients treated with 3x6 MU interferon-a per
      week with (n = 26) and without (n = 46) ribavirin (1000-1200 mg/day). Serum HCV
      RNA was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and
      the NS5A2209-2248 region was analyzed by sequencing of PCR products or individual
      clones. RESULTS: Compared with HCV-1b prototype sequences, 19 patients (26%) had
      no amino acid changes (prototype), 47 patients (65%) had 1-3 mutations
      (intermediate type) and six patients (8%) had at least 4 mutations in the
      NS5A2209-2248 region (mutant type). Nine of the 12 patients with sustained
      virological response were infected with an intermediate type HCV-1b, the
      remaining three patients revealed a mutant type HCV-1b. A sustained virological
      response was achieved in three of four patients with a mutant type HCV-1b treated
      with interferon-alpha and ribavirin, but in none of the mutant type HCV-1b
      infected patients treated with interferon-a alone. Quasispecies analysis of HCV
      in the NS5A2209-2248 region showed only minor heterogeneity of the amino acid
      sequence. CONCLUSIONS: The prevalence of mutant type HCV-1b isolates in European
      patients is low. In patients treated with combination therapy interferon-a and
      ribavirin, a correlation between mutant type HCV-1b isolates and sustained
      virological response was observed. The discrepancies between previous studies
      appear to be related to the efficacy of antiviral treatment and to the low
      prevalence of mutant type HCV-1b isolates in Western countries.

PMID- 10406178
TI  - Why is the interferon sensitivity-determining region (ISDR) system useful in
      Japan?
AB  - BACKGROUND/AIMS: The amino acid sequence of NS5A2209-2248, named the "interferon
      sensitivity-determining region" (ISDR), has been reported to correlate with
      responsiveness of interferon (IFN) therapy to patients with the hepatitis C virus
      (HCV) genotype-1b, by several Japanese authors. However, European authors have
      failed to find this phenomenon, suggesting a difference in HCV-1b isolates
      between Japan and Europe. METHODS: We compared the HCV-1b nucleotide sequences of
      our Japanese patients and those of other countries quoted from GenBank, using the
      envelope 1 sequence. RESULTS: A phylogenetic tree analysis revealed two
      characteristic groups from a geographical viewpoint: one group (NJ group)
      consists of almost entirely non-Japanese isolates, and the other (J group) of
      almost entirely Japanese isolates. The isolates other than the NJ and J groups
      are characterized by their specific nucleotide residue, constructing an
      individual group (W group). Japanese HCV-1b isolates consist of the J group and W
      group (approximately 40% and 60%, respectively). Comparative study between the
      two groups in Japanese patients treated with IFN revealed a strong correlation
      between ISDR type and IFN responsiveness only in the J group, but not in the W
      group. CONCLUSIONS: These observations convinced us that the existence of the
      Japan-specific J group is one reason why the ISDR system is useful only in Japan.

PMID- 10406180
TI  - Infection with a novel human DNA virus (TTV) has no pathogenic significance in
      patients with liver diseases.
AB  - BACKGROUND/AIMS: A recently identified DNA virus, termed TT virus (TTV), has been
      associated with post-transfusional hepatitis, and a high prevalence of TTV
      infection in patients with acute or chronic liver disease of unknown etiology has
      been reported from Japan, but few data are available about TTV infection in other
      countries. METHODS: Using hemi-nested-PCR amplification to detect TTV-DNA
      sequences in serum, we investigated TTV infection in blood donors and in patients
      with liver diseases of varied etiology. RESULTS: The prevalence of TTV infection
      was 13.7% in blood donors (23/168), 18.6% in chronic hepatitis C (19/102), 28.6%
      in chronic hepatitis B (16/56), 29.9% in hepatocellular carcinoma (20/67), 9.1%
      in cryptogenic chronic liver disease (2/22) and 39.6% in fulminant hepatitis
      (19/48). The prevalence of TTV infection in patients with virus-induced or
      idiopathic fulminant hepatitis was similar. Comparison of TTV-infected and non
      infected patients did not reveal significant differences concerning demographic,
      epidemiological or histopathological features. In patients with hepatitis C,
      response to interferon therapy was not related to TTV infection. Phylogenetic
      analysis of TTV isolates showed that at least three different types of TTV are
      present in Spain. CONCLUSIONS: Our data suggest that TTV infection is frequent
      among blood donors and patients with acute liver disease. However, pathogenic
      effects associated with TTV infection were not observed.

PMID- 10406179
TI  - Long-term response to interferon alpha is unrelated to "interferon sensitivity
      determining region" variability in patients with chronic hepatitis C virus-1b
      infection.
AB  - BACKGROUND/AIMS: Contradictory data have been reported about the predictive value
      of the variability in interferon sensitivity determining region (ISDR) of
      hepatitis C virus (HCV) genotype-1b on response to interferon-alpha (IFN-alpha)
      therapy. The aim of this study was to examine this issue in a series of patients
      with long-term response to IFN treatment. METHODS: We retrospectively analyzed 24
      patients with chronic HCV genotype-1b infection treated with IFN-alpha (total
      dose median 677, range 216-1350 MU) selected in 6 Italian Liver Units. These
      patients were defined as true long-term responders (LTR) since they showed
      persisting biochemical and virological responses to IFN treatment (mean follow-up
      38 months). HCV genomes from pretreatment serum samples were amplified and
      directly sequenced. The ISDR amino-acid sequences obtained were aligned and
      compared with the published sequence of HCV-J. RESULTS: Amino-acid substitutions
      were found in 23 of the 24 patients, and 22 of them showed an H to R amino-acid
      change at codon 2218. Fourteen patients showed only one mutation (at codon 2218),
      two had 2, five had 3, one had 4 and one had 5 mutations. When we compared the
      ISDR sequences from the 24 LTR with those of non-responders (NR), we found no
      significant correlation between the number of mutations and the response to
      therapy. CONCLUSIONS: Our results demonstrate that the persisting efficacy of IFN
      treatment in patients with chronic HCV is not related to the number of ISDR amino
      acid substitutions of the infecting viruses. Further studies are needed to verify
      whether other NS5A sequences outside the ISDR might be involved in the mechanisms
      of IFN resistance.

PMID- 10406181
TI  - Hepatic cytochrome P450 is directly inactivated by nitric oxide, not by
      inflammatory cytokines, in the early phase of endotoxemia.
AB  - BACKGROUND/AIMS: Although the activity of the liver in metabolizing and
      eliminating various drugs decreases in endotoxemia, the mechanism remains to be
      elucidated. The generation of nitric oxide by the inducible type of nitric oxide
      synthase increases in endotoxemia. Nitric oxide readily reacts with heme proteins
      such as cytochrome P450 that metabolize various compounds, including steroids and
      eicosanoids. The purpose of this study was to determine the effect of nitric
      oxide on the function of hepatic cytochrome P450 in endotoxemic rats. METHODS: To
      determine the dynamic aspects of nitric oxide metabolism, hepatic levels of the
      inducible type of nitric oxide synthase and heme-iron nitrosyl complexes, and
      plasma levels of nitrite and nitrate were determined in rats before and after
      intravenous administration of lipopolysaccharide. Changes in the levels of P450
      isoforms and testosterone hydroxylation activity in hepatic microsomes were also
      determined. To evaluate in vivo CYP3A2 activity, midazolam sleep time was
      measured. RESULTS: When lipopolysaccharide increased the hepatic inducible type
      of nitric oxide synthase and plasma levels of nitric oxide metabolites, the
      intensity of low-spin signal of electron spin resonance responsible for the
      ferric form of P450 decreased with a concomitant increase in heme-iron nitrosyl
      complexes in the liver. Lipopolysaccharide-related nitric oxide generation is
      followed by an early decrease in the levels of cytochrome P450 and of
      testosterone hydroxylation activity in liver microsomes. Midazolam sleep time was
      prolonged by lipopolysaccharide. All these early changes were prevented by the
      inhibitor of nitric oxide synthase, N(G)-iminoethyl-L-ornithine. Moreover,
      lipopolysaccharide suppressed the gene expression of CYP2C11 and CYP3A2.
      Decreases in levels of cytochrome P450 and their mRNAs were more pronounced at 24
      h after LPS administration, but apparently they are NO-independent. CONCLUSIONS:
      These results suggest that lipopolysaccharide-induced modulation of cytochrome
      P450 may occur via the interplay of two different mechanisms and that, especially
      in the early phase, nitric oxide-dependent inhibition is more important.

PMID- 10406182
TI  - Characterization of ion transport mechanisms involved in bombesin-stimulated
      biliary secretion in rat cholangiocytes.
AB  - BACKGROUND/AIMS: Bombesin is a neuropeptide which stimulates fluid and
      bicarbonate secretion from cholangiocytes by stimulating Cl-/HCO3- exchange.
      However, the underlying regulation and interactions of ion transporters and
      channels mediating this bombesin-stimulated biliary secretion are not well
      characterized. The aim of the study was to characterize the ion transport
      processes involved in bombesin-stimulated secretion in polarized cholangiocytes
      in comparison with those of secretin. METHODS: Isolated bile duct units (IBDU)
      were prepared from normal rat liver. Biliary secretion induced by bombesin was
      measured by quantitative video-microscopy in the presence and absence of
      inhibitors. RESULTS: Bombesin-stimulated secretion was inhibited by H2-DIDS,
      NPPB, BaCl2, TEA, and acetazolamide. However, in contrast to secretin, bombesin
      stimulated secretion was not inhibited by disruption of microtubules.
      CONCLUSIONS: Bombesin-stimulated biliary secretion is dependent on anion
      exchangers, Cl- and K+ channels, and carbonic anhydrase but not on microtubules.
      Bombesin regulates secretion in cholangiocytes by different mechanisms from those
      established for secretin.

PMID- 10406183
TI  - Sclerosing cholangitis in adults with cystic fibrosis: a magnetic resonance
      cholangiographic prospective study.
AB  - BACKGROUND/AIMS: Liver disease is a leading cause of morbidity in adult patients
      with cystic fibrosis. Diagnosis of limited liver involvement in asymptomatic
      patients is important since a safe and effective treatment with ursodeoxycholic
      acid can be used. We carried out a prospective open study to describe the
      intrahepatic biliary lesions using magnetic resonance cholangiography. METHODS:
      Twenty-seven adult patients with cystic fibrosis were prospectively enrolled,
      whatever their hepatobiliary status. All patients underwent liver function tests,
      ultrasonography and magnetic resonance cholangiography. Magnetic resonance
      cholangiograms were acquired on a Philips 1.5 Tesla unit using a 3D TSE MR
      sequence. Acquisition parameters (120 slices, 1.6 mm thickness, interslice
      overlap 0.8 mm) were followed by MIP reconstruction in two orthogonal planes.
      Magnetic resonance cholangiography images were assessed for the presence of
      stenosis, dilatations and rigidity corresponding to current criteria of
      cholangitis. Among the 27 cystic fibrosis patients, 18 (Group I) fulfilled none
      of the clinical, biological or ultrasonographic criteria of liver disease; the
      remaining nine (Group II) fulfilled the criteria for liver disease. In every
      patient, current causes of secondary sclerosing cholangitis had been excluded.
      RESULTS: All the Group II patients had abnormal magnetic resonance cholangiograms
      with features resembling those of primary sclerosing cholangitis in five, and
      simple biliary lesions in four. Nine Group I patients had abnormal magnetic
      resonance cholangiograms with primary sclerosing cholangitis-like lesions in five
      and simple biliary lesions in four. Magnetic resonance cholangiography anomalies
      were always dilatations, either isolated or associated with strictures and
      rigidity, both resembling those seen in cholangitis. They were seen in all the
      patients with known liver disease and in half the patients without evidence of
      liver disease. CONCLUSION: This study confirms the high frequency of intrahepatic
      biliary abnormalities in CF patients, which is probably underestimated by
      clinical, biological and ultrasonographic evaluation. The magnetic resonance
      cholangiography technique could be useful to detect early intrahepatic biliary
      tract involvement in cystic fibrosis patients.

PMID- 10406184
TI  - Expression of cyclins D1, D2 and E correlates with proliferation of rat stellate
      cells in culture.
AB  - BACKGROUND/AIMS: Regulation of cell cycle progression of cultured rat stellate
      cells was studied. METHODS: DNA synthesis was determined by the uptake of
      [3H]thymidine or 5-bromo-2'-deoxyuridine. Cell cycle distribution was analyzed
      using FACScan of cellular DNA stained with propidium iodide. Expression of
      cyclins and cyclin-dependent kinase 4 was evaluated by Western and Northern
      blotting. RESULTS: DNA synthesis of primary-cultured stellate cells was found to
      accelerate 48 h after plating. Cell cycle analysis revealed that more than 93% of
      the cells were in G0/G1 phase during the first 48 h after plating. The cell
      population in S phase abruptly increased to about 16% 72 h after culture and
      shifted to G2/M phase thereafter. The level of proteins and mRNAs for cyclins D1,
      D2 and E started to increase 48 h after culture with a concomitant expression of
      platelet-derived growth factor receptor beta, while the level of cyclin-dependent
      kinase 4 and its mRNA remained unchanged. On the other hand, stellate cells
      remained in G1 phase when they were cultured in the presence of 3-isobutyl-1
      methylxanthine or dibutyryl cAMP after plating. Attenuation of the expression of
      cyclins D1, D2 and E and platelet-derived growth factor receptor beta, but not
      cyclin-dependent kinase 4 was found in stellate cells cultured with these agents.
      Further analysis revealed that LY294002, a selective inhibitor of
      phosphatidylinositol 3-kinase, suppressed DNA synthesis and cyclin D1 expression
      in a dose-dependent manner without affecting platelet-derived growth factor
      receptor beta expression. CONCLUSIONS: Induction of G1 cyclins may play crucial
      roles in cell cycle transition of cultured stellate cells from G1 to S.
      Expression of platelet-derived growth factor receptor beta and activation of
      phosphatidylinositol 3-kinase may be involved in the process.

PMID- 10406185
TI  - Improvement in liver fibrosis, functionality and hemodynamics in CCI4-cirrhotic
      rats after injection of the Liver Growth Factor.
AB  - BACKGROUND/AIMS: Most substances used in experimental models of cirrhosis are
      chosen either as protectors of lipid peroxidation, as antifibrogenic agents or as
      vitamins, among others. In this report, we analyze the improvement produced, in
      established cirrhosis (CCl4 plus phenobarbital) in rats, by intraperitoneal
      injection of Liver Growth Factor, a hepatic mitogen with activity both in vivo
      and in vitro. METHODS: Following confirmation of CCl4-induced cirrhosis, Liver
      Growth Factor (4.5 microg per ratx2 injections/week for 3 weeks) was administered
      to one group of rats (Cirr+LGF). The remaining rats (Cirr) received saline. The
      groups were compared in terms of serum enzymes, tissue damage, total liver
      collagen, collagenase activity, microsomal enzyme activities, splanchnic and
      systemic hemodynamics and portosystemic shunting. RESULTS: Treatment of rats
      presenting CCl4-induced cirrhosis with Liver Growth Factor decreased serum
      aminotransferase levels and increased levels of serum albumin and total protein.
      The Liver collagen content was lower in rats treated with Liver Growth Factor
      (2.96 vs. 4.32 mg/g liver, p<0.01). Microscopic studies revealed that the livers
      of rats receiving Liver Growth Factor showed decreases in fibrosis, necrosis and
      inflammatory infiltration, as well as a recovery of architectural integrity.
      Liver function was improved after treatment with Liver Growth Factor, as
      indicated by the rate constant for elimination of aminopyrine, which increased
      from 0.0063 to 0.0170 (p<0.05). This increase was accompanied by a higher total
      amount of cytochrome P-450 as well as of certain P-450 isoenzymes, especially
      those that are hormone-dependent, such as P-450 3A. The improved liver histology
      and function observed in Cirr+LGF rats was associated with decreases in portal
      pressure (14.4 vs. 9.4 mm Hg, p<0.01) and portosystemic shunting (55.8 vs. 11.5%,
      p<0.01), as well as increases in mean arterial pressure and systemic vascular
      resistance, and a reduction in ascites. CONCLUSIONS: Administration of the
      hepatic mitogen, Liver Growth Factor, to CCl4-cirrhotic rats decreased liver
      collagen and reorganized the hepatic extracellular matrix, resulting in an
      improvement in liver function, reduced portal pressure and amelioration of
      ascites.

PMID- 10406186
TI  - Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis: implication for a
      potential link between retinoid loss and TGF-beta mediated fibrogenesis in vivo.
AB  - BACKGROUND/AIMS: During hepatic fibrosis, hepatic stellate cells (HSCs) transform
      into myofibroblastic cells and lose their intracellular droplets of retinyl
      esters, the storage form of vitamin A. Recently, we have demonstrated that 9,13
      di-cis-retinoic acid (RA), a geometric isomer identified as a stable and major
      metabolite of vitamin A in circulation, stimulates the synthesis of plasminogen
      activator (PA) and induces PA/plasmin-dependent latent transforming growth factor
      (TGF)-beta activation in HSC cultures, probably via induction and activation of
      RA receptor (RAR) alpha. The aim of the present study was to address a potential
      link between the loss of retinyl esters to increased formation of RA(s), which
      might play a role in facilitating TGF-beta-mediated liver fibrogenesis in vivo.
      METHODS: We examined the effect of 9,13-di-cis-RA on transactivating activity of
      RARalpha in HeLa cells as well as its effect on PA- and TGF-beta-dependent
      collagen synthesis in rat and human HSC cultures. We measured the changes in 9,13
      di-cis-RA levels both during activation of rat HSCs in vitro and during porcine
      serum-induced rat hepatic fibrosis in vivo and correlated this with RAR
      alpha/beta, PA, TGF-beta and type I procollagen mRNA expression in the fibrotic
      liver. RESULTS: 9,13-di-cis-RA transactivated RARalpha, and provoked PA/plasmin
      and TGF-beta-dependent procollagen synthesis in HSCs. 9,13-di-cis-RA levels were
      increased both in activated HSCs in vitro and in fibrotic liver accompanying the
      enhanced expression of RAR alpha/beta, PA, TGF-beta and procollagen in vivo.
      CONCLUSIONS: These findings suggest a potential link between 9,13-di-cis RA
      formation and hepatic fibrosis via formation of TGF-beta in vivo, and thus
      provide further insight into the biologic role of retinoids during hepatic
      fibrogenesis.

PMID- 10406187
TI  - S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo
      controlled, double-blind, multicenter clinical trial.
AB  - BACKGROUND/AIM: The efficacy of S-adenosylmethionine (AdoMet) in the treatment of
      liver cell injury has been demonstrated in several experimental models. The aim
      of this study was to investigate the effects of AdoMet treatment in human
      alcoholic liver cirrhosis. METHODS: A randomized, double-blind trial was
      performed in 123 patients treated with AdoMet (1200 mg/day, orally) or placebo
      for 2 years. All patients had alcoholic cirrhosis, and histologic confirmation of
      the diagnosis was available in 84% of the cases. Seventy-five patients were in
      Child class A, 40 in class B, and 8 in class C. Sixty-two patients received
      AdoMet and 61 received placebo. RESULTS: At inclusion into the trial no
      significant differences were observed between the two groups with respect to sex,
      age, previous episodes of major complications of cirrhosis, Child classification
      and liver function tests. The overall mortality/liver transplantation at the end
      of the trial decreased from 30% in the placebo group to 16% in the AdoMet group,
      although the difference was not statistically significant (p = 0.077). When
      patients in Child C class were excluded from the analysis, the overall
      mortality/liver transplantation was significantly greater in the placebo group
      than in the AdoMet group (29% vs. 12%, p = 0.025), and differences between the
      two groups in the 2-year survival curves (defined as the time to death or liver
      transplantation) were also statistically significant (p = 0.046). CONCLUSIONS:
      The present results indicate that long-term treatment with AdoMet may improve
      survival or delay liver transplantation in patients with alcoholic liver
      cirrhosis, especially in those with less advanced liver disease.

PMID- 10406188
TI  - Clinical usefulness of serum matrix metalloproteinase-2 concentration in patients
      with chronic viral liver disease.
AB  - BACKGROUND/AIMS: The production of matrix metalloproteinase (MMP)-2 was reported
      to be increased in chronically diseased livers. Our aims in the present study
      were to elucidate the clinical usefulness of the serum MMP-2 concentration in
      chronic viral liver disease. METHODS: We measured serum MMP-2 concentrations with
      a sandwich enzyme immunoassay in 62 patients with chronic hepatitis, 35 patients
      with liver cirrhosis, 55 patients with hepatocellular carcinoma and 24 healthy
      individuals. The assay detects proMMP-2 and proMMP-2 complexed with tissue
      inhibitor of metalloproteinase-2, but not active forms of MMP-2. The liver MMP-2
      content was also measured in autopsied cirrhotic and non-cirrhotic livers.
      Gelatin zymography and gel filtration chromatography were carried out using the
      serum. RESULTS: The serum MMP-2 concentration was significantly increased in the
      liver cirrhosis and hepatocellular carcinoma patients, but not in the patients
      with chronic hepatitis. There was no significant difference in the serum MMP-2
      level between the liver cirrhosis and hepatocellular carcinoma groups. In the
      patients with chronic viral liver disease, serum MMP-2 concentration showed the
      best correlation with the degree of liver fibrosis and with serum hyaluronate
      level. The zymography of serum showed the majority of MMP-2 in serum exists as a
      proMMP-2. The chromatography of serum revealed a single peak at the position of
      about 90 kDa corresponding to an MMP-2 complexed with tissue inhibitor of
      metalloproteinases-2. The liver MMP-2 content was markedly increased in the
      cirrhotic livers compared with the non-cirrhotic livers, and was positively
      correlated with the liver collagen content. When investigating the utility of the
      serum MMP-2 test for differentiating liver cirrhosis from chronic hepatitis, the
      utility of serum MMP-2 was equal to that of serum hyaluronate, which is known as
      the best current test for diagnosing liver cirrhosis. CONCLUSIONS: The serum MMP
      2 concentration reflects mainly the amount of proMMP-2 complexed with tissue
      inhibitor of metalloproteinase-2. The serum MMP-2 level was markedly increased in
      cirrhotic patients, and may be explained by an overproduction in the cirrhotic
      liver. In the clinical state, the measurement of serum MMP-2 was as useful a test
      for diagnosing liver cirrhosis as is the serum hyaluronate level.

PMID- 10406189
TI  - The role of nitric oxide in the inhibition of gastric epithelial proliferation in
      portal hypertensive rats.
AB  - BACKGROUND/AIM: Portal hypertension is associated with inhibition of gastric
      epithelial proliferation and increased gastric nitric oxide synthase activity.
      Whether the nitric oxide inhibits gastric epithelial proliferation is unclear.
      METHODS: Portal vein ligation was performed to induce portal hypertension in
      rats. The rats were treated for 7 days with either vehicle or N(G)-nitro-L
      arginine methyl ester (L-NAME) at 5 mg/kg or 25 mg/kg doses (gastric gavage,
      twice a day). Sham-operated rats treated with vehicle served as controls.
      Hemodynamic parameters were measured using radiolabeled microspheres in
      anesthetized animals. Gastric epithelial proliferation was assessed by evaluating
      the proliferative cell nuclear antigen labeling index. RESULTS: The cardiac index
      and gastric fundic blood flow were higher, and the gastric fundic proliferative
      cell nuclear antigen labeling index was lower in the portal hypertensive rats
      than in the controls. In portal hypertensive rats, the 5 mg/kg dose of L-NAME
      decreased the cardiac index and increased the gastric fundic proliferative cell
      nuclear antigen labeling index to levels similar to those found in the controls,
      but did not affect gastric fundic blood flow significantly. The 25 mg/kg dose of
      L-NAME further decreased both the cardiac index and the gastric fundic blood
      flow, but did not affect the gastric proliferative cell nuclear antigen labeling
      index significantly. CONCLUSIONS: In portal hypertensive rats, the correction of
      systemic hyperdynamic circulation by NO inhibition is associated with
      normalization of gastric epithelial proliferation. Excessive nitric oxide may
      inhibit gastric epithelial proliferation in portal hypertension.

PMID- 10406190
TI  - Evidence against a role for endotoxin in the hyperdynamic circulation of rats
      with prehepatic portal hypertension.
AB  - BACKGROUND/AIMS: Excessive formation of nitric oxide may mediate the generalized
      vasorelaxation and hyporesponsiveness to vasoconstrictors observed in portal
      hypertensive states. Endotoxin, released from the bowel and detoxified by the
      liver, could stimulate inducible nitric oxide synthase directly or indirectly via
      the cytokine cascade. This study investigated the effect of chronic
      intraperitoneal injection of polymyxin B, a neutralizing antagonist of endotoxin,
      on the hemodynamics of partially portal vein-ligated (PVL) rats. METHODS:
      Concomitantly with endotoxin (600 EU) and dactinomycin (80 microg), polymyxin B
      (0.1 mg) or normal saline (N/S) was administered via an intraperitoneal route to
      male Sprague-Dawley rats. Twenty-four hours later, mean arterial pressure was
      determined. In PVL rats polymyxin B (0.1 mg in 5 cc N/S) or N/S was given
      intraperitoneally twice daily from 2 days prior to operation until 5 days (short
      term) or 14 days (long-term) after the operation. Long-term polymyxin B- or N/S
      treated sham-operated rats were included as controls. Hemodynamic studies with a
      thermodilution technique were performed at the end of treatment. Blood samples
      were collected from another series of PVL rats with long-term treatment to
      determine plasma levels of endotoxin and tumor necrosis factor-alpha. Plasma
      levels of endotoxin and tumor necrosis factor-alpha were measured by Limulus
      assay and the ELISA method, respectively. RESULTS: With the dosage of 0.1 mg
      polymyxin B, hypotension in rats subjected to endotoxin and dactinomycin
      administration could be corrected (polymyxin B vs. placebo: 130.0+/-7.7 vs.
      108.8+/-6.7 mm Hg, p<0.05). However, long-term or short-term treatment with the
      same dosage of polymyxin B failed to ameliorate the hyperdynamic circulation of
      PVL rats. In addition, long-term treatment with polymyxin B did not change
      systemic and portal hemodynamics in sham-operated rats. Plasma levels of
      endotoxin and tumor necrosis factor-alpha were comparable in PVL rats treated
      with long-term polymyxin B or N/S (p>0.05). CONCLUSIONS: Our findings do not
      support the role of endotoxin in the hyperdynamic circulation of PVL rats.

PMID- 10406191
TI  - Sorbitol removal by the metastatic liver: a predictor of systemic toxicity of
      intra-arterial chemotherapy in patients with liver metastases.
AB  - BACKGROUND/AIM: Hepatic arteriovenous shunting in the metastatic liver reduces
      the advantages of intraarterial infusion of chemotherapeutic agents because of
      the passage of drugs into the systemic circulation. The aim of this study was to
      quantitatively assess spontaneous functional hepatic arteriovenous shunting in
      patients with liver metastases and to determine its implication in the increase
      in systemic toxic effects of intra-arterial infusion chemotherapy with
      floxuridine. METHODS: Twenty-five patients who underwent implantation of arterial
      ports for regional chemotherapy of liver metastases were studied. Functional
      hepatic arterio-venous shunting was evaluated through the bioavailability of
      intra-arterially administered D-sorbitol, a safe, natural compound whose kinetic
      features make its hepatic clearance flow dependent. In addition, D-sorbitol
      hepatic clearance (a parameter reflecting functional liver blood flow) and common
      liver function tests were evaluated for each studied patient. Patients were then
      grouped with respect to the percentage of medically-assessed liver occupation by
      metastases and with respect to systemic toxicity of the chemotherapeutic
      treatment. Both univariate and multivariate analyses by Student's t-test and
      stepwise logistic regression, respectively, were performed in both groups for
      each of the evaluated parameters (age, liver function tests, D-sorbitol hepatic
      clearance and arterial bioavailability). RESULTS: Arterial bioavailability of D
      sorbitol ranged between 0.05 and 0.72 and was significantly greater in patients
      with more than 50% liver occupation (0.39+/-0.19) compared with those with minor
      liver involvement (0.17+/-0.13; p = 0.003); it was also significantly greater in
      patients experiencing high-grade systemic toxicity (0.40+/-0.19) compared with
      those with low-grade toxicity (0.16+/-0.11; p<0.001). Multivariate analysis
      showed that arterial bioavailability of D-sorbitol was the only parameter among
      those evaluated which was able to predict systemic toxicity of this kind of
      chemotherapy. CONCLUSIONS: Our results show that, in the metastatic liver,
      arterial bioavailability of D-sorbitol, an index of functional arteriovenous
      shunting, varies widely, is significantly greater in patients with massive liver
      occupation and it is a good predictor of systemic toxicity of intra-arterial
      regional chemotherapy with floxuridine.

PMID- 10406192
TI  - Purification of antigenic peptide from murine hepatoma cells recognized by Class
      I major histocompatibility complex molecule-restricted cytotoxic T-lymphocytes
      induced with B7-1-gene-transfected hepatoma cells.
AB  - BACKGROUND/AIM: It has been reported that expression of costimulatory molecules,
      such as B7, on tumors is essential for priming tumor-specific cytotoxic T
      lymphocytes (CTLs). Here, we have attempted to induce murine hepatoma-specific
      CTLs by immunizing with the B7-1-gene-expressing hepatoma cells, and to identify
      the epitope(s) presented on the hepatoma cells. METHODS: The B7-1-gene encoding
      plasmid was transferred into the murine hepatoma cell line, Hepa1-6. Syngeneic
      C57BL/6 mice were immunized with the B7-1-transfected cells via various routes to
      prime CTLs. The mild acid elution method was used to isolate antigenic fractions
      from the class-I major histocompatibility complex (MHC) molecules on the Hepa1-6
      cells. Cytotoxicity was measured by standard 51Cr-releasing assay. The effect of
      the CTLs on hepatoma growth was evaluated in hepatoma-bearing SCID mice to which
      the cells were preadministered. RESULTS: A clone, termed L1, highly expressing
      the B7-1-gene, has been established. Killer cells generated from mice immunized
      intraperitoneally with L1 cells eliminated both L1 and Hepa1-6 cells, and also
      another syngeneic hepatoma cell line, Hepa1-clc7. The killer cells were CD8+ and
      the class-I MHC molecule-restricted CTLs which might recognize hepatoma-specific
      antigenic peptide(s) in association with the D(b)class-I MHC molecules. A
      functional peptide fraction was obtained from eluted fluid of the Hepa1-6 cells.
      In addition, intravenous preadministration of the CTLs inhibited the hepatoma
      growth in SCID mice. CONCLUSIONS: The hepatoma epitope-specific CTLs which
      suppressed hepatoma growth in vivo could be generated with the B7-1-gene
      transfected hepatoma cells. These results will be useful in establishing
      immunotherapy against hepatocellular carcinoma.

PMID- 10406193
TI  - Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using
      matched and simulated controls: 5-year survival. Multi-centre group.
AB  - BACKGROUND/AIMS: Alcoholic cirrhosis is the most common cause of liver
      transplantation in US males. The limited number of donor livers calls for
      "prioritisation", favouring those patients who will benefit most. The aim was to
      assess the efficacy of liver transplantation in patients with alcoholic
      cirrhosis. METHODS: We compared the survival of 169 transplanted patients with
      two conservatively treated control groups, one of 169 patients matched for
      prognostic factors (age, cirrhosis severity, bleeding history) and one of 169
      simulated patients. RESULTS: The probability of survival to 5 years in the
      transplanted group was 66% (95% confidence interval 58-74%) vs. 52% (44-60; p =
      0.03) in the matched group and 54% (51-57; p = 0.01) in the simulated controls.
      Transplantation was associated with survival (relative risk = 1.51; p = 0.02),
      independently of risk score (risk = 2.07; p<0.001), indication, period of
      inclusion, centre experience, and alcohol abstinence. Patients with severe
      disease (Pugh C11-15) benefited most in terms of 5-year survival: 58% (44-72) vs.
      31% (17-45; p = 0.008) in the matched and 35% (30-40; p<0.001) in the simulated
      control groups. For patients at lower risk there was no significant difference.
      CONCLUSIONS: Liver transplantation increases the 5-year survival of patients with
      severe alcoholic cirrhosis. In patients at lower risk, efficacy of
      transplantation should be confirmed by longer follow-up or by randomised trial.

PMID- 10406195
TI  - Peliosis hepatis with initial presentation as acute hepatic failure and
      intraperitoneal hemorrhage in children.
AB  - Peliosis hepatis, a condition characterized by the presence of blood-filled
      lacunar spaces in the liver, usually has a chronic presentation pattern and is
      mainly reported in adult patients in association with chronic wasting disorders
      and after administration of various drugs. The present report concerns two
      previously healthy young children in whom peliosis hepatis initially presented as
      acute hepatic failure and who had Escherichia coli pyelonephritis. Both patients
      had active intraperitoneal hemorrhage from the peliotic liver lesions, and liver
      ultrasonography showed multiple hypoechoic areas of different sizes, which in
      this context should suggest the diagnosis. One child died from hypovolemic shock
      and the other recovered. This study indicates that acute peliosis hepatis can be
      a serious life-threatening disease in children.

PMID- 10406194
TI  - Immunosuppressant FK506 inhibits inducible nitric oxide synthase gene expression
      at a step of NF-kappaB activation in rat hepatocytes.
AB  - BACKGROUND/AIMS: Recent evidence indicates that an increase in nitric oxide
      production after liver transplantation is associated with acute allograft
      rejection. Nitric oxide mediates cellular injury under various pathological
      conditions in the liver. Studies were performed to determine whether the
      immunosuppressants FK506 and cyclosporin A directly influence gene expression of
      inducible nitric oxide synthase by interleukin 1beta in hepatocytes. METHODS:
      Primary cultures of rat hepatocytes were treated with interleukin 1beta in the
      presence and absence of FK506 or cyclosporin A. Release of nitrite (nitric oxide
      metabolite) into culture medium, levels of inducible nitric oxide synthase
      protein and mRNA, and activation of nuclear factor-kappaB were compared with the
      two drugs. RESULTS: Interleukin 1beta increased levels of inducible nitric oxide
      synthase protein and inducible nitric oxide synthase mRNA, as well as nitric
      oxide production, in the cultured hepatocytes. Nuclear factor-kappaB, an
      important transcription factor in inducible nitric oxide synthase gene expression
      in response to inflammation, also appeared in the nuclear fraction of hepatocytes
      after addition of interleukin 1beta. FK506 markedly inhibited the nitric oxide
      formation, inducible nitric oxide synthase protein synthesis and inducible nitric
      oxide synthase mRNA expression induced by interleukin 1beta, but cyclosporin A
      had no effects. Furthermore, FK506 inhibited nuclear factor-kappaB activation and
      decreased mRNA levels of the p50/p65 subunits of nuclear factor-kappaB.
      CONCLUSIONS: These results demonstrate that FK506, but not cyclosporin A,
      inhibits the induction of inducible nitric oxide synthase expression during
      nuclear factor-kappaB activation. FK506 may influence liver function during
      diseases by modulating the nitric oxide pathway, in addition to its
      immunosuppressive effect.

PMID- 10406196
TI  - Images in hepatology. Gas in the portal vein.

PMID- 10406197
TI  - The direct interplay between HCV NS5A protein and interferon transduction signal:
      from clinical to basic science.

PMID- 10406198
TI  - Role of S-adenosyl-L-methionine in the treatment of liver diseases.

PMID- 10406199
TI  - Endotoxemia: an unnecessary but aggravating condition in portal hypertension?

PMID- 10406200
TI  - A suggested extension of the HCV ISDR does not alter our former conclusions on
      its predictive value for IFN response.

PMID- 10406201
TI  - Quantitative determination of free intracellular amino acids in single human
      polymorphonuclear leucocytes. Recent developments in sample preparation and high
      performance liquid chromatography.
AB  - The described procedure allows quantitative, highly precise and reproducible
      analysis of free amino acid concentrations in single polymorphonuclear leucocytes
      (PMLs). This method is superior to previously described procedures with regard to
      sample size, PML separation, sample preparation and stability, as well as the
      chosen fluorescence high-performance liquid chromatography procedure, and can
      satisfy the high demands for ultra-sensitive and comprehensive amino acid
      analysis, especially for the continuous surveillance of severe diseases and organ
      dysfunction.

PMID- 10406202
TI  - Chromatographic study of magnesium and calcium binding to immobilized human serum
      albumin.
AB  - The use of immobilized human serum albumin (HSA) as a stationary phase in
      affinity chromatography has been shown to be useful in resolving optical
      antipodes or to investigate interactions between drugs and protein. However, to
      our knowledge, no inorganic ion binding has been studied on this immobilized
      protein type. To do this, the human serum albumin stationary phase was
      assimilated to a weak cation-exchanger by working with a mobile phase pH equal to
      6.5. A study of the eluent ionic strength effect on ion retention was carried out
      by varying the buffer concentrations and the column temperatures. The
      thermodynamic parameters for magnesium and calcium transfer from the mobile to
      the stationary phase were determined from linear van't Hoff plots. An enthalpy
      entropy compensation study revealed that the type of interaction was independent
      of the mobile phase composition. A simple model based on the Gouy-Chapman theory
      was considered in order to describe the retention behavior of the test cations
      with the mobile phase ionic strength. From this theoretical approach, the
      relative charge densities of the human serum albumin surface implied in the
      binding process were estimated at different column temperatures.

PMID- 10406203
TI  - Mutual separation of hinge-glycopeptide isomers bearing five N
      acetylgalactosamine residues from normal human serum immunoglobulin A1 by
      capillary electrophoresis.
AB  - Immunoglobulin A1 (IgA1) from normal human serum is known to have O-linked sugar
      chains, sialylated Galbeta1,3GalNAc, in the hinge portion. In order to reduce the
      microheterogenity of the sugar chain, the hinge glycopeptide prepared from IgA1
      was sequentially treated with neuraminidase and beta-galactosidase. The asialo-,
      agalacto-hinge glycopeptide (HGP-SG) composed of a 33-mer peptide (HP33) and N
      acetylgalactosamine (GalNAc) residues was obtained. The HGP-SG was separated into
      three major peaks, A, B and C, by high-performance liquid chromatography (HPLC).
      Each glycopeptide fraction was further separated by capillary electrophoresis
      (CE). Peaks A, B and C with HPLC abundantly contained HP33 bearing five and six N
      acetylgalactosamine residues (HGP33-5,6GN), HGP33-4,5GN and HGP33-3,4GN,
      respectively. Among these glycopeptide peaks, only the HGP33-5GN peak was partly
      split into two peaks based on the CE analysis - HGP33-5GN-alpha and -beta. The
      glycopeptide, HGP25-5GN shortened by the thermolysin digest of HGP33-SG was also
      well separated into the alpha and beta forms by CE analysis. No differences in
      their mass and peptide portion were observed between HGP25-5GN-alpha and -beta.
      Therefore, the obtained result might indicate that HGP25-5GN-alpha was an isomer
      of HGP25-5GN-beta differing in its stereospecific structure of the peptide
      portion and/or the attachment site of the GalNAc residue.

PMID- 10406204
TI  - Comparative determination of purine compounds in carotid plaque by capillary zone
      electrophoresis and high-performance liquid chromatography.
AB  - Allantoin, uric acid (UA), hypoxanthine (Hx) and xanthine (X) were determined on
      carotid plaque by capillary zone electrophoresis (CZE) and high-performance
      liquid chromatography (HPLC). Comparison of the results showed that capillary
      zone electrophoresis may have similar or even superior analytical performance to
      HPLC, especially for the determination of allantoin in biological samples.

PMID- 10406205
TI  - Method for liquid-liquid extraction of blood surrogates for assessing human
      exposure to jet fuel.
AB  - A baseline method of liquid-liquid extraction for assessing human exposure to JP
      8 jet fuel was established by extracting several representative compounds ranging
      from very volatile to semi-volatile organic compounds, including benzene,
      toluene, nonane, decane, undecane, tridecane, tetradecane and pentadecane, from
      PBS buffer. Some specific techniques for solvent selection, solvent evaporation,
      and GC analysis were developed to accommodate this wide range of constituents of
      JP-8. The application of the established method to the extraction and
      quantitative analysis of JP-8 from PBS and bovine plasma was demonstrated.

PMID- 10406206
TI  - Extraction and high-performance liquid chromatographic separation of selected
      pyrene and benzo[a]pyrene sulfates and glucuronides: preliminary application to
      the analysis of smokers' urine.
AB  - In the study of the complex mixture of urinary metabolites derived from
      polycyclic aromatic hydrocarbon compounds, it is desirable to simplify the
      analysis through separation of classes of compounds. We have developed a liquid
      chromatography (LC) method for the separation of selected sulfate and glucuronide
      conjugate isomers derived from hydroxybenzo[a]pyrenes (OH-BaP) and
      hydroxypyrenes. This LC method was utilized in the preliminary analysis of the
      urine of smokers by combining it with an extraction technique employing tetra-n
      butyl-ammonium ion as a coupling agent to generate a 1:1 complex, extractable in
      chloroform at low pH prior to LC analysis.

PMID- 10406207
TI  - 17alpha-ethyl-5beta-estrane-3alpha, 17beta-diol, a biological marker for the
      abuse of norethandrolone and ethylestrenol in slaughter cattle.
AB  - The metabolism of the illegal growth promoter ethylestrenol (EES) was evaluated
      in bovine liver cells and subcellular fractions of bovine liver preparations.
      Incubations with bovine microsomal preparations revealed that EES is extensively
      biotransformed into norethandrolone (NE), another illegal growth promoter.
      Furthermore, incubations of monolayer cultures of hepatocytes with NE indicated
      that NE itself is rapidly reduced to 17alpha-ethyl-5beta-estrane-3alpha, 17beta
      diol (EED). In vivo tests confirmed that, after administration of either EES or
      NE, EED is excreted as a major metabolite. Therefore, it was concluded that, both
      in urine and faeces samples, EED can be used as a biological marker for the
      illegal use of EES and/or NE. Moreover, by monitoring EED in urine or faeces
      samples, the detection period after NE administration is significantly prolonged.
      These findings were further confirmed by three cases of norethandrolone abuse in
      a routine screening program for forbidden growth promoters.

PMID- 10406208
TI  - Specific high-performance liquid chromatography assay for determination of
      rifabutin plasma concentration following Extrelut column extraction.
AB  - A specific, precise and accurate assay for determination of rifabutin in human
      plasma using Extrelut column extraction was developed and validated. Rifabutin
      concentrations were calculated with a standard curve ranging from 5 to 800 ng ml(
      1). using a split-curve approach. Chromatographic peaks were separated by means
      of a 5 microm Symmetry Shield RP8 using a KH2PO4 (0.05 M) buffer-acetonitrile
      mobile phase. Detection wavelength was set at 275 nm. Chromatography was carried
      out at room temperature (20-25 degrees C). The limit of quantification was 5 ng
      ml(-1). The recovery was over 71%. The intra-day precision of the assay was 5, 7,
      and 1% while the inter-day precision was 11.2, 8.1, and 5.8% at concentrations of
      30, 150 and 500 ng ml(-1), respectively. The accuracy ranged from 99 to 108%.
      Forty of the drugs most commonly administered to HIV-positive patients were found
      not to interfere with the assay. The assay has been used in a comparative study
      of rifabutin pharmacokinetics in HIV-positive patients with or without wasting
      syndrome. reserved.

PMID- 10406209
TI  - Simultaneous quantitation of etoposide and its catechol metabolite in human
      plasma using high-performance liquid chromatography with electrochemical
      detection.
AB  - Etoposide, a highly active and widely used antineoplastic agent, is O
      demethylated to its active catechol metabolite. A high-performance liquid
      chromatographic assay method for the simultaneous quantitation of etoposide and
      etoposide catechol in human plasma was established. Etoposide and etoposide
      catechol were extracted from plasma using chloroform and methanol followed by
      phase separation, evaporation of the organic phase, and reconstitution of the
      residue. Chromatography was accomplished using a reversed-phase phenyl analytical
      column (390 mm x 3.9 mm I.D.) with a mobile phase of 76.6% 25 mM citric acid-50
      mM sodium phosphate (pH 2.4)-23.4% acetonitrile pumped isocratically at 1 ml/min
      with electrochemical detection. The limit of detection for etoposide was 1.2 nM
      and for etoposide catechol was 0.2 nM. The precision (CV) for etoposide ranged
      from 0.7 to 3% and for the catechol metabolite from 1 to 6%; accuracy of
      predicted values ranged from 97 to 106% and 94 to 103%, respectively. The assay
      was linear from 0.1 to 10 microM for etoposide and from 0.005 to 0.5 microM for
      etoposide catechol in plasma. Recovery of etoposide and etoposide catechol ranged
      from 93 to 95% and 90 to 98%, respectively. Stability of etoposide and etoposide
      catechol in human plasma containing ascorbic acid stored at -70 degrees C for one
      year was demonstrated. This assay procedure is suitable for evaluation of
      etoposide and etoposide catechol pharmacokinetics in plasma following etoposide
      administration.

PMID- 10406211
TI  - Separation of eleven central nervous system drugs by capillary zone
      electrophoresis.
AB  - Several strategies to improve the separation of 11 central nervous system drugs
      (antipsychotics and antidepressants) with capillary zone electrophoresis were
      applied: the variation of the pH of the buffering background electrolyte, its
      ionic strength, addition of inclusion-complex forming beta-cyclodextrin or
      polyvinylpyrrolidone (PVP), respectively, as a replaceable, soluble, polymeric
      pseudo-stationary phase. Best separation was achieved at pH 2.5 and 35 mmol/l
      ionic strength (phosphate buffer), with 0.5% (w/v) PVP.

PMID- 10406210
TI  - Simultaneous quantitative determination of cilostazol and its metabolites in
      human plasma by high-performance liquid chromatography.
AB  - A high-performance liquid chromatographic (HPLC) method for the simultaneous
      determination of cilostazol, a quinolinone derivative, and its known metabolites
      OPC-13015, OPC-13213, OPC-13217, OPC-13366, OPC-13269, OPC-13326 and OPC-13388 in
      human plasma was developed and validated. Cilostazol, its metabolites and two
      internal standards, OPC-3930 and OPC-13112, were extracted from human plasma by a
      combination of liquid-liquid and liquid-solid phase extractions, with combined
      organic solvents of n-butanol, methanol, chloroform, methyl-tert.-butyl ether,
      and a Sep-Pak silica column. The combined extract was then evaporated and the
      residue was reconstituted in ammonium acetate buffer (pH 6.5). The reconstituted
      solution was injected onto a HPLC system and was subjected to reversed-phase HPLC
      on a 5 microm ODS-80TM column to obtain quality chromatograph and good peak
      resolution. A gradient mobile phase with different percentages of acetonitrile in
      acetate buffer (pH 6.5) was used for the resolution of analytes. Cilostazol, its
      metabolites and the two internal standards were well separated at baseline from
      each other with resolution factor being 74 and 138. This HPLC method was
      demonstrated to be specific for all analytes of interest with no significant
      interference from the endogenous substances of human plasma. The lower limit of
      quantitation was 20 ng/ml for cilostazol and all metabolites. The method was
      validated initially for an extended linear range of 20-600 ng/ml for all
      metabolites and cilostazol, and has been revised later for a linear range of 20
      1200 ng/ml for cilostazol and two major and active metabolites OPC-13015 and OPC
      13213. The overall accuracy (relative recovery) of this method was established to
      be 98.5% to 104.9% for analytes with overall precision (CV) being 1.5% to 9.0%.
      The long-term stability of clinical plasma samples was established for at least
      one year at -20 degrees C. Two internal standards of OPC-3930 and OPC-13112 were
      evaluated and validated. However, the data indicated that there was no
      significant difference for all accuracy and precision obtained by using either
      OPC-3930 or OPC-13112. OPC-3930 was chosen as the internal standard for the
      analysis of plasma samples from clinical studies due to its shorter retention
      time. During the validation standard curves had correlation coefficients greater
      than or equal to 0.998 for cilostazol and the seven metabolites. These data
      clearly demonstrate the reliability and reproducibility of the method.

PMID- 10406212
TI  - High-performance liquid chromatography determination of residue levels on chicken
      carcasses treated with cetylpyridinium chloride.
AB  - Cetylpyridinium chloride (CPC) has been found to be effective in reducing
      contamination of chicken carcasses from a variety of microorganisms, including
      Escherichia coli O157:H7, Salmonella typhimurium, Campylobacter jejuni, Aeromonas
      hydrophila, Listeria monocytogenes, and Staphylococcus aureus. A procedure has
      been developed to determine residue levels on chicken carcasses after CPC
      treatment. For the analysis, chicken carcasses were extracted with 95% ethanol.
      The CPC concentration in the extract was measured by high-performance liquid
      chromatography (HPLC) with ultraviolet detection using dodecylpyridinium chloride
      (DPC) as an internal standard. The method was validated in the concentration
      range of 3-200 microg/ml CPC in ethanolic extract. This assay is rapid, precise,
      and accurate.

PMID- 10406213
TI  - Determination of idarubicin and idarubicinol in rat plasma using reversed-phase
      high-performance liquid chromatography and fluorescence detection.
AB  - A reversed-phase high-performance liquid chromatographic method is described for
      the simultaneous determination of idarubicin and idarubicinol in rat plasma.
      Blood samples were analyzed from 16 rats which had received an intravascular dose
      of 2.25 mg kg(-1) idarubicin. After deproteinization with acetonitrile, the
      separation was performed with a LiChrospher 100 RP-18 column (5 microm), using
      fluorescence detection (excitation: 485 nm/emission: 542 nm). The mean recovery
      was 95.6% for idarubicin and 90.7% for idarubicinol, respectively. The detection
      limit was 0.25 ng ml(-1) using an injection volume of 50 microl. Daily relative
      standard deviation (RSD) was 3.2% (10 ng idarubicin/ml, n=10) and 4.4% (10 ng
      idarubicinol/ml, n=10).

PMID- 10406214
TI  - Strategies toward predicting peptide cellular permeability from computed
      molecular descriptors.
AB  - The therapeutic efficacy of an orally administered drug is dictated not only by
      its pharmacological properties such as potency and selectivity, but also its
      pharmacokinetic properties such as its access to the site of activity. Thorough
      evaluation of the physicochemical and biological barriers to drug delivery is
      essential to the selection and successful development of drug candidates. We have
      demonstrated previously that cellular permeability, as a primary component of
      drug delivery, is principally dependent upon the desolvation potential of the
      polar functionalities in the molecule and, secondarily, upon the solute
      lipophilicity [Conradi, R.A., Hilgers, A.R., Ho, N.F.H., Burton, P.S. (1992). The
      influence of peptide structure on transport across Caco-2 cells. II. Peptide bond
      modification which results in improved permeability. Pharm. Res. 9, 473-479].
      Increasingly sophisticated computational methods are becoming available for
      describing molecular structural features proposed to correlate with such
      molecular physicochemical determinants of permeability. Herein we examine the
      relationships of various computationally derived molecular geometric descriptors
      for a set of peptides and peptidomimetics, in the context of experimentally
      measured hydrogen-bond potentials and lipophilicities, with their cellular
      permeabilities. These descriptors include molecular volume, polar and non-polar
      surface areas and projected molecular cross-sectional areas. Particular attention
      is paid to the roles of solvation treatments and other computational factors in
      descriptor generation, deconvolution of cellular transport mechanisms and
      statistical analyses of the resulting data for the development of valid,
      structure-based and mechanistically meaningful models of cellular permeability.
      No significant correlation of cellular permeability with computed descriptors was
      found. This was primarily because of our inability to identify surrogates for
      hydrogen-bond desolvation potential for the solutes from among these descriptors.

PMID- 10406215
TI  - Synthesis and evaluation of the physicochemical properties of esterase-sensitive
      cyclic prodrugs of opioid peptides using coumarinic acid and phenylpropionic acid
      linkers.
AB  - In an attempt to improve the membrane permeabilities of opioid peptides, we have
      synthesized cyclic prodrugs of [Leu5]-enkephalin and DADLE using a coumarinic
      acid or a phenylpropionic acid linker. The synthesis of the coumarinic acid- and
      phenylpropionic acid-based cyclic prodrugs followed similar strategies. Key
      intermediates were the compounds with the C-terminal amino acids of opioid
      peptides (L-Leu, [Leu5]-enkephalin; D-Leu, DADLE) attached to the phenol hydroxyl
      group and the remaining amino acids of the peptide linked via the N-terminal
      amino acid (L-Tyr) attached to the carboxylic acid groups of the prodrug moieties
      (coumarinic acid or propionic acid). Cyclization of these linear precursors gave
      the cyclic prodrugs in 30-50% yields. These cyclic prodrugs exhibited excellent
      transcellular permeation characteristics across Caco-2 cell monolayers, an in
      vitro model of the intestinal mucosa. To correlate the cellular permeabilities of
      these cyclic prodrugs with their physicochemical properties, we calculated their
      Stokes-Einstein molecular radii from their diffusion coefficients which were
      determined by NMR and we determined their membrane interaction potentials using
      immobilized artificial membrane (IAM) column chromatography. The cyclic prodrugs
      exhibited molecular radii similar to those of the parent compounds, [Leu5]
      enkephalin and DADLE. However, these cyclic prodrugs were shown to have much
      higher membrane interaction potentials than their corresponding opioid peptides.
      Therefore, the enhanced cellular permeation of the cyclic prodrugs is apparently
      due to the alteration of their lipophilicity and hydrogen bonding potential, but
      not their molecular sizes.

PMID- 10406216
TI  - The effect of conformation on the membrane permeation of coumarinic acid- and
      phenylpropionic acid-based cyclic prodrugs of opioid peptides.
AB  - In an earlier study using Caco-2 cells, an in vitro cell culture model of the
      intestinal mucosa, we have shown that the coumarinic-based (3 and 4) and the
      phenylpropionic acid-based (5 and 6) cyclic prodrugs were more able to permeate
      the cell monolayers than were the corresponding opioid peptides, [Leu5]
      enkephalin (1, H-Tyr-Gly-Gly-Phe-Leu-OH) and DADLE (2, H-Tyr-D-Ala-Gly-Phe-D-Leu
      OH). In an attempt to explain the increased permeation of the cyclic prodrugs, we
      have determined the possible conformations of these cyclic prodrugs in solution,
      using spectroscopic techniques (2D-NMR, CD) and molecular dynamics simulations.
      Spectroscopic as well as molecular dynamic studies indicate that cyclic prodrug 4
      exhibits two major conformers (A and B) in solution. Conformer A exhibited a type
      I beta-turn at Tyr1-D-Ala2-Gly3-Phe4. The presence of a turn was supported by ROE
      cross-peaks between the NH of D-Ala2 and the NH of Gly3 and between the NH of
      Gly3 and the NH of Phe4. Conformer B of cyclic prodrug 4 consisted of type II
      beta-turns at the same positions. The type II turn was stabilized by hydrogen
      bonding, thus forming a more compact structure, whereas the type I turn did not
      exhibit similar intramolecular hydrogen bonding. Spectroscopic data for compounds
      3, 5 and 6 are consistent with the conclusion that these cyclic prodrugs have
      solution structures similar to those observed with cyclic prodrug 4. The
      increased lipophilicity and well-defined secondary structures in cyclic prodrugs
      3-6, but not in the linear peptides 1 and 2, could both contribute to the
      enhanced ability of these prodrugs to permeate membranes.

PMID- 10406217
TI  - Synthesis and evaluation of the physicochemical properties of esterase-sensitive
      cyclic prodrugs of opioid peptides using an (acyloxy)alkoxy linker.
AB  - The objective of this work was to synthesize the cyclic prodrugs 1 and 2 of
      [Leu5]-enkephalin (Tyr-Gly-Gly-Phe-Leu-OH) and DADLE (Tyr-D-Ala-Gly-Phe-D-Leu
      OH), respectively, using an (acyloxy)alkoxy linker. The cyclic prodrugs 1 and 2
      were synthesized via a convergent method using the (acyloxy)alkoxy promoiety that
      connected the C- and N-terminus of the peptides. The key intermediates were
      compounds 6a and 9a for cyclic prodrug 1 and compounds 6b and 9b for cyclic
      prodrug 2. The key intermediates 6a and 9a (or 6b and 9b) were coupled to give
      compound 10a (or 10b). The N- and C-terminus protecting groups were removed from
      10a and 10b to give compounds 11a and 11b, respectively, which were then treated
      with HBTU to give 1 and 2 in 40% and 53% yields, respectively. The cyclic
      prodrugs 1 and 2 exhibited Stokes-Einstein molecular radii similar to those of
      [Leu5]-enkephalin and DADLE; however, the cyclic prodrugs were shown to be
      significantly more lipophilic than the corresponding opioid peptides, as
      determined by partitioning experiments using immobilized artificial membrane
      (IAM) column chromatography. In addition, the cyclic prodrugs exhibit stable
      solution conformations, which reduce their hydrogen bonding potentials. Based on
      these physicochemical characteristics, the cyclic prodrugs 1 and 2 should have
      exhibited better transcellular flux across the Caco-2 cell monolayer than [Leu5]
      enkephalin and DADLE, respectively. However, the cyclic prodrugs 1 and 2 were
      shown in separate studies to be substrates for P-glycoprotein, which
      significantly reduced their ability to permeate across Caco-2 cell monolayers.
      When P-glycoprotein was inhibited, the permeability characteristics of prodrugs 1
      and 2 were consistent with their physicochemical properties.

PMID- 10406218
TI  - The effect of conformation of the acyloxyalkoxy-based cyclic prodrugs of opioid
      peptides on their membrane permeability.
AB  - In an earlier study using Caco-2 cells, an in vitro cell culture model of the
      intestinal mucosa, we have shown that the acyloxyalkoxy-based cyclic prodrugs 3
      and 4 of the opioid peptides [Leu5]-enkephalin(1, H-Tyr-GLY-Gly-Phe-Leu-OH) and
      DADLE(2, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH), respectively, were substrates for
      apically polarized efflux systems and therefore less able to permeate the cell
      monolayers than were the opioid peptides themselves. In an attempt to explain how
      structure may influence the recognition of these cyclic prodrugs as substrates by
      the apically polarized efflux systems, we have determined the possible solution
      conformations of 3 and 4 using spectroscopic techniques (2D-NMR, CD) and
      molecular dynamics simulations. Spectroscopic as well as computational studies
      indicate that cyclic prodrug 4 exhibits a major and a minor conformer in a ratio
      of 3:2 where both conformers exhibit gamma and beta-turn structures.
      Spectroscopic, as well as molecular dynamics, studies indicate that the
      difference between the two conformers involves a cis/trans inversion occurring at
      the amide bond between the promoiety and Tyr1. The major conformer has a trans
      amide bond between the promoiety and Tyr1, whereas the minor conformer has a cis
      amide bond. The spectroscopic data indicate that cyclic prodrug 3 has a structure
      similar to that of the major conformer in cyclic prodrug 4. It has recently been
      reported that a particular arrangement of polar groups and spatial separation
      distances is required for substrate recognition by P-glycoprotein. When the
      conformation of the acyloxyalkoxy linker was investigated in the major and minor
      conformers of cyclic prodrug 4, with respect to distances between the polar
      functional groups, this ideal fixed spatial orientation was observed.
      Interestingly this same spatial orientation of polar functional groups was not
      observed for other cyclic prodrugs prepared by our laboratory using different
      chemical linkers (coumarinic acid and phenylpropionic acid) but the same opioid
      peptides that had previously been shown not to be substrates for the apically
      polarized efflux systems. Therefore, we hypothesize that the structure and/or the
      flexibility of the acyloxyalkoxy linker itself allows cyclic prodrugs 3 and 4 to
      adopt conformations that permit ideal arrangement of polar groups in the linker
      and their fixed spatial orientation. This possibly induces the substrate activity
      of cyclic prodrugs 3 and 4 for the apically polarized efflux systems.

PMID- 10406219
TI  - Binding and internalization of an ICAM-1 peptide by the surface receptors of T
      cells.
AB  - The objective of this work was to evaluate the binding characteristics of a
      cyclic peptide, cyclo (1, 12)-Pen1-Pro2-Arg3-Gly4-Gly5-Ser6-Val7-Leu8-V al9-Thr10
      Gly11-Cys12-OH (cIBR), to Molt-3 T cells. This cIBR peptide is derived from
      sequence numbers 11-20 of intercellular adhesion molecule-1 (ICAM-1). Binding
      studies were performed using a fluorescence-labeled peptide (FITC-cIBR) in which
      the fluorescence marker fluorescein 5-isothiocyanate (FITC) was conjugated to the
      N-terminal of the cIBR peptide. The binding affinity of the FITC-cIBR peptide to
      Molt-3 T cells was evaluated using a FACScan flow cytometer. The binding
      specificity of the FITC-cIBR peptide was also confirmed by inhibition of binding
      using unlabeled peptide (cIBR). The results show that FITC-cIBR binds to two
      populations of T cells with different affinities; population 1 has high cell
      numbers (75%) but low affinity, and population 2 has high binding affinity but
      low cell numbers (25%). Binding to both populations was saturable and could be
      inhibited by the unlabeled peptide (cIBR), suggesting a receptor-mediated binding
      process. In addition to binding, receptor-mediated internalization was also
      observed for population 2; this was confirmed by confocal microscopy and
      temperature-dependence studies at 37 degrees C and 4 degrees C. The binding and
      internalization of this peptide may be carried out by surface receptors on Molt-3
      T cells such as LFA-1. In the future, the binding and internalization of cIBR
      peptide can be utilized as a method of targeted drug delivery to leukocytes for
      the treatment of leukocyte-related diseases.

PMID- 10406221
TI  - Characterization and comparison of leuprolide degradation profiles in water and
      dimethyl sulfoxide.
AB  - The effect of solvent on the rate of leuprolide degradation and on the structure
      of the degradation products was explored. Leuprolide solutions (370 mg/mL) were
      prepared in water and dimethyl sulfoxide (DMSO) for delivery in DUROS osmotic
      implants. Both solvent systems demonstrated better than 90% stability after 1
      year at 37 degrees C, where the DMSO formulation afforded better stability than
      the aqueous formulation and was used in subsequent clinical trials. The rate of
      leuprolide degradation in DMSO was also observed to accelerate with increasing
      moisture content, indicating that the aprotic solvent minimized chemical
      degradation. Interestingly, leuprolide degradation products varied with
      formulation vehicle. The proportions of leuprolide degradation products observed
      to form in water and DMSO at 37 degrees C were hydrolysis > aggregation >
      isomerization > oxidation and aggregation > oxidation > hydrolysis >
      isomerization, respectively. Specifically, more N-terminal hydrolysis and
      acetylation were observed under aqueous conditions, and increased Trp oxidation
      and Ser beta-elimination were seen under non-aqueous conditions. Furthermore, the
      major chemical degradation pathway changed with temperature in the DMSO
      formulation (decreasing oxidation with increasing temperature), but not in the
      aqueous formulation.

PMID- 10406220
TI  - Structural recognition of an ICAM-1 peptide by its receptor on the surface of T
      cells: conformational studies of cyclo (1, 12)-Pen-Pro-Arg-Gly-Gly-Ser-Val-Leu
      Val-Thr-Gly-Cys-OH.
AB  - The purpose of this study is to elucidate the solution conformation of cyclic
      peptide 1 (cIBR), cyclo (1, 12)-Pen1-Pro2-Arg3-Gly4-Gly5-Ser6-Val7-Leu8-V al9
      Thr10-Gly11-Cys12-OH, using NMR, circular dichroism (CD) and molecular dynamics
      (MD) simulation experiments. cIBR peptide (1), which is derived from the sequence
      of intercellular adhesion molecule-1 (ICAM-1, CD54), inhibits homotypic T-cell
      adhesion in vitro. The peptide hinders T-cell adhesion by inhibiting the
      leukocyte function-associated antigen-1 (LFA-1, CD11a/CD18) interaction with ICAM
      1. Furthermore, Molt-3 T cells bind and internalize this peptide via cell surface
      receptors such as LFA-1. Peptide internalization by the LFA-1 receptor is one
      possible mechanism of inhibition of T-cell adhesion. The recognition of the
      peptide by LFA-1 is due to its sequence and conformation; therefore, this study
      can provide a better understanding for the conformational requirement of peptide
      receptor interactions. The solution structure of 1 was determined using NMR, CD
      and MD simulation in aqueous solution. NMR showed a major and a minor conformer
      due to the presence of cis/trans isomerization at the X-Pro peptide bond. Because
      the contribution of the minor conformer is very small, this work is focused only
      on the major conformer. In solution, the major conformer shows a trans
      configuration at the Pen1-Pro2 peptide bond as determined by HMQC NMR. The major
      conformer shows possible beta-turns at Pro2-Arg3-Gly4-Gly5, Gly5-Ser6-Val7-Leu8,
      and Val9-Thr10-Gly11-Cys12. The first beta-turn is supported by the ROE
      connectivities between the NH of Gly4 and the NH of Gly5. The connectivities
      between the NH of Ser6 and the NH of Val7, followed by the interaction between
      the amide protons of Val7 and Leu8, support the presence of the second beta-turn.
      Furthermore, the presence of a beta-turn at Val9-Thr10-Gly11-Cys12 is supported
      by the NH-NH connectivities between Thr10 and Gly11 and between Gly11 and Cys12.
      The propensity to form a type I beta-turn structure is also supported by CD
      spectral analysis. The cIBR peptide (1) shows structural similarity at residues
      Pro2 to Val7 with the same sequence in the X-ray structure of D1-domain of ICAM
      1. The conformation of Pro2 to Val7 in this peptide may be important for its
      binding selectivity to the LFA-1 receptor.

PMID- 10406222
TI  - Ion-binding and pharmacological properties of Tyr6 and Tyr9 antamanide analogs.
AB  - In order to investigate the antiproliferative properties of antamanide, we have
      synthesized and studied two antamanide analogs where the phenylalanine residue in
      positions 6 or 9 is substituted by tyrosine, their corresponding linear forms and
      the cyclic and linear des Phe5,Phe6-Tyr9-analogs. Antamanide and its biologically
      active synthetic analogs are able to form highly stable complexes with metal
      ions, particularly Na+, K+ and Ca2+. We studied the ion-binding properties of the
      Tyr-antamanide analogs by CD and Tb3+ -mediated fluorescence in acetonitrile. In
      this medium the far-and near-UV CD spectra of the neat Tyr6-antamanide analog are
      very similar to that of the parent cyclic decapeptide. Substantial differences
      occur on the contrary in the CD spectra of the neat Tyr9-antamanide, particularly
      in the regions at 220 nm and 270-290 nm. In acetonitrile, as already found for
      antamanide, the interaction with the above-mentioned metal ions always produces
      evident changes in the far- and near-UV CD spectra of both analogs. On the
      contrary, the CD spectra of the linear deca- and octa- and of the cyclic octa
      analogs are affected by the presence of metal ions only in the near-UV region. In
      the same solvent the Tb3+ -mediated fluorescence spectra of all the synthetic
      peptides are remarkably affected by the addition of ions. On the basis of the
      spectral total changes, by using either or both the spectroscopic techniques, it
      has been possible to determine the ion binding constants for all the linear and
      cyclic Tyr-antamanide analogs and to compare them with that of the parent
      peptide. The antitoxic and antiproliferative activities of these antamanide
      analogs have been tentatively correlated to their ion-binding properties. A
      preliminary account of this work was given in (1).

PMID- 10406223
TI  - Binding of cations to individual gamma-carboxyglutamate residues of conantokin-G
      and conantokin-T.
AB  - Conantokin-G (con-G) and conantokin-T (con-T) are naturally occurring gamma
      carboxyglutamate (Gla)-containing peptides that interact with multivalent cations
      in functionally relevant manners. Selective 13C-enrichment of Cgamma and Cdelta
      in each of the Gla residues has allowed metal binding affinities to be measured
      at individual side chains. Con-T possesses two metal binding sites, one with high
      affinity at Gla10/Gla14 and another with weak binding at Gla3/Gla4. Con-G
      contains two sites of comparable low affinity for Ca2+. Analysis of the 13C line
      widths of con-G in the presence of Mg2+ allowed the order of metal binding to be
      determined, with Gla10/Gla14 loading before the Gla3/Gla4/Gla7 cluster. While the
      variant peptide, apo-con-T[Lys7Gla], was shown to have a very low alpha-helical
      content, this peptide binds a second metal with much greater affinity than wild
      type con-T. This provides additional evidence that Gla7 in con-G is primarily
      responsible for destabilizing the apo-form, but is an important ligand for metal
      chelation. The residue-specific alpha-helical stabilities of con-G and con-T in
      their metal-free and metal-loaded states were estimated by determining rates of
      proton exchange from backbone peptide bond amides with deuterium atoms from 2H20
      containing solvents. For both peptides, the lifetimes of protons on several
      peptide bond amides increased as metals of higher affinity were bound to the
      peptides, with the longest half-lives found in the region of the alpha-helical
      turn stabilized by the Gla10/Gla14 metal coordination site. We propose that Gla10
      and Gla14 constitute the primary tight metal ion binding site in both peptides.
      This detailed analysis with physiologically relevant metal cations is crucial for
      deciphering the roles of critical amino acids in the bioactivity of the
      conantokin peptides.

PMID- 10406224
TI  - Control of ditryptophan cross-linking: dihydrotryptophan as a tryptophan
      precursor in peptide synthesis.
AB  - In neat trifluoroacetic acid, tryptophan side chains cross-link to form a
      diastereomeric mixture of tryptophan dimers. Convergent oxidation with 2,3
      dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) converts tryptophan dimers to
      ditryptophan. Since cross-link formation is under thermodynamic control, there
      has been no simple way of controlling the regiochemistry of the cross-linking
      process when more than one tryptophan side chain is present. Here, we show that
      dihydrotryptophan (Dht) can be incorporated into peptides as a tryptophan
      precursor, which reforms tryptophan upon treatment with DDQ. Dihydrotryptophan
      was prepared as a mixture of gammaS and gammaR diastereomers and the indoline
      nitrogen was protected with a Cbz group. The resulting amino acid, Nalpha-BOC
      Dht(Cbz)-OH, was then incorporated into peptides as a mixture of diastereomers.
      Dht was resistant to tryptophan cross-linking in neat trifluoroacetic acid and
      was converted back to tryptophan during convergent oxidation of tryptophan
      dimers. While Dht is useful for control of ditryptophan regiochemistry and as a
      potential tryptophan analog, it is not a general strategy for Trp protection
      since DDQ is unlikely to be compatible with easily oxidized amino acids such as
      cysteine.

PMID- 10406227
TI  - Endoscopic ultrasound staging of esophageal cancer: assuming responsibility.

PMID- 10406226
TI  - Gastroesophageal reflux disease and a HAPPI quality of life.

PMID- 10406225
TI  - Laparoscopic antireflux surgery: silver bullet or the emperor's new clothes?

PMID- 10406228
TI  - Liver disease in the pregnant patient. American College of Gastroenterology.

PMID- 10406229
TI  - Increasing patient adherence to gastroenterology treatment and prevention
      regimens.
AB  - Many gastroenterology treatments would be minimally effective if patients did not
      adhere to prescribed therapeutic regimens. However, considerable evidence exists
      that patients often do not adhere. Factors associated with nonadherence include
      the physician's or other health care provider's behavior, the prescribed regimen,
      and the illness. These factors affect patient adherence such that: 1) patients do
      not have the skills or knowledge necessary to complete an assignment; 2) patients
      do not believe that they will be helped by the prevention or intervention
      activity, or they do not accept the activity because they do not believe that its
      value will outweigh its costs; and 3) patients' environments are not supportive
      of, or interfere with, adherence. Strategies that can increase adherence include
      attention to the physician/patient relationship, direct skill training, setting
      up a reward structure, and reminders, among others. Specific methods that
      gastroenterology health care providers can utilize to enhance adherence in their
      practice are presented.

PMID- 10406230
TI  - Adenomas and adenoma-like DALMs in chronic ulcerative colitis: a clinical,
      pathological, and molecular review.
AB  - Dysplasia in chronic ulcerative colitis (CUC) is categorized as either flat or
      associated with a raised lesion or mass (dysplasia-associated lesion or mass
      [DALM]). One specific subtype of DALM consists of an isolated discrete "adenoma
      like" polypoid dysplastic lesion that is difficult to distinguish from a sporadic
      adenoma that occurs coincidentally in patients with CUC. Sporadic adenomas are,
      by definition, also polypoid dysplastic lesions, but their development is
      unrelated to the underlying colitis. The clinical distinction between CUC
      associated polypoid dysplastic lesions and sporadic adenomas is important because
      the former is an indication for colectomy whereas the latter is usually treated
      by simple polypectomy. This review focuses on the clinical, pathological, and
      molecular aspects of polypoid dysplastic lesions and sporadic adenomas in CUC.
      There are a variety of clinical and pathological features that can be used to
      distinguish these lesions, but none of these features are entirely specific for
      either type of neoplasm. Furthermore, there is recent evidence to suggest that
      the molecular pathogenesis of CUC-associated polypoid dysplasia is different, in
      terms of the order and timing of genetic events, in comparison to sporadic
      adenomas and, thus, this information may be used to distinguish these lesions in
      the near future. Few studies have evaluated the natural history of CUC-related
      polypoid dysplastic lesions and sporadic adenomas. However, recent reports
      indicate that the majority of these lesions will follow a relatively benign
      course with a low risk of progression to flat dysplasia or adenocarcinoma. This
      review also summarizes the current provisional treatment recommendations for CUC
      patients with an adenoma-like polypoid dysplastic lesion.

PMID- 10406231
TI  - The influence of in vitro nitroimidazole resistance on the efficacy of
      nitroimidazole-containing anti-Helicobacter pylori regimens: a meta-analysis.
AB  - OBJECTIVE: The aim of this study was to determine the influence of nitroimidazole
      resistance (NIR) on the efficacy of treatment for Helicobacter pylori (H. pylori)
      infections by meta-analysis of the world literature. METHODS: A MEDLINE search, a
      manual search of all major gastroenterological journals from 1993 to 1997, and
      abstracts of gastroenterological and H. pylori meetings from 1993 to 1997 were
      performed. All treatment studies using a nitroimidazole and providing data about
      the medication used, dose frequency, total daily dose, duration of treatment, and
      eradication results in relation to NIR were included. Eradication had to be
      assessed by two biopsy-based tests or a urea breath test > or = 4 wk after
      treatment. Individual studies were pooled into groups according to the medication
      used and the duration of treatment. The pooled estimate of the odds ratio (OR) of
      NIR for treatment failure and its 95% confidence interval (95% CI) were
      calculated for each group using the logit method. To detect any possible bias,
      funnel plots (plots of effect estimates against sample size) were constructed.
      RESULTS: A total of 91 treatment arms, including a total of 4823 patients, were
      evaluated. The pooled ORs of NIR for treatment failure (95% CI) of proton pump
      inhibitors, bismuth, and quadruple regimens were 5.2 (3.8-7.1), 5.9 (4.1-8.3),
      and 7.0 (3.1-16.0), respectively. Eradication rates were 90% in susceptible
      strains but <75% in resistant strains. In susceptible strains, neither treatment
      duration nor the choice of the second antibiotic influenced efficacy. In
      resistant strains, tetracycline was more effective than amoxicillin (bismuth
      regimens), and the longer the duration of regimens (bismuth-amoxicillin regimens)
      the more effective they were. Only quadruple regimens given for > or = 1 wk were
      effective in resistant strains. CONCLUSIONS: NIR decreases treatment efficacy.
      Treatment duration and choice of other drugs influence the impact of NIR on
      treatment efficacy. If NIR is present, a nitroimidazole-containing regimen should
      be avoided or a quadruple regimen should be given for > 1 wk.

PMID- 10406232
TI  - Colonic motility in man: features in normal subjects and in patients with chronic
      idiopathic constipation.
AB  - The human colon is still a relatively unknown viscus, especially concerning its
      motor activity. However, in recent years, techniques have been perfected that
      allow a better understanding of colonic motility, especially through prolonged
      recording periods. In this way, it has been demonstrated that the viscus
      contracts according to a circadian trend, is responsive to physiological stimuli
      (meals, sleep), and features high amplitude, propulsive contractions that are
      part of the complex dynamic of the defecatory process. These physiological
      properties and their alterations in patients with chronic idiopathic constipation
      are reviewed in this article.

PMID- 10406233
TI  - Outcome of erosive reflux esophagitis after Nissen fundoplication.
AB  - OBJECTIVE: The aim of this study was to compare the utilization of health care
      resources and long term outcome of erosive esophagitis in patients treated with
      and without open Nissen fundoplication. METHODS: A population of 35,725 patients
      with erosive esophagitis was extracted from the computerized database of the US
      Department of Veterans Affairs. Subjects were stratified by severity of disease
      into erosive esophagitis alone versus erosive esophagitis complicated by
      esophageal ulcers or peptic strictures. During a mean follow-up period of 4.2 yr
      (range 1-12 yr), the consumption of health care resources, except for
      medications, was compared between case and control subjects treated with and
      without fundoplication, respectively. RESULTS: Among patients with complicated
      erosive esophagitis, 5,064 control subjects were treated without, and 542 case
      subjects were treated with, fundoplication. Cases incurred less recurrence of
      esophageal erosions (controls: 56% vs cases: 46%), esophageal ulcers (38% vs
      33%), and peptic strictures (43% vs 32%) during follow-up. Among patients with
      erosive esophagitis but no complications, 29,514 control subjects were treated
      without, and 605 case subjects were treated with, fundoplication. Cases did not
      experience any change in the recurrence of esophageal erosions (controls: 25% vs
      cases: 24%). Irrespective of treatment type, none of the case or control subjects
      with erosive esophagitis alone developed esophageal ulcers or peptic strictures
      during follow-up. Compared with controls, however, after fundoplication in
      erosive esophagitis alone, cases incurred more dysphagia (2.6% vs 4.6%),
      postsurgical syndromes (0.8% vs 1.7%), as well as more outpatient visits (34 vs
      40 visits/patient) and outpatient procedures (2.7 vs 4.3 procedures/patient).
      CONCLUSIONS: Fundoplication improves the clinical outcome of erosive esophagitis
      in patients with concomitant esophageal ulcers and strictures, but not in
      patients without such complications. Fundoplication does not reduce the
      consumption of health care resources.

PMID- 10406234
TI  - The long term results of open antireflux surgery in a community-based health care
      center.
AB  - OBJECTIVE: There is no previous study concerning long term results of open Nissen
      fundoplication performed by general surgeons in a nonspecialized unit. METHODS:
      Of 45 consecutive patients in a general provincial center, 39 were available for
      follow-up after a mean period of 78 months. All patients were interviewed using a
      standard questionnaire, and 35 of them consented to undergo endoscopy. RESULTS:
      Of the patients, 85% had no or only mild reflux symptoms. The figures for
      dysphagia, flatulence, and bloating were 31%, 67%, and 46%, respectively.
      Endoscopy showed defective fundic wrap in 37% of the patients and erosive
      esophagitis in 29%. Five patients (13%) with recurrent esophagitis were referred
      for H2-blocker or omeprazole medication, and five others (13%) were scheduled for
      repeat antireflux surgery. CONCLUSIONS: The results were somewhat worse in regard
      to prevalence of defective fundic wrap and recurrent esophagitis than in other
      reports, which were from specialized units.

PMID- 10406235
TI  - Quality of life in patients with heartburn but without esophagitis: effects of
      treatment with omeprazole.
AB  - OBJECTIVE: Because improvement in quality of life (QoL) is an important
      therapeutic goal in patients with heartburn but without esophagitis, the aim of
      the present study was to compare the impact of omeprazole 20 mg or 10 mg daily
      with that of placebo on QoL in patients with heartburn as the predominant
      symptom. METHODS: QoL was measured at baseline and after 4 wk using two validated
      questionnaires, the Psychological General Well-Being (PGWB) index and the
      Gastrointestinal Symptom Rating Scale. RESULTS: The two questionnaires were
      completed by 163 patients in the omeprazole 20 mg group, 163 in the omeprazole 10
      mg group, and 82 in the placebo group. The reflux dimension of the
      Gastrointestinal Symptom Rating Scale showed a significant improvement in terms
      of reflux symptoms on omeprazole 20 mg versus omeprazole 10 mg and placebo, and
      on omeprazole 10 mg compared with placebo. The total score of the PGWB index
      improved significantly more on both doses of omeprazole than on placebo. The mean
      scores rose from 96.8 to 103.9 on omeprazole 20 mg, from 98.4 to 106.0 on
      omeprazole 10 mg, and from 98.0 to 100.6 on placebo. All dimensions of the PGWB
      index improved on treatment with omeprazole, but the improvements were most
      pronounced in the dimensions depicting anxiety, depressed mood, and self-control.
      CONCLUSIONS: It is concluded that treatment with omeprazole 20 mg and omeprazole
      10 mg restores QoL to a level comparable with that observed in a healthy
      population.

PMID- 10406236
TI  - Prevalence and distribution of Helicobacter pylori in gastroesophageal reflux
      disease: a study from the East.
AB  - OBJECTIVES: The relationship between Helicobacter pylori infection and
      gastroesophageal reflux (H. pylori) disease (GERD) is controversial. In Asian
      populations, the prevalence of H. pylori infection is high and GERD is relatively
      uncommon. The aim of this study was 1) to test the hypothesis that H. pylori
      protects the esophagus against GERD, and 2) to study the pattern of H. pylori
      colonization and gastritis in GERD. METHODS: We conducted a prospective case
      control study in which patients with GERD and asymptomatic controls were compared
      for the prevalence of H. pylori infection. Diagnosis of GERD was based on
      symptoms of heartburn that improved with acid-suppressive therapy and/or
      endoscopic evidence of erosive esophagitis. H. pylori status was determined by
      serology and, when endoscopy was indicated, was confirmed by rapid urease test
      and histology. Gastric biopsies were examined under hematoxylin and eosin and
      Giemsa stains. Density of H. pylori colonization and activity of gastritis at
      different parts of stomach were graded and compared according to Updated Sydney
      system. RESULTS: A total of 106 patients with GERD and 120 age- and sex-matched,
      asymptomatic controls were enrolled. The prevalence of H. pylori infection was
      significantly lower in GERD patients (31%) compared with controls (61%, p <
      0.001, odds ratio 0.229, 95% confidence interval 0.13-0.41). H. pylori-infected
      GERD patients showed significantly more severe gastritis in the antrum than in
      other parts of stomach (mean inflammatory scores: antrum; 3.3 +/- 1.63*, body;
      1.85 +/- 1.31; fundus; 1.65 +/- 0.58; cardia, 1.65 +/- 1.39; *p < 0.005). H.
      pylori colonization was found less commonly and at lower density at the cardia
      compared with other parts of the stomach. CONCLUSIONS: H. pylori infection
      protects against the development of GERD, and carditis is unlikely to play an
      important role.

PMID- 10406237
TI  - Deterioration of esophageal motility with age: a manometric study of 79 healthy
      subjects.
AB  - OBJECTIVE: Data are limited on the effect of age on esophageal function. We
      evaluated whether aging influences the motor activity of the esophagus. METHODS:
      Standard esophageal manometry was performed in 79 healthy, nonpaid volunteers of
      both sexes, 18-73 yr of age. Lower (LES) and upper esophageal sphincter (UES)
      characteristics and the properties of esophageal peristaltic waves were assessed
      by age groups: < or = 25 yr, 26-35 yr, 36-45 yr, 46-55 yr, 56-65 yr, and > 65 yr.
      RESULTS: Age correlated inversely with LES pressure and length, UES pressure and
      length, and peristaltic wave amplitude and velocity, and correlated directly with
      the proportion of simultaneous contractions. Age was inversely correlated with
      the upper limits of normality (95th percentiles) of LES pressure (r = -0.943, p =
      0.005), UES pressure (r = -0.943, p = 0.005), middle and lower peristaltic wave
      amplitude (r = -0.947, p = 0.004, and r = -0.844, p = 0.035, respectively),
      upper/middle peristaltic progression speed (r = -0.943, p = 0.005), and the
      proportion of simultaneous contractions (r = 0.926, p = 0.008), but not with the
      lower normal limits (5th percentiles) of these variables. Gender did not affect
      esophageal motility variables. The 95th percentiles of LES pressure differed by
      20 mm Hg, those of lower peristaltic amplitude by 82 mm Hg, and those of percent
      simultaneous contractions by a factor of 2, between the younger and the older age
      groups. CONCLUSIONS: The results suggest that normal esophageal motility
      deteriorates with advancing age. Thus, age-related normality limits of esophageal
      pressures should be considered before establishing the manometric diagnosis of
      hypercontractile esophageal motility disorders.

PMID- 10406238
TI  - Assessment of esophageal emptying post-pneumatic dilation: use of the timed
      barium esophagram.
AB  - OBJECTIVES: The reported success rate of pneumatic dilation in patients with
      achalasia varies from 50% to 93%. This wide variability may be due to using
      symptom relief post-dilation as the only assessment of success. There are no
      studies comparing subjective symptom improvements to objective improvement in
      esophageal emptying after pneumatic dilation. METHODS: Patients with achalasia
      undergoing pneumatic dilation from 1995 to 1997 were evaluated. Pre- and post
      dilation symptoms were recorded using a standardized scoring system. Barium
      column height was measured 1 min and 5 min after upright ingestion to assess
      esophageal emptying. Based on percentage of total symptom and barium height
      improvement post-dilation, patients were grouped according to one of nine
      outcomes; the association between subjective and objective parameters of
      improvement was tested. RESULTS: A total of 37 patients underwent 53 pneumatic
      dilations. There was a significant association (p < 0.001) between improvement in
      patient symptoms and barium height. In 38 of 53 (72%) pneumatic dilations, the
      degree of symptom and barium height improvement was similar. Near complete
      symptom resolution was reported after 26 dilations. In eight of 26 (31%) patients
      however, there was < 50% improvement in barium height (group A). Compared with
      the 16 patients with 91-100% improvement in both symptoms and barium height
      (group B), forward stepwise regression identified age as the only difference
      between the two groups, with group A patients being significantly (p = 0.04)
      older. CONCLUSIONS: Objective assessment of esophageal emptying pre- and post
      dilation identifies an important subset of patients with poor esophageal emptying
      who report near complete symptom resolution. This group may benefit from any
      early repeat pneumatic dilation.

PMID- 10406239
TI  - Epidemiological evaluation of recurrent stomatitis, nitrates in drinking water,
      and cytochrome b5 reductase activity.
AB  - OBJECTIVE: Our aim was to examine a possible correlation between drinking water
      nitrate concentration, recurrent stomatitis, and cytochrome b5 reductase
      activity. Dietary nitrate can form nitrite in vivo. This can cause
      methemoglobinemia in the red blood cells. Cytochrome b5 reductase is an enzyme in
      the red blood cells that reduces methemoglobin back to hemoglobin. METHODS: Five
      areas were selected in the State of Rajasthan, India, having drinking water
      nitrate concentration (as nitrate) of 26, 45, 95, 222, and 459 mg of NO3/L. House
      schedules were prepared in these areas in accordance with a statistically
      designed protocol. We selected 193 age- and weight-matched persons, representing
      10% of the total population in each of these areas. Detailed history was taken
      for recurrent stomatitis, medical examination was conducted, and blood samples
      were taken to ascertain cytochrome b5 reductase activity in the selected
      population. Collected data were statistically analyzed to ascertain a
      relationship between nitrate concentration, cytochrome b5 reductase activity, and
      percent stomatitis, using Microsoft Excel software. RESULTS: This study suggests
      that there is a significant interdependence between drinking water nitrate
      concentration, cytochrome b5 reductase activity, and recurrent stomatitis.
      CONCLUSION: Increased cytochrome b5 reductase activity primarily induced by the
      presence of high nitrate concentration in drinking water could be the cause for
      recurrent stomatitis.

PMID- 10406240
TI  - Simplified lansoprazole suspension--a liquid formulation of lansoprazole-
      effectively suppresses intragastric acidity when administered through a
      gastrostomy.
AB  - OBJECTIVE: Lansoprazole suppresses intragastric acidity when given as
      nonencapsulated intact granules. Because the administration of granules via small
      bore tubes may still be problematic, we studied the effect of a liquid
      formulation of lansoprazole obtained by suspending the contents of a standard 30
      mg capsule in 10 cc of 8.4% NaHCO3. METHODS: Six men with an established
      gastrostomy had a baseline 24-h intragastric pH study. Through the gastrostomy,
      they then received 7 days of once-daily dosing with 30 mg lansoprazole as intact
      granules in orange juice. After a 7-day washout period, they then received 7 days
      of once-daily dosing with the liquid formulation. Intragastric pH monitoring was
      repeated after each dosing period. RESULTS: Baseline mean intragastric pH was 1.8
      +/- 0.5 (SD). This increased to 4.5 +/- 0.5 with lansoprazole granules in orange
      juice, and to 5.1 +/- 1.1 after the liquid formulation. At baseline, intragastric
      pH was >3, 4, and 5 for 19.5%, 12.7%, and 8.1%, respectively, of the 24-h
      recording period. Corresponding values after lansoprazole granules in orange
      juice were 77.5%, 67%, and 49.6% (p < 0.01 for each comparison with baseline).
      After the liquid formulation, the corresponding values were 84%, 77.9%, and 65.9%
      respectively (p < 0.01 for each comparison with baseline; p > 0.05 for each
      comparison with lansoprazole granules in orange juice). CONCLUSIONS: A liquid
      formulation of lansoprazole suppressed intragastric acidity when given through a
      gastrostomy. The degree of suppression was comparable to that obtained with
      intact nonencapsulated granules in orange juice.

PMID- 10406241
TI  - Phospholipid association reduces the gastric mucosal toxicity of aspirin in human
      subjects.
AB  - OBJECTIVE: In previous studies on rats, we have shown that aspirin (ASA)-induced
      injury to the gastric mucosa is markedly reduced or completely abolished if ASA
      is chemically associated with the phospholipid, phosphatidylcholine (PC). We have
      also shown that the protective effect of PC does not influence the ability of ASA
      to inhibit mucosal cyclooxygenase (COX) activity in the stomach and other
      tissues. We therefore sought to assess the effect of PC-associated ASA (ASA/PC)
      on the gastric mucosa of normal volunteers and to compare the results with the
      use of ASA alone. METHODS: Sixteen normal healthy subjects were administered ASA
      or ASA/PC in a randomized, double-blind, crossover study. The subjects received
      ASA in a dose of 650 mg three times a day for 3 days or an equivalent dose of ASA
      chemically associated with PC. Endoscopy was performed at baseline and again on
      the morning of day 4, after the subjects had taken the final dose of the test
      drug. On both occasions, antral biopsy specimens were obtained for the assessment
      of mucosal COX activity and prostaglandin concentration. RESULTS: The number
      (mean +/- SD) of gastric erosions seen with the ASA/PC formulation was
      significantly less than when ASA was used alone (8.7 +/- 10.7 vs 2.9 +/- 4.3; p <
      0.025). A similar trend was seen in the duodenum but the difference was
      statistically not significant. The antral mucosal COX activity, as well as the
      level of prostaglandin 6-keto PGF1alpha, were reduced significantly (80-88%) and
      to a similar extent by both ASA and ASA/PC. CONCLUSIONS: The present study shows
      that acute aspirin-induced damage to the gastric mucosa can be reduced by
      chemically associating ASA with PC. The mechanism of mucosal protection provided
      by this compound is not related to any alteration in the ability of ASA to
      inhibit mucosal COX activity. We believe this protection is attributable to the
      maintenance of the defensive hydrophobic barrier of the gastric mucosa.

PMID- 10406242
TI  - Helicobacter pylori in the Canadian arctic: seroprevalence and detection in
      community water samples.
AB  - OBJECTIVE: Many North American arctic communities are characterized by risk
      markers associated with Helicobacter pylori (H. pylori) infection, including
      overcrowded housing and inadequate water supply and sanitation systems. Our aim
      was to determine the seroprevalence of H. pylori infection in two traditional
      Inuit communities in the central Canadian arctic and to test for the presence of
      H. pylori, by polymerase chain reaction (PCR), in local water supplies. METHODS:
      Samples of venous whole blood from adults and capillary blood from children were
      collected and analyzed by enzyme immunoassay and Helisal Rapid Test,
      respectively, for IgG antibody to H. pylori. Antibodies to CagA were detected by
      enzyme immunoassay, and ABO and Lewis antigens were also determined. Demographic
      and clinical information were collected by questionnaire. Water samples from each
      community were tested for H. pylori by PCR. RESULTS: One hundred-thirty (50.8%)
      of 256 subjects from the two communities were positive for H. pylori IgG
      antibodies. Seropositive subjects were more likely to be male, compared with
      seronegative individuals (p = 0.01). Antibody status did not differ with respect
      to age, community, alcohol or cigarette use, number of persons per household,
      gastrointestinal complaints or previous investigations, medications, or presence
      of blood group O, Lewis a-b+. CagA antibodies were detected in 78 (61.9%) of 126
      H. pylori-seropositive subjects tested; however, 41 (35.3%) of 116 H. pylori
      seronegative subjects were also CagA positive. Water samples taken from the water
      delivery truck in Chesterfield Inlet and two lakes near Repulse Bay were positive
      for H. pylori. CONCLUSION: The seroprevalence of H. pylori in the study group was
      higher than rates in southern Canadian populations, but lower than the
      seroprevalence previously documented in a Canadian subarctic Indian (First
      Nations) community. The detection of H. pylori in local water supplies may
      indicate a natural reservoir for the organism or possible contamination from
      human sewage.

PMID- 10406243
TI  - Evaluation of a new enzyme immunoassay for detecting Helicobacter pylori in
      feces: a prospective pilot study.
AB  - OBJECTIVE: There is an increasing interest in noninvasive tests for detecting
      Helicobacter pylori (H. pylori) infection. Unlike serological and urea breath
      tests, the possibility of searching for H. pylori in feces has been scarcely
      investigated. The aim of this prospective pilot study was to evaluate the
      usefulness of a new enzyme immunoassay for detecting H. pylori antigens in feces,
      as a predictor of H. pylori status in the pre- and posttreatment settings.
      METHODS: One hundred and fifty-four symptomatic, anti-H. pylori untreated
      patients (Group A) and 116 anti-H. pylori treated patients (Group B) underwent
      gastroscopy with biopsies of the antrum and corpus for histology (H) and rapid
      urease test (RUT). In the anti-H. pylori treated group, a 13C-urea breath test
      (UBT) was also performed. In Group A, H. pylori status was defined as positive or
      negative when both H and RUT gave concordant positive or negative results. In
      Group B, the patients were considered eradicated if all three tests were
      negative. A stool specimen was collected from all patients the day after
      gastroscopy, and tested by using an enzyme immunoassay commercial kit for
      detecting H. pylori antigens in feces (HpSAT). RESULTS: Eighty-five patients in
      Group A (55%) and 44 in Group B (38%) were H. pylori infected. On the whole,
      HpSAT showed a sensitivity of 94% and specificity of 86%. In Group A and Group B,
      sensitivity and specificity were 94% versus 93%, and 90% versus 82%, respectively
      (p < 0.05). CONCLUSIONS: HpSAT seems to be a reliable method for predicting H.
      pylori status in anti-H. pylori untreated patients. Conversely, the test appears
      less suitable to evaluate the outcome of the eradicating treatment. Consequently,
      it is likely to be accepted for the primary diagnosis of H. pylori status,
      particularly in dyspeptic young patients.

PMID- 10406244
TI  - Helicobacter pylori infection rates in duodenal ulcer patients in the United
      States may be lower than previously estimated.
AB  - OBJECTIVE: Published studies have estimated the rate of Helicobacter pylori (H.
      pylori) infection in patients with duodenal ulcer disease to be as high as 95%;
      the majority of remaining duodenal ulcers have been attributed to the use of
      ulcerogenic drugs such as nonsteroidal antiinflammatory drugs (NSAIDs). We aimed
      to assess the H. pylori prevalence rates of U.S. duodenal ulcer patients in
      large, well-controlled studies. METHODS: More than 2900 patients with
      endoscopically diagnosed non-NSAID duodenal ulcers were enrolled in a series of
      six placebo-controlled, double-blind studies conducted in the United States that
      assessed H. pylori using a combination of tests. Patients were considered
      infected with H. pylori only if culture growth was observed, or both histological
      and CLOtest results were positive. Patients were considered uninfected if the
      results of at least two tests were negative. Patients with missing test results,
      results of only a single test, or conflicting test results were not evaluable for
      H. pylori assessment. RESULTS: Of the 2394 endoscopically diagnosed evaluable
      duodenal ulcer patients, 73% (1737) were confirmed infected with H. pylori at
      study entry. CONCLUSIONS: The results of six carefully designed and controlled
      studies suggest that an assumed H. pylori infection rate of approximately 95% may
      overestimate the actual rate of H. pylori infection in duodenal ulcer patients in
      the United States. Although H. pylori infection is an important factor in the
      etiology of noniatrogenic duodenal ulcer disease, other factors may predominate
      in some patients and should not be overlooked in determining an appropriate
      course of treatment. The empiric use of antibiotic therapy for ulcer patients
      without confirmation of the presence of H. pylori cannot be recommended.

PMID- 10406245
TI  - Prediction of resource utilization and case cost for acute nonvariceal upper
      gastrointestinal hemorrhage at a Canadian community hospital.
AB  - OBJECTIVE: Upper gastrointestinal hemorrhage (UGIH) is common, and thus imposes a
      substantial burden on health care resources. We describe resource utilization and
      cost for management of acute nonvariceal UGIH, and studied their variation among
      population subgroups. METHODS: Resource utilization and direct medical case costs
      were extracted for consecutive admissions for nonvariceal UGIH at a large
      community hospital in southern Ontario through chart review and adaptation of an
      administrative case cost database. Univariate and multiple regression models were
      then developed to identify independent demographic predictors of case cost and
      length of stay. RESULTS: Among 116 eligible admissions the average length of stay
      and case cost were 4.26 days and Can$2690, respectively (Can$1 = US$0.70). Both
      cost and length of stay demonstrated significant univariate relationships with
      age, comorbid illness, prior peptic ulcer disease (PUD), and prior UGIH. Age and
      prior PUD persisted as independent predictors in multiple regression models. An
      inverse transformation of total case cost allowed these variables to explain 26%
      of the total variance. CONCLUSIONS: Resource utilization for management of acute
      nonvariceal UGIH at a Canadian community hospital varies substantially among
      population subgroups, but correlates independently with age and prior ulcer
      history. Careful attention must be paid to practice environments and demographic
      profiles before economic models of strategies to prevent or treat UGIH are
      applied to specific subpopulations.

PMID- 10406246
TI  - Do we practice what we preach? clinical decision making and utilization of
      endoscopic ultrasound for staging esophageal cancer.
AB  - OBJECTIVES: Endosonography is accurate for staging esophageal cancer. However,
      whether detailed staging impacts clinical decision making, whether endosonography
      is perceived as a useful modality, and what factors influence the utilization of
      endosonography have not been studied. METHODS: One hundred gastroenterologists
      were surveyed about staging and management of esophageal cancer, including: 1)
      management by stage; 2) perceived usefulness of endosonography; 3) availability
      of endosonography; and 4) number of patients referred. RESULTS: Clinical
      decisions varied by incremental differences in tumor stage. However, only 27 of
      66 respondents (40.9%) judged endosonography to be very useful or essential for
      the evaluation of esophageal cancer and only 22 (33.3%) had referred a patient.
      Perceived usefulness and availability were independent factors strongly
      associated with referral for endosonography. Among 18 respondents to whom
      endosonography was available and who considered it useful, 14 (77.9%) had
      referred a case. In contrast, a conservative management was not associated with
      either perceived usefulness of or referral for endosonography. CONCLUSIONS:
      Clinicians recognize the importance of detailed staging for management of
      esophageal cancer. Despite this, they underestimate the utility of endosonography
      and fail to refer patients for appropriate evaluation. Lack of perceived
      usefulness and unavailability are important independent barriers to utilization
      of endosonography in clinical practice.

PMID- 10406247
TI  - Topical pharyngeal anesthesia does not improve upper gastrointestinal endoscopy
      in conscious sedated patients.
AB  - OBJECTIVE: We undertook this study to determine whether topical pharyngeal
      anesthesia with conscious sedation is superior to conscious sedation alone, with
      respect to procedure performance or tolerance in patients undergoing diagnostic
      upper gastrointestinal endoscopy. METHODS: Ninety-five patients undergoing
      diagnostic upper endoscopy with conscious sedation were randomized to receive
      either topical pharyngeal anesthesia with 2% tetracaine/14% benzocaine spray or
      no pharyngeal anesthesia. Conscious sedation was achieved in all patients using
      intravenous midazolam and meperidine. Patients were asked to rate their pretest
      anxiety, comfort during endoscopy, recollection of the procedure, and willingness
      to undergo subsequent examinations using a 100-mm visual analog scale.
      Additionally, they were asked to estimate procedure duration and rate their
      tolerance for topical pharyngeal anesthesia. All examinations were performed by
      two endoscopists who were blinded to whether or not patients had received
      pharyngeal anesthesia. Endoscopists were asked to determine whether they believed
      that patients had received topical pharyngeal anesthesia and to estimate ease of
      esophageal intubation and procedure performance using a 100-mm visual analog
      scale. Procedure duration and doses of midazolam and meperidine were measured.
      RESULTS: The two groups did not differ with respect to age, gender, and previous
      endoscopic history. There were no significant differences between the two groups
      with respect to pretest anxiety, procedural comfort, and willingness to undergo
      subsequent examinations. Patients receiving topical pharyngeal anesthesia rated
      it as moderately unpleasant. Endoscopists were able to discriminate patients who
      received pharyngeal anesthesia from those who did not with a sensitivity of 0.73
      and a specificity of 0.59. There were no significant differences between the two
      groups with respect to ease of intubation, procedure performance, procedure
      duration, and dosing of midazolam or meperidine. CONCLUSIONS: In patients
      undergoing diagnostic upper endoscopy using intravenous midazolam and meperidine,
      the use of topical pharyngeal anesthesia does not improve patient tolerance or
      procedure performance. Elimination of this agent in the performance of diagnostic
      upper endoscopy will save time and money without adversely affecting patient care
      or outcomes.

PMID- 10406248
TI  - Flumazenil in children after esophagogastroduodenoscopy.
AB  - OBJECTIVE: Our aim was to evaluate if the routine use of the benzodiazepine
      antagonist flumazenil would shorten postprocedure recovery times after
      esophagogastroduodenoscopy in pediatric patients receiving standard intravenous
      conscious sedation with the benzodiazepine diazepam in combination with
      meperidine. METHODS: Upper endoscopy was performed using intravenous conscious
      sedation with standardized doses of diazepam and meperidine on 29 children, age
      range 6-18 yr. Patients were randomized in a double-blind fashion to receive
      either intravenous normal saline (placebo) or 0.01 mg/kg (maximum, 1.0 mg)
      flumazenil within 5 min of procedure completion. Evaluation of the degree of
      sedation using a modified Observer' s Assessment of Alertness/Sedation Scale was
      performed presedation, immediately before reversal solution administration, and
      serially over 60 min after reversal solution injection. RESULTS: Fifteen patients
      received flumazenil and 14 received placebo; patient group composition did not
      vary significantly in age and weight. Fifty-four percent of flumazenil patients
      and 30% of control patients achieved full alertness within 10 min of reversal
      solution injection. However, this difference between groups was not significant
      (p > 0.45). Resedation or side effects directly attributable to flumazenil were
      not observed. CONCLUSIONS: A single postsedation dose of flumazenil is well
      tolerated in children >6 yr old. However, its routine use after
      esophagogastroduodenoscopy is of questionable benefit in shortening recovery time
      in this age group.

PMID- 10406249
TI  - Patient attitudes toward undergoing colonoscopy without sedation.
AB  - OBJECTIVE: The vast majority of patients undergoing colonoscopy in the United
      States are given sedation. There are a number of potential advantages to
      performing colonoscopy without sedation. We sought to determine the attitude of
      patients toward unsedated colonoscopy in our three practice settings (a
      university medical center, a cancer center, and a Veterans Affairs medical
      center), and to see if there were factors that predicted willingness to try it.
      METHODS: Four-hundred thirty-four adult patients undergoing outpatient
      colonoscopy completed questionnaires before and after their procedures providing
      demographic information and assessing willingness to undergo colonoscopy without
      sedation. Patients were routinely given meperidine and midazolam for their
      procedures unless they specifically requested that they be unsedated (10
      patients). RESULTS: Only 16.9% of our patients were willing to undergo
      colonoscopy on their preprocedure questionnaire. Willingness increased modestly
      on the postprocedure questionnaire to 22.6% (p = 0.01). Logistic regression
      analysis disclosed that male gender, having a college degree, low anxiety based
      on preprocedure anxiety scales, and lower doses of sedative drugs used during
      colonoscopy were the best predictors of willingness to undergo colonoscopy
      without sedation in the future. CONCLUSIONS: Only about a fifth of patients
      undergoing colonoscopy in our three practice settings expressed a willingness to
      try colonoscopy unsedated. Male gender, higher levels of education, and low
      anxiety scores on simple scales of preprocedure anxiety may help to predict
      willingness. Efforts to substantially increase the frequency of patients willing
      to undergo colonoscopy without sedation will likely require increased patient
      counseling and education.

PMID- 10406250
TI  - Gallbladder emptying and somatostatin and cholecystokinin plasma levels in celiac
      disease.
AB  - OBJECTIVE: Gallbladder hypomotility in celiac disease has been attributed to
      decreased cholecystokinin secretion. The possible influence of somatostatin,
      which inhibits gallbladder motility, however, has never been evaluated. In this
      study gallbladder emptying and cholecystokinin and somatostatin plasma levels
      were evaluated in response to a fatty meal in patients with celiac disease at
      diagnosis and after long-term gluten-free diet and in controls. METHODS:
      Gallbladder volume and plasma levels of cholecystokinin and somatostatin were
      measured by ultrasonography and radioimmunoassay, respectively, at 0 time and 30,
      60, 75, and 90 min after an oral fatty meal (227 kcal, 45% fat) in 10 celiac
      patients at diagnosis and after 18 months of successful gluten-free diet and in
      10 healthy subjects. The pattern of gallbladder emptying was evaluated by mixed
      factorial analysis of variance and the curve fitting by multiple regression
      analysis. RESULTS: Patients at diagnosis had significantly greater fasting
      gallbladder volume and higher somatostatin plasma levels than controls (25.7 +/-
      SD 9.7 ml vs 16.8 +/- 7.0 ml, p = 0.021 and 9.3 +/- 4.6 vs 4.8 +/- 3.4 pmol/L, p
      = 0.023, respectively), significantly lower fatty meal-induced gallbladder
      ejection fraction (55 +/- 11.2% vs 76 +/- 7.2%, p = 0.005), and cholecystokinin
      peak and smaller area under the cholecystokinin secretion curve (3.1 +/- 2.3
      pmol/L vs 10.5 +/- 6.9 pmol/L, p = 0.028 and 157 +/- 142 pmol/L/90 min vs 453 +/-
      229 pmol/L/90 min, p = 0.028, respectively). The two groups had a similar
      emptying pattern (p = 0.8913) expressed by a significant quadratic term of the
      emptying function (p = 0.0001). The mean overall emptying volume was
      significantly greater in patients than in controls (p = 0.0007). Gluten-free diet
      normalized these findings. CONCLUSIONS: In patients at diagnosis, elevated
      somatostatin levels were associated with increased gallbladder fasting volume,
      whereas decreased cholecystokinin secretion was responsible for the reduced
      gallbladder emptying. Gluten-free diet reversed these abnormalities.

PMID- 10406251
TI  - Budesonide for the treatment of collagenous colitis: first results of a pilot
      trial.
AB  - OBJECTIVE: Collagenous colitis is a chronic watery diarrhea disorder
      characterized by a subepithelial collagen layer and a lymphoplasmacytic
      infiltration within the lamina propria. However, no standard treatment has been
      introduced by controlled clinical trials. Aim of the present pilot trial was to
      investigate the clinical effects of orally administered budesonide (3 mg t.i.d.)
      in 7 patients with collagenous colitis. In addition, the histomorphological
      changes after budesonide treatment were described in a group of 3 patients.
      METHODS: The study was performed as an open label pilot trial. Study end point
      was the clinical remission of collagenous colitis defined by stool frequency and
      stool consistency. RESULTS: The results indicate a rapid and sustained clinical
      response in all patients. Stool frequency significantly decreased (p < 0.001)
      from 10.43 +/- 5.56 per day (4-20 per day) to 3.3 +/- 1.2 (1-5 per day) after 10
      days and to 1.86 +/- 0.69 per day (1-3 per day) after 10 wk. Moreover stool
      consistency changed from watery (6 patients) or soft (1 patient) to soft (1
      patient) or solid (6 patients). Clinical improvement was achieved within the
      first 10 days in all patients and maintained after dose reduction. In 3 patients
      no diarrhea recurred within 7, 12, or 15 months after treatment with budesonide
      was terminated. In these patients control biopsies were taken and showed a marked
      regression of both characteristics, the collagen band and the lymphoplasmacytic
      infiltration. CONCLUSIONS: With respect to the preliminary data from this pilot
      trial, budesonide with its high topical and low systemic effects seems to be of
      therapeutic clinical benefit in collagenous colitis. A therapeutic effect could
      be demonstrated for both therapeutic goals, the clinical response and
      morphological changes. Further studies on the effects of budesonide on mucosal
      collagen metabolism and long-term follow-up are warranted.

PMID- 10406253
TI  - Small bowel metastases from primary carcinoma of the lung: clinical findings and
      outcome.
AB  - OBJECTIVE: Symptomatic small bowel metastases from primary carcinoma of the lung
      have been rarely reported. The aim of this study was to describe clinical
      presentation and outcome in a series of patients. METHODS: Between 1984 and 1996,
      1544 patients with lung cancer were referred to our institution for surgery and
      1399 were operated on. Seven of them developed a symptomatic small bowel
      metastasis. Clinical, radiological, and pathology records were reviewed. RESULTS:
      In 6 of 7 patients, the lung cancer was previously operated on from 0.5 to 24
      months before the diagnosis of small bowel metastasis. In 1 patient, the primary
      tumor was diagnosed after small bowel metastasis resection. Clinical symptoms at
      presentation were acute peritonitis in 2 patients, progressive digestive
      obstruction in 3, and gastrointestinal bleeding in 2. The diagnosis was suspected
      on abdominal ultrasonography in 2 cases, and small bowel radiography in 3 cases.
      It was confirmed either by computed tomographic scan or by push enteroscopy. All
      patients underwent operation (intestinal resection in 6 and bypass in 1) with no
      postoperative death. Small bowel metastases were located in the jejunum in 2
      patients, in the ileum in 3, and in both sites in 2. Histological features of the
      metastases were identical to the primary tumor: squamous cell carcinoma (n = 3),
      undifferentiated large cell carcinoma (n = 2), adenosquamous carcinoma (n = 1),
      and adenocarcinoma (n = 1). In 6 patients, small bowel metastases were associated
      with other metastatic sites. Six patients died within 8 months after metastasis
      resection. One patient was alive 22 months after bowel resection. CONCLUSIONS:
      Symptomatic small bowel metastases can occur early in the course of lung cancer.
      Resection should be considered as the best palliative treatment to prevent bowel
      obstruction or peritonitis.

PMID- 10406252
TI  - Increased intraluminal release of eosinophil granule proteins EPO, ECP, EPX, and
      cytokines in ulcerative colitis and proctitis in segmental perfusion.
AB  - OBJECTIVE: The role of the eosinophil granulocyte in bowel mucosa in inflammatory
      bowel disease still remains obscure. The present study was performed in order to
      elucidate the local eosinophil activity and activating cytokines in the inflamed
      lesions of colon and rectum in patients with ulcerative colitis and proctitis.
      METHODS: The activity of intestinal eosinophils with respect to the release of
      granule proteins was studied in 18 patients (10 with colitis and 8 with isolated
      proctitis) and 18 healthy controls, using intraluminal segmental perfusion of the
      sigmoid colon and rectum. The released amounts of eosinophil granule proteins:
      eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil
      protein X (EPX) to perfusion fluid were determined by radioimmunoassays. The
      intraluminal release of possible eosinophil priming cytokines
      granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 8 (IL
      8), were analyzed by immunoassays. RESULTS: The mucosal release of ECP, EPO, and
      EPX was increased 10- to 20-fold in patients with colitis and proctitis compared
      with controls. The intraluminal release of GM-CSF and IL-8, was several-fold
      enhanced in patients with colitis and proctitis. We also found a correlation
      between all three eosinophil granule proteins and the levels of IL-8/GM-CSF in
      the sigmoidal segments of patients with colitis. CONCLUSIONS: We conclude that
      the increased release of ECP, EPO, and EPX to colorectal perfusion fluid indicate
      eosinophil involvement in the local disease in patients with colitis and
      proctitis. IL-8 and GM-CSF may play a role in eosinophil accumulation and priming
      in colitis.

PMID- 10406254
TI  - Low plasma cholesterol: a correlate of nondiagnosed celiac disease in adults with
      hypochromic anemia.
AB  - OBJECTIVE: Hypochromic anemia is at times attributable to nondiagnosed celiac
      disease. The aim of this study was to define the correlates of celiac disease in
      anemic adults without overt malabsorption. METHODS: One hundred patients with
      hypochromic anemia and without diarrhea underwent a complete diagnostic work-up,
      including screening for celiac disease, i.e., upper endoscopy with duodenal
      biopsy and search of antiendomysium antibodies. RESULTS: Patients with
      hypochromic anemia were from two different Divisions and were analyzed as a
      single group because they were not significantly different for any variable.
      Hypochromic anemia was attributable to celiac disease in 10 patients. Compared to
      anemic patients without celiac disease, anemic patients with celiac disease had
      significant or borderline significant differences for plasma cholesterol (
      17.9%), albumin (-9.4%), and body mass index (-11.8%), but not for gender
      distribution, age, weight, height, blood hemoglobin, mean corpuscolar volume,
      plasma iron, and ferritin. All anemic patients with celiac disease had plasma
      cholesterol < 156 mg/100 ml. Within the entire cohort of anemic patients, plasma
      cholesterol inversely related to prevalence of celiac disease (p < 0.001); also
      plasma albumin and body mass index inversely related to celiac disease, but
      coefficients were borderline significant (p = 0.056 and 0.052, respectively).
      CONCLUSIONS: The data suggest that among patients with hypochromic anemia, plasma
      cholesterol in the high-to-normal range could be used to exclude the presence of
      celiac disease. Other nutritional markers are less sensitive as indices of risk
      of celiac disease. Hematological indices are not of help to define the risk of
      celiac disease in anemic patients without signs of malabsorption.

PMID- 10406255
TI  - Discrepancies between reported food intolerance and sensitization test findings
      in irritable bowel syndrome patients.
AB  - OBJECTIVE: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder
      with clinical signs typical of "intestinal" food allergies or intolerance. The
      aim of this study was to characterize the clinical features of IBS patients
      suspected of suffering from adverse reactions to food. METHODS: The study
      involved 128 consecutive IBS patients divided into four groups according to their
      main symptom on presentation at our outpatient clinic. A detailed medical history
      was recorded, paying particular attention to any allergies and reported
      intolerance to food. Each patient was screened for allergies; intestinal
      permeability tests was performed in randomly selected patients from different
      groups. Findings were analyzed using the chi2 test. RESULTS: Adverse reactions to
      one or more foods were reported by 80 patients (62.5%); skin prick tests (SPT)
      were positive in 67 patients (52.3%) with no significant differences between
      patients complaining of different symptoms. Patients who reported a food
      intolerance had more positive SPTs than those who did not (47 of 80 [58.7%] vs 20
      of 48 [41.7%]); this difference was not statistically significant, although it
      suggests a trend (p < 0.0610). There was little consistency between the specific
      foods reported to cause intolerance and those resulting from the tests (11 of 80
      patients, 13.7%). The intestinal permeability test was normal in 29 of 33
      patients (87.9%). CONCLUSIONS: More than 50% of IBS patients were found
      sensitized to some food or inhalant without any typical clinical signs. Patients
      were unable to identify potentially offending foods. The lack of a correlation
      between SPT results and reported food allergies needs further investigation to
      clarify the pathophysiology and improve the diagnosis of intestinal food
      allergies.

PMID- 10406256
TI  - Increased prevalence of sicca complex and fibromyalgia in patients with irritable
      bowel syndrome.
AB  - OBJECTIVE: As many as 70% of patients with fibromyalgia complain of the symptoms
      of irritable bowel syndrome (IBS), but there is a clinical impression that IBS
      patients do not suffer from fibromyalgia as frequently. The sicca complex (dry
      eyes and mouth) is also commonly observed in fibromyalgia, but its prevalence in
      IBS has not been evaluated. Our objective was to assess the frequency of
      fibromyalgia and sicca complex in secondary care patients with IBS. METHODS:
      Forty-six secondary care patients with IBS and 46 healthy controls were assessed
      by a rheumatologist for the presence of fibromyalgia and objective evidence of
      sicca complex (Schirmer and Rose-Bengal tests). Psychological status was also
      assessed (HAD questionnaire). RESULTS: Thirteen (28%) IBS patients suffered from
      fibromyalgia, compared with five (11%) controls, a difference of 17% (95%
      confidence intervals [CI], 2-33%). Fifteen (33%) IBS patients versus three (6%)
      controls had sicca complex, a difference of 27% (95% CI, 11-45%). CONCLUSIONS:
      These results suggest that the prevalence of fibromyalgia in IBS is approximately
      half that of IBS in fibromyalgia. Furthermore, sicca complex seems to be another
      complaint that should be added to the list of extracolonic manifestations of IBS.
      Study of the overlap between functional disorders presenting to different
      specialties may give new insights into the pathophysiology of these puzzling
      conditions.

PMID- 10406257
TI  - Late disappearance of hepatitis C virus RNA from peripheral blood mononuclear
      cells in patients with chronic hepatitis C in sustained response after alpha
      interferon therapy.
AB  - OBJECTIVE: We aimed to investigate the modifications of HCV RNA (genomic and
      antigenomic strands) in peripheral blood mononuclear cells (PBMCs) of long-term
      responder patients to alpha-interferon therapy, and their usefulness as criteria
      of definitive HCV eradication. METHODS: We studied 10 patients with chronic
      hepatitis C with > 1 yr of sustained response after alpha-interferon therapy
      (normal alanine aminotransferase [ALT] and negative serum HCV RNA). Serum HCV RNA
      and genotyping were determined. Approximately 2 and 4 yr after completion of
      treatment we investigated the presence of HCV RNA (genomic and antigenomic
      strands) in PBMCs. Eight of 10 patients were rebiopsed 2 yr after discontinuation
      of treatment. RESULTS: The mean follow-up was 46.6 +/- 4.6 months (range, 39-51
      months). In this period, all patients remained in sustained response. In the
      first determination, all patients had HCV RNA genomic strands and two patients
      had antigenomic strands detectable in PBMCs. Two years later only two patients
      had genomic and none had antigenomic strands detectable. After 4 yr of sustained
      response, eight of 10 patients lost HCV RNA from PBMCs. CONCLUSIONS: In the long
      term follow-up, the majority of patients with chronic hepatitis C with sustained
      response after alpha-interferon therapy progressively lost HCV RNA from PBMCs.
      This determination in PBMCs is not a predictor of response.

PMID- 10406258
TI  - Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2.
AB  - OBJECTIVE: Susceptibility to autoimmune hepatitis (AIH) type 1 has been
      associated with DRB1*03, DRB1*04, and DRB3 alleles in European and North-American
      whites, with DRB1*04 in Japan, and with DRB1*04 and DRB1*13 in Latin America.
      Very few studies have been performed on AIH type 2. The aim of the present study
      was to evaluate the association of AIH types 1 and 2 with HLA-DR and DQ loci.
      METHODS: We performed HLA-DRB and -DQB1 typing by polymerase chain reaction
      amplification with sequence-specific primers (PCR-SSP) in 139 AIH patients. Most
      had AIH type 1 associated with circulating anti-smooth muscle antibody with F
      actin specificity or antinuclear antibody. Twenty-eight patients presented AIH
      type 2 with anti-liver/kidney microsome type 1 or anti-liver cytosol type 1
      antibodies. RESULTS: We observed a significant increase of DRB1*13 (70% vs 26% of
      controls, p < 0.00001) and DRB3 (93% vs 69% of controls, p < 0.00001) in AIH type
      1 patients. Analysis of patients without DRB1*13 disclosed a secondary
      association with DRB1*03 (70% vs 30% of controls, p = 0.0001) and either the
      DRB1*13 or the DRB1*03 alleles were present in the majority of these patients
      (91% vs 48% of controls, p = 0.001). Comparison of DRB1*13- and DRB1*03-positive
      subjects revealed that the former alleles conferred susceptibility to younger
      patients with AIH type 1. DQB1 typing showed a significant increase in DQB1*06
      (68% vs 41% of controls, p = 0.00007) in strong linkage disequilibrium with
      DRB1*13, and a decrease in DQB1*0301 (8% vs 47% of controls, p(c) = 0.0003). On
      the other hand, HLA typing of patients with AIH type 2 disclosed a significant
      increase in the DRB1*07 (68% vs 20% of controls, p(c) < 0.00014), DRB4 (79% vs
      43% of controls, p(c) = 0.004), and DQB1*02 (86% vs 42%, p = 0.00002) alleles.
      After exclusion of DRB1*07, a secondary association with HLA-DRB1*03 was further
      observed in these patients (78% vs 30%, p = 0.007) and most of them had either
      DRB1*07 or DRB1*03 (93% vs 44% of controls, p(c) < 0.0001). CONCLUSIONS: Our data
      indicate that predisposition to AIH types 1 and 2 is associated, respectively,
      with the DRB1*13 or DRB1*03 and DRB1*07 or DRB1*03 alleles, and suggest that
      protection against type 1 disease may be conferred by DQB1*0301. In addition, the
      cluster of DRB1*13 in children with AIH type 1 also supports the concept that
      different HLA alleles might influence the onset of the disease.

PMID- 10406259
TI  - Standards for selecting percutaneous ethanol injection therapy or percutaneous
      microwave coagulation therapy for solitary small hepatocellular carcinoma:
      consideration of local recurrence.
AB  - OBJECTIVE: Percutaneous ethanol injection therapy (PEIT) and percutaneous
      microwave coagulation therapy (PMCT) are effective treatments for small
      hepatocellular carcinoma (HCC). There are no clear standards, however, for the
      selection of PEIT or PMCT. We determined standards based on local recurrence.
      METHODS: The subjects were 88 patients with solitary HCC measuring < or = 30 mm
      in diameter, who were treated by PEIT (n = 45) or PMCT (n = 43) and judged to be
      cured using computerized tomography (CT) with contrast medium after treatment.
      Patient characteristics, including age, gender, viral markers, Child-Pugh
      classification, tumor size, tumor cell differentiation, and serum alpha
      fetoprotein (AFP) concentration we analyzed, and the factors influencing the
      local recurrence in the PEIT and PMCT groups were determined, using univariate
      and multivariate analysis. RESULTS: Univariate analysis indicated that tumor cell
      differentiation and serum AFP concentration influenced local recurrence in the
      PEIT group, and tumor size did so in the PMCT group. Multivariate analysis
      revealed that tumor cell differentiation influenced local recurrence in the PEIT
      group, and tumor size did so in the PMCT group. PEIT was effective for treating
      well-differentiated HCC, and PMCT was effective for treating HCC measuring < or =
      15 mm in diameter. PMCT was superior to PEIT for treating patients with HCC
      measuring < or = 15 mm in diameter. In such cases with well-differentiated HCC,
      PEIT was as effective as PMCT. CONCLUSIONS: The selection of PEIT or PMCT to
      treat patients with HCC should be based on tumor size and cell differentiation.

PMID- 10406260
TI  - Serum thrombopoietin levels in patients with chronic hepatitis and liver
      cirrhosis.
AB  - OBJECTIVE: Thrombocytopenia is a common manifestation of cirrhosis. The aim of
      this study was to examine the relationship between serum thrombopoietin
      concentrations, circulating platelet levels, and the stage of hepatic fibrosis in
      patients with chronic viral hepatitis. METHODS: The study included 48 patients
      with chronic viral hepatitis (14 with stage 1 fibrosis; five with stage 2
      fibrosis; three with stage 3 fibrosis; 26 with cirrhosis) and 30 healthy
      volunteers. Serum thrombopoietin levels were measured using an enzyme-linked
      immunosorbent assay. Spleen size, platelet counts, and prothrombin time were
      measured. RESULTS: Thrombopoietin levels of patients with fibrosis stage 1 (2.50
      +/- 1.60 fmol/ml) or stage 2 (1.89 +/- 0.65) were significantly higher than those
      in patients with cirrhosis (1.21 +/- 0.55) or healthy volunteers (1.26 +/- 0.74).
      Mean platelet counts of patients with cirrhosis (8.0 +/- 4.6 x 10(4)/microl) were
      significantly lower than those with fibrosis stage 1 (18.6 +/- 3.9) or stage 2
      (16.0 +/- 5.8), or healthy volunteers (24.5 +/- 7.3). Patients with cirrhosis had
      larger spleens (30.9 +/- 18.4 cm2) than those with fibrosis stage 1 (18.2 +/-
      6.4). Platelet counts showed a significant inverse relationship to spleen size (p
      = -0.51, p < 0.0005) and a significant positive relationship with thrombopoietin
      levels (p = 0.34, p < 0.02). Thrombopoietin levels were significantly correlated
      to prothrombin time (p = 0.45, p < 0.005). CONCLUSIONS: Serum thrombopoietin
      levels are elevated in patients with an early stage of chronic viral hepatitis.
      As the disease progresses from mild fibrosis to cirrhosis, decreased production
      of thrombopoietin may contribute to the further development of thrombocytopenia
      in cirrhosis.

PMID- 10406261
TI  - Stromal mast cells and nerve fibers in various chronic liver diseases: relevance
      to hepatic fibrosis.
AB  - OBJECTIVE: Recently, mast cells have been postulated to play a role in
      fibrogenesis in primary biliary cirrhosis (PBC) and alcoholic liver disease
      (ALD). There are only a few reports on nerve fibers in normal and pathological
      human livers. METHODS: We simultaneously investigated mast cells and nerve fibers
      in the stroma by single and double immunostainings and by quantitative
      morphometry in six normal livers and in 178 liver biopsies of PBC (n = 49),
      autoimmune hepatitis (n = 12), chronic hepatitis B (n = 37), chronic hepatitis C
      (n = 41), and ALD (n = 39). RESULTS: The densities of tryptase-positive mast
      cells, chymase-positive mast cells, and S-100-positive nerve fibers in the stroma
      were significantly higher in these chronic liver diseases than in normal livers.
      There were no significant differences in their densities among these chronic
      liver diseases. The densities of tryptase- and chymase-positive mast cells
      correlated significantly with degree of fibrosis, and density of nerve fibers
      correlated roughly with degree of fibrosis. Double immunostainings showed that
      some mast cells were in close contact with nerve fibers, and that, in selected
      cases, the percentages of mast cells positive for only tryptase (MC(T)) and those
      positive for both tryptase and chymase (MC(TC)) were 26% and 74%, respectively.
      CONCLUSIONS: These results suggest that mast cells and nerve fibers are involved
      in fibrogenesis in chronic liver diseases, regardless of their etiologies,
      probably by secreting fibrogenic substances. Some mast cells are innervated, and
      this innervation may stimulate mast cells to secrete fibrogenic substances,
      leading to hepatic fibrosis.

PMID- 10406263
TI  - A new strategy for the application of CA19-9 in the differentiation of
      pancreaticobiliary cancer: analysis using a receiver operating characteristic
      curve.
AB  - OBJECTIVE: Clinicians might be misled in interpreting an elevated CA19-9 when
      differentiating pancreaticobiliary cancer from benign clinical conditions such as
      acute cholangitis or cholestasis, because in these conditions, the concentration
      of CA19-9 may also be elevated. The aims of our study were to calculate new
      individual cutoff values for CA19-9 according to clinical situations using a
      receiver operating characteristic (ROC) curve and to define a new strategy for
      interpreting CA19-9 in pancreaticobiliary cancer. METHODS: One hundred sixty
      patients with pancreatic diseases (cancer 90, benign disease 70), 322 patients
      with biliary tract diseases (biliary cancer 152, benign disease 170), and 20,035
      asymptomatic controls were enrolled in the present study. An ROC curve was
      described by plotting the sensitivity on the y-axis against 1-specificity on the
      x-axis for each of several cutoff values. RESULTS: The area under the ROC curve
      was significantly greater for pancreatic cancer than for biliary cancer (p <
      0.05). For patients with pancreatic cancer, CA19-9 proved to be useful. At a
      cutoff value of 37 U/ml, sensitivity and specificity were 76.7% and 87.1%,
      respectively. For patients with biliary cancer, CA19-9 was not helpful. However,
      when patients with biliary disease were divided into two groups according to the
      presence of cholangitis or cholestasis, CA19-9 proved to be more useful for the
      group without cholangitis or cholestasis than for the group with cholangitis or
      cholestasis (p < 0.05). In the former group, the sensitivity and specificity of
      CA19-9 were 77.6% and 83%, respectively, at the cutoff value of 37 U/ml. For the
      latter group, the sensitivity and specificity of CA19-9 were 74% and 41.5%
      respectively, whereas the specificity reached 87% at 300 U/ml. CA19-9 in
      diagnosing pancreatic cancer was useful regardless of accompanying acute
      pancreatitis or cholestasis. The serum concentration of CA19-9 in asymptomatic
      individuals was 9.42 +/- 9.95 U/ml. Only 1 of 157 patients with a concentration
      of CA19-9 above 37 U/ml was found to have gallbladder cancer. The positive and
      negative predictive values were 0.65% and 0.78%, respectively. CONCLUSIONS: The
      use of CA19-9 for the differentiation of pancreaticobiliary cancer should be
      applied individually, depending on the clinical situation.

PMID- 10406262
TI  - Prognosis of esophageal squamous cell carcinoma: analysis of clinicopathological
      and biological factors.
AB  - OBJECTIVE: Esophageal squamous cell carcinoma (ESCC) is rather common among the
      Chinese, but the therapeutic outcome is dismal. Knowledge of the prognostic
      factors in cancerous patients may influence therapeutic strategy. However,
      systemic analyses of clinicopathological and biological factors for patients with
      ESCC are few, and the results are controversial. METHODS: Between 1985 and 1996,
      117 patients undergoing en bloc esophagectomy and gastric substitution were
      enrolled. None had neoadjuvant treatment. Postoperative adjuvant therapy was
      provided for patients at and beyond stages IIa. Clinical responses were followed
      routinely. Flow cytometry was used to measure DNA ploidy and synthesis-phase
      fraction (SPF) of the resected esophageal tissues from all patients.
      Immunohistochemistry was also used to examine the expression of proliferating
      cell nuclear antigen (PCNA), epidermoid growth factor receptor (EGFR), HER-2/neu,
      and p53 in the pathological sections. Clinical correlation was evaluated by chi2
      with Fisher's exact test, and survival by log-rank test. RESULTS: The overall
      survival rates were 74% for 1 yr, 48% for 3 yr, and 38% for 5 yr. TNM tumor
      staging, the number of diseased lymph nodes (N < or = 3 or N > 3), degree of cell
      differentiation, DNA ploidy, SPF, and lymphovascular invasion were more useful
      than biological markers, such as PCNA, EGFR, HER-2/neu, and p53, for the
      prognosis of ESCC. Multivariate analysis revealed significant correlation of
      tumor staging and number of diseased lymph nodes with patient survival after
      surgery. CONCLUSIONS: En bloc esophagectomy may provide a rather satisfactory
      survival rate for patients with early stage ESCC. However, for patients with
      distant lymph node metastasis and those with more than three lymph nodes
      involved, radical surgical resection, even combined with postoperative
      chemoradiotherapy, cannot improve survival. The prognostic value of biological
      markers, including PCNA, EGFR, HER-2/neu, and p53, however, is limited.

PMID- 10406264
TI  - Long term treatment of biliary stricture due to chronic pancreatitis with a
      metallic stent.
AB  - The exact role of endoprostheses in the management of chronic pancreatitis
      associated biliary strictures has not yet been clearly established. We report an
      unusual case of a patient with this condition who was treated for an unexpectedly
      long term with a self-expanding metallic endoprosthesis. There has only been one
      previous report of the use of metallic stents in this situation. It appears that
      metallic endoprostheses may have a role to play in the management of selected
      patients who have chronic pancreatitis-associated bile duct stricture.

PMID- 10406265
TI  - Pseudo Sister Mary Joseph's nodule.
AB  - The Sister Mary Joseph's nodule is a significant finding in the physical
      examination. It is sometimes the only indication of an intra-abdominal metastatic
      malignancy. We report a patient who presented with an umbilical nodule that was
      discovered to be an omphalith. A review of the literature discusses the Sister
      Mary Joseph's nodule and this unusual finding.

PMID- 10406266
TI  - Mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum with chromosomal
      translocation of the t(11;18)(q21;q21) and an additional aberration of trisomy 3.
AB  - A rare case of primary mucosa-associated lymphoid tissue lymphoma (MALT) of the
      rectum is reported. A 56-yr-old man was referred to our hospital for further
      examination and treatment of rectal neoplasm. A physical examination and
      laboratory data showed no special abnormalities. However, endoscopic colorectal
      observation revealed multiple red and slightly elevated nodular lesions with
      erosive changes of the rectum. The lesions were composed of diffuse, small
      atypical lymphoid cells (i.e., centrocyte-like cells) and were stained with L26
      and BCL-2 but not cyclin D1. Surface markers of cells obtained from biopsy
      specimens were CD5-, CD10-, CD19+, CD20+, kappa+, and lambda-. No BCL-2 gene
      rearrangement was observed. The clonal karyotype of t(11;18)(q21;q21) was
      observed in six of nine lymphoid cells. Trisomy was also identified two of 144
      cells by fluorescence in situ hybridization. We report a rare case of the rectal
      MALT lymphoma bearing characteristic chromosomal aberrations; t(11;18)(q21;q21)
      and trisomy 3. We suggest that chromosomal analysis using biopsy specimens may be
      useful for the diagnosis of MALT lymphoma.

PMID- 10406267
TI  - Ampullary somatostatinoma in a patient with Merkel cell carcinoma.
AB  - A 59-yr-old white man with Merkel cell carcinoma of his right leg status post
      extensive skin resection and chemotherapy had dilated hepatic and common bile
      ducts on a routine follow-up abdominal CT scan. A 1.9-cm ampullary mass was
      appreciated on endoscopy. Histology showed psammoma bodies and positive
      immunoperoxidase staining consistent with a somatostatinoma. Merkel cell tumors
      and somatostatinomas are extremely rare neuroendocrine tumors derived from neural
      crest cells. Associations have been found between somatostatinomas and other
      islet cell tumors with multiple endocrine neoplasia syndromes, but no reported
      association has been published between islet cell tumors and Merkel cell tumors.
      This patient represents the first documented case of Merkel cell carcinoma and
      somatostatinoma in a single patient. Such an occurrence may represent a
      previously undescribed neuroendocrine tumor syndrome, and this possibility should
      be considered when either tumor is diagnosed.

PMID- 10406268
TI  - Intraductal papillary-mucinous tumor of the pancreas: presentation in a young
      adult.
AB  - Intraductal papillary-mucinous tumor (IPMT) of the pancreas is a premalignant
      lesion that can result in the hypersecretion of mucous and subsequent
      pancreatitis. In this report, one of the youngest cases of IPMT is described.
      Initial pancreaticogram was normal. Pathognomonic changes of the pancreatic duct
      were found only years later; otherwise, the recurrent pancreatitis seen in this
      patient might have been repeatedly misdiagnosed as idiopathic. Pre- and
      perioperative evaluation resulted in pancreaticoduodenectomy for what was felt to
      be a curative resection. However, the patient suffered an aggressive metastatic
      course. More extensive surgery may be needed in IPMT, such as total
      pancreatectomy, especially in cases of diffuse ductal dilation of the pancreas.

PMID- 10406269
TI  - Enteroscopic identification of an adenocarcinoma of the small bowel in a patient
      with previously unrecognized hereditary nonpolyposis colorectal cancer syndrome.
AB  - Tumors of the small bowel are uncommon and seldom suspected on a clinical basis.
      Together with the relative inaccessibility of the small bowel to endoscopic
      investigation, the rarity of these tumors undoubtedly delays their diagnosis. The
      case reported is of a patient with an adenocarcinoma of the jejunum presenting as
      gastrointestinal bleeding of obscure origin. Diagnosis was by push enteroscopy,
      after several years of unsuccessful radiological and upper and lower endoscopic
      evaluation. The patient's family fulfilled the Amsterdam criteria for hereditary
      nonpolyposis colorectal cancer syndrome, which was previously unrecognized. This
      report emphasizes the value of push enteroscopy and the limits of radiography of
      the small bowel when investigating patients with obscure GI bleeding. It also
      underlines the importance of a careful evaluation of the pedigree (concerning
      history of colorectal and extracolonic cancer) of all patients, including those
      who present with adenocarcinoma of the small bowel; it is similarly important to
      consider the possibility of small bowel cancer in members of families with
      hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.

PMID- 10406270
TI  - Azathioprine in refractory sprue.
AB  - We report a patient with life-threatening refractory sprue who was dependent on
      high doses of corticosteroids to prevent severe diarrhea, malabsorption, and
      villous atrophy. Azathioprine allowed tapering of corticosteroids to lower doses,
      while maintaining remission in histology and in objective measures of
      malabsorption. Immunosuppressive therapy, however, is not without risks,
      particularly in patients with associated hypoglobulinemia.

PMID- 10406271
TI  - Clostridium difficile-associated diarrhea after short term vaginal administration
      of clindamycin.
AB  - A 32-yr-old woman developed frequent watery diarrhea with occult blood after 3
      days treatment with clindamycin vaginal cream. Clostridium difficile toxin was
      demonstrated in stool samples and was considered the cause of an antibiotic
      associated diarrhea. No other antibiotic was used at least 3 months before the
      start of diarrhea. To our knowledge, antibiotic-associated diarrhea after vaginal
      application has previously been reported only once.

PMID- 10406272
TI  - Rapunzel syndrome--a case report.
AB  - The gastric trichobezoars usually occur in young girls, often those with
      psychiatric disorders. Rarely these are known to extend from the stomach to the
      small intestine as a tail, when they are termed the Rapunzel syndrome. Until
      1997, only 10 such cases have been reported in the literature. We report another
      case in which we could extract the trichobezoar by gastrotomy and enterotomy.

PMID- 10406273
TI  - Pseudomembranous colitis after itraconazole therapy.
AB  - A 53-yr-old man was admitted with new onset of abdominal pain and nonbloody
      diarrhea 1 month after exposure to the antifungal agent itraconazole. Flexible
      sigmoidoscopy demonstrated the presence of pseudomembranes, and subsequent
      evaluation excluded other causes of diarrhea. Disruption of the resident fungal
      flora of the colon by itraconazole is proposed as the mechanism by which this
      patient developed pseudomembranous colitis. This association has not previously
      been reported.

PMID- 10406274
TI  - Mesalamine-induced granulomatous hepatitis.
AB  - A 42-yr-old man with ulcerative colitis was admitted for investigation of
      prolonged fever associated with cholestatic liver tests. Endoscopic retrograde
      cholangiopancreatography demonstrated a normal biliary tree, and liver biopsy
      showed granulomata. A clinical diagnosis of drug-induced granulomatous hepatitis
      was established as the symptoms disappeared after cessation of mesalamine therapy
      and recurred on rechallenge. Although the differential diagnosis of fever and
      hepatitis in patients with inflammatory bowel disease is wide, in this case
      mesalamine is the most likely cause.

PMID- 10406275
TI  - Ascites associated with the initial presentation of Crohn's disease.
AB  - We report a case of a 23-yr-old patient who was initially admitted with severe
      Crohn's ileocolitis complicated by a large amount of exudative ascites. There was
      no evidence of malignancy, portal hypertension, or inflammation in any organ
      other than the bowel. We present the clinical course and response to treatment
      and discuss the possible mechanisms by which Crohn's disease might contribute to
      the development of exudative ascites.

PMID- 10406276
TI  - Hyperplastic gastric polyps: medical management is feasible.

PMID- 10406277
TI  - Surgery for severe constipation: categorization is key.

PMID- 10406278
TI  - Use of a surgical endostapler for division of Zenker's diverticulum: a valuable
      refinement of the transoral technique?

PMID- 10406279
TI  - Esophageal cryptococcosis in a patient with AIDS.

PMID- 10406280
TI  - Intestinal tuberculosis.

PMID- 10406281
TI  - Colon carcinoma causing bowel obstruction in a 22-yr-old.

PMID- 10406282
TI  - Decrease in serum concentrations of Helicobacter pylori IgG antibodies during
      antituberculosis therapy: the possible eradication by rifampicin and
      streptomycin.

PMID- 10406283
TI  - A "tacky" situation.

PMID- 10406284
TI  - Barrett's metaplasia and Helicobacter pylori infection.

PMID- 10406285
TI  - Role of computed tomography in diagnosis of diffuse cavernous hemangioma of the
      rectum.

PMID- 10406286
TI  - Pancreatic abscess due to Streptococcus salivarius after dental manipulation.

PMID- 10406287
TI  - Transient marked decrease in serum transaminases in chronic hepatitis C after
      surgery.

PMID- 10406288
TI  - Triple therapy prevents HIV but not HCV transmission after needlestick injury.

PMID- 10406289
TI  - Plummer-Vinson syndrome and postcricoid carcinoma: late complications of
      unrecognized celiac disease.

PMID- 10406291
TI  - Retroperitoneal hemorrhage after diagnostic colonoscopy: an unusual complication.

PMID- 10406292
TI  - Increased prevalence of mutations of the cystic fibrosis gene in idiopathic
      chronic and recurrent pancreatitis.

PMID- 10406293
TI  - Lansoprazole and glottis edema.

PMID- 10406290
TI  - Hyperphosphatemia-hypocalcemia in gastroschisis.

PMID- 10406294
TI  - Re: Anticipation in Crohn's disease may be influenced by gender and ethnicity of
      the transmitting parent.

PMID- 10406295
TI  - Prenatally diagnosed hypoplastic left heart syndrome--outcomes after postnatal
      surgery.
AB  - OBJECTIVE: To identify prenatally diagnosed cases of hypoplastic left heart
      syndrome (HLHS) and then to determine postnatal outcomes after surgical
      interventions. METHODS: An ultrasound and pediatric cardiology database was used
      to identify all fetuses diagnosed prenatally from 1991-1996 with HLHS. Fetal
      karyotypes were performed on cultured amniocytes. After diagnosis, parents were
      given several management options: pregnancy termination before 22 weeks,
      postnatal hospice care, or surgery using the Norwood procedure or cardiac
      transplantation. Ultrasound and echocardiography findings were later compared to
      karyotype results and postnatal outcome data. RESULTS: Fifteen fetuses with HLHS
      were identified. Two (16%) chromosome abnormalities and three (20%) structural
      defects were detected. Three mothers (20%) opted for pregnancy termination, two
      (13%) chose postnatal hospice care, and one aneuploid fetus had an intrauterine
      death. Nine parents (60%) chose surgery for their infants; however, one infant
      was not an appropriate surgical candidate due to a coexisting diaphragmatic
      hernia. Eight infants underwent surgery and two survived (25%). Of the four
      infants scheduled to undergo the Norwood procedure, one died preoperatively, two
      died intraoperatively, and one infant survived and is doing well at age 8 months.
      Of the four infants scheduled for cardiac transplantation, two died awaiting
      transplant and one died postoperatively. One infant survived cardiac
      transplantation but has microcephaly and developmental delay at age two.
      CONCLUSIONS: In prenatally diagnosed HLHS at our institution, the survival rate
      following surgery for infants felt to be the best candidates was only 25%.

PMID- 10406296
TI  - Pneumonia as a complication of pregnancy.
AB  - OBJECTIVE: To identify risk factors for the development of antepartum pneumonia
      and to describe maternal and perinatal outcome in pregnant women with pneumonia.
      METHODS: The study group consisted of 59 women with antepartum pneumonia.
      Pneumonia was defined by the presence of lower respiratory tract symptoms,
      radiographic findings, no other source of infection, and at least two of the
      following: oral temperature > or =38 degrees C, white blood cell count > or
      =15,000/ml, auscultatory findings, and/or positive sputum cultures. For
      comparison, a control group (n = 118) of pregnant women was formed by selecting
      the first mother who delivered immediately before and after an index study
      subject. RESULTS: Mothers in the study group were significantly more likely than
      women in the control group to have either a history of asthma (P = 0.022) or an
      admission hematocrit < or =30% (P < 0.001). Women with pneumonia were also more
      likely to receive a tocolytic agent (P < 0.001) and/or beta-methasone to enhance
      fetal lung maturity (P < 0.001). In addition, study subjects delivered at an
      earlier mean gestational age (P = 0.002) and had infants who weighed
      significantly less (P = 0.003) than mothers in the control group. Multivariate
      analysis indicated that women with asthma or anemia had more than a five-fold
      increase in the risk of developing pneumonia during pregnancy (P = 0.013), and
      mothers with pneumonia were significantly more likely to deliver before 34 weeks
      gestation (P = 0.04). CONCLUSIONS: Pneumonia during pregnancy was associated with
      maternal anemia and asthma. In addition, preterm labor with tocolysis and/or beta
      methasone was more common in women with pneumonia, and these women were more
      likely to deliver preterm and have low birthweight infants compared to women
      without pneumonia.

PMID- 10406297
TI  - Amniotic fluid glucose and cytokines values in the early diagnosis of amniotic
      infection in patients with preterm labor and intact membranes.
AB  - OBJECTIVE: Our goal was to compare sensitivity, specificity, and predictive
      values of glucose and cytokines [interleukin-1 (IL-1), interleukin-6 (IL-6),
      interleukin-8 (IL-8), and tumor necrosis factor (TNF)] in amniotic fluid (AF) to
      detect an AF-positive culture. METHODS: Amniocentesis was performed on 113
      patients with preterm labour (PTL) and intact membranes. Fluid was cultured for
      aerobic and anaerobic bacteria, and for mycoplasmas. AF analysis included
      cytokines and glucose determinations. RESULTS: The prevalence of positive AF
      cultures was 11.5% (13/113). Anaerobic bacteria were isolated in 9 patients
      (69.2%). The glucose <16 mg/dl and cytokines values; IL-1 >640 pg/ml, IL-6
      >55,000 pg/ml, IL-8 >1,000 pg/ml, TNF >672 pg/ml, were significantly correlated
      (P < 0.01) with AF culture result. Glucose had a sensitivity of 69.2% and a
      specificity of 96% for the prediction of positive AF culture. The sensitivity and
      specificity of the cytokines ranged from 61.5-53.4% and 79.8-8.99%, respectively.
      CONCLUSIONS: In the diagnosis of the AF-positive culture, glucose <16 mg/dl is
      more sensitive than cytokines.

PMID- 10406298
TI  - Assessment of fetal nasal fluid flow by two-dimensional color Doppler
      ultrasonography during pregnancy.
AB  - OBJECTIVE: The purpose of this study was to evaluate the development of fetal
      lung function during normal pregnancy by analysis of breathing movement-related
      fetal nasal fluid flow waveforms including its regularity and inspiratory peak
      velocity using two-dimensional color Doppler and pulse Doppler ultrasonography.
      METHODS: Sixty-eight normal fetuses between 26 and 39 weeks of gestation were
      examined. Breathing movement-related fetal nasal fluid flow waveforms were
      recorded. Regularity, frequency, and inspiratory fetal nasal fluid flow peak
      velocity and transverse lung area were measured. The relationships of these
      parameters were analyzed. RESULTS: A regular pattern of breathing movement
      related fetal nasal fluid flow waveforms appeared at 28 weeks of gestation and
      the appearance of a regular pattern increased to term. In 31 cases there was a
      regular pattern: frequency of fetal nasal fluid flow decreased and the peak flow
      velocity increased with advancing gestational age. Positive correlation between
      inspiratory fetal nasal fluid flow peak velocity and both gestational age and
      fetal transverse lung area was found. CONCLUSIONS: The changes in inspiratory
      fetal nasal fluid flow peak velocity depend on structural and functional
      maturation with advancing gestation. The measurement of breathing-movement
      related fetal nasal fluid flow waveforms using two-dimensional color Doppler
      ultrasonography appears useful for evaluating fetal lung function.

PMID- 10406299
TI  - Pregnancy outcome in patients requiring parenteral nutrition.
AB  - OBJECTIVE: The purpose of this retrospective study was to evaluate maternal and
      perinatal outcomes and complications of parenteral nutrition during pregnancy in
      our institution. METHODS: This study was a review of medical records of all women
      who required parenteral nutrition during pregnancy at our institution from 1990
      1997. The frequency of maternal and perinatal complications was calculated.
      RESULTS: Twenty-six pregnancies required parenteral nutrition for the following
      indications: hyperemesis gravidarum (n = 16), cholecystitis/pancreatitis (n = 3),
      small bowel obstruction (n = 2), intracranial bleed (n = 2), ulcerative colitis
      (n = 1), and other (n = 2). The mean gestational age at initiation of therapy was
      16.2 weeks and the mean duration of therapy was 30.6 days. Five pregnancies were
      terminated prior to fetal viability. Of the remaining pregnancies, obstetric
      complications occurred in 11, including two cases of idiopathic preterm labor
      resulting in preterm deliveries. Maternal complications resulting from the
      central venous catheters included four infections, two thromboses, one occlusion,
      one pneumothorax, and one catheter dislodgment. The complication rate for
      centrally inserted central catheters (50%) was significantly greater than the
      rate for peripherally inserted central catheters (9%). CONCLUSIONS: Successful
      outcomes can be achieved in obstetric patients requiring parenteral nutrition. In
      this group of patients, the frequency of maternal complications secondary to
      centrally inserted central venous catheters was greater than that reported in
      nonpregnant patients. Peripherally inserted central catheters may be preferable
      when parenteral nutrition is required during pregnancy.

PMID- 10406300
TI  - Economic evaluation of prenatal carrier screening for fragile X syndrome.
AB  - OBJECTIVE: The objective of this study was to conduct an economic evaluation of
      routine prenatal carrier testing for fragile X syndrome. METHODS: This economic
      analysis was conducted from the societal perspective. A cost-benefit equation was
      developed based on the premise that the cost of routinely offering prenatal
      carrier testing for fragile X syndrome should be at least equal to, or less than,
      the cost of the current practice of not offering such testing. Sensitivity
      analyses included key assumptions regarding therapeutic abortion rates (50-100%)
      and patient screening acceptance rates (50-80%). RESULTS: A policy of routinely
      offering prenatal carrier testing for fragile X syndrome may be beneficial only
      if the cost per screening test is less than $120 during the first year of the
      screening program, or less than $240 when the program reaches its full maturity.
      Given the current cost per screening test of $250, prenatal screening for carrier
      status for fragile X syndrome carries the potential for annual losses of
      approximately $10 to $195 million in the United States. In addition,
      approximately 46-115 fetal lives may be lost due to invasive genetic procedures.
      CONCLUSIONS: Prenatal screening for fragile X syndrome may be economically
      beneficial only if the cost of the prenatal screening test for carrier
      identification is considerably less than the current cost.

PMID- 10406301
TI  - Placenta accreta: comparison of cases managed with and without pelvic artery
      balloon catheters.
AB  - OBJECTIVE: To describe our experience with the use of prophylactic pelvic artery
      balloon catheters in cases of placenta accreta diagnosed by antenatal ultrasound
      and to compare these cases with contemporary controls. METHODS: In this
      prospective study, all patients seen at our institution between January 1994 and
      August 1997 with the antenatal sonographic diagnosis of placenta accreta were
      offered prophylactic preoperative pelvic artery balloon catheterization. Patients
      who were delivered by cesarean hysterectomy for unsuspected placenta accreta in
      our institution during the same time interval served as controls. Five patients
      with the sonographic diagnosis of placenta accreta underwent prophylactic pelvic
      artery balloon catheterization. Surgical outcomes in patients who received
      balloon catheters were compared with those managed without them. Statistical
      analysis was performed using the Mann-Whitney U test. RESULTS: Five patients with
      placenta accreta or one of its variants were correctly identified with antenatal
      ultrasonography. Of the five patients who underwent pelvic artery balloon
      catheterization, all had placenta accreta and four required cesarean
      hysterectomy. The mean estimated blood loss, transfusion requirement, and length
      of hospitalization in patients undergoing hysterectomy managed with and without
      the balloon catheters was not different (P > 0.06). CONCLUSIONS: Antenatal
      sonographic diagnosis of placenta accreta enables preoperative planning. In our
      experience, use of pelvic artery balloon occlusion catheters in patients
      requiring a cesarean hysterectomy for placenta accreta did not improve surgical
      outcomes compared with patients managed without them. These preliminary findings
      are based on a small number of patients; therefore, further investigation is
      needed.

PMID- 10406302
TI  - Value of maintenance therapy with oral tocolytics: a systematic review.
AB  - OBJECTIVE: The objective was to perform a systematic review of prospective
      randomized trials evaluating the efficacy of oral tocolytics in the prevention of
      recurrent preterm labor and its associated complications. METHODS: A MEDLINE
      search of English language articles published since 1966 was performed to
      identify studies of maintenance oral tocolytic therapy. Studies were included in
      the review which: 1) randomized patients to an oral tocolytic after stabilization
      with parenteral therapy; 2) reported results for either a placebo or a control
      group; and 3) included patients with intact membranes only. These studies were
      analyzed for nine outcomes, including incidence of preterm delivery, incidence of
      recurrent preterm labor, latency from treatment to delivery, gestational age,
      birthweight, admission to an intensive care nursery (ICN), incidence of
      respiratory distress syndrome (RDS), incidence of intraventricular hemorrhage
      (IVH), and perinatal mortality. RESULTS: Seven studies met the inclusion
      criteria, four of which used oral terbutaline for the treatment arm (two had a
      control group, and two had a placebo group), and one used oral ritodrine (with a
      placebo group). Of the remaining two, one used oral ritodrine and oral magnesium
      chloride (with a control group), and the other used oral terbutaline and oral
      magnesium chloride (with a placebo group). The results of the individual studies
      suggest that there was no beneficial effect of oral tocolytic therapy on the
      incidence of preterm delivery (odds ratio (OR) range: 0.7-2.0), incidence of
      preterm labor recurrence (OR range: 0.6-3.2), ICN admission (OR range: 1.3-2.0),
      incidence of RDS (OR range 0.1-4.3), incidence of IVH (OR range 0.3-2.0),
      perinatal mortality (OR range: 1.6-4.3), or gestational age at delivery.
      CONCLUSIONS: We concluded that a meta-analysis based on the available studies is
      not possible due to the fact that there is little that these seven studies have
      in common with respect to treatment comparisons. In addition, inconsistent
      definitions of outcome variables makes pooling this data inappropriate and
      invalid. Therefore, well-designed, large, randomized trials are needed to
      evaluate the efficacy of oral tocolytics in improving perinatal outcome.

PMID- 10406303
TI  - Endocrinological and biophysical responses to further reduction in oxygenation
      following sustained hypoxemia in fetal goats.
AB  - OBJECTIVE: The purpose of this study was to determine fetal endocrinological and
      biophysical responses to the further reduction in oxygenation following prolonged
      nonacidemic hypoxemia in fetal goats. METHODS: Seven further hypoxic experiments
      were performed after prolonged (24-h) nonacidemic hypoxemia, caused by an
      infusion of nitrogen into the maternal trachea and by reducing uterine arterial
      blood flow in four chronically instrumented goat fetuses at 123-131 days'
      gestation. We measured arginine vasopressin, adrenocorticotropic hormone,
      cortisol, and catecholamines as endocrinological parameters. Fetal heart rate,
      fetal blood pressure, and fetal breathing movement were observed as biophysical
      parameters. RESULTS: Fetal arterial pO2 was significantly decreased from 27.0 +/-
      1.2 mmHg (control) to 18.0 +/- 0.7 mmHg and 11.3 +/- 1.3 mmHg at the end of the
      prolonged hypoxemia and the further hypoxia, respectively. The further hypoxia
      induced reductions in fetal heart rate, increases in fetal blood pressure, and a
      series of gasping. Arginine vasopressin and catecholamines were elevated
      significantly by the further hypoxia. Although adrenocorticotropic hormone and
      cortisol were increasingly elevated, they did not reach a significant level.
      CONCLUSIONS: Some specific fetal responses-excessive elevations of fetal
      catecholamines, arginine vasopressin, accompanied with fetal gasping-were
      observed during further severe hypoxia.

PMID- 10406304
TI  - Fetal complication after external cephalic version at term: case report and
      literature review.
AB  - We report a case of fetal distress following external cephalic version at term,
      which resulted in delivery by emergency cesarean section of an anemic, acidemic
      infant. The characteristics of the fetal heart rate tracing, the clinical
      findings, and a positive Kleihauer-Betke test after delivery suggest that
      fetomaternal hemorrhage or placental abruption was the most likely cause of the
      fetal distress. We review the incidence of the reported fetal complications after
      external version.

PMID- 10406305
TI  - Acute oligohydramnios and deteriorating fetal biophysical profile associated with
      severe preeclampsia.
AB  - Acute changes in fetal biophysical profile (BPP) status usually include rapid
      cessation of all nonessential acute biophysical activities, yet not necessarily
      an acute decrease in the amniotic fluid volume, or oligohydramnios. A 36-year-old
      para 3 with early third-trimester severe preeclampsia, mild placental abruption,
      and fetal growth restriction, with a reassuring BPP of 8/8, was managed
      expectantly with intravenous magnesium sulfate, hydralazine, and intramuscular
      corticosteroids. Within 20 h of admission a marked change in the BPP was noted,
      with a score of 0/8. Amniotic fluid index (AFI), which on admission had been
      20.1, progressively became 0, despite a stable normovolemic maternal status. At
      immediate cesarean, a mildly acidotic and hypoxic fetus was delivered which
      subsequently did well. This case supports the concept that acute oligohydramnios
      may develop rapidly in the presence of acute fetal hypoxemia.

PMID- 10406306
TI  - Extensive spontaneous retroperitoneal hemorrhage: an unusual complication of
      heparin anticoagulation during pregnancy.
AB  - A 27-year-old patient at 13 weeks' gestation maintained on subcutaneous
      heparinization due to hemoglobin S and hemoglobin C (SC) sickle cell disease and
      previous splenic vein thrombosis presented with spontaneous acute onset of severe
      left lower abdominal and groin pain. The pain, which radiated to the anterior
      aspect of the thigh, was associated with nausea and vomiting and was exacerbated
      by extension of the left lower extremity. The patient was hemodynamically stable,
      yet during the first 24 h of hospitalization a marked decrease in hematocrit from
      29% to 22% occurred. Contrast computed tomography (CT) revealed an extensive
      abdominal-pelvic, retroperitoneal hematoma extending approximately 15 cm in
      length from above L5 cephalad to below the greater trochanter of the left femur
      caudally. The retroperitoneal hemorrhage self-tamponaded and did not require
      surgical management. The dosage of heparin was decreased and maintained with
      appropriate activated partial prothrombin (aPTT) levels. To our knowledge, this
      is the first report of a spontaneous retroperitoneal hemorrhage complicating
      heparin anticoagulation in pregnancy. Unusual hemorrhagic complications of
      anticoagulation therapy are discussed.

PMID- 10406308
TI  - Life and death in otolaryngology: mechanisms of apoptosis and its role in the
      pathology and treatment of disease.
AB  - OBJECTIVES: To review recent advances in our understanding of programmed cell
      death, or apoptosis, and discuss implications of these basic science advances in
      our understanding of causes and potential treatments of a variety of diseases of
      the head and neck. DATA SOURCES: Basic science literature relevant to the study
      of apoptosis and its clinical implications. CONCLUSIONS: Apoptosis is now
      understood to be important in the normal development and survival of all
      multicellular organisms. Deregulation of this normally tightly controlled process
      underlies a variety of disease states, including neoplasia, autoimmune disease,
      and disorders of the central nervous system. A better understanding of this
      process and its regulation may help otolaryngologists better understand diseases
      relevant to this specialty and will lead to improved therapeutic interventions.

PMID- 10406307
TI  - Twin delivery after myomectomy, in vitro fertilization, and embryo reduction in
      an infertile woman.
AB  - A 28-year-old patient had metroplasty performed because of necrosis of a uterine
      fibroid. During follow-up, the left adnexa were removed because of a recurrent
      left ovarian cyst. The triplet gestation achieved by in vitro fertilization was
      reduced to twins. The living premature newborns were delivered abdominally.

PMID- 10406310
TI  - Initial results from the national registry for juvenile-onset recurrent
      respiratory papillomatosis. RRP Task Force.
AB  - OBJECTIVE: To characterize the spectrum of juvenile-onset recurrent respiratory
      papillomatosis (RRP) in the United States and to obtain data about the natural
      course of the disease and its response to treatment. SETTING: Twenty tertiary
      care pediatric otolaryngology centers throughout the United States. PATIENTS: All
      patients with active RRP aged less than 18 years at the participating sites. MAIN
      OUTCOME MEASURES: Number of surgical procedures performed per year, progression
      of papillomas to previously nondiseased anatomical sites, drug interventions and
      other adjuvant therapy, and need for tracheostomy. RESULTS: Data were collected
      from 399 children enrolled from January, 1, 1997, through December 31, 1998.
      There were 51.9% male; 62.7% white, 28.3% black, 9.0% other or unknown racial
      group; 10.8% Hispanic ethnicity. Mean age at diagnosis was 3.8 years (range, 0.1
      16.3 years) and mean duration of disease was 4.4 years (range, 0.03-18.9 years).
      The mean number of surgical procedures per child was 4.4 per year (range, 0.2
      19.3 per year). Children whose RRP was diagnosed at younger ages (<3.0 years)
      were 3.6 times more likely to have more than 4 surgical procedures per year
      (P=.001) and almost 2 times more likely to have 2 or more anatomical sites
      affected (P=.008) than were children whose RRP was diagnosed at later ages (> or
      =3.0 years), after adjusting for sex, race, and years of treatment. CONCLUSIONS:
      Children whose disease was diagnosed before age 3 years were more likely than
      children aged 3 years or older to have more severe disease as measured by the
      mean number of surgical procedures performed and by the number of anatomical
      sites affected. The registry will form the basis for future analysis on the
      outcome of disease, natural course of RRP under management strategies, prevention
      strategies, and public health importance.

PMID- 10406309
TI  - Role of Bcl-xL protein in differentiation and apoptosis of human middle ear
      cholesteatoma epithelium.
AB  - OBJECTIVE: To compare the mechanisms of proliferation, differentiation, and
      apoptosis in middle ear cholesteatoma epithelium with those of normal external
      ear canal epithelium. DESIGN: The localizations of the expression of Bcl-xL
      protein and involucrin and the presence of apoptotic cells were determined for
      tissue slices of middle ear cholesteatoma epithelium and compared with the
      findings for normal external ear canal epithelium. In addition, SCC-25/bcl-xL
      transfectants showing the overexpression of Bcl-xL were used to investigate the
      effect of this protein on the expression of involucrin, which is a marker of
      epithelial cell differentiation. MATERIALS: Cholesteatoma tissue specimens were
      surgically excised from 10 patients. Normal skin specimens collected from the
      external ear canal of the 10 patients were used as control specimens. RESULTS:
      The expression of Bcl-xL was detected in the vicinity of the basal cell layer of
      both the cholesteatoma epithelium and the normal external ear canal epithelium.
      Conversely, the expression of involucrin (ie, a marker of epithelial cell
      differentiation) increased in proportion to the shallowness of the epithelial
      layer. In situ labeling detected apoptotic cells in the spinous and granular cell
      layers of cholesteatoma tissue sections and similar findings in the normal
      external skin specimens. Western blot analysis confirmed that the expression of
      involucrin protein was the same in both wild-type SCC-25 cells and the SCC-25/bcl
      xL transfectants. CONCLUSIONS: In both the cholesteatoma epithelium and the
      normal external ear canal epithelium, differentiation and apoptosis begin when
      the epithelial cells separate from the basal cells. The mechanisms behind these
      changes, at least in apoptosis, appear to be controlled by the expression of the
      Bcl-xL protein.

PMID- 10406311
TI  - Safety of pediatric short-stay tonsillectomy.
AB  - OBJECTIVE: To determine the safety of a relatively brief (<3-hour) period of
      postoperative observation prior to discharge in children undergoing outpatient
      tonsillectomy. DESIGN: Retrospective chart review. SETTING: Tertiary care
      children's hospital and public teaching hospital. PATIENTS: The records of all
      patients (12 years of age who underwent tonsillectomy or adenotonsillectomy from
      November 1995 through July 1997 were reviewed. A total of 143 patients scheduled
      for ambulatory treatment were identified; 9 were excluded owing to insufficient
      follow-up. The remaining 134 patients made up the study group. MAIN OUTCOME
      MEASURES: (1) Duration of observation prior to discharge; (2) complication rates.
      RESULTS: The mean age of the study population was 6.1+/-2.6 (mean+/-SD) years.
      Obstructive sleep apnea was an indication for surgery in 86.5%. Eleven (8.2%) of
      134 planned outpatients were electively admitted from the recovery room for
      inpatient observation, most often because of respiratory compromise. Patients
      admitted from the recovery room were significantly younger (mean age, 4.0 years)
      than those who were discharged as planned (6.3 years, P<.001). One hundred twenty
      three patients were discharged from the recovery room as anticipated, following a
      mean+/-SD duration of postoperative observation of 144+/-48 minutes. Overall, 5
      (4.1%) of these 123 outpatients suffered complications after discharge. Two
      patients (1.6%) experienced primary bleeding, both at 8 hours after surgery. Four
      patients (3.2%) were readmitted. The complication rate did not vary significantly
      with the duration of postoperative observation (P= .71). CONCLUSION: A short
      postoperative observation period is safe, with a low rate of complications, in
      appropriately selected children scheduled for ambulatory tonsillectomy.

PMID- 10406312
TI  - Cholesteatomas associated with ventilation tube insertion.
AB  - OBJECTIVES: To determine the incidence of cholesteatoma formation associated with
      ventilation tube (VT) placement and to identify and analyze the variables and
      risk factors that may predict or predispose to this complication. DESIGN: We
      reviewed the medical records of 2829 children following VT insertion between the
      years 1978 and 1997 to obtain 1- to 20-year follow-up data. SETTING: Departments
      of Otolaryngology-Head and Neck Surgery and outpatient clinics of 2 tertiary
      referral academic medical centers. PATIENTS: A study population of 2829 children,
      ranging in age from 1.2 to 14 years (5575 ears), underwent a total of 6701 VT
      placements. MAIN OUTCOME MEASURE: Cholesteatomas were considered a complication
      of VT placement whenever they developed at or near the site of the tube
      insertion. RESULTS: Cholesteatomas directly attributed to VT placement occurred
      in 1.1% of the ears that were operated on. A higher incidence occurred (1) in
      children younger than 5 years, (2) when Goode T-tubes were used, (3) in cases
      with repeated insertions of tubes, (4) with intubation exceeding 12 months, and
      (5) in cases with frequent post-operative otorrhea. CONCLUSIONS: Cholesteatoma
      formation associated with VT placement occurs in 1.1% of the ears that are
      operated on, and therefore it should be discussed with patients or parents prior
      to surgery. Periodic and long-term follow-up microscopic examinations of the
      eardrum should be performed in all patients following tubal extrusion or removal,
      especially in those at high risk for developing a secondary cholesteatoma, to
      detect this complication as early as possible.

PMID- 10406313
TI  - Relationship of passive cigarette smoking to otitis media.
AB  - OBJECTIVE: To determine the effect of passive smoking on otitis media with
      effusion (OME) and recurrent otitis media (ROM). DESIGN: A case-control study of
      children who received ventilation tubes and who were followed up for 1 year to
      determine the risk of developing postoperative otorrhea and early extrusion in
      relation to exposure to passive cigarette smoke. SETTING: Otorhinolaryngology
      Clinic of Istanbul School of Medicine, Istanbul, Turkey. PATIENTS: A total of 166
      children 3 to 7 years old who required tympanostomy tubes because of OME and ROM
      (case group) compared with an age-matched control group of 166 children. The
      control group consisted of children who did not meet and never had met criteria
      for insertion of tympanostomy tubes. MAIN OUTCOME MEASURES: Statistical analysis
      of factors associated with a higher prevalence of OME or ROM, postoperative
      otorrhea, and early tube extrusion. RESULTS: Passive smoking was a significant
      risk factor for OME and ROM. The case group was exposed to a mean of 19.6
      cigarettes per day vs 14.4 cigarettes per day for the control group (P<.004).
      Only maternal smoking was a significant factor (P<.001); no association was found
      with paternal smoking. Prospective follow-up of the case group showed no
      significant difference in the clinical course of OME and ROM between maternally
      exposed and non-maternally exposed children. CONCLUSIONS: Passive smoking
      increases the risk of OME and ROM in children between 3 and 7 years old. The
      avoidance of daily exposure to domestic tobacco smoke could have a public health
      impact.

PMID- 10406314
TI  - Evaluation of orbital stress dissipation in pediatric and adult skulls using
      electronic speckle pattern interferometry.
AB  - OBJECTIVES: To measure and quantitatively compare the degree of force dissipation
      in pediatric and adult skulls subjected to similar dynamic forces. DESIGN: An
      anatomical study using electronic speckle pattern interferometry, which allows
      generation of displacement vectors after application of a force. SUBJECTS: Five
      human skulls (3 pediatric and 2 adult). INTERVENTION: Each skull was subjected to
      a reproducible and quantifiable force created by a steel ball pendulum striking a
      precise periorbital focus: (1) infraorbital foramen, (2) supraorbital notch, (3)
      malar eminence, and (4) nasofrontal suture. Electronic speckle pattern
      interferometry was used to construct interferogram fringe patterns to determine
      skull regions with the greatest degree of displacement. RESULTS: Interferogram
      analysis revealed that the adult skull has a tendency to dissipate force with
      minimal resultant displacement. In contrast, the pediatric skulls demonstrated
      greater displacements (ie, increased fringe density) at the same periorbital
      foci. CONCLUSIONS: The pediatric skull dissipates periorbital stress differently
      than the adult skull, as illustrated by quantitative interferogram analysis. This
      finding parallels clinical data that demonstrate a varying pattern of fractures
      in pediatric and adult skulls related to craniofacial development.

PMID- 10406315
TI  - Rigid tracheobronchoscopy-induced bacteremia in the pediatric population.
AB  - OBJECTIVE: To assess the incidence of bacteremia following rigid
      tracheobronchoscopy in children to determine whether use of prophylactic
      antibiotics is warranted in pediatric patients at risk for perioperative
      endocarditis. DESIGN: Prospective nonrandomized clinical study. SETTING:
      Specialty care referral center. PATIENTS: Patients younger than 18 years
      undergoing diagnostic rigid tracheobronchoscopy for airway assessment. Twenty
      five patients (14 boys and 11 girls) were enrolled. The mean age was 5.2 years
      (range, 10 months to 13 years). INTERVENTIONS: Blood samples for culture were
      obtained intraoperatively at 2 time intervals. The first culture was obtained
      after the induction of mask anesthesia prior to airway instrumentation; the
      second, within 5 minutes following the completion of tracheobronchoscopy. Blood
      cultures were performed under sterile technique and were placed into 20 mL of
      brain heart infusion broth. All cultures were incubated at 35 degrees C and
      observed for growth over a 14-day period. RESULTS: There were no documented cases
      of bacterial growth in blood cultures. All blood cultures, obtained before and
      after tracheobronchoscopy, were negative for bacterial growth after incubation
      for 14 days. Two culture bottles yielded contaminant organisms. CONCLUSIONS:
      Rigid tracheobronchoscopy in the pediatric population is a low-risk procedure for
      the development of bacteremia. This may bear on present guidelines regarding
      perioperative antibiotic prophylaxis for endocarditis in the high-risk
      population.

PMID- 10406316
TI  - Nasal fossae dimensions in the neonate and young infant: a computed tomographic
      scan study.
AB  - OBJECTIVE: To determine normal values in the size of nasal fossae to better
      delineate the concept of nasal stenosis in young infants with nasal obstruction
      and without choanal atresia. DESIGN: Case series. SETTING: Referral center.
      PATIENTS: Consecutive sample of 62 infants (aged 0 to 6 months) with no
      craniofacial anomalies who underwent conventional axial computed tomography scans
      for a neurologic disorder. INTERVENTION: From computer-stored images, the slices
      taken at the level of the nasal fossae floor and those just above were examined.
      The length and 10 measurements of the width of the nasal fossae were used to
      determine normal values. RESULTS: Most measurements, even the length of the nasal
      fossae, were positively correlated to the age of the patient (R = .44). In the
      age 0 to 2 months group, the median length was 29.35 mm (range, 21.3-40.4 mm). It
      was 31.5 mm in the age 4 to 6 months group (range, 25.3-36.9 mm). The anterior
      bony aperture seems to be the most accurate distance for the assessment of
      neonatal nasal fossae stenosis. Its median width was 13.5 mm (range, 8.8-17.2
      mm). Large variations characterized the dimensions of the middle nasal fossae and
      the choanae: median values were 7.6 mm (range, 4.9-13.5 mm) and 14.3 mm (range,
      10.8-19.0 mm), respectively. CONCLUSIONS: This study defined the normal range of
      variation for the main dimensions of the nasal fossae in the horizontal plane.
      These can be used as a basis for determining nasal stenosis in cases of neonatal
      obstruction.

PMID- 10406318
TI  - Histopathologic changes of the soft palate after laser-assisted
      uvulopalatoplasty.
AB  - OBJECTIVE: To assess late histopathologic changes of the soft palate after laser
      assisted uvulopalatoplasty in patients with snoring and mild obstructive sleep
      apnea. DESIGN: A nonrandomized, histopathologic controlled study. SUBJECTS AND
      INTERVENTIONS: Palatal surgical specimens were removed from 10 patients with
      snoring and obstructive sleep apnea in whom laser-assisted uvulopalatoplasty was
      not successful and who subsequently underwent uvulopalatopharyngoplasty. The mean
      interval between the last laser treatment and uvulopalatopharyngoplasty was 24
      months. The patients' specimens were compared with those of a control group
      consisting of 12 palates and uvulae excised during uvulopalatopharyngoplasty.
      RESULTS: After laser-assisted uvulopalatoplasty, all soft palates displayed
      marked and progressive pathologic changes that increased with every additional
      treatment and extended far beyond the point of laser beam application. The loose
      connective tissue present in the lamina propria was replaced by diffuse fibrosis,
      which also extended to the central layer, on the expanse of seromucous glands and
      muscle fibers. Other changes included ulceration of the oral epithelium and a
      patchy inflammatory reaction. CONCLUSIONS: Extensive thermal-induced changes,
      involving the 3 layers of the organ, were found. They are compatible with
      clinical observations reported elsewhere and are probably responsible for the
      worsening of the obstructive sleep apnea status and the sensation of the
      pharyngeal dryness that developed months after the laser-assisted
      uvulopalatoplasty. Although it has immediate benefits, the procedure is still
      relatively new and all its implications are as yet unknown.

PMID- 10406317
TI  - Does the presence of a tracheoesophageal fistula predict the outcome of laryngeal
      cleft repair?
AB  - OBJECTIVE: To determine if the presence of a tracheo-esophageal fistula (TEF)
      alters outcome following laryngeal cleft repair. DESIGN: A retrospective review
      of patients diagnosed and treated for laryngeal clefts, with a minimum follow-up
      period of 1 year. SETTING: An academic tertiary care children's hospital.
      PATIENTS: Twenty-five pediatric patients diagnosed and surgically treated for
      laryngeal cleft. MAIN OUTCOME MEASURES: Each chart was reviewed to determine if
      patients with a laryngeal cleft had been diagnosed with TEF and had undergone a
      surgical TEF repair procedure. The success of the surgery was evaluated based on
      the resolution of symptoms and the endoscopic evaluation of the repair site.
      RESULTS: Twenty-five patients were reviewed for study purposes. Fourteen had a
      history of TEF repair and 11, no history of TEF. All 25 patients underwent
      surgical repair of the laryngeal cleft. Twelve of the 14 patients with a history
      of TEF repair experienced a breakdown of the laryngeal cleft repair. Only 1 of
      the 11 patients with no history of TEF experienced such a breakdown. In 8 of 9
      patients with a laryngotracheoesophageal type I cleft, surgical repair was not
      successful. CONCLUSIONS: In our series, patients with laryngeal clefts who also
      had a history of TEF had a much higher incidence of breakdown of cleft repair
      compared with patients with no history of TEF. This finding is not conclusive and
      requires further investigation. The failure of cleft repair correlated with the
      severity of the cleft. The importance of these associations may lead to enhanced
      surgical planning and realistic preoperative family expectations.

PMID- 10406319
TI  - Pediatric angioedema: ten years' experience.
AB  - OBJECTIVE: To clarify the cause, clinical course, and management of children with
      angioedema. DESIGN: Retrospective review. SETTING: Urban tertiary care hospital
      for children. PATIENTS: Consecutive sample of all children hospitalized from
      January 1, 1987, to December 31, 1997, with the diagnosis of angioedema. Complete
      records permitting analysis were available for 10 patients. MAIN OUTCOME
      MEASURES: Sex, age, site, symptoms at initial examination, cause, therapeutic
      management, and clinical outcome. RESULTS: Seven boys and 3 girls, a mean age of
      7.7 years, had angioedema of the head or neck, most often facial (8/10 [80%]).
      Manifesting symptoms, in addition to swelling, were tenderness or pain in 4
      children (40%), dyspnea in 3 (30%), dysphagia (including drooling and spitting)
      in 3 (30%), and hoarseness in 1 (10%). Angioedema was due to food in 4 children
      (40%), insect bites in 3 (30%), infection in 2 (20%), and an antibiotic in 1
      (10%). Treatment was pharmacological in all cases. No child required intubation
      or tracheotomy. Care in the intensive care unit was necessary for 1 child (10%).
      CONCLUSIONS: Pediatric angioedema exhibits a different cause and clinical
      manifestations than does adult angioedema. Prompt diagnosis and early treatment
      with an intravenous corticosteroid, an antihistamine, and/or epinephrine lead to
      rapid resolution and may, in appropriately staffed settings, avoid the need for
      care in the intensive care unit or airway intervention. Management algorithms
      based on adult experience must be modified to account for the milder pediatric
      manifestations of this immunologic disease.

PMID- 10406320
TI  - Four-duct ligation: a simple and effective treatment for chronic aspiration from
      sialorrhea.
AB  - OBJECTIVES: To determine the effectiveness of bilateral submandibular and parotid
      duct ligation on children with severe neuromuscular impairment and chronic
      aspiration of salivary secretions and to identify any predictable anatomical
      connections between the submandibular duct and sublingual glands. DESIGN: Case
      series; retrospective anatomical study of adult cadaveric submandibular gland
      specimens. SETTING: Academic tertiary referral medical center. PATIENTS: Five
      children with severe neuromuscular impairment and recurrent aspiration
      pneumonitis. INTERVENTION: The children underwent bilateral submandibular and
      parotid duct ligation. The oral cavities of 8 cadavers were dissected to identify
      anatomical connections between the submandibular duct and sublingual glands. MAIN
      OUTCOME MEASURES: Incidence of postoperative aspiration pneumonitis; gross
      anatomical connections between the submandibular duct and sublingual gland in
      cadaveric specimens. RESULTS: No postoperative airway obstruction, infection, or
      xerostomia was noted, and technetium scanning confirmed control of salivary
      secretions from major salivary glands. Caregivers noted diminished salivary
      secretions and no aspiration pneumonia. CONCLUSIONS: This new, simple intraoral
      procedure controls aspiration pneumonitis with minimal surgical dissection and
      has less morbidity than procedures involving major salivary gland excision.
      Ranula formation, a common complication of submandibular duct transposition, is
      unlikely in this procedure because the sublingual ducts are not interrupted.

PMID- 10406321
TI  - Complications of the translabyrinthine approach for the removal of acoustic
      neuromas.
AB  - OBJECTIVE: To report the complications that occurred during a large series of
      surgical procedures for the removal of acoustic neuromas using the
      translabyrinthine approach. DESIGN: Retrospective analysis. SETTING: Neuro
      otology practice with academic affiliation. Procedures were performed at either a
      university medical center or a community hospital in conjunction with a
      neurosurgery team. PATIENTS: A total of 258 patients (142 men, 116 women; mean
      age, 51 years) underwent the translabyrinthine approach during a 14-year period.
      All patients had a histologically proven diagnosis of acoustic neuroma. RESULTS:
      There were no deaths. There were 3 cases (1.1%) of neurovascular compromise.
      There were 20 cases (7.8%) of cerebrospinal fluid leak, 16 (80%) of which
      presented as rhinorrhea and 4 (20%) as incisional leaks. The leaks at the
      incision responded to conservative management, while rhinorrhea usually required
      more aggressive means of closure. Four patients (1.6%) were diagnosed as having
      bacterial meningitis. Complete gross tumor removal was not achieved in 4 patients
      (1.6%). Facial nerve function, as measured by the House-Brackmann system, was
      recorded in all patients at 1 year: 76% had a score of I or II; 18%, a score of
      III or IV; and 6%, a score of V or VI. Other complications included 3 cases of
      pneumonia, 1 case of severe gastric hemorrhage, and 1 case of wound infection.
      CONCLUSIONS: The results of this series generally agree with those of other large
      series and demonstrate the safety and effectiveness of the translabyrinthine
      approach in excising acoustic neuromas.

PMID- 10406322
TI  - Internal carotid artery dissection following rigid esophagoscopy.
AB  - A case of internal carotid artery dissection that developed after rigid
      esophagoscopy is described. The diagnosis was suggested by the clinical
      presentation and confirmed by the findings of radiological examinations. Internal
      carotid artery dissection is a rare condition of controversial etiology. Most
      frequently, the cause is unknown and the condition is termed idiopathic. A few
      cases have occurred after forceful cervical extensions and manipulations. The
      pathogenesis in our case is uncertain: while the rigid esophagoscopy is the most
      probable cause, the intubation and spontaneous carotid artery dissection cannot
      be ruled out.

PMID- 10406324
TI  - Quiz case 1. Posterior laryngeal cleft, type 3.

PMID- 10406323
TI  - Frey syndrome: treatment with temporoparietal fascia flap interposition.
AB  - There is a 10% to 48% reported incidence of clinically significant gustatory
      sweating after parotid surgery or injury. Various medical and surgical treatments
      have been used in the attempt to treat this socially embarrassing condition.
      These treatments are not always effective and often have unwanted risks and
      adverse effects. They also do not address the post-parotidectomy defect.
      Prevention of Frey syndrome and correction of the postoperative contour deformity
      after parotidectomy have recently been achieved by interposition of
      temporoparietal fascia flap between the parotid gland and the cheek skin flap at
      the time of parotidectomy. This article presents the first report (to our
      knowledge) of an established case of Frey syndrome being treated with
      temporoparietal fascia flap interposition.

PMID- 10406325
TI  - Quiz case 2. Large vestibular aqueduct syndrome (LVAS).

PMID- 10406326
TI  - Pathogenesis of obstructive sleep apnea.
AB  - Obstructive sleep apnea is a fairly common disorder with significant adverse
      health consequences. However, the pathogenetic mechanisms remain incompletely
      understood. Upper airway (UA) patency is determined by several neuromuscular and
      nonneuromuscular factors including (1) UA dilating muscle activity, (2) the
      collapsing transmural pressure generated during inspiration, (3) changes in
      caudal traction, (4) vasomotor tone, and (5) mucosal adhesive forces. This review
      addresses the effect of sleep on UA function and how these factors conspire to
      cause UA obstruction.

PMID- 10406327
TI  - Clinical presentations of obstructive sleep apnea syndrome.
AB  - Obstructive sleep apnea syndrome (OSAS) is a common but still underrecognized
      disorder. It affects 2% to 4% of middle-aged adults, a significant proportion of
      whom are female. The spectrum of clinical presentations of OSAS and their
      severity is variable, ranging from neurocognitive complaints to cardiorespiratory
      failure. OSAS has a significant impact on quality of life, cardiovascular
      morbidity, and mortality. Its major sequelae include daytime somnolence and its
      consequences (motor vehicle accidents, poor work performance, disrupted social
      interactions), systemic and pulmonary hypertension, and ischemic heart disease.
      Treatment of OSAS results in improvement in symptoms, quality of life, and blood
      pressure control, and may improve mortality. An expansion of our understanding of
      this condition has resulted in increased awareness of its consequences, but the
      recognition of OSAS in clinical practice is still delayed. Identification of
      these patients in clinical practice requires attention to risk factors (history
      of snoring and witnessed apneas, obesity, increased neck circumference,
      hypertension, family history) and careful examination of the upper airway.
      Clinical impression alone, however, has poor (50% to 60%) sensitivity and
      specificity (63% to 70%) and the diagnosis is usually obtained on
      polysomnography. Physicians and other health care professionals need to be aware
      of the progress made in this area and recognize the necessity for prompt
      evaluation and treatment of these patients.

PMID- 10406328
TI  - The behavioral morbidity of obstructive sleep apnea.
AB  - The behavioral morbidity associated with obstructive sleep apnea (OSA) includes
      symptoms of excessive daytime sleepiness (EDS), neurocognitive deficits,
      psychological problems, and possibly an increased chance of accidents. EDS is
      among the most frequently reported symptoms in patients diagnosed with OSA. The
      available data suggest that the primary cause of EDS is sleep fragmentation. The
      subjective measures of sleepiness include the sleep wake activity inventory and
      the epworth sleepiness scale. Sleepiness can also be evaluated objectively in the
      sleep laboratory using the multiple sleep latency test or the maintenance of
      wakefulness test. The neurocognitive manifestations of OSA include impairments in
      vigilance, concentration, memory, and executive function. There is no agreed on
      consensus as to how to best quantify neurocognitive deficits in this population.
      Symptoms consistent with depression or personality changes have also been
      described, but are likely to be correlates of EDS and/or the chronicity of the
      disorder. Manifestations of the behavioral morbidity of OSA are reversible, but
      dependent on the degree of normalization in sleep-disordered breathing and the
      individual's sleep habits.

PMID- 10406329
TI  - Diagnostic techniques in obstructive sleep apnea.
AB  - Only in the last 25 years has sleep apnea been recognized as a very common
      disorder and important cause of mortality. Overnight, attended polysomnography
      remains the reference diagnostic tool for sleep apnea, although the technology
      for diagnosis continues to evolve rapidly. In many instances, screening and
      ambulatory monitoring devices can provide similar, clinically relevant
      information, but larger validation studies including long-term clinical outcomes
      are necessary.

PMID- 10406330
TI  - Cardiovascular morbidity in obstructive sleep apnea.
AB  - The repetitive respiratory events that characterize obstructive sleep apnea (OSA)
      are each followed by abrupt increases in heart rate and in pulmonary and systemic
      artery pressure and by sudden decreases in right and left ventricular stroke
      volume. The changes in systemic pressure may be profound, with patients who are
      normotensive while awake having systolic pressures approaching 300 mm Hg after
      apnea termination. Because of these dramatic hemodynamic oscillations during
      sleep, many clinicians and investigators have postulated a connection between
      sleep-disordered breathing and cardiovascular morbidity and even mortality. This
      review critically examines the evidence for such a causal relationship. We begin,
      however, by reviewing the normal hemodynamic changes that occur during sleep. We
      then describe the acute hemodynamic events associated with OSA. Finally, we
      summarize the evidence for and against a causal connection between sleep apnea
      and cardiovascular morbidity.

PMID- 10406331
TI  - Medical management of obstructive sleep apnea.
AB  - The last 20 years have seen remarkable gains in our understanding of the
      pathophysiology of sleep-disordered breathing. The rapid growth in both
      scientific and clinical knowledge has been fueled by the development of
      nonsurgical therapies for obstructive sleep apnea (OSA). These medical therapies
      have provided the avenue for public acceptance of the diagnosis and treatment of
      this common medical condition. However, medical therapy requires active patient
      participation, to achieve the desired outcomes of improved sleep continuity,
      daytime functioning, and quality of life. Conservative therapies, such as weight
      loss and patient positioning; and pharmacological therapies, have been
      disappointing. Positive pressure therapy has become the treatment of choice for
      the vast majority of OSA patients. Oral appliances offer an acceptable treatment
      alternative for select patients. Present research indicates that these mechanical
      approaches can produce significant decreases in the frequency and severity of
      sleep-disordered breathing and nocturnal oxyhemoglobin desaturation. Preliminary
      data from ongoing studies suggest that these interventions will reduce long-term
      morbidity and possibly mortality.

PMID- 10406333
TI  - Clinical and imaging features of testicular torsion: role of ultrasound.
AB  - The early and accurate diagnosis of testicular torsion remains a clinical
      challenge. The implications of a missed diagnosis have emphasized the need for a
      non-invasive test for confirming testicular ischaemia; a problem highlighted by
      difficulties in establishing the diagnosis clinically. Understandably, the advent
      of colour Doppler ultrasound (CDUS) (and subsequently 'power' Doppler and
      microbubble ultrasound contrast), has been greeted with enthusiasm. However, as
      in other fields of medicine, a policy placing sole reliance on a single technique
      is likely to be flawed. This review will critically evaluate the role of CDUS and
      other imaging modalities in the diagnosis of testicular torsion.

PMID- 10406332
TI  - Surgical management of obstructive sleep apnea.
AB  - Obstructive sleep apnea syndrome (OSAS) is most commonly the result of
      unfavorable anatomic configuration of the pharyngeal airway. Although
      tracheostomy bypasses the pharyngeal airway, other surgical approaches to OSAS
      modify the pharyngeal airway by extirpation of soft tissue or modification of the
      underlying craniofacial skeleton. Frequently more than one anatomic alteration is
      required for effective therapy. The techniques applied are determined by
      radiological and endoscopic assessment. Multiple techniques may be required and
      may be applied either in one surgical session or in sequential sessions.

PMID- 10406334
TI  - Thoracic foreign bodies in adults.
AB  - AIM: The aim of this pictorial essay is to illustrate a range of imaging
      manifestations of thoracic foreign bodies. METHODS AND RESULTS: The essay
      includes documented intrathoracic foreign bodies introduced by inhalation,
      aspiration, penetrating trauma or ingestion. Imaging modalities include chest
      radiography and computed tomography (CT). CONCLUSIONS: The majority of foreign
      bodies are seen on the plain chest radiograph. CT is helpful in demonstrating the
      presence of radiolucent foreign bodies and determining the exact location of the
      foreign bodies within the airways or lung parenchyma.

PMID- 10406335
TI  - Comparison of MR imaging with CT in depiction of tumour extension into the
      pterygopalatine fossa.
AB  - The computed tomography (CT) and magnetic resonance imaging (MRI) results of 30
      consecutive patients with tumours in the skull base, and who had abnormalities of
      the pterygopalatine fossa (PPF) on CT or MRI, were retrospectively compared with
      respect to visualization of tumour infiltration into the PPF. CT did not depict
      the abnormalities in the PPF in five patients (17%), while unenhanced T1-weighted
      MR images depicted tumour infiltration in all patients. Obliteration of PPF fat
      was better visualized on CT than T2-weighted and proton density weighted MR
      images, as were bony abnormalities. On MRI, intracranial extension was seen in
      eight of 25 patients with extracranial tumour. MRI is a sensitive method of
      demonstrating both tumour infiltration of the PPF and perineural tumour spread.

PMID- 10406336
TI  - The vertical displacement sign: a technique for differentiating between left and
      right ribs on the lateral chest radiograph.
AB  - AIM: To evaluate a new approach to the differentiation of the right and left
      ribs, the vertical displacement sign, and to compare its efficacy with the big
      rib sign. MATERIALS AND METHODS: One hundred and nine lateral chest radiographs
      that clearly showed both the gastric air bubble sign and the cardiac silhouette
      sign were retrospectively reviewed by two radiologists. Each study was evaluated
      by consensus. Each radiograph was assessed for suitability of reading with each
      technique. Suitable radiographs were then reviewed using both the big rib sign
      and vertical displacement sign independently. RESULTS: Applicability of the
      vertical displacement sign [107 of 109 (98%)] was greater than that of the big
      rib sign [95 of 109 (87%)] (P = 0.0017). The accuracy of the vertical
      displacement sign [105 of 107 (98%)] was higher than that of the big rib sign [74
      of 95 (78%)] (P < 0.001). CONCLUSION: The vertical displacement sign seems to be
      a reliable technique for the differentiation of right and left ribs on the
      lateral chest radiograph and can be used as a complementary technique when the
      big rib sign is not applicable.

PMID- 10406337
TI  - Cystic kidney disease presenting in infancy.
AB  - AIM: The clinical, histological and imaging findings of 12 children with
      ultrasound features of severe renal cystic disease presenting in the first year
      of life were reviewed. METHODS AND RESULTS: Two children had cystic dysplasia and
      four had autosomal dominant polycystic disease. Two had a malformation syndrome,
      one a variant of Meckel syndrome and the other Bardet Biedl syndrome. One had
      autosomal recessive polycystic disease and in three there was no final diagnosis.
      Intravenous urography gave non-specific information. In six cases clinical
      findings combined with imaging established a diagnosis. Diagnosis was established
      by biopsy in two and gave supportive evidence in one. Outlook for renal function
      is variable. One child has had a transplant and one is on dialysis awaiting a
      transplant. Three have a degree of renal failure and one has died. Six have
      normal renal function. Renal cystic disease is the common pathway for a
      heterogeneous group of disorders as shown in these children. CONCLUSION: It is
      emphasized that a specific diagnosis could not be made from the renal sonographic
      appearances alone, nor could any prognostic implications for renal function be
      made. Contrast retention on intravenous urography was also insufficiently
      specific to be of value. Ultrasound of the parents was the most useful imaging
      procedure and should be done in all cases.

PMID- 10406338
TI  - Pseudosubluxation of C2 on C3 in polytraumatized children--prevalence and
      significance.
AB  - AIM: Pseudosubluxation of C2 on C3 is a recognized physiological variant in the
      upper cervical spine radiographs of normal children. The aim of this study was to
      determine the prevalence of this variant in children admitted with serious
      polytrauma, and to explore its significance in this setting. PATIENTS AND
      METHODS: A retrospective review was performed of 138 patients under 16 years of
      age admitted with polytrauma via The Helicopter Emergency Medical Service. All
      patients wore hard collars and underwent immediate horizontal beam lateral
      cervical spine radiography. Normal and C2/C3 pseudosubluxation groups were
      defined using standard criteria. The two groups were compared in terms of age,
      presence of an endotracheal tube, injury severity, and outcome. RESULTS: There
      were 108 (78.3%) children in the normal group and 30 (21.7%) in the C2/C3
      pseudosubluxation group. No significant differences in sex ratio, intubation
      status, injury severity, or outcome were found. Patients in the pseudosubluxation
      group were significantly younger. CONCLUSION: In paediatric polytrauma it is
      essential to establish the integrity of the cervical spine promptly as this will
      deter unnecessary further imaging and investigation. In our study 21.7% of cases
      had C2/C3 pseudosubluxation on admission radiographs. We have shown that C2/C3
      pseudosubluxation has no significant association with intubation status, injury
      severity, or outcome. We conclude that C2/C3 pseudosubluxation can be considered
      a benign variant even in the setting of polytrauma.

PMID- 10406339
TI  - Pain after small bowel meal and pneumocolon: a randomized controlled trial of
      carbon dioxide versus air insufflation.
AB  - AIM: To determine whether the use of CO2 rather than air insufflation results in
      less pain and/or distension in patients undergoing small bowel meal (SBM) and
      pneumocolon (PC). MATERIALS AND METHODS: One hundred patients for SBM and PC were
      randomized to receive either air or carbon dioxide (CO2) as the insufflating gas.
      Both the patient and radiologist were blinded to the gas being used. Patients
      were given a questionnaire to complete the following day. The degree and duration
      of abdominal pain and swelling were scored on a visual analogue scale from 0 to
      100. RESULTS: Seventy-nine patients replied. The mean pain score was 28.1 for
      patients receiving air and 20.35 for those receiving CO2 (P < 0.05). The duration
      of pain was 9.0 h in the air group and 6.0 h in the CO2 group (P < 0.05). The
      mean abdominal swelling score was 27.1 for patients receiving air and 17.1 for
      those receiving CO2 (P < 0.05). The duration of swelling was 8.8 h in the air
      groups and 7.3 h in the CO2 group (P = 0.16). CONCLUSION: In patients presenting
      for SBM and PC, the severity and duration of abdominal pain and distension are
      significantly reduced by the use of CO2 rather than air.

PMID- 10406340
TI  - Stereotactic 14G core biopsy of non-palpable breast cancer: what is the
      relationship between the number of core samples taken and the sensitivity for
      detection of malignancy?
AB  - AIM: Percutaneous 14-gauge core biopsy (CB) guided by digital stereotactic
      mammography is now an established technique in the investigation of women with
      non-palpable suspicious mammographic lesions. Diagnostic sensitivity of CB is
      affected both by the nature of the mammographic abnormality and by the number of
      core samples taken. METHODS AND RESULTS: A retrospective review of 500 women who
      have undergone CB in our institution showed that in 235 cases, invasive or non
      invasive carcinoma was found on final surgical histology. Correlation between CB
      result and surgical histology revealed a significant increase in sensitivity for
      the diagnosis of malignancy if a larger number of cores were taken (84.3% for two
      cores and 90.2% for five cores vs. 97.9% for six or more cores). This trend was
      maintained when patients were subdivided according to mammographic abnormality,
      either soft tissue mass or microcalcifications. The effect on diagnostic
      sensitivity of increasing the number of tissue cores obtained was most pronounced
      in patients with microcalcifications graded as low or moderately suspicious for
      malignancy (70.1% for two cores and 79.1% for five cores vs 94.0% for six or more
      cores). The presence of an invasive component in a malignant lesion was correctly
      diagnosed using CB in 79.2% overall if at least six cores were taken. If the
      mammographic lesion was a soft tissue mass, this figure rose to 95.7%, but was
      only 35.7% if the visible lesion was composed of microcalcifications alone.
      CONCLUSION: Our series confirms the reliability of stereotactic CB in the
      diagnosis of breast carcinoma. Diagnostic sensitivity is improved by increasing
      the number of cores taken (to six or more), particularly in women with
      mammographic microcalcifications of an equivocal nature.

PMID- 10406341
TI  - CT and MRI manifestations of central nervous system infection following
      allogeneic bone marrow transplantation.
AB  - AIM: To determine the frequency, microbiological diversity and radiological
      patterns of central nervous system (CNS) infection following allogeneic bone
      marrow transplantation (BMT). PATIENTS AND METHODS: Two neuroradiologists
      retrospectively reviewed the computed tomography (CT) and magnetic resonance
      imaging (MRI) examinations of a large cohort of bone marrow recipients. The
      radiological findings were correlated with clinical, microbiological and
      pathological data. RESULTS: During an 8-year period 406 patients underwent
      allogeneic BMT; a total of 11 infections of the CNS were diagnosed in nine
      patients [sino-orbital aspergillosis (3), cerebral aspergillosis (2), pseudomonas
      (1), listeria (1), human herpes virus-6 (1), herpes zoster (1), toxoplasmosis (1)
      and progressive multifocal leucoencephalopathy (1)]. The radiological
      abnormalities could be divided into one or more of the following pathological
      entities: (i) focal lesions, (ii) invasive sinusitis, (iii) cerebral infarction,
      (iv) demyelination, (v) encephalitis and (vi) meningitis/hydrocephalus.
      CONCLUSIONS: Approximately 2% of bone marrow recipients developed an infection of
      the CNS. The spectrum of infection changed over time and was related to
      predictable deficits in host immunity. The radiological appearances were diverse
      and corresponded to several different pathological processes.

PMID- 10406342
TI  - Buckling of the tethering catheter causes migration of a temporary caval filter
      to the right atrium.
AB  - AIM: To report problems in the tethering catheter shaft of the Tempofilter,
      temporary caval filter. MATERIALS AND METHODS: Two cases are reported where the
      tethering catheter shaft of the Tempofilter buckled within the jugular vein.
      RESULTS: Buckling of the tethering shaft caused cephalic migration of the filter
      into the right atrium. Both filters were uneventfully removed without adverse
      sequelae. CONCLUSION: These cases demonstrate another mechanism of tethering
      shaft shortening which results in unexpected migration of the filter. This device
      is potentially dangerous because of the liability of the tethering cather to
      buckle at or near the insertion site with cephalic migration of the filter.
      Improvements in the tethering catheter mechanism need to be made before further
      patient usage.

PMID- 10406343
TI  - A positioning device to allow rotation for cine-MRI of the distal radioulnar
      joint.
AB  - 'Cine-mode' magnetic resonance imaging (MRI) is useful in the diagnosis and
      treatment of patients with disorders of joint motion. We have designed a device
      for imaging of the distal radioulnar joint by cine-MRI. Five normal wrists and
      eight patients with rheumatoid arthritis were investigated prior to surgery for
      subluxation of the distal radioulnar joint. Normally, the radius moves in a
      constant arc around the ulna, whereas in rheumatoid wrists the centre of rotation
      varies continuously with increase in rotation. The device should prove helpful in
      imaging disorders of the distal radioulnar joint.

PMID- 10406344
TI  - Dural cavernous haemangioma with bony infiltration.

PMID- 10406345
TI  - 'Aneurysm' of nephrostomy catheter complicating extracorporeal shock-wave
      lithotripsy.

PMID- 10406346
TI  - Successful use of a covered nitinol self-expanding stent to seal a malignant
      fistula of the common bile duct.

PMID- 10406347
TI  - Prevalence of antinuclear antibodies in a rural population.
AB  - Exposure to environmentally and occupationally encountered toxicants can be
      associated with the development of certain autoimmune diseases and with the
      induction of antinuclear antibodies (ANA). Some chemicals used in the
      agricultural industry are known to affect immune function but their roles in the
      induction of autoimmunity in general, and ANA in particular, have not been
      reported previously. This study was undertaken to establish the prevalence of ANA
      in a rural population and to determine environmental and occupational exposures
      with which they are associated. This cross-sectional study represented one
      component of an interdisciplinary project (Prairie Ecosystem Study [PECOS], Eco
      Research Program, Tri-Council Secretariat of Canada) designed to explore, in a
      rural population, the roles of environmental exposures as determinants of human
      health status. Information regarding lifetime, current, and main occupational
      exposures in the rural-dwelling study population was derived from a self
      administered questionnaire. Sera from consenting subjects, collected during the
      months of February and March 1996, were assayed for ANA by indirect
      immunofluorescence on HEp-2 cells. The study population comprised 322 adult
      subjects (mean age 49.3+/-14.7 yr; range 16-87 yr). Statistical analyses adjusted
      for age and sex revealed that the presence of ANA among the participants was
      associated with a current agricultural occupation that included oilseed
      production, hog production, or poultry production. There was a significant
      association between ANA positivity and a current main farming operation of crop
      production. There was also an association among individual participants between
      lifetime exposure to the insecticide class of pesticides and the presence of ANA.
      In this rural study population, ANA positivity was significantly associated with
      lifetime exposure specifically to carbamate, organochlorine (including aldrin,
      chlordane, dieldrin, endrin, heptachlor, and lindane, but excluding DDT and
      methoxychlor), and pyrethroid insecticides and to phenoxyacetic acid herbicides,
      including 2,4-D. After adjustment for age, sex, and other insecticide exposures,
      multivariate analyses indicated that ANA positivity was associated with current
      oilseed production and with lifetime exposure to pyrethroid insecticides. In a
      rural population, ANA were associated with production of certain crops and
      certain animals and exposure to specific pesticides. The data indicate that some
      occupational exposures related to the agricultural industry are associated with
      the presence of ANA, a serologic expression of autoimmunity.

PMID- 10406348
TI  - Sensitivities and gene-expressions of Escherichia coli mutants deficient in DNA
      repair and reactive oxygen species scavenging capacity exposed to natural
      sunlight.
AB  - Sensitivities to sunlight of Escherichia coli mutants deficient in DNA repair
      capacities such as excision and recombination repair and their wild-type strain
      were compared. Higher sensitivities to sunlight were clearly observed in the
      mutant than wild-type strain, indicating that exposure to sunlight induces DNA
      damage which is repaired by DNA repair mechanisms. In order to assess the role of
      generation of reactive oxygen species (ROS) in DNA damage induced by exposure to
      natural sunlight, the kat-sod assay was performed using E. coli mutant strains
      deficient in ROS scavenging enzymes such as superoxide dismutase and/or catalase.
      Natural sunlight induced a significant generation of ROS, suggesting a
      possibility that sunlight induced ROS may be involved in DNA damage in bacterial
      cells.

PMID- 10406349
TI  - Use of tetrandrine to differentiate between mechanisms involved in silica-versus
      bleomycin-induced fibrosis.
AB  - Animals exposed to silica or bleomycin (BLM) develop pulmonary fibrosis.
      Tetrandrine (TT) has been shown to inhibit stimulant-induced macrophage
      respiratory burst and effectively reduce silica-induced lung injury. The present
      study employed TT as a probe to assess the differences in mechanisms involved in
      silica- and BLM-induced pulmonary responses. Rats received a single intratracheal
      instillation of silica (40 mg/rat, sacrificed 4 wk postexposure) or BLM (1 mg/kg
      or approximately 0.25 mg/rat, sacrificed up to 2 wk postexposure). TT was
      administered orally at 18 mg/kg, 3 times/wk for desired time periods beginning 5
      d before silica or BLM exposure. Both the silica and BLM exposures resulted in a
      significant increase in lung weight, total protein, lactate dehydrogenase (LDH),
      and phospholipids (PL) content in the acellular fluid from the first lavage, and
      hydroxyproline content in the lung tissue. Alveolar macrophages (AM) isolated
      from rats exposed to silica or BLM exhibited significant increases in secretion
      of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-alpha), and
      transforming growth factor beta (TGF-beta). TT treatment significantly lowered
      the silica- or BLM-induced increase in lung weight, while marginally reducing the
      release of IL-1 and TNF-alpha by AM. TT, however, markedly inhibited the silica
      induced increase in the acellular protein, LDH and PL, hydroxyproline content,
      and the production of TGF-beta by AM but had no marked effect on these same
      parameters in BLM-exposed rats. Histological examination of rats exposed to BLM
      for 14 d showed pulmonary inflammation and fibrosis. TT treatment had only a
      small effect on limiting the extent of these lesions and did not significantly
      affect their severity. In summary, data indicate that many inflammatory and
      fibrotic effects of in vivo silica exposure are substantially attenuated by TT,
      whereas the stimulation by BLM is only marginally affected by this drug. Since TT
      acts to attenuate AM-mediated reactions, these results suggest that AM may play a
      pivotal role in silica-induced fibrotic development and may be less involved in
      the pathogenesis of BLM-induced fibrosis.

PMID- 10406350
TI  - Perceptions of on-site hunters: environmental concerns, future land use, and
      cleanup options at the Savannah river site.
AB  - The Department of Energy owns land in 34 states, and most of these lands have
      been off limits to the public for over 50 years. Although some parts of each site
      are contaminated, most of many sites are not. With the ending of the Cold War,
      the department is considering alternative land uses. In this article, the
      perceptions of hunters and fishermen allowed on site for a limited time were
      examined, about environmental concerns, future land use, and cleanup options.
      Although loss of jobs was the foremost concern, preserving parts of the site had
      more support as a future land use than continuing the nuclear mission, and nearly
      three-quarters of the sample supported cleanup, regardless of cost. On-site
      employment was a significant indicator of lower concern about safety and
      environmental issues, less support for designating the site for research, and
      more concern for maintaining jobs.

PMID- 10406351
TI  - Comparison of benzo[a]pyrene DNA adduct formation in the skin of two strains of
      mice selected for resistance (DBA/2) or susceptibility (C3H/HeN) to contact
      dermatitis.
AB  - Two strains of mice were selected for resistance (DBA/2) or susceptibility
      (C3H/HeN) to contact dermatitis. Benzo[a]pyrene-DNA adduct formations was
      compared in the two mouse strains by a postlabeling procedure to determine if
      there was a significant effect. Results showed that adduct profiles in DBA/2 and
      C3H/HeN dermis were qualitatively similar. The total binding levels were higher
      in DBA/2 mice on the d 2 and the d 10. DNA adduct formation has been shown to
      inversely correlate with skin allergy induction. Data suggest that the expression
      of the genes responsible for the differences in responsiveness to chemical
      induced contact dermatitis in mouse may play an important role in benzo[a]pyrene
      DNA adduct formation.

PMID- 10406352
TI  - Making AIDS a business imperative.

PMID- 10406353
TI  - Lancet electronic research archive in international health and eprint server.

PMID- 10406354
TI  - Mycophenolate mofetil for Crohn's disease?

PMID- 10406355
TI  - Consensus and controversy over resuscitation of the newborn infant.

PMID- 10406356
TI  - HIV infection: where have all the T cells gone?

PMID- 10406357
TI  - Scientific misconduct: exaggerated fear but still real and requiring a
      proportionate response.

PMID- 10406358
TI  - Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced
      left-ventricular function after acute myocardial infarction. TRACE Study Group.
      Trandolapril Cardiac Evaluation.
AB  - BACKGROUND: The survival benefit from the use of inhibitors of angiotensin
      converting enzyme (ACE) in patients with acute myocardial infarction is usually
      presented in terms of risk ratios and lives saved per 1000 people treated. A more
      relevant way to present the extent of benefit would be in terms of an increase in
      life expectancy, but this approach has not previously been possible because of
      limited data on long-term outcome. We aimed to calculate the effect of
      trandolapril on life expectancy with follow-up data from the Trandolapril Cardiac
      Evaluation (TRACE) Study. METHODS: The TRACE study previously showed a
      significant survival benefit with trandolapril in patients with reduced left
      ventricular function after an acute myocardial infarction who were treated for at
      least 2 years. We ascertained the survival status of all patients in the TRACE
      study in June, 1998, at which time they had been followed up for a minimum of 6
      years. We estimated life expectancy as median lifetime, which was the time for
      50% of the patients to have died. Change in life expectancy is expressed as
      change in median lifetime. Analysis was by intention to treat. FINDINGS: The life
      expectancy of patients was 4.6 years for those given placebo versus 6.2 years for
      those on trandolapril. Thus, for patients on trandolapril, median lifetime was
      increased by 15.3 months or 27% (95% CI 7 to 51). Analysis of follow-up after the
      end of the study indicated no decrease of this benefit during the course of
      double-blind treatment; continued use of trandolapril was recommended at study
      closure. INTERPRETATION: In patients with severely reduced left-ventricular
      function, long-term treatment with an ACE inhibitor during the critical period
      after myocardial infarction is associated with a substantial increase in life
      expectancy.

PMID- 10406359
TI  - Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy:
      a multicentre randomised double-blind study. Vigabatrin European Monotherapy
      Study Group.
AB  - BACKGROUND: Vigabatrin is a newly licensed drug for use in patients with
      epilepsy. We investigated whether this drug was comparable to standard first-line
      monotherapy in efficacy and incidence of adverse events. METHODS: We enrolled 459
      patients with newly diagnosed, previously untreated partial epileptic seizures
      from 44 European centres and randomly assigned them carbamazepine 600 mg daily
      (n=230) or vigabatrin 2 g daily (n=229). After initial maintenance doses were
      reached, doses were adjusted downwards (in the case of adverse events) or upwards
      (in the case of seizures) by the clinician. The primary outcome was time to
      withdrawal because of lack of efficacy or adverse events. Secondary outcomes
      included efficacy (time to 6-month remission of seizures, time to first seizure
      after initial dose stabilisation), and adverse events (incidence and severity).
      Analysis was by intention to treat. FINDINGS: Time to withdrawal for lack of
      efficacy or adverse events did not differ between groups (p=0.318). Vigabatrin
      was better tolerated than carbamazepine with fewer withdrawals, but was more
      frequently associated with psychiatric symptoms (58 [25%] vs 34 [15%]) and weight
      gain (25 [11%] vs 12 [5%]). Carbamazepine was associated with rash (22 [10%] vs
      seven [3%]). All efficacy outcomes favoured carbamazepine and failed to show
      equivalence between the two drugs. No significant difference was found for time
      to achieve 6 months of remission from seizures (p=0.058), but the most powerful
      outcome, time to first seizure after the first 6 weeks from randomisation, showed
      carbamazepine to be significantly more effective than vigabatrin (p=0.0001).
      INTERPRETATION: Vigabatrin seems less effective but better tolerated than
      carbamazepine, which is the first-choice drug for the treatment of partial
      epilepsies. Vigabatrin cannot therefore be recommended as a first-line drug for
      monotherapy in this group of patients.

PMID- 10406360
TI  - Relation of human papillomavirus status to cervical lesions and consequences for
      cervical-cancer screening: a prospective study.
AB  - BACKGROUND: A relation has been established between infection with high-risk
      types of human papillomavirus and development of cervical cancer. We investigated
      a role for testing for human papillomavirus as part of cervical-cancer screening.
      METHODS: We monitored by cytology, colposcopy, and testing for high-risk human
      papillomavirus 353 women referred to gynaecologists with mild to moderate and
      severe dyskaryosis. The median follow-up time was 33 months. At the last visit we
      took biopsy samples. Our primary endpoint was clinical progression, defined as
      cervical intraepithelial neoplasia (CIN) 3, covering three or more cervical
      quadrants on colposcopy, or a cervical-smear result of suspected cervical cancer.
      FINDINGS: 33 women reached clinical progression. All had persistent infection
      with high-risk human papillomavirus. The cumulative 6-year incidence of clinical
      progression among these women was 40% (95% CI 21-59). In women with end histology
      CIN 3, 98 (95%) of 103 had persistent infection with high-risk human
      papillomavirus from baseline. Among women with mild to moderate dyskaryosis at
      baseline, a second test for human papillomavirus at 6 months predicted end
      histology CIN 3 better than a second cervical smear. INTERPRETATION: Persistent
      infection with high-risk human papillomavirus is necessary for development and
      maintenance of CIN 3. All women with severe dyskaryosis should be referred to
      gynaecologists, whereas women with mild to moderate dyskaryosis should be
      referred only after a second positive test for high-risk human papillomavirus at
      6 months.

PMID- 10406361
TI  - Behavioural management in nursing and residential homes: a randomised controlled
      trial.
AB  - BACKGROUND: As more and more elderly people are being cared for in residential
      and nursing homes, how best can their psychiatric needs be met? We report on
      evaluation of a behavioural intervention by an old-age psychiatry hospital
      outreach team. METHODS: This randomised controlled trial of a training and
      education intervention over 6 months was done in south Manchester, UK. 12 matched
      nursing and residential homes were randomised to the control or intervention
      group and within each, the staff selected 10 residents whose behavioural problems
      made them difficult to care for. Care staff in the intervention homes attended
      seminars from the hospital outreach team and received weekly visits from a
      psychiatric nurse to assist in developing care planning skills. The main outcome
      measures were cognitive impairment and depression, behavioural disturbance, and
      functional ability, assessed by the geriatric mental state schedule, Crichton
      Royal behaviour rating scale, and Barthel index, respectively. FINDINGS:
      Residents in the intervention group had significantly improved scores for
      depression (before-and-after change difference -0.5 [95% CI -0.8 to -0.1]) and
      for cognitive impairment (-0.7 [-1.1 to -0.2]) but not for behaviour rating or
      Barthel index. INTERPRETATION: Elderly residents can benefit from improved
      quality of care achieved by training from a hospital outreach team.

PMID- 10406362
TI  - Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based
      assay. HpSA European study group.
AB  - BACKGROUND: Helicobacter pylori is a common human pathogen implicated in certain
      gastrointestinal diseases. In the search for new non-invasive techniques to
      diagnose H. pylori infection, we evaluated an EIA for H. pylori antigen in stool
      (HpSA). METHODS: In a prospective multicentre study, stool specimens from 501
      patients (276 men, 225 women; age range 17-88 years, mean 52) undergoing
      gastroscopy in 11 centres throughout Europe were tested with HpSA and the carbon
      13-urea breath test. At endoscopy, four biopsy samples were taken for histology
      (haematoxylin and eosin) and H. pylori detection (giemsa in both antrum and
      corpus, culture and rapid urease test). Patients were defined as positive for H.
      pylori if histology (antrum, corpus, or both) and urease test were positive, or
      if culture was positive. Patients classified as having H. pylori infection
      received an eradication regimen; 107 were reassessed 4 weeks after therapy.
      FINDINGS: Of 272 patients with H. pylori infection by the predefined criteria,
      256 were positive by HpSA (sensitivity 94.1% [95% CI 90.6-96.6]). Of 219 patients
      without infection, 201 were negative by HpSA (specificity 91.8% [87.3-95.1]).
      INTERPRETATION: The stool assay was a reliable and easy-to-use tool for diagnosis
      of H. pylori infection. The test was accurate even shortly after treatment.

PMID- 10406363
TI  - High incidence of secondary brain tumours after radiotherapy and antimetabolites.
AB  - BACKGROUND: Brain tumours rarely occur in survivors of childhood acute
      lymphoblastic leukaemia after cranial radiotherapy. An unusually high frequency
      of brain tumours seen among children enrolled in one of our leukaemia treatment
      protocols, Total Therapy Study XII, prompted us to identify the potential causes
      of this complication. METHODS: We assessed clinical, biological, and
      pharmacokinetic features in all 52 children who received prophylactic cranial
      radiotherapy. We compared the cumulative incidence of brain tumours between
      subgroups, and with that of 421 children who received radiotherapy in previous
      studies. FINDINGS: The incidence of brain tumours among irradiated children (six
      of 52, 12.8% [SE 5.0]) was high compared with patients in the same study who did
      not receive radiotherapy (none of 101; p=0.0008) and with other protocols that
      included cranial radiotherapy (p<0.0001). Of the six children, four had
      erythrocyte concentrations of thioguanine nucleotide metabolites higher than the
      70th percentile for the entire cohort, and three had a genetic defect in
      thiopurine catabolism. The 8-year cumulative incidence of brain tumour among
      children with defective versus wild-type thiopurine methyltransferase phenotype
      was 42.9% (SE 20.6) versus 8.3% (4.7; p=0.0077). This protocol differed from
      previous protocols, in that more intensive systemic antimetabolite therapy was
      given before and during radiotherapy. INTERPRETATION: These data support the
      elimination of prophylactic radiotherapy for acute lymphoblastic leukaemia except
      in patients at high risk of central-nervous-system relapse. Underlying genetic
      characteristics and treatment variables may be associated with an increased risk
      of radiation-associated brain tumours.

PMID- 10406364
TI  - A 4-year-old with a rash.

PMID- 10406365
TI  - Postoperative pain and subcutaneous oxygen tension.
AB  - Surgical patients randomly assigned to standard pain control had postoperative
      subcutaneous oxygen partial pressures that were significantly less than patients
      given better pain treatment. Our data suggest that control of postoperative pain
      is a major determinant of surgical-wound infection and should be given the same
      consideration as maintaining adequate vascular volume and normothermia.

PMID- 10406367
TI  - Sclerosing pancreato-cholangitis responsive to steroid therapy.
AB  - Four patients with weight loss, jaundice, a sonolucent swelling of the pancreas,
      and multiple bile-duct strictures are described. These cases of sclerosing
      pancreato-cholangitis responded to steroid therapy.

PMID- 10406366
TI  - Mutations of the cationic trypsinogen gene in patients with chronic pancreatitis.
AB  - Nine out of 48 (19%) patients referred to a pancreatic clinic with a presumed
      diagnosis of idiopathic chronic pancreatitis have been shown to have mutations in
      the cationic trypsinogen gene (PRSSI), consistent with a previously unsuspected
      diagnosis of hereditary pancreatitis.

PMID- 10406368
TI  - Magnetisation transfer magnetic resonance imaging demonstration of perilesional
      gliosis--relation with epilepsy in treated or healed neurocysticercosis.
AB  - We describe a case of healed neurocysticercosis with seizures, in which
      magnetisation transfer contrast showed a large area of presumed perilesional
      gliosis not visible on conventional spin echo magnetic resonance imaging.

PMID- 10406370
TI  - Association of seropositivity for Chlamydia pneumoniae and coronary artery
      disease in heterozygous familial hypercholesterolaemia.
AB  - In patients with familial hypercholesterolaemia heterozygous for the North
      Karelia (Finland) mutation, the presence of unequivocal coronary heart disease
      was significantly associated with high titres of IgG and IgA antibodies to
      Chlamydia pneumoniae.

PMID- 10406369
TI  - Haemodynamic analysis of efficacy of compression hosiery in elderly fallers with
      orthostatic hypotension.
AB  - Ten elderly people with orthostatic hypotension and a history of falls were
      studied by continuous recording of blood pressure and heart rate during passive
      tilting from supine to 90 degrees head-up tilt. Compression hosiery significantly
      decreased the change in systolic blood pressure.

PMID- 10406371
TI  - Delays in stroke referrals.
AB  - Assessment of acute stroke by hospital physicians will have to speed up if we are
      to expect referral to hospital and computed tomography (both previously targets
      of criticism) to improve.

PMID- 10406373
TI  - Experts give practical advice in reproductive medicine.

PMID- 10406374
TI  - The science of haptics gets in touch with prosthetics.

PMID- 10406372
TI  - Dementia, intelligence, and the competence to complete advance directives.
AB  - At referral, a fifth of patients with dementia were competent to complete advance
      directives. Competence was significantly related to higher premorbid IQ estimated
      by the National Adult Reading Test.

PMID- 10406375
TI  - From affluence to poverty.

PMID- 10406376
TI  - Home HIV kits unreliable.

PMID- 10406377
TI  - Deal struck for Russians with tuberculosis.

PMID- 10406378
TI  - Handling of scientific dishonesty in the Nordic countries. National Committees on
      Scientific Dishonesty in the Nordic Countries.
AB  - Despite a widely recognised need, most countries still have no coherent system to
      deal with scientific misconduct. Committees have been established by the national
      medical research councils in Denmark (1992), Norway (1994), and Sweden (1997),
      and by the Ministry of Education in Finland (1994), to deal with scientific
      misconduct--ie, to initiate preventive measures, to investigate alleged cases, or
      both. Each committee includes both scientifically and legally qualified members.
      The employing institutions are responsible for possible sanctions or punishments.
      So far, 47 cases have been accepted for investigation, the majority (25) being
      Danish. Disputed authorship was the most frequent reason for investigation.
      Junior researchers made complaints in only three of the investigated cases.
      Investigations have been completed in 37 cases; in nine cases, dishonesty was
      revealed--two of them were related to the same researchers. Cooperation between
      the four Nordic committees has shown close agreement on specific issues and
      cases, despite minor differences in definitions, organisation, and procedures.

PMID- 10406380
TI  - Rapid assessment, injecting drug use, and public health.

PMID- 10406379
TI  - Heparin, cell adhesion, and pathogenesis of inflammatory bowel disease.
AB  - Tissue repair involves a close interplay between growth factors and cell adhesion
      molecules. The normal healing process may be disrupted by pathophysiological
      states such as inflammation, due to loss of growth factors, cell adhesion
      molecules, or both, which results in a reduced rate of healing. Such events may
      occur in inflammatory bowel disease during mucosal restitution. We postulate that
      the beneficial response to heparin observed in inflammatory bowel disease may
      result from mechanisms in addition to anticoagulation. These include the
      restoration of high-affinity receptor binding by antiulcerogenic growth factors,
      such as basic fibroblast growth factor, that normally rely on the presence of
      heparan sulphate proteoglycans, such as syndecan-1, as co-receptors. Loss of
      syndecan-1 has been observed in the ulcerated mucosa of patients with
      inflammatory bowel disease. This loss may lead to impaired binding of basic
      fibroblast growth factor and a reduced rate of ulcer healing. We suggest that
      heparin restores high-affinity receptor binding of basic fibroblast growth, and
      so increases the rate of mucosal recovery.

PMID- 10406381
TI  - Health risks of genetically modified foods.

PMID- 10406382
TI  - Health risks of genetically modified foods.

PMID- 10406383
TI  - Health risks of genetically modified foods.

PMID- 10406385
TI  - Health risks of genetically modified foods.

PMID- 10406384
TI  - Health risks of genetically modified foods.

PMID- 10406386
TI  - Antiphospholipid antibodies and thrombosis.

PMID- 10406387
TI  - Antiphospholipid antibodies and thrombosis.

PMID- 10406388
TI  - Antiphospholipid antibodies and thrombosis.

PMID- 10406389
TI  - Antiphospholipid antibodies and thrombosis.

PMID- 10406390
TI  - Failure of randomisation by "sealed" envelope.

PMID- 10406391
TI  - Psychological issues in diabetes.

PMID- 10406392
TI  - Use of fluoride.

PMID- 10406393
TI  - Improvements in childhood mortality in The Gambia.

PMID- 10406394
TI  - Perinatal information system (SIP): a clinical database in Latin America and the
      Caribbean.

PMID- 10406395
TI  - Promoting vitamin A status.

PMID- 10406396
TI  - ApoE genotype and protease-inhibitor-associated hyperlipidaemia.

PMID- 10406397
TI  - Dioxins, Coca-Cola, and mass sociogenic illness in Belgium.

PMID- 10406398
TI  - History of breastfeeding and medical profession.

PMID- 10406399
TI  - Aspartame and the internet.

PMID- 10406400
TI  - Evolution of micturition in man.

PMID- 10406401
TI  - Quintessence of dust.

PMID- 10406402
TI  - The Nobel chronicles. 1961: Georg von Bekesy (1899-1972).

PMID- 10406403
TI  - Sjogren's syndrome comes of age.

PMID- 10406405
TI  - Rheumatic diseases in North America's indigenous peoples.
AB  - OBJECTIVES: There are at least 3 million North American Indians and Eskimos in
      North America. The epidemiology of rheumatic diseases in Native North Americans
      differs from that described for the remainder of the North American population.
      An enhanced understanding of rheumatic diseases in these indigenous people may
      provide valuable clues to the cause of these disorders and improve rheumatologic
      care. METHODS: The world literature was searched for all reports of rheumatic
      diseases in North American Indians and Eskimos. The reports were reviewed and the
      findings summarized by disease process. RESULTS: Many Native American groups have
      high prevalence rates of rheumatoid arthritis (RA), systemic lupus erythematosus,
      connective tissue diseases, and spondyloarthropathies. There appears to be a
      correlation between the pattern of rheumatic diseases in Native North Americans
      and the patterns of migration and ancestry. In general, Amerind Indians have
      increased rates of RA and connective tissue disease, while Na-Dene Indians and
      Eskimos have high rates of spondyloarthropathies. The RA seen in Native Americans
      is generally severe, seropositive, with an early age of onset, and frequent
      extraarticular manifestations. Many Native American groups have very high
      frequencies of the RA shared epitope. The majority of Native American and Eskimo
      groups also have high frequencies of HLA-B27, and some of the world's highest
      prevalence rates of spondyloarthropathies are described in these groups. Although
      some groups show a marked tendency to develop either Reiter's syndrome or
      ankylosing spondylitis, psoriatic and enteropathic arthritis are rare.
      CONCLUSIONS: The excess rheumatic disease seen in this population is most likely
      genetic in origin. Because of the combination of high rates of rheumatic disease
      and relative genetic homogeneity, Native North Americans represent a singular
      opportunity to study genetic contributions to rheumatic disease. For clinicians,
      the index of suspicion for rheumatic diseases in North American Indians and
      Eskimos should be high, and the severe disease and sometimes atypical
      presentations kept in mind.

PMID- 10406404
TI  - The use of oral pilocarpine in xerostomia and Sjogren's syndrome.
AB  - OBJECTIVES: To analyze the role of oral pilocarpine in the treatment of
      xerostomia of Sjogren's syndrome (SS). METHODS: The medical literature was
      reviewed for all studies using oral pilocarpine to treat xerostomia caused by SS
      or radiotherapy registered in the MedLine Silver Platter database from 1966 to
      1998. RESULTS: All the studies identified excluded elderly individuals with
      cardiac or pulmonary disease. Patients with postradiation xerostomia and
      incomplete resection of the salivary glands were more likely to benefit from oral
      pilocarpine when there was sufficient residual glandular function than patients
      with radical surgery for head and neck cancer (HNC). However, patients with SS
      and other inflammatory disorders seemed to benefit from oral pilocarpine, when
      compared with patients with postradiation xerostomia. The optimal dose of oral
      pilocarpine, which was less likely to cause side effects, was 5 mg four times
      daily. A recent multi-center study in SS patients suggests that oral pilocarpine
      is effective and safe for long-term administration. Although some studies did not
      show evidence for increased salivary gland secretion rate as measured by
      sialometry, symptoms improved, perhaps because of increased secretion from the
      minor salivary glands or better conditioning of the oral mucosa. CONCLUSIONS:
      Oral pilocarpine is likely to benefit patients with SS by reducing the symptoms
      of xerostomia, even if the salivary gland secretion rate does not increase.
      Further controlled studies are needed in patients with SS and should include
      elderly patients with cardiovascular disease treated with moderate doses of oral
      pilocarpine.

PMID- 10406406
TI  - Minocycline-induced autoimmune syndromes: an overview.
AB  - OBJECTIVE: To increase awareness of minocycline-induced autoimmune syndromes.
      METHODS: Review of relevant publications from the American and European
      literature. RESULTS: Four minocycline-induced syndromes have been described in 82
      patients: serum sickness, drug-induced lupus, autoimmune hepatitis, and
      vasculitis. Aside from sporadic cases of serum sickness, all other syndromes
      occurred in patients treated for acne. Drug-induced lupus and hepatitis were by
      far the most common events (66 cases). Except for serum sickness, which presented
      shortly (mean, 16 days) after minocycline, the autoimmune syndromes manifested
      after protracted use (mean, 25.3 months). As expected, the patients with acne
      were young (mean, 19.7 years). The most frequent symptoms were arthralgia,
      followed by arthritis, fever, and rash (73, 45, 38, and 29 patients,
      respectively). Serologically, antinuclear antibodies were the most common finding
      (63 positive of 68 tests); perinuclear anti-neutrophilic cytoplasmic antibodies
      (pANCA), when assayed, were similarly frequent (20 of 24 tests). Surprisingly,
      anti-histone antibodies were uncommon, even among patients with drug-induced
      lupus (4 of 31 tests). The clinical and serological features of the separate
      syndromes may overlap. The diagnostic value of pANCA, as well as its possible
      role in minocycline-induced autoimmunity, are discussed. CONCLUSIONS: Minocycline
      has the potential to evoke a variety of clinical and serological autoimmune
      expressions. The number of published reports may underestimate the frequency of
      this condition, which should be suspected and investigated in young patients with
      autoimmune manifestations.

PMID- 10406407
TI  - Sonographic imaging of normal and osteoarthritic cartilage.
AB  - OBJECTIVES: This study was undertaken to describe representative sonographic
      features of normal and osteoarthritic cartilage. METHODS: Sonographic evaluation
      was performed with real-time ultrasound equipment, using 7.5-, 10-, 13-, 15-, and
      20-MHz transducers. Normal and osteoarthritic cartilage has been studied in
      healthy subjects and in patients with osteoarthritis. RESULTS: Ultrasonography
      allows a safe, quick, and careful evaluation of both normal and osteoarthritic
      cartilage. A spectrum of images ranging from loss of cartilage transparency to
      marked narrowing of the cartilage layer can be depicted clearly in patients with
      osteoarthritis. Loss of clarity of the cartilaginous band and loss of the normal
      sharpness of the synovial space-cartilage interface are the earlier features of
      cartilage damage. CONCLUSIONS: Although the value of ultrasonography in the
      evaluation of articular cartilage remains to be determined, this imaging method
      can be regarded as a useful bedside procedure for initial diagnostic screening of
      osteoarthritic femoral condylar cartilage.

PMID- 10406408
TI  - Comparative clinical and epidemiological study of hypersensitivity vasculitis
      versus Henoch-Schonlein purpura in adults.
AB  - OBJECTIVES: To assess the incidence and clinical features of adults with
      hypersensitivity vasculitis (HV) and Henoch-SchOnlein purpura (HSP) in a well
      defined population. METHODS: Retrospective study of an unselected population of
      adult patients (>20 years) with biopsy-proven cutaneous vasculitis diagnosed as
      having HV or HSP who presented at a primary hospital between 1988 and 1997.
      Patients with cutaneous vasculitis secondary to collagen vascular diseases,
      neoplasia, severe infections, and those with other well-defined clinical entities
      were excluded. Patients were classified as having either HV or HSP according to
      the criteria proposed by Michel et al (J Rheumatol 1992;19:721-28). RESULTS:
      Fifty-six adults (35 men/21 women), were classified as having HV and 27 adults as
      having HSP (19 men/8 women). The annual incidence rate for HV was 29.7/million
      and 14.3/million for HSP. At the onset of the disease, adults with HSP were
      younger than those with HV (46+/-18 years versus 59+/-18 years in HV; P = .005).
      Precipitating events were found in 50% of HV and in 30% of HSP patients. A
      history of drug therapy before the onset of vasculitis was found in 46% of HV and
      in 26% of HSP (P = .074). At disease onset, skin lesions were the most common
      manifestation in both groups. During the disease course, adults with HSP had
      joint manifestations more commonly (59% in HSP v25% in HV; P < .003) and more
      gastrointestinal (82% v 5% in HV; P < .001) and renal complications (48% v 5% in
      HV; P < .001). HSP subjects required more aggressive therapy consisting of
      steroids (P < .001) or cytotoxic agents (P < .001). After 37+/-28 (median, 31)
      months, complete recovery was observed in 98% of adults with HV. After 40+/-27
      (median, 36) months, complete recovery was observed in only 67% of adults with
      HSP (P < .001). Renal insufficiency was observed in 8% of adults with HSP.
      CONCLUSIONS: In adults, HV and HSP as defined by these criteria, behave as two
      well-differentiated diseases. HV has a milder course and lack of severe
      complications, and HSP a higher risk of gastrointestinal and renal complications.

PMID- 10406409
TI  - Insufficiency fractures of the tibia and fibula.
AB  - OBJECTIVE: Insufficiency fractures (IF) occur when normal or physiological
      muscular activity stresses a bone that is deficient in mineral or elastic
      resistance. IF of the tibia and fibula are probably less common than IF of the
      ribs, vertebrae, hip, pelvis, and distal ulna, and therefore they are frequently
      underrecognized and mistaken for other conditions. Our aim was to analyze the
      main features and outcome of IF of the tibia and fibula in patients attending our
      Rheumatology Service. METHODS: IF was considered when occurring spontaneously or
      with minimal trauma. Between January 1984 and July 1997, 25 patients were
      diagnosed as having IF of the tibia and fibula. The main predisposing factors,
      clinical features, therapy, and outcome were retrospectively reviewed. RESULTS:
      All the patients except four were women (mean age, 66+/-12 years). Three cases
      were diagnosed between 1984 and 1990 (0.42 cases/year) and 22 between 1991 and
      1997 (three cases/year). Eighteen patients had an underlying condition:
      rheumatoid arthritis (RA, 13 cases), psoriatic arthritis (2), systemic lupus
      erythematosus (SLE) (1), kidney transplant (1), and Crohn's disease (1). Eleven
      patients had osteoporotic fractures in other locations. Risk factors for
      osteoporosis were corticosteroids (13 cases), prolonged immobilization (10),
      early menopause (2), and methotrexate therapy (10). All patients had pain on
      weight bearing and marked functional impairment, 16 had local inflammatory signs,
      and 10 had deformity. In only five patients the diagnosis of IF was considered at
      the first examination. The diagnostic delay was 76+/-117 days (median, 21). The
      initial radiograph was diagnostic in 20 patients, and in the remaining the
      diagnosis was made by computed tomography (CT) scan (three cases), magnetic
      resonance imaging (MRI) (1), and bone scan (1). IF were located as follows: tibia
      (10 cases), fibula (seven), tibia and fibula (eight). Nineteen patients were
      treated with conservative management, four received no specific treatment, and
      two required surgery. Sixteen patients were hospitalized for a mean period of
      12+/-8 days. Most patients had complete recovery. The high frequency of IF seen
      in RA patients is probably due to the severe disease in patients treated by our
      Service and that such patients have a higher risk for osteoporosis and its
      complications. CONCLUSIONS: IF of the tibia and fibula are probably more common
      than previously thought. They usually occur in patients with underlying rheumatic
      diseases, mainly RA, and are frequently mistaken for other joint and bone
      conditions. Despite a frequent delay in diagnosis, they have a good prognosis
      with conservative management. Nonetheless, a higher index of suspicion may avoid
      unnecessary investigations and treatments.

PMID- 10406411
TI  - Manifesto for emergency medicine in Europe. Council of the European Society for
      Emergency Medicine.

PMID- 10406410
TI  - Diabetic muscle infarction presenting as a knee effusion.

PMID- 10406412
TI  - Systemically circulating oxidative species in human deep venous thrombosis.
AB  - To investigate the hypothesis that plasmatic changes of lipoperoxidative markers
      are associated with deep venous thrombosis (DVT), peripheral venous blood samples
      were obtained from 10 patients with venographically proven DVT before starting
      anticoagulant therapy, and 36+/-3 and 60+/-3 hours later. Values of
      myeloperoxidase (MPO), 4-hydroxynonenal (HNE) and malondialdehyde (MDA) were
      compared with those of 10 age-matched control subjects. Despite individual
      variations, mean plasma MPO level was higher in the DVT group (p < 0.01), as were
      average plasma MDA (p < 0.001) and HNE (p < 0.01) levels. Separate analysis of
      the DVT cases showed that higher values of MDA, HNE and MPO were found in
      patients with either co-morbid diseases or clinically silent pulmonary embolism
      (PE). Good evidence exists for considering DVT a condition associated with an
      apparently excessive free radical production not buffered by efficient defence
      systems. A role of DVT itself cannot be excluded, but PE or other co-morbid
      diseases may participate in the oxidative stress. If confirmed in a larger series
      of patients, these findings could shed new light on the plasmatic changes
      associated with the propagation and complications of DVT, which in turn could
      have therapeutic implications.

PMID- 10406413
TI  - Prospective application of risk scores in the interhospital transport of
      patients.
AB  - We carried out a prospective evaluation of 172 patients using our own risk score
      for patients transferred from the emergency department of a community hospital in
      Tudela, Spain, to main centres, during 1988. Although the data go back almost 10
      years, this scoring has not been internationally published and is at present
      widely applied in Spain. Patients scoring less than 7 points were transferred
      under specialized nursing supervision (Group I), and those scoring equal to or
      over 7 points were transferred in a specially equipped intensive care unit
      surface ambulance and supervised by a physician and a nurse (Group II). There
      were 102 patients in Group I and 70 in Group II. Complications arising during
      transfer were defined as minor or serious. A low overall incidence of
      complications was recorded--a total of 29 cases (16.9% of all transfers). The
      incidence of complications was significantly higher in Group II patients (p <
      0.005). One patient from Group II died during transport. All patients from Group
      II were admitted to the ICUs compared with only 20 (18.6%) from Group I (p <
      0.001). Of a total of 23 deaths in hospital, nine were from Group I and 14 from
      Group II. During the first 24 hours after admission, six patients died from Group
      II and none from Group I. The application of risk scores has permitted to assign
      effectively technical and human resources for a safe interhospital transfer of
      critically ill patients.

PMID- 10406414
TI  - Emergency aid and rescue services in Turkey (ambulance services).
AB  - This article outlines the recent status of ambulance services provided by
      Emergency Aid and Rescue Services (EARS) in the Republic of Turkey. EARS would
      seem to be the future model of emergency medical systems (EMS) in Turkey.

PMID- 10406415
TI  - International development of emergency medical systems: educational techniques
      for the future.
AB  - An ongoing collaborative partnership between the University of Massachusetts
      Medical Center, Boston University Medical Center, the Armenian Ministry of
      Health, and the Emergency Hospital of Yerevan, Armenia has been established since
      1993. The primary goal of this partnership is to reform and improve the delivery
      of emergency medical care through a process of education and training that is
      reproducible, practical, and self-sustaining for the advancement of health care
      into the future. A six-step educational process was developed, using Armenia as
      the initial model site for this format. Through the development of a regional
      training center and two emergency medicine training curricula, the partnership
      has trained over 1800 health care workers and first responders. Preliminary
      results from pre- and post-course examinations show a significant overall
      improvement in scores. An ongoing trauma database collection also shows
      significant improvement in the number of advanced life support measures being
      implemented since the inception of this educational training programme. This
      educational strategy has subsequently been replicated in nine similar
      partnerships in other countries of the New Independent States, formed after the
      dissolution of the former Soviet Union in 1990. We believe this six-step
      educational format is effective for the development and improvement of emergency
      medical systems in developing countries worldwide.

PMID- 10406416
TI  - Impact of a chest pain clinic on recurrency of symptoms and readmissions among
      patients early discharged from hospital after acute myocardial infarction was
      ruled out.
AB  - This paper evaluates the impact of an early revisit including symptom evaluation
      and an exercise electrocardiogram on recurrency of symptoms and readmissions
      during 1 year of follow-up among patients coming to hospital with chest pain or
      an initial suspicion of acute myocardial infarction (AMI) but in whom the
      suspicion was quickly ruled out. Patients below the age of 65 admitted to the
      emergency department (ED) at Sahlgrenska Hospital due to chest pain or other
      symptoms raising a suspicion of AMI who were either directly discharged from the
      ED or discharged within 1 day after having AMI ruled out. Patients were allocated
      to two groups: (1) patients being re-evaluated in a chest pain clinic less than a
      week after discharge from hospital (intervention group) and (2) patients handled
      routinely with no formalized follow-up (control group). The intervention group
      (n=484) and the control group (n=374) were comparable at baseline. During 1 year
      of follow-up, patients in the intervention group had a lower rate of readmissions
      to the ED than patients in the control group (17.4% versus 24.9%, p < 0.05) and a
      lower rate of rehospitalizations (15.9% versus 23.3%, p < 0.05). The proportion
      of patients being on sick leave at any time during the follow-up did not differ
      and neither did the recurrency of symptoms. The introduction of a chest pain
      clinic for patients early discharged from hospital after having AMI ruled out
      indicated beneficiency in terms of a lower rate of readmissions to the ED and a
      lower requirement of rehospitalizations. However, a methodological weakness in
      the randomization procedure suggest carefulness in interpretation.

PMID- 10406417
TI  - Oscillating saw injuries during removal of plaster.
AB  - The aim of this study was to assess the incidence of injuries to patients who
      have had a plaster cast removed by oscillating circular saw at the Alexandra
      Hospital, Redditch, and to recommend measures to avoid such injuries. The record
      of each patient who had his/her plaster removed was kept in the plaster room and
      later studied. Over a 12-month period (1995-96), 3875 plaster casts were removed;
      28 patients (0.72%) sustained abrasions or burns over the skin. Recently there
      has been a sudden rise in the number of cases who sustained injury or burns by
      oscillating saw following plaster cast removal and a few patients have demanded
      compensation from the hospital. These incidences prompted the start of this
      study. The identified cause of injury was the removal of a plaster cast by an
      inexperienced, ill-trained user or blunt saw blade. Strict protocols were
      required and have been introduced at the Alexandra Hospital to avoid litigation.

PMID- 10406418
TI  - Demographic differences in the resuscitation knowledge and skills of the Standard
      First Aid Class ambulance crews in Japan.
AB  - This study was undertaken to determine the frequency and type of continuing
      education required in areas with various populations and evaluate the
      resuscitation knowledge and skills possessed by Standard First Aid Class (SFAC)
      ambulance crews, who play a major role as prehospital care providers in Japan.
      Two hundred SFAC ambulance crews were classified into four subgroups based on the
      population of the areas they serve a population greater than 400,000, 150,000
      400,000, 50,000-150,000 and less than 50,000. A survey regarding continuing
      education in each area revealed that the EMS systems with smaller populations had
      less adequate continuing education than in larger populated areas. A written test
      consisted of 80 multiple choice questions showed no difference among each
      population subgroup. In the five-point skills test, however, it was demonstrated
      that the resuscitation skills, particularly those required for the airway
      management, of SFAC ambulance crews in the areas populated by less than 50,000
      had deteriorated more than those in larger communities. These findings re
      emphasized the importance of adequate continuing education in low-volume, part
      time, rural EMS systems where lack of clinical exposure is a significant limiting
      factor for skill retention.

PMID- 10406419
TI  - Prehospital emergency care.
AB  - Prehospital care is a diverse and complex entity. Recent studies have begun to
      emphasize the importance of all aspects of care in the community, leading through
      to critical analysis of the process of prehospital care provision. This paper
      examines the various aspects of prehospital care and discusses the various
      elements which need to be considered to provide effective care prior to patients
      being attended to at hospital.

PMID- 10406420
TI  - Triage and casemix in accident and emergency medicine.

PMID- 10406421
TI  - Neurogenic pulmonary oedema after generalized epileptic seizure.
AB  - The diagnosis 'tonic clonic seizure' is frequently established by emergency
      physicians on scene. In patients with epilepsy mortality due to accidents,
      asphyxia, cardiac arrhythmias or postictal neurogenic pulmonary oedema (NPO) is
      twice as high as in the general population. We report a case of acute pulmonary
      oedema after a tonic clonic seizure. Following this event, the patient developed
      respiratory insufficiency and evidence of pulmonary oedema not associated with
      the classic aetiologies of congestive heart failure, aspiration or toxic
      exposure. The patient survived the incident after aggressive prehospital
      treatment, long-term intensive care and subsequent rehabilitation. A systematic
      case analysis and an introduction to the pathophysiology of NPO are presented. We
      recommend a positive approach to the management of NPO consisting primarily of
      interventions to stabilize vital functions, decrease intracranial pressure and
      normalize vegetative dysregulation. Emergency physicians need to consider the
      possibility of NPO in all cases of pulmonary oedema of unknown origin.

PMID- 10406422
TI  - An acute zinc chloride poisoning in a child: was chelator therapy effective?
AB  - An acute zinc chloride poisoning due to ingestion is a rare event. Symptoms
      include: corrosive pharyngeal lesions, vomiting and lethargy. Laboratory findings
      may include hyperglycaemia, hyperamylasaemia, exocrine pancreatic insufficiency
      and renal insufficiency. This case report describes an accidental zinc chloride
      poisoning in a child, with lethargy as the most pronounced clinical sign.
      Clinical evaluation and chelator therapy are discussed.

PMID- 10406423
TI  - Evidence-based medicine--little hope for a critical debate.

PMID- 10406424
TI  - The hype of evidence-based medicine.

PMID- 10406425
TI  - Randomized control trials and evidence-based medicine--what's in a name?

PMID- 10406426
TI  - Prehospital research and clinical decision-making.

PMID- 10406427
TI  - Genetic susceptibility to cancer. ICRP publication 79. Approved by the Commission
      in May 1997. International Commission on Radiological Protection.
AB  - A Task Group of the ICRP Committee 1 (Radiation Effects) has reviewed relevant
      data with the objective of advising the Main Commission of the ICRP on the
      possible implications for radiological protection of emerging views on genetic
      susceptibility to cancer (Chapter 1). Chapter 2 considers DNA damage and its
      processing/repair after ionising radiation and serves principally to demonstrate
      that a few rare cancer-prone, human recessive genetic disorders show DNA repair
      deficiency and profound increases in radiosensitivity. Less dramatic changes in
      radiosensitivity are also apparent in a wider range of such disorders. The
      cellular mechanisms that underly the association between DNA damage processing
      and tumorigenesis are discussed. Chapter 3 reviews the mechanisms and genetics of
      solid tumours illustrating the ways in which mutations in proto-oncogenes, tumour
      suppressor genes together with those in DNA repair and cell cycle control genes
      can contribute to tumour development. Specific examples are given of how germ
      line mutation of such genes can predispose to familial cancer. It is judged that
      up to 5% of all solid tumours have a recognisable genetic component. Heritable
      organ-specific effects are most usual and cancers of the breast and colon tend to
      show the most obvious genetic components. Clearly discernible genetic effects are
      seen when rare dominant germ line mutations express strongly as familial cancer
      (high penetrance mutations), but the existence of perhaps less rare low
      penetrance mutations and gene-gene interactions are recognised but not well
      understood. Chapter 4 considers the mechanisms and genetics of lympho
      haemopoietic tumours. Specific chromosomal translocations and proto-oncogene
      activation events are much more frequent in human leukaemia/lymphoma than in
      solid tumours. Genetic predisposition to leukaemia/lymphoma is found in a number
      of non-familial recessive genetic disorders of DNA processing and/or chromosomal
      instability. Familial manifestation of susceptibility to these tumours is,
      however, extremely rare. The genetic component, although poorly defined, is
      judged to be less than that of solid tumours and expressed largely in childhood.
      Chapter 5 reviews and discusses limited data that comment upon tumorigenic
      radiosensitivity in cancer-prone genetic conditions. From knowledge of the
      fundamental processes involved it is judged that in most, but not all, cases
      genetic susceptibility to spontaneous tumours will be accompanied by a greater
      than-normal risk after radiation. A review of epidemiological, clinical and
      experimental data relevant to this issue suggests that although a wide range of
      different sensitivities may be involved, a factor of 10 increase in sensitivity
      broadly accords with the limited human data available. This interim judgement of
      a factor of 10 increase in radiation risk in such human genetic disorders is made
      for the purposes of illustrative modelling and calculation. In addition, specific
      attention is given to breast cancer risk in heterozygotes for the radiosensitive
      human disorder, ataxia-telangiectasia; this association, while in no way
      discounted, is judged to be less strong than that claimed by some. Chapter 6
      discusses and develops computational modelling procedures that aim to describe
      the impact of genetic factors on radiation-tumorigenesis in human populations.
      Estimates of the prevalence of known cancer-prone genetic disorders are made but
      breast cancer susceptibility is used to illustrate the application of the model
      developed. The most important message to emerge from this work is that, even at
      an assumed high level of radiation sensitivity, the prevalence of familial (high
      penetrance) genetic disorders in the population is too low (<1%) for there to be
      a significant impact on risk in typical human populations. In principle, however,
      there is the potential for such impact in atypical inbred sub-populations where
      these mutations can be more common. (ABSTRACT TRUNCATED)

PMID- 10406428
TI  - Family doctors and patients: is effective nutrition interaction possible?

PMID- 10406429
TI  - Dietary advice in British General Practice.
AB  - Diet is a major determinant of health. It is now clear that at least as far as
      reducing the content of fat and sugar and increasing the content of fruit and
      vegetables is concerned, considerable gains can reasonably be expected if
      populations can be persuaded to alter their life style. In Western societies
      family medicine/general practice forms the front line of the Health Service and
      in the United Kingdom the contact rate between the population and primary care
      doctors now averages five encounters a year and relationships last an average of
      eleven years. This gives primary care, particularly in the form of
      multiprofessional teams of doctors and nurses, a substantial opportunity to
      explain the principles of healthy eating. Primary care worldwide is increasingly
      taking on responsibility for advising on life style, for example with smoking,
      immunisation, family planning etc. The provision of dietary advice in primary
      care is already common in the management of many chronic diseases, like
      hypertension and hyperlipidaemia, where over 90% of patients are exclusively
      managed in family medicine. It is probable that the provision of dietary advice
      will in future extend beyond diseased patients and will play a much higher role
      in relation to healthy patients.

PMID- 10406430
TI  - What can we generalize from research on patient education and clinical health
      promotion to physician counseling on diet?
AB  - OBJECTIVE: This paper explores the status of knowledge development from clinical
      trials and other studies of patient education and clinical health promotion.
      DESIGN: It asks what this cumulative literature has to offer dietary counseling
      of patients by family doctors. A series of meta-analyses of drug education and
      preventive health education research in clinical settings provide a starting
      framework for guidelines on dietary counseling. CONCLUSIONS: Smoking cessation
      studies, in particular, have mounted in quantity and quality to the greatest
      extent and offer the clearest statement on what can be achieved, under what
      conditions, and with what support beyond the physician's counseling session or
      sessions. The Precede-Proceed Model offers a further guide to assuring the
      comprehensiveness of approaches to dietary change-enabling and reinforcing the
      change, not just predisposing it through admonitions and altering of knowledge,
      attitudes and beliefs. The specific evidence supporting the application of a
      patient counseling algorithm based on the Precede-Proceed model is reviewed here.

PMID- 10406431
TI  - Nutrition guidance by primary care physicians: models and circumstances.
AB  - The perception of primary care physicians of the ability to influence the
      lifestyle and eating habits of patients is an important factor in nutrition
      guidance practices. This perception is based on assumptions about the kind of
      influencing process that is effective or not and on the capacity of primary care
      physicians to play an effective role in these processes. The first elements is
      dealt with in this article. Three models are distinguished. The first model is
      the prescription model, based on a medical optimum and on information transfer as
      a metaphor. The second model is the persuasion model, based on a medical optimum,
      but presupposing blockades that have to be cornered by persuasive communication.
      The third is the interaction model. It is not based upon a medical but on an
      efficacy optimum, and on sharing of information and continuous involvement of the
      client in the interaction. Behind these three models we can perceive different
      views on communication and knowledge. Moreover, these three models are more or
      less appropriate with regard to different circumstances. The current stress on
      the psychological, social and cultural meaning of food and the new information
      context in which clients live, asks for more attention to the interaction model.

PMID- 10406432
TI  - ICPC-code approach of nutritional questions in general practice: a look at the
      future.
AB  - The Dutch College of General Practitioners is developing a computerised consult
      supporting system on nutrition that is integrated in the widely used GP
      Information System. Connected to every ICPC-code (International Code of Primary
      Care) for diagnosis relevant nutritional information is available. Short items
      simple sentences with respect to the content-provide the main nutritional
      information, needed to inform the patient within the limited consultation time.
      Background information is the second level and is reachable by clicking on the
      coloured items in the first part. After all the patients' practical advice is the
      last part of this so-called: 'P-module of nutrition'.

PMID- 10406433
TI  - Fitting nutrition into the medical model: the role of decision analytic cost
      effectiveness techniques.
AB  - Physicians are accustomed to making decisions based on information regarding the
      prevalence of disease, symptoms, physical signs, laboratory test results, and the
      risks and benefits of alternative treatments. If nutritional assessment and
      therapeutics are to become more common components of medical practice,
      significant barriers in each of these areas must be overcome. Even rudimentary
      dietary assessment is often missing from physician education. Dietary assessment
      tools that are readily available and that have demonstrated usefulness are
      largely unknown. In addition, many nutritional interventions have not been
      formally investigated in randomized, controlled trials, and thus their cost
      effectiveness remains unknown. We present one approach to these issues by
      discussing the construction of a decision model examining strategies for vitamin
      D and calcium screening. The application of medical decision making techniques to
      problems in clinical nutrition illustrates how findings from research studies may
      be used to determine the risks, benefits and costs of alternative population
      based health related nutrition policies which can then be applied by physicians
      in their daily interactions with patients.

PMID- 10406434
TI  - The relevance of clinical nutrition education and role models to the practice of
      medicine.
AB  - Clinical nutrition is concerned with the diagnosis and treatment of diseases that
      affect the intake, absorption, and metabolism of dietary constituents and with
      the promotion of health through the prevention of diet related diseases. Adult
      diseases of clinical nutrition encompass the most common causes of mortality in
      the developed world and include obesity with its co-morbidities of hypertension,
      diabetes, dyslipidemias, increased risks of cardiovascular disease, some cancers,
      and pulmonary failure; intestinal disorders related to inadequate nutrient
      absorption; eating disorders; and malnutrition associated with chronic illness
      and surgical trauma. Scientific advances on the relationship of dietary
      substances to the cellular mechanisms of disease occur with regularity and
      frequency. Yet, despite the prevalence of nutritional disorders in clinical
      medicine and increasing scientific evidence on the significance of dietary
      modification to disease prevention, present day practitioners of medicine are
      typically untrained in the relationship of diet to health and disease. In the
      absence of reliable medical advice on nutrition, patients increasingly turn to
      herbal dietary supplements, costly diet schemes for weight reduction, and other
      unproved and potentially harmful remedies. Standardization of curricula for
      nutrition education of medical students and trainees and the provision of
      knowledgeable clinical nutrition specialist educators and role models in medical
      institutions is increasingly relevant to the cost-effective integration of
      nutritional concepts into medical practice.

PMID- 10406435
TI  - Cross-sectional and longitudinal analyses of nutrition guidance by primary care
      physicians.
AB  - OBJECTIVE: To investigate in primary care physicians (PCPs) the determinants of a
      nutrition guidance practice ('noticing patients' overweight and guidance of
      treatment'), as well as their mechanism of action, in a cross-sectional and a
      longitudinal approach. DESIGN: Mixed longitudinal design. Five years follow up
      study of a previous cross-sectional study in October 1992. SUBJECTS: A
      representative sample of 675 Dutch PCPs, in practice for 5 up to 20y.
      INTERVENTIONS: A shortened version of the Wageningen PCPs Nutritional Practices
      Questionnaire was mailed to the subjects in August 1997. MAIN OUTCOME MEASURE: To
      obtain with the LISREL-program a model of the mechanism of action of determinants
      of the dependent variable 'noticing patients' overweight and guidance of
      treatment' with an adequate fit of the empirical data, both in the cross
      sectional and in the longitudinal approach. RESULTS: The same set of predisposing
      factors and intermediary factors explains the dependent variable both in two
      different representative cross-sectional study populations of PCPs, and in a
      cohort cross-sectional study at two points in time. Two dynamic LISREL-models
      were developed (the 'determinant-longitudinal approach' and the 'early behaviour
      longitudinal approach') which explain the dependent variable. The latter model
      has, as added value, a gain in explained variance. In 5 y time, the dependent
      variable decreased significantly (P < 0.001). CONCLUSIONS: This study reconfirms
      that PCPs' nutritional guidance practices are determined partly directly by
      predisposing factors, and indirectly via driving forces and barriers. However
      this study also reveals that an important nutrition guidance practice of PCPs,
      'noticing patients' overweight and guidance of treatment', shows a significant
      decrease over the last 5 y. At the same time, two of the four predisposing
      factors and two of the three driving factors also decreased significantly. As
      research findings indicate that the role of diet in health and disease becomes of
      greater influence PCPs need to be activated to apply their responsibility in this
      field within a multi-faceted approach.

PMID- 10406436
TI  - Who gets what treatment for obesity? A survey of GPs in Scotland.
AB  - OBJECTIVE: To describe the types and delivery of obesity treatment currently
      favoured by General Practitioners (GPs) working in Scotland. DESIGN:
      Representative cross-sectional survey using a postal questionnaire which included
      case stories as stimuli for questions about the GPs' nutrition guidance to
      overweight female patients. SUBJECTS: A systematic sample of 1400 general
      practitioners (GPs) from a total of 3593 GPs working in Scotland in 1997.
      RESULTS: From 1363 eligible GPs, 609 returned the full questionnaire and a
      further 132 took part in a telephone mini-interview. Net response was 54.4%
      (741/1363). Almost half of the GPs (45.6%) reported that they had read the recent
      national clinical guideline for integrating obesity prevention with weight
      management (SIGN 1996). The majority of GPs (89.6%) agreed that nutrition has an
      important role to play in the management of disease and 82.4% agreed that they
      can offer healthy eating advice to patients. However, only 34.8% of GPs believed
      that they had been successful in treating overweight patients. Routinely used
      treatments involve either a dietitian, practice nurse and/or a commercial
      slimming group and realistic weight loss was considered one criteria of
      successful treatment by some GPs. Age, year qualified and location of practice
      were found to have little influence over variations in GP treatment while weak
      associations between gender of GP and treatment were found. CONCLUSIONS: The
      readership of the clinical guidelines in Scotland has been moderate so far
      although a multidisciplinary approach to obesity treatment is recognised. Further
      investigations of any relationships between nutrition education-obesity treatment
      are needed.

PMID- 10406437
TI  - Moving beyond information: evaluation of a nutrition education tool based on a
      theoretical model.
AB  - OBJECTIVE: This study investigated the relative effectiveness of a nutrition
      education brochure based on a theoretical model versus a more traditional
      information-based brochure in getting subjects to accurately assess daily calcium
      intake, make a plan to increase intake if needed, and to implement the plan.
      DESIGN: A randomized trial involving 216 women between the ages of 19-49y.
      Subjects were randomly assigned to a group which received educational materials
      containing an interactive brochure designed using the Motivation Generating model
      (Calcium CalculatorS), or to a group which received a calcium information
      brochure (An Appetite for Good Health). Within a two week period the women were
      contacted by telephone to assess use of materials, calcium intake assessment
      information, and plans for dietary change. SETTING: Subjects were recruited at
      five fitness centres in the Vancouver area. The research was conducted by the
      Institute of Health Promotion Research at the University of British Columbia.
      RESULTS: Results indicated significantly greater numbers of subjects conducting
      self- assessment and increased group accuracy for calcium intake assessment in
      subjects using the interactive brochure. CONCLUSION: Use of a theoretical model
      designed to create behaviour change such as the Motivation Generating Model can
      increase specific behaviours which may lead to improvements in dietary
      consumption.

PMID- 10406438
TI  - Strength and weakness of a nutrition communication strategy to health opinion
      formers: examples from a case study.
AB  - BACKGROUND: The nutritional image of diary products is challenged by the fact
      that milk fat contributes to a high intake of saturated fatty acids. On the other
      hand milk is promoted as an important source of calcium and other important
      micronutrients. In order to balance the debate on the nutritional value of milk
      Danish Dairy Board in 1991 initiated a strategy for nutrition communication
      directed at health opinion formers. In 1997 an evaluation study was performed.
      OBJECTIVE: The purpose of this study was: (1) to estimate the image of dairy
      products among selected opinion formers, (2) to elucidate the opinion formers'
      attitude to the engagement of the Danish Dairy Board in nutrition communication,
      (3) to disclose barriers and possibilities for future collaboration among
      important health opinion formers and the dairy industry on nutrition
      communication about milk and milk products. MATERIALS AND METHODS: Twenty
      important Danish health opinion formers representing the authorities, nutrition
      science, the medical community, the government, the parliament and media took
      part in the study. All the participants were interviewed by phone or in person
      following an interview guide. RESULTS: On the whole there is support for the
      official recommendation of daily consumption of half a litre of milk and 25 g of
      cheese-preferably the low fat varieties. The majority of the informants strongly
      urge the diary industry to produce more tasty low fat products and to promote
      them heavily through marketing campaigns. It is recognised as a positive feature
      that the diary industry in Denmark in a formulated nutrition policy has taken on
      a co-responsibility for public health. But it is put forward that this public
      policy obliges the dairy industry even more strongly to live up to their
      responsibility, which only a few of the opinion leaders find is the case. The
      informants find a dialogue with highly qualified nutrition staff of the industry
      as a prerequisite for future collaboration. It is recommended that the dairy
      industry invests more resources in visualising its co-responsibility for public
      health and that a two string strategy is implemented: 1. Product-related
      nutrition communication putting dairy products into a holistic perspective and 2.
      General nutrition information activities in collaboration with authorities and
      other interested parties (ideal organisations or producers of e.g. vegetables and
      bread).

PMID- 10406439
TI  - Population attitudes towards changing dietary habits and reliance on general
      practitioners in Spain.
AB  - OBJECTIVE: To investigate the relationship between population attitudes towards
      modifying food behaviour and reliance on General Practitioners (GPs) as nutrition
      educators. DESIGN: Personal interview in a random sample of the general
      population of the Canary Islands as part of the Canary Islands Nutrition Survey.
      SUBJECTS: 1747 individuals aged 6-74y. MAIN OUTCOME MEASURES: Attitudes towards
      changing food behaviour and reliance on GPs. RESULTS: Response rate was 67%.
      Physicians were the most reliable source of nutrition information with 79% of the
      population considering them as highly reliable. More than 60% of the population
      showed a favourable attitude towards increasing fruit and vegetables and towards
      decreasing alcohol, sugar and pastries. Reliance on GPs was associated with
      better attitudes towards increasing fruits, decreasing meat, pastries, sugar and
      losing weight. CONCLUSIONS: Population attitudes towards changing certain dietary
      behaviours were associated with having the greatest reliance on GPs.

PMID- 10406440
TI  - Nutrition education for medical students: the University of Otago experience.
AB  - Nutrition education for medical students in the University of Otago, New Zealand,
      has been adapted to comply with the newly introduced system-based teaching.
      Clinical cases provide the focus for class demonstrations, tutorials, self
      directed learning and a limited number of lectures. In the preclinical curriculum
      nutrition is taught primarily in the Metabolism, Blood, Heart and Circulation,
      Endocrine and Cancer modules. The concept of nutrient requirements for growth and
      development and the maintenance of health; the various methods used for assessing
      dietary intakes and nutritional status as well as nutrition issues relevant to
      obesity are covered in the Metabolism module. The role of nutritional factors in
      the aetiology of disease is stressed in the other modules. Emphasis in the
      clinical curriculum is on the dietary management of some disease states. Students
      are also given insights into nutrition research and public health aspects of
      nutrition. This integration of nutrition teaching into the curriculum has been
      extremely well received by students but is labour intensive.

PMID- 10406441
TI  - What nutrition knowledge and skills do primary care physicians need to have, and
      how should this be communicated?
AB  - The last Heelsum workshop agreed that general practitioners should concentrate on
      dietary advice for treatment or secondary prevention, though nutritional advice
      for health is part of the doctor's work with pregnancy, infants and the very old.
      Nutrition prescriptions contrast with drug prescriptions. For drugs information
      is authoritative, evidence-based and easily available. Drug prescriptions are
      potentially liable to litigation. Dietary prescriptions are less serious and more
      the patient's responsibility. Nutrition information comes in a plethora of
      different forms, some of it unscientific, some out of date, some commercially
      biased. While waiting for some system (?authoritative, ?electronic) that can help
      general practitioners (GPs) organise nutrition information, there are three
      modern books that have been written by nutrition specialists for GPs in the
      English language (there may be others in North America) and another was written
      for practice nurses. As well as general books like this most large countries have
      expert reports on some nutritional topics by government committees available for
      reference. In relating foods and food components to disease, most of the reliable
      evidence is about their effect on risk factors-plasma cholesterol, blood glucose,
      blood pressure or body weight. A smaller amount of evidence relates food intake
      data from large cohort studies to incidence of disease. Very few randomised
      controlled trials (the ultimate evidence-based medicine) have been achieved for
      nutrition. Dietary recommendations may have to change with time because of new
      research-and drugs. Advice for secondary prevention of coronary heart disease is
      shown as an example of this.

PMID- 10406443
TI  - Dutch research into the development and impact of computer-tailored nutrition
      education.
AB  - OBJECTIVE: The aim of the present paper is to describe the essential elements of
      computer-tailored nutrition education and to study the impact of written computer
      tailored nutrition education in comparison to general written nutrition advice.
      DESIGN: The impact of computer-tailored nutrition education was studied in three
      randomised trials as compared to general nutrition education. The data of the
      three studies were taken together and re-analysed. SUBJECTS: Random samples of
      employees at two work sites and a self-selected sample of the Dutch adult
      population. The total number of subjects was 1309. Response rates were between
      45% in one of the work sites and 88% in the self-selected sample. INTERVENTIONS:
      Subjects in the experimental condition received computer-tailored nutrition
      education. With computer-tailoring, expert individualised nutrition education can
      be realised through an automated process for relatively large target groups with
      relatively low costs per person. MAIN OUTCOME MEASURES: The impact on changes in
      fat intake were studied. The use and appreciation of the intervention was also
      assessed. RESULTS: Subjects who received computer-tailored advice had a lower
      mean fat score at post-test, adjusted for baseline intake levels. Subjects who
      received tailored advice were more likely to have read and discussed the
      nutrition advice. CONCLUSION: The results point to the conclusion that printed
      computer-tailored nutrition education is superior to general written nutrition
      education.

PMID- 10406442
TI  - A four week residential program for primary health care patients to control
      obesity and related heart risk factors: effective application of principles of
      learning and lifestyle change.
AB  - OBJECTIVE: To test the short and long-term effectiveness of a four week
      residential program for primary health care patients to control obesity and
      related risk factors for cardio-vascular disease (CVD), especially blood pressure
      (BP). DESIGN: Prospective clinical study, with follow up after 1 and 5 y.
      SETTING: Vindeln Patient Education Centre, Vindeln, and Department of Social
      Medicine, University of Umea, Sweden. SUBJECTS: Approximately 2500 individuals,
      with two or more of the traditional risk factors for CVD, participated in the
      program. This report describes a subsample of 100 consecutive patients, 52+/-9 y,
      53 men, with obesity and/or high BP. INTERVENTION: Four week residential program
      with lectures and group discussions as well as practical sessions in smaller
      groups (meal preparations, physical exercise, etc). The patients were followed-up
      medically in their home area. OUTCOME MEASURES: Weight and blood pressure.
      RESULTS: Dramatic reductions of weight and, especially, of blood pressure (BP)
      occurred during the residential weeks, and the reductions were pronounced also
      after 1 y. After 5 y, the total mean weight among men with initial BMI > or = 30
      kg/m2 was still 5 kg lower, and diastolic and systolic BP among those with
      hypertension was 15 and 20 mm Hg lower, respectively, than before the program.
      CONCLUSIONS: The full-time participation in the residential program and the
      enrollment and commitment of the patients may explain the clinical outcome. A
      level of predisposition greater than that required of most weight- and BP-control
      programs was confirmed and a great preventive or therapeutic potential was
      indicated. The study illustrates an effective application of the Precede-Proceed
      model of health promotion planning.

PMID- 10406444
TI  - The NECTAR-study: development of nutrition modules for general practice
      vocational training; determinants of nutrition guidance practices of GP-trainees.
      Nutrition Education by Computerized Training And Research.
AB  - OBJECTIVE: To identify determinants of nutrition guidance practices of general
      practitioner-trainees (GP-trainees), to investigate whether these determinants
      differ from those found by experienced general practitioners; to reveal
      educational directions towards the development of computer-based instruction on
      nutrition. DESIGN: Cross-sectional study by means of validated questionnaires.
      SUBJECTS: All GP-trainees in training at the eight university departments for
      vocational training in the Netherlands in September, 1998 (n = 985). MAIN OUTCOME
      MEASURES: Reliability of determinants of nutrition guidance practices was
      calculated by means of Crohnbach's alpha. The mechanism of action of determinants
      was identified by means of linear structural relationship analysis (LISREL) using
      a model developed for GPs. RESULTS: Crohnbach's alphas for factors ranged from
      0.58-0.90. The empirical GP-trainee-data fitted with the corresponding GP-model
      on the mechanism of action. CONCLUSIONS: The same predisposing factors, driving
      forces and barriers as found with GPs were identified with GP-trainees. Comparing
      the GP-and GP-trainee-models, only minor differences were found in the path
      coefficients between factors. Lack of nutrition training and education proved to
      be of great influence on the extent of nutrition information given. The GP
      trainee-model will be of use in developing computer-based instruction on
      nutrition. It is expected that GPs may also benefit from this instruction.

PMID- 10406445
TI  - Developments and challenges in family practice nutrition education for residents
      and practicing physicians: an overview of the North American experience.
AB  - The history of nutrition education in family medicine residency training and
      continuing medical education (CME) in North America is briefly reviewed. Past
      efforts have been successful in improving knowledge and attitudes toward
      nutrition. Some of the barriers to physicians providing nutrition services to
      their patients, such as poor reimbursement for those services, are largely
      outside the domain of medical educators. However, the education and training of
      family practice residents and practicing physicians in nutrition has not yet
      fully matured. Strategies are needed that impact physician counseling behaviors.
      Strengthening the content of certification examinations, providing evidence that
      brief counseling strategies impact patient outcomes, and role modeling counseling
      through multimedia delivery are three educational strategies with potential.

PMID- 10406446
TI  - Streamlining nutritional care for the physician's office.
AB  - OBJECTIVE: Nutritional care needs are overlooked in clinical practice. We review
      nutritional needs and describe an approach for improving nutritional care in
      clinical practice. DESIGN: Data from a controlled trial and several population
      cohorts. SETTING: Primary care practices and a population survey in New Hampshire
      and Vermont, USA. SUBJECTS: The controlled trial involved 1651 persons aged
      70+years. The cohorts include information from 1879 persons aged 12+.
      INTERVENTION: All patients completed standard surveys which included information
      about nutritional needs. 22 practices participated in the trial. RESULTS: The
      higher the BMI, the less healthy the population. 15 30% of patients report
      problems or concerns with eating/weight and nutrition. Patients with problems or
      concerns are often bothered by other health and social problems. Patients who
      have productive interactions with clinicians have improved nutritional care and
      are more likely to report help with eating problems (68% vs 86%; Odds ratio 5.0
      (95% CI: 0.9-27.0). CONCLUSIONS: Nutritional issues are common and complex. A
      productive provider-patient interaction can improve the nutritional care of
      patients. Essential elements for a productive interaction include an informed,
      educated patient and a provider (or clinical team) prepared to assess and manage
      the broad range of issues that are important to the patient. Technology
      facilitates necessary feedback between patient and provider.

PMID- 10406447
TI  - How to improve the impact of nutrition guidance by general physicians: public
      health versus individual patient?
AB  - This paper will review the impacts that family physicians might exert over their
      patients' health, wellbeing and nutrition status. It commences with the
      examination of some of the characteristics of public health and family medicine
      as well as those of the societies in which family medicine is practised. This
      leads on to a discussion of several food, nutrition and consumer-related agendas
      which set the context for the work of family physicians. These agendas delineate
      the scope of family physicians' nutritional guidance. They suggest that current
      nutrition goals are one subset of a wider range of possibilities. Finally,
      several courses of action are proposed which may improve family physicians'
      impact on patients' lives.

PMID- 10406448
TI  - Nutritional guidance in general practice--a conceptual framework.
AB  - BACKGROUND AND OBJECTIVE: The general practitioner is the personal doctor for
      patients and families in the community. This paper explores the inclusion of
      nutrition guidance in the overall methods of general practice care. DESIGN: Three
      dominant factors of nutrition guidance have been identified: the disease or risk
      factor, the individual and the socio-cultural context. These factors were
      considered against the main features of general practice-the defined
      epidemiology, the focus on individual needs, family orientation and continuity of
      care. RESULTS: General practice is particularly effective in individual
      counselling and addressing individual beliefs and values as many patients are
      consulting more than once each year. Approximately 16% of all presented episodes
      of illness relate directly to nutritional guidance and provide 'critical'
      individual incidents. For the large majority of situations nutrition guidance is
      promoting healthy food, on which individual needs require emphasis of specific
      aspects (salt, fat, fibre, starch). CONCLUSIONS: It is proposed to focus
      nutrition guidance in general practice primarily on individual needs, and use
      identified health problems as critical incidents to enhance nutritional changes.
      Coordination with public campaigns can reinforce the effectiveness of this
      individual approach. Concepts like the Stages of Change provide a model for
      nutrition guidance that are based on continuity of care. From this a framework
      for individual nutrition guidance is presented, based on individual needs in the
      context of social values. Presented health problems over time are used as
      critical incidents to motivate nutritional change, implement it and preserve new
      nutritional behaviour.

PMID- 10406449
TI  - Family doctors and patients: is effective nutrition interaction possible?
      Summarised points from the discussion.

PMID- 10406450
TI  - The 1998 Nobel prize in Medicine: clinical implications for 1999 and beyond.

PMID- 10406451
TI  - Different prevalence of asymptomatic atherosclerotic lesions in males and
      females.
AB  - The detection of atherosclerotic lesions in asymptomatic healthy subjects is
      possible using ultrasound. Populations can be investigated in order to detect
      differences in early and asymptomatic atherosclerosis due to gender and risk
      factors. This study investigated 2605 male (21-69 years) and 1601 female (20-70
      years) employees and civil servants of the city of Dusseldorf, Germany. The
      ultrasound investigations were performed with an ATL device, type Ultramark 4
      plus, and a 7.5-MHz linear transducer on the carotid and proximal femoral
      arteries. An atherosclerotic lesion was defined as visibly different from the
      intima by its echogenicity and by being larger than 1 mm. A thickening of the
      intima media complex was not considered to be atherosclerosis. The prevalence of
      atherosclerotic lesions in male subjects was higher than those in female subjects
      regardless of age. In male subjects it was 5.3% (30-39 years), 19.8% (40-49
      years), 36.7% (50-59 years) and 47.7% (60-70 years). The female subjects had a
      prevalence of 2.1%, 8.4%, 17.5% and 37.7% in the corresponding age groups. Risk
      factors such as smoking, hypertension and hypercholesterolemia were higher in men
      than in women. The increase of atherosclerotic lesions from one decade to another
      was highest in women between 50 and 59 years and 60 and 70 years. This large
      increase could not be explained by a similar increase in risk factors. It was
      therefore concluded that male subjects had a higher prevalence of atherosclerosis
      at earlier ages than females, but female subjects showed a postmenopausal rise in
      prevalence.

PMID- 10406452
TI  - Incidence and determinants of mortality and cardiovascular events in diabetes
      mellitus: a meta-analysis.
AB  - Patients with diabetes mellitus are at increased risk of developing
      atherosclerotic disease. The extent of this additional risk and its determinants
      are not well known, but this information is needed for sample-size estimations in
      intervention studies. Therefore, a meta-analysis of epidemiologic studies on this
      subject was performed. Medline was searched from 1966 onwards, including the
      reference lists of all relevant publications. A total of 27 prospective follow-up
      studies in the English language that allowed calculation of the unadjusted
      incidence of one of the predefined outcome events were included. The influence of
      age, sex, type of diabetes, duration of diabetes, year of study, HbA1c,
      cholesterol level, blood pressure and smoking on these incidences was studied by
      means of univariate Poisson regression analysis. Overall total mortality was 2.9%
      per year (95% CI 2.8-3.0; 27 studies), and for death from all vascular causes was
      1.4% per year (95% CI 1.3-1.4; 16 studies). Only two studies were found that
      reported on the incidence of the composite outcome 'event death from all vascular
      causes, non-fatal myocardial infarction, or non-fatal stroke'. In univariate
      analysis, age, year of study, total cholesterol and systolic blood pressure were
      positively related to total mortality and death from all vascular causes. After
      adjustment for age, or limiting the analyses to studies in patients with type 2
      diabetes only (n = 11), these relationships remained statistically significant.
      In conclusion, the overall yearly total mortality in diabetes mellitus is 2.9%
      and for death from all vascular causes is 1.4%. There are few data on the
      incidence of composite cardiovascular outcome events.

PMID- 10406453
TI  - Combination of pressure and velocity parameters in the non-invasive diagnosis of
      aorto-iliac disease.
AB  - Three different femoral artery flow velocity parameters in combination with
      segmental pressure measurements were evaluated for their respective diagnostic
      value in identifying the presence or absence of hemodynamically significant aorto
      iliac disease. A total of 60 patients (119 legs) were examined both non
      invasively and with arteriography. Doppler flow velocities were recorded using a
      5-MHz CW Doppler velocity metering system. Of the three parameters used (peak
      velocity, decay time and deceleration), a decay time of 220 ms yielded the most
      practical discriminant value. The accuracy increases when in addition the upper
      thigh/arm pressure ratio values are considered. The results indicate that the
      combination of femoral artery decay time with the upper thigh/arm pressure index
      provides a simple and accurate non-invasive screening method to confirm or rule
      out aorto-iliac disease. This helps to determine whether the patient is a
      candidate for arteriography and for potential surgical intervention.

PMID- 10406454
TI  - An analysis of limb-threatening lower extremity wound complications after 1090
      consecutive coronary artery bypass procedures.
AB  - The objective of this study was to examine and characterize limb-threatening
      lower extremity wound or soft tissue complications after coronary artery bypass
      (CABG) and determine risk factors for their cause. While minor wound problems of
      the leg after CABG are not uncommon, serious limb-threatening complications,
      though less frequent, do occur and are often de-emphasized in the surgical
      literature. A review of 1090 consecutive CABG procedures performed from January
      1, 1995 through December 31, 1995 was instituted, which screened for limb
      threatening lower extremity wound or soft tissue complications defined as wounds
      that: required additional surgery for treatment; prolonged the length of stay; or
      which required lengthy home health nursing for treatment. Minor lymph leaks, leg
      swelling, infections or wound problems treated as an outpatient were excluded. Of
      1090 patients, 54 (5.0%) experienced a limb-threatening lower extremity
      complication. Complications were categorized as vein harvest incision non-healing
      (n = 36, 66.7%), decubitus ulceration (n = 11, 20.4%), forefoot
      ischemia/embolization (n = 10, 18.5%), groin hematoma/abscess (n = 6, 11.1%),
      severe cellulitis (n = 3, 5.6%), or a combination (n = 12, 22.2%). Statistically
      significant risk factors by univariate and bivariate analysis for a complication
      included older age (68 years vs 62 years, p = 0.007), female sex (57% vs 28%, p <
      0.001), diabetes (57% vs 33%, p = 0.005) and longer pump time (129 min vs 114
      min, p = 0.009). These complications necessitated five major lower extremity
      amputations and nine revascularization procedures. Chronic lower extremity
      ischemia from peripheral vascular disease (PVD) was a major contributing factor
      for the development of wounds in at least 23 (42.6%) of these patients, though
      suspected in only 10 (43.5%) preoperatively. A non-healing vein harvest incision
      below the knee of a patient retrospectively found to have inadequate distal
      circulation for healing occurred in 17 (31.5%) of the total 54 cases. It was
      concluded that non-healing vein incisions, decubitus ulcers and forefoot ischemic
      lesions frequently occurring in older diabetic females with undetected pre
      existing PVD, comprise the majority of limb-threatening leg complications after
      CABG. Nearly one-third of the complications may have been avoided had the vein
      harvest incision not been made at the ankle of a patient with unappreciated PVD.

PMID- 10406455
TI  - Fibroblast growth factor as therapy for critical limb ischemia: a case report.
AB  - In an attempt to avert impending, primary amputation, an 85-year-old woman with
      chronic critical leg ischemia was enrolled in an experimental protocol to induce
      therapeutic angiogenesis. Treatment consisted of six consecutive, weekly
      intravenous infusions of recombinant basic fibroblast growth factor (bFGF).
      Angiographic evaluation was performed before and after therapy. The patient's
      clinical response was monitored through serial measurements of the ankle/brachial
      index and by repetitive assessment of limb flow by mercury strain-gauge
      plethysmography. A beneficial clinical response was detectable by week 4 of
      therapy, which was characterized by an improved walking distance, relief of
      ischemic pain, a marked reduction in analgesic consumption, and healing of
      persistent, unresponsive, painful inflammation of the hallux. The clinical
      improvement was sustained throughout the remaining weeks of therapy and follow-up
      evaluation. Plethysmography documented improved blood flow; specifically, the
      augmentation of digital flow was sustained and correlated with the marked
      improvement in the patient's clinical status.

PMID- 10406456
TI  - Iron-mediated cardiovascular injury.
AB  - Iron is an essential element for normal cellular function and general health.
      However, iron may play a pathologic role in certain cardiac conditions including
      reperfusion injury, hemochromatosis, beta-thalassemia and coronary
      atherosclerosis. It also may play a role in injury due to anthracycline
      cardiotoxicity. Removal of iron via phlebotomy for hemochromatosis and chelation
      therapy for beta-thalassemia are proven treatments. Cell culture, and isolated
      organ and animal studies suggest that depleting iron stores may prevent
      reperfusion injury, restenosis and even atherogenesis. This article will review
      mechanisms by which iron overload states and normal iron stores contribute to
      cardiovascular pathophysiology and the accumulating evidence that iron chelation
      may prevent restenosis and atherogenesis.

PMID- 10406457
TI  - Analysis of functional domains of angiotensin II type 2 receptor involved in
      apoptosis.
AB  - We previously demonstrated that the intracellular third loop (i3 loop) of
      angiotensin II type 2 receptor (AT2) plays a key role in mediating the biological
      functions of this receptor. To determine which residues are important for AT2
      signaling, mutated receptors with serial deletions within the i3 loop were stably
      expressed in PC12 cells. Deletion of residues 240-244 within the intermediate
      portion of the i3 loop resulted in a complete loss of AT2-mediated apoptosis,
      inhibition of extracellular signal-regulated kinases (ERK), and SHP-1 activation.
      In contrast to well characterized heptahelical receptors, the AT2 functions were
      not affected by deletions of the amino- or carboxyl-terminal portions of the i3
      loop. Alanine substitutions further demonstrated that lysine 240, asparagine 242,
      and serine 243 are key residues for AT2-induced apoptosis, ERK inhibition, and
      SHP-1 activation. To examine whether a functional link exists between activation
      of SHP-1 and apoptosis, we used a catalytically inactive SHP-1 mutant and
      demonstrated that preventing SHP-1 activation strongly attenuates AT2-induced ERK
      inhibition and apoptosis. Our data demonstrate that the intermediate portion of
      the i3 loop is important for AT2 function and that SHP-1 is a proximal effector
      of the AT2 receptor that is implicated in the inhibition of ERKs and in the
      apoptotic effect of this receptor.

PMID- 10406458
TI  - Compartmentation of cyclic adenosine 3',5'-monophosphate signaling in caveolae.
AB  - The cAMP-signaling pathway is composed of multiple components ranging from
      receptors, G proteins, and adenylyl cyclase to protein kinase A. A common view of
      the molecular interaction between them is that these molecules are disseminated
      on the plasma lipid membrane and random collide with each other to transmit
      signals. A limitation to this idea, however, is that a signaling cascade
      involving multiple components may not occur rapidly. Caveolae and their principal
      component, caveolin, have been implicated in transmembrane signaling,
      particularly in G protein-coupled signaling. We examined whether caveolin
      interacts with adenylyl cyclase, the membrane-bound enzyme that catalyzes the
      conversion of ATP to cAMP. When overexpressed in insect cells, types III, IV, and
      V adenylyl cyclase were localized in caveolin-enriched membrane fractions.
      Caveolin was coimmunoprecipitated with adenylyl cyclase in tissue homogenates and
      copurified with a polyhistidine-tagged form of adenylyl cyclase by
      Ninitrilotriacetic acid resin chromatography in insect cells, suggesting the
      colocalization of adenylyl cyclase and caveolin in the same microdomain. Further,
      the regulatory subunit of protein kinase A (RIIalpha, but not RIalpha) was also
      enriched in the same fraction as caveolin. Gsalpha was found in both caveolin
      enriched and non-caveolin-enriched membrane fractions. Our data suggest that the
      cAMP-signaling cascade occurs within a restricted microdomain of the plasma
      membrane in a highly organized manner.

PMID- 10406459
TI  - A dominant role for the Raf-MEK pathway in forskolin, 12-O-tetradecanoyl-phorbol
      acetate, and platelet-derived growth factor-induced CREB (cAMP-responsive element
      binding protein) activation, uncoupled from serine 133 phosphorylation in NIH 3T3
      cells.
AB  - In this study we describe that platelet-derived growth factor (PDGF), 12-O
      tetradecanoyl-phorbol-acetate (TPA), and forskolin induced CREB (cAMP-responsive
      element-binding protein) Ser-133 phosphorylation with comparable magnitude and
      kinetics in NIH 3T3 cells. While forskolin was the most potent activator of CREB,
      TPA or PDGF modestly increased CREB activity. The role of protein kinase C,
      protein kinase A, and the Raf-MEK kinase pathway in the activation and Ser-133
      phosphorylation of CREB by these three stimuli was investigated. We found that
      inhibition of the Raf-MEK kinase pathway efficiently blocks transcriptional
      activation of CREB by all three stimuli. This dominant involvement of Raf-MEK in
      CREB transcriptional activation seems to be uncoupled from CREB Ser-133
      phosphorylation. We further demonstrate that although inhibition of Raf-MEK
      represses forskolin-induced CREB activation, forskolin by itself failed to
      activate ERK1/2 and Elk-1 mediated transcription. These results suggest that a
      basal level of Raf-MEK activity is necessary for both PDGF- and forskolin-induced
      CREB activation, independent of CREB Ser-133 phosphorylation.

PMID- 10406460
TI  - Stat5-mediated regulation of the human type II 3beta-hydroxysteroid
      dehydrogenase/delta5-delta4 isomerase gene: activation by prolactin.
AB  - Altered PRL levels are associated with infertility in women. Molecular targets at
      which PRL elicits these effects have yet to be determined. These studies
      demonstrate transcriptional regulation by PRL of the gene encoding the final
      enzymatic step in progesterone biosynthesis: 3beta-hydroxysteroid
      dehydrogenase/delta5-delta4 isomerase (3beta-HSD). A 9/9 match with the consensus
      Stat5 response element was identified at -110 to -118 in the human Type II 3beta
      HSD promoter. 3beta-HSD chloramphenicol acetyltransferase (CAT) reporter
      constructs containing either an intact or mutated Stat5 element were tested for
      PRL activation. Expression vectors for Stat5 and the PRL receptor were
      cotransfected with a -300 --> +45 3beta-HSD CAT reporter construct into HeLa
      cells, which resulted in a 21-fold increase in reporter activity in the presence
      of PRL. Promoter activity showed an increased response with a stepwise elevation
      of transfected Stat5 expression or by treatment with increasing concentrations of
      PRL (max, 250 ng/ml). This effect was dramatically reduced when the putative
      Stat5 response element was removed by 5'-deletion of the promoter or by the
      introduction of a 3-bp mutation into critical nucleotides in the element.
      Furthermore, 32P-labeled promoter fragments containing the Stat5 element were
      shifted in electrophoretic mobility shift assay experiments using nuclear
      extracts from cells treated with PRL, and this complex was supershifted with
      antibodies to Stat5. These results demonstrate that PRL has the ability to
      regulate expression of a key human enzyme gene (type II 3beta-HSD) in the
      progesterone biosynthetic pathway, which is essential for maintaining pregnancy.

PMID- 10406461
TI  - A role for the mitogen-activated protein kinase in mediating the ability of
      thyrotropin-releasing hormone to stimulate the prolactin promoter.
AB  - The hypothalamic hormone, TRH, stimulates PRL secretion and gene transcription.
      We have examined the possibility that the mitogen-activated protein kinase (MAPK)
      may play a role in mediating TRH effects on the PRL gene. TRH was found to
      stimulate sustained activation of MAPK in PRL-producing, GH3 cells, consistent
      with a possible role in transcriptional regulation. A kinase-defective,
      interfering MAPK kinase (MAPKK) mutant reduced TRH induction of the PRL promoter.
      Treatment with the MAPKK inhibitor, PD98059, blocked TRH-induced activation of
      MAPK and also reduced TRH induction of a PRL-luciferase reporter gene, confirming
      that MAPK activation is necessary for TRH effects on PRL gene expression.
      Previous studies have demonstrated that the PRL promoter contains binding sites
      for members of the Ets family of transcription factors, which are important for
      mediating MAPK responsiveness of the PRL promoter. Mutation of specific Ets sites
      within the PRL promoter reduced responsiveness to both TRH and MAPK. The finding
      that DNA elements required for MAPK responsiveness of the PRL gene colocalize
      with DNA elements required for TRH responsiveness further supports a role for
      MAPK in mediating TRH effects on the PRL gene. We also explored the signaling
      mechanisms that link the TRH receptor to MAPK induction. Occupancy of the TRH
      receptor results in activation of protein kinase C (PKC) as well as increases in
      the concentration of Ca2+ due to release from intracellular stores and entry of
      Ca2+ through Ca2+ channels. A PKC inhibitor, GF109203X, and an L-type Ca2+
      channel blocker, nimodipine, both partially reduced TRH-induced MAPK activation
      and PRL promoter activity. The effects of the two inhibitors were additive. These
      studies are consistent with a signaling pathway involving PKC- and Ca2+-dependent
      activation of MAPK, which leads to phosphorylation of an Ets transcription factor
      and activation of the PRL promoter.

PMID- 10406462
TI  - Ligand-independent coregulator recruitment by the triply activatable OR1/retinoid
      X receptor-alpha nuclear receptor heterodimer.
AB  - OR1 is a member of the superfamily of steroid/thyroid hormone nuclear receptors
      and recognizes DNA as a heterodimer with the 9-cis-retinoic acid receptor RXR
      (retinoid X receptor). The heterodimeric complex has been shown to be
      transcriptionally activatable by the RXR ligand as well as certain oxysterols via
      OR1, but to date uniquely also by heterodimerization itself. Recent studies on
      other members of the superfamily of nuclear receptors have led to the
      identification of a number of nuclear receptor-interacting proteins that mediate
      their regulatory effects on transcription. Here, we address the question of
      involvement of some of these cofactors in the three modes of activation by the
      OR1/RXRalpha complex. We show that in vitro the steroid receptor coactivator SRC
      1 can be recruited by RXRalpha upon addition of its ligand, and to OR1 upon
      addition of 22(R)-OH-cholesterol, demonstrating that the latter can act as a
      direct ligand to OR1. Additionally, heterodimerization is sufficient to recruit
      SRC-1 to OR1/RXRalpha, indicating SRC-1 as a molecular mediator of dimerization
      induced activation. In transfection experiments, coexpression of a nuclear
      receptor-interacting fragment of SRC-1 abolishes constitutive activation by
      OR1/RXRalpha, which can be restored by over-expression of full-length SRC-1. This
      constitutes evidence for an in vivo role of SRC-1 in dimerization-induced
      activation by OR1/RXRalpha. Additionally, we show that the nuclear receptor
      interacting protein RIP140 binds in vitro to OR1 and RXRalpha with requirements
      distinct from those of SRC-1, and that binding of the two cofactors is
      competitive. Taken together, our results suggest a complex modulation of
      differentially induced transactivation by OR1/RXR coregulatory molecules.

PMID- 10406463
TI  - The adenovirus E1A protein is a potent coactivator for thyroid hormone receptors.
AB  - The thyroid hormone receptors interact with several different cofactors when
      activating transciption. In this study, we show that the adenovirus E1A
      oncoprotein functions as a strong coactivator for the thyroid hormone receptor
      (TR), and that TR and E1A synergistically activate transcription via direct (DR4)
      or palindromic (IRO) hormone-responsive sites. Cotransfection experiments using
      different isoforms of the chicken TR and E1A show synergistic, ligand-enhanced
      transactivation. This transactivation is accomplished through a direct, ligand
      independent interaction between TR and E1A. The interaction domains in TR are
      localized to the DNA-binding domain and to the carboxy-terminal part of the
      ligand-binding domain. In E1A, the regions of interactions are localized to the
      conserved regions 1 and 3. Both of these domains in E1A are required for a 40
      fold enhancement of TR-mediated activation in transfection experiments. Taken
      together, we show that E1A strongly enhances transcriptional activation, which
      suggests that it serves as a bridging factor between the receptor and other
      components of the transcription machinery.

PMID- 10406464
TI  - Identification of mouse TRAP100: a transcriptional coregulatory factor for
      thyroid hormone and vitamin D receptors.
AB  - Nuclear hormone receptors (NRs) regulate transcription in part by recruiting
      distinct transcriptional coregulatory complexes to target gene promoters. The
      thyroid hormone receptor (TR) was recently purified from thyroid hormone-cultured
      HeLa cells in association with a complex of novel nuclear proteins termed TRAPs
      (thyroid hormone receptor-associated proteins) ranging in size from 20 to 240
      kDa. The TRAP complex markedly enhances TR-mediated transcription in vitro,
      suggesting a coactivator role for one or more of the TRAP components. Here we
      present the mouse cDNA for the 100-kDa component of the TRAP complex (mTRAP100).
      The mTRAP100 protein contains seven LxxLL motifs thought to be potential binding
      surfaces for liganded NRs, yet surprisingly fails to interact with TR and other
      NRs in vitro. By contrast, mTRAP100 coprecipitates in vivo with another component
      of the TRAP complex (TRAP220), which directly contacts TR and the vitamin D
      receptor in a ligand-dependent manner. Our findings thus suggest that TRAP100 is
      targeted to NRs in association with TRAP complexes specifically containing
      TRAP220. Transient overexpression of mTRAP100 in mammalian cells further enhances
      ligand-dependent transcription by both TR and the vitamin D receptor, revealing a
      functional role for mTRAP100 in NR-mediated transactivation. The presence of an
      intrinsic mTRAP100 transactivation function is suggested by the ability of
      mTRAP100 to activate transcription constitutively when tethered to the GAL4 DNA
      binding domain. Collectively, these findings suggest that TRAP100, in concert
      with other TRAPs, plays an important functional role in mediating transactivation
      by specific NRs.

PMID- 10406465
TI  - Synergistic activation of the prolactin promoter by vitamin D receptor and GHF-1:
      role of the coactivators, CREB-binding protein and steroid hormone receptor
      coactivator-1 (SRC-1).
AB  - PRL gene expression is dependent on the presence of the pituitary-specific
      transcription factor GHF-1/Pit-1, which is transcribed in a highly restricted
      manner in cells of the anterior pituitary. In pituitary GH3 cells, vitamin D
      increases the levels of PRL transcripts and stimulates the PRL promoter. We have
      analyzed the role of GHF-1 and of the vitamin D receptor (VDR) to confer vitamin
      D responsiveness to the PRL promoter. For this purpose we have used nonpituitary
      HeLa cells, which do not express GHF-1. We found that VDR activates the PRL
      promoter both in a ligand-dependent and -independent manner through a sequence
      located between positions -45/-27 in the proximal 5'-flanking region. This
      sequence also confers VDR and vitamin D responsiveness to a heterologous
      promoter. In the context of the PRL gene, VDR requires the presence of GHF-1 to
      activate the promoter. Truncation of the last 12 C-terminal amino acids of VDR,
      which contain the ligand-dependent activation function (AF2), abolishes
      regulation by vitamin D, suggesting that binding of coactivators to this region
      mediates ligand-dependent stimulation of the PRL promoter by the receptor.
      Indeed, expression of the coactivators, steroid hormone receptor coactivator-1
      (SRC-1) and CREB-binding protein (CBP), significantly enhances the stimulatory
      effect of vitamin D mediated by the wild-type VDR but not by the AF2 mutant
      receptor. Furthermore, CBP also increases the activation of the PRL promoter by
      GHF-1 and the ligand-independent activation by both wild-type and mutant VDR.

PMID- 10406466
TI  - The nuclear receptor corepressor N-CoR regulates differentiation: N-CoR directly
      interacts with MyoD.
AB  - Classical ligand-activated nuclear receptors (e.g. thyroid hormone receptor,
      retinoic acid receptor), orphan nuclear receptors (e.g. Rev-erbAalpha/beta),
      Mad/Max bHLH (basic helix loop helix)-LZ proteins, and oncoproteins, PLZF and
      LAZ3/BCL6, bind DNA and silence transcription by recruiting a repressor complex
      that contains N-CoR (nuclear receptor corepressor)/SMRT (silencing mediator of
      retinoic acid and thyroid hormone receptor), Sin3A/B, and HDAc-1/-2 proteins. The
      function of the corepressor, N-CoR, in the process of cellular differentiation
      and coupled phenotypic acquisition, has not been investigated. We examined the
      functional role of N-CoR in myogenesis (muscle differentiation), an ideal
      paradigm for the analysis of the determinative events that govern the cell's
      decision to divide or differentiate. We observed that the mRNA encoding N-CoR was
      suppressed as proliferating myoblasts exited the cell cycle, and formed
      morphologically and biochemically differentiated myotubes. Exogenous expression
      of N-CoR (but not RIP13) in myogenic cells ablated 1) myogenic differentiation,
      2) the expression of the myoD gene family that encode the myogenic specific bHLH
      proteins, and 3) the crucial cell cycle regulator, p21Waf-1/Cip-1 mRNA.
      Furthermore, N-CoR expression efficiently inhibits the myoD-mediated myogenic
      conversion of pluripotential C3H10T1/2 cells. We demonstrate that MyoD-mediated
      transactivation and activity are repressed by N-CoR. The mechanism involves
      direct interactions between MyoD and N-CoR; moreover, the interaction was
      dependent on the amino-terminal repression domain (RD1) of N-CoR and the bHLH
      region of MyoD. Trichostatin A treatment significantly stimulated the activity of
      MyoD by approximately 10-fold and inhibited the ability of N-CoR to repress MyoD
      mediated transactivation, consistent with the involvement of the corepressor and
      the recruitment of a histone deacteylase activity in the process. This work
      demonstrates that the corepressor N-CoR is a key regulator of MyoD activity and
      mammalian differentiation, and that N-CoR has a multifaceted role in myogenesis.

PMID- 10406467
TI  - Molecular modeling of human P450c17 (17alpha-hydroxylase/17,20-lyase): insights
      into reaction mechanisms and effects of mutations.
AB  - P450c17 (17alpha-hydroxylase/17,20-lyase) catalyzes steroid 17alpha-hydroxylase
      and 17,20-lyase activities in the biosynthesis of androgens and estrogens. These
      two activities are differentially regulated in a tissue-specific and
      developmentally programmed manner. To visualize the active site topology of human
      P450c17 and to study the structural basis of its substrate specificity and
      catalytic selectivity, we constructed a second-generation computer-graphic model
      of human P450c17. The energetics of the model are comparable to those of the
      principal template of the model, P450BMP, as determined from its crystallographic
      coordinates. The protein structure analysis programs PROCHECK, WHATIF, and SurVol
      indicate that the predicted P450c17 structure is reasonable. The hydrophobic
      active site accommodates both delta4 and delta5 steroid substrates in a
      catalytically favorable orientation. The predicted contributions of positively
      charged residues to the redox-partner binding site were confirmed by site
      directed mutagenesis. Molecular dynamic simulations with pregnenolone, 17-OH
      pregnenolone, progesterone, and 17-OH-progesterone docked into the substrate
      binding pocket demonstrated that regioselectivity of the hydroxylation reactions
      is determined both by proximity of hydrogens to the iron-oxo complex and by the
      stability of the carbon radicals generated after hydrogen abstraction. The model
      explains the activities of all known naturally occurring and synthetic human
      P450c17 mutants. The model predicted that mutation of lysine 89 would disrupt
      17,20-lyase activity to a greater extent than 17alpha-hydroxylase activity;
      expression of a test mutant, K89N, in yeast confirmed this prediction. Hydrogen
      peroxide did not support catalysis of the 17,20-lyase reaction, as would be
      predicted by mechanisms involving a ferryl peroxide. Our present model and
      biochemical data suggest that both the hydroxylase and lyase activities proceed
      from a common steroid-binding geometry by an iron oxene mechanism. This model
      will facilitate studies of sex steroid synthesis and its disorders and the design
      of specific inhibitors useful in chemotherapy of sex steroid-dependent cancers.

PMID- 10406468
TI  - Identification of a retinoic acid-inducible element in the murine PTH/PTHrP
      (parathyroid hormone/parathyroid hormone-related peptide) receptor gene.
AB  - We have shown previously that the PTH/PTHrP (PTH-related peptide) receptor mRNA
      becomes expressed very early in murine embryogenesis, i.e. during the formation
      of extraembryonic endoderm. Retinoic Acid (RA) is a potent inducer of
      extraembryonic endoderm formation and PTH/PTHrP-receptor expression in embryonal
      carcinoma (EC) and embryonal stem (ES) cells. Using the P19 EC cell line, we have
      characterized promoter elements of the murine PTH/PTHrP-receptor gene that are
      involved in this RA-induced expression. The data show that RA-induced expression
      of the PTH/ PTHrP-receptor gene is mediated by the downstream P2 promoter.
      Analysis of promoter reporter constructs in transiently transfected P19 cells
      treated with RA identified an enhancer region between nucleotides -2714 and -2702
      upstream of the P2 transcription start site that is involved in the RA effect.
      This region matches a consensus hormone response element consisting of a direct
      repeat with an interspacing of 1 bp (R-DR1). The R-DR1 efficiently binds retinoic
      acid receptor-alpha (RARalpha)-retinoid X receptor-alpha (RXRalpha) and chicken
      ovalbumin upstream promoter (COUP)-transcription factor I (TFI)-RXRalpha
      heterodimers and RXRalpha and COUP-TFI homodimers in a bandshift assay using
      extracts of transiently transfected COS-7 cells. RA differentiation of P19 EC
      cells strongly increases protein binding to the R-DR1 in a band-shift assay. This
      is caused by increased expression of RXR (alpha, beta, or gamma) and by the
      induction of expression of RARbeta and COUP TFI/TFII, which bind to the R-DR1 as
      shown by supershifting antibodies. The presence of RXR (alpha, beta, or gamma) in
      the complexes binding to the R-DR1 suggests that RXR homodimers are involved in
      RA-induced expression of the PTH/PTHrP-receptor gene. The importance of the R-DR1
      for RA-induced expression of PTH/ PTHrP-receptor was shown by an inactivating
      mutation of the R-DR1, which severely impairs RA-induced expression of PTH/PTHrP
      receptor promoter reporter constructs. Since this mutation does not completely
      abolish RA-induced expression of PTH/PTHrP-receptor promoter reporter constructs,
      sequences other than the R-DR1 might also be involved in the RA effect. Finally,
      we show that the RA-responsive promoter region is also able to induce expression
      of a reporter gene in extraembryonic endoderm of 7.5 day-old transgenic mouse
      embryos.

PMID- 10406470
TI  - Functional analysis of the mouse ICER (Inducible cAMP Early Repressor) promoter:
      evidence for a protein that blocks calcium responsiveness of the CAREs (cAMP
      autoregulatory elements).
AB  - Although Ca2+ and cAMP mediate their effects through distinct pathways, both
      signals converge upon the phosphorylation of the cAMP response element (CRE)
      binding protein, CREB, thereby activating transcription of CRE-regulated genes.
      In WEHI7.2 thymocytes, cAMP increases the expression of the inducible cAMP early
      repressor (ICER) gene through CRE-like elements, known as cAMP autoregulatory
      elements (CAREs). Because Ca2+ -and cAMP-mediated transcription converge in
      WEHI7.2 thymocytes, we examined the effect of Ca2+ fluxes on the expression of
      the ICER gene in these cells. Despite the presence of multiple CAREs within its
      promoter, ICER gene transcription was not activated by Ca2+. Moreover, Ca2+
      attenuated the stimulatory effect of cAMP on ICER expression. Transient
      expression of reporter constructs demonstrated that when these CAREs were placed
      in a different DNA promoter context, the elements became responsive to Ca2+.
      Detailed studies using chimeric promoter constructs to map the region responsible
      for blocking the transcriptional response to Ca2+ indicated that a small portion
      of the ICER promoter was necessary for the effect. Southwestern blot analysis
      identified a 83-kDa nuclear protein that bound specifically to that region. The
      relative binding activity of the factor to the ICER promoter and mutant promoter
      sequences correlated with an inhibition of Ca2+ -activated gene expression in
      WEHI7.2 cells. These data suggest that the factor functions as a putative Ca2+ 
      activated repressor of CREB/CRE-mediated transcription. Thus, depending on the
      surrounding context in which the CRE is located, CREs of individual genes can be
      regulated separately by Ca2+ and cAMP despite the convergence of these two
      signaling pathways.

PMID- 10406469
TI  - Cloning of interferon-stimulated gene 17: the promoter and nuclear proteins that
      regulate transcription.
AB  - A member of the interferon-stimulated gene (ISG) family encodes a 17-kDa
      ubiquitin homolog called ISG17 that is induced in the bovine uterine endometrium
      by interferon-tau (IFN-tau) during early pregnancy. The bovine (b) ISG17 cDNA
      shares 30% identity with a tandem ubiquitin repeat and 70% identity with human
      (h) ISG15. The present experiments were designed to sequence the bISG17 gene,
      compare general structure with the hISG15 gene, and to identify transcription
      factors that were induced by IFN-tau in bovine endometrial (BEND) cells. The
      promoter of the bISG17 gene was similar to the hISG15 gene in placement of a
      tandem IFN-stimulatory response element (ISRE) at position -90, but unique in the
      presence of three additional ISREs at positions -123, -332, and -525. IFN-tau (25
      nM) induced nuclear proteins in BEND cells that interacted with a tandem bISG17
      ISRE in electrophoretic mobility shift assay (EMSA). IFN-regulatory factor-1 (IRF
      1) bound to this ISRE based upon supershift EMSA using antiserum against IRF-1.
      IFN-tau activated STAT-1 (signal transducer and activator of transcription-1) and
      -2 by 0.5 h, and IRF-1 by 2 h in BEND cells. It is concluded that the bISG17 gene
      is similar to the hISG15 gene, retains an ISRE that interacts with IRF-1, and is
      possibly induced initially by the STATs and later by IRF-1 in response to IFN-tau
      during early pregnancy.

PMID- 10406471
TI  - In vitro laser welding of amniotic membranes.
AB  - OBJECTIVE: To test in vitro the feasibility of welding amniotic membranes using
      Nd:YAG laser energy. STUDY DESIGN: Fresh fetal membranes from term pregnancies
      were washed and cut into 1 cm2 pieces. Pooled cryoprecipitate (CPT), 50% albumin
      (Alb), or polytetrafluoroethilene (e-PTFE) were used as solder medium. The
      optimal settings of the laser were determined. Results were assessed
      quantitatively and semi-quantitatively using Pearson Chi-square analysis.
      RESULTS: Laser welding of amniotic membranes was successful in 82.6% of
      experiments with e-PTFE and in 10.7% of experiments with CPT (P < 0.001). The
      strength of the welding was also significantly better with e-PTFE (P < 0.001).
      Optimal results were obtained using 1-7 Watts and 0.1-1 seconds. Laser welding
      was unsuccessful in 100% of experiments with Alb. CONCLUSIONS: Laser welding of
      fetal membranes can be accomplished with e-PTFE and to a lesser degree with the
      CPT using Nd:YAG energy under low wattage-high exposure settings. Further studies
      are underway to test other grafting or soldering materials.

PMID- 10406472
TI  - Optimal parameters for laser tissue soldering. Part I: tensile strength and
      scanning electron microscopy analysis.
AB  - BACKGROUND AND OBJECTIVES: The use of liquid and solid albumin protein solders to
      enhance laser tissue repairs has been shown to significantly improve
      postoperative results. The published results of laser-solder tissue repair
      studies have, however, indicated inconsistent success rates. This can be
      attributed to variations in laser irradiance, exposure time, solder composition,
      chromophore type, and concentration. An in vitro study was performed using
      indocyanine green-doped albumin protein solders in conjunction with an 808 nm
      diode laser to determine optimal laser and solder parameters for tissue repair in
      terms of tensile strength and stability during hydration. STUDY DESIGN/MATERIALS
      AND METHODS: Twenty-five different combinations of laser irradiance (6.4, 12.7,
      19.1, 25.5, 31.8 W/cm2) and exposure time (20, 30, 40, 50, 100 or 40, 60, 80,
      100, 200 seconds) were used. The effect of changing bovine serum albumin (BSA)
      concentration (25% and 60%) and indocyanine green (ICG) dye concentration (2.5
      mg/ml and 0.25 mg/ml) of the protein solder on the tensile strength of the
      resulting bonds was investigated. The effect of hydration on bond stability was
      also investigated using both tensile strength and scanning electron microscopy
      analysis. RESULTS: Tensile strength was observed to decrease significantly with
      increasing irradiance. An optimum exposure time was found to exist where further
      irradiation did not improve the tensile strength of the bond. Tensile strength
      was found to be greatly improved by increasing the BSA concentration. Finally,
      the lower ICG dye concentration increased the penetration depth of the laser
      light in the protein solder leading to higher tensile strengths. The strongest
      repairs were formed by using 6.4 W/cm2 irradiation for 50 seconds with a protein
      solder composed of 60% BSA and 0.25mg/ml ICG. In addition, the solid protein
      solder provided more stable adhesion to the tissue than did the liquid protein
      solder when the tissue was submerged in a hydrated environment. CONCLUSIONS: This
      study greatly enhances the current understanding of the various factors affecting
      the soldering process. It provides a strong basis for optimization of the laser
      light delivery parameters and the solder constituents to achieve strong and
      reliable laser tissue repairs.

PMID- 10406473
TI  - Long-pulsed alexandrite laser-assisted hair removal at 5, 10, and 20 millisecond
      pulse durations.
AB  - BACKGROUND: Several laser systems with varying wavelengths, pulse durations, and
      energy fluences are currently utilized for hair removal. However, the ideal laser
      parameters and treatment candidates for photoepilation remain largely unknown.
      The medical literature lacks a wealth of experimental data to sufficiently
      document the long-term safety and efficacy of laser-assisted hair removal. This
      study examines the clinical efficacy and side effect profile of long-pulsed
      alexandrite laser-assisted hair removal utilizing laser pulse durations of either
      5, 10, or 20 milliseconds (ms). STUDY DESIGN/METHODS: Laser-assisted hair removal
      was performed on 36 subjects with a long-pulsed alexandrite laser. Areas of
      unwanted hair growth on the face, back, and legs were divided linearly into four
      1 cm2 or 2 cm2 quadrants. Experimental regions included a control quadrant and
      three additional quadrants, which were treated with the alexandrite laser using
      an average fluence of 18 J/cm2, with a 10 mm spot size at either a 5, 10, or 20
      ms pulse duration. Hair counts and photographs were obtained before treatment,
      immediately following irradiation, 1 week and 1, 3, and 6 months postoperatively.
      RESULTS: All laser-treated quadrants displayed a significant delay in hair
      regrowth compared to control nontreated quadrants at postoperative week 1 and
      months 1 and 3. Hair counts were reduced by 66% at 1 month, 27% at 3 months, and
      4% at 6 months. No significant differences in clinical efficacy or side effect
      profiles were observed between treatment quadrants, yet a trend towards less post
      treatment erythema and hyperpigmentation was noted with the 20 ms pulse duration.
      CONCLUSIONS: Equivalent long-term hair removal for up to 6 months was achieved
      with the long-pulsed alexandrite laser at 5, 10, and 20 ms pulse durations at an
      average fluence of 18 J/cm2. Side effects were limited and transient.

PMID- 10406474
TI  - Quantitative fluorescein angiography following diode laser retinal
      photocoagulation.
AB  - OBJECTIVE: An in vivo study was done to establish if laser-induced damage of the
      retina could be quantified using fluorescein angiography. METHOD: This study was
      carried out on rabbit eyes (n = 6) with an 810 nm diode laser (spot diameter: 500
      microm, pulse duration: 1 second, power: 100 mW-400 mW) adapted on a slit lamp.
      Fluorescence measurements were performed with a fundus camera connected to a
      fluorescence imaging system. Fluorescence staining of the retina was evaluated by
      mathematical modeling. Lesions were correlated to laser parameters and to
      histologic data. RESULTS: Image analysis shows that the laser lesions stained
      progressively. Fluorescence appears first at the borders of the lesion exhibiting
      a fluorescent ring. A progressive increase of the fluorescence into the central
      zone is observed. The maximum fluorescence intensity into the center of the laser
      spot is obtained after a delay depending on the laser energy. Below 100 +/- 20
      mW, lesions are detectable by fluorescence imaging only. A fluorescence plateau
      appears for a threshold light dose above 200 +/- 20 mW. Mathematical modeling
      demonstrates that quantitative assessment of laser-induced damage to the retina
      is feasible using fluorescence imaging. CONCLUSION: The quantification of
      fluorescence staining in terms of both intensity and time can contribute to a
      better quantification of laser-induced damage. At last, since laser damage may
      mimic naturally occurring pathology, this method should also be considered to
      quantify different types of lesions.

PMID- 10406475
TI  - Detection of transplant vasculopathy in a rat aortic allograft model by
      fluorescence spectroscopic optical analysis.
AB  - BACKGROUND AND OBJECTIVE: Transplant vasculopathy is a leading cause of late
      cardiac graft loss. We have examined laser-induced fluorescence (LIF)
      spectroscopy as an optical diagnostic tool for detection of intimal plaque
      development and inflammatory cellular invasion in a rat model of aortic allograft
      transplant. STUDY DESIGN/MATERIALS AND METHODS: Infrarenal aortic segments were
      transplanted from Lewis to Sprague Dawley rats. A range of vasculopathy
      development was produced by treatment with a viral anti-inflammatory protein. LIF
      spectra were recorded from the intima of aortic implants at 28 days. Fluorescence
      intensity was analyzed for correlation with vasculopathy development. RESULTS:
      Significant differences in LIF intensity at 400-450 nm (P < or = 0.05 by ANOVA)
      were detected. LIF emission was correlated with plaque growth (R2 = 0.980),
      vessel narrowing (R2 = 0.964), and cellular invasion (R2 = 0.971) by regression
      analysis. CONCLUSION: LIF optical analysis provides a nontraumatic diagnostic
      approach for detection of atherosclerosis prior to cardiac transplant or during
      development of vasculopathy after transplant.

PMID- 10406476
TI  - Promotional effects of CO2 laser on DMBA-induced hamster buccal pouch
      carcinogenesis as shown by immunohistochemistry of the placental form of
      glutathione S-transferase.
AB  - BACKGROUND AND OBJECTIVE: The purpose of the present study was to investigate the
      kinetics of the expression of the placental form of glutathione S-transferase
      (GST-P), a useful marker of premalignant lesions, and cell proliferation after
      CO2 laser surgery on the carcinogen-initiated epithelium. STUDY DESIGN/MATERIALS
      AND METHODS: CO2 laser incisions were made on buccal pouch epithelium of 36
      hamsters after initiation by 9,10-dimethyl-1,2-benzanthracene (DMBA) (group 1,
      G1), and scalpel incisions were similarly made on 33 animals (group 2, G2).
      Twenty animals not treated further after initiation were used as DMBA-treated
      controls. Incidence of malignant transformation, expression of GST-P, and cell
      proliferation were examined. RESULTS: The incidence of malignant transformation
      in G1 and G2 increased significantly (G1: P < 0.001; G2: P < 0.05) compared with
      that in DMBA-treated controls. GST-P expression of hyperplasia in G1 and G2
      decreased significantly (P < 0.001) compared with that in DMBA-treated controls.
      In hyperplasia, cell proliferation of the GST-P-negative area was significantly
      (P < 0.001) higher than that of the GST-P-positive area. CONCLUSION: The
      incisions, particularly by the CO2 laser, on the initiated areas made expression
      of GST-P decrease and cell proliferation increase in the GST-P-negative areas.
      These incisions may serve to promote malignant transformation.

PMID- 10406477
TI  - A preliminary study of healing of superpulsed carbon dioxide laser incisions in
      the hard palate of monkeys.
AB  - BACKGROUND AND OBJECTIVE: Prior studies of laser wound healing using different
      animal models have shown a delayed tissue response after carbon dioxide (CO2)
      laser application. This article reports on the preliminary findings of healing of
      superpulsed CO2 laser and scalpel incisions in the hard palate of monkeys. STUDY
      DESIGN/MATERIALS AND METHODS: Twelve parallel incisions using a superpulsed,
      continuous wave CO2 laser and a scalpel were performed in the hard palate of each
      of two adult monkeys at 3, 7, and 14 days time schedules. Power levels of 2.0,
      4.0, and 6.0 Watts were used for the laser incisions. Wounds were harvested,
      fixed in 10% formalsaline for at least 48 hours and processed routinely. Each
      specimen was embedded in paraffin wax at 90 degrees to the surface epithelium and
      5 microm thick sections prepared for staining with haematoxylin and eosin,
      Periodic acid Schiff and Masson-trichrome at a step-serial interval of 100
      microm. Sections were evaluated independently. RESULTS: According to the clinical
      findings we showed a wound closure in all of the wounds (laser and scalpel
      incisions) at 3, 7, and 14 days of healing. Histologically, we showed that laser
      incisions at three and seven days demonstrated an increased, power setting
      dependent tissue necrosis and marked inflammatory response with minimal
      organization compared to scalpel incisions. At 14 days both types of incisions
      exhibited complete wound healing of the epithelium and connective tissue.
      DISCUSSION AND CONCLUSIONS: According to these preliminary results, superpulsed
      CO2 laser tends to produce more pronounced changes (due to tissue thermal damage)
      with corresponding greater inflammatory reaction and delay in tissue organization
      only initially.

PMID- 10406478
TI  - Photodynamic modulation of wound healing with BPD-MA and CASP.
AB  - BACKGROUND AND OBJECTIVE: Wound healing is an intricate process requiring the
      orchestration of cells, growth factors, cytokines, and the extracellular matrix.
      Cytokines, specifically TGF-beta, are believed to be instrumental in sustaining
      the fibrotic process, which leads to scarring. Photodynamic therapy (PDT) uses
      potent photosensitizers, which induce a wide range of effects on cells and the
      extracellular matrix. The influences of PDT on wound healing are not well known.
      STUDY DESIGN/MATERIALS AND METHODS: Seven full-thickness incisional wounds were
      placed on each of 24 hairless Sprague Dawly rats, three wounds on one flank
      serving as dark controls and four on the contralateral side treated with PDT.
      Wounds were created two days before, one hour before, or one hour after red light
      exposure with an argon ion pumped dye laser. Twelve rats were injected with 0.25
      mg/kg or 0.5 mg/kg of the PDT drug, BPD-MA, and the other 12 with 5 mg/kg or 10
      mg/kg of the PDT drug, CASP, 3 and 24 hours prior to irradiation of light,
      respectively. At low doses of both photosensitizers, animals were irradiated with
      1, 5, 10, and 20 J/cm2. At higher doses of BPD-MA and CASP animals were treated
      with 10, 20, 50, and 100 J/cm2 of light. Wounds were examined each day for 14
      days and noted for edema, erythema, inflammation, necrosis, and quality of
      scarring. Wounds were also photographed at day 0, 2, 5, 8, and 14 post
      irradiation. All animals were sacrificed 14 days after irradiation and the wounds
      were evaluated by light microscopy. RESULTS: Grossly, animals treated with 0.25
      mg/kg BPD-MA showed no effect with PDT. Animals treated with 0.5 mg/kg BPD, and 5
      and 10 mg/kg CASP showed responses that varied with both light and drug dose.
      Erythema, edema, inflammation, and necrosis attributed to PDT were all observed,
      but there was no apparent influence of PDT on either the rate or final appearance
      of wound healing. Histologically, there were no apparent differences between
      treated and untreated sites, regardless of the drug, dose of light, or time of
      irradiation. CONCLUSION: A single PDT treatment given before or after skin wounds
      does not apparently alter wound healing even when PDT caused brisk inflammatory
      reactions. PDT may have effects that were not detected. We conclude that PDT does
      not greatly influence incisional skin wound healing in the rat model.

PMID- 10406479
TI  - Factor analysis of cancer Fourier transform infrared evanescent wave fiberoptical
      (FTIR-FEW) spectra.
AB  - BACKGROUND AND OBJECTIVE: The purpose of this study is to isolate pure
      biochemical compounds' eigenspectra and to classify skin cancer tumors. STUDY
      DESIGN/MATERIALS AND METHODS: Fourier transform infrared fiberoptic evanescent
      wave (FTIR-FEW) spectra, in the middle infrared (MIR) region, of human normal
      skin tissue and cancer tumors were analyzed using chemical factor analysis.
      RESULTS: Eigenspectra of biochemical species were isolated and some of the
      eigenspectra have been preliminarily identified as due to protein peptide bond
      and lipid carbonyl vibrations. Cluster analysis was used for classification and
      good agreement with prior pathological classifications, specifically for normal
      skin tissue and melanoma tumors, has been found. However the cluster analysis
      suggests substantial variability in basaloma tumor biochemical characteristics.
      In addition this study has demonstrated that chemical factor analysis can be
      carried out directly on raw data to extract biochemical component eigenspectra
      and classify skin states. Most importantly, it has been demonstrated that the
      combination of FTIR-FEW technique and chemical factor analysis has potential as a
      clinical diagnostic tool.

PMID- 10406480
TI  - The structure of the nuclear hormone receptors.
AB  - The functions of the group of proteins known as nuclear receptors will be
      understood fully only when their working three-dimensional structures are known.
      These ligand-activated transcription factors belong to the steroid-thyroid
      retinoid receptor superfamily, which include the receptors for steroids, thyroid
      hormone, vitamins A- and D-derived hormones, and certain fatty acids. The
      majority of family members are homologous proteins for which no ligand has been
      identified (the orphan receptors). Molecular cloning and structure/function
      analyses have revealed that the members of the superfamily have a common
      functional domain structure. This includes a variable N-terminal domain, often
      important for transactivation of transcription; a well conserved DNA-binding
      domain, crucial for recognition of specific DNA sequences and protein:protein
      interactions; and at the C-terminal end, a ligand-binding domain, important for
      hormone binding, protein: protein interactions, and additional transactivation
      activity. Although the structure of some independently expressed single domains
      of a few of these receptors have been solved, no holoreceptor structure or
      structure of any two domains together is yet available. Thus, the three
      dimensional structure of the DNA-binding domains of the glucocorticoid, estrogen,
      retinoic acid-beta, and retinoid X receptors, and of the ligand-binding domains
      of the thyroid, retinoic acid-gamma, retinoid X, estrogen, progesterone, and
      peroxisome proliferator activated-gamma receptors have been solved. The secondary
      structure of the glucocorticoid receptor N-terminal domain, in particular the
      taul transcription activation region, has also been studied. The structural
      studies available not only provide a beginning stereochemical knowledge of these
      receptors, but also a basis for understanding some of the topological details of
      the interaction of the receptor complexes with coactivators, corepressors, and
      other components of the transcriptional machinery. In this review, we summarize
      and discuss the current information on structures of the steroid-thyroid-retinoid
      receptors.

PMID- 10406481
TI  - Synthesis of 19-oxygenated derivatives of the competitive inhibitor of aromatase,
      5-androstene-4,17-dione.
AB  - 19-Hydroxy- and 19-oxo-steroids 13 and 15, respectively, which are potential
      metabolites of the aromatase inhibitor 5-androstene-4,17-dione (3), were
      synthesized from 19-(tert-butyldimethylsilyloxy)androst-5-en-17-one (5) or 4beta
      acetoxyandrost-5-en-17-one (16), respectively, through 5alpha-bromo-4beta-hydroxy
      6beta,19-epoxyandrostan+ ++-17-one (10) as a key intermediate in each sequence.
      Reaction of the 19-siloxy compound 5 with Br2 gave 5alpha-bromo-6beta,19-epoxide
      8, which was treated with N,N'-dimethylacetamide followed by reaction with N
      bromoacetamide and 0.28 M HCIO4, to yield compound 10. On the other hand,
      treatment of the 4beta-acetoxy steroid 16 with N-bromoacetamide-HCI04 followed by
      oxidation with Pb (IV) acetic acid and I2 under irradiation and subsequent
      hydrolysis with K2CO3 also produced compound 10 and in better yield than that in
      the above synthesis. Jones oxidation of the 4beta-ol 10 followed by reductive
      debromination with zinc dust yielded the 19-ol 13 in low yield as well as
      6beta,19-epoxy-4-one 12 as the major product. Furthermore, the major product 12
      was converted into the 19-ol 13 in moderate yield from compound 12 through
      acetolysis and subsequent alkaline hydrolysis. The 19-oxo steroid 15 was obtained
      after treatment of compound 13 with pyridinium dichromate. Compounds 13 and 15
      were analyzed as the methoxime-trimethylsilyl and methoxime
      dimethylisopropylsilyl derivatives and the methoxime derivative, respectively,
      using gas chromatography-mass spectrometry.

PMID- 10406482
TI  - Xenoestrogen interaction with human sex hormone-binding globulin (hSHBG).
AB  - This study reports on some environmental chemicals with estrogenic activity
      (xenoestrogens) and their binding interaction for human plasma sex-hormone
      binding globulin (hSHBG). The binding affinity constant of these xenoestrogens
      was measured in equilibrium conditions by solid phase binding assay, and their
      ability to displace endogenous testosterone and estradiol from hSHBG binding
      sites was determined with an ammonium sulfate precipitation assay in native
      plasma from normal men and women. The data showed that some of these
      xenoestrogens bind hSHBG, with a reversible and competitive binding activity for
      both [3H]testosterone and [3H]17beta-estradiol and with no apparent decrease in
      the number of hSHBG binding sites. Their respective binding affinity constants
      were low, ranging from 0.02 to 7.8 10(5) 1 x mol(-1). However, in native plasma
      from normal men and women, they were able to dose-dependently increase
      concentrations of hSHBG-unbound testosterone and/or estradiol. In this study, 4
      nonylphenol and 4-tertoctylphenol, two alkylphenols used as surfactants in many
      commercial products, and bisphenol A and O-hydroxybiphenyl, widely used in the
      plastics industry, were identified as potent hSHBG-ligands. Additionally, the
      flavonoid phytoestrogens genistein and naringenin were also identified as hSHBG
      ligands, whereas their glucoside derivatives, genistin and naringin, had no
      binding activity for hSHBG. From these data, it is suggested that hSHBG binding
      may transport some contaminant xenoestrogens into the plasma and modulate their
      bioavailability to cell tissues. On the other hand, xenoestrogens may also
      displace endogenous sex steroid hormones from hSHBG binding sites and disrupt the
      androgen-to-estrogen balance. Whether xenoestrogen SHBG ligands could reach high
      enough concentrations in the blood to expose humans to any such effect merits
      further investigation.

PMID- 10406483
TI  - Evaluation of the antiviral activity of natural sulfated polyhydroxysteroids and
      their synthetic derivatives and analogs.
AB  - Disodium 3beta,21-dihydroxypregn-5-en-20-one disulfate (2), sodium 3beta,21
      dihydroxypregn-5-en-20-one 3-sulfate (3), sodium 3beta,21-dihydroxypregn-5-en-20
      one 21-sulfate (4), and disodium 3beta,6alpha-dihydroxy-5alpha-pregnan-20-one
      disulfate (6) have been synthesized and completely characterized for the first
      time from readily available materials. Sulfation was performed using
      triethylamine-sulfur trioxide complex in dimethylformamide as the sulfating
      agent. Selective sulfation of 3beta,21-dihydroxypregn-5-en-20-one rendered sodium
      3beta,21-dihydroxypregn-5-en-20-one 3-sulfate (3) as the major compound. The
      synthetic sulfated steroids as well as natural disulfated polyhydroxysteroids (7
      9) isolated by us from the antarctic ophiuroid Astrotoma agassizii and the
      synthetic derivatives disodium 2beta,3alpha,21-trihydroxy-(20R)-cholesta-5,24
      diene 3-acetate, 2,21-disulfate (7a) and 2beta,3alpha,21-trihydroxy-(20R)
      cholesta-5,24-diene (7b) were comparatively evaluated for their inhibitory effect
      on the replication of one DNA (HSV-2) and two RNA (PV-3, JV) viruses. In general,
      steroids with sulfate groups at C-21 and C-2 or C-3 were the most effective in
      their inhibitory action against HSV-2 and also proved to be active against PV-3
      and JV.

PMID- 10406484
TI  - Elimination of cross-reactivity by addition of an excess of cross-reactant for
      radioimmunoassay of 17alpha-hydroxypregnenolone.
AB  - Polyclonal antiserum against 3beta,17alpha-dihydroxypregn-5-en-20-one-19-O
      (carboxymethyl )-oxime bovine serum albumin (17alpha-hydroxypregnenolone-19
      CMO:BSA), was raised in rabbits. Its main structural determinants were the
      substituents on D-ring as demonstrated by its 107% cross-reaction with 17alpha
      hydroxyprogesterone. This unspecificity was almost completely eliminated by
      addition of the excess of the cross-reactant directly to the analytical system.
      The contribution of the cross-reactant from the sample in such a system became
      negligible due to saturation of the populations of polyclonal antibodies
      recognizing the analyte as well as the cross-reactant. The possible interference
      of 17alpha-hydroxypregnenolone-3-sulfate was avoided by inserting ether
      extraction. The analytical system appeared to be stable to differences in cross
      reactant concentrations even in samples from patients with pathologically
      elevated serum levels of 17alpha-hydroxyprogesterone. The radioimmunoassay was
      compared with the system using the unspecific antiserum alone, but after
      separation of the cross-reactants by HPLC. As demonstrated by parallel
      measurement of 125 samples of human plasma from both sexes and various ages
      either before and/or after adrenocorticotropin stimulation and 17 samples with
      elevated basal of human plasma 17alpha-hydroxyprogesterone levels, an excellent
      correlation was achieved between both methods. The method, based on a simple
      addition of the cross-reactant, avoids the time-consuming chromatographic
      separation and, in comparison with the other approaches for improving the
      specificity of polyclonal antisera, is efficient and rapid. Mathematical analysis
      of the relations in equilibrium demonstrates that such a simple approach is an
      efficient way for improvement of immunoassay specificity using some polyclonal
      antisera.

PMID- 10406485
TI  - Site-directed mutagenesis studies of the NADPH-binding domain of rat steroid
      5alpha-reductase (isozyme-1) I: analysis of aromatic and hydroxylated amino acid
      residues.
AB  - Previous studies have shown that the reduced nicotinamide adenine dinucleotide
      phosphate (NADPH)- binding domain of rat liver microsomal steroid 5alpha
      reductase isozyme-1 (r5alphaR-1) is in a highly conserved region of the
      polypeptide sequence (residues 160-190). In this study, we investigated, by site
      directed mutagenesis, the role of hydroxylated and aromatic amino acids within
      the NADPH-binding domain. The r5alphaR-1 cDNA was cloned into a pCMV vector, and
      the double strand site-directed mutagenesis method was used to create mutants
      Y179F, Y179S, Y189F, Y189S, S164A, S164T, and Y187F, which were subsequently
      expressed in COS-1 cells. Kinetic studies of the expressed enzymes showed that
      the mutation Y179F resulted in an approximately 40-fold increase in the Km for
      NADPH versus wild-type, with only a 2-fold increase in the Km for testosterone.
      The mutants Y189F and S164A showed smaller increases (4 and 6-fold) in Kms for
      NADPH and no significant change in the Km for testosterone, whereas Y189S had
      kinetic properties similar to the wild-type r5alphaR-1. Mutants Y179S and S164T
      both resulted in inactive enzymes, whereas F187Y showed an approximately 5-fold
      decrease in Km for NADPH and a significant increase (approximately 18-fold) in
      the Km for testosterone. The results suggest that the -OH functionality of Y179
      is involved in cofactor binding, but is not essential for the activity of the
      enzyme, whereas the -OH functionalities of Y189 and S164 play lesser roles in
      cofactor binding to r5alphaR-1 and may not be required for enzyme activity. On
      the other hand, the residue F187 may be important for the binding of both NADPH
      and testosterone.

PMID- 10406486
TI  - Synthesis of 6- and 7-hydroxyestradiol 17-sulfates: the potential metabolites of
      estradiol 17-sulfate by female rat liver microsomes.
AB  - The potential ring-B hydroxylated metabolites of estradiol 17-sulfate (1) by
      female rat liver microsomes were chemically prepared as authentic compounds. They
      are 6alpha- and 6beta-hydroxyestradiol 17-sulfates (7 and 9), and 7alpha- and
      7beta-hydroxyestradiol 17-sulfates (12 and 16), whose synthetic procedures are
      described.

PMID- 10406487
TI  - Peritoneal dialysis: global update.

PMID- 10406488
TI  - Adequacy, nutrition, and clinical outcomes.

PMID- 10406489
TI  - Are adequacy targets for peritoneal dialysis meaningful?

PMID- 10406490
TI  - Is target Kt/V and patient survival different between Asian and Western
      continuous ambulatory peritoneal dialysis (CAPD) patients?

PMID- 10406491
TI  - Peritoneal dialysis: adequacy beyond Kt/V.

PMID- 10406492
TI  - Critical interpretation of adequacy parameters in peritoneal dialysis and
      hemodialysis.

PMID- 10406493
TI  - Pathogenic role of advanced glycation end-products (AGEs): an overview.

PMID- 10406494
TI  - AGE accumulation in peritoneal membrane and cavity during peritoneal dialysis and
      its effect on peritoneal structure and function.

PMID- 10406495
TI  - Carbonyl stress: increased carbonyl modification of tissue and cellular proteins
      in uremia.
AB  - Advanced glycation end-products (AGEs) are formed during non enzymatic glycation
      and oxidation (glycoxidation) reactions. This process is accelerated in diabetics
      owing to hyperglycemia, and it has been implicated in the pathogenesis of
      diabetic complications. Surprisingly, AGEs increase in normoglycemic uremic
      patients to a much greater extent than in diabetics. AGE accumulation in uremia
      cannot be attributed to hyperglycemia nor simply to a decreased removal by
      glomerular filtration. Recently gathered evidence has suggested that, in uremia,
      the increased carbonyl compounds derived from carbohydrates and lipids modify
      proteins not only by glycoxidation reaction but also by lipoxidation reaction
      ("carbonyl stress"). Carbonyl stress has been implicated in the pathogenesis of
      long-term uremic complications such as dialysis-related amyloidosis. With regard
      to continuous ambulatory peritoneal dialysis (CAPD), the peritoneal cavity
      appears to be in a state of severe overload of carbonyl compounds derived from
      CAPD solution containing high glucose, from heat sterilization of the solution,
      and from uremic circulation. Carbonyl stress might modify not only peritoneal
      matrix proteins and alter their structures, but also react with mesothelial and
      endothelial cell surface proteins and initiate a range of inflammatory responses.
      Carbonyl stress might therefore contribute to the development of peritoneal
      sclerosis in patients with long-term CAPD.

PMID- 10406496
TI  - Pharmacological modulation of AGEs: a unique role for redox-active metal ions.

PMID- 10406497
TI  - Analysis of non enzymatic glycosylation in vivo: impact of different dialysis
      solutions.
AB  - BACKGROUND: Glucose-containing dialysis solutions in peritoneal dialysis (PD)
      patients induce non enzymatic glycosylation (NEG) within the peritoneal cavity.
      The subsequent formation of advanced glycosylation end-products (AGEs) may be
      implicated in the functional deterioration of the peritoneal membrane in long
      term PD patients. AIM OF THE STUDY AND PARAMETERS: Measurement of NEG by the
      determination of percent glycation of albumin and IgG (GP), and of AGEs by
      measuring pentosidine content of protein in 4-hour effluents (Peff) and serum.
      SUBJECTS: In 5 patients each, a comparison was made between 3.86% glucose and
      1.36% glucose (GP and Peff), and between 3.86% glucose and 7.5% icodextrin
      (Peff). Nine patients with clinically severe ultrafiltration failure (UFF) were
      compared to nine patients treated with PD for 1 month. Six of the patients with
      UFF were treated with non glucose dialysis solutions and Peff was studied again
      after 6 weeks. RESULTS: No difference was found between Peff comparing 3.86%
      glucose to either 1.36% glucose or icodextrin. GP were higher in 3.86% glucose
      than in 1.36%. Glycated/non glycated (G/NG) protein clearance ratios were 1.29
      for albumin and 1.12 for IgG (p = 0.003). In contrast to GP, both Peff and serum
      pentosidine were higher in the UFF patients than in the recently started
      patients. Peff, but not GP, correlated with duration of PD (r = 0.67, p = 0.04).
      In 5 of 6 patients treated with non glucose dialysate, Peff decreased while serum
      pentosidine was stable. DISCUSSION: These data show that 4-hour Peff contents are
      not influenced by glucose concentration or osmolality, in contrast to GP. The
      relation between Peff and duration of PD, and the effect of non glucose dialysate
      on Peff, suggest that long-term glucose exposure is an important determinant of
      membrane glycosylation. Thus Peff probably reflects the long-term effects of
      intraperitoneal glycosylation of peritoneal membrane proteins. Treatment with non
      glucose dialysis solutions may result in "washout" of glycosylated proteins from
      the peritoneal membrane.

PMID- 10406498
TI  - Changes in the peritoneal interstitium and their effect on peritoneal transport.
AB  - Transperitoneal transport is a complicated process that includes diffusion and
      convection across the walls of blood microvessels into tissue interstitium,
      transport through the interstitium, and final passage across the peritoneum to
      the dialysis solution in the cavity. The purpose of this paper is to briefly
      review the normal physiology of this process and then to summarize the events
      that occur in response to inflammation within the cavity. These events begin with
      stimulation of macrophages, which in turn secrete cytokines. The cytokines
      stimulate mesothelial cells and fibroblasts in the tissue to synthesize and
      secrete other mediators. Those mediators initiate the complex events through
      which leukocytes migrate from blood vessel lumens through the interstitium and
      into the cavity. Much of the available data is from model in vitro systems, and
      therefore in vivo events must be deduced or hypothesized.

PMID- 10406499
TI  - Alterations in water and solute transport with time on peritoneal dialysis.
AB  - Peritoneal ultrafiltration capacity and small-solute transport characteristics
      seem to be relatively stable in most patients treated with PD for up to 3 years.
      However, in patients treated with PD for 4 years or more, there is a tendency
      towards increasing diffusive transport for small solutes as well as a tendency
      towards decreasing net UF, whereas the peritoneal protein clearances seem to be
      reduced or stable. Loss of UFC is a well-known complication during long-term PD
      treatment, and the risk for loss of UFC may be as high as 50% after 6 years on
      PD. Several different mechanisms of UFC loss have been reported. In particular,
      the most common mechanism for loss of UFC is increased diffusive transport
      resulting in rapid glucose absorption and thus rapid loss of the osmotic driving
      force. Also reported as causes of UFC loss have been: reduced efficiency of the
      osmotic agent (perhaps owing to decreased transcellular water transport); loss of
      peritoneal surface area with slow solute transport owing to fibrosis and the
      formation of adhesions (during the late stage of sclerosing peritonitis); and
      increased peritoneal fluid absorption. In individual patients, a combination of
      several mechanisms may be involved in the apparent UFC failure.

PMID- 10406500
TI  - Impact of peritoneal membrane function on long-term clinical outcome in
      peritoneal dialysis patients.
AB  - It is increasingly clear that peritoneal membrane transport status has clinical
      implications. The role of the peritoneum in dialysis delivery becomes paramount
      once residual renal function is lost, particularly as the membrane
      characteristics may change for the worse with time on treatment. These findings
      have several important implications: Clinicians need to take solute transport
      characteristics into account as they assess their patients. Adverse effects of
      high solute transport include reduced ultrafiltration, solute removal (in
      particular, sodium), and increased peritoneal protein losses. A need exists to
      replace lost residual renal function, not just with enhanced solute removal, but
      also with adequate salt and water removal. The interpretation of urea and
      creatinine clearances in anuric PD patients needs further consideration and
      validation. Hypoalbuminemia in PD patients will result from the combined effects
      of high protein losses, over-hydration, comorbidity, and malnutrition.

PMID- 10406501
TI  - Role of transcellular water channels in peritoneal dialysis.

PMID- 10406502
TI  - Blood flow does not limit peritoneal transport.
AB  - OBJECTIVE: We investigated the assumption that blood flow to the microvessels
      underlying the peritoneum does not limit solute or water exchange between the
      blood and the dialysis fluid. DESIGN: Small plastic chambers were affixed to the
      serosal side of the liver, cecum, stomach, and abdominal wall of anesthetized
      rats. Solutions that contained labeled solutes or that were made hypertonic were
      placed into the chambers, which restricted the area of transfer across the tissue
      to the base of the chamber and which permitted calculation of mass or water
      transfer rates on the basis of area. The local blood flow was monitored
      continuously with a laser Doppler flowmeter during three periods of observation:
      control, after 50%-70% reduction of the blood flow, and postmortem. RESULTS: Urea
      transfer across all serosa, except for the liver, showed no difference in mean
      mass transfer coefficient (cm/min) between control (0.0038-0.0046) and after 70%
      flow reduction (0.0037-0.0040), but demonstrated a significant decrease with
      blood flow equal to zero (0.0020). These tissues demonstrated small but
      insignificant decreases in osmotic water flow into the chamber (0.7-0.9
      microL/min/cm2 under control conditions versus 0.4-0.7 microL/min/cm2 with
      reduced blood flow). The liver demonstrated limitations in water and solute
      transport with a 70% decrease in blood flow. CONCLUSION: Because the liver makes
      up a small part of the peritoneal area, we conclude that large drops in blood
      flow do not limit overall solute or water transfer across the peritoneum during
      dialysis, and therefore acute peritoneal dialysis may be an appropriate modality
      for ICU patients in shock and renal failure.

PMID- 10406503
TI  - Intraperitoneal addition of hyaluronan improves peritoneal dialysis efficiency.
AB  - BACKGROUND: It has been shown that hyaluronan (HA) can decrease peritoneal fluid
      absorption. It is not known, however, how various molecular weights and various
      concentrations of hyaluronan affect peritoneal fluid absorption rate. METHODS: A
      study of 4-hour dwells, with frequent dialysate and blood sampling, was performed
      in male Sprague-Dawley rats (6-7 rats in each group) with 131I albumin as an
      intraperitoneal volume marker. Each rat was infused intraperitoneally with 25 mL
      of 1.5% glucose solution alone or 1.5% glucose solution containing hyaluronan at
      various molecular weights (MW-85 kD, 280 kD, 500 kD, and 4 MD) or containing
      hyaluronan of MW 500 kD at various concentrations (0.01%, 0.05%, 0.1%, 0.5%). Two
      additional groups were infused with 40 mL of 1.36% glucose dialysate alone or
      1.36% glucose dialysate with 0.01% hyaluronan (MW 500 kD) to test the effect of
      hyaluronan when high dialysate fill volume was used. RESULTS: Addition of 0.01%
      hyaluronan significantly decreased peritoneal fluid absorption rate (K(E)) (by
      22%, p < 0.01). The decrease was more marked with hyaluronan at high MW or high
      concentration, or with high dialysate fill volume. The net ultrafiltration tended
      to be higher in all hyaluronan groups compared to their control groups except in
      the 4 MD group; this difference was mainly due to a lower K(E) in all the
      hyaluronan groups. The direct lymphatic flow was significantly decreased in the
      0.5% HA group. The transcapillary ultrafiltration rate (Qu) was significantly
      lower in the 4 MD group as compared to the control group. No difference in Qu was
      found between the other groups as compared to their control groups. CONCLUSIONS:
      (1) Intraperitoneal addition of hyaluronan may increase net peritoneal fluid
      removal, mainly because hyaluronan decreases peritoneal fluid absorption rate.
      The decrease was more marked when high dialysate fill volume was used, indicating
      that intraperitoneal addition of hyaluronan can prevent the decreased net
      ultrafiltration caused by an increase in dialysate fill volume. (2) The decrease
      in peritoneal fluid absorption rate may be both MW-dependent and concentration
      dependent: that is, a higher MW as well as a higher concentration of hyaluronan
      result in a more marked decrease in peritoneal fluid absorption rate. (3) Low
      concentrations of high MW hyaluronan may also decrease Qu. However, Qu did not
      decrease when high concentrations of hyaluronan were used despite a significant
      decrease in peritoneal fluid absorption rate.

PMID- 10406504
TI  - Automated peritoneal dialysis: when and how to do it.

PMID- 10406505
TI  - Advantages and disadvantages of automated peritoneal dialysis compared to
      continuous ambulatory peritoneal dialysis.

PMID- 10406506
TI  - Automated peritoneal dialysis in Asia.
AB  - The socioeconomic statuses of Asian countries are diverse, and government
      reimbursement policies for renal replacement programs vary greatly from one
      country to another. Both factors affect not only the availability of treatment,
      but also the choice of dialysis modality. A close correlation is demonstrated
      between the dialysis treatment rate for end-stage renal disease (ESRD) and the
      gross domestic product (GDP) per capita income. A biphasic relationship with the
      GDP per capita income and the peritoneal dialysis (PD) utilization rate is
      observed, in that the countries with the highest and lowest treatment rates tend
      to have lower PD utilization rates, whereas countries with modest treatment rates
      tend to have higher PD utilization rates. In contrast, countries with high
      continuous ambulatory peritoneal dialysis (CAPD) utilization rates have the
      lowest automated peritoneal dialysis (APD) utilization rates. The low APD
      utilization rates are due to fact that, in most instances, patients themselves
      must purchase the APD machine, and the machines are relatively more expensive in
      Asian Pacific countries. Continuous cycling peritoneal dialysis (CCPD) is most
      frequently practiced. Generally, convenience for employment is the main
      indication for the utilization of APD. Other important indications are the
      convenience of treatment in young or elderly uremic patients. Contrary to the
      practice in CAPD treatment, detailed documentation of dialysis adequacy and
      nutritional status is not routinely done in patients undergoing APD treatment in
      most Asian Pacific countries. In conclusion, APD is an underdeveloped treatment
      modality in the renal replacement programs of Asian Pacific countries. The low
      utilization of APD is clearly influenced by non medical factors including
      government reimbursement policy and the cost of PD machines.

PMID- 10406507
TI  - Major and minor risk factors for cardiovascular disease in continuous ambulatory
      peritoneal dialysis patients.
AB  - Uremia in general and peritoneal dialysis in particular bring with them risk
      factors for the development of cardiovascular disease. These factors include
      multiple lipid abnormalities, hyperhomocysteinemia, abdominal obesity, chronic
      inflammation, hypoalbuminemia, oxidative stress, and AGE formation. When these
      are combined with conventional risk factors, one can appreciate why the incidence
      of cardiovascular disease is so high in peritoneal dialysis patients. Treatment
      strategies should address each of these risks appropriately.

PMID- 10406508
TI  - Hypertension in continuous ambulatory peritoneal dialysis patients: what do we
      know and what can we do about it?
AB  - Despite many advantages of CAPD in maintaining hemodynamic stability,
      approximately 50%-60% of CAPD patients have hypertension and require
      antihypertensive treatment. ACE inhibitors and beta-blockers are the preferred
      first-line antihypertensive drugs in these patients, but some patients may
      require additional long-acting calcium antagonists to enhance antihypertensive
      effects. Despite antihypertensive treatment, many patients often fail to maintain
      BP within optimal ranges, and this fact may contribute to the high incidences of
      cardiovascular morbidity and mortality. Vigilance is clearly desirable by the
      patient and the physician to maintain BP within target ranges most of the time.
      Because dialysis patients also have many other cardiovascular risk factors, the
      strategy to decrease cardiovascular mortality should be a combined effort
      targeting all potential risk factors at the same time.

PMID- 10406509
TI  - Role of hypoalbuminemia in the genesis of cardiovascular disease in dialysis
      patients.
AB  - Our objective was to review the articles about the association between
      hypoalbuminemia and atherosclerotic or thrombotic cardiovascular disease (CVD)
      and to look for possible explanations for the role of hypoalbuminemia. Increased
      incidences of CVD were reported in patients with hypoalbuminemia owing to renal
      or other diseases. Hypoalbuminemia increases plasma levels of lipoprotein(a),
      fibrinogen, and arachidonic acid metabolites; it also increases platelet
      aggregability and blood viscosity, all of which may contribute to the development
      of CVD. This cause effect association is thought to be "dependent." Changes in
      atherogenic lipoproteins or lipids, such as LDL cholesterol, triglycerides, and
      apolipoprotein B, are controversial in hypoalbuminemic dialysis patients,
      possibly because coexistent malnutrition and volume status can affect both
      albumin and lipids. In our recent study, there was a negative correlation between
      serum albumin and C-reactive protein, D-dimer (an index of intravascular
      thrombogenesis), and von Willebrand factor (a marker for endothelial cell
      injury), but infusion of albumin did not affect the level of these parameters,
      which suggests that the correlations may be an effect-effect association by a
      confounding variable, such as inflammation. In conclusion, hypoalbuminemia is
      associated with cardiovascular disease via two pathways: one, a "dependent" cause
      effect association; the other, an effect-effect association.

PMID- 10406510
TI  - Cardiovascular problems in peritoneal dialysis patients: a short overview.

PMID- 10406511
TI  - Effects of recombinant human erythropoietin on functional and injury endothelial
      markers in peritoneal dialysis patients.
AB  - Clinical effects of recombinant human erythropoietin (rHuEPO) such as thrombosis,
      convulsions, hyperviscosity, hypertension, and angiogenic effect in culture cells
      have been described. We studied the rHuEPO effect on endothelial damage markers
      and endothelial function markers: tissue-type plasminogen activator (t-PA),
      nitrate (NO3), thrombomodulin (TM), and von Willebrand factor (vWF). Twenty-six
      peritoneal dialysis patients treated with rHuEPO and 19 controls were included.
      The study design for rHuEPO patients consisted of four periods: long-term
      treatment (rHuEPO-1); 2 months of withdrawal (rHuEPO-2); and 4 months on 5000
      IU/week rHuEPO subcutaneously, with markers being measured after 2 months (rHuEPO
      3) and after 4 months (rHuEPO-4). After 2 months of rHuEPO withdrawal, a decrease
      in hemoglobin level appeared (11+/-1.8 g/dL to 9.2+/-1.5 g/dL, p < 0.01). After
      rHuEPO reintroduction, this value reached 10.6+/-1.5 g/dL at two months, and
      11.1+/-1.4 g/dL at four months. A significant increase in t-PA ratio was observed
      from two months without rHuEPO to two months on rHuEPO, returning to previous
      values after four months. Similarly, TM increased for patients with creatinine
      clearances (CrC) < 5 mL/min. No changes in the higher-than-normal plasma vWF
      levels were found during the various periods. A statistically significant lower
      value was found in controls compared with rHuEPO-4 patients. A statistically
      significant increase in NO3 levels was observed in the pre-venous occlusion (VO)
      test immediately after the re-introduction of rHuEPO. This increment returned to
      prior values four months after rHuEPO was reintroduced. Our results show that
      rHuEPO treatment causes an increase in some endothelial damage markers (TM, t-PA)
      and modifies endothelial function markers (t-PA ratio, NO3). These changes might
      favor thrombosis and atherosclerosis.

PMID- 10406512
TI  - Survival and complications of 225 catheters used in continuous ambulatory
      peritoneal dialysis: one-center experience in Northern Greece.
AB  - This study reports our experience with permanent peritoneal catheters. From July
      1983 until December 1997, 225 catheters were implanted surgically in 207 patients
      (120 males, 87 females) with mean age of 58+/-16 years (range: 2-82 years), and a
      mean duration of continuous peritoneal dialysis (CAPD) of 21.9+/-21.3 months
      (range: 1-145 months). Two hundred and seventeen catheters were used in 199
      patients suffering from end-stage renal disease (ESRD), and 8 catheters in 8
      patients with end-stage heart failure resistant to medical therapy. One patient
      used 3 catheters and 16 patients used 2 catheters. The catheters used were:
      Tenckhoff, 2; Oreopoulos-Zellerman-1 (OZ-1), 10; OZ-2, 205; and OZ-pediatric, 8.
      All catheters were implanted by the same surgical team, through a paramedian
      incision under local anesthesia. By life table analysis, the actuarial survival
      rates at 1 year, 2 years, 3 years, and 5 years were 97%, 92%, 87%, and 82%
      respectively for all catheters. The catheter-related complications were: 5
      obstructions, 2 dislodgments, 13 dialysate leaks (6 early; 7 late), 90 exit
      site/tunnel infections (in 56 patients), 2 cuff extrusions, and 37 hernias (in 31
      patients). Eighteen catheters were replaced for persistent peritonitis (15
      cases), dislodgment (1 case), obstruction (1 case), and accidental shortening (1
      case). The total observation period was 4526 patient-months. The overall
      incidence of peritonitis was one episode per 15 patient-months, and of exit
      site/tunnel infections was one episode per 50 patient-months, with a significant
      improvement during the last years. We conclude that OZ catheters implanted
      surgically through a paramedian incision have a very high survival rate and a low
      complication rate.

PMID- 10406513
TI  - The effect of continuous ambulatory peritoneal dialysis on change in serum
      leptin.
AB  - OBJECTIVE: Elevated serum leptin can contribute to anorexia and poor nutrition in
      patients with chronic renal failure, because leptin is elevated in chronic renal
      failure patients with or without dialysis, especially in chronic ambulatory
      peritoneal dialysis (CAPD) patients. The aim of this study was to find whether
      leptin can be removed by peritoneal dialysis (PD) and to analyze factors that can
      affect serum leptin after start of CAPD by observing the change in serum leptin
      shortly after start of CAPD and its correlation with body mass index (BMI), with
      serum insulin, and with residual renal function. DESIGN: Twenty patients who
      started CAPD during the observation period were studied. Serum leptin was
      measured by radioimmunoassay before start of CAPD, 3-5 days after start of CAPD,
      and 1 month and 3 months after start of CAPD. Simultaneously, body weight, serum
      insulin, and residual renal function were measured. To compensate for the
      circardian rhythm of leptin, removal of leptin was assessed by measuring
      dialysate leptin divided by average serum leptin before and after a peritoneal
      equilibration test (PET). RESULTS: Leptin was eliminated by PD with a dialysate
      to-serum ratio of 0.16+/-0.07, which was comparable to removal of beta2
      microglobulin (0.14+/-0.06). The mean serum leptin concentrations did not
      decrease after 3-5 days of CAPD (8.4+/-13.1 ng/mL-->11.9+/-18.0 ng/mL) despite
      its removal by PD, and levels increased markedly to 189% of basal serum leptin 1
      month after start of PD and to 260% of basal serum leptin 3 months after start of
      PD. Correlation coefficients (Spearman's rho) between change of serum leptin and
      change of BMI, of serum insulin, of glomerular filtration rate (average of urine
      creatinine clearance and urine urea clearance) were 0.267 (p > 0.05, n = 20),
      0.441 (p > 0.05, n = 16), 0.706 (p > 0.05, n = 8) respectively. CONCLUSION:
      Leptin is removed by peritoneal dialysis. Serum leptin did not decrease in 5 days
      after the start of PD despite its removal by PD, but increased markedly
      thereafter, within 3 months after start of PD. We could not find a significant
      correlation between the change in leptin and the change in BMI. Factors other
      than fat-mass gain can stimulate leptin increase shortly after start of PD.

PMID- 10406514
TI  - The effect of dialysate dwell on gastric emptying time in patients on continuous
      ambulatory peritoneal dialysis.
AB  - METHODS AND PATIENTS: We evaluated gastric emptying time (GET) with a technetium
      (Tc) 99m-sulfur colloid gastric emptying scan in 11 patients on continuous
      ambulatory peritoneal dialysis (CAPD) (6 males, 5 females) and in 14 controls. We
      investigated the effect of dialysate dwell on GET by studying the subjects twice:
      once without dialysate in the abdomen (drained) and once with 2 L of dialysate in
      the abdomen (full). We also investigated the relationship between body surface
      area (BSA) and delayed gastric emptying. RESULTS: (1) The mean gastric emptying
      rate in 120 minutes in patients on CAPD when drained (67.8%+/-13.4%) was not
      different from that in controls (65.4%+/-8.6%). (2) The mean gastric emptying
      rate in 120 minutes in patients on CAPD when full was significantly slower than
      that when drained (55.6%+/-14.6% versus 67.8%+/-13.4%, p < 0.05). In four of the
      11 patients (36.4%), gastric emptying was extremely delayed from normal to
      abnormal range when full. (3) The BSA of patients who had extremely delayed GET
      from normal to abnormal range was smaller than that of patients who had minimal
      delayed or unchanged GET when full (1.5+/-0.11 m2 versus 1.74+/-0.22 m2).
      CONCLUSION: This study showed that patients on CAPD had normal gastric emptying
      when drained, and that gastric emptying was delayed by dialysate dwell,
      especially in patients who has less than 1.5 m2 of body surface area. Therefore,
      we suggest that, based on adequacy, intermittent nocturnal peritoneal dialysis or
      a small volume of dialysate be considered for patients with small body surface
      area.

PMID- 10406516
TI  - How to set up a peritoneal dialysis program: Indian experience.

PMID- 10406515
TI  - Pre-dialysis glycemic control is an independent predictor of mortality in type II
      diabetic patients on continuous ambulatory peritoneal dialysis.
AB  - OBJECTIVE: To evaluate the impact of pre-dialysis glycemic control on clinical
      outcomes for type II diabetic patients on continuous ambulatory peritoneal
      dialysis (CAPD). MATERIALS AND METHODS: One hundred and one type II diabetic
      patients receiving CAPD for at least 3 months were enrolled in a single
      institute. The patients were classified into two groups according to status of
      glycemic control. In the good glycemic control group, more than 50% of blood
      glucose determinations were within 3.3-11.0 mmol/L and glycosylated hemoglobin
      (HbA1C) levels were within 5%-10% at all times. In the poor glycemic control
      group, less than 50% of blood glucose determinations were within 3.3-11.0 mmol/L,
      or HbA1C levels were above 10% at least 6 months before peritoneal dialysis was
      started. In addition to glycemic control status, pre-dialysis serum albumin,
      cholesterol levels, residual renal function, peritoneal membrane function, and
      modes of glycemic control were also recorded. RESULTS: The patients with good
      glycemic control had significantly better survival than those with poor glycemic
      control (p < 0.01). There was no significant difference in pre-dialysis morbidity
      between two groups. No significant differences were observed in patient survival
      between patients with serum albumin above 30 g/L and those with serum albumin
      under 30 g/L; between those with cholesterol levels above or below 5.2 mmol/L;
      and between those with different peritoneal membrane solute transport
      characteristics as evaluated by a peritoneal equilibration test (PET).
      Furthermore, there was no significant difference in survival between patients who
      controlled blood sugar by diet and those who controlled it by insulin.
      Cardiovascular disease and infection are the major causes of death in both
      groups. Although good glycemic control predicts better survival, it does not
      change the pattern of mortality in diabetic patients maintained on CAPD.
      CONCLUSIONS: Glycemic control before starting dialysis is a predictor of survival
      for type II diabetic patients on CAPD. Patients with poor glycemic control
      predialysis are associated with increased morbidity and shortened survival.

PMID- 10406517
TI  - Animal models for peritoneal dialysis.

PMID- 10406518
TI  - Mathematical models for peritoneal transport characteristics.
AB  - Four mathematical models and for the description of peritoneal transport of fluid
      solutes are reviewed. The membrane model is usually applied for (1) separation of
      transport components, (2) formulation of the relationship between flow components
      and their driving forces, and (3) estimation of transport parameters. The three
      pore model provides correct relationships between various transport parameters
      and demonstrates that the peritoneal membrane should be considered heteroporous.
      The extended three-pore model discriminates between heteroporous capillary wall
      and tissue layer, which are assumed to be arranged in series; the model improves
      and modifies the results of the three-pore model. The distributed model includes
      all parameters involved in peritoneal transport and takes into account the real
      structure of the tissue with capillaries distributed at various distances from
      the surface of the tissue. How the distributed model may be applied for the
      evaluation of the possible impact of perfusion rate on peritoneal transport, as
      recently discussed for clinical and experimental studies, is demonstrated. The
      distributed model should provide theoretical bases for the application of other
      models as approximate and simplified descriptions of peritoneal transport.
      However, an unsolved problem is the theoretical description of bi-directional
      fluid transport, which includes ultrafiltration to the peritoneal cavity owing to
      the osmotic pressure of dialysis fluid and absorption out of the peritoneal
      cavity owing to hydrostatic pressure.

PMID- 10406519
TI  - The potential of gene therapy in the peritoneal cavity.
AB  - Gene therapy is a promising new treatment modality based on molecular genetic
      modification to achieve a therapeutic benefit. We believe that gene therapy in
      the peritoneal cavity holds considerable promise, and we describe strategies by
      which genetic modification can be used to treat a variety of disease states or
      conditions. First, we can envision a strategy, based on genetic modification of
      the peritoneal membrane, to improve the practice of peritoneal dialysis through
      the production of proteins that would be of therapeutic value in preventing
      membrane damage and in preserving or enhancing its function as a dialyzing
      membrane. Second, the membrane could be genetically modified for either local or
      systemic delivery of therapeutic proteins. This approach could be applied to a
      variety of pathologies or conditions that require either sustained or transient
      delivery of therapeutic proteins, such as enzymes or growth factors. Third, gene
      transfer has already been incorporated into several strategies for the treatment
      of intra-abdominal carcinomas, and it has been effective in animal models of
      ovarian and bladder cancer and of peritoneal mesothelioma. Finally, gene transfer
      can be a valuable tool in increasing our understanding of the biology of the
      peritoneal membrane. By being able to manipulate the expression of specific genes
      through gene transfer, their role in various (patho)physiological processes can
      be identified. In summary, gene therapy in the peritoneal cavity has significant
      potential to address a variety of diseases or pathophysiological conditions, and
      to further our knowledge of peritoneal cavity biology.

PMID- 10406520
TI  - Hydrostatic and osmotic pressures modulate partitioning of tissue water in
      abdominal muscle during dialysis.
AB  - OBJECTIVES: To investigate the effect of simultaneous exposure of anterior
      abdominal muscle (AAM) to changes in intraperitoneal hydrostatic pressure (Pip)
      and to osmolality of peritoneal fluid on total tissue water (TTW) and on the
      pattern of distribution of TTW in the AAM. DESIGN: A pilot study of single 60-min
      dwells in anesthetized Sprague-Dawley (SD) rats, dialyzed with either isotonic
      (290 mOsm/kg) or hypertonic (510 mOsm/kg) dialysis solutions at nominal Pip of 0
      mmHg or 6 mmHg. MEASUREMENTS: TTW (from dry-weight-to-wet-weight ratios) can be
      divided into the extracellular volume [theta(ec), from quantitative
      autoradiography (QAR) with 14C-mannitol] and intracellular volume (theta(ic) =
      TTW - theta(ec)). Theta(ec) = theta(if) + theta(iv), where theta(if) =
      interstitial volume and theta(iv) = vascular volume [from QAR with 131I
      immunoglobulin G (IgG)]. All measured parameters are standardized to tissue dry
      weight and expressed as mean +/- standard error. RESULTS: Regardless of the
      osmolality of the dialysis solution, elevation of Pip to 6 mmHg results in tissue
      expansion, primarily in theta(if), which is doubled to 1.71+/-0.11 mL/g dry
      weight and 1.60+/-0.17 mL/g dry weight with isotonic and hypertonic dialysis,
      respectively, as compared to controls (0.64+/-0.04 mL/g dry weight). The local
      theta(iv) was not affected by Pip or osmolality of the bathing solution. The
      overall theta(iv) is 0.046+/-0.006 mL/g dry weight. A two-way analysis of
      variance (ANOVA) to access the effect of osmolality and Pip on theta(ic)
      demonstrated no significant change in theta(ic) (F = 1.2, p > 0.1) as calculated
      for controls (3.13+/-0.19 mL/g dry weight), after isotonic dialysis (3.13+/-0.20
      mL/g dry weight), or after hypertonic dialysis (2.77+/-0.30 mL/g dry weight).
      CONCLUSION: Elevation of Pip to 6 mmHg significantly increased TTW and expanded
      the tissue. Tissue expansion is primarily in interstitium (theta(if)), which is
      doubled from control value regardless of dialysis fluid osmolality.

PMID- 10406521
TI  - A simple and fast method to estimate peritoneal membrane transport
      characteristics using dialysate sodium concentration.
AB  - BACKGROUND: The peritoneal equilibration test (PET) is widely used to classify a
      patient's peritoneal transport characteristics. However, PET is laborious and the
      prediction of fluid removal based on PET is generally poor. It is believed that
      osmosis by glucose occurs partially through transcellular water channels,
      resulting in sieving of sodium and decrease of dialysate sodium concentration
      when using hypertonic glucose dialysate. OBJECTIVE: In this study, we
      investigated the possibility of using dialysate sodium concentration to classify
      the patient's peritoneal transport characteristics. METHODS: A 6-hour dwell study
      with frequent dialysate and plasma sampling was performed in 46 patients using 2
      L of 3.86% glucose dialysate with 131I-albumin as an intraperitoneal volume (IPV)
      marker. The peritoneal transport of sodium, creatinine, glucose, and fluid was
      evaluated. RESULTS: The dialysate sodium concentration at 240 min (D(Na240))
      significantly correlated with D/P creatinine (r = 0.76, p < 0.001) and D/D0
      glucose (r = -0.83, p < 0.001) at 240 min of the dwell (better than dialysate
      sodium concentration at any other time of the dwell). DNa240 also significantly
      correlated with IPV at 240 min of the dwell (r = -0.61, p < 0.001)(better than
      D/P creatinine and D/D0 glucose). There were significant correlations between
      D(Na240) and the sodium-sieving coefficient (r = 0.71, p < 0.001) and the
      diffusive mass transfer coefficient for sodium (r = 0.50, p < 0.001). When using
      D(Na240) to divide the patients into four groups, as in the PET method, no
      significant difference was found between the two methods. CONCLUSION: Using 3.86%
      glucose solution, D(Na240) can be used instead of D/P creatinine to classify
      patients into different transport groups. D(Na240) provides a better prediction
      of peritoneal fluid transport and reflects both the diffusive and convective
      transport properties of the membrane. As only one dialysate sample (and no blood
      sample) is needed, D(Na240) may offer important clinical advantages compared with
      PET.

PMID- 10406522
TI  - Early-start dialysis in diabetic nephropathy.

PMID- 10406523
TI  - The role of protein kinase C activation in the pathogenesis of diabetic vascular
      complications.
AB  - Many vascular diseases in diabetes are known to be associated with the activation
      of the diacylglycerol (DAG)-protein kinase C (PKC) pathway. The major source of
      DAG that is elevated in diabetes is de novo synthesis from glycolytic
      intermediates. Among the various PKC isoforms, the beta-isoform has been shown to
      be persistently activated in diabetic animals. Multiple lines of evidence have
      shown that many vascular alterations in diabetes--such as a decrease in the
      activity of Na+-K+-adenosine triphosphatase (Na+-K+-ATPase), and increases in
      extracellular matrix, cytokines, permeability, contractility, and cell
      proliferation--are caused by activation of PKC. Inhibition of PKC by two
      different kinds of PKC inhibitors, LY333531, a selective PKC-beta-isoform
      inhibitor, and d-alpha-tocopherol, were able to prevent or reverse the various
      vascular dysfunctions in diabetic rats. These results have also provided in vivo
      evidence that DAG-PKC activation could be responsible for the hyperglycemia
      induced vascular dysfunctions in diabetes. Clinical studies are now being
      performed to clarify the pathogenic roles of the DAG-PKC pathway in developing
      vascular complications in diabetic patients.

PMID- 10406524
TI  - Future of interventions in diabetic nephropathy: antioxidants.

PMID- 10406525
TI  - Favorable treatment outcome with neutralizing anti-transforming growth factor
      beta antibodies in experimental diabetic kidney disease.

PMID- 10406526
TI  - Gene therapy for diabetic nephropathy.
AB  - Gene therapy has been considered for a broad array of diseases. Recent
      investigation has suggested that gene therapy may be applied to the treatment of
      diabetes mellitus and associated pathologies involving several organs. In the
      kidney, glomerulopathy is the most typical pathologic feature. This article
      addresses potential strategies towards gene therapy for diabetic glomerular
      disease.

PMID- 10406527
TI  - Neuropathy and quality of life in diabetic continuous ambulatory peritoneal
      dialysis patients.
AB  - Diabetes mellitus is the commonest cause of end-stage renal failure and is
      associated with considerable morbidity. Neuropathy is one of the most serious
      complications of diabetes, linked to the incidence of nephropathy and
      retinopathy. The prevalence of neuropathy increases with age and duration of
      diabetes. Peripheral sensorimotor neuropathy is the main manifestation of
      neurological damage in diabetes, while autonomic neuropathy, a devastating
      complication, is also present in a large number of patients with long-term
      diabetes. Clinical features of autonomic neuropathy are mainly cardiovascular
      disorders and abnormal visceral function. One of the most important sequelae of
      neuropathy is the development of the insensitive foot at risk of ulceration,
      deformation, Charcot neuroarthropathy, and amputation. Prevention, education, and
      identification of the at-risk patient are the key elements in managing these
      severe complications. Dialysis, and mainly peritoneal dialysis, still remains the
      main renal replacement therapy for end-stage renal disease (ESRD) diabetic
      patients. It is obvious from many studies that diabetes and its complications are
      major risk factors associated with poorer survival rates, increased morbidity,
      and decreased quality of life. Few, if any, data are available specifically
      evaluating quality of life in continuous ambulatory peritoneal dialysis (CAPD)
      diabetic patients. Fewer data are available estimating the impact of neuropathy
      on the quality of life of such patients. Specific studies must be carried out to
      further investigate quality-of-life issues and neuropathy in this vulnerable
      group of patients.

PMID- 10406528
TI  - Nutrition in diabetic patients undergoing continuous ambulatory peritoneal
      dialysis.

PMID- 10406529
TI  - The effect of various dialysis solutions on peritoneal membrane viability.

PMID- 10406530
TI  - Biocompatibility and new fluids.

PMID- 10406531
TI  - The referral pattern of end-stage renal disease patients and the initiation of
      dialysis: a European perspective.

PMID- 10406532
TI  - Continuum and integration of pre-dialysis care and dialysis modalities.

PMID- 10406533
TI  - Tuberculous peritonitis.
AB  - Although the general incidence of peritonitis has declined considerably with
      improvement in connectology, tuberculous peritonitis is still a major problem in
      patients who are from endemic regions and who belong to high-risk groups. The
      problem stems mainly from less sensitive diagnostic tools. Confirmation of
      tuberculous peritonitis is based on mycobacterial culture of the peritoneal
      fluid, which takes a few weeks. For patients in whom tuberculous peritonitis
      cannot be confirmed, therapeutic trial has been recommended. Treatment of
      tuberculous peritonitis consists in removing the peritoneal catheter and
      initiating antituberculosis medications, though the dosage and duration of
      antituberculosis medication are not yet well defined. Early initiation of
      antituberculosis medication has been shown to preserve good ultrafiltration and
      solute clearance by the peritoneal membrane.

PMID- 10406534
TI  - Fungal peritonitis--current status 1998.

PMID- 10406535
TI  - Comparative study of pharmacokinetics of once daily and continuous
      intraperitoneal netilmycin in continuous ambulatory peritoneal dialysis patients
      with peritonitis.

PMID- 10406536
TI  - Nutritional problems in peritoneal dialysis: an overview.

PMID- 10406537
TI  - Metabolic acidosis as a catabolic factor in peritoneal dialysis patients.

PMID- 10406538
TI  - Malnutrition, cardiac disease, and mortality.

PMID- 10406539
TI  - Taste buds and neuronal markers in patients with chronic renal failure.
AB  - OBJECTIVE: To study the number of taste buds and, with the use of specific
      markers for peripheral nervous tissue, to study the neuronal pattern in taste
      buds from 36 patients with chronic renal failure (CRF), 19 renal transplant
      recipients, and 40 healthy subjects. Of the patients with CRF, 17 patients had
      not started dialysis, 12 patients were on peritoneal dialysis, and 7 patients
      were on hemodialysis. DESIGN: From all subjects, two or three fungiform papillae
      were collected from the anterior part of the tongue. Cryostat sections were cut
      and inspected under light microscopy to determine the presence of taste buds. The
      sections were subsequently incubated with primary rabbit antibodies against
      protein gene product 9.5, substance P, and nerve growth factor receptor. RESULTS:
      Using these antibodies, no differences between the groups were observed. However,
      patients with CRF had fewer taste buds than control subjects. CONCLUSION: No
      immunohistochemical differences were observed between patients with CRF and
      healthy controls. However, patients with CRF had significantly fewer fungiform
      taste buds, suggesting an important factor contributing to the well-known
      impairment of taste acuity in this patient group.

PMID- 10406540
TI  - Peritoneal dialysis as long-term treatment: comparison of technique survival
      between Asian and Western populations.

PMID- 10406541
TI  - Can peritoneal dialysis be maintained in patients without residual renal
      function?

PMID- 10406542
TI  - How to maintain fluid balance in long-term peritoneal dialysis.

PMID- 10406543
TI  - Nutritional status in long-term peritoneal dialysis.

PMID- 10406544
TI  - Effect of peritoneal dialysis on peritoneal macrophages.

PMID- 10406545
TI  - Effect of peritoneal dialysis on peritoneal cell biology: peritoneal fibroblasts.
AB  - Despite the fact that the characterization of human peritoneal fibroblast biology
      and function is, at present, only in its early stages, the evidence available to
      date clearly indicates that direct interactions of peritoneal macrophages and
      fibroblasts may significantly contribute to the production of chemotactic and pro
      inflammatory factors within the peritoneal cavity. In vitro models studying human
      peritoneal fibroblasts in two-dimensional or three-dimensional culture systems
      will further contribute to our understanding of the regulatory processes involved
      in peritoneal inflammation and fibrosis. In addition, the development of novel
      peritoneal dialysis solutions will have not only to examine the effect of these
      solutions on immune cells and the peritoneal mesothelium, but also to take into
      consideration the potential impact on peritoneal fibroblast function.

PMID- 10406546
TI  - The role of protein kinase C activity in the proliferation of peritoneal
      fibroblasts.
AB  - OBJECTIVE: To clarify the effect of glucose on peritoneal sclerosis, we performed
      several experiments to determine how glucose influences the proliferation of, and
      the production of extracellular matrix proteins by, peritoneal fibroblasts. The
      effect of heparin on these phenomena was also studied. DESIGN: Using rat
      peritoneal fibroblasts, cells were cultured in four separate media: M199 with 5%
      fetal bovine serum (FBS) (control medium), control medium with 4% glucose
      (glucose medium), glucose medium with H7 [an inhibitor of protein kinase C (PKC)]
      50 micromol, and glucose medium with heparin 50 microg/mL. Cell proliferation and
      concentrations of procollagen 3 peptide (P3P) and hyaluronic acid (HA) in the
      supernatants were evaluated at 24 hours, 72 hours, and 120 hours after culture.
      PKC activity in cytosolic and cell membrane fractions were measured 30 minutes
      after incubation in control medium and in glucose medium with and without
      heparin. RESULTS: Glucose accelerated cell proliferation 24 hours after culture,
      but inhibited it 120 hours after culture. Glucose stimulated the production of HA
      from these cells 72 hours and 120 hours after culture, but it did not stimulate
      the production of P3P at any time. Heparin and H7 inhibited cell proliferation by
      glucose 24 hours after culture. Heparin and H7 also inhibited the production of
      HA in the peritoneal fibroblasts after culture, but did not affect the production
      of P3P. Glucose accelerated PKC activity in cell membrane, but not in cytosol.
      Heparin inhibited the elevated PKC activity of the membrane fraction by glucose.
      CONCLUSION: Glucose may accelerate the proliferation of, and HA production in,
      peritoneal fibroblasts by stimulation of cellular PKC activity. Heparin
      suppresses these phenomena by inhibiting PKC activity.

PMID- 10406547
TI  - Substrate and inhibitor for nitric oxide synthase during peritoneal dialysis in
      rabbits.
AB  - OBJECTIVE: To investigate the possible influence of nitric oxide (NO) on
      peritoneal transport during non infected peritoneal dialysis. DESIGN: A chronic
      peritoneal dialysis model in New Zealand White rabbits (2624 g; range: 2251-3034
      g) was used. In 13 rabbits, 250 mg/L L-arginine, a substrate for NO synthesis,
      was added to 3.86% glucose dialysate. N(G)-monomethyl-L-arginine (L-NMMA) 25
      mg/L, an inhibitor of NO synthase, was added to the dialysate in 10 rabbits.
      Standard peritoneal permeability analyses in rabbits (SPAR) were performed to
      analyze the effects of these interventions on solute and fluid transport during 1
      hour dwells. The addition of 4.5 mg/L nitroprusside to the dialysate in 5
      separate experiments was used for validation of this model. MAIN OUTCOME: For the
      transport of urea and creatinine, mass transfer area coefficients (MTACs) were
      calculated. Furthermore, the glucose absorption, the peritoneal albumin
      clearance, peritoneal fluid kinetics, and the dialysate-to-plasma (D/P) ratio of
      nitrate were calculated. RESULTS: Nitroprusside caused an 86% (48%-233%) increase
      in albumin clearance, which is similar to the nitroprusside-induced increase
      found in humans. Contrary to the findings in human studies, no effect was found
      on the clearances of urea and creatinine, or on peritoneal fluid kinetics. This
      suggests a lower sensitivity of the rabbit peritoneal membrane for the effect of
      NO on small-solute transport. L-arginine affected neither the MTACs of urea and
      creatinine, nor the absorption of glucose. Also, peritoneal fluid kinetics were
      similar. Peritoneal albumin clearance increased 18% (-24%-609%). This result
      resembles the NO-mediated effects of nitroprusside. Addition of L-NMMA caused no
      change in the transport rate of small solutes, in albumin clearance, or in fluid
      profile. This result suggests that NO synthase is not induced during non infected
      peritoneal dialysis, which accords with previous studies. CONCLUSION: This rabbit
      dialysis model can be used for analyzing the effects of interventions on
      peritoneal permeability characteristics, although the rabbit peritoneal membrane
      is probably less sensitive to NO compared to that of humans. L-Arginine-induced
      effects are similar to those of nitroprusside, which suggests that these effects
      are possibly mediated by NO. Because L-NMMA did not affect peritoneal transport,
      it is unlikely that NO is involved in the regulation of peritoneal permeability
      during stable continuous ambulatory peritoneal dialysis.

PMID- 10406548
TI  - Effect of N-acetylglucosamine on function of peritoneal leukocytes.
AB  - OBJECTIVE: To compare effects of N-acetylglucosamine (NAG)-based and glucose
      based dialysis fluids on the function of peritoneal leukocytes in conditions of
      peritoneal dialysis. DESIGN: In vitro experiments on ex vivo isolated rat
      peritoneal leukocytes. MATERIALS: Peritoneal leukocytes were isolated from rats
      on chronic peritoneal dialysis. On alternate days, fluid exchanges were performed
      with NAG-based or glucose-based dialysis solutions. After a 4-hour dwell,
      dialysate was drained and peritoneal leukocytes were incubated in vitro +/-
      lipopolysaccharide (LPS). Production of nitrites (index of NO synthesis), tumor
      necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and interferon
      gamma (IFN-gamma) by unstimulated or stimulated peritoneal leukocytes originating
      from NAG-based or glucose-based fluid was measured. RESULTS: Dialysate cell count
      was lower during exchanges with NAG-based fluid (2113+/-615 cells/microL) as
      compared to glucose-based fluid (3643+/-1108 cells/microL; p < 0.01).
      Differential cell count was similar in both studied groups. Unstimulated
      peritoneal leukocytes from NAG-based dialysate produced more NO (nitrites)
      (0.65+/-0.07 micromol per 10(6) cells) than did cells from glucose-based
      dialysate (0.26+/-0.09 micromol per 106 cells, p < 0.01). Stimulated peritoneal
      leukocytes from NAG-based dialysate produced more cytokines than did cells from
      glucose-based dialysate: TNFalpha, 135.2+/-37.0 pg versus 70.2+/-21.8 pg per
      10(6) cells respectively, p < 0.01; IL-1beta, 143.2+/-60.9 pg versus 99.1+/-22.4
      pg per 10(6) cells respectively, p < 0.05; IFN-gamma, 16.2+/-12.5 pg versus 6.0+/
      1.8 pg per 10(6) cells respectively, p < 0.01. CONCLUSIONS: We demonstrated that
      rat peritoneal leukocytes exposed in vivo to NAG-based dialysis fluid have better
      ability to produce inflammatory mediators than do peritoneal leukocytes from the
      same donor, but exposed in vivo to glucose-based dialysis solution.

PMID- 10406549
TI  - Bicarbonate/lactate dialysis solution improves in vivo function of peritoneal
      host defense in rats.
AB  - OBJECTIVE: To assess the in vivo peritoneal inflammatory reaction in rats
      dialyzed with neutral, bicarbonate-lactate-buffered dialysis fluid. METHODS:
      Chronic peritoneal dialysis was performed for 4 weeks in Wistar rats with two
      solutions: (1) 40 mmol/L lactate-buffered fluid, pH 5.2, with a glucose
      concentration of 2.27 g/dL (Lac); and, (2) 15 mmol/L lactate and 25 mmol/L
      bicarbonate-buffered fluid, pH 7.0-7.5, with a glucose concentration of 2.27 g/dL
      (Bic-Lac). After 4 weeks, two peritoneal equilibration tests (PET 1 and PET 2)
      were performed in all animals with each respective solution. PET 1 was done with
      test solutions alone, whereas, on a subsequent day, PET 2 was performed with test
      solutions supplemented with endotoxin [lipopolysaccharide (LPS)] to induce
      peritonitis. RESULTS: During PET 1 no consistent differences were detected in
      peritoneal permeability between the Lac and Bic-Lac groups. Total dialysate cell
      count in the Bic-Lac animals was lower than in rats treated with Lac fluid: that
      is, at 8 hours, the respective counts were 1858+/-524 cells/microL versus 2785+/
      1162 cells/microL (p < 0.01). Dialysate from animals dialyzed with Bic-Lac
      contained more macrophages (at 4 hours: 53.6%+/-35.8% versus 35.8%+/-8.8%, p <
      0.001) and fewer neutrophils (at 4 hours: 3.6%+/-1.8% versus 15.4%+/-6.1%, p <
      0.001) as compared to those dialyzed with the Lac solution. Concentration of
      nitrites in 8-hour dwell dialysate samples from Bic-Lac rats was lower than that
      in the Lac group (0.98+/-0.28 micromol/mL versus 2.32+/-0.87 micromol/mL, p <
      0.002), but cytokine levels in the dialysates were comparable. During PET 2, the
      increase in peritoneal permeability resulting from the LPS-induced inflammatory
      response was similar for both test solutions. Dialysate cell count was higher in
      the Lac group versus the Bic-Lac group (at 8 hours: 8789+/-4862 cells/microL
      versus 3961+/-581 cells/microL, p < 0.001), contained more neutrophils (at 8
      hours: 80.0%+/-11.3% versus 54.8%+/-4.4%, p < 0.001) and fewer macrophages (at 8
      hours: 6.8%+/-5.6% versus 21.2%+/-3.3%, p < 0.05). During peritonitis, we found a
      higher overall dialysate concentration of both tumor necrosis factor (TNFalpha:
      +53%, p < 0.05) and of interferon gamma (IFN-gamma: +303%, p < 0.02), in the Bic
      Lac group than in the Lac group. CONCLUSIONS: A lower dialysate cell count,
      higher percentage of macrophages, and lower percentage of neutrophils in
      dialysate suggest that Bic-Lac fluid induces a diminished nonspecific
      inflammatory response of the peritoneal cavity during dialysis. However, after in
      vivo stimulation, peritoneal cells from animals dialyzed with Bic-Lac solution
      possess an augmented ability to produce inflammatory cytokines.

PMID- 10406550
TI  - Nitric oxide production in peritoneal macrophages from peritoneal dialysis
      patients with bacterial peritonitis.
AB  - Nitric oxide (NO) is produced by various cell types, and it is an important
      mediator in many biological processes, including macrophage-mediated cellular
      host defense. The relevance and amount of NO production in peritonitis during
      peritoneal dialysis (PD) treatment is still not clear. We studied whether human
      peritoneal macrophages (PMphi) isolated from healthy PD patients or PD patients
      with peritonitis showed different spontaneous or lipopolysaccharide
      (LPS)/interferon gamma (IFN-gamma)-induced NO production (LPS, 1 ng/mL-10
      microg/mL; IFN-gamma, 10-1000 U/mL; incubation between 6-48 hours; measured by
      Griess reagent). Results were compared with human blood monocytes (HBM) isolated
      from buffy coats. Inducible nitric oxide synthetase (iNOS) mRNA expression was
      looked for in PMphi by reverse transcriptase polymerase chain reaction (RT-PCR).
      Furthermore, plasma (P) and peritoneal dialysate effluent (D) nitrite
      concentrations were measured in vivo. The dialysate-to-plasma ratio (D/P) of
      nitrite concentration was inverse in the case of peritonitis compared to
      infection-free patients (peritonitis D/P = 1.3, non peritonitis D/P = 0.4; p <
      0.01). PMphi from peritonitis patients produced higher amounts of NO than did
      those from infection-free patients (0.040+/-0.044 nmol per microgram cell protein
      versus 0.018+/-0.015 nmol per microgram cell protein, p < 0.05). NO release could
      not be further enhanced by stimulation with LPS plus IFN-gamma (1 ng/mL, 250
      U/mL, respectively). However, NO production in PMphi from infection-free patients
      increased during in vitro stimulation (0.044+/-0.031 nmol per microgram cell
      protein versus 0.018+/-0.015 nmol per microgram cell protein, p < 0.01). An
      increase of iNOS mRNA expression could be demonstrated by RT-PCR. Blood monocytes
      from healthy donors also increased NO release during cytokine stimulation
      (0.032+/-0.015 nmol per microgram cell protein versus 0.019+/-0.009 nmol per
      microgram cell protein, p < 0.05). Our results indicate that significant amounts
      of NO are released intraperitoneally in the case of bacterial peritonitis. PMphi
      represent a site of NO production, though the absolute amounts released in vitro
      are only moderate. NO production can be induced in PMphi and HBM by LPS/IFN-gamma
      stimulation in vitro.

PMID- 10406552
TI  - Effects of commercial glucose-based peritoneal dialysates on peripheral blood
      phagocytes apoptosis.
AB  - BACKGROUND: Variable glucose-lactate-based peritoneal dialysates have negative
      effects on peritoneal macrophages and peripheral blood leukocytes, reducing the
      capacity of leukocytes for chemotaxis, bacterial killing. But few reports exist
      on cell apoptosis. To investigate the effects of glucose-lactate-based peritoneal
      dialysates on cultured phagocytes (monocytes and neutrophils), we focused on
      studying phagocyte apoptosis after brief exposure to commercial peritoneal
      dialysates. METHODS: Cell apoptosis is measured by flow cytometry (FCM) to detect
      phosphatidylserine (PS) exposure on early apoptotic cells using fluorescein
      labeled annexin V. To mimic the composition of dialysate in vivo, where the
      freshly instilled solution mixes with the residual dialysate from the previous
      cycle, we performed the experiments using a mixture of fresh and spent dialysate
      (9:1). In our transient exposure experiments, monocytes and neutrophils were
      separately incubated in each of the test solutions (1.5% glucose and 4.25%
      glucose dialysates) for 10 minutes or 30 minutes and afterward separated and
      resuspended in RPMI 1640 medium and cultured over the indicated time. RESULTS:
      After exposure to 1.5% glucose dialysates for 10 minutes, monocytes and
      neutrophils exhibited normally spontaneous apoptosis. After exposure to 4.25%
      glucose dialysate, monocytes underwent apoptosis increasingly, 21%+/-5.0% versus
      9.8%+/-3.6% (p < 0.05) at 24 hours and 47%+/-6.2% versus 16%+/-4.0% (p < 0.01) at
      72 hours compared with controls. For neutrophils, the results were discouraging:
      hypertonic dialysate not only increased apoptosis [65.36%+/-2.6% versus 34.17% +/
      8.52% (p < 0.01) at 72 hours], but also induced cell necrosis. When Incubation
      time was prolonged for 30 minutes, 1.5% dialysate acted like 4.25% dialysate,
      with the rate of apoptosis increasing rapidly [40%+/-4.0% versus 16%+/-4.0% (p <
      0.01) at 72 hours for monocytes, and 66.90%+/-5.6% versus 34.17%+/-8.52% (p <
      0.01) at 72 hours for neutrophils]. CONCLUSION: Glucose-lactate-based peritoneal
      dialysates can induce peripheral blood phagocyte apoptosis in vitro, which
      indicates that glucose plays an important role in triggering cell apoptosis.
      Therefore, looking for new, physiologic peritoneal dialysis fluids to replace
      conventional fluids is reasonable.

PMID- 10406551
TI  - Effects of peritoneal rest on peritoneal transport and peritoneal membrane
      thickening in continuous ambulatory peritoneal dialysis rats.
AB  - OBJECTIVE: To evaluate the effects of peritoneal rest on peritoneal transport and
      morphology in a rat model of peritoneal dialysis. DESIGN: Twenty-four rats
      (Sprague-Dawley, male, 250-300 g) were divided into three groups: group 1
      (control, n = 6) without dialysis, group 2 (n = 9) sacrificed immediately after 3
      weeks of dialysis, and group 3 (n = 9) sacrificed after 4 weeks of peritoneal
      rest after 3 weeks of dialysis. Both dialysis groups were dialyzed twice daily
      with an intraperitoneal instillation volume of 25 mL of 3.86% dextrose solution
      for 3 weeks. Peritonitis was induced by supplementing the dialysis fluid with
      lipopolysaccharide (5 microg/mL) on days 8, 10, and 12 in both dialysis groups.
      Peritoneal equilibration tests were performed on each animal at baseline. The
      equilibration tests were repeated at the 4th and the 8th week of dialysis.
      Morphometric analyses of the peritoneal membrane were carried out in tissue
      specimens obtained at the time of sacrifice. RESULTS: The D/D0 ratio for glucose
      at two hours in groups 2 and 3 at the beginning of week 4 was significantly lower
      than at baseline, indicating an increase in peritoneal permeability to glucose
      after 3 weeks of dialysis. D/D0 in group 3 at the beginning of week 8, after 4
      weeks of peritoneal rest, was significantly higher than at week 4. The drain
      volume in groups 2 and 3 at week 4 was significantly lower than at baseline;
      however, the drain volume in group 3 at week 8 was significantly higher than at
      week 4. The thickness of the parietal peritoneal membrane in group 3 was
      significantly greater than in group 1 and less than in group 2 (group 1, 11.4+/
      7.6 microm; group 2, 37.5+/-18.4 microm; group 3, 21.4+/-12.1 microm).
      CONCLUSIONS: Peritoneal rest improves ultrafiltration in rats by decreasing the
      hyperpermeability of glucose and also reduces the degree of peritoneal
      thickening. These data suggest that dialysis-induced changes in peritoneal
      transport and morphology are reversible under the conditions of peritoneal rest
      in this experimental model.

PMID- 10406553
TI  - Renal bone disease in peritoneal dialysis.

PMID- 10406554
TI  - Renal osteodystrophy in pre-dialysis patients: ethnic difference?
AB  - The purpose of the present study is to investigate whether an ethnic difference
      exists in the incidence of renal osteodystrophy between Asian and Western
      countries in end-stage renal disease (ESRD) patients. We evaluated bone histology
      in 58 pre-dialysis patients (28 male, 30 female; mean age: 47.7 years). All
      patients had bone biopsies with quantitative histomorphometry and serological
      parameters such as intact PTH, osteocalcin, total alkaline phosphatase, and basal
      and deferoxamine-stimulated serum aluminum levels. We observed that 91.4% of all
      evaluated patients showed renal osteodystrophy before the start of dialytic
      therapy. Mild osteitis fibrosa were observed in 21 patients (36.2%), severe
      osteitis fibrosa in 5 patients (8.6%), mixed lesions in 7 patients (12.1%),
      osteomalacia in 6 patients (10.3%), aplastic bone disease in 14 patients (24.1%),
      and normal bone in 5 patients (8.6%). Among the bone histomorphometric
      parameters, fibrosis area rate (%) showed the best correlation with intact PTH,
      and osteocalcin and osteoid area rate (%) with total alkaline phosphatase.
      Aluminum-related bone disease was not observed. Among patients with aplastic bone
      disease, only 14.3% showed aluminum deposition of any significance (5% <
      stainable bone surface aluminum < 25%). In the diabetic patients, aplastic bone
      disease was most common, but no case was related to aluminum intoxication. In
      conclusion, the distribution of renal osteodystrophy in our study was different
      from that of Western countries in pre-dialysis patients. Our patients tended to
      have more mild-form osteitis fibrosa and normal findings, and less severe-form
      osteitis fibrosa and aplastic bone disease. Aluminum-related bone disease was not
      observed.

PMID- 10406555
TI  - Calcitriol, lanthanum carbonate, and other new phosphate binders in the
      management of renal osteodystrophy.

PMID- 10406556
TI  - Beta2-microglobulin and renal bone disease.
AB  - Dialysis-related amyloidosis (DRA) is characterized by amyloid deposition mainly
      in bone and joint structures, presenting as carpal tunnel syndrome, destructive
      arthropathy, and subchondral bone erosions and cysts. Beta2-microglobulin has
      been demonstrated to be a major constituent of amyloid fibrils. DRA occurs not
      only in patients undergoing long-term hemodialysis, but also in patients
      undergoing continuous ambulatory peritoneal dialysis. The incidence of this
      complication increases with the duration of dialytic therapy and the age of the
      patient. While a definitive diagnosis of DRA can be made only by histological
      findings, various imaging techniques often support diagnosis. The molecular
      pathogenesis of this complication remains unknown. Recent studies have, however,
      suggested a pathogenic role of a new modification of beta2-microglobulin in
      amyloid fibrils--that is, the advanced glycation end-products (AGEs) formed with
      carbonyl compounds derived from autoxidation of both carbohydrates and lipids
      ("carbonyl stress"). Therapy for DRA is limited to symptomatic approaches and
      surgical removal of amyloid deposits. High-flux biocompatible dialysis membranes
      could be used to delay DRA development.

PMID- 10406557
TI  - Socioeconomic aspects of peritoneal dialysis in North America: role of non
      medical factors in the choice of dialysis.
AB  - Patients initiating dialysis therapy must make a choice between hemodialysis (HD)
      and peritoneal dialysis (PD). Controversy persists over the relative merits of
      each modality in the treatment of end-stage renal disease (ESRD). Issues relating
      to survival, morbidity, economics, and patient characteristics will all determine
      the final choice of therapy. Non medical factors are the most important
      determinant of dialysis modality selection. In the United States, HD has been the
      more commonly used modality, while PD is underrepresented. This disparity arises
      from multiple factors including reactions (sometimes incorrect) to the healthcare
      financing structure, physician biases, and changing demographic patterns in the
      ESRD population. We discuss these issues and present collected evidence showing
      that increased use of PD may have substantial overall benefit.

PMID- 10406558
TI  - Socioeconomic aspects of peritoneal dialysis: role of non medical factors in
      chronic dialysis--dialysis in Asia, regional differences.

PMID- 10406559
TI  - New solutions for peritoneal dialysis in adult and pediatric patients.
AB  - The standard PD solutions used today contain physiological electrolyte profiles
      similar to that of interstitial fluids and are supplemented with glucose as the
      osmotic agent. Improvements in solution composition during the last 20 years have
      been largely restricted to minor changes in buffer and electrolyte levels. Newer
      PD solutions, on the other hand, are designed to manage comorbidities associated
      with patients on maintenance dialysis, to tailor the ultrafiltration profile
      based upon dwell time, and to better preserve peritoneal membrane function and
      host defenses. The evidence to date indicates that, in malnourished PD patients
      (children and adults), IP amino acids improve protein nutritional status,
      particularly if low protein intakes are a cause of the malnutrition. The
      availability of glucose polymers allows the clinician to complement standard
      glucose-based formulations with one that can provide improved ultrafiltration in
      both CAPD and APD patients for long dwells, and in patients experiencing
      ultrafiltration loss owing to a large effective peritoneal surface area. Owing to
      the reduced calorie and carbohydrate load, glucose polymers may also offer long
      term metabolic advantages. Although the control of acid-base balance can be well
      managed in the vast majority of patients with a 35-40 mmol/L lactate solution,
      the development and clinical evaluation of bicarbonate-based solutions is
      underway as a result of concern over the potentially bioincompatible nature of
      acidic lactate formulations. To date, in vitro, ex vivo, and limited clinical
      studies show that such formulations, and in particular bicarbonate/lactate
      combinations are efficacious and well tolerated, and show improved peritoneal
      cell function versus conventional solutions. In conclusion, ongoing research and
      development has produced a new generation of PD solutions that, to various
      degrees, meet different criteria established for an ideal PD solution for chronic
      adult and pediatric patients on PD. These criteria include good clearance and
      ultrafiltration, supply of nutrition, iso-osmolality, physiologic pH, bicarbonate
      buffer, and minimal absorption of the osmotic agent. Several of the new solutions
      have already demonstrated clinical utility in controlled clinical trials and are
      commercially available in Europe. Wider clinical use will further add to our
      understanding of the impact of these formulations on patient outcomes.

PMID- 10406560
TI  - Value of intraperitoneal amino acids in children treated with chronic peritoneal
      dialysis.

PMID- 10406561
TI  - Consequences of intermittent calcitriol therapy in pediatric patients with
      secondary hyperparathyroidism.

PMID- 10406562
TI  - Current practice of peritoneal dialysis in children: results of a longitudinal
      survey. Mid European Pediatric Peritoneal Dialysis Study Group (MEPPS).
AB  - Since 1993, the Mid European Pediatric Peritoneal Dialysis Study Group (MEPPS)
      has been accumulating epidemiological data regarding the practice of peritoneal
      dialysis (PD) in children. More than 200 children have been evaluated to date.
      While treatment modalities were evenly distributed in 1993, automated peritoneal
      dialysis (APD) has emerged as the preferred mode of therapy during the last few
      years. Technique survival was 95% at 2 years, but decreased to 65% after 4 years
      of treatment, the main reasons for treatment failure being recurrent peritonitis,
      ultrafiltration failure, or both. Most centers use double-cuff curled Tenckhoff
      catheters with an upward pointing exit site. The first catheter was still
      functioning in 82% of patients after 1 year, and in 57% of patients after 4 years
      of treatment. While the overall peritonitis incidence between 1993 and 1997 was 1
      episode per 17 months, it was much higher in children below 6 years of age.
      Empirical PD prescription resulted in a mean total weekly creatinine clearance of
      57 L/1.73 m2/week in both continuous ambulatory peritoneal dialysis (CAPD) and
      APD patients, while average total weekly Kt/V urea was higher in APD-treated
      (2.45) than in CAPD-treated children (1.96). Antihypertensive treatment was
      required in 40%-50% of patients; oral phosphate binders in 75%-80%; bicarbonate
      substitution in 30%; potassium binders in 7%-14%; and NaCl supplementation in 9%
      21% of patients. While growth retardation had a prevalence of 57%, body mass
      relative to height was in the normal range. After one year of dialysis, 20% of
      patients received growth hormone treatment. In conclusion, peritoneal dialysis in
      children, preferably performed as APD, achieves technique survival rates similar
      to those reported for adults. Young children are at increased risk for
      peritonitis. The current empirical PD prescription is of limited efficacy in
      terms of small-solute and fluid removal.

PMID- 10406563
TI  - Treatment of peritonitis in pediatric continuous peritoneal dialysis.

PMID- 10406564
TI  - Prevention and treatment of exit-site and tunnel infections in pediatric
      continuous peritoneal dialysis.

PMID- 10406565
TI  - The optimal approach to peritoneal dialysis prescription in children.
AB  - OBJECTIVE: To describe the optimal approach to peritoneal dialysis (PD)
      prescription in children. DESIGN: Review of the available literature. RESULTS:
      Unlike the situation in adults, the main method used for PD in children is
      automated peritoneal dialysis (APD). The prone position, while resting, permits
      the dialysis prescription to use a higher fill volume (IPV), as in continuous
      ambulatory peritoneal dialysis (CAPD), and is also probably more effective than
      PD in an upright position. However, because APD is limited to 10 hours, the
      dialytic effectiveness of nocturnal APD should avoid two potential risks: (1) use
      of too high an IPV per exchange, inducing lymphatic reabsorption, a factor in
      unsuitable water and sodium balance [Fischbach M. Peritoneal dialysis
      prescription for neonates. Perit Dial Int. 1996; 16(Suppl):S52-4]; and (2) use of
      too short a dwell time per exchange, limiting the purification of creatinine and
      phosphate despite an apparently adequate urea purification (Malhotra C, Murota
      GH, Tzamaloukas AH. Creatinine clearance and urea clearance in PD: What to do in
      case of discrepancy. Perit Dial Int. 1997; 17:532-5).

PMID- 10406567
TI  - The 1997 Report of the Japanese National Registry data on pediatric peritoneal
      dialysis patients.
AB  - OBJECTIVE: We have collected data on pediatric patients less than 16 years of age
      from the National Registry of Chronic Peritoneal Dialysis (PD). We present our
      experience with this population. DESIGN: The database details the patient
      numbers, age, outcome, cause of death, reason for terminating PD therapy, type of
      PD therapy, peritonitis, and catheter survival. PATIENTS: Of 807 patients, 70
      patients (8.7%) were under 1 year of age, and 268 patients (33.2%) were under 6
      years of age, clearly indicating that PD was the treatment of choice in young
      children. The duration on PD was 5 years or more in 200 patients (24.8%), which
      showed an increase in long-term PD patients from 11% in 1991. Patients on
      automated PD (APD) increased to 75% in 1997 from 9% in 1991. RESULTS: The
      outcomes for the total patient population of 807 as of the end of 1997 is: 253
      patients (31.4%) were being successfully treated with PD, 87 patients (10.8%)
      died, 238 patients (29.5%) received a kidney transplant, and 121 (15.0%) were
      transferred to hemodialysis. The patient survival rate was 91% in 3 years and 86%
      in 5 years. The technique survival rate was 83% in 3 years and 71% in 5 years.
      The rate of peritonitis was 1 episode per 30 patient-months. The mean catheter
      duration was 2.25 years. CONCLUSION: The patient and technique survival rates,
      the peritonitis rate, and the catheter survival improved recently. However, these
      data were worse in younger children (less than 6 years of age), indicating that
      extra-careful management is needed for this young age group.

PMID- 10406566
TI  - Long-term experience with growth hormone treatment in children with chronic renal
      failure.
AB  - After a decade of experience with recombinant human growth hormone (rhGH) in
      children with chronic renal failure (CRF), the long-term efficacy and safety of
      the drug is now established. In prepubertal children, partial catch-up growth is
      achieved during the first three treatment years, followed by sustained percentile
      parallel growth. Discontinuation of rhGH treatment results in catch-down growth
      in 75% of patients. Treatment efficacy is inversely correlated with age and
      baseline height velocity, and positively influenced by genetic target height and
      residual renal function. Skeletal maturation is not accelerated, suggesting a
      true increase in final height potential. Side effects are limited to a
      stimulation of insulin secretion, which is not associated with changes in glucose
      tolerance, and occasional cases of benign intracranial hypertension. In summary,
      the advent of rhGH has opened a new era in the management of growth failure in
      CRF. Available evidence suggests that treatment should start in early childhood
      and early in the course of renal failure, and should be continued at least until
      renal transplantation. It remains to be seen whether the beneficial effect of
      rhGH on height observed during the prepubertal period will result in an eventual
      increase in adult height.

PMID- 10406568
TI  - The Italian Pediatric Chronic Peritoneal Dialysis Registry.

PMID- 10406569
TI  - Peritoneal dialysis in children: issues for the 21st century.

PMID- 10406570
TI  - Pediatric peritoneal dialysis in Korea: practical solutions to the problems of
      peritoneal dialysis for children.
AB  - PURPOSE: To find and solve the common problems of peritoneal dialysis (PD) by
      analyzing the clinical data of pediatric PD performed in Korea. METHODS: We
      looked at 264 cases of continuous ambulatory peritoneal dialysis (CAPD) and acute
      PD that were performed in 18 institutions of pediatric nephrology in Korea from
      November 1987 to October 1997. RESULTS: CAPD was performed in 114 cases. The mean
      age of the patients was 10.5+/-6.6 years, and the male-to-female ratio was 1.4:1.
      The original causes of end-stage renal disease (ESRD) were proven in 92 cases
      (81%). The most common renal diseases were focal segmental glomerulosclerosis
      (17%), reflux nephropathy (11%), and chronic glomerulonephritis (11%). Mean
      duration of CAPD was 20 months+/-16.9 months. Peritonitis was the most common
      complication, and the peritonitis incidence was 0.96 episode per patient-year.
      Other complications were exit-site infection in 10 cases, obstruction in 7 cases,
      and leakage of dialysate in 6 cases. The most common etiologic organism of
      peritonitis was Staphylococcus aureus and the next most common was coagulase
      negative staphylococcus. Acute PD was performed in 150 cases. The most common
      underlying causes were congenital heart disease, hemolytic uremic syndrome,
      sepsis, and dehydration. The mean duration was 10.3+/-11.3 days. The most common
      complication was peritonitis (78.3%). The most common etiologic organisms of
      peritonitis were Staphylococcus aureus, coag-neg staphylococcus, Acinetobacter,
      and Pseudomonas. CONCLUSION: Reflux nephropathy should be emphasized in early
      diagnosis and treatment to prevent ESRD. Incidence of congenital anomaly (7%) as
      a original cause of ESRD was relatively low in Korea. Growth status was not
      significantly improved after CAPD. In acute PD, the incidence of peritonitis
      rapidly increased at 2 weeks after the start of dialysis.

PMID- 10406571
TI  - Individualized prescription of peritoneal dialysis therapy?
AB  - Prescribing PD has become more challenging, but also more rewarding and
      stimulating in recent years. The number of technical aids and strategies has
      increased, and a potential exists to optimize clearances and ultrafiltration in a
      way that has not been seen before and that will, it is to be hoped, translate
      into better patient outcomes. It is crucial, however, that the technologies and
      strategies be applied with an awareness of the individual patient's particular
      lifestyle, aspirations, and social circumstances. A failure to consider these
      factors may lead to noncompliance and, ultimately, to "burnout" and technique
      failure. Patients must be educated about the importance of clearance targets so
      that they will accept the alterations in, or the onerous aspects of, the
      prescriptions they require. Successful prescribing of PD requires an awareness of
      both clearance and lifestyle factors so that the two can be integrated to give an
      effective and acceptable regimen. Finally, cost factors should also be
      considered.

PMID- 10406572
TI  - Continuous ambulatory peritoneal dialysis in high-risk patients: patients with
      cardiovascular diseases--role of the nurse.
AB  - Most patients receiving renal replacement therapy have cardiovascular disease.
      The most frequent conditions are left ventricular hypertrophy and coronary artery
      disease. Hemodialysis is associated with a characteristic spectrum of acute
      complications (such as hypotension, sudden death) that can be explained by
      typical dialysis-induced effects on the heart. With continuous peritoneal
      dialysis (CAPD) some of the cardiovascular complications are ameliorated owing to
      slow ultrafiltration and absence of an arteriovenous fistula. CAPD might be
      concluded to be the preferable option in patients with cardiovascular disease,
      but a few disadvantages, such as hyperlipidemia and hyperinsulinemia, also exist.
      Nurses also play an important role in the therapeutic success and outcomes of
      these patients.

PMID- 10406573
TI  - The disabled continuous ambulatory peritoneal dialysis patient--the nurse's role.

PMID- 10406574
TI  - Teaching continuous ambulatory peritoneal dialysis exchange procedures: impact on
      nurses.

PMID- 10406575
TI  - Evaluation of patient education.

PMID- 10406576
TI  - Comparison of two different Kt/V methods in continuous ambulatory peritoneal
      dialysis patients.
AB  - Dialysis adequacy has gained particular interest for the assessment of the
      quality of dialysis in patients undergoing hemodialysis (HD) and continuous
      ambulatory peritoneal dialysis (CAPD). Kt/V is used as a test of dialysis
      adequacy in HD and CAPD patients. The aim of this study was to compare two
      different Kt/V methods in CAPD patients. A practical method for the calculation
      of Kt/V will be suggested at the end of this prospective study. The study group
      included 28 patients. Each patient received CAPD therapy four times per day.
      During the study, CAPD dialysate samples for a period of 24 hours were obtained
      by two different methods. One is a modified method for obtaining samples by the
      patient at home; the other is the conventional method. For study purposes only,
      we told the patients using the modified method to bring all the bags to the
      center (contrary to the aim of the modified method). In the first method
      (modified method), CAPD patients collected 24-hour dialysate and urine samples at
      home and brought all of the materials to the hospital. A 10 mm3 dialysate sample
      was drawn from each CAPD dialysate bag, and then a total of 40 mm3 dialysate was
      mixed in a beaker. A sample of 10 mm3 of dialysate was taken from the mixture in
      the beaker, and then this dialysate sample, urine, and 5 mm3 venous blood were
      sent to the laboratory for urea nitrogen (UN) and creatinine level
      determinations. In addition to these tests, 24-hour dialysate and urine volumes
      and the patients' weight and height were measured, and Kt/V values were
      calculated. In the second method (classic method), all the bags from the 24-hour
      period were collected and mixed in a big bucket, and then a 10 mm3 sample was
      taken. The remaining procedures were the same as for the first method. Mean Kt/V
      values were calculated separately for the two methods and were found to be 2.48
      by the modified method and 2.52 by the classic method. The results of the two
      methods were compared with the Wilcoxon paired t-test, which showed no
      statistically significant difference (p = 0.5228). In conclusion, two different
      Kt/V methods can be used in CAPD patients. However, the modified method is easily
      performed, and CAPD patients can collect and take the dialysate and urine samples
      at home, and bring these materials to the renal unit without transportation
      problems.

PMID- 10406577
TI  - Nutritional status of Korean peritoneal dialysis patients.
AB  - OBJECTIVES: To assess the nutritional status of Korean peritoneal dialysis (PD)
      patients and to compare with data from Western literature, and to elucidate
      independent factors determining nutritional status and death. DESIGN: Cross
      sectional single-center study. SETTING: Kidney Center, Soon Chun Hyang University
      Hospital. MATERIALS: Ninety-eight CAPD patients were included. Of these, 54
      patients were male, 32 patients were diabetic, mean age was 47.9+/-13.1 years,
      and mean duration of CAPD was 22.3+/-21.6 months. The patients were followed
      until death, transfer to hemodialysis (HD) or other units, transplantation, or
      until 3 years had elapsed after the first evaluation. METHODS: Nutritional status
      was assessed by subjective global assessment (SGA), biochemical and
      anthropometric measurements, fat-free edema-free (FFEF) body mass by creatinine
      (Cr) kinetics, protein equivalent of total nitrogen appearance (PNA), and urea
      kinetic studies. RESULTS: By SGA score, 53.1% of patients were classified as
      normal, 44.9% with mild-to-moderate malnutrition, and 2% with severe
      malnutrition. Patients with malnutrition were significantly older and had higher
      peritonitis rates, lower serum albumin (Alb), blood urea nitrogen (BUN), serum
      Cr, FFEF body mass, mid arm muscle circumference, and PNA (p < 0.05). On stepwise
      multiple regression analysis, the SGA score was negatively correlated with age
      and peritonitis rate (p < 0.01). At the end of the 3-year follow-up period, 11
      patients were still on CAPD, 26 had died, 51 had transferred to HD and 5 to other
      units, 3 patients had been transplanted, and 2 patients were lost to follow-up.
      Patients who died during follow-up were older and had higher peritonitis rates
      and lower total serum protein, Alb, Cr, and FFEF body mass when compared to those
      who survived (p < 0.05). Independent predictors of death were age, peritonitis
      rate, and serum Alb (p < 0.01). CONCLUSION: Malnutrition was as common in Korean
      PD patients as reported in the Western literature. Our data suggests that, to
      prevent malnutrition and early death, it is important to reduce the peritonitis
      rate, to improve protein intake, and to prescribe an adequate dose of peritoneal
      dialysis.

PMID- 10406578
TI  - Comparison of nutritional status between peritoneal dialysis and hemodialysis
      patients.

PMID- 10406579
TI  - Malnutrition: detection and intervention.
AB  - Malnutrition is common in patients with renal failure. Causes of malnutrition in
      this population are varied and sometimes specific to the method of renal
      replacement therapy. No single marker absolutely identifies malnutrition or
      tracks changes in status. Renal dietitians use a variety of parameters and
      techniques to identify malnutrition because many of the traditional markers can
      be skewed by renal disease and its comorbidities. Once malnutrition is
      identified, treatment is also complex and not well defined. Treatment is usually
      progressive in nature, ranging from intense nutritional counseling to total
      parenteral nutrition. Further research is needed to define optimal nutrition
      status, to refine techniques to maintain optimal nutrition status, to simplify
      the identification of malnutrition, and to improve the treatment for
      malnutrition.

PMID- 10406580
TI  - The response of the slow atrioventricular nodal pathway to temperature.
AB  - The present study attempted to determine the lowest temperature at which the slow
      atrioventricular nodal pathway responds to heating and the temperature necessary
      for successful ablation of the slow pathway in patients with atrioventricular
      nodal reentrant tachycardia (AVNRT). The study group comprised 23 consecutive
      patients (14 women, 9 men) with symptomatic AVNRT. Radiofrequency current was
      delivered at the slow pathway potential recording site using a HAT 200S catheter
      ablation system. Successful radiofrequency ablation of the slow pathway was
      achieved in all 23 patients. Junctional beats, suggesting the response of the
      slow pathway to temperature, were detected in 62 of the total 136 applications.
      The temperature measured at the first junctional beat was 45.4+/-4.2 degrees C.
      The maximum temperature required for the successful ablation of AVNRT ranged from
      45 to 88 degrees C. There were no complications except for 1 patient with
      transient atrioventricular (AV) block. There were no recurrences of AVNRT during
      follow-up. The lowest temperature at which the slow pathway was responsive to
      heat was quite similar to that for accessory pathways or the AV junction.
      However, the temperature required for the successful ablation of AVNRT differed
      markedly among the patients.

PMID- 10406582
TI  - Incidence of pulmonary thromboembolism in Japan.
AB  - Pulmonary thromboembolism (PTE) is considered an uncommon disease in Japan and
      there are not any reported prospective studies on the incidence of PTE in Japan.
      The objective of the present study was to determine the number of patients with
      PTE per year in a prospective study using a questionnaire. Letters were sent to
      clinical departments in university schools of medicine or medical colleges, and
      to hospitals with more than 100 beds. The diagnosis of PTE was to be confirmed by
      (1) pulmonary artery stenosis or occlusion on pulmonary angiography, (2) mismatch
      of pulmonary perfusion scintigraphy and pulmonary ventilation scintigraphy, (3)
      changes on pulmonary perfusion scintigraphy performed twice, or (4) autopsy. The
      questionnaire elicited 2,341 replies (the withdrawal rate was 40.7%). In 231
      hospitals, 237 patients were diagnosed definitely during the study period of 2
      months from 1 August to 30 September 1996. From this it was estimated that there
      are 3,492 (95% confidence interval: 3,280-3,703) patients with PTE per year,
      which implies that the incidence is 28 persons per 1,000,000 people per year,
      confirming that PTE is rare in Japan.

PMID- 10406583
TI  - Regional left ventricular myocardial contraction abnormalities and asynchrony in
      patients with hypertrophic cardiomyopathy evaluated by magnetic resonance spatial
      modulation of magnetization myocardial tagging.
AB  - Global left ventricular (LV) pump function is generally preserved in patients
      with hypertrophic cardiomyopathy (HCM). However, it is unknown whether regional
      myocardial contractility is impaired, especially in nonhypertrophied regions. The
      purpose of this study was to evaluate regional LV myocardial contraction in
      patients with HCM using magnetic resonance (MR) spatial modulation of
      magnetization (SPAMM) myocardial tagging. The study group comprised 20 patients
      with asymmetric septal hypertrophy (HCM group) and 16 age-matched normal patients
      (control group), and data were collected using transthoracic M-mode and 2
      dimensional echocardiography, and MR SPAMM myocardial tagging. The systolic
      strain ratio, maximum systolic strain velocity, and time from end-diastole to
      maximum systolic strain (deltaT) in the anterior, ventricular septal, inferior
      and lateral regions for 2 LV short-axis sections at the levels of the chordae
      tendineae and papillary muscles were measured at 50-ms intervals by MR myocardial
      tagging. The end-diastolic anterior and ventricular septal wall thicknesses and
      LV mass index were significantly different between the HCM and control groups.
      The systolic strain ratio for all 4 walls, particularly the anterior and
      ventricular septal regions, was significantly lower in the HCM group. In the HCM
      group, the maximum systolic strain velocity was significantly lower and deltaT
      was significantly shorter for all 4 walls, particularly the anterior and
      ventricular septal regions. The standard deviation for the deltaT, calculated
      from the deltaT for the 8 regions of the 2 LV short-axis sections, was
      significantly greater in the HCM group. In conclusion, regional LV myocardial
      contraction is impaired in both hypertrophied and nonhypertrophied regions, and
      systolic LV wall asynchrony occurs in patients with HCM.

PMID- 10406581
TI  - Apical hypertrophic cardiomyopathy and hepatitis C virus infection.
AB  - The familial form of hypertrophic cardiomyopathy (HCM) is attributed to mutations
      in the genes for contractile proteins, but the etiology of non-familial form
      remains unknown. This study was designed to examine the clinical features,
      histopathologic changes, and hepatitis C virus (HCV) genomes in patients with HCM
      associated with HCV infection. Anti-HCV antibody was present in the sera of 9 of
      65 patients (13.8%) with HCM versus 2.41% in a control population of voluntary
      blood donors in Japan, a statistically significant difference (p<0.0001). Among
      these 9 patients, 6 had ace-of-spades-shaped deformities of the left ventricle
      with apical hypertrophy. Myocardial fibrosis was found in all patients, and mild
      cellular infiltration was observed in 5 patients. Type 1b HCV RNA was present in
      the sera of 5 of the 9 patients. The copy number of HCV was 5.5x10(3)-8.6x10(5)
      genomes/ml serum, and multiple clones of HCV were detected in the sera of each
      patient by an analysis of the hypervariable regions using fluorescent single
      strand conformation polymorphism. Positive strands of HCV were found in the
      hearts of 5 patients, and negative strands in the hearts of 2 patients. A high
      prevalence of HCV infection was found in patients with HCM, particularly of the
      apical variety, suggesting that HCV is an important causal agent in the
      pathogenesis of the disease.

PMID- 10406584
TI  - Exercise-induced changes in plasma atrial natriuretic peptide and brain
      natriuretic peptide concentrations in healthy subjects with chronic sleep
      deprivation.
AB  - Recent observations have shown that plasma levels of atrial natriuretic peptide
      (ANP) and brain natriuretic peptide (BNP) correlate with cardiac function or
      prognosis in heart failure patients. However, relatively little is known about
      changes in their plasma concentration during commonly occurring physiological
      states such as fatigue. Therefore, this study was designed to examine the
      physiological changes of plasma ANP and BNP concentrations using a chronic sleep
      deprivation model. Bicycle ergometer cardiopulmonary exercise tests were
      performed in 10 healthy volunteers (mean age: 22.7 years). Blood samples for
      measuring ANP and BNP were drawn during the resting state and immediately after
      each exercise test. Cardiac output (CO) was measured during the exercise test by
      the impedance method. The study conditions were designed as follows: (A) a day
      following a period of normal sleep (control state) and (B) a day preceded by 1
      month during which sleep lasted <60% of normal (chronic sleep-deprived state).
      Results were as follows. (1) Peak oxygen uptake and peak CO decreased during the
      sleep-deprived state compared with the control state. (2) There was no difference
      between peak heart rates measured during exercise under the 2 conditions. (3)
      Plasma ANP concentration during exercise increased significantly during the
      control state, whereas only a tendency toward increase was observed during the
      sleep-deprived state. (4) Plasma BNP concentration during exercise tended to
      increase in the control state compared with the resting state, whereas there was
      no difference in plasma BNP between after exercise and resting state in the sleep
      deprived state. These results indicate that changes of ANP or BNP induced by
      exercise tended to be decreased by chronic sleep deprivation.

PMID- 10406585
TI  - Gadolinium-DTPA-enhanced magnetic resonance imaging and functional outcome in
      patients with acute myocardial infarction.
AB  - This study was designed to test the hypothesis that Gadolinium-diethylenetriamine
      pentaacetic acid (Gd-DTPA)-enhanced magnetic resonance images (MRI) reflect the
      severity of ischemic injury during the acute and chronic phases of myocardial
      infarction (MI). Twenty-nine patients with their first acute MI underwent Gd-DTPA
      enhanced MRI in the first week (4.2+/-0.3 days) and at 1 month after onset. Pairs
      of left ventriculograms were compared with Gd-DTPA-enhanced magnetic resonance
      images, classified into 3 pattern groups: hyper-enhancement, with and without a
      central hypo-enhanced region (P1 and P2, respectively), and non-enhancement (P3).
      In the acute phase of MI, P1 was found in 10, P2 in 11, and P3 in 8 patients. One
      month later, the image pattern had changed from P1 to P2 in a single patient,
      from P2 to P3 in 4 patients, and had remained identical in the others. Patients
      with P3 showed improvement of anterior wall motion in the 1-month follow-up
      study, and had higher TIMI flow grades and lower peak creatine kinase values than
      those without recovery. Thus, Gd-DTPA-enhanced magnetic resonance images, closely
      reflecting the severity of myocardial injury, are useful in predicting myocardial
      functional recovery after MI.

PMID- 10406586
TI  - Kinetics of pulmonary gas exchange during and while recovering from exercise in
      patients after anterior myocardial infarction.
AB  - The effect of exercise intensity on gas exchange kinetics was investigated during
      exercise and recovery, as well as the relationship between the kinetics during
      exercise and recovery. Twenty-three patients with a history of anterior
      myocardial infarction performed low-intensity (38.7+/-8.3 W) and high-intensity
      (68.8+/-15.0 W) exercise for 6 min. The time constants of oxygen uptake (VO2),
      carbon dioxide output (VCO2) and minute ventilation (VE) were significantly
      prolonged during high intensity exercise compared with low-intensity exercise
      (61.2+/-8.6 vs 52.3+/-10.3 s, p<0.005 for the time constant of VO2). The time
      constant of VO2 was similar during exercise and during recovery from exercise of
      high (61.2+/-8.6 vs 66.2+/-12.2 s) as well as low intensity (52.3+/-10.3 vs
      55.0+/-10.1 s). However, the time constants of VCO2 and heart rate were
      significantly shorter during recovery than during exercise. The time constants of
      VCO2 and VE were significantly longer than that of VO2 during both exercise and
      recovery. In the present study, it was found that (1) the gas exchange kinetics
      were influenced by the intensity of exercise; (2) the kinetics during recovery
      did not necessarily reflect the kinetics during exercise except for VO2; and (3)
      the kinetics of VCO2 and VE were delayed as compared with the VO2 kinetics. These
      characteristics should be taken into account when using gas exchange kinetics to
      estimate cardiopulmonary responses to exercise in patients with left ventricular
      dysfunction.

PMID- 10406587
TI  - Unsuitability of corrected QT dispersion as a marker for ventricular arrhythmias
      and cardiac sudden death after acute myocardial infarction.
AB  - The present study investigated whether corrected QT (QTc) dispersion could play a
      role as a marker of ventricular arrhythmias and sudden cardiac death after acute
      myocardial infarction (MI). The study included 76 males and 24 females with a
      mean age of 60+/-11 years. Standard 12-lead ECGs were recorded during the
      recovery phase (15+/-9 days) after the onset of MI. The QTc was calculated
      according to Bazett's formula and QTc dispersion was calculated as the difference
      between the maximum and minimum QTc intervals. Patients were divided into 2
      groups: 21 patients (group A) had a QTc dispersion of > or =80ms, and the other
      79 patients (group B) had a QTc dispersion of <80ms in the recovery stage (15+/-9
      days). Clinical, angiographical, and Holter monitoring data, and prognosis (mean
      follow-up period 29+/-18 months) were compared between these 2 groups. The
      frequencies of early coronary reperfusion and recanalization of infarct-related
      vessels during the recovery phase were significantly higher in group B than group
      A. The left ventricular ejection fraction was also higher in group B than group A
      (51+/-12 vs 43+/-12%, p=0.0029). There were no significant differences in the
      number of premature ventricular contractions, the percentage of patients with
      repetitive ventricular arrhythmias, or in the frequency of sudden cardiac death
      during the follow-up period between the 2 groups. In summary, QTc dispersion in
      the recovery stage is not a useful marker for ventricular arrhythmias or sudden
      cardiac death after acute MI, although increased QTc dispersion may correlate
      with an ineffective early coronary reperfusion and with the degree of depressed
      left ventricular function.

PMID- 10406588
TI  - Combined effects of probucol and benzafibrate on lipoprotein metabolism and liver
      cholesteryl ester transfer protein mRNA in cholesterol-fed rabbits.
AB  - Probucol decreases and bezafibrate increases plasma high density lipoprotein
      cholesterol (HDL-C) levels in humans. This study was performed to determine
      whether the HDL-C-lowering effects of probucol could be reversed by treatment
      with bezafibrate in hypercholesterolemic rabbits. Forty-nine normolipidemic
      Japanese White rabbits were divided into 5 groups [group 1: normal chow; group 2:
      0.2% cholesterol (Ch) diet; group 3: 0.2% Ch and 1% probucol diet; group 4: 0.2%
      Ch and 1% bezafibrate diet; group 5: 0.2% Ch and 1% probucol plus 1% bezafibrate
      diet] and treated for 8 weeks. Plasma lipids, cholesteryl ester transfer protein
      (CETP) activity in the lipoprotein-deficient plasma fraction, CETP mRNA in liver
      tissue and plasma drug concentrations were investigated. Serum total cholesterol
      (TC) increased after the rabbits in groups 2, 3, 4 and 5 were fed Ch, but
      overall, no significant differences were observed in serum TC and triglyceride
      (TG) among these groups. Serum HDL-C levels increased (p<0.01) in the bezafibrate
      treated group, but a significant (p<0.05) reduction in HDL-C was observed in both
      the Ch + probucol (group 3) and Ch + probucol plus bezafibrate (group 5) groups;
      no significant difference was observed between groups 3 and 5. Significant
      correlation (p<0.01) was found between serum low density lipoprotein cholesterol
      (LDL-C) levels and plasma probucol concentrations in groups 3 and 5, but no
      correlation was found between plasma concentrations of probucol/bezafibrate and
      serum HDL-C levels. CETP activity in the lipoprotein-deficient plasma fraction
      increased in the Ch-, Ch + probucol-, and Ch + probucol and bezafibrate-fed
      groups (groups 2, 3 and 5, respectively), whereas a significant reduction in this
      activity was observed in the Ch + bezafibrate-fed group (group 4). An analysis of
      covariance showed that the CETP activity responded more sensitively to drug
      treatment than did the serum HDL-C level. CETP mRNA in liver tissue was assessed
      by Northern blotting at 8 weeks, but no changes were observed among the 5 groups.
      Probucol decreased and bezafibrate increased serum HDL-C levels, through CETP
      activity without affecting liver CETP mRNA levels, and the decrease in HDL-C
      levels produced by probucol could not be reversed by bezafibrate.

PMID- 10406589
TI  - Histological observations and the process of ultrasound contrast agent
      enhancement of tissue plasminogen activator thrombolysis with ultrasound
      exposure.
AB  - Although the enhancement of tissue plasminogen activator (tPA) induced
      thrombolysis by ultrasound has been reported to be augmented by ultrasound
      contrast agents (UCA), few data exist regarding its process. The present study
      evaluated the effect of a galactose based UCA on the efficacy of ultrasonic
      enhancement of tPA thrombolysis and observed the serial changes in the acoustic
      property and histopathology. A catheter-type transducer capable of ultrasound
      emission in both continuous (CW) and pulsed wave (PW) was used. The tPA
      thrombolysis was studied in 30 artificial white thrombi, which were assigned to 4
      study groups based on insonation modes and with and without UCA. Each sample was
      suspended in 100ml saline in a beaker. Five minutes after tPA (8000U)
      administration, ultrasound was applied for 10min. For the UCA-treated groups, UCA
      (0.25g) was added 5 min after the start of ultrasound exposure. The alteration of
      the thrombus was monitored with echography. Weight reduction of the thrombus was 
      25+/-6% in PW and -30+/-7% in CW, which was significantly enhanced by UCA
      treatment, 40+/-3% (p<0.005) in PW+UCA and -43+/-7% (p<0.005) in CW+UCA. The area
      of thrombus echo image minimally decreased with ultrasound alone (-12+/-6%: PW, 
      23+/-11%: CW). In the UCA groups, UCA induced a remarkable reduction of size (
      36+/-3%: PW+UCA, -43+/-7%: CW+UCA) with a high-echo intensity in the superficial
      layer of the thrombus, where multiple cavity formation was observed by light
      microscope. UCA markedly enhanced the effect of ultrasound on tPA thrombolysis.
      The altered acoustic property and corresponding histological microcavity
      formation in the shallow layer within the thrombus suggests that UCA augmented
      infiltration of tPA into the thrombus.

PMID- 10406590
TI  - Postmortem evaluation of morphologic changes in the infarcted myocardium that
      predict ventricular septal rupture in acute anteroseptal infarction.
AB  - Although thinning of the ventricular wall due to infarct expansion (septal
      aneurysm) may contribute to ventricular septal rupture (VSR), spatial factors
      predisposing to this mechanical complication have not been fully demonstrated. To
      identify the morphologic predictors of VSR, a retrospective postmortem study was
      performed on 17 hearts with acute anteroseptal myocardial infarction, comprising
      7 with VSR and 10 without rupture. Infarct size and the extent of wall thinning
      were quantified. Wall thinning was defined as a decrease of less than 50% of
      thickness of the noninfarcted wall. The total infarct size did not differ among
      the groups. In the free wall (FW), the infarct was smaller in hearts with VSR
      than in those with a ruptured FW (p<0.05) or no rupture (p<0.01). The septal
      involvement was more extensive in patients with VSR than in those with FW rupture
      (p<0.05). Septal thinning was more extensive in hearts with VSR than in those
      with FW rupture (p<0.05) or non-rupture (p<0.05). A combination of a small
      infarct of the FW and a large septal infarct may contribute to the formation of
      septal aneurysm, which is believed to predispose to VSR. The presence of a small
      infarct of the anterior septum may be another setting for postinfarction septal
      rupture.

PMID- 10406591
TI  - Reduced size of liquefaction necrosis of mitral annular calcification in chronic
      renal failure by using low calcium concentration hemodialysis.
AB  - A report is presented of a liquefaction necrosis of mitral annular calcification
      in a patient with chronic renal failure and secondary hyperparathyroidism who had
      been managed by hemodialysis for 11 years. The mass was echogenic with an echo
      lucent area inside, high density on computed tomography and low intensity on
      magnetic resonance imaging. The uptake of gallium-67 (67Ga)-citrate and the bone
      agent technetium-99m-methylene diphosphate (99mTc-MDP) was seen in the mass.
      These findings were compatible with liquefaction necrosis of the mitral annular
      calcification. After treatment with low calcium concentration hemodialysis, the
      size of the mass reduced with disappearance of the echo-lucent area on the
      echocardiography and there was no uptake of 67Ga-citrate or 99mTc-MDP.
      Liquefaction necrosis might be the early and reversible form of mitral annular
      calcification. When a tumorlike echogenic mass at the base of mitral leaflets is
      seen in patients with predisposing factors for mitral annular calcification,
      consider the possibility of this specific form of mitral annular calcification in
      order to avoid any unnecessary surgical intervention.

PMID- 10406592
TI  - A case of vasospastic angina presenting Brugada-type ECG abnormalities.
AB  - An electrophysiological study and a provocative test of coronary artery spasm was
      attempted in a 68-year-old man who was having syncopal attacks and chest pain.
      His electrocardiogram had the characteristics of Brugada syndrome and ventricular
      fibrillation (VF) was induced by programmed electrical stimulation. ST-segment
      elevation became exaggerated by procainamide, which could not prevent the
      induction of VF. Coronary angiography revealed no stenotic lesions, and spasm in
      the left coronary artery was induced by intracoronary administration of
      acetylcholine with similar chest pain to that experienced before. Under treatment
      with diltiazem and flecainide, which suppressed the induction of VF, the patient
      experienced no recurrence of symptoms despite persistent ST-segment elevation. No
      previous reports have described coronary spasm associated with Brugada-type ECG
      abnormalities, and patients with syncope should be evaluated carefully.

PMID- 10406593
TI  - Analysis of heart rate variability during head-up tilt testing in a patient with
      idiopathic postural orthostatic tachycardia syndrome (POTS).
AB  - A 16-year-old boy was diagnosed with idiopathic postural orthostatic tachycardia
      syndrome (POTS) during head-up tilt testing. During a passive tilt, the patient's
      heart rate (HR) increased by 30 beats/min within 5 min. After 25 min of tilting,
      his HR further increased to 133 beats/min and he began to complain of
      lightheadedness and weakness without hypotension. Power spectral analysis of HR
      variability during the tilt test revealed that the ratio of low and high
      frequency powers increased with the onset of orthostatic intolerance. Propranolol
      (10mg every morning) dramatically alleviated his clinical symptoms, and he has
      been asymptomatic with gaining weight after discontinuing his crowded train
      commuting.

PMID- 10406594
TI  - A case of diffuse pulmonary arteriovenous fistula.
AB  - A 30-year-old Japanese woman was admitted to hospital for dyspnea. She had a
      history of corrective surgery for a large atrial septal defect and partial
      anomalous pulmonary venous drainage, which had produced cyanosis in her infancy.
      However, her cyanosis continued postoperatively. Angiography revealed a double
      inferior vena cava (IVC), with the left IVC connected with the hemiazygos vein
      and the right IVC with the left atrium through a very small orifice. Most of the
      blood from the 2 IVCs flowed into the superior vena cava via the distended azygos
      and hemiazygos veins. Pulmonary arteriography revealed no abnormal structures.
      Pulmonary arterial pressure was normal. There was marked pulmonary venous oxygen
      desaturation. Perfusion lung scintigraphy revealed multiple segmental perfusion
      defects. These findings suggested the presence of diffuse microscopic pulmonary
      arteriovenous fistulas bilaterally in the lungs. The patient appears to be the
      first reported adult case of microscopic and diffuse arteriovenous fistulas.
      Neither resection of the arteriovenous fistulas nor corrective surgery for the
      diversion was indicated, and heart-lung transplantation might be the only
      treatment able to relieve her dyspnea.

PMID- 10406595
TI  - Corneal transplant suture adjustment.

PMID- 10406596
TI  - MRI for metallic foreign bodies?

PMID- 10406597
TI  - Phacoemulsification and silicone oil removal through a single incision.

PMID- 10406599
TI  - Retinal arterial occlusion with LIF using rTPA.

PMID- 10406598
TI  - Phacoemulsification and silicone oil removal through a single incision.

PMID- 10406600
TI  - Can laser photocoagulation of eyes with high-risk drusen prevent vision loss from
      age-related macular degeneration?

PMID- 10406601
TI  - A prospective comparative study of the AMO ARRAY zonal-progressive multifocal
      silicone intraocular lens and a monofocal intraocular lens.
AB  - OBJECTIVE: To evaluate the safety and effectiveness of a zonal-progressive
      multifocal silicone intraocular lens (IOL). DESIGN: Prospective, nonrandomized,
      fellow eye comparative trial. PARTICIPANTS: Four hundred fifty-six subjects were
      enrolled at 14 investigational sites in the United States; 400 subjects achieved
      1-year follow-up. A subset of 123 subjects (102 at 1 year) were enrolled in a
      monofocal fellow eye control substudy; subjects were implanted with the
      multifocal IOL in one eye and a comparable monofocal IOL in the fellow eye.
      METHODS: Cataract extraction and implantation of a zonal-progressive multifocal
      silicone IOL was performed using the surgeon's standard technique. Subjects were
      followed at six postoperative examination intervals through 1 year. MAIN OUTCOME
      MEASURES: The key efficacy measures were mean uncorrected and corrected distance
      and near visual acuity at 1 year after surgery. RESULTS: In the monofocal fellow
      eye control substudy, the multifocal eyes showed a mean 2-line increase over
      monofocal eyes for uncorrected and distance-corrected near visual acuity (P <
      0.0001). Mean uncorrected distance visual acuity was similar between multifocal
      and monofocal eyes (P = 0.116). A significantly higher proportion of bilateral
      multifocal subjects reported that they could function comfortably without glasses
      at near (81%, 96 of 118) compared with multifocal/monofocal subjects (56%; 93 of
      165; P < 0.001) and unilateral multifocal subjects (58%; 56 of 97; P < 0.001).
      Low-contrast visual acuity was reduced in multifocal eyes by approximately 1
      Snellen line. However, no perceived disadvantages attributable to the reduction
      in low-contrast acuity were found. Although the perception of halos and glare
      increased in the multifocal eyes, good visual function remained, and nearly all
      subjects were satisfied with the results of their surgery. CONCLUSIONS: In a
      large study that included a subset of subjects with paired eye compared with
      those with monofocal lenses, this zonal-progressive multifocal lens provided a
      high level of uncorrected and corrected distance vision, improved uncorrected and
      distance-corrected near vision, reduced spectacle dependency, and a high level of
      patient satisfaction despite some loss of low-contrast visual acuity and
      increased reports of halos and glare.

PMID- 10406602
TI  - Effectiveness of monitored anesthesia care in cataract surgery.
AB  - OBJECTIVE: To determine the need for monitored anesthesia care in cataract
      surgery by evaluating the incidence of intervention by anesthesia personnel and
      by looking for associated risk factors. DESIGN: Nonrandomized, prospective case
      series with analysis of consecutive cataract surgery cases. PARTICIPANTS: A total
      of 1006 consecutive cataract surgery patients at an ambulatory surgery center
      over a 6-month period. METHODS: Routine cataract surgery was performed with the
      patient under local anesthesia. A detailed questionnaire was completed by the
      anesthesia personnel at the conclusion of each phase (before, during, and after)
      of cataract surgery. MAIN OUTCOME MEASURES: Age, medical history, and
      preoperative electrocardiogram (EKG) were analyzed as predictors for intervention
      by anesthesia personnel. The nature of the patient's problem and the type of
      intervention by anesthesia personnel were recorded. RESULTS: In 1006 consecutive
      cataract surgery cases, intervention by anesthesia personnel was required in 376
      (37.4%) cases. No preoperative identifying characteristics were found to be
      reliable predictors of the need for intervention. There were no statistically
      significant differences in preoperative EKG and some medical conditions such as
      heart disease, diabetes, and thyroid disease between patients who received
      intervention and those who did not. Certain subgroups of patients did show a
      statistically significantly greater incidence of intervention, including systemic
      hypertensives (41.4%) versus nonhypertensives (34.5%) (P = 0.030), patients with
      pulmonary disease (49.3%) versus no pulmonary disease (36.5%) (P = 0.043),
      patients with renal disease (68.8%) versus no renal disease (36.9%) (P = 0.019),
      and patients with cancer (61.9%) versus no cancer (36.3%) (P = 0.001).
      Intervention was also required in 61.1 % of patients younger than 60 years of age
      compared to 36.5% of those patients 60 years of age and older (P = 0.005).
      CONCLUSIONS: Because intervention is required in more than one third of cataract
      surgery cases and the authors cannot reliably predict those patients at risk,
      monitored anesthesia care seems justified in cataract surgery with the patient
      under local anesthesia.

PMID- 10406603
TI  - Potential acuity pinhole: a simple method to measure potential visual acuity in
      patients with cataracts, comparison to potential acuity meter.
AB  - OBJECTIVE: To describe the potential acuity pinhole (PAP) test and compare its
      accuracy to the potential acuity meter (PAM) in predicting visual outcome after
      cataract surgery. STUDY DESIGN: Prospective case series. PARTICIPANTS: A total of
      56 preoperative patients with cataracts participated. MAIN OUTCOME MEASURES:
      Accuracy of predicting postoperative distance visual acuity was measured.
      METHODS: Lines of inaccuracy were calculated by subtracting actual postoperative
      best-corrected distance visual acuity (BCVA) from predicted values. Variables
      analyzed were method of prediction, preoperative BCVA, and preoperative spherical
      equivalent. RESULTS: The PAP test predicted visual outcomes within 2 lines in
      100%, 100%, and 56% of eyes with preoperative BCVA of 20/50 and better (group 1),
      20/60 to 20/100 (group II), and 20/200 and worse (group III), respectively. The
      PAM predictions within 2 lines for the same groups were 42%, 47%, and 0%,
      respectively. Mean lines of inaccuracy of PAP predictions were 0.83, 1.11, and
      3.50 lines for groups I, II, and III, respectively. Mean lines of inaccuracy for
      PAM predictions were 2.50, 2.68, and 6.22 lines for the same groups. Differences
      in lines of prediction between PAM and PAP were 1.67 (P = 0.004), 1.58 (P =
      0.0002), and 2.72 lines (P = 0.0001) for groups I, II, and III, respectively.
      There was no statistically significant correlation between PAP predictions and
      preoperative myopic spherical equivalent. CONCLUSIONS: The PAP test is a simple,
      inexpensive, and relatively reliable method to estimate visual outcome after
      uncomplicated cataract surgery in eyes with no coexisting disease. It is less
      accurate in patients with preoperative BCVA worse than 20/200. It appears to be
      more predictive than PAM.

PMID- 10406604
TI  - The treatment of traumatic optic neuropathy: the International Optic Nerve Trauma
      Study.
AB  - OBJECTIVE: To compare the visual outcome of traumatic optic neuropathy treated
      with corticosteroids, treated with optic canal decompression surgery, or observed
      without treatment. DESIGN: Comparative nonrandomized interventional study with
      concurrent treatment groups. PARTICIPANTS: A total of 133 patients with traumatic
      optic neuropathy (127 unilateral and 6 bilateral) who had an initial visual
      assessment within 3 days of injury. At least 1 month of follow-up was required
      for inclusion in the primary analysis. INTERVENTIONS: On the basis of treatment
      received within 7 days of injury, patients with unilateral injuries were
      categorized as being in one of three treatment groups: untreated (n = 9),
      corticosteroid (n = 85), or optic canal decompression surgery (n = 33). MAIN
      OUTCOME MEASURE: Visual acuity. RESULTS: Visual acuity increased by > or = 3
      lines in 32% of the surgery group, 57% of the untreated group, and 52% of the
      steroid group (P = 0.22). The surgery group had more patients whose initial
      vision was no light perception. After adjustment for the baseline visual acuity,
      there were no significant differences between any of the treatment groups. There
      was no indication that the dosage or timing of corticosteroid treatment or the
      timing of surgery was associated with an increased probability of visual
      improvement. CONCLUSIONS: No clear benefit was found for either corticosteroid
      therapy or optic canal decompression surgery. The number of patients studied was
      sufficient to rule out major effects in the treatment groups, although clinically
      relevant effects in specific subgroups could have been missed. These results and
      the existing literature provide sufficient evidence to conclude that neither
      corticosteroids nor optic canal surgery should be considered the standard of care
      for patients with traumatic optic neuropathy. It is therefore clinically
      reasonable to decide to treat or not treat on an individual patient basis.

PMID- 10406605
TI  - Are optic disc drusen inherited?
AB  - OBJECTIVE: To conduct family studies of the incidence of optic disc drusen and
      related optic disc anomalies among relatives of those affected. DESIGN:
      Retrospective case series with prospective examination of patients and their
      relatives using B-scan ultrasonography and color photography. PARTICIPANTS: A
      total of 27 relatives of 7 probands with bilateral optic disc drusen were
      examined. MAIN OUTCOME MEASURES: Presence of optic disc drusen on clinical
      examination or B-scan ultrasonography and presence of related anomalies,
      including absence of optic disc cup and presence of anomalous vasculature.
      RESULTS: Only 1 of 27 relatives had optic disc drusen (3.7%). Thirty of 53 eyes
      had anomalous vessels (57%), and 26 eyes had no optic cup (49%). CONCLUSION: The
      primary pathology of optic disc drusen is likely to be an inherited dysplasia of
      the optic disc and its blood supply, which predisposes to the formation of optic
      disc drusen.

PMID- 10406607
TI  - Positron emission tomography scan in cortical visual loss in patients with
      organophosphate intoxication.
AB  - OBJECTIVE: To determine the cerebral metabolism of patients with cortical visual
      loss. DESIGN: Two observational case studies. TESTING: Two patients who survived
      acute organophosphate poisoning with respiratory failure experienced severe
      visual loss despite relatively normal ophthalmic examination results. Magnetic
      resonance imaging of the brain revealed no abnormality of the visual system in
      either patient. Positron emission tomography (PET) was performed in these 2
      patients and in 12 normal subjects with fluorine-18 fluorodeoxyglucose (FDG) as a
      tracer to measure cerebral glucose metabolism for the estimation of neurologic
      deficit in the visual cortex. MAIN OUTCOME MEASURES: The FDG uptake values were
      measured as nanoCurie per cubic centimeters of tissue (nCi/cc). The relative
      uptake index in visual cortex was computed as the ratio of uptake of FDG in each
      region of visual cortex to that of cerebellum (regional visual
      cortex/cerebellum). RESULTS: Hypometabolism was observed in the visual cortex of
      both patients. The relative uptake index of FDG in visual cortex (visual
      cortex/cerebellum) was significantly decreased in those patients compared with
      normal subjects. CONCLUSIONS: In patients with cortical visual loss, conventional
      neuroimaging techniques can fail to visualize damage that can be detected by PET
      scanning, and PET analysis may be helpful in estimating the metabolic deficit of
      visual cortex and in establishing the organic nature of cortical visual loss in
      these patients.

PMID- 10406606
TI  - An ice test for the diagnosis of myasthenia gravis.
AB  - OBJECTIVE: To determine whether ice application to a ptotic eyelid can
      differentiate myasthenic from nonmyasthenic ptosis. DESIGN: Prospective,
      multicenter, nonrandomized, comparative trial. PARTICIPANTS: Twenty patients with
      myasthenia gravis (MG) and ptosis were evaluated in the neuro-ophthalmology
      service. CONTROL SUBJECTS: Twenty patients with nonmyasthenic ptosis evaluated in
      the same locale. METHODS: Palpebral fissures were measured before and immediately
      after a 2-minute application of ice to the ptotic eyelid. MAIN OUTCOME MEASURES:
      The difference in palpebral fissures in millimeters before and after ice
      application. Two or more millimeters of improvement after ice application was
      considered a positive ice test result. RESULTS: A positive ice test result was
      noted in 16 of the 20 (80%) patients with MG and in none of the 20 patients
      without MG (P < 0.001). Of the 4 patients with MG and complete ptosis, 3 had a
      negative ice test result. CONCLUSIONS: The ice test is a simple, short, specific,
      and relatively sensitive test for the diagnosis of myasthenic ptosis. The
      sensitivity of the ice test in patients with complete ptosis decreases
      considerably.

PMID- 10406608
TI  - Pathologic causes of the superior oblique click syndrome.
AB  - PURPOSE: To describe the clinical features in two patients with superior oblique
      click syndrome and the pathologic causes of their symptoms. DESIGN: Two
      observational case reports. PARTICIPANTS: Two patients. METHODS: The clinical
      histories, results of physical examinations, treatment, and pathologic findings
      in two patients with superior oblique click syndrome are reviewed and analyzed
      with reference to the literature. MAIN OUTCOME MEASURES: Relief of symptoms.
      RESULTS: Both patients were operated on; one was found to have a schwannoma and
      the other a giant cell tumor of tendon sheath as causes of their symptoms.
      Symptoms were relieved by removal of the lesions and have not recurred.
      CONCLUSION: Definite pathologic lesions may cause the superior oblique click
      syndrome.

PMID- 10406610
TI  - Suck and spit, don't blow: orbital emphysema after decompression surgery.
AB  - PURPOSE: To describe the occurrence of vision-threatening orbital emphysema in
      patients awakening from orbital decompression surgery and to assess risk factors
      and preventive measures. DESIGN: Small noncomparative case series. PARTICIPANTS:
      Three patients undergoing bilateral orbital two-wall decompression experienced
      significant orbital emphysema associated with persistent coughing and Valsalva at
      the time of extubation. INTERVENTION: In two patients, symptoms resolved with
      simple observation, whereas one patient required sedation, topical anesthesia
      around the endotracheal tube, and needle decompression of trapped air. MAIN
      OUTCOME MEASURES: Visual acuity, pupils, visual fields, and sensorimotor
      examination. RESULTS: No patient experienced a permanent deficit of visual or
      sensorimotor function. CONCLUSIONS: Acute orbital emphysema can occur after
      orbital decompression surgery despite the large bony opening created. Violent
      coughing spells at the time of extubation are more common in patients with a
      history of heavy tobacco use and may be causative. Opening the periorbita may be
      another specific predisposing risk factor. Knowledge of this dangerous
      phenomenon, along with appropriate perioperative management, may prevent this
      complication from occurring.

PMID- 10406609
TI  - Direct orbital manometry in patients with thyroid-associated orbitopathy.
AB  - PURPOSE: To determine orbital tissue tension and orbital compartment compliance
      in patients with and without thyroid-associated orbitopathy (TAO). DESIGN:
      Prospective case series. PARTICIPANTS: Orbits of patients with TAO (18 orbits)
      and control patients without TAO (35 orbits) were studied. METHODS: An orbital
      manometer was designed to directly measure orbital tissue tension in patients
      undergoing ocular or orbital surgery. MAIN OUTCOME MEASURES: Tissue tension was
      recorded before, during, and for 5 minutes after a 5-ml retrobulbar injection of
      anesthetic. Orbital compliance was calculated as change in volume divided by
      change in tissue tension. RESULTS: Resting orbital tissue tension was 4.4 +/- 2.2
      mmHg (mean +/- SD) in normal orbits and 9.7 +/- 4.8 mmHg in orbits of TAO
      patients (P = 0.0005) Following retrobulbar injection, orbital tissue tension
      rose to 12.0 +/- 3.6 mmHg (P = 0.0000000000000006 compared with baseline) in the
      control group and to 36.3 +/- 15.2 mmHg in the TAO group (P = 0.0000007 compared
      with baseline, and P = 0.000008 TAO group versus control group). Orbital
      compartment compliance was 0.80 +/- 0.50 ml/mmHg in the control group and 0.27 +/
      0.21 ml/mmHg in the TAO group (P = 0.00001). Resting orbital tissue tension in 8
      TAO orbits with compressive optic neuropathy was 12.4 +/- 4.9 mmHg, and was 7.8
      +/- 3.5 mmHg in 10 orbits of TAO patients without compressive optic neuropathy (P
      < 0.05). No adverse events occurred. CONCLUSIONS: Retrobulbar injection causes
      consistent measurable changes in orbital tissue tension. Orbital manometry safely
      demonstrated higher orbital tissue tension and lower orbital compartment
      compliance in the orbits of TAO patients versus those of normal subjects. Resting
      orbital tissue tension was higher in the orbits of TAO patients with compressive
      optic neuropathy than in those orbits without. Compressive optic neuropathy may
      partially result from an orbital compartment syndrome in some patients with TAO.
      Directly assessing orbital dynamics in vivo may prove useful as an adjunct in the
      clinical evaluation of patients with TAO and other orbital disorders.

PMID- 10406611
TI  - Retained stenting material: an unusual cause of dacryocystorhinostomy failure.
AB  - OBJECTIVE: To highlight a troubling cause of dacryocystorhinostomy (DCR) failure
      and to alert ophthalmologists to the potential problems that can result when
      stenting material is not removed and becomes retained after DCR. DESIGN:
      Consecutive noncomparative case series. PARTICIPANTS: Twelve patients who
      underwent revision DCR from February 1994 to January 1997. INTERVENTION:
      Endoscopic DCR, pre- and postoperative nasal endoscopy, preoperative computerized
      tomography (CT), and pre- and postoperative Jones testing. RESULTS: Fourteen
      revision endoscopic procedures were performed on 12 patients with recurrent
      epiphora following DCR. Failure was due to retained stenting material in six
      patients, a small bony rhinostomy in three patients, excessive scar formation
      within the rhinostomy in two patients, and improper location of the rhinostomy in
      one patient. Preoperative endoscopy and CT scan each correctly identified the
      retained sponge or tubing in four of six patients. CONCLUSIONS: Fastening a small
      sponge to Silastic tubing and positioning it within the DCR site in an attempt to
      retard DCR stenosis can be associated with a poor outcome and should be avoided.
      The nasal endoscope provided excellent visualization of pathology within the
      lacrimal sac and was a valuable tool. Retained stenting material should be
      considered in patients with persistent epiphora following DCR or intubation prior
      to any decision to commit a patient to permanent Jones tube placement.

PMID- 10406612
TI  - Monocanalicular lesions: to reconstruct or not.
AB  - OBJECTIVE: To evaluate the success rate of a simple surgical method for the
      treatment of a monocanalicular lacrimal lesion. DESIGN: Retrospective
      noncomparative case series. PARTICIPANTS: Thirteen consecutive patients with
      monocanalicular trauma who were seen from August 1995 to March 1998. In six
      patients, the canaliculus was lacerated as a result of an external injury and in
      seven patients as a result of tumor removal (iatrogenic injury). INTERVENTION:
      Reapproximation of the orbicularis muscle and skin overlying the torn canaliculus
      without reanastomosis of the lacerated canaliculus. In those patients in whom the
      canaliculus was sacrificed as part of the removal of an eyelid tumor, no attempt
      was made to reconstruct the canaliculus. MAIN OUTCOME MEASURES: Symptomatology,
      patency of the lacrimal passage, fluorescein dye disappearance test, and patient
      satisfaction. RESULTS: In all patients the injured canaliculus was totally
      blocked, but despite this none of the patients complained of inconvenient tearing
      either indoors or outdoors. The ipsilateral unharmed canaliculus was functioning
      normally in such a way that the fluorescein dye instillation test showed residual
      dye in six patients after 2 minutes and in none of the patients after 5 minutes.
      All patients were satisfied with the functional and cosmetic result. CONCLUSION:
      Nonrepair of a monocanalicular lesion is a valid approach that results in little
      or no morbidity.

PMID- 10406613
TI  - Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review.
AB  - OBJECTIVE: To identify resistance patterns to the fluoroquinolones for patients
      with bacterial keratitis. DESIGN: Retrospective observational case series.
      PARTICIPANTS: All cases of bacterial keratitis presenting to the Charles T.
      Campbell Ophthalmic Microbiology Laboratory at the Eye and Ear Institute of
      Pittsburgh from January 1993 to December 1997 were reviewed. A total of 1053
      ocular isolates from 825 cases of bacterial keratitis were identified. MAIN
      OUTCOME MEASURES: In vitro laboratory susceptibility testing of ocular isolates
      to ciprofloxacin and ofloxacin was determined by the Kirby-Bauer disk diffusion
      method and interpreted using the National Committee for Clinical Laboratory
      Standards serum standards. RESULTS: The number of cases of bacterial keratitis
      per year decreased from 284 in 1993 to 75 in 1997. The ratio of gram-positive to
      gram-negative organisms changed from 81.8%:18.2% in 1993 to 51.4%:48.6% in 1997
      (chi-square, 66.00; degrees of freedom, 4; P < 0.000001). Resistance of
      Staphylococcus aureus to ciprofloxacin significantly increased annually from 5.8%
      in 1993 to 35.0% in 1997 (chi-square, 19.80; degrees of freedom, 4; P < 0.0001)
      and for ofloxacin from 4.7% to 35.0% over the same period (chi-square, 21.32;
      degrees of freedom, 4; P < 0.001). Streptococcus species and coagulase-negative
      Staphylococcus species showed significant resistance to both fluoroquinolones but
      no change in resistance over the study period. The gram-negative organisms showed
      good susceptibility to the fluoroquinolones. CONCLUSIONS: This in vitro study
      shows a significant increased resistance of S. aureus to the fluoroquinolones
      from 1993 to 1997. In addition, gaps in fluoroquinolone coverage for
      Streptococcus and coagulase-negative Staphylococcus species raise concern for the
      use of monotherapy in treating bacterial keratitis. Contrary to what might be
      expected, the distribution of gram-positive to gram-negative organisms has
      shifted, with a decrease in the number of gram-positive organisms identified,
      while the number of gram-negative isolates has remained stable.

PMID- 10406614
TI  - Ciprofloxacin-resistant Pseudomonas keratitis.
AB  - OBJECTIVE: To determine ciprofloxacin resistance of corneal isolates of
      Pseudomonas and to review the clinical response to topical therapy in cases of
      ciprofloxacin-resistant Pseudomonas keratitis, where medical therapy was begun
      with 0.3% ciprofloxacin. DESIGN: Retrospective noncomparative case series.
      PARTICIPANTS: Medical and microbiology records of 141 culture-proven cases of
      Pseudomonas keratitis, examined between January 1991 and June 1998, were reviewed
      retrospectively. METHODS: All isolates of the Pseudomonas species from corneal
      scrapings were tested for their susceptibility to routinely used antibiotics by
      the Kirby-Bauer disc-diffusion method. The minimum inhibitory concentration of
      ciprofloxacin was determined by the agar-dilution method for most of the isolates
      found resistant to ciprofloxacin. Clinical response to initial therapy with 0.3%
      ciprofloxacin was determined in cases of keratitis caused by ciprofloxacin
      resistant Pseudomonas. MAIN OUTCOME MEASURES: Resistance of Pseudomonas isolates
      to ciprofloxacin and clinical response to initial therapy with 0.3%
      ciprofloxacin. RESULTS: By use of the in vitro antimicrobial susceptibility test,
      22 cases of keratitis caused by ciprofloxacin-resistant Pseudomonas were
      identified. The minimum inhibitory concentration of ciprofloxacin for these
      isolates was > or =16 microg/ml (mean = 43 microg/ml). Gentamicin resistance
      occurred in 63.6% of isolates also, but 90.9% ciprofloxacin-resistant isolates
      were susceptible to amikacin. Fifteen (76.7%) of 19 patients who initially
      received ciprofloxacin did not show any clinical improvement even after 3 days of
      intensive medical therapy. The infiltrate resolved in all 8 cases where the
      antibiotic therapy was modified on the basis of susceptibility test. Four eyes
      were subjected to penetrating keratoplasty, and three were eviscerated following
      failure of treatment with ciprofloxacin. CONCLUSION: True resistance to
      ciprofloxacin is emerging in ophthalmology even among Pseudomonas isolates;
      therefore, the empiric treatment of infectious keratitis with ciprofloxacin
      monotherapy must be critically reviewed at this time.

PMID- 10406615
TI  - Evaluation of the shell vial technique for detection of ocular adenovirus.
      Community Ophthalmologists of Pittsburgh, Pennsylvania.
AB  - PURPOSE: The shell vial technique is a cell culture method that uses
      centrifugation and immunofluorescence to decrease the time required for a
      positive test. The authors evaluated the shell vial technique as a diagnostic
      test to detect adenovirus in conjunctival specimens of patients with adenoviral
      conjunctivitis. DESIGN: Retrospective and prospective case series. PARTICIPANTS:
      Forty-six patients with adenoviral culture-positive ocular infection. METHODS:
      The minimum time of incubation (days) that was required for testing clinical
      isolates with the shell vial was determined with adenovirus serotypes 5 and 8. In
      a masked retrospective study, 25 true-positive (frozen clinical samples) and 25
      true-negative specimens were tested for the presence of adenovirus using the
      shell vial technique. The 25 true-negative samples included herpes simplex virus,
      Chlamydia trachomatis, Haemophilus influenzae, Streptococcus pneumoniae, and
      Staphylococcus aureus. In a prospective study, 21 patients who later tested
      positive in cell culture for adenovirus were concurrently tested with shell vial.
      MAIN OUTCOME MEASURES: The time of incubation was determined in days, and the
      sensitivity, specificity, positive and negative predictive values, and the
      efficacy of the shell vial test were determined. RESULTS: The minimal time of
      incubation for testing ocular samples by shell vial was 3 days. In the
      retrospective study, the sensitivity, specificity, positive predictive value,
      negative predictive value, and efficacy were 92%, 100%, 100%, 93%, and 96%,
      respectively. Comparably (P = 0.99), in the prospective study the sensitivity,
      specificity, positive predictive value, negative predictive value, and efficacy
      were 95%, 100%, 100%, 96%, and 97%, respectively. The shell vial (93%, 43 of 46)
      was equivalent (P = 0.42) to cell culture (100%, 46 of 46) for detecting
      adenovirus, but a positive result was obtained in significantly less time (3 days
      versus 9.41 +/- 6.23 days) (P = 0.00001). CONCLUSIONS: The shell vial technique
      was found to be a definitive method for identifying adenovirus from ocular
      specimens. A clear benefit for the ophthalmologist is that the test can provide a
      faster positive result (3 days) compared with conventional cell culture, which
      can take 1 to 3 weeks for adenovirus isolation.

PMID- 10406616
TI  - Scleritis: a clinicopathologic study of 55 cases.
AB  - OBJECTIVE: By a clinicopathologic study, to evaluate the histopathologic features
      associated with various causes of scleritis. DESIGN: Retrospective observational
      case series. PARTICIPANTS: Enucleated globes or biopsy specimens obtained from 55
      cases of clinically diagnosed necrotizing scleritis. METHODS: On the basis of
      their histologic appearance, these cases were divided into four morphologic
      groups: (1) zonal necrotizing granulomatous scleral inflammation; (2) nonzonal
      diffuse scleral inflammation, with or without granulomatous process; (3)
      necrotizing inflammation with microabscesses, with or without evidence of micro
      organisms in the section studied; and (4) sarcoidal granulomatous inflammation.
      The clinical charts were reviewed for the presence of any associated disease.
      RESULTS: There were 14 (25.4%) cases in the first group; 12 had clinical evidence
      of systemic autoimmune diseases, including 8 cases of rheumatoid arthritis and 1
      each of polychondritis, Goodpasture syndrome, Wegener granulomatosis, and
      collagen vascular disease; of the remaining 2 cases, 1 patient had a history of
      herpes zoster ophthalmicus, and the other had no history of any systemic
      autoimmune or infectious disease. None of the 19 (34.5%) patients characteristic
      of group 2 had any history of systemic autoimmune or infectious disease. Eleven
      of the 21 (38.2%) patients in group 3 had infections, including Pseudomonas spp.,
      gram-positive cocci, Haemophilus spp., Actinomyces spp., and fungi; in the 10
      remaining cases, no micro-organisms could be detected. The one case in group 4
      was diagnosed as sarcoidosis. CONCLUSIONS: On the basis of their histologic
      features, rheumatoid scleritis and related systemic autoimmune-mediated
      necrotizing scleral inflammations could be differentiated from either idiopathic
      or infectious scleritis; however, the histologic features of rheumatoid scleritis
      were similar to those of necrotizing scleritis associated with other systemic
      autoimmune diseases.

PMID- 10406617
TI  - Ocular findings in allogeneic stem cell transplantation without total body
      irradiation.
AB  - OBJECTIVE: To evaluate the ophthalmologic complications in hematologic patients
      after allogeneic stem cell transplantation (ASCT) without total body irradiation.
      DESIGN: Retrospective noncomparative case series. PARTICIPANTS: A total of 150
      ASCT patients. INTERVENTION: Ophthalmologic examinations of 130/150 patients were
      made, with particular attention to the occurrence of graft-versus-host disease
      (GVHD). RESULTS: One hundred thirty patients with a mean age of 35.5 (SD 10.6)
      years at the time of ASCT were followed up for a mean of 12 months (range 3-60
      months). GVHD developed in 73 patients (56.2%). Of 130 patients, 52 (40.0%) had
      ocular complications, and 29 (22.3%) of those had GVHD. Keratoconjunctivitis
      sicca was diagnosed in 13 (10.0%) patients, and 12 (9.2%) had different stages of
      pseudomembranous conjunctivitis. Cataract developed in 3 patients (2.3%) in the
      observation period, and 7 (5.4%) had keratitis. Six (4.6%) patients had uveitis,
      and 8 (6.2%) had retinal hemorrhages. No ischemic retinopathy was found.
      Bilateral optic disc edema developed in 10 (7.7%) patients. CONCLUSIONS: Fewer
      ocular complications were observed in this series than in earlier studies, and
      the visual outcome was favorable. Cyclosporine has been linked to the development
      of optic disc edema and ischemic retinal lesions. The latter condition was not
      observed in the study patients, and the optic disc edema resolved within 1 year
      in all patients without any detectable visual impairment, in spite of
      continuation of the drug. Seven patients had acute GVHD at the time of optic disc
      edema, which is considered to be another manifestation of acute GVHD.

PMID- 10406618
TI  - Ophthalmic abnormalities in patients with cutaneous T-cell lymphoma.
AB  - OBJECTIVE: To determine the frequency of ophthalmic abnormalities in patients
      with cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome) and T-cell
      lymphoma involving the skin and to describe the clinical course of the disease
      with selected examples. DESIGN: Retrospective, clinic-based, cross-sectional
      study. PARTICIPANTS: A computerized diagnostic retrieval system was used to
      identify all patients with T-cell lymphoma involving the skin who were examined
      at the Mayo Clinic (Rochester, Minnesota) between January 1, 1976 and December
      31, 1990. The medical records of affected patients were reviewed. MAIN OUTCOME
      MEASURES: Identification of ophthalmic abnormalities. RESULTS: During the 15-year
      interval from 1976 through 1990, cutaneous T-cell lymphoma was diagnosed in 2155
      patients. Of these, 42 (1.95%; 26 male and 16 female) had at least one ophthalmic
      abnormality attributable to the disease. The diagnoses in these 42 patients were
      mycosis fungoides in 19, clinical variants of T-cell lymphoma of the skin (most
      commonly peripheral T-cell lymphoma) in 11, and Sezary syndrome in 12.
      Cicatricial eyelid ectropion was the most common finding, affecting 17 (40.4%) of
      the 42 patients. Thirty-seven patients had findings that, although probably not a
      direct consequence of cutaneous T-cell lymphoma, have been cataloged in previous
      studies. CONCLUSION: Although ophthalmic abnormalities in patients with cutaneous
      T-cell lymphoma are relatively uncommon, the manifestations of the disease are
      diverse and frequently difficult to treat.

PMID- 10406619
TI  - Multifocal intraocular malignant melanoma: report of two cases and review of the
      literature.
AB  - PURPOSE: To describe two eyes from two patients with multifocal primary
      intraocular melanoma. DESIGN: Two case reports. METHODS: The history and
      histologic findings in the enucleated eyes of two patients with multifocal
      intraocular melanoma are described in comparison to previously reported cases.
      MAIN OUTCOME MEASURES: Pathologic examination of enucleated eyes. RESULTS: One of
      the two eyes contained mixed cell type melanomas, and one eye contained spindle
      cell type melanomas. Examination of serial sections showed no continuity between
      the intraocular melanomas. There were no associated ocular or systemic conditions
      with the multifocal intraocular melanomas. CONCLUSIONS: Multifocal primary
      intraocular melanoma is rare. There is no known predisposing factor to this
      condition.

PMID- 10406620
TI  - Extraocular extension of unrecognized choroidal melanoma simulating a primary
      optic nerve tumor: report of two cases.
AB  - BACKGROUND: Orbital extraocular extension of choroidal melanoma is well known and
      is usually detected in eyes with medium and large tumors, but it is very rare
      with small melanomas. It is particularly unusual for choroidal melanomas of any
      size to invade the optic nerve or its meninges. DESIGN: Two case reports.
      PARTICIPANTS: Two patients with small, relatively inconspicuous juxtapapillary
      pigmented choroidal lesions were referred with the diagnosis of primary optic
      nerve tumor. Both demonstrated a large nodular tumor in the meninges of the optic
      nerve, immediately posterior to the globe. METHODS: Retrospective review of
      clinical records and histopathology. RESULTS: In both cases, orbital magnetic
      resonance imaging confirmed the presence of a hyperintense enhancing nodular mass
      near the anterior portion of the optic nerve, prompting optic nerve biopsy in one
      case. Subsequent fundus examination disclosed a small juxtapapillary pigmented
      choroidal lesion measuring 1.0 mm or less in thickness. These observations
      suggested that the optic nerve tumor might be nodular extraocular extension of a
      small choroidal melanoma. Modified enucleation was performed in both cases, and
      histopathologic examination revealed a nodule of malignant melanoma within the
      meninges that compressed the optic nerve and extended extraocularly from a small,
      relatively inapparent juxtapapillary choroidal melanoma. In both cases, the
      extraocular component was large and symptomatic, whereas the intraocular
      component was inconspicuous. CONCLUSIONS: Small juxtapapillary choroidal
      melanomas can exhibit prominent extension into the orbit. All patients with
      orbital tumors should have careful ophthalmoscopy.

PMID- 10406621
TI  - Diagnosis and management of divergence weakness in adults.
AB  - OBJECTIVE: To determine how frequently neurologic disease accompanies divergence
      weakness, the stability of the eye movement disorder, and the response to
      treatment. DESIGN: Prospective, interventional, noncomparative case series.
      PARTICIPANTS AND METHODS: Seventeen consecutive adult patients (28-96 years of
      age) with divergence weakness were prospectively evaluated from 1991 to 1997.
      MAIN OUTCOME MEASURES: Ocular alignment was measured at distance and near and in
      up, down, left, and right gaze. Fusional divergence amplitudes were measured at
      distance. The presence or absence of associated neurologic disease was noted. The
      response to treatment (prisms or strabismus surgery or both) was recorded.
      RESULTS: None of the patients had concurrent neurologic disease. Thirteen
      patients remained stable, 3 improved, and 1 progressed. Sixteen patients were
      treated successfully: 12 with prisms and 4 with strabismus surgery; 1 patient was
      not treated. CONCLUSION: Divergence weakness is usually an isolated condition
      that tends to remain stable and respond to treatment with either prisms or
      strabismus surgery.

PMID- 10406622
TI  - Ab-interno goniotrabeculotomy versus mitomycin C trabeculectomy for adult open
      angle glaucoma: a 2-year randomized clinical trial.
AB  - OBJECTIVE: To evaluate the effect of ab-interno goniotrabeculotomy (AIGT) on the
      intraocular pressure (IOP) in adult patients with primary open-angle glaucoma
      (POAG), compared with the effects of mitomycin C trabeculectomy (MT). DESIGN:
      Prospective, randomized, clinical trial. PARTICIPANTS: Thirty-two eyes of 32
      patients with medically uncontrolled POAG. INTERVENTION: Standard limbus-based
      trabeculectomy with adjunct mitomycin C (0.3 mg/mL for 3 minutes) in 16 eyes of
      16 patients; AIGT was performed in 16 eyes of 16 patients. The groups were
      matched for age, preoperative IOP, duration of preoperative antiglaucoma
      treatment, use of preoperative beta-blockers and parasympathomimetics, and use of
      beta-blockers in the fellow eye. The IOP (average of the two highest values
      measured in the diurnal curve, from 8 AM to 6 PM, every 2 hours) and
      complications were recorded 1, 3, 6, 12, 18, and 24 months after surgery. MAIN
      OUTCOME MEASURES: Identification of complications and IOP. RESULTS: All patients
      were followed up for 24 months. More postoperative complications occurred in the
      MT group during the 2-year follow-up. One month after surgery, IOP was 10 +/-
      1.46 mmHg (range, 8-13) in the MT group and 12.12 +/- 1.63 mmHg (range, 8-14) in
      the AIGT group (Student's t test, P = 0.001). Three months after surgery, IOP was
      11.5 +/- 1.59 mmHg (range, 8-14) and 12.75 +/- 1.57 mmHg (range, 10-16) in the MT
      and AIGT groups, respectively (Student's t test, P = 0.033). From the 6th to the
      24th postoperative month, no statistically significant difference in IOP was
      found between the two groups. At the end of follow-up, 14 of 16 eyes (87.5%) of
      the AIGT group and 13 of the 16 eyes (81.25%) of the MT group showed an IOP < or
      = 14 mmHg. CONCLUSION: Ab-interno goniotrabeculotomy appears to be a viable and
      safe surgical treatment for adult POAG. More extended follow-up, however, and a
      larger series of patients are needed to ascertain the actual effectiveness of
      this procedure in adult POAG.

PMID- 10406623
TI  - Ocular amyloidosis and secondary glaucoma.
AB  - OBJECTIVE: To report the clinical and histopathologic findings in two cases of
      secondary glaucoma associated with amyloidosis. DESIGN: Two case reports.
      METHODS: Retrospective review of clinical findings, course, and treatment of the
      two patients. The histopathologic findings from available biopsy material were
      also reviewed. MAIN OUTCOME MEASURES: Intraocular pressure (IOP), visual field
      changes, and surgical outcome. RESULTS: The first case describes a 76-year-old
      woman with orbital amyloidosis who developed gradual unilateral elevation of IOP
      that was poorly responsive to medical therapy and underwent filtration surgery.
      Episcleral venous pressure was elevated on the affected side, and histopathologic
      analysis of the conjunctival tissue confirmed perivascular amyloid deposits,
      further suggesting raised episcleral venous pressure to be a possible mechanism
      of glaucoma. The second case describes a 47-year-old white woman with familial
      amyloid neuropathy with a transthyretin cys-114 mutation. The association of
      glaucoma with this mutation has not been described previously. Persisting
      elevation of IOP in one eye was initially responsive to topical antiglaucoma
      medications but eventually required filtration surgery. Amyloid particles were
      found in the aqueous and on the lens surface. Histopathologic analysis of the
      aqueous and sclerectomy specimens demonstrated amyloid, suggesting outflow
      obstruction as a possible mechanism of glaucoma. Conjunctival buttonholing
      complicated filtration surgery in both cases, and the leaks eventually resolved
      with good control of IOP. CONCLUSIONS: Amyloid associated with glaucoma may
      involve different pathophysiologic mechanisms. The elevated IOP may not respond
      well to medical therapy. Cautious surgical manipulation of the conjunctiva is
      warranted in these cases.

PMID- 10406625
TI  - A malignant glaucoma-like syndrome following pars plana vitrectomy.
AB  - OBJECTIVE: To report two cases of a malignant glaucoma-like syndrome following
      pars plana vitrectomy. DESIGN: Two interventional case reports. INTERVENTION: The
      first patient was treated with a neodymium:YAG laser peripheral iridectomy with
      hyaloidectomy and with intracameral tissue plasminogen activator. The second
      patient was treated with a posterior approach iridectomy through residual
      hyaloid, zonules, and iris. MAIN OUTCOME MEASURES: Axial anterior chamber depth
      and intraocular pressure (IOP). RESULTS: The interventions resulted in deepening
      of the anterior chambers and normalization of IOPs. CONCLUSION: A pseudomalignant
      glaucoma syndrome may be related to obstruction of aqueous flow, either by
      residual anterior hyaloid or by fibrin and other inflammatory debris at the level
      of the ciliary body-zonular apparatus. Treatment of this syndrome involves
      restoring aqueous flow to the anterior chamber by disrupting the residual
      anterior hyaloid or clearing fibrin or inflammatory debris. The clinician should
      not disregard the possibility of a pseudomalignant glaucoma syndrome following
      vitrectomy despite the fact that vitrectomy has traditionally been considered a
      curative treatment for malignant glaucoma.

PMID- 10406624
TI  - Laser-induced drusen reduction improves visual function at 1 year. Choroidal
      Neovascularization Prevention Trial Research Group.
AB  - OBJECTIVE: To describe the relationship of laser-induced drusen reduction to
      change in visual function at 1 year among patients enrolled in the Choroidal
      Neovascularization Prevention Trial (CNVPT). DESIGN: Comparison of groups with
      and without drusen reduction; follow-up of a randomized controlled trial.
      PARTICIPANTS: Evaluations of drusen and visual acuity at baseline and at 1 year
      were performed for 351 eyes of the 432 eyes enrolled in the CNVPT Bilateral
      Drusen Study and Fellow Eye Study (81%). One hundred eighty-four eyes were
      assigned to observation, and 167 eyes were assigned to laser treatment. Eyes with
      conditions that precluded an analysis of drusen reduction, such as those that
      developed choroidal neovascularization (CNV) within the first year, are excluded
      from this analysis. METHODS: Change in macular drusen between initial visit and
      after 1 year was assessed by side-by-side grading by evaluators masked to
      information on visual function. Visual acuity, contrast threshold, and critical
      print size were measured by certified visual function examiners. MAIN OUTCOME
      MEASURES: Change in visual acuity is the primary outcome. Change in contrast
      threshold and change in critical print size are secondary outcome measures.
      RESULTS: Laser-treated eyes with 50% or more drusen reduction at 1 year had more
      1- and 2-line increases in visual acuity and less losses in visual acuity
      compared with laser-treated eyes with less drusen reduction or with observed eyes
      (P = 0.001). Similar improvements were noted for contrast threshold but not
      critical print size at 1 year. CONCLUSIONS: Laser-induced drusen reduction is
      associated with improved visual acuity and contrast sensitivity in eyes at 1
      year. Longer term effects of laser-induced drusen reduction on visual function
      require additional observation. The overall potential value of laser treatment in
      eyes with high-risk drusen requires consideration of not only short-term effects
      on vision but also the effects of CNV and atrophy on vision.

PMID- 10406626
TI  - Digital red-free photography for the evaluation of retinal blood vessel
      displacement in epiretinal membrane.
AB  - OBJECTIVE: To evaluate the displacement of retinal blood vessels during the
      natural course of epiretinal membrane (ERM) formation. DESIGN: Consecutive
      observational case series. PARTICIPANTS: Thirteen patients (13 eyes) diagnosed
      with unilateral idiopathic ERM and 10 normal fellow eyes of the same patients
      served as a control group and constituted the study group. TESTING: All eyes
      underwent digital red-free filter photography of the fundus using the Topcon
      Imagenet-1024 System. Photographs were taken on entry to the study and again
      after 8 to 13 months. Distances were measured between the major and minor blood
      vessel junctions at the upper and lower temporal arcades and between the disc
      margin and vessel junctions temporal to the macula on follow-up examinations. To
      clearly visualize vessel shift, both photographs of each patient were overlaid
      using the peripheral landmarks of major blood vessel crossings as reference
      points. MAIN OUTCOME MEASURES: The parameters measured were shifting of blood
      vessels caused by the ERM formation. The distances were measured in micrometers
      using the measurement feature of the Topcon Imagenet System. RESULTS: Blood
      vessel shift (range, 30 microm-434 microm) was noted in all 13 eyes, but in 15
      measurements the shift was less than 30 microm and was considered as no shift. In
      four eyes (31%), the distances decreased in all directions, indicating
      contraction of the ERM. In four eyes (31%), the distances increased in all
      directions, indicating release of the ERMs. A mixed pattern of release and
      contraction of the ERM in the same eye was noted in five eyes (38%). No shift of
      blood vessels was noted in the control eyes. Findings on image overlay
      corresponded with the objective measurements. CONCLUSIONS: Noninvasive digital
      red-free photography is an informative tool for the objective measurement of the
      vessel displacement during ERM formation. Contraction and release of the ERM were
      noted.

PMID- 10406628
TI  - Macular hole surgery with internal-limiting membrane peeling and intravitreous
      air.
AB  - OBJECTIVE: To examine the results of macular hole surgery using pars plana
      vitrectomy, internal-limiting membrane peeling, and intravitreous air in a series
      of consecutive patients. DESIGN: A retrospective, interventional, noncomparative
      case series. PATIENTS: Fifty consecutive patients (58 eyes) with full-thickness
      macular holes. INTERVENTION: All eyes underwent a pars plana vitrectomy with
      internal-limiting membrane peeling and intravitreous air, and patients were asked
      to position face-down for only 4 days. MAIN OUTCOME MEASURES: Status of macular
      holes, visual acuity, and associated findings and complications. RESULTS: All
      patients had postsurgical follow-up of 6 months or greater. Eight eyes (14%)
      presented with stage-2 macular holes, 48 eyes (83%) with stage-3 macular holes,
      and 2 eyes (3%) with stage-4 macular holes. Only 26 eyes (45%) had a macular
      epiretinal membrane seen before surgery. Fifty-three (91 %) of the 58 macular
      holes were closed with 1 operation, and 55 (95%) had closure of the macular holes
      with subsequent operations. Five (9%) of 58 eyes had an initial visual acuity of
      20/50 or better, and 31 eyes (53%) had a final visual acuity of 20/50 or better.
      Of the 45 eyes with symptoms of less than 6 months' duration, 44 (98%) had
      macular holes that were closed with 1 operation and 27 (60%) had a final visual
      acuity of 20/50 or better. Of the 13 eyes with symptoms of 6 months' duration or
      longer, 9 (69%) had macular holes that were closed with 1 operation and 4 (31 %)
      had a final visual acuity of 20/50 or better. Complications attributed to the
      operation included retinal tears, retinal detachments, postoperative macular
      puckers, and macular light toxicity. CONCLUSIONS: The anatomic and visual results
      in this series are good. The current technique is similar to that of conventional
      macular hole surgery except for the use of intravitreous air, internal-limiting
      membrane peeling in all eyes, and only 4 days of postoperative positioning. This
      study would suggest that peeling of the internal-limiting membrane is an
      important adjuvant for successful closure of macular holes.

PMID- 10406627
TI  - Angiographic and histologic effects of fundus photodynamic therapy with a
      hydrophilic sensitizer (mono-L-aspartyl chlorin e6).
AB  - PURPOSE: To demonstrate the efficacy of the photosensitizer mono-L-aspartyl
      chlorin e6 (NPe6) in closing choroidal vessels at low energy levels, that tissue
      uptake and clearance are rapid, and that low concentrations of drug are needed to
      achieve clinical effects. DESIGN: Experimental animal study. ANIMALS: Pigmented
      rabbits and Japanese monkeys were used in this study. METHODS: Using a modified
      664-nm diode laser, the fundi of pigmented rabbits and Japanese monkeys were
      irradiated after intravenous administration of NPe6 (2-100 mg/kg). Time from
      injection to irradiation varied from 5 to 15 minutes, and duration of exposure
      varied from 1 to 10 seconds. Power output at the corneal surface was either 3.6
      or 5.9 mW. Animals were examined by indirect ophthalmoscopy and fluorescein
      angiography at 2 hours and 7 days after treatment. After enucleation 7 days after
      treatment, specimens were prepared for light and electron microscopy. MAIN
      OUTCOME MEASURES: Angiographic evidence of occlusion and histopathologic evidence
      of retinal damage. RESULTS: Both clinical and histopathologic examination
      demonstrated effects on the choroidal vasculature and the retinal pigment
      epithelium, including necrosis of endothelial cells and occlusion in choroidal
      vessels, particularly within the choriocapillaris, at low energy levels.
      Overlying neurosensory retina was minimally affected. Fluorescein angiography of
      lesions treated with 2 mg/kg and laser fluence of 2.3 to 7.5 J/cm2 showed a
      normal appearance 2 hours after treatment, which changed to early hypofluorescent
      and later hyperfluorescent lesions 7 days after treatment. In contrast, those
      animals receiving the 10-mg/kg dose and laser fluence of 0.46 to 0.75 J/cm2
      showed marked hypofluorescence of choroidal lesions and occlusion of retinal
      vessels 7 days after treatment. CONCLUSIONS: Effective occlusion of normal
      choroidal vessels was achieved at 2 mg/kg using 2.3 to 7.5 J/cm2 or at 10 mg/kg
      using 0.46 to 0.75 J/cm2 with minimal injury to overlying neurosensory retina.

PMID- 10406629
TI  - Silicone oil in the repair of pediatric complex retinal detachments: a
      prospective, observational, multicenter study.
AB  - OBJECTIVE: To report anatomic and visual acuity outcomes, as well as
      complications, after using 1000-centistoke silicone oil as a retinal tamponade
      for the treatment of complex retinal detachments in a pediatric population.
      DESIGN: A prospective, observational, multicenter study. PARTICIPANTS: The study
      cohort consisted of 205 patients 16 years of age or younger (211 eyes) treated at
      community and university-based ophthalmology clinics for complex retinal
      detachments associated with trauma, proliferative vitreoretinopathy (PVR), giant
      retinal tear (GRT), or retinopathy of prematurity (ROP). INTERVENTION: Vitrectomy
      surgery for complex retinal detachment with 1000-centistoke silicone oil as the
      retinal tamponade. MAIN OUTCOME MEASURES: Anatomic outcomes include complete
      retinal attachment and macular attachment. Visual acuity outcomes include
      ambulatory vision (> or = 4/200) and preservation of preoperative visual acuity.
      Complications include rates of secondary intraocular pressure (IOP) elevation (>
      or = 30 mmHg), hypotony (< or = 5 mmHg), corneal opacification (including band
      keratopathy, corneal edema, and corneal abrasions), oil emulsification, and
      cataract. All outcome measures were assessed 6, 12, and 24 months after surgery
      and at last examination. RESULTS: At the 6-month examination, the retina was
      completely attached in 43 (57%) of 76 eyes in the trauma group, 24 (63%) of 38
      PVR eyes, 23 (68%) of 34 GRT eyes, and 6 (33%) of 18 ROP eyes. The macula was
      attached in 60 (79%), 33 (87%), 26 (76%), and 8 (44%) eyes, respectively.
      Ambulatory vision was achieved in 19 (25%) eyes in the trauma group, 18 (47%) PVR
      eyes, 19 (56%) GRT eyes, and 4 (22%) ROP eyes. Visual acuity was preserved in 53
      (70%), 26 (68%), 28 (82%), and 9 (50%) eyes, respectively. The corresponding
      rates of complications for traumatic, PVR, GRT, and ROP eyes were: elevated IOP-3
      (4%) of 76, 1 (3%) of 38, 1 (3%) of 34, and 0 (0%) of 18; hypotony--9 (12%), 3
      (8%), 2 (6%), and 2 (11%); corneal opacity--25 (33%), 8 (21%), 15 (44%), and 5
      (28%); emulsification--4 (5%), 1 (3%), 3 (9%), and 1 (6%); and cataract in phakic
      eyes--1 (33%) of 3, 2 (67%) of 3, 2 (50%) of 4, and 1 (33%) of 3. CONCLUSIONS:
      Retinal reattachment and preserved visual acuity were achieved in the majority of
      eyes using vitrectomy and silicone oil retinal tamponade. Complete retinal and
      macular attachment was achieved less frequently in ROP eyes than in eyes in the
      other diagnostic groups. Use of 1000-centistoke silicone oil can be considered in
      the management of pediatric complex retinal detachments associated with multiple
      etiologies.

PMID- 10406630
TI  - A small foveal avascular zone may be an historic mark of prematurity.
AB  - OBJECTIVE: To compare in children the area and diameter of the foveal avascular
      zone (FAZ) of former preterm infants, when no significant retinopathy of
      prematurity (ROP) developed, to the area and diameter of the FAZ of former term
      infants. DESIGN: Retrospective observational case series and literature review.
      PARTICIPANTS: Forty-nine children (39 former preterm infants and 10 former term
      infants) between the ages of 1 and 17 years had fluorescein angiograms. All of
      these children had been appropriate weight for gestational age at birth and had
      no genetic disorders. Neither eye of any of these children had any macular
      ectopia or vessel traction, had been treated for active ROP, had developed active
      ROP >stage 3 mild, or had any refractive error > +/- five diopters. Every child
      had a visual acuity of 20/40 or better in both eyes. METHODS: The area and
      greatest diameter of the FAZ were measured using digital image analysis of masked
      fundus fluorescein angiograms. Variables of gender, race, multiple birth,
      gestational age, birth weight, ROP stage, age, and refraction at the time of
      fluorescein angiography, and final visual acuity were recorded. RESULTS:
      Increasing FAZ area and greatest diameter correlated significantly with
      increasing gestational age and birth weight: FAZ area (microm2) versus
      gestational age (weeks) (R/F/P = 0.88/166.70/<0.0001); FAZ greatest diameter
      (microm) versus gestational age (weeks) (R/F/P = 0.87/151.10/<0.0001); FAZ area
      (micro/m2) versus birth weight (g) (R/F/P = 0.88/167.06/<0.0001); and FAZ
      greatest diameter (microm) versus birth weight (g) (R/F/P = 0.87/148.74/
      <0.0001). A small or absent FAZ was found in all former preterm infants who had
      been < or = 30 weeks gestational age or had weighed < or = 1100 g at birth. A
      normal FAZ was present in all children who had been > or = 36 weeks gestational
      age or had weighed > or = 2650 g at birth. None of the other parameters studied
      correlated with FAZ area or greatest diameter. CONCLUSION: This study provides
      evidence that the FAZ in developing humans is initially densely vascularized with
      a fine meshwork of inner retinal vessels during vasculogenesis. This vascular
      meshwork undergoes regression by apoptosis in all infants > or = 36 weeks
      gestational age at birth to form a normal FAZ, but apoptosis almost never occurs
      in preterm infants < or = 30 weeks gestational age at birth. Although there is no
      effect on final visual acuity, a small or absent FAZ may be an historic mark of
      prematurity.

PMID- 10406631
TI  - Optic nerve head and retinal nerve fiber layer analysis. American Academy of
      Ophthalmology.

PMID- 10406632
TI  - 4,10-dihydro-5H-thieno[3,2-c][1]benzazepine derivatives and 9,10-dihydro-4H
      thieno[2,3-c][1]benzazepine derivatives as orally active arginine vasopressin
      receptor antagonists.
AB  - Synthesis and structure-activity relationships (SAR) of arginine vasopressin
      receptor (AVP) antagonists are described. Potent and orally active compounds are
      prepared when tricyclic 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine moiety
      in VPA-985 1 is replaced with a compound 7 or 12.

PMID- 10406633
TI  - 5-fluoro-2-methyl-N-[5-(5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-yl carbonyl)
      2-pyridinyl]benzamide (CL-385004) and analogs as orally active arginine
      vasopressin receptor antagonists.
AB  - Synthesis and structure-activity relationships (SAR) of orally active arginine
      vasopressin (AVP) receptor antagonists are discussed. Potent and orally active
      AVP receptor antagonists are produced when ring A of VPA-985 (1) is replaced with
      a 3-pyridinyl unit (2b).

PMID- 10406634
TI  - A mutational study of a Diels-Alderase catalytic antibody.
AB  - Site-directed mutagenesis was used to probe the mechanism of antibody 39-A11,
      which catalyzes the Diels-Alder reaction of substrate 1 and 2 to give cycloadduct
      3. Mutations that lead to improved packing interactions with the diene afford an
      order of magnitude increase in catalytic activity.

PMID- 10406635
TI  - Substrate-selective mechanisms in biocatalysis demonstrated with a versatile and
      efficient aldolase antibody.
AB  - A structure-activity relationship study with a series of aldol substrates shows
      that the mechanism of the antibody 38C2-catalyzed retrograde aldol reaction
      depends on the nature of the substrate With electron-deficient substrates an
      early deprotonation precedes the C-C bond cleavage while with electron-rich
      substrates the catalytic mechanism involves an initial C-C bond cleavage leading
      to a positively charged intermediate.

PMID- 10406636
TI  - Synthesis and evaluation of 1,4,5,6-tetrahydropyridazine derivatives as influenza
      neuraminidase inhibitors.
AB  - 1,4,5,6-Tetrahydropyridazine derivative 15 and its C-5 epimer 19, which possessed
      side chains similar to GS4071, were synthesized via a hetero Diels-Alder
      reaction, and evaluated as influenza neuraminidase inhibitors. Compounds 15 and
      19 exhibited a microM range of influenza neuraminidase inhibitory activity.

PMID- 10406637
TI  - Synthesis and identification of conformationally constrained selective MMP
      inhibitors.
AB  - We have discovered a new series of potent conformationally constrained MMP
      Inhibitors that are selective for MMP-13 over MMP-1.

PMID- 10406638
TI  - Thiazole-derived potent, highly bioavailable short duration growth hormone
      secretagogues.
AB  - Replacement of the phenyl in 3 with a 2-pyridyl or 4-thiazolyl group resulted in
      increased potency in the rat pituitary cell GH release assay and in beagles.

PMID- 10406639
TI  - Solid phase synthesis and biological activities of [Arg8]-vasopressin
      methylenedithioether.
AB  - Solid phase synthesis of [Arg8]-vasopressin methylenedithioether, an analog of
      vasopressin which contains an extra methylene group between the two sulfur atoms
      of Cys1 and Cys6, is described. Methylene insertion occurred easily when the
      thiol free peptide on a solid support was treated with tetrabutylammonium
      fluoride in dichloromethane at room temperature for 3 h. The uterotonic in vitro,
      pressor, and antidiuretic activities of the compound were reduced in comparison
      to [Arg8]-vasopressin by one order of magnitude.

PMID- 10406640
TI  - The discovery of rofecoxib, [MK 966, Vioxx, 4-(4'-methylsulfonylphenyl)-3-phenyl
      2(5H)-furanone], an orally active cyclooxygenase-2-inhibitor.
AB  - The development of a COX-2 inhibitor rofecoxib (MK 966, Vioxx) is described. It
      is essentially equipotent to indomethacin both in vitro and in vivo but without
      the ulcerogenic side effect due to COX-1 inhibition.

PMID- 10406641
TI  - On the analogy between forskolin and D-glucose.
AB  - 2-O-Acetyl-D-glucose was synthesized in order to evaluate the influence of an
      acyl group on the binding with the glucose carrier protein (GluT); as its
      affinity neighbours that of glucose itself, the glucose-forskolin analogy appears
      to be coincidental and several explanations are proposed.

PMID- 10406642
TI  - Synthesis and preliminary biological evaluation of new alpha-amino amide
      anticonvulsants incorporating a dextromethorphan moiety.
AB  - Dextromethorphan 1 is an effective neuroprotectant in animal models of epilepsy
      and ischemia but showed side-effects during clinical trials limiting its
      potential use in a clinical setting. Here we describe the enantioselective and
      enantiospecific syntheses and the initial in vitro and in vivo biological
      evaluation of new hybrid structures between 1 and a previously disclosed alpha
      amino amide anticonvulsant (3).

PMID- 10406643
TI  - Steroid-DNA conjugates: improved triplex formation with 5-amido-(7-deoxycholic
      acid)-dU incorporated oligonucleotides.
AB  - The synthesis of oligodeoxyribonucleotides incorporating 7-deoxycholic acid
      conjugated at C5 of dU is described. When used as third strand, these form
      oligonucleotide triplexes with higher stability compared to unmodified controls
      at physiological pH.

PMID- 10406644
TI  - Substituted coumarins as esterase-sensitive prodrug moieties with improved
      release rates.
AB  - Our laboratory has recently reported a coumarin-based prodrug system for the
      preparation of esterase-sensitive prodrugs of amines, peptides, and
      peptidomimetics. However, the release from this prodrug system was undesirably
      slow for some drug moieties. In this report, we describe the synthesis and
      evaluation of several substituted coumarin-based prodrugs of model amines with
      significantly increased release rates.

PMID- 10406645
TI  - Orally bioavailable nonpeptide vitronectin receptor antagonists containing 2
      aminopyridine arginine mimetics.
AB  - A peptide RGD analog containing a novel 2-aminopyridine arginine mimetic was
      discovered to have good affinity and selectivity for the vitronectin receptor.
      Incorporation of the 2-aminopyridine arginine mimetic into the 3-oxo-1,4
      benzodiazepine-2-acetic acid integrin antagonist series led to novel and potent
      nonpeptide vitronectin receptor antagonists with promising levels of oral
      bioavailability.

PMID- 10406646
TI  - Orally bioavailable nonpeptide vitronectin receptor antagonists with efficacy in
      an osteoporosis model.
AB  - A new series of potent nonpeptide vitronectin receptor antagonists, based on a
      novel carbocyclic Gly-Asp mimetic, has been discovered. A representative of this
      series, SB 265123 (4), has 100% oral bioavailability in rats, and is orally
      active in vivo in the ovariectomized rat model of osteoporosis.

PMID- 10406647
TI  - Multiple parallel synthesis of N,N-dialkyldipeptidylamines as N-type calcium
      channel blockers.
AB  - Selective N-type Voltage Sensitive Calcium Channel (VSCC) blockers have shown
      utility in several models of stroke and pain. A series of N,N
      dialkyldipeptidylamines with potent functional activity at N-type VSCC's has been
      identified. Multiple parallel synthesis of a focused array of thirty compounds
      using polymer-supported quenching reagents and preliminary pharmacology are
      presented. Eighteen compounds were identified with an IC50 below 1 microM in an
      in vitro functional assay.

PMID- 10406648
TI  - Structure-activity relationship analysis of substituted 4-quinolinamines,
      antagonists of immunostimulatory CpG-oligodeoxynucleotides.
AB  - On the basis of a systematic SAR analysis of substituted quinolines, a derivative
      32 was synthesized that shows half-maximal inhibition of the immunostimulatory
      effect of CpG-oligodeoxynucleotides in vitro at the concentration of 0.24 nM.

PMID- 10406649
TI  - From histamine to imidazolylalkyl-sulfonamides: the design of a novel series of
      histamine H3-receptor antagonists.
AB  - Histamine was converted to a selective histamine H3-receptor antagonist by
      capping the primary amine with 2-naphthalenesulfonyl chloride. Higher receptor
      affinity and lower variability in the data from the various bioassays were
      achieved with the 2-naphthalensulfonamides of histamine homologues.

PMID- 10406650
TI  - Synthesis of 8-Oxa analogues of norcocaine endowed with interesting cocaine-like
      activity.
AB  - In order to further explore the importance of cocaine's bridge nitrogen atom in
      binding to the dopamine transporter (DAT), we have synthesized the previously
      known racemic 8-oxa-norcocaines 3-6 in which the nitrogen atom has been replaced
      by oxygen. Additionally, to avoid incorrect interpretations of biological data
      that may stem from the use of racemic materials, several of these analogues were
      synthesized and tested in non-racemic form. (-)-8-Oxa-norcocaine (3) was found to
      bind to the cocaine recognition site and to inhibit the dopamine transporter with
      potencies only about 8-fold and 4-fold, respectively, less than those of
      norcocaine (2). (-)-8-Oxa-pseudonorcocaine (4) as well as (+)-8-oxa-norcocaine
      (3) were found to be comparable in activity to (-)-oxa-norcocaine. These
      pharmacological findings support our earlier suggestion that cocaine is likely to
      bind in its neutral form to the DAT.

PMID- 10406651
TI  - Synthesis and structure-activity relationships of new non-steroidal progesterone
      receptor ligands.
AB  - In order to study structure-activity relationships, a series of new non-steroidal
      progesterone receptor ligands based on PF1092A was synthesized with structural
      modifications (mostly introduction or removal of a methyl group) at the 3-, 4-, 5
      , 7- or 9-position in the 6-acetoxy-4a, 5, 6, 7-tetrahydro-3, 4a, 5
      trimethylnaphtho[2,3-b]furan-2(4H)-one skeleton. Critical positions for high
      binding affinity to the progesterone receptor were identified.

PMID- 10406652
TI  - Novel halogenated sulfonamides inhibit the growth of multidrug resistant MCF
      7/ADR cancer cells.
AB  - In this report, we describe the synthesis of halogenated benzenesulfonamide
      compounds and their ability to inhibit the growth of HeLa, MCF-7 and MCF-7/ADR
      tumor cells in vitro. The multidrug resistance (MDR) phenotype of certain cells
      does not affect their sensitivity to these compounds. These agents belong to a
      family of compounds previously shown to bind irreversibly to cysteine-239 of beta
      tubulin. Consistent with this mechanism of action, the cytotoxicities of these
      compounds appear to correlate with their ability to undergo nucleophilic aromatic
      substitution.

PMID- 10406653
TI  - Synthesis and antibacterial properties of beta-diketone acrylate bioisosteres of
      pseudomonic acid A.
AB  - A series of beta-diketone acrylate bioisosteres 4 of pseudomonic acid A 1 have
      been synthesized and evaluated for their ability to inhibit bacterial isoleucyl
      tRNA synthetase and act as antibacterial agents. A number of analogues have
      excellent antibacterial activity. Selected examples were shown to afford good
      blood levels and to be effective in a murine infection model.

PMID- 10406654
TI  - Lipase-catalysed acylation of prostanoids.
AB  - Natural prostaglandins (PG) F2alpha and E1 as well as (+)-cloprostenol were
      regioselectively 11-acylated using Novozym 435 as a catalyst and vinyl acetate as
      an acyl donor. Unlike the above compounds the 15-OH group of PGE2 was also
      acylated with a significant velocity under the same conditions. The
      enantiospecificity of the lipase-catalysed 11-acetylation of cloprostenol was
      established by separate treatment of(+)- and (-)-cloprostenols.

PMID- 10406655
TI  - Synthesis of water-soluble phenytoin prodrugs.
AB  - The synthesis of novel water-soluble phenytoin derivatives, bearing an ionizable
      group, and a preliminary study for in vitro blood hydrolysis are reported. The
      results show that hydrolysis of amino esters 8 is very fast, much more than that
      of fosphenytoin.

PMID- 10406656
TI  - The synthesis of water soluble prodrugs analogs of echinocandin B.
AB  - A facile synthesis of phosphonate and phosphate ester prodrugs on the phenolic
      hydroxy of two echinocandin semisynthetic derivatives is reported. The water
      solubility and stability profiles of the ECB compounds varied with the choice of
      alkyl group used. In some cases, the ester prodrugs with small aliphatic side
      chains retained antifungal activity while enhancing water solubility.

PMID- 10406657
TI  - Potent, elective human beta3 adrenergic receptor agonists containing a
      substituted indoline-5-sulfonamide pharmacophore.
AB  - A series of compounds possessing an N-substituted indoline-5-sulfonamide
      pharmacophore was prepared and evaluated for their human beta3 adrenergic
      receptor agonist activity. The SAR of a wide range of urea and heterocyclic
      substituents is discussed. 4-Octyl thiazole compound 8c was the most potent and
      selective compound in the series, with 2800-fold selectivity over beta1 binding
      and 1400-fold selectivity over beta2 binding.

PMID- 10406659
TI  - Synthesis of a transition state analogue for the hydrolysis of cocaine:
      assistance to phosphonylation of a 3beta-hydroxytropane by a neighbouring amide
      group.
AB  - A simple synthesis of phenylphosphonate monoester analogues of the transition
      state for hydrolysis of the benzoyl ester group in cocaine is provided by the
      reaction of 2beta-amido-3beta-tropanols with phenylphosphonyl dichloride. Steric
      hindrance to phosphonylation of the hydroxyl is overcome because the neighbouring
      2beta-amido group participates in the reaction. The intramolecular assistance by
      the amide to formation of the phosphonate ester is influenced by the electronic
      environment of the amide group.

PMID- 10406658
TI  - Analogs of 4-(3-bromo-8-methyl-10-methoxy-6,11-dihydro-5H-benzo[5,6]-cyclo
      hepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N-oxide as inhibitors
      of farnesyl protein transferase.
AB  - A series of 3-substituted analogs 3 of 4-(3-bromo-8-methyl-10-methoxy-6,11
      dihydro-5H-benzo[5,6]-cyclohepta[1,2 b]pyridin-11-yl)-1-(4
      pyridinylacetyl)piperidine N-oxide 2 was prepared and evaluated as FPT
      inhibitors. The objective of this study was to identify other substituents at C3
      in this series of FPT inhibitors that would have the FPT potency enhancement
      similar to that found for a C3 bromo substituent. The 3-methyl analog 17b was
      found to be tenfold less active than 2, and other C3 substituents having more
      steric bulk were found to cause a further reduction in activity.

PMID- 10406660
TI  - Miller-Dieker syndrome and trisomy 5p in a child carrying a derivative chromosome
      with a microdeletion in 17p13.3 telomeric to the LIS1 and the D17S379 loci.
AB  - Trisomy 5p and Miller-Dieker syndromes frequently are the result of unbalanced
      segregations of reciprocal translocations of chromosomes 5 and 17 with other
      autosomes. The critical regions for the expression of the mentioned syndromes
      have been mapped to 5p13-->pter, and 17p13.3-->pter. In this report, we describe
      an 8-year-old girl with mental retardation, postnatal growth deficiency,
      generalized muscular hypotonia, seizures, microcephaly, cortical atrophy, partial
      agenesis of corpus callosum, cerebral ventriculomegaly, facial anomalies, patent
      ductus arteriosus, pectus excavatum, long fingers, and bilateral talipes
      equinovarus caused by the presence of a 46,XX,der(17)t(5;17)(p13.1;p13.3)mat
      chromosome complement. Cytogenetic studies of the family confirmed a balanced
      reciprocal translocation (5;17)(p13.1;p13.3) in her mother, maternal grandfather,
      maternal aunt, and a female first cousin. Fluorescence in situ hybridization
      studies on the mother and the proposita using three probes, which map to distal
      17p, confirmed the reciprocal translocation in the mother and a terminal deletion
      in the patient, which resulted in the retention of LIS1 and D17S379 loci and
      deletion of the 17p telomere. These findings and the phenotype of the proposita,
      strongly suggest that genes telomeric to LIS1 and locus D17S379 are involved in
      many clinical findings, including the minor facial anomalies of the Miller-Dieker
      syndrome.

PMID- 10406661
TI  - Small deletions in the type II collagen triple helix produce kniest dysplasia.
AB  - Kniest dysplasia is a moderately severe type II collagenopathy, characterized by
      short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and
      hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the
      predominant protein of cartilage, have been identified in a number of individuals
      with Kniest dysplasia. All but two of these previously described mutations cause
      in-frame deletions in type II collagen, either by small deletions in the gene or
      splice site alterations. Furthermore, all but one of these mutations is located
      between exons 12 and 24 in the COL2A1 gene. We used heteroduplex analysis to
      identify sequence anomalies in five individuals with Kniest dysplasia. Sequencing
      of the index patients' genomic DNA identified four new dominant mutations in
      COL2A1 that result in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp
      deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14
      and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12
      junction, deleting the splice donor site, was identified in the fifth case. The
      latter three mutations are predicted to result in exon skipping in the mRNA
      encoded from the mutant allele. These data suggest that Kniest dysplasia results
      from shorter type II collagen monomers, and support the hypothesis that
      alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads
      to the Kniest dysplasia phenotype.

PMID- 10406662
TI  - BRCA1 IVS16+6T-->C is a deleterious mutation that creates an aberrant transcript
      by activating a cryptic splice donor site.
AB  - Results and conclusions are presented that characterize BRCA1 IVS16+6T-->C as a
      deleterious mutation. BRCA1 transcripts from peripheral blood mononuclear cells
      of a breast cancer patient with the transition IVS16+6T-->C show the loss of a
      heterozygous base within codon 871. Additionally, an aberrant RNA splicing
      product which incorporates 69 bases of the 5' end of intron 16 at the junction of
      exons 16 and 17 is produced solely from the allele with IVS16+6T-->C. This
      insertion contains two in-frame stop codons and encodes a protein truncated at
      residue 1662 (plus 13 residues encoded by the intron). The aberrant transcript is
      specifically associated with the intronic variant since it was contained within
      the insertion. Furthermore, sequence analysis of the heterozygous base within
      codon 871 demonstrates that the two RNA products, productive mRNA and aberrantly
      spliced RNA, are contributed to exclusively by separate alleles. Finally, the
      aberrant transcript is produced by the activation of a cryptic splice site which
      has greater homology with the primate consensus splice sequence than the mutated
      exon 16 donor site.

PMID- 10406663
TI  - Ring 2 chromosome: ten-year follow-up report.
AB  - Cote et al. [1981: Ann Genet 24:231-235] suggested that ring chromosomes without
      a preceding deletion share a common pattern of phenotypic anomalies, independent
      of what chromosome is involved. The phenotype of such a "general ring syndrome"
      consists of growth failure without malformations, few or no minor anomalies, and
      mild-to-moderate mental retardation. We report on a patient with a ring 2
      chromosome with features suggestive of Silver-Russell syndrome at birth and
      striking postnatal growth retardation with minor intellectual involvement
      supporting Cote's suggestion. This would be the ninth case of ring 2 chromosome
      published; the patient is the longest reported survivor, with a 10-year follow
      up.

PMID- 10406664
TI  - Predictive value of the triple screening test for the phenotype of Down syndrome.
AB  - Maternal serum alpha-fetoprotein (MSAFP), human chorionic gonadotropin (hCG), and
      unconjugated estriol (uE3) are routinely measured in the second trimester
      ("triple" test) and combined with maternal age to evaluate risk for fetal Down
      syndrome. Triple test results and clinical findings were retrospectively reviewed
      for 30 newborns with Down syndrome to determine whether analyte values or second
      trimester risks for Down syndrome were more extreme in affected pregnancies where
      cardiac or other severe congenital malformations were present compared to those
      cases where major anatomical abnormalities were absent. Mean MS-AFP, uE3,
      maternal age, and second trimester Down syndrome risk were all similar in the two
      groups of pregnancies. However, hCG concentrations did appear to be higher in the
      group of Down syndrome pregnancies with anatomical anomalies (mean 1.74 MoM
      versus 1.19 MoM) (P<0.05). Overall, there was no significant difference in the
      incidence of major anomalies in patients with screen-positive test results versus
      those cases that were not identified by the triple test. Prenatal counseling
      should therefore reflect the general expectations of the Down syndrome phenotype
      that have been established from live-born infants with this disorder.

PMID- 10406666
TI  - A 100-year-old anatomical specimen presenting with boomerang-like skeletal
      dysplasia: diagnostic strategies and outcome.
AB  - The Museum Vrolik collection of human anatomy comprises 360 recently redescribed
      specimens with congenital anomalies. The specimen described here dated from 1881
      and presented with a general embryonic appearance, disproportionate short
      stature, brachycephaly, widened cranial sutures, hypertelorism, microphthalmia,
      bilateral cleft lip and palate, micrognathia, short and curved limbs,
      polysyndactyly, and abnormal female genitalia. Conventional radiography was
      hampered by decalcification of the skeleton, due to acidification of the
      preservation fluid. The use of additional imaging techniques, i.e., mammography,
      computerized tomography with three-dimensional reconstruction, and magnetic
      resonance imaging eventually led us to conclude that the condition of our
      specimen was similar to Piepkorn type skeletal dysplasia, boomerang dysplasia,
      and a condition described by Carpenter and Hunter [1982: J Med Genet 19:311-315],
      though none of these diagnoses seemed fully applicable.

PMID- 10406665
TI  - Cognitive and behavior profile of preschool children with chromosome 22q11.2
      deletion.
AB  - A microscopic deletion of chromosome 22q11.2 has been identified in most patients
      with the DiGeorge, velocardiofacial syndrome, conotruncal anomaly face syndrome,
      and in some patients with isolated conotruncal cardiac anomalies. This study
      presents the neurodevelopmental outcome, including cognitive development,
      language development, speech, neuromuscular development, and behavioral
      characteristics of 40 preschool children (ages 13 to 63 months) who have been
      diagnosed with the 22q11.2 deletion. The impact of cardiac disease, cardiac
      surgery, and the palatal anomalies on this population was also studied. In the
      preschool years, children with a 22q11.2 deletion are most commonly found to be
      developmentally delayed, have mild hypotonia, and language and speech delays. The
      more significantly delayed children are at high risk to be subsequently diagnosed
      with mild or moderate mental retardation. The global delays and the variations in
      intelligence found are directly associated with the 22q11.2 deletion and are not
      explained by physical anomalies such as palatal defects or cardiac defects, or
      therapeutic interventions such as cardiac surgery. Our findings demonstrate that
      there is a pattern of significant speech disorders within this population. All of
      the children had late onset of verbal speech. Behavioral outcomes included both
      inhibition and attention disorders. Early intervention services are strongly
      recommended beginning in infancy to address the delays in gross motor skills,
      speech and language, and global developmental delays.

PMID- 10406667
TI  - Atrioventricular canal defect without Down syndrome: a heterogeneous
      malformation.
AB  - The atrioventricular canal defect (AVCD) is one of the congenital heart defects
      most frequently associated with extracardiac anomalies. The association of AVCD
      with Down syndrome and heterotaxy has been studied extensively. However, little
      information is available about the prevalence of genetic syndromes and additional
      cardiac malformations in patients with AVCD and visceroatrial situs solitus
      without Down syndrome. This paper reviews the genetic and cardiologic
      characteristics of patients with non-Down AVCD and situs solitus in the
      literature and our series of 203 consecutive patients. In our experience, 132
      (65%) of the patients have nonsyndromic AVCD, while 71 (35%) have non-Down
      syndromic AVCD. Chromosomal imbalances were detected in 7 cases (3%), Mendelian
      syndromes or associations in 44 (22%), and extracardiac anomalies without an
      identifiable syndrome in 20 (10%). Deletion 8p is prevalent among those with
      chromosomal imbalances. Noonan, Ellis-van Creveld, oro-faciodigital, Smith-Lemli
      Opitz syndromes and VACTERL cases are frequent among patients with recognizable
      or identifiable nonchromosomal conditions. Based on this analysis of the type of
      AVCD and prevalence of associated cardiac anomalies in the different groups of
      patients, we found that: 1) the complete form is prevalent in patients with
      chromosomal imbalances; 2) the complete form is more frequently associated with
      additional cardiac defects, mainly left side obstructive lesions; and 3)
      additional cardiac anomalies are prevalent in syndromic patients. In conclusion,
      AVCD is a congenital heart defect with great variability in the anatomic patterns
      and heterogeneity of causes also in the subset without Down syndrome and without
      heterotaxy. The peculiar anatomic subtypes of this cardiac defect are associated
      with specific genetic conditions.

PMID- 10406668
TI  - Andersen syndrome autosomal dominant in three generations.
AB  - Andersen syndrome is a rare entity and comprises potassium sensitive periodic
      paralysis, ventricular arrhythmia, and an unusual facial appearance; syncope and
      sudden death have also been reported. The recognition of the characteristic face
      permits an early diagnosis in order to detect the severe systemic manifestations
      that are associated with this syndrome. The genetic defect is not linked to any
      other form of potassium sensitive periodic paralysis nor is it related to that of
      the long QT syndrome; nevertheless, a prolonged QT interval can be detected in a
      significant proportion of the cases. Sixteen cases of this syndrome have been
      described. We report on a three-generation family with 10 affected members. To
      our knowledge, this is the largest number of cases reported in one family. We
      noted some additional minor anomalies such as broad forehead and malar
      hypoplasia. Our patients had variable expression in the classical triad and of
      the severity of the systemic manifestations. Five of 8 affected studied members
      did not have a long QTc, which has been suggested as a constant finding in this
      syndrome.

PMID- 10406669
TI  - Blepharo-cheilo-dontic (BCD) syndrome in two Mexican patients.
AB  - The combination of lagophthalmia, ectropion of the lower eyelids, distichiasis,
      euryblepharon, cleft lip/palate, and oligodontia was recently named blepharo
      cheilo-dontic (BCD) syndrome. Different combinations of these signs have been
      found sporadically, with autosomal dominant inheritance. Ectropion of the lower
      eyelids, lagophthalmia, and bilateral cleft lip/palate appear to be the more
      common manifestations. We report on two unrelated patients with bilateral cleft
      lip/palate and lagophthalmia. One of these two patients had familial cleft
      lip/palate in two generations, probably as a variable expression of an autosomal
      dominant gene.

PMID- 10406670
TI  - Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a
      fibroblast growth factor receptor 2 mutation.
AB  - Fibroblast growth factor receptor (FGFR) mutations have been found in
      craniosynostosis syndromes with and without limb and/or dermatologic anomalies.
      Ocular manifestations of FGFR2 syndromes are reported to include shallow orbits,
      proptosis, strabismus, and hypertelorism, but no ocular anterior chamber,
      structural abnormalities have been reported until now. We evaluated three
      unrelated patients with severe Crouzon or Pfeiffer syndrome. Two of them had
      ocular findings consistent with Peters anomaly, and the third patient had opaque
      corneae, thickened irides and ciliary bodies, and shallow anterior chambers with
      occluded angles. Craniosynostosis with and without cloverleaf skull deformity,
      large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge,
      choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also
      present. These patients had airway compromise, seizures, and two died by age 15
      months. All three cases were found to have the same FGFR2 Ser351Cys (1231C to G)
      mutation predicted to form an aberrant disulfide bond(s) and affect ligand
      binding. Seven patients with isolated Peters anomaly, two patients with Peters
      plus syndrome, and three cases with typical Antley-Bixler syndrome were screened
      for this mutation, but none was found. These phenotype/genotype data demonstrate
      that FGFR2 is involved in the development of the anterior chamber of the eye and
      that the Ser351Cys mutation is associated with a severe phenotype and clinical
      course.

PMID- 10406671
TI  - Exclusion of linkage of Shwachman-Diamond syndrome to chromosome regions 6q and
      12q implicated by a de novo translocation.
AB  - Shwachman-Diamond syndrome is a rare genetic disorder of unknown pathogenesis
      involving exocrine pancreatic insufficiency and hematological and skeletal
      abnormalities. There is broad clinical variability; the extent of heterogeneity
      is unknown but comparisons within a large cohort of patients show no striking
      differences between patients of families with single or multiple affected
      offspring. Segregation analysis of a cohort of 69 families has suggested an
      autosomal recessive mode of inheritance. A single constitutional de novo
      chromosome rearrangement was reported in a Japanese patient involving a balanced
      translocation, t(6;12)(q16.2;q21.2), thereby suggesting possible loci for a
      genetic defect. Evenly spaced microsatellite markers spanning 26-32 cM intervals
      from D6S1056 to D6S304 and D12S375 to D12S346 were analyzed for linkage in
      members of 13 Shwachman-Diamond syndrome families with two or three affected
      children. Two-point lod scores were calculated for each marker under assumptions
      of recessive inheritance and complete penetrance. Negative lod scores indicated
      exclusion of both chromosome regions. Further, affected sibs were discordant for
      inheritance of chromosomes in most families based on constructed haplotypes. The
      cytogenetic abnormality is not associated with most cases of Shwachman-Diamond
      syndrome.

PMID- 10406672
TI  - Detection of a rare Wilson disease mutation associated with arylsulfatase A
      pseudodeficiency.
AB  - We have studied a patient with Wilson disease (WD), belonging to a family
      segregating late-onset, dominant cerebellar ataxia. Analysis of the WD gene
      showed that the patient is a compound heterozygote, carrying the 14His1069Gln
      mutation from the father and the 8Gly710Ser mutation from the mother. The
      8Gly710Ser is a mutation described previously only in a Swedish patient. Our
      patient is also homozygous for arylsulfatase A pseudodeficiency. This genetic
      defect, which has been reported in association with other neuropsychiatric
      syndromes, has not been described in WD.

PMID- 10406673
TI  - Keratosis pilaris and ulerythema ophryogenes associated with an 18p deletion
      caused by a Y/18 translocation.
AB  - We present a patient with partial monosomy of the short arm of chromosome 18
      caused by de novo translocation t(Y;18) and a generalized form of keratosis
      pilaris (keratosis pilaris affecting the skin follicles of the trunk, limbs and
      face-ulerythema ophryogenes). Two-color FISH with centromere-specific Y and 18
      DNA probes identified the derivative chromosome 18 as a dicentric with
      breakpoints in p11.2 on both involved chromosomes. The patient had another normal
      Y chromosome. This is a third report the presence of a chromosome 18p deletion
      (and first case of a translocation involving 18p and a sex chromosome) with this
      genodermatosis. Our data suggest that the short arm of chromosome 18 is a
      candidate region for a gene causing keratosis pilaris. Unmasking of a recessive
      mutation at the disease locus by deletion of the wild type allele could be the
      cause of the recessive genodermatosis.

PMID- 10406674
TI  - Dandy-Walker malformation with postaxial polydactyly: further evidence for
      autosomal recessive inheritance.
AB  - We describe an infant with Dandy-Walker malformation and tetramelic postaxial
      polydactyly type 1A. Parental consanguinity reinforces previous suggestions for
      autosomal recessive inheritance.

PMID- 10406675
TI  - Case of partial trisomy 2q3 with clinical manifestations of Marshall-Smith
      syndrome.
AB  - We describe a girl with physical anomalies, accelerated skeletal maturation,
      failure to thrive, and respiratory difficulties consistent with a diagnosis of
      Marshall-Smith syndrome (MSS). Chromosome analysis showed an inverted duplication
      of chromosome 2 [46,XX,inv dup(2)(q37q32) de novo] identified by G banding and
      confirmed by FISH. Several cases of trisomy 2q3 have been reported and
      established a syndrome, but the present case is the first to be associated with
      accelerated skeletal maturation and a clinical picture resembling MSS. This
      raises the possibility that the cause of MSS involves the q3 region of chromosome
      2. Few reports of MSS include study of the karyotype, although the chromosomes
      were apparently normal in those cases where they have been examined. We suggest
      that karyotyping be undertaken with particular attention to the 2q3 region in
      patients with suspected MSS. It also would be prudent to assess bone age in all
      children with trisomy 2q.

PMID- 10406676
TI  - I1307K APC variant in non-Ashkenazi Jewish women affected with breast cancer.

PMID- 10406677
TI  - Small supernumerary ring X chromosome in a four-month-old girl.

PMID- 10406678
TI  - Wrinkly skin syndrome and the syndrome of cutis laxa with growth and
      developmental delay represent the same disorder.

PMID- 10406679
TI  - Familial biliary atresia.

PMID- 10406680
TI  - Coated and active stents: an introduction.

PMID- 10406681
TI  - Mechanisms of drug loading and release kinetics.
AB  - In an effort to overcome the limitations of local drug delivery associated with
      the use of catheters, drug-loaded stents have been developed. Loading of such
      stents is achieved through either drug absorption (incorporation into a matrix)
      or drug adsorption (surface layering). The type of drug binding determines the
      elution profile/release kinetics of the drug, while the therapeutic target
      determines both the choice of drug used and the manner in which it is bound, i.e.
      eluting or non-eluting. While non-eluting stents have clinically reduced
      thrombotic complications following stent implantation, current experimental work
      concentrates on the use of eluting stents to combat restenosis.

PMID- 10406682
TI  - Coated stents: local pharmacology.
AB  - Despite excellent restoration of acute vessel perfusion, coronary stenting has
      been limited by subacute thrombosis within 3-10 days and by neointimal
      proliferation leading to restenosis by 6 months post-intervention. A variety of
      pharmacotherapeutics have been utilized in an attempt to prevent these sequelae.
      Drug regimens that reduce thrombosis have the potential for serious toxicities,
      and no regimen to date has been shown clinically to reduce the incidence of
      restenosis. Local drug delivery via stents coated with immobilized drug or coated
      with a drug-releasing polymer matrix offers the possibility of focal therapeutic
      drug effect within target tissues without serious side-effects arising from
      systemic drug administration. Before the promise of this treatment modality is
      realized, however, a more detailed understanding is needed of the local
      pharmacologic influences on drug activity. Drug-device parameters, such as stent
      surface area and mode of drug attachment, and drug-tissue parameters, including
      drug solubility in and non-specific binding to tissues, interact in a complex
      manner to determine local tissue drug dose, distribution and, consequently,
      effect.

PMID- 10406684
TI  - Synthetic polymers.
AB  - For several decades, synthetic polymers have been the subject of study for
      vascular applications. Several materials have been tested to date, both for
      coating and replacing metal stents. While conflicting data between some of these
      studies exist, these may in part be related to characteristics secondary to the
      synthetic polymer itself: surface characteristics (roughness, porosity,
      contaminants), bulk, fragmentation and degradation rate in the case of
      bioabsorbable polymers. Knowledge of the healing characteristics of the coated
      stents or stent grafts are essential for successful long-term results.

PMID- 10406683
TI  - Metallic surface modification.
AB  - The potential beneficial effect of metal surface treatment using electrochemical
      polishing on stent thrombogenicity and neointimal hyperplasia was evaluated in a
      rat A-V model and a porcine coronary model. Thrombogenicity of polished stents
      (n=6) was compared to non-polished stents (n=5) in a rat A-V shunt model using
      125I-fibrinogen and 51Cr-labelled platelets. Total clot weight after 30 min was
      significantly lower in the polished stents (32.1+/-2.8 vs 18.1+/-4.4: p<0.001).
      Also, 125I-fibrinogen deposition was significantly lower in the polished stents
      (1.30+/-0.07 vs 0.66+/-0.04: p<0.001). Platelet deposition was, however, not
      significantly reduced (12.7+/-3.4 vs 9.87+/-1.9, NS). Subsequently, the effect of
      electrochemical polishing on neointimal hyperplasia was evaluated in a porcine
      coronary model. Polished (n=10) and non-polished stents (n=10) were randomly
      implanted in the right coronary artery of healthy pigs. Neointimal hyperplasia
      was significantly decreased in the polished stents (0.56+/-0.28 vs 0.94+/-0.34
      mm2: p<0.01).

PMID- 10406685
TI  - Biomimicry 1: PC.
AB  - The surface properties of stents can be modified by coating them, for example
      with a polymer. Phosphorylcoline (PC) is the major component of the outer layer
      of the cell membrane. The haemo- and biocompatibility of a PC-containing polymer
      is thus based on biomimicry, and has been confirmed by several experiments
      showing much reduced thrombogenicity of PC-coated surfaces, and porcine coronary
      artery implants showing no sign of adverse effect. Clinical experience with the
      PC-coated BiodivYsio appears favourable. The PC coating can be tailored for take
      up and controlled elution of various drugs for stent-based local delivery, a
      property which is being actively explored.

PMID- 10406686
TI  - Biomimicry, vascular restenosis and coronary stents.
AB  - Biomimicry is in its earliest stages and is being considered in the realm of
      tissue engineering. If arterial implants are to limit neointimal thickening,
      purely passive structures cannot succeed. Bioactivity must be present, either by
      pharmacologic intervention or by fabricating a 'living stent' that contains
      active cellular material. As tissue engineering evolves, useful solutions will
      emerge from applying this knowledge directly to vascular biologic problems
      resulting from angioplasty, stenting, and vascular prosthesis research.

PMID- 10406687
TI  - On the production of radioactive stents.
AB  - In the last few years, radioactive stents has been proved to inhibit neointima
      formation. This paper describes the actual status of producing such radioactive
      stents. After a short discussion of the different radioisotopes suitable for
      radioactive stents, potential production methods are discussed. The ion beam
      implantation of P-32 applied at the Karlsruhe Research Centre shall be described
      in more detail.

PMID- 10406688
TI  - Comparative pathology: radiation-induced coronary artery disease in man and
      animals.
AB  - The occurrence of coronary artery disease following mediastinal radiation for
      malignancies has long been debated. However, the development of coronary
      pathology in young individuals following radiation who lack risk factors for
      atherosclerosis is highly suggestive of a cause-and-effect relationship. By far
      the most convincing pathologic changes are adventitial scarring and medial
      atrophy with severe intimal atherosclerotic disease consisting of necrotic core,
      fibrous tissue, and calcification. Initial clinical studies in patients with
      coronary atherosclerosis treated with intraluminal radiation following stenting
      hold great promise in the treatment and prevention of restenosis. There are
      little or no data, however, on long-term effects of intra-coronary radiation
      therapy in man. Therefore, it may be important to study the chronic effects of
      radiation in animal models in order to predict what is likely to occur in humans.
      We evaluated the effects of varying doses (0.15-23.0 microCi of 32P) of beta
      particle-emitting radioactive stents in pig coronary arteries at 1 and 6 months.
      At 1 month, there were dose-dependent changes in the morphology of the intima and
      media. High activities (>3 microCi) caused medial necrosis with fibrin deposition
      in the media and intima, with interspersed red cells most marked in regions
      surrounding the stent struts. Only rare smooth muscle cells (SMCs) and
      inflammatory cells were seen away from the stent struts. In the intermediate (1
      microCi) stent activity group, the neointima was expanded by SMCs and a
      proteoglycan-rich matrix with focal endothelialization of the luminal surface.
      Neovascular capillaries and extravascular red cells were present adjacent to
      stent struts. At low activities (<0.5 microCi), the neointima was significantly
      smaller than control stents and consisted of SMCs and matrix with complete
      endothelialization of the luminal surface. The neointimal cell density of the
      media and intima decreased with increasing doses of radiation. In pigs 6 months
      after radioactive stenting (activities ranging from 0.5-12 microCi 32P), >3.0
      microCi radioactive stents induced marked neointimal thickening, with changes
      similar to atherosclerosis, consisting of necrotic debris containing cholesterol
      clefts surrounded by macrophage collections, fibrosis, and focal calcification.
      There was increased adventitial thickening in the radiated vs non-radiated
      arteries. The intermediate stent activity (1.0 microCi) also showed greater
      neointimal thickening (vs control stents) and consisted mostly of SMCs in a
      proteoglycan-rich matrix. At <1.0 microCi, there were minimal differences seen
      between radiated and control non-radiated stented arteries. The media was
      unevenly injured in all stent activities and varied from less than to
      significantly greater than controls. These data suggest that radiation-induced
      coronary atherosclerosis seen in man is partially simulated in normal porcine
      coronary arteries 6 months following high-dose beta-particle-emitting radioactive
      stent placement. There is greater fibrosis and thickness of the adventitia and
      focal attenuation of the media in man and severe luminal narrowing in pig
      coronary arteries treated with high doses of radiation. Only long-term clinical
      follow up and careful autopsy studies will determine if endoluminal or intra
      arterial radiation is a viable means of reducing restenosis in man.

PMID- 10406689
TI  - Heparin-coating of coronary stents.
AB  - The development of the end-point attached HC stent should be regarded against the
      early unfavourable results with uncoated stents in the pre-IVUS- and pre
      ticlopidine era. Despite this, results of pilot- and randomized trials show a
      surprising low incidence of (sub)acute stent thrombosis under challenging
      circumstances like acute coronary events. Considering the quite low incidence of
      early complications of non-coated second generation stents it may require very
      large trials to test the clinical efficacy of the HC coating against non-coated
      devices. However, even if the 'added value' of the HC coating is never
      scientifically proven, it has helped to a large degree to enhance the penetration
      of stent-therapy in interventional cardiology. Unlike the situation in 1992, very
      few cardiologists will now oppose the statement that stents contribute to the
      state of the art treatment of patients with angina pectoris or acute myocardial
      infarction.

PMID- 10406690
TI  - Antithrombotic stent coatings: hirudin/iloprost combination.
AB  - Neointimal formation after stent implantation can cause luminal narrowing, called
      restenosis. Restenosis is induced by initial platelet adhesion and thrombus
      formation followed by immunocyte adhesion on the stent surface and on the injured
      vessel wall. The thrombus releases factors, which activates the proliferation of
      smooth muscle cells. Stents, coated with an antithrombotic surface, may prevent
      platelet adhesion and subsequent smooth muscle cell proliferation. This paper
      will review stent coating with poly-LD-lactic acid, a biodegradable polymer
      containing Iloprost, a synthetic prostacycline, and PEG-Hirudin as a method for
      reducing of restenosis.

PMID- 10406691
TI  - Local delivery of glycoprotein IIb/IIIa receptor inhibitors using drug eluting
      stents.

PMID- 10406692
TI  - Anti-inflammatory stent coatings: dexamethasone and related compounds.
AB  - The dexamethasone-eluting stent was a well-tolerated and effective means of
      providing sustained site-specific drug delivery to the porcine coronary artery
      wall for 28 days, although longer-term biocompatibility of the polymer coating
      was not assessed. Dexamethasone did not reduce the neointimal hyperplastic
      response to injury, despite sustained tissue levels of drug.

PMID- 10406693
TI  - Antiproliferative stent coatings: Taxol and related compounds.
AB  - The implantation of stents can prevent vessels from post interventional elastic
      recoil and appears to limit adverse remodelling. In order to inhibit in-stent
      restenosis, an additional release of antiproliferative agents from the stent
      itself might lead to a synergistic reduction of lumen renarrowing. Paclitaxel
      (Taxol) is a microtubule-stabilizing agent with potent antiproliferative
      activity. Unlike other antimitotic agents of the colchicine type, it shifts the
      microtubule equilibrium towards assembly, leading to reduced proliferation,
      migration and signal transduction. Moreover, important biological processes, such
      as the activation of some protein kinases, are associated with microtubule
      depolymerization and are therefore inhibited by paclitaxel. Several experimental
      in vitro and in vivo studies using local paclitaxel delivery to inhibit
      proliferation and lumen renarrowing have been performed already--with very
      encouraging results.

PMID- 10406694
TI  - Gene therapy for coronary artery disease: The University of Michigan Program.
AB  - Recent studies show that the cyclin dependent kinase inhibitor KIP/CIP family
      members function as regulators of VSMC proliferation. The prevention and
      treatment of cell proliferation in arteries after percutaneous intervention,
      represents an attractive target for gene therapy. Targeting of cell cycle
      regulatory proteins might inhibit cell proliferation and migration, and induce
      withdrawal from the cell cycle. Furthermore, these studies suggest that genetic
      approaches are feasible and that local expression of a regulatory gene is
      sufficient to abrogate lesion formation in different animal models of vascular
      diseases.

PMID- 10406695
TI  - Gene therapy to prevent restenosis, the Boston experience.
AB  - The delivery of genetic material to the vessel wall is being explored as a means
      to treat disorders of the vasculature. Gene therapy offers the possibility to
      directly or indirectly influence the molecular pathways that are disregulated.
      With regard to postangioplasty restenosis, gene therapy is most often aimed at
      inhibition of vascular smooth muscle cell (VSMC) proliferation. Here, we review
      the results of studies in our laboratories that have investigated a number of
      different strategies to inhibit proliferative vessel wall lesions. These
      strategies include the administration of genes that block cell cycle progression,
      induce apoptosis, or promote the growth of vascular endothelium.

PMID- 10406696
TI  - Modification of molecular events in coronary restenosis using coated stents: The
      Mayo Clinic Approach.
AB  - Restenosis remains the major problem in interventional cardiology today. The
      intracoronary stent is an indispensable part of the interventional coronary
      practice. Restenosis rates, using current third generation devices in
      straightforward lesions are now less than 10%. Advances in stenting have had a
      remarkable effect on the safety and efficacy of clinical practice. Now that
      stents are easily deployed, and have shown substantive clinical impact, questions
      arise about the future of stenting. Answers to this question centre on several
      remaining problems with current stent technology and interaction with the biology
      of coronary arteries. One method to accomplish this is to have the material of
      the stent interact directly with the vessel. This can be achieved by better stent
      materials, or by impregnating the stent with drugs or genes to modify the vessel
      wall. This chapter will describe several such approaches under consideration.

PMID- 10406697
TI  - Seeding of intravascular stents by the xenotransplantation of genetically
      modified endothelial cells.
AB  - A novel approach of cell seeding of stents using xenotransplanted endothelium is
      proposed. The advantages of this approach are that these doubly transgenic
      animals will provide a limitless supply of endothelial cells producing
      controllable levels of active compound. These foreign cells will act as Trojan
      horses, graciously accepted at face value by the host organism, but capable of
      modifying the pathophysiological response to vessel damage, typified by the
      process of restenosis. Once implanted, the production of the bioactive compound
      is under exogenous control by means of 'designer' genes coding for modified cell
      surface receptors, which are introduced with the transgene to provide
      controllable levels of compound. Interaction of an orally administered compound
      with the modified cell receptor will switch on the transgene, while in its
      absence the transgene remains dormant. We have been able to show the feasibility
      this type of approach has for other animal species, and it shows great potential
      for application to humans.

PMID- 10406698
TI  - Meeting address. The devil is in the details.

PMID- 10406699
TI  - Comparison of castile soap, benzalkonium chloride, and bacitracin as irrigation
      solutions for complex contaminated orthopaedic wounds.
AB  - OBJECTIVE: The purpose of the present study was to determine the effects of
      cleaning a contaminated orthopaedic wound with different classes of wound
      irrigation solutions. STUDY DESIGN: Rats with a contaminated orthopaedic wound
      were randomized into treatment groups: normal saline (NS), castile soap (CS),
      benzalkonium chloride (BzC), bacitracin (Abx), or sequential irrigation with BzC,
      CS, and NS. INTERVENTION: Pseudomonas aeruginosa [P. aeruginosa; 1 x 10(6) colony
      forming units (CFU)], or Staphylococcus aureus (S. aureus; 1 x 10(6) CFU) were
      placed into a paravertebral wound (containing a wire implant placed through a
      spinous process) and allowed to incubate for fifteen minutes. The wound was then
      irrigated with three liters of either NS, 0.05 percent CS, 0.03 percent BzC, Abx
      (33,000 units per liter) or underwent a sequential irrigation treatment (one
      liter each of BzC, CS, NS). MAIN OUTCOME MEASUREMENTS: The animals were observed
      daily for wound complications for fourteen days and then killed, and cultures of
      the wound were obtained. RESULTS: Pseudomonas aeruginosa: Both CS and the
      sequential irrigation treatment significantly lowered the rate of positive wound
      cultures when compared with NS (p < 0.05). Irrigation with BzC resulted in a
      higher rate of positive wound cultures and complications. The sequential
      irrigation treatment prevented the wound complications associated with irrigation
      with BzC alone. Staphylococcus aureus: Only BzC irrigation significantly lowered
      the rate of positive wound cultures when compared with NS (p < 0.05). CONCLUSION:
      The rate of positive wound cultures due to P. aeruginosa is effectively reduced
      by irrigation with CS alone or by the sequential irrigation treatment. When used
      alone, the antiseptic BzC results in a higher rate of positive wound cultures and
      wound complications. The wound complications seen with irrigation with BzC alone
      are prevented by the sequential irrigation treatment (BzC followed by CS and NS).
      The rate of positive wound cultures in this model due to S. aureus is not
      decreased by irrigation with CS; however, the rate of positive wound cultures is
      safely and effectively decreased with the use of BzC.

PMID- 10406700
TI  - Computed tomographic scanning of cervical spine fractures: does it influence
      treatment?
AB  - OBJECTIVE: To determine whether the superior sensitivity of computed tomography
      (CT) results in changes in treatment plans for cervical spine fractures that have
      been diagnosed on plain films alone. DESIGN: Retrospective review of radiographic
      studies for cervical spine trauma. SETTING/PARTICIPANTS: An orthopaedic spine
      surgeon (SS), an orthopaedic traumatologist (OT), an orthopaedic spine fellow
      (SF), and an orthopaedic chief resident (CR) were independently presented thirty
      nine cases of cervical spine trauma imaged with adequate plain radiographs and
      with CT. MAIN OUTCOME MEASURES: Agreement was measured by calculation of kappa
      coefficients. RESULTS: The detection rate of total fractures on plain radiographs
      alone ranged from 47 percent to 71 percent, and the diagnosis changed an average
      53 percent of cases. Change in treatment plans ranged from 10 percent (SS) to 46
      percent (CR) of cases. Of these changes, undertreatment occurred as follows: SS
      =3 percent, OT =8 percent, SF =36 percent, and CR = 46 percent. The mean kappa
      coefficient for intraobserver agreement of treatment plans was 0.69. The
      experienced observers demonstrated "excellent" agreement with an average kappa
      coefficient of 0.85, whereas the mean coefficient for inexperienced observers was
      0.54 or "moderate" agreement. Complete diagnostic agreement occurred between the
      experienced observers after review of both the plain films and CT scans. The
      interobserver agreement of treatment plans for the experienced observers
      increased from 0.79 to 0.88. CONCLUSIONS: CT scanning afforded additional
      information for all observers. Experienced observers can reliably determine
      treatment plans for cervical spine trauma diagnosed on plain films alone, whereas
      inexperienced observers are less reliable. For the experienced observers,
      interobserver agreement on treatment plans increased after the addition of CT.

PMID- 10406701
TI  - Biomechanical comparison of bending and torsional properties in retrograde
      intramedullary nailing of humeral shaft fractures.
AB  - OBJECTIVE: To establish whether the bending and torsional stiffness of an
      implanted nail are influenced by nail design and nail-bolt interface, this study
      compared two implanted retrograde nail systems: the AO/ASIF unreamed humeral nail
      (UHN) and the Russell-Taylor (RT) nail. DESIGN: Pair randomization. SETTING:
      Mechanical laboratory testing. SPECIMENS: Twelve pairs of freshly harvested
      cadaveric humeri. METHODS: Transverse fractures were simulated with a
      standardized midshaft osteotomy and a three-millimeter gap. Both nails were
      proximally and distally interlocked. The RT nail has a single interlock at its
      base and tip. The UHN has double interlocking both proximally and distally. The
      screw hole design of the RT nail features slots, whereas the UHN has round screw
      holes. MAIN OUTCOME MEASURES: Anteroposterior and mediolateral bending stiffness
      and torsional stiffness. RESULTS: The RT nail showed higher bending stiffness in
      anteroposterior and mediolateral bending. Large differences were seen in the
      torsional characteristics: for the first 30 degrees, the RT nail showed a much
      lower resistance against torsion than the UHN. Analysis of variance of stiffness
      at four, six, and eight newton-meters showed statistical significance (p <
      0.0001). Torsional stiffness, defined as the slope of a straight line
      approximated to between 75 and 100 percent of the maximum torque, was very
      similar in both nails. CONCLUSION: The torsional differences between the two nail
      systems are attributable to the nail-bolt interface of the RT nail. This dynamic
      system allows a clinically relevant degree of movement. The greater resistance to
      rotatory forces of the UHN is explained by the fact that the interlocking at its
      tip and base creates a static rather than a dynamic system.

PMID- 10406702
TI  - Common and external iliac artery injuries associated with pelvic fractures.
AB  - BACKGROUND: Common and external iliac artery injuries associated with pelvic
      fractures are uncommon. The diagnosis of such injuries is based on clinical
      findings and confirmed by arteriography. DESIGN: Retrospective chart review.
      SETTING: University Level I trauma center. PATIENTS: Five men and three women,
      aged seventeen to seventy-six years, with injuries to the common and external
      iliac arteries associated with pelvic fractures. RESULTS: All patients sustained
      complex pelvic fractures associated with multiple blunt injuries. Five injuries
      occurred on the right side. Two patients had an associated right vertical shear
      pelvic fracture. In five patients, vascular injury was diagnosed in the first six
      hours after admission. One patient presented with an aneurysm of the right common
      iliac artery two months after his initial injury. All patients underwent surgical
      repair with an interposition graft, which failed in two patients, who underwent
      vascular reconstruction ten hours after the injury. One patient died of
      associated injuries. CONCLUSIONS: Arterial hyperextension with intimal damage
      seems to be the most likely cause of this injury. Ideally, an extraperitoneal
      approach should be attempted to minimize blood losses and, due to the size of the
      iliac vessels, an interposition graft should be used for reconstruction.

PMID- 10406703
TI  - Regulation of osteoblast levels during bone healing.
AB  - OBJECTIVE: To confirm the occurrence of programmed cell death of osteoblasts
      during bone healing and to evaluate the role of interleukin-1beta (IL-1beta) in
      regulating osteoblast concentration. STUDY DESIGN: Electron microscopic study of
      the response of rats to a controlled bone injury, and a randomized controlled
      study of the effect of IL-1beta administered continuously for three days.
      METHODS: A standardized defect (1.1 millimeter in diameter, 0.5 millimeter deep)
      was created unilaterally on the anteromedial surface of the tibia. In some
      animals, the injury site was recovered five days after operation and processed
      for ultrastructural evaluation of osteoblasts in the callus. In another group, IL
      1beta was delivered to the bone defect using micro-osmotic pumps (0.5
      nanograms/hour); control rats received vehicle only. The bones were recovered one
      to fourteen days after injury, and concentrations of proliferating cells,
      osteoblasts, and apoptotic bodies were determined. The amount of callus that
      formed in the defect was measured. RESULTS: Osteoblasts in the callus exhibited
      ultrastructural changes characteristic of cells undergoing apoptosis, including
      condensation of chromatin, membrane blebbing, formation of apoptotic bodies, and
      phagocytosis by nearby osteoblasts. Addition of IL-1beta significantly increased
      the number of osteoblasts at the injury site and significantly decreased the
      number of apoptotic bodies in relation to the number of osteoblasts. The amount
      of callus in the bone defect was not affected by IL-1beta treatment. CONCLUSION:
      The role of programmed cell death of osteoblasts as a normal concomitant of bone
      healing was confirmed. Evidence was found suggesting that IL-1beta mediated the
      appearance and disappearance of osteoblasts, possibly by affecting the rates of
      differentiation and apoptosis, respectively. Understanding these mechanisms
      conceivably could lead to the ability to control osteoblast levels at an injury
      site.

PMID- 10406704
TI  - Functional outcome and quality of life in patients with Type B ankle fractures: a
      two-year follow-up study.
AB  - OBJECTIVES: To compare a specific score designed for ankle fractures with a
      general quality-of-life instrument as an outcome measure, and to describe the two
      year results for patients with Type B ankle fractures. DESIGN: Follow-up study.
      SETTING: Large teaching hospital, Sweden. PATIENTS: Fifty-three patients, aged
      nineteen to sixty-three years, treated operatively for Type B ankle fractures.
      Forty-one patients completed the follow-up. MAIN OUTCOME MEASUREMENTS: Olerud
      Molander Ankle Score (OMA score), Short Form-36 Health Survey (SF-36), and a
      visual analogue scale (VAS). RESULTS: A significant correlation was found between
      the OMA score and SF-36 subscores for physical functioning, physical and
      emotional role function, social functioning, and bodily pain (p < 0.05). VAS for
      physical symptoms correlated with the OMA score and with all SF-36 subscores (p <
      0.001). The mean OMA score was 84 (standard deviation = 22.5); 64 percent of
      patients scored 90 or more. Patients with an OMA score <90 more often had a B3
      type fracture (p < 0.05) and more often considered themselves as not recovered
      compared with patients with an OMA score > or =90 (p < 0.001). Only thirteen
      patients (36 percent) reported a complete recovery. Sixteen patients (44 percent)
      had work-related problems and twenty-two (61 percent) had some problems with
      sport activities. The SF-36 subscores for physical functioning, physical and
      emotional role function, vitality, and mental health were lower compared with an
      average Swedish population (p < 0.05). CONCLUSIONS: Our results suggest that the
      SF-36 Health Survey may be useful in measuring outcome after an ankle fracture,
      that disability, i.e., self-perceived limitations in everyday life, is common
      after B-type ankle fractures.

PMID- 10406705
TI  - Early wound complications of operative treatment of calcaneus fractures: analysis
      of 190 fractures.
AB  - OBJECTIVES: The purpose of the present study was to discover any associations
      between preoperative variables and the occurrence of wound complications in the
      surgical treatment of calcaneus fractures. DESIGN: Retrospective review. SETTING:
      A Level 1 trauma center. PATIENTS: One hundred seventy-nine patients, with 190
      fractured calcanei, were studied. INTERVENTION: Each patient underwent open
      reduction and internal fixation for calcaneus fractures with standard techniques.
      MAIN OUTCOME MEASUREMENTS: The age, sex, preexisting medical conditions, social
      history, and mechanism of injury of each patient were recorded. Note was made of
      the status of the soft tissue injury, if any. The time from injury to surgical
      stabilization was recorded, as was the type of incision used, use of preoperative
      antibiotics, and type of wound closure. The patients' records were reviewed for
      wound complications. These complications were classified as those that could be
      treated nonsurgically and those that required surgical management. RESULTS:
      Records from July 1992 to July 1998 showed 179 patients who underwent operative
      stabilization of a calcaneus fracture. Eleven had bilateral fractures, for a
      total of 190 fractured calcanei. The average age was thirty-five years. Nine
      patients were diabetics. One hundred eleven of the patients reported current use
      of cigarettes. Eighteen of the fractures were open. A standard, L-shaped lateral
      approach to the calcaneus was used in each case. Stabilization was achieved by
      using standard techniques, with plates and screws. In all cases, a two-layer
      wound closure was used. Forty-eight patients (25 percent) developed some form of
      wound complication. Forty (21 percent) of these required surgical treatment.
      Statistical analysis identified diabetes (p = 0.02; relative risk 3.4), smoking
      (p = 0.03; relative risk 1.2), and open fractures (p < 0.0001; relative risk 2.8)
      as risk factors for wound complication. The presence of more than one risk factor
      increased the relative risk of a wound complication requiring surgery.
      CONCLUSION: Smoking, diabetes, and open fractures all increase the risk of wound
      complication after surgical stabilization of calcaneus fractures. Cumulative risk
      factors increase the likelihood of wound complications. Patients who have the
      risk factors identified in this study should be counseled as to the possible
      complications that may arise after surgery. In patients with multiple risk
      factors, consideration should be given to nonsurgical management.

PMID- 10406706
TI  - Reduction of posterior hip dislocations in the lateral position using traction
      countertraction: safer for the surgeon?
AB  - Closed reduction of a hip dislocation is a physically demanding task for the
      orthopaedic surgeon. The most commonly used methods for reduction of the hip
      involve vigorous axial traction on the lower extremity with the patient in the
      supine position, using an assistant who attempts to hold the pelvis down. The
      surgeon generally stands over the patient to pull up on the bent knee, which puts
      the surgeon at risk for a low back injury and, if done while the patient remains
      on a stretcher, can put the surgeon at risk for a fall from a height. Reduction
      in the prone position is advocated by some, but caring for the sedated patient in
      the prone position can be difficult and the patient's pelvis tends to roll off
      the edge of the stretcher, preventing the achievement of hip flexion, which is
      desirable in achieving reduction. We describe a traction-countertraction
      technique that appears to be significantly less dangerous for the surgeon. In
      this technique the hip is reduced with the patient remaining on the stretcher in
      the lateral position. In addition, fluoroscopy can be carried out during the
      reduction maneuver, and the images can be quite helpful in adjusting the
      direction of manipulative forces.

PMID- 10406707
TI  - Anatomical reconstruction of the patellar tendon: a new technique with hamstring
      tendons and iliotibial tract.
AB  - A new technique of patellar tendon reconstruction was performed in a patient who
      lost tendon and tibial tuberosity during wide excision surgery for a malignancy.
      In this procedure, the tendon was anatomically replaced by a graft composed of
      ipsilateral hamstring tendons and iliotibial tract, with the biomechanical
      conditions considered. Both ends of the graft were secured in the size-matched
      bone tunnels in the patella and tibia by screw post fixation, which is a
      technique established in ligament reconstruction surgery in the knee joint. At
      the twenty-month follow-up, the result was deemed successful.

PMID- 10406709
TI  - Intraarticular heterotopic ossification in the knee following intramedullary
      nailing of the fractured femur using a retrograde method.
AB  - The cases of a forty-five-year-old woman and a twenty-year-old man who developed
      severe intraarticular and periarticular heterotopic ossification around the knee
      following intramedullary nailing of a femur fracture using a retrograde
      technique. The association of musculoskeletal heterotopic ossification with
      closed head injuries seems well established and can occur in and around the knee
      following retrograde intramedullary nailing. This complication may occur more
      often than has been reported.

PMID- 10406708
TI  - Salvage of open tibial fracture with segmental loss of tibial nerve: case report
      and review of the literature.
AB  - We report a case history, treatment, and follow-up of an open comminuted distal
      tibial fracture with significant soft tissue loss and segmental loss of the
      tibial nerve and posterior tibial artery. This constellation of injuries with an
      insensate plantar foot has often been an indication for amputation. In this
      instance, a functional distal extremity was salvaged with the use of Ilizarov
      fixation, delayed primary tibial nerve cable grafting, and staged soft tissue
      coverage. Clinical follow-up and review of the literature on the techniques used
      are offered for consideration.

PMID- 10406710
TI  - Repair of supracondylar femur fracture and unilateral knee replacement at the
      same surgery.
AB  - In patients who are candidates for a total knee arthroplasty and suffer a
      periarticular fracture of the femur, the arthroplasty may be performed after bony
      union of the fracture or immediately, in conjunction with the fracture repair.
      Herein we present the case of a sixty-year-old female with rheumatoid arthritis
      and a supracondylar fracture of the right femur in whom total knee arthroplasty
      and retrograde nail insertion were addressed at one surgery; the outcome was
      favorable. The transverse extraarticular fracture pattern in this patient was
      advantageous for simultaneous procedures; had the fracture been more comminuted
      or intraarticular, it might not have been possible to perform both procedures at
      the same time.

PMID- 10406711
TI  - Wrist impairment.

PMID- 10406712
TI  - Ultrasound for detection of fracture healing.

PMID- 10406713
TI  - The architecture of Mourera fluviatilis (Podostemaceae): developmental morphology
      of inflorescences, flowers, and seedlings.
AB  - Mourera fluviatilis from northern South America is a spectacular member of the
      Podostemaceae (river-weeds). Its raceme-like inflorescences are up to 64 cm long
      and have 40-90 flowers arranged in two opposite rows. Inflorescence development
      starts with the initiation of a double-sheathed (dithecous) bract in a terminal
      position. All lateral bracts (again dithecous) are initiated in basipetal order
      along the two flanks of the inflorescence. Each gap between two neighboring
      bracts contains a single flower. The flowers are bisexual, each with a whorl of
      16-20 ligulate tepals and 14-40 stamens, which are arranged in one or two whorls.
      Floral development starts with the formation of a girdling primordium rim around
      a two-lobed primordial gynoecium. Stamen and tepal initiation is centrifugal on
      the girdling primordium. The anthers are introrse or extrorse, depending on
      stamen position. Seedlings develop two entire, threadlike cotyledons, followed by
      forked filamentous leaves, which arise from the plumular pole. The radicular pole
      of the hypocotyl develops into a claw-shaped holdfast that fixes the young plant
      to the rock. The developmental morphologies of Mourera fluviatilis and other
      members of the Mourera group (including Lonchostephus and Tulasneantha) fit well
      with the Podostemoideae bauplan known from other New World genera, such as
      Apinagia and Marathrum.

PMID- 10406714
TI  - The internal cuticle of Cirsium horridulum (Asteraceae) leaves.
AB  - Leaf internal cuticle has not previously been studied in detail, and yet its
      existence has profound implications for the path of water movement. The internal
      cuticle forms a uniform layer on the inner periclinal epidermal walls that border
      substomatal cavities. This cuticle is continuous with the external cuticle
      through the stomatal pores. The thickness of the internal cuticle on nonstomatal
      epidermal cells is approximately one-third that of the external cuticle on the
      same cells. On both the abaxial and adaxial sides of the leaf the internal
      cuticle forms irregularly shaped islands bordered by mesophyll cells. The size of
      the islands coincides with the epidermal area of the substomatal cavity. The
      internal cuticle remains intact and connected to the external cuticle after
      incubation in cellulytic enzymes. After treatment with sulfuric acid or
      chloroform, both cuticles remain intact. The autofluorescence of both cuticles is
      increased by staining with auramine O. These results indicate that large portions
      of the leaf epidermis are covered by both an internal and an external cuticle.

PMID- 10406715
TI  - Ultrastructure of stomatal development in Arabidopsis (Brassicaceae) leaves.
AB  - Stomatal development was studied in wild-type Arabidopsis leaves using light and
      electron microscopy. Development involves three successive types of stomatal
      precursor cells: meristemoid mother cells, meristemoids, and guard mother cells
      (GMCs). The first two types divide asymmetrically, whereas GMCs divide
      symmetrically. Analysis of cell wall patterns indicates that meristemoids can
      divide asymmetrically a variable number of times. Before meristemoid division,
      the nucleus and a preprophase band of microtubules become located on one side of
      the cell, and the vacuole on the other. Meristemoids are often triangular in
      shape and have evenly thickened walls. GMCs can be detected by their roughly oval
      shape, increased starch accumulation, and wall thickenings on opposite ends of
      the cells. Because these features are also found in developing stomata, stomatal
      differentiation begins in GMCs. The wall thickenings mark the division site in
      the GMC since they overlie a preprophase band of microtubules and occur where the
      cell plate fuses with the parent cell wall. Stomatal differentiation in
      Arabidopsis resembles that of other genera with kidney-shaped guard cells. This
      identification of stages in stomatal development in wild-type Arabidopsis
      provides a foundation for the analysis of relevant genes and of mutants defective
      in stomatal patterning, cell specification, and differentiation.

PMID- 10406716
TI  - Inheritance of resistance to anti-microtubule dinitroaniline herbicides in an
      "intermediate" resistant biotype of Eleusine indica (Poaceae).
AB  - Inheritance of resistance to the anti-microtubule dinitroaniline herbicides was
      investigated in a goosegrass biotype displaying an intermediate level of
      resistance (I). Reciprocal crosses were made between the I biotype and previously
      characterized susceptible (S) or resistant (R) biotypes. Eight F(1) hybrids were
      identified, and F(2) populations were produced by selfing. The dinitroaniline
      herbicide response phenotype (DRP) of F(1) plants, and F(2) seedlings was
      determined using a root-growth bioassay. The DRP of F(1) plants of S * I was
      "susceptible" (i.e., identical to the S parental plants), and the DRP of F(1)
      plants of I * R was "intermediate" (i.e., identical to the I parental plants).
      Nonparental phenotypes were not observed in F(1) plants. Results indicated
      susceptibility to be dominant over intermediate resistance and intermediate
      resistance to be dominant over high resistance. Analysis of reciprocal crosses
      ruled out any role for cytoplasmic inheritance. When treated at the
      discriminating concentration (e.g., 0.28 ppm oryzalin), F(2) seedlings of S * I
      were classified as either S or I phenotype, and F(2) seedlings of I * R were
      classified as either I or R phenotype. Again, nonparental phenotypes were not
      observed. The 3:1 (S:I or I:R) segregation ratios in F(2) seedlings were
      consistent across all eight F(2) families. The results show that dinitroaniline
      herbicide resistance in the I biotype of goosegrass is inherited as a single,
      nuclear gene. Furthermore, it suggests that dinitroaniline resistance in
      goosegrass is controlled by three alleles at a single locus (i.e., Drp-S, Drp-i,
      and Drp-r).

PMID- 10406717
TI  - Wind pollination and reproductive assurance in Linanthus parviflorus
      (Polemoniaceae), a self-incompatible annual.
AB  - Wind pollination was experimentally demonstrated in Linanthus parviflorus
      (Polemoniaceae), a predominantly beefly-pollinated, self-incompatible annual.
      Seed set in plants enclosed in mesh tents that excluded pollinators but allowed
      airborne pollen flow provided evidence for wind pollination, and the extent of
      seed set due to wind pollination was compared to that in open-pollinated controls
      and pollen-supplemented treatments. Additional controls were included to test for
      possible confounding effects of the mesh tent. Mean seed number in open
      pollinated plants was 72.8-81.1% of that in pollen-supplemented plants, while
      wind pollination alone produced 49.5-52.2%, a smaller but substantial proportion
      of seed set with pollen supplementation. Further evidence for wind pollination
      was found in a comparison of sites differing in the extent of wind exposure in
      two populations of L. parviflorus. Airborne pollen counts were higher in exposed
      sites than in protected sites, and the difference was marginally significant.
      Seed set was significantly pollen limited in protected sites, but not in exposed
      sites. Taken together, the data suggest that wind pollination provides some
      reproductive assurance in this obligately outcrossing species. Wind pollination
      is hypothesized to represent an alternative to selfing as an evolutionary
      solution to the problem of temporal or spatial variation in pollination
      visitation.

PMID- 10406718
TI  - Why be a honeyless honey mesquite? Reproduction and mating system of nectarful
      and nectarless individuals.
AB  - Populations of Prosopis glandulosa var. torreyana in the Chihuahuan desert have a
      fixed dimorphic system of nectar production in which half the individuals produce
      nectar (are nectarful) and the other half are nectarless. We analyzed the impact
      of nectar production on different estimates of fitness, comparing nectarful
      against nectarless individuals in size, mating system, seed traits, and fruit set
      in a 1-ha scrubland. Of the reproductive individuals (358), 46% were nectarful
      and 54% were nectarless. Neither tree size nor flowering phenology differed
      between nectar morphs. Fixation indices (F) for both progeny (F = -0.2) and
      adults (F = -0.45) were negative, and high heterozygosities were found in adults
      and progeny (H = 0.45). No differences were found between nectar morphs for F, H,
      and single (t(s) = 1.1) and multilocus (t(m) = 1.03) outcrossing rates.
      Controlled pollinations showed differences between selfing and control treatments
      with no differences between nectar morphs. Nectarless individuals produced
      significantly more pollen grains than did nectar producers, but all other
      measured floral traits showed no differences. Nectarful trees were visited by
      pollinators 21 times more often and had a significantly higher overall fruit set
      than did nectarless trees. No differences between nectar morphs in seed mass or
      in percentage seed germination were found, but heavier seeds tended to have
      higher heterozygosities. Both morphs had similar success as females, but
      nectarless trees had ~7% higher male function. We discuss three possible
      scenarios for the evolution of the fixed dimorphism in nectar production, two
      involving unstable phases (substitution of one morph by the other, and evolution
      towards dioecy) and one stable scenario (maintenance of the dimorphic system).

PMID- 10406719
TI  - Sexual expression and genetic diversity in populations of Cryptogramma crispa
      (Pteridaceae).
AB  - The reproductive biology of Cryptogramma crispa, a tetraploid species with a
      broad circumboreal and alpine distribution, growing mainly in siliceous boulder
      fields and crevices, was studied in the laboratory by growing gametophytes in
      plates with both solidified agar media and sterilized soil. In addition, an
      electrophoretic study of isozymes was carried out on frond samples from five
      natural populations, as an additional source of evidence concerning the breeding
      system and the genetic structure of sporophyte populations. Populations
      throughout the Iberian range of the species were selected for this study, and a
      Scottish population was included to represent plants from outside our local area
      and ecology. The morphological development of gametophytes is of the Adiantum
      type. All multispore cultures developed into a bigametophytic system, consisting
      in most cases of male and female prothalli. This pattern of sexual expression
      provides evidence for outcrossing as the main breeding system in this species.
      Moreover, there is good evidence that the species possesses an antheridiogen
      system to promote outcrossing. The long time needed by gametophytes to produce
      gametangia, and afterwards to fertilize and produce sporophytes, might be the
      primary reason why so few young sporophytes are found in the wild. The values of
      the percentage of polymorphic loci and the similarity levels obtained from the
      isozyme analyses indicate a level of genetic variability that would be expected
      in an outcrossing species. All these characteristics are usually associated with
      diploid fern species rather than polyploid species.

PMID- 10406720
TI  - Comparison of common cytotypesof Andropogon gerardii(Andropogoneae, Poaceae).
AB  - Many plant species contain populations with more than one polyploid cytotype, but
      little is known of the mechanisms maintaining several cytotypes in a population.
      Andropogon gerardii cytotypes were compared to evaluate different models of
      autopolyploid cytotype coexistence. The enneaploid (90 chromosome, 9x) cytotype
      was found to be larger and taller than the hexaploid (60 chromosome, 6x)
      cytotype. Seed production is significantly more efficient in hexaploids, but seed
      production per area was not significantly different. The two cytotypes are not
      exomorphologically separable in the field because of great plasticity in response
      to environmental variation and wide variation within each cytotype. These data
      suggest cytotypic variation is maintained by natural selection.

PMID- 10406721
TI  - Inbreeding depression and selfing rates in a self-compatible, hermaphroditic
      species, Schiedea membranacea (Caryophyllaceae).
AB  - Inbreeding depression and selfing rates were investigated in Schiedea membranacea
      (Caryophyllaceae), a hermaphroditic species endemic to the Hawaiian Islands. Most
      theoretical models predict high inbreeding depression in outcrossing
      hermaphroditic species and low inbreeding depression in inbreeding species.
      Although high outcrossing rates and high levels of inbreeding depression are
      characteristic of many species of Schiedea, self- fertilization is common among
      relatives of hermaphroditic S. membranacea, and high selfing rates and low levels
      of inbreeding depression were predicted in this species. Sixteen individuals
      grown in the greenhouse were used to produce selfed and outcrossed progeny.
      Inbreeding depression, which was evident throughout the stages measured
      (percentage viable seeds per capsule, mean seed mass, percentage seed
      germination, percentage seedling survival, and biomass after 8 mo), averaged
      0.70. Inbreeding depression among maternal families varied significantly for all
      measured traits and ranged from -0.12 to 0.97. Using isozyme analysis, the
      multilocus selfing rate varied from 0.13 to 0.38 over 4 yr. Contrary to the
      initial prediction of high selfing and low inbreeding depression based on
      phylogenetic relationships within Schiedea, low selfing rates and high levels of
      inbreeding depression were found in S. membranacea. These results indicate that
      outcrossing is stable in this species and maintained by high levels of inbreeding
      depression.

PMID- 10406722
TI  - Genetic structure of Helianthus occidentalis (Asteraceae) in a preserve
      withfragmented habitat.
AB  - We examined the spatial genetic structure of Helianthus occidentalis Riddell ssp.
      occidentalis Riddell (western sunflower) to determine whether this species is
      highly clonal and whether the distance between prairie patches influences genetic
      differentiation. In the Edge of Appalachia Preserve System, Ohio, this species is
      restricted to prairie patches that have a clumped distribution in the forest
      matrix. Data from this insect-pollinated forb with gravity-dispersed seed were
      compared to data from the same patches for Asclepias verticillata, an insect
      pollinated species with wind-dispersed seed. Allozyme electrophoresis was used to
      collect genetic data from H. occidentalis samples from eight patches in four
      regions. Genetic data from three polymorphic loci indicted that this species is
      not highly clonal. Genetic differentiation was greater among patches within a
      region than among regions, suggesting that gene flow among patches is more
      limited in H. occidentalis than in A. verticillata. Founder effect may also have
      contributed to observed genetic differences among patches as some of these
      populations may have re-established after release from human use. As habitat
      fragmentation is increasing in the preserve, it is also likely that genetic
      differentiation may be increasing. Therefore, monitoring of genetic structure is
      necessary to further assess the effect of fragmentation.

PMID- 10406723
TI  - Effects of fire on the demography of the endangered, geophytic herb Silene
      spaldingii (Caryophyllaceae).
AB  - Understanding the effects of disturbances such as fire on plant demography helps
      elucidate the mechanisms that cause changes in community composition. I studied
      the effects of spring and fall fires on Silene spaldingii, an endangered
      perennial herb of grasslands in northwest Montana. Individual S. spaldingii
      plants were mapped, and size and flowering were recorded for 1 yr prior and 5 yr
      subsequent to the burn treatments. Enhanced seedling recruitment (70-410%) and a
      22% increase in population size were the principal effects of fire on S.
      spaldingii, and fall burn plots had lower recruitment than spring burn plots.
      These effects were apparent for 2-3 yr following the treatments. Fire had no
      detectable effect on the survival of adults or recruits of S. spaldingii. Silene
      spaldingii exhibits prolonged dormancy in which plants do not produce aboveground
      vegetation for one to several consecutive years. Results suggest that fire has a
      positive effect on the population dynamics of S. spaldingii by removing litter
      and creating safe sites for recruitment. Prescribed fire should be an important
      tool for managing populations of this rare plant.

PMID- 10406724
TI  - Chromosome numbers in Compositae. XVIII.
AB  - Chromosome numbers and other cytogenetic data were determined from
      microsporocytes in 316 collections including 13 tribes of Compositae, mostly from
      Africa, Australia, Mexico, Central America, and South America. First reports are
      provided for 66 species and the genera Cassinia (2n ~ 14(II)), Feldstonia (2n =
      11(II)), Gochnatia (2n ~ 23(II)), and Pseudoconyza (n = 10). In addition, new
      chromosome numbers are established at the generic level in Acourtia, Calea,
      Craspedia, Gnaphalium, Helipterum, Liabum, Leucheria, Smallanthus, Trixis, and
      Viguiera and at the specific level in 13 additional species.

PMID- 10406725
TI  - Major lineages within Apiaceae subfamily Apioideae: a comparison of chloroplast
      restriction site and DNA sequence data.
AB  - Traditional sources of taxonomic characters in the large and taxonomically
      complex subfamily Apioideae (Apiaceae) have been confounding and no
      classification system of the subfamily has been widely accepted. A restriction
      site analysis of the chloroplast genome from 78 representatives of Apioideae and
      related groups provided a data matrix of 990 variable characters (750 of which
      were potentially parsimony-informative). A comparison of these data to that of
      three recent DNA sequencing studies of Apioideae (based on ITS, rpoCl intron, and
      matK sequences) shows that the restriction site analysis provides 2.6-3.6 times
      more variable characters for a comparable group of taxa. Moreover, levels of
      divergence appear to be well suited to studies at the subfamilial and tribal
      levels of Apiaceae. Cladistic and phenetic analyses of the restriction site data
      yielded trees that are visually congruent to those derived from the other recent
      molecular studies. On the basis of these comparisons, six lineages and one
      paraphyletic grade are provisionally recognized as informal groups. These groups
      can serve as the starting point for future, more intensive studies of the
      subfamily.

PMID- 10406726
TI  - Phylogenetic relationships of the Hamamelidaceae inferred from sequences of
      internal transcribed spacers (ITS) of nuclear ribosomal DNA.
AB  - Intergeneric relationships in the Hamamelidaceae have long been controversial. In
      this study, sequences of the internal transcribed spacers of nuclear ribosomal
      DNA were used to reconstruct the phylogeny for the Hamamelidaceae. Three major
      clades were recognized in the ITS-based phylogenetic tree: (1) Mytilaria
      Exbucklandia-Rhodoleia, (2) Disanthus, and (3) the Hamamelidoideae. Within the
      Hamamelidoideae there were three well-supported lineages: (1) Corylopsis
      Loropetalum-Tetrathyrium-Maingaya-Matudaea, (2) Eustigmateae sensu Endress, plus
      Molinadendron-Dicoryphinae, and (3) Hamamelis-Fothergilleae sensu Endress,
      excluding Matudaea and Molinadendron. The Exbucklandioideae sensu Endress were
      not monophyletic, nor were the tribes in the Hamamelidoideae in their current
      circumscriptions except for the Corylopsideae. Strap-shaped petals, apetaly, and
      wind pollination have evolved three times independently in the Hamamelidaceae
      s.s. (Hamamelidaceae minus Altingioideae), suggesting that homoplasy should be
      considered in future classifications of the family.

PMID- 10406727
TI  - Incongruence between chloroplast and species phylogenies in Eucalyptus subgenus
      Monocalyptus (Myrtaceae).
AB  - Seventy-eight polymorphic cpDNA (chloroplast DNA) characters were found in 13
      closely related taxa from Eucalyptus series Amygdalinae (subgenus Monocalyptus)
      and seven potential outgroup taxa. The strict consensus of six cladograms
      generated from cpDNA data confirmed monophyly of Monocalyptus. However, cpDNA
      phylogeny within Monocalyptus was incongruent with taxonomic classification,
      being more related to geography, even when accessions were from divergent series.
      Monocalyptus cpDNA formed two major clades. On the island of Tasmania cpDNA was
      restricted to a single clade, exhibited very little variation, and was
      phylogenetically related to cpDNA found in central and western Victoria. In
      contrast, cpDNA of mainland monocalypt taxa was more variable, even within the
      Amygdalinae. Four out of six Tasmanian Amygdalinae species were polymorphic. The
      difference between cpDNA of replicates was often greater than differences between
      species from different series. The low level of cpDNA variation and extensive
      morphological intergradation between the Tasmanian endemics suggest recent
      speciation. However, the transfer of cpDNA through hybridization between lineages
      is the most likely explanation for the observed sharing of cpDNA across series.
      This study highlights that the geographical pattern to cpDNA variation in
      Eucalyptus may be an important source of information on past plant distributions
      in Australia.

PMID- 10406728
TI  - Nuclear ribosomal DNA phylogeny and its implications for evolutionary trends in
      Mexican Bursera (Burseraceae).
AB  - The genus Bursera (Burseraceae) is one of the most diversified and abundant
      groups of plants of the tropical dry forests of Mexico. In order to provide a
      basis for better understanding of its evolutionary biology, we reconstructed a
      phylogeny of 57 species and varieties using the nucleotide sequences of the
      internal transcribed spacer regions (ITS1 and ITS2) of 18S-26S and the 5.8S
      coding region of nuclear ribosomal DNA. We used four species of the allied genera
      Commiphora and Boswellia and one species of Spondias (Anacardiaceae) as
      outgroups. Our results support the views that Bursera is monophyletic and more
      closely related to Commiphora than to Boswellia. The division of Bursera into
      sections Bullockia and Bursera is also strongly supported by our phylogeny.
      Several other subclades also had high bootstrap values, especially within section
      Bursera. We use the phylogeny as a basis for discussing evolutionary tendencies
      in bark, leaves, breeding systems, and fruits.

PMID- 10406729
TI  - Minimally invasive cardiac surgery.

PMID- 10406730
TI  - Reducing errors in medicine.

PMID- 10406731
TI  - Chaperones for genital examination.

PMID- 10406732
TI  - Treating behavioural and psychological signs in Alzheimer's disease.

PMID- 10406733
TI  - Saving lives or sustaining the public's health?

PMID- 10406734
TI  - BMA wants presumed consent for organ donors.

PMID- 10406735
TI  - German drug agency approves mifepristone.

PMID- 10406738
TI  - In brief 

PMID- 10406736
TI  - London whistleblower left with career in tatters.

PMID- 10406737
TI  - Anaesthetists do not need separate consent before surgery.

PMID- 10406739
TI  - Florida jury finds tobacco companies guilty of fraud.

PMID- 10406740
TI  - Tobacco could be used to produce interleukin 10.

PMID- 10406741
TI  - Doctors fear that inequalities are slipping down agenda 

PMID- 10406743
TI  - Scientists raise possibility of vaccine for Alzheimer's disease 

PMID- 10406742
TI  - Quebec nurses enter third week of strike 

PMID- 10406745
TI  - Educator with a vision 

PMID- 10406744
TI  - Childhood thyroid cancers rise 10-fold in the ukraine 

PMID- 10406746
TI  - Breast feeding and obesity: cross sectional study.
AB  - OBJECTIVE: To assess the impact of breast feeding on the risk of obesity and risk
      of being overweight in children at the time of entry to school. DESIGN: Cross
      sectional survey SETTING: Bavaria, southern Germany. METHODS: Routine data were
      collected on the height and weight of 134 577 children participating in the
      obligatory health examination at the time of school entry in Bavaria. In a
      subsample of 13 345 children, early feeding, diet, and lifestyle factors were
      assessed using responses to a questionnaire completed by parents. SUBJECTS: 9357
      children aged 5 and 6 who had German nationality. MAIN OUTCOME MEASURES: Being
      overweight was defined as having a body mass index above the 90th centile and
      obesity was defined as body mass index above the 97th centile of all enrolled
      German children. Exclusive breast feeding was defined as the child being fed no
      food other than breast milk. RESULTS: The prevalence of obesity in children who
      had never been breast fed was 4.5% as compared with 2.8% in breastfed children. A
      clear dose-response effect was identified for the duration of breast feeding on
      the prevalence of obesity: the prevalence was 3.8% for 2 months of exclusive
      breast feeding, 2.3% for 3-5 months, 1.7% for 6-12 months, and 0.8% for more than
      12 months. Similar relations were found with the prevalence of being overweight.
      The protective effect of breast feeding was not attributable to differences in
      social class or lifestyle. After adjusting for potential confounding factors,
      breast feeding remained a significant protective factor against the development
      of obesity (odds ratio 0.75, 95% CI 0.57 to 0.98) and being overweight (0.79,
      0.68 to 0.93). CONCLUSIONS: In industrialised countries promoting prolonged
      breast feeding may help decrease the prevalence of obesity in childhood. Since
      obese children have a high risk of becoming obese adults, such preventive
      measures may eventually result in a reduction in the prevalence of cardiovascular
      diseases and other diseases related to obesity.

PMID- 10406747
TI  - Does zygosity influence the metabolic profile of twins? A population based cross
      sectional study.
AB  - OBJECTIVE: To study the influence of zygosity on the metabolic variables involved
      in the pathophysiology of type 2 diabetes. DESIGN: Population based cross
      sectional study. SETTING: Odense University Hospital, Denmark. PARTICIPANTS: 125
      monozygotic twin pairs and 178 dizygotic twin pairs of the same sex born between
      1921 and 1940. MAIN OUTCOME MEASURES: Clinical characteristics of monozygotic and
      dizygotic twins with or without a family history of type 2 diabetes. RESULTS:
      Absolute prevalences of type 2 diabetes and impaired glucose tolerance according
      to the World Health Organisation criteria were similar in both the monozygotic
      and the dizygotic twins as were measurements of height, weight, body mass index,
      waist to hip ratio, and fasting plasma glucose and insulin concentrations. During
      the oral glucose tolerance test, monozygotic twins had a higher incremental
      plasma insulin area under the curve than dizygotic twins (10.05 (SD 0.68) v 9.89
      (0.72) pmol/lxminutes, P<0.01) indicating insulin resistance. In twins with
      normal glucose tolerance and without first degree relatives or co-twins with type
      2 diabetes or impaired glucose tolerance, both the glucose and insulin areas
      under the curve were higher among monozygotic twins (glucose 214.4 (88.3) v 189.8
      (78.4) mmol/lxminutes, P<0.05; insulin 20 040 (14 865-32 554) v 17 625 (12 330-23
      640) pmol/lxminutes, P=0.08). CONCLUSION: Zygosity influences both plasma glucose
      and plasma insulin concentrations during an oral glucose tolerance test. This
      supports an intrauterine influence on glucose homeostasis and perhaps on insulin
      resistance in humans.

PMID- 10406748
TI  - Dynamics of bed use in accommodating emergency admissions: stochastic simulation
      model.
AB  - OBJECTIVE: To examine the daily bed requirements arising from the flow of
      emergency admissions to an acute hospital, to identify the implications of
      fluctuating and unpredictable demands for emergency admission for the management
      of hospital bed capacity, and to quantify the daily risk of insufficient capacity
      for patients requiring immediate admission. DESIGN: Modelling of the dynamics of
      the hospital system, using a discrete-event stochastic simulation model, which
      reflects the relation between demand and available bed capacity. SETTING:
      Hypothetical acute hospital in England. SUBJECTS: Simulated emergency admissions
      of all types except mental disorder. MAIN OUTCOME MEASURES: The risk of having no
      bed available for any patient requiring immediate admission; the daily risk that
      there is no bed available for at least one patient requiring immediate admission;
      the mean bed occupancy rate. RESULTS: Risks are discernible when average bed
      occupancy rates exceed about 85%, and an acute hospital can expect regular bed
      shortages and periodic bed crises if average bed occupancy rises to 90% or more.
      CONCLUSIONS: There are limits to the occupancy rates that can be achieved safely
      without considerable risk to patients and to the efficient delivery of emergency
      care. Spare bed capacity is therefore essential for the effective management of
      emergency admissions, and its cost should be borne by purchasers as an essential
      element of an acute hospital service.

PMID- 10406749
TI  - The rise in emergency admissions--crisis or artefact? Temporal analysis of health
      services data.

PMID- 10406751
TI  - Review of randomised controlled trials of traditional Chinese medicine.

PMID- 10406750
TI  - Use of chaperones in clinics for genitourinary medicine: survey of consultants.

PMID- 10406752
TI  - Surgeons' and occupational health departments' awareness of guidelines on post
      exposure prophylaxis for staff exposed to HIV: telephone survey.

PMID- 10406754
TI  - The future of the woman physician 

PMID- 10406755
TI  - The ideal 

PMID- 10406753
TI  - Possible interaction between clindamycin and cyclosporin.

PMID- 10406756
TI  - Improving quality in general practice: qualitative case study of barriers faced
      by health authorities.
AB  - OBJECTIVES: To identify and assess the barriers that health authorities face as
      they manage quality improvements in general practice in the context of the NHS
      reforms. DESIGN: Qualitative case study. SETTING: Three UK health authorities: a
      rural health authority in the south west, a deprived inner city health authority
      in the north east, and an affluent suburban health authority in the south east.
      PARTICIPANTS: Senior and junior managers. MAIN OUTCOME MEASURES: Structure of
      strategic and organisational management, and barriers to the leadership and
      management of quality improvement in general practice. RESULTS: Seven barriers
      were identified: absence of an explicit strategic plan for general practice,
      competing priorities for attention of the health authority, sensitivity of health
      professionals, lack of information due to poor quality of clinical data, lack of
      authority to implement change, unclear roles and responsibilities of managers
      within the organisations, and isolation from other authorities or organisations
      facing similar challenges. CONCLUSIONS: The health authorities faced significant
      barriers that would impede their ability to fulfil their responsibilities in the
      new NHS and that would reduce their capacity to contribute to quality
      improvements in general practice.

PMID- 10406758
TI  - Lesson of the week: exacerbating cervical spine injury by applying a hard collar.

PMID- 10406760
TI  - Alternative definitions 

PMID- 10406757
TI  - Recent advances: diagnostic radiology.

PMID- 10406759
TI  - Evidence based case report. Sore throat: diagnostic and therapeutic dilemmas.

PMID- 10406761
TI  - ABC of intensive care: other supportive care.

PMID- 10406762
TI  - The private finance initiative: planning the "new" NHS: downsizing for the 21st
      century.

PMID- 10406763
TI  - Understanding controlled trials: baseline imbalance in randomised controlled
      trials.

PMID- 10406764
TI  - Magic and medicine 

PMID- 10406765
TI  - Cholesterol lowering margarine may not be useful in healthy fat modified diet.

PMID- 10406766
TI  - Diet and the prevention of cancer. Author's recommendations are not justified.

PMID- 10406767
TI  - Anomalies occur in registrations of fetal deaths in multiple pregnancies.

PMID- 10406768
TI  - Should immunisation against hepatitis B take priority over provision of clean
      drinking water?

PMID- 10406769
TI  - Chlamydia screening can have high take-up rates if right methodology is used.

PMID- 10406770
TI  - Effect of discussion and deliberation on public's views of priority setting. More
      data are needed for readers to make judgment about study.

PMID- 10406771
TI  - Probiotics used in trials should be independently checked microbiologically.

PMID- 10406772
TI  - Patient education is way to influence maternal requests for caesarean section.

PMID- 10406773
TI  - Use of mini-mental state examination by GPs to diagnose dementia may be
      unnecessary.

PMID- 10406774
TI  - Conservative management of genuine stress incontinence in women. Study's flaws
      may be misleading.

PMID- 10406775
TI  - Private medical care surely benefits NHS indirectly.

PMID- 10406777
TI  - William alexander dawson 

PMID- 10406776
TI  - Economics of PFI in the NHS.

PMID- 10406779
TI  - The BMA in belfast 

PMID- 10406778
TI  - The BMA's annual representative meeting 

PMID- 10406781
TI  - Performing arts: the consulting room 

PMID- 10406780
TI  - Over our dead bodies: port arthur and Australia's fight for gun control 

PMID- 10406782
TI  - In the grip of spin 

PMID- 10406783
TI  - Digital imaging 

PMID- 10406784
TI  - Making a mark 

PMID- 10406785
TI  - In england now 

PMID- 10406786
TI  - The wisdoms of other disciplines 

PMID- 10406788
TI  - Zygosity influences glucose homeostasis and insulin resistance in twins 

PMID- 10406787
TI  - Breast feeding seems to reduce the risk of obesity in children 

PMID- 10406789
TI  - Spare capacity in beds is essential to accommodate emergencies 

PMID- 10406790
TI  - Rise in hospital admission may be an artefact 

PMID- 10406792
TI  - Health authorities fail to manage quality improvement in general practice 

PMID- 10406791
TI  - Many randomised trials of traditional chinese medicine exist but are of poor
      quality 

PMID- 10406793
TI  - Structural basis for the specificity of ubiquitin C-terminal hydrolases.
AB  - The release of ubiquitin from attachment to other proteins and adducts is
      critical for ubiquitin biosynthesis, proteasomal degradation and other cellular
      processes. De-ubiquitination is accomplished in part by members of the UCH
      (ubiquitin C-terminal hydrolase) family of enzymes. We have determined the 2.25 A
      resolution crystal structure of the yeast UCH, Yuh1, in a complex with the
      inhibitor ubiquitin aldehyde (Ubal). The structure mimics the tetrahedral
      intermediate in the reaction pathway and explains the very high enzyme
      specificity. Comparison with a related, unliganded UCH structure indicates that
      ubiquitin binding is coupled to rearrangements which block the active-site cleft
      in the absence of authentic substrate. Remarkably, a 21-residue loop that becomes
      ordered upon binding Ubal lies directly over the active site. Efficiently
      processed substrates apparently pass through this loop, and constraints on the
      loop conformation probably function to control UCH specificity.

PMID- 10406794
TI  - Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast
      autophagy pathway.
AB  - Autophagy is an intracellular bulk degradation system that is ubiquitous for
      eukaryotic cells. In this process, cytoplasmic components are enclosed in
      autophagosomes and delivered to lysosomes/vacuoles. We recently found that a
      protein conjugation system, in which Apg12p is covalently attached to Apg5p, is
      indispensable for autophagy in yeast. Here, we describe a novel coiled-coil
      protein, Apg16p, essential for autophagy. Apg16p interacts with Apg12p-conjugated
      Apg5p and less preferentially with unconjugated Apg5p. Moreover, the coiled-coil
      domain of Apg16p mediates self-multimerization that leads to cross-linking of
      Apg5p molecules and formation of a stable protein complex. Apg16p is not
      essential for the Apg12p-Apg5p conjugation reaction. These results suggest that
      the Apg12p-Apg5p conjugate requires Apg16p to accomplish its role in the
      autophagy pathway, and Apg16p is a key molecule as a linker to form the Apg12p
      Apg5p-Apg16p multimer.

PMID- 10406795
TI  - Clathrin functions in the absence of heterotetrameric adaptors and AP180-related
      proteins in yeast.
AB  - The major coat proteins of clathrin-coated vesicles are the clathrin triskelion
      and heterotetrameric associated protein (AP) complexes. The APs are thought to be
      involved in cargo capture and recruitment of clathrin to the membrane during
      endocytosis and sorting in the trans-Golgi network/endosomal system. AP180 is an
      abundant coat protein in brain clathrin-coated vesicles, and it has potent
      clathrin assembly activity. In Saccharomyces cerevisiae, there are 13 genes
      encoding homologs of heterotetrameric AP subunits and two genes encoding AP180
      related proteins. To test the model that clathrin function is dependent on the
      heterotetrameric APs and/or AP180 homologs, yeast strains containing multiple
      disruptions in AP subunit genes, as well as in the two YAP180 genes, were
      constructed. Surprisingly, the AP deletion strains did not display the phenotypes
      associated with clathrin deficiency, including slowed growth and endocytosis,
      defective late Golgi protein retention and impaired cytosol to vacuole/autophagy
      function. Clathrin-coated vesicles isolated from multiple AP deletion mutants
      were morphologically indistinguishable from those from wild-type cells. These
      results indicate that clathrin function and recruitment onto membranes are not
      dependent upon heterotetrameric adaptors or AP180 homologs in yeast. Therefore,
      alternative mechanisms for clathrin assembly and coated vesicle formation, as
      well as the role of AP complexes and AP180-related proteins in these processes,
      must be considered.

PMID- 10406796
TI  - PKCalpha regulates beta1 integrin-dependent cell motility through association and
      control of integrin traffic.
AB  - Protein kinase C (PKC) has been implicated in integrin-mediated spreading and
      migration. In mammary epithelial cells there is a partial co-localization between
      beta1 integrin and PKCalpha. This reflects complexes between these proteins as
      demonstrated by fluorescense resonance energy transfer (FRET) monitored by
      fluorescence lifetime imaging microscopy and also by coprecipitation.
      Constitutive complexes are observed for the intact PKCalpha and also form with
      the regulatory domain in an activation-dependent manner. Expression of PKCalpha
      causes upregulation of beta1 integrin on the cell surface, whereas stimulation of
      PKC induces internalization of beta1 integrin. The integrin initially traffics to
      an endosomal compartment in a Ca(2+)/PI 3-kinase/dynamin I-dependent manner and
      subsequently enters an endocytic recycling pathway. This induction of endocytosis
      by PKCalpha is a function of activity and is not observed for the regulatory
      domain. PKCalpha, but not PKCalpha regulatory domain expression stimulates
      migration on beta1 integrin substrates. This PKCalpha-enhanced migratory response
      is inhibited by blockade of endocytosis.

PMID- 10406797
TI  - A Salmonella virulence protein that inhibits cellular trafficking.
AB  - Salmonella enterica requires a type III secretion system, designated Spi/Ssa, to
      survive and proliferate within macrophages. The Spi/Ssa system is encoded within
      the SPI-2 pathogenicity island and appears to function intracellularly. Here, we
      establish that the SPI-2-encoded SpiC protein is exported by the Spi/Ssa type III
      secretion system into the host cell cytosol where it interferes with
      intracellular trafficking. In J774 macrophages, wild-type Salmonella inhibited
      fusion of Salmonella-containing phagosomes with lysosomes and endosomes, and
      interfered with trafficking of vesicles devoid of the microorganism. These
      inhibitory activities required living Salmonella and a functional spiC gene.
      Purified SpiC protein inhibited endosome-endosome fusion in vitro. A Sindbis
      virus expressing the SpiC protein interfered with normal trafficking of the
      transferrin receptor in vivo. A spiC mutant was attenuated for virulence,
      suggesting that the ability to interfere with intracellular trafficking is
      essential for Salmonella pathogenesis.

PMID- 10406798
TI  - Got1p and Sft2p: membrane proteins involved in traffic to the Golgi complex.
AB  - Traffic through the yeast Golgi complex depends on a member of the syntaxin
      family of SNARE proteins, Sed5p, present in early Golgi cisternae. Sft2p is a non
      essential tetra-spanning membrane protein, found mostly in the late Golgi, that
      can suppress some sed5 alleles. We screened for mutations that show synthetic
      lethality with sft2 and found one that affects a previously uncharacterized
      membrane protein, Got1p, as well as new alleles of sed5 and vps3. Got1p is an
      evolutionarily conserved non-essential protein with a membrane topology similar
      to that of Sft2p. Immunofluorescence and subcellular fractionation indicate that
      it is present in early Golgi cisternae. got1 mutants, but not sft2 mutants, show
      a defect in an in vitro assay for ER-Golgi transport at a step after vesicle
      tethering to Golgi membranes. In vivo, inactivation of both Got1p and Sft2p
      results in phenotypes ascribable to a defect in endosome-Golgi traffic, while
      their complete removal results in an ER-Golgi transport defect. Thus the presence
      of either Got1p or Sft2p is required for vesicle fusion with the Golgi complex in
      vivo. We suggest that Got1p normally facilitates Sed5p-dependent fusion events,
      while Sft2p performs a related function in the late Golgi.

PMID- 10406799
TI  - Crystal structure of plant aspartic proteinase prophytepsin: inactivation and
      vacuolar targeting.
AB  - We determined at 2.3 A resolution the crystal structure of prophytepsin, a
      zymogen of a barley vacuolar aspartic proteinase. In addition to the classical
      pepsin-like bilobal main body of phytepsin, we also traced most of the
      propeptide, as well as an independent plant-specific domain, never before
      described in structural terms. The structure revealed that, in addition to the
      propeptide, 13 N-terminal residues of the mature phytepsin are essential for
      inactivation of the enzyme. Comparison of the plant-specific domain with NK-lysin
      indicates that these two saposin-like structures are closely related, suggesting
      that all saposins and saposin-like domains share a common topology. Structural
      analysis of prophytepsin led to the identification of a putative membrane
      receptor-binding site involved in Golgi-mediated transport to vacuoles.

PMID- 10406800
TI  - A single amino acid in E-cadherin responsible for host specificity towards the
      human pathogen Listeria monocytogenes.
AB  - Human E-cadherin promotes entry of the bacterial pathogen Listeria monocytogenes
      into mammalian cells by interacting with internalin (InlA), a bacterial surface
      protein. Here we show that mouse E-cadherin, although very similar to human E
      cadherin (85% identity), is not a receptor for internalin. By a series of domain
      swapping and mutagenesis experiments, we identify Pro16 of E-cadherin as a
      residue critical for specificity: a Pro-->Glu substitution in human E-cadherin
      totally abrogates interaction, whereas a Glu-->Pro substitution in mouse E
      cadherin results in a complete gain of function. A correlation between cell
      permissivity and the nature of residue 16 in E-cadherins from several species is
      established. The location of this key specificity residue in a region of E
      cadherin not involved in cell-cell adhesion and the stringency of the interaction
      demonstrated here have important consequences not only for the understanding of
      internalin function but also for the choice of the animal model to be used to
      study human listeriosis: mouse, albeit previously widely used, and rat appear as
      inappropriate animal models to study all aspects of human listeriosis, as opposed
      to guinea-pig, which now stands as a small animal of choice for future in vivo
      studies.

PMID- 10406801
TI  - VEGF contributes to postnatal neovascularization by mobilizing bone marrow
      derived endothelial progenitor cells.
AB  - Vascular endothelial growth factor (VEGF) has been shown to promote
      neovascularization in animal models and, more recently, in human subjects. This
      feature has been assumed to result exclusively from its direct effects on fully
      differentiated endothelial cells, i.e. angiogenesis. Given its regulatory role in
      both angiogenesis and vasculogenesis during fetal development, we investigated
      the hypothesis that VEGF may modulate endothelial progenitor cell (EPC) kinetics
      for postnatal neovascularization. Indeed, we observed an increase in circulating
      EPCs following VEGF administration in vivo. VEGF-induced mobilization of bone
      marrow-derived EPCs resulted in increased differentiated EPCs in vitro and
      augmented corneal neovascularization in vivo. These findings thus establish a
      novel role for VEGF in postnatal neovascularization which complements its known
      impact on angiogenesis.

PMID- 10406802
TI  - Cloning and characterization of a novel Mg(2+)/H(+) exchanger.
AB  - Cellular functions require adequate homeostasis of several divalent metal
      cations, including Mg(2+) and Zn(2+). Mg(2+), the most abundant free divalent
      cytoplasmic cation, is essential for many enzymatic reactions, while Zn(2+) is a
      structural constituent of various enzymes. Multicellular organisms have to
      balance not only the intake of Mg(2+) and Zn(2+), but also the distribution of
      these ions to various organs. To date, genes encoding Mg(2+) transport proteins
      have not been cloned from any multicellular organism. We report here the cloning
      and characterization of an Arabidopsis thaliana transporter, designated AtMHX,
      which is localized in the vacuolar membrane and functions as an electrogenic
      exchanger of protons with Mg(2+) and Zn(2+) ions. Functional homologs of AtMHX
      have not been cloned from any organism. Ectopic overexpression of AtMHX in
      transgenic tobacco plants render them sensitive to growth on media containing
      elevated levels of Mg(2+) or Zn(2+), but does not affect the total amounts of
      these minerals in shoots of the transgenic plants. AtMHX mRNA is mainly found at
      the vascular cylinder, and a large proportion of the mRNA is localized in close
      association with the xylem tracheary elements. This localization suggests that
      AtMHX may control the partitioning of Mg(2+) and Zn(2+) between the various plant
      organs.

PMID- 10406803
TI  - The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of
      cytosolic Fe/S proteins.
AB  - Iron-sulfur (Fe/S) cluster-containing proteins catalyse a number of electron
      transfer and metabolic reactions. Little is known about the biogenesis of Fe/S
      clusters in the eukaryotic cell. Here, we demonstrate that mitochondria perform
      an essential role in the synthesis of both intra- and extra-mitochondrial Fe/S
      proteins. Nfs1p represents the yeast orthologue of the bacterial cysteine
      desulfurase NifS that initiates biogenesis by producing elemental sulfur. The
      matrix-localized protein is required for synthesis of both mitochondrial and
      cytosolic Fe/S proteins. The ATP-binding cassette (ABC) transporter Atm1p of the
      mitochondrial inner membrane performs an essential function only in the
      generation of cytosolic Fe/S proteins by mediating export of Fe/S cluster
      precursors synthesized by Nfs1p and other mitochondrial proteins. Assembly of
      cellular Fe/S clusters constitutes an indispensable biosynthetic task of
      mitochondria with potential relevance for an iron-storage disease and the control
      of cellular iron uptake.

PMID- 10406804
TI  - WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto
      oncogene.
AB  - The Wilms' tumor suppressor gene, WT1, encodes a zinc finger transcription factor
      that has been demonstrated to negatively regulate several growth factor and
      cognate receptor genes. However, inconsistent with its tumor suppressor function,
      WT1 has also been demonstrated to be required to inhibit programmed cell death in
      vitro and in vivo. Moreover, anaplastic Wilms' tumors, which typically express
      wild-type WT1, display extreme resistance to chemotherapeutic agents that kill
      tumor cells through the induction of apoptosis. Although p53 mutations in
      anaplastic Wilms' tumors have been associated with chemoresistance, this event is
      believed to occur late during tumor progression. Therefore, since dysregulated
      WT1 expression occurs relatively early in Wilms' tumors, we hypothesized that WT1
      was required to transcriptionally upregulate genes that provide a cell survival
      advantage to tumor cells. Here we demonstrate that sporadic Wilms' tumors
      coexpress WT1 and the anti-apoptotic Bcl-2 protein. Using rhabdoid cell lines
      overexpressing WT1, we show that WT1 activates the endogenous bcl-2 gene through
      a transcriptional mechanism. Transient transfections and electromobility shift
      assays demonstrate that WT1 positively stimulates the bcl-2 promoter through a
      direct interaction. Moreover, WT1 expressing cells displaying upregulated Bcl-2
      were found to be resistant to apoptosis induced by staurosporine, vincristine and
      doxorubicine. These data suggest that in certain cellular contexts, WT1 exhibits
      oncogenic potential through the transcriptional upregulation of anti-apoptotic
      genes such as bcl-2.

PMID- 10406805
TI  - Transcriptional regulation by the gamma5 subunit of a heterotrimeric G protein
      during adipogenesis.
AB  - The adipocyte enhancer-binding protein (AEBP1) is a novel transcriptional
      repressor with carboxypeptidase activity. A two-hybrid screen was conducted to
      identify components of AEBP1 that might be important in regulating its activity.
      The gamma5 subunit of a heterotrimeric G protein was shown to bind specifically
      to AEBP1 and to attenuate its transcriptional repression activity. Adipogenic
      stimulation selectively decreased the Ggamma5 level and enhanced the
      transcriptional repression activity of AEBP1 during mitotic clonal expansion at
      the onset of adipogenesis. Thus, the actions of Ggamma5 and AEBP1 are directly
      linked, which could provide the basis for the regulation of transcription at the
      onset of differentiation. This report shows that a signal-transducing molecule is
      involved, by direct protein-protein interaction, in the regulation of
      transcription during adipogenesis.

PMID- 10406806
TI  - Serpent regulates Drosophila immunity genes in the larval fat body through an
      essential GATA motif.
AB  - Insects possess a powerful immune system, which in response to infection leads to
      a vast production of different antimicrobial peptides. The regulatory regions of
      many immunity genes contain a GATA motif in proximity to a kappaB motif. Upon
      infection, Rel proteins enter the nucleus and activate transcription of the
      immunity genes. High levels of Rel protein-mediated Cecropin A1 expression
      previously have been shown to require the GATA site along with the kappaB site.
      We provide evidence demonstrating that the GATA motif is needed for expression of
      the Cecropin A1 gene in larval fat body, but is dispensable in adult fat body. A
      nuclear DNA-binding activity interacts with the Cecropin A1 GATA motif with the
      same properties as the Drosophila GATA factor Serpent. The GATA-binding activity
      is recognized by Serpent-specific antibodies, demonstrating their identity. We
      show that Serpent is nuclear in larval fat body cells and haemocytes both before
      and after infection. After overexpression, Serpent increases Cecropin A1
      transcription in a GATA-dependent manner. We propose that Serpent plays a key
      role in tissue-specific expression of immunity genes, by priming them for
      inducible activation by Rel proteins in response to infection.

PMID- 10406808
TI  - An insulator element and condensed chromatin region separate the chicken beta
      globin locus from an independently regulated erythroid-specific folate receptor
      gene.
AB  - We have identified a folate receptor gene upstream of the chicken beta-globin
      locus and separated from it by a 16 kbp region of silent chromatin. We find that
      this receptor is expressed only at a stage of erythroid differentiation (CFU-E)
      preceding the activation of beta-globin genes, consistent with the role of folate
      receptors in proliferation. This discovery raises the question of how these two
      loci are regulated during erythropoiesis. Our data suggest that the folate
      receptor gene and the beta-globin locus are regulated independently. We show that
      a 3.3 kbp DNA region upstream of the folate receptor gene is sufficient to induce
      strong expression of a transgene in CFU-E stage cells. We also find that the
      region between the beta-globin locus and the folate receptor gene is fully
      methylated and condensed at this stage of differentiation. Its 3' boundary
      coincides with the 5' beta-globin insulator. We speculate that the 5' beta-globin
      boundary element might be important for the proper regulation of two adjacent
      domains activated at two different stages during differentiation.

PMID- 10406807
TI  - PLENA and FARINELLI: redundancy and regulatory interactions between two
      Antirrhinum MADS-box factors controlling flower development.
AB  - We report the discovery of an Antirrhinum MADS-box gene, FARINELLI (FAR), and the
      isolation of far mutants by a reverse genetic screen. Despite striking
      similarities between FAR and the class C MADS-box gene PLENA (PLE), the
      phenotypes of their respective mutants are dramatically different. Unlike ple
      mutants, which show homeotic conversion of reproductive organs to perianth organs
      and a loss of floral determinacy, far mutants have normal flowers which are
      partially male-sterile. Expression studies of PLE and FAR, in wild-type and
      mutant backgrounds, show complex interactions between the two genes. Double
      mutant analysis reveals an unexpected, redundant negative control over the B
      function MADS-box genes. This feature of the two Antirrhinum C-function-like
      genes is markedly different from the control of the inner boundary of the B
      function expression domain in Arabidopsis, and we propose and discuss a model to
      account for these differences. The difference in phenotypes of mutants in two
      highly related genes illustrates the importance of the position within the
      regulatory network in determining gene function.

PMID- 10406809
TI  - Positioning of sigma(S), the stationary phase sigma factor, in Escherichia coli
      RNA polymerase-promoter open complexes.
AB  - The sigma(S) subunit of RNA polymerase is the master regulator of the general
      stress response in Escherichia coli and is required for promoter recognition of
      many stationary phase genes. We have analysed open complexes of Esigma(S) RNA
      polymerase, using sigma(S) derivatives carrying single cysteine residues at nine
      different positions to which the reagent FeBABE has been tethered. All
      holoenzymes but one formed transcriptionally active open complexes at three
      different promoters (osmY, galP1 and lacUV5). The chemical nuclease FeBABE can
      cleave DNA in proximity to the chelate. The overall cutting pattern of Esigma(S)
      open complexes does not depend on the nature of the promoter and is similar to
      that obtained with Esigma(70), but extends towards the downstream part of the
      promoter. The strongest cleavages are observed with FeBABE positioned on
      cysteines in regions 2.2 to 3.1. In contrast to sigma(70), region 2.1 of sigma(S)
      appears to be far from DNA. Region 4.2 of sigma(S) appears less accessible than
      its counterpart in sigma(70) and FeBABE positioned in the turn of the helix-turn
      helix (HTH) motif in region 4.2 reacts only weakly with the -35 promoter element.
      This provides a structural basis for the minor role of the -35 sequence in
      sigma(S)-dependent promoter recognition.

PMID- 10406810
TI  - hnRNP A/B proteins are required for inhibition of HIV-1 pre-mRNA splicing.
AB  - Splicing of the human immunodeficiency virus type 1 (HIV-1) pre-mRNA must be
      inefficient to provide a pool of unspliced messages which encode viral proteins
      and serve as genomes for new virions. Negative cis-regulatory elements (exonic
      splicing silencers or ESSs) are necessary for HIV-1 splicing inhibition. We
      demonstrate that heterogeneous nuclear ribonucleoproteins (hnRNPs) of the A and B
      group are trans-acting factors required for the function of the tat exon 2 ESS.
      Depletion of hnRNP A/B proteins from HeLa cell nuclear extract activates splicing
      of tat exon 2 pre-mRNA substrate. Splicing inhibition is restored by addition of
      recombinant hnRNP A/B proteins to the depleted extract. A high-affinity hnRNP A1
      binding sequence can substitute functionally for the ESS in tat exon 2. These
      results demonstrate that hnRNP A/B proteins are required for repression of HIV-1
      splicing.

PMID- 10406812
TI  - Mechanism of DNA segregation in prokaryotes: ParM partitioning protein of plasmid
      R1 co-localizes with its replicon during the cell cycle.
AB  - The parA locus of plasmid R1 encodes a prokaryotic centromere-like system that
      mediates genetic stabilization of plasmids by an unknown mechanism. The locus
      codes for two proteins, ParM and ParR, and a centromere-like DNA region (parC) to
      which the ParR protein binds. We showed recently that ParR mediates specific
      pairing of parC-containing DNA molecules in vitro. To obtain further insight into
      the mechanism of plasmid stabilization, we examined the intracellular
      localization of the components of the parA system. We found that ParM forms
      discrete foci that localize to specific cellular regions in a simple, yet dynamic
      pattern. In newborn cells, ParM foci were present close to both cell poles.
      Concomitant with cell growth, new foci formed at mid-cell. A point mutation that
      abolished the ATPase activity of ParM simultaneously prevented cellular
      localization and plasmid partitioning. A parA-containing plasmid localized to
      similar sites, i.e. close to the poles and at mid-cell, thus indicating that the
      plasmid co-localizes with ParM. Double labelling of single cells showed that
      plasmid DNA and ParM indeed co-localize. Thus, our data indicate that parA is a
      true partitioning system that mediates pairing of plasmids at mid-cell and
      subsequently moves them to the cell poles before cell division.

PMID- 10406811
TI  - Repressor binding to a dorsal regulatory site traps human eIF4E in a high cap
      affinity state.
AB  - Eukaryotic translation initiation involves recognition of the 5' end of cellular
      mRNA by the cap-binding complex known as eukaryotic initiation factor 4F (eIF4F).
      Initiation is a key point of regulation in gene expression in response to
      mechanisms mediated by signal transduction pathways. We have investigated the
      molecular interactions underlying inhibition of human eIF4E function by
      regulatable repressors called 4E-binding proteins (4E-BPs). Two essential
      components of eIF4F are the cap-binding protein eIF4E, and eIF4G, a multi
      functional protein that binds both eIF4E and other essential eIFs. We show that
      the 4E-BPs 1 and 2 block the interaction between eIF4G and eIF4E by competing for
      binding to a dorsal site on eIF4E. Remarkably, binding of the 4E-BPs at this
      dorsal site enhances cap-binding via the ventral cap-binding slot, thus trapping
      eIF4E in inactive complexes with high affinity for capped mRNA. The binding
      contacts and affinities for the interactions between 4E-BP1/2 and eIF4E are
      distinct (estimated K(d) values of 10(-8) and 3x10(-9) for 4E-BP1 and 2,
      respectively), and the differences in these properties are determined by three
      amino acids within an otherwise conserved motif. These data provide a
      quantitative framework for a new molecular model of translational regulation.

PMID- 10406813
TI  - Council honorees and the nobel prize : our continued anniversary celebration 

PMID- 10406814
TI  - Jay michael sullivan 936-1999 

PMID- 10406815
TI  - Evidence for linkage between essential hypertension and a putative locus on human
      chromosome 17.
AB  - Several clinical and animal studies indicate that essential hypertension is
      inherited as a multifactorial trait with a significant genetic and environmental
      component. In the stroke-prone spontaneously hypertensive rat model,
      investigators have found evidence for linkage to blood pressure regulatory genes
      (quantitative trait loci) on rat chromosomes 2, 10, and X. In 1 human study of
      French and UK sib pairs, evidence for linkage has been reported to human
      chromosome 17q, the syntenic region of the rat chromosome 10 quantitative trait
      loci (QTL). Our study confirms this linkage (P=0.0005) and refines the location
      of the blood pressure QTL.

PMID- 10406816
TI  - Association of the G(s)alpha gene with essential hypertension and response to
      beta-blockade.
AB  - We examined whether the GNAS1 locus, encoding the G(s) protein alpha-subunit
      (G(s)alpha), is implicated in the genetic causes of essential hypertension. A
      common silent polymorphism (ATT-->ATC, Ile(131)) was identified in exon 5 of the
      G(s)alpha gene by single-strand conformation polymorphism analysis and DNA
      sequencing. This polymorphism consists of the presence (+) or absence (-) of a
      restriction site for FokI. Only 1 other rare allele was found in the coding
      region; the high GC content of the 5' noncoding sequence prevented mutation
      scanning of the promoter region of the gene. There was a significant difference
      in frequency of the FokI alleles between 268 white hypertensives (FokI+:FokI-,
      51%:49%) and a matched group of 231 control subjects (FokI+:FokI-, 58%:42%)
      (P=0.02). Multiple regression analysis showed that the FokI genotype was
      independently related to the level of untreated systolic blood pressure in 294
      well-characterized white hypertensives (P=0.01) but not in normotensives. The
      influence of the FokI allele on blood pressure (BP) response to beta-blockade was
      examined in 114 of the patients randomly assigned to this class of drug.
      Significant differences in frequency of the FokI allele were observed in the good
      responders (FokI+:FokI-, 62.5%:37.5%, n=36) versus the poor responders
      (FokI+:FokI-, 41.7%:58.3%, n=30) after beta-blocker therapy (P=0.02). In a
      multiple regression analysis, the G(s)alpha genotype was the only independent
      predictor of BP response. These results suggest that the GNAS1 locus might carry
      a functional variant that influences BP variation and response to beta-blockade
      in essential hypertension.

PMID- 10406817
TI  - Glucagon receptor gene mutation (Gly40Ser) in human essential hypertension: the
      PEGASE study.
AB  - A missense mutation (Gly40Ser) in exon 2 of the glucagon receptor gene (GCG-R)
      was shown to reduce ligand affinity and impair cAMP response. We conducted a case
      control study with a sample of 741 French hypertensive patients with moderate to
      severe hypertension and 412 normotensive control subjects, who were genotyped for
      this biallelic variant by use of hybridization with allele-specific
      oligonucleotides. The Gly40Ser polymorphism was not significantly associated with
      hypertension in the whole study population, although the frequency of 40Ser
      carriers in hypertensive subjects was double that in normotensive subjects (3.1%
      in hypertensives versus 1.5%; P=0.087). However, the separate analysis of both
      genders revealed that 40Ser allele carriers were significantly more frequent
      (P=0. 035) among male patients (17/429; 4.0%) than among normotensive male
      controls (2/242; 0.8%), whereas no significant difference was observed in female
      subjects (6/312 in hypertensives and 4/170 in normotensives). Further studies are
      required to interpret the significance of this association.

PMID- 10406818
TI  - Exercise training-induced blood pressure and plasma lipid improvements in
      hypertensives may be genotype dependent.
AB  - Exercise training improves cardiovascular disease risk, but individual responses
      are highly variable. We hypothesized that common polymorphic gene variations
      would affect these responses. Sedentary obese hypertensive older men who had
      undergone exercise training were typed at the apolipoprotein (apo) E, angiotensin
      converting enzyme (ACE), and lipoprotein lipase (LPL) loci. Individuals of all
      genotype subgroups were generally similar before training; they also changed body
      weight, body composition, and &f1;O(2)max similarly with training. ACE
      insertion/insertion (II) and insertion/deletion (ID) genotype individuals (n=10)
      tended to reduce systolic blood pressure more with training than
      deletion/deletion (DD) individuals (n=8) (-10 versus -5 mm Hg, P=0. 16). ACE II
      and ID individuals decreased diastolic blood pressure more with training than DD
      individuals (-10 versus -1 mm Hg, P<0. 005). Systolic blood pressure reductions
      with training were also larger in apoE3 and E4 (n=15) than apoE2 men (n=3) (-10
      versus 0 mm Hg, P<0.05). The same trend was evident for diastolic blood pressure
      (-7 versus -3 mm Hg), but the difference was not significant. Systolic (14 versus
      -6 mm Hg, P=0.08) and diastolic (-9 versus -5 mm Hg, P=0.10) blood pressure
      reductions tended to be greater in LPL PvuII +/+ (n=4) than +/- and -/-
      individuals (n=14). Systolic (-10 versus 3 mm Hg, P<0.05) and diastolic (-9
      versus 2 mm Hg, P<0.05) blood pressure reductions were larger in LPL HindIII +/+
      and +/- (n=15) than -/- persons (n=3), respectively. LPL PvuII -/- individuals
      (n=3) had larger increases in HDL cholesterol (11 versus 2 mg/dL, P<0.05) and
      HDL(2) cholesterol (8 versus 0 mg/dL, P<0.05) than LPL PvuII +/- and +/+
      individuals (n=15). These results are consistent with the possibility that apoE,
      ACE, and LPL genotypes may identify hypertensives who will improve blood
      pressure, lipoprotein lipids, and cardiovascular disease risk the most with
      exercise training.

PMID- 10406819
TI  - Endothelial nitric oxide gene knockout mice: cardiac phenotypes and the effect of
      angiotensin-converting enzyme inhibitor on myocardial ischemia/reperfusion
      injury.
AB  - We tested the hypothesis that nitric oxide (NO) released by endothelial NO
      synthase (eNOS) is not only important in blood pressure regulation but also
      involved in cardiac function and remodeling and in the cardioprotective effect of
      angiotensin-converting enzyme inhibitors (ACEi). With the use of a 2D Doppler
      echocardiography system equipped with a 15-MHz linear transducer, we evaluated
      left ventricular (LV) morphology and function in conscious eNOS knockout mice
      (eNOS(-/-); n=15) and their wild-type littermates (eNOS(+/+); n=16). We also
      studied whether in eNOS(-/-) mice (1) myocardial ischemia/reperfusion injury is
      more severe and (2) the cardioprotective effect of ACEi is diminished or absent.
      In comparison with the wild type, eNOS(-/-) mice had significantly increased
      systolic blood pressure (128+/-3 versus 108+/-5 mm Hg; P<0.001) and decreased
      heart rate (531+/-22 versus 629+/-18 bpm; P<0.001) associated with increased LV
      posterior wall thickness (0.80+/-0.04 versus 0.64+/-0.02 mm; P<0.001) and LV mass
      (18.3+/-0.9 versus 13.1+/-0.5 mg/10 g body weight; P<0.01). Despite hypertension
      and LV hypertrophy, LV chamber dimension, shortening fraction and ejection
      fraction (indicators of LV contractility), and cardiac output did not differ
      between the 2 strains, which indicates that LV function in eNOS(-/-) mice is well
      compensated. We also found that in eNOS(+/+) mice, ACEi decreased the ratio of
      myocardial infarct size to area at risk from 62.7+/-3.9% to 36.3+/-1.6% (P<0.
      001), whereas in eNOS(-/-) mice this effect of ACEi was almost abolished: the
      ratio of myocardial infarct size to area at risk was 67.2+/-2.9% in the vehicle
      treated group and 62.7+/-3.9% in mice treated with ACEi. Moreover, infarct size
      in vehicle-treated eNOS(-/-) mice was not significantly different from eNOS(+/+)
      mice given the same treatment. We concluded that (1) endothelium-derived NO plays
      an important role in the regulation of blood pressure homeostasis; (2) NO
      released under basal conditions has no significant impact on cardiac function;
      and (3) ACEi protect the heart against ischemia/reperfusion injury in mice and
      that this effect is mediated in part by endothelium-derived NO.

PMID- 10406820
TI  - Rat angiotensin-converting enzyme promoter regulation by beta-adrenergics and
      cAMP in endothelium.
AB  - To shed light on mechanisms of angiotensin-converting enzyme (ACE) upregulation,
      we used a rabbit endothelial cell model to characterize intracellular pathways of
      beta-adrenergic stimulation. In these cells, ACE activity is increased by
      isoproterenol (ISO). The stably transfected 1273-bp ACE promoter is stimulated by
      ISO in the presence of isobutyl methylxanthine. This effect is abolished by
      propranolol. Promoter stimulation is mimicked by cholera toxin, forskolin, and
      8BrcAMP, but not by 8BrcGMP. Promoter stimulation by ISO and isobutyl
      methylxanthine is blocked by protein kinase A inhibitors, indicating that beta
      adrenergic stimulation of the ACE gene depends on phosphorylation of protein
      kinase A targets. Activation by cAMP, resistance to phorbol ester, and lack of
      synergism between cAMP and phorbol ester suggest that promoter regulation is due
      to cAMP responsive element rather than to activating protein-2 sequences. Okadaic
      acid potentiation of 8BrcAMP induction indicated that promoter activation by cAMP
      is regulated by phosphatases controlling activation of typical cAMP responsive
      element regulated genes. In summary, beta-adrenergic activation of rat ACE
      promoter is specific; uses G(s) proteins, adenylyl cyclase, protein kinase A; and
      probably includes cAMP responsive element-like sequences.

PMID- 10406821
TI  - Endothelium-derived contracting factor in carotid artery of hypertensive Dahl
      rats.
AB  - The present study is designed to investigate whether acetylcholine (ACh) elicits
      an endothelium-derived contracting factor (EDCF) and whether it contributes to
      decreased relaxant response induced by ACh in Dahl rats. Dahl salt-sensitive (DS)
      and -resistant (DR) rats were fed a 0.4% NaCl or an 8% NaCl diet for 4 weeks.
      High sodium intake significantly increased blood pressure in DS rats but not in
      DR rats. The carotid rings were suspended for isometric tension recording. ACh
      caused an endothelium-dependent contraction in carotid rings from hypertensive DS
      rats but not from normotensive Dahl rats. Atropine, indomethacin, SQ29548, or ONO
      3708 (prostaglandin H(2) [PGH(2)]/thromboxane A(2) [TXA(2)] receptor antagonist)
      abolished ACh-induced contraction, and OKY-046 (inhibitor of TXA(2) synthetase)
      partially attenuated the contraction. High sodium intake significantly enhanced
      contraction evoked by U46619, a PGH(2)/TXA(2) receptor agonist, in both DS and DR
      rats. In contrast, ACh-induced relaxation was significantly depressed in the
      rings from hypertensive DS rats, and ONO-3708 partially improved the depressed
      relaxation. Administration of ONO-8809 (an orally active PGH(2)/TXA(2) receptor
      antagonist; 30 micrograms per body per day) for 4 weeks neither reduced blood
      pressure nor improved the depressed ACh-induced relaxation in hypertensive DS
      rats. These results suggest that ACh causes release of EDCF in carotid rings of
      hypertensive DS rats, which is likely to be PGH(2) and TXA(2). The EDCF
      contributed in part to the depressed ACh-induced relaxation.

PMID- 10406822
TI  - Effects of L-arginine on atherogenesis and endothelial dysfunction due to
      secondhand smoke.
AB  - Secondhand smoke (SHS) and hypercholesterolemia increase cardiovascular risk. We
      hypothesized that L-arginine, the precursor of nitric oxide (NO), might protect
      against atherogenesis and endothelial dysfunction caused by SHS. The effects of L
      arginine supplementation (2.25% solution ad libitum) and SHS (smoking chambers
      for 10 weeks) were examined in 32 hypercholesterolemic rabbits. Eight normal
      rabbits served as controls. Acetylcholine- and nitroglycerin-induced
      vasorelaxation was assessed in aortic rings precontracted with norepinephrine.
      Hypercholesterolemia increased intimal lesion area (P=0.012), reduced endothelium
      dependent relaxation (P=0.009), and reduced basal (P=0.005) and stimulated
      (P<0.0005) production of NOs. SHS increased intimal lesion area (P=0. 01)
      norepinephrine-induced contraction (P=0.001) and reduced endothelium-dependent
      relaxation (P=0.02). SHS-induced increase in norepinephrine contraction was
      abolished by the inhibition of NO synthase and removal of endothelium. L-Arginine
      improved endothelium-dependent relaxation (P=0.001) and attenuated SHS-induced
      endothelial dysfunction (P=0.007) and atherogenesis (P=0. 001). Basal production
      of nitrogen oxides correlated inversely with intimal lesion area (r=-0.66;
      P<0.0005) and stimulated production of NOs correlated with endothelium-dependent
      relaxation (r=-0.66; P<0. 001). SHS causes endothelial dysfunction and increased
      adrenergic responsiveness and atherogenesis in hypercholesterolemic rabbits.
      Chronic dietary supplementation with the NO precursor L-arginine mitigates these
      effects. The adverse vascular consequences of SHS appear to be mediated via
      deleterious effects on endothelial function.

PMID- 10406823
TI  - Blood pressure and the progression of carotid atherosclerosis in middle-aged men.
AB  - Elevated blood pressure has consistently been associated with increased
      prevalence of preclinical atherosclerosis and with increased risk of clinical
      atherosclerotic cardiovascular disease (CVD). However, there is no prospective
      evidence of the association between blood pressure and the progression of
      preclinical atherosclerosis. We therefore investigated the relationships of
      systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure
      to the 4-year increase in the measures of early carotid atherosclerosis, the mean
      and maximal common carotid intima-media thickness (IMT), assessed by B-mode
      ultrasonography, in 1026 men aged 42 to 60 years. Men with the SBP of <120, 120
      to 126, 127 to 134, 135 to 143, and >143 mm Hg (fifths) had an increase in the
      mean IMT of 0.074, 0.090, 0.110, 0.136, and 0.158 mm per 4 years (P<0.001 for
      difference between groups, P<0.001 for linear trend) and in the maximal IMT of
      0.212, 0.221, 0.279, 0.286, and 0.315 mm per 4 years, (P<0.001, P<0.001),
      respectively, adjusting for other atherosclerotic risk factors, including DBP.
      Also, pulse pressure, when adjusted for other risk factors including mean
      arterial pressure, was directly associated with the IMT increase. DBP was not
      independently related to the IMT increase. This is the first documentation to
      show that mildly elevated SBP and pulse pressure accelerate the progression of
      preclinical atherosclerosis. This study provides further evidence for the finding
      that systolic hypertension is a more important risk factor for atherosclerosis
      and consequent CVD than diastolic hypertension. Therefore, more attention should
      be paid to the level of SBP in the evaluation of CVD risk and in the treatment of
      hypertension.

PMID- 10406824
TI  - Impact of nativity and race on "Stroke Belt" mortality.
AB  - The southeastern region of the United States has been recognized for 6 decades as
      an area of excess cerebrovascular mortality rates. While the reasons for the
      disease variation remain an enigma, South Carolina has consistently been the
      forerunner of the "Stroke Belt." To determine the effects of nativity
      (birthplace) on stroke mortality rates in South Carolina, proportional mortality
      ratios (PMRs) were calculated for stroke deaths in South Carolina during 1980
      1996 according to birthplace and stratified by gender, race, age, and educational
      status. The analyses revealed a graded risk of stroke by birthplace, with the
      highest PMRs (95% CI) among individuals born in South Carolina (104.8 [103.4 to
      106.3]), intermediate PMRs in those born in the Southeast other than South
      Carolina (92.5 [90.2 to 94.9]), and lowest PMRs for those born outside the
      Southeast (77.4 [74.9 to 80.1]). The lower stroke PMRs for individuals born
      outside the Southeast were more striking in blacks (51.8 [45.2 to 59.3]) than in
      whites (84.9 [82.0 to 88.0]) and for men (73.3 [69.5 to 77.3]) than women (83.5
      [79.9 to 87.3]). The findings, particularly in blacks, were not explainable by
      gender, differences in age, and/or markers of educational and socioeconomic
      status. These findings suggest that nativity is a significant risk marker for the
      geographic variation in stroke mortality. Moreover, the regional disparities for
      nativity and subsequent stroke mortality appear to be greater in blacks than in
      whites and for men than for women. An understanding of factors linking birthplace
      to risk for cerebrovascular mortality could facilitate efforts directed at stroke
      prevention.

PMID- 10406825
TI  - Cardiac consequences of prolonged exposure to an isolated increase in aortic
      stiffness.
AB  - In elderly patients, aortic stiffness is a major determinant of increased end
      systolic stress leading to left ventricular (LV) hypertrophy with impaired
      cardiac performance. However, in a rat model of aortic elastocalcinosis (induced
      by vitamin D(3)-nicotine [VDN] treatment), brief exposure (1 month) to increased
      aortic stiffness modified neither cardiac function nor cardiac structure. Here we
      report the impact of longer exposure (3 months) to aortic stiffness. Three months
      after induction of aortic stiffness, aortic characteristic impedance was measured
      in awake rats, 8 control and 10 VDN. Stroke volume was measured (electromagnetic
      probe) at baseline and after acute volume overload. LV weight/body weight ratio,
      collagen, and myosin heavy chain (MHC) contents were determined. Although aortic
      characteristic impedance increased (controls, 32+/-2; VDN rats, 50+/-8 10(3)
      dyne. s/cm(5); P=0.0248), stroke volume was maintained in VDN rats at baseline
      (controls, 223+/-18; VDN, 211+/-13 microL) and after volume overload (controls,
      378+/-14; VDN, 338+/-15 microL). However, LV weight/body weight ratio (controls,
      1.54+/-0.07; VDN, 1.73+/-0.05 g/kg; P=0.0397) and LV collagen content (controls,
      31+/-4; VDN, 52+/-4 microgram/g dry wt; P=0.0192) increased. A shift from alpha
      MHC (controls, 82+/-2%; VDN, 69+/-3%; P=0.0056) to beta-MHC (controls, 18+/-2%;
      VDN, 31+/-3%; P=0. 0056) was also observed. Three months' exposure to increased
      aortic stiffness in VDN rats induced LV hypertrophy with moderate interstitial
      fibrosis and a shift in the MHC-isoform pattern. Such structural adaptation
      maintains LV performance.

PMID- 10406826
TI  - Bioactivity and interactions of adrenomedullin and brain natriuretic peptide in
      patients with heart failure.
AB  - Plasma concentrations of the recently discovered hormones adrenomedullin (ADM),
      from vascular tissue, and brain natriuretic peptide (BNP), secreted by
      myocardium, are elevated in patients with heart failure. We tested the hypotheses
      that short-term increments in circulating levels of these hormones, within the
      pathophysiological range, would have biological effects and that the 2 hormone
      systems interact. Eight patients with heart failure (left ventricular ejection
      fractions <35%) received 4-hour infusions of BNP (3.0 pmol. kg(-1). min(-1))
      alone, ADM (2.7 pmol. kg(-1). min(-1) and 5.4 pmol. kg(-1). min(-1) for 2 hours
      each) alone, ADM and BNP combined, and placebo. BNP and ADM infusions raised
      plasma levels of the respective peptide within the pathophysiological range.
      Arterial blood pressure fell (P<0.05) with all peptide infusions, but cardiac
      output was unchanged. Heart rate increased with ADM and combined infusions
      (P<0.01). Sodium excretion rose (P<0.05), and creatinine clearance was sustained
      during both BNP and combined infusions. Urine volume increased in response to BNP
      alone (P=0.02). Despite a >2-fold increase in plasma renin with both ADM and
      combined infusions (P<0.05), plasma aldosterone remained lower than time-matched
      placebo levels. Plasma noradrenaline was increased by combined, BNP, and higher
      dose ADM infusions (P<0.05). ADM suppressed plasma cGMP (P<0.05) and inhibited
      the plasma cGMP response to BNP (P<0.05). The vascular hormones ADM and BNP,
      produced by myocardium, at plasma concentrations within the pathophysiological
      range have hemodynamic, renal, and hormonal effects and measurable interactions
      in patients with heart failure.

PMID- 10406827
TI  - Effects of glutathione on red blood cell intracellular magnesium: relation to
      glucose metabolism.
AB  - Recent evidence suggests that the endogenous antioxidant glutathione may play a
      protective role in cardiovascular disease. To directly investigate the role of
      glutathione in the regulation of glucose metabolism in hypertension, we studied
      the acute effects of in vivo infusions of this antioxidant (alone or in
      combination with insulin) on whole body glucose disposal (WBGD) using euglycemic
      glucose clamp and the effects on total red blood cell intracellular magnesium
      (RBC-Mg) in hypertensive (n=20) and normotensive (n=30) subjects. The
      relationships among WBGD, circulating reduced/oxidized glutathione (GSH/GSSG)
      levels, and RBC-Mg in both groups were evaluated. The in vitro effects of
      glutathione (100 micromol/L) on RBC free cytosolic magnesium (Mg(i)) were also
      studied. In vivo infusions of glutathione (15 mg/minx120 minutes) increased RBC
      Mg in both normotensives and hypertensives (1.99+/-0.02 to 2.13+/-0.03 mmol/L,
      P<0.01, and 1.69+/-0.03 to 1.81+/-0.03 mmol/L, P<0.01, respectively). In vitro
      GSH but not GSSG increased Mg(i) (179+/-3 to 214+/-5 micromol/L, P<0.01). In
      basal conditions, RBC-Mg values were related to GSH/GSSG ratios (r=0.84,
      P<0.0001), and WBGD was directly, significantly, and independently related to
      both GSH/GSSG ratios (r=0.79, P<0.0001) and RBC-Mg (r=0.89, P<0.0001). This was
      also true when hypertensive and control groups were analyzed separately. On
      multivariate analysis, basal RBC-Mg (t=6.81, P<0.001), GSH/GSSG (t=3. 67,
      P<0.02), and blood pressure (t=2.89, P<0.05) were each independent determinants
      of WBGD, with RBC-Mg explaining 31% of the variability of WBGD. These data
      demonstrate a direct action of glutathione both in vivo and in vitro to enhance
      intracellular magnesium and a clinical linkage between cellular magnesium,
      GSH/GSSG ratios, and tissue glucose metabolism.

PMID- 10406828
TI  - Vasodilatory effects of troglitazone improve blood pressure at rest and during
      mental stress in type 2 diabetes mellitus.
AB  - The present study examined the hemodynamic mechanisms of blood pressure (BP)
      lowering by troglitazone in patients with type 2 diabetes mellitus (DM) at rest
      and during a mental arithmetic test (MAT). Twenty-two patients with DM with
      normal to high-normal BP and 12 controls matched for age, gender, glucose
      tolerance, and BP were studied. DM subjects showed significantly higher systolic
      BP response during MAT than controls (157 versus 139 mm Hg; P<0.01). All 22 DM
      patients and 5 of 12 controls had systolic BP >140 mm Hg during MAT. Heart rate
      and diastolic BP were not significantly different between the 2 groups. The DM
      group was then randomized to receive troglitazone (n=10; 400 mg/d) or glyburide
      (n=12; 20 mg/d). MAT was repeated after 6 months of treatment. Both treatments
      reduced glucose equally (-1.7 mmol/L for troglitazone and -1.5 mmol/L for
      glyburide), but only troglitazone reduced insulin (-15 microU/mL; P<0.001) and C
      peptide (-0.9 ng/mL; P<0.02) levels. Troglitazone significantly reduced BP at
      baseline (P<0.05) and systolic BP response to MAT (P<0.01), whereas glyburide did
      not affect BP at baseline or during MAT. Stroke volume and cardiac output did not
      change with either drug, but troglitazone decreased peripheral vascular
      resistance (-112 dyne. s. cm(-5); P<0.05). Improved insulin resistance rather
      than an improved glycemic control is associated with lower resting and stress BP
      values in patients with DM. A reduction in vascular resistance may be a primary
      hemodynamic mechanism of the manner in which troglitazone lowers BP. Insulin
      sensitizers may offer potential therapeutic advantage in subjects with DM with
      elevated BP.

PMID- 10406829
TI  - Attenuated in vitro coronary arteriolar vasorelaxation to insulin-like growth
      factor I in experimental hypercholesterolemia.
AB  - Insulin and insulin-like growth factor (IGF) 1 affect coronary vasoactivity.
      Experimental hypercholesterolemia is associated with coronary atherogenesis and
      altered vasomotor regulation. Because the IGF axis is altered during
      atherogenesis, we postulated that experimental hypercholesterolemia is associated
      with an altered coronary vasoactive response to IGF-1 in vitro. Coronary arteries
      and arterioles from pigs fed either a normal or high-cholesterol diet for 10
      weeks were contracted with endothelin-1 and relaxed with cumulative
      concentrations of insulin or IGF-1 (10(-12) to 10(-7) mol/L). Control arterioles
      were also incubated with the nitric oxide synthase inhibitor 10(-4) mol/L N(G)
      monomethyl-L-arginine (L-NMMA) or the potassium channel blocker 10(-2) mol/L
      tetraethylammonium (TEA), contracted with endothelin-1, and relaxed with insulin
      or IGF-1. Experimental hypercholesterolemia (1) increased serum cholesterol
      (9.5+/-1.0 versus 1.9+/-0.08 mmol/L; P<0.0001), (2) caused coronary arterial and
      arteriolar endothelial dysfunction in vitro (attenuated vasorelaxation to
      bradykinin), (3) did not alter the epicardial response to either insulin (P=0.80)
      or IGF-1 (P=0.12), and (4) significantly attenuated the arteriolar response to
      IGF-1 (maximal relaxation of 79+/-6% versus 42+/-8%; P=0.01) but not insulin
      (43+/-6% versus 53+/-7%; P=0.99). Control arteriolar vasorelaxation to IGF-1 was
      attenuated by both L-NMMA (P<0.001) and TEA (P=0.01), whereas only L-NMMA
      attenuated insulin (P<0.001). Staining for IGF-1 and IGF binding protein 2 was
      increased (P<0.05) in arterioles of cholesterol-fed pigs. IGF-1 and insulin are
      therefore coronary arteriolar vasorelaxants through different mechanisms.
      Experimental hypercholesterolemia is associated with resistance to the coronary
      arteriolar vasorelaxing effects of IGF-1 but not insulin, in conjunction with
      increased ligand and binding-protein expression. The IGF axis may contribute to
      the altered coronary vasoactivity in hypercholesterolemia.

PMID- 10406830
TI  - Cyclooxygenase-2 inhibition decreases renin content and lowers blood pressure in
      a model of renovascular hypertension.
AB  - It has been proposed that the macula densa participates in the regulation of
      increased renin expression in renovascular hypertension (RVH) and that
      prostaglandins may be among the mediators of macula densa function. We have
      previously shown that in renal cortex, cyclooxygenase-2 (COX-2) expression is
      localized to the macula densa and surrounding cortical thick ascending limb and
      increases in high-renin states, such as salt restriction and angiotensin
      converting enzyme inhibition. In the present studies, we examined the effect of
      the selective COX-2 inhibitor SC58236 on plasma renin activity (PRA) and renal
      renin expression in RVH in rats. The aorta was coarcted between right and left
      renal arteries, and animals received either SC58236 or vehicle for 1 week. At day
      8, vehicle-treated coarcted rats were hypertensive (mean carotid arterial blood
      pressure: 138+/-3 versus 87+/-2 mm Hg in sham-operated controls; n=9 to 11;
      P<0.001) and exhibited a disparity of kidney size (ratio left/right kidney:
      0.78+/-0.04 versus 1.02+/-0.02; n=9 to 10; P<0.001). PRA increased significantly
      (84.6+/-6.5 versus 9.0+/-1.4 ng angiotensin I [Ang I] per milliliter per hour;
      n=8 to 9; P<0.01). In the coarcted rats, neither renin mRNA expression nor renin
      activity of the right kidney was altered (renin/GAPDH mRNA: 1.12+/-0.05-fold
      levels in control rats; n=6; P=NS; renin activity: 23.4+/-1.8 versus 27.1+/-3.4
      ng Ang I per hour per milligram protein; n=8 to 9; P=NS). However, the renin mRNA
      of the left kidney increased to 3.0+/-0.6-fold of control (n=6), and the renin
      activity increased to 189.0+/-28.6 ng Ang I per hour per milligram protein (n=8;
      P<0.01). Expression of COX-2 mRNA and immunoreactive protein increased in the
      affected left kidney but was not different from control in the unaffected right
      kidney. SC58236 treatment to coarcted rats did not affect kidney size (ratio
      left/right kidney: 0.79+/-0.06; n=9). However, PRA was significantly decreased
      compared with the vehicle-treated coarcted rats (19.8+/-2. 8 ng Ang I per
      milliliter per hour; n=9; P<0.01). The left kidney renin mRNA and renin content
      were also decreased (1.7+/-0.3-fold control; n=6; P<0.05; and 45.7+/-7.6 ng Ang I
      per hour per milligram protein; n=9; P<0.01, respectively), while renin mRNA and
      renin content of the right kidney were not altered. SC58236 lowered mean arterial
      blood pressure (122+/-5 mm Hg; n=14; P<0.05 compared with vehicle). A significant
      correlation was observed between PRA and mean blood pressure (r=0.75; P<0.01). In
      summary, these studies indicate that the selective COX-2 inhibitor SC58236
      decreases renin production and release in RVH and suggest an important role for
      COX-2 regulation of the renin-angiotensin system.

PMID- 10406831
TI  - Role of sympathetic nervous system in cyclosporine-induced rise in blood
      pressure.
AB  - To clarify the role of the sympathetic nervous system in the development of
      cyclosporine A (CsA)-induced rise in blood pressure (BP), the effects of CsA on
      24-hour ambulatory BP (ABP) were studied in patients with familial amyloid
      polyneuropathy (FAP) who underwent a liver transplantation. On the basis of
      autonomic function tests, patients with absent or mild-to-moderate sympathetic
      damage (Group A, n=11, age 29 to 43 years, disease duration 2 to 6 years) and
      patients with severe sympathetic damage (Group B, n=9, age 27 to 38 years,
      disease duration 3 to 9 years) were identified. Both groups were followed for 1
      year. The daily doses of CsA and the CsA whole blood trough levels between the
      groups did not differ. Pretransplantation values of daytime and nighttime ABP
      were, respectively, 117+/-8/76+/-7 mm Hg and 108+/-12/68+/-9 mm Hg in group A and
      107+/-6/66+/-4 mm Hg (P<0.05 group A versus group B) and 102+/-6/62+/-4 mm Hg in
      group B. In response to CsA, BP increased in all patients, but more so in
      patients of group B than in patients of group A. One year after transplantation,
      daytime and nighttime ABP had increased by 6+/-9/3+/-11% and 12+/-10/14+/-14% in
      group A and by 12+/-6/13+/-10% (P<0.05) and 21+/-11/27+/-21% (P<0.01) in group B.
      In both groups, the increase in nighttime ABP was greater than the increase in
      daytime ABP, which resulted in an attenuation or, even, a reversal of the diurnal
      BP rhythm. Because the rise in BP was greater in patients with more advanced
      sympathetic dysfunction, the sympathetic nervous system appears to counteract the
      CsA-induced rise in BP rather than causing it. This implies involvement of
      factors other than sympathetic activation in the pathogenesis of CsA-induced rise
      in BP in patients with familial amyloid polyneuropathy.

PMID- 10406832
TI  - Brain renin-angiotensin system and ouabain-induced sympathetic hyperactivity and
      hypertension in Wistar rats.
AB  - In Dahl salt-sensitive rats on a high salt diet or normotensive rats with chronic
      central infusion of sodium, increased brain "ouabain" results in sympathetic
      hyperactivity and hypertension, possibly by activating the brain renin
      angiotensin system. In the present study, we tested whether the hypertension
      caused by exogenous ouabain also depends on activation of brain renin-angiotensin
      system. In Wistar rats, ouabain (50 micrograms/d) was infused subcutaneously for
      14 days with the use of osmotic minipumps. Concomitantly, in one group, the
      angiotensin II type 1 receptor blocker losartan (1 mg/kg per day) was infused
      intracerebroventricularly. On day 15, mean arterial pressure, heart rate, central
      venous pressure, and renal sympathetic nerve activity were recorded in conscious
      rats at rest and in response to air-jet stress, intracerebroventricular injection
      of the alpha(2)-agonist guanabenz (25 and 75 micrograms) or angiotensin II (30
      ng), acute volume expansion, and ramp changes of blood pressure by +/-50 mm Hg
      with phenylephrine and nitroprusside. Compared with control rats, in rats treated
      with ouabain, resting mean arterial pressure was significantly increased (111+/-4
      versus 93+/-3 mm Hg; P<0.05), and increases or decreases in mean arterial
      pressure, heart rate, and renal sympathetic nerve activity in response to air
      stress or guanabenz were enhanced significantly. These effects of ouabain were
      prevented when losartan was given concomitantly. Maximal slopes of arterial
      baroreflex control of renal sympathetic nerve activity and heart rate tended to
      be decreased in ouabain-treated versus control rats and were significantly
      increased in ouabain-treated rats with versus without losartan. No differences in
      cardiopulmonary baroreflex function were detected. It seems that by day 14 to 15,
      the central effect of ouabain on baroreflex control prevails over its peripheral
      sensitizing effect on baroreceptors, leading to a tendency of desensitization.
      These results indicate that chronic administration of ouabain activates the brain
      renin-angiotensin system, resulting in decreased sympathoinhibition and increased
      sympathoexcitation, impairment of baroreflex function, and hypertension.

PMID- 10406833
TI  - Preactivated peripheral blood monocytes in patients with essential hypertension.
AB  - The purpose of this study was to investigate the possible involvement of human
      peripheral blood monocytes in the pathology of hypertensive disease. We
      determined the in vitro secretion patterns of proinflammatory cytokines obtained
      from isolated peripheral monocytes from normal controls and from hypertensive
      patients either after in vitro stimulation with angiotensin II (Ang II) with or
      without preincubation with an Ang II type 1 receptor antagonist (losartan) or
      after stimulation with lipopolysaccharide. Blood samples were obtained from 22
      patients with essential hypertension (before any drug administration or after
      interruption of antihypertensive therapy) and from 24 normotensive healthy
      individuals used as a control group. Peripheral blood monocytes were isolated by
      density gradient centrifugation and plastic adherence. The state of monocyte
      activity was determined by the capacity to secrete tumor necrosis factor-alpha
      (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6, (IL-6) either
      spontaneously or after stimulation. Cytokine concentrations were determined in
      culture supernatants by specific ELISA. Proinflammatory cytokine levels were
      assessed by semiquantitative reverse transcribed polymerase chain reaction. After
      stimulation with Ang II, the IL-1beta secretion of peripheral blood monocytes was
      significantly increased in hypertensive patients versus healthy individuals
      (P<0.05). In contrast, in monocytes preincubated with losartan before exposure to
      Ang II, IL-1beta secretion was diminished in both groups to comparable levels.
      The secretion of IL-1beta and TNF-alpha was significantly increased in peripheral
      blood monocytes from hypertensive patients versus healthy individuals after
      stimulation with lipopolysaccharide (TNF-alpha, P<0.02; IL-1beta, P<0.05).
      Upregulation of IL-1beta and TNF-alpha secretion in peripheral blood monocytes
      from hypertensive patients was also seen at the RNA level. Our results indicate
      preactivated peripheral blood monocytes in hypertensive patients. Ang II may be
      directly involved in the process of monocyte activation.

PMID- 10406834
TI  - Induction of interleukin-6 expression by angiotensin II in rat vascular smooth
      muscle cells.
AB  - Recent studies suggest that atherosclerosis is a kind of inflammatory process and
      that cytokine plays important roles in this process. Although it is generally
      accepted that angiotensin II (Ang II) plays an important role in atherogenesis,
      the role of Ang II in cytokine production has not been explored. In this report,
      we investigated the effect of Ang II on the production of interleukin-6 (IL-6),
      which is a multifunctional proinflammatory cytokine in rat vascular smooth muscle
      cells. Ang II significantly increased the expression of IL-6 mRNA and protein in
      a dose-dependent manner (10(-10) to 10(-6) mol/L). The expression of IL-6 mRNA
      induced by Ang II showed 2 peaks at 30 minutes and 12 to 24 hours after
      stimulation. The effect of Ang II on IL-6 release and mRNA expression was
      completely blocked by an Ang II type 1 receptor antagonist, CV11974; however, an
      Ang II type 2 receptor antagonist, PD123319, showed no effect. Chelating of
      intracellular Ca(2+) with BAPTA-AM, inhibition of tyrosine kinase with genistein,
      and inhibition of mitogen-activated protein kinase kinase with PD98059 completely
      abolished the effect of Ang II. However, downregulation of protein kinase C by
      pretreatment with a phorbol ester for 24 hours or a specific protein kinase C
      inhibitor, calphostin C, did not affect the Ang II-induced expression of IL-6
      mRNA. Deletion and mutational analysis of IL-6 gene promoter showed that cAMP
      responsive element was important for Ang II-induced IL-6 gene expression. Gel
      mobility shift assay showed an increase of cAMP-responsive element binding
      protein by Ang II. These results provide new insights into Ang II signaling and
      the role of Ang II in the progression of inflammatory changes of blood vessels.

PMID- 10406835
TI  - Contribution of extracellular signal-regulated kinase to angiotensin II-induced
      transforming growth factor-beta1 expression in vascular smooth muscle cells.
AB  - We have previously demonstrated that angiotensin II (Ang II) contributes to the
      increase in aortic transforming growth factor-beta(1) (TGF-beta(1)) mRNA levels
      in hypertensive rats. However, the molecular mechanism whereby Ang II promotes
      TGF-beta(1) expression in vascular smooth muscle cells (VSMCs) is poorly
      understood. In this study, we examined the role of extracellular signal-regulated
      kinase (ERK) in Ang II-mediated TGF-beta(1) expression in VSMCs and the role of
      Ang II in aortic ERK activity of stroke-prone spontaneously hypertensive rats.
      Treatment of quiescent VSMCs with 100 nmol/L Ang II induced rapid phosphorylation
      and activation of ERK1 and ERK2 with a peak at 5 minutes followed by an increase
      in activator protein-1 (AP-1) DNA binding activity, as shown by gel mobility
      shift assay. An increase in TGF-beta(1) mRNA was shown by Northern blot analysis.
      Treatment of VSMCs with PD98059, a specific inhibitor of the ERK pathway,
      attenuated both the activation of AP-1 and the increase in TGF-beta(1) mRNA
      induced by Ang II. Inhibition of Ang II-induced AP-1 activation with c-fos
      antisense oligodeoxynucleotide led to a significant reduction of TGF-beta(1) mRNA
      in VSMCs. Furthermore, in vivo treatment of stroke-prone spontaneously
      hypertensive rats with losartan, an Ang II type 1 receptor antagonist, decreased
      aortic ERK activity. Thus, we show that ERK, through AP-1 activation, is involved
      in Ang II-induced TGF-beta(1) mRNA expression in VSMCs and suggest that ERK may
      participate in vascular remodeling of hypertension. However, it remains to be
      determined whether the increase in TGF-beta(1) mRNA leads to the increase in its
      active protein.

PMID- 10406836
TI  - Genistein inhibits pressure-induced expression of c-fos in isolated mesenteric
      arteries.
AB  - We have previously demonstrated that elevating intraluminal pressure from 90 to
      140 mm Hg in isolated mesenteric arteries increases the expression of proto
      oncogenes. These proto-oncogenes encode nuclear transcription factors that
      regulate the expression of target genes during various stages of the cell cycle.
      Thus, pressure-induced proto-oncogene expression may represent a mechanism by
      which pressure can induce growth and/or proliferation of vascular smooth muscle.
      The purpose of this study was to determine the intracellular signals that
      contribute to the pressure-induced increase in c-fos expression. Small mesenteric
      arteries were isolated from male Wistar rats and transferred to a dual-vessel
      chamber. The arteries were cannulated and slowly equilibrated to initial
      conditions (90 mm Hg, 37 degrees C) while being continuously superfused with a
      HEPES-bicarbonate-buffered Krebs' solution. After the equilibration period, the
      intraluminal pressure in 1 artery was increased to 140 mm Hg for 1 hour. In
      experiments designed to determine the intracellular signals involved in the
      pressure-induced increase in c-fos expression, specific inhibitors were
      introduced to the superfusate reservoir of both arteries before the pressure
      increase. The arteries were then fixed in phosphate-buffered formalin and
      embedded in paraffin blocks. Sections of paraffin-embedded arteries were fixed on
      slides, and the expression of c-fos was determined by in situ hybridization with
      the use of (35)S-labeled riboprobes. The pressure-induced expression of c-fos was
      not inhibited by nitrendipine (10 micromol/L), a calcium-free Krebs' solution
      containing EGTA (1 to 2 mmol/L), calphostin C (0.1 micromol/L), or cytochalasin D
      (0.4 micromol/L) but was inhibited by genistein (30 micromol/L). The results
      suggest that activation of a tyrosine kinase is required for pressure-induced c
      fos expression, but the signaling pathway does not require extracellular calcium
      entry, intact actin filaments, or protein kinase C. As we have shown previously,
      the expression of c-fos correlated with wall stress.

PMID- 10406838
TI  - Serum uric acid and cardiovascular events in successfully treated hypertensive
      patients.
AB  - To determine whether pretreatment and/or in-treatment serum uric acid (SUA) is
      independently and specifically associated with cardiovascular events in
      hypertensive patients, we examined the 20-year experience of 7978 mild-to
      moderate hypertensive participants in a systematic worksite treatment program.
      Clinical evaluation and treatment were protocol-directed. SUA was measured at
      entry and annually thereafter. Subjects were stratified according to gender
      specific quartile of baseline SUA. Blood pressures at entry and in-treatment
      were, respectively, 152.5/95.6 and 138.9/85.4 mm Hg. SUA was normally distributed
      with a mean of 0.399+/-0.0893 and 0. 321+/-0.0833 mmol/L for men and women,
      respectively. Subjects with highest SUA were heavier, had greater evidence of
      cardiovascular disease (CVD), higher systolic blood pressure, higher creatinine,
      more frequent diuretic use, and lower prevalence of diabetes. During an average
      follow-up of 6.6 years (52 751 patient-years), 548 CVD events (183 mortal) and
      116 non-CVD events occurred. In bivariate analysis, the association of SUA to CVD
      was more robust in nonwhites than whites and in patients at low versus high CVD
      risk. In multivariate analysis, CVD incidence was significantly associated with
      SUA with a hazard ratio of 1.22 (95% confidence interval 1.11 to 1.35),
      controlling for other known cardiovascular risk factors, including serum
      creatinine, body mass index, and diuretic use. Despite blood pressure control,
      SUA levels increased during treatment and were significantly and directly
      associated with CVD events, independently of diuretic use and other
      cardiovascular risk factors.

PMID- 10406837
TI  - Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular
      calcium increase in the aorta of spontaneously hypertensive rats.
AB  - Torasemide is a loop diuretic that is effective at low once-daily doses in the
      treatment of arterial hypertension. Because its antihypertensive mechanism of
      action may not be based entirely on the elimination of salt and water from the
      body, a vasodilator effect of this drug can be considered. In the present study,
      the ability of different concentrations of torasemide to modify angiotensin II
      (Ang II)-induced vascular responses was examined, with the use of an organ bath
      system, in endothelium-denuded aortic rings from spontaneously hypertensive rats.
      Ang II-induced increases of intracellular free calcium concentration
      ([Ca(2+)](i)) were also examined by image analysis in cultured vascular smooth
      muscle cells (VSMCs) from spontaneously hypertensive rats. A dose-response curve
      to Ang II was plotted for cumulative concentrations (from 10(-9) to 10(-6) mol/L)
      in endothelium-denuded aortic rings (pD(2)=7.5+/-0.3). Isometric contraction
      induced by a submaximal concentration of Ang II (10(-7) mol/L) was reduced in a
      dose-dependent way by torasemide (IC(50)=0.5+/-0.04 micromol/L). Incubation of
      VSMCs with different concentrations of Ang II (from 10(-10) to 10(-6) mol/L)
      resulted in a dose-dependent rise of [Ca(2+)](i) (pD(2)=7.5+/-0.3). The
      stimulatory effect of [Ca(2+)](i) induced by a submaximal concentration of Ang II
      (10(-7) mol/L) was blocked by torasemide (IC(50)=0.5+/-0.3 nmol/L). Our findings
      suggest that torasemide blocks the vasoconstrictor action of Ang II in vitro.
      This action can be related to the ability of torasemide to block the increase of
      [Ca(2+)](i) induced by Ang II in VSMCs. It is proposed that these actions might
      be involved in the antihypertensive effect of torasemide observed in vivo.

PMID- 10406839
TI  - Renal injury and salt-sensitive hypertension after exposure to catecholamines.
AB  - We investigated whether chronic infusion of phenylephrine could induce structural
      and functional changes in the kidney of rats with the subsequent development of
      salt-sensitive hypertension. Rats were infused with phenylephrine (0.15 mmol/kg
      per day) by minipump, resulting in a moderate increase in systolic blood pressure
      (BP) (17 to 25 mm Hg) and a marked increase in BP variability as measured by an
      internal telemetry device. After 8 weeks, the phenylephrine infusion was stopped
      with the return of BP to normal, and a nephrectomy was performed for histological
      studies. Glomeruli were largely spared, but focal tubulointerstitial fibrosis was
      present, with the de novo expression of osteopontin by injured tubules,
      macrophage and "myofibroblast" accumulation, and focal increases in mRNA for
      transforming growth factor beta by in situ hybridization. Peritubular capillaries
      at sites of injury had distorted morphology with shrinkage, rounding, and focal
      rarefaction, and endothelial cell proliferation was also identified. Rats were
      randomized to a high (8% NaCl or 1.36 mol/kg) or low (0.1% NaCl or 17 mmol/kg)
      salt diet. After 4 to 8 weeks, phenylephrine-treated rats on a high salt diet
      developed marked hypertension, which was in contrast with phenylephrine-treated
      rats placed on a low salt diet or vehicle-treated rats given a high salt diet.
      Hypertension after phenylephrine exposure correlated with the initial mean
      systolic BP (r(2)=0.99) and the degree of BP lability (r(2)=0.99) during the
      phenylephrine infusion, the amount of osteopontin expressed in the initial
      biopsy/nephrectomy (r(2)=0.74), and the final glomerular filtration rate
      (r(2)=0.58). These studies provide a mechanism by which a markedly elevated
      sympathetic nervous system can induce salt-dependent hypertension even when the
      hyperactive sympathetic state is no longer engaged.

PMID- 10406840
TI  - Evolutionary considerations in relating oligosaccharide diversity to biological
      function.
AB  - The oligosaccharide chains (glycans) attached to cell surface and extracellular
      proteins and lipids are known to mediate many important biological roles.
      However, for many glycans, there are still no evident functions that are of
      obvious benefit to the organism that synthesizes them. There is also no clear
      explanation for the extreme complexity and diversity of glycans that can be found
      on a given glycoconjugate or cell type. Based on the limited information
      available about the scope and distribution of this diversity among taxonomic
      groups, it is difficult to see clear trends or patterns consistent with different
      evolutionary lineages. It appears that closely related species may not
      necessarily share close similarities in their glycan diversity, and that more
      derived species may have simpler as well as more complex structures. Intraspecies
      diversity can also be quite extensive, often without obvious functional
      relevance. We suggest one general explanation for these observations, that glycan
      diversification in complex multicellular organisms is driven by evolutionary
      selection pressures of both endogenous and exogenous origin. We argue that
      exogenous selection pressures mediated by viral and microbial pathogens and
      parasites that recognize glycans have played a more prominent role, favoring
      intra- and interspecies diversity. This also makes it difficult to appreciate and
      elucidate the specific endogenous roles of the glycans within the organism that
      synthesizes them.

PMID- 10406841
TI  - Pseudomonas aeruginosa binds to neoglycoconjugates bearing mucin carbohydrate
      determinants and predominantly to sialyl-Lewis x conjugates.
AB  - Pseudomonas aeruginosa plays an important role in the colonization of the airways
      of patients suffering from cystic fibrosis. It binds to the carbohydrate part of
      respiratory and salivary mucins and its binding to cystic fibrosis mucins is even
      higher, suggesting that qualitative or/and quantitative modifications of the
      carbohydrate chains may be involved in this process. In order to find out the
      best carbohydrate receptors for P.aeruginosa, a flow cytometry technique using a
      panel of polyacrylamide based glycoconjugates labeled with fluorescein was
      developed. The neoglycoconjugates contained neutral, sialylated or sulfated
      chains analogous to carbohydrate determinants found at the periphery of
      respiratory mucins (Le(a), Le(y), Le(x), sialyl- and 3'-sulfo-Le(x), and blood
      group A determinants). We used also neoglycoconjugates containing Gal(alpha1
      2)Galbeta and sialyl- N -acetyllactosamine determinants. The interaction of these
      glycoconjugates with the nonpiliated strain of P.aeruginosa, 1244-NP, was
      saturable except for the glycoconjugates containing blood group A or sialyl- N 
      acetyllactosamine epitopes. The measure of Kd indicated that strain 1244-NP had a
      higher affinity for the glycoconjugate bearing the sialyl-Le(x)determinant than
      for all the other glycoconjugates studied. The role of sialic acid was confirmed
      by competition assay using mainly sialylated mucin glycopeptides. In order to
      find out if this behavior was the same for pathological strains as for the 1244
      NP mutant, four mucoid strains of P.aeruginosa isolated from cystic fibrosis
      patients were analyzed with the Le(x)neoglycoconjugate, its sialylated and its
      sulfated derivatives. Individual variations in the binding of these strains to
      the three glycoconjugates were observed. However, three strains out of four had a
      higher affinity for the sialyl-Le(x)than for the 3'-sulfo-Le(x)derivative.

PMID- 10406842
TI  - Fingerprinting of large oligosaccharides linked to ceramide by matrix-assisted
      laser desorption/ionization time-of-flight mass spectrometry: highly
      heterogeneous polyglycosylceramides of human erythrocytes with receptor activity
      for Helicobacter pylori.
AB  - Highly microheterogeneous polyglycosylceramides (PGCs) of human erythrocytes with
      an average composition of about 25 monosaccharides linked to ceramide were
      analyzed by matrix-assisted laser desorption-ionization time-of-flight mass
      spectrometry (MALDI-TOF MS). The human gastric pathogen Helicobacter pylori was
      earlier shown to bind this glycosphingolipid mixture by thin-layer chromatogram
      binding assay. The receptor activity was present along the whole nonresolved
      chromatographic interval. Mass spectra of intact PGCs were compared with
      corresponding spectra of oligosaccharides enzymatically released from the
      ceramides. Two subfractions of PGCs containing less than one and more than one
      sialic acid residue per molecule were used. MALDI-MS spectra were recorded in
      both linear and reflectron mode with the accuracies of </=0.08% and </=0.02%,
      respectively, which allowed determination of the constituent parts of the
      detected ions in form of ceramide and number of hexoses, N-acetylhexosamines,
      fucoses and sialic acids. Molecular species were found based on ceramide with
      mainly sphingosine and fatty acids 24:0 and 24:1 (with less amounts of 22:0), and
      with a total number of monosaccharides ranging from 11 (neutral, m/z = 2605 for
      [M+Na](+)) to 41 (one sialic acid, m/z = 8057 for [M-H](-)). The saccharide
      composition obtained supported a successively extended and branched N 
      acetyllactosamine core with substitutions of fucoses (0 up to 8) and sialic acid
      (0 to 1). The reliable molecular analysis of large oligosaccharides linked to
      ceramide using this approach will be of great help for the further structure
      analysis in order to define the epitope for the sialic acid-dependent binding by
      the bacterium.

PMID- 10406843
TI  - Molecular cloning and characterization of cDNA coding for beta1, 2N
      acetylglucosaminyltransferase I (GlcNAc-TI) from Nicotiana tabacum.
AB  - In plants as well as in animals beta1, 2N-acetylglucosaminyltransferase I (GlcNAc
      TI) is a Golgi resident enzyme that catalyzes an essential step in the
      biosynthetic pathway leading from oligomannosidic N-glycans to complex or hybrid
      type N-linked oligosaccharides. Employing degenerated primers deduced from known
      GlcNAc-TI genes from animals, we were able to identify the cDNA coding for GlcNAc
      TI from a Nicotiana tabacum cDNA library. The complete nucleotide sequence
      revealed a 1338 base pair open reading frame that codes for a polypeptide of 446
      amino acids. Comparison of the deduced amino acid sequence with that of already
      known GlcNAc-TI polypeptides revealed no similarity of the tobacco clone within
      the putative cytoplasmatic, transmembrane, and stem regions. However, 40%
      sequence similarity was found within the putative C-terminal catalytic domain
      containing conserved single amino acids and peptide motifs. The predicted domain
      structure of the tobacco polypeptide is typical for type II transmembrane
      proteins and comparable to known GlcNAc-TI from animal species. In order to
      confirm enzyme activity a truncated form of the protein containing the putative
      catalytic domain was expressed using a baculovirus/insect cell system. Using
      pyridylaminated Man(5)- or Man(3)GlcNAc(2)as acceptor substrates and HPLC
      analysis of the products GlcNAc-TI activity was shown. This demonstrates that the
      C-terminal region of the protein comprises the catalytic domain. Expression of
      GlcNAc-TI mRNA in tobacco leaves was detected using RT-PCR. Southern blot
      analysis gave two hybridization signals of the gene in the amphidiploid genomes
      of the two investigated species N. tabacum and N.benthamiana.

PMID- 10406844
TI  - Structural heterogeneity in the core oligosaccharide of the S-layer glycoprotein
      from Aneurinibacillus thermoaerophilus DSM 10155.
AB  - The surface layer glycoprotein of Aneurinibacillus thermoaerophilus DSM 10155 has
      a total carbohydrate content of 15% (by mass), consisting of O-linked
      oligosaccharide chains. After proteolytic digestion of the S-layer glycoprotein
      byPronase E and subsequent purification of the digestion products by gel
      permeation chromatography, chromatofocusing and high-performance liquid
      chromatography two glycopeptide pools A and B with identical glycans and the
      repeating unit structure -->4)-alpha-l-Rha p -(1-->3)-beta-d- glycero -d- manno 
      Hep p -(1--> (Kosma et al., 1995b, Glycobiology, 5, 791-796) were obtained.
      Combined evidence from modified Edman-degradation in combination with liquid
      chromatography electrospray mass-spectrometry and nuclear magnetic resonance
      spectroscopy revealed that both glycopeptides contain equal amounts of the
      complete core structure alpha-l-Rha p -(1-->3)-alpha-l-Rha p -(1-->3)-beta-d-Gal
      p NAc-(1-->O)-Thr/Ser and the truncated forms alpha-l-Rha p -(1-->3)-beta-d-Gal p
      NAc-(1-->O)-Thr/Ser and beta-d-Gal p NAc-(1-->O)-Thr/Ser. All glycopeptides
      possessed the novel linkage types beta-d-Gal p NAc-(1-->O)-Thr/Ser. The different
      cores were substituted with varying numbers of disaccharide repeating units. By
      300 MHz proton nuclear magnetic resonance spectroscopy the complete carbohydrate
      core structure of the fluorescently labeled glyco-peptide B was determined after
      Smith-degradation of its glycan chain. The NMR data confirmed and complemented
      the results of the mass spectroscopy experiments. Based on the S-layer
      glycopeptide structure, a pathway for its biosynthesis is suggested.

PMID- 10406845
TI  - Genomic organization and promoter activity of glucosidase I gene.
AB  - Glucosidase I initiates the processing of asparagine (N-) linked glycoproteins by
      removing the distal alpha1,2-linked glucosyl residue of the tetradecasaccharide
      Glc(3)Man(9)GlcNAc(2). The gene encoding this enzyme was isolated and its
      structural organization and promoter activity determined. The major transcript
      for glucosidase I on northern blot appeared to be 3.1 kb; Southern blotting and
      DNA sequencing indicated the size of the gene to be 6.8 kb, comprising four exons
      separated by three introns. The first exon encodes the cytoplasmic tail and
      transmembrane domain; the fourth encodes the putative catalytic domain of the
      enzyme. Exon-intron junctions are flanked by consensus splice donor and acceptor
      sequences. Transcription initiation sites were mapped by primer extension,
      ribonuclease protection assay and RT-PCR analysis. Primer extension results
      showed multiple initiation sites at -150, -156, and -272 bp relative to the
      translation initiation codon ATG. Sequence analysis of 5' flanking region showed
      no canonical TATA box, a high GC content, Sp1 and ETF binding sites (typical of a
      housekeeping gene promoter). Also noteworthy, the promoter region contains
      several generic STAT factor binding sites, one nearly perfect, and two half GR
      binding elements. Other cis- acting elements recognized by transcription factors
      such as AP-2, NF-kappaB, estrogen receptor, and progesterone receptor (PR) were
      also present in the putative promoter region. To determine the promoter activity,
      a construct encompassing the region between -2114 to -5 bp of the putative
      promoter was ligated to the chloramphenicol acetyltransferase (CAT) reporter
      plasmid and transiently transfected into COS 7 cells. CAT assay results clearly
      show transcriptional activity of the promoter.

PMID- 10406846
TI  - Evaluation of high-performance anion-exchange chromatography with pulsed
      electrochemical and fluorometric detection for extensive application to the
      analysisof homologous series of oligo- and polysialic acids in bioactive
      molecules.
AB  - Our previous studies have shown extensively diverse structures in oligo/polymers
      of sialic acid (oligo/polySia) that are expressed often in developmentally
      regulated manner on animal glycoconjugates. The aim of this study was to
      establish highlysensitive and specific methods that can be used to identify
      diverse types of oligo/polySia and thus can be applied to studies of biological
      phenomena associated with the differential expression of oligo/polySia chains
      with different degree of polymerization (DP). As model compounds, we analyzed
      five different homologous series of oligo/polySia, (-->8Neu5Acalpha2-->)(n), (-
      >9Neu 5Acalpha2-->)(n), (-->8Neu5Gcalpha2-->)(n), (-->5-O(glycolyl)-Neu5Gcalpha2-
      >)(n), and Neu5Gc9SO(4)alpha2-->(-->5-O(glycolyl)-Neu5Gcalpha2--> )(n),
      ()expressed in various biopolymers. The latter two structures have recently been
      identified in sea urchin egg receptor for sperm. First we examined application of
      high-performance anion-exchange chromatography (HPAEC) on a CarboPac PA-100
      column with pulsed electrochemical detection (PED) to new types of
      oligo/polySiacompounds and confirmed that resolution of high polymers (DP >70) of
      sialic acids was remarkable as reported previously. However, there are
      limitations in sensitivity and selectivity in PED that become significant when
      material is available only in a minute amount or material contained a large
      proportion of protein. These limitations can be circumvented by fluorometric
      detection of oligo/polySia tagged with 1,2-diamino-4, 5-methyl-enedioxybenzene
      (DMB) at the reducing terminal residues after separation on a MonoQ HR5/5 column.
      The latter method can be applied to any type of oligo/polySia we examined if we
      choose the derivatization conditions and is more sensitive and specific than the
      method with PED for analysis of oligo/polySia with DP up to 25.

PMID- 10406847
TI  - Role of a conserved acidic cluster in bovine beta1,4 galactosyltransferase-1
      probed by mutagenesis of a bacterially expressed recombinant enzyme.
AB  - The truncated catalytic domain of bovine beta1,4 galactosyltransferase-1 was
      expressed as inclusion bodies in E.coli and folded to generate 10-15 mg of active
      enzyme per liter of bacterial culture after extraction and purification under
      denaturing conditions. Mutations were introduced to investigate the roles of
      Trp312, Asp318, and Asp320, components of a highly conserved region of sequence
      in all known beta4GT-1 homologues that includes a cluster of acidic residues.
      Near and far UV CD spectra of the mutants indicate that the substitutions did not
      perturb the secondary and tertiary structure of beta4GT-1, and steady state
      kinetic studies indicate only minor effects on the response to an essential metal
      cofactor. However substitutions for the two aspartyl residues result in a
      reduction in catalytic efficiency of a magnitude that suggests they are important
      for catalysis. It seems possible that this anionic center may act in stabilizing
      a carbocation formed from the galactose component of the donor substrate in the
      transition state, reflecting a common reaction mechanism for beta
      galactosyltransferase reactions.

PMID- 10406849
TI  - Vesicular-integral membrane protein, VIP36, recognizes high-mannose type glycans
      containing alpha1-->2 mannosyl residues in MDCK cells.
AB  - The 36 kDa vesicular-integral membrane protein, VIP36, has been originally
      isolated from MDCK cells as a component of glycolipid-enriched detergent
      insoluble complexes containing apical marker proteins, and its luminal domain
      shows homology to leguminous plant lectins and ERGIC-53. As the first step to
      identify the functional role of VIP36, the carbohydrate binding specificity of
      VIP36 was investigated using a fusion protein of glutathione- S -transferase and
      luminal domain of VIP36 (Vip36). It was found that VIP36 recognizes high-mannose
      type glycans containing alpha1-->2 Man residues and alpha-amino substituted
      asparagine. The binding of Vip36 to high-mannose type glycans was independent of
      Ca(2+)and theoptimal condition was pH 6.0 at 37 degrees C. The concentration at
      which half inhibition of the binding by Man(7-9).GlcNAc(2). N Ac. Asn occurred
      was 1.0 x 10(-9)M. The association constant between Man(7-9).GlcNAc(2)in porcine
      thyroglobulin and immobilized Vip36 was 2.1 x 10(8)M(-1)as determined by means of
      a biosensor based on surface plasmon resonance. These results indicate that VIP36
      functions as an intracellular lectin recognizing glycoproteins which possess high
      mannose type glycans, (Manalpha1-->2)(2-4).Man(5). GlcNAc(2).

PMID- 10406848
TI  - Glycosylation of a CNS-specific extracellular matrix glycoprotein, tenascin-R, is
      dominated by O-linked sialylated glycans and "brain-type" neutral N-glycans.
AB  - As a member of the tenascin family of extracellular matrix glycoproteins,
      tenascin-R is located exclusively in the CNS. It is believed to play a role in
      myelination and axonal stabilization and, through repulsive properties, may
      contribute to the lack of regeneration of CNS axons following damage. The
      contrary functions of the tenascins have been localized to the different
      structural domains of the protein. However, little is known concerning the
      influence of the carbohydrate conjugated to the many potential sites for N - and
      O -glycosylation (10-20% by weight). As a first analytical requirement, we show
      that >80% of the N -glycans in tenascin-R are neutral and dominated by complex
      biantennary structures. These display the "brain-type" characteristics of outer
      arm- and core-fucosylation, a bisecting N -acetylglucosamine and, significantly,
      an abundance of antennae truncation. In some structures, truncation resulted in
      only a single mannose residue remaining on the 3-arm, a particularly unusual
      consequence of the N -glycan processing pathway. In contrast to brain tissue,
      hybrid and oligomannosidic N -glycans were either absent or in low abundance. A
      high relative abundance of O -linked sialylated glycans was found. This was
      associated with a significant potential for O -linked glycosylation sites and
      multivalent display of the sialic acid residues. These O -glycans were dominated
      by the disialylated structure, NeuAcalpha2-3Galbeta1-3(NeuAcalpha2-6)GalNAc. The
      possibility that these O -glycans enable tenascin-R to interact in the CNS either
      with the myelin associated glycoprotein or with sialoadhesin on activated
      microglia is discussed.

PMID- 10406888
TI  - Genotoxic studies of vanadium pentoxide (V(2)O(5)) in male mice. II. Effects in
      several mouse tissues.
AB  - Vanadium pentoxide (V2O5) was tested for its ability to induce genotoxic damage
      in six different organs (liver, kidney, lung, spleen, heart, and bone marrow) of
      mice by using the alkaline Single Cell Gel Electrophoresis (SCGE) assay. Animals
      were sacrificed 24 h after i.p. administration of the vanadium pentoxide of 23.0,
      11.5, or 5.75 microg/g (corresponding to the LD50, 1/2 LD50 and 1/4 LD50,
      respectively). In all tissues and organs evaluated (except for bone marrow), V2O5
      increased the number of cells with damage. Our results showed that i.p. injection
      of V2O5 induced DNA damage in different organs and tissues, and that this kind of
      damage can be observed even 24 h after treatment. The analysis of DNA migration
      and the distribution of DNA damage showed that there are differences in
      sensitivity between organs and tissues to this compound. In addition the
      sensitivity of SCGE assay allows the detection of long term DNA damage and the
      possibility to compare it in various tissues and target organs.

PMID- 10406889
TI  - Effects of glutathione depletion on selenite- and selenate-induced embryotoxicity
      in cultured rat embryos.
AB  - Effects of depletion of reduced glutathione (GSH) on selenium (Se) embryotoxicity
      in cultured rat embryos were examined. Rat embryos at day 9.5 of gestation were
      cultured for 48 h in the presence of Se as either sodium selenite at 10 and 20
      microM or sodium selenate at 30 and 100 microM. Embryonic GSH was depleted by the
      addition of 0.1 mM of L-buthionine-[S,R]-sulfoximine (BSO) without
      embryotoxicity, i.e., significant growth retardation and malformation of the
      embryos. Selenite at 10 microM or selenate at 100 microM significantly increased
      the incidence of malformation of the embryos. The incidence of selenite-induced
      malformation of the embryos at 20 microM was significantly decreased with BSO. On
      the contrary, the incidence of selenate-induced malformation at 30 microM was
      significantly increased with BSO. It was noted that the major malformed regions
      of the embryos by the embryotoxic concentration of BSO alone were the same to
      those affected by selenite or selenate. It was considered from these results that
      embryonic GSH was involved in the embryotoxicity of selenite and selenate. The
      embryotoxicity of selenate may not be mediated through the reduction to selenite.
      It was suggested that the formation of selenodiglutathione and the oxidative
      stress were involved in the embryotoxicity of selenite and selenate,
      respectively.

PMID- 10406890
TI  - Induction of micronuclei in mouse bone marrow after combined X-rays
      cyclophosphamide and X-rays-mitomycin C treatments.
AB  - The induction of micronuclei in polychromatic erythrocytes of bone marrow of
      Pzh:SWISS mice after combined treatment with X-rays and cyclophosphamide (CP) or
      X-rays and mitomycin C (MMC) were investigated. Combinations of high (1.00 Gy +
      100 mg/kg bw CP and 1. 00 Gy + 5.25 mg/kg bw MMC) and low (0.25 Gy + 25 mg/kg bw
      CP and 0. 25 Gy + 1.75 mg/kg bw MMC) doses were used. Both chemicals enhanced the
      mutagenic effects caused by irradiation. After combined treatment with high doses
      of X-rays + CP and X-rays + MMC at different sample times increases in frequency
      of micronuclei were observed. Mutagenic effects were found also after treatment
      with two low doses, when irradiation alone produced no effects. The effects of
      combined treatments are generally similar to the additive effect of the single
      treatments.

PMID- 10406891
TI  - Effect of some phthalate esters in human cells in the comet assay.
AB  - Phthalate esters are among the most extensively used industrial chemicals and are
      widely distributed in the environment. Di-(2-ethylhexyl)phthalate (DEHP) and its
      hydrolysis product mono-(2-ethylhexyl)phthalate (MEHP) have been examined for
      genotoxic activity on previous occasions. Only MEHP was found to cause chromosome
      damage in CHO cells but was without effect in the sister chromatid exchange and
      hypoxanthine guanine phosphoribosyl assay. DEHP was found to be a weak direct
      acting mutagen in Salmonella typhimurium strain TA100, the mutagenic activity of
      which could be abolished by rat liver microsomes (S9 mix). The clastogenicity and
      weak mutagenicity suggest a possible contributory role for these compounds in the
      observed carcinogenicity of the phthalates, which have been thought predominantly
      to be linked to cancer pathology through proliferation of hepatic peroxisomes.
      The present study showed that these compounds could produce DNA damage in human
      blood cells in the Comet assay and also, that rat liver microsomes could abolish
      the effect of DEHP. Thus in the intact animal, no response may be observed.

PMID- 10406892
TI  - A study of ENU-induced mutagenesis in the mouse using the restriction site
      mutation (RSM) assay.
AB  - We report here the application of the restriction site mutation (RSM) assay to
      study the induction of mutations by the alkylating agent ENU. Specifically,
      mutations were sought in the spleen and bone marrow of mice 3, 10, and 100 days
      after being treated with ENU; this was compared to data previously published from
      our laboratory on ENU-induced testes mutations. It was found that the ENU-induced
      mutations were all at GC bases implicating the O(6)-ethylguanosine adduct. The
      mutations detected reached a peak at day 10 in the spleen and were detectable to
      a lesser extent at 100 days, which is similar to the testes data. In the bone
      marrow, the mutation level rose until day 100, although the level remained below
      that of the spleen and testes. However, by studying the mutations detected in
      control animals, it was found that spontaneous mutational events were detectable
      at the day 100 time point in all three tissues. Hence the spleen, testes, and
      bone marrow mutations at day 100 in the ENU-treated samples were probably
      spontaneous mutational events with very few genuine ENU-induced mutations
      remaining in any of these tissues after 100 days. This paper also demonstrates
      the applicability of the inverse RSM methodology in the detection of ENU-induced
      mutations, whereby mutations can be detected by the conversion of one restriction
      site to another. The iRSM assay appears to be particularly suitable to studying
      alkylating agents due to their known sequence specific mutation induction. We
      also show a comparison of the bone marrow micronucleus data with the RSM assay
      and show that both assays are capable of detecting the genotoxicity of ENU to the
      mouse bone marrow in vivo.

PMID- 10406893
TI  - Effects of uracil calculi on cell growth and apoptosis in the BBN-initiated
      Wistar rat urinary bladder mucosa.
AB  - The different potential of initiated and non-initiated urinary bladder mucosa
      (UBM) to develop neoplasia was quantitatively evaluated in the male Wistar rat.
      Initiation of carcinogenesis was accomplished with N-butyl-N-(4-hydroxybutyl)
      nitrosamine (BBN). Stimuli for cell proliferation and apoptosis were obtained by
      exposure followed by withdrawal of 3% Uracil in the diet. The proliferation index
      (PI) was estimated in UBM immunostained for the proliferating nuclear cell
      antigen (PCNA). The apoptotic index (AI) and the density of papillary/nodular
      hyperplasia (PNH) were estimated in hematoxilin-eosin stained sections. PNH was
      the main proliferative response to the mechanical irritation by uracil,
      irrespective of previous initiation with BBN. Uracil exposure induced higher PI
      and PNH density in the initiated rats. After uracil withdrawal, there was a
      significant increase of the AI in both uracil-treated groups, which correlated
      well to the respective PNH density. However, at the end of the experiment, PNH
      incidence and density were significantly higher in the BBN-initiated mucosa,
      which also presented 18% incidence of papillomas and 27% of carcinomas.
      Therefore, under prolonged uracil calculi trauma, the UBM of BBN-initiated Wistar
      rats gives rise to epithelial proliferative lesions that progress to neoplasia
      through acquired resistance to apoptosis.

PMID- 10406894
TI  - Genotoxicity studies on the phenoxyacetates 2,4-D and 4-CPA in the Drosophila
      wing spot test.
AB  - The phenoxyacetates 2,4-D and 4-CPA were evaluated for genotoxicity using the
      Drosophila melanogaster wing spot test, which assesses for somatic mutation and
      recombination events. Third-instar larvae trans-heterozygous for two recessive
      mutations affecting the expression of wing trichomes, multiple wing hairs (mwh),
      and flare (flr) were treated by chronic feeding with different concentrations of
      the two chemicals. Feeding lasted until pupation of the surviving larvae and the
      genotoxic effects induced were evaluated in adults for the appearance of wing
      blade cell clones with the mwh, flr, or mwh-flr phenotypes. Exposure to 2,4-D, at
      the highest concentration evaluated (10 mM), induced a weak but significant
      increase in the frequency of two of the categories of recorded spots: large
      single and total spots; in contrast, the 4-CPA treatments failed to induce any
      significant increase in the frequency of evaluated spots. When the heterozygous
      larvae for mwh and the multiple inverted TM3 balancer chromosome were treated
      with the chemicals, no increases were detected, either after the 2,4-D nor the 4
      CPA treatments.

PMID- 10406895
TI  - The contribution of autologous transplant in lymphoma.

PMID- 10406896
TI  - The scientific appeal of malignant lymphomas.

PMID- 10406897
TI  - Frequent mutation of bcl-6 proto-oncogene in high grade, but not low grade, MALT
      lymphomas of the gastrointestinal tract.
AB  - BACKGROUND AND OBJECTIVE: Knowledge regarding the molecular pathogenesis and
      histogenesis of gastrointestinal mucosa-associated lymphoid tissue non-Hodgkin's
      lymphomas (MALT-NHL) is limited. Mutations of BCL-6, a zinc finger transcription
      factor implicated in lymphoid development, occur frequently in lymphomas and
      represent a histogenetic marker of B-cell transit through the germinal center.
      The distribution of BCL-6 mutations in gastrointestinal MALT-NHL was analyzed in
      this study. DESIGN AND METHODS: This study was based on 26 gastrointestinal MALT
      NHL, including 16 cases of low grade histology and 10 cases of high grade
      histology. Mutations of BCL-6 were investigated by a combination of polymerase
      chain reaction-single strand conformation polymorphism and DNA direct sequencing
      analysis. RESULTS: Mutations of BCL-6 occurred in 6/10 high grade MALT-NHL,
      whereas they were absent from all low grade cases tested (n = 16; p = 0.001).
      MALT-NHL harboring BCL-6 mutations included 5 cases of gastric MALT-NHL and 1
      case of jejunal MALT-NHL. Mutations were predominantly represented by single
      nucleotide substitutions which were multiple in most cases. All sequence
      alterations were unique to individual cases of gastrointestinal MALT-NHL.
      INTERPRETATION AND CONCLUSIONS: Mutations of BCL-6 occur frequently in high grade
      gastrointestinal MALT-NHL and display characteristics similar to those of BCL-6
      mutations harbored by other B-cell lymphomas. The association of high grade MALT
      NHL with BCL-6 mutations corroborates their histogenetic derivation from germinal
      center-related B-cells and may be of potential pathogenetic relevance for these
      disorders.

PMID- 10406898
TI  - 13q14 deletion in non-Hodgkin's lymphoma: correlation with clinicopathologic
      features.
AB  - BACKGROUND AND OBJECTIVE: 13q14 deletion frequently occurs as a single anomaly in
      chronic lymphocytic leukemia (CLL) with favorable prognosis. This study was
      performed to assess the distribution of 13q14 deletion in non-Hodgkin's lymphoma
      (NHL) and to analyze its correlation with salient clinicopathologic features.
      DESIGN AND METHODS: One hundred and twenty-five NHL were analyzed by cytogenetics
      and by interphase fluorescence in situ hybridization (FISH), using a 13q14 cosmid
      probe recognizing DNA sequences between the Rb gene and the D13S25 marker.
      Clinical records all patients were surveyed. RESULTS: A 13q14 rearrangement was
      present in the stemline in 10 patients; 15 additional cases were shown by FISH to
      carry 13q14 deletion in 55-90% of the interphase cells, giving a 20% overall
      incidence for this anomaly. Six of 44 patients had a low-grade NHL, 14/28 had
      mantle cell lymphoma (MCL), 5/42 had a high grade NHL (p<0.0001). There was not
      correlation between 13q, karyotype status and complexity. A statistically
      significant association was found between 13q-, presence of splenomegaly and PB
      involvement, lower probability of attaining complete remission (CR) and shorter
      survival. These findings were not simply a function of the association of 13q-
      with MCL. In multivariate analysis, a complex karyotype had prognostic importance
      (p=0.0078), along with age (p=0.01), histology (p=0.001), LDH (p=0.03), PS
      (p=0.001), sex (p=0.03) and splenomegaly (p=0.02). INTERPRETATION AND
      CONCLUSIONS: 13q14 deletion represented an early chromosome change and showed a
      preferential association with MCL, though it was found in virtually all principal
      histologic subtypes, irrespective of clinical stage, karyotype status and
      complexity. Patients with 13q14 deletions had a low CR rate, suggesting that
      genes relevant to lymphomagenesis are located in this chromosome segment that
      warrants molecular cytogenetic investigation.

PMID- 10406899
TI  - Secondary chromosome changes in mantle cell lymphoma.
AB  - BACKGROUND AND OBJECTIVE: Mantle cell lymphomas (MCLs) comprise a rare but
      distinct clinicopathological entity usually associated with t(11;14). This
      translocation is regarded as a primary event, but it has been suggested that
      other as yet unidentified genetic alterations are required for development and
      progression of MCL. DESIGN AND METHODS: In order to identify recurrent secondary
      changes that might point towards specific chromosomal regions contributing to the
      pathogenesis of MCL we studied 43 MCL cases in which clonal chromosomal
      abnormalities have been found during cytogenetic analysis. RESULTS: In this
      series 83% of cases were characterized by t(11;14) and in the majority of them
      the t(11;14) was associated with multiple other chromosomal aberrations.
      Recurrent secondary changes were found in which imbalances of genetic material
      prevailed, losses being more common than gains. The former involved thirteen
      chromosomes, especially 13, 6q, 9q, 11q, 8/8p, 10/10p, and 14, whereas recurrent
      gains affected 3/3q. Non-randomly occurring breakpoints were relatively
      infrequent. The identified anomalies were also involved in aberrations observed
      in the group of MCL not associated with t(11;14). Some of them are shared with
      other B-cell proliferations. INTERPRETATION AND CONCLUSIONS: The data presented
      here indicate that MCL is characterized by consistently occurring secondary
      chromosome changes. Their significance for the development and/or progression of
      MCL needs to be elucidated and confirmed by further investigations.

PMID- 10406900
TI  - Core needle biopsy is effective in the initial diagnosis of mediastinal lymphoma.
AB  - BACKGROUND AND OBJECTIVE: With the development and refinement of guidance
      modalities for percutaneous biopsies, many investigators have reported studies
      supporting the role of guided core needle biopsy in the diagnosis of mediastinal
      lymphoma. The aims of this report are to evaluate the efficacy of findings at
      core needle biopsy of mediastinal masses on patient care and define the key
      determinants of clinical success. DESIGN AND METHODS: Fluoroscopy-guided (in 75
      patients) and computed tomography-guided (in 8 patients) core needle biopsies
      were performed in 83 patients with mediastinal lymphoma: all but one of the
      patients were at first diagnosis. All the biopsies were performed using a
      Menghini needle (from 1.2 mm to 1.8 mm). In the vast majority of cases the 1.8 mm
      gauge was employed. RESULTS: The overall sensitivity for the diagnosis of
      lymphoma was 81% (67/83 cases). In the remaining 16 patients the lymphoma
      diagnosis was reached either by mediastinoscopy (11 cases) or anterior
      mediastinotomy (3 cases) or core needle biopsy of the lung (1 case); one patient
      was treated directly after the needle biopsy had been unsuccessful because he
      needed rapid therapy. In 77/82 (93%) patients it was possible to assess the
      specific histotype. There was no operative mortality; all the biopsies were
      performed on an outpatient basis. INTERPRETATION AND CONCLUSIONS: Our data
      indicate that core needle biopsy should be considered as an effective and safe
      procedure in the diagnosis of patients with mediastinal lymphoma with the
      possibility of determining the tumor subtype and subsequent specific treatment.

PMID- 10406901
TI  - Diagnostic role of gallium scanning in the management of lymphoma with
      mediastinal involvement.
AB  - BACKGROUND AND OBJECTIVE: Therapy of both Hodgkin's disease (HD) and aggressive
      non-Hodgkin's lymphoma (NHL) with mediastinal presentation at the time of
      diagnosis is frequently followed by radiological detection of residual masses.
      Computed tomography (CT) scanning is generally unable to detect the differences
      between tumor tissue and fibrosis. Gallium-67-citrate single photon emission
      ((67)GaSPECT) can potentially differentiate residual active tumor tissue from
      fibrosis. DESIGN AND METHODS: Seventy-five patients with HD or aggressive NHL
      presenting mediastinal involvement (64% with a bulky mass) were studied with CT
      and (67)GaSPECT at the end of combined modality therapy (chemo- and radiation
      therapy). RESULTS: After treatment, 3/3 (100%) patients with positive (67)GaSPECT
      and negative CT scan relapsed while only 1/18 (6%) patients with both negative
      (67)GaSPECT and CT scan did so. At the same time, 54 patients had a positive
      restaging CT scan (abnormal mass < 10% of size of initial mass). Of these
      patients, 13 had a positive (67)GaSPECT, 10 of whom (77%) relapsed; 41 had a
      negative (67)GaSPECT of whom 5 (12%) relapsed. The 4-year actuarial relapse-free
      survival rate was 90% for those with negative scans compared with 23% for gallium
      positive patients (p < 0.000000). INTERPRETATION AND CONCLUSIONS: In lymphoma
      patients with mediastinal involvement, (67)GaSPECT should be considered, at least
      in patients who are CT positive, the imaging technique of choice for monitoring
      and differentiating the nature of any residual masses.

PMID- 10406902
TI  - Usefulness of thrombopoietin in the diagnosis of peripheral thrombocytopenias.
AB  - BACKGROUND AND OBJECTIVE: Thrombocytopenia of peripheral origin is basically due
      to platelet destruction or splenic sequestration. Thrombopoietin (TPO) regulates
      platelet production stimulating megakaryocyte proliferation and maturation. The
      evaluation of TPO levels may be a useful tool in the diagnosis of
      thrombocytopenias of unknown origin. We tried to determine the value of TPO
      levels in some thrombocytopenias classically considered as peripheral. DESIGN AND
      METHODS: Serum TPO levels and platelet counts were measured in 32
      thrombocytopenic patients with liver cirrhosis (LC) and 23 with chronic hepatitis
      C (CHC) viral infection, in 54 patients with a clinical and serological diagnosis
      of autoimmune thrombocytopenic purpura (AITP), and in 88 patients infected with
      the human immunodeficiency virus (HIV). RESULTS: Patients with LC, AITP and HIV
      had lower platelet counts than patients with CHC. The degree of thrombocytopenia
      did not, however, correlate with the TPO levels. HIV infected patients (246+/-304
      pg/mL) and AITP patients (155+/-76 pg/mL) had higher TPO levels than controls
      (121+/-58 pg/mL). TPO levels in patients with CHC (125+/-40 pg/mL) did not differ
      from those in control subjects, but were slightly decreased in patients with LC
      (104+/-56 pg/mL). INTERPRETATION AND CONCLUSIONS: Reduced TPO production could be
      involved in the development of thrombocytopenia in LC patients, but not in
      patients with early stages of CHC viral infection. HIV and AITP patients had
      slightly raised levels of TPO. As TPO levels are normal or slightly increased in
      most peripheral thrombocytopenias, these data alone are not sufficient to
      distinguish the different types of peripheral thrombocytopenia. They may,
      however, be a useful tool for differentiating some central and peripheral
      thrombocytopenias.

PMID- 10406903
TI  - Evaluation of acquired platelet dysfunctions in uremic and cirrhotic patients
      using the platelet function analyzer (PFA-100 ): influence of hematocrit
      elevation.
AB  - BACKGROUND AND OBJECTIVE: Patients with end-stage renal disease or advanced
      cirrhosis develop bleeding disorders characterized by defective interaction of
      platelets with damaged subendothelium. The anemia associated with both clinical
      entities has a negative influence on hemostasis. We evaluated alterations of
      platelet function in patients suffering from end-stage renal disease (n=21) or
      hepatic cirrhosis (n=20) using standard aggregometric techniques and the recently
      developed platelet function analyzer (PFA-100 ). The impact of low hematocrit was
      also analyzed. DESIGN AND METHODS: The hemostatic capacity of platelets was
      tested in the PFA-100 using citrated blood and standard cartridges containing
      collagen-ADP (COL-ADP) or collagen-epinephrine (COL-Epi). The hemodynamic
      influence of hematocrit was also evaluated in blood aliquots in which hematocrit
      was experimentally increased by adding red blood cells from the same patient.
      RESULTS: Aggregation studies demonstrated abnormal responses to several agonists
      in both group of patients. Closure times obtained by the PFA-100 for control
      blood samples were 87+/-3 sec for COL-ADP and 113+/-5 sec with COL-EPi
      cartridges. Closure times in uremic and cirrhotic patients with average
      hematocrits of 0.26 and 0.27 respectively were significantly prolonged (139+/-12
      and 125+/-14 sec, respectively with COL-ADP and 194+/-29 and 151+/-15 sec with
      COL-Epi cartridges). A 5% increase in the hematocrit caused a reduction in the
      closure time to 111+/-7 sec (COL-ADP) and 143+/-14 sec (COL-Epi) in the uremic
      group and to 86+/-4 sec (COL-ADP) and 115+/-16 sec (COL-Epi) in the cirrhotic
      group. Our studies confirm the platelet dysfunction in uremic and cirrhotic
      patients. INTERPRETATION AND CONCLUSIONS: The PFA-100 device proved to be useful
      for testing alterations of primary hemostasis in these acquired disorders and was
      sensitive enough to detect modifications in hemostasis caused by elevations in
      hematocrit. Conventional aggregometric tests were able to identify the intrinsic
      platelet abnormality in uremic and cirrhotic conditions, while the PFA-100 seemed
      more sensitive in detecting the negative influence of the hematocrit reduction.

PMID- 10406904
TI  - Serum phospholipids are the main environmental determinants of activated factor
      VII in the most common FVII genotype. European Union Concerted Action "Clotart".
AB  - BACKGROUND AND OBJECTIVE: Numerous studies have emphasized the role of
      triglyceride-rich lipoproteins and of Factor VII (FVII) polymorphisms in
      determining levels of FVII activity. DESIGN AND METHODS: This study was
      undertaken to evaluate the role of other lipid fractions and the interaction
      between lipids and FVII in subjects with recognised genotypes. Volunteer subjects
      (n=459) from 5 European countries were studied. Blood samples were drawn
      irrespective of the time of day or fasting status. Levels of FVII activity
      (FVIIc), activated FVII (FVIIa) and FVII antigen (FVIIAg) were evaluated with
      reference to a number of lipid parameters (HDL-, LDL- and total cholesterol,
      triglycerides, phospholipids, lipoprotein(a), and apoliproptein A1). The two most
      common FVII polymorphisms were analyzed in combination (353R/Q and 5'F7; alleles
      M1/M2 and A1/A2, respectively). RESULTS: Homozygotes for the A1 and M1 alleles
      (M11/A11) had significantly higher FVII levels. At multiple regression analysis
      the strongest predictor of FVIIa and FVIIc was the concentration of
      phospholipids. This interaction was confined to the A11M11 genotype subjects.
      INTERPRETATION AND CONCLUSIONS: These data indicate that lipids contribute mainly
      to FVIIa levels through their phospholipid content, and that the degree of this
      contribution is strictly dependent on FVII genotypes.

PMID- 10406905
TI  - Homozygotes for prothrombin gene 20210 A allele in a thrombophilic family without
      clinical manifestations of venous thromboembolism.
AB  - BACKGROUND AND OBJECTIVE: A new genetic risk factor for venous thromboembolism
      has recently been described which involves a G to A transition at position 20210
      in the 3' untranslated region of the prothrombin gene. To date, only a few
      homozygotes for this mutation have been reported and in most of cases, they
      suffered from thrombotic disease. Here, we describe a pedigree including both
      heterozygous and homozygous subjects for prothrombin (PT) 20210 A. DESIGN AND
      METHODS: This family was recruited in 1996 as part of our GAIT (Genetic Analysis
      of Idiopathic Thrombophilia) project. To qualify for the GAIT study, a pedigree
      was required to have at least 10 living individuals in three or more generations
      (i.e. extended pedigree). The pedigrees were selected through probands with
      idiopathic thrombophilia. A complete set of plasma and DNA determinations related
      to hemostasis was performed on this family. RESULTS: The plasma studies yielded
      normal results in all of the individuals. The family members who had a history of
      thromboembolism were heterozygous carriers of the PT 20210 A variant. In
      addition, 4 relatives who were heterozygous, and two who were homozygous for this
      A allele, failed to show clinical manifestations. These two homozygotes were 51
      and 19 years old. INTERPRETATION AND CONCLUSIONS: This case exemplifies the
      complexity of thrombotic disease since individuals homozygous for a mutant gene
      do not exhibit symptoms while heterozygous individuals often do exhibit the
      disease. This case suggests that the new genetic risk factor for thrombosis (i.e.
      PT 20210 A) may not be as strong as most of the previously described genetic risk
      factors.

PMID- 10406906
TI  - Monitoring oral anticoagulant treatment from plasma stored for up to 48 hours and
      frozen plasma.
AB  - BACKGROUND AND OBJECTIVE: The number of patients being referred for lifelong
      anticoagulant treatment has increased markedly in the last years. The prothrombin
      time test is sometimes difficult to perform the same day as sample collection.
      The aim of this study is to determine International Normalized Ratio (INR) and
      vitamin-K dependent factor levels of frozen plasma and plasma stored for up 48
      hours. DESIGN AND METHODS: The INR of 84 patients receiving acenocoumarol were
      determined fresh (0 hours), on samples stored between 2 degrees C and 8 degrees C
      for 24 hours and 48 hours, and on frozen samples (-40 degrees C) using 4
      different thromboplastin reagents (Thromboplastin IS; Thromborel; Simplastin; and
      Thromboplastin D+G). In addition, factors II, VII, IX, X were determined in 34 of
      these patients in all these situations. We used the interclass correlation
      coefficient to compare the results obtained at 0 hours and the results obtained
      in the subsequent measurements. Both measurement and proportional errors were
      also estimated by linear regression analysis. RESULTS: The correlation
      coefficient of the INR between fresh and frozen plasma was 0.98, 0.98, 0.92 and
      0.97 for IS, Thromborel, Simplastin and D+G respectively. The correlation between
      0 and 24 hours was 0. 98, 0.91, 0.95 and 0.85 for IS, Thromborel, Simplastin and
      D+G respectively. By 48 hours although IS still had r=0.94, Thromborel,
      Simplastin, and D+G had r=0.55, r=0.50 and r=0.81, respectively. By 24 hours in
      stored plasma and in frozen plasma the activity of vitamin-K dependent factors
      was slightly reduced (r=0.97 at 24h/r=0. 94 with frozen plasma for factor II,
      r=0.92/0.96 for factor VII, r=0. 83/0.98 for factor IX, and r=0.98/0.95 for
      factor X). By 48 hours however, significant reductions were noted in the activity
      of these factors (r=0.94 for factor II, r=0.88 for factor VII, r=0.70 for factor
      IX, and r=0.98 for factor X). INTERPRETATION AND CONCLUSIONS: The INR can be
      reliable determined in frozen plasma and in plasma stored at 2-8 degrees C for up
      to 24 hours.

PMID- 10406907
TI  - The belgian experience in unrelated donor bone marrow transplantation:
      identification of center experience as an important prognostic factor.
AB  - BACKGROUND AND OBJECTIVE: We reviewed all unrelated donor bone marrow transplants
      (UDBMT) performed in Belgium up to December 1995 to identify prognostic factors
      for relapse, transplant-related mortality and survival. DESIGN AND METHODS: A
      total of 163 UDBMT were performed in 92 males and 71 females aged 1-55 (median
      26) years. Patients were transplanted for ALL (n=35), AML (n=34), CML (n=51),
      other myeloid malignancies (n=14), SAA (n=21) or miscellaneous other diseases
      (n=8). Most patients had advanced disease; a few patients were in CR1 (n=10) or
      early chronic phase (CP) of CML (n=5). RESULTS: Overall survival at 5 yrs was 17%
      (95% confidence interval: 8-32%), but survival was significantly better for
      patients with non-malignant disorders (55% at 4 yrs). The relapse rate +/-SE was
      projected to be 40 (28-54)% at 5 yrs, 36 (20-56)% for standard-risk and 68 (43
      85)% for high-risk malignancies (p=0.0029). There was no relapse in CML patients
      transplanted in 1st CP compared to 68% at 4 yrs with more advanced CML
      (p=0.0033). Grade II-IV acute graft-versus-host disease (aGVHD) occurred in 55%
      by day 100 and was strongly modulated by age, ranging from 41% in <20-yr-old to
      80% in >40-yr-old patients (p=0. 0021). Transplant-related mortality (TRM) was
      projected to be 72 (52-87)% at 5 yrs including 2 very late deaths from lung
      fibrosis and secondary cancer. Main causes of death were original disease in 27,
      secondary malignancy in 2, GVHD in 28, interstitial pneumonia in 21, other
      infections in 19, and miscellaneous toxic causes in 21 patients. In multivariate
      analysis, the relapse rate was strongly dependent on the disease status
      (p=0.0029), TRM being significantly worse with older age (p=0.0049), and overall
      survival being significantly worse in more advanced disease (p=0.0006), after a
      second transplant (p=0.0166), in centers of smaller size (p=0.0316) and in older
      patients (NS). INTERPRETATION AND CONCLUSIONS: Although results have improved
      somewhat in recent years, UDBMT remains a procedure with a high TRM. UDBMT should
      be performed in patients with less advanced diseases and in centers with more
      experience, particularly in the treatment of adult patients.

PMID- 10406908
TI  - Therapeutic potentials of angiostatin in the treatment of cancer.
AB  - The discovery of specific endothelial inhibitors such as angiostatin and
      endostatin not only increases our understanding of the functions of these
      molecules in the regulation of physiological and pathological angiogenesis, but
      also provides an important therapeutic strategy for cancer treatment. Recent
      studies have demonstrated that the angiostatin protein significantly suppresses
      the growth of a variety of tumors in mice. However, the dosages of angiostatin
      protein used in these animal studies seem to be too high for clinical trials. In
      addition, repeated injections and long-term treatment with angiostatin are
      required to reach its maximal antitumor effect. In this article, I will discuss
      several alternative approaches that may become feasible to move angiostatin
      therapy from animal experiments into the clinic. In particular, I will emphasize
      the therapeutic potentials of angiostatin gene therapy and more potent
      angiogenesis inhibitors that are related to angiostatin.

PMID- 10406909
TI  - AlphaIFN-induced hematologic and cytogenetic remission in chronic eosinophilic
      leukemia with t(1;5).
AB  - Chronic eosinophilic leukemia (CEL) is a myeloproliferative disease characterized
      by excessive eosinophilic proliferation with clonal cytogenetic abnormalities.
      The most frequent cytogenetic abnormality is a break in the q 31-35 region of
      chromosome 5, where genes encoding for IL-3, IL-5 and GM-CSF (all cytokines
      involved in eosinophilopoiesis) are located. We report the case of a patient with
      CEL with t(1;5) (q23;q31), who obtained complete hematologic and major
      cytogenetic response after two years of alpha-interferon (alpha-IFN) therapy. Two
      other cases of complete response to alpha-IFN are reported in the literature. A
      trial with alpha-IFN could be considered as front line treatment in this rare
      disease.

PMID- 10406910
TI  - Spur cell hemolytic anemia of severe liver disease.

PMID- 10406911
TI  - Anticoagulant pseudothrombocytopenia with platelet satellitism.

PMID- 10406912
TI  - Measurement of prothrombin time in patients on oral anticoagulant therapy: effect
      of two different evacuated tubes.

PMID- 10406913
TI  - Allogeneic peripheral blood stem cell transplantation in children with
      hematologic malignancies. AIEOP-BMT Group (Italian Association for Pediatric
      Hematology and Oncology-Bone Marrow Transplant Group)

PMID- 10406914
TI  - 4.2 Nippon mutation in a non-Japanese patient with hereditary spherocytosis.

PMID- 10406915
TI  - Nosocomial infections due to enterococci in patients with acute leukemia.

PMID- 10406916
TI  - Transplacental transmission of EDTA-dependent pseudothrombocytopenia.

PMID- 10406917
TI  - Autologous peripheral blood stem cell transplantation in a patient with multiple
      sclerosis and concomitant Ph+ acute leukemia.

PMID- 10406918
TI  - Life threatening lung toxicity induced by low doses of bleomycin in a patient
      with Hodgkin's disease.

PMID- 10406919
TI  - Intrauterine anemia due to parvovirus B19: successful treatment with intravenous
      immunoglobulins.

PMID- 10406920
TI  - Intramural hematoma of stomach after splenectomy for idiopathic thrombocytopenic
      purpura.

PMID- 10406921
TI  - Leukemoid reaction preceding the diagnosis of colorectal carcinoma by four years.

PMID- 10406922
TI  - Acenocoumarol and 6-mercaptopurine: an important drug interaction.

PMID- 10406923
TI  - Ambient air particles: effects on cellular oxidant radical generation in relation
      to particulate elemental chemistry.
AB  - Epidemiologic studies have reported causal relationships between exposures to
      high concentrations of ambient air particles (AAP) and increased morbidity in
      individuals with underlying respiratory problems. Polymorphonuclear leukocytes
      (PMN) are frequently present in the airways of individuals exposed to particles.
      Upon particulate stimulation the PMN may release reactive oxygen species (ROS),
      which can result in tissue damage and injury. In this study a wide range of AAP
      samples from divergent sources (1, natural dust; 2, oil fly ash; 2, coal fly ash;
      5, ambient air; and 1, carbon black) were analyzed for elemental content and
      solubility in relation to their ability to generate ROS. Elemental analyses were
      carried out in AAP and dH(2)O-washed AAP using energy dispersive x-ray
      fluorescence (XRF). Percent of sample mass accounted for by XRF-detectable
      elements was 1.2% (carbon black); 22-29% (natural dust and ambient air
      particles); 13-22% (oil fly ash particles); 28-49% (coal fly ash particles). The
      major proportion of elements in most of these particles were aluminosilicates and
      insoluble iron, except oil-derived fly ash particles in which soluble vanadium
      and nickel were in highest concentrations, consistent with particle acidity as
      measured in the supernatants. Human blood-derived monocytes and PMN were exposed
      to AAP and dH(2)O-washed particles, and generation of ROS was determined using
      luminol-enhanced chemiluminescence (LCL) assay. All the particles induced
      chemiluminescence response in the cells, except carbon black. The oxidant
      response of monocytes induced by AAP (with the exception of oil fly ash
      particles) was less than the response elicited by PMN. The LCL response of PMN in
      general increased with all washed particles, with oil fly ash (OFA) and one urban
      air particle showing statistically significant (p < 0. 05) differences between
      dH(2)O-washed and unwashed particles. The LCL activity in PMN induced by both
      particles and dH(2)O-washed particles was significantly correlated with the
      insoluble Si, Fe, Mn, Ti, and Co content of particles (p < 0.05). No relationship
      between LCL activity in PMN and soluble transition metals such as V, Cr, Ni, and
      Cu was noted. Pretreatment of the particles with a metal ion-chelator,
      deferoxamine, did not affect LCL in PMN, suggesting that metal ions are not
      related to the induction of LCL in PMN. Particulate S content and acidity of the
      particles as measured in the supernatants did not relate to LCL activity in PMN.
      These results point to the possibility that the insoluble constituents of the
      particles are related to LCL in PMN. Since some of these dusts are capable of
      depositing in the lungs and can cause infiltration of PMN, the ability to
      activate those cells may contribute to particulate toxicity.

PMID- 10406924
TI  - Effects of pre-existing rhinitis on ozone-induced mucous cell metaplasia in rat
      nasal epithelium.
AB  - Ozone causes rhinitis and nasal epithelial alterations. The toxicity of ozone on
      nasal airways with pre-existing rhinitis has not been investigated. The present
      study was designed to determine the effect of endotoxin-induced rhinitis on ozone
      induced epithelial alterations, especially mucous cell metaplasia (MCM), in the
      nasal transitional epithelium (NTE) of rats. Six h prior to daily inhalation
      exposure, male F344/N rats were intranasally instilled with saline or endotoxin
      (100 microgram/day). Rats were killed 2 h or 4 days after 3-day (8 h/day)
      exposure to ozone (0.5 ppm) or filtered air (0 ppm). The maxilloturbinate from
      one nasal passage was processed for morphometric analyses of the numbers of
      neutrophils and epithelial cells and the amount of intraepithelial mucosubstances
      (IM) in the NTE. The maxilloturbinate from the other nasal passage was processed
      for a mucin-specific (rMuc-5AC) mRNA analysis. At 2 h postexposure,
      endotoxin/ozone-exposed rats had 48 and 3 times more neutrophils in the NTE than
      did saline/air- and saline/ozone-exposed rats, respectively. Ozone-exposed rats
      had 35% more NTE cells and 2-fold more mucin mRNA than did saline/air-exposed
      rats, independent of endotoxin exposure. At 4 days postexposure, endotoxin/ozone
      exposed rats had 5 and 2 times more IM and mucous cells, respectively, than did
      saline/air- and saline/ozone-exposed rats. Though endotoxin/air-exposed rats
      killed at 2 h postexposure had more neutrophils (40-fold), epithelial cells (27%)
      and mucin mRNA (2-fold) in the NTE than did saline/air-exposed rats, no MCM was
      present in those rats killed at 4 days postexposure. The results of the present
      study indicated that pre-existing rhinitis augments ozone-induced MCM.

PMID- 10406925
TI  - Comparative toxicokinetics of chlorinated and brominated haloacetates in F344
      rats.
AB  - Chloro, bromo, and mixed bromochloro haloacetates (HAs) are by-products of
      drinking water disinfection and are hepatocarcinogenic in rodents. We compared
      the toxicokinetics of a series of di-HAs, dichloro (DCA), bromochloro (BCA),
      dibromo (DBA) and tri-HAs: trichloro (TCA), bromodichloro (BDCA), chlorodibromo
      (CDBA), and tribromo (TBA) after iv and oral dosing (500 micrometer/kg) in male
      F344 rats. The blood concentrations of the HAs after iv injection declined in a
      bi-exponential manner with a short but pronounced distributive phase. The
      structural features that had the greatest influence on the disposition of HAs
      were substitution of a halogen for a hydrogen and the degree of bromine
      substitution. All di-HAs had blood elimination half-lives of less than 4 h (DCA >
      DBA, BCA) compared to the tri-HAs, which had half-lives that varied from 0.6 to
      8.0 h (TCA > BDCA > CDBA > TBA). The urinary excretion of all di-HAs was low and
      accounted for less than 3% of the dose in contrast to the tri-HAs, where urinary
      excretion accounted for at least 30% of the dose. Toxicokinetic analysis
      indicated the steady-state apparent volume of distribution varied between 301 and
      881 ml/kg among the HAs, but the variation was not statistically significant (P >
      0.17). The blood concentration-time profiles for all di-HAs after oral dosing was
      complex and exhibited multiple peaks. This did not appear to be due to
      enterohepatic recirculation, as bile duct cannulated animals also displayed
      similar profiles. In contrast, the profiles for the tri-HAs did not exhibit
      multiple peaking after oral dosing and could be described using a one-compartment
      pharmacokinetic model. The oral bioavailability of the HAs varied between 30%
      (DBA) and 116% (TCA), depending on the number of halogen substituents and the
      degree of bromine substitution. In general, three patterns of elimination for the
      HAs can be broadly described: low metabolism with moderate renal clearance (TCA),
      high metabolism and renal clearance (BDCA, CDBA, TBA), and high metabolism, low
      renal clearance (DCA, BCA, DBA).

PMID- 10406926
TI  - The role of lysosomes in the cellular distribution of thioridazine and potential
      drug interactions.
AB  - The purpose of the present study was to investigate the contribution of lysosomal
      trapping to the total tissue uptake of thioridazine and to potential drug
      distribution interactions between thioridazine and tricyclic antidepressants
      (imipramine, amitriptyline) or selective serotonin reuptake inhibitors (SSRIs;
      fluoxetine, sertraline). The experiment was carried out on slices of various rat
      tissues as a system with intact lysosomes. Thioridazine and antidepressants (5
      microM) were incubated separately or jointly with the tissue slices in the
      absence or presence of "lysosomal inhibitors," i.e., ammonium chloride or
      monensin. The results show that the contribution of lysosomal trapping to the
      total tissue uptake of thioridazine is as important as phospholipid binding. A
      high degree of dependence of thioridazine tissue uptake on the lysosomal trapping
      is the cause of substantial distributive interactions between thioridazine and
      the investigated antidepressants at the level of cellular distribution.
      Thioridazine and the antidepressants, both tricyclic and SSRIs, mutually
      decreased their tissue uptake. The potency of antidepressants to decrease
      thioridazine uptake was similar to that of lysosomal inhibitors. In general, the
      observed interactions between thioridazine and antidepressants occurred only in
      those tissues in which thioridazine showed lysosomotropism (the lungs, liver,
      kidneys, brain, and muscles) but were not observed in the presence of ammonium
      chloride. The above finding provides evidence that the interactions proceeded at
      the level of lysosomal trapping. In the adipose tissue and heart no lysosomal
      trapping of thioridazine was detected and those tissues were not the site of such
      an interaction. Since the organs and tissues involved in the distributive
      interactions constitute a major part of the organism and take up most of the
      total drug in the body, the interactions occurring in them may cause a
      substantial shift of the drugs to organs and tissues poor in lysosomes, e.g. the
      heart and muscles. An in vivo study into the thioridazine-imipramine interaction
      showed that joint administration of the drugs under study (10 mg/kg ip) increased
      drug concentration ratios of lysosome-poor tissue/plasma and lysosome
      poor/lysosome-rich tissue. Considering serious side effects of thioridazine and
      tricyclic antidepressants (cardiotoxicity, anticholinergic activity), the
      thioridazine-antidepressant combinations studied should be approached with
      respect to the appropriate dose adjustment.

PMID- 10406927
TI  - In vitro and in vivo study of the antithyroid side effects of trimeprazine.
AB  - Trimeprazine (TMP), a phenothiazine used as antipsychotic drug, was previously
      shown to induce a decrease in thyroid hormone serum levels in rats. Different
      mechanisms might be involved, mainly (i) a central mechanism, involving a
      reduction of thyroid-stimulating hormone (TSH) secretion; (ii) a peripheral
      mechanism, acting upon the synthesis of thyroid hormones, by inhibition of
      thyroperoxidase (TPO) or trapping of molecular iodine present in the thyroid
      gland. These different hypotheses were investigated in the present study, using
      in vitro and in vivo experiments. In vitro studies concerned TMP and its three
      main metabolites: trimeprazine sulphoxide (TSO), N-desmethyl trimeprazine (NDT),
      and 3-hydroxy-trimeprazine (3-OHT). TMP and TSO expressed a high affinity for
      iodine in vitro, contrary to NDT, which did not complex iodine. Only 3-OHT
      inhibited TPO in vitro. Administration of 5 mg/kg TMP ip twice daily for 11 days
      to Wistar rats induced a decrease of free triiodothyronine and free thyroxine
      (fT(3) and fT(4)) and a trend toward an increase of TSH serum levels. Thyroid
      concentrations of TMP, NDT, and TSO were significantly higher than serum levels,
      while 3-OHT was never detected. An iodine-supplemented diet administered to a
      group of rats treated with TMP significantly increased the thyroid concentration
      of TMP and TSO, but not that of NDT, while it did not affect the concentrations
      observed in serum and other organs. The increase in plasma TSH is not consistent
      with the central mechanism hypothesis, and the absence of TPO inhibition by TMP,
      TSO, and NDT contradicts the TPO inhibition hypothesis. On the contrary, three
      findings support the hypothesis of iodine trapping through formation of a complex
      with TMP and TSO: these molecules complex iodine in vitro, they accumulate in the
      thyroid, and their thyroid concentration is increased when the rats are fed an
      iodine-supplemented diet.

PMID- 10406928
TI  - Mechanisms of chlorophyllin anticarcinogenesis: dose-responsive inhibition of
      aflatoxin uptake and biodistribution following oral co-administration in rainbow
      trout.
AB  - Chlorophyllin (CHL) is a potent blocking agent against aflatoxin B(1) DNA
      adduction and tumorigenesis in the trout model, but mechanisms responsible for
      this chemoprotection in vivo are not well established. This study employed
      aflatoxin B(2) (AFB(2)), a structural analogue of AFB(1) that cannot be
      metabolized directly to the 8,9-exo-epoxide electrophile, to investigate CHL
      effects on carcinogen uptake and distribution kinetics following oral exposure in
      trout. CHL was shown to form an AFB(2) complex in vitro with a dissociation
      constant (K(d) = 1.92 +/- 0.13 microM) comparable to that with AFB(1). Following
      gavage, [(3)H]AFB(2) equivalents distributed rapidly from the stomach to other
      organs including blood, liver, and eventually to bile as a major repository. Bile
      was found to contain almost entirely parent AFB(2) 1 h after gavage, with a
      single metabolite dominating 3-24 h and an additional metabolite prominent by 48
      h after gavage. Addition of sufficient CHL (>/=13.9 mM) to assure >99%
      complexation of AFB(2) (0.906 microM) in the gavage mix resulted in 80-90%
      reduction in AFB(2) equivalents in liver and bile 3 h after gavage. In three
      separate kinetic studies of up to 120 h postgavage, addition of >/=13.9 mM CHL to
      the gavage mix reproducibly and markedly delayed the rate of AFB(2) loss from
      stomach, retarded its appearance in blood, liver, and bile, and reduced peak
      AFB(2) concentrations in those tissues by up to 60%. Introduction of a food bolus
      immediately after gavage prolonged AFB(2) residence in stomach and intestine but
      did not abrogate the inhibitory effects of CHL on AFB(2) uptake and distribution.
      These results demonstrate that oral co-treatment with CHL under conditions where
      complex formation is initially assured, substantially reduces AFB(2) systemic
      uptake and target organ bioavailability in the trout.

PMID- 10406929
TI  - Chlorophyllin chemoprevention in trout initiated by aflatoxin B(1) bath
      treatment: An evaluation of reduced bioavailability vs. target organ protective
      mechanisms.
AB  - Chlorophyllin (CHL) is known to inhibit DNA adduction and hepatocarcinogenesis in
      trout when administered at doses up to 4000 ppm in the diet with aflatoxin B(1)
      (AFB(1)). The principal protective mechanism is believed to involve CHL:AFB(1)
      complex formation, which may reduce systemic carcinogen absorption. However,
      mechanisms operative within the target organ in situ have not been ruled out. The
      present study used alternative CHL and AFB(1) exposures as well as hepatic
      metabolism studies to distinguish these mechanisms. Duplicate lots of 150 rainbow
      trout each were initiated by brief water bath exposure to 0.1 ppm AFB(1), with or
      without 500 ppm CHL in the water. The addition of 500 ppm CHL to the water bath,
      under conditions where AFB(1) is calculated to be >99% sequestered as the
      CHL:AFB(1) complex, reduced hepatic AFB(1)-DNA adduction by 95% and reduced
      hepatocarcinogenesis from 20.5% to 2%, compared with exposure to AFB(1) alone.
      Inclusion of 500 ppm CHL in the water bath also significantly reduced total body
      burden and hepatic levels of AFB(1) as well as AFB(2), a structural analogue of
      AFB(1) unable to directly form the 8,9-epoxide proximate electrophile but equally
      capable of complexing with CHL. By contrast, internal target organ CHL loading by
      pretreatment of trout with 4000 ppm dietary CHL for 7 days prior to (and 2 days
      following) AFB(1) waterbath exposure had no effect on AFB(1)-DNA adduction or
      tumorigenicity. Dietary CHL up to 8000 ppm had no effect on hepatic CYP2K1,
      CYP1A, glutathione transferase, UDP-glucuronosyl transferase, or, with one
      exception, the relative ratios among hepatic AFB(1) metabolites in vivo. These
      results support the hypothesis that CHL:AFB(1) complex formation and reduced
      systemic AFB(1) bioavailability is a principal mechanism for CHL chemoprevention
      in this model and that in situ target organ inhibitory mechanisms are relatively
      insignificant.

PMID- 10406931
TI  - Preconception urethane or chromium(III) treatment of male mice: multiple
      neoplastic and non-neoplastic changes in offspring.
AB  - Increase in neoplasia in offspring after preconception exposure of parents
      presents puzzling features such as high frequency of effects and lack of
      Mendelian inheritance. The present study examined the hypothesis that
      preconception carcinogenesis involves an increase in the rate of occurrence of
      neoplasms with a spontaneous incidence. Male NIH Swiss mice (12 per group) were
      exposed 2 weeks before mating (once, ip) to urethane (1.5 g/kg) or chromium(III)
      chloride (1 mmol/kg). Offspring (48-78/sex/group) were examined for all grossly
      apparent changes when moribund or at natural death, followed by histopathological
      diagnosis and statistical analysis. Significant exposure-related changes occurred
      in multiple organs. Ten to 20 percent of offspring showed changes related to
      paternal exposure, including at least one sired by most treated males.
      Pheochromocytomas occurred in both male and female offspring after both
      treatments, with none in controls. These neoplasms are rare in mice and suggest
      endocrine dysfunction as a component of preconception carcinogenesis. This was
      supported by increases in thyroid follicular cell and Harderian gland tumors,
      ovarian cysts, and uterine abnormalities. Lung tumors were increased in female
      offspring only. Effects seen in offspring only after paternal urethane exposure
      were an increase in preneoplasia/neoplasia in the glandular stomach (males) and
      in females, increased lymphoma but decreased incidence of histiocytic sarcoma.
      Increases in incidence of male reproductive gland tumors and of renal non
      neoplastic lesions occurred only after chromium exposure. Thus, preconception
      exposure of fathers to toxicants had a significant impact on both neoplastic and
      non-neoplastic changes in almost all tissues in which these lesions often occur
      naturally during the aging process.

PMID- 10406930
TI  - Toxicology and pharmacokinetics of DTGM, a fusion toxin consisting of a truncated
      diphtheria toxin (DT388) linked to human granulocyte-macrophage colony
      stimulating factor, in cynomolgus monkeys.
AB  - We developed a fusion toxin consisting of the catalytic and translocation domains
      of diphtheria toxin linked to human granulocyte-macrophage colony-stimulating
      factor (GM-CSF) (DTGM) for the treatment of patients with acute myeloid leukemia
      (AML). Our goal in this study was to determine the toxicity and pharmacokinetics
      of DTGM in cynomolgus monkeys (Macacca fascicularis), which possess cross
      reactive GM-CSF receptors. Four groups of young adult monkeys (6 males and 12
      females) were treated with five daily bolus iv infusions of 1, 5, 7.5, and 10
      microgram/kg DTGM. Monkeys (2 males and 2 females) treated at 1 microgram/kg/day
      showed no significant side effects. Monkeys (2 males and 2 females) treated at 5
      microgram/kg/day showed Grade 1-2 thrombopenia (NCI common toxicity criteria) on
      day 9. In contrast, monkeys (6 females) treated at 7.5 microgram/kg/day developed
      Grade 3 neutropenia, Grade 1-2 thrombopenia, Grade 1-3 anemia, and Grade 1-3
      hypoalbuminemia. The neutropenia developed by day 4 in the 7.5 microgram/kg/day
      monkeys and by day 3 or 5 in the 10 microgram/kg/day monkeys and resolved in both
      groups by day 9, but the thrombopenia, anemia, and hypoalbuminemia persisted
      until day 16. Monkeys (2 male and 2 female) treated with 10 microgram/kg/day
      showed Grade 4 neutropenia that resolved by day 8 and Grade 2-3 anemia,
      hypoalbuminemia, and thrombopenia. Three of the animals developed sepsis. DTGM
      plasma half-life was 30 min with a peak concentration of 0.1 microgram/mL or 2 nM
      (1000-fold higher than the IC50 in vitro for AML blasts). Immune responses were
      minimal in all animals tested at 14 and 28 days with anti-DTGM levels <1
      microgram/mL. All four animals at 10 microgram/kg died or were euthanized, and
      necropsies were performed. Animals necropsied on days 4 and 6 showed marked
      apoptosis and hypoplasia in the marrow, which was completely resolved for animals
      necropsied on day 9. No injury to other organs, including kidney, heart, liver,
      central nervous system, or lung, was seen. The drug was selectively toxic to
      malignant or differentiated myeloid cells with little toxicity to myeloid
      progenitors or other organs. Minimal effects in nontarget tissues make DTGM a
      promising candidate chemotherapeutic agent.

PMID- 10406932
TI  - Role of glutathione S-transferase 8-8 in allylamine resistance of vascular smooth
      muscle cells in vitro.
AB  - Allylamine (AA) is a cardiovascular toxin that causes lesions resembling
      atherosclerosis in several mammalian species. AA's toxic effects are thought to
      be exerted through its conversion to acrolein (AC), a potent electrophilic
      alkylating agent and atherogen. Semicarbazide sensitive amine oxidase (SSAO)
      catalyzes the oxidation of AA to AC. Glutathione S-transferases (GST) can
      catalyze the first step of detoxification of AC to mercapturic acid. Our previous
      studies suggest that the isozyme rGST8-8 is a principal defense against
      electrophilic stress exerted by alpha,beta-unsaturated carbonyls such as AC. In
      the present studies, we use cultured rat vascular smooth muscle cells (VSMC) to
      examine the relative roles of SSAO and rGST8-8 in the cytotoxic effects of the
      atherogens, AA and AC. Exposure derived AA-resistant cells (VSMC-AA) were 3.5
      fold more resistant to AA when compared to VSMC and 1.8-fold more resistant to
      acrolein. SSAO activity was 2-fold higher in VSMC-AA than in VSMC. Consistent
      with the role of SSAO in biotransformation of AA, the SSAO inhibitor
      semicarbazide (SC; 100 microM) provided nearly complete protection from AA to
      both VSMC-AA and VSMC. As expected, SC did not affect the cytotoxicity of AC.
      Pretreatment with 100 microM sulfasalazine (SS), a GST inhibitor, potentiated AA
      and AC toxicity in both VSMC-AA and VSMC, indicating a protective role of GST.
      Catalytic efficiency (K(cat)/K(m)) of GSTs was higher toward 4-hydroxynonenal (4
      HNE) (0.65 mM(-1) s(-1)) than toward 1-chloro-2, 4-dinitrobenzene (CDNB) (0.14
      mM(-1) s(-1)) for VSMC. In VSMC-AA, K(cat)/K(m) was increased 4.1-fold toward
      CDNB (0.58 mM(-1) s(-1)) and 6-fold toward 4HNE (3.9 mM(-1) s(-1)) when compared
      to VSMC, indicating a preferential increase in VSMC-AA of GST isozymes which
      utilize alpha,beta-unsaturated carbonyls. Western blots confirmed induction of
      rGST8-8 in VSMC-AA. Expression of recombinant mGSTA4 (the mouse homolog of rGST8
      8) in VSMC caused a 1.6-fold increase in resistance to AA and AC. This resistance
      was fully reversed by 50 microM SS. Our results demonstrate that GSTs are an
      important defense against electrophilic atherogens and that isozymes with high
      activity toward alpha,beta-unsaturated carbonyls are particularly important in
      the vascular wall.

PMID- 10406933
TI  - Comparative neurochemical effects of repeated methyl parathion or chlorpyrifos
      exposures in neonatal and adult rats.
AB  - Several studies have reported higher sensitivity based on lethality in young
      animals compared to adults following acute exposure to organophosphorus
      insecticides (OPs). We propose that age-related differences in sensitivity to OPs
      may differ qualitatively and quantitatively with different OPs and varying
      exposure conditions (e. g., high vs. low dose, acute vs. repeated). To test this
      hypothesis, we treated neonatal (7 days of age) and adult (90 days of age) rats
      with either methyl parathion (MPS) or chlorpyrifos (CPF) daily for 14 days and
      measured neurochemical endpoints {cholinesterase (ChE) inhibition, total
      muscarinic receptor ([(3)H]quinuclidinyl benzilate, QNB) and muscarinic M2
      subtype-preferential ([(3)H]AF-DX 384) binding} in frontal cortex and striatum at
      timepoints both during (1 day after the 7(th) and 14(th) dose) and after (8 days
      after the 14(th) dose) exposures. Repeated CPF exposures were associated with
      relatively similar degrees of ChE inhibition between the age groups during dosing
      but more extensive inhibition was noted in adults after termination of exposures.
      Relatively similar changes in muscarinic receptor binding were also noted between
      age groups following CPF exposures. Moreover, the degree of muscarinic receptor
      binding reduction relative to ChE inhibition appeared similar in both age groups
      following CPF exposures. In contrast, ChE activity and muscarinic receptor
      binding were generally more reduced in neonatal relative to adult brain regions
      following repeated MPS exposures. Furthermore, the relationship between the
      degree of ChE inhibition and the reduction in cortical muscarinic receptor
      binding appeared different between the age groups, i.e., more extensive reduction
      was noted in neonates compared to adults with a given level of ChE inhibition. We
      conclude that OP-selective differences in in vivo ChE sensitivity, differential
      rates of enzyme recovery following inhibition, and age-dependent differences in
      muscarinic receptor adaptations can all influence the nature of age-related
      susceptibility to OPs.

PMID- 10406934
TI  - Modulation of testosterone-metabolizing hepatic cytochrome P-450 enzymes in
      developing Sprague-Dawley rats following in utero exposure to p,p'-DDE.
AB  - 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) causes sexual developmental
      aberrations in male rats through a likely mechanism of androgen receptor
      antagonism. DDE is also known to induce liver cytochrome P-450 (CYP). The
      expression of CYP enzymes is regulated by steroid hormones, which, in turn, are
      inactivated in the liver by CYP-catalyzed hydroxylations and subsequent
      conjugations. This study was undertaken to examine the potential of in utero DDE
      exposure to affect the developmental expression of the hepatic CYP enzymes that
      are responsible for testosterone hydroxylations. Pregnant Sprague-Dawley rats
      were dosed daily by gavage with DDE at 0, 10, or 100 mg/kg body weight or with
      flutamide at 40 mg/kg body weight from gestation day 14 to 18. Additional adult
      male rats were given seven daily doses of DDE at 100 mg/kg. Liver samples were
      collected from the offspring of the dosed dams on postnatal days (PND) 10 and 21
      and from the adult rats a day after the last dosing. Assays for regioselective
      and sterospecific testosterone hydroxylase activities were performed using
      hepatic microsomal preparations. Specific liver CYP proteins were detected by
      immunoblotting. While the CYP2B1 and 3A1 and their hydroxylated testosterone
      products were highly elevated by the DDE treatments in both adult and developing
      rats, the responses of 2C11 and 2A1 were development-dependent. The flutamide
      treatment had little effect on CYP enzyme expression. This study demonstrated
      that developing offspring rats are susceptible to the hepatic CYP enzyme
      modulating action of DDE following its administration to the pregnant dams.

PMID- 10406935
TI  - Deregulation of the signaling pathways controlling urokinase production. Its
      relationship with the invasive phenotype.
AB  - We review the evidence in support of the notion that, upon experimental oncogenic
      transformation or in spontaneous human cancers, mitogenesis and expression of
      urokinase (uPA) and its receptor (uPAR) are activated through common signaling
      complexes and pathways. It is well documented that uPA, uPAR or
      metalloproteinases (MMPs) are overexpressed in tumor cells of mesenchymal or
      epithelial origin and these molecules are required for tumor invasion and
      metastasis. Furthermore, oncogenic stimuli, which may render the transformed
      cells tumorigenic and metastatic in vivo, activate, in a constitutive fashion,
      the extracellular-regulated kinases (Erk 1 and 2) classical mitogenic pathway and
      others such as the NH(2)-Jun-kinase (Jnk). Cells from human tumors or oncogene
      transformed cells overexpress uPA and uPAR, and also show a sustained activation
      of the above-mentioned signaling modules. In this paper we show that the
      classical mitogenic pathway involving Ras-Erk, PKC-Erk or Rac-JNK, among others,
      is activated by growth factors or endogenously by oncogenes, and constitutively
      activates uPA and uPAR expression. All the data obtained from human tumors or
      experimental systems, incorporated into a general model, indicate that oncogenic
      stimuli lead to the constitutive activation of mitogenesis and uPA and its
      receptor expression, through the activation of the same classical and
      nonclassical signaling complexes and pathways that regulate cell proliferation.
      We also discuss contrasting points of view. For instance, what governs the
      differential regulation of mitogenesis and the signal that leads to protease
      overexpression in a way that allows normal cells during physiological events to
      respond to growth factors, and proliferate without overexpressing extracellular
      matrix (ECM) proteases? Or how can cells remodel their microenvironment without
      proliferating? What restrains benign tumors from overexpressing tumor-associated
      proteases when they certainly have the mitogenic signal fully activated? This may
      occur by the differential regulation of transcriptional programs and recent
      reports reviewed in this paper may provide an insight into how this occurs at the
      signaling and transcriptional levels.

PMID- 10406936
TI  - An ethanol-inducible MDR ethanol dehydrogenase/acetaldehyde reductase in
      Escherichia coli: structural and enzymatic relationships to the eukaryotic
      protein forms.
AB  - An ethanol-active medium-chain dehydrogenase/reductase (MDR) alcohol
      dehydrogenase was isolated and characterized from Escherichia coli. It is
      distinct from the fermentative alcohol dehydrogenase and the class III MDR
      alcohol dehydrogenase, both already known in E. coli. Instead, it is reminiscent
      of the MDR liver enzyme forms found in vertebrates and has a K(m) for ethanol of
      0.7 mM, similar to that of the class I enzyme in humans, however, it has a very
      high k(cat), 4050 min(-1). It is also inhibited by pyrazole (K(i) = 0.2 microM)
      and 4-methylpyrazole (K(i)= 44 microM), but in a ratio that is the inverse of the
      inhibition of the human enzyme. The enzyme is even more efficient in the reverse
      direction of acetaldehyde reduction (K(m) = 30 microM and k(cat) = 9800 min(-1)),
      suggesting a physiological function like that seen for the fermentative non-MDR
      alcohol dehydrogenase. Growth parameters in complex media with and without
      ethanol show no difference. The structure corresponds to one of 12 new alcohol
      dehydrogenase homologs present as ORFs in the E. coli genome. Together with the
      previously known E. coli MDR forms (class III alcohol dehydrogenase, threonine
      dehydrogenase, zeta-crystallin, galactitol-1-phosphate dehydrogenase, sensor
      protein rspB) there is now known to be a minimum of 17 MDR enzymes coded for by
      the E. coli genome. The presence of this bacterial MDR ethanol dehydrogenase,
      with a structure compatible with an origin separate from that of yeast, plant and
      animal ethanol-active MDR forms, supports the view of repeated duplicatory
      origins of alcohol dehydrogenases and of functional convergence to
      ethanol/acetaldehyde activity. Furthermore, this enzyme is ethanol inducible in
      at least one E. coli strain, K12 TG1, with apparently maximal induction at an
      enthanol concentration of approximately 17 mM. Although present in several
      strains under different conditions, inducibility may constitute an explanation
      for the fairly late characterization of this E. coli gene product.

PMID- 10406937
TI  - Identification of defensins in human lymphocyte nuclei.
AB  - The cell nucleus plays an essential role in all aspects of cell function and
      regulation. Most of the nuclear proteins/peptides are synthesized in the
      cytoplasm and transported into the nucleus through the nuclear pore complexes.
      The nuclear proteins/peptides conjugate with each other and interact in
      transcriptional activation/inactivation. Several of the high molecular mass
      transcription factors (> 30 kDa) have been identified and characterized. However,
      the information on the low molecular mass proteins/peptides of the nucleus is
      limited. We have investigated these low molecular mass proteins/peptides from the
      nucleus of human peripheral blood lymphocytes using reversed-phase high
      performance liquid chromatography (RP-HPLC). The HPLC fractions were further
      analysed by matrix assisted laser desorption/ionization time of flight (MALDI
      TOF) mass spectrometry, electrospray ionization time of flight (ESI-TOF) mass
      spectrometry and electrospray ionization fourier transform ion cyclotron
      resonance (ESI-FTICR) mass spectrometry for mass determination. Using this
      combination of mass spectrometry techniques and microsequence analysis, we have
      shown that human lymphocyte nuclei contain defensins, a mixture of human
      neutrophil granule peptide 1, 2 and 3.

PMID- 10406938
TI  - The concentration of adrenodoxin reductase limits cytochrome p450scc activity in
      the human placenta.
AB  - We have previously reported that cytochrome P450scc activity in the human
      placenta is limited by the supply of electrons to the P450scc [Tuckey, R. C.,
      Woods, S. T. & Tajbakhsh, M. (1997) Eur. J. Biochem. 244, 835-839]. The aim of
      the present study was to determine whether it is adrenodoxin reductase,
      adrenodoxin or both which limits cytochrome P450scc activity and hence
      progesterone synthesis in the placenta. We found that the concentrations of
      adrenodoxin reductase and adrenodoxin in placental mitochondria were both
      considerably lower than the concentrations of these proteins in the bovine
      adrenal cortex. When P450scc activity assays were carried out at high
      mitochondrial protein concentrations, we found that the addition of exogenous
      adrenodoxin reductase to sonicated mitochondria rescued pregnenolone synthesis to
      a level above that for intact mitochondria, showing that adrenodoxin is near
      saturating in vivo. In contrast, pregnenolone synthesis by sonicated mitochondria
      was almost zero even after the addition of human adrenodoxin. This shows that the
      concentration of endogenous adrenodoxin reductase was insufficient to support
      appreciable rates of pregnenolone synthesis, even when concentrated mitochondrial
      samples were used. Comparative studies with human and bovine adrenodoxin
      reductase have revealed that a twofold higher concentration of human adrenodoxin
      reductase is required for maximal P450scc activity in the presence of saturating
      human adrenodoxin. Thus, not only is the adrenodoxin concentration low in
      placental mitochondria, but the amount required for maximal P450scc activity is
      higher than that for the bovine reductase. Overall, the data indicate that the
      adrenodoxin reductase concentration limits the activity of P450scc in placental
      mitochondria and hence determines the rate of progesterone synthesis.

PMID- 10406939
TI  - Analysis of functional regions of YPM, a superantigen derived from gram-negative
      bacteria.
AB  - The bacterial superantigens, staphylococcal enterotoxins and streptococcal
      pyrogenic exotoxins, are grouped in a family by the conservation of amino acid
      sequence and polypeptide folding patterns. In the case of Yersinia
      pseudotuberculosis-derived mitogen (YPM), however, there is no noticeable
      homology with this family, although many of the in vitro functional features
      conform to the criteria for a superantigen. To study the mode of action of YPM at
      the molecular level, we first generated a number of YPM point mutants with
      reduced T-cell proliferative activity using random mutagenesis and localized the
      amino acid positions involved in either major histocompatibility complex class II
      or T-cell receptor Vbeta-interaction. Plotting the elucidated positions on the
      hydrophilicity profile suggested that they reside mostly on the outer portion of
      the molecule. We also report that the two cysteines positioned almost at opposing
      ends of the YPM molecule are connected by an S-S bond the destruction of which
      causes fatal damage. Finally, we obtained evidence that YPM partially competes
      with staphylococcal enterotoxin E for human leukocyte antigen-DR binding. This
      raises the question of whether these different types of superantigens have
      acquired the same function by genetic convergence or originated from a common
      ancestral gene.

PMID- 10406940
TI  - The relevance of N-linked glycosylation to the binding of a ligand to guanylate
      cyclase C.
AB  - The role of carbohydrate moieties at the N-linked glycosylation sites of
      guanylate cyclase C (GC-C), a receptor protein for guanylin, uroguanylin and heat
      stable enterotoxin, in ligand binding and structural stability was examined using
      site-directed mutagenesis of the putative N-linked glycosylation sites in the
      extracellular domain (ECD) of porcine GC-C. For this purpose, eight mutant
      proteins of ECD (N9A, N20A, N56A, N172A, N261A, N284A, N334A and N379A) and six
      mutant proteins of the complete GC-C (N9A, S11A, N172A, T174A, N379A and T381A)
      were prepared, in which Ala replaced Asn, Ser and Thr at the N-linked
      glycosylation consensus sites. All the mutant proteins showed a ligand-binding
      affinity (K(d)) similar to those of the wild-type proteins, although the deletion
      of a carbohydrate moiety at each of the N-linked glycosylation sites affected the
      ligand-binding ability of ECD or GC-C to some degree. However, the mutant
      proteins of ECD (N379A) and GC-C (N379A and T381A) showed considerably decreased
      binding ability in the context of maximum capacity (B(max)) to a ligand, despite
      the fact that the expression levels of these mutant proteins were nearly the same
      as the wild-type proteins. Moreover, the mutant protein of ECD (N379A) was
      considerably less stable to a denaturant. These results clearly indicate a
      crucial role for the carbohydrate moiety at N379, which is located near the
      transmembrane region, in structural stability, the ability to bind to a ligand
      and the cyclase catalytic activity of GC-C, and provide a route for the
      elucidation of the mechanism of the interaction between GC-C and a ligand.

PMID- 10406941
TI  - Cytochrome c-dependent methacrylate reductase from Geobacter sulfurreducens AM-1.
AB  - Geobacter sulfurreducens AM-1 can use methacrylate as a terminal electron
      acceptor for anaerobic respiration. In this paper, we report on the purification
      and properties of the periplasmic methacrylate reductase, and show that the
      enzyme is dependent on the presence of a periplasmic cytochrome c (apparent K(m)
      = 0.12 microM). The methacrylate reductase was found to be composed of only one
      polypeptide with an apparent molecular mass of 50 kDa and to contain, bound
      tightly but not covalently, 1 mol of FAD per mol. The N-terminal amino acid
      sequence showed sequence similarity to a periplasmic fumarate reductase from
      Shewanella putrefaciens. However, methacrylate reductase did not catalyze the
      reduction of fumarate. The periplasmic cytochrome c, which was also purified, had
      an apparent molecular mass of 30 kDa and contained approximately 4 mol of
      heme.mol(-1). Cells of G. sulfurreducens AM-1 grown on acetate and methacrylate
      as an energy source were found to contain all the enzymes required for the
      oxidation of acetate to CO(2) via the citric acid cycle.

PMID- 10406942
TI  - Import and processing of heart mitochondrial cyclophilin D.
AB  - Cyclophilins are a family of cyclosporin-A-binding proteins which catalyse
      rotation about prolyl peptide bonds. A mitochondrial isoform in mammalian cells,
      cyclophilin D, is a component of the permeability transition pore that is formed
      by the adenine nucleotide translocase and the voltage-dependent anion channel at
      contact sites between the inner and outer membrane. This study investigated the
      submitochondrial location of cyclophilin D by following the fate of radiolabelled
      protein following import. Precursor [(35)S]cyclophilin D was expressed in vitro
      from a PCR-generated cDNA. The precursor was imported by rat heart mitochondria
      and processed in a single step to a 21-kDa protein that was identical (SDS/PAGE)
      to an in vitro expressed mature protein and a cyclophilin D purified from rat
      heart mitochondria. No further modification of the mature protein could be
      demonstrated. Fractionation of mitochondria following import established that
      cyclophilin D locates only to the matrix. It is concluded that cyclophilin D
      binding to the permeability transition pore must occur at the inner face of the
      mitochondrial inner membrane.

PMID- 10406943
TI  - Detection and characterization of a mannan-binding lectin from the mosquito,
      Anopheles stephensi (Liston).
AB  - Two lectins from the serum of the mosquito, Anopheles stephensi (Liston), with
      distinct characteristics, were detected by agglutination of various animal
      erythrocytes. The lectins were developmental stage-specific and/or sex-related.
      One adult female-specific lectin was identified as mannan-specific, and named
      mosquito mannan-binding lectin (MBL). MBL cross-reacted immunologically with
      antibodies against a previously characterized cockroach lectin, Blaberus
      discoidalis lectin (BDL1), and its activity was almost completely blocked by the
      antibodies. Mosquito MBL agglutinated erythrocytes from human, sheep, goat and
      rabbit, but not chicken or mouse, and agglutination was inhibited by mannan and
      nitrophenol-modified sugar derivatives, but not by simple sugars. Using affinity
      chromatography with immobilized mannan on Sepharose 6B, the mosquito MBL was
      partially purified. Purified mosquito MBL shared biochemical properties with
      BDL1, containing two subunits of molecular mass of 28 and 30 kDa under reducing
      conditions in SDS/PAGE. Its activity is dependent on Ca(2+), and it is stable at
      pH 7-9 and at temperatures less than 30 degrees C.

PMID- 10406945
TI  - Colocalization of sterol isomerase and sigma(1) receptor at endoplasmic reticulum
      and nuclear envelope level.
AB  - SR31747A is a sigma ligand previously described as having original
      immunosuppressive properties. Two SR31747A targets were recently identified and
      termed sigma(1) or SR-BP-1 (SR31747A-binding protein-1) and hSI (human sterol
      isomerase). In order to characterize these proteins further, we examined their
      expression and localization at the subcellular level. Based on the amino acid
      sequence deduced from the cloned hSI, anti-hSI polyclonal antibody was raised
      against the N-terminal fragment of the protein. Using this antibody, we performed
      Western-blot experiments to demonstrate the presence of hSI in various B and T
      cell lines, and hSI expression was quantified in these cell lines by flow
      cytometry and estimated at 15 000-30 000 sites per cell. Subcellular localization
      studies by both confocal and electron microscopy, performed on THP1 cells with
      anti-hSI antibody and with the previously described anti-(SR-BP-1) monoclonal
      antibody, demonstrated that: (a) hSI was colocalized with SR-BP-1; (b) hSI and SR
      BP-1 were associated with the endoplasmic reticulum and with the outer and inner
      membranes of the nuclear envelope; (c) both proteins were delocalized during the
      cell cycle at the mitosis step when the nuclear membranes disappeared. Taken
      together our results suggest that both SR31747A-binding proteins not only play a
      role in sterol metabolism but indirectly affect lipoprotein functions.

PMID- 10406944
TI  - Homocysteine decreases endothelin-1 production by cultured human endothelial
      cells.
AB  - Hyperhomocysteinemia is believed to be responsible for the development of
      vascular disease via several mechanisms, including the impairment of endothelial
      cell functionality. In-vitro studies have demonstrated that homocysteine
      decreases the production or bioavailability of vasodilator autacoids, such as
      prostacyclin and NO. Here, we show that the treatment of human endothelial cells
      with noncytotoxic homocysteine concentrations leads to a dose-dependent decrease
      in both the secretion of the vasoconstrictor agent endothelin-1 (ET-1) and the
      level of its mRNA. Homocysteine had an inhibitory effect at pathophysiological
      (0.1 and 0.5 mmol.L(-1)) and pharmacological noncytotoxic (1.0 and 2.0 mmol.L(
      1)) concentrations. Mean percentage variation from control for ET-1 production
      was -36. 2 +/- 18.9% for 0.5 mmol.L(-1) homocysteine and -41.5 +/- 26.8% for 1.0
      mmol.L(-1) homocysteine, after incubation for 8 h. Mean percentage variation from
      control for steady-state mRNA was -17.3 +/- 7.1% for 0.5 mmol.L(-1) homocysteine
      and -46.0 +/- 10.1 for 1.0 mmol.L(-1) homocysteine, after an incubation time of 2
      h. ET-1 production was also reduced by incubation with various other thiol
      compounds containing free thiol groups, but not by incubation with thiol
      compounds with no free thiol group. Co-incubation of cells with homocysteine and
      the sulfhydryl inhibitor N-ethylmaleimide prevented the effect of homocysteine on
      ET-1 production, confirming a sulfhydryl-dependent mechanism. Based on the
      reciprocal feedback mechanism controlling the synthesis of vasoactive mediators,
      these preliminary data suggest a mechanism by which homocysteine may selectively
      impair endothelium-dependent vasodilation by primary inhibition of ET-1
      production.

PMID- 10406946
TI  - Purification and characterization of a highly enantioselective epoxide hydrolase
      from Aspergillus niger.
AB  - The epoxide hydrolase from Aspergillus niger was purified to homogeneity using a
      four-step procedure and p-nitrostyrene oxide (pNSO) as substrate. The enzyme was
      purified 246-fold with 4% activity yield. The protein is a tetramer composed of
      four identical subunits of molecular mass 45 kDa. Maximum activity was observed
      at 40 degrees C, pH 7.0, and with dimethylformamide as cosolvent to dissolve
      pNSO. Hydrolysis of pNSO was highly enantioselective, with an E value (i.e.
      enantiomeric ratio) of 40 and a high regioselectivity (97%) for the less hindered
      carbon atom of the epoxide. This enzyme may be a good biocatalyst for the
      preparation of enantiopure epoxides or diols.

PMID- 10406947
TI  - Tropomodulin isolated from rabbit skeletal muscle inhibits filament formation of
      actin in the presence of tropomyosin and troponin.
AB  - Tropomodulin is a tropomyosin-binding protein, originally isolated from human
      erythrocytes. Tropomodulin is currently regarded as the sole actin pointed-end
      capping protein [Weber, A., Pennise, C.R., Babcock, G.G. & Fowler, V.M. (1994) J.
      Cell Biol. 127, 1627-1635]. This work first describes a procedure for the
      purification of tropomodulin from rabbit skeletal muscle. Tropomodulin almost
      completely inhibited filament formation of actin in the presence of tropomyosin
      and troponin. For the maximal inhibition of actin polymerization, approximately
      0.10, 0.12 and 0.003 mol of tropomyosin, troponin and tropomodulin per mol of
      actin were required, respectively. Fluorescence-intensity measurements, electron
      microscopy and sedimentation experiments revealed that only very short fragments
      and amorphous aggregates, but not filaments, were formed when actin was
      copolymerized with tropomyosin, troponin and tropomodulin by the addition of 50
      mM KCl at pH 8.0. The effects of tropomyosin, troponin and tropomodulin were more
      remarkable on Ca-actin than on Mg-actin. It appears that tropomodulin caps both
      the pointed and barbed ends of tropomyosin- and troponin-bound actin filaments.

PMID- 10406948
TI  - Selective uptake of cholesteryl ester from low density lipoprotein is involved in
      HepG2 cell cholesterol homeostasis.
AB  - Low density lipoprotein (LDL) can follow either a holoparticle uptake pathway,
      initiated by the LDL receptor (LDLr), and be completely degraded, or it can
      deliver its cholesteryl esters (CE) selectively to HepG2 cells. Although high
      density lipoprotein-CE selective uptake has been shown to be linked to cell
      cholesterol homeostasis in nonhepatic cells, there is no available information on
      the effect of LDL-CE selective uptake on hepatic cell cholesterol homeostasis. In
      order to define the role of the LDL-CE selective uptake pathway in hepatic cell
      cholesterol homeostasis, we used a cellular model that expresses constitutively a
      LDLr antisense mRNA and that shows LDLr activity at 31% the normal level (HepG2
      all cells). The addition of a specific antibody anti-LDLr (IgG-C7) reduces LDL
      protein degradation (LDLr activity) to 7%. This cellular model therefore
      reflects, above all, LDL-CE selective uptake activity when incubated with LDL.
      The inactivation of LDLr reduces LDL-protein association by 78% and LDL-CE
      association by only 43%. The LDL-CE selective uptake was not reduced by the
      inactivation of LDLr. The activities of the various enzymes involved in cell
      cholesterol homeostasis were measured in normal and LDLr-deficient cells during
      incubation in the absence or presence of LDL as a cholesterol source.
      Essentially, 3-hydroxy-3-methylglutaryl coenzyme A reductase and acyl coenzyme
      A:cholesterol acyltransferase (ACAT) activities responded to LDL in LDLr
      deficient cells as well as in normal HepG2 cells. Inhibition of lysosomal
      hydrolysis with chloroquine abolished the effect measured on ACAT activity in the
      presence of LDL, suggesting that CE of LDL, but not free cholesterol, maintains
      cell cholesterol homeostasis. Thus, in HepG2 cells, when LDLr function is
      virtually abolished, LDL-CE selective uptake is coupled to cell cholesterol
      homeostasis.

PMID- 10406949
TI  - A cytosolic domain of the erythropoietin receptor contributes to endoplasmic
      reticulum-associated degradation.
AB  - The erythropoietin receptor (EPO-R) is the cellular target for erythropoietin
      (EPO), the primary hormone that mediates the proliferation of immature
      erythroblasts and their differentiation into mature erythrocytes. Unusual
      features of the EPO-R are its short half-life (t(1/2) 1-2 h), its degradation via
      multiple pathways and the fact that less than 1% of total cellular EPO-R
      molecules are found on the cell surface. The contribution of EPO-R structural
      determinants to the regulation of its intracellular metabolism is still unclear.
      The epidermal growth factor receptor (EGF-R), unlike the EPO-R, is efficiently
      transported to the cell surface and displays a much longer metabolic half-life.
      To determine which EPO-R cytosolic domains are involved in intracellular
      degradation, we studied chimeric receptor molecules constructed of EGF-R
      extracellular and transmembrane parts, linked to the full length or truncated
      cytosolic part of the EPO-R. The chimeras were expressed in transiently
      transfected COS 7 cells and stably expressed in Ba/F3 cells. Our experiments
      indicate that the cytosolic part of the EPO-R contains determinants that mark it
      for rapid degradation, in association with the endoplasmic reticulum (ER). This
      degradation was insensitive to brefeldin A and was inhibited by specific
      proteasomal inhibitors. A truncated EGF-R/EPO-R chimera containing only 50 amino
      acids of the EPO-R membrane-proximal cytosolic part was also rapidly degraded
      suggesting that these 50 amino acids are involved in receptor degradation.

PMID- 10406950
TI  - 6-Hydroxycyclohex-1-ene-1-carbonyl-CoA dehydrogenase and 6-oxocyclohex-1-ene-1
      carbonyl-CoA hydrolase, enzymes of the benzoyl-CoA pathway of anaerobic aromatic
      metabolism in the denitrifying bacterium Thauera aromatica.
AB  - Benzoyl-CoA is a common intermediate in the anaerobic bacterial metabolism of
      many aromatic substrates. Two enzymes and ferredoxin of the central benzoyl-CoA
      pathway in Thauera aromatica have been purified so far. Benzoyl-CoA reductase
      reduces the aromatic ring with reduced ferredoxin yielding cyclohexa-1,5-diene-1
      carbonyl-CoA [Boll, M. & Fuchs, G. (1995) Eur. J. Biochem. 234, 921-933]. Dienoyl
      CoA hydratase subsequently adds one molecule of water and thereby produces 6
      hydroxycyclohex-1-ene-1-carbonyl-CoA [Laempe, D., Eisenreich, W., Bacher, A., &
      Fuchs, G. (1998) Eur. J. Biochem. 255, 618-627]. Here two new enzymes, which
      convert this intermediate to the noncyclic product 3-hydroxypimelyl-CoA, were
      purified from T. aromatica and studied. 6-Hydroxycyclohex-1-ene-1-carbonyl-CoA
      dehydrogenase is an NAD(+)-specific beta-hydroxyacyl-CoA dehydrogenase that
      catalyzes 6-hydroxycyclohex-1-ene-1-carbonyl-CoA + NAD(+) --> 6-oxocyclohex-1-ene
      1-carbonyl-CoA + NADH + H(+). 6-Oxocyclohex-1-ene-1-carbonyl-CoA hydrolase acts
      on the beta-oxoacyl-CoA compound and catalyzes the addition of one molecule of
      water to the double bound and the hydrolytic C-C cleavage of the alicyclic ring,
      6-oxocyclohex-1-ene-1-carbonyl-CoA + 2 H(2)O --> 3-hydroxypimelyl-CoA. The genes
      for both enzymes, had and oah, were cloned, had was overexpressed in Escherichia
      coli and the recombinant protein was purified. Hence, presumably all enzymes of
      the central benzoyl-CoA pathway of anaerobic aromatic metabolism from this
      organism have now been purified and studied and the corresponding genes have been
      cloned and sequenced.

PMID- 10406951
TI  - Refolding of recombinant alpha and beta subunits of the Rhodospirillum rubrum
      F(0)F(1) ATP synthase into functional monomers that reconstitute an active
      alpha(1)beta(1)-dimer.
AB  - The alpha subunit from the Rhodospirillum rubrum F(0)F(1) ATP synthase
      (RrF(1)alpha) was over-expressed in unc operon-deleted Escherichia coli strains
      under various growth conditions only in insoluble inclusion bodies. The
      functional refolding of urea-solubilized RrF(1)alpha was followed by measuring
      its ability to stimulate the restoration of ATP synthesis and hydrolysis in beta
      less R. rubrum chromatophores reconstituted with pure native or recombinant
      RrF(1)beta [Nathanson, L. & Gromet-Elhanan, Z. (1998) J. Biol. Chem. 273, 10933
      10938]. The refolding efficiency was found to increase with decreasing
      RrF(1)alpha concentrations and required high concentrations of MgATP, saturating
      approximately 60% when 50 microgram protein.mL(-1) were refolded in presence of
      50 mM MgATP. Size-exclusion HPLC of such refolded RrF(1)alpha revealed a 50-60%
      decrease in its aggregated form and a parallel appearance of its monomeric peak.
      RrF(1)beta refolded under identical conditions appeared almost exclusively as a
      monomer. This procedure enabled the isolation of large amounts of a stable
      RrF(1)alpha monomer, which stimulated the restoration of ATP synthesis and
      hydrolysis much more efficiently than the refolded alpha mixture, and bound ATP
      and ADP in a Mg-dependent manner. Incubation of both RrF(1)alpha and beta
      monomers, which by themselves had no ATPase activity, resulted in a parallel
      appearance of activity and assembled alpha(1)beta(1)-dimers, but showed no
      formation of alpha(3)beta(3)-hexamers. The RrF(1)-alpha(1)beta(1)-ATPase activity
      was, however, very similar to the activity observed in isolated native
      chloroplast CF(1)-alpha(3)beta(3), indicating that these dimers contain only the
      catalytic nucleotide-binding site at their alpha/beta interface. Their inability
      to associate into an alpha(3)beta(3)-hexamer seems therefore to reflect a much
      lower stability of the noncatalytic RrF(1) alpha/beta interface.

PMID- 10406952
TI  - A role for the immunoglobulin-like domain of the human IL-6 receptor.
      Intracellular protein transport and shedding.
AB  - Interleukin (IL)-6, IL-11 and cililary neurotrophic factor (CNTF) belong to the
      same family of hematopoietic and neurotrophic cytokines. Their receptor complexes
      contain a cytokine-binding alpha receptor and the common glycoprotein (gp)130
      subunit for signal transduction. The extracellular parts of the alpha-receptor
      subunits consist of a membrane-proximal cytokine-binding domain and an N-terminal
      immunoglobulin (Ig)-like domain with unknown function. We examined the role of
      the Ig-like domain of IL-6R by constructing deletion mutants lacking the Ig
      domain (IL-6RDeltaIg and soluble IL-6RDeltaIg). IL-6RDeltaIg was shed as
      effectively as wild-type IL-6R from transfected COS-7 cells upon 4beta-phorbol 12
      myristate 13-acetate (PMA) treatment, whereas nonstimulated shedding of IL
      6RDeltaIg was not observed. The shed sIL-6RDeltaIg from PMA-treated cells, as
      well as the transmembrane IL-6RDeltaIg, had the same biological activity as wild
      type sIL-6R, as measured by the induction of haptoglobin secretion in HepG2-IL-6
      cells and IL-6-dependent proliferation of IL-6RDeltaIg transfected BAF/gp130
      cells. In COS-7 cells transfected with IL-6RDeltaIg or soluble IL-6RDeltaIg cDNA,
      transport of the deletion mutants through the secretory pathway appeared to be
      delayed because a sizeable proportion of the mutants was detected as an endo-beta
      N-acetylglucosaminidase-sensitive intermediate, suggesting that transport and
      processing of the DeltaIg mutants on the secretory pathway were impaired. These
      experiments suggest that the Ig-like domain of the IL-6R is important for
      intracellular transport of IL-6R through the secretory pathway. Furthermore, the
      Ig-like domain is necessary for noninduced shedding of the IL-6R, whereas it has
      no function in PKC-dependent shedding of the IL-6R.

PMID- 10406953
TI  - Biosynthesis of bitter acids in hops. A (13)C-NMR and (2)H-NMR study on the
      building blocks of humulone.
AB  - The biosynthesis of humulone, an antibacterial bitter acid from hops, was studied
      by isotope-incorporation experiments using (13)C-labelled glucose or (2)H(2)O.
      (13)C enrichments, (2)H enrichments and (13)C(13)C coupling patterns identify
      isovaleryl-CoA, malonyl-CoA and dimethylallyl pyrophosphate as precursors for
      humulone. Dimethylallyl pyrophosphate, which serves as a building block for the
      bitter acid, is generated via the deoxyxylulose pathway of terpenoid
      biosynthesis. The data confirm that a symmetrical intermediate is involved in
      humulone formation.

PMID- 10406954
TI  - Phosphorylation, dephosphorylation and DNA-binding of the Bradyrhizobium
      japonicum RegSR two-component regulatory proteins.
AB  - Under low oxygen conditions, induction of many genes required for nitrogen
      fixation in Bradyrhizobium japonicum depends on the redox-responsive
      transcriptional activator NifA which is encoded in the fixR-nifA operon. Basal
      expression of this operon depends on the response regulator RegR and a DNA
      element located around position -68 in the fixR-nifA promoter region. To
      investigate the functional properties of RegR and the interaction with its
      putative cognate kinase, RegS, we overproduced and affinity-purified RegR and a
      truncated soluble variant of RegS (RegS(C)), both as N-terminally His(6)-tagged
      proteins. RegS(C) autophosphorylated when incubated with [gamma-(32)P]ATP, and it
      catalyzed the transfer of the phosphoryl label to RegR. The phosphorylated form
      of RegS(C) exhibited phosphatase activity on RegR-phosphate. Chemical stability
      tests and site-specific mutagenesis identified amino acids H219 and D63 of RegS
      and RegR, respectively, as the phosphorylated residues. Competition experiments
      with isolated domains demonstrated that the N-terminal but not the C-terminal
      domain of RegR interacts with RegS(C). Band-shift experiments revealed that
      phosphorylated RegR had at least eightfold enhanced DNA-binding activity compared
      with dephosphorylated RegR or the mutant protein RegR-D63N, which cannot be
      phosphorylated. In conclusion, the RegSR proteins of B. japonicum exhibit
      functional properties in vitro that are typical of two-component regulatory
      systems.

PMID- 10406955
TI  - Evidence that oleoyl-CoA and ATP-dependent elongations coexist in rapeseed
      (Brassica napus L.).
AB  - The elongation of different substrates was studied using several subcellular
      fractions from Brassica napus rapeseed. In the presence of malonyl-CoA, NADH and
      NADPH, very-long-chain fatty acid (VLCFA) synthesis was observed from either
      oleoyl-CoA (acyl-CoA elongation) or endogenous primers (ATP-dependent
      elongation). No activity was detected using oleic acid as precursor. Acyl-CoA and
      ATP-dependent elongation activities were mainly associated with the 15 000 g/25
      min membrane fraction. Reverse-phase TLC analysis showed that the proportions of
      fatty acids synthesized by these activities were different. Acyl-CoA elongation
      increased up to 60 microM oleoyl-CoA, and ATP-dependent elongation was maximum at
      1 mM ATP. Both activities increased with malonyl-CoA concentration (up to 200
      microM). Under all conditions tested, acyl-CoA elongation was higher than ATP
      dependent elongation, and, in the presence of both ATP and oleoyl-CoA, the
      elongation activity was always lower. ATP strongly inhibited acyl-CoA elongation,
      whereas ATP-dependent elongation was slightly stimulated by low oleoyl-CoA
      concentrations (up to 15 microM) and decreased in the presence of higher
      concentrations. CoA (up to 150 microM) had no effect on the ATP-dependent
      elongation, whereas it inhibited the acyl-CoA elongation. These marked
      differences strongly support the presence in maturing rapeseed of two different
      elongating activities differently modulated by ATP and oleoyl-CoA.

PMID- 10406956
TI  - Mouse fibulin-2 gene. Complete exon-intron organization and promoter
      characterization.
AB  - Fibulin-2, an extracellular matrix protein containing tandem arrays of calcium
      binding epidermal growth factor-like motifs, is present in the basement membrane
      and stroma of many tissues. Its expression pattern suggested an essential role in
      organogenesis, particularly in embryonic heart development. In this study, we
      cloned the extreme 5' end of the mouse fibulin-2 cDNA, isolated phage and cosmid
      clones encoding the entire gene, and functionally characterized the promoter. The
      gene was found to consist of 18 exons spanning 55 kb of DNA. The exon-intron
      organization reflected the modular structure of the protein. Exon 9 was subjected
      to alternative splicing. All splice junctions conformed to the GT/AG rule, except
      that GC instead of GT was found in the splice donor site of exon 4. The gene
      lacked TATA and CAAT boxes but contained an initiator element (Inr) and several
      consensus Sp1 binding sites surrounding the transcription start sites. By
      transient transfection of promoter deletion constructs, a 0.46-kb region
      containing the clustered Sp1 sites was found to confer a high promoter activity.

PMID- 10406957
TI  - Terminal truncations in amp C beta-lactamase from a clinical isolate of
      Pseudomonas aeruginosa.
AB  - AmpC beta-lactamases from strains of Pseudomonas aeruginosa have previously been
      shown to be heterogeneous with respect to their isoelectric point (pI). In order
      to elucidate the origin of this heterogeneity enzymes were isolated from a
      clinical isolate of a multiresistant P. aeruginosa strain and biochemically
      characterized. The purification was accomplished in four chromatographic steps
      comprising dye-affinity, size-exclusion, hydrophobic interaction chromatography,
      and chromatofocusing; this resulted in five forms with pI values of 9.1, 8.7,
      8.3, 8.2, and 7.6. When analysed by SDS/PAGE and agarose IEF each separated beta
      lactamase appeared to be both size- and charge-homogeneous. The specific
      activities of the variants were very similar. MS of each isolated beta-lactamase
      form showed minor differences in molecular mass (range 40.0-40.8 kDa). MS of the
      beta-lactamase with a pI of 8.2 demonstrated the presence of two subforms. The N
      terminal sequences of three of the beta-lactamases were identical to the
      published sequence [Lodge, J.M. , Minchin, S.D., Piddock, L.J.V. & Busby, J.W.
      (1990) Biochem. J. 272, 627-631], while two variants were truncated by two amino
      acid residues, one of which was acidic. The previously published sequence
      contains an alanine as the ultimate residue, but two of the beta-lactamases
      showed a substitution of Ala371 for arginine, whereas in the remaining forms C
      terminal truncations by one and three residues were found. Our results indicate
      that the P. aeruginosa strain does not harbour multiple copies of the ampC gene,
      but rather that the five beta-lactamase isoforms are products of a single
      structural gene. The combinations of the identified N- and/or C-terminal
      truncations explained the multiple pI values of the beta-lactamase isoforms.

PMID- 10406958
TI  - Structural and membrane-binding properties of saposin D.
AB  - Saposin D is generated together with three similar proteins, saposins A, B and C,
      from a common precursor, called prosaposin, in acidic organelles such as late
      endosomes and lysosomes. Although saposin D has been reported to stimulate the
      enzymatic hydrolysis of sphingomyelin and ceramide, its physiological role has
      not yet been clearly established. In the present study we examined structural and
      membrane-binding properties of saposin D. At acidic pH, saposin D showed a great
      affinity for phospholipid membranes containing an anionic phospholipid such as
      phosphatidylserine or phosphatidic acid. The binding of saposin D caused
      destabilization of the lipid surface and, conversely, the association with the
      membrane markedly affected the fluorescence properties of saposin D. The presence
      of phosphatidylserine-containing vesicles greatly enhanced the intrinsic tyrosine
      fluorescence of saposin D, which contains tyrosines but not tryptophan residues.
      The structural properties of saposin D were investigated in detail using advanced
      MS analysis. It was found that the main form of saposin D consists of 80 amino
      acid residues and that the six cysteine residues are linked in the following
      order: Cys5-Cys78, Cys8-Cys72 and Cys36-Cys47. The disulfide pattern of saposin D
      is identical with that previously established for two other saposins, B and C,
      which also exhibit a strong affinity for lipids. The common disulfide structure
      probably has an important role in the interaction of these proteins with
      membranes. The analysis of the sugar moiety of saposin D revealed that the single
      N-glycosylation site present in the molecule is mainly modified by high-mannose
      type structures varying from two to six hexose residues. Deglycosylation had no
      effect on the interaction of saposin D with phospholipid membranes, indicating
      that the glycosylation site is not related to the lipid-binding site. The
      association of saposin D with membranes was highly dependent on the composition
      of the bilayer. Neither ceramide nor sphingomyelin, sphingolipids whose
      hydrolysis is favoured by saposin D, promoted its binding, while the presence of
      an acidic phospholipid such as phosphatidylserine or phosphatidic acid greatly
      favoured the interaction of saposin D with vesicles at low pH. These results
      suggest that, in the acidic organelles where saposins are localized, anionic
      phospholipids may be determinants of the saposin D topology and, conversely,
      saposin D may affect the lipid organization of anionic phospholipid-containing
      membranes.

PMID- 10406959
TI  - Effect of glucose and deoxyglucose on the redistribution of calcium in ehrlich
      ascites tumour and Zajdela hepatoma cells and its consequences for mitochondrial
      energetics. Further arguments for the role of Ca(2+) in the mechanism of the
      crabtree effect.
AB  - The distribution of Ca(2+) in intact cells was monitored with fluorescent probes:
      fura-2 for cytosolic [Ca(2+)] and rhod-2 for mitochondrial [Ca(2+)]. It was found
      that in neoplastic cells, such as Ehrlich ascites tumour and Zajdela hepatoma,
      but not in non-malignant cells, such as fibroblasts, glucose and deoxyglucose
      elicited release of Ca(2+) from endoplasmic reticulum stores and an increase in
      Ca(2+) concentration in the cytosol. Parallel to this, a decrease in the rate of
      Ca(2+) extrusion from the cell and an enhanced uptake of Ca(2+) by mitochondria
      were observed. The increase in mitochondrial [Ca(2+)] was accompanied by an
      increase in the mitochondrial membrane potential and the reduction state of
      nicotinamide nucleotides. F(1)F(o)-ATPase in submitochondrial particles of
      Zajdela hepatoma was strongly inhibited in the presence of micromolar Ca(2+)
      concentrations, whereas this activity in submitochondrial particles from rat
      liver appeared to be less sensitive to Ca(2+). Indications of glycosylation of
      Ehrlich ascites tumour cell proteins were also obtained. These data strengthen
      the proposal [Bogucka, K., Teplova, V.V., Wojtczak, L. and Evtodienko, Y. V.
      (1995) Biochim. Biophys. Acta 1228, 261-266] that the Crabtree effect is produced
      by mobilization of cell calcium, which is subsequently taken up by mitochondria
      and inhibits F(1)F(o)-ATP synthase.

PMID- 10406960
TI  - PepS from Streptococcus thermophilus. A new member of the aminopeptidase T family
      of thermophilic bacteria.
AB  - The proteolytic system of lactic acid bacteria is essential for bacterial growth
      in milk but also for the development of the organoleptic properties of dairy
      products. Streptococcus thermophilus is widely used in the dairy industry. In
      comparison with the model lactic acid bacteria Lactococcus lactis, S.
      thermophilus possesses two additional peptidases (an oligopeptidase and the
      aminopeptidase PepS). To understand how S. thermophilus grows in milk, we
      purified and characterized this aminopeptidase. PepS is a monomeric
      metallopeptidase of approximately 45 kDa with optimal activity in the range pH
      7.5-8.5 and at 55 degrees C on Arg-paranitroanilide as substrate. PepS exhibits a
      high specificity towards peptides possessing arginine or aromatic amino acids at
      the N-terminus. From the N-terminal protein sequence of PepS, we deduced
      degenerate oligonucleotides and amplified the corresponding gene by successive
      PCR reactions. The deduced amino-acid sequence of the PepS gene has high identity
      (40-50%) with the aminopeptidase T family from thermophilic and extremophilic
      bacteria; we thus propose the classification of PepS from S. thermophilus as a
      new member of this family. In view of its substrate specificity, PepS could be
      involved both in bacterial growth by supplying amino acids, and in the
      development of dairy products' flavour, by hydrolysing bitter peptides and
      liberating aromatic amino acids which are important precursors of aroma
      compounds.

PMID- 10406961
TI  - Actin and nucleotide induced conformational changes in the vicinity of Lys553 in
      myosin subfragment 1.
AB  - Bertrand et al. [Bertrand, R., Derancourt, J. & Kassab, R. (1995) Biochemistry
      34, 9500-9507] reported that 6-[fluoresceine-5(and 6)-carboxamido] hexanoic acid
      succinimidyl ester (FHS) selectively modifies Lys553, which is part of the strong
      actin-binding site of myosin subfragment 1 (S1). We found that the reaction of
      FHS with Lys533 is accompanied by a decrease in the fluorescence intensity of the
      reagent. The rate of the FHS reaction increased with increasing pH implying that
      the unprotonated form of the epsilon-amino group of Lys553 reacts with FHS.
      Addition of 0.4 M KCl reduced the rate of reaction significantly, which indicates
      ionic strength-dependent changes in the structure of S1. Limited trypsinolysis of
      S1 before the FHS reaction also decreased the rate of the reaction showing that
      the structural integrity of S1 is needed for the reactivity of Lys553. ATP, ADP,
      ADP.BeF(x), ADP.AlF(4), ADP.V(i) and pyrophosphate significantly decreased the
      rate of Lys553 labelling, suggesting nucleotide-induced conformational changes in
      the environment of Lys553. The fluorescence emission spectrum of the Lys553-bound
      FH moiety and the quenching of its fluorescence by nitromethane was not
      influenced by nucleotides, implying that the chemical reactivity but not the
      accessibility of Lys553 was decreased by the nucleotide-induced conformational
      change. In the presence of ATP when the M(**)ADP.P(i) state of the ATPase cycle
      is predominantly populated, the reaction rate decreased more than in the case of
      the S1.ADP.AlF(4)(-) and S1.ADP.V(i) complexes, which are believed to mimic the
      M(**)ADP.P(i) state. This indicates that the conformation of the S1-ADP.AlF(4)(-)
      and S1.ADP.V(i) complexes in the vicinity of Lys553 does not resemble the
      structure of the M(**)ADP.P(i) state. The rate of Lys553 labelling decreased
      strongly in the presence of actin. The nitromethane quenching of the Lys553-bound
      FHS was not influenced by actin, which indicates that the reduced reaction rate
      is not due to steric hindrance caused by the bulky protein but by actin induced
      conformational changes in the vicinity of Lys553.

PMID- 10406962
TI  - Cloning, expression and characterization of an A6-related protein.
AB  - By interaction cloning (yeast two-hybrid system) using the catalytic domain of
      protein kinase Czeta (PKCzeta) as bait, we cloned a human full-length cDNA with
      62% nucleotide homology to the A6 protein recently cloned and characterized by
      Beeler et al. [Beeler, J.F., LaRochelle, W.J., Chedid, M., Tronick, S.R. &
      Aaronson, S. A. (1994) Mol. Cell. Biol. 14, 982-988]. The deduced amino acid
      sequence (349 amino acids) of the A6-related protein (A6rp) contained potential
      actin-binding sites and ATP-binding sites. We also cloned the murine homolog of
      A6rp. Human A6rp was expressed in an in-vitro transcriptional/translational
      system with an apparent molecular mass of 40 kDa and as a glutathione S
      transferase (GST) fusion protein in bacteria. A polyclonal anti-(A6rp) was raised
      in rabbits and used for the identification of A6rp by immunoblotting. A6rp was
      found to be expressed at the mRNA and the protein levels in all cells and tissues
      investigated. GST-A6rp was phosphorylated by PKCzeta but not significantly by
      other PKC isoenzymes. Moreover, it was phosphorylated by casein kinase 2 and most
      effectively by the tyrosine kinase Src. In contrast to GST-A6rp, GST-A6 was also
      phosphorylated by PKC isoforms other than PKCzeta and strongly by CK2, but just
      weakly by Src. In contrast to the results of Beeler et al. on beta-galactosidase
      A6, we were unable to demonstrate autokinase activity or tyrosine phosphorylation
      of either GST-A6 or GST-A6rp. In accordance with the potential ATP-binding sites,
      both proteins were able to bind ATP.

PMID- 10406963
TI  - Molecular cloning and functional characterization of a snake venom
      metalloprotease.
AB  - A cDNA clone, MT-d, encoding metalloprotease precursor was isolated from snake
      (Agkistrodon halys brevicaudus) venom gland cDNA library. MT-d-I protein
      containing both metalloprotease and disintegrin domains, and MT-d-II protein
      containing the metalloprotease domain only were expressed in Escherichia coli and
      refolded successfully into their functional forms. Each of the refolded enzyme
      species exhibited distinct substrate specificity. Proteolytic activity of the MT
      d-1 was able to hydrolyse type I gelatin, type-III and V collagens in contrast
      with the catalytic function of MT-d-II. MT-d-I protein having metalloprotease
      activity was also able to inhibit platelet aggregation. Functionally active MT-d
      I protein underwent autoproteolytic processing in vitro to produce
      metalloprotease and disintegrin; this processing was accompanied by significant
      changes in the substrate specificity of the enzyme activity. Experimental
      evidence strongly suggests that the disintegrin domain in the metalloprotease
      precursor modulates the catalytic function of the enzyme in hydrolysing
      extracellular matrix proteins.

PMID- 10406964
TI  - Transforming growth factor beta regulates clusterin gene expression via
      modulation of transcription factor c-Fos.
AB  - Transforming growth factor-beta (TGFbeta) induces gene expression of the
      glycoprotein clusterin in a variety of cell types via a consensus AP-1 binding
      site. Here, we demonstrate, by supershift analysis, that JunB, JunD, Fra1, Fra2,
      and c-Fos bound to AP-1 but that prior treatment of the cells with TGFbeta
      reduced dramatically c-Fos binding, suggesting that c-Fos might be playing a
      negative regulatory role in clusterin gene expression. Transient cotransfection
      assays in mink lung epithelial (CCL64) cells, using a human c-Fos expressing
      plasmid together with a clusterin promoter/reporter construct or the artificial
      TGFbeta-inducible reporter construct 3TPLux, revealed that c-Fos was indeed
      repressive for TGFbeta-induced promoter transactivation. Further, we demonstrate
      that in stable c-Fos-overexpressing cell lines, TGFbeta induction of endogenous
      clusterin mRNA, as well as clusterin promoter transactivation are blocked. Co
      transfection with c-Fos deletion constructs revealed that the C-terminal region,
      including the homologue box 2 motif and the extreme C-terminal serine
      phosphorylation sites (Ser362 and Ser374) are required for repression of
      clusterin and 3TPLux transactivation. TGFbeta treatment of CCL64 cells resulted
      in the induction of c-Fos mRNA but caused no alternation in total c-Fos protein
      levels. The results suggest that the c-Fos represses clusterin gene expression,
      maintaining a low basal level in the absence of TGFbeta, and that TGFbeta,
      presumably through its effects on c-Fos protein synthesis and/or stability,
      abrogates the repression of c-Fos, thereby resulting in gene expression.

PMID- 10406965
TI  - The efficient export of NADP-containing glucose-fructose oxidoreductase to the
      periplasm of Zymomonas mobilis depends both on an intact twin-arginine motif in
      the signal peptide and on the generation of a structural export signal induced by
      cofactor binding.
AB  - The periplasmic, NADP-containing glucose-fructose oxidoreductase of the gram
      negative bacterium Zymomonas mobilis belongs to a class of redox cofactor
      dependent enzymes which are exported with the aid of a signal peptide containing
      a so-called twin-arginine motif. In this paper we show that the replacement of
      one or both arginine residues results in drastically reduced translocation of
      glucose-fructose oxidoreductase to the periplasm, showing that this motif is
      essential. Mutant proteins which, in contrast to wild-type glucose-fructose
      oxidoreductase, bind NADP in a looser and dissociable manner, were severely
      affected in the kinetics of plasma membrane translocation. These results strongly
      suggest that the translocation of glucose-fructose oxidoreductase into the
      periplasm uses a Sec-independent apparatus which recognizes, as an additional
      signal, a conformational change in the structure of the protein, most likely
      triggered by cofactor binding. Furthermore, these results suggest that glucose
      fructose oxidoreductase is exported in a folded form. A glucose-fructose
      oxidoreductase:beta-galactosidase fusion protein is not lethal to Z. mobilis
      cells and leads to the accumulation of the cytosolic preform of wild-type glucose
      fructose oxidoreductase expressed in trans but not of a typical Sec-substrate
      (OmpA), indicating that the glucose-fructose oxidoreductase translocation
      apparatus can be blocked without interfering with the export of essential
      proteins via the Sec pathway.

PMID- 10406966
TI  - Post-translational modifications of the insect sulfakinins: sulfation,
      pyroglutamate-formation and O-methylation of glutamic acid.
AB  - We identified and chemically characterized the two major forms of sulfakinins
      from an extract of 800 corpora cardiaca/corpora allata complexes of the American
      cockroach, Periplaneta americana. Bioactivity during the purification was
      monitored by measuring heart beat frequency in a preparation in situ. By Edman
      degradation analysis and MS, these main forms were identified as having the
      primary structures Pea-SK [EQFDDY(SO(3)H)GHMRFamide] and Lem-SK-2
      [pQSDDY(SO(3)H)GHMRFamide]. The sulfation was confirmed by UV, MS and peptide
      synthesis. In addition, post-translationally modified sulfakinins of both major
      forms were isolated and identified. Firstly, nonsulfated forms of these peptides
      are present in considerable amounts in the corpora cardiaca/allata. Secondly, the
      N-terminally blocked Pea-SK and the nonblocked Lem-SK-2 occur naturally in
      neurohaemal release sites. Thirdly, modified Pea-SK with O-methylated glutamic
      acid occurs which is not an artefact of peptide purification. The major forms of
      the sulfakinins were shown to be highly active on both the heart and hindgut with
      threshold concentrations of approximately 5 x 10(-10) M (heart) and 2 x 10(-9) M
      (hindgut).

PMID- 10406968
TI  - Molecular cloning of a human UDP-galactose:GlcNAcbeta1,3GalNAc beta1, 3
      galactosyltransferase gene encoding an O-linked core3-elongation enzyme.
AB  - Using the full-length amino-acid sequences of the human beta1,3
      galactosyltransferase (beta3GalT)-I, -II and III enzymes as query, we have
      identified an additional member of the beta3GalT gene family within a sequenced
      region of the human chromosome 21 as found in GenBank. The novel human beta3GalT
      V gene included an open reading frame of 933 bp encoding a protein of 310 amino
      acids with a short N-terminal cytoplasmic tail, a single predicted transmembrane
      domain and a large lumenal catalytic domain. The human beta3GalT-V protein showed
      34%, 27%, 31% and 23% sequence identity with the human beta3GalT-I, -II, -III and
      -IV enzymes, respectively. The expression of beta3GalT-V as a recombinant protein
      in Sf9 insect cells confirmed the galactosyltransferase activity catalyzed by
      this enzyme. Similarly to beta3GalT-I, -II and -III, the beta3GalT-V enzyme used
      beta-linked GlcNAc as an acceptor, but unlike the former enzymes beta3GalT-V
      exhibited a marked preference for the O-linked core3 GlcNAcbeta1,3GalNAc
      substrate. The beta3GalT-V gene was mainly expressed in human small intestine and
      to a lesser extent in pancreas and testis. Although beta3GalT-V transcripts were
      not detected in normal colon tissue, based on Northern analysis, beta3GalT-V mRNA
      was found in the adenocarcinoma cell line Colo 205.

PMID- 10406967
TI  - Expression of a higher plant light-harvesting chlorophyll a/b-binding protein in
      Synechocystis sp. PCC 6803.
AB  - A chimeric lhcb gene, coding for Lhcb, a higher plant chlorophyll a/b-binding
      light-harvesting complex of photosystem II (LHCII), was constructed using the
      Synechocystis sp. PCC 6803 psbA3 promoter and a modified lhcb gene from pea. This
      construct drives synthesis of full-length, mature Lhcb under the control of the
      strong psbA3 promoter that usually drives expression of the D1 protein of
      photosystem II. This chimeric gene was transformed into a photosystem I
      less/chlL(-) Synechocystis sp. PCC 6803 strain that is unable to synthesize
      chlorophyll in darkness. In the resulting strain, a high level of lhcb transcript
      was detected and transcript accumulation was enhanced by addition of exogenous Zn
      chlorophyllide b. The chimeric lhcb gene was translated to produce full-length
      Lhcb as demonstrated by pulse-labeling: a new radioactively labeled band of a
      size corresponding to full-length Lhcb was visible on autoradiograms. Using
      Triton X-114 phase fractionation, this labeled protein band was found to
      partition to the phase containing integral membrane proteins, indicating that the
      pulse-labeled Lhcb is readily integrated into the membrane. However, Lhcb was
      rapidly degraded and did not accumulate in thylakoid membranes to levels that
      were detectable other than by pulse labeling. Upon immunological detection with
      LHCII antibodies, a small protein (approximately 8 kDa) was found specifically in
      the lhcb-containing mutant. We interpret this protein to be a degradation product
      of the full-length Lhcb. This fragment was stabilized by supplementing cells with
      xanthophylls, which incorporated into thylakoid membranes only in the mutant
      carrying lhcb. The lutein/chlorophyll ratio of thylakoids of this mutant was
      about 1 : 10. These results indicate that in this cyanobacterial system Lhcb is
      synthesized, integrated into the membrane, and then degraded to a approximately 8
      kDa fragment that is stabilized by pigment binding and does not require the
      presence of chlorophyll b.

PMID- 10406969
TI  - Engineering of conformations of plasminogen activator inhibitor-1. A crucial role
      of beta-strand 5A residues in the transition of active form to latent and
      substrate forms.
AB  - The serpin (serine proteinase inhibitor) family is of general protein chemical
      interest because of its ability to undergo large conformational changes, in which
      the surface-exposed reactive centre loop (RCL) is inserted as strand 4 in the
      large central beta-sheet A. Loop insertion is an integral part of the inhibitory
      mechanism and also takes place at conversion of serpins to the latent state,
      occurring spontaneously only in plasminogen activator inhibitor-1 (PAI-1). We
      have investigated the importance of beta-strand 5A residues for the activity and
      latency transition of PAI-1. An approximately fourfold increase in the rate of
      latency transition resulted from His-substitution of Gln324 (position 334 in the
      alpha(1)-proteinase inhibitor template numbering), which interacts with the
      underlying alpha-helix B. The side chains of Gln321 and Lys325 (template residues
      331 and 335, respectively) form hydrogen bonds to the peptide backbone of a loop
      connecting alpha-helix F and beta-strand 3A. While substitution with Ala of
      Glu321 had only minor effects on the properties of PAI-1, substitution with Ala
      of Lys325 led to stabilization of the inhibitory activity at incubation
      conditions leading to conversion of wild-type PAI-1 to a substrate form, and to
      an anomalous reaction towards a monoclonal antibody, which induced a delay in the
      latency transition of the mutant, but not wild-type PAI-1. We conclude that the
      anchoring of beta-strand 5A plays a crucial role in loop insertion. These
      findings provide new information about the mechanism of an important example of
      protein conformational changes.

PMID- 10406970
TI  - Chemical and antigenic structure of the O-polysaccharide of the
      lipopolysaccharides from two Acinetobacter haemolyticus strains differing only in
      the anomeric configuration of one glycosyl residue in their O-antigens.
AB  - In a previous study [Pantophlet, R., Brade, L., Dijkshoorn, L., and Brade, H.
      (1998) J. Clin. Microbiol. 36, 1245-1250] the O-polysaccharide of the
      lipopolysaccharides (LPS) from Acinetobacter haemolyticus strains 57 and 61
      exhibited indistinguishable banding-patterns following Western blot and
      immunostaining with homologous or heterologous rabbit antiserum. In this report,
      the molecular basis for the observed cross-reactivity was elucidated, by
      determining the chemical structure of the polysaccharides by compositional
      analysis and NMR spectroscopy. The structures are: [sequence: see text] for
      strain 61 [GulpNAcA, 2-acetamido-2-deoxy-gulopyranosyluronic acid; ManpNAcA, 2
      acetamido-2-deoxy-mannopyranosyluronic acid; QuipN4N, 2,4-diamino-2,4,6-trideoxy
      glucopyranose; acyl (S)-3-hydroxybutyryl], thus, differing only in the anomeric
      configuration of the QuipN4N residue. The antigenic structures were determined by
      generating murine monoclonal antibodies, which were characterized by Western blot
      using LPS as antigen, by ELISA using LPS and de-O-acylated LPS as solid-phase
      antigens, and by ELISA inhibition studies using LPS, polysaccharide, and de-O
      acylated LPS as inhibitors. Of the four antibodies selected, two were specific
      for the respective LPS moieties and two were cross-reactive. All antibodies were
      found to require the presence of the O-acetyl group for reactivity.

PMID- 10406971
TI  - Dynamin and rab5 regulate GRK2-dependent internalization of dopamine D2
      receptors.
AB  - Dopamine D2 receptors (D2Rs; short form, which is one of the alternative splicing
      variants) expressed in COS-7 cells are internalized in an agonist-dependent
      manner only when G protein-coupled receptor kinase 2 (GRK2) is coexpressed [Ito,
      K., Haga, T., Lameh, J. & Sadee, W., (1999) Eur. J. Biochem. 260, 112-119]. We
      have examined the effects of coexpression of dynamin, a small molecular mass GTP
      binding protein, rab5A, and their mutants on the internalization of D2Rs in the
      presence of both dopamine (10 or 100 microM) and GRK2. The rate and extent of D2R
      internalization was increased or decreased by coexpression of dynamin I or a
      dominant-negative form of dynamin I (dynamin I K44E), respectively. The effects
      of coexpressing these two dynamins were more prominent at 10 microM dopamine than
      at 100 microM. In the presence of 10 microM dopamine, internalization of D2R was
      completely suppressed when dynamin I K44E was coexpressed, and the half-life (t
      1/2) of D2R internalization decreased relative to cells not expressing dynamin
      from 82 to 29 min when dynamin I was coexpressed. Internalization of D2Rs was
      facilitated or suppressed by coexpression of a constitutively active form of
      rab5A (rab5A Q79L) or a dominant-negative form of rab5A (rab5A S34N),
      respectively. The t 1/2 of D2R internalization at 10 microM dopamine decreased
      from 82 to 16 min in cells coexpressing rab5A Q79L. The effect of coexpression of
      rab5A S34N was more apparent at 100 microM dopamine than at 10 microM; the t 1/2
      of D2R internalization at 100 microM dopamine increased from 20 to 56 min and the
      proportion of internalized D2Rs after 120 min decreased from 53 to 28%. These
      results indicate that the internalization of D2Rs is dependent on the action of
      dynamin as well as GRK2, and is regulated by the action of rab5A.

PMID- 10406973
TI  - Transcranial Doppler ultrasound.

PMID- 10406974
TI  - Sir William Osler (1849-1919).

PMID- 10406975
TI  - Benign multiple sclerosis.

PMID- 10406976
TI  - Clinical and magnetic resonance imaging heterogeneity in multiple sclerosis.

PMID- 10406977
TI  - What basal forebrain lesions cause amnesia?

PMID- 10406978
TI  - Jaws: diversities of gnathological history and temporomandibular joint
      enterprise.

PMID- 10406979
TI  - Benign multiple sclerosis? Clinical course, long term follow up, and assessment
      of prognostic factors.
AB  - OBJECTIVE: To establish the characteristics of patients following a benign course
      of multiple sclerosis and evaluate the importance of potential prognostic
      factors. Also, an assessment of the value of the Kurtzke EDSS as a prognostic
      indicator has been undertaken in patients previously determined to have benign
      multiple sclerosis, after 10 years of follow up. METHODS: A prevalence study in
      the Coleraine, Ballymena, Ballymoney, and Moyle districts of Northern Ireland
      used the Kurtzke expanded disability scale score (EDSS) in 259 patients with
      multiple sclerosis. Of these, 181 had had multiple sclerosis for>/=10 years, 36
      having benign disease (EDSS</=3.0) >/=10 years after onset. Clinical and
      demographic details of the various patient groups, including the minimal record
      of disability, were compared. The 1987 study in Northern Ireland identified 33
      patients with benign multiple sclerosis. Twenty eight were available for follow
      up in 1996 along with 42 contemporary non-benign patients. RESULTS: Patients with
      benign multiple sclerosis were predominantly women (ratio 4.1:1 v 2.1:1) and
      younger at onset (25.8 v 31.2 years). Commonest symptoms at onset were sensory
      and optic neuritis (33.3% each). Patients with late onset (older than 40 years)
      were less likely to have a benign course, more likely to have a progressive
      course from onset, significantly more likely to have motor disturbance at
      presentation, and had a lesser female predominance. Optic neuritis was
      significantly more common in those with a younger age at onset. In the follow up
      study, patients with benign multiple sclerosis continued to have a more
      favourable course than non-benign counterparts but progression of disability and
      to the secondary progressive phase remained significant. CONCLUSIONS: The
      association of female sex, early onset, and presentation with optic neuritis and
      sensory symptoms with a favourable course is confirmed. However, although the
      EDSS does provide a useful indicator of prognosis, the label "benign multiple
      sclerosis" is often temporary as apparently benign disease often becomes
      disabling.

PMID- 10406980
TI  - Clinical and MRI study of brain stem and cerebellar involvement in Japanese
      patients with multiple sclerosis.
AB  - OBJECTIVES: To investigate the clinical and MRI features of brain stem and
      cerebellar lesions in Japanese patients with multiple sclerosis. METHODS: A
      retrospective study of 66 consecutive Japanese patients with multiple sclerosis
      (42 women and 24 men) was done by reviewing the medical records and MRI films.
      Forty nine patients were diagnosed as having clinically definite multiple
      sclerosis and 17 patients as having clinically probable multiple sclerosis
      according to Poser's criteria. Prevalence rates of each brain stem and cerebellar
      manifestation and frequency and distribution of MRI lesions in these patients
      were studied. RESULTS: Forty three patients (65%) had one or more infratentorial
      manifestations. Cranial nerves were clinically involved in 28 patients (42%), and
      most of the lesions were identified by MRI. Among them, manifestations of facial,
      trigeminal, and abducens nerves were relatively common. Cerebellar ataxia was
      found in 20 patients (30%). The MRI study showed that the lesions responsible for
      ataxia in these patients were mainly found in the cerebellar peduncles, but
      cerebellar hemispheric lesions were detected in only four patients (6.4%).
      CONCLUSION: The low frequency (6.4%) of the cerebellar MRI lesions in these
      patients is in sharp contrast with the figures reported for white patients with
      multiple sclerosis (50%-90%). Racial and genetic differences may have an
      influence on the susceptibility of each part of the CNS to demyelination in
      multiple sclerosis.

PMID- 10406981
TI  - Validation of Italian multiple sclerosis quality of life 54 questionnaire.
AB  - OBJECTIVES: Health related quality of life (HRQOL) inventories are multi
      dimensional measures of patient-centred health status developed for clinical
      research. The MS quality of life 54 (MSQOL-54) is an MS-specific HRQOL inventory
      originally devised for English speaking patients. It consists of a core measure,
      the 36-item short form health survey (SF-36) previously adapted into Italian, and
      18 additional items exploring domains relevant to patients with MS (MS-18
      module). The authors translated and culturally adapted into Italian the MS-18
      module of the MSQOL-54 questionnaire, and clinically validated the whole
      questionnaire. METHODS: The MS-18 module was translated following the methodology
      of the International Quality of Life Assessment (IQOLA) project. The MSQOL-54 was
      validated in 204 consecutive patients with MS seen between April and September
      1997 at three participating centres. The questionnaire was explained by the
      physician who also administered the expanded disability status scale (EDSS) and
      mini mental status scale examination, and the patient filled in the MSQOL-54 and
      Beck depression inventory questionnaires (BDI), with assistance if required. The
      contribution of impairments and disabilities to MSQOL-54 scores were assessed,
      and mean scores were compared with normative data for the general Italian
      population, and with the original sample of United States MS patients. RESULTS:
      The mean age of the 204 patients was 42 years; mean EDSS score was 4.5 (range 0
      8. 5). Patients' participation in the assessment was satisfactory, and all scales
      satisfied the usual psychometric standards. The characteristics of the United
      States sample matched those of our patients in all but gender (72% United States
      patients v 52% Italian patients were women), and education (90% United States
      patients and 44% Italian patients completed high school); MSQOL-54 profiles were
      also similar. The EDSS was significantly associated with the physical health
      composite but not with the mental health composite score. Multiple linear
      regression modelling showed that age and BDI independently predicted physical
      health composite (p < 0.001), and mental health composite (p < 0.001). Clinical
      worsening in the previous year had an independent effect on the physical health
      composite (p < 0.001). CONCLUSIONS: The Italian version of MSQOL-54 is easy to
      administer and is well accepted by patients. Neurological impairment has a
      limited influence on perceived quality of life, while age and depressive symptoms
      has a major influence.

PMID- 10406982
TI  - Basal forebrain amnesia: does the nucleus accumbens contribute to human memory?
AB  - OBJECTIVE: To analyse amnesia caused by basal forebrain lesions. METHODS: A
      single case study of a patient with amnesia after bleeding into the anterior
      portion of the left basal ganglia. Neuropsychological examination included tests
      of attention, executive function, working memory, recall, and recognition of
      verbal and non-verbal material, and recall from remote semantic and
      autobiographical memory. The patient's MRI and those of other published cases of
      basal forebrain amnesia were reviewed to specify which structures within the
      basal forebrain are crucial for amnesia. RESULTS: Attention and executive
      function were largely intact. There was anterograde amnesia for verbal material
      which affected free recall and recognition. With both modes of testing the
      patient produced many false positive responses and intrusions when lists of
      unrelated words had been memorised. However, he confabulated neither on story
      recall nor in day to day memory, nor in recall from remote memory. The lesion
      affected mainly the nucleus accumbens, but encroached on the inferior limb of the
      capsula interna and the most ventral portion of the nucleus caudatus and globus
      pallidus, and there was evidence of some atrophy of the head of the caudate
      nucleus. The lesion spared the nucleus basalis Meynert, the diagnonal band, and
      the septum, which are the sites of cholinergic cell concentrations. CONCLUSIONS:
      It seems unlikely that false positive responses were caused by insufficient
      strategic control of memory retrieval. This speaks against a major role of the
      capsular lesion which might disconnect the prefrontal cortex from the thalamus.
      It is proposed that the lesion of the nucleus accumbens caused amnesia.

PMID- 10406983
TI  - When the left brain is not right the right brain may be left: report of personal
      experience of occipital hemianopia.
AB  - OBJECTIVES: To make a personal report of a hemianopia due to an occipital
      infarct, sustained by a professor of neurology. METHODS: Verbatim observation of
      neurological phenomena recorded during the acute illness. RESULTS: Hemianopia,
      visual hallucinations, and non-occipital deficits without extraoccipital lesions
      on MRI, are described and discussed. CONCLUSIONS: Hemianopia, due to an occipital
      infarct, without alexia, is not a disability which precludes a normal
      professional career. Neurorehabilitation has not been necessary.

PMID- 10406984
TI  - Novel mutation in the myelin protein zero gene in a family with intermediate
      hereditary motor and sensory neuropathy.
AB  - OBJECTIVES: To determine the molecular basis for autosomal dominant intermediate
      hereditary motor and sensory neuropathy (HMSN) in a four generation family. The
      gene defects in families with intermediate HMSN are not known, but it has been
      suggested that most have X linked HMSN. METHODS: All participating family members
      were examined clinically. Genomic DNA was obtained from 10 affected and seven
      unaffected members. Linkage analysis for the known HMSN loci was first performed.
      Mutations in the peripheral myelin protein zero gene (PMP0) were sought in two
      affected members, using one unaffected member for comparison, by amplification of
      the six exons of the gene followed by single strand conformation polymorphism
      (SSCP) analysis, dideoxy fingerprinting (ddF), and sequencing. Subsequently, the
      mutation was screened for in all affected and unaffected members in the family
      using Alu I digestion and in 100 unrelated control subjects using "snap back"
      SSCP analysis. Sequencing of cDNA from a sural nerve biopsy from an affected
      member was also performed. RESULTS: The clinical phenotype was of variable
      severity, with motor nerve conduction velocities in the intermediate range.
      Linkage to PMP0 was demonstrated. Analysis of genomic DNA and cDNA for PMP0
      identified a novel codon 35 GAC to TAC mutation. The mutation produces an
      inferred amino acid change of aspartate to tyrosine at codon six of the processed
      protein (Asp6Tyr) in the extracellular domain and was present in all affected
      family members but not in 100 unrelated controls. CONCLUSIONS: The present
      findings further extend the range of phenotypes associated with PMP0 mutations
      and indicate that families with "intermediate" HMSN need not necessarily be X
      linked as previously suggested.

PMID- 10406985
TI  - Hyperreflexia in Guillain-Barre syndrome: relation with acute motor axonal
      neuropathy and anti-GM1 antibody.
AB  - OBJECTIVES: To investigate the incidence of hyperreflexia in patients with
      Guillain-Barre syndrome (GBS), and its relation with electrodiagnosis of acute
      motor axonal neuropathy (AMAN), antiganglioside GM1 antibody, and Campylobacter
      jejuni infection. It was reported that patients with AMAN in northern China often
      had hyperreflexia in the recovery phase. METHODS: In 54 consecutive Japanese
      patients with GBS, sequential findings of tendon reflexes were reviewed. By
      electrodiagnostic criteria, patients were classified as having AMAN or acute
      inflammatory demyelinating polyneuropathy (AIDP). Anti-GM1 and anti-C jejuni
      antibodies were measured by enzyme linked immunosorbent assays. RESULTS: Seven
      (13%) patients developed hyperreflexia with the spread of the myotatic reflex to
      other segments in the early recovery phase, one of whom already had hyperreflexia
      in the acute progressive phase. Of the seven patients, six had AMAN and all seven
      had anti-GM1 antibodies, whereas only two had anti-C jejuni antibodies.
      Hyperreflexia was more often found in patients with AMAN than AIDP (6/23 v 1/18,
      p=0. 002), and in patients with anti-GM1 antibodies than without them (7/26 v
      0/28, p=0.01). Hyperreflexic patients had milder peak disabilities than patients
      without hyperreflexia (p=0.03). Increased motor neuron excitability in the
      hyperreflexic patients was supported by increased soleus H-reflex amplitudes and
      the appearance of H-reflexes in the small hand or foot muscles. CONCLUSIONS:
      Hyperreflexia often occurs in patients with GBS especially with AMAN, anti-GM1
      antibodies, and milder disease. Increased motor neuron excitability further
      characterises the subgroup of patients with GBS with AMAN and anti-GM1
      antibodies.

PMID- 10406986
TI  - Detection of meningeal fibrosis after subarachnoid haemorrhage by assaying
      procollagen propeptides in cerebrospinal fluid.
AB  - OBJECTIVE: To study whether meningeal collagen synthesis under normal conditions
      is reflected in the CSF and whether a meningeal fibroproliferative reaction or
      fibrosis after subarachnoid haemorrhage can be detected by measuring markers of
      collagen synthesis in the CSF. METHODS: Serum samples and CSF were collected from
      56 patients with various neurological symptoms and from nine patients with a
      recent subarachnoid haemorrhage. The concentrations of the carboxyterminal
      propeptide of type I procollagen (PICP) and the aminoterminal propeptide of type
      III procollagen (PIIINP) were measured using radioimmunoassays. RESULTS: The
      mean(SD) concentration of PICP was 75.2 (SD 13.6) microgram/l and that of PIIINP
      3.56 (SD 0.91) microgram/l in the CSF of the controls, and the CSF/serum ratios
      were 0.74 (SD 0.24) for PICP and 1.34 (SD 0.48) for PIIINP. A 1.4-fold increase
      in both the PICP (p=0.001) and the PIIINP (p=0.001) concentration was found in
      patients with a neurological disease and with an abnormal CSF leucocyte count or
      protein concentration. In eight patients with a recent subarachnoid haemorrhage
      the PICP was 5.9-fold higher (p<0.001) and the PIIINP concentration 7.7-fold
      higher (p<0.001) than that in the controls, whereas no difference was found in
      the serum values. Similar high concentrations were also found in a patient from
      whom the CSF sample was obtained before operation for aneurysm. CONCLUSIONS: The
      intrathecal compartment is a site for active collagen synthesis under normal
      conditions. The synthesis rate is markedly increased in patients with a recent
      subarachnoid haemorrhage, suggesting a fibroproliferative reaction or fibrosis.
      Assays of procollagen propeptides may be useful in the clinical diagnosis of
      meningeal fibrosis and their use may enable the identification of diseases and
      symptoms aetiologically related to meningeal fibrosis.

PMID- 10406989
TI  - Regulation of parkinsonian speech volume: the effect of interlocuter distance.
AB  - This study examined the automatic regulation of speech volume over distance in
      hypophonic patients with Parkinson's disease and age and sex matched controls.
      There were two speech settings; conversation, and the recitation of sequential
      material (for example, counting). The perception of interlocuter speech volume by
      patients with Parkinson's disease and controls over varying distances was also
      examined, and found to be slightly discrepant. For speech production, it was
      found that controls significantly increased overall speech volume for
      conversation relative to that for sequential material. Patients with Parkinson's
      disease were unable to achieve this overall increase for conversation, and
      consistently spoke at a softer volume than controls at all distances (intercept
      reduction). However, patients were still able to increase volume for greater
      distances in a similar way to controls for conversation and sequential material,
      thus showing a normal pattern of volume regulation (slope similarity). It is
      suggested that speech volume regulation is intact in Parkinson's disease, but
      rather the gain is reduced. These findings are reminiscent of skeletal motor
      control studies in Parkinson's disease, in which the amplitude of movement is
      diminished but the relation with another factor is preserved (stride length
      increases as cadence-that is, stepping rate, increases).

PMID- 10406987
TI  - (123)I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson's disease.
AB  - OBJECTIVES: (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is
      clinically used to estimate local myocardial sympathetic nerve damage in some
      forms of heart disease, autonomic nerve disturbance in diabetic neuropathy, and
      disturbance of the autonomic nervous system in neurodegenerative disease. In the
      present study, examinations were performed to clarify (1) the proportion of
      cardiac sympathetic nerve disturbance in Parkinson's disease, (2) the usefulness
      of (123)I-MIBG myocardial scintigraphy to detect sympathetic nerve disturbances
      compared with autonomic function tests, (3) cardiac function in patients who have
      a decreased MIBG uptake in (123)I-MIBG myocardial scintigraphy, (4) the
      usefulness of (123)I-MIBG myocardial scintigraphy to differentiate Parkinson's
      disease from the other neurological diseases mimicking it. METHODS: (123)I-MIBG
      myocardial scintigraphy was performed, together with autonomic function tests and
      cardiac examinations in 46 patients with Parkinson's disease and 25 patients with
      vascular parkinsonism, essential tremor, or multiple system atrophy. RESULTS: In
      an anterior image study, the average count per pixel in heart to mediastinum
      (H/M) ratio decreased in 80% of the patients with Parkinson's disease in the
      early phase and 84% in the late phase. The mean H/M ratio in Parkinson's disease
      was significantly lower than that in controls and the other diseases. The H/M
      ratio tended to decrease with the disease progression. In almost half of the
      patients in Hoehn and Yahr stage I, the H/M ratio was already decreased. The
      sympathetic skin response in upper and lower limbs, head up tilt test, and
      coefficient of variation of R-R interval were abnormal in 17%, 31%, 30%, and 17%
      of the patients, respectively. All the patients with abnormal autonomic functions
      were in Hoehn and Yahr stage III, IV, or V. Echocardiography showed normal left
      ventricular function. Twenty four hour Holter electrocardiography detected no
      serious arrhythmias except for one patient with non-sustained ventricular
      tachycardia. CONCLUSION: (123)I-MIBG myocardial scintigraphy might detect early
      disturbances of the sympathetic nervous system in Parkinson's disease and might
      give useful diagnostic information to differentiate vascular parkinsonism,
      essential tremor, and multiple system atrophy from Parkinson's disease.

PMID- 10406988
TI  - Mutations producing premature termination of translation and an amino acid
      substitution in the sterol 27-hydroxylase gene cause cerebrotendinous
      xanthomatosis associated with parkinsonism.
AB  - OBJECTIVES: Mutational analysis of the sterol 27-hydroxylase (CYP27) gene was
      performed on three patients from two Japanese families who had cerebrotendinous
      xanthomatosis (CTX) associated with parkinsonism. METHODS: Clinical evaluations,
      brain MRI studies, and laboratory analyses were completed on the three patients.
      The CYP27 gene was analysed for mutations by PCR amplification of gene segments
      followed by direct sequencing. RESULTS: Two different, homozygous mutations were
      identified in these families. One is a novel transition, substituting T for G at
      Glu162 (GAG) resulting in a stop codon (TAG). The other is also a transition,
      substituting T for C at Arg441 (CGG) resulting in Trp (TGG). The second is
      located in two amino acids ahead of the heme ligand binding site (Cys443) of the
      protein likely rendering it non-functional. It is the most common CTX mutation in
      Japanese patients. CONCLUSIONS: CTX with parkinsonism is caused by mutations with
      a severe impact on enzyme function. The two mutations described here are likely
      to cause loss of function because they are chain terminating or affect an
      essential site in the protein.

PMID- 10406990
TI  - Association of the APOE epsilon4 allele with disease activity in multiple
      sclerosis.
AB  - OBJECTIVES: Allelic variants of the APOE gene are known to influence the course
      of many neurological diseases and there is increasing evidence that
      apolipoprotein E (APOE) is a pivotal component in reinnervation and dendritic
      remodelling after neuronal injury. Previous studies did not show significant
      differences in the APOE allele frequencies in multiple sclerosis compared with
      controls but did not examine for correlation with disease severity. This study
      explores the relation of APOE genotypes with the disease severity. METHODS:
      Ninety five patients with multiple sclerosis were studied. Age of onset, type,
      and activity of the disease were recorded prospectively and genotyping was
      performed according to standard protocols. RESULTS: APOE allele frequencies of
      the group as a whole, the relapsing group, or the primary progressive group were
      not significantly different from those reported from matched historical controls.
      The epsilon4 allele was found to be more common in patients with a more
      aggressive type of multiple sclerosis (odds ratio=2.95, p=0.03). CONCLUSIONS:
      Although APOE does not seem to be implicated in the early pathogenesis of the
      disease, patients possessing the epsilon4 allele might have a reduced capacity
      for neuronal remodelling after relapses.

PMID- 10406991
TI  - Bilateral ballism in a patient with overlapping Fisher's and Guillain-Barre
      syndromes.
AB  - A 29 year old woman developed diplopia and ataxic gait. Neurological examination
      showed total ophthalmoplegia, cerebellar ataxia, and areflexia. Moreover, there
      was muscle weakness in all four limbs. An overlap of Fisher's and Guillain-Barre
      syndromes was dignosed. On day 5 she suddenly developed involuntary flinging
      movements that affected the face and four limbs. Surface EMG showed 1.5-2 Hz
      rhythmic grouping discharges. The involuntary movements were considered ballism.
      This is the first report of a patient with Guillain-Barre syndrome and a related
      disorder who showed ballism.

PMID- 10406992
TI  - Alterations of muscarinic acetylcholine receptor subtypes in diffuse lewy body
      disease: relation to Alzheimer's disease.
AB  - OBJECTIVES: Dementia associated with Lewy bodies in cortical and subcortical
      areas is classified as dementia of the non-Alzheimer type and termed diffuse Lewy
      body disease (DLBD). The generic term "dementia with Lewy bodies (DLB)" was
      proposed in the international workshop on Lewy body dementia to include the
      similar disorders presenting Lewy bodies. In DLB, a lower level of choline
      acetyltransferase (ChAT) activity in the neocortex was found compared with that
      in Alzheimer's disease. The purpose of the present study was to determine the
      total amount of muscarinic acetylcholine receptors (mAChRs) and relative
      proportion of each subtype (m1-m4) of mAChRs in the frontal and temporal cortex
      of seven DLBD and 11 Alzheimer's disease necropsied brains. METHODS: A
      [(3)H]quinuclidinyl benzilate (QNB) binding assay and an immunoprecipitation
      assay using subtype-specific antibodies were performed. Each antibody was raised
      against fusion proteins containing peptides corresponding to the third
      intracellular (i3) loops of the respective mAChR subtype. RESULTS: The total
      amounts of mAChRs were significantly lower in the preparations of temporal
      cortices from DLBD and Alzheimer's disease than in those from dead controls
      (seven cases). In both diseases, the proportion of the m3 receptor in the frontal
      cortex was significantly increased and that of the m4 receptor in the temporal
      cortex was significantly decreased compared with the control specimens. The
      proportions of the m1 and m2 subtypes were significantly different in the
      temporal cortex. The proportion of the m1 receptor was significantly greater in
      the DLBD brains, whereas that of the m2 receptor was significantly greater in the
      Alzheimer's disease brains than in the controls. CONCLUSIONS: The m1 receptor is
      the major subtype in the cerebral cortex, and m2 is known to be present at
      presynaptic terminals. The higher proportions of m1 in DLBD and m2 in Alzheimer's
      disease suggest that the manner of degeneration in the cholinergic system is
      different between the diseases. It is hypothesised that a severe depletion of
      presynaptic cholinergic projective neurons causes the upregulation of m1 receptor
      in the temporal cortex in DLBD.

PMID- 10406993
TI  - Extrapyramidal involvement in amyotrophic lateral sclerosis: backward falls and
      retropulsion.
AB  - Three patients with sporadic amyotrophic lateral sclerosis (ALS) presented with a
      history of backward falls. Impaired postural reflexes and retropulsion
      accompanied clinical features of ALS. Hypokinesia, decreased arm swing, and a
      positive glabellar tap were noted in two of these three patients. Cognitive
      impairment, tremor, axial rigidity, sphincter dysfunction, nuchal dystonia,
      dysautonomia, and oculomotor dysfunction were absent. Brain MRI disclosed
      bilateral T2 weighted hyperintensities in the internal capsule and globus
      pallidus in one patient. Necropsy studies performed late in the course of ALS
      have shown degeneration in extrapyramidal sites-for example, the globus pallidus,
      thalamus, and substantia nigra. Clinically, backward falls and retropulsion may
      occur early in ALS. This may reflect extrapyramidal involvement.

PMID- 10406994
TI  - A family with pseudodominant Friedreich's ataxia showing marked variation of
      phenotype between affected siblings.
AB  - A family with pseudodominant Friedreich's ataxia is described showing marked
      variation of phenotype between affected siblings. The mother of this family (III
      3) developed a spastic ataxic tetraplegia with neuropathy at 34 years of age; her
      husband, who was unrelated, was clinically normal. Of their nine children, two
      (IV-2, IV-3), including one with multiple sclerosis (IV-3), developed a mild
      spinocerebellar degeneration in the third decade. Three in their late 20s had an
      asymptomatic spinocerebellar degeneration (IV-4, IV-5, IV-6) and one was confined
      to a wheelchair at 15 years with typical Friedreich's ataxia (IV-9). Three other
      siblings (IV-1, IV-7, IV-8) were clinically normal. The father proved to be
      heterozygous for the triplet repeat expansion at the Friedreich's ataxia locus
      and all clinically affected members were homozygous for alleles in the expanded
      size range. This family confirms that homozygote-heterozygote mating is the
      genetic basis for some families with apparent autosomal dominant Friedreich's
      ataxia.

PMID- 10406995
TI  - Continuous haemodynamic monitoring in an unusual case of swallow induced syncope.
AB  - A 69 year old man is described with a 12 year history of intermittent syncope
      associated with ingesting solid food, mainly after having fasted. He was taking
      enalapril, propranolol, bendrofluazide (bendroflumethiazide), omeprazole,
      finasteride, and aspirin. Detailed investigations, including gastrointestinal
      evaluation, measurement of various gut hormones, and autonomic testing, indicated
      no abnormality. A liquid meal, performed before fasting, failed to elicit an
      episode. However, a solid meal after an overnight fast provoked near-syncope.
      Continuous non-invasive haemodynamic monitoring (with a Portapres II) indicated a
      short lived rise in blood pressure and heart rate, followed by severe
      hypotension, a fall in stroke volume and cardiac output, and then bradycardia.
      This favoured an initial increase in sympathetic activity, followed by
      vasodepression due to sympathetic withdrawal or activation of humoral
      vasodilatatory mechanisms, with bradycardia secondary to impaired cardiac
      filling. Withdrawal of enalapril abolished the episodes. The unusual nature of
      this case, in which haemodynamic recordings continuously were made during and
      after swallow syncope, induced soon after food ingestion, is discussed.

PMID- 10406996
TI  - Giant cell arteritis of the cervical radicular vessels presenting with
      diaphragmatic weakness.
AB  - The clinical and histopathological details of a patient who succumbed to giant
      cell arteritis (GCA) of the cervical radicular vessels are described. The initial
      clinical presentation, with diaphragmatic weakness, has not previously been
      reported. Normal inflammatory indices and the unusual presentation prevented
      diagnosis during life, but GCA should be considered in the differential diagnosis
      of any unexplained neuropathic or radiculopathic syndrome, as corticosteroid
      therapy may lead to recovery. This is the first account of the pathological
      findings in cervical radiculopathy associated with GCA.

PMID- 10406997
TI  - Intracranial dural fistula as a cause of diffuse MR enhancement of the cervical
      spinal cord.
AB  - Spinal MR findings are reported in a patient with progressive myelopathy and
      intracranial dural arteriovenous fistula draining into spinal veins. Associated
      with previously reported abnormalities on T1 weighted and T2 weighted images,
      postcontrast T1 weighted images disclosed diffuse intense enhancement of the
      cervical cord itself. This enhancement decreased after endovascular treatment.

PMID- 10406998
TI  - A note on the use of botulinum toxin.

PMID- 10406999
TI  - Epileptic psychoses and anticonvulsant drug treatment.
AB  - Forty four consecutive patients with epilepsy and psychoses were studied
      retrospectively for psychotic episodes associated with changes in antiepileptic
      drug therapy. Twenty seven patients (61%) developed their first episode of
      psychosis unrelated to changes in their antiepileptic drug regimen. Twenty three
      of these patients developed psychoses with temporally unrelated changes in
      seizure frequency. Many patients had chronic schizophrenia-like psychotic
      symptoms. Seventeen patients (39%) developed their first episode of psychosis in
      association with changes in their antiepileptic drug regimen. Twelve patients
      developed psychoses temporally related to seizure attenuation or aggravation.
      Many of their psychotic symptoms were polymorphic with a single episode or
      recurrent episodes. No marked differences were found in the various clinical
      backgrounds between the two groups. In the drug-related group, seven patients
      developed psychoses after starting add-on therapy with a new antiepileptic drug,
      six after abruptly discontinuing their drugs, and four after taking an overdose
      of antiepileptic drugs. Based on the present findings, drug regimens should be
      changed gradually and compliance should be maintained to prevent epileptic
      psychoses.

PMID- 10407000
TI  - Clinical significance of intracranial developmental venous anomalies.
AB  - OBJECTIVES: Venous angiomas, or developmental venous anomalies (DVAs), represent
      the most often occurring cerebral vascular malformation. The clinical
      significance of a DVA is, however, at present unclear. METHODS: A retrospective
      analysis was carried out on two series of consecutive cranial MRIs performed
      between January 1990 and August 1996 in a university department of neuroradiology
      and in a large radiological private practice. The medical records of all patients
      in whom a DVA was diagnosed were screened to identify the specific complaint
      which necessitated the imaging procedure. RESULTS: A total of 67 patients with
      DVA could be identified. In 12 patients an associated cavernoma was found. The
      main reason for performing the MRI was the evaluation of seizures or of
      headaches. In all patients with DVA in whom an intracerebral haemorrhage was
      diagnosed an associated cavernoma was present at the site of the haemorrhage.
      None of the 67 patients showed an association between the complaints that led to
      the MRI and the location of the DVA. CONCLUSIONS: DVAs do not seem to be
      associated with a specific clinical presentation. In a significant percentage of
      cases, however, coexisting cavernomas are found which have a defined bleeding
      potential and should be treated independently of the DVA. This study supports the
      hypothesis that DVAs are a congenital abnormality of venous drainage without
      clinical significance.

PMID- 10407001
TI  - Herpes simplex encephalitis after brain surgery: case report and review of the
      literature.
AB  - Intracranial infection after neurosurgical intervention most often is caused by
      bacteria. A rare case of fatal herpes simplex encephalitis after removal of a
      meningioma is described and similar cases reported in the literature are
      reviewed. Recent diagnostic tools, including detection of herpes viral DNA
      sequences by polymerase chain reaction, complement clinical suspicion and
      facilitate mandatory early diagnosis, because herpes encephalitis, without rapid
      initiation of treatment, may lead to severe disability or death.

PMID- 10407002
TI  - Imaging and laboratory investigation in herpes simplex encephalitis.
AB  - A 14 day old baby presented with signs of an acute encephalitis. Clinically,
      herpes simplex encephalitis (HSE) was suspected. Early MRI and EEG were normal
      and there was rapid clinical improvement. A negative polymerase chain reaction
      (PCR) result on the initial CSF sample seemed to make HSE most unlikely. This
      diagnosis was subsequently proved after demonstration of specific antibody
      production using immunoelectrophoresis of the CSF. The child had extensive damage
      to brain tissue. The need for sequential analysis of CSF in making or refuting
      this diagnosis is illustrated.

PMID- 10407003
TI  - A blinding headache and two black eyes.

PMID- 10407004
TI  - Chronic misuse of paint thinners.

PMID- 10407005
TI  - Multiple sclerosis associated with syringomyelia.

PMID- 10407006
TI  - Management of acute and chronic pain 

PMID- 10407007
TI  - Neuropathology of dementing disorders 

PMID- 10407008
TI  - Instrumented spinal surgery. Principles and technique 

PMID- 10407009
TI  - Surgical disorders of the peripheral nerves 

PMID- 10407010
TI  - Muscarinic receptor activity has multiple effects on the resting membrane
      potentials of CA1 hippocampal interneurons.
AB  - Inhibitory interneurons appear to be an important target for the muscarinic
      actions of cholinergic inputs to the hippocampus. We investigated the effect of
      muscarinic receptor activity on the membrane potential (V(m)) and currents of rat
      hippocampal CA1 interneurons using whole-cell recording from visually identified
      CA1 interneurons. The predominant response observed was a muscarinic
      depolarization that was detected in interneurons from all layers of CA1. This
      depolarization was mediated by at least two mechanisms: a reduction in a
      potassium current and a mechanism that depended on extracellular sodium. Other
      interneurons responded to muscarinic agonists with a hyperpolarization or a
      biphasic response (hyperpolarization followed by depolarization).
      Hyperpolarizations and biphasic responses were found in all layers of CA1 but
      more frequently in stratum radiatum and stratum lacunosum moleculare. Muscarinic
      hyperpolarization was caused by the activation of a barium- and cesium-sensitive
      inwardly rectifying potassium channel. A small number of interneurons, primarily
      in or bordering the stratum pyramidale, produced slow membrane potential (0.04
      Hz) oscillations. Many interneurons did not respond to muscarinic activity at
      all; half of these were in the stratum oriens. There was no strong correlation
      between any changes in V(m) response to muscarine and morphology, as determined
      by reconstruction of the interneurons. It was not possible to predict the
      morphology or the layer distribution of an interneuron based on the type of
      muscarinic membrane potential response it had. This lack of correlation between
      muscarinic function and morphology implies a greater complexity of interneuron
      function than has been realized previously.

PMID- 10407011
TI  - Muscarinic receptor activity induces an afterdepolarization in a subpopulation of
      hippocampal CA1 interneurons.
AB  - Cholinergic input to the hippocampus may be involved in important behavioral
      functions and the pathophysiology of neurodegenerative diseases. Muscarinic
      receptor activity in interneurons of the hippocampus may play a role in these
      actions. In this study, we investigated the effects of muscarinic receptor
      activity on the excitability of different subtypes of interneurons in rat
      hippocampal CA1. Most interneurons displayed an afterhyperpolarizing potential
      (AHP) after depolarization by injected current or synaptic stimulation. In the
      presence of a muscarinic agonist, the AHP of a subset of these interneurons was
      replaced by an afterdepolarization (ADP), often of sufficient magnitude to evoke
      action potentials in the absence of further stimulation. The ADP was insensitive
      to cadmium and low extracellular calcium. It was blocked by low extracellular
      sodium but not by tetrodotoxin or low concentrations of amiloride. Muscarinic
      ADPs were sometimes observed in isolation but were often accompanied by
      depolarizing, hyperpolarizing, or biphasic changes in the membrane potential.
      Interneurons with muscarinic ADPs were found in all strata of CA1 and did not
      fall into a single morphological classification. The potential functions of the
      prolonged action potential output of interneurons produced by the ADP could
      include changes in hippocampal circuit properties and facilitation of the release
      of peptide cotransmitters in these interneurons.

PMID- 10407012
TI  - Alterations in AMPA receptor subunit expression after experimental spinal cord
      contusion injury.
AB  - The AMPA-preferring subtype of ionotropic glutamate receptors (GluRs) is a hetero
      oligomeric ion channel assembled from various combinations of four subunits:
      GluR1, GluR2, GluR3, and GluR4. Antagonists of these receptors can mitigate the
      effects of experimental spinal cord injury (SCI), indicating that these receptors
      play a significant role in pathophysiology after spinal trauma. We tested the
      hypothesis that SCI alters expression of AMPA receptors using a standardized
      thoracic weight-drop model of rat contusive spinal cord injury. AMPA receptor
      subunit expression was measured at 24 hr and at 1 month after SCI with
      quantitative Western blot analysis and in situ hybridization. GluR2 protein
      levels were preferentially reduced near the injury site 24 hr after SCI. This
      reduction persisted at 1 month. At a cellular level, a significant decrease in
      both GluR2 and GluR4 mRNA was found in spared ventral motor neurons adjacent to
      the injury site and distal to it, with other AMPA subunit mRNAs maintained at
      control levels. In contrast, only GluR1 mRNA was decreased in the sympathetic
      preganglionic neurons of the intermediolateral horn. These results suggest
      population-specific and long-lasting changes in neuronal AMPA receptor
      composition, which may alter response to glutamate after SCI. These alterations
      may contribute not only to acute neuropathological consequences of injury, but
      they may also be partially responsible for the altered functional state of
      preserved tissue seen chronically after SCI.

PMID- 10407014
TI  - Vascular endothelial growth factor has neurotrophic activity and stimulates
      axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the
      peripheral nervous system.
AB  - Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells, and
      it promotes angiogenesis in vivo. Here we report that VEGF(165) has neurotrophic
      actions on cultured adult mouse superior cervical ganglia (SCG) and dorsal root
      ganglia (DRG), measured as axonal outgrowth. Maximal effect was observed at 10-50
      ng/ml for SCG and 100 ng/ml for DRG. VEGF-induced axonal outgrowth was inhibited
      by the mitogen-activated protein kinase kinase inhibitor PD 98059 but not by the
      protein kinase inhibitor K252a. VEGF also increased survival of both neurons and
      satellite cells and the number of proliferating Schwann cells.
      Immunocytochemistry and immunoblotting revealed that VEGF was expressed in
      virtually all nerve cells in the SCG but only in a population of small-diameter
      (<35 micrometers) neurons representing approximately 30% of the neurons in DRG.
      Immunostaining showed that the VEGF receptor fetal liver kinase receptor (flk-1)
      was found on nerve cell bodies in DRG and to a lesser extent on neurons in SCG.
      Growth cones of regenerating axons from both types of ganglia exhibited flk-1
      immunoreactivity, as did Schwann cells. We conclude that VEGF has both
      neurotrophic and mitogenic activity on cells in the peripheral nervous system.

PMID- 10407013
TI  - Three GABA receptor-mediated postsynaptic potentials in interneurons in the rat
      lateral geniculate nucleus.
AB  - Inhibition is crucial for the thalamus to relay sensory information from the
      periphery to the cortex and to participate in thalamocortical oscillations.
      However, the properties of inhibitory synaptic events in interneurons are poorly
      defined because in part of the technical difficulty of obtaining stable recording
      from these small cells. With the whole-cell recording technique, we obtained
      stable recordings from local interneurons in the lateral geniculate nucleus and
      studied their inhibitory synaptic properties. We found that interneurons
      expressed three different types of GABA receptors: bicuculline-sensitive GABA(A)
      receptors, bicuculline-insensitive GABA(A) receptors, and GABA(B) receptors. The
      reversal potentials of GABA responses were estimated by polarizing the membrane
      potential. The GABA(A) receptor-mediated responses had a reversal potential of
      approximately -82 mV, consistent with mediation via Cl(-) channels. The reversal
      potential for the GABA(B) response was -97 mV, consistent with it being a K(+)
      conductance. The roles of these GABA receptors in postsynaptic responses were
      also examined in interneurons. Optic tract stimulation evoked a disynaptic IPSP
      that was mediated by all three types of GABA receptors and depended on activation
      of geniculate interneurons. Stimulation of the thalamic reticular nucleus evoked
      an IPSP, which appeared to be mediated exclusively by bicuculline-sensitive
      GABA(A) receptors and depended on the activation of reticular cells. The results
      indicate that geniculate interneurons form a complex neuronal circuitry with
      thalamocortical and reticular cells via feed-forward and feedback circuits,
      suggesting that they play a more important role in thalamic function than thought
      previously.

PMID- 10407015
TI  - Potentiation of quantal catecholamine secretion by glibenclamide: evidence for a
      novel role of sulphonylurea receptors in regulating the Ca(2+) sensitivity of
      exocytosis.
AB  - Electrochemical detection of quantal catecholamine release from PC-12 cells
      revealed that glibenclamide, an inhibitor of ATP-sensitive K(+) channels,
      potentiated Ca(2+)-dependent exocytosis evoked by raised extracellular [K(+)] and
      by exposure of cells to caffeine. Glibenclamide was without effect on voltage
      gated Ca(2+) currents, membrane potential, or rises of [Ca(2+)](i) evoked by
      either raised extracellular [K(+)] or caffeine. The dependence of K(+)-evoked
      secretion on extracellular Ca(2+) was shifted leftward in the presence of
      glibenclamide, with a small increase in the plateau level of release, suggesting
      that glibenclamide primarily increased the Ca(2+) sensitivity of the exocytotic
      apparatus. Enhancement of secretion by glibenclamide was reversed by pinacidil
      and cromakalim, indicating that the effects of glibenclamide were mediated via an
      action on a sulfonylurea receptor. These results demonstrate that sulfonylurea
      receptors can modulate Ca(2+)-dependent exocytosis via a mechanism downstream of
      Ca(2+) influx or mobilization.

PMID- 10407016
TI  - kappa-Opioid tolerance and dependence in cultures of dopaminergic midbrain
      neurons.
AB  - Repeated cocaine exposure upregulates kappa opioids and their receptors in the
      mesocorticolimbic system; the ensuing kappa-mediated dysphoria appears to
      contribute to addiction and withdrawal. As a potential rehabilitation strategy to
      reverse cocaine-induced kappa sensitization, the present study used tritiated
      dopamine release assays to examine the induction of kappa-opioid tolerance in
      cultured mesencephalic neurons. Administration of the kappa agonist U69,593
      inhibited tetrodotoxin-sensitive, spontaneous (EC(50) = 1.5 nM), and potassium
      stimulated (EC(50) = 10 nM) release. These effects were blocked by pertussis
      toxin and by the kappa antagonist nor-binaltorphimine. The 2 d agonist exposure
      (1 microM) caused a shift in the U69,593 dose-response curve that was greater in
      the potassium-stimulated paradigm (140-fold) than in the spontaneous release
      assay (sixfold). These results were attributable to the attenuation of kappa
      receptor signaling mechanisms and to dependence. In the stimulated release assay,
      attenuation of kappa signaling caused by 4 hr of U69,593 exposure recovered with
      a half-life of 1.1 hr, whereas attenuation after 144 hr of exposure recovered
      slowly (t(1/2) = 20 hr). In the spontaneous release assay, attenuation of kappa
      opioid signaling occurred slowly (t(1/2) = 22 hr), and resensitization after a
      144 hr exposure was rapid (t(1/2) < 1 hr). kappa-Opioid dependence was observed
      after 144 hr of U69,593 exposure. Thus multiple mechanisms of adaptation to kappa
      opioid exposure occur in mesocorticolimbic neurons. These data support the idea
      that the administration of kappa opioids might facilitate drug rehabilitation.

PMID- 10407017
TI  - Glutamate receptors mediate TTX-resistant synchronous activity in the rat
      hippocampus.
AB  - 4-Aminopyridine (4-AP) is a well known convulsant that enhances the release of
      both excitatory and inhibitory neurotransmitters in the CNS. Low concentrations
      of 4-AP (approximately 100 microM) readily induce synchronized discharges in the
      hippocampus that are blocked by tetrodotoxin (TTX), suggesting that they require
      Na(+)-dependent action potentials in addition to the enhanced release of
      neurotransmitters. However, in the present study we have found that higher
      concentrations of 4-AP (1 mM) in combination with 5 mM tetraethylammonium (TEA)
      induce spontaneous synchronized discharges in rat hippocampal slices that are
      resistant to blockade by TTX. These synchronous discharges are evident in field
      potential recordings, which progress from the hilus to CA1 at 0.023 +/- 0.002
      m/sec and in intracellular recordings from the hilar mossy cells and CA3
      pyramidal cells. In some slices exposed to 4-AP and TEA, smaller-amplitude
      asynchronous responses also were recorded. 4-AP-induced spontaneous discharges
      are blocked by 20 microM DNQX and by 100 microM Cd(2+) but are resistant to
      blockade by either 25 microM bicuculline or 25 microM D-APV. These results
      suggest that the activation of postsynaptic AMPA receptors is necessary to
      produce TTX-resistant synchronized discharges. The laminar profile of field
      potentials recorded in CA3 and CA1 suggests that glutamate is released from axons
      of CA3 pyramidal cells despite the blockade of fast axonal Na(+) channels by TTX.
      Synchronous discharges may result from glutamate released at proximal recurrent
      collaterals after spontaneous Ca(2+) spikes in CA3 pyramidal cells.

PMID- 10407018
TI  - Determinants of excitability at transition zones in Kv1.1-deficient myelinated
      nerves.
AB  - This study examines the role of K channel segregation and fiber geometry at
      transition zones of mammalian nerve terminals in the peripheral nervous system.
      Mutant mice that are deficient in Kv1.1, a fast Shaker K channel normally
      localized beneath the myelin sheath, display three types of cooling-induced
      abnormal hyperexcitability localized to regions before the transition zones of
      myelinated nerves. The first type is stimulus-evoked nerve backfiring that is
      absent at birth, peaks at postnatal day 17 (P17), and subsides in adults. The
      second type is spontaneous activity that has a more delayed onset, peaks at P30,
      and also disappears in older mice (>P60). TEA greatly amplifies this spontaneous
      activity with an effective dosage of approximately 0.7 mM, and can induce its
      reappearance in older mutant mice (>P100). These first two types of
      hyperexcitability occur only in homozygous mutants that are completely devoid of
      Kv1.1. The third type occurs in heterozygotes and represents a synergism between
      a TEA-sensitive channel and Kv1.1. Heterozygotes exposed to TEA display no overt
      phenotype until a single stimulation is given, which is then followed by an
      indefinite phase of repetitive discharge. Computer modeling suggests that the
      excitability of the transition zone near the nerve terminal has at least two
      major determinants: the preterminal internodal shortening and axonal slow K
      channels. We suggest that variations in fiber geometry create sites of inherent
      instability that is normally stabilized by a synergism between myelin-concealed
      Kv1.1 and a slow, TEA-sensitive K channel.

PMID- 10407019
TI  - alpha-Synuclein shares physical and functional homology with 14-3-3 proteins.
AB  - alpha-Synuclein has been implicated in the pathophysiology of many
      neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's
      disease. Mutations in alpha-synuclein cause some cases of familial PD
      (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many
      neurodegenerative diseases show accumulation of alpha-synuclein in dystrophic
      neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that alpha
      synuclein shares physical and functional homology with 14-3-3 proteins, which are
      a family of ubiquitous cytoplasmic chaperones. Regions of alpha-synuclein and 14
      3-3 proteins share over 40% homology. In addition, alpha-synuclein binds to 14-3
      3 proteins, as well as some proteins known to associate with 14-3-3, including
      protein kinase C, BAD, and extracellular regulated kinase, but not Raf-1. We also
      show that overexpression of alpha-synuclein inhibits protein kinase C activity.
      The association of alpha-synuclein with BAD and inhibition of protein kinase C
      suggests that increased expression of alpha-synuclein could be harmful.
      Consistent with this hypothesis, we observed that overexpression of wild-type
      alpha-synuclein is toxic, and overexpression of alpha-synuclein containing the
      A53T or A30P mutations exhibits even greater toxicity. The activity and binding
      profile of alpha-synuclein suggests that it might act as a protein chaperone and
      that accumulation of alpha-synuclein could contribute to cell death in
      neurodegenerative diseases.

PMID- 10407020
TI  - Estrogen stimulates a transient increase in the number of new neurons in the
      dentate gyrus of the adult female rat.
AB  - To determine whether a sex difference exists in the production of hippocampal
      cells during adulthood, we examined proliferating cells and their progeny in
      adult rats using the thymidine analog bromodeoxyuridine (BrdU) combined with
      immunohistochemistry for markers of neurons and glia. Additionally, to determine
      whether ovarian hormones affect cell proliferation, we examined the numbers of
      BrdU-labeled cells at different estrous cycle stages and after ovarian steroid
      manipulation. Stereological analyses of the numbers of BrdU-labeled cells
      revealed that females produced more cells than males in the dentate gyrus but not
      in the subventricular zone. The production of new hippocampal cells in females
      appears to be affected by ovarian hormone levels; ovariectomy diminished the
      number of BrdU-labeled cells, an effect reversed by estrogen replacement. A
      natural fluctuation in cell proliferation was also noted; females produced more
      cells during proestrus (when estrogen levels are highest) compared with estrus
      and diestrus. Many of these cells acquired neuronal characteristics, including
      the formation of dendrites and expression of Turned-On-After-Division 64 kDa, a
      marker of immature granule neurons, and the calcium-binding protein calbindin, a
      marker of mature granule neurons. However, examination of the numbers of pyknotic
      cells and the numbers of BrdU-labeled cells at longer survival times revealed
      that many new cells in the dentate gyrus eventually degenerate. Consistently the
      number of labeled cells in females is no longer higher than that observed in
      males by 2 weeks after the last BrdU injection. These findings suggest that
      estrogen-enhanced cell proliferation during proestrus results in more immature
      neurons in the hippocampal formation of females compared with males and present
      the possibility that these new cells exert an important influence on hippocampal
      function.

PMID- 10407021
TI  - Directing gene expression to gustducin-positive taste receptor cells.
AB  - We have demonstrated that an 8.4 kb segment (GUS(8.4)) from the upstream region
      of the mouse alpha-gustducin gene acts as a fully functional promoter to target
      lacZ transgene expression to the gustducin-positive subset of taste receptor
      cells (TRCs). The GUS(8. 4) promoter drove TRC expression of the beta
      galactosidase marker at high levels and in a developmentally appropriate pattern.
      The gustducin minimal 1.4 kb promoter (GUS(1.4)) by itself was insufficient to
      specify TRC expression. We also identified an upstream enhancer from the distal
      portion of the murine gustducin gene that, in combination with the minimal
      promoter, specified TRC expression of transgenes. Expression of the lacZ
      transgene from the GUS(8.4) promoter and of endogenous gustducin was coordinately
      lost after nerve section and simultaneously recovered after reinnervation,
      confirming the functionality of this promoter. Transgenic expression of rat alpha
      gustducin restored responsiveness of gustducin null mice to both bitter and sweet
      compounds, demonstrating the utility of the gustducin promoter.

PMID- 10407022
TI  - Robust regeneration of adult sensory axons in degenerating white matter of the
      adult rat spinal cord.
AB  - We have recently reported that minimally disturbed adult CNS white matter can
      support regeneration of adult axons by using a novel microtransplantation
      technique to inject minute volumes of dissociated adult rat dorsal root ganglion
      neurons directly into adult rat CNS pathways (Davies et al., 1997). This
      atraumatic injection procedure minimized scarring and allowed considerable
      numbers of regenerating adult axons immediate access to the adult CNS glial
      terrain where they rapidly extended for long distances. A critical question
      remained as to whether degenerating white matter at acute and chronic stages (up
      to 3 months) after injury could still support regeneration. To investigate this,
      we have microtransplanted adult sensory neurons into degenerating white matter of
      the adult rat spinal cord several millimeters rostral to a severe lesion of the
      dorsal columns. Regeneration of donor sensory axons in both directions away from
      the site of transplantation was robust even within white matter undergoing
      fulminant Wallerian degeneration despite intimate contact with myelin. Along
      their route, the regrowing axons extended large numbers of collaterals into the
      adjacent dorsal horn. However, after entering the lesion, the rapidly extending
      growth cones stopped and became dystrophic within high concentrations of reactive
      glial matrix. Our results offer compelling evidence that the major environmental
      impediment to regeneration in the adult CNS is the molecular barrier that forms
      directly at the lesion site, and that degenerating white matter beyond the glial
      scar has a far greater intrinsic ability to support axon regeneration than
      previously thought possible.

PMID- 10407023
TI  - Subcellular localization of full-length and truncated Trk receptor isoforms in
      polarized neurons and epithelial cells.
AB  - Neurotrophins affect neuronal development and plasticity via spatially localized
      effects, yet little is known about the subcellular distribution of the Trk
      neurotrophin receptors and the impact of this distribution on neurotrophin
      action. To address this, we examined the subcellular location of full-length TrkB
      and TrkC tyrosine kinase receptors and truncated TrkB isoforms after transfection
      of Madin-Darby canine kidney (MDCK) cells, dissociated primary hippocampal
      neurons, and cortical neurons within intact brain slices. Myc-, herpes virus
      glycoprotein (HVG)-, or FLAG-derived epitope-tagged receptor isoforms were
      created to allow their unambiguous identification and localization after
      transfection. All tagged receptors were appropriately synthesized, and full
      length myc-TrkB and myc-TrkC mediated appropriate neurotrophin-signaling events.
      We found that full-length TrkB receptors were excluded from the apical domain of
      MDCK cells but that TrkC receptors were present in both apical and basolateral
      domains. Full-length TrkB and TrkC were found throughout transfected primary
      cultured hippocampal neurons and transfected neurons in neocortical brain slices
      and showed no evidence of vectorial sorting. Truncated forms of TrkB were also
      homogeneously distributed in MDCK cells, dissociated hippocampal neurons, and
      cortical neurons within slice preparations. Levels of full-length and truncated
      TrkB were examined in postsynaptic densities; both receptor isoforms were present
      but only moderately enriched in these structures. Together, these findings
      suggest that Trk receptors are uniformly distributed in both axonal and dendritic
      compartments and that local neurotrophin responses are controlled by other
      mechanisms.

PMID- 10407024
TI  - Rabphilin knock-out mice reveal that rabphilin is not required for rab3 function
      in regulating neurotransmitter release.
AB  - Rab3A and rab3C are GTP-binding proteins of synaptic vesicles that regulate
      vesicle exocytosis. Rabphilin is a candidate rab3 effector at the synapse because
      it binds to rab3s in a GTP-dependent manner, it is co-localized with rab3s on
      synaptic vesicles, and it dissociates with rab3s from the vesicles during
      exocytosis. Rabphilin contains two C(2) domains, which could function as Ca(2+)
      sensors in exocytosis and is phosphorylated as a function of stimulation.
      However, it is unknown what essential function, if any, rabphilin performs. One
      controversial question regards the respective roles of rab3s and rabphilin in
      localizing each other to synaptic vesicles: although rabphilin is mislocalized in
      rab3A knock-out mice, purified synaptic vesicles were shown to require rabphilin
      for binding of rab3A but not rab3A for binding of rabphilin. To test whether
      rabphilin is involved in localizing rab3s to synaptic vesicles and to explore the
      functions of rabphilin in regulating exocytosis, we have now analyzed knock-out
      mice for rabphilin. Mice that lack rabphilin are viable and fertile without
      obvious physiological impairments. In rabphilin-deficient mice, rab3A is targeted
      to synaptic vesicles normally, whereas in rab3A-deficient mice, rabphilin
      transport to synapses is impaired. These results show that rabphilin binds to
      vesicles via rab3s, consistent with an effector function of rabphilin for a
      synaptic rab3-signal. Surprisingly, however, no abnormalities in synaptic
      transmission or plasticity were observed in rabphilin-deficient mice; synaptic
      properties that are impaired in rab3A knock-out mice were unchanged in rabphilin
      knock-out mice. Our data thus demonstrate that rabphilin is endowed with the
      properties of a rab3 effector but is not essential for the regulatory functions
      of rab3 in synaptic transmission.

PMID- 10407025
TI  - The stoned proteins regulate synaptic vesicle recycling in the presynaptic
      terminal.
AB  - The Drosophila stoned locus was identified 25 years ago on the basis of stress
      sensitive behavioral mutants (Grigliatti et al., 1973). The locus is dicistronic
      and encodes two distinct proteins, stoned A and stoned B, which are expressed
      specifically in presynaptic terminals at central and peripheral synapses. Several
      stoned mutant alleles cause embryonic lethality, suggesting that these proteins
      are essential for synaptic function. Physiological analyses at the stoned synapse
      reveal severe neurotransmission defects, including reduced and asynchronous
      neurotransmitter release and rapid fatigue after repetitive stimulation. At the
      EM level, stoned synapses show a depletion of synaptic vesicles and a concomitant
      increase in membrane-recycling intermediates. Mutant terminals also display a
      specific mislocalization of the synaptic vesicle protein synaptotagmin. These
      results suggest that the stoned proteins are essential for the recycling of
      synaptic vesicle membrane and are required for the proper sorting of
      synaptotagmin during endocytosis.

PMID- 10407026
TI  - Ca(2+)-permeable AMPA receptors induce phosphorylation of cAMP response element
      binding protein through a phosphatidylinositol 3-kinase-dependent stimulation of
      the mitogen-activated protein kinase signaling cascade in neurons.
AB  - Ca(2+)-permeable AMPA receptors may play a key role during developmental
      neuroplasticity, learning and memory, and neuronal loss in a number of
      neuropathologies. However, the intracellular signaling pathways used by AMPA
      receptors during such processes are not fully understood. The mitogen-activated
      protein kinase (MAPK) cascade is an attractive target because it has been shown
      to be involved in gene expression, synaptic plasticity, and neuronal stress.
      Using primary cultures of mouse striatal neurons and a phosphospecific MAPK
      antibody we addressed whether AMPA receptors can activate the MAPK cascade. We
      found that in the presence of cyclothiazide, AMPA caused a robust and direct (no
      involvement of NMDA receptors or L-type voltage-sensitive Ca(2+) channels) Ca(2+)
      dependent activation of MAPK through MAPK kinase (MEK). This activation was
      blocked by GYKI 53655, a noncompetitive selective antagonist of AMPA receptors.
      Probing the mechanism of this activation revealed an essential role for
      phosphatidylinositol 3-kinase (PI 3-kinase) and the involvement of a pertussis
      toxin (PTX)-sensitive G-protein, a Src family protein tyrosine kinase, and
      Ca(2+)/calmodulin-dependent kinase II. Similarly, kainate activated MAPK in a PI
      3-kinase-dependent manner. AMPA receptor-evoked neuronal death and arachidonic
      acid mobilization did not appear to involve signaling through the MAPK pathway.
      However, AMPA receptor stimulation led to a Ca(2+)-dependent phosphorylation of
      the nuclear transcription factor CREB, which could be prevented by inhibitors of
      MEK or PI 3-kinase. Our results indicate that Ca(2+)-permeable AMPA receptors
      transduce signals from the cell surface to the nucleus of neurons through a PI 3
      kinase-dependent activation of MAPK. This novel pathway may play a pivotal role
      in regulating synaptic plasticity in the striatum.

PMID- 10407027
TI  - Supralinear summation of synaptic inputs by an invertebrate neuron: dendritic
      gain is mediated by an "inward rectifier" K(+) current.
AB  - Dendritic processing of glutamatergic synaptic inputs was investigated in the
      anterior pagoda cell of leech. We observed that below spike threshold, the
      amplitude of individual EPSPs decreased with hyperpolarization and that
      simultaneous stimulation of pairs of synaptic inputs leads to the supralinear
      summation of EPSPs. Voltage-clamp measurements revealed a hyperpolarization
      activated, Ba(2+)-sensitive, fast, noninactivating K(+) conductance that depends
      on the external [K(+)]. These features are those of an "inward rectifier," Kir.
      Microsurgery experiments, in combination with electrophysiological measurements,
      revealed an inhomogeneous spatial distribution of the Kir conductance.
      Furthermore, on surgical removal of the neurites that contain the Kir
      conductance, the amplitude of EPSPs from the remaining synaptic inputs increased
      with hyperpolarization. A model cell, with the Kir conductance as the sole
      voltage-dependent conductance, reproduced qualitatively the observed voltage
      dependence of individual EPSPs as well as the supralinear summation of EPSP
      pairs.

PMID- 10407028
TI  - Disruption of a retinal guanylyl cyclase gene leads to cone-specific dystrophy
      and paradoxical rod behavior.
AB  - One of two orphan photoreceptor guanylyl cyclases that are highly conserved from
      fish to mammals, GC-E (or retGC1) was eliminated by gene disruption. Expression
      of the second retinal cyclase (GC-F) as well as the numbers and morphology of
      rods remained unchanged in GC-E null mice. However, rods isolated from such mice,
      despite having a normal dark current, recovered from a light flash markedly
      faster. Unexpectedly, the a- and b-waves of electroretinograms (ERG) from dark
      adapted null mice were suppressed markedly. Cones, initially present in normal
      numbers in the retina, disappeared by 5 weeks, based on ERG and histology. Thus,
      the GC-E-deficient mouse defines a model for cone dystrophy, but it also
      demonstrates that morphologically normal rods display paradoxical behavior in
      their responses to light.

PMID- 10407029
TI  - Intracellular Ca(2+) oscillations in luteinizing hormone-releasing hormone
      neurons derived from the embryonic olfactory placode of the rhesus monkey.
AB  - To understand the mechanism of pulsatile luteinizing hormone-releasing hormone
      (LHRH) release, we examined whether cultured LHRH neurons exhibit spontaneous
      intracellular Ca(2+) ([Ca(2+)](i)) signaling. The olfactory placode and the
      ventral migratory pathway of LHRH neurons from rhesus monkey embryos at embryonic
      ages 35-37 were dissected out and cultured on glass coverslips. Two to five weeks
      later, cultured cells were labeled with fura-2 and examined for [Ca(2+)](i)
      signaling by recording changes in [Ca(2+)](i) every 10 sec for 30-175 min. Cells
      were fixed and immunostained for LHRH and neuron-specific enolase. In 20
      cultures, 572 LHRH-positive cells exhibited [Ca(2+)](i) oscillations at an
      interpulse interval (IPI) of 8.2 +/- 0.7 min and a duration of 88.8 +/- 2.9 sec.
      LHRH-negative neurons in culture exhibited only occasional [Ca(2+)](i)
      oscillations. In 17 of 20 cultures with LHRH-positive cells, [Ca(2+)](i)
      oscillations occurred synchronously in 50-100% of the individual cells, whereas
      [Ca(2+)](i) oscillations in cells in the remaining three cultures did not
      synchronize. Strikingly, in 12 of 17 cultures the synchronization of [Ca(2+)](i)
      oscillations repeatedly occurred in complete unison at 52.8 +/- 3.0 min
      intervals, which is similar to the period observed for LHRH release, whereas in 5
      of 17 cultures the less tight synchronization of [Ca(2+)](i) oscillations
      repeatedly occurred at 23.4 +/- 4.6 min intervals. IPI of [Ca(2+)](i)
      oscillations in cells with tight synchronization and less tight synchronization
      did not differ from IPI in cells without synchronization. The results indicate
      that LHRH neurons derived from the monkey olfactory placode possess an endogenous
      mechanism for synchronization of [Ca(2+)](i) oscillations. Whether
      synchronization of [Ca(2+)](i) oscillations relates to neurosecretion remains to
      be investigated.

PMID- 10407030
TI  - Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic
      stroke linked to neural damage.
AB  - Nitric oxide (NO) is a new intercellular messenger that occurs naturally in the
      brain without causing overt toxicity. Yet, NO has been implicated as a mediator
      of cell death in cell death. One explanation is that ischemia causes
      overproduction of NO, allowing it to react with superoxide to form the potent
      oxidant peroxynitrite. To address this question, we used immunohistochemistry for
      citrulline, a marker for NO synthase activity, and 3-nitrotyrosine, a marker for
      peroxynitrite formation, in mice subjected to reversible middle cerebral artery
      occlusion. We show that ischemia triggers a marked augmentation in citrulline
      immunoreactivity but more so in the peri-infarct than the infarcted tissue. This
      increase is attributable to the activation of a large population (approximately
      80%) of the neuronal isoform of NO synthase (nNOS) that is catalytically inactive
      during basal conditions, indicating a tight regulation of physiological NO
      production in the brain. In contrast, 3-nitrotyrosine immunoreactivity is
      restricted to the infarcted tissue and is not present in the peri-infarct tissue.
      In nNOS(Delta/Delta) mice, known to be protected against ischemia, no 3
      nitrotyrosine immunoreactivity is detected. Our findings provide a cellular
      localization for nNOS activation in association with ischemic stroke and
      establish that NO is not likely a direct neurotoxin, whereas its conversion to
      peroxynitrite is associated with cell death.

PMID- 10407031
TI  - Overexpression of brain-derived neurotrophic factor enhances sensory innervation
      and selectively increases neuron number.
AB  - Target-derived neurotrophin growth factors have significant effects on the
      development and maintenance of the mammalian somatosensory system. Studies of
      transgenic mice that overexpress neurotrophins NGF and neurotrophin 3 (NT-3) at
      high levels in skin have shown increased sensory neuron number and enhanced
      innervation of specific sensory ending types. The effects of two other members of
      this family, BDNF and NT-4, on sensory neuron development are less clear. This
      study examined the role of brain-derived neurotrophic factor (BDNF) using
      transgenic mice that overexpress BDNF in epithelial target tissues of sensory
      neurons. BDNF transgenic mice had an increase in peripheral innervation density
      and showed selective effects on neuron survival. Neuron number in trigeminal
      ganglia, DRG, and SCG were unchanged, although a 38% increase in neurons
      comprising the placode-derived nodose-petrosal complex occurred. BDNF transgenic
      skin showed notable enhancement of innervation to hair follicles as detected by
      PGP9.5 immunolabeling. In nonhairy plantar skin, Meissner corpuscle sensory
      endings were larger, and the number of Merkel cells with associated innervation
      was increased. In trigeminal ganglia, neurons expressing trkB receptor were
      increased threefold, whereas trkA-positive neurons doubled. Analysis of trkB by
      Northern, reverse transcription-PCR, and Western assays indicated a modest
      increase in the expression of the T1 truncated receptor and preferential
      distribution to the periphery. These data indicate that skin-derived BDNF does
      not enhance survival of cutaneous sensory neurons, although it does promote
      neurite innervation of specific sites and sensory end organs of the skin.

PMID- 10407032
TI  - Caspase-8 and caspase-3 are expressed by different populations of cortical
      neurons undergoing delayed cell death after focal stroke in the rat.
AB  - A number of studies have provided evidence that neuronal cell loss after stroke
      involves programmed cell death or apoptosis. In particular, recent biochemical
      and immunohistochemical studies have demonstrated the expression and activation
      of intracellular proteases, notably caspase-3, which act as both initiators and
      executors of the apoptotic process. To further elucidate the involvement of
      caspases in neuronal cell death induced by focal stroke we developed a panel of
      antibodies and investigated the spatial and temporal pattern of both caspase-8
      and caspase-3 expression. Our efforts focused on caspase-8 because its "apical"
      position within the enzymatic cascade of caspases makes it a potentially
      important therapeutic target. Constitutive expression of procaspase-8 was
      detectable in most cortical neurons, and proteolytic processing yielding the
      active form of caspase-8 was found as early as 6 hr after focal stroke induced in
      rats by permanent middle cerebral artery occlusion. This active form of caspase-8
      was predominantly seen in the large pyramidal neurons of lamina V. Active caspase
      3 was evident only in neurons located within lamina II/III starting at 24 hr
      after injury and in microglia throughout the core infarct at all times examined.
      Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end
      labeling, gel electrophoresis of DNA, and neuronal cell quantitation indicated
      that there was an early nonapoptotic loss of cortical neurons followed by a
      progressive elimination of neurons with features of apoptosis. These data
      indicate that the pattern of caspase expression occurring during delayed neuronal
      cell death after focal stroke will vary depending on the neuronal phenotype.

PMID- 10407033
TI  - Modulation of glioma cell migration and invasion using Cl(-) and K(+) ion channel
      blockers.
AB  - Human malignant gliomas are highly invasive tumors. Mechanisms that allow glioma
      cells to disseminate, migrating through the narrow extracellular brain spaces are
      poorly understood. We recently demonstrated expression of large voltage-dependent
      chloride (Cl(-)) currents, selectively expressed by human glioma cells in vitro
      and in situ (Ullrich et al., 1998). Currents are sensitive to several Cl(-)
      channel blockers, including chlorotoxin (Ctx), (Ullrich and Sontheimer; 1996;
      Ullrich et al; 1996), tetraethylammonium chloride (TEA), and tamoxifen (Ransom
      and Sontheimer, 1998). Using Transwell migration assays, we show that blockade of
      glioma Cl(-) channels specifically inhibits tumor cell migration in a dose
      dependent manner. Ctx (5 microM), tamoxifen (10 microM), and TEA (1 mM) also
      prevented invasion of human glioma cells into fetal rat brain aggregates, used as
      an in vitro model to assess tumor invasiveness. Anion replacement studies suggest
      that permeation of chloride ions through glioma chloride channel is obligatory
      for cell migration. Osmotically induced cell swelling and subsequent regulatory
      volume decrease (RVD) in cultured glioma cells were reversibly prevented by 1 mM
      TEA, 10 microM tamoxifen, and irreversibly blocked by 5 microM Ctx added to the
      hypotonic media. Cl(-) fluxes associated with adaptive shape changes elicited by
      cell swelling and RVD in glioma cells were inhibited by 5 microM Ctx, 10 microM
      tamoxifen, and 1 mM TEA, as determined using the Cl(-)-sensitive fluorescent dye
      6-methoxy-N-ethylquinolinium iodide. Collectively, these data suggest that
      chloride channels in glioma cells may enable tumor invasiveness, presumably by
      facilitating cell shape and cell volume changes that are more conducive to
      migration and invasion.

PMID- 10407034
TI  - Promoter transgenics reveal multiple gonadotropin-releasing hormone-I-expressing
      cell populations of different embryological origin in mouse brain.
AB  - Gonadotropin-releasing hormone-I (GnRH-I) is thought to be expressed by a single,
      highly spatially restricted group of neurons, which originate in the olfactory
      placode and migrate through the nose into the medial septum and hypothalamus from
      where they control fertility. Transgenic mice bearing a 13.5 kb GnRH-I-lacZ
      reporter construct were derived and found to express high levels of beta
      galactosidase mRNA and protein within the septohypothalamic GnRH neurons in a
      correct temporal and spatial manner. Unexpectedly, low levels of beta
      galactosidase were also present in three further populations of cells within the
      lateral septum, bed nucleus of the stria terminalis, and tectum. Analysis of wild
      type mice with three different GnRH-I antibodies revealed distinct and transient
      patterns of GnRH-I peptide expression during development in all three of these
      populations revealed by transgenics. The synthesis of GnRH by cells of the
      lateral septum was the most persistent and remained until the third postnatal
      week. Embryonic "small eye" Pax-6 null mice, which fail to develop an olfactory
      placode, were also examined and shown to have equivalent populations of GnRH-I
      immunoreactive cells in the lateral septum, tectum, and bed nucleus of the stria
      terminalis but none of the migrating cells that form the septohypothalamic GnRH
      population. These results prove that so-called "ectopic" expression in promoter
      transgenic lines can reflect authentic developmental patterns of gene expression.
      They further provide the first demonstration in mammalian brain that multiple
      neuronal populations of different embryological origin express GnRH-I peptide
      during embryonic and postnatal development.

PMID- 10407035
TI  - Molecular evidence for the early specification of presumptive functional domains
      in the embryonic primate cerebral cortex.
AB  - To identify molecules that may play a role in the initiation of cerebral cortical
      area formation, we examined the expression of the Eph receptors and their
      ligands, the ephrins, during primate corticogenesis. We selected the macaque
      monkey neocortex because of its clear areal subdivisions, large surface area,
      protracted development (gestation = 165 d), and similarity to the human brain. In
      situ hybridizations, performed at early [embryonic day 65 (E65)], middle (E80),
      and late (E95) stages of cortical development, revealed that EphA system family
      members are expressed in distinct gradients and laminar and areal domains in the
      embryonic neocortex. Indeed, several regionally restricted molecular patterns are
      already apparent within the cortical plate at E65, before the formation of
      thalamocortical connections, suggesting that the initial expression of some EphA
      system members is regulated by programs intrinsic to cortical cells. For example,
      EphA3, EphA6, and EphA7 are all selectively expressed within the presumptive
      visual cortex. However, although EphA6 and EphA7 are present throughout this
      region, EphA3 is only expressed in the prospective extrastriate cortex,
      suggesting that cortical cells harbor functional biases that may influence the
      formation of appropriate synaptic connections. Although several patterns of early
      gene expression are stable (e.g., EphA3, EphA4, and EphA6), others change as
      development proceeds (e.g., EphA5, EphA7, ephrin-A2, ephrin-A3, and ephrin-A5),
      perhaps responding to extrinsic cues. Thus, at E95, after connections between the
      cortical plate and thalamus have formed, receptor subtypes EphA3, EphA5, EphA6,
      and EphA7 and the ligand ephrin-A5 are expressed in posterior regions, whereas
      EphA4 and ephrin-A2 and ephrin-A3 are either uniformly distributed or anteriorly
      biased. Taken together, our results demonstrate molecular distinctions among
      cells of the embryonic primate neocortex, revealing hitherto unrecognized
      compartmentalization early in corticogenesis.

PMID- 10407036
TI  - Targeted mutagenesis of the POU-domain gene Brn4/Pou3f4 causes developmental
      defects in the inner ear.
AB  - Targeted mutagenesis in mice demonstrates that the POU-domain gene Brn4/Pou3f4
      plays a crucial role in the patterning of the mesenchymal compartment of the
      inner ear. Brn4 is expressed extensively throughout the condensing mesenchyme of
      the developing inner ear. Mutant animals displayed behavioral anomalies that
      resulted from functional deficits in both the auditory and vestibular systems,
      including vertical head bobbing, changes in gait, and hearing loss. Anatomical
      analyses of the temporal bone, which is derived in part from the otic mesenchyme,
      demonstrated several dysplastic features in the mutant animals, including
      enlargement of the internal auditory meatus. Many phenotypic features of the
      mutant animals resulted from the reduction or thinning of the bony compartment of
      the inner ear. Histological analyses demonstrated a hypoplasia of those regions
      of the cochlea derived from otic mesenchyme, including the spiral limbus, the
      scala tympani, and strial fibrocytes. Interestingly, we observed a reduction in
      the coiling of the cochlea, which suggests that Brn-4 plays a role in the
      epithelial-mesenchymal communication necessary for the cochlear anlage to develop
      correctly. Finally, the stapes demonstrated several malformations, including
      changes in the size and morphology of its footplate. Because the stapes anlage
      does not express the Brn4 gene, stapes malformations suggest that the Brn4 gene
      also plays a role in mesenchymal-mesenchymal signaling. On the basis of these
      data, we suggest that Brn-4 enhances the survival of mesodermal cells during the
      mesenchymal remodeling that forms the mature bony labyrinth and regulates
      inductive signaling mechanisms in the otic mesenchyme.

PMID- 10407037
TI  - Site-specific migration and neuronal differentiation of human neural progenitor
      cells after transplantation in the adult rat brain.
AB  - Neural progenitor cells obtained from the embryonic human forebrain were expanded
      up to 10(7)-fold in culture in the presence of epidermal growth factor, basic
      fibroblast growth factor, and leukemia inhibitory growth factor. When
      transplanted into neurogenic regions in the adult rat brain, the subventricular
      zone, and hippocampus, the in vitro propagated cells migrated specifically along
      the routes normally taken by the endogenous neuronal precursors: along the
      rostral migratory stream to the olfactory bulb and within the subgranular zone in
      the dentate gyrus, and exhibited site-specific neuronal differentiation in the
      granular and periglomerular layers of the bulb and in the dentate granular cell
      layer. The cells exhibited substantial migration also within the non-neurogenic
      region, the striatum, in a seemingly nondirected manner up to approximately 1-1.5
      mm from the graft core, and showed differentiation into both neuronal and glial
      phenotypes. Only cells with glial-like features migrated over longer distances
      within the mature striatum, whereas the cells expressing neuronal phenotypes
      remained close to the implantation site. The ability of the human neural
      progenitors to respond in vivo to guidance cues and signals that can direct their
      differentiation along multiple phenotypic pathways suggests that they can provide
      a powerful and virtually unlimited source of cells for experimental and clinical
      transplantation.

PMID- 10407038
TI  - Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of
      basic fibroblast growth factor.
AB  - Mounting evidence indicates that extracellular factors exert proliferative
      effects on neurogenetic precursors in vivo. Recently we found that systemic
      levels of basic fibroblast growth factor (bFGF) regulate neurogenesis in the
      brain of newborn rats, with factors apparently crossing the blood-brain barrier
      (BBB) to stimulate mitosis. To determine whether peripheral bFGF affects
      proliferation during adulthood, we focused on regions in which neurogenesis
      persists into maturity, the hippocampus and the forebrain subventricular zone
      (SVZ). In postnatal day 1 (P1) rats, 8 hr after subcutaneous injection (5 ng/gm
      body weight), bFGF increased [(3)H]thymidine incorporation 70% in hippocampal and
      SVZ homogenates and elicited twofold increases in mitotic nuclei in the dentate
      gyrus and the dorsolateral SVZ, detected by bromodeoxyuridine
      immunohistochemistry. Because approximately 25% of proliferating hippocampal
      cells stimulated in vivo expressed neuronal traits in culture, bFGF-induced
      mitosis may reflect increased neurogenesis. bFGF effects were not restricted to
      the perinatal period; hippocampal DNA synthesis was stimulated by peripheral
      factor in older animals (P7-P21), indicating the persistence of bFGF-responsive
      cells and activity of peripheral bFGF into late development. To begin defining
      underlying mechanisms, pharmacokinetic studies were performed in P28 rats; bFGF
      transferred from plasma to CSF rapidly, levels rising in both compartments in
      parallel, indicating that peripheral factor crosses the BBB during maturity.
      Consequently, we tested bFGF in adults; peripheral bFGF increased the number of
      mitotic nuclei threefold in the SVZ and olfactory tract, regions exhibiting
      persistent neurogenesis. Our observations suggest that bFGF regulates ongoing
      neurogenesis via a unique, endocrine-like pathway, potentially coordinating
      neuron number and body growth, and potentially providing new approaches for
      treating damaged brain during development and adulthood.

PMID- 10407039
TI  - Migration defects of cdk5(-/-) neurons in the developing cerebellum is cell
      autonomous.
AB  - Cyclin-dependent kinase 5 (Cdk5) is a member of the family of cell cycle-related
      kinases. Previous neuropathological analysis of cdk5(-/-) mice showed significant
      changes in CNS development in regions from cerebral cortex to brainstem. Among
      the defects in these animals, a disruption of the normal pattern of cell
      migrations in cerebellum was particularly apparent, including a pronounced
      abnormality in the location of cerebellar Purkinje cells. Complete analysis of
      this brain region is hampered in the mutant because most of cerebellar
      morphogenesis occurs after birth and the cdk5(-/-) mice die in the perinatal
      period. To overcome this disadvantage, we have generated chimeric mice by
      injection of cdk5(-/-) embryonic stem cells into host blastocysts. Analysis of
      the cerebellum from the resulting cdk5(-/-) left arrow over right arrow cdk5(+/+)
      chimeric mice shows that the abnormal location of the mutant Purkinje cells is a
      cell-autonomous defect. In addition, significant numbers of granule cells remain
      located in the molecular layer, suggesting a failure to complete migration from
      the external to the internal granule cell layer. In contrast to the Purkinje and
      granule cell populations, all three of the deep cerebellar nuclear cell groupings
      form correctly and are composed of cells of both mutant and wild-type genotypes.
      Despite similarities of the cdk5(-/-) phenotype to that reported in reeler and
      mdab-1(-/-) (scrambler/yotari) mutant brains, reelin and disabled-1 mRNA were
      found to be normal in cdk5(-/-) brain. Together, the data further support the
      hypothesis that Cdk5 activity is required for specific components of neuronal
      migration that are differentially required by different neuronal cell types and
      by even a single neuronal cell type at different developmental stages.

PMID- 10407040
TI  - Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant
      mouse stargazer.
AB  - The spontaneous recessive mutant mouse stargazer (stg) begins to show ataxia
      around postnatal day 14 and display a severe impairment in the acquisition of
      classical eyeblink conditioning in adulthood. These abnormalities have been
      attributed to the specific reduction in brain-derived neurotrophic factor (BDNF)
      and the subsequent defect in TrkB receptor signaling in cerebellar granule cells
      (GCs). In the stg mutant cerebellum, we found that EPSCs at mossy fiber (MF) to
      GC synapses are devoid of the fast component mediated by AMPA-type glutamate
      receptors despite the normal slow component mediated by NMDA receptors. The
      sensitivity of stg mutant GCs to exogenously applied AMPA was greatly reduced,
      whereas that to NMDA was unchanged. Glutamate release from MF terminals during
      synaptic transmission to GCs appeared normal. By contrast, AMPA receptor-mediated
      EPSCs were normal in CA1 pyramidal cells of the stg mutant hippocampus. Thus,
      postsynaptic AMPA receptor function was selectively impaired in stg mutant GCs,
      although the transcription of four AMPA receptor subunit genes in the stg GC was
      comparable to the wild-type GC. We also examined the cerebellum of BDNF knockout
      mice and found that their MF-GC synapses had a normal AMPA receptor-mediated EPSC
      component. Thus, the impaired AMPA receptor function in the stg mutant GC is not
      likely to result from the reduced BDNF-TrkB signaling. These results suggest that
      the defect in MF to GC synaptic transmission is a major factor that causes the
      cerebellar dysfunction in the stg mutant mouse.

PMID- 10407041
TI  - Development of topography within song control circuitry of zebra finches during
      the sensitive period for song learning.
AB  - Refinement of topographic maps during sensitive periods of development is a
      characteristic feature of diverse sensory and motor circuits in the nervous
      system. Within the neural system that controls vocal learning and behavior in
      zebra finches, axonal connections of the cortical nucleus lMAN demonstrate
      striking functional and morphological changes during vocal development in
      juvenile males. These circuits are uniquely important for song production during
      the sensitive period for vocal learning, and the overall size of these brain
      regions and their patterns of axonal connectivity undergo dramatic growth and
      regression during this time. Axonal connections to and from lMAN are
      topographically organized in adult males that have already learned song. We
      wondered whether the large-scale changes seen in lMAN circuitry during the time
      that vocal behavior is being learned and refined could be accompanied by the
      emergence of topographic mapping. However, results presented herein demonstrate
      that most of these song-control circuits show the same broad patterns of axonal
      connectivity between subregions of individual nuclei at the onset of song
      learning as seen in adult birds. Thus, coarse topographic organization is not
      dependent on the types of experience that are crucial for vocal learning.
      Furthermore, this maintenance of topographic organization throughout the period
      of song learning is clearly not achieved by maintenance of static axonal arbors.
      In fact, because the volumes of song-control nuclei are growing (or regressing),
      topography must be maintained by active remodeling of axonal arbors to adapt to
      the changes in overall size of postsynaptic targets. A salient exception to this
      pattern of conserved topography is the projection from lMAN to the motor cortical
      region RA: this pathway is diffusely organized at the onset of song learning but
      undergoes substantial refinement during early stages of song learning, suggesting
      that remodeling of axonal connections within this projection during the period of
      vocal learning may signify the production of increasingly refined vocal
      utterances.

PMID- 10407042
TI  - Loss of distal axons and sensory Merkel cells and features indicative of muscle
      denervation in hindlimbs of P0-deficient mice.
AB  - Mice lacking the major Schwann cell myelin component P0 show a severe
      dysmyelination with pathological features reminiscent of the Dejerine-Sottas
      syndrome in humans. Previous morphological and electrophysiological studies on
      these mice did not only demonstrate a compromised myelination and myelin
      maintenance, but were suggestive of an impairment of axons as well. Here, we
      studied the axonal pathology in P0-deficient mice by quantitative electron
      microscopy. In addition, we investigated epidermal receptor end organs by
      immunocytochemistry and muscle pathology by histochemistry. In proximal sections
      of facial and femoral nerves, axon calibers were significantly reduced, whereas
      the number of myelin-competent axons was not diminished in 5- and 17-month-old P0
      deficient mice. However, in distal branches of the femoral and sciatic nerve
      (digital nerves innervating the skin of the first toe) the numbers of myelin
      competent axons were reduced by 70% in 6-month-old P0-deficient mice.
      Immunolabeling of foot pads revealed a corresponding loss of Merkel cells by 75%,
      suggesting that survival of these cells is dependent on the presence or
      maintenance of their innervating myelinated axons. In addition, quadriceps and
      gastrocnemius muscles showed pathological features indicative of denervation and
      axonal sprouting. These findings demonstrate that loss of an important myelin
      component can initiate degenerative mechanisms not only in the Schwann cell but
      also in the distal portions of myelinated axons, leading to the degeneration of
      specialized receptor end organs and impairment of muscle innervation.

PMID- 10407043
TI  - Increased anxiety and impaired pain response in puromycin-sensitive
      aminopeptidase gene-deficient mice obtained by a mouse gene-trap method.
AB  - A mouse mutation, termed goku, was generated by a gene-trap strategy. goku
      homozygous mice showed dwarfism, a marked increase in anxiety, and an analgesic
      effect. Molecular analysis indicated that the mutated gene encodes a puromycin
      sensitive aminopeptidase (Psa; EC 3. 4.11.14), whose functions in vivo are
      unknown. Transcriptional arrest of the Psa gene and a drastic decrease of
      aminopeptidase activity indicated that the function of Psa is disrupted in
      homozygous mice. Together with the finding that the Psa gene is strongly
      expressed in the brain, especially in the striatum and hippocampus, these results
      suggest that the Psa gene is required for normal growth and the behavior
      associated with anxiety and pain.

PMID- 10407045
TI  - Synaptic control of spiking in cerebellar Purkinje cells: dynamic current clamp
      based on model conductances.
AB  - Previous simulations using a realistic model of a cerebellar Purkinje cell
      suggested that synaptic control of somatic spiking in this cell type is mediated
      by voltage-gated intrinsic conductances and that inhibitory rather than
      excitatory synaptic inputs are more influential in controlling spike timing. In
      this paper, we have tested these predictions physiologically using dynamic
      current clamping to apply model-derived synaptic conductances to Purkinje cells
      in vitro. As predicted by the model, this input transformed the in vitro pattern
      of spiking into a different spike pattern typically observed in vivo. A net
      inhibitory synaptic current was required to achieve such spiking, indicating the
      presence of strong intrinsic depolarizing currents. Spike-triggered averaging
      confirmed that the length of individual intervals between spikes was correlated
      to the amplitude of the inhibitory conductance but was not influenced by
      excitatory inputs. Through repeated presentation of identical stimuli, we
      determined that the output spike rate was very sensitive to the relative balance
      of excitation and inhibition in the input conductances. In contrast, the accuracy
      of spike timing was dependent on input amplitude and was independent of spike
      rate. Thus, information could be encoded in Purkinje cell spiking in a precise
      spike time code and a rate code at the same time. We conclude that Purkinje cell
      responses to synaptic input are strongly dependent on active somatic and
      dendritic properties and that theories of cerebellar function likely need to
      incorporate single-cell dynamics to a greater degree than is customary.

PMID- 10407044
TI  - Shunting versus inactivation: analysis of presynaptic inhibitory mechanisms in
      primary afferents of the crayfish.
AB  - Primary afferent depolarizations (PADs) are associated with presynaptic
      inhibition in both vertebrates and invertebrates. In the present study, we have
      used both anatomical and electrophysiological techniques to analyze the relative
      importance of shunting mechanisms versus sodium channel inactivation in mediating
      the decrease of action potential amplitude, and thereby presynaptic inhibition.
      Experiments were performed in sensory afferents of a stretch receptor in an in
      vitro preparation of the crayfish. Lucifer yellow intracellular labeling of
      sensory axons combined with GABA immunohistochemistry revealed close appositions
      between GABA-immunoreactive (ir) fibers and sensory axons. Most contacts were
      located on the main axon at the entry zone of the ganglion, close to the first
      branching point within the ganglion. By comparison, the output synapses of
      sensory afferents to target neurons were located on distal branches. The location
      of synaptic inputs mediating spontaneous PADs was also determined
      electrophysiologically by making dual intracellular recordings from single
      sensory axons. Inputs generating PADs appear to occur around the first axonal
      branching point, in agreement with the anatomical data. In this region, small
      PADs (3-15 mV) produced a marked reduction of action potential amplitude, whereas
      depolarization of the membrane potential by current injection up to 15 mV had no
      effect. These results suggest that the decrease of the amplitude of action
      potentials by single PADs results from a shunting mechanism but does not seem to
      involve inactivation of sodium channels. Our results also suggest that GABAergic
      presynaptic inhibition may act as a global control mechanism to block
      transmission through certain reflex pathways.

PMID- 10407046
TI  - Glutamate-triggered events inducing corticostriatal long-term depression.
AB  - Repetitive activation of corticostriatal fibers produces long-term depression
      (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons.
      This form of synaptic plasticity might be considered the possible neural basis of
      some forms of motor learning and memory. In the present study, intracellular
      recordings were performed from rat corticostriatal slice preparations to study
      the role of glutamate and other critical factors underlying striatal LTD. In
      current-clamp, but not in voltage-clamp experiments, brief focal applications of
      glutamate, as well as high-frequency stimulation (HFS) of corticostriatal fibers,
      induced LTD. This pharmacological LTD and the HFS-induced LTD were mutually
      occlusive, suggesting that both forms of synaptic plasticity share common
      induction mechanisms. Isolated activation of either non-NMDA-ionotropic glutamate
      receptors (iGluRs) or metabotropic glutamate receptors (mGluRs), respectively by
      AMPA and t-ACPD failed to produce significant long-term changes of
      corticostriatal synaptic transmission. Conversely, LTD was obtained after the
      simultaneous application of AMPA plus t-ACPD. Moreover, also quisqualate, a
      compound that activates both iGluRs and group I mGluRs, was able to induce this
      form of pharmacological LTD. Electrical depolarization of the recorded neurons
      either alone or in the presence of t-ACPD and dopamine (DA) failed to mimic the
      effects of the activation of glutamate receptors in inducing LTD. However,
      electrical depolarization was able to induce LTD when preceded by
      coadministration of t-ACPD, DA, and a low dose of hydroxylamine, a compound
      generating nitric oxide (NO) in the tissue. None of these compounds alone
      produced LTD. Glutamate-induced LTD, as well as the HFS-induced LTD, was blocked
      by L-sulpiride, a D2 DA receptor antagonist, and by 7-nitroindazole monosodium
      salt, a NO synthase inhibitor. The present study indicates that four main factors
      are required to induce corticostriatal LTD: (1) membrane depolarization of the
      postsynaptic neuron; (2) activation of mGluRs; (3) activation of DA receptors;
      and (4) release of NO from striatal interneurons.

PMID- 10407048
TI  - Effects of the sodium channel blocker tetrodotoxin on acute white matter
      pathology after experimental contusive spinal cord injury.
AB  - Focal microinjection of tetrodotoxin (TTX), a potent voltage-gated sodium channel
      blocker, reduces neurological deficits and tissue loss after spinal cord injury
      (SCI). Significant sparing of white matter (WM) is seen at 8 weeks after injury
      and is correlated to a reduction in functional deficits. To determine whether TTX
      exerts an acute effect on WM pathology, Sprague Dawley rats were subjected to a
      standardized weight-drop contusion at T8 (10 gm x 2.5 cm). TTX (0. 15 nmol) or
      vehicle solution was injected into the injury site 5 or 15 min later. At 4 and 24
      hr, ventromedial WM from the injury epicenter was compared by light and electron
      microscopy and immunohistochemistry. By 4 hr after SCI, axonal counts revealed
      reduced numbers of axons and significant loss of large (>/=5 micrometer)-diameter
      axons. TTX treatment significantly reduced the loss of large-diameter axons. In
      addition, TTX significantly attenuated axoplasmic pathology at both 4 and 24 hr
      after injury. In particular, the development of extensive periaxonal spaces in
      the large-diameter axons was reduced with TTX treatment. In contrast, there was
      no significant effect of TTX on the loss of WM glia after SCI. Thus, the long
      term effects of TTX in reducing WM loss after spinal cord injury appear to be
      caused by the reduction of acute axonal pathology. These results support the
      hypothesis that TTX-sensitive sodium channels at axonal nodes of Ranvier play a
      significant role in the secondary injury of WM after SCI.

PMID- 10407047
TI  - Distinct patterns of neuropeptide gene expression in the lateral hypothalamic
      area and arcuate nucleus are associated with dehydration-induced anorexia.
AB  - We have investigated the hormonal and hypothalamic neuropeptidergic substrates of
      dehydration-associated anorexia. In situ hybridization and hormone analyses of
      anorexic and paired food-restricted rats revealed two distinct profiles. First,
      both groups had the characteristic gene expression and endocrine signatures
      usually associated with starvation: increased neuropeptide Y and decreased
      proopiomelanocortin and neurotensin mRNAs in the arcuate nucleus (ARH); increased
      circulating glucocorticoid but reduced leptin and insulin. Dehydrated animals are
      strongly anorexic despite these attributes, showing that the output of leptin-
      and insulin-sensitive ARH neurons that ordinarily stimulate eating must be
      inhibited. The second pattern occurred only in anorexic animals and had two
      components: (1) reduced corticotropin-releasing hormone (CRH) mRNA in the
      neuroendocrine paraventricular nucleus (PVH) and (2) increased CRH and
      neurotensin mRNAs in the lateral hypothalamic (LHA) and retrochiasmatic areas.
      However, neither corticosterone nor suppressed PVH CRH gene expression is
      required for anorexia after dehydration because PVH CRH mRNA in dehydrated
      adrenalectomized animals is unchanged from euhydrated adrenalectomized controls.
      We also showed that LHA CRH mRNA was strongly correlated with the intensity of
      anorexia, increased LHA CRH gene expression preceded the onset of anorexia, and
      dehydrated adrenalectomized animals (which also develop anorexia) had elevated
      LHA CRH gene expression with a distribution pattern similar to intact animals.
      Finally, we identified specific efferents from the CRH-containing region of the
      LHA to the PVH, thereby providing a neuroanatomical framework for the integration
      by the PVH of neuropeptidergic signals from the ARH and the LHA. Together, these
      observations suggest that CRH and neurotensin neurons in the LHA constitute a
      novel anatomical substrate for their well known anorexic effects.

PMID- 10407049
TI  - Illusory arm movements activate cortical motor areas: a positron emission
      tomography study.
AB  - Vibration at approximately 70 Hz on the biceps tendon elicits a vivid illusory
      arm extension. Nobody has examined which areas in the brain are activated when
      subjects perceive this kinesthetic illusion. The illusion was hypothesized to
      originate from activations of somatosensory areas normally engaged in
      kinesthesia. The locations of the microstructurally defined cytoarchitectonic
      areas of the primary motor (4a and 4p) and primary somatosensory cortex (3a, 3b,
      and 1) were obtained from population maps of these areas in standard anatomical
      format. The regional cerebral blood flow (rCBF) was measured with (15)O-butanol
      and positron emission tomography in nine subjects. The left biceps tendon was
      vibrated at 10 Hz (LOW), at 70 or 80 Hz (ILLUSION), or at 220 or 240 Hz (HIGH). A
      REST condition with eyes closed was included in addition. Only the 70 and 80 Hz
      vibrations elicited strong illusory arm extensions in all subjects without any
      electromyographic activity in the arm muscles. When the rCBF of the ILLUSION
      condition was contrasted to the LOW and HIGH conditions, we found two clusters of
      activations, one in the supplementary motor area (SMA) extending into the caudal
      cingulate motor area (CMAc) and the other in area 4a extending into the dorsal
      premotor cortex (PMd) and area 4p. When LOW, HIGH, and ILLUSION were contrasted
      to REST, giving the main effect of vibration, areas 4p, 3b, and 1, the frontal
      and parietal operculum, and the insular cortex were activated. Thus, with the
      exception of area 4p, the effects of vibration and illusion were associated with
      disparate cortical areas. This indicates that the SMA, CMAc, PMd, and area 4a
      were activated associated with the kinesthetic illusion. Thus, against our
      expectations, motor areas rather than somatosensory areas seem to convey the
      illusion of limb movement.

PMID- 10407050
TI  - Neural correlates of perceived brightness in the retina, lateral geniculate
      nucleus, and striate cortex.
AB  - Brightness changes can be induced in a static gray field by modulating the
      luminance of surrounding areas. We used this induction phenomenon to investigate
      the neural representation of perceived brightness. Extracellular recordings were
      made in striate cortex, the lateral geniculate nucleus (LGN), and the optic tract
      of anesthetized cats using stimuli that produced brightness induction. While a
      cell's receptive field (RF) was covered by uniform gray illumination, the
      luminance of rectangular flanking regions was modulated sinusoidally in time,
      inducing brightness changes in the RF. We looked for a correspondence between the
      modulation of a cell's response and stimulus conditions that did or did not
      produce perceptual changes in brightness. We found that the responses of retinal
      ganglion cell axons in the optic tract were never correlated with brightness. On
      the other hand, many neurons in striate cortex and a small fraction in the LGN
      responded in a phase-locked manner at the temporal frequency of the flank
      modulation, even though the flanks were 3-7 degrees beyond the edges of the RF.
      Only in striate cortex were cells found that had responses correlated with
      brightness under all stimulus conditions. These findings suggest that brightness
      information is explicitly represented in the responses of neurons in striate
      cortex as part of a neural representation of object surfaces.

PMID- 10407051
TI  - 5-HT1B receptor knock-out mice exhibit increased exploratory activity and
      enhanced spatial memory performance in the Morris water maze.
AB  - In an attempt to characterize the contribution of the 5-HT1B receptor to
      behavior, 5-HT1B knock-out (KO) mice were subjected to a battery of behavioral
      paradigms aimed at differentiating various components of cognitive and emotional
      behaviors. In an object exploration task, wild-type (WT) and 5-HT1B KO mice did
      not differ in locomotor activity. 5-HT1B KO mice, however, displayed lower
      thigmotaxis (an index of anxiety) associated with a higher level of object
      exploratory activity, but no genotype differences were observed in the elevated
      plus maze. 5-HT1B KO mice also displayed a lack of exploratory habituation. In
      the spatial version of the Morris water maze, 5-HT1B KO mice showed higher
      performances in acquisition and transfer test, which was not observed in the
      visual version of the task. No genotype differences were found in contextual fear
      conditioning, because both WT and 5-HT1B KO mice were able to remember the
      context where they had received the aversive stimulus. The deletion of the 5-HT1B
      receptor, associated with appropriate behavioral paradigms, thus allowed us to
      dissociate anxiety from response to novelty, and perseverative behavior (lack of
      habituation) from adaptive behavioral inhibition underlying cognitive flexibility
      (transfer stage in the water maze). The deletion of the 5-HT1B receptor did not
      result in significant developmental plasticities for other major 5-HT receptor
      types but may have influenced other neurotransmission systems. The 5-HT1B
      receptor may be a key target for serotonin in the modulation of cognitive
      behavior, particularly in situations involving a high cognitive demand.

PMID- 10407052
TI  - Addiction-prone Lewis but not Fischer rats develop compulsive running that
      coincides with downregulation of nerve growth factor inducible-B and neuron
      derived orphan receptor 1.
AB  - We have examined the effects of chronic voluntary running for 30 d on the levels
      of nerve growth factor inducilble-B (NGFI-B) and neuron-derived orphan receptor 1
      (NOR1) mRNAs in Fischer and Lewis rats. The aim was to compare the addiction
      prone Lewis rat strain to the Fischer strain in a plausible model for natural
      reward. The Lewis strain ran markedly more than the Fischer strain, as indicated
      by the length of running per day when given free access to running wheels. Both
      strains progressively increased their amount of daily running. By day 14, Lewis
      rats had reached a maximal level corresponding to 10 km/d, which slowly decreased
      to approximately 8 km/d. Fischer rats ran considerably less, averaging
      approximately 1. 5 km/d by day 30. After 30 d of running, levels of mRNA encoding
      NGFI-B and Nor1 were decreased in cerebral cortex in Lewis but not Fischer rats.
      The downregulation of NGFI-B mRNA in Lewis rats could not be attenuated by the
      opioid receptor antagonist naloxone. Instead, naloxone by itself downregulated
      NGFI-B in striatum and cerebral cortex in both strains. In contrast, naloxone had
      no effect on Nor1 mRNA levels, although the running-induced downregulation of
      Nor1 was, in most cases, attenuated by naloxone. Data from the present study
      suggest that the same genetic factors contributing to the drug addiction-prone
      behavior of Lewis rats also control the excessive running behavior and that this
      coincides with downregulation of transcription factors of the NGFI-B family.

PMID- 10407053
TI  - Cognitive deficits in a genetic mouse model of the most common biochemical cause
      of human mental retardation.
AB  - Phenylalanine hydroxylase (Pah)-deficient "PKU mice" have a mutation in the Pah
      gene that causes phenylketonuria (PKU) in humans. PKU produces cognitive deficits
      in humans if it is untreated. We report here the first evidence that the genetic
      mouse model of PKU (Pah(enu2)) also produces cognitive impairments. PKU mice were
      impaired on both odor discrimination reversal and latent learning compared with
      heterozygote littermates and with wild-type mice of the same BTBR strain. A small
      container of cinnamon-scented sand was presented on the right or left, and nutmeg
      scented sand was presented on the other side; left-right location varied over
      trials. Digging in sand of the correct scent was rewarded by finding
      phenylalanine-free chocolate. To prevent scent cuing, new containers were used on
      every trial, and both containers always contained chocolate. Digging in the
      incorrect choice was stopped before the chocolate was uncovered. Once criterion
      was reached, the other scent was rewarded. PKU mice were impaired on reversals 2,
      3, and 4. They were also impaired in latent learning. On day 1, half the mice
      were allowed to explore a maze and discover the location of water. On day 2, all
      mice were water-deprived and were placed in the maze. Whereas pre-exposed wild
      type and heterozygous mice showed evidence that they remembered the location of
      the water and hence could find the water faster on day 2, pre-exposed PKU mice
      showed no significant benefit from their pre-exposure on day 1.

PMID- 10407054
TI  - Differential activation of adenylyl cyclases by spatial and procedural learning.
AB  - Adenylyl cyclases (ACs) are involved in a variety of advanced CNS functions,
      including some types of learning and memory. At least nine AC isoforms are
      expressed in the brain, which are divisible into three broad classes based on the
      ability of Ca(2+) to modulate their activity. This study examined the hypothesis
      that different learning tasks would differentially activate ACs in selected brain
      regions. The ability of forskolin or Ca(2+) to enhance AC activity in the
      hippocampus, parietal cortex, striatum, and cerebellum was examined after mice
      had been trained in either a spatial or procedural learning task using a Morris
      water maze. Sensitivity of ACs to forskolin was enhanced to a greater degree in
      most brain regions after procedural learning, but Ca(2+)-sensitive ACs in the
      hippocampus were more sensitive to spatial learning. Because nonspecific
      behavioral elements, such as stress or motor activity, were similar in both
      experimental tasks, these results provide the first evidence that acquisition of
      different kinds of learning is associated with selective changes in particular AC
      species in a mammalian brain and support the idea that different biochemical
      processing, involving particular isoforms of ACs, subserves different memory
      systems.

PMID- 10407056
TI  - Interdependence of multiple theta generators in the hippocampus: a partial
      coherence analysis.
AB  - The extracellularly recorded theta oscillation reflects a dynamic interaction of
      various synaptic and cellular mechanisms. Because the spatially overlapping
      dipoles responsible for the generation of theta field oscillation may represent
      different mechanisms, their separation might provide clues with regard to their
      origin and significance. We used a novel approach, partial coherence analysis, to
      reveal the various components of the theta rhythm and the relationship among its
      generators. Hippocampal field activity was recorded by a 16-site silicon probe in
      the CA1-dentate gyrus axis of the awake rat. Field patterns, recorded from
      various intrahippocampal or entorhinal cortex sites, were used to remove activity
      caused by a common source by the partialization procedure. The findings revealed
      highly coherent coupling between theta signals recorded (1) from the hippocampal
      fissure and stratum (str.) oriens of the CA1 region and (2) between CA1 stratum
      radiatum and the dentate molecular layer. The results of partial coherence
      analysis indicated that rhythmic input from the entorhinal cortex explained theta
      coherence between signals recorded from the hippocampal fissure and str. oriens
      but not the coherence between signals derived from str. radiatum and the dentate
      molecular layer. After bilateral lesions of the entorhinal cortex, all signals
      recorded from both below and above the CA1 hippocampal pyramidal cell layer
      became highly coherent. These observations indicate the presence of two,
      relatively independent, theta generators in the hippocampus, which are mediated
      by the entorhinal cortex and the CA3-mossy cell recurrent circuitry,
      respectively. The CA3-mossy cell theta generator is partially suppressed by the
      dentate gyrus interneuronal output in the intact brain. We suggest that timing of
      the action potentials of pyramidal cells during the theta cycle is determined by
      the cooperation between the active CA3 neurons and the entorhinal input.

PMID- 10407055
TI  - Interactions between hippocampus and medial septum during sharp waves and theta
      oscillation in the behaving rat.
AB  - The medial septal region and the hippocampus are connected reciprocally via
      GABAergic neurons, but the physiological role of this loop is still not well
      understood. In an attempt to reveal the physiological effects of the
      hippocamposeptal GABAergic projection, we cross-correlated hippocampal sharp wave
      (SPW) ripples or theta activity and extracellular units recorded in the medial
      septum and diagonal band of Broca (MSDB) in freely moving rats. The majority of
      single MSDB cells (60%) were significantly suppressed during SPWs. Most cells
      inhibited during SPW (80%) fired rhythmically and phase-locked to the negative
      peak of the CA1 pyramidal layer theta waves. Because both SPW and the negative
      peak of local theta waves correspond to the maximum discharge probability of CA1
      pyramidal cells and interneuron classes, the findings indicate that the activity
      of medial septal neurons can be negatively (during SPW) or positively (during
      theta waves) correlated with the activity of hippocampal interneurons. We
      hypothesize that the functional coupling between medial septal neurons and
      hippocampal interneurons varies in a state-dependent manner.

PMID- 10407057
TI  - Direct agonists for serotonin receptors enhance locomotor function in rats that
      received neural transplants after neonatal spinal transection.
AB  - We analyzed whether acute treatment with serotonergic agonists would improve
      motor function in rats with transected spinal cords (spinal rats) and in rats
      that received transplants of fetal spinal cord into the transection site
      (transplant rats). Neonates received midthoracic spinal transections within 48 hr
      of birth; transplant rats received fetal (embryonic day 14) spinal cord grafts at
      the time of transection. At 3 weeks, rats began 1-2 months of training in
      treadmill locomotion. Rats in the transplant group developed better weight
      supported stepping than spinal rats. Systemic administration of two directly
      acting agonists for serotonergic 5-HT(2) receptor subtypes, quipazine and (+/-)-1
      [2, 5]-dimethoxy-4-iodophenyl-2-aminopropane), further increased weight-supported
      stepping in transplant rats. The improvement was dose-dependent and greatest in
      rats with poor to moderate baseline weight support. In contrast, indirectly
      acting serotonergic agonists, which block reuptake of 5-HT (sertraline) or
      release 5-HT and block its reuptake (D-fenfluramine), failed to enhance motor
      function. Neither direct nor indirect agonists significantly improved locomotion
      in spinal rats as a group, despite equivalent upregulation of 5-HT(2) receptors
      in the lumbar ventral horn of lesioned rats with and without transplants. The
      distribution of immunoreactive serotonergic fibers within and caudal to the
      transplant did not appear to correspond to restoration of motor function. Our
      results confirm our previous demonstration that transplants improve motor
      performance in spinal rats. Additional stimulation with agonists at subtypes of 5
      HT receptors produces a beneficial interaction with transplants that further
      improves motor competence.

PMID- 10407059
TI  - Continuous functional magnetic resonance imaging reveals dynamic nonlinearities
      of "dose-response" curves for finger opposition.
AB  - Linear experimental designs have dominated the field of functional neuroimaging,
      but although successful at mapping regions of relative brain activation, the
      technique assumes that both cognition and brain activation are linear processes.
      To test these assumptions, we performed a continuous functional magnetic
      resonance imaging (MRI) experiment of finger opposition. Subjects performed a
      visually paced bimanual finger-tapping task. The frequency of finger tapping was
      continuously varied between 1 and 5 Hz, without any rest blocks. After continuous
      acquisition of fMRI images, the task-related brain regions were identified with
      independent components analysis (ICA). When the time courses of the task-related
      components were plotted against tapping frequency, nonlinear "dose- response"
      curves were obtained for most subjects. Nonlinearities appeared in both the
      static and dynamic sense, with hysteresis being prominent in several subjects.
      The ICA decomposition also demonstrated the spatial dynamics with different
      components active at different times. These results suggest that the brain
      response to tapping frequency does not scale linearly, and that it is history
      dependent even after accounting for the hemodynamic response function. This
      implies that finger tapping, as measured with fMRI, is a nonstationary process.
      When analyzed with a conventional general linear model, a strong correlation to
      tapping frequency was identified, but the spatiotemporal dynamics were not
      apparent.

PMID- 10407058
TI  - Novel injury mechanism in anoxia and trauma of spinal cord white matter:
      glutamate release via reverse Na+-dependent glutamate transport.
AB  - Spinal cord injury is a devastating condition, with much of the clinical
      disability resulting from disruption of white matter tracts. Recent reports
      suggest a component of glutamate excitotoxicity in spinal cord injury. In this
      study, the role of glutamate and mechanism of release of this excitotoxin were
      investigated in rat dorsal column slices subjected to 60 min of anoxia or 15 sec
      of mechanical compression at a force of 2 gm in vitro. The broad-spectrum
      glutamate antagonist kynurenic acid (1 mm) and the selective AMPA antagonist
      GYKI52466 (30 microm) were protective against anoxia (compound action potential
      amplitude recovered to 56 vs 27% without drug). GYKI52466 was also effective
      against trauma (65 vs 35%). Inhibition of Na(+)-dependent glutamate transport
      with dihydrokainate or l-trans-pyrrolidine-2,4-dicarboxylic acid (1 mm each)
      protected against anoxia (65-75 vs 25%) and trauma (70 vs 35%). The depletion of
      cytosolic glutamate in axon cylinders and oligodendrocytes by anoxia was
      completely prevented by glutamate transport inhibition. Immunohistochemistry
      revealed that a large component of injury occurred in the myelin sheath and was
      prevented by AMPA receptor blockade or glutamate transport inhibitors. We
      conclude that release of glutamate by reversal of Na(+)-dependent glutamate
      transport with subsequent activation of AMPA receptors is an important mechanism
      in spinal cord white matter anoxic and traumatic injury.

PMID- 10407060
TI  - Exposing rats to a predator blocks primed burst potentiation in the hippocampus
      in vitro.
AB  - This study evaluated the effects of acute psychological stress (cat exposure) in
      adult male rats on electrophysiological plasticity subsequently assessed in the
      hippocampus in vitro. Two physiological models of memory were studied in CA1 in
      each recording session: (1) primed burst potentiation (PBP), a low-threshold form
      of plasticity produced by a total of five physiologically patterned pulses; and
      (2) long-term potentiation (LTP), a suprathreshold form of plasticity produced by
      a train of 100 pulses. Three groups of rats were studied: (1) undisturbed rats in
      their home cage (home cage); (2) rats placed in a chamber for 75 min (chamber);
      and (3) rats placed in a chamber for 75 min in close proximity to a cat
      (chamber/stress). At the end of the chamber exposure period, blood samples were
      obtained, and the hippocampus was prepared for in vitro recordings. Only the
      chamber/stress group had elevated (stress) levels of corticosterone. The major
      finding was that PBP, but not LTP, was blocked in the chamber/stress group. Thus,
      the psychological stress experienced by the rats in response to cat exposure
      resulted in an inhibition of plasticity, which was localized to the intrinsic
      circuitry of the hippocampus. This work provides novel observations on the
      effects of an ethologically relevant stressor on PBP in vitro and of the relative
      insensitivity of LTP to being modulated by psychological stress. We discuss the
      relevance of these electrophysiological findings to our behavioral work showing
      that predator stress impairs spatial memory.

PMID- 10407061
TI  - Impaired odor adaptation in olfactory receptor neurons after inhibition of
      Ca2+/calmodulin kinase II.
AB  - Odor adaptation in vertebrate olfactory receptor neurons (ORNs) is commonly
      attributed to feedback modulation caused by Ca(2+) entry through the transduction
      channels, but it remains unclear and controversial whether this Ca(2+)-mediated
      adaptation resides in the cAMP-gated channel alone or whether other molecules of
      the transduction cascade are modulated as well. Attenuation of adenylyl cyclase
      activity by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has also been
      proposed as a mechanism for adaptation. To test this in intact ORNs, we have
      compared the properties of adaptation induced by a sustained (8 sec) or brief
      (100 msec) odor stimulus. Although adaptation induced by both types of stimuli
      occurs downstream from the odor receptors and is Ca(2+)-dependent, only
      adaptation induced by a sustained pulse involves alterations in the odor response
      kinetics, consistent with a reduction in the rate of adenylyl cyclase activation.
      By disrupting CaMKII to block adenylyl cyclase attenuation using a specific
      peptide inhibitor of CaMKII, autocamtide-2-related inhibitory peptide (AIP), we
      show that this reaction is necessary for odor adaptation in vivo. With CaMKII
      disrupted, adaptation induced by a sustained stimulus is significantly impaired:
      the onset rate of adaptation is decreased by threefold, and the recovery rate
      from adaptation is increased by up to sixfold. In contrast, adaptation induced by
      a brief odor pulse is unaffected, demonstrating that the effect of AIP must be
      highly specific. The results indicate that CaMKII controls the temporal response
      properties of ORNs during odor adaptation. We propose that CaMKII plays a
      prominent role in odor perception.

PMID- 10407062
TI  - Development of a polyclonal antibody with broad epitope specificity for advanced
      glycation endproducts and localization of these epitopes in Bruch's membrane of
      the aging eye.
AB  - PURPOSE: To develop an antibody that recognizes a variety of advanced glycation
      endproduct (AGE) epitopes. METHODS: Glycolaldehyde was used to modify bovine
      serum albumin and HPLC analysis was used to measure pentosidine formation as an
      indicator of AGE formation. A polyclonal anti-AGE antibody was synthesized by
      injecting glycolaldehyde-incubated keyhole limpet hemocyanin into rabbits,
      affinity purified using AGE modified bovine serum albumin coupled to an affinity
      resin column, and characterized by immunoblot analysis. RESULTS: HPLC analysis of
      glycolaldehyde treated bovine serum albumin detected high levels of pentosidine
      formation, suggesting that glycolaldehyde is a potent precursor for pentosidine.
      By immunoblot analysis, our antibody recognized carboxymethyllysine and
      pentosidine, two well-characterized AGEs, as well as other AGE epitopes.
      Immunohistochemical evaluation showed evidence of AGEs in Bruch's membrane
      (including basal laminar deposits and drusen), choroidal extracellular matrix,
      and vessel walls in an 82 year old nondiabetic globe. A similar staining pattern
      was observed in an age-matched diabetic control. In contrast, no staining was
      seen with the antibody in a 20 month old nondiabetic globe. CONCLUSIONS: A unique
      anti-AGE antibody was synthesized that recognizes a variety of AGE epitopes
      including carboxymethyllysine and pentosidine. Its best use might be in broad
      surveys of the age-dependent accumulation of a large number of AGE epitopes that
      might not be revealed by antibodies to pentosidine or CML.

PMID- 10407064
TI  - Elastase activated liposomal delivery to nucleated cells.
AB  - The specific activation of liposomes for delivery has been explored by enzyme
      mediated cleavage of a peptide substrate covalently conjugated to a fusogenic
      lipid. We have previously shown an elastase sensitive peptide conjugated to 1, 2
      dioleoyl-sn-glycero-3-phosphoethanolamine [corrected] (DOPE) could be activated
      by enzymatic cleavage, triggering liposome-liposome lipid mixing and fusion with
      erythrocyte ghosts (Pak et al., Biochim. Biophys. Acta, 1372 (1998) 13-27).
      Further optimization of this system has been aimed at obtaining substrate
      cleavage at or below physiological elastase levels and to demonstrate triggered
      delivery to living cells. Therefore a new peptide-lipid, MeO-suc-AAPV-DOPE (N
      methoxy-succinyl-Ala-Ala-Pro-Val-DOPE), has been developed that exhibits greater
      sensitivity and selectivity for elastase cleavage and subsequent conversion to
      DOPE. This peptide-lipid was used with DODAP (dioleoyl dimethylammonium propane,
      a pH dependent cationic lipid) in a 1:1 mol ratio with the expectation that
      endocytosis would lead to a liposome with an overall positive charge if enzymatic
      cleavage had occurred. Elastase treated liposomes displayed pH dependent
      enhancement of binding, lipid mixing, and delivery of 10000 MW dextrans, relative
      to untreated liposomes, when incubated with HL60 human leukemic cells. Heat
      denatured elastase did not activate DODAP/MeO-suc-AAPV-DOPE liposomes, indicating
      enzymatic activity of elastase is necessary. Liposomes bound to ECV304
      endothelial cells at physiological pH could be activated by elastase to deliver
      an encapsulated fluorescent probe, calcein, into the cell cytoplasm. These
      results suggest enzyme substrate peptides linked to a fusogenic lipid may be used
      to elicit specific delivery from liposomes to cells.

PMID- 10407063
TI  - The transcription factor Sp3 interacts with promoter elements of the lens
      specific MIP gene.
AB  - PURPOSE: To characterize the cis regulatory elements and their interaction with
      transcription factors responsible for the lens specific expression of the MIP
      gene, which encodes the Major Intrinsic Protein of the lens fiber membranes.
      METHODS: Study interaction of factors present in newborn mouse lens nuclear
      extracts with DNA fragments corresponding to mouse MIP gene 5' flanking sequence
      by electrophoresis mobility shift assay (EMSA) and DNase I footprinting. RESULTS:
      We found a high degree of identity in the first 100 bp of 5' flanking sequence of
      mice and humans, however, a lower degree of conservation is observed further
      upstream. We have found by DNase I footprinting analysis that lens specific
      factors may interact with the first 100 bp of 5' flanking sequence. A domain
      containing an E box, conserved in mouse and human, may interact with a lens
      specific factor. However, general factors may interact with a NF-1 binding site.
      An overlapping GC and CT box is present in the mouse MIP gene. In the human MIP
      gene GC and CT boxes are found in different domains of the MIP gene promoter.
      Both CT boxes interact with factors present in lens nuclear extracts including
      Sp3. They are able to interact with purified Sp1but not with Sp1 present in mouse
      lens nuclear extracts. CONCLUSIONS: The transcription factor Sp3 may play an
      important role in regulating MIP gene expression in the lens.

PMID- 10407065
TI  - The role of ceramide composition in the lipid organisation of the skin barrier.
AB  - The lipid lamellae in the stratum corneum (SC) play a key role in the barrier
      function of the skin. The major lipids are ceramides (CER), cholesterol (CHOL)
      and free fatty acids (FFA). In pig SC at least six subclasses of ceramides
      (referred to as CER 1, 2-6) are present. Recently it was shown that in mixtures
      of isolated pig SC ceramides (referred to as CER(1-6)) and CHOL two lamellar
      phases are formed, which mimic SC lipid organisation very closely [J.A. Bouwstra
      et al., 1996, J. Lipid Res. 37, 999-1011] [1]. Since the CER composition in SC
      originating from different sources/donors often varies, information on the effect
      of variations in CER composition on the SC lipid organisation is important. The
      results of the present study with mixtures of CHOL including two different CER
      mixtures that lack CER 6 (CER(1-5) mixtures) revealed that at an equimolar molar
      ratio their lipid organisation was similar to that of the equimolar CHOL:CER(1-6)
      and CHOL:CER(1,2) mixtures, described previously. These observations suggest that
      at an equimolar CHOL:CER ratio the lipid organisation is remarkably insensitive
      toward a change in the CER composition. Similar observations have been made with
      equimolar CHOL:CER:FFA mixtures. The situation is different when the CHOL:CER
      molar ratio varies. While in the CHOL:CER(1-6) mixture the lamellar organisation
      hardly changed with varying molar ratio from 0.4 to 2, the lamellar organisation
      in the CHOL:CER(1-5) mixtures appeared to be more sensitive to a change in the
      relative CHOL content, especially concerning the changes in the periodicities of
      the lamellar phases. In summary, these findings clearly indicate that at an
      equimolar CHOL:CER molar ratio the lamellar organisation is least sensitive to a
      variation in CER composition, while at a reduced CHOL:CER molar ratio the CER
      composition plays a more prominent role in the lamellar phases. This observation
      may have an implication for the in vivo situation when both the CER composition
      and the CHOL:CER molar ratio change simultaneously.

PMID- 10407066
TI  - Stabilized plasmid-lipid particles: factors influencing plasmid entrapment and
      transfection properties.
AB  - Previous work has shown that plasmid DNA can be encapsulated in small 'stabilized
      plasmid-lipid particles' (SPLP) composed of 1, 2-dioleyl-3
      phosphatidylethanolamine (DOPE), the cationic lipid N, N-dioleyl-N,N
      dimethylammonium chloride (DODAC) and poly(ethylene glycol) (PEG) conjugated
      ceramides (PEG-Cer), employing a detergent dialysis procedure. These SPLP have
      potential as vectors for in vivo gene therapy. This study is aimed at
      characterizing the influence of the cationic lipid and PEG-Cer species on SPLP
      formation and in vitro transfection properties. It is shown that the transfection
      potency of SPLP is sensitive to the cationic lipid species employed, the size of
      the PEG polymer incorporated in the PEG-ceramide and the length of the acyl chain
      contained in the ceramide anchor. With regard to the influence of cationic lipid,
      the transfection levels achieved were highest for SPLP containing N-[2, 3
      (dioleyloxy)propyl]-N,N-dimethyl-N-cyanomethylammonium chloride (DODMA-AN) and
      lowest for SPLP containing 3-beta-[N-(N', N'-dimethylaminoethyl)carbamoyl]
      cholesterol (DC-CHOL), according to the series DODMA-AN>N-[2,3
      (dioleyloxy)propyl]-N,N, N-trimethylammonium chloride (DOTMA)>DODAC>N,N-distearyl
      N, N-dimethylammonium chloride (DSDAC)>DC-CHOL. Incorporation of short (PEG(750))
      PEG polymers in the PEG-ceramide components resulted in modest improvements in
      transfection levels over PEG(2000) and PEG(5000) polymers, however variation of
      the length of the acyl chain contained in the hydrophobic ceramide anchor from
      octanoyl (PEG-CerC(8)) to myristoyl (PEG-CerC(14)) to arachidoyl (PEG-CerC(20))
      had the most dramatic effects. Transfection levels achieved for SPLP containing
      PEG-CerC(8) were substantially larger than observed for SPLP containing PEG
      CerC(14) or PEG-CerC(20), consistent with a requirement for the PEG-ceramide to
      dissociate from the SPLP surface for maximum transfection potency. It is also
      shown that the ability of SPLP to be accumulated into cells is a dominant factor
      influencing transfection potency, and that the transfection potency of SPLP that
      are accumulated is at least equivalent to that of cationic lipid-plasmid DNA
      complexes.

PMID- 10407067
TI  - Perturbations induced by alpha- and beta-endosulfan in lipid membranes: a DSC and
      fluorescence polarization study.
AB  - The interaction of alpha- and beta-endosulfan isomers with lipid bilayers was
      searched by differential scanning calorimetry (DSC) and fluorescence polarization
      of 2-, 6- and 12-(9-anthroyloxy) stearic acids (2-AS, 6-AS and 12-AS) and 16-(9
      anthroyloxy) palmitic acid (16-AP). Both endosulfan isomers, at insecticide/lipid
      molar ratios ranging from 1/40 to 1/1, shift the phase transition midpoint to
      lower temperature values and broaden the transition profile of
      dipalmitoylphosphatidylcholine (DPPC) bilayers. At insecticide/lipid molar ratios
      of 1/40, the isomers fully abolish the bilayer pretransition. Conversely to beta
      endosulfan, alpha-endosulfan promotes a new phase transition, centered at 35.4
      degrees C, in addition to the main phase transition of DPPC. Therefore, the alpha
      isomer may undergo a heterogeneous distribution in separate domains in the plane
      of the membrane, whereas the beta-isomer may undergo a homogeneous distribution.
      Fluorescence polarization data indicate that alpha-endosulfan increases the lipid
      structural order in the regions probed by 2-AS and decreases it in the regions
      probed by 6-AS, 12-AS and 16-AP. On the other hand, the beta-isomer produces
      disordering effects in the upper regions of the bilayers, probed by 2-AS, and
      ordering in deeper regions, probed by 6-AS, 12-AS and 16-AP, mainly in the gel
      phase. The incorporation of cholesterol into DPPC bilayers progressively
      decreases the effects of beta-isomer which are vanished at 20 mol% cholesterol.
      However, this and higher cholesterol concentrations did not prevent alpha
      endosulfan membrane interaction, as revealed by DSC and fluorescence
      polarization. The distinct effects promoted by alpha- and beta-endosulfan are
      discussed in terms of molecular orientation and positioning within the bilayer.
      Apparently, the alpha-isomer preferentially locates closer to the phospholipid
      headgroups whereas the beta-isomer distributes in deeper domains of the bilayer.

PMID- 10407068
TI  - Inhibitory effect of KW-3902, an adenosine A(1) receptor antagonist, on p
      aminohippurate transport in OK cells.
AB  - KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine) is a novel potent and
      selective adenosine A(1) receptor antagonist. We examined the effect of KW-3902
      on p-aminohippurate (PAH) transport in opossum kidney (OK) epithelial cells.
      Pretreatment for 3 h with KW-3902 inhibited the transcellular transport of PAH
      across OK cell monolayers from the basal to the apical side. The uptake of PAH
      across the basolateral membrane of OK cells was inhibited by KW-3902 pretreatment
      in a time- and concentration-dependent manner. A kinetic analysis revealed that
      the inhibitory effect of KW-3902 on the basolateral PAH uptake was due to an
      increase in the Michaelis constant (K(m)) as well as a decrease in the maximum
      uptake rate (V(max)), showing that the inhibition was a mixed type. Pretreatment
      with adenosine deaminase or 8-cyclopentyl-1,3-dipropylxanthine, another selective
      adenosine A(1) receptor antagonist, also decreased the basolateral PAH uptake. KW
      3902 pretreatment had no effect on the concentration of intracellular alpha
      ketoglutarate which exchanges for PAH across the basolateral membrane of OK
      cells. These results suggest that KW-3902 has an inhibitory effect on PAH
      transport in OK epithelial cells.

PMID- 10407069
TI  - Mutations in the white gene of Drosophila melanogaster affecting ABC transporters
      that determine eye colouration.
AB  - The white, brown and scarlet genes of Drosophila melanogaster encode proteins
      which transport guanine or tryptophan (precursors of the red and brown eye colour
      pigments) and belong to the ABC transporter superfamily. Current models envisage
      that the white and brown gene products interact to form a guanine specific
      transporter, while white and scarlet gene products interact to form a tryptophan
      transporter. In this study, we report the nucleotide sequence of the coding
      regions of five white alleles isolated from flies with partially pigmented eyes.
      In all cases, single amino acid changes were identified, highlighting residues
      with roles in structure and/or function of the transporters. Mutations in w(cf)
      (G589E) and w(sat) (F590G) occur at the extracellular end of predicted
      transmembrane helix 5 and correlate with a major decrease in red pigments in the
      eyes, while brown pigments are near wild-type levels. Therefore, those residues
      have a more significant role in the guanine transporter than the tryptophan
      transporter. Mutations identified in w(crr) (H298N) and w(101) (G243S) affect
      amino acids which are highly conserved among the ABC transporter superfamily
      within the nucleotide binding domain. Both cause substantial and similar
      decreases of red and brown pigments indicating that both tryptophan and guanine
      transport are impaired. The mutation identified in w(Et87) alters an amino acid
      within an intracellular loop between transmembrane helices 2 and 3 of the
      predicted structure. Red and brown pigments are reduced to very low levels by
      this mutation indicating this loop region is important for the function of both
      guanine and tryptophan transporters.

PMID- 10407071
TI  - Amphiphilic and hydrophilic nature of sheep and human platelet phosphotyrosine
      phosphatase forms.
AB  - To date, although at least 75 different PTPases (protein-tyrosine-phosphate
      phosphohydrolase, EC 3.1.3.48) have been identified, those detected in platelets
      are rather scarce. Based on previous results from our laboratory, we investigated
      the existence of new PTPases in platelets. Triton X-114 phase partitioning of
      Triton X-100-solubilized human and sheep platelet membranes allowed PTPase to be
      recovered in the detergent-rich (40-35%, respectively) and -poor phases (60-65%,
      respectively). Sedimentation analyses of both phases from the sheep species
      revealed hydrophilic 6S and 3.7S, and amphiphilic 7.5S and 10.3S PTPase forms.
      Sedimentation analyses of human platelet membrane-associated or cytosolic PTPase
      revealed hydrophilic 6.7S and 4.3S, and amphiphilic 5.5S and 10.8S forms, or
      hydrophilic 4S, 5.9S and 6.9S forms, respectively. Western blot analysis using
      monoclonal antibodies (MoAb) against human PTP1B, PTP1C, PTP1D and RPTPalpha
      (mouse anti-human PTPase MoAbs) showed that RPTPalpha was not present in
      platelets and that the PTP1C type and PTP1D type (but probably not the PTP1B
      type) were expressed in sheep species. Immunoblots also revealed that all PTPases
      detected were mainly membrane-associated, with similar percentages of cellular
      distribution in both species. All PTPases were mainly recovered in the detergent
      poor phases from the Triton X-114 phase partitioning, although PTP1D from human
      species was also significantly present (30%) in the detergent-rich phase.
      Additionally, all PTPases sedimented within the same PTPase peak in sucrose
      gradients (sedimentation coefficients around 4S). These findings indicate that
      amphiphilic and hydrophilic PTPases different from PTP1B, PTP1C, PTP1D or
      RPTPalpha, with higher sedimentation coefficients and with higher activity when O
      phosphotyrosine or a synthetic peptide phosphorylated on tyrosine were used as
      substrates, are present in platelets.

PMID- 10407070
TI  - Gene transfection efficiency of tracheal epithelial cells by DC-chol-DOPE/DNA
      complexes.
AB  - We evaluated the transfection efficiency of five different cationic
      liposome/plasmid DNA complexes, during the in vitro gene transfer into human
      epithelial tracheal cell lines. A dramatic correlation between the transfection
      efficiency and the charge ratio (positive charge of liposome to negative charge
      of DNA) has been found. DC-Chol-DOPE was found to be the most effective liposome
      formulation. Therefore, a morphological and structural analysis of DC-Chol-DOPE
      liposomes and DC-Chol-DOPE/DNA complexes, has been performed by transmission
      electron microscopy (TEM) and by confocal laser scanning microscopy (CLSM),
      respectively. The process of interaction between DC-Chol-DOPE/DNA complexes and
      human epithelial tracheal cells has been studied by CLSM. These results raise
      some issues for in vivo gene therapy.

PMID- 10407072
TI  - Lamellarity of cationic liposomes and mode of preparation of lipoplexes affect
      transfection efficiency.
AB  - Transfection of NIH-3T3 cells by a human growth hormone expression vector
      complexed with liposomes composed of N-(1-(2, 3-dioleoyloxy)propyl)-N,N,N
      trimethylammonium chloride (DOTAP) with or without helper lipids was studied. The
      transfection efficiency was dependent on the lamellarity of the liposomes used to
      prepare the lipoplexes. Multilamellar vesicles (MLV) were more effective than
      large unilamellar vesicles (LUV) of approximately 100 nm, irrespective of lipid
      composition. The optimal DNA/DOTAP mole ratio for transfection was </=0.5, at
      which only 10-30% of DOTAP in the lipoplex is neutralized. Prolonged incubation
      time of lipoplexes before addition to cells slightly decreased the level of
      transfection. A major influence on the lipofection level was found when the mode
      of lipoplex preparation was varied. Mixing plasmid DNA and DOTAP/DOPE (1:1) LUV
      in two steps instead of one step resulted in a higher lipofection when at the
      first step the DNA/DOTAP mole ratio was 0.5 than when it was 2.0. Only static
      light-scattering measurement, which is related to particle size and particle size
      instability, revealed differences between the lipoplexes as a function of
      lamellarity of the vesicles (MLV or LUV), mixing order, and number of mixing
      steps. Other physical properties of these lipoplexes were dependent only on the
      DNA/DOTAP mole ratio, i.e. the extent of DOTAP neutralization (as monitored by
      ionization of the fluorophore 4-heptadecyl-7-hydroxycoumarin) and the extent of
      defects in lipid organization (as monitored by level of exposure of the
      fluorophore 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3, 5-hexatriene to water).
      The secondary and tertiary structure of DNA in lipoplexes was evaluated by
      circular dichroism spectroscopy. The results of this study point out that the
      structure of lipoplexes should be physicochemically characterized at two
      different levels: the macro level, which relates to size and size instability,
      and the micro level, which relates to the properties described above which are
      involved in the intimate interaction between the plasmid DNA and the lipids. At
      the micro level, all parameters are reversible, history-independent and are
      determined by DNA/DOTAP mole ratio. On the other hand, the macro level (which is
      the most important for transfection efficiency) is history-dependent and not
      reversible.

PMID- 10407073
TI  - Hydrogen peroxide production from reactive liposomes encapsulating enzymes.
AB  - Reactive cationic and anionic liposomes have been prepared from mixtures of
      dimyristoylphosphatidylcholine (DMPC) and cholesterol incorporating
      dimethyldioctadecylammonium bromide and DMPC incorporating phosphatidylinositol,
      respectively. The liposomes were prepared by the vesicle extrusion technique and
      had the enzymes glucose oxidase (GO) encapsulated in combination with horseradish
      peroxidase (HRP) or lactoperoxidase (LPO). The generation of hydrogen peroxide
      from the liposomes in response to externally added D-glucose substrate was
      monitored using a Rank electrode system polarised to +650 mV, relative to a
      standard silver-silver chloride electrode. The effects of encapsulated enzyme
      concentration, enzyme combinations (GO+HRP, GO+LPO), substrate concentration,
      electron donor and temperature on the production of hydrogen peroxide have been
      investigated. The electrode signal (peroxide production) was found to increase
      linearly with GO incorporation, was reduced on addition of HRP and an electron
      donor (o-dianisidine) and showed a maximum at the lipid chain-melting temperature
      from the anionic liposomes containing no cholesterol. To aid interpretation of
      the results, the permeability of the non-reactive substrate (methyl glucoside)
      across the bilayer membranes was measured. It was found that the encapsulation of
      the enzymes effected the permeability coefficients of methyl glucoside,
      increasing them in the case of anionic liposomes and decreasing them in the case
      of cationic liposomes. These observations are discussed in terms of enzyme
      bilayer interactions.

PMID- 10407074
TI  - Phase diagram of 1,2-dioleoylphosphatidylethanolamine (DOPE):water system at
      subzero temperatures and at low water contents.
AB  - The phase behavior of partially hydrated 1, 2-dioleoylphosphatidylethanolamine
      (DOPE) has been studied using differential scanning calorimetry and X-ray
      diffraction methods together with water sorption isotherms. DOPE liposomes were
      dehydrated in the H(II) phase at 29 degrees C and in the L(alpha) phase at 0
      degrees C by vapor phase equilibration over saturated salt solutions. Other
      samples were prepared by hydration of dried DOPE by vapor phase equilibration at
      29 degrees C and 0 degrees C. Five lipid phases (lamellar liquid crystalline,
      L(alpha); lamellar gel, L(beta); inverted hexagonal, H(II); inverted ribbon,
      P(delta); and lamellar crystalline, L(c)) and the ice phase were observed
      depending on the water content and temperature. The ice phase did not form in
      DOPE suspensions containing <9 wt% water. The L(c) phase was observed in samples
      with a water content of 2-6 wt% that were annealed at 0 degrees C for 2 or more
      days. The L(c) phase melted at 5-20 degrees C producing the H(II) phase. The
      P(delta) phase was observed at water contents of <0.5 wt%. The phase diagram,
      which includes five lipid phases and two water phases (ice and liquid water), has
      been constructed. The freeze-induced dehydration of DOPE has been described with
      the aid of the phase diagram.

PMID- 10407075
TI  - Cell-attached recordings of the volume-sensitive anion channel in rat pancreatic
      beta-cells.
AB  - The cell-attached configuration of the patch-clamp technique was used to study
      the volume-sensitive anion conductance in isolated rat pancreatic beta-cells at
      the single-channel level. In unstimulated cells, current level was close to zero.
      Exposure of cells to a 33% hypotonic solution resulted in the generation of an
      inward current at 0 mV pipette potential. A similar inward current was elicited
      by a rise in glucose concentration or by addition of alpha-ketoisocaproate. In
      contrast, the sulphonylurea tolbutamide was ineffective. The inward current
      evoked by hypotonic solutions consisted of occasional discreet channel events
      interspersed with periods of current noise which could not be clearly resolved
      into unitary channel events. Stimulation with glucose resulted in a predominantly
      noisy pattern of current. With a reduced [Cl(-)] pipette solution, regular
      channel openings could be resolved in the presence of a stimulatory glucose
      concentration, with a calculated conductance of 215 pS. Channel activity could
      also be recorded in excised inside-out patches, though rapid 'rundown' occurred
      under such conditions. It is concluded that hypotonic solutions and glucose
      activate the volume-sensitive anion channel in the cell-attached configuration by
      increasing channel open probability. This generates an inward current in non
      voltage-clamped cells. The channel showed complex kinetics which depended in part
      upon extracellular [Cl(-)].

PMID- 10407076
TI  - Time domain dielectric spectroscopy study of human cells. II. Normal and
      malignant white blood cells.
AB  - The dielectric properties of human lymphocyte suspensions were studied by time
      domain dielectric spectroscopy (TDDS). Nine populations of malignant and normal
      lymphocytes were investigated. Analysis of the dielectric parameters of cell
      structural parts were performed in the framework of Maxwell-Wagner mixture
      formula and the double-shell model of cell. The specific capacitance of the cell
      membranes was estimated by the Hanai-Asami-Koisumi formula. It was shown that the
      dielectric permittivity, capacitance and conductivity values of cell membranes
      are higher for normal lymphocytes than for the malignant ones. The difference of
      the same parameters for normal B- and T-cells is also discussed.

PMID- 10407078
TI  - Demonstration of a Na(+)/H(+) exchanger NHE1 in fresh bovine corneal endothelial
      cell basolateral plasma membrane.
AB  - Apical and basolateral plasma membranes of fresh bovine corneal endothelial cells
      were isolated using positively charged polyacrylamide beads. Marker enzyme assays
      demonstrated that the isolated apical and basolateral plasma membrane domains
      could be isolated and separated with relative purity. Western blotting with a
      polyclonal anti-NHE1 antibody detected a protein of 70 kDa in the basolateral
      plasma membrane isolate. NHE1 immunoreactivity was not detected in the apical
      membrane sample. This suggests that the Na(+)/H(+) exchanger, NHE1, is strictly
      localised to the basolateral membrane of fresh bovine corneal endothelial cells.

PMID- 10407077
TI  - Design of immuno-enzymosomes with maximum enzyme targeting capability: effect of
      the enzyme density on the enzyme targeting capability and cell binding
      properties.
AB  - Immuno-enzymosomes have been proposed for the targeting of enzymes to cancer
      cells to achieve site specific activation of anticancer prodrugs. Previously, we
      reported that the enzyme beta-glucuronidase (GUS), capable of activating
      anthracycline-glucuronide prodrugs, can be coupled to the surface of
      inmunoliposomes directed against human ovarian cancer cells (OVCAR-3). This study
      aimed at the design of an immuno-enzymosome formulation with maximum enzyme
      targeting capability. By purification of the commercially available enzyme beta
      glucuronidase (GUS), a 2-fold increase in the enzyme specific activity and a 4
      fold increase in the enzymatic activity of immuno-enzymosomes was achieved. As a
      result, upon incubation with human ovarian cancer cells (OVCAR-3), cell
      associated enzymatic activity increased correspondingly. The optimized immuno
      enzymosomes were shown to bind to the target cells in a specific fashion. Above a
      GUS/Fab' molar ratio of 0.5, impairment of the target cell binding ability of the
      immuno-enzymosomes was observed. This was likely due to a steric hindrance effect
      mediated by the presence of large amounts of bulky GUS molecules on the liposome
      surface. Nevertheless, increasing the GUS density on the surface of the immuno
      enzymosomes to levels by far exceeding the GUS/Fab' molar ratio of 0.5, yielded a
      considerably improved enzyme targeting capability.

PMID- 10407080
TI  - Gene synthesis, bacterial expression and purification of the Rickettsia
      prowazekii ATP/ADP translocase.
AB  - The Rickettsia prowazekii ATP/ADP translocase (Tlc) is the first member of a new
      family of ATP/ADP exchangers that includes both prokaryotic and eukaryotic
      proteins. We optimized the codon usage for expression of tlc in Escherichia coli
      by means of gene synthesis, expressed the synthetic gene in E. coli, and purified
      a modified Tlc that contained a C-terminal tag of 10 consecutive histidine
      residues by immobilized metal affinity chromatography. Although codon usage in R.
      prowazekii is very different from E. coli, the optimization of the codon usage by
      itself was insufficient to improve expression. However, the change of the cloning
      vector from pET11a to pT7-5 led to a 3-10-fold increase in the specific ATP
      transport rate by cells expressing the synthetic construct. The authenticity of
      the purified protein was confirmed by N-terminal amino acid sequencing and a
      matrix assisted laser desorption/ionization mass spectrometry.

PMID- 10407079
TI  - Multiple effects of mercuric chloride on hexose transport in Xenopus oocytes.
AB  - HgCl(2) had both stimulatory and inhibitory effects on [(3)H]2-deoxyglucose (DG)
      uptake in Xenopus laevis oocytes. The Hg dose response was complex, with 0.1-10
      microM Hg increasing total DG uptake, 30-50 microM Hg inhibiting, and
      concentrations >100 microM increasing uptake. Analyses of the effects of Hg on DG
      transport kinetics and cell membrane permeability indicated that low
      concentrations of Hg stimulated mediated uptake, intermediate concentrations
      inhibited mediated uptake, but high Hg concentrations increased non-mediated
      uptake. 10 microM Hg increased the apparent V(max) for DG uptake, but caused
      little or no change in apparent K(m). Phenylarsine oxide prevented the increase
      in DG uptake by 10 microM Hg, suggesting that the increase was due to transporter
      recruitment. Microinjecting low doses of HgCl(2) into the cell increased mediated
      DG uptake. Higher intracellular doses of Hg increased both mediated and non
      mediated DG uptake. Both insulin and Hg cause cell swelling in isotonic media
      and, for insulin, this swelling has been linked to the mechanism of hormone
      action. Osmotically swelling Xenopus oocytes stimulated DG transport 2-5-fold and
      this increase was due to an increased apparent V(max). Exposing cells to 10
      microM Hg or 140 nM insulin both increased cellular water content by 18% and
      increased hexose transport 2-4-fold. These data indicate that low concentrations
      of Hg and insulin affect hexose transport in a similar manner and that for both
      an increase cellular water content could be an early event in signaling the
      increase in hexose transport.

PMID- 10407081
TI  - Molecular recognition of concanavalin A on mannoside diacetylene lipid monolayer
      at the air-water interface.
AB  - The interaction of p-10,12-pentacosadiyne-1-n-phenylamide alpha-D-mannopyranoside
      (MPDA) with protein concanavalin A (Con A) was studied at the air/water
      interface. The expansion of molecular area of PDA (10,12-pentacosadiynoic
      acid)/MPDA mixed monolayer after injection of Con A in subphase shows strong
      interaction between Con A and the monolayer. The maximum expansion of molecular
      area decreases as the molar ratio of MPDA increases due to the steric hindrance
      effect. By using enzyme mannosidase to cut-off the mannoside headgroup of MPDA,
      expansion of molecular area was greatly reduced, indicating that the binding of
      Con A is specific to the mannoside headgroup. The kinetics of the binding fits to
      the first order bimolecular reaction model. Fluorescence quenching of fluorescein
      isothiocyanate labeled Con A after injection into the subphase gives a direct
      proof of the molecular recognition.

PMID- 10407082
TI  - Comparison between in vitro lipid peroxidation in fresh sheep platelets and
      peroxidative processes during sheep platelet ageing under storage at 4 degrees C.
AB  - Incubation of sheep platelet crude membranes with xanthine oxidase
      (XO)/hypoxanthine/Fe(2+)-ADP revealed: (i) a fast peroxidative response - with a
      maximal linear rate of 14 nmol malondialdehyde (MDA) equivalents/mg protein, as
      evidenced by the thiobarbituric acid test - and a decrease in the polyunsaturated
      fatty acid (PUFA) content of the platelet crude membranes; (ii) a decrease in the
      lipid fluidity in the deep lipid core of the membranes but not at the membrane
      surface; (iii) a dramatic inhibitory effect on glucose 6-phosphatase (Glc-6-Pase)
      but not on acetylcholinesterase activity. Platelets were also aged by storage at
      4 degrees C in their own plasma or in Seto additive solution. In these media,
      platelet aggregates were visible and the effects on platelet phospholipids, PUFA,
      lipid extract fluorescence, crude membrane fluidity and membrane-bound enzyme
      activities were assessed for comparison with those observed in in vitro lipid
      peroxidation. The sensitivity of membranes from stored platelets to lipid
      peroxidation was also assessed. Storage of platelets in plasma for 5 days was
      associated with different changes in their crude membranes such as decreases in
      arachidonic acid contents, the decrease not being avoided by the presence of
      phospholipase A(2) inhibitors, increases in MDA equivalents, conjugated dienes
      and lipid extract fluorescence, decreases in the amounts of MDA equivalents
      formed by platelet crude membranes treated with the oxidizing agents, changes in
      membrane fluidity and inhibition of Glc-6-Pase. All these alterations were less
      pronounced or even abolished after platelet storage in Seto. These findings
      suggest that platelet lipid peroxidation due to XO/hypoxanthine/Fe(2+)-ADP and
      platelet membrane alterations observed after platelet ageing under storage at 4
      degrees C share common features. Also, as regards the prevention of peroxidative
      processes, Seto solution permits better storage of sheep platelets than plasma.

PMID- 10407083
TI  - Intravenous administration of superoxide dismutase entrapped in long circulating
      liposomes. II. In vivo fate in a rat model of adjuvant arthritis.
AB  - Rheumatoid arthritis (RA) is a prevalent and debilitating autoimmune disease that
      affects the joints. RA is characterized by an infiltration of the affected joint
      by blood-derived cells. In response to activation, these cells generate reactive
      oxygen species, resulting in an oxidative stress situation. One approach to
      counteract this oxidative stress situation is the use of antioxidants as
      therapeutic agents. The free radical scavenger enzyme superoxide dismutase (SOD)
      may be used as a therapeutic agent in rheumatoid arthritis, but its rapid
      elimination from the circulation is a major limitation. Targeted delivery of SOD
      may overcome this limitation. In this study, the utility of PEGylated liposomes
      (PEG-liposomes) for targeting SOD to arthritic sites was explored. The targeting
      of SOD to arthritic sites following intravenous administration of both PEG
      liposomes and positively charged liposomes lacking PEG but containing
      stearylamine (SA-liposomes) in rats with adjuvant arthritis was studied. At 24 h
      post injection, the blood levels of long circulating liposomes with a mean size
      of 0.11 micrometer and 0.20 micrometer were 8- and 3-fold higher, respectively,
      as compared to the SA-liposomes. The majority of SOD administered in liposomal
      form remains within the liposomes when they circulate in the bloodstream. The
      highest target uptake was observed with PEG-liposomes with a mean size of 0.11
      micrometer and the lowest uptake with the SA-liposomes. These results demonstrate
      that SOD can be targeted to inflamed sites most efficiently via small-sized PEG
      liposomes. Small-sized PEG-coated liposomes are to be preferred if prolonged
      circulation and enhanced localization of SOD at arthritic sites are desired.

PMID- 10407084
TI  - Elicitins trap and transfer sterols from micelles, liposomes and plant plasma
      membranes.
AB  - Using elicitins, proteins secreted by some phytopathogenic Oomycetes
      (Phytophthora) known to be able to transfer sterols between phospholipid
      vesicles, the transfer of sterols between micelles, liposomes and biological
      membranes was studied. Firstly, a simple fluorometric method to screen the sterol
      carrier capacity of proteins, avoiding the preparation of sterol-containing
      phospholipidic vesicles, is proposed. The transfer of sterols between DHE
      micelles (donor) and stigmasterol or cholesterol micelles (acceptor) was directly
      measured, as the increase in DHE fluorescence signal. The results obtained with
      this rapid and easy method lead to the same conclusions as those previously
      reported, using fluorescence polarization of a mixture of donor and acceptor
      phospholipid vesicles, prepared in the presence of different sterols. Therefore,
      the micelles method can be useful to screen proteins for their sterol carrier
      activity. Secondly, elicitins are shown to trap sterols from purified plant
      plasma membranes and to transfer sterols from micelles to these biological
      membranes. This property should contribute to understand the molecular mechanism
      involved in sterol uptake by Phytophthora. It opens new perspectives concerning
      the role of such proteins in plant-microorganism interactions.

PMID- 10407085
TI  - TTX-sensitive Na(+) and nifedipine-sensitive Ca(2+) channels in rat vas deferens
      smooth muscle cells.
AB  - The inward currents in single smooth muscle cells (SMC) isolated from epididymal
      part of rat vas deferens have been studied using whole-cell patch-clamp method.
      Depolarising steps from holding potential -90 mV evoked inward current with fast
      and slow components. The component with slow activation possessed voltage
      dependent and pharmacological properties characteristic for Ca(2+) current
      carried through L-type calcium channels (I(Ca)). The fast component of inward
      current was activated at around -40 mV, reached its peak at 0 mV, and disappeared
      upon removal of Na ions from bath solution. This current was blocked in dose
      dependent manner by tetrodotoxin (TTX) with an apparent dissociation constant of
      6.7 nM. On the basis of voltage-dependent characteristics, TTX sensitivity of
      fast component of inward current and its disappearance in Na-free solution it is
      suggested that this current is TTX-sensitive depolarisation activated sodium
      current (I(Na)). Cell dialysis with a pipette solution containing no macroergic
      compounds resulted in significant inhibition of I(Ca) (depression of peak I(Ca)
      by about 81% was observed by 13 min of dialysis), while I(Na) remained unaffected
      during 50 min of dialysis. These data draw first evidence for the existence of
      TTX-sensitive Na(+) current in single SMC isolated from rat vas deferens. These
      Na(+) channels do not appear to be regulated by a phosphorylation process under
      resting conditions.

PMID- 10407086
TI  - Cellular uptake of liposomes targeted to intercellular adhesion molecule-1 (ICAM
      1) on bronchial epithelial cells.
AB  - Previously, it was demonstrated that immunoliposomes, bearing anti-intercellular
      adhesion molecule-1 (ICAM-1) antibodies (mAb F10.2), can specifically bind to
      different cell types expressing ICAM-1. In this study, we have quantified the
      amount of immunoliposomes binding to IFN-gamma activated human bronchial
      epithelial cells (BEAS-2B) in vitro and studied the subsequent fate of cell-bound
      anti-ICAM-1 immunoliposomes. We demonstrate that binding of the immunoliposomes
      to the epithelial cells depends on the liposome concentration used. After binding
      to the cell surface, the anti-ICAM-1 immunoliposomes are rapidly internalised by
      the epithelial cells. Sixty percent of cell-bound immunoliposomes were
      internalised by the epithelial cells within 1 h of incubation at 37 degrees C.
      The results indicate that ICAM-1 targeted immunoliposomes may be used as carriers
      for the intracellular delivery of anti-inflammatory drugs to sites of
      inflammation characterised by an increased expression of ICAM-1.

PMID- 10407087
TI  - Measurement of human brain dexfenfluramine concentration by 19F magnetic
      resonance spectroscopy.
AB  - OBJECTIVE: The goals of this study were to quantitate the brain concentration of
      the anorectic drug dexfenfluramine (DF) in human subjects receiving clinical
      doses of DF and to determine whether human brain DF concentrations approach those
      reported to cause irreversible neurochemical changes in animals. Each subject's
      brain DF concentration was measured several times over an extended period of DF
      treatment to determine whether drug accumulation in the brain would plateau or
      continue to increase throughout the treatment period. DESIGN: Fluorine magnetic
      resonance spectroscopy (19F-MRS) was used to directly detect and quantitate brain
      levels of the fluorinated drug dexfenfluramine and its active metabolite dex
      norfenfluramine (dNF). Patients received 15 mg dexfenfluramine BID for 90 days.
      19F-MRS measurements were performed at baseline and at three times during the
      treatment period. PARTICIPANTS: Twelve women (age 38-54 years) who were obese,
      with body mass indices of 28. 4-37.4, but otherwise healthy. RESULTS: The
      combined concentration of DF and nDF reached steady-state in the human brain
      after approximately 10 days of treatment. The steady-state brain concentration
      averaged approximately 4 microM and did not tend to increase significantly during
      the 90 day treatment period. CONCLUSIONS: These results demonstrate that
      fluorinated drugs can be quantified using 19F MRS at concentrations below 10
      microM in the human brain. The time-course data suggest that brain DF
      concentrations parallel DF plasma pharmacokinetics in humans. Measured brain
      dexfenfluramine/nor-dexfenfluramine concentrations were well below levels
      previously found to cause irreversible brain alterations in animals.

PMID- 10407088
TI  - Amnesic effects of the anticholinergic drugs, trihexyphenidyl and biperiden:
      differences in binding properties to the brain muscarinic receptor.
AB  - An amnesic effect of anticholinergic drugs was previously described from several
      behavioral studies. We examined this effect induced by trihexyphenidyl and
      biperiden, clinically used in the parkinsonism and schizophrenic patients, by
      using passive avoidance tasks. Both of these drugs (0.1-10 mg/kg, s.c.) showed
      dose-dependent amnesic effects in the acquisition and retrieval phases. However,
      the effect induced by trihexyphenidyl was transient, whereas that of biperiden
      was long-lasting. To clarify the reason for the different duration of the amnesic
      activity, binding to the muscarinic receptor was examined. In the Scatchard
      analysis, trihexyphenidyl competed with [(3)H]quinuclidinyl benzilate ([(3)H]QNB)
      on the muscarinic receptor (showed increased K(d) and unchanged B(max) value),
      while biperiden decreased [(3)H]QNB binding (B(max) value) significantly.
      Furthermore, in an exchange assay for receptor inactivation, trihexyphenidyl
      binding to muscarinic receptors was exchanged by [(3)H]QNB completely, but
      biperiden decreased the exchangeable binding of [(3)H]QNB in a dose dependent
      manner (0.1-100 nM). These results suggested that the binding of trihexyphenidyl
      and biperiden to muscarinic receptor might be completely reversible and partially
      irreversible, respectively, whereas the K(i) values of these two drugs were
      similar. In conclusion, this difference in binding property may explain the
      difference in the time-course of the amnesic effect induced by trihexyphenidyl
      and biperiden.

PMID- 10407089
TI  - Antinociceptive effects of brain rewarding system in the developing rabbit:
      behavioral and electrophysiological analysis.
AB  - The modulating effects of electrical stimulation (ES) in the reward sites (RSs)
      of the hypothalamus and adjacent brain areas on the defensive reaction (DR) in
      response to peripheral noxious stimulation (PNS) and on evoked potentials (EPs)
      recorded in the thalamic centromedian-parafascicular complex (CM-Pf) to the same
      PNS have been investigated in 20-40-, 41-60-day old and 3-5-month old rabbits.
      Previously, RSs were identified by the method of intracranial self-stimulation
      (ICSS). Behavioral and electrophysiological testings successively performed on
      each rabbit first awake and then anaesthetized have revealed the ES in all
      investigated RSs to inhibit DR and EPs. These effects were not observed if the
      stimulating electrode tip was localized in emotionally neutral brain sites. In
      behavioral testings, the antinociceptive effect of rewarding stimulation was
      positively correlated with the ICSS intensity in given brain sites regardless of
      the age of the rabbits. In electrophysiological testings, a similar dependence of
      nociceptive EPs inhibition on emotional values of stimulated brain sites
      (determined as a rate of lever pressings during ICSS) was discovered only in 20
      40-day and 3-5-month old rabbits. Stimulation of low emotional value RSs (low
      rate (LR)-rabbits) exerted a weaker inhibitory influence in 3-5-month old rabbits
      in comparison with 20-40- and 41-60-day old rabbits both in behavioral and
      electrophysiological testings. The weakest antinociceptive effect of rewarding
      stimulation among the rabbits with a high rate of lever pressings (HR-rabbits)
      was found in 41-60-day olds in electrophysiological testings. In 41-60-day old
      rabbits, we have observed a discrepancy between the behavioral analgesia and its
      electrophysiological correlates. It may be suggested that the observed
      peculiarities of antinociceptive influences produced by RSs ES are determined by
      the age factors of neurotransmitter brain systems.

PMID- 10407090
TI  - The neurotensinergic synaptic innervation of vasopressin containing neurons in
      the rat hypothalamic paraventricular nucleus.
AB  - A recent physiological report suggested that neurotensin could inhibit the
      vasopressin releasing from vasopressin-producing neurons in the hypothalamic
      paraventricular nucleus but not in the supraoptic nucleus. In the present study,
      the synaptic relationship between the neurotensin-like immunoreactive and
      vasopressin-like immunoreactive neurons has been examined using a pre-embedding
      double immunostaining technique in the rat hypothalamic paraventricular nucleus.
      At the light microscopic level, many neurotensin-like immunoreactive fibers were
      found near the vasopressin-like immunoreactive neurons. At the electron
      microscopic level, the neurotensin-like immunoreactive fibers were identified as
      axon terminals that made many synapses on the vasopressin-like immunoreactive
      perikarya and dendrites. The synapses were both asymmetrical and symmetrical.
      These findings of the present study suggest that the inhibitory effect of
      neurotensin on the vasopressin neurons in the hypothalamic paraventricular
      nucleus may be due to the direct synapses made by neurotensin-like immunoreactive
      axon terminals on the vasopressin-like immunoreactive neurons.

PMID- 10407091
TI  - Global ischemia-induced inhibition of the coupling ratio of calcium uptake and
      ATP hydrolysis by rat whole brain microsomal Mg(2+)/Ca(2+) ATPase.
AB  - Ischemia is associated with a loss of cytosolic calcium homeostasis.
      Intracellular stores, particularly in endoplasmic reticulum, are critical for the
      maintenance of calcium homeostasis. Recent studies have shown that ischemia
      significantly inhibited microsomal calcium uptake mediated by Mg(2+)/Ca(2+)
      ATPase, the major mechanism of endoplasmic reticulum calcium sequestration. This
      study was initiated to determine whether the decreased calcium uptake caused by
      ischemia was the result of inhibition of Mg(2+)/Ca(2+) ATPase activity or an
      uncoupling of calcium uptake from ATP hydrolysis. The microsomal Mg(2+)/Ca(2+)
      ATPase specific inhibitor thapsigargin partially inhibited ATPase activity and
      completely inhibited calcium uptake. ATPase inhibited by thapsigargin was
      considered microsomal Mg(2+)/Ca(2+) ATPase. Ischemia from 5 to 60 min had no
      significant effect on thapsigargin sensitive ATPase activity. However, under
      identical conditions, increasing ischemia from 5 to 60 min significantly
      inhibited microsomal calcium uptake. Comparing calcium uptake to ATP hydrolysis
      as ischemia increased from 5 to 60 min revealed that the coupling ratio of
      calcium molecules sequestered to ATP molecules hydrolyzed became significantly
      decreased. The results demonstrated that the effect of ischemia on microsomal
      calcium uptake was mediated by an uncoupling of calcium transport from
      Mg(2+)/Ca(2+) ATPase activity.

PMID- 10407092
TI  - Differential recruitment of hypothalamic neuroendocrine and ventrolateral medulla
      catecholamine cells by non-hypotensive and hypotensive hemorrhages.
AB  - We performed c-fos expression experiments in conscious rats to quantify the
      threshold and extent of activation of hypothalamic neuroendocrine cells in
      response to non-hypotensive and hypotensive hemorrhages allowing us to assess
      whether their pattern of recruitment corresponded to known oxytocin, vasopressin
      and ACTH release patterns. Also, because previous studies have implicated
      ventrolateral medulla catecholamine cells in the generation of certain
      hypothalamic neuroendocrine cell responses, we examined the response of
      ventrolateral medulla catecholamine cells to non-hypotensive and hypotensive
      hemorrhages and directly tested their role in regulating neuroendocrine cell
      responses to hypotensive hemorrhage. Animals were subjected to hemorrhages of 0,
      4, 8, 12 or 16 ml/kg BW, the latter two levels being hypotensive. We found that
      only supraoptic nucleus vasopressin cells were significantly activated by the
      smallest non-hypotensive hemorrhage (4 ml/kg), which corresponds to reports that
      only vasopressin is released into the plasma after a small hemorrhage.
      Hypotensive hemorrhages resulted in significant recruitment of paraventricular
      and supraoptic oxytocin and vasopressin cells and parvocellular cells of the
      medial division of the paraventricular nucleus. Vasopressin cells were recruited
      in much greater numbers than oxytocin cells, which is in agreement with previous
      findings that there is a greater release of vasopressin than oxytocin into the
      plasma after hypotensive hemorrhage. In addition, medial parvocellular cells of
      the paraventricular nucleus, most likely to be tuberoinfundibular-projecting
      corticotropin-releasing factor cells, were activated by hypotensive hemorrhage
      only when arterial pressure dropped below 60 mmHg which also corresponds well
      with the plasma release response of ACTH. Ventrolateral medulla catecholamine
      cells were only recruited by hypotensive hemorrhages. While caution must be
      exercised in interpreting an absence of response, this certainly suggests that
      catecholamine cells are unlikely to have a role in the activation of supraoptic
      neurosecretory cells in response to non-hypotensive hemorrhages. Unilateral
      lesions of the ventrolateral medulla catecholamine cell column, corresponding
      primarily to the location of A1 noradrenergic cells, significantly reduced the
      hypotensive hemorrhage-induced activation of hypothalamic vasopressin, oxytocin
      and medial parvocellular paraventricular nucleus cells. This suggests that A1
      noradrenergic cells contribute to the activation of these neuroendocrine cell
      populations, including oxytocin cells, which is an unexpected finding. More
      significantly, however, because the reduction in responsiveness after A1 lesions
      was similar for all cell categories, it seems likely that other factors must
      determine the differential recruitment of hypothalamic neuroendocrine cells in
      response to a hypotensive hemorrhage.

PMID- 10407093
TI  - Increased c-fos expression in spinal lumbosacral projection neurons and
      preganglionic neurons after irritation of the lower urinary tract in the rat.
AB  - Chemical irritation of the lower urinary tract (LUT) induces c-fos expression in
      neurons in the lumbosacral (L(6) and S(1)) spinal cord. This study used axonal
      tracing with fluorescent dyes to identify the types of spinal neurons expressing
      Fos immunoreactivity (IR) after LUT irritation in the rat. Fos-IR was detected in
      lateral and medial superficial dorsal horn, the sacral parasympathetic nucleus
      (SPN) and lamina X around the central canal. Fos-IR was detected in spinal
      neurons projecting to supraspinal sites (brainstem and hypothalamus), in
      preganglionic neurons (PGN) and in unlabeled segmental interneurons. A
      substantial percentage (20%) of dye labeled PGN exhibited Fos-IR after LUT
      irritation; and a larger percentage (36%) exhibited Fos-IR after electrical
      stimulation of the pelvic nerve which contains afferent pathways from all of the
      pelvic organs. The majority (average 55%) of Fos-positive neurons projecting to
      supraspinal sites were also located in the region of the SPN. A selective
      distribution of different types of neurons was detected in this region: PGN were
      located ventral to the spinal projection neurons which in turn were located
      ventral to the majority of unidentified Fos-positive neurons. The distribution of
      Fos-positive PGN and projection neurons was similar in spinal intact and spinal
      transected animals indicating that c-fos expression was mediated by monosynaptic
      afferent input or input from segmental interneurons and was not due to activation
      of supraspinal micturition reflex pathways.

PMID- 10407094
TI  - Immunohistochemical demonstration of a neuronal calmodulin-binding protein, NAP
      22, in the rat spinal cord.
AB  - Neuron-enriched acidic protein having a molecular mass of 22 kDa, NAP-22, is a
      newly isolated calmodulin-binding protein and is phosphorylated with protein
      kinase C (PKC). This protein is localized to biological membrane via
      myristoylation and found in the membrane fraction of the brain and in the
      synaptic vesicle fraction. To reveal the NAP-22 distribution in vivo, we
      investigated the spinal cord of the 4-5-week old rats using light and electron
      microscopy. NAP-22 immunoreactivity was observed in the gray matter with
      dorsoventral gradient of reactivity. Distinct reactivity was demonstrated in the
      nerve terminals and dendritic spines. Some reactions were also observed in the
      thin nerve fibers. NAP-22 immunoreactivity was associated mainly with pre- and
      postsynaptic membranes, synaptic vesicles and outer mitochondrial membranes. In
      the nerve terminals, NAP-22 was colocalized with synaptic vesicle proteins such
      as synapsin I or synaptobrevin 2. About 80% of the nerve terminals having
      immunoreactivity for synapsin I or synaptobrevin 2 showed NAP-22
      immunoreactivity. From these results, NAP-22 is confirmed to be distributed in
      the synaptic region of the spinal cord and is involved in the synaptic function
      relating to PKC.

PMID- 10407095
TI  - Effect of paired transcranial magnetic stimulation on the cortical silent period.
AB  - OBJECTIVE: To investigate the behaviour of silent period (SP) during paired
      magnetic cortical stimulation. BACKGROUND: Paired cortical magnetic stimulation
      is known to inhibit or facilitate motor evoked potentials (MEPs), but no
      attention has been paid to its effect on SP. METHODS: SP was measured in the
      contracted first dorsal interosseus muscle after paired cortical stimuli at given
      interstimulus intervals (ISIs) in eight healthy subjects. Test stimulus intensity
      was fixed at 110% of resting threshold (RT), while three levels of conditioning
      stimulus intensities at 40%, 65% and 90% RT were separately employed. We also
      examined the effect of progressively increasing the test stimulus intensity (120
      150 RT) on SP while maintaining stable conditioning stimulus intensity. RESULTS:
      65% RT conditioning stimulus shortened the SP at 1-3 ms ISIs with MEP size
      reduction, and prolonged the SP at 15-20 ms ISIs without affecting MEP size. 90%
      RT conditioning stimulus showed only SP prolongation, while 40% RT showed only SP
      shortening at 1 ms ISI. The SP shortening at 2 ms ISI was the most evident with
      120% RT test stimulus, but without correlation with the MEP size. The SP
      prolongation at 15 ms ISI was maximal with 110% RT test stimulus and then almost
      abolished with 150% RT. The SP shortening at short intervals might be due not
      only to spinal but also to suprasegmental mechanisms, conceivably mediating
      cortical excitatory drive to the corticospinal tract. The SP prolongation at
      intermediate intervals might be due to activation of slowly conducting, intra- or
      sub-cortical polysynaptic pathways exerting a facilitatory drive on the cortical
      inhibitory interneurons.

PMID- 10407096
TI  - FMRFamide immunoreactivity and the invasion of adenohypophyseal cells into the
      neural lobe in the developing pituitary of the tree shrew Tupaia belangeri.
AB  - Ontogenetic development of FMRFamide immunoreactivity in the cells and nerve
      fibers of the pituitary was studied in the tree shrew Tupaia belangeri. Up to the
      26th day of gestation (E26), no FMRFamide immunoreactivity was visible. From E27
      onwards it increased continuously until prenatally, on E41, the adult pattern was
      reached in the adenohypophysis, although at a lower intensity. In the adult
      Tupaia, as in the other mammals studied so far, a finely stained FMRFamide
      immunoreactive fiber network was visible in the neural lobe and the infundibular
      stalk. As in several other adult mammals including man, endocrine cells in the
      pars intermedia and numerous scattered cells in the pars distalis were labeled,
      in contrast to several reports on rats and our studies on Galago, showing no
      FMRFamide-immunoreactive cells in these locations of the pituitary. With
      reference to the 'basophil invasion', we found FMRFamide-immunoreactive endocrine
      cells invading the neural lobe from the pars intermedia during the pituitary
      development. The distribution pattern of FMRFamide immunoreactivity in Tupaia
      indicates that the mammalian counterparts of FMRFamide may function as
      neuromodulators, neurotransmitters or as hormones already in defined prenatal
      stages.

PMID- 10407097
TI  - Long-lasting c-fos and NGF mRNA expressions and loss of perikaryal parvalbumin
      immunoreactivity in the development of epileptogenesis after ethacrynic acid
      induced seizure.
AB  - A single cerebroventricular injection of ethacrynic acid (EA), a Cl(-)-ATPase
      inhibitor, induces generalized tonic-clonic convulsions in mice. To clarify
      whether such convulsive stimulus triggers a long-lasting rearrangement of the
      neural circuitry culminating in seizure susceptibility, we examined molecular,
      cellular and behavioral changes following the EA-induced seizure. The expression
      of immediate early gene c-fos mRNA as an index for cellular activation increased
      biphasically, with an early transient increase at 60 min and a late prolonged
      increase on the 10th to 14th day post-EA administration, most remarkably in the
      hippocampus and pyriform cortex. On the 14th day post-EA seizure, subconvulsive
      dose of kainic acid (5-17.5 mg/kg) caused severe (stage 5) seizure in 77% of the
      mice, with 70% mortality. In addition, the expression of nerve growth factor
      (NGF) also showed biphasic increases with close spatiotemporal correlation with c
      fos expression. Moreover, the number of cell somata and the density of axon
      fibers of parvalbumin (PARV)-positive cells, a subpopulation of GABAergic
      interneurons, decreased in area dentata, CA1 and CA3 on the 7th and 14th day post
      EA seizure. In area dentata and CA1, the density of glutamic acid decarboxylase
      (GAD)-positive cells also decreased on the 14th day. Thus, the transient EA
      induced seizures appear to develop seizure susceptibility by causing damage of a
      subpopulation of inhibitory interneurons along with increases in the expression
      of c-fos and NGF in limbic structures.

PMID- 10407098
TI  - A single pretreatment with MK-801 or cocaine enhances their locomotor stimulant
      effects in rats.
AB  - A single dose of MK-801 (1.0 mg/kg, s.c.) induces an enhanced locomotor response
      to a subsequent lower dose of MK-801 (0.3 mg/kg) administered 4, 7 or 14 days
      later in young adult rats (>90 days). MK-801 (1.0 mg/kg) administration did not
      significantly enhance the effects of cocaine (10, 20 mg/kg) administered 7 days
      later. Cocaine (20 mg/kg) enhanced the effect of a subsequent dose of 10 mg/kg
      cocaine, but did not significantly alter the response to a higher dose cocaine
      (20 mg/kg) or of MK-801 (0.1 or 0.3 mg/kg) again given 7 days later. MK-801 (1.0
      mg/kg) did not significantly enhance the locomotor response to a second dose of
      MK-801 (0.3 mg/kg) in 28-day-old rats tested 7 days after the initial dose, but
      did enhance the effects of a lower (0.1 mg/kg) dose. These findings indicate that
      even a single dose of a stimulant such as MK-801 and cocaine can induce enduring
      changes in sensitivity to subsequent doses of the same stimulants in young adult
      rats. The lack of significant effects seen in cross-sensitization studies
      suggests that separate mechanisms maybe involved in the sensitization to cocaine
      and MK-801. The more pronounced enhancement of activity in the older animals is
      in accord with previous findings that sensitization processes are developmentally
      regulated.

PMID- 10407099
TI  - Effects of electrical stimulation of thalamic nucleus submedius and
      periaqueductal gray on the visceral nociceptive responses of spinal dorsal horn
      neurons in the rat.
AB  - Electrical stimulation of the nucleus submedius (Sm) has been shown to suppress
      the viscerosomatic reflex (VSR), which is evoked by colorectal distension (CRD).
      We have examined the effects of focal electrical stimulation (0.3 ms, 50 Hz, 100
      microA, 10 s) of the Sm and the periaqueductal gray (PAG) on the excitatory
      responses evoked by CRD in spinal dorsal horn neurons within the L6-S1 region in
      the urethane-anesthetized Wistar rats. Extracellular recordings were made from 32
      spinal excitatory CRD responses. All of these neurons were convergent neurons
      with cutaneous receptive fields. The majority of the neurons (27/32) were wide
      dynamic range (WDR) neurons (responding to noxious and non-noxious cutaneous
      stimuli) while the remaining five neurons were nociceptive specific (NS) neurons
      (responding only to noxious cutaneous stimuli). The effects of electrical
      stimulation applied to 28 sites within the Sm were assessed for spinal neurons.
      Electrical stimulation in seven sites within the Sm (25%) inhibited the CRD
      excitatory response of dorsal horn neurons, while in two sites (7%) the same
      stimulation yielded facilitation. Electrical stimulation in the majority of the
      sites in the Sm (19/28, 68%) did not affect spinal excitatory CRD responses. On
      the other hand, electrical stimulation of the PAG clearly inhibited 20 of 22
      (90%) CRD excitatory responses. These results suggest that the majority of Sm
      neurons may suppress VSR activity at a supraspinal reflex center rather than via
      a descending inhibition of spinal visceral nociceptive transmission, as is the
      case for the PAG.

PMID- 10407100
TI  - Spatio-temporal analysis of light-induced Fos expression in the retina of rd
      mutant mice.
AB  - Rd mutant mice are visually blind but they maintain the ability of synchronising
      their circadian rhythms to the external light-dark cycles. We used
      immunocytochemical procedures to detect light-induced Fos expression in the rd
      mice retina. We found that Fos is expressed in the rd retina in an unattenuated
      pattern through the entire life of the animal. Furthermore, we have found that
      cells expressing Fos are distributed throughout the whole retina, while opsin
      expression takes place only in the dorsal half of the retina in the 1-year old rd
      mice. Finally, we found that light induces Fos expression in the rd retina at the
      same levels during the subjective day as during the subjective night, whereas in
      the suprachiasmatic nucleus (SCN), Fos is stimulated by light only during the
      subjective night. Our results support the hypothesis that new, undiscovered
      photoreceptors are implicated in light perception for the circadian system.

PMID- 10407101
TI  - Characterization and regional distribution of nitric oxide synthase in the human
      brain during normal ageing.
AB  - Nitric oxide (NO) is a highly diffusible cellular mediator generated from L
      arginine by the enzyme nitric oxide synthase (NOS). As little is known about the
      regional distribution of NOS in the human brain, we examined the distribution
      pattern of nitric oxide synthase activity in 28 regions of the human brain using
      the [(3)H]L-citrulline formation assay. To elucidate which isoforms contribute to
      the total NOS activity we performed Western blot analysis of neuronal, inducible
      and endothelial NOS. We further determined brain levels of arginine and
      citrulline as a potential index of NOS activity pre mortem. NOS activity appears
      to remain unaltered during ageing and is independent of post mortem delay, gender
      or sample storage time. We identified a regional pattern of NOS distribution with
      highest levels of NOS activity in the substantia innominata, cerebellar cortex,
      nucleus accumbens and subthalamicus, whereas lowest levels were measured in the
      corpus callosum, thalamus, occipital cortex, and dentate nucleus. nNOS was
      measured throughout the brain, in contrast iNOS and eNOS were not detectable. We
      therefore conclude that primarily nNOS is responsible for NOS activity in the
      human brain. Levels of citrulline were higher than those of arginine, but did not
      correlate with the enzyme activity, suggesting that these parameters are
      unsuitable for testing NOS activity premortem. The characterization and
      topographical pattern of NOS in the human brain during normal ageing may assist
      our understanding of the physiological role of NO and its relevance in
      Parkinson's and Alzheimer's disease, alcoholism, schizophrenia and AIDS.

PMID- 10407102
TI  - Differential effects of 192IgG-saporin and NMDA-induced lesions into the basal
      forebrain on cholinergic activity and taste aversion memory formation.
AB  - Mnemonic deficits resulting from excitotoxic lesion of the basal forebrain have
      been classically attributed to the resulting depletion of cortical acetylcholine
      activity. In this study, we have performed a detailed analysis of the cholinergic
      status of the insular cortex (IC) following local injections of either 192IgG
      saporin (192IgG-sap) or N-methyl-D-aspartate (NMDA) directly into the nucleus
      basalis magnocellularis (NBM). By means of in vivo microdialysis, we show that
      the immunotoxin lesion results in an almost complete lack of extracellular
      acetylcholine release, whereas NMDA-induced lesions result in a marginal
      reduction in cortical cholinergic activity. Choline-acetyltransferase activity in
      the IC further confirmed this differential pattern of cortical deafferentation.
      Surprisingly, however, only NMDA-induced lesions showed a strong disruptive
      effect upon taste aversion learning whereas no detectable deficits could be found
      following 192IgG-sap lesions. By combining intrabasal injections of 192IgG-sap
      with acute pre-training infusions of the cholinergic antagonist scopolamine into
      the IC, a strong disruption of taste aversion was attained. These results imply
      that residual cholinergic activity, following 192IgG-saporin lesions, might be
      still critical for normal cortical mediation of memory processing. They also
      support the role of basal forebrain in mediating learning and memory processes,
      and demonstrate that mnemonic deficits resulting from excitotoxic lesions of the
      basal forebrain are not the sole result of cortical acetylcholine activity
      hypofunction.

PMID- 10407103
TI  - Predominant expression of group-II metabotropic glutamate receptors in the
      goldfish brain.
AB  - Group-II metabotropic glutamate (mGlu) receptors (mGlu2/3 receptors) were highly
      expressed in various regions (telencephalon, optic tectum, and cerebellum, but
      not vagal lobe) of the goldfish brain. In the goldfish telencephalon, expression
      of mGlu2/3 receptors was even higher than in the rat cerebral cortex. In
      contrast, mGlu5 receptors showed low levels of expression in all goldfish brain
      regions, whereas mGlu1a receptors were only expressed in the goldfish cerebellum.
      Pharmacological activation of group-II mGlu receptors with the selective
      agonists, 2R,4R-4-aminopyrrolidine-2, 4-dicarboxylic acid and (2S,2'R,3'R)-2-(2,3
      dicarboxycyclopropyl) glycine, reduced the evoked release of glutamate from
      goldfish brain synaptosomes, whereas agonists of group-I and -III mGlu receptors
      (3, 5-dihydroxyphenylglycine and L-2-amino-4-phosphonobutanoate) were inactive.
      The predominance of group-II over group-I mGlu receptors in the goldfish brain
      may provide a natural defense against excitotoxic neuronal death and contribute
      to the unusually high resistance of goldfish against hypoxic brain damage.

PMID- 10407105
TI  - Intra-periaqueductal grey injection of galanin increases the nociceptive response
      latency in rats, an effect reversed by naloxone.
AB  - The nociceptive response latencies were increased significantly after intra
      periaqueductal grey (PAG) administration of 1.0 or 3.0 nmol of galanin, but not
      0.3 nmol, in rats. The effect of galanin was attenuated by following injection of
      5.5 nmol of naloxone into PAG. These results indicate an anti-nociceptive role of
      galanin, and a possible interaction between galanin and opioid peptides in PAG in
      rats.

PMID- 10407104
TI  - Immunohistochemical localization of connective tissue growth factor in the rat
      central nervous system.
AB  - Connective tissue growth factor (CTGF) is an immediate early growth-responsive
      gene but its distribution and significance in the central nervous system (CNS)
      are unknown. We investigated the distribution of CTGF-like immunoreactivity (CTGF
      IR) in the rat CNS using a specific antiserum against CTGF oligopeptide. The
      majority of CTGF-IR was observed in astrocytes. Ependymal cells lining the wall
      of the cerebral ventricle and tanycytes lining the central canal of the spinal
      cord showed the strongest CTGF-IR, while there was a diffuse but weak signal in
      the gray matter of the spinal cord. CTGF-IR was also detected in the cytoplasm of
      a subpopulation of pyramidal neurons in the cerebral cortex. Our results showed
      that CTGF-IR is widely distributed in the CNS at both regional and cellular
      levels, suggesting a complex functional role in the CNS.

PMID- 10407106
TI  - Substance P-immunoreactive boutons closely appose inspiratory protruder
      hypoglossal motoneurons in the cat.
AB  - In anesthetized cats, we recorded intracellularly from 26 hypoglossal motoneurons
      which were antidromically activated following electrical stimulation of either
      the medial or lateral branches of the hypoglossal nerve. Twenty-one of these
      neurons were protruder motoneurons 6 of which had inspiratory activity. Three of
      the protruder motoneurons with inspiratory activity were filled with Neurobiotin
      and found to be closely apposed to substance P-like immunoreactive nerve
      terminals.

PMID- 10407108
TI  - Attenuation of dopamine uptake in vivo following priming with estradiol benzoate.
AB  - Dopamine (DA) uptake and clearance were examined using in vivo voltammetry
      following injection of DA (200 microM) into the nucleus accumbens of
      ovariectomized (OVX) or OVX-estrogen-primed rats (estradiol benzoate, EB, 10
      microg 48 and 24 h prior to experiment). The rate of DA uptake was significantly
      attenuated in steroid-treated animals: this decrease was accompanied by a
      significant increase in DA clearance time. Quinpirole (0.5 mg/kg) modulated the
      kinetics of DA uptake in OVX but not EB-primed rats. These data suggest that DA
      clearance can be regulated by physiological doses of EB.

PMID- 10407107
TI  - Differential effects of neuropeptide Y and the mu-agonist DAMGO on 'palatability'
      vs. 'energy'.
AB  - Differential effects of neuropeptide Y (NPY) and mu-opioid DAMGO on
      'palatability' vs. 'energy'. A variety of studies suggest that NPY is an
      important manager of energy metabolism. In contrast, the opioid peptides appear
      to influence the 'rewarding' aspects of feeding. In the current study, we
      stimulated feeding by injecting NPY (110 pmol) or the mu-opioid agonist DAMGO (2
      nmol) into the paraventricular nucleus of rats. Following injection, rats were
      given free access to laboratory chow and a 10% sucrose solution. Animals injected
      with saline derived 10% of their kilocalories from the chow and 90% from the
      sucrose solution (total kcal/4 h=12.2+/-1. 0). Those rats injected with NPY
      derived 48% of their energy from chow and 52% from the sucrose solution (total
      kcal/4 h=24.8+/-1.7). The DAMGO-injected rats derived only 15% of their
      kilocalories from chow and the remainder from the sucrose solution (total kcal/4
      h=23. 0+/-2.3). Thus, while NPY and DAMGO both stimulated energy intake compared
      to saline controls (P<0.0001), the effect on intake of a palatable dilute energy
      solution (0.4 kcal/g) vs. a 'bland' laboratory chow (3.95 kcal/g) was different.
      The results of this study reinforce the notion that NPY has a major effect on
      energy needs, whereas opioids influence the 'rewarding' characteristics of foods.

PMID- 10407109
TI  - Clorgyline and deprenyl attenuate striatal malonate and 3-nitropropionic acid
      lesions.
AB  - We have previously shown that dopamine depletion reduces striatal damage elicited
      by the mitochondrial neurotoxins malonate and 3-nitropropionic acid (3NP).
      Metabolism of dopamine by monoamine oxidase results in the formation of hydrogen
      peroxide, which may mediate dopamine toxicity. In this study, administration of
      the monoamine oxidase inhibitors clorgyline and deprenyl resulted in a 42% and
      75% reduction in lesion volumes in malonate- and 3NP-treated animals,
      respectively, compared to controls.

PMID- 10407110
TI  - Expression of NADPH-diaphorase and colocalization with Fos in the brain neurons
      of the rat following visceral noxious stimulation.
AB  - We used double staining immunocytochemical techniques to determine whether nitric
      oxide (NO) and Fos immunoreactivity induced by noxious visceral stimulation were
      colocalized in the neurons of the supraspinal areas. We observed a considerable
      increase in Fos-positive neurons in many brain areas after noxious stimulation
      but only 15% of the Fos-positive neurons colocalized Nicotinamide Adenine
      Dinucleotide Phosphate Diaphorase (NADPH-d). The NADPH-d positive cells showed
      perikarya and cytoplasmic processes laying next to or more frequently apposed to
      Fos-positive neurons. This anatomical finding supported the hypothesis that also
      at supraspinal level NO is released near the neurons specifically activated and
      diffuses through the source cells to act on adjacent neurons playing a role in
      the central processing of pain transmission and modulation.

PMID- 10407111
TI  - Reversal of morphine tolerance and dependence by melatonin: possible role of
      central and peripheral benzodiazepine receptors.
AB  - Possible reversal by melatonin of morphine-induced tolerance and dependence was
      studied in mice. A 10-day repeated injection regimen was followed to induce
      morphine tolerance and dependence. Co-administration of melatonin (1-10 mg/kg,
      i.p.) with morphine (10 mg/kg, s.c.) during the induction phase (day 1 to 9)
      reversed the development of opioid tolerance and dependence tested on 10th day.
      On the other hand acute administration of melatonin (1-10 mg/kg) on the 10th day,
      ie. during the expression phase of morphine dependence, it reduced the incidence
      of naloxone-induced withdrawal jumps without affecting the tolerance to analgesic
      effect. Co-administration of flumazenil (2 mg/kg, i.p.), a central benzodiazepine
      (BZ) receptor antagonist had no effect on melatonin response, whereas peripheral
      antagonist for BZ receptor PK11195 (2 mg/kg, i.p.) significantly reversed the
      attenuating effect of melatonin on physical dependence both during induction and
      expression phase of morphine tolerance and dependence. These observations suggest
      that melatonin reverses development of tolerance and dependence to morphine, and
      this action possibly involved peripheral benzodiazepine receptors.

PMID- 10407112
TI  - Poly(ADP-ribose) polymerase is found in both the nucleus and cytoplasm of human
      CNS neurons.
AB  - There is evidence that inhibitors of poly(ADP-ribose) polymerase (PARP) may be
      therapeutically useful in neurodegenerative diseases. Using immunocytochemistry,
      we have investigated the distribution of PARP in the human CNS. Some neuronal
      groups showed cytoplasmic staining in addition to the expected staining of
      nuclei. Considerable variation between different neuronal groups was noted: motor
      neurons in the spinal cord showed greatest cytoplasmic staining, whereas staining
      was virtually absent in other neurons, notably in the hippocampus. These results
      indicate that PARP can be associated with sub-cellular components other than the
      nucleus, and may indicate additional roles for this enzyme.

PMID- 10407113
TI  - Visualisation of AMPA binding sites in the brain stem of normotensive and
      hypertensive rats.
AB  - The present study has employed in vitro receptor autoradiography with (S)-[(3)H]
      5-fluorowillardiine (10 nM) to visualise the presence of alpha-amino-3-hydroxy-5
      methylisoxazole-4-propionic acid (AMPA) binding sites in the brain stems of adult
      (16-18 weeks) normotensive (Wistar-Kyoto (WKY) and Don Ryu (DRY)) and
      Spontaneously Hypertensive (SHR) rats. Similar topographic distribution and
      density of (S)-[(3)H]-5-fluorowillardiine binding was observed in the nucleus
      tractus solitarius (NTS) of all three strains. Specific (S)-[(3)H]-5
      fluorowillardiine binding sites were also visualised in sections of nodose
      ganglion from adult WKY rats, demonstrating that vagal afferent perikarya possess
      AMPA binding sites. However, while unilateral vagal deafferentation did not
      result in a significant decrease in binding site density in the caudal half of
      the rat NTS, the visualisation of AMPA binding sites on the nodose ganglion is
      consistent with the existence of a population of binding sites on vagal afferent
      terminals. In the caudal half of the rat NTS, AMPA binding sites appear to be
      predominantly postsynaptic in nature.

PMID- 10407115
TI  - Differential control of sympathetic drive to the rat tail artery and kidney by
      medullary premotor cell groups.
AB  - Sympathetic activity was recorded from the renal nerve and the ventral tail
      artery of anesthetized rats while neurons in three sympathetic premotor groups,
      the rostroventrolateral medulla (RVLM), rostroventromedial medulla (RVMM) and
      medullary raphe, were activated by microinjections of sodium glutamate (1-15 nl,
      50 mM). RVLM activation increased renal nerve activity by 27+/-3% but caused
      small, inconsistent effects on the tail outflow (+15+/-10%). Raphe neuron
      stimulation had little effect on the renal nerve (+8+/-3%), but strongly
      increased tail sympathetic unit activity (+125+/-28%). RVMM neurons had little
      effect on either outflow. These results indicate that different premotor cell
      groups have different sympathetic actions.

PMID- 10407114
TI  - Induction of glial cell line-derived neurotrophic factor receptor proteins in
      cerebral cortex and striatum after permanent middle cerebral artery occlusion in
      rats.
AB  - In an attempt to elucidate whether glial cell line-derived neurotrophic factor
      (GDNF) receptors are induced after ischemic brain injury, possible expression of
      immunoreactive GDNF receptor-alpha1 (GFRalpha-1) and c-ret (RET) was examined at
      3, 8, or 24 h after permanent middle cerebral artery occlusion (MCAO) in rats.
      Immunohistochemical study showed that both GFRalpha-1 and RET staining cells
      which were not detected in sham control brain, were present in the ipsilateral
      cortex and caudate at 3 to 8 h after permanent MCAO, and then decreased but
      remained to some extent at 24 h. Positive cells for both GDNF receptors were
      predominantly in cortical neurons of ischemic penumbral area. Western blot
      analysis confirmed the induction of those receptors after permanent MCAO. This
      rapid induction of GFRalpha-1 and RET, which correlates with the similar
      induction of GDNF under these conditions, may play a role in the early response
      to ischemic brain injury.

PMID- 10407116
TI  - The effects of RB101, a mixed inhibitor of enkephalin-catabolizing enzymes, on
      carrageenin-induced spinal c-Fos expression are completely blocked by beta
      funaltrexamine, a selective mu-opioid receptor antagonist.
AB  - We have demonstrated that pre-administered RB101 (40 mg/kg, i.v.), a mixed
      inhibitor of enkephalin-catabolizing enzymes, decreased spinal c-Fos expression
      induced 1 h and 30 min after intraplantar (i.pl.) carrageenin (41% reduction,
      p<0.01). These effects were completely blocked by pre-administered beta
      funaltrexamine (10 mg/kg, i.v., 24 h prior to stimulation), a selective long
      lasting mu-opioid receptor antagonist. In conclusion, these results clearly
      demonstrate that the effects of endogenous enkephalins on noxiously evoked spinal
      c-Fos expression are essentially mediated via mu-opioid receptors.

PMID- 10407117
TI  - Phosphatidylcholine and phosphatidylethanolamine metabolites may regulate brain
      phospholipid catabolism via inhibition of lysophospholipase activity.
AB  - Brain levels of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE),
      abundant metabolites of phosphatidylcholine and phosphatidylethanolamine, are
      increased in several disorders of the human brain. To determine whether
      accumulation of these compounds may alter phospholipid metabolism, we assessed
      the ability of GPE and GPC to modulate the activities of phospholipase A(2),
      lysophospholipase, and other enzymes involved in phospholipid metabolism, in
      preparations of human brain parietal cortex. GPC and GPE acted as competitive
      inhibitors of lysophospholipase activity, but failed to alter the activity of the
      other enzymes tested. Our results suggest that GPC and GPE may normally act to
      inhibit lysophospholipid hydrolysis, thereby reducing the rate of membrane
      phospholipid degradation.

PMID- 10407119
TI  - Mossy fiber sprouting in the dentate gyrus in a newly developed epileptic mutant,
      Ihara epileptic rat.
AB  - We examined the correlation between seizure activity and development of mossy
      fiber sprouting in the hippocampal formation using Timm staining in a newly
      developed Ihara epileptic rat (IER). The sprouting of mossy fibers were clearly
      shown in the inner molecular portion of the dentate gyrus and in the stratum
      oriens of CA3 pyramidal cell layer with repeated seizures. A positive correlation
      between the frequency of generalized tonic and clonic convulsions and the Timm
      staining score in molecular layer of dentate gyrus was revealed. Sprouting of
      mossy fiber in IER seems to be linked with seizure activities resulting from
      epileptic bursts, not to the genetic mutation.

PMID- 10407118
TI  - Persistent activation of calcium-activated and calcium-independent protein kinase
      C in response to electrical afterdischarge from peptidergic neurons of aplysia.
AB  - The purpose of this work was to investigate the effects of electrical
      afterdischarge on protein kinase C (PKC) activity from bag cell neurons (BCNs) of
      Aplysia. Bilateral clusters of BCNs were divided: one cluster was stimulated to
      afterdischarge, the other was a control. Clusters were processed for PKC activity
      assay 5-120 min after electrical stimulation. Afterdischarge triggered a rapid
      and persistent increase in both calcium-activated and calcium-independent PKC
      activity.

PMID- 10407120
TI  - Phosphacan immunoreactivity is associated with perineuronal nets around
      parvalbumin-expressing neurones.
AB  - A special feature of the extracellular matrix in adult brains of various species
      is the concentration of certain components around different sub-populations of
      neurones, giving rise to net-like structures termed perineuronal nets. Recently,
      some of these components have been identified but the function of these nets has
      yet to be resolved. Using immunofluorescence microscopy, we report here that
      phosphacan, a chondroitin sulphate proteoglycan, is an additional component of
      Wisteria floribunda labelled perineuronal nets surrounding parvalbumin-expressing
      neurones in rat cerebral cortex. Glycoproteins such as tenascin-C and -R have
      been identified in perineuronal nets and the present detection of phosphacan
      immunoreactivity in the same entity is of potential physiological importance
      because of their previously described interactions.

PMID- 10407121
TI  - Cerebrovascular evidence for a GABAergic modulation of the cholinergic
      vasodilatatory basalocortical system in the rat.
AB  - The present work is aimed to study the functional relevance of GABAergic
      cholinergic interactions on the modulation of cerebral blood flow (CBF) exerted
      by the basalocortical system. Injections of GABA into the substantia innominata
      (SI) induce increases in blood flow in several cortical areas and inhibit partly
      the increases in cortical blood flow induced by cholinergic activation of this
      structure. Blockade of local GABAergic receptors by picrotoxin induced almost
      similar effects. These findings suggest that local GABAergic neurones of the SI
      exert a complex cortical cerebrovascular modulation at a resting and an activated
      state.

PMID- 10407122
TI  - The axonal arborization of single nigrostriatal neurons in rats.
AB  - Neurons of the substantia nigra pars compacta (SNc) were iontophoretically
      injected with biotin dextran and their anterogradely labeled axons individually
      reconstructed from serial sagittal sections. Most nigrostriatal axons travelled
      directly to the striatum, where they branched abundantly. Other axons arborized
      profusely in various extrastriatal structures, including the globus pallidus, the
      entopeduncular and subthalamic nuclei, and branched only sparsely in the
      striatum. This heterogeneous organization of the nigrostriatal projection allows
      single SNc neurons to influence differently striatal neurons and to act directly
      upon extrastriatal components of the basal ganglia via a highly patterned set of
      collaterals.

PMID- 10407123
TI  - Efferent connections of the anteromedial nucleus of the thalamus of the rat.
AB  - The projections from the anteromedial nucleus of the thalamus (AM) were
      investigated using anterograde and retrograde tracing techniques. AM projects to
      nearly the entire rostrocaudal extent of limbic cortex and to visual cortex.
      Anteriorly, AM projects to medial orbital, frontal polar, precentral agranular,
      and infraradiata cortices. Posteriorly, AM projects to retrosplenial granular,
      entorhinal, perirhinal and presubicular cortices, and to the subiculum. Further,
      AM projects to visual cortical area 18b, and to the lateral and basolateral
      nuclei of the amygdala. AM projections are topographically organized, i.e.,
      projections to different cortical areas arise from distinct parts of AM. The
      neurons projecting to rostral infraradiata cortex (IRalpha) are more caudally
      located in AM than the neurons projecting to caudal infraradiata cortex (IRbeta).
      The neuronal cell bodies that project to the terminal field in area 18b are
      located primarily in ventral and lateral parts of AM, whereas neurons projecting
      to perirhinal cortex and amygdala are more medially located in AM. Injections
      into the most caudal, medial part of AM (i.e., the interanteromedial [IAM]
      nucleus) label terminals in the rostral precentral agranular, caudal IRbeta, and
      caudal perirhinal cortices. Whereas most AM axons terminate in layers I and V-VI,
      exceptions to this pattern include area 18b (axons and terminals in layers I and
      IV-V), the retrosplenial granular cortex (axons and terminals in layers I and V),
      and the presubicular, perirhinal, and entorhinal cortices (axons and terminals
      predominantly in layer V). Together, these findings suggest that AM influences a
      widespread area of limbic cortex.

PMID- 10407124
TI  - Tapping into spinal circuits to restore motor function.
AB  - Motivated by the challenge of improving neuroprosthetic devices, the authors
      review current knowledge relating to harnessing the potential of spinal neural
      circuits, such as reflexes and pattern generators. If such spinal interneuronal
      circuits could be activated, they could provide the coordinated control of many
      muscles that is so complex to implement with a device that aims to address each
      participating muscle individually. The authors' goal is to identify candidate
      spinal circuits and areas of research that might open opportunities to effect
      control of human limbs through electrical activation of such circuits. David
      McCrea's discussion of the ways in which hindlimb reflexes in the cat modify
      motor activity may help in developing optimal strategies for functional
      neuromuscular stimulation (FNS), by using knowledge of how reflex actions can
      adapt to different conditions. Michael O'Donovan's discussion of the development
      of rhythmogenic networks in the chick embryo may provide clues to methods of
      generating rhythmic activity in the adult spinal cord. Serge Rossignol examines
      the spinal pattern generator for locomotion in cats, its trigger mechanisms,
      modulation and adaptation, and suggests how this knowledge can help guide
      therapeutic approaches in humans. Hugues Barbeau applies the work of Rossignol
      and others to locomotor training in human subjects who have suffered spinal cord
      injury (SCI) with incomplete motor function loss (IMFL). Michel Lemay and Warren
      Grill discuss some of the technical challenges that must be addressed by
      engineers to implement a neuroprosthesis using electrical stimulation of the
      spinal cord, particularly the control issues that would have to be resolved.

PMID- 10407125
TI  - Central actions of nitric oxide in regulation of autonomic functions.
AB  - The identification of nitric oxide (NO) as a gaseous, nonconventional
      neurotransmitter in the central nervous system has led to an explosion of studies
      aimed at learning about the roles of NO, not only at a cellular level, but also
      in regulating the activity of specific physiological systems that are coordinated
      by the brain. In the 1980s, publications began to appear which pointed to a role
      for NO in regulating peripheral autonomic function. In the 1990s, it became
      apparent that NO also acts centrally to affect autonomic responses. In this
      review, I will discuss the state of the current knowledge about the central role
      of NO in physiological functions which are related specifically to the control of
      sympathetic output. Studies which do not differentiate a central from a
      peripheral role for NO in these functions have not been included. After a brief
      discussion about the cellular events in which NO is involved, the distribution of
      NO-producing neurons in central autonomic areas of the brain will be presented.
      The more general actions of central NO in regulating sympathetic activity, as
      assessed with i.c.v. injections of pharmacological agents, will be followed by
      more specific sites of action achieved with microinjections into discrete brain
      areas. The review will be concluded with discussions about central NO in two
      physiological states of sympathetic imbalance, hypertension and stress.

PMID- 10407126
TI  - A neuronal model of attentional spotlight: parietal guiding the temporal.
AB  - Recent studies have reported an attentional feedback that highlights neural
      responses as early along the visual pathway as the primary visual cortex. Such
      filtering would help in reducing informational overload and in performing serial
      visual search by directing attention to individual locations in the visual field.
      The magnocellular (M) and parvocellular (P) subdivisions are two of the major
      parallel pathways in primate vision that originate in the retina and carry
      distinctly different types of information. The M pathway, characterized by its
      high sensitivity to movement and to low contrast stimuli, forms the predominant
      visual input into the dorsal, parietal stream in the neocortex. The P inputs,
      characterized by their colour selectivity and higher spatial resolution, are
      channeled mainly into the ventral, temporal stream. It is proposed that the
      attentional spotlight originates in the dorsal stream and helps in serially
      searching the field for conjunction of the relevant target features in the
      temporal stream, effectively performing a gating function on all visual inputs.
      This model predicts that a defect limited to the magnocellular or the dorsal
      pathway can lead to widespread deficits in cognitive abilities, including those
      functions that are largely based on parvocellular information. For example, the
      model provides a neural mechanism linking a peripheral defect in the
      magnocellular pathway to the reading disabilities in dyslexia. Even though there
      has been strong evidence for a magnocellular deficit in dyslexia, the paradox has
      been that the cognitive disability seems to be related to P pathway function. The
      scheme proposed here shows how M input may be vital for controlling sequential
      attention during reading.

PMID- 10407127
TI  - Neuroglial activation repertoire in the injured brain: graded response, molecular
      mechanisms and cues to physiological function.
AB  - Damage to the central nervous system (CNS) leads to cellular changes not only in
      the affected neurons but also in adjacent glial cells and endothelia, and
      frequently, to a recruitment of cells of the immune system. These cellular
      changes form a graded response which is a consistent feature in almost all forms
      of brain pathology. It appears to reflect an evolutionarily conserved program
      which plays an important role in the protection against infectious pathogens and
      the repair of the injured nervous system. Moreover, recent work in mice that are
      genetically deficient for different cytokines (MCSF, IL1, IL6, TNFalpha,
      TGFbeta1) has begun to shed light on the molecular signals that regulate this
      cellular response. Here we will review this work and the insights it provides
      about the biological function of the neuroglial activation in the injured brain.

PMID- 10407128
TI  - Laminar redistribution of a glial subtype in the chick optic tectum.
AB  - Lamination is a central feature of structural organization and segregation within
      the central nervous system. Afferent fibers typically restrict their synapses to
      only one or a few specific laminae in the target region. Astroglial cells act as
      boundary markers for functional segregation of inputs in somatosensory cortex and
      the olfactory bulb and might also help to segregate particular connections in the
      neostriatum. This work presents evidence that a subset of astroglial cells
      expressing the carbohydrate recognized by tomato lectin are enriched in retino
      non-recipient laminae of the chick optic tectum. This segregation is dependent
      upon retinal innervation; enucleated chick tecta contain cells that bind tomato
      lectin but do not segregate into their normal laminae. These results suggest that
      tomato lectin positive astrocytes of the superficial chick tectum play a role in
      defining or restricting lamina specific connections of retinal axons.

PMID- 10407129
TI  - Kinetics of the migration of neurons to rat somatosensory cortex.
AB  - The laminar location of a neuron in the mature cortex is defined by early events
      in its ontogeny. In the present study, quantitative [(3)H]thymidine ([(3)H]dT)
      autoradiography was used to define some of these early events. Four indices were
      calculated: a proliferation index (indicative of the fraction of cells that was
      cycling), the leaving fraction (the fraction of cells that permanently left the
      cycling population and migrated to cortex, the release time (the time post
      mitotic cells remained in the proliferative zone(s) before initiating their
      migrations), and the rate of migration. The proliferation index was relatively
      high on G13 and progressively declined to a nadir on G21. In contrast, the
      leaving fraction was lowest on G13 and on G21. The release time for a particular
      subpopulation did not vary with the time of origin. On the other hand, the
      release time for the earliest generated cells was significantly shorter than it
      was for the remaining population of cells labeled by a particular injection of
      [(3)H]dT. The mean rate of migration was affected by neither the time of origin
      nor the timing of the onset of migration. Thus, once a cell becomes permanently
      post-mitotic, the behavior of the young neuron (as defined by its release time
      and rate of migration) is highly ordered. It is the time of origin, as determined
      by the desynchrony of the cycling activity of proliferating cells, that
      determines the ultimate disposition of a cortical neuron.

PMID- 10407130
TI  - Maternal dietary choline availability alters mitosis, apoptosis and the
      localization of TOAD-64 protein in the developing fetal rat septum.
AB  - Maternal changes in dietary choline availability alter brain biochemistry and
      hippocampal development in the offspring resulting in lifelong behavioral changes
      in the offspring. In order to better understand the relationship between maternal
      diet, brain cytoarchitecture and behavior, we investigated the effects of choline
      availability on cell proliferation, apoptosis and differentiation in the fetal
      rat brain septum. Timed-pregnant rats on day E12 were fed AIN-76 diet with
      varying levels of dietary choline for 6 days. We found that choline deficiency
      (CD) significantly decreased the rate of mitosis in the progenitor
      neuroepithelium adjacent to the septum. In addition, we found an increased number
      of apoptotic cells in the septum of CD animals compared to controls (3.5+/-0.5
      vs. 1.7+/-0.5 apoptotic cells per section; p<0.05). However, CD had no effect on
      apoptosis in the indusium griseum (IG), a region of cortex dorsal to the septum.
      Using an unbiased image analysis method and a monoclonal antibody we found a
      decreased expression of the TOAD-64 kDa protein, a marker of commitment to
      neuronal differentiation during fetal development, in the dorsal lateral septum
      of CD animals. CD also decreased the expression of TOAD-64 kDa protein in the IG
      and cortical plate adjacent to the septum. These results show that dietary
      choline availability during pregnancy alters the timing of mitosis, apoptosis and
      the early commitment to neuronal differentiation by progenitor cells in regions
      of the fetal brain septum, as well as hippocampus, two brain regions known to be
      associated with learning and memory.

PMID- 10407131
TI  - Intrinsic electrophysiology of neurons in thalamorecipient layers of developing
      rat auditory cortex.
AB  - During early postnatal life, several critical events contribute to the functional
      development of rat sensory neocortex. Thalamocortical innervation of sensory
      cortex is completed during the first postnatal week and extrathalamic innervation
      develops over the first several weeks. In auditory cortex, acoustic-evoked
      potentials first occur in week 2 and develop most rapidly over weeks 2-3. Thus,
      rapid functional maturation of cortical circuits in sensory cortex occurs during
      the second and third postnatal weeks. The electrophysiological properties of
      cortical neurons that receive afferent inputs during this time may play an
      important role in development and function. In this study we examined the
      intrinsic electrophysiology, including spiking patterns, of neurons in layers
      II/III and IV of auditory cortex during postnatal weeks 2 and 3. Many neurons
      displayed characteristics consistent with previous descriptions of response
      classes (regular spiking, fast spiking, intrinsic bursting). In addition, we
      identified two groups, Rectifying and On-spiking neurons, that were characterized
      by (i) brief spike trains in response to maintained intracellular
      depolarizations, and (ii) striking outward rectification upon depolarization.
      Unusually brief spike trains (1-2 spikes) and short spike latencies (<10 ms)
      further distinguished On-spiking from Rectifying cells. Biocytin labeling
      demonstrated that On-spiking and Rectifying cells could be either pyramidal or
      nonpyramidal neurons. The intrinsic physiology of these cell groups may play an
      important role in auditory cortex function.

PMID- 10407132
TI  - Developmental expression of corticotropin-releasing factor in the postnatal
      murine cerebellum.
AB  - Corticotropin-releasing factor (CRF) is present in climbing and mossy fibers and
      both have a distinct pattern of distribution in the adult cerebellar cortex. The
      intent of this developmental study is to determine when the lobular pattern of
      CRF distribution emerges, and to analyze the morphogenesis of CRF immunoreactive
      climbing and mossy fibers in individual cerebellar lobules. Between postnatal day
      (P)0 and P3, CRF-immunoreactive (IR) punctate elements are present throughout the
      cerebellum. By P3, there is a decrease in the density of staining in the white
      matter and punctate elements become concentrated within the developing cortex.
      Between P3 and P7 CRF-IR, varicosities circumscribe Purkinje cell bodies, and are
      present in the internal and external granule cell layers. Between P10 and P12,
      there is a major reduction in the density of CRF-IR puncta, especially in the
      internal and external granule cell layers. Varicosities remain around Purkinje
      cell bodies and some extend into the molecular layer. During this interval, CRF
      IR profiles are first evident in axonal configurations characteristic of
      developing climbing fibers, although there are lobular differences in the degree
      of maturation of this afferent system. Axonal enlargements characteristic of
      immature mossy fibers can first be seen at P10 in lobules IX and X; they cannot
      be differentiated until P12-14 in more rostral or lateral lobules. CRF-IR fibers
      in lobules IX and X, the vestibulocerebellum, develop into mature climbing and
      mossy fibers before any other area of the cerebellum. In other lobules of the
      cerebellum the gradient of maturation for these axonal phenotypes is from medial
      to lateral and posterior to anterior. Between P10 and P12, CRF-IR climbing fibers
      are present in all lobules of the cerebellum. After P12, few climbing fibers are
      observed in the anterior lobe of the cerebellum at midvermal levels; those
      present are only faintly immunolabeled. Based on its early expression and uniform
      distribution between P0 and P10, CRF could have a role in cerebellar development.
      After this age, as climbing and mossy fiber terminal phenotypes mature, and the
      differential adult patterns of distribution emerge, CRF likely begins to function
      as a neuromodulator as has been shown in the adult cerebellum.

PMID- 10407133
TI  - Differential expression of three classes of voltage-gated Ca(2+) channels during
      maturation of the rat cerebellum in vitro.
AB  - Voltage-gated Ca(2+) channels provide a mode of Ca(2+) influx that is essential
      for intracellular signaling in many cells. Semi-quantitative reverse
      transcription-polymerase chain reaction (RT-PCR) was used to assess the relative
      amounts of mRNAs encoding three classes of Ca(2+) channels (alpha1A, alpha1B and
      alpha1E) during development, in cultures established from prenatal rat cerebellar
      cortex. Ca(2+) channel transcript levels were standardized to a constitutive
      marker (cyclophilin). For all three classes of Ca(2+) channels, transcript levels
      were highest at early stages (4-10 days in vitro) and declined with age. This
      developmental pattern was differentially regulated by a depolarizing agent,
      tetraethylammonium chloride (TEA, 1 mM). Chronic depolarization yielded a
      significant elevation in transcript levels for alpha1B (N-type) and alpha1E (R
      type) Ca(2+) channels during neuronal maturation (10-21 days in vitro), but
      dramatically suppressed transcript levels for the alpha1A (P-type) Ca(2+) channel
      at all stages of development. The effects of TEA on alpha1A, alpha1B and alpha1E
      transcript levels were mimicked by increasing external K(+) (from 5 to 10 mM).
      The regulatory effects of depolarization on transcript levels were dependent on
      extracellular Ca(2+) for alpha1E but not for alpha1A. For alpha1B, transcript
      levels depended on extracellular Ca(2+) only for increased K(+) as the
      depolarizing stimulus, but not for TEA. These results suggest that levels of
      Ca(2+) channel transcripts in rat cerebellum are developmentally regulated in
      vitro and can be influenced differentially by transmembrane signaling via chronic
      depolarization and Ca(2+) entry. Dynamic regulation of Ca(2+) channel expression
      may be relevant to the different functional roles of Ca(2+) channels and their
      regional localization within neurons.

PMID- 10407134
TI  - The preoptic area/anterior hypothalamus of different strains of mice: sex
      differences and development.
AB  - While sex differences in neural morphology in the preoptic area/anterior
      hypothalamus (POA/AH) have been demonstrated in many species, their existence in
      mice have been controversial. Given the increased use of transgenic and gene
      disrupted mice, we characterized sex differences using Nissl stains, and the
      immunocytochemical location of estrogen receptor-alpha (ER-alpha) and galanin in
      the POA/AH of two widely used strains, C57BL/6 and 129SvEv, and a mixed strain
      (C57BL/6x129Sv); the wild-type littermates of steroidogenic factor-1 (SF-1) gene
      disrupted mice. Cell grouping was not a reliable marker of sex. In adults, cells
      located beneath the anterior commissure (AC) were reliably larger in females than
      males in 129SvEv, but not in the other strains. Caudally, cells in a group medial
      to the medial extension of the bed nucleus of the stria terminalis (BST) were
      significantly larger in males than females in C57BL/6J and SF-1 gene-disrupted
      wild-types. Cell groups discernible by embryonic day (E) 18 were not sexually
      dimorphic for cell size in C57BL/6J mice at E18 or postnatal day (P) 4. The
      pattern of distribution of cells containing ER-alpha was similar among the
      strains, reduced in the group medial to the BST; a pattern established by P0.
      Galanin-containing cells and fibers were seen from E15 to adulthood ventral to
      the AC. Caudally, a smaller group ventromedial to the BST was found only in
      129SvEv adults. Sex differences in neural morphology which develop within the
      POA/AH depend upon multiple factors, particularly including genetic background.

PMID- 10407135
TI  - A novel mammalian T-box-containing gene, Tbr2, expressed in mouse developing
      brain.
AB  - We have identified and characterized a new member of the mammalian brain-specific
      T-box gene family, Tbr2, which is closely related to mouse Tbr1, and to the
      Xenopus earliest mesodermal gene, Eomesodermin. As Tbr1, Tbr2 is predominantly
      expressed in some regions of the developing brain, but in a strikingly
      complementary manner. On embryonic day 14.5 (E14.5), Tbr2 mRNA expression was
      observed in the mesencephalon and rhombencephalon in contrast to Tbr1 which was
      expressed mostly in the telencephalon. At this stage, Tbr2 mRNA was readily
      detectable in the postmitotic and differentiating neurons located in various
      brain regions, i.e., oculomotor, red, trigeminal, vestibular, facial, and
      hypoglossal nuclei. However, expression of Tbr2 in these nuclei became
      undetectable on E18.5. In contrast, Tbr2 mRNA expression was detected in the
      hippocampus only from E18.5 onwards. Whereas Tbr2 expression disappeared in most
      parts of the mature adult brain, it remained detectable in the hippocampus and
      olfactory bulb, regions where some neuronal precursors retain their
      differentiation potential. These results suggest that Tbr2 may play a crucial
      role in differentiating neurons rather than in proliferating or already
      differentiated neurons. In addition, similarly to Xenopus Eomesodermin, mouse
      Tbr2 showed biphasic expression; a first peak around E6.5 and a second peak
      around E14.5, suggesting that Tbr2 may also be important at early stages of
      gastrulation.

PMID- 10407136
TI  - Regulation of metallothionein-3 mRNA by thyroid hormone in developing rat brain
      and primary cultures of rat astrocytes and neurons.
AB  - Metallothionein-3 (MT-3) is a brain specific member of the MT family. Unlike
      other members of this family, MT-3 has been shown to act as a neuronal growth
      inhibitory factor. MT-3 mRNA abundance increases throughout the developmental
      period, reaching adult levels by postnatal day 21. The role of thyroid hormone in
      the developmental regulation of MT-3 mRNA was tested because thyroid hormone is
      known to regulate brain gene expression. Furthermore, gestational hypothyroidism
      results in developmental brain abnormalities. Hypothyroidism was induced in
      pregnant dams by the administration of PTU from gestational day 7, resulting in a
      4- to 6-fold increase in pup MT-3 mRNA abundance on the day of birth (day 0) and
      on postnatal day 3. Normal pups did not reach this level of brain MT-3 mRNA until
      postnatal day 21. Administration of thyroxine (T(4), 2 microg/g) to pups on
      postnatal day 1 or day 20 resulted in a decrease in MT-3 mRNA abundance on
      postnatal day 21, regardless of when the injection was given. Furthermore,
      addition of T(4) to primary cultures of brain (olfactory bulb) astrocytes and
      neurons from 4-day-old rats resulted in a significant decrease in MT-3 mRNA in 24
      h. Given the neuronal growth inhibitory function of MT-3, these data suggest that
      MT-3 may play a role in the CNS-related consequences of hypo- and hyperthyroidism
      during development.

PMID- 10407137
TI  - Developmental appearance of nuclear GM1 in neurons of the central and peripheral
      nervous systems.
AB  - Previous studies demonstrated expression of GM1 ganglioside in the nuclear
      envelope of differentiating neuroblastoma cells and cultured cerebellar granule
      cells from neonatal rat brain. In the present study, relatively few of the latter
      cells were shown to possess a nucleus with appreciable GM1 during the first few
      days in culture, but increasing numbers of such cells possessed GM1-expressing
      nuclei as morphological differentiation progressed. This phenomenon reached a
      plateau by the 8th day in culture, approximately 90% of observed nuclei showing
      cytochemical evidence of GM1 at that time. Cerebral cortical neurons from
      embryonic rat brain in culture also gave clear evidence of GM1 in the nuclear
      membrane. Similar results were obtained with cultured neurons from the superior
      cervical ganglion from embryonic rats, demonstrating developmental appearance of
      GM1 in the nuclear envelope of PNS neurons. Cytochemical evidence for GM1 in
      purified nuclei from freshly isolated cortical neurons of neonatal rat brain
      indicated that expression of nuclear GM1 is not an artifact of cell culture.
      Study of NG108-15 neuroblastoma x glioma hybrid cells showed upregulation of
      nuclear GM1 to lag somewhat behind neurite outgrowth, suggesting nuclear GM1 to
      have a functional role subsequent to onset of morphological differentiation.

PMID- 10407138
TI  - Mechanisms for regulating electron transfer in multi-centre redox proteins.
AB  - Protein-mediated electron transfer is a key process in nature. Many of the
      proteins involved in such electron transfers are complex and contain a number of
      redox-active cofactors. The very complexity of these multi-centre redox proteins
      has made it difficult to fully understand the various electron transfer events
      they catalyse. This is sometimes because the electron transfer steps themselves
      are gated or coupled to other processes such as proton transfer. However, with
      the molecular structures of many of these proteins now available it is possible
      to probe these electron transfer reactions at the molecular level. It is becoming
      apparent that many of these multi-centre redox proteins have rather subtle and
      elegant ways for regulating electron transfer. The purpose of this article is to
      illustrate how nature has used different approaches to control electron transfer
      in a number of different systems. Illustrative examples include: thermodynamic
      control of electron transfer in flavocytochromes b(2) and P450 BM3; a novel
      control mechanism involving calmodulin-binding-dependent electron transfer in
      neuronal nitric oxide synthase; the probable gating of electron transfer by ATP
      hydrolysis in nitrogenase; conformational gating of electron transfer in
      cytochrome cd(1); the regulation of electron transfer by protein dynamics in the
      cytochrome bc(1) complex; and finally the coupling of electron transfer to proton
      transfer in cytochrome c oxidase.

PMID- 10407139
TI  - New insights into an old protein: the functional diversity of mammalian
      glyceraldehyde-3-phosphate dehydrogenase.
AB  - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was considered a classical
      glycolytic protein examined for its pivotal role in energy production. It was
      also used as a model protein for analysis of protein structure and enzyme
      mechanisms. The GAPDH gene was utilized as a prototype for studies of genetic
      organization, expression and regulation. However, recent evidence demonstrates
      that mammalian GAPDH displays a number of diverse activities unrelated to its
      glycolytic function. These include its role in membrane fusion, microtubule
      bundling, phosphotransferase activity, nuclear RNA export, DNA replication and
      DNA repair. These new activities may be related to the subcellular localization
      and oligomeric structure of GAPDH in vivo. Furthermore, other investigations
      suggest that GAPDH is involved in apoptosis, age-related neurodegenerative
      disease, prostate cancer and viral pathogenesis. Intriguingly, GAPDH is also a
      unique target of nitric oxide. This review discusses the functional diversity of
      GAPDH in relation to its protein structure. The mechanisms through which
      mammalian cells may utilize GAPDH amino acid sequences to provide these new
      functions and to determine its intracellular localization are considered. The
      interrelationship between new GAPDH activities and its role in cell pathologies
      is addressed.

PMID- 10407140
TI  - Study of the (S)-hydroxynitrile lyase from Hevea brasiliensis: mechanistic
      implications.
AB  - Investigations of the (S)-selective hydroxynitrile lyase from Hevea brasiliensis
      were performed by electrospray mass spectroscopy, (1)H-NMR and with an enzyme
      activity assay. For the trans-cyanohydrin reaction (transcyanation) a two step
      reaction could be established. The results furthermore indicate a fast
      deactivation of the enzyme at low pH and a strong substrate dependence of its
      stability. They rule out an enzyme-HCN complex or a covalently bound carbonyl
      compound. Therefore the earlier postulated reaction intermediate as well as the
      proposed action of the catalytic triad have to be reevaluated. The calculated
      molecular mass could be confirmed by mass spectroscopy.

PMID- 10407141
TI  - Evidence of heterogeneous 1-anilinonaphthalene-8-sulfonate binding to beta
      lactoglobulin from fluorescence spectroscopy.
AB  - Steady-state and dynamic fluorescence titrations show that: (a) the complex
      between beta-lactoglobulin (BLG) and 1-anilinonaphthalene-8-sulfonate (ANS)
      displays a heterogeneous equilibrium with large changes in the binding strength
      vs. pH and ion concentration; and (b) the fluorescence response of bound ANS
      reveals two separate lifetimes that suggest two different sites (or binding
      modes). While steady-state fluorescence titrations yield effective values of the
      binding constant and of the bound ANS quantum efficiency, it is shown that, by
      combining steady-state fluorescence and lifetime decay of ANS, it is possible to
      give quantitative estimates of the association constants for each site. When
      heading from the acid (pH approximately 2) to the native state (pH approximately
      6) the main result is a very large reduction of the effective binding constant.
      This and the results of titrations vs. ionic strength suggest that electrostatic
      interactions are a major contribution to ANS binding to BLG.

PMID- 10407143
TI  - Adapting protein solubility by glycosylation. N-glycosylation mutants of Coprinus
      cinereus peroxidase in salt and organic solutions.
AB  - Protein solubility is a fundamental parameter in biology and biotechnology. In
      the present study we have constructed and analyzed five mutants of Coprinus
      cinereus peroxidase (CIP) with 0, 1, 2, 4 and 6 N-glycosylation sites. All
      mutants contain Man(x)(GlcNAc)(2) glycans. The peroxidase activity was the same
      for wild-type CIP and all the glycosylation mutants when measured with the large
      substrate 2,2'-azino-bis(-3-ethylbenzthiazoline-6-sulfonic acid). The solubility
      of the five CIP mutants showed a linear dependence on the number of carbohydrate
      residues attached to the protein in buffered solution of both ammonium sulfate
      (AMS) and acetone, increasing in AMS and decreasing in acetone. Moreover, the
      change in free energy of solvation appears to be a constant, though with opposite
      signs in these solvents, giving DeltaDeltaG degrees (sol)=-0.32+/-0.05 kJ/mol per
      carbohydrate residue in 2.0 M AMS, a value previously obtained comparing ordinary
      and deglycosylated horseradish peroxidase, and 0. 37+/-0.10 kJ/mol in 60 v/v%
      acetone.

PMID- 10407142
TI  - Molecular oxygen oxidizes the porphyrin ring of the ferric alpha-hydroxyheme in
      heme oxygenase in the absence of reducing equivalent.
AB  - Heme oxygenase catalyzes the regiospecific oxidative degradation of iron
      protoporphyrin IX (heme) to biliverdin, CO and Fe, utilizing molecular oxygen and
      electrons donated from the NADPH-cytochrome P-450 reductase. The catalytic
      conversion of heme proceeds through two known heme derivatives, alpha-hydroxyheme
      and verdoheme. In order to assess the requirement of reducing equivalents in the
      second stage of heme degradation, from alpha-hydroxyheme to verdoheme, we have
      prepared the alpha-hydroxyheme complex with rat heme oxygenase isoform-1 and
      examined its reactivity with molecular oxygen in the absence of added electrons.
      Upon reaction with oxygen, the majority of the alpha-hydroxyheme in heme
      oxygenase is altered to a species which exhibits an optical absorption spectrum
      with a broad Soret band, along with the minority which is converted to verdoheme.
      The major product species, which is electron paramagnetic resonace-silent, can be
      recovered to the original alpha-hydroxyheme by addition of sodium dithionite. We
      have also found that oxidation of the alpha-hydroxyheme-heme oxygenase complex by
      ferricyanide or iridium(IV) chloride yields a species which exhibits an optical
      absorption spectrum and reactivity similar to those of the main product of the
      oxygen reaction. We infer that the oxygen reaction with the ferric alpha
      hydroxyheme-heme oxygenase complex forms a ferric-porphyrin cation radical. We
      conclude that in the absence of reducing agents, the oxygen molecule functions
      mainly as an oxidant for the porphyrin ring and has no role in the oxygenation of
      alpha-hydroxyheme. This result corroborates our previous conclusion that the
      catalytic conversion of alpha-hydroxyheme to verdoheme by heme oxygenase requires
      one reducing equivalent along with molecular oxygen.

PMID- 10407145
TI  - Bovine lens crystallins do contain helical structure: a circular dichroism study.
AB  - In order to settle a recent discussion on the secondary structure of lens
      crystallins, we have measured the circular dichroism (CD) spectra of alpha-,
      beta(H)-, and beta(L)-crystallin from 178 to 250 nm and of gamma-crystallin from
      168 to 250 nm. The results were analysed by means of a newly developed algorithm
      that almost doubles the reliability of secondary structure prediction and that
      allows discrimination between alpha- and 3(10)-helical, and between extended and
      polyproline beta-type structure. The results indicate that the crystallins
      studied contain a non-negligible amount of alpha-helical structure, although at
      least 50% of it is in the form of single and/or distorted loops. In alpha
      crystallin, which is related to the chaperones, the helical content is lower than
      in beta- and gamma-crystallin. In some cases, the helices may play a role in DNA
      binding by the crystallins.

PMID- 10407144
TI  - Conformational structure and binding mode of glyceraldehyde-3-phosphate
      dehydrogenase to tRNA studied by Raman and CD spectroscopy.
AB  - Recently it has been suggested that glyceraldehyde-3-phosphate dehydrogenase
      (GAPDH) play a role in nuclear tRNA export. As the structural basis of binding of
      GAPDH to tRNA is as yet unknown, we have employed Raman and CD spectroscopy as
      probes of the solution structures of GAPDH from rabbit and tRNA(Phe) from brewers
      yeast. Additionally, we have obtained the Raman and CD spectra of GAPDH when
      bound to tRNA(Phe). In the complex we find the following results: (a) The most
      part of the tRNA(Phe) structure is conserved, but with a slight perturbation
      toward a B-like form. (b) No significant changes in the secondary structure of
      the protein upon binding are observed. (c) The surface enhanced Raman spectra are
      consistent with a GAPDH-tRNA(Phe) complex molecular model that involves the
      insertion of TRNA(Phe) into the GAPDH tetramer groove containing the R and P
      axes. (d) The specific interactions that occur between GAPDH and the tRNA(Phe)
      involve, mainly, stacking between nucleobases and aromatic amino-acid residues,
      and ionic interactions of basic amino-acid residues with phosphate groups of the
      ribose-phosphate backbone. The above stacking interactions are also supported by
      the significant relatedness that we have found between an amino-acid sequence
      (residues 303-308) of GAPDH and RNP2 binding motifs of some RNA binding proteins.

PMID- 10407146
TI  - Molecular docking studies on interaction of diverse retinol structures with human
      alcohol dehydrogenases predict a broad role in retinoid ligand synthesis.
AB  - Some members of the human alcohol dehydrogenase (ADH) family possess retinol
      dehydrogenase activity and may thus function in production of the active nuclear
      receptor ligand retinoic acid. Many diverse natural forms of retinol exist
      including all-trans-retinol (vitamin A(1)), 9-cis-retinol, 3,4-didehydroretinol
      (vitamin A(2)), 4-oxo-retinol, and 4-hydroxy-retinol as well as their respective
      carboxylic acid derivatives which are active ligands for retinoid receptors. This
      raises the question of whether ADHs can accommodate all these different retinols
      and thus participate in the activation of several retinoid ligands. The crystal
      structures of human ADH1B and ADH4 provide the opportunity to examine their
      active sites for potential binding to many diverse retinol structures using
      molecular docking algorithms. The criteria used to score successful docking
      included achievement of distances of 1.9-2.4 A between the catalytic zinc and the
      hydroxyl oxygen of retinol and 3.2-3.6 A between C-4 of the coenzyme NAD and C-15
      of retinol. These distances are sufficient to enable hydride transfer during the
      oxidation of an alcohol to an aldehyde. By these criteria, all-trans-retinol, 4
      oxo-retinol, and 4-hydroxy-retinol were successfully docked to both ADH1B and
      ADH4. However, 9-cis-retinol and 3,4-didehydroretinol, which have more
      restrictive conformations, were successfully docked to only ADH4 which possesses
      a wider active site than ADH1B and more easily accommodates the C-19 methyl
      group. Furthermore, docking of all retinols was more favorable in the active site
      of ADH4 rather than ADH1B as measured by force field and contact scores. These
      findings suggest that ADH1B has a limited capacity to metabolize retinols, but
      that ADH4 is well suited to function in the metabolism of many diverse retinols
      and is predicted to participate in the synthesis of the active ligands all-trans
      retinoic acid, 9-cis-retinoic acid, 3, 4-didehydroretinoic acid, 4-oxo-retinoic
      acid, and 4-hydroxy-retinoic acid.

PMID- 10407147
TI  - Characterization of human acid sphingomyelinase purified from the media of
      overexpressing Chinese hamster ovary cells.
AB  - A rapid purification method was developed to isolate milligram quantities of
      human acid sphingomyelinase from the media of overexpressing Chinese hamster
      ovary cells. The purified, recombinant enzyme (rhASM) had physical and kinetic
      characteristics that were consistent with those reported for the non-recombinant
      enzyme, including an acidic pH optimum and sensitivity to sulfhydryl reducing
      reagents and the zinc specific chelator, 1, 10-phenanthroline. A novel assay
      using fluorescently conjugated sphingomyelin was developed to explore the
      substrate binding properties of rhASM. Substrate binding required a fatty acid
      chain length of at least six carbons and the presence of the phosphocholine
      headgroup on sphingomyelin. Substrate binding also required an acidic pH, and was
      inhibited by pretreatment of the enzyme with sulfhydral reducing reagents or 1,10
      phenanthroline. rhASM was rapidly internalized by cultured skin fibroblasts from
      Niemann-Pick disease (NPD) patients, and approximately 50% of this uptake was
      dependent on the mannose 6-phosphate receptor system. Studies using FITC-labeled
      rhASM revealed that by 1 h the internalized enzyme was localized to acidic
      compartments and could degrade sphingomyelin, the first demonstration that a
      lysosomal sphingolipid hydrolase can be fluorescently labeled and retain its
      biological activity. Intravenous injection of rhASM into ASM knock-out mice
      showed that the t(1/2) in the plasma was less than 5 min, and that the majority
      of the injected enzyme was taken up by the liver, followed by the spleen. Thus,
      these studies lay the foundation for future structure/function investigations of
      ASM, further investigations into this enzyme's role in ceramide mediated signal
      transduction, and the evaluation of enzyme replacement therapy for NPD using the
      mouse model.

PMID- 10407149
TI  - Characterization of two members of a novel malic enzyme class.
AB  - The Gram-negative bacterium Rhizobium meliloti contains two distinct malic
      enzymes. We report the purification of the two isozymes to homogeneity, and their
      in vitro characterization. Both enzymes exhibit unusually high subunit molecular
      weights of about 82 kDa. The NAD(P)(+) specific malic enzyme [EC 1.1.1.39]
      exhibits positive co-operativity with respect to malate, but Michaelis-Menten
      type behavior with respect to the co-factors NAD(+) or NADP(+). The enzyme is
      subject to substrate inhibition, and shows allosteric regulation by acetyl-CoA,
      an effect that has so far only been described for some NADP(+) dependent malic
      enzymes. Its activity is positively regulated by succinate and fumarate. In
      contrast to the NAD(P)(+) specific malic enzyme, the NADP(+) dependent malic
      enzyme [EC 1.1.1.40] shows Michaelis-Menten type behavior with respect to malate
      and NADP(+). Apart from product inhibition, the enzyme is not subjected to any
      regulatory mechanism. Neither reductive carboxylation of pyruvate, nor
      decarboxylation of oxaloacetate, could be detected for either malic enzyme. Our
      characterization of the two R. meliloti malic enzymes therefore suggests a number
      of features uncharacteristic for malic enzymes described so far.

PMID- 10407148
TI  - Stability and binding properties of wild-type and c17s mutated human sterol
      carrier protein 2.
AB  - The temperature- and solvent-induced denaturation of both the SCP2 wild-type and
      the mutated protein c71s were studied by CD measurements at 222 nm. The
      temperature-induced transition curves were deconvoluted according to a two-state
      mechanism resulting in a transition temperature of 70.5 degrees C and 59.9
      degrees C for the wild-type and the c71s, respectively, with corresponding values
      of the van't Hoff enthalpies of 183 and 164 kJ/mol. Stability parameters
      characterizing the guanidine hydrochloride denaturation curves were also
      calculated on the basis of a two-state transition. The transitions of the wild
      type occurs at 0.82 M GdnHCl and that of the c71s mutant at 0.55 M GdnHCl. These
      differences in the half denaturation concentration of GdnHCl reflect already the
      significant stability differences between the two proteins. A quantitative
      measure are the Gibbs energies DeltaG(0)(D)(buffer) at 25 degrees C of 15.5
      kJ/mol for the wild-type and 8.0 kJ/mol for the mutant. We characterized also the
      alkyl chain binding properties of the two proteins by measuring the interaction
      parameters for the complex formation with 1-O-Decanyl-beta-D-glucoside using
      isothermal titration microcalorimetry. The dissociation constants, K(d), for wild
      type SCP2 are 335 microM at 25 degrees C and 1.3 mM at 35 degrees C. The
      corresponding binding enthalpies, DeltaH(b), are -21. 5 kJ/mol at 25 degrees C
      and 72.2 kJ/mol at 35 degrees C. The parameters for the c71s mutant at 25 degrees
      C are K(d)=413 microM and DeltaH(b)=16.6 kJ/mol. These results suggest that both
      SCP2 wild-type and the c71s mutant bind the hydrophobic compound with moderate
      affinity.

PMID- 10407150
TI  - Formation of betaA3/betaB2-crystallin mixed complexes: involvement of N- and C
      terminal extensions.
AB  - The sequence extensions of the beta-crystallin subunits have been suggested to
      play an important role in the oligomerization of these eye lens proteins. This,
      in turn, may contribute to maintaining lens transparency and proper light
      refraction. In homo-dimers of the betaA3- and betaB2-crystallin subunits, these
      extensions have been shown by (1)H-NMR spectroscopy to be solvent-exposed and
      highly flexible. In this study, we show that betaA3- and betaB2-crystallins
      spontaneously form mixed betaA3/betaB2-crystallin complexes, which, from
      analytical ultracentrifugation experiments, are dimeric at low concentrations (<1
      mg ml(-1)) and tetrameric at higher protein concentrations. (1)H-NMR spectroscopy
      reveals that in the betaA3/betaB2-crystallin tetramer, the N-terminal extensions
      of betaA3-crystallin remain water-exposed and flexible, whereas both N- and C
      terminal extensions of betaB2-crystallin lose their flexibility. We conclude that
      both extensions of betaB2-crystallin are involved in protein-protein interactions
      in the betaA3/betaB2-crystallin hetero-tetramer. The extensions may stabilize and
      perhaps promote the formation of this mixed complex.

PMID- 10407151
TI  - Biosensor measurement of the interaction kinetics between insulin-like growth
      factors and their binding proteins.
AB  - The binding kinetics of human insulin-like growth factor binding protein (IGFBP)
      1-6 for recombinant human insulin-like growth factor (IGF) I and II were measured
      and compared in the present study using surface plasmon resonance biosensor
      technique. Different concentrations of IGFBPs (5-100 nM) were allowed to interact
      with the immobilized IGF-I or IGF-II on sensor chip surface. Both des(1-3)IGF-I
      and insulin are known to bind weakly to the IGFBPs and therefore are used as
      negative controls for the binding experiments. The resultant sensorgrams were
      analyzed by using simple 1:1 binding model to derive both the association rate
      (k(a)) and dissociation rate (k(d)) constants for IGFBP-IGF interactions. The
      k(a) values of IGFBPs are in the range of 1x10(4) to 9x10(5) M(-1) s(-1) for IGF
      I and 7x10(3) to 1.7x10(6) M(-1) s(-1) for IGF-II, respectively. The orders of
      k(a) for both IGF-I and IGF-II are IGFBP-3>IGFBP-5>IGFBP-6>IGFBP-4>IGFBP-2>++
      +IGFBP-1. The k(d) values of IGFBPs are in the range of 1.5x10(-5) to 2x10(-4) s(
      1) for IGF-I and 3.6x10(-5) to 3.7x10(-4) s(-1) for IGF-II, respectively. The
      order of k(d) for IGF-I is IGFBP-6>IGFBP-5>IGFBP-4>IGFBP-3>IGFBP-2>++ +IGFBP-1
      and that for IGF-II is IGFBP-5>IGFBP-6>IGFBP-2>IGFBP-4>IGFBP-3>++ +IGFBP-1,
      respectively. The equilibrium affinity constants (K(A)) were calculated based on
      the ratio of k(a)/k(d) and were more precise than the published literature values
      based on competitive radioligand binding assays. The systematic study enables a
      direct comparison on the IGF-binding properties among the various IGFBPs, and the
      kinetic data provide additional information to delineate the physiological role
      of different IGFBPs in vivo.

PMID- 10407152
TI  - Accelerated secretion of mutant beta-lactoglobulin in Saccharomyces cerevisiae
      resulting from a single amino acid substitution.
AB  - Transformed yeasts producing a mutant form of bovine beta-lactoglobulin (beta
      LG), W19Y, in which Trp(19) was replaced with Tyr, were shown to secrete 6 times
      more than those producing wild type beta-LG. Northern blot analysis suggested
      that the enhanced level of secretion was not the result of upregulated
      transcription of W19Y. The ratio of the amount of W19Y secreted into the
      supernatant to the amount of W19Y remaining inside the cells was much larger than
      that in the case of wild type beta-LG as shown by immunoblot analysis. A
      pulse/chase experiment revealed that the speed of secretion of W19Y was
      significantly accelerated, compared to wild type beta-LG. These results indicated
      that W19Y was more efficiently and rapidly transported in the course of secretion
      than wild type beta-LG. Our previous study showed that the DeltaG of unfolding of
      W19Y in water is 6.9 kcal/mol smaller than that of wild type beta-LG.
      Furthermore, immunoblot analysis of intracellular beta-LG under non-reducing
      conditions indicated that W19Y as well as wild type beta-LG maintained a specific
      folded structure inside the yeast cells, whereas other non-secretable mutant beta
      LGs with Phe or Ala at position 19 (W19F and W19A, respectively) did not. These
      data suggest that low molecular stability and the maintenance of a specific
      folded structure inside the yeast cells are prerequisites for efficient and rapid
      secretion. W19Y was more efficiently secreted than wild type beta-LG also in
      transformed ern1 mutant yeast cells expressing only a basal level of BiP which is
      considered to function in quality control in the endoplasmic reticulum (ER) by
      playing an important role in determining the secretion efficiency of secretory
      proteins. Thus, the reason for the enhanced secretion of W19Y is considered to be
      that the improved folding ability of W19Y can allow the half-life of the W19Y-BiP
      complex to become shorter than that of the wild type beta-LG-BiP complex, leading
      to faster translocation of W19Y into transport vesicles, or that W19Y can fold in
      a BiP-independent manner in the ER of the yeast cells. Our findings demonstrate
      that the amount of protein secreted can be improved by alteration of a single
      amino acid residue crucial for its structure.

PMID- 10407153
TI  - Interactive binding to the two principal ligand binding sites of human serum
      albumin: effect of the neutral-to-base transition.
AB  - The relationship between the two principal ligand binding sites, sites I and II,
      on human serum albumin (HSA) was quantitatively and qualitatively examined by
      equilibrium dialysis and fluorescence spectroscopy. Among the three subsite
      markers to site I, only the binding of dansyl-L-asparagine (DNSA), which is a
      subsite Ib marker (K. Yamasaki et al., Biochim. Biophys. Acta 1295 (1996) 147),
      was inhibited by the simultaneous binding of a site II ligand, such as ibuprofen
      and diazepam. This indicates that, in contrast to subsite Ib, subsites Ia and Ic
      do not strongly interact with site II. The thermodynamic characteristics for the
      coupling reaction between DNSA and ibuprofen and between DNSA and diazepam, which
      gave positive coupling free energies and negative values for both coupling
      enthalpy and entropy, indicated that the reaction process was entropically
      driven. Increase of pH from 6.5 to 8.2 caused an increase in coupling constant
      and entropy for the mutual antagonism between DNSA and the site II ligands on
      binding to HSA. The site II ligand-induced red-shift of lambda(max) and solvent
      accessibility of DNSA in subsite Ib were decreased when the albumin molecule was
      isomerized from the neutral (N) to the base (B) conformation in the physiological
      pH region. Based on these findings, we conclude that a 'competitive' like strong
      allosteric regulation exists for the binding of these two ligands to the N
      conformer, whereas for the B conformer this interaction can be classified as
      nearly 'independent'. Since the distance between Trp-214, which resides within
      the site I subdomain, and Tyr-411, which is involved in site II, is increased by
      6 A during the N-B transition (N.G. Hagag et al., Fed. Proc. 41 (1982) 1189), we
      propose a mechanism for the pH-dependent antagonistic binding between subsite Ib
      and site II, which involves the transmission of ligand-induced allosteric effects
      from one site to another site, modified by changes in the spatial relationship of
      sites I and II caused by the N-B transition.

PMID- 10407154
TI  - Structure and stability of recombinant protein depend on the extra N-terminal
      methionine residue: S6 permutein from direct and fusion expression systems.
AB  - Two permuted variants of S6 ribosomal protein were obtained in direct and fusion
      expression systems, respectively. The product of direct expression contained the
      extra N-terminal methionine residue. The structural properties and conformational
      stability of these permuteins were compared using 1-D (1)H-NMR, circular
      dichroism, intrinsic fluorescence, differential scanning calorimetry and
      resistance to urea-induced unfolding. A pronounced difference in all the
      parameters studied has been demonstrated. This means that the structure of
      recombinant protein can be sensitive to peculiarities of the expression and
      purification procedures, leading particularly to the presence or absence of the
      Met at the first position in the target protein sequence.

PMID- 10407155
TI  - NMR study of the sites of human hemoglobin acetylated by aspirin.
AB  - Acetylation of hemoglobin by aspirin and other acetylating agents has been used
      to generate hemoglobin analogs with altered structural and functional properties,
      and may prove useful in the treatment of sickle cell disease. We have studied the
      acetylation of human hemoglobin using [1'-(13)C]acetylsalicylic acid in
      combination with two-dimensional HMQC and HSQC NMR analysis. The spectra of the
      acetylated hemoglobin exhibit a number of well resolved resonances. Several
      spectral assignment strategies were used: blocking the 2, 3-DPG binding site non
      covalently with inositol hexaphosphate or covalently with a cross-linking agent,
      selective carbamylation of the N-terminal valine amino groups with cyanate, spin
      labeling the hemoglobin at betaCys93, and analysis of a hemoglobin triple mutant:
      betaV1MH2DeltaK144R, in which betaLys144 is replaced by an arginine residue.
      These studies support the conclusion that the most rapidly acetylated residue is
      betaLys82 rather than betaLys144, as previously reported. Further, it is apparent
      that acetyl betaLys82 can give rise to several resonances due to additional
      acetylation of betaLys82' or other nearby residues. An additional assignment
      strategy involving comparison of the chemical shifts of the acetyl resonances
      observed for adducts of diamagnetic carbonmonoxyhemoglobin with the shifts
      observed in paramagnetic cyanomethemoglobin provides information about the
      location of the acetyl derivatives relative to the heme irons. This approach is
      limited, however, by the lack of well defined structural information for the
      lysine residues on the protein surface. Additional tentative assignments have
      also been made, using the above approaches.

PMID- 10407156
TI  - Nucleotide-dependent bisANS binding to tubulin.
AB  - Non-covalent hydrophobic probes such as 5, 5'-bis(8-anilino-1
      naphthalenesulfonate) (bisANS) have become increasingly popular to gain
      information about protein structure and conformation. However, there are
      limitations as bisANS binds non-specifically at multiple sites of many proteins.
      Successful use of this probe depends upon the development of binding conditions
      where only specific dye-protein interaction will occur. In this report, we have
      shown that the binding of bisANS to tubulin occurs instantaneously, specifically
      at one high affinity site when 1 mM guanosine 5'-triphosphate (GTP) is included
      in the reaction medium. Substantial portions of protein secondary structure and
      colchicine binding activity of tubulin are lost upon bisANS binding in absence of
      GTP. BisANS binding increases with time and occurs at multiple sites in the
      absence of GTP. Like GTP, other analogs, guanosine 5'-diphosphate, guanosine 5'
      monophosphate and adenosine 5'-triphosphate, also displace bisANS from the lower
      affinity sites of tubulin. We believe that these multiple binding sites are
      generated due to the bisANS-induced structural changes on tubulin and the
      presence of GTP and other nucleotides protect those structural changes.

PMID- 10407157
TI  - Ca(2+) and Zn(2+) binding properties of peptide substrates of vertebrate
      collagenase, MMP-1.
AB  - To understand the role of Ca(2+) in vertebrate in the structure and action of
      collagenase, we have examined peptides that interact with recombinant human
      fibroblast collagenase for their affinities towards Ca(2+) and Zn(2+) in a non
      polar solvent. Two of the peptides, GPQGIAGQ and GNVGLAGA, had sequences in
      collagen which are, respectively, cleaved and not cleaved by collagenase. A third
      peptide, PSYFLNAG, had a collagenase-cleaved sequence in ovostatin, a globular
      protein substrate. Peptides TVGCEECTV and CLPREPGL were derived from TIMP-1; the
      former competitively inhibits collagenase while the latter does not. The relative
      rates of hydrolysis of the peptides by collagenase had the order
      GPQGIAGQ>PSYFLNAG>GNVGLAGA. Circular dichroism spectral data in trifluoroethanol
      showed that while the TIMP control peptide, CLPREPGL, bound only Zn(2+), the
      other four peptides bound both Ca(2+) and Zn(2+) with definite stoichiometries.
      Ca(2+) could displace Zn(2+) in the substrate peptides while Zn(2+) displaced
      Ca(2+) in the TIMP peptide. GPQGIAGQ, PSYFLNAG and TVGCEECTV formed
      peptide:Ca(2+):Zn(2+) ternary complexes. Our results suggest that both collagen
      and globular protein substrates of collagenase may bind Ca(2+) and Zn(2+) in the
      enzyme's active site. This, in turn, may account for the known importance of the
      non-catalytic Ca(2+) and Zn(2+) in collagenase activity.

PMID- 10407159
TI  - Purification and properties of major alpha-D-mannosidase in the luminal fluid of
      porcine epididymis.
AB  - A lysosomal type alpha-D-mannosidase was successfully purified by DEAE-Sephacel,
      Red-Amicon and Superdex 200 column chromatographies from porcine cauda epididymal
      fluid. The purified enzyme consisted of 63 and 51 kDa subunits at equimolar
      amounts. It cleaved alpha1-2 linked mannosyl residues and less but significantly
      cleaved alpha1-3 and alpha1-6 linked mannosyl residues in the high-mannose
      oligosaccharides. The optimal pH to hydrolyze oligosaccharide was in the acidic
      pH range (pH 3.5 approximately 4.0). Total alpha-D-mannosidase activities in the
      porcine epididymal fluid increased from proximal to distal caput epididymis,
      which maintained to cauda epididymis. At least two kinds of alpha-D-mannosidase
      (lysosomal type enzyme and 135 kDa alpha-D-mannosidase (MAN2B2)) were contained
      in the porcine epididymal fluid. The activity of the lysosomal type enzyme is
      much higher than MAN2B2 at the physiological pH. These results suggest that the
      lysosomal type alpha-D-mannosidase is the predominantly active enzyme in the
      luminal fluid of porcine epididymis and that it participates in the glycoprotein
      modification on the sperm surface during epididymal transit.

PMID- 10407158
TI  - Cloning, sequencing and further characterization of acylpeptide hydrolase from
      porcine intestinal mucosa.
AB  - Acylpeptide hydrolase was purified to homogeneity from porcine intestinal mucosa
      using a seven-step procedure including ammonium sulfate precipitation, gel
      filtration as well as anion exchange and affinity chromatography. The specific
      activity of the enzyme reached 105000 nmol/mg protein per min and the
      purification was as high as 5500-fold. This tetrameric enzyme is composed of four
      apparently identical subunits, the molecular mass of which was estimated to be 75
      kDa, based on the results of amino acid analysis and gel electrophoresis
      performed under denaturing conditions. It is likely that the NH(2)-terminal
      residue may be acetylated, while serine was found to be the COOH-terminal
      residue. The hydrolytic activity of the enzyme toward N-acetyl-L-alanine p
      nitroanilide at the optimum pH value was increased twofold in the presence of the
      chloride anion. The K(m) value calculated from the kinetics of the hydrolysis of
      acetylalanyl peptides was found to be 0.7+/-0.1 mM, whereas the V(max) values
      decreased from 200 to 50 nmol/min per microgram of enzyme, depending on the
      peptidic chain lengths. The V(max) value of the synthetic substrate (250 nmol/min
      per microgram of enzyme) was 25-500% higher than those of the acetylalanyl
      peptides, depending on the peptide chain length, although the enzyme affinity was
      slightly lower (1.8 mM as compared with 0.7 mM). In line with data on other
      animal species and on various tissues, the enzyme seemed likely to be a serine
      protease, since it was readily inhibited by diisopropyl fluorophosphate and
      diethyl pyrocarbonate. A 2377-nucleotide long cDNA coding for the enzyme was
      isolated from pig small intestine. The deduced amino acid sequence consisted of
      731 residues and showed a single different amino acid with that of the porcine
      liver APH, except the N-terminal amino acid which is still probably lacking.

PMID- 10407160
TI  - Crystallization and preliminary X-ray diffraction analysis of a myotoxic
      phospholipase A(2) homologue from Bothrops neuwiedi pauloensis venom.
AB  - Crystals of a myotoxic phospholipase A(2) from Bothrops neuwiedi pauloensis have
      been obtained. They diffracted at 2.5 A resolution using a synchrotron radiation
      source and belong to space group P3(1)21. Preliminary analysis shows that there
      are two molecules in the asymmetric unit.

PMID- 10407161
TI  - Fluorimetric detection of enzymatic activity associated with the human tumor
      suppressor Fhit protein.
AB  - The human tumor suppressor Fhit protein exhibits diadenosine triphosphatase
      activity, hydrolyzing Ap(3)A to AMP and ADP. We report that Fhit protein
      efficiently cleaves the fluorogenic Ap(3)A analog diethenoadenosine triphosphate
      giving support to establish a simple fluorimetric assay for quantification of
      Fhit enzyme. Fluorimetric assays were initially tested to demonstrate that
      diethyl pyrocarbonate and suramin inhibit Fhit enzyme.

PMID- 10407162
TI  - Effect of redox state on unfolding energetics of heme proteins.
AB  - Both the enthalpic and entropic contributions to unfolding of three heme
      proteins, cytochrome b(562), cytochrome c and myoglobin, are larger for the
      reduced than for the oxidized form. Thus, the higher thermodynamic stability of a
      reduced, as compared to an oxidized, heme protein is the net result of a large
      increase of favorable enthalpy and a small increase in unfavorable entropy. Upon
      comparing the unfolding energetics of the heme proteins to those of other single
      domain proteins I find that protein length is the primary determinant of the
      thermodynamics.

PMID- 10407163
TI  - Molecular cloning, functional expression and purification of a glucan branching
      enzyme from Neisseria denitrificans(1).
AB  - The nucleotide sequence containing the complete structural information for a
      glucan branching enzyme was isolated from a Neisseria denitrificans genomic
      library. The gene was expressed in Escherichia coli and the active recombinant
      protein was purified. The deduced protein of 762 amino acids with a calculated
      molecular weight of 86313 Da shows similarity to the primary protein sequences of
      other known glucan branching enzymes. Amino acid sequencing of the isolated
      protein by Edman degradation confirmed the deduced start codon of the structural
      gene of the glucan branching enzyme. The purified glucan branching enzyme has a
      stimulating effect on the Neisseria amylosucrase activity.

PMID- 10407164
TI  - Nucleotide sequence, heterologous expression and novel purification of DNA ligase
      from Bacillus stearothermophilus(1).
AB  - The gene for DNA ligase (EC 6.5.1.2) from thermophilic bacterium Bacillus
      stearothermophilus NCA1503 has been cloned and the complete nucleotide sequence
      determined. The ligase gene encodes a protein 670 amino acids in length. The gene
      was overexpressed in Escherichia coli and the enzyme has been purified to
      homogeneity. Preliminary characterisation confirms that it is a thermostable,
      NAD(+)-dependent DNA ligase.

PMID- 10407165
TI  - Polymorphism and evolution of collagenolytic serine protease genes in
      crustaceans.
AB  - Two genomic DNA fragments encoding crustacean collagenolytic serine protease
      genes show coding fragments that span 1522-1526 base pairs and contain seven
      exons encoding the complete amino acid sequence of two enzymes, CHYA and CHYB. As
      in serine protease genes from other organisms, the region coding for the residues
      around the active site is split by two introns. Although the introns differ from
      those of other organisms in size and nucleotide sequence, their number and
      location are more or less the same as found in mammalian chymotrypsin or elastase
      genes that evolved lately, but different for trypsin genes. Meanwhile, the
      junction that occurs between the propeptide and the maturation site is only found
      in the shrimp genes. This is also the case for the junction located 13 amino
      acids after the active site aspartic acid in these genes. Between 40 and 50
      copies of the genes are reported by Southern analysis. Seven different genes
      within ChyA Pv family present 0-6% base changes, whereas five different genes
      belonging to ChyB Pv family show changes of up to 27% in the short studied
      portion of exon 4. This last family presents a mosaic organization of the coding
      parts, which are also expressed in the hepatopancreas of the shrimp as the
      variant PVC5 cDNA.

PMID- 10407166
TI  - Kainic acid-induced seizure upregulates Na(+)/myo-inositol cotransporter mRNA in
      rat brain.
AB  - A major organic osmolyte, myo-inositol protects cells from perturbing effects of
      high intracellular concentrations of electrolytes. Myo-inositol is accumulated
      into cells through Na(+)/myo-inositol cotransporter (SMIT). In order to
      investigate the regulation of SMIT in generalized seizure, we employed Northern
      blot analysis and in situ hybridization to study the changes in SMIT mRNA
      expression in kainic acid-injected rats. Northern blot analysis demonstrated that
      SMIT mRNA began to increase in the brain 2 h after onset of seizure, and peaked
      at 12 h. In situ hybridization revealed rapid increase of SMIT mRNA (2 h of
      seizure) in the CA3 hippocampal pyramidal cells and in the dentate granular
      cells. Then, at 4-6 h SMIT mRNA expression was observed in the other limbic
      structure such as amygdala and piriform cortex. Finally, in neocortex and in CA1
      pyramidal cells, SMIT mRNA was slowly increased and peaked at 12 h.
      Microautoradiogram demonstrated that cells expressed SMIT mRNA were mainly
      neurons. These results suggest that SMIT mRNA is upregulated by kainic acid
      induced seizure primarily in structures involved in seizure activity.

PMID- 10407167
TI  - Osmotic activation of the hypothalamo-neurohypophysial system reversibly
      downregulates the NMDA receptor subunit, NR2B, in the supraoptic nucleus of the
      hypothalamus.
AB  - NMDA receptor activation produces a characteristic pattern of neuronal firing in
      magnocellular neuroendocrine cells (MNCs) of the supraoptic nucleus of the
      hypothalamus (SON) which has been associated with greater hormone release in vivo
      and in vitro. In addition, i.c.v. administered NMDA receptor blockers suppress
      the dehydration-induced rise in plasma vasopressin and drinking. To investigate
      the role of NMDA receptor subunits in the neuroendocrine functions of the
      magnocellular neuroendocrine cells of the hypothalamus, we examined the effects
      of osmotic stimulation on the protein expression of the NMDA receptor subunits,
      NR1 and NR2B, important in binding glycine and glutamate, respectively.
      Homogenates of SON, paraventricular nucleus of the hypothalamus (PVN), cortex and
      lateral hypothalamus from control rats and rats given 2% saline water to drink
      for 4-10 days were subjected to SDS-PAGE and Western blot analysis. This saline
      water drinking regimen produced a significant rise in plasma osmolality levels.
      NR1 and NR2B immunoreactivity was detected in SON, PVN, lateral hypothalamus and
      cortex but not in liver homogenates using subunit-specific polyclonal antibodies
      and quantified using computer-assisted densitometry. Mean NR2B immunoreactivity
      was significantly lower in SON (29%) and PVN homogenates (23%) from saline
      treated rats than in those from control rats. In addition, the effect of
      dehydration on NR2B was regionally specific since no significant changes in NR2B
      expression were observed in homogenates of cortex and lateral hypothalamus.
      Rehydration allowed recovery of plasma osmolality as well as NR2B protein levels
      in the SON. These results suggest that changes in NMDA receptor subunit
      expression contribute to the plasticity manifested by in magnocellular
      neuroendocrine cells in response to osmotic activation of the hypothalamo
      neurohypophysial system. In addition, our results indicate that NMDA receptors on
      SON and PVN MNCs may contribute to neuroendocrinological functions associated
      with body fluid homeostasis.

PMID- 10407168
TI  - Molecular characterization of a new member of the protein 4.1 family (brain 4.1)
      in rat brain.
AB  - In addition to the well-known erythroid 4.1 gene, two human genes (KIAA0338 and
      4.1G) have recently been identified as members of the protein 4.1 family of
      genes. We compared the expression levels of these three genes and found that the
      KIAA0338 gene was predominantly expressed in human brain. To further characterize
      this novel protein 4.1, called brain 4.1, we isolated rat brain 4.1 cDNA and
      analyzed its gene products in rat brain. The results indicated that the mRNA and
      protein products of the brain 4.1 gene were more abundant in brain compared to
      any other tissues examined. The brain 4.1 mRNA appeared as multiple bands with
      estimated sizes of 3.9 kb, 6.2 kb and 8.7 kb on RNA blotting analysis, and was
      found to consist of various alternative forms as reported previously for the
      erythroid 4. 1 gene. As for the brain 4.1 gene product, many isoforms discernible
      by immunoblotting analysis were also observed depending on the tissue type and
      the brain region. The existence of multiple forms of the brain 4.1 implies that
      it has multiple and diverse functions like the erythroid 4.1 gene product.

PMID- 10407169
TI  - Up-regulation of vasopressin V(1a) receptor mRNA in rat facial motoneurons
      following axotomy.
AB  - We have reported previously that axotomy induced a marked increase of vasopressin
      receptor binding in the adult rat facial nucleus, suggesting an increased number
      of vasopressin receptors. These receptors were pharmacologically
      undistinguishable from peripheral V(1a) vasopressin receptors. In the present
      study, we show, using in situ hybridization and reverse transcriptase-polymerase
      chain reaction (RT-PCR), that axotomy regulates the expression of the vasopressin
      V(1a) receptor mRNA in the facial nucleus. Results were obtained from adult male
      rats killed 1 week following crush of the right facial nerve. In situ
      hybridization was performed with a (35)S-labelled riboprobe. A specific
      hybridization signal was detected in both left and right facial nuclei, with a
      significantly higher intensity in the nucleus ipsilateral to the lesion. V(1a)
      receptor transcripts were found associated with large facial motoneuronal cell
      bodies, not with other cells present in the nucleus, i.e., glial or epithelial
      cells. RT-PCR analysis of unlesioned facial tissue revealed the presence of mRNAs
      encoding vasopressin V(1a), vasopressin V(1b) and oxytocin receptors, whereas
      only the V(1a) receptor mRNA was found to be increased following axotomy in the
      lesioned facial tissue. These data suggest that the axotomy-induced expression of
      vasopressin receptors in the rat facial nucleus is due, at least to a large
      extent, to an increase of the V(1a) vasopressin receptor mRNA in facial
      motoneurons.

PMID- 10407170
TI  - CREB mediates the cAMP-responsiveness of the tyrosine hydroxylase gene: use of an
      antisense RNA strategy to produce CREB-deficient PC12 cell lines.
AB  - cAMP initiates the PKA signaling cascade in rat pheochromocytoma PC12 cells,
      resulting in transcriptional activation of the tyrosine hydroxylase (TH) gene.
      This effect is mediated primarily through the cAMP responsive element (CRE),
      located at position -45 to -38 within the TH gene promoter. In this study, we
      applied an antisense RNA strategy to evaluate the role of the cAMP responsive
      element binding protein (CREB) in regulating TH gene expression. CREB antisense
      RNA expression vectors were stably introduced into PC12 cells to generate cell
      lines deficient in CREB. CREB protein and mRNA levels were diminished up to 90%
      in the stably transfected cell lines. Promoter analysis experiments demonstrated
      that cAMP-mediated inducibility of either TH gene proximal promoter activity or
      the activity of the TH CRE by itself fused upstream of a basal promoter was
      diminished in CREB-deficient cell lines. PKA activity in the CREB-deficient cell
      lines was comparable to the activity in control cell lines. In addition, neither
      ATF1, nor CREM proteins were significantly down-regulated in the CREB-deficient
      cells. Most significantly, the cAMP-inducibility of endogenous TH mRNA was
      completely blocked in the CREB-deficient cells, indicating that the response of
      the endogenous gene to cAMP was dependent on CREB. These results support the
      hypothesis that CREB (not other CRE-binding proteins) is the key transcription
      factor that is required for regulating TH gene expression in response to cAMP.
      Furthermore, our studies indicate that these CREB-deficient PC12 cells are
      excellent tools to study the participation of CREB in gene regulation.

PMID- 10407171
TI  - L-arginine uptake, the citrulline-NO cycle and arginase II in the rat brain: an
      in situ hybridization study.
AB  - Nitric oxide (NO) is synthesized from a unique precursor, arginine, by nitric
      oxide synthase (NOS). In brain cells, arginine is supplied by protein breakdown
      or extracted from the blood through cationic amino acid transporters (CATs).
      Arginine can also be recycled from the citrulline produced by NOS activity,
      through argininosuccinate synthetase (AS) and argininosuccinate lyase (AL)
      activities, and metabolized by arginase. NOS, AS and AL constitute the so-called
      citrulline-NO cycle. In order to better understand arginine transport, recycling
      and degradation, we studied the regional distribution of cells expressing CAT1,
      CAT3, AS, AL, neuronal NOS (nNOS) and arginase II (AII) in the adult rat brain by
      non-radioisotopic in situ hybridization (ISH). CAT1, AL and AII presented an
      ubiquitous neuronal and glial expression, whereas CAT3 and AS were confined to
      neurons. nNOS was restricted to scattered neurons and a few brain nuclei and
      layers. We demonstrate by this study that cells expressing nNOS all appear to
      express the entire citrulline-NO cycle, whereas numerous cells expressing AL do
      not express AS. The differential expression of these genes within the same
      anatomical structure could indicate that intercellular exchanges of citrulline-NO
      cycle metabolites are relevant. Thus vicinal interactions should be taken into
      account to study their regulatory mechanisms.

PMID- 10407173
TI  - Circadian regulation of iodopsin and clock is altered in the retinal degeneration
      chicken retina.
AB  - We are interested in determining if the visual phototransduction cascade plays a
      role in light entrainment of photoreceptor circadian oscillators. In this study,
      we compared mRNA levels of iodopsin and the chicken homolog of Clock (cClock) in
      the retinas of normal and rd (retinal degeneration) chickens that lack functional
      rod and cone phototransduction cascades. Iodopsin is a circadian-regulated,
      photoreceptor-specific gene expressed in chicken retina, and Clock is a
      transcription factor that has been shown to play a role in the circadian clock
      mechanism in mouse and Drosophila. The results of our analyses show that cClock
      and iodopsin transcript levels undergo daily oscillations in retinas of normal
      animals housed under 12 h light:12 h dark (12L:12D) conditions, and that these
      oscillations are maintained in the absence of light. Levels of these transcripts
      in the retinas of rd/rd chickens housed under cyclic light conditions did not
      change significantly over the course of a 12L:12D cycle; however, there was
      evidence that the photoreceptor oscillators were entrained in these animals.
      Comparisons of our normal and rd/rd data suggest that there are at least two
      light entrainment pathways that impinge on the oscillators found in photoreceptor
      cells, one of which is effectively disabled by the GC1 null mutation carried by
      the rd chicken.

PMID- 10407172
TI  - Neuropeptide Y receptor subtype with unique properties cloned in the zebrafish:
      the zYa receptor.
AB  - Neuropeptide Y (NPY) belongs to a family of structurally related neuroendocrine
      peptides for which five different G-protein-coupled receptor subtypes have been
      cloned in mammals. To identify additional subtypes we have performed PCR with
      degenerate primers in different species. We describe here the cloning and
      pharmacological profile of a unique NPY receptor subtype in the zebrafish that
      has tentatively been called the zYa receptor. It has 46-50% amino acid identity
      to the mammalian Y1, Y4 and y6 receptors and the previously cloned zebrafish
      receptors zYb and zYc, and only about 27% to Y2 and Y5. The zYa receptor binds
      NPY and PYY from mammals as well as zebrafish with high affinities and has a K(d)
      of 28 pM for porcine (125)I-PYY. It has a unique binding profile displaying some
      features in common with each of the mammalian Y1, Y2 and Y5 receptors. In a
      microphysiometer assay the receptor responds with extracellular acidification.
      Chromosomal mapping in the zebrafish genome of zYa, zYb and zYc receptor genes
      indicates a possible orthologous relationship between zYc and mammalian y6, but
      identifies no obvious mammalian ortholog for zYa (zYb is a recent copy of zYc in
      the fish lineage). These results imply that previous studies of NPY in fishes,
      which have striven to interpret the effects within the framework of mammalian Y1,
      Y2, and Y5 receptors, need to be reevaluated. Thus, the sequence comparisons,
      pharmacological properties, and chromosomal localization suggest that the zYa
      receptor is a novel NPY receptor subtype which is likely to be present also in
      mammals.

PMID- 10407174
TI  - Pineal nitric oxide synthase, but not heme oxygenase, mRNA is suppressed by
      continuous exposure to light.
AB  - We have previously shown that exposure of rats to constant light (LL) induced a
      decrease in NO synthase (NOS) activity in the pineal gland. We report here that
      the use of the sensitive technique of RT-PCR has demonstrated that mRNA for
      neuronal NOS is present in the pineal, and that it is photoneurally regulated.
      There was a marked decrease in pineal neuronal NOS mRNA levels in continuous
      light conditions, similar to the changes seen in NOS enzyme activity. Inducible
      NOS was not present in the pineal, and there was evidence that the
      photoregulatable form was not endothelial NOS. The mRNA for two isoforms of heme
      oxygenase, the enzyme responsible for the generation of the putative
      neuromodulator carbon monoxide, was also present in the pineal, but neither
      isoform was photoregulated. Using immunodetection, it was not possible to
      identify the presence of NOS protein, other than to a minimal extent, even though
      NOS activity was clearly present. NADPH-diaphorase staining and in situ
      hybridization were carried out in an attempt to identify the precise location of
      neuronal NOS message. A strong NADPH-diaphorase reaction was present in
      sympathetic nerve fibers of the pineal, but pinealocytes showed no or only very
      weak labelling. In situ hybridization was also unable to identify neuronal NOS
      message in pinealocytes. These data thus also suggest the possible presence of a
      pineal-specific NOS isoenzyme.

PMID- 10407175
TI  - cDNA cloning and expression of a novel serine protease in the mouse brain.
AB  - A cDNA for a novel serine protease, termed brain type granzyme K (B-GRK) was
      cloned from the mouse brain. The cDNA codes a protein similar to granzyme K (GRK)
      but completely different at the N-terminus. Genomic Southern and PCR analysis of
      the gene suggests B-GRK is the alternative transcription form of GRK. B-GRK and
      GRK have a different organ-specific expression pattern: B-GRK is expressed in the
      brain, while GRK is expressed in the spleen. The recombinant fusion protein was
      detected in the neuro2a cells transfected with a plasmid containing B-GRK
      sequence. The mRNA for B-GRK/GRK was detected in cerebral cortex, hippocampus and
      diencephalon of the mouse brain. In situ hybridization for B-GRK/GRK revealed
      that several regions in the forebrain and hypothalamus express the mRNA.
      Developmental analysis showed that in the prenatal stage, the mRNA was expressed
      also in pituitary and pineal body in addition to the brain.

PMID- 10407176
TI  - Serotonin receptor subtype gene expression in the hippocampus of aged rats
      following chronic amitriptyline treatment.
AB  - The raphe-hippocampal 5-HT system plays a key role in the modulation of mood,
      memory and neuroendocrine responses. In the elderly, there is an increased
      incidence of disturbances of these functions. We examined the effects of ageing
      and of chronic antidepressant treatment upon 5-HT receptor subtype mRNA
      expression in the hippocampus and raphe of cognitively tested rats. Amitriptyline
      treatment decreased 5-HT1A receptor mRNA expression in the dorsal raphe nucleus
      of the aged rats (24% fall compared to saline treated controls, p<0.01) but not
      in the young rats. Neither age nor amitriptyline (10 mg/kg, i.p.) administration
      for 10 weeks altered 5-HT1A, 5-HT2A, 5-HT2C or 5-HT7 receptor mRNA expression in
      any hippocampal subregion. This suggests a difference in responsiveness to
      amitriptyline with ageing originating at the level of the raphe 5-HT1A
      autoreceptor gene expression.

PMID- 10407177
TI  - Reduction with age in methylcytosine in the promoter region -224 approximately 
      101 of the amyloid precursor protein gene in autopsy human cortex.
AB  - Methylation status of cytosines and its changes with age in the promoter region (
      226 approximately -101) of the amyloid precursor protein (APP) was analyzed using
      bisulfite genomic sequencing in the cerebral cortex of human autopsy brain.
      Cytosines at 13 locations were methylated in at least one of the cases studied.
      Methylcytosines at these locations was more frequent in cases </=70 years old
      (26%) than in cases >70 years old (8%) (p<0.05). Cytosines at -207, -204, -200,
      and -182 are frequently methylated, and the frequency of methylcytosine in these
      locations was significantly higher in cases </=70 years old (55%) than cases >70
      years old (5%) (p<0.01). These cytosines constituted one of the 9-bp-long GC-rich
      elements (GGGCGC G/A GG) or an 11-bp inverted repeat (GGCCGT CGGCC). The present
      findings indicate that some cytosines, particularly those at -207 approximately 
      182, in the promoter region of the APP gene are frequently methylated and suggest
      that their demethylation with age may have some significance in the development
      of Abeta deposition in the aged brain. The relative importance of these elements
      in the total promoter activity of the APP gene remains to be definitively
      established.

PMID- 10407178
TI  - Distribution of mRNA encoding a nitrobenzylthioinosine-insensitive nucleoside
      transporter (ENT2) in rat brain.
AB  - Nucleoside transporters may play a role in regulating levels of extracellular
      adenosine and adenosine receptor activity. Two members of the equilibrative
      nucleoside transporter family have recently been cloned. ENT1 is potently
      inhibited by nitrobenzylthioinosine (NBMPR) (K(i) approximately 1 nM) and was
      previously found to have a wide distribution in rat and human brain. ENT2 is
      insensitive to inhibition by NBMPR at low nanomolar concentrations and there is
      limited information describing its distribution in rat brain. The present study
      used RT-PCR, northern blot and in situ hybridization and detected rENT2
      transcript in several brain regions including hippocampus, cortex, striatum and
      cerebellum. Our results indicate a wide cellular and regional distribution for
      ENT2 in rat brain, similar to ENT1, indicating that control of adenosine levels
      in brain is achieved by multiple transport processes.

PMID- 10407179
TI  - Discordant expression of c-Ret and glial cell line-derived neurotrophic factor
      receptor alpha-1 mRNAs in response to motor nerve injury in neonate rats.
AB  - Adult motoneurons can survive following axotomy, whereas neonate motoneurons
      result in cell death. Following hypoglossal nerve axotomy in neonate rat, Glial
      cell line-Derived Neurotrophic Factor (GDNF) receptor alpha-1 (GFRalpha-1) mRNA
      expression was dramatically suppressed in the injured motoneurons, while a slight
      increase of c-Ret mRNA expression was observed. In adult, both GFRalpha-1 and c
      Ret mRNAs increased substantially after axotomy. The present result suggests that
      the difference of motoneuron fate after axotomy may be partly due to the
      coordinate or discordant responses of GFRalpha-1 and c-Ret expression to nerve
      injury.

PMID- 10407180
TI  - Activation of p53 and its target genes p21(WAF1/Cip1) and PAG608/Wig-1 in
      ischemic preconditioning.
AB  - A brief, 3 min period of global forebrain ischemia in the rat, induced by
      bilateral common carotid occlusion combined with hypotension, confers resistance
      to hippocampal pyramidal neurons against a subsequent 10 min ischemia, which is
      normally lethal to these cells. The molecular mechanisms underlying this ischemic
      preconditioning, or tolerance, are poorly understood. The tumor suppressor p53 is
      a transcription factor implicated in neuronal death following various insults,
      including cerebral ischemia. p53 is activated in response to cellular stress,
      e.g. hypoxia and DNA damage. Using in situ hybridization, we investigated the
      hippocampal mRNA expression of p53, and two of its target genes, p21(WAF1/Cip1)
      and the recently cloned PAG608/Wig-1, in a two-vessel occlusion model of ischemic
      preconditioning. We also evaluated changes in the protein levels of p53 and
      PAG608/Wig-1 using immunohistochemistry. The mRNA levels of all three genes
      increased in the ischemia sensitive CA1 region both following 3 min (non-lethal)
      preconditioning and 10 min of (lethal) nonconditioned ischemia. In contrast,
      after 10 min of ischemia preconditioned by a 3 min ischemic insult 48 h earlier,
      no upregulation of these genes was detected in the CA1. Following 10 min of
      nonconditioned ischemia, increased neuronal immunostaining of p53 and PAG608/Wig
      1 was observed in the hippocampus, which was less pronounced following 3 min of
      preconditioning ischemia and 10 min of preconditioned ischemia. Our results
      demonstrate that activation of p53 and its response genes p21(WAF1/Cip1) and
      PAG608/Wig-1 occurs in the brain following lethal as well as non-lethal ischemic
      insults, and that ischemic preconditioning markedly diminishes this activation.

PMID- 10407181
TI  - Decreased (45)Ca(2)(+) uptake in P/Q-type calcium channels in homozygous
      lethargic (Cacnb4lh) mice is associated with increased beta3 and decreased beta4
      calcium channel subunit mRNA expression.
AB  - The mutated gene in the lethargic (Cacnb4lh) mouse model of absence seizures
      encodes the beta4 subunit of voltage-gated calcium channels (VGCCs), leading to
      decreased mRNA expression of a beta4 subunit that is truncated and cannot bind to
      alpha1 subunits of VGCCs. In this study we accomplished two goals. First, we
      studied the functional consequence of altered VGCCs by examining the effects of a
      selective P/Q-type channel antagonist on KCl-induced (45)Ca(2)(+) uptake in brain
      synaptosomes from Cacnb4lh homozygotes and non-epileptic controls (designated by
      +/+). We found that depolarization-induced (45)Ca(2)(+) uptake was significantly
      reduced in the brains of Cacnb4lh homozygotes, and that the reduced uptake was
      completely accounted for by reduced function of P/Q-type calcium channel. Second,
      we examined VGCC subunit composition to determine if other subunits were altered
      in addition to the mutation affecting beta4 subunits in Cacnb4lh homozygotes;
      when alterations were found, we determined if they were regional or global. We
      used in situ hybridization histochemistry (ISHH) to analyze the neuro-anatomic
      distribution of beta4, beta1b, beta2, beta3, alpha1A, alpha1B, alpha1C, alpha1E,
      and alpha1G subunit mRNAs in brain sections from matched Cacnb4lh homozygotes and
      +/+ controls. Our results indicated that expression of beta4 subunit mRNA is
      globally reduced throughout the brains of Cacnb4lh homozygotes, in contrast to a
      small but significant global increase in the expression of beta3 subunit mRNA.
      There were no significant differences in expression of the other VGCC subunit
      mRNAs examined. Together, these findings indicate that a host of changes in VGCC
      subunit composition accompany reduced function of P/Q-type channels in homozygous
      lethargic mice.

PMID- 10407182
TI  - Hippocampal BDNF mRNA shows a diurnal regulation, primarily in the exon III
      transcript.
AB  - Endogenous expression levels of brain-derived neurotrophic factor (BDNF) mRNA
      were assessed using in situ hybridization to investigate whether there is a
      natural diurnal fluctuation in BDNF mRNA expression in the hippocampus of rats
      housed with a normal (12:12 h) light/dark cycle. BDNF expression was increased
      during lights out (dark-cycle) to 134%-158% of light-cycle levels in hippocampal
      regions CA1, CA3, and hilus. In addition, expression levels of the four BDNF
      transcript forms, exons I-IV, were assessed to evaluate whether expression of
      specific BDNF transcripts exhibited differential endogenous fluctuation. All
      exons had lowest levels of expression at either noon or 6 p.m. Significant
      correlations were found between exon expression level and time, with elevated
      expression occurring at dark-cycle timepoints. The exon III transcript showed the
      greatest diurnal change in expression in all hippocampal fields, with dark-cycle
      expression elevated to 219-419% of light-cycle expression level. In addition to
      exon III, dark-cycle exon II mRNA levels were elevated in all hippocampal
      subfields, to 140-180% of light-cycle levels, suggesting that the endogenous
      fluctuation in BDNF expression results predominantly from activation of the
      promoters linked to exons II and III. Previously we have shown that physical
      activity increases BDNF expression. The naturally occurring rise in BDNF
      expression during the dark-cycle, the time when rats are most physically active,
      may be due to increased activity and arousal levels. Because BDNF has a role in
      plasticity, the increase in BDNF expression during the time that a rat is
      maximally interacting with its surroundings may be part of an ongoing stimulus
      encoding mechanism, or may be a mechanism to maximize information storage about
      the environment.

PMID- 10407183
TI  - Downregulation of DNA (cytosine-5-)methyltransferase is a late event in NGF
      induced PC12 cell differentiation.
AB  - DNA methylation patterns are a critical component of the epigenetic machinery
      that controls the expression of genetic programs in vertebrates. DNA
      methyltransferase gene (dnmt1) encodes the enzyme catalyzing the methylation of
      DNA during replication. We tested the hypothesis that the expression of dnmt1 is
      regulated with the developmental state of neuronal cells. We show that DNA
      methyltransferase (Dnmt1) activity is sharply reduced 4 days after induction of
      differentiation of PC12 cells with NGF. Similarly, the adult brain expresses
      reduced levels of Dnmt1 activity. We propose that the level of Dnmt1 is
      downregulated to adjust the activity of the DNA methyltransferase to a different
      role in mature post-mitotic neurons. Both the abundance of dnmt1 mRNA as well as
      the Dnmt1 polypeptide are downregulated. Downregulation of dnmt1 parallels other
      indicators of withdrawal from the cell cycle such as induction of p21, and
      downregulation of the S phase maker PCNA (proliferating cell nuclear antigen).
      The temporal pattern of downregulation of dnmt1 in nerve growth factor (NGF)
      induced PC12 cells is different from myotube differentiation where downregulation
      of DNA methyltransferase and demethylation is an early event and was proposed to
      play a causal role in differentiation. We propose that NGF differentiation of
      PC12 cells represents a different paradigm of involvement of DNA methylation in
      terminal differentiation.

PMID- 10407184
TI  - Promoter activity of the beta-amyloid precursor protein gene is negatively
      modulated by an upstream regulatory element.
AB  - Alzheimer's disease (AD) is characterized by the aggregation of the amyloid beta
      peptide (Abeta) which is generated from a larger beta-amyloid precursor protein
      (betaAPP). An overexpression of the betaAPP gene in certain areas of the AD brain
      has been suggested to be an important factor in the neuropathology of AD. Here we
      have further characterized an upstream regulatory element (URE) located between 
      2257 and -2234 of the human betaAPP promoter. In addition to its location in the
      promoter, BLAST search reveals that URE is present in several introns of the
      betaAPP gene and is also detected in many other genes. For functional studies,
      two promoter regions were cloned upstream of the reporter gene, chloramphenicol
      acetyl transferase (CAT): (i) phbetaE-B - the plasmid that contains the human (h)
      promoter region (-2832 to +101) including URE, and (ii) prhbetaE-B - the plasmid
      that contains the rhesus (rh) promoter region excluding URE as it lacks a 270 bp
      region of the hbetaAPP promoter (-2435 to -2165). Transient transfection studies
      indicate that phbetaE-B displayed significantly less CAT-promoter activity than
      prhbetaE-B in C6, PC12 and SK-N-SH cells. To determine the role of URE in a
      heterologous promoter, a pbetaURE construct was made by subcloning URE in an
      enhancerless promoter vector pCATP. The pbetaURE-CAT construct displayed
      threefold to fourfold less promoter activity than pCATP when different cell lines
      were transfected with the plasmids. URE interacts with a novel protein(s) as
      determined by the electrophoretic mobility shift assay (EMSA). Although the core
      DNA region of URE resembles with the NF-kB element, URE-binding protein is not
      related to the NF-kB transcription factor. When EMSA was performed with specific
      competitors in different cell lines, the labeled URE probe was not competed by
      the oligonucleotides specific for either the AP3, NF-1 or NF-kB transcription
      factor. The migration of the URE-protein complex was different from the NF-kB
      protein complex in the EMSA gel. A distinct URE-specific nuclear factor was also
      detected in frontal cortex of a normal human brain. These results suggest that
      the URE region acts as a repressor element, that the URE-binding protein is not
      related to the known transcription factors tested, and that the protein is
      present in astrocytic, neuroblastoma, PC12 cells and in the human brain.

PMID- 10407185
TI  - TGF-beta(1), regulation of alzheimer amyloid precursor protein mRNA expression in
      a normal human astrocyte cell line: mRNA stabilization.
AB  - The transforming growth factor, TGF-beta(1), has been found to be increased in
      the central nervous system of Alzheimer's disease (AD) patients, elevates amyloid
      precursor protein (APP) mRNA levels in rat primary astrocytes, and may initiate
      or promote the deposition of amyloid-beta (Abeta) peptide in AD. Excess APP
      production in AD, which potentially leads to amyloidogenesis, is in part due to
      over expression of APP mRNA. The production of APP in a normal human cell line in
      contrast to transformed or animal cells provides a meaningful model to study the
      regulation of APP gene expression by cytokines that promotes amyloidogenesis.
      Here, we report that TGF-beta(1) treatment of human astrocytes markedly elevated
      APP mRNA levels, and also increased the half-life of APP message by at least five
      fold. Under this condition, as detected by mobility shift and UV cross-linking
      analysis, a novel 68 kDa RNA-protein complex was formed, involving an 81
      nucleotide (nt) fragment within the 3'-untranslated region (UTR), but not the 5'
      UTR and coding region of APP mRNA. Insertion of the 3'-UTR onto the
      chloramphenicol acetyl transferase (CAT) mRNA conferred TGF-beta(1) mediated mRNA
      stability in transfected human astrocytes. On the other hand, the same insert
      carrying a deletion of the APP mRNA cis-element fragment had no effect on CAT
      mRNA stability. A model of APP mRNA regulation is presented in which TGF-beta(1)
      induced stabilization of APP message involves the binding activity of a 68 kDa
      RNA-protein complex within the 3'-UTR, which is likely linked to a reduction in
      the rate of APP mRNA decay.

PMID- 10407186
TI  - Probing for drug-induced multiplex signal transduction pathways using high
      resolution two-dimensional gel electrophoresis: application to beta-adrenoceptor
      stimulation in the rat C6 glioma cell.
AB  - Whole-cell [(32)P]-protein phosphorylation assays and two-dimensional gel
      electrophoresis (2-DGE) were applied to the analysis of the beta-adrenoceptor
      (betaAR)-linked signal transduction pathway. Rat C6 glioma cells were stimulated
      with isoproterenol and the protein lysates were resolved by 2-DGE. Two
      dimensional [(32)P]-phosphoprotein 'maps' were generated depicting the modulation
      of intracellular proteins after isoproterenol stimulation versus unstimulated
      cells. A total of 274 distinct phosphoprotein spots were detected, of which 200
      were up-regulated, 69 were down-regulated, and 5 remained unchanged. An
      evaluation of isoproterenol's activity across several kinase pathways was
      performed using a computer-generated 2-DGE template incorporating the location
      and identification of individual signaling phosphoprotein intermediaries. The
      template served as a 'reference map' for drug treatment comparisons. We observed
      a significant increase in the phosphorylation states of several nuclear
      transcription factors, notably CREB-1, ATF-1, NFkappaB/IkappaBalpha and ELK-1,
      but not c-Jun. A parallel series of radioimmunoprecipitation studies confirmed
      our 2-DGE findings. Moreover, isoproterenol increased the phosphorylation state
      of PKC and of several MAPK-dependent pathway kinases which correlated with a
      significant increase in their endogenous kinase activity. Isoproterenol's effects
      on PKA, PKC and ERK-dependent activities were blocked by propranolol, a betaAR
      antagonist. In conclusion, an acute isoproterenol stimulus induced multiplex
      pathway modulation via the betaAR in the C6 glioma cell indicating that signaling
      pathway cross-talk is an essential feature for the regulation of cellular
      function. Moreover, the immediate advantages of the 2-DGE analytical approach
      were apparent, and further development of the protein database will provide a
      valuable tool to screen for broad-based drug-mediated signaling activities.

PMID- 10407187
TI  - Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate
      gyrus of the adult rat hippocampus.
AB  - The occurrence of radiation-induced apoptosis in normal brain was investigated
      using an animal model of radiosurgery. Adult male Fischer rats aged 3 to 4 months
      were subjected to single dose convergent beam irradiation (10 Gy). Apoptotic cell
      death was determined by in situ labeling of DNA nick ends (TUNEL) and light
      microscopic evaluation of cell morphology. Five hours after irradiation, a highly
      significant increase of apoptotic cells in the subgranular zone of the dentate
      gyrus was paralleled by a corresponding significant decrease of cells
      immunoreactive for the proliferation marker Ki-67. Morphology, location and
      distribution of cells affected by radiation-induced apoptosis in the dentate
      gyrus subgranular zone, together with NeuN-immunohistochemistry, support the
      contention that these cells belong to the immature progenitor population
      responsible for neurogenesis in the adult rat hippocampus.

PMID- 10407188
TI  - Rapid activation of heat shock factor-1 DNA binding by H2O2 and modulation by
      glutathione in human neuroblastoma and Alzheimer's disease cybrid cells.
AB  - Because cellular signaling systems are critical mediators of responses to
      oxidative stress, a condition associated with neurodegenerative disorders, the
      redox-dependent regulation of heat shock factor-1 (HSF-1) was investigated in
      human neuroblastoma SH-SY5Y cells. Exposure of cells to 200 microM H2O2 caused a
      rapid increase in HSF-1 DNA binding that was evident within 10 min, and caused a
      robust increase that reached levels 8-fold the basal activity. In comparison, the
      transcription factors, activator protein-1 (AP-1) and early growth response-1
      (EGR-1), were activated more slowly and to a lesser extent. Activation of HSF-1
      DNA binding activity was associated with a cytosolic to nuclear translocation of
      HSF-1 protein, and was detected with concentrations of H2O2 of 100 microM and
      greater. Intracellular glutathione modulated H2O2-induced HSF-1 DNA binding
      activity, as depletion of glutathione caused HSF-1 to be activated with lower
      concentrations of H2O2 (25 microM) and supplementation of glutathione blocked HSF
      1 activation by 100 to 400 microM H2O2. Alzheimer's disease (AD) and control
      cybrid cells (SH-SY5Y cells in which the mitochondria were replaced with platelet
      mitochondria from AD or matched control subjects) were used to test the effects
      of the chronic oxidative stress caused by the excessive production of reactive
      oxygen intermediates (ROIs) in AD cybrids on HSF-1 activity. Basal and maximal
      (induced by H2O2 in glutathione-depleted cells) HSF-1 DNA binding activity were
      lower in AD than control cybrids, suggesting that the cells had compensated for
      excessive ROIs. These results indicate that the activation of HSF-1 is highly
      sensitive to oxidative stress and is regulated by endogenous antioxidant
      mechanisms.

PMID- 10407189
TI  - The tumor-suppressor gene, p53, is induced in injured brain regions following
      experimental traumatic brain injury.
AB  - A growing body of evidence suggests that neurons undergo apoptotic cell death
      following traumatic brain injury (TBI). Since the expression of several tumor
      suppressor and cell cycle genes have been implicated in neuronal apoptosis, the
      present study used in situ hybridization (ISH) histochemistry to evaluate the
      regional and temporal patterns of expression of the mRNAs for the tumor
      suppressor gene, p53, and the cell cycle gene, cyclin D1, following lateral fluid
      percussion (FP) brain injury in the rat. Anesthetized adult male Sprague-Dawley
      rats (n=16) were subjected to lateral FP brain injury of moderate severity (2.4
      2.7 atm), while sham controls (n=6) were surgically prepared but did not receive
      brain injury. Animals were killed by decapitation at 6 h (n=6 injured and 2
      sham), 24 h (n=6 injured and 2 sham), or 3 days (n=4 injured and 2 sham), and
      their brains processed for ISH. Little to no expression of p53 mRNA was observed
      in sham brains. At 6 h post-injury, p53 mRNA was induced predominantly in cells
      that are vulnerable to TBI, such as those in the contused cortex, lateral and
      medial geniculate nuclei of the thalamus, and the CA(3) and hilar neurons of the
      hippocampus. Increased p53 mRNA was also detected in hippocampal CA(1) neurons,
      cells that are relatively resistant to FP brain injury. Levels of p53 mRNA
      returned to sham levels in all regions of the injured brain by 24 h. In contrast
      to p53, cyclin D1 mRNA was detectable in the brains of uninjured animals and was
      not altered by brain injury. These results suggest that the tumor suppressor gene
      p53, but not cyclin D1, is upregulated and may participate in molecular response
      to TBI.

PMID- 10407190
TI  - Molecular cloning of the arylalkylamine-N-acetyltransferase and daily variations
      of its mRNA expression in the Syrian hamster pineal gland.
AB  - The arylalkylamine-N-acetyltransferase (AA-NAT) expressed in the vertebrate
      pineal gland catalyzes the N-acetylation of the serotonin into N-acetylserotonin
      and is considered to be the rate limiting enzyme of the pineal melatonin
      synthesis. Indeed, dramatic changes in its activity throughout the 24-h period
      drive the large day/night variations in plasma melatonin concentrations.
      Recently, AA-NAT was cloned in the rat pineal. In this species, AA-NAT mRNA
      variations were demonstrated to be responsible of the well known AA-NAT activity
      and plasma melatonin circadian fluctuations. In the Syrian hamster, the pineal
      melatonin secretion pattern is characterized by a late-night short-duration peak
      of melatonin synthesis. We investigated whether this typical pattern could be due
      to a late-night delayed pineal AA-NAT mRNA expression. The first part of our
      study was dedicated to the molecular cloning of a Syrian hamster AA-NAT cDNA. A
      PCR-generated clone of 1045 bp encoding the AA-NAT has been isolated and
      sequenced. In situ hybridization using an AA-NAT cRNA probe revealed that the AA
      NAT mRNA expression undergoes strong daily fluctuations in the Syrian hamster
      pineal, with undetectable level in the second half of the light period and a
      dramatic increase at night. After lights off, the AA-NAT mRNA expression requires
      6-7 h to reach its maximum expression. This result thus suggests that the
      transcription of the AA-NAT mRNA in the Syrian pineal gland determines the lag
      period in pineal responsiveness and melatonin synthesis to darkness.

PMID- 10407191
TI  - Two related G protein-coupled receptors: the distribution of GPR7 in rat brain
      and the absence of GPR8 in rodents.
AB  - GPR7 and GPR8, orphan G protein-coupled receptor (GPCR) genes, expressed in the
      brain and periphery share highest sequence identity to each other and significant
      similarity with opioid and somatostatin receptors. To further our knowledge of
      GPR7's physiological function, we performed in situ hybridization analyses of rat
      brain to reveal specific patterns of expression in the brain. GPR7 mRNA was found
      to be discretely localized in areas of the amygdala, hippocampus, hypothalamus
      and cortex. We previously reported that GPR7 was highly conserved in both human
      and rodent orthologs while GPR8 was not found in the rodent [9]. We speculated
      that GPR8 originated after the divergence of the human and rodent. Using primers
      designed from human GPR8, we isolated lemur GPR8 and subsequently aligned human,
      monkey, and lemur GPR8 orthologs to design primers recognizing highly conserved
      regions of GPR8. Using these primers, orthologs of GPR7 and GPR8 were isolated by
      the PCR from rabbit, tree shrew, and flying lemur, as well as GPR7 in the rat.
      Subsequent analysis of the clones obtained demonstrated that both GPR7 and GPR8
      sequences were highly conserved amongst the species studied, but a rodent GPR8
      was not isolated. The absence of a GPR8 gene in the rodent suggests that GPR8
      originated from gene duplication of GPR7 after the rodent line diverged from the
      rabbit, tree shrew, flying lemur, lemur, monkey and human lines. In addition, the
      taxonomic distribution of GPR8 is consistent with molecular studies grouping
      rabbits with primates, tree shrews and flying lemurs rather than with rodents.

PMID- 10407192
TI  - Interferon-gamma induces proliferation but not apoptosis in murine astrocytes
      through the differential expression of the myc proto-oncogene family.
AB  - Interferon-gamma (IFN-gamma) is a cytokine mainly secreted by activated T
      lymphocytes. Treatment of mouse astrocytes in vitro with IFN-gamma augmented the
      basal expression of the primary response proto-oncogenes c-myc and L-myc as
      detected by Northern blotting. Such inductions were maximal at doses of 10 U/ml
      and after 60 min of treatment. Astrocytes fully differentiated in vitro do not
      express N-myc mRNA nor are induced to express it by exposure to IFN-gamma. As
      demonstrated by flow cytometry, the common protein product of the myc family was
      present in the nucleus of the cells. The specificity of IFN-gamma induction was
      demonstrated when antibodies against IFN-gamma completely suppressed the
      overinduction of these mRNAs. No apoptotic death can be detected in astrocytes
      treated with IFN-gamma at doses that induce c-myc expression. Conversely,
      treatment with a dose of 10 U/ml induced cells proliferation in astrocytic cells
      as measured by (3)H-thymidine incorporation.

PMID- 10407193
TI  - Deafferentation induced changes in GAD67 and GluR2 mRNA expression in mouse
      somatosensory cortex.
AB  - Partial vibrissectomy in adult mice induces body map plasticity in SI barrel
      cortex. To examine if the disturbed balance of cortical activation affects the
      excitatory and inhibitory neurotransmitter systems, we studied glutamic acid
      decarboxylase (GAD 67) and AMPA receptor subunit GluR2 mRNA expression in the
      barrel cortex. At varying times post-vibrissectomy, sparing row C of whiskers on
      one side of the snout, the brains were processed for in situ hybridization using
      specific [(35)S]oligonucleotides to detect the laminar localization of GAD67 and
      GluR2 mRNAs. Three and seven days after vibrissectomy, the expression of GAD67
      was decreased in the deafferented cortex, while 30 days post-lesion, no effects
      were observed. At 3 days post-lesion, an ipsilateral decrease in GAD67 mRNA
      expression was also observed. No decreases in GluR2 transcripts were found in the
      deafferented cortex, but an increased expression was observed in the
      representation of the spared row C of whiskers 3 days after vibrissectomy. Seven
      and 30 days post lesion no changes in GluR2 expression were found. These data
      indicate that in the barrel cortex, peripheral deafferentation transiently
      regulates GAD67 and GluR2 expression at the transcriptional level. We suggest
      that this may be a manifestation of adaptive processes.

PMID- 10407194
TI  - Molecular cloning, expression and characterization of a bovine serotonin
      transporter.
AB  - The serotonin transporter (SERT) is a member of a highly homologous family of
      sodium/chloride dependent neurotransmitter transporters responsible for reuptake
      of biogenic amines from the extracellular fluid. SERT constitutes the
      pharmacological target of several clinically important antidepressants. Here we
      report the molecular cloning of SERT from the bovine species. Translation of the
      nucleotide sequence revealed 44 amino acid differences compared to human SERT.
      When transiently expressed in HeLa cells and compared with rat and human SERTs
      the K(m) value for uptake was increased 2-fold. V(max) and B(max) were both
      increased about 4-fold indicating the turnover number is conserved. The
      pharmacological profile revealed a decreased sensitivity towards imipramine,
      desipramine, citalopram, fluoxetine and paroxetine compared with human SERT,
      while the sensitivity towards 3, 4-methylenedioxymethamphetamine (MDMA) was
      mainly unchanged. RT-PCR amplification of RNA from different tissues demonstrated
      expression of SERT in placenta, brain stem, bone marrow, kidney, lung, heart,
      adrenal gland, liver, parathyroid gland, thyroid gland, small intestine and
      pancreas.

PMID- 10407195
TI  - Glutamate decarboxylase isoforms in thalamic nuclei in lethargic mouse model of
      absence seizures.
AB  - To test the hypothesis that altered GABA synthesis within nucleus reticularis
      thalami (NRT) neurons regulates absence seizures, we analyzed and quantitated the
      distribution of GAD(67) and GAD(65), the rate-limiting enzymes of GABA synthesis,
      in thalamic nuclei from the Cacnb4lh model of absence seizures and non-epileptic
      (+/+) controls. In situ hybridization and Western blot results indicate a
      significant increase in GAD(67) expression (mRNA and protein) per cell but no
      change in GAD(65) in Cacnb4lh mice. These data suggest that GABA-synthesis is
      maintained or increased in NRT neurons in the Cacnb4lh mouse model.

PMID- 10407196
TI  - Age-related relationship between mRNA expression of GABA(B) receptors and calcium
      channel beta4 subunits in cacnb4lh mice.
AB  - In previous studies we found increased GABA(B) receptor number in 8-week-old
      homozygous Cacnb4lh mice compared to nonepileptic (+/+) littermates. In this
      study, we examined the relationship between Cacnb4 and GABA(B) receptor mRNA
      expression in brains from Cacnb4lh homozygotes and (+/+) controls. We found a
      significant correlation between the magnitude of increased GABA(B) receptor and
      decreased Cacnb4 mRNA expression in 8-week-old mice. In contract, in 6-month-old
      mice, there was no change in GABA(B) receptor or Cacnb4 mRNA expression. These
      findings suggest that the factor(s) responsible for decreased Cacnb4 and
      increased GABA(B) receptor mRNA expression abate in older mice.

PMID- 10407197
TI  - Magneto-encephalographic correlates of the lateralized readiness potential.
AB  - To determine the onset of movement-related EEG activity accompanying stimulus
      induced movements, it is commonly isolated from overlapping stimulus-related
      activity by a subtraction procedure, yielding the lateralized readiness potential
      (LRP). In order to elucidate the generation of the LRP and to explore whether
      magnetoencephalographic (MEG) measures have advantages over the LRP as a measure
      of response selection, MEG activity was recorded in four healthy adults during
      self-paced and stimulus-induced hand movements. Self-paced movements were
      preceded by readiness fields in all subjects, explained by sources in
      contralateral and (for 2/8 response sides) also ipsilateral hemispheres. Movement
      related activity preceding stimulus-induced movements could only be modeled
      adequately when stimulus-related activity was removed by subtracting MEG signals
      for left and right hand movements. Thus identified source locations showed no
      systematic deviation from the sources for readiness fields, supporting a
      generation of the movement-related activity in primary motor cortex. The
      corresponding source waveforms allowed latency determinations of motor cortex
      activity as markers for response-choice timing. MEG thus provides information on
      the time course of hand-specific motor cortex activation for each hemisphere
      separately, where the electro-encephalographic LRP provides a composite measure
      for both hemispheres.

PMID- 10407198
TI  - Memory in patients with subcortical infarction--an auditory event-related
      potential study.
AB  - Event-related potentials (ERPs) were recorded from 21 patients with subcortical
      infarction (mean age, 62.1 years) and 14 normal control subjects (mean age, 62.7
      years) as they listened to lists of words or pronounceable non-words. Some words
      were repeated immediately after initial presentation (lag 0), while others were
      repeated after five intervening words (lag 5), or after 2 to 4 min (lag 11-77).
      The subjects were asked to push a button upon hearing the occasional non-words.
      The Auditory-Verbal Learning Test (AVLT) also was administered to the patients to
      examine explicit memory. The mean N400 amplitude, appearing between 300 and 800
      ms after the stimulus, was smaller in patients with subcortical infarction than
      in control subjects. The N400 in response to repeated words at lags 0, 5 and 11
      77 was attenuated for both the patient and control groups. On the AVLT the total
      number of recalled words and number of words after interference were
      significantly decreased in patients relative to controls, while recognition was
      relatively preserved. The results suggest that lexical processing and retrieval
      mechanism of explicit memory are disturbed in patients with subcortical
      infarction, but implicit memory measured by this N400 paradigm is relatively
      preserved.

PMID- 10407199
TI  - Characteristics of visual evoked potentials generated by motion coherence onset.
AB  - Prior studies have shown that an electrophysiological correlate of visual motion
      processing can be found in the N2, a transient negativity occurring at about 200
      ms in the visual evoked potential (VEP). In most of the studies, N2 was triggered
      by the onset of a coherent motion. Results of our first experiment revealed that
      topography of the negative potential can be modified by motion direction
      information. In contrast to the onset of uncorrelated motion of pixels in a
      random dot kinematogram (RDK) correlated motion leads to an right hemispheric
      amplitude advantage. Hemispheric differences can be increased when the negativity
      is triggered by the onset of a coherent motion direction preceded by uncorrelated
      motion in RDKs. In a second experiment, we examined whether the negativity
      elicited by direction is related to the strength of the impression of motion
      direction measured psychophysically. The latter was modified by varying the
      percentage of correlated moving pixels in the RDK. Increasing the proportion of
      these 'direction signals' was associated with both an increase in the strength of
      the impression of motion direction and an increase in VEP amplitude. Mean
      correlations of electrophysiological and psychophysical data, which exceeded 0.7,
      revealed a higher sensitivity of the right hemisphere. The close relationship
      between the global motion impression and VEP negativity indicate that
      electrophysiological correlates of processing stages within visual motion
      analysis can be isolated. The recorded negativity seems to be associated
      primarily with the process of global motion integration.

PMID- 10407200
TI  - Dissociation of human caudate nucleus activity in spatial and nonspatial working
      memory: an event-related fMRI study.
AB  - We employed a novel event-related fMRI design and analysis technique to explore
      caudate nucleus contributions to spatial and nonspatial working memory. The
      spatial condition of a delayed-response task revealed greater mnemonic activation
      in four of six subjects when the delay period preceded immediately a probe
      stimulus requiring an overt motor response, as contrasted with a probe requiring
      no response. This effect was not seen in frontal or parietal cortical areas, and
      was seen in the caudate nucleus in a formally identical object condition in just
      one of six subjects. We hypothesized that this pattern of activity represented
      spatially dependent motor preparation. A second experiment confirmed this
      hypothesis: delay-period activity of the caudate nucleus showed greater time
      dependence in a task that featured spatial and motoric memory demands than in a
      comparable nonspatial task that featured the same response contingencies. These
      results suggest an important subcortical locus of the dissociation between
      spatial and nonspatial working memory, and a role for the human caudate nucleus
      in the integration of spatially coded mnemonic information with motor preparation
      to guide behavior.

PMID- 10407201
TI  - The time course of the BOLD response in the human auditory cortex to acoustic
      stimuli of different duration.
AB  - The relationship between activity within the human auditory cortices and the
      duration of heard tones was investigated by measuring the hemodynamic response
      with functional magnetic resonance imaging. We demonstrate that there is no
      significant influence of stimulus duration as used here on the intensity and
      spatial extent of the hemodynamic response in the auditory cortices. We found
      however, that the time course of the hemodynamic response to the repeated
      stimulus presentation exhibited a characteristic decline after the first stimulus
      exposure during the activation period. The possible reasons for this time course
      are currently unknown, however, several factors may be involved, including top
      down mechanisms and/or the interplay of tissue perfusion and oxygen consumption.

PMID- 10407202
TI  - Human face perception traced by magneto- and electro-encephalography.
AB  - The temporal and spatial processing of face perception in normal subjects was
      traced by magnetoencephalography (MEG) and electroencephalography (EEG). We used
      5 different visual stimuli: (1) face with opened eyes, (2) face with closed eyes,
      (3) eyes, (4) scrambled face, and (5) hand, and they were shown in random order.
      Subjects were asked to count the number of hand stimuli. To analyze the
      complicated brain responses to visual stimuli, we used brain electric source
      analysis (BESA) as the spatio-temporal multiple source model. In MEG recording,
      the 1M and 2M components were identified in all subjects. The 1M component was
      recorded to all kinds of stimuli. The 2M component was clearly identified only to
      face stimulation in all subjects, but to eyes stimulation in only 3 subjects with
      a small amplitude. The 2M component was not identified to scrambled face nor hand
      stimulation. The 2M component was recorded from the right hemisphere in all
      subjects, but in only 5 of 10 subjects from the left hemisphere. The mean peak
      latencies of the 1M and 2M components were approximately 132 and 179 ms,
      respectively. The interpeak latency between 1M and 2M was approximately 47 ms on
      average but the interindividual difference was large. There was no significant
      difference of the 2M latency between face with opened eyes and face with closed
      eyes. The 1M component was generated in the primary visual cortex in the
      bilateral hemispheres, and the 2M component was generated in the inferior
      temporal cortex, around the fusiform gyrus. In the EEG recording, face-specific
      components, positive at the vertex, P200 (Cz), and the negative at the temporal
      areas, N190 (T5') and N190 (T6'), were clearly recorded. The EEG results were
      fundamentally compatible with the MEG results. The amplitude of the component
      recorded from the right hemisphere was significantly larger than that from the
      left hemisphere. These findings suggest that the fusiform gyrus is considered to
      play an important role in face perception in humans, and that the right
      hemisphere is more dominant. Face perception takes place approximately 47 ms
      after the primary response to visual stimulation in the primary visual cortex,
      but the period of information transfer to the fusiform gyrus is variable among
      subjects. Detailed temporal and spatial analyses of the processing of face
      perception can be achieved with MEG.

PMID- 10407203
TI  - Effects of exogenous and endogenous attention on visually guided hand movements.
AB  - Attention can be directed to a peripheral location by either a peripheral visual
      stimulus or a central cue indicating the likely location of an upcoming target.
      The present study examined the effects of peripheral and central cuing on
      reaching. When the target was presented in a location different from that
      indicated by either type of attentional cue, movements with short latencies (<200
      ms) were mostly initiated toward the cued location. When the target was presented
      90 degrees away from the direction indicated by the attentional cue, movements
      with intermediate latencies (200-300 ms) were often initiated in directions
      intermediate between the cue and the target, and the latencies of movements
      initiated toward the target were prolonged. This suggests that the location of an
      attentional cue was utilized as an initial value in the process specifying
      movement direction, and this was gradually modified by signals related to target
      location. When peripheral and central cues were combined in the same trials,
      effects of peripheral cues were substantially diminished, compared to when they
      were examined separately. Furthermore, movements were seldom initiated in
      directions intermediate between the two cues, suggesting that effects of
      peripheral and central cues are combined independently from the process that
      specifies movement direction.

PMID- 10407204
TI  - Event-related neural activity associated with the Stroop task.
AB  - The time course of neural activity supporting performance during the Stroop task
      was investigated using event-related brain potentials (ERPs). Four spatially and
      temporally distinct modulations were observed differentiating the ERPs elicited
      by incongruent trials from the ERPs elicited by congruent, neutral, or word
      identification trials. Two of these modulations reflected increased negativity
      over the fronto-central region and positivity over the fronto-polar region for
      incongruent trials and may reflect conflict detection and resolution processes.
      The other modulations, distributed over the left parietal and temporo-parietal
      regions, may reflect the activity of a meaning-based conceptual level system
      active during congruent, neutral, and word identification trials; and the
      activity of a perceptual level system supporting task performance when only color
      information can guide an efficient response on incongruent trials.

PMID- 10407206
TI  - The recognition potential and the word frequency effect at a high rate of word
      presentation.
AB  - The short latency of the recognition potential (RP) suggests that it might be
      evoked at a high rate, which could speed noise reduction through averaging. Words
      were presented at 800 ms intervals. Mean RP latency for 16 subjects was 266 ms
      for high and 292 ms for low frequency words. The difference was statistically
      significant. The data suggest that word frequency affects an early stage of
      processing, which operates by the time the RP is evoked.

PMID- 10407205
TI  - Event-related potentials reveal memory deficits in Parkinson's disease.
AB  - To evaluate whether patients with Parkinson's disease (PD) exhibit deficits in
      memory tested indirectly, we measured event-related potentials (ERPs) in 23
      patients with nondemented PD and 14 age-matched control subjects. The auditory
      N400 component was measured during an indirect repetition priming paradigm. Some
      words were repeated immediately after initial presentation (lag 0), while others
      were repeated after five intervening words (lag 5) or at lags 11-77. Subjects
      were required to push a button to the occasional nonwords (targets). The N400
      amplitudes were quantified in latency window between 300 and 800 ms for the
      different conditions. The N400 amplitudes for the first presentation were
      significantly lower in PD patients than controls for both words and nonwords. The
      N400 in the control group was attenuated for lag 0, lag 5, and lags 11-77
      repetitions, while the attenuation in PD patients was noted only for lag 0
      repetition. The data suggest that memory assessed in this fashion is impaired in
      PD patients.

PMID- 10407207
TI  - Postconcussive symptoms in children with mild closed head injuries.
AB  - OBJECTIVE: To examine the incidence and neuropsychological, behavioral, and
      neuroimaging correlates of postconcussive symptoms (PCS) in children with mild
      closed head injuries (CHI). DESIGN: 26 Children with mild CHI and 8 of their
      uninjured siblings, from 8 to 15 years old, were recruited prospectively and
      assessed at baseline (ie, within 7 days of injury) and at 3 months postinjury.
      Parents rated PCS, motivation and affective lability, and behavioral adjustment.
      Baseline ratings assessed premorbid functioning retrospectively, and follow-up
      ratings assessed postinjury status. On both occasions, children completed
      neuropsychological testing, and those with mild CHI also underwent magnetic
      resonance imaging (MRI). RESULTS: Children with mild CHI did not differ from
      siblings in baseline ratings of premorbid PCS but displayed higher ratings on
      several PCS at 3 months postinjury. Thirty-five percent of children with mild CHI
      showed increases in PCS, compared with baseline premorbid ratings, but none of
      the siblings did so. Children with mild CHI whose PCS increased from premorbid
      levels showed poorer neuropsychological functioning at baseline than did children
      whose PCS did not increase, although the differences had partially resolved by 3
      months. They also displayed decreased motivation over time. Their behavioral
      adjustment was poorer and they had smaller white matter volumes on MRI, but the
      latter differences were present at baseline and did not change over time,
      suggesting that they existed prior to the injury. CONCLUSION: Postinjury
      increases in PCS occur in a sizable minority of children with mild CHI and more
      often than among uninjured siblings. Increases in PCS following mild CHI are
      associated with premorbid neurological and psychosocial vulnerability, but also
      with postinjury decrements in neuropsychological and neurobehavioral functioning.

PMID- 10407208
TI  - Prediction of neurobehavioral outcome 1-5 years post pediatric traumatic head
      injury.
AB  - OBJECTIVE: To examine the neurobehavioral status of children with traumatic head
      injury (THI) and to identify variables that predict outcome. DESIGN:
      Retrospective chart review, with follow-up 1-5 years after injury. Outcome
      predictor variables were identified through stepwise regression analysis.
      SETTING: Level one trauma center and pediatric rehabilitation program. PATIENTS:
      71 Children with THI, selected from a four-year series of consecutive admissions.
      MEASURE: Vineland Adaptive Behavior Scales-Survey Edition. RESULTS: Significant
      predictors of better neurobehavioral status at follow-up included absence of a
      premorbid learning problem (p <.01), older age at injury (p <.01), and normal
      pupillary response (p <.001) and higher cerebral perfusion pressure (p <.0001)
      during critical care management. CONCLUSIONS: Neurobehavioral outcome after THI
      is influenced by premorbid psychosocial variables as well as by critical care
      management.

PMID- 10407209
TI  - Cognitive and behavioral outcome following mild traumatic head injury in
      children.
AB  - OBJECTIVES: To investigate outcome in children with mild traumatic head injury
      (THI) at 1 week and 3 months postinjury and to identify factors associated with
      persisting problems. DESIGN: Postconcussional symptomatology, behavior ratings,
      and neuropsychological test performance were examined at 1 week and 3 months
      postinjury. SETTING: Participants were recruited from successive presentations to
      emergency departments of two major hospitals. PARTICIPANTS: 130 Children with
      mild THI were compared with 96 children having other minor injuries as controls.
      RESULTS: Children with mild THI experienced headaches, dizziness, and fatigue but
      exhibited no cognitive impairments, relative to controls, at 1 week postinjury.
      By 3 months, symptoms had resolved. However, 17% of children showed significant
      ongoing problems. They were more likely to have a history of previous head
      injury, learning difficulties, neurological or psychiatric problems, or family
      stressors. CONCLUSIONS: Persisting problems following mild head injury in
      children are more common in those with previous head injury, preexisting learning
      difficulties, or neurological, psychiatric, or family problems. These "at-risk"
      children should be identified in the emergency department and monitored.

PMID- 10407210
TI  - Empirically supported psychological and behavioral therapies in pediatric
      rehabilitation of TBI.
AB  - This article examines the empirical support for psychological therapies for
      children with traumatic brain injury (TBI). Empirical support for psychological
      treatments of noninjured children provides a foundation upon and a framework in
      which to discuss applications to children with neurobehavioral dysfunction.
      Behavioral interventions to address externalizing behaviors have received the
      greatest focus, whereas there is a paucity of work that pertains to internalizing
      features and prosocial behavior such as assertiveness. Although the systematic
      study of psychological intervention lags far behind the rapidly increasing
      knowledge of neurobehavioral sequelae to TBI, there are promising directions that
      stem from initial findings.

PMID- 10407211
TI  - Pediatric family-centered rehabilitation.
AB  - Family-centered rehabilitation programs are derived from a philosophy of heath
      care delivery known as family-centered care. The principles of family-centered
      care are presented with clinical examples. Its origins are reviewed, and the 10
      year process of implementation of family-centered care practice and policy at a
      children's rehabilitation center are described. Profound changes in behavior are
      required of the health care professionals as meaningful collaboration with
      families develops. Key elements of a family-centered rehabilitation program
      include meaningful participation by families in medical decision making and an
      institutional culture flexible enough to respond to the ongoing collaboration
      between families and practitioners.

PMID- 10407212
TI  - The family burden of injury interview: reliability and validity studies.
AB  - OBJECTIVE: To assess the reliability and validity of a new instrument, the Family
      Burden of Injury Interview (FBII) was designed to assess the impact of childhood
      traumatic head injuries (THI) on the family. PARTICIPANTS: 99 Mothers of school
      age children who experienced THI. RESULTS: The FBII Total Score revealed group
      differences between families of children with severe THI and families of children
      with moderate THI. The measure also showed concurrent and predictive
      relationships to measures of the general impact of injury on families and
      maternal and child functioning. CONCLUSION: The FBII is a promising tool for
      measuring the impact of injury-related stressors on the family.

PMID- 10407213
TI  - Neuroimaging in pediatric traumatic head injury: diagnostic considerations and
      relationships to neurobehavioral outcome.
AB  - Contemporary neuorimaging techniques in child traumatic brain injury are
      reviewed, with an emphasis on computerized tomography (CT) and magnetic resonance
      (MR) imaging. A brief overview of MR spectroscopy (MRS), functional MR imaging
      (fMRI), single-photon emission computed tomography (SPECT), and
      magnetoencephalography (MEG) is also provided because these techniques will
      likely constitute important neuroimaging techniques of the future. Numerous
      figures are provided to illustrate the multifaceted manner in which traumatic
      deficits can be imaged and the role of neuroimaging information as it relates to
      TBI outcome.

PMID- 10407214
TI  - Brain injury, cognitive impairment, and donepezil.

PMID- 10407215
TI  - Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their
      receptors on tumors.
AB  - In view of non-specific toxicity of most chemotherapeutic agents against normal
      cells, the development of targeted chemotherapy is warranted. Efficient targeting
      of chemotherapeutic drugs to the cancerous area could be of great benefit for
      patients with advanced or metastatic tumors. Targeted cytotoxic peptide
      conjugates are hybrid molecules composed of a peptide carrier which binds to
      receptors on tumors and a cytotoxic moiety. New cytotoxic analogs of LHRH, AN-152
      in which doxorubicin (DOX) is linked to [d-Lys(6)]LHRH, and AN-207 which consists
      of 2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity
      binding and are much less toxic and more effective in vivo than their respective
      radicals in inhibiting tumor growth in LHRH receptor-positive models of human
      ovarian, mammary, or prostatic cancer. These results suggest that targeted
      cytotoxic LHRH analogs such as AN-207 could be considered for treatment of these
      cancers. The presence of receptors for bombesin-like peptides on a wide variety
      of tumors prompted us to use some of our bombesin/gastrin-releasing peptide
      antagonists as carrier molecules. Cytotoxic bombesin analogs, such as AN-215
      containing AN-201, might find application in the treatment of small cell lung
      carcinoma (SCLC), and colorectal, gastric, pancreatic, mammary, and prostatic
      cancers. Since somatostatin receptors are found in various human neoplasms and
      the receptor subtypes to which octapeptide analogs bind with high affinity have
      been identified, we synthesized several cytotoxic somatostatin analogs including
      AN-162 and AN-238 containing DOX and 2-pyrrolino-DOX respectively, linked to
      octapeptide RC-121. Cytotoxic somatostatin analog AN-238 efficaciously inhibits
      growth of human breast or prostate cancers expressing somatostatin receptors-2
      and -5 and can be used for receptor-targeted chemotherapy. Cytotoxic somatostatin
      analogs might also find applications for the therapy of human pancreatic,
      colorectal, and gastric cancer as well as brain tumors and non-SCLC. Cytotoxic
      compounds linked to analogs of hormonal peptides like LHRH, bombesin, and
      somatostatin that can be targeted to certain tumors possessing receptors for
      those peptides could be an important addition to oncological armamentarium.

PMID- 10407216
TI  - Mechanisms of multiple endocrine neoplasia type 1: evidence for regulation of the
      AP-1 family of transcription factors by menin.

PMID- 10407218
TI  - Exercise-induced GH secretion is enhanced by the oral ingestion of melatonin in
      healthy adult male subjects.
AB  - There is evidence that melatonin may play a role in modulating pituitary
      secretion, although the mechanisms are unclear. We examined the effects of a
      single dose of oral melatonin (5mg) on exercise-induced GH secretion. In a
      randomised, double-blind, placebo-controlled study, seven healthy male subjects
      undertook an initial period of graded bicycle ergometric exercise to determine
      maximum workload and oxygen uptake (VO(2max)). Subjects were subsequently studied
      on two further occasions, receiving either melatonin or placebo in random order
      at the onset of each study (-60min). At 0 min a period of bicycle exercise was
      performed for 8 min at a workload corresponding to 70% of that achieved at
      VO(2max). Serum GH and IGF-binding protein-1 (IGFBP-1) concentration was measured
      at 15-min intervals from the onset of the study until 120 min post-exercise.
      Blood was also sampled for the measurement of plasma glucose, insulin, non
      esterified fatty acids, IGFBP-3, melatonin and vasopressin concentration. There
      was an exercise-induced increase in GH concentration following melatonin which
      was greater compared with placebo as assessed by both area under the curve
      (P<0.01) and peak increase in GH levels (P<0.01). The peak increase in IGFBP-1
      levels post-exercise was also significantly greater following melatonin compared
      with placebo (P<0. 01) but did not quite reach levels of significance as measured
      by area under the curve (P=0.07). Since exercise-induced GH secretion is thought
      to be mediated predominantly through a hypothalamic pathway, it seems likely that
      melatonin facilitates GH secretion at a hypothalamic level.

PMID- 10407217
TI  - Effect of TRH on beta-gonadotropin subunits in patients with pituitary
      microincidentalomas.
AB  - OBJECTIVE: To explore the hypothesis that most of the pituitary abnormalities
      compatible with the diagnosis of microadenoma, and detected in about 10% of the
      normal adult population, represent asymptomatic gonadotropinomas. DESIGN:
      Patients diagnosed with pituitary microincidentalomas at the Institute of
      Endocrinology of the Tel Aviv Medical Center were evaluated. Circulating beta
      subunits of gonadotropin hormones were measured before and 30, 45, 60 and 90 min
      after the intravenous injection of 400 microgram TRH. PATIENTS: Twenty-two
      patients with pituitary incidentaloma and 16 normal volunteers were tested.
      RESULTS: In 16 of the 22 patients, an abnormal beta-subunit response was detected
      after the TRH challenge. Three patients had an abnormal increase in both beta-FSH
      and beta-LH after TRH administration. Isolated pathological beta-FSH or beta-LH
      responses were demonstrated in five and eight patients respectively. Six patients
      had normal basal and stimulated gonadotropin subunit values, raising the
      possibility that their lesions were not pituitary microadenomas. There was a
      significant overall difference between the response to TRH of the patient and
      control groups. In the gonadotropin positive group, comprising 16 patients, serum
      beta-FSH increased from 6.4+/-1.6 ng/ml to 9.2+/-1.3 ng/ml (P=0.042) 1 h after
      TRH stimulation, whereas no changes were detected in the control group after TRH
      injection (basal: 4.1+/-0.8 ng/ml, peak: 5.1+/-0.8 ng/ml; P=0.15). Serum beta-LH
      increased from 10.5+/-3.2 ng/ml to 23.4+/-4.9 ng/ml (P=0.0037) at this time, in
      contrast to a lack of response in controls (basal: 6.4+/-1.5 ng/ml, peak: 8.2+/
      2.3 ng/ml; P=0.24). CONCLUSION: In about 73% of patients with pituitary
      incidentalomas smaller than 10 mm, TRH elicits an increase in gonadotropin beta
      subunits. This observation raises the possibility that non-functioning pituitary
      micro- and macroadenomas, which share a similar response to TRH, originate in a
      common ancestor cell type, probably a pituitary gonadotrope.

PMID- 10407219
TI  - Sexual dimorphism in the maturation of the pituitary-gonadal axis, assessed by
      GnRH agonist challenge.
AB  - OBJECTIVE: To assess whether the maturational changes of the pituitary--gonadal
      axis in a healthy population show gender-specific changes and to establish
      normative data for the different Tanner stages. DESIGN: Prospective, cross
      sectional study. METHODS: The GnRH agonist leuprolide acetate (500 microgram) was
      administered s.c. to 60 boys and 81 girls (age range, 5--17 years). Serum
      steroids and gonadotropins were determined at 0 and 24 h and at 0, 3 and 24 h
      after GnRH agonist challenge respectively, whereas IGF-I, IGF-binding protein-1
      (IGFBP-1), IGFBP-3 and sex hormone-binding globulin were measured at baseline.
      RESULTS: Baseline and peak LH responses to the agonist in late puberty, and basal
      and peak FSH levels at all Tanner stages, were higher in girls than in boys.
      Girls showed higher IGF-I levels than boys throughout puberty, sharper decreases
      in IGFBP-1 and earlier and greater increases in 17-hydroxypregnenolone,
      dehydroepiandrosterone (DHEA) and DHEA-sulfate. Testosterone responses to the
      agonist increased during puberty in males, and showed no changes in females.
      Conversely, estradiol responses rose throughout puberty in females and remained
      unchanged until late puberty in males. CONCLUSION: Leuprolide acetate stimulates
      gonadotropin and gonadal steroid secretion during puberty in both sexes and
      increases FSH levels in prepubertal girls. Pubertal maturation of gonadotrope
      function is gender specific, as it appears to involve increases in both the
      releasable and reserve pools of LH in males, and of LH and FSH in females. The
      earlier increase in Delta(5)-steroids in girls may suggest a sharper rise in
      ovarian cytochrome P450c17 activity along the Delta(5)-steroid pathway, while the
      failure of estradiol to increase in response to leuprolide acetate in early
      pubertal males suggests a late maturation of aromatase activity.

PMID- 10407220
TI  - Protective effect of dehydroepiandrosterone against lipid peroxidation in a human
      liver cell line.
AB  - OBJECTIVE: Dehydroepiandrosterone (DHEA) is a widely studied steroid hormone with
      multi-functional properties. Reports suggest that some of the many activities of
      DHEA are due to its protective effect against lipid peroxidation. Nevertheless,
      the antioxidant properties of DHEA are still the subject of debate. The aim was
      to evaluate whether its two opposed effects on lipid peroxidation reported in the
      literature may be dependent on schedule and doses used. METHODS: Chang liver
      cells, a line derived from normal human liver, were grown in media containing
      either no steroids (control) or DHEA at concentrations ranging from 0.1
      micromol/l to 50 micromol/l. At specific times, cultures were halted and cells
      received a pro-oxidant stimulus (cumene (CuOOH) 0.5 mmol/l), at which time cell
      viability (by trypan blue staining and lactate dehydrogenase (LDH) release) and
      thiobarbituric acid reactive substances (TBARS) concentration
      (spectrophotometrical assay) were evaluated. RESULTS: At concentrations ranging
      from 0.1 micromol/l to 1 micromol/l, DHEA protects Chang liver cells against
      lipid peroxidation and/or death induced by cumene. This effect disappears if the
      concentration is increased to 10 micromol/l; at higher concentrations (50
      micromol/l) a pro-oxidant/cytotoxic effect of DHEA appears. CONCLUSIONS: DHEA
      exhibits two opposed effects on lipid peroxidation; depending on its
      concentration it acts either to limit or to induce oxidative stress. The
      threshold concentration at which the pro-oxidant activity of DHEA prevails is not
      far in excess of that having an antioxidant effect. Either effect of DHEA on
      lipid peroxidation is only evident after a 'lag-phase'.

PMID- 10407221
TI  - Effects of anabolic-androgenic steroid use or gonadal testosterone suppression on
      serum leptin concentration in men.
AB  - OBJECTIVE: Serum leptin concentration shows a sexual dimorphism that is not
      accounted for by gender differences in adiposity. A strong inverse association
      exists between serum leptin and testosterone concentrations in men, pointing to a
      likely influence of gonadal sex steroids on serum leptin concentration. The aim
      of this study was to investigate whether manipulation of sex steroid hormones in
      men would alter serum leptin concentration independently of changes in fat mass.
      DESIGN AND METHODS: The effects of sex steroid suppression on serum leptin
      concentration were investigated in nine healthy men in whom testosterone had been
      reversibly suppressed for 5 weeks after treatment with intramuscular triptorelin.
      The effects of sex steroid supplementation were investigated in nine male
      bodybuilders who self-administered anabolic--androgenic steroids (AAS) for a mean
      period of 6.5 weeks. A control group received no hormonal treatment. RESULTS:
      Testosterone concentration was significantly reduced by triptorelin
      administration (7.32+/- 1.92ng/ml at baseline compared with 1.15+/-0.57ng/ml at 5
      weeks, P=0.002). High-dose AAS use was confirmed by urine analysis. Body fat
      percentage was unaffected by the AAS or triptorelin intervention (P>0.19). Leptin
      concentration was significantly reduced after one cycle of AAS use (2.40+/-0.
      98ng/ml off cycle compared with 1.63+/-0.37ng/ml on cycle, P=0.012), and was
      significantly increased by triptorelin administration (2. 96+/-1.50ng/ml at
      baseline compared with 6.63+/-4.67ng/ml at five weeks, P=0.004). No significant
      change occurred in the control group. CONCLUSION: Androgenic sex hormone
      supplementation decreases serum leptin concentration, whereas suppression
      increases serum leptin concentration, independently of changes in body fat mass
      in healthy men. The sexual dimorphism evident in serum leptin concentration is
      likely to be due to a suppressive effect of testosterone on serum leptin
      concentration in males.

PMID- 10407222
TI  - Plasma pancreatic polypeptide response to secretin.
AB  - OBJECTIVE: Intravenously administered secretin stimulates pancreatic polypeptide
      (PP) release in patients with endocrine enteropancreatic tumors, but data in
      patients with nontumorous disorders are controversial. Therefore, we aimed to
      evaluate the plasma PP pattern after secretin administration in healthy subjects
      and in patients with gastroduodenal diseases investigated for recurrent ulcer
      disease and/or hypergastrinemia. METHODS: Synthetic secretin was given as an
      intravenous bolus (2U/kg) in ten patients with Zollinger Ellison syndrome, ten
      with duodenal ulcer, ten with atropic gastritis and ten healthy volunteers. Blood
      samples were taken before and at regular intervals for 30min after secretin
      injection. Plasma PP and gastrin levels were measured by radioimmunoassay.
      RESULTS: Secretin promptly and significantly (P<0.01) increased PP plasma levels
      in all groups of subjects without any differences in peak values. There were no
      significant correlations between PP and gastrin plasma levels. CONCLUSIONS:
      Secretin at pharmacological doses is a powerful stimulus for PP release.

PMID- 10407223
TI  - Premenstrual attacks of acute intermittent porphyria: hormonal and metabolic
      aspects - a case report.
AB  - We report the case of a 38-year-old woman with acute intermittent porphyria
      (AIP). Following the observation of an acute AIP attack in the patient's father,
      the diagnosis was established after genetic and biochemical examinations. At the
      age of 29, eight months after delivery of her first and only child, the patient
      was hospitalized due to a first proven attack of AIP. In the following years she
      suffered several premenstrual AIP attacks, with clinical symptoms ranging from
      abdominal pain to paralysis. One attack was accompanied by an increased urinary
      catecholamine output, strongly indicating adrenergic hyperactivity. The
      precipitation of acute episodes by secretion of gonadotrophins and a severe
      hyponatraemia due to a syndrome of inappropriate anti-diuretic hormone secretion
      indicated hypothalamic involvement in the pathogenesis of AIP. This patient has
      experienced an evolution of treatment regimens. At first, acute attacks were
      treated by i.v. hypertonic glucose. Afterwards propranolol was instituted as a
      maintenance therapy. Later on, i.v. injections of haem arginate were very
      successful in resolving acute AIP episodes. However, until therapy with an LHRH
      analogue was started, the patient continued to suffer premenstrual AIP attacks.
      These LHRH analogues cause hypothalamic inhibition of gonadotrophin secretion,
      with stabilization of endogenous ovarian steroid production at a low level, and
      therefore may be effective in preventing acute exacerbations of this disease.
      Since this patient went on a fixed regimen of an LHRH analogue combined with the
      lowest dose oestrogen patch her quality of life has improved substantially and
      she has not required hospitalization, now for over 3 years.

PMID- 10407224
TI  - Presence of a soluble inhibitor of thyroid iodination in primary cultures of
      thyroid cells.
AB  - Monolayer cultures of thyroid cells lose their iodide organification capacity a
      few days before the disappearance of thyroid peroxidase (TPO) activity. The
      present studies were performed in order to clarify this point. The above
      mentioned difference was due to the presence of an inhibitor in the monolayer
      thyroid cells culture, given that total homogenate prepared from confluent cells
      caused a significant inhibition of activity of TPO from fresh tissue. The
      inhibitor was localized in the 105000g supernatant of the homogenate of the cell
      culture, but not in a similar preparation obtained from fresh thyroid. It is
      thermostable, dialyzable and has a molecular weight of less than 2 kDa. Addition
      of the inhibitor at the end of the reaction of tyrosine iodination failed to
      alter the results. This fact suggests that the compound does not destroy the
      iodinated product. The presence of the cytosolic inhibitor was observed in
      monolayer thyroid cell cultures of different species (bovine, porcine, rat and
      human) but not in free follicles cultures.

PMID- 10407225
TI  - Thyrotropin regulates tyrosine sulfation of thyroglobulin.
AB  - OBJECTIVE: To study the regulation of thyroglobulin sulfation by thyrotropin
      (TSH) and iodide. Sulfation, a widespread post-translational modification of
      proteins, is involved in various biological activities. Thyroglobulin has been
      reported to be sulfated but, to date, the role of sulfate residues in the
      metabolism and function of thyroglobulin is not known; moreover, the regulation
      of thyroglobulin sulfation has not been yet investigated. METHODS: The effect of
      TSH on thyroglobulin sulfation was studied in porcine thyroid cells cultured on
      porous collagen-coated filters. Cells cultured with or without TSH and with or
      without iodide (KI) were incubated for 4 days with radioactive sulfate. The
      specific radioactivity of thyroglobulin subunit (330kDa) was determined from
      apical media analyzed by electrophoresis. Enzymatic hydrolysates of the purified
      thyroglobulin were separated by oligosaccharide affinity chromatography and thin
      layer chromatography; alkaline hydrolysates were analyzed only by thin-layer
      chromatography. RESULTS: Thyroglobulin secreted by TSH-stimulated cells
      incorporated about twofold less radioactive sulfate. Iodide slightly modified
      this incorporation. Enzymatic hydrolysates of purified thyroglobulin showed
      sulfate residues bound essentially to complex oligosaccharide units. Alkaline
      hydrolysis was necessary to release all sulfated amino acids (tyrosine and
      serine). In the absence of TSH the proportion of tyrosine sulfate was
      dramatically increased: 24% compared with 7% (+KI) or 5% (-KI). The ratio of
      specific radioactivity of thyroglobulin to the specific radioactivity of
      intracellular inorganic sulfate (determined in each culture condition) gave the
      number of sulfated residues incorporated: 46 (-TSH) and 31 (+TSH) per mol
      thyroglobulin. From this distribution, we deduced the number of residues bound to
      complex oligosaccharide units and to tyrosine. Thus TSH decreased the number of
      sulfate residues on tyrosine from 11 to 2 per mol thyroglobulin. CONCLUSIONS: TSH
      regulates the binding of sulfate groups to tyrosine residues. Iodide exerts a
      slight control over this process.

PMID- 10407226
TI  - Prolonged low-dose infusion of human parathyroid hormone does not increase
      femoral cancellous bone volume in ovariectomized rats.
AB  - OBJECTIVE: Daily injections of human parathyroid hormone (hPTH) increase bone
      volume in various animal species and in osteoporotic women. For hPTH to be widely
      accepted as an anabolic therapy for treating postmenopausal osteoporosis
      alternative delivery options need to be explored to replace the need for daily
      patient subcutaneous self-injection. Among these are inhalation, oral delivery
      and the use of programmable implanted minipumps to deliver the peptide. While
      infusion of high doses of PTH causes bone loss and hypercalcemia, no studies have
      assessed the effects of prolonged infusion of low doses of PTH on bone growth.
      DESIGN AND METHODS: [Leu(27)]-cyclo(Glu(22)-Lys(26))-hPTH-(1--31)NH(2) was
      delivered by Alzet minipumps to ovariectomized rats for 6 weeks after which
      histomorphometric indices (cancellous bone volume, trabecular thickness, mean
      trabecular number) of bone formation were measured in distal femurs. RESULTS:
      Infusing low doses (0.05 and 0.1 nmole/100g body weight/day) of the hPTH analog,
      [Leu(27)]-cyclo(Glu(22)-Lys(26))-hPTH-(1--31)NH(2), for 6 weeks does not prevent
      the ovariectomy-induced loss of rat femoral cancellous bone volume, trabecular
      thickness or trabecular number. CONCLUSION: These results support the absolute
      requirement of daily injections for the osteogenic action of hPTH on bone.

PMID- 10407228
TI  - The secretory patterns of growth hormone in pregnant and hysterectomized ewes.
AB  - This work was undertaken to determine the secretory patterns of GH during
      pregnancy, and to evaluate the effect, if any, of hysterectomy during early
      pregnancy on subsequent secretion of GH in ewes. The concentrations of GH were
      determined in the plasma of jugular blood samples collected at 15-min intervals
      during a 6-h period on days 20, 40, 60, 80, 100 and 120 post-mating, and three
      times per week between days 29 and 120 post-mating from 5 pregnant ewes and from
      5 ewes from which the gravid uterus was removed on day 30 post-mating. A pulse
      analysis program (Pulsar) was used to analyse the secretory patterns of GH in
      individual profiles of the serial sampling period. In the two groups of ewes,
      peripheral concentrations of GH fluctuated in an episodic manner during the
      frequent blood sampling of any stage of the post-mating period examined. The
      overall GH concentrations, the basal GH concentrations, the frequency and the
      amplitude of GH pulses remained fairly stable between days 20 and 120 post-mating
      in the two groups of ewes. The parameters of GH secretion were not different
      between the two groups of ewes. The secretory patterns of GH, as determined in
      plasma of blood collected three times per week between days 29 and 120 post
      mating were also not different between the two groups of ewes. In conclusion,
      results of this study show that (i) the pulsatile secretion of GH does not change
      as pregnancy advances, and (ii) hysterectomy performed during early pregnancy
      does not subsequently affect the secretory patterns of GH. These findings suggest
      that the gravid uterus and/or the feto-placental unit secretory products are
      unlikely to be involved in the control of GH secretion during pregnancy in the
      ewe.

PMID- 10407227
TI  - Method of transfection affects the cAMP-mediated induction of the RIIbeta subunit
      of protein kinase A in Sertoli cells: inhibition of response by increase in
      intracellullar calcium.
AB  - mRNA for the regulatory subunit RIIbeta of cAMP-dependent protein kinase is
      stimulated more than 50-fold by cAMP in primary cultures of rat Sertoli cells. We
      have previously shown that this induction involves regulation of transcriptional
      activation as well as mRNA stabilization. The rat RIIbeta gene contains no cAMP
      response element (CRE), and the induction of RIIbeta mRNA is slow and requires on
      going protein synthesis. When a construct containing the 5'-flanking region of
      the RIIbeta gene upstream of a CAT reporter was transfected into Sertoli cells by
      the calcium phosphate method, low and variable responses to cAMP (three- to
      fivefold) were observed, whereas a 15- to 20-fold increase in reporter activity
      by cAMP was observed after lipofectamine transfection. Interestingly, when a
      vector containing CRE elements upstream of a reporter gene was transfected into
      Sertoli cells, the responses to cAMP were similar regardless of the transfection
      method used. We have also demonstrated that increased intracellular levels of
      calcium by A23187 and thapsigargin dramatically inhibit cAMP-mediated induction
      of RIIbeta mRNA, but not the mRNA for the CRE-containing RIalpha gene.
      Furthermore, decreased cAMP responsiveness of endogenous RIIbetamRNA (but not
      RIalpha) was also observed in calcium phosphate-transfected Sertoli cells but not
      in lipofectamine-transfected cells. Thus, calcium-mediated reduction in cAMP
      response appears to be a gene-specific phenomenon.

PMID- 10407229
TI  - Missense variants in the human peroxisome proliferator-activated receptor-gamma2
      gene in lean and obese subjects.
AB  - The peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) is almost
      uniquely expressed in adipose tissue and is of major importance for fat cell
      differentiation and lipid metabolism. This study was undertaken to assess whether
      two missense variants in the PPARgamma2 gene are associated with early-onset
      obesity. A previously described polymorphism encoding for an amino acid exchange
      in codon 12 (Pro12Ala) was detected with allele frequencies of 0.13 in 296
      markedly obese children and adolescents and 0.14 in 130 lean individuals. A
      Pro115Gln variant, which had been linked to obesity in Germans in a previous
      association study, was not detected in any of our obese or lean subjects, who are
      also of German origin. We conclude from our data that these two variants in the
      PPARgamma2 gene are unlikely to contribute to the high prevalence of early-onset
      obesity.

PMID- 10407230
TI  - Estimating the sample size for a t-test using an internal pilot.
AB  - If the sample size for a t-test is calculated on the basis of a prior estimate of
      the variance then the power of the test at the treatment difference of interest
      is not robust to misspecification of the variance. We propose a t-test for a two
      treatment comparison based on Stein's two-stage test which involves the use of an
      internal pilot to estimate variance and thus the final sample size required. We
      evaluate our procedure's performance and show that it controls the type I and II
      error rates more closely than existing methods for the same problem. We also
      propose a rule for choosing the size of the internal pilot, and show that this is
      reasonable in terms of the efficiency of the procedure.

PMID- 10407231
TI  - Analysing repeated measurements data: a practical comparison of methods.
AB  - A variety of methods are available for analysing repeated measurements data where
      the outcome is continuous. However, there is little information on how
      established methods, such as summary statistics and repeated measures analysis of
      variance (RMAOV), compare in practice with methods that have become available to
      applied statisticians more recently, such as marginal models (based on
      generalized estimating equation methodology) and multilevel models (that is,
      hierarchical random effects models). The aim of this paper is to exemplify the
      use of these methods, and directly compare their results by application to a
      clinical trial data set. The focus is on practical aspects rather than technical
      issues. The data considered were taken from a clinical trial of treatments for
      asthma in 240 children, in which a baseline and four post-randomization
      measurements of outcomes were taken. The simplicity of the method of summary
      statistics using the post-randomization mean of observations provided a useful
      initial analysis. However, fixed time effects or treatment-time interactions
      cannot be included in such an analysis, and choice of appropriate weighting when
      there is substantial missing data is problematic. RMAOV, marginal models and
      multilevel models generally provided similar estimates and standard errors for
      the treatment effects, although in one example with a relatively complex variance
      structure the marginal model produced less efficient estimates. Two advantages of
      multilevel models are that they provide direct estimates of variance components
      which are often of interest in their own right, and that they can be naturally
      extended to handle multivariate outcomes.

PMID- 10407232
TI  - Case-control isotonic regression for investigation of elevation in risk around a
      point source.
AB  - Stone's isotonic regression method for analysing count data to estimate disease
      risk in relation to a point source of environmental pollution is now routinely
      used. This paper develops the corresponding procedure for case-control data
      consisting of the locations of individual cases with controls with associated
      covariate information. In this setting, the generalized likelihood ratio
      statistic to test the null hypothesis of constant risk against the alternative
      that risk is a monotone non-increasing function of distance from the point source
      is intractable. An approximate Monte Carlo test is described, extending an exact
      test proposed by Bithell for the situation in which there are no covariates.
      Interval estimates of risk as a function of distance from the point source are
      constructed by simulation of the sampling distribution of the isotonic regression
      estimator. The methodology is illustrated by two applications: one to the
      relative risk of larynx cancers and lung cancers near a now-disused industrial
      incinerator; the other to the risk of asthma in children in relation to distance
      of residence from the nearest main road.

PMID- 10407233
TI  - A threshold causal model for clinical trials with departures from intended
      treatment.
AB  - Randomized clinical trials often are planned to study a specific intervention.
      However, the collection of data on treatment actually received often reveals
      variable levels of treatment exposure (or 'dose') across subjects, due to non
      compliance or other reasons. This paper presents a new method, using such 'dose'
      data as well as control group responses, to assess a causal dose-response
      relationship. The specific model utilizes a threshold function and incorporates a
      random effect term to allow for heterogeneous treatment responses among subjects.
      Further modelling of the random effects allows for reduction of error variance
      and control for potential confounders. The threshold dose is estimated using a
      residual variance criterion based on a transformed model. Estimates of standard
      errors and confidence intervals are obtained using a bootstrap procedure. The
      method is applied to data from an AIDS clinical trial. A simulation study
      demonstrates the adequacy of the threshold estimates for particular sample sizes
      and error variances. The limitations of this essentially exploratory method, as
      well as some possible extensions, are discussed. 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- 10407234
TI  - Monte Carlo estimation of extrapolation of quality-adjusted survival for follow
      up studies.
AB  - The expected quality-adjusted survival (QAS) for an index population with a
      specific disease can be estimated by summing the product of the survival function
      and the mean quality of life function of the population. In many follow-up
      studies with heavy censoring, the expected QAS may not be well estimated due to
      the lack of data beyond the close of follow-up. In this paper, we first created a
      reference population from the life tables of the general population according to
      the Monte Carlo method. Secondly, we fitted a simple linear regression line to
      the logit of the ratio of quality-adjusted survival functions for the index and
      reference populations up to the end of follow-up. Finally, combining information
      on the reference population with the fitted line, we predicted the expected
      quality-adjusted survival curve beyond the follow-up period for the index
      population. Simulation studies have shown that the simple Monte Carlo estimation
      procedure is a potential approach for estimating expected QAS and the survival
      function beyond the follow-up with a certain degree of accuracy.

PMID- 10407235
TI  - A test to detect replication in HIV serological data labelled by birth date based
      on the number of matching pairs in a sample.
AB  - Diagnoses of HIV infection are reported to the Public Health Laboratory Service
      (PHLS) by microbiologists through a voluntary confidential surveillance scheme.
      Names are not recorded on the database but the date of birth of the individual
      concerned is usually available. This paper discusses a statistical method to
      detect repeated counting of individuals in these and similar data based on the
      number of matching pairs in the sample. The test is based on the theoretical
      result that the null hypothesis of all birth dates equally likely and all
      individuals distinct minimizes the expected number of matching pairs in the
      sample. Five of the 16 birth years in the sample taken in 1991 show evidence of
      more replication than would be expected by chance using a 5 per cent level test.
      When the test is repeated taking into account a small but statistically
      significant seasonal variation in the birth rate, the results are very similar.

PMID- 10407236
TI  - Use of hierarchical models for meta-analysis: experience in the metabolic ward
      studies of diet and blood cholesterol.
AB  - Overviews that combine single effect estimates from published studies generally
      use a summary statistic approach where the effect of interest is first estimated
      within each study and then averaged across studies in an appropriately weighted
      manner. Combining multiple regression coefficients from publications is more
      problematic, particularly when there are differences in study design and
      inconsistent reporting of effect sizes and standard errors. This paper describes
      the use of a hierarchical model in such circumstances. Its use is illustrated in
      a meta-analysis of the metabolic ward studies that have investigated the effect
      of changes in intake of various dietary lipids on blood cholesterol. These
      studies all reported average blood cholesterol for groups of individuals who were
      studied on one or more diets. Thirty-one studies had randomized cross-over
      designs, 12 had matched parallel group designs, 12 had non-randomized Latin
      square designs and 16 had other uncontrolled designs. The hierarchical model
      allowed the different types of comparison (within-group between-diet, between
      matched group) that were made in the various studies to each contribute to the
      overall estimates in an appropriately weighted manner by distinguishing between
      study variation, within-study between-matched-group variation and within-group
      between-diet variation. The hierarchical models do not require consistent
      specification of effect sizes and standard errors and hence have particular
      utility in combining results from published studies where the relationships
      between a dependent variable and two or more predictors have been investigated
      using heterogeneous methods of analysis.

PMID- 10407237
TI  - The analysis of a bivariate multi-state Markov transition model for rheumatoid
      arthritis with an incomplete disease history.
AB  - In many long-term chronic diseases, patients pass through an observable sequence
      of ordered clinical states as their condition progressively worsens. Often the
      information on which disease state the patient is in is incompletely recorded,
      usually with information only available on the occasion of a clinic visit. This
      article describes a novel analysis of data from a clinical trial, in which
      several such outcome measures of disease state have been recorded simultaneously.
      The article is motivated by the analysis of a multi-centre double-blind placebo
      controlled clinical study into the effect of continual low dose corticosteroid
      treatment on the progression of X-ray scores for patients with rheumatoid
      arthritis. Previous methods of analysis of such data have been based on an
      independence analysis, thus ignoring any correlation that may exist between the
      outcomes. This article shows that such an approach can lead to biased
      underestimates of the covariate effects if an independence model is used. Biased
      estimates of the covariate effects were found when the model was fitted to the
      trial data. The bivariate model was also shown to provide a significantly better
      fit to the data. However, the bivariate model did prove more difficult to fit,
      and both models demonstrated a highly significant treatment effect with
      comparable clinical effect.

PMID- 10407238
TI  - Reporting delay and corrected incidence of multiple sclerosis.
AB  - The incidence of multiple sclerosis can be adjusted for reporting delay in a way
      similar to that for AIDS incidence as described in this paper. Two models are
      applied to data from the Danish Multiple Sclerosis Registry. The first simply
      describes the delay distribution, the second is a regression model. For the
      latter it is shown how goodness-of-fit assessment for both time-dependent and
      time-independent covariates can be handled using ideas from the Cox proportional
      hazards model. The goodness-of-fit analysis shows that people with onset age
      below 40 years and people with onset age from 40 years and above should be
      analysed separately and this is done throughout the paper. The incidences are
      adjusted with the two estimated delays and an estimate of the variance for the
      adjusted incidence is given. Finally the crude incidences are compared with the
      adjusted ones. We find that the incidence has been increasing since 1965 but
      mostly for people with onset age below 40 years.

PMID- 10407239
TI  - Longitudinal data analysis (repeated measures) in clinical trials.
AB  - Longitudinal data is often collected in clinical trials to examine the effect of
      treatment on the disease process over time. This paper reviews and summarizes
      much of the methodological research on longitudinal data analysis from the
      perspective of clinical trials. We discuss methodology for analysing Gaussian and
      discrete longitudinal data and show how these methods can be applied to clinical
      trials data. We illustrate these methods with five examples of clinical trials
      with longitudinal outcomes. We also discuss issues of particular concern in
      clinical trials including sequential monitoring and adjustments for missing data.
      A review of current software for analysing longitudinal data is also provided.
      Published in 1999 by John Wiley & Sons, Ltd. This article is a US Government work
      and is the public domain in the United States.

PMID- 10407240
TI  - Re: Age-period-cohort models of chronic disease rates. II: graphical approaches
      by C. Robertson and P. Boyle, Statistics in Medicine, 17, 1325-1340 (1998)

PMID- 10407241
TI  - Re: Exact tests of equivalence and efficacy with a non-zero lower bound for
      comparative studies by I. S. F. Chan, Statistics in Medicine, 17, 1403-1413
      (1998)

PMID- 10407242
TI  - Author's reply 

PMID- 10407243
TI  - Preface 

PMID- 10407245
TI  - Discussion 

PMID- 10407244
TI  - Optimum biased-coin designs for sequential treatment allocation with covariate
      information.
AB  - Randomized optimum designs of biased-coin type are compared with other strategies
      for the sequential allocation of two or more treatments in a clinical trial. The
      emphasis is on the variance of estimated treatment contrasts. This variance,
      which depends on the design strategy employed, may be interpreted as the number
      of patients on whom information is lost. Simulations provide clear plots of the
      evolution of this loss during the course of the clinical trial.

PMID- 10407246
TI  - Bootstrap methods for adaptive designs.
AB  - Adaptive designs generate dependent sequences of random variables that are not
      exchangeable. Therefore, it is not obvious how to employ a resampling scheme for
      confidence interval estimation. We propose a simple procedure where observed
      response rates from an adaptive experiment are input to a simulation program. The
      program then generates sequences from the adaptive sampling scheme. We compare,
      via simulation, three bootstrap confidence intervals with the asymptotic
      confidence interval for two adaptive designs useful for clinical trials. A simple
      ranking of simulated response rates yields a confidence interval approximation
      with coverage close to 1-alpha in most cases. The method allows us to incorporate
      such complexities as staggered entry and delayed response. We give an example of
      its utility on a clinical trial of fluoxetine in depression.

PMID- 10407248
TI  - Discussion 

PMID- 10407247
TI  - Optimization of testing times and critical values in sequential equivalence
      testing.
AB  - In long-term clinical trials, interim analyses are planned to reduce the number
      of patients needed. To meet this issue in a practical way, group sequential
      designs are used. Most of these trials are conducted with the objective of
      demonstrating differences in efficacy of treatments, for example, to show
      superiority of a new drug or experimental treatment to a control. However, an
      increasing number of trials are designed to establish equivalence in efficacy or
      bioequivalence. This paper deals with group sequential test procedures in two
      sided equivalence trials. Optimized designs with respect to sample size behaviour
      are constructed. Tables containing optimal testing times and corresponding
      optimal critical values or values to construct an underlying alpha-spending
      function, respectively, are provided. An example illustrates their use when
      planning interim analyses in equivalence trials.

PMID- 10407249
TI  - Unobserved covariates in the two-sample comparison of survival times: a maximum
      efficiency robust test.
AB  - In analysing a clinical trial with the logrank test, the hazards between the two
      groups are usually assumed to be proportional. Nevertheless, this hypothesis is
      no longer valid with unobserved covariates. As a consequence, there is a loss of
      power of the logrank test for testing the null hypothesis H(0) of no treatment
      effect. We propose a test suited for taking into account unobserved covariates.
      The proposed approach is based on a proportional hazard frailty model whereby the
      omitted covariates are considered as an unobserved frailty variable. The
      procedure is as follows. In a first step, the weighted logrank test optimal for
      testing H(0) against a general proportional hazard frailty model is obtained and
      its specialization for a gamma frailty variable is derived. In a second step, the
      proposed test is obtained by combining the maximin efficiency robustness
      principle and the gamma frailty distribution properties. Simulation studies
      investigate the power properties of the test for different frailty distributions.
      A breast cancer clinical trial is analysed as an example. The proposed test might
      be recommended rather than the logrank for practical situations in which one
      expects heterogeneity related to omitted covariates.

PMID- 10407250
TI  - Discussion 

PMID- 10407251
TI  - Visit-driven endpoints in randomized HIV/AIDS clinical trials: impact of missing
      data on treatment difference measured on summary statistics.
AB  - In randomized HIV/AIDS clinical trials, CD4 lymphocyte counts and plasma HIV-1
      RNA measurements are often used as endpoints. The comparison between treatment
      groups is mainly based on a summary measure of outcome, so-called summary
      statistic. Such analyses are often complicated by missing data occurring as drop
      outs. For the most currently used summary statistics in these trials, we examined
      the impact of missing data occurring as drop-outs on test size, in order to help
      choosing between these statistics. A simulation of missing-data patterns was
      performed, using HIV-1 plasma RNA measurements as the main endpoint, to compare
      the effect of three plausible informative patterns, depending on treatment group,
      and on baseline or current plasma viral load, on eight different summary
      statistics. Missing data resulted in test sizes over the nominal value for the
      area under the curve minus baseline, the least-squares slope, the slope estimated
      with use of a mixed effects linear model, assuming a linear trend over the entire
      study, the difference between baseline and nadir, and the difference between
      baseline and week 24. The difference between baseline and week 8 was an
      acceptable summary with respect to the test size, but did not reflect accurately
      the durability of the effect of treatment. Two criteria appeared as the best
      summary statistics: the slope estimated by a mixed effects model, with a change
      of slope after two weeks of treatment, and to a lesser degree, the area under the
      curve after carrying forward the last observation.

PMID- 10407252
TI  - Discussion 

PMID- 10407253
TI  - Estimation of the treatment effect in a clinical trial when recurrent events
      define the endpoint.
AB  - Recurrent events are frequently encountered in clinical trials when individuals
      may experience an event more than once. Examples are common in medical research,
      including infectious episodes, myocardial infarctions and hospital admissions.
      However, when only the first event is considered, there is a loss of information.
      Furthermore, the analysis of recurrent events is complicated by the dependence of
      the related failure times of each subject, that is, the occurrence of an event
      influences the risk of other events. Thus, naive statistical methods that
      consider recurrent events as independent observations will produce misleading
      conclusions. We recommend the use of a marginal hazards model that is derived
      from the multivariate generalization of the Cox proportional hazards model. This
      marginal model allows estimation of the relative risk of recurrence in clinical
      trials, taking into account the dependence between the recurring events of a same
      individual without explicit modelling. Two applications are used to compare the
      results of the marginal model analysis with those of usual methods: (i) a placebo
      controlled randomized clinical trial performed to evaluate the efficacy of an
      immunostimulant in the prevention of recurrences of infectious rhinitis in
      adults; (ii) a randomized clinical trial comparing transfusions of plasma rich in
      anti-HIV1 versus transfusions of seronegative plasma in the prevention of
      opportunist infections. To analyse recurrent events, usual methods are often
      irrelevant and the marginal model allows use of all the available information to
      accurately estimate the relative risk of recurrences. Moreover, it enables the
      estimation of the relative risk for each rank of recurrence.

PMID- 10407254
TI  - Discussion 

PMID- 10407255
TI  - Combining different phases in the development of medical treatments within a
      single trial.
AB  - In the development of medical treatments, identification of promising therapies
      and inference on selected treatments are usually performed in subsequent separate
      trials. An adaptive two-stage design is proposed for the situation of multiple
      treatments to be compared with a control, allowing integration of both steps
      within a single confirmatory trial controlling the multiple level alpha. After
      the interim analysis, the trial may be terminated early or is continued with a
      second stage, where the set of treatments may be reduced due to lack of efficacy
      or to safety problems. The procedure is highly flexible with respect to the
      distributional assumptions, stopping rules and selection criteria and allows a
      completely free recalculation of the sample size for the second stage.
      Simulations show that the method may be substantially more powerful than
      classical one-stage multiple treatment designs with the same total sample size.
      As in conventional strategies with a series of separate experiments, a reasonable
      selection strategy has to be applied in order to prevent proceeding with non
      optimal treatments.

PMID- 10407256
TI  - Continual reassessment methods in phase I trials of the combination of two drugs
      in oncology.
AB  - Most phase I trials in oncology use standard methods for treating successive
      groups of patients with increasing doses in order to determine the maximum
      tolerated dose (MTD). These methods have been criticized because they treat many
      patients at suboptimal dose levels, and do not provide an accurate estimation of
      the best dose level. Continual reassessment methods for the study of toxicity in
      single agent phase I trials have recently been advocated since they present many
      advantages over traditional methods. Although the advantages of these methods are
      recognized by most clinical investigators, their use is not widespread and their
      advantages have not yet been universally accepted. A maximum likelihood continual
      reassessment method was conducted retrospectively and compared to the originally
      planned standard method in a two drug combination phase I trial in order to study
      its applicability in this setting. Calculations from the binomial distributions
      and simulations were used for identifying the MTD, for the proportion of patients
      treated at the MTD or at one dose level just below, and for the proportion of
      patients treated at doses above the MTD. If the new method had been applied in
      this study, the MTD would have been reached much earlier, since, most of the
      time, higher dose levels were recommended. This result shows the feasibility of
      the new method in a two-drug setting and its use should be encouraged since fewer
      patients are treated at suboptimal dose levels or at dose levels above the MTD.

PMID- 10407257
TI  - A new approach to modelling the relationship between in vitro and in vivo drug
      dissolution/absorption.
AB  - A major goal of the pharmaceutical scientist is finding a relationship between an
      in vitro characteristic of an oral dosage form and its in vivo performance. One
      such relationship between drug dissolution (or absorption) in vivo and that in
      vitro is known as an 'in vitro-in vivo correlation' (IVIVC) whose importance
      stems from the fact that it may be used to minimize the number of human studies
      required during product development, assist in setting meaningful in vitro
      dissolution specifications and justify biowaivers for scale-up and post approval
      changes. A number of ways of describing an IVIVC have been reported with 'level
      A' being the most informative and therefore most desirable. In the majority of
      cases reported to date, both the model and the statistical methods employed for
      level A IVIVC are very simplistic. The model assumes that the rate and extent of
      dissolution in vivo are the same as those in vitro. The statistical methods
      ignore the repeated measures nature of the data and use a response variable as an
      independent variable without accounting for measurement error. This paper
      describes some new models which include the simple model as a special case. The
      modelling approach is based on considering the time at which a drug molecule
      enters solution (in vitro or in vivo) to be a random variable. The in vitro and
      in vivo distributions are then related to one another using a proportional odds,
      proportional hazards or proportional reversed hazards model. The models can be
      extended by adding a linear time component which describes a time varying
      relationship. Following the addition of random effects to these structural models
      in order to account for the repeated measures nature of the data collected, the
      models may be described as generalized linear mixed effects models. The models
      were fitted to some data sets using a maximum likelihood based method and the
      results indicate that these models have potential for describing an in vitro-in
      vivo relationship which cannot be described using the currently available models.

PMID- 10407258
TI  - Discussion 

PMID- 10407259
TI  - Multivariate outlier detection applied to multiply imputed laboratory data.
AB  - In clinical laboratory safety data, multivariate outlier detection methods may
      highlight a patient whose laboratory measurements do not follow the same pattern
      of relationships as the majority of patients, although their individual
      measurements are not found to be outlying when considered one at a time. Missing
      data problems are often dealt with by imputing a single value as an estimate of
      the missing value. The completed data set may then be analysed using traditional
      methods. A disadvantage of using single imputation is the underestimation of
      variability, with a corresponding distortion of power in hypothesis testing.
      Multiple imputation methods attempt to overcome this problem, and in this paper a
      study is described which considers the application of multivariate outlier
      detection methods to multiply imputed clinical laboratory safety data sets. Three
      different proportions of missing data are generated in laboratory data sets of
      dimensions 4, 7, 12 and 30, and a comparison of eight multiple imputation methods
      is carried out. Two outlier detection techniques, Mahalanobis distance and
      generalized principal component analysis, are applied to the multiply imputed
      data sets, and their performances are discussed. Measures are introduced for
      assessing the accuracy of the missing data results, depending on which method of
      analysis is used.

PMID- 10407260
TI  - Discussion 

PMID- 10407261
TI  - Role of NaOH-extractable cell wall proteins Ccw5p, Ccw6p, Ccw7p and Ccw8p
      (members of the Pir protein family) in stability of the Saccharomyces cerevisiae
      cell wall.
AB  - The Saccharomyces cerevisiae cell wall contains more than 20 identified
      mannoproteins. Some of them can be released from the wall by hot
      SDS/mercaptoethanol treatment and are, therefore, considered as disulphide-linked
      or non-covalently attached to wall structural components. A number of covalently
      linked cell wall proteins are released after SDS extraction. They can be divided
      into these extractable by glucanases and those which can be released with 30 mM
      NaOH. The SDS-extractable proteins either possess enzymatic activities or are
      homologues of enzymes, mainly glucanases. Nothing is known, however, about the
      function of covalently linked proteins. In order to investigate the role of NaOH
      extractable cell wall proteins, genes encoding all four identified members of
      this family of Pir proteins, CCW5, CCW6, CCW7 and CCW8, were disrupted and the
      phenotype of the mutants obtained was examined. They grew somewhat more slowly,
      were larger and irregularly shaped, and showed pronounced susceptibility to cell
      wall synthesis inhibitors like Calcofluor white and Congo red. In addition, the
      triple and the quadruple deletants had a decreased mating ability. All these
      properties were more obvious the more of these genes were disrupted, indicating
      that probably all members of this protein family are at least functionally
      equivalent in the cell wall.

PMID- 10407262
TI  - The topoisomerase I poison camptothecin generates a Chk1-dependent DNA damage
      checkpoint signal in fission yeast.
AB  - The protein kinase Chk1 is essential for the DNA damage checkpoint. Cells lacking
      Chk1 are hypersensitive to DNA-damaging agents such as UV light and gamma
      irradiation because they fail to arrest the cell cycle when DNA damage is
      generated. Phosphorylation of Chk1 occurs after DNA damage and is dependent on
      the integrity of the DNA damage checkpoint pathway. We have tested whether a
      topoisomerase I inhibitor, camptothecin (CPT), generates DNA damage in the
      fission yeast Schizosaccharomyces pombe that results in Chk1 phosphorylation. We
      demonstrate that Chk1 is phosphorylated in response to CPT treatment in a time-
      and dose-dependent manner and that phosphorylation is dependent on an intact DNA
      damage checkpoint pathway. Furthermore, we show that cells must be actively
      dividing in order for CPT to generate a Chk1-responsive DNA damage signal. This
      observation is consistent with a model whereby the cytotoxic event caused by CPT
      treatment is the production of a DNA double-strand break resulting from the
      collision of a DNA replication fork with a trapped CPT-topoisomerase I cleavable
      complex. Cells lacking Chk1 are hypersensitive to CPT treatment, suggesting that
      the DNA damage checkpoint pathway can be an important determinant for CPT
      sensitivity or resistance. Finally, as a well-characterized, soluble agent that
      specifically causes DNA damage, CPT will allow a biochemical analysis of the
      checkpoint pathway that responds to DNA damage.

PMID- 10407263
TI  - A proposal for nomenclature of aldehyde dehydrogenases in Saccharomyces
      cerevisiae and characterization of the stress-inducible ALD2 and ALD3 genes.
AB  - The complete sequencing of the genome of Saccharomyces cerevisiae indicated that
      this organism contains five genes encoding aldehyde dehydrogenases. YOR374w and
      YER073w correspond to the mitochondrial isoforms and we propose as gene names
      ALD4 and ALD5, respectively. YPL061w has been described as the cytoplasmic
      constitutive isoform and named ALD6. We characterize here the tandem-repeated
      ORFs YMR170c and YMR169c as the cytoplasmic stress-inducible isoforms, with gene
      names ALD2 and ALD3, respectively. The expression of ALD2 and ALD3 is dependent
      on the general-stress transcription factors Msn2,4 but independent of the HOG MAP
      kinase pathway. ALD3 is induced by a variety of stresses, including osmotic
      shock, heat shock, glucose exhaustion, oxidative stress and drugs. ALD2 is only
      induced by osmotic stress and glucose exhaustion. A double null mutant, ald2
      ald3, exhibited unchanged sensitivity to any of the above stresses. The only
      phenotype detected in this mutant was a reduced growth rate in ethanol medium as
      compared to the wild type.

PMID- 10407264
TI  - Overproduction of the Opi1 repressor inhibits transcriptional activation of
      structural genes required for phospholipid biosynthesis in the yeast
      Saccharomyces cerevisiae.
AB  - Transcription of structural genes required for phospholipid biosynthesis in the
      yeast Saccharomyces cerevisiae is repressed by high concentrations of inositol
      and choline. The ICRE (inositol/choline-responsive element), which is necessary
      and sufficient for regulation by phospholipid precursors, functions as a binding
      site for the heterodimeric Ino2/Ino4 activator. ICRE-dependent transcription
      becomes constitutive in the absence of the Opi1 repressor. Opi1 contains a
      leucine zipper motif and two glutamine-rich stretches. In this work we describe a
      molecular analysis of OPI1 function and expression. Opi1 mutant variants altered
      at the leucine zipper and a glutamine-rich region, respectively, were no longer
      functional repressors. In contrast, an Opi1 deletion variant lacking the N
      terminal 106 amino acids still mediated negative regulation. Although the leucine
      zipper suggests that Opi1 may act as a DNA-binding protein, our data do not
      support a direct interaction with the ICRE. Despite its function as an antagonist
      of INO2 and INO4, expression of OPI1 is stimulated by an upstream ICRE.
      Overexpression of OPI1 under control of the GAL1 promoter severely inhibited
      activation of ICRE-dependent genes, leading to inositol-requiring cells. Growth
      inhibition of GAL1-OPI1 was observed with INO2 and INO4 alleles activated by
      either the natural promoter or a heterologous control region. Although induction
      of GAL1-OPI1 strongly repressed ICRE-dependent gene expression, the concentration
      of the Ino2/Ino4 activator remained unchanged. This finding suggests that
      differential expression of phospholipid biosynthetic genes may occur even in the
      presence of a constant amount of the specific activator.

PMID- 10407265
TI  - Deletion of the carbonic anhydrase-like gene NCE103 of the yeast Saccharomyces
      cerevisiae causes an oxygen-sensitive growth defect.
AB  - The yeast protein Nce103p encoded by the gene NCE103 (YNL036w) was described by
      Cleves et al. (1996) as a substrate of the non-classical export pathway which
      acts independently of the classical pathway through the ER and the Golgi
      compartments. However, the predicted amino acid sequence of Nce103p shows high
      levels of identities to carbonic anhydrases of pro- and eukaryotes. A nce103
      Delta deletion strain did not grow on a rich peptone-yeast extract-glucose medium
      under normal aerobic conditions at pH values of 3.0-8.0, but grew like wild-type
      in an oxygen-free nitrogen or oxygen-reduced atmosphere over this pH range, and
      was more sensitive to H(2)O(2) than wild-type. No carbonic anhydrase activity
      could be detected in crude extracts prepared from wild-type, nce103-Delta mutants
      or in strains transformed with a multicopy plasmid carrying the NCE103 gene.
      Expression of the Medicago sativa carbonic anhydrase gene (Coba de la Pena et
      al., 1997), in a yeast expression cassette on a multicopy plasmid, complemented
      the growth defects caused by the nce103-Delta deletion and carbonic anhydrase
      activity could be readily detected in the crude extract. The ability of the
      nce103-Delta deletion strain to grow like wild-type under anaerobic conditions
      suggests that the protein encoded by NCE103 is required for protection against
      certain products of an oxidative metabolism and can be replaced in this function
      by the Medicago sativa carbonic anhydrase. A NCE103 promoter-LacZ fusion in a
      wild-type background showed that NCE103 is poorly transcribed under aerobic
      conditions and at an undetectable level under anaerobic conditions.

PMID- 10407266
TI  - A systematic nomenclature for new translation initiation factor genes from S.
      pombe and other fungi.
AB  - Eukaryotic translation initiation factors and their corresponding genes have been
      characterized using biochemical and genetic methods from a variety of different
      organisms. The designations of the factors relate to their apparent roles in the
      biochemical process. Many gene names indicate genetic interactions with other
      genes or the functional attributes used to identify them. On the other hand,
      progress in systematic sequencing of the genomes of organisms like Saccharomyces
      cerevisiae and Schizosaccharomyces pombe has revealed many genes homologous to
      known translation initiation factor genes. The genes defined by the systematic
      sequencing approach are assigned numerical designations completely unrelated to
      their biological function. So far there have been publications on only three
      genes encoding translation initiation factors from Schizosaccharomyces pombe. We
      therefore see this an an ideal opportunity to propose a systematic and logical
      nomenclature for genes encoding translation initiation factor genes that can be
      applied to all further genes of this type that are characterized in this fission
      yeast.

PMID- 10407267
TI  - The three copies of the ATP1 gene are arranged in tandem on chromosome II of
      Saccharomyces cerevisiae S288C.
AB  - In the yeast Saccharomyces cerevisiae there are three copies of the F(1)F(0)
      ATPase alpha-subunit gene ATP1 on chromosome II (Takeda et al., 1995). However,
      after genome analysis using S. cerevisiae strain S288C, only one ATP1 gene
      sequence was observed (Feldman et al., 1994; Obermaier et al., 1995). To check
      whether the number of copies of ATP1 is strain-dependent or not, we carried out
      three different experiments: (a) long-PCR analyses of total DNAs isolated from
      several reference strains, carried out by preparing 29-mer oligonucleotides based
      on the 5'- and 3'- up- and downstream regions of the ATP1 nucleotide sequence
      using the data from the genome project to synthesize primers; (b) restriction
      analyses of chromosome II from the reference strains with SplI; and (c) long-PCR
      analyses of prime clones 70113 and 70804, both of which contained two ATP1 gene
      copies, ATP1a and ATP1b, and ATP1b and ATP1c, respectively, using 30 nucleotides
      just inside the 3'-end (sense) and 5'-end (antisense) of the ATP1-coding region
      as primers. In the case of the long-PCR experiments, the reference strains DC5,
      SEY2102, W303-1A, W303-1B, LL20 and DBY746, as well as strain S288C, generated a
      DNA fragment of approximately 32 kb, which hybridized with ATP1. During SplI
      digestion, a DNA fragment of more than 50 kb which hybridized with ATP1, was
      obtained from all reference strains. In the case of prime clone analyses using
      the long-PCR experiments, the distance between ATP1a and ATP1b or ATP1b and ATP1c
      was approximately 10 kb or 7 kb, respectively. The S288C strain generated these
      two DNA fragments, as do the other strains. These results showed that all these
      strains contained three copies of ATP1 on chromosome II.

PMID- 10407268
TI  - Three genes whose expression is induced by stress in Saccharomyces cerevisiae.
AB  - In this work we report the isolation and characterization of three genes induced
      by different stress conditions in the yeast Saccharomyces cerevisiae. These
      genes, named GRE1, GRE2 and GRE3, were identified by the differential display
      technique using total RNAs obtained from yeast grown under hyperosmotic
      conditions. Northern analysis of RNA obtained from different growth conditions
      shows that their corresponding transcripts accumulate not only in response to
      osmotic stress but also to ionic, oxidative and heat stress. Analysis of the
      deduced amino acid sequences indicated that GRE1, GRE2 and GRE3 correspond to
      ORFs YPL223C, YOL151W and YHR104W, respectively. Additionally, it suggested that
      GRE1 encodes a hydrophilic polypeptide that it is not homologous to any known
      protein but has features resembling the late embryogenesis abundant (LEA)
      proteins characterized in higher plants; GRE2 encodes a putative reductase with
      similarity to plant dihydroflavonol-4-reductases; and GRE3 codifies for a keto
      aldose reductase highly related to fungal xylose-reductases. The three genes are
      induced in the late growth phases in agreement with the presence of PDS elements
      in their promoter regions. The three of them are under the control of the HOG
      pathway, even though GRE1 and GRE2 promoter regions do not present the consensus
      core STRE sequence. In addition, GRE1 and GRE3 are regulated negatively by the
      cAMP-PKA transduction pathway and positively by the transcriptional factors Msn2p
      and Msn4p. Gene disruptions of the GRE genes did not show a phenotype in any of
      the tested stress conditions.

PMID- 10407270
TI  - Yeast Industry Platform.

PMID- 10407269
TI  - DNA sequencing and analysis of a 67.4 kb region from the right arm of
      Schizosaccharomyces pombe chromosome II reveals 28 open reading frames including
      the genes his5, pol5, ppa2, rip1, rpb8 and skb1.
AB  - 67 393 bp of contiguous DNA located between markers cdc18 and cdc14 on the right
      arm of fission yeast chromosome II has been sequenced as part of the European
      Union Schizosaccharomyces pombe genome sequencing project. The complete sequence,
      contained in cosmid clones c15C4 and c21H7, has been determined on both strands.
      Sequence analysis shows that it contains 28 open reading frames capable of coding
      for proteins, 16 split by one or more introns, but no tRNA, rRNA or transposon
      sequences. The gene density is one per 2. 4 kb. Six genes have been previously
      described (his5, pol5, ppa2, rip1, rpb8 and skb1) and 22 are novel. Of the novel
      genes, 14 have significant similarity with proteins of known function, three have
      similarities with proteins of unknown function and five show no extensive
      similarities with known proteins. Sequence similarities suggest that three of the
      novel genes encode ATP-dependent RNA helicases, two encode transcription factor
      components and others encode a G-protein, a dehydrogenase, a Rab escort protein,
      an Abc1-like protein, a lipase, an ATP-binding transport protein, an amino acid
      permease, an acid phosphatase and a mannosyltransferase.

PMID- 10407271
TI  - Functional analysis of 12 ORFs from Saccharomyces cerevisiae chromosome II.
AB  - Twelve different ORFs have been deleted from the right arm of Saccharomyces
      cerevisiae chromosome II; namely YBR193c, YBR194w, YBR197c, YBR198c, YBR201w,
      YBR203w, YBR207w, YBR209w, YBR210w, YBR211c, YBR217w and YBR228w. Tetrad analysis
      of heterozygous deletant strains revealed that YBR193c, YBR198c and YBR211c are
      essential genes for vegetative growth. No effects were detected in any of the
      haploid deletion mutants for the rest of the ORFs with respect to growth, gross
      morphology or mating.

PMID- 10407272
TI  - Disruption of six open reading frames on chromosome X of Saccharomyces cerevisiae
      reveals a cluster of four essential genes.
AB  - In this study we report the construction and basic phenotypic analysis of six
      Saccharomyces cerevisiae deletion mutants. The open reading frames (ORFs) YJL008C
      (gene symbol CCT8), YJL010C, YJL011C, YJL012C, YJL017W, and YJL020C from
      chromosome X have been disrupted by integration of deletion cassettes, comprising
      the bacterial KanMX4 marker gene and terminal long (LFH) or short (SFH) flanking
      sequences that are homologous to the 5' and 3' untranslated regions of the
      respective ORFs. For correct disruption of ORF YJL008C, it was necessary to
      construct a deletion cassette flanked by 300-350 bp long target guide sequences
      by LFH-PCR. Transformations using ORF YJL008C gene disruption cassettes
      synthesized by standard SFH-PCR exclusively resulted in false-positive or
      multiple integration events, probably because seven additional genes homologous
      to CCT8 exist in the yeast genome. The other five ORFs have been disrupted using
      cassettes generated by SFH-PCR, comprising terminal homologous regions of
      approximately 50 bp to each target site. Correct genomic integration of the
      reporter modules was verified by analytical PCR and Southern hybridization.
      Deletion of YJL008C, YJL010C, YJL011C, and YJL012C was found to be lethal, as
      shown by sporulation and tetrad analysis. This result is in contrast to the
      finding that only 16-20% of the genes in S. cerevisiae are estimated to be
      essential. The four essential genes described in this work are clustered, while
      the two other non-essential ORFs are separated by further ORFs. Although the two
      viable deletion mutants were tested against 60 different inhibitors, heavy metal
      ions and salts, no phenotype could be detected that co-segregated with the
      deletion during meiosis.

PMID- 10407273
TI  - Disruption and basic functional analysis of six novel ORFs of chromosome XV from
      Saccharomyces cerevisiae.
AB  - We report the disruption and functional analysis of six open reading frames
      (ORFs) from chromosome XV, namely YOL155c, YOL154w, YOL119c, YOL118c, YOR301w and
      YOR306c, in FY1679 and CEN.PK2 backgrounds. We constructed replacement cassettes
      and cloned each ORF into the pRS416 centromeric plasmid. No obvious phenotype was
      observed for the corresponding deleted strains with respect to growth, mating or
      sporulation. YOL155c encodes a protein with a secretion signal and putative GPI
      anchor recognition site and is possibly a cell wall protein, although its
      deletion did not present morphogenetic defects under any of the conditions
      tested. Although YOL119c and YOR306c are members of the monocarboxylate permease
      family, the growth of the double disruptant in acetate, lactate and pyruvate was
      similar to that of the parental strains.

PMID- 10407274
TI  - Disruption of six Saccharomyces cerevisiae novel genes and phenotypic analysis of
      the deletants.
AB  - As a part of the EUROFAN programme, six open reading frames from Saccharomyces
      cerevisiae (YNL083w, YNL086w, YNL087w, YNL097c, YDL100c and YOR086c) were
      disrupted in two genetic backgrounds, FY1679 and W303. Individual deletions in
      diploid strains and tetrad analysis of heterozygous deletants revealed that none
      of them is essential. Basic phenotypic analysis did not reveal any significant
      difference between the parental and mutant strains. Although YNL087w and YOR086c
      are 55% identical, the double disruptant also behaves the same as the parental
      cells. Ydl100p seems to be involved in metal detoxification, the phenotype of the
      null mutants being enhanced when the assays are performed at 37 degrees C.

PMID- 10407275
TI  - Construction and genetic analysis of S. cerevisiae deletants of six novel ORFs
      from chromosome II.
AB  - We have constructed S. cerevisiae strains carrying genomic deletions of six ORFs
      from the left arm of chromosome II (YBL018c, YBL019w, YBL024w, YBL042c, YBL043w
      and YBL046w) in both FY1679 and W303 backgrounds. We have found that YBL018c is
      an essential gene in yeast, whereas the other five genes are non-essential. We
      have developed plasmids carrying deletion cassettes that can be used to delete
      any of the six genes in S. cerevisiae by transforming to G418-resistance, as well
      as centromeric plasmids containing the cognate genes.

PMID- 10407276
TI  - Epitope tagging of yeast genes using a PCR-based strategy: more tags and improved
      practical routines.
AB  - Epitope tagging of proteins as a strategy for the analysis of function,
      interactions and the subcellular distribution of proteins has become widely used.
      In the yeast Saccharomyces cerevisiae, molecular biological techniques have been
      developed that use a simple PCR-based strategy to introduce epitope tags to
      chromosomal loci (Wach et al., 1994). To further employ the power of this
      strategy, a variety of novel tags was constructed. These tags were combined with
      different selectable marker genes, resulting in PCR amplificable modules. Only
      one set of primers is required for the amplification of any module. Furthermore,
      convenient laboratory techniques are described that facilitate the genetic
      manipulations of yeast strains, as well as the analysis of the epitope-tagged
      proteins.

PMID- 10407277
TI  - Chemotyping of yeast mutants using robotics.
AB  - By now, the EUROFAN programme for the functional analysis of genes from the yeast
      genome has attained its cruising speed. Indeed, several hundreds of yeast mutants
      with no phenotype as tested by growth on standard media and no significant
      sequence similarity to proteins of known function are available through the
      efforts of various laboratories. Based on the methodology initiated during the
      pilot project on yeast chromosome III (Yeast 13, 1547-1562, 1997) we adapted it
      to High Throughput Screening (HTS), using robotics. The first 100 different gene
      deletions from EUROSCARF, constructed in an FY1679 strain background, were run
      against a collection of about 300 inhibitors. Many of these inhibitors have not
      been reported until now to interfere in vivo with growth of Saccharomyces
      cerevisiae. In the present paper we provide a list of novel growth conditions and
      a compilation of 49 yeast deletants (from chromosomes II, IV, VII, X, XIV, XV)
      corresponding to 58% of the analysed genes, with at least one clear and stringent
      phenotype. The majority of these deletants are sensitive to one or two compounds
      (monotropic phenotype) while a distinct subclass of deletants displays a hyper
      pleiotropic phenotype with sensitivities to a dozen or more compounds. Therefore,
      chemotyping of unknown genes with a large spectrum of drugs opens new vistas for
      a more in-depth functional analysis and a more precise definition of molecular
      targets.

PMID- 10407278
TI  - Disruption of six novel yeast genes located on chromosome II reveals one gene
      essential for vegetative growth and two required for sporulation and conferring
      hypersensitivity to various chemicals.
AB  - A PCR-based method for targeted gene deletion by kanMX4 module was used to
      construct complete deletion mutants of six individual open reading frames from
      chromosome II: YBR128c, YBR131w, YBR133c, YBR137w, YBR138c and YBR142w. The ORFs
      were deleted in two diploid strains, FY1679 and W303. Sporulation and tetrad
      analysis revealed that only one ORF, YBR142w, encoding a putative DEAD-box RNA
      helicase, is an essential gene. A systematic phenotypic analysis of the deleted
      mutants was carried out. Homozygous diploids ybr128cDelta/ybr128cDelta and
      ybr131wDelta/ybr131wDelta did not sporulate. The ybr131cDelta mutant whether
      haploid or homozygous diploid, in addition displayed an increased sensitivity to
      Caffeine, Calcium and Zinc, and to emphasize this phenotype we named the gene
      CCZ1. ORF YBR133c was independently reported by others as Histone Synthetic
      Lethal (HSL7) (Ma et al., 1996). We found that the aberrant morphology
      characteristic for ybr133cDelta (hsl7Delta) cells was observed in W303 but not in
      FY1679 genetic background. Furthermore, we observed that deletion of YBR133c had
      a pleiotropic effect under a wide range of conditions, including increased
      sensitivity to calcium, caffeine, calcofluor white, vanadate and verapamil. The
      effects of the deletion were reinforced in W303 background. We found no
      phenotypic effects of the two remaining deletions, ybr137wDelta and ybr138cDelta.

PMID- 10407279
TI  - A large-scale sonication assay for cell wall mutant analysis in yeast.
AB  - The complete yeast genome contains a large number of genes of unknown biological
      function. Simple, rapid and reliable specific screens are valuable tools in
      exploring gene function via systematic phenotypic analysis of large mutant
      collections. This report provides a new approach for monitoring changes in cell
      wall strength, based on the deleterious effects caused by ultrasound on the yeast
      cell surface. Sonication can thus be used for the screening of mutants affected
      in the architecture or stability of the cell wall, since such mutants are
      expected to have an altered sensitivity to this treatment compared to that of a
      wild-type. The experimental procedure, consisting in the quantification of
      damaged cells after a mild sonication treatment, by means of flow cytometry, can
      be applied on a large scale. The usefulness of the sonication assay as a primary
      screen for cell wall-related mutants is evaluated on the collection of calcofluor
      white-hypersensitive and -resistant mutants obtained by Lussier et al. (1997). A
      further phenotypic characterization of the sonication-hypersensitive mutants
      within the calcofluor white collection is also presented.

PMID- 10407280
TI  - A fast method to diagnose chromosome and plasmid loss in Saccharomyces cerevisiae
      strains.
AB  - We have developed a simple, fast and reliable method for the analysis of genetic
      stability in budding yeast strains. The assay relies on our previous finding that
      cells expressing the green fluorescent protein (GFP) can be detected and counted
      by flow cytometric analysis (FACS) (Niedenthal et al., 1996). Expression of a gfp
      carrying CEN-plasmid in a wild-type strain resulted in the emission of strong
      fluorescence from 80% of the cell population. Strong fluorescence and presence of
      the plasmid, determined by the presence of the URA3 genetic marker, was strictly
      correlated. Expression of this plasmid in 266 yeast strains, each carrying a
      complete deletion of a novel, non-essential gene identified in the S. cerevisiae
      sequencing project, pinpointed 12 strains with an increased level of mitotic
      plasmid loss. Finally we have shown that measurement of mitotic loss of
      artificial chromosome fragments equipped with the gfp expression cassette can be
      performed quantitatively using FACS.

PMID- 10407282
TI  - Formation of macrocyclic oligoferrocenes: a matrix-assisted laser
      desorption/ionization mass spectrometric study.
AB  - Oligomeric ferrocenes were investigated simultaneously by matrix-assisted laser
      desorption/ionization time of flight mass spectrometry (MALDI-TOFMS). The
      oligomers were obtained by the reaction of tetrahydro-4,4,8,8-tetramethyl-4,8
      disila-s-indacene-3a,7a-diyldilithium (Li(2)L) with FeCl(2).1.5 THF (THF =
      tetrahydrofuran). Depending on the reaction conditions up to ten linear-chain and
      eleven cyclic ferrocene oligomers with masses between 1139 and 5071 Da could be
      detected unambiguously. The most abundant macrocycles contained ten and seven
      iron atoms when the reactions were carried out at -20 and 25 degrees C,
      respectively. The chains had cyclopentadienes as end groups and formally resulted
      from replacing one iron of a cycle by two hydrogens, which corresponds to a mass
      difference of 54 Da. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407281
TI  - A critical investigation of the effects of the radio frequency potential on the
      trapping of externally injected ions in ion trap mass spectrometry.
AB  - The sensitivity of all ion trap mass spectrometry (ITMS) methods is dependent on
      the trapping efficiency of the instrument. For ITMS instruments utilizing
      external ion sources, such as laser desorption, trapping efficiency is known to
      depend on the phase and amplitude of the radio frequency (RF) potential applied
      to the ring electrode at the time of ion introduction. It is remarkable that, in
      a considerable body of literature, no consensus exists regarding the effects of
      these parameters on the efficacy of trapping externally generated ions. In this
      paper, a summary of the literature is presented in order to highlight significant
      discrepancies. New laser desorption ion trap mass spectrometry (LD-ITMS) data are
      also presented, from which conclusions are drawn in our effort to clarify some of
      the confusion. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407283
TI  - Correlation between biological activity and energies of electronic transitions in
      benzodiazepines. Negative ion mass spectrometry and ultraviolet absorption
      spectroscopy study of some derivatives.
AB  - A correlation between the energies of electronic singlet transitions in
      benzodiazepines and their biological activity, which was revealed earlier by
      means of negative ion mass spectrometry with resonance electron capture, has been
      verified with a UV absorption spectroscopy investigation. Also, it has been noted
      that the energies of electronic singlet transitions in benzodiazepines are close
      in value to the ionization energies of atoms Cs, Rb, K, Na, Li and Tl, the
      cations of which are known to play an important role in nerve cell excitation
      processes. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407284
TI  - Copper and iron interactions with angiotensin-converting enzyme inhibitors. A
      study by fast-atom bombardment tandem mass spectrometry.
AB  - Fast atom bombardment, combined with high-energy collision-induced tandem mass
      spectrometry, has been used to investigate gas-phase metal-ion interactions with
      captopril, enalaprilat and lisinopril, all angiotensin-converting enzyme
      inhibitors.Suggestions for the location of metal-binding sites are presented. For
      captopril, metal binding occurs most likely at both the sulphur and the nitrogen
      atom. For enalaprilat and lisinopril, binding preferably occurs at the amine
      nitrogen. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407285
TI  - Determination of electron affinity of carbonyl radicals by means of negative ion
      mass spectrometry.
AB  - Appearance energies of [M-H](-) ions from carbonyl compounds R-CO-R' (R,R' = H,
      CH(3), NH(2), OH) have been measured by means of negative ion mass spectrometry
      in resonant electron capture mode. Values of electron affinity of the
      corresponding radicals, CH(2)&dbond;C(X)O, NH&dbond;C(X)O and O&dbond;C(X)O, have
      been determined. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407286
TI  - Gas phase reaction rate measurements in Fourier transform mass spectrometry.
AB  - Determination of the concentration of neutral polycyclic aromatic hydrocarbon
      molecules in the mass spectrometer for reaction rate measurement is investigated.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407287
TI  - Liquid chromatography/mass spectrometric determination of trans-resveratrol in
      wine using a tandem solid-phase extraction method.
AB  - Liquid chromatography/mass spectrometry (LC/MS) with electrospray ionization has
      been successfully applied to the determination of trans-resveratrol (3,5,4'
      trihydroxystilbene) in wine. Of a range of analytical conditions that were
      tested, optimum results were obtained by the use of reversed-phase high
      performance liquid chromatography (HPLC) using a mixture of methanol and ammonium
      acetate as the mobile phase. The negative-ion spectrum of trans-resveratrol
      showed pseudo-molecular ion, [M - H](-), which was the most abundant ion, and low
      fragment ions corresponding to the losses of hydroxyl groups of the phenol
      nucleus. Enhanced selectivity for the separation between trans-resveratrol and
      endogenous wine constituents was afforded by sample purification with a tandem
      solid-phase extraction method. The approach permits detection at low
      concentration of trans-resveratrol. The combination of improved sample
      pretreatment and an isocratic chromatographic system in conjunction with internal
      standardization forms the basis of a new assay for the quantitation of trans
      resveratrol in wine. Full-scan mass spectra were readily obtained from 8 ng of
      trans-resveratrol, while a limit of detection of 200 pg (signal-to-noise ratio 3)
      was attained in the selected ion monitoring mode. The application of LC/MS to the
      determination of trans-resveratrol in wines is demonstrated by the analysis of
      red wines. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407288
TI  - Shape resonances in slow electron scattering by aromatic molecules. I.
      Anthraquinone derivatives.
AB  - A series of anthraquinone (C(14)O(2)H(8)) derivatives has been studied by means
      of electron capture negative ion mass spectrometry (ECNI-MS), photoelectron
      spectroscopy (PES), and AM1 quantum chemical calculations. Mean lifetimes of
      molecular negative ions M(-.) (MNI) have been measured. The mechanism of long
      lived MNI formation in the epithermal energy region of incident electrons has
      been investigated. A simple model of a molecule (a spherical potential well with
      the repulsive centrifugal term) has been applied for the analysis of the energy
      dependence of cross sections at the first stage of the electron capture process.
      It has been shown that a temporary resonance of MNI at the energy approximately
      0.5 eV corresponds to a shape resonance with lifetime 1-2.10(-13) s in the f
      partial wave (l = 3) of the incident electron. The next resonant state of MNI at
      the energy approximately 1.7 eV has been associated with the electron excited
      Feshbach resonance (whose parent state is a triplet npi* transition). In all
      cases the initial electron state of the MNI relaxes into the ground state by
      means of a radiationless transition, and the final state of the MNI is a nuclear
      excited resonance with a lifetime measurable on the mass spectrometry timescale.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407289
TI  - Molecular distribution of some commercial nonylphenol ethoxylates using matrix
      assisted laser desorption/ionization time-of-flight mass spectrometry.
AB  - Nonylphenol ethoxylates (NPEs) belong to a group of nonionic surfactants that are
      collectively referred to as alkylphenol ethoxylates (APEs). APEs find widespread
      use in heavy-duty commercial and household cleaning formulations, shampoos, and
      industrial processing, i.e. textile manufacture. Their environmental impact
      depends on the molecular distribution and the extent of their biodegradation in
      municipal sewage systems, waterways and rivers. We have established two sample
      preparation methods that have enabled the determination of the molecular
      distributions of six commercial nonylphenol ethoxylates using matrix-assisted
      laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS).
      In both methods, alpha-cyano-4-hydroxycinnamic acid, dissolved in
      acetonitrile/tetrahydrofuran, was used as the matrix. In one set of experiments,
      the NPEs were dissolved in an acetonitrile/tetrahydrofuran solvent system prior
      to mixing with the matrix solution, and the resulting MALDI-TOF mass spectra
      produced mostly sodiated molecules [M + Na](+). The NPEs, all having the formula
      4-(C(9)H(19))-C(6)H(4)-(OCH(2)CH(2))(n)-OH, are Surfonic (R)N-95, N-100, N-102, N
      120, N-150 and N-300. Surfonic N-95 and N-100 gave n values of 5-20; Surfonic N
      102, N-120, N-150, and N-300 gave n values of 5-21, 5-22, 8-25 and 15-40,
      respectively. In order to develop a sample preparation method that could be used
      with less polar NPEs, we dissolved the NPEs (except N-300) in pentane prior to
      mixing with the matrix solution, and found that the MALDI spectral quality was
      unaffected by the solvent systems. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407290
TI  - Knudsen cell mass spectrometric investigation of the PbO-ZrO(2)-TiO(2) system.
AB  - Knudsen effusion mass spectrometry (KEMS) was used for direct determination of
      lead oxide activity as a function of temperature in various regions of the PbO
      ZrO(2)-TiO(2) system. From the results, the enthalpy, Gibbs free energy and
      entropy of formation of PbTiO(3) (PT), PbZrO(3) (PZ) and Pb(Zr,Ti)O(3) (PZT) were
      evaluated. In addition, the single phase widths of Pb(Zr(0.5)Ti(0.5))O(3) and
      PbTiO(3) perovskite structures were determined at 1100 K. The reaction rate of
      PZT synthesis in vacuo was followed by direct measurement of the change of PbO
      activity with time. Lead oxide activity in stoichiometric Pb(Zr(0.5)Ti(0.5))O(3),
      PbTiO(3) and Pb(0.968)(Zr(0.5)Ti(0.5))O(2.968) (3% lead deficient) at 850 degrees
      C was found to be 0.40, 0.45 and 0.1, respectively. PZT, PT and PZ powder samples
      prepared by a solid state procedure were also measured, all revealing lead
      deficiency. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407291
TI  - The analysis of alkyl-capped alcohol ethoxylates and alcohol ethoxycarboxylates
      from alcohol ethoxylates by atmospheric pressure chemical ionization mass
      spectrometry.
AB  - Alcohol ethoxylates (AEs) are nonionic surfactants. They are industrially
      important compounds that have historically been difficult to analyze, with the
      best results to date achieved through derivatization (e.g., silylation) followed
      by analysis by gas chromatography/mass spectrometry (GC/MS). Recently, mass
      spectrometric techniques such as field desorption (FD), time-of-flight secondary
      ion mass spectrometry (TOF-SIMS), fast atom bombardment (FAB), electrospray
      ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) have
      been employed to analyze surfynol(R) 4xx. In an effort to produce low-cost alkyl
      capped AEs and anionic detergents from AEs, a fast and reliable measure of the
      product yields and conversions from AEs is required in research. We found that
      the product yields and conversions from reactions of AEs, obtained by the
      employment of atmospheric pressure chemical ionization (APCI), were in good
      agreement with those obtained from proton nuclear magnetic resonance spectroscopy
      ((1)H-NMR). Therefore, APCI can be used as a validated tool for studying AE
      reactions. Mixtures that contain either silylated or unsilylated ethoxylates
      and/or carboxylates yield the same APCI mass spectra. Copyright -Copyright 1999
      John Wiley & Sons, Ltd.

PMID- 10407292
TI  - High throughput liquid chromatography/mass spectrometric analyses using a novel
      multiplexed electrospray interface.
AB  - A novel four- channel multiplexed electrospray liquid chromatography interface is
      described. This device has been used to analyse both single components and
      mixtures by liquid chromatography/mass spectrometry (LC/MS) as well as synthetic
      samples prepared by automated procedures. These data provided unambiguous
      molecular weight assignments to both major components and synthetic by-products
      in these samples. In this work particular attention has also been paid to the
      elimination of interchannel crosstalk. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407293
TI  - Interaction between explosive and analyte layers in explosive matrix-assisted
      plasma desorption mass spectrometry.
AB  - An HMX/insulin two-layer system was chosen as a model for further investigation
      of the matrix properties of explosive materials for protein analytes in plasma
      desorption mass spectrometry. The dependencies of the molecular ion yield and
      average charge state as a function of the analyte thickness were studied. An
      increase in the charge state of multiply protonated molecular species was
      confirmed as the major matrix effect, with the average charge state z at the
      smallest thickness studied being higher than in matrix-assisted laser
      desorption/ionization and closer to the value obtained in electrospray ionization
      under standard acidic conditions. Observed charge state distributions are
      significantly narrower than the corresponding Poisson distributions, which
      suggests that the protonation of insulin is limited in plasma desorption by the
      number of basic sites in the molecule, similar to electrospray ionization. Both
      the curve displaying total molecular ion yield and the one showing the total
      charge (proton) yield as a function of the insulin thickness have maxima at a
      thickness different from an insulin monolayer. These observations diminish the
      significance of a matrix/analyte interface mechanism for the explosive matrix
      assistance. Instead, a mechanism related to the chemical energy release during
      conversion of the explosive after the ion impact is proposed. As additional
      mechanisms, enhanced protonation of the analyte through collisions with products
      of the explosive decay is considered, as well as electron scavenging by other
      products, which leads to a higher survival probability of positively charged
      protein molecular ions. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407294
TI  - The effects of sample preparation methods on the variability of the electrospray
      ionization response for model drug compounds.
AB  - A post-column infusion system was developed in order to analyze suppression of
      electrospray ionization (ESI) tandem mass spectrometry response in the presence
      of endogenous plasma interferences. By enabling direct detection of these
      interfering components, this experimental system was used to analyze the ability
      of several common extraction procedures to remove endogenous plasma components
      that cause changes in the ESI response of model drug substances. Methyl-t-butyl
      ether (MTBE) liquid-liquid, Oasis and Empore solid-phase, and acetonitrile (ACN)
      protein precipitation sample preparation methods were tested using the post
      column infusion system. In all cases, ACN protein precipitation samples showed
      the greatest amount of ESI response suppression while liquid-liquid extracts
      demonstrated the least. In addition, the three test compounds, phenacetin,
      caffeine, and a representative Merck compound, demonstrated that ESI response
      suppression is compound dependent. Suppression was greatest with caffeine, the
      most polar analyte, and the smallest for the Merck compound, the least polar
      analyte. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407295
TI  - Memory effects in combining isotope ratio monitoring with isotope dilution mass
      spectrometry.
AB  - Combining isotope ratio monitoring with isotope dilution techniques provides very
      accurate results in the quantitative analysis of volatile organic chemical
      compounds by gas chromatography/mass spectrometry (GC/MS). However, this method
      requires that spikes highly enriched in (13)C be used. This may lead to memory
      effects which will be investigated in more detail. They occur when the component
      of the mixture to be investigated exhibits an isotope ratio which is different
      from that of the component eluted earlier from the column during the
      chromatographic separation process. A residue of this component, which is shown
      in the gas chromatogram as tailing, falsifies the result of the isotope ratio
      measurement. This also leads to false amount-of-substance measurement results.
      Memory effects can be avoided by using spikes of low (13)C content, by adjusting
      the composition of the reference solution to that of the sample, or by ensuring
      effective sample preparation, thus separating disturbing mixture components prior
      to the measurement. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407296
TI  - Electrospray ionization multiple-stage tandem mass spectrometric analysis of
      diglycosyldiacylglycerol glycolipids from the bacteria Bacillus pumilus.
AB  - Electrospray ionization (ESI) combined with multiple-stage tandem mass
      spectrometry (MS(n)) was used to directly analyze the glycolipid mixture from
      bacteria Bacillus pumilus without preliminary separation. Full scan ESI-MS
      revealed the composition of picomole quantities of glycerolglycolipid species
      containing C(14)-C(19) fatty acids, some of which were monounsaturated. Two main
      components were identified from their molecular masses and fragmentation
      pathways. The fragmentation pathway of the known compound compared with the
      investigated compound verified the proposed structure as 1(3)-acyl-2
      pentadecanoyl-3(1)-O-[beta-D-glucopyranosyl-(1-->6)-O-beta-D-glucopyranosyl]-sn
      glycerols. A comparison of the multiple tandem mass spectra of the different
      alkali-metal cation adducts indicates that the intensity of fragments and the
      dissociation pathways are dependent on the alkali-metal type. The basic
      structures of glycerolglycolipids were reflected clearly from the fragmentation
      patterns of the sodium cations. The intense fragments of the sugar residue from
      the precursor ions were obtained from the lithiated adduct ions. ESI-MS(n)
      spectra of [M + K](+) ions did not provide as much fragmentation as [M + Na](+)
      and [M + Li](+) adducts, but their spectra allow the position of glycerol
      acylation to be determined. On the basis of MS(2) spectra of [M + K](+) ions, it
      was established that all components have a C(15:0) fatty acid at the sn-2
      position of the glycerol backbone and C(14)-C(19) acids at the sn-1 position of
      the glycerol backbone. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407297
TI  - Precise mass measurement of a double-stranded 500 base-pair (309 kDa) polymerase
      chain reaction product by negative ion electrospray ionization Fourier transform
      ion cyclotron resonance mass spectrometry.
AB  - Electrospray ionization Fourier transform ion cyclotron resonance mass
      spectrometry (ESI-FTICRMS) has been used to determine the mass of a double
      stranded 500 base-pair (bp) polymerase chain reaction (PCR) product with an
      average theoretical mass of the blunt-ended (i.e. unadenylated) species of 308
      859.35 Da. The PCR product was generated from the linearized bacteriophage Lambda
      genome which is a double-stranded template. Utilization of ethanol precipitation
      in tandem with a rapid microdialysis step to purify and desalt the PCR product
      was crucial to obtain a precise mass measurement. The PCR product (0.8 pmol/uL)
      was electrosprayed from a solution containing 75% acetonitrile, 25 mM piperidine,
      and 25 mM imidazole and was infused at a rate of 200 nL/min. The average
      molecular mass and the corresponding precision were determined using the charge
      states ranging from 172 to 235 net negative charges. The experimental mass and
      corresponding precision (reported as the 95% confidence interval of the mean) was
      309 406 +/- 27 Da (87 ppm). The mass accuracy was compromised due to the fact
      that the PCR generates multiple products when using Taq polymerase due to the non
      template directed 3'-adenylation. This results in a mixture of three PCR products
      with nearly identical mass (i.e. blunt-ended, mono-adenylated and di-adenylated)
      with unknown relative abundances that were not resolved in the spectrum. Thus,
      the experimental mass will be a weighted average of the three species which,
      under our experimental conditions, reflects a nearly equal concentration of the
      mono- and di-adenylated species. This report demonstrates that precise mass
      measurements of PCR products up to 309 kDa (500 bp) can be routinely obtained by
      ESI-FTICR requiring low femtomole amounts. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407298
TI  - Rapid Commun. Mass Spectrom. 13, 740 ?lpar;1999?rpar; by J. W. Hager,
      ?ldquo;Performance Optimization and Fringing Field Modifications of a
      24?hyphen;mm Long RF?hyphen;only Quadrupole Mass Spectrometer?rdquo;

PMID- 10407299
TI  - Selected papers from the Stable Isotope Mass Spectrometry Users Group (SIMSUG)
      meeting. Exeter, United Kingdom, 19-20 January 1999.

PMID- 10407300
TI  - High precision delta(17)O isotope measurements of oxygen from silicates and other
      oxides: method and applications.
AB  - The use of infrared laser-assisted fluorination to release oxygen from milligram
      quantities of silicates or other oxide mineral grains is a well-established
      technique. However, relatively few studies have reported the optimisation of this
      procedure for oxygen-17 isotope measurements. We describe here details of an
      analytical system using infrared (10 um) laser-assisted fluorination, in
      conjunction with a dual inlet mass spectrometer of high resolving power (
      approximately 250) to provide (17)O and (18)O oxygen isotope measurements from
      0.5-2 mg of silicates or other oxide mineral grains. Respective precisions (1) of
      typically 0.08 and 0.04 per thousand are obtained for the complete analytical
      procedure. Departures from the mass-dependent oxygen isotope fractionation line
      are quantified by Delta(17)O; our precision (1) of such measurements on
      individual samples is shown to be +/-0.024 per thousand. In turn, this permits
      the offset between parallel, mass-dependent fractionation lines to be
      characterised to substantially greater precision than has been possible hitherto.
      Application of this system to investigate the (17)O versus (18)O relationship for
      numerous terrestrial whole-rock and mineral samples, of diverse geological
      origins and age, indicates that the complete data set may be described by a
      single, mass-dependent fractionation line of slope 0.5244+/- 0.00038 (standard
      error). Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407301
TI  - A laser extraction/combustion technique for in situ delta(13)C analysis of
      organic and inorganic materials.
AB  - A CO(2) laser extraction system is described for in situ delta(13)C analysis of
      organic and inorganic materials. Carbonaceous compounds volatilized by the laser
      are quantitatively converted to CO(2) gas by a combustion furnace mounted after
      the sample chamber. Gases produced by the laser and combustion processes are
      swept by helium carrier gas and separated by a packed gas chromatography column
      prior to their introduction to an isotope ratio monitoring mass spectrometer. A
      sample of lentil bean was analyzed at a spatial resolution of 200 um and yielded
      delta(13)C values with precision of +/- 0.3 per thousand. The accuracy of
      delta(13)C measurements was better than +/- 0.5 per thousand from NBS 22 (mineral
      oil), USGS 24 (graphite), and IAEA CO-1 (calcium carbonate). Copyright 1999 John
      Wiley & Sons, Ltd.

PMID- 10407302
TI  - Isotope ratio monitoring gas chromatography/Mass spectrometry of D/H by high
      temperature conversion isotope ratio mass spectrometry.
AB  - Of all the elements, hydrogen has the largest naturally occurring variations in
      the ratio of its stable isotopes (D/H). It is for this reason that there has been
      a strong desire to add hydrogen to the list of elements amenable to isotope ratio
      monitoring gas chromatography/mass spectrometry (irm-GC/MS). In irm-GC/MS the
      sample is entrained in helium as the carrier gas, which is also ionized and
      separated in the isotope ratio mass spectrometer (IRMS). Because of the low
      abundance of deuterium in nature, precise and accurate on-line monitoring of D/H
      ratios with an IRMS requires that low energy helium ions be kept out of the m/z 3
      collector, which requires the use of an energy filter. A clean mass 3 (HD(+.))
      signal which is independent of a large helium load in the electron impact ion
      source is essential in order to reach the sensitivity required for D/H analysis
      of capillary GC peaks. A new IRMS system, the DELTA(plus)XL(trade mark), has been
      designed for high precision, high accuracy measurements of transient signals of
      hydrogen gas. It incorporates a retardation lens integrated into the m/z 3
      Faraday cup collector. Following GC separation, the hydrogen bound in organic
      compounds must be quantitatively converted into H(2) gas prior to analysis in the
      IRMS. Quantitative conversion is achieved by high temperature conversion (TC) at
      temperatures >1400 degrees C. Measurements of D/H ratios of individual organic
      compounds in complicated natural mixtures can now be made to a precision of 2 per
      thousand (delta notation) or, better, with typical sample amounts of
      approximately 200 ng per compound. Initial applications have focused on compounds
      of interest to petroleum research (biomarkers and natural gas components), food
      and flavor control (vanillin and ethanol), and metabolic studies (fatty acids and
      steroids). Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407303
TI  - Routine analysis by high precision gas chromatography/mass selective
      detector/isotope ratio mass spectrometry to 0.1 parts per mil.
AB  - Stable isotope methods are potentially quite useful for validating natural or
      enhanced mineral degradation of contaminants. For this reason, a continuous flow
      gas chromatograph (GC), isotope ratio mass spectrometer (IRMS) has been coupled
      with a quadrupole mass selective detector (MSD) to allow simultaneous mass
      spectral and stable carbon isotope ratio data to be obtained from a single
      chromatographic analysis. This allows the target contaminant and any extra
      cellular degradation intermediates to be both qualified and quantified.
      Previously acceptable limits of precision (0.3 parts per mil) are undesirable
      given the small fractionation observed during aerobic degradation. To further
      understand the fate of organic contaminants and to gain information about the
      metabolic degradative pathway employed by a microorganism, routine isotopic
      analyses on a range of analytes have been performed. Quantities of sample
      producing mass-44 ion beam signal (I(44)) of 2 x 10(-10) to 1 x 10(-8) A were
      analysed. When the IRMS was tuned for high sensitivity, ion source nonlinearities
      were overcome by peak height correction from an algorithm that was produced using
      known isotopic standards of varying concentrations. This led to sample accuracy
      of <0.01 per thousand and sample precision of 0.1 per thousand. Copyright 1999
      John Wiley & Sons, Ltd.

PMID- 10407304
TI  - ConFlo III - an interface for high precision delta(13)C and delta(15)N analysis
      with an extended dynamic range.
AB  - A newly developed interface coupling a CHN combustion device (elemental analyser
      'EA') to an isotope ratio mass spectrometer is described and evaluated. The
      purpose of the device is to extend the dynamic range of delta(13)C and delta(15)N
      analysis from less than 2 orders of magnitude to more than 3 orders of magnitude.
      Carbon isotope ratio measurements of atropine as a model compound have been
      performed analysing between 1 ug to 5 mg C with acceptable to excellent precision
      (0.6 to 0.06 per thousand, delta-notation). The correction due to the blank
      signal is critical for sample amounts smaller than 4 ug C. The maximum sample
      weight is determined by the combustion capacity of the EA. Larger sample amounts
      are measured using dilution of a small part of the EA effluent with helium. The
      dilution mechanism works virtually free of isotope fractionation. Copyright 1999
      John Wiley & Sons, Ltd.

PMID- 10407305
TI  - Experimental calibration and field investigation of the oxygen isotopic
      fractionation between biogenic aragonite and water.
AB  - Marine molluscs have long been recognised as potential records of palaeoclimate
      change using the patterns and differences in the stable isotopic composition of
      the carbonate shells. The aim of this study is to improve the robustness of this
      approach for aragonitic molluscs by completing the first experimental calibration
      of the fractionation between water and biogenic aragonite. Fractionation factors
      were calibrated by growing specimens of the freshwater mollusc Lymnaea peregra
      under controlled conditions of water temperature and isotopic composition.
      Fifteen populations of L. peregra were maintained at constant temperature and
      isotopic conditions for five months (at five different temperatures and using
      three different water compositions). Water samples and temperature measurements
      were taken regularly throughout the experiment. The temperature dependence of the
      fractionation factor, between 8 and 24 degrees C, is given by: 1000 ln
      alpha=16.74x(1000T(-1))-26.39 (T in Kelvin) and the relationship between
      temperature (T), delta(18)O(carb) and delta(18)O(wat) is given by: T=21.36
      4.83xdelta(+ degrees )O(carb)-delta(+ degrees )O(wat) (T is in degrees C,
      delta(18)O(carb) is with respect to Vienna Pee Dee Belemnite (PDB), the
      International Atomic Energy Agency (IAEA) replacement standard for PDB, and
      delta(18)O(wat) is with respect to Vienna standard mean ocean water (VSMOW)) The
      outcome of the controlled experiment is compared with previous studies on
      synthetic, and biogenic, calcite and aragonite from field and laboratory
      investigations. These comparisons suggest that although a vital offset exists
      between the fractionation of isotopes in synthetic and biogenic aragonite for
      molluscs in general, there is no vital effect that is specific either to
      freshwater, or to individual, genera. Therefore, the calibrated relationship may
      be used for any freshwater or marine mollusc to derive palaeotemperatures
      providing the isotopic composition of the environmental water can be reliably
      constrained. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407306
TI  - Standardization for oxygen isotope ratio measurement - still an unsolved problem.
AB  - Numerous organic and inorganic laboratory standards were gathered from nine
      European and North American laboratories and were analyzed for their delta(18)O
      values with a new on-line high temperature pyrolysis system that was calibrated
      using Vienna standard mean ocean water (VSMOW) and standard light Antartic
      precipitation (SLAP) internationally distributed reference water samples.
      Especially for organic materials, discrepancies between reported and measured
      values were high, ranging up to 2 per thousand. The reasons for these
      discrepancies are discussed and the need for an exact and reliable calibration of
      existing reference materials, as well as for the establishment of additional
      organic and inorganic reference materials is stressed. Copyright 1999 John Wiley
      & Sons, Ltd.

PMID- 10407307
TI  - Measurement of urinary total 13C and 13C urea by isotope ratio mass spectrometry
      after administration of lactose [13C]-ureide.
AB  - A method of measuring total 13C excreted in urine after oral administration of
      lactose [13C]-ureide was developed using isotope ratio mass spectrometry.
      Furthermore, a method to measure 13C urea excreted in the urine was developed.
      Each urine sample collected over a 24 hour period, after administration of the
      tracer dose, was analysed for both total 13C and 13C urea. Combustion of the
      dried urine samples allowed measurement of the total 13C content. Treatment of
      urine samples with urease (EC 3.5.1.5) and analysis by isotope ratio mass
      spectrometry of the CO2 evolved allowed measurement of 13C urea in the urine
      sample. The total 13C and 13C urea content of each urine sample, obtained
      throughout the protocol, were compared to total 13C and 13C urea contents of a
      urine sample taken before the test. This allowed calculation of the fraction of
      tracer incorporated into urea and the fraction of tracer excreted in total.
      Analyses showed that approximately 15% of the dose administered, in terms of 13C,
      was recovered in the urine over the sampling period. Further analysis for urinary
      13C urea showed that less than 1% of the label was incorporated into urea
      excreted over the sampling period.

PMID- 10407308
TI  - Determination of the oxygen-18/oxygen-16 isotope ratios of sugar, citric acid and
      water from single strength orange juice.
AB  - The ratio of the stable isotopes of oxygen (18O/16O) has been measured in the
      sugar, citric acid and water from authentic single strength orange juices,
      originating from a number of different countries. The sugars and citric acid were
      recovered from the juices and their 18O/16O ratios were determined by
      pyrolysis/continuous flow-isotope ratio mass spectrometry (Py/CF-IRMS). The
      18O/16O ratio of the fruit juice water was determined by the carbon dioxide/water
      equilibration method. The delta 18O/1000 values of 45 different sugars ranged
      from +29.1 to +38.8/1000 and 15 citric acids ranged from +18.9 to +25.4/1000. The
      delta 18O/1000 value of the water present in the same samples ranged from -2.1 to
      +7.8/1000. A correlation was evident between the delta 18O/1000 values of the
      sugar, citric acid and water from the juices. This information can be used to
      improve the assessment of the authenticity of commercial 'freshly squeezed'
      orange juices. The detection of the presence of reconstituted orange juice
      concentrate in 'freshly squeezed' orange juices was improved by 37% using
      regression analysis of the combined water and sugar delta 18O/1000 ratios when
      compared to the use of delta 18O/1000 ratios of fruit juice water alone.

PMID- 10407310
TI  - Molecular insight into soil carbon turnover.
AB  - Curie-point pyrolysis-gas chromatography coupled on-line to mass spectrometry (Py
      GC/MS) and isotope ratio mass spectrometry (Py-GC/IRMS) were used to determine
      the individual turnover rate of specific carbohydrates, lignin, lipids and N
      containing compounds from French arable soils. The analysed soils were
      cultivated, either continuously with a C3 plant (wheat delta(13)C-value = -25.2
      per thousand), or transferred to a C4 plant (maize delta(13)C-value = -11.4 per
      thousand) cropping 23 years ago. Most pyrolysis products identified were related
      to carbohydrates (furans), lipids (hydrocarbons and derivatives of benzene),
      proteins (nitriles and pyrrole) and lignins (phenols). The relative yield of all
      individual pyrolysis products was similar in the samples from the maize and
      control wheat soil. The isotopic enrichment between identical pyrolysis products
      from the two soils varied from 1 to 12 delta (delta) units, indicating that after
      23 years of cultivation 7 to 90% of their C was derived from maize. This suggests
      a slow mean turnover time varying from 9 to 220 years. Based on the differences
      in isotopic enrichment of chemical structures after vegetation change the
      pyrolysis products could be divided into three groups: (i) pyrolysis products
      with a nearly complete C4 signal, e. g. phenol, derived from lignin degradation
      products, (ii) pyrolysis products with an intermediate isotopic enrichment of 6-8
      per thousand, most likely to be a composite of remaining (possibly physically
      protected) fragments derived from both maize and native wheat, and (iii)
      pyrolysis products showing only low enrichments in (13)C of 1-3 per thousand.
      Most of their precursors were found to be proteinaceaous materials. This
      indicates that proteins or peptides are indeed preserved during decomposition and
      humification processes occurring in the soil. Our study highlights the potential
      of Py-GC/MS-C-IRMS to further novel insights into the dynamics of soil organic
      constituents. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407309
TI  - Stable isotopes in ecosystem science: structure, function and dynamics of a
      subtropical Savanna.
AB  - Stable isotopes are often utilized as intrinsic tracers to study the effects of
      human land uses on the structural and functional characteristics of ecosystems.
      Here, we illustrate how stable isotopes of H, C, and O have been utilized to
      document changes in ecosystem structure and function using a case study from a
      subtropical savanna ecosystem. Specifically, we demonstrate that: (1) delta 13C
      values of soil organic carbon record a vegetation change in this ecosystem from
      C4 grassland to C3 woodland during the past 40-120 years, and (2) delta 2H and
      delta 18O of plant and soil water reveal changes in ecosystem hydrology that
      accompanied this grassland-to-woodland transition. In the Rio Grande Plains of
      North America, delta 13C values of plants and soils indicate that areas now
      dominated by C3 subtropical thorn woodland were once C4 grasslands. delta 13C
      values of current organic matter inputs from wooded landscape elements in this
      region are characteristic of C3 plants (-28 to -25/1000), while those of the
      associated soil organic carbon are higher and range from -20 to -15/1000.
      Approximately 50-90% of soil carbon beneath the present C3 woodlands is derived
      from C4 grasses. A strong memory of the C4 grasslands that once dominated this
      region is retained by delta 13C values of organic carbon associated with fine and
      coarse clay fractions. When delta 13C values are evaluated in conjunction with
      14C measurements of that same soil carbon, it appears that grassland-to-woodland
      conversion occurred largely within the past 40-120 years, coincident with the
      intensification of livestock grazing and reductions in fire frequency. These
      conclusions substantiate those based on demographic characteristics of the
      dominant tree species, historical aerial photography, and accounts of early
      settlers and explores. Concurrent changes in soil delta 13C values and organic
      carbon content over the past 90 years also indicate that wooded landscape
      elements are behaving as sinks for atmospheric CO2 by sequestering carbon derived
      from both the previous C4 grassland and the present C3 woody vegetation. Present
      day woodlands have hydrologic characteristics fundamentally different from those
      of the original grasslands. Compared to plants in remnant grasslands, tree and
      shrub species in the woodlands are rooted more deeply and have significantly
      greater root biomass and density than grasslands. delta 18O and delta 2H values
      of plant and soil water confirm that grassland species acquire soil water
      primarily from the upper 0.5 m of the soil profile. In contrast, trees and shrubs
      utilize soil water from throughout the upper 4 m of the profile. Thus, soil water
      that formerly may have infiltrated beyond the reach of the grassland roots and
      contributed to local groundwater recharge or other hydrologic fluxes may now be
      captured and transpired by the recently formed woodland plant communities. The
      natural abundances of stable isotopes revealed fundamental information regarding
      the impacts of human land use activities on the structure and function of this
      subtropical savanna. Stable isotopes provided direct, spatially explicit evidence
      for dramatic changes in ecosystem physiognomy and demonstrated some functional
      consequences for the hydrologic cycle. Furthermore, grassland-to-woodland
      conversion has been geographically extensive in the worlds' drylands, suggesting
      that these ecosystem-level changes in vegetation structure, carbon cycling, and
      hydrology may have implications for regional/global biogeochemistry and climate.

PMID- 10407311
TI  - Isotopic ((13)C) fractionation during plant residue decomposition and its
      implications for soil organic matter studies.
AB  - Carbon isotopic fractionations in plant materials and those occurring during
      decomposition have direct implications in studies of short-and longer-term soil
      organic matter dynamics. Thus the products of decomposition, the evolved CO(2)
      and the newly formed soil organic matter, may vary in their (13)C signature from
      that of the original plant material. To evaluate the importance of such
      fractionation processes, the variations in (13)C signatures between and within
      plant parts of a tropical grass (Brachiaria humidicola) and tropical legume
      (Desmodium ovalifolium) were measured and the changes in (13)C content
      (signatures) during decomposition were monitored over a period of four months. As
      expected the grass materials were less depleted in (13)C (-11.4 to -11.9 per
      thousand) than those of the legume (-27.3 to -25.8 per thousand). Root materials
      of the legume were less (1.5 per thousand) depleted in (13)C compared with the
      leaves. Plant lignin-C was strongly depleted in (13)C compared with the bulk
      material by up to 2.5 per thousand in the legume and up to 4.7 per thousand in
      the grass. Plant materials were subsequently incubated in a sand/nutrient
      solution/microbial inoculum mixture. The respiration product CO(2) was trapped in
      NaOH and precipitated as CaCO(3), suitable for analysis using an automated C/N
      analyser coupled to an isotope ratio mass spectrometer. Significant depletion in
      (13)C of the evolved CO(2) was observed during the initial stages of
      decomposition probably as a result of microbial fractionation as it was not
      associated with the (13)C signatures of the measured more decomposable fractions
      (non-acid detergent fibre and cellulose). While the cumulative CO(2)-(13)C
      signatures of legume materials became slightly enriched with ongoing
      decomposition, the CO(2)-C of the grass materials remained depleted in (13)C.
      Associated isotopic fractionation correction factors for source identification of
      CO(2-)C varied with time and suggested errors of 2-19% in the estimation of the
      plant-derived C at 119 days of incubation in a soil of an intermediate (-20.0 per
      thousand) (13)C signature. Analysis of the residual material after 119 days of
      incubation showed little or no change in the (13)C signature partly due to the
      incomplete decomposition at the time of harvesting. Copyright 1999 John Wiley &
      Sons, Ltd.

PMID- 10407312
TI  - Natural 13C abundance: a tool to trace the incorporation of dung-derived carbon
      into soil particle-size fractions.
AB  - During the decay of 13C enriched dung patches, the; delta 13C signal of surface
      soil (1-5 cm) increased with a temporary maximum after 42 d. To understand the
      underlying processes, we investigated the incorporation of dung-derived C into
      soil particle-size fractions. Dung, collected from beef steers fed on maize
      (delta 13C = -15.36/1000) or ryegrass (delta 13C = -25.67/1000), was applied in
      circular patches to a C3 pasture at North Wyke, UK. Triplicates were sampled from
      surface soil (1-5 cm) at 14, 28, 42, and 70 d after application, pooled,
      separated into fine (< 0.2 micron) and coarse clay (0.2-2 microns), silt plus
      fine sand (2-250 microns), and coarse sand (250-2000 microns), and analyzed for
      total C, N, and delta 13C. As particle-size diameter decreased, the C/N ratios
      decreased and delta 13C values increased at all plots due to increasing microbial
      alteration of soil organic matter. After dung application, ca. 60% of dung
      derived C in soil was recovered in the 0.2-250 microns fractions during the whole
      experiment. The proportion of dung-derived C in the fine clay peaked 42 d after
      dung application, coinciding with the delta 13C maximum in the bulk soil and the
      maximum leaching rate measured in lysimeters at this time in another study at the
      same sites. The percentage of dung-derived C as particulate C in the coarse sand
      fraction increased until the end of the experiment. We conclude that
      incorporation of C into soil from decomposing dung patches involved both
      temporary sorption of leached dung C to < 0.2 micron fractions and continuous
      accumulation of particulate C (> 250 microns).

PMID- 10407313
TI  - Stable isotopic studies of earthworm feeding ecology in tropical ecosystems of
      Puerto Rico.
AB  - Feeding strategies of earthworms and their influence on soil processes are often
      inferred from morphological, behavioral and physiological traits. We used (13)C
      and (15)N natural abundance in earthworms, soils and plants to explore patterns
      of resource utilization by different species of earthworms in three tropical
      ecosystems in Puerto Rico. In a high altitude dwarf forest, native earthworms
      Trigaster longissimus and Estherella sp. showed less (15)N enrichment ((15)N = 3
      6 per thousand) than exotic Pontoscolex corethrurus ((15)N =7-9 per thousand)
      indicating different food sources or stronger isotopic discrimination by the
      latter. Conversely, in a lower altitude tabonuco forest, Estherella sp. and P.
      corethrurus overlapped completely in (15)N enrichment ((15)N = 6-9 per thousand),
      suggesting the potential for interspecific competition for N resources. A
      tabonuco forest converted to pasture contained only P. corethrurus which were
      less enriched in (15)N than those in the forest sites, but more highly enriched
      in (13)C suggesting assimilation of C from the predominant C(4) grass. These
      results support the utility of stable isotopes to delineate resource partitioning
      and potential competitive interactions among earthworm species. Copyright 1999
      John Wiley & Sons, Ltd.

PMID- 10407314
TI  - A dynamic study of earthworm feeding ecology -using stable isotopes.
AB  - Changes in the specific diet of earthworms with time in relation to landuse
      changes and two different climates were studied by analysing (13)C and (15)N
      natural abundance in soils and animals. Soil samples from three depths (0-10, 10
      20 and 20-30 cm) and earthworms were collected from two sites: Santiago
      (Northwest Spain) and North Wyke (Southwest England) both consisting of
      replicated long-term grasslands and recently converted to maize plots. Earthworms
      were hand-sorted in the field at the peak of the maize growth and after
      harvesting at both sites. In the Spanish plots, nine and eight earthworm species,
      all belonging to the three ecological categories (epigeic, anecic and endogeic),
      were found under maize and permanent pasture, whereas at the English site five
      and seven different species were, respectively, identified. At both sites (13)C
      isotopic values of the earthworm tissues reflected changes in diet from C(3) to
      C(4) with epigeic and epi/anecic worms in the maize plots showing one delta unit
      difference in relation to the ones found in the grassland plots. Anecic worms
      seemed to be less responsive to landuse changes. The higher (13)C values of the
      Spanish soils were also reflected in the earthworm tissues when compared with the
      English samples. (15)N values showed no clear relationship with the cropping
      treatments but were clearly related to the ecological grouping, with endogeic
      worms reaching the highest values whereas for the epigeic and epi/anecic species
      the lowest values were obtained. This finding was also previously recorded by
      other authors1 and suggests that, in the future, stable isotope techniques could
      also be a useful tool in taxonomic studies. Copyright 1999 John Wiley & Sons,
      Ltd.

PMID- 10407316
TI  - Carbon stable isotopes reveal complex trophic interactions in lake plankton.
AB  - The lower trophic linkages in lake plankton food webs are generally described as
      relatively simple, even accounting for the additional complexity of potential
      'microbial looping'. Crustacean zooplankton are frequently amalgamated into one
      trophic functional group as grazers of autotrophic production. The carbon stable
      isotope ratios for separated zooplankton species, particulate organic matter
      (POM) and phytoplankton from a number of lakes in Finland and the UK were
      analysed. These revealed greater complexity in trophic interactions than would
      otherwise be observed if the zooplankton had been represented by a mixed sample.
      Grazing zooplankton were usually depleted in (13)C relative to the bulk POM on
      which they might feed, with (13)C deviating by up to 17 per thousand There were
      no consistent differences between (13)C values for copepods and cladocerans.
      Predatory cladocerans were generally enriched by greater than 1 per thousand
      compared to their putative prey. We suggest that care in separating the
      zooplankton species for stable isotope analysis may expose otherwise undetected
      sources of carbon and facilitate unravelling trophic links further up the food
      web. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407315
TI  - Should growing and adult animals fed on the same diet show different delta 15N
      values?
AB  - Animals usually show a delta 15N value that is slightly higher than that of their
      food. The value of this enrichment appears to be fairly constant among species
      (approximately 3/1000). This phenomenon is more and more widely used in
      ecological research to study individual diets or the trophic structure of whole
      communities. However, very little is known about the mechanisms that actually
      explain how this trophic isotopic enrichment occurs. Most ideas about these
      mechanisms are only expressed verbally, so that it is difficult to get a clear
      picture of what is actually known, and how these pieces of knowledge interact. We
      propose a very simple model that describes mathematically what is currently known
      on the trophic isotopic enrichment phenomenon in animals. This model cannot
      replace actual measurements and investigations about the mechanisms explaining
      the phenomenon. However, it allows the clarification of some ideas such as what
      conditions have to be fulfilled in order for the trophic isotopic enrichment to
      occur. Our formalization accounts for all the known features of the trophic
      isotopic enrichment phenomenon that we consider in this paper in both a
      qualitative and quantitative manner (at least for orders of magnitude). A
      prediction of the theory, that can be tested, is that growing animals should show
      the same delta 15N values as those of adults fed the same diet if the total
      amount of nitrogen they assimilate during their growth is large compared to the
      total nitrogen content of their adult body. It seems likely that this condition
      is fulfilled in most cases.

PMID- 10407317
TI  - Interpreting early land management through compound specific stable isotope
      analyses of archaeological soils.
AB  - Compound specific stable isotope analyses of managed soils using isotope ratio
      mass spectrometry have been undertaken as a means of determining early land use
      practices. delta (15)N amino acid signals demonstrate differences between manured
      grassland, unmanured grassland and continuous cereal cultivation under long-term
      experimental land use control conditions, with delta (15)N in hydrophobic amino
      acids providing the most distinctive signals. Analysis of early modern/medieval
      and of Bronze age anthropogenic soils from Orkney demonstrates that such signals
      are retained in archaeological contexts. delta (13)C analyses of n- alkanoic acid
      components of the fossil, Bronze Age, anthropogenic soils suggest a major
      terrestrial input to these soils, with uniform composition of formation
      materials. Surficial soils demonstrate the assimilation of isotopically lighter
      carbon, providing a means of assessing the mobility of the n- alkanoic acids
      within soils and sediments. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407318
TI  - Plant delta(15)N associated with arbuscular mycorrhization, drought and nitrogen
      deficiency.
AB  - It has long been evident that plant (15)N chiefly reflects the processes which
      fractionate (15)N/(14)N rather than the (15)N of plant N source(s). It has
      emerged recently that one of the most important fractionating processes
      contributing to the whole plant (15)N is the presence/absence, type or species of
      mycorrhiza, especially when interacting with nutrient deficiency. Ecto- and
      ericoid mycorrhizas are frequently associated with (15)N-depleted foliar (15)N,
      commonly as low as -12 per thousand. As shown by the present study, plants having
      no mycorrhiza, or those infected with various species of arbuscular mycorrhiza
      (AM)-forming fungi, interact with varying concentrations of soil nitrogen [N] and
      moisture to enrich plant (15)N by as much as 3.5 per thousand. Hence the lack of
      a mycorrhiza, or variation in the species of AM-forming fungal associations, can
      account for about 25% of the usually reported variations of foliar (15)N found in
      field situations and do so by (15)N enrichment rather than depletion. Copyright
      1999 John Wiley & Sons, Ltd.

PMID- 10407319
TI  - 15N Analysis of nitric oxide and nitrous oxide by cryotrap enrichment using a gas
      chromatograph quadrupole mass spectrometer and its application to (15)N-tracer
      investigations of NO/N(2)O formation in soil.
AB  - Nitric oxide (NO) and nitrous oxide (N(2)O) are two important trace gases in the
      atmosphere. Determining the concentration and (15)N abundance of NO and N(2)O in
      air is difficult owing to their very low concentration in the atmosphere (NO < 1
      ppb(v); N(2)O approximately 0.32 ppm(v)). Although (15)N analysis of N(2)O in
      ambient concentrations can be carried out using a gas chromatograph quadrupole
      mass spectrometer system (GC-QMS) and a dosage of 2 mL of air by means of a
      sample loop, this system is not sensitive enough to measure the ambient
      concentration of NO and its (15)N abundance. Therefore the concentration of NO
      must be enriched by cryotrapping (cooling with liquid nitrogen). The (15)N
      analytical method developed enables the sensitive and sufficiently precise
      measurement of (15)N-enriched NO in air. Furthermore, the analytical equipment
      developed greatly improves existing (15)N(2)O analysis using the GC-QMS
      technique. An application of the (15)N analysis method will be shown for an
      investigation on the NO and N(2)O formation in black earth soil after
      (15)NH(4)(+), (15)NO(3)(-) and (15)NO(2)(-) labelling. Copyright 1999 John Wiley
      & Sons, Ltd.

PMID- 10407320
TI  - The use of static mass spectrometry to determine the combined stable isotopic
      composition of small samples of atmospheric methane.
AB  - Global budgets of atmospheric trace gases are increasingly being constrained by
      means of stable isotope measurements. Published analytical techniques for
      studying the parallel stable isotopic composition of methane (delta(13)C and
      deltaD) require prohibitively large quantities of methane for analysis, making
      them unsuitable for studies where sample size is small, e.g. soil methane fluxes.
      A highly sensitive static mass spectrometer has been developed which uniquely
      uses CH(4) as the analyte. The method requires only 8 ng of CH(4) for analysis
      (<10 mL ambient air), making replicated measurements of the isotopic composition
      of CH(4) in small samples feasible for the first time. This paper provides the
      first detailed description of the instrumentation and the analytical technique.
      The technique has been used to analyse small samples of air collected in
      Snowdonia over 21 months. The combined stable isotopic composition (delta(17)M)
      ranged from 29.5 to 35.5 per thousand, with an average value of 32.2 per
      thousand, and was strongly correlated with wind direction (p <0.01, r(2) = 0.71).
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407321
TI  - Determination of (15)N in (15)N-enriched nitrite and nitrate in aqueous samples
      by reaction continuous flow quadrupole mass spectrometry.
AB  - The (15)N tracer method is the most suitable method for studying complex N
      transformation processes in microbiology and biochemistry. It entails the
      constant determination of the (15)N abundance of the inorganic nitrogen (N)
      compounds nitrite and nitrate. However, (15)N analytical methods are time
      consuming, difficult to automate, and require at least 10 ug of N per
      determination. An additional obstacle in the case of nitrite is that it usually
      only occurs in very small amounts (ppb) dwarfed by much larger quantities of
      nitrate (ppm). More useful is an approach in which the N compound is selectively
      converted into a gaseous form suitable for direct measurement by mass
      spectrometry. By using this 'reaction continuous-flow mass spectrometry' (R/CFMS)
      we developed methods for the (15)N determination of nitrite and nitrate from
      tracer experiment samples, i.e. artificially enriched in (15)N. Because both
      methods are based on the same principle, one continuous flow setup connected
      directly to a quadrupole mass spectrometer for all determinations was used.
      Nitrite and nitrate are reduced to NO by iodide and titanium(III) chloride,
      respectively. The technique developed ensures a precision of relative standard
      deviation </=3% if at least 0.5 and 2 ug N with an abundance of >/=1 at.% are to
      be measured for nitrite and nitrate, respectively. Copyright 1999 John Wiley &
      Sons, Ltd.

PMID- 10407322
TI  - Direct equilibration of soil water for delta(18)O analysis and its application to
      tracer studies.
AB  - Current methods for stable oxygen isotopic (delta (18)O) analysis of soil water
      rely on separation of water from the soil matrix before analysis. These
      separation procedures are not only time consuming and require relatively large
      samples of soil, but also have been shown to introduce a large potential source
      of error. Current research at Queen's University Belfast is focused on using
      direct equilibration of CO(2) with the pore water to eliminate this extraction
      step using the automated Multiprep system and a Micromass Prism III isotope ratio
      mass spectrometer (IRMS). The findings of this research indicate the method is
      less time consuming, more reliable, and reproducible to within accepted limits
      (+/-0.1% per thousand delta (18)O). In this study the direct equilibration method
      is used to analyse delta (18)O tracer profiles in the unsaturated zone of field
      soils, concurrently with chloride tracer profiles, which can be used to assess
      infiltration rates and mechanisms through the unsaturated zone. Copyright 1999
      John Wiley & Sons, Ltd.

PMID- 10407323
TI  - Metallocenes as cationizing agents in the characterization of polystyrenes and
      polyethylene glycols by matrix-assisted laser desorption/ionization time-of
      flight mass spectrometry.
AB  - Very little work has been done on exploring the transition metals as suitable
      cationizing agents for the analysis of polymers by matrix-assisted laser
      desorption/ionization time-of-flight (MALDI-TOF). This paper reports on the
      characterization of polystyrenes and polyethylene glycols with select
      metallocenes as cationizing agents. It was found that ferrocene, nickelocene and
      cobaltocene did indeed cationize the polymer and that, at higher molecular
      weights, very little if any metal clusters were observed. It was also found that
      the signal intensity was improved for the higher molecular weight polymers.

PMID- 10407324
TI  - Analysis of formaldehyde in the headspace of urine from bladder and prostate
      cancer patients using selected ion flow tube mass spectrometry.
AB  - We have used selected ion flow tube mass spectrometry (SIFT-MS) to determine the
      concentration of formaldehyde in the headspace of urine from patients suffering
      from bladder and prostate cancer and from several healthy subjects as controls.
      We address the potential problems associated with the use of ion chemistry to
      quantify formaldehyde in the presence of the relatively large number densities of
      water molecules and show that formaldehyde can be quantified in urine headspace
      using analysis by SIFT-MS. These studies show that formaldehyde is clearly
      elevated in the headspace of the urine from the cancer patients as compared with
      urine from the healthy controls. Thus, with further improvements in the
      methodology and the sensitivity of our SIFT-MS technique, formaldehyde
      quantification in urine headspace using this new analytical method could be a
      valuable non-invasive indicator of the presence of early-stage tumours in the
      body.

PMID- 10407325
TI  - Studies in organic mass spectrometry. Part 24dagger electron ionization mass
      spectra of some aryl(2-nitrobenzo
AB  - The main fragmentation routes of eighteen title compounds and of three 5-chloro
      derivatives have been investigated with the aid of linked scan (B/E = constant)
      spectrometry, accurate mass measurements and deuterium labelling. Copyright 1999
      John Wiley & Sons, Ltd.

PMID- 10407326
TI  - The onset of coulomb explosions in polyatomic molecules 
AB  - With the development of high intensity femtosecond lasers, the ionisation and
      dissociation dynamics of molecules has become an area of considerable interest.
      Using the technique of femtosecond laser mass spectrometry (FLMS), the molecules
      carbon disulphide, pyrimidine, toluene, cyclohexanone and benzaldehyde are
      studied with pulse widths of 50 fs in the near infrared (IR) wavelength region
      (790 nm). Results are presented and contrasted for laser beam intensities around
      10(15) and 10(16) W cm(-2). For the lower intensities, the mass spectra yield
      dominant singly charged parent ions. Additionally, the appearance of doubly
      charged parent ions is evident for carbon disulphide, toluene and benzaldehyde
      with envelopes of doubly charged satellite species existing in these local
      regions. Carbon disulphide also reveals a small triply charged component. Such
      atomic-like features are thought to be a strong fingerprint of FLMS at these
      intensities. However, upon increasing the laser intensity to approximately 10(16)
      W cm(-2), parent ion dominance decreases and the appearance of multiply charged
      atomic species occurs, particularly carbon. This phenomenon has been attributed
      to Coulomb explosions in which the fast absorption of many photons may produce
      transient highly ionised parent species which can subsequently blow apart.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407327
TI  - Secondary ion yields produced by keV atomic and polyatomic ion impacts on a self
      assembled monolayer surface 
AB  - A suite of keV polyatomic or 'cluster' projectiles was used to bombard unoxidized
      and oxidized self-assembled monolayer surfaces. Negative secondary ion yields,
      collected at the limit of single ion impacts, were measured and compared for both
      molecular and fragment ions. In contrast to targets that are orders of magnitude
      thicker than the penetration range of the primary ions, secondary ion yields from
      polyatomic projectile impacts on self-assembled monolayers show little to no
      enhancement when compared with monatomic projectiles at the same velocity. This
      unusual trend is most likely due to the structural arrangement and bonding
      characteristics of the monolayer molecules with the Au(111). Copyright 1999 John
      Wiley & Sons, Ltd.

PMID- 10407328
TI  - Post-column metal complexation of quinolone antibiotics in a quadrupole ion trap.
AB  - Post-column addition of a metal salt and an auxiliary chelating ligand via a
      sheath flow offers an alternative strategy for promoting electrospray ionization
      of analytes via metal cationization. In the present study, a high-performance
      liquid chromatography (HPLC) mass spectrometer interface that incorporates a
      modified ionspray source that allows either online metal cationization or
      protonation is reported. The analytical utility of metal complexation is
      evaluated relative to protonation as a means for efficient ionization and
      generation of structurally diagnostic ions during HPLC separation. To improve
      metal cationization, an auxiliary chelating ligand is added to the sheath flow to
      coordinate the metal and stabilize the resulting complexes. The methodology was
      verified using a series of quinolone antibiotics as model analytes. Relative
      reaction efficiencies were compared for the protonation vs. metal complexation
      modes, and it was found that metal complexation with an auxiliary chelating
      ligand gave a three to five times better detection limit than protonation for the
      quinolones. Detector linearity and optimal reaction conditions are also reported.

PMID- 10407330
TI  - A mass spectrometric study of the vaporization of boron phosphate (BPO(4)) 
AB  - The vaporization behavior of boron phosphate has been studied by using Knudsen
      effusion mass spectrometry. The vapor over BPO(4) consists of B(2)O(3),
      P(4)O(10), PO(2), BPO(4) (platinum cell) and B(2)O(3), PO, PO(2), BPO(3), BPO(4)
      (molybdenum cell). Standard enthalpies of formation and atomization (kJ/mol) were
      derived for BPO(4) (g) (-1000 +/- 15 and 2863 +/- 16) and for BPO(3) (g) (-731 +/
      15 and 2347 +/- 16), respectively. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407329
TI  - Uniform molecular analysis using femtosecond laser mass spectrometry 
AB  - The potential of femtosecond laser time-of-flight mass spectrometry (FLMS) for
      uniform quantitative analysis of molecules has been investigated. Various samples
      of molecular gases and vapours have been studied, using ultra-fast (
      approximately 50 fs) laser pulses with very high intensity (up to 1.6 x 10(16)
      Wcm(-2)) for non-resonant multiphoton ionisation/tunnel ionisation. Some of these
      molecules have high ionisation potentials, requiring up to ten photons for non
      resonant ionisation. The relative sensitivity factors (RSF) have been determined
      as a function of the laser intensity and it has been demonstrated that for
      molecules with very different masses and ionisation potentials, uniform
      ionisation has been achieved at the highest laser intensities. Quantitative laser
      mass spectrometry of molecules is therefore a distinct possibility. Copyright
      1999 John Wiley & Sons, Ltd.

PMID- 10407331
TI  - Determining a 'safe' high-mass limit in matrix-assisted laser
      desorption/ionisation time-of-flight mass spectra of coal derived materials with
      reference to instrument noise 
AB  - Three methods for determining a 'safe' estimate for high-mass limits of MALDI
      spectra of coal derived liquids were explored, using a sample of coal-tar pitch
      and its pyridine-insoluble fraction. Co-addition of increasing numbers of single
      shot spectra (10, 30, 50 and 100 pulses) showed visually observable reductions in
      noise levels, consistent with robust and statistically meaningful signals. Three
      separate types of post-acquisition calculation were used to identify high-mass
      limits of the spectra. (i) A literature method indicated high-mass limits similar
      to those observed visually-as a shift from baseline at the highest masses, nearly
      350 000 u for the coal tar pitch and about 390 000 u for its pyridine insoluble
      fraction. (ii) Comparing instrument signal with pre-selected multiples of the
      standard deviation, upper mass estimates of between 40-60 000 u for the coal-tar
      pitch and about 95 000 u for its pyridine-insoluble fraction were found. (iii)
      Calculation of the slope was used to identify 'lift-off' of the spectrum from
      baseline. The angle between the smoothed spectrum and the baseline was matched to
      a pre-selected value (e.g. 0.5 degrees and 1 degrees ). However, the arbitrary
      specification of the key parameter did not establish this last method on a firm
      basis. The choice of a criterion for estimating high-mass limits of MALDI spectra
      remains a semi-quantitative procedure; a reasonably conservative high-mass limit
      may be estimated by comparison of signal with five times the standard deviation.
      However, evaluation of size exclusion chromatograms of the present samples using
      polystyrene standards suggests that molecular mass distributions of pitch samples
      arrived at by MALDI mass spectrometry are, at least partly, determined by the
      limitations of available instruments. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407332
TI  - Charge derivatization of peptides to simplify their sequencing with an ion trap
      mass spectrometer.
AB  - The low energy collision-induced dissociation of fixed-charge derivatives
      [tris(2,4,6-trimethoxyphenyl)phosphonium] of peptides was investigated using an
      electrospray ion trap mass spectrometer. The fixed charge directed the
      fragmentation pattern and generated solely N-terminal fragments with minimal
      internal rearrangement, regardless of the presence and position of basic amino
      acids in the peptide chain. Generally only b-type ions, accompanied by less
      intense a-type ions, were observed, depending on the collision energy. It was
      observed that the fixed charge controlled the fragmentation beyond typical MS/MS,
      and thus the capacity of the ion trap to perform multiple stage fragmentation
      (MS(n)) was found particularly useful for obtaining the complete sequence
      information of the peptides.

PMID- 10407333
TI  - Interpretation of electrospray and atmospheric pressure chemical ionization mass
      spectra of 10-formyl-7,8-dihydrofolic acid and 5-formyl-5,6,7,8-tetrahydropteroic
      acid.
AB  - Interpretation of positive- and negative-ion electrospray ionization (ESI) and
      atmospheric pressure chemical ionization (APCI) mass spectra of 10-formyl-7,8
      dihydrofolic acid (10-FDHFA) and 5-formyl-5, 6,7,8-tetrahydropteroic acid (5
      FTHPA) is discussed. ESI mass spectra enable unambiguous molecular weight (MW)
      determination. In addition to the determination of MW, APCI mass spectra also
      make possible structure elucidation of 10-FDHFA and 5-FTHPA. ESI and APCI are
      complementary ionization techniques and appear to be useful alternatives to
      conventional electron ionization (EI) for the structure elucidation of non
      volatile carboxylic acids. Prior to mass spectral analysis, the acids
      investigated were separated by reverse-phase high-performance liquid
      chromatography (HPLC).

PMID- 10407334
TI  - Investigating the use of an octupole ion guide for ion storage and high-pass mass
      filtering to improve the quantitative performance of electrospray ion trap mass
      spectrometry.
AB  - An octupole radio frequency (rf) ion guide was evaluated for storage and
      filtering of ions generated by electrospray prior to introduction into an ion
      trap mass spectrometer. The control of the rf potential on the ion guide enabled
      its operation as a high-pass mass filter, removing low-mass chemical noise that
      would normally fill the ion trap and result in reduced sensitivity, mass
      resolution, and dynamic range. Also, the ion guide can serve to store the high
      pass filtered ions during the ion trap mass analysis, enabling nearly 100% duty
      cycle and reduction of the cycle time by a factor of two. The linearity,
      precision, and detection limits of the liquid chromatography (LC) electrospray -
      ion guide-ion trap MS/MS system were evaluated for the determination of ceftiofur
      in milk. A linear calibration (linear correlation coefficient of 0.986) from 2
      200 ppb was obtained with a relative standard deviation for replicate analysis of
      less than 8%. A quantitation detection limit of 100 pg of ceftiofur on-column (2
      ppb) was achieved from a milk extract. This detection limit is nearly a factor of
      10 lower compared with the determination on the same electrospray ion trap system
      not using a rf ion guide for high-pass mass filtering and ion storage.

PMID- 10407335
TI  - Matrix-assisted laser desorption/ionization mass spectrometry in evaluation of
      protein profiles of infant formulae.
AB  - Breast-feeding is the nutritional model in humans, and is continued after birth
      for variable periods. Milk represents an essential source of growth from both
      nutritional and functional points of view. When nursing is not possible,
      indicated or sufficient, artificial feeding becomes essential. Substitutes for
      mother's milk are usually obtained by modifying the composition of cow's milk
      either qualitatively or quantitatively. The changes usually involve enzymatic
      and/or thermal treatment, and for this reason a description of the protein
      profiles of milk formulae is of great interest. After examination of the results
      obtained by matrix-assisted laser desorption/ionization (MALDI) in the
      characterization of protein profiles of cow's milk after different thermal
      treatments, the application of this analytical technique in the above context
      appeared interesting. MALDI data for eleven milk formulae, directly acquired from
      the market, are described and discussed. Results indicate that MALDI mass
      spectrometry is a particularly powerful method which may be employed either
      during the production stages of milk formulae or to study the relationships
      between milk protein content and clinical formula evaluation.

PMID- 10407336
TI  - Mass spectral fragmentation of cis- and trans-1a,3-disubstituted 1, 1-dichloro
      1a,2,3,4-tetrahydro-1H-azirino[1,2-a] [1, 5]benzodiazepines.
AB  - The mass spectrometric behaviour of six cis- and trans-1a, 3-disubstituted 1,1
      dichloro-1a,2,3,4-tetrahydro-1H-azirino[1,2-a][1, 5]benzodiazepines has been
      studied with the aid of mass-analysed ion kinetic energy spectrometry and exact
      mass measurements under electron impact ionization. All compounds show a tendency
      to eliminate a neutral propene or styrene molecule from the diazepine ring and to
      simultaneously eliminate a chlorine atom from the aziridine ring to yield
      azirino[1,2-b][1,3]benzimidazole ions, and to lose hydrogen chloride plus propene
      or styrene to give quinoxaline ions. All compounds also show a tendency to
      eliminate N=CCl(2) or HN=CCl(2) to produce dihydro- or tetrahydroquinoline ions,
      and to eliminate sequentially hydrogen chloride and a chlorine atom to yield
      pyrrolo[1,2-a][1, 3]benzimidazole ions.

PMID- 10407337
TI  - Characterization of the glycosylation of recombinant endopolygalacturonase I from
      Aspergillus niger.
AB  - The carbohydrate chains of recombinant endopolygalacturonase I (EPG I) from
      Aspergillus niger were characterized using a combination of mass spectrometric
      techniques. High performance liquid chromatography (HPLC) in conjunction with
      electrospray ionization mass spectrometry was used to separate the components of
      EPG I liberated by trypsin digestion. In-source collision-induced dissociation
      (CID) was utilized to fragment the digestion products entering the mass
      spectrometer, and the generation of carbohydrate fragment ions allowed for the
      identification of glycopeptides. The masses of the resulting glycans were
      calculated and entered into a carbohydrate database to search for possible
      structures. The primary sequences of the carbohydrate chains were confirmed by
      digesting aliquots of the intact glycopeptide with endo- and exoglycosidases and
      then analyzing the digestion products using matrix-assisted laser
      desorption/ionization mass spectrometry. These experiments demonstrated that one
      of the two N-linked sites of EPG I was occupied by a series of high-mannose
      structures, the second N-linked site was not occupied, and no O-linked sites were
      detected.

PMID- 10407338
TI  - Matrix-assisted laser desorption/ionization mass spectrometry of deoxynucleotides
      labeled with an IMI dye.
AB  - The four major deoxynucleotides of DNA, and adduct mixtures resulting from
      separate reactions of 5'-dAMP and 5'-dGMP with benzo[a]pyrene diolepoxide (BPDE),
      were analyzed by matrix-assisted laser desorption/ionization mass spectrometry
      (MALDI-MS) after labeling of their phosphate group with an IMI dye. The latter
      reagent comprises an imidazole functional group attached to a BODIPY (4,4
      difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene+ ++) fluorophore. Good
      sensitivity was observed in the detection of the IMI-labeled products by MALDI
      MS: 300-500 fmol in the laser spot (1% of the 30-50 pmol sample on the target)
      gave a signal-to-noise (S/N) of >/=30 from 20-30 superimposed laser shots. The
      BPDE reaction products, after the IMI labeling, were also subjected to capillary
      electrophoresis with laser-induced fluorescence detection, which revealed a
      complex mixture of products. Overall the results encourage the further
      development of this 'IMI-postlabeling' methodology as an alternative to (32)P
      postlabeling for the detection of DNA adducts.

PMID- 10407340
TI  - A versatile system of high-flow high performance liquid chromatography with
      tandem mass spectrometry for rapid direct-injection analysis of plasma samples
      for quantitation of a beta-lactam drug candidate and its open-ring
      biotransformation product.
AB  - A bioanalytical method has been developed and validated for quantitation of a
      beta-lactam drug candidate and its open-ring biotransformation product utilizing
      high-flow high-performance liquid chromatography (HPLC) for on-line purification
      of plasma samples and electrospray tandem mass spectrometry for detection and
      quantitation. The HPLC system used two columns: an Oasis column (1 x 50 mm, 30
      microm) as the on-line extraction column and a conventional C18 column (2 x 50
      mm, 5 microm) as the analytical column. Each plasma standard or quality control
      (QC) sample (50 microL) was mixed with 50 microL of a working solution of the
      internal standard in aqueous 0.5 M ammonium acetate (pH 4.0). Portions (10
      microL) of these samples were then injected into an Oasis column with a mobile
      phase consisting of 100% aqueous 1 mM formic acid at a high flow rate (4.0
      mL/min), with the effluent from the Oasis column directed to waste and not to the
      mass spectrometer. After the purification step, the Oasis column effluent was
      directed to the analytical column and the mass spectrometer and the analytes were
      eluted with methanol/aqueous 1 mM formic acid (70:30) at a flow rate of 1.0
      mL/min. The total analysis time was 1.6 min per sample. The standard curve range
      was 0.980 to 250 ng/mL. The accuracy, inter-day precision and intra-day precision
      were within 10% for both compounds.

PMID- 10407339
TI  - Elimination of difluorocarbene from the molecular ions of alpha, alpha,alpha
      trifluorocresols with a fluorine atom migration in an ion trap mass spectrometer.
AB  - The elimination of difluorocarbene (CF(2)) from the molecular ions of m
      alpha,alpha,alpha-trifluorocresol (MW 162, 1) and p-alpha, alpha, alpha
      trifluorocresol (MW 162, 2) upon electron impact have been investigated using a
      quadrupole ion trap mass spectrometer. This reaction involves a fluorine (F) atom
      migration from the trifluoromethyl group to the benzene ring. In the case of 1,
      an F atom migrates via a four-membered ring transition state to give rise to the
      molecular ion of p-fluorophenol (MW 112, 5) and a small amount of o-fluorophenol
      (MW 112, 3). On the other hand, in the case of 2, an F atom migrates to the ipso
      position of the benzene ring via a three-membered ring transition state to give
      rise to 5(+). These conclusions were confirmed by the comparison of the energy
      resolved mass spectra (collision-induced dissociation (CID) spectra versus
      collision energy) of the m/z 112 ions from 1(+) and 2(+) with those of reference
      compounds, o-, m- and p-fluorophenol (3-5).

PMID- 10407341
TI  - Electron impact fragmentation patterns of 3,3-dimethyl-1, 2-norbornane
      derivatives 
AB  - The electron impact mass spectra of several 3,3-dimethyl-1, 2-norbornanediols,
      diamines, amino alcohols and related derivatives have been studied and their
      fragmentation pathways discussed. Different fragmentation patterns were observed,
      depending not only on the nature of the substituents, but also on their relative
      positions on the norbornane framework. In general, the dominant peaks in the
      spectra of these compounds originate from initial C1-C2 bond cleavage (alpha
      cleavage) with charge retention on the heteroatom (oxygen or nitrogen) attached
      at the bridgehead position, followed by hydride shift and loss of the C2-C3
      fragment by homolytic cleavage of the C3-C4 bond. This fragmentation pathway
      leads to a highly stabilized cyclopentenylimmonium or cyclopentenyloxonium ion,
      which constitutes the base peak in the spectra in most of the studied compounds.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407342
TI  - Mass spectra of aminoacyl adenylate pentacoordinated phosphorus compounds 
AB  - Aminoacyl adenylate pentacoordinated phosphorus compounds were analyzed by field
      desorption (FD) and fast atom bombardment (FAB) mass spectrometries, together
      with the B/E linked scan technique, and their mass spectral fragmentation
      pathways were investigated. For the five bonds (one P-N bond, three P-O bonds and
      one mixed anhydride bond P-O-CO), the cleavage usually occurred more on the P-N
      bond, the mixed anhydride bond and the O-C bond adjacent to the P-O bond, and
      less on the P-O bond. Ion YH(+), corresponding to water loss from protonated
      2',3'-O-isopropylidene-adenosine, was the base peak. The results reflect the
      structural characteristics of aminoacyl adenylate pentacoordinated phosphorus
      compounds. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407343
TI  - Electron impact mass spectral characteristics and fragmentation pathways of
      isomeric tetradecadien-1-ols 
AB  - Characteristics of mass spectra of isomeric tetradecadien-1-ols were investigated
      by electron impact mass spectrometry, and mass spectral fragmentation pathways
      were proposed based on collision-induced dissociation experiments and mass
      analyzed ion kinetic energy spectrometry. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407344
TI  - Ion-molecule reactions of 2-methoxyethanol with some amines, carboxylic acids and
      amino acids under chemical ionization conditions 
AB  - 2-Methoxyethanol chemical ionization of amines, carboxylic acids and amino acids
      has been found to produce numerous adduct ions. The most intense adduct ions for
      amines are [M + H](+) and [M + 77](+), for carboxylic acids [M + 27](+), [M +
      59](+) and [M + 77](+), and for amino acids [M + H](+), [M + 13](+), [M + 27](+)
      and [M + 77](+). Either the adduct ion [M + H](+) or [M + 77](+) was the most
      abundant ion found for amino acids. The proton affinities of amino acids are
      noticed to control the formation of the [M + H](+) and [M + 77](+) ions. The
      relative abundance of [M + 13](+) and [M + 27](+) ions varied for different amino
      acids being most intense for phenylalanine and aspartic acid. Copyright 1999 John
      Wiley & Sons, Ltd.

PMID- 10407345
TI  - Analysis of cyclic boronated and trimethylsilylated phenolalkylamines by gas
      chromatography and electron impact mass spectrometry 
AB  - The side chain of phenolalkylamines containing a bifunctional group was
      derivatized as the cyclic boronate, and then the residual phenolic group was
      trimethylsilylated. The resulting derivatives were single reaction products in
      each case, with good gas chromatographic properties and informative mass spectra
      to afford prominent molecular ions by gas chromatography with electron impact
      mass spectrometry (GC/EI-MS). The cyclic boronated-trimethylsilylated derivatives
      yielded the isotope pattern for boron ((10)B:(11)B =-1:4.2) and characteristic
      ions [M](+), [M - H](+), [M - CH(3)](+), [M - RBO](+), [M - TMSO](+), and [M -
      TMSO - C(6)H(5)](+) ions in the mass spectra. In order to distinguish between m-
      and p-phenolalkylamines, the mass spectra of the cyclic phenylboronated
      trimethylsilylated (PBA-TMS) derivatives were compared with those of the
      trimethylsilylated (TMS) derivatives. The TMS derivatives of octopamine (p-) and
      norfenefrine (m-) showed identical mass spectra, while the PBA-TMS derivatives
      had mass spectra sufficiently different from one other to distinguish between the
      isomers. The most prominent ion of the PBA-TMS derivative is the [M - H](+) ion
      (m/z 310) for octopamine and the [M](+) ion (m/z 311) for norfenefrine. Copyright
      1999 John Wiley & Sons, Ltd.

PMID- 10407346
TI  - Electron impact mass spectra of 1a,3-disubstituted 1,1-dichloro-1,1a, 2,3
      tetrahydroazirino [2,1-d][1,5]benzothiazepines.
AB  - The mass spectrometric behaviour of eight 1a,3-disubstituted 1, 1-dichloro
      1,1a,2,3-tetrahydroazirino[2,1-d][1,5]benzothiazepines has been studied with the
      aid of mass-analyzed ion kinetic energy spectrometry and exact mass measurements
      under electron impact ionization. All compounds show a tendency to eliminate a
      chlorine radical from the aziridine ring and then eliminate a neutral propene or
      substituted/unsubstituted styrene from the thiazepine ring to yield 1,4
      benzothiazine ions. They can also lose hydrogen chloride and a chlorine radical,
      or lose two chlorine atoms, to undergo a ring enlargement rearrangement to
      produce 1,6-benzothiazocine ions, which can further eliminate propyne or
      phenylacetylene, or small molecular fragments, to yield some abundant fragment
      ions.

PMID- 10407347
TI  - Mass spectral fragmentation patterns of 1a,3-diaryl-1,1,4, 4-tetrachloro-1a,2,3,4
      tetrahydro-1H-azirino
AB  - The mass spectrometric behaviour of three 1a,3-diaryl-1,1,4, 4-tetrachloro
      1a,2,3,4-tetrahydro-1H-azirino-[2,1-e][1, 6]benzothiazocines has been studied
      with the aid of mass-analyzed ion kinetic energy spectro--metry and exact mass
      measurements under electron impact ionization. All compounds show a tendency-to
      eliminate a neutral substituted/unsubstituted 1,1-dichlorostyrene from the eight
      membered thiazocine ring to yield azirino[2,1-c][1, 4]benzothiazine ions, which
      can then lose a chlorine radical and a sulfur-atom to form azirino[2,1
      c][1,4]benzothiazine ions and dihydroquinoline ions. All compounds could also
      eliminate a chlorine radical plus hydrogen chloride, stepwise or consecutively,
      to undergo a ring enlargement rearrangement to produce nine-membered 1, 7
      benzothiazonine ions. The [M(+) - Cl] ions could undergo a four-membered ring
      rearrangement to yield 1,5-benzothiazepine ions by loss of 1,1-dichlorostyrene or
      styrene ions and HCl, and undergo alpha, alpha-cleavage to form benzothiazine
      ions by loss of arylchlorocyclopropane. The [M(+) - Cl - HCl] ions could further
      eliminate some atoms, small molecules or molecular fragments to form some
      abundant fragment ions. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407348
TI  - Internal energy content of n-butylbenzene, bromobenzene, iodobenzene and aniline
      molecular ions generated by two-photon ionization at 266 nm. A photodissociation
      study 
AB  - A technique to investigate photodissociation kinetics on a nanosecond time scale
      has been devised for molecular ions generated by multiphoton ionization (MPI)
      using mass-analyzed ion kinetic energy spectrometry. The branching ratio or rate
      constant has been determined for the photodissociation of the n-butylbenzene,
      bromobenzene, iodobenzene, and aniline molecular ions generated by MPI at 266 nm.
      The ion internal energies have been estimated by comparing the measured kinetic
      data with the previous energy dependence data. The analysis has shown that only
      those molecular ions generated by two-photon ionization contribute to the
      photodissociation signals. Around half of the available energy has been found to
      remain as molecular ion internal energy in the two-photon ionization process.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407349
TI  - Structural characterisation of N-linked glycan mixtures by precursor ion scanning
      and tandem mass spectrometric analysis 
AB  - 2-Aminoacridone (2-AMAC) labelled N-linked glycan pools were analysed directly by
      a hybrid quadrupole orthogonal acceleration time-of-flight mass spectrometer (Q
      Tof) in the precursor ion scanning and tandem mass spectrometry (MS/MS) modes.
      The use of a precursor ion scanning strategy on this instrument provides a rapid
      and sensitive method of screening glycan mixtures, without prior separation by
      chromatographic methods. It allows facile and preliminary characterisation of
      glycans into different classes, for example, high-mannose or complex glycans.
      Preliminary sequencing information for each glycan is obtained in the initial
      precursor ion scanning mode, but further sequencing information of selected
      glycans can be obtained using the MS/MS mode. Copyright 1999 John Wiley & Sons,
      Ltd.

PMID- 10407350
TI  - Isolation of NO(3)(-)-N as 1-phenylazo-2-naphthol (Sudan-1) for measurement of
      delta(15)N 
AB  - The conversion of nitrate (NO(3)(-)) to 1-phenylazo-2-naphthol (Sudan-1) has been
      examined as a method for natural abundance measurement of delta(15)N of NO(3)(-).
      The reaction results in dilution of NO(3)(-)-N with only one reagent-derived N
      and the product is readily concentrated from dilute samples by reverse phase
      chromatography. There is systematic isotopic fractionation during the reaction,
      but this can be allowed for by analysing known NO(3)(-) standards along with each
      sample set. Sudan-1 prepared from surface water samples containing approximately
      50 &mgr;g NO(3)(-)-N can be analysed by automated continuous flow isotope ratio
      mass spectrometry with a precision of 0.2 per thousand (one standard deviation)
      and the accuracy is not affected by interference from other nitrogenous species
      in the sample or reagents. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407351
TI  - Identification of wheat varieties using matrix-assisted laser
      desorption/ionisation time-of-flight mass spectrometry and an artificial neural
      network 
AB  - A novel tool for variety identification of wheat (Triticum aestivum L.) has been
      developed: an artificial neural network (ANN) is used to classify the gliadin
      fraction analysed by matrix-assisted laser desorption/ionisation time-of-flight
      mass spectrometry (MALDI-TOFMS). The robustness of this novel method with respect
      to various experimental parameters has been tested. The results can be
      summarised: (i) With this approach 97% of the wheat varieties can be classified
      correctly with a corresponding correlation coefficient of 1.0, (ii) The method is
      fast since the time of extracting gliadins from flour can be reduced to 20 min
      without significant decrease in overall performance, (iii) The storage of flour
      or extracts under standard conditions does not influence the classification
      ability (i. e. the generalisation ability) of the method, and (iv) The
      classification obtained is not influenced by the identity of the operator making
      the analysis. This study demonstrates that a combination of an ANN and MALDI
      TOFMS analysis of the gliadin fraction provides a fast and reliable tool for the
      variety identification of wheat. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407352
TI  - Investigation of the quantitative properties of the quadrupole orthogonal
      acceleration time-of-flight mass spectrometer with electrospray ionisation using
      3,4-methylenedioxymethamphetamine 
AB  - This paper describes the investigation of the potential of a quadrupole
      orthogonal acceleration time-of-flight mass spectrometer (Q-TOF) equipped with an
      atmospheric pressure ionisation interface for quantitative measurements of small
      molecules separated by reversed phase liquid chromatography. To this end, the
      detection limits and linear dynamic range in particular were studied in an
      LC/MS/MS experiment using 3,4-methylenedioxymethamphetamine standards and 3,4
      methylenedioxyethylamphetamine for internal standardisation. In a second phase,
      the experiment was repeated with real biological extracts (whole blood, serum,
      and vitreous humour). A calibration for 3,4-methylenedioxymethamphetamine and its
      metabolite 3,4-methylenedioxyamphetamine was prepared in each of these matrices
      again using 3,4-methylenedioxyethylamphetamine as internal standard. The
      resulting quantitative data were compared with those obtained by liquid
      chromatography with fluorescence detection for the same extracts. The Q-TOF
      results revealed excellent sensitivity and a linear dynamic range of nearly four
      decades (2-10 000 pg on-column, r(2) = 0.9998, 1/x weighting). Furthermore, all
      the calibration curves prepared in biological material were superimposable,
      LC/MS/MS and LC-fluorescence, and the quantitative results for actual samples
      compared very favourably. It was concluded that the Q-TOF achieves a linear
      dynamic range for quantitative LC/MS/MS work exceeding that of fluorescence
      detection and at much better absolute sensitivity. Copyright 1999 John Wiley &
      Sons, Ltd.

PMID- 10407353
TI  - Evaluation of protein profile of human milk by matrix-assisted laser
      desorption/ionization mass spectrometry.

PMID- 10407354
TI  - A method to significantly lessen the sample contamination of the vacuum interface
      of an on-axis electrospray ion source by adding a mechanical shutter 

PMID- 10407355
TI  - Surface mass spectrometry of molecular species.
AB  - This tutorial discusses the predominant methods available for surface mass
      spectrometry (MS) of molecular species: thermal desorption spectroscopy, laser
      desorption MS, secondary ion MS, post-ionization of desorbed neutrals and surface
      matrix-assisted laser desorption/ionization. Each of these has the capability to
      analyze molecular species that are chemisorbed, physisorbed, covalently bound to
      or the predominant component of a solid surface. These surface MS methods are
      briefly described, then their capabilities demonstrated using data predominantly
      from the authors' work. Comparisons are made with related methods in conventional
      MS. A very brief discussion is provided on the importance of complementing
      surface MS data with data from x-ray photoelectron spectroscopy and other surface
      analysis tools.

PMID- 10407356
TI  - Structure determination of 4-azido-2-pyrimidinone nucleoside analogs using mass
      spectrometry.
AB  - The nucleoside prodrugs 4-azido-ara-C and 2'-fluoro-2', 3'-dideoxy-4-azido-ara-C
      and their base-catalyzed reaction products were thoroughly characterized by mass
      spectrometry. The structures of the base-catalyzed reaction products were
      determined and confirmed using a combination of high-resolution and tandem mass
      spectrometry with deuterium exchange. An intra-molecular rearrangement reaction
      occurred in 4-azido-ara-C at physiological pH leading to the formation of a 2',6
      anhydro product. A nucleoside of similar structure, 2'-fluoro-2'3'-dideoxy-4
      azido-ara-C was studied to determine if the formation of the 2',6-anhydro ring
      was due to the presence of the 4-azido group or the arabinose 2'-OH group. The 6
      position of 2'-fluoro-2',3'-dideoxy-4-azido-ara-C was found to be unreactive at
      physiological pH, but could add ammonia under strongly basic conditions (pH 11.0,
      ammonia solution). Finally, the formation of an intriguing tetrazole ring by the
      4-azido moiety was observed.

PMID- 10407357
TI  - Collision-induced dissociation of protonated MK-0991: novel ring opening of a
      cyclic hexapeptide in the gas phase.
AB  - Electrospray ionization tandem mass spectrometry was applied to probe the
      collision-induced dissociation (CID) of protonated MK-0991 {(4R,5S)-5-[(2
      aminoethyl)amino]-N(2)-(10, 12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithyl-L
      threonyl-trans -4- hydroxy-L-prolyl-(S)-4-hydroxy-(4-hydroxyphenyl)-L-threonyl
      threo-3-h ydroxy-L-or-nithyl-trans-3-hydroxy-L-proline cyclic (6-1)-peptide} in
      the gas phase; MK-0991 is a newly developed, broad-spectrum pneumocandin
      antifungal drug. The study showed that protonated MK-0991 (m/z 1094) undergoes
      specific ring opening under the CID conditions to form two protonated linear
      peptides at m/z 1076 and 1034. This is different from the commonly observed ring
      opening of a cyclic peptide that occurs by the cleavage of the N-acyl bonds in
      many places on the peptide backbone. The structures of the two linear peptides
      were elucidated on the basis of their tandem mass spectra. The results strongly
      indicate that the specific ring opening of MK-0991 is affected by the
      ethylenediamine side-chain formed from the modification of one of the ornithine
      amino acids in this cyclic hexapeptide.

PMID- 10407358
TI  - Evaluation of bumetanide as a matrix for prompt fragmentation matrix-assisted
      laser desorption/ionization and demonstration of prompt fragmentation/post-source
      decay matrix-assisted laser desorption/ionization mass spectrometry.
AB  - Bumetanide was evaluated as a matrix for prompt fragmentation matrix-assisted
      laser desorption/ionization (MALDI) experiments on peptides. Both the MALDI mass
      spectrum and some physical properties of bumetanide were compared with those of
      some commonly used matrices. Bumetanide was then evaluated for prompt
      fragmentation MALDI by comparing the prompt fragmentation produced using
      bumetanide with that for alpha-cyano-4-hydroxycinnamic acid and 2, 5
      dihydroxybenzoic acid. Bumetanide was also evaluated for use in a mixed matrix
      with alpha-cyano-4-hydroxycinnamic acid. A 4 : 1 matrix mixture was found to be
      useful for the post-source decay analysis of a prompt fragment ion. The prompt
      fragmentation/post-source decay analysis experiment is demonstrated on a prompt
      fragment ion from the oxidized b-chain of insulin.

PMID- 10407359
TI  - Imaging time-of-flight secondary ion mass spectrometry of solid-phase peptide
      syntheses.
AB  - Imaging time-of-flight secondary ion mass spectrometry (TOF-SIMS) of solid-phase
      peptide syntheses carried out by the Merrifield and Sheppard strategies is
      described. Mixtures of resin beads mixed at random from batch syntheses or
      obtained in combinatorial chemistry by the mix and split technique, where each
      bead is functionalized by a unique peptide, were analyzed directly without any
      chemical cleavage of the growing chains to assess the nature of the growing
      structure on any bead of the mixture without its isolation.

PMID- 10407360
TI  - Intramolecular proton transfers in stereoisomeric gas-phase ions and the kinetic
      nature of the protonation process upon chemical ionization 
AB  - The isobutane chemical ionization (CI) mass spectra of cis- and trans-1-butyl-3-
      and -4-dimethylaminocyclohexanols and of their methyl ethers exhibit abundant [MH
      - H(2)O](+) and [MH - MeOH](+) ions respectively. On the other hand, only the
      MH(+) ions of the cis-isomers exhibit significant [MH - H(2)O](+) and [MH -
      MeOH](+) ions under collision-induced dissociation (CID) conditions. The non
      occurrence of water and methanol elimination in the CID spectra of the trans
      isomers indicates retention of the external proton at the dimethylamino group in
      the MH(+) ions that survive after leaving the ion source and the first quadrupole
      of the triple-stage quadrupole ion separating system, and the trans-orientation
      of the two basic sites does not allow proton transfer from the dimethylamino
      group to the hydroxyl or methoxyl. Such transfer is allowed in the cis-amino
      alcohols and amino ethers via internal hydrogen-bonded (proton-bridged)
      structures, resulting in the elimination of water and methanol from the surviving
      MH(+) ions of these particular stereoisomers upon CID. The abundant [MH - ROH](+)
      ions in the isobutane-CI mass spectra of the trans-isomers indicates protonation
      at both basic sites, affording two isomeric MH(+) ions in each case, one
      protonated at the dimethylamino group and the other at the less basic oxygen
      function. These results show that the isobutane-CI protonation of the amino
      ethers and amino alcohols is a kinetically controlled process, occurring
      competitively at both basic sites of the molecules, despite the large difference
      between their proton affinities ( approximately 25 and approximately 35 kcal mol(
      1); 1 kcal = 4.184 kJ). Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10407361
TI  - Electrospray ionization mass spectrometric method for the determination of
      cannabinoid precursors: N-acylethanolamine phospholipids (NAPEs).
AB  - N-Acylethanolamine phospholipids (NAPEs) serve as endogenous precursors of N
      acylethanolamines (NAEs), e.g. N-arachidonoylethanolamine (anandamide) and N
      palmitoylethanolamine that are endogenous ligands of cannabinoid receptors. Under
      physiological conditions, NAPE is found in very low concentrations in mammalian
      tissue (3-12 nmol g(-1)). However, pathophysiological conditions may increase the
      endogenous NAPE levels, which again may cause an increase in endocannabinoid
      concentrations. This paper presents a simple and selective method for the
      determination of NAPE standards using negative electrospray ionization mass
      spectrometry (ESI-MS). The procedure provides complete positioning of all acyl
      and alkenyl groups contained in each NAPE species. The calibration curve for
      standard NAPE was linear over the range 100 fmol-50 pmol (0.1-50 ng) per
      injection. The lower limit of detection (signal-to-noise ratio of 3) was 100
      fmol, implying that this method is superior to previous methods for the
      determination of NAPE. These results suggest that this ESI-MS method can be used
      to identify and quantify NAPE species in mammalian tissues and provide
      information on the corresponding NAEs to be released from the endogenous NAPE
      pool.

PMID- 10407362
TI  - Contrasting behavior of tetracene and perylene in collision-induced dissociation:
      a theoretical interpretation.
AB  - Dimethyl ether chemical ionization mass spectrometry of polycyclic aromatic
      hydrocarbons (PAHs) leads to [M + 13](+) and [M + 45](+) ions. The process
      leading to these ions is sensitive to the proton affinity of the PAH. Collision
      induced dissociation observations on [M + 45](+) ion also show that tetracene has
      a peculiar reactivity in comparison with perylene, despite the similar physico
      chemical properties of these two molecules. Ab initio calculations were used to
      establish a potential energy profile for the mechanistic pathway of [M + 13](+)
      and [M + 45](+) formation. [M + 45](+) ions result from the addition of CH(3)-O
      CH(2)(+) to PAHs. A 1,2-hydride transfer followed by a 1,4-proton transfer and a
      loss of methanol subsequently lead to the formation of [M + 13](+) ions. For
      tetracene, the 1,2-hydride transfer does not occur, as it would lead to a
      thermodynamically unstable non-planar ion.

PMID- 10407363
TI  - Separation and detection of carcinogen-adducted oligonucleotides.

PMID- 10407364
TI  - Specific Stimulatory Effect of LH on the Synthesis of delta4 Gestagens and
      Androgens in Adrenocortical Cells in vitro.
AB  - The aim of this study was to answer the question whether gonadotropins are able
      to stimulate the synthesis of delta4 gestagens and androgens in adrenals by the
      same way as in gonads. Adrenal cells of male guinea pigs (n=12) and
      adrenocortical cells of sows (n=2) were isolated with collagenase 1A and DNA-se
      and used in two separate experiments. Cell suspensions divided in quadruplicate
      number of aliquots for each test were preincubated (1 h) and then incubated (h)
      with high purity pLH-USDA, pLH-GPZ (this was used only in one experiment), pFSH
      NIH (the residual contamination of this preparation with ACTH was not excluded)
      and ACTH1-24. The concentrations of progesterone (P), 17alpha-hydroxyprogesterone
      (OH-P), androstenedione (A), testosterone (T) and cortisol (F) in the incubated
      cells were estimated by RIA. The stimulatory effect of two high purity pLH
      preparations on P, A and T synthesis in guinea pig adrenal cells and pig
      adrenocortical cells was demonstrated. Moreover, the synthesis of OH-P in pig
      adrenocortical cells was also stimulated. It may be concluded that these results
      are specific for LH, since the used pLH-USDA was deprived of any residual ACTH
      contamination and pLH-GPZ was chromatographically homogenous. These preparations
      also showed indirect evidences of the activation of steroid 3beta-hydroxysteroid
      dehydrogenase/isomerase (3beta HSD) which catalyses the synthesis of these four
      delta4 steroids from their delta5 path precursors. The LH dependent activation of
      this enzyme in adrenals, which was demonstrated in this work, supported the well
      known observations of its independence of ACTH. As high as 6-times increase of P
      synthesis and 2-5 times increase of OH-P synthesis under the influence of pLH in
      pig adrenocortical cells (consistent with the species of LH) needs the induction
      of the labile protein i synthesis, since the cholesterol transport into
      mitochondria and the extent of pregnenolone and its derivatives synthesis depends
      on that protein. The influence of LH on adrenal steroidogenesis indicates that
      adrenal cells are the target not only for ACTH but also for LH. The influence of
      the used pFSH specimen on adrenal steroidogenesis resembles that of ACTH,
      including the increase of cortisol synthesis. Due to this similarity and lack of
      evidences of excluding residual ACTH contamination of such pFSH specimen, these
      results are considered nonspecific. Thus, the problem of FSH influence on adrenal
      steroidogenesis is still open. Regardless of that, the presented demonstration of
      specific LH effect appears to be an original contribution to the basic knowledge
      on adrenal steroidogenesis.

PMID- 10407365
TI  - Thymidine Kinase (EC 2.7.1.21) Activity in Homogenates of Human Thyroid Tissue,
      Following the Exposure to Epidermal Growth Factor (EGF) in vitro.
AB  - The activity of thymidine kinase (TK - EC 2.7.1.21) was measured in human thyroid
      tissue homogenates incubated in vitro. This enzyme functions as a part of the
      pyrimidine salvage pathway involved in DNA synthesis. The thyroid tissue was
      obtained from the thyroids of patients thyroidectomized at the Department of
      Endocrine Surgery, Medical University of lodz because of: 1. non-toxic nodular
      goiter (NTNG): tissue macroscopically unchanged, woman 46 yrs; 2. non-toxic
      adenoma (NTA), woman 37 yrs; 3. toxic adenoma (TA), woman 45 yrs. The tissue was
      incubated for 4 hours in RPMI 1640 medium (Gibco), containing Hepes buffer, 15 %
      FCS and the examined substance - epidermal growth factor (EGF) - used in five
      different concentrations (0.1 ng/ml, 1 ng/ml, 10 ng/ml, 100 ng/ml, 1000 ng/ml).
      The TK activity was measured according to Cheng and Prusoff (1974) as modified by
      Greger and Draminski (1989). The reaction products were separated by ascending
      chromatography. It was found that: 1. TK activity in thyroid tissue from NTNG and
      NTA did not significantly differ from control incubations without EGF, while it
      was significantly higher in the thyroid tissue from TA; 2. in the range of
      concentrations from 1 ng/ml to 1000 ng/ml, EGF increased TK activity in the
      macroscopically unchanged tissue from NTNG; 3. the incubation of the tissue from
      NTA with EGF resulted in the increase of TK activity in a concentration-dependent
      manner; 4. EGF stimulated TK activity in the tissue from TA, but the difference
      was significant only after the lowest EGF concentration. The obtained results
      suggest a possible role of EGF in the pathogenesis of NTNG, as well as of NTA and
      TA in humans.

PMID- 10407366
TI  - Growth Hormone (GH) but not IGF-I-Secretion is Stimulated in Aged Rats by Chronic
      Hexarelin and GHRP-6 administration.
AB  - The present studies were designed to investigate in aged rats (22-24 months old)
      the effectiveness and specificity of acute hexarelin (HEXA) administration on the
      release of growth hormone (GH), the minimal dose of the peptide that produces the
      maximal GH secretion and the effects of long term treatment with HEXA or growth
      hormone releasing peptide (GHRP-6) on plasma levels of GH and IGF-1. To select
      the appropriate anesthetic to obtain serial blood samples, the GH releasing
      activity of HEXA (30 ug/kg i.v.) was tested in young rats anesthetized with
      tribromoethanol and ketamine-xylazine, and the results were compared with those
      obtained from conscious freely moving rats. When compared to the changes found in
      conscious rats, the GH-response to HEXA was increased by ketamine-xylazine
      anesthesia, while it was decreased by tribromoethanol. Therefore, all subsequent
      experiments were performed in conscious freely moving rats. To determine the
      minimal effective dose of HEXA and GHRP-6 in aged animals, different doses (5,
      10, 20, 40, and 80 ug/kg) of either HEXA or GHRP-6 were administered
      subcutaneously to young and aged rats. It was found that 20 ug/kg bw of HEXA or
      GHRP-6 was the minimal dose producing the maximal GH response. Plasma PRL and LH
      determinations in the animals injected with the minimal dose showed that HEXA and
      GHRP-6 stimulate the GH release specifically. Based on the results obtained in
      the latter experiments, young and aged rats were chronically treated with s.c.
      injections of 20 ug/kg twice a day for 15 or 30 days. At the end of the
      experiments, animals were acutely tested with s.c. injection of the same dose (20
      ug/kg). It was found that both young and aged animals released GH in response to
      the repeated administration of GH releasing peptides after 15 days of treatment.
      However, after 30 days of treatment plasma GH did not change when young and aged
      HEXA treated animals were acutely tested with such peptide, but increased
      significantly in the GHRP-6 treated animals when they were acutely tested with
      GHRP-6. In response to the long term treatment with the GH-releasing peptides,
      plasma IGF-I levels increased in young animals when they were acutely tested with
      the corresponding peptide. However, plasma IGF-I levels in aged rats were not
      modified by the acute administration of either HEXA or GHRP-6 after 15 or 30 days
      of treatment. This study showed that: 1. HEXA and GHRP-6 stimulated GH release in
      aged rats and the magnitude of GH responses was similar to that in young rats; 2.
      the minimal dose of HEXA and GHRP-6 resulting in maximal GH response was 20 g/kg
      and such dose of HEXA specifically stimulated GH secretion in aged rats; 3.
      fifteen but not 30 days treatment of aged rats with such small dose of HEXA
      resulted in a similar GH response to subsequent stimulation with the same
      peptide; 4. plasma IGF-I responses to an acute administration of HEXA or GHRP-6
      in rats chronically treated with the same peptide vanished with aging.

PMID- 10407367
TI  - The Effect of Glibornuride on Plasma Atrial Natriuretic Factor Levels in Patients
      with Newly Diagnosed NIDDM.
AB  - The aim of this clinical trial was to study the participation of plasma atrial
      natriuretic factor (ANF) in the risk of developing diabetic nephropathy by
      increasing the intraglomerular pressure. The effect of glibornuride on the plasma
      ANF levels and natriuresis was estimated in 10 newly diagnosed NIDDM patients and
      10 control subjects. At base line, plasma ANF levels (15.05+/-2.32 pg/ml and
      11.13+/-0.85 pg/ml) and the urinary sodium and potassium excretion rates were
      similar in patients and control subjects, respectively. Similarly, intravenous
      saline infusion (2 mmol/kg/60 min) resulted in remarkable elevation of plasma ANF
      levels in patients and in controls (28.89+/-4.72 pg/ml and 20.18+/-2.48 pg/ml,
      respectively) and in increased urinary sodium and potassium excretion rates in
      both groups. In contrast, after a single dose of 50 mg glibornuride p.o. the
      saline infusion did not increase ANF levels (15.13+/-1.00 pg/ml), while
      natriuresis but not kaliuresis persisted. All tests were performed during
      euglycemic clamp. It was suggested that glibornuride, with its natriuretic effect
      through the ATP sensitive potassium channels on the apical membrane of the thick
      ascending limb of loop of Henle and cortical collecting duct cells might inhibit
      the elevation of plasma ANF levels in response to extracellular fluid volume
      expansion. Similarly, with its natriuretic effect, it protects the diabetic
      patients against possible sodium retention. This result is considered noteworthy,
      since the inhibition of plasma ANF elevation in early diabetes by glibornuride
      may prevent glomerular hypertension and subsequent development of nephropathy.

PMID- 10407368
TI  - Relaxin as a Regulator of Porcine Granulosa Cell Steroidogenesis and
      Proliferation.
AB  - The influence of relaxin (RLX; 0.001 to 1.0 ug ml-1) on the ovarian steroid
      secretion and proliferation of granulosa cells (GCs) cultured for 48 and 72 h was
      studied in the presence or absence of gonadotropins. RLX increased ovarian
      steroid release in a dose dependent manner, but even the highest dose used (1.0
      ug ml-1) had no effect on steroid secretion. FSH increased the RLX stimulated
      steroid release with the exception of the highest dose used. LH in the presence
      of RLX showed lower effect on GCs steroid secretion. The highest dose of RLX
      added to the serum free medium in presence of FSH enhanced the (3H)-thymidine
      labelling of GCs. These results, together with the reports by others
      demonstrating that RLX is produced by porcine GCs, suggest the intraovarian
      effect of RLX on granulosa cell functions and show that this polypeptide hormone
      probably acts indirectly to promote follicle growth and steroidogenesis.

PMID- 10407369
TI  - Preovulatory dynamics of Steroids Demonstrated in vivo by Ovarian Follicles of
      Cyclic and Superovulated Rat Females.
AB  - The destiny of individual follicles, especially their growth and atresia, appears
      to be directly related to particular steps of steroid metabolism. Since the
      superovulatory treatment results in insufficiently documented changes in
      follicular steroid levels, it was decided to search for detailed profiles of
      these steroids and then to compare them with these of regularly cycling females.
      Thus, the preovulatory follicles were isolated from superovulated immature and
      intact mature female Wistar rats. Mature females with regular 4-day estrous cycle
      were sacrificed consecutively every 2 or 3 h on the day of pro-estrus. Immature
      (24 day old) females were injected with PMSG (30 IU) and 56 h later with hCG (20
      IU) and sacrificed at 0, 24, 48 and 56 h, and then every 2 or 3 h until 72 h
      after the PMSG treatment. In both animal models isolated follicles were
      homogenized and then the concentration of estradiol, androgen and progesterone
      was estimated by RIA. The follicles of cycling and PMSG/hCG injected rats showed
      different dynamics of steroid contents. Nevertheless, in both models a peak of
      androgen content appeared a few hours earlier than that of progesterone. During
      the progesterone peak or immediately after that a sharp fall in androgen content
      was found which was followed by a decrease in estradiol concentration. The
      follicles of superovulated rats contained lower amounts of estradiol,
      progesterone and especially of androgens which were much lower than these in the
      follicles of cyclic rats. In PMSG/hCG-derived preovulatory follicles the
      predominance of androgens over estradiol was maintained longer than in the
      follicles developing during physiological estrous cycle. These results suggest
      that the PMSG/hCG model of superovulation is marked by the induction of massive
      follicular atresia. Therefore, neither morphological nor biochemical alterations
      observed in PMSG/hCG-derived ovarian follicles should be considered as fully
      physiological changes.

PMID- 10407371
TI  - Sleeping sickness rediscovered.

PMID- 10407370
TI  - Toxoplasma gondii and the professor.

PMID- 10407372
TI  - New molecular targets for filariasis drug discovery.

PMID- 10407373
TI  - Post-transmission schistosomiasis.

PMID- 10407374
TI  - Zoonoses in West Africa: impact and control.

PMID- 10407375
TI  - Parasites can regulate wildlife populations.

PMID- 10407376
TI  - Unheard-of numbers and invitations on the Web.

PMID- 10407378
TI  - Websites of interest

PMID- 10407377
TI  - Alveolar echinococcosis in humans: the current situation in Central Europe and
      the need for countermeasures.
AB  - Alveolar echinococcosis (AE) in humans is caused by a larval stage (metacestode)
      of Echinococcus multilocularis, which exhibits a tumor-like growth, initially in
      the liver, with the potential to induce serious disease. At the end of the 1980s,
      E. multilocularis was known to occur in four countries of Central Europe, but has
      now been identified in ten countries. Red foxes are the principal definitive
      hosts of E. multilocularis and sources of human infection, but dogs and cats can
      also be infected. Growing populations of foxes and their increasing immigration
      to urban areas are new risk factors. Human AE is rare but its potential high
      fatality rate, considerable costs of treatment and the persisting infection risk
      should be reasons for health authorities in European countries to establish
      coordinated systems of surveillance and risk assessment in combination with
      measures to reduce morbidity and mortality of AE in the human population. Here,
      J. Eckert and P. Deplazes outline the current epidemiological situation in
      Central Europe, and discuss options for surveillance, prevention and control.

PMID- 10407379
TI  - Veterinary parasitology: looking to the next millennium.
AB  - 'Veterinary parasitology' has traditionally been concerned with the control of
      parasites of livestock and companion animals, with emphasis on chemotherapy and
      immunoprophylaxis. This will continue, but there must be less reliance on
      chemical control; the development of alternative strategies will be a major goal
      over the next ten years. Here, Andrew Thompson takes an optimistic look at the
      challenges, strengths and opportunities for veterinary parasitology as we enter
      the next millennium. In the space available here, he can only 'scratch the
      surface' about what the future holds for veterinary parasitology, and will
      attempt to identify the major trends that are emerging, some of which will be the
      subject of future in-depth articles in Parasitology Today.

PMID- 10407380
TI  - Antigen presentation by macrophages harboring intravesicular pathogens.
AB  - Resting macrophages can be host cells for the replication of several protozoan
      parasites and bacteria. Upon activation, infected cells mobilize potent
      microbicidal mechanisms that eliminate the intracellular pathogen. This
      transition from a resting to an activated state is mediated by the interaction
      with specific T cells that recognize pathogen-derived peptides complexed to major
      histocompatibility complex (MHC) molecules at the surface of host cells. In this
      review, Peter Overath and Toni Aebischer discuss antigen presentation in infected
      macrophages from a cell biological point of view, a perspective that has
      important implications for the design of subunit vaccines.

PMID- 10407381
TI  - Biochemical peculiarities and drug targets in Cryptosporidium parvum: lessons
      from other coccidian parasites.
AB  - There is an urgent need for effective medicines for treating human and animal
      cryptosporidiosis. In the absence of drugs being found using an empirical route,
      the structure-based approach may be the better option for discovering new
      chemotherapeutic agents against these diseases. With this objective, what
      possible drug targets are there? Here, Graham Coombs speculates on the best
      putative targets for chemotherapeutic attack, and reviews what is known and what
      can be deduced about the biochemical features of Cryptosporidium parvum, the
      causative agent of cryptosporidiosis, emphasizing the ways in which the parasite
      differs biochemically from its mammalian hosts.

PMID- 10407382
TI  - Ribonucleotide reductase: A new target for antiparasite therapies.
AB  - New treatments are required urgently for the control of parasitic protozoan
      diseases of humans and animals. One approach is the development of subunit
      vaccines; the other focuses on identifying and exploiting specific differences in
      essential functions between the host and parasite. One enzyme currently
      attracting attention is ribonucleotide reductase, an essential component in the
      biosynthesis of DNA. In this article, Geoffrey Ingram and Jane Kinnaird examine
      differences between the host and parasite enzymes and assess possible means of
      therapeutic intervention.

PMID- 10407383
TI  - The human immune response during cutaneous leishmaniasis: NO problem.
AB  - During some helminth infections, increased expression of the low-affinity
      receptor for IgE (CD23/FcepsilonRII) by macrophages and/or increased levels of
      plasma IgE have been seen, but their role in host protection or disease
      progression remains unclear. Recently, crosslinking of CD23 was shown to promote
      intracellular killing of Leishmania parasites in human macrophages, a phenomenon
      involving the production of tumor necrosis factor alpha and nitric oxide (NO).
      Based upon various in vitro and in vivo studies of human cutaneous leishmaniasis,
      Djavad Mossalayi, Michel Arock, Dominique Mazier, Philipe Vincendeau and Ioannis
      Vouldoukis here propose a model for an immune response that involves CD23-IgE
      mediated NO release during protection, as well as during active cutaneous
      leishmaniasis.

PMID- 10407384
TI  - Nested PCR for the detection of Cryptosporidium parvum.

PMID- 10407385
TI  - More differences in energy metabolism between Trypanosomatidae.

PMID- 10407386
TI  - Reply

PMID- 10407387
TI  - Malaria vaccine trials.

PMID- 10407389
TI  - Cystic fibrosis treatment: a new era?

PMID- 10407388
TI  - Centres of expertise to safeguard future of French pharmaceutical industry.

PMID- 10407390
TI  - QT interval prolongation by non-cardiovascular drugs: issues and solutions for
      novel drug development.
AB  - In 1997, the Committee for Proprietary Medicinal Products (CPMP) issued a
      document concerning the potential of non-cardiovascular drugs to cause
      prolongation of the QT interval of the electrocardiogram. This article reviews
      several aspects of this complex problem, including a preclinical strategy (in
      vitro electrophysiology in human cardiac cells and in vivo pharmacologically
      validated conscious dogs) to satisfy the expectations of the CPMP. In particular,
      the discussion stresses the danger of drugs prolonging the QT interval in
      patients with concurrent cardiac risk factors and the need for rigorous clinical
      testing to determine the risk of fatal cardiac events for drugs with the
      propensity to prolong QT.

PMID- 10407392
TI  - Liposomes, micelles and microemulsions as new delivery systems for cytotoxic
      alkaloids.
AB  - This review describes the design and performance of specialized delivery systems,
      such as liposomes, micellar solutions and microemulsions, for the administration
      of cytotoxic alkaloids. Special attention is directed towards three types of
      compound, Vinca, Camptotheca and Taxus alkaloids, which have been previously
      indicated as of promise as antitumour agents but which still present serious
      drawbacks. In this respect, this review analyses different delivery strategies
      that are able to substantially improve the therapeutic applicability of such
      antitumour drugs.

PMID- 10407391
TI  - Regulation of the intestinal epithelial paracellular barrier.
AB  - Paracellular transport of orally-administered drugs, the passage of molecules
      between adjacent intestinal epithelial cells, is impeded by a range of structural
      and functional features found in the intestine. An increased knowledge of the
      mechanisms that govern the paracellular barrier will enable the pharmaceutical
      scientist to design novel and rational formulations and delivery platforms that
      will improve the oral bioavailability of therapeutic molecules, particularly
      proteins and peptides, which would be taken-up by the paracellular pathway.

PMID- 10407393
TI  - Monitor: progress and profiles.

PMID- 10407394
TI  - The Central Melanocortin System and Energy Homeostasis.
AB  - Obesity is a significant health problem owing to increased risk for diabetes and
      cardiovascular disease, and several lines of evidence suggest that alterations in
      the central melanocortin system might account for some of the genetic
      contribution to obesity in humans. First, the phenotypic aspects and dominant
      inheritance of the melanocortin obesity syndromes in the mouse are more like
      human obesity than other murine obesity syndromes. Second, studies recently
      published present two rare cases of familial obesity resulting from null alleles
      of the proopiomelanocortin (POMC) gene, providing the first evidence that the
      melanocortin pathway in humans subserves the same function in regulation of
      energy homeostasis as it does in the rodent. Additional studies suggest that
      heterozygous mutations in the melanocortin 4 receptor might be a common reason
      for genetic predisposition to obesity in children. Research on the central
      melanocortin system in rodents suggests that this system might be a fundamental
      component of the adipostat, the mechanism by which energy stores are held
      relatively constant, and this hypothesis will be the focus of this review.

PMID- 10407395
TI  - TGF-beta Family Members and Gonadal Development.
AB  - Several members of the transforming growth factor beta (TGF-beta) family are
      involved in gonadal development; namely, TGF-beta itself, inhibins, activins,
      anti-Mullerian hormone (AMH) and GDF-9. These proteins do not affect initial
      gonadal organogenesis but play either a stimulatory or inhibitory role in the
      division and differentiation of gonadal cells and in meiotic maturation in the
      female. Furthermore, as shown by transgenic mouse technology, both AMH and
      inhibin act as tumor suppressors.

PMID- 10407396
TI  - Potentiation of Bradykinin Actions by ACE Inhibitors.
AB  - Angiotensin I-converting enzyme (kininase II; ACE) inhibitors, antibodies to ACE
      and slowly cleaved substrates of ACE potentiate the effect of bradykinin and its
      analogs on their B2 receptors independently of blocking peptide metabolism. ACE
      inhibitors also resensitized the receptors desensitized by the ligand
      (tachyphylaxis). The studies were performed on isolated organs and cells co
      transfected with the receptor and the enzyme or constitutively expressing them.
      This enhancement of the effect of B2 ligands is attributed to a crosstalk between
      the enzyme and the receptor, and not to a direct action on the receptors. It
      might reflect some of the local activities of ACE inhibitors.

PMID- 10407397
TI  - Glucagon-like Peptide 1 (GLP-1): An Intestinal Hormone, Signalling Nutritional
      Abundance, with an Unusual Therapeutic Potential.
AB  - The incretin hormone, glucagon-like peptide 1 (GLP-1) has many actions; namely:
      (1) it enhances all steps of insulin biosynthesis and potentiates glucose-induced
      secretion; (2) it seems to have trophic effects on pancreatic cells; (3) it
      inhibits glucagon secretion; (4) it inhibits hepatic glucose production and
      lowers blood glucose, but does not produce severe hypoglycaemia; (5) it inhibits
      postprandial gastrointestinal motility and secretion; and (6) it reduces appetite
      and food intake. Because of this, current research is focusing upon development
      of a clinically practicable therapy for type 2 diabetes mellitus based on GLP-1.

PMID- 10407398
TI  - Hypothalamic Peptides in Human Brain Diseases.
AB  - The human hypothalamus is subdivided into some 20 well-defined nuclei that have a
      multitude of specific functions from the time of birth to the moment we die.
      Hypothalamic nuclei show structural and functional differences not only in
      relation to classic neuroendocrine disorders, such as diabetes insipidus,
      climacteric flushes and Kallman's syndrome, but also in relation to gender and
      sexual orientation, to adaptive processes such as non-thyroidal illness and in
      psychiatric disorders such as depression.

PMID- 10407400
TI  - An Estrogen Receptor Paradox: Why Do Estrogen and Tamoxifen Antagonize Each
      Other's Activity?

PMID- 10407399
TI  - Male Skeletal Health and Osteoporosis.
AB  - Osteoporosis has long been considered to be a disease of the aging female
      skeleton. As awareness of the pervasiveness of this disorder heightens, men are
      also being shown to be at risk for osteoporosis. The purpose of this article is
      to review what is known about the factors in the male that lead to acquisition,
      maintenance and loss of bone, as well as new insights into a group of men whose
      osteoporosis, although severe, remains to be explained.

PMID- 10407402
TI  - Beyond proteins.
AB  - Increased understanding of the biological principles of protein structure and
      folding, combined with advances in protein-synthetic chemistry, should not only
      allow us to borrow from biology but also to depart from it and so produce protein
      like, but non-protein, molecules and molecular devices. However, radical
      departures from protein-like forms into more-robust and truly novel 'smart'
      polymers and materials first require a solution to the protein-folding problem
      using only fundamental physicochemical principles. Any such practical solution
      may not come from raw computing power alone but rather from a deeper
      understanding of topological principles.

PMID- 10407401
TI  - Safe biotechnology 9: values in risk assessment for the environmental application
      of microorganisms. The Safety in Biotechnology Working Party of the European
      Federation of Biotechnology.
AB  - Risk assessment for the deliberate release of microorganisms into the environment
      is traditionally carried out on a case-by-case basis. In a similar approach to
      that used when assessing human pathogenicity, we propose an alternative approach
      by introducing risk classes to facilitate or complement this type of risk
      assessment. These consider several sets of scenarios that address the different
      values that need to be protected. Examples of this approach include risk-class
      definitions for soil fertility and biodiversity.

PMID- 10407403
TI  - Microfluidic devices for DNA analysis.
AB  - Microfabricated electrophoresis devices allow us to perform short-tandem-repeat
      genotyping assays in under 2 min and sequence single-stranded DNA in under 15
      min. This is 10-100 times faster than standard slab-gel and capillary systems.
      The microdevice format is the natural extension of 100 years of gradual
      improvements to electrophoresis but operates in an almost-perfect way, limited
      only by the sieving medium.

PMID- 10407404
TI  - Cytokines: from technology to therapeutics.
AB  - Cytokines are playing an ever-increasing role in the treatment of human disease.
      The characterization of these proteins plays a vital role in their development as
      useful therapeutic agents. Physicochemical techniques can produce information
      about the structure and composition of cytokine therapeutics but cannot yet
      predict their biological activity, for which biological assays are required.
      Because of the large number of techniques available and the variety of products
      requiring analysis, the tests used to characterize cytokine products must be both
      appropriate for the product and adequately controlled if the information they
      provide is to be of value.

PMID- 10407405
TI  - Immobilized enzymes: crystals or carriers?
AB  - The advantages of immobilized over soluble enzymes arise from their enhanced
      stability and ease of separation from the reaction media, leading to significant
      savings in enzyme consumption. Immobilization methods range from binding to
      prefabricated carrier materials to packaging in enzyme crystals or powders.
      During their use, mass-transfer effects can produce substrate or pH gradients,
      which reduce the reaction rates and product yields. The costs of immobilized
      enzymes must be minimized in order to increase their competitiveness for
      technical applications.

PMID- 10407406
TI  - 'Smart' polymers and what they could do in biotechnology and medicine.
AB  - Stimulus-responsive or 'smart' polymers undergo strong conformational changes
      when only small changes in the environment (e. g. pH, temperature, ionic
      strength) occur. These changes result in phase separation from aqueous solution
      or order-of-magnitude changes in hydrogel size. Smart polymers are used in
      bioseparation and drug delivery, for the development of new biocatalysts, as
      biomimetic actuators, and as surfaces with switchable hydrophobic-hydrophilic
      properties.

PMID- 10407407
TI  - Glycans in post-Golgi apical targeting: sorting signals or structural props?
AB  - A recent model proposed that N-glycans serve as apical targeting signals for
      soluble and membrane proteins in epithelial cells and neurons by interacting with
      lectin sorters in the trans-Golgi network. However, we believe that a number of
      experimental observations support an alternative hypothesis, that N-glycans play
      a facilitative role, by providing structural support or preventing aggregation of
      the proteins for example, thereby allowing interaction of proteinaceous apical
      sorting signals with the sorting machinery. This article discusses the
      experimental data currently available and how they relate to the proposed models.

PMID- 10407408
TI  - Cryptochromes--bringing the blues to circadian rhythms.
AB  - Cryptochromes are blue/UV-A-absorbing photoreceptor proteins discovered
      originally in plants and so named because their nature proved elusive in over a
      century of research. Now we know that the photoreceptor essential for proper
      seedling establishment in blue light has homologues in the animal kingdom - in
      insects, in mice and in humans. In recent months, evidence has emerged pointing
      to a common role for cryptochromes in all of these organisms in entraining the
      circadian clock, a biochemical timing mechanism running within cells,
      synchronizing metabolism to the daily light-dark cycle and having consequences on
      a much larger scale in the regulation of behaviour such as the sleep-wake cycle.

PMID- 10407409
TI  - Nuclear bodies: multifaceted subdomains of the interchromatin space.
AB  - Higher-eukaryotic nuclei contain numerous morphologically distinct substructures
      that are collectively called nuclear bodies. Although the precise functions of
      these subdomains remain unknown, elucidation of their molecular composition has
      been the subject of a great deal of research in recent years. Changes in the
      constitution of these nuclear inclusions are associated with disease phenotypes.
      The wide variety of components that concentrate within these subdomains makes
      them a likely interface for multiple cellular processes, including transcription,
      RNA processing, transport, RNP assembly, protein modification, apoptosis and cell
      cycle control. This review discusses the different types of nuclear bodies, with
      emphasis on the two most prominent subtypes - the coiled and PML bodies.

PMID- 10407410
TI  - Getting across the nuclear pore complex.
AB  - The nuclear pore complex (NPC) connects the cytoplasm and nucleus through the
      nuclear envelope and serves as the pipeline for moving material between the two
      compartments. Macromolecules that move through the NPC range in size from the
      very small (for example, ions and ATP) to the very large (for example,
      ribonucleoprotein particle complexes). Unlike translocation across other
      organelle membranes, proteins do not have to be unfolded to be transported
      through the NPC, and the NPC also routinely transports large, multicomponent
      substrates in both directions. This review focuses on current understanding of
      the different mechanisms by which macromolecules move across the NPC.

PMID- 10407413
TI  - Careers-perspective interview.

PMID- 10407411
TI  - Integrin-linked kinase (ILK): a regulator of integrin and growth-factor
      signalling.
AB  - Interaction of cells with the extracellular matrix (ECM) results in the
      regulation of cell growth, differentiation and migration by coordinated signal
      transduction through integrins and growth-factor receptors. Integrins achieve
      signalling by interacting with intracellular effectors that couple integrins and
      growth-factor receptors to downstream components. One well-studied effector is
      focal-adhesion kinase (FAK), but recently another protein kinase, integrin-linked
      kinase (ILK), has been identified as a receptor-proximal effector of integrin and
      growth-factor signalling. ILK appears to interact with and be influenced by a
      number of different signalling pathways, and this provides new routes for
      integrin-mediated signalling. This article discusses ILK structure and function
      and recent genetic and biochemical evidence about the role of ILK in signal
      transduction.

PMID- 10407412
TI  - An exegesis of IAPs: salvation and surprises from BIR motifs.
AB  - The BIR (baculovirus IAP repeat) motif is a conserved sequence of approximately
      70 amino acids that was identified originally in the 'inhibitor of apoptosis'
      (IAP) family of proteins. BIR-containing proteins (BIRPs) are found in viruses,
      yeast and metazoans. Recent genetic analysis of a nematode BIRP demonstrated an
      essential role in cytokinesis instead of apoptosis. It is likely that BIRs
      originated in eukaryotes to serve a role in cytokinesis and/or mitotic spindle
      function during cell division and that, with gene duplication, the more recent
      adaptation of some BIRPs to the regulation of apoptosis was possible. IAPs
      interact with a variety of proteins, including members of the caspase protease
      family. This article discusses current research on the structure and function of
      the BIR motifs and how it could provide insight into the function of BIRPs in
      cell division.

PMID- 10407414
TI  - Kang tsou (1932-1999) 

PMID- 10407417
TI  - Reply 

PMID- 10407415
TI  - Fatty acids, diacylglycerol, Ins(1,4,5)P3 receptors and Ca2+ influx.

PMID- 10407416
TI  - Coherent oscillations and short-term plasticity in corticothalamic networks.
AB  - The neocortex and thalamus are a unified oscillatory machine. Different types of
      brain rhythms, which characterize various behavioral states, are combined within
      complex wave-sequences. During the stage of sleep that is associated with low
      frequency and high-amplitude brain rhythms, the excitatory component of a
      cortically generated slow oscillation is effective in triggering thalamically
      generated rhythms and in increasing their spatiotemporal coherence over
      widespread territories. Thus, the study of coherent oscillations, as they appear
      naturally during states of vigilance in animals and humans, requires intact-brain
      preparations in which the neocortex and thalamus engage in a permanent dialog.
      Sleep oscillations are associated with rhythmic spike-bursts or spike-trains in
      thalamic and cortical neurons, which lead to persistent excitability changes
      consisting of increased depolarizing responses and decreased inhibitory
      responses. These short-term plasticity processes could be used to consolidate
      memory traces acquired during wakefulness, but can also lead to paroxysmal
      (hypersynchronous) episodes, similar to those observed in some epileptic
      seizures.

PMID- 10407418
TI  - Unbiased stereology?

PMID- 10407419
TI  - Crustacean studies and the early history of GABA.

PMID- 10407420
TI  - Marrow-mindedness: a perspective on neuropoiesis.
AB  - There are pluripotent stem cells in the adult brain that might not be very
      different from those found in bone marrow. Recent and profound advances in the
      field of neuropoiesis, which often rely on insights from studies of hematopoiesis
      and in some instances use cross-paradigms with this field, have already revealed
      that bone marrow has much in common with so-called 'brain marrow'. Proliferative
      primogenitors and developmentally regulated molecules are hallmarks of both
      neuropoiesis and hematopoiesis. This article will focus on recent advances in
      neuropoiesis within a central core of the mature brain that is referred to as
      brain marrow, discussing its pluripotency and proliferative capacity, in vitro
      and molecular assays used in its study, and markers of neuropoietic
      stem/progenitor cells. As hematopoiesis research has led to the discovery of
      numerous morphogenetic factors, it is anticipated that studies of neuropoiesis
      should also uncover many new factors and genes that affect the growth and
      differentiation of neural cells. Recent breakthroughs in the stem-cell field
      prompt an inclusion of rationale for the persistence of normal stem/progenitor
      cells even in the aged brain. By analogy with hematopoiesis research, a thorough
      investigation of brain marrow should provide basic insights into developmental
      and persistent neurogenesis while anticipating cell-transplant and gene therapies
      for debilitating neurological diseases.

PMID- 10407421
TI  - New prospects for human stem-cell therapy in the nervous system.
AB  - It would be of enormous benefit if human neural tissue could be generated in
      vitro as this would allow screening for neuroactive compounds, and provide a
      source of tissue for testing cellular and gene therapies for CNS disorders. It is
      now well established that pluripotent embryonic stem cells (ES cells) from the
      mouse can be propagated in culture and differentiated into a range of tissues,
      including neuronal and glial cells. In other studies, more-restricted neural stem
      cells have been isolated from both the developing and adult rodent brain. Current
      reports now describe similar pluripotent and neural stem cells cultured from
      human embryos. While the exact nature of these cells continues to be explored,
      they can be grown for extended periods of time while retaining the capacity for
      neuronal and glial differentiation. In some cases, they have been shown to
      integrate into the developing or damaged adult brain. This article reviews their
      biology, with a focus on the possible links between ES-cell and neural stem-cell
      technologies, and the strategies used to isolate and expand defined cell
      populations.

PMID- 10407422
TI  - Signalling through the JAK-STAT pathway in the developing brain.
AB  - The JAK -STAT (Janus kinase-signal transducer and activator of transcription)
      signalling pathway that is stimulated by cytokines has been much investigated in
      haematopoietic cells, but recent data indicate that this pathway is also present
      and active during neuronal and glial differentiation. Furthermore, it is now
      clear that growth factors other than the classical cytokines can act through this
      pathway and that physiological inhibitors of this signalling cascade exist. Thus,
      the JAKs, the STATs and their specific inhibitors could be molecules with
      important roles in the CNS.

PMID- 10407423
TI  - Parental behaviour in Kentish plovers: who cares?

PMID- 10407424
TI  - The panda and the phage: compensatory mutations and the persistence of small
      populations.

PMID- 10407425
TI  - The cuckoo chick tricks their reed warbler foster parents, but what about other
      host species?

PMID- 10407426
TI  - Biological drivers of zooplankton patchiness.
AB  - Until recently, biological drivers of plankton aggregation were under
      appreciated, because most studies concentrated on physical processes. New
      technological advances, novel experiments and theory have shifted focus to the
      pivotal role of behaviour in plankton patch dynamics. Our review highlights four
      biological drivers of zooplankton spatial patchiness and brings together recent
      research on well studied marine and freshwater taxa, primarily copepods and
      cladocerans. Diverse and powerful behavioural responses by zooplankton to
      physical and chemical signals are shown to contribute to the formation and
      breakdown of zooplankton patches over several different spatial scales.

PMID- 10407427
TI  - Evolutionary consequences of diploid-polyploid hybrid zones in wild species.
AB  - Hybrid zones between cytotypes with different ploidy levels are particularly
      interesting for studying the ecology and the evolution of reproductive
      interactions between closely related taxa. Diploid-polyploid hybrid zones differ
      fundamentally from those between diploids in that they reflect certain conditions
      that are characteristic of the early stage of polyploid establishment, and allow
      tests of hypotheses relating to the dynamics and evolution of polyploid
      complexes. Recent theoretical and empirical studies have provided important data
      on the evolution of isolating mechanisms in diploid-polyploid contact zones, but
      have also shown that introgression might counteract the evolution of isolating
      mechanisms.

PMID- 10407428
TI  - Coevolution while you wait: Varroa jacobsoni, a new parasite of western
      honeybees.
AB  - The mite Varroa jacobsoni is a brood parasite of the Asian hive bee, Apis cerana.
      The recent switch in host from A. cerana to the western honeybee, Apis mellifera,
      offers an exceptional opportunity for studying preadaptation and host-parasite
      relations. The fact that this host shift appears to have happened on at least two
      separate occasions, with differing outcomes, must be unique. At another level,
      the rapacious spread of this mite throughout the world is testimony to the
      ineffectiveness of international quarantine laws.

PMID- 10407429
TI  - The responsive C and N biogeochemistry of the temperate forest floor.
AB  - Soil organic matter is often viewed as comprising large pools of carbon and
      nitrogen with long residence times. However, the organic horizon that lies on the
      soil surface in temperate forests is a dynamic component of ecosystem carbon and
      nitrogen cycling. Responses to elevated inputs of nitrogen in this organic layer
      are emerging as key facets of ecosystem retention or loss of dissolved nitrogen.
      Research along nitrogen deposition gradients in the USA and Europe reveals a link
      between the ratio of organic carbon:nitrogen in the forest floor and nitrogen
      turnover rates, nitrification and leaching losses. Characteristics and processes
      in the forest floor are now recognized as key indicators or determinants of
      ecosystem 'nitrogen status'.

PMID- 10407430
TI  - Reply from R.V. Sole, S.C. Manrubia, M.J. Benton, S. Kauffman and P. Bak.

PMID- 10407431
TI  - Reply from M. Soler and J.J. Soler.

PMID- 10407432
TI  - Noninvasive genetic sampling: look before you leap.
AB  - Noninvasive sampling allows genetic studies of free-ranging animals without the
      need to capture or even observe them, and thus allows questions to be addressed
      that cannot be answered using conventional methods. Initially, this sampling
      strategy promised to exploit fully the existing DNA-based technology for studies
      in ethology, conservation biology and population genetics. However, recent work
      now indicates the need for a more cautious approach, which includes quantifying
      the genotyping error rate. Despite this, many of the difficulties of noninvasive
      sampling will probably be overcome with improved methodology.

PMID- 10407434
TI  - Cytokinin cycles cells.

PMID- 10407433
TI  - Animal behavior: an essential component of invasion biology.
AB  - A major challenge of invasion biology lies in the development of a predictive
      understanding of invasion processes. Attempts to identify the proximate causes of
      invasion success or to predict rates of spread seldom emphasize behavioral
      characteristics. Recent experimental work, however, illustrates that insight into
      the proximate causes of animal invasions often hinges on a careful assessment of
      behavioral mechanisms. For this reason, behavioral analyses should be more fully
      integrated into research on biological invasions. In addition to enhancing a
      general understanding of invasion processes, such approaches provide potentially
      underused opportunities for basic research in animal behavior.

PMID- 10407435
TI  - The molecular mechanism of sodium influx to root cells.

PMID- 10407436
TI  - Transgenes and agriculture - going with the flow?

PMID- 10407437
TI  - Plant sugar sensing and signaling - a complex reality.

PMID- 10407438
TI  - ReplyellipsisThe sugar sensing story.

PMID- 10407439
TI  - The ups and downs of gravitropism

PMID- 10407440
TI  - Developmental biology of the cereal endosperm.
AB  - The recent application of immunohistochemistry and molecular techniques has
      revealed that endosperm development depends on a genetic program that combines an
      ancient process for cellularization (similar to that seen in late Paleozoic seed
      ferns) with a mechanism for specifying asymmetric cell fates that has parallels
      to signaling processes in mammals. Progress has been further accelerated by the
      recent realization that the conserved nature of nuclear endosperm development
      extends beyond the grass species, to include dicots, such as Arabidopsis. It is
      anticipated that these ongoing studies will provide invaluable tools for the
      improvement of yield and grain quality in cereal crops.

PMID- 10407441
TI  - High resolution FISH in plants - techniques and applications.
AB  - Fluorescence in situ hybridization (FISH) is an effective and accurate
      cytogenetic tool for mapping single copy and repetitive DNA sequences on
      chromosomes. Attempts to increase the detection sensitivity of very small
      chromosomal targets, and to improve the spatial resolution of signals derived
      from flanking sequences, have led to the development of a variety of novel
      techniques: it is now possible to perform in situ hybridizations on interphase
      nuclei, meiotic pachytene chromosomes and isolated chromatin (DNA fibres). The
      recent application of these techniques has indicated that a spatial resolution of
      1 kb between adjacent targets and a sensitivity of targets smaller than 1 kb is
      now feasible. Here, we describe the benefits of these novel chromosome analysis
      techniques and discuss their relevance for the study of plant genomes.

PMID- 10407442
TI  - How plants make ends meet: DNA double-strand break repair.
AB  - DNA double-strand breaks (DSBs) lead to serious genomic deficiencies if left
      unrepaired. Recent studies have provided new insight into the mechanisms, the
      mutants and the genes involved in DSB repair in plants. These studies indicate
      that high fidelity DSB repair via homologous recombination is less frequent than
      non-homologous end-joining. Interestingly, non-homologous end-joining in plants
      is more error-prone than in other species, being associated with various
      rearrangements that often include deletions and insertions (filler DNA). We
      discuss the mechanism of error-prone DSB repair, which is probably an important
      driving force in plant genome evolution.

PMID- 10407443
TI  - Ethylene perception and signaling: an evolutionary perspective.
AB  - Ethylene signal transduction, as revealed by studies in Arabidopsis, provides an
      interesting example of how information-processing systems have evolved in plants.
      The ethylene signal is perceived by a family of receptors composed of structural
      elements that are characteristic of bacterial signaling proteins. In plants,
      these receptors transmit the signal by interacting with proteins that are
      eukaryotic in origin. The ethylene sensor domain of the receptors forms a
      membrane-associated structure that uses a copper cofactor to bind ethylene. This
      novel protein motif appears to have originated early in the evolution of
      photosynthetic organisms.

PMID- 10407444
TI  - Molecular pieces to the puzzle of the interaction between potassium and sodium
      uptake in plants.
AB  - Potassium uptake is vital for plant growth but in saline soils sodium competes
      with potassium for uptake across the plasma membrane of plant cells. This can
      result in high Na+:K+ ratios that reduce plant growth and eventually become
      toxic. Our understanding of the molecular basis underlying the interaction
      between essential potassium and toxic sodium was limited until the recent cloning
      and electrophysiological characterization of several genes encoding different
      types of molecules that are involved in K+ and Na+ transport. These molecules,
      and their regulation, are important in determining the K+:Na+ homeostasis of
      plants in saline soils, although it is not yet known which is most critical in
      determining the K+:Na+ ratios in whole plants.

PMID- 10407445
TI  - GFP-based FRET microscopy in living plant cells.

PMID- 10407446
TI  - Malaria drug trials--an ethical dilemma?

PMID- 10407447
TI  - Design-based counting techniques: the real problems.

PMID- 10407449
TI  - Reply 

PMID- 10407448
TI  - Reply 

PMID- 10407450
TI  - Self-organized criticality in ecology and evolution.

PMID- 10407452
TI  - To repeat or block, in experiments?

PMID- 10407451
TI  - How should cuckoo chicks signal in different host nests?

PMID- 10407453
TI  - "Lifepoint": a case study in using social science community identification data
      to guide the implementation of a needle exchange program.
AB  - The public health benefits of needle exchange programs (NEPs) are well known.
      NEPs lower risk factors for HIV transmission by providing injection drug users
      (IDUs) with clean syringes and needles; harm reduction materials; and referrals
      to drug, sexually transmitted disease, mental health, and medical treatment
      facilities. While exchange programs continue to be implemented, there have been
      few reports illustrating how social science and community assessment research can
      be used to guide the development of NEPs. Using the Lifepoint needle exchange
      program in Milwaukee as a case study, this paper shows how social science methods
      can be used to understand IDU culture through the community identification
      process, link qualitative and observational findings to program decision making,
      and guide the implementation and operation of a needle exchange. The community
      identification process showed that there were different IDU subcultures in the
      city indicating that the NEP would need to be tailored to meet the distinctive
      needs of multiple drug use networks. Ethnographic field observations and key
      informant and systems representative interviews resulted in a two-stage NEP
      planning process that included a community task force on IDUs and of the
      development of methods to operationalize community assessment findings into the
      operating plan of the NEP. This process illustrates the importance of integrating
      a systematic community analysis in the planning of a NEP.

PMID- 10407455
TI  - Assisting persons living with HIV/AIDS to return to work: programmatic steps for
      AIDS service organizations.
AB  - The objective of this study was to develop a comprehensive picture of the
      concerns and needs of persons living with HIV/AIDS who are interested in
      returning to work. To collect information in this new area, a series of focus
      groups was conducted with a random sample of clients from AIDS Project Los
      Angeles who were currently unemployed and expressed a desire to return to work.
      The results indicate a range of concerns among individuals with HIV/AIDS about
      returning to work, such as a loss of or change in medical benefits, the need for
      flexibility in employment to address ongoing medical needs, concerns regarding
      disclosure of their HIV/AIDS status, the possibility of job related
      discrimination, and the need to address the practical aspects of reentering the
      labor market after a prolonged absence. The findings suggest a series of action
      steps for AIDS service organizations and others to address the needs of persons
      with HIV/AIDS in this new area.

PMID- 10407454
TI  - An evaluation of the use of drama to communicate HIV/AIDS information.
AB  - This study evaluated the effectiveness of three dramas created to disseminate
      HIV/AIDS information. Predrama and postdrama interviews were conducted with a
      cohort of randomly selected audience members from ten separate performances in
      Tamil Nadu state, India (N = 93); an interview was also conducted with a
      postdrama--only comparison group (N = 99). The results showed that a significant
      increase in HIV/AIDS-related knowledge occurred as a result of watching the
      drama. Before the drama, audiences had relatively high levels of accurate
      knowledge about HIV/AIDS but lower knowledge levels of common HIV/AIDS
      misconceptions. The drama reduced these misconceptions. The drama also increased
      the level of reported intentions to treat HIV positive individuals more kindly.
      This research demonstrates that drama can be an effective medium for
      communicating HIV/AIDS information and can reduce knowledge gaps associated with
      low levels of formal education. Drama can also be used to convey socioemotive and
      sensitive material and could find wide applicability in many settings.

PMID- 10407456
TI  - The importance of AIDS-related knowledge for mid-life and older women.
AB  - Although the AIDS epidemic has had a major impact on the lives of women
      throughout the world, there is little knowledge regarding risk factors,
      transmission factors, prevention methods, and results of prevention efforts for
      older women, even though almost 10% of all AIDS cases in the United States are
      among those 50 years and older. This article reports results on AIDS knowledge
      and risks from the Massachusetts Women's Health Study, a longitudinal community
      based study of middle-aged women. AIDS-related questions were asked of this
      sample at their last study interview, which occurred in 1995 when the women were
      aged 58-67. Results indicate that this sample of older, predominantly Caucasian
      women are quite knowledgeable about transmission factors but are less
      knowledgeable about early interventions and their own risk status. Many are also
      likely to know someone with HIV or AIDS. Even though these women are generally at
      low risk, they may be at higher risk than they perceive. They may also be
      significant disseminators of knowledge to friends and relatives who may be at
      risk, and thus could represent an important target group for AIDS educational
      programs.

PMID- 10407458
TI  - This is my story: a descriptive analysis of a peer education HIV/STD risk
      reduction program for women living in housing developments.
AB  - Descriptive, qualitative data was collected from 30 women who participated in the
      Centers for Disease Control and Prevention-funded Perinatal HIV Reduction and
      Education Demonstration Activities (PHREDA) Project. Women were primarily
      heterosexual, welfare-dependent, African-American mothers. Staff trained women to
      conduct HIV/STD education as peer volunteers. The theory-based educational
      components consisted of role model stories developed by women about their
      experiences with HIV/STDs and discussion groups to build behavioral and
      communication skills. Women were given role-model stories and safer sex supplies
      to initiate conversations about women's health and sexual safety in their
      communities. PHREDA groups allowed women to identify their risk reduction,
      sexual, and family issues. Role model stories provided a validating medium
      through which high-risk women explored reproductive health risk and planned steps
      toward behavioral change. Descriptive data from peer volunteers can provide an
      important perspective on small group, peer-based community HIV/STD reduction
      interventions.

PMID- 10407457
TI  - Amphetamine use and its correlates among youths living with HIV.
AB  - Amphetamine use and its correlates are examined among youths living with HIV
      (YLH) to determine whether its use is associated with increased transmission acts
      and poor health. Amphetamine use, other HIV-related risk acts, T-cell counts,
      emotional distress, coping style, and symptoms of HIV are examined in 337 YLH.
      One third of YLH engaged in amphetamine use in their lifetime, and 21% of youths
      reported current use (i.e., in the last 3 months). Compared with those who never
      used, users initiated other drug use at younger ages, used more types of drugs,
      reported more emotional distress, and employed escape coping significantly more
      often. Compared with those who have never used (never-users), users also had more
      sexual partners and more sexual encounters. Although users and never-users do not
      differ on physical symptoms or whether they have been diagnosed with AIDS, users
      of amphetamines report significantly higher T-cell counts than never-users.
      Despite poor psychosocial functioning, amphetamine users have higher T-cell
      counts than other YLH; future research must examine longitudinally if a quadratic
      relationship exists between amphetamine use and health status. The continued high
      risk profile of transmission acts among users suggests that preventive
      interventions must target specific drugs used by YLH.

PMID- 10407460
TI  - Estimation of nonpaternity in the Mexican population of Nuevo Leon: a validation
      study with blood group markers.
AB  - A method for estimating the general rate of nonpaternity in a population was
      validated using phenotype data on seven blood groups (A1A2BO, MNSs, Rh, Duffy,
      Lutheran, Kidd, and P) on 396 mother, child, and legal father trios from Nuevo
      Leon, Mexico. In all, 32 legal fathers were excluded as the possible father based
      on genetic exclusions at one or more loci (combined average exclusion probability
      of 0.694 for specific mother-child phenotype pairs). The maximum likelihood
      estimate of the general nonpaternity rate in the population was 0.118 +/- 0.020.
      The nonpaternity rates in Nuevo Leon were also seen to be inversely related with
      the socioeconomic status of the families, i.e., the highest in the low and the
      lowest in the high socioeconomic class. We further argue that with the moderately
      low (69.4%) power of exclusion for these seven blood group systems, the
      traditional critical values of paternity index (PI > or = 19) were not good
      indicators of true paternity, since a considerable fraction (307/364) of
      nonexcluded legal fathers had a paternity index below 19 based on the seven
      markers. Implications of these results in the context of genetic-epidemiological
      studies as well as for detection of true fathers for child-support adjudications
      are discussed, implying the need to employ a battery of genetic markers (possibly
      DNA-based tests) that yield a higher power of exclusion. We conclude that even
      though DNA markers are more informative, the probabilistic approach developed
      here would still be needed to estimate the true rate of nonpaternity in a
      population or to evaluate the precision of detecting true fathers.

PMID- 10407459
TI  - Coping among HIV negative and HIV positive female injection drug users.
AB  - The study examined the psychosocial determinants of coping ability in a cohort of
      249 HIV positive and HIV negative female injection drug users (IDUs), using a
      cross-sectional retrospective design. Information collected using a structured
      questionnaire included data on psychosocial risk and protective factors in the
      personality, family, and peer domains, HIV status, and coping ability. Coping
      ability was associated with conventionality, greater control of emotions, less
      psychopathology, and family cohesion in both HIV positive and HIV negative
      subjects. The psychosocial factors affected coping in HIV positive and HIV
      negative IDUs via two different mediational models. The interactional findings
      supported the influence of risk/protective interactions in both groups. The
      findings demonstrate the impact of the interplay between personality factors and
      external support on coping ability in female IDUs.

PMID- 10407461
TI  - Developmental components of resting ventilation among high- and low-altitude
      Andean children and adults.
AB  - This paper evaluates the age-associated changes of resting ventilation of 115
      high- and low-altitude Aymara subjects, of whom 61 were from the rural Aymara
      village of Ventilla situated at an average altitude of 4,200 m and 54 from the
      rural village of Caranavi situated at an average altitude of 900 m. Comparison of
      the age patterns of resting ventilation suggests the following conclusions: 1)
      the resting ventilation (ml/kg/min) of high-altitude natives is markedly higher
      than that of low-altitude natives; 2) the age decline of ventilation is similar
      in both lowlanders and highlanders, but the starting point and therefore the age
      decline are much higher at high altitude; 3) the resting ventilation that
      characterizes high-altitude Andean natives is developmentally expressed in the
      same manner as it is at low altitude; and 4) the resting ventilation (ml/kg/min)
      of Aymara high-altitude natives is between 40-80% lower than that of Tibetans.

PMID- 10407462
TI  - Hyperostosis frontalis interna: an anthropological perspective.
AB  - Hyperostosis frontalis interna (HFI) is manifested by the accretion of bone on
      the inner table of the frontal bone. Despite the vast literature on HFI,
      ambiguity exists as to its etiology, osteogenesis, demography, and history. This
      stimulated the present broad-scale study of HFI which included the evaluation of
      1,706 early 20th century skulls (1,007 males and 699 females) from the Hamann
      Todd and Terry human osteological collections, as well as 2,019 pre-19th century
      East-Mediterranean, Amerindian, and Central European skulls. In addition, 72
      cadavers were dissected for gross inspection and histology. Special attention was
      paid to the relationship of the brain and meninges to endocranial lesions. HFI is
      an independent condition, not a symptom of a more generalized syndrome as
      suggested in the past. It can appear in a variety of forms but each is the result
      of the same process and probably of the same etiology. Investigators' previous
      failure to recognize the mild stages of HFI (types A and B) as an early form of
      the general HFI process led to erroneous statistics and interpretations of
      observations. HFI should also be considered a phenomenon separate from HCI,
      hyperostosis cranialis diffusa (HCD), and other endostoses, even when it appears
      in association with them. To avoid ambiguity and facilitate the description of
      cranial hyperostoses, uniform nomenclature (HFI, HCD) has been recommended. HFI
      is rarely seen in historic populations, regardless of geographical origin. It is
      most commonly found among females and is believed to be associated with prolonged
      estrogen stimulation. While its magnitude of manifestation and frequency are much
      higher in females, HFI is not a purely female phenomenon. Males with hormonal
      disturbances such as atrophic testis were found to manifest HFI type D. HFI is
      associated with age insofar as it is much less frequent in females under 40 years
      of age. Although advanced cases of HFI (types C and D) have been observed in
      individuals as young as 40 years of age, it is more frequently found after age
      60. The frequency of HFI type D will not increase from age 60. Type-predicted
      analysis by cohort reveals significant ethnic differences. Changes in African
      American (AA) females appear earlier in life and progress more rapidly than in
      European American (EA) females. Analysis of radiographs shows a discrepancy
      between the anatomic prevalence of HFI and its radiological recognition, which is
      very poor for mild cases. This apparently resulted in the misconceptions that HFI
      is entirely an old-age phenomenon, and that it is exclusively female.
      Histological analysis shows that the inner table along with the closely attached
      dural layer play a major role in the osteogenesis of HFI. Contrary to previous
      models, no evidence for diploe or ectocranial plate involvement was found.
      Cadaver study suggests that the predilection for the frontal area may be related
      to an altered blood supply and/or vascular stretching.

PMID- 10407463
TI  - Metric analyses of an early holocene human skeleton from Gua Gunung Runtuh,
      Malaysia.
AB  - A nearly complete human skeleton dating to the Early Holocene (epi-Paleolithic
      culture) excavated from Gua Gunung Runtuh, Malaysia, is described. Cranial,
      dental, and limb bone measurements are recorded on the skeleton, and compared
      with early and modern skeletal samples from Southeast Asia and Australia. The
      comparisons demonstrate that the Gua Gunung specimen is most similar to
      Australian Aborigines in dental and limb measurements, while the cranial
      measurements indicate a close affinity to Mesolithic samples from Malaysia and
      Flores. These findings further suggest that the Gua Gunung skeleton, as well as
      other fossils from Tabon and Niah, are representative of an early group of people
      who occupied Sundaland during the late Pleistocene, and may be the ancestors of
      Australian Aborigines. Some of the dental and limb bone measurements exhibited by
      the ancestors persist in Southeast Asian populations until the early Holocene.
      Differences in cranial traits have, however, accumulated since the late
      Pleistocene in Australian Aborigines and early Southeast Asian peoples.

PMID- 10407464
TI  - The evolution of human speech: the role of enhanced breathing control.
AB  - Many cognitive and physical features must have undergone change for the evolution
      of fully modern human language. One neglected aspect is the evolution of
      increased breathing control. Evidence presented herein shows that modern humans
      and Neanderthals have an expanded thoracic vertebral canal compared with
      australopithecines and Homo ergaster, who had canals of the same relative size as
      extant nonhuman primates. Based on previously published analyses, these results
      demonstrate that there was an increase in thoracic innervation during human
      evolution. Possible explanations for this increase include postural control for
      bipedalism, increased difficulty of parturition, respiration for endurance
      running, an aquatic phase, and choking avoidance. These can all be ruled out,
      either because of their evolutionary timing, or because they are insufficiently
      demanding neurologically. The remaining possible functional cause is increased
      control of breathing for speech. The main muscles involved in the fine control of
      human speech breathing are the intercostals and a set of abdominal muscles which
      are all thoracically innervated. Modifications to quiet breathing are essential
      for modern human speech, enabling the production of long phrases on single
      expirations punctuated with quick inspirations at meaningful linguistic breaks.
      Other linguistically important features affected by variation in subglottal air
      pressure include emphasis of particular sound units, and control of pitch and
      intonation. Subtle, complex muscle movements, integrated with cognitive factors,
      are involved. The vocalizations of nonhuman primates involve markedly less
      respiratory control. Without sophisticated breath control, early hominids would
      only have been capable of short, unmodulated utterances, like those of extant
      nonhuman primates. Fine respiratory control, a necessary component for fully
      modern language, evolved sometime between 1.6 Mya and 100,000 ya.

PMID- 10407465
TI  - Seed handling in chimpanzees (Pan troglodytes) and redtail monkeys (Cercopithecus
      ascanius): implications for understanding hominoid and cercopithecine fruit
      processing strategies and seed dispersal.
AB  - Primates are confronted with an array of constraints in feeding on fruit,
      including the removal of adhesive, energy-rich pulp from seeds. In this paper, I
      discuss how primates meet this challenge and present data on the fruit-processing
      and seed-handling behavior of chimpanzees and redtail monkeys in Kibale National
      Park, Uganda. These data are then related to these species' services as seed
      dispersers. Particular attention was paid to the methods by which primates
      removed pulp from seeds, the density of seed clumps that they deposited (by
      spitting, dropping, or defecating) to the forest floor, and the distance seeds
      were moved from parent trees. Distance and density differences in chimpanzee and
      redtail seed dispersal resulted from distinct fruit-processing and seed-handling
      methods. It was observed, in general, that redtail monkeys engaged in fine oral
      processing and were seed spitters: most seeds were dispersed in close proximity
      to parent trees (84% of spat seeds < 10 m of parent tree), and deposited singly
      (100% seeds spat singly). In contrast, chimpanzees were coarse fruit processors
      and seed swallowers: seeds were defecated in denser clumps (e.g., a mean of 149
      large seeds/dung sample and hundreds of small seeds/dung sample), far from parent
      trees. I evaluate the factors that shape patterns of fruit processing in
      hominoids and cercopithecines, and argue that the observed seed handling
      differences can be attributed to differences in digestive retention times, oral
      anatomy, and alternative mechanisms by which to avoid the cost of seed ballast.

PMID- 10407466
TI  - Incisor microwear, diet, and tooth use in three Amerindian populations.
AB  - Incisor microwear patterns have been shown to reflect aspects of diet and
      ingestive behaviors in a wide range of nonhuman primates. While some studies have
      suggested that anterior dental microwear might be used to infer unusual front
      tooth use practices in archaeological populations, quantitative work on modern
      human incisors has thus far been limited. In this study we examined dental
      microwear on the maxillary central incisors of three groups of humans: Aleutian
      Islanders (n = 16), Arikara from the Mobridge Site in South Dakota (n = 15), and
      a Late Woodland Bluff sample from Jersey County, Illinois (n = 17). High
      resolution replicas were prepared and examined by scanning electron microscopy
      following conventional procedures. Photomicrographs were taken at consistent
      locations on the labial surface, and microwear was quantified using Microware 3.0
      (Ungar, 1997). Statistical test results revealed significant differences among
      the groups in microwear feature densities, sizes, and shapes. The Aleut, Arikara,
      and Illinois Bluff samples showed a gradient of increasing microwear density,
      increasing linearity in feature shape, and decreasing feature size. These
      differences evidently correspond to amount of meat consumption, and apparently to
      degree of use of the incisors in heavy loading. No differences were observed
      between groups in heterogeneity of feature orientations, and no sex-related
      differences were found. Associations between incisor microwear on the one hand
      and subsistence practice and anterior tooth use on the other likely have
      important implications for the study of hominid paleobiology.

PMID- 10407467
TI  - Phalangeal morphology of the paromomyidae (?primates, plesiadapiformes): the
      evidence for gliding behavior reconsidered.
AB  - A comparative morphometric analysis of isolated proximal and intermediate
      phalanges attributed to the paromomyids Ignacius graybullianus and Phenacolemur
      simonsi was undertaken to test the hypothesis that these fossil phalanges exhibit
      evidence of a dermopteran-like interdigital patagium. Linear dimensions were
      collected for the fossil phalanges and a comparative sample of associated
      proximal and intermediate phalanges representing extant tree squirrels, tree
      shrews, dermopterans (colugos), gliding rodents and marsupials, and prosimian
      primates. Quantitative data indicate that the proximal and intermediate phalanges
      of paromomyids are most similar in their overall shape to those of the
      dermopteran Cynocephalus. The proximal phalanges of paromomyids and colugos
      possess well-developed flexor sheath ridges and broad, high shafts, whereas the
      intermediate phalanges of these taxa are most similar to one another in their
      trochlear morphology. Discriminant analysis indicates that all of the paromomyid
      intermediate phalanges resemble those from colugo toes more so than those from
      colugo fingers. Moreover, the relative length and midshaft proportions of both
      the proximal and intermediate phalanges of paromomyids closely resemble those of
      several squirrels that lack an interdigital patagium. The following conclusions
      are drawn from this study: 1) paromomyids share a number of derived phalangeal
      features with modern dermopterans that may be indicative of a phylogenetic
      relationship between them, 2) existing intermediate phalanges of paromomyids are
      inconsistent with the "mitten gliding" hypothesis because they do not possess the
      distinctive length and midshaft proportions characteristic of colugo manual
      intermediate phalanges, and 3) paromomyids share with colugos and the scaly
      tailed squirrel Anomalurus several aspects of phalangeal morphology functionally
      related to frequent vertical clinging and climbing on large-diameter arboreal
      supports.

PMID- 10407468
TI  - Effect of protein intake during training on biochemical and performance variables
      in sled dogs.
AB  - OBJECTIVE: To determine effects of protein intake on blood variables, plasma
      volume, and maximal oxygen uptake (VO2max) in sled dogs undergoing rigorous
      training. ANIMALS: 32 Alaskan sled dogs, between 2 and 6 years old. PROCEDURE:
      Dogs were assigned to 1 of 4 groups on the basis of age, sex, and ability.
      Isocaloric diets containing 18% (diet A), 23% (diet B), 29% (diet C), or 35%
      (diet D) of energy as protein were assigned randomly to each group and fed 1
      month before and during a 12-week training period. Maximal oxygen uptake was
      measured at 0 (before training) and 12 weeks. Body weight, protein and energy
      intake, plasma volume, PCV, hemoglobin concentration, and serum biochemical
      variables were measured at 0, 8, and 12 weeks. RESULTS: Serum biochemical
      variables, PCV, and hemoglobin concentration remained within reference ranges for
      all dogs. Dogs fed diet A had a decrease in VO2max and a greater rate of soft
      tissue injury throughout training, compared with dogs fed the other diets. At 12
      weeks, dogs fed diets C and D had greater serum sodium concentration and
      hemoglobin concentration than did dogs fed diet A. Dogs fed diet D also had more
      plasma volume at 12 weeks than did dogs of any other group. CONCLUSIONS AND
      CLINICAL RELEVANCE: Consumption of a diet with 18% dietary protein on an energy
      basis (3.0 g of protein/kg of body weight) is insufficient to meet the metabolic
      requirements of sled dogs in training. For intense interval work, a diet with 35%
      dietary protein as energy (6.0 g of protein/kg) may provide a performance
      advantage by promoting an increase in plasma volume.

PMID- 10407469
TI  - Safety and efficacy of vaccination of pregnant gilts against porcine reproductive
      and respiratory syndrome.
AB  - OBJECTIVE: To determine the safety and efficacy of vaccination of pregnant gilts
      with an attenuated strain of porcine reproductive and respiratory syndrome virus
      (PRRSV). ANIMALS: 16 pregnant gilts. PROCEDURE: Pregnant gilts free of antibodies
      for PRRSV were assigned (4 gilts/group) to the following groups: group I,
      untreated controls; group II, vaccinated on day 60 of gestation; group III,
      vaccinated on day 60 of gestation and exposed to virulent PRRSV on day 90 of
      gestation; and group IV, exposed to virulent PRRSV on day 90 of gestation. Safety
      and efficacy of vaccination was evaluated by group comparisons of prenatal and
      postnatal survival of fetuses and pigs, respectively, and by the condition and
      rate of weight gain of liveborn pigs. RESULTS: Collective (prenatal and
      postnatal) death losses up to day 15 after farrowing (conclusion of study) were
      similar for groups I (7/47, 14.9%) and II (7/44, 16.9%) but were greater for
      group III (18/49, 36.7%) and were greater still for group IV (23/37, 62.2%). Mean
      body weight 15 days after farrowing was greatest for pigs in litters of group I
      (4.46 kg) and progressively less for the other groups (3.87, 3.76, and 2.18 kg
      for groups II, III, and IV, respectively). CONCLUSIONS: Using these conditions,
      vaccination of gilts during midgestation appeared to be safe. However, it
      provided only partial protection against subsequent exposure to virulent virus.
      CLINICAL RELEVANCE: Attenuated-PRRSV vaccines may have to be administered to
      naive gilts > 30 days before conception to provide maximum protection throughout
      gestation.

PMID- 10407470
TI  - Restriction fragment length polymorphism analysis of strains of porcine
      reproductive and respiratory syndrome virus by use of a nested-set reverse
      transcriptase-polymerase chain reaction.
AB  - OBJECTIVE: To increase the timeliness and sensitivity of a procedure that uses
      viral nucleic acid amplification followed by restriction fragment length
      polymorphism (RFLP) analysis for identifying strains of porcine reproductive and
      respiratory syndrome virus (PRRSV). SAMPLE POPULATION: 24 strains of PRRSV.
      PROCEDURE: A nested-set reverse transcriptase-polymerase chain reaction (RT-PCR)
      was developed and compared with a nonnested-set RT-PCR for sensitivity in
      amplifying known quantities of infective PRRSV. Once reaction conditions were
      optimized, the nested-set RT-PCR was tested for effectiveness with 24 strains of
      PRRSV isolated from swine. RESULTS: The nested-set RT-PCR was 100- to 1,000-fold
      more sensitive than the nonnested-set RT-PCR, detecting as little as 1 infective
      unit of PRRSV/ml of sample. It also was generally as sensitive as the combination
      of steps, namely virus isolation or propagation and nonnested-set RT-PCR,
      currently used routinely for amplifying PRRSV prior to RFLP analysis, and it was
      effective for amplifying all of the 24 strains of PRRSV tested. Using this RT
      PCR, all tests were completed within 1.5 days (including RFLP analysis), compared
      with the > 7 days often required for the currently used method involving virus
      isolation and propagation. CONCLUSIONS: The nested-set RT-PCR was generally as
      sensitive as the combination of methods now used for PRRSV amplification prior to
      RFLP analysis, and it can markedly reduce the time required for testing. CLINICAL
      RELEVANCE: Presumptive identification of PRRSV strains can be provided in a more
      timely manner by use of a nested-set RT-PCR.

PMID- 10407471
TI  - Myeloperoxidase activity of the large intestine in an equine model of acute
      colitis.
AB  - OBJECTIVE: To determine whether quantification of myeloperoxidase (MPO) activity
      could be a useful laboratory technique to detect granulocyte infiltration in
      equine intestinal tissues. SAMPLE POPULATION: Intestinal tissue (inflamed or
      healthy) collected from 16 age- and sex-matched Shetland Ponies. PROCEDURE:
      Intestinal tissue MPO activity was determined, and histologic assessment of
      adjacent specimens from healthy and inflamed intestine was done. RESULTS:
      Intestinal tissue MPO activity and histopathologic score increased with time
      after castor oil challenge and peaked at 16 hours in an equine diarrhea model in
      which individual ponies provided their own control tissues. CONCLUSIONS:
      Intestinal tissue inflammation scores correlated positively with tissue MPO
      activity in adjacent specimens. CLINICAL RELEVANCE: Tissue MPO assay may be a
      useful laboratory tool to quantify intestinal mucosal inflammation in ponies.

PMID- 10407472
TI  - Comparison of stance time and velocity as control variables in force plate
      analysis of dogs.
AB  - OBJECTIVE: To investigate effects of the use of stance time or velocity as
      control variables on ground reaction forces in lame dogs. ANIMALS: 12 dogs with
      pelvic osteotomies. PROCEDURE: Data for ground reaction forces were obtained
      preoperatively and at 2, 4, 6, 8, 12, 16, 20, 24, and 28 weeks postoperatively,
      using velocity and stance time as control variables. Ground reaction forces
      obtained were compared between the 2 methods of data collection, as were
      velocities and stance times of the trials. RESULTS: Significant differences in
      ground reaction forces were not found between the use of velocity or stance time
      as a control variable at any time. Also, significant differences in stance times
      or velocities were not found between the 2 methods of data collection. Greatest
      variation in stance time and velocity was found during periods of greatest
      lameness. CONCLUSIONS AND CLINICAL RELEVANCE: Use of stance time as a control
      variable in force plate analysis does not lead to significantly different results
      from use of velocity as a control variable, indicating that either method may be
      used in force plate analysis of dogs.

PMID- 10407473
TI  - Influence of restricted food intake on estrous cycles and pseudopregnancies in
      dogs.
AB  - OBJECTIVE: To examine effects of restricted food intake on estrous cycle
      frequency, interestrus interval, and pseudopregnancy prevalence in dogs. ANIMALS:
      28 female Labrador Retrievers. PROCEDURE: Dogs were paired by body weight when
      they were 6 weeks old and fed so that the limit-fed pair-mate received 75% of the
      amount of food offered to its maintenance-fed counterpart. Estrous cycle,
      interestrus interval, and pseudopregnancy data were recorded. RESULTS: Mean
      annual frequency of estrous cycles and duration of interestrus intervals did not
      differ between feeding groups. Prevalence of clinically evident pseudopregnancy
      was significantly greater among females that were maintenance fed, although
      results of endocrinologic testing did not identify a mechanism for this
      observation. CONCLUSIONS AND CLINICAL RELEVANCE: Pseudopregnancy in dogs can be
      influenced by physiologic factors related to nutrition. Clinicians should
      consider a variety of physiologic and environmental factors when evaluating
      reproductive function in dogs.

PMID- 10407474
TI  - Persistence of maternal antibodies against Mycoplasma agassizii in desert
      tortoise hatchlings.
AB  - OBJECTIVE: To investigate Mycoplasma agassizii-specific maternal antibodies in
      desert tortoise (Gopherus agassizii) hatchlings. SAMPLE POPULATION: Plasma from
      43 captive-reared desert tortoise hatchlings. PROCEDURE: ELISA for M agassizii
      specific antibodies was performed. Four hatchlings from 4 clutches of 3 M
      agassizii-seropositive females with chronic upper respiratory tract disease
      (URTD) were tested on the day of hatching (set 1), and 20 hatchlings from 4
      clutches of 4 M agassizii-seropositive females with URTD and 19 hatchlings from 4
      M agassizii-seronegative healthy females were tested at 4, 8, 12, and 29 months
      old (set 2). Immunoblot analysis was performed to determine immunoglobulin
      classes in yolk and plasma of hatchlings. To determine infection status of
      hatchlings, yolk, egg shell membranes (set 1), and nasal lavage fluid (sets 1 and
      2) were examined for M agassizii by use of polymerase chain reaction. RESULTS:
      Yolk and hatchling plasma had significantly lower amounts of specific antibodies
      than did plasma from adult females. The IgG and IgM antibodies were transferred,
      but M agassizii-specific antibodies were of the IgG class. Hatchlings were not
      infected with mycoplasmas. Offspring of sick females had significantly higher
      specific antibody titers than did offspring of healthy females. Titers were still
      significantly different in 1-year-old hatchlings. CONCLUSIONS: Desert tortoise
      females transfer specific IgG and IgM antibodies to their offspring that are
      still detectable after 1 year. CLINICAL RELEVANCE: Infection with M agassizii may
      be misdiagnosed in hatchlings with persistent maternal antibodies. Passively
      acquired antibodies may have a role in pathogenesis of mycoplasma-induced
      respiratory tract disease and other diseases.

PMID- 10407475
TI  - Pharmacokinetics and pharmacologic effects of the S(-) isomer of bupivacaine
      after intravenous and epidural administration in dogs.
AB  - OBJECTIVE: To determine pharmacokinetic variables and pharmacologic effects of
      the S(-) isomer of bupivacaine (S[-]-BPV) in dogs. ANIMALS: 6 adult male Beagles.
      PROCEDURE: Dogs received S(-)-BPV (1 mg/kg of body weight) i.v., and 15 days
      later, the same dogs received 1.8 mg/kg epidurally. Pharmacokinetic variables and
      pharmacologic effects were determined for each route of administration. RESULTS:
      After i.v. administration, plasma concentration versus time curves were adjusted,
      using biexponential equations that indicated a rapid distribution phase followed
      by a slower elimination phase, with a mean +/- SD half-life of 33.5 +/- 17.0
      minutes. Mean plasma clearance was 21.0 +/- 10.7 ml/min/kg, and mean volume of
      distribution at steady state was 0.8 +/- 0.2 L/kg. After i.v. administration,
      mean peak plasma concentration was 2.6 +/- 0.7 micrograms/ml; after epidural
      administration, it was 0.9 +/- 0.5 microgram/ml at approximately 3 minutes. Half
      life after epidural administration was 5 times longer than that observed after
      i.v. administration. Motor block began immediately after the end of epidural
      administration and lasted for 3 to 4 hours. Changes in systolic blood pressure
      and heart rate after epidural administration were slight but occurred at the same
      time that plasma concentration peaked. After i.v. administration, motor block or
      variations in physiologic variables studied were not observed. CONCLUSIONS AND
      CLINICAL RELEVANCE: In dogs, the pharmacologic behavior of S(-)-BPV was similar
      to that of the bupivacaine racemate, but motor block attributable to S(-)-BPV
      lasted longer than that attributable to the racemate, with lower plasma
      concentrations observed at equivalent sample collection times.

PMID- 10407476
TI  - Use of breath hydrogen testing to detect experimentally induced disaccharide
      malabsorption in healthy adult dogs.
AB  - OBJECTIVE: To develop a noninvasive method to detect disaccharide malabsorption
      in dogs by measuring hydrogen concentration ([H2]) in exhaled breath before and
      after experimentally induced disaccharide malabsorption. ANIMALS: 8 healthy mixed
      breed dogs. PROCEDURE: [H2] was measured every 30 minutes for 8 hours after
      administration of disaccharide solutions (lactose, 0.5 g/kg of body weight;
      lactose, 1.0 g/kg; sucrose, 2.0 g/kg; maltose, 1.5 g/kg; and lactose [0.5 g/kg]
      and sucrose [2.0 g/kg]) to determine reference ranges of [H2] for each solution,
      which were compared with [H2] in dogs with experimentally induced disaccharide
      malabsorption. To induce disaccharide malabsorption, dogs were given a mild
      overdose of lactose (1.5 g/kg) or a disaccharidase inhibitor. In the latter
      experiment, acarbose (10 mg/kg, PO) was given with the combination of lactose
      (0.5 g/kg) and sucrose (2 g/kg), and with maltose (1.5 g/kg). RESULTS: Overdosing
      with lactose resulted in [H2] persistently outside the reference range for
      lactose in 5 of 8 dogs. Acarbose administration resulted in [H2] persistently
      outside the reference range in 7 of 8 dogs that received a combination of sucrose
      and lactose but did not consistently affect [H2] after administration of maltose.
      CONCLUSIONS: Disaccharide malabsorption resulted in [H2] outside the reference
      ranges in most of the adult dogs studied, suggesting that the technique may be
      useful in detecting naturally occurring disaccharidase deficiency.

PMID- 10407477
TI  - In vitro allergen-induced degranulation of pulmonary mast cells from horses with
      recurrent airway obstruction (heaves).
AB  - OBJECTIVE: To determine the capacity of pulmonary mast cells (PMC) to degranulate
      in response to various potential allergens and other secretagogues in horses with
      recurrent airway obstruction (heaves) and clinically normal horses before and
      after exposure to moldy hay. ANIMALS: 5 horses with heaves and 5 clinically
      normal horses. PROCEDURES: Heaves was characterized as an increased clinical
      respiratory score and maximum change in transpulmonary pressure of > 20 cm H2O
      after exposure. Bronchoalveolar lavage was performed during each period. Washed
      and resuspended cells were exposed for 20 minutes at 37 C with whole
      reconstituted freeze-dried preparations of Aspergillus fumigatus, Alternaria
      tenuis, and Ambrosia elatior, fungal extracts of Aspergillus fumigatus,
      Alternaria tenuis, and Micropolyspora faeni; A23187; and compound 48/80.
      Histamine release (HR) was used as a marker of degranulation. RESULTS: Compared
      with clinically normal horses, HR was significantly greater from PMC from horses
      with heaves during remission and exacerbation in response to whole preparations
      and extracts of Aspergillus fumigatus and whole preparations of Alternaria
      tenuis. Extracts of Alternaria tenuis caused significantly greater HR from PMC
      from horses with heaves during exacerbation. Histamine was also released from PMC
      in response to A23187 and to changes in osmolality of the medium, but only as a
      result of cell lysis by compound 48/80. CONCLUSIONS: Increased degranulation of
      PMC after antigenic challenge may contribute to the pathogenesis of heaves in
      horses. CLINICAL RELEVANCE: Strategies for prevention and treatment that
      attenuate degranulation of PMC may assist in the clinical management of horses
      with heaves.

PMID- 10407478
TI  - Upregulation of thyroid hormone receptor beta 1 and beta 2 messenger RNA in the
      myocardium of dogs with dilated cardiomyopathy or chronic valvular disease.
AB  - OBJECTIVE: To investigate whether expression of thyroid hormone receptor (TR)
      messenger RNA (mRNA) is changed in the myocardium of dogs with heart failure.
      ANIMALS: 21 dogs. PROCEDURE: Concentrations of TR alpha 2, beta 1, and beta 2
      mRNA in the myocardium were determined for clinically normal dogs (n = 7) and
      dogs with heart failure caused by dilated cardiomyopathy (DCM; 7) or chronic
      valvular disease (CVD; 7). Concentrations were quantified by use of reverse
      transcription-polymerase chain reaction and ELISA. RESULTS: The ratio of
      expression of TR alpha 2, beta 1, and beta 2 mRNA was typically 100:10:1.
      Differences in concentration of TR alpha 2 mRNA among the 3 groups of dogs were
      not detected, but concentrations of TR beta 1 and beta 2 mRNA were greater in
      diseased myocardium. Thyroid hormone receptor beta 1 mRNA was upregulated
      approximately threefold, and TR beta 2 mRNA was upregulated approximately
      eightfold in myocardium of dogs with DCM and CVD, compared with clinically normal
      dogs. There was no difference in TR beta 1 and beta 2 mRNA upregulation between
      dogs with DCM and CVD. CONCLUSIONS AND CLINICAL RELEVANCE: Altered regulation of
      transcription of the TR beta gene may be one facet of the myocardial phenotype in
      heart failure. Because this phenotypic response did not differ on the basis of
      cause (DCM vs CVD), it appears to be a secondary effect of heart failure and the
      alteration in metabolism of thyroid hormone. Treatment of dogs with heart failure
      with thyroid hormone or thyroid hormone analogues may improve cardiac
      performance.

PMID- 10407479
TI  - Evaluation of commercially available Escherichia coli J5 bacterin as protection
      against experimental challenge with Pasteurella multocida in rabbits.
AB  - OBJECTIVE: To evaluate the ability of commercially available Escherichia coli J5
      bacterin to protect rabbits from experimental challenge with Pasteurella
      multocida. ANIMALS: 40 P multocida-free New Zealand White rabbits. PROCEDURES:
      Rabbits were assigned to 1 of 4 groups of 10 rabbits each. Three of the groups
      were inoculated SC with J5 bacterin at 8 weeks old. Inoculation was repeated 3
      and 6 weeks later. The fourth group was not inoculated and served as controls.
      Groups 1, 2, and 3 were given 10(9), 10(8), and 10(7) colony forming units (CFU),
      respectively. Response was monitored by titer assessment, using an E coli J5
      antigen capture ELISA. Five weeks after the last inoculation, all rabbits were
      challenged with P multocida and observed for an additional 5 weeks. Clinical,
      hematologic, serologic, culture, and necropsy data were collected. RESULTS:
      Inoculation of rabbits with 10(9) CFU of E coli J5 bacterin-induced titers that
      were significantly greater than titers of rabbits vaccinated with 10(8) or 10(7)
      CFU or those in controls. The incidence of acute bacteremia was lower in rabbits
      with high titers. At necropsy, prevalence of lesions typical of P multocida was
      not significantly different among groups. Prevalence of histologic lesions was
      also not significantly different among groups. CONCLUSIONS AND CLINICAL
      RELEVANCE: Although the bacterin induced considerable antibody response and
      possibly reduced the rate of bacteremia, antibodies were not protective against
      long-term colonization or infection of the frontal sinuses or tympanic bullae by
      the challenge strain of P multocida. This bacterin in its currently available
      form is unlikely to aid in reducing the prevalence of pasteurellosis in rabbits.

PMID- 10407480
TI  - Complementary DNA cloning, tissue distribution, and synthesis of canine brain
      natriuretic peptide.
AB  - OBJECTIVE: To determine complimentary DNA (cDNA) sequence and tissue distribution
      of canine brain natriuretic peptide (BNP), and to investigate whether synthesis
      of canine BNP increases in association with cardiovascular dysfunction. ANIMALS:
      5 healthy adult mixed-breed dogs and 3 healthy adult Beagles. PROCEDURE: Total
      RNA was extracted from normal canine hearts and was used in a reverse
      transcription-polymerase chain reaction (RT-PCR) procedure to isolate canine BNP
      cDNA. Sequence of the isolated cDNA was analyzed. Gene expression of canine BNP
      in various tissues from 2 mixed-breed dogs was investigated, using RT-PCR and
      northern blot analyses. Moreover, messenger RNA (mRNA) expression of canine BNP,
      using northern blot analysis, was compared between grossly normal hearts from 3
      Beagles and hearts from 3 mixed-breed dogs with acute myocardial infarction
      created by surgical ligation. RESULTS: The cDNA sequence and deduced amino acid
      residues of canine BNP precursor were 420 base pairs and 140 residues,
      respectively. Messenger RNA expression of canine BNP was detectable in the atria
      but not in the ventricles and the other tissues. Messenger RNA expression of
      canine BNP was, however, detectable in the infarcted portion of the ventricles.
      The amount of canine BNP mRNA in the infarcted ventricles was significantly
      increased, compared with that of noninfarcted ventricles. CONCLUSION: The cDNA
      sequence of canine BNP was determined. Expression of canine BNP mRNA was detected
      not only in the atria but also in infarcted ventricles. Synthesis of canine BNP
      increases in association with ischemic myocardial injury. Canine BNP may be used
      as an indicator of severity of ventricular myocardial injury.

PMID- 10407481
TI  - Doppler echocardiographic study of left and right ventricular function during
      dobutamine stress testing in conscious healthy dogs.
AB  - OBJECTIVE: To evaluate left and right ventricular filling and ejection
      performances by use of Doppler echocardiography in healthy, conscious dogs
      submitted to dobutamine stress testing. ANIMALS: 10 unsedated, healthy adult
      Beagles. PROCEDURE: Doppler echocardiography was performed during cardiac stress
      testing on each dog twice at 24-hour intervals. Dobutamine was infused in 10
      micrograms/kg of body weight/min incremental dosages, from 12.5 to 42.5
      micrograms/kg/min. Duration of each step was 15 minutes. Doppler measurements
      were recorded at baseline and at each stage of dobutamine infusion, whereas
      aortic diameter was measured at baseline and at peak dosage by use of two
      dimensional echocardiography. RESULTS: Dobutamine infusion induced a significant
      increase in velocity time integrals and in peak flow velocities at the aortic,
      pulmonic, mitral, and tricuspid valves. Acceleration time-to-deceleration time
      ratio at the aortic wave also was increased significantly. On the other hand,
      ejection time, acceleration time, and deceleration time at the aortic and
      pulmonic valves and peak flow velocity of the E wave-to-peak flow velocity of the
      A wave ratio at the mitral and tricuspid valves decreased significantly during
      the test. The acceleration time-to-deceleration time ratio at the pulmonic wave
      was unchanged. A significant, progressive increase in cardiac index also was
      observed during dobutamine infusion, with a maximal increase of 104% from
      baseline. This was mediated initially by an increase in stroke index and, at
      higher dosages, by an increase in heart rate. CONCLUSIONS AND CLINICAL RELEVANCE:
      Doppler echocardiography performed during dobutamine stress testing may be a
      reliable method of assessing myocardial function in dogs with cardiovascular
      disease.

PMID- 10407482
TI  - Techniques for evaluation of right ventricular relaxation rate in horses and
      effects of inhalant anesthetics with and without intravenous administration of
      calcium gluconate.
AB  - OBJECTIVES: To determine the most repeatable method for evaluating right
      ventricular relaxation rate in horses and to determine and compare effects of
      isoflurane or halothane with and without the added influence of intravenously
      administered calcium gluconate on right ventricular relaxation rates in horses.
      ANIMALS: 6 Thoroughbred horses from 2 to 4 years old. PROCEDURE: 6 models (2 for
      monoexponential decay with zero asymptote, 3 for monoexponential decay with
      variable asymptote, and 1 for biexponential decay) for determining right
      ventricular relaxation rate were assessed in conscious and anesthetized horses.
      The 2 methods yielding the most repeatable results then were used to determine
      right ventricular relaxation rates in horses anesthetized with isoflurane or
      halothane before, during, and after i.v. administration of calcium gluconate.
      Right ventricular pressure was measured, using a catheter-tip high-fidelity
      pressure transducer, and results were digitized at 500 Hz from minimum rate of
      change in ventricular pressure. RESULTS: 2 models that used monoexponential decay
      with zero asymptote repeatedly produced an estimate for relaxation rate and were
      used to analyze effects of anesthesia and calcium gluconate administration on
      relaxation rate. Isoflurane and halothane each prolonged right ventricular
      relaxation rate, with greater prolongation evident in halothane-anesthetized
      horses. Calcium gluconate attenuated the anesthesia-induced prolongation in right
      ventricular relaxation rate, with greater response obtained in isoflurane
      anesthetized horses. CONCLUSIONS AND CLINICAL RELEVANCE: Right ventricular
      relaxation rate in horses is assessed best by use of a monoexponential decay
      model with zero asymptote and nonlinear regression. Intravenous administration of
      calcium gluconate to isoflurane-anesthetized horses best preserves myocardial
      relaxant function.

PMID- 10407483
TI  - Use of a urea breath test to evaluate short-term treatments for cats naturally
      infected with Helicobacter heilmannii.
AB  - OBJECTIVE: To evaluate efficacy of 3 short-term treatments in cats naturally
      infected with Helicobacter heilmannii. ANIMALS: 29 cats infected with H
      heilmannii that had positive results for a urea breath test, rapid urease test,
      and Helicobacter species-specific polymerase chain reaction test. PROCEDURES:
      Cats anesthetized for routine surgical procedures were randomly allocated to 4
      groups: group 1, control cats; group 2, cats treated with azithromycin,
      tinidazole, ranitidine, and bismuth once daily for 4 days; group 3, cats treated
      with clarithromycin, metronidazole, ranitidine, and bismuth twice daily for 4
      days; and group 4, cats treated with clarithromycin, metronidazole, ranitidine,
      and bismuth twice daily for 7 days. Efficacy was determined on the basis of
      results of a urea breath test performed 10 and 42 days after end of treatment.
      RESULTS: Ten days after treatment, 0 of 4, 4 of 6, 11 of 11, and 8 of 8 cats in
      groups 1 to 4, respectively, had a negative result for a urea breath test. Forty
      two days after treatment, 0 of 4, 3 of 6, 7 of 11, and 4 of 8 cats in groups 1 to
      4, respectively, still had a negative result. CONCLUSIONS AND CLINICAL RELEVANCE:
      Treatments used in this study regularly suppressed breath 13CO2 production.
      However, although 23 of 25 (92%) cats had negative results for a urea breath test
      10 days after treatment, only 14 of 25 (56%) cats still had negative results 42
      days after treatment. It is difficult to achieve a definitive long-term cure in
      cats naturally infected with H heilmannii.

PMID- 10407484
TI  - Development and usefulness of new polymerase chain reaction-based tests for
      detection of different alleles at codons 136 and 171 of the ovine prion protein
      gene.
AB  - OBJECTIVE: To develop new and improved tests to detect alleles at codons 136 and
      171 of the ovine prion protein locus and to evaluate the frequency of these
      alleles. ANIMALS: 159 Suffolk sheep belonging to 3 flocks. PROCEDURE: Polymerase
      chain reaction (PCR) analysis that contained diagnostic restriction site
      variation for each allele were developed for the relevant gene regions. Alleles
      were determined by analyzing DNA isolated from buccal swab specimens or blood
      samples. RESULTS: At codon 136, frequencies of the alanine and valine alleles
      were found to be 97 and 3%, respectively. At codon 171, frequencies of the
      glutamine, arginine, and histidine alleles were found to be 57, 41, and 2%,
      respectively. CONCLUSIONS: Little variation was detected in codon 136, whereas
      noteworthy variation was found in codon 171; > 40% of the alleles at this locus
      coded for glutamine. Because the glutamine allele at codon 171 confers
      susceptibility to scrapie, reduction of its frequency is of importance to
      management of sheep flocks. CLINICAL RELEVANCE: Genotyping of sheep, using the
      tests reported here, should facilitate selective breeding programs designed to
      decrease the risk of scrapie.

PMID- 10407485
TI  - Pharmacokinetics and therapeutic efficacy of rimantadine in horses experimentally
      infected with influenza virus A2.
AB  - OBJECTIVE: To determine pharmacokinetics of single and multiple doses of
      rimantadine hydrochloride in horses and to evaluate prophylactic efficacy of
      rimantadine in influenza virus-infected horses. ANIMALS: 5 clinically normal
      horses and 8 horses seronegative to influenza A. PROCEDURE: Horses were given
      rimantadine (7 mg/kg of body weight, i.v., once; 15 mg/kg, p.o., once; 30 mg/kg,
      p.o., once; and 30 mg/kg, p.o., q 12 h for 4 days) to determine disposition
      kinetics. Efficacy in induced infections was determined in horses seronegative to
      influenza virus A2. Rimantadine was administered (30 mg/kg, p.o., q 12 h for 7
      days) beginning 12 hours before challenge-exposure to the virus. RESULTS:
      Estimated mean peak plasma concentration of rimantadine after i.v. administration
      was 2.0 micrograms/ml, volume of distribution (mean +/- SD) at steady-state
      (Vdss) was 7.1 +/- 1.7 L/kg, plasma clearance after i.v. administration was 51 +/
      7 ml/min/kg, and beta-phase half-life was 2.0 +/- 0.4 hours. Oral administration
      of 15 mg of rimantadine/kg yielded peak plasma concentrations of < 50 ng/ml after
      3 hours; a single oral administration of 30 mg/kg yielded mean peak plasma
      concentrations of 500 ng/ml with mean bioavailability (F) of 25%, beta-phase half
      life of 2.2 +/- 0.3 hours, and clearance of 340 +/- 255 ml/min/kg. Multiple doses
      of rimantadine provided steady-state concentrations in plasma with peak and
      trough concentrations (mean +/- SEM) of 811 +/- 97 and 161 +/- 12 ng/ml,
      respectively. Rimantadine used prophylactically for induced influenza virus A2
      infection was associated with significant decreases in rectal temperature and
      lung sounds. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of
      rimantadine to horses can safely ameliorate clinical signs of influenza virus
      infection.

PMID- 10407486
TI  - Influence of feeding on serum feline trypsin-like immunoreactivity.
AB  - OBJECTIVE: To determine whether feeding causes a change in feline trypsin-like
      immunoreactivity (fTLI) in serum from healthy cats. ANIMALS: 6 healthy domestic
      shorthair cats. PROCEDURES: For the first 12 days of the study, 3 cats were fed a
      high-protein, high-fat (diet 1), and the other 3 were fed a maintenance (diet 2).
      On day 12, diets were switched, and cats were fed the other diet for the
      remaining 12 days of the study. On days 11 and 23, food was withheld for 24
      hours, and baseline serum fTLI was measured. Cats were offered food equivalent to
      half their daily caloric maintenance requirements, and serum fTLI was measured 1,
      2, 4, 6, 12, and 24 hours later. Uneaten food was removed after 1 hour. RESULTS:
      Overall mean +/- SD serum fTLI was 22.7 +/- 5.8 micrograms/L when cats were fed
      diet 1 and 21.1 +/- 5.0 micrograms/L when cats were fed diet 2. There was no
      significant difference in serum fTLI over time or between diets. However, there
      was a statistically significant, but clinically unimportant (mean increase, 1.7
      micrograms/L), increase in serum fTLI, compared with baseline values, 1 hour
      after cats were fed diet 2 but not when cats were fed diet 1. CONCLUSIONS AND
      CLINICAL RELEVANCE: A maintenance diet may cause a clinically unimportant
      increase in serum fTLI 1 hour after feeding in healthy cats. Results suggest that
      for healthy cats, it is not necessary to withhold food before collecting samples
      for determination of fTLI in serum. Whether feeding changes fTLI in serum from
      cats with disorders of the exocrine portion of the pancreas remains to be
      determined.

PMID- 10407487
TI  - Adrenergic, cholinergic, and nonadrenergic-noncholinergic intrinsic innervation
      of the jejunum in horses.
AB  - OBJECTIVE: To determine the major neurotransmitters that regulate contractile
      activity in the jejunum of horses. SAMPLE POPULATION: Jejunal specimens from 65
      horses without gastrointestinal tract lesions. PROCEDURE: Jejunal smooth muscle
      strips, oriented in the plane of the circular or longitudinal muscular layer,
      were suspended isometrically in muscle baths. Neurotransmitter release was
      induced by electrical field stimulation (EFS) delivered at 30 and 70 V
      intensities and at various frequencies on muscle strips maintained at low or high
      muscle tone. To detect residual nonadrenergic-noncholinergic neurotransmission,
      the response of muscle to EFS in the presence of adrenergic and cholinergic
      blockade was compared with the response in the presence of tetrodotoxin. RESULTS:
      Atropine (ATR) decreased the contractile response of muscle strips to EFS under
      most conditions. However, ATR increased the contractile response of high-tone
      circular muscle. Adrenergic blockade generally increased the muscle responses to
      30 V EFS and in high-tone longitudinal muscle but decreased contractile responses
      in high-tone circular muscle. Tetrodotoxin significantly altered the responses to
      EFS, compared with adrenergic and cholinergic receptor blockade. CONCLUSIONS:
      Acetylcholine and norepinephrine appear to be important neurotransmitters
      regulating smooth muscle contractility in the equine jejunum. They induce
      contraction and relaxation, respectively, in most muscle preparations, although
      they may cause opposite effects under certain conditions. In addition,
      nonadrenergic-noncholinergic excitatory and inhibitory influences were detected.
      CLINICAL RELEVANCE: Acetylcholine or norepinephrine release within the myenteric
      plexus of horses may alter gastrointestinal motility.

PMID- 10407488
TI  - Biosafety and antibody responses of adult bison bulls after vaccination with
      Brucella abortus strain RB51.
AB  - OBJECTIVE: To evaluate clearance, antibody responses, potential shedding, and
      histologic lesions in reproductive tissues of adult bison bulls after vaccination
      with Brucella abortus strain RB51. ANIMALS: 61 two- and 3-year-old bison bulls.
      PROCEDURE: 12 bison bulls were vaccinated s.c. with B abortus strain RB51, 3 were
      inoculated s.c. with 0.15 M NaCl, and antibody responses were evaluated. Various
      specimens were obtained to evaluate bacterial shedding. Four vaccinates and 1
      control were necropsied 10, 20, and 30 weeks after vaccination. In a separate
      experiment, bison bulls were vaccinated s.c. with 0.15 M NaCl, or by hand or
      ballistically with strain RB51. Antibody responses were monitored 6 weeks after
      vaccination and during necropsy 13 weeks after vaccination. Tissue specimens
      obtained during necropsy from both studies were evaluated bacteriologically and
      histologically. RESULTS: Strain RB51 was recovered at various times from semen of
      3 of 12 vaccinated bison bulls in experiment 1. During necropsy, strain RB51 was
      recovered 10 and 20, but not 30, weeks after vaccination. In experiment 2, strain
      RB51 was recovered from lymphoid tissues of hand- and ballistic-vaccinated bison
      bulls during necropsy. In both experiments, microscopic lesions in testes,
      epididymis, and seminal vesicles were minimal and did not differ between strain
      RB51-vaccinated and saline-inoculated bison bulls. CONCLUSIONS AND CLINICAL
      RELEVANCE: Strain RB51 does not induce relevant inflammatory lesions in
      reproductive tissues of adult bison bulls. Shedding of strain RB51 in semen may
      be transient in some bison bulls; however, the importance of this observation is
      unknown.

PMID- 10407489
TI  - Tissue factor in atherosclerosis.
AB  - Thrombosis is a key feature of the initiation and progression of atherosclerosis
      and its clinical sequelae. Acute thrombosis can lead to arterial occlusion and
      consequently provoke myocardial infarction, unstable angina, stroke and sudden
      death. Acute thrombosis can also be a complication of arterial bypass surgery,
      balloon angioplasty, atherectomy, or coronary artery stenting. The thrombotic
      response is influenced by several factors, among them the thrombogenicity of the
      vessel wall and of certain blood components as well as their interaction with the
      lipid pool. Tissue factor (TF) is considered to be the primary cofactor of
      cellular origin that is involved in activation of the coagulation pathway. The
      active form of TF has been shown to be present in specimens of human coronary
      artery in association both with acellular lipid areas and with macrophages and
      smooth muscle cells, which suggests that TF plays a major role in determining
      plaque thrombogenicity. We discuss here what is currently known about the role of
      tissue factor in atherogenesis, and focus attention on pharmacological approaches
      in this area.

PMID- 10407490
TI  - Atheroprotective mechanisms of HDL.
AB  - The aim of this review was to bring together results obtained from studies on
      different aspects of HDL as related to CHD and atherosclerosis. As
      atherosclerosis is a multistep process, the various components of HDL can
      intervene at different stages, such as induction of monocyte adhesion molecules,
      prevention of LDL modification and removal of excess cholesterol by reverse
      cholesterol transport. Transgenic technology has provided a model for
      atherosclerosis, and permitted evaluation of the contributions of different HDL
      components towards the global effect. The availability of apo AIV transgenic mice
      amplified the results obtained from apo AI overexpressors with respect to
      prevention of atherosclerosis. Prevention of atherosclerosis in apo E deficient
      mice by relatively small amounts of macrophage derived apo E may open new
      possibilities for therapeutic intervention. Contrary to early notions, increased
      plasma levels of CETP, even in the presence of low but functionally normal HDL,
      were atheroprotective. The extent to which paraoxonase and apo J participate in
      prevention of human atherosclerosis needs further evaluation. The findings that
      LCAT overexpression in rabbits was atheroprotective in contrast to increase in
      atherosclerosis in h LCAT tg mice, which was only partially corrected by CETP
      expression, call for some caution in the extrapolation of results from transgenic
      animals to humans. The important discovery of SR-BI as the receptor for selective
      uptake of CE from HDL revived interest in the clearance of CE from plasma. This
      pathway supplies also the vital precursor for steroidogenesis in adrenals and
      gonads and was shown to be dependent on apo AI.

PMID- 10407491
TI  - Accelerated atherosclerosis and premature calcified cartilaginous metaplasia in
      the aorta of diabetic male Apo E knockout mice can be prevented by chronic
      treatment with 17 beta-estradiol.
AB  - Epidemiological data indicate that estrogens significantly reduce the risk of
      morbidity and mortality due to cardiovascular diseases in postmenopausal women.
      Although numerous animal studies demonstrated inhibition of early atheromatous
      lesion formation by estrogen treatment in several species, information about the
      potential benefits of estrogens on complex, advanced atherosclerotic lesions is
      still lacking. The present study was designed to test whether chronic treatment
      with 17 beta-estradiol affects hyperglycemia-induced premature advanced lesion
      formation in 40-week-old male apolipoprotein E-deficient (Apo E-KO) mice. In
      order to accelerate advanced lesion formation, we treated male Apo E-KO mice with
      streptozotocin (STZ) at the age of 6 weeks. Two weeks later the STZ-treated mice
      received a slow release pellet containing either 17 beta-estradiol or placebo.
      STZ treatment caused sustained hyperglycemia without changes in serum total
      cholesterol or triglyceride levels compared to citrate control mice. STZ-treated
      Apo E-KO mice developed significantly more lesions in some (but not all) parts of
      the aorta and its main branches, and caused premature calcified cartilaginous
      metaplasia in the lesions of the proximal aorta. Chronic treatment with 17 beta
      estradiol lead to a significant decrease in blood glucose and triglyceride
      levels, reduced the lesion area in all vascular segments studied and prevented
      cartilaginous metaplasia in STZ-treated Apo E-KO mice. The results of this study
      show that STZ treatment leads to significant acceleration of atherosclerotic
      lesion formation and premature occurrence of calcified cartilaginous areas in Apo
      E-KO mice, which could be effectively prevented by chronic estrogen treatment.

PMID- 10407492
TI  - Scavenger receptor deficiency leads to more complex atherosclerotic lesions in
      APOE3Leiden transgenic mice.
AB  - Apolipoprotein (apo) E3Leiden is a dysfunctional apo E variant associated with
      familial dysbetalipoproteinemia in humans. Transgenic mice carrying the
      APOE3Leiden gene develop hyperlipidemia and are highly susceptible to diet
      induced atherosclerosis. An early step in atherosclerosis is foam cell formation,
      which is thought to result from the unrestricted uptake of modified lipoproteins
      by macrophages. To investigate the role of the macrophage scavenger receptor type
      I and II (MSR-A) in this process, APOE3Leiden transgenic mice were crossed onto a
      MSR-A deficient background and the development of atherosclerosis was examined.
      In view of recent results with apo E deficient mice (Suzuki H et al., A role for
      the macrophage scavenger receptors in atherosclerosis. Nature 1997; 386(6622):292
      296), absence of the MSR-A in APOE3Leiden mice was expected to lead to a
      reduction of atherosclerosis. In our study we compared APOE3Leiden/MSR-A
      deficient mice (E3L MSR-A -/-) to APOE3Leiden/MSR-A wild-type mice (E3L MSR-A
      +/+). These animals were fed an atherogenic diet for 10 weeks. Quantification of
      the lesion area showed no significant difference between E3L MSR-A -/- and E3L
      MSR-A +/+ mice although there was a trend towards the development of larger
      lesions in the E3L MSR-A -/- mice. All lesions were typed according to their
      cellular composition. In both male and female E3L MSR-A -/- mice, significantly
      more severe lesions developed as compared to E3L MSR-A +/+ mice. These results
      indicate that the effect of MSR-A deficiency on atherogenesis may depend on the
      presence or absence of apo E.

PMID- 10407493
TI  - Sequence polymorphisms in the apolipoprotein(a) gene and their association with
      lipoprotein(a) levels and myocardial infarction. The ECTIM Study.
AB  - Lp(a) concentrations are largely determined by apo(a) isoform size, but several
      studies have shown that apo(a) isoforms could not entirely explain the increase
      of Lp(a) levels observed in patients with coronary heart disease (CHD). Since up
      to 90% of the variance in Lp(a) levels has been suggested to be attributable to
      the apo(a) locus, the hypothesis that polymorphisms of the apo(a) gene other than
      size could contribute to the increase of Lp(a) levels in CHD patients must be
      considered. This hypothesis was tested in the ECTIM Study comparing 594 patients
      with myocardial infarction and 682 control subjects in Northern Ireland and
      France. In addition to apo(a) phenotyping, five previously described
      polymorphisms of the apo(a) gene were genotyped: a (TTTTA)n repeat at position 
      1400 from the ATG, a G/A at -914, a C/T at -49, a G/A at -21 and a Met/Thr
      affecting amino acid 4168. As reported earlier [Parra HJ, Evans AE, Cambou JP,
      Amouyel P, Bingham A, McMaster D, Schaffer P, Douste-Blazy P, Luc G, Richard JL,
      Ducimetiere P, Fruchart JC, Cambien F. A case-control study of lipoprotein
      particles in two populations at contrasting risk for coronary heart disease. The
      ECTIM study. Arterioscler Thromb 1992; 12:701-707], mean Lp(a) levels were higher
      in cases than in controls (20.7 vs 14.6 mg/dl in Belfast, 17.2 vs 8.9 mg/dl in
      France, P < 0.001 for case-control and population differences). In the present
      study, mean apo(a) isoform size differed significantly between cases and controls
      (25.7 vs 26.6 kr in Belfast, 25.9 vs 27.4 kr in France, P < 0.001 for case
      control and P = 0.13 for population difference). After adjustment for apo(a)
      isoforms, Lp(a) levels remained significantly higher in cases than in controls
      (difference, 4.6 mg/dl; P < 0.001). Genotype and allele frequencies did not
      differ significantly between cases and controls for any of the five polymorphisms
      studied. The five polymorphisms were in strong linkage disequilibrium and had a
      combined heterozygosity of 0.83. In multivariate regression analysis adjusted for
      apo(a) isoforms, only the (TTTTA)n polymorphism was significantly associated with
      Lp(a) levels; it explained 4.5% of Lp(a) variability in cases and 3.1% in
      controls. The Lp(a) case/control difference was not reduced after taking into
      account the (TTTTA)n effect. We conclude that the increase of Lp(a) levels
      observed in MI cases, and which was not directly attributable to apo(a) size
      variation, was not related to the five polymorphisms of the apo(a) gene
      considered.

PMID- 10407494
TI  - Differential cholesteryl ester accumulation in two human vascular smooth muscle
      cell subpopulations exposed to aggregated LDL: effect of PDGF-stimulation and HMG
      CoA reductase inhibition.
AB  - Vascular smooth muscle cells (VSMC) are a major component of atheromatous plaque
      and they exhibit a high heterogeneity in morphology and proliferative activity.
      Two cell subpopulations from the media of human pulmonary artery were isolated
      according to the kinetics of outgrowth from the explants; the first wave of cell
      outgrowth (VSMC-I) and the second wave (VSMC-II) were separately cultured. They
      were characterized by premitotic DNA synthesis ([3H]thymidine incorporation) and
      cholesterol synthesis ([14C]acetate incorporation). DNA and cholesterol synthesis
      were approximately 13- and 5-fold, respectively, higher in VSMC-I than in VSMC
      II. When these subpopulations were exposed to 100 micrograms/ml of aggregated low
      density lipoproteins (agLDL), their cholesteryl ester (CE) content increased 4.3
      fold over that induced by native LDL. The increase in CE induced by native or
      agLDL was approximately 2.7-fold higher in VSMC-I than in VSMC-II. These results
      suggest that agLDL uptake is related, at least in part, to the cellular
      proliferative status. Platelet derived growth factor (PDGF) did not increase
      agLDL uptake in any subpopulation, although it efficiently promoted proliferative
      activity in both cell types and increased native LDL uptake and cholesterol
      synthesis in VSMC-II. Simvastatin strongly inhibited CE accumulation from agLDL
      in VSMC-I, either unstimulated or PDGF-stimulated (> 80% inhibition). In
      contrast, it only blocked agLDL uptake in PDGF stimulated VSMC-II (50%
      inhibition). Our results indicate that the quantitative effect of simvastatin on
      CE accumulation from agLDL is dependent on phenotypic cell characteristics and it
      can be modulated in response to mitogenic stimulus.

PMID- 10407495
TI  - The in vitro and ex vivo antioxidant properties, and hypolipidemic activity of
      CGP 2881.
AB  - This report describes the in vitro and ex vivo antioxidant properties of a new
      antioxidant, CGP 2881. This compound is structurally similar to probucol, in that
      both compounds contain bis-tertiary butyl phenyl groups. However, CGP 2881
      consistently inhibited CuSO4 (Cu2+)- and macrophage (MO)-induced oxidation of
      human low density lipoproteins (LDL) more potently than equimolar concentrations
      of probucol. CGP 2881 (1 mumol/l) prolonged the lag phase of diene formation
      during Cu(2+)-induced LDL oxidation by 3.4 versus 1.5-fold prolongation with 1
      mumol/l probucol (P < 0.05 vs CGP 2881). The IC50 for inhibiting the formation of
      Cu(2+)-induced thiobarbituric acid-reactive substances (TBARS) was 0.15 mumol/l
      for CGP 2881, versus approximately 10 mumol/l for probucol. The IC50 for MO
      induced oxidation of LDL (TBARS) was 0.64 mumol/l. In contrast, 1 mumol/l
      probucol failed to inhibit MO-induced oxidation of LDL. Treatment of cholic
      acid/cholesterol-fed rats with CGP 2881 (50 mg/kg per day, orally for 5 days)
      inhibited ex vivo Cu(2+)-induced oxidation (TBARS) of the very low density
      lipoproteins (VLDL) + LDL lipoprotein fraction by 93% versus vehicle controls (P
      < 0.0001), and prolonged the lag phase for Cu(2+)-induced diene formation by 3.4
      fold over vehicle-treated controls. Five days of orally administered CGP 2881
      reduced plasma total cholesterol and LDL cholesterol levels to 55 and 54% of
      vehicle-treated controls, respectively (P < 0.05). In contrast, probucol had no
      appreciable effect on plasma total cholesterol or LDL cholesterol levels, unless
      administered for longer than 5 days. Treatment of hypercholesterolemic rabbits
      with 50 mg/kg per day orally for 5-12 days delayed the lag phase of diene
      formation during LDL oxidation by 4.3-fold over controls. However, the relative
      antioxidant potencies of CGP 2881 and probucol seen with oral administration to
      hypercholesterolemic rabbits were reversed when the compounds were given
      intravenously. In addition, the effects of these antioxidants were potentiated
      when given to normocholesterolemic rabbits compared to hypercholesterolemic
      animals. These data establish that CGP 2881 demonstrates hypolipidemic activity
      and is a substantially more potent antioxidant than probucol (in vitro and ex
      vivo). CGP 2881 may be useful as a new antioxidant tool in the effort to better
      understand the atherogenicity of oxidized LDL (oxLDL).

PMID- 10407497
TI  - High levels of human apolipoprotein A-I and high density lipoproteins in
      transgenic mice do not enhance efflux of cholesterol from a depot of injected
      lipoproteins. Relevance to regression of atherosclerosis?
AB  - The role of high density lipoprotein (HDL) and apolipoprotein A-I (apo A-I)in
      promoting cholesterol efflux from cultured cells and attenuation of development
      of atherosclerosis in transgenic (tg) animals has been well documented. The aim
      of the present study was to determine whether high levels of human (h) apo A-I
      will enhance cholesterol removal in vivo. h apo A-I in sera of tg mice was 429 +/
      18 and 308 +/- 10 mg/dl in male and female mice, the ratio of phospholipid (PL)
      to apo A-I was 0.94 in tg and 2.4 and 1.9 in male and female controls, taking
      mouse apo A-I as 100 mg/dl. The removal of lipoprotein cholesterol injected in
      the form of cationized low density lipoprotein (cat-LDL) into the rectus femoris
      muscle of h apo A-I tg is compared with control mice. After injection of cat-LDL
      labeled with [3H]cholesterol, the labeled cholesterol was cleared from the depot
      with a t 1/2 of about 4 days in both control and tg mice. The clearance of the
      exogenous cholesterol mass was initially much slower, it approached the t 1/2 of
      about 4 days between day 8 and 14 but there was no difference between tg and
      control mice. Cholesterol efflux from cultured macrophages exposed to media
      containing up to 10% serum was 56% higher with serum from tg mice than controls.
      In conclusion, the efflux of cholesterol from a localized depot of cat-LDL was
      not enhanced in h apo A-I tg mice. It appears, therefore, that while an increase
      above physiological levels of apo A-I or plasma HDL does play a pivotal role in
      the prevention of initiation and progression of early stages of atherosclerosis,
      the effectiveness of such an increase for the regression stage remains still to
      be demonstrated.

PMID- 10407498
TI  - Monokine stimulation of interleukin-11 production by human vascular smooth muscle
      cells in vitro.
AB  - Human vascular smooth muscle cells (VSMC) are a component of blood vessels, and
      secrete a variety of cytokines in atherosclerotic loci. Interleukin-11 (IL-11), a
      member of IL-6-like cytokines, is reported to be involved in inflammation and
      tissue remodeling, both of which are observed in atherosclerosis. However, no
      information is available as to the production of IL-11 by VSMC. Therefore, the
      expression of IL-11 in VSMC is investigated. The amounts of IL-11 protein and
      mRNA were determined by enzyme-linked immunosorbent assay (ELISA) and Northern
      blot analysis, respectively. The expression of IL-11 in VSMC was also
      immunohistochemically determined. IL-1 alpha, transforming growth factor-beta
      (TGF beta) and, to a lesser extent, tumor necrosis factor-alpha (TNF alpha)
      stimulated the IL-11 production by VSMC, and the stimulatory effects of IL-1
      alpha and TGF beta on IL-11 production were dose-dependent. IL-1 alpha and TNF
      alpha synergistically augmented TGF beta-stimulated IL-11 production by VSMC.
      Immunohistochemical staining also revealed the expression of IL-11 protein in
      VSMC. Furthermore, IL-1 alpha, TGF beta, and TNF alpha induced IL-11 gene
      expression in VSMC. Because IL-6-like cytokines are reported to be
      cytoprotective, monokine-stimulated IL-11 may have a potent protective role in
      atherosclerotic lesions.

PMID- 10407496
TI  - Low-density lipoprotein augments interleukin-1-induced vascular adhesion molecule
      expression in human endothelial cells.
AB  - In this study, the effect of low density lipoproteins (LDL) on the ability of the
      vascular endothelium to respond to vascular cell adhesion molecule 1 (VCAM-1)
      activation by a cytokine was investigated. After a 4-day pre-exposure to 240
      mg/dl of LDL, human umbilical vein endothelial cells (HUVECs) were
      hyperresponsive to minute amounts of interleukin 1 alpha (IL-1 alpha) as
      demonstrated by an augmentation of VCAM-1 gene expression. Furthermore, in
      response to LDL exposure, endothelial recruitment of monocytes induced by minute
      amounts of IL-1 alpha was increased. This enhancing effect was blocked by an anti
      VCAM antibody. The increased response appears not to be due to changes in IL-1
      binding affinity or induction of endogenous IL-1 alpha. Transient transfection of
      HUVECs with a reporter driven by the VCAM promoter showed that LDL increased
      cellular response to IL-1 alpha by 46%. LDL itself does not increase NF-kappa B
      binding in endothelial cells (ECs). However, after a 2-day LDL incubation, NF
      kappa B binding could be induced by over 63% with a very low dose of IL-1 alpha.
      IL-1 alpha at this dose (which activates NF-kappa B, but not AP-1) also enhanced
      LDL-activated AP-1 binding. This cross-enhanced effect may be an important
      intracellular signaling mechanism for EC activation. The results from this study
      provide new clues to understanding the mechanisms governing combined risk factors
      for atherosclerosis.

PMID- 10407499
TI  - Lipoprotein(a) plasma concentrations after renal transplantation: a prospective
      evaluation after 4 years of follow-up.
AB  - The highly atherogenic lipoprotein(a) [Lp(a)] is significantly elevated in
      patients with renal disease. It is discussed controversially whether Lp(a)
      concentrations decrease after renal transplantation and whether the mode of
      immunosuppressive therapy influences the Lp(a) concentrations. In a prospective
      study the Lp(a) concentrations before and on average 48 months after renal
      transplantation were measured in 145 patients. The determinants of the relative
      changes of Lp(a) concentrations were investigated in a multivariate analysis.
      Patients treated by CAPD showed a larger decrease of Lp(a) than hemodialysis
      patients, reflecting their markedly higher Lp(a) levels before transplantation.
      The relative decrease of Lp(a) was higher with increasing Lp(a) concentrations
      before transplantation in combination with an increasing molecular weight of
      apolipoprotein(a) [apo(a)]. That means that the relative decrease of Lp(a) is
      related to the Lp(a) concentration and the apo(a) size polymorphism. With
      increasing proteinuria and decreasing glomerular filtration rate, the relative
      decrease of Lp(a) became less pronounced. Neither prednisolone nor cyclosporine
      (CsA) had a significant impact on the Lp(a) concentration changes. Azathioprine
      (Aza) was the only immunosuppressive drug which had a dose-dependent influence on
      the relative decrease of Lp(a) levels. These data clearly demonstrate a decrease
      of Lp(a) following renal transplantation which is caused by the restoration of
      kidney function. The relative decrease is influenced by Aza but not by CsA or
      prednisolone.

PMID- 10407500
TI  - Evidence of a major locus for lipoprotein lipase (LPL) activity in addition to a
      pleiotropic locus for both LPL and fasting insulin: results from the HERITAGE
      Family Study.
AB  - A major gene hypothesis for heparin releasable plasma lipoprotein lipase (PH-LPL)
      activity was assessed using segregation analyses of data on 495 members in 98
      normolipidemic sedentary families of Caucasian descent who participated in the
      HERITAGE Family Study. Segregation analyses were performed on PH-LPL adjusted for
      age, and on PH-LPL activity adjusted for age and fasting insulin. Prior to
      adjustment for insulin, neither a major gene effect nor a multifactorial
      component could be rejected, and support for a major gene was equivocal i.e.
      neither the Mendelian transmission nor the no transmission (equal tau s) models
      were rejected. However, after adjusting for the effects of insulin, a major gene
      effect on PH-LPL activity was unambiguous. The putative locus accounted for 60%
      of the total phenotypic variance, and the homozygous recessive form affected 10%
      (q2) of the sample (i.e. gene frequency (q) = 0.31), and led to a low PH-LPL
      value. The lack of a significant multifactorial effect suggested that the
      familial etiology of PH-LPL activity adjusted for insulin was likely to be
      primarily a function of the major locus. In conclusion, the present study is the
      first to report segregation analyses on PH-LPL activity prior to and after
      adjusting for insulin, and suggests that there is an indication of a pleiotropic
      genetic effect on PH-LPL activity and insulin, in addition to a major gene effect
      on PH-LPL activity alone.

PMID- 10407501
TI  - Smoking and atherosclerosis in youth.
AB  - Coronary heart disease is the most common cause of death in the US. Studies have
      demonstrated that smoking is a major risk factor for coronary heart disease and
      that a positive relationship occurs between smoking and aortic and coronary
      atherosclerosis in adults. In 1985, a multicenter cooperative study,
      Pathobiological Determinants of Atherosclerosis in Youth (PDAY), was organized to
      study atherosclerosis in trauma victims 15-34 years of age. Reports from this
      study have demonstrated that smoking is strongly associated with the prevalence
      and extent of grossly visible raised lesions in the abdominal aorta but only
      weakly associated with similar lesions in the right coronary artery. Coronary
      arteries from 50 smokers and 50 non-smokers were classified microscopically using
      a system developed by the American Heart Association in order to determine the
      stage at which smoking affects atherosclerosis. Smokers had over twice as many
      advanced lesions, types IV and V, as non-smokers (32 vs 14%) and fewer early
      lesions, types I, II, III, as non-smokers (38 vs 62%). The prevalence of advanced
      or types IV and V lesions (32%) was over twice that of intermediate or type III
      lesions (14%) in smokers. The opposite relationship was observed in non-smokers
      (14 vs 26%). This observation suggest that intermediate lesions progress rapidly
      into advanced lesions in smokers and that intima formerly having early lesions is
      replaced by intima with raised lesions.

PMID- 10407502
TI  - Effects of intensive lipid lowering by low-density lipoprotein apheresis on
      regression of coronary atherosclerosis in patients with familial
      hypercholesterolemia: Japan Low-density Lipoprotein Apheresis Coronary
      Atherosclerosis Prospective Study (L-CAPS).
AB  - Twenty-five heterozygous familial hypercholesterolemic patients treated with LDL
      apheresis and drugs and 11 patients treated with drugs underwent follow-up
      angiography 2.3 years later. One-hundred thirteen lesions were measured by
      quantitative angiography. Mean LDL-cholesterol levels during the trial were 140
      +/- 34 mg/dl in the apheresis group and 170 +/- 58 mg/dl (P < 0.05) in the
      control group. The mean changes in minimal lumen diameter of lesions were +0.19
      +/- 0.30 mm (improved) in the apheresis group (n = 76) and -0.44 +/- 0.40 mm
      (worsened) in the control group (n = 37) (P < 0.0001). When progression and
      regression were defined as a change in minimal lumen diameter of +/- 0.67 mm, in
      the apheresis group, two (8%) patients had progression, 19 (76%) stayed unchanged
      and four (16%) had regression, but in the control group seven (64%) patients had
      progression and four (36%) stayed unchanged. The frequency of regression or no
      change was significantly higher in the apheresis group than in the control group
      (P < 0.004). Intensive cholesterol lowering therapy with LDL-apheresis and lipid
      lowering drugs can achieve a substantial decrease in LDL-cholesterol levels to
      induce regression of coronary lesions in familial hypercholesterolemic patients
      with advanced coronary artery disease.

PMID- 10407503
TI  - Antioxidants, but not B-group vitamins increase the resistance of low-density
      lipoprotein to oxidation: a randomized, factorial design, placebo-controlled
      trial.
AB  - We have conducted an intervention trial to assess the effects of antioxidants and
      B-group vitamins on the susceptibility of low-density lipoprotein (LDL) to
      oxidation. A total of 509 men aged 30-49 from a local workforce were screened for
      total plasma homocysteine. The 132 selected (homocysteine concentration > or =
      8.34 mumol/l) men were randomly assigned, using a factorial design, to one of
      four groups receiving supplementation with B group vitamins alone (1 mg folic
      acid, 7.2 mg pyridoxine, 0.02 mg cyanocobalamin), antioxidant vitamins (150 mg
      ascorbic acid, 67 mg alpha-tocopherol, 9 mg beta-carotene), B vitamins with
      antioxidant vitamins, or placebo. Intervention was double-blind. A total of 101
      men completed the 8-week study. The lag time of LDL isolated ex vivo to oxidation
      (induced by 2 mumol/l cupric chloride) was increased in the two groups receiving
      antioxidants whether with (6.88 +/- 1.65 min) or without (8.51 +/- 1.77 min) B
      vitamins, compared with placebo (-2.03 +/- 1.50) or B-vitamins alone (-3.34 +/-
      1.08) (Mean +/- S.E., P < 0.001). Antibodies to malondialdehyde (MDA) modified
      LDL were also measured, but there were no significant changes in titers of these
      antibodies in any group of subjects whether receiving antioxidants or not.
      Contrast analysis showed that there was no interaction between antioxidants and B
      group vitamins. This study indicates that while B-group vitamins lower plasma
      homocysteine they do not have an antioxidant effect. Thus B-group vitamins and
      antioxidants appear to have separate, independent effects in reducing
      cardiovascular risk.

PMID- 10407504
TI  - An approach to ascertain probands with a non-traditional risk factor for carotid
      atherosclerosis.
AB  - In our previous studies of the determinants of carotid plaque area (CPA), we used
      a linear multiple regression model, which permitted us to control for the
      presence of known risk factors in order to reveal the contribution of putative
      new risk factors. We recognized that this approach could identify patients whose
      observed CPA was excessive when considering traditional risk factors. Subjects
      whose observed CPA markedly exceeded the expected CPA were easily identified
      because of their deviation from the regression line that was derived using all
      members of the study sample. We classified such subjects as having 'unexplained
      atherosclerosis' relative to the overall study sample when traditional risk
      factors were included as independent variables. We then examined the plasma
      homocyst(e)ine concentration in members of the subgroup with 'unexplained
      atherosclerosis'. We found a significantly higher mean plasma concentration of
      homocyst(e)ine in the subgroup with 'unexplained atherosclerosis', compared to
      rest of the study sample (20.4 +/- 4.3 vs. 13.2 +/- 3.2 mumol/l, P < 0.005). We
      also found that significantly more subjects with 'unexplained atherosclerosis'
      had plasma homocyst(e)ine concentrations in excess of 14 mumol/l compared to the
      rest of the study sample (52 vs. 33%, P < 0.002). We thus propose that systematic
      identification of subjects with 'unexplained atherosclerosis' relative to the
      rest of a well-characterized study sample might be a useful approach to identify
      subjects in whom there are newer, non-traditional determinants of predisposition
      to atherosclerosis.

PMID- 10407505
TI  - Lipoprotein lipase gene mutations, plasma lipid levels, progression/regression of
      coronary atherosclerosis, response to therapy, and future clinical events.
      Lipoproteins and Coronary Atherosclerosis Study.
AB  - Mutations in human lipoprotein lipase (LPL) gene are potential risk factors for
      susceptibility to coronary artery disease (CAD). The objectives of this study
      were to determine the influence LPL mutations Asn291Ser and Ser447Ter on plasma
      lipid levels, regression and progression of CAD, clinical events rate, and
      response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis
      Study (LCAS) population. LCAS is a double blind, randomized, placebo-controlled
      study designed to test the influence of fluvastatin on progression or regression
      of CAD. The Asn291Ser and Ser447Ter genotypes were determined by polymerase chain
      reaction (PCR) and restriction enzyme digestion. Fasting plasma lipid profiles
      were measured and quantitative coronary angiography was performed at baseline and
      2.5 years following randomization. Fatal and non-fatal cardiovascular events
      during the follow-up period were recorded. A total of 4% (14/363) and 18%
      (62/352) of the subjects had the Asn291Ser and Ser447Ter mutations, respectively.
      Overall, there was no statistically association between the Asn291Ser and
      Ser447Ter mutations and the baseline or final mean plasma levels of lipids,
      number of coronary lesions, total occlusions, the mean minimal lumen diameter
      (MLD) stenoses and the clinical events rate. However, patients with the Ser447Ter
      variant had a slightly higher baseline high density lipoprotein-cholesterol (HDL
      C) level (46.2 +/- 12 vs 43.2 +/- 11, P = 0.057), less increase in plasma HDL
      levels in response to fluvastatin therapy (3 vs 11%, P = 0.056) and a higher
      cardiovascular events rate (23 vs 13%, P = 0.056). Thus, the Ser447Ter variant
      had a modest influence on plasma HDL levels and the rate of cardiovascular
      events. These changes were of borderline statistical significance. Neither the
      Ser447Ter nor the Asn291Ser mutation had a major impact on susceptibility to CAD,
      progression or regression of CAD, clinical events rate or response to fluvastatin
      therapy in LCAS population.

PMID- 10407506
TI  - Detection of a new compound heterozygote (del G916/G1401A) for lipoprotein lipase
      deficiency and a comparative haplotype analysis of the mutant lipoprotein lipase
      gene from Japanese patients.

PMID- 10407508
TI  - Unusual inheritance of severe primary hypercholesterolemia.

PMID- 10407507
TI  - European Lipoprotein Club: report of the 21st Annual Conference, Tutzing,
      September 28-October 1, 1998.
AB  - Molecular biology and genetics were the hallmarks of the conference. Attendees
      from 20 European countries participated in lively discussions with international
      speakers. The opening round table session entitled 'Genetic approach to complex
      diseases' was chaired by Harald Funke. Steve Humphries (London) presented
      association studies and Harald Funke (Munster) presented multiparameter analyses,
      as models of genetic epidemiological approaches to atherosclerosis. Gerd Utermann
      (Innsbruck) showed, through sib pair linkage analysis, how apo (a) gene
      polymorphism determines plasma levels of Lp(a). Klaus Lindpainter (Basel)
      described novel genetic strategies heading for a more targeted medicine, through
      the identification of genetic mechanisms of disease and therapeutic responses.
      Session I, chaired by Richard James (Geneva) and Guido Franceschini (Milano), on
      'Basic mechanisms of action of drugs' highlighted molecular and cellular actions
      by which present (fibrates, statins) or future (ACAT or MTP inhibitors) drugs or
      hormones may modulate lipoprotein metabolism. Marten Hofker (Leiden) and Philippa
      Talmud (London) chaired Session II on 'Regulation of gene expression', which
      reported cellular regulations by nuclear receptors (PPARs), or the regulation of
      lipid trafficking by membrane receptors (SR-BI, Megalin, Apo-E receptor,
      scavenger receptors) or by intracellular (IFN gamma signalling pathways) or
      extracellular proteins (lipases). Beyond gene expression, Session III, 1st part,
      entitled 'Lipoprotein modifying enzymes' was chaired by Katriina Aalto-Setala
      (Tampere). Roles of lipases (HL, LPL) and transfer proteins (CETP, PLTP), as well
      as structures of lipid binding molecules (LCAT, apolipoproteins), were further
      explored. The 'Gene interactions' session chaired by Rudolph Poledne (Prague),
      and 'Novelties' chaired by Hans Dieplinger (Innsbruck), reported elegant models
      of cross-bred, tissue specific knock-out or YAC-transgenic mice for lipoprotein
      metabolism, and descriptions of gene interactions in polygenic disorders or new
      loci for familial lipid disorders (familial combined hyperlipidemia, metabolic
      syndrome and Tangier disease) in humans.

PMID- 10407509
TI  - Medped FH: a paradigm for other common monogenic diseases in South Africa.

PMID- 10407510
TI  - MedPed in Vienna.

PMID- 10407511
TI  - Cytoplasmic Ca2+ oscillations in human leukemia T-cells are reduced by 50 Hz
      magnetic fields.
AB  - The effect of 50 Hz magnetic fields on the cytosolic calcium oscillator in Jurkat
      E6.1 cells was investigated for field strengths within the range from 0 to 0.40
      mT root mean square. The intracellular Ca2+ concentration data were collected for
      single Jurkat cells that exhibited a sustained spiking for at least 1 h while
      repeatedly exposing them to an alternating magnetic field in 10-min intervals
      interposed with nonexposure intervals of the same length. The obtained data were
      analysed by computing spectral densities of the Ca2+ oscillating patterns for
      each of these 10-min intervals. For every single-cell experiment the spectra of
      all exposure as well as nonexposure periods were then averaged separately. A
      comparison between the resulting averages showed that the total spectral power of
      the cytosolic Ca2+ oscillator was reduced by exposure of the cells to an
      alternating magnetic field and that the effect increased in an explicit dose
      response manner. The same relationship was observed within the 0-10 mHz (10 x 10(
      3) Hz) subinterval of the Ca2+ oscillation spectrum. For subintervals at higher
      frequencies, the change caused by the exposure to the magnetic field was not
      significant.

PMID- 10407512
TI  - Human sleep in 60 Hz magnetic fields.
AB  - This report describes a double-blind, laboratory-based study of 24 healthy young
      men in which sufficient data were collected to examine the effects of
      intermittent versus continuous exposure to a 60 Hz, 28.3 microT magnetic field on
      multiple EEG measures of night sleep. Intermittent, but not continuous or sham
      exposure, was associated with less total sleep time, reduced sleep efficiency,
      increased time in Stage II sleep, and decreased REM sleep. Subjects exposed
      intermittently to the field also reported sleeping less well and feeling less
      rested in the morning than subjects in the other two groups. All observed effects
      were significant at P < or = .04 or less. The public health relevance of these
      results cannot be assessed as yet. Poor sleep quality, however, can have a
      detrimental influence on worker safety and performance, and has been associated
      with decrements in memory and learning processes. Additional research appears
      warranted.

PMID- 10407513
TI  - 60 Hz magnetic fields and central cholinergic activity: effects of exposure
      intensity and duration.
AB  - In previous research, we have found that acute exposure to a 60 Hz magnetic field
      caused a decrease in cholinergic activity in the frontal cortex and hippocampus
      of the rat. In the present study, the effects of exposure to different
      intensities of the magnetic field and durations of exposure were investigated.
      Rats were exposed to a 60 Hz magnetic field for 60 min at a flux density of
      either 0.5, 1.0, 1.5, or 2.0 mT. A significant decrease in cholinergic activity
      was observed in the frontal cortex and hippocampus immediately after exposure to
      the 2.0 mT field. No significant effect was observed at lower intensities. In
      another experiment, effect of exposure to a 1.0 mT magnetic field for 30, 45, 60,
      and 90 min was investigated. A decrease in cholinergic activity was found in both
      brain areas after 90 min of exposure. No significant effect was observed after
      shorter durations of exposure. In a further experiment, the exposure duration was
      extended to 3 h at flux densities of 0.5, 0.1, and 0.05 mT. A significant
      decrease in cholinergic activity was observed in the frontal cortex and
      hippocampus of the rat immediately after exposure to all the intensities. It is
      concluded that the intensity and duration of exposure interact. By increasing the
      duration of exposure, effects can be observed at lower intensities.

PMID- 10407514
TI  - Effects of 50 Hz magnetic fields on gap junctional intercellular communication.
AB  - To explore whether the extremely low frequency (ELF) electromagnetic fields
      (EMFs) may act as cancer promoters or be synergistic with 12-O
      tetradecanoylphorbol-13-acetate (TPA) in cancer promotion, an experiment was
      conducted on the effects of 50 Hz magnetic fields (MFs) on gap junctional
      intercellular communication (GJIC) of Chinese hamster lung (CHL) cells. Lucifer
      dye was loaded into CHL cells by iontophoretic injection, and the number of dye
      coupled cells (DCC) 5 min after the injection was adopted as the index of GJIC.
      The effects of TPA at different concentrations and magnetic fields at different
      intensities, combined with 5 ng/ml TPA, were studied. The results showed that the
      suppression of TPA on GJIC was dependent on TPA concentration; the threshold
      concentration of TPA for CHL cells was between 1 and 5 ng/ml. After exposure to
      0.8 mT magnetic field for 24 h, the number of DCC decreased to 6.08 +/- 1.59,
      whereas the number of DCC in the control group was 9.84 +/- 2.27 (P < .05). When
      the cells were exposed at 0.2, 0.4, and 0.8 mT for 24 h, combined with 5 ng/ml
      TPA treatment during the last 1 h, the number of DCC decreased to 5.52 +/- 1.53,
      5.00 +/- 1.22, and 4.00 +/- 1.29, respectively, which were significantly lower
      than the values for the group treated with 5 ng/ml TPA alone (6.38 +/- 1.39). It
      is suggested that certain intensities of 50 Hz magnetic field might act as cancer
      promoters, be additive with other promoters in cancer promotion, or both.

PMID- 10407515
TI  - Exposure of rats to a 50-Hz, 100 muTesla magnetic field does not affect the ex
      vivo production of interleukins by activated T or B lymphocytes.
AB  - Two separate, independent experiments were conducted to evaluate the effects of
      exposure of rats to a 50-Hz linearly polarized, 100 microT magnetic field (MF) on
      the ex vivo production of interleukins (ILs) by mitogen-stimulated splenic
      lymphocytes. IL-1 and IL-2 were determined by proliferation assays, using IL
      dependent murine T cell lines. In the first experiment, female Sprague-Dawley
      rats were treated with 7,12-dimethylbenz[a]anthracene (DMBA] at a dose of 20 mg
      per rat (four weekly gavage doses of 5 mg), and were either MF-exposed or sham
      exposed for 14 weeks. This experimental protocol has previously been shown to
      result in a significant increase in breast cancer growth in response to MF
      exposure. Furthermore, MF exposure at 50-100 microT for 3 months was recently
      found to induce a suppressed ex vivo proliferation of splenic T cells in response
      to mitogen stimulation, which could be a result of reduced IL production of
      spleen lymphocytes. However, the present experiments failed to demonstrate any
      significant difference between MF- and sham-exposed groups in production of IL-1
      by mitogen-activated splenic B cells. In a second experiment, shorter MF exposure
      periods were studied with respect to IL production from mitogen-stimulated B and
      T cells. Groups of rats were MF- or sham-exposed for 1 day, 1 week, or 2 weeks,
      followed by preparation and activation of spleen lymphocytes. No significant
      difference in IL-1 or IL-2 production from stimulated B or T cells was seen. The
      data indicate that in vivo MF exposure of rats does not affect the ex vivo IL
      production of B or T lymphocytes, suggesting that the recently reported changes
      in T cell proliferation in response to MF exposure may not be mediated via
      alterations in B or T cell IL production.

PMID- 10407516
TI  - Determinants of power-frequency magnetic fields in residences located away from
      overhead power lines.
AB  - The Wertheimer-Leeper wire code, originally developed as a surrogate for magnetic
      field exposure, has been associated with childhood leukemia in several
      epidemiologic investigations. However, these and other studies indicate that most
      between-residence variability in measured magnetic fields remains unexplained by
      wire codes. To better understand this remaining variability, engineering and
      demographic data were examined for 333 underground (UG) and very-low current
      configuration (VLCC) single-family or duplex residences, selected from a database
      of nearly 1000 residences specifically because their magnetic fields are most
      likely affected negligibly by overhead power lines. Using linear regression
      techniques, four factors predictive of the log-transformed residential field were
      identified: the square-root of the 24-h average net service drop current (this
      current is equivalent to the current in the grounding system), the log of the
      number of service drops on the same secondary serving the residence, residence
      age (four categories), and area type (rural, suburban, or urban). Complete data
      on ground current and service drops, the two factors with the strongest
      individual relationships to measured fields, were available for only half of the
      residences in the sample. However, these data were determined to be "missing at
      random" according to established statistical criteria. The full-sample or
      "composite" models thus relied on a method similar to regression imputation,
      accounting for missing data with binary dummy variables. When applied to the
      samples from which they were derived, these models accounted for 25% of the
      variance of the log-spot-measured magnetic field values in the full sample, while
      models that considered only those residences with complete data (n = 167)
      explained about 35%. The model validated well against a sample of 201 ordinary
      low current configuration (OLCC) homes selected from the same database.

PMID- 10407517
TI  - Residential magnetic field measurements in France: comparison of indoor and
      outdoor measurements.
AB  - Residential magnetic field (MF) measurements were performed for the first time in
      a representative sample of French dwellings. Exposure levels were assessed by two
      methods: indoor and outdoor measurements. Linear and logistic regression models
      were used to determine factors associated with the time-weighted average (TWA)
      home MF. TWA magnetic field magnitudes were approximately log-normally
      distributed with geometric means under 0.010 microT for both indoor and outdoor
      measurements. Only 5% of the dwellings presented indoor MF levels greater than
      0.120 microT (1.2 mG). Both indoor and outdoor MF variations were explained by
      three factors: wiring configuration, the dwelling's location (i.e., urban or
      rural), and housing characteristics (individual houses or apartment building).
      The reliability of outdoor spot measurements with 30-min bedroom recordings was
      assessed by an intraclass correlation coefficient. The measurements were accurate
      in rural areas and small towns. In urban centers, local MF variations spoil the
      outdoor measurement's reliability. If indoor measurements are taken as the
      reference method, the use of outdoor instead of indoor measurement leads to an
      important decrease in statistical power. Further assessment of MF near high power
      transmission lines is necessary to evaluate the usefulness of outdoor spot
      recordings near such lines. The urban MF environment also has to be explored to
      identify extraneous sources.

PMID- 10407518
TI  - Ultrawideband radiation and pentylenetetrazol-induced convulsions in rats.
AB  - New non-ionizing pulsed systems using ultrawideband (UWB) require safety
      assessment before they can be used by either military or civilian communities.
      The development of directed energy weaponry intended for use against
      electronically vulnerable targets, as well as ground-probing radar systems, have
      used fast-rise-time high-peak-power electromagnetic pulses characteristic of UWB
      emitters. It has been postulated that these ultrashort pulses might produce
      electromagnetic transients resulting in tissue damage. Several challenges to this
      notion have been posed, however. One report found that rats exposed to UWB after
      receiving a convulsant drug tended toward longer latency to the onset of
      convulsions than the no-exposure group. Although not statistically significant,
      the presence of this trend prompted the present study. An ED99 dose of the
      convulsant pentylenetetrazol (PTZ) or saline was given just before UWB or sham
      exposure and resultant seizure activity was recorded. The data from the current
      study show no effect of UWB exposure on PTZ-induced seizure activity, thereby not
      supporting the tissue damage concerns, at least for the exposure parameters used
      here.

PMID- 10407519
TI  - Looking forward to the era of subspecialties of anesthesia of Taiwan in the
      coming millennium.

PMID- 10407520
TI  - The dose effect of propofol on cerebrovascular reactivity to carbon dioxide in
      rabbits.
AB  - BACKGROUND: Propofol has several properties beneficial to intracranial operation
      such as reduction in cerebral metabolic rate and cerebral blood flow (CBF) in a
      dose-dependent manner while leaving autoregulation intact. Several studies have
      demonstrated that the responsiveness of CBF to changes in arterial carbon dioxide
      tension (PaCO2) is maintained during propofol anesthesia in both humans and
      animals. These studies showed a significant difference in the CBF-CO2 reactivity
      slope between awake and propofol anaesthetized groups, but no comparison with
      different doses of propofol was made. To determine the dose effect of propofol on
      cerebrovascular CO2 reactivity, we used laser Doppler flowmetry (LDF) to detect
      the changes of CBF during propofol anesthesia. METHODS: Ten rabbits were studied
      using LDF on the parietal cortex. After surgical preparation, anesthesia was
      maintained with 66% N2O in O2, morphine 10 mg/kg and pancuronium. Three
      experimental conditions were studied sequentially with intravenous administration
      of the following drugs: (1) normal saline (control), (2) propofol 20 mg/kg/h
      i.v., (3) propofol 40 mg/kg/h i.v. Mean arterial pressure, rectal temperature and
      hematocrit were kept constant. The arterial carbon dioxide tension (PaCO2) was
      adjusted to three levels during each condition: 20-25 mmHg (hypocapnia), 35-40
      mmHg (normocapnia) and 45-50 mmHg (hypercapnia). CBF was measured continuously
      and recorded after the target PaCO2 had been reached. RESULTS: There were no
      differences among all conditions in mean arterial pressure and heart rate. The
      changes of CBF as PaCO2 increased at the three different CO2 levels during each
      of the conditions were significantly different. The slope of CBF-CO2 reactivity
      among three different propofol doses was not significantly different.
      CONCLUSIONS: These data indicate that cerebral vasomotor responsiveness to CO2
      during propofol anesthesia is preserved and that the slope of CBF-CO2 reactivity
      is independent of propofol doses as mean arterial blood pressure is maintained.

PMID- 10407521
TI  - The significance of pain among Chinese patients with cancer in Hong Kong.
AB  - BACKGROUND: The purposes of the survey were to review the significance of pain
      and its associate factors among Chinese cancer patients in Hong Kong. METHODS: It
      was a retrospective, cross-sectional survey. One hundred Chinese cancer patients
      were recruited by convenience from hospices and oncology units in Hong Kong. Data
      of patients' demographic profile, pain relief measures and pain status were
      collected by interview. RESULTS: It was found that the presence of current pain
      among the subjects was 77.0% which was similar to that reported in the United
      States and United Kingdom. It indicates that the cancer patients in Hong Kong
      share the same extent of problem as those in the West. This highlights the needs
      for managing pain as a priority. Unlike the data showed in the West, the pain
      intensity in the 77% clustered at the lower end of the NRS. Thus, more than three
      quarters of the subjects had pain but the majority of them had mild pain. This
      result is contradictory with the findings in the western countries. It is
      possible that this discrepancy is caused by a number of factors related to
      culture, family network support, perceptual processes in abstractions and
      properties of the tools employed in the assessment of pain intensity. Seventy-six
      percent of the patients had regular analgesics for their pain. Among them, apart
      from analgesics, seventeen received massage, three resorted to psychological
      counseling and four used other pain relief method, e.g. acupuncture. There was
      also a significant difference as to the types of cancer and the current pain
      intensity (n = 81, X2 = 15.01, P = 0.04). The differences were demonstrated in
      liver vs. lung cancers, and liver vs. colorectal cancers (Tukey-HSD test, P <
      0.05). Those with lung cancer experienced more pain than those with liver cancer.
      Similarly, those with liver cancer had more severe pain than those with
      colorectal cancer. However, there was no association between the presence of
      metastasis and pain on admission, current pain intensity and pain for the past
      week. CONCLUSIONS: This survey on the significance of pain demonstrates the
      extent of the problem in Chinese cancer patients in Hong Kong. It highlights the
      priority of need in cancer pain management.

PMID- 10407523
TI  - Selective lumbar spinal nerve block, a review.
AB  - Selective spinal nerve block is a useful tool in today's multidisciplinary
      approach to the diagnosis and treatment of low back pain. The indications,
      sources of spinal pain, block technique, result interpretation, complications and
      clinical applications relevant to the subject are discussed. The value of a
      spinal nerve block relies on an understanding of the pain elements in the back,
      nerve innervations and careful patient selection. If the technique is performed
      properly and the results are interpreted cautiously, selective spinal nerve block
      may prove helpful, especially for patients from whom diagnostic information is
      inadequate. In some cases, therapeutic effect including that from surgical
      intervention can be achieved selectively at the symptomatic root. However,
      controversy remains and therefore well designed clinical studies are needed to
      provide more information about the validity of this diagnostic and therapeutic
      modality.

PMID- 10407522
TI  - Low dose ketamine and midazolam as supplements for spinal anesthesia.
AB  - BACKGROUND: Low dose ketamine and midazolam together were used as supplements
      during spinal anesthesia to provide analgesia for insertion of spinal needle and
      intraoperative sedation. METHODS: Two regimens of drug combination (ketamine 0.5
      mg/kg and midazolam 0.05 mg/kg in group I, n = 30; ketamine 0.5 mg/kg and
      midazolam 0.1 mg/kg in group II, n = 30) were administered intravenously before
      proceeding lumbar puncture. RESULTS: Systolic and diastolic arterial blood
      pressure, heart rate, and arterial oxygen saturation did not change significantly
      before and after the administration of drugs. Most patients in both groups showed
      good analgesic response to the lumbar puncture. The medications induced a brief
      unconsciousness (4.1 min in group I; 8.5 min in group II). The time from drug
      administration to recovery of mental orientation was 8.8 min in group I and 15.1
      min in group II. The regimens also provided intraoperative sedation. Patients in
      group II appeared to be more depressed than group I in the first 30 min. None of
      the patients had significant respiratory disturbance, involuntary movement, or
      recall to spinal puncture. There were 7 patients in group I and 4 patients in
      group II who experienced dreaming. CONCLUSIONS: The use of low dose ketamine
      together with midazolam as supplement for spinal anesthesia is helpful in
      anesthetic practice.

PMID- 10407524
TI  - Unsuspected pheochromocytoma with abdominal aortic aneurysm--a case report.
AB  - This case report describes the peri-operative management of a 65-year-old man
      with an unsuspected pheochromocytoma. He underwent emergent surgery for a
      rupturing abdominal aortic aneurysm. During surgery his blood pressure changed
      dramatically and was resistant to drug treatment. A pheochromocytoma was
      suspected, but the emergency precluded immediate investigation. A second
      hypertension episode occurred in the intensive care unit, and CT revealed an
      abnormal adrenal mass. Surgery for the pheochromocytoma was carried out
      successfully later, with the hypertension being managed very carefully. We
      considered that exposure to extraordinary catecholamine levels from the
      pheochromocytoma might have contributed to the development of the abdominal
      aortic aneurysm.

PMID- 10407525
TI  - Isobaric spinal anesthesia for paraplegic patients.
AB  - It has long been understood that patients with spinal cord injury (SCI) above T6
      7 may develop autonomic hyperreflexia (AH) and pose an anesthetic challenge. To
      date, there is no consensus regarding anesthesia management of these patients
      among anesthesiologists. Many anesthetic techniques have been proposed and used
      with varying success, but none of them is uniformly successful. Topical
      anesthetics may not block the stretch receptors and AH might still be initiated.
      A deep anesthesia with potent volatile agents is often necessary to prevent or
      treat AH. Thus, the incidence of hypotension is no different than that associated
      with neuraxial anesthesia. Failures with potent vasodilators such as sodium
      nitroprusside also have been reported. Currently, the block of the afferent
      pathways by neuraxial anesthesia is considered to be the most effective means of
      preventing AH. However, because the level of neuraxial anesthesia is difficult to
      detect in SCI patients, excessive high level block and subsequent severe
      hypotension may occur. When an isobaric solution is used, due to the lack of
      baricity/patient position interaction, migration of the local anesthetic is
      usually insignificant, so the level of anesthesia is easier to control and
      predict. In the past fifteen years (1982-1997), we have used isobaric spinal
      anesthesia (ISA) in thirteen patients with SCI for various surgical procedures.
      Although four of these patients had previous history of AH, there was not a
      single incidence of AH during the perioperative period. Our favorable experiences
      lead us to believe that ISA is a useful anesthetic technique for SCI patients
      undergoing surgery.

PMID- 10407526
TI  - Fatal pulmonary embolism in a child undergoing extra-ventricular drainage surgery
      -a case report.
AB  - Thromboembolism is rather common in neurological patients and patients with brain
      tumor, who are bed-ridden or with partial immobile limb. In serious instances
      morbidity and mortality are inevitable. We present a case report on a fatal
      pulmonary embolism in a 2-year-old girl who underwent extra-ventricular drainage
      procedure under general anesthesia for occipital subdural effusion, a sequela of
      the former surgery undertaken to remove the choroid plexus papilloma 13 days ago.
      Sudden cardiac arrest occurred during induction of anesthesia and she finally
      succumbed in spite of vigorous cardiopulmonary resuscitation. Transthoracic and
      transesophageal echocardiography performed in the course of resuscitation
      disclosed thrombi of various sizes scattering in right atrium, the right
      ventricle, main pulmonary trunk, and the left pulmonary artery. The cause of
      death was thought to be severe obstruction of right ventricular outflow tract by
      large thrombi. The etiological factors which possibly led to the thrombosis were
      discussed, and the methods of diagnosis and treatment were also explored.

PMID- 10407527
TI  - HELLP syndrome with antepartum pulmonary edema--a case report.
AB  - A 44-year-old pregnant female with a gestation of 29 weeks suddenly developed
      abdominal pain, nausea, vomiting, and laboratory study showed anemia, elevated
      liver enzymes, and lower platelets. HELLP syndrome was diagnosed and urgent
      delivery was needed. In order to correct the plasma volume and platelet
      deficiency, 6 units of both fresh frozen plasma and platelets, were given before
      operation. However, acute pulmonary edema was noted in the antepartum period.
      After vigorous treatment, she gave birth to a male infant. The postoperative
      course was smooth and she and her baby were discharged eleven days later. This
      case reminded us once again of the importance and necessity of invasive
      monitoring in fluid management of these patients.

PMID- 10407528
TI  - Ephedrine-induced complete atrioventricular block with ventricular asystole
      during rapid concomitant phenytoin infusion: a case report.
AB  - Ephedrine is widely used to elevate blood pressure, however, one should be
      cautious to use it concomitantly with phenytoin infusion in neurosurgical
      procedures. A 59-year-old female was admitted for craniotomy with removal of
      metastatic brain tumor. During operation phenytoin infusion was given to
      forestall postoperative seizure. Hypotension, bradycardia and complete
      atrioventricular block followed by ventricular asystole suddenly occurred when
      the patient was given ephedrine to elevate the blood pressure to see the
      hemostatic effect close to the end of operation. We discontinued the phenytoin
      infusion and immediately injected 1.5 mg epinephrine. She was successfully
      resuscitated. We conclude that when phenytoin is used intraoperatively it should
      be administered by an infusion pump at a rate of less than 25 mg/min and under
      continuous monitoring of cardiac rhythm, heart rate, and blood pressure. When
      pressure support is required, the use of a pure alpha-agonist may minimize the
      risk of adverse reactions in the presence of phenytoin infusion.

PMID- 10407529
TI  - Epiglottic hematoma secondary to endotracheal intubation.
AB  - Though trauma related to direct laryngoscopy may occur anywhere from the lips to
      the glottis, damage to the epiglottis during intubation is a rare complication.
      Although large hematoma formation in the epiglottis after intubation is uncommon,
      its nature is potentially lethal. We report a case of epiglottic hematoma
      secondary to endotracheal intubation.

PMID- 10407531
TI  - The effects of increasing the reverse curve of Spee in a lower archwire examined
      using a dynamic photo-elastic gelatine model.
AB  - This paper describes the development and testing of a dynamic in vitro photo
      elastic model for evaluating the effects of orthodontic mechanics on an entire
      arch of teeth. A model of a mandibular arch was made and the teeth were embedded
      in a gelatine material with a high level of mechanical creep which permitted
      tooth movement in response to orthodontic forces. The excellent photo-elastic
      properties of this material also facilitated the analysis of the stress
      distribution around the roots of the teeth. The model of a mandibular arch was
      used to investigate the tooth movements and stress distributions produced by
      increasing the reverse curve of Spee in a 0.018 x 0.025-inch stainless steel
      archwire. The results revealed that a 1-mm reverse curve of Spee increased the
      arch length by 1.6 mm, but increasing the reverse curve of Spee to 5 mm did not
      increase arch length further. Photo-elastic analysis showed an increased stress
      distribution around the roots of the incisors and molars as the reverse curve of
      Spee was increased in the archwire.

PMID- 10407532
TI  - Bone response to orthodontic loading of endosseous implants in the rabbit
      calvaria: early continuous distalizing forces.
AB  - The purpose of this experimental study was to evaluate the effect of early
      orthodontic loading on the stability and bone-implant interface of titanium
      implants in a rabbit model. Twenty-four short threaded titanium fixtures were
      inserted in the calvarial mid-sagittal suture of 10 rabbits. Two weeks following
      insertion, 20 implants (test group) were subjected to continuous distalization
      forces of 150 g for a period of 8 weeks. The remaining four implants (control
      group) were left unloaded for the same follow-up interval. Clinically, all
      implants except for one test fixture were stable, and exhibited no mobility or
      displacement throughout the experimental loading period. Histologically, all
      stable implants were well-integrated into bone. No differences could be found
      between the pressure and tension surfaces of the test implants relative to bone
      quality and density within a range of 1000 microns from the fixture surface.
      Similarly, qualitative differences were not observed between the apical and
      coronal portions of test fixtures. Morphometrically, a mean percentage bone-to
      implant contact of 76.00 +/- 18.73 per cent was found at the test pressure sides,
      75.00 +/- 11.54 per cent at the test tension sides, and 68.00 +/- 15.55 per cent
      at the control unloaded surfaces. No statistically significant differences in the
      percentage of bone-to-metal contact length fraction were found between test
      pressure surfaces, test tension surfaces, and unloaded control surfaces. Marginal
      bone resorption around the implant collar or immediately beneath it was found in
      roughly the same percentage of analysed sites in the test and control fixtures.
      In contrast, slight bone apposition was demonstrated at the implant collar of the
      test pressure surfaces, while no apposition or resorption were observed in the
      test tension zones. This study suggests that short endosseous implants can be
      used as anchoring units for orthodontic tooth movement early in the post
      insertion healing period.

PMID- 10407533
TI  - Neural modulation of inflammatory reactions in dental tissues incident to
      orthodontic tooth movement. A review of the literature.
AB  - This article reviews the current knowledge of the biological aspects of dental
      tissue changes incident to orthodontic tooth movement. The inflammatory nature of
      these tissue changes was first recognized in the early 1970s, and since then a
      number of morphological and quantitative investigations have been published in
      support of this view. The studies dealing with vascular and cellular dental
      tissue changes, as well as those concerned with inflammatory mediators present at
      sites of orthodontic tooth movement are systematized and presented accordingly.
      Special emphasis is placed upon the role of the sensory nerve fibres and their
      neuropeptides in the control, and development of an inflammatory process, i.e.
      their role in tooth movement.

PMID- 10407534
TI  - Intra-oral temperature variation over 24 hours.
AB  - This study aimed to investigate temperature variation at archwire sites adjacent
      to the maxillary right central incisor and first premolar, its correlation with
      ambient temperature, and the influence of inter-racial variation. Twenty young
      adult male subjects were randomly selected (13 Asian, seven Caucasian).
      Thermocouples were attached to the labial archwire component of custom-made
      orthodontic retainers at the two intra-oral sites. A third thermocouple measured
      ambient temperature. A data-logger recorded temperatures at 5-second intervals
      over a 24-hour period. Temperatures ranged from 5.6 to 58.5 degrees C at the
      incisor and from 7.9 to 54 degrees C at the premolar, with medians of 34.9
      degrees C and 35.6 degrees C, respectively. Ambient temperature correlated poorly
      with the intra-oral temperatures. The Asian and Caucasian groups had
      significantly different temperature distributions. On average during the 24-hour
      period, temperatures at the incisor site were in the range of 33-37 degrees C for
      79 per cent of the time, below it for 20 per cent, and above it for only 1 per
      cent of the time. Corresponding figures for the premolar site were 92, 6, and 2
      per cent. At both archwire sites the most frequent temperatures were in the range
      of 35-36 degrees C. The data presented demonstrate that the temperature at sites
      on an archwire in situ varies considerably over a 24-hour period and that racial
      differences may exist. This information should be considered during the
      manufacture and use of temperature-sensitive orthodontic materials, in particular
      nickel-titanium archwires and springs.

PMID- 10407535
TI  - A 3D computer-aided design system applied to diagnosis and treatment planning in
      orthodontics and orthognathic surgery.
AB  - The purpose of this article is to describe a newly developed 3D computer-aided
      design (CAD) system for the diagnostic set-up of casts in orthodontic diagnosis
      and treatment planning, and its preliminary clinical applications. The system
      comprises a measuring unit which obtains 3D information from the dental model
      using laser scanning, and a personal computer to generate the 3D graphics. When
      measuring the 3D shape of the model, to minimize blind sectors, the model is
      scanned from two different directions with the slit-ray laser beam by rotating
      the mounting angle of the model on the measuring device. For computed simulation
      of tooth movement, the representative planes, defined by the anatomical reference
      points, are formed for each individual tooth and are arranged along a guideline
      descriptive of the individual arch form. Subsequently, the 3D shape is imparted
      to each of the teeth arranged on the representative plane to form an arrangement
      of the 3D profile. When necessary, orthognathic surgery can be simulated by
      moving the mandibular dental arch three-dimensionally to establish the optimum
      occlusal relationship. Compared with hand-made set-up models, the computed
      diagnostic cast has advantages such as high-speed processing and quantitative
      evaluation on the amount of 3D movement of the individual tooth relative to the
      craniofacial plane. Trial clinical applications demonstrated that the use of this
      system facilitated the otherwise complicated and time-consuming mock surgery for
      treatment planning in orthognathic surgery.

PMID- 10407536
TI  - Thin-plate spline analysis of treatment effects of rapid maxillary expansion and
      face mask therapy in early Class III malocclusions.
AB  - An effective morphometric method (thin-plate spline analysis) was applied to
      evaluate shape changes in the craniofacial configuration of a sample of 23
      children with Class III malocclusions in the early mixed dentition treated with
      rapid maxillary expansion and face mask therapy, and compared with a sample of 17
      children with untreated Class III malocclusions. Significant treatment-induced
      changes involved both the maxilla and the mandible. Major deformations consisted
      of forward displacement of the maxillary complex from the pterygoid region and of
      anterior morphogenetic rotation of the mandible, due to a significant upward and
      forward direction of growth of the mandibular condyle. Significant differences in
      size changes due to reduced increments in mandibular dimensions were associated
      with significant shape changes in the treated group.

PMID- 10407537
TI  - Craniofacial morphology in 6-year-old Icelandic children.
AB  - The purpose of the study was to describe the craniofacial characteristics of 6
      year-old Icelandic children, make a normative standard for children with an Angle
      Class I molar relationship, and compare them to those with an Angle Class II
      molar relationship. The material consisted of the radiographs of 363 children,
      184 (50.7 per cent) boys and 179 (49.3 per cent) girls with a mean age of 6 years
      7 months (range: 5 years 7 months-7 years 8 months). Twenty-two reference points
      were digitized and processed by standard methods with the Dentofacial Planner
      computer software program. The 33 variables calculated included both angular and
      linear. Two sample t-tests were used to study the differences between different
      groups. Only minimal differences could be noted between sexes in sagittal and
      vertical angular measurements. Linear measurements, on the other hand, were
      usually larger for the boys. When compared with Norwegian material of the same
      age group, similar trends were observed between sexes in both studies, but the
      Icelandic children showed slightly more mandibular prognathism and a lower
      mandibular plane angle. When compared with children with an Angle Class I molar
      relationship, children with an Angle Class II molar relationship did not have a
      different maxillary prognathism nor a different mandibular length. Cranial base
      dimensions were all significantly greater and the cranial base flexure was also
      significantly more obtuse in the distal group.

PMID- 10407538
TI  - Long-term effect of the chincap on hard and soft tissues.
AB  - The short- and long-term effects of the chincap used in combination with a
      removable appliance to procline upper incisors were analysed cephalometrically in
      23 patients with Class III malocclusions. The overall changes were compared with
      growth changes in a closely matched control sample of untreated Class III
      patients. There was no evidence that the chincap retarded growth of the mandible.
      During treatment, there was an increase in mandibular length and facial height.
      The lower incisors retroclined and the upper incisors proclined. The incisor
      relationship was corrected. Soft tissue changes included an increase in
      nasolabial angle and improvement in soft-tissue profile, including the nose.
      Skeletal post-treatment changes included further mandibular growth associated
      with an increase in angle SNB and Wits measurement. Facial height also increased
      significantly. The Class I overjet was maintained, although slightly diminished.
      The soft tissue nose, upper and lower lip, and chin moved anteriorly, and the
      nasal tip and chin moved inferiorly. At the end of the study period there were no
      significant skeletal or soft tissue differences between the treated and control
      groups. The only significant contrasts were in the overjet and the overbite.
      Chincap therapy combined with an upper removable appliance to procline the upper
      incisors is effective in producing long-term correction of the incisor
      relationship by retroclination of lower incisors, proclination of upper incisors,
      and redirection of mandibular growth in a downward direction. The direction of
      growth at the chin is maintained subsequent to treatment, as are the changes in
      incisor inclination, although in diminished form. There are corresponding
      improvements in the soft tissue profile.

PMID- 10407539
TI  - Cheek and tongue pressures in the molar areas and the atmospheric pressure in the
      palatal vault in young adults.
AB  - The pressures acting on the maxillary and mandibular posterior teeth from the
      tongue and cheeks were measured in 24 adults aged 22-29 years. In addition, the
      pressure in the palatal vault was recorded. The pressure at two maxillary (buccal
      and lingual) and two mandibular (buccal and lingual) measuring points, and in the
      palatal vault was recorded simultaneously. Repeated recordings of the pressures
      at rest, and during chewing and swallowing were made. The pressures at rest were
      of similar magnitude (about 2 g/cm2) at the buccal and lingual sides of the
      mandibular posterior teeth. The median resting pressure at the maxillary
      posterior teeth was 2.7 g/cm2 on the buccal side and 1.0 g/cm2 on the lingual
      side. The difference in the maxilla was significant, but not in the mandible. It
      was concluded that the equilibrium of tooth position is maintained by the
      pressure from the cheeks and the tongue. During chewing and swallowing the
      pressures on the lingual side of the teeth were greater than those on the buccal
      side. At rest about half of the subjects had a negative pressure at the palatal
      vault, but no correlations between the resting pressure at the palatal vault and
      the resting pressures on the teeth were found.

PMID- 10407540
TI  - The effects of sandblasting on the bond strength of molar attachments--an in
      vitro study.
AB  - This study evaluated the effect of sandblasting foil mesh molar tube bases on the
      shear bond strength obtained when bonding to first molar teeth. Fifty-two
      recently extracted first molar teeth were etched with 35 per cent phosphoric acid
      gel for 30 seconds. Twenty-six sandblasted 'A' Company molar tube attachments and
      26 non-sandblasted attachments were then bonded to the teeth using Phase II
      orthodontic bonding resin. After storage in water for 24 hours at 37 degrees C,
      the specimens were debonded in a direction parallel to the buccal surface.
      Survival analysis using the Weibull function revealed that for a 90 per cent
      probability of survival, the predicted bond strengths for sandblasted and non
      sandblasted bases were 1.76 and 1.66 MPa, respectively. For larger shear
      stresses, the probabilities of bond survival with sandblasted molar tubes were
      greater than with non-sandblasted molar tubes although the differences were
      small, which may be explained by the large proportion of bond failures which
      occurred at the resin to enamel interface in both groups. It was concluded that
      sandblasting foil mesh bases is likely to provide only a minimal improvement in
      clinical performance when bonding to molar teeth.

PMID- 10407541
TI  - Emerging role of pacing therapies for congestive heart failure.

PMID- 10407542
TI  - Sudden cardiac death.

PMID- 10407543
TI  - Treatment of acute myocardial infarction: does the type of hospital make a
      difference? PPAMI Study Group.
AB  - There is sparse data on the treatment practices being followed for acute
      myocardial infarction at various hospitals that differ in their financial
      infrastructure, availability of facilities and attachment to a medical college.
      In this prospective observational study, we evaluated the treatment practices for
      acute myocardial infarction, its appropriateness based on ACC/AHA guidelines and
      possible influence by type of hospital and certain patient characteristics.
      Thrombolysis, beta-blockers and angiotensin-converting enzyme-I inhibitors were
      used in 674 (63%), 506 (47%) and 413 (38%) respectively of 1072 patients.
      However, when evaluated according to ACC/AHA guidelines, appropriate use was
      noted in 83 percent, 78 percent and 99.3 percent, respectively. Thrombolysis was
      inappropriately denied to 14.7 percent patients whereas in 2.4 percent it was
      used contrary to recommendations. The most common reason for ineligibility for
      thrombolysis was late arrival. Beta-blockers were denied to 25.1 percent
      patients. Decision on use of angiotensin-converting enzyme-I was appropriate in
      most patients. Aspirin was used in 1027 (95.8%) patients. Government hospitals
      were least likely to thrombolyse a patient as compared to private, industrial and
      voluntary hospitals; however, this difference was not seen with the use of beta
      blockers and angiotensin-converting enzyme-I. Hospitals attached to medical
      colleges follow guidelines for use of thrombolysis and beta-blockers more closely
      than non-teaching hospitals. To conclude, evaluation of appropriateness of a
      therapeutic modality is of greater clinical significance than mere absolute use.
      Benefits of thrombolytic therapy can be extended by minimising pre-hospital
      delay; and there is scope for improved utility of beta-blockers which are cost
      effective. In addition, the hospital type also has an impact on the treatment
      practice being followed for acute myocardial infarction.

PMID- 10407544
TI  - Prospective observational study of primary angioplasty of the infarct-related
      artery for acute myocardial infarction.
AB  - Primary angioplasty has been shown to reduce rates of in-hospital mortality,
      recurrent ischaemia and infarction. However, the role of primary stenting and
      abciximab is presently undergoing evaluation. This study attempted to examine the
      feasibility, safety and outcomes of primary angioplasty in the treatment of acute
      myocardial infarction. Data in 100 patients who underwent primary angioplasty for
      evolving acute myocardial infarction was prospectively analysed to assess the
      safety and efficacy of various modalities. Twenty patients were in Killip class
      III and above. Multivessel (2 or more vessels) disease was noted in more than 52
      cases. Procedural success was 99 percent; 86 patients received primary stenting,
      majority of them had Kalam-Raju stent implantation. Adjunct treatment included
      abciximab infusion in 22 and intra-aortic balloon pump support in 12. Overall
      mortality rate was six percent with a mortality of 2.2 percent in non-cardiogenic
      shock patients. Recurrent ischaemic events were noted in five, three of them had
      successful reperfusion with repeat angioplasty. None of the patients had
      emergency coronary artery bypass surgery. It is concluded that primary
      angioplasty is safe and effective with high procedural success. Recurrent
      ischaemic events are low, possibly due to routine use of stenting and selective
      use of abciximab.

PMID- 10407545
TI  - Haemodynamic effects of leg raising in patients undergoing coronary artery bypass
      grafting.
AB  - Twenty patients undergoing elective coronary artery bypass grafting were studied
      prospectively to evaluate the haemodynamic effects of passive leg raising. The
      patients were divided into two groups: those having good left ventricular
      function with ejection fraction of 0.50 or more (group I, n = 10) and those
      having poor left ventricular function with ejection fraction of upto 0.35 (group
      II, n = 10). Morphine-based anaesthetic technique was used and standard
      haemodynamic measurements were obtained at following stages: (1) control--20 to
      30 min after induction of anaesthesia; (2) one minute, and (3) five min after
      raising both the legs; (4) one min, and (5) five min after the legs were
      repositioned. In group I, heart rate decreased from 71 +/- 9 to 66 +/- 8
      beats/min (p < 0.001) at stage 1 and persisted throughout the study period. This
      was accompanied by a decrease in cardiac index, although, the statistical
      significance was achieved at stage 3 and 4 only. The haemodynamic changes
      observed in group II were of more severe magnitude. The heart rate decreased from
      90 +/- 13 to 84 +/- 13 beats/min at stage 1 (p < 0.05) and persisted throughout
      the study with maximum decrease of 14 percent occurring at stage 3. The cardiac
      index decreased significantly from 2.4 +/- 0.3 to 2.0 +/- 0.5 L/min/m2 (p < 0.05)
      at stage 1. This persisted throughout the study except that it recovered at stage
      4. The maximum decrease in cardiac index (20%) occurred at stage 2. In addition,
      systemic vascular resistance increased significantly from 1458 +/- 255 to 1830 +/
      420 dyne.sec.cm-5 (p < 0.05) at stage 1 and persisted throughout the study
      period. We conclude that passive leg raising should be undertaken with caution in
      patients with coronary artery disease especially in those who have poor left
      ventricular function.

PMID- 10407546
TI  - An epidemiological study of blood pressure in school children (5-14 years) in
      Delhi.
AB  - Distribution patterns of blood pressure were studied in a randomised sample of
      10,215 school children (5,709 boys 4,506 girls) in the age group 5-14 years in
      Delhi. The mean values of systolic and diastolic blood pressure (SBP and DBP)
      increased with age in both sexes. The cut-off points for high blood pressure were
      based on average SBP and/or DBP values of 95th percentile or greater for each
      age. The values for SBP ranged from 70 mm Hg to 140 mm Hg and for DBP from 36 mm
      Hg to 100 mm Hg for the age group 5-9 years. In the age group 10-14 years, the
      values for SBP and DBP ranged from 72 mm Hg to 160 mm Hg and from 46 mm Hg to 120
      mm Hg, respectively. The prevalence of hypertension (systolic, diastolic or both)
      was 11.9 percent in boys and 11.4 percent in girls, an insignificant difference.
      Anthropometric variables like height, weight and body mass index showed positive
      correlation with systolic as well as diastolic blood pressure but the waist-hip
      ratio showed negative correlation coefficient with blood pressure. Family history
      of hypertension in one or both the parents was present in 20.4 percent children
      with high blood pressure compared to 6.8 percent in normotensives. Family history
      or diabetes was also significantly higher in hypertensive children (5.4%) than in
      normotensives (3.1%).

PMID- 10407547
TI  - Growth hormone therapy in patients with dilated cardiomyopathy: preliminary
      observations of a pilot study.
AB  - The effects of growth hormone in six patients with dilated cardiomyopathy were
      evaluated in this study. The patients were studied at baseline, after six months
      of therapy and at six months after stopping the treatment. They were given two
      units of growth hormone on alternate days by subcutaneous injection. There was
      marked improvement in the symptomatic class with treatment (NYHA class 3.4 +/-
      0.5 vs 2 +/- 0; p = 0.04). There was also significant increase in the
      inteventricular septal wall thickness (6.4 +/- 1.5 mm vs 10.4 +/- 0.5 mm; p =
      0.04). Left ventricular posterior wall thickness also increased significantly
      (7.2 +/- 1.3 mm vs 10.2 +/- 0.8 mm; p = 0.04). These changes were partially
      reversed by the end of six months of treatment but the symptomatic status of
      these patients was better than before. The administration of growth hormone for
      six months in patients with dilated cardiomyopathy results in significant
      improvement in the symptomatic class, which could be considered as an additional
      line of management in patients with heart failure in dilated cardiomyopathy.

PMID- 10407548
TI  - Adult cyanotic congenital heart disease: surgical experience.
AB  - Cyanotic congenital heart diseases constitute about 10 percent of total
      congenital heart disease cases in adults in the developing world. Prolonged
      cyanosis and old age adversely affect the outcome of surgery, thus posing a
      challenge to the cardiac surgeons. This study was conducted to assess the
      feasibility, safety and outcome of surgery in this group of patients. From
      January 1991 to December 1997, a total of 303 patients, aged 14 to 54 years (mean
      19.8 +/- 1.5 years) with diagnosis of various cyanotic congenital heart diseases
      were operated at our institute. There were 210 males (69.3%). Two hundred and
      forty-seven patients (81.5%) had tetralogy of Fallot's physiology, 51 patients
      (16.8%) had single ventricle physiology and five (1.6%) had other lesions. Sixty
      six patients (21.7%) had pre-operative complications such as haemoptysis,
      epistaxis, cerebrovascular accidents, brain abscess and infective endocarditis.
      Sixty patients (19.8%) had previous palliative shunts and 26 patients (8.5%) had
      coil embolisation of major aortopulmonary collaterals prior to surgery; 229
      patients (75.5%) underwent biventricular repair, 52 (17.1%) had univentricular
      repair, 22 (7.7%) had palliative shunts and one patient had open ligation of a
      major aortopulmonary collateral in addition. In-hospital mortality was 3.3
      percent. Follow-up period ranged from five months to seven years (mean 4.2 +/-
      1.8 years). There were two late deaths. Of the 291 survivors, 11 were lost to
      follow-up. Two hundred and fifty-eight patients (92.1%) are in New York Heart
      Association class I. Significant residual defects warranting reoperation were
      present in four patients (1.3%). It is concluded that congenital heart surgery in
      older cyanotic patients can be performed safely with satisfactory results.

PMID- 10407549
TI  - Minimally invasive atrial septal defects repair.
AB  - This study reviews the current method of atrial septal defect closure at our
      institute with a minimally invasive approach without median sternotomy. From
      September 1997 to August 1998, 37 patients (13 males, 24 females) with mean age
      36.5 years (range 18-67 years) underwent atrial septal defect closure by right
      anterior thoracotomy. Femoral vessels were cannulated through a small groin
      incision and extracorporeal circulation was established. Venous drainage was
      assisted with a centrifugal pump. Aortic crossclamping was performed through the
      intact chest wall using a special transthoracic clamp with sliding rod design
      inserted through a separate tiny 3 mm incision in the right second intercostal
      space in the mid clavicular line. Mean duration of cardiopulmonary bypass and
      aortic crossclamp time was 35 +/- 14 and 23 +/- 7 minutes respectively; mean
      endotracheal intubation time after surgery 6.2 +/- 3 hours; mean ICU stay 10.6 +/
      2.8 hours; mean length of thoracotomy incision 7.2 +/- 1.8 cm; and, mean
      hospital stay 4.2 +/- 1.8 days. There was no post-operative neurological
      dysfunction or femoral cannulation related complication. There was no
      perioperative or late mortality. No residual atrial septal defect was observed by
      transoesophageal echocardiography in any patient. The procedure described here
      provides secure closure of the atrial septal defects in minimally invasive
      fashion with good results.

PMID- 10407550
TI  - Bidirectional ventricular tachycardia and familial periodic paralysis: a case
      report.

PMID- 10407551
TI  - A family with arrhythmogenic right ventricular dysplasia.

PMID- 10407552
TI  - Reduplication of the mitral valve.

PMID- 10407553
TI  - Percutaneous balloon dilatation of rheumatic mitral stenosis associated with cor
      triatriatum.

PMID- 10407554
TI  - Transcatheter glue occlusion of bilateral coronary-pulmonary arterial fistulae.

PMID- 10407555
TI  - Percutaneous retrieval of a broken catheter fragment from the left common carotid
      artery.

PMID- 10407556
TI  - Non-surgical treatment of major coronary artery perforation using a stent graft.

PMID- 10407557
TI  - Emerging role of ACE inhibitors in prevention of myocardial infarction and
      unstable angina.

PMID- 10407558
TI  - Antibiotic treatment for acute coronary syndromes--fact or fiction.

PMID- 10407559
TI  - Copyright problems in journal publishing.

PMID- 10407560
TI  - Bypass for malignant duodenal obstruction--politics of change: therapeutic.
      Selective! Prophylactic?

PMID- 10407561
TI  - Gastric outlet obstruction in carcinoma gall bladder.
AB  - BACKGROUND: Gastric outlet obstruction is occasionally reported to occur in
      advanced gall bladder malignancy and may require palliative surgery. A review of
      39 patients who required gastroenterostomy for symptomatic or incipient gastric
      outlet obstruction in carcinoma gall bladder is presented. METHODS: This
      retrospective review included 24 women and 15 men over nine years who underwent
      gastrojejunostomy for locally advanced neoplasms of the gall bladder. RESULTS:
      Twenty two patients with carcinoma gall bladder had symptomatic gastric outlet
      obstruction whereas in 17 patients gastrojejunostomy had been performed for
      intraoperatively assessed impending obstruction. Thirty-four patients had
      concomitant jaundice. In most cases, there was obstruction of the first two parts
      of the duodenum, mostly by direct tumoral infiltration (64%). All patients
      underwent anterior gastrojejunostomy, with billoenteric bypass in 15 patients.
      There were two postoperative deaths. Eight patients developed postoperative
      delayed gastric emptying; all settled on conservative management, though two
      patients had recurrent refractory vomiting. Thirty patients had no vomiting till
      a follow up ranging from 36 days to 11 months. CONCLUSIONS: Gastric outlet
      obstruction may frequently complicate gall bladder cancer and a satisfactory
      palliation can be achieved in most patients by gastrojejunostomy.

PMID- 10407562
TI  - A monoclonal antibody-based test system for detection of Entamoeba histolytica
      specific coproantigen.
AB  - BACKGROUND: Diagnosis of amebiasis based on stool microscopy or demonstration of
      anti-amebic antibodies has limitations. A diagnostic system based on
      demonstration of the parasite product in clinical specimens holds promise.
      METHODS: Murine monoclonal antibodies were developed against an Entamoeba
      histolytica-specific coproantigen. A monoclonal antibody (MoAb) 3D10 was employed
      in a double-antibody sandwich microELISA system for the detection of amebic
      coproantigen in fecal specimens. The system was evaluated in three groups of
      subjects: 63 patients with intestinal amebae, 27 with non-amebic parasitosis, and
      57 apparently healthy controls. RESULTS: The MoAb 3D10 belonged to IgG1 isotype
      and recognized three antigens, with mol. wt. 36, 25 and 17 kDa in the crude
      extract of E. histolytica (HM1-IMSS), and an amebic coproantigen with MW 36 kDa
      in the stool supernatant from patients with intestinal amebae. The coproantigen
      was detected in the stool eluates of 56 (89%) patients with intestinal amebae and
      in none of the stool eluates from other subjects, thereby giving this system a
      sensitivity of 89% and specificity of 100% for the detection of intestinal
      amebae. CONCLUSIONS: This monoclonal antibody recognizes as intact epitope on the
      E. histolytica-specific coproantigen. The validity of the MoAb-based microELISA
      system needs to be established.

PMID- 10407563
TI  - Mucocutaneous exposure to body fluids during digestive endoscopy: the need for
      universal precautions.
AB  - BACKGROUND: Endoscopy personnel are at high risk of exposure to infectious body
      fluids during endoscopy. There are no studies documenting the frequency of such
      exposure. AIM: To determine the frequency of exposure to body fluids, and factors
      that may modify the risk of exposure during digestive endoscopy. METHODS: During
      a 10-month period, 948 endoscopy procedures done by two endoscopists were
      assessed for the occurrence of splashes to uncovered parts of the body. Odds
      ratio was used to determine any change in the exposure risk with different risk
      factors. RESULTS: The overall frequency of splash to any part of the body was
      13.2% (95% CI 10.8-15.9). Common sites of exposure were the eyes, face, forearms
      and feet. Splash to the skin of the face, forearms and feet occurred in 9.5% (95%
      CI 7.5-11.8). The risk remained unchanged during therapeutic endoscopy, assisted
      endoscopy, or endoscopy with biopsy or cytology. Using video endoscopy led to
      significant reduction in splashes on the skin. Overall splash rate to the eyes
      was 4.1% (95% CI 2.9-5.6). This remained unchanged during therapeutic endoscopy,
      assisted endoscopy, and endoscopic biopsy or cytology sampling. The risk was not
      reduced during video endoscopy. CONCLUSIONS: Endoscopy results in muco-cutaneous
      exposure to potentially infectious body fluids in 13% or more procedures. The
      risk of exposure is not reduced by video endoscopy, or by avoiding
      instrumentation of the biopsy channel. We recommend that all endoscopists and
      endoscopy assistants must follow universal precautions.

PMID- 10407564
TI  - Lowered sympathetic reactivity in patients with non-bleeding duodenal ulcers.
AB  - BACKGROUND: Autonomic dysfunction has been associated with duodenal ulcer. We
      assessed autonomic reactivity in patients with duodenal ulcer. METHODS: Ten
      patients with non-bleeding active duodenal ulcers and ten age- and sex-matched
      healthy subjects were investigated for parasympathetic reactivity (heart rate
      response to deep breathing, Valsalva maneuver and head-up tilt test) and
      sympathetic reactivity (blood pressure response to hand grip, head-up tilt and
      cold pressor test). Anxiety status was measured by evaluating responses to a
      questionnaire. RESULTS: The duodenal ulcer patients showed normal parasympathetic
      reactivity, lowered sympathetic reactivity and high anxiety score. When compared
      to control subjects, they had significantly lower diastolic blood pressure change
      in response to hand grip (median [range]; difference in values 12 [4-16] mmHg vs
      16 [10-22] mmHg) and head up tilt (1 [-6-4] vs 6 [2-10] mmHg). CONCLUSIONS:
      Patients with duodenal ulcer have lowered sympathetic reactivity; this may be
      involved in causation by decreasing mucosal protection.

PMID- 10407567
TI  - Pseudoaneurysm in gall bladder fossa following laparoscopic cholecystectomy.
AB  - A 32-year-old lady presented with severe hematemesis and melena after
      laparoscopic cholecystectomy. Initial ultrasonography and spiral CT suggested a
      vascular lesion in the gall bladder fossa. Selective hepatic angiography
      confirmed the presence of a pseudoaneurysm close to the surgical clip and filling
      through the right hepatic artery. This was treated with coil embolization,
      resulting in cessation of hematemesis and amelioration of symptoms.

PMID- 10407566
TI  - Epidemiology of digestive tract cancers in India. V. Large and small bowel.
AB  - The large bowel is a leading site for cancers in developed countries whereas
      small bowel cancers are rare worldwide. The incidence rates of both large and
      small bowel cancer are low in India, and rectal cancer is more common than colon
      cancer. The incidence rates of colon cancer in eight population registries vary
      from 3.7 to 0.7/100,000 among men and 3 to 0.4/100,000 among women. For rectal
      cancer the incidence rates range from 5.5 to 1.6/100,000 among men and 2.8 to
      0/100,000 among women. One intriguing observation is the occurrence of rectal
      cancer in young Indians. Rural incidence rates for large bowel cancers in India
      are approximately half of urban rates. Based on data from eight registries, we
      estimate that, in the year 2001, the incidence of large bowel cancer in India
      will be 18,427 in men and 13,092 in women. Immigrant studies reveal an increase
      in incidence as compared to the rates in native counterparts. Reliable time
      trends for India are available only from the Bombay registry. Significant
      increase in the incidence of colon cancer has been reported for both men and
      women over two decades, but the rates of rectal cancer are steady. The low
      incidence of large bowel cancers in Indians can be attributed to high intake of
      starch and the presence of natural antioxidants such as curcumin in Indian
      cooking. The role of hereditary factors has been evaluated in a few studies. Some
      studies have reported the occurrence of both FAP and HNPCC in India. There are no
      Indian studies on large bowel cancer prevention. The prevalence of adenomas is
      rare in elderly Indians undergoing colonoscopy, even in those with large bowel
      cancers. Small bowel cancers are extremely rare in India and no analytical
      studies have been published. Hospital-based data suggest that lymphomas of small
      bowel are more common than carcinomas. In conclusion, the incidence of large and
      small bowel adenomas and cancers is low in Indians. Increase in the incidence of
      large bowel cancers in immigrants and urban Indians compared to rural populations
      supports a role for environmental risk factors including diet. High rates of
      rectal cancers in young Indians could suggest a different etiopathogenesis, which
      is neither inherited nor traditional diet-related.

PMID- 10407565
TI  - Prospective evaluation of medication-induced esophageal injury and its relation
      to esophageal function.
AB  - BACKGROUND: Few prospective studies are available on the incidence of medication
      induced esophageal injury (MIEI). AIMS: To prospectively study the occurrence of
      MIEI with indomethacin and doxycycline and the predictive factors for its
      development. METHODS: In an operator-blinded study, 51 patients (age 16-65 y)
      requiring indomethacin (n = 24) or doxycycline (27) underwent symptom evaluation,
      endoscopy and scintigraphy before and after 7 days of therapy. MIEI was defined
      as de novo occurrence or worsening of pre-existing esophagitis or development of
      esophageal ulcer. RESULTS: Pre-therapy endoscopy was normal in 32 patients and
      revealed esophagitis in 19 (grade I--11, grade II--8). Post-therapy, 16 patients
      developed esophageal symptoms, which appeared earlier with doxycycline (2.0 [0.8]
      vs 4.1 [1.7] days, p = 0.016). MIEI developed in 23 patients--de novo esophagitis
      in 16, worsening of esophagitis in 6; 5 patients developed ulcer. Seven of 12
      patients with hiatus hernia developed MIEI. Presence of pre-therapy
      gastroesophageal reflux disease did not predict MIEI. There was no difference in
      pre- or post-therapy transit values between patients with and without MIEI;
      patients who developed ulcers had significantly slower esophageal transit (p <
      0.05). There was no difference in esophageal transit or occurrence of MIEI
      between patients who received indomethacin or doxycycline; however, 5 of 8
      patients with hiatus hernia who received doxycycline developed MIEI (p = 0.02;
      relative risk 3.96 [CI 1.2-12.7]). CONCLUSIONS: 40% of patients receiving
      doxycycline or indomethacin developed MIEI; 10% developed ulcers. Hiatus hernia
      increased the risk for MIEI.

PMID- 10407568
TI  - Enterogenous duplication cyst presenting as obstructed inguinal hernia.
AB  - We report a 5-year-old boy with enterogenous tubular duplication cyst presenting
      as obstructed inguino-scrotal hernia.

PMID- 10407569
TI  - HBsAg carrier with simultaneous amebic liver abscess and acute hepatitis E.
AB  - Hepatitis E virus (HEV) infection and amebiasis are waterborne diseases that are
      endemic in India. However, their co-occurrence has never been described. We
      report a patient who presented with fever, jaundice and tender hepatomegaly and
      on investigation was found to have coexisting acute hepatitis E and amebic liver
      abscess. Incidentally, he was also an HBsAg carrier.

PMID- 10407570
TI  - Esophageal carcinoma with spread to mesenteric and iliac lymph nodes.
AB  - Carcinoma of the esophagus can metastasize to unusual sites. We report a patient
      with esophageal carcinoma with retrograde spread to the mesenteric and iliac
      lymph nodes from celiac nodes, demonstrated by magnetic resonance imaging and
      confirmed by FNAC.

PMID- 10407571
TI  - Isolated common bile duct tuberculosis.
AB  - We report a patient with isolated involvement of common bile duct by
      tuberculosis. The diagnosis was established by histological examination of the
      resected specimen. Surgery and antitubercular chemotherapy resulted in complete
      recovery.

PMID- 10407572
TI  - Carcinoid tumor of common hepatic duct.
AB  - Primary carcinoid tumors of the biliary tract are extremely rare. We report a 36
      year-old woman with recurrent acute cholangitis who was diagnosed to have a
      carcinoid in the common hepatic duct, with enlarged local nodes. She underwent
      local resection. I-131 metaiodobenzyl guanidine (MIBG) scanning postoperatively
      showed no uptake in the tumor bed.

PMID- 10407573
TI  - Multiple myeloma presenting as acute pancreatitis.
AB  - Acute pancreatitis is a very uncommon presenting feature of multiple myeloma. We
      report an elderly non-alcoholic man presenting with acute abdominal pain and
      rapidly progressing renal failure. Investigations revealed lytic lesions in the
      vertebrae and skull, M band on urine electrophoresis, and radiological and
      biochemical evidence of acute pancreatitis. The patient died despite conservative
      management of the pancreatitis.

PMID- 10407574
TI  - Prevalence of HBsAg in visceral leishmaniasis (kala-azar)

PMID- 10407575
TI  - Relation of gastric juice vitamin C levels with H. pylori infection.

PMID- 10407577
TI  - Lymphoid development from hematopoietic stem cells.
AB  - Mechanisms and pathways for commitment to the lymphoid lineage from hematopoietic
      stem cells (HSC) remain controversial. The interleukin-7 receptor (IL-7R)
      transduces nonredundant signals for both T- and B-cell development. Recently, we
      identified a clonogenic common lymphoid progenitor population in mouse bone
      marrow that can give rise to T, B, and natural killer (NK) cells, but lacks
      myeloid differentiation capacity. These cells are not self-renewing stem cells,
      but progenitors that have a limited life span. HSC do not express IL-7R, and the
      upregulation of the IL-7R occurs at the stage of common lymphoid progenitors. The
      IL-7R mediates nonredundant signals to reinforce the survival of developing T
      cells, and to promote rearrangement of immunoglobulin heavy chain genes in B-cell
      progenitors. Thus, common lymphoid progenitors exist in early hematopoiesis, and
      expression of the IL-7R is a critical step in the initiation of lymphoid
      development from HSC.

PMID- 10407576
TI  - HBV DNA amplification by polymerase chain reaction in patients with serological
      evidence of chronic hepatitis B infection.

PMID- 10407578
TI  - Hematopoietic stem cell gene therapy: a current overview.
AB  - Retrovirus-mediated gene transfer into murine hematopoietic stem cells and
      reconstitution of syngeneic mice have demonstrated persistence and functioning of
      the transgenes over extended periods of time. In contrast, clinically relevant
      levels of gene transfer into large animal and human stem cells have not been
      widely achieved. Results of current clinical gene transfer studies have raised
      fundamental questions about the physiology of primitive human hematopoietic cells
      and gene therapy vectors. Efforts are being undertaken to answer these problems
      and to develop more efficient gene therapy strategies.

PMID- 10407580
TI  - Clonality analysis of granulocytes and T lymphocytes in healthy females by the
      PCR-based HUMARA method.
AB  - Clonality analysis utilizing X-chromosome inactivation has been used in the study
      of various diseases, including hematological malignancies. The human androgen
      receptor gene (HUMARA) assay is the newest of such methods, and the majority of
      the female population can be assessed by this relatively simple procedure. One
      problem in using these clonality analysis methods, however, is that there may be
      significant variation in Lyonization in blood cells in normal individuals. To
      determine the diversity in X-chromosome methylation patterns, which reflect
      Lyonization, assessed by the HUMARA assay in the supposedly normal population, we
      analyzed granulocytes and T cells from 97 relatively young (18- to 35-year-old)
      healthy female volunteers. We found that the methylation patterns in the two
      HUMARA alleles were distributed even more widely, both in granulocytes and in T
      cells, than previously reported with other methods. We also found that the
      deviation of methylation in granulocytes and T cells was well correlated. Thus,
      we conclude that appropriate controls from the same individuals, such as T cells
      in the case of stem cell disorders, should always be employed to conclusively
      determine whether certain cells of hematopoietic origin are clonal.

PMID- 10407579
TI  - Evaluation of the blue formazan spot test for screening glucose 6 phosphate
      dehydrogenase deficiency.
AB  - Several screening tests for glucose 6 phosphate dehydrogenase (G6PD) deficiency
      have been reported thus far, and a standardized method of testing was proposed by
      the International Council for Standardization in Hematology (ICSH). The screening
      test used in any particular laboratory depends upon a number of factors such as
      cost, time required, temperature, humidity, and availability of reagents. In this
      study, a direct comparison between three different G6PD screening methods has
      been undertaken. In 71 cases (50 hematologically normal volunteers, 9 hemizygous
      G6PD-deficient males, and 12 heterozygous deficient females), the blue formazan
      spot test (BFST) was compared with the conventional methemoglobin reduction test
      (HiRT) and the ICSH-recommended fluorescent spot test (FST-ICSH). In all cases,
      the results obtained with the three screening tests were correlated with the
      enzyme activity assayed spectrophotometrically. In hemizygous G6PD-deficient
      males, all cases were equally detected with the three methods: BFST (4.7-6.64,
      controls: 11.1-13.4), BMRT (score +3 in all 9 cases), and FST (no fluorescence in
      9 cases). In heterozygous G6PD-deficient females, two methods detected 7 out of
      12 cases (BFST: 8.71-11.75, controls: 11.1-13.4; and BMRT: score +3 in 7 cases),
      whereas the FST-ICSH missed all 12 cases that presented a variable degree of
      fluorescence. Although the sensitivity for G6PD-deficient carrier detection is
      the same for the BMRT and the BFST, the latter has the advantage of being
      semiquantitative and not merely qualitative. Unfortunately, none of the three
      screening tests compared here allowed the detection of the 100% heterozygote
      carrier state of G6PD deficiency.

PMID- 10407581
TI  - Treatment of infant acute lymphoblastic leukemia in Japan. Childhood Leukemia
      Study Group of the Ministry of Health and Welfare (Kouseisho).
AB  - Although current chemotherapeutic regimens cure as many as 70% of children with
      acute lymphoblastic leukemia (ALL), infants continue to show a poor outcome. In
      this paper, we describe the outcome in 37 ALL infants treated between 1989 and
      1995 in Japan. Patients had characteristic findings of infant ALL, including
      hyperleukocytosis > 100 x 10(9)/l (15/37, 41%), blast cells with a CD10-negative
      phenotype (30/37, 81%), and 11q23/MLL involvement (21/37, 57%). Seven were
      treated according to Aggressive Treatment Research Group protocol, 15 according
      to the Ministry of Health and Welfare protocol, and 15 according to protocols of
      other institutions. The 3-year overall event-free survival (EFS) was 33%. The EFS
      was 13% for infants aged < 26 weeks at diagnosis and 43% for infants aged > 26
      weeks. Infants who had blast cells with CD10 negative phenotype with 11q23/MLL
      involvement were also associated with poor prognosis. However, infants with CD10
      positive blasts without 11q23/MLL involvement had a better outcome (EFS 75%).
      These results suggest that intensive chemotherapy is effective for patients with
      good prognostic factors, but for infants with poor prognostic factors a more
      aggressive approach such as stem cell transplantation might be necessary.

PMID- 10407582
TI  - Chronic lymphocytic leukemia is infrequent in Mexican mestizos.
AB  - Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults living
      in Western countries, and accounts for approximately 30% of adult leukemias. In a
      15-year period in a single institution, we identified 19 patients with CLL in a
      group of 211 adults with leukemia (9% of adult leukemias). Of these 19 CLL
      patients, 8 had a Caucasian phenotype, 4 were born outside the country, and only
      11 were Mexican mestizos. On the other hand, in a multicenter experience
      involving 1968 Mexican adults with leukemia, CLL represented 6.6% of the cases, a
      figure significantly lower than that reported in Caucasians (P < 0.01). CLL is
      the least frequent type of leukemia in Mexican mestizos, and this low prevalence
      may stem from the genetic origin of this racial group. The data also suggest a
      genetic predisposition of Caucasians to suffer from this disease.

PMID- 10407583
TI  - Successful treatment of cytomegalovirus retinitis in a patient with malignant
      lymphoma: a case report and review of the literature.
AB  - A 52-year-old Japanese woman was diagnosed as having angioimmunoblastic T-cell
      lymphoma (stage IV-B). She received 6 courses of chemotherapy including
      cyclophosphamide, doxorubicin, vincristine, and prednisolone every two weeks
      (biweekly CHOP), and was considered to be in partial remission. She complained of
      loss of visual acuity in her right eye during her last cycle of chemotherapy.
      Cytomegalovirus (CMV) retinitis was suspected from the characteristic
      ophthalmoscopic appearance. This diagnosis was further supported by the detection
      of CMV DNA in blood and antigens in polymorphonuclear leukocytes, a sign of CMV
      reactivation. Although DNAemia and antigenemia became negative, retinitis
      remained slightly active despite a 4-week systemic treatment of ganciclovir.
      Intraocular injection of ganciclovir was started and continued until the
      retinitis became inactive ophthalmoscopically. The patient received high-dose
      chemotherapy with peripheral blood stem cell transplantation and achieved
      complete remission. During the after this therapy no recurrence of CMV infections
      was observed. This case shows that 1) a quick and accurate diagnosis of CMV
      retinitis was possible by applying DNAemia and antigenemia and 2) intensive
      treatment for the CMV infection enabled the accomplishment of cure-oriented
      chemotherapy of the lymphoma without the recurrence of CMV retinitis.

PMID- 10407584
TI  - L-asparaginase induced complete remission in Epstein-Barr virus positive,
      multidrug resistant, cutaneous T-cell lymphoma.
AB  - A 30-year-old man was admitted to our hospital with subcutaneous tumors and a
      high fever. Based on biomicroscopic findings of the tumor, the patient was
      diagnosed as having diffuse, medium, well-differentiated malignant lymphoma.
      Immunochemical analysis showed that CD3, CD4, CD25, and TCR beta were positive,
      and in situ hybridization revealed Epstein-Barr virus-encoded small RNAs in the
      nuclei of the lymphoma cells. Despite the patient's resistance to multidrug
      therapy, complete remission was achieved using L-asparaginase. This case is
      unique because of its peculiar clinical course and a possible association with
      the Epstein-Barr virus. L-asparaginase may be an important treatment in other
      patients who exhibit some of these characteristics.

PMID- 10407585
TI  - Successful treatment of relapsed T-cell non-Hodgkin's lymphoma with allogeneic
      peripheral blood stem cell transplantation with double conditioning.
AB  - We report a patient with T-cell non-Hodgkin's lymphoma (NHL) who relapsed after
      treatment with relatively intensive third-generation chemotherapy, VACOP-B, and
      who was safely and effectively treated with allogeneic peripheral blood stem cell
      transplantation (allo PBSCT) with double conditioning. The first conditioning
      consisted of carboplatin and etoposide. Twenty-one days later, the second
      conditioning was performed with cytosine arabinoside, cyclophosphamide, and total
      body irradiation (AraC/Cy/TBI). Between the periods of the first and second
      conditioning, autologous (auto) PBSCT (4.4 x 10(5) colony-forming units
      granulocyte/macrophage (CFU-GM)/kg, 3.8 x 10(6) CD34+ cells/kg) was performed to
      rescue marrow aplasia after the first conditioning. After the second
      conditioning, allo PBSCT (2.1 x 10(5) CFU-GM/kg, 8.2 x 10(6) CD34+ cells/kg) was
      performed from a human leukocyte antigen-identical sibling. Marrow reconstitution
      after allo PBSCT was rapid. Grade I acute graft-vs.-host disease (GVHD) involving
      skin and chronic GVHD on the eye was observed. No severe transplantation-related
      complications occurred. With a follow-up of 22 months after allogeneic PBSCT, the
      patient is alive without evidence of the disease. This case shows that allo PBSCT
      with intensive double conditioning may become a new treatment strategy to achieve
      long-term disease-free survival for young NHL patients of resistant relapse with
      a great deal of tumor burden and invasion of lymphoma cells in bone marrow.

PMID- 10407586
TI  - Myelofibrosis following pelvic irradiation for cervical carcinoma.

PMID- 10407587
TI  - Therapy-related acute myeloid leukemia with t(10;11)(q23;p15) following
      successful chemotherapy for acute promyelocytic leukemia with t(15;17)(q22;q21)

PMID- 10407588
TI  - Successful induction therapy of natural killer/cytotoxic T-lymphocyte cells in
      the treatment of Langerhans' cell histiocytosis.

PMID- 10407589
TI  - Short-term effects of fluvastatin, a hydroxylmethylglutaryl-coenzyme A reductase
      inhibitor, on coagulation and the fibrinolytic system in patients with
      hypercholesterolemia.

PMID- 10407590
TI  - Assessing reproductive technology. A commentary.

PMID- 10407591
TI  - The U.K. Human Fertilisation and Embryology Authority. How it has contributed to
      the evaluation of assisted reproduction technology.
AB  - The Human Fertilisation and Embryology Act of the United Kingdom was passed in
      1990, leading to the formation of the Human Fertilisation and Embryology
      Authority (HFEA), the first statutory body to regulate and control assisted
      conception anywhere in the world. The principal function of the HFEA is to
      license and monitor clinics that carry out in vitro fertilization (IVF), donor
      insemination (DI), and embryo research. Information on over 135,000 treatment
      cycles, 20,000 pregnancies, and 25,000 babies following IVF has now been
      collected as part of the regulatory process, and these data have permitted
      unbiased and accurate evaluation of treatment efficacy using pregnancy and live
      birth rates. The treating clinics are required by law to provide information on
      the outcome of all births, including neonatal mortality and congenital
      malformations, but there is no systematic validation of these data using medical
      records or any follow-up of treated women, or babies, over time. In addition, the
      strict confidentiality of data supplied to the HFEA means that outside
      researchers have been unable to access the database for research projects. Thus,
      at the present time, it is not possible to evaluate the long-term safety of
      assisted conception procedures using HFEA data. There is reasonable scientific
      evidence to justify full investigation of the health of both treated women and
      resulting children. Particular health outcomes requiring evaluation include
      obstetric complications, preterm births, cerebral palsy, and cancer. The HFEA has
      recognized the need for follow-up studies and is currently investigating ways of
      enabling research projects using HFEA data to be undertaken.

PMID- 10407592
TI  - Surveillance of assisted reproductive technology in the United States. An update.
AB  - The Centers for Disease Control and Prevention published the first Assisted
      Reproductive Technology (ART) Pregnancy Success Rate Report in 1997. This article
      presents a description of the law that initiated the public report, a description
      of the surveillance system used to accumulate data for the report, and some of
      the results from ART cycles initiated in 1995.

PMID- 10407593
TI  - Coalition building and public opinion. New reproductive technologies and Canadian
      civil society.
AB  - The process of technology assessment is evolving. The process of policy
      development for technology is the least understood in the cycle of technology
      assessment. The process of policy development, which should involve extensive
      consultation and a broad-based research and evaluation program, is often fraught
      with difficulties and can cause further analysis or the assessment process to
      come grinding to a halt. This article reviews some social, political, and ethical
      issues and the role of civil society in influencing the technology assessment
      process for new reproductive technologies in Canada. It is written from the
      perspective of one of the Deputy Directors of Research and Evaluation for the
      Royal Commission on New Reproductive Technologies and highlights the strengths
      and difficulties of technology assessment when civil society and technology
      assessment come face to face. A brief update by a policy analyst in Health Canada
      on the current situation of legislation on new reproductive technologies has been
      provided and is included at the end of this article.

PMID- 10407594
TI  - Social and ethical aspects of in vitro fertilization.
AB  - In vitro fertilization (IVF) stands out as one of the contemporary period's most
      extraordinary technologies, and its social and ethical consequences among the
      most far reaching. Despite its uncertain effectiveness and medical consequences,
      IVF has contributed significantly to the medicalization of infertility and the
      increasingly imperative character of reproductive technology. New developments in
      IVF, particularly oocyte donation, have created new definitions of treatable
      infertility and new social needs for IVF; when the technology does not result in
      pregnancy or healthy babies, these developments have created profound new
      disappointments. IVF and the commodification of the extracorporeal embryo have
      also confused the social meaning and legal definition of parenthood. Ultimately
      the relationship between prospective parents, infertility specialists, and the
      embryos that they create is a highly ambiguous one. This ambiguity is likely to
      be a long-term characteristic of efforts to develop, use, and assess assisted
      reproductive technologies.

PMID- 10407595
TI  - Long-term effects on women of assisted reproduction.
AB  - The long-term health sequelae for women from assisted reproductive technology
      (ART) have not been studied extensively. There are a number of reasons that
      women's health may be compromised after ART procedures, including the
      consequences of the increased incidence of multiple births, operative deliveries,
      and preterm infants, the possible adverse effects of the drug regimens used for
      ovarian stimulation, and the instrumentation involved in ART procedures. In this
      paper we review the existing literature in these areas. It emphasizes the effects
      of the drugs used for ovarian stimulation, and in particular the incidence of
      cancer among women who have undergone ART. The review indicates that there is
      cause for concern about the long-term effects on women from ART treatments. It
      highlights the lack of research undertaken in almost all areas related to women's
      long-term health after ART. In the area of ART and cancer, it draws attention to
      the lack of conclusive evidence in relation to the posited association between
      fertility treatments and cancer, resulting from the limited number of very large
      studies and the need for longer follow-up periods. We make a number of
      recommendations regarding further research that is needed to address the current
      shortcomings in the published literature.

PMID- 10407596
TI  - Children after in vitro fertilization. An overview of the literature.
AB  - This paper provides an overview of the effects of in vitro fertilization (IVF) on
      the children born from it. One of the main problems with IVF to date remains the
      high incidence of multiple pregnancies, which carry an inherent higher risk of
      preterm delivery and, therefore, of increased morbidity and mortality in
      newborns. Further, singleton pregnancies and twin pregnancies from IVF compared
      to control singleton or twin pregnancies appear to be at higher risk of preterm
      birth and low birth weight. Whether this is an effect of the procedure per se or
      is related to maternal factors, or a combination of both, remains to be studied.
      The risk of congenital malformations does not, with the available data, seem to
      be elevated. As of now, it remains unclear whether embryo freezing is a safe
      procedure. Psychomotor development of children born through IVF does not seem to
      be disturbed. Until further and more extensive studies are conducted, it remains
      unclear whether IVF poses long-term risks for the children.

PMID- 10407597
TI  - The efficacy and adverse effects of in vitro fertilization and embryo transfer.
AB  - This paper examines the current status of in vitro fertilization and embryo
      transfer (IVF-ET) as a treatment for various types of infertility. We reviewed
      studies on the efficacy and safety of IVF-ET and intracytoplasmic sperm injection
      (ICSI) plus IVF-ET, compared with conventional treatment or no treatment for
      various infertility diagnoses. Material retrieved included English language
      publications between 1992 and January 1997 that reported the results of
      prospective controlled clinical trials, cohort studies, and retrospective
      comparative studies with large series, and reviews presenting risks,
      complications, and longer-term health consequences associated with IVF-ET and
      ICSI. No adequate prospective comparative studies of sufficient power on the use
      of IVF-ET for specific infertility diagnoses have been reported to date. Most of
      the published reports concerning results with IVF-ET as a treatment of
      infertility have been based upon small, uncontrolled studies, with various
      methodological weaknesses. Reported results are not directly comparable. There
      are few follow-up data on outcomes after pregnancy is established or on long-term
      health consequences of the use of IVF-ET on mothers and their babies. IVF-ET has
      diffused widely without comprehensive assessment of its efficacy and safety. The
      available evidence supports its use only for severe bilateral tubal occlusion.
      For other diagnoses of infertility the evidence is limited and does not establish
      whether IVF-ET is effective. Long-term, well-designed, prospective clinical
      trials are required to determine when and for what indications IVF-ET is
      effective and what its health effects are on both mothers and their babies.

PMID- 10407598
TI  - Can we measure the social importance of health care?
AB  - This paper examines the extent to which it is possible to measure the social
      importance, or macro benefits, of health care. In contrast to the many micro
      studies of the benefits of specific health care interventions, methodology
      relating to such macro benefits is at a very rudimentary stage. A theoretical
      model is presented that seeks to capture the social consequences of a health care
      system. In light of this model, three existing empirical approaches to answering
      the question are examined: the inventory approach, the avoidable mortality
      approach, and the production function approach. All three have severe limitations
      in terms of the underlying theoretical model, data availability, and analytic
      tools employed. A more fruitful approach may be to investigate the value of
      undertaking a direct survey of citizens' attitudes toward their health care
      system.

PMID- 10407600
TI  - Estimating the effect of cesarean section rate on health outcome. Evidence from
      Swedish hospital data.
AB  - This paper tests the null hypothesis of a zero effect of cesarean section rate on
      health outcome against the alternative of a positive effect. Using data from 59
      hospitals in Sweden from 1988-92, we specify two separate linear regression
      models for health outcome, one with perinatal mortality, and the other with rate
      of asphyxia, as dependent variable. We estimate the models by single-year cross
      section regressions and as pooled data systems. The null hypothesis cannot be
      rejected, i.e., we do not find any significant positive effect of cesarean
      section rate on health outcome. Thus, we conclude that an increase in cesarean
      section rate does not imply lower perinatal mortality or lower rate of asphyxia.
      This in turn indicates that the minimum cesarean section rate is optimal.

PMID- 10407599
TI  - Pamidronate for the prevention of skeletal-related events in multiple myeloma.
      What does the public think it is worth?
AB  - Multiple myeloma is a disorder of the bone marrow that is associated with bone
      pain and osteolytic lesions. These complications can lead to the development of
      pathologic fractures and severe patient morbidity. However, the results of a
      recent randomized trial in patients with multiple myeloma demonstrated that
      single 90 mg monthly doses of pamidronate as an adjunct to chemotherapy reduced
      the incidence of skeletal-related events and improved patients' quality of life.
      A cost-benefit analysis using an ex-ante insurance willingness-to-pay (WTP)
      approach was conducted from a Canadian societal perspective to estimate the net
      cost or benefit of prophylactic pamidronate therapy for patients with multiple
      myeloma. This included direct costs for drug administration and hospital savings
      secondary to avoiding skeletal-related events. One hundred Canadian taxpayers
      were then interviewed to ascertain their maximum WTP for the benefits of
      pamidronate. The WTP survey instrument was simple to administer and easily
      understood by participants. Respondents stated that they would be willing to pay
      an average of Can $3,364 (95% CI: $2,096, $4,632) as an income tax increase to be
      paid over their lifetime for the value offered by the product. The benefit was
      then subtracted from the overall cost of nine monthly doses of pamidronate
      ($4,153) producing a net societal cost of $789 per patient (95% CI: (-$479,
      $2,057). The administration of monthly pamidronate therapy in multiple myeloma
      patients produces a situation of cost neutrality (societal benefits = costs).
      Additional clinical trials to identify high-risk patient subgroups that would
      most benefit from the drug are needed.

PMID- 10407601
TI  - Gender differences in the treatment of patients with acute myocardial ischemia
      and infarction in England.
AB  - We conducted a retrospective cohort study based on a case note review to
      determine whether there are differences in the treatment pathways followed for
      men and women admitted with acute myocardial ischemia and infarction after
      adjusting for differences in case mix. Women were as likely as men to receive
      thrombolysis, but were less likely subsequently to undergo exercise testing
      (adjusted odds ratio, 0.58; 95% CI, 0.40-0.84) or angiography (adjusted odds
      ratio, 0.62; 95% CI, 0.39-0.99). Coronary anatomy was the strongest predictor of
      revascularization regardless of sex. Women with diagnosed cardiac pain are less
      likely than men to be placed on the investigative pathways that lead to
      revascularization. Those women who are investigated are as likely as men to
      undergo revascularization. These findings are independent of the effects of age,
      angina grade, comorbidity, or cardiac risk factors. Clinicians' and patients'
      beliefs and preferences about treatment require investigation.

PMID- 10407602
TI  - The valuation of informal care in economic appraisal. A consideration of
      individual choice and societal costs of time.
AB  - This article discusses the individual's choice to engage in informal care as an
      issue for economic evaluation. Traditional methods used in economic evaluation
      studies for valuing time spent on informal care are discussed and an alternative
      method is put forward that incorporates the quality of life of caregivers as an
      outcome measure to represent the effects on caregivers. The methodological issues
      concerning the valuation of informal caregivers' time are becoming more important
      as new drugs and other health care technologies are introduced for patients with
      diseases that are typically associated with informal care.

PMID- 10407603
TI  - Optimization of peripheral blood stem cell collection by leukopheresis.
      Interaction between economic and clinical assessment of an innovation.
AB  - Using the example of substitution of peripheral blood stem cell (PBSC) collection
      to bone marrow harvest for autologous transplantation in cancer patients, our
      study attempts to illustrate how economic assessment, starting at an early stage
      of medical innovation, can influence the development and diffusion process of a
      new technological procedure whose optimal design has not yet been established.
      Two cost minimization studies comparing costs for obtaining a clinically
      reinfusable graft using bone marrow harvest or alternatively various protocols of
      PBSC collection contributed to a change in the French clinical standard for this
      procedure.

PMID- 10407604
TI  - The DiSC assay. A cost-effective guide to treatment for chronic lymphocytic
      leukemia?
AB  - The differential staining cytotoxicity (DiSC) assay involves in vitro drug panel
      testing against patient tumor cells to identify optimal therapy. This
      observational study investigated whether DiSC assay guided treatment could
      improve outcome in patients with chronic lymphocytic leukemia. A cohort of 178
      patients were categorized either as sensitive to drugs in vitro and receiving a
      sensitive drug in vivo, sensitive in vitro but not treated with a sensitive drug,
      or having disease resistant to all drugs tested in vitro. Response and survival
      for these patient categories were compared using multivariate regression
      techniques. Patients receiving a sensitive drug, compared with those who though
      having sensitivity did not, had a higher remission rate (odds ratio, 6.5; 95% CI,
      2.91-14.53) and reduced death rate (hazard ratio, 0.29; 95% CI, 0.16-0.53).
      Having adjusted for all known confounding factors, the results suggest that in
      vitro drug sensitivity is an important independent prognostic variable to include
      in future trials, and that the DiSC assay may be a cost-effective use of health
      resources: the estimated incremental cost-effectiveness was 1,470 Pounds per life
      year gained. A randomized controlled trial is required to confirm the benefit and
      estimate reliably the potential impact of assay-guided choice of therapy.

PMID- 10407605
TI  - A European version of the Appropriateness Evaluation Protocol. Goals and
      presentation. The BIOMED I Group on Appropriateness of Hospital Use.
AB  - This paper describes the development and testing of a European version of the
      Appropriateness Evaluation Protocol (AEP). It stemmed from the original U.S.
      version and the multiple adaptations and modifications made previously and
      separately by researchers in European countries. The group was particularly
      concerned with developing a common list of reasons for inappropriate admissions
      and days of stay, since the principal goal was to enable an understanding of
      inappropriate hospital use and potential solutions within local health and social
      care systems. Developing a common EU-AEP included several steps. First, each
      national instrument was translated from the national language to English. These
      back translations were compared with each other and with the US-AEP. A working
      group analyzed the content of the lists of reasons published in the literature
      and proposed a novel conceptual approach. On the basis of workshop discussions, a
      draft of a common European version was circulated to each participant for
      agreement. In the EU-AEP, the clinical criteria for the appropriateness of
      admission include 10 related to patient condition and five to clinical services.
      The criteria for the appropriateness of days of care include 10 covering medical
      services, six for life support/nursing services, and eight related to patient
      condition. The proposed core list of reasons of inappropriateness distinguish
      clearly between two concepts: a) the level of care required by the patient; and
      b) the reason why this level of care was not used. The first list would thus
      refer to the nature of resources and facilities required, while the second would
      focus more on the efficient organization of those resources. A validated European
      tool to assess inappropriate hospital admissions and hospital days of stay and
      their causes might be used to assess the need for resources for inpatient care as
      well as for outpatient care. Assessing the reasons for inadequacies might lead
      also to the examination of organizational questions. Finally, a common tool
      allows comparisons between countries concerning the frequency of inappropriate
      admissions and days of stay and their reasons in relation to the different
      organizations of health care across Europe.

PMID- 10407606
TI  - Continuous computer simulation analysis of the cost-effectiveness of screening
      and treating diabetic retinopathy.
AB  - This paper analyzes the cost-effectiveness of screening and treating diabetic
      retinopathy (DR) by simulating the disease progress continuously with existing
      data. A new computer simulation based on Monte Carlo techniques and logistic
      transformation follows cohorts from diabetes onset until death in five care
      scenarios. For younger-onset patients, ophthalmic care reduces the prevalence of
      blindness by 52% or greater while savings in disability facilities and production
      losses surpass direct costs. For older-onset patients, less favorable results
      appear. Financial benefits surpass costs for juvenile-onset patients. For other
      patients, the net costs of ophthalmic care seem lower than in other health care
      programs.

PMID- 10407607
TI  - Modeling cost of treatment with new topical treatments for glaucoma. Results from
      France and the United Kingdom.
AB  - Several new topical agents have been introduced recently and it can be expected
      that the treatment of glaucoma will change, depending on how effectively these
      agents control intraocular pressure (IOP). IOP is considered the major risk
      factor in the development of glaucomatous damage. In order to estimate the impact
      of these new agents on the cost of treating glaucoma, a simulation model was
      created to estimate the cost of treating patients with a recent diagnosis of
      primary open-angle glaucoma or ocular hypertension in different countries. The
      Markov model is based on retrospective chart reviews in different countries and
      calculates only cost, not outcome. Results are presented for France and the
      United Kingdom, where current treatment appeared to be comparable. Average one
      year costs per patient with current treatment were FF2,389 (US $389) and 380
      pounds (US $627), respectively. Costs with the new treatments were lower than
      with current therapy.

PMID- 10407608
TI  - Telemedicine. What happens in remote consultation.
AB  - The results of a field study of three sites that used video to link primary care
      medical centers to hospitals are reported. The analysis was concerned with
      identifying the people involved, the tasks carried out in collaboration at each
      end of the link, and how the different communications facilities helped or
      hindered. The results are summarized as six task characteristics and their design
      implications for this model of telemedical consultation are discussed.

PMID- 10407609
TI  - A short history of INAHTA. International Network of Agencies for Health
      Technology Assessment.
AB  - The need for better communication and collaboration between health technology
      assessment agencies led to the formation of an International Network of Agencies
      for Health Technology Assessment (INAHTA). The network now comprises 27 agencies
      and has been successful in improving exchange of information and in undertaking
      joint health technology assessment projects. Issues for the future include
      possible changes to criteria for membership and identification of resources for
      more extensive programs.

PMID- 10407610
TI  - Using appropriate comparisons in economic evaluations. An exercise in Belgium.
AB  - This paper considers standard effective treatments for non-Hodgkin's lymphoma and
      early breast cancer in premenopausal women. The literature assesses the
      treatments' effectiveness, and expected charges for different treatments in the
      context of the Belgian Health Insurance System are compared. Ovariectomy in
      breast cancer (770 ECU) and conventional chemotherapy in non-Hodgkin (2,745
      lymphoma ECU) prove equally effective and are less costly in comparison with
      chemotherapy (1,904 ECU) in breast cancer or chemotherapy and autologous bone
      marrow transplantation (19,262 ECU) in non-Hodgkin's lymphoma. Further unbiased
      insights in competitive treatments' costs and outcome could save money and
      enhance developments in cancer care.

PMID- 10407611
TI  - Technology evolution: the technology spectrum and its application to orthopedic
      technologies.
AB  - The evolution of clinical technologies presents potential adopters with
      considerations in planning for clinical program development that include the
      stage and the rate of a technology's evolution. This paper presents a conceptual
      framework for these considerations and applies the framework to orthopedic
      technologies. Eight orthopedic surgeons were asked to assess 14 orthopedic
      technologies and position each of them along a spectrum of research, clinical,
      and adopted technologies. The distribution of responses for each technology-year
      combination is presented, and estimates of central tendency, dispersion, and
      variances provide measures of the change in the distribution of responses over
      time for each technology and the change in the degree of rater consensus over
      time for each technology. While orthopedic trauma was chosen to illustrate the
      technology spectrum model, the model and assessment methodology is applicable to
      other medical specialties as well. Adoption of this framework in a hospital
      setting should enable more systematic and effective clinical program development.

PMID- 10407612
TI  - Report from the Alberta Heritage Foundation for Medical Research.

PMID- 10407613
TI  - Report from the Catalan Agency for Health Technology Assessment (CAHTA).

PMID- 10407615
TI  - Report from the Department of Epidemiology, Social Medicine, and Health System
      Research, Medizinische Hochschule Hannover, Germany.

PMID- 10407614
TI  - Reports from the University HealthSystem Consortium.

PMID- 10407616
TI  - Physicians as Good Samaritans. Should they receive immunity for their negligence
      when responding to hospital emergencies?

PMID- 10407618
TI  - Contaminated polio vaccines. Will the next shot be fired in the courtroom?

PMID- 10407617
TI  - Clinical trial results, physicians, and insider trading.

PMID- 10407619
TI  - Medicaid eligibility rules for the elderly long-term care applicant. History and
      developments, 1965-1998.

PMID- 10407620
TI  - Infectivity, distribution, and persistence of the entomopathogenic nematode
      Steinernema carpocapsae all strain (Rhabditida: Steinernematidae) applied by
      sprinklers or boom sprayer to dry-pick cranberries.
AB  - We evaluated infectivity, distribution, and persistence of commercially produced
      Steinernema carpocapsae (Weiser) All strain applied through solid set sprinkler
      irrigation or boom sprayer to 2 dry-pick cranberry farms on peat soil in British
      Columbia in 1993. Most infectivity assays used Galleria mellonella (L.) larvae.
      When possible, larvae of the target pest, Otiorynchus sulcatas (F.) were used as
      assay organisms. Nematodes in almost all samples of nematode suspensions diluted
      from shipping containers, from spray tanks, or collected in cups after passage
      through application equipment were infective to G. mellonella larvae. When O.
      sulcatus larvae were used as assay organisms, 93% (n = 14) of assays from the
      spray tank and 67% (n = 12) of assays after application showed infectivity. In
      the spring, sprinklers delivered nematodes to only 15 of 20 sample points on the
      0.2-ha plot; delivery by the boom sprayer was better but 2 of 20 points on the
      0.2-ha plot received approximately twice as many nematodes as the other points.
      In the fall, nematode delivery by both systems was more even. However, the
      average number of nematodes per milliliter of sprayed water collected from the 20
      samples on each farm after each application did not correspond to the rates of
      nematodes applied. Persistence of nematodes in the soil was encouraging, but
      percentage of infectivity was lower than expected. After application in the
      spring, assays using G. mellonella larvae showed the presence of infective
      nematodes in soil samples (0-5 and 5-10 cm deep) on each sampling day (0, 3, 7,
      and 25) after application by boom sprayer, and on days 0, 3, and 7 after
      application through sprinklers. In the fall, G. mellonella assays showed
      infective nematodes in soil samples on each sampling day (0, 3, 7, and 25) after
      application by boom sprayer, and on days 0, 3, 7, 35, 60, 135, and 250 after
      application through sprinklers. In the spring, when assays lasted 4 d, percentage
      of infectivity rose to a maximum of 45% on the 3rd d after application by boom
      sprayer and declined thereafter. In the fall, when assays lasted 10 d, percentage
      of infectivity rose to a maximum of 58% on the 7th d after application through
      sprinklers and remained between 20 and 58% until day 135, declining thereafter;
      infectivity after boom application remained between 37 and 45% on days 3 and 7,
      and began to decline on day 25. Nematode infectivity was not compromised in peat
      soil, muck, or silty clay loam, but infectivity in loam (that may have contained
      nematicide residues) was very low. We suggest that the inconsistent control of O.
      sulcatus by S. carpocapsae on British Columbia cranberry farms may be partially
      explained by problems associated with application and factors related to nematode
      entry into the soil.

PMID- 10407621
TI  - Entomopathogenic nematodes to control black vine weevil (Coleoptera:
      Curculionidae) on strawberry.
AB  - We investigated the potential of heterorhabditid nematodes to control larvae of
      the black vine weevil, Otiorhynchus sulcatus (F.), in 2 field experiments in
      commercial strawberry plantings. In both experiments, nematodes were applied
      directly onto the straw mulch, or onto the soil after temporary removal of the
      mulch. Heterorhabditis marelatus Lui & Berry (Rhabditida: Heterorhabditidae)
      reduced numbers of weevil larvae and the percentage of plants infested in both
      experiments, irrespective of straw removal. In the 1st field experiment, a sponge
      packed H. marelatus formulation produced lower numbers of O. sulcatus larvae per
      strawberry plant (mean O. sulcatus larvae per plant = 0.7) and proportion of
      infested plants (42%) compared with a vermiculite formulation (mean O. sulcatus
      larvae per plant = 1.8, proportion infested plants 67%) and an untreated control
      (mean O. sulcatus larvae per plant = 1.9, proportion infested plants 75%). In the
      first 2 wk after application, more H. marelatus were found in soil samples
      collected from plots treated with sponge-packed nematodes, than from plots
      treated with vermiculite-formulated nematodes. In the 2nd field experiment,
      sponge-packed formulations of H. bacteriophora Poinar (Rhabditida:
      Heterorhabditidae) and H. marelatus were tested. H. marelatus caused a reduction
      in both numbers of weevil larvae (mean O. sulcatus larvae per plant = 0.1) and
      proportion of infested plants (9%) but H. bacteriophora did not (mean O. sulcatus
      larvae per plant = 0.45, proportion infested plants 34%). More H. bacteriophora
      were recovered from soil samples than H. marelatus during the first 7 d of this
      experiment. However, laboratory studies revealed no difference in the persistence
      of these 2 nematodes in sand.

PMID- 10407622
TI  - Role of S-100 staining in differentiating leprosy from other granulomatous
      diseases of the skin.
AB  - Since Mycobacterium leprae are rarely demonstrable in the tuberculoid spectrum of
      leprosy, a confirmatory diagnosis of leprosy can be made on the basis of finding
      active destruction of cutaneous nerves by granulomatous inflammation in a skin
      biopsy. Immunoperoxidase staining for S-100 protein, which is a marker for
      Schwann cells, was used to delineate nerves in lesional skin biopsies of 25
      patients with tuberculoid and borderline tuberculoid leprosy as well as 15
      controls with nonleprous granulomatous inflammation. Four different patterns of
      nerve damage were observed: infiltrated, fragmented, absent, and intact. All of
      the nonleprous granulomatous dermatoses showed only intact nerves, either inside
      or outside the granuloma, and so S-100 staining can be used to rule out leprosy.

PMID- 10407623
TI  - Pregnancy and leprosy: a comprehensive literature review.
AB  - The interaction between pregnancy, leprosy and leprosy reactions was examined in
      a systematic literature review. Several retrospective case series and one
      retrospective cohort study but only one prospective cohort study were identified
      in the English literature. Type 1 (reversal) reactions were particularly likely
      to occur during the post partum. This temporal association was also present for
      both overt and silent neuritis. Type 2 (erythema nodosum leprosum) reactions
      occur throughout pregnancy and during lactation, and may be severe and recurrent.
      No prospective, controlled studies were found that documented the complications
      of pregnancy in women treated with multidrug therapy regimens. Our study
      highlights the need for such studies, with appropriate controls, on women
      throughout pregnancy and lactation so that risk factors for reaction and neuritis
      during pregnancy can be identified and quantified.

PMID- 10407624
TI  - Cluster of leprosy cases in Kona, Hawaii; impact of the Compact of Free
      Association.
AB  - International travel and migration will continue to contribute to the changing
      patterns of Hansen's disease (HD) in the United States. The majority of cases
      will be immigrants and refugees entering the country from leprosy-endemic
      regions. The Compact of Free Association, through its provision of free travel
      between the Freely Associated States and the United States without need for
      health screening, has created new public health issues. This cluster of HD cases
      in Kona, Hawaii, U.S.A., highlights the difficulties in detecting and monitoring
      the spread of disease in immigrant populations. This is a growing problem only
      likely to worsen in the coming years. In groups with cultural, language or other
      socioeconomic barriers, special and creative methods may be needed to tackle the
      problems of detection, treatment and education. Clinicians must remain mindful of
      the diagnosis of HD in high-risk groups.

PMID- 10407625
TI  - Serum markers of treatment success in leprosy.
AB  - Intercellular adhesion molecule-1 (ICAM-1) and E-selectin and other variables
      were evaluated as possible markers of the success of multidrug therapy (MDT) in
      leprosy. Multibacillary (MB, N = 45) and paucibacillary (PB, N = 29) leprosy
      patients were examined during MDT, which typically lasted 12 months for MB and 6
      months for PB patients. Serum values for total protein, albumin, immunoglobulin
      gamma (IgG), ICAM-1, and E-selectin (selectin) were recorded, as were lesion
      type, number, and distribution. Response at the end of therapy was assessed as
      good, fair, or poor. The bacterial index (BI) of lesions was measured at the
      beginning and end of therapy. The earlier reported findings of this investigation
      are herein re-examined. RESULTS: age and lowered serum albumin correlated with
      the poorer condition of the patients, as did elevated selectin. Albumin was
      inversely correlated with the BI (p = 0.008) in MB patients, and IgG was
      positively correlated (p = 0.009). ICAM and E-selectin alone were not useful
      markers of individual patient condition. A regression combining serum albumin
      under 41 g/l, age and E-selectin was able to identify 85% of the patients in
      poorer condition. CONCLUSION: serum albumin was a useful nonspecific marker of
      both patient condition and infection. Age is an important negative factor in
      patient response. Albumin and IgG correlate with the BI and with each other (p =
      0.011) in MB patients, but not in PB patients.

PMID- 10407626
TI  - Dermal extracellular matrix in cutaneous leprosy lesions.
AB  - Thirty-eight biopsies of cutaneous lesions from leprosy patients [borderline
      tuberculoid (BT) 14, borderline lepromatous (BL) 18, lepromatous (LL) 6] were
      processed for staining of some extracellular matrix (ECM) components (collagen,
      proteoglycans, elastic fibers and fibronectin). Specific histological staining
      and the indirect immunofluorescence method with antibodies to collagen and
      fibronectin were utilized. The ECM of the normal dermis was strikingly modified
      in the inflammatory infiltrate. By Gomori's reticulin and anti-fibronectin
      immunostaining, replacement of the dense interlaced collagen fibers with a
      reticular mesh was observed in the infiltrate. The immunoreactivity obtained with
      anti-type I and anti-type III collagens showed positive fibrils and a lumpy
      pattern in the lepromatous and tuberculoid lesions with a higher amount in the
      lepromatous lesions. The lack of clear-cut boundaries between the normal dermis
      and the inflammatory infiltrate in the lepromatous (BL, LL) lesions was
      correlated with the blurred limits of the clinical lesions of this pole of the
      leprosy spectrum. Absence of elastic fibers in the infiltrate was a constant
      finding, and fuchsin-positive microfibrils were found in some infiltrates. The
      clear zone of lepromatous lesions was devoid of oxytalan fibers. Elaunin fiber
      rings around sweat gland acini were present even when the leprosy infiltrate was
      seen enveloping them. The original ECM is replaced by a newly assembled one,
      which is suited for the dynamic nature of the inflammatory process. The trophic
      effects of the ECM upon the cutaneous epithelial structures are modified so that
      atrophy and late degeneration ensues. These ECM modifications contribute,
      therefore, to the biological alterations of the skin functions in leprosy.

PMID- 10407627
TI  - Roles of tumor necrosis factor-alpha and transforming growth factor-beta in
      regulating intercellular adhesion molecule-1 expression on murine peritoneal
      macrophages infected with M. leprae.
AB  - Profiles of intercellular adhesion molecule-1 (ICAM-1) expression on murine
      peritoneal macrophages (M phi s) infected with Mycobacterium leprae during
      cultivation were examined with special reference to the regulatory effects of
      tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF
      beta). When M phi s were infected with M. leprae or stimulated with heat-killed
      M. leprae at day 0, their ICAM-1 expression, measured in terms of the ratio of M
      phi s positively stained with anti-ICAM-1 antibody (Ab), rapidly increased,
      peaking during days 1 to 3 and thereafter fell, returning to the normal level by
      day 7. The addition of TNF-alpha or anti-TGF-beta Ab inhibited the middle phase
      (day 7) downregulation of M phi ICAM-1 expression, although the late-phase (day
      14) downregulation of ICAM-1 was not prevented by them. M. leprae-infected M phi
      s released small amounts of TNF-alpha and significant amounts of TGF-beta into
      the culture medium. This may indicate that M. leprae-infected M phi s produced
      the majority of TNF-alpha in a membrane-bound form. Alternatively, endogenous TNF
      alpha might upregulate M phi ICAM-1 expression even at very low concentrations.
      In any case, these findings indicate the central roles of TNF-alpha and TGF-beta
      in the early phase upregulation and the middle-to-late phase downregulation,
      respectively, of ICAM-1 expression by M. leprae-infected M phi s.

PMID- 10407628
TI  - Susceptibility of "et," the spontaneously mutating CD1-derived nude mouse, to
      infection of M. lepraemurium.
AB  - We have studied the susceptibility to infection by Mycobacterium lepraemurium
      (MLM) of a nude, hypothymic, CD1-derived, spontaneous mouse mutant called "et"
      because of its extraterrestrial appearance. We found that despite their
      hypothymia, et/et mice were not more susceptible to infection by MLM than their
      euthymic et/+ counterparts. Infection of both et/et and et/+ mice with 50 x 10(6)
      bacilli by the intraperitoneal route led only to a mild infection with low levels
      of antimycobacterial antibodies and a small number of lesions. These lesions were
      indicative of reactive hepatitis and hyaline perisplenitis with lymphoid
      hyperplasia. Some small bacilliferous granulomas were also observed at the end of
      the experiment (5 months of infection). CD1 mice behave in a rather "resistant"
      manner to the infection by MLM. It is clear that the nu gene is not necessarily
      linked to the thymus defect, and it is also clear that the hypothymia of et/et
      mice does not obviously affect their general cell-mediated immune competence.

PMID- 10407629
TI  - Complete DNA sequence analysis for 16S ribosomal RNA gene of the leproma-derived,
      cultivable and nerve-invading mycobacterium HI-75.
AB  - The complete 1493 nucleotide sequence of the 16SrRNA gene of the leproma-derived
      and cultivable mycobacterium HI-75 strain was analyzed to elucidate the taxonomic
      characteristics by direct sequencing of the polymerase chain reaction (PCR)
      products. The results revealed that the sequence of mycobacterium HI-75 was
      mostly similar to that of Mycobacterium scrofulaceum with 5 bases differences in
      the sequenced 1493 bases (0.35%) of the 16SrRNA gene. M. leprae differed from the
      strain with 47 bases (3.3%). Sasaki and Hamit reported the nerve-invasive
      activity of the inoculated mycobacterium HI-75 in nude mice or the 131I-treated
      immunocompromised Swiss mice. The results indicate that mycobacterium HI-75 could
      be a mutant of M. scrofulaceum possessing the ability to invade the peripheral
      nerve in addition to developing leproma-like lesions.

PMID- 10407630
TI  - Leprosy elimination--urgent action required.

PMID- 10407631
TI  - Hypersensitivity reaction over lesions of post-kala-azar dermal leishmaniasis
      mimicking type 1 reaction in leprosy.

PMID- 10407632
TI  - A lost talisman: catastrophic decline in yields of leprosy bacilli from
      armadillos used for vaccine production.

PMID- 10407633
TI  - Effect of zafirlukast on leprosy reactions.

PMID- 10407634
TI  - Effect of prophylactic corticosteroids on the incidence of reactions in newly
      diagnosed multibacillary leprosy patients.

PMID- 10407635
TI  - On not being enough and the therapist's ego ideal.

PMID- 10407636
TI  - Consultation from the position of the third.

PMID- 10407637
TI  - Psychosis as the sickness unto death: treatment impasse, consultation, and
      resolution.

PMID- 10407638
TI  - Psychotherapy consultation: taking the transference.

PMID- 10407639
TI  - The pose of knowing and the ambivalence of being known.

PMID- 10407640
TI  - Karen Horney's vision of the self.

PMID- 10407641
TI  - A brief note on Ingram's (1997) concept of interiorization.

PMID- 10407642
TI  - The real self and psychic interiority: a response to Drs. Paris, Horner, and
      Spero.

PMID- 10407644
TI  - Sexual satisfaction in male infertility.
AB  - Infertility is proposed to be a continuing stressor for couples suffering from
      involuntary childlessness. A long duration of the desire for a child and,
      correspondingly, a longer period of diagnostic and treatment procedures could
      have a negative impact on sexual satisfaction, thus leading to an unfavorable
      psychological circuit. The present evaluation should clarify the state of sexual
      satisfaction and relationships, with relevant parameters in 68 men with fertility
      problems, of couples with involuntary childlessness. Subjects reported relatively
      high average levels of present sexual satisfaction with only nonsignificant lower
      scores (p = .08) compared to recalled sexual satisfaction prior to diagnosis of
      infertility. Multiple regression analyses revealed that a positive age difference
      between men and their spouses (p = .042) and a higher weekly coitus frequency (p
      = .002) were the only significant parameters associated independently with higher
      sexual satisfaction. Neither the age of partners, attitudes toward sexuality,
      treatment duration, duration of the partnership and the duration of the desire
      for a child, nor andrological findings had an influence on present sexual
      satisfaction. The results propose that treatment duration and duration of the
      desire for a child may not necessarily be connected to lowered sexual
      satisfaction in infertile males and that coitus frequency seems to be an
      indicator of sexual satisfaction in this patient group.

PMID- 10407643
TI  - Eliciting an immune response by plasmid DNA encoding a human sperm protein (HSD
      1).
AB  - The cDNA encoding a human sperm membrane designated as HSD-1 was isolated from a
      human testis lambda gt11 cDNA expression library and assigned the accession
      number U12978 by GenBank. HSD-1 was conjugated to an eukaryotic expression
      plasmid (pRSV) to construct the recombinant plasmid pRSV-HSD-1. Female mice were
      inoculated intramuscularly with the plasmid DNA and the expression of HSD-1 was
      determined. HSD-1 mRNAs were detected in myocytes and endomysial connective
      tissue cells of the quadriceps muscle by in situ hybridization. Spleen of
      inoculated animals contained an increased number of cytotoxic T lymphocytes,
      phagocytes, and plasma cells. Fertility of the treated animals was not affected.
      Thus, intramuscular inoculation of female mice with the plasmid DNA (pRSV-HSD-1)
      results in the expression of HSD-1 and may elicit a tissue-mediated immune
      response.

PMID- 10407645
TI  - Relationship between hormone levels and testicular biopsies of azoospermic men.
AB  - This study was conducted to evaluate the testicular biopsies and the sera levels
      of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2),
      testosterone (T), and prolactin (PRL) in 96 azoospermic men attending the
      Andrology Clinic. Plasma levels of FSH were the most common hormone abnormality
      in the evaluation of azoospermia. Plasma levels of LH and T were useful only in
      azoospermic men with hypogonadism, whereas plasma PRL levels rarely occurred in
      azoospermia.

PMID- 10407646
TI  - Spontaneous occurrence of vasculitis-like lesions in male reproductive tissues in
      mice: a histological study.
AB  - Vasculitis involving testes, epididymides, and vasa deferentia is considered to
      be a rare disease but has often been reported in man. In the present study,
      reproductive tissues of young and aged mice were examined to determine whether
      spontaneous vasculitis occurs in them. Testes, ductuli efferentes, epididymides,
      and vasa deferentia were obtained from young and aged BALB/c mice together with
      some nonreproductive organs for histological observation at the light microscopic
      level. The examination revealed that vasculitis-like lesions comparable to those
      in man were significantly present in the epididymides and vasa deferentia of aged
      but not young mice. However, no significant lesions were found in the testes and
      ductuli efferentes. Furthermore, other organs, such as salivary glands, thyroid
      glands, livers, pancreases, and kidneys, were also negative for the lesions.
      These results indicate that the epididymis and vas deferens are spontaneously apt
      to be affected by vasculitis-like lesions with advancing age, but that the
      lesions are not due to a systemic vasculitis disease.

PMID- 10407647
TI  - Quantitative ultramorphological (QUM) analysis of human sperm: diagnosis and
      management of male infertility.
AB  - The advantages of quantitative ultramorphological (QUM) sperm analysis in the
      diagnosis and treatment of male infertility are presented. QUM methodology is
      based on three elements: (1) complementary SEM and TEM observations of 7 sperm
      cell subcellular organelles: acrosome, postacrosomal lamina, nucleus, neck,
      axoneme, mitochondrial sheath, and outer dense fibers; (2) systematic
      classification of the specific ultramorphological malformations into 4
      pathological and the normal categories, which indicate the morphological state of
      each subcellular organelle; and (3) comparison between well-defined reference
      groups with opposite fertility status or treatment conditions. QUM analysis has
      enabled the establishment of two indices that optimally express the in vivo and
      in vitro male fertility potential: The Natural Fertility Index (NFI), which
      allowed an accurate prediction (97% sensitivity and 90% specificity) of 80% of
      the naturally fertile and suspected infertile male patients, and the in vitro
      fertilization (IVF) score, which enabled prediction of 76% of the nonfertilizing
      and 90% of the fertilizing IVF groups. Validation tests confirmed these data. QUM
      also enabled assessment of ultramorphological indications for varicocele and
      radiation exposure: Both male factor etiologies indicated a persistent effect on
      the natural fertility potential, as expressed by structural changes in the
      nucleus. Varicocele was found to cause defects in the sperm head organelles
      related to early spermatid development, whereas ionizing radiation resulted in
      amorphous head shape. Criteria for specific non-in vitro therapeutic
      interventions such as varicocelectomy, follicle-stimulating hormone (FSH)
      administration, and acupuncture treatment were established. A varicocele index,
      which enabled the correct classification of 79 and 89% of the patients pre- and
      post-high ligation, respectively, was suggested to be a good indicator for
      varicocele which affects the fertility potential. Males exhibiting idiopathic
      impairment of sperm acrosome and nucleus were found to be potential responders to
      FSH treatment, whereas patients exhibiting low sperm activity proved to be good
      candidates for acupuncture treatment. Indications for selecting the optimal
      appropriate assisted reproduction technique (ART) procedure were found: Patients
      with a low Natural Fertility Index should be recommended for ART. A first choice
      ART selection should be performed according to an ART index based on the
      ultramorphological examination of the tail axoneme. The above index enabled
      correct prediction of 78% of the patients who achieved pregnancy following
      conventional ART (intrauterine insemination or IVF) and 74% of those whose wives
      conceived only following intracytoplasmic sperm injection. QUM sperm analysis is
      clinically informative, nontraumatic, and in the long run also cost-effective.
      This analysis should be performed when the male infertility factor cannot be
      clearly diagnosed by routine tests and prior to the first ART trial.

PMID- 10407648
TI  - Deletion of Y chromosome involving the DAZ (deleted in azoospermia) gene in XX
      males.
AB  - The testicular histology and the presence or absence of 32 Y DNA loci was
      investigated, with a focus on the long arm of Y chromosome (Yq) interval 6, by
      means of a polymerase chain reaction strategy in 2 XX males. Seminiferous tubules
      lined by only Sertoli cells and a slight thickening of tubular walls were
      observed. The men showed an absence of 32 Y DNA loci. These facts suggest that
      severe spermatogenic impairment is caused by deletions of Yq interval 6 in XX
      males.

PMID- 10407649
TI  - Influence of progesterone and GABAA receptor on calcium mobilization during human
      sperm acrosome reaction.
AB  - At fertilization, mammalian sperm has to undergo morphological changes of
      acrosome, namely acrosome reaction (AR), during which a dramatic increase of
      cytosolic calcium in consequence of extracellular calcium influx induces
      acrosomal exocytosis. It has been reported that progesterone is capable of
      inducing mammalian sperm AR. Several authors insisted that the agent, which was
      so far understood to bind with intracellular receptor, might act as an agonist
      against cell surface r-aminobutyric acid with type A (GABAA) receptor. The mode
      of action is, however, still in controversy. To investigate whether progesterone
      induced AR is mediated by GABAA receptor, the present study examined
      pharmacologically the actions of progesterone on the morphological changes of
      acrosome and calcium mobilization during human sperm AR. Progesterone (15 microM)
      stimulated AR and increased cytosolic calcium, and the AR rate was further
      promoted by the coexistence of GABA (15 microM). Then these phenomena were
      suppressed by an antagonist of GABAA receptor (bicuculline, 10 microM), a blocker
      of GABAA receptor-coupled chloride channel (picrotoxin, 200 microM) and an
      antagonist of receptor-operated calcium channel (Lantan, 250 microM),
      respectively. These results indicated that the complex work of GABAA receptor
      chloride channel and receptor operated calcium channel might participate in
      progesterone-induced AR and the transient increase of cytosolic calcium.

PMID- 10407650
TI  - Prostate-specific antigen (PSA) in human seminal plasma.
AB  - Prostate-specific antigen (PSA) was measured in seminal plasma and serum of 113
      men under investigation for involuntary barrenness. PSA in seminal plasma was 0.4
      +/- 0.3 (median 0.35) mg/mL and in serum 0.6 +/- 0.5 (median 0.6) ng/mL. The
      concentrations in these 2 compartments were independent of each other. The
      determination of PSA in neither blood serum nor seminal plasma brought new
      essentials for fertility status.

PMID- 10407651
TI  - Maturation-related changes in distribution of lectin receptors in baboon (Papio
      anubis) spermatozoa during epididymal maturation.
AB  - Changes in distribution of surface glycoproteins in baboon sperm were studied by
      lectin blotting techniques. In baboon, several changes in sperm surface occur
      during epididymal passage. These changes include increased staining of band that
      was observed with the WGA binding glycoproteins of 140, 80, 52, and 46 kDa; Con A
      bands of 66, 37, and 26 kDa; and the PNA binding glycoprotein of 114 kDa. A
      second change was the loss of preexisting band that was observed with RCA binding
      glycoproteins of 120, 80, 58, 53, 46, and 37 kDa; and the Con A band of 80 kDa. A
      final change was noted with Con A binding in which six bands of 8, 9, 12, 14, 18,
      and 21 kDa were added as the sperm matured through the cauda epididymis. These
      findings present new information on the changes in distribution of surface
      glycoproteins in baboon sperm during epididymal passage. There was some
      reorganization of the molecular structure of the sperm during epididymal
      maturation.

PMID- 10407653
TI  - Complex protein assemblies as molecular machines. 668th Meeting. Glasgow, United
      Kingdom. Abstracts.

PMID- 10407654
TI  - Heteroduplex cleavage analysis using S1 nuclease.

PMID- 10407652
TI  - Cyclophosphamide modulates gene expression in neonatal rat testis following
      antenatal exposure to fetuses during testicular differentiation.
AB  - The present study was designed to evaluate the altered gene expression in
      neonatal rat testis after antenatal exposure of cyclophosphamide (one time single
      dose of either 2, 10, or 20 mg/kg body weight) to the developing fetuses,
      especially at the time of male sex differentiation. The rationale behind these
      experiments is to know about the involvement of Y-chromosome gene-dependent
      product(s) associated with gonadal dysfunction. Using SDS-polyacrylamide gel
      electrophoresis and photosensitive silver staining technique, the study shows
      that the variety of proteins of different molecular weight ranges 40,000 to
      127,000 Da are modulated by cyclophosphamide exposure to the developing testis.
      Interestingly, the overexpression of one protein of 74,500 Da was observed both
      in supernatant as well as in pallet fractions. The qualitative and quantitative
      regulation of newly synthesized protein appearance or disappearance is observed
      in a dose-dependent manner.

PMID- 10407655
TI  - Improvement of SSCP analysis by use of denaturants.

PMID- 10407656
TI  - Subcellular fractionation of group B Streptococcus.

PMID- 10407657
TI  - Use of GFP as a reporter for the facile analysis of sequence-specific proteases.

PMID- 10407658
TI  - Cost-effective staining of DNA with SYBR green in preparative agarose gel
      electrophoresis.

PMID- 10407659
TI  - Prevention of anomalous band mobility in A + G sequencing ladders of 3'-end
      labeled DNA.

PMID- 10407660
TI  - System for PCR identification of cDNA ends (SPICE).

PMID- 10407661
TI  - Transfer RNA reduces the formation of primer artifacts during quantitative PCR.

PMID- 10407662
TI  - New series of Drosophila expression vectors suitable for behavioral rescue.

PMID- 10407663
TI  - S. pombe expression vector with 6x(His) tag for protein purification and
      potential for ligation-independent cloning.

PMID- 10407664
TI  - Black cellular spreading and motility assay.

PMID- 10407665
TI  - Alternative procedure for two-dimensional separation of phosphoamino acids.

PMID- 10407666
TI  - Rapid DNA extraction from ferns for PCR-based analyses.

PMID- 10407667
TI  - Rapid, economical filter alternative to chromosomal DNA centrifugation in the
      alkaline lysis plasmid protocol.

PMID- 10407668
TI  - Large-scale preparation of sequence-ready bacterial artificial chromosome DNA
      using QIAGEN columns.

PMID- 10407669
TI  - Biological sequence analysis using regular expressions.

PMID- 10407670
TI  - Application of the green fluorescent protein as a reporter for Ace1-based, two
      hybrid studies.
AB  - The two-hybrid system in Saccharomyces cerevisiae is a genetic approach for the
      detection of of protein-protein interactions in vivo. This technology relies on
      the the activity of separated DNA-binding and transactivation domains of specific
      transcription factors to reconstitute an active transcription factor complex if
      interacting proteins are fused to these domains. Interactions are consequently
      detected through the activity of reporter genes. The two-hybrid technology has
      been successfully applied for the determination of interactions between numerous
      proteins of several organisms. Conventional reporter systems, such as the beta
      galacatosidase from Escherichia coli, suffer from a variety of drawbacks,
      including the requirement for external substrates. In this report, we describe an
      alternative version of the two hybrid system using the combined advantages of the
      copper-inducible transcription factor Acel together with the yeast
      metallothionein gene CUP1 and the green fluorescence protein from aquatic
      invertebrates as reporters. This technique allows the copper-dependent monitoring
      of protein-protein interactions in living yeast cells.

PMID- 10407671
TI  - Generation of vector-insensitive dig-labeled probes from large cosmid library
      inserts using PCR.
AB  - We have devised a general method for producing vector-insensitive probes from
      clones in which insert DNA (ca. 40 kb) could not be amplified in one piece nor be
      excised from the vector sequence. The method involves PCR and vector-specific
      primers in combination with restriction digestion and ligation. It yields
      specific PCR products that could subsequently be labeled using DIG-11-dUTP in a
      single-cycle PCR. In colony blot hybridization, the probes were specific for the
      insert DNA from which the probe was derived and, importantly, did not detect
      vector sequences.

PMID- 10407672
TI  - Eukaryotic conditional expression system.
AB  - Existing conditional expression systems can be classified in two major categories
      that are based either on the induction or on the de-repression of transcription.
      The system described here combines both mechanisms, since a unique transcription
      factor can be shifted from a repression to a stimulation activity by simply
      changing its ligand. The resulting advantage of this system is the complete
      absence of basal expression before active induction. The principle of this method
      is based on the unexpected ability of the chimeric protein containing the DNA
      binding domain of the yeast Gal4 transcription factor fused to the COOH half of
      the estradiol receptor (GalER), to act as a repressor when bound to the drug 4OH
      tamoxifen, in the context of a previously described optimized Gal4-responsive
      promoter. The efficacy of this system has been assessed in transient expression
      assays using the chloramphenicol acetyl transferase (CAT), and in situ, through
      the activity of a Gal4 responsive beta-galactosidase gene.

PMID- 10407674
TI  - Rapid quantitation of gene therapy specific CFTR expression using the
      amplification refractory mutation system.
AB  - Gene therapy offers the potential of correcting genetic disorders such as cystic
      fibrosis (CF). By complementing the non-functional endogenous cystic fibrosis
      transmembrane conductance regulator (CFTR) gene with a functional transgene, we
      anticipate it may alleviate the disease phenotype. All approaches to CF gene
      therapy rely upon sensitive assays to monitor delivery, expression and
      maintenance of CFTR vectors. Here, we describe the adaptation of the
      amplification refractory mutation system (ARMS) to discriminate between different
      forms of CFTR. A LightCycler PCR machine allows realtime continuous fluorescence
      monitoring of rapid-cycle PCR. We show quantitation of and discrimination between
      expression of endogenous (wild-type or mutant) CFTR and the introduced transgene.

PMID- 10407673
TI  - Purification of proteins fused to either the amino or carboxy terminus of the
      Mycobacterium xenopi gyrase A intein.
AB  - The Mycobacterium xenopi gyrase A mini-intein has been engineered to yield a
      controllable N-terminal or C-terminal, single-splice-junction autocleavage
      element. When combined with an affinity tag, these modified mini-inteins can be
      used to purify target proteins after a single combined chromatography/cleavage
      step. Cleavage at the intein N terminus was induced with thiol reagents, while
      cleavage at the intein C terminus was induced by a temperature shift to 16
      degrees-25 degrees C. Different preferences for the residue immediately preceding
      the intein were observed during thiol-induced, N-terminal splice-junction
      cleavage of the M. xenopi gyrase A mini-intein vs. the Saccharomyces cerevisiae
      vacuolar ATPase, subunit A (VMA) intein present in the IMPACT purification
      system. Furthermore, the M. xenopi gyrase A mini-intein C-terminal autocleavage
      vector allows isolation of polypeptides with N-terminal cysteine residues that
      are active in the Intein Mediated Protein Ligation method of protein
      semisynthesis.

PMID- 10407675
TI  - Detection of low-frequency mutations in exon 8 of the TP53 gene by constant
      denaturant capillary electrophoresis (CDCE).
AB  - We extended our development of the means to measure point mutations at the DNA
      level to the problem of detecting TP53 gene variants in the area around tumors
      where mutant fractions are expected to be as low as one mutant per 1000 wild-type
      (WT) sequences. We met this criterion by using the following methods. The TP53
      exon 8 sequence was amplified from genomic DNA samples under conditions of high
      polymerase fidelity using a fluorescein-labeled primer. This mixture of WT and
      mutant sequences was converted to heteroduplexes of mutant and WT sequences by
      melting and re-annealing. The mixture was resolved by capillary gel
      electrophoresis under appropriate constant denaturing conditions. Using laser
      induced fluorescence, we found that fractions as low as 1/1000 could be detected
      without any prior enrichment for mutant sequences, and that the melting
      properties of the amplified DNA will leave "fingerprints" in the electropherogram
      that can be used to identify the specific mutation. This method is fast and
      robust and should be applicable to clinical analyses in which rapid scanning for
      any mutation in an exonic sequence is important.

PMID- 10407676
TI  - Absolute quantitation of specific mRNAs in cell and tissue samples by comparative
      PCR.
AB  - A comparative PCR assay, for the absolute quantitation of specific mRNAs in cell
      and tissue samples, has been designed to overcome problems with previous
      techniques. cDNAs made from the RNAs are co-amplified with "competitor" plasmid
      templates under conditions in which reagents are not limiting at the equivalence
      point, thereby preventing competition between target and competitor templates and
      distinguishing the assay from competitive PCR assays. The cDNAs are serially
      diluted, and competitor templates concentrations are kept constant, rather than
      vice versa, as occurs in competitive PCR assays. Products from target and
      competitor templates are resolved by electrophoresis and measured by
      phosphorescent or fluorescent imagery. Both products are measured to minimize
      errors in the competitor:target ratio. A synthetic external standard RNA is
      included in the tissue lysis solution and co-purified with endogenous mRNAs,
      thereby being subjected to identical losses of yield during subsequent
      procedures. The determination of the number of copies of external standard cDNA
      allows inefficiencies of RNA extraction and cDNA synthesis to be taken into
      account. Standard concentrations of plasmids containing the endogenous target
      sequences are also measured, so that corrections can be made for discrepancies
      due to unequal amplification of target and competitor sequences. These
      corrections, together with the use of an external standard and the PCR conditions
      chosen, allow for the accurate, specific and sensitive determination of the
      absolute number of mRNA copies in a sample.

PMID- 10407677
TI  - Chemiluminescent detection of sequential DNA hybridizations to high-density,
      filter-arrayed cDNA libraries: a subtraction method for novel gene discovery.
AB  - A chemiluminescent approach for sequential DNA hybridizations to high-density
      filter arrays of cDNAs, using a biotin-based random priming method followed by a
      streptavidin/alkaline phosphatase/CDP-Star detection protocol, is presented. The
      method has been applied to the Brugia malayi genome project, wherein cDNA
      libraries, cosmid and bacterial artificial chromosome (BAC) libraries have been
      gridded at high density onto nylon filters for subsequent analysis by
      hybridization. Individual probes and pools of rRNA probes, ribosomal protein
      probes and expressed sequence tag probes show correct specificity and high signal
      to-noise ratios even after ten rounds of hybridization, detection, stripping of
      the probes from the membranes and rehybridization with additional probe sets.
      This approach provides a subtraction method that leads to a reduction in
      redundant DNA sequencing, thus increasing the rate of novel gene discovery. The
      method is also applicable for detecting target sequences, which are present in
      one or only a few copies per cell; it has proven useful for physical mapping of
      BAC and cosmid high-density filter arrays, wherein multiple probes have been
      hybridized at one time (multiplexed) and subsequently "deplexed" into individual
      components for specific probe localizations.

PMID- 10407678
TI  - Temporal, spatial and tissue-specific expression of a myogenin-lacZ transgene
      targeted to the Hprt locus in mice.
AB  - A lacZ transgene, expressed by the myogenin promoter, was introduced into the
      mouse hypoxanthine phosphoribosyltransferase (Hprt) locus by gene targeting in
      embryonic stem cells. Embryos between E10.5-E18.5 days were analyzed for
      expression of the transgene after staining for beta-galactosidase activity.
      Transgene expression was restricted to the skeletal muscle lineages reflecting a
      similar temporal and spatial pattern previously demonstrated for the endogenous
      myogenin gene. Additionally, a second transgene, MC1tk, showed expression in 87%
      of the clones when targeted to Hprt. This strategy, called targeted transgenesis,
      provides control for analyzing promoter sequences and for comparing various
      transgenes expressed by the same promoter.

PMID- 10407679
TI  - pSURF-2, a modified BAC vector for selective YAC cloning and functional analysis.
AB  - A modified bacterial artificial chromosome (BAC) vector, pSURF-2, adapted for the
      selective subcloning of yeast artificial chromosome (YAC) sequences was
      constructed. DH10B-U, a pyrF derivative of the highly transformable E. coli
      strain DH10B was also constructed and used for the detection of Ura+ recombinants
      carrying DNA linked to YAC right arms. The vector's properties were illustrated
      in two main ways. (i) An intact 25-kb YAC containing a mouse tyrosinase minigene
      was cloned into pSURF-2. Appropriately spliced tyrosinase RNA was detected by
      reverse transcription (RT)-PCR in extracts of cells transiently lipofected with
      the cloned YAC. (ii) Cells expressing human cystic fibrosis transmembrane
      conductance regulator (CFTR) from an integrated pSURF-2 recombinant containing a
      cDNA expression cassette were selected using the hygromycin-resistance (HyTK)
      marker of the vector and characterized by RT-PCR and immunoprecipitation. The
      unique I-SceI site and HyTK marker of pSURF-2 are designed to facilitate
      subsequent functional studies of cloned DNA.

PMID- 10407680
TI  - Automated system for capture and detection of nucleic acids.
AB  - A fully automated nucleic acid analysis system is described, which offers
      positive sample identification, improved sensitivity and reduced user interaction
      compared to conventional techniques. The system relies on the sequence-specific
      capture of DNA onto solid-phase particles, confirming product identity without
      the problems of interpretation and lack of sequence information inherent in gel
      based analyses. The system can be used for sequence confirmation, mutation
      analysis and semiquantitative detection of PCR products.

PMID- 10407681
TI  - The Cell Transplant Society 4th International Congress. Montreux, Switzerland,
      March 21-24, 1999. Abstracts.

PMID- 10407682
TI  - Soluble cytokine receptors: basic immunology and clinical applications.
AB  - Cytokine activity is tightly regulated at multiple levels. Soluble cytokine
      receptors (sCR) contribute to the regulation of cytokine activity by modulating
      the ability of cytokines to bind their membrane receptors and generating a
      response. Endogenous sCR are generated by proteolytic cleavage or "shedding" of
      the membrane receptor and/or by translation from alternatively spliced messages
      different from those encoding the membrane forms. The resulting soluble receptors
      retain their ligand-binding ability and with some exceptions act as competitive
      inhibitors of the binding and biologic activity of their ligand, both in vitro
      and in vivo. However, sCR can also have certain effects on cytokines, such as
      structural stabilization, protection from proteolysis, and prolonged in vivo half
      life, which are consistent with an added role as carrier proteins, and which may
      under some conditions result in potentiation of cytokine activity in vivo. The
      exact contribution of endogenous sCR to the regulation of immune or inflammatory
      responses has not yet been established unequivocally. Nonetheless, evidence
      indicates that the levels of certain sCR in serum and biological fluids correlate
      with immunological activation and/or disease activity in a variety of clinical
      conditions. Hence, sCR levels may have significant value as markers in disease
      management and prognosis. Moreover, sCR have also shown promising potential as
      immunotherapeutic agents for a variety of clinical disorders, including sepsis,
      inflammation, and autoimmune and malignant diseases.

PMID- 10407683
TI  - Hirschsprung disease and other enteric dysganglionoses.
AB  - Hirschsprung disease has become a paradigm for multigene disorders because the
      same basic phenotype is associated with mutations in at least seven distinct
      genes. As such, the condition poses distinct challenges for clinicians, patients,
      diagnostic pathologists, and basic scientists, who must cope with the
      implications of this genetic complexity to comprehend the pathogenesis of the
      disorder and effectively manage patients. This review focuses on the anatomic
      pathology, genetics, and pathogenesis of Hirschsprung disease and related
      conditions. The nature and functions of "Hirschsprung disease genes" are examined
      in detail and emphasis is placed on the importance of animal models to this
      field. Where possible, potential uses and limitations of new data concerning
      molecular genetics and pathogenesis are discussed as they relate to contemporary
      medical practices.

PMID- 10407684
TI  - Neoplasms of the lung.

PMID- 10407685
TI  - Environmental tobacco smoke and lung cancer incidence.
AB  - Tobacco smoking has been irrefutably linked to lung cancer risk. Exposure to
      environmental tobacco smoke and lung cancer risk has been more controversial.
      Various sources have claimed confounding factors such as diet and classification
      bias could account for the reported link. We review the available evidence and
      some recent papers on this topic and conclude that the evidence linking
      environmental tobacco smoke and lung cancer is unequivocal and cannot be
      explained by confounding factors.

PMID- 10407687
TI  - Usefulness of positron emission tomography imaging in the management of lung
      cancer.
AB  - Positron emission tomography imaging is useful for the characterization of the
      solitary pulmonary nodule and mediastinal staging. Potential future applications
      include extrathoracic staging to help to determine the ideal site for possible
      tissue diagnosis, to guide treatment plans, and to monitor the response to
      therapy and recurrence. Positron emission tomography may also predict prognosis.
      This review discusses the uses of positron emission tomography, the current
      literature, and the clinical guidelines for positron emission tomography imaging.

PMID- 10407686
TI  - Combined-modality therapy in the nonsurgical management of unresectable stage III
      non-small cell lung cancer.
AB  - Combined chemotherapy and radiation for patients with unresectable non-small cell
      lung cancer has recently been associated with a survival advantage compared with
      radiation alone; however, despite this apparent improvement in survival, the
      optimal strategy to combine these two modalities has not yet been defined. Both
      local tumor control and distant micrometastatic disease remain problems, limiting
      the curative ability of current combined-modality programs. Over the past year,
      accelerated radiation schedules have been shown to improve both local tumor
      control and survival in a selected patient population compared with standard
      radiotherapy. Some work has centered on the incorporation of novel chemotherapy
      agents into combined-modality regimens, with encouraging results from phases I
      and II. Finally, although the benefit for combined-modality therapy has generally
      been limited to good performance status of patients with minimal weight loss,
      some data have shown the feasibility of the combined approach in high-risk
      patient populations. Several ongoing cooperative group phase III trials will help
      to better define the optimal approach to manage this high-risk patient
      population.

PMID- 10407688
TI  - Disorders of pulmonary circulation.

PMID- 10407689
TI  - The role of newer diagnostic techniques in the diagnosis of pulmonary embolism.
AB  - Among the evolving techniques for the diagnosis of acute pulmonary embolism,
      contrast enhanced spiral CT takes a particularly prominent role because it is
      available at most centers, it images the pulmonary embolism directly, and it is
      minimally invasive. It has not yet been fully evaluated, however. Magnetic
      resonance angiography also has appeal for similar reasons. Few patients have been
      studied, however. Magnetic resonance angiography for pulmonary embolism is still
      in the early testing phase. Transesophageal echocardiography can image pulmonary
      embolism in central pulmonary arteries, but preliminary tests suggest that it has
      a low negative predictive value and cannot be used to exclude pulmonary embolism.
      Finally, it seems that a rapid and sensitive technique for measuring d-dimer may
      now be available, which may assist in eliminating the diagnosis of acute
      pulmonary embolism in a significant percentage of patients in whom the diagnosis
      is suspected.

PMID- 10407691
TI  - Upper extremity deep vein thrombosis.
AB  - Upper extremity deep-vein thrombosis has recently been recognized as being a more
      common and less benign disease than previously reported. It arises generally in
      the presence of recognizable risk factors, such as central venous catheters and
      cancer. However, as many as 20% of patients present with apparently spontaneous
      episodes. The prevalence of inherited coagulation defects in patients with this
      disease ranges from 10% to 26%. The clinical picture of upper extremity DVT is
      characterized by pain, edema, and functional impairment, although it may be
      completely asymptomatic. Because the prevalence of this thrombotic disease is
      less than 50% among symptomatic subjects, objective diagnosis is mandatory prior
      to instituting an anticoagulant treatment. When available, compression
      ultrasonography (alone or associated with Doppler or color Doppler facilities)
      should be the preferred initial diagnostic test. However, contrast venography may
      be necessary before anticoagulants are withheld because of negative findings on
      compression ultrasonography. Pulmonary embolism complicates upper extremity deep
      vein thrombosis in up to 36% of patients and may even be the presenting
      manifestation of this disorder. Its long-term clinical course is complicated by
      recurrent thromboembolism and post-thrombotic sequelae. Among the therapeutic
      options advocated for the therapy of upper extremity deep-vein thrombosis,
      unfractionated or low molecular weight heparin followed by at least 3 months of
      oral anticoagulants should be regarded as the treatment of choice. Thrombolysis
      and surgical procedures may be indicated in selected cases. The prevention of
      this disease requires the institution of appropriate pharmacologic measures
      (i.e., low-dose unfractionated or low molecular weight heparin or low-dose
      warfarin) whenever an indwelling central venous catheter is indicated. This
      review suggests that upper extremity deep-vein thrombosis is at least as serious
      a disease entity as deep-vein thrombosis of the lower extremities.

PMID- 10407690
TI  - Heparin and low molecular weight heparin for treatment of acute pulmonary
      embolism.
AB  - Pulmonary embolism occurs in more than 175,000 patients each year in the United
      States. The objectives of treatment are to prevent death from the existing
      embolus, to prevent death and morbidity from recurrent pulmonary embolism, and to
      prevent morbidity from recurrent deep-vein thrombosis. For patients with adequate
      cardiorespiratory reserve, the primary objective is to prevent recurrent
      pulmonary embolism. Anticoagulant therapy with intravenous unfractionated heparin
      or subcutaneous low molecular weight heparin followed by oral anticoagulant
      treatment for at least 3 months is the treatment of choice for most of these
      patients. Clinical trials indicate that the effectiveness of intravenous heparin
      depends on achieving an adequate heparin effect (activated partial thromboplastin
      time above lower limit) during the initial 24 hours. A validated protocol for
      intravenous heparin should be used to lessen the likelihood of delayed
      heparinization. Low molecular weight heparin given subcutaneously either once or
      twice daily is as effective as intravenous heparin for the treatment of patients
      with deep-vein thrombosis and submassive pulmonary embolism. Low molecular weight
      heparin enables many patients with uncomplicated deep-vein thrombosis to be
      treated in an outpatient setting.

PMID- 10407692
TI  - Risk factors for venous thromboembolism in pregnancy.
AB  - Venous thromboembolism remains the leading cause of maternal mortality in the
      United Kingdom. In this review we highlight studies that have documented the
      incidence of objectively confirmed venous thromboembolism in pregnancy, consider
      the effect of pregnancy on the coagulation and fibrinolytic systems, and examine
      in detail current knowledge of the risk factors for the development of this
      condition.

PMID- 10407693
TI  - Diagnosis of deep venous thrombosis and pulmonary embolism in pregnancy.
AB  - Accurate diagnosis of deep venous thrombosis and pulmonary embolism is required
      because treatment can be lifesaving, although inappropriate anticoagulation
      exposes the mother and fetus to hemorrhage and other hazards. Clinicians must be
      aware of which patients are at risk, as deep venous thrombosis is frequently
      asymptomatic. Clinical diagnosis is unreliable for deep venous thrombosis and
      pulmonary thromboembolism; therefore, objective tests are required. Venography is
      the gold standard test for deep venous thrombosis but is invasive. It has been
      superseded by less invasive tests such as compression ultrasound. This test,
      although not yet rigorously scrutinized in pregnancy, is now the first-line
      investigation. Where doubt remains, venography, CT, and magnetic resonance
      imaging have a role. Ventilation-perfusion scanning is the pivotal test for
      pulmonary thromboembolism for pregnancy, and it need not expose the fetus to
      excess radiation. If the results of this test are unclear, deep venous ultrasound
      can guide management of suspected pulmonary thromboembolism, thus avoiding
      pulmonary angiography.

PMID- 10407694
TI  - Treatment and prevention of venous thromboembolic disease in pregnancy.
AB  - Pulmonary embolism is a major, but potentially preventable, cause of maternal
      mortality in North America and Europe. Because venous thromboembolism is an
      infrequent cause of maternal morbidity, there are few randomized clinical trials
      to guide clinical decision-making with respect to treatment, prevention, and
      evaluation of innovative management modalities such as low molecular weight
      heparin. This article focuses on the evidence supporting the current guidelines
      for the pharmacologic management of venous thromboembolic disease in pregnancy.

PMID- 10407695
TI  - Useful tests on the pleural fluid in the management of patients with pleural
      effusions.
AB  - Examination of the pleural fluid is useful in establishing the etiology of a
      pleural effusion. Transudative pleural effusions can be differentiated from
      exudative pleural effusions by measuring the levels of protein and lactic acid
      dehydrogenase in the pleural fluid and serum. If a patient clinically appears to
      have a transudative pleural effusion, but the pleural fluid meets exudative
      criteria, demonstration that the albumin levels is more than 1.2 gm/dl higher in
      the serum than in the pleural fluid provides evidence that the effusion is
      transudative. The gross appearance of the pleural fluid should always be noted.
      Other tests that routinely should be obtained on exudative pleural fluids are
      Gram stain and cultures, cell counts and differential, glucose, amylase, lactic
      acid dehydrogenase, cytology, and a marker for tuberculous pleuritis. The
      diagnosis of tuberculous pleuritis is strongly suggested by a pleural fluid
      adenosine deaminase level above 45 IU/L or a gamma interferon level above 3.7
      U/ml.

PMID- 10407696
TI  - Treatment of malignant pleural effusions.
AB  - Malignant pleural effusions are common in cancer patients with advanced disease.
      These patients usually present with chest pain, cough, and progressive shortness
      of breath, all of which may cause significant impairment in quality of life.
      Therapeutic options include systemic treatment; thoracentesis; or, most commonly,
      tube drainage and sclerotherapy. These procedures are usually palliative and are
      performed depending on patients' symptoms, underlying medical conditions, extent
      of disease, performance status, and prognosis. This review focuses on the
      diagnosis and treatment of patients with malignant pleural effusions.

PMID- 10407697
TI  - Thoracoscopy and video-assisted thoracic surgery.
AB  - Thoracoscopy is an old technique that has been recently revived with the
      development of video-endoscopic technology. Video-assisted thoracic surgery
      (VATS) is now an established surgical approach with proven benefits in the
      management of pleural diseases. It has been found to be particularly useful in
      establishing the diagnosis of pleural metastasis with an option for treatment. It
      also has an established therapeutic role in the management of the fibrinopurulent
      phase of empyema and the treatment of hemothorax. The technique is still
      continually evolving, and refinement of instrumentation promises to further
      reduce surgical trauma in selected procedures.

PMID- 10407698
TI  - Pleural mesothelioma.
AB  - The increasing incidence of malignant pleural mesothelioma (MPM), better
      knowledge of its pathogenesis with a strong implication of asbestos fibers, and
      some promising therapeutic results have led to a new interest in the management
      of patients with this disease. The diagnosis of MPM is easier because of new
      immunohistochemical markers that recognize the mesothelial cells with good
      specificity and sensitivity on pleural biopsy samples ideally obtained by
      thoracoscopy. Moreover, this endoscopic procedure allows the physician to make
      the diagnosis of MPM at an early stage, which is the key of the therapeutic
      management of this disease. If radiotherapy is necessary in preventing the
      malignant seeding after pleural procedures in patients, the lack of comparative
      studies did not show the superiority of a given treatment against another. A new
      international staging of the disease, however, allows physicians to discriminate
      several groups of patients for such comparative studies--in particular, for
      testing the efficacy of intrapleural therapy, e.g., cytokines--for early-stage
      MPM and multimodal management, i.e., extrapleural pneumonectomy, radiotherapy,
      and chemotherapy for more advanced diseases, has led to prolonged survival in
      carefully selected patients. To reach this target, all patients must be enrolled
      in protocols. The usual pessimism for the management of patients with malignant
      pleural mesothelioma is over.

PMID- 10407700
TI  - Bibliography. Current world literature. Neoplasms of the lung.

PMID- 10407701
TI  - Bibliography. Current world literature. Disorders of pulmonary circulation.

PMID- 10407699
TI  - Tension pneumothorax.
AB  - The diagnosis of tension pneumothorax has typically been taught as the presence
      of hemodynamic compromise with an expanding intrapleural space air mass. This may
      occur quickly or gradually, depending on the degree of lung injury and
      respiratory state of the patient. Experimentally, tension pneumothorax is a
      multifactorial event that manifests a state of central hypoxemia, compensatory
      mechanisms, and mechanical compression on intrathoracic structures. Studies using
      animal models suggest that over hypotension is a delayed finding that immediately
      precedes cardiorespiratory collapse. Recognition of early signs and symptoms
      associated with tension pneumothorax, e.g., progressive hypoxemia, tachycardia,
      and respiratory distress, can alert medical personnel to the need for rapid
      decompression before physiologic decompensation.

PMID- 10407702
TI  - Bibliography. Current world literature. Diseases of the pleura.

PMID- 10407703
TI  - Problem-based learning in a clerkship is debated.

PMID- 10407704
TI  - Getting a feeling for that family practice feeling.

PMID- 10407705
TI  - Combining educational process and medical content during preceptor faculty
      development.

PMID- 10407706
TI  - Precepting preclinical students.
AB  - Preclinical preceptors have an opportunity to imprint students with good clinical
      work habits, professionalism, and excitement for medical education. While
      attention to the multiple roles of the preclinical preceptor can add
      responsibilities to a busy physician's day, the chance to influence the
      development of future physicians is deeply gratifying.

PMID- 10407707
TI  - Sex talk: what makes it hard to learn sexual history taking?

PMID- 10407708
TI  - Are vaccination rates higher if providers receive free vaccines and follow
      contraindication guidelines?
AB  - BACKGROUND AND OBJECTIVES: Economics has been suggested as a barrier to
      vaccination, but data that link clinician reports to actual immunization rates
      are limited. This study examined the relationship between clinicians' self-report
      regarding likelihood of vaccinating and actual age at vaccination from a registry
      of children seen by the clinicians. METHODS: Standardized telephone survey
      results of 29 providers were compared to the immunization records of children
      seeing these providers, using analysis of contingency tables (on time versus
      late) and conditional hierarchical linear models with log age at diphtheria
      tetanus-pertussis (DTP)#3, DTP#4, and measles-mumps-rubella (MMR)#1 as the
      dependent variables. RESULTS: Children seeing providers likely to refer an
      uninsured child for immunization were vaccinated at a later log age at DTP#4 but
      not for DTP#3 or MMR#1 than children seeing providers unlikely to refer.
      Vaccination rates were higher for MMR#1 (77% versus 48%), DTP#3 (84% versus 71%),
      and DTP#4 (82% versus 66%) among providers who received free vaccine, compared
      with children seen by providers who did not receive free vaccine. These results
      remained significant in the hierarchical analyses. Providers likely to vaccinate
      an 18-month-old with watery diarrhea had higher vaccination rates than those
      unlikely to vaccinate for MMR#1, DTP#3, and DTP#4; the results were also
      significant in the hierarchical analyses. CONCLUSION: Children are vaccinated
      later in the practices of providers who are likely to refer uninsured children to
      a public vaccine clinic for vaccination, who do not receive free vaccine
      supplies, or who overinterpret contraindications.

PMID- 10407709
TI  - Does telephone contact with a physician's office staff improve mammogram
      screening rates?
AB  - BACKGROUND AND OBJECTIVES: Mammography is an important screening tool for the
      early detection of breast cancer. However, mammogram screening rates are low,
      despite interventions to improve them. We investigated two methods to improve
      mammogram screening and compared mammogram rates among women who received these
      interventions to mammogram screening rates in a control group. We also
      investigated the costs involved in these interventions. METHODS: We studied
      mammogram screening rates of three randomized groups of women ages 50 and older
      from the Deighton Family Practice Center in Southfield, Mich. All women had had a
      mammogram 1 year previously and were due for another mammogram. Our control group
      (n = 110) received no intervention. The second group of women (n = 102) received
      a reminder letter from the radiology department. The third group (n = 86)
      received a reminder letter followed by a phone call from the physician's office
      staff if no mammogram had been obtained within 8 weeks after the due date for the
      mammogram. All three groups were monitored for 14 weeks after the due date to
      determine mammogram screening rates in each group. RESULTS: A mammogram was
      obtained by 33% of women in group 1, 37% of women in group 2, and 57% of women in
      group 3. The mammogram screening rate of the third group was significantly
      greater than in the first two groups. In the third group, the additional cost
      added by the phone call intervention was $9 per mammogram obtained. CONCLUSION:
      Mammogram screening rates are increased when patients are contacted by both a
      reminder letter and a phone call.

PMID- 10407710
TI  - Shorter dosing interval of opiate solution shortens hospital stay for methadone
      babies.
AB  - BACKGROUND AND OBJECTIVES: Methadone maintenance is the standard of care for
      pregnant opiate addicts. However, withdrawal of an infant from methadone after
      birth often results in a lengthy hospital stay. This study identified potentially
      modifiable factors that are associated with the length of hospital stay of
      infants of mothers on methadone. METHODS: This study used a retrospective case
      series of patients from a university hospital in Texas. Eligible participants
      included 41 neonates born between January 1991 and December 1996 to mothers
      taking methadone at time of delivery. Charts were reviewed for factors relating
      to administration of opiates to the newborn, and the length of the hospital stay
      was recorded for each infant. Bivariate and multiple regression analyses were
      performed using length of hospital stay as the outcome measure. RESULTS: Higher
      peak dose of tincture of opiate solution (TOS) and longer dosing interval were
      found to be related to longer length of hospital stay. These variables explained
      23% of the variation in length of stay. CONCLUSIONS: Lower peak doses of TOS and
      shorter dosing intervals may be associated with shorter hospital stays for
      infants with neonatal abstinence syndrome secondary to maternal methadone
      treatment.

PMID- 10407711
TI  - Using a flow sheet to improve performance in treatment of elderly patients with
      type 2 diabetes.
AB  - BACKGROUND AND OBJECTIVES: Numerous studies have shown that physicians do not
      provide all the preventive and therapeutic care recommended for patients with
      diabetes. This study determined if use of a medical record flow sheet could
      increase compliance with seven quality-of-care indicators developed by the
      American Diabetes Association. METHODS: Subjects included Medicare enrollees with
      type 2 diabetes. Following an analysis of baseline data, physicians in the
      practice used a flow sheet that contained recommended guidelines for diabetes
      care. Staff inserted the flow sheet into the records of patients included in the
      baseline sample. Physicians and staff also received education about use of the
      flow sheet. The post-intervention sample consisted of the same subjects, if they
      had been seen by the practice during a 3-month period. RESULTS: The records of
      114 subjects were reviewed at baseline. Of these subjects, 109 received care
      during the study period. Improvement was shown in six of the seven quality
      indicators and was also observed in the performance of post-intervention rates
      for patients whose flow sheet was used, compared with those for whom it was not
      used. CONCLUSIONS: The results indicate that education and performance in
      diabetes care can improve with the use of a flow sheet.

PMID- 10407712
TI  - The efficacy and safety of budesonide inhalation suspension: a nebulizable
      corticosteroid for persistent asthma in infants and young children.
AB  - OBJECTIVE: This study evaluated the efficacy and safety of four dosing regimens
      of budesonide inhalation suspension in children ages 6 months to 8 years with
      moderate persistent asthma. METHODS: This 12-week, randomized, double-blind,
      placebo-controlled, parallel-group study involved 481 children at 38 centers
      throughout the United States. Active treatment groups were budesonide inhalation
      suspension .25 mg once daily (QD), .25-mg two times daily (BID), .5-mg BID, or 1
      mg QD. Efficacy was assessed by recording nighttime and daytime asthma symptoms,
      use of rescue medication, and discontinuation from the study because of worsening
      asthma and/or a requirement for systemic steroids. Objective measures of
      pulmonary function were assessed in children who were capable of consistently
      performing pulmonary function tests; peak expiratory flow (PEF) measurements were
      recorded twice daily on diary cards, and spirometry was recorded at clinic
      visits. RESULTS: Baseline patient demographics, nighttime and daytime symptom
      scores, and pulmonary function data were similar across placebo and budesonide
      treatment groups. The majority of patients were male (64%) with a mean age of
      55.0 +/- 26.3 months. The mean duration of asthma was 34.2 +/- 22.9 months, and
      mean baseline forced expiratory volume in 1 second (FEV1) was 79.8% of predicted,
      with 29.1% reversibility. Significant improvements in nighttime and daytime
      asthma symptoms scores were observed in budesonide treatment groups, compared
      with placebo. The mean change from baseline to week 0-12 for nighttime and
      daytime asthma symptom scores was significantly greater for the .25-mg BID, .5-mg
      BID, and 1-mg QD budesonide treatment groups, compared with placebo; significant
      clinical improvement was observed by the second week of treatment. The lowest
      budesonide dose used (.25 mg QD) resulted in numerical improvements in symptom
      scores that were not statistically significant when compared to placebo.
      Significant improvements in morning PEF were observed in all budesonide treatment
      groups, except for the .25-mg QD group, compared with placebo. All treatment
      groups showed numerical improvement in FEV1, but only the .5-mg BID dose was
      significantly different from placebo. CONCLUSIONS: The results of this study
      demonstrate that budesonide inhalation suspension is effective and well tolerated
      for infants and young children with moderate persistent asthma. Budesonide
      inhalation suspension is an important therapeutic option for young children who
      are not able to use other available delivery devices.

PMID- 10407713
TI  - Precept-Assist. a computerized, data-based evaluation system.
AB  - BACKGROUND AND OBJECTIVES: Traditional methods of resident evaluation have
      several limitations, including recall bias and memory decay. We developed a real
      time, computerized, data-based evaluation system and determined 1) the
      feasibility of using such a system in an ambulatory care teaching center and 2)
      the types of evaluation data such a computer-based evaluation system provides to
      residency directors, faculty, and residents. METHODS: We developed Precept
      Assist, a computerized, data-based evaluation system. Reports from the system
      provide quantitative data, summative reports, and qualitative comments regarding
      specific competencies of residents. Following each precepting encounter between a
      faculty member and a resident, the faculty member entered into the system an
      array of coded information on the resident's level of performance, competencies
      achieved, and procedural skills. RESULTS: We have entered more than 15,000 pieces
      of evaluative data on 4,504 precepting encounters. The average time to enter data
      was about 40 seconds per encounter. Reports were generated to monitor each
      resident's progress through the program. The information was used to generate
      learning plans tailored to each resident's needs. CONCLUSIONS: Precept-Assist was
      useful for evaluating the performance of residents in this study.

PMID- 10407714
TI  - Review of University of British Columbia Family Practice Resident Research
      Projects 1990-1997.
AB  - BACKGROUND: Resident research projects can be an important component of building
      a strong and diversified research presence in family medicine. One of the
      requirements for graduation from the University of British Columbia (UBC) Family
      Practice Residency Program is that family practice residents complete a scholarly
      piece of work. METHODS: UBC family practice resident projects from 1990-1997 were
      reviewed and classified by methodology. A survey was sent to 251 former residents
      to determine 1) if their project was published, 2) if not, was there any interest
      in publication, and 3) what were the main reasons for not pursuing publication.
      Fifteen projects were selected as suitable for publication and were, with
      permission of the resident, submitted to medical journals. RESULTS: Sixty-nine
      percent of the resident projects involved data collection and hypothesis testing,
      and 40% were cross-sectional, of which patient surveys were the most common
      method. A total of 190 former residents (71%) have responded to our survey. Seven
      percent of respondents stated that their project had been published, and 55%
      would have liked to have tried to publish their project. Of the 15 resident
      projects we submitted for publication, seven were accepted. CONCLUSIONS: Family
      practice residents are capable of producing a wide variety of research projects.
      Only a minority of projects are being published despite the fact that the
      majority of residents are interested in pursuing publication. Greater assistance
      by faculty can increase publication of research projects.

PMID- 10407715
TI  - Diabetes education program use and patient-perceived barriers to attendance.
AB  - BACKGROUND AND OBJECTIVES: Although self-management education is an essential
      component of optimal diabetes care, diabetes education programs are greatly
      underused. This study examined the use of diabetes education programs by a
      university-based family practice patient population in Philadelphia. Predictors
      of program attendance, as well as patient-perceived barriers to attendance, were
      identified. METHODS: A survey designed to collect information on demographics,
      clinical factors associated with diabetes, experience with diabetes education,
      and reasons for nonattendance at education programs was administered to 150
      patients with diabetes. RESULTS: Twenty-two percent of the subjects had attended
      a diabetes education program. Female gender, insulin use, and higher degree of
      obesity were positively associated with education program attendance. Physician
      recommendation was an important predictor of attendance. Significant barriers to
      attendance included lack of awareness of programs, misperceptions about what
      programs involved, structural barriers, and health beliefs. CONCLUSIONS: Diabetes
      education programs are underused. Physicians can improve program attendance and
      outcomes for people with diabetes by implementing interventions designed to
      address the identified barriers.

PMID- 10407716
TI  - What predicts change in marital interaction over time? A study of alternative
      models.
AB  - This is a report on what predicts the deterioration of affective marital
      interaction over a 4-year period. Four models were compared for their ability to
      predict Time-2 dysfunctional marital interaction (a set of reliable predictors of
      marital dissolution). These four models were: (1) baseline physiology at Time-1;
      (2) interaction physiology at Time-1; (3) a balance model based on the ratio of
      positivity to negativity at Time-1; and, (4) cognitions about the relationship
      operationalized from our coding of the Oral History Interview. All four models
      predicted Time-2 dysfunctional marital interaction. All four models were also
      able to predict change, operationalized as predicting Time-2 interaction,
      controlling for Time-1 interaction, that is, using a covariance regression
      analysis. The most powerful model in predicting change was the balance ratio
      model.

PMID- 10407717
TI  - How stable is marital interaction over time?
AB  - This is a report of the degree of stability in affective marital interaction over
      a 4-year period. There were statistically significant levels of stability in
      overall emotionality, and in positive and negative affect, particularly for
      wives. There was also stability for specific affects but, except for humor and
      listener backchannels, these varied with gender. Women were more stable than men
      in overall negative and positive affect. Men were more stable than women in
      belligerence, contempt, and tension/fear. Women were more stable than men in
      whining.

PMID- 10407718
TI  - Building a science of couple relationships: comments on two articles by Gottman
      and Levenson.

PMID- 10407719
TI  - Surviving cancer competently intervention program (SCCIP): a cognitive-behavioral
      and family therapy intervention for adolescent survivors of childhood cancer and
      their families.
AB  - Psychological reactions to having had childhood cancer often continue after
      treatment ends, for survivors and their parents. Based on our previous research,
      we developed an intervention program for adolescent survivors of childhood
      cancer, their parents, and siblings. Surviving Cancer Competently: An
      Intervention Program--SCCIP--is a one-day family group intervention that combines
      cognitive-behavioral and family therapy approaches. The goals of SCCIP are to
      reduce symptoms of distress and to improve family functioning and development.
      SCCIP is described and data from a pilot study of 19 families are presented.
      Program evaluation data indicated that all family members found SCCIP helpful.
      Standardized measures administered before the intervention and again at 6 months
      after SCCIP showed that symptoms of posttraumatic stress and anxiety decreased.
      Changes in family functioning were more difficult to discern. Overall, the
      results were promising with regard to the feasibility of the program and its
      potential for reducing symptoms of distress for all family members.

PMID- 10407721
TI  - The therapist's inner conversation in family therapy practice: some ideas about
      the self of the therapist, therapeutic impasse, and the process of reflection.
AB  - In this article, a distinction is made between the outer therapeutic conversation
      and the therapist's inner conversation. The therapeutic conversation is a circle
      of meaning in which both the therapist and the clients play a part. The
      therapist's inner conversation is described as a negotiation between the self of
      the therapist and his role. In this process of negotiation the therapist has to
      take seriously, not only his observations, but also what is evoked in him by
      these observations, that is, images, moods, emotions, associations, memories, and
      so on. Furthermore, therapeutic impasse is conceptualized as a paralysis of the
      circle of meaning and of the therapist's inner conversation. A process of
      reflection is proposed as a way out of the impasse. In that process, the inner
      conversation of the therapist is externalized with the help of an outsider. In
      the final part of this article, a case study illustrates the importance of these
      ideas for the family therapy practice.

PMID- 10407720
TI  - Parentification and its impact on adolescent children of parents with AIDS.
AB  - Parentification refers to children or adolescents assuming adult roles before
      they are emotionally or developmentally ready to manage those roles successfully.
      We assess predictors and outcomes of parentification among adolescent children of
      Parents with AIDS (PWAs) in two phases. In Phase 1, relationships among parental
      AIDS-related illness, parent drug use, parent and adolescent demographics, and
      parentification indicators (parental, spousal, or adult role-taking) were
      assessed among 183 adolescent-parent pairs (adolescents: 11 to 18 years, M = 14.8
      years, 54% female; parents: 80% female). Adult role-taking was associated with
      maternal PWAs, female adolescents, and greater parent drug use. Greater parental
      AIDS-related illness predicted more spousal and parental role-taking. Parent drug
      use predicted more parental role-taking. In Phase 2, we examined the impact of
      parentification on later adolescent psychological adjustment (N = 152
      adolescents). Adult role-taking predicted more internalized emotional distress;
      parental role-taking predicted externalized problem behaviors: sexual behavior,
      alcohol and marijuana use, and conduct problems. Given these dysfunctional
      outcomes, we discuss interventions to mitigate parentification among children of
      PWAs.

PMID- 10407722
TI  - Their home is their castle: learning to do in-home family therapy.
AB  - The client's home is emerging as a typical site in which family therapy is
      delivered, yet training programs tend to train students in an office-based model.
      This qualitative study examines the process that three student interns went
      through as they learned to do home-based therapy after having been trained in a
      clinic setting. All three found that the experience of working in the clients'
      homes challenged their beliefs about therapy as well as the models of a
      professional relationship; all reformulated their views on therapy because of
      this challenge. A model is proposed that describes the students' journey from
      being a clinic-based to becoming a home-based therapist.

PMID- 10407723
TI  - The association between parental reports of attachment style and family dynamics,
      and offspring's reports of adult attachment style.
AB  - This research assessed the association between parents' reports of attachment
      styles and their perceptions of family environment, on the one hand, and
      offspring's reports of adult attachment styles, on the other. The sample included
      98 Israeli young adults who completed the adult attachment style scale, and their
      mothers and fathers who completed this scale, as well as FACES III, and the
      conflict and expressiveness subscales of the Family Environment Scale. Findings
      revealed associations between parents' and offspring's reports of attachment
      styles, which were qualified by gender matching. They also indicated independent
      and differential contributions of the examined dimensions of perceived family
      environment to offspring's attachment styles. The discussion attempts to
      integrate attachment theory with a family system perspective.

PMID- 10407724
TI  - [Sleep-related respiratory disorders. Great need for research in diagnosis and
      therapy].

PMID- 10407725
TI  - [Vestibular schwannoma (acoustic neurinoma). Changes in a disease picture and in
      therapy?].

PMID- 10407726
TI  - [Leisure time noise. Hearing damage in every 10th adolescent is possible].

PMID- 10407727
TI  - [Surgical therapy of sleep-related respiratory disorders].
AB  - Before the invention of CPAP therapy, the only effective surgical treatment for
      obstructive sleep apnea syndrome was tracheotomy. Now, surgical approaches mainly
      focus on two anatomical sites. Each procedure influences either the retropalatal
      or retrolingual portion of the pharynx. They might be applied individually,
      synchronously with other procedures, or sequentially with other therapeutic
      devices. Common methods of velar surgery include uvulopalatopharyngoplasty
      (UPPP), Laser-assisted uvuloplasty (LAUP), radiofrequency or uvulaflap. These
      techniques are indicated mainly in patients with mild OSAS. Other procedures
      focus on the posterior airway space (PAS), including operations that reduce the
      volume of the tongue or base of tongue. In selected patients, an enlargement of
      the retrolingual airway is gained by osteosynthetic techniques. Improvement of
      the nasal airway passage is gained by performing a septoplasty and/or conchotomy.
      In this paper, the different methods and their indications for surgical therapy
      will be explained and the results are summarized.

PMID- 10407728
TI  - [Hearing loss caused by leisure noise].
AB  - Although noise in general can induce hearing loss, environmental noise represents
      an important risk for children, teenagers and young adults. Epidemiological
      investigations now support the occurrence of an increasing number of irreversible
      hearing losses in these groups. Major causes of hearing loss are toys (guns),
      explosives and electroacoustically amplified music delivered by head sets or
      heard in discotheques and open air concerts. Clinical indications are discussed.

PMID- 10407730
TI  - [Validating a 7-channel ambulatory polygraph unit. 2: Simultaneous
      polysomnography].
AB  - PURPOSE: For some time, the ambulatory diagnosis of respiratory disturbances
      during sleep has included the use of seven-channel recording units. One of these
      systems is the POLY-MESAM unit (MAP, Germany). METHODS: The aim of the present
      study was to validate the POLY-MESAM system by simultaneously performing 12
      channel polysomnography. Forty-nine patients (45 males and 4 females) with
      different severities of obstructive sleep-related breathing disorders were
      included. Obstructive sleep apnea was diagnosed, when an apnea-hypopnea index
      (AHI) > 15 was found by polysomnography. The sensitivity and specificity for POLY
      MESAM were calculated on the basis of the polysomnographic AHI. RESULTS: The
      sensitivity of POLY-MESAM for detecting patients with an AHI > 15 was 86.4% and
      the specificity was 100%. CONCLUSIONS: The POLY-MESAM system was easy to use. The
      sensitivity and specificity for the MESAM4 unit were 92% and 97% respectively,
      which was similar to POLY-MESAM. Additionally, POLY-MESAM provided the
      possibility for distinguishing the different kinds of apneas. Thus, POLY-MESAM
      was considered to be a useful development of the previous MESAM4 unit. In some
      cases, use of the POLY-MESAM unit resulted in underestimation of the AHI. POLY
      MESAM produced false-negative results in patients with mild to moderate OSA. This
      finding was reflected in the relatively poorer sensitivity of the method (86.4%).
      Cardiorespiratory sleep studies (as possible with POLY-MESAM) are best limited to
      patients for whom the diagnosis of OSA is highly probable or as a follow-up tool
      in selected circumstances.

PMID- 10407729
TI  - [Validating a 7-channel ambulatory polygraphy unit. 1: Operating instructions for
      the physician and patient].
AB  - PURPOSE: For some time, the ambulatory diagnosis of sleep-related breathing
      disorders has included the use of seven-channel recording units. One such unit is
      the POLY-MESAM (MAP, Martinsried, FRG). The first part of the present study
      prospectively investigated the handling of the system for physicians and
      patients, its technical reliability, reliability of the software used and the
      results in comparison to handscoring. METHODS: In all, 104 patients (95 males, 9
      females) were studied for different severities of obstructive sleep-related
      breathing disorders. The first 51 patients were connected to the POLY-MESAM in
      the evening within the clinic. The patients then slept at home and returned the
      next day. Another 53 patients received only a short briefing in the clinic and
      connected themselves at home to the POLY-MESAM System. Each patient's status was
      monitored by means of a visual analogue scale. Automatic evaluation of the data
      was compared with the results of manual scoring. RESULTS: From the data recorded
      only 6% of the results were not usable. Patients acceptances of the system were
      very high (94.3%). On average each patient required 21 minutes for attaching and
      detaching the device. Scoring and instructing the patients required an average of
      23 min. Regarding the apnea-hypopnea index (AHI), the correlation between
      automatic (AHI = 11.1) and manual (AHI = 11.3) evaluations was high. Analysis of
      snoring turned out to be insufficient. CONCLUSIONS: The POLY-MESAM proved to be
      reliable and user-friendly. Our findings show that the system can be recommended
      for outpatient screening of sleep-related breathing disorders, with patients able
      to manage the system without help. Validation by using simultaneous
      polysomnography is the subject of part two of the study.

PMID- 10407731
TI  - [Risks of upper eyelid gold implantation in peripheral facial paralysis].
AB  - Peripheral facial paresis is often accompanied by incomplete closure of the
      eyelids and may lead to varying degrees of keratopathy. Conservative therapeutic
      measures are often not sufficient. To achieve better lid closure tarsorraphy has
      been the primary method of treatment but has certain functional and cosmetic
      drawbacks for the patient. Alternatively gold weight implants have been used to
      close the upper lid by the force of gravity and if needed can be combined with
      further reconstructive facial surgery. From May 1994 to January 1997 29 patients
      with peripheral facial paralysis were treated with gold weight upper lid
      implants. Postoperative closure of the lids was sufficient in all cases, and
      there was a statistically significant decrease in lagophthalmos and improvement
      in keratopathy. Complications observed included ptosis (n = 5), cosmetically
      unacceptable bulging of the gold implant (n = 5), extrusion of the implant (n =
      1) and the development of a low-grade corneal astigmatism (n = 7). In all cases
      of astigmatism correction was achieved by the fitting of cylinder glasses. In
      all, functional results achieved showed that the gold implant was superior to the
      cosmetically bothersome tarsorraphy.

PMID- 10407732
TI  - [Measuring therapy success in laryngeal paralysis based on voice parameters].
AB  - The clinical courses of vocal rehabilitation of patients with different degrees
      of laryngeal paralysis can proceed very differently, but usually do not
      correspond with the physical changes of glottic function seen on laryngoscopy and
      stroboscopy. In this study 43 patients with laryngeal paralyses were examined, of
      whom 28 had regeneration of nerve function. Fifteen did not show any improvement
      in glottal function. All patients were asked to describe their voices, after
      which subjective data were compared to objective findings concerning vocal
      penetrating capacity, voice attack, volume, and capacity. In particular, voice
      capacity, attack, and vocal penetrating capacity were found to be valid in
      reflecting therapeutic effects and for estimating voice capability.

PMID- 10407733
TI  - [Highly differentiated liposarcoma of the larynx].
AB  - Liposarcomas are very rare malignancies in the larynx. At present only a few case
      reports have been described in the available literature. These cases have been
      highly differentiated liposarcomas, just like our case. The unremarkable clinical
      picture of these tumors is that of a soft, lipomatous, smooth limited tumor.
      Findings first appear to be consistent with a lipoma and not a malignancy. Our
      case of a 23-year-old man is the youngest patient with a laryngeal liposarcoma
      described thus far. We discuss the surgical procedure used, especially in view of
      a local recurrence rate of approximately 60%, as well as additional radiotherapy.
      The treatment of choice is extensive local tumor resection. Chemotherapy is
      presently not useful for highly differentiated liposarcomas.

PMID- 10407734
TI  - [Neurinoma of the major petrosus nerve].
AB  - Facial nerve schwannomas are rare benign tumors, when occurring, they are located
      most frequently in the distal fallopian canal and present as extracranial masses.
      The predominant symptom is a progressive facial nerve paralysis. We report a 20
      year-old woman with an intracranial schwannoma originating from the greater
      superficial petrosal nerve that had wide extension into the pterygopalatine
      fossa. The motor facial nerve including the geniculate ganglion was not affected.
      The patient presented with vertigo, progressive hearing loss and mild facial
      nerve synkinesis but without a lacrimation deficit. The tumor was detected by
      computed tomography and magnetic resonance imaging. The schwannoma was completely
      removed using an intracranial, extradural middle fossa approach during which
      complete preservation of the motor facial nerve was possible. To our knowledge
      this is the first reported case of an isolated schwannoma of the greater
      superficial petrosal nerve without involvement of the motor facial nerve.

PMID- 10407735
TI  - [Microsurgical reanastomosis of the parotid duct].
AB  - Deep injuries to the parotid region may result in trauma to vital structures:
      i.e., the parotid gland and duct and the facial nerve and its branches. While
      there is no doubt concerning primary microsurgical reconstruction of injuries to
      the facial nerve clinical approaches for treating disruptions of the parotid duct
      have been controversial. A case report is presented of a secondarily
      reanastomosed parotid duct following complete transection. The microsurgical
      technique and its indications are discussed.

PMID- 10407736
TI  - [Experiences with color-coded duplex ultrasound in the ENT area].

PMID- 10407737
TI  - [Unusual form change of the nasal tip. Solitary, myxoid neurofibroma of the nasal
      tip].

PMID- 10407738
TI  - [Uncertain bone density in projection of the upper pyramidal edge. Calcification
      of the lateral ventricular choroid plexus].

PMID- 10407739
TI  - [Laryngospasm].

PMID- 10407740
TI  - [Reimbursement in double-sided partial thyroid resection and additional bilateral
      neurolysis].

PMID- 10407741
TI  - [Sinusitis in children].

PMID- 10407742
TI  - Listening psychoanalytically to the Shoah half a century on.
AB  - The author discusses the repercussions of the Nazi genocide of the Jews on
      descendants of victims and survivors, with particular reference to
      identifications. A typical vampiric form of identification is discussed, in which
      the subject is stated to be neither alive nor dead, unborn, in an imageless,
      timeless and spaceless condition, and imprisoned in an earlier generation's
      traumas. Analysis of such cases must, the author shows, tackle the genocide
      induced fantasies of a vampire complex involving infanticide and parricide in
      addition to the incestuous and parricidal wishes of the Oedipus complex. These
      ideas are illustrated by a case history in which the female patient concerned,
      although born after the Shoah, carried the unrepresentable parental traumas
      within her to the detriment of her affective and professional life. The patient
      was effectively linked with her mother in a deadly circulation through
      communicating vessels, which was repeated in the transference countertransference
      constellation and resulted in a disavowal of both birth and death, mediated by
      the genocidal project. The author shows how the analysand was gradually released
      from this vampiric fusion and became able to reappropriate her secondary
      narcissistic and oedipal identifications, the resulting triangulation opening the
      way to sublimation and creativity.

PMID- 10407743
TI  - Putting into words, putting to rest and putting aside the ancestors. How an
      analysand who was heir to the Armenian genocide of 1915 worked through mourning.
AB  - The author discusses the intergenerational psychic transmission of collective
      trauma on the basis of her personal experience as a descendant of victims of the
      Armenian genocide of 1915. She shows how the processes of transmission are
      encumbered within a diaspora community such as hers by the incorporation of
      objects in the throes of mourning, the invalidation of prohibitions by murder
      become-law, and lack of differentiation between the sexes. A parallel is drawn
      between the characteristic secrecy of the genocidal project on the part of the
      perpetrators and the sense of illegitimacy of the victims' descendants,
      exacerbated in the case of the Armenian catastrophe by the refusal of the state
      that inherited the genocide to confess to it and consequently its erasure from
      Western consciousness. The author describes how she was enabled to emerge from
      confinement in the trauma by her French schooling and her analysis, and
      subsequently became able to work through mourning and writing, by divulging the
      secret and in particular the publication of her father's deportation diary. The
      written text is seen as a shroud in which the dead can finally be interred.
      Presenting an episode from her schooldays, she demonstrates the importance of her
      immersion in French culture in allowing her to achieve the necessary linguistic
      and psychic distance from her heritage.

PMID- 10407744
TI  - The impact of psychoanalytic theory and a two-person psychology on the
      empathising analyst.
AB  - Traditionally 'empathy' has been viewed from the perspective of a one-person
      psychology and 'the facts' discovered via empathic understanding have been
      thought to reflect accurately what the patient was experiencing, ideally
      uncontaminated by anything coming from the analyst. In contrast to this position,
      the author argues that the analyst always actively influences what he discovers
      empathically. Specifically, the analyst's theoretical biases always shape what he
      empathically understands. The contributions of Owen Renik and, to a lesser
      extent, Irwin Hoffman are critically examined, with a focus on how their two
      person perspectives shape the analyst's ability to empathise. Their clinical
      stances, which emphasise the role of corrective emotional experiences and
      countertransference enactments, are compared to what the author calls an
      'integrated stance', which attempts to integrate elements of one- and two-person
      psychologies while retaining interpretation as primary in bringing about change.
      It is concluded that the techniques advocated by Renik and Hoffman potentially
      restrict empathic understanding in two ways. First, they take positions that
      limit the development of regressive transference reactions. Second, because they
      de-emphasise monitoring countertransference urges, they actively facilitate more
      frequent countertransference enactments, which then may not be interpreted as
      fully as by the analyst working from an 'integrated stance'. Clinical examples
      are used to illustrate differences between these two stances.

PMID- 10407745
TI  - The narcissistic scenarios of parenthood.
AB  - The authors begin by pointing out that Freud always considered parent-child
      relations in terms of the child's psychic development and took little account of
      the parents' experience of the relationship and its psychic effects on them. They
      recall Freud's distinction between the anaclitic and narcissistic modes of
      relationship and show how these are unconsciously embodied and enacted in varying
      proportions in the cases observed in their own clinical practice of therapeutic
      consultations with parents and young children. After a review of the relevant
      psychoanalytic literature, the authors present their concept of the narcissistic
      scenarios of parenthood, which include parental projection on to the child,
      parental counter-identification, a specific aim and a relational dynamic that is
      acted out. Depending on the individual situation, the effects may help to
      structure the developing psyche or, if the narcissistic element is excessive,
      they may be pathological. The authors consider the literature on the application
      of psychoanalysis to therapeutic interventions with parents and children,
      stressing the technical importance of establishing a therapeutic focus. These
      ideas are illustrated by a detailed case history showing the interaction between
      a mother and a 4-year-old girl and how it was modified by a short therapy. The
      differences between interpretation in this situation and in the classical
      psychoanalytic setting are explained, and the paper ends with some comments on
      the transmission of psychic elements from generation to generation.

PMID- 10407746
TI  - Some functions of being fair and just--or not, in clinical psychoanalysis.
AB  - The author suggests that the concepts of fairness and justice might be
      psychoanalytically useful. They are social ideas but often arise clinically.
      Since psychoanalysis is about intimate and internal events, the wide social and
      legal settings associated with formal justice are not addressed. Fairness and
      informal justice arise more intimately and are central here. Fairness is
      concerned with thorough consideration of an issue. To be fair, the people
      involved must be considered with impartiality before a decision. Justice
      generally is more formal, aiming to ensure the integrity of a system, its parts
      and individual members. It is noted that psychopathogenic conditions can arise in
      conflicting situations involving fairness and justice. Clinical illustrations
      suggest that the psychoanalytic process can implicitly aim to resolve their after
      effects. Technique is addressed in this light. A central suggestion emerges here.
      The philosopher Jurgen Habermas proposes that justice rests essentially upon
      opportunity for argumentation between all those affected. The author suggests
      that psychoanalytic therapy is likewise a constructive argumentation.

PMID- 10407747
TI  - The difficult freedom from a plan.
AB  - The author attempts to describe a tendency among analysts in connection with
      presenting clinical material to become either too dogmatic or too insecure,
      either idealising knowledge or uncertainty. Both extremes may also mean
      idealising intellectualisation. Instead, the author suggests that these
      tendencies arise as a reaction towards complex psychological strategies from the
      patient, and that these strategies need to become clarified, instead of the
      analyst intervening prematurely with the mentioned extreme tendencies. In order
      to do so, the analyst needs to be free from inner automatic programmes. Two
      clinical vignettes are described where the analyst's own repression plays a part
      in his interventions. Freud's technical papers are analysed concerning frame
      factors and technical recommendations and the author shows how Freud's classical
      technique is modern in its emphasis on freedom and preliminary truth in
      interpretations. Freud's papers also seem to agree with Bion's motto 'without
      memory or desire', which the author discusses as the freedom from a programme. He
      recommends three governing mottoes for the area of interventions, in order not to
      idealise the image of psychoanalysis and psychoanalysts. He concludes with a
      third clinical vignette that underlines the connection between classical analysis
      and modern analysts who emphasise the freedom from idealised programmes within
      the psychoanalytic frame.

PMID- 10407748
TI  - Flight into sanity. Jones's allegation of Ferenczi's mental deterioration
      reconsidered.
AB  - In 'The Life and Work of Sigmund Freud', Volume III, Ernest Jones explained
      Ferenczi's final contributions as the product of a mental deterioration based on
      a progressive psychosis. Erich Fromm collected various testimonies by witnesses
      of Ferenczi's last years, all contrasting with Jones's assertions, and challenged
      Jones's manner of writing history. However, since Fromm was himself a dissident,
      and his witnesses were pupils, relatives or friends of Ferenczi's, they were
      discarded as 'partisans'. The present study aims at reconsidering the question of
      Ferenczi's insanity on the basis of many unpublished documents. The consulted
      documents do not support Jones's allegation of Ferenczi's insanity. At the same
      time, they show that Jones's allegation was not a one-man fabrication, but
      reflected a shared belief, eliciting many questions about the nature of this
      belief, the lack of scrutiny that characterised its spreading, and its possible
      function within the psychoanalytic community. It is suggested that Ferenczi's
      personality and teaching, especially his emphasis on the need to accept the
      patient's criticism, contrasted with the dominant conception of psychoanalysis,
      based on the analyst's infallibility.

PMID- 10407749
TI  - Sigmund Freud and the Crick-Koch hypothesis. A footnote to the history of
      consciousness studies.
AB  - The author describes Crick and Koch's recently developed theory of the
      neurophysiological basis of consciousness as synchronised neural oscillations.
      The thesis that neural oscillations provide the neurophysiological basis for
      consciousness was anticipated by Sigmund Freud in his 1895 'Project for a
      scientific psychology'. Freud attempted to solve his neuropsychological 'problem
      of quality' by means of the hypothesis that information concerning conscious
      sensory qualities is transmitted through the mental apparatus by means of neural
      'periods'. Freud believed that information carried by neural oscillations would
      proliferate across 'contact-barriers' (synapses) without inhibition. Freud's
      theory thus appears to imply that synchronised neural oscillations are an
      important component of the neurophysiological basis of consciousness. It is
      possible that Freud's thesis was developed in response to the experimental
      research of the American neuroscientist M. M. Garver.

PMID- 10407750
TI  - Ghosts in the swamp. Some aspects of splitting and their relationship to parental
      losses.
AB  - The author describes some aspects of the analysis of a woman who was suffering
      from bulimia and extreme withdrawal from life. It emerged that she was frightened
      of her parents' internal objects, which she experienced as vengeful ghosts who
      were preventing her from developing her life or personality. She was identified
      with these ghosts to the extent of feeling that she was not supposed to survive.
      The author argues that fear of her parents' internal ghosts had contributed to a
      split in the patient not only between idealised and persecutory objects but also
      between material and psychic modes of functioning. It is suggested that the
      patient came to understand some of these fears in relation to the analyst's
      internal objects in the transference. Reasons for the patient's vulnerability to
      parental internal objects and projections are suggested, including her jealousy
      of her own siblings, which seems paralleled by her hypersensitivity to her
      parents' internal siblings. The fear of these objects is seen to be partly a
      function of her own projections and partly the result of unmourned losses in her
      parents' childhoods.

PMID- 10407751
TI  - When all is said ... a phenomenological enquiry into post-termination experience.
AB  - The empirical phenomenological research method (Giorgi, 1985) is used to make a
      preliminary enquiry into the post-termination experience for a small number of
      subjects who have completed a psychoanalysis or psychoanalytic psychotherapy. The
      results are presented and discussed in the context of the existing post
      termination literature. While the findings support some current post-termination
      expectations, such as the capacity for self-analysis and a process of mourning,
      they potentially refute the idea that these unfold chronologically, with one post
      termination stage being contingent upon another. The pre-termination phase
      emerged as important for these subjects, especially in relation to the
      termination and post-termination boundaries, which were recalled as being
      determined largely by the analyst. The findings indicate that the experience of
      the pre-termination process may have a particular impact on how the analyst is
      held in mind after the analysis has been terminated.

PMID- 10407752
TI  - Countertransference past and present: a review of the concept.

PMID- 10407753
TI  - Psychoanalysis and chaos theory.

PMID- 10407754
TI  - Non-interpretive mechanisms in psychoanalytic therapy.

PMID- 10407755
TI  - On violence.

PMID- 10407756
TI  - [Genetic components in autoimmune diseases].

PMID- 10407757
TI  - [Mucoviscidosis. Also a disease in adulthood?].

PMID- 10407758
TI  - [Multiple endocrine neoplasia].

PMID- 10407759
TI  - [Hereditary amyloidosis].

PMID- 10407760
TI  - [Hereditary gastrointestinal tumors].

PMID- 10407761
TI  - [Hemochromatosis and Wilson disease].

PMID- 10407762
TI  - [Genetics in cardiology. An update].

PMID- 10407763
TI  - [Genetically-induced kidney diseases].

PMID- 10407764
TI  - [Functional abdominal complaints. Functional dyspepsia and irritable colon].

PMID- 10407765
TI  - [Acute ischemia of the legs and rapidly progressing renal failure in a 39-year
      old patient].

PMID- 10407766
TI  - [26-year-old patient with cutaneous leishmaniasis and an initial diabetes
      mellitus manifestation].

PMID- 10407767
TI  - [D-dimer determination in acute thromboses].

PMID- 10407768
TI  - [Serology in herpes infection].

PMID- 10407769
TI  - [Freedom from seizures in epilepsy].

PMID- 10407770
TI  - [Recent anticonvulsants].

PMID- 10407772
TI  - Neurochemistry and defects of biogenic amine neurotransmitter metabolism.
AB  - The purpose of the current review is to present a brief background examining the
      mechanisms controlling synthesis, storage, release and action of the biogenic
      amine neurotransmitters and to provide examples of newly defined conditions that
      expand our awareness of the diversity and complexity of the inherited diseases
      that affect these important regulators of central and peripheral homeostasis.

PMID- 10407771
TI  - Functional magnetic resonance imaging: clinical applications and potential.
AB  - Demonstration that contrast in magnetic resonance images can be generated based
      on differences in blood oxygenation has led to an explosion of interest in so
      called functional magnetic resonance imaging (FMRI). FMRI can be used to map
      increases in blood flow that accompany local synaptic activity in the brain. The
      technique has proved remarkably sensitive and has been used to map a broad range
      of cognitive, motor and sensory processes in the brain entirely non-invasively.
      More recently, efforts have been made to extend this technique to the analysis of
      clinical problems. A major application is for presurgical localization of
      cerebral functions, e.g. in the surgical treatment of epilepsy. The technique
      also is beginning to provide information on functional consequences of abnormal
      brain development. Perhaps most exciting are applications to neurological
      impairments that are not associated with structural abnormalities, such as
      learning problems, dyslexia and movement disorders. It is possible that useful
      applications of FMRI may be found for directly mapping sites of action of CNS
      active drugs. Although the extent of the potential clinical applications of this
      new brain mapping technique is not clear, the widespread availability of MRI
      scanners suggests that the technique should in some form soon become a routine
      tool in major neuroradiological centres.

PMID- 10407773
TI  - A review of biochemical and molecular genetic aspects of tyrosine hydroxylase
      deficiency including a novel mutation (291delC).
AB  - An overview is given of the current knowledge on the human tyrosine hydroxylase
      gene and on the biochemical aspects of diagnosing defects in this gene.
      Diagnostic biochemical findings are described in four cases of genetically
      confirmed tyrosine hydroxylase deficiency. Decreased CSF levels of homovanillic
      acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), together with
      normal pterin and CSF tyrosine and 5-hydroxyindoleacetic acid (5-HIAA)
      concentrations are the diagnostic hallmarks of tyrosine hydroxylase deficiency.
      At the metabolite level the diagnosis can only be made reliably in CSF. Strict
      adherence to a standardized lumbar puncture protocol and adequate reference
      values are essential for diagnosis of this 'new' treatable neurometabolic
      disorder. Measurements of HVA, vanillylmandelic acid (VMA) or catecholamines in
      urine are not relevant for diagnosing tyrosine hydroxylase deficiency. The
      diagnosis should be considered in all children with unexplained hypokinesia and
      other extrapyramidal symptoms. Three of our patients are homozygous for a
      mutation in exon 6 (698G > A) of the tyrosine hydroxylase gene and one patient
      was compound heterozygous for the same mutation and a novel truncating mutation
      in exon 3 (291delC).

PMID- 10407774
TI  - Inborn errors of neurotransmitter receptors.
AB  - Inborn errors of neurotransmitter receptors are recently described gene mutations
      that directly affect receptor function. Currently three conditions are known to
      be caused by this mechanism: hyperekplexia; two forms of congenital inherited
      myasthenic syndromes; and autosomal dominant nocturnal frontal lobe epilepsy.
      Here, neurotransmitters, their receptors and known inborn errors of receptor
      function are reviewed.

PMID- 10407775
TI  - Glutaric aciduria type I: from clinical, biochemical and molecular diversity to
      successful therapy.
AB  - The biochemical hallmark of glutaric aciduria type I (GA I) due to glutaryl-CoA
      dehydrogenase deficiency is the accumulation of glutaric acid, and to a lesser
      degree of 3-hydroxyglutaric and glutaconic acids. Abnormal metabolites vary from
      gross organic aciduria to only slightly or intermittently elevated or even normal
      excretion of glutaric acid, making the diagnosis sometimes difficult. Close to
      100 pathogenic mutations have been identified in the gene encoding glutaryl-CoA
      dehydrogenase. Specific mutations correlate with low or no excretion of glutaric
      acid, but there appears to be no correlation between genotype and clinical
      phenotype. GA I causes unique age- and location-specific neuropathological
      sequelae. Starting in the second half of gestation, maturation of the frontal and
      temporal cortex is hindered, leading to the characteristic appearance of
      frontotemporal atrophy. Between 6 and 18 months of age, relatively mild
      neurological symptoms may become exacerbated by fever or a catabolic state in the
      course of common infections or routine immunizations, by fasts required for
      surgery, or by minor head injuries. Putamen and caudate are destroyed, resulting
      in a permanent movement disorder that is similar to cerebral palsy and ranges
      from extreme hypotonia to choreoathetosis to rigidity with spasticity. Recently,
      the underlying pathophysiology could be delineated to an environmentally
      triggered age- and location-specific overstimulation of the NMDA 2B receptor
      subtype. Current therapy prevents brain degeneration in more than 90% of affected
      infants who are treated prospectively. Without treatment, more than 90% of
      affected children will develop severe neurological disabilities. Recognition of
      this disorder before the brain has been injured is essential to treatment. GA I
      may be recognized in routine neonatal screening performed with tandem mass
      spectrometry by an elevation of glutarylcarnitine. Where this is not done, timely
      diagnosis depends on the recognition of relatively nonspecific physical findings
      such as hypotonia, irritability, macrocephaly, on the detection of suggestive
      abnormalities in neuroimaging and on quantitative urinary organic acid analysis
      by gas chromatography--mass spectrometry.

PMID- 10407776
TI  - Glutaric aciduria type I: pathomechanisms of neurodegeneration.
AB  - In organotypic corticostriatal and hippocampal slice cultures from rat brain, 3
      hydroxyglutaric acid but not glutaric and glutaconic acids induced
      neurodegeneration by activation of NMDA receptors. Electrophysiological
      investigations (Xenopus laevis oocytes expressing glutamate receptors; rat mixed
      cortex culture) revealed no direct interaction of 3-hydroxyglutaric acid with
      glutamate receptors. We speculate that 3-hydroxyglutaric acid induces a mild
      energy deprivation that interferes with the voltage-dependent Mg(2+)-block of
      NMDA receptors.

PMID- 10407777
TI  - D-2-hydroxyglutaric aciduria: further clinical delineation.
AB  - It has recently been recognized that D-2-hydroxyglutaric aciduria is a distinct
      neurometabolic disorder with a severe and a mild phenotype. Whereas the clinical
      and neuroimaging findings of the severe phenotype were homogeneous among the
      patients, the findings in the mild phenotype were much more variable, leaving the
      clinical picture poorly defined. We were able to collect the clinical,
      biochemical and neuroimaging data on an additional 8 patients with D-2
      hydroxyglutaric aciduria, 4 with the severe and 4 with the mild phenotype. With
      the new information, it becomes clear that the mild phenotype shares the
      essential characteristics of the severe phenotype. The most frequent findings,
      regardless of the clinical phenotype, are epilepsy, hypotonia and psychomotor
      retardation. Additional findings, mainly occurring in the severe phenotype, are
      episodic vomiting, cardiomyopathy, inspiratory stridor and apnoeas. The most
      consistent MRI finding is enlargement of the lateral ventricles, occipital more
      than frontal. Regardless of the clinical phenotype, early MRI shows in addition
      subependymal cysts and signs of delayed cerebral maturation. Later MRI may reveal
      multifocal cerebral white-matter abnormalities. Two patients had vascular
      abnormalities, but it is as yet unclear whether these are related to D-2
      hydroxyglutaric aciduria or are incidental findings.

PMID- 10407778
TI  - 4-Aminobutyrate aminotransferase (GABA-transaminase) deficiency.
AB  - 4-Aminobutyrate aminotransferase (GABA-transaminase, GABA-T, EC 2.6.1.19)
      deficiency (McKusick 137150), an inborn error of GABA degradation, has until now
      been documented in only a single Flemish child. Compared to the other defects of
      GABA degradation, succinic semialdehyde dehydrogenase (SSADH, EC 1.2.1.24)
      deficiency with > 150 patients (McKusick 271980) and pyridoxine-dependent
      seizures with > 100 patients ('putative' glutamic acid decarboxylase (GAD, EC
      4.1.1.15) deficiency; McKusick 266100), GABA-T deficiency is very rare. We
      present a summary of the clinical, biochemical, enzymatic and molecular findings
      on the index proband, and a recently identified second patient, with GABA-T
      deficiency. The phenotype in both included psychomotor retardation, hypotonia,
      hyperreflexia, lethargy, refractory seizures and electroencephalographic
      abnormalities. In an effort to elucidate the molecular basis of GABA-T
      deficiency, we isolated and characterized a 1.5 kb cDNA encoding human GABA-T, in
      addition to a 41 kb genomic clone which encompassed the GABA-T coding region.
      Standard methods of cloning and sequencing revealed an A-to-G transition at
      nucleotide 754 of the coding region in lymphoblast cDNAs derived from the index
      proband. This mutation resulted in substitution of an invariant arginine at amino
      acid 220 by lysine. Expression of the mutant in E. coli, followed by isolation
      and enzymatic characterization of the recombinant protein, revealed an enzyme
      whose Vmax was reduced to 25% of wild-type activity. The patient and father were
      heterozygous for this allele; the second allele in the patient remains
      unidentified. Genomic Southern analysis revealed that the second proband most
      likely harbours a deletion in the 3' region of the GABA-T gene.

PMID- 10407779
TI  - Defects in activation and transport of fatty acids.
AB  - The oxidation of long-chain fatty acids in mitochondria plays an important role
      in energy production, especially in skeletal muscle, heart and liver. Long-chain
      fatty acids, activated to their CoA esters in the cytosol, are shuttled across
      the barrier of the inner mitochondrial membrane by the carnitine cycle. This
      pathway includes four steps, mediated by a plasma membrane carnitine transporter,
      two carnitine palmitoyltransferases (CPT I and CPT II) and a carnitine
      acylcarnitine translocase. Defects in activation and uptake of fatty acids affect
      these four steps: CPT II deficiency leads to either exercise-induced
      rhabdomyolysis in adults or hepatocardiomuscular symptoms in neonates and
      children. The three other disorders of the carnitine cycle have an early onset.
      Hepatic CPT I deficiency is characterized by recurrent episodes of Reye-like
      syndrome, whereas severe muscular and cardiac signs are associated with episodes
      of fasting hypoglycaemia in defects of carnitine transport and translocase.
      Convenient metabolic investigations for reaching the diagnosis of carnitine cycle
      disorders are determination of plasma free and total carnitine concentrations,
      determination of plasma acylcarnitine profile by tandem mass spectrometry and in
      vitro fatty acid oxidation studies, particularly in fresh lymphocytes.
      Application of the tools of molecular biology has greatly aided the understanding
      of the carnitine palmitoyltransferase enzyme system and confirmed the existence
      of different related genetic diseases. Mutation analysis of CPT II defects has
      given some clues for correlation of genotype and phenotype. The first molecular
      analyses of hepatic CPT I and translocase deficiencies were recently reported.

PMID- 10407781
TI  - Recognition and management of fatty acid oxidation defects: a series of 107
      patients.
AB  - In a personal series of 107 patients, we describe clinical presentations, methods
      of recognition and therapeutic management of inherited fatty acid oxidation (FAO)
      defects. As a whole, FAO disorders appear very severe: among the 107 patients,
      only 57 are still living. Including 47 siblings who died early in infancy, in
      total 97 patients died, of whom 30% died within the first week of life and 69%
      before 1 year. Twenty-eight patients presented in the neonatal period with sudden
      death, heart beat disorders, or neurological distress with various metabolic
      disturbances. Hepatic presentations were observed in 73% of patients (steatosis,
      hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome). True hepatic failure was
      rare (10%); cholestasis was observed in one patient with LCHAD deficiency.
      Cardiac presentations were observed in 51% of patients: 67% patients presented
      with cardiomyopathy, mostly hypertrophic, and 47% of patients had heart beat
      disorders with various conduction abnormalities and arrhythmias responsible for
      collapse, near-miss and sudden unexpected death. All enzymatic blocks affecting
      FAO except CPT I and MCAD were found associated with cardiac signs. Muscular
      signs were observed in 51% of patients (of whom 64% had myalgias or paroxysmal
      myoglobinuria, and 29% had progressive proximal myopathy). Chronic neurologic
      presentation was rare, except in LCHAD deficiency (retinitis pigmentosa and
      peripheral neuropathy). Renal presentation (tubulopathy) and transient renal
      failure were observed in 27% of patients. The diagnosis of FAO disorders is
      generally based on the plasma acylcarnitine profile determined by FAB-MS/MS from
      simple blood spots collected on a Guthrie card. Urinary organic acid profile and
      total and free plasma carnitine can also be very helpful, mostly in acute
      attacks. If there is no significant disturbance between attacks, the diagnosis is
      based upon a long-chain fatty acid loading test, fasting test, and in vitro
      studies of fatty acid oxidation on fresh lymphocytes or cultured fibroblasts.
      Treatment includes avoiding fasting or catabolism, suppressing lipolysis, and
      carnitine supplementation. The long-term dietary therapy aims to prevent periods
      of fasting and restrict long-chain fatty acid intake with supplementation of
      medium-chain triglycerides. Despite these therapeutic measures, the long-term
      prognosis remains uncertain.

PMID- 10407783
TI  - Genomics, mutations and the Internet: the naming and use of parts.
AB  - Mutations are the source of genetic variation and diversity; by their effect,
      some are neutral, others are pathogenic. In contemporary genetics, mutations
      appear at the interface between genomics (structural and functional) and genetics
      (heredity), where they serve gene discovery and mapping (genomics) and generate
      challenges to modify their phenotypic effects (medical genetics). Assuming the
      human genome harbours 80,000 transcribed genes each possessing at least 100
      different (germline) alleles in a typical population, how then to record and
      recover data on at least 8 million human alleles? Bioinformatics is the essential
      resource to create the corresponding accessible digital libraries (genomic and
      locus-specific mutation databases) for this purpose, a goal to which The HUGO
      Mutation Database Initiative (Science 279: 10-11, 1998) aspires. Guidelines now
      exist for naming alleles (Hum Mutat 11: 1-3, 1998). The principles behind the
      practice are illustrated by PAHdb (http:/(/)www.mcgill.ca/ pahdb), a prototype
      locus-specific mutation database (NAR 26: 220-225, 1998), and by prototype
      genomic mutation databases (HGMD (NAR 26: 285-287, 1998),
      http:/(/)www.uwcm.ac.uk/uwcm/mg/hgmd0.h tml; the EBI mutation database,
      http:/(/)www2.ebi.ac.uk/mutations/; and OMIM, http:/(/)www.ncbi.nlm.
      nih.gov/Omim.html).

PMID- 10407780
TI  - Disorders of mitochondrial fatty acyl-CoA beta-oxidation.
AB  - In recent years tremendous progress has been made with respect to the enzymology
      of the mitochondrial fatty acid beta-oxidation machinery and defects therein.
      Firstly, a number of new mitochondrial beta-oxidation enzymes have been
      identified, including very-long-chain acyl-CoA dehydrogenase (VLCAD) and
      mitochondrial trifunctional protein (MTP). Secondly, the introduction of tandem
      MS for the analysis of plasma acylcarnitines has greatly facilitated the
      identification of patients with a defect in fatty acid oxidation (FAO). These two
      developments explain why the number of defined FAO disorders has increased
      dramatically, making FAO disorders the most rapidly growing group of inborn
      errors of metabolism. In this review we describe the current state of knowledge
      of the enzymes involved in the mitochondrial oxidation of straight-chain,
      branched-chain and (poly)unsaturated fatty acyl-CoAs as well as disorders of
      fatty acid oxidation. The laboratory diagnosis of these disorders is described,
      with particular emphasis on the methods used to identify the underlying enzyme
      defect and the molecular mutations. In addition, a simple flowchart is presented
      as a guide to the identification of mitochondrial FAO-disorders. Finally,
      treatment strategies are discussed briefly.

PMID- 10407784
TI  - The spectrum of mutations of the aspartoacylase gene in Canavan disease in non
      Jewish patients.
AB  - Canavan disease is an infantile neurodegenerative disease that is caused by
      mutations in the gene encoding the enzyme aspartoacylase. It has mainly been
      reported in Jewish families. Genotyping of newly diagnosed patients is essential
      for the carrier identification and prenatal diagnosis. The sequence of the coding
      region was determined in 15 non-Jewish patients and 9 new mutations were
      identified: Y109X, P183H, V186F, M195R, P280L, P280S, A287T, 245insA, and a
      tentative missplicing mutation which leads to skipping of exon 5. The common pan
      European mutation, A305E, was identified in 40% of the alleles and the overall
      detection rate was 93%.

PMID- 10407782
TI  - Automated mutation analysis.
AB  - Automated mutation analysis brings with it a vastly increased capacity in the
      number of test samples that can be processed at a time, as well as much improved
      test reproducibility. Until now, the introduction of automation into this field
      had been restricted to the use of semiautomated sequencing systems to make the
      most of the sequence information extractable from a single lane in an
      electrophoretic gel or in a polymer-filled glass capillary. Much effort is now
      being directed into harnessing the potential of DNA microarrays (DNA chips) and
      there is increasing interest in the potential of matrix-assisted mass
      spectrometry for determining the detail of large nucleic acid molecules.
      Meanwhile, there are other important recent developments already available,
      including robotic workstations, the further development of the allele-specific
      oligonucleotide assay into microtitre formats, and its use with fluorescence for
      real-time quantitative PCR analysis. Implementation of these developments in
      appropriate settings can further streamline the routine of molecular diagnostic
      laboratories, allowing them to take greater advantage of the recent surge of gene
      discoveries and their associated disease-causing mutations.

PMID- 10407785
TI  - The neuronal ceroid-lipofuscinoses (Batten disease): a new class of lysosomal
      storage diseases.
AB  - The neuronal ceroid-lipofuscinoses (Batten disease) are a group of severe
      neurodegenerative disorders characterized clinically by visual loss, seizures and
      psychomotor degeneration, and pathologically by loss of neurons and lysosomal
      accumulation of autofluorescent storage material resembling ageing pigment. To
      date, eight genetic loci have been identified (CLN1-8). Four CLN genes have been
      isolated (CLN1, CLN2, CLN3 and CLN5) and their gene products have been
      characterized. CLN1 is a lysosomal palmitoyl-protein thioesterase (PPT) and CLN2
      is a lysosomal pepstatin-insensitive peptidase. CLN3 and CLN5 are proteins with
      multiple membrane-spanning regions and have no homologies to other proteins that
      would suggest their function. The CLN3 protein is associated with lysosomal
      membranes and the intracellular location of the CLN5 protein is unknown.
      Therefore, there is ample evidence that the neuronal ceroid-lipofuscinoses
      represent a new class of lysosomal storage disorders.

PMID- 10407786
TI  - Spinal muscular atrophy.
AB  - Spinal muscular atrophy is a common cause of disability in childhood and is
      characterized by weakness and wasting of voluntary muscle. It is frequently
      fatal. The gene for this disorder has been identified as the SMN gene and is part
      of a highly complex duplicated region of chromosome 5 that is subject to a high
      rate of gene deletion and gene conversion. The severity of muscle weakness
      correlates with the amount of full-length SMN protein produced. Molecular genetic
      studies support a model in which patients are compound heterozygotes of deleted
      and converted alleles that predicts a progressively decreasing amount of protein
      product with severity of muscle weakness. The function of SMN is beginning to be
      understood and it appears to be involved in ribonucleoprotein biogenesis and thus
      indirectly in post-transcriptional processing of mRNA. There are theoretical
      grounds for motor neurons having a cell-specific vulnerability to disturbances of
      mRNA processing and transport and these are briefly reviewed.

PMID- 10407788
TI  - Tandem mass spectrometry--the potential.
AB  - We summarize the current status of the use of tandem mass spectrometry for the
      detection of inherited metabolic disorders and the investigation of the
      pathophysiology of these conditions. We also indicate some of the more recent
      developments of this technology that have potential diagnostic applications.

PMID- 10407787
TI  - X-linked cardioskeletal myopathy and neutropenia (Barth syndrome) (MIM 302060).
AB  - X-linked cardioskeletal myopathy, neutropenia and abnormal mitochondria (MIM
      302060) (synonyms: Barth syndrome, 3-methylglutaconic acid-uria type II,
      endocardial fibroelastosis type 2) has been reported in patients and families
      from Europe, North America and Australia. Previous studies characterized the main
      components of the disease: dilated cardiomyopathy, skeletal myopathy,
      neutropenia, 3-methylglutaconic aciduria and diminished statural growth.
      Respiratory chain impairments have been found in several studies, without
      pinpointing a single enzyme complex. 3-Methylglutaconic aciduria is shared with
      several other disorders that affect the respiratory chain. Previous studies
      excluded a block in the major pathway of leucine catabolism. We performed leucine
      loading, accompanied by fasting, in patients and observed a significant rise of 3
      methylglutaconic acid and 3-methylglutaric acid. Taken together with the absence
      of an enzymatic block in the major leucine catabolic route, the possibility
      remains that the increased basal excretion of 3-methylglutaconic acid and other
      products of branched-chain amino acids is the result of overload of this pathway
      or--more likely--mitochondrial leakage. Linkage studies have localized the gene
      to the Xq28 region. The associated tafazzin gene (TAZ), has been fully
      characterized recently, and mutations located in conserved regions have been
      reported. Carrier detection and prenatal diagnosis have now become possible
      through mutation analysis. Sequence homology of the TAZ gene to a highly
      conserved superclass of acyltransferases (Neuwald's hypothesis) predicts a
      glycerophospholipid as the missing end product. This points to the (lipid)
      structure of the inner mitochondrial membrane as a promising new area of
      research.

PMID- 10407789
TI  - Population newborn screening for inherited metabolic disease: current UK
      perspectives.
AB  - Some of the generally accepted criteria for screening programmes are
      inappropriate for newborn metabolic screening as they ignore the family dimension
      and the importance of timely genetic information. Uncritical application of such
      criteria creates special difficulties for screening by tandem mass spectrometry,
      which can detect a range diseases with widely different natural histories and
      responsiveness to treatment. Further difficulties arise from increasing demands
      for direct proof of the effects of screening on long-term morbidity and
      mortality. The randomized controlled trial is held to be the gold standard, but
      for ethical and practical reasons it will be impossible to achieve for such
      relatively rare diseases. This approach also oversimplifies the complex matrix of
      costs and benefits of newborn metabolic screening. A more workable approach could
      involve Bayesian synthesis, combining quantitative performance data from
      carefully designed prospective pilot studies of screening with existing
      experience of the natural history, diagnosis, and management of the individual
      disorders concerned.

PMID- 10407790
TI  - Female hypoactive sexual disorder: case studies of physiologic androgen
      replacement.
AB  - Menopause, surgical or naturally occurring, with reduced or deficient ovarian
      functioning has a major impact on morbidity and mortality in mid- to late life. A
      growing body of literature notes the role of androgens in maintaining women's
      health and emotional well-being. The administration of physiologic levels of
      testosterone replacement therapy as an adjunct to estrogen replacement requires
      further investigation. The Sexual Energy Scale was used to measure the patient's
      subjective experience of vitality or sexual energy with androgen replacement
      therapy. Three cases of women who had undergone a total abdominal hysterectomy
      with bilateral oophorectomy with complaints consistent with female hypoactive
      sexual desire disorder and free testosterone levels of < 2.0 pg/ml are presented.
      Physiologic androgen replacement is helpful in increasing sexual desire for some
      women.

PMID- 10407791
TI  - The sexual struggles of 23 clergymen: a follow-up study.
AB  - Nineteen clergymen, 17 of whom were Catholic, were followed up 1 to 6 years after
      their initial evaluation in a program designed to assess the sexual offenses and
      rehabilitation potential of offending professionals. Methods used included a
      semistructured interview with a research psychiatrist and a repeat of the MCMI
      III. At follow-up, the clergymen were relatively psychologically healthy. The
      vast majority of the men had returned to previous or higher levels of vocational
      functioning and felt that they had benefited from their initial evaluation and
      therapy. None of those who were initially suspected of sexual compulsivity met
      criteria for excessive sexual expression at follow-up, and none had re-offended.
      The typical clergyman, whether heterosexual or homosexual, was struggling with
      loneliness, masturbation conflicts, and the wish to be known beyond their role by
      others. The confrontative style of the evaluators in pursuing the veracity of the
      clergy's initial explanations of their behaviors and the use of penile
      plethysmography were the primary objections to the methods used. Brief
      psychotherapy seemed to be a cost-effective, well-received intervention for
      clergy struggling with their sexual conflicts.

PMID- 10407792
TI  - Characteristics of couples applying for bibliotherapy via different recruitment
      strategies: a multivariate comparison.
AB  - This study compared characteristics of couples with different sexual dysfunctions
      who were recruited for participation in a bibliotherapy program via two routes:
      in response to media advertisements and through their presence on a waiting list
      for therapist-administered treatment in an outpatient sexology clinic. Data were
      collected from 492 subjects (246 couples). Male sexology patients were younger
      than media-recruited males. However, type of sexual dysfunction accounted for a
      substantially larger proportion of variance in the demographic and psychometric
      data. An interaction effect of recruitment strategy and sexual dysfunction type
      was found with respect to female anorgasmia. We conclude from the absence of
      differences between the two study groups that the Wills and DePaulo (1991) model
      of help-seeking behavior for mental problems does not apply to couples with
      sexual dysfunctions joining a bibliotherapy program who either primarily
      requested professional treatment or who responded to media advertising.

PMID- 10407793
TI  - Prevalence of sexual dysfunction in women seeking services at family planning
      centers in Tehran.
AB  - In the present study, a modified standardized sexual function questionnaire,
      along with a test of knowledge about and attitude toward sexuality, was
      administered to 300 healthy women, ages 16 through 53, who sought services at
      family planing centers in Tehran, Iran. All participants were married. The
      greatest percentages had two children (35%) and were housewives (69%). Some 72%
      were well educated, and 1% were illiterate; 74% of the women had moderate
      knowledge about sexuality, and 53% had a conservative attitude toward sexuality.
      The study revealed the prevalence of inhibited desire (15%), inhibited orgasm
      (26%), lack of lubrication (15%), vaginismus (8%), and dyspareunia (10%); 38% of
      the women had at least one sexual dysfunction. The most common sexual
      difficulties reported were "too little foreplay before intercourse" and "partner
      chooses inconvenient time" (8% each). Despite these difficulties, 51% of the
      sample reported that their overall sexual relationship was satisfactory.
      Knowledge about sexuality was significantly correlated with orgasm experience,
      higher knowledge being associated with more orgasm experience. There were
      significant correlations between attitude toward sexuality and sexual function
      (orgasm, desire, lubrication); a conservative attitude was associated with more
      sexual dysfunction. Spousal sexual dysfunction had a significant negative
      correlation with sexual function in the woman.

PMID- 10407794
TI  - Gender differences related to heterosexual condom use: the influence of
      negotiation styles.
AB  - The present study had three primary goals. The first was to identify gender
      differences related to negotiation styles associated with condom use. We
      hypothesized that women would report engaging in more negotiation behaviors
      associated with condom use than men. The second goal was to determine whether the
      relationships between intentions to use condoms and past condom use for women and
      men were moderated by negotiation behaviors. The third goal was to examine gender
      differences in responses to an open-ended question inquiring why participants did
      not use condoms. Male and female college students (N = 219) anonymously completed
      a series of measures. The results indicated that women and men have unique roles
      in the negotiation process; women play a more active role in negotiation of
      condom use, while men play a more reactive role. The relationship between
      intentions to use condoms and past condom use increased for men when their
      partners were more active in the process of deciding whether to use condoms.
      Responses to the open-ended item revealed that women identified perceptions of
      low risk as the most common reason for not using condoms, while men identified
      the inconvenience or unavailability of condoms as the most common reason. The
      implications of these results are discussed as they relate to health efforts to
      increase condom use.

PMID- 10407795
TI  - The nonsexual marriage: assessing viability and treatment options.
AB  - This article is intended to be heuristic--to encourage conceptual, clinical, and
      empirical attention to assessment issues and clinical interventions in dealing
      with the multicausal, multidimensional problem of nonsexual marriages. Many of
      these marriages can be revitalized, while for others the sexual problem is
      indicative of a nonviable relationship. Assessment issues are explored with
      implications for treatment strategies.

PMID- 10407796
TI  - Sexuality following breast cancer.
AB  - This article provides sex and marital therapists with detailed, multifaceted
      descriptions of sexuality after breast cancer based on survey responses from 863
      breast cancer survivors. One third of women reported that breast cancer had had a
      negative impact on her sex life, and most reported negative changes in at least
      some areas. Nonetheless, breast cancer survivors did not differ from age-matched,
      healthy women on a standard measure of sexuality. Women who were most likely to
      report a negative impact on sexuality from cancer were those who had experienced
      changes in hormonal status, problems in their relationships, and difficulties
      with vaginal dryness. On the basis of these findings, we offer suggestions for
      health professionals and therapists treating breast cancer survivors.

PMID- 10407797
TI  - [Retinoblastoma].

PMID- 10407799
TI  - [Optician must take the prism eyeglasses back].

PMID- 10407798
TI  - [Follow-up of retinoblastoma during homeopathic therapy].

PMID- 10407800
TI  - [Current status of infrared photoablation of the cornea].
AB  - BACKGROUND: IR-photothermal ablation has, for some time, been described as an
      alternative to UV photoablation with Excimer lasers. Both procedures are based on
      different laser-tissue-interactions. IR solid state lasers have cost advantages
      over UV laser technology and allow a broader clinical use. New beam shaping
      principals had to be developed. IN-VITRO: Systematic biophysical investigations,
      recently using tunable Free Electron Lasers, have described the ablation
      efficiency, the collateral thermal adverse effects, the surface properties and
      particle size, and the dynamic behaviour of the particle ejection, all as a
      function of wavelengths (and thus of different absorbers in the corneal tissue),
      of energy and of different pulselengths. The free running Er:YAG laser is
      suitable and well investigated, the optic parametrical oscillator (OPO) with
      supershort pulses a more recent alternative. IN VIVO: First in vivo photoablation
      with different Er:YAG lasers has proved the principle feasibility of IR
      photoablation. Histology of enucleated human eyes indicates that the wound
      healing and repair after IR photoablation is not principally different from UV
      PRK. The evaluation of the achievable optical quality of the cornea in vivo as
      well as data on the stability resp. regression of the ablation profiles are still
      pending.

PMID- 10407801
TI  - [Erbium laser phacoemulsification--a clinical pilot study].
AB  - INTRODUCTION: From August 1997 to March 1998, we performed a prospective pilot
      study to examine erbium laser phacoemulsification in cataract surgery under
      clinical conditions and to determine the side effects of this method. PATIENTS
      AND METHOD: 34 patients (40 eyes) with senile cataract were recruited. Slit lamp
      findings, keratometry, best corrected visual acuity, refraction, pachymetry,
      endothelial cell count and intraocular pressure were determined preoperatively
      and on 1st, 4th, 14th and 60th postop day according to a standardised protocol
      (single pulse energy between 10 and 20 mJ, frequency of application 60 Hz,
      average phaco time 3 min, total energy 38.5 mJ). The operations were done with
      the erbium laser system MCL 29, Aesculap-Meditec Co., Jena, Germany. RESULTS: A
      total emulsification of the nucleus was possible in 36 of 40 eyes (90%) (nucleus
      hardness between 0 and 3). A partial emulsification of the nucleus in nucleus
      hardness 3 was possible in 2 eyes, in nucleus hardness 4 in 1 eye and in nucleus
      hardness 2 in 1 eye (4 eyes--10%). Visual acuity increased from 0.3 preop to 0.8
      two months postop (median). Intraocular pressure decreased from 16 mm Hg
      preoperatively to 13 mm Hg two months postoperatively (median). The increase of
      corneal thickness was not statistically significant compared to baseline. The
      decrease of endothelial cell count was 0.96%. Postoperative complications which
      are not known in ultrasonic phacoemulsification did not appear in erbium laser
      phacoemulsification. CONCLUSION: Erbium laser phacoemulsification is a surgical
      method that makes the emulsification of softer nuclei under clinical conditions
      possible with a low rate of complications also in the beginning of the learning
      curve. For higher nucleus hardnesses, technical and surgical parameters have to
      be optimised. Advantages of erbium laser phacoemulsification compared to
      ultrasonic phacoemulsification are less energy transmission into the eye, no
      heating of anterior chamber, impossibility of corneal burns and easier access in
      eyes that are deep into the orbit. Especially advantageous is the high protection
      of endothelium by erbium laser phacoemulsification. A prospective controlled
      comparative study to ultrasonic emulsification is desirable.

PMID- 10407802
TI  - [Bacterial keratitis in patients with and without contact lens anamnesis].
AB  - BACKGROUND: The study shows differences between contact lens wearers and patients
      without history of contact lenses regarding the spectrum of etiological agents in
      bacterial keratitis. Based on microbiological analysis, there are given
      recommendations for an optimal initial antibiotic treatment in both groups.
      MATERIAL AND METHODS: From 1989 to 1997 smears, scrapings and corneal biopsies
      were taken from 218 patients with bacterial keratitis. The causing pathogens were
      isolated on directly inoculated culture media and identified by staining and
      microscopy. The resistance pattern of a total of 275 germs was analysed for
      different antibiotics. RESULTS: The most frequently isolated germs were
      Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus spp.,
      Propionibacterium acnes and Pseudomonas aeruginosa. Whereas sensitive gram
      positive germs were predominating in contact lens wearers as well as in non
      contact lens wearers, multiresistant gram-negative germs could nearly exclusively
      be isolated from contact lens wearers. Frequently administered antibiotics like
      aminoglycosides and quinolones are effective in infections caused by
      Staphylococcus spp., but increasing resistance could be seen to Streptococcus
      spp. In this case, erythromycin is very sensitive. Gram-negative germs like
      Pseudomonas aeruginosa are sensitive to quinolones and some aminoglycosides (e.g.
      tobramycin). CONCLUSION: In contact lens wearers, more aggressive germs have to
      be considered than in non-contact lens wearers. In such cases, frequently
      administered antibiotics like amino-glycosides are not effective. To cover
      problematic gram-negative germs we recommend the application of quinolones
      alternating with erythromycin. The latter one is more effective than quinolones
      and aminoglycosides in case of Streptococcus spp. co-involvement.

PMID- 10407803
TI  - [Keratoconus screening with wave-front parameters based on topography height
      data].
AB  - BACKGROUND: The image-forming properties of a keratoconus eye are degraded even
      in the early stage of this disease. The purpose of this study was to develop
      keratoconus detection scheme based on topography height data independent of the
      currently used system which avoids the disadvantages of detection algorithms
      currently used in clinical practice. PATIENTS AND METHODS: Eighty-eight patients
      with keratoconus (46 with mild and 42 with severe clinical signs) and a control
      group of 40 normal subjects were included in this study. A decomposition of
      corneal topography height data into orthogonal Zernike polynomials was performed
      using the commercially available corneal topographer TMS-1. Expansion
      coefficients of the different groups were compared to evaluate significant
      differences. Elevated terms were used to detect the disease. The statistical
      significance of this detection scheme was compared to those given by the
      keratoconus detection software of the TMS-1. From the elevated Zernike terms a
      neural network was constructed and optimized for dividing keratoconus patients
      and normal controls. RESULTS: Some low-order Zernike coefficients with a radial
      order n < 8 were found to be elevated in patients with keratoconus and were used
      to define a new detection algorithm. This index performed at least as well
      (sensitivity in mild/severe keratoconus 93.4%/100% with a specificity of 100%) as
      keratoconus detection schemes based on the Klyce-Maeda and the Rabinowitz-Klyce
      indices as well as the I-S value and the Surface Asymmetry Index SAI in our study
      population. CONCLUSIONS: Zernike decomposition of corneal topography height data
      allows a definition of an exact and robust algorithm for detection of
      keratoconus. It avoids the drawbacks of refractive power based definitions and is
      independent on the individual topographer design.

PMID- 10407804
TI  - [Cyclocryocoagulation in treatment of therapy refractory glaucoma: a
      retrospective analysis of 185 cryocoagulation procedures].
AB  - BACKGROUND: For several years it has been discussed whether cyclocryotherapy is
      still an up-to-date treatment of resistant inadequately controlled glaucoma. This
      retrospective study investigates the clinical aspects of 185 cyclocryotherapies
      between 1988 and 1997. PATIENTS AND METHODS: At the University Eye Clinic of
      Tubingen, 114 patients received in 119 eyes (64.3%) one cyclocryotherapy, and in
      66 eyes (35.7%) multiple cyclocryotherapies. The standard surgical techniques for
      cyclocryotherapy can be summarized as followed: probe placements per eye, 4 to 6;
      location of probe placement, inferior circumference (63.9%); distance of the
      applicator from limbus, 3 mm (50.7%); temperature of the probe tip, -70 degrees C
      (34.2%); and time of the treatment, 60 seconds (89.9%). RESULTS: Intraocular
      pressure was on average 33.8 mm Hg before treatment. In all analysed glaucoma
      types intraocular pressure was lowered to 10.2 mm Hg (30%). The most frequent
      type of glaucoma was the neovascular glaucoma (55%). One year after treatment,
      this type showed on average, relative to all other types of glaucoma, the highest
      intraocular pressure (28.1 mm Hg) and a lowering of intraocular pressure by 8.3
      mm Hg (22.7%). Half a year after cyclocryotherapy, a highly significant (p <
      0.002) reduction of antiglaucomatous medication was achieved in comparison to the
      preoperative medication. CONCLUSION: Despite the fact that cyclocryotherapy is
      not always effective, it is an ambulant surgical technique easy to apply, non
      invasive, cost-effective and can be repeated to lower intraocular pressure in
      resistant chronic glaucoma. We conclude that cyclocryotherapy will remain useful
      until new techniques, like the diode laser cyclophototherapy (especially
      ultrasonic controlled), are developed as alternative therapies.

PMID- 10407805
TI  - [Contrast enhancement in the public environment--improvement in orienting
      capacity of visually handicapped patients].
AB  - BACKGROUND: Partially sighted often experience problems in orientation in public
      areas. Individual visual aids can only be used with limitations. Improving light
      intensity and colour contrasts of timetables, information signs, direction
      symbols, etc. can provide remedies. Experimentally substantiated directives do
      not yet exist. PATIENTS AND METHODS: Experiments were conducted in 231 partially
      sighted subjects (binocular vision < 0.3) diagnosed as experiencing dullness when
      watching the media, having maculopathies, glaucomas, or dystrophic alterations of
      the retina or choroid, and in 43 normal subjects to determine the subjective
      assessment of colour and light-intensity contrasts. The presented contrast
      patterns were Hartmann-characters as infield (3.3 degrees) with a rectangular
      surround (19.5 degrees x 14.3 degrees). Three experimental series were carried
      out in which subjects assigned 14 non-coloured/non-coloured contrasts, 35 non
      coloured/colour contrasts and 30 colour/colour contrasts to any of the five
      assessment classes of extremely poor, poor, optimal, sharp, extremely sharp. The
      colour contrasts consisted of combinations of yellow, green, red, purple, blue,
      and non-coloured. RESULTS: For non-coloured/non-coloured, the subjects preferred
      positive contrasts (bright infield, dark surround). Preferred contrast levels
      were 0.91 to 0.99 for positive contrasts and -0.96 to -0.99 for negative
      contrasts. For colour/non-coloured contrasts, 90% of the partially sighted
      preferred yellow as the foreground colour with a contrast level above 0.89. For
      colour/colour contrasts, optimal assessments of 90% of all partially sighted were
      yellow/purple and yellow/blue with contrast levels above 0.90. The determined
      results are applicable for the exact experimental contrast settings only. A field
      manual was prepared for planning and design of contrasts suited for the partially
      sighted in public areas. CONCLUSIONS: Partially sighted, in subjective contrasts
      assessment, prefer bright characters of signs on a dark background for both non
      coloured and colour contrasts with contrast levels above 0.9. Yellow was the
      preferred infield colour.

PMID- 10407806
TI  - [Image properties of spherical as aspheric intraocular lenses].
AB  - BACKGROUND: One reason for the problems that pseudophakic patients have with
      their mesopic vision is the spherical aberration of the implanted intraocular
      lens (IOL). Therefore we developed an aspheric IOL that will minimize this
      aberration. Starting with a 22 diopter lens we checked whether it is possible to
      keep the aspheric surface of the lens constant while changing the second radius
      to cover a larger range of needed refractive power. Afterwards we also checked
      whether the theoretical results correspond to the practically tested image
      quality. METHODS: We analyzed the image quality of the aspheric lenses
      theoretically by calculating the optimal defocused geometrical spot size. For the
      ray tracing we used the Gullstrand schematic eye model with an aspheric cornea.
      The calculated spot sizes were compared to those of a spherical IOL. Subsequently
      we compared the quality of both lenses by imaging an USAF-test target through a
      model eye. RESULTS: We were able to design an aspherical IOL to improve the
      optical performance up to the limit of diffraction. When the second radius was
      changed, the spot size enlarged as we expected, but it was considerable smaller
      than that of the respective spherical IOL. The image quality that we tested with
      the model eye was considerably better with the aspherical lens than with the
      spherical lens. CONCLUSIONS: It is possible to improve the optical performance of
      intraocular lenses by aspherization. The production procedure can be kept simple
      by aspherizing only one side of the lens. The refractive power can be changed by
      varying the radius of the spherical side. In our opinion aspheric IOL's should be
      used especially for cataract patients with a pupil size of 5 mm and more.

PMID- 10407807
TI  - [Optic nerve sheath meningioma with intraocular invasion--a case report].
AB  - BACKGROUND: In case a sonographically high reflective intraocular tumor is
      detected, some different processes with calcium embedding could be considered.
      PATIENT: A 56 year-old female patient was seen in our department for the first
      time because of secondary glaucoma of the amaurotic right eye. The left eye has
      had no morphological changes and visual acuity was 5/5. CASE HISTORY: More than
      20 years ago the patient had noticed decreased visual acuity of the right eye for
      the first time. 10 years ago in a first report from another eye hospital, a large
      white tumor in the area of the optic disc had been described. Sonographic size
      was 12 x 8 mm, 5.3 mm prominence. Visual acuity was perception of light with
      incorrect projection. A CT scan showed an inhomgeneous structure of calcification
      in the area of the right optic disc which continued along the optic nerve to
      intracranial structures. Enucleation was performed. Histopathological examination
      showed meningothelial meningeoma (grade I WHO) with its origin in the dural
      sheath of the optic nerve and intraocular growth. A postoperative MRI confirmed
      the intracranial spreading of the meningeoma along the dural sheath of the
      optical nerve. A meningeoma of the olfactorius region was found as a second
      independent tumor. CONCLUSION: The intraocular spread of an optical nerve sheath
      meningeoma is a rare case.

PMID- 10407808
TI  - [Hyperplastic persistent pupillary membrane--surgical procedure].
AB  - BACKGROUND: Persistent pupillary membranes are a common congenital anomaly seen
      in 95% of neonates. Extensive persistent pupillary membranes, occluding the
      visual axis and resulting in reduced visual acuity, are relatively uncommon. CASE
      REPORT: A 4-year-old male infant was seen in our hospital with reduced visual
      acuity of his left eye. Slit-lamp examination revealed a dense, extensive,
      persistent pupillary membrane associated with anterior polar cataract. We
      performed an excision of the pupillary membrane, lens aspiration of the lens
      material, posterior capsulorhexis, anterior vitrectomy and placement of a
      posterior chamber-intraocular lens in the capsular bag. 8 weeks after operation
      visual acuity improved to 0.25. CONCLUSIONS: Dense pupillary membranes associated
      with polar cataract require early surgical treatment. Membranectomy, lens
      aspiration and implantation of an intraocular lens clear the visual axis and
      optimize the treatment of amblyopia.

PMID- 10407809
TI  - [Chronic liver disease after treatment of malignancies in children].
AB  - Chemotherapy, which has greatly improved the prognosis of children with malignant
      diseases, is potentially hepatotoxic. Furthermore, there is a risk for viral
      hepatitis acquired by blood products. In this study we looked for hepatotoxicity
      and for chronic viral hepatitis during and after chemotherapy in 50 unselected
      children with malignant diseases. 29 children had been treated for leukemia or
      lymphoma, 19 for solid tumors, 2 for histiocytosis. All patients had been treated
      before 1991 and had received blood products not screened for hepatitis C
      antibodies. In 18 girls and 32 boys aged 12.3 years (range 6.7-24.5 years)
      hepatitis B- and hepatitis C-serology and liver function tests were measured
      during a routine check-up 3.6 years (range 0.5-11.8 years) after the last
      chemotherapy. Liver function tests during chemotherapy were reviewed
      retrospectively. During chemotherapy 86% of children showed increased ALT and AST
      levels, 10% had levels above 500 U/l. At follow up 16 children (32%) had
      pathological liver function tests, especially slightly increased AST and ALT, 13
      of these 16 patients had chronic hepatitis C. In contrast only 2 of 34 patients
      with normal liver function tests had a viral hepatitis (p = 0.001). Patients with
      elevation of AST and ALT above 100 U/l during chemotherapy had significantly more
      often a viral hepatitis than those with normal or slightly elevated
      aminotransferases. Our study shows that hepatocellular damage is a frequent
      complication following chemotherapy. However this progresses to chronic liver
      disease very rarely unless the patient acquired a viral hepatitis. The prevalence
      of chronic hepatitis C was very high in our patients. As screening of blood
      products for hepatitis C-antibodies is routinely performed since 1991 this
      problem is likely to have decreased.

PMID- 10407811
TI  - [The feasibility of preoperative autologous blood donation in children].
AB  - According to the experience to date, autologous blood donation is feasible in
      children and is not accompanied by an increased risk as compared to adult
      patients. If indicated, autologous blood donation should therefore be offered to
      pediatric patients using the same criteria as in adults. Problems specific to
      blood donation in children may arise from limited compliance of the children. In
      addition, the amount of the blood drawn and the amount of the anticoagulant has
      to be adjusted according to the weight of the child. This may present
      difficulties especially in smaller facilities, since there are no blood donation
      systems available to date that specifically suit the pediatric patient. The
      necessary manipulations to adjust the blood donation system to the weight of the
      child might enhance the risk of bacterial contamination.

PMID- 10407810
TI  - [Persistent Lactobacillus casei subspecies rhamnosus bacteremia in a 14 year old
      girl with acute myeloid leukemia. A case report].
AB  - The present clinical observation is related to a 14-year-old girl suffering from
      acute myeloid leukemia. The clinical course was complicated by episodes of severe
      enterocolitis, E. coli- septicemia, pancreatitis and pneumonia. In the course of
      continued cytostatic and antibiotic treatment a persistent asymptomatic
      Lactobacillus casei subsp. rhamnosus-bacteremia became detectable by a total of
      18 blood cultures. Microbial cultures of the faeces revealed colony-forming
      unites of this germ in orders of 10(9)/g. Antibiotic eradication attempts
      according to the resistogram were not successful. The Lactobacillus-bacteremia
      disappeared only after 13 months when the cytostatic therapy was terminated. An
      adjuvant influence of the Lactobacillus infection on the outcome of the
      underlying disease cannot be excluded.

PMID- 10407812
TI  - The CNS symptoms of rotavirus infections under the age of two.
AB  - BACKGROUND: Since isolation of the Rotavirus (RV), there is rapidly growing
      concern about the possible involvement of RV in Central Nervous System (CNS)
      disorders, especially in Japan. We looked for symptomatic CNS involvement in a
      large series of RV infections and it's possible risk factors in a European
      setting. METHODS: Two-year retrospective survey based at the University
      Children's Hospital of Freiburg, Germany, a secondary and tertiary care centre
      with a urban and rural catchment area of 400,000 people. First, the case records
      of all 366 inpatients aged under two years excreting RV were searched for signs
      and symptoms of CNS involvement. Second, records of all 32 patients hospitalised
      with meningitis/encephalitis during the study period were checked for evidence of
      RV infection. RESULTS: In 15 of 366 children signs of CNS involvement (seizures,
      meningeal and encephalitic signs) were found. They were older (p = 0.023), had
      higher temperatures (p = 0.001) and CRP values (p = 0.019). Five of the fifteen
      had underlying neurological diseases, two had an additional salmonella infection
      and one suffered from hypernatraemic toxicosis. In the remaining seven children,
      higher temperature (p = 0.037) and older age (p = 0.05) remained significant risk
      factors. CNS-signs occurred in 2% of RV-excreting children, a rate equal to the
      prevalence of febrile seizures among all inpatients during the study period
      (2.2%). Of all 32 patients hospitalised with a diagnosis of meningitis or
      encephalitis only four had their stools tested for RV, all with a negative
      result. CONCLUSIONS: CNS symptoms in children aged less than two years with
      rotavirus diarrhoea have the same clinical epidemiology as febrile seizures and
      thus, in general, don't need additional diagnostic procedures.

PMID- 10407813
TI  - Diagnosis and stage-related treatment of disseminated intravascular coagulation
      in meningococcal infections.
AB  - Disseminated intravascular coagulation (DIC) is a frequent complication of
      meningococcal sepsis in children. Despite the availability of potent antibiotics,
      mortality in meningococcal disease remains high (about 10%), rising to 40% in
      patients presenting in severe shock and consecutive DIC. As the clinical course
      and the severity of manifestations of systemic meningococcal infections varies
      there is a need for early diagnosis of the infection and of the stage of
      coagulopathy in order to reduce the high mortality rate. Few and rapidly
      available parameters are needed to classify the wide spectrum of clinical and
      laboratory findings in patients with DIC. The parameters include partial
      thromboplastin time, prothrombin time, plasma levels of fibrinogen, antithrombin
      III (AT III), fibrin monomers and D-dimer concentration, fibrin degradation
      products and the thrombocyte count. Monitoring the course of hemostasis findings
      in 28 pediatric patients (age between 3 months and 8 years, mean 3.1 years) with
      systemic meningococcal infections we observed a change of coagulation parameters
      already in the first stages of the infection: A prolongation of partial
      thromboplastin time mean 69.1 sec (range 22-150 sec, normal 30-45 sec), a
      decrease of prothrombin time to 45.7% (range 13-71%, normal 70-100%) and of AT
      III to an average level of 70% (normal 85-125%) was found 1 to 4 (-6) hours after
      admission. The following deterioration of prothrombin time and partial
      thromboplastin time turned out to be statistically significant (p < 0.05, signed
      rank test). The monitoring of hemostasis parameters mentioned above made it to
      possible define the stage of coagulopathy and thus to start a stage related
      therapy. Treatment consisted of shock control by liquid substitution,
      compensation of metabolic acidosis, correction of clotting disorders (AT III and
      heparin in case of pre-DIC; AT III and fresh frozen plasma in case of advanced
      DIC), antibiotic treatment (beta-lactam antibiotics e.g. cefotaxime or
      ceftriaxone), and--when necessary--catecholamine infusions. An early assessment
      of the coagulation disorders in meningococcal disease can be based on few
      coagulation parameters. Thus an appropriate treatment can be arranged in order to
      prevent a fatal outcome of meningococcal sepsis and to protect against the
      development of a Water-house-Friderichsen-syndrome.

PMID- 10407814
TI  - [Diagnosis and therapy of Lyme borreliosis in children. Practice guideline of the
      German Society for Pediatric Infectious Diseases].
AB  - Lyme borreliosis is the most frequent tickborne++ disease of man in the Northern
      hemisphere. A variety of systems may be involved. The most frequent
      manifestations in childhood include erythema migrans, meningitis, cranial nerve
      palsy and arthritis. Erythema migrans usually is easily recognised and
      determination of antibodies to Borrelia burgdorferi should not be performed.
      Childhood neuroborreliosis is characterised mostly by aseptic meningitis with or
      without cranial nerve palsy, in most cases facial palsy. Basic CSF findings often
      show a combined evidence of lymphocytic pleocytosis, IgM-class dominance in
      intrathecal humoral immune++ response, and blood-CSF barrier dysfunction.
      Calculation of the Borrelia burgdorferi specific antibody index (according to
      Reiber) proved to be the most sensitive method for detecting intrathecal
      synthesis of specific antibodies. Lyme arthritis presents initially as episodic
      oligoarthritis, mostly involving the knee joint, and may turn into chronic
      monoarthritis of the knee; usually high titers of IgG antibodies to Borrelia
      burgdorferi are found. The rarer manifestations encephalomyelitis, chronic
      arthritis, carditis and inflammatory eye disease may be difficult to diagnosis
      due to clinical ambiguity and problems in the interpretation of serological
      results. Antibodies to Borrelia burgdorferi found by sensitive Elisa must always
      be confirmed by immunoblot analysis, but sometimes immunoblot analysis is more
      sensitive than Elisa. Treatment is by antibiotics, amoxicillin or doxyciclin for
      erythema migrans, and i.v. third generation cephalosporins for all other
      manifestations. Even after successful antibiotic therapy, antibodies may persist
      for months and years and no further antibiotic treatment is necessary in the
      absence of attributable clinical manifestations. The differentiation between a
      persisting immune response and a persisting infection therefore has to be based
      upon the clinical symptoms, non-specific laboratory data and the development of
      the antibody titers.

PMID- 10407815
TI  - [Complicated malaria tropica in an infant].
AB  - We report on a five month-old infant from Cameroon, who was admitted because of
      febrile gastroenteritis after living in Germany for two weeks. Since the patient
      was somnolent, had a parasitaemia of Plasmodium falciparum of 230,000/microliter,
      a haemoglobin concentration of 5.3 g/dl and a thrombocytopenia, a complicated
      falciparum malaria was diagnosed. Treatment was started immediately with
      intravenous 20 mg quinine/kg bw as a loading dose, followed by 10 mg/kg bw every
      12 hours, combined with intravenous clindamycin 10 mg/kg bw bd. Red blood cells
      were transfused once. The parasitaemia dropped to 2000 trophozoites/microliter
      within 48 hours. No asexual stages were detectable from the third day of
      treatment on. Weekly controls for the following four weeks remained negative. The
      mortality rate of complicated malaria is 50% in the first year of life, which can
      be reduced by early treatment. We present this case to draw attention to
      therapeutic options in infants.

PMID- 10407816
TI  - [Detection of antibacterial activity in the urine of children: a comparison of
      three tests].
AB  - BACKGROUND: Detection of antibacterial activity in urine is important for the
      diagnosis of urinary tract infections and for assessment of patient compliance
      with antibiotic therapy. METHOD: Urines of paediatric inpatients were examined by
      the Bacillus subtilis agar diffusion test and two commercial test strips (Micur
      BT and Urotest AB). RESULTS: 566 urines of 431 patients were examined. The B.
      subtilis agar diffusion test was the most reliable method (accuracy 98.8%). Micur
      BT showed a comparatively low specificity (87.6%) and Urotest AB had a
      comparatively low sensitivity (86.0%). CONCLUSION: The B. subtilis agar diffusion
      test is the most reliable method for detection of antibacterial activity in the
      urine of children.

PMID- 10407817
TI  - [Combination therapy of high frequency oscillatory ventilation, NO inhalation and
      surfactant replacement in a child with acute respiratory distress syndrome].
AB  - We report about a child with severe ARDS after burning trauma who did not respond
      to conventional treatment with controlled pressure ventilation under conditions
      of permissive hypercapnia and changing of the infants's body position. A combined
      treatment with high frequency oscillatory ventilation, inhalation of nitric oxide
      and surfactant replacement improved the pulmonary status. Twelve days after the
      accident the boy could be extubated and 5 weeks later he could be discharged
      without any pulmonary and neurologic handicap. The use of these therapeutic tools
      may help to avoid the necessity of the invasive extracorporeal life support.

PMID- 10407818
TI  - [A comparative study about the therapeutic effect of theophylline and doxapram in
      apnoeic disorders].
AB  - The objective of this study was to prove the superiority of doxapram compared to
      theophylline therapy in apneas of prematurity in very low birth weight infants.
      Therefore all VLBW infants (gestational age < 35 weeks) were randomized if they
      had in a 2 hours-interval more than 2 apneas, 4 bradycardias or 4 oxygen
      desaturations. They received either theophylline (loading dose 5 mg/kg b. w., 3
      mg/kg b. w. bid) or doxapram by continuous infusion of 0.5 mg/kg/h. Apneas,
      bradycardias and desaturations were recorded from the trend analysis of our
      monitoring system over the first 3-days and a 7 days period and compared
      statistically (Mann-Whitney U-test). Plasma levels of both drugs and a
      polysomnographic recording were obtained during steady state conditions in
      parallel to a behavioral observation according to Prechtl. The recorded events
      were again compared using the Mann-Whitney U-test. Twenty patients were treated
      with theophylline, 14 with doxapram. In 9 patients of each group we could perform
      a polysomnography and behavioral observation. The incidence of apneas,
      bradycardias and desaturations in a 7 days-interval was not significantly
      different between both groups. Analyzing the first 3 days of treatment, however,
      we could detect a significantly lower rate of apneas in the doxapram group (2.5
      apneas compared to 7 in the theophylline group, p < 0.037). In the
      polysomnographic recording and in our behavioral observations we could not record
      any significant differences between both groups. Therefore we can conclude that
      theophylline and doxapram are comparable in the treatment of apneas of
      prematurity, however, doxapram is superior to theophylline in reducing the rate
      of apneas in the first 3 days of treatment.

PMID- 10407819
TI  - Pulmonary veno-occlusive disease, antiphospholipid antibody and pulmonary
      hypertension in an adolescent.
AB  - Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension
      (PH); Antiphospholipid antibody (APL) is another known cause of pulmonary
      hypertension, due to recurrent pulmonary thromboembolism. The coincidence of both
      causes, PVOD and APL, without thromboembolism, in PH has not been reported
      previously in children. A 12.5-year-old boy presented with a one year history of
      fatigue. Pulmonary hypertension was diagnosed by echocardiography. Pulmonary
      function tests revealed a moderate restrictive pattern and elevated granulocytes
      were detected in bronchoalveolar lavage. An isolated high-titer APL was detected.
      Open lung biopsy established the diagnosis of PVOD, with no evidence of pulmonary
      thrombosis, but with accompanying interstitial and alveolar cellular
      infiltration. We speculate that APL may have played a role in the pathogenesis of
      PVOD. Prednisone++ improved the symptoms of the interstitial pneumonitis and was
      stopped; on follow up of 30 months, the patient ist in stable condition on
      therapy with nifedipin, phenprocoumon and digoxin. CONCLUSIONS: PVOD and APL may
      be present simultaneously as a rare cause of PH. Interstitial pneumonitis may
      accompany PVOD and produce the leading symptoms. Open lung biopsy is essential
      for early establishment of the diagnosis.

PMID- 10407820
TI  - [Meeting of the Pediatric Work Group AIDS in Germany (PAAD) on May 8-9, 1998 in
      Frankfurt/Main].

PMID- 10407821
TI  - [Round window membrane defect in divers].
AB  - BACKGROUND: The rupture of the round window membrane is a special form of
      traumatic inner ear deafness. Because of the changing pressure levels, divers are
      at risk of developing such a membrane rupture, especially if tube function is
      disturbed. As the popularity of diving as a sport increases, ENT specialists have
      to deal with diving related problems increasingly frequently. PATIENTS AND
      METHODS: Seven cases of divers are presented in whom a tympanotomy was performed
      following the diagnosis of a rupture of the round window membrane. The symptoms
      and intraoperative findings are discussed and the otologic and diving literature
      is reviewed. Following a case report, the pathophysiology, clinical symptoms and
      differential diagnosis of round window ruptures are discussed controversially.
      Possible therapeutical consequences are described. RESULTS: None of our patients
      exhibited the classical triad of deafness, tinnitus, and vertigo as described in
      the diving literature. The leading symptom in our patients was the loss of
      hearing; only two patients had vertigo. Tinnitus was found in half of the
      patients. Intraoperative a rupture of the round window membrane was presumed in
      five divers. CONCLUSIONS: If disturbance of inner ear function does occur
      concurrently with diving, a rupture of the round window membrane must be
      considered. An otologic examination must be performed in any diver with a loss of
      hearing and/or signs of a barotrauma of the middle ear. After differential
      diagnosis to exclude other possibilities, a tympanotomy to cover the round window
      membrane should be performed if symptoms persist more than 24 hours.

PMID- 10407822
TI  - [Genotoxic effect on human mucous membrane biopsies of the upper aerodigestive
      tract].
AB  - BACKGROUND: In numerous epidemiologic studies, environmental and occupational
      substances such as sodium dichromate (Na2Cr2O7), benzo[a]pyren (B(a)P), and
      N'nitroso-diethanolamine (NDELA) have been shown to be of potential carcinogenic
      risk on human epithelial cells in the upper aerodigestive tract. METHODS: Using
      the alkaline microgel electrophoresis technique (comet assay). mucosal cells
      isolated from biopsies of the upper aerodigestive tract (nose, paranasal sinuses,
      mouth, pharynx, larynx, and tonsils) were used to analyze target sites for
      different genotoxic substances and specific sensitivities of each donor. The
      cells were freshly isolated by enzymic digestion. 0.5-1 x 10(6) cells per donor
      were obtained with viabilities between 80-100%. After in vitro incubation, the
      cells were subsequently subjected to the single cell microgel electrophoresis
      assay. Results were evaluated regarding the personal history of each donor,
      focusing on previous exposure to tobacco, alcohol, and occupational compounds.
      RESULTS: Na2Cr2O7 induced strong genotoxic damage in the nasal and paranasal
      sinus epithelia as well as in mucosa cells of the larynx. NDELA caused
      significant damage in mouth cavity epithelia and showed also to be harmful
      towards mucosa of pharynx and larynx. B(a)P induced fewer DNA strand breaks in
      mucosal cells of mouth, pharynx and larynx. Significant differences between
      individuals were apparent for tissue samples from different donors. The genotoxic
      damage induced in cells of donors with a history of chronic alcohol consumption
      was significantly higher than in cells of patients without chronic abuse of
      alcohol. CONCLUSIONS: The data shows that DNA damage in human epithelial cells of
      the upper aerodigestive tract induced by environmental and occupational
      substances can be demonstrated using the microgel electrophoresis technique. The
      influence of chronic alcohol consumption on the genotoxic effects of substances
      such as NDELA and B(a)P showed the importance of evaluating preexisting
      compounding factors.

PMID- 10407823
TI  - [Immunohistologic and molecular genetic studies of the effect of glutathione-S
      transferases on the development of squamous epithelial carcinomas in the area of
      the head-neck].
AB  - BACKGROUND: While cigarette smoking and alcohol consumption are the major risk
      factors for the development of head and neck carcinomas, it is assumed that
      genetic factors contribute to risk. The aim of this study was to characterize the
      influence of the carcinogen metabolizing glutathione-S-transferases on
      susceptibility to head and neck carcinomas. PATIENTS AND METHODS: Polymorphisms
      at GSTM1, M3, T1 and P1 gene loci were determined in 398 head and neck cancer
      patients and 216 controls using polymerase chain reaction and restriction enzyme
      digestion. The epithelial distribution of the GSTs was determined by
      immunohistochemical methods. RESULTS: The GSTM1 A/B genotype was less frequent in
      all tumor groups compared with controls. The GSTM3 B/B genotype was reduced only
      in the laryngeal cancer group whereas GSTP1 A/A showed significant differences
      between pharyngeal cancer patients and controls. Accordingly, GSTM3 was expressed
      only in the cilia of the laryngeal respiratory epithelium. In contrast, GSTP1 was
      distributed throughout all outer layers of the squamous cell epithelium.
      CONCLUSIONS: While GSTM1 seems to influence susceptibility to all head and neck
      cancers, GSTM3 and P1 reflected site-specific differences. Thus GSTM3 appears to
      be associated with altered risk only to laryngeal cancer whereas GSTP1 is likely
      to influence pharyngeal cancer risk.

PMID- 10407824
TI  - [Case report of a basaloid squamous epithelial carcinoma of the oropharynx:
      clinical and histopathologic markers of an aggressive tumor entity].
AB  - BACKGROUND: Basaloid squamous cell carcinoma is a variant of squamous cell
      carcinoma which is located predominantly in the upper aerodigestive tract. The
      cardinal histopathologic feature is a biphasic cellular pattern of basaloid and
      squamous components in a close relationship. Major differential diagnoses include
      adenoid cystic, adeno, squamous, adenosquamous, and basal cell carcinomas. This
      entity may commonly pose diagnostic difficulties, especially on small biopsy
      material, if only the basaloid component of the tumor is included. CASE REPORT: A
      tumor of the oropharynx (T2) was detected in a 61-year-old man. After endoscopic
      biopsy, this tumor was histologically identified as an adenocarcinoma. A very
      rapid tumor growth became obvious during the patient's staging. After
      pharyngectomy and neck dissection, the histopathological diagnosis was corrected
      to a basaloid squamous cell carcinoma. The definite diagnosis was not made on
      biopsy material, because only the basaloid component of the tumor was included.
      DISCUSSION: Basaloid squamous carcinoma is a biologically aggressive tumor with
      high proliferative activity and a propensity to destructive local growth and
      early regional and distant metastasis. Literature predominantly indicates that
      basaloid squamous cell carcinoma is an aggressive variant of squamous cell
      carcinoma and is prognostically worse than the regular squamous cell carcinoma.
      CONCLUSION: Because of the aggressive biological behavior of basaloid squamous
      cell carcinoma, radical surgery combined with radiation and chemotherapy is the
      treatment of choice.

PMID- 10407825
TI  - [Diagnostic procedure in primary ciliary dyskinesia].
AB  - BACKGROUND: Primary ciliary dyskinesia (PCD) is usually diagnosed by
      ultrastructural investigations of nasal or bronchial mucosa. Less invasive
      techniques for quick and cost-effective diagnosis of PCD should be evaluated.
      METHODS: In 32 patients with suspected PCD, saccharin transport time, ciliary
      beating of nasal respiratory epithelium, and ultrastructure of nasal mucosa
      biopsies were investigated. RESULTS: In 13 patients, PCD was excluded by a normal
      saccharin transport time (< 20 min). In 19 patients, respiratory cells were
      obtained by nasal brushing. Frequency, coordination, and amplitude of ciliary
      beating were examined using interference contrast microscopy and scored. PCD was
      excluded in 10 of 19 patients, who revealed normal ciliary activity. In the
      remaining 9 patients, nasal mucosa specimens for ultrastructural investigation
      were obtained. Ultrastructural alterations indicating PCD were found 4 of 9
      specimens, in 2 specimens no cilia were found and in 3 specimens alterations
      indicating secondary inflammatory alterations were found. CONCLUSIONS: PCD may be
      efficiently excluded in several cases using cost-effective diagnostic techniques.
      The definite diagnosis in the remaining cases requires ultrastructural
      investigations which should be performed in specialized centers. In the present
      study, PCD in a carefully preselected group had a surprisingly high prevalence.

PMID- 10407826
TI  - [Rhinoscleroma: a case report].
AB  - BACKGROUND: Rhinoscleroma is a rare infectious disease of the upper respiratory
      tract caused by Klebsiella rhinoscleromatis. The nasal mucosa represents the
      primary region of occurrence which is most likely a result of respiratory
      transmission. Without adequate++ treatment, the disease can potentially spread to
      the rest of the upper and middle respiratory tract within a period of several
      years. Healing often occurs with extensive scarring and adhesions of the nose,
      palate and larynx. A life threatening late stage manifestation includes
      subglottic stenosis requiring immediate surgical intervention. Medical treatment
      primarily consists of a long-term course of antibiotics. Ciprofloxacin
      (Fluoroquinolon) has proved to be one of the most effective drugs. CASE REPORT:
      We report about a 33 year-old Egyptian male, who presented in our department with
      a 10 year history of a previously, only temporarily successfully treated
      rhinoscleroma. His main symptoms were nasal obstruction, epistaxis and
      inspiratory stridor. FINDINGS: We began treatment with Ciprofloxacin over a four
      week period, which lead to an improvement of his symptoms. The treatment was
      considered complete after several biopsies and smears were negative for live
      specimens. We then chose to reduce the scar tissue that was causing obstruction
      in the larynx and the nose. CONCLUSION: The rhinoscleroma is a rare disease in
      geographic areas with poor hygiene and can mimic several other infectious and
      malignant diseases. Treatment should include a long-term antimicrobial therapy
      and surgical intervention in cases with symptomatic obstruction.

PMID- 10407827
TI  - [Technique for the assessment of vestibular compensation--clinical
      observation/quantitative neuro-otometry?].
AB  - PROBLEM: Reliable evaluation of vestibular compensation in indispensable to
      determine whether labyrinth surgery or vestibular neurectomy is indicated. It is
      also important for postoperative follow-up. Vestibular compensation can manifest
      itself differently in distinct frequency ranges. METHOD: Twenty volunteers were
      examined in five distinct situations of daily vestibular stimulation. Measurement
      of angular and linear head acceleration was performed using accelerometers fixed
      on the volunteers' head. A 200 Hz AD fed data to a PC database. FFT was used for
      data analysis. RESULTS: Stimulus frequency of the vestibular system varies
      between 0.01 and 2 Hz. Most of the patients suffering from vestibular lesions
      showed a reduced vestibulo ocular reflex (VOR) below 0.1 Hz. In all cases of
      unilateral vestibular function loss, there was a correlation between the symptoms
      during movement and the corresponding frequency range of the distinct motion
      pattern. Rotatory vestibular pendular testing was used to document vestibular
      disorders in patients who had normal findings in routine vestibular testing.
      DISCUSSION: Clinical use of rotatory vestibular pendular testing results must be
      performed using broad stimulus frequency spectra (0.01-0.06 Hz). This method must
      be used in preoperative examination before labyrinth surgery as well as in
      estimating individual tolerance for vestibular stimulation in daily situations.

PMID- 10407828
TI  - [Orientational evaluation of otolith function by eye counter-rolling in patients
      with various kinds of vertigo].
AB  - BACKGROUND: Measurement of ocular counterrolling (OCR) is well known as a simple
      method to evaluate the peripheral vestibular organ, especially the otolith organ.
      But it has rarely been used because of the difficulty in differentiating between
      pathologically reduced OCR and the wide physiological variation of this
      parameter. PATIENTS: In this study, the OCR of 55 patients with unclarified
      vertigo (n = 20), vestibular neuronitis (n = 15), Meniere's disease (n = 10), and
      benign paroxysmal positional nystagmus (n = 10) were evaluated and compared to a
      control group (n = 30) with the intention of diagnosing peripheral vestibular
      dysfunction and establishing a differential diagnosis. The test sequence was
      carried out with Vesta goggles by Panares and included head tilts of 5 degrees,
      15 degrees, and 30 degrees to the left and right. RESULTS: The results show a
      significantly reduced OCR in patients suffering from peripheral vestibular
      disorders when compared to the control group. CONCLUSION: There is no specific
      finding for a specific type of vestibular lesion, but otolith function is
      affected in several disorders as measured by ocular counterrolling.

PMID- 10407829
TI  - [Thermographic detection of heat radiation in caloric vestibular function tests].
AB  - BACKGROUND: Since Barany; caloric irrigations in the external ear canal have been
      used for unilateral stimulation of the peripheral vestibular system. However, the
      mechanism of heat transfer from the auditory canal to the vestibular organ is not
      completely known. From the physical point of view, three mechanisms may be
      discussed: heat conduction via the bone, convection via the middle ear gas, or
      radiation. Feldmann et al. (1991) singled out radiation as a very important
      factor in this regard. Using high-resolution thermography, we were able to "see"
      radiation almost directly in temporal bone experiments. METHODS: Using the system
      of infrared thermovision specially adapted for close-up studies, the effect of
      calorization can be observed and documented in colored planar thermograms. Fresh
      temporal bone specimens had to be prepared so as to permit simultaneous
      observation of the tympanic membrane and the medial tympanic wall. RESULTS:
      Changes in temperature were readily visible during experimental caloric tests:
      turning blue indicated cooling and red indicated warming. In the caloric test
      with 44 degrees C or 30 degrees C water, changes in color of the eardrum appeared
      immediately. At the very same time, however, an area of the medial tympanic wall
      also changed color. This velocity of transfer cannot be attained by conduction or
      convection: heat radiation is the only possible explanation. This could only be
      demonstrated at the very onset of the reaction; subsequent thermograms became
      more and more diffuse. In this stage the heat transfer may also be effected by
      conduction and/or convection. CONCLUSIONS: Thermography demonstrates that
      radiation is a very important factor in heat transfer; at least in the initial
      phase of calorization.

PMID- 10407830
TI  - [Formation of cholesteatomas after middle ear ventilation. Independent proof
      presented to the Duisburg federal court--2 OH 39/96].

PMID- 10407831
TI  - [Guidelines/algorithms of the German Society of Otorhinolaryngology, Head and
      Neck Surgery. Guideline: hearing aid management. German Society of
      Otorhinolaryngology, Head and Neck Surgery].

PMID- 10407832
TI  - [Interesting case no. 23. Abnormal site of the jugular vein, so-called right
      megabulbus].

PMID- 10407833
TI  - [Economic aspects of psychotherapy management in psychosomatics and psychiatry. A
      systematic survey of the literature].
AB  - Economic evaluations have become more and more important in the somatotherapeutic
      field. This survey's objective was to examine if the current economic evaluation
      techniques can be applied to psychotherapy. 8 data banks, 17 key words from the
      psychotherapeutic field and 14 economic key words were used, the identified
      original studies were classified in accordance with Drummond, the methodical
      quality of each study was assessed at a score between 0 and 10 points. 21 studies
      were found: 16 cost-benefit analyses, 4 cost-effectiveness analyses and one cost
      utility analysis. The quality of the representation of the clinical results (mean
      value 8.6) was better than that of the economic results (mean value 6.1). It was
      perfectly possible to evaluate psychotherapeutic interventions with regard to
      economic aspects by means of the current techniques but in most cases there was a
      considerable lack of quality in both representation and calculation. Furthermore
      the evaluation type of cost-utility analysis, which is the only one that takes
      quality of life aspects into consideration and therewith seems to be the most
      appropriate approach regarding the psychotherapeutic field, has been greatly
      ignored.

PMID- 10407834
TI  - [Anhedonia--a general nosology surmounting correlate of a dysfunctional
      dopaminergic reward system?].
AB  - The dopaminergic reward system is activated by primary rewarding factors such as
      food, sexual activity and parental care. Its activation enhances the occurrence
      of behaviors which induced the stimulation of dopaminergic neurotransmission.
      Indications of a dysfunction of the dopaminergic reward system are found in major
      depression, schizophrenia, and addictive disorders. It has been hypothesized that
      dysfunction of the dopaminergic reward system is associated with anhedonia, the
      inability to experience pleasure. However, animal studies indicate that a
      reduction of central dopaminergic neurotransmission is associated with a decrease
      in incentive salience of reward-indicating stimuli and not with anhedonia per se.
      Sensitization of dopaminergic neurotransmission, on the other hand, seems to
      induce cue-dependent craving in addicted patients. In schizophrenia, phasic,
      stimulus-dependent dopamine release in the striatum may play a role in the
      abnormal attribution of salience to previously neutral stimuli.

PMID- 10407835
TI  - [Psychopathological correlates of dopaminergic dysfunction in alcoholic and
      schizophrenic patients].
AB  - It has been suggested that anhedonia, the loss of pleasure, is associated with a
      dysfunction of the dopaminergic reward system in schizophrenic and alcohol
      dependent patients. In a series of neuroendocrinological and brain imaging
      studies, we examined pre- and postsynaptic mechanisms of dopaminergic
      neurotransmission in non-human primates and in schizophrenic and alcohol
      dependent patients. Among alcoholics, we found indicators of a sensitization of
      dopaminergic neurotransmission, which was associated with the relapse risk, but
      not with anhedonia or depression. Schizophrenics with neuroleptic blockade of
      striatal dopamine D2 receptors displayed psychomotor slowing and reduced
      motivation, but not anhedonia. Primate studies pointed to the importance of a
      temporocortical dysfunction in the pathogenesis of phasic dopaminergic
      dysregulation in the striatum. These observations indicate that a dysfunction of
      stimulus-dependent dopamine release may be associated with motivational deficits
      caused by a reduction in incentive salience, but not with anhedonia.

PMID- 10407836
TI  - [Neuropsychological deficits in the initial acute episode of schizophrenia. A
      comparison with chronic schizophrenic patients].
AB  - By administering an extensive battery of neuropsychological tests, cognitive
      performance of 66 patients with first episode schizophrenia, 49 patients with
      chronic schizophrenia and 40 healthy controls has been assessed in the areas of
      memory functions, speech and cognitive flexibility/abstraction. The three groups
      were comparable with regard to age, gender and education. Both patient groups
      showed a significant generalized neuropsychological impairment relative to
      controls. Patients with first episode were most impaired in visual motor
      processing and attention (VSM). Besides impairment in VSM, performance in
      abstraction/flexibility was significantly worse in chronic schizophrenics
      compared to first episode schizophrenics. Our findings suggest that
      neuropsychological functions are already impaired at the onset of the illness.
      Whether cognitive impairment in performance that is attributed to frontal
      dysfunctions is deteriorating during the course of the illness or is predicting
      an unfavourable course can only be answered by prospective follow-up studies.

PMID- 10407837
TI  - [Dimensions of schizophrenic symptomatology. Comparative testing of several
      theoretical models in a first-episode population sample].
AB  - The issue of this study was the investigation of the dimensional structure of non
      psychotic and psychotic symptoms in 232 first-episode schizophrenic patients (ICD
      9 295., 297., 298.3, 298.4). The study was conducted within the ABC-Schizophrenia
      Study. The three-factor-model of Liddle with three factors (psychomotor poverty,
      disorganisation, reality distortion) was replicated for the time at first
      admission. The model is also valid for first-episode-patients as well as to
      chronic patients. The comparison of the three-factor-model of Liddle with Crow's
      dual process model, Andreasen's bipolar model and the "severity-liability" model
      was done by means of confirmatory factor analysis. The comparison shows that at
      first admission, the three-factor-model fitted in best with the data. In contrast
      to previous analyses within the ABC-Study, in which positive correlations have
      been found between positive and negative symptoms, no positive correlation exists
      between Liddle's negative and positive dimensions. This may be the consequence of
      the subdivision of the positive dimension into the two dimensions disorganisation
      and psychotic symptoms. As within the three-factor-model only the negative
      dimension and disorganisation correlated weekly, the three dimensions are best
      viewed as relatively independent for the time at first admission. There are no
      associations between sex, type of onset, age at onset and the three dimensions of
      Liddle's model. Patients with the familial load are more disorganized and
      patients with obstetric complications show more negative symptoms. While the
      negative dimension shows a high stability over five years, the dimensions
      "disorganisation" and "positive symptoms" are not stable over time. However,
      there is a high degree of correlation for the dimensions "disorganization" and
      "positive symptoms" among cross-sections while the negative dimension was
      independent of the other two dimensions. The negative dimension is a highly
      significant predictor for social disability and social development over five
      years, whereas the dimensions "disorganization" and "positive symptoms" have no
      prognostic importance for the outcome in the long term.

PMID- 10407839
TI  - [Psychosis, language and literature].
AB  - There have always been debates about possible correlations between creative
      genius and mental illness, not only among psychiatrists but also among scientists
      of art and literature. Especially modern literary texts may show formal
      similarities to psychotic speech, which leads to the question, whether not only
      artists, but also people in psychotic states are able to create literature. This
      article points out the loosened semantic stability in psychotic speech, which
      equals a loss of common ground in the use of signs and symbols. In terms of
      Gadamer's hermeneutics, texts produced by psychotic people cannot be understood,
      they are mere form. Even in hermetic literary texts, the semantic code can be
      offended, but in deliberate artistic intention, which finds its communicative
      purpose in breaking the symbolic order.

PMID- 10407838
TI  - [Dimensions of bizarre, idiosyncratic thinking. Relationship between thought
      disorders and affect].
AB  - In the present study disorders of thinking were studied in normals, patients with
      neurotic disorders, borderline patients and both acute and chronic
      schizophrenics. Disorders of thinking were assessed by the Holtzman Inkblot
      Technique. By a factor analysis, different dimensions of disordered thinking
      characteristic of the different diagnostic groups could be identified. Among
      others two dimensions of schizophrenic thought disorder and one of borderline
      thought disorder could be identified. This latter dimension showed high
      correlations with anxiety and hostility. This was true for a dimension of
      productive schizophrenics thought disorders, but not for a dimension of negative
      schizophrenics thought disorders.

PMID- 10407840
TI  - [Psychoeducational-psychotherapeutic treatment of schizophrenic patients and
      their caregivers. II. Supplementary findings at a 2-year follow-up].
AB  - In this study we investigated whether, in conjunction with neuroleptics, a
      psychoeducational and cognitively oriented treatment for schizophrenic
      outpatients and their key-persons can improve the course of schizophrenic illness
      within a 2-year follow-up. This prospective randomized study covered a total of
      191 schizophrenic patients (according to DSM-III-R) and comprised a
      psychoeducational training and cognitive psychotherapy for patients and
      counseling for their key persons in various combinations. Patients were examined
      before, immediately after and 2 years after the end of the intervention. Patients
      in the treatment groups reduced their overall psychopathology and their attention
      deficit. For patients receiving all three treatment conditions, there was a
      relevant preventive effect with regard to the rehospitalization rate appearing
      during the second year of the follow-up. We conclude that in the mid-term, a
      combination of psychoeducational and cognitively oriented therapy for patients
      and their keypersons can improve the course of schizophrenic illness.

PMID- 10407841
TI  - [Drug-dependent offenders committed for disciplinary action. Results of a cross
      sectional survey].
AB  - In comparison to the middle of the 80th, the group of patients who are addicted
      to legal and illegal drugs and are treated in special forensic hospitals, has
      significantly changed. Polyvalent dependence is the predominant diagnosis. There
      has been an increase in violence of index delinquency. In the middle of the 80th,
      most of the patients were committed because of criminal offences against the BtMG
      (German law to sentence drug abusers). Today, robbery turns out to be the
      "classical" index delinquency. The problem of defining "false admission" to a
      forensic hospital has to be considered in a multidimensional way.

PMID- 10407842
TI  - ['Methadone substitution therapy and driving'. Results of an experimental study].
AB  - The aim of our experimental study was to gain informations and data on the
      driving ability of patients undergoing a methadone substitution programme as well
      as to explore the influence of an HIV infection. 28 patients, five of them HIV
      positive, were compared to a control group equal in age, sex and education. For
      the traffic relevant tests the methadone patients showed significantly reduced
      performance. Six of the methadone patients passed the tests in a way regarded to
      have sufficient driving skills. We were unable to prove an influence of HIV
      infection on driving skills when lacking relevant somatic and neuropsychiatric
      symptoms. There was no significant correlation between the test results and
      patients age or dose of medication. We conclude that in general methadone
      substitution does not implicate driving inability although the majority of our
      patients showed some reduction of their psychomotoric skills.

PMID- 10407843
TI  - [Cost-efficacy analysis of clinically evaluated therapeutic programs. An expanded
      withdrawal therapy in alcohol dependence].
AB  - BACKGROUND: Cost-effectiveness analyses complete clinical evaluation studies and
      thereby support the a well based estimation of therapy efficiency. AIM: A
      qualified (extended) alcohol withdrawal treatment programme (II), which was
      previously described and evaluated by face-to-face follow-up studies, was
      analyzed with regard to cost-effectiveness. SAMPLE: 57 alcohol-dependent
      patients, which had undergone programme II, were compared with 37 patients after
      a medical detoxification programme (I). METHODS: Health insurance data (number
      and length of all hospitalizations, days of incapacity to work, days of financial
      substitution for incapacity to work) were assessed for the five years before and
      after index therapy and for each year, separately. RESULTS: While there were no
      substantial differences for the time before index therapy, programme II patients
      were hospitalized after index therapy (i) less frequently (3.5 + 4.4 vs. 7.3 +
      11.3 times), (ii) for fewer days (66 + 75 vs. 136 + 167) than programme I
      patients, and they received financial support for fewer days (67 +/- 73 vs 220 +/
      187 days). CONCLUSION: Considering a somewhat better clinical outcome of
      programme II vs. programme I patients (14% greater abstinence rate within one
      year) the significantly lower rates and fewer days of follow-up hospitalisations
      support a sufficient efficiency of the extended alcohol withdrawal treatment
      programme.

PMID- 10407844
TI  - [Hallervorden-Spatz syndrome. Differential diagnosis of early onset dementia].
AB  - We report the history of a 38 year old patient who began to develop mental
      deterioration at the age of 26. After a time of 7 years neurological signs like
      writing dystonia occurred. Hallervorden-Spatz-Disease (HSD) was diagnosed at the
      age of 36 in vivo with the clinical presentation of severe dystonia, rigidity,
      dementia, and typical signal loss in the globus-pallidus the reticular part of
      the substantia nigra, and the nucleus ruber in the T-2 weighted MRI. The "eye-of
      the-tiger"-sign, a bilateral hyperintensity in the rostral globus pallidus, was
      not observed in follow-up examinations. HSD is a rare autosomal-recessive or
      sporadic disease of unknown etiology. In one third of the patients a dementing
      process is the first clinical sign of the disorder, and is a rare differential
      diagnosis of early onset dementia.

PMID- 10407845
TI  - [Help in explaining to Turkish-speaking patients about the central affects of
      pharmaceuticals. Fact or fiction?].
AB  - Handouts in their mother tongue might be helpful in informing patients who do not
      speak German about medications that are prescribed. A survey among 97 producers
      of CNS active drugs used in neurology and psychiatry showed that only two patient
      information leaflets on preparations and nine on specific disorders are available
      in Germany. The producers who answered were mostly open-minded and mentioned
      causes like the legal situation and logistic problems.

PMID- 10407846
TI  - [Glutamate receptor agonists and alcohol dependence. Preclinical findings].

PMID- 10407847
TI  - ['Catatonic dilemma'. Comments on the article by H. Lausberg and R.Hellweg.
      Nervenarzt (1998) 69:818-822].

PMID- 10407848
TI  - Molecular analysis of a spontaneous dystrophin 'knockout' dog.
AB  - We have determined the molecular basis for skeletal myopathy and dilated
      cardiomyopathy in two male German short-haired pointer (GSHP) littermates.
      Analysis of skeletal muscle demonstrated a complete absence of dystrophin on
      Western blot analysis. PCR analysis of genomic DNA revealed a deletion
      encompassing the entire dystrophin gene. Molecular cytogenetic analysis of
      lymphocytes from the dam and both dystrophic pups confirmed a visible deletion in
      the p21 region of the affected canine X chromosome. Utrophin is up-regulated in
      the skeletal muscle, but does not appear to ameliorate the dystrophic canine
      phenotype. This new canine model should further our understanding of the
      physiological and biochemical processes in Duchenne muscular dystrophy.

PMID- 10407849
TI  - Behavioral characterization of mdx3cv mice deficient in C-terminal dystrophins.
AB  - Cognitive deficits are frequently associated with Duchenne muscular dystrophy
      (DMD). They might be due to a deficiency in the brain isoforms of the 427 kDa
      full-length dystrophin, and/or to altered expression of other C-terminal
      dystrophin-gene products (Dp71, Dp140) also found in brain. Mdx mice, which only
      lack full-length dystrophin in both muscle and brain, were previously shown to
      have moderate learning and memory deficits. In the present study, we investigated
      behavioral responses in mdx3cv mutants, which have altered expression of all the
      dystrophin-gene products. Contrary to the original mdx mice, mdx3cv mice showed
      enhanced anxiety-related behaviors and reduced locomotion as compared to control
      mice. Although those perturbations might be related to the lack in C-terminal
      dystrophins, they do not seem sufficient to induce strong learning deficits in
      this mutant. Indeed, we showed that mdx3cv mice may display similar or weaker
      deficits during the learning of a bar-pressing task, as compared to mdx mice. The
      relevance of the mdx3cv mutant as a model to study the cognitive deficits
      associated with DMD is discussed.

PMID- 10407850
TI  - Mitochondrial 3243 A-->G mutation (MELAS mutation) associated with painful muscle
      stiffness.
AB  - The mitochondrial mutation A-->G at nucleotide position 3243 is associated with
      mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
      (MELAS) and other mitochondrial encephalomyopathies. We found this mutation in a
      61-year-old patient who developed at the age of 54 a myopathy with painful muscle
      stiffness as the predominant symptom. Additionally hypacusis, a mild hemisensory
      syndrome and impaired glucose tolerance were present. Muscle histopathology
      showed few ragged red fibers. The mutation was detected heteroplasmatically in
      DNA from muscle and blood. So far painful muscle stiffness has not been a known
      phenotype of the 3243 mutation.

PMID- 10407851
TI  - A second locus for autosomal dominant myopathy with proximal muscle weakness and
      early respiratory muscle involvement: a likely chromosomal locus on 2q21.
AB  - We recently mapped a locus for a new variant of autosomal dominant myopathy
      (Swedish families) with proximal muscle weakness, early respiratory muscle
      involvement, and unique muscle biopsy findings to chromosomal region 2q24-31. In
      this study, a French family with a similar clinical phenotype and pathology
      (muscle biopsy) was investigated to see whether the disease gene associated with
      the myopathy is mapped to the same region as the one in the Swedish families;
      however, chromosomal region 2q24-q31 was completely excluded. In order to
      localise the disease gene for the French family, a genome-wide scan was performed
      using polymorphic microsatellite markers. A maximum two-point lod score of 2.11
      (the highest lod score that can be achieved in this family) was obtained for the
      markers in the region between D2S1272 and D2S1260, spanning 4 cM. This result
      suggests that the gene responsible for the French form is likely to be located on
      chromosome 2q21.

PMID- 10407852
TI  - Myopathy in very-long-chain acyl-CoA dehydrogenase deficiency: clinical and
      biochemical differences with the fatal cardiac phenotype.
AB  - A 30-year-old man suffered since the age of 13 years from exercise induced
      episodes of intense generalised muscle pain, weakness and myoglobinuria. Fasting
      ketogenesis was low, while blood glucose remained normal. Muscle mitochondria
      failed to oxidise palmitoylcarnitine. Palmitoyl-CoA dehydrogenase was deficient
      in muscle and fibroblasts, consistent with deficiency of very-long-chain acyl-CoA
      dehydrogenase (VLCAD). The gene of this enzyme had a homozygous deletion of three
      base pairs in exon 9, skipping lysine residue 238. Fibroblasts oxidised
      myristate, palmitate and oleate at a rate of 129, 62 and 38% of controls. In
      contrast to patients with cardiac VLCAD deficiency, our patient had no lipid
      storage, a normal heart function, a higher rate of oleate oxidation in
      fibroblasts and normal free carnitine in plasma and fibroblasts. 31P-nuclear
      magnetic resonance spectroscopy of muscle showed a normal oxidative
      phosphorylation as assessed by phosphocreatine recovery, but a significant
      increase in pH and in Pi/ATP ratio.

PMID- 10407853
TI  - Infantile lipid storage myopathy with nocturnal hypoventilation shows abnormal
      low-affinity muscle carnitine uptake in vitro.
AB  - An infant with respiratory insufficiency, cardiomyopathy, lipid storage myopathy
      and low muscle carnitine was diagnosed as having 'Ondine's curse' because of
      recurrent nocturnal hypoventilation. Carnitine uptake was studied in 20-day-old
      cultured muscle, where two distinct saturable transport components are
      recognized: the high- and low-affinity-uptake. Experimental evidence suggests
      that low-affinity-uptake is muscle-specific, operating at physiological carnitine
      concentration. In the patient's cultured myotubes, the low-affinity-uptake K(m)
      was 260% of controls (P < 0.01), whereas kinetic parameters of high-affinity
      uptake were normal. The high K(m) indicates an immature or altered carnitine
      muscle carrier, which may decrease the physiologic carnitine uptake.

PMID- 10407854
TI  - Prenatal diagnosis in a family affected with beta-sarcoglycan muscular dystrophy.
AB  - We present here the first prenatal diagnosis in beta-sarcoglycan muscular
      dystrophy. The consultand was an 11-week pregnant mother of a girl diagnosed at
      the age of 3 years with beta-sarcoglycan muscular dystrophy based on the
      identification of two nonsense mutations in her beta-sarcoglycan gene and on the
      absence of beta-sarcoglycan in her muscle biopsy. The direct search for these
      mutations in the chorionic villus DNA of the fetus showed that the fetus did not
      inherit her sister mutations and thus, was reported as unaffected. We suggest
      that direct gene mutation detection is more reliable than linkage or protein
      study in the prenatal diagnosis of sarcoglycanopathies.

PMID- 10407855
TI  - Decreased expression of laminin beta 1 in chromosome 21-linked Bethlem myopathy.
AB  - Muscle biopsies of four patients affected by chromosome 21-linked Bethlem
      myopathy were investigated by means of immunohistochemistry, with monoclonal
      antibodies for laminin chains, dystrophin and dystrophin associated
      glycoproteins. The objective of this study was to determine whether an altered
      molecular structure of collagen type VI, characteristic of Bethlem myopathy,
      could influence the expression of the protein complex linking the extracellular
      matrix with the subsarcolemmal cytoskeleton. Normal expression of all proteins
      was found except for laminin beta 1, along with an age related progressive
      deficiency of this protein in the muscle fibre basal lamina. This study shows
      that Bethlem myopathy linked to chromosome 21 is associated with a secondary
      decrease in laminin beta 1 expression.

PMID- 10407856
TI  - Specific removal of the nonsense mutation from the mdx dystrophin mRNA using
      antisense oligonucleotides.
AB  - The mdx mouse, which carries a nonsense mutation in exon 23 of the dystrophin
      gene, has been used as an animal model of Duchenne muscular dystrophy to evaluate
      cell or gene replacement therapies. Despite the mdx mutation, which should
      preclude the synthesis of a functional dystrophin protein, rare, naturally
      occurring dystrophin-positive fibres have been observed in mdx muscle tissue.
      These dystrophin-positive fibres are thought to have arisen from an exon-skipping
      mechanism, either somatic mutations or alternative splicing. Increasing the
      frequency of these fibres may offer another therapeutic approach to reduce the
      severity of Duchenne muscular dystrophy. Antisense oligonucleotides have been
      shown to block aberrant splicing in the human beta-globin gene. We wished to use
      a similar approach to re-direct normal processing of the dystrophin pre-mRNA and
      induce specific exon skipping. Antisense 2'-O-methyl-oligoribonucleotides,
      directed to the 3' and 5' splice sites of introns 22 and 23, respectively in the
      mdx pre-mRNA, were used to transfect myoblast cultures. The 5' antisense
      oligonucleotide appeared to efficiently displace factors normally involved in the
      removal of intron 23 so that exon 23 was also removed during the splicing of the
      dystrophin pre-mRNA. Approximately 50% of the dystrophin gene mRNAs were missing
      this exon 6 h after transfection of primary mdx myotubes, with all transcripts
      showing skipping of exon 23 after 24 h. Deletion of exon 23 does not disrupt the
      reading frame and should allow the synthesis of a shorter but presumably
      functional Becker-like dystrophin. Molecular intervention at dystrophin pre-mRNA
      splicing has the potential to reduce the severity of a Duchenne mutation to the
      milder Becker phenotype.

PMID- 10407857
TI  - X-linked dilated cardiomyopathy and the dystrophin gene.
AB  - X-linked dilated cardiomyopathy (XLDC) represents a well known genetic disease,
      allelic to Duchenne and Becker muscular dystrophies and caused by dystrophin gene
      mutations. XLDC is a rare disease and only few families have been fully
      characterised. In several of them, the dystrophin mutations show a different
      pattern of expression in cardiac compared to skeletal muscle. In the families
      with the most severe cardiac phenotype, the cardiac muscle is usually unable to
      produce dystrophin, due to a specific effect that the mutation(s) have on the
      gene transcription in this tissue. The skeletal muscle escapes the dystrophic
      changes by maintaining dystrophin synthesis via exon skipping or alternative
      splicing that the heart is not able to put in place. In this paper we have
      reviewed the families with X-linked dilated cardiomyopathy reported so far; in
      addition we provided novel transcription data on two families we previously
      described. The aim of this review is to attempt a genotype-phenotype correlation
      and speculate on common pathogenic mechanisms underlying this disease.

PMID- 10407858
TI  - Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy.
AB  - A cross-sectional study in a cohort of DNA proven carriers of Duchenne (DMD) and
      Becker (BMD) muscular dystrophy was undertaken with the following objectives: (1)
      to estimate the frequency of electrocardiographic (ECG) and echocardiographic
      abnormalities; (2) to establish the proportion of carriers with dilated
      cardiomyopathy and (3) to assess possible associations between dilated
      cardiomyopathy and genotype. One hundred and twenty nine DMD and BMD carriers,
      aged 18-60 years, were traced through the files of the central register kept at
      the department of Human Genetics in Leiden. Investigations included full medical
      history, physical examination, ECG and two-dimensional and M-mode
      echocardiographic examination. Forty-seven percent had ECG changes. Thirty-six
      percent (DMD 41%, BMD 27%) had at least one abnormality as is usually found in
      the male patients. Echocardiographic examination was abnormal in 36% (DMD 38%,
      BMD 34%). Dilated cardiomyopathy was found in seven DMD carriers (8%), and in
      none of BMD carriers. In addition, 18% had left ventricle dilatation (DMD 19%,
      BMD 16%). Only 38% had a completely normal investigation of the heart. We found
      no association between genotype and cardiac manifestations. Our study underlines
      that cardiac involvement is part of the dystrophinopathies. Carriers should be
      told about the increased risk of this complication when asking genetic advice. It
      also implicates that a complete cardiological evaluation should be performed at
      least once in all carriers. If left ventricle dilatation or dilated
      cardiomyopathy is present a yearly follow up is needed, in order to start timely
      therapy.

PMID- 10407860
TI  - Neuromuscular disorders: gene location.

PMID- 10407861
TI  - Mitochondrial encephalomyopathies: gene mutation.

PMID- 10407859
TI  - Cognitive and psychological profile of a Tunisian population of limb girdle
      muscular dystrophy.
AB  - This study assesses the cognitive functioning of a Tunisian population suffering
      from limb girdle muscular dystrophy (LGMD). The population was randomly selected
      from patients referred to the outpatient clinic of the National Institute of
      Neurology of Tunis. The only criterion for inclusion was the absolute proof of
      this type of disease through clinical assessments, an immunohistochemical muscle
      study (dystrophin positive) and linkage study. Over a 2-year period, 16 cases
      were identified. Cognitive function was measured by individual IQ testing using a
      language-free, motor-reduced and cultural-free intelligence test. This test
      relies on adequate visual discrimination and spatial relationship skills;
      therefore, a test to appraise perceptual skills was administered to rule out
      potential deficiencies in these abilities. The results showed that this
      population was functioning well within normal limits of cognitive abilities (IQ
      of 102 +/- 3 mean +/- SEM). Additionally, the study looked upon the emotional
      adjustment of this population. Four projective cards were administered (eliciting
      themes of family confrontation, school attitude, dependence/anxiety and conflicts
      with parents/depression). Clinical indicators were recorded for each card. The
      findings were compared with a similar population in terms of demographic
      characteristics and referred to an outpatient psychology clinic for emotional and
      behavioral difficulties. The results showed that the LGMD population had a higher
      number of clinical indicators and a specific profile characterized by low self
      esteem with feelings of sadness and internalized culpability.

PMID- 10407862
TI  - Autologous peripheral blood stem cell transplantation in childhood tumors.

PMID- 10407863
TI  - Childhood myelodysplastic syndromes.

PMID- 10407864
TI  - The total care unit for pediatric hematology and oncology, Princess Margaret
      Hospital for Children, Perth, Australia.
AB  - The total care unit for the treatment of pediatric hematology/oncology in Perth,
      Australia is so named to embody the philosophy of multidisciplinary care of
      children and their families. Where possible, patients are treated according to
      randomized controlled trials of the large cooperative Children's Cancer Group.
      There is a seamless association of clinical and laboratory research. Hemopoietic
      stem cell transplantation is managed within the unit, as well as treatment of a
      range of non-malignant hematological disorders. Long-term follow-up of survivors
      of childhood cancer is coordinated from the unit.

PMID- 10407866
TI  - Right atrial catheter-related complications in pediatric oncology patients: the
      situation in a developing country.
AB  - The complications of right atrial catheters (RACs) in pediatric oncology patients
      are unknown for centers in developing countries. This study examined the
      complications of RACs at Ankara University Medical School, Turkey. A total of 90
      RACs were placed in 61 children for long-term chemotherapy with a total
      experience of 15,536 catheter days. The rate of catheter-related sepsis was 4.9
      episodes per 1000 catheter days. Coagulase-negative staphylococci and Candida
      species were the most common organisms, accounting for 25.0 and 13.1% of all
      organisms, respectively. The most common reasons for the removal of the RACs were
      infection (42.4%) and dislodgement (32.2%). The rates of complications were
      significantly higher in this study than in western studies. This increase could
      be explained by the differences in catheter care practices in the Turkish center.
      In conclusion, the use of RACs in a developing country necessitates an appraisal
      of the benefits and risks for each patient and improvement of catheter care
      procedures.

PMID- 10407865
TI  - Feasibility and safety of peripheral blood stem cell collection in children with
      poor-prognosis solid tumors: a single center experience.
AB  - This study reports the data of 32 children with poor-prognosis solid tumors who
      had 78 PBSC harvests on Fenwall CS-3000plus after mobilization mainly by
      different treatment protocol chemotherapy regimens followed by G- or GM-CSF (92%
      of patients) or by G-/GM-CSF alone (8%). Timing of procedure was predicted by
      studying the blood count. When the white blood cell and platelet count reached a
      median of 8.1 (0.9-37.3) and 95 (16-338) x 10(9)/L, respectively, the median
      number of 2.7 (0.005-16.8) x 10(6) CD34+/kg with 1.5 (0.005-11.6) x 10(6)
      CD34+/kg for 1 blood volume processed was obtained per procedure. In the group of
      13 patients with low body weight (median 14 [10-20] kg) 32 leukophereses were
      performed. The extracorporal line was primed with donor red blood cells in the
      patients with the weight below 15 kg. No difference was observed in CD34+ content
      in harvests whether GM-CSF was begun on day +1 or on day +3 after chemotherapy.

PMID- 10407867
TI  - Serum CA 125 levels in children with non-Hodgkin's lymphoma.
AB  - To evaluate the role of serum CA 125 levels for the diagnosis, follow-up, and
      prognosis in childhood non-Hodgkin's lymphomas (NHL), 44 children (35 newly
      diagnosed patients and 9 patients with relapsed or progressive disease, median
      age 6.5 years, M/F ratio 2.1) with NHL were included in this study. CA 125 levels
      in serum and/or ascites and effusions were measured by radioimmunoassay. The
      upper limit of normal was 35 IU/mL. The correlation of CA 125 levels with tumoral
      location and treatment results were investigated. A total of 27 (61.4%) patients
      had increased and 17 patients had normal serum CA 125 levels. Fifteen patients
      with increased CA 125 levels had malignant ascites, pleural effusion, or both,
      although none with normal CA 125 levels had any serous membrane involvement. The
      mean CA 125 levels were 72.5 IU/mL in patients with no serosal involvement
      (ascites or effusion) and, 144.0, 273.7, 324.3 IU/mL in patients with pleural
      effusion, ascites, and ascites + effusion, respectively. The mean CA 125 levels
      in ascites and pleural effusion were 202.1 and 156.2 IU/mL, respectively, and
      were similar to the corresponding serum levels. The increased CA 125 levels
      returned to normal in 18 patients whose diseases were in remission during the
      follow-up. One-year survival rate for newly diagnosed patients was 80.2 and 87.5%
      in patients with increased and normal serum CA 125 levels, respectively. In
      conclusion, CA 125 levels were significantly higher in patients with serous
      membrane involvement and there was a correlation between treatment response and
      marker levels. Little is known about the expression of CA 125 in NHLs. This is
      the first report suggesting that serum CA 125 levels can be a useful marker for
      the follow-up of childhood NHL. CA 125 seems to be a promising tumor marker in
      the assessment of prognosis and therapeutic response in non-Hodgkin's lymphomas.

PMID- 10407868
TI  - Nutrition, morbidity, and survival in South African children with Wilms' tumor.
AB  - Fifty-nine children with Wilms' tumor (WT) were divided into a normal or poorly
      nourished group according to anthropometric parameters. The 2 groups were
      compared for morbidity and survival. There was no difference in the median age or
      stage of disease in the 38 well nourished and 21 poorly nourished children. There
      was no difference in the number of children in the normal or poorly nourished
      group who developed a raised urea or creatinine level, febrile episodes, severe
      stomatitis, varicella, or upper or lower respiratory infections, or who needed
      intravenous antibiotics, parenteral nutrition, or red cell and platelet
      transfusions. Projected survival rate was 56 and 74% for normal and poorly
      nourished children, respectively (p = .3). Poor nutrition at diagnosis, as
      determined by anthropometry, had no effect on the morbidity of treatment or
      survival in children with WT. Based on these results, selective dietary
      supplementation instead of routine intensive parenteral nutritional support for
      all children with WT is recommended in countries with limited resources.

PMID- 10407869
TI  - The role of parvovirus B19 infection in childhood acute lymphoblastic leukemia.
AB  - The authors hypothesized that parvovirus B19 with its hematotropic effects has
      the potential to precipitate varying forms of cytopenia in patients prior to or
      at the diagnosis of acute lymphoblastic leukemia (ALL). Consequently, and in view
      of the increasing number of cases reported, this retrospective study evaluated,
      for the first time, the possible role of parvovirus B19 infection in pediatric
      patients suffering from ALL, by investigating the frequency and clinical
      relevance of this infection at the time of the malignant diagnosis or, when
      applicable, during a phase of pre-ALL. Furthermore, a review of reported
      parvovirus B19 infections in pediatric ALL patients is presented. The serum of 65
      consecutive pediatric patients with a diagnosis of ALL was examined for possible
      parvovirus B19 infection employing the polymerase chain reaction and ELISA
      techniques. Specific IgG was demonstrated in 30% of the patients. One patient
      diagnosed with pre-ALL had evidence of parvovirus B19 DNA in the serum during
      pancytopenia 5 months prior to the onset of ALL. The results suggest that there
      is an insignificant chance of finding a parvovirus B19 infection in pediatric
      patients with ALL at the time of diagnosis. However, parvovirus B19 infection may
      infrequently serve as a prodrome to ALL.

PMID- 10407870
TI  - Immunocompetent cells and lymphocyte reactivity to mitogens in levamisole-treated
      brain tumor children.
AB  - This study investigated the influence of levamisole therapy on immunocompetent
      cells and lymphocyte reactivity to mitogens in 25 children with brain tumor.
      Eleven (11/25) patients were receiving chemotherapy and immunomodulating drug
      levamisole 3 months after neurosurgery, during maintenance chemotherapy, 2.5
      mg/kg of body weight per os, for three consecutive days every 2 weeks, for 6-12
      months. The proportion of lymphocytes, proportion and number of T- and B
      lymphocytes and natural killer (NK) cells, as well as lymphocyte reactivity to
      mitogens were significantly lower in non-levamisole-treated patients than in the
      healthy controls (N = 18). Therapy with levamisole significantly augments the
      proportion of T lymphocytes, the number of T lymphocytes, NK cells, and the
      lymphocyte reactivity to concanavalin A (Con A). Depression of the NK cells and
      the lymphocyte reactivity to mitogens were much more pronounced in those patients
      who developed recurrences. Levamisole shortened the period of secondary
      immunodeficiency in immunocompromised children with brain tumor.

PMID- 10407871
TI  - Could cisplatin as a front-line treatment in childhood non-Hodgkin's lymphoma be
      a promising therapy?
AB  - Non-Hodgkin's lymphomas (NHL) were often erroneously diagnosed as other
      malignancies and treated accordingly. In this study cisplatin combined with
      vincristine, cyclophosphamide, and Adriamycin was used incidentally as a front
      line treatment in seven children with NHL, because the initial histologic
      diagnosis was that of a sarcoma. After reevaluation three patients had Ki-1
      anaplastic large cell lymphoma of T-cell origin, two abdominal B-cell diffuse
      high-grade NHL, one mediastinal diffuse large B-cell lymphoma, and one B-cell
      lymphoma in the stomach. They received at least two courses of cisplatin combined
      regimen and continued with other protocols for NHL. All patients showed an
      extremely good response from the first course of therapy and the masses vanished
      completely. They were followed up for a mean time of 29.5 months and are all in
      complete remission. The data indicate that cisplatin is active against NHL and
      might be a promising alternative front-line therapy.

PMID- 10407872
TI  - Childhood myelodysplastic syndromes in a Brazilian population.
AB  - Fourteen pediatric cases of myelodysplastic syndrome according to French-American
      British Co-operative Group (FAB) criteria were identified in a retrospective
      review of all cases of hematologic malignancies referred to the Pediatric
      Oncology division of the Cancer Hospital A. C. Camargo over a 12-year period: 1
      case of refractory anemia, 8 cases of refractory anemia with excess of blasts,
      and 1 case of refractory anemia with excess of blasts in transformation. Three
      children had features consistent with chronic myelomonocytic leukemia, and one
      child was diagnosed with secondary myelodysplastic syndrome. The median age was
      3.5 years (1 month-11 years). In 11/14 cases the disease evolved to acute
      leukemia. In 3 patients blasts had morphological and cytochemical features of
      lymphoblasts. Two of these patients had a good response to acute lymphoblastic
      leukemia chemotherapy protocol. The time of progression to leukemia in these
      cases was shorter than in those who evolved to acute myeloid leukemia. The
      authors believe this to be the first series of pediatric myelodysplastic syndrome
      documented in Brazil. Cases were characterized by aggressive FAB type,
      conspicuous cell atypias in all 3 hemopioetic cell lines, and a high rate of
      evolution to acute leukemia.

PMID- 10407873
TI  - Acute leukemias in children from the city of Kiev and Kiev region after the
      Chernobyl NPP catastrophe.
AB  - During 1993-1997, 247 cases of childhood acute leukemia (AL) were analyzed among
      inhabitants of the city of Kiev and Kiev region, excluding the most contaminated
      areas belonging to the strict control zone. The criteria of an FAB classification
      supplemented by immunophenotyping data were applied. The AL pattern was shown to
      be quite typical except for several peculiar features characteristic of this
      regional group of patients, especially the absence of age peaks in children with
      acute myelogenous leukemias (AML), increased frequency of the T1 variant in T
      cell acute lymphoblastic leukemia (ALL), and higher levels of M4 and M5 variants
      in AML. A typical variant of M5a-AML with minimal signs of differentiation was
      found.

PMID- 10407874
TI  - Successful unrelated umbilical cord blood transplantation in a child with Omenn's
      syndrome.
AB  - Omenn's syndrome is a variant of combined immunodeficiency disease (CID). Like
      other CID forms, it causes death unless the patient receives a bone marrow
      transplant (BMT). Previous reports have shown that BMTs from unrelated donors in
      Omenn's syndrome have very poor results, with a high rate of infections during
      transplantation and graft rejection, when compared with transplants from related
      donors or patients with other CID. This study discusses the case of a 19-month
      old child with Omenn's syndrome, who received an unrelated cord blood stem cell
      transplant (CBT). Donor and recipient had 1 HLA-Ag mismatched on HLA-B.
      Symptomatology improved early after CBT. The child achieved leukocytes and
      platelet engraftment and was discharged on day +34. His follow-up has been
      uneventful and at this time, 27 months after CBT, immune functions have been
      recovered.

PMID- 10407875
TI  - A case of myelodysplastic syndrome complicated by pulmonary alveolar proteinosis
      with a high serum KL-6 level.
AB  - Serious hematological diseases often cause respiratory disorders. Because these
      are related to the prognoses of patients with hematological diseases, their early
      diagnosis is necessary. This study describes a 6-year-old girl with
      myelodysplastic syndrome complicated by pulmonary alveolar proteinosis who showed
      a remarkable increase in her serum KL-6 level. Three years and 2 months after the
      end of therapy for neonatal melanoma, a diagnosis of myelodysplastic syndrome
      with leukemic change was made. Ten months after the onset of leukemia, she had
      respiratory distress with an increased serum KL-6 level of 75,000 U/mL (reference
      range; < 500 U/mL). Despite various treatments for pulmonary complications, she
      died 3 months after developing respiratory distress. A diagnosis of pulmonary
      alveolar proteinosis was made at autopsy. Earlier treatment of respiratory
      distress could be achieved if serum KL-6 levels were examined earlier.

PMID- 10407876
TI  - Megadose methylprednisolone for Kasabach-Merritt syndrome.

PMID- 10407877
TI  - Physiological and behavioral effects of an antivertigo antihistamine in adults.
AB  - 12 neurologically normal adults were tested before and after administration of
      meclizine, an over-the-counter medication for motion sickness. A battery of four
      tests was used: (1) distortion-product otoacoustic emissions, (2) the Repeated
      Evoked Potentials version of the Auditory Brainstem Response, (3) quantitative
      electroencephalography measured over the left and right sides of the auditory
      cortex, and (4) a hand-eye coordination task. The battery required approximately
      1.5 hr. to complete. Each subject was tested with the battery in each of eight
      longitudinal sessions: three times on a control day (9 am, 1 pm, 3 pm--no
      medication); the same times on a second day one week later (medication at
      approximately 11:30 am), and 24- and 48-hr. check-up sessions following the
      medication day. Analysis indicated changes in all components, with details
      suggesting the site(s) of action of this type of antihistamine. The cross-section
      of the auditory system yielded by this battery makes it possible to observe
      effects at the periphery, in the brainstem, and in the cortex, including evidence
      linking otoacoustic emissions with central auditory physiology. Implications
      range from cautions regarding the use of antihistamines to physiological support
      for employing such medications to enhance patients' response to vestibular
      rehabilitation as well as to improve performance in learning-disordered children.

PMID- 10407878
TI  - Perceptual defense mechanisms in Crohn's disease and panic disorder.
AB  - The defense organization of Crohn's disease and Panic Disorder was studied with a
      well-validated tachistoscopic paradigm, the Defense Mechanism Test. Three sex-
      and age-matched groups of 34 subjects (Crohn, Panic, and Nonclinical) were
      compared on the main codings of defense. Crohn patients were characterized by
      stereotypy and lack of recognition of the threat. The Panic group presented
      clearly higher frequencies of protocols with repression, isolation, and
      disappearance of the threat. Especially was the strongest variant of isolation,
      barrier-isolation, typical of the defensive substructure of panic patients.

PMID- 10407879
TI  - Clarifying the issues: a reply to Masling.
AB  - Masling (1998) stated that we did not find the effects of subliminal
      psychodynamic activation because of experimental artifacts. We reject his
      assertion that our failure to uncover effects was due to procedural problems and
      reassert our claim that the method was sound.

PMID- 10407880
TI  - New methodological advice for research in subliminal psychodynamic activation.
AB  - Recent integration among approaches to perception without awareness has brought
      the usefulness of Subliminal Psychodynamic Activation into renewed focus. Several
      authors have discussed the possible detrimental impact on interpretation when
      control phrases are used that for some participants may be less than affectively
      neutral (e.g., Fudin, 1986; Greenberg, 1997). In this continuing commentary, we
      argue that the neutrality of a substantive stimulus is an insoluble issue, and
      instead the suitability of controls for a given study should be emphasized. Also,
      we discuss the apparent confusion between experimental psychodynamics and efforts
      to answer Greenwald's 1992 "two-word challenge."

PMID- 10407881
TI  - Lavender aromatherapy in recovery from exercise.
AB  - 20 men were randomly assigned to a control or an experimental group. After
      baseline screening, all subjects performed moderate physical exercise for 2 min.,
      then rested for 10 min., during which the experimental group was exposed to
      lavender aromatherapy. Recovery measures included diastolic and systolic blood
      pressure, mean arterial pressure, pulse pressure, and heart rate. As the mean
      difference in diastolic blood pressure fell just short of statistical
      significance, further study with larger groups is required.

PMID- 10407882
TI  - Motor performance with a simulated artificial limb.
AB  - The present study was conducted to examine performance differences on a reaching
      and grasping task related to an activity of daily living. This involved either
      the anatomical limb or a simulated artificial limb. College-aged volunteers (2
      men and 4 women), one of whom was left-handed, performed the reaching and
      grasping task. The apparatus, placed on a table before the seated participant,
      was a square wooden board which contained a starting key and holes for the
      insertion and removal of a small Fiberglas dowel. At the beginning of the trial
      the participant depressed the start key, reached forward and grasped the dowel,
      and then returned the dowel to a finishing hole located directly in front of the
      start key. The results of 2 (side) x 2 (type of limb) repeated-measures
      multivariate analyses of variance on the mean and standard deviation of the
      movement times showed a significant main effect for type of limb (Wilks lambda
      3,3 = .047 and .079, respectively, p < .05). Analyses of variance on mean total
      transport time, extension time, flexion time, and their standard deviations
      showed that times were slower and less consistent with the prosthesis for all
      measures. These results and those of later research should be focused on the
      development of training principles for both therapists and individuals with an
      amputation. In addition, the simulated prosthesis is an excellent experimental
      model for basic and clinical research in the control and acquisition of
      coordinated movement.

PMID- 10407883
TI  - Effects of praying and a working memory task in participants trained in
      meditation and controls on the occurrence of spontaneous thoughts.
AB  - So-called "intrusive thoughts" appear independently from external stimuli and are
      the cause of severe disturbances in depressed patients. Following Baddeley's 1986
      discoveries regarding "articulatory suppression," we investigated the influence
      of praying and of a working memory task on the number of spontaneous thoughts
      reported by 20 subjects compared to the control (quiet) state. Two groups of
      subjects were tested: those trained in meditation and controls. Significant
      reduction in simultaneous thought arousal was obtained during both the working
      memory task and the recitation of prayer. In all three experimental conditions,
      meditation practitioners reported significantly fewer spontaneous thoughts.

PMID- 10407884
TI  - Relative contribution of lateral inhibition to the Delboeuf and Wundt-Hering
      illusions.
AB  - It has been suggested that lateral neural interactions contribute to some
      illusions with intersecting or converging line elements but cannot be present in
      figures that lack these components. Most attempts to ascertain the contribution
      of neural interactions in visual illusions have involved changes in the actual
      pattern of illusion. It has now been demonstrated that certain forms of
      intermittent light stimulation can enhance lateral inhibitory activity. The Wundt
      Hering and the Delboeuf illusions were tested under continuous illumination and
      "shaped" intermittent illumination which augments lateral inhibition. As
      expected, the Delboeuf illusion was unchanged with increased lateral inhibition
      while the magnitude of the Wundt-Hering illusion increased.

PMID- 10407885
TI  - Kinematics of kicking as a function of different sources of constraint on
      accuracy.
AB  - The kinematics of kicking were investigated using five experienced players at
      soccer. They were required to kick powerfully balls of two sizes under conditions
      with defined and undefined targets. High-velocity cameras were used for three
      dimensional analysis. Analysis indicated that the defined target condition led to
      lower movement speeds and shorter movement times, while balls' sizes influenced
      only time after peak velocity.

PMID- 10407886
TI  - Some psychological aspects of tinnitus.
AB  - Tinnitus rarely can be cured. The patient, however, needs help to avoid countless
      ineffective treatments and considerable cost. The clinical examination of
      patients with severe and chronic tinnitus must include associated psychological
      disturbances. After all medical and audiological treatments have failed, tinnitus
      patients often are advised to "learn to live with it." The aim of psychosocial
      treatment is assisting patients in the identification of aggravating factors in
      tinnitus and teaching them various coping skills.

PMID- 10407888
TI  - Are nonproper chopstick holders clumsier than proper chopstick holders in their
      manual movements?
AB  - To examine the working hypothesis that a lack of childhood training in the fine
      detailed finger movements illustrated by learning to use chopsticks properly as a
      child has later rendered such individuals clumsier in the execution of other more
      adult-like motor movements, four experiments were conducted. Groups of proper and
      nonproper users (both males and females) performed a task of picking up rice
      grains (Exp. 1), a pin-down task (Exp. 2), a task of unfastening nuts from bolts
      (Exp. 3), and a knot-tying task (Exp. 4). Only on the rice-grain transfer task
      and the knot-tying task, proper chopstick users showed better performance than
      nonproper users. On the pin-down task and the nuts-and-bolts task, no difference
      was found between groups. These results suggest that there is no clear evidence
      to support the hypothesis that a lack of early training for proper chopstick use
      makes such individuals more clumsy as adults in at least some motor movements.

PMID- 10407887
TI  - Earwitness recall and identification: comparison of the cognitive interview and
      the structured interview.
AB  - 77 undergraduates instructed to act as kidnap victims heard taped instructions
      given by a mock abductor. Two days later witnesses' recall of the culprit's
      monologue was tested using either a Cognitive Interview or a Structured
      Interview. Participants then rated the abductor's voice for nine speech
      characteristics and attempted to identify his voice from an audiotaped lineup. No
      significant differences were found between the two interview conditions for
      accuracy or error rates in free recall, for ratings of descriptive voice
      characteristics, or for performance in voice identification. These earwitness
      results are consistent with eyewitness investigations which have yielded no
      positive influence of the cognitive interview on identification. It is concluded
      that the success of the cognitive interview is best explained through its
      influence on social components of interviewing.

PMID- 10407889
TI  - Effects of hypnotizability on performance of a Stroop task and event-related
      potentials.
AB  - The effect of hypnotizability on verbal reaction times and event-related
      potentials during performance of a Stroop color-naming task was studied. The
      Stroop stimuli (colored words) were randomly presented to 5 high and 5 low
      hypnotizable subjects in the right and left peripheral visual fields during both
      waking state and hypnotic induction conditions. Unlike studies in which the
      Stroop stimuli were foveally presented to the subjects, the highly hypnotizable
      subjects did not show prolonged verbal reaction times in either waking or
      hypnotic conditions. There was a marked deterioration in performance accuracy,
      however, for highly hypnotizable subjects during hypnosis. Event-related
      potentials indicated that the highly hypnotizable subjects showed a reduced P3a
      amplitude and a decreased N2b latency to the visual stimuli in both waking and
      hypnotic conditions, suggesting a lack of orienting to or disengagement from
      peripherally occurring stimuli.

PMID- 10407890
TI  - Attention and estimated line length.
AB  - Whether attention affects the estimated length of a line has been debated for a
      long time. Some authors have found estimated length to increase with attention;
      others have found that it decreased. The present study further investigated this
      problem with two experiments. The first confirmed that estimated length decreased
      with attention; however, this result had low reliability. The second experiment
      indicated that estimated length significantly decreased with attention for some
      participants and significantly increased for others. This finding accounts for
      the low reliability of the first experiment and for the conflicting results of
      previous studies. Implications of opposite effects of attention for models of
      sensory intensity are discussed. An interpretation of these effects in terms of
      response preferences is proposed.

PMID- 10407891
TI  - Failure to confirm the Rauscher and Shaw description of recovery of the Mozart
      effect.
AB  - The Mozart effect is an increase in spatial reasoning scores detected immediately
      after listening to the first movement of a Mozart piano sonata. Rauscher and Shaw
      (1998) suggested that failure to produce a Mozart effect could arise from
      carryover effects of a spatial reasoning pretest which may interfere with the
      effect of listening to Mozart. They cited an unpublished study in which a verbal
      distractor was inserted between the pretest and listening condition, and the
      manipulation produced the recovery of a Mozart effect. This experiment attempted
      to confirm the unpublished study. 206 college students were exposed to one of
      three sequences, pretest-Verbal distractor material-Mozart, pretest-Mozart-Verbal
      distractor material, and pretest-Verbal distractor material. An immediate
      posttest indicated no significant difference on solution of paper folding and
      cutting items among the three groups. The results do not support Rauscher and
      Shaw (1998). Our negative results are consistent with prior failures in other
      laboratories to produce a Mozart effect.

PMID- 10407893
TI  - Capacity for mental imagery and its spontaneous use.
AB  - The aim of this study was to investigate whether the capacity to form mental
      images influences the frequency with which subjects use mental images. Two tests
      measuring capacity for mental imagery were given to 283 undergraduates, a self
      assessment and a performance test. Frequency of spontaneous use of mental imagery
      was also measured. Subjects with high self-assessed ability to form images used
      mental imagery spontaneously more often than those with low self-assessed imaging
      ability.

PMID- 10407892
TI  - Isokinetic knee muscle strength of individuals with mental retardation, a
      comparative study.
AB  - The purpose of this study was to assess differences in isokinetic muscle torque
      in the knee among mentally retarded individuals with Down syndrome, mentally
      retarded individuals without Down syndrome, and sedentary subjects without mental
      retardation (ns of 7, 8, and 12, respectively). Subjects performed strength tests
      to knee extension and flexion on a Cybex II isokinetic dynamometer. The measure
      was peak torque at angular velocities of 60, 120, and 300 degrees/sec. For the
      Mentally Retarded subjects with and without Down syndrome, the test was performed
      on two separate days 24 hr. apart. For Sedentary subjects, testing was performed
      on one day. Their scores indicated significantly higher values of torque than the
      two other groups. Also, subjects with Down syndrome had inferior muscle torque of
      lower extremities than peers in the Mentally Retarded Group.

PMID- 10407894
TI  - Dependence of deltoid muscle activity upon initial angles of shoulder abduction
      prior to flexion.
AB  - The present study was undertaken to investigate the hypothesis that the direction
      and selectivity of an appropriately modified version of shoulder flexion is
      dependent upon initial angles of shoulder abduction. Analysis indicated that
      initial small angles of shoulder abduction were associated with longer
      electromyographic (EMG) durations of the agonist (anterior deltoid) muscle.
      Moreover, as initial angles became smaller, EMG onsets of the antagonist
      (posterior deltoid muscle) occurred nearer to those of the agonist. Modulations
      of duration of the agonist EMG activity can be explained by changes in amplitude
      of movement. Two possible interpretations of the changes of EMG onset of the
      antagonist in accordance with different initial angles of shoulder abduction are
      considered. One concerns the effect of the change on the load of the upper limb,
      dependent on different angles of shoulder abduction. The second concerns the
      changing role of the antagonist to a synergist, dependent upon decreased initial
      angles of shoulder abduction prior to the shoulder flexion. Based on the present
      findings, it is suggested that angles of shoulder abduction are an important
      determinant of agonist-antagonist muscle activity of the deltoid during flexion
      of the shoulder.

PMID- 10407895
TI  - "I'm all right Jack" in Russia too.
AB  - The percentage of voters supporting the new constitution for the Russian
      Federation in 1993 was negatively associated with the death rate in the 55
      oblasts and krais (provinces and territories).

PMID- 10407896
TI  - Stress and sleep patterns of college students.
AB  - The present study investigated the relationship between stress and sleep. A self
      report measure was used to assess three domains: environmental events,
      personality mediators, and emotional responses. It was hypothesized that one or
      more of the domains would predict seven different aspects of sleep. 227 college
      students completed the Derogatis Stress Profile and the Sleep Questionnaire.
      Analysis indicated that scores on emotional response were the best predictor of
      five different sleep aspects: depth of sleep, difficulties in waking up, quality
      and latency of sleep, negative affect in dreams, and sleep irregularity. Presence
      of environmental events was the best predictor for the length of sleep only. It
      was concluded that research looking at the effects of stress on sleep must
      consider all three components of stress and that perhaps the emotional response
      to stress is the best predictor of sleep complaints.

PMID- 10407897
TI  - Intertester reliability of hand-held dynamometry: a concise summary of published
      research.
AB  - Literature describing the use of hand-held dynamometry was examined to determine
      whether conclusions could be drawn regarding intertester reliability. 18 studies
      reporting intertester reliability coefficients were found and summarized. These
      suggest that high intertester reliability can be obtained, but that it is in
      jeopardy if tester strength is low relative to the forces being measured.

PMID- 10407898
TI  - Experimental comparison of brightness judgments obtained by rating and bisection
      methods.
AB  - The consistency of psychophysical scales obtained by different measurement
      procedures is an important topic for research. Two experiments tested whether the
      scales obtained by the rating and bisection methods were consistent. 40
      university students bisected intervals on the brightness continuum and
      subsequently rated the brightnesses determined by such bisections, or they first
      rated brightnesses and then bisected brightness intervals. Analysis shows the
      scales obtained by these methods were mutually consistent when a large number of
      response categories (the integers from 0 to 100) were used for ratings. When a
      small number of response categories (the integers from 0 to 6) were used, the
      methods were consistent only when ratings were produced after the bisections.
      This suggests that bisections may have increased the consistency of the rating
      scale by generating an internal representation of equally spaced sensory
      magnitudes subsequently used for ratings.

PMID- 10407899
TI  - Representational momentum in children: dynamic information and analogue
      representation.
AB  - Two groups of children and a control group of adults completed a visual memory
      task previously shown to produce representational momentum in adults. In the
      task, a computer-animated target was shown moving either horizontally or
      vertically, and the target vanished without warning. After the target vanished,
      observers indicated the location at which it had vanished. Both children and
      adults exhibited representational momentum, i.e., indicated locations slightly
      beyond where the target actually disappeared, and the magnitude of
      representational momentum was larger for younger children than adults.
      Implications of the results for issues of sensitivity to dynamics and for
      reliance on analogue representation are discussed.

PMID- 10407900
TI  - Resource for temporal information processing in interval production.
AB  - The resource required to process temporal information in interval production was
      investigated. 12 undergraduates performed 4-sec. interval production and
      nontemporal tasks, the probe digit task and the missing digit task. Although both
      tasks required memory search and employed the same modality for input and for
      responding, the probe digit task required a phonological resource and the missing
      digit task required a spatial resource. Analysis showed that both concurrent
      nontemporal tasks caused interval productions to be longer, suggesting that the
      temporal processing required a resource which both tasks used commonly. This
      resource may be a general purpose, capacity-limited resource associated with a
      central executive function in working memory.

PMID- 10407901
TI  - Field dependence-independence of basketball referees.
AB  - This study examined the field dependence-independence of basketball referees. A
      total of 205 subjects (nonathletes, athletes active in individual or team sports,
      and referees) completed the Group Embedded Figures Test. Analysis indicated no
      significant differences among referees due to age, group, or number of years
      officiating. Statistically significant lower scores were obtained by team-sport
      players and referees than by nonathletes. Mean scores of team-sport players and
      referees did not differ significantly.

PMID- 10407902
TI  - A path model of the relationship between career indecision, androgyny, self
      efficacy, and self-esteem.
AB  - Utilizing a path model, this study investigated the relationship between
      Androgyny and career decision-making among 91 high school girls. The constructs
      included in the model were Androgyny as assessed by the Bem Sex-role Inventory,
      Self-esteem as assessed by the Rosenberg Self-esteem Scale, Self-efficacy as
      assessed by the Wulff-Steitz Career Self-efficacy Scale, and Career Indecision as
      assessed by the Osipow Career Decision Scale. The results indicated that
      Androgyny scores were significantly associated with those on Self-esteem, Self
      esteem with Self-efficacy, and Self-efficacy with Career Indecision. The results
      are discussed in terms of the usefulness of path models in clarifying complex
      interrelationships.

PMID- 10407903
TI  - Functional equivalence for response programming of actually performing versus
      imagining movements.
AB  - The present study was conducted to test the hypothesis that response programming
      occurs when movements are only imagined. 12 subjects were required to react and
      produce the sequence of same or different force by squeezing a handle as quickly
      and accurately as possible after the two reaction signals which were separated by
      the interstimulus interval of 1 sec. The reaction time to initiate the second
      response was examined when the first response is covertly performed, but the
      second response is actually performed. The reaction times to initiate the second
      responses were significantly shorter for imagining and actually performing
      different movements or the control condition. There was no significant difference
      in reaction time between the conditions with the same movements. These findings
      were interpreted as evidence for functional equivalence for response programming
      of actually performing versus imagining movements.

PMID- 10407904
TI  - Relations between biased tonicity of the body and vertical judgement in
      poststroke hemiplegic persons.
AB  - The influence of muscular tension upon visual vertical judgement in a standing
      posture was investigated in 16 hemiplegic persons and 12 normal elderly persons.
      The normal elderly group showed that their judgements of verticality were
      accurate and stable. In hemiplegic persons, judgements were displaced opposite to
      the side in which there was high tension in the body. Differences between groups
      in body tension and the side to which judgement was displaced were significant.
      The peculiar judgement errors made by hemiplegic persons are thus an
      overcorrection for tonicity. It was related to one's own body perception.

PMID- 10407905
TI  - Use of the School Performance Rating Scale with children treated for attention
      deficit hyperactivity disorder.
AB  - The School Performance Rating Scale was developed to assess academic performance
      of children diagnosed with attention deficit hyperactivity disorder. The most
      frequent concern of professionals, parents, and teachers is the child's
      performance and achievement in school; however, assessments are seldom obtained
      pretest and posttest. The scale has yet to be standardized so its association
      with academic behavior was estimated with the ADD-H Comprehensive Teachers'
      Rating Scale. 24 elementary-school children were given both scales after being
      diagnosed and treated for ADHD, following evaluation by a multidisciplinary team
      at a medical university's child-development clinic. A positive correlation of .8
      was found between scores on the School Performance Rating Scale and .6 with
      Attention and Social Skills from the ADD-H Comprehensive Teachers' Rating Scale.
      Standardization of the scale would allow clinicians more specific
      identifications.

PMID- 10407906
TI  - An experiment in time perception: separating rate of presentation from type of
      estimation.
AB  - An experiment was conducted to distinguish between studies which show main
      effects versus interaction effects regarding estimations of time as a function of
      the rate (fast or slow) of digit presentation and the type (immediate or delayed)
      of time estimation. Undergraduate volunteers (36 men and 103 women) gave
      retrospective estimates of time following a short-term memory filler task
      consisting of memorizing a series of random digits (1-5) which varied in length
      (25 or 50 digits). Rate was manipulated by altering the interstimulus interval
      between digits (100 msec. or 1,300 msec.) or by varying the length of the list. A
      multivariate analysis of variance showed significant main effects for type of
      time estimation (delayed estimates were longer than immediate), length of list
      (estimates for 50 digits were longer than for 25), and interstimulus interval
      (estimates for 1,300 msec. were longer than for 100 msec.) yet, contrary to Pedri
      and Hesketh in 1993, there were no significant interactions among the variables.
      Each of the independent variables was associated with effects on time estimation
      and short-term memory which were the same at all levels of the other variables.
      Task variables were discussed as a potential source of variance among past
      studies.

PMID- 10407908
TI  - Role of geons in object recognition across ages.
AB  - Little research has been conducted regarding the developmental implications of
      Biederman's 1987 Recognition by Components theory. The present study compared
      objects fragmented according to this theory, i.e., vertices were left intact and
      midsegments were deleted, with objects that were randomly fragmented. A total of
      169 students from three age groups (first grade, fourth grade, and college)
      participated. Approximately half of the participants viewed pictures with intact
      vertices and half viewed the randomly fragmented pictures. Analysis showed that
      participants recognized more pictures across groups; however, there were no
      significant differences between the two sets of pictures. This finding suggests
      that vertices are important but are not necessary for object recognition. The
      role of midsegments in object recognition is also discussed.

PMID- 10407907
TI  - Motiveless firesetting: implicating partial limbic seizure kindling by revived
      memories of fires in "Limbic Psychotic Trigger Reaction".
AB  - 23 unselected juvenile firesetters (M age 12.0 yr.) consisted of seven with
      schizophrenia, three with organic mental disorder, six with posttraumatic stress
      disorder, two with severe mental retardation, and two with conduct disorders.
      Three previously nondestructive boys (M age 11.0 yr.), all of them loners, did
      not fit such traditional diagnoses. Their fleeting (c. 20 min.) symptoms included
      flat affect, autonomic arousal, and delusions or hallucinations. It appeared that
      their motiveless, unplanned acts were each preceded by a chance encounter with an
      individualized stimulus which revived the three boys' repeatedly ruminated
      memories of intermittently experienced merely moderate stresses associated with
      fire, smoke, or matches. Such a sequence of events is characteristic of seizure
      kindling. One boy's abnormal EEG was congruent with seizures in the temporal lobe
      area, which includes the amygdala, i.e., that part of the limbic system
      particularly susceptible to seizure kindling. The three boys' consistent
      symptomatology was very similar to that reported for 17 men with bizarre
      homicidal acts implicating a kindled partial seizure called "Limbic Psychotic
      Trigger Reaction." In primates, too, similar partial nonconvulsive "behavioral
      seizures" with psychosis-like symptoms can be elicited through experiential
      kindling.

PMID- 10407909
TI  - Judo--the gentle way: a replication of studies on martial arts and aggression.
AB  - There have been numerous studies of the effects of traditional martial arts
      training on aggressiveness, most reporting a decline in aggressiveness with
      training. The majority of these studies have examined students of karate or
      taekwondo, disciplines emphasizing strikes and blocks. In contrast, this cross
      sectional study examined the effects of traditional judo training on
      aggressiveness by looking at 51 judo students. Furthermore, we incorporate into
      our analysis two variables generally associated with aggression, age and sex, to
      control for their effects. Aggressiveness declined as expected across training
      and ages, but surprisingly sex had no effect in this setting.

PMID- 10407910
TI  - Perception of dioxin and other risks in Japan: replication and extension.
AB  - Previous research has shown that the common understanding of risk may be
      expressed by factor-analytic models that represent how fatal are risks and how
      voluntarily one assumes such threats. We investigated whether a similar
      representation would model Japanese participants' risk perception. Moreover,
      because Japanese newscasts concentrated their coverage exclusively on dioxin
      during the period of this research, we expected that those who were exposed to
      such newscasts would more frequently develop greater environmental awareness. We
      also examined whether this "news-exposed group's" knowledge about dioxin was
      consistent with the known facts regarding dioxin. Analysis showed that the two
      factors adequately modeled the Japanese sample's risk representation (N = 473)
      and that the news-exposed group (n = 188) did exhibit higher environmental
      awareness. Implications for risk research are discussed.

PMID- 10407911
TI  - Muscle test comparisons of congruent and incongruent self-referential statements.
AB  - This study investigated differences in values of manual muscle tests after
      exposure to congruent and incongruent semantic stimuli. Muscle testing with a
      computerized dynamometer was performed on the deltoid muscle group of 89 healthy
      college students after repetitions of congruent (true) and incongruent (false)
      self-referential statements. The order in which statements were repeated was
      controlled by a counterbalanced design. The combined data showed that
      approximately 17% more total force over a 59% longer period of time could be
      endured when subjects repeated semantically congruent statements (p < .001).
      Order effects were not significant. Over-all, significant differences were found
      in muscle-test responses between congruent and incongruent semantic stimuli.

PMID- 10407912
TI  - Motoric encoding and retention of pictures in Alzheimer's disease.
AB  - 20 patients with Alzheimer's disease were shown line drawings of common objects
      on two trials. During the second trial they were asked to pantomime an action for
      the object and then provided a standard motoric cue or were asked to name it and
      then provided a standard semantic cue. Semantic cueing served as a stimulus
      processing control condition. Memory for pictures was assessed at a 48-hr. delay
      interval using a yes-no recognition-memory procedure. Discrimination of stimulus
      pictures from distractors at 48 hours was similar for the motoric and control
      (semantic) encoding condition. These findings suggest that motoric encoding does
      not enhance long-term retention of episodic memories for pictures in such
      patients.

PMID- 10407913
TI  - Evaluation of three types of blinks with the use of electro-oculogram and
      electromyogram.
AB  - Three kinds of blinks, spontaneous, reflex, and voluntary, were measured for 11
      men using electromyogram (EMG) at the orbicularis oculi muscle on the right side
      and electro-oculogram (EOG) in the vertical direction to the right eyelid. The
      amplitude and the duration time were defined here from the raw waves of the EMG
      and the EOG for the three kinds of blinks. The amplitude of the EMG indicated
      that the mean value for the spontaneous blinks was significantly smaller than
      that of the voluntary blinks and the mean duration of the EMG shows the value for
      the spontaneous blinks was smaller than that for the reflex and the voluntary
      blinks. The EMG for the spontaneous blinks had a smaller amplitude and a shorter
      duration time than the other blinks. The EOG amplitude indicated that the mean
      value for the spontaneous blinks was significantly smaller than that for the
      voluntary blinks, but there was no significant difference between the spontaneous
      blinks and the other blinks for the duration of the EOG. The amplitude and the
      duration for both the EMG and the EOG discriminated any two types of blinks from
      three blinks by statistical test. Those values for the EMG and the EOG are
      effective indices for the evaluation of blinks. Moreover, the coefficients of
      variation of the amplitude and durations of EMG and EOG for three kinds of blinks
      denote their characteristics. Multiple discriminant analysis distinguished the
      types of blinks simultaneously. The resultant maximum correct rate for the three
      blinks reaches to be 81.8%. So far, it has been difficult to discriminate the
      blinks quantitatively, but the procedures presented here are able to solve the
      difficulty.

PMID- 10407914
TI  - Order of item difficulty on picture arrangement: extending the discussion to the
      WAIS-III.
AB  - Past examinations of the order of item difficulty on the 10-item WAIS-R Picture
      Arrangement subtest indicated that the items had not been arranged in increasing
      order of difficulty. Examination of the clinical data for 50 consecutive
      assessment referrals [means for age, education, Full Scale IQ, and Picture
      Arrangement subtest scaled score were 46.4 (SD = 10.2), 12.6 (SD = 1.1), 96.7 (SD
      = 12.6), and 10.6 (SD = 3.3), respectively] on the 11-item WAIS-III subtest
      suggested that the current order of items may not be in order of increasing
      difficulty. Clinical relevance of these findings and research on the order of
      item difficulty are discussed.

PMID- 10407915
TI  - [Psychosocial rehabilitation today and tomorrow. Therapeutic adaptations to
      altered life styles].

PMID- 10407916
TI  - [Faces of work in the psychiatry, yesterday-today-tomorrow].

PMID- 10407917
TI  - [Neurobiological substrates of psychiatric diseases--what can be achieved through
      therapy?].

PMID- 10407919
TI  - [Occupational reintegration of mentally disabled in the labor market].

PMID- 10407918
TI  - [Psychiatric vocational therapy--concepts, practice and scientifically-based
      results].
AB  - Work therapy is a widespread form of socio-therapy. In contrast to
      pharmacological and somatic forms of treatment, proof of efficacy is difficult to
      produce in multimodal therapy of psychiatric patients. Within the framework of an
      extensive study on vocational rehabilitation of mentally ill patients, we carried
      out a naturalistic follow-up study of 112 mostly schizophrenic patients attending
      outpatient work therapy programmes. The courses of illness and rehabilitation
      were documented prospectively over a three-year period. At the end of the study
      23% of the patients were integrated into the open labour market, 25% were working
      in sheltered employment, 25% remained in work therapy, and 27% were unemployed.
      Controlled studies with schizophrenic patients show, that work therapy
      contributes to improved vocational integration, a reduction of rehospitalizations
      and a stabilisation of the psychopathological status.

PMID- 10407920
TI  - [Disease as a biographical event].

PMID- 10407921
TI  - [Significance of work for mentally ill people in social relationships.
      Sociological commentary on vocational rehabilitation].

PMID- 10407922
TI  - [Success of new treatments for schizophrenics, as shown by the example of modern
      antipsychotic drugs].

PMID- 10407923
TI  - [What are the goals of psychiatric rehabilitation, and which have been
      accomplished?].

PMID- 10407924
TI  - American Society of Regional Anesthesia (ASRA) 24th annual meeting. Philadelphia,
      Pennsylvania, USA. May 6-9, 1999. Abstracts.

PMID- 10407925
TI  - Anterior tibial translation during eccentric, isokinetic quadriceps work in
      healthy subjects.
AB  - The effect of increasing isokinetic, eccentric quadriceps torques on sagittal
      translation of the tibia was examined in six healthy volunteers and compared to
      the translation at 20 degrees of knee flexion during a drawer test with 90 N
      force. The tibial translation increased in a linear fashion with a mean of 0.5 mm
      per 20% torque increase. In 20 degrees of knee flexion, 10% of eccentric
      quadriceps peak torque consumed 80% of the anterior tibial translation induced by
      the 90 N Lachman test while eccentric quadriceps peak torque utilized 100% of the
      translation at the same test. The in vivo relation between muscle force and
      tibial translation is of importance in the treatment of patients with injury to
      the cruciate ligaments. The results indicate that an already low eccentric
      quadriceps torque causes a tibial translation that reaches the limit of the
      passive knee joint displacement where strain is assumed to develop in the
      anterior cruciate ligament. Already low eccentric quadriceps torque levels may
      therefore be harmful during rehabilitation after anterior cruciate ligament
      surgery.

PMID- 10407926
TI  - EMG activity of the iliopsoas muscle and leg kinetics during the soccer place
      kick.
AB  - The purpose of the study was to develop a method to record intramuscular
      electromyogram (EMG) from the iliopsoas muscle and to relate this activity to the
      kinetics during the soccer place kick. Seven skilled soccer players performed 3
      maximal velocity place kicks. The kicks were filmed with a high-speed camera (400
      Hz) and EMG recordings were obtained from 5 muscles of the kicking leg, including
      wire electrodes inserted into the m. iliopsoas. The EMG signals were compared to
      the kinetics of the kicking leg, which were calculated from the digitised film.
      The results showed hardly any torque reversal about the hip joint before impact.
      Angular deceleration of the thigh segment did not increase the angular velocity
      of the shank (work -3.57 to 0.0%). M. iliopsoas was active during the entire
      kicking motion (average EMG 65.1-100.9%), even in the period when the thigh was
      decelerating. Wire electrodes can successfully be applied to EMG recordings of
      fast unloaded movements.

PMID- 10407927
TI  - Choice of jumping strategy in two standard jumps, squat and countermovement jump-
      effect of training background or inherited preference?
AB  - Six male subjects, three professional ballet dancers and three elite volleyball
      players, performed maximal vertical jumps from 1) a static preparatory position
      (squat jump), 2) starting with a countermovement (countermovement jump) and 3) a
      specific jump for ballet and for volleyball, respectively. The jumps were
      recorded on highspeed film (500 Hz) combined with registration of ground reaction
      forces, and net joint moments were calculated by inverse dynamics. The purpose
      was to investigate the choice of strategy in two standard jumps, squat jump and
      countermovement jump. The volleyball jump was performed with a sequential
      strategy and the ballet jump was performed with a simultaneous strategy. In the
      two standard jumps, the choice of strategy was individual and not related to
      training background. This was additionally confirmed in a test of seven ballet
      dancers and seven volleyball players.

PMID- 10407928
TI  - Glycogen concentration in human skeletal muscle: effect of prolonged insulin and
      glucose infusion.
AB  - To study the upper limit of glycogen storage in human muscle, two healthy male
      subjects were infused with glucose and insulin for 8 h reaching plasma
      concentrations of about 21 mM glucose and approximately 2000 microU/ml insulin.
      Prior to the infusion subjects performed for 1 h one-legged knee-extensor
      exercise at 75% of their maximum one-legged work capacity in order to lower
      muscle glycogen stores in one leg. During the 8-h hyperglycemic clamp procedure,
      glycogen concentrations increased and levelled off at 2- and 5-fold above the pre
      infusion levels in the resting and the working leg, respectively. However, the
      absolute glycogen levels reached in both legs were quite similar, close to 4 g
      per 100 g wet muscle (about 1000 mumol/g d.w.), independent of prior exercise.
      Previous studies have shown that glycogen levels, after a bout of glycogen
      depleting exercise and subsequent ingestion of a carbohydrate-rich diet for 3
      days, can be increased to values around 3-4 g per 100 g wet muscle. It appears
      that the maximal attainable glycogen concentration in human muscle seems to be
      close 4 g per 100 g wet muscle. This glycogen level can thus be reached either by
      a prolonged infusion of supra-physiological concentrations of glucose and insulin
      or by glycogen-depleting exercise followed by ingestion of a carbohydrate-rich
      diet.

PMID- 10407929
TI  - Neck muscle ultrasonography of male weight-lifters, wrestlers and controls.
AB  - The purpose of this cross-sectional study was to evaluate the effect of different
      sport training regimens on the size of the neck semispinalis capitis muscle
      (SECM). The cross-sectional area (CSA) and the linear dimensions of the SECM were
      measured bilaterally by real-time ultrasonography. Ten young Finnish elite level
      weight-lifters, 8 freestyle wrestlers and 10 controls (all male) participated in
      the study. Muscle CSA was significantly larger in wrestlers than in weight
      lifters or controls (P < 0.001). There was no significant difference in size
      between the right and left SECM in any of the subject groups, but the variation
      between sides (smaller vs. larger) was significantly higher in wrestlers than
      weight-lifters (P < 0.05). CSA correlated with the multiplied linear dimensions
      (r = 0.80, P < 0.000). Neck muscle: ultrasonography appeared to be a useful
      method in evaluating the differences between two groups of athletes.

PMID- 10407930
TI  - The effects of preexercise stretching on muscular soreness, tenderness and force
      loss following heavy eccentric exercise.
AB  - The present study sought to investigate the effects of preexercise stretching on
      delayed onset muscle soreness (DOMS), i.e. soreness, tenderness and loss of
      muscle force, that usually occurs after strenuous or unaccustomed eccentric
      exercise. Ten female volunteers performed 10 sets of 10 maximal isokinetic
      eccentric contractions for knee flexion with both legs after a 5-min ergometer
      cycling warm-up. Prior to the exercise for one leg, randomly chosen, 4 x 20 s of
      static stretching for the hamstring muscle group was implemented. Rated soreness,
      tenderness on algometer pressure and loss of maximal eccentric contractile force
      was evaluated preexercise and 24, 48 and 96 h postexercise. The exercise bout
      produced severe DOMS, with parameters peaking and troughing at 48 h postexercise.
      However, no significant differences were found, regarding any of the parameters,
      when comparing stretched and nonstretched legs. The present study thus suggests
      that preexercise static stretching has no preventive effect on the muscular
      soreness, tenderness and force loss that follows heavy eccentric exercise.

PMID- 10407931
TI  - Toward a better prescription of the prone back extension exercise to strengthen
      the back muscles.
AB  - This study investigated the level of resistance and the level of muscle
      activation of the prone back exercise. Fifteen male subjects with no previous
      history of low back injury performed two repetitions of seven exercises. These
      consisted of four maximal isometric voluntary contractions (MVC) and three prone
      back extension (PBE) exercises. The subject was lying prone on a table, the upper
      body was suspended off the end of the table and the legs and thighs were secured
      to the table with straps. Three starting positions from the horizontal were
      investigated, 0 degree, 30 degrees and 60 degrees, and were compared with MVC to
      quantify the level of effort needed to perform the task. The results showed that
      the three PBE exercises require a level of resistance and a level of muscle
      activation generally under 40% of the maximum capacity of healthy subjects.
      Muscle activity of the erector spinae (ES) was slightly greater when the exercise
      started at 60 degrees, compared to 0 degree and 30 degrees. During the static
      phase of the PBE exercises, the level of resistance remained at 40% relative to
      the peak reaction moment of the MVC, but muscular activity of ES tended to work
      at a lower activity level. In conclusion, since for healthy subjects PBE
      exercises are low resistance exercises, they seem to be more specifically
      designed to develop muscular endurance of the back muscles.

PMID- 10407932
TI  - Comparison of arthroscopic one-incision and two-incision techniques for
      reconstruction of the anterior cruciate ligament.
AB  - The purpose of this study was to assess the outcome of arthroscopic anterior
      cruciate ligament reconstruction performed using either the 'one-incision'
      technique or the rear-entry 'two-incision' technique. A series of 221 consecutive
      patients who underwent anterior cruciate ligament reconstruction was reviewed
      retrospectively. In the study population, two subgroups were defined. Group A
      consisted of 118 patients who underwent reconstruction using the one-incision
      transtibial endoscopic technique and Group B consisted of 103 patients who
      underwent reconstruction using the two-incision technique. The groups were
      comparable in terms of age, sex and activity level. The follow-up was performed
      after 47 (40-68) months in Group A and 55 (40-68) months in Group B. The Lysholm
      score at the final follow-up was significantly lower in Group A (90, 38-100) than
      in Group B (94, 34-100) (P = 0.002). The median KT-1000 total side-to-side
      difference was 1.5 (-6 to 7.5) mm in Group A, and 2.0 (-3.5 to 9) mm in Group B
      (n.s.). No significant difference between the groups was found when the IKDC
      evaluation system was used. Four intra-operative complications were registered in
      Group A and none in Group B (P = 0.06). No significant difference was found in
      terms of anterior knee pain, the one-leg-hop quotient or the activity level at
      the final follow-up. In this study the two methods gave similar and satisfactory
      results. Serious intraoperative complications were, however, recorded in four
      cases when the one-incision technique was used.

PMID- 10407933
TI  - Long-term functional outcome after surgery of chronic ankle instability. A 5-year
      follow-up study of the modified Evans procedure.
AB  - Chronic ankle instability is a rather common consequence of poorly healed rupture
      of the lateral ligaments of the ankle. In some rare cases, instability symptoms
      can be caused by general laxity of the joints, but since these cases are normally
      bilateral, they can easily be distinguished from posttraumatic instability. This
      report presents the long-term (average follow-up 4.6 years) functional outcome
      after a modified Evans tenodesis of 48 patients. The follow-up examination
      consisted of a questionnaire evaluating the subjective assessment of the ankle,
      and clinical examination measuring ankle stability, range of motion and swelling,
      and atrophy of the calf muscles. Additionally, the functional recovery of the
      ankle was assessed by a standardized performance test protocol. According to the
      subjective assessment, 25 subjects (52%) considered the ankle fully recovered, or
      at least much better than before surgery. In the performance test, however, only
      17 subjects (35%) achieved an excellent or good score. In the performance test
      protocol, two functional tests, walking down a staircase and balancing on a
      square beam, best demonstrated the impaired function of the injured ankle. The
      modified Evans procedure could restore the stability of the ankle to the
      preinjury level, although the ankle range of motion was significantly impaired,
      and swelling of the ankle and atrophy of the calf muscles were frequent findings
      at the follow-up. In conclusion, surgical treatment of chronic ankle instability
      by the Evans procedure restores the mechanical stability of the joint, but too
      frequently the function of the ankle does not return to the pre-injury level.

PMID- 10407934
TI  - "Little league elbow"--acute traction apophysitis in an adolescent badminton
      player.
AB  - A case of an acute traction apophysitis, "little league elbow", in an adolescent
      badminton player is presented. After a period of intense badminton activity, the
      patient developed typical signs of inflammation related to his elbow. X-ray
      showed soft tissue calcifications and ultrasound showed intra-articular swelling
      and a possible apophysitis related to the elbow. After a period of immobilization
      followed by low activity he could return to normal sports activity.

PMID- 10407935
TI  - [Febrile convulsions: assessment of current status].
AB  - Febrile seizures are the most frequent neurologic disorders during childhood. The
      pathogenesis is not clear even today. Viral infections of the upper airways,
      exanthema subitum, acute otitis media, infection of the urinary tract and febrile
      reactions after vaccination are the most frequent precipitating factors.
      Predictors in identifying children with very high risk of recurrence are young
      age at onset, family history of febrile seizures in a first-degree relative, a
      history of recurrent febrile seizures and a lower degree of fever at the onset of
      febrile seizures. A family history of epilepsy, neurodevelopmental abnormalities
      and a lower degree of fever at the onset of febrile convulsion are predictors of
      later epilepsy in children who have febrile seizures. The prognosis of febrile
      seizures is very good. In the acute situation, rectal diazepam should be given in
      the event of prolonged febrile seizures (> 3 minutes) only. Intermittent diazepam
      therapy and long-term antiepileptics are not recommended. The best prophylactic
      treatment is education and reassurance for parents and children.

PMID- 10407936
TI  - [Iodine-induced hyperthyroidism (iodine-induced Basedow's disease): a current
      disease picture].
AB  - Iodine-induced thyrotoxicosis or "jodbasedow phenomenon" has been reported
      throughout the world since iodine has been administered to treat endemic goitre.
      Nowadays, iodinated radiocontrast agents and the antiarrhythmic drug amiodarone
      are the most common sources of excess iodine load subsequently leading to iodine
      induced thyrotoxicosis, especially in elderly patients with underlying goitre.
      The aim of the study was to identify the number of cases of iodine-induced
      thyrotoxicosis among patients with thyrotoxicosis in a large urban hospital. Over
      an 18-month period thyrotoxicosis has been diagnosed in a total of 39 patients.
      Eight patients with iodine-induced thyrotoxicosis (5 female, 3 male; mean age
      60.6 years) have been identified (20%). In all patients with iodine-induced
      thyrotoxicosis, iodine exposure with a mean iodine dose of 21.5 g was documented
      2 to 16 weeks before diagnosis (iodinated radiocontrast agents in 5 patients,
      amiodarone in 2 patients, kelp tablets in 1 patient). Clinical features were
      predominantly tachyarrhythmias and heart failure, while 6 of 8 patients had
      goitre (thyroid volume 31 to 193 ml). Thyroid antibodies were not detected.
      Diagnosis was confirmed in 5 of 8 patients with increased urinary iodine
      concentrations (3436 to > 6000 nmol/24 h), and in 3 of 8 patients with a low
      tracer uptake in thyroid scintigraphy (1 to 4%). Treatment consisted of
      methimazole in all patients, additional tional beta-blockers and lithium in 4
      patients, and prednisone in 5 patients. The mean treatment ment duration was 9.2
      months, and patients became euthyroid after a mean treatment duration of 6.4
      weeks. One patient (with still elevated free thyroxine levels) died of myocardial
      infarction 4 weeks after antithyroid drug therapy had been installed. The
      incidence, mechanisms and features of iodine-induced thyrotoxicosis are
      discussed. Iodine-induced thyrotoxicosis is a common disease, and the recognition
      and treatment of iodine-induced thyrotoxicosis, particularly in elderly patients
      and patients with goitre, are of clinical importance.

PMID- 10407937
TI  - [Early diagnosis of familial adenomatous polyposis based on multiple osteomas of
      the facial skull].
AB  - We describe a 21-year-old patient hospitalised because of a dislocated mandibular
      fracture and accidentally found to have multiple osteomas of the skull. A
      subsequent gastroenterological examination revealed the presence of multiple
      polyps in the large intestine, typical of familial adenomatous polyposis. A
      disease causing germline mutation in the adenomatous polyposis coli gene was
      identified by molecular genetic analysis. Although extracolonic features such as
      multiple osteomas, multiple epidermal cysts and desmoids are frequently found,
      most cases without a family history of familial adenomatous polyposis or
      colorectal cancer are only diagnosed because of colonic disease manifestations
      with colorectal cancer already present. This case report strikingly illustrates
      that in the absence of a family history the presence of extracolonic features
      allows presymptomatic diagnosis in familial adenomatous polyposis patients before
      colorectal cancer has developed.

PMID- 10407938
TI  - [Tablets in stool? A common problem!].
AB  - Patients and their physicians are often thrown into doubt by the excretion of
      apparently intact tablets in stools after oral drug administration. This occurs
      whenever patients receive certain pharmaceutical forms designed to prolong the
      rate of drug release. The active compound is continuously released during
      intestinal passage of these pharmaceutical forms and their insoluble coats are
      visibly excreted into stools wholly or in part. The assumption that the drug was
      not released from the tablet in these cases is therefore erroneous and no further
      action is required.

PMID- 10407939
TI  - Occupational Raynaud's phenomenon.

PMID- 10407940
TI  - [Malignant diseases concomitant with AIDS].

PMID- 10407941
TI  - [Small thyroid carcinomas: biological characteristics, diagnosis and therapy].
AB  - Small thyroid carcinomas (< or = 1.5 cm), including microcarcinomas (< or = 1.0
      cm) (n = 39), were found in 53 patients (41%) with a papillary (n = 130) and in 4
      cases (4%) with a follicular (n = 110) carcinoma. The tumour was clinically
      manifested by palpability or by the presence of nodal metastases in 1/3 of
      patients. Concomitant diagnoses were colloid goitre (n = 24), cellular adenoma (n
      = 11), Graves' disease (n = 6), and Hashimoto's thyroiditis (n = 4). Nodal
      involvement, multifocal tumour, and extrathyroidal extent (pT4) were present in
      9%, 19%, and 8% of cases respectively. Small follicular carcinomas were minimally
      invasive in all instances. According to the age-related prognostic TNM
      classification, 52 patients (91%) were in the low risk category. 18% of the
      patients underwent uni- or bilateral partial lobectomy, 35% hemithyroidectomy,
      and 47% total thyroidectomy, according to the extent and nature of the
      concomitant benign disease, whereas hemi- or total thyroidectomy was performed in
      the patients with known cancer. Four of 5 patients with stage pT4 cancer and all
      patients with nodal involvement underwent total thyroidectomy with radioiodine (n
      = 8 [14%]). Postoperative morbidity was 0%. During the follow-up period of 1-17
      (x = 5.5) years no tumour-related death and no serious recurrence was noted. One
      node recurrence was removed 1 year following treatment of a stage III pT1aN1b
      papillary carcinoma; the patient died 4 years later accidentally without residual
      disease. These results confirm that cases with a potentially favourable course
      can be defined and treated selectively by less radical measures. Small carcinomas
      (< or = 1.5 cm) belong to these favourable tumours with a cancer mortality rate
      of virtually 0%, and the aim of treatment is to prevent curable recurrences: node
      positivity is an important risk factor, and therefore radioiodine is reserved for
      carcinomas with nodal involvement and also for the occasional small pT4-tumour.

PMID- 10407942
TI  - Sports activity, physical activity and fitness of 9- to 19-year-old teenagers in
      the canton of Vaud (Switzerland).
AB  - BACKGROUND: The protective effects of physical activity and fitness on
      cardiovascular health have clearly been shown among adults and, to a lesser
      extent, among children and adolescents. However, data are currently lacking
      pertaining to children and adolescents living in Switzerland. OBJECTIVES: To
      gather data on the physical fitness and physical/sports activity of children and
      adolescents aged 9 to 19 years. METHODS: From September 1996 until March 1997,
      3540 subjects (1778 girls, 1762 boys) from the canton of Vaud were enrolled in a
      multifaceted study which included a battery of 7 tests measuring different
      components of fitness, anthropometric measures and a self-administered
      questionnaire assessing physical activity, health and lifestyles. RESULTS: Most
      of the respondents practise sports on a regular basis but boys engage in physical
      and sports activities much more often than girls: 75% of boys versus 56% of girls
      spent at least one hour a day in activities inducing sweating, an index of
      moderate to vigorous physical activity (p < 0.001). Depending on the grade, 56 to
      74% of girls and 62 to 88% of boys reported participation in sports clubs (p <
      0.01); current participation ranges from 33 to 46% among girls and 64 to 69%
      among boys (p < 0.001). Participation in physical and sports activities was lower
      after age 15 than before, and also lower among girls than among boys. As far as
      fitness is concerned, girls exhibit greater flexibility than boys, while the
      latter exhibit greater strength and endurance, especially after age 15.
      Calculated values for the BMI and VO2max are within the ranges published in the
      international literature for both sexes. CONCLUSION: Programmes and strategies
      which aim to increase physical activities should be gender-specific and should
      especially target adolescents aged over 15. Physical/sports activities and
      fitness could and should be monitored using both a battery of tests and self
      administered questionnaires.

PMID- 10407943
TI  - [Type 2 diabetes mellitus and coronary heart disease].
AB  - Coronary artery disease is the most common cause of morbidity and mortality in
      subjects with type 2 diabetes mellitus. The risk of coronary artery disease,
      myocardial infarction and mortality from myocardial infarction is markedly
      increased in type 2 diabetic patients compared with non-diabetics. Diabetic
      patients with acute myocardial infarction should receive thrombolytic therapy as
      rapidly as possible and for the same indications as non-diabetics. Diabetic
      retinopathy is not a contraindication to treatment. The management of diabetic
      patients should also include medication with aspirin, beta-blockers and ACE
      inhibitors. An insulin-glucose infusion during acute myocardial infarction,
      followed by insulin injections subcutaneously, reduces mortality by about 30%
      after 12 months and improves long-term prognosis. Thus, insulin-glucose infusion
      in diabetic patients with acute myocardial infarction, especially in those with a
      high blood glucose level (> 11 mmol/l), seems advisable. Diabetic patients
      benefit from secondary prevention by drug therapy (aspirin, lipid lowering with
      statins, beta-blockers and ACE-inhibitors) to the same extent as, or more than,
      non-diabetic patients.

PMID- 10407945
TI  - [Late determination of virilization].

PMID- 10407944
TI  - [Treatment of proximal deep venous thrombosis of the legs by low-molecular-weight
      heparin: a systematic review].
AB  - It is difficult to draw conclusions from published meta-analysis on the treatment
      of proximal deep vein thrombosis by low molecular weight heparins in view of
      methodological problems related to selection of the studies and the addition of
      early and late complications. To determine the efficacy and safety of
      subcutaneous low molecular weight heparins in the initial treatment of proximal
      deep vein thrombosis we reviewed all published randomised controlled studies
      comparing this treatment to the standard intravenous unfractionated heparin
      regimen. Adverse events were taken into account up to 48 hours after cessation of
      heparin treatment. Results point towards equivalent or greater efficacy, with
      reduction in thrombosis size, and safety of low molecular weight heparin. The
      mortality rate was low (0-1.2%). Incidence of recurrent venous thromboembolism (0
      2%) or major bleeding (0-2.4%) was also low, though such events were linked to a
      high mortality rate (9-16%). Thrombocytopenia occurred in 0 to 2.5% of cases.

PMID- 10407946
TI  - Effect of environmental tobacco smoke exposure on respiratory symptoms in
      children. SCARPOL Team. Swiss Study on Childhood Allergy and Respiratory Symptoms
      with Respect to Air Pollution, Climate and Pollen.
AB  - AIMS: This study determines the prevalence of exposure to environmental tobacco
      smoke and its relation to respiratory and allergic symptoms among schoolchildren
      in Switzerland. METHODS: We studied 4470 children aged 6-14 years as part of a
      multicentre study (SCARPOL study--Swiss Study on Childhood Allergy and
      Respiratory Symptoms with Respect to Air Pollution, Climate and Pollen) conducted
      in Switzerland between 1992 and 1993. Environmental tobacco smoke exposure,
      maternal smoking during pregnancy and respiratory symptoms were assessed by means
      of a self-administered parental questionnaire. RESULTS: Forty-seven percent of
      all children were exposed to environmental tobacco smoke. Sixteen percent of the
      mothers smoked during pregnancy. Children exposed to environmental tobacco smoke
      at home had an increased risk of respiratory infections (odds ratio (OR) 1.19,
      95% confidence intervals (CI) 1.03, 1.37). The risk increased if they were
      exposed to maternal smoking (OR 1.25, CI 1.06, 1.48) and if the mother also
      smoked during pregnancy (OR 1.42, CI 1.14, 1.76). Wheezing (OR 1.36, CI 1.03,
      1.80) and repeated coughing (OR 1.36, CI 1.14, 1.61) were only associated with
      maternal smoking. Children exposed to more than 20 cigarettes per day were at
      highest risk for respiratory problems. CONCLUSION: Almost half of all
      schoolchildren in Switzerland, especially those from lower socioeconomic classes,
      are exposed to environmental tobacco smoke. Children with environmental tobacco
      smoke exposure suffer significantly more often from respiratory symptoms.
      Maternal smoking during pregnancy additional to current smoking further increases
      the risk of respiratory morbidity. These findings underline the importance of
      prevention strategies to reduce the prevalence of smoking and its impact on
      children's health.

PMID- 10407947
TI  - [Laparoscopic palliation of pancreatic carcinoma: initial experiences].
AB  - The greater part of patients presenting with pancreatic cancer is irresectable at
      the time of diagnosis. They are in need of palliative treatment. We report our
      first experience with a new concept of laparoscopic palliation based on the
      findings of preoperative imaging and diagnostic laparoscopy. Between 1995 and
      1998, 10 patients underwent laparoscopic palliation. In 3 cases laparoscopic
      double bypass and 7 patients gastroenterostomy was performed, in some instances
      combined with endoscopic stenting. Postoperative morbidity was 10% for
      laparoscopic palliation. There was no mortality in laparoscopic bypass surgery.
      Postoperative hospital stay averaged 11 days. Our preliminary experience strongly
      suggests that laparoscopic palliation may greatly reduce the three major
      drawbacks of open bypass surgery, i.e. high morbidity and mortality, and long
      postoperative hospital stay. Prospective trials in larger study populations will
      be needed to define the place of this technique in the palliation of pancreatic
      cancer.

PMID- 10407948
TI  - [Pericardial involvement in an HIV-infected patient].
AB  - Pericarditis and myocarditis are frequent in patients infected with human
      immunodeficiency virus (HIV), but most cases are asymptomatic or masked by signs
      and symptoms of other organ system disease. We present a case of cardiac
      tamponade, secondary to a disseminated tuberculosis infection, in a patient with
      HIV infection. In HIV-infected patients with symptomatic pericardial effusion,
      about two thirds have an identifiable cause. A review of the literature
      emphasises the role of pericardiocentesis in the management of these patients.

PMID- 10407949
TI  - [Modern therapeutic possibilities in Parkinson disease].
AB  - Several new methods for the treatment of patients suffering from Parkinson's
      disease have been introduced during the last few years. COMT inhibitors are
      available in addition to levodopa with a decarboxylase inhibitor. COMT inhibitors
      enhance and prolong the effect of single levodopa doses. Severe side effects have
      been mentioned in connection with the COMT inhibitor tolcapone in recent months.
      Several new dopaminergic agonists now provide efficacious monotherapy in the
      early stages of the disease. This brings about a reduction in late problems of
      treatment such as dyskinesias and fluctuations. Stereotaxic operations in the
      pallidum and the subthalamic afford relief for these late complications of
      treatment in selected patients.

PMID- 10407950
TI  - [Fatal cure].

PMID- 10407951
TI  - [Consumer trends in heroin and cocaine use: learning from an unfortunate
      controversy].

PMID- 10407952
TI  - Physical fitness and sport activity of children and adolescents: methodological
      aspects of a regional survey.
AB  - Measurement of physical fitness and physical activity in children and adolescents
      raise a lot of methodological issues, explaining the scarcity of surveys in
      European countries and in Switzerland. This article exposes the design and the
      methods used in a survey on physical fitness, physical activity and health
      conducted in a region of Switzerland, and discuss the choice of the instruments
      and the quality control procedure selected to measure physical activity and
      physical fitness. The survey was conducted in a sample of 3540 students 9-19
      years-old and included a battery of physical fitness tests, anthropometrics
      measurements and a self-report questionnaire on physical activity, sports
      activity and life styles. An ancillary study in a sub sample assessed daily
      physical activity with a pedometer, dietary intake with a 3-day dietary record,
      serum lipids and nutritional status. Some results are displayed as example.
      Quality control techniques are exposed and the choice of the instrument to assess
      physical fitness, physical activity, sports, and dietary intake are discussed.
      Local reference tables are now available for fitness tests and the practicability
      of fitness testing has been demonstrated in physical education. The research
      process has induced the sensitisation of schools toward health promotion through
      physical activity.

PMID- 10407953
TI  - [Freiburg Questionnaire of physical activity--development, evaluation and
      application].
AB  - Aim of the present study was to design a questionnaire to assess health related
      physical activity, to validate the instrument and to apply it to a population
      sample. Reliability of the questionnaire was evaluated by test-retest
      investigations with intervals of two weeks and six months. High correlations
      between the repeated administrations reflect a good reliability of our
      instrument. Only gardening and cycling, as well as the depending basic and total
      activity, showed typically seasonal variations. Validity was established by
      correlating physical activity data with maximum oxygen uptake. Maximum oxygen
      uptake correlated with sport activities (partial correlation coefficient: r =
      0.422, p < 0.01). Evaluated data were consistent. People rating themselves as
      "more active than their coevals" were indeed more active in sport (r = 0.334, p <
      0.01) and total activity (r = 0.282, p < 0.05). Studying activity patterns of a
      population sample of adult residents of Freiburg (systematic random sampling, n =
      612, 20-98 years) we found total physical activity of 9.2 hours per week
      (median), with activities of low to moderate intensities dominating. Age and
      gender are important determinants of the activity patterns. According to the
      recommendation of Paffenbarger (2000 kcal/week total physical activity) 40% of
      the residents of Freiburg did not reach the recommended energy expenditure.
      Compared to the recommendation of the American College of Sports Medicine (1000
      kcal/week by training) 63% of the population sample were not active enough.

PMID- 10407954
TI  - [Female life courses and health--results of a study of national survey data of 50
      69-year-old women in East and West Germany].
AB  - The aim of the study was to examine the impact of different forms of combining
      family and paid work on the health status of women. The study was a secondary
      analysis of cross-sectional data from the National Health Survey and included
      1530 women, aged 50 to 69 years, from East and West Germany. Three groups were
      composed to describe different forms of family and occupation in the life course
      (family or occupational career, combination of family and occupation).
      Additionally, aspects of the social situation, resources and burdens as well as
      indicators of health behaviour were included in the analyses. The most remarkable
      result was a significantly worse state of health of employed and childless women
      (occupational career), aged 50 to 59 years. This finding remained after
      adjustment for different potential factors of influence. Considering the
      increasing proportion of women without children in modern societies, longitudinal
      analyses would be necessary to investigate the long term effect of familial and
      occupational factors on the health status of women.

PMID- 10407955
TI  - An indirect method for the estimation of osteoporotic fractures from injury and
      fracture profiles.
AB  - Study objective was to develop a valid epidemiological method for the estimation
      of osteoporotic fracture risk, using administrative databases and accounting for
      variable baseline risks of injury. Design is the secondary analysis of inpatient
      and outpatient utilization data. A baseline injury risk was estimated by the
      incidence of primary utilization of medical services for soft tissue injuries
      (ICD-9 diagnostic codes 910-929), and the risk profile was compared after
      normalization with the overall primary utilization rate for fractures (ICD-9
      diagnostic codes 800-829). The setting is a county with approximately 100,000
      inhabitants in the former East Germany. Participants were all inhabitants of the
      county who had a physician contact (inpatient or outpatient) during 1987-1988, as
      well as hospital inpatients for all of Germany in 1989. The number of fractures
      increased with age, especially in women, when compared to the number of fractures
      expected from the incidence of soft tissue injury. Similar patterns were
      identified in hospitalization data from East and West Germany. Estimating the
      prevalence of osteoporosis directly from certain "osteoporotic" fracture types
      associated with higher age is potentially biased, since it neglects the
      underlying risk of injury. Our model distinguished the osteoporotic fracture risk
      as the excess risk over an expected injury-related fracture risk for a given age
      and sex, and may allow a more valid quantification of osteoporotic fractures in
      different populations.

PMID- 10407956
TI  - [High performance sports and backache: the value of functional analysis and
      progressive dynamic strength training of the trunk muscles. Case report of a 15
      year-old high performance tennis player].

PMID- 10407957
TI  - [Risk of injuries in snow boarding].
AB  - Survey of a group of injured snowboarders and analysis of their sustained
      injuries and risk factors in comparison to experience level and equipment. 55% of
      all injuries occurred within the first 7 days of learning how to ride the
      snowboard. The affected body region of 36% of all injuries and 53% of the severe
      injuries was the wrist. The primary mechanism of injury was through low-velocity
      falls on hard or icy snow, essentially a loss of balance with backward fall onto
      out-stretched arms leading to hyperextension and trauma to the wrist.

PMID- 10407958
TI  - [Pattern and risk of injuries of profile athletes in snow boarding].
AB  - During winter 1994/95 and 1995/96 a retrospective study was carried out in which
      datasets supported by questionnaires from 31 female and 64 male professional
      snowboarders were evaluated. Included were personal data and details of other
      types of sports. Also the personal style preferred and equipment used was
      integrated. Particularly of interest were the localization and causes of injury
      patterns with the degrees of severity and overexertion disorders. Among the
      professionals the most frequent injuries occurred in the metacarpals and fingers
      (37.3%), the shoulder (36.0%), knee joints (33.3%) and the ankles (28%). The
      predominating pattern of severe joint injuries were capsular/ligament lesions and
      fractures. Overexertion syndromes in the knee were predominant, followed by thigh
      and ankle-joint strains. In the alpine group the incidence of injuries and
      strains, the knee was the most frequent. 75 professionals suffered 195 traumas.
      In relation to 1000 snowboarding hours, the risk of injury among the
      professionals is 0.8. Self induced injuries were mostly cause of misjudgement in
      specific situations (40.1%).

PMID- 10407959
TI  - [Accident statistics at "indoor climbing walls"].
AB  - During a period of 6 month the risk of significant injuries on indoor climbing
      walls was survived. A total of 25,163 visitors were registrated at the 10 walls.
      Overall only 4 significant injuries were found, the injury-risk per visit was
      0.016%.

PMID- 10407960
TI  - [15 years insurance statistics of incidents and accident types of combat sports
      injuries of the Rhineland-Pfalz Federal Sports Club].
AB  - The primary intention of this study is the grouping of sports accidents, being
      described by the athletes in their own words in a classification system of
      specific accident classes with regard to specific motions and topography. The
      investigation is based on the data of the sports insurance Gerling-Konzern during
      a 15-year period in Rhineland Palatinate (1981-1995). The study is based on the
      insurance documents and clinical protocols if available. 137 accident protocols
      were related to this 15-year period including weight lifting (n = 1) and martial
      arts (n = 136). Listed in hierarchical order we received the following results:
      judo (n = 47), karate (n = 44), wrestling (n = 22), taekwondo (n = 9), boxing (n
      = 7), ju-jutsu (n = 5), fencing (n = 1) and aikido (n = 1). In accordance to
      accident types there were no sex related differences. As special preventive
      measures we suggest the use of protective mouthguards and solid glasses,
      proprioceptive training and physiological taping for knee, ankle and elbow
      joints.

PMID- 10407961
TI  - [Sports and physical load bearing capacity after spondylodesis in patients with
      Scheuermann kyphosis].
AB  - In this investigation it was examined which is the effect of an extensive
      spondylodesis by patients with Scheuermann's kyphosis on their sport activity and
      their physical load capacity. Between 1983 and 1990, 10 patients with severe
      kyphosis secondary to Scheuermann's disease underwent surgical correction and
      spinal fusion. In 1997 all 10 patients were clinically and radiologically
      examined and interviewed at an average follow-up of 9.6 years. At the time of
      follow-up one patient was active in top sports, seven patients in normal sport,
      two patients were members in a sports-club and one patient was not interested in
      sport. Eight patients went in for sports regulary. Mostly the patients were
      active in gymnastics, cycling and swimming. At follow-up almost all patients
      found that their physical load capacity and the behaviour in relation to back
      pain were better than before operation. Half of the patients were exposed to a
      middle physical load in the daily life. The presented study shows that patients
      after extensive spondylodesis for Scheuermann's kyphosis and clear reduction of
      pain are not automatically limited in the daily life, both for sport and
      professional activity. However, generalized recommendations for the physical load
      capacity of the operated patient cannot be given, and an individualized decision
      must be taken for each case.

PMID- 10407962
TI  - [Craniocerebral trauma in sports. With recommendations for prevention].
AB  - Traumatic brain injury (TBI) is found in many sports. A mild head injury
      (concussion of brain) is found in more than 80%, mainly in sports with contact to
      others. Especially affected by death are air sports, horse riding and cycling,
      whereby brain damage often is the leading injury. With the example of a cycling
      accident the possible processing dynamics of a mild head injury with secondary
      brain damage through an intracranial hematoma is demonstrated in the following.
      For the assessment of sports ability, there is often made the division with
      symptoms as confusion, amnesia and unconsciousness after a mild head injury
      (scale 1-3). According to the gravitational scale of cerebral concussion, an
      adequate sports break should be kept. Postcommotional symptoms prove sports
      inability. A chronic brain damage is not rarely found in some combative sports.
      In this case the injury may result in a traumatic encephalopathia with the
      evaluation of dementia and in some cases also Parkinson's disease is observed. To
      prevent a TBI there should be worn an adequate protective headgear especially by
      children in training and in sports contests concerning risk sports. Further
      recommendations for prevention are presented and with them there will also be
      responded to sports ability in neurosurgical diseases.

PMID- 10407963
TI  - Reasons for living versus reasons for dying: examining the internal debate of
      suicide.
AB  - The Reasons for Living vs. Reasons for Dying (RFL/RFD) Assessment was used to
      obtain suicidal outpatients' top five reasons for living and for dying,
      respectively. Forty-nine suicidal university counseling center patients provided
      173 RFL and 145 RFD responses. These responses were organized into eight RFL
      coding categories and nine RFD coding categories. Two coders trained in the
      RFL/RFD coding system showed high levels of interrater reliability (KRFL = .81;
      KRFD = .80). Chi-square results for RFL and RFD coding categories showed that the
      coding categories were not equally salient to these suicidal patients.

PMID- 10407964
TI  - Conceptions of death and suicide in children ages 6-12 and their implications for
      suicide prevention.
AB  - Interviews were conducted with 65 public school children in Grades 1-5 concerning
      their understanding of and experiences with death and suicide, and investigating
      the development of the Piagetian concepts of life and age. By third grade,
      children have an elaborate understanding of suicide, and younger children
      generally understand "killing oneself," although their understanding of death and
      living may be immature. Children learn about suicide from television and
      discussions with other children, but they rarely discuss suicide with adults. The
      level of development of the concept of suicide is related to maturity rather than
      specific experiences. Implications for primary prevention are discussed.

PMID- 10407966
TI  - Incidence of suicidal ideation and behavior in the United States, 1994.
AB  - Completed suicides reflect only a portion of the impact of suicidal behavior;
      sublethal behaviors cause morbidity and can signal treatable problems such as
      depression. There is no national quantification of nonlethal suicidal behaviors.
      The present study used a random-digit-dialed telephone survey to estimate the 12
      month incidence of suicidal ideation, planning, and attempts among U.S. adults.
      Of 5,238 respondents, 5.6% (representing about 10.5 million persons) reported
      suicidal ideation, 2.7% (about 2.7 million) made a specific suicide plan, and
      0.7% (about 700,000) made a suicide attempt (estimate = 1.1 million attempts).
      Hence, suicidal behaviors are not uncommon and occur along a continuum ranging
      from ideation to completed suicides. Preventing nonlethal precursor behaviors may
      prevent deaths.

PMID- 10407965
TI  - Suicidal ideation among adolescent school children, involvement in bully-victim
      problems, and perceived social support.
AB  - Relationships among suicidal ideation, involvement in bully-victim problems at
      school, and perceived social support were investigated with samples of adolescent
      students (N = 1103 and N = 845) attending secondary school in South Australia.
      Results obtained from self-reports and peer nomination procedures to identify
      bullies and victims indicated that involvement in bully-victim problems at
      school, especially for students with relatively little social support, was
      significantly related to degree of suicidal ideation.

PMID- 10407967
TI  - Reliability and sensitivity of suicide certification in higher-income countries.
AB  - World Health Organization age-, sex-, and cause-specific mortality data for the
      United States and 19 other democratic higher-income countries were utilized to
      assess the reliability and sensitivity of suicide certification for purposes of
      cross-national research. Data are found to be highly reliable across age and sex
      (rs > 0.92; P < 0.001). Relative discrepancies between official suicide rates
      (putative lower limits) and projected upper limits vary widely internationally.
      Austrian and Dutch suicide certification is the most sensitive. Least sensitive
      is certification for certain subpopulations in Finland, Greece, Ireland, Israel,
      and the United Kingdom. We recommend similar analyses be performed for routine,
      low-cost surveillance of suicide data quality, and to guide choice of population
      groups for multivariate comparative research.

PMID- 10407968
TI  - The subjective experience of problem irresolvability and suicidal behavior:
      dynamics and measurement.
AB  - This article presents the dynamics and measurement of a relatively unstudied
      concept in children's and adolescents' suicidal behavior: the subjective
      experience of problem irresolvability (SEPI). This concept relates to the
      youngsters' sense of lack of control due to being pressured to resolve
      irresolvable problems within the family circle. The first study describes the
      construction and factor analysis of the SEPI scale as well as its relationship to
      suicidal tendencies, perceived parental care, and self-esteem. The second study
      presents a repeated factor analysis and the association between the SEPI scale
      and suicidal tendencies, hopelessness, depression, anxiety, and commitment to
      parents. The results suggest that the scale has a 4-factor structure with sound
      psychometric properties that distinguish successfully between suicidal
      adolescents on the one hand, and psychiatric and normal adolescents on the other.
      The SEPI was also found to be associated with the various studied variables.

PMID- 10407969
TI  - The role of objective personality inventories in suicide risk assessment: an
      evaluation and proposal.
AB  - Objective personality assessment instruments offer a comparatively underutilized
      source of clinical data in attempts to evaluate and predict risk for suicide. In
      contrast to focal suicide risk measures, global personality inventories may be
      useful in identification of long-standing styles that predispose persons to
      eventual suicidal behavior. This article reviews the empirical literature
      regarding the efficacy of established personality inventories in predicting
      suicidality. The authors offer several recommendations for future research with
      these measures and conclude that such objective personality instruments offer
      only marginal utility as sources of clinical information in comprehensive suicide
      risk evaluations. Personality inventories may offer greatest utility in long-term
      assessment of suicide risk.

PMID- 10407970
TI  - High rates of paraquat-induced suicide in southern Trinidad.
AB  - The suicide rate in Trinidad and Tobago is much greater than that of its English
      speaking Caribbean neighbors. Many of these suicides are paraquat induced. This
      research reviewed the deaths due to suicide in the area with the greatest
      agricultural activity in Trinidad for 1996 and identified, for further
      demographic and etiological investigation, cases in which paraquat was ingested
      as the agent of suicide. Of 48 cases of suicide for the year, 39 (81.3%) were due
      to paraquat poisoning. The incidence of paraquat-induced suicide was 8.0 per
      100,000. Among the males, 47.8% were in the age group 25-34 (p < 0.001), and
      among the females 50.0% were in the 15-24 age group (p < 0.05). Family-of-origin
      disputes were the most frequently cited precipitant, followed by marital
      problems. Individuals of East Indian origin accounted for 89% of the suicide
      victims (p < 0.001). When compared with suicide by other methods in the country,
      these findings confirm that paraquat poisoning is a significant means of suicide
      in Trinidad and that young East Indian individuals are particularly vulnerable.

PMID- 10407971
TI  - Bereavement after a physician-assisted suicide: a speculation based on theory.

PMID- 10407972
TI  - [Morphology, hemoperfusion and function of the thyroid gland].

PMID- 10407973
TI  - [Color doppler ultrasonographic detection of focal thyroid nodules].
AB  - AIM: To determine if colour Doppler sonography is a sensitive tool to detect
      solitary hot thyroid nodules. METHODS: All patients evaluated in our ultrasound
      laboratory during study period also underwent thyroid sonography. If one or more
      nodules with a diameter of at least 8 mm were present, thyroid scientigraphy was
      performed. Hyperperfusion within the nodule compared to the surrounding tissue
      indicated autonomy according to the study protocol. RESULTS: 1010 patients were
      screened. 385 had one or more nodules, 309 of them with a diameter of more than 8
      mm. Among these patients a hot nodule was proved with scintigraphy in 120 cases.
      116 of these 120 patients were correctly identified with colour Doppler
      sonography. CONCLUSION: Colour Doppler sonography is a reliable method to detect
      solitary hot or hyperperfused thyroid nodules and to identify a risk group of
      patients prior to the administration of x-ray contrast media.

PMID- 10407974
TI  - Percutaneous radiofrequency thermal ablation combined with transcatheter arterial
      embolization in the treatment of large hepatocellular carcinoma.
AB  - PURPOSE: To evaluate whether the combination of hepatic segmental transcatheter
      arterial embolization (TAE) with percutaneous radiofrequency (RF) ablation can
      increase the volume of coagulation necrosis to treat patients with large
      hepatocellular carcinoma (HCC). METHOD: Fourteen patients with cirrhosis and HCC
      whose greatest diameter ranged from 3.8 to 6.8 cm (mean, 5.2 cm) underwent
      segmental TAE followed within 3 days by RF interstitial thermal ablation with an
      expandable needle electrode inserted into the tumour under sonographic guidance,
      after local anesthesia. We made one or more needle electrode insertions depending
      on tumor shape. Posttreatment necrosis was evaluated by ultrasonography, dynamic
      computed tomography (CT) and alpha-fetoprotein dosage in all cases, repeated
      every three to four months. RESULTS: Tumor ablation was obtained in one session
      in 11 (78%) patients (with one needle electrode insertion in 8 patients), in two
      sessions in 1, in three sessions in 2. In a mean follow-up of 13.2 months (range
      6-23) two patients died from unrelated causes; one patient showed multinodular
      HCC 6 months after the treatment; 4 patients developed new lesions, treated by a
      new course of RF ablation (3 cases) or by surgery (1 case); therefore 11/12
      patients still in follow-up were disease-free. No fatal complications were
      observed. One month after the treatment, fluid collection at the site of the
      ablated tumor was observed in one patient which was percutaneously drained.
      CONCLUSIONS: Percutaneous RF thermal ablation performed after TAE effectively
      treated HCCs larger than tumors suitable for segmental TAE or RF application
      alone; the result was achieved in two thirds of the cases in a single session
      with only one needle electrode insertion.

PMID- 10407975
TI  - Chest ultrasound in diagnosis of pulmonary embolism in comparison to helical CT.
AB  - To many people die because of undiagnosed pulmonary embolism. Common pulmonary
      embolism is the most unexpected mortal event in necropsy, antemortem correctly
      diagnosed in 18-39%. The diagnostic value of chest ultrasound (CUS) has been
      investigated. METHODS: 117 (68 women, 49 men) patients with clinical suspicion of
      pulmonary embolism underwent chest sonography and spiral computed tomography
      (CT). Final diagnosis has been made by CT respective with echo-cardiography,
      venous duplex sonography and fibrin dimer tests. RESULTS: Finally, 70 patients
      suffered from pulmonary embolism. The chest sonograms showed averaged 1.5 x 2.8
      cm (0.5-8.5) large triangular or rounded hypoechoic lesions, mean 2.6 pro
      patient, similar in form and size as in CT. Fresh reperfusionable infarcts were
      homogenous and hypoechoic. Older infarcts were well demarcated, mainly wedge
      shaped. A hyperechoic reflex in the center corresponds to the bronchiole: a sign
      of segmental involvement. The sensitivity of chest ultrasound was 94%, the
      specificity 87%, positive predictive value 92%, negative predictive value 91%,
      accuracy 91%. Overall 61 patients had PE in CT, in 47 (67%) cases a direct emboli
      detection was possible. 14 patients had peripheral lung consolidations without
      detectable emboli, but fibrin-dimer tests were positive in all cases, there was
      deep vein thrombosis diagnosed and they showed signs of PE in echocardiography.
      Spiral CT showed a sensitivity of 85%, a specificity and a positive predictive
      value of 100%, a negative predictive value of 83% and an accuracy of 92%.
      CONCLUSION: CUS can improve diagnosis of pulmonary embolism. Sonography also
      reveals small infarcts which remain undetected with other imaging procedure such
      as helical CT.

PMID- 10407976
TI  - [Ultrasound guided forceps biopsy of the pleura].
AB  - AIM: Between cytology of pleural effusion and thorascopy there is a gap for
      another non invasive biopsy method to diagnose pleural diseases, especially since
      Adam's and Ramel's blind pleural biopsy is uncommon. Therefore it is suggestive
      to test feasibility and usefulness of pleural forceps biopsy. METHOD: It is
      possible to take biopsies under ultrasound guidance with the help of a biopsy
      forceps from the diaphragmatic pleura or pleural appositions through a 2.5 mm
      canula with a stop cock and a rubber vent. The specimen can be used for
      histological or immunohistochemical examinations. The procedure is coducted in a
      closed system to avoid pneumothorax. The puncture was done in 12 patients with a
      puncturable pleural effusion. RESULTS: In 11 of 12 patients it was possible to
      get the final diagnosis. In one of three cases of mesotheliomas a rebiopsy was
      necessary. In 9 cases a malign tumor was diagnosed, effusion cytology was
      negative in 4 of 7 tumors. In 5 patients with a history of a former tumor pleural
      carcinosis was related three times correctly to the former cancer and twice to a
      secondary cancer. In one case a fibrous plaque was found. There were two patients
      with pleuritis, in one case a pulmonary tuberculosis was found 8 weeks later. In
      one patient with a mesothelioma inoculated metastasis were present in the sites
      of the punctures. In all pleural forceps punctures we got enough biopsy material
      for histological and immunohistochemical diagnosis. CONCLUSION: The ultrasound
      guided forceps biopsy of the pleura is a very promising less invasive method to
      diagnose pleural tumors. Additional improvements of the equipment are possible.
      Definitive evaluation of the procedure especially in infectious pleural diseases
      requires a higher number of cases.

PMID- 10407977
TI  - [Value of ultrasound guided piezoelectric shock wave lithotripsy in the treatment
      of pancreatic stones].
AB  - AIM: Most patients with pancreatic duct stones have been treated with
      lithotripters that use x-ray for stone targeting. We wanted to evaluate
      ultrasound guided lithotripsy in clinical use. METHODS: In a prospective clinical
      study 80 patients (62 men) with symptomatic obstructive chronic pancreatitis were
      treated with a piezoelectric lithotripter under ultrasound guidance (two in-line
      4-MHz-Scanners). RESULTS: Stone targeting by ultrasound guidance was possible in
      76 patients. Fragmentation succeeded in 53 patients (70%). Complete or partial
      stone clearance was achieved in 43 patients, a success rate of 54%. CONCLUSION:
      Ultrasound guided shock wave lithotripsy of pancreatic duct stones plays an
      important role in the treatment of chronic pancreatitis.

PMID- 10407978
TI  - [Noninvasive, accurate and reliable measurement of cervical spine motion with a
      3D real-time ultrasound motion analyzer].
AB  - AIMS: The kinematic analysis of cervical spine motion is important to assess
      objectively the effects of therapeutic interventions. In this study, precision
      and reliability of a 3D ultrasound motion analyser was determined. Using this
      tool the physiologic range of movement of healthy volunteers was assessed. The
      aim was to test the clinical practicability of this system. METHODS: The active
      and passive cervical spine range of motion of 20 healthy volunteers with a mean
      age of 23 years (range 19-28 years) was determined using a CMS 3D ultrasound
      realtime motion analyser (Zebris Medizintechnik, Tubingen, Germany). Precision
      was assessed by comparison with a precision goniometer. Two observers determined
      the inter-rater and retest reliability and the Pearson correlation coefficients
      were calculated. RESULTS: The maximum measurement difference between CMS and
      precision goniometer was 0.6 degree. Inter-rater- and retest reliability
      correlated significantly (0.84 < r < 0.96, p < 0.001). The range of motion found
      by the CMS corresponded well with motion values determined using other devices.
      CONCLUSIONS: The range of motion of the cervical spine can be assessed accurately
      and reliably using a 3D ultrasound motion analyser. The CMS motion analyser is
      suitable for clinical practice.

PMID- 10407979
TI  - [Diagnostic ultrasonography of the sternoclavicular joint].
AB  - PURPOSE: To evaluate the value of ultrasonography in the diagnosis of swelling
      and lesions of the sternoclavicular joint (SCG). MATERIAL AND METHODS: We
      analysed the sonograms of 20 SCG of 18 patients with pain and swelling of the
      SCG. Ultrasonography was performed just after the clinical examination, using a
      7.5 MHz linear scanner. RESULTS: All examinations of the SCG produced distinct
      and clear sonographical findings. We showed that luxations of the SCG as well as
      tumors and local inflammation can be identified. CONCLUSION: Ultrasonographic
      examination is a noninvasive, time sparing and economical diagnostic tool for
      clarifying the differential diagnosis of lesions of the SCG and establish may a
      therapy regimen.

PMID- 10407980
TI  - [Atypical gallstone ileus: radiologic and sonographic findings].
AB  - We report on a case of an atypically located gallstone ileus as a rare
      complication of cholecystolithiasis. A 61-year old lady with a history of
      diabetes type II and nephrolitiasis presented with abdominal pain lasting for 8
      days and with vomiting and diarrhoea. Physical examination revealed a palpable
      tumour and pain in the left lower abdomen. An extensive elevation of blood sugar,
      CRP and leukocytosis was found. Initially X-ray of the abdomen and sonography
      showed signs of a subileus. Additionally a 5 x 2 cm mass with dorsal shadowing
      was detected by ultrasound. Gallbladder and the biliary system were normal. The
      sonographic suspicion of a gallstone ileus was confirmed by a subsequent CT scan.
      Under operation the gallstone was found in the distal Jejunum. A gallstone ileus
      must be included in the differential diagnosis of a tumour in the left lower
      abdomen. A tumour with dorsal shadowing and signs of a subileus may be the only
      sonographic findings of a gallstone ileus.

PMID- 10407981
TI  - [Reconstructive surgery of the efferent urinary tract in pelvic exenteration of
      gynecological tumors].
AB  - In locally advanced or recurrent tumors of the female genital tract anterior or
      total exenteration may be mandatory in case of tumor invasion into the lower
      urinary tract or if a second course of radiation therapy is not feasible. The
      management of resection and reconstruction of the affected lower urinary tract
      has to be well integrated into the gynecological therapeutic concept. In 11/32
      patients the reconstruction of the partially resected lower urinary tract was
      feasible with preservation of a functionally intact urinary bladder. Urinary
      diversion following pelvic exenteration was achieved in 13/17 patients with a
      continent urinary reservoir and in 4/17 patients with an ileal conduit. Operative
      reinterventions were needed only in patients with continent urinary diversion in
      5 cases. All these patients had a past history of primary radiation therapy of
      their gynecological tumor. In the remaining other 11 patients with a history of
      primary radiation therapy no complications occurred. 9 of 32 patients survived
      the operative procedure 40.8 (25-57) month with no evidence of recurrent tumor.
      Continent urinary diversion represents an excellent therapeutic option for
      replacement of function lost due to exenterative pelvic surgery. Stringent
      selection of patients is mandatory to consider the presented therapeutic concept
      a reasonable tool in the management of the described clinical situations.

PMID- 10407982
TI  - [Trials with a new potentially biodegradable ureteral stent. In vitro results
      with GX 100-15 LB].
AB  - We detected a special plastic, which is stable in an acid environment and
      dissolvable in a basic one. Our preliminary in-vitro results show that the tested
      material therefore seems principally designed for developing biodissolvable
      stents for temporary urinary diversion out of the upper urinary tract. Stableness
      and dissolution could be steered by manipulating the pH.

PMID- 10407983
TI  - [Extravesical correction of the uretero-vesicle junction].
AB  - In correction of the ureterovesical junction, the pathology can be corrected
      using an extravesical or intravesical technique. We performed an extravesical
      antireflux procedure with the dismembered or non-dismembered technique in 117
      ureters between March 1991 and March 1996 at our Department of Pediatric Urology.
      The success rate was 94.9% (111 renal units). Postoperative morbidity and
      complications were minimal, hematuria and bladder spasms were not seen.
      Associated pathology like paraostial diverticula, megaureter with the necessity
      for modeling and ureter duplex do not compromise the success rate.

PMID- 10407984
TI  - [Increased incidence of renal cell carcinoma in central Europe. Does diagnostic
      increase reflect a true increase in incidence?].
AB  - In the last years the incidence of renal cell carcinoma diagnosis increased about
      15-20%. The main aim of this study was to analyse the reason of the increase of
      incidence. In the present autopsy series comprising 23,801 autopsies the
      percentage of patients who died of renal cell carcinoma is 1.77% in Jena and
      1.55% in Koniggratz (200,000 inhabitants each). Over this time the incidence of
      renal cell carcinoma in autopsies has increased. In spite of the increased amount
      of incidentally found renal cell carcinomas since beginning widespread use of
      ultrasonography the percentage of clinically recognized renal cell carcinomas on
      the total of all found renal cell carcinomas in autopsies is nearly constant
      about the 12-year period in Jena and 10-year period in Koniggratz. Thus, the
      increased number of radical nephrectomies is not only caused by widespread use of
      ultrasonography. The increasing trend of the incidence of renal cell carcinoma
      seems to be real.

PMID- 10407985
TI  - [Colony stimulating factors in polychemotherapy of testicular tumors. A
      comparison between G-CSF and GM-CSF].
AB  - Colony-stimulating factors (CSF) are frequently used in cases of cytostatic
      therapy of patients with testicular cancer assuming that they support
      hematopoietic recovery and, thus, shorten duration of neutropenia as well as
      reduce infections. Currently, G-CSF and GM-CSF are clinically used. In the
      present study efficacy and toxicity of these two drugs were investigated and
      compared in patients with testicular cancer treated by standard chemotherapy.
      Studying 83 chemotherapy cycles applied to 31 patients with advanced germ cell
      tumors the effectivity and the side effects of the two CSF were examined by
      questioning, clinical evaluation, and blood chemistry studies. G-CSF (480
      micrograms subcutaneously (s.c.)) were used in 55 and GM-CSF (400 micrograms
      s.c.) in 28 chemotherapeutic cycles. The indications consisted in the treatment
      of leukocytopenia on the one hand and in the prophylaxis in subsequent cycles on
      the other hand. No difference between the two CSF could be found either with
      regard to postponement of the next cycle (G-CSF: 6.8 vs. GM-CSF: 7.3 days), or to
      the number of injections per cycle (G-CSF: 8 vs. GM-CSF: 12.5), or to the
      leukocyte (G-CSF: 2.1 vs. GM-CSF: 1.6 x 10(3)/microliter) or platelet nadir (G
      CSF: 0.5 vs. GM-CSF: 0.5 x 10(5)/microliter; mean values of all cycles,
      respectively). Both CSF did not seem to influence the production of platelets.
      However, a difference between the two CSF was demonstrated with respect to the
      toxicity. Frequency (G-CSF: 38.5% vs. GM-CSF: 69.3%) as well as intensity of side
      effects causing a change of the drug (G-CSF: n = 1 vs. GM-CSF: n = 7) were lower
      in the case of G-CSF. In conclusion, these data demonstrate no difference was
      seen between G-CSF and GM-CSF with respect to the efficacy in patients with
      testicular cancer treated by standard chemotherapy. However, the use of G-CSF
      seems to be associated with lower toxicity.

PMID- 10407986
TI  - [Surgical correction of penile deviation. Nesbit vs. Schroeder-Essed method].
AB  - 60 patients with a marked penile deviation [40 because of a congenital penile
      deviation (CPD) and 20 as a result of the Peyronie's disease] were questioned
      about the result of the operation by means of a questionnaire in a retrospective
      study with an average follow-up of 45 month. The Nesbit procedure had been used
      with 49 of these 60 patients, the modified Schroeder-Essed technique had been
      used with 11 patients. There were 15 patients (25%) in all, who suffered a
      relapse. In spite of the continual use of non-absorbable suture material with the
      Schroeder-Essed technique, the number of relapses was in this group plainly
      higher than in the Nesbit group (55% and 18% respectively). In our opinion this
      is caused by the insufficient tensile strength of pure plications. Regardless of
      the operating method, patients suffering from IPP showed a higher number of
      relapses than patients having a CPD (35% and 20% respectively). The reason for
      this might be the fact that one can never rule out completely the possibility of
      a further progress of the disease. 71% of the patients in the Nesbit group were
      satisfied with the results of the operation, in the Schroeder-Essed group there
      were only 36%. Irrespective of the operating method, IPP patients complained
      moreoften about late complications and erection problems after the operation and
      were more rarely satisfied with the result than patients with a CPD (50% and 73%
      respectively). We put this down to the fact that patients with a CPD and patients
      suffering from IPP represent very different collectives as far as age structure
      and morbidity are concerned. IPP patients frequently have erection problems even
      before the operation. Especially with IPP patients, preoperative erectile
      disfunction must be excluded, in the case of their occurrence there are to prefer
      other programmes of therapy.

PMID- 10407987
TI  - [Effectiveness and tolerance of 1 dosage forms (subcutaneous and intramuscular)
      of decapeptyl depot in patients with advanced prostate carcinoma].
AB  - The intramuscular (i.m.) administration of Decapeptyl Depot has been approved in
      Germany for the treatment of advanced hormone dependent prostate cancer since
      July 1990. In this study a reformulated Decapeptyl Depot, administered as a first
      line endocrine therapy, was injected intramuscularly (i.m.) or subcutaneously
      (s.c.) every 28 days for 6 months. At 12 different hospitals, 52 prostate cancer
      patients were treated, whereby 25 patients received a s.c. injection and 27
      patients a i.m. injection. Testosterone was measured as the main parameter: after
      28 days, both the s.c. and the i.m. application form of Decapeptyl Depot
      successfully reduced initial testosterone levels of at least 2.3 ng/ml to steady
      state castration levels below 1.2 ng/ml, maintaining this complete suppression
      for the entire length of the trial (168 days). Decapeptyl Depot was well
      tolerated and very acceptable to the patients in both groups. Side effects were
      few and predictable, being largely associated with decreased testosterone
      concentrations. No cumulation in triptorelin serum levels was observed within the
      6 months of treatment. Decapeptyl Depot, administered subcutaneously or
      intramuscularly was effective and safe in the treatment of patients with advanced
      prostate cancer.

PMID- 10407989
TI  - [Testicular metastasis of prostatic carcinoma 3 years after subcapsular
      orchiectomy. A case report].
AB  - Metastatic cancer to the testis is a rare phenomenon of prostate carcinoma with
      only 80 cases reported in the literature. Most of these secondary testicular
      tumors were diagnosed on routine pathohistological examination of testicular
      tissue after plastic orchiectomy. In none of these cases metachronous development
      of these metastases has been described. For the first time we report on a 75-year
      old patient who developed a prostate carcinoma metastatis to the right testicle
      three years after undergoing subcapsular orchiectomy. This case shows that the
      urologist has to think about a metastatic cancer when he sees a testicular tumor
      also after plastic orchiectomy.

PMID- 10407988
TI  - [Intra- and peri-renal gas formation. Bilateral emphysematous pyelonephritis].
AB  - Bilateral emphysematous pyelonephritis is an extremely rare, rapidly progressive
      and life-threatening intrarenal and perirenal infection. It is associated with
      diabetes mellitus, obstruction of the upper urinary tract and the presence of gas
      forming coliform bacteria. As it presents as a severe acute pyelonephritis, a
      high index of suspicion and computer-tomographic imaging are essential to make
      the diagnosis. Only immediate combined medical and (bilateral) surgical therapy
      can reduce the high patient mortality. Postoperatively, computer-tomographic
      monitoring is recommended to follow the response to therapy.

PMID- 10407990
TI  - [Bilateral testicular tumors. Contralateral benign lesions in germ cell tumors of
      the testis].
AB  - Bilateral testicular tumors account for approximately 3.5% of all testicular
      malignancies and to our knowledge about 800 cases are reported in the literature.
      An even more seldom event is the appearance of a testicular germ cell tumor with
      a contralateral benign non-germ cell tumor. We report the 6th case of such a
      coincidence. The dignity of a contralateral tumor should be assured by frozen
      section and in case of benign histology organ preserving therapy is indicated.
      Even in cases of bilateral testis cancer tumor enucleation may be considered, if
      the strict conditions for resection and follow-up are respected.

PMID- 10407991
TI  - [Disorders of calcium and phosphate homeostasis].

PMID- 10407992
TI  - [Guidelines by German urologists for diagnosis of benign prostatic hyperplasia
      syndrome. German Society of Urology].

PMID- 10407993
TI  - [Therapeutic spectrum of blood stem cell transplantation].

PMID- 10407994
TI  - Hepatopulmonary syndrome.
AB  - The hepatopulmonary syndrome (HPS) is a rare complication of liver cirrhosis and
      is characterised by the typical triad of liver cirrhosis, arterial hypoxemia, and
      intrapulmonary vascular dilatation. Except for pleural effusions associated with
      liver cirrhosis no other disease of the lungs or the heart is detectable. The
      structural hallmark of HPS is dilatation of pulmonary precapillary vessels which
      impairs diffusion-perfusion and causes unequal ventilation-perfusion. The
      diagnosis of HPS is based on PaO2 measurements when breathing room air and 100%
      oxygen. The increased intrapulmonary vascular diameter allows microbubbles to
      traverse the lung capillaries when agitated saline is administered intravenously.
      Only on rare occasions is a patient limited by his pulmonary impairment, the
      leading morbidity is that of liver disease and its classical complications. Drug
      therapy is of no proven benefit, oxygen supplementation might improve dyspnea.
      Vascular embolisation of discrete arteriovenous shunts, if present, or liver
      transplantation may dramatically improve pulmonary function in selected patients.

PMID- 10407995
TI  - Transplantation of related and unrelated umbilical cord blood stem cells in
      Austria. Austrian Working Party for Stem Cell Transplantation. Austrian Society
      of Hematology and Oncology.
AB  - Allogeneic bone marrow transplantation is limited by the availability of suitable
      HLA-matched donors and the risk of graft versus host disease (GvHD). In an
      attempt to overcome these limitations umbilical cord blood (UCB), has become a
      further alternative. UCB transplantations in Austria were started in 1991. As of
      September 31, 1998, six patients have been transplanted. Diagnoses were severe
      aplastic anaemia (SAA) (n = 2), acute lymphoblastic leukaemia (ALL) (n = 1),
      familial hemophagocytic syndrome (FHL) (n = 2) and chronic myelomonocytic
      leukaemia (CMML) (n = 1). Three patients received UCB grafts from HLA-identical
      siblings and three patients from unrelated donors, of whom two were disparate at
      two HLA loci (A/B) and one mismatched at one locus (C). Five patients were
      engrafted with complete donor hematopoiesis, with a median time of 26.5 days
      (range 14 to 39 days) to an ANC count of > or = 0.5 x 10(9)/L and a median time
      of 42.5 days (range 24 to 67 days) to a platelet count of > or = 20 x 10(9)/L.
      One patient with FHL had partial engraftment and died due to reactivation of
      cytomegalovirus (CMV) infection and CMV pneumonia on day +25. Of the five
      patients surviving the post-transplant period, one with CMML had a relapse on day
      +128 and died after a HLA-matched bone marrow transplantation from the same
      sibling donor in the second relapse. Another patient with ALL relapsed on day
      +200 but is still alive under palliative treatment; one patient with SAA showed
      graft rejection and autologous hematopoietic reconstitution and later had a
      successful CD34(+)-selected allogeneic peripheral stem cell transplant from a C
      locus mismatched unrelated donor. Two patients (one with SAA and one with FHL)
      are alive with complete remission of the underlying disease. This report reflects
      the experience and results of UCB transplantation in Austria and discusses the
      position of UCB transplantation in the context of the other stem cell
      alternatives available today.

PMID- 10407996
TI  - Prevalence of self-reported cervical cancer screening and impact on cervical
      cancer mortality in Austria.
AB  - Pap smear screening was introduced in Austria in the late 1960's and was
      recommended annually for all women older than 20 years ever since. This is an
      opportunistic screening. The evaluation has to rely on population based data
      (mortality, stage distribution, screening prevalence). In a representative cross
      sectional study (women aged 20-69 years, n = 933, conducted in 1995), 76%
      reported at least one Pap screening during their life; the highest prevalence
      (88%) was reported by women aged 50-59 years, the lowest prevalence (65%) by
      women aged 60-69 years. Forty-eight per cent of all women reported that they had
      undergone screening at least 4 times (40-49 years: 57%, 20-29 years: 34%).
      Between 1980 and 1996, mortality due to cancer of the uterus, part unspecified
      (ICD-9: 179), decreased by 54% (P = 0.0001) and that of cancer of the cervix (ICD
      9: 180) by 44% (P = 0.0001). Since 1980, age-specific incidence rates of invasive
      disease decreased (P = 0.0001) in all 10-year age groups (20-29 years: -59%, 30
      39 years: -48%, 40-49 years: -34%, 50-59 years: -62%, 60-69 years: -59%). The
      incidence of preinvasive disease increased significantly (P = 0.001) in the age
      groups 20-29 years by 30% and 30-39 years by 45%, respectively. No significant
      changes are observed in other age groups. Opportunistic screening has reduced
      mortality from cervical cancer and particularly limited the increase among
      younger women, but the high proportion of cancer deaths from uterine cancer, in
      part unspecified, obscures the actual trend. We estimate that the true mortality
      from cervical cancer has been nearly halved between 1980 and 1996. Most of this
      reduction must be attributed to the screening activities in the 1970's and we
      expect a further decrease as a result of the expanded screening activities in the
      1980's.

PMID- 10407997
TI  - Sequence-specific transcription factors during glucocorticoid-induced apoptosis
      in acute lymphoblastic leukemia cells.
AB  - Glucocorticoids (GC) are known to induce programmed cell death (apoptosis) in
      certain hematologic malignancies, but the molecular basis of this clinically
      significant phenomenon is poorly understood. GC act via binding to their specific
      receptor, a ligand-activated transcription factor, and might induce apoptosis by
      transcriptional activation of "death" or repression of "survival" genes. GC
      regulate gene expression directly, i.e. via GC responsive elements, or indirectly
      by modulating the activity of other transcription factors such as AP-1, NF-KB,
      Oct, Ets, and CREB. To analyze possible alterations in the activity of these
      transcription factors during GC-induced apoptosis, we performed electrophoretic
      mobility shift assays using the human acute T-cell leukemia line CCRF-CEM C7H2 as
      a model system. Although AP-1 was highly inducible by phorbol ester treatment, it
      was almost undetectable in logarithmically growing cells and apparently
      unregulated during GC-induced apoptosis. Thus, alterations in AP-1 activity do
      not appear to be involved in GC-induced apoptosis. Oct, Ets, and CREB DNA binding
      activity were detectable prior to and during GC treatment, and appeared to have
      been down-regulated after 48 hours. At this time, however, cells had already
      undergone considerable apoptosis, and this downregulation might reflect cell
      death-associated protein degradation. In contrast, NF-KB DNA binding activity was
      reduced 12 to 24 hours after GC exposure but reached levels equal to or higher
      than pre-treatment levels after 48 hours. Thus, while AP-1, Oct, Ets, and CREB
      may not be involved in GC-induced apoptosis, the maintenance of NF-KB levels
      suggests that it may participate in this form of cell death.

PMID- 10407998
TI  - Ceftriaxone associated hemolysis.
AB  - A 48-year-old immunocompetent women treated with ceftriaxone 2 g daily i.v. for
      late Lyme borreliosis developed severe haemolytic anaemia. The patient had
      previously received the same antibiotic two times without any side effects. The
      first clinical signs began to appear on the seventh day of treatment. The patient
      developed severe anaemia with a haemoglobin level of 45 mg/l on day 10;
      thereafter she ceased to receive the antibiotic. The outcome was favourable. The
      clinical course and serologic results suggest that severe anaemia was induced by
      ceftriaxone and that drug adsorption as well as immune complex mechanisms were
      involved in the pathogenesis.

PMID- 10407999
TI  - The role of heat shock proteins in the immunity theory of atherosclerosis.

PMID- 10408000
TI  - [HMA CoA reductase inhibitors].

PMID- 10408001
TI  - [Prevention of coronary heart diseases in clinical practice. Comment on the
      recommendations of the Second Joint Task Force of European Societies for
      Prevention of Coronary Disease].
AB  - The Second Joint Task Force of European Societies on Coronary Prevention (EAS
      European Atherosclerosis Society, ESC-European Society of Cardiology, ESH
      European Society of Hypertension) have established recommendations for the
      prevention of coronary heart disease in cooperation with the representatives of
      the International Society of Behavioral Medicine, the European Society of General
      Medicine/Family Medicine, and the European Heart-Network. These recommendations
      of the year 1998 are commented by Austrian cardiologists and lipidologists and
      supplemented with recent clinical findings.

PMID- 10408002
TI  - [Pharmacology of HMG CoA reductase inhibitors (statins)].
AB  - Statins without doubt belong to the most potent cholesterol and LDL-C lowering
      drugs. The mode of action is the stimulation of the LDL receptor activity in
      addition to a reduction of the assembly and biosynthesis of cholesterol-rich
      lipoproteins in the liver. The statins differ in their pharmakocinetic and
      pharmakodynamic properties in a qualitative and quantitative manner. Most of the
      pleiotropic effects of the statins are beneficial but not evenly distributed. The
      statins with the highest efficacy for reduction of cholesterol and triglycerides
      are atorvastatin and simvastatin. Statins are poor on side-effects, at maximal
      doses, however, it is important to consider drug interaction with other
      medication which are degraded by cytochrome-P450 oxidoreductase 3A4. Statins
      belong to the class of drugs which proved to reduce the total mortality in
      primary and secondary prevention of CHD. This is caused not only by the action on
      plasma lipids but also by their protective effect on endothelial cells, smooth
      muscle cells and platelets. In this way, they were found to stabilize
      atherosclerotic plaques. Because of these proven effects statins are nowadays
      applied also in patients with coronary heart diseases whose lipid values are
      relatively low and were considered as "normal" 5 to 10 years ago.

PMID- 10408003
TI  - [Statins in secondary prevention of coronary heart disease].
AB  - Cardiovascular diseases are the major cause of death in European and many other
      countries. During the last years, our understanding of the risk factors and the
      possibilities of an effective prevention of coronary heart disease (CHD) has
      substantially increased. Since patients with established CHD are at a very high
      risk for a further coronary event, secondary prevention plays a predominant role.
      Above all, the effectiveness of secondary prevention by lowering LDL cholesterol
      by statins has been impressively demonstrated by a number of controlled clinical
      trials. Various international task forces have published recommendations with
      regard to the cholesterol level indicating intervention and goals of treatment.
      With the currently available statins these goals can be reached in most cases.
      Diet is an integral part of overall management. It is important to target also
      for the intervention of the other risk factors (smoking, physical inactivity,
      hypertension, diabetes and overweight).

PMID- 10408004
TI  - [Statins in primary prevention of coronary heart disease].
AB  - Lowering of LDL-cholesterol by 25 to 30% with statins resulted in a highly
      significant reduction of coronary event rates in 2 large primary prevention
      trials. In the West of Scotland Primary Prevention Study (WOSCOPS)
      hypercholesterolemic asymptomatic men were treated with either 40 mg of
      pravastatin or placebo, in the Airforce/Texas Coronary Atherosclerosis Prevention
      Study (AFCAPS/TexCAPS) 6605 men and women with average levels of LDL-cholesterol
      and low levels of HDL-cholesterol were treated with either 20 to 40 mg of
      lovastatin or placebo. Moreover, in the WOSCOP study a marked reduction of total
      mortality was observed which approached the level of statistical significance.
      Several groups of experts have recently developed guidelines for the use of
      statins in prevention of atherosclerotic vascular disease. There are major
      differences in the goals for lowering of LDL-cholesterol and in the levels at
      which initiation of lipid lowering by drugs is advocated. In most of these
      recommendations graded target levels for LDL-cholesterol are suggested which are
      guided by the level of global risk. According to the recommendations of the
      American National Cholesterol Education Program (NCEP) LDL-cholesterol should be
      lowered below 130 mg/dl in asymptomatic individuals at high absolute risk and
      below 160 in individuals with a moderate increase in risk. The Joint Task Force
      of European and other Societies on Coronary Prevention recently developed
      guidelines, which suggest that in primary prevention lipid lowering by drugs
      should be restricted to individuals whose 10 year CHD risk exceeds 20% or will
      exceed 20% if projected to age 60. In these individuals LDL-cholesterol levels
      should be lowered to less than 115 mg/dl. The International Task Force for
      Prevention of Coronary heart disease recently published recommendations which
      suggest, that LDL-cholesterol should be reduced below 100 mg/dl in asymptomatic
      individuals at very high coronary risk, while it should be lowered below 135
      mg/dl in individuals at moderately increased risk and below 160 mg/dl in subjects
      with a small increase in risk. In conclusion, results of 2 landmark trials in
      primary prevention of coronary heart disease demonstrated that lowering of LDL
      cholesterol by statins is one of the most effective strategies to reduce coronary
      risk. It should be applied most aggressively in subjects at the highest overall
      risk. Nevertheless, non-pharmacologic measures are still considered as the
      preferred strategy for the reduction of coronary risk in the setting of primary
      prevention.

PMID- 10408005
TI  - [Statins in diabetic hyperlipidemia].
AB  - Several placebo-controlled prospective multicenter trials showed convincing
      evidence that cholesterol lowering with statins reduced mortality due to coronary
      heart disease. Subgroup analyses of diabetic patients demonstrated significant
      reduction of coronary death rates in diabetics even more pronounced than that
      observed with the nondiabetic population. In some studies significant reduction
      of strokes was also achieved by lipid lowering. In one diabetic subgroup stroke
      reduction nearly reached significance despite low number of patients. New studies
      are currently in progress investigating the effect of lipid lowering specifically
      for diabetic patients. Some of these studies are designed to evaluate the effects
      of drugs acting primarily on triglycerides, such as the fibrates, or showing
      both, triglyceride and cholesterol reduction, like some newer statins, especially
      atorvastatin. The dyslipidemia encountered most frequently with diabetics is an
      increase of triglycerides and low HDL-cholesterol. Because of the high
      cardiovascular risk of diabetics the target levels of LDL-cholesterol in
      secondary and primary prevention should not exceed 100 mg/dl as in secondary
      prophylaxis in patients without diabetes.

PMID- 10408006
TI  - [Statins--attaining goal values--with reference to recent studies].
AB  - Recent lipid intervention studies led to the implementation of lipid lowering
      therapy in the cardiovascular risk management. These secondary as well as primary
      prevention studies share the effect of HMG-CoA-reductase inhibition. Despite
      varying product properties there seem to be no major differences in risk
      reduction between the drugs. One could argue the main action of the statins,
      lipid lowering, is the most prominent mode of action. A new study (AirForce/Texas
      Coronary Atherosclerosis Prevention Study) extended that to patients with
      relatively low total cholesterol levels (mean 221 mg/dl with a slightly lowered
      LDL-C of 37 mg/dl, LDL-C of 150 mg/dl) successfully treated with lovastatin in
      primary prevention. That supports the concept to reach lipid levels as low as
      possible in the longer term, even if the absolute clinical event reduction in
      primary prevention is not so impressive. On the contrary, in secondary
      prevention: in the AVERT-study in patients with a 82% mean stenosis in one vessel
      PTCA-treated patients with conventional drug therapy were compared to such
      without PTCA and aggressive lipid lowering therapy (resulting LDL-C 77 mg/dl).
      One could be surprised that the "intervention group" was not better, though
      representing the usual clinical procedere. Interestingly, borderline significant
      (p < 0.046 at a level of significance of p < 0.045), results were in favor for
      the drug treated group. Such data could, if confirmed in further investigations,
      change cardiovascular disease management to aggressive lipid lowering prior to or
      instead invasive management, especially in initial therapy of CVD and diabetes
      mellitus type II.

PMID- 10408007
TI  - [Aggressive therapy and combination therapy in severe hyperlipidemia].
AB  - In cases of severe hyperlipidemia, we have very effective therapeutic tools
      nowadays. LDL-apheresis is still the most effective therapy for familial
      hypercholesterolemia, especially in its homocygous form. In combination with
      statins, LDL-cholesterol can be lowered by 80%. Most other genetic and secondary
      hyperlipidemias can effectively be treated by lipid lowering drugs. This
      aggressive treatment gains more and more on importance in view of the tough
      recommendations of specific scientific societies. Atorvastatin and simvastatin
      can lower LDL-cholesterol by 60%. In this report different therapies and
      combination therapies for hyperlipidemia are discussed.

PMID- 10408008
TI  - [Biology of aging].

PMID- 10408009
TI  - [Replicative senescence as a model of aging: the role of oxidative stress and
      telomere shortening--an overview].
AB  - Replicative senescence is characterized by the irreversible loss of division
      potential of cultivated human and animal cells. Correlations between the
      replicative potential in vitro and the age of the donor or the maximal lifespan
      of the species suggest replicative senescence to be an appropriate model for
      aging. Telomeres of human somatic cells shorten with each cell division but are
      stabilized at constant length in tumors and immortal cells by the enzyme
      telomerase. The assumption of a causal role of telomere shortening for the
      limited lifespan of cells in vitro was borne out recently. We could demonstrate
      oxidative stress as a main reason for telomere shortening. Telomeres are sensors
      for oxidative damage in the genome. Telomeres shorten during in vivo aging as
      well; however, there are significant differences between individuals. Telomere
      erosion might play a major role for the aging of the immune system. Our data
      suggest that telomere shortening in vivo could reflect the cumulative amount of
      oxidative damage to the organism. It might be useful as a biomarker of aging.

PMID- 10408010
TI  - [Age related changes in cellular signal transduction of glucocorticoid hormones
      in rat brain].
AB  - Chronic or repeated stress can induce a damage of neurons, especially in
      hippocampus, by which the degree of damage differs in various species. Sapolski
      has reported that there is a correlation between hippocampal degeneration,
      disturbed feedback reaction, and hypersecretion of glucocorticoids. The aim of
      this study was to investigate if the signal transmission via glucocorticoid
      receptors (GR) in the brain of male wistar rats of two age groups (5-6 and 17-24
      months, respectively) is changed in aging and which cytoplasmic
      factors/modulators participate in this process. The binding of 3H-dexamethasone
      to cytosolic GR, the transformation, translocation, and nuclear binding of GR
      complexes (GRC) were studied before and after physiological stress. The influence
      of cytoplasmic modulators ASTP1) and HSP 70(1)), isolated from brain cytosol and
      purified, and of exogenous PK C1) was also tested in parallel incubation systems.
      Whereas old control animals showed a higher cytosolic concentration of unoccupied
      GR than young ones, this was significantly reduced only in old stressed rats 60
      min after stress compared to old controls. The part of transformed GRC, bound to
      isolated nuclei, was somewhat lower in old than in young rats before and after
      stress. The nuclear GRC binding could be slightly elevated by addition of ASTP
      and HSP 70, resp., at the heat transformation of GRC; however, by simultaneous
      addition of PK C it was significantly increased in both age groups. The GRC
      binding also rose significantly in stressed animals compared to controls, after
      simultaneous addition of PK C to more than double of initial assays in young
      animals. Purified ASTP, isolated from brain cytosol of young animals, showed a
      higher 32P-incorporation after phosphorylation in vitro than that from old
      animals. The reduced phosphorylation of ASTP could be one possible cause of the
      retarded transformation/translocation and the reduced nuclear binding of GRC
      together with the restricted expression of HSP 70 and decreased PK C activity in
      the old rat brain.

PMID- 10408012
TI  - [Clinical laboratory diagnosis and aging. 1: Results of data evaluation of
      clinico-chemical laboratory values in a study of aging].
AB  - The results of the determination of 24 basic blood chemistry variables from 262
      men and 239 women, half of each group 44.4 +/- 0.9 and 63.0 +/- 0.9 (men) and
      44.4 +/- 0.9 and 62.8 +/- 0.8 years old (women), resp., are compared. In men,
      only 6 analytes show significant differences between the age groups: Alanine
      aminotransferase decreases, aspartate aminotransferase decreases, iron decreases
      with p < 0.05; sodium increases, calcium decreases, protein (serum) decreases
      with p < 0.001. In women, 16 analytes, compared between both groups, are
      significantly different: Urea, uric acid, creatinine, triglycerides, total
      cholesterol, LDL cholesterol, LDL-C/HDL-C ratio, alanine aminotransferase,
      alkaline phosphatase, gamma-glutamyltransferase, sodium and ferritin are
      increased in the older group, whereas HDL cholesterol, iron, transferrin, and
      total protein are decreased. The sex differences are more distinct in the group
      of 44 years old persons than in the 63 years old one. These results will be
      completed by the comparison with the evaluation of the stored laboratory values
      of 9923 patients between 20 and 89 years old.

PMID- 10408011
TI  - [Modulation of oxidative stresses in human aging skin].
AB  - Oxidative stress (UV irradiation, free radicals) plays a significant role in
      aging. Coenzyme Q10 (CoQ10) and exogenously applied antioxidants can
      significantly reduce the formation of oxidative stress with increasing age. In
      our in vitro and in vivo experiments concerning the parameters of ultraweak
      photon emission (UPE), intracellular thiol status, mitochondrial membrane
      potential and cell vitality, we demonstrated a diminished resistance in
      keratinocytes of old donors against UV irradiation. This reduced epidermal
      resistance against oxidative stressors, i.e. UV irradiation, can be improved by
      topical application of CoQ10 and antioxidants like alpha-glucosylrutin (15).
      Furthermore, our in vivo investigations show that wrinkles around the region of
      the eyes ("crow feet") could be reduced by long-term application of CoQ10.

PMID- 10408013
TI  - [Clinical laboratory diagnosis and aging. 2: Suitability of clinico-chemical
      basic parameters as markers ob biological aging].
AB  - In 262 men (about half of them 44.4 +/- 0.9 and 63.0 +/- 0.9 years old, resp.)
      and 239 women (about half of them 44.4 +/- 0.9 and 62.8 +/- 0.8 years old, resp.)
      the results of 12 clinical chemical analytes were used to calculate laboratory
      indices which were compared with the biological age in accordance with Ries. The
      indices were calculated by using concentrations of alkaline phosphatase, iron,
      total protein, total cholesterol, glucose, uric acid, urea, HDL cholesterol,
      creatinine, LDL cholesterol, transferrin, and triglycerides. Only in the younger
      group of women are the correlations between laboratory indices and biological age
      significant. In the same group, several single parameters also significantly
      correlate with pre-aging. Among them are alkaline phosphatase, the LDL-C/HDL-C
      ratio, bilirubin, triglycerides, and glucose.

PMID- 10408014
TI  - [Histological biomorphosis of human heart valve. II. Morphometric studies].
AB  - Previous polarization-microscopical measurements combined with silver-staining
      methods at histological sections of the bicuspid valve and the tricuspid valve in
      the region of fibrosa showed (similar to that of the corresponding tendinous
      cords) for middle-aged persons a distinct difference in the collagen composition
      in comparison between high pressure vs. low pressure system. The aim of the
      current study was the morphometric investigation of the collagen composition, of
      the relative content of total collagen (measured as relative number of total
      collagen fibers per measuring area), and of the cell-collagen relation in
      dependence of age and possibly on sex in the high and low pressure system,
      respectively. Tissue samples of atrioventricular valves of 67 probands of both
      sexes were available. The probands were healthy with regard to heart and
      circulation and distributed in 3 age groups (1st to 2nd decade, 3rd to 5th
      decade, and 6th to 9th decade). After corresponding preliminary treatment, the
      histological sections of tissue samples were evaluated by a suitable combination
      of polarization-microscopical, immuno-histochemical, and morphometrical
      methodology. The thickness of the heart valves was measured by microscopic image
      analysis. A rise of the number of fibers per measuring area (ma) for both sexes
      and both valves was observed with increasing age. The slopes of the linear
      regression curves and the mean values of the numbers of collagenous fibers/ma
      (for each age group) were different between both sexes. They depend upon the
      valve considered. Analogous to these results, the differentiated statements were
      possible to the number of fibers/ma and to the percentages of the fiber species
      by the distinction between the collagen types I and III in the fibrosa of the
      heart valves. Whereas the relative numbers of fibers/ma rose with increasing age,
      the number of cell (fibroblasts, fibrocytes) nuclei for both valves and sexes
      slightly decreased. For the latter, there was no difference between high and low
      pressure system in contrast to the collagenous fibers. The opposite age-dependent
      behavior of the collagenous fibers and of their producing cells during the
      biomorphosis of the heart valves could be explained with the collagen turn-over.

PMID- 10408015
TI  - [Biogerontology: status and current developments].
AB  - Biogerontology is defined by the interdisciplinary research on causes and
      mechanisms of biological aging--aiming to unravel the mystery of human
      senescence. Here the state of this research area is presented separately in two
      parts: (1) activities and appreciation of biogerontology as a scientific
      discipline in Germany compared mainly to the USA, (2) recent developments in the
      scientific content and progress in the research of aging. As for Germany, except
      for some special items the fast growing importance of biogerontology is not
      reflected by research activities in this field, organization, social
      acknowledgement, and attraction for the younger generation of academics. Some
      reasons probably responsible for this critical situation are indicated. A rough
      sketch is made about the international publication activities in biogerontology
      following data of leading biomedical literature data banks. Main scientific,
      contents and trends are discussed. The stochastic damage theories of aging,
      mainly the dominating "Free Radical Theory of Aging" (40) or similar "Oxidation
      Hypotheses of Aging" (82)--commercially heavily supported by sellers of
      "Antioxidants"--are criticized from an evolutionary point of view. Such theories
      are not compatible with the evidence for the adaptive role of senescence as
      outlined recently (5). This evolutionary theory of aging and its application to
      an intensified research on the identification of the genetic program of
      regenerative syntheses and senescence in metazoic organisms offers a firm base
      for the future research on aging.

PMID- 10408016
TI  - [Decreased stimulation of glycosaminoglycan synthesis in cultured human skin
      fibroblasts within the scope of in vitro aging caused by interleukin 1].
AB  - Addition of human recombinant interleukin-1 (IL-1 alpha or IL-1 beta) to culture
      medium (supplemented MEM without or with 1%, 10%, or 20% fetal calf serum (FCS))
      of human skin fibroblasts exerted a stimulating effect in a dose-dependent manner
      on glycosaminoglycan (GAG) synthesis, including hyaluronic acid synthesis, of
      young (Phase II) skin fibroblasts in concentrations of 4, 20, or 100 pg/ml.
      Stimulation was due to increase in total GAGs, namely extracellular (secreted
      into culture medium) and cell-bound (pericellular) GAGs. Stimulation with 100 or
      200 pg/ml IL-1 beta led to a relative increase (total GAGs: 100%) in hyaluronic
      acid from 49% to 64 (-FCS) and from 79% to 92% (+10% FCS), respectively. The
      increase in total GAG synthesis was mainly due to increased synthesis of
      hyaluronic acid. Maximum stimulation, with and without FCS, was reached by 100
      pg/ml IL-1 beta. Compared to young (Phase II) cells senescent (Phase III) cells
      showed significantly diminished stimulation of hyaluronic acid synthesis by IL-1
      beta. Both, IL-1 alpha and IL-1 beta, showed no influence on DNA synthesis. These
      results suggest that both, IL-1 beta and IL-1 alpha, stimulate GAG and especially
      hyaluronic acid synthesis, but not DNA synthesis, in vitro. The diminished
      response of GAG and hyaluronic acid synthesis during ageing of these in vitro
      cultured fibroblasts gives support to the hypothesis that similar processes might
      occur during ageing in organisms.

PMID- 10408017
TI  - [Decisions and attitudes in treatment of incompetent, chronically ill, aged
      patients. A comparison between nurses and physicians: why does no one ask the
      nurse?].
AB  - Health care decision making in incompetent severely ill patients presents many
      difficult medical, ethical, and legal problems for the physician. At the same
      time nurses represent the group of medical professionals who have the closest
      contact with the patient and who have to carry out most of the decisions and
      instructions. Treatment decisions and their determinants have been assessed by
      means of a questionnaire based on three case scenarios offering three different
      levels of available information of the patient's wishes (no information, DNR
      order, advance directive). Responses of 191 doctors and 182 nurses have been
      analyzed. In both groups ethical factors and patient wishes were regarded as the
      most important. With an increasing level of information about the patient's will
      the compliance increased in both groups, being more pronounced among the nurses.
      The more important the will of the patient was estimated, the less difficult were
      the decisions, the less aggressive was the treatment level chosen, the less
      frequent rescuscitation was made, and the more helpful the information on
      patient's will were experienced. These important relationships occurred mainly in
      the nurses. Furthermore, age and level of dementia were related with the
      decisions though with less importance. The more legal aspects were regarded the
      more aggressive treatment options were chosen. Hospital cost were less important
      and did not influence the decision making. The results indicate that a more
      frequent use of advance directives would foster patient autonomy and at the same
      time lessen the burden on the medical staff. A comprehensive education of both
      the medical professions and the general public seems warranted.

PMID- 10408018
TI  - [Documentation/quality assurance].

PMID- 10408019
TI  - [Legal aspects of quality assurance in medicine according to SGB V].
AB  - The German social security legislation has recognized only recently the concern
      of quality assessment in the field of social and medical services. The legal
      frame for quality assessment in the field of medical treatment was enacted in the
      sickness insurance provision (Social Code-Book V) only in 1989. Quality
      assessment is considered to be a part of the production of medical services and,
      therefore, is regulated in the context of providing medical services. The legal
      provisions do not establish standards for quality and quality assessment. Due to
      the variety of medical services, quality assessment is not regulated in an
      exhaustive or systematic manner. According to the law, providers of medical
      services (doctors, hospitals) are bound to participate in quality assessment. As
      internal quality assessment prevails in the definition of the various measures of
      quality assessment and the control of quality in all fields of medical treatment,
      external quality assessment is also prescribed for hospitals. Because the
      establishment of quality assessment is considered to be a part of the service
      production organization, consumers (patients) or their representatives are not
      involved in the definition, establishment, and control of quality assessment. The
      participation of patients should be provided by law.

PMID- 10408020
TI  - [The Geriatric Minimum Data Set (Gemidas) of the Federal Association of Clinical
      Geriatric Facilities e. V. as an instrument for quality assurance in inpatient
      geriatrics].
AB  - BACKGROUND: Geriatric medicine in Germany is faced with an increasing demand for
      continuous documentation and evaluation of its effectiveness and efficiency.
      Hence, the Federal Association (FA) of Clinical Geriatric Departments
      (Bundesarbeitsgemeinschaft der Klinisch-Geriatrischen Einrichtungen e.V.) has
      funded a working group on improving quality management in geriatrics by
      developing criteria for quality standards. METHODS: In 1996, the FA working group
      achieved consensus on the definition of the Geriatric Minimum Data Set (Gemidas)
      which covered (i) core information about a patient's age, sex, living
      arrangement, and (ii) basic characteristics of the hospital course such as
      location prior to admission and past discharge, leading and accompanying
      diagnoses, newly prescribed technical aids, objective functional status on
      admission and at discharge (e.g., Barthel Index (BI), Timed Up & Go (TUG), and
      intensity of professional care (PPR)), as well as subjectively evaluated
      attainment of treatment goals. This initial report describes the instrument and
      presents analyses of its feasibility for routine clinical practice and data
      consistency. RESULTS: Twenty out of 27 hospitals (74%) integrated Gemidas
      successfully in daily routine, 75% of which (15 hospitals, total n = 10,567
      patients) instantaneously collected data on constant numbers of patients per
      month. Multivariate regression analyses used to decompose variances of the
      instrument's central indicators (e.g., BI, TUG, PPR) revealed a satisfactory
      dimensionality and high consistency (e.g., covering 59% of variance in BI with
      53% of variance uniquely attributable to patient characteristics), as well as
      sensitivity to differences between hospitals (e.g., 12% of variance in duration
      of stay uniquely attributable to hospital differences after controlling for
      patients' characteristics). CONCLUSION: Gemidas appears to be a feasible quality
      assurance instrument in geriatrics, suitable for compiling its data into a
      central registry database, which may then be used for analyses across and between
      hospitals. However, some modifications are still necessary and more detailed
      analyses needed, before final recommendations can be made.

PMID- 10408021
TI  - [Expectations of training and career in geriatric care].
AB  - Historically, the profession of geriatric nurse has arisen from the care of the
      sick and has developed very differently from region to region. A question as to
      the status of development of the profession of geriatric nurse cannot be answered
      by reference to the current status of legislation on professional law matters. If
      experts in that field focus too long on such matters, there is a danger that
      decisive developments in the profession of geriatric nurse take place outside
      their field of vision. This longitudinal survey involving trainees in their first
      year of training has revealed a series of interesting links and developments
      which had not been reckoned with. In the core training areas, for example,
      expected modes of behaviour with specific regard to age, education and gender
      were outlined which should result, in terms of the consequences for training, in
      measures to improve quality. Furthermore, there is a need for criteria to assure
      the quality of the training of geriatric nurses so as to guarantee a minimum
      quality standard. For example, there is currently a lack of any binding framework
      curriculum and provisions assuring the quality of the manpower and facilities
      available at training locations. Also questionable is the level of qualification
      of those who supervise the practical training of trainees at such locations and
      the whole area of further training of teaching staff.

PMID- 10408022
TI  - [Documentation procedures in geriatrics--on unreliability of routinely gathered
      clinic data].
AB  - We analyzed quality assurance protocol records of 532 geriatric hospital patients
      in comparison to an administration database concerning data on "length of stay"
      information (LOS). Doctors handwritten quality assurance protocol records
      corresponded in 74.25% of cases to administration data. 14.47% of cases were
      registered with different LOS; 11.28% of LOS information was missing. The
      increasing amount of documentation tasks in German geriatric hospitals is
      discussed. CONCLUSION: We assume that not only discrete well known information
      (admission and discharge dates, LOS) are contaminated by documentation failure
      but also data on functional status of geriatric patients which may have important
      influence on external data processing.

PMID- 10408023
TI  - [Pathophysiologic effects of nitric oxide (NO) and endothelin-1 in global
      cerebral ischemia in an animal model--an overview].
AB  - These studies were performed in an attempt to clarify some of the
      pathophysiologic mechanisms which occur during and after global ischemia. Both
      nitric oxide and endothelin were demonstrated in gerbils to participate in
      responses to ischemia. It was shown that endogenous nitric oxide influences early
      postischemic reperfusion, systemic blood pressure and postischemic dopamine
      metabolism. Furthermore, the results indicated that nitric oxide played a role in
      dopamine release and that preischemic intracerebral nitric oxide formation
      significantly decreased ischemic dopamine release. In addition, ischemic release
      of endothelin-1 was detected; participation of nitric oxide in this release was
      observed. Further indication of functional interactions between nitric oxide and
      endothelin-1 in postischemic reperfusion were indicated by observations that
      endothelin-1 antagonists inhibited early hypoperfusion caused by Nitro-L-arginin
      and late hypoperfusion caused by endogenous endothelin-1. Nitric oxide was shown
      to decrease edema formation during the early postischemic period but contribute
      to edema formation during the late postischemic period. The findings indicate the
      importance of nitric oxide in stroke and ischemia.

PMID- 10408024
TI  - [Laboratory findings in elderly patients: a forgotten aspect of laboratory
      medicine?].
AB  - Reference values, which would be related to the individual "biological age" and
      which would be needed for laboratory investigations of geriatric patients, are at
      the moment not usual. Thereafter, for rational interpretation of laboratory
      results, the knowledge of "preanalytical variations" is of crucial importance.
      These are systematically discussed in the present contribution. In principle, one
      distinguish between "biological variations" and "preanalytical errors". The first
      are characterized by the following "factors": "permanent" (age, genetics), "long
      time" (age), "intermediate" (life style, climate, nutrition), and "short time"
      (circadian, postprandial, and orthostatic effects). The significance of
      "preanalytical errors" is accentuated by the fact that many of "geriatric
      institutions" are serviced by the laboratories, which are not situated close to
      them.

PMID- 10408025
TI  - [Sex differences in morphologic aging processes].
AB  - According to Max Burger (2) it is justified to speak of sexual divergence of
      biomorphosis. Morphometrical investigations have proved the existence of such
      sexual differences. The following results were obtained: The first example
      concerns the increase of fatty tissue in parathyroid glands which we measured on
      histological slides of 135 human samples by means of the point counting method.
      The fatty tissue of males was shown to increase continuously with statistic
      significance, whereas this process stops in females during their generative phase
      between the 2nd and 5th decade. Evidence for the sexual divergence was also
      obtained by investigating the fatty tissue between the bundles of muscle fibers
      of the tongue, however, without being able to statistically verify these results.
      We found the same sexual differences by measuring the muscle cell regression and
      connective tissue proliferation in the ciliary muscle of human eyes and tunica
      muscularis of the small intestine as well. All findings prove that the female is
      able to stay biologically younger during her generative activity compared to
      males. After menopause the aging processes speed up in female tissues without
      making up for the "age lead" of males. It is also worth mentioning that
      macroscopic anthropometric features do confirm the same fact, e.g., length and
      breadth of human auricles, ranging in age from 18 to 51 years.

PMID- 10408026
TI  - [Accidental fall-induced, proximal femoral fracture in the elderly--etiology and
      rehabilitation].
AB  - 55 patients aged 65 years and older with a fracture of the proximal end of femur
      caused by a fall who have been admitted to the Medizinisch-Geriatrische Klinik
      Albertinen-Haus Hamburg for rehabilitation during the period of half a year took
      part in the study. Aim of the study was to describe the success of treatment as
      well as to prevent further falls by identifying the reason for their recent fall.
      Three defined moments are the basis of this analysis: admission and discharge of
      the Albertinen-Haus and a follow-up research four years later by interviewing
      their general practitioners. In addition the general physical condition and life
      surroundings prior to the fall have been evaluated by an anamnestic
      questionnaire. The average age was 81.1 years. All but three had been living at
      home prior to the fall and 72% could be discharged to their home after
      rehabilitation. Five patients died while still at hospital. The reason for
      falling has been classified into intrinsic and extrinsic factors. Twenty-six
      patients (47.3%) toppled due to an extrinsic and 20 (36.4%) due to an intrinsic
      cause. In nine cases (16.4%) no reason could be identified. No correlation
      between the patient's age and the success of treatment was found. However, the
      fear to fall again had a significant negative influence on the success of
      treatment. The inquiry of 45 patients four years later showed that 42.2% were
      living at home and 31.1% in a nursing home. Within the four years 26.7% died;
      93.7% of the surviving patients were able to walk.

PMID- 10408027
TI  - [Therapeutic neoangiogensis].

PMID- 10408028
TI  - The LQT syndromes--current status of molecular mechanisms.
AB  - Our knowledge on the molecular genetics of inherited cardiac arrhythmias is very
      recent in comparison to the advances of genetics achieved in other inherited
      cardiac disorders. This is related to the high mortality and early disease onset
      of these arrhythmias resulting in mostly small nucleus families. Thus,
      traditional genetic linkage studies that are based on the genetic information
      obtained from large multi-generation families were made difficult. In 1991, the
      first chromosomal locus for congenital long-QT (LQT) syndrome was identified on
      chromosome 11p15.5 (LQT1 locus) by linkage analysis. Meanwhile, the disease
      causing gene at the LQT1 locus (KCNQ1), a gene encoding a K+ channel subunit of
      the IKs channel, and three other, major genes, all encoding cardiac ion channel
      components, have been identified. Taken together, LQT syndrome turned out to be a
      heterogeneous channelopathy. Moreover, the power of linkage studies to reveal the
      genetic causes of the LQT syndrome was also important to identify unknown but
      fundamental channel components that contribute to the ion currents tuning
      ventricular repolarization. In-vitro expression of the altered ion channel genes
      demonstrated in each case that the altered ion channel function produces
      prolongation of the action potential and thus the increasing propensity to
      ventricular tachyarrhythmias. Since these ion channels are pharmacological
      targets of many antiarrhythmic (and other) drugs, individual and potentially
      deleterious drug responses may be related to genetic variation in ion channel
      genes. Very recently, also in acquired LQT syndrome, which is a frequent clinical
      disorder in cardiology a genetic basis has been proposed in part since mutations
      in LQT genes have been specifically found. The discovery of ion channel defects
      in LQT syndrome represents the major achievement in our understanding and implies
      potential therapeutic options. The knowledge of the genomic structure of the LQT
      genes now offers the possibility to detect the underlying genetic defect in 80
      90% of all patients. With this specific information, containing the type of ion
      channel (Na+ versus K+ channel) and electrophysiological alteration by the
      mutation (loss-of-function versus change-of-function mutation), gene-directed,
      elective drug therapies have been initiated in genotyped LQT patients. Based on
      preliminary data, that were supported by in vitro studies, this approach may be
      useful in recompensating the characteristic phenotypes in some LQT patients.
      Mutation detection is a new diagnostic tool which may become of more increasing
      importance in patients with a normal QTc or just a borderline prolongation of the
      QTc interval at presentation. These patients represent approximately 40% of all
      familial cases. Moreover, LQT3 syndrome and idiopathic ventricular fibrillation
      are allelic disorders and genetically overlap. In both mutations in the LQT3 gene
      SCN5A encoding the Na+ channel alpha-subunit for INa have been reported. Thus,
      the clinical nosology of inherited arrhythmias may be reconsidered after
      elucidation of the underlying molecular bases. Meanwhile, genotype-phenotype
      correlations in large families are on the way to evaluate intergene,
      interfamilial, and intrafamilial differences in the clinical phenotype reflecting
      gene specific, gene-site specific, and individual consequences of a given
      mutation. LQT syndrome is phenotypically heterogeneous due to the reduced
      penetrance and variable expressivity associated with the mutations. This paper
      discusses the current data on molecular genetics and genotype-phenotype
      correlations and the implications for diagnosis and treatment.

PMID- 10408029
TI  - [Risk of invasive diagnosis with retrograde catheterization of the left ventricle
      in patients with acquired aortic valve stenosis].
AB  - In patients with aortic valve stenosis, the determination of the transstenotic
      pressure gradient is usually performed by cardiac catheterization with retrograde
      passage of the aortic valve. The aim of this study was to determine
      retrospectively the risk of the invasive examination with retrograde
      catheterization of the left ventricle and predictors for an increased risk. From
      1984 to 1995, 457 patients (63 +/- 11 years) with aortic stenosis were
      investigated in the Medizinische Klinik Tubingen. In 435 patients (95.2%), the
      retrograde catheterization of the left ventricle was successful; in 19 cases a
      transseptal left heart catheterization was performed, and in 3 patients an
      invasive determination of the pressure gradient was not assessed. Complications
      occurred in 39 patients (8.5%). 5 patients died due to the catherization
      procedure (mortality rate 1.1%), 2 of them as a consequence of perforation of the
      left ventricle, one patient of heart failure, one of myocardial infarction, and
      another of fulminant pulmonary embolism. Four procedures (0.9%) were complicated
      by cerebral embolism, in 3 patients a pericard tamponade occurred, and in one
      case caused by transseptal punction of the interatrial septum. The most
      complications were peripheral vascular problems in 19 patients (4.2%). Predictors
      for increased risk dur to retrograde catheterization were age > 70 years (p =
      0.008) and aortic valve area < or = 0.7 cm2 (p = 0.02). patients with a doppler
      echocardiographic instantaneous pressure gradient > or = 70 mm Hg were more
      likely to sustain a complication (p = 0.04). The retrograde catheterization of a
      stenotic aortic valve was successful in most cases. In approximately 2% of
      patients, complications occurred which can be attributed directly to retrograde
      catheterization and with significant higher frequency in patients over 70 years
      and with severe stenosis. Especially in these cases, invasive determination of
      the gradient should not be performed if reliable doppler echocardiographic
      information is available.

PMID- 10408030
TI  - [Determinants of treatment costs of unstable angina pectoris].
AB  - BACKGROUND AND AIM: Unstable angina, a common serious clinical entity, is
      associated with a high rate of complications. The aim of our study was to
      evaluate treatment costs of patients with uncomplicated and complicated follow-up
      in order to evaluate the economic consequences of new therapeutic strategies,
      like the introduction of GPIIb/IIIa blockers at our hospital. METHODOLOGY: All
      103 patients who were admitted to the medical intensivecare unit of Johann
      Wolfgang Goethe-University Hospital, Frankfurt am Main between March 2, 1992 and
      October 31, 1997 for unstable angina of Braunwald class III B were enrolled in
      the study. Clinical events were the occurrence of refractory ischemia,
      nontransmural or transmural myocardial infarction or cardiac death. The following
      were documented: duration of treatment in the ICU and in the general ward,
      cardiac catheterizations, balloon angioplasties (PTCA), and bypass operations.
      Treatment costs were calculated on the basis of daily rates, flat rates, and
      special fees. RESULTS: Following successful primary treatment, a clinical event
      occurred in 48 of the 103 patients, recurrent refractory ischemia in 34 patients,
      nontransmural infarction in eight patients, transmural infarction in three
      patients, and death in four patients. Patients with events were significantly
      less likely to have had a history of PTCA (38% vs 60%, p < 0.05) and were
      significantly less likely to be undergoing long-term treatment with aspirin (63%
      vs 80%, p < 0.05). Other sociodemographic data as well as the initial treatment
      strategies were comparable. The occurrence of a complication significantly
      prolonged the duration of treatment in the ICU from 2.6 days (95%-CI [2.1; 3.0])
      to 3.6 days (95%-CI [3.1; 4.1]) and the total duration of treatment from 7.0 days
      (95%-CI [5.7; 8.4]) to 12.8 days (95%-CI [9.6; 16.1]). The total treatment costs
      rose accordingly from DM 14,360 (95%-CI [12,360; 16,360]) to DM 26,690 (95%-CI
      [23,150; 30,240]). CONCLUSION: The data show that ischemic complications
      following successful primary treatment of unstable angina constitute a common
      problem. Such complications are associated with significantly more intensive
      treatment and significantly longer hospitalization times, resulting in a near
      doubling of treatment costs.

PMID- 10408032
TI  - [Left ventricular remodeling after aortic valve replacement].
AB  - The aim of the study was the assessment of left ventricular (LV) systolic
      function and left ventricular mass following aortic valve replacement (AVR) due
      to aortic valve stenosis as well as the influence of regression of LV hypertrophy
      in patients with normal and impaired LV systolic function prior to surgery. 74
      patients with severe aortic valve stenosis (29 female, 45 male, mean age 66 +/-
      18 years) were divided into 2 groups according to LV ejection fraction (EF):
      Group 1 with EF > 50% (n = 40); Group 2 with EF < or = 50% (n = 34). Furthermore,
      patients were differentiated into a group A without (n = 53) and a group B with
      aortic regurgitation (< or = II degrees, n = 21). All patients were examined by
      transthoracic echocardiography before and 1 month after surgery. There was a
      significant decrease of LV enddiastolic and endsystolic volume indices following
      AVR in group 2 and group B. Patients with preoperatively lower EF (group 2)
      showed an increase in LV ejection fraction from 39 +/- 10% before AVR to 47 +/-
      11% after AVR (p < 0.001), whereas patients with preoperative normal EF (group 1)
      showed a significant decrease in EF (from 62 +/- 8% to 57 +/- 10%, p < 0.05).
      Also patients with combined aortic valve disease before AVR had an increase of EF
      after surgery (from 45 +/- 14% to 56 +/- 14%, p < 0.03). There were significant
      decreases of interventricular septum thickness and LV posterior wall thickness in
      group 1 and group A, whereas a significant decrease of LV enddiastolic diameter
      index was noted only in group B. Improvement of the NYHA functional class could
      be demonstrated in group 2 from 2.8 +/- 0.7 before to 2.2 +/- 0.6 after AVR, as
      well as in group B from 2.9 +/- 0.7 before to 1.9 +/- 0.7 after surgery. In
      conclusion, patients with impaired LV function or combined aortic valve disease
      showed a significant improvement of left ventricular systolic function after AVR,
      while patients with normal LV function presented a slight decrease of EF. There
      was a significant regression of left ventricular muscle mass in all groups
      independent of the left ventricular functional status.

PMID- 10408031
TI  - [Lipid intervention and coronary heart disease in men less than 56 years of age.
      The Coronary Intervention Study: CIS].
AB  - The CIS was undertaken with the aim to evaluate the effects of lipid
      modifications on angiographic progression and regression of CAD in patients with
      CAD and hypercholesterolemia. The design included a multicenter randomized,
      double-blind, parallel, placebo-controlled comparison, with target and safety
      limits for adjusting the trial medication depending on the LDL cholesterol level
      (LDL-C) achieved, i.e., up to 40 mg of simvastatin (S) or placebo (P) daily, add
      on medication (up to 3 x 4 g Colestyramin), and diet counselling. Male patients,
      average age 49 (< or = 56) years, were included with angiographic CAD and a
      screening total cholesterol of 207-350 mg/dl, who were not due to undergo
      coronary bypass surgery or PTCA, who did not suffer from serious other disease
      (e.g., diabetes mellitus), and who had not undergone coronary bypass surgery
      previously. RESULTS: All baseline variables were comparable in the treatment
      groups, with 129 patients taking S and 125 taking P. Of these 254 patients 217
      had their final study visit and 207 underwent a second angiography after an
      average treatment time of 2.3 years under an average daily dose of 37 mg S. 205
      pairs of films were available for analysis. Vital information was obtained of all
      patients until closure of the data bank, half a year after the last study
      angiography. Five deaths occurred within the study period, 12 through March 15,
      1995 (S: 1/6, P: 4/6). 37 patients (S: 18, P: 19) discontinued trial drug and
      protocol. Concomitant CAD medication was comparable in both groups, except lipid
      lowering add-on medication which was significantly higher in the P group (38%
      versus 13%). Significant changes in lipid levels, on treatment, were observed in
      the S group amounting to a mean difference in LDL-C of -35%, in Apo-Protein B
      (ApoB) of -30%, in VLDL-C of -37%, and in triglycerides (TG) of -27%, and in HDL
      C of +6%, in comparison to the control group; these differences were even greater
      in 137 fully compliant patients: -41, -36, -39, -31, and +7%, respectively.
      Progression in the S group was significantly less, as defined by the two primary
      target criteria: 1) the minimum obstruction diameter (MOD), determined by
      quantitative coronary angiography (QCA), decreased about five times less in
      comparison to the control group (S: by -0.017; P: -0.0954 mm), and 2) the
      standardized visual global change score (GCS) deteriorated almost three times
      less in the S group (by +0.20) than in the P group (+0.58). Of the secondary
      target criteria, the mean lumen diameter (QCA) also developed a significant
      difference (S: -0.20; P: +0.23 mm; p = 0.0006) with a trend toward regression in
      the S group. The QCA-%-stenosis deteriorated three- to four-times less in the S
      group as compared to the control group (S: by 0.69%; P: by 2.73%; p = 0.0022),
      and the number of patients with angiographic progression was nearly halved (S:
      30%; P: 56%; p < 0.0000). These differences were determined by intention to treat
      analysis (ITT), and they were obtained in spite of lipid lowering add-on
      medication in 38% of the P patients; they turned out to be more pronounced in 137
      fully compliant patients, in an analysis "as treated". The mean decrease in LDL-C
      serum level caused by S was significantly correlated to the decrease in
      progression, and multivariate regression analysis of both treatment groups
      identified LDL-C (or ApoB) and TG as independent predictors of progression.
      Progression appeared to be most pronounced in low and medium sized lesions, and
      the beneficial effect of lipid intervention dominated in lesions with 12-56% QCA
      stenosis severity. A small fraction of patients who suffered from exercise
      induced angina, with ST-segment-depression at the beginning of the study,
      experienced a significant improvement under S as compared to P treatment.
      Although the study was not designed to show differences in clinical events, the
      combined number of all major cardiovascular events tended to be less frequent in
      the S than in the C gr

PMID- 10408033
TI  - [Atypical hypertrophic cardiomyopathy with calcified, left ventricular apical
      thrombosis].
AB  - A case of atypical hypertrophic cardiomyopathy (HCM) with a calcified apical
      thrombus is presented. A 42 year old asymptomatic patient was admitted for
      evaluation of an abnormal electrocardiogram (ECG) which was recorded when the
      patient suffered from a bronchitis. The ECG showed giant negative T-waves in
      leads II, III, aVF, V3 to V6 associated with high QRS voltages in the precordial
      leads. The chest X-ray and fluoroscopy demonstrated a calcification in projection
      to the apical region of the heart. Echocardiography and the left ventricular (LV)
      cineangiography showed hypertrophy of the apical LV myocardium and an
      obliteration of the apical LV cavity. Magnetic resonance imaging identified a
      calcified thrombus in the apical cavity of the LV in the setting of an atypical
      HCM.

PMID- 10408035
TI  - [Therapy of dilated cardiomyopathy with growth hormone].

PMID- 10408034
TI  - [Deformation of a coronary stent as a sequela of resuscitation].
AB  - We report a case of LAD-stent deformation by extracorporeal cardiopulmonary
      resuscitation (CPR) shortly after stent implantation. To our knowledge, this is
      the first reported case. During an emergency PTCA, stents were implanted into the
      RCA and LAD. Patency was proven by angiography before the patient left the
      cardiac laboratory. Thirty minutes later the patient underwent CPR because of
      ventricular fibrillation. The patient died in cardiogenic shock. Postmortem
      examination showed a distinctly deformed LAD-stent. The case proves the
      possibility of a deformation of a coronary stent by resuscitation.

PMID- 10408036
TI  - [Guidelines for diagnosis and therapy].

PMID- 10408038
TI  - [Concentrating on weaknesses or compensating by strengths? Comparison of 2
      strategies for remediation of children with comprehensive reading-spelling
      disorder].
AB  - Our study compares the efficiency and acceptance of two different methods of
      treating dyslexia in children. The first method addresses the most commonly
      encountered deficits in sequential processing. It relies primarly upon the
      "Kieler Lese-Rechtschreibaufbau". The second proceeds from the child's relative
      resources with regard to simultaneous processing as described by Kaufman.
      Training materials are those prescribed by Kaufman. Normally gifted primary
      school third-graders were trained in two groups (n = 13 and n = 12) and achieved
      a mean SIF score of SW = 101 on the K-ABC. As expected, the children scored
      significantly lower on the SED scale (SW = 95) than on the SGD scale (SW = 105).
      At the beginning of the respective training program their spelling ability fell
      1.5 SD below the class mean. One year of regular weekly one-hour training
      according to the simultaneous processing method was significantly more successful
      than training in sequential processing, whereas girls improved significantly more
      than boys regardless of the method used. Acceptance of the methods did not vary.
      This result requires careful consideration and should be replicated in younger
      samples such as first- and second-graders in the early stages of learning to read
      and write, and/or in children whose dyslexia is more severe than that encountered
      in the current sample. It underscores that determination of an adequate method of
      remediation entails more than the mere identification of the underlying deficits.

PMID- 10408037
TI  - [Social competence in children with social adjustment disorders].
AB  - Teachers and parents of a sample of 1774 students at three grade levels (4th, 6th
      and 8th grades) were asked to judge the social competence of the children by
      means of the social competence questionnaire by Buhrmester et al. (1988). These
      ratings were correlated with the social status of the pupils, with peer
      statements on aggressive behavior and victimization and with the teachers'
      ratings of behavior in class and towards fellow pupils. Teachers proved to be
      more critical than parents, crediting boys with less social competence than
      girls, though this difference diminished in the higher grades. Ratings of social
      competence differed significantly both with regard to respective social status,
      as well as to frequent involvement in aggressive disputes as reported by peers.
      Children rated by the teachers as hyperactive were no less socially competent
      than aggressive or aggressive-hyperactive children. Victims of peer aggression
      and particularly shy and withdrawn children were rated the least socially
      competent by parents and teachers. Implications for the training of the social
      skills of children with peer relationship problems are discussed.

PMID- 10408039
TI  - [Discriminant analytic determination of prognostic variables from child
      psychiatric examination for school achievement in special education studies].
AB  - Scores on tests administered to learning disabled children in grade one during
      their examination by a child psychiatrist were analyzed for their predictive
      value with regard to the children's subsequent academic careers and type of
      school later attended. Upon starting school the learning disabled children
      exhibited marked deficits in intelligence and language and motor development.
      Variables predictive of the type of school to be attended later were intelligence
      scores and motor performance.

PMID- 10408040
TI  - [Standards for expert assessment of credibility].
AB  - Expert judgment of the credibility of children's statements in cases of abuse is
      frequently requested of specialists in psychology and child and adolescent
      psychiatry, the latter being mandatory if psychopathology is present in the
      child. Assessment and judgment must meet standards of quality. Important
      innovations include a systematic procedure, avoidance of suggestive techniques
      for exploration and the application of a so-called criteria-based analysis of the
      child's statement. To exemplify the standards a case of an allegation of false
      expert judgment is presented.

PMID- 10408041
TI  - [Clinical significance of attachment research for the premature infant group: an
      overview of most recent research].

PMID- 10408042
TI  - [Follow-up of dissociative disorders in childhood and adolescents--a review of
      the literature].

PMID- 10408044
TI  - [Extracorporeal shockwave therapy in heel spur--analysis of the literature].

PMID- 10408043
TI  - [Sports after lumbar microsurgical nucleotomy].

PMID- 10408045
TI  - [Risk of peri-articular ossification in hip joint replacement].

PMID- 10408046
TI  - [Pain radiotherapy in chronic degenerative lumbar syndrome].

PMID- 10408047
TI  - [Therapeutic local anesthesia in postnucleotomy syndrome].

PMID- 10408048
TI  - [Preoperative radiation for prevention of heterotopic ossifications after hip
      endoprosthesis replacement].

PMID- 10408050
TI  - [Computer-assisted orthopedic surgery (CAOS) in hip joint prosthetics].

PMID- 10408049
TI  - [Strengthening ischio-crural musculature in femoro-patellar pain syndrome with
      knee splint].

PMID- 10408051
TI  - [Status of cementation technique in total hip endoprostheses in Germany].
AB  - AIM: The correlation between improved cementing techniques and improved long-term
      results after total hip arthroplasty (THA) is well documented. The purpose of
      this study was to assess the use of modern cementing techniques in Germany.
      METHODS: A detailed questionaire regarding cement and bone preparation, cementing
      techniques on actabulum and femur, and implants used was sent to 584 German
      orthopaedic and trauma hospitals, as well as to visiting surgeons with an
      interest in THA. In total, 333 questionaires were available for evaluation and
      statistical analysis. RESULTS: In this survey, Palacos bone cement is used in
      84%, low viscosity cement in 9%. Cement chilling is performed in 58%. Mixing is
      done by hand without vacuum mixing systems in 53%, the mixing time is
      standardised in 66%. For the femur 83% and for the acetabulum 74% preserve
      cancellous bone, 13% use pulsed lavage. Cement application is done via cement gun
      in 97%, in 41% in a retrograde manner and in 18% without drainage of the
      intramedullary canal. A cement pressurising technique is used in 63% for the
      femur and in 57% for the acetabulum. A cement mantle of less than 2 mm is
      attempted in 41%. More than 50 different stem design are implanted with the
      Muller straight stem being used most often, followed by anatomic designs. Almost
      50% of hips are used with a 28 mm head, and almost 50% are implanted with a 32 mm
      head. Half the heads are ceramic, half are metal. CONCLUSIONS: The results from
      this survey document, that overall only slightly more than 10% of hips are
      implanted using second/third generation (modern) cementing techniques with
      application of pulsed lavage. This has implications on the number of
      arthroplasties that may require revision. From the data available the current
      status of cementing technique in Germany cannot be judged satisfactory.

PMID- 10408052
TI  - [Proximal fixation of hip endoprostheses with porous surface: results of 6
      years].
AB  - PROBLEM: The anatomically shaped pcl (ESKA) total hip replacement has a porous
      coating of the proximal stem and the cup to allow for bony ingrowth. The tip of
      the stem is polished. METHOD: We report the results of 96 THR 6.2 years (5.25
      6.7) after implantation. RESULTS: There were no revisions during this period. One
      stem showed radiographic loosening at follow-up. There was stress-shielding in
      9.4% in contrast to the concept of proximal fixation. Thigh-pain was found in
      9.4%. One patient demonstrated disabling thigh-pain despite radiologic bony
      ingrowth. By drilling the femur distal to the tip of the stem a remarkable relief
      was achieved. CONCLUSION: Despite numerous cases of stress-shielding (9.4%), bony
      ingrowth occurs in 97%. The tcl-THR performs sufficiently after 6 years of
      implantation.

PMID- 10408054
TI  - [Comparative static biomechanical studies of tripod surface structures of
      cementless endoprostheses].
AB  - AIM: While the importance of stability of endoprosthetic surface structures has
      been recognized for some time there is a lack of comparative surveys and
      assessment indices that would permit comparison and improvement of surfaces on
      cementless endoprostheses. METHOD: Using separately produced, systematically
      mounted specimen pieces of endoprosthetic surfaces with isolated non-linked
      elements of varying shapes and sizes, stability parameters and stability
      behaviour are described. Results of tripode-structures are compared to spherical
      surfaces. RESULT: These investigations show clearly that geometrical attributes,
      the orientation and the contact of surface elements to the endoprosthetic stem
      influence the stability considerably more than the size of these surface
      elements. CONCLUSION: Using tripode-elements with different orientation, size and
      density, a differentiated formation of cementless endoprosthetic surfaces is
      possible.

PMID- 10408053
TI  - [Experiences with a hydroxyapatite-coated, macroporous surface hip
      endoprosthesis].
AB  - INTRODUCTION: Cementless hip arthroplasty is not completely satisfactory--even
      with macroporous structured surface. Medium term results are sometimes
      disappointing because of insufficient secondary stability. Thus our aim was to
      improve fixation by additional coating with hydroxyapatite. METHODS: 200
      consecutive patients who had hydroxyapatite-coated cementless hip replacement
      with a macroporous hip prosthesis (09/92-03/96) were studied prospectively. All
      patients were included in a prospective follow up schedule according to the
      criteria of Johnston et al. As measure of clinical outcome we calculated Harris
      Hip Score as well as Enghs Score to assess radiologic fixation and stability.
      RESULTS: 91% could be followed up regularly. No revision because of aseptic
      loosening had to be done. Analysis of clinical results showed almost painless
      patients from early after the operation--especially no thigh pain. Average HHS
      after 2 years was 97. Radiological evaluation showed early and complete
      osteointegration of all components. According to Engh-Score they are stable and
      well fixed. CONCLUSION: HA coated macroporous implants provide some striking
      advantages, which encouraged us to continue with this system. By early and secure
      bony ingrowth a fibrous interface is avoided and thereby also long-lasting thigh
      pain.

PMID- 10408055
TI  - [Stress analysis of an anatomically-adapted femur shaft prosthesis (Lubinus
      SPII)].
AB  - OBJECTIVE: Very good clinical long-term results of the Lubinus SP II hip
      prosthesis stem were reported in the literature. We therefore asked whether there
      is a relationship between these findings with biomechanical data of strain gauge
      measurements. METHOD: 14 strain gauges were applied at a femur being measured at
      10 different load cases before and after implantation of the stem. RESULTS: After
      stem implantation a similar patterns of principal stress distributions was
      observed, however, the magnitude was markedly reduced. A striking reduction of
      the hoop stresses at the femoral calcar was seen in the case of a missing collar
      contact. Even in the case of a perfect collar contact the hoop stresses were
      diminished after strem implantation. The S-shaped physiological stem did not
      correspond with a specific stress pattern measured at the femoral surface.
      CONCLUSION: These results suggest that the stresses at the femoral calcar may be
      lower than the limits of bone growth while the other parts of the femur are more
      physiologically stressed. However, the prosthesis may tolerate a missing collar
      contact during a long follow-up period. The large experimental data file
      presented here could be used to validate future finite element analyses which
      could evaluate the stress distribution within internal parts of the bone and the
      cement layer.

PMID- 10408056
TI  - [Nerve lesions after hip prosthesis implantation--fate or treatment error?].
AB  - INTRODUCTION: Nerve lesions after hip arthroplasty are common complications which
      may imply the reproach of a treatment mistake. Thus, the decisive question to the
      expert runs: fate or treatment mistake? METHODS: Retrospective analysis of all
      cases dealt with at the medical expert commission of the General Medical Council
      Nordrhein during 1977-1997 in respect of the damage mechanisms and expert
      judgments. RESULTS: As long as diagnosis and therapy were set on time, nerve
      lesions after hip arthroplasty due to extension, pressure or placement of the leg
      were evaluated as fateful (81%). Delayed treatment as well as incorrect operation
      technique, -indication, or inadequate documentation were judged as a treatment
      mistake (19%). CONCLUSION: Nerve lesions after hip arthroplasty cannot always be
      avoided and thus do not directly imply a treatment mistake. Immediate therapy and
      precise documentation are important to minimize the damage.

PMID- 10408057
TI  - [Peripheral nerve lesions after total hip endoprosthesis].
AB  - AIM OF THE STUDY: Lesions of peripheral nerves are serious complications
      associated with total hip replacements. Prognostic factors and treatment concepts
      have not been sufficiently defined. Improvements can occur spontaneously. This
      study aimed to evaluate risk factors and diagnostic aids, such as the velocity of
      nerve conduction (VNC) and electromyography (EMG). Furthermore, the effect of
      prognostic factors as well as conservative and invasive therapeutic measures on
      the regression of clinical symptoms was examined. METHOD: From 1990 to 1996 1833
      patients underwent total hip replacement. 1447 procedures were primary total hip
      replacements and 386 were revisions. 14 femoral nerve lesions (0.8%), 7 sciatic
      nerve lesions (0.4%) and 8 peroneal nerve lesions (0.4%) occurred. 19 patients
      were examined clinically, electromyographically and by means of VNC, 10 patients
      only clinically. In 5 patients a neurolysis was performed within the first
      postoperative year. All 29 patients underwent a recall examination in 1997 to
      evaluate the development of the clinical symptoms and if possible, VNC and EMG
      were performed. RESULTS: Of the 7 patients with sciatic nerve lesions, two were
      free from symptoms at the time of recall, two still complained about residual
      symptoms and two showed no improvement of the lesion. One patient did not appear
      for follow-up. Of the 8 patients with peroneal nerve lesions, five were free from
      symptoms at the time of their recent examination, two showed residual symptoms
      and one patient did not appear. Of the 14 patients with femoral nerve lesions,
      four had recovered completely, eight showed residual symptoms, one patient did
      not improve and one patient had died. CONCLUSIONS: Prognostic statements
      regarding the improvement after nerve lesions are possible only to a limited
      degree. However, it was found that the motor function tended to recover earlier
      than sensibility. We could not determine with clinical evaluations why some
      patients showed an improvement of their lesion while others did not. As well no
      clear correlation between the EMG and VNC results and the recession of the
      symptoms could be established.

PMID- 10408058
TI  - [Destruction of the gliding inlay of a hip endoprosthesis caused by intra
      articular cement particles].
AB  - In this case study of a 78-year-old female with a Hybrid-TEP prosthesis,
      extensive damage of the polyethylene inlay and strong foreign-body reaction in
      the neighboring soft tissue were seen four years following implantation. The
      introduction of just a few cement particles during implantation of hip prosthesis
      may lead to considerable damage of especially the polyethylene cup as well as the
      metal backing component. Wear particles from the prosthesis then can lead to
      unfavorable reactions within the surrounding tissue, including resorption of bone
      in the femoral neck and consequent loosening of the implant. Critical to the
      success of hip prosthesis implantation is a clean cementing technique.

PMID- 10408059
TI  - [Blood loss in total hip prosthesis implantation: lateral versus supine
      position].
AB  - We performed a prospective randomized study to determine blood loss differences
      between supine or lateral patient position, during surgery in elective total hip
      replacement. Between January and October 1996, 64 consecutive cases of total hip
      replacements were randomly scheduled for a procedure either in the supine or in
      the lateral position. Of the 56 cases evaluated, 29 were operated in the supine
      position (SP) and 27 in the lateral position (LP). The standardized implantations
      were performed without cement and the blood loss was measured. The calculated
      loss of Hb on the day of operation was 235 g Hb +/- 17 (mean +/- s.e.) in the SP
      group and 177 g Hb +/- 14 in the LP group, respectively, (unpaired t-test p =
      0.01). The calculated loss of Hb after five postoperative days was 227 g Hb +/-
      24 (mean +/- s.e.) in the SP group and 179 g Hb +/- 24 in the LP group,
      respectively, p < 0.2. The net loss of Hb after five postoperative days was
      calculated by subtracting all perioperative blood substitutions (Cellsaver,
      autologous and homologous blood) resulting in 340 g Hb +/- 21 (mean +/- s.e.) in
      the SP group and 272 g Hb +/- 21 in the LP group, respectively, p = 0.02. The
      blood loss in primary cementless total hip replacement surgery can be
      significantly reduced by performing the procedure in the lateral position
      compared to that in the supine position. The blood loss is limited to the day of
      operation, as indicated by the stable Hb-levels thereafter.

PMID- 10408061
TI  - [Decreased acetabular anteversion and femur neck antetorsion cause pain and
      arthrosis. 2: Etiology, diagnosis and therapy].
AB  - ETIOLOGY: Differences in the anteversion of the acetabulum and the femur must be
      attributed to the different rotational postures of the fetus as investigations
      and experiments have shown. After delivery there is a spontaneous improvement,
      but in perhaps 15% of the joints, diminished or increased acetabular or femoral
      anteversion will persist during later life. The results of the investigation of
      Part 1 are compared with the literature. So far no correlations between AA/FA and
      different clinical consequences have been reported. The deformity of diminished
      AA and FA is found as a singular entity, also as one of the causes of slipped
      capital femoral epiphysis. It is frequently combined with coxa vara, also with
      deep acetabula and occasionally with developmental hip dysplasia and children
      with PFFD. DIAGNOSIS: A hint for diagnosis is the limited range of internal
      rotation and an excess of external rotation of the hip besides some changes in
      the projection of femur and acetabulum. A CT in prone position with a summation
      of tomographic slices of the femoral neck and other details are necessary to
      measure AA and FA correctly. THERAPY: Therapy is indicated when pain occurs and
      osteoarthritis is developing. Decreased femoral anteversion is corrected by
      rotational osteotomies. Significant differences of acetabular anteversion are
      treated by rotation of the acetabulum after triple pelvic osteotomy. The normal
      value of acetabular and femoral anteversion to be achieved is 15 to 20 degrees.

PMID- 10408060
TI  - [Decreased acetabular anteversion and femur neck antetorsion cause pain and
      arthrosis. 1: Statistics and clinical sequelae].
AB  - PROBLEM: This paper investigates which angles of acetabular (AA) and femoral
      antversion (FA) have to be considered as normal and which ones cause changes in
      range of movements, pain and osteoarthrosis. METHOD OF INVESTIGATION: 15-20
      degrees of anteversion of AA and FA were tested regarding normality. Diminished
      anteversion angles were divided in groups -2 and -3, and increased angles in
      groups +2 and +3. RESULTS: The material consisted of 356 hip joints with
      computerized tomographies, investigated separately in different deformities.
      Changes in range of movement, pain and osteoarthrosis were minimal in the normal
      angle group 1 and increasing in the extreme angle groups -2 and -3 and +2 and +3.
      Diminished AA and FA cause a decrease of internal rotation of the hip and an
      increase of external rotation, pain and osteoarthrosis. When groups of diminished
      AA or FA angles were found combined with the normal angle group 1 or increased
      angles of AA or FA (+2/+3), the pathological consequences were compensated or
      diminished especially by higher FA angles and less by AA angles. The results in
      all investigations were statistically significant if the number of observations
      was large enough. The instability index of McKibbin was used in the different
      angle groups of deviation from normal. Adding the angles of AA and FA together
      gives a good impression of the degree of instability or rigidity and the
      prognosis of the joint. SIGNIFICANCE: In children and adults diminished AA and FA
      are quite frequent. They cause pain and osteoarthrosis, but are diagnosed seldom.

PMID- 10408062
TI  - [Comparison of the prognostic value of the Catterall and Herring classification
      in patients with Perthes disease].
AB  - QUESTION: Investigation of the predictive value of the Catterall- as compared to
      the Herring-classification in patients with Perthes disease. METHOD: A
      radiological follow-up study including 53 patients with a total of 59 affected
      hips was carried out. In the initial diagnosis the Catterall-, Waldenstrom- and
      Herring-stages were assessed. The epiphyseal ratio, the head-neck ratio and the
      lateral subluxation were measured and compared at the time of diagnosis,
      fragmentation stage and in a follow-up examination, which was carried out 4, 9
      years after diagnosis on the average. The results of the follow-up examination
      were assessed using the Mose-classification and compared as well. In addition the
      two classifications were compared as to the necessity of an upgrading. RESULTS:
      Both classifications yielded similar descriptions of the radiomorphometric
      course. There was a good correlation between the results of Herring A and
      Catterall I, Herring B and Catterall II and III and Herring C and Catterall IV.
      Upgradings were necessary in the Herring- and the Catterall-classification in 21
      cases, and 18 cases, respectively. CONCLUSION: The predictive values of both
      classifications are comparable.

PMID- 10408063
TI  - [Primary correction of scoliosis with the Wilmington corset].
AB  - QUESTION: As part of our study, the effectiveness and patient's acceptance of the
      Wilmington-brace is to be evaluated. The effectiveness can be documented with the
      help of the primary correction achieved, especially in light of the fact, that
      the primary correction and the long-term results are directly dependant upon one
      another. MATERIAL AND METHOD: We examined a total of 52 patients with an
      idiopathic scoliosis treated in a thermoplast brace. The group consisted of 38
      female and 14 male patients (average age 11.6 years). The angulation was measured
      with the help of the Cobb-angle and the rotation with the method described by
      Nash and Moe. The skeletal age was classified according to Risser's-sign. The
      angle determinations were carried out at three separate points in time--at first
      presentation, prior to bracing and four to six weeks following bracing. RESULTS:
      The patients presented with an average angulation of 31 degrees. The average
      correction achieved in the Wilmington-brace was 41%. This corresponds to a
      correction of 13 degrees. The best primary correction (45%) was obtained in the
      thoracolumbar spine. Those patients with the smallest deformity at the onset of
      treatment showed the best results. The scoliosis with a large primary deformity
      and a marked rotation of the vertebral bodies responded poorly to correction.
      Advanced age or skeletal maturity were also limiting factors. Physical therapy
      had a positive influence on the amount of primary correction obtained. CLINICAL
      RELEVANCE: The Wilmington-brace (thermoplast) allows for a good primary
      correction of idiopathic scoliosis. The simplicity of application and the low
      production costs are also positive attributes.

PMID- 10408064
TI  - [Keller-Brandes operation: long-term outcome in young patients with hallux
      valgus].
AB  - PURPOSE: Aim of this retrospective study was to analyse the long term results (10
      16 years) after Keller-Brandes' operation for correction of hallux valgus in the
      younger patient. METHODS: From 1980 to 1986 fifty-one patients (77 feet) at the
      age of 40 years or younger at the time of surgery (19-40 years, [symbol: see
      text] 34 years), were operated according to a resection-arthroplasty at our
      institution. 24 patients (37 feet) were evaluated retrospectively after 10 to 16
      years (median: 13 years) in respect to their clinical outcome. Radiological
      evaluation was performed preoperatively in 23 feet and in 34 feet at follow up.
      Analysis was performed using a standardized questionnaire based on the HMIS-Score
      of the American Foot and Ankle Society, an additional clinical score, weight
      bearing radiographs, the patient's record and clinical investigation inclusive
      pedobarographic analysis. RESULTS: Seventy-six % of the patients revealed very
      good or good subjective overall results. The HMIS-Score revealed excellent or
      good results in only 57%. Cosmetic was rated very good or good in 64%, 70% of the
      patients were painfree. Average ROM of the MTP I-joint ranged from 25 degrees
      flexion to 45 degrees extension. Radiological analysis at follow up: hallux
      valgus angle-correction: 28 degrees to 19 degrees, no change of the
      intermetatarsal angle (11 degrees), proximal shift of sesamoids: 9.4 mm to 14.4
      mm, neoarticulation gap: 0-2 mm in 23 feet and 3-5 mm in 11 feet, arthritis of IP
      joint: 82%: none; 18%: moderate; correction of sesamoid position: 1.7 to 1.4.
      Metatarsalgia was observed in 27% (10 feet). CONCLUSION: Lateral weight transfer
      to the lesser metatarsal heads is caused by defunction of the great toe
      postoperatively which may lead to metatarsalgia (transfer-metatarsalgia). Besides
      pain relief younger patients require satisfying functional and cosmetic long-term
      results. To be capable of meeting these requirements, adequate joint preserving
      procedures like basal or distal metatarsal osteotomies conjuncted with soft
      tissue procedures should be preferred in respect to the grade of the deformity.

PMID- 10408065
TI  - [Osteoma cutis, a case report from the orthopedic viewpoint].
AB  - Osteoma cutis is a benign cutaneous disease which causes a primary heterotopic
      ossification of the skin. Corresponding to the appearance it is possible to
      distinguish four modifications. The enlargement of osteoma cutis can disturb the
      function of joints and statics. The etiology of the disease is unknown. Hamartoma
      or metaplasia is subject of discussion. It is important to mark off osteoma cutis
      from pseudohypoparathyreoidism (Albright-syndrome++).

PMID- 10408066
TI  - [Imaging diagnosis in suspected inflammatory rheumatoid axial skeleton diseases
      (sacroilitis)].
AB  - Involvement of the sacroiliac joints is a hallmark of the spondyloarthropathies,
      especially in ankylosing spondylitis. The conventional diagnostic imaging of
      sacroiliitis in early stages might cause problems, because sensitivity of
      conventional radiographic methods is known to be too low in early stages of the
      disease. Magnetic resonance imaging of the sacroiliac joints certainly enables
      one to detect acute as well as chronic inflammatory changes in all stages of the
      disease. The potential disadvantages of this method are the dependency on the
      examiner, the lack of standardization, and the relatively high costs. Therefore,
      the "Workgroup of Diagnostic Imaging in Rheumatology of the Regional Center of
      Rheumatology of Berlin" including experienced rheumatologists, skeletal
      radiologists, and orthopedists acquired an imaging graduation for detection of
      sacroiliitis in consideration of the clinical background, the technical details
      of the methods, questions of ionizing radiation exposure, and cost effectiveness.

PMID- 10408067
TI  - [Radiosynoviorthesis in the treatment plan of chronic inflammatory joint
      diseases].
AB  - The effectiveness of radiosynovirothesis in the local treatment of chronically
      inflammatory joint diseases, especially rheumatoid arthritis, was evaluated.
      SUBJECTS AND METHODS: Follow-up examinations of 415 joints in 115 patients up to
      4.5 years after intraarticular application of beta-emitting yttrium-90, rhenium
      186, and erbium-169 were evaluated. The examination protocol included estimation
      of joint circumference, range of active joint moving capability, fist-bending
      power, and radiological assessment of joint destruction. Subjective assessment of
      pain, swelling, and joint function by the patients was evaluated by means of a
      score with three levels. RESULTS: The mean range of active joint moving
      capability increased in all joint subgroups, compared with the initial
      examination, with exception of ankle joints examined more than 30 months after
      therapy. The mean joint circumference decreased in all joint subgroups. Good to
      excellent results were achieved in up to 66% of joints, satisfying results in up
      to 21%, and no improvement or further deterioration was noted in 13% according to
      subjective assessment by patients themselves. Treatment proved most effective in
      joints with poor or no alteration in X-ray examinations. CONCLUSIONS: In the
      local treatment of chronically inflammatory joint diseases--especially beyond
      systemic drug therapy and local corticoid therapy--, radiosynoviorthesis is a low
      invasive method, which may provide long-term relief of pain and swelling as well
      as improvement of joint function.

PMID- 10408068
TI  - [Cartilage oligomeric matrix protein (COMP): the role of a non-collagen cartilage
      matrix protein as a marker of disease activity and joint destruction in patients
      with rheumatoid arthritis and osteoarthritis].
AB  - Today, we can assess criteria to predict the tissue destruction and progression
      of Rheumatoid Arthritis (RA) and Osteoarthritis (OA) only in a late stage of the
      disease. It would be an advantage to have biochemical markers of disease activity
      and joint destruction to optimize therapy. PATIENTS AND METHODS: In this cross
      sectional study with 37 RA and 20 OA patients (disease duration 119 +/- 130
      months for RA and 41 +/- 73 months for OA), ESR, CRP, disease activity score
      (DAS), the functional status of RA (American College of Rheumatology), and the
      radiological scoring systems of Larsen and Kellgren/Lawrence, respectively, were
      used as parameters for disease activity and joint destruction. Cartilage
      oligomeric matrix protein (COMP) was measured with an enzyme-linked immunosorbent
      assay (ELISA) in serum and synovial fluid, COMP fragments with immunoblot in the
      synovial fluid. RESULTS: The mean COMP value in synovial fluid was 38 ug/ml (RA)
      and 46 ug/ml (OA); 6.5 ug/ml (RA) and 3.4 ug/ml (OA) in serum. RA patients had a
      higher amount of small COMP fragments in synovial fluid than OA patients. In RA
      patients, there was a significant positive correlation between disease activity
      (DAS) and COMP in synovial fluid and serum, a negative correlation between
      functional status of RA and serum COMP and between radiologic joint destruction
      of the knee and serum COMP. In OA patients, there was a significant correlation
      of joint space width and synovial fluid COMP. DISCUSSION: A high clinical disease
      activity (DAS) correlated with high COMP values in serum and synovial fluid and
      with increasing proteolytic activity (higher amount of small COMP fragments
      especially in RA). An increased turnover of cartilage matrix in joint
      inflammation might explain this correlation. The correlation of decreased COMP
      with decreased functional status in RA and increased joint destruction is
      compatible with a loss of cartilage and less turnover. The correlation between
      joint space width and increased COMP in OA patients with short disease duration
      might be explained with a higher turnover of the cartilage matrix in the early
      stage of the disease.

PMID- 10408069
TI  - [In vitro transduction of human osteoblast cell populations with retroviral
      vectors].
AB  - OBJECTIVES: The involvement of cytokines in degeneration and inflammation of
      human tissue is well established. Interleukin-1 (IL-1) is a major agent in the
      pathophysiology of periarticular bone resorption in rheumatoid arthritis and in
      osteoporosis. Because the use of recombinant cytokines and growth factors is
      limited due to their short half lives, techniques are needed to get a permanent
      release of these therapeutic proteins. The rational of this study was to show
      that retroviral transduction of human osteoblastic cells is possible in vitro
      using the marker gene LacZ and the potentially therapeutic gene encoding for
      human interleukin-1 receptor antagonist protein (IL-1Ra). Different transduction
      techniques were combined to improve the rate of transduction in vitro. METHODS:
      Osteoblastic cells were isolated from human spongious bone and cultured in vitro.
      The beta-galactosidase (LacZ) gene and the cDNA of IL-1Ra were introduced into
      the isolated cells by retrovirus mediated gene transfer. LacZ activity was
      determined by Xgal staining, IL-1Ra was measured quantitatively by ELISA.
      RESULTS: The transfer of retroviral IL-1Ra led to IL-1Ra expression of 8614 to
      10,089 pg IRAP/50,000 cells/48 h. By combining different techniques to improve
      transduction, the X-gal staining established a rate of transduction of 60%.
      CONCLUSION: Our results demonstrate that retroviral transduction of human
      osteobalstic cells is possible in vitro, and leads to high levels of the
      synthesized transgene product. The rate of retroviral transduction can be
      accelerated in vitro.

PMID- 10408070
TI  - [An unusual case of Heberden arthrosis in a young man].
AB  - Heberden nodes affect mainly middle-aged women. Inheritance is autosomal dominant
      in female and autosomal recessive in male patients. We report the case of a young
      man who presented already with 12 years of age with pain in the distal finger
      joints. There were no other clinical or serological signs for other rheumatoid
      diseases, like psoriatic or rheumatoid arthritis. Radiologic findings were
      consistent with Heberden's osteoarthritis of the finger joints. The joint changes
      remained clinically and radiologically stable during a time period of more than
      15 years. The HLA typing revealed the haplotype HLA A1, B8 and DR4, in accordance
      with former studies which reported a higher frequency of HLA A1, B8 in families
      with primary osteoarthritis (early onset osteoarthritis of the large joints in
      combination with Heberden nodes).

PMID- 10408071
TI  - [Psoriatic arthritis with synchondrosis sternal superior manifestation].
AB  - We describe the imaging procedures for the diagnosis of manubriosternal joint
      arthritis in a 64 years old man with psoriatic arthritis. Involvement of the
      manubriosternal joint (synchondrosis sternalis) in psoriatic arthritis is a rare
      manifestation. The findings of bone-scintigraphy, conventional radiography and
      arthrosonography of the manubriosternal joint arthritis are compared and
      discussed.

PMID- 10408072
TI  - [25 years HLA B27--report on the "B27 and Beyond" NIH Conference].

PMID- 10408074
TI  - [Efficacy of ultrasound screening in pregnancy].
AB  - OBJECTIVE: The purpose of this study was to examine the effectiveness of
      ultrasound screening in pregnancy. MATERIAL AND METHODS: Therefore, it was
      registered whether fetal malformations in a study population of 11,172 deliveries
      were already diagnosed before birth. RESULTS: 341 defects were found in 297
      children from mothers who had had prenatal care. Most anomalies were seen in the
      urogenital tract (n = 98; 28.7%), the heart (n = 67; 19.6%), the connective
      tissue (n = 39; 11.4%), the gastrointestinal tract (n = 32; 9.4%), and in the
      central nervous system (n = 33; 9.7%). Chromosomal anomalies (n = 22; 6.5%) and
      orofacial defects (n = 21; 6.2%) were more rare. 8.8% of all defects were lethal,
      37% severe. 237 (69.5%) were classified as "diagnosable by ultrasound
      prenatally". 125 of them (53%) were identified prenatally, with high rates of 71%
      in central nervous system, 65.5% in intestinal and 54% in urogenital tract, while
      the detection rate was only 13.6% in chromosomal and 3.3% in cardiac defects.
      Only 14.3% were found before 24 weeks of gestation. CONCLUSIONS: Thus, the
      effectiveness of ultrasound screening has to be improved by adequate measures.

PMID- 10408073
TI  - [The effects of hormone replacement therapy on ovarian function in premenopausal
      women after hysterectomy].
AB  - OBJECTIVE: Examining the consequences of temporary postoperative hormone
      replacement therapy following hysterectomy for the function of the ovaries and
      the subjective well-being of women. MATERIAL AND METHODS: Hormone profiles
      (Estradiol, FSH, LH, Testosterone, DHEA) and typical estradiol deficiency
      phenomena were investigated prospectively in premenopausal hysterectomized women
      with intact ovaries. Group 1 (n = 21) was replaced transdermally following
      surgery for 3 weeks with estradiol patch 0.05 mg daily. Group 2 (n = 21) got no
      hormones. RESULTS: Group 1 had a remarkable decrease of estradiol after 10 days
      to 59% and after 6 weeks to 71% of the starting point. Gonadotropins showed an
      increase in this group. In group 2 without replacement there was only a small
      decrease of estradiol after 10 days and after 6 weeks the level was higher than
      before hysterectomy. Testosterone also decreased in group 1 to 64% of the level
      before surgery after 6 weeks, whereas in the comparing group it was 87%. On the
      other hand in group 1 only 2 of 21 women, but 10 of 21 in group 2 showed
      climacteric-like symptoms. CONCLUSIONS: HRT over 3 weeks induces ovarian
      suppression, which is still seen 6 weeks after hysterectomy. But hormonally
      treated women have clearly less subjective complaints.

PMID- 10408075
TI  - [Validity of cardiotocography in the detection of umbilical cord complications].
AB  - OBJECTIVE: The purpose of this study was to investigate the validity of
      cardiotocography for the detection of cord complications. MATERIAL AND METHODS: A
      low-risk population of 4196 cases was selected in which cord complications have
      been recognized in 34.3%. Cases with cord complications and controls were paired
      by parity, gestational age, maternal age and mode of delivery. 25 pairs were
      randomly selected. 50 tracings were presented twice to 4 obstetricians in a
      double-blind manner. As parameters for the determination of the validity of fetal
      monitoring the reliability, positive (ppv) and negative predictive value (npv),
      sensitivity and specificity were used. Inter- and intra-observer variability were
      also examined. RESULTS: Reliability 52%, ppv 52%, npv 52%, sensitivity 46%,
      specificity 58%. Interobserver variability: All 4 obstetricians agreed in 47 of
      100 evaluations. The level of agreement was higher in the controls (63%) than in
      the cord complication group (56%). The intraobserver variability was 25%.
      CONCLUSIONS: Cardiotocography is not useful for the detection of cord
      complications. The range of possibilities has not been exploited yet, even for
      the evaluation of the fetal state.

PMID- 10408077
TI  - [A scanning microscopy study of the peritoneum in mice after application of a CO2
      pneumoperitoneum].
AB  - OBJECTIVE: The application of a CO2-pneumoperitoneum in operative laparoscopy
      presumably leads to basic alterations of the intraperitoneal homeostasis. In
      order to better understand the pathophysiology of this phenomenon, the
      morphologic alterations of the mesothelium after CO2-application will be
      examined. MATERIAL AND METHODS: In 36 mice (C 57, black mice) a CO2
      pneumoperitoneum with an intraperitoneal pressure of 6 mm Hg was applied for 30
      minutes. After 1, 2, 6, 12, 24, 48, 72 and 96 hours each of 4 animals were killed
      and the entire peritoneum was examined by scanning electron microscopy. RESULTS:
      Already after 1 hour mesothelial cells became cuboidal, were detached and showed
      condensation. After 2 hours this initial reaction reached its peak; immature
      cells then attached to the free basal membrane. After 96 hours the entire
      mesothelium was regenerated. CONCLUSIONS: The morphologic integrity of the
      mesothelium is temporarily disturbed by a CO2-pneumoperitoneum. Reasons for this
      phenomenon may be either the abdominal pressure or a CO2-induced surface
      acidosis. In further studies, the influence of the described phenomena on
      intraperitoneal formation of metastases will be examined.

PMID- 10408076
TI  - [Toxoplasmosis-antibody seroprevalence in Mecklenburg-Western Pomerania].
AB  - OBJECTIVE: The aim of this study was to get a general idea of the antibody
      prevalence of toxoplasmosis within the different agegroups of the population of
      Mecklenburg-Western Pomerania. 4854 serums (collected between 1994 and 1996) from
      different institutions of the federal state were investigated with the "Toxo
      Competitions Test LTXC)" at the Mini-Vidas divice (bio Merieux). MATERIAL AND
      METHODS: An antibody prevalence rate of 59% was found. As expected, with rising
      age a continuing increase was recognisable. The antibody prevalence rate with the
      male test persons amounted to 58.5%, with the female test persons to 59.3%, and
      within the pregnant women 63.2%. RESULTS: Therefore 36.8% of pregnant women have
      got no toxoplasmosis antibodies, i.e. they are exposed to the danger of a primary
      infection. Within pregnant women aged between 20 and 40 an increase of antibody
      prevalence of 1% per year of age was recognisable. There was only a small share
      of pregnant women (10.5%), but they confirm the facts known from literature.
      CONCLUSIONS: More than 1/3 of our test persons hadn't had toxoplasmosis
      antibodies. Therefore in order to reduce the danger of a primary infection in
      pregnant women a screening before pregnancy in recommendable.

PMID- 10408078
TI  - [Leiomyoma of the female urethra].
AB  - Extrauterine leiomyomas of the female urogenital tract are seldomly described in
      the present literature. We report on a 47-year-old patient with a large
      suburethral leiomyoma, which was misinterpreted as a vaginal descensus. Aspects
      of diagnosis and treatment are discussed.

PMID- 10408080
TI  - [Pregnancy and hormone replacement therapy in a patient with resistant ovary
      syndrome].
AB  - We report on the case of a 32-year-old woman with "resistant ovary syndrome". The
      patient received hormone replacement therapy sequentially with 2 mg estradiol
      valerate and 2 mg estradiol valerate/0.15 mg levonorgestrel (Klimonorm,
      Jenapharm, Germany) respectively, because of secondary amenorrhea and premature
      menopause. Under this therapy she conceived and had a delivery at term following
      an inconspicuous pregnancy. The case report emphasizes the rare but possible
      spontaneous remission of "resistant ovary syndrome" as a variant of premature
      menopause and is discussed in terms of the literature.

PMID- 10408079
TI  - [Laparoscopic Galvin-TeLinde hysterectomy for treatment of a microinvasive
      cervical carcinoma].
AB  - The original technique of laparoscopical Galvin-TeLinde-hysterectomy in patients
      with FIGO IA1 cervical cancer is presented. Differences between this technique
      and classical abdominal procedure are discussed. Based on the presented case the
      authors discuss the significance of laparoscopy in cervical cancer treatment.

PMID- 10408081
TI  - Bilateral massive edema of the ovary.
AB  - We present a case of synchronic bilateral ovary mass edema. In spite of the
      patient's age and the difficulties of the intraoperative study it reveals a high
      likelihood of malignancy in the preoperative stage.

PMID- 10408082
TI  - [Computer-based image analysis for experimental and clinical morphology-
      principles, utilization and marginal limits].
AB  - The new computer based image analysis techniques are powerful tools for
      mophometrical and quantitative image analysis in case of clinical and
      experimental morphology. Digital image analysis requires a distinction between
      two phases 1. generation of fundamental data (x,y coordinates and grey values of
      the pixel) and 2. calculation of parameters from these data. Stereological
      procedures are very powerful in quantifying morphological phenomenons, but
      computer based image analysing techniques allow multiple analysis of
      morphological objects and analysis of statistical distributions. There is great
      scientific benefit using modern computer based image analysing techniques.

PMID- 10408083
TI  - Diclofenac interactions: tetrakis[mu-2-(2,6-dichloroanilino)phenylacetato]-1:2
      kappa 8O:O'-diacetone-1 kappa O,2 kappa O-dicopper(II)(Cu-Cu) acetaldehyde
      solvate.
AB  - The structure of the centrosymmetric dimeric copper(II) title compound,
      [Cu2(C14H10Cl2NO2)4(C3H6O)2] C2H4O, has been determined and compared with the
      structures of analogous O-bridged CuII dimers. Polarographic experiments on
      aqueous solutions containing a mixture of the CuII ion and diclofenac have been
      used to determine both the formation constant [1 (1) x 10(8)] and the solubility
      product [2 (1) x 10(-12)] of the complex.

PMID- 10408084
TI  - The red form of [Re(phen)(CO)3(H2O)]-CF3SO3.H2O.
AB  - The coordination geometry of the cations in the red form of aquatricarbonyl(1,10
      phenanthroline-N,N')rhenium(I) trifluoromethanesulfonate hydrate,
      [Re(C12H8N2)(CO)3-(H2O)]CF3SO3.H2O, is approximately octahedral, with a facial
      arrangement of the linearly coordinated carbonyl ligands. The phenanthroline
      (phen) ligands interleave to form a columnar pi-stacked structure.

PMID- 10408085
TI  - Dipotassium naphthalene-1,8-dicarboxylate-potassium bicarbonate.
AB  - The title substance, tripotassium naphthalene-1,8-dicarboxylate bicarbonate,
      3K+.C12H6O4(2-).HCO3-, crystallized in the centrosymmetric space group Pbca.
      There is a single hydrogen bond. In it, the O and H atoms are ordered and OD...OA
      is 2.651 (3) A. There is a single significant intermolecular C-H...O interaction,
      with C...OA = 3.480 (5) A. Each potassium ion is coordinated by an irregular
      polyhedron of O atoms. These three polyhedra contain eight, eight and five
      members; each O atom is a member of at least two polyhedra. Structural
      comparisons are made with tetrapotassium naphthalene-1,4,5,8-tetracarboxylate
      hexahydrate.

PMID- 10408086
TI  - (C2H10N2)[Co(H2O)6](HPO4)2: a supramolecular three-dimensional hydrogen-bonding
      network.
AB  - The title compound, ethylenediammonium hexaaquacobalt bis(hydrogenphosphate),
      consists of [Co(H2O)6]2+ and [enH2]2+ cations (en is ethylenediamine), and
      [HPO4]2- anions interconnected by an extensive intermolecular three-dimensional
      hydrogen-bonding network. The [enH2]2+ cations play an important role in the
      templating effect. Both [Co(H2O)6]2+ cations are situated on inversion centers.
      The average Co-O and P-O bond distances are 2.075 (6) and 1.54 (2) A,
      respectively.

PMID- 10408087
TI  - Hydrogen bonding in quinolinium-4-carboxylate dihydrate.
AB  - The title acid, C10H7NO2.2H2O, crystallized in the non-centrosymmetric space
      group Cc with one zwitterionic organic molecule and two water molecules in the
      asymmetric unit. One N-H...O and four O-H...O hydrogen bonds are present in this
      structure, with donor-acceptor distances ranging from 2.688 (2) to 2.852 (3) A.
      These hydrogen bonds generate a three-dimensional network. Structural comparisons
      are made with anhydrous quinoline-4-carboxylic acid.

PMID- 10408088
TI  - Network of C-H...O interactions in 1,2-naphthalenedicarboxylic anhydride.
AB  - The title substance, C12H6O3, crystallized in the centrosymmetric space group
      P2(1)/c with one molecule in the asymmetric unit. Four significant C-H...O
      interactions have C...O distances ranging from 3.313 (2) to 3.453 (2) A. They
      link each molecule directly to eight neighbors, generating a three-dimensional
      network. The anhydride group is compared with those in phthalic anhydride and
      1,4,5,8-naphthalenetetracarboxylic 1,8:4,5-dianhydride.

PMID- 10408089
TI  - Crystallographic evidence for the electronic distribution in (2,4-cyclopentadien
      1-yl-idenehydrazono)triphenylphosphorane.
AB  - The title compound, C23H19N2P, can be graphically represented by several
      canonical forms. Its crystal structure analysis shows a clear bond alternation in
      the cyclopentadiene ring, which continues in the azo substructure, indicating
      that the resonance form containing the nonaromatic neutral cyclopentadienylidene
      moiety describes the actual hybrid form better than other 'inner ionic' resonance
      forms containing the aromatic anionic cyclopentadienylic portion. The preference
      for an s-transoid (E) geometry for the P1-N1-N2-C1 substructure was also
      confirmed over the other possible s-cisoid (Z) conformer.

PMID- 10408090
TI  - Chiral recognition between host and guest: a binaphthyl-18-crown-6 host with D
      phenylglycinium methyl ester perchlorate guest. A difficult structure solved with
      CRUNCH.
AB  - The complex between (R)-4,5,7,8,10,11,13,14,16,17-decahydro-2,19-
      diphenyldinaphtho[2,1-q:1',2'-s][1,4,7,-
      10,13,16]hexaoxa[2,5,8,11,14,17,19]cycloicosaheptene {Chemical Abstracts name:
      (R)-4,5,7,8,10,11,13,14,16,17-decahydro-2,19- diphenyldinaphtho[2,1-q:1',2'
      s][1,4,7,-10,13,16]hexaoxacycloic osin} and D-2-phenylglycinium methyl ester
      perchlorate, C9H12NO2+.ClO4-.C42H40O6.-H2O, crystallizes in the orthorhombic
      space group P2(1)2(1)2(1) with two C9H12NO2+.C42H40O6 complexes, two ClO4- ions
      and two molecules of water in the asymmetric unit. Crystal data: M(r) = 924.44, a
      = 23.048 (7), b = 34.383 (6), c = 11.992 (6) A, V = 9503 (6) A3, Z = 8, Dx =
      1.292 Mg m-3, F(000) = 3904, mu(Cu K alpha) = 1.261 mm-1, T = 175 K, R = 0.0896
      for all 7784 reflections, 1208 parameters refined in three blocks with 29
      restraints. Nearly twenty years elapsed between the first data collection and the
      solution of the structure with the direct-methods program CRUNCH. The structural
      details are of interest because enantiomers of this host show a high degree of
      discrimination between enantiomers of alpha-amino acids and their esters. The
      crystal structure demonstrates the influence of C-H...O and C-H...pi interactions
      on the unexpected orientation of the guest in the host cavity. The same
      orientation is found in both of the unique complexes, and the geometric details
      are in agreement with solution studies.

PMID- 10408091
TI  - Growth properties of a folA null mutant of Escherichia coli K12.
AB  - In Escherichia coli, dihydrofolate reductase is required for both the de novo
      synthesis of tetrahydrofolate and the recycling of dihydrofolate produced during
      the synthesis of thymidylate. The coding region of the dihydrofolate reductase
      gene, folA, was replaced with a kanamycin resistance determinant. Unlike earlier
      deletions, this mutation did not disrupt flanking genes. When the mutation was
      transferred into a wild-type strain and a thymidine-(thy) requiring strain, the
      resulting strains were viable but slow growing on rich medium. Both synthesized
      less folate than their parents, as judged by the incorporation of radioactive
      para-aminobenzoic acid. The derivative of the wild-type strain did not grow on
      any defined minimal media tested. In contrast, the derivative of the thy
      requiring strain grew slowly on minimal medium with thy but exhibited
      auxotrophies on some combinations of supplements. These results suggest that when
      folates are limited, they can be distributed appropriately to folate-dependent
      biosynthetic reactions only under some conditions.

PMID- 10408092
TI  - Biodegradation of cyanide compounds by a Pseudomonas species (S1).
AB  - A Pseudomonas sp. (S1), isolated from soil by an enrichment technique was tested
      for its potential to degrade different cyanide compounds. Further,
      biodegradation/biotransformation of binary mixtures of the cyanide compounds by
      the culture was also studied. The results indicated that the culture could grow
      on the following nitriles by using them as carbon and nitrogen sources:
      acetonitrile, butyronitrile, acrylonitrile, adiponitrile, benzonitrile,
      glutaronitrile, phenylacetonitrile, and succinonitrile. Studies on the
      biodegradation of these cyanide compounds in binary mixtures showed that the
      presence of acrylonitrile or KCN delayed the degradation of acetonitrile in a
      mixture, while none of the other cyanide compounds affected the degradation of
      one another. The transformation products of the nitriles were their corresponding
      acids, and similarly, KCN was also directly transformed to formic acid. Studies
      on the transformation of these cyanide compounds showed that the rate of
      transformation of nitriles to their corresponding carboxylic acids was
      acrylonitrile > acetonitrile > adiponitrile > benzonitrile > KCN. This culture
      has the unique characteristic of transforming representatives of saturated
      aliphatic, aliphatic olefinic, aromatic, and aralkyl nitriles, as well as alkali
      cyanide, to their corresponding carboxylic acids.

PMID- 10408094
TI  - Isolation and partial characterisation of extracellular keratinase from a wool
      degrading thermophilic actinomycete strain Thermoactinomyces candidus.
AB  - The keratinase production by the thermophilic actinomycete strain
      Thermoactinomyces candidus was induced by sheep wool as the sole source of carbon
      and nitrogen in the cultivation medium. For complete digestion of wool by the
      above strain, both keratinolytic serine proteinase and cellular reduction of
      disulfide bonds were involved. Evidence was presented that substrate induction
      was a major regulatory mechanism and the keratinase biosynthesis was not
      completely repressed by addition of other carbon (glucose) and nitrogen (NH4C1)
      sources. The enzyme was purified 62-fold by diethylaminoethyl-anion exchange and
      Sephadex G-75 gel permeation chromatographies. Sodium dodecyl sulfate
      polyacrylamide gel electrophoresis indicated that the purified keratinase is a
      monomeric enzyme with a molecular mass of 30 kDa. The pH and temperature optima
      were determined to be 8.6 and 70 degrees C, respectively. The purified
      thermophilic keratinase catalyses the hydrolysis of a broad range of substrates
      and displays higher proteolytic activity against native keratins than other
      proteinases. Ca2+ was found to have a stabilizing effect on the enzyme activity
      at elevated temperatures.

PMID- 10408093
TI  - Degradation of morpholine, piperidine, and pyrrolidine by mycobacteria: evidences
      for the involvement of a cytochrome P450.
AB  - Nine bacterial strains that grew on morpholine and pyrrolidine as sole carbon,
      nitrogen, and energy sources were isolated from three different environments with
      no known morpholine contamination. One of these strains could also degrade
      piperidine. These bacteria were identified as Mycobacterium strains. A
      phylogenetic analysis based on the partial 16S rDNA sequences indicated that the
      isolated strains clustered within the fast growing group of mycobacteria. When
      the above-mentioned cyclic amines were used as growth substrates, the synthesis
      of a soluble cytochrome P450 was induced in all these bacteria. Other laboratory
      strains, Mycobacterium fortuitum and Mycobacterium smegmatis mc(2)155, were
      tested for their abilities to degrade morpholine. Neither of them degraded
      morpholine but could use pyrrolidine and piperidine. The growth of M. fortuitum
      and M. smegmatis mc(2)155 on these compounds involved a soluble cytochrome P450,
      suggesting that mycobacterial strains are naturally able to use pyrrolidine and
      have developed a similar enzymatic pathway to metabolize this amine.

PMID- 10408095
TI  - Detection of Lawsonia intracellularis in faeces of swine from the main producing
      regions in Brazil.
AB  - Swine proliferative enteropathy is an enteric disease caused by Lawsonia
      intracellularis which affects animals between 6 and 20 weeks of age, causing
      diarrhea, anorexia, and poor growth. The presence of L. intracellularis was
      evaluated in the faecal samples of 636 swine from 75 randomly chosen herds in the
      main swine-producing regions of Brazil. The pathogen was detected by the
      polymerase chain reaction method (PCR) using L. intracellularis specific primers.
      A 319-bp DNA fragment specific for L. intracellularis was produced on
      amplification of DNA from the faeces of pigs with proliferative enteropathy.
      Equal amounts of DNA extracted from the faeces of animals from the same herd were
      pooled together and, once L. intracellularis was detected, the faecal material of
      each animal was analyzed separately. The incidence of L. intracellularis was
      33.4% in the state of Santa Catarina, 29.4% in Parana, 26.3% in Minas Gerais,
      16.7% in Mato Grosso, and 7.1% in Sao Paulo. The presence of the pathogenic agent
      was detected in samples from 15 farms, representing a total incidence of 20%.
      Although 46 animals (7.2%) were shown to be infected, 11% did not present any
      symptoms of swine proliferative enteropathy. The use of PCR allowed the detection
      of L. intracellularis in swine farms and the evaluation of the incidence of
      proliferative enteropathy in different regions of Brazil.

PMID- 10408096
TI  - Removal of phenolic compounds from a petrochemical effluent with a methanogenic
      consortium.
AB  - A methanogenic consortium was used to degrade phenol and ortho- (o-) cresol from
      a specific effluent of a petrochemical refinery. This effluent did not meet the
      local environmental regulations for phenolic compounds (178 mg/L), oils and
      greases (61 mg/L), ammoniacal nitrogen (75 mg/L) or sulfides (3.2 mg/L). The
      consortium, which degrades phenol via its carboxylation to benzoic acid, was
      progressively adapted to the effluent. Despite the very high effluent toxicity
      (EC50 of 2% with Microtox), the adapted consortium degraded 97% of 156 mg/L
      phenol in the supplemented effluent after 13 days in batch cultures (serum
      bottle). The addition of proteose peptone to the effluent is essential for phenol
      degradation. o-cresol was also transformed but not meta- or para-cresols. A
      continuous flow fixed-film anaerobic bioreactor was developed with the
      consortium. Treating the effluent with the bioreactor reduced phenol and phenolic
      compounds concentrations by 97 and 83%, respectively, for a hydraulic residence
      time of 6 h. This treatment also reduced by about half the effluent toxicity.
      Oils and greases and ammoniacal nitrogen were not affected. Similar
      microbiological forms were observed in serum bottles and in the bioreactors with
      or without the petrochemical effluent. These results indicate that this
      methanogenic consortium can treat efficiently the phenolic compounds in this
      specific petrochemical effluent.

PMID- 10408097
TI  - Regulation of cellulose-inducible structures of Clostridium cellulovorans.
AB  - Scanning electron microscopy was used to detect ultrastructural protuberances on
      the cellulolytic anaerobe Clostridium cellulovorans. Numerous ultrastructural
      protuberances were observed on cellulose-grown cells, but few were detected on
      glucose-, fructose-, cellobiose-, or carboxymethylcellulose (CMC)-grown cells.
      Formation of these protuberances was detected within 2 h of incubation in
      cellulose medium, but 4 h incubation was required before numerous structures were
      observed on the cells. When a soluble carbohydrate or CMC was mixed with
      cellulose-grown cells, the ultrastructural protuberances could no longer be
      detected. In fact, no protuberances were observed within 5 min following the
      addition of glucose, cellobiose, or methylglucose to cellulose-grown cells. The
      presence of these protuberances corresponded with the binding of the Bandeiraea
      simplicifolia BSI-B4 isolectin to the cell. Cellulose-grown cells had a greater
      level of observable lectin binding than cellobiose-grown cells, and lectin
      binding was not detected on glucose- or fructose-grown cells. In addition, lectin
      binding ability was lost by cellulose-grown cells following the addition of
      glucose, fructose, or methylglucose to the cellulose medium. A cellulose-affinity
      protein fraction expressing cellulase activity was also detected in cell extracts
      of cellobiose- or cellulose-grown cultures. However, this protein fraction was
      not detected in extracts of glucose-grown cultures, and was rapidly lost (within
      5 min) following the addition of glucose to cellulose-grown cultures. The ability
      of C. cellulovorans to adhere to cellulose was also affected by the energy
      substrate, but not in the same manner as the protuberance formation or the
      cellulase-containing protein fraction. Rather, cellobiose-, cellulose-, and CMC
      grown cultures adhered to cellulose, but this adherence was not affected by
      addition of glucose to the medium. This is the first report that soluble
      carbohydrates caused the rapid loss of some cellulose-inducible systems of C.
      cellulovorans.

PMID- 10408098
TI  - Staphylococcus aureus isogenic mutant, deficient in toxic shock syndrome toxin-1
      but not staphylococcal enterotoxin A production, exhibits attenuated virulence in
      a tampon-associated vaginal infection model of toxic shock syndrome.
AB  - Since menstrual toxic shock syndrome (MTSS) is associated with a predominant
      clone of Staphylococcus aureus which produces both toxic shock syndrome toxin-1
      (TSST-1) and staphylococcal enterotoxin A (SEA), we sought to clarify the role of
      TSST-1 in a tampon-associated vaginal infection model in New Zealand White (NZW)
      rabbits, using isogenic tst+/sea+ S. aureus mutants in which tst was inactivated
      by allelic replacement. Rabbits infected with the tst-/sea+ strain became ill
      within 3 days, with fever, weight loss, conjunctival hyperemia, and lethargy.
      Mortality was significantly higher with the tst+/sea+ strain compared to its tst
      /sea+ isogenic derivative (4/13 vs. 0/14; p < 0.05, Fisher's exact test, 2
      tailed). Mean fever index was higher (p < 0.005; t test, 2-tailed) and weight
      loss more sustained among survivors in the tst+/sea+ group. Furthermore, culture
      filtrates from the tst+/sea+ strain induced a significantly greater response in
      mitogenesis and TNF alpha secretion from rabbit splenocytes in vitro compared to
      the tst-/sea+ isogenic derivative. Thus, regardless of the role of SEA, TSST-1
      significantly contributed to both morbidity and mortality in this tampon
      associated vaginal infection model in NZW rabbits. This is the first
      demonstration of the potential role of TSST-1 and SEA in the pathogenesis of MTSS
      with a MTSS-associated clinical S. aureus strain in a relevant animal model.

PMID- 10408099
TI  - Fate of Cryptosporidium oocysts, Giardia cysts, and microbial indicators during
      wastewater treatment and anaerobic sludge digestion.
AB  - The extent of reduction in selected microorganisms was tested during both aerobic
      wastewater treatment and anaerobic digestion of sludge at the wastewater
      treatment plant in Ottawa to compare the removal of two encysted pathogenic
      protozoa with that of microbial indicators. Samples collected included the raw
      wastewater, the primary effluent, the treated wastewater, the mixed sludge, the
      decanted liquor, and the cake. All of the raw sewage samples were positive for
      Cryptosporidium oocysts and Giardia cysts, as well as for the other
      microorganisms tested. During aerobic wastewater treatment (excluding the
      anaerobic sludge digestion), Cryptosporidium and Giardia were reduced by 2.96
      log10 and 1.40 log10, respectively. Clostridium perfringens spores, Clostridium
      perfringens total counts, somatic coliphages, and heterotrophic bacteria were
      reduced by approximately 0.89 log10, 0.96 log10, 1.58 log10, and 2.02 log10,
      respectively. All of the other microorganisms were reduced by at least 3.53
      log10. Sludge samples from the plant were found to contain variable densities of
      microorganisms. Variability in microbial concentrations was sometimes great
      between samples, stressing the importance of collecting a large number of samples
      over a long period of time. In all cases, the bacterial concentrations in the
      cake (dewatered biosolids) samples were high even if reductions in numbers were
      observed with some bacteria. During anaerobic sludge digestion, no statistically
      significant reduction was observed for Clostridium perfringens, Enterococcus sp.,
      Cryptosporidium oocysts, and Giardia cysts. A 1-2 log10 reduction was observed
      with fecal coliforms and heterotrophic bacteria. However, the method utilized to
      detect the protozoan parasites does not differentiate between viable and
      nonviable organisms. On the other hand, total coliforms and somatic coliphages
      were reduced by 0.35 log10 and 0.09 log10, respectively. These results
      demonstrate the relative persistence of the protozoa in sewage sludge during
      wastewater treatment.

PMID- 10408100
TI  - Growth and survival of uninjured and sublethally heat-injured Escherichia coli
      O157:H7 on beef extract medium as influenced by package atmosphere and storage
      temperature.
AB  - The effect of atmospheric composition and storage temperature on growth and
      survival of uninjured and sublethally heat-injured Escherichia coli O157:H7,
      inoculated onto brain heart infusion agar containing 0.3% beef extract (BEM), was
      determined. BEM plates were packaged in barrier bags in air, 100% CO2, 100% N2,
      20% CO2: 80% N2, and vacuum and were stored at 4, 10, and 37 degrees C for up to
      20 days. Package atmosphere and inoculum status (i.e., uninjured or heat-injured)
      influenced (P < 0.01) growth and survival of E. coli O157:H7 stored at all test
      temperatures. Growth of heat-injured E. coli O157:H7 was slower (P < 0.01) than
      uninjured E. coli O157:H7 stored at 37 degrees C. At 37 degrees C, uninjured E.
      coli O157:H7 reached stationary phase growth earlier than heat-injured
      populations. Uninjured E. coli O157:H7 grew during 10 days of storage at 10
      degrees C, while heat-injured populations declined during 20 days of storage at
      10 degrees C. Uninjured E. coli O157:H7 stored at 10 degrees C reached stationary
      phase growth within approximately 10 days in all packaging atmospheres except
      CO2. Populations of uninjured and heat-injured E. coli O157:H7 declined
      throughout storage for 20 days at 4 degrees C. Survival of uninjured populations
      stored at 4 degrees C, as well as heat-injured populations stored at 4 and 10
      degrees C, was enhanced in CO2 atmosphere. Survival of heat-injured E. coli
      O157:H7 at 4 and 10 degrees C was not different (P > 0.05). Uninjured and heat
      injured E. coli O157:H7 are able to survive at low temperatures in the modified
      atmospheres used in this study.

PMID- 10408101
TI  - Survival of insect pathogenic and human clinical isolates of Photorhabdus
      luminescens in previously sterile soil.
AB  - Most characterized strains of the bacterium Photorhabdus luminescens are
      symbionts of entomopathogenic nematodes, whereas other strains have been isolated
      from human clinical specimens. The ability of P. luminescens strains to survive
      and grow in soil has received limited attention, with some studies indicating
      these bacteria have little or no ability to persist in soil. Survival and (or)
      growth of P. luminescens strains in previously sterilized soil, and examination
      of different soil amendments on their numbers in soil, have not been previously
      reported. Entomopathogenic P. luminescens (ATCC 29999) and a human clinical
      isolate (ATCC 43949) were introduced into a soil that had been sterilized by
      autoclaving, with or without different soil amendments, and bacterial numbers
      were estimated over time by viable plate count. In the previously sterilized soil
      receiving no exogenous amendments, numbers fell drastically over a week's time,
      followed by an increase in numbers by day 30. Treatments involving the addition
      of calcium carbonate and gelatin or casamino acids to soil usually resulted in
      higher bacterial numbers. For some sampling dates and soil treatments, there were
      statistically significant differences between the numbers of the two bacterial
      strains recovered from soil. The two strains of P. luminescens used in this study
      were able to survive and grow after being inoculated into previously sterilized
      soil.

PMID- 10408102
TI  - The differentiation of traumatic and heat-related fractures in burned bone.
AB  - Interpretations of antemortem and perimortem trauma are complicated when dealing
      with cases involving extreme exposure to fire. This investigation attempts to
      discern the signatures of perimortem trauma from heat related trauma. Femora of
      domestic pig, sus scrofa, with minimal soft tissue and articulated patellae were
      subjected to varying traumatic forces. Skeletal elements were impacted with blunt
      and sharp forces, cut with varying instruments, subjected to torsional forces of
      shot. Bones were burned in various situations in conjunction with Knox County
      Rural/Metro Fire Department training exercises conducted in Knox County,
      Tennessee. Following recovery, fragments were subjected to radiographic,
      macroscopic, and microscopic analyses. Skeletal elements were reconstructed to
      permit accurate comparison with pre-fire visual records. In addition, fracture
      surfaces were examined under both transmitted light and scanning electron
      microscopy in an attempt to discern surface signatures of the causal fracture
      (trauma, heat, or situational). Results indicate that signatures of sharp force
      trauma remain evident following incineration. Furthermore, radiopaque spatter was
      not observed in any shot specimen. However, these initial findings suggest that
      the interpretation of blunt force and torsional trauma requires a rigorous
      examination and comparison of fracture patterns in conjunction with surface
      morphology.

PMID- 10408103
TI  - Preliminary data on the usefulness of internal transcribed spacer I (ITS1)
      sequence in Cannabis sativa L. identification.
AB  - A method is described to identify an unknown sample of plant material of forensic
      interest as Cannabis sativa L. The method consists in comparing the sequence of
      the nuclear ribosomal DNA Internal Transcribed Spacer I (ITS1) of the unknown
      sample with a Cannabis sequence. Our preliminary results show that the ITS1 is an
      ideal molecule for the identification of a sample suspected to be marijuana.

PMID- 10408104
TI  - Minimal standards for the performance and interpretation of toxicology tests in
      legal proceedings.
AB  - There have been several high profile criminal and civil cases that have been
      litigated in recent years involving toxicologic analyses and interpretations of
      blood, urine, and other specimens for drugs of abuse. Disputes have erupted
      between prominent toxicologists and laboratory scientists as to the validity and
      interpretation of the data presented. The disputes centered around the fact that
      the procedures used in these cases had not been properly validated with
      analytical noise being misinterpreted as a positive result. As with any analyses,
      forensic tests must be conducted in a manner such that they meet the minimum
      standards accepted within the toxicology community. No conclusions as to presence
      or absence of drug, its concentration, or its physiologic effects can be made if
      there is a failure to meet these basic standards. Several cases are presented
      where these standard tenets may not have been followed.

PMID- 10408105
TI  - Postmortem stability and interpretation of beta 2-agonist concentrations.
AB  - This paper describes a series of stability and redistribution studies aimed at
      understanding the presence and significance of beta 2-agonists in asthma deaths.
      Salbutamol and terbutaline were shown to be stable in postmortem blood at 23
      degrees C for 1 week, 4 degrees C for 6 months and -20 degrees C for 1 to 2
      years. However, fenoterol was shown to degrade at 23 degrees C (83% loss), 4
      degrees C (93% loss) and -20 degrees C (66% loss) over the same time. Salbutamol
      concentrations detected in blood taken at the time of body admission to the
      mortuary were not significantly different from the concentrations detected in
      blood taken from the same cases at the time of autopsy (45 h later). This
      suggests that significant postmortem redistribution of salbutamol is unlikely to
      occur during this period. Postmortem blood concentrations of at least salbutamol
      are likely to reflect the concentration of these drugs in the body at the time of
      death.

PMID- 10408106
TI  - Aqueous phase hexylchloroformate derivatization and solid phase microextraction:
      determination of benzoylecgonine in urine by gas chromatography-quadrupole ion
      trap mass spectrometry.
AB  - A derivatization/solid phase microextraction (SPME) method for the determination
      of benzoylecgonine in urine was developed. The derivatization is conducted
      directly in 1 mL of urine while sonicating for 3 min with 12 microL of hexyl
      chloroformate and 70 microL of a mixture containing acetonitrile:water:hexanol:2
      dimethylaminopyridine (5:2:2:1 v/v), yielding benzoylecgonine hexyl ester (BHE)
      as the product. After the 3 min period, an aliquot of 250 microL is transferred
      to a vial for SPME. After the desired extraction time the 100 microns
      polydimethylsiloxane SPME fiber was transferred to the GC-MS for separation and
      analysis with a quadrupole ion trap mass spectrometer. The hexyl chloroformate
      derivatization and SPME procedures were optimized for compatibility and
      sensitivity. The method was found linear for 0.10 to 20.0 micrograms/mL (r2 =
      0.999) of benzoylecgonine in urine using benzoylecgonine-d3 as an internal
      standard (1.5 micrograms/mL). Intra-day precisions were 8.8 and 6.8% RSD for 0.30
      microgram/mL and 17 micrograms/mL benzoylecgonine standards in urine (n = 6),
      respectively. Inter-day precision (n = 3) were < or = 3.3% RSD, indicating good
      reproducibility. A detection limit of 0.03 microgram/mL (S/N = 3) was achieved,
      thus making the SPME method a simplified alternative to SPE for GC-MS
      confirmation after EMIT tests for benzoylecgonine which have a cutoff of 0.30
      microgram/mL. Quantitative results by SPME and SPE of two clinical urine
      specimens known positive for cocaine by EMIT were in excellent agreement.
      Benzoylecgonine was detected by the derivatization/SPME method in 22 out of 22
      other urine specimens known positive for cocaine.

PMID- 10408107
TI  - Determination of postmortem interval from old skeletal remains by image analysis
      of luminol test results.
AB  - The luminol test is routinely used in forensic serology to locate blood traces
      and identify blood stains not visible to the naked eye; its sensitivity is
      reported as ranging from 1:100,000 to 1:5,000,000. To evaluate the possibility of
      correlating the postmortem interval with blood remnants in bone tissue, the
      luminol test was performed on 80 femurs with a known time of death, grouped in
      five classes. Powdered bone (30 mg) was recovered from compact tissue of the mid
      shaft of each femur and was treated with 0.1 mL of Luminol solution (Sirchie
      Finger Print Laboratories, Inc.). The reactions were observed in a dark room and
      filmed by a TV camera equipped with a recording tape. An intense
      chemiluminescence was observed after a few seconds in all 20 femurs with a PMI
      ranging from 1 month to 3 years. On the 20 femurs with a PMI ranging from 10-15
      years, a clear chemiluminescence was visible with the naked eye in 80% of the
      sample. Among the 20 femurs with a PMI ranging from 25 to 35 years, a weaker
      chemiluminescence appeared in 7 femurs (33% of the sample). In the 10 femurs with
      a PMI ranging from 50 to 60 years, a faint reaction was observed only in a single
      femur. In none of the ten femurs with a PMI over 80 years was chemiluminescence
      observed. The image of each reaction was computerized and analyzed for gray
      scale. The results of image analysis show a possible quantitative relationship
      between the PMI and luminol chemiluminescence in powdered bone.

PMID- 10408108
TI  - Child abduction: aged-based analyses of offender, victim, and offense
      characteristics in 550 cases of alleged child disappearance.
AB  - Crimes against children, particularly cases involving abduction and/or homicide,
      continue to be problematic as both a social phenomenon and judicial
      responsibility. Such cases routinely receive immense community and media
      attention and rapidly overwhelm investigative resources. Research in the area of
      childhood victimization, however, has only recently gained national prominence.
      While numerous studies on child abuse and neglect have been conducted, research
      on child abduction and homicide remains scant. Previous studies examining child
      abduction suffer from limited geographical scope or fail to base predictive
      analyses on victim characteristics. The current study reports the results of a
      nationally representative sample (47 states, the District of Columbia, and Puerto
      Rico) of 550 cases of alleged child abduction obtained from Federal Bureau of
      Investigation files for the period 1985 through 1995. Study results demonstrate
      that both offender and offense characteristics vary significantly according to
      victim age, gender, and race. Such differences appear critical to crime
      reconstruction, criminal profiling, and investigative resolution. Additionally,
      these data suggest that current child abduction prevention programs may emphasize
      inaccurate offender traits.

PMID- 10408109
TI  - The psychological impact of stalking on female undergraduates.
AB  - This study examined the psychological impact of stalking upon female
      undergraduates, a population previously determined to experience a surprising
      stalking prevalence rate. Despite common understanding that stalking has
      deleterious effects, there have been no previous efforts to systematically assess
      them with standardized measures. Thirty-six female stalking victims were compared
      with 43 females who had been harassed and 48 controls. Psychological impact was
      assessed with the Posttraumatic Stress Disorder Scale, the Symptom Checklist-90
      R, and the Self-Report Interpersonal Trust Scale. Stalked subjects endorsed
      significantly more PTSD symptoms and with greater severity than the harassed or
      control subjects. Stalked subjects also had significantly higher scores on
      several subscales of the SCL-90, and had significantly higher positive symptom
      totals and distress indices.

PMID- 10408110
TI  - Revisiting arson from an outpatient forensic perspective.
AB  - Progress in the understanding of individuals who commit arson has been on a slow
      but steady course over the past two decades. From our review of court-ordered
      outpatient forensic psychiatric evaluation of individuals charged with arson over
      a five-year period, preliminary prototypical profiles of the psychotic, mentally
      retarded, alcohol abusing, and mood-disordered firesetter are offered. The
      clinical-legal relevance of our results are explored.

PMID- 10408111
TI  - Dementia as a risk factor for homicide.
AB  - We report a patient with dementia due to B-12 deficiency and syphilis who
      presented to a forensic hospital after killing his ex-wife with a gun. Despite
      current awareness on the occurrence of aggression and violence in patients with
      dementia, there has been no report discussing dementia secondary to an infectious
      or nutritional origin causing homicide or severe violent behavior. We discuss
      possible mechanisms and several predisposing factors for violent behavior in the
      elderly. We also discuss use and access of a gun in demented patients and its
      complications. We recommend availability of neuropsychiatric assessments in the
      elderly, limitation of gun access to demented patients and inquiry about weapon
      possession in the elderly.

PMID- 10408112
TI  - Characteristics of gunshot wounds in the skull.
AB  - The analysis of trauma to the skeleton is an important aspect of forensic case
      work, but most pathology references devote limited attention to this topic. This
      paper describes various aspects of gunshot wounds, including entrance and exit
      patterns, angle and path, range of fire and velocity, and caliber of the bullet,
      based on observations of a series of known cases. Skeletal remains of 21 victims
      of gunshot wounds were studied. In most cases, there was documentation of the
      investigation, autopsy, and victim's identity. Each case was analyzed in terms of
      wound location, shape, size and exit/entry surface area ratio, beveling, and
      direction of shooting Skull entry wounds were most often round or oval. Unusual
      shapes were observed in bones like the mandible and mastoid process, but were
      also found to be triangular, nearly rectangular or irregular. Tunneling was
      observed in the mastoid process. The expected internal beveling was obvious in
      all but one skull. External beveling of an entry wound was only observed in one
      case (parietal bone). Exit wounds were roughly round, oval, square, and
      rectangular and were always more irregular than entry wounds. External beveling
      of exit wounds was observed in most vault bones, but there was none in the orbit,
      maxilla, greater wing of the sphenoid, temporal, or left occipital bone.
      Tangential gunshot wounds were seen in a mastoid process, zygomatic process,
      mandibular ramus and condyle, and occipital condyle. Most of the exit to entry
      surface area ratios (cm2) varied from 1.4 to 2.0. In four cases the ratio
      indicated that entrances were larger than exists. In conclusion, understanding of
      gunshot wound characteristics is an important matter to interpret distance,
      velocity, direction and sometimes caliber size. Assessment of this nature of
      gunshot wounds helps reconstruct events surrounding the death.

PMID- 10408113
TI  - Calculation of percent shrinkage in human fetal diaphyseal lengths from fresh
      bone to carbonized and calcined bone using Petersohn and Kohler's data.
AB  - Calculation of age from fetal and newborn remains may be problematic, and when
      these remains are altered by maceration, decomposition or burning, age may be
      more difficult to discern. When soft tissue indicators are transformed, then two
      techniques exist for accurate age determination; dental development, which may
      prove difficult given the degree of tissue alteration; and appearance, size and
      fusion of ossification centers, including diaphyseal length, which may yield
      inaccurate ages if shrinkage is not accounted for. This study is undertaken to
      facilitate age calculation by systematically re-evaluating diaphyseal shrinkage
      and determine shrinkage rates from wet to carbonized states and wet to calcined
      states using Petersohn and Kohler's data, originally published in German and then
      published in Fazekas and Kosa (1978:362-369). Average shrinkage, standard
      deviation, minimum and maximum values are calculated for each diaphysis and then
      for all diaphyses between 4-10 lunar months (LM) and for newborns. Associated
      values for carbonized diaphyses are: 4 LM--32.50% +/- 12.12%; 5 LM--14.04% +/-
      4.44%; 6 LM--6.78% +/- 1.06%; 7 LM--4.18% +/- 0.31%; 8 LM--3.47% +/- 0.42%; 9 LM-
      3.05% +/- 0.18%; 10 LM--2.46% +/- 0.67%; and in newborns 2.16% +/- 0.29%. Similar
      values for calcined diaphyses are: 4 LM--40.11% +/- 17.51%; 5 LM--18.29% +/-
      4.42%; 6 LM--9.84% +/- 1.27%; 7 LM--9.82% +/- 0.51%; 8 LM--9.42% +/- 0.72%; 9 LM-
      9.45% +/- 0.33%; 10 LM--8.94% +/- 0.37%; and in newborns 8.96% +/- 0.49%. These
      findings suggest that percent shrinkage due to carbonization and calcination is
      greatest in the earliest age groups, decreasing substantially with advancing age.
      The rates of shrinkage, however, vary by the burning process utilized and age
      group studied. These general findings are similar to those of Petersohn and
      Kohler, yet specific values for percent shrinkage vary greatly from values cited
      in this analysis. These data provide a means to assess the degree of shrinkage
      that occurs for each diaphysis for each given age group.

PMID- 10408114
TI  - Allocation of crania to groups via the "new morphometry".
AB  - An investigation regarding the variation in cranial morphology between American
      blacks and whites was conducted using triangulation schemes of inter-landmark
      distances and converting these to three dimensional coordinate data. A least
      squares superimposition method and Euclidean distance analysis were utilized to
      obtain parameters for classifying individuals in our sample, consisting of 19
      black and nineteen white crania from the William M. Bass, III Donated and
      Forensic collections curated at the University of Tennessee, Knoxville. Thirty
      six caliper measurements were collected on each skull based on 14 homologous
      cranial landmarks (nasion, bregma, lambda, prosthion, subspinale, basion,
      frontomalare (left and right), zygoorbitale (left and right), zygotemporale (left
      and right), and left and right asterion). The results are compared to traditional
      discriminant analysis. The classification results using the new morphometry are
      comparable to traditional discriminant analysis. However, the new morphometry can
      provide information as to the specific location of morphological variation that
      cannot be obtained with discriminant analysis.

PMID- 10408115
TI  - Japanese population study of a Y-linked dinucleotide repeat DNA polymorphism.
AB  - A polymorphic CA repeats (YCA II) was previously reported on the human Y
      chromosome. We have used a simple technique based on polymerase chain reaction
      amplification followed by native polyacrylamide gel electrophoresis to study the
      inheritance, the genetic stability, and the allele frequency distribution of this
      polymorphism in the Japanese. We found seven haplotypes which were tentatively
      designated as: A[(CA)19/(CA)21], B[(CA)19/(CA)22], C[(CA)19/(CA)23],
      D[(CA)19/(CA)19], E[(CA)21/(CA)21], F[(CA)22/(CA)22], and G[(CA)23/(CA)23]. The
      frequencies of these haplotypes were: A, 0.21; B, 0.29; C, 0.37; D, 0.02; E,
      0.02; F, 0.07; G, 0.01. There was complete concordance with each father-son
      pairs. The results indicate the dinucleotide system YCA II is very useful for
      investigation of forensic samples, especially mixed stains in sexual offence
      cases.

PMID- 10408116
TI  - PCR-based identification of postmortem microbial contaminants--a preliminary
      study.
AB  - Investigation of postmortem blood can reveal the presence of significant ethanol
      levels. However, in some instances it cannot easily be determined if the source
      of ethanol is from ingestion or from postmortem endogenous fermentation by
      contaminating microbes. Described here is a robust polymerase chain reaction
      (PCR)-based method for detecting the presence of common ethanol producing
      microbial contaminants in human blood. A set of DNA primers were designed for use
      in PCR to amplify and detect the genomic DNA from humans and three test
      microorganisms Escherichia coli, Proteus vulgaris, and Candida albicans. A rapid
      and reproducible protocol was developed for isolating genomic DNA from mixed
      human blood-microorganism samples that yields a suitable template for PCR. The
      organism-specific primer pairs can detect the presence of the target
      microorganisms in human blood at concentrations as low as 10 colony forming
      units/mL. The PCR products readily can be detected after agarose gel
      electrophoresis. This method provides an additional means of rapidly identifying
      microbial contaminants in postmortem blood samples.

PMID- 10408117
TI  - Validation studies of an immunochromatographic 1-step test for the forensic
      identification of human blood.
AB  - An immunochromatographic 1-step test for the detection of fecal occult blood was
      evaluated for applicability for the forensic identification of human blood in
      stained material. The following experiments were conducted: 1) determination of
      the sensitivity and specificity of the assay; 2) evaluation of different
      extraction media for bloodstains (sterile water, Tris buffer pH 7.5 provided in
      the test kit, 5% ammonia); 3) analysis of biological samples subjected to a
      variety of environmental insults; and 4) evaluation of casework samples. This
      immunochromatographic 1-step occult blood test is specific for human (primate)
      hemoglobin and is at least an order of magnitude more sensitive than previous
      methods for detecting human hemoglobin in bloodstains. The antigen is insensitive
      to a variety of environmental insults, except for exposure to certain detergents
      and household bleaches and prolonged exposure to certain preparations of luminol.
      The entire assay can be conducted in field testing conditions within minutes.
      When in the laboratory the supernatant from a DNA extraction is used for the
      assay, there is essentially no consumption of DNA for determining the presence of
      human hemoglobin in a forensic sample. The data demonstrate that this test is
      robust and suitable for forensic analyses.

PMID- 10408118
TI  - The detection of cocaine in hair specimens using micro-plate enzyme immunoassay.
AB  - The analysis of hair for drugs of abuse is becoming increasingly popular and is
      under consideration by the Division of Health and Human Services as a possible
      alternative or adjunct to urinalysis in workplace programs. The detection of
      cocaine in human hair using a commercially available micro-plate enzyme
      immunoassay is described for the first time. Sample size and incubation time were
      the major variables in the optimization of the method. In order to validate the
      procedure, the method was applied to 105 consecutive hair samples routinely
      received into our laboratory. The samples were simultaneously analyzed by the
      Micro-Plate immunoassay (EIA), as well as our current fluorescence polarization
      immunoassay (FPIA) procedure and gas chromatography-mass spectrometry (GC/MS).
      The sensitivity of the EIA and FPIA assays were 75% and 67.8% respectively;
      specificity 97.4% and 80.5% respectively; and efficiency 91.4 and 77.1%
      respectively. The Micro-Plate EIA was shown to be a valid alternative to other
      immunoassay screening methods for the detection of cocaine in hair by
      demonstrating increased sensitivity, specificity and efficiency over our current
      technique.

PMID- 10408119
TI  - Removal of a PCR inhibitor and resolution of DNA STR types in mixed human-canine
      stains from a five year old case.
AB  - The analysis of biological trace evidence from a reopened investigation into a
      1991 murder from Vernon, B.C. revealed mixed human and dog bloodstains on blue
      jean pants that contained a PCR inhibitory substance. The presence of the
      inhibitory substance was detected by the inhibition caused from adding a small
      aliquot of the test DNA extract into a PCR reaction designed to produce a known
      standard product. The removal of the PCR inhibitory substance was accomplished by
      treating the extracted DNA with Thiopropyl Sepharose 6B beads. DNA profiles from
      two human contributors and a canine were obtained using species specific
      polymorphic STR markers. The two human DNA profiles obtained from blue jean pants
      were resolved, one matched the suspect and the other matched the victim. The DNA
      profile from the canine component matched that obtained from the known sample of
      the victim's dog who was also slain during the assault. This evidence along with
      other DNA typing evidence was critical in obtaining a resolution of the case.

PMID- 10408120
TI  - Paternity analysis when the putative father is missing: first case in Chile.
AB  - Genetic marker analysis is a powerful tool for solving paternity-related problems
      when the putative father is missing. This report describes the first time this
      approach was employed in Chile to solve such a problem. In the case presented,
      the alleged father was missing as a result of the political detentions that took
      place in Chile during 1973. It was not possible to obtain any biological sample
      from him because he was missing. Thus, the case was resolved by means of genetic
      marker analysis of the alleged father's close relatives.

PMID- 10408121
TI  - Identification of a skeleton using DNA from teeth and a PAP smear.
AB  - Identification of unknown living or deceased persons using dental treatment
      records is an established forensic technique. However, some cases remain
      unidentified, especially when antemortem dental records are not available for
      comparison to postmortem dental records. Cytological smears have been previously
      reported to be potential sources of DNA reference samples which can be compared
      to DNA recovered from found human remains. The case described here involves an
      adult skeleton which exhibited extensive, complex dental restorative treatment. A
      putative identification of the found skeleton as a missing woman was established
      using circumstantial evidence found at the scene. However, it became important to
      establish a positive identification using reliable scientific methods. When it
      was discovered that antemortem dental records were not available because the
      treatment was completed in another country and the treating dentist could not be
      found, cytological smears stained with Papanicolaou (PAP) stain obtained from the
      putative decedent's medical records were used as a reference DNA sample. DNA was
      recovered from the teeth of the skeleton using cryogenic grinding. Comparison of
      the genotypes resulted in the conclusion that the DNA originated from the same
      source. The use of PAP smears in this way is seen as a valuable resource in cases
      where positive identification using traditional dental and medical records is not
      possible.

PMID- 10408122
TI  - The contribution of forensic geology and other trace evidence analysis to the
      investigation of the killing of Italian Prime Minister Aldo Moro.
AB  - In May 1978 the body of the kidnapped Italian Prime Minister, murdered by the Red
      Brigades, was found in a car parked in the center of Rome. This paper discusses
      the findings from the investigations conducted on the evidence found on Mr.
      Moro's clothes, shoes (beach sand, bitumen, vegetals and polyester fragments),
      and on the car. To get a comprehensive picture of the characteristics of the
      various pieces of evidence, use was made of a multiple-technique approach. The
      sand was identified as coming from the seashore close to Rome. A tract of shore
      with a limited number of roads leading to the beach was defined as compatible
      with the textural and compositional characteristics of the sand. The study of the
      vegetal fragmenta suggested that they had been picked up in a period of time
      close to the killing. Thermosetting polyester, of the type used in boat
      manufacturing was found under the fenders, in the tires and inside the car, as
      well as under Mr. Moro's shoes, supporting proximity of a beach. Pollen analysis
      showed that adhesion of volcanic soil to the car fenders antedated adhesion of
      the sand.

PMID- 10408124
TI  - Three fatalities involving phosphine gas, produced as a result of methamphetamine
      manufacturing.
AB  - In August of 1996, Sheriff's deputies investigated the deaths of three
      individuals suspected to have been overcome by phosphine gas. Phosphine is an
      extremely toxic gas, and is generally seen in the farming industry where it is
      used as a grain fumigant. It can also be generated as a by-product during the
      manufacturing of methamphetamine. Chemicals and equipment consistent with the
      manufacturing of methamphetamine were noted at the location, as well as an
      apparent reaction mixture heated to near dryness. Drager tubes detected an
      atmospheric phosphine concentration in excess of 0.3 parts per million (ppm), the
      Threshold Limit Value. Deputies had initially assessed the scene with no
      protective equipment, raising concerns about phosphine toxicity and the effects
      of exposure. The objectives of this paper are to describe how phosphine is formed
      during the manufacture of methamphetamine, to review the toxicity, health effects
      and symptoms of exposure, to address the safety concerns regarding potential
      exposure to law enforcement personnel, and to describe the protective equipment
      available for personnel who respond to clandestine laboratories.

PMID- 10408123
TI  - Postmortem diagnosis of unsuspected diabetes mellitus established by
      determination of decedent's hemoglobin A1c level.
AB  - Although approximately 15.7 million Americans have diabetes mellitus, with the
      vast majority having type 2 diabetes, it is estimated that as many as 5.4 million
      are undiagnosed. The present case illustrates that undiagnosed diabetes can be a
      factor in otherwise unexplained deaths. A 39-year-old white male with no
      significant past medical history other than alcohol abuse was found deceased at
      his residence. The manner of death appeared to be natural, but no anatomic cause
      was found. Toxicological analysis revealed a blood ethanol level of 0.02 g/dL and
      was negative for drugs of abuse. Analysis of the vitreous fluid revealed a
      glucose level of 502 mg/dL. The blood glucose level was 499 mg/dL, and the
      hemoglobin A1c (HbA1c) level was 10.6%. Only trace urine ketones were detected,
      suggesting that the death was the result of hyperglycemic hyperosmolar non
      ketosis (HHNK) from unsuspected diabetes. The postmortem HbA1c value serves as a
      definitive indicator of prolonged hyperglycemia. In order to aid the
      interpretation of the clinical data, this case is discussed in conjunction with a
      similar case of a known diabetic patient.

PMID- 10408125
TI  - Prediction of the dermal penetration of polycyclic aromatic hydrocarbons (PAHs):
      a hierarchical QSAR approach.
AB  - Attempts were made to develop hierarchical quantitative structure-activity
      relationship (QSAR) models for the dermal penetration of polycyclic aromatic
      hydrocarbons (PAHs) using four classes of theoretical structural parameters;
      viz., topostructural, topochemical, geometric, and quantum chemical descriptors;
      and physicochemical properties such as molecular weight (MW) and lipophilicity
      (log P--octanol/water). The results show that topostructural, topochemical, and
      geometric descriptors and molecular weight are equally effective in predicting
      the dermal penetration of PAHs. Quantum chemical parameters did not make any
      improvements in the predictive power of the QSAR models.

PMID- 10408126
TI  - Molecular search of new active drugs against Toxoplasma gondii.
AB  - Molecular connectivity has been applied to the search of new compounds with
      activity against the protozoan Toxoplasma gondii, using a stepwise linear
      discriminant analysis (SLDA) which is able to classify a compound according its
      activity either as active or as inactive. Among the selected compounds,
      andrographolide and dibenzotiophene sulfone stand out, both with IC50 values
      lower than 1 microgram/ml, which are comparable to these of drugs such as
      sulfamethoxazole, pyrimethamine and trimethoprim, with IC50 values equal to 1.1,
      0.04 and 2.31 micrograms/ml, respectively. These results confirm the usefulness
      of our topological approach for the selection and design of new-lead drugs active
      against Toxoplasma gondii.

PMID- 10408127
TI  - [The role of nurse anesthetist in Taiwan (questionnaire report)].
AB  - BACKGROUND: Anesthesia as a specialty was introduced to Taiwan for over 40 years.
      In early days, there were quite a number of nurse anesthetists who were trained
      to share the heavy burden of anesthetic work. However, due to the increasing
      demand for better anesthetic quality, the role of nurse anesthetists is open to
      discussion. METHODS: Questionnaires were sent to anesthesiologists working in
      medical centers, regional hospitals, and district hospitals. We hoped to find out
      the present working condition of nurse anesthetists and what their future role
      would be. RESULTS: Over one-half of the questionnaires collected agree that nurse
      anesthetists should not conduct anesthesia by their own, and that they should
      only help prepare patients and drugs for anesthesia. CONCLUSIONS: Anesthesia as a
      highly specialized field of medicine should be conducted by qualified and well
      trained anesthesiologists only. Training for nurse anesthetists should be
      confined to preparation of drugs and care of patients only.

PMID- 10408128
TI  - 8th European Symposium on Urolithiasis. Parma, Italy, June 9-12, 1999. Abstracts.

PMID- 10408130
TI  - [Primary care and family medicine].

PMID- 10408129
TI  - [Study of the diuretic efficacy and tolerability of therapy with Rocchetta
      mineral water in patients with recurrent calcium kidney stones].
AB  - The diluition of urine decreases the risk of stone formation by lowering the
      concentration of calcium, oxalate and uric acid, but involves a simultaneous
      decrease of the concentration of the inhibitors of crystallization. On the other
      hand the ion content of the drinking water used for stone prevention could by
      itself modify urine composition. We tested the effect of the administration of a
      mild-calcium high-bicarbonate content water on urine composition of a group of
      calcium renal stone formers. A group of 40 calcium renal stone formers was
      instructed to drink 3 l/day of a mild-calcium (57 mg/l) and high-bicarbonate (180
      mg/l) content water (Rocchetta) for a 7 day period. A 24-h collection was
      obtained before and after water administration for analyses of calcium,
      magnesium, oxalate and citrate. Urine volume was significantly increased after
      water administration (1601 +/- 357 vs 1878 +/- 339). Daily urinary calcium,
      magnesium and citrate were significantly increased, whereas daily urinary oxalate
      was unchanged after water administration. In conclusion the mild-calcium high
      bicarbonate content water administration seems suitable for stone prevention
      because of the increased excretion of urinary inhibitors counterbalancing
      increased urinary calcium excretion.

PMID- 10408131
TI  - [On the 15th anniversary of the Atencion Primaria journal].

PMID- 10408132
TI  - [Atencion Primaria journal in MEDLINE: an analysis of the first 7 years of
      indexing (1989-1995)].
AB  - OBJECTIVES: To evaluate the validity of the information of bibliometric interest
      retrieved from MEDLINE and referred to the articles published by Atencion
      Primaria journal from 1989 to 1995. To describe the presence of this journal and
      its evolution among the journals of its own thematic group (Family Practice)
      during the same period. DESIGN: Retrospective descriptive study. MATERIAL:
      MEDLINE database on SilverPlatter, 1997 edition. MEASUREMENTS: In a first step,
      all the documents published by the spanish journal during this period have been
      revised. Secondly, with a sample of 385 documents that comes from 24 issues
      selected at random, it has been analysed the indexing of the following fields:
      title in english (TI), original title (TO), authors (AU), bibliographic citation
      (SO), year of publication (PY), country of publication (CP) and type of
      publication (PT). The field institutional address of primary author (AD) will be
      studied exhaustively. The number of articles indexed coming from the different
      journals of the Family Practice group, and their evolution during the studied
      period were analysed, as the countries and languages of publication of these
      journals. The spanish journal has been compared with the rest of its thematic
      group in type of publications and type of studies (PT field). MAIN RESULTS:
      MEDLINE hasn't indexed 158 out of 1865 (8.47%) of the documents published by the
      journal from 1985 to 1995. This percentage becomes 4.04% when reply letters, that
      MEDLINE doesn't indexed, are not considered. MEDLINE offers the field AD for the
      papers published by the Spanish journal from 1990. From this moment on the field
      AD appears in 95% of the indexed documents. The 30% of the registers without the
      AD field, don't have institutional address in the original document. The
      institution or centre that MEDLINE cites firstly in the AD field, coincide with
      the one of the first author, in 99% of the cases. The number of authors is
      correct in all cases, even if in 3.37 +/- 1.8% there are typographical mistakes.
      TO, SO, PY and CP fields are always corrected. Nevertheless MEDLINE modifies in
      66.7 +/- 4.7% of the documents the english title (TI field). The presence of the
      spanish journal in the Family Practice group has continuously increased in global
      terms from its inclusion in MEDLINE database, even if its relative contribution
      has stayed the same, around a 14%, in the course of the period analysed. There
      are differences between the spanish journal and the rest of the journals of its
      thematic group in type of publications and type of studies. CONCLUSIONS: The
      analysis of the 7 first years of the Atencion Primaria indexing bring us to
      affirm that MEDLINE can be used to obtain valid information to describe some
      bibliometric aspects interesting for the scientific production, mainly coming
      from primary care spanish professionals, and published in this journal.
      Translations into english of the titles that appears in the english summary had
      to be improved. Institutional address had to be always and more clearly provided.
      The presence of the spanish journal among the journals of its thematic group is
      important (14%), even if its profile in type of publications and type of studies
      is significantly different.

PMID- 10408133
TI  - [Scientific production of Spanish professionals in primary health care (1990
      1997). A bibliometric analysis from MEDLINE].
AB  - OBJECTIVES: To describe the scientific production of primary care (PC) spanish
      professionals, during the current decade, using MEDLINE database. To identify
      which factors would explain the differences in the scientific production of PC
      professionals among Spanish autonomous communities (AACC). DESIGN: Retrospective,
      descriptive and analytical study. It has been designed a search strategy that
      will be used to retrieve this production from 1990 to 1997. MATERIAL: 1014
      documents published in 44 journals during the analysed period. MEASUREMENTS:
      Chronological evolution, authors, institutional addresses, geographic
      distribution, journals and thematic areas of this scientific production were
      analysed. The scientific production of any AACC was studied according to its
      socio-economic and human resources data. By uni and multivariant analysis we
      studied if the differences in PC professional's scientific production among the
      AACC are explained by socio-economic variables, available human resources and the
      degree of implementation of the new PC model in any AACC. MAIN RESULTS: During
      the studied period, it was detected from MEDLINE an increase in the scientific
      production of the spanish PC professionals, either in articles published by
      Atencion Primaria journal (73.7%), as in other Spanish journals (22.6%) and non
      Spanish (3.7%) journals. In 71.9% of the documents the first author comes from a
      primary care centre. The main thematic areas treated in the articles are family
      practice and primary care topics, but a quarter of them tackled clinical topics.
      The only variable that explained the differences in the scientific production of
      these professionals among AACC was the bigger or lower increment of people
      covered by the new PC model in any AACC during the analysed period. This variable
      only explained 20% of the variability. The level of provincial income was
      significantly and inversely correlated with its scientific production.
      CONCLUSIONS: It can be set the suitability of MEDLINE for bibliometric studies of
      the scientific production of the spanish PC professionals. In global terms it has
      been detected an increment of this production. The degree of implementation of
      the new PC model in any AACC, has partially explained the differences in the
      scientific production of their PC professionals.

PMID- 10408134
TI  - [Duration of the editorial process of the Atencion Primaria journal].
AB  - OBJECTIVE: To quantify how long the different steps in the process of editing the
      manuscripts received by the journal Atencion Primaria took. DESIGN:
      Retrospective, descriptive study. SETTING: The journal Atencion Primaria.
      PARTICIPANTS: Manuscripts submitted for publication in the sections Original
      articles, Short articles and Letters to the Editor between January 1 and June 30
      1997 (6 months). MEASUREMENTS AND MAIN RESULTS: Retrospectively, information was
      collected on the dates of receipt, of sending out to referees, receipt of their
      views and comments, sending back to the authors, receipt of their modified text
      or reply, of final decision on acceptance or rejection, and of publication if
      accepted. Of the 132 original and short articles received, 22 (16.7%) were
      awaiting a final decision. Of the remaining 110, 53 (48.2%) had been rejected and
      57 (51.8%) accepted. The length of each step in the editorial process was less
      than 30 days for half the manuscripts. The time elapsed from receipt to editorial
      decision was less than 45 days in half the cases and 60 days on average. The time
      from acceptance to publication was 137 days on average. CONCLUSIONS: How long
      each step in the editorial process took can be considered acceptable, although
      the wide variability in the times taken by authors to modify their manuscripts is
      striking. Mechanisms must be sought to avoid the excessive delay in the
      publication of research, by increasing the speed of the referees' reviews and of
      authors' modifications.

PMID- 10408135
TI  - [Development of the semFYC. A 15-year journey].

PMID- 10408136
TI  - [15 years of family medicine, 15 years of the Atencion Primaria journal (1984
      1999)].

PMID- 10408137
TI  - [The training of the family physician].

PMID- 10408138
TI  - [Professional competence of the family physician in Spain].

PMID- 10408139
TI  - [Investigation and primary care].

PMID- 10408140
TI  - [Demanding patients, competent professionals, and clinical managers: keys of
      primary health care in the Twenty-First Century].

PMID- 10408141
TI  - Tumor necrosis factor inhibitors for rheumatoid arthritis.
AB  - Tumor necrosis factor antagonists such as infliximab and etanercept represent a
      new and powerful approach to managing RA. In studies published to date, TNF
      antagonists appear to be safe and effective agents for short-term therapeutic use
      in RA. Defining when in the course of RA to use TNF antagonists and determining
      the effectiveness of combinations of these biologic agents with DMARDs or other
      cytokine antagonists are areas of current and future studies. Other cytokine
      antagonists that may be promising subjects for further study are IL-1
      antagonists. Like TNF, IL-1 is a member of the inflammatory cascade, but may play
      a different role in the development of inflammatory arthritis. In animal models,
      inhibition of TNF suppressed the inflammatory response while IL-1 antagonism
      prevented joint destruction (2). These results imply that combination therapy
      providing inhibition of both IL-1 and TNF might be an effective treatment in
      humans with RA, but clinical trials in humans have not yet been performed.
      Studies are underway in people with early RA to determine if the new TNF
      inhibitors are more effective or safer than currently available therapies, such
      as methotrexate. Other agents that inhibit TNF activity are also being tested at
      this time in people with RA.

PMID- 10408143
TI  - [Active life expectancy in Germany].
AB  - Using the method of multistate life-tables, the article presents results on
      active life expectancy on the basis of the German Socio-Economic Panel Survey
      (SOEP). Different determinants of mortality and morbidity are revealed by event
      history analysis. Results show that men live a greater proportion of their lives
      without disability than do women. Results on the association between
      mortality/morbidity and socio-economic factors suggest that studies which usually
      focussed either on mortality or on morbidity cannot fully explain differences in
      active life expectancy.

PMID- 10408142
TI  - [Lymphomas and leukemias in population-related cancer registries in Germany].
AB  - BACKGROUND: A German Federal law enacted in 1995 aims at nation-wide cancer
      registration, the details of realization based on local regulations being left to
      the individual Federal states. The impact of different approaches and regulations
      on the results of registration was investigated at three well-established records
      in the Saarland, Hamburg and North-Rhine Westphalia, taking the group of lymphoma
      and leukaemia (ICD 200-208) taken as an example. MATERIAL AND METHODS: Incidence
      and mortality rates calculated by the record files for the period from 1987 to
      1994 were compared. The resulting mortality/incidence ratios were compared as
      well as the percentage of cases in each register with death certificates (DCO) as
      the only information source. RESULTS: There was a distinct increase of incidence
      rates visible in Hamburg and Munster. As far as the male patients was concerned,
      both records attained the level of Saarland at the end of the period. However,
      the leukaemia and lymphoma mortality figures for males and females was about 10%
      lower for Saarland than in the comparative regions. The male mortality incidence
      ratio was 0.55 for Saarland versus 0.60 average in Hamburg and Munster at the end
      of the period. In Saarland and Hamburg there was a decrease of DCO-cases from 14%
      to less than 6% in 1994. More constant values around 11% could be observed in the
      Munster registry. The distribution of diagnosis within the group as well as age
      specific incidence rates for the selected diagnosis "lymphatic leukaemia" (ICD
      204) and "Hodgkin's disease" (ICD 201) yielded only slight differences.
      CONCLUSION: The increase of incidence rates in Munster and Hamburg indicates more
      complete reporting. Assuming that the survival rates are the same in the three
      regions, the lower mortality in Saarland points to lower morbidity. Hence in
      spite of a definite approximation the cancer registries in Hamburg and Munster do
      not reach the level of completeness of the Saarland cancer registry. This may be
      due to the informed patient consent required by regional law for reports to the
      registry. To achieve completeness a special reporting procedure for pathological
      and haematological Institutes is mandatory. Simple indicators should be available
      in each registry for continuous estimation of completeness. Standardised case
      definitions and rules for the coding of diagnosis in cancer registries will
      improve national and international comparability and feasibility of data
      exchange.

PMID- 10408144
TI  - [ENT expert assessment for federal health insurance in North Rhine. A
      contribution to the internal discussion of quantitative and qualitative
      optimization of the expert witness process].
AB  - Contribution to an Internal Discussion on Quantitative and Qualitative
      Optimisation of Expertising Procedures: The medical advisory and expertising
      Services of the German statutory sickness insurance are according to German
      social legislation authorised to request supporting documents direct from the
      treating physicians or hospitals. The consultant medical expertiser for ENT
      diseases at Cologne worked out the percentage of requests that resulted in
      "further investigations" and the amount of work involved. A document form was
      used to record all such requests for a given period. 154 expertising procedures
      concerning ENT diseases were counted within a period of 5 weeks. 47% of the
      patients concerned pertained to workers' sickness insurance funds and 29% to
      guilds sickness insurance funds. Two thirds of all requests were channelled
      through the statutory sociomedical preconsultant service and one-third were sent
      by post. 55% of all the requested documents were considered to be "complete" and
      45% "incomplete". N = 100 requests were initial and N = 54 were follow-up
      requests. The answers received were considered satisfactory and final in 62% of
      the requests, whereas "further inquiries" were considered necessary in n = 58
      (38%) of the cases. 80% of the cases in which the requests resulted in
      satisfactory information, were approved for sickness insurance payment and
      approximately 20% were rejected. The average period of time that elapsed between
      a request for more information and the reply and the final expertising given to
      and passed on to the patient by the statutory insurance body was 2 weeks. In
      cases where "further inquiries" are considered necessary, three additional
      working days are usually required in the Cologne ENT diseases area. If the
      statutory sociomedical preconsultant service procedure could be intensified, this
      would result in better channelling of requests by the ENT medical and advisory
      service of the stautory sickness insurance bodies. A more pronounced examination
      by the statutory sociomedical preconsultant service could minimise the need for
      additional requests, follow-ups and "further inquiries" and could increase the
      speed of completion of approved or rejected insurance cases from 14 days to at
      the most one day or even 0 days. This pilot study was conducted to encourage the
      local bodies to optimise their work. In the long run good quality of work,
      patient satifaction and patients' job security will result and will be the corner
      stones of modern quality assurance and quality management in North-Rhine
      Westphalian medical expertising and consultant services in association with the
      relevant statutory sickness insurance bodies.

PMID- 10408145
TI  - [Conditions for medical disability according to section 125 SGB III].
AB  - The section 125 of the German Social Statute Book No. III (unemployment
      insurance) determines the conditions for an unemployed insured person who is
      unable to work due to a disease. Ascertainment of the existence of the medical
      conditions governed by section 125 is not only a task for the physicians of the
      unemployment insurance, it is also a task for the doctors of the pension
      insurance and of the health insurance. Hence it is very important that all
      medical experts of social insurances are in consensus in view of these medical
      requirements. In this paper the medical conditions for section 125 are described:
      The disease must be so serious that the unemployed insured person will be unable
      to return to work within the next six months. The inability to work will be
      continuous. In this case the unemployment insurance continues to pay unemployment
      benefit in spite of the inability to work until the pension insurance body agrees
      to pay a pension.

PMID- 10408146
TI  - [Comparative presentation of current economic evaluation studies for
      phenylketonuria screening].
AB  - A systematic review was undertaken to assess the economic value of PKU screening
      in the framework of newborn screening for inborn errors of metabolism. Therefore,
      seven international studies on this topic were connected and examined with regard
      to differences and similarities. The relation between costs and benefits of PKU
      screening programmes goes from 1:1,2 up to 1:9,25. The differences can be
      explained by varying incidence of PKU (in international comparison) and
      particularly by methodical differences in the respective study designs. This
      aspect is pointed out while taking up and emphasising the necessity of
      standardisation in economic evaluation studies. Furthermore, future developments
      (chances, trends, changes) in newborn screening are discussed, based on the
      potential use of new technologies.

PMID- 10408147
TI  - [Social work in public health service as reflected by selected studies--a
      description of current status].
AB  - First of all the author gives a historical review of the importance of social
      work in public health service. The complementary cooperation between medical
      doctors and social workers is also described. The author then examines the
      activities of social workers in public health service on the basis of selected
      journals and the titles of these papers by graduates from medical "officer of
      health" courses of the Akademie fur offentliches Gesundheitswesen Dusseldorf. The
      results show that social work is still a part of counsel and care by the pubic
      health service. Offers for new target groups are suggested. Another important
      aspect is the cooperation with other interest groups such as resident doctors or
      institutions outside the public health office. Better presentation of the
      profession of social workers is also an important issue.

PMID- 10408148
TI  - [Quality and identity of terminal care in the hospital exemplified by the SPES
      VIVA Palliative Project].
AB  - In an attempt to contribute to the improvement of fatally ill and dying patients
      in hospitals, the palliative care project SPES VIVA represents a model scheme by
      a care concept of contents, personal and spatial definitions [3]. In order to
      receive an indirect expert verification of success, doctors and nurses of our
      hospital and of another one were interrogated during the same period. Although we
      know of the problems inherent in the method, a total of 158 voluntar participants
      in the study enabled US to compare the results of a preceding poll by W. George
      et al. of 1988 [2] to prove at least some effects. The SPES VIVA work enhanced
      the identification of the employed with their work and gave us hints on how to
      improve the situation of dying patients in our hospital. In comparison with the
      group of doctors, nurses more often tend to see "too many life-prolongation
      measures".

PMID- 10408150
TI  - [Increasing personal responsibility as a public health goal].
AB  - Self-management as one of the central categories of public health needs special
      factors to be promoted which will enable people to become independent, self
      responsible and self-confident. This will succeed under the condition that
      patient autonomy is promoted, the predominant biomedical model of disease is
      developed further and health politics is understood as part of comprehensive
      social politics. Increased individual responsibility will only then be capable of
      bearing and stable in future if the entire social network is included into the
      promotion of health-related behaviour.

PMID- 10408149
TI  - [Transmission of infectious diseases during imprisonment--results of a study and
      introduction of a model project for infection prevention in Lower Saxony].
AB  - The increasing imprisonment rate of drug users is linked to a spread of
      infectious diseases in prisons (HIV and Hepatitis B and C). Several studies
      indicate a close correlation of imprisonment and transmission of infectious
      diseases. An analysis of international studies showed that worldwide in several
      cases transmissions of HIV-infection during imprisonment have been discovered.
      The cross-sectional examination presented here is describing the situation in the
      women's prison of Vechta (Lower-Saxony). Empirical data on the prevalence of
      infections with HIV, HBV, HCV and Lues of the years 1992 to 1994 were recorded.
      Moreover the scientific interest also included on the diagnosis of
      seroconversions. Discovered seroconversions were examinated on a possible
      transmission in custody. The spread of infectious diseases in prisons led to the
      demand for an alignment of internal drug aid services with external, tried and
      tested prophylaxis models. The availability of sterile syringes is included. The
      basic comparability of health care inside and outside prison (principle of
      equivalence) is not only demanded and recommended by the prison law [4] but also
      by international organisations [27]. As the first provencial government, the
      state of Lower Saxony in Germany has started to develop infection prophylaxis
      offers in two prisons (in the women's prison in Vechta since April 15th 1996 and
      in the men's prison of Lingen I, department Gross Hesepe since July 15th 1996) in
      1996. These offers include the provision of sterile injection equipment to
      intravenous drug addicts (ivDA). Modalities of the practice and first experiences
      documented by the schientific evaluation are presented.

PMID- 10408151
TI  - Possible role of bradykinin on stimulus-secretion coupling in adrenal chromaffin
      cells.
AB  - Nonapeptide bradykinin is known to be a central nervous system neurotransmitter
      and to play a role in regulation of neuronal function. However, few details are
      known of the function of its peptide on stimulus-secretion coupling in neuronal
      cells. In this article, the role of bradykinin on catecholamine biosynthesis,
      secretion and Ca2+ movement in adrenal chromaffin cells as a model for
      catecholamine-containing neurons are examined. Bradykinin receptors are
      classified as B1 and B2 receptor subtypes. These receptors are present on the
      adrenal chromaffin cell membrane. Bradykinin increases the influx of Ca2+ and the
      turnover of phosphoinositide through the stimulation of bradykinin B2 receptor.
      The secretion of catecholamine from the cells is initiated by the raise of
      [Ca2+]i. An increase in [Ca2+]i and production of diacylglycerol stimulate the
      activation of calcium-dependent protein kinases. These kinases stimulate the
      activation of tyrosine hydroxylase, a rate-limiting enzyme in the biosynthesis of
      catecholamine. Otherwise, bradykinin increases Ca2+ efflux from the cells through
      the stimulation of the bradykinin-B2 receptor. This action may be explained by an
      extracellular Na(+)-dependent mechanism, probably through acceleration of
      Na+/Ca2+ exchange. It is interesting that bradykinin, which stimulates the
      biosynthesis and secretion of catecholamine in adrenal chromaffin cells, plays a
      role in the termination of calcium-signal transduction through the stimulation of
      Ca2+ efflux from the cells.

PMID- 10408152
TI  - Why does arterial blood pressure rise actively during REM sleep?
AB  - A large fluctuation in autonomic function is one of the most important
      characteristics of REM sleep. Arterial blood pressure (AP) increases during the
      transition from non-REM to REM sleep, showing phasic surges during REM sleep. REM
      associated AP changes involve 1) a long-term recovery process after surgery, 2)
      circadian rhythm, 3) relationships with ambient temperature. REM-associated AP
      changes are mediated by sympathetic nerves, buffered by baroreflex, abolished in
      decerebrated cats, and related to hippocampal theta activity in rats.
      Furthermore, the midbrain dopaminergic system has been recently found to be
      involved in increases in REM-associated AP.

PMID- 10408153
TI  - Antisperm antibody: a monkey wrench in conception/magic bullet of contraception?
AB  - Antisperm antibodies can cause infertility by interacting with spermatozoa
      through immunoglobulin binding protein thereby blocking their penetrance of
      cervical mucus and/or by interfering with sperm-egg interaction. However, these
      antibodies appear not to be cytotoxic to embryos since a high implantation rate
      and consequently high pregnancy rate were achieved by IVF-ET treatment of women
      with antisperm antibodies. Also the finding that these antibodies do not appear
      to cause any deleterious clinical symptoms and have yet be associated with
      infertility suggested that sperm antigens are promising candidates in the
      development of immunocontraceptives. Some synthetic peptides corresponding to
      segments of human sperm antigens have effectively induced infertility in female
      rats when administered as an immunogen. Different peptides, adjuvants and routes
      of administration should be studied to determine the optimum conditions for
      inducing high antisperm antibody titers in the host. Moreover, identification of
      various steps and factors that are involved in regulating the production of
      antisperm antibodies such as immunoglobulin binding factor may open new paths in
      the treatment of immunological infertility and at the same time lead to a more
      effective immunocontraceptive.

PMID- 10408154
TI  - Effects of vitamin E and vitamin C supplementation on plasma lipid peroxidation
      and on oxidation of apolipoprotein B-containing lipoproteins in experimental
      hyperthyroidism.
AB  - Increasing numbers of experimental and epidemiological studies suggest the
      involvement of free radicals in the pathogenesis of various disease entities.
      Similarly, oxidative processes have been implicated as playing roles in the
      genesis of hyperthyroidism-induced damage. In this study, we investigated the
      effects of vitamin E and vitamin C on plasma lipid peroxidation and the
      susceptibility of apolipoprotein B (apo B)-containing lipoproteins to oxidation
      in experimental hyperthyroidism. The study animals were initially divided into a
      control group (Group C) and a hyperthyroid group. The latter was further re
      grouped later according to their vitamin supplementation status: Hyperthyroid
      group without vitamin supplementation (Group H), hyperthyroid group with vitamin
      E supplementation (Group H+E) and hyperthyroid group with vitamin C
      supplementation (Group H+C). Malondialdehyde (MDA) level was measured as an
      indicator of plasma lipid peroxidation. The apo B-containing lipoproteins were
      separated by precipitation and incubated with copper sulphate. The MDA levels of
      this non-HDL fraction were measured prior to and after 1, 2 and 3 hours of
      incubation. Plasma MDA levels showed no significant differences among groups.
      Whereas MDA levels measured in non-HDL fraction were significantly higher in
      Group H than Group C. Group H+E and Group H+C had significantly lower MDA levels
      than Group H in all these measurements. This finding strongly indicates an
      increased susceptibility of apo B-containing lipoproteins to oxidation in
      hyperthyroidism, and that vitamin E as well as vitamin C supplementation protect
      these lipoproteins from copper-induced oxidation.

PMID- 10408156
TI  - Growth characteristics of T-cell tropic HIV-1 vpu gene mutants in human
      peripheral blood mononuclear cells.
AB  - A mutant designated NL-E65, which lacks the expression of entire vpu gene, was
      constructed from T-cell tropic wild-type (wt) human immunodeficiency virus type 1
      (HIV-1) clone and monitored for its replication property in human cells, along
      with a mutant NL-Ss which expresses a C-terminal truncated Vpu. The mutant NL-Ss
      could grow in two cell lines and in all peripheral blood mononuclear cell (PBMC)
      preparations to some extent, with kinetics similar to those of wt virus.
      Likewise, the mutant NL-E65 exhibited a replication property typical to the vpu
      mutant in the two cell lines and in all PBMC cultures, growing at a low level.
      Along with the results previously reported, these data indicate that HIV-1 Vpu is
      dispensable for virus replication in any of the types of cells so far tested.

PMID- 10408155
TI  - Biologic markers in prostatic intraepithelial neoplasia: immunohistochemical and
      cytogenetic analyses.
AB  - OBJECTIVE: We evaluated the biological properties of High-grade prostatic
      intraepithelial neoplasia (PIN) by immunohistochemistry and fluorescence in situ
      hybridization (FISH) analysis in relation to normal tissue and carcinoma lesions.
      MATERIALS AND METHODS: Immunohistochemical staining and FISH were performed on 23
      formalin-fixed radical prostatectomy specimens taken from patients with PIN.
      Assays were performed using MIB-1, chromogranin A (CGA) and an anti-androgen
      receptor antibody (AR). A centromere probe for chromosome 8 was used to test for
      aneuploidy. RESULTS: The MIB-1 index of cancerous specimens (16.2 +/- 10.5%) was
      significantly higher than that of benign (1.9 +/- 1.6%, p < 0.0001) or PIN (4.0
      +/- 4.5%, p < 0.0001) specimens. The percentage of CGA positive cells was
      significantly lower in normal tissue (1.2 +/- 1.8%) than in PIN (3.5 +/- 2.9%, p
      = 0.012) or carcinoma (5.4 +/- 4.9%, p = 0.005) lesions. Positive staining for AR
      was consistently observed in the nuclei of both benign and malignant epithelial
      cells, but positive cytoplasmic staining was also seen in PIN epithelial cells.
      No significant difference in FISH detected anomalies were found between PIN and
      carcinoma specimens. CONCLUSIONS: Our studies concerning proliferative activity,
      NE differentiation and chromosomal anomalies of prostatic specimens support the
      hypothesis that PIN is a biologically intermediate stage in the pathogenesis of
      prostatic carcinoma. The cellular distribution of AR was altered in PIN cells,
      but the role of AR in PIN is not yet clear.

PMID- 10408157
TI  - The utility and limitations of an ultrasonic miniprobe in the staging of gastric
      cancer.
AB  - To determine the utility and limitations of an ultrasonic miniprobe (UMP) in the
      staging of gastric cancer, we evaluated 46 patients who underwent endoscopic
      ultrasonography (EUS) using an UMP and who were histologically determined to have
      gastric cancers. In every case, UMP findings were compared with histopathological
      findings after treatment. The total accuracy of UMP relative to the depth of
      tumor invasion was 71.7% (33/46 cases). Accuracy with respect to T1-m tumor
      diagnosis was 75.7% (22/29 cases), and for T1-sm, 76.9% (10/13 cases), but
      accuracy for T2 tumor diagnosis was low, due to ultrasound attenuation. When the
      analysis was carried out based on the size of tumor, the accuracy for UMP was
      50.0% (9/18 cases) for all tumors over 20 mm and 85.7% (24/28 cases) for all
      tumors smaller than 20 mm. We conclude that UMP is suitable for investigation of
      tumor extension when the lesion is superficial and/or small gastric cancers which
      do not cause ultrasonic attenuation, but not when the tumor is large or located
      in certain sites, although conventional EUS is useful in some of these cases.

PMID- 10408158
TI  - Prevention of the initial testosterone surge induced by a luteinizing hormone
      releasing hormone analogue in prostate cancer patients: the endocrinological
      effects of pretreatment with chlormadinone acetate.
AB  - We investigated the endocrinological effects of pretreatment with chlormadinone
      acetate (CMA) in preventing the initial testosterone surge induced by a
      luteinizing hormone-releasing hormone (LH-RH) analogue. A total of 25 patients
      with previously untreated prostate cancer were included in this study. The
      patients were randomly assigned to 2 treatment groups: Group 1; CMA therapy was
      begun 4 weeks before the initial LH-RH analogue injection. Group 2; CMA therapy
      was begun 2 weeks before the initial LH-RH analogue injection. After the initial
      LH-RH analogue injection, CMA was administered during this study. After LH-RH
      analogue application, the mean values of serum luteinizing hormone (LH) and
      testosterone increased in both groups on day 3. However, LH and testosterone
      levels remained beneath pretreatment values in both groups. The mean relative PSA
      levels did not significantly increased on day 3 and day 7 in both groups. Our
      results indicate that pretreatment with CMA for 2 weeks was sufficient to prevent
      the initial testosterone surge in the maximal androgen blockade which was
      associated with CMA.

PMID- 10408159
TI  - Surgical management of infants with mitral valve stenosis or atresia without
      diminutive ascending aorta.
AB  - The surgical strategy in infants with mitral valve stenosis or atresia without
      diminutive ascending aorta remains to be established, including the potential for
      biventricular repair as a definitive operation. Our surgical experience of six
      infants with mitral valve stenosis (4 patients) or atresia (2 patients) without
      diminutive ascending aorta was evaluated based on three important factors: left
      ventricular volume; the nature of the systemic outflow obstruction; and the type
      of mitral valve anomaly. Two patients with systemic outflow tract diameter less
      than 65% of normal underwent systemic outflow tract reconstruction, and the other
      patients with outflow tract diameter more than 68% of normal were able to
      maintain systemic circulation without repair. Only one patient with mitral valve
      stenosis without left ventricular outflow tract obstruction underwent a
      successful open mitral valvotomy as a biventricular repair after first-stage
      palliation. The left ventricle of the other patients did not grow after first
      stage palliation. Due to progressive subaortic narrowing, pulmonary artery
      banding should be avoided in patients with mitral atresia due to absent
      atrioventricular connection who are future Fontan candidates. Most patients with
      this lesion can be expected to become candidates for safe Fontan-type repair.

PMID- 10408160
TI  - Effect of freeze-dried soybean curd (tofu) on various bodily functions.
AB  - The present study was designed to examine the effect of freeze-dried soybean curd
      (tofu) on various bodily functions. The dietary experiment consisted of 4 days of
      a non-prescribed ordinary diet, 10 days of an experimental diet that contained
      190 g of meat contributing about 38 g of protein (hereinafter referred to as the
      "meat period"), and 39 days of an experimental diet that contributed vegetable
      protein, i.e., freeze-dried tofu, corresponding to the protein that 190 g of meat
      would provide (hereinafter referred to as the "freeze-dried tofu period"). Three
      eggs (about 150 g) and 180 ml of cow's milk were prescribed for the daily diet,
      and staple and other foods were dispensed freely during both the meat and the
      freeze-dried tofu periods. The results showed that serum cholesterol levels and
      diastolic blood pressure significantly decreased in the freeze-dried tofu period
      as compared with the meat period. Freeze-dried tofu was found to be a valuable
      food for preventing lifestyle-related chronic diseases.

PMID- 10408161
TI  - Usefulness of the zung self-rating depression scale for schizophrenics.
AB  - OBJECTIVE: This study was performed to provide psychometric data concerning the
      Zung Self-Rating Depression Scale (SDS) when administered to schizophrenics.
      METHODS: The subjects were 110 schizophrenic inpatients (50 females and 60 males)
      who were diagnosed according to the DSM-IV criteria for schizophrenia. Informed
      consent was obtained from all subjects. RESULTS: 1) Cronbach's alpha for the SDS
      was .81, and reached the acceptable range for internal consistency. 2) Test
      retest reliability coefficient for the total SDS was comparatively high
      (Spearman's rho = .87, p < .001, N = 19), but those for SDS items revealed
      variability among items. 3) The mean total SDS score for the 15 patients with
      depression was significantly different from the group of patients without
      depression. 4) None of the 20 items or total SDS was significantly correlated
      with extrapyramidal symptoms. CONCLUSIONS: Overall, the findings demonstrate the
      usefulness of the SDS for schizophrenics. However, due to findings of mixed
      reliability, caution should be exercised when using the SDS for these patients.

PMID- 10408162
TI  - Relationships between activity of daily living, and oral cavity care and the
      number of oral cavity microorganisms in patients with cerebrovascular diseases.
AB  - We examined the relationships among the activity of daily living (ADL), oral
      cavity care, and the number of oral cavity microorganisms in 40 patients with
      cerebrovascular diseases (CVD). The CVD patients were classified into 4 groups,
      I, II, III and IV based on their ADL and the method used for oral cavity care.
      The ADL was highest in group I and lowest in group III. Only the patients of only
      group III could not eat by themselves and were receiving naso-esophageal feeding.
      Oral cavity care was performed by the patients themselves in groups I and IV, but
      was performed by caregivers in groups II and III. The group IV patients had no
      teeth, but could eat by themselves using full dentures. The numbers of
      microorganisms in the pharyngeal swabs from the 4 groups were measured and
      expressed as colony-forming units (cfu). The numbers of both Staphylococci spp.
      and Candida spp. were significantly higher in group III than in the other groups.
      Moreover, Pseudomonas aeruginosa was isolated only from patients of group III (in
      about 66%). The oral cavity care by caregivers was almost the same in groups II
      and III, but the numbers of oral cavity microorganisms were significantly higher
      in group III than in group II. These results indicated that microorganisms grow
      more easily in the oral cavities of CVD patients with low ADL compared with CVD
      patients with higher ADL, and that eating is thought to be important for the
      prevention of an increase of microorganisms in the oral cavity.

PMID- 10408163
TI  - The N400 event-related potential in aphasia.
AB  - Although the N400 component of event-related potentials (ERPs) is suggested to
      reflect language processing, exactly which language processing functions N400 is
      sensitive to is not clear. We investigated this component in aphasic patients
      with some impairments of language processing. Meaningful and meaningless words in
      Kana (Japanese characters) were used as stimuli under a visual oddball paradigm.
      Increases in N400 latency and amplitude in the aphasic group were significant in
      comparison with the control group. In the aphasic group, N400 latency correlated
      significantly with the performance intelligence quotient employed besides
      language quotients. Moreover, the N400 effects were seen more clearly in the left
      hemisphere than in the right hemisphere for both groups. We propose that the
      abnormal variations in amplitude or latency of N400 in the aphasic group reflect
      language processing functions (controlled processing and automatic processing)
      that are different between slight and severe cases of aphasia. Moreover, N400
      effects are sensitive to intellectual abilities besides language ability. We also
      suggest that N400 effects in the left hemisphere for the aphasic group are a
      reflection of active language processing as the substitution function.

PMID- 10408165
TI  - Phantom steatosis of the liver: report of a case.
AB  - A patient, referred under a diagnosis of metastatic liver tumors, was found to
      have multiple areas of focal fatty change (FFC) which, during follow-up,
      exhibited discordant evolutions. To our knowledge, this phenomenon-regression of
      a FFC lesion with concurrent appearance or progression of other similar lesions
      in the same patient, has been reported in only one previous case. FFC can be
      strongly suggested by clinical, biochemical and radiologic criteria. However, an
      exact diagnosis can only be made with biopsy. To avoid misdiagnosing a malignancy
      as FFC and vice versa, biopsy should be performed without hesitation in all
      patients in whom a change in approach is possible.

PMID- 10408164
TI  - Long-term observation of subcutaneous tissue reaction to synthetic auditory
      ossicle (Bioceram) in rats.
AB  - To evaluate biocompatibility to tissue in long-term implantation, Bioceram discs
      made of aluminum oxide (Al2O3) were implanted subcutaneously within the
      interscapular region of 64 rats for six to 20 months. Histological sections
      stained with haematoxylin and eosin (H&E) and the surface of the implant material
      were observed using light microscopy. Different cell types and the thickness of
      fibrous capsules surrounding the implants were examined quantitatively by light
      microscopy. Small numbers of macrophages (2.8 +/- 0.7%) and lymphocytes (2.7 +/-
      0.9%) were observed at six months after implantation, gradually decreasing to
      zero at 16, 18 and 20 months. Neither neutrophils nor foreign body giant cells
      were seen in any specimens. The thickness of fibrous capsules surrounding the
      implants was closely related to the shape of the implant, but there was no
      significant change between six and 20 months after implantation. No change in
      Bioceram surfaces were observed under stereoscopic microscopy from six to 20
      months after implantation. The study results indicate that Bioceram is a
      satisfactory biocompatible material for reconstructive surgery from the viewpoint
      of long-term tissue response. Present results of experiments with Bioceram are
      also compared to previous results with Apaceram and different tissue responses of
      the two materials are discussed.

PMID- 10408166
TI  - Cognitive behavioral approaches to the patients suffering from depression due to
      maladjustment in the work place: two case reports.
AB  - The authors report two cases of depression in which Beck's cognitive therapy was
      effective. Case 1 was a 32-year-old man who had been troubled with the recurrent
      depression for about eight years in spite of regular medication. Case 2 was a 30
      year-old man who had been chronically depressed for one year. Maladjustment in
      the work place was involved in the development of their depressive symptoms.
      Through the psychotherapeutic sessions, they were encouraged to identify their
      cognitive distortions such as emotional reasoning, all-or-nothing thinking and
      disqualifying the positive, and assisted to modify their cognitive distortions by
      means of cognitive behavioral techniques. Gradually gaining self-efficacy, they
      became able to cope well with their present problems. Both of them finally
      recovered from depression and, especially in case 1, he could overcome
      recurrence. The active ingredients in successful cognitive therapy were
      discussed. It was also stressed that the capacity to be sufficiently
      introspective to identify negative automatic thoughts and to be sufficiently
      logical to understand how the thoughts are distorted was requisite for this
      therapy.

PMID- 10408168
TI  - Low morale in the British National Health Service (NHS): the causes and some
      proposals for improvement. NHS Consultants' Association.

PMID- 10408167
TI  - One autopsy case of an elderly traffic accident victim with tetralogy of Fallot.
AB  - The case of a 61-year-old male traffic accident victim with Tetralogy of Fallot
      (TOF) is reported. The autopsy revealed massive hemorrhages in the subcutaneous
      tissue, muscle, and subarachnoidal space. Furthermore, multiple fractures of
      ribs, sternum and thoracic vertebrae were observed. Histopathological examination
      revealed changes characteristic of trauma, such as acute lung congestion, acute
      renal cortical necrosis, and embolization in the lungs and kidney. These autopsy
      and histological observations indicated that traumatic shock was cause of his
      death. Moreover, histologically, we observed changes due to his congenital heart
      disease, such as right ventricular hypertrophy, heart failure cells in the lungs,
      sclerosis of the liver, and hyaline degeneration in the kidney. Furthermore,
      ischemic changes, shrinkage or loss of neurons, were seen in hippocampus, and
      swelling of astrocytes in both cortex and hippocampus were also observed. These
      observations lead us to speculate that a hypoxic episode may have caused his
      accidental death while driving.

PMID- 10408169
TI  - The reform of the reform of the British National Health Service.
AB  - Beginning with a reminder of the main features and effects of the profound
      changes to the NHS made by the Conservative government in 1990, this account then
      reviews the incoming Labour government's proposals as set out in the White Paper
      "The New NHS." An analysis, based on the formal response of the NHS Consultants'
      Association to the White Paper, welcomes many of the new initiatives but shows
      how the Conservative "Internal Market" is being modified, not removed, and the
      proposals fall short of restoring the public service ethos. In conclusion, the
      arguments and strategy being employed by the Association are described.

PMID- 10408170
TI  - The neoliberal triad of anti-health reforms: government budget cutting,
      deregulation, and privatization.
AB  - This paper presents the author's experiences and perceptions of the neoliberal
      triad of anti-health reforms--government budget cutting, deregulation, and
      privatization--which have been promulgated worldwide by the World Bank and the
      International Monetary Fund. The causes of this phenomenon are analyzed, and
      specific alternative health policies are recommended. The role of epidemiology in
      documenting the damages to health resulting from the anti-health reforms is
      discussed. Finally, the paper emphasizes the need not only for national
      organizational strategies but for action on the international level. The
      opponents of privatization need to meet together, to exchange experiences, and to
      develop effective strategies on a world scale that can be applied in industrial
      and developing nations.

PMID- 10408171
TI  - Policy options for prevention: the case of alcohol.
AB  - Reducing the availability of alcohol through alcohol control policies such as
      excise taxes and the minimum legal drinking age has been effective in reducing a
      wide range of alcohol-related problems, including traffic crashes, liver
      cirrhosis, and violence. Alcohol control policies may be classified into two
      overlapping categories--public and institutional policies. Some policies such as
      alcohol server training may be either mandated by governmental jurisdictions or
      voluntarily adopted by individual institutions, which include alcohol retail
      establishments, other businesses, worksites, schools, colleges/universities, law
      enforcement agencies, religious institutions, insurance agencies, and alcohol
      producers. Public policies may be mandated by national, state/provincial, or
      local governments to regulate where, when, and how alcohol is sold and consumed.
      This paper describes the wide array of public and institutional policies
      available to reduce alcohol-related problems. Summaries of research evaluating
      specific alcohol control policies are provided when available.

PMID- 10408172
TI  - Charles V. Chapin (1856-1941), "Dean of City Health Officers".

PMID- 10408173
TI  - Detection of chromatin-bound PCNA in mammalian cells and its use to study DNA
      excision repair.
AB  - Compelling evidence indicates that proliferating cell nuclear antigen (PCNA) is
      an indispensable factor not only in DNA replication but in nucleotide excision
      repair (NER), alternative pathway of base excision repair (BER), and mismatch
      repair. The common function of PCNA in each of these is to assist in the
      initiation of DNA synthesis by providing a scaffolding clamp as a trimer
      catalyzed by RF-C at the 3'-OH terminus of a nascent DNA strand, to which DNA
      polymerase delta or epsilon can bind. Interestingly, DNA synthesis is reported to
      be ingeniously inhibited in replication, but not in NER owing to the interaction
      with CDKN1A (formerly known as p21/WAF1/CIP1). Furthermore, several proteins,
      XPG, FEN1, and DNA ligase I, recently were shown to competitively bind to the
      same region of PCNA, the interdomain connector loop, to which DNA polymerase
      delta or epsilon also binds. PCNA therefore seems to have a regulatory role in
      these DNA transactions. The in vitro reconstituted experimental system has been a
      powerful tool to obtain these lines of evidence, but another approach,
      immunofluorescence studies, also has been a contributor. In fact, the involvement
      of PCNA in DNA replication, NER, and BER has for the first time been indicated by
      a unique method that makes visible only in vivo chromatin-bound PCNA. The
      usefulness of this method and the importance of cooperative studies done with in
      vitro and in vivo experimental systems is discussed in terms of DNA excision
      repair.

PMID- 10408174
TI  - Long-term exposure to a magnetic field (5 mT at 60 Hz) increases X-ray-induced
      mutations.
AB  - Exposure to extremely low frequency magnetic field (ELFMF) at 400 mT has been
      shown to induce mutations (Mutat. Res., 349: 109-114, 1996; Int. J. Radiat.
      Biol., 71: 75-79, 1997; and Biochem. Biophys. Res. Commun., 243: 579-584, 1998).
      However, whether ELFMF at low flux densities (under 1 mT) induces mutations is
      debatable. We investigated the effect of long-term exposure to 5 mT ELFMF at 60
      Hz on mutant frequency. Chinese hamster ovary K1 (CHO-K1) cells were exposed or
      sham-exposed to 5 mT ELFMF for up to 6 weeks with or without X-irradiation (3
      Gy), and the mutant frequency of the hypoxanthine-guanine phosphoribosyl
      transferase (HPRT) gene was analyzed. Long-term exposure to 5 mT ELFMF did not
      increase mutations, suggesting a threshold for mutation induction greater than
      115 mA/m2 or a magnetic density of 5 mT. However, enhancement of the X-ray
      induced mutation rate was observed after treatment with X-irradiation followed by
      long-term exposure to 5 mT ELFMF. At little as a 1-week exposure to ELFMF after X
      irradiation enhanced the mutation rate. We also found that 400 mT exposure
      enhanced the mutation rate induced by X-irradiation (Mutat. Res., 349: 109-114,
      1996). These results suggest that exposure to more than 5 mT ELFMF may promote X
      ray-induced mutations.

PMID- 10408175
TI  - Effects of protein kinase inhibitors on the accumulation kinetics of p53 protein
      in normal human embryo cells following X-irradiation.
AB  - DNA-damaging agents induce phosphorylation of the p53 protein, resulting in its
      accumulation in the nucleus. To clarify the signal transduction pathway(s)
      involved in p53 protein accumulation in normal human embryo cells following X
      irradiation, the effects of three protein kinase inhibitors were examined.
      Quercetin, an inhibitor of heat-shock response, dose dependently suppressed the
      p53 accumulation induced by X-rays at more than 100 microM. No suppression,
      however, was observed with calphostin-C, a specific inhibitor of protein kinase
      C, in the range of 0.05 to 0.25 microM. Wortmannin was the most potent inhibitor
      of p53 accumulation. Its suppressive effect appears within a few minutes of
      pretreatment with a dose of 25 microM, but posttreatment was less effective. Our
      findings suggest that PKC is not involved in X-ray-induced p53 accumulation in
      normal human embryo cells and that a wortmannin-sensitive pathway acts as a
      sensor of DNA damage.

PMID- 10408176
TI  - Cloning of the oxidative stress-responsive genes in Caenorhabditis elegans.
AB  - Defense systems against free radicals and reactive oxygen species minimize the
      lethal and mutagenic consequences of these destructive agents. To investigate the
      genetic response to oxidative stress in a eukaryote, we cloned and characterized
      oxidative stress-responsive genes by comparing gene expression in the free-living
      nematode Caenorhabditis elegans under atmospheric conditions and high oxygen
      concentrations using a method of RNA arbitrarily primed polymerase chain reaction
      method (RAP-PCR). We identified four genes whose expression levels increase under
      high oxygen. These encoded 18 s, 5.8 s and 26 s rRNAs, 16 kDa heat shock proteins
      (hsp16-1 and 16-48) and a vacuolar ATPase G subunit. In addition, we also
      established that oxi-1, an oxidative stress-responsive gene we previously cloned,
      encodes a family of proteins related to human E6-AP ubiquitin-protein ligase. The
      similarity between human and nematode was 54% in one conserved amino acid region.

PMID- 10408177
TI  - High incidence of meningioma among Hiroshima atomic bomb survivors.
AB  - Since the atomic bomb explosions in Hiroshima and Nagasaki, high incidences of
      leukemia, thyroid cancer and other tumors have been reported as atomic bomb
      induced tumors. We investigated the incidence of meningioma among Hiroshima
      atomic bomb survivors. Sixty-eight patients surgically treated for meningioma who
      had been within 2.0 km of the hypocenter of the explosion were identified. Six
      hundred and seven non-exposed patients with meningioma were also studied.
      Treatment dates were from 1975 to 1992. The incidences of meningioma among 68
      subjects within 2.0 km and 607 non-exposed patients were 8.7 and 3.0 cases per
      10(5) persons per year, respectively. The incidences of meningioma among the
      survivors of Hiroshima in 5-year intervals since 1975 were 5.3, 7.4, 10.1, and
      14.9, respectively. The incidences of meningioma classified by distances from the
      hypocenter of 1.5-2.0 km, 1.0-1.5 km and less than 1.0 km were 6.3, 7.6 and 20.0,
      respectively. The incidences of meningioma classified by doses to the brain of 0
      0.099 Sv, 0.1-0.99 Sv and more than 1.0 Sv were 7.7, 9.2 and 18.2, respectively.
      The incidence of meningioma among Hiroshima atomic bomb survivors has increased
      since 1975. There was a significant correlation between the incidence and the
      dose of radiation to the brain. The present findings strongly suggest that
      meningioma is one of the tumors induced by atomic bombing in Hiroshima.

PMID- 10408178
TI  - Generalized concept of the LET-RBE relationship of radiation-induced chromosome
      aberration and cell death.
AB  - The frequency of chromosome aberrations per traversal of a nucleus by a charged
      particle at the low dose limit increases proportionally to the square of the
      linear energy transfer (LET), peaks at about 100 keV/micron and then decreases
      with further increase of LET. This has long been interpreted as an excessive
      energy deposition over the necessary energy required to produce a biologically
      effective event. Here, we present an alternative interpretation. Cell traversed
      by a charged particle has certain probability to receive lethal damage leading to
      direct death. Such events may increase with an increase of LET and the number of
      charged particles traversing the cell. Assuming that the lethal damage is
      distributed according to a Poisson distribution, the probability that a cell has
      no such damage is expressed by e-cLx, where c is a constant, L is LET, and x is
      the number of charged particles traversing the cell. From these assumptions, the
      frequency of chromosome aberration in surviving cells can be described by Y =
      alpha SD + beta S2D2 with the empirical relation Y = alpha D + beta D2 in the low
      LET region, where S = e-cL, alpha is a value proportional to LET, beta is a
      constant, and D is the absorbed dose. This model readily explains the empirically
      established relationship between LET and relative biological effectiveness (RBE).
      The model can also be applied to clonogenic survival. If cells can survive and
      they have neither unstable chromosome aberrations nor other lethal damage, the
      LET-RBE relationship for clonogenic survival forms a humped curve. The
      relationship between LET and inactivation cross-section becomes proportional to
      the square of LET in the low LET region when the frequency of a directly lethal
      events is sufficiently smaller than unity, and the inactivation cross-section
      saturates to the cell nucleus cross-sectional area with an increase in LET in the
      high LET region.

PMID- 10408179
TI  - Computing the Cox model for case cohort designs.
AB  - Prentice (1986) proposed a case-cohort design as an efficient subsampling
      mechanism for survival studies. Several other authors have expanded on these
      ideas to create a family of related sampling plans, along with estimators for the
      covariate effects. We describe how to obtain the proposed parameter estimates and
      their variance estimates using standard software packages, with SAS and S-Plus as
      particular examples.

PMID- 10408180
TI  - A parametric estimation procedure for relapse time distributions.
AB  - In a relapse clinical trial patients who have recovered from some recurrent
      disease (e.g., ulcer or cancer) are examined at a number of predetermined times.
      A relapse can be detected either at one of these planned inspections or at a
      spontaneous visit initiated by the patient because of symptoms. In the first case
      the observations of the time to relapse, X, is interval-censored by two
      predetermined time-points. In the second case the upper endpoint of the interval
      is an observation of the time to symptoms, Y. To model the progression of the
      disease we use a partially observable Markov process. This approach results in a
      bivariate phase-type distribution for the joint distribution of (X, Y). It is a
      flexible model which contains several natural distributions for X, and allows the
      conditional distributions of the marginals to smoothly depend on each other. To
      estimate the distributions involved we develop an EM-algorithm. The estimation
      procedure is evaluated and compared with a non-parametric method in a couple of
      example based on simulated data.

PMID- 10408181
TI  - Accelerated test models for system strength based on Birnbaum-Saunders
      distributions.
AB  - Recent research in cumulative damage models for strengths of systems has yielded
      various statistical distributions that incorporate a system size variable and
      follow a generalized Birnbaum-Saunders form. These models can be unified as a
      three-parameter Birnbaum-Saunders-type family of distributions, where the third
      parameter arises from the size variable through the cumulative damage approach.
      In this paper, the generalized three-parameter Birnbaum-Saunders distribution is
      characterized, and examples of cumulative damage models for system strength that
      fit this form are given. Also, estimation and asymptotic theory are developed for
      the generalized distribution, and illustrations are presented for experimental
      strength data for carbon composite materials.

PMID- 10408183
TI  - A random coefficient degradation model with random sample size.
AB  - In testing product reliability, there is often a critical cutoff level that
      determines whether a specimen is classified as "failed." One consequence is that
      the number of degradation data collected varies from specimen to specimen. The
      information of random sample size should be included in the model, and our study
      shows that it can be influential in estimating model parameters. Two-stage least
      squares (LS) and maximum modified likelihood (MML) estimation, which both assume
      fixed sample sizes, are commonly used for estimating parameters in the repeated
      measurements models typically applied to degradation data. However, the LS
      estimate is not consistent in the case of random sample sizes. This article
      derives the likelihood for the random sample size model and suggests using
      maximum likelihood (ML) for parameter estimation. Our simulation studies show
      that ML estimates have smaller biases and variances compared to the LS and MML
      estimates. All estimation methods can be greatly improved if the number of
      specimens increases from 5 to 10. A data set from a semiconductor application is
      used to illustrate our methods.

PMID- 10408182
TI  - Strategies for cohort sampling under the Cox proportional hazards model,
      application to an AIDS clinical trial.
AB  - In some studies that relate covariates to times of failure it is not feasible to
      observe all covariates for all subjects. For example, some covariates may be too
      costly in terms of time, money, or effect on the subject to record for all
      subjects. This paper considers the relative efficiencies of several designs for
      sampling a portion of the cohort on which the costly covariates will be observed.
      Such designs typically measure all covariates for each failure and control for
      covariates of lesser interest. Control subjects are sampled either from "risk
      sets" at times of observed failures or from the entire cohort. A new design in
      which the sampling probability for each individual depends on the amount of
      information that the individual can contribute to estimated coefficients is shown
      to be superior to other sampling designs under certain conditions. Primary focus
      of our designs is on time-invariant covariates, but some methods easily
      generalize to the time-varying setting. Data from a study conducted by the AIDS
      Clinical Trials Group are used to illustrate the new sampling procedure and to
      explore the relative efficiency of several sampling schemes.

PMID- 10408184
TI  - Ordering properties of convolutions of exponential random variables.
AB  - Convolutions of independent random variables are usually compared. In this paper,
      after a synthetic comparison with respect to hazard rate ordering between sums of
      independent exponential random variables, we focus on the special case where one
      sum is identically distributed. So, for a given sum of n independent exponential
      random variables, we deduce the "best" Erlang-n bounds, with respect to each of
      the usual orderings: mean ordering, stochastic ordering, hazard rate ordering and
      likelihood ratio ordering.

PMID- 10408185
TI  - [Incidence of immunogenic hyperthyroidism after radioiodine therapy of focal
      thyroid gland autonomy. Results of a multicenter study].
AB  - BACKGROUND: There are case reports in the literature that patients occasionally
      develop immunogenic hyperthyroidism 2 to 14 months following iodine-131-therapy
      of focal, non-immunogenic, autonomous thyroid nodules with a prevalence between
      0.05 and 2.5%. Purpose of this multicenter evaluation was to assess the
      appearance of this phenomenon in a larger patient population. PATIENTS AND
      METHODS: So far 2867 patients out of 4 university hospitals are included in our
      study focusing on the appearance of pathologically elevated levels of thyrotropin
      receptor-antibodies (TRAb) combined with hyperthyroidism following iodine
      therapy. Records of the patients were screened for pre- and post-therapeutic
      biochemical tests, scintigraphic uptake patterns and ultrasound findings of the
      thyroid. RESULTS: Nineteen of 2867 patients with pretherapeutically scintigraphic
      "hot nodules" developed recurrent hyperthyroidism suggestive for immunogenic
      genesis 2 to 12 months following iodine-131-therapy (elevated TRAb-levels,
      homogeneous uptake in Tc-99m-pertechnetate scans). Pretherapeutically, 9 of these
      patients presented with a strictly focal scintigraphic uptake-pattern, 10 cases
      with a mixed disseminated-focal pattern. Because of missing pretherapeutic TRAb
      tests in 8/9 patients presenting with a strictly focal scintigraphic uptake
      pattern, postradiogenic immunogenic hyperthyroidism could be reliably assessed in
      1 case only. CONCLUSION: One could speculate that iodine-131-therapy may
      stimulate immunogenic mechanisms finally leading to immunogenic hyperthyroidism.
      Posttherapeutically observed hyperthyroidism following iodine-treatment might be
      based on an exacerbation of a preexisting--clinically not relevant/detectable-
      immunothyropathia. Also pretherapeutic TRAb-negative immunogenic hyperthyroidism
      could not be definitely excluded. Our multicenter data collected in a large
      patient population show similar results to the case reports of immunogenic
      hyperthyroidism following iodine-131-treatment in smaller populations. Therfore,
      the occurrence of this phenomenon plays a minor role regarding to its prevalence.
      Therapeutical consequences in treatment of functional thyroid autonomy are not
      recommended.

PMID- 10408186
TI  - [Motility disorders of the esophagus in patients with apoplectic infarct during
      the acute illness phase].
AB  - BACKGROUND: Prolonged oropharyngeal dysphagia occurs in up to 45% of patients
      presenting with a unilateral hemiplegic stroke. The aim of this study was to
      investigate esophageal motility in patients with hemiplegic stroke and to
      evaluate, whether detected motility disorders improve within 10 days after the
      beginning of symptoms. PATIENTS AND METHODS: Fifteen patients with hemiplegic
      stroke and dysphagia underwent esophageal manometry within the first 2 days after
      admission to the hospital and 10 days later. Eighteen healthy volunteers served
      as controls. RESULTS: The following parameters showed no significant differences
      between the 2 study days (day 2: day 10: controls, p-value [comparison with
      controls]): resting pressure of the lower esophageal sphincter: 21 +/- 3 mm Hg:
      20 +/- 3 mm Hg: 18 +/- 2 mm Hg, NS, contraction amplitude: 67 +/- 8 mm Hg: 72 +/-
      11 mm Hg: 78 +/- 9 mm Hg, NS, duration of contraction: 4.2 +/- 1.0 s: 4.2 +/- 0.9
      s: 2.2 +/- 0.7 s, p < 0.001, and contraction velocity: 6.3 +/- 1.1 cm/s: 5.2 +/-
      0.9 cm/s: 3.2 +/- 0.8 cm/s, p < 0.001. As far as the contraction pattern was
      concerned, on both study days significant pathologic contraction patterns were
      seen compared with normal controls. Normal propulsive contractions were seen in
      54 +/- 5%: 60 +/- 6%: 96 +/- 5%, p < 0.001. Patients with no dysphagia after 10
      days still had demonstrable abnormal motility patterns. CONCLUSION: The findings
      indicate that manometrically demonstrable pathologic motility patterns of the
      tubular esophagus in patients without oropharyngeal dysphagia after 10 days do
      not induce the symptom dysphagia. The function of the esophagus seems not to be
      impaired by these measurable pathologic contractions.

PMID- 10408187
TI  - [Angiology update].

PMID- 10408188
TI  - [Progressive multifocal leukoencephalopathy].
AB  - PATHOGENESIS: Progressive multifocal leukoencephalopathy is a demyelinating
      disease of the central nervous system caused by infection and reactivation of JC
      virus. About 5% of all HIV-infected patients develop this fatal disease. Although
      pathogenesis is not completely understood, progressive multifocal
      leukoencephalopathy is thought to be a persistent infection. The kidneys, bone
      marrow, peripheral blood lymphocytes and the brain itself are candidates for
      latency sites of JC-virus. Loss of T-helper-cells in the course of HIV-infection
      or other immunosuppressive states result in reactivation of JC-virus. DIAGNOSIS:
      Progressive multifocal leukoencephalopathy can be diagnosed by focal neurological
      symptoms, radiographic signs in magnetic resonance imaging and detection of JC
      virus in brain tissue or cerebrospinal fluid. TREATMENT: A specific therapy is
      not yet available or established. Highly active antiretroviral therapy (HAART)
      and cidofovir are promising and may prove useful in the near future.

PMID- 10408189
TI  - [An unusual cause of hepatorenal symptoms].
AB  - CASE REPORT: A 65-year-old patient with normal blood pressure had an exclusive
      elevation of the cholestasis enzymes (alkaline phosphatase 297 U/l, gamma-GT 315
      U/l) and elevated bilirubin levels (1.4 mg/dl) since August 1994. A biopsy of the
      liver in March 1995 showed features of a "subacute viral hepatitis"; DD drug
      induced or toxic lesions. Serological tests gave no support for an acute
      hepatitis. Intra- or extrahepatic cholestasis could not be proved neither by
      ultrasound nor by an endoscopic retrograde cholangiopancreatography. Since
      November 1995 serum creatinine increased up to 1.7 mg/dl (March 1995 1.1 mg/dl)
      and proteinuria (2.1 g/d) developed. Due to worsening of renal function (serum
      creatinine 2.8 mg/dl) and increasing proteinuria (3.5 g/d) without nephrotic
      syndrome, a kidney biopsy was performed. Histologically an amyloidosis (type A
      lambda) was proven, involving glomerula, kidney vessels and tubules. Further
      biopsies from the stomach and the duodenum showed profound infiltration of the
      mucosa and submucosa with amyloid. Therefore, staining of the liver biopsy of
      March 1995 with congo red proved the diagnosis of liver amyloidosis. By a punch
      biopsy of the iliac crest a low-grade non-Hodgkin's lymphoma could be identified
      as the cause for this generalized amyloidosis. DISCUSSION: In the present case,
      the reason for these unusual hepatorenal symptoms with unclear cholestasis over
      years as the first clinical symptom and a succeeding progressive renal
      insufficiency with proteinuria could be found by the use of kidney biopsy and
      extending the analysis of a liver sample taken by biopsy 1 year ago.
      Immunoglobulin light chains produced by a low-grade non-Hodgkin's lymphoma caused
      a generalized amyloidosis type A lambda. CONCLUSION: As a consequence, by an
      occurrence of unusual hepatorenal symptoms with cholestasis and progressive renal
      failure, amyloidosis should be considered as a pathogenetic factor.

PMID- 10408190
TI  - [Diagnosis of autoimmune hepatitis].

PMID- 10408191
TI  - [Launois-Bensaude benign symmetrical lipomatosis].

PMID- 10408192
TI  - [Clinical research in Germany].

PMID- 10408193
TI  - [Responsibilities of clinical pharmacology in the early phase of drug
      development].
AB  - The path of a new drug from the idea to the product may be divided into 2 phases,
      namely drug discovery and drug development. Due to the scientific progress new
      and simple methods could be developed to determine the biological efficacy of a
      large number of compounds. During the first part of drug development necessary
      requirements for the first use in man are met by performing preclinical
      pharmacological, toxicological and pharmacokinetic investigations in the animal
      and in in-vitro testing. After a first clinical-pharmacological profile of the
      new substance has been established during phase I on the basis of which a
      decision for the continuation of the clinical trial is made, the aim of phases II
      and III is now to answer the important questions of the therapeutic efficacy and
      tolerability in a large number of patients with the target indication. Due to the
      continuously increasing time and costs of drug development, drug development
      should be streamlined combining preclinical and early clinical phases as an
      exploratory stage and later clinical development as a confirmatory stage. The
      development and appropriate use of surrogates and models may be helpful to
      determine drug actions in human and to assist in dose selection as the main
      requirement for a successful large clinical trial in the confirmatory stage.
      Identifying the genes responsible for the huge variations in how different
      patients respond to a drug, in terms of both the product's effectiveness and its
      side effects, and genotyping patients before including in large clinical trials
      may prevent selecting the wrong patient population and avoid expensive repetition
      of these studies. Taking responsibility as the link between research and
      development gives clinical pharmacology a major opportunity to assume a pivotal
      role in drug development. To reach this goal, clinical pharmacology must be fully
      integrated in the whole process of drug development from the candidate selection
      until the approval.

PMID- 10408194
TI  - [Asthma therapy in children and adults. Comment on the contribution by Wettengel
      R., et al. Recommendations of the German Respiratory League in the German Society
      of Pneumology].

PMID- 10408195
TI  - Prevalence of malingering in suicidal psychiatric inpatients: a replication.
AB  - The MMPI-2, L, F, and K validity scales were administered to 21 (42%) suicide
      attempters and 29 (58%) ideators who had been hospitalized as being at risk for
      committing suicide. These inpatients were also asked to rate anonymously how much
      they had "exaggerated on purpose or lied about being suicidal to a staff member"
      during their current hospitalizations. The three MMPI-2 validity scores of the
      inpatients were not associated with self-reported malingering, and 6 (12%) of the
      inpatients reported malingering. This rate was comparable to the 10% rate which
      had previously been found by Rissmiller, et al. in 1998.

PMID- 10408196
TI  - Risk perception: unrealistic optimism or realistic expectancy.
AB  - The current study investigated risk perception and Unrealistic Optimism as a
      function of involvement in risk. 74 undergraduate students were asked to rate how
      likely they were to encounter various negative consequences relative to various
      comparison targets (child, peer, and parent) and specified their actual
      involvement in risk-taking. Over-all, 37 High and 37 Low Risk-takers rated
      harmful events similarly, adding support for disputing the hypothesis that risk
      takers consider themselves to be invulnerable. When these older adolescents
      compared themselves with children, they rated their personal risk of engaging in
      the health threatening behaviors as higher. Adolescents can realistically
      appraise the differences between themselves and children and view themselves as
      more likely to encounter the negative outcomes of risk-taking behaviors.
      Implications are discussed.

PMID- 10408197
TI  - Pilot study on the relationship between personality traits and skin conductivity
      of specific surface points as measured by Motoyama's apparatus.
AB  - This pilot study used Motoyama's electrodermal response-measuring apparatus to
      test resting skin conductivity from 28 extremity digit surface coordinates of 33
      subjects who also were administered the Eysenck Personality Inventory on an
      alternatively assigned basis for the dimensions of extraversion and neuroticism.
      Correlations show significant relationships between neuroticism and extraversion
      raw scores on two of the 14 bilateral finger surface coordinates.

PMID- 10408198
TI  - Comparison of MMPI-A, Marks and Briggs, and MMPI-2 norms for juvenile
      delinquents.
AB  - A study was conducted to compare scores of juvenile delinquents on the new MMPI-A
      to previous research and to compare 3 sets of norms for adolescents: the MMPI-A,
      the Marks-Briggs adolescent norms, and the MMPI-2 adult norms. Subjects, 11 boys
      and 11 girls, were hospitalized adolescents, aged 14 to 17 years, with a history
      of conduct problems. Analysis of MMPI-A scale scores for boys indicated elevated
      T-score means on scales F (64), Hs (64), Pd (65), Pa (68), Pt (68), Sc (70), and
      Ma (66). Mean T scores for girls on the MMPI-A were elevated on scales of F (62),
      Pd (64), and Sc (62). The findings that the mean T score for scales Pd, Sc, and
      Ma are elevated for this population is consistent with previous research on
      juvenile delinquents. In general, the MMPI-A scale elevations were lowest,
      followed by the Marks-Briggs norms. The MMPI-2 T-score means were the most
      elevated. One of the limitations of the present investigation is an extremely
      small sample. Until further research is conducted on larger samples, clinicians
      concerned about the different norms are encouraged to plot MMPI-A scores on both
      adolescent and adult norms. It is also recommended that the MMPI-A be included as
      part of an assessment battery with other objective tests, clinical observation,
      and patient report.

PMID- 10408199
TI  - Scales for teachers' assessment of inhibition and security seeking in
      kindergarten children.
AB  - For young children separation from their primary caregivers can give rise to
      feelings of emotional insecurity, which are manifested by inhibition of behavior
      and seeking security from a substitute caregiver. The present study examined the
      quality of two new scales, the Inhibition Scale and the Security Seeking Scale,
      developed for teachers' assessment of inhibition and security-seeking behaviors.
      Participants were 121 kindergarten children. Reliability and short-term stability
      of both scales proved to be good. Relationships with four major dimensions of
      personality, Extraversion, Conscientiousness, Agreeableness, and Emotional
      Stability, were examined by means of teachers' judgements on the School Behavior
      Checklist Revised. The validity of the Inhibition Scale and the Security Seeking
      Scale was supported by the findings. Scores on both scales appeared to be
      negatively related to those on Extraversion and Emotional Stability. The negative
      association with scores on Extraversion was stronger for scores on the Inhibition
      Scale than for those on the Security Seeking Scale. Neither scale was related to
      the nonemotional dimension Conscientiousness. In addition, scores on both the
      Inhibition and Security Seeking Scale appeared negatively related to the time
      passed since entry into kindergarten.

PMID- 10408200
TI  - Sequelae of abortion and relinquishment of child custody among women with major
      psychiatric disorders.
AB  - A growing number of women with major psychiatric disorders frequently consider
      the choice of abortion or relinquishment of the custody of children.
      Psychological reactions to abortion and relinquishment of custody were assessed
      and contrasted among 119 hospitalized women of M age 40 yr. and psychiatric
      patients. An original questionnaire was developed to assess emotional symptoms,
      psychiatric signs, attitudes, and satisfaction with the decision regarding the
      loss of a fetus or child. As hypothesized, reported sequelae of relinquishments
      of custody were rated as significantly more severe than sequelae of abortion.
      Dissatisfaction with choice, negative attitudes, religious affiliation, and
      involuntary removal of a child from custody were predictive of distress following
      abortion or relinquishment. The findings show that increased efforts are needed
      to help women with psychiatric difficulties cope with reproductive planning and
      losses.

PMID- 10408201
TI  - Homosexual parents and questions of character: a response to Cameron and Cameron.
AB  - Cameron and Cameron introduced appellate court decisions as a new data source for
      content analyses. In using this source they have shown praiseworthy clarity in
      describing their methods. Their report, however, appears to show an over-weaning
      bias against homosexuals which is the fatal flaw of this study.

PMID- 10408202
TI  - Homosexual parents: why appeals cases approximate the "gold standard" for science
      -a reply to Duncan.
AB  - Unlike the unverifiable claims of volunteers in studies of homosexual parenting,
      an alert ex-spouse is ready to testify as to the falsity of any claim by the
      other spouse in custody proceedings. Further, a greater variety of professionals
      are involved in getting at the "truth." We argue that examination of an unbiased
      corpus of such appeals cases is far more apt to reflect the underlying "reality"
      about homosexual parenting than studies performed on volunteers.

PMID- 10408203
TI  - Vocal expression of anger and cardiovascular reactivity within dyadic
      interactions.
AB  - This experiment was conducted to examine whether the vocal expression of anger
      correlated with cardiovascular reactivity within dyadic interactions.
      Participants selected three social issues on which they had a strong opinion and,
      with a confederate who opposed their views, debated these opinions in each of the
      three vocal styles. The three vocal styles were (1) Anger-out during which they
      described their view in a loud, fast voice, (2) Mood-incongruent during which
      they described their view in a soft, slow voice, and (3) Anger-in during which
      they listened to the confederate oppose their view and only responded from a list
      of neutral phrases given to them. Cardiovascular reactivity measures (heart rate
      and blood pressure) were taken during the initial baseline and the three
      expression of anger conditions. Both the anger-out and mood-incongruent vocal
      styles significantly correlated with systolic blood pressure and heart-rate
      reactivity measures. The disparity between the results of this experiment and
      previous ones on anger and cardiovascular response may be related to differences
      in the method of anger-arousal (memory-evoked versus dyadic interactions).
      Results are discussed in terms of similarities to active and passive coping and
      defensiveness.

PMID- 10408204
TI  - Sun-safety behavior among elementary school children: the role of knowledge,
      social norms, and parental involvement.
AB  - 98 children in Grades 4, 5, and 6 were surveyed in 1997 for their knowledge of
      sunlight's harmful effects, attitude toward and frequency of usage of sun-safety
      devices, perceived peer pressure against sun-safe behavior, and parental
      encouragement for practicing sun-safe behavior. Children exhibited low knowledge
      of harmful effects of sun exposure and perceived the threat as remote. Of the two
      primary determinants of sunscreen usage, parental reminders and a positive
      attitude towards sunscreen use, the former was dominant. The knowledge of harmful
      effects of sun exposure, the primary focus of most interventions, does not appear
      to be the most critical variable influencing children's sun-safety behavior;
      parental involvement does.

PMID- 10408205
TI  - Family perceptions of future programming needs in a sample of individuals with
      mental retardation.
AB  - The present study examined parents' perceived programming needs of their children
      with mental retardation. Parents (44 mothers, 8 fathers) of individuals attending
      programming in an agency for mental retardation responded to a telephone survey.
      Analysis showed parents were most concerned about future housing needs. A
      significant difference was found between older and younger parents in their
      perception of future needs.

PMID- 10408206
TI  - No evidence for a close relationship between personality traits and circadian
      cortisol rhythm or a single cortisol stress response.
AB  - Personality traits measured with the Eysenck Personality Questionnaire-Revised
      did not show associations with basal or stimulated concentrations of cortisol in
      a sample of 81 subjects. Cortisol responses to a single exposure to psychosocial
      stress as well as circadian salivary-free cortisol patterns did not distinguish
      between subjects with high or low scores on Extraversion, Neuroticism, or
      Psychoticism, respectively.

PMID- 10408207
TI  - Self-schemas in social phobia and panic disorder.
AB  - A modified Stroop color-naming task was used to investigate whether social phobia
      and panic disorder are associated with a hypervigilance to social and physical
      threat-related cues, respectively, as predicted by Beck's cognitive theory of
      anxiety disorders. Color-naming latencies of 13 individuals with social phobia
      and 15 with panic disorder for words representing social and physical threats,
      respectively, were compared to matched neutral control words. The results did not
      support the hypothesis that the self-schemas of individuals with panic disorder
      are hypersensitive to information association with physical threat and that
      persons with social phobia are overly concerned with social threat.

PMID- 10408208
TI  - Objective and projective personality assessment: the TEMAS and the Behavior
      Assessment System for Children, self-report of personality.
AB  - The TEMAS and Self-report of Personality of the Behavior Assessment System for
      Children were administered to 71 youngsters aged 8 to 13 years. Preliminary data
      suggest that, although the two measures assess several similarly named
      constructs, the data are complementary. This appears to reflect the fact that the
      TEMAS Personality Functions measure children's skills in coping with emotionally
      laden situations, whereas the Behavior Assessment System for Children measures
      the emotion or skill in question independent of situational context.

PMID- 10408209
TI  - Belief in life after death, religiosity and fear of death.
AB  - In a sample of 34 undergraduates, belief in life after death was associated with
      religiosity but not with the fear of death.

PMID- 10408210
TI  - Exploring the effects of tape-recording on personality assessment.
AB  - This study examined the possible influence of audio and video recording of
      personality assessment measures on anxiety. Undergraduate students in psychology
      were randomly assigned to Audiotape, Videotape, or Control conditions and given
      the State-Trait Anxiety Inventory and Rorschach Inkblot Method. A one-way
      multivariate analysis of variance indicated no significant differences among
      these conditions on the Spielberger, et al. State-Trait Anxiety Inventory, A
      State scale, and five Rorschach measures of situational anxiety. Tape-recording
      itself did not seem to affect the anxiety indices of these frequently used
      personality assessments.

PMID- 10408211
TI  - The blame attributed to rape victims.
AB  - Holding the rape victim more responsible was associated with femininity scores of
      both 21 male and 53 female college students.

PMID- 10408213
TI  - Research productivity in the areas of child abuse and domestic violence.
AB  - Research productivity in the areas of child abuse and domestic violence was
      reviewed for the years 1990-1996 by examining articles published in Child Abuse
      and Neglect, the Journal of Family Violence, and the Journal of Interpersonal
      Violence. To examine productivity across institutions, quantification of
      productivity was based on ordinal position of authorship as previously used.
      Productivity across these three journals was also summed based on the 1987
      composite productivity index formula of Howard, et al., and the data were
      compared with a productivity assessment based on a search process in the PsycLIT
      database. Rank-order correlations between the raw productivity total, the
      composite measure, and productivity based on first-authored publications in
      PsycLIT were all significant. The findings suggest that the composite measure
      represents a good estimate of productivity across the three journals and that
      publication in these three journals provides a good representation of research in
      the general areas of child abuse and domestic and interpersonal violence. The
      findings, along with implications regarding the relative utility of such
      information for selection of graduate programs that have a strong research focus
      on child abuse or domestic violence, are discussed.

PMID- 10408212
TI  - Psychogenic or dissociative fugue: a clinical investigation of five cases.
AB  - Dissociative fugue (formerly psychogenic fugue) is a rare and little understood
      dissociative disorder. Following a review of the pertinent literature, five cases
      of dissociative fugue are described. These cases were systematically studied with
      a comprehensive history, mental status examination, physical and neurological
      evaluation, review of previous medical and psychiatric records, and psychological
      testing including MMPI, WAIS-R, electroencephalogram, and Dissociative
      Experiences Scale. An unexpected finding was that, in some cases, associated
      criminal activity may allow the person with dissociative fugue to continue to
      function in spite of their loss of memory and original identity.

PMID- 10408214
TI  - Comparison of Swedish and American preschool children's attitudes toward elderly
      persons.
AB  - Attitudes toward elderly persons were examined for 40 4- and 5-yr.-old children,
      20 from Sweden and 20 from the United States, enrolled in full-day preschool
      programs. Subjects were matched for age, socioeconomic status, and parents' age
      and marital status. One-half of each group were male and one-half were female.
      The Social Attitude Scale of Ageist Prejudice was used to assess children's
      attitudes toward elderly persons. One-way analysis of variance indicated no
      significant differences in scores between the groups.

PMID- 10408215
TI  - Assessing the multidimensionality of the 12-item General Health Questionnaire.
AB  - The present study assessed a variety of factor structures identified by various
      authors as underlying the 12-item General Health Questionnaire and proposed an
      alternative structure based on an analysis of item content. Using confirmatory
      factor analytic techniques (LISREL), the data indicated that the presently
      proposed factor structure, comprising three factors (Self-esteem, Stress, and
      successful Coping), fits better than structures previously identified. The
      findings contribute to understanding of the 12-item General Health Questionnaire
      by separating Self-esteem and Stress, two dimensions often treated as one factor,
      and by identifying a third dimension of Successful Coping which is proposed to
      reflect individuals' perceived efficacy in interacting with the environment.

PMID- 10408216
TI  - Factor structure and subtest differences on the Preschool Behavior Questionnaire
      in a Latino, African-American, Euro-American, and Asian preschool population.
AB  - This study examined the factor structure of the Preschool Behavior Questionnaire
      in a sample of African-American, Euro-American, Asian, and Hispanic children. The
      sample consisted of 304 children (141 boys, 163 girls) 3- and 4-yr.-old and
      enrolled in Head Start. A principal component analysis with a varimax rotation
      was conducted and two- and three-factor solutions were extracted. A two-factor
      solution produced a clear interpretive structure representing Fowler and Park's
      1979 Aggressive-Hyperactive-Distractible and Anxious-Fearful factors. Even though
      a three-factor solution was statistically appropriate, extracting more than two
      factors yielded dimensions difficult to interpret. Examination of subscale
      differences among ethnic groups indicated significant group effect for ethnicity.
      Further examination showed that Euro-American children are rated significantly
      higher on the Anxious subtest than Latino, African-American, and Asian children,
      but there were no other subscale differences. Clinical and research implications
      are discussed.

PMID- 10408217
TI  - Professional isolation and occupational stress in teachers.
AB  - The aim of the study was to investigate the relationship between professional
      isolation of teachers and their occupational stress. A systematic random sample
      of 1,110 teachers in Quebec were administered French Canadian versions of the
      UCLA Loneliness Scale and Teacher Stress Inventory. Analysis gave, as expected, a
      positive and significant correlation between isolation and occupational stress.
      This highlights the importance of looking for ways to reduce professional
      isolation of teachers.

PMID- 10408218
TI  - Effects of familial pain models on daily pain indices and performance during the
      cold pressor task.
AB  - To understand better the role of pain history in current response to pain
      episodes, this research examined pain-related indices from the patient's family
      of origin and their relationships to the patient's coping with acute pain.
      Participants were 42 healthy men and women who provided information about their
      own and their family's pain history and then were administered a cold pressor
      task. High frequency of family pain modeling was associated with higher frequency
      of current pain episodes, more types of pain, greater intensity, and also lower
      physiological arousal and subjective pain ratings during the cold pressor. The
      findings underscore the relationships between familial pain modeling and current
      pain-related functioning.

PMID- 10408219
TI  - Degree-granting institutions and characteristics of psychologists with both
      diplomate and fellow status in counseling psychology.
AB  - Psychologists (44 men, 6 women) were identified as individuals who received both
      Fellow status from Division 17 of the APA and ABPP Diplomate status in Counseling
      Psychology. Years of postdoctoral experience acquired prior to gaining the
      credentials averaged 13.1 (SD = 6.1) for the Division 17 Fellow and 9.8 (SD =
      4.7) for the ABPP Diplomate. 25 different degree-granting institutions provided
      training for the 50 whose careers exemplify the scientist-practitioner approach
      to their work. Columbia graduated 9 of these psychologists, whereas Ohio State
      and Minnesota graduated 5 each. In regard to degree specialty, 37 (74%) gained
      their degrees from counseling or counseling psychology programs, whereas 11 (22%)
      gained their degrees from other types of psychology programs. These psychologists
      tended to work in academic institutions and to publish an average of 57 journal
      articles per year.

PMID- 10408220
TI  - Empirically derived factor indices for the Beck Depression Inventory.
AB  - Factor analytic studies of the Beck Depression Inventory routinely yield a small
      number of factors that parsimoniously summarize the 21 items of the inventory. To
      improve the utility of such factor data within clinical or applied research
      settings, the present study aimed to develop a set of empirically derived
      depression indices based on the factor structure of the Beck Depression
      Inventory. In Study 1, principal-axis factor analysis of the responses of 303
      undergraduate students yielded a 2-factor solution that accounted for 33% of the
      common variance. Easily calculated factor indices were developed to reflect
      individual performance on each factor, and normative data from the sample were
      used to establish preliminary guidelines for evaluating severity on each index.
      In Study 2, analyses of the factor-index scores obtained from a clinical sample
      of 55 medical patients supported the utility of the index scores for
      discriminating among various aspects of dysphoric experience.

PMID- 10408221
TI  - Relationship between perceived problem-solving and career maturity: implications
      for minority and disadvantaged premedical students.
AB  - This study examined the relationship between career maturity of minority and
      disadvantaged premedical students and their self-appraised problem-solving. 83
      students enrolled in a special program took the Medical Career Development
      Inventory and the Problem-solving Inventory one week apart. Pearson product
      moment correlations and a stepwise multiple regression analysis indicated a
      significant relationship between scores for the students' appraisal of their
      problem-solving and their career maturity. Implications for intervention
      strategies for the present population are discussed.

PMID- 10408222
TI  - Wine consumption and suicide rates.
AB  - When state monopolies ended, changes in wine sales in six states were not
      associated consistently with an increase in the suicide rate.

PMID- 10408223
TI  - Sex roles and body image.
AB  - The hypothesis that women scoring as Sex-typed have less favorable body image
      than women scoring as Androgynous or Cross-sexed was tested using the Personal
      Attributes Questionnaire of Spence and Helmreich and the Body Esteem Scale of
      Franzoi and Shields. These were completed by 121 Euro-American female
      undergraduates in psychology. Analysis indicated that women classified as Sex
      typed and Undifferentiated scored significantly lower than women classified as
      Androgynous and Cross-sexed on Sexual Attractiveness, Weight Concern, and
      Physical Condition subscales of the Body Esteem Scale, and the two groups had a
      significantly different mean profile. In addition, the Sex-typed group had a
      significantly different mean profile based on the three body-image subscales from
      that of women scoring as Androgynous but not those classed as Cross-sexed. As
      expected, there were no differences on body image between women classed as Sex
      typed and Undifferentiated.

PMID- 10408224
TI  - The effect of feeding carrots on immunoglobulin E production and anaphylactic
      response in mice.
AB  - Carrot juice was administered orally to BALB/c mice immunized intraperitoneally
      with dinitrophenylated (DNP)-OVA for about 1 month. The titers of DNP-specific
      IgE, DNP-specific IgG, and the levels of total IgE in mouse sera were determined.
      The DNP-specific IgE production by mice fed carrot juice was significantly
      inhibited. On the other hand, the DNP-specific IgG production and the level of
      total IgE in mice fed carrot juice were not significantly different from those in
      control mice. We also examined the effect of feeding carrots on immediate-type
      hypersensitivity. One hour after antigen stimulation, the ears of mice fed
      carrots swelled less than those of control mice. Furthermore, the rise in serum
      histamine in the mice fed carrots under active systemic anaphylaxis was lower
      than in controls. We then examined the pattern of cytokine production by spleen
      cells from mice followed by restimulation with DNP-OVA in vitro. The spleen cells
      from the mice fed carrots produced more interferon-gamma than those from the
      control group. In contrast, the spleen cells from the mice fed carrots produced
      less interleukin-4 than those from the control group. Furthermore, the
      interleukin-12 production of the spleen cells from mice fed carrots was also
      higher than that of the control group. These findings suggest that feeding
      carrots improves the helper T cell (Th)1/Th2 balance, inhibiting specific IgE
      production and antigen-induced anaphylactic response.

PMID- 10408225
TI  - Participation of cytosolic protein phosphatase in regulation of NADPH oxidase in
      polymorphonuclear leukocytes.
AB  - Calyculin A, a protein phosphatase inhibitor, enhanced phorbol 12-myristate 13
      acetate (PMA)-induced superoxide anion (O2-) production and translocation of the
      cytosolic NADPH oxidase factor, p47phox, to the plasma membrane in guinea pig
      polymorphonuclear leukocytes (PMNs). When PMNs were treated with t-(5-isoquino
      line-sulfonyl)-3-methyl-piperazine (H-7), a protein kinase C (PKC) inhibitor,
      after exposure to PMA, inhibition of O2- production and of translocation of
      p47phox to the membrane fraction in PMA-stimulated PMNs were observed. When
      calyculin A was added to the PMA-stimulated PMNs after the addition of H-7, O2-
      production was again observed, and translocation of p47phox to the membrane
      fraction also occurred. The activity of NADPH oxidase, the amount of p47phox and
      the level of phosphorylation of p47phox in the membrane fraction prepared from
      PMA-stimulated PMNs, were reduced by the addition of the cytosol fraction from
      unstimulated PMNs. These reductions were attenuated by calyculin A. These results
      indicate that the active form of NADPH oxidase in PMNs can be reconstituted after
      the active complex of the enzyme has disappeared once, and that one of the
      mechanisms of regulation of this enzyme activity involves the phosphorylation of
      p47phox in the cyotosol and dephosphorylation of phosphorylated p47phox in the
      NADPH oxidase complex by protein kinase and protein phosphatase, respectively.

PMID- 10408226
TI  - H-NMR and mass spectral study of a D-enriched acetylenic norlignan, asparenyol,
      from cultured cells of Asparagus officinalis.
AB  - A suspension of cultured cells of Asparagus officinalis fed L-phenyl-D5-alanine
      2,3,3-D3 (D5-phe) and DL-phenylalanine-3,3-D2 (D2-phe) yielded D-enriched
      asparenyol, 4-[5-(4-methoxyphenoxy)-3-penten-1-ynyllphenol (1). A H-NMR spectral
      study indicated that incorporation of deuterium atoms into the chains of the
      products was restricted to the C-9 position. The molecular ion regions of the MS
      of D-enriched metabolites, 1(D8-200), 1(D8-100) and 1(D8-50), obtained from
      feeding experiments using 200 mg, 100 mg and 50 mg of Ds-phe, respectively,
      coincided with the theoretical spectra. This confirmed that a single
      phenylalanine molecule supplies the nine carbon atoms in the -CH=CH-CH2-O-C6H4-O-
      moiety of 1. The biosynthetic sequence forming 1 as a norlignan class of
      metabolite is considered.

PMID- 10408227
TI  - Contribution of flavin-containing monooxygenase and cytochrome P450 to imipramine
      N-oxidation in rat hepatic microsomes.
AB  - Enzymatic formation of desipramine (DMI) and imipramine N-oxide (IMINO) was
      kinetically characterized in rat liver microsomes at pH 8.5 and 7.5. The
      formation of IMINO was quickly suppressed by the preincubation of microsomes at
      37 degrees C at pH 8.5, but the suppression was comparatively gentle at pH 7.5.
      In kinetic studies, the formation of DMI was monophasic at the two pH points, and
      a substrate inhibition was observed at pH 8.5, but not at pH 7.5. In contrast,
      the formation of IMINO was biphasic at both pH points, Le., the summation of a
      low-Km phase and a high-Km phase. Methimazole (MZ), an inhibitor of flavin
      containing monooxygenase (FMO), markedly suppressed the low-Km phase of IMINO
      formation at both pH points. MZ also suppressed DMI formation at pH 8.5, but it
      elevated DMI formation at pH 7.5. SKF 525-A, an inhibitor of cytochrome P450
      (CYP), markedly suppressed DMI formation at both pH points. The inhibitor
      suppressed IMINO formation in the high-Km phase of the biphasic kinetics at both
      pH points, whereas it stimulated the activity of the low-Km phase at pH 7.5.
      These results suggest that CYP enzyme(s) are mainly responsible for DMI formation
      at pH 8.5 and 7.5, and FMO enzyme(s) also are involved in IMI N-demethylation at
      a higher pH range in rat liver microsomes, at least in part. In the formation of
      IMINO, FMO is a major enzyme at both pH points, and CYP may also contribute to
      the N-oxide formation to some extent at pH 8.5.

PMID- 10408228
TI  - Lipogenic action of the novel oral antidiabetic agent HQL-975 in genetically
      obese diabetic KK-Ay mice.
AB  - HQL-975 (3-{4-12-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxyl-phenyl}-2S- propylamino
      propionic acid) is a new oral antidiabetic agent which has been shown to be
      effective in insulin-resistant diabetic animals. In the present study, we
      examined the effects of HQL-975 on glucose utilization and insulin action in KK
      Ay mice with genetically obese non-insulin diabetes. (1) Dietary administration
      of HQL-975 (19 mg/kg/d for 7 d) improved hyperglycemia, hyperlipidemia and
      hyperinsulinemia in the mice. (2) The HQL-975-treated mice showed enhanced net
      glucose utilization, that is, glucose was significantly incorporated into total
      lipids in the white adipose tissue (WAT) and liver, and into glycogen in the
      diaphragm for the last 24 h of the drug administration period. (3) Treatment
      improved the decreased stimulative action of insulin in the epididymal WAT and
      the agent increased insulin-stimulated lipogenesis from both glucose and acetate.
      (4) Treatment also increased the activity of lipogenic enzymes such as glycerol-3
      phosphate dehydrogenase and fatty acid synthetase. (5) In vitro exposure of WAT
      to HQL-975 enhanced lipogenesis in the presence of insulin. From these findings,
      we conclude that HQL-975 improves glucose utilization of KK-Ay mice through the
      enhancement of insulin action, which is associated with its lipogenic effects.

PMID- 10408229
TI  - Mutagenicity of potassium alkanediazotates in Chinese hamster V79 cells and their
      alkylating activity.
AB  - Alkanediazohydroxides are the key intermediates of carcinogenic N-nitroso
      compounds, and exist as geometrical isomers. In this paper, the mutagenicity and
      cytotoxicity of (E)- and (Z)-potassium alkanediazotates, precursors of
      alkanediazohydroxides, in Chinese hamster V79 cells were investigated. Mutagenic
      and cytotoxic activities of (E)-diazotates were dose-dependent, and activity
      decreased with an increase in the alkyl chain length; methyl>ethyl>propyl, butyl.
      On the other hand, (Z)-diazotates were less mutagenic and cytotoxic than (E)
      diazotates, however (Z)-potassium methanediazotate did show weak mutagenicity. To
      compare chemical reactivity with biological activity, alkylating activity towards
      nicotinamide in an aqueous phosphate buffer system was evaluated as an index of
      the chemical reactivity of diazotates. Using a fluorometric HPLC method,
      alkylated nicotinamides were detected with high sensitivity in the reaction with
      all diazotates tested. The alkylating activity of (Z)-methanediazotate was higher
      than that of the corresponding (E)-diazotate, but the other isomers with ethyl,
      propyl and butyl groups had similar reactivity under the conditions used. The
      activity decreased by increasing the alkyl chain-length, which correlated well
      with the mutagenicity in V79 cells and also with that in Salmonella typhimurium,
      which we reported earlier. The results for (E)-diazotates were similar to the
      corresponding N-nitroso-N-(hydroxymethyl)alkylamines, further supporting the
      notion that alpha-hydroxy nitrosamines decompose through alkanediazohydroxide and
      alkylate DNA, and suggests that geometrical isomerism influences the
      carcinogenicity of -nitroso compounds in mammals.

PMID- 10408230
TI  - Improvement in the turnover rate of the stratum corneum in false aged model rats
      by the administration of geniposidic acid in Eucommia ulmoides Oliver Leaf.
AB  - We earlier reported that collagen synthesis in false aged model rats was
      stimulated by the administration of a methanol extract from the leaves of
      Eucommia ulmoides OLIVER. When the methanol extract was fractionated to n-hexane,
      ethyl acetate, acetone and methanol fractions by silica gel chromatography, we
      discovered that geniposidic acid and aucubin, contained in the acetone fraction,
      were the active ingredients. In the current study, we set out to examine if
      active compounds found in the Eucommia ulmoides OLIVER leaf (EUOL) improved the
      low turnover rate in the stratum corneum of false aged model rats. The turnover
      rate in the stratum corneum in rats was measured as 50% dansyl chloride clearance
      day. In the first experiment, administration of a 2.4% water soluble methanol
      extract (WSME) of EUOL, along with an 11% protein diet, led to a 20% higher
      turnover rate in the stratum corneum (p<0.05, Mann-Whitney) than the control
      value. The WSME mainly contained iridoid mono-glycosides such as geniposidic
      acid. In the second experiment, treatment with geniposidic acid similarly caused
      a higher turnover rate in the stratum corneum, increasing turnover by 23%
      (p<0.05, Mann-Whitney) compared to the control value. In this paper we reveal
      that the WSME contains compounds effective against aging, and one of them is
      geniposidic acid.

PMID- 10408231
TI  - Antioxidative activity of indenestrol A, a diethylstilbestrol metabolite.
AB  - To elucidate the various activities of synthetic estrogens, the antioxidative
      activities of diethylstilbestrol (DES) and related metabolic analogs were
      examined. The antioxidative activities were assessed in terms of the inhibitory
      effect on Fe2+(-) and ascorbic acid-induced peroxidation of egg
      phosphatidylcholine (egg PC), and also superoxide scavenging ability using cyclic
      voltammetry. Moreover, after in vivo administration of the test compounds to
      mice, the animals were subjected to hyperoxia, and catalase, glutathione
      peroxidase and superoxide dismutase activities in the brain, lungs and liver were
      measured. The results indicated that indenestrol A, one of the metabolites of
      DES, had the strongest antioxidative activity among the test compounds under both
      in vivo and in vitro conditions.

PMID- 10408232
TI  - Synthesis and characterization of lipophilic 1-[18F]fluoroalkyl-2-nitroimidazoles
      for imaging hypoxia.
AB  - In order to develop new imaging markers for brain hypoxia, two lipophilic
      nitroimidazoles, 1-(3-fluoropropyl)-2-nitroimidazole (FPN) and 1-(8-fluorooctyl)
      2-nitroimidazole (FON) were synthesized and labeled with fluorine-18. The
      octanol/water partition coefficients were measured as an indication of
      lipophilicity, giving values of logP=0.28 for FPN and logP=2.72 for FON,
      respectively, which are in the range thought to be optimal for the diffusion of
      molecules across the blood-brain barrier. It was suggested from a comparative
      study of in vitro radiosensitization in V79 cells that these lipophilic analogs
      may have reduction potentials close to those of fluoromisonidazole (FMISO) and
      misonidazole (MISO), known hypoxic cell radiosensitizers. The preparation of 18F
      labeled FON (18FON) and FPN (18FPN) was achieved via two-steps through
      [18F]fluoride ion displacement of tosylate precursors, in reasonable
      radiochemical yields. Tissue distribution of 18FPN and 18FON in normal rats and
      tumor-bearing mice after intravenous injection was investigated and compared to
      the behavior of 18F-labeled FMISO (18FMISO), a proven hypoxic imaging agent. The
      high lipophilicity of 18FON and 18FPN resulted in increased initial uptake into
      normal rat brain, relative to 18FMISO, followed by a rapid washout from brain.
      Both of these lipophilic analogs had significantly lower tumor uptake and lower
      tumor-to-blood ratios than 18FMISO, suggestive of a poor trapping mechanism
      within the tumor tissue. Neither 18FON or 18FPN offers improved biological
      properties over 18FMISO as a potential agent for use in brain hypoxic imaging.

PMID- 10408233
TI  - Genetic analysis of nothoapiol formation in Perilla frutescens.
AB  - A new essential oil chemotype of Perilla frutescens was found in that plant
      variety from Che-ju island in Korea. The steam-distilled oil of this plant was
      examined by GC-MS and 32 compounds were identified. Its principal constituents
      were beta-caryophyllene, dillapiol and nothoapiol. Also, crossing experiments
      were performed between the new chemotype and known chemotypes to clarify the
      genetic control of the production of nothoapiol. The gene Na, which promotes
      conversion from dillapiol to nothoapiol, was suggested, and was considered to be
      closely linked with the allele D.

PMID- 10408234
TI  - Anti-carcinogenic activity of Taraxacum plant. I.
AB  - An extract of the roots of Taraxacum japonicum (Compositae) exhibited strong anti
      tumor-promoting activities on the two-stage carcinogenesis of mouse skin tumor
      induced by dimethylbenz[a] anthracene (DMBA) as an initiator and 12-O
      tetradecanoylphorbol-13-acetate (TPA) as a promoter, as well as on that induced
      by DMBA and fumonisin B1. Further, the extract exhibited anti-tumor-initiating
      activity on the two-stage carcinogenesis of mouse skin tumor induced by (+/-)-(E)
      methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexen amide (NOR-1) as an
      initiator and TPA as a promoter. These results suggested that an extract of the
      roots of the Taraxacum plant could be a valuable chemopreventive agent against
      chemical carcinogenesis.

PMID- 10408235
TI  - Anti-carcinogenic activity of Taraxacum plant. II.
AB  - Eleven triterpenoids (1-11) from the roots of Taraxacum japonicum (Compositae)
      were examined for their inhibitory effects on Epstein-Barr virus early antigen
      (EBV-EA) induced by the tumor promoter, 12-O-tetrade-canoylphorbol-13-acetate
      (TPA), in Raji cells as a primary screening test for anti-tumor-promoters (cancer
      chemopreventive agents). Of these triterpenoids, taraxasterol (1) and taraxerol
      (7) exhibited significant inhibitory effects on EBV-EA induction, but the
      inhibitory effects of their acetates 2 and 8 were weaker than those of 1 and 7.
      Furthermore, 1 and 7 exhibited potent anti-tumor-promoting activity in the two
      stage carcinogenesis tests of mouse skin using 7,12-dimethylbenz[a]anthracene
      (DMBA) as an initiator and TPA as a promoter, and 1 showed a remarkable
      inhibitory effect on mouse spontaneous mammary tumors using C3H/OuJ mouse. These
      results strongly suggested that taraxasterol (1) could be a valuable
      chemopreventive agent.

PMID- 10408236
TI  - Development of an oral formulation of azetirelin, a new thyrotropin-releasing
      hormone (TRH) analogue, using n-lauryl-beta-D-maltopyranoside as an absorption
      enhancer.
AB  - The effects of formulation factors on the enhancement of colonic absorption of
      azetirelin by n-lauryl-beta-maltopyranoside (LM) were studied in rats.
      Coadministration of LM with a small volume of azetirelin solution to the proximal
      colon increased the AUC of the drug by 8.7-fold. There were no significant
      differences in the LM-induced absorption profiles of azetirelin between unligated
      and ligated colon. The addition of a viscous polymer to the drug solution, which
      delayed the in vitro release of both azetirelin and LM, reduced the promoting
      effects of LM. These results suggest that the action of LM is not affected by
      sample spreading in the colonic lumen, whereas a rapid release of both azetirelin
      and LM from the formulation is necessary to maximize the efficacy of LM.
      Utilizing the balloon sonde method, the effects of LM were also confirmed in the
      colonic loop of dogs. Based on these results, an enteric capsule formulation of
      azetirelin containing LM and citric acid (CA), a potential inhibitor of the
      bacterial degradation of azetirelin in the distal intestine, was prepared and its
      performance was evaluated in fasted dogs. The bioavailability of azetirelin after
      the oral administration of this enteric capsule with LM and CA was 43.5% compared
      with a bioavailability of 14.9% in capsules without LM and CA. Therefore, the
      delivery of azetirelin and LM to the lower intestine, together with a rapid
      release of capsule contents, are feasible for the improved peroral
      bioavailability of azetirelin.

PMID- 10408238
TI  - Influence of enzyme distribution and diffusion on permeation profile of prodrug
      through viable skin: theoretical aspects for several steady-state fluxes in two
      transport directions.
AB  - A physical modeling and theoretical simulation aspect for the simultaneous
      transport and metabolism of prodrug in viable skin were described to understand
      the influence of enzyme distribution and diffusion. The physical model was
      formulated assuming that the viable epidermis and dermis have distinct
      diffusional and metabolic characteristics and that the metabolic reaction in each
      layer follows a first-order kinetics. The differential equations were
      analytically solved, and the steady-state flux of prodrug into receiver and that
      of metabolite into receiver and donor and the total flux in forward (epidermis to
      dermis) and backward (dermis to epidermis) directions were derived. The flux of
      prodrug in the forward direction always equals that in the backward direction.
      The metabolite flux into receiver became transport direction-dependent when the
      diffusional characteristic of epidermis was different from that of dermis
      regardless of enzyme distribution. The metabolite flux into donor in the backward
      direction relative to that in the forward direction increased with increase of
      dermis/epidermis ratio of any parameters among metabolic rate constant, partition
      coefficient and diffusion coefficient of prodrug and metabolite. The difference
      of total flux between the 2 transport directions was caused by the difference in
      metabolic rate constant, partition coefficient and diffusion coefficient of
      prodrug between epidermis and dermis. The higher any parameters were for dermis,
      the higher was total flux in the backward direction.

PMID- 10408237
TI  - Effect of dosage form on stereoisomeric inversion of ibuprofen in volunteers.
AB  - Twelve healthy volunteers were given ibuprofen racemate in two different dosage
      forms, a suspension and a tablet. The plasma concentration-time profiles of S-
      and R-ibuprofen were determined and the R-ibuprofen inversion clearance was
      calculated. Although the area under the curve was almost the same in both the
      suspension and tablet studies, the inversion clearance was larger in the
      suspension study than in the tablet study (1.18+/-0.65 and 0.72+/-0.63 l/h, shown
      as the mean+/-S.D.). The Michaelis-Menten parameters for this inversion process
      were then determined in vitro with human liver microsomes (1.3+/-0.2 mM for Km
      and 3.1+/-0.3 nmol/min/mg protein for Vmax, shown as the mean+/-S.D.). These
      parameters indicated that the stereoisomeric inversion of R-ibuprofen in the
      liver was not likely to be saturated at the plasma concentrations measured in the
      volunteer study. The profile of the plasma concentration ratio between S
      ibuprofen and R-ibuprofen revealed a difference in the early phase of these two
      studies. Therefore the inversion difference between those two studies probably
      resulted from the difference in the absorption phase of each dosage form. Our
      study demonstrated that R-ibuprofen inversion could be affected by alteration of
      dosage form.

PMID- 10408240
TI  - Application of a non-linear dispersion model to analysis of the renal handling of
      p-aminohippurate in isolated perfused rat kidney.
AB  - To analyze the renal handling of therapeutic compounds observed as a non-linear
      process with a diffusion phenomenon, we employed a non-linear dispersion model
      described with a partial differential equation and solved it by using the finite
      difference method with an implicit scheme in a model dependent analysis. In this
      study, the renal handling of p-aminohippurate (PAH) was investigated in isolated
      perfused rat kidney, in which a 50 microl bolus of injection solution containing
      [3H]PAH and [14C]inulin was administered rapidly into the renal artery. The
      venous outflows were then collected for 15 min with a fraction collector. The
      renal extraction ratio of PAH was decreased from 65% to 18% as the PAH
      concentration in the injection solution was increased from 2 microM to 10 mM. The
      PAH outflow profile changed as the extraction process became saturated. With the
      non-linear dispersion model, the Michaelis-Menten parameters for the PAH
      extraction process were estimated by a model fitting calculation. The calculated
      values were 0.83 micromol/min/kidney for Vmax and 89 microM for Km. It was
      demonstrated that the model dependent analysis with a non-linear dispersion model
      is a useful approach to characterize renal drug handling, and is probably
      applicable for examining other non-linear processes which involve a diffusion
      phenomenon.

PMID- 10408239
TI  - Single dose pharmacokinetics and pharmacodynamics of oxazepam in normal and renal
      dysfunction rats.
AB  - The purpose of this work was to investigate the disposition characteristics and
      pharmacodynamics of a benzodiazepine, oxazepam, in renal dysfunction rats. For
      the in vivo experiment, normal and renal dysfunction rats were given 40 mg/kg of
      oxazepam as the bolus dose. A quantitative electroencephalographic (EEG) method
      was used as the surrogate measure of the pharmacological response. The oxazepam
      concentration in plasma and cerebrospinal fluid (CSF) was assayed by the HPLC
      method. The steady-state volume of distribution and clearance based on total and
      unbound plasma did not change in renal dysfunction rats. Amplitude changes in the
      EEG induced by oxazepam in normal and renal dysfunction rats were characterized
      by a log-concentration response model or sigmoidal Emax model. The
      pharmacodynamic parameters from these models were not altered in renal
      dysfunction. In in vitro binding studies for gamma-aminobutyric acid (GABA)
      benzodiazepine receptor complex, the oxazepam-induced effect was not potentiated
      by the plasma dialysate from renal dysfunction rats. Thus, it was suggested that
      the brain sensitivity to benzodiazepines was not altered in renal insufficiency.

PMID- 10408241
TI  - Cyclic monoterpene extract from cardamom oil as a skin permeation enhancer for
      indomethacin: in vitro and in vivo studies.
AB  - The in vitro and in vivo effect of pretreatment by cardamom oil, a crude drug
      extract, in ethanol/water vehicles on the transdermal delivery of indomethacin
      was investigated. The cyclic monoterpene components in cardamom oil were also
      determined and quantified in this study. The permeation of indomethacin was
      significantly enhanced after pretreatment of cardamom oil both in the in vitro
      and in vivo studies. The result of various pre-treatment periods showed that the
      indomethacin flux decreased as the length of the pretreatment increased. Both
      natural cardamom oil and a cyclic monoterpene mixture composed of the components
      of the oil showed similar enhancement on indomethacin permeation, indicating
      cyclic monoterpenes are the predominant components altering the barrier property
      of stratum corneum. The results also showed that three minor components in
      cardamom oil (alpha-pinene, 6.5%; beta-pinene, 4.8%; alpha-terpineol, 0.4%) had a
      synergistic effect with 1,8-cineole (59.3%) and d-limonene (29.0%) to enhance the
      permeation of indomethacin.

PMID- 10408242
TI  - Inhibitory effects of hydrolyzable tannins from Melastoma dodecandrum Lour. on
      nitric oxide production by a murine macrophage-like cell line, RAW264.7,
      activated with lipopolysaccharide and interferon-gamma.
AB  - An extract of Melastoma dodecandrum LOUR. with 80% aqueous acetone (MDL)
      inhibited nitric oxide (NO) production by a murine macrophage-like cell line,
      RAW264.7, activated with lipopolysaccharide (LPS) and recombinant mouse
      interferon-gamma (IFN-gamma). On further fractionation of the extract, the
      majority of the inhibitory activity was recovered in the 50% methanol extracts,
      which contained hydrolyzable tannins. Among the latter, casuarinin, casuarictin,
      pedunclagin and nobotannin B exhibited strong inhibitory activities toward NO
      production, with ID50 values between 2.0 and 5.1 microM. Both MDL and the
      purified tannins significantly reduced the induction of the inducible nitric
      oxide synthase (iNOS) protein in the course of macrophage activation with LPS and
      IFN-gamma. In addition, the NO production by macrophages preactivated with LPS
      and IFN-gamma for 16 h was also inhibited by these tannins, with IC50 values
      around 30-130 microM, but not by MDL. These results suggest that MDL has the
      pharmacological ability to suppress NO production by activated macrophages and
      that the hydrolyzable tannins have major inhibitory activities.

PMID- 10408243
TI  - Purification, properties and reactivity of the esterase from Micrococcus sp.
AB  - The esterase from Micrococcus sp., which hydrolyzes n-propyl-2
      fluorocyclopropanecarboxylate (3) enantioselectively, was highly purified by
      three types of chromatography. The purified enzyme was inactivated by Hg and
      diisopropyl fluorophosphate (DFP). It was a monomer with a molecular weight of
      about 35000. The enzyme exhibits esterase activity towards many aliphatic propyl
      esters. The enantioselectivity for substrate (3) using purified enzyme did not
      differ from that of crude enzyme.

PMID- 10408244
TI  - Plasma levels of free and sulfoconjugated catecholamines in patients with
      atherosclerosis.
AB  - We have studied the relationship between free and sulfoconjugated catecholamines
      (CAs) in the plasma of patients with various cardiovascular diseases and have
      described the physiological significance of sulfoconjugated CAs in plasma. In the
      present study, we measured free and sulfoconjugated dopamine (DA) and
      noradrenaline (NA) in the plasma of patients with atherosclerosis (AS). Results
      showed that the plasma levels of free DA and NA in patients with atherosclerosis
      were higher than those in control subjects. Moreover, it was also observed that
      the plasma levels of conjugated DA and NA in patients had a tendency to be higher
      than the levels in control subjects. These results suggest the involvement of
      free CAs in atherosclerosis and that elevated free CAs may be converted to
      sulfoconjugated forms in patients with atherosclerosis.

PMID- 10408245
TI  - Stimulation of cellular XTT reduction by cytochrome oxidase inhibitors.
AB  - XTT reducing activity by CHO and L1210 cells was found to be stimulated by the
      presence of cytochrome oxidase inhibitors such as NaN3 or KCN. Among the other
      respiratory chain inhibitors, antimycin A (a complex III inhibitor) and
      chlorpromazine inhibited cellular XTT reduction, and rotenone and malonate showed
      slight inhibition and no effect, respectively. It is suggested that XTT reduction
      is coupled with the respiratory chain via cytochrome c, which is located between
      complexes III and IV (cytochrome oxidase).

PMID- 10408246
TI  - Effects of NMDA receptor antagonists on morphine tolerance: a c-Fos study in the
      lumbar spinal cord of the rat.
AB  - This study investigated the contribution of NMDA receptors to the development of
      tolerance to the antinociceptive properties of morphine at the level of the
      spinal cord dorsal horn. The expression of c-Fos protein following intraplantar
      (i.pl.) injection of carrageenin (6 mg/150 microl of saline) was used. In naive
      rats, acute intravenous (i.v.) administration of morphine (3 mg/kg) decreased the
      total number per section of Fos-Like-Immunoreactive (Fos-LI) neurons by 51%,
      observed at 2 h after injection of carrageenin. In tolerant rats, acute morphine
      did not significantly modify the total number of Fos-like immunoreactive
      neurons/section. In rats receiving chronic morphine and chronic injections of the
      non-competitive ((+)-MK 801 maleate: (5R,10S)-(+)-5-methyl-10,11-dihydro-5H
      dibenzo[a,d]cyclohepten-5,1 0-imine) or the competitive (LY 235959: [3S
      (3alpha,4a alpha,6beta,8a alpha)]-Decahydro-6-(phosphonomethyl)-3
      isoquinolinecarboxylic+ ++ acid) NMDA receptor antagonists, only partial
      tolerance to the acute effects of morphine were observed (decrease of 42% and
      38%, respectively). Administration of an antagonist at the strychnine-insensitive
      glycine site of the NMDA receptor ((+)-HA-966: R(+)-3-Amino-1-hydroxypyrrolidin-2
      one) did not affect the development of morphine tolerance. These findings suggest
      that compounds attenuating the actions of the NMDA receptor via blockade of the
      glycine modulatory site may be substantially different from those acting at the
      ion channel of the NMDA receptor complex. This in vivo experiment in freely
      moving animals demonstrates for the first time an attenuation of tolerance at the
      cellular level.

PMID- 10408247
TI  - Autoradiographic analysis of 5-HT2A binding sites in the brain of Sardinian
      alcohol-preferring and nonpreferring rats.
AB  - The density of 5-HT2A binding sites in the brain of Sardinian alcohol-preferring
      (sP) and nonpreferring (sNP) rats was evaluated, using [3H]ketanserin for
      quantitative autoradiography. The highest [3H]ketanserin binding levels were
      found in the anterior olfactory nucleus, prefrontal cortex, medial prefrontal
      cortex, post-genual anterior cingulate cortex, insular cortex and claustrum.
      Statistically significant differences between sP and sNP rats were found in
      prefrontal cortex, medial prefrontal cortex and post-genual anterior cingulate
      cortex, where sP rats showed about 20% lower [3H]ketanserin binding levels. No
      significant difference was found in other areas, although some of them showed
      slightly lower [3H]ketanserin binding density in sP rats. The 5-HT2A receptor
      agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane hydrochloride
      (DOI), microinjected into the medial prefrontal cortex, induced a lower number of
      wet dog shakes in sP than in sNP rats. These results indicate a different density
      of 5-HT2A binding sites, and a different functional regulation of 5-HT2A receptor
      mechanisms in discrete brain areas of sP, in comparison to sNP rats. These
      findings, and those showing lower levels of 5-HT in the frontal cortex of sP
      rats, suggest that altered 5-HT function in fronto-cortical areas could be linked
      to the genetic predisposition to high voluntary ethanol intake in these rats.

PMID- 10408248
TI  - Enalapril and moexipril protect from free radical-induced neuronal damage in
      vitro and reduce ischemic brain injury in mice and rats.
AB  - Angiotensin-converting enzyme inhibitors have been demonstrated to protect
      spontaneously hypertensive rats from cerebral ischemia. The present study
      investigated the protective effect of enalapril and moexipril in models of
      permanent focal cerebral ischemia in normotensive mice and rats. To elucidate the
      mechanism of neuroprotection the influence of these angiotensin-converting enzyme
      inhibitors on glutamate-, staurosporine- or Fe2+/3+-induced generation of
      reactive oxygen species and neuronal cell death in primary cultures from chick
      embryo telencephalons was studied. Treatment with moexipril or enalapril dose
      dependently reduced the percentage of damaged neurons, as well as mitochondrial
      reactive oxygen species generation induced by glutamate, staurosporine or
      Fe2+/3+. Furthermore, moexipril and enalapril attenuated staurosporine-induced
      neuronal apoptosis as determined by nuclear staining with Hoechst 33258. In mice,
      1 h pretreatment with enalapril (0.03 mg/kg) or moexipril (0.3 mg/kg)
      significantly reduced brain damage after focal ischemia as compared to control
      animals. Additionally, moexipril (0.01 mg/kg) was able to reduce the infarct
      volume in the rat model after focal cerebral ischemia. The results of the present
      study indicate that the angiotensin-converting enzyme inhibitors enalapril and
      moexipril promote neuronal survival due to radical scavenging properties.

PMID- 10408249
TI  - Intrarenal angiotensin converting enzyme inhibition in spontaneously hypertensive
      rats.
AB  - We examined the hypotensive effect of enalapril in relation to the local renin
      angiotensin system of the kidney in spontaneously hypertensive rats (SHR). Oral
      administration of enalapril for 7 days decreased mean arterial blood pressure and
      renal tissue angiotensin II concentration without affecting plasma angiotensin II
      concentration in SHR. The enalapril treatment did not affect maximum binding of
      angiotensin II to renal tubules and glomeruli in SHR. In normotensive Wistar
      Kyoto rats, no significant changes in mean arterial blood pressure, renal and
      plasma angiotensin levels were observed with enalapril treatment. Direct infusion
      of enalapril into the renal medullary interstitium decreased mean arterial blood
      pressure in association with the reduction of renal tissue angiotensin II
      concentration without changes in plasma angiotensin II concentration in SHR.
      These observations suggest that the inhibition of angiotensin conversion in the
      kidney is important for the hypotensive action of enalapril.

PMID- 10408250
TI  - Pentoxifylline improves circulatory failure and survival in murine models of
      endotoxaemia.
AB  - Pentoxifylline, a methylxanthine derivative, has been widely used to improve
      erythrocyte deformability and capillary blood circulation in patients with
      claudication and cerebrovascular disorders as well as in animals with sepsis.
      Here, we investigate the effects of pentoxifylline on the hypotension, vascular
      hyporeactivity to noradrenaline, release of tumour necrosis factor-alpha (TNF
      alpha) and nitric oxide (NO), and inducible NO synthase protein expression in a
      rat model of circulatory shock induced by bacterial endotoxin (Escherichia coli
      lipopolysaccharide). In addition, we have evaluated the effect of pentoxifylline
      on the 36-h survival rate in a murine model of endotoxaemia. Male Wistar-Kyoto
      rats were anaesthetised and instrumented for the measurement of mean arterial
      pressure and heart rate. Injection of lipopolysaccharide (10 mg/kg, i.v.)
      resulted in a significant fall in mean arterial pressure and an increase of heart
      rate. In contrast, animals pretreated with pentoxifylline (3 mg/kg, i.v., at 30
      min prior to lipopolysaccharide) maintained a significantly higher mean arterial
      pressure but showed no effect on the tachycardia when compared to rats given only
      lipopolysaccharide (lipopolysaccharide-rats). The pressor effect of noradrenaline
      (1 microg/kg, i.v.) was also significantly reduced after the treatment of rats
      with lipopolysaccharide. Similarly, rings of thoracic aorta obtained from
      lipopolysaccharide-rats showed a significant reduction in the contractile
      responses elicited by noradrenaline (1 microM). Pretreatment of
      lipopolysaccharide-rats with pentoxifylline partially, but significantly,
      prevented this lipopolysaccharide-induced hyporeactivity to noradrenaline in vivo
      and ex vivo. The injection of lipopolysaccharide resulted in bell-shape changes
      in plasma TNF-alpha level which reached a peak at 60 min, whereas the effect of
      lipopolysaccharide on the plasma level of nitrate (an indicator of NO formation)
      was increased in a time-dependent manner. This increase of both TNF-alpha and
      nitrate levels induced by lipopolysaccharide was significantly reduced in
      lipopolysaccharide-rats pretreated with pentoxifylline. Endotoxaemia for 240 min
      caused a significantly increased protein expression of inducible NO synthase in
      the lung. In lipopolysaccharide-rats pretreated with pentoxifylline, inducible NO
      synthase protein expression in lung homogenates was attenuated by 48 +/- 5%.
      Treatment of conscious mice with a high dose of endotoxin (60 mg/kg, i.p.)
      resulted in a survival rate of only 10% at 36 h (n = 20). However, therapeutic
      application of pentoxifylline (3 mg/kg, i.p. at 0, 6, 15 and 24 h after
      lipopolysaccharide) increased the 36-h survival to 35% (n = 20). Thus,
      pentoxifylline protects against circulatory failure and improves survival in
      rodents with severe endotoxaemia. These effects may be due to inhibition of the
      release of TNF-alpha and of the induction of inducible NO synthase.

PMID- 10408251
TI  - Effects of alpha1-adrenoceptor antagonists on agonist and tilt-induced changes in
      blood pressure: relationships to uroselectivity.
AB  - We evaluated the uroselectivity of a series of alpha1-adrenoceptor antagonists by
      comparing their potency against phenylephrine-induced increases in urethral
      perfusion pressure and diastolic blood pressure in the anesthetized rabbit and
      pithed rat. In the rabbit, Rec 15/2739 (N-[3-[4-(2-methoxyphenyl)-1
      piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl -4H-1-benzopyran-8-carboxamide) as
      well as analogs with a chlorine substituent on the methoxyphenyl ring (Rec
      15/2869) or this substituent combined with the replacement of the phenyl
      substituent on the pyran ring by cyclohexyl (Rec 15/3011) were 2-6-fold more
      potent against the urethral vs. vascular response to phenylephrine. Rec 15/2841
      (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-cyc lohexy-4H-1
      benzopyran-8-carboxamide) was only 1.5-fold more potent against the urethral
      response. SL 89.0591 and tamsulosin also showed selectivity for the urethral
      response (2-2.5-fold), while the quinazolines produced equipotent blockade of
      urethral and vascular responses (selectivity ratio = 0.9-1.1). The urethral
      selectivities of Rec 15/2739 and its derivatives were confirmed by evaluation of
      the response to tilt in sedated, hypovolemic rabbits. Phenylephrine challenge
      assays did not show any of the antagonists, with the exception of terazosin at
      300 microg kg(-1), to be uroselective in the rat (selectivity ratios = 0.2-1.5);
      potentiation of tilt-induced hypotension in the anesthetized rat showed
      substantial differences from the rabbit, with Rec 15/2739, but not Rec 15/3011
      and Rec 15/2841 showing orthostatic effects equivalent to that observed for
      prazosin. Hence, Rec 15/2739 was uroselective in the rabbit, but not in the rat,
      while two of its close structural analogs were highly uroselective in both
      species. An assay for orthostatic activity in the conscious rat yielded different
      results, showing prazosin and terazosin, but not Rec 15/2739, to cause a reversal
      of the pressor response to tilt. Hence, the apparent uroselectivity of an alpha1
      adrenoceptor antagonist is both species- and assay-dependent.

PMID- 10408252
TI  - Gastroprotections of escins Ia, Ib, IIa, and IIb on ethanol-induced gastric
      mucosal lesions in rats.
AB  - Effects of escins Ia, Ib, IIa, and IIb isolated from horse chestnuts on ethanol
      induced gastric mucosal lesions and the roles of capsaicin-sensitive afferent
      neurons, endogenous nitric oxide (NO), sulfhydryls, prostaglandins, as well as
      gastric secretion and the sympathetic nervous system, were investigated in rats.
      Test samples were given orally to fasted rats 1 h before ethanol (1.5 ml/rat,
      p.o.) treatment or ligation of the pylorus. Escins Ia-IIb (10-50 mg/kg) potently
      inhibited ethanol-induced gastric mucosal lesions, whereas desacylescins I and II
      (50 mg/kg) showed no such effect. These active saponins (10 and 20 mg/kg) did not
      decrease the gastric secretion. The gastroprotections of escins Ia-IIb were
      attenuated by the pretreatment with capsaicin, N(G)-nitro-L-arginine methyl
      ester, and indomethacin, but not by N-ethylmaleimide. The effects of escins Ia
      IIb were also attenuated in streptozotocin-induced diabetic rats, in which the
      activity of the sympathetic nervous system was abnormal. These results suggest
      that the gastroprotections of escins Ia-IIb on ethanol-induced gastric mucosal
      lesions are acid-independent, whereas endogenous prostaglandins, NO, capsaicin
      sensitive afferent neurons, and the sympathetic nervous system participate.

PMID- 10408254
TI  - Triglyceride-lowering effect of a novel insulin-sensitizing agent, JTT-501.
AB  - JTT-501, 4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3, 5
      isoxazolidinedione, is a novel insulin-sensitizing agent. We investigated the
      triglyceride-lowering activity of JTT-501 in a high-fat (HF) rat model. The HF
      rats showed insulin resistance with elevation of fasting insulin levels and
      reduction of insulin-stimulated glucose oxidation. There was also a tendency
      towards increased basal insulin and triglyceride levels. Oral administration of
      JTT-501 (3-30 mg kg(-1) day(-1) for 7 days) reduced basal triglyceride levels
      dose dependently with a minimum effective dose of 3 mg kg(-1) day(-1).
      Furthermore, regarding triglyceride metabolism, JTT-501 (30 mg kg(-1) day(-1) for
      15 days, p.o.) decreased hepatic triglyceride output rate and serum triglyceride
      half-life (T1/2). In contrast, pioglitazone (30 mg kg(-1) day(-1) for 15 days,
      p.o.) reduced T1/2, but did not affect hepatic triglyceride output rate. We
      conclude that JTT-501 possesses potent triglyceride-lowering activity due to its
      inhibition of triglyceride secretion from the liver and enhancement of
      triglyceride disposal in peripheral tissues.

PMID- 10408253
TI  - CCK1 and CCK2 receptors regulate gastric pepsinogen secretion.
AB  - The present study investigated (1) the pharmacological profile of cholecystokinin
      (CCK) receptor subtypes involved in the regulation of gastric pepsinogen
      secretion, (2) the influence of gastric acidity on peptic responses induced by
      CCK-8-sulfate (CCK-8S) or gastrin-I; and (3) the mechanisms accounting for the
      effects of CCK-like peptides on pepsinogen secretion. In anaesthetized rats, i.v.
      injection of CCK-8S or gastrin-I increased both pepsinogen and acid secretion.
      The pepsigogue effect of CCK-8S was higher than that of gastrin-I, whereas acid
      hypersecretion after CCK-8S was lower than that induced by gastrin-I. Peptic
      output following CCK-8S was partly blocked by i.v. injection of the CCK1 receptor
      antagonist, devazepide (-75.3%), or the CCK2 receptor antagonist, L-365,260
      [3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 yl)-N'-(3
      methyl-phenyl)urea; -27.9%], but was fully prevented by combined administration
      of devazepide and L-365,260. The gastric acid hypersecretory effect of CCK-8S was
      enhanced by devazepide (+84.5%) and blocked by L-365,260. In contrast, the
      gastric secretory actions of gastrin-I were insensitive to devazepide, but
      abolished by L-365,260. Excitatory effects of CCK-8S and gastrin-I were not
      modified by vagotomy or atropine, whereas cimetidine or alpha
      fluoromethylhistidine (irreversible blocker of histidine decarboxylase) partly
      prevented acid hypersecretion induced by both peptides without affecting their
      pepsigogue effects. After pretreatment with omeprazole, both CCK-8S and gastrin-I
      failed to stimulate acid secretion, while they increased pepsinogen output. In
      rats with gastric perfusion of acid solutions, CCK-8S or gastrin-I increased
      peptic output in a pH-independent manner either with or without pretreatment with
      omeprazole. Ablation of capsaicin-sensitive sensory nerves as well as application
      of lidocaine to the gastric mucosa failed to modify the excitatory effects of CCK
      8S or gastrin-I on pepsinogen and acid secretion. Blockade of the nitric oxide
      (NO) synthase pathway by N(G)-nitro-L-arginine-methyl ester prevented the
      pepsigogue actions of both CCK-8S and gastrin-I (-61.8% and -71.7%,
      respectively), without affecting the concomitant increase in acid output. In
      addition, both these peptides significantly increased the release of NO breakdown
      products into the gastric lumen. The present results suggest that: (1) both CCK1
      and CCK2 receptors mediate the peptic secretory responses induced by CCK-like
      peptides; (2) the excitatory inputs of CCK-8S and gastrin-I to chief cells are
      not driven through acid-dependent mechanisms or capsaicin-sensitive afferent
      sensory nerves; and (3) under in vivo conditions, the stimulant actions of CCK
      like peptides on pepsinogen secretion are mediated, at least in part, by an
      increase in NO generation.

PMID- 10408255
TI  - Selectivity of dihydropyridines for cardiac L-type and sympathetic N-type Ca2+
      channels.
AB  - The blocking effects of cilnidipine and other dihydropyridines on L-type cardiac
      Ca2+ channels (I(Ca,L)) and N-type sympathetic Ca2+ channel currents (I(Ca,N))
      were studied using a whole-cell patch-clamp technique. At -80 mV, cilnidipine had
      little inhibitory effect below concentrations of 1 microM on I(Ca,L) (IC50 value;
      17 microM). However, 1 microM cilnidipine strongly shifted the steady-state
      inactivation curve of I(Ca,L) toward negative potentials without changing the
      current-voltage relationship. Each action of cilnidipine was characterized by a
      high affinity for the inactivated channel in preference to the resting channel.
      The IC50 values of dihydropyridines for I(Ca,L) were in the range between 0.01
      and 10 microM, and those for I(Ca,N) were between 3 and 30 microM. Cilnidipine
      had the strongest affinity for I(Ca,N) among the dihydropyridines tested. These
      results suggest that cilnidipine did not cause hypotension-evoked tachycardia
      deficiency by depression of cardiac L-type channels but by sympathetic N-type
      channels blockade.

PMID- 10408256
TI  - Protein kinase C epsilon-dependent pathway of extracellular signal-regulated
      protein kinase activation by P2Y1 and P2Y2 purinoceptors that activate cytosolic
      phospholipase A2 in endothelial cells.
AB  - The aim of this study was to investigate the stimulating effects on arachidonic
      acid release of P2Y1 and P2Y2 receptor-selective agonists, 2-methylthio-ATP
      (2MeSATP) and UTP, respectively, in bovine pulmonary artery endothelial cells.
      Exposure of cells to 2MeSATP and UTP led to the release of arachidonic acid, a
      response which was abolished by the removal of extracellular Ca2+ and methyl
      arachidonyl fluorophosphonate. Phorbol 12-myristate 13-acetate (PMA) itself not
      only stimulated arachidonic acid release but also played a permissive role in the
      response to UTP. However, PMA failed to enhance the arachidonic acid response
      induced by 2MeSATP, probably due to greater attenuation of the [Ca2+]i increase
      caused by 2MeSATP than UTP. Inhibition of protein kinase C with Ro 31-8220 (1-[3
      (amidinothio) propyl-1H-indoyl-3-yl]-3-(1-methyl-1H-indoyl-3-yl)-maleimide 
      methane sulphate) and staurosporine, but not with Go 6976 (12-(-2-cyanoethyl)
      6,7,12,13-tetrahydro-13-methyl-5-oxo-indolo(2, 3-a)pyrrolo(3,4-c)carbazole),
      reduced the arachidonic acid response of 2MeSATP, UTP and PMA. PMA-induced
      potentiation of the UTP response reached a maximum after a 1-h preincubation,
      then declined and eventually lost its effect when the preincubation lasted up to
      8 h. Among the protein kinase C isoforms present in endothelial cells, betaI and
      epsilon could be down-regulated by treatment with PMA for 4-24 h. PD 098059 (2-(2
      Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) inhibited extracellular signal
      regulated protein kinase activation, cytosolic phospholipase A2 phosphorylation
      and arachidonic acid release caused by 2MeSATP, UTP and PMA. Taken together, our
      results demonstrate that P2Y1 and P2Y2 purinoceptors mediate arachidonic acid
      release by activating cytosolic phospholipase A2 through an elevation of [Ca2+]i
      and protein kinase C epsilon-, extracellular signal-regulated protein kinase
      dependent phosphorylation.

PMID- 10408257
TI  - Troglitazone inhibits the capacitative Ca2+ entry in endothelial cells.
AB  - To investigate the effects of troglitazone on the capacitative Ca2+ entry, we
      monitored changes in cytosolic Ca2+ concentrations ([Ca2+]i) induced by
      thapsigargin in fura-2-loaded porcine endothelial cells in situ and in primary
      culture. In aortic valve endothelial cells in situ, thapsigargin induced
      sustained elevation of [Ca2+]i. Both troglitazone and SKF 96365 inhibited the
      steady state increase in [Ca2+]i in a concentration-dependent manner. At 30
      microM, troglitazone and SKF 96365 inhibited the [Ca2+]i elevation to 19.4 +/-
      3.6% and 43.9 +/- 4.5%, respectively. In aortic endothelial cells in primary
      culture, both troglitazone (10 microM) and SKF 96365 (100 microM) completely
      inhibited the thapsigargin-induced [Ca2+]i increase. The EC50 value of
      troglitazone (1.4 +/- 0.1 microM) was lower than that of SKF 96365 (10.0 +/- 3.3
      microM). We suggest that troglitazone would be a useful tool to investigate the
      capacitative Ca2+ entry.

PMID- 10408258
TI  - Recombinant human erythropoietin stimulates vascular endothelial growth factor
      release by glomerular endothelial cells.
AB  - We designed the present study to address the question of whether recombinant
      human erythropoietin stimulates DNA synthesis and vascular endothelial growth
      factor (VEGF) secretion in vitro using cultured bovine glomerular endothelial
      cells (GENs). Recombinant human erythropoietin dose-dependently stimulated the
      proliferation of GENs in culture, and this proliferative effect was inhibited by
      1 microg/ml anti-VEGF antiserum. The increase in VEGF concentrations in the
      supernatants containing 10 U/ml rHuEpo was abolished by incubation with 10
      microg/ml of anti-human rHuEPO antiserum, 0.2 microg/ml actinomycin D or 10
      microg/ml cycloheximide. Taken together, rHuEpo stimulates GEN proliferation in
      vitro and VEGF release from these cells is associated with stimulation of RNA
      dependent DNA and protein synthesis.

PMID- 10408259
TI  - Can suicide research lead to suicide prevention?

PMID- 10408260
TI  - Autism: not an extremely rare disorder.
AB  - OBJECTIVE: To study autism over time in order to ascertain whether there has been
      an increase in its prevalence in recent years. METHOD: All English language
      papers on the prevalence of autism were reviewed. Ten of the studies retrieved
      were not used in the final analysis because they did not meet full criteria for
      inclusion in the review. The remaining 20 studies, published between 1966 and
      1997, were subdivided into US studies (n=2) and non-US studies (n=18), and the
      latter group was subdivided into four 8-year periods. RESULTS: The early studies
      yielded prevalence rates of under 0.5 in 1000 children, whereas the later ones
      showed a mean rate of about 1 in 1000. There was a marked difference in
      prevalence rates between those studies that included some children born before
      1970 (low rates) and those that included only children born in 1970 and after
      (high rates). This is probably due to the lower rates obtained by use of criteria
      strictly based on Kanner's description of his syndrome. The US studies reported
      atypically low rates. There was a highly significant estimated increase with
      calendar year in the non-US studies (3.8% per year). CONCLUSION: It is concluded
      that autism is considerably more common than was previously believed. The
      possible reasons for the higher reported rates are discussed.

PMID- 10408261
TI  - Are risk factors for suicide universal? A case-control study in India.
AB  - OBJECTIVE: The majority of suicides in India occur in the young. Indian society,
      religion and culture are very different to those in the West. The aim of the
      present study was to identify the risk factors for completed suicide. METHOD: A
      population-based case-control study employing the 'psychological autopsy'
      technique was conducted. In total, 100 completed suicides and 100 neighbourhood
      controls were studied. RESULTS: The odds ratios for the risk factors were 19.5
      (CI, 7.32-73.35) for presence of an Axis I disorder, 12.75 (CI, 4.69-48.59) for
      family history of psychopathology and 15.1 (CI, 2.4-93.9) for life events in the
      previous month. CONCLUSION: The presence of an Axis I disorder, family history of
      psychopathology and recent life events were all found to be significant risk
      factors. These findings suggest that risk factors for completed suicide are
      universal across countries and cultures.

PMID- 10408262
TI  - Attempted suicide and major public holidays in Europe: findings from the WHO/EURO
      Multicentre Study on Parasuicide.
AB  - OBJECTIVE: The aim of the study was to examine the relationship between suicide
      attempts and major public holidays in Europe. METHOD: The analysis was based on
      data on 24 388 suicide attempts by persons aged 15 years or older in the period
      1989-1996. Data from 13 centres (representing 11 countries) participating in the
      WHO/EURO Multicentre Study on Parasuicide were analysed. The analysis of the
      fluctuation of suicide attempts around public holidays was based on the daily
      number of suicide attempts for each centre. For each day in the period under
      examination a mean number of suicide attempts (mu) was calculated. The analysis
      was based on the assumption that the data followed a Poisson distribution. The
      observed number of daily suicide attempts was compared with the expected number
      of attempts. A multiplicative model for the expected number in each centre was
      developed. RESULTS: Before Christmas there were fewer suicide attempts than
      expected, and after Christmas there were approximately 40% more attempts than
      expected. In addition, more attempts than expected were registered on New Year's
      Day. In countries where people have the day off work on Whit Monday there were
      significantly fewer attempts during the 3 days before, but where Whit Monday is a
      normal working day significantly fewer attempts occurred on the Monday to
      Wednesday after Whit Sunday. CONCLUSION: There appears to be a transposition of a
      significant number of suicide attempts from before (and during) a major public
      holiday until after it. The division of holidays into non-working and working
      days showed that a 'holiday effect' could only be found around major public
      holidays, particularly Christmas, Easter and Whitsun. These findings support the
      theory of the 'broken-promise effect' for major public holidays.

PMID- 10408263
TI  - Time trends in suicide mortality in Lithuania.
AB  - OBJECTIVE: The aim of this study was to analyse the time trends of suicides
      during the period 1970-1995 in Lithuania, and to assess the importance of the
      effects of age, period and birth cohort as risk factors. METHOD: Trends in
      suicides and average annual changes were based on logarithmic regression
      analysis. For assessment of the effects of age, period and birth cohort on
      suicide mortality, a log-linear regression model with parameters representing
      age, period and cohort effects was fitted. RESULTS: Between 1970 and 1995 age
      standardized suicide rates almost doubled. There was an increase in suicides in
      birth cohorts of males from 1910 to 1950, and in cohorts born after 1965. In
      females, an increase was observed in all successive birth years from 1905 to 1925
      and after 1970. The period effect in males and the cohort effect in females were
      dominant. CONCLUSION: It is unlikely that suicide rates will decrease in the near
      future.

PMID- 10408264
TI  - Assessing varying degrees of lethality in depressed adolescent suicide
      attempters.
AB  - OBJECTIVE: Understanding the lethality of suicide attempts and its relation to
      other psychological variables may improve clinical judgement with regard to
      suicide risk. METHOD: The lethality of suicidal behaviour was examined in 60
      hospitalized adolescent in-patients who had recently attempted suicide. Subjects
      were divided into non-lethal, low-lethal and high-lethal groups based on the
      qualities of their suicidal acts. RESULTS: The groups did not differ in terms of
      hopelessness, depression, substance abuse or self-esteem. Moreover, they did not
      differ significantly in diagnoses of major depression, adjustment disorder,
      substance abuse and bipolar disorder. The group of high-lethal attempters was the
      only group with several individuals diagnosed with a major depressive episode and
      comorbid attention deficit disorder. The high-lethal group also reported the
      strongest desire to end their lives. CONCLUSION: Based on lethality of suicide
      attempts, adolescent suicide attempters can be differentiated in terms of the
      wish to die as well as some instances of diagnostic comorbidity. However, they
      may not be differentiated in terms of severity of depression or hopelessness,
      demographic variables and other aspects of suicidal behaviour.

PMID- 10408265
TI  - MMPI variables predictive of schizophrenia in the Copenhagen High-Risk Project: a
      25-year follow-up.
AB  - Moldin et al. (1) have identified a cluster of Minnesota Multiphasic Personality
      Inventory (MMPI) scales that discriminate adolescents at risk for schizophrenia
      from those not at risk. The present study examines how well Moldin's scales
      predict schizophrenic decompensation in a sample of 207 Danish adolescents at
      high genetic risk for schizophrenia. Subjects were assessed using a modified, 304
      item MMPI in 1962 (mean age= 15.1 years) and diagnosed in 10-year and 25-year
      follow-ups. Premorbidly, schizophrenic subjects (n=31) scored higher than
      subjects with no mental illness on the frequency (F) and psychoticism (PSY)
      scales. When paranoid and non-paranoid preschizophrenics were separated, three
      scales (F, Pz (paranoid schizophrenia) and PSY) significantly discriminated
      paranoid preschizophrenics. Discriminant function analyses confirmed these
      results. It is concluded that the MMPI may be useful for identifying
      schizophrenia premorbidly.

PMID- 10408266
TI  - The fertility and fecundity of patients with psychoses.
AB  - OBJECTIVE: Previous research has suggested that patients with schizophrenia have
      fewer offspring compared to the general population. Reduced fertility in a
      disorder with a strong genetic component and an apparently stable incidence has
      implications for models of genetic transmission. There is also a need to obtain
      contemporary estimates of the prevalence of parenthood among subjects with
      psychotic disorders in order to inform service planning. The aim of this study
      was to determine the fertility and fecundity of a representative sample of
      individuals with psychoses who were in contact with mental health services, and
      to explore the interactions between age at first diagnosis and fertility. METHOD:
      All clients of two community mental health clinics and an extended-care
      psychiatric hospital were surveyed. Data on diagnosis, age at first diagnosis,
      and the number and age of offspring were collected. Based on interviews with the
      proband and chart review, a genogram of the probands' family was drawn that
      identified sex, age, affected status and the number of offspring for each patient
      and their siblings. RESULTS: In total, 36% of all patients were parents. Most
      women with psychoses (59%) were mothers. Patients with psychoses had fewer
      offspring compared to their unaffected same-sex siblings. This was especially the
      case for men with non-affective psychoses. Higher levels of fertility were
      associated with a later age at first diagnosis. CONCLUSION: The consistent
      finding of reduced 'reproductive fitness' in those with non-affective psychoses
      needs to be incorporated in the genetic epidemiology of these disorders. Despite
      this reduction in fertility and fecundity, many patients with psychoses are
      parents. Services need to remain mindful of the special needs of these patients.

PMID- 10408267
TI  - Symptom classification of schizophrenia changes with the duration of illness.
AB  - Our starting hypothesis was that schizophrenic symptomatology changes over time.
      This hypothesis explains conflicting reports on schizophrenic symptom structures
      as a consequence of different durations of illness in the samples studied to
      date. Therefore a sample of 258 schizophrenic in-patients (with ICD-10 diagnoses
      F20) was categorized according to illness duration. A factor analysis was
      performed on the 8 items of the Manchester Scale for three subgroups (duration <
      10 years, 10> or =20 years and > or = 20 years). For those patients whose illness
      duration was less than 10 years, 'formal thought disorder' was not related to any
      other mental state, whereas for those whose duration was 10 years or longer, it
      was correlated with 'negative symptoms'. In the < 10 years group, 'anxiety and
      depression syndrome' and 'positive symptoms' formed one complex, but these
      symptoms were separated into two distinct syndromes in the > or = 20 years group.
      Thus we were able to demonstrate that the classification of symptoms changes with
      increasing duration of illness.

PMID- 10408268
TI  - Prelingually profoundly deaf schizophrenic patients who hear voices: a
      phenomenological analysis.
AB  - OBJECTIVE: The aims of the study were to examine claims that profoundly deaf
      schizophrenic patients report auditory hallucinations, and to evaluate proposed
      explanations that such patients are really describing other symptoms, or that the
      phenomenon is restricted to those who had heard and understood language prior to
      becoming deaf. METHOD: A total of 17 schizophrenic/schizoaffective patients with
      onset of profound deafness prior to the age of 2 years underwent structured
      psychiatric interview. RESULTS: Ten patients (59%) gave accounts of verbal
      auditory hallucinations with description of content. These did not appear to be
      attributable to other psychotic experiences and showed typical characteristics of
      schizophrenic hallucinations. The symptom was present in six patients who had
      been deaf from birth or early infancy. CONCLUSION: These findings suggest that
      auditory hallucinations are a common phenomenon in profoundly prelingually deaf
      schizophrenic patients, which cannot be accounted for by the above explanations.

PMID- 10408269
TI  - Early visual information processing and the Defence Mechanism Test in
      schizophrenia.
AB  - OBJECTIVE: The aim of this study was to determine whether impairment in visual
      information processing measured by backward masking was related to high threshold
      values in the Defence Mechanism Test (DMT) in patients with schizophrenia.
      METHOD: A total of 20 patients with schizophrenia according to DSM-IV, most of
      whom were out-patients, were studied with backward masking and a modified version
      of the DMT (DMTm). RESULTS: Nine of the patients showed an impairment in backward
      masking. There was a relationship between impairment in backward masking and the
      DMTm with either no or a late C-phase (correct perception in DMTm) in the first
      series, and a late perception of the peripheral person in the second series.
      There was no relationship for the other 14 threshold values. The patients did not
      have high threshold values in the DMTm as was expected. CONCLUSION: In this
      sample consisting mainly of out-patients, there were few relationships between
      impairment in backward masking and high threshold values in DMTm. Their visual
      information processing was not as disturbed as expected. Most previous studies on
      both backward masking and the DMT in patients with schizophrenia have been
      conducted among in-patients, who could be expected to be more disturbed than the
      out-patients in the present study. The results of studies on in-patients with
      schizophrenia must not be generalized to include out-patients, and vice versa.

PMID- 10408270
TI  - Subjective and external assessments of quality of life in schizophrenia:
      relationship to insight.
AB  - OBJECTIVE: This study assessed the manner in which insight influenced
      schizophrenic patients' evaluation of their objective life conditions and the
      concurrent validity between patients' and clinicians' assessments of patients'
      global quality of life. METHOD: Forty out-patients who fulfilled DSM-III-R
      criteria for schizophrenia were independently interviewed using the Lancashire
      Quality of Life Profile and the Standard of Living Interview. Insight was
      assessed using a self-report questionnaire, the Insight Scale. RESULTS: For
      insightful patients there was a significant but modest correlation between
      objective and subjective indicators of quality of life. Likewise, a significant
      correlation between subjective and external evaluations of global quality of life
      was limited to those individuals who had good insight. CONCLUSION: Diminished
      insight may limit the usefulness of the self-report methodology for assessing
      quality of life for some individuals with schizophrenia.

PMID- 10408272
TI  - Proton NMR relaxation studies of solid tyrosine derivatives and their mixtures
      with L-leucinamide.
AB  - Proton NMR relaxation time measurements were carried out on solid tyrosine
      derivatives: acetyl-L-tyrosine ethyl ester (Ac-Tyroet), N-carbobenzyloxy-L
      tyrosine ethyl ester (CBZ-Tyroet), N-trifluoroacetyl-L-tyrosine ethyl ester (TFAc
      Tyroet) and their mixtures with L-leucinamide. It was found that spin-lattice
      relaxation was driven mainly by methyl group rotation it low temperature for the
      pure solids and the mixtures. Benzene ring flipping motion and a third motion
      (possibly whole molecule tumbling) were found to be responsible for relaxing Ac
      Tyroet and CBZ-Tyroet at high temperature. However, these motions were highly
      hindered in TFAc-Tyroet. Molecular tumbling motion was detected in the
      supercooled liquid mixtures of L-leuNH/CBZ-Tyroet and L-leuNH/Ac-Tyroet, while
      this motion is absent in the mixture L-leuNH/TFAc-Tyroet. The hindered motion in
      TFAc-Tyroet may be one of the factors affecting its ability to form a supercooled
      liquid with L-leucinamide.

PMID- 10408273
TI  - To what extent does the centerband and each spinning sideband contain
      contributions from different crystallites of the powder sample?
AB  - It is shown that due to the destructive interference of the magnetization paths
      of crystallites taking place during the rotor period at slow spinning regime, the
      contribution of different crystallites to the centerband and to each spinning
      sideband is strongly weighted. For this, a separated-local-field experiment is
      used to tag the crystallites contributing to a given spinning sideband at
      different spinning speeds. The orientation dependence of spinning sidebands is
      also responsible for different lineshapes of the centerband and of each spinning
      sidebands observed under conditions of off-magic angle spinning.

PMID- 10408271
TI  - Very fast MAS and MQMAS NMR studies of the spectroscopically challenging minerals
      kyanite and andalusite on 400, 500, and 800 MHz spectrometers.
AB  - The well-characterized minerals kyanite and andalusite have long presented great
      challenges in using solid state 27Al NMR to determine the isotropic chemical
      shift deltaCS, quadrupole coupling constant e2qQ/h, and asymmetry parameter eta
      for each of the inequivalent aluminum sites in these minerals. Indeed, these
      minerals have frequently been used to test advances in instrumentation. Recent
      advances in magnet technology (up to 18.8 T = 800 MHz 1H) and in MAS probe
      technology (spinning up to 35 kHz and considerably stronger rf) and refinements
      of the two-dimensional, multiple quantum magic angle spinning (MQMAS) technique
      suggested that these developments could be profitably used to study kyanite and
      andalusite by solid state 27Al NMR. The benefit of being able to study kyanite
      both by MAS and MQMAS techniques on 400, 500, and 800 MHz spectrometers is
      demonstrated. The two octahedral aluminum sites with the largest (and nearly
      equal) e2qQ/h values give overlapping 1D MAS or 2D 3QMAS signals at all three
      field strengths. Nevertheless, quantitatively accurate 3Q signal intensities at
      9.4 T for all four octahedral aluminum sites (with e2qQ/h values up to 10 MHz)
      allow more detailed analysis. Even if the 3Q signal intensities are not
      quantitative, their isotropic shifts provide an approach (if accurate e2qQ/h and
      eta values are available) other than deconvolution of the MAS spectrum for
      calculating deltaCS values. For andalusite, 34 kHz MAS on the 800 MHz
      spectrometer significantly narrows the extremely broad signal for the octahedral
      aluminum, and only slight difficulties are encountered in quantitating the
      relative amounts of AlO5 and AlO6 present. Even with e2qQ/h = 15.3 MHz, the
      octahedral aluminum in andalusite gives a signal in a MQMAS experiment, albeit of
      reduced intensity. As appropriate, we discuss some of the benefits and
      limitations of these advances in instrumentation and of different experimental
      approaches for studying non-integral spin quadrupolar nuclei in solids.

PMID- 10408274
TI  - Multiple-quantum relaxation in the magic-angle-spinning NMR of 13C spin pairs.
AB  - We determine the decay rate constants of zero-, double- and single-quantum
      coherence for 13C spin pairs in magic-angle-spinning solid-state NMR. The double
      quantum coherence is excited by a C7 pulse sequence and converted into zero
      quantum coherence by a frequency-selective pair of pi/2 pulses. The zero-quantum
      coherence is reconverted into observable magnetization by a second pair of pi/2
      pulses followed by a second C7 sequence. In a magnetically dilute system where
      the 13C-13C distance is 0.296 nm, the relaxation rate constants are consistent
      with a model of uncorrelated random fields at the two labeled 13C sites. In a
      fully-labelled system with a short 13C-13C distance of 0.153 nm, the measured
      rate constants are inconsistent with the uncorrelated random field model.

PMID- 10408276
TI  - Management of gunshot wounds: the Johannesburg experience.
AB  - The Johannesburg hospitals see large numbers of gunshot wounds and there is,
      therefore, considerable experience in their management. Historically, management
      has been dictated by experimental theories of wounding mechanisms. More modern
      work has indicated that some of these theories have been somewhat misleading, and
      some traditional means of management have changed. The basic military surgical
      lessons of the excision of dead tissue, delayed primary suture remain valid, it
      is the understanding of tissue damage and the more logical response which has
      changed. It is the wound as encountered which is managed, irrespective or the
      theoretical velocity of the bullet. The Johannesburg practice is outlined with
      regard to regions of the body, with discussion of, among others, the conservative
      management of gunshot wounds of the abdomen, primary repair of the colon, non
      operative management of certain limb wounds. The practice is summarised, based on
      considerable experience and the logistic implications of large numbers and may be
      useful to surgeons less experienced in gunshot wound management.

PMID- 10408275
TI  - 13C cross-polarization magic angle spinning NMR and gauge-independent atomic
      orbital, coupled Hartree-Fock calculations of buspirone analogues. Part 2.
      Hydrochlorides and perchlorates of 1-arylpiperazine-4-alkylimides.
AB  - 13C cross-polarization (CP) magic angle spinning (MAS) solid state NMR spectra of
      hydrochlorides and perchlorates of buspirone analogues (2-5) were recorded. In
      the spectra for each compound, one set of signals appeared, in agreement with
      single crystal X-ray diffraction data indicating the presence of one molecule per
      crystal unit. The resonances of 2-5 hydrochlorides were assigned by comparison
      with the solution chemical shifts. For perchlorate 2b and diperchlorate 2c, the
      reasonable assignment of signals was made with the aid of the theoretical
      studies. Ab initio calculations of the carbon shieldings were performed by means
      of the GIAO-CHF method for two model systems: perchlorate and diperchlorate of
      quinoline-(N-methyl)piperazine. As no remarkable differences between carbon
      chemical shifts of hydrochlorides 3-5 in solid state and in solution were
      observed, it was concluded that in solution these compounds adopted the same
      conformation as in the solid state.

PMID- 10408277
TI  - Management of shotgun wounds: do we need classification systems?
AB  - BACKGROUND: Shotguns cause a wide variety of injuries, depending on the weapon
      victim distance and the type of the gun and pellets. It has been suggested that
      the probability of significant internal injuries cannot be predicted using
      physical examination alone, and several wound classification systems have been
      proposed to facilitate clinical decision-making. OBJECTIVE: To evaluate the
      sensitivity of clinical examination and assess the role of a new classification
      system to detect significant injuries caused by shotguns. PATIENTS AND METHODS:
      The medical records of 56 consecutive patients admitted to a Level I trauma
      center with shotgun wounds from January 1994 to December 1996 were reviewed.
      Clinical examination was the main tool to select patients for emergency operation
      or nonoperative management. Wounds were classified by the number of body areas
      (abdomen, chest, head and neck, extremities) involved: grade I involved more than
      two areas, grade II two adjacent areas, and grade III one area. RESULTS: Twelve
      patients had type I wounds, 25 had type II wounds, and 19 had type III wounds.
      Nineteen major operations for intrathoracic, intra-abdominal or peripheral
      vascular injuries were done on 16 patients, as well as 10 orthopedic,
      ophthalmological and urological procedures and three emergency room
      thoracotomies,. No differences were found in the incidence of operations,
      morbidity, mortality, or length of hospital stay among the three groups. Clinical
      examination was 100% sensitive and 93% specific in identifying the presence of
      significant organ injuries and need for emergency operation. Three patients had
      unnecessary abdominal explorations because they received anesthesia for other
      procedures and could not be reliably followed up clinically. CONCLUSIONS:
      Clinical examination is the most reliable tool to identify patients who require
      emergency operation after shotgun wounds. Classification systems provide only
      crude information and do not predict reliably the presence of significant
      internal injuries.

PMID- 10408278
TI  - The relationship between levels of neutrophil-related factors and the degree of
      surgical stress.
AB  - To find a method for estimating the degree of surgical stress, 53 patients were
      divided into 3 groups according to operation time (group I, > or =5 h or more;
      group II, 1-4 h; and group III, <1 h) and measurement of neutrophil-related
      factors was performed. The postoperative levels of chemiluminescence (CL)
      generated by neutrophils (5.5 x 10(8)cpm) in group I was significantly higher
      than that in group II (2.1 x 10(8)cpm). The postoperative levels of CL in whole
      blood (5.7, 2.9, 1.0 x 10(6)cpm for groups I, II and III, respectively) and
      plasma lactoferrin levels (Lf) (653, 302, 143 ng/ml) were highest in group I and
      lowest in group III. The serum iron (Fe) level (24, 32, 58 microg/dl for groups
      I, II, III) was highest in group III and lowest in group I. In conclusion, whole
      blood CL, neutrophil CL, Lf and Fe levels after surgery can be useful indicators
      of the degree of surgical stress.

PMID- 10408279
TI  - Recurrence after thoracoscopic surgery for spontaneous pneumothorax.
AB  - AIM: The purpose of this study was to examine the cause and risk of recurrence
      after thoracoscopic surgery for spontaneous pneumothorax. METHODS: A total of 204
      patients under 60 years of age who underwent axillary thoracotomy and 139
      patients who underwent thoracoscopic surgery were compared. In addition, among
      the patients who underwent thoracoscopic surgery, recurrent and non recurrent
      cases were reviewed and compared. RESULTS: Postoperative recurrence rate was
      significantly higher among the thoracoscopic surgery group. There were some
      significant differences between the recurrent and non recurrent cases in the
      Brinkman index, the duration from the onset of pneumothorax to the initial
      consultation, and the number of patients who had past history of pneumothorax.
      The recurrence rate was higher in patients with an air leak in the chest drainage
      tube before operation than in patients without an air leak. CONCLUSIONS:
      Appropriate training under supervision of experienced surgeons is necessary for
      minimizing complications and procedure failures. A history of heavy smoking or an
      air leak in the chest drainage tube before surgery may be an index of recurrence
      after surgery.

PMID- 10408280
TI  - Hyaline vascular Castleman's disease of the mediastinum.
AB  - Castleman's disease is rare and can be present in many sites and with a variety
      of symptoms. Surgery is always recommended for localized lesions to remove the
      mass as completely as possible, reserving other treatment modalities for
      unresectable cases.

PMID- 10408281
TI  - Transdiaphragmatic graft replacement for coarctation suprarenal abdominal aorta.
AB  - A 17-year-old boy was referred to us with severe hypertension, headache and
      intermittent lower extremity claudication. Approximately 3 months prior to
      admission, he began to experience headache and pain in the posterior aspect of
      the right thigh and calf upon walking only 20 m. Occasionally, similar symptoms
      developed in the left leg which were nearly always of the same intensity as on
      the right. Arterial blood pressure on admission to our hospital was 220/140 mmHg
      in the arm. After physical examination and diagnostic tests, he was operated on
      with the diagnosis of coarctation of the abdominal aorta. The purpose of this
      paper is to report on a patient having an area of coarctation just above the
      level of renal arteries who presented with severe hypertension and intermittent
      claudication and in whom there was complete relief of signs and symptoms after
      appropriate surgical intervention.

PMID- 10408282
TI  - Transcutaneous oxygen tension (TcPO2) in the testing period of spinal cord
      stimulation (SCS) in critical limb ischemia of the lower extremities.
AB  - BACKGROUND: Spinal cord stimulation (SCS) improves microcirculatory blood flow,
      relieves ischemic pain and reduces amputation rate in patients with severe
      peripheral arterial occlusive disease. AIM: To evaluate the transcutaneous oxygen
      tension (TcPO2) measurements as a specific prognostic parameter in the prediction
      for permanent device implantation in a prospective controlled study in patients
      with lower limb ischemia. METHODS: 45 patients (35 men, 10 women; mean age 65
      years, range: 46-70 years) were submitted to implantation of a spinal cord
      electrical generator for rest pain, trophic lesions dry gangrene in severe lower
      limb ischemia, after failed conservative or surgical treatment. The clinical
      status was classified as Fontaine's stages III and IV and the main pathology was
      essentially due to atherosclerosis and diabetic vascular disease. Pedal
      transcutaneous oxygen tension (TcPO2), ankle and toe pressure Doppler
      measurements were performed before, 2 weeks and 4 weeks after implantation.
      RESULTS: After 18 months follow-up, pain relief was > 75% and limb salvage was
      achieved in 26 patients. In 9 patients, a partial success with pain relief > 50%
      and limb salvage was obtained for at least 6 months. In 10 patients, the method
      failed, and the patients' limbs were amputated. TcPO2 was assessed on the dorsum
      of the foot. Clinical improvement and SCS success was associated with an increase
      of TcPO2, within the first 2 weeks after implantation (temporary period). Limb
      salvage was achieved in those patients who presented significant TcPO2 increase
      within the first 2 weeks of the testing period (from 21.6 mmHg to 29.5 mmHg in
      the patients with rest pain, P = 0.035, from 15.2 mmHg to 21.1 mmHg, P = 0.035 in
      those with trophic lesions < 3 cm2, and in those with trophic lesions > 3 cm2,
      from 12.4 mmHg to 17.3 mmHg) independently of the stage of the disease and of the
      initial TcPO2 value. TcPO2 changes were related to the presence of adequate
      paresthesias and warmth in the painful area during the trial period. The systolic
      ankle/brachial blood pressure index did not change under stimulation.
      CONCLUSIONS: In patients with failed conservative and surgical treatment for
      severe critical lower limb ischemia, the SCS increases the skin blood flow, is
      associated with a significant pain relief and could prove an excellent
      alternative therapy that improves the quality of life. We also demonstrate that
      TcPO2 increase within a test period of 2 weeks, is a predictive index of SCS
      therapy success and should be considered in terms of cost effect before the final
      decision for permanent implantation.

PMID- 10408283
TI  - Microsurgical free tissue transfer: a valuable reconstructive procedure--review
      of 75 cases.
AB  - A total of 75 cases of microsurgical composite tissue transfer to reconstruct
      defects of the head and neck, trunk, upper and lower extremities performed at the
      American University of Beirut Medical Center between January 1992 and December
      1997 were evaluated in a retrospective study. There was a failure rate of 6.6%
      and a complication rate of 13.3%. Our results show that free tissue transfer can
      be considered as a safe and viable treatment option in a wide variety of clinical
      situations including early soft tissue coverage of complex extremity wounds, limb
      sparing procedures for malignant neoplasms, reconstruction of the head and neck
      area, treatment of chronic osteomyelitis, and finally reconstruction of the foot
      in patients with severe diabetic neuropathy and peripheral vascular disease. A
      brief discussion of the history of microvascular free tissue transfers as well as
      their value in modern reconstructive surgery is also presented.

PMID- 10408284
TI  - A 70% hepatectomy in the rat using a microsurgical technique.
AB  - An experimental model of 70% hepatectomy in the rat using a microsurgical
      technique is described. An operative microscope (Carl Zeiss 10x2) dissection made
      it possible to identify the hilar anatomical variations and then to avoid
      unexpected damage to the arterio-portal and biliary branches belonging to the
      remaining hepatic parenchyma. The use of this microsurgical technique allows for
      a more homogenous experimental model because it avoids the functional impairment
      of the remaining liver.

PMID- 10408285
TI  - Open drainage versus overlapping method in the treatment of hepatic hydatid cyst
      cavities.
AB  - In order to compare the results of open drainage and overlapping methods, 58
      consecutive patients with uncomplicated hepatic hydatid disease were investigated
      between January 1990 and January 1997. The cavities were obliterated by
      overlapping method in 26 patients and were left open into the peritoneal cavity
      following partial pericystectomy in 32 patients. Postoperative complications and
      follow-up results of ultrasonography (US) and computed tomography (CT) were
      compared between the two groups. In total, there were 56 cysts in the obliterated
      group and 83 cysts in the open drainage group. There was no significant
      difference in age, sex, mean diameter of the cysts, US features of the cysts
      according to the Gharbi classification, and median follow-up. Mean hospital stay
      was 10 days in the overlapping group and 7.5 days in the open drainage group (P =
      0.033). No postoperative complication was observed in the obliterated group and
      nearly half of the cyst cavities could not be detected in the early postoperative
      period by US and CT. Pleural effusion (n = 1) and biliary fistula (n = 1) were
      detected in the open drainage group which disappeared spontaneously. In the open
      drainage group, US and CT surveillance revealed that the cyst cavities were
      reduced in size and the echo pattern was changed in the early postoperative
      period, whereas the appearance changed into pseudotumor view in the late
      postoperative period. In conclusion, the cyst cavities disappear perfectly in the
      overlapping group. Treating the cyst cavity by open drainage is an easy,
      effective and safe technique. Open drainage can be a 'method of choice' for
      patients with multiple hydatid cysts and for cysts where management is difficult
      or unamenable to other methods, but the residual cyst cavities may be
      misinterpreted as a new cyst by an inexperienced radiologist.

PMID- 10408287
TI  - Benign epithelial cyst of the spleen with a high production of carbohydrate
      antigen 19-9.
AB  - A rare case of an epithelial splenic cyst showing a high production of the
      carbohydrate antigen 19-9 (CA19-9) is presented. A 19-year-old female with high
      fever and loss of appetite was diagnosed as having a splenic cyst. Laboratory
      data revealed unusually elevated serum levels of both CA19-9 and CA125. The
      histological diagnosis was an epithelial splenic cyst, and immunohistochemically
      the wall of the splenic cyst was strongly positive for CA19-9 and slightly
      positive for both CA125 and CEA. Fluid in the splenic cyst contained quite high
      levels of CA19-9, CA125 and CEA. After splenectomy, the serum levels of CA19-9
      and CA125 gradually decreased. These findings suggested that the splenic cyst
      produced CA19-9, CA125 and CEA. And with very high levels of CA19-9 and CA1 25 in
      the cyst, some had entered into systemic circulation.

PMID- 10408286
TI  - Mucosa-associated lymphoid tissue (MALT) of the gallbladder: a
      clinicopathological correlation.
AB  - OBJECTIVE: Lymph follicles are frequently found on histological examination of a
      surgically removed gallbladder. The significance of these lymph follicles is not
      clearly understood. The aim of this study was to examine the clinicopathological
      correlation between the lymph follicles in the gallbladder morphologically and
      the mucosa-associated lymphoid tissue (MALT) in the gut. METHODS: The
      gallbladders were fixed and cut serially. The tissue slices were processed in the
      routine manner for a histological examination. The histological criteria for MALT
      in this study was defined as the presence of lymph follicles with germinal
      centers in the lamina propria mucosae in approximately equal numbers in all
      portions of the gallbladders from the neck to the fundus. Biliary bile obtained
      at surgery was cultured for a bacteriological examination in the hospital
      laboratory. The types of gallstones were classified according to the
      Classification of Gallstones by the Japanese Society of Gastroenterology.
      RESULTS: Of the 1341 patients, 158 (11.8%) patients fulfilled the histological
      criteria, including 64 men and 94 women with an average age of 64.2 years.
      Gallstones were present in 89.2% of the patients, and 74.5% of these were calcium
      bilirubinate gallstones. Cultures of the bile were positive in 95.4% of the
      patients. A variety of bacterial species were thus found, most commonly
      Escherichia coli and Klebsiella spp. Grossly, the gallbladders usually showed a
      granular appearance of the mucosa. CONCLUSION: The MALT in the gallbladder is not
      a rare condition and is frequently encountered in clinical practice. This
      lymphoid tissue may represent a mucosal and morphological immune phenomenon for
      infection rather than a substrate for the development of low-grade B-cell
      lymphoma.

PMID- 10408288
TI  - Non-traumatic colorectal perforations.
AB  - Over a 6 year period, between January 1992 and December 1997, 30 patients with
      non-traumatic colorectal perforations undergoing laparotomy were reviewed. The
      aim of this study was to evaluate predictions on the prognosis using the Mannheim
      Peritonitis Index (MPI) and to evaluate the risk of this complication. The mean
      age of the patients was 56.4 years (range 16-88 years). The male:female ratio was
      19:11. All patients showed signs of peritonitis and underwent emergency
      operations. In 50% (15) of the patients, tumor was the cause. According to the
      MPI scoring, there were 18 patients with an MPI score of 26 or less and 12
      patients with an MPI score of 27 or more. For patients with a score less than 27
      the mortality rate was zero (0/18) and for score greater than 26, 66.6% (8/12).
      Overall mortality was 26.6% (8/30). Of 15 patients with perforated colorectal
      cancers, four patients died (26.6%). The mortality rate for benign perforations
      was 26.6% (4/15) also. In conclusion, colorectal cancers are the most common
      cause of the non-traumatic colorectal perforations. Patients with an MPI score
      greater than 26 represent the highest risk group.

PMID- 10408289
TI  - Self-expanding prostheses as a palliative method in treating advanced colorectal
      cancer.
AB  - AIM: This work presents the results of the use of self-expanding prosthesis as a
      definitive palliative method for eliminating colorectal obstructions caused by
      advanced and unresectable tumours. PATIENTS: A total of 41 cases were included
      (29 men, 12 women) with an average age of 70.12 years (range 46-95 years). All
      cases were showed symptoms of acute intestinal obstruction. Wallstent prostheses
      were inserted. RESULTS: Locally unresectable colorectal tumours were disseminated
      in five cases, metastasis in 28 cases and other tumours in eight cases. In all
      patients the appropriate insertion was performed, eliminating the obstruction in
      38 (92.6%) cases in 24-96 h. The morbidity rate was 6/41 cases (14.6%) with
      slight rectal discomfort in five and one case of bleeding. Posterior tolerance of
      the prostheses was good. FOLLOW-UP: Two spontaneous rejections, three episodes of
      subocclusion because of faecal impact and two obstructions caused by an invasion
      of tumours occurred. Overall, 33 cases (80.4%) died within 1-18 months, average
      of 4.5 months survival. CONCLUSIONS: Wallstent endoprostheses is a good
      alternative avoiding a colostomy and providing a good tolerance and comfort for
      the patient until death.

PMID- 10408290
TI  - Intra-abdominal and retroperitoneal liposarcomas.
AB  - Nine primary intra-abdominal or retroperitoneal liposarcomas, of which eight were
      recurrent tumors, were surgically resected and enrolled in this study.
      Histopathological examination of primary tumors revealed that the number of well
      differentiated, pleomorphic and myxoid type was two, four and three,
      respectively. In two recurrent cases, histological differentiation changed from
      well-differentiated type into myxoid or pleomorphic types. Prognoses of patients
      with large tumors (a 20 cm) were significantly poorer than for patients with
      small tumors (< 20 cm). Labelling index of Ki-67 of recurrent tumors increased in
      two cases. The tumor size affected prognoses of patients with intra-abdominal or
      retroperitoneal liposarcoma. Combined resection was important to get a tumor-free
      margin.

PMID- 10408291
TI  - Pulmonary capillary hemangiomatosis in an asymptomatic elderly patient.
AB  - Thoracic hemangiomatosis is an extremely rare condition of the thorax of unknown
      origin: thin-walled capillary blood vessels infiltrate the lung parenchyma, blood
      vessels, interlobular septa, bronchiolar walls and pleura. The infiltration of
      pulmonary veins and venules induces secondary pulmonary veno-occlusive disease
      and pulmonary hypertension with a slowly progressive clinical course. This
      condition can be associated with vascular dementia and disseminated intravascular
      coagulation (DIC).

PMID- 10408292
TI  - Use of permanent dual lumen catheters for long-term haemodialysis.
AB  - Permanent dual lumen catheters (PDLC) provide alternative vascular access in
      patients considered unsuitable for arteriovenous fistula, arteriovenous graft or
      peritoneal dialysis. Experience with their use for long-term haemodialysis is
      presented. Between January 1990 and April 1994, 101 catheters were inserted into
      63 patients (median age 62 years). A PDLC was the primary vascular access type in
      5 patients. Of the first catheters, 70% were inserted percutaneously into the
      subclavian vein. The median duration of catheter use was 168 days (range 5-1582
      days). The overall cumulative observed catheter survival rate was 94% at 6
      months, 89% at 1 year and 75% at 4 years following insertion. The major
      complications were blockage and catheter related infection occurring in 28% and
      15% of catheters, respectively. Death and blockage were the commonest reasons for
      catheter removal. PDLC play a vital role in the provision of access for long-term
      dialysis and should be considered the access type of choice in patients with
      limited life expectancy.

PMID- 10408294
TI  - Use of the inferior epigastric artery as a jump graft for reconstruction of a
      lower pole artery for renal transplantation.
AB  - Before a kidney can be transplanted, the reconstruction of a damaged lower pole
      artery is vital to preserve the blood supply of the ureter.

PMID- 10408293
TI  - Generation of HLA-DP transgenic pigs for the study of xenotransplantation.
AB  - The shortage of human organs has prompted scientists to seek xenogeneic sources
      of donors. To date, DAF, MCP, and CD59 transgenic pigs have been generated to
      inhibit hyperacute rejection. However, besides hyperacute rejection, acute and
      chronic rejection must also be considered in the use of porcine organs for
      xenotransplantation. The role of HLA-II in transgenic xeno-organ transplantation
      remains to be elucidated. By microinjecting 1655 embryos, we have generated one
      stillborn HLA-DR and two live HLA-DP transgenic pigs: P113-7 (male, carrying one
      copy of exogene) and P113-8 (female, carrying 2-3 copies of exogenes). The gene
      status of the live transgenic pigs was confirmed by PCR, Southern blot, and PCR
      product sequencing analysis. The expression of transgenes in these transgenic
      pigs were confirmed by RT-PCR analysis and immunohistochemical staining of frozen
      sections of ear tissue.

PMID- 10408295
TI  - Adrenal adenoma with foci of oncocytes in a patient with pre-Cushing's syndrome.
AB  - A case of unilateral adrenal adenoma with foci of oncocytes in a 64-year-old
      woman is reported. The tumour manifested clinically pre-Cushing's syndrome with
      autonomous steroidogenesis which was insufficient to cause typical features of
      Cushing's syndrome. Whether the pathogenesis of oncocytes and adenoma cells,
      which were thought to have some metabolic deficiency in the present tumour, are
      linked remains to be determined.

PMID- 10408296
TI  - Infectious complications of combination anticancer chemotherapy for urogenital
      cancers.
AB  - We reviewed the infectious complications in 207 courses of anticancer
      chemotherapy to 93 patients with urogenital cancer. Thirty episodes (14.5%) of
      neutropenic fever containing 9 cases (4.3%) of infection were observed. Five
      patients (16.7%) had pyelonephritis, one (3.3%) had acute prostatitis, two (6.6%)
      had pneumonia and one (3.3%) had bacteraemia. Multivariate analysis revealed that
      the infectious complications during anticancer chemotherapy were mainly
      associated with urinary diversion, hydronephrosis and duration of severe
      neutropenia (<500/mm3). These results suggest that infectious complications
      should be prevented in patients with urinary diversion, hydronephrosis and severe
      neutropenia during anticancer chemotherapy for urogenital cancer.

PMID- 10408297
TI  - Percutaneous renal biopsy: three years of experience with the biopty gun in 761
      cases--a survey of results and complications.
AB  - From 1.1.1993 to 12.31.1995 we performed 761 consecutive biopsies on 509 non
      selected patients. The most frequent diagnoses in 351 biopsies (39.4%) on native
      kidneys were 262 cases of glomerulonephritis (74.6%) and 167 of so-called benign
      nephrosclerosis (47.6%). With 410 biopsies (60.6%) on allograft kidneys 219 cases
      (78%) showed signs of interstitial rejection, 14 cases (5%) vascular and 49 cases
      (17%) interstitial as well as vascular rejection. Only after 5 biopsies (0.66%)
      clinical relevant complications (3 perirenal haematomas, 1 AV fistula, 1 vesical
      tamponade) appeared. Again percutaneous renal biopsy is proven to be a
      diagnostically efficient and safe tool at the same time even when used in a large
      number of non-selected patients, so that an ambulant performance may be
      discussed. The relatively frequent diagnosis of a so-called benign
      nephrosclerosis seems to indicate the need for an intensified examination of this
      disease.

PMID- 10408298
TI  - Indinavir crystallization and urolithiasis.
AB  - The crystallization of indinavir in synthetic urine at different pH values and
      indinavir concentrations was kinetically studied. It was found that precipitation
      time notably decreases at urinary pH values above 6.0. The effects of some
      products as potential crystallization inhibitors were studied. Some natural
      saponins such as escin and glycyrrhizic acid provoked a notable increase in the
      precipitation time of indinavir, this pointing out their possible use to prevent
      renal tubular solid deposition.

PMID- 10408299
TI  - Renocutaneous fistulae: a rare complication of extracorporeal shock wave
      lithotripsy.

PMID- 10408300
TI  - Iatrogenic reno-jejunal fistula.
AB  - The development of a reno-jejunal fistula following a Roux-en-Y cystojejunostomy
      for an incorrectly diagnosed pancreatic pseudocyst is described. Up to now, this
      is the second case of iatrogenic reno-jejunal fistula reported in literature.
      Reno-jejunal fistulas are exceedingly rare and are usually consequences of
      urologic pathologies of infectious origin. Reno-jejunal fistulas of iatrogenic
      origin are even rarer, only one case being referred in literature [1]. Herein the
      second case is reported.

PMID- 10408301
TI  - Endometriosis of the urinary bladder.
AB  - Although every seventh or eighth case of endometriosis is found to have urinary
      involvement, this type of endometriosis is still rarely recognized. The symptoms
      are not specific and are frequently suggestive of a neoplastic process. On the
      basis of our two cases of histopathologically two types of endometriosis as well
      as literature review the practical significance of endometriosis in urology is
      described. In each patient who previously underwent a gynaecological or surgical
      procedure in the abdominal cavity, endometriosis of the bladder is likely to
      occur. This possibility should not be ruled out, otherwise it could lead to
      misdiagnosis and inappropriate treatment.

PMID- 10408302
TI  - A solitary hydatid cyst of the retrovesical region.
AB  - A 70-year-old man presented with a large suprapubic mass. Ultrasonography
      revealed that the mass was cystic and displaced the bladder anteriorly and
      superiorly. Computed tomography suggested that the mass could be an echinococcal
      cyst. Computed tomography also showed that the patient had bilateral
      hydroureteronephrosis. Echinoccocal haemagglutination was positive at 1:320
      dilution. The patient underwent surgical exploration during which the cyst was
      found to be located in the retrovesical region. The cyst was completely excised
      and the pathologic examination confirmed the diagnosis.

PMID- 10408303
TI  - Granulomatous hepatitis following intravesical bacillus Calmette-Guerin therapy.
AB  - Although intravesical bacillus Calmette-Guerin (BCG) administration is an
      effective method in the treatment of superficial urinary bladder carcinoma, some
      complications may arise such as a granulomatous reaction either in the urinary
      tract or, in rare cases, outside the urinary tract. We report in this paper a
      case of granulomatous hepatitis following intravesical BCG administration.

PMID- 10408304
TI  - Long-term follow-up and evaluation of autoaugmentation cystoplasty
      (detrusorotomy) in an animal model.
AB  - OBJECTIVE: To evaluate long-term follow-up of an autoaugmentation (detrusorotomy)
      technique, in puppies. PATIENTS AND METHODS: In 10 mongrel puppies, bladder
      capacities were reduced to nearly half their original volume by 10 per cent
      formalin instillations. In 7 puppies, the muscular coat of the bladder was split
      open widely down to the mucosal layer, from the bladder neck anteriorly, to the
      trigone posteriorly while the mucosa was kept exposed and intact. Three puppies
      were kept as controls. RESULTS: Mean post-instillation bladder capacity was 15.40
      ml. One week after detrusorotomy the bladder capacity averaged up to 20.00 ml; 3
      weeks later up to 20.43 ml; and 3 months later up to 34.28 ml and were well up to
      3 months. However, at the termination of an additional 9-month period, the
      bladders of 4 of the remaining five dogs were seen to decrease in volume except
      the one with an accidental omental adherence to the exposed mucosa which kept the
      detrusorotomy intact. CONCLUSION: Post-detrusorotomy volume could be retained if
      a graft, e.g. omentum, gut segment, amniotic membrane or lyophilized dura is
      inserted at the time of intervention, in-between the split musculature to line
      the exposed mucosa externally and to prevent re-adhesion of the muscular edges.

PMID- 10408305
TI  - Analysis of protooncogene c-erbB-2 in benign and malignant human prostate.
AB  - In this report, we characterized the c-erbB-2 gene and its product in prostatic
      cancer cells. Three prostatic cancer cell lines (PC3, DU145 and TSU-Pr1), one
      primary prostatic cancer and four benign prostatic hyperplasias (BPH) were
      studied. In reverse transcribed polymerase chain reaction, c-erbB-2 mRNA was
      demonstrated in all three cell lines and prostatic cancer tissues as well as BPH.
      The c-erbB-2 protein was expressed higher in prostatic cancer cells and tissues
      as compared with benign tissue by enzyme immunoassay, but it was not
      statistically significant. Immunohistochemical study, with the monoclonal
      antibody SV2-61gamma that recognizes the extracellular domain of c-erbB-2, showed
      that all the prostatic tissues and cells had reactivity. Antigenicity was mainly
      in the cytoplasm. Analysis of genomic DNA failed to disclose gene amplifications
      or rearrangements of c-erbB-2 in both prostatic cancer and BPH. The sequence of
      amplified c-erbB-2, which corresponds to transmembrane domain, disclosed wild
      type in all prostatic cancer cells. These results demonstrate that although the
      number is limited, c-erbB-2 gene and protein are expressed in prostatic cancers
      and benign prostates. In the previous studies on c-erbB-2 expression in prostatic
      tissue, mainly conducted by immunohistochemistry, its frequency varies among each
      study, ranging from less than 0% to 100%. Therefore, to evaluate the c-erbB-2 in
      prostatic tissue precisely, it is also necessary to detect mRNA of c-erbB-2 as
      demonstrated in our study.

PMID- 10408306
TI  - Prostate cancer and neuroendocrine differentiation.
AB  - A retrospective study was conducted in 41 patients with adenocarcinoma of the
      prostate to investigate the correlation between pathological stage, Gleason score
      and neuroendocrine differentiation in order to evaluate the prognostic
      significance of neuroendocrine differentiation. Patients' ages ranged from 50 to
      84 (mean 69.1) years. Clinical staging was done by rectal examination, serum PSA,
      transrectal ultrasonography, bone scan and abdominal CT followed by pathological
      staging after the operation. After that malignant prostatic tissue sections
      obtained from radical prostatectomy and transurethral prostatectomy specimens
      were stained with haemotoxylin-eosin and Gleason scores were determined. From
      each patient paraffin blocks representative of the primary prostate
      adenocarcinoma were chosen for immunohistochemical staining with monoclonal
      neuron specific enolase and chromogranin A antibodies for the determination of
      neuroendocrine differentiation. Neuroendocrine cells were found to be present in
      53.66% of the patients. The incidence of neuroendocrine differentiation was
      higher in poorly differentiated (Gleason 7-10) tumours when compared to
      moderately and well differentiated tumours (Gleason <7) although not
      statistically significant (p=0.09). Although the percentage of neuroendocrine
      differentiation was greater in advanced prostate carcinoma (stage C, D) than
      localized (stage A, B) the difference was not statistically significant (p=0.18).
      Nevertheless, a significant correlation was present between Gleason score and
      pathological stage (p=0.002). In 34 cases followed for 5 years there was no
      relationship between the presence of neuroendocrine cells and 5-year tumour
      progression (p=0.41). However, significant increase in tumour progression rate
      was observed with increase in Gleason score (p=0.02) and pathological stage
      (p=0.00001). As a conclusion, no significant correlation was found between
      neuroendocrine differentiation and prognostic markers such as Gleason score and
      pathological stage in adenocarcinoma of the prostate.

PMID- 10408307
TI  - Influence of preoperative vesicle biopsy on the decision for radical
      prostatectomy.
AB  - PURPOSE: The presence of seminal vesicle invasion (SVI) by prostate cancer is
      difficult to detect clinically and is associated with poor prognosis. The aim of
      our study was to identify the efficacy of transrectal ultrasound-guided seminal
      vesicle biopsies in the detection of seminal vesicle invasion (SVI) in patients
      with prostate cancer. MATERIALS AND METHODS: One hundred transrectal ultrasound
      guided seminal vesicle biopsies were performed in 50 patients with clinically
      localized prostate cancer. Every patient underwent two biopsies, one for each
      seminal vesicle. Radical retropubic prostatectomy was performed in all cases and
      the specimens with the attached seminal vesicles were examined for the presence
      of prostate cancer invasion. RESULTS: Of a total of 100 seminal vesical biopsies
      87 were identified as seminal vesicle by characteristic epithelium. Cancer was
      found in 7 (8%) biopsies, confirmed in all cases by pathology in the surgical
      specimen. Eighty biopsies (40 patients) were normal. Pathological analysis of
      these 40 radical prostatectomy specimens revealed that 6 seminal vesicles (5
      patients) were invaded by prostate cancer (6 false negative biopsies, 7.5%).
      Transrectal ultrasound images of 15 seminal vesicles were suspicious for invasion
      while 85 were normal. Of the 15 suspicious cases 11 were invaded by cancer
      (73.3%). Of the sonographically benign seminal vesicles 5 (5.88%) were invaded by
      cancer. Our data were analyzed by the ARCUS PRO-STAT statistical package.
      CONCLUSIONS: We suggest that transrectal ultrasound-guided seminal vesicle biopsy
      is useful and reliable for a more exact preoperative staging of prostate cancer,
      therefore helpful in correct decision making for radical prostatectomy.

PMID- 10408308
TI  - Adenosquamous carcinoma of the prostate.
AB  - We present an unusual variant of prostatic adenocarcinoma with obvious squamous
      differentiation. The squamous component is represented by cells that contain
      vesicular or hyperchromatic nuclei and large acidophilic cytoplasm. We could
      demonstrate immunohistochemically the presence of prostate specific antigen (PSA)
      and glial fibrillary acidic protein (GFAP) in these tumour cells. Either in
      adenocarcinomatous or malignant squamous components, the prostatic epithelial
      cells showed the two markers, namely PSA, GFAP, which may reflect the
      multidirectional differentiation of these cells from a pluripotent origin.

PMID- 10408309
TI  - Evaluation of serum arginase activity in benign prostatic hypertrophy and
      prostatic cancer.
AB  - Activities of arginase, prostatic acid phosphatase (PAP) and prostate specific
      antigen (PSA) were determined in sera of healthy male controls, benign prostatic
      hypertrophy (BPH) and prostatic cancer patients. Serum arginase activity in the
      cancer group (22.8+/-11.6 U/l) was significantly lower than in both the control
      (33.64+/-16.19 U/l) and the BPH group (58.8+/-11.6 U/l) (p<0.001, respectively),
      while the BPH group had significantly higher levels compared to the controls
      (p<0.05). However, serum arginase levels in all groups had no statistically
      significant correlation with PAP and PSA. Serum arginase activity correlated
      inversely with the Gleason grades. These results suggest that serum arginase
      assay may be used for the pretreatment evaluation of patients with prostatic
      diseases.

PMID- 10408310
TI  - Comparing the anti-inflammatory effects of corticotherapy and non-steroid anti
      inflammatory drugs in infertile patients with infectious aetiology.
AB  - To compare the anti-inflammatory effectiveness of corticotherapy and nonsteroid
      anti-inflammatory drugs (NSAID), we examined 126 infertile men with infectious
      aetiology. Seventy-seven patients were on corticotherapy and antibiotherapy
      (thirty-eight patients on high-dose and thirty-nine patients on low-dose
      corticotherapy). Forty-nine patients had antibiotherapy and NSAID. According to
      our results in both the high- and low-dose groups sperm motility significantly
      improved, but in the high dose group more side effects were reported. In order to
      overcome the effects of infections on male infertility, we prefer corticotherapy
      instead of NSAID because it is more effective than NSAID.

PMID- 10408311
TI  - Seminal fructose levels in male infertility: relationship with sperm
      characteristics.
AB  - The relationship between seminal fructose concentration and sperm characteristics
      was investigated in semens of 187 suspected infertile men without evidence of
      disturbances in the seminal vesicular function. Sperm density, viability,
      motility, morphologically oval sperm, and 10 categories of defective spermatozoa
      (small, large, amorphous, round-head, double-head, pin-head, tapering, mid-piece
      defects, tail defects, and combined defects) were assessed in 6 levels of seminal
      fructose concentration, as follows: (1) 0 to 1.0 mg/ml; (2) 1.1 to 2.0 mg/ml; (3)
      2.1 to 3.0 mg/ml; (4) 3.1 to 4.0 mg/ml; (5) 4.1 to 5.0 mg/ml; (6) >5.0 mg/ml.
      None of the sperm characteristics analyzed had shown statistically significant
      differences among the study groups. It is concluded that seminal fructose levels
      detected in the routine of semen analysis give no information on the clinical
      usefulness in defective sperm formation.

PMID- 10408312
TI  - The relation of optical density of seminal plasma with serum FSH and LH levels in
      azoospermic patients.
AB  - The aim was to investigate the relation between optical density of seminal
      plasma, serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
      levels in azoospermic patients and to establish criteria depending on optical
      density measurements in order to estimate serum FSH and LH levels. Optical
      density of seminal plasma and serum FSH and LH levels were measured in 45
      azoospermic patients. The semen samples with an optical density (OD) of more than
      0.5 showed normal levels of FSH and LH, while those with less than 0.5 were
      observed to have high levels of FSH and LH. The optical density of seminal plasma
      can be used in the prediction of serum FSH and LH levels in azoospermic patients.

PMID- 10408313
TI  - Bilateral epididymoorchitis secondary to brucellosis.

PMID- 10408314
TI  - A stormy transplant case with happy ending.
AB  - A 12-year-old female patient with end-stage renal failure whose primary disease
      was reflux nephropathy, was first admitted for augmentation cystoplasty by using
      an ileum segment because of contracted urinary bladder. Four months later, she
      had a renal transplantation from her father on March 28th 1997. The first three
      days after the operation were uneventful. On the fourth day, she presented a
      severe rejection episode and was treated with steroid and ATG. A urinary fistula
      developed and she underwent surgery again on the 14th postoperative day. At
      surgery, apical resection + omentoplasty + nephrostomy + DJ replacement were
      performed. The postoperative period after the second operation was full of
      problems for both the patient and the transplantation team. She was discharged
      from hospital on the 40th postoperative day with excellent renal function (a
      serum creatinine level of 1 mg/dl) and with full recovery.

PMID- 10408315
TI  - Bathing before sleep in the young and in the elderly.
AB  - In this study we investigated the effects of bathing on the quality of sleep in
      30 elderly people (ages 65-83 years) and in 30 young people (ages 17-22 years) in
      their homes. Room temperature did not vary significantly during the nights that
      data were acquired, ranging from 8 to 12 degrees C. After bathing and at the
      beginning of sleep, the mean (SE) rectal temperatures of the young and the
      elderly were 37.8 (0.08) and 37.5 (0.07) degrees C, respectively, and were higher
      by 0.7 (0.13) and 0.6 (0.07) degrees C, respectively, than when the subjects had
      not bathed. At the beginning of the sleep after bathing in the young subjects,
      skin temperature was 32.5 (0.24) and 1.5 (0.34) degrees C higher than when those
      subjects had not bathed. In the elderly, however, there were no significant
      differences in skin temperature with and without prior bathing because they used
      electric blankets during sleep. After bathing, the young people reported "warmth"
      in their hands and/or legs, while the elderly more often reported "good sleep" or
      "quickness of falling asleep". During the first 3 h of sleep, body movements were
      less frequent after bathing for both the young and the elderly subjects. The
      results suggest that a bath before sleep enhances the quality of sleep,
      particularly in the elderly.

PMID- 10408316
TI  - Influence of menstrual cycle and oral contraceptives on tolerance to
      uncompensable heat stress.
AB  - In this study we examined the influence of menstrual cycle phase and oral
      contraceptive use on thermoregulation and tolerance during uncompensable heat
      stress. Eighteen women (18-35 years), who differed only with respect to oral
      contraceptive use (n = 9) or non-use (n = 9), performed light intermittent
      exercise at 40 degrees C and 30% relative humidity while wearing nuclear,
      biological and chemical protective clothing. Their responses were compared during
      the early follicular (EF, days 2-5) and mid-luteal (ML, days 19-22) phases of the
      menstrual cycle. Since oral contraceptives are presumed to inhibit ovulation, a
      quasi-early follicular (q-EF) and quasi-mid-luteal (q-ML) phase was assumed for
      the users. Estradiol and progesterone measurements verified that all subjects
      were tested during the desired phases of the menstrual cycle. Results
      demonstrated that rectal temperature (Tre) was elevated in ML compared with EF
      among the non-users at the beginning and throughout the heat-stress trial. For
      the users, Tre was higher in q-ML compared with q-EF at the beginning, and for 75
      min of the heat-stress exposure. Tolerance times were significantly longer during
      EF [128.1 (13.4) min, mean (SD)] compared with ML [107.4 (8.6) min] for the
      nonusers, indicating that these women are at a thermoregulatory advantage during
      the EF phase of their menstrual cycle. For the users, tolerance times were
      similar in both the q-EF [113.0 (5.8) min] and q-ML [116.8 (11.2) min] phases and
      did not differ from those of the non-users. It was concluded that oral
      contraceptive use had little or no influence on tolerance to uncompensable heat
      stress, whereas tolerance was increased during EF for non-users of oral
      contraceptives.

PMID- 10408317
TI  - Expression of developmental myosin and morphological characteristics in adult rat
      skeletal muscle following exercise-induced injury.
AB  - The extent and stability of the expression of developmental isoforms of myosin
      heavy chain (MHCd), and their association with cellular morphology, were
      determined in adult rat skeletal muscle fibres following injury induced by
      eccentrically-biased exercise. Adult female Wistar rats [274 (10) g] were either
      assigned as non-exercised controls or subjected to 30 min of treadmill exercise
      (grade, -16 degrees; speed, 15 m x min(-1)), and then sacrificed following 1, 2,
      4, 7, or 12 days of recovery (n = 5-6 per group). Histologically and
      immunohistologically stained serial, transverse cryosections of the soleus (S),
      vastus intermedius (VI), and tibialis anterior (TA) muscles were examined using
      light microscopy and digital imaging. Fibres staining positively for MHCd (MHCd+)
      were seldom detected in the TA. In the VI and S, higher proportions of MHCd+
      fibres (0.8% and 2.5%, respectively) were observed in rats at 4 and 7 days post
      exercise, in comparison to all other groups combined (0.2%, 1.2%; P < or = 0.01).
      In S, MHCd+ fibres were observed less frequently by 12 days (0.7%) than at 7 days
      (2.6%) following exercise. The majority (85.1%) of the MHCd+ fibres had
      morphological characteristics indicative of either damage, degeneration, repair
      or regeneration. Most of the MHCd+ fibres also expressed adult slow, and/or fast
      myosin heavy chain. Quantitatively, the MHCd+ fibres were smaller (< 2500
      microm2) and more angular than fibres not expressing MHCd. Thus, there was a
      transient increase in a small, but distinct population of MHCd+ fibres following
      unaccustomed, functional exercise in adult rat S and VI muscles. The observed
      close coupling of MHCd expression with morphological changes within muscle fibres
      suggests that these characteristics have a common, initial exercise-induced
      injury-related stimulus.

PMID- 10408318
TI  - Effect of carbohydrate ingestion and hormonal responses on ratings of perceived
      exertion during prolonged cycling and running.
AB  - This randomized, double-blind, placebo-controlled study was designed to determine
      the influence of exercise mode, and 6% carbohydrate (C) versus placebo (P)
      beverage ingestion, on ratings of perceived exertion (RPE) and hormonal
      regulation to 2.5 h of high-intensity running and cycling (approximately 75%
      maximum oxygen uptake) by ten triathletes who acted as their own controls.
      Statistical significance was set at P < or = 0.05. The pattern of change in RPE
      over time was significantly different between C and P ingestion (P < 0.001) and
      between running and cycling modes (P = 0.001). The lowest RPE values were seen in
      the C-cycling sessions and the highest in the P-running sessions. The pattern of
      change in the respiratory exchange ratio and fat and carbohydrate oxidation rates
      were significantly different between the C and P conditions but not between the
      running and cycling modes. C relative to P ingestion (but not exercise mode) was
      associated with higher plasma levels of glucose and insulin and lower plasma
      cortisol and growth hormone levels. The pattern of change in plasma levels of
      catecholamines and lactate did not differ between the C and P conditions. These
      data indicate that a lower RPE was associated with a higher level of carbohydrate
      oxidation, higher plasma glucose and insulin levels, and lower plasma cortisol
      and growth hormone levels during cycle exercise following C supplementation as
      compared to P feeding. These findings support a physiological link between RPE
      and carbohydrate substrate availability as well as selected hormonal regulation
      during cycle exercise.

PMID- 10408319
TI  - Effects of movement speed and joint position on knee flexor torque in healthy and
      post-surgical subjects.
AB  - Coactivation of knee flexors during knee extension assists in joint stability by
      exerting an opposing torque to the anterior tibial displacement induced by the
      quadriceps. This opposing torque is believed to be generated by eccentric muscle
      actions that stiffen the knee, thereby attenuating strain to joint ligaments,
      particularly the anterior cruciate ligament (ACL). However, as the lengths of
      knee muscles vary with changes in joint position, the magnitude of
      flexor/extensor muscle force coupling may likewise vary, possibly affecting the
      capacity for active knee stabilization. The purpose of this study was to assess
      the effect of changes in movement speed and joint position on
      eccentric/concentric muscle action relationships in the knees of uninjured (UNI)
      and post-ACL-surgery (INJ) subjects (n = 14). All subjects were tested for
      maximum eccentric and concentric torque of the contralateral knee flexors and
      extensor muscles at four isokinetic speeds (15 degrees-60 degrees x s(-1)) and
      four joint position intervals (20 degrees-60 degrees of knee flexion). Eccentric
      flexor torque was normalized to the percentage of concentric flexor torque
      generated at each joint position interval for each speed tested (flexor E-C
      ratio). In order to estimate the capacity of the knee flexors to resist active
      knee extension, the eccentric-flexor/concentric-extensor ratios were also
      computed for each joint position interval and speed (flexor/extensor E-C ratio).
      The results revealed that eccentric torque surpassed concentric torque by 3%-144%
      across movement speeds and joint position intervals. The magnitude of the flexor
      E-C ratio and flexor/extensor E-C increased significantly with speed in both
      groups of subjects (P < 0.05) and tended to rise with muscle length as the knee
      was extended; peak values were generated at the most extended joint position (20
      degrees-30 degrees). Although torque development patterns were symmetrical
      between the contralateral limbs in both groups, between-group comparisons
      revealed significantly higher flexor/extensor E-C ratios for the INJ group
      compared to the UNI group (P < 0.05), particularly at the fastest speed tested
      (60 degrees x s(-1)). The results indicate that joint position and movement speed
      influence the eccentric/concentric relationships of knee flexors and extensors.
      The INJ subjects appeared to accommodate to surgery by developing the eccentric
      function of their ACL and normal knee flexors, particularly at higher speeds and
      at more extended knee joint positions. This may assist in the dynamic
      stabilization of the knee at positions where ACL grafts have been reported to be
      most vulnerable to strain.

PMID- 10408320
TI  - Do fire-fighters develop specific ventilatory responses in order to cope with
      exercise whilst wearing self-contained breathing apparatus?
AB  - In the present study we compared the ventilatory performance whilst wearing self
      contained breathing apparatus (SCBA) during exercise, of a group of male fire
      fighters (FF, n = 8), with a matched group of male civilians (CV, n = 7). The
      mean (SEM) physiological characteristics of the subjects (FF vs CV) were: age 31
      (2) years vs 32 (4) years; height 179 (2) cm vs 183 (3) cm, P < 0.05; mass 80 (2)
      kg vs 84 (3) kg; maximum oxygen uptake 4.52 (0.14) 1 x min(-1) vs 4.39 (0.27) 1 x
      min(-1). Volunteers performed a 23-minute fire-fighting simulation (Firetest),
      without and with SCBA (Fire-fighter II, Siebe-Gorman/North Safety, Cheshire, UK).
      During SCBA wear, the FF group used significantly less air and rated their
      breathlessness significantly lower than the CV group. The mean tidal volume
      (V(T)) of the FF group remained constant between non-SCBA and SCBA wear
      conditions, but the CV group increased their mean V(T) by 18%, (P < 0.01). There
      were no significant between-group differences during the Firetest in total breath
      duration, inspiratory or expiratory duration, breathing frequency (fb), or heart
      rate. These data suggest that the respiratory responses of firefighters while
      wearing SCBA, which are characterised by increases in (fb) but not V(T), may help
      to reduce their breathlessness during exercise while wearing SCBA.

PMID- 10408321
TI  - Changes in membrane fluidity and lipid peroxidation of skeletal muscle
      mitochondria after exhausting exercise in rats.
AB  - We studied the effects of exhausting exercise and exercise training on skeletal
      muscle mitochondrial membrane fluidity and lipid peroxidation in rats. The first
      part of the study involved 60 untrained rats divided into six equal groups. Of
      the total number 10 rats were sedentary and acted as controls. The remaining 50
      rats exercised to exhaustion and were sacrificed at 0-h, 24-h, 48-h, 72-h, and 96
      h post-exercise. The second part of the study involved 40 rats which were divided
      into four equal groups. Of these 10 rats were sedentary and acted as controls.
      The remaining 30 rats underwent 8 weeks of exercise training. They were then
      subjected to a single period of exhausting exercise and were sacrificed at 0-h,
      24-h and 48-h post-exercise. Membrane fluidity was measured using the
      fluorescence polarization method. Lipid peroxidation was estimated by determining
      the thiobarbituric acid-reactive substances (TBARS) in mitochondria. In the
      untrained rats, mitochondrial fluorescence polarization and TBARS contents were
      significantly increased post-exercise compared with the sedentary controls (P <
      0.05). They did not return to near control levels until 96 h and 48 h,
      respectively. In the trained rats, fluorescence polarization was raised compared
      with the sedentary controls but this was significantly lower than those measured
      at the same times of the untrained group post-exercise (P < 0.05). Exhausting
      exercise decreased membrane fluidity and increased lipid peroxidation in rat
      skeletal muscle mitochondria. These effects were relieved to some extent by
      exercise training.

PMID- 10408322
TI  - Breath-to-breath "noise" in the ventilatory and gas exchange responses of
      children to exercise.
AB  - The purposes of this investigation were to quantify the noise component of child
      breath-by-breath data, investigate the major determinants of the breath-to-breath
      noise, and to characterise the noise statistically. Twenty-four healthy children
      (12 males and 12 females) of mean (SD) age 13.1 (0.3) years completed 25 min of
      steady-state cycle ergometry at an exercise intensity of 50 W. Ventilatory and
      gas exchange variables were computed breath-by-breath. The mean (SD) oxygen
      consumption (VO2) ranged from 0.72 (0.16) to 0.92 (0.26) l x min(-1); mean (SD)
      carbon dioxide production (VCO2) ranged from 0.67 (0.20) l x min(-1) to 0.85
      (0.16) l x min(-1); and mean (SD) minute ventilation ranged from 17.81 (3.54) l x
      min(-1) to 24.97 (5.63) l x min(-1). The majority of the breath-to-breath noise
      distributions differed significantly from Gaussian distributions with equivalent
      mean and SD parameters. The values of the normalised autocorrelation functions
      indicated a negligible breath-to-breath correlation. Tidal volume accounted for
      the majority of the VO2 (43%) and VCO2 (49%) variance. The breath-to-breath noise
      can be explained in terms of variations in the breathing pattern, although the
      large noise magnitude, together with the relatively small attainable response
      amplitudes in children reduces the certainty with which ventilatory and gas
      exchange kinetics can be measured.

PMID- 10408323
TI  - Plasma catecholamine responses to four resistance exercise tests in men and
      women.
AB  - The plasma adrenaline ([A]) and noradrenaline ([NA]) concentration responses of
      nine men and eight women were investigated in four resistance exercise tests
      (E80, E60, E40 and E20), in which the subjects had to perform a maximal number of
      bilateral knee extension-flexion movements at a given cycle pace of 0.5 Hz, but
      at different load levels (80%, 60%, 40% and 20% of 1 repetition maximum,
      respectively). The four test sessions were separated by a minimal interval of 3
      rest days. The number of repetitions (Repmax), the total work (Wtot) done
      normalized for the lean body mass and the heart rate (HR) responses were similar
      in the two groups in each test. In addition, no differences were found between
      the two groups in [A] and [NA] either before or after the exercise tests. The
      postexercise [NA], both in the men [10.8 (SD 7.0) nmol x l(-1)] and in the women
      [11.7 (SD 7.4) nmol x l(-1)], was clearly the highest in E20, where also the
      Repmax, WtOt, the total amount of integrated electromyograph activity in the
      agonist muscles and the peak postexercise blood lactate concentration [men 8.3
      (SD 1.6) vs women 7.3 (SD 0.9) mmol x l(-1), ns] were significantly higher than
      in the other tests. Although the postexercise [A] in E20 both in the men [7.1 (SD
      6.0) nmol x l(-1)] and in the women [5.2 (SD 2.0) nmol x l(-1)] were higher than
      in E80 [men 3.1 (SD 4.2), women 2.1 (SD 2.0) nmol x l(-l)] (P < 0.05), they were
      not significantly different from E60 [men 3.6 (SD 1.9), women 4.0 (SD 3.3) nmol x
      l(-1)] and E40 [men 3.8 (SD 4.1), women 5.8 (SD 4.0) nmol x l(-1)] in either
      group. The present study did not indicate any sex differences in performance and
      in plasma catecholamine responses in different exhausting resistance exercise
      tests performed with the knee extensor muscles. In both groups the plasma [NA]
      response was clearly the largest in the longest exercise with the greatest amount
      of muscle activity and work done, and with the largest blood lactate response.
      The differences in the plasma [A] responses between the exercises tended to be
      somewhat smaller.

PMID- 10408325
TI  - Effects of 30 days of creatine ingestion in older men.
AB  - In this investigation we evaluated the effects of oral creatine (Cr)
      supplementation on body composition, strength of the elbow flexors, and fatigue
      of the knee extensors in 20 males aged 60-82 years who were randomly administered
      Cr or placebo (P) in a double-blind fashion. Subjects ingested either 20 g of Cr
      or P for 10 days, followed by either 4 g of Cr or P, respectively, for 20 days.
      Tests were conducted pre-supplementation and following 10 and 30 days of
      supplementation. Leg fatigue was determined using an isokinetic dynamometer;
      subjects performed 5 sets of 30 maximal voluntary contractions at 180 degrees x
      s(-1), with 1 min of recovery between sets. The strength of the elbow flexors was
      assessed using a modified preacher bench attached to a strain gauge. There was a
      significant interaction (P < 0.05; group x time) in leg fatigue following
      supplementation. However, this interaction appears to have resulted from a
      combination of the improved fatigue score by the Cr-supplemented group and the
      decreased fatigue score by the P-supplemented group, because when the simple main
      effects were analyzed for the groups individually, there was no significant
      difference over time for either of the groups. There were no significant
      differences in body mass, body density, or fat-free mass as assessed by
      hydrostatic weighing, or strength between the Cr-supplemented or P-supplemented
      groups. These data suggest that 30 days of Cr-supplementation may have a
      beneficial effect on reducing muscle fatigue in men over the age of 60 years, but
      it does not affect body composition or strength.

PMID- 10408324
TI  - Water immersion delays the oxygen uptake response to sitting arm-cranking in
      humans.
AB  - We investigated the effect of central hypervolaemia during water immersion up to
      the xiphoid process on the oxygen uptake (VO2) and heart rate (HR) response to
      arm cranking. Seven men performed a 6-min arm-cranking exercise at an intensity
      requiring a VO2 at 80% ventilatory threshold both in air [C trial, 29 (SD 9) W]
      and immersed in water [WI trial, 29 (SD 11) W] after 6 min of sitting. The VO2
      (phase 2) and HR responses to exercise were obtained from a mono-exponential fit
      [f(t) = baseline + gain x (1 - e(-(t-TD)/tau))]. The response was evaluated by
      the mean response time [MRT; sum of time constant (tau) and time delay (TD)]. No
      significant difference in VO2 and HR gains between the C and WI trials was
      observed [VO2 0.78 (SD 0.1) vs 0.80 (SD 0.2) l x min(-1), HR 36 (SD 7) vs 37 (SD
      8) beats x min(-1), respectively]. Although the HR MRT was not significantly
      different between the C and WI trials [17 (SD 3), 19 (SD 8) s, respectively), VO2
      MRT was greater in the WI trial than in the C trial [40 (SD 6), 45 (SD 6) s,
      respectively; P < 0.05]. Assuming no difference in VO2 in active muscle between
      the two trials, these results would indicate that an increased oxygen store
      and/or an altered response in muscle blood distribution delayed the VO2 response
      to exercise.

PMID- 10408326
TI  - Variability of the fatigue response of paralyzed skeletal muscle in relation to
      the time after spinal cord injury: mechanical and electrophysiological
      characteristics.
AB  - The aim of this study was to determine the effect of the time after spinal cord
      injury (less than and greater than 10 months) on the mechanical and
      electrophysiological characteristics of muscle fatigue of the paralyzed
      electrically stimulated quadriceps muscle. Morphologically and histochemically, a
      relationship was observed between muscle fatigue and the delay from injury,
      revealing a critical period of enzymatic turning and a maximum peak of atrophy
      around the 10th month after the injury, followed by a long-term stabilization.
      Knee-torque output and M-wave variables (amplitude, latency, duration, and root
      mean square, RMS) of two muscular heads of the quadriceps were recorded in 19
      paraplegic patients during a 120-s isometric contraction. The fatiguing muscle
      contraction was elicited by supramaximal continuous 20-Hz electrical stimulation.
      Compared to the chronic group, the acutely paralyzed group showed a greater
      resistance to fatigue (amount and rate of force decline, P < or = 0.01), smaller
      alterations of the M-wave amplitude and RMS, and a limited decrease of the muscle
      fiber conduction velocity (P < 0.05). Mechanical and electrophysiological changes
      during fatigue provided a clear functional support of the transformation of
      skeletal muscle under the lesion and of the existence of a critical period of
      muscular turn. In conclusion, when considering the artificial restoration of
      motor function, the evolution of the endurance and force-generating capabilities
      of the muscle actuator must be taken into account, particularly when tasks
      require important safety conditions (e.g., standing and walking).

PMID- 10408327
TI  - Effects of aerobic exercise on serum leptin levels in obese women.
AB  - It has been demonstrated that leptin concentrations in obese patients may be
      altered by weight loss. We examined the effects of a 9-week aerobic exercise
      program on serum leptin concentrations in overweight women (20-50% above ideal
      body mass) under conditions of weight stability. Sixteen overweight women, mean
      (SE) age 42.75 (1.64) years, comprised the exercise group which adhered to a
      supervised aerobic exercise program. A graded exercise treadmill test was
      conducted before and after the exercise program to determine maximal oxygen
      uptake (VO2max) using open-circuit spirometry. The women demonstrated improved
      aerobic fitness (VO2max increased 12.29%), however, body fat and the body mass
      index did not change significantly [42.27 (1.35)-41.87 (1.33)%]. Fourteen women,
      age 40.57 (2.80) years, did not exercise over the same time period and served as
      a control group. Serum leptin levels were not significantly altered for either
      the exercise [28.00 (2.13)-31.04 (2.71) ng x ml(-1)] or the control group [33.24
      (3.78)-34.69 (3.14) ng x mg(-1)]. The data indicate that 9 weeks of aerobic
      exercise improves aerobic fitness, but does not affect leptin concentrations in
      overweight women.

PMID- 10408328
TI  - Determination of the velocity associated with the longest time to exhaustion at
      maximal oxygen uptake.
AB  - The so-called velocity associated with VO2max, defined as the minimal velocity
      which elicits VO2max in an incremental exercise protocol (v(VO2max)), is
      currently used for training to improve VO2max. However, it is well known that it
      is not the sole velocity which elicits VO2max and it is possible to achieve
      VO2max at velocities lower and higher than v(VO2max). The goal of this study was
      to determine the velocity which allows exercise to be maintained the longest time
      at v(VO2max). Using the relationship between time to exhaustion at VO2max in the
      all-out runs at 90%, 100%, 120% and 140% of v(VO2max) and distance run at VO2max,
      the velocity which elicits the longest time to exhaustion at VO2max (CV') was
      determined. For the six subjects tested (physical education students), this
      velocity was not significantly different from v(VO2max) (16.96+/-0.92 km x h(-1)
      vs 17.22+/-1.12 km x h(-1), P = 0.2 for CV' and v(VO2max), respectively) and
      these two velocities were correlated (r = 0.88, P = 0.05).

PMID- 10408329
TI  - The concept of critical velocity: a brief analysis.

PMID- 10408330
TI  - Effects of training and creatine supplement on muscle strength and body mass.
AB  - The purpose of this study was to test the effect of creatine supplement on the
      size of the extra- and intracellular compartments and on the increase of
      isokinetic force during a strength training-program. Twenty-five healthy male
      subjects (age 22.0+/-2.9 years) participated in this experiment. Seven subjects
      formed the control-group. They did not complete any training and did not have any
      dietary supplement. The eighteen other subjects were randomly divided into a
      creatine- (n = 8) and a placebo-group (n = 10). They were submitted to a
      controlled strength-training program for 42 days followed by a detraining period
      of 21 days. Creatine and placebo were given over a period of 9 weeks. The size of
      the body water compartments was assessed by bioimpedance spectroscopy and the
      isokinetic force was determined during a single squat by means of an isokinetic
      dynamometer. These measurements were completed beforehand, at the end of the
      training period, and after the determining period. Both placebo- and creatine
      group increased the isokinetic force by about 6% after the training period,
      showing that creatine ingestion does not induce a higher increase of the force
      measured during a single movement. No change in body mass was observed in the
      control- and placebo-groups during the entire experiment period while the body
      mass of the creatine-group was increased by 2 kg (P < 0.001). This change can be
      attributed partially to an increase (P = 0.039) in the body water content
      (+1.11), and more specifically, to an increase (P < 0.001) in the volume of the
      inter-cellular compartment (+0.61). Nevertheless, the relative volumes of the
      body water compartments remained constant and therefore the gain in body mass
      cannot be attributed to water retention, but probably to dry matter growth
      accompanied with a normal water volume.

PMID- 10408331
TI  - Echocardiographic evidence of concentric left ventricular enlargement in female
      weight lifters.

PMID- 10408332
TI  - Purification and characterization of an acid proteinase from mesophilic Mucor sp.
      solid-state cultures.
AB  - The fourth-day extract of a solid-state culture of the mesophilic Mucor sp. (M
      105) strain showed a high milk-clotting activity and a clotting/proteolytic
      activity ratio similar to that of commercial preparations from microbial origin
      used in cheese manufacture. After ultrafiltration of the crude extract, the milk
      clotting proteinase was purified in two steps: ion-exchange followed by size
      exclusion chromatography. Enzyme homogeneity was assessed by HPLC, SDS-PAGE and N
      terminal residue determination. A pI value of 4.21 was obtained and a molecular
      weight of 33 kDa was calculated from size-exclusion chromatography and SDS-PAGE
      data. The optimum pH for proteolytic activity towards dimethylcasein was in the
      3.0-3.5 range. The proteinase retained 26 and 13% of its proteolytic activity
      after a 30-min incubation period, at pH 5.0 and 50 and 60 degrees C,
      respectively. This evidenced a lower heat stability than that of the thermophilic
      enzymes currently used in the cheese industry and also than that of bovine
      chymosin. The enzyme was fully inhibited by pepstatin A and no effect was
      observed with PMSF, p-CMPS or EDTA. The N-terminal amino acid sequence:
      GTGTVPVTDDGNLNEYYXTVTVGXP was compared with those from other fungal enzymes.

PMID- 10408333
TI  - Pepsin as a catalyst for peptide synthesis: formation of peptide bonds not
      typical for pepsin substrate specificity.
AB  - Porcine pepsin in water solutions containing 15-28% of dimethylformamide at pH 5
      and 20-37 degrees C catalysed the formation of peptide bonds between Z-Ala-Ala
      Phe-OH and various amino acid or peptide derivatives. Substrate binding subsite
      S1' of pepsin demonstrated broad specificity in these reactions but revealed a
      certain preference for hydrophobic amino acid residues, including non-proteinous
      homophenylalanine, p-nitrophenylalanine, S-methylcysteine, as well as for those
      that contained, in addition to the hydrophobic elements, a group capable of
      donating a hydrogen bond, e.g. o-nitrotyrosine. This observation increases the
      range of peptides that might be prepared by pepsin-catalysed synthesis.

PMID- 10408334
TI  - Preparation and properties of novel gramicidin S analogs possessing a tri-, tetra
      or pentamethylene bridge between ornithine side chains.
AB  - Gramicidin S (GS) analogs in which the Ndelta atoms of the two Orn side chains
      are linked by an oligomethylene bridge [-(CH2)n-; n=3-5] were prepared via the
      bis(p-nitrobenzenesulfonyl) derivative [Orn(NBS)2,2']GS. For comparison the
      nonbridged secondary amino group-containing analog [Orn(Me)2,2']GS was also
      prepared. 1H NMR and CD spectral analysis indicated that these analogs adopt the
      same beta-sheet conformation as GS. The antimicrobial activities of these analogs
      were very similar, but were slightly dependent on the bridge chain length, the
      trimethylene-bridged analog being the most potent.

PMID- 10408335
TI  - Synthesis and biological evaluation of a pyoverdin-beta-lactam conjugate: a new
      type of arginine-specific cross-linking in aqueous solution.
AB  - Arginine specific reagents such as phenylglyoxal and other alpha-dioxo compounds
      react with arginine side chains by forming adducts with a stoichiometry of 2:1 or
      a mixture of 2:1 and 1:1. These adducts are labile in neutral and slightly
      alkaline aqueous solution. We developed a new type of cross-linking reaction with
      aliphatic beta-dioxo compounds. They can be used for the well-defined,
      irreversible covalent attachment of molecules carrying a primary amino group to
      arginyl residues of water soluble peptides. The reaction proceeds under mild
      conditions in aqueous solution, essentially without the formation of side
      products. A pyoverdin-cephalexin conjugate was synthesized in order to promote
      its cellular uptake by Pseudomonas aeruginosa. Preliminary biological
      investigations of the conjugate indicated that it enters the bacterial cell via
      the pyoverdin-mediated iron uptake pathway.

PMID- 10408336
TI  - Enzymatic synthesis of vasoactive intestinal peptide analogs by transglutaminase.
AB  - Vasoactive intestinal peptide is an amino acceptor and donor substrate for tissue
      transglutaminase (TGase) in vitro. This peptide contains a single glutamine
      residue, Gln16, which was identified as the amino acceptor substrate. Different
      gamma(glutamyl16)amine derivatives of vasoactive intestinal peptide were
      synthesized enzymatically in vitro. The modification is very fast when compared
      with that of many native substrates of TGase. The analogs 1,3-diaminopropane,
      putrescine, cadaverine, spermidine, spermine, glycine ethyl ester and mono
      dansylcadaverine of the peptide were purified by high-performance liquid
      chromatography on a reverse-phase column and were analyzed by electrospray mass
      spectrometry. When amines were absent in the assay mixture as an external amino
      donor, lysine residue occurring in the peptide was an effective amino donor site
      for TGase. Only one of the three lysine residues of vasoactive intestinal
      peptide, namely Lys21, was demonstrated to be involved in both inter- and
      intramolecular cross-link formation.

PMID- 10408337
TI  - Fibril formation by amyloid-beta proteins may involve beta-helical protofibrils.
AB  - We have proposed that amyloid fibrils contain subunits (protofibrils) that are
      formed from beta-strands wound into continuous 2-3 nm-diameter beta-helices.
      Subsequent lateral aggregation of the beta-helices to form the widely observed 5
      12 nm-diameter fibrils could be promoted by hydrophobic residues on the exterior
      of the postulated beta-helix. A number of short peptide fragments of the amyloid
      beta (A beta) proteins, such as A beta34-42 [LMVGGVVIA], the nine-residue,
      carboxyl-terminal portion of A beta1-42, can also form amyloid fibrils. In the
      present study, it was found that a beta-helix formed from A beta34-42 accounts
      for features suggested by published rotational resonance solid-state NMR data,
      including an anomalous conformation about the Gly-37-Gly-38 region and
      exaggerated pleating. An analogue of A beta34-42 was synthesized in which the
      hydrophobic groups on the exterior of the postulated beta-helix were replaced
      with glutamates, giving LEVGGVEIE. The analogue was completely soluble at pH 7,
      but at pH 2.5 it produced 2-2.5 nm-diameter fibrils which did not associate into
      larger-diameter bundles. The results of this study support the proposal that
      amyloid fibrils are formed from beta-helical subunits.

PMID- 10408338
TI  - Serotonin uptake stimulating peptide found in plasma of normal individuals and in
      some autistic urines.
AB  - We have isolated a tripeptide from normal plasma and autistic urines which
      stimulates the uptake of serotonin (5-HT) into platelets. This peptide was
      purified by high-performance liquid chromatography (HPLC) and characterized by
      sequenation and mass-spectrometry. Synthetic peptide showed co-chromatography
      with the biological sample in the HPLC systems used. Close to 60% of the autistic
      children diagnosed using the Diagnostic Statistical Manual III-R had an increased
      HPLC peak eluting like this peptide in their urines compared with controls.

PMID- 10408339
TI  - V3 loop-derived peptide SPC3 inhibits infection of CD4- and galactosylceramide-
      cells by LAV-2/B.
AB  - SPC3, a synthetic multibranched peptide including the GPGRAF consensus motif of
      the human immunodeficiency virus type 1 (HIV-1) gp120 V3-loop is a potent
      inhibitor of HIV infection of human CD4+ lymphocytes, macrophages and CD4
      /galactosylceramide+ human colon epithelial cells and is currently tested in
      phase II clinical trials (FDA protocol 257 A). The antiviral property of SPC3 was
      further investigated for its ability to inhibit LAV-2/B, an HIV-2 clone with a
      CD4-independent tropism. SPC3 inhibited the LAV-2/B-mediated infection of B-cell
      line which does not express the CD4 and the galactosylceramide molecules on their
      cell surface, suggesting an SPC3-sensitive CD4/galactosylceramide-independent
      pathway of viral infection in HIV susceptible cells. The molecular mechanism of
      the peptide inhibition was also investigated. The data suggested that the SPC3
      mediated inhibition does not result from a direct competition between SPC3 and
      gp120 binding to the cell surface of the target cell.

PMID- 10408340
TI  - Functional and structural consequences of aromatic residue substitutions within
      the kringle-2 domain of tissue-type plasminogen activator.
AB  - Aromatic amino acid residues within kringle domains play important roles in the
      structural stability and ligand-binding properties of these protein modules. In
      previous investigations, it has been demonstrated that the rigidly conserved
      Trp25 is primarily involved in stabilizing the conformation of the kringle-2
      domain of tissue-type plasminogen activator (K2tpA), whereas Trp63, Trp74, and
      Tyr76 function in omega-amino acid ligand binding, and, to varying extents, in
      stabilizing the native folding of this kringle module. In the current study, the
      remaining aromatic residues of K2tPA, viz., Tyr2, Phe3, Tyr9, Tyr35, Tyr52, have
      been subjected to structure-function analysis via site-directed mutagenesis
      studies. Ligand binding was not significantly influenced by conservative amino
      acid mutations at these residues, but a radical mutation at Tyr35 destabilized
      the interaction of the ligand with the variant kringle. In addition, as reflected
      in the values of the melting temperatures, changes at Tyr9 and Tyr52 generally
      destabilized the native structure of K2tPA to a greater extent than changes at
      Tyr2, Phe3, and Tyr35. Taken together, results to date show that, in concert with
      predictions from the crystal structure of K2tpA, ligand binding appears to rely
      most on the integrity of Trp63 and Trp74, and aromaticity at Tyr76. With regard
      to aromatic amino acids, kringle folding is most dependent on Tyr9, Trp25, Tyr52,
      Trp63, and Tyr76. As yet, no obvious major roles have been uncovered for Tyr2,
      Phe3, or Tyr35 in K2tpA.

PMID- 10408341
TI  - Synthesis and secondary structural studies of penta(acetyl-Hmb)A beta(1-40).
AB  - The Fmoc solid phase synthesis of A beta(1-40), a strongly aggregating peptide
      found in Alzheimer's disease brain, was performed using 2-hydroxy-4-methoxybenzyl
      (Hmb) backbone amide protection. Hmb-Gly residues were incorporated using
      N(alpha)-Fmoc-Hmb-Gly-OH rather than N,O-bisFmoc-Hmb-Gly-OPfp. Amino acid
      acylation of the sterically hindered Hmb-amino acids was monitored using 'semi-on
      line' MALDI-TOF-MS in a novel application of this technique which significantly
      simplified the successful incorporation of these residues. Standard coupling
      conditions in N,N-dimethylformamide (DMF) were used throughout the synthesis.
      Comparative structural studies of acetyl-Hmb-protected and native A beta(1-40)
      were performed to investigate the structural basis of Hmb-mediated
      disaggregation. The incorporation of backbone amide protection was observed by
      circular dichroism spectroscopy and gel electrophoresis to strongly affect the
      solution structure of A beta(1-40). Despite the reported structure-breaking
      activity of Hmb groups, penta(acetyl-Hmb)A beta(1-40) was found to adopt both
      alpha-helix and intermolecular beta-sheet conformations. In 100% TFE a mixed
      alpha-helix/random coil structure was formed by the protected peptide indicating
      reduced alpha-helical propensity relative to A beta(1-40). The protected peptide
      formed beta-sheet structures in aqueous buffer. Gel electrophoresis indicated
      that, unlike native A beta(1-40), penta(acetyl-Hmb)A beta(1-40) did not form
      large aggregate species.

PMID- 10408343
TI  - Insertion of an electronegative sulfur atom in the side chain of position 5 of
      angiotensin II: changes in the tachyphylactic properties of the peptide.
AB  - Angiotensin II (AII) analogs bearing n-Leu, Met or S-substituted groups for
      cysteine at position 5 were studied regarding their agonistic and tachyphylactic
      properties. It was shown that these analogs lowered the relative affinity towards
      the AT1 receptor as determined by contractile responses, which could be due to
      the removal of the beta-branching residue at position 5. Insertion of a sulfur
      atom in a different position away from the attached backbone carbon atom
      presented no significant difference in EC50 values for these analogs.
      Interestingly, the S-bearing analogs at position 5 were full agonists but the
      tachyphylactic property was lost, in contrast to [n-Leu5]AII, which still induced
      reduction of the contractile responses. Nevertheless after replacing the Asp with
      Sar in position 1 (Sar1) tachyphylaxis was again established. It is concluded
      that the insertion of Met or an S-substituted cysteine into the side chain at
      position 5 of AII may promote interactions with its receptor due to the slight
      electronegative character of the sulfur atom and changes in the restricted
      conformational freedom of the Ile5 residue in the AII molecule. This was overcome
      by Sar1, probably through interactions due to its fully protonated N-terminal
      amino group and favoring the conformation responsible for the tachyphylaxis
      phenomenon.

PMID- 10408342
TI  - Selective isopeptide bond formation: coupling ubiquitin(67-76) with histone
      2A(114-128) by use of the transfer active ester condensation technique.
AB  - A peptide, ubiquitin(67-76)-histone 2A(114-128) fragment (UBH2AF), was
      synthesized by selective formation of an isopeptide bond between the C-terminus
      of ubiquitin(67-76) and the epsilon-amino group of lysine-119 in histone 2A(114
      128) which contained 4 lysine residues at positions 118, 119, 125 and 127,
      respectively. The transfer active ester condensation technique, together with the
      Tnm amine protecting group, were used successfully in the peptide segment
      coupling reaction. [structure: see text]

PMID- 10408344
TI  - Continuous-flow solid-phase peptide synthesis using polystyrene resins.

PMID- 10408345
TI  - Expression of complement regulator proteins in primary and metastatic malignant
      melanoma.
AB  - The expression of complement regulatory antigens C3b/C4b receptor, (CD35)
      membrane cofactor protein (CD46), decay accelerating factor (CD55), and
      homologous restriction factor 20 (CD59) was determined immunohistochemically on
      ten primary malignant melanomas, 16 metastatic lesions, and ten melanocytic nevi.
      All of the melanocytic nevi and 9/10 primary melanomas showed both expression of
      CD46 and CD59. In one primary melanoma lacking CD46, expression of CD35 could be
      detected. In metastatic melanoma, 9/16 metastases were CD46+/CD59+, two were CD46
      /CD59+, one CD46+/CD59-, and four CD46-/CD59-. Additionally, CD55 could be
      detected in two CD46+/CD59+ metastases, and CD35 in one. Expression or lack of
      complement regulatory antigens did not correlate with the expression of GD2, GD3,
      HMB-45 or S-100. In conclusion, some cases of metastatic melanoma show loss of
      normal expression of complement regulatory proteins. This might have implications
      on the immune response or the efficacy of immune therapy in malignant melanoma.

PMID- 10408346
TI  - Tumor microvessels in melanoma express the beta-2 chain of laminin. Implications
      for melanoma metastasis.
AB  - The ultrastructural localization of an amorphous matrix to the interface between
      microvessel endothelium and tumor cells has been recently reported in a series of
      melanomas. Laminin expression as documented by immunohistochemistry was localized
      to microvessels in melanomas showing the amorphous matrix. In order to identify
      more precisely the type of laminin present in this amorphous material,
      immunostaining was carried out on cryostat sections from 16 human melanoma
      specimens. Four murine monoclonal antibodies directed against the alpha-3, beta
      2, beta-3 and gamma-2 laminin chains were employed. In the melanomas studied,
      alpha3, beta3 and gamma2 laminin chains showed only minimal focal vascular
      positivity. In contrast, the beta2 (16/16 cases) laminin chain exhibited a
      consistent positivity in an angiocentric pattern about tumor microvessels. In all
      melanomas, some tumor cells seemed to spread along the abluminal surface of the
      small vessels, exhibiting a pericytic location, particularly along the
      intratumoral projections formed by the beta2 laminin chain. Given the role of
      laminin in migration and tumor progression, the results suggest a role of the
      beta2 laminin chain in melanoma spread, promoting tumor migration along the
      abluminal surface of vessel, a phenomenon which has been termed extra-vascular
      migratory metastasis.

PMID- 10408347
TI  - Differential expression of c-Met in Kaposi's sarcoma according to progression
      stage and HIV infection status.
AB  - Several cytokines, growth factors and the HIV transactivator Tat have been shown
      to be involved in the pathogenesis of Kaposi's sarcoma (KS). Hepatocyte growth
      factor/scatter factor (HGF) is an angiogenic cytokine that stimulates
      proliferation of spindle cells cultured from human KS lesions. The receptor for
      HGF, the c-Met protein, is expressed by endothelial cells, dermal dendrocytes and
      KS tumor cells both in vitro and in vivo. KS cells synthesize and secrete HGF and
      express the hepatocyte growth factor receptor (c-Met), thus providing an
      autocrine loop for tumor proliferation and neovascularization which can be
      enhanced by proinflammatory cytokines. We studied the immunohistochemical
      expression of c-Met in 40 cases of classical Kaposi's sarcoma (C-KS) and AIDS
      associated cutaneous Kaposi's sarcoma (AIDS-KS), including 22 plaque stage
      lesions (12 AIDS-KS cases) and 18 tumor stage lesions (7 AIDS-KS cases).
      Statistically significant differences in the average intensity of
      immunohistochemical staining according to the type of lesions progression stages)
      and the serologic status of the patients were identified. The staining intensity
      of c-Met was stronger in tumors than in plaques. When only plaques were taken
      into consideration, the mean staining score was nearly twice as high in C-KS as
      in AIDS-KS.

PMID- 10408348
TI  - An immunohistochemical study of the apocrine type of cutaneous mixed tumors with
      special reference to their follicular and sebaceous differentiation.
AB  - An immunohistochemical analysis of 8 cases of the apocrine type of cutaneous
      mixed tumor is reported. Histologically, 7 cases of the tumor were suggested to
      have follicular and/or sebaceous differentiation. Carcinoembryonic antigen (CEA),
      epithelial membrane antigen and gross cystic disease fluid protein-15 were
      present in the inner surface and/or in the luminal cell bodies of the tubular
      structures. CEA and non-specific cross-reacting antigen were also detected in the
      keratinous cysts. Positive reactions for S-100 protein and vimentin were observed
      in the solid nests, the outer layer of the tubular structures and some stromal
      cells. However, smooth muscle actin was only focally expressed in the outer cells
      of the tubular nests in one case. Involucrin was positive in the inner layers of
      the keratinous cysts. Various staining patterns were observed in the keratin
      immunohistochemistry. The solid nests showed heterogeneous expressions of
      CK1/5/10/14, CK7, CK10/11, CK14, CK8/18 and CK19. The inner cells of the tubular
      structures were constantly positive for CK7, CK8/18 and CK19, and heterogeneously
      for CK1/5/10/14, CK10/11 and CK14. The outer cells were heterogeneously positive
      for CK1/5/10/14 and CK14. The keratinous cysts showed positive reactions for
      CK1/5/10/14 throughout the whole cell layers, and for CK14 in the basal layer.
      The inner layers in some keratinous cysts expressed CK6, CK10/11 and CK17, but
      only CK10 in others. CK13 was positively stained in the transitional portion
      between the matricial structure and the column of shadow cells in the cyst wall
      in only one case. When compared with the immunohistochemistry of the normal skin,
      the apocrine type of cutaneous mixed tumor can show various immunophenotypical
      patterns similar to those of entire structures of hair follicles, sebaceous
      glands and all components of apocrine glands, that is to say, the
      folliculosebaceous-apocrine unit.

PMID- 10408349
TI  - Epstein Barr virus-associated lymphoproliferative-disorders primarily involving
      the skin.
AB  - In cases of solid organ or bone marrow transplantation, up to 2 to 10% of
      patients may develop lymphoproliferative disorders (LPD), often induced by
      Epstein-Barr virus (EBV). Despite a morphology mimicking malignant lymphoma, in
      some cases the lesions will disappear completely after the degree of
      immunosuppression is lowered. Lately, similar processes have been described in
      non-transplant, immunosuppressed patients. A SNOMED search was performed on the
      database of three hospitals between 1990 and 1997, to identify patients with
      immunosuppression-related lymphoproliferative disorders (IR-LPD) involving
      primarily the skin. Two patients were identified. One was 2 years after kidney
      transplantation, and the other was being treated with methotrexate for
      dermatomyositis. In both biopsies, there was a diffuse perivascular proliferation
      of large lymphocytes with ample cytoplasm and pleomorphic nuclei, associated with
      extensive dermal and subcutaneous necrosis. Immunohistochemical studies revealed
      expression of CD20, CD45RO, CD43, CD30, EBV-LMP1, and EBV-NA2 by the atypical
      lymphocytes in both cases and, in one case, of the EBV-transcriptional
      replication activation protein. In both cases the lesions completely disappeared
      and have not recurred. Primary involvement of the skin by IR-LPD is very rare.
      Based on our results, it is possible that some of these cases in the skin contain
      EBV and co-express CD30 and T- and B-cell markers. The diagnosis of IR-LPD should
      be considered in cutaneous lymphoid proliferations in immunosuppressed patients.
      Before rendering an unequivocal diagnosis of malignant lymphoma, reduction of
      immunosuppression and follow-up of 4-8 weeks should be considered.

PMID- 10408350
TI  - Conjunctival melanocytic nevi of childhood.
AB  - Two young patients with conjunctival compound nevi are presented to illustrate
      two types of abnormalities that lead to difficulty in distinction of these nevi
      from invasive melanomas. In Case 1, inflammation is associated with disruption of
      the nevus cell architecture and cytologic atypia. In Case 2, the occurrence of a
      combined nevus (compound and blue nevus types) in the conjunctiva leads to
      diagnostic problems. Circumscription of the lesions, lack of mitoses in the
      substantia propria, and lack of pagetoid spread of atypical cells in the adjacent
      conjunctival epithelium support benign diagnoses in both cases.

PMID- 10408351
TI  - Congenital CD34-positive granular cell dendrocytosis.
AB  - Granular cell tumors involving the skin are mostly acquired lesions. The Schwann
      cell origin of these lesions is supported by positive immunostaining for S-100
      protein and myelin basic protein. S-100- granular cell lesions rarely have been
      described in association with fibrous papules or dermatofibromas. The congenital
      variety of S-100- granular cell tumors occurs almost exclusively in the gingiva.
      The cell origin of these lesions is not well delineated. We report a hitherto
      undescribed case of a congenital cutaneous lesion which is histologically
      characterized by diffuse dermal infiltrates of S-100- but CD34+ granular dermal
      dendrocytes. The granular appearance of these CD34+ dendrocytes is attributed to
      an abundance of phagolysosomes. The pathogenetic mechanism of this unusual lesion
      remains to be elucidated.

PMID- 10408352
TI  - Sialadenoma papilliferum of the palate: case report and literature review.
AB  - Sialadenoma papilliferum (SP) is a rare tumor of salivary gland ducts which bears
      a strong histologic resemblance to the more common syringocystadenoma
      papilliferum (SCAP). We report a case occurring on the palate of a 50-year-old
      man, and review the clinical and histologic features of this tumor. Because of
      the histologic similarities between these two tumors and squamous papillomas,
      polymerase chain reaction (PCR) for human papilloma virus (HPV) DNA was performed
      on this tumor and on two cases of SCAP, with negative results. To our knowledge,
      this is the first case report of SP in the dermatopathology literature.

PMID- 10408353
TI  - Factor XIIIa-positive dendrocytes in malignant melanoma.

PMID- 10408354
TI  - Tools of the trade: statistical analysis in dermatopathology articles.
AB  - Statistical analysis of research results provides powerful tools for
      understanding the data from projects. A prospective review of the statistical
      methods utilized in 100 consecutive articles in the recent literature relevant to
      dermatopathology was performed. The majority of papers, 75%, did not contain
      statistical analyses. A wide variety of methods were utilized in the papers that
      did have statistical analyses including methods in the following categories: t
      test, contingency tables, multiple regression, multiple comparisons,
      nonparametric tests, life tables, and survival tests. Nine of the 25 papers
      utilizing statistical analysis had problems in the methods. These problems
      included treating categorical data as a continuous variable, multiple
      comparisons, subgroup analysis, and discordance of statistics and conclusions. It
      is important to understand the underlying assumptions of statistical methods to
      use the appropriate tets. These are tools of the trade for dermatopathology
      investigators.

PMID- 10408355
TI  - A novel approach for studying angiogenesis: a human skin equivalent with a
      capillary-like network.
AB  - Angiogenesis results from an ordered set of events that can be modulated in vivo
      by a variety of angiogenesis-enhancing or inhibiting agents. We review in vitro
      angiogenesis models and the agents that enhance or inhibit angiogenesis. We also
      discuss a new in vitro angiogenesis model created within a skin equivalent.
      Briefly, endothelial cells were combined with the cutaneous cells of a standard
      skin equivalent and cultured in a chitosan cross-linked collagen
      glycosaminoglycan scaffold of this endothelialized skin. This model enables the
      formation of capillary-like structures in a coculture environment containing
      newly synthesized extracellular matrix by fibroblasts and keratinocytes. Several
      morphological characteristics associated with the microvasculature in vivo were
      observed in the endothelialized skin equivalent such as histotypic organization
      of tubular structures, basement membrane deposition, and intercellular junction
      formation.

PMID- 10408356
TI  - Mechanisms of altered sequestration and efflux of chemotherapeutic drugs by
      multidrug-resistant cells.
AB  - This review considers the mechanisms associated with the pleiotropic resistance
      of cancer cells to chemotherapeutic drugs, and more particularly those related to
      intracellular pH (pHi). The multidrug resistance (MDR) phenomenon responsible for
      the decreased accumulation and increased efflux of cytotoxic drugs is generally
      associated with excess levels of P-glycoproteins (Pgps) encoded by MDR genes
      and/or the multidrug resistance-associated protein (MRP). MDR cell lines, derived
      from normal or tumor cells, frequently exhibit abnormally elevated pHi and
      changes in the production of various proteins. Recent studies have suggested
      that, in addition to the impact of the ATP-dependent membrane transporters Pgp
      and MRP on drug transport, other mechanisms linked to pHi changes in MDR cells
      may play an important role in drug resistance. We have shown that alkalinization
      of the acidic compartments (endosomes and lysosomes) by lysosomotropic agents
      could stimulate the efflux of vinblastine from drug-resistant mouse renal
      proximal tubule cells. The fact that weak base chemotherapeutic drugs can be
      sequestered within the acidic organelles of MDR cells sheds new light on the
      cellular mechanisms of drug resistance.

PMID- 10408357
TI  - Lead and catechol hematotoxicity in vitro using human and murine hematopoietic
      progenitor cells.
AB  - In vitro cloning assays for hematopoietic myeloid and erythroid precursor cells
      have been used as screening systems to investigate the hematotoxic potential of
      environmental chemicals in humans and mice. Granulocyte-monocyte progenitors (CFU
      GM) from human umbilical cord blood and from mouse bone marrow (Balb/c and
      B6C3F1) were cultured in the presence of lead and the benzene metabolite
      catechol. Erythroid precursors (BFU-E) from human umbilical cord blood were
      cultured in the presence of lead. The in vitro exposure of the human and murine
      cells resulted in a dose-dependent depression of the colony numbers. The
      concentration effect relationship was studied. Results showed that: (1) Based on
      calculated IC50 values, human progenitors are more sensitive to lead and catechol
      than are murine progenitors. The dose that caused a 50% decrease in colony
      formation after catechol exposure was 6 times higher for murine cells (IC50 = 24
      micromol/L) than for human cord blood cells (IC50 = 4 micromol/L). Lead was 10-15
      times more toxic to human hematopoietic cells (IC50 = 61 micromol/L) than to
      murine bone marrow cells from both mice strains tested (Balb/c, IC50 = 1060
      micromol/L; B6C3F1, IC50 = 536 micromol/L). (2) A lineage specificity was
      observed after exposure to lead. Human erythroid progenitors (hBFU-E) (IC50 =
      3.31 micromol/L) were found to be 20 times more sensitive to the inhibitory
      effect of lead than were myeloid precursors (hCFU-GM) (IC50 = 63.58 micromol/L).
      (3) Individual differences in the susceptibility to the harmful effect of lead
      were seen among cord blood samples. (4) Toxicity of lead to progenitor cells
      occurred at environmentally relevant concentrations.

PMID- 10408358
TI  - Different induction of adaptive response to ionizing radiation in normal and
      neoplastic cells.
AB  - Since the beneficial effects of low-dose radiation (0.01 Gy) are usually observed
      in normal cells, we investigated whether the adaptive response was induced by low
      dose radiation in neoplastic cells of different origin as well as in normal
      cells. Cell lines used in this experiment were as follows: mouse lymphocytes
      (NL); L929 cells established from mouse connective tissue; primary mouse
      keratinocytes (PK); line 308 from mouse papilloma; X-ray sensitive lymphoma
      cells, L5178Y-S and EL-4 cells from mouse lymphoma. The adaptive response was
      determined by cell survival and apoptosis. The involvement of apoptosis in the
      adaptive response was examined by ELISA and TUNEL assay. Adaptive response was
      induced by pretreatment with low-dose radiation of 0.01 Gy in normal cells such
      as NL, L929, and PK, but not in L5178Y-S, EL-4, and line 308 cells. In addition,
      the reduction of apoptosis by pretreatment with low-dose radiation was observed
      in NL, L929, and PK, but not in L5178Y-S, EL-4, and line 308 cells. These results
      suggested that the adaptive response could be induced by pretreatment with low
      dose radiation and the phenomena were observed in normal cells, not in neoplastic
      cells. In addition, pretreatment with low-dose radiation reduced apoptosis,
      suggesting that an anti-apoptotic pathway may be involved in the adaptive
      response.

PMID- 10408359
TI  - Predictivity of an in vitro model for acute and chronic skin irritation
      (SkinEthic) applied to the testing of topical vehicles.
AB  - An in vitro human reconstructed epidermis model (SkinEthic) used for screening
      acute and chronic skin irritation potential was validated against in vivo data
      from skin tolerability studies. The irritation potential of sodium lauryl sulfate
      (SLS), calcipotriol and trans-retinoic acid was investigated. The in vitro
      epidermis-like model consists of cultures of keratinocytes from human foreskin on
      a polycarbonate filter. The modulation of cell viability, the release and gene
      expression of proinflammatory cytokines, interleukins 1alpha and 8, and
      morphological changes were evaluated during 3 days as endpoints representative
      for an inflammatory reaction. The cumulative irritation potential of the topical
      products was evaluated in a human clinical study by visual scoring and
      biophysical measurement of inflammatory skin reaction after repeated 24 h
      applications over 3 weeks under Finn chamber patches. All topical products that
      were nonirritating in the human study were noncytotoxic and did not induce
      cytokine expression in the in vitro acute model (day 1 exposure). All irritating
      controls exhibited specific cell viability and cytokine patterns, which were
      predictive of the in vivo human data. The ranking of mild to moderate skin
      irritation potential was based on the lack of cytotoxicity and the presence of
      cytokine patterns including gene expression specific for each irritant, using the
      chronic in vitro model (up to 3 days exposure). The human reconstructed epidermis
      model SkinEthic was shown to be a reliable preclinical tool predicting the
      irritation potential of topical products. Moreover, it is a useful model in a two
      step tiered strategy for screening acute and chronic irritation potential for the
      selection of vehicles for new topical drugs.

PMID- 10408360
TI  - Structure and functions of the interaction domains of C1r and C1s: keystones of
      the architecture of the C1 complex.
AB  - C1r and C1s, the proteases responsible for activation and proteolytic activity of
      the C1 complex of complement, share similar overall structural organizations
      featuring five nonenzymic protein modules (two CUB modules surrounding a single
      EGF module, and a pair of CCP modules) followed by a serine protease domain.
      Besides highly specific proteolytic activities, both proteases exhibit
      interaction properties associated with their N-terminal regions. These properties
      include the ability to bind Ca2+ ions with high affinity, to associate with each
      other within a Ca2+-dependent C1s-C1r-C1r-C1s tetramer, and to interact with C1q
      upon C1 assembly. Precise functional mapping of these regions has been achieved
      recently, allowing identification of the domains responsible for these
      interactions, and providing a comprehensive picture of their structure and
      function. The objective of this article is to provide a detailed and up-to-date
      overview of the information available on these domains, which are keystones of
      the assembly of C1, and appear to play an essential role at the interface between
      the recognition function of C1 and its proteolytic activity.

PMID- 10408361
TI  - Modular organization of proteins containing C1q-like globular domain.
AB  - The first step in the activation of the classical pathway of complement cascade
      by immune complexes involves the binding of the six globular heads of C1q to the
      Fc regions of immunoglobulin G (IgG) or immunoglobulin M (IgM). The globular
      heads of C1q are located C-terminal to the six triple-helical stalks present in
      the molecule, each head is considered to be composed of the C-terminal halves (3
      x 135 residues) of one A-, one B- and one C-chain. It is not known if the C
      terminal globular regions, present in each of the three types of chains, are
      independently folded modules (with each chain having distinct binding properties
      towards immunoglobulins) or whether the different binding functions of C1q are
      dependent upon a globular structure which relies on contributions from all three
      chains. Recent reports of recombinant production and characterisation of soluble
      globular head regions of all the three chains indicate that the globular regions
      of C1q may adopt a modular organization, i.e., each globular head of C1q may be
      composed of three, structurally and functionally, independent domains, thus
      retaining multivalency in the form of a heterotrimer. Modules of the same type as
      the C1q C-terminal module are also found in a variety of noncomplement proteins
      that include the C-terminal regions of the human type VIII and type X collagens,
      precerebellin, the chipmunk hibernation proteins, the human endothelial cell
      protein, multimerin, the serum protein, Acrp-30 which is secreted from mouse
      adipocytes, and the sunfish inner-ear specific structural protein. The C1q
      molecule is the only one of these proteins for which, to date, a function has
      been ascribed to the module. The existence of a shared structural region between
      C1q and certain collagens may suggest an evolutionarily common ancestral
      precursor. Various structural and biochemical data suggest that these modules may
      be responsible for multimerisation through patches of aromatic residues within
      them.

PMID- 10408363
TI  - Functional properties of soluble CD21.
AB  - Soluble receptors may display immunoregulatory properties by blocking
      interactions between ligands and their membrane receptors or by triggering
      specific biologic responses through interaction with counter part membrane
      receptors. A natural soluble form of CD21 that is cleaved from lymphocyte
      membrane CD21 circulates in normal human serum. Soluble CD21 retains the capacity
      to bind iC3b and CD23, the known ligands of membrane CD21. In a similar fashion
      to IgE complexes, another ligand of CD23, the soluble CD21 was shown to
      efficiently trigger CD23-signalling pathways in human monocytes. By inducing
      release of proinflammatory cytokines and upregulating expression of molecules
      involved in antigen presentation, soluble CD21 modulates critical monocyte
      functions that may be relevant to allergic and inflammatory disorders.

PMID- 10408364
TI  - Structure and functions of proteases which cleave human C3 and are expressed on
      normal or tumor human cells: some are involved in tumorigenic and metastatic
      properties of human melanoma cells.
AB  - Human C3 is a multipotent molecule which participates to different events
      involved in immune response as complement activation, antigen presentation, cell
      cell interactions and cell proliferation. Thus, proteinases which cleave C3 may
      modify C3-dependent cellular functions. This led us to identify two membrane
      associated proteinases which cleave human C3: (a) A p57 serine proteinase
      expressed on human erythrocyte membranes--This p57 proteinase shared antigenic
      determinants with ankyrine and may be involved in clearance of immune complexes;
      (b) A p41 cysteine proteinase, which shares antigenic determinants, amino-acid
      sequence and specific activity with procathepsin-L--This p41 C3-cleaving cyteine
      proteinase is also involved in tumorigenic and metastatic properties of human
      melanoma in nude mice. Indeed, pretreatment of highly tumorigenic and metastatic
      melanoma cells with anti-p39 Ab totally abolished their tumorigenicity and
      significantly decreased the number of experimental lung metastases in nude mice.
      Furthermore, overexpression of procathepsin-L in nonmetastatic melanoma cells
      increased their tumorigenicity and switched their phenotype to highly metastatic
      cells in nude mice. Altogether, these data support that expression and secretion
      of procathepsin-L, which cleaves human C3, might be one of the multiple
      mechanisms by which tumor cells escape the immune surveillance.

PMID- 10408362
TI  - Regulation of complement activation by C-reactive protein.
AB  - C-reactive protein (CRP) is an acute-phase serum protein and a mediator of innate
      immunity. CRP binds to microbial polysaccharides and to ligands exposed on
      damaged cells. Binding of CRP to these substrates activates the classical
      complement pathway leading to their uptake by phagocytic cells. Complement
      activation by CRP is restricted to C1, C4, C2 and C3 with little consumption of
      C5-9. Surface bound CRP reduces deposition of and generation of C5b-9 by the
      alternative pathway and deposition of C3b and lysis by the lectin pathway. These
      activities of CRP are the result of recruitment of factor H resulting in
      regulation of C3b on bacteria or erythrocytes. Evidence is presented for direct
      binding of H to CRP. H binding to CRP or C3b immobilized on microtiter wells was
      demonstrated by ELISA. Attachment of CRP to a surface was required for H binding.
      H binding to CRP was not inhibited by EDTA or phosphocholine, which inhibit
      ligand binding, but was inhibited by a 13 amino acid CRP peptide. The peptide
      sequence was identical to the region of CRP that showed the best alignment to H
      binding peptides from Streptococcus pyogenes (M6) and Neisseria gonorrhoeae
      (Por1A). The results suggest that CRP bound to a surface provides secondary
      binding sites for H resulting in greater regulation of alternative pathway
      amplification and C5 convertases. Complement activation by CRP may help limit the
      inflammatory response by providing opsonization with minimal generation of C5a
      and C5b-9.

PMID- 10408365
TI  - Systemic lupus erythematosus and complement deficiency: clues to a novel role for
      the classical complement pathway in the maintenance of immune tolerance.
AB  - Complete deficiency of C1q, the first component of the classical pathway of
      complement activation, is almost invariably associated with the development of
      systemic lupus erythematosus. Understanding why complement deficiency results in
      the specific autoimmune phenotype of SLE may provide valuable clues to the role
      of complement in the maintenance of immune tolerance. The following review will
      focus on the characteristics of complement-deficient SLE and the experimental
      evidence in support of our hypothesis that C1q may critically influence the
      immune response to self-antigen contained within surface blebs generated by
      apoptotic cells.

PMID- 10408366
TI  - The factor H protein family.
AB  - The factor H gene family provides a prime example of a multidomain
      multifunctional protein family whose individual members are defined by conserved
      common structural elements and display diverse but often overlapping functions.
      The six identified members of this protein family represent secreted plasma
      proteins that are primarily synthesized in the liver. Here, we summarize the
      current understanding of the function of these proteins and suggest a common role
      in complement control. Factor H is the best characterized member and acts as a
      complement regulator. The protein displays cofactor activity for factor I in the
      degradation of the central complement component C3b, acts as a decay accelerating
      factor for the C3 convertase, C3bBb and is a competitor for factor B binding to
      C3b. Factor H is a multifunctional protein and displays functions outside the
      complement system: it binds to the cellular integrin receptor (CD11b/CD18),
      interacts with cell surface glycosaminoglycans and also binds to the surface of
      certain pathogenic microorganisms. In addition, factor H has several binding
      sites for the C3 protein. The factor H-like protein 1 (FHL-1) or reconectin
      shares the complement regulatory functions with factor H and interacts with
      heparin. The protein displays cell spreading activity and binds to the N-terminus
      of the streptococcal M protein. The function of the factor H-related proteins
      (FHR-1 to FHR-4) is currently under investigation. These proteins are differently
      distributed. Three proteins (FHR-1, FHR-2 and FHR-4) are constituents of
      lipoproteins, while FHR-3 interacts with heparin. Binding to C3b and C3d has been
      demonstrated for FHR-3 and FHR-4 and the two proteins display a cofactor related
      activity.

PMID- 10408367
TI  - Therapeutic intervention with complement and beta-glucan in cancer.
AB  - Complement (C) has two major effector systems available for host defense. The
      membrane attack complex (MAC) generated from components C5-C9 can form membrane
      penetrating lesions that lead to cell death by causing a rapid loss of
      cytoplasmic components. The MAC is only effective against pathogens with outer
      phospholipid membranes, and cannot kill gram-positive bacteria or yeast whose
      membranes are protected by cell walls. The most important effector mechanism of C
      is the opsonization of microbial pathogens with the serum protein C3 that leads
      to their high avidity attachment to the C3-receptors of phagocytic cells.
      Pathogens that activate complement are first coated with the C3b fragment of C3,
      which is rapidly proteolyzed into the iC3b fragment by serum factor I. These iC3b
      fragments serve to promote the high avidity attachment of the 'iC3b-opsonized'
      pathogens to the iC3b-receptors (CR3, CD11b/CD18) of phagocytic cells and natural
      killer (NK) cells, stimulating phagocytosis and/or cytotoxic degranulation. Host
      cells, including neoplastic tumor cells, have been endowed with natural
      mechanisms for self-protection against both the MAC and the cytotoxic activation
      of CR3. This review discusses a novel type of immunotherapy for cancer that uses
      soluble yeast beta-glucan to override the normal resistance of iC3b-opsonized
      tumor cells to the cytotoxic activation of phagocyte and NK cell CR3, allowing
      this important effector mechanism of the C system to function against tumor cells
      in the same way that it normally functions against bacteria and yeast. Moreover,
      the cytotoxic activation of beta-glucan-primed NK cell CR3 by iC3b-opsonized
      tumors is shown to be accompanied by a tumor-localized secretion of the cytokines
      TNFalpha, IFNalpha, IFNgamma, and IL-6.

PMID- 10408368
TI  - Molecular remodeling of complement regulatory proteins for xenotransplantation.
AB  - In pig-to-human discordant xenotransplantation, human complement is a major
      barrier against long survival of xenografts. Human complement regulatory proteins
      expressed on xenografts have been adapted as safeguards against host-induced
      hyperacute rejection of xenografts. For successful xenotransplantation, there
      have been many attempts to generate molecules with potent human complement
      regulatory activity but without activities related to harmful functions such as
      infection, immunosuppression and signal transduction devastating cellular
      homeostasis. Here, we summarize the strategy by which molecules for
      xenotransplantation should be designed and propose a GPI-anchored form of
      monomeric human C4bp as a candidate for efficient protection of swine xenografts
      from human complement attack.

PMID- 10408369
TI  - Lysis via the lectin pathway of complement activation: minireview and lectin
      pathway enhancement of endotoxin-initiated hemolysis.
AB  - Lysis via the newly discovered lectin pathway of complement activation is
      reviewed. Mannan-coated erythrocytes sensitized with MBL are lysed in human serum
      containing Mg-EGTA via the lectin pathway by a process which requires alternative
      pathway amplification. The inhibitory activities of C4bp and factor H, which are
      augmented in the presence of MBL, regulate this hemolysis. Lectin pathway
      activity is enhanced by IgG, which inhibits H activity, and is inhibited by C
      reactive protein, which enhances the activity of H. Lectin pathway hemolysis in
      Mg-EGTA also is seen in other species, and is particularly intense and does not
      require alternative pathway amplification in the guinea pig. New investigations
      using E-RaLPS as the MBL-binding agent allowed comparison with classical pathway
      activation by rabbit anti-RaLPS using the same indicator cell. E-RaLPS-MBL are
      lysed in human serum-Mg-EGTA, and alternative pathway amplification is required.
      The addition of rabbit anti-E to E-RaLPS-MBL leads to significant enhancement of
      lysis in Mg-EGTA, much greater than Ig enhancement of hemolysis via the
      alternative pathway. Lectin pathway activation also enhances the antibody
      independent C activation of the classical C pathway via C1q by ReLPS, as well as
      the direct activation of the alternative C pathway by wild type LPS. Thus,
      potentiation of reactions initiated at sites of IgG deposition and Ig-independent
      complement activation represents another characteristic of the lectin pathway.

PMID- 10408370
TI  - Control of host complement activation by the Echinococcus granulosus hydatid
      cyst.
AB  - Cystic hydatid disease is caused by the multicellular parasite Echinococcus
      granulosus. The hydatid cyst, being a long-lived, large, antigenic structure
      lodged in the host's internal organs, could potentially elicit major inflammatory
      responses. However, in practice, the cyst causes only minimal local inflammation.
      The complement system is a major pathway to immune-mediated inflammation. Recent
      results have shown that the host-exposed structure of the cyst, the hydatid cyst
      wall (HCW), fails to trigger the complement system strongly. We have carried out
      a wide survey for the mechanisms making the cyst wall relatively complement
      inert. The results of those studies are summarised in this work, with emphasis on
      the most recently identified of the complement inhibitory mechanisms. This is
      based on a non-protein heat-stable, parasite inhibitor of the activation of host
      complement factor B.

PMID- 10408371
TI  - Viral complement regulatory proteins.
AB  - The inactivation of complement provides cells and tissues critical protection
      from complement-mediated attack and decreases the associated recruitment of other
      inflammatory mediators. In an attempt to evade the host immune response, viruses
      have evolved two mechanisms to acquire complement regulatory proteins. They can
      directly seize the host cell complement regulators onto their outer envelope
      and/or they can produce their own proteins which are either secreted into the
      neighboring intercellular space or expressed as membrane-bound proteins on the
      infected host cell. The following review will concentrate on the viral homologues
      of the mammalian complement regulatory proteins, specifically those containing
      complement control protein (CCP) repeats.

PMID- 10408372
TI  - Complement systems in invertebrates. The ancient alternative and lectin pathways.
AB  - The complement system in higher vertebrates is composed of about thirty proteins
      that function in three activation cascades and converge in a single terminal
      pathway. It is believed that these cascades, as they function in the higher
      vertebrates, evolved from a few ancestral genes through a combination of gene
      duplications and divergences plus pathway duplication (perhaps as a result of
      genome duplication). Evidence of this evolutionary history is based on sequence
      analysis of complement components from animals in the vertebrate lineage. There
      are fewer components and reduced or absent pathways in lower vertebrates compared
      to mammals. Modern examples of the putatively ancestral complement system have
      been identified in sea urchins and tunicates, members of the echinoderm phylum
      and the protochordate subphylum, which are sister groups to the vertebrates. Thus
      far, this simpler system is composed of homologues of C3, factor B, and mannose
      binding protein associated serine protease suggesting the presence of simpler
      alternative and lectin pathways. Additional components are predicted to be
      present. A complete analysis of this invertebrate defense system, which evolved
      before the invention of rearranging genes, will provide keys to the primitive
      beginnings of innate immunity in the deuterostome lineage of animals.

PMID- 10408373
TI  - The complement regulator C4b-binding protein analyzed by molecular modeling,
      bioinformatics and computer-aided experimental design.
AB  - Molecular modeling and bioinformatics have gained recognition as scientific
      disciplines of importance in the field of biomedical research. Molecular modeling
      not only allows to predict the three-dimensional structure of a protein but also
      helps to define its function. Careful incorporation of the experimental findings
      in the structural/theoretical data provides means to understand molecular
      mechanisms for highly complex biological systems. C4b-binding protein (C4BP) is
      composed of one beta-chain and seven alpha-chains essentially built from three-
      and eight-complement control protein (CCP) modules, respectively, followed by a
      non-repeat carboxy-terminal region involved in polymerization of the chains. C4BP
      is involved in the regulation of the complement system and interacts with many
      molecules such as C4b, Arp, protein S and heparin. Here, we report experimental
      and computer data obtained for C4BP. Protein modeling together with site directed
      mutagenesis indicate that R39, R64 and R66 from the C4BP alpha-chain form a key
      binding site for heparin, suggesting that this region could be of major
      importance for interaction with C4b. We also propose that the first CCP of the
      C4BP beta-chain displays a key hydrophobic surface of major importance for the
      interaction with the coagulation cofactor protein S.

PMID- 10408374
TI  - Genetic disruption of the murine complement C3 promoter region generates
      deficient mice with extrahepatic expression of C3 mRNA.
AB  - Genetic deficiencies of the complement protein C3 occur naturally in humans and
      animal models and have been induced in mice by targeted deletion of the C3 gene.
      The study of these deficiencies has provided evidence for C3 functions in immune
      responses. C3 deficient mice were generated by replacing the 5'-flanking region
      of the C3 gene with the neomycin-resistance (neo) gene. Serum from these mice had
      no detectable C3 protein or complement activity. Challenge with Streptococcus
      pneumoniae revealed approximately 2000-fold increase in bacteremia as compared to
      littermate controls. C3 mRNA was absent in the liver, but it was detected in the
      lung, kidney, fat tissue, heart and spleen. Metabolic labeling of the lung tissue
      and peritoneal macrophages showed synthesis of pro-C3, but no post-synthetic
      intracellular processing of the protein and no secretion of mature C3. cDNA
      analysis at the cap site indicated that extrahepatic transcription of the
      targeted gene was initiated in the neo cassette, close to the C3/neo junction and
      predicted a primary translation product lacking the leader peptide. The data
      indicate that these mice provide a good animal model for the study of complete C3
      deficiencies and a potential probe for tissue-specific C3 gene regulatory
      elements.

PMID- 10408375
TI  - Different stimulating effects of complement C3b and complete Freund's adjuvant on
      antibody response.
AB  - Upon activation, complement C3 undergoes a conformational change and acquires the
      capacity to covalently bind to other proteins such as antigen and to interact
      with specific receptors; therefore, C3 is involved in cell mediated immune
      response. The adjuvant effect produced by linking C3-fragments to antigen has
      recently been described. We injected C3b-Ag complexes consisting of one molecule
      of C3b ester linked to one molecule of HEL to immunised mice, and we compared the
      C3b adjuvant activity with that of complete Freund's adjuvant. IgG titers
      elicited by HEL emulsified in CFA (HEL + CFA) were higher than those elicited by
      HEL-C3b, but decreased rapidly after a peak response around day 45 whereas HEL
      C3b resulted in a continuous increase of anti-HEL response. Mice immunised with
      HEL + CFA then boosted with HEL-C3b gave significantly higher response than those
      boosted with HEL + CFA, indicating more efficient memory cell restimulation by
      C3b. HEL + CFA leads to better priming than HEL-C3b when mice are boosted with
      HEL-C3b. Thus, adjuvant effect of C3b is different from that of CFA, leading to
      more stable IgG production and better memory stimulation.

PMID- 10408376
TI  - Targeting of influenza epitopes to murine CR1/CR2 using single-chain antibodies.
AB  - Single-chain variable fragment (scFv) antibodies are genetically engineered
      molecules comprising the variable regions responsible for specific binding. scFv
      that recognize certain surface molecules on professional antigen presenting cells
      could therefore be suitable for targeting Ag to these cells. We have produced an
      scFv that recognizes murine complement receptors 1 and 2 (CR1/CR2) and
      genetically fused it with different numbers of influenza hemagglutinin peptides
      which contain both B and T cell epitopes. The CR1/CR2 specific hybridoma 7G6 was
      used for RT-PCR to obtain the variable regions, which were then combined to
      create an scFv fragment. The influenza hemagglutinin intersubunit peptide HA317
      41 (IP) was engineered to the N terminus of the scFv in one, two or three copies.
      The so obtained IP(1-3)7G6scFv still bound the complement receptors; the peptides
      in the construct were recognized by the peptide specific monoclonal IP2-11-1 on
      Western blots and ELISAs. The CR1/CR2 positive B lymphomas A20 and 2PK3 presented
      the peptide to an I-Ed restricted IP specific T cell hybridoma more efficiently
      when incubated with the IP(1)7G6 constructs as compared to the free peptide. The
      results suggest that scFv could work as targeting devices in subunit vaccines.

PMID- 10408377
TI  - Decay acceleration of the complement alternative pathway C3 convertase.
AB  - An ELISA-based method is described for analyzing the mechanism by which the decay
      of the alternative pathway C3 convertase is accelerated by C3 regulatory
      proteins. Using this assay, we show that human decay-accelerating factor (DAF)
      and factor H are active on mature convertase complexes (C3bBb) but not on their
      nascent precursor (C3bB). This finding has implications on the mechanisms of
      action of these two regulators. The complement convertases cleave the serum
      protein C3, and the resulting C3b activation fragments covalently attach to
      nearby targets where they direct antigen selection, immune clearance, and cell
      lysis. Several proteins, including the membrane protein DAF, and the serum
      protein factor H, limit convertase activity by promoting their irreversible
      dissociation. An understanding of the biochemical mechanisms providing for their
      activities would be helpful for the therapeutic control of the complement
      response.

PMID- 10408378
TI  - Phosphorylation of the complement component, C9, by an ecto-protein kinase of
      human leukemic cells.
AB  - Ecto-protein kinases (ecto-PK) are surface constituents of many, if not all,
      animal cell types; normal, transformed or malignant. The occurrence of ecto-PK on
      the surface of human leukemia cell lines was described [Paas, Y., Fishelson, Z.,
      1995. Shedding of tyrosine and serine/threonine ecto-PK from human leukemic
      cells. Arch. Biochem. Biophys. 316 780-788.]. These ecto-PKs have been shown to
      phosphorylate several exogenous substrates, including the complement C9 protein,
      an essential component of the terminal complement system. C9 is phosphorylated by
      ecto-PK of K562 cells on serine residue(s). Phosphorylation occurs in the N
      terminal C9a portion produced by cleavage of phosphorylated C9 with human alpha
      thrombin. C9 polymers generated upon incubation of C9 with ZnCl2 do not serve as
      substrates for the K562 ecto-PK. In contrast, unfolded C9, obtained by reduction
      and alkylation, serves as a superior substrate for the K562 ecto-PK. Native C9
      phosphorylation produced a rather low stoichiometry of incorporated phosphate
      (around 3%) per C9. Despite that, the phosphorylated C9 expressed reduced
      hemolytic activity. The complement-sensitive variant of K562 (K562/S) did not
      express the C9 phosphorylating activity. Various PK inhibitors tested failed to
      block C9 phosphorylation. Only heparin and 2,3-diphosphoglycerate (dpGA)
      prevented C9 phosphorylation, indicating that the ecto-PK is related to the
      casein kinase CK2. C9 can be phosphorylated by ecto-PK from other tumor cells,
      including Jurkat, SK-OV-3 and BT-474. These results suggest that extracellular
      phosphorylation of C9 may serve as a protective mechanism against complement in
      tumor cells.

PMID- 10408379
TI  - Tyrosine phosphorylation and activation of Janus kinase 1 and STAT3 by sublytic
      C5b-9 complement complex in aortic endothelial cells.
AB  - The pathway involving Janus kinase (JAK) and signal transducers and activators of
      transcription (STATs) plays an important role in differentiation and
      proliferation of cells initiated by receptor activation. In the present study we
      identified the JAK and STAT proteins activated by C5b-9 in human aortic
      endothelial cells (AEC). JAK1 but not JAK2 was tyrosine phosphorylated in
      response to sublytic C5b-9. STAT3 was rapidly tyrosine phosphorylated also by C5b
      9. Pertussis toxin inhibited the C5b-9 induced JAK1 activation. However,
      phosphorylation of STAT3 was not inhibited by Pertussis toxin, although C5b-9
      induced a time-dependent nuclear translocation of STAT3. These observations
      indicated that JAK1 is phosphorylated by C5b-9 through activation of trimeric G
      proteins of the Gi/Go family. Raf-1 and ERK1 were also activated by C5b-9 in
      human AEC in a G protein dependent manner. Therefore, JAK1 activity may be
      involved in activation of Raf-1 and ERK1 via G proteins activated by C5b-9. This
      study demonstrates the ability of membrane-inserted C5b-9 to activate JAK1 and
      STAT3 proteins, thus defining new signalling pathway by which C5b-9 may regulate
      gene activation.

PMID- 10408381
TI  - Inhibition of human and mouse complement-dependent hemolytic activity by mouse
      fibronectin.
AB  - Not only does mouse complement (C) have low hemolytic activity, but mouse serum
      has an inhibiting effect on hemolysis by human C. To purify and identify the
      putative mouse serum factor inhibiting human C activity, a sequential procedure
      of fractionated precipitation by PEG, followed by chromatographies with a heparin
      Sepharose column, a phenyl-Sepharose column, a Protein G column, and a gel
      filtration column was performed. The amino acid sequence analyses of two
      polypeptides obtained by digestion of the purified serum factor with TPCK-trypsin
      revealed that it was mouse fibronectin (FN). Highly purified mouse FN, but not
      human FN, has an inhibiting effect on human C-dependent hemolysis. Moreover, the
      hemolysis of sensitized rabbit erythrocytes by mouse C was also inhibited by the
      addition of mouse FN in a dose-dependent fashion, but not by the addition of
      human FN. These results suggest that FN is the putative internal C inhibitor in
      the mouse system.

PMID- 10408380
TI  - Deposition of complement C3 and factor H in tissue traumatized by burn injury.
AB  - Activation of complement is known to accompany burn injury. To study deposition
      of complement proteins within tissue traumatized by burn we employed the
      technique of intravital microscopy using a murine dorsal skinfold chamber model.
      C3, factor H, factor B, HSA, and transferrin were labeled fluorescently and
      injected into the tail vein of mice which had been subjected to a small third
      degree burn within the skin fold. Only C3 and factor H deposited within blood
      vessels of the traumatized tissue. Binding was specific because it occurred only
      in and proximal to burn sites, and neither C3 nor factor H was observed to
      accumulate in blood vessels of healthy tissue. Furthermore, fluorescently
      labelled HSA, factor B, and transferrin all failed to deposit at or around burn
      loci. The deposition of C3 and factor H occurred within 10 min of injury and was
      intravascular occurring in major blood vessels, capillaries, and post-capillary
      venules, with little evidence of accumulation in the interstitium. Since both C3
      fragments and factor H are recognized as adhesion molecules by granulocyte
      receptors, these deposited proteins could promote leukocyte accumulation, thereby
      contributing to an initiation of an inflammatory cascade at a site of burn
      injury.

PMID- 10408382
TI  - Neutralization of complement regulatory proteins augments lysis of breast
      carcinoma cells targeted with rhumAb anti-HER2.
AB  - The capacity of recombinant human monoclonal anti-p185HER2 IgG (rhumAb anti-HER2)
      to activate human complement was investigated. Complement activation by rhumAb
      anti-HER2 on various human breast carcinoma cell lines resulted in deposition of
      complement proteins on these cells. Complement activation was also observed in a
      solid-phase binding assay, in which purified p185HER2 was immobilized onto a
      microtiter plate. rhumAb anti-HER2 induced some complement-mediated tumor cell
      lysis by rabbit complement, but not by human complement. Analysis of membrane
      complement regulatory proteins (mCRP) on breast carcinoma cells revealed a
      heterogenous expression of CD46, CD55 and CD59. After blocking the mCRP activity
      with specific antibodies, rhumAb anti-HER2 induced about 15% lysis of p185HER2
      expressing tumor cells. Tumor cell sensitization with rabbit polyclonal anti
      tumor antiserum following mCRP neutralization, augmented cell lysis from 10 to
      80%. Expression of mCRP was upregulated by treatment with PMA, and correlated
      with increased protection of the tumor cells from complement lysis. These results
      suggest that humanized antibodies like rhumAb anti-HER2 promote complement
      activation leading to tumor cell phagocytosis and cell-mediated cytotoxicity.
      They further demonstrate that a successful tumor immunotherapeutical approach,
      based on antibody and complement treatment, requires mCRP neutralization.

PMID- 10408383
TI  - Derivation of RNA aptamer inhibitors of human complement C5.
AB  - Specific aptamer inhibitors of the human complement C5 component were produced by
      the SELEX methodology of directed evolution of nucleic acid ligands. The SELEX
      procedure started with a pool of random-sequence, 2'F-pyrimidine-modified
      nuclease-stabilized RNA, and after twelve rounds of iterative C5 binding and
      nucleic acid amplification an evolved RNA pool was obtained which contained the
      highest affinity binders to the C5 protein. The evolved RNA pool was then cloned
      and sequenced, and individual clones were analyzed for binding and function.
      Twenty-eight clones (out of sixty) were identified which bound C5 (termed
      aptamers). Seven of these aptamers formed a closely related sequence homology
      family; these aptamers bound C5 with a Kd 20-40 nM and also inhibited human serum
      hemolytic activity. In addition, these aptamers inhibited zymosan-induced
      generation of C5a. Aptamer inhibition of both C5b and C5a suggests that aptamer
      binding inhibits cleavage of C5 by the C5 convertase of both pathways. One of the
      inhibitory aptamer sequences was truncated to yield a 38-mer 2'F RNA aptamer
      which retained C5 binding and inhibitory activity. The structure of this aptamer
      is predicted to be a stem-loop containing thirteen base pairs, and also
      containing two bulges. The affinity of this aptamer was improved by performing a
      second biased SELEX experiment, where the randomized starting RNA pool uses a
      template where the individual base compositions are biased toward a specific
      sequence. This second SELEX experiment produced an aptamer with a Kd of 2-5 nM
      which retained functional activity. Another SELEX to rat C5 produced an aptamer
      with binding and inhibitory properties virtually identical with the human
      aptamer. The human and rat aptamers are being evaluated for complement inhibition
      in vitro and in vivo as potential therapeutics for treatment of human disease.

PMID- 10408384
TI  - C1-inhibitor attenuates hyperacute rejection and inhibits complement, leukocyte
      and platelet activation in an ex vivo pig-to-human perfusion model.
AB  - Xenotransplantation may be a future alternative due to increased shortage of
      organs. Classical complement activation is central in hyperacute rejection in pig
      to-human combinations. We investigated the effects of C1-inhibitor (C1-INH), a
      regulator of the complement and contact systems, on hyperacute rejection. Pig
      kidneys were perfused with fresh human blood to which either C1-INH (n = 6) or
      human serum albumin (n = 6) was added. The survival of the C1-INH perfused
      kidneys (mean 327 min) was significantly longer (p < 0.00001) than the controls
      (79 min). C1-INH substantially inhibited complement activation (C1rs-C1-INH
      complexes, C4bc, C3bc and terminal complement complex) (p < 0.001 for all)
      compared with the marked complement activation in the controls. No contact
      activation was found. Leukocytes and platelets were substantially activated
      (counts, myeloperoxidase, beta-thromboglobulin, thrombospondin, soluble P
      selectin) in the control group, and this activation was markedly reduced by C1
      INH (p < 0.02 for all). Immunohistochemistry showed less C1q, C3, TCC, IgG and
      fibrin deposition in the C1-INH group. C1-INH may be useful to attenuate
      hyperacute rejection, probably through inhibition of complement. The reduced
      activation of neutrophils and platelets may mainly be secondary to inhibition of
      complement.

PMID- 10408386
TI  - Bcl10 mutations in malignancy.

PMID- 10408387
TI  - Does the surgeon matter in the management of ovarian cancer?

PMID- 10408385
TI  - Renal, central nervous system and pancreatic overexpression of recombinant
      soluble Crry in transgenic mice. A novel means of protection from complement
      mediated injury.
AB  - Crry is a potent complement regulator that inhibits classical and alternative
      pathway C3 convertases in rodents. We have produced transgenic animals expressing
      Crry as a recombinant soluble protein driven by the broadly active
      metallothionein-I promoter. These animals have high serum and urinary levels of
      rsCrry leading to inhibition of complement activity. In nephrotoxic serum
      nephritis (NSN), injected antibodies bind to glomeruli, leading to complement
      activation and subsequent glomerular injury and albuminuria. We have shown that
      rsCrry can block such injury and reduce albuminuria by as much as 75%.
      Corresponding to the reduction in albuminuria was the complete absence of C3
      staining in glomeruli by immunofluorescence microscopy in 17/20 transgene
      positive animals. Support for a local source of protective rsCrry in this model
      is provided by the demonstration of Crry transgene mRNA in the glomerulus and a
      very high fractional excretion of rsCrry in the urine. Therefore, rsCrry
      expression markedly ameliorates an antibody-induced disease model in vivo. In
      addition, local synthesis of Crry in other organs that are targets of immune
      injury has been found. For example, Crry transgene mRNA is present throughout the
      central nervous system and in pancreatic islets. Thus, continuous complement
      inhibition at the C3 convertase step appears to be feasible and is effective in
      complement-mediated injury states. A number of disease models affecting these
      target organs can be tested using these mice.

PMID- 10408388
TI  - The role of human melanoma cell ICAM-1 expression on lymphokine activated killer
      cell-mediated lysis, and the effect of retinoic acid.
AB  - Intercellular adhesion molecule (ICAM-1) exists as a membrane-associated form
      (mICAM-1) on the surface of tumour cells as well as a soluble form (sICAM-1).
      This study analyses the ability of all-trans retinoic acid (RA) to alter both
      sICAM and mICAM-1 expression in C8161 and Hs294T human melanoma cell lines and
      investigates the involvement of ICAM-1 in the interaction between tumour and
      lymphokine-activated killer (LAK) cells using the Cr-51 release assay. Our data
      showed that 4-day pretreatment of the tumour cells with 10(-7) M RA and 10(-6) M
      RA induced an increase in lysis of both cell lines and also increased mICAM-1
      expression without having any effect on sICAM-1 levels. Addition of blocking ICAM
      1 antibody (10 microg ml(-1)) to the C8161 cells at an effector:tumour cell ratio
      of 40:1 caused a 2.3-fold reduction in lysis of tumour cells and a 3-fold
      reduction in lysis of RA-treated cells. Blocking ICAM-1 antibody at optimum
      concentrations of 5 microg ml(-1) reduced lysis 1.8-fold in control Hs294T cells
      and 1.3-fold in RA-treated cells. Blocking the HLA-ABC complex had no effect on
      lysis. The more highly metastatic C8161 cells were found to secrete 4-fold
      greater levels of sICAM-1 than the poorly metastatic Hs294T cells and addition of
      sICAM-1 to the assay failed to affect lysis of either cell line but did induce a
      2-fold decrease in lysis of RA-treated C8161 cells. Collectively, these data
      provide further evidence for ICAM-1 involvement in the tumour/LAK cell response
      and indicates that the RA-induced increase in mICAM-1 levels are partly
      responsible for the increase in susceptibility of the tumour cells. sICAM-1
      appears to be unimportant in evasion of the tumour cells from LAK cell lysis, but
      may play a role in evasion of RA-treated C8161 cells.

PMID- 10408390
TI  - Regulation of vascular endothelial growth factor expression in human colon cancer
      by interleukin-1beta.
AB  - Expression of vascular endothelial growth factor (VEGF), an important angiogenic
      factor in colon cancer, is tightly regulated by factors in the microenvironment.
      However, specific factors indigenous to the organ microenvironment of colon
      cancer growth that regulate VEGF expression in human colon cancer are not well
      defined. We investigated interleukin-1beta (IL-1beta) induction of VEGF
      expression in colon cancer cells and the mechanism by which this occurs. HT29
      human colon cancer cells were treated with IL-1beta for various periods.
      Induction of VEGF mRNA by IL-1beta peaked at 24 h (> fivefold) and returned to
      baseline by 48 h. SW620 human colon cancer cells also reached a peak induction of
      VEGF mRNA 24 h after treatment with IL-1beta. VEGF was induced at a dose range
      between 1 and 20 ng ml(-1) of IL-1beta. IL-1beta induction of VEGF was also
      confirmed at the protein level. To examine the mechanism for VEGF induction by IL
      1beta, we transiently transfected VEGF promoter-reporter constructs into HT29
      cells. IL-1beta increased the activity of the VEGF promoter-reporter construct.
      Pretreatment of HT29 cells with dactinomycin abrogated the induction of VEGF mRNA
      by IL-1beta. The half-life of VEGF mRNA was not prolonged by treatment with IL
      1beta. These findings suggest that IL-1beta regulates VEGF expression in human
      colon cancer cells by increasing transcription of the VEGF gene.

PMID- 10408391
TI  - Induction of Fos protein expression in spinal cord neurons of tumour-bearing
      rats.
AB  - The absence of discernible abnormal symptoms such as pain, often leading to
      delayed diagnosis in cancer patients, may be indicative of a dysregulation in
      sensory transmission between the tumour and the central nervous system. We
      explored expression of Fos protein in spinal cord neurons in rats, during the
      development of the MAT-LyLu prostatic adenocarcinoma grafted on the hind limb.
      The tumour triggered the densest Fos labelling in the L3-L5 lumbar segments,
      ipsilateral to the grafted limb. The labelling, detected at day 5, increased
      until day 10 and dropped off thereafter. The ventral horn (except lamina IX) was
      the most densely labelled region. Histological examination of the grafted limbs
      demonstrated that no inflammatory reaction accompanied the tumour growth. Rats
      exhibited no behavioural alterations either spontaneous or induced by handling.
      These results demonstrate that signals are sent to the central nervous system by
      the peripheral tumour. Considering both the behavioural and histological
      observations, it is unlikely that spinal activity reflects a painful state. The
      nature of these signals, inefficient to trigger the appropriate reaction of the
      organism against the tumour, remain to be determined with regard to the
      pharmacologically active compounds synthesized and released by the tumour cells.

PMID- 10408389
TI  - Keratoacanthomas have an immunosuppressive cytokine environment of increased IL
      10 and decreased GM-CSF compared to squamous cell carcinomas.
AB  - To investigate the relationship between keratoacanthoma (KA) and squamous cell
      carcinoma (SCC), cytokine mRNA in 12 KA and eight SCC were compared. Normal skin
      was also studied. Reverse transcription polymerase chain reaction (RT-PCR) was
      used to quantitate mRNA in each sample utilizing DNA standards. Glyceraldehyde-3
      phosphate dehydrogenase (GAPDH) was used as an internal control, and CD3delta as
      an indication of the T-cell infiltrate. KAs showed a significant increase in
      interleukin (IL)-10, and a decrease in granulocyte macrophage colony-stimulating
      factor (GM-CSF) mRNA compared to SCCs. CD3delta mRNA was also increased in the
      KAs. There was no difference between KAs and SCCs in expression of lymphotoxin
      alpha, IL-2, interferon-gamma (IFN-gamma), IL-13, transforming growth factor-beta
      (TGF-beta), or the pro-inflammatory cytokines IL-8 or tumour necrosis factor
      alpha (TNF-alpha). These results indicate that KAs spontaneously resolve in an
      immunosuppressive environment. KAs grow rapidly over a period of weeks and then
      involute. It is possible that a suppressed immune response enables unimpeded
      growth and that the KA cells rapidly undergo the finite number of cell divisions
      of which they are capable, and then die without reaching immortality.

PMID- 10408392
TI  - A quantitative analysis of the reduction in oxygen levels required to induce up
      regulation of vascular endothelial growth factor (VEGF) mRNA in cervical cancer
      cell lines.
AB  - The presence of hypoxia (low oxygen concentrations) in solid tumours correlates
      with poor prognosis, increased metastasis, and resistance to radiotherapy and
      some forms of chemotherapy. Malignant cells produce an angiogenesis factor,
      vascular endothelial growth factor (VEGF), which may increase metastatic ability
      and is up-regulated in the presence of hypoxia. Clinical data for cancers of the
      cervix and head and neck relate oxygen levels in the tumour to treatment outcome.
      This suggests the possibility that the presence of VEGF mRNA might be used as a
      marker for relevant levels of hypoxia. Suspension cultures of three human
      cervical cancer cell lines, SiHa, ME-180 and HeLa, were used to investigate up
      regulation of VEGF mRNA levels following exposure to precisely defined oxygen
      concentrations for 2 or 4 h. An oxygen sensor was used to confirm the actual
      levels of dissolved oxygen present. The oxygen concentrations which caused half
      maximal upregulation (the Km value) of VEGF mRNA level in the three cell lines
      were similar except for one instance (Km at 4 h: SiHa 27.0 +/- 5.7 microM, ME-180
      16.8 +/- 3.3 microM, HeLa 13.0 +/- 1.8 microM, SiHa and HeLa P = 0.01). The Km
      values for the HeLa cell line as measured at 2 h (24.9 +/- 0.8 microM) and 4 h
      (13.0 +/- 1.8 microM) were significantly different (P < 0.0001). VEGF mRNA half
      lives measured in air were consistent with values in the literature (SiHa 59.8 +/
      5.8 min, ME-180 44.4 +/- 7.2 min, HeLa 44.5 +/- 6.3 min). Differences in oxygen
      consumption at low oxygen concentrations were noted between the different cell
      lines. Stirring in suspension culture was found to induce VEGF mRNA in SiHa
      cells. The presence of VEGF mRNA may be a marker for radiobiologic hypoxia.

PMID- 10408393
TI  - Comparative effect of ALA derivatives on protoporphyrin IX production in human
      and rat skin organ cultures.
AB  - Samples of human and rat skin in short-term organ culture exposed to ALA or a
      range of hydrophobic derivatives were examined for their effect on the
      accumulation of protoporphyrin IX (PpIX) measured using fluorescence
      spectroscopy. With the exception of carbobenzoyloxy-D-phenylalanyl-5-ALA-ethyl
      ester the data presented indicate that, in normal tissues, ALA derivatives
      generate protoporphyrin IX more slowly than ALA, suggesting that they are less
      rapidly taken up and/or converted to free ALA. However, the resultant depot
      effect may lead to the enhanced accumulation of porphyrin over long exposure
      periods, particularly in the case of ALA-methyl ester or ALA-hexyl ester,
      depending on the applied concentration and the exposed tissue. Addition of the
      iron chelator, CP94, greatly increased PpIX accumulation in human skin exposed to
      ALA, ALA-methyl ester and ALA-hexyl ester. The effect in rat skin was less
      marked.

PMID- 10408395
TI  - Low density lipoprotein and liposome mediated uptake and cytotoxic effect of N4
      octadecyl-1-beta-D-arabinofuranosylcytosine in Daudi lymphoma cells.
AB  - Low density lipoprotein (LDL) receptor-mediated uptake and cytotoxic effects of
      N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) were studied in Daudi
      lymphoma cells. NOAC was either incorporated into LDL or liposomes to compare
      specific and unspecific uptake mechanisms. Binding of LDL to Daudi cells was not
      altered after NOAC incorporation (K(D) 60 nM). Binding of liposomal NOAC was not
      saturable with increasing concentrations. Specific binding of NOAC-LDL to Daudi
      cells was five times higher than to human lymphocytes. LDL receptor binding could
      be blocked and up- or down-regulated. Co-incubation with colchicine reduced NOAC
      LDL uptake by 36%. These results suggested that NOAC-LDL is taken up via the LDL
      receptor pathway. In an in vitro cytotoxicity test, the IC50 of NOAC-LDL was
      about 160 microM, whereas with liposomal NOAC the IC50 was 40 microM. Blocking
      the LDL receptors with empty LDL protected 50% of the cells from NOAC
      cytotoxicity. The cellular distribution of NOAC-LDL or NOAC-liposomes differed
      only in the membrane and nuclei fraction with 13% and 6% respectively. Although
      it is more convenient to prepare NOAC-liposomes as compared to the loading of LDL
      particles with the drug, the receptor-mediated uptake of NOAC-LDL provides an
      interesting rationale for the specific delivery of the drug to tumours that
      express elevated numbers of LDL receptors.

PMID- 10408394
TI  - Water-soluble aluminium phthalocyanine-polymer conjugates for PDT: photodynamic
      activities and pharmacokinetics in tumour-bearing mice.
AB  - The potential use of unsubstituted aluminium phthalocyanine (AlClPc) as a
      sensitizer for photodynamic therapy (PDT) of cancer has not been fully exploited
      in spite of its higher efficiency as compared to the sulphonated derivatives.
      This is largely due to the strong hydrophobic character of AlClPc which renders
      the material difficult to formulate for in vivo administration. We prepared two
      water-soluble derivatives of AlClPc by axial coordination of polyethyleneglycol
      (PEG, MW 2000) or polyvinylalcohol (PVA, MW 13,000-23,000) to the central
      aluminium ion. Their photodynamic activities were evaluated in vitro against the
      EMT-6 mouse mammary tumour cells and in vivo against the EMT-6 and the colon
      carcinoma Colo-26 tumours implanted intradermally in Balb/c mice.
      Pharmacokinetics were studied in the EMT-6 tumour-bearing mice. After 1 h
      incubation, the light dose required to kill 90% of cells (LD90) was at least
      three times less for AlClPc (Cremophor emulsion) as compared to AlPc-PEG and AlPc
      PVA, while after 24 h incubation all three preparations were highly phototoxic.
      All three dye preparations induced complete EMT-6 tumour regression in 75-100% of
      animals at a low drug dose (0.25 micromol kg(-1)) following PDT (400 J cm(-2),
      650-700 nm) at 24 h pi. Complete tumour regression in the Colo-26 tumour model
      was obtained in 30% of mice at a dose of 2 micromol kg(-1). In the non-cured
      animals, AlPc-PVA induced the most significant tumour growth delay. This dye
      showed a prolonged plasma half-life (6.8 h) as compared to AlClPc (2.6 h) and
      AlPc-PEG (23 min), lower retention by liver and spleen and higher tumour-to-skin
      and tumour-to-muscle ratios. Our data demonstrate that addition of hydrophilic
      axial ligands to AlPc, while modifying in vitro and in vivo kinetics, does not
      reduce the PDT efficiency of the parent molecule. Moreover, in the case of the
      polyvinylalcohol derivative, axial coordination confers advantageous
      pharmacokinetics to AlPc, which makes this photosensitizer a valuable, water
      soluble candidate drug for clinical PDT of cancer.

PMID- 10408397
TI  - Ribozyme inhibition of the protein kinase C alpha triggers apoptosis in glioma
      cells.
AB  - Although protein kinase C has been shown to be involved in a wide range of
      biological functions, the precise role of each isoform in a specific cell
      function remains to be clarified. Here we demonstrate that a ribozyme specific
      for the human protein kinase C alpha (PKC alpha), a classical PKC isoform,
      induces cell death in glioma cell lines. This cell death was identified as
      apoptosis by morphologic alterations and endonucleosomal DNA fragmentation. The
      inhibition of PKC alpha gene expression by the ribozyme resulted in a significant
      reduction in Bcl-xL gene expression, a protein that inhibits apoptosis and is
      overexpressed in glioma cells. Taken together, our data suggest that the PKC
      alpha ribozymes are a potent inducer of apoptosis in glioma cells, which may act
      through suppressing Bcl-xL gene expression and/or activity. PKC alpha ribozymes
      may prove useful in the management of malignant gliomas.

PMID- 10408396
TI  - Isoflavones inhibit intestinal epithelial cell proliferation and induce apoptosis
      in vitro.
AB  - There have been many reports that high soya-based diets reduce the risk of
      certain types of cancer. This effect may be due to the presence of high levels of
      isoflavones derived from the soya bean, particularly genistein which has been
      shown to be a protein tyrosine kinase (PTK) inhibitor and have both oestrogenic
      and anti-oestrogenic properties. We have examined the effect of genistein and a
      number of novel synthetic analogues on both normal (IEC6, IEC18) and transformed
      (SW620, HT29) intestinal epithelial cell lines. Responses were compared to those
      elicited by oestradiol, the anti-oestrogen tamoxifen, and the tyrosine kinase
      inhibitor tyrphostin. Genistein and tamoxifen were potent inhibitors of cell
      proliferation. Of seven novel isoflavones tested, none were more potent
      inhibitors than genistein, and all displayed similar relative activities across
      the different cell lines. In addition to inhibiting cell proliferation, cell
      death via apoptosis was observed when the cells were exposed to the isoflavones
      and all but one exhibited PTK inhibitory activity. These data suggest that by
      reducing proliferation and inducing apoptosis, possibly due in part to PTK
      inhibition, isoflavones may have a role in protecting normal intestinal
      epithelium from tumour development (reducing the risk) and may reduce colonic
      tumour growth.

PMID- 10408398
TI  - BCL10 is rarely mutated in human prostate carcinoma, small-cell lung cancer, head
      and neck tumours, renal carcinoma and sarcomas. MPT Collaborators, St George's
      Hospital Collaborators.
AB  - We have used single-strand conformation polymorphism (SSCP) analysis to screen
      for mutations in the BCL10 gene in 81 primary prostate carcinomas, 20 squamous
      cell cancers of the head and neck, 15 small-cell lung cancer cell lines, 24 renal
      carcinoma cell lines and 13 sarcoma cell lines. We failed to find evidence of
      somatically acquired mutations of the BCL10 gene suggesting that BCL10 does not
      play a major role in the development of these malignancies.

PMID- 10408399
TI  - Mutations in Bcl10 are very rare in colorectal cancer.
AB  - Bcl10 is a recently identified gene reported to be involved commonly in human
      malignancy (Willis et al (1999) Cell 96: 1-20). To investigate whether it is
      frequently mutated in colorectal cancer we have analysed a series of 132
      colorectal cancers and eight colorectal cancer cell lines for mutations in Bcl10.
      One feature of the Bcl10 gene is that it harbours two polyadenine tracts. These
      repeating elements in genes can be prone to a high rate of mutation if there is
      defective mismatch repair. To examine the possibility that Bcl10 may be
      preferentially mutated in mismatch repair-deficient cancers, 49 of the tumours
      and cell lines were known to be replication error (RER)-positive and, of these,
      ten were from individuals harbouring germline mutations in hMLH1 or hMSH2. No
      pathogenic mutations were detected in the tumours and only one mutation was found
      in the colorectal cancer cell lines. These results indicate that Bcl10 is
      unlikely to be involved in the pathways of colorectal carcinogenesis.

PMID- 10408400
TI  - Lack of Bcl10 mutations in testicular germ cell tumours and derived cell lines.
AB  - Aberrations within Bcl10, a gene involved in execution of apoptosis, has most
      recently been found in a variety of cancers, including cell lines of testicular
      germ cell tumours of adolescents and adults (TGCTs). To study this in more
      detail, we screened exons 2 and 3 of this gene for mutations in a larger series
      of cell lines as well as primary TGCTs by single-strand conformation polymorphism
      and endonuclease restriction analysis. Because no aberrations were detected, we
      conclude that inactivation of Bcl10 by mutation is at least far less important in
      the development of TGCTs than proposed.

PMID- 10408401
TI  - Bcl10 is not a target for frequent mutation in human carcinomas.
AB  - The recently described Bcl10 gene has been suggested to be a major target gene
      for inactivation in a variety of human cancers. In order to further evaluate the
      role of this gene in human adult malignancies, we have analysed a series of
      carcinomas for mutations in the Bcl10 gene. We have screened a panel of 174
      carcinoma samples in total, comprised of 47 breast, 36 epithelial ovarian, 36
      endometrial, 12 cervical, 23 colorectal and 20 head/neck carcinomas, all
      unselected for grade or stage. This panel reflects, in part, tumours reported to
      have involvement of the 1p22 region of chromosome 1, the region harbouring the
      Bcl10 gene. No deleterious mutations were detected in any of the samples
      analysed, strongly suggesting that Bcl10 is not a common target for inactivation
      in adult malignancies and that BCL10 is not the gene targeted for frequent
      inactivation at 1p22.

PMID- 10408402
TI  - 125I-labelled human chorionic gonadotrophin (hCG) as an elimination marker in the
      evaluation of hCG decline during chemotherapy in patients with testicular cancer.
AB  - The rate of reduction in the concentration of serum human chorionic gonadotrophin
      (hCG) following chemotherapy for germ cell tumours may follow a complex pattern,
      with longer apparent half-life during later stages of chemotherapy, even in
      patients treated successfully. The commonly used half-life of less than 3 days
      for hCG to monitor the effect of chemotherapy in patients with germ cell tumours
      of the testis may represent too simple a model. 125I-labelled hCG was injected
      intravenously in 27 patients with germ cell tumours and elevated hCG during
      chemotherapy. The plasma radioactivity and hCG concentrations were followed.
      During chemotherapy, the plasma disappearance of hCG showed a biphasic pattern,
      with an initial fast and a later slow component in all patients. Using the steep
      part of the hCG plasma disappearance curve, five patients who achieved long-term
      remission had half-lives longer than 3 days (3.6-6.8 days), whereas four out of
      five patients not achieving long-term remission had half-lives shorter than 3
      days. After the third treatment cycle, eight patients who achieved long-term
      remission had hCG half-lives longer than 3 days (7.4-17.0 days). In these
      patients, the plasma disappearance of [125I]hCG was equivalent to that of hCG.
      Thus, the slow decline of hCG represented a slow plasma disappearance rather than
      a hCG production from vital tumour cells and could, consequently, not be used to
      select patients for additional or intensified chemotherapy. The concept of a
      fixed half-life for plasma hCG during treatment of hCG-producing germ cell
      tumours is inappropriate and should be revised. Difficulties in interpreting a
      slow decline of hCG may be overcome by comparing the plasma disappearance of
      total hCG with the plasma disappearance of [125I]hCG.

PMID- 10408403
TI  - Validation of 125I-hCG as a marker for elimination of hCG and stability of 125I
      hCG after in vivo injection in humans.
AB  - We have recently introduced 125I-hCG as an elimination marker in patients with
      human chorionic gonadotrophin (hCG) producing testicular cancer. 125I-hCG is a
      well-known reagent in clinical biochemistry and is used extensively in hCG
      assays. Previous studies have shown that the iodination process leaves the hCG
      molecule mainly intact. The iodination, purification and stability of 125I-hCG
      tracer are described. The aim of the present study was to determine whether or
      not 125I is associated with hCG after the injection of 125I-hCG intravenously
      (i.v.) in humans. Three different methods were used. Following injection of 125I
      hCG, the plasma disappearance of radioactivity and hCG were followed for a period
      of 28 days in 13 normal subjects. Serum from a normal healthy male following
      injection of 125I-hCG was analysed using a double antibody direct binding
      radioimmunoassay specific for holo-hCG and high performance liquid chromatography
      (HPLC). Following injection of 125I-hCG in eight normal healthy males and five
      normal healthy females, the disappearance of radioactivity and hCG showed
      identical paths in the 28 days follow-up period. The bindable radioactive
      fraction of immunologically active hCG in serum of a normal healthy male
      following injection of 125I-hCG was between 57.0% and 72.1%, and was constant
      over time. HPLC showed similar elution pattern of serum from a normal healthy
      male injected i.v. with 125I-hCG and 125I-hCG. Using three different methods, we
      were able concurrently to demonstrate the association of 125I with hCG in humans
      up to 28 days after injection of radiolabelled hCG i.v. Thus, information about
      the expected elimination of hCG can be obtained by following the elimination of
      activity in plasma after injection of 125I-hCG.

PMID- 10408404
TI  - Assessment of long-term quality of life in patients with anal carcinomas treated
      by radiotherapy with or without chemotherapy.
AB  - This study was conducted to assess long-term Quality of Life (QOL) in patients
      treated by radiotherapy with or without chemotherapy for anal carcinomas.
      Patients with a maximum age of 80 years, and who were alive at least 3 years
      following completion of treatment with a functioning anal sphincter and without
      active disease, were selected for this study. Of 52 such patients identified, 41
      (79%) were evaluable. There were 35 females and six males with a median age of 71
      years (55-80). The median follow-up interval was 116 months (range 37-218). QOL
      was assessed using two self-rating questionnaires developed by the European
      Organization for Research and Treatment of Cancer: one for cancer-specific QOL
      (EORTC QLQ-C30) and one for site-specific QOL (EORTC QLQ-CR38). For the function
      scales a higher score represents a higher level of functioning (100 being the
      best score), whereas for the symptom scales a higher score indicates a higher
      level of symptomatology/problems (0 being the best score). For the QLQ-C30, the
      functional scale scores ranged from 71 (global quality of life) to 85 (role
      function) and the symptom scale scores from 6 (nausea-vomiting) to 28
      (diarrhoea). For the QLQ-CR38 module the functional scale scores ranged from 13
      (sexual functioning) to 74 (body image) and for the symptom scale scores from 5
      (weight loss) to 66 (sexual dysfunction in males). None of the functional and
      symptom scale scores seemed to be better in patients with longer follow-up. In
      patients treated with sphincter conservation for anal carcinomas, long-term QOL
      as measured by the EORTC QLQ-C30 and QLQ-CR38 appears to be acceptable, with the
      exception of diarrhoea and perhaps sexual function. Moreover, the subset of
      patients who presented with severe complications and/or anal dysfunction showed
      poorer scores in most scales.

PMID- 10408405
TI  - A combination of gemcitabine and 5-fluorouracil in advanced pancreatic cancer, a
      report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).
AB  - In a randomized clinical trial, gemcitabine (GEM) was more effective than 5
      fluorouracil (5-FU) in advanced pancreatic cancer patients. GEM and 5-FU have
      different mechanisms of action and their combination, from a theoretical point of
      view, could result in a higher activity. To test activity and feasibility of such
      a combination, a multi-institutional phase II study was initiated in November
      1996 by the Italian Group for the study of Digestive Tract Cancer (GISCAD).
      Primary objectives of this study were to determine the activity in terms of
      response rate and clinical benefit, while the secondary objective was toxicity.
      According to the optimal two-stage phase II design, 54 patients were enrolled.
      Schedule was: GEM 1000 mg m(-2) intravenous (i.v.), and 5-FU 600 mg m(-2) bolus
      i.v. weekly for 3 weeks out of every 4. All the 54 patients were symptomatic
      (pain, weight loss, dyspepsia). A clinical benefit was obtained in 28 patients
      (51%) (95% confidence interval (CI) 38-64%). Two patients achieved a partial
      response and 34 a stable disease. Median survival for all the patients was 7
      months. Side-effects were mild: no gastrointestinal or haematological grade 3-4
      toxicity (WHO) were recorded. We observed only six episodes of grade 2 (WHO)
      leukopenia and seven episodes of thrombocytopenia. Although the non-randomized
      design of this study suggests caution in the interpretation of these data, in
      consideration of the low incidence of toxicity and the favourable results
      obtained in terms of clinical benefit, it may be worthwhile to test more active
      schedules of 5-FU (continuous infusion) in combination with gemcitabine.

PMID- 10408406
TI  - The increment of micronucleus frequency in cervical carcinoma during irradiation
      in vivo and its prognostic value for tumour radiocurability.
AB  - A potential usefulness of micronucleus assay for prediction of tumour
      radiosensitivity has been tested in 64 patients with advanced stage (II B-IV B)
      cervical carcinoma treated by radiotherapy. The study of cellular
      radiosensitivity in vitro was conducted in parallel with the study of cellular
      damage after tumour irradiation in vivo. Radiosensitivity of in vitro cultured
      primary cells isolated from tumour biopsies taken before radiotherapy was
      evaluated using cytokinesis-block micronucleus assay. Frequency of micronuclei
      per binucleated cell (MN/BNC) at 2 Gy was used as a measure of radiosensitivity.
      Radiation sensitivity in vivo was expressed as per cent increment of micronucleus
      frequency in cells isolated from biopsy taken after 20 Gy (external irradiation,
      10 x 2 Gy) over the pre-treatment spontaneous micronucleus level and was called
      MN20. Very low correlation (r = 0.324) was observed between micronucleus
      frequency in vitro and in vivo. Although micronucleus frequency at 2 Gy differed
      widely between tumours evaluated (mean MN/BNC was 0.224; range 0.08-0.416), no
      significant correlation was observed between this parameter and clinical outcome.
      The average increment of micronucleus frequency after 20 Gy amounted to 193% of
      spontaneous level (range 60-610%) and was independent of spontaneous
      micronucleation before radiotherapy. In contrast to in vitro results, these from
      in vivo assay seem to have a predictive value for radiotherapy of cervix cancer.
      The micronucleus increment in vivo that reached at least 117.5% of pretreatment
      value (first quartile for MN20 data set) correlated significantly with better
      tumour local control (P < 0.008) and overall survival (P < 0.045). Our results
      suggest that evaluation of increment of micronucleus frequency during
      radiotherapy (after fixed tested dose of 20 Gy) offers a potentially valuable
      approach to predicting individual radioresponsiveness and may be helpful for
      individualization of treatment strategy in advanced stage cervical cancer.

PMID- 10408407
TI  - Minimal breast cancer: evaluation of histology and biological marker expression.
AB  - Ninety-eight minimal breast cancers (MBCs) diagnosed between 1975 and 1990, and
      all originally considered to be invasive were found, on review, to form three
      groups: (a) 28 predominantly invasive carcinomas < or = 10 mm ('predominant
      invasive'); (b) 48 predominantly ductal carcinoma in situ (DCIS) lesions with
      definite foci of invasion each < or = 10 mm ('predominant DCIS'); and (c) 22 DCIS
      without evidence of invasion ('pure DCIS'). Tumour histology and
      immunohistochemical expression of Ki-67, c-erbB2, p53, oestrogen receptor (ER),
      progesterone receptor (PR), and Bcl-2 were compared. The major finding was the
      contrasting features in the two invasive groups, with significant differences in
      their extent of invasion (P < 0.0001), tumour grade (P = 0.03), DCIS type (P =
      0.008) and in marker expression. In the predominant invasive group, the
      infiltrative component was usually greater than 5 mm, low-grade and associated
      with well-differentiated DCIS. Expression of Ki-67, c-erbB2 and p53 was generally
      low, and that of ER, PR and Bcl-2 high. The predominant DCIS group in contrast
      had a much smaller, commonly high-grade, invasive component, usually with poorly
      differentiated DCIS and the reverse pattern of marker expression. Although not
      significant, survival of patients in the predominant invasive group was slightly
      better. These findings suggest that invasive MBCs should perhaps be treated as
      separate entities, in order to aid more appropriate selection of treatment.

PMID- 10408408
TI  - Expression and up-regulation of interleukin-6 in oesophageal carcinoma cells by n
      sodium butyrate.
AB  - Recently, the serum level of interleukin (IL)-6 has been shown to correlate with
      disease progression and prognosis of cancer patients. However, the available
      information about the source and the pathophysiological regulation of IL-6 in
      cancer cells is limited. Thus, in this study, we tried to identify the source and
      the clinical roles of serum IL-6 in patients with oesophageal squamous cell
      carcinoma (ESCC), and then further to characterize the biological regulation of
      IL-6 in ESCC cell lines. Sera and tissue specimens from 80 consecutive patients
      with ESCC were collected between 1993 and 1997. Additionally, three ESCC cell
      lines were used for in vitro study. The concentration of serum IL-6 was measured
      by enzyme-linked immunosorbent assay (ELISA), and correlated the survival time
      with measured IL-6 level. Expressions of IL-6, IL-6R alpha (IL-6 receptor alpha)
      and gp130 in pathological sections and cell lines were characterized by
      immunological staining. Detection of IL-6 mRNA was determined by in situ
      hybridization (ISH) and reverse transcription-polymerase chain reaction (RT-PCR).
      Up-regulation of IL-6 by n-sodium butyrate (n-BT) was studied in ESCC cell lines.
      The levels of serum IL-6 in patients with ESCC were significantly higher than
      those in the healthy controls. Serum levels of IL-6 were also shown to correlate
      with disease progression and survival. However, sCD8 levels and lymphocyte counts
      in the peripheral blood were not parallel to the changed pattern of serum IL-6.
      In pathological sections and ESCC cell lines, message of IL-6 was identified by
      ISH in cancer cells. Expression of IL-6 mRNA was further confirmed with RT-PCR in
      ESCC cell lines. Although IL-6 was detected in some ESCC cell lines, IL-6 gene
      expression and protein production could be induced or enhanced by n-BT treatment
      in all three cell lines. The serum levels of IL-6 are frequently elevated at
      diagnosis of ESCC, and are associated with poor prognosis. IL-6 that could be
      produced by cancer cells is up-regulated by n-BT.

PMID- 10408409
TI  - The expression of p73 is increased in lung cancer, independent of p53 gene
      alteration.
AB  - p73 gene, a new p53 homologue, has been identified: it supposedly acts as tumour
      suppressor gene in neuroblastoma. To clarify whether p73 might be involved in
      lung carcinogenesis, we examined p73 expression in resected lung cancer and
      paired normal lung in 60 cases using semi-quantitative reverse transcription
      polymerase chain reaction (RT-PCR). We also examined p73 gene status in three
      representative cases using Southern blot, and p53 gene alteration in 49 cases
      using PCR-single-strand conformation polymorphism (PCR-SSCP) and direct sequence.
      In 87% of the cases (52/60) p73 expression in tumour was more than twice as high
      as that in paired normal lung tissues, and the difference between p73 expression
      in tumour and normal lung tissue was significant (P < 0.0001). However, Southern
      blot analysis revealed that none of the cases showed p73 gene amplification.
      Compared with clinicopathological characteristics, p73 expression correlates
      significantly with histological differences and age of patient, independently (P
      < 0.05). Concerning p53 gene status, 43% (21/49) showed p53 gene alteration, but
      there was no correlation between p73 overexpression and p53 gene alteration. Our
      results suggest that need for further functional analysis of the role of p73 in
      lung carcinogenesis.

PMID- 10408410
TI  - Serum concentrations of vascular endothelial growth factor and nitrite as an
      estimate of in vivo nitric oxide in patients with gastric cancer.
AB  - The importance of tumour angiogenesis in the process of tumour growth and
      progression in solid tumours has been widely accepted. Among many angiogenic
      factors, vascular endothelial growth factor (VEGF) has been shown to play a major
      role in the development and dissemination of the malignant tumours. Nitric oxide
      (NO) production was also observed in solid tumour tissues. NO has been reported
      to play an important role for the mitogenic effect of VEGF in the angiogenic
      process. However, little is known about the correlation between VEGF and NO in
      circulating levels. Therefore, we investigated serum VEGF and NO concentrations
      in human gastric cancers as well as healthy individuals, and examined the
      influence of tumour stage on circulating level of VEGF. The study consisted of 11
      healthy individuals and 37 patients with primary gastric cancer who did not
      receive any prior therapy. Patients were categorized into four groups according
      to TNM classification. The level of VEGF165 in preoperative sera of gastric
      cancer patients and healthy donors was assayed using the quantitative sandwich
      enzyme immunoassay technique. NO concentration was estimated indirectly from
      serum nitrite. The ANOVA test showed a significant difference in serum VEGF165
      concentrations between tumour stages (P < 0.001). A striking relationship was
      found between serum NO levels and tumour stage (P < 0.001). A significant
      difference was also seen between healthy individuals and patients with stage 1
      disease. The present study suggested that large tumour burden was associated with
      significantly increased levels of VEGF165 and NO.

PMID- 10408411
TI  - Labelling indices in human tumours: to apply corrections or not--that is the
      question.
AB  - The advent of halogenated pyrimidines (bromodeoxyuridine, BrdU; idoxuridine, IdU)
      and antibodies to recognize them has opened new horizons for the measurement of
      proliferation in human tumours. These precursors of DNA can be given to patients
      and a single biopsy can be taken to measure in a flow cytometer both the fraction
      of labelled cells and their rate of movement through the S phase. From these two
      parameters the potential doubling time, T(POT), can be calculated. To measure
      both parameters simultaneously a compromise is made in the time of assessing the
      labelling index (LI). LI should ideally be assessed after a very short interval,
      e.g. 0.5-1 h, to avoid the contaminating influence of any cells dividing between
      injection and biopsy. However, an interval of 4-8 h is considered necessary to
      assess T(S) from the relative movement of cells through the S phase. Several
      techniques exist to correct for cell division if the interval is long. The
      simplest correction, which only corrects for the division of labelled cells, is
      most widely used. Downward correction factors of at least 10% are commonly
      applied, reducing the observed LI values. In this paper we illustrate graphically
      the dependence of the appropriate correction factor on various cell kinetic
      parameters. The duration of G2 is the most critical parameter for both the size
      and direction of any correction factor. The G2 phase has previously been shown to
      be about three times longer in human tumours than in rodents. If G2+M is as long
      as 6 h, the main artefact of the intervals between injection and biopsy up to 7 h
      is that the observed LI is too low because of division of unlabelled G2 cells. A
      correction of up to 10% is needed but in an upward direction. A nomogram of
      probable correction factors as a function of sampling interval is provided. We
      show from flow cytometric data that G2+M may be shorter than 4 h for head and
      neck tumours. It is recommended that the correction factor established by gating
      the flow histogram should always be checked against this nomogram, or that no
      correction factor should be applied. We have used this mathematical approach to
      re-evaluate two sets of published LI data for rectal and colorectal tumours. We
      show that the mathematical correction of each data point leads to a 30% increase
      in the median value, compared to the simple gating procedure. We question whether
      other of the published series of LI values gained with BrdU or IdU may also
      substantially underestimate the true LI values, if a simple gating procedure has
      been used in an attempt to reduce the impact of divided S phase cells.

PMID- 10408412
TI  - Ultrasound assessment of ovarian cancer risk in postmenopausal women with CA125
      elevation.
AB  - We have previously shown that, in asymptomatic post-menopausal women, serum CA125
      elevation is associated with a 36-fold increase in risk of ovarian cancer. This
      study was undertaken to assess the value of pelvic ultrasound for further
      stratification of ovarian cancer risk. Of 22,000 post-menopausal women, aged > or
      = 45 participating in an Ovarian Cancer Screening Trial, 741 with a CA125 > or =
      30 U ml(-1) underwent pelvic ultrasonography. Twenty index cancers (primary
      invasive epithelial carcinomas of the ovary and fallopian tube) were diagnosed
      amongst these 741 women during a median follow-up of 6.8 years. Ultrasound
      results separated the women with CA125 elevation into two groups. Those with
      normal ovarian morphology had a cumulative risk (CR) of index cancer of 0.15%
      (95% confidence interval (CI) 0.02-1.12) which is similar to that of the entire
      population of 22,000 women (0.22%, 95% CI 0.18-0.30). In contrast, women with
      abnormal ovarian morphology had a CR of 24% (15-37) and a significantly increased
      relative risk (RR) of 327 (156-683). Ultrasound can effectively separate post
      menopausal women with raised CA125 levels into those with normal scan findings
      who are not at increased risk of index cancer and those with abnormal findings
      who are at substantially increased risk of index cancer.

PMID- 10408413
TI  - Significance of serum-soluble CD95 (Fas/APO-1) on prognosis in renal cell cancer
      patients.
AB  - Serum-soluble CD95 (sCD95) levels for 72 renal cell cancer patients were
      significantly higher than those of 17 healthy donors. Twenty-one of 72 patients
      had elevated (defined as more than mean of healthy donors + 2 s.d.) sCD95. The
      disease-specific survival rate was significantly lower in the elevated sCD95
      group. Serum sCD95 level was shown to be an independent prognostic factor by
      univariate and multivariate analysis, indicating a possible significant role in
      determining treatment strategies.

PMID- 10408414
TI  - E-cadherin gene mutations are rare in adenocarcinomas of the oesophagus.
AB  - Reduced expression of E-cadherin, a cell-cell adhesion molecule, is observed in
      oesophageal adenocarcinomas and correlates with less favourable pathological
      parameters and survival. To determine if genetic events lead to reduced E
      cadherin expression in these patients, we screened all 16 exons of the E-cadherin
      gene for mutations with the polymerase chain reaction single-strand conformation
      polymorphism analysis (PCR-SSCP) technique in 49 resection specimens, including
      four loco-regional lymph node metastases, four established cell lines and four
      xenografts. Fifteen exon-spanning primer pairs were used, and in nine amplicons
      aberrant bands were detected. Sequencing of the amplicons revealed a one base
      pair deletion (codon 120; exon 3) in cell lines JROECL 47 and JROECL 50 leading
      to a premature downstream stop codon. Polymorphisms were identified for amplicons
      1, 4/5, 11, 12, 13, 14 and 16 corresponding with data from the literature. Three
      new polymorphisms were detected for amplicons 2, 3 and 4/5. Loss of
      heterozygosity (LOH) of the E-cadherin locus on 16q22.1 was examined with four
      polymorphic markers. LOH was found in 31 of the 48 informative cases (65%). These
      results show that, despite the frequent LOH of the E-cadherin locus, mutations in
      the E-cadherin gene are rare events and can not be held responsible for down
      regulation of E-cadherin observed in the majority of adenocarcinomas of the
      oesophagus.

PMID- 10408415
TI  - Prognostic significance of bcl-2 expression in leiomyosarcoma of the uterus.
AB  - We examined bcl-2 expression as well as p53 expression and mutation in human
      uterine smooth muscle tumours to determine the influence of bcl-2 expression on
      prognosis in patients with uterine leiomyosarcomas. bcl-2 protein was expressed
      in nearly all benign smooth muscle tumours but in only 57% of leiomyosarcomas.
      Benign smooth muscle tumours were usually negative for p53 protein, but 16 out of
      21 (76%) leiomyosarcomas were positive. A p53 gene mutation was detected in nine
      of the 16 leiomyosarcomas that showed p53-positive staining. A significant
      positive correlation was observed between p53 mutation and p53 expression,
      between the number of mitoses and the Ki-67 labelling index, and between clinical
      stage and p53 mutation. A significant negative correlation was observed between
      bcl-2 expression and p53 mutation, and between bcl-2 expression and p53
      overexpression. Univariate survival analysis revealed that bcl-2 expression, p53
      mutation and clinical stage (stage 1 vs stages 2-4) all showed a significant
      correlation with prognosis. In a multivariate stepwise regression analysis,
      positive bcl-2 expression and stage 1 disease were the independent predictors of
      a favourable prognosis. Our results suggest that bcl-2 is frequently expressed in
      human uterine smooth muscle tumours, and that its expression may correlate with a
      favourable prognosis in patients with uterine leiomyosarcoma.

PMID- 10408416
TI  - hMSH2 and GTBP expression in advanced stage epithelial ovarian cancer.
AB  - Defects in DNA mismatch repair have been associated with both hereditary and
      sporadic forms of human cancer. Most of the attention has been focused on the
      incidence and genetics of mismatch repair defects, while little is known about
      the expression levels of the mismatch repair proteins and their significance in
      cancer cell biology. In this study, both the expression levels of hMSH2 and GTBP
      proteins were investigated by Western blotting in 20 untreated epithelial ovarian
      cancers. For these analyses, a commercial anti-hMSH2 monoclonal antibody and a
      newly generated mouse monoclonal anti-GTBP antibody were used. hMSH2 and GTBP
      proteins were detected by Western blotting in 19 out of 20 (95%) samples analysed
      and were found to be directly correlated (r= +0.51, P = 0.025). hMSH2 expression
      was significantly higher in ovarian cancer cells originating from solid tumours
      than from ascites (H = 4.5, P = 0.033), whereas GTBP content did not
      significantly differ according to the origin of cancer cells. No statistically
      significant differences were found in the distribution of hMSH2 and GTBP levels
      according to the age of the patients, grade of differentiation, histotype and
      extent of surgical debulking. The amount of hMSH2 protein was demonstrated to be
      significantly lower in stage IV than in stage III patients (H = 7.35, P = 0.007).
      Moreover, significantly lower hMSH2 levels were observed in non-responding
      patients compared to patients who achieved complete or partial response to
      cisplatin-based chemotherapy (H = 4.88, P = 0.027). Conversely, GTBP levels were
      not distributed differently according to stage of disease and chemotherapy
      response. Our study suggests a possible involvement of hMSH2 in ovarian cancer
      cell biology and susceptibility to chemotherapy. The possible biological and/or
      clinical role of GTBP expression in ovarian cancer patients remains to be
      elucidated.

PMID- 10408417
TI  - Detection of regional melanoma metastases by ultrasound B-scan, cytology or
      tyrosinase RT-PCR of fine-needle aspirates.
AB  - Physical examination and ultrasound B-scan screening are important follow-up
      procedures in melanoma patients with regional disease. However, they do not allow
      definite diagnosis of suspicious lesions. Fine-needle aspiration cytology (FNAC)
      enhances the diagnostic accuracy in such patients but, unfortunately, reaches its
      technical limits, particularly when very small or necrotic lesions are examined.
      We therefore tested whether tyrosinase reverse transcription polymerase chain
      reaction (RT-PCR) of fine-needle aspirates (FNA-PCR) could help to increase
      diagnostic sensitivity. With clinical follow-up in 69 melanoma patients 81
      regional lymph nodes were detected by ultrasound B-scan examination, nine of whom
      appeared to be palpable. Technically, FNAC was successful in all 81 lymph nodes,
      while FNA-PCR failed to obtain RNA at detectable levels in two lymph nodes of two
      patients. Of 79 lesions which have been completely evaluated by B-scan, FNAC and
      FNA-PCR, 44 proved to be melanoma metastases by histopathology, while the
      remaining 35 lesions were finally classified as non-specific lymph nodes. Of the
      44 melanoma metastases 80% (n = 35) have been detected by B-scan, 90% (n = 39) by
      FNAC and 100% (n = 44) by FNA-PCR (P < 0.05 vs FNAC, P < 0.005 vs B-scan). In the
      subclass of lesions with diameters below 10 mm the sensitivities were 72% (n =
      13), 78% (n = 14) and 100% (n = 18) respectively. In 35 regional lymph nodes
      classified as benign lesions, FNAC was always negative while FNA-PCR produced one
      positive result. Neither of these methods did produce false positive results in
      15 control lymph nodes of non-melanoma patients. We conclude, that FNA-PCR might
      have superior sensitivity as compared to FNAC or ultrasound B-scan, particularly
      in melanoma lesions with diameters below 10 mm.

PMID- 10408418
TI  - Possible permanent down regulation of oestrogen receptor expression during fetal
      life and breast cancer risk.

PMID- 10408419
TI  - Long-term nature of depression.
AB  - Many, if not most, people with depression are at high risk to develop a recurrent
      and potentially chronic disorder, characterized by deleterious effects on
      vocational, social, and family functioning. Recent evidence also suggests that
      recurrent episodes of severe depression are associated with changes in brain
      function that further heighten vulnerability and functional impairment. The best
      way to deal with these sobering problems is prevention via vigorous treatment of
      the index episode (to produce complete remission) and more routine use of longer
      term models of prophylactic therapy. After briefly reviewing the relevant data on
      epidemiology and natural history, this article focuses on the 4 "arms" of
      preventative treatment: psychoeducation, pharmacotherapy, adherence, and
      psychotherapy. Like the modern approach to treatment of hypertension, a
      conscientious and integrated approach to preventative therapy saves lives and has
      profoundly beneficial effects for our patients, their loved ones, and society.

PMID- 10408420
TI  - New developments in the treatment of depression.
AB  - Depression is a widespread, recurrent disease that sometimes remains inadequately
      managed by current drug therapy. There is a need to develop better
      antidepressants that ideally would have a more rapid onset of action, a higher
      response rate, and improved long-term efficacy. The latest generation of
      antidepressants have novel dual modes of action, and the results of recent
      clinical trials indicate that they may have superior efficacy to established drug
      therapies such as tricyclic antidepressants (TCAs) and selective serotonin
      reuptake inhibitors (SSRIs). Dual acting drugs, such as venlafaxine, a serotonin
      norepinephrine reuptake inhibitor, and mirtazapine, a noradrenergic and specific
      serotonergic antidepressant, have been shown to have a rapid onset of action. The
      long-term efficacy of mirtazapine and of venlafaxine was also found to be
      superior to that of TCAs. Pindolol was found to accelerate response to SSRI
      therapy. However, these results were dependent on the patient population. These
      studies clearly suggest that the latest generation of antidepressants offer a
      more rapid response to treatment, an improved response rate, and superior long
      term efficacy than conventional therapy. The clinical importance of these results
      should not be overlooked.

PMID- 10408422
TI  - Strategies and tactics in the management of maintenance treatment for depressed
      patients.
AB  - This article focuses on the strategies and tactics in the clinical management of
      maintenance treatment for depressed patients. The phases of treatment,
      indications for maintenance treatment, steps necessary to prepare patients for
      maintenance treatment (e.g., attaining optimal symptomatic control, providing
      knowledge, and developing a constructive attitude toward chronic disease
      management), teaching patients to measure symptoms during treatment, and clinical
      tips for managing symptomatic "blips" and recurrences during maintenance
      treatment are discussed.

PMID- 10408421
TI  - Models of antidepressant action.
AB  - Although immediate pharmacologic targets can be identified for most
      antidepressant treatments, elucidation of the critical biological mechanisms
      leading to symptom relief has defied decades of research. In this review,
      selected neurotransmitter, biochemical, and anatomic models of antidepressant
      action are considered with regard to their explanatory power and therapeutic
      applicability. Monoamine models have been a focus of research attention on
      antidepressant action, an appropriate emphasis in that virtually all
      antidepressant medications have high affinity for monoamine substrates.
      Furthermore, prevailing monoamine models have suggested some promising
      therapeutic strategies. Nevertheless, these models are ultimately incomplete and
      do not fully explain important clinical limitations of current treatment: delayed
      response, incomplete efficacy, and unsustained remissions. Continued therapeutic
      advancements will likely require the development of models of antidepressant
      action that extend beyond the monoamines.

PMID- 10408423
TI  - Management of sexual side effects of antidepressant therapy.
AB  - Sexual dysfunction occurs in over one third of the general population and has
      many causes, including psychosocial factors, general medical illness,
      nonpsychiatric medication, psychiatric disorders, and psychotropic medications.
      Psychosocial causes are the most prevalent, but many frequently used medications,
      such as diuretics, beta-blockers, and H2-blockers, can also cause sexual
      dysfunction. Sexual dysfunctions occur in many psychiatric disorders, including
      mood disorders, schizophrenia, substance abuse, and anxiety disorders. In
      addition, over half the patients with major depression will have some sexual
      dysfunction. Although much attention has been paid to sexual dysfunction
      associated with the selective serotonin reuptake inhibitors (SSRIs), many other
      commonly used psychotropics are associated with a variety of sexual dysfunction,
      including haloperidol, benzodiazepines, stimulants, and drugs of abuse. With
      regard to SSRIs, sexual dysfunction occurs in 50% or more of such patients, which
      is substantially higher than the rates reported in the Physicians' Desk
      Reference. The reason for this discrepancy is that patients will not
      spontaneously report sexual problems and must be questioned about such problems
      directly. A variety of strategies exist to manage antidepressant-induced sexual
      dysfunction, including waiting, reducing the antidepressant dose, use of drug
      holidays, use of adjunctive pharmacotherapy, and switching antidepressants. Use
      of an antidepressant with a low prevalence of sexual side effects, such as
      bupropion, nefazodone, and mirtazapine, may also be considered.

PMID- 10408424
TI  - Learning by incentive.

PMID- 10408425
TI  - Protesters seek US ban on embryo stem-cell work...as Wisconsin researcher awaits
      go-ahead.

PMID- 10408426
TI  - EMBO backs single electronic repository. European Molecular Biology Organization.

PMID- 10408427
TI  - NIH office plans research on misconduct.

PMID- 10408428
TI  - German agency to boost bioinformatics.

PMID- 10408429
TI  - European embryology experts offer to advise on ethics of cloning.

PMID- 10408431
TI  - How flies fly.

PMID- 10408430
TI  - Tests for BSE evaluated. Bovine spongiform encephalopathy.

PMID- 10408432
TI  - Developmental biology. Bonsai flies.

PMID- 10408433
TI  - Alzheimer's disease. Antibody clears senile plaques.

PMID- 10408434
TI  - Chloroplasts. Ever decreasing circles.

PMID- 10408435
TI  - Evolutionary biology. Dirty eating for healthy living.

PMID- 10408436
TI  - Oleg Ptitsyn (1929-99)

PMID- 10408437
TI  - Mitochondria and germ-cell death.

PMID- 10408438
TI  - Origin of life from apatite dating?

PMID- 10408439
TI  - Nicotine withdrawal and road accidents.

PMID- 10408440
TI  - Single gene circles in dinoflagellate chloroplast genomes.
AB  - Photosynthetic dinoflagellates are important aquatic primary producers and
      notorious causes of toxic 'red tides'. Typical dinoflagellate chloroplasts differ
      from all other plastids in having a combination of three envelope membranes and
      peridinin-chlorophyll a/c light-harvesting pigments. Despite evidence of a
      dinoflagellete satellite DNA containing chloroplast genes, previous attempts to
      obtain chloroplast gene sequences have been uniformly unsuccessful. Here we show
      that the dinoflagellate chloroplast DNA genome structure is unique. Complete
      sequences of chloroplast ribosomal RNA genes and seven chloroplast protein genes
      from the dinoflagellate Heterocapsa triquetra reveal that each is located alone
      on a separate minicircular chromosome: 'one gene-one circle'. The genes are the
      most divergent known from chloroplast genomes. Each circle has an unusual
      tripartite non-coding region (putative replicon origin), which is highly
      conserved among the nine circles through extensive gene conversion, but is very
      divergent between species. Several other dinoflagellate species have minicircular
      chloroplast genes, indicating that this type of genomic organization may have
      evolved in ancestral peridinean dinoflagellates. Phylogenetic analysis indicates
      that dinoflagellate chloroplasts are related to chromistan and red algal
      chloroplasts and supports their origin by secondary symbiogenesis.

PMID- 10408441
TI  - Chlorophyll b and phycobilins in the common ancestor of cyanobacteria and
      chloroplasts.
AB  - Photosynthetic organisms have a variety of accessory pigments, on which their
      classification has been based. Despite this variation, it is generally accepted
      that all chloroplasts are derived from a single cyanobacterial ancestor. How the
      pigment diversity has arisen is the key to revealing their evolutionary history.
      Prochlorophytes are prokaryotes which perform oxygenic photosynthesis using
      chlorophyll b, like land plants and green algae (Chlorophyta), and were proposed
      to be the ancestors of chlorophyte chloroplasts. However, three known
      prochlorophytes (Prochloron didemni, Prochlorothrix hollandica and
      Prochlorococcus marinus) have been shown to be not the specific ancestors of
      chloroplasts, but only diverged members of the cyanobacteria, which contain
      phycobilins but lack chlorophyll b. Consequently it has been proposed that the
      ability to synthesize chlorophyll b developed independently several times in
      prochlorophytes and in the ancestor of chlorophytes. Here we have isolated the
      chlorophyll b synthesis genes (chlorophyll a oxygenase) from two prochlorophytes
      and from major groups of chlorophytes. Phylogenetic analyses show that these
      genes share a common evolutionary origin. This indicates that the progenitors of
      oxygenic photosynthetic bacteria, including the ancestor of chloroplasts, had
      both chlorophyll b and phycobilins.

PMID- 10408442
TI  - Improved auditory spatial tuning in blind humans.
AB  - Despite reports of improved auditory discrimination capabilities in blind humans
      and visually deprived animals, there is no general agreement as to the nature or
      pervasiveness of such compensatory sensory enhancements. Neuroimaging studies
      have pointed out differences in cerebral organization between blind and sighted
      humans, but the relationship between these altered cortical activation patterns
      and auditory sensory acuity remains unclear. Here we compare behavioural and
      electrophysiological indices of spatial tuning within central and peripheral
      auditory space in congenitally blind and normally sighted but blindfolded adults
      to test the hypothesis (raised by earlier studies of the effects of auditory
      deprivation on visual processing) that the effects of visual deprivation might be
      more pronounced for processing peripheral sounds. We find that blind participants
      displayed localization abilities that were superior to those of sighted controls,
      but only when attending to sounds in peripheral auditory space.
      Electrophysiological recordings obtained at the same time revealed sharper tuning
      of early spatial attention mechanisms in the blind subjects. Differences in the
      scalp distribution of brain electrical activity between the two groups suggest a
      compensatory reorganization of brain areas in the blind that may contribute to
      the improved spatial resolution for peripheral sound sources.

PMID- 10408443
TI  - Distortion of proximodistal information causes JNK-dependent apoptosis in
      Drosophila wing.
AB  - Distinct and evolutionarily conserved signal-transduction cascades mediate the
      survival or death of cells during development. The c-Jun amino-terminal kinases
      (JNKs) of the mitogen-activated protein kinase superfamily are involved in
      apoptotic signalling in various cultured cells. However, the role of the JNK
      pathway in development is less well understood. In Drosophila, Decapentaplegic
      (Dpp; a homologue of transforming growth factor-beta) and Wingless (Wg; a Wnt
      homologue) proteins are secretory morphogens that act cooperatively to induce
      formation of the proximodistal axis of appendages. Here we show that either
      decreased Dpp signalling in the distal wing cells or increased Dpp signalling in
      the proximal wing cells causes apoptosis. Inappropriate levels of Dpp signalling
      lead to aberrant morphogenesis in the respective wing zones, and these apoptotic
      zones are also determined by the strength of the Wg signal. Our results indicate
      that distortion of the positional information determined by Dpp and Wg signalling
      gradients leads to activation of the JNK apoptotic pathway, and the consequent
      induction of cell death thereby maintains normal morphogenesis.

PMID- 10408444
TI  - The mPer2 gene encodes a functional component of the mammalian circadian clock.
AB  - Circadian rhythms are driven by endogenous biological clocks that regulate many
      biochemical, physiological and behavioural processes in a wide range of life
      forms. In mammals, there is a master circadian clock in the suprachiasmatic
      nucleus of the anterior hypothalamus. Three putative mammalian homologues (mPer1,
      mPer2 and mPer3) of the Drosophila circadian clock gene period (per) have been
      identified. The mPer genes share a conserved PAS domain (a dimerization domain
      found in Per, Arnt and Sim) and show a circadian expression pattern in the
      suprachiasmatic nucleus. To assess the in vivo function of mPer2, we generated
      and characterized a deletion mutation in the PAS domain of the mouse mPer2 gene.
      Here we show that mice homozygous for this mutation display a shorter circadian
      period followed by a loss of circadian rhythmicity in constant darkness. The
      mutation also diminishes the oscillating expression of both mPer1 and mPer2 in
      the suprachiasmatic nucleus, indicating that mPer2 may regulate mPer1 in vivo.
      These data provide evidence that an mPer gene functions in the circadian clock,
      and define mPer2 as a component of the mammalian circadian oscillator.

PMID- 10408445
TI  - Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the
      PDAPP mouse.
AB  - Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology
      of Alzheimer's disease (AD). Familial forms of the disease have been linked to
      mutations in the amyloid precursor protein (APP) and the presenilin genes.
      Disease-linked mutations in these genes result in increased production of the 42
      amino-acid form of the peptide (Abeta42), which is the predominant form found in
      the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which
      overexpresses mutant human APP (in which the amino acid at position 717 is
      phenylalanine instead of the normal valine), progressively develops many of the
      neuropathological hallmarks of Alzheimer's disease in an age- and brain-region
      dependent manner. In the present study, transgenic animals were immunized with
      Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age)
      or at an older age (11 months), when amyloid-beta deposition and several of the
      subsequent neuropathological changes were well established. We report that
      immunization of the young animals essentially prevented the development of beta
      amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the
      older animals also markedly reduced the extent and progression of these AD-like
      neuropathologies. Our results raise the possibility that immunization with
      amyloid-beta may be effective in preventing and treating Alzheimer's disease.

PMID- 10408446
TI  - Generation of GTP-bound Ran by RCC1 is required for chromatin-induced mitotic
      spindle formation.
AB  - Chromosomes are segregated by two antiparallel arrays of microtubules arranged to
      form the spindle apparatus. During cell division, the nucleation of cytosolic
      microtubules is prevented and spindle microtubules nucleate from centrosomes (in
      mitotic animal cells) or around chromosomes (in plants and some meiotic cells).
      The molecular mechanism by which chromosomes induce local microtubule nucleation
      in the absence of centrosomes is unknown, but it can be studied by adding
      chromatin beads to Xenopus egg extracts. The beads nucleate microtubules that
      eventually reorganize into a bipolar spindle. RCC1, the guanine-nucleotide
      exchange factor for the GTPase protein Ran, is a component of chromatin. Using
      the chromatin bead assay, we show here that the activity of chromosome-associated
      RCC1 protein is required for spindle formation. Ran itself, when in the GTP-bound
      state (Ran-GTP), induces microtubule nucleation and spindle-like structures in M
      phase extract. We propose that RCC1 generates a high local concentration of Ran
      GTP around chromatin which in turn induces the local nucleation of microtubules.

PMID- 10408447
TI  - Orientation of DNA replication establishes mating-type switching pattern in S.
      pombe.
AB  - The fission yeast Schizosaccharomyces pombe normally has haploid cells of two
      mating types, which differ at the chromosomal locus mat1. After two consecutive
      asymmetric cell divisions, only one in four 'grand-daughter' cells undergoes a
      'mating-type switch', in which genetic information is transferred to mat1 from
      the mat2-P or mat3-M donor loci. This switching pattern probably results from an
      imprinting event at mat1 that marks one sister chromatid in a strand-specific
      manner, and is related to a site-specific, double-stranded DNA break at mat1.
      Here we show that the genetic imprint is a strand-specific, alkali-labile DNA
      modification at mat1. The DNA break is an artefact, created from the imprint
      during DNA purification. We also propose and test the model that mat1 is
      preferentially replicated by a centromere-distal origin(s), so that the strand
      specific imprint occurs only during lagging-strand synthesis. Altering the origin
      of replication, by inverting mat1 or introducing an origin of replication,
      affects the imprinting and switching efficiencies in predicted ways. Two
      dimensional gel analysis confirmed that mat1 is preferentially replicated by a
      centromere-distal origin(s). Thus, the DNA replication machinery may confer
      different developmental potential to sister cells.

PMID- 10408448
TI  - Single kinesin molecules studied with a molecular force clamp.
AB  - Kinesin is a two-headed, ATP-driven motor protein that moves processively along
      microtubules in discrete steps of 8 nm, probably by advancing each of its heads
      alternately in sequence. Molecular details of how the chemical energy stored in
      ATP is coupled to mechanical displacement remain obscure. To shed light on this
      question, a force clamp was constructed, based on a feedback-driven optical trap
      capable of maintaining constant loads on single kinesin motors. The instrument
      provides unprecedented resolution of molecular motion and permits mechanochemical
      studies under controlled external loads. Analysis of records of kinesin motion
      under variable ATP concentrations and loads revealed several new features. First,
      kinesin stepping appears to be tightly coupled to ATP hydrolysis over a wide
      range of forces, with a single hydrolysis per 8-nm mechanical advance. Second,
      the kinesin stall force depends on the ATP concentration. Third, increased loads
      reduce the maximum velocity as expected, but also raise the apparent Michaelis
      Menten constant. The kinesin cycle therefore contains at least one load-dependent
      transition affecting the rate at which ATP molecules bind and subsequently commit
      to hydrolysis. It is likely that at least one other load-dependent rate exists,
      affecting turnover number. Together, these findings will necessitate revisions to
      our understanding of how kinesin motors function.

PMID- 10408449
TI  - Corneal thickness measurements with the Topcon SP-2000P specular microscope and
      an ultrasound pachymeter.
AB  - OBJECTIVE: To compare the reproducibility of measurements obtained with a new
      pachymetry instrument, the Topcon specular microscope (Topcon SP-2000P; Topcon
      America Corp, Paramus, NJ), with those obtained by ultrasound pachymetry.
      METHODS: Corneal thickness was measured in 40 eyes of 40 patients 3 times each
      with the Topcon SP-2000P and an ultrasound pachymeter (DGH 500, DGH Technology
      Inc, Exton, Pa) by 2 separate investigators. Comparisons included average
      thickness as measured by each instrument, average thickness for each instrument
      as measured by each investigator, and differences in thickness due to corneal
      abnormalities. RESULTS: Mean corneal thickness measured by the Topcon instrument
      was significantly less (32 microm; P<.001) than the mean value obtained with the
      ultrasound pachymeter. Similarly, mean values obtained with the 2 instruments by
      the 2 investigators were significantly different (P<.001 and .008 for
      investigators 1 and 2, respectively), with the Topcon value less than the
      ultrasound value in both cases. Both instruments detected abnormalities in
      corneal thickness equally well. However, the measurements obtained with the
      Topcon instrument by the 2 investigators were more consistent (no significant
      difference [P=.32]) than those obtained with the ultrasound unit (difference was
      significant [P=.02]). CONCLUSIONS: The new noncontact Topcon specular microscope
      provides measurements of corneal thickness that are somewhat less than those of
      ultrasound pachymetry, but that seem to be more consistent from one operator to
      another, possibly as a result of the elimination of observer bias induced by
      probe placement required by the ultrasound unit. This consistency may be
      important in the comparison of measurements by different operators over time in
      patients being followed up after refractive surgery or other therapeutic
      interventions.

PMID- 10408450
TI  - Surface cytologic features on intraocular lenses: can increased biocompatibility
      have disadvantages?
AB  - OBJECTIVE: To compare the anterior surface cytologic features and effect on blood
      aqueous barrier of polymethyl methacrylate, silicone, and hydrogel intraocular
      lens (IOL) implants to give an indication of their biocompatibility. METHODS:
      This prospective study was performed at an English-teaching hospital. Ninety eyes
      were randomized to receive a polymethyl methacrylate, silicone, or hydrogel
      implant. A standardized surgical protocol was performed by a single surgeon using
      phacoemulsification. Patients were seen at intervals for 1 year. Measurements of
      visual acuity, contrast sensitivity, and anterior chamber laser flare and cells
      were obtained; and an assessment of lens cytologic features using specular
      microscopy of the anterior IOL surface was performed. RESULTS: Visual acuity and
      contrast sensitivity were not significantly different among the 3 groups.
      Hydrogel IOLs were associated with fewer inflammatory cells on their surface than
      polymethyl methacrylate and silicone IOLs (P<.001), but with significantly more
      lens epithelial cells (LECs) (P<.001). Patients with hydrogel implants without
      LECs had greater blood-aqueous barrier breakdown than those with LECs.
      CONCLUSIONS: The hydrogel IOLs were associated with a reduced inflammatory cell
      reaction but had many more LECs on their anterior surface. Those IOLs associated
      with increased blood-aqueous barrier damage did not develop LECs. If an IOL is
      too biocompatible, then it may incite the growth of LECs over its surface, which
      could have disadvantages.

PMID- 10408451
TI  - Optic nerve hypoplasia with isolated tortuosity of the retinal veins: a marker of
      endocrinopathy.
AB  - OBJECTIVE: To investigate whether children with optic nerve hypoplasia and
      pituitary hormone insufficiencies have specific ocular fundus characteristics
      that may facilitate early diagnosis and treatment. DESIGN: From May 15, 1995,
      through December 15, 1997, 17 children (8 girls and 9 boys, aged 0.3 to 13 years)
      with optic nerve hypoplasia were referred to the Department of Pediatric
      Ophthalmology, Children's Hospital, Goteborg, Sweden, and divided into 2 groups
      dependent on the presence (n = 8) or absence (n = 9) of pituitary deficiency.
      Morphological characteristics of the ocular fundus were evaluated by digital
      image analysis of fundus photographs, and the morphological characteristics of
      the brain structures were studied by magnetic resonance imaging. RESULTS: An
      isolated venous tortuosity noted among the children with optic nerve hypoplasia
      and endocrinopathy was the morphological ocular fundus variable that
      discriminated between the 2 groups of patients with optic nerve hypoplasia. Both
      groups of children demonstrated significantly reduced optic disc, cup, and
      neuroretinal rim area and few vascular branching points. CONCLUSION: Optic nerve
      hypoplasia with isolated tortuosity of the retinal veins may potentially help the
      ophthalmologist in identifying children who should undergo a thorough diagnostic
      workup of endocrine function.

PMID- 10408452
TI  - Thermotherapy for retinoblastoma.
AB  - OBJECTIVE: To evaluate the results of thermotherapy for retinoblastoma. DESIGN:
      Prospective, nonrandomized analysis of the treatment method. PARTICIPANTS: A
      total of 188 retinoblastomas in 80 eyes of 58 patients who were treated with
      thermotherapy. MAIN OUTCOME MEASURES: Tumor response and ocular adverse effects.
      RESULTS: Of 188 retinoblastomas treated with thermotherapy, mean tumor base was
      3.0 mm and tumor thickness was 2.0 mm. Complete tumor regression was achieved in
      161 tumors (85.6%), and 27 tumors (14.4%) developed recurrence. Using univariate
      analysis, the predictors of local tumor recurrence were male sex (P = .005), no
      color change ("no visible take") in tumor after treatment (P = .01), increasing
      number of treatment sessions (P = .002), and previous use of chemoreduction (P =
      .02). By multivariate analysis, the most important predictors of local tumor
      recurrence were male sex (P = .01) and previous use of chemoreduction (P = .03),
      the latter likely reflecting the fact that these tumors were initially larger
      with more ominous findings, and required chemoreduction therapy to reduce them to
      a size amenable to focal treatment with thermotherapy. When evaluating
      thermotherapy variables as a function of tumor size, it was apparent that larger
      tumors (> or =3.0-mm base) required greater energy and time than did smaller
      tumors (<3.0-mm base). Comparison of treatment variables for larger vs smaller
      tumors was as follows: number of treatment sessions, 3.3 vs 2.3; spot size, 1.7
      vs 1.3 mm; power, 540 vs 370 mW; treatment duration, 49 vs 14 minutes; and
      coupling of thermotherapy with chemotherapy, 79% vs 48% of cases (P < or =.001
      for each variable). Complications of thermotherapy in the 80 eyes included focal
      iris atrophy in 29 eyes (36%), peripheral focal lens opacity in 19 eyes (24%),
      retinal traction in 4 eyes (5%), retinal vascular obstruction in 2 eyes (2%), and
      transient localized serous retinal detachment in 2 eyes (2%). There were no cases
      of corneal scarring, central lens opacity, iris or retinal neovascularization, or
      rhegmatogenous retinal detachment. All eyes with focal lens opacity demonstrated
      adjacent focal iris atrophy. By multivariate analysis, the predictors of
      thermotherapy-induced focal iris atrophy were increasing number of treatment
      sessions (P = .001) and increasing tumor base (P = .02). CONCLUSIONS:
      Thermotherapy is used for relatively small retinoblastomas without associated
      vitreous or subretinal seeds. This treatment provides satisfactory control for
      selected retinoblastomas, with 86% of tumors demonstrating lasting regression.
      Tumors that measure 3.0 mm or larger in base at the time of thermotherapy require
      more intense treatment than smaller tumors and are at greatest risk for ocular
      complications such as focal iris atrophy and focal paraxial lens opacity.

PMID- 10408453
TI  - Diplopia secondary to aniseikonia associated with macular disease.
AB  - OBJECTIVE: To provide an explanation for diplopia and the inability to fuse in
      some patients with macular disease. METHODS: We identified 7 patients from our
      practices who had binocular diplopia concurrent with epiretinal membranes or
      vitreomacular traction. A review of the medical records of all patients was
      performed. In addition to complete ophthalmologic and orthoptic examinations,
      evaluation of aniseikonia using the Awaya New Aniseikonia Tests (Handaya Co Ltd,
      Tokyo, Japan) was performed on all patients. RESULTS: All patients were referred
      for troublesome diplopia. Six of the patients had epiretinal membranes and 1 had
      vitreomacular traction. All 7 patients had aniseikonia, ranging from 5% to 18%.
      In 5 of the patients the image in the involved eye was larger, and in the other 2
      patients it was smaller than in the fellow eye. All patients had concomitant
      small-angle strabismus and at least initially did not fuse when the deviation was
      offset with a prism. Response to optical management and retinal surgery was
      variable. CONCLUSIONS: Aniseikonia caused by separation or compression of
      photoreceptors can be a contributing factor to the existence of diplopia and the
      inability to fuse in patients with macular disease. Concomitant small-angle
      strabismus and the inability to fuse with prisms may lead the clinician to the
      incorrect diagnosis of central disruption of fusion. Surgical intervention does
      not necessarily improve the aniseikonia.

PMID- 10408454
TI  - Nonsurgical management of binocular diplopia induced by macular pathology.
AB  - OBJECTIVE: To treat binocular diplopia secondary to macular pathology. METHODS:
      Seven patients underwent evaluation and treatment. All had constant vertical
      diplopia caused by various maculopathies, including subretinal
      neovascularization, epiretinal membrane, and central serous retinopathy. Visual
      acuity ranged from 20/20 to 20/30 in the affected eye. All except 1 patient had a
      small-angle, comitant hyperdeviation with no muscle paresis. Sensory evaluation
      demonstrated peripheral fusion and reduced stereoacuity. Neither prism correction
      nor manipulation of the refractive errors corrected the diplopia. A partially
      occlusive foil (Bangerter) of density ranging from 0.4 to 1.0 was placed in front
      of the affected eye to restore stable, single vision. RESULTS: The Bangerter foil
      eliminated the diplopia in all patients. Two patients elected not to wear the
      foil; 1 patient was afraid of becoming dependent, and the other was bothered by
      the visual blur. Visual acuity in the affected eye was reduced on average by 3
      lines. All patients maintained the same level of sensory fusion, with only 2
      having reduced stereoacuity. Symptoms returned when the foil was removed or its
      density was reduced. CONCLUSION: Low-density Bangerter foils provide an
      effective, inexpensive, and aesthetically acceptable management for refractory
      binocular diplopia induced by macular pathology, allowing peripheral fusion to be
      maintained.

PMID- 10408455
TI  - The Asian upper eyelid: an anatomical study with comparison to the Caucasian
      eyelid.
AB  - OBJECTIVE: To evaluate the differences between Asian and Caucasian upper eyelid
      anatomy through cadaver dissection, histopathological study, and magnetic
      resonance imaging. MATERIALS AND METHODS: Upper eyelids of 9 Korean and 5
      Caucasian cadavers were dissected, and then were studied microscopically with
      hematoxylin-eosin, Masson trichrome, and elastin stains. Four healthy young
      Korean men were studied by dynamic high-resolution magnetic resonance imaging
      with regard to demonstration of upper eyelid structure. RESULTS: More
      subcutaneous and suborbicularis fat, with a pretarsal fat component, is present
      in Asian eyelids. The Asian double eyelids showed an amount of fat intermediate
      between Asian single eyelids and Caucasian eyelids. Asian single eyelids showed
      fusion of the orbital septum to the levator aponeurosis below the superior tarsal
      border, while fusion is above the superior tarsal border in Caucasians. The
      preaponeurotic fat pad descends anteriorly to the tarsal plate in the Asian
      single eyelid, but not in the Caucasian eyelid. A pretarsal fat pad is identified
      in the Asian single eyelids. CONCLUSIONS: The causes of absent or lower crease in
      the Asian upper eyelid are as follows: (1) the orbital septum fuses to the
      levator aponeurosis at variable distances below the superior tarsal border; (2)
      preaponeurotic fat pad protrusion and a thick subcutaneous fat layer prevent
      levator fibers from extending toward the skin near the superior tarsal border;
      and (3) the primary insertion of the levator aponeurosis into the orbicularis
      muscle and into the upper eyelid skin occurs closer to the eyelid margin in
      Asians. Structural differences relating to increased fat in the Asian upper
      eyelid include the presence of a pretarsal fat pad and a moderate fat increase in
      the double Asian eyelid.

PMID- 10408456
TI  - Eyelid healing after carbon dioxide laser skin resurfacing: histological
      analysis.
AB  - OBJECTIVE: To clarify in vivo healing of eyelid skin after carbon dioxide (CO2)
      laser resurfacing. DESIGN: Patients requesting upper eyelid blepharoplasty
      consented to undergo previous CO2 laser skin resurfacing of the upper eyelid skin
      segments to be excised at various time intervals. After blepharoplasty, the skin
      specimens were analyzed histopathologically by 2 masked pathologists. PATIENTS:
      Eight patients with Fitzpatrick skin types I and II. INTERVENTION: Upper eyelid
      CO2 laser resurfacing 1,2, 4, or 12 weeks before planned upper eyelid
      blepharoplasty. MAIN OUTCOME MEASURES: Epidermis: thickness, polarity, contour,
      and constituents. Dermis: repair zone thickness, vascular and inflammatory
      pattern, collagen deposition, and elastic fiber changes. RESULTS: The epidermis
      regenerated within 7 to 10 days. By 3 months, the epidermis revealed flattening
      of the rete peg pattern with restoration of polarity, keratinocytes, and
      melanocytes. The 3-month dermis demonstrated a fibrotic repair zone (500-700
      microm), new elastic fibers, and telangiectatic capillaries. CONCLUSIONS: Eyelids
      heal similarly to other skin regions treated by CO2 laser resurfacing. This
      cutaneous healing is analogous to that previously reported with use of chemical
      peels. Histological changes may explain the skin smoothing and wrinkle reduction
      seen clinically.

PMID- 10408457
TI  - Serum autoantibodies to optic nerve head glycosaminoglycans in patients with
      glaucoma.
AB  - BACKGROUND: Serum autoantibodies that cross-react with glycosaminoglycans have
      been proposed to play a significant role in specific tissue injury in patients
      with systemic autoimmune diseases. OBJECTIVE: To investigate whether serum
      immunoreactivity to glycosaminoglycans is present in patients with glaucoma who
      have aberrant serum autoantibodies to DNA, RNA, nuclear proteins, or retinal
      proteins, as proteoglycans and their glycosaminoglycan side chains are important
      components of the optic nerve head and its vasculature. METHODS: We performed
      Western blotting using patient serum samples and human optic nerve head
      homogenates that were treated with or without specific glycosaminoglycan
      degrading enzymes. Monoclonal antibodies that recognize different determinants of
      glycosaminoglycans were used to identify specific substrate antigenicity. We
      compared the serum immunoreactivity to glycosaminoglycans in 60 age-matched
      patients with normal-pressure glaucoma, 36 patients with primary open-angle
      glaucoma, and 20 control subjects by enzyme-linked immunosorbent assay. In
      addition, immunohistochemistry was performed to compare the distribution patterns
      of glycosaminoglycans in the optic nerve head of postmortem eyes of age-matched
      patients with normal-pressure glaucoma, primary open-angle glaucoma, and control
      subjects. RESULTS: Western blotting demonstrated that serum samples from patients
      with glaucoma who have circulating autoantibodies can recognize optic nerve head
      proteoglycans, including chondroitin sulfate and heparan sulfate. The level of
      serum autoantibodies binding purified chondroitin sulfate and heparan sulfate
      glycosaminoglycans in an enzyme-linked immunosorbent assay was approximately 100%
      higher in patients with normal-pressure glaucoma than that in control subjects
      and approximately 50% higher than that in patients with primary open-angle
      glaucoma. We also observed increased immunostaining of glycosaminoglycans in the
      optic nerve head of eyes with glaucoma, particularly those with normal
      intraocular pressure, compared with control eyes. CONCLUSION: There are increased
      levels of autoantibodies recognizing glycosaminoglycans of the optic nerve head
      in the serum samples of some patients with glaucoma. CLINICAL RELEVANCE: These
      autoantibodies may increase the susceptibility of the optic nerve head to damage
      in these patients by changing the functional properties of the lamina cribrosa,
      its vasculature, or both.

PMID- 10408458
TI  - Cidofovir and experimental herpetic stromal disease.
AB  - OBJECTIVE: To compare topical cidofovir with topical trifluridine for the
      prevention and treatment of herpes simplex type 1 stromal keratitis in rabbits.
      METHODS: The RE strain of herpes simplex virus 1 was injected into the central
      stroma of both eyes of New Zealand white rabbits. Two to 3 days after virus
      inoculation, the rabbits were randomized to treatment groups of 10 each and
      treated with 1% trifluridine administered 5 or 7 times a day, 1%, 0.5%, or 0.2%
      cidofovir administered twice a day, fluorometholone administered twice a day, or
      balanced salt solution (BSS) administered twice a day (control) until day 21
      after injection. The treated corneas were examined 3 times a week and the
      severity of stromal keratitis was graded in a masked fashion. To evaluate the
      ability of cidofovir to treat established stromal disease, groups of 10 rabbits
      each were inoculated with herpes simplex virus and treated with 1% cidofovir
      twice a day, 1% trifluridine 5 times a day, fluorometholone twice a day, or BSS
      twice a day beginning on day 7 after virus inoculation through day 21. RESULTS:
      Treatment with 0.2% cidofovir twice a day was not effective in preventing the
      appearance of stromal disease (P = .89), whereas treatment with 0.5% (P<.001) or
      1% (P<.001) cidofovir twice a day or 1% trifluridine 5 times a day (P<.001) or 7
      times a day (P = .006) significantly reduced the appearance of stromal keratitis
      on the 8 evaluation days, compared with BSS treatment (F test analysis of
      variance). There was no difference between the eyes treated with 0.5% cidofovir
      twice a day and those treated with 1% trifluridine 5 times a day. Treatment with
      1% cidofovir was not effective in treating established stromal disease.
      CONCLUSIONS: Cidofovir and trifluridine are highly effective in preventing the
      appearance of herpetic stromal disease. Cidofovir is as effective as, but no more
      effective than, trifluridine in this model. Neither cidofovir nor trifluridine
      benefits established stromal disease, however. CLINICAL RELEVANCE: Cidofovir is a
      new, potent antiviral that seems similar in efficacy to trifluridine and is
      effective in the prevention of the development of stromal herpes, but is not
      effective in the treatment of established stromal disease in which
      hypersensitivity predominates.

PMID- 10408459
TI  - Reporter expression persists 1 year after adeno-associated virus-mediated gene
      transfer to the optic nerve.
AB  - OBJECTIVE: To determine the foci and duration of protein expression following
      virus-mediated gene transfer to the optic nerve. METHODS: A cytomegalovirus (CMV)
      promoter was linked to a lacZ-SV40 polyA reporter gene or a humanized green
      fluorescent protein (hgfp) reporter gene, then inserted into a bacterial plasmid
      containing adeno-associated virus (AAV) terminal repeat sequences. The CMV-lacZ
      or the CMV-hgfp construct were injected into the vitreous cavity of strain-13
      guinea pigs. Controls consisted of eyes injected with AAV without the promoter
      and reporter elements or eyes that received no injections. The eyes and optic
      nerves were processed for beta-galactosidase immunohistochemistry and hgfp
      fluorescence analyses. Cellular transduction at the messenger RNA (mRNA) level
      was evaluated by in situ reverse transcription-polymerase chain reaction.
      RESULTS: Weekly fundus photography, done for 1 month, documented the absence of
      any ocular abnormality due to the viral injections. No in vivo hgfp fluorescence
      of the retina was visualized. Beta-galactosidase histochemical analysis of eye
      cups that received the lacZ gene construct showed blue lacZ staining of the optic
      nerve head at 2 weeks. Light microscopy revealed the blue beta-galactosidase
      reaction product in fibers, glial cells, and blood vessels of the optic nerve
      head and retrobulbar nerve. Histochemistry showed absence of beta-galactosidase
      in the optic nerve at 3 to 12 months, but immunochemistry showed the persistence
      of beta-galactosidase in fibers, glial cells, and blood vessels as late as 1 year
      after a single ocular injection. In the retina, histochemical staining showed
      evidence of lacZ at 3 months, but not later. In situ reverse transcription
      polymerase chain reaction revealed brown lacZ mRNA reaction product in ganglion
      cells of the retina. Control eyes that received AAV without the promoter and
      reporter elements and the eyes that received no viral injections and were
      processed for beta-galactosidase showed no reporter gene expression in any ocular
      tissue or cell type. CONCLUSIONS: Viral-mediated gene transfer can be
      successfully accomplished in the optic nerve. Further evaluation is needed to
      determine whether the level of protein expression at 1 year after injection,
      which is clearly reduced relative to shorter postinjection time, is sufficient
      for therapeutic purposes. CLINICAL RELEVANCE: We have previously shown that gene
      therapy with catalase suppressed experimental optic neuritis at 1 month after
      injection. Viral-mediated gene transfer may be a powerful technique for the
      treatment of optic neuropathies, particularly for recurrences of optic neuritis,
      if long-term expression of transduced protein can be demonstrated in the optic
      nerve.

PMID- 10408460
TI  - Childbearing history associated with improved survival in choroidal melanoma.
AB  - BACKGROUND: Research in cutaneous melanoma suggests that women may experience
      better tumor-dependent survival than men, and some studies have shown that the
      advantage is specific to childbearing. OBJECTIVE: To examine whether childbearing
      may be a favorable prognostic factor in melanoma of the uveal tract. DESIGN:
      Prospective follow-up study. SETTING: Hospital. MAIN OUTCOME MEASURE: Death from
      metastatic choroidal melanoma. METHODS: We evaluated a consecutive series of 1818
      patients with choroidal melanoma, 748 parous and 165 nulliparous women and 905
      men, after treatment with proton irradiation. Three hundred fifty-two deaths from
      metastasis were documented in follow-up. RESULTS: Overall multivariate-adjusted
      death rates from metastasis were approximately 25% higher in nulliparous women
      (relative risk [RR], 1.23; 95% confidence interval [CI], 0.83-1.82) and men (RR,
      1.25; 95% CI, 1.00-1.56) than in women who had given birth. The protective
      influence of parity was strongest in the early period following diagnosis and
      treatment (RR, 1.58; 95% CI, 0.88-2.86, and RR, 1.51; 95% CI, 1.04-2.19, in
      nulliparous women and men, respectively, during the first 36 months of follow
      up). The level of protection increased with the number of live births (P for
      trend, .04). CONCLUSION: These data provide support for the hypothesis that a
      history of childbearing confers protection from death in choroidal melanoma.

PMID- 10408461
TI  - Acute care hospital utilization by patients with visual impairment.
AB  - OBJECTIVE: To assess whether visual impairment contributes to average length of
      stay (ALOS) within inpatient care facilities. METHODS: We used the New York State
      Department of Health's Statewide Planning and Research Cooperative System
      (SPARCS) data for 1993, containing 1 principal diagnosis code and up to 8
      secondary diagnosis codes for approximately 2.6 million hospital discharges. We
      evaluated ALOS differences in patients with and without visual impairment and in
      patients with eye pathologic conditions, including eye surgery. Visual impairment
      is not a primary admitting diagnosis, but may be coded as a secondary diagnosis.
      Eye pathology comprises a large variety of conditions, including corneal ulcers,
      abscesses, corneal deposits, edema, cataracts, vitreous hemorrhages, and many
      other eye disorders (ICD-9-CM codes 360-368.9 and 370-379). RESULTS: The ALOS was
      13.4 days for patients with visual impairment (N = 5764), 11.9 days for patients
      with either eye pathology or visual impairment (N = 60,085), and 8.2 days for
      patients with no visual impairment (N = 2,546,586). Using a series of
      multivariate models that controlled for the variables of age, sex, and payer
      source, as well as disease, disorders, and ophthalmology procedures, we found
      that the existence of visual impairment added 2.4 days to the ALOS (P<.001),
      while eye pathology combined with a secondary diagnosis of visual impairment
      added 1.8 days to the ALOS (P<.001). CONCLUSIONS: Visual impairment contributes
      significantly to hospital length of stay. A better understanding of the
      functional care needs of patients with visual impairment in an acute care setting
      and at the time of discharge from the hospital may contribute to reducing excess
      ALOS and its related costs while improving the quality of patient care.

PMID- 10408462
TI  - The statesman, the artist, and the ophthalmologist: Clemenceau, Lautrec, and
      Meyer.

PMID- 10408463
TI  - Ki-1-positive anaplastic large-cell lymphoma of the eyelid.
AB  - Ki-1-positive anaplastic large-cell lymphoma is an uncommon form of non-Hodgkin
      lymphoma. It lies within a spectrum of recently identified lymphoproliferative
      disorders. The entities within this spectrum share similar clinical and
      histopathologic characteristics that can make the diagnosis challenging. We
      report a case of Ki-1-positive anaplastic large-cell lymphoma involving the right
      upper eyelid of a 45-year-old woman and describe the light microscopic,
      immunohistochemical, and ultrastructural features. A pertinent review of the
      English-language literature is presented.

PMID- 10408464
TI  - Lymphocytic hypophysitis associated with dacryoadenitis: an autoimmunologically
      mediated syndrome.
AB  - We report a rare case of lymphocytic hypophysitis followed by dacryoadenitis.
      Lymphocytic hypophysitis is a rare disease that can easily be mistaken for
      neoplastic proliferation. Because combination with rheumatoid arthritis,
      thyroiditis, or pernicious anemia is frequent, an immunological pathogenesis is
      likely.

PMID- 10408465
TI  - Retinal hamartoma in oral-facial-digital syndrome.
AB  - Only recently have intraocular findings been described in oral-facial-digital
      syndrome (OFDS), including 5 cases of chorioretinal colobomas and 1 case of optic
      nerve coloboma. We report a case of a new ocular anomaly associated with this
      syndrome: a retinal hamartoma in a male infant with OFDS. The patient had
      bilateral retinal masses that were suspicious for retinoblastoma because of a
      family history of retinoblastoma. Physical examination and imaging studies of the
      retinal masses could not differentiate between retinoblastoma, hamartoma, or
      persistent hyperplastic primary vitreous. Subsequent pathologic study of an
      enucleated globe was diagnostic of a retinal hamartoma. This case further
      illustrates the heterogeneity of ocular anomalies in OFDS and underscores the
      importance of a complete ophthalmologic evaluation in patients with this
      syndrome.

PMID- 10408466
TI  - Subconjunctival corticosteroid injections for nonnecrotizing anterior scleritis.

PMID- 10408467
TI  - Bilateral bacterial keratitis after laser in situ keratomileusis in a patient
      with human immunodeficiency virus infection.

PMID- 10408468
TI  - Clostridium perfringens endophthalmitis following cataract surgery.

PMID- 10408469
TI  - Branch retinal arteriolar occlusion associated with familial factor V Leiden
      polymorphism and positive rheumatoid factor.

PMID- 10408470
TI  - Can blinding trachoma be eliminated worldwide?

PMID- 10408471
TI  - Fundus and fluorescein documentation of hypomelanosis of Ito.

PMID- 10408472
TI  - All prepapillary arterial loops are not alike.

PMID- 10408473
TI  - All prepapillary arterial loops are not alike.

PMID- 10408474
TI  - Regulation of retinal and optic nerve blood flow.

PMID- 10408475
TI  - A metered way of life.

PMID- 10408476
TI  - Screening for lung cancer: time to think positive.

PMID- 10408477
TI  - Weighing up disability.

PMID- 10408478
TI  - Nurse-led telephone-advice lines.

PMID- 10408479
TI  - V cholerae non-O1: implications for man?

PMID- 10408481
TI  - Cancer risk in patients on dialysis.

PMID- 10408480
TI  - Whither Mycobacterium vaccae?

PMID- 10408482
TI  - Ombudsman's third report.

PMID- 10408484
TI  - Early Lung Cancer Action Project: overall design and findings from baseline
      screening.
AB  - BACKGROUND: The Early Lung Cancer Action Project (ELCAP) is designed to evaluate
      baseline and annual repeat screening by low-radiation-dose computed tomography
      (low-dose CT) in people at high risk of lung cancer. We report the baseline
      experience. METHODS: ELCAP has enrolled 1000 symptom-free volunteers, aged 60
      years or older, with at least 10 pack-years of cigarette smoking and no previous
      cancer, who were medically fit to undergo thoracic surgery. After a structured
      interview and informed consent, chest radiographs and low-dose CT were done for
      each participant. The diagnostic investigation of screen-detected non-calcified
      pulmonary nodules was guided by ELCAP recommendations, which included short-term
      high-resolution CT follow-up for the smallest non-calcified nodules. FINDINGS:
      Non-calcified nodules were detected in 233 (23% [95% CI 21-26]) participants by
      low-dose CT at baseline, compared with 68 (7% [5-9]) by chest radiography.
      Malignant disease was detected in 27 (2.7% [1.8-3.8]) by CT and seven (0.7% [0.3
      1.3]) by chest radiography, and stage I malignant disease in 23 (2.3% [1.5-3.3])
      and four (0.4% [0.1-0.9]), respectively. Of the 27 CT-detected cancers, 26 were
      resectable. Biopsies were done on 28 of the 233 participants with non-calcified
      nodules; 27 had malignant non-calcified nodules and one had a benign nodule.
      Another three individuals underwent biopsy against the ELCAP recommendations; all
      had benign non-calcified nodules. No participant had thoracotomy for a benign
      nodule. INTERPRETATION: Low-dose CT can greatly improve the likelihood of
      detection of small non-calcified nodules, and thus of lung cancer at an earlier
      and potentially more curable stage. Although false-positive CT results are
      common, they can be managed with little use of invasive diagnostic procedures.

PMID- 10408483
TI  - Cancer in patients on dialysis for end-stage renal disease: an international
      collaborative study.
AB  - BACKGROUND: Previous studies have suggested that the frequency of cancer is
      higher in patients with end-stage renal disease (ESRD) than in the general
      population, but have not established whether this increase is confined to certain
      cancers or to certain categories of ESRD patients. The aim of this study was to
      examine the risk of cancer in a large cohort of patients treated by dialysis but
      not transplantation. METHODS: We assembled a cohort of 831,804 patients who
      received dialysis during the period 1980-94 for ESRD in the USA, Europe,
      Australia, or New Zealand. We compared the observed frequency of cancer among
      these patients during 2,045,035 person-years of follow-up with the frequency of
      cancer in the respective background populations. FINDINGS: During average follow
      up of 2.5 years, 25,044 (3%) of 831,804 patients developed cancer compared with
      an expected number of 21,185 (standardised incidence ratio 1.18 [95% CI 1.17
      1.20]). We observed a higher risk of cancer in patients younger than 35 years
      (3.68 [3.39-3.99]), and the risk gradually decreased with increasing age. High
      risks were observed for cancer of the kidney (3.60 [3.45-3.76]), bladder (1.50
      [1.42-1.57]), and thyroid and other endocrine organs (2.28 [2.03-2.54]). Excess
      cancers appeared in several organs for which viruses have been suspected as
      causative agents, whereas cancers of the lung, colorectum, prostate, breast, and
      stomach were not consistently increased. INTERPRETATION: The overall risk of
      cancer is increased in patients with ESRD, and the distribution of tumour types
      resembles the pattern seen after transplantation (although we have no data to
      make the comparison with skin cancer). The excess risk can largely be ascribed to
      effects of underlying renal or urinary-tract disease, or of loss of renal
      function, on the kidney and bladder, and to increased susceptibility to viral
      carcinogenesis. The relative risk, which is especially high in younger patients,
      gradually diminishes with age.

PMID- 10408485
TI  - Use of point-of-care test in identification of patients who can benefit from
      desmopressin during cardiac surgery: a randomised controlled trial.
AB  - BACKGROUND: Platelet dysfunction is a major cause of excessive microvascular
      bleeding after cardiac surgery. A new point-of-care test (hemoSTATUS) can
      identify patients at risk of excessive bleeding. We aimed to find out whether
      patients who can benefit from desmopressin during cardiac surgery can be
      identified by this test. METHODS: We enrolled 203 patients scheduled for elective
      cardiac surgery in a prospective, double-blind, placebo-controlled trial.
      Patients with abnormal hemoSTATUS clot-ratio results (<60% of maximum in channel
      5) after discontinuation of cardiopulmonary bypass were randomly assigned
      desmopressin (n=50) or placebo (n=51). Patients with normal clot ratios were
      included in an untreated control group (n=72). FINDINGS: Intraoperative platelet
      counts and clot ratios were significantly higher in the untreated control group
      than in the study-drug groups. In intensive care, clot ratios in patients who
      received desmopressin were similar to those in the untreated control group,
      despite significantly lower platelet counts, but were lower in the placebo group
      than in the other two groups (p=0.0001). Compared with the placebo group,
      patients who received desmopressin had less blood loss in 24 h (mean 624 [SD 209]
      vs 1028 mL [682] p=0.0004) and required less transfusion of red blood cells (1.1
      [022] vs 2.2 U [0.32] p=0.009), platelets (0.1 [0.04] vs 1.9 U [4.5] p=0.0001),
      and fresh-frozen plasma (0.1 [0.07] vs 0.75 U [0.21] p=0.0008), and had less
      total blood-donor exposures (1.56 [0.31] vs 5.2 [0.8] p=0.0001). Placebo patients
      also had substantially higher blood loss and transfusion requirements than
      untreated control patients. INTERPRETATION: Patients identified with hemoSTATUS
      as being at increased risk of excessive bleeding after cardiac surgery can
      benefit from administration of desmopressin. Further studies are, however, needed
      to confirm these findings as well as to identify the mechanism of action and
      safety of desmopressin in the clinical setting.

PMID- 10408486
TI  - Multiple-informant ranking of the disabling effects of different health
      conditions in 14 countries. WHO/NIH Joint Project CAR Study Group.
AB  - BACKGROUND: The Global Burden of Disease study provided international statistics
      on the burden of diseases, combining mortality and disability, that can be used
      for priority setting and policy making. However, there are concerns about the
      universality of the disability weights used. We undertook a study to investigate
      the stability of such weighting in different countries and informant groups.
      METHODS: 241 key informants (health professionals, policy makers, people with
      disabilities, and their carers) from 14 countries were asked to rank 17 health
      conditions from most disabling to least disabling. Kruskal-Wallis ANOVA was used
      to test for differences in ranking between countries or informant groups and
      Kendall tau-B correlations to measure association between different rank orders.
      FINDINGS: For 13 of 17 health conditions, there were significant (p<0.05)
      differences in ranking between countries; in the comparison of informant groups,
      there were significant differences for five of the 17 health conditions. The
      overall rank order in the present study was, however, almost identical to the
      ranking of the Global Burden of Disease study, which used a different method.
      Most of the rank correlations between countries were between 0.50 and 0.70
      (average 0.61 [95% CI 0.59-0.64]). The average correlation of rank orders between
      different informant groups was 0.76. INTERPRETATION: Rank order of disabling
      effects of health conditions is relatively stable across countries, informant
      groups, and methods. However, the differences are large enough to cast doubt on
      the assumption of universality of experts' judgments about disability weights.
      Further studies are needed because disability weights are central to the
      calculation of disability-adjusted life years.

PMID- 10408487
TI  - Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed
      pulmonary tuberculosis: a randomised controlled trial. Durban Immunotherapy Trial
      Group.
AB  - BACKGROUND: Mycobacterium vaccae, an environmental saprophyte, has immunogenic
      properties that enhance the host immune response. Immunotherapy with M. vaccae
      has been suggested to shorten short-course antituberculosis chemotherapy. We
      tested the hypothesis that the addition of M. vaccae to standard short-course
      antituberculosis chemotherapy would decrease the time to achieve a negative
      sputum culture. METHODS: Patients with newly diagnosed tuberculosis were randomly
      assigned an injection of saline (placebo) or M. vaccae on day 8. All patients
      received antituberculosis chemotherapy with rifampicin, isoniazid, pyrazinamide,
      and ethambutol. Sputum samples were checked by microscopy and culture every week
      for the first 8 weeks and monthly until the end of chemotherapy at 6 months. The
      primary outcome was the time to a negative sputum culture in the first 8 weeks.
      Intention-to-treat analysis was used and time to sputum clearance was assessed by
      log-rank test and Cox's proportional-hazards regression. FINDINGS: 172 patients
      received M. vaccae and 175 patients received placebo. At 8 weeks, 70 patients in
      the M. vaccae group and 65 patients in the placebo group had a negative culture;
      there was no difference between groups in the time to a negative culture
      (p=0.83). There was no interaction between HIV status and treatment.
      INTERPRETATION: M. vaccae immunotherapy has no benefit when added to standard
      antituberculosis chemotherapy.

PMID- 10408489
TI  - A breathless accountant who blew up balloons.

PMID- 10408488
TI  - Quantitative PCR of mycobacterial and propionibacterial DNA in lymph nodes of
      Japanese patients with sarcoidosis.
AB  - BACKGROUND: The causes of sarcoidosis are not known. The DNA of Mycobacterium
      tuberculosis has been detected in some sarcoid lesions. In Japan,
      Propionibacterium acnes has been isolated from such lesions, but whether this
      indigenous bacterium is related to the disease is unclear. We used PCR to
      estimate the number of genomes of these bacteria in sarcoid lesions, to identify
      any link between sarcoidosis and these two bacterial species. METHODS: We
      examined formalin-fixed and paraffin-embedded sections of biopsy and surgical
      samples from lymph nodes of 15 patients with sarcoidosis, 15 patients with
      tuberculosis, and 15 patients with gastric cancer (controls). Quantitative PCR
      was done to amplify segments of 16 S ribosomal RNA of P. acnes and P. granulosum
      and of insertion sequence 6110 of M. tuberculosis. PCR products were identified
      and the quantities of the products were estimated in terms of the fluorescence of
      oligonucleotide reporter probes. The numbers of bacterial genomes in samples were
      estimated from standard curves of serially diluted bacterial DNA. FINDINGS:
      Genomes of M. tuberculosis were found in samples from all 15 patients with
      tuberculosis, from three patients with sarcoidosis, and in one control sample.
      Genomes of P. acnes were found in 12 of the 15 patients with sarcoidosis, in two
      tuberculosis patients, and three controls. The difference in the estimated number
      of P. acnes genomes between individuals with and without sarcoidosis was similar
      to that in the number of M. tuberculosis between people with and without
      tuberculosis. There were 5x10(5) P. acnes genomes in sarcoidosis and 3x10(6) M.
      tuberculosis genomes in tuberculosis, respectively, on average per microg of
      total DNA. The three patients with sarcoidosis but without P. acnes all had P.
      granulosum DNA in their biopsy samples; the number of genomes of the bacterium
      was 5x10(5). INTERPRETATION: These findings suggest that propionibacteria had
      resided or proliferated ectopically in the sarcoid lesions, whether there was a
      connection with the disease or not. Propionibacteria are a more likely cause than
      mycobacteria of sarcoidosis.

PMID- 10408490
TI  - Erectile dysfunction in spina bifida is treatable.
AB  - We undertook a prospective, blinded, randomised, placebo-controlled, dose
      escalation, crossover study that showed that erectile dysfunction in spina bifida
      is medically treatable, specifically with sildenafil citrate.

PMID- 10408491
TI  - Nigral endothelial dysfunction, homocysteine, and Parkinson's disease.
AB  - We found increased levels of atherosclerosis-inducing homocysteine in
      parkinsonian patients with long-term application of levodopa compared with
      previously untreated parkinsonian patients and controls. We conclude that
      antiparkinsonian treatment with levodopa promotes occurrence of vascular disease
      in Parkinson's disease.

PMID- 10408492
TI  - Venous thromboembolism among new users of different oral contraceptives.
AB  - New use of third generation oral contraceptives is associated with a four-fold
      increased risk of venous thromboembolism compared with users of second generation
      oral contraceptives, particularly among young, healthy women.

PMID- 10408493
TI  - Myocarditis and primary Sjogren's syndrome.
AB  - We describe congestive heart failure caused by autoimmune myocarditis in a
      patient with primary Sjogren's syndrome. Only after corticosteroids were given
      did the symptoms and laboratory abnormalities disappear.

PMID- 10408494
TI  - Combined sentinel lymph-node mapping and bone-marrow micrometastatic analysis for
      improved staging in breast cancer.
AB  - In a prospective study of 29 patients with clinically node-negative breast
      cancer, sampling of rib marrow was superior to sampling of iliac-crest marrow for
      detection of micrometastases. Combination of marrow micrometastatic analysis with
      sentinel lymph-node mapping may improve accuracy of staging in breast cancer.

PMID- 10408495
TI  - Mortality during adjuvant treatment of early breast cancer with cyclophosphamide,
      methotrexate, and fluorouracil. International Breast Cancer Study Group.
AB  - Combined chemotherapy for early breast cancer with cyclophosphamide,
      methotrexate, and fluorouracil has low associated mortality, but related deaths
      were seen among women aged 65 years or older in International Breast Cancer Study
      Group trials.

PMID- 10408496
TI  - Treatment with interferon-alpha in patients with chronic hepatitis and mood or
      anxiety disorders.
AB  - We prospectively studied 50 patients treated with interferon-alpha for chronic
      hepatitis and found no evidence that patients with a pre-existing mood or anxiety
      disorder were more likely than other patients to interrupt the interferon-alpha
      therapy.

PMID- 10408497
TI  - Helicobacter pylori in sheep milk.
AB  - Helicobacter pylori was recovered from sheep milk, suggesting a role for animals
      in transmission. H. pylori may be a commensal in the sheep, which may be H.
      pylori's ancestral host.

PMID- 10408498
TI  - Public-health threat of measles-vaccine refusal spelled out.

PMID- 10408499
TI  - Testing time as resistant HIV-1 faces next wave of attack.

PMID- 10408500
TI  - Whose article is it anyway?

PMID- 10408501
TI  - Millions choke while stoves burn.

PMID- 10408502
TI  - Medical significance of peroxisome proliferator-activated receptors.
AB  - Peroxisome proliferator-activated receptors (PPAR) were discovered in 1990,
      ending 25 years of uncertainty about the molecular mechanisms of peroxisome
      proliferation. Subsequently, PPARs have improved our understanding of adipocyte
      differentiation. But there is more to PPARs than solving a puzzle about an
      organelle (the peroxisome) long considered an oddity, and their medical
      significance goes beyond obesity too. Enhanced PPAR type alpha expression
      protects against cardiovascular disorders though the role of enhanced PPARgamma
      expression seems less favourable. PPAR mechanisms, mainly via induction of more
      differentiated cell phenotypes, protect against some cancers. The differentiation
      of many cell types (hepatocyte, fibroblast, adipocyte, keratinocyte, myocyte, and
      monocyte/macrophage) involves PPARs, and these nuclear receptors are now
      attracting the attention of many medical specialties and the pharmaceutical
      industry.

PMID- 10408503
TI  - The early modern debate about foreign drugs: localism versus universalism in
      medicine.

PMID- 10408504
TI  - Hormone replacement therapy. Clinical Synthesis Panel on HRT.

PMID- 10408505
TI  - Effect of zidovudine on perinatal HIV-1 transmission and maternal viral load.
      Pediatric AIDS Clinical Trials Group 076 Study Group.

PMID- 10408506
TI  - Effect of zidovudine on perinatal HIV-1 transmission and maternal viral load.

PMID- 10408507
TI  - Effect of zidovudine on perinatal HIV-1 transmission and maternal viral load.

PMID- 10408508
TI  - Effect of zidovudine on perinatal HIV-1 transmission and maternal viral load.

PMID- 10408509
TI  - Debate on Di Bella therapy.

PMID- 10408510
TI  - Debate on Di Bella therapy.

PMID- 10408511
TI  - Stroke from traumatic arterial dissection.

PMID- 10408512
TI  - Stroke from traumatic arterial dissection.

PMID- 10408513
TI  - Tuberculosis chemoprophylaxis for infants and teenagers.

PMID- 10408514
TI  - Promotion of exclusive breastfeeding.

PMID- 10408515
TI  - Naturally acquired immunity to vivax malaria.

PMID- 10408516
TI  - Thrombosis in pregnancy.

PMID- 10408517
TI  - Contamination of animal feed by multiresistant enterococci.

PMID- 10408518
TI  - Drug development output: what proportion for tropical diseases?

PMID- 10408519
TI  - Ciprofloxacin in typhoid fever.

PMID- 10408520
TI  - Performance of doctors.

PMID- 10408521
TI  - Fair trade for less developed countries?

PMID- 10408522
TI  - Mental health of refugees from Kosovo.

PMID- 10408523
TI  - Auditory hallucinations and the bicameral mind.

PMID- 10408524
TI  - Web health fraud monitors face formidable task.

PMID- 10408525
TI  - The Nobel chronicles. 1962: Francis Harry Compton Crick (b 1916); James Dewey
      Watson (b 1928); Maurice Hugh Frederick Wilkins (b 1916).

PMID- 10408526
TI  - CACNA1A mutations: hemiplegic migraine, episodic ataxia type 2, and the others.

PMID- 10408527
TI  - "Pure" hereditary spastic paraplegias: the story becomes complicated.

PMID- 10408528
TI  - Von Hippel-Lindau disease: how does one gene cause multiple tumors?

PMID- 10408529
TI  - Consent issues in the management of cerebrovascular diseases: a position paper of
      the American Academy of Neurology Ethics and Humanities Subcommittee.

PMID- 10408530
TI  - Thrombolytic stroke therapy: past, present, and future.
AB  - Until 1995, treatment of strokes consisted exclusively of efforts to prevent
      recurrence. Proof that tissue plasminogen activator is useful for acute
      management is changing the approach to stroke patients. The development process
      has been difficult and the current treatment recommendations have been
      controversial. Recent successful clinical trials lend additional credence to
      these concepts. Future treatment strategies will probably include combinations of
      thrombolytics and neuroprotectants of various types. However, the need to
      initiate treatment rapidly after stroke onset is likely to continue.

PMID- 10408531
TI  - Matrix metalloproteinases in inflammatory demyelination: targets for treatment.
AB  - Matrix metalloproteinases (MMPs) degrade all protein components of the
      extracellular matrix. Functionally, they contribute to several different
      physiologic conditions, such as angiogenesis or bone remodeling, as well as
      pathologic conditions in humans, such as rheumatoid arthritis and tumor growth.
      MMPs seem to be important in the pathogenesis of inflammatory demyelinating
      diseases of the central and peripheral nervous system, especially in MS and in
      Guillain-Barre syndrome (GBS). Key mechanisms in the genesis of inflammatory
      demyelination, such as leukocyte recruitment, blood-brain barrier or blood-nerve
      barrier breakdown, myelin destruction, and release of disease-promoting
      cytokines, are considered to be MMP-dependent processes. In experimental
      autoimmune encephalomyelitis, an animal model of MS, and experimental autoimmune
      neuritis, an animal model of GBS, different synthetic inhibitors targeting MMP
      activity are able to suppress and even reverse ongoing disease. This evidence
      points to MMPs as new targets for treatment in inflammatory demyelination.

PMID- 10408532
TI  - Genetic heterogeneity in Italian families with familial hemiplegic migraine.
AB  - OBJECTIVE: To verify linkage to chromosome 19p13, to detect mutations in the
      CACNA1A gene, and to correlate genetic results to their clinical phenotypes in
      Italian families with familial hemiplegic migraine (FHM). BACKGROUND: FHM is an
      autosomal dominant disease, classified as a subtype of migraine with aura. Only a
      proportion of FHM patients have been associated with chromosome 19p13. Among
      these, four missense mutations within the CACNA1A gene in five unrelated families
      have been described. METHODS: A linkage study was performed in 19 patients
      affected by FHM from five families by studying microsatellite markers associated
      with the 19p13 region. All familial and seven additional sporadic patients with
      FHM were analyzed to search for mutations within the CACNA1A gene by applying the
      double gradient-denaturant gradient electrophoresis technique. RESULTS: Lod score
      values did not establish significantly linkage to chromosome 19. However, seven
      new genetic variants were detected: six were new polymorphisms. The seventh was a
      missense mutation present in family 1, and it was associated with a hemiplegic
      migraine phenotype without unconsciousness and cerebellar ataxia. Because this
      missense mutation is absent in the general population and cosegregates with the
      disease, it may be a pathologic mutation. CONCLUSIONS: Genetic heterogeneity of
      FHM has been shown in familial and sporadic FHM patients of Italian origin. The
      new missense mutation-G4644T-is associated with milder clinical features compared
      with typical FHM.

PMID- 10408533
TI  - A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia.
AB  - OBJECTIVE: To identify the disease-causing mutation and to characterize
      penetrance and phenotypic variability in a large pedigree with episodic ataxia
      type 2 (EA-2) previously linked to chromosome 19. BACKGROUND: Mutations in the
      CACNA1A gene on chromosome 19 encoding a calcium channel subunit cause EA-2,
      which is characterized by recurrent attacks of imbalance with interictal eye
      movement abnormalities. METHODS: The authors used single-strand conformation
      polymorphism (SSCP) analysis to screen for point mutations, and direct sequencing
      to identify mutations in CACNA1A. Allele-specific oligonucleotides were designed
      to detect the presence of the diseased allele in members of their pedigree as
      well as in normal control subjects. RESULTS: Reassessment of members of the
      pedigree revealed two notable clinical features. Diffuse weakness during attacks
      of ataxia was a prominent complaint. Two affected individuals had had episodic
      hemiplegia, one with typical migraine headaches. SSCP analysis revealed aberrant
      bands in exon 29 in affected members but not in normal control subjects. Direct
      sequencing of exon 29 identified a C-to-T change at position 4914 of the coding
      sequence of CACNA1A, predicting an early stop code at codon 1547. Two
      asymptomatic mutation carriers demonstrated the incomplete penetrance of this
      mutation. CONCLUSIONS: A nonsense mutation in CACNA1A causes episodic ataxia and
      complaint of weakness, and may be associated with hemiplegia.

PMID- 10408534
TI  - A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic
      migraine and ataxia.
AB  - OBJECTIVE: To search for mutations in the calcium channel gene CACNA1A and to
      study the genotype-phenotype correlation in a family with a severe familial
      hemiplegic migraine (FHM) phenotype and a slowly progressive cerebellar ataxia.
      BACKGROUND: CACNA1A gene mutations on chromosome 19 are involved in approximately
      50% of FHM families. The association of FHM and cerebellar ataxia has been
      reported in a small number of FHM families, all linked to chromosome 19. METHODS:
      The proband, in addition to typical hemiplegic migraine attacks, experienced
      severe episodes during which hemiplegia was associated with acutely altered
      consciousness and fever lasting several days. She, as well as her affected
      sister, developed a permanent, late-onset cerebellar ataxia and cerebellar
      atrophy evident on MRI. Linkage analysis was performed and the whole CACNA1A
      gene, 47 exon-intron boundaries, was analyzed by double gradient-denaturing
      gradient gel electrophoresis (DG-DGGE). RESULTS: Genetic studies suggested
      linkage to chromosome 19p13, and DG-DGGE analysis detected a heteroduplex
      fragment in exon 13 of the CACNA1A gene. By direct sequencing, a G-to-A
      substitution resulting in an arginine to glutamine change at codon 583 in the
      second putative voltage sensor domain of the channel alpha1A-subunit, was
      identified, possibly representing the disease-causing mutation. The proband and
      her affected sister were treated with acetazolamide, reporting freedom from new
      FHM attacks but no benefit in the progression of ataxia. CONCLUSIONS: The
      combination of episodic dysfunction and permanent deficit could depend on the
      variety of functions of calcium channels and their distribution in the nervous
      system.

PMID- 10408535
TI  - Phenotypic analysis of autosomal dominant hereditary spastic paraplegia linked to
      chromosome 8q.
AB  - OBJECTIVE: To describe clinical, electrophysiologic, neuroimaging, and muscle
      biopsy features in a hereditary spastic paraplegia (HSP) kindred linked to a new
      HSP locus on chromosome 8q. BACKGROUND: HSP is a genetically diverse group of
      disorders characterized by insidiously progressive spastic weakness in the legs.
      We recently analyzed a Caucasian kindred with autosomal dominant HSP and
      identified tight linkage to a novel HSP locus on chromosome 8q23-24. METHODS:
      Clinical analysis, nerve conduction studies, electromyography, somatosensory
      evoked potentials, MRI of brain and spinal cord, and muscle biopsy for
      mitochondrial analysis were performed in members of the first HSP kindred linked
      to chromosome 8q. RESULTS: Fifteen individuals showed insidiously progressive
      spastic paraparesis beginning between ages 22 and 60 years (average, 37.2 years).
      Spinal cord MRI in 1 moderately affected subject showed significant atrophy of
      the thoracic spinal cord as determined by cross-sectional area measurements.
      Somatosensory evoked potential recording, electromyography, nerve conduction
      studies, and muscle biopsy, including histochemical and biochemical analysis of
      mitochondrial function, were normal. CONCLUSIONS: The phenotype in this family is
      that of typical, but severe, uncomplicated HSP. Other than apparently increased
      severity, there were no clinical features that distinguished this family from
      autosomal dominant HSP linked to loci on chromosomes 2p, 14q, and 15q. This
      clinical similarity between different genetic types of autosomal dominant HSP
      raises the possibility that genes responsible for these clinically
      indistinguishable disorders may participate in a common biochemical cascade.
      Normal results of muscle histochemical and biochemical analysis suggest that
      mitochondrial disturbance, a feature of chromosome 16-linked autosomal recessive
      HSP due to paraplegin gene mutations, is not a feature of chromosome 8q-linked
      autosomal dominant HSP and may not be a common factor of HSP in general.

PMID- 10408536
TI  - Genetic localization of a new locus for recessive familial spastic paraparesis to
      15q13-15.
AB  - OBJECTIVE: To characterize a new gene locus for familial spastic paraparesis
      (FSP). BACKGROUND: FSP is a genetically heterogeneous group of upper motor neuron
      syndromes. It can be inherited as an autosomal dominant, autosomal recessive, or
      X-linked disorder. Four loci for autosomal dominant FSP have been genetically
      mapped, and two genes have been shown responsible for the X-linked type. In
      addition, two loci for autosomal recessive type have been reported and mapped to
      chromosomes 8q and 16q. The gene for the 16q locus has been characterized as a
      mitochondrial protein. METHODS: Eight recessive FSP families from America and
      Europe were used for genetic linkage analysis. The known recessive loci (8q and
      16q) and the X-linked loci (PLP and L1CAM genes) were screened through PCR
      amplification, followed by linkage analysis, single-strand conformational
      polymorphism, or both. RESULTS: All the families except one revealed lack of
      linkage to the known loci for recessive and X-linked types of FSP. One of the
      eight families showed data consistent with linkage to the previously
      characterized 8q locus. Analysis of all the families for possible linkage to
      other candidate loci revealed significant positive lod scores for markers in
      chromosome 15q. The maximum multipoint combined lod score for the non-8q families
      was Z = 3.14 for markers D15S1007, D15S971, D15S118, and D15S1012, at a distance
      of 6.41 cM from the marker D15S1007, in between D15S971 and D15S118. CONCLUSIONS:
      Our data suggest a new locus for recessive FSP linked to chromosome 15q, and that
      this may be the most common one.

PMID- 10408537
TI  - Randomized trial of interferon beta-1a in chronic inflammatory demyelinating
      polyradiculoneuropathy.
AB  - OBJECTIVE: To test the safety and efficacy of interferon beta-1a (IFN-beta) in
      treatment-resistant chronic inflammatory demyelinating polyradiculoneuropathy
      (CIDP). BACKGROUND: Current treatment regimens leave 4% to 30% of patients with
      CIDP with moderate or severe disability. IFN-beta has been reported as beneficial
      in one treatment-resistant patient. METHODS: Ten consecutive treatment-resistant
      patients were randomized in a double-blind, crossover design to receive placebo
      or IFN-beta (3 MIU for 2 weeks and then 6 MIU for 10 weeks) subcutaneously three
      times weekly, followed by 4 weeks without treatment, and then the opposite
      treatment for 12 weeks. The primary outcome measure was "clinically important"
      improvement by specified amounts in any three of eight clinical measures: timed
      10-m walk, Ambulation Index, expanded Medical Research Council sum score, nine
      hole peg test time, Functional Independence Measure, Hammersmith Motor Ability, a
      new Guy's Neurological Disability Scale, and the EuroQoL quality-of-life scale.
      These and motor median nerve conduction studies were measured before and after 12
      weeks of each treatment. RESULTS: Clinically important improvement was observed
      in one patient while taking IFN-beta and two patients while taking placebo. There
      was no significant difference between IFN-beta and placebo in the change in any
      of the individual clinical or neurophysiological measures between the beginning
      and end of treatment. There were no serious adverse events. CONCLUSION: This
      trial shows that IFN-beta is safe but not efficacious in treatment-resistant
      CIDP.

PMID- 10408538
TI  - Matrix metalloproteinase upregulation in chronic inflammatory demyelinating
      polyneuropathy and nonsystemic vasculitic neuropathy.
AB  - OBJECTIVE: To determine the expression pattern and cellular source of matrix
      metalloproteinases (MMPs) in chronic inflammatory demyelinating polyneuropathy
      (CIDP) and nonsystemic vasculitic neuropathy (NSVN). BACKGROUND: MMPs are
      endopeptidases involved in tissue destruction and infiltration by immune cells in
      multiple sclerosis and Guillain-Barre syndrome. Enzyme inhibitors of MMPs
      attenuate clinical symptoms in corresponding animal models of these diseases. MMP
      inhibition may therefore be a novel approach for the treatment of CIDP and NSVN.
      However, the spectrum of MMPs expressed in chronic inflammatory neuropathies has
      not been established. METHODS: The expression of MMP-2, MMP-3, MMP-7, and MMP-9
      in T cells, macrophages, and stromal cells in CIDP, NSVN, and noninflammatory
      neuropathies (NIN) was quantitated by immunohistochemistry. Results were
      correlated with clinical and electrophysiologic findings. RESULTS: The production
      of MMP-2 and MMP-9 is increased in nerve tissue in CIDP and NSVN compared with
      NIN. T cells are the predominant source of MMP-2 and MMP-9 in CIDP and NSVN,
      whereas macrophages contribute only to a minor extent. Stromal cells of the
      perineurium/epineurium are an additional source of MMP-2 in NSVN, but not in
      CIDP. Expression of MMP-3 and MMP-7 was not detectable in CIDP or NSVN.
      Expression of MMP-2 and MMP-9 did not correlate with clinical disease activity
      and electrophysiologic measurements. CONCLUSIONS: The upregulation of MMP-2 and
      MMP-9 is a specific feature of CIDP and NSVN, and selective inhibitors of these
      enzymes could be used to prevent inflammatory tissue damage. The similar increase
      of MMP-2 and MMP-9 in both demyelinating (CIDP) and nondemyelinating (NSVN)
      neuropathies raises doubts about whether MMPs play a primary role in
      demyelination.

PMID- 10408539
TI  - 1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS
      medulla.
AB  - OBJECTIVE: To determine whether short echo-time (TE) proton magnetic resonance
      spectroscopic imaging (1H-MRSI) can detect in vivo differences in signal
      intensities of specific metabolites in the medulla of patients with ALS compared
      with healthy individuals and whether these metabolites could be useful surrogate
      markers of disease. BACKGROUND: 1H-MRSI can detect N-acetylaspartate + N
      acetylaspartylglutamate (abbreviated NAx), which is localized to neurons, and
      glutamate (Glu) + glutamine (Gln), abbreviated Glx, which may be important in ALS
      pathogenesis. The medulla is an ideal region to study ALS because of its high
      density of nuclei and fiber tracts that frequently undergo degeneration, even
      when more rostral brain regions show minimal pathology. METHODS: Ten patients
      with ALS and seven healthy control subjects underwent short TE 1H-MRSI on a 1.5 T
      clinical imaging system. Signal intensities of NAx and Glx were normalized to
      creatine-phosphocreatine and compared between groups. RESULTS: Compared with
      normal subjects, the medulla of patients with ALS had 17% lower NAx (p = 0.03)
      and 55% higher Glx (p = 0.02) signals. Bulbar symptoms, represented by the ALS
      Functional Rating Scale, correlated with Glx (r = -0.68, p = 0.03) but not NAx (r
      = 0.22, p = 0.53). CONCLUSION: There is in vivo 1H-MRSI evidence of neuronal
      degeneration or loss and excess Glu + Gln in the medulla of patients with ALS.
      Although this cross-sectional study cannot identify which change occurred first,
      the higher Glx signal in the medulla of patients with more dysarthria and
      dysphagia is consistent with the hypothesis of Glu excitotoxicity in ALS
      pathogenesis. Longitudinal 1H-MRSI studies of the medulla (and other brain
      regions) in more patients with ALS are required to confirm these findings and to
      determine whether such metabolite changes will be useful in monitoring disease
      progression, in clinical diagnosis, and in understanding the pathogenesis of ALS.

PMID- 10408540
TI  - Autosomal dominant progressive external ophthalmoplegia: distribution of multiple
      mitochondrial DNA deletions.
AB  - OBJECTIVE: To relate signs and symptoms to morphologic changes and presence of
      multiple mitochondrial DNA (mtDNA) deletions in a patient with autosomal dominant
      progressive external ophthalmoplegia (adPEO) and mitochondrial myopathy.
      BACKGROUND: An etiologic association between the somatic multiple mtDNA deletions
      in adPEO and clinical manifestations other than the myopathy has so far not been
      demonstrated. METHODS: The authors investigated a patient with adPEO and
      multiorgan system manifestations including levodopa-responsive parkinsonism. She
      died at age 61 years of pancreatic carcinoma. Autopsy tissue specimens were
      investigated for morphologic alterations and occurrence of mtDNA deletions by
      Southern blot and long-extension PCR analyses. RESULTS: The patient had carcinoma
      of the pancreas with metastases to liver, lymph nodes, and bone marrow. The brain
      revealed slight gliosis of the gray and white matter and degeneration of the
      substantia nigra. The myocardium showed focal areas with loss and atrophy of
      myocytes and fibrosis. Analysis of mtDNA revealed multiple deletions in different
      regions of the brain, skeletal muscle, and myocardium. Twenty-five different
      mtDNA deletions were identified. Most of these were flanked by large direct
      sequence repeats. Six identical deletions were found in muscle and brain.
      CONCLUSIONS: These findings indicate that somatic multiple mtDNA deletions are
      associated with degenerative tissue changes and clinical manifestations in adPEO.

PMID- 10408541
TI  - Chronic subthalamic nucleus stimulation reduces medication requirements in
      Parkinson's disease.
AB  - OBJECTIVE: To reduce antiparkinsonian medication in parkinsonian patients with
      bilateral high frequency subthalamic nucleus (STN) stimulation. BACKGROUND:
      Parkinsonian syndromes are characterized by hyperactivity of the STN. Preliminary
      data indicate that functional inactivation of the STN may reduce the requirement
      for dopaminergic therapy in PD. METHODS: Bilateral quadripolar leads were
      implanted stereotactically in the STN of seven patients with advanced PD (mean
      age, 57.4 years; mean disease duration, 15.4 years). High-frequency stimulation
      was applied for 24 hours a day. Following implantation, antiparkinsonian
      medication was reduced to the minimum possible and stimulation was gradually
      increased. The patients were evaluated in the practically defined "off" and "on"
      conditions using the Unified Parkinson's Disease Rating Scale (UPDRS) and the
      Schwab & England scale. The average follow-up was 16.3+/-7.6 months. A battery of
      neuropsychological tests was applied before and 9 months after the implant.
      RESULTS: Parkinsonian features improved in all patients--the greatest change seen
      in rigidity, then tremor, followed by bradykinesia. Compared with the presurgical
      condition, off-drug UPDRS motor scores improved by 41.9% on the last visit (p =
      0.0002), UPDRS activities of daily living (ADL) scores improved by 52.2% (p =
      0.0002), and the Schwab & England scale score improved by 213% (p = 0.0002). The
      levodopa-equivalent daily dose was reduced by 65%. Night sleep improved in all
      patients due to increased mobility at night, and in five patients insomnia was
      resolved. All patients gained weight after surgery and their appetite increased.
      The mean weight gain at the last follow-up was 13% compared with before surgery.
      During the last visit, the stimulation amplitude was 2.9+/-0.5 V and the total
      energy delivered per patient averaged 2.7+/-1.4 W x10(-6). The results of patient
      self-assessment scales indicated a marked improvement in five patients and a
      moderate improvement in the other two. The neuropsychological data showed no
      changes. Side effects were mild and tolerable. In all cases, a tradeoff between
      the optimal voltage and the severity of side effects made it possible to control
      parkinsonian signs effectively. The most marked side effects directly related to
      STN stimulation consisted of ballistic or choreic dyskinesias of the neck and the
      limbs elicited by contralateral STN stimulation above a given threshold voltage,
      which varied depending on the individual. CONCLUSIONS: Parkinsonian signs can be
      controlled by bilateral high-frequency STN stimulation. The procedure is well
      tolerated. On-state dyskinesias were greatly reduced, probably due to the
      reduction of total antiparkinsonian medication. Bilateral high-frequency STN
      stimulation compensated for drug reduction and elicited dyskinesias, which differ
      from those observed following dopaminergic medication. ADL improved
      significantly, suggesting that some motor tasks performed during everyday chores,
      and that are not taken into account in the UPDRS motor score, also improved.

PMID- 10408542
TI  - Short-term effects of high-dose 17beta-estradiol in postmenopausal PD patients: a
      crossover study.
AB  - OBJECTIVE: To examine the effect of 17beta-estradiol on the severity of the
      cardinal signs of PD in postmenopausal women. BACKGROUND: Although the impact of
      estrogens on the manifestations of PD has not been subjected to rigorous study,
      their use is generally thought to be associated with a detrimental
      antidopaminergic effect. METHODS: A double-blind, placebo-controlled, two-arm
      crossover study of high-dose transdermal 17beta-estradiol was conducted in eight
      postmenopausal women with mild to moderate PD, all but one of whom exhibited
      levodopa-induced dyskinesias. Patients were randomized initially to either
      hormonal treatment or placebo for 2 weeks, followed by a 2-week washout period,
      and then another 2-week crossover treatment period. Active treatment employed
      four skin patches each releasing 0.1 mg of estradiol daily, replaced every 2 to 3
      days. RESULTS: After 10 days of treatment a significant reduction was observed in
      the antiparkinsonian threshold dose of IV levodopa. Mean duration and magnitude
      of the antiparkinsonian response to threshold or high doses of levodopa were
      unchanged, and dyskinesia scores were unaltered during 17beta-estradiol treatment
      compared with placebo. No worsening in "on" time or motor ratings with estrogen
      treatment was documented. CONCLUSIONS: 17beta-estradiol appears to display a
      slight prodopaminergic (or antiparkinsonian) effect without consistently altering
      dyskinesias. Standard postmenopausal replacement therapy with transdermal 17beta
      estradiol is likely to be well tolerated by many female parkinsonian patients.

PMID- 10408543
TI  - Deficient activation of the motor cortical network in patients with writer's
      cramp.
AB  - OBJECTIVE: To study regional cerebral blood flow (rCBF) in patients with simple
      writer's cramp using PET to identify regions that malfunction. BACKGROUND:
      Several lines of evidence indicate impaired cortical function in patients with
      focal dystonia, but the precise pathophysiology is still unknown. METHODS: Seven
      patients with writer's cramp were compared with seven age- and sex-matched
      control subjects. Control subjects and patients were scanned during sustained
      contraction, tapping, and writing with the right hand. After realignment and
      stereotactic normalization of the scans, all tasks were compared with a rest
      condition. For each task, an intra- and intergroup comparison was performed using
      statistical parametric mapping. For each condition and within groups, rCBF
      correlation analysis was performed between some selected regions that were
      activated during movement. RESULTS: In control subjects and patients, significant
      increases of rCBF were observed for each task in areas already known to be
      activated in motor paradigms. The intergroup comparison disclosed less activation
      in writer's cramp patients for several areas for all three tasks. This decrease
      reached significance for the sensorimotor cortex during the sustained contraction
      task and for the premotor cortex during writing. rCBF correlation analysis showed
      different patterns between control subjects and patients. At rest and during
      writing, the correlations between the putamen and premotor cortical regions and
      between the premotor cortical regions themselves were stronger in control
      subjects. CONCLUSIONS: Deficient activation of premotor cortex and decreased
      correlation between premotor cortical regions and putamen suggest a dysfunction
      of the premotor cortical network in patients with writer's cramp possibly arising
      in the basal ganglia. The dysfunction is compatible with a loss of inhibition
      during the generation of motor commands, which in turn could be responsible for
      the dystonic movements.

PMID- 10408544
TI  - Long-term reorganization of motor cortex outputs after arm amputation.
AB  - OBJECTIVE: To investigate the reorganization of the corticospinal system long
      after arm amputation at different levels. METHODS: Focal transcranial magnetic
      stimulation (TMS) was performed in 15 patients 21 to 65 years after arm
      amputation at the level of the forearm, upper arm, or shoulder. Cortically
      elicited electromyographic responses were investigated in muscles immediately
      proximal to the stump. TMS was performed on a skull surface grid overlying the
      motor cortex. The response threshold, number of effective stimulation sites, and
      the sum of the amplitudes elicited at these sites were evaluated for slightly
      contracted muscles. RESULTS: Seven of eight patients with forearm amputation had
      larger stimulation effects in the biceps supplied by the motor cortex
      contralateral to amputation, as indicated by variable patterns of lowered
      response thresholds, increased response amplitudes, or increased numbers of
      effective stimulation sites. In seven patients with a more proximal amputation,
      the motor responses were investigated in the deltoid and trapezoid muscle. In
      only two of them, the motor cortex contralateral to amputation showed an
      increased excitability. Three patients presented with a higher excitability of
      the motor cortex contralateral to the intact arm and two with a balanced type of
      excitability. CONCLUSION: Reorganization of the motor system can be present more
      than 20 years after amputation. Furthermore, differential patterns of reorganized
      corticospinal output were found for different stump muscles, which might be due
      to varying amounts of ipsilateral corticospinal projections.

PMID- 10408545
TI  - An analysis of the costs of ischemic stroke in an Italian stroke unit.
AB  - OBJECTIVE: To determine the direct costs of hospital care of acute ischemic
      stroke in a large Italian hospital, and to identify the main components of such
      costs. BACKGROUND: Cost containment in stroke care requires an up-to-date
      assessment of expenditures in the different areas of stroke management. However,
      costs may vary among countries because of different health system organizations.
      METHODS: All patients with ischemic stroke admitted during 1996 were considered.
      Total cost was the sum of a daily component, reflecting personnel wages and
      general care, and an ancillary component, reflecting mostly investigations and
      treatments. The real costs were used, not fixed charges. RESULTS: We included 245
      patients, with a mean length of stay (LOS) of 13.1+/-7.0 days, and an in-hospital
      case fatality rate of 8.2%. The mean total cost per patient was 5,087,000+/
      2,536,000 Italian Lira (LIT; $3,289+/-$1,640), with a mean cost per day of
      388,000 LIT ($251). Approximately 80% of total costs were due to the daily
      component and 20% to the ancillary component. A multiple linear regression model
      of length of stay, which determines the daily cost, showed that the Rankin score
      at entry, the clinical syndrome type, and the destination at discharge
      independently contributed to LOS. A second linear regression model showed that
      younger age and longer LOS significantly increased ancillary costs. CONCLUSIONS:
      The containment of hospital costs of ischemic stroke may be achieved mostly
      through measures that reduce LOS, such as effective treatments and a quicker
      deployment.

PMID- 10408546
TI  - Long-term follow-up of aneurysms developed during extracranial internal carotid
      artery dissection.
AB  - OBJECTIVE: To evaluate the clinical course of aneurysms developed during
      extracranial internal carotid artery (ICA) dissection. BACKGROUND: Aneurysms
      developed during extracranial ICA dissection are detected angiographically in 5
      to 40% of cervical artery dissections. The clinical and radiologic course of
      these aneurysms is not known, and it is not known how they should be treated.
      METHODS: Fifty-eight consecutive patients with extracranial ICA dissection were
      reviewed, and those with radiographically detectable dissecting aneurysm at the
      acute stage or during early follow-up were included in this study. All patients
      had regular clinical and MR angiography examinations. Sixteen patients (27.5%)
      with a total of 20 ICA dissecting aneurysms were followed for a mean period of
      36.9+/-21 months (range, 10 to 93 months). RESULTS: No clinical symptoms
      suggestive of aneurysmal rupture or embolization from the aneurysm were
      identified. Extracranial ICA aneurysms remained unchanged in 65% of patients,
      were resolved in 5% of patients, and decreased in size in 30% of patients.
      CONCLUSIONS: The clinical course of dissecting aneurysms was benign, although
      spontaneous radiologic resolution occurred rarely. Medical management with
      antiplatelet therapy alone (after early anticoagulation) is generally sufficient,
      and surgical management was seldom required.

PMID- 10408547
TI  - Antithrombotic treatment of ischemic stroke among patients with occlusion or
      severe stenosis of the internal carotid artery: A report of the Trial of Org
      10172 in Acute Stroke Treatment (TOAST).
AB  - OBJECTIVE: To examine the responses to early IV administration of an
      anticoagulant or placebo started within 24 hours of stroke among persons with an
      ipsilateral occlusion or severe stenosis of the internal carotid artery (ICA)
      identified by carotid duplex imaging. BACKGROUND: Patients with ischemic stroke
      of the cerebral hemisphere secondary to an ipsilateral occlusion or severe
      stenosis of the ICA generally have a poor prognosis. Early, accurate
      identification of these patients might permit improved treatment. METHODS:
      Exploratory analysis of outcomes at 7 days and 3 months was performed among
      patients enrolled in the Trial of Org 10172 in Acute Stroke Treatment (TOAST) who
      had an ischemic stroke in the cerebral hemisphere ipsilateral to an occlusion or
      a stenosis >50% of the ICA identified by carotid duplex imaging. RESULTS:
      Regardless of treatment, patients with duplex evidence of an occlusion of the ICA
      had more severe strokes and poorer outcomes at 7 days and 3 months than patients
      who had a stenosis. Favorable outcomes at 7 days were noted in 64 of 119 patients
      given danaparoid (53.8%) and 41 of 108 patients treated with placebo (38.0%; p =
      0.023). By 3 months, favorable outcomes were noted in 82 patients given
      danaparoid (68.3%) and 58 patients administered placebo (53.2%; p = 0.021).
      CONCLUSIONS: Early identification by duplex imaging of an occlusion or severe
      stenosis of the ICA ipsilateral to a hemispheric ischemic stroke might improve
      selection of patients who could be treated with emergent anticoagulation. Further
      testing of this approach is needed.

PMID- 10408549
TI  - MRI white matter hyperintensities: three-year follow-up of the Austrian Stroke
      Prevention Study.
AB  - OBJECTIVE: To determine the rate, clinical predictors, and cognitive consequences
      of MRI white matter hyperintensity evolution over 3 years. METHODS: In the
      setting of the Austrian Stroke Prevention Study, 1.5-T MRI was performed at
      baseline and at a 3-year follow-up in 273 community-dwelling elderly (mean age,
      60+/-6.1 years) without neuropsychiatric disease. At each visit individuals
      underwent a structured clinical interview and examination, EKG, echocardiography,
      extensive laboratory workup, and demanding neuropsychological testing. MR images
      were read by three independent raters, and the change of white matter
      hyperintensities from baseline was assessed by direct image comparison. The
      change was graded as absent, minor, or marked. Minor change was defined as a
      difference of no more than one to four punctate lesions between both scans. A
      change was considered to be marked if there was a difference of more than four
      abnormalities or a transition to early-confluent and confluent lesions. RESULTS:
      Combined ratings indicated lesion progression in 49 individuals (17.9%). Lesion
      progression was minor in 27 participants (9.9%) and was marked in 22 (8.1%).
      Regression of white matter hyperintensities did not occur. Diastolic blood
      pressure (odds ratio, 1.07/mm Hg) and early-confluent or confluent white matter
      hyperintensities at baseline (odds ratio, 2.62) were the only significant
      predictors of white matter hyperintensity progression. Lesion progression had no
      influence on the course of neuropsychological test performance over the
      observational period. CONCLUSIONS: White matter hyperintensities progress in
      elderly normal subjects. Our data may be used as a reference for future
      observational and interventional studies on white matter hyperintensity
      progression in various CNS diseases. The lack of an association between lesion
      progression and cognitive functioning needs to be explored further.

PMID- 10408548
TI  - Baseline NIH Stroke Scale score strongly predicts outcome after stroke: A report
      of the Trial of Org 10172 in Acute Stroke Treatment (TOAST).
AB  - OBJECTIVE: To compare the baseline National Institutes of Health Stroke Scale
      (NIHSS) score and the Trial of Org 10172 in Acute Stroke Treatment (TOAST) stroke
      subtype as predictors of outcomes at 7 days and 3 months after ischemic stroke.
      METHODS: Using data collected from 1,281 patients enrolled in a clinical trial,
      subtype of stroke was categorized using the TOAST classification, and neurologic
      impairment at baseline was quantified using the NIHSS. Outcomes were assessed at
      7 days and 3 months using the Barthel Index (BI) and the Glasgow Outcome Scale
      (GOS). An outcome was rated as excellent if the GOS score was 1 and the BI was 19
      or 20 (scale of 0 to 20). Analyses were adjusted for age, sex, race, and history
      of previous stroke. RESULTS: The baseline NIHSS score strongly predicted outcome,
      with one additional point on the NIHSS decreasing the likelihood of excellent
      outcomes at 7 days by 24% and at 3 months by 17%. At 3 months, excellent outcomes
      were noted in 46% of patients with NIHSS scores of 7 to 10 and in 23% of patients
      with scores of 11 to 15. After multivariate adjustment, lacunar stroke had an
      odds ratio of 3.1 (95% CI, 1.5 to 6.4) for an excellent outcome at 3 months.
      CONCLUSIONS: The NIHSS score strongly predicts the likelihood of a patient's
      recovery after stroke. A score of > or =16 forecasts a high probability of death
      or severe disability whereas a score of < or =6 forecasts a good recovery. Only
      the TOAST subtype of lacunar stroke predicts outcomes independent of the NIHSS
      score.

PMID- 10408550
TI  - A longitudinal study of brain atrophy in relapsing multiple sclerosis. The
      Multiple Sclerosis Collaborative Research Group (MSCRG).
AB  - OBJECTIVE: To determine if progressive brain atrophy could be detected over 1-
      and 2-year intervals in relapsing MS, based on annual MR studies from the
      Multiple Sclerosis Collaborative Research Group (MSCRG) trial of interferon beta
      1a (Avonex). METHODS: All subjects had mild to moderate disability, with baseline
      expanded disability status scores ranging from 1.0 to 3.5, and at least two
      relapses in the 3 years before study entry. Atrophy measures included third and
      lateral ventricle width, brain width, and corpus callosum area. RESULTS:
      Significant increases were detected in third ventricle width at year 2 and
      lateral ventricle width at 1 and 2 years. Significant decreases in corpus
      callosum area and brain width were also observed at 1 and 2 years. Multiple
      regression analyses suggested that the number of gadolinium-enhancing lesions at
      baseline was the single significant contributor to change in third ventricle
      width. Atrophy over 1 and 2 years as indicated by enlargement of the third and
      lateral ventricle and shrinkage of the corpus callosum was greater for patients
      entering the trial with enhancing lesions. Greater disability increments over 1
      and 2 years were associated with more severe third ventricle enlargement.
      CONCLUSION: In patients with relapsing MS and only mild to moderate disability,
      significant cerebral atrophy is already developing that can be measured over
      periods of only 1 to 2 years. The course of cerebral atrophy in MS appears to be
      influenced by prior inflammatory disease activity as indicated by the presence of
      enhancing lesions. Brain atrophy measures are important markers of MS disease
      progression because they likely reflect destructive and irreversible pathologic
      processes.

PMID- 10408551
TI  - A longitudinal study of cerebral glucose metabolism, MRI, and disability in
      patients with MS.
AB  - OBJECTIVE: To study the time-related changes in cerebral metabolic rate of
      glucose (CMRglc) in MS patients and to correlate these with changes in MRI lesion
      load and disability. BACKGROUND: Measurements of MRI lesion load and neurologic
      disability are used widely to monitor disease progression in longitudinal studies
      of MS patients, but little is known about the associated changes in cerebral
      neural function. METHODS: The authors studied 10 patients with clinically
      definite MS who underwent serial measurements of CMRglc, MRI T2-weighted total
      lesion area (TLA), and clinical evaluation of disability (Expanded Disability
      Status Scale [EDSS]) over a period of approximately 2 years (three examinations).
      CMRglc was calculated using PET and 18-fluorodeoxyglucose (FDG). RESULTS: The
      global cortical CMRglc decreased with time (p<0.001) and the most pronounced
      reductions of CMRglc were detected in frontal and parietal cortical areas. There
      was a statistically significant increase of disability (p<0.01) and TLA (p<0.05)
      measurements during the study, but changes in CMRglc were not correlated to
      changes in TLA and EDSS. CONCLUSIONS: Global cortical cerebral metabolism in MS
      is decreased significantly during a 2-year observation period, suggesting a
      deterioration of cortical activity with disease progression. The time-related
      changes of cortical CMRglc are statistically stronger than changes in TLA
      measurements and neurologic disability, and might be a useful secondary measure
      of treatment efficacy.

PMID- 10408553
TI  - Seizure frequency and the health-related quality of life of adults with epilepsy.
AB  - OBJECTIVE: To compare the health-related quality of life (HRQL) of a nonsurgical
      sample of adults with epilepsy with that of age- and gender-equivalent norms, and
      to analyze the relative importance of seizure frequency, time since last seizure,
      gender, and comorbidity on HRQL in the epilepsy sample. METHODS: Data were
      obtained from 139 adults with epilepsy from three US centers and published norms
      on the Medical Outcomes Study Short-Form 36 (SF-36). Patients were classified
      according to number of seizures over the prior 4 weeks (zero, one to five, six or
      more). Bivariate and multivariate modeling was used. RESULTS: HRQL scores for
      seizure-free patients were similar to the general population. Significant
      differences between seizure frequency groups were found for seven domains and the
      physical and mental component summary scales of the SF-36 (p<0.001). No
      differences were found in bodily pain. The largest differences were in physical
      role and social functioning, and general health (p<0.001). In the multivariate
      model, seizure frequency was a significant inverse predictor of HRQL across all
      domains (p<0.01 to 0.001). Men reported poorer physical function than women
      (p<0.05), and patients with a comorbid condition had poorer HRQL in the areas of
      pain (p<0.05) and general health perception (p<0.01). Time since last seizure was
      not related uniquely to HRQL. CONCLUSIONS: Seizure-free adults can have HRQL
      levels comparable with those of the general population. As seizure frequency
      increases, patients report more impaired HRQL, regardless of time since last
      seizure, gender, and comorbid status. Potential for difficulties in HRQL should
      be considered in clinical assessment and in evaluating treatment outcomes.

PMID- 10408552
TI  - A humoral response to oligodendrocyte-specific protein in MS: a potential
      molecular mimic.
AB  - OBJECTIVE: To determine the antibody response to oligodendrocyte-specific protein
      (OSP) in patients with MS. BACKGROUND: OSP is a recently identified CNS-specific
      myelin protein that is abundant and therefore a candidate autoantigen in MS.
      METHODS: The presence of anti-OSP antibodies was determined using Western blot
      analysis, peptide blots, and ELISA in patients with MS and in other neurologic
      and normal control subjects. RESULTS: Using Western blot analysis, seven patients
      with relapsing-remitting MS (RRMS) were found to contain anti-OSP antibodies in
      their CSF that were not present in control subjects. Peptide mapping determined
      that the antibody response was directed to a seven aa peptide (OSP 114-120),
      which has 71% homology with several common pathogenic proteins. Using OSP 114-120
      as antigen, ELISAs were performed on CSF from 85 MS and 51 control patients.
      Eighty percent of the samples from RRMS patients followed at the University of
      California at Los Angeles had an ELISA reading above 0.55 optical density units,
      whereas all 20 control CSF samples had values less than 0.55 U. Similar results
      were found in specimens from an outside research bank. ELISAs performed on CSF
      using homologous viral peptides as antigen showed a close correlation with anti
      OSP 114-120 ELISA readings, and in some, the readings were higher than those
      using OSP peptides. CONCLUSIONS: There is a specific humoral response directed
      against a region of OSP in RRMS patients that cross-reacts with several common
      viral peptides. This suggests a possible role for molecular mimicry in the
      development of MS.

PMID- 10408554
TI  - Visual field defects after temporal lobe resection: a prospective quantitative
      analysis.
AB  - OBJECTIVE: To evaluate and quantify prospectively visual field changes in
      patients undergoing temporal lobe resections for intractable epilepsy.
      BACKGROUND: Visual field abnormalities occur after temporal lobe resections for
      epilepsy; however, we have not encountered published reports using automated
      static visual field analysis. METHODS: Humphrey visual fields (program 30-2) were
      obtained before and after partial temporal lobe resection in 32 consecutive
      patients with intractable epilepsy. A quantitative point-by-point analysis was
      made in the affected superior quadrant, and the defects were averaged for the
      whole patient group. RESULTS: Thirty-one patients developed a visual field
      defect, but none was aware of the defect. The points nearest fixation were
      relatively spared. The defects were greatest in the sector closest to the
      vertical meridian in the eye ipsilateral to the resection. The ipsilateral and
      contralateral mean field defects also differed in both topography and depth. A
      significant correlation was found between the extent of lateral temporal lobe
      resection and the degree of the defect in the contralateral eye. CONCLUSIONS:
      There are differences in the shape and depth of the ipsilateral and the
      contralateral field defects not previously reported. These findings demonstrate
      that certain fibers from the ipsilateral eye travel more anteriorly and laterally
      in Meyer's loop, and support the hypothesis that visual field defects due to
      anterior retrogeniculate lesions are relatively incongruous because of anatomic
      differences in the afferent pathways. Automated perimetry is a sensitive method
      of evaluating and quantifying visual field defects.

PMID- 10408555
TI  - Diffusion mapping applied to mesial temporal lobe epilepsy: preliminary
      observations.
AB  - OBJECTIVE: To evaluate whether diffusion mapping could lateralize intractable
      seizures in mesial temporal lobe epilepsy (MTLE) patients. BACKGROUND: Animal
      seizure models show acute postictal depression of the apparent diffusion
      coefficient of water (ADCw), interictal normalization, then chronic elevation.
      METHODS: The hippocampal plane was imaged with five diffusion weightings along
      each axis. Three orthogonal ADCw maps were averaged to produce an isotropic ADCw
      map. RESULTS: In all eight MTLE patients, ADCw was elevated by a mean of 10+/-3%
      (p<0.01, paired t-test) interictally in the ipsilateral hippocampus, where side
      of seizure focus was determined electrographically with corroboration by
      volumetric MRI studies. Measured ADCw values in phantoms and five normal brains
      agree with published values. CONCLUSIONS: Brain tissue with interictally
      increased ADCw may represent an epileptogenic region with neuronal loss, gliosis,
      and expanded extracellular space (hippocampal sclerosis). Thus, diffusion mapping
      may confirm seizure lateralization.

PMID- 10408556
TI  - Pathologic findings in a steroid-responsive optic nerve infarct in giant-cell
      arteritis.
AB  - OBJECTIVE: To investigate the pathophysiologic mechanism of optic nerve
      infarction in giant-cell arteritis (GCA). BACKGROUND: Previous pathologic reports
      of optic nerve infarction in GCA involved patients who were blind at the time of
      death. The optic nerve infarcts were primarily retrolaminar in localization.
      Simultaneous short ciliary and ophthalmic artery vasculitis was found in all
      patients. METHODS: Clinical neurologic and ophthalmologic examination, temporal
      artery biopsy, and neuroimaging tests were performed in a patient with an
      anterior ischemic optic neuropathy secondary to GCA. Pathologic examination of
      the viscera, eye, and brain were performed at autopsy 1 month later. RESULTS: A
      prelaminar/retrolaminar infarct was found in this patient. Subsiding vasculitis
      was limited to the short ciliary arteries, sparing the central retinal, pial, and
      ophthalmic arteries. CONCLUSIONS: The authors believe that the visual improvement
      observed in this patient was the result of preserved, anterior optic nerve
      collateral circulation, as well as the neuroprotective and anti-inflammatory
      effect of the corticosteroids.

PMID- 10408557
TI  - An inherited prion disease with a PrP P105L mutation: clinicopathologic and PrP
      heterogeneity.
AB  - OBJECTIVE: To clarify a clinical and neuropathologic phenotype of an inherited
      prion disease associated with a missense mutation at codon 105 in the prion
      protein (PrP) gene that was originally described as a variant of Gerstmann
      Straussler-Scheinker disease demonstrating spastic paraparesis. METHODS: Two
      siblings from a Japanese family are described. PrP gene analyses, neuropathologic
      studies with immunohistochemistry, and Western blot analysis of the PrP were
      performed. RESULTS: Both patients showed a missense (proline-->leucine) mutation
      at codon 105 and a methionine/valine polymorphism at codon 129 of the PrP gene.
      Clinically, Patient 1 presented with progressive spastic paraparesis, ataxia, and
      dementia. Patient 2, the sister of Patient 1, showed prominent action myoclonus
      and dementia. Neuropathologically, multiple PrP-positive amyloid plaques and
      diffuse PrP deposition in the deep cortical layers were found in the cerebral
      cortex with primarily frontal dominant atrophy in both patients. Tau-positive
      pathologic structures including neurofibrillary tangles, neuropil threads, and
      dystrophic neurites around the plaques were abundant in the brain of Patient 2.
      In contrast, the tau pathology was scarce in Patient 1. Western blot analysis of
      the brain showed different patterns of detergent-insoluble PrP fragments between
      the patients. CONCLUSIONS: Despite the identical codon 105 mutation and codon 129
      polymorphism of the PrP gene, remarkable clinical and neuropathologic
      differences, and PrP heterogeneity were present between the affected siblings.
      The phenotypic variability might be related to PrP heterogeneity.

PMID- 10408558
TI  - Relation of education to brain size in normal aging: implications for the reserve
      hypothesis.
AB  - OBJECTIVE: To examine the relations between education and age-related changes in
      brain structure in a nonclinical sample of elderly adults. BACKGROUND: Education
      may protect against cognitive decline in late life--an observation that has led
      to the "reserve" hypothesis of brain aging. Little is known, however, about the
      effect of education on age-related changes in brain structure. METHODS:
      Quantitative MRI of the brain was performed in 320 elderly volunteers (age range,
      66 to 90 years) living independently in the community (Mini-Mental State
      Examination scores > or =24), all of whom were participants in the Cardiovascular
      Health Study. Blinded measurements of global and regional brain size were made
      from T1-weighted axial images using computer-assisted edge detection and trace
      methodology. High measurement reliabilities were obtained. RESULTS: Regression
      analyses (adjusting for the effects of intracranial size, sex, age, age-by-sex
      interactions, and potential confounders) revealed significant main effects of
      education on peripheral (sulcal) CSF volume-a marker of cortical atrophy. Each
      year of education was associated with an increase in peripheral CSF volume of
      1.77 mL (p<0.03). As reported previously, main effects of age (but not education)
      were observed for all of the remaining brain regions examined, including cerebral
      hemisphere volume, frontal region area, temporoparietal region area, parieto
      occipital region area, lateral (Sylvian) fissure volume, lateral ventricular
      volume, and third ventricle volume. CONCLUSIONS: The authors' findings
      demonstrate a relation between education and age-related cortical atrophy in a
      nonclinical sample of elderly persons, and are consistent with the reserve
      hypothesis as well as with a small number of brain imaging studies in patients
      with dementia. The neurobiological basis and functional correlates of this
      education effect require additional investigation.

PMID- 10408559
TI  - A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's
      disease.
AB  - BACKGROUND: Previous studies suggest a potential benefit from nonsteroidal anti
      inflammatory drugs (NSAIDs) in Alzheimer's disease (AD). Prescribing NSAIDs,
      however, carries the risk of significant gastrointestinal adverse events.
      OBJECTIVES: To study whether treatment with an NSAID prevents expected decline in
      AD patients and evaluate whether co-administration of the gastro-protective
      agent, misoprostol, with an NSAID is safe in AD. METHODS: The efficacy and safety
      of diclofenac in combination with misoprostol (D/M) was evaluated in 41 patients
      with mild-moderate AD in a prospective 25-week, randomized, double-blind placebo
      controlled trial. Efficacy measures comprised the Alzheimer's Disease Assessment
      Scale cognitive and noncognitive subsections, Global Deterioration Scale,
      Clinical Global Impression of Change, Mini-Mental State Examination, Instrumental
      Activities of Daily Living, Physical Self-Maintenance Scale, and a caregiver
      rated Global Impression of Change. RESULTS: There were no group differences with
      any of the outcome measures in an intent-to-treat analysis. There were some
      nonsignificant trends for the placebo group to have deteriorated more than the
      D/M-treated patients. Withdrawal rates were 12 of 24 in the D/M group and 2 of 17
      in the placebo group. There were no serious drug-related adverse events.
      CONCLUSIONS: This pilot study, with small treatment numbers, did not demonstrate
      a significant effect of NSAID treatment in AD, but the trends observed justify
      further investigations with a larger number of participants. D/M is safe in AD
      patients, but its tolerability is not optimal.

PMID- 10408560
TI  - Preclinical memory decline in cognitively normal apolipoprotein E-epsilon4
      homozygotes.
AB  - OBJECTIVE: To determine, in a cross-sectional evaluation of nondemented
      individuals, if age-related memory decline is influenced by apolipoprotein E
      (apoE) genotype. BACKGROUND: The apoE-4 allele is an important risk factor for
      AD. PET in cognitively normal apoE-4 carriers (mean age, 56 years) shows reduced
      cerebral metabolism suggestive of very early AD that precedes clinically evident
      memory loss or MRI-based hippocampal atrophy. METHODS: Tests of immediate and
      delayed recall (primary outcome measures) and other neuropsychological measures
      (secondary outcome measures) were given to three genetically defined groups of
      cognitively normal individuals (age, 49 to 69 years) including apoE-4 homozygotes
      (n = 25), apoE-4 heterozygotes (n = 25, all epsilon3/4), and apoE-4 noncarriers
      (n = 50). Groups were matched for age, gender, and educational background. Cross
      sectional comparisons between the genetic subgroups of the relationship between
      age and test score were performed for each neuropsychological measure. RESULTS:
      There were no intergroup differences in mean scores on any neuropsychological
      measure, but tests sensitive to immediate and delayed recall showed a significant
      negative correlation with age in the apoE-4 homozygote group relative to the
      noncarrier group. CONCLUSION: Consistent with previous neuropsychological studies
      of early AD, this cross-sectional study suggests that age-related memory decline
      occurs earlier in cognitively healthy apoE-4 homozygotes than in apoE-4
      heterozygotes and noncarriers, and precedes clinically detectable AD.

PMID- 10408561
TI  - VHL gene inactivation in an endolymphatic sac tumor associated with von Hippel
      Lindau disease.
AB  - The authors present a case of endolymphatic sac tumor, a rare adenomatous tumor
      of the temporal bone, in a patient with von Hippel-Lindau (VHL) disease.
      Sequencing and microsatellite analysis of DNA samples from the tumor showed a 1
      base pair deletion in exon 1 of the VHL gene and loss of heterozygosity at
      chromosome 3p25.5, the locus for the VHL gene. The results indicate that VHL gene
      inactivation contributed to the oncogenesis of endolymphatic sac tumor and
      provide molecular genetic proof that this tumor is associated with VHL disease.

PMID- 10408562
TI  - Transient MRI enhancement in a patient with seizures and previously resected
      glioma: use of MRS.
AB  - A 35-year-old man presented with partial seizures 10 years after resection of a
      left-sided glioblastoma multiforme. At the old operative site MRI demonstrated
      extensive cortical and white matter gadolinium enhancement, and PET showed
      hypermetabolism. Biopsy of the area was postponed when MRS showed a normal
      biochemical spectrum. MRI and PET abnormalities resolved after control of the
      seizures. MRS is noninvasive and can provide essential information in the
      management of patients with seizures and previously treated cerebral neoplasms.

PMID- 10408563
TI  - Trigeminal neuropathy secondary to perineural invasion of head and neck
      carcinomas.
AB  - Perineural spread of head and neck cancer is an uncommon cause of cranial
      neuropathy. We studied five patients with cranial neuropathy resulting from
      perineural spread of head and neck carcinomas. Trigeminal neuropathy with facial
      pain or paresthesias was the most common clinical manifestation. MRI in the
      coronal plane under gadolinium enhancement established the diagnosis by
      visualization of the lower divisions of the trigeminal nerve. Perineural tumor
      spread can cause headaches in patients with head and neck cancer.

PMID- 10408564
TI  - Familial trigeminal neuralgia and contralateral hemifacial spasm.
AB  - A patient was evaluated with familial trigeminal neuralgia (TN) and contralateral
      hemifacial spasm. The mother of the patient, 5 of 10 siblings, and 1 nephew also
      had TN confirmed by neurologists. The transmission of TN was suggestive of an
      autosomal dominant inheritance. This family provides additional evidence of a
      genetic basis for TN in selected cases and also provokes further speculation on a
      common unifying hypothesis of pathophysiology in cranial rhizopathies.

PMID- 10408565
TI  - Relative risk of Creutzfeldt-Jakob disease with cadaveric dura transplantation in
      Japan.
AB  - By May 1996, 43 cases of Creutzfeldt-Jakob disease with cadaveric dura
      transplantation were reported during a nationwide survey in Japan. With the
      assumption that the number of patients receiving the transplantation each year
      was 20,000, the incidence of the disease among patients receiving cadaveric dura
      grafts was compared with the annual incidence in the general population.
      Cumulative incidence was between 0.017 and 0.048%. The estimated relative maximum
      risk was 104.9, and even the minimum relative risk was as high as 29.2.

PMID- 10408566
TI  - Lethal capillary leak syndrome after a single administration of interferon beta
      1b.
AB  - Interferon beta-1b (IFNbeta-1b) is a potent immunomodulatory drug in the
      treatment of MS. We report a lethal capillary leak syndrome after the
      administration of IFNbeta-1b in a patient with disseminated white matter disease,
      monoclonal gammopathy, and acquired C1 inhibitor (C1-INH) deficiency. IFNbeta-1b
      may cause a transient release of proinflammatory cytokines finally resulting in
      an uninhibited activation of the complement cascade in patients with C1-INH
      deficiency.

PMID- 10408567
TI  - Antibodies to prothrombin in patients with Sneddon's syndrome.
AB  - Antiprothrombin antibodies (aPT), a new serologic marker of antiphospholipid
      syndrome, were studied in 46 patients randomly selected from 73 with Sneddon's
      syndrome and 20 matched normal controls. aPT were elevated in 26 patients (57%)
      and were not found in any of the controls. The addition of aPT data increased the
      proportion of Sneddon's syndrome patients with at least one type of
      antiphospholipid syndrome marker from 65 to 78%. The finding that aPT are common
      in Sneddon's syndrome supports the hypothesis that Sneddon's syndrome is a form
      of antiphospholipid syndrome.

PMID- 10408568
TI  - Multiple cerebral infarctions associated with ovarian hyperstimulation syndrome.
AB  - A 26-year-old woman on human menopausal gonadotrophin-human chorionic
      gonadotrophin therapy for sterility showed multiple cerebral infarctions
      associated with ovarian hyperstimulation syndrome. A hypercoagulable state
      (hemoconcentration, increased plasma levels of D-dimer and thrombin-antithrombin
      III complex, and decreased protein S activity) was associated with her
      thromboembolic events. Cerebral infarction associated with mild neurologic
      deficits may be overlooked in patients with ovarian hyperstimulation syndrome.

PMID- 10408569
TI  - Small head size is related to low Mini-Mental State Examination scores in a
      community sample of nondemented older adults.
AB  - The objective of this analysis was to determine the relationship, if any, of head
      size to performance on a cognitive screening test among elderly nondemented
      adults participating in a community-based survey. The study sample included 825
      subjects (533 women, 292 men), age 70 to 95 years. Multivariate analyses, with
      adjustment for age and education, revealed that smaller head size was associated
      with low Mini-Mental State Examination (MMSE) scores (i.e., below the 10th
      percentile) in both men and women. For every 1-centimeter increment in head size,
      there was a corresponding reduction of approximately 20% in the probability of a
      low MMSE score.

PMID- 10408570
TI  - Serum leptin changes in epileptic patients who gain weight after therapy with
      valproic acid.
AB  - Weight gain has been recognized as an adverse effect of valproic acid therapy,
      but there are are no data about serum leptin levels in patients receiving this
      drug. To evaluate if valproic acid treatment in epileptic patients in whom
      obesity develops modifies serum levels of insulin and leptin, 40 female patients
      with epilepsy were evaluated before therapy and after 1 year of therapy. At the
      end of follow-up, 15 patients were obese and showed higher serum leptin and
      insulin levels than patients who did not gain weight. As in other types of
      obesity, elevation of serum leptin concentrations is related to the increase in
      body mass index.

PMID- 10408572
TI  - Cerebral amyloid angiopathy with unilateral hemorrhages, mass effect, and
      meningeal enhancement.

PMID- 10408571
TI  - Cerebrospinal fluid findings in CADASIL.

PMID- 10408573
TI  - Topiramate-treated cluster headache.

PMID- 10408575
TI  - De novo status epilepticus due to multiple cerebral hamartomas.

PMID- 10408574
TI  - Atherosclerosis is not implicated in association of APOE epsilon4 with AD.

PMID- 10408576
TI  - A guideline for discontinuing antiepileptic drugs in seizure-free patients.

PMID- 10408577
TI  - Perfusion- and diffusion-weighted magnetic resonance imaging in transient global
      amnesia.

PMID- 10408578
TI  - Facilitory paratonia and frontal lobe functioning.

PMID- 10408579
TI  - Distinct light microscopic changes in HIV-associated nemaline myopathy.

PMID- 10408580
TI  - Varicella zoster virus-associated focal vasculitis without herpes zoster.

PMID- 10408581
TI  - Brain size, head size, and intelligence quotient in monozygotic twins.

PMID- 10408582
TI  - Maculopathy in spinocerebellar ataxia type 7.

PMID- 10408583
TI  - Does the treatment of isolated systolic hypertension prevent dementia?

PMID- 10408584
TI  - Exercise and hypertension.

PMID- 10408585
TI  - The magnitude and duration of ambulatory blood pressure reduction following acute
      exercise.
AB  - The purpose of this study was to observe the magnitude and duration of the
      ambulatory blood pressure (BP) reduction following exercise and to identify the
      peak intervals of BP reduction throughout the 24-h diurnal period. Subjects were
      25 normo- (N = 116.7/ 78.2+/-10.0/7.2 mm Hg) and 21 hypertensive (H =
      140.8/96.9+/-13.9/9.6 mm Hg) adults. Twenty-four hour ambulatory blood pressures
      (SBP = systolic and DBP = diastolic) were recorded following exercise (E = 50 min
      @ 50% VO2 max) and during a non-exercise control day (C). The 24-h pressures were
      compared between the E and C days for (1) duration and magnitude of the BP
      reduction following exercise, and for (2) the time of day for the diurnal
      patterns to exhibit reductions in BP. No BP differences were found for N between
      E and C days. Significant reductions in BP were found for 24-h average SBP
      (decrease 6.8 mm Hg) and DBP (decrease 4.1 mm Hg), daytime (06.00-22.00 hrs) SBP
      (decrease 6.9 mm Hg) and DBP (decrease 3.3 mm Hg), and sleep (22.00-06.00) SBP
      (decrease 5.1 mm Hg) and DBP (decrease 4.4 mm Hg) for H subjects only. H also
      demonstrated an 11 h reduction in SBP (chi = decrease 8.3+/-2.2 mm Hg) and 4h
      reduction in DBP (chi = decrease 6.0+/-1.7 mm Hg) following exercise. For the
      diurnal variation, the peak interval of reduction in SBP (chi = 17.0+/-2.6 mm Hg)
      was for 11 h; from 11.00-21.00 hrs. For DBP, a significant reduction (chi =
      decrease 5.7+/-0.7 mm Hg) was found for 5 h; from 11.00-15.00 h. Thus, exercise
      reduces both systolic and diastolic BP for a significant length of time
      postexercise as well as reduces pressures during the time of day that typically
      exhibits higher diurnal pressures.

PMID- 10408586
TI  - A meta-analysis of randomised controlled trials (RCT) among healthy normotensive
      and essential hypertensive elderly patients to determine the effect of high salt
      (NaCl) diet of blood pressure.
AB  - To examine the effect of chronic NaCl ingestion on blood pressure (BP) in the
      elderly, a meta-analysis was undertaken of 11 randomised controlled trials of
      which five included patients > or =60 years of age only and six included patients
      with a mean age close to 60 years. The following databases were used: Medline,
      Embase, Current Contents, The Cochrane Library, the AMI and IPA databases. Mean
      erect systolic and diastolic blood pressures (SBP/DBP) on chronic (> or =9 weeks)
      high and low NaCl diets were recorded, the pooled mean effect, the pooled
      standard error and 95% confidence intervals (Cl) were calculated and linear
      regression was used to evaluate the potential association between NaCl intake and
      BP. When all trials were pooled, a chronic high NaCl diet significantly increased
      mean SBP and DBP by 5.58 mm Hg (95%Cl 4.31-6.85) and 3.5 mm Hg (95%Cl 2.62-4.38)
      respectively. There was a significant association between the level of NaCl
      intake and SBP (P = 0.05, r2 = 0.37) but not DBP (P = 0.76, r2 = 0.01). When
      trials were pooled separately, a chronic high NaCl diet increased SBP by 5.46 mm
      Hg (95%Cl 3.56-7.36) and DBP by 2.63 mm Hg (95%Cl 1.18-4.08) in trials including
      patients > or =60 years of age only, and increased SBP by 3.27 mm Hg (95%Cl 1.23
      5.31) and DBP by 2.69 mm Hg (95%Cl 1.44-3.94) in trials including patients with a
      mean age close to 60 years. These data suggest that a chronic high NaCl diet in
      elderly patients with essential hypertension is associated with an increase in
      SBP and DBP, the association is significant for both SBP and DBP but more marked
      for SBP than DBP, the effect is more pronounced the older the patient and NaCl
      dose strongly predicts SBP in older patients.

PMID- 10408587
TI  - Reproducibility of salt sensitivity testing using a dietary approach in essential
      hypertension.
AB  - To investigate the reproducibility of salt sensitivity testing using a dietary
      approach, 30 essential hypertensive patients underwent salt sensitivity testing
      on an outpatient basis twice with a 6 month interval. At both tests casual and 24
      h ambulatory blood pressure (24-h BP) was recorded on habitual diet, then after a
      6-day period on a low salt diet (aiming at 50 mmol/day), and finally after a 6
      day period on a high salt diet (supplementation with sodium chloride tablets
      aiming at 250 mmol/day). Subjects showing > or =10% increase in mean BP when
      changing from low to high dietary salt intake were classified as salt sensitive.
      Dietary salt intake was assessed as 24-h urinary sodium excretion. Based on 24-h
      BP recordings eight patients were characterised as salt sensitive (SS) and 22 as
      salt resistant (SR) in the first test, and three of the initial SS and 15 of the
      initial SR patients maintained their salt sensitivity status at the second test.
      Based on casual BP recordings 13 patients were characterised as SS and 17 as SR
      in the first test, and three of the initial SS and 13 of the initial SR patients
      maintained their salt sensitivity status at the second test. Thus, salt
      sensitivity status was reproducible in 60% when using 24-h BP, and in 53% when
      using casual BP measurements. There was no difference in baseline BP in dietary
      salt intake between the two tests. In the total study population, no significant
      correlation was found between the change in casual or 24-h BP during salt
      repletion in the first and second test. In conclusion casual and 24-h BP response
      to a 200 mmol/24h change in dietary salt intake is highly individual and varies
      over time. Characterisation of salt sensitivity using a dietary approach in out
      patients is reproducible in only 53-60% of the patients.

PMID- 10408588
TI  - Tracking and factors predicting rising in 'tracking quartile' in blood pressure
      from childhood to adulthood: Odense Schoolchild Study.
AB  - This prospective study determines the degree of tracking and investigates factors
      predicting a rise in blood pressure (BP) quartile in a cohort of 1369 subjects
      who were followed for 11 years from childhood into young adulthood. In 900 of
      these subjects BP, height, weight, physical fitness and BP responses to a maximal
      exercise testing were measured both at baseline and at follow-up. BP, weight,
      height and body mass index (BMI) were divided into sex-specific quartiles at both
      examinations. Tracking was evaluated by examining the tendency of remaining in
      the same quartile from baseline to follow-up and by measuring product-moment
      correlation coefficients. Tracking in the upper and lower quartile for BP,
      weight, height and BMI were significant. Odds ratios for staying in the upper or
      lower quartile through the follow-up period ranged from 1.6 to 2.4 for diastolic
      BP and from 2.1 to 3.1 for systolic BP. The range of correlation coefficients for
      the anthropometric measurements were 0.57-0.75, for diastolic BP 0.12-0.22 and
      for systolic BP 0.34-0.36 respectively. Changes in weight or relative weight as
      well as BP response to an exercise test were the factors which predicted a rise
      in quartile through the 11 years of follow-up. The existence of the inevitable
      regression to the mean problem in large longitudinal studies of BP was
      demonstrated by the finding of baseline BP being a significant factor in the
      prediction of rising in systolic, diastolic or both systolic and diastolic BP
      quartiles.

PMID- 10408589
TI  - Spectral analysis of heart rate variability in elderly non-dipper hypertensive
      patients.
AB  - To assess by autoregressive model the frequency domain heart rate variability
      (HRV) during clinostatism and after passive orthostatic load (head-up tilt), 81
      hypertensive and normotensive subjects (42 men and 39 women) were subdivided into
      four groups: 20 adult normotensive subjects (Group 1); 21 elderly normotensive
      subjects (Group 2); 20 elderly hypertensive subjects with nocturnal blood
      pressure (BP) falls (Group 3); and 20 elderly hypertensive subjects without
      nocturnal BP falls (Group 4). They were chosen to assess the influence of aging
      and arterial hypertension on sympathetic-parasympathetic balance. The age-related
      decrease observed in nearly all HRV spectral frequency components (normalised
      units [NUs], high frequency [HF] and low frequency [LF]) was reported in elderly
      patients in rest conditions. LF indexes resulted in decreases in Group 3 and
      these data seemed to be emphasised in Group 4. After passive tilt, spectral data
      were recorded as follows: 25.3+/-1.8 vs 17.8+/-2.2 HF, Group 2 vs Group 1,
      P<0.001; 72.5+/-0.8 vs 75.6+/-1.8 LF, P< 0.001, Group 2 vs Group 1. Both
      sympathetic and parasympathetic indexes were lower in Group 3 (44.6+/-1.1 vs
      72.5+/-0.8 LF, P< 0.001, Group 3 vs Group 2; 9.9+/-1.8 vs 25.3+/-1.8 HF, P <
      0.001, Group 3 vs Group 2) and data became clearer in Group 4 (8.5 2.1 vs 9.9+/
      1.8 HF, P< 0.001; 40.4+/-1.5 vs 44.6+/-1.1 LF, Group 4 vs Group 3). The
      established influence of aging on autonomic nervous system activity appears to be
      increased by arterial hypertension due to worsening of the sympathetic
      parasympathetic response to standardised stimulation. The loss of nocturnal BP
      declines in arterial hypertension was found to occur in association with a
      decrease in autonomic nervous system activity.

PMID- 10408590
TI  - The epidemiology of elevated blood pressure as an estimate for hypertension in
      Aydin, Turkey.
AB  - BACKGROUND: Hypertension is an important public health problem, with some
      variability of its epidemiological properties in different populations.
      OBJECTIVES: The purpose of this study was to estimate the prevalence of
      hypertension and to determine the hypertension awareness, treatment and control
      rates in Aydin, a Turkish province. METHODS: Of 1600 coincidentally selected
      people aged over 18 years in Aydin, 1480 (92.5%) had their blood pressure (BP)
      measured and answered a standard questionnaire in 1995. RESULTS: Estimates of the
      prevalence of hypertension and its control were computed using two different
      criteria to define hypertension: BP > or =140/90 mm Hg or on treatment and BP >
      or =160/95 mm Hg or on treatment. Overall, the estimated prevalence of
      hypertension was 29.6% (for BP > or =140/90 mm Hg or on treatment). Hypertension
      prevalence increased progressively with age, from 9% in 18- to 29-year-olds to
      70.6% in those 70-79 years of age. Women had a significantly higher prevalence
      than men (34.1% vs 26.0% respectively). Overall, 57.9% of hypertensive
      individuals were aware that they had high BP, and 82.1% of aware hypertensives
      were being treated with antihypertensive medications, but only 19.8% of treated
      hypertensives were under control (systolic pressure <140 mm Hg and diastolic
      pressure <90 mm Hg). In addition, housewives, unemployed, and the less educated
      individuals had greater mean systolic and diastolic BP. CONCLUSIONS: Our results
      indicate that hypertension is highly prevalent in Aydin, Turkey, and the
      detection and control of hypertension is unsatisfactory.

PMID- 10408591
TI  - Lisinopril versus enalapril: evaluation of trough:peak ratio by ambulatory blood
      pressure monitoring.
AB  - In 34 out-patients with essential hypertension, the antihypertensive effect and
      the trough-to-peak ratios of once-daily enalapril or lisinopril were compared by
      ambulatory blood pressure monitoring (ABPM) according to a crossover design. The
      drug dose was titrated and a thiazide diuretic was added if necessary to attain a
      target office BP of less than 140/90 mm Hg. Both drugs significantly lowered BP
      but the effect of lisinopril was greater (P < 0.009): day- and night-time mean BP
      fell from 152/98 and 135/84 mm Hg, respectively to 133/85 and 118/74 mm Hg with
      enalapril and to 129/83 and 116/70 mm Hg with lisinopril. BP goal was reached
      with an average dose of 18 mg enalapril with 8 mg hydrochlorothiazide and with 17
      mg lisinopril combined with 6 mg diuretic. Trough:peak ratio values, which were
      calculated after Fourier analysis of ABPM data in individual patients, were
      independent of drug dose. The combination with the diuretic resulted in slightly
      higher trough:peak ratios than with ACE inhibitor monotherapy, but the difference
      was not significant. The median trough:peak ratio in patients when using
      enalapril-based therapy was 0.48 and, when taking lisinopril-based treatment, it
      was 0.65 (n = 28, P < 0.005). A significant correlation was found between
      trough:peak ratio and changes in daytime mean arterial pressure (MAP; Spearman r=
      0.43) and night-time MAP (r= 0.66). When 24-h ABPM was performed starting 24 h
      after last drug intake, both ACE inhibitors still had a significant
      antihypertensive effect (P < 0.001), which was similar for both drugs. Eleven
      patients reported minor side effects. Four patients stopped ACE-inhibitor
      treatment because of cough. The data show that lisinopril has a longer duration
      of action than enalapril.

PMID- 10408592
TI  - Double-blind comparison of eprosartan and enalapril on cough and blood pressure
      in unselected hypertensive patients. Eprosartan Study Group.
AB  - The effects of a new angiotensin receptor antagonist, eprosartan (200 or 300 mg
      b.i.d.) and enalapril (5-20 mg u.i.d.) on cough and blood pressure were compared
      in a 26-week, double-blind, randomised, parallel-group, multicentre,
      international study involving 528 patients with hypertension. Uptitration of
      doses was based on clinic blood pressure measurements during the first 12 weeks,
      after which hydrochlorothiazide (12.5-25 mg/day) could be added. The frequency
      and intensity of cough was assessed by a standardised questionnaire administered
      at each clinic visit. The primary end-point was the incidence of persistent, dry
      cough not due to upper respiratory infection; change in sitting diastolic blood
      pressure and overall incidence of cough were secondary end-points. During the
      first 12 weeks of double-blind therapy, enalapril treatment was associated with a
      3.45-fold higher risk of definite cough (14/261 vs 4/259, P = 0.018). Overall
      cough incidence (from spontaneous reports from patients, or investigator's
      observation) was also more frequent with enalapril, as compared to eprosartan.
      Both agents reduced blood pressure significantly compared to baseline, although
      the eprosartan-treated group had a slightly higher response rate (defined as
      sitting diastolic blood pressure <90 mm Hg, or at least a 10 mm Hg reduction from
      baseline), both at end of titration (70.3% vs 62.6%, P < 0.05) and after 26 weeks
      (81.7% vs 73.5%, P= 0.018). These data suggest that, in unselected hypertensive
      patients, eprosartan is associated with less cough and a somewhat higher
      responder rate than enalapril.

PMID- 10408593
TI  - Evidence for an ephaptic feedback in cortical synapses: postsynaptic
      hyperpolarization alters the number of response failures and quantal content.
AB  - The amplitude of excitatory postsynaptic potentials and currents increases with
      membrane potential hyperpolarization. This has been attributed to an increase in
      the driving force when the membrane potential deviates from the equilibrium
      potential of the respective ions. Here we report that in a subset of neocortical
      and hippocampal synapses, postsynaptic hyperpolarization affects traditional
      measures of transmitter release: the number of failures, coefficient of variation
      of response amplitudes, and quantal content, suggesting increased presynaptic
      release. The result is compatible with the hypothesis of Byzov on the existence
      of electrical (or "ephaptic") linking in purely chemical synapses. The linking,
      although negligible at neuromuscular junctions, could be functionally significant
      in influencing transmitter release at synapses with high resistance along the
      synaptic cleft. Our findings necessitate reconsideration of classical amplitude
      voltage relations for such synapses. Thus, synaptic strength may be enhanced by
      hyperpolarization of the postsynaptic membrane potential. The positive ephaptic
      feedback could account for "all-or-none" excitatory postsynaptic potentials at
      some cortical synapses, large evoked and spontaneous multiquantal events and a
      high efficacy of large "perforated" synapses whose number increases following
      behavioural learning or the induction of long-term potentiation.

PMID- 10408594
TI  - High-frequency population oscillations are predicted to occur in hippocampal
      pyramidal neuronal networks interconnected by axoaxonal gap junctions.
AB  - In hippocampal slices, high-frequency (125-333 Hz) synchronized oscillations have
      been shown to occur amongst populations of pyramidal neurons, in a manner that is
      independent of chemical synaptic transmission, but which is dependent upon gap
      junctions. At the intracellular level, high-frequency oscillations are associated
      with full-sized action potentials and with fast prepotentials. Using simulations
      of two pyramidal neurons, we previously argued that the submillisecond synchrony,
      and the rapid time-course of fast prepotentials, could be explained, in
      principle, if the requisite gap junctions were located between pyramidal cell
      axons. Here, we use network simulations (3072 pyramidal cells) to explore further
      the hypothesis that gap junctions occur between axons and could explain high
      frequency oscillations. We show that, in randomly connected networks with an
      average of two gap junctions per cell, or less, synchronized network bursts can
      arise without chemical synapses, with frequencies in the experimentally observed
      range (spectral peaks 125-182 Hz). These bursts are associated with fast
      prepotentials (or partial spikes and spikelets) as observed in physiological
      recordings. The critical assumptions we must make for the oscillations to occur
      are: (i) there is a background of ectopic axonal spikes, which can occur at low
      frequency (one event per 25 s per axon); (ii) the gap junction resistance is
      small enough that a spike in one axon can induce a spike in the coupled axon at
      short latency (in the model, a resistance of 273 M omega works, with an
      associated latency of 0.25 ms). We predict that axoaxonal gap junctions, in
      combination with recurrent excitatory synapses, can induce the occurrence of high
      frequency population spikes superimposed on epileptiform field potentials.

PMID- 10408595
TI  - Cortically-induced coherence of a thalamic-generated oscillation.
AB  - Oscillatory patterns in neocortical electrical activity show various degrees of
      large-scale synchrony depending on experimental conditions, but the exact
      mechanisms underlying these variations of coherence are not known. Analysis of
      multisite local field potentials revealed that the coherence of spindle
      oscillations varied during different states. During natural sleep, the coherence
      was remarkably high over cortical distances of several millimeters, but could be
      disrupted by artificial cortical depression, similar to the effect of
      barbiturates. Possible mechanisms for these variations of coherence were
      investigated by computational models of interacting cortical and thalamic
      neurons, including their intrinsic firing patterns and various synaptic receptors
      present in the circuitry. The model indicates that modulation of the excitability
      of the cortex can affect spatiotemporal coherence with no change in the thalamus.
      The highest level of coherence was obtained by enhancing the excitability of
      cortical pyramidal cells, simulating the action of neuromodulators such as
      acetylcholine and noradrenaline. The underlying mechanism was due to cortex
      thalamus-cortex loops in which a more excitable cortical network generated a more
      powerful and coherent feedback onto the thalamus, resulting in highly coherent
      oscillations, similar to the properties measured during natural sleep. In
      conclusion, these experiments and models are compatible with a powerful role for
      the cortex in triggering and synchronizing oscillations generated in the
      thalamus, through corticothalamic feedback projections. The model suggests that
      intracortical mechanisms may be responsible for synchronizing oscillations over
      cortical distances of several millimeters through cortex-thalamus-cortex loops,
      thus providing a possible cellular mechanism to explain the genesis of large
      scale coherent oscillations in the thalamocortical system.

PMID- 10408596
TI  - Properties of a hyperpolarization-activated cation current in interneurons in the
      rat lateral geniculate nucleus.
AB  - A hyperpolarization-activated cation conductance contributes to the membrane
      properties of a variety of cell types. In the thalamus, a prominent
      hyperpolarization-activated cation conductance exists in thalamocortical cells,
      and this current is implicated in the neuromodulation of complex firing
      behaviors. In contrast, the GABAergic cells in the reticular nucleus in the
      thalamus appear to lack this conductance. The presence and role of this cation
      conductance in the other type of thalamic GABAergic cells, local interneurons, is
      still unclear. To resolve this issue, we studied 54 physiologically and
      morphologically identified local interneurons in the rat dorsal lateral
      geniculate nucleus using an in vitro whole-cell patch recording technique. We
      found that hyperpolarizing current injections induced depolarizing voltage sags
      in these geniculate interneurons. The I-V relationship revealed an inward
      rectification. Voltage-clamp study indicated that a slow, hyperpolarization
      activated cation conductance was responsible for the inward rectification. We
      then confirmed that this slow conductance had properties of the hyperpolarization
      activated cation conductance described in other cell types. The slow conductance
      was insensitive to 10 mM tetraethylammonium and 0.5 mM 4-aminopyridine, but was
      largely blocked by 1-1.5 mM Cs+. It was permeable to both K+ and Na+ ions and had
      a reversal potential of -44 mV. The voltage dependence of the hyperpolarization
      activated cation conductance in interneurons was also studied: the activation
      threshold was about -55 mV, half-activation potential was about -80 mV and
      maximal conductance was about 1 nS. The activation and deactivation time
      constants of the conductance ranged from 100 to 1000 ms, depending on membrane
      potential. The depolarizing voltage sags and I-V relationship were further
      simulated in a model interneuron, using the parameters of the hyperpolarization
      activated cation conductance obtained from the voltage-clamp study. The time
      course and voltage dependence of the depolarizing voltage sags and I-V
      relationship in the model cell were very similar to those found in geniculate
      interneurons in current clamp. Taken together, the results of the present study
      suggest that thalamic local interneurons possess a prominent hyperpolarization
      activated cation conductance, which may play important roles in determining basic
      membrane properties and in modulating firing patterns.

PMID- 10408597
TI  - Input-and layer-dependent synaptic plasticity in the rat perirhinal cortex in
      vitro.
AB  - The perirhinal cortex is crucially important in several forms of memory. Whilst
      it is important to understand the underlying mechanisms of this role in memory,
      little is known about the synaptic physiology or plasticity of this region of
      transitional cortex. In this study, we recorded evoked field potentials in
      superficial layers (approximately layer I) of the perirhinal cortex in vitro. One
      stimulating electrode was placed on the temporal side and the other on the
      entorhinal side of the rhinal sulcus in either the superficial or intermediate
      layers (approximately layers II/III). Paired stimuli resulted in depression of
      the second response. Paired-pulse depression was maximal at a 200-ms interpulse
      interval. Low-frequency stimulation resulted in synaptic depression, which
      returned to baseline within 60 min. The magnitude of both paired-pulse depression
      and low-frequency stimulation-induced depression was significantly greater at
      synapses activated from the temporal intermediate pathway than the other three
      pathways. Long-term potentiation, stable for at least 60 min, was induced by high
      frequency stimulation of intermediate but not superficial pathways. Long-lasting
      depression (depotentiation) was induced by low-frequency stimulation following
      the induction of long-term potentiation. The induction of both long-term
      potentiation and depotentiation was N-methyl-D-aspartate receptor dependent. The
      group I/II metabotropic glutamate receptor antagonist (S)-alpha-methyl-4
      carboxyphenylglycine was without effect on either of these forms of plasticity.
      Thus, both long- and short-lasting forms of synaptic plasticity exist at synapses
      in the perirhinal cortex, and these may mediate the changes in neuronal responses
      associated with visual recognition memory.

PMID- 10408598
TI  - Differential expression of immediate-early genes, c-fos and zif268, in the visual
      cortex of young rats: effects of a noradrenergic neurotoxin on their expression.
AB  - We investigated the expression pattern of two immediate-early genes, zif268 and c
      fos, under various visual conditions using immunohistochemical and northern blot
      analysis in the visual cortex of young rats. The basal expression of c-fos was
      low and was further reduced by dark rearing that lasted for one week. A marked
      and transient increase was induced upon visual stimulation applied immediately
      after dark rearing. Zif268 showed a relatively high basal level. Its expression
      was reduced by dark rearing of the animals, but returned rapidly to the basal
      expression level following the introduction of light. Administration of N-(2
      chloroethyl)-N-ethyl-2-bromobenzylamine, a selective noradrenergic neurotoxin,
      suppressed the basal expression of c-fos messenger RNA. The response of c-fos to
      photo-stimulation was also significantly lower in the visual cortex of N-(2
      chloroethyl)-N-ethyl-2-bromobenzylamine-treated young rats. In contrast, no
      significant change in zif268 expression was detected between normal and N-(2
      chloroethyl)-N-ethyl-2-bromobenzylamine-treated animals. These findings suggest
      that differential expression of these immediate-early genes is involved in the
      activity-dependent regulation of cortical function. One possibility is that the
      noradrenergic system controls cortical function, including plasticity, by
      modifying the expression of c-fos.

PMID- 10408600
TI  - Alterations in the ryanodine receptor calcium release channel correlate with
      Alzheimer's disease neurofibrillary and beta-amyloid pathologies.
AB  - Investigation of the integrity of the ryanodine receptor in Alzheimer's disease
      is important because it plays a critical role in the regulation of calcium
      release from the endoplasmic reticulum in brain, impairment of which is believed
      to contribute to the pathogenesis of Alzheimer's disease. The present study
      compared ryanodine receptor levels and their functional modulation in particulate
      fractions from control and Alzheimer's disease temporal cortex, occipital cortex
      and putamen. Relationships between ryanodine receptor changes and the progression
      of Alzheimer's disease pathology were determined by examining autoradiographic
      [3H]ryanodine binding in entorhinal cortex/anterior hippocampus sections from 22
      cases that had been staged for neurofibrillary changes and beta-amyloid
      deposition. A significant (P < 0.02) 40% decrease in the Bmax for [3H]ryanodine
      binding and significantly higher IC50 values for both magnesium and Ruthenium Red
      inhibition of [3H]ryanodine binding were detected in Alzheimer's disease temporal
      cortex particulate fractions compared to controls. Immunoblot analyses showed
      Type 2 ryanodine receptor holoprotein levels to be decreased by 20% (P < 0.05) in
      these Alzheimer's disease cases compared to controls. No significant differences
      were detected in [3H]ryanodine binding comparing control and Alzheimer's disease
      occipital cortex or putamen samples. The autoradiography study detected increased
      [3H]ryanodine binding in the subiculum, CA2 and CA1 regions in cases with early
      (stage I-II) neurofibrillary pathology when compared to Stage 0 cases. Analysis
      of variance of data with respect to the different stages of neurofibrillary
      pathology revealed significant stage-related declines of [3H]ryanodine binding in
      the subiculum (P < 0.02) with trends towards significant decreases in CA1, CA2
      and CA4. Post-hoc testing with Fisher's PLSD showed significant reductions (74
      94%) of [3H]ryanodine binding in the subiculum, and CA1-CA4 regions of the late
      isocortical stage (V-VI) cases compared to the early entorhinal stage I-II cases.
      [3H]Ryanodine binding also showed significant declines with staging for beta
      amyloid deposition in the entorhinal cortex (P < 0.01) and CA4 (P < 0.05) with
      trends towards a significant decrease in the dentate gyrus. We conclude that
      alterations in ryanodine receptor binding and function are very early events in
      the pathogenesis of Alzheimer's disease, and may be fundamental to the
      progression of both neurofibrillary and beta-amyloid pathologies.

PMID- 10408599
TI  - A double dissociation within the hippocampus of dopamine D1/D5 receptor and beta
      adrenergic receptor contributions to the persistence of long-term potentiation.
AB  - We compared the effects of the D1/D5 receptor antagonist SCH-23390 with the beta
      adrenergic receptor antagonist propranolol on the persistence of long-term
      potentiation in the CA1 and dentate gyrus subregions of the hippocampus. In
      slices, SCH-23390 but not propranolol reduced the persistence of long-term
      potentiation in area CA1 without affecting its induction. The drugs exerted
      reverse effects in the dentate gyrus, although in this case the induction of long
      term potentiation was also affected by propranolol. The lack of effect of SCH
      23390 on the induction and maintenance of long-term potentiation in the dentate
      gyrus was confirmed in awake animals. The drug also had little or no effect on
      the expression of inducible transcription factors. In area CA1 of awake animals,
      SCH-23390 blocked persistence of long-term potentiation beyond 3 h, confirming
      the results in slices. To rule out a differential release of catecholamines
      induced by our stimulation protocols between brain areas, we compared the effects
      of the D1/D5 agonist SKF-38393 with the beta-adrenergic agonist isoproterenol on
      the persistence of a weakly induced, decremental long-term potentiation in CA1
      slices. SKF-38393 but not isoproterenol promoted greater persistence of long-term
      potentiation over a 2-h period. In contrast, isoproterenol but not SKF-38392
      facilitated the induction of long-term potentiation. These data demonstrate that
      there is a double dissociation of the catecholamine modulation of long-term
      potentiation between CA1 and the dentate gyrus, suggesting that long-term
      potentiation in these brain areas may be differentially consolidated according to
      the animal's behavioural state.

PMID- 10408601
TI  - Subfield- and layer-specific changes in parvalbumin, calretinin and calbindin
      D28K immunoreactivity in the entorhinal cortex in Alzheimer's disease.
AB  - The entorhinal cortex, which is involved in neural systems related to memory, is
      selectively degenerated in early Alzheimer's disease. Here, we examined
      neuropathological changes in the eight entorhinal subfields in post mortem
      Alzheimer's disease subjects using Thionin and Bielschowsky stains and
      parvalbumin, calretinin and calbindin-D28k immunohistochemistry. Both
      histological stains revealed the most dramatic cell loss and neurofibrillary
      tangle formation to be in layers II and V of the lateral, intermediate and caudal
      subfields. In accordance, immunohistochemical staining showed that neurons and
      fibres that contain calcium-binding proteins were also more frequently altered in
      these subfields than in the rostromedial subfields. Detailed analysis further
      revealed that non-principal cells containing parvalbumin or calbindin-D28k showed
      morphological alterations early in the entorhinal pathology of Alzheimer's
      disease, whereas non-principal neurons containing calretinin were better
      preserved even in Alzheimer's disease patients with severe entorhinal pathology.
      The degeneration of parvalbumin-immunoreactive neurons and basket-like networks
      and calbindin-positive non-principal neurons was observed mainly in layer II,
      where the calretinin-positive non-principal neurons formed aggregates especially
      at late stages of the disease. The pyramidal-shaped neurons containing either
      calretinin or calbindin-D28k were often preserved, although morphological
      alterations were observed. Our findings indicate that specific subfields of the
      entorhinal cortex involving neurons that contain distinct calcium-binding
      proteins are differentially vulnerable in Alzheimer's disease. This could have an
      impact on the topographically organized inputs and outputs of the entorhinal
      cortex in Alzheimer's patients.

PMID- 10408602
TI  - Effects of intrasubthalamic injection of dopamine receptor agonists on
      subthalamic neurons in normal and 6-hydroxydopamine-lesioned rats: an
      electrophysiological and c-Fos study.
AB  - Subthalamic neuronal activity is controlled by a dopaminergic innervation, which
      may act via D1 and D2 dopamine receptors. This study investigates the effect of
      apomorphine and the selective D1 and D2 agonists, SKF 82958 and quinpirole
      respectively, in normal and 6-hydroxydopamine-lesioned rats. The effect of
      microinjection of these drugs into the subthalamic nucleus was assessed by
      recording unit activity and the expression of the c-Fos-immunoreactive protein in
      the subthalamic nucleus. Dopaminergic agonists reduced the discharge rate and did
      not induce c-Fos expression in the normal rat. Apomorphine and quinpirole
      increased the discharge rate and induced a strong expression of c-Fos-like
      immunoreactive proteins, whereas SKF 82958 induced a decrease of the discharge
      rate and a slight expression of c-Fos in 6-hydroxydopamine-lesioned rats. The
      striking contrast in the changes obtained with apomorphine and quinpirole in
      normal and 6-hydroxydopamine-lesioned rats is discussed in relation to a
      hyperexpression of D2 dopaminergic receptors on the GABAergic terminals into the
      subthalamic nucleus. These results show that, in normal rats, dopamine agonists
      exert an inhibitory control on subthalamic neurons via D1 and D2 receptors.
      However, in 6-hydroxydopamine-lesioned rats, the hyperactivity of subthalamic
      neurons is also reduced by D1 receptor agonist but not by D2 dopamine agonists.
      This last result points out one aspect of the complex mechanisms underlying the
      physiopathology of Parkinson's disease.

PMID- 10408603
TI  - Nucleus accumbens dopamine depletions make rats more sensitive to high ratio
      requirements but do not impair primary food reinforcement.
AB  - It has been suggested that nucleus accumbens dopamine is involved in the process
      of enabling organisms to overcome work-related response costs. One way of
      controlling work requirements in operant schedules is to use fixed ratio
      schedules with different ratio requirements. In the present study, the effects of
      nucleus accumbens dopamine depletions were assessed using four schedules: fixed
      ratio 1, 4, 16, and 64. Rats with nucleus accumbens dopamine depletions showed
      behavioral deficits that were highly dependent upon the ratio value; there were
      no effects of dopamine depletions on fixed ratio 1 lever pressing, but as ratio
      value got larger, the impairment became much greater. In a separate experiment,
      pre-feeding to reduce food motivation was shown to produce a different pattern,
      such that performance on all ratio schedules was substantially impaired. Thus,
      aspects of food reinforcement that are involved in fixed ratio 1 performance are
      highly sensitive to food motivation, but are largely unaffected by nucleus
      accumbens dopamine depletions. Nevertheless, nucleus accumbens dopamine
      depletions affected the elasticity of demand for food, and enhanced "ratio
      strain", i.e. they exacerbated the response-suppressing effects of increasing
      ratio value.

PMID- 10408604
TI  - The role of mesoprefrontal dopamine neurons in the acquisition and expression of
      conditioned fear in the rat.
AB  - The mesoprefrontal dopamine neurons are sensitive to physical, pharmacological
      and psychological stressors. In this report, the role of these neurons in the
      response to classical fear conditioning was investigated. 6-Hydroxydopamine
      lesions to the medial prefrontal cortex reduced dopamine levels to about 13% of
      controls but did not alter behavior during the acquisition of fear conditioning.
      As expected, conditioned fear increased dopamine metabolism (3,4
      dihydroxyphenylacetic acid/dopamine ratio) in the nucleus accumbens in sham
      lesion rats. The medial prefrontal 6-hydroxydopamine lesions did not alter this
      effect. During the expression, however, lesioned rats demonstrated a delayed
      extinction of the conditioned response without an overall increase in the initial
      conditioned response. This effect was consistent in rats receiving 6
      hydroxydopamine lesions before or after the acquisition period. The calculated
      rates of extinction showed that the 6-hydroxydopamine lesioned rats had a reduced
      rate of extinction, but not acquisition, of fear conditioning. The results
      presented in this manuscript indicate that the mesoprefrontal dopamine neurons
      are involved in co-ordinating the normal extinction of a fear response but do not
      alter the acquisition of fearful behaviors. These data are consistent with the
      conclusion that the mesoprefrontal dopamine neurons are involved in maintaining
      the animal's response adaptability with regards to stress-related changes in the
      external environment.

PMID- 10408605
TI  - Isoforms of alpha1E voltage-gated calcium channels in rat cerebellar granule
      cells--detection of major calcium channel alpha1-transcripts by reverse
      transcription-polymerase chain reaction.
AB  - In primary cultures of rat cerebellar granule cells, transcripts of voltage-gated
      Ca2+ channels have been amplified by reverse transcription-polymerase chain
      reaction and identified by sequencing of subcloned polymerase chain reaction
      products. In these neurons cultured for six to eight days in vitro, fragments of
      the three major transcripts alpha1C, alpha1A, and alpha1E are detected using
      degenerated oligonucleotide primer pairs under highly stringent conditions. Whole
      cell Ca2+ current recordings from six to eight days in vitro granule cells show
      that most of the current is due to L-type (25%), P-type (33%) and R-type (30%)
      Ca2+ channels. These data support the correlation between alpha1A and P-type Ca2+
      channels (G1) and between alpha1E and R-type channels (G2 and G3). By including
      specific primer pairs for alpha1E the complimentary DNA fragments of indicative
      regions of alpha1E isoforms are amplified corresponding to the three most
      variable regions of alpha1E, the 5'-end, the II/III-loop, and the central part of
      the 3'-end. Although the complementary DNA fragments of the 5'-end of rat alpha1E
      yield a uniform reverse transcription-polymerase chain reaction product, its
      structure is unusual in the sense that it is longer than in the cloned rat
      alpha1E complementary DNA. It corresponds to the alpha1E isoform reported for
      mouse and human brain and is also expressed in cerebellum and cerebrum of rat
      brain as the major or maybe even the only variant of alpha1E. While fragments of
      a new rat alpha1E isoform are amplified from the 5'-end, three known fragments of
      the II/III-loop and two known isoforms homologue to the 3'-coding region are
      detected, which in the last case are discriminated by a 129 base pair insertion.
      The shift of the alpha1E expression from a pattern seen in cerebellum (alpha1Ee)
      to a pattern identified in other regions of the brain (alpha1E-3) is discussed.
      These data show that: (i) alpha1E is expressed in rat brain as a structural
      homologue to the mouse and human alpha1E; and (ii) rat cerebellar granule cells
      in primary culture express a set of alpha1E isoforms, containing two different
      sized carboxy termini. Since no new transcripts of high-voltage-activated Ca2+
      channels genes are identified using degenerate oligonucleotide primer pairs, the
      two isoforms differentiated by the 129 base pair insertion might correspond to
      the two R-type channels, G2 and G3, characterized in these neurons. Functional
      studies including recombinant cells with the different proposed isoforms should
      provide more evidence for this conclusion.

PMID- 10408606
TI  - Cerebellar granule cells acquire transferrin-free iron by a carrier-mediated
      process.
AB  - In this study, the mechanism of transferrin-free iron uptake by brain neuronal
      cells was investigated using the cultured cerebellar granule cells. Effects of
      incubation time, iron concentration, temperature and other divalent metals on the
      cellular uptake were determined. After five days of plating, the cells were
      incubated with different concentrations of transferrin-free iron in isotonic
      sucrose solution at different temperatures for a certain time. The cellular
      transferrin-free iron uptake was analysed by measuring the cellular radioactivity
      with a gamma-counter. The result showed that the cultured cerebellar granule
      cells had the capacity to acquire transferrin-free iron at pH 6.5, at which it
      was demonstrated that transferrin binds iron very poorly and only very little
      transferrin can be internalized by reticulocytes and HeLa cells. The iron uptake
      by cells increased with incubation time in a linear manner at a rate of 0.1076
      pmol/microg protein/min within the first 10 min. The uptake was time- and
      temperature-dependent, iron concentration saturable, and inhibited by several
      divalent metal ions, such as Co2+, Zn2+, Mn2+ and Ni2+. These characteristics of
      transferrin-free iron uptake by the cultured cerebellar granule cells observed in
      this study, similar to those obtained from cells outside of the brain, implied
      that a carrier-mediated iron transport system might be present on the membrane of
      this type of brain neuronal cells. In addition, no significant difference in
      malondialdehyde measurement was found when the cells were incubated without or
      with the lower concentrations of iron (< 4 microM) for 20 min at 37 degrees C,
      demonstrating that this system was valid for studying membrane iron transport in
      this type of brain neuronal cell.

PMID- 10408607
TI  - Infusion of neurosteroids into the rat nucleus basalis affects paradoxical sleep
      in accordance with their memory modulating properties.
AB  - The neurosteroids pregnenolone sulfate and allopregnanolone affect memory
      processes in an opposite manner, pregnenolone sulfate acts as a potent memory
      enhancer whereas allopregnanolone impairs memory performance. The mechanisms
      underlying these memory modulating properties have yet to be elucidated. We have
      previously reported that infusions of either neurosteroid into the nucleus
      basalis magnocellularis, one of the main forebrain cholinergic nuclei,
      differentially affect spatial memory in rats. The relationships between memory
      performance and paradoxical sleep are well documented, therefore we investigated
      whether neurosteroids infused into the nucleus basalis magnocellularis affected
      the sleep-wakefulness cycle in rats, measured by electroencephalographic
      recordings. Results show that pregnenolone sulfate (5 ng) increased by 12%,
      whereas allopregnanolone (2 ng) decreased by 24%, the duration of paradoxical
      sleep in the 24 h interval following injection compared to control recordings.
      Pregnenolone sulfate inhibits GABA(A) receptors whereas allopregnanolone
      stimulates them. Since cholinergic neurons of the nucleus basalis magnocellularis
      are GABA-modulated, it may be postulated that these neurosteroids modify
      paradoxical sleep by acting on the cholinergic transmission. This may account, at
      least in part, for the memory modulating properties of these compounds.

PMID- 10408608
TI  - Parvalbumin-immunoreactive, fast-spiking neurons in the medial septum/diagonal
      band complex of the rat: intracellular recordings in vitro.
AB  - The medial septum/diagonal band complex is composed predominantly of cholinergic
      and GABAergic neurons, and it projects to the hippocampal formation. A proportion
      of the GABAergic neurons contain parvalbumin, a calcium-binding protein that has
      previously been localized in fast-spiking, non-accommodating GABAergic neurons in
      the cerebral cortex and neostriatum. The aim of the present study was to
      determine whether parvalbumin is localized preferentially in a similar
      electrophysiological class of neuron in the medial septum/diagonal band complex.
      The study was carried out using in vitro intracellular recording, intracellular
      biocytin filling and parvalbumin immunocytochemistry. Three main classes of
      neurons were identified according to standard criteria: burst-firing, slow-firing
      and fast-firing neuronal populations. The fast-firing neurons were subdivided
      into two subpopulations based on whether or not they displayed accommodation. The
      fast-spiking, non-accommodating cells were furthermore found to be spontaneously
      active at resting potentials, and to possess action potentials of significantly
      (P < 0.05) shorter duration (half width: 0.61 +/- 0.12 ms) than those of the
      regular-spiking, accommodating neurons (1.0 +/- 0.34 ms). Of the neurons that
      were successfully filled with biocytin and processed for parvalbumin
      immunoreactivity, 82% of the fast-spiking, non-accommodating cells possessed
      parvalbumin immunoreactivity, while none of the regular-spiking, accommodating
      neurons were found to be immunoreactive for parvalbumin. The slow-firing neurons,
      shown previously to be cholinergic, did not stain for parvalbumin
      immunoreactivity, in agreement with studies showing parvalbumin to be localized
      solely in GABAergic neurons in the medial septum/diagonal band complex. In
      conclusion, these findings suggest the presence of a previously uncharacterized
      population of neurons in the medial septum/diagonal band complex that generate
      high-frequency, non-adaptive discharge. This property correlates with the
      localization of parvalbumin in these neurons, which suggests that parvalbumin
      fulfils the same role in the medial septum/diagonal band complex that it does in
      other parts of the brain. The fast-spiking neurons in the medial septum/diagonal
      band complex may play an essential role in the GABAergic influence of the septum
      on the hippocampal formation.

PMID- 10408609
TI  - Distribution and cellular localization of the serotonin type 2C receptor
      messenger RNA in human brain.
AB  - The regional and cellular distribution of serotonin type 2C receptor messenger
      RNA was investigated in autopsy samples of human brain by in situ hybridization
      histochemistry. The main sites of serotonin receptor type 2C messenger RNA
      expression were the choroid plexus, cerebral cortex, hippocampus, amygdala, some
      components of the basal ganglia, the substantia nigra, the substantia innominata
      and the ventromedial hypothalamus, suggesting that this receptor might be
      involved in the regulation of different brain functions. Interestingly, in all
      regions examined, the serotonin type 2C receptor messenger RNA was always
      restricted to subpopulations of cells, suggesting a specific role, perhaps
      determined by regionality. A comparison of the in situ hybridization results with
      those previously obtained by means of radioligand binding experiments suggested
      that in most of the areas analysed the serotonin type 2C receptors were located
      at axon terminals.

PMID- 10408610
TI  - Central serotonin depletion modulates the behavioural, endocrine and
      physiological responses to repeated social stress and subsequent c-fos expression
      in the brains of male rats.
AB  - Intraspecific confrontation has been used to study effect of depleting central
      serotonin on the adaptation of male rats to repeated social stress (social
      defeat). Four groups of adult male rats were used (serotonin depletion/sham:
      stressed; serotonin depletion/sham: non-stressed). Central serotonin was reduced
      (by 59-97%) by a single infusion of the neurotoxin 5,7-dihydroxtryptamine (150
      microg) into the cerebral ventricles; levels of dopamine and noradrenaline were
      unaltered (rats received appropriate uptake blockers prior to neurotoxic
      infusions). Sham-operated animals received solute only. Rats were then either
      exposed daily for 10 days to a second larger aggressive male in the latter's home
      cage, or simply transferred to an empty cage (control procedure). Rats with
      reduced serotonin failed to show the increased freezing behaviour during the pre
      defeat phase of the social interaction test characteristic of sham animals. There
      was no change in the residents' behaviour. Core temperature increased during
      aggressive interaction in sham rats, and this did not adapt with repeated stress.
      By contrast, stress-induced hyperthermia was accentuated in serotonin-reduced
      rats as the number of defeat sessions increased. Basal core temperature was
      unaffected by serotonin depletion. Heart rate increased during social defeat, but
      this did not adapt with repeated stress; serotonin depletion had no effect on
      this cardiovascular response. Basal corticosterone was increased in serotonin
      depleted rats, but the progressive reduction in stress response over days was not
      altered. C-fos expression in the brain was not altered in control (non-stressed)
      rats by serotonin reduction in the areas examined, but there was increased
      expression after repeated social stress in the medial amygdala of 5-HT depleted
      rats. These experiments show that reduction of serotonin alters responses to
      repeated social stress in male rats, and suggests a role for serotonin in the
      adaptive process.

PMID- 10408611
TI  - Nitric oxide and sleep in the rat: a puzzling relationship.
AB  - To date, only a few studies indicate that nitric oxide may play a role in the
      regulation of the sleep-wake cycle. However, data reported are controversial and
      the part played by nitric oxide in sleep-wake cycle regulation still remains
      uncertain. In the present report, we studied the effects on sleep amounts of two
      different nitric oxide synthase inhibitors: N-nitro-L-arginine methyl ester, a
      non-selective nitric oxide synthase inhibitor, and 7-nitro-indazole, a specific
      inhibitor of neuronal nitric oxide synthase. The above compounds were
      administered via two routes, i.e. intraperitoneally or locally in the dorsal
      raphe nucleus, a structure involved in sleep regulation. In order to evaluate
      their efficiency to inhibit nitric oxide synthesis in the rat brain, they were
      first administered intraperitoneally to a group of animals, and the cortical
      release of nitric oxide was determined by means of voltammetric measurements. N
      Nitro-L-arginine methyl ester (100 mg/kg, i.p.) did not affect the cortical
      release of nitric oxide, whereas it increased both slow-wave sleep and
      paradoxical sleep durations. On the contrary, 7-nitro-indazole (40 mg/kg, i.p.)
      significantly decreased the cortical release of nitric oxide (-25%) and
      paradoxical sleep duration. Furthermore, following microinjection of either N
      nitro-L-arginine methyl ester or 7-nitro-indazole at 100 ng/0.20 microl into the
      nitric oxidergic cell area of the dorsal raphe nucleus, decreases in paradoxical
      sleep duration were obtained (-32.8% and -25.3%, respectively). The results
      obtained support the existence of a duality in the sleep regulation modalities
      exerted by nitric oxide, i.e. a peripheral inhibiting influence and a central
      facilitating role for the nitric oxide-serotoninergic neurons of the dorsal raphe
      nucleus.

PMID- 10408612
TI  - Immunohistochemical distribution of the prohormone convertase PC5-A in rat brain.
AB  - Prohormone convertase 5 is an endoprotease of the kexin/subtilisin-like family,
      which has been postulated to play a role in the proteolytic maturation of a
      variety of pro-peptides in the mammalian brain. In order to gain insight into the
      functional role of prohormone convertase 5 in the central nervous system, the
      regional, cellular and subcellular distributions of the enzyme were investigated
      by immunohistochemistry in rat brain using an N-terminal-directed specific
      antibody shown previously to recognize both the mature and unprocessed forms of
      the enzyme. Throughout the brain, prohormone convertase 5 immunoreactivity was
      concentrated within nerve cell bodies and proximal dendrites. No prohormone
      convertase 5 immunoreactivity was associated with astrocytes, as confirmed by the
      absence of prohormone convertase 5 immunolabeling in cells immunopositive for the
      glial protein S-100alpha. Within neurons, prohormone convertase 5
      immunoreactivity was concentrated within the Golgi apparatus, as revealed
      immunohistochemically within the same sections using antibodies against the
      medial cisternae protein MG-160. It was also present within small vesicular-like
      elements distributed throughout the cytoplasm of perikarya and dendrites, but not
      of axons, as confirmed by its lack of co-localization with the synaptic terminal
      marker Dynamin-1. These results suggest that prohormone convertase 5 is active
      within early compartments of the neuronal regulated secretory pathway and that it
      is unlikely to be released with its processed substrates. At the regional level,
      prohormone convertase 5-immunoreactive perikarya were distributed extensively
      throughout the forebrain. The most numerous and intensely labeled were detected
      in the olfactory bulb, cerebral cortex, globus pallidus, endopeduncular and
      subthalamic nuclei, septum, diagonal band of Broca, magnocellular and medial
      preoptic areas, supraoptic and arcuate nuclei of the hypothalamus, and
      anterodorsal, laterodorsal, paraventricular and reticular nuclei of the thalamus.
      Moderate to dense neuronal labeling was also evident in the olfactory tubercle,
      caudate-putamen, claustrum, bed nucleus of the stria terminalis, substantia
      innominata, hippocampus, amygdala, and remaining thalamic and hypothalamic
      nuclei. This widespread distribution suggests that prohormone convertase 5 is
      involved in the processing of a variety of neuropeptide and/or neurotrophin
      precursors in mammalian brain.

PMID- 10408613
TI  - Release-depletion and receptor-mediated neuronal internalization of endogenous
      neurotensin in the stellate ganglion of the cat.
AB  - The release and depletion of neurotensin in sympathetic preganglionic axon
      terminals and internalization in principal ganglion cells were investigated in
      the cat stellate ganglion by means of combined immunohistochemical staining,
      image analysis and confocal microscopy. Neurotensin stored in preganglionic
      boutons was released by 40 or 5 Hz electrical stimulation of preganglionic
      nerves, being depleted to 7.4 and 19.2% of control levels by continuous
      stimulation lasting 20 or 160 min (both stimuli delivered 48,000 pulses). Once
      released, neurotensin was internalized by the principal ganglion cells as
      evidenced by a ring of bright spot-like granules in the perinuclear region
      indicating the sites of intracellular neurotensin accumulation. Neurotensin
      internalization was time-dependent, thus, different content was found when the
      time between the end of stimulation and start of perfusion was varied. The onset
      of neurotensin internalization appeared in the first minutes, intracellular
      accumulation was evident at 20 min, maximal internalization occurred at 120 min
      and, 24 h later internalized neurotensin content had faded. Internalization was
      partially blocked by the nonpeptide neurotensin antagonist SR48692. These data
      provide evidence of presynaptic neurotensin release and depletion by electrical
      stimulation with varied frequencies. They also provide evidence for in situ
      receptor-mediated internalization of endogenously released neurotensin, raising
      the possibility that internalization may represent, in addition to some kind of
      turnover dynamics, an important part of the mechanisms of neuropeptide signaling.

PMID- 10408614
TI  - The transport rate of cholera toxin B subunit in the retinofugal pathways of the
      chick.
AB  - This study investigated the transport rate of the tracer, cholera toxin B
      subunit, within the retinofugal pathway of the chick hatchlings. Following
      intraocular injections, the chicks were allowed to survive for various time
      periods. The immunoreactivity of cholera toxin B subunit was then examined in the
      retinofugal pathways. Two hours post-injection, retinal ganglion cells began to
      take up the tracer and transport it to the most rostroventral portion of the
      optic tectum. After a 4 h survival period, the labeled retinal axons
      progressively innervated all retinofugal targets. Within the tectum, the labeling
      density varied from layer to layer with heavily labeled terminals in layer 5b,
      less label in layer 7 and the most diffuse label in layers 2-4. Scattered
      labeling was seen in the nucleus dorsolateralis anterior thalami, pars lateralis,
      the nucleus geniculatus lateralis, pars ventralis, the nucleus basal optic root,
      the nucleus lateralis anterior thalami, and the pretecal lentiformis nucleus of
      mesencephalon. After 6- and 8 h survival periods, increased labeling was seen in
      all retinofugal nuclei. There were increased numbers of retinal terminals in all
      retinorecipient layers of the tectum. It was noted that some of the retinal axons
      "overshot" into layers deeper than layer 7. In addition, retinal projections were
      found scattered throughout the ipsilateral nucleus basal optic root. Maximal
      labeling in all retinofugal targets was observed at a 10 h survival period. The
      present study suggests that cholera toxin B subunit can be used to trace retinal
      axons along their retinofugal paths up to the small terminal zones at a rate of
      4.25 mm/h or 102 mm/day. Also, evidence of synchronous retinal terminations in
      layers 5b and 7 indicates that the transport of cholera toxin B subunit is
      independent of axon diameters of retinal ganglion cells. Finally, given the
      changing status of the embryo, the rapid transport of cholera toxin B subunit can
      be applied for tracing developing pathways.

PMID- 10408615
TI  - Protection of excitotoxic neuronal death by gluconate through blockade of N
      methyl-D-aspartate receptors.
AB  - Excitotoxic neuronal death is mediated primarily by the N-methyl-D-aspartate
      receptor. N-methyl-D-aspartate induces two forms of excitotoxicity in CA1
      pyramidal neurons of cultured rat hippocampal slices: the rapidly developing form
      that depends on external Na+ and Cl-, and the delayed form that requires external
      Ca2+ but not Cl-. Consistent with this notion, replacement of external Cl- with
      glucuronate, isethionate or methylsulfate attenuated or delayed selectively the
      rapid excitotoxicity. However, gluconate substituting for Cl- blocked both rapid
      and delayed forms of excitotoxicity. Gluconate also reduced N-methyl-D-aspartate
      induced membrane currents recorded from CA1 neurons in a dose-dependent manner.
      This dose-dependence was remarkably similar to that observed for protection of N
      methyl-D-aspartate-induced neuronal death by gluconate. Although gluconate
      chelated Ca2+ most strongly among the four Cl- substitutes examined, excitotoxic
      neuronal death could be protected by 7 mM gluconate without Ca2+ chelating
      action. The voltage-dependent Mg2+ block of N-methyl-D-aspartate receptors was
      not affected by gluconate. Gluconate suppressed the N-methyl-D-aspartate
      component of excitatory synaptic currents evoked in CA1 neurons. We conclude that
      protection of excitotoxic neuronal death by gluconate at low doses (<20 mM) is
      due to its antagonistic action on N-methyl-D-aspartate receptors. Gluconate is a
      widely used substitute for Cl-. Our unexpected findings give a warning that the
      results of any of the experiments concerning excitotoxicity or glutamate
      receptors obtained by gluconate substituting for Cl- must be interpreted with
      caution.

PMID- 10408616
TI  - Mg2+-dependent modification of the N-methyl-D-aspartate receptor following graded
      hypoxia in the cerebral cortex of newborn piglets.
AB  - The present study tests the hypothesis that Mg2+ modification of N-methyl-D
      aspartate receptor ion channel opening is altered during hypoxia and correlates
      with the progressive decrease in cerebral energy metabolism induced by hypoxia.
      Studies were performed in five normoxic and nine hypoxic ventilated piglets. In
      the hypoxic group, varying degrees of cerebral energy metabolism were achieved by
      administration of different fractions of inspired oxygen (FiO2) (5-9%) for
      varying durations of time and were documented by cortical tissue phosphocreatine
      levels. [3H]Dizocilpine maleate binding was performed with increasing
      concentrations of MgSO4 from 0.01 to 15 mM in cortical P2 membrane fractions.
      Mg2+ percentage activation and Mg2+ 50% inhibitory concentrations (IC50) were
      determined. The mean +/- S.D. phosphocreatine value was 3.0 +/- 1.3 micromol/g
      brain in the normoxic group and 1.4 +/- 1.0 micromol/g brain in the hypoxic group
      (P < 0.01). Low concentrations of Mg2+ (0.01-1 mM) increased [3H]dizocilpine
      maleate binding in the normoxic group (to 137 +/- 26% of baseline), significantly
      greater than in the hypoxic group (109 +/- 13%, P < 0.05). Receptor activation
      correlated with brain tissue levels of phosphocreatine, with percentage maximal
      activation decreasing linearly as phosphocreatine levels decreased (r=0.7).
      Higher levels of Mg2+ (1.5-15 mM) caused inhibition of [3H]dizocilpine maleate
      binding, with IC50 levels significantly higher in the normoxic group (3.2 +/- 1.1
      mM) than in the hypoxic group (1.9 +/- 0.4 mM). Mg2+ IC50 values decreased in a
      linear fashion as phosphocreatine values decreased (r=0.9). The data demonstrate
      that, as brain cell energy metabolism decreases during hypoxia, maximal receptor
      activation by low levels of Mg2+ decreases and receptor inhibition by high levels
      of Mg2+ increases in a linear fashion. We speculate that, during hypoxia,
      dephosphorylation of the ion channel of the N-methyl-D-aspartate receptor
      increases Mg2+ blockade of the receptor by increasing Mg2+ accessibility to its
      binding site and that receptor modification may be initiated by subtle decreases
      in cortical oxygenation in the newborn brain.

PMID- 10408617
TI  - Methylprednisolone and vitamin E therapy in perinatal hypoxic-ischemic brain
      damage in rats.
AB  - To study the efficacy of methylprednisolone/vitamin E in reducing cerebral edema
      and improving the ultimate neuropathological outcome in perinatal cerebral
      hypoxia-ischemia, 40 seven-day postnatal rats were subjected to right common
      carotid artery ligation followed by exposure to 8% oxygen at 37 degrees C for 3
      h. The animals were divided into groups. Twenty rat pups received an
      intraperitoneal injection of 30 mg/kg body weight methylprednisolone and vitamin
      E (100 U/kg) immediately following cerebral hypoxia-ischemia. Control animals
      received either no therapy (n = 10) or an equivalent volume of normal saline (n =
      10). After 72 h of recovery from hypoxia-ischemia, the animals were killed and
      their brains were examined to measure the water contents in the right and left
      hemispheres (29 rat pups), whereas the others were killed at 21 days for
      neuropathological examination. Methylprednisolone/vitamin E-treated rats had
      significantly less water content in the right hemisphere (87.08 +/- 0.28%, mean
      +/- S.E.M.) than saline-treated animals (89.07 +/- 0.37%, mean +/- S.E.M., P <
      0.0001). Methylprednisolone/vitamin E significantly reduced water content in the
      right hemisphere of the brain. Neuropathological study was performed on nine rat
      pups. The brains of four methylprednisolone/vitamin E- and five saline-treated
      pups were examined at the end of the 21-day recovery period. Two groups of the
      right cerebral cortex included thinning of the cortex. Significantly less damage
      was seen in the methylprednisolone/vitamin E-treated pups. Our study suggests
      that trials of methylprednisolone/vitamin E might be effective if they are given
      to the mother at risk of fetal hypoxia during labor or to the hypoxic infant
      right after delivery in preventing hypoxic brain damage.

PMID- 10408618
TI  - Hypoxia during early developmental period induces long-term changes in the
      dopamine content and release in a mesencephalic cell culture.
AB  - The present study was conducted to elucidate the long-term effects of exposure to
      hypoxia of dopaminergic neurons during the early developmental period. Primary
      mesencephalic cell cultures prepared from fetal rats and containing 0.5-2% of
      dopaminergic neurons were exposed to hypoxia between in vitro days 1 and 6, the
      putative critical developmental period. Changes in the content, release and
      uptake of dopamine were found to depend on the degree of hypoxia and on the
      duration of exposure. Following moderate hypoxia (7 h, 5% O2) on two consecutive
      days between in vitro days 1 and 3, the cultures showed a small increase in the
      dopamine levels, by 16%. After severe hypoxia (0% O2/95% N2 for 24 h), during the
      same time window, the cellular dopamine content was elevated by 100%. Moreover,
      severe hypoxia produced long-lasting modulations of the dopaminergic system. On
      in vitro day 14, cells exhibited increased levels of 3,4-dihydroxyphenylacetic
      acid and homovanillic acid (by 34% and 55%, respectively), and elevations of both
      the spontaneous and potassium-stimulated dopamine release by 70%. The dopamine
      transport and metabolism of cells exposed to hypoxia between in vitro days 4 and
      6 remained unchanged with regard to long-term effects. The present study provides
      strong evidence for the induction of long-term changes in dopaminergic cells due
      to hypoxia during the critical developmental period in mesencephalic culture. The
      developmental period capable of inducing long-lasting changes in dopamine
      metabolism is restricted to in vitro days 1-3.

PMID- 10408619
TI  - Ontogeny of neurotrophin receptor trkC expression in the rat forebrain and
      anterior hypothalamus with emphasis on the suprachiasmatic nucleus.
AB  - There is little information about neurotrophic regulation in the developing rat
      hypothalamus. In the present study, we therefore examined the expression of
      neurotrophin receptor TrkC in the developing forebrain and hypothalamus. In situ
      hybridization of coronal sections revealed that on the 15th day of gestation,
      trkC messenger RNA expression is homogeneously distributed over the neocortex,
      septum, thalamus, hypothalamus, hippocampus, rhinencephalon and the amygdala.
      Exceptions were the anteroventral nucleus of the hypothalamus and the striatum,
      which showed higher levels of trkC messenger RNA expression, and the germinal
      zones which were devoid of trkC messenger RNA. After birth, the homogeneous
      staining pattern changes into a heterogeneous staining pattern like that found in
      adulthood. TrkC expression is observed in the area of the suprachiasmatic nucleus
      as early as E17 and continues until adulthood. The presence of the TrkC receptor
      in the E17 suprachiasmatic nucleus suggests that neurotrophin-3 plays a role in
      development of this structure and that application of neurotrophin-3 could
      stimulate neuronal survival and neuritic outgrowth in a suprachiasmatic nucleus
      transplantation model.

PMID- 10408620
TI  - Expression of the genes for alpha-type and beta-type calcitonin gene-related
      peptide during rat embryogenesis.
AB  - Throughout rat embryogenesis we analysed the expression patterns of the three
      mature transcripts generated from the two calcitonin gene-related peptide genes:
      calcitonin, alpha-calcitonin gene-related peptide, and beta-calcitonin gene
      related peptide messenger RNAs. In addition, we examined in parallel the
      distribution of calcitonin gene-related peptide and calcitonin immunoreactivity.
      Of the three transcripts, beta-calcitonin gene-related peptide messenger RNA was
      first detected in sensory ganglia on embryonic day 14, and by embryonic day 15
      was seen to a lesser degree in motor neurons and autonomic ganglia. Starting at
      embryonic day 16, however, the highest levels of beta-calcitonin gene-related
      peptide messenger RNA were found in motor neurons rather than sensory ganglia.
      Alpha-calcitonin gene-related peptide messenger RNA was first detected on
      embryonic day 16 in both sensory ganglia and motor neurons, but at lower levels
      than beta-calcitonin gene-related peptide, particularly in the motor neurons of
      the spinal cord. By embryonic day 20, transcripts for alpha- and beta-calcitonin
      gene-related peptide were expressed in distinct brain regions. High levels of
      alpha-calcitonin gene-related peptide messenger RNA were detected in hypoglossal,
      facial, and parabrachial nuclei, and moderate levels in the trigeminal motor and
      ambiguus nuclei. By contrast, beta-calcitonin gene-related peptide messenger RNA
      was detected at low levels in hypoglossal, ambiguus, facial, and parabrachial
      nuclei, and at high levels in the trigeminal nucleus. In the oculomotor-trochlear
      nucleus, beta-calcitonin gene-related peptide messenger RNA was the sole isotype
      expressed. Low levels of messenger RNA for both calcitonin gene-related peptide
      transcripts were appreciated in the inferior olive. Outside the nervous system,
      alpha-calcitonin gene-related peptide messenger RNA was weakly expressed in the
      thyroid gland and beta-calcitonin gene-related peptide messenger RNA in the
      thymus. Throughout embryogenesis, calcitonin gene-related peptide
      immunoreactivity usually followed the expression of either alpha- or beta
      calcitonin gene-related peptide messenger RNA. Calcitonin messenger RNA and
      protein were detected only in the thyroid gland from embryonic day 18 onward.
      This work shows that of the three mature transcripts produced by the two
      calcitonin gene-related peptide genes, beta-calcitonin gene-related peptide
      messenger RNA is the predominant transcript produced early in rat embryogenesis.
      However, by perinatal stages alpha-calcitonin gene-related peptide shows the
      highest expression in the brain and spinal cord. In autonomic ganglia, beta
      calcitonin gene-related peptide is either the sole or the predominant transcript.
      Unlike the chick embryo in which calcitonin messenger RNA is expressed early in
      the CNS, in rat it was only expressed outside the nervous system in the thyroid
      gland during the last days of embryogenesis.

PMID- 10408621
TI  - Immunocytochemical evidence of vesicular localization of the orphan transporter
      RXT1 in the rat spinal cord.
AB  - Rxt1, a member of the Na+/Cl- orphan transporter family, exhibits numerous
      features suggesting a role as plasma membrane transporter. Despite numerous
      attempts, its substrate has not yet been identified, although immunocytochemical
      studies have shown that Rxt1 distribution generally matches that of glutamate or
      GABA. In order to further characterize Rxt1, its detailed immunocytochemical
      distribution in the rat spinal cord and dorsal root ganglia was studied at both
      light microscope and ultrastructural levels. The widespread distribution of Rxt1
      in spinal cord and ganglia cannot be correlated with any known classical or
      peptidergic transmitter. Rxt1 is expressed in a subpopulation of glutamatergic
      primary afferent fibers, in large and medium-sized ganglion cells, while small
      glutamate cells exhibit generally no Rxt1-like immunoreactivity. In the spinal
      cord, Rxt1-immunoreactive cell body distribution is quite ubiquitous since Rxt1
      is expressed in all laminae in various neuronal types like interneurons, some
      projection neurons and motoneurons. Some of these neurons are cholinergic. At the
      electron microscope level, the peroxidase labeling was never localized to the
      plasma membrane, but rather associated with different organelles including the
      outer membrane of small synaptic vesicles and large granular vesicles. This
      localization resembles that of vesicular transporters detected with the same
      method and suggests that Rxt1, in contrast to other Na+/Cl- transporters, is
      expressed on vesicles. This was confirmed using a pre-embedding silver
      intensified colloidal gold method. Indeed, most gold particles appeared to be
      localized into the axoplasm on synaptic vesicle accumulations; only few gold
      particles were observed close to the plasma membrane. These results suggest that
      Rxt1, despite its molecular characteristics predicting a plasma membrane
      localization, might be a vesicular transporter.

PMID- 10408622
TI  - Blockade of 5-hydroxytryptamine (serotonin)-2 receptors alters interleukin-1
      induced changes in rat sleep.
AB  - Recent data suggest that interleukin-1-induced enhancement of non-rapid eye
      movement sleep is mediated, in part, by the serotonergic system. To determine if
      sleep changes induced by interleukin-1 are mediated by a specific serotonergic
      receptor subtype, we evaluated interleukin-1 effects on sleep in rats pretreated
      with the 5-hydroxytryptamine (serotonin)-2 receptor antagonist ritanserin.
      Ritanserin (0.63 mg/kg, intraperitoneally) by itself did not alter sleep-wake
      behavior, although it did reduce cortical brain temperature. Interleukin-1 (5 ng,
      intracerebroventricularly) enhanced non-rapid eye movement sleep, suppressed
      rapid eye movement sleep, and induced a moderate febrile response. Pretreatment
      with ritanserin completely blocked the febrile response to interleukin-1 and
      abolished the interleukin-1-induced enhancement in non-rapid eye movement sleep
      that occurred during postinjection hours 3-4, without altering interleukin-1
      effects on rapid eye movement sleep. The present data suggest that serotonin may
      partially mediate interleukin-1 effects on sleep by interacting with 5
      hydroxytryptamine (serotonin)-2 receptors. These results also suggest that
      interactions between the serotonergic system and interleukin-1 may be important
      in regulating sleep-wake behavior.

PMID- 10408623
TI  - Action potential-dependent calcium transients in myenteric S neurons of the
      guinea-pig ileum.
AB  - Simultaneous intracellular microelectrode recording and Fura-2 imaging was used
      to investigate the relationship between intracellular calcium ion concentration
      ([Ca2+]i) and excitability of tonic S neurons in intact myenteric plexus of the
      guinea-pig ileum. S neurons were impaled in myenteric ganglia, at locations near
      connections with internodal strands. The calcium indicator Fura-2 was loaded via
      the recording microelectrode. The estimated [Ca2+]i of these neurons was
      approximately 95 nM (n = 25). Intracellular current injection (200 ms pulses, 0.2
      nA, delivered at 0.05 Hz) resulted in action potential firing throughout the
      stimulus pulse, accompanied by transient increases in [Ca2+]i (to approximately
      240 nM, n = 12). Increasing the number of evoked action potentials by increasing
      stimulus duration (100-500 ms) or intensity (0.05-0.3 nA) produced
      correspondingly larger [Ca2+]i transients. Single action potentials rarely
      produced resolvable [Ca2+]i events, while short bursts of action potentials
      (three to five events) invariably produced resolvable [Ca2+]i increases. Some
      neurons demonstrated spontaneous action potential firing, which was accompanied
      by sustained [Ca2+]i increases. Action potential firing and [Ca2+]i increases
      were also observed by activation of slow synaptic input to these neurons, in
      cases where the slow depolarization initiated action potential firing. Action
      potentials (evoked or spontaneous) and associated [Ca2+]i transients were
      abolished by tetrodotoxin (1 microM). Omega-conotoxin GVIA (100 nM) reduced
      [Ca2+]i transients by approximately 67%, suggesting that calcium influx through N
      type calcium channels contributes to evoked [Ca2+]i increases. The S neurons in
      this study showed prominent afterhyperpolarizations following bursts of action
      potential firing. The time-course of afterhyperpolarizations was correlated with
      the time-course of evoked [Ca2+]i transients. Afterhyperpolarizations were
      blocked by tetrodotoxin and reduced by omega-conotoxin GVIA, suggesting that
      calcium influx through N-type channels contributes to these events. The
      electrical properties of Fura-2-loaded neurons were not significantly different
      from properties of neurons recorded without Fura-2 injection, suggesting that
      Fura-2 injection alone does not significantly influence the electrical properties
      of these cells. These data indicate that myenteric S neurons in situ show
      prominent, activity-dependent increases in [Ca2+]i. These events can be generated
      spontaneously, or be evoked by intracellular current injection or synaptic
      activation. [Ca2+]i transients in these neurons appear to involve action
      potential-dependent opening of N-type calcium channels, and the elevation in
      [Ca2+]i increase may underlie afterhyperpolarizations and regulate excitability
      of these enteric neurons.

PMID- 10408625
TI  - Differential subcellular immunolocalization of voltage-gated calcium channel
      alpha1 subunits in the chinchilla cristae ampullaris.
AB  - The immunohistochemical localization of alpha1A, alpha1B, alpha1C, alpha1D and
      alpha1E voltage-gated calcium channel subunits was investigated in the chinchilla
      cristae ampullaris and Scarpa's ganglia at the light and electron microscopy
      level with the use of specific antipeptide antibodies directed against these
      subunits. The stereocilia membrane of type I and type II hair cells was
      immunoreactive for alpha1B along its entire length. The basolateral membrane of
      both types of hair cells was alpha1B, alpha1C and alpha1D immunoreactive. Neurons
      in the Scarpa's ganglia and afferent nerve terminals in the cristae were
      immunoreactive for alpha1C and alpha1B. No specific immunoreactivity to alpha1A
      or alpha1E was seen in the sensory epithelia or ganglia. These findings are
      consistent with the presence of alpha1B (N-type channel), alpha1C and alpha1D (L
      type channels) in the vestibular hair cells, and alpha1B (N-type channel) and
      alpha1C (L-type channel) in primary vestibular neurons.

PMID- 10408626
TI  - Microangiographic changes following cerebral contusion in rats.
AB  - The purpose of this study was to investigate the acute changes due to cerebral
      contusion in the large vessels and microvasculature in the rat. Thirty adult
      Sprague-Dawley rats underwent craniectomy performed in the left parietal region,
      producing a burr hole approximately 8-12 mm in diameter. The dura was left intact
      and a solid glass rod with a base diameter of 6 mm and weighing 5.2 g was dropped
      on the brain. Silicone rubber perfusion was performed at 24 h (10 rats) and 48 h
      (10 rats). Ten rats served as normal controls. The perfused brains were cleared
      using the alcohol-methylsalicylate technique. The results showed that the
      arterial and venous systems were clearly visualized by silicone rubber
      microangiography in the normal rat. Silicone rubber microangiography provided an
      excellent three-dimensional method for defining the distribution of the
      vasculature of the normal and contusioned rat brain, and was helpful in
      elucidating the pathophysiology of post-traumatic ischemia and hemorrhages of the
      brain. The brain displayed marked ischemia and hemorrhage at the contusion site.
      The hemorrhages were distributed throughout regions of white and gray matter at
      the injury site. All contusioned animals of those superficial arteries were
      irregularly filled or unfilled. The present study suggests that the pathogenesis
      of the post-traumatic brain may be related to damage of the superficial arteries
      and their arterial branches. Comparison of the brains from animals killed at 24
      and 48 h following contusion revealed that the contusion was more severe 24 h
      after the vascular damage than after 48 h. Therefore, in the brains that were
      killed at 48 h, the contusion site was less avascular than those at the earlier
      times.

PMID- 10408624
TI  - Co-expression in Xenopus neurons and neuroendocrine cells of messenger RNA
      homologues of exocytosis proteins DOC2 and munc18-1.
AB  - The proteins munc18-1 and DOC2 are assumed to play a role in docking of synaptic
      vesicles in neurotransmitter exocytosis at the presynaptic junction. As the
      proteins are known to interact, they should co-exist within neurons. We have
      tested this hypothesis for exocytosis of both classical and peptidergic
      messengers, by investigating the distribution of the messenger RNAs of munc 18-1
      and DOC2 homologues in the brain and pituitary gland of the clawed toad Xenopus
      laevis, using in situ hybridization. For this purpose we cloned a partial
      complementary DNA encoding Xenopus unc18 (xunc18) and used a corresponding RNA
      probe, together with an RNA probe for Xenopus DOC2. At the messenger RNA level
      DOC2 and xunc18 were found to be expressed throughout the Xenopus brain. All
      brain nuclei expressing DOC2-messenger RNA showed xunc18-messenger RNA expression
      as well. Co-expression was shown at the individual cell level in consecutive
      sections of large-sized neurons. A strong expression was demonstrated in the
      suprachiasmatic and magnocellular nuclei and in peptidergic endocrine cells in
      the intermediate and anterior lobes of the pituitary gland, suggesting roles of
      DOC2 and xunc18 in messenger release from peptidergic secretory systems. Combined
      in situ hybridization and immunocytochemical analyses show that neuropeptide Y
      containing cells in the suprachiasmatic nucleus also express DOC2 and xunc18
      messenger RNAs. Since these cells have a high secretory activity, controlling the
      activity of the pituitary pars intermedia, the levels of expression of DOC2 and
      xunc18 may be indicators for neuronal secretory activity. The present data
      represent the first evidence for the co-existence of DOC2 and munc18-1 and
      suggest co-ordinate action of these proteins at the level of brain nuclei,
      individual neurons and endocrine cells.

PMID- 10408627
TI  - Prevention of ultraviolet radiation-induced suppression of contact
      hypersensitivity by Aloe vera gel components.
AB  - We have recently reported that Aloe vera gel contains small molecular weight
      immunomodulators, G1C2F1, that restore ultraviolet B (UVB)-suppressed accessory
      cell function of epidermal Langerhans cells (LC) in vitro. In the present study
      we evaluated the UVB-protective activity of G1C2F1 in vivo. Exposure of the
      shaved abdominal skin of mice to 2.4 KJ/m2 of UVB radiation resulted in
      suppression of contact sensitization through the skin to 41.1%, compared to
      normal unirradiated skin. Topical application of G1C2F1 immediately after
      irradiation reduced this suppression significantly. The percentage recovery of
      UVB-suppressed contact hypersensitivity (CHS) response was 52.3, 77.3, and 86.6%
      when the irradiated skin was treated once with 0.1, 0.5, and 2.5 mg/ml of G1C2F1
      containing cream, respectively. G1C2F1 did not show nonspecific stimulatory
      activity on CHS response. The present study, together with the previous
      observation, show that Aloe vera gel contains small molecular weight
      immunomodulators that prevent UVB-induced immune suppression in the skin by
      restoration of UVB-induced damages on epidermal LC.

PMID- 10408628
TI  - Oral administration of hot water extracts of Chlorella vulgaris reduces IgE
      production against milk casein in mice.
AB  - Hot water extract of Chlorella vulgaris (CVE) is a biological response modifier
      (BRM) which enhances resistance to Listeria monocytogenes through augmentation of
      helper T cell type 1 (Thl) responses producing gamma-interferon (gammaIFN). We
      show here that oral administration of CVE in mice suppressed the production of
      immunoglobulin (Ig)E against casein antigen accompanied by increased gammaIFN and
      IL-12 mRNA expression. Oral administration of CVE enhanced Thl response to casein
      in the spleen of casein immunized mice. CVE may be useful for prevention of
      allergic diseases with a predominant Th2 response.

PMID- 10408629
TI  - Complement modulatory activity of bisbenzylisoquinoline alkaloids isolated from
      Isopyrum thalictroides--I. Influence on classical pathway in human serum.
AB  - Eleven bisbenzylisoquinoline alkaloids (BBI) were isolated from the plant
      Isopyrum thalictroides (L.). Treatment of normal human serum (NHS) with BBI
      resulted in a diminution of the haemolytic activity of the classical pathway
      (CP). The mode of action of the main alkaloids isopyruthaline (It1),
      fangchinoline (It2) and isotalictrine (It3) on CP activation was investigated in
      vitro. The inhibition was time- and temperature-related and for Itl and It3
      depended on the concentration of Ca2+ and Mg2+ ions. It was established that the
      substances reduced C1 haemolytic activity. It2 and It3 enhanced the complement
      consumption caused by heat aggregated human IgG (HAGG). The BBI prevented the
      formation of C3 convertase of the classical pathway. The loss of haemolytic
      activity was partially restored by the addition of C142 reagent (zymosan-treated
      guinea pig serum) to alkaloids-treated NHS. The addition of the late components
      C3-9 (EDTA-treated rat sera) recovered to some extent the haemolytic activity of
      It1-treated NHS, but not of It2- and It3-treated NHS.

PMID- 10408630
TI  - Complement modulatory activity of bisbenzylisoquinoline alkaloids isolated from
      Isopyrum thalictroides--II. Influence on C3-9 reactions in vitro and
      antiinflammatory effect in vivo.
AB  - The main alkaloids isopyruthaline (It1), fangchinoline (It2) and isothalictrine
      (It3), isolated from Isopyrum thalictroides (L.) were investigated in complement
      mediated reactions. The alkaloids influenced the alternative pathway (AP)
      activity in normal human serum (NHS). They enhanced the inhibitory action of
      complement activators--carrageenan (Car), zymosan (Zy), hydrogen peroxide (HP)
      and high temperature via classical pathway (CP) in NHS. Substances strongly
      potentiated the action of zymosan and cobra venom (CV) in guinea pig serum (GPS).
      It was established that they could provoke C3 conversion in NHS and mouse sera
      (MS). The antiinflammatory properties of the alkaloids were evaluated in mouse
      paw oedema induced by CV, Zy and histamine (His). Isopyruthaline and
      isothalictrine suppressed paw swelling in CV- and Zy-oedema. They were applied in
      Zy-induced multiple organ dysfunction syndrome (MODS) in mice. The alkaloids
      inhibited the increase of the serum complement activity provoked by the injection
      of zymosan. Itl lowered the mortality rate of mice with MODS if its application
      proceeded Zy. An increase of the number of mice without tissue injury was
      established after treatment with It1 and It3.

PMID- 10408631
TI  - Analysis of in vivo immunosuppressive and in vitro interaction with constitutive
      heat shock protein 70 activity of LF08-0299 (Tresperimus) and analogues.
AB  - LF08-0299 (Tresperimus) is a new immunosuppressive analogue of Gusperimus (15
      deoxyspergualin or DSG). Despite the fact that its mechanism of action remains
      unknown, DSG has previously been demonstrated to bind specifically to Hsc70
      protein, a constitutive or cognate member of heat shock protein 70 family. Herein
      we further explore whether immobilised LF08-0299 will selectively retain the heat
      shock protein Hsc70. We analysed the correlation between biological activity in
      vivo in the prevention of murine graft-vs-host disease (GVHD) and the ability in
      vitro in dissociating Hsc70 from LF08-0299 resin for LF08-0299 and structural
      analogues. The Hsc70 protein bound to the LF08-0299 immobilised specifically via
      the spermidine primary amino group and could be successfully eluted from the
      column by various analogues of LF08-0299. All immunosuppressants tested were able
      to competitively bind Hsc70 although some biological inactive compounds could as
      well. Our data suggests that LF08-0299 and its active analogue effects were not
      mediated directly through the interaction of molecules with Hsc70. The mechanism
      of action probably occurred by more than one step, the first being the binding of
      Hsc70.

PMID- 10408632
TI  - Myeloid progenitor cells mediate immune suppression in patients with head and
      neck cancers.
AB  - Patients with squamous cell carcinomas of the head and neck (HNSCC) have profound
      defects in their immune defenses. We have shown that among the mechanisms that
      contribute to this immune dysfunction are immune inhibitory CD34+ progenitor
      cells, whose levels become elevated in the peripheral blood and within the tumor
      tissue. One goal of our studies is to overcome the immune inhibitory activities
      of tumor-induced CD34+ progenitor cells by stimulating their differentiation into
      cells, such as dendritic or monocytic cells, that can stimulate immune reactivity
      to autologous cancer. Results of in vitro analyses with CD34+ suppressor cells of
      HNSCC patients and of in vivo studies in animal tumor models have shown the
      capacity of tumor-induced CD34+ cells to differentiate into cells that
      phenotypically resemble monocytic or dendritic cells. Whether these cells can
      differentiate into dendritic cells in HNSCC patients is currently being tested.
      Less clear is whether the pathway by which the tumor-induced CD34+ cells
      differentiate will result in cells having the full capacity to function as potent
      stimulators of immune reactivity to autologous tumor.

PMID- 10408634
TI  - Neutrophil function in workers exposed to organophosphate and carbamate
      insecticides.
AB  - Neutrophil function in 40 workers occupationally exposed to carbamate and
      organophophate insecticides were examined and compared to those of non-exposed
      individuals. Phagocytosis and intracellular killing of Candida albicans and
      Candida pseudotropicalis by neutrophils were studied. Two species of Candida were
      used since in individuals with myeloperoxidase deficiency neutrophils are unable
      to kill Candida albicans, while Candida pseudotropicalis can be effectively
      lysed. Phagocytosis of both antigens was normal in all the workers studied. On
      the other hand, there was a considerable reduction in the ability of neutrophils
      from exposed workers to kill Candida albicans whereas Candida pseudotropicalis
      was effectively lysed. This finding indicates some interference with the
      myeloperoxidase activity in the exposed population. The levels of cholinesterase
      activity in all workers were normal. These results demonstrate that exposure to
      carbamates and organophophates insecticides may lead to changes in neutrophil
      function even in workers presenting no impairment in the cholinesterase activity.

PMID- 10408633
TI  - Effects of corticosteroids on HCV infection.
AB  - The risk factors for clinical recurrent hepatitis C in liver transplant
      recipients are not clearly defined. It has been suggested that the
      corticosteroids included in the treatments of patients undergoing allograft
      rejection might induce acute hepatitis by increasing HCV replication. In this
      study we investigated the effects of corticosteroid boluses on HCV viremia in
      liver allograft recipients treated for acute rejection. Since we had previously
      developed a model of HCV replication in peripheral blood mononuclear cells (PBMC)
      in vitro, we also studied the effects of corticosteroids on HCV replication in
      vitro. A transient peak of HCV viremia was observed in patients treated with
      corticosteroid boluses for an acute allograft rejection. In the cell cultures,
      corticosteroids induced an increase of the total amount of viral RNA detectable.
      Our results demonstrate that corticosteroids induce an increase of hepatitis C
      virus replication in vivo and in vitro.

PMID- 10408635
TI  - Contribution of zinc to reduce CD4+ risk factor for 'severe' infection relapse in
      aging: parallelism with HIV.
AB  - Aging and HIV have parallelism in immunodeficiency status because of the
      appearance of infections or relapse leading to death in both conditions. HIV-RNA
      is predictor for HIV progression correlated with CD4+ depletion. CD4+ and plasma
      zinc levels (zincaemia) may be predictors for infections relapse in aging because
      of zinc relevance for normal immune efficiency against infections and for CD4+
      growth. Moreover, zincaemia decreases in aging and infection. A total of 67
      elderly subjects affected by infections resistant to antibiotic therapy were
      recruited. A total of 28 HIV+ subjects with HAART therapy were also used. CD4+
      depletion (507 mm3) and zincaemia deficiency (76 microg/dl), as compared to CD4+
      (700-1100 mm3) and zincaemia (85-100 microg/dl; age 40-75 years) normal ranges,
      are possible limits (Cox hazard regression) for severe infections relapse, such
      as chronic obstructive bronchitis and bronchopneumonia by bacteria or Candida
      complication, in aging. CD4+ and zincaemia values are within the lower limits of
      normal range in urinary tract infections. Zincaemia and HIV-RNA or CD4+ are
      inversely correlated (r = 0.57 and r = 0.72, respectively) in HIV+ HAART treated
      subjects. Consequently there is no appearance of opportunistic infections.
      Parallelism between aging and HIV may exist because of the resemblance in marked
      zinc deficiency and CD4+ depletion with high scores in relative risks for severe
      infections relapse. Supplementing zinc (12 mg Zn++/day) for one month in infected
      elderly subjects and HAART therapy in HIV+ subjects reduces risk scores in CD4+
      and zincaemia deficiencies for infections relapse, suggesting that the zinc
      beneficial effect may be independent either by HIV-virus or pathogen agents
      involved. While HAART may reduce the occurrence of opportunistic infections in
      HIV by means of also major zinc bioavailability, supplementing zinc can be
      recommended in elderly people as resistance to infections. Since zinc deficiency
      is correlated with CD4+ depletion, this latter may also be good diagnostic marker
      to detect 'clear immunodeficiency' in aging, as in HIV condition.

PMID- 10408636
TI  - Immunomodulatory effect of Nigella sativa proteins fractionated by ion exchange
      chromatography.
AB  - Whole Nigella sativa (N. sativa) proteins were purified on a DEAE Sephadex A50
      ion exchange column. Complete fractionation was achieved in four peaks. Analysis
      of the purified peaks was carried out by sodium dodecyl sulphate polyacrylamide
      gel electrophoresis. Whole N. sativa showed a number of protein bands ranging
      from 94-10 kDa molecular mass. In mixed lymphocyte cultures (MLC), whole N.
      sativa and its purified proteins were found stimulatory as well as suppressive
      and this effect varied from one donor to another. Maximum stimulation (mean +
      S.E. of % relative index was 63.73 + 20.78) was observed with fractionated N.
      sativa proteins (P1) (10 microg/ml) in MLC. In MLC, also N. sativa peaks (P1 and
      P2) were stimulatory at all concentrations (10 microg/ml, 1 microg/ml or 0.1
      microg/ml) used. However, a uniformly suppressive effect of N. sativa and its all
      four peaks at a concentration of 10 microg/ml was noticed when lymphocytes were
      activated with pokeweed mitogen (PWM). The effect of N. sativa proteins was
      further evaluated on the production of cytokines which were measured by using
      specific enzyme-linked immunosorbent assay. Large quantities of IL-1beta were
      secreted by whole N. sativa in culture medium with non-activated peripheral blood
      mononuclear cells (PBMC) (450 pg/ml) and with allogeneic cells (410 pg/ml).
      Fractionated N. sativa was less effective when compared with whole N. sativa
      proteins. No effect on IL-4 secretion was seen either by using non-activated, PWM
      activated or allogeneic-cells. Whole N. sativa suppressed as well as stimulated
      the production of IL-8 in non-activated and PWM-activated PBMC respectively. All
      N. sativa peaks with protein concentration of 2 microg/ml were stimulatory for
      the induction of IL-8 by PWM-activated cells. However, no effect on IL-8 was seen
      either with whole N. sativa or its peaks when allogeneic PBMC were used.
      Stimulatory effect of whole N. sativa and fractionated proteins was also noticed
      on the production of TNF-alpha either using non-activated or mitogen activated
      cells.

PMID- 10408637
TI  - Biosynthesis and characterization of poly(3-hydroxybutyrate-co-3-hydroxyvalerate)
      produced by Burkholderia cepacia D1.
AB  - Copolyesters of 3-hydroxybutyrate (3HB) and 3-hydroxyvalerate (3HV) were produced
      by Burkholderia cepacia D1 at 30 degrees C in nitrogen-free culture solutions
      containing n-butyric acid and/or n-valeric acid. When n-valeric acid was used as
      the sole carbon source, the 3HV fraction in copolyester increased from 36 to 90
      mol% as the concentration of n-valeric acid in the culture solution increased
      from 1 to 20 g/l. The addition of n-butyric acid to the culture solution resulted
      in a decrease in the 3HV fraction in copolyester. The copolymers biosynthesized
      by this method were mixtures of random copolymers having a wide variety of
      composition of the 3HV component. The melting points of the fractionated
      copolymers show a concave curve with the minimum at the 3HV content of
      approximately 40 mol%. The alpha-parameter of lattice indices of the P(3HB)
      crystal for the fractionated copolymers largely increased as the 3HV composition
      increased. Biodegradability of the copolymer increased with the lower content of
      3HV composition and/or the lower crystallinity.

PMID- 10408638
TI  - On the interchain associations in aqueous solutions of a succinoglycan
      polysaccharide.
AB  - Formation of interchain associations between succinoglycan chains have been
      studied by comparing weight average molecular weight, intrinsic viscosity of
      succinoglycan as a function of the conditions to prepare the solutions (polymer
      concentration, the heating temperature adopted compared with Tm). The different
      solutions obtained were characterized by their Newtonian viscosity, the storage
      and loss moduli and their sensitivity to the temperature. It was found that
      interchain associations, first stabilized mainly during the disorder-order
      transition convert to more stable associations by aging at temperatures below but
      not too far from Tm. These associations appear from succinoglycan solutions
      characterized by an overlap parameter higher than about 8 and modify only very
      slightly the conformational transition parameters obtained from microcalorimetry
      measurements.

PMID- 10408640
TI  - Thermal helix-coil transition in UV irradiated collagen from rat tail tendon.
AB  - The thermal helix-coil transition in UV irradiated collagen solution, collagen
      film and pieces of rat tail tendon (RTT) were compared. Their thermal stability's
      were determined by differential scanning calorimeter (DSC) and by viscometric
      measurements. The denaturation temperatures of collagen solution, film and pieces
      of RTT were different. The helix-coil transition occur near 40 degrees C in
      collagen solution, near 112 degrees C in collagen film, and near 101 degrees C in
      pieces of RTT. After UV irradiation the thermal helix-coil transition of collagen
      samples were changed. These changes depend on the degree of hydratation.

PMID- 10408639
TI  - Substrate and binding specificities of bacterial polyhydroxybutyrate
      depolymerases.
AB  - The substrate specificities of three extracellular polyhydroxybutyrate (PHB)
      depolymerases from Alcaligenes faecalis (PhaZ Afa), Pseudomonas stutzeri (PhaZ
      Pst), and Comamonas acidovorans (PhaZ Cac), which are grouped into types A and B
      based on the position of a lipase box sequence in the catalytic domain, were
      examined for films of 12 different aliphatic polyesters. Each of these PHB
      depolymerases used was capable of hydrolyzing poly(3-hydroxybutyrate) (P(3HB)),
      poly(3-hydroxypropionate) (P(3HP)), poly(4-hydroxybutyrate) (P(4HB)),
      poly(ethylene succinate) (PESU), and poly(ethylene adipate) (PEA) but could not
      hydrolyze another seven polyesters. In addition, the binding characteristics of
      substrate binding domains from PhaZ Afa, PhaZ Cac, and PHB depolymerase from
      Comamonas testosteroni (PhaZ Cte) were studied by using fusions with glutathione
      S-transferase (GST). All of fusion proteins adsorbed strongly on the surfaces of
      polyester granules of P(3HB), P(3HP), and poly(2-hydroxypropionate) (P(2HP))
      which was not hydrolyzed by the PHB depolymerases used in this study, while they
      did not bind on Avicel and chitin granules. The adsorption kinetics of the fusion
      proteins to the surface of P(3HB) and P(2HP) granules were found to obey the
      Langmuir isotherm. The cross-area per molecule of fusion protein bound to P(3HB)
      granules was estimated to be 12+/-4 nm2/molecule. It has been suggested that the
      active sites in catalytic domains of PHB depolymerases have a similar
      conformational structure, and that several amino acids in substrate-binding
      domains of PHB depolymerases interact specifically with the surface of
      polyesters.

PMID- 10408641
TI  - Thermal properties of corn gluten meal and its proteic components.
AB  - Thermal properties of corn gluten meal (CGM) and of its extracted proteic
      components (zein and glutelin) at 0% moisture content, is studied by dynamic
      mechanical thermal analysis (DMTA) and modulated differential scanning
      calorimetry (MDSC). The glass transition temperature (Tg) on first heating, is
      measured at 176 and 174 degrees C, respectively, for hot-air-dried and native
      CGM. For zein and glutelin isolated fractions, the measured Tg values are 164 and
      209 degrees C, respectively. The calculated Tg from using Matveev's method
      (Matveev YI. Spec Publ R Soc Chem 1995;156;552) is in good agreement with
      experimental data for zein, a well defined protein. MDSC allows the measurement
      of change in heat capacity at Tg (deltaCp) with a single heating scan, avoiding
      sample alteration, and deltaCp values are 0.365 J/g per K for zein and 0.184 J/g
      per K for glutelin. The differences observed in Tg, relaxation temperatures,
      deltaCp and tan delta peak height are related to differences in the structure of
      the proteins, through the cross-linkages and hydrogen or van der Waals
      interactions. Experimental data from DMTA and MDSC, and the Couchman-Karasz
      thermodynamic approach indicate that CGM behaves as a miscible blend of its
      components, with high non-polar interactions between zein and glutelin proteins.

PMID- 10408642
TI  - Solution conformation of brazzein by 1H nuclear magnetic resonance: resonance
      assignment and secondary structure.
AB  - Brazzein is a sweet-tasting protein isolated from the fruit of the West African
      plant Pentadiplandra brazzeana Baillon. It is the smallest and the most water
      soluble sweet protein discovered so far, it is also highly thermostable. The
      proton NMR study of brazzein at 600 MHz (pH 3.5, 300K) is presented. Complete
      sequence specific assignment of the individual backbone and sidechain proton
      resonances were achieved using through-bond and through-space connectivities
      obtained from standard two-dimensional NMR techniques. The secondary structure of
      brazzein contains one alpha-helix (residues 21-29), one short 3(10)-helix
      (residues 14-17), two strands of antiparallel beta-sheet (residues 34-39, 44-50)
      and probably a third strand (residues 5-7) near the N-terminus.

PMID- 10408643
TI  - The effects of polyols on the thermal stability of calf thymus DNA.
AB  - The effects on thermal denaturation of calf thymus DNA (ct-DNA) and its
      conformational changes induced by the presence in solution of different polyols,
      namely glycerol, i-erytritol, L( -- ) and D( + ) arabitol, D-mannitol, D-sorbitol
      and myo-inositol, have been investigated by means of differential scanning
      calorimetry (DSC) and circular dichroism (CD). By increasing the concentration of
      these additives a decrease in both the denaturation enthalpy (deltadH) and
      temperature of the maximum of the denaturation peak (Tmax) of DNA is observed.
      The values of these thermodynamic parameters depend on both the nature and
      concentration of the solute. The overall destabilization of DNA molecule has been
      related to the different capability of polyhydric alcohols to interact with the
      polynucleotide solvation sites replacing water and to the modification of the
      electrostatic interactions between the polynucleotide and its surrounding
      atmosphere of counterions. The particular behaviour of L( -- ) arabitol, which
      showed a much greater destabilizing ability compared to the other polyols, was
      further investigated and attributed to a direct more effective interaction with
      the double helix of DNA. CD spectra showed only a slight alteration of DNA-B
      structure in the presence of all the molecules here studied, except for L( -- )
      arabitol where the DNA molecule seems to undergo a meaningful conformational
      change. The salt concentration dependence of DNA thermal stability in the
      presence of L( -- ) arabitol indicates a conformational change of polynucleotide
      towards a more extended conformation.

PMID- 10408644
TI  - Problem-solving in real-life-type situations: the effects of anterior and
      posterior lesions on performance.
AB  - Clinical studies have described patients who show marked impairments in everyday
      life, including planning, problem-solving and decision-making. Several factors
      potentially contribute to such impairments, including difficulties in generating
      possible problem solutions, and difficulties in selecting an appropriate
      solution. The present study describes the performance of participants with
      unilateral anterior or posterior lesions compared to healthy controls in ability
      to solve real-life-type problems. These covered a range of everyday interpersonal
      situations, and were presented both in video and story format. Participants also
      carried out a set of more abstract neuropsychological tests. Those with brain
      lesions showed impairment relative to controls in both everyday problem-solving
      and on more abstract tests involving executive function and memory. The anterior
      group was impaired on more aspects of everyday problem-solving than the posterior
      group, showing reduced fluency in generating possible solutions, and also
      impairment in selecting appropriate problem solutions. The implications of the
      findings for our understanding of impairments in everyday life problem-solving
      after brain injury are discussed.

PMID- 10408645
TI  - The electrophysiology of incidental and intentional retrieval: ERP old/new
      effects in lexical decision and recognition memory.
AB  - Event-related brain potentials (ERPs), recorded from a 128-sensor array were used
      to differentiate brain processes associated with intentional vs incidental memory
      retrieval. Two experiments examined ERP differences between old (studied) and new
      (non-studied) words and pseudowords while subjects performed either a recognition
      memory task or lexical decision task. Previous research has related a P600
      old/new effect to the recollection of details, and the present experiments show
      that this effect was not amplified by intentional retrieval. The P600 effect was
      larger for words than pseudowords. An earlier (300 to 500 ms), frontally maximal,
      N400-like old/new effect ('FN400') was similar for words and pseudowords. A
      third, previously unidentified, mid-frontal, old/new effect was associated with
      only pseudoword recognition from 300 to 500 ms. Results are discussed with
      respect to dual-process theories of recognition memory.

PMID- 10408646
TI  - Slowing of reaction time in Parkinson's disease: the involvement of the frontal
      lobes.
AB  - This study investigated the possibility that the previously mixed findings
      relating to cognitive deficits in Parkinson's disease might be attributable to
      inhomogeneity within the patients sampled, with attentional deficits occurring
      only for those Parkinson's patients who also have additional frontal lobe
      impairment. Twenty-five patients with idiopathic Parkinson's disease were
      classified as showing frontal dysfunction, or not, on the basis of their
      performance on the Wisconsin Card Sorting Test and the picture arrangement
      subtest of the WAIS. The two groups, and a control group of normal elderly
      subjects matched for age and IQ, undertook tests of visual attention designed to
      dissociate baseline response speed from central information processing speed.
      Error rates did not differ between the groups. Performance of the non-frontally
      impaired Parkinson's group was indistinguishable from that of the controls. By
      contrast, the 'frontally impaired' Parkinson's group responded significantly more
      slowly than the controls. Further analyses indicated that for the frontally
      impaired Parkinson's group, information processing and automatic functions were
      unimpaired but there was a generalised slowing (as reflected by increased
      baseline response time) which may represent a non-specific global cognitive
      impairment. These findings suggest that the frontal lobes may be implicated in
      slowed response speed in Parkinson's disease.

PMID- 10408647
TI  - Functional anatomy of intrinsic alertness: evidence for a fronto-parietal
      thalamic-brainstem network in the right hemisphere.
AB  - Alertness, the most basic intensity aspect of attention, probably is a
      prerequisite for the more complex and capacity demanding domains of attention
      selectivity. Behaviorally, intrinsic alertness represents the internal
      (cognitive) control of wakefulness and arousal; typical tasks to assess optimal
      levels of intrinsic alertness are simple reaction time measurements without
      preceding warning stimuli. Up until now only parts of the cerebral network
      subserving alertness have been revealed in animal, lesion, and functional imaging
      studies. Here, in a 15O-butanol PET activation study in 15 right-handed young
      healthy male volunteers for this basic attention function we found an extended
      right hemisphere network including frontal (anterior cingulate-dorsolateral
      cortical)-inferior parietal-thalamic (pulvinar and possibly the reticular
      nucleus) and brainstem (ponto-mesencephalic tegmentum, possibly involving the
      locus coeruleus) structures, when subjects waited for and rapidly responded to a
      centrally presented white dot by pressing a response key with the right-hand
      thumb.

PMID- 10408648
TI  - Impaired spelling in Alzheimer's disease: a linguistic deficit?
AB  - Different kinds of real words and pronounceable pseudowords (PWs) were presented
      for writing to dictation to patients with the diagnosis of probable Alzheimer's
      disease (AD) and to age- and education-matched healthy controls. Though spelling
      less accurately on all tasks, AD patients responded in a manner generally
      qualitatively similar to controls. Except for a slightly enhanced effect of
      spelling regularity in real word writing accuracy, AD patients showed the same
      sensitivity to various lexical, orthographic and phonological variables as
      controls. Both groups showed no difference in spelling accuracy for words and PWs
      with regular vs ambiguous spelling patterns, and groups also showed similar
      orthographic preferences when spelling PWs having several different acceptable
      pronunciations. Finally, AD patients and controls produced similar types of
      errors when spelling real words. Dementia severity was related to the overall
      accuracy, but not to the pattern, of spelling responses. It is suggested that the
      decline in response accuracy in cognitively demanding writing tasks in patients
      with more advanced dementia is most likely due to semantic impairment and
      impairments of nonlinguistic functions of attention, executive control and
      praxis, rather than to a disturbance within language specific processes.

PMID- 10408649
TI  - Verbal memory in non-demented patients with idiopathic Parkinson's disease.
AB  - This study assessed the verbal memory functions of 20 patients with idiopathic
      Parkinson's Disease (PD) without any clinical evidence of dementia and 20 Medical
      Control (MC) patients with similar levels of physical disability. Performance was
      compared on tests of immediate recall, word list learning in intentional and
      incidental contexts, word completion priming, remote memory, metamemory and
      awareness of mnestic abilities. Significant differences were found in new
      learning of verbal material under incidental but not intentional learning
      conditions. Group differences were also observed on measures of remote memory and
      metamemory. The groups did not differ in word completion priming performance or
      recognition memory. These findings are consistent with other evidence suggesting
      that PD patients without dementia may have subtle cognitive deficits that affect
      memory performance. These may be attributable to impairments of attention
      allocation, formulation of retrieval strategies, and effortful learning
      associated with frontal lobe dysfunction. The group differences could not be
      attributed to impairments of intellectual functions, verbal fluency, level of
      physical disability, or mood disturbance.

PMID- 10408650
TI  - A cognitive activation study of memory for spatial relationships.
AB  - Twelve neurologically normal right-handed subjects were asked to remember the
      locations of eight representational drawings, presented one at a time, together
      with two landmarks (white squares), on a computer screen. Subjects were then
      scanned using positron emission tomography (PET) while performing forced-choice
      recognition of object location in four conditions, using either the original
      landmarks or two of the other objects as cues. In two conditions, the absolute
      location of the objects was unchanged from the time of encoding (fixed-array
      conditions), whereas in the other two, the location of the objects was shifted,
      although the spatial relationship among the objects and landmarks was maintained
      (shifted-array conditions). Subjects were also scanned in a control condition
      that made the same perceptual and motor demands as the recognition tasks but that
      had no mnemonic component. Compared to the control condition, all of the
      recognition tasks activated both the dorsal and ventral visual pathways
      bilaterally, but with notable asymmetries. In particular, activation in the
      right, but not left, inferior temporal gyrus (area 37) was observed when both
      shifted-array conditions were compared to their respective cue-matched fixed
      array conditions. The recognition conditions with landmark cues were associated
      with focal increases in regional cerebral blood flow (rCBF) in the region of the
      right parahippocampal gyrus. The results support previous reports of involvement
      of the right mesial temporal region in object-location memory tasks, and suggest
      that right inferotemporal cortex is involved in extracting the invariant
      relational features of a visual scene.

PMID- 10408652
TI  - Semantic category interference effects upon the reach-to-grasp movement.
AB  - In the present study the kinematics of the reach-to-grasp movement towards a
      target object in the presence of distractors was investigated. Three experiments
      were conducted. In the first experiment, there were three conditions, (a) the
      target alone, (b) the target presented with a distractor object that was
      semantically similar to the target and (c) the target presented with a distractor
      object that was semantically different from the target. The same conditions were
      repeated for the second experiment but the size of the distractors were also
      manipulated. For the third experiment the target was presented with a distractor
      object that was semantically different from the target but similar in shape. In
      the first experiment interference effects were observed in kinematic parameters
      of the grasp, but not for the reach component when the target and the distractor
      were semantically different. In the second and the third experiment, similar
      results were found. Results are discussed in terms of conflicting processing
      between objects pertaining to different semantic categories.

PMID- 10408651
TI  - Visuospatial attention in line bisection: stimulus modulation of pseudoneglect.
AB  - Neglect and pseudoneglect are asymmetries of spatial attention which are often
      assumed to possess a fundamental theoretical and neurological relationship to
      each other, although this assumption has never been directly tested and there is
      as yet no unifying quantitative theory. A total of 217 subjects participated in
      five experiments demonstrating that both the magnitude and direction of bisection
      errors in normal subjects (pseudoneglect) are modulated by stimulus factors that
      similarly influence the magnitude and direction of neglect. Stimulus positional
      uncertainty did not abolish pseudoneglect, indicating that bisection judgements
      are made within an object-centered frame of reference. Backward masking line
      stimuli had no influence on the magnitude of pseudoneglect, signifying that
      pseudoneglect is not a byproduct of covert directional scanning of the line
      stimulus in iconic or short-term visual memory. Finally, bisection errors are
      influenced by the direction of contrast gradients imposed on line stimuli, such
      that perceived line midpoint is drawn toward the lower-contrast line end. The
      magnitude and direction of pseudoneglect are modulated by stimulus factors that
      also influence the magnitude and direction of neglect. Both phenomena are
      succinctly described as biases in attention (i.e., neglect is a right-bias,
      whereas pseudoneglect is a left-bias). The two phenomena are modulated by
      stimulus factors as follows. Line length: there is an increased bias with
      increasing line length for both phenomena, and a cross-over to an reversed bias
      for short lines. Azimuthal line position: an increasing bias accompanies
      increasing leftward placement for both phenomena. Line aspect ratio: there is a
      decreasing bias with increasing line height for both phenomena. Line elevation:
      there is a decreasing bias with increasing elevation for neglect, and an
      increasing bias with increasing elevation for pseudoneglect. The only case in
      which a factor's influence on the two phenomena is discrepant is for elevation,
      and this difference is explicable. Taken together these congruencies strongly
      support the notion that neglect and pseudoneglect are phenomena that are twin
      manifestations of parameter changes in a unitary set of underlying hemispheric
      attentional asymmetries.

PMID- 10408653
TI  - Dichotic listening in patients with situs inversus: brain asymmetry and situs
      asymmetry.
AB  - In order to investigate the relation between situs asymmetry and functional
      asymmetry of the human brain, a consonant-vowel syllable dichotic listening test
      known as the Standard Dichotic Listening Test (SDLT) was administered to nine
      subjects with situs inversus (SI) that ranged in age from 6 to 46 years old (mean
      of 21.8 years old, S.D. = 15.6); the four males and five females all exhibited
      strong right-handedness. The SDLT was also used to study twenty four age-matched
      normal subjects that were from 6 to 48 years old (mean 21.7 years old, S.D. =
      15.3); the twelve males and twelve females were all strongly right-handed and
      served as a control group. Eight out of the nine subjects (88.9%) with SI more
      often reproduced the sounds from the right ear than sounds from the left ear;
      this is called right ear advantage (REA). The ratio of REA in the control group
      was almost the same, i.e., nineteen out of the twenty-four subjects (79.1%)
      showed REA. Results of the present study suggest that the left-right reversal in
      situs inversus does not involve functional asymmetry of the brain. As such, the
      system that produces functional asymmetry in the human brain must independently
      recognize laterality from situs asymmetry.

PMID- 10408654
TI  - Apraxia and motor-skill acquisition in Alzheimer's disease are dissociable.
AB  - Many patients with Alzheimer's disease (AD) are apraxic and the apraxia has been
      posited to be related to a loss of movement representations. Whereas patients
      with Alzheimer's disease have been reported to demonstrate normal motor learning
      on a rotor pursuit skill acquisition task, it is unknown whether AD subjects who
      are apraxic demonstrate normal skill-learning. We tested subjects with probable
      AD and normal controls on a rotor pursuit task. We also tested the AD subjects
      for ideomotor apraxia. Subjects with AD who were apraxic had normal motor
      learning. In addition, praxis score did not correlate with performance on the
      skill-acquisition task. The results suggest that ideomotor praxis and motor
      learning are at least partly dissociable.

PMID- 10408655
TI  - 14C-deoxyglucose mapping of the monkey brain during reaching to visual targets.
AB  - The strategies used by the macaca monkey brain in controlling the performance of
      a reaching movement to a visual target have been studied by the quantitative
      autoradiographic 14C-DG method. Experiments on visually intact monkeys reaching
      to a visual target indicate that V1 and V2 convey visuomotor information to the
      cortex of the superior temporal and parietoccipital sulci which may encode the
      position of the moving forelimb, and to the cortex in the ventral part and
      lateral bank of the intraparietal sulcus which may encode the location of the
      visual target. The involvement of the medial bank of the intraparietal sulcus in
      proprioceptive guidance of movement is also suggested on the basis of the
      parallel metabolic effects estimated in this region and in the forelimb
      representations of the primary somatosensory and motor cortices. The network
      including the inferior postarcuate skeletomotor and prearcuate oculomotor
      cortical fields and the caudal periprincipal area 46 may participate in sensory
      to-motor and oculomotor-to-skeletomotor transformations, in parallel with the
      medial and lateral intraparietal cortices. Experiments on split brain monkeys
      reaching to visual targets revealed that reaching is always controlled by the
      hemisphere contralateral to the moving forelimb whether it is visually intact or
      'blind'. Two supplementary mechanisms compensate for the 'blindness' of the
      hemisphere controlling the moving forelimb. First, the information about the
      location of the target is derived from head and eye movements and is sent to the
      'blind' hemisphere via inferior parietal cortical areas, while the information
      about the forelimb position is derived from proprioceptive mechanisms and is sent
      via the somatosensory and superior parietal cortices. Second, the cerebellar
      hemispheric extensions of vermian lobules V, VI and VIII, ipsilateral to the
      moving forelimb, combine visual and oculomotor information about the target
      position, relayed by the 'seeing' cerebral hemisphere, with sensorimotor
      information concerning cortical intended and peripheral actual movements of the
      forelimb, and then send this integrated information back to the motor cortex of
      the 'blind' hemisphere, thus enabling it to guide the contralateral forelimb to
      the target.

PMID- 10408657
TI  - Royal College of Physicians of Edinburgh Consensus Conference on Medical
      Management of Stroke, 26-27 May 1998.

PMID- 10408656
TI  - Near-infrared oximetry of the brain.
AB  - Near-infrared (IR) light easily penetrates biological tissue, and the information
      offered by in vivo spectroscopy of cerebral oxygenation is detailed and comes
      with a high temporal resolution. Near-IR light spectroscopy (NIRS) reflects
      cerebral oxygenation during arterial hypotension, hypoxic hypoxaemia and hypo-
      and hypercapnia. As determined by dual-wavelength NIRS, the cerebral O2
      saturation integrates the arterial O2 content and the cerebral perfusion, and as
      established for skeletal muscle, NIRS obtains information on tissue oxygenation
      and metabolism beyond that obtained by venous blood sampling. Caveats of cerebral
      NIRS include insufficient light shielding, optode displacement and a sample
      volume including muscle or the frontal sinus mucous membrane. The relative
      influence from the extracranial tissue is minimized by optode separation and
      correction for an extracranial sample volume, or both. The natural pigment
      melatonin and also water are of little influence to spectroscopic analysis of
      cerebral oxygenation, whereas bilirubin systematically lowers ScO2 and attenuates
      the detection of changes in cerebral oxygenation. By NIRS, reduction of
      cytochrome oxidase is demonstrated during hypoxic hypoxaemia and head-up tilt
      induced arterial hypotension, but the changes are small. In the clinical setting,
      NIRS offers useful information in patients with both systemic and local cerebral
      circulatory impairment, for example, during cranial trauma, surgery on the
      cerebral arteries, orthostasis and acute heart failure. Whereas mapping of the
      brain circulation is needed for jugular venous sampling to reflect either global
      or local oxygenation, the determination of cerebral oxygenation by NIRS has the
      advantage of localized monitoring of the cerebral cortex.

PMID- 10408659
TI  - Long-term outcome of percutaneous endoscopic gastrostomy feeding in patients with
      dysphagic stroke.
AB  - OBJECTIVE: investigation of length of survival, complications, level of
      dependence and recovery of swallow in patients who received percutaneous
      endoscopic gastrostomy (PEG) feeding for dysphagia due to stroke. DESIGN: a
      retrospective case note analysis of patients treated between 1991 and 1995 and
      telephone survey of modified Barthel index in October 1996. SETTING: Cardiff
      Royal Infirmary and the University Hospital of Wales in Cardiff. SUBJECTS: 126
      patients who had PEG inserted after dysphagic stroke. MAIN OUTCOME MEASURES:
      complications of PEG, length of survival, duration of PEG feeding, recovery of
      swallow and modified Barthel index score. RESULTS: median length of follow-up was
      31 months (range 4-71). Median duration of PEG use was 127 days (range 1-1372).
      For patients with PEG inserted within 2 weeks the median duration was 52 days
      (range 2-1478). At follow up 36 (29%) had had PEG removed, 72 (57%) had died with
      PEG in use, 10 (8%) still had PEG and were nil by mouth and five (4%) had PEG in
      use with swallow recovered. The median survival was 305 days. Thirty-five (28%)
      patients died in hospital. Aspiration pneumonia was the commonest complication.
      Thirty-three patients were alive in October 1996. The modified Barthel index for
      nursing home patients was 4 (range 0-13) and for patients at home 11 (range 2
      20). CONCLUSION: PEG feeding is safe and well tolerated in patients with
      dysphagic stroke. Early PEG placement (within 2 weeks) is worthwhile with many
      going on to have long-term feeding. Although overall mortality is high, some
      patients have a long-term survival and a few attain a reasonable level of
      function in daily living activities. Late recovery of swallow occurs and patients
      should have follow-up swallowing assessment.

PMID- 10408658
TI  - Proximal femoral fracture: achievements and prospects.

PMID- 10408660
TI  - Carotid disease in acute stroke.
AB  - BACKGROUND: the Oxfordshire Community Stroke Project (OCSP) devised a simple
      clinical classification for acute stroke which predicted mortality, functional
      recovery and patterns of recurrent stroke. We aimed to determine whether this
      could predict the presence of carotid disease and be used to select which
      patients with acute stroke should be referred for carotid imaging with a view to
      subsequent carotid endarterectomy. METHODS: we assessed patients with acute
      stroke admitted to seven hospitals over a 10-month period. Patients were
      classified according to the OCSP system and their carotid arteries investigated
      using portable continuous wave Doppler. Those with abnormal portable assessments
      had colour duplex Doppler imaging. RESULTS: of 305 patients with proven or
      probable cerebral infarction, severe (70-99%) ipsilateral carotid stenosis was
      found in 16 (16%) of the 101 with partial anterior circulation infarct (PACI),
      four (4%) of the 100 with total anterior circulation infarct (TACI), none of the
      80 with lacunar infarct (LACI) and one (4%) of the 24 with posterior circulation
      infarct (POCI). Complete ipsilateral carotid occlusion was found in 25 (25%) of
      the TACI group, 11 (11%) of the PACI group, three (4%) of the LACI group and none
      of the POCI group. Severe carotid stenosis or occlusion was more common in the
      ipsilateral than the contralateral carotid artery for the TACI and PACI groups
      (chi2 P< 0.05), but there was no difference between ipsilateral and contralateral
      carotid disease in the LACI and POCI groups. If the OCSP classification is used
      to detect patients with 70-99% carotid stenosis, then the sensitivity is 76% and
      specificity is 70%. CONCLUSION: these findings suggest that ipsilateral carotid
      disease is an important cause of stroke for those with anterior circulation
      infarcts but not for those with LACI or POCI. Subjects with PACI should be
      referred for early carotid imaging to identify those with severe disease who may
      be suitable for elective carotid surgery.

PMID- 10408661
TI  - Endoscopic retrograde cholangiopancreatography in elderly patients.
AB  - BACKGROUND: the presentation of common bile duct disease, value of investigations
      and treatment outcome in elderly patients undergoing endoscopic retrograde
      cholangiopancreatography (ERCP) were assessed. METHODOLOGY: the clinical
      presentation, liver function tests, full blood counts, abdominal ultrasound and
      ERCP results were assessed retrospectively in 101 patients (59 women, 42 men;
      mean age 83 years, range 75-100) sequentially investigated for possible common
      bile duct disease. RESULTS: 59 patients had common bile duct gallstones, 35 had
      malignant biliary obstruction (13 with co-existing common bile duct stones) and
      seven had other outcomes. In the malignant-alone group 68% of those who had
      jaundice presented painlessly compared with 24% in the gallstones-alone group;
      49% of the gallstones-alone group had pain compared with 28% of the malignant
      group. In the gallstones-alone group 43% had atypical presentations (non-specific
      symptoms or painless jaundice). Non-specific symptoms were found in 19% of the
      gallstones-alone group but in only 5% of the malignant group. Of the patients who
      had common bile duct stones, 18% had pancreatic or biliary malignancy. The co
      existence of gallstones and malignancy was emphasized by eight patients in whom
      the clinical and ultrasound diagnosis was of common bile duct stones but
      malignancy was detected by ERCP. The sensitivity of ultrasound was 86% for
      detecting dilated common bile ducts was 86%, but only 69% for diagnosing
      gallstones within the common bile duct and 67% for diagnosing pancreatic masses.
      Ultrasound and ERCP were in agreement in 60 patients (60%). Endoscopic clearance
      of common bile duct gallstones was successful in 53 of 54 attempts (98%).
      Palliative ERCP treatment was performed in 30 patients who had malignant biliary
      obstruction and was successful in 22 (73%); in a further four patients (13%) an
      endoprothesis was successfully inserted percutaneously. The commonest
      complication of ERCP was cholangitis (four patients); pancreatitis and biliary
      perforation occurred in one patient each. Twenty-two patients (63%) who had
      malignancy died during follow-up, the mean survival being 11.3 weeks (range 3
      days-2 years). Carcinoma of the ampulla was associated with a relatively good
      prognosis (three patients survived 18 months or more). CONCLUSION: in elderly
      patients, common bile duct stones often present atypically and co-existence with
      malignancy is not unusual; ampullary carcinoma has a relatively good prognosis
      and ERCP is a safe and effective procedure in the management of biliary
      obstruction.

PMID- 10408662
TI  - Jaw reflexes in healthy old people.
AB  - OBJECTIVE: to investigate variations in the masseteric myotatic reflex (jaw-jerk)
      and the silent period from the 5th to the 9th decades of life. SUBJECTS AND
      METHODS: electromyographic data were recorded from the masseter muscle of the
      preferred chewing side by surface electrodes, using a computerized recording and
      analysis system. Chin taps were applied with a neurologist's hammer during
      mandibular rest and at 40% intercuspal clenching in 30 healthy people aged from
      49 to 87 years. The influence of age, gender and silent period type were analysed
      by multiple regression analysis (P < or = 0.05). RESULTS: even in the very old
      subjects all reflexes were elicited, at least once. However, with increasing age
      the overall occurrence of the jaw-jerk reflex at rest (%) and its amplitude, at
      rest and at clench, were reduced, while its latency at rest was significantly
      increased (P < or = 0.05). No age effects were recorded in most parameters of the
      jaw-jerk reflex at clench and in the silent period. Women showed a tendency for
      reduced latencies of the jaw-jerk and the early silent period and increased
      silent period duration (P < or = 0.05). They also had a steeper decline in
      myotatic reflex activity, particularly at rest. CONCLUSION: simple masseteric
      reflex activity is maintained until very old age, particularly when elicited
      during contraction of the jaw elevators.

PMID- 10408663
TI  - Risk of admission within 4 weeks of discharge of elderly patients from the
      emergency department--the DEED study. Discharge of elderly from emergency
      department.
AB  - OBJECTIVE: to identify risk factors for admission for patients aged 75 years and
      older after discharge from the emergency department (DEED: discharge of elderly
      from emergency department). DESIGN: Prospective evaluation of discharged elderly
      patients from the emergency department who were followed up after 4 weeks.
      SETTING: emergency department of a teaching hospital for 1 year. SUBJECTS:
      patients aged 75 and over discharged to their home or hostel. MAIN OUTCOME
      MEASURES: demographic data, indices of function and cognitive status and
      admission to hospital within 4 weeks. RESULTS: 468 patients aged 75 and over
      (mean age 81.7 years; range 75-98) were enrolled; 80 patients (17.1%) were
      admitted to hospital during the subsequent 4 weeks. Risk factors for admission
      included dependence in the following activities of daily living (relative risk;
      95% confidence interval): bathing (2.41; 1.32-4.41); dressing (2.38; 1.22-4.63);
      stairs (1.60; 1.09-2.33); finance (1.66; 1.23-2.25); shopping (1.39; 1.12-1.73)
      and transport (1.61; 1.25-2.06), as well as use of a community nurse (1.88; 1.12
      3.17). Logistic regression analysis found two variables to be significant in
      predicting admission or not: dependence in transport and use of a community
      nurse. CONCLUSIONS: older patients are at increased risk of readmission within 4
      weeks of being sent home from the emergency department. It is possible to
      identify high-risk patients by a questionnaire. This allows targeting of these
      patients for more intensive follow-up in an attempt to ameliorate further
      deteriorations in their health.

PMID- 10408664
TI  - The effect of walking aids on exercise capacity and oxygenation in elderly
      patients with chronic obstructive pulmonary disease.
AB  - BACKGROUND: high walking frames may improve exercise capacity in young patients
      with chronic obstructive pulmonary disease (COPD). We have assessed the effect of
      Zimmer, rollator and gutter frames on 6-min walking distance and on arterial
      oxygenation during exercise in elderly patients with COPD. METHODS: 27 out
      patients (15 men) aged 70-82 (mean 75) years were recruited. Exclusions
      comprised: COPD exacerbation or oral steroid use within 6 weeks, confusional
      state, participation in a pulmonary rehabilitation programme and exercise
      limitation by other diseases. Subjects completed 6-min walk tests unaided and
      with the three frames on four separate days in random order 30 min after
      nebulized salbutamol (5 mg) and ipratropium (0.5 mg) and were accompanied by an
      investigator blinded to results of all other walk tests undertaken. Oxygen
      saturation (SaO2) was monitored by finger probe during exercise. Grouped t-tests
      were used to compare distances and reductions in SaO2. RESULTS: Unaided, the mean
      (SEM) 6-min walk distance was 210 (16) m and fall in oxygen saturation was 6.0
      (1.1)%. Use of a rollator frame did not significantly affect either of these
      values. Using the Zimmer frame reduced the mean distance to 165 (13) m (t=5.2, P
      < 0.001 vs unaided walk) with an SaO2 fall similar to that recorded during the
      unaided walk. Using the gutter frame increased the mean distance to 234 (150) m
      (t=3. 1, P=0.004 vs unaided walk) and reduced the fall in SaO2 to 3.7 (0.8)%
      (t=2.3, P=0.03 vs unaided walk). CONCLUSIONS: gutter frames improve exercise
      capacity and SaO2 during exercise in elderly COPD patients who remain symptomatic
      on optimal therapy, whereas unwheeled Zimmer frames have a deleterious effect in
      such patients.

PMID- 10408665
TI  - The prevalence of diagnoses, impairments, disabilities and handicaps in a
      population of elderly people living in a defined geographical area: the Gospel
      Oak project.
AB  - OBJECTIVE: to measure the prevalence of impairments, disabilities and handicaps
      in a geographically-defined elderly population. DESIGN: cross-sectional analysis
      of an interview survey. SETTING: a single North London electoral ward (district).
      PARTICIPANTS: 654 residents (74%) over the age of 65 years were interviewed from
      a register of 889. A random sample of 225 had additional data collected which are
      reported in this analysis. MAIN OUTCOME MEASURES: point prevalence and
      distribution of the total number of reported diagnoses, impairments and
      disabilities, and distributions of the Office of Population Censuses and Surveys
      (OPCS) disability scale and the London Handicap Scale scores. RESULTS:
      participants had a median of three reported diagnoses and two impairments. Forty
      three percent were in the least disabled OPCS disability category (i.e. below the
      disability threshold) and 41% were able to undertake all of 12 basic activities
      of daily living without difficulty. Overall handicap scores were heavily skewed
      towards no health-related disadvantage, with a median score of 83 out of 100, and
      37% having a score of 90 or more. All indicators showed deteriorating health with
      increasing age, but age-adjusted gender differences were small. CONCLUSIONS: an
      elderly population's health problems were classified using a comprehensive
      framework, revealing high prevalences of diagnoses, impairments, disabilities and
      handicaps. The schema is appropriate for health care needs assessment and is a
      suitable basis for describing the population's health.

PMID- 10408667
TI  - Fruit and vegetable consumption in later life.
AB  - OBJECTIVE: to assess levels of fruit and vegetable consumption in elderly people,
      and to examine the socio-economic, physical and psychological factors which
      influence this consumption. METHODS: a three-phase survey: face to face
      interviews; self-completed dietary diaries with a food frequency questionnaire;
      and follow-up face-to-face interviews. PARTICIPANTS: 445 elderly people (aged
      65+) randomly selected from general practitioner lists in urban Nottingham and
      rural Nottinghamshire, Lincolnshire and Leicestershire. RESULTS: the recommended
      target of five portions of fruit and vegetables a day was achieved by less than
      half the respondents: 37% of those living in the urban area and 51% of those
      living in the rural area. Low fruit and vegetable consumption was particularly
      associated with being male, smoking and having low levels of social engagement.
      CONCLUSIONS: most elderly people consume less than the recommended levels of
      fruit and vegetables. Health programmes promoting fruit and vegetable consumption
      may not be successfully reaching elderly people and need to target those
      particularly at risk of low consumption.

PMID- 10408666
TI  - Effect of zinc or zinc plus arginine supplementation on antibody titre and
      lymphocyte subsets after influenza vaccination in elderly subjects: a randomized
      controlled trial.
AB  - OBJECTIVE: to evaluate whether oral supplementation with zinc or zinc/arginine
      increases the antibody response to influenza vaccine or modulates the lymphocyte
      phenotype in elderly subjects. DESIGN: a randomized controlled trial with two
      supplemented groups and one control group. SETTING: a community nursing home.
      PARTICIPANTS: 384 subjects aged 64-100 (mean age 82 years) examined in three
      separate studies. INTERVENTION: oral supplementation with zinc (400 mg/day) or
      zinc plus arginine (4 g/day) for 60 days starting 15 days before influenza
      vaccination. The control groups received vaccine only. MEASUREMENTS:
      haematological and nutritional indices, antibody titre against influenza viral
      antigens, lymphocyte phenotype. RESULTS: supplementation with zinc or zinc plus
      arginine increased zinc plasma concentrations restoring the age-related
      impairment in zinc concentrations to values found in younger people. The antibody
      titre against influenza viral antigens was not increased in zinc or zinc/arginine
      supplemented groups in comparison with subjects receiving vaccine alone. The
      number of CD3, CD4 or CD8 lymphocytes was not affected by zinc or zinc/arginine
      supplementation. CONCLUSION: prolonged supplementation with zinc or zinc/arginine
      restores zinc plasma concentrations but is ineffective in inducing or
      ameliorating the antibody response after influenza vaccination in elderly
      subjects.

PMID- 10408668
TI  - Prevalence of coronary heart disease, associated manifestations and
      electrocardiographic findings in elderly Finns.
AB  - OBJECTIVE: to study the prevalence of coronary heart disease (CHD) and its
      clinical manifestations among Finnish elderly people in a cross-sectional
      epidemiological survey in the rural district of Lieto, southwestern Finland, with
      special emphasis on the overlap of CHD manifestations with electrocardiogram
      (ECG) findings and factors associated with CHD. DESIGN: observational population
      based study. SETTING: Health Centre in Lieto, Finland, 1990-91. SUBJECTS: 488 men
      and 708 women aged 64-97 years. MAIN OUTCOME MEASURES: angina pectoris (AP) and
      dyspnoea were recorded using the London School of Hygiene cardiovascular
      questionnaires. Resting ECG findings were analysed and coded. Minnesota codes 1.1
      1.3, 4.1-4.4, 5.1-5.3 or 7.1 were interpreted as ischaemic. The medical history
      of cardiovascular diseases was based on medical records. RESULTS: the prevalence
      of AP was 9.1% [95% confidence interval (CI): 6.7-12.0] among men and 4.9% (3.5
      6.8) among women. The respective figures for myocardial infarction (MI) were
      13.9% (10.9-17.0) and 6.5% (4.8-8.6). Ischaemic ECG findings were common: 32.9%
      (28.7-37.1) of men and 39.3% (35.7-43.0) of women had such changes, whereas only
      a minority of them reported typical AP. The total prevalence of CHD, including
      AP, MI, past coronary artery by-pass operation or angioplasty or ischaemic ECG
      findings, was 37.7% (33.4-42.0) in men and 42.0% (38.3-45.6) in women. Among men,
      a higher prevalence of CHD was associated with increasing age [odds ratio (OR)
      1.81; 95% .CI: 1.20-2.73] and a history of having smoked in the past (OR 1.66;
      1.06-2.59), whereas among women it was associated with increasing age (OR 2.02;
      1.48-2.77) and a lower educational level (OR 2.30; 1.37-3.86). CONCLUSION: the
      prevalence of CHD among elderly people is high and the clinical picture of the
      disease is variable. The nature of CHD seems to be less severe among elderly
      women compared with men. Minor ECG changes, especially in the ST and T segments,
      are common with ageing and should not necessarily be interpreted as ischaemic.
      However, these findings combined with atypical chest pain or dyspnoea in an
      elderly person may indicate the possibility of CHD.

PMID- 10408669
TI  - Alcohol and mortality: is there a U-shaped relation in elderly people?
AB  - OBJECTIVE: to assess the relation between alcohol intake and mortality among
      seven cohorts of middle-aged and elderly Danes. DESIGN: Prospective population
      study with baseline assessment of alcohol- and tobacco consumption, educational
      level and body mass index, and a mean of 11.5 years follow-up of mortality.
      SUBJECTS: 16304 men and women aged 50 years or more. MAIN OUTCOME MEASURE: number
      and time of deaths from 1974 to 1995 as ascertained by the national central
      person register. RESULTS: the effect of alcohol intake on mortality did not
      differ between middle-aged (50-64 years, mean = 56.6 years) and elderly subjects
      (>64 years old, mean = 69.9 years). There was a U-shaped risk function in both
      age groups, which persisted also when adjusting for age, sex, smoking habits,
      level of education and body mass index. Abstaining women had a relative risk of
      1.29 (95% confidence limits 1.17-1.42) as compared with light drinkers (1-6
      (drinks per week), while the relative risk for abstaining men was 1.22 (95%
      confidence limits; 1.08 to 1.37) as compared with light drinkers. Heavy drinking
      women (>28 drinks per week) had a relative risk of 1.23 (95% confidence limits;
      0.85 to 1.78) and heavy drinking men (more than 69 drinks per week) had a
      relative risk of 2.11 (95% confidence limits 1.66-2.69), both compared with light
      drinkers. CONCLUSION: among the middle-aged and elderly women and men, a light
      alcohol intake is associated with lower mortality than abstention or heavy
      drinking.

PMID- 10408670
TI  - Physical activity and dehydroepiandrosterone sulphate, insulin-like growth factor
      I and testosterone in healthy active elderly people.
AB  - OBJECTIVE: to examine the association of physical activity and cardio-respiratory
      fitness with dehydroepiandrosterone sulphate (DHEAS), insulin-like growth factor
      I (IGF-I) and testosterone in healthy elderly people. DESIGN: cross-sectional
      study. SETTING: university research department and department of geriatric
      medicine. PARTICIPANTS: 60 independent, community-dwelling elderly subjects (26
      men and 34 women) aged 66-84 who volunteered to participate. MEASUREMENTS:
      physical activity was evaluated by the Questionnaire d'Activite Physique Saint
      Etienne and expressed by three indices: mean habitual daily energy expenditure
      (MHDEE), daily energy expenditure (DEE) [comprising activities with intensities
      corresponding to at least three metabolic equivalents (MET; 3.5 ml.kg1 x min1 of
      oxygen consumption)] and sport activity. Cardio-respiratory fitness was expressed
      by maximal oxygen consumption (VO2max). RESULTS: In women, DHEAS correlated with
      VO2max (partial correlation: r=0.33; P=0.05), MHDEE (r=0.50; P=0.002), DEE > 3
      METs (r=0.49; P=0.003) and sport activity (r=0.35; P=0.04) whereas IGF-I
      correlated with MHDEE (r=0.48; P=0.004). DHEAS was correlated with IGF-I (r=0.43;
      P < 0.02) and with testosterone (r=0.41; P < 0.02). No such correlation was found
      in men. CONCLUSION: lower habitual physical activity is related to lower levels
      of circulating DHEAS and IGF-I independently of age and anthropometric measures.
      Lower maximal aerobic capacity is associated with lower DHEAS concentrations, in
      healthy elderly women.

PMID- 10408671
TI  - The use of general practitioner elderly beds in community hospitals.

PMID- 10408672
TI  - Euthanasia and old age.

PMID- 10408673
TI  - The use of the Short Form (SF)-36 questionnaire for older adults.

PMID- 10408675
TI  - The use of the Short Form (SF)-36 questionnaire for older adults.

PMID- 10408674
TI  - The use of the Short Form (SF)-36 questionnaire for older adults.

PMID- 10408676
TI  - Hip protectors and hip fractures.

PMID- 10408677
TI  - The Nottingham Longitudinal Study of Activity and Ageing: a methodological
      overview.
AB  - OBJECTIVES: first, to describe the background and methodological approach to the
      assessment of customary physical activity, health and psycho-social status used
      by the Nottingham Longitudinal Study of Activity and Ageing; second, to provide
      information on the sampling strategy and survey response rates for three waves of
      data collection; and, third, to provide information on the reliability and
      validity of the survey assessments. DESIGN: longitudinal study. SUBJECTS: 1042
      people originally aged 65 and over, randomly sampled from general practitioner
      lists in Nottingham, UK. METHODS: a descriptive overview of response rates (%),
      instrument reliability (alpha coefficients) and intercorrelations among measured
      outcomes (correlation coefficients and principal components analysis). MAIN
      OUTCOME MEASURES: questionnaire-assessed levels of physical activity;
      instrumental measurements of handgrip strength, weight, demi-span and shoulder
      flexibility; brief assessments of depression, social engagement, life
      satisfaction and cognitive impairment. RESULTS: the study achieved a baseline
      (TI) response rate of 80%, with re-interview rates of 88% and 73% for T2 (1989)
      and T3 (1993) surveys respectively. For both men and women, factor scores derived
      from first principal components extracted from T1 survey data showed significant
      (r > or = 0.4; P < 0.001) product moment correlations with instrumental
      measurements of handgrip strength and shoulder flexibility. All the brief
      assessment measures showed satisfactory levels of reliability (alpha > or = 0.7).

PMID- 10408678
TI  - Longitudinal changes in selected physical capabilities: muscle strength,
      flexibility and body size.
AB  - OBJECTIVES: first, to record, in a representative sample of older men and women,
      longitudinal changes in (i) maximal voluntary strength of the handgrip muscles,
      (ii) maximal range of movement in the shoulder joint and (iii) body weight and
      skeletal size; second, to explore associations between the changes in muscle
      strength and both customary physical activity and health outcomes. DESIGN:
      longitudinal analyses of survivors measured at baseline, and 4-year and 8-year
      follow-ups. PARTICIPANTS: 350 survivors of a random sample originally aged 65 and
      over. RESULTS: over 8 years average loss of body weight was slight but
      significant at about 2 kg (less than 5%). Loss of shoulder range was negligible,
      while loss of muscle strength was significant at about 40 N (less than 2% per
      year). Demispan remained stable across all three points of measurement. These
      mean values concealed substantial variation in the rate of loss of strength,
      which was twice as fast in the older groups, especially in the women. These
      losses could not be attributed to worsening health, although this was observed.
      All the respondents had at least two chronic health problems at the 8-year stage.
      For the changes in handgrip strength, reduced reported habitual use of the
      handgrip muscles and increased symptoms of anxiety and depression were
      significant independent covariates in addition to age and time (all P < 0.0001).
      CONCLUSION: there are significant independent associations between the loss of
      muscle strength in old age and both decline in physical activity and increase in
      depression scores. This is strongly suggestive of causal links and confirms the
      need to encourage physical activity and control depression in order to maintain
      strength and function in old age.

PMID- 10408679
TI  - Stability and change in levels of habitual physical activity in later life.
AB  - OBJECTIVES: to describe stability and change in levels of customary physical
      activity assessed in recall-based questionnaire surveys of older people conducted
      in 1985, 1989 and 1993. DESIGN: longitudinal study. SUBJECTS: 1042 people
      originally aged 65 and over randomly sampled from general practitioner lists in
      Nottingham, UK. METHODS: logistic and multiple regression analyses, intraclass
      correlation coefficients. MAIN OUTCOME MEASURES: self-reported time spent per day
      walking and shopping; self-reported time spent per week in other indoor, outdoor
      and leisure activities; frequency of performance of strength and flexibility
      activities. RESULTS: among survivors, activity levels at baseline tended to be
      higher than those of their non-surviving peers. Overall, 8-year change between
      1985 and 1993 was characterized by progressively declining activity levels.
      Nevertheless, in both trajectories and stability profiles, differences did emerge
      among the seven activity categories studied. At least one in four respondents
      increased the time they spent walking, and approximately one in three respondents
      increased the time they spent shopping between 1985 and 1993. CONCLUSIONS: these
      findings suggest that, while some activity variables show levels of stability
      consistent with trait-like constructs, others are clearly more labile. While the
      present data cannot offer a definitive explanation for these differences, it
      seems reasonable that within each activity the influence of ability, opportunity
      and need interact to determine levels of participation.

PMID- 10408680
TI  - Gender and longitudinal changes in physical activities in later life.
AB  - OBJECTIVES: to describe gender differences in levels of, and longitudinal changes
      in, habitual physical activity among older people. DESIGN: longitudinal study.
      PARTICIPANTS: sub-groups of survivors (with sample sizes dependent on the
      availability of complete datasets, ranging from 303-344) assessed on three
      occasions: 1985, 1989 and 1993 in Nottingham, UK. All were 65 years and over in
      1985. METHODS: descriptive presentation (median and range values) of quantitative
      longitudinal data by gender across five activity categories assessed in a recall
      based questionnaire. MAIN OUTCOME MEASURES: participation in walking, shopping,
      indoor, outdoor and leisure activities. RESULTS: while levels of indoor and
      outdoor activities were marked by decline for both sexes, gender differentials
      were maintained over the 8 years of the study, with women showing higher levels
      of activity participation indoors and men showing higher levels of activity
      participation outdoors. In levels of walking/shopping activity, however, there
      was evidence of gender differentials reducing over time. CONCLUSIONS: within
      these cohorts of older people traditional gender roles continue to exert a strong
      influence on levels and types of habitual physical activity well into later life.
      In some areas of activity, however, temporal changes provide some evidence of
      gender convergence consistent with late-life transitions in marital status and
      dependency.

PMID- 10408681
TI  - Customary physical activity and physical health outcomes in later life.
AB  - OBJECTIVES: to explore associations between customary physical activity and three
      longitudinal outcomes: 12-year all-cause mortality, 12-year disease-specific
      mortality and 8-year change in general practitioner and personal social service
      use. DESIGN: longitudinal study. SUBJECTS: 1042 people originally aged 65 and
      over randomly sampled from general practitioner lists in Nottingham, UK. METHODS:
      Cox regression survival and logistic regression analyses. MAIN OUTCOME MEASURES:
      questionnaire-assessed levels of physical activity; 12-year mortality; reported
      health and personal social service contacts in month prior to interview. RESULTS:
      on the basis of factor scores derived from the interview questionnaire, activity
      levels were graded as high, intermediate or low, with respondents grouped
      accordingly. Relative to the high activity group, 12-year mortality was
      significantly increased in both the intermediate [adjusted hazard ratio (HR) =
      1.53; 95% confidence interval (CI) = 1.10-2.14; P < 0.05] and low (HR = 1.75; 95%
      CI = 1.24-2.48; P < 0.005) activity groups for men, and in the low activity group
      (HR= 1.73; 95% CI = 1.28-2.33; P < 0.001) for women. Lower levels of activity
      were also associated with an increased likelihood of using health and personal
      social services 8 years after the initial interview, and an increased risk among
      men of having respiratory disease recorded as the primary cause of death. All
      models were adjusted for age, health and smoking status and weight category as
      measured at baseline. CONCLUSIONS: the results are consistent with the conclusion
      that, among elderly people, health gain resulting from higher customary physical
      activity levels can promote a longer and more independent later life.

PMID- 10408682
TI  - Customary physical activity and psychological wellbeing: a longitudinal study.
AB  - OBJECTIVES: to assess longitudinal relationships between habitual levels of
      physical activity and indices of psychological wellbeing in older people. DESIGN:
      baseline assessment with 4- and 8-year follow-ups. SUBJECTS: 1042 people
      originally aged 65 and over randomly sampled from general practitioner lists in
      Nottingham, UK. METHODS: logistic regression analysis of selected T1 (1985) and
      T2 (1989) variables, with depression at T2 as dependent; multiple regression
      analyses of selected T1, T2 and T3 (1993) variables, with life satisfaction at T2
      (model 1) or T3 (model 2) as dependent. MAIN OUTCOME MEASURES: questionnaire
      assessed levels of physical activity; 14-item Symptoms of Anxiety and Depression
      scale; 13-item Life Satisfaction Index; health, demographic and social activity
      variables. RESULTS: in the logistic regression model, depression at T2 was most
      strongly associated with depression [odds ratio (OR) = 7.13; 95% confidence
      interval (CI) = 3.25-15.64; P < 0.001] and lower physical health status (OR =
      1.26 per unit change in score; 95% CI = 1.17-1.42; P < 0.001) at T1. Lower levels
      of outdoor/leisure activities at T1 were also associated with some increased risk
      of depression 4 years later (OR = 0.92 per hour of activity; 95% CI = 0.85-0.99;
      P < 0.05). Similar predictive patterns emerged from the multiple regression
      analyses where, in both models, earlier levels of life satisfaction, social
      engagement and health accounted for most of the explained variance in life
      satisfaction (R2 = 0.42 for model 1; R2 = 0.35 for model 2). Again, however,
      earlier levels of physical activity (as walking and housework) did contribute
      significantly, although modestly, to longitudinal changes in morale. CONCLUSIONS:
      while the results provide some support for the conclusion that physical activity
      contributes independently to the promotion and maintenance of psychological
      wellbeing in later life, this contribution is, at best, extremely modest.

PMID- 10408683
TI  - United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) Strategy Group
      workshop. Improvements in patient access to new anti-cancer medicines.

PMID- 10408684
TI  - Borderline ovarian tumours in Vaud, Switzerland: incidence, survival and second
      neoplasms.
AB  - Between 1976 and 1996, 176 borderline ovarian tumours were registered in the
      Cancer Registry of the Swiss canton of Vaud, corresponding to an age-adjusted
      incidence (world standard) of 2.7 in 100,000. Incidence rose from 1.7 per 100,000
      during 1976-81 to 2.7 per 100,000 during 1987-91, and then levelled off; 58% of
      cases were serous and 41% mucinous. Relative survival was 94% at 10 years; 18
      second neoplasms were observed, compared with 10.3 expected, and there was a
      significant excess of invasive ovarian cancers (four observed, including three
      synchronous, compared with 0.4 expected).

PMID- 10408685
TI  - Maternal pregnancy hormone levels in an area with a high incidence (Boston, USA)
      and in an area with a low incidence (Shanghai, China) of breast cancer.
AB  - Characteristics probably associated with the fetal hormonal milieu have recently
      been shown to increase (birth size indicators, prematurity, neonatal jaundice) or
      decrease (pregnancy toxaemia) breast cancer risk in the female offspring.
      However, it is unknown whether differences in pregnancy hormone levels may
      contribute to the marked geographical variation in breast cancer incidence. We
      have compared, in a highly standardized manner, pregnancy hormone levels in a
      population with high incidence and one with low incidence of breast cancer. Three
      hundred and four pregnant Caucasian women in Boston and 334 pregnant Chinese
      women in Shanghai were enrolled from March 1994 to October 1995. Levels of
      oestradiol, oestriol, prolactin, progesterone, human growth hormone, albumin and
      sex hormone-binding globulin were measured in maternal blood at weeks 16 and 27
      of gestation and compared between the two study sites using non-parametric
      Wilcoxon's rank-sum test. Demographical, anthropometrical and pregnancy
      characteristics were ascertained through interview, and relevant variables
      concerning delivery and the newborn were abstracted from medical records and
      paediatric charts. During the first visit, median serum levels of all studied
      hormones were statistically significant, and in most instances substantially,
      higher among Chinese women, who have a low incidence of breast cancer, compared
      with American women, who have a high incidence of breast cancer. An analogous
      pattern was evident during the second visit, although the relative differences
      tended to be smaller. Further research is needed to identify lifestyle or other
      exogenous determinants of pregnancy hormone levels, as well as possible
      mechanisms by which they may influence carcinogenic processes in the breast and
      possibly other organs.

PMID- 10408686
TI  - Striking increase in incidence of prostate cancer in men aged < 60 years without
      improvement in prognosis.
AB  - Increased awareness and improved diagnostic techniques have led to earlier
      diagnosis of prostate cancer and increased detection of subclinical cases,
      resulting in improved prognosis. We postulated that the considerable increase in
      incidence under age 60 is not attributable only to increased detection. To test
      this hypothesis, we studied incidence, mortality and relative survival among
      middle-aged patients diagnosed in south-east Netherlands and East Anglia (UK)
      between 1971 and 1994. Prostate-specific antigen (PSA) testing did not occur
      before 1990. Between 1971 and 1989, the age-standardized incidence at ages 40-59
      increased from 8.8 to 12.5 per 10(5) in The Netherlands and from 7.0 to 11.6 per
      10(5) in East Anglia. Five-year relative survival did not improve in East Anglia
      and even declined in southeast Netherlands from 65% [95% confidence interval (CI)
      47-83) in 1975-79 to 48% (CI 34-62) in 1985-89. Mortality due to prostate cancer
      among men aged 45-64 years increased by 50% in south-east Netherlands and by 61%
      in East Anglia between 1971 and 1989, but decreased slightly in the 1990s.
      Because other factors adversely influencing the prognosis are unlikely, our
      results indicate an increase in the incidence of fatal prostate cancer among
      younger men in the era preceding PSA testing.

PMID- 10408687
TI  - Estimating relative survival among people registered with cancer in England and
      Wales.
AB  - Because routinely collected survival data for cancer patients in England and
      Wales do not typically specify cause of death, conventional estimates of survival
      in cancer patients based on such data are a measure of their mortality from all
      causes rather than their mortality due to cancer. As a result, trends in survival
      over time are difficult to interpret because changes in overall survival may well
      reflect changes in the risk of death from other causes, rather than from the
      cancer of interest. One way of overcoming this problem is to use some form of
      'relative survival' defined as a measure of survival corrected for the effect of
      other independent causes of death. Since this concept was first introduced,
      various methods for calculating relative survival have been proposed and this had
      led to some confusion as to the most appropriate choice of estimate. This paper
      aims to provide an introduction to the concept of relative survival and reviews
      some of the suggested methods of estimation. In addition, a particularly simple,
      but robust approach, is highlighted based on expected and observed mortality.
      This method is illustrated using preliminary data from the Office for National
      Statistics on cancer survival in patients born after 1939 and diagnosed with
      cancer during 1972-84. The examples presented, although limited to analyses on a
      small number of selected sites, highlight some encouraging trends in survival in
      people aged under 35 diagnosed with leukaemia, Hodgkin's disease and testicular
      cancer during this period.

PMID- 10408688
TI  - Vitamins A, C and E and the risk of breast cancer: results from a case-control
      study in Greece.
AB  - Although several dietary compounds are hypothesized to have anticarcinogenic
      properties, the role of specific micronutrients in the development of breast
      cancer remains unclear. To address this issue, we assessed intake of retinol,
      beta-carotene, vitamin C and vitamin E in relation to breast cancer risk in a
      case-control study in Greece. Eight hundred and twenty women with histologically
      confirmed breast cancer were compared with 1548 control women. Dietary data were
      collected through a 115-item semiquantitative food frequency questionnaire. Data
      were modelled by logistic regression, with adjustment for total energy intake and
      established breast cancer risk factors, as well as mutual adjustment among the
      micronutrients. Among post-menopausal women, there was no association between any
      of the micronutrients evaluated and risk of breast cancer. Among premenopausal
      women, beta-carotene, vitamin C and vitamin E were each inversely associated with
      breast cancer risk, but after mutual adjustment among the three nutrients only
      beta-carotene remained significant; the odds ratio (OR) for a one-quintile
      increase in beta-carotene intake was 0.84 (95% confidence interval 0.73-0.97).
      The inverse association observed with beta-carotene intake, however, is slightly
      weaker than the association previously observed with vegetable intake in these
      data, raising the possibility that the observed beta-carotene effect is accounted
      for by another component of vegetables.

PMID- 10408689
TI  - Higher risk for acute childhood lymphoblastic leukaemia in Swedish population
      centres 1973-94. Swedish Child Leukaemia Group.
AB  - A population-based sample of acute childhood leukaemia cases in Sweden 1973-94
      was analysed by a geographical information system (GIS) for spatial leukaemia
      distribution in relation to population density. The annual incidence rate for
      acute lymphoblastic leukaemia (ALL) was 3.6, and for acute non-lymphoblastic
      leukaemia (ANLL) 0.7, cases per 100,000 children. Incidence rates in population
      centres, constituting 1.3% of Sweden's land area and approximately 80% of the
      population, compared with the rest of Sweden showed a statistically significant
      excess of ALL [odds ratio (OR) 1.68; 95% confidence interval (CI) 1.44-1.95], but
      not ANLL (OR 1.13; 95% CI 0.98-1.32). An increasing trend, however not
      statistically significant, was found for ALL incidence with both increasing
      population density in parishes and increasing degree of urbanity in
      municipalities. These findings support the theories that some environmental
      factors associated with high population density, such as infectious agents, may
      be of aetiological importance for childhood acute lymphoblastic leukaemia.

PMID- 10408690
TI  - BRCA1 mutations and other sequence variants in a population-based sample of
      Australian women with breast cancer.
AB  - The frequency, in women with breast cancer, of mutations and other variants in
      the susceptibility gene, BRCA1, was investigated using a population-based case
      control-family study. Cases were women living in Melbourne or Sydney, Australia,
      with histologically confirmed, first primary, invasive breast cancer, diagnosed
      before the age of 40 years, recorded on the state Cancer Registries. Controls
      were women without breast cancer, frequency-matched for age, randomly selected
      from electoral rolls. Full manual sequencing of the coding region of BRCA1 was
      conducted in a randomly stratified sample of 91 cases; 47 with, and 44 without, a
      family history of breast cancer in a first- or second-degree relative. All
      detected variants were tested in a random sample of 67 controls. Three cases with
      a (protein-truncating) mutation were detected. Only one case had a family
      history; her mother had breast cancer, but did not carry the mutation. The
      proportion of Australian women with breast cancer before age 40 who carry a
      germline mutation in BRCA1 was estimated to be 3.8% (95% CI 0.3-12.6%). Seven
      rare variants were also detected, but for none was there evidence of a strong
      effect on breast cancer susceptibility. Therefore, on a population basis, rare
      variants are likely to contribute little to breast cancer incidence.

PMID- 10408691
TI  - Granulocyte, granulocyte-macrophage, and macrophage colony-stimulating factors
      can stimulate the invasive capacity of human lung cancer cells.
AB  - We and other researchers have previously found that colony-stimulating factors
      (CSFs), which generally include granulocyte colony-stimulating factor (G-CSF),
      granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony
      stimulating factor (M-CSF), promote invasion by lung cancer cells. In the present
      study, we studied the effects of these CSFs on gelatinase production, urokinase
      plasminogen activator (uPA) production and their activity in human lung cancer
      cells. Gelatin zymographs of conditioned media derived from human lung
      adenocarcinoma cell lines revealed two major bands of gelatinase activity at 68
      and 92 kDa, which were characterized as matrix metalloproteinase (MMP)-2 and MMP
      9 respectively. Treatment with CSFs increased the 68- and 92-kDa activity and
      converted some of a 92-kDa proenzyme to an 82-kDa enzyme that was consistent with
      an active form of the MMP-9. Plasminogen activator zymographs of the conditioned
      media from the cancer cells showed that CSF treatment resulted in an increase in
      a 48-55 kDa plasminogen-dependent gelatinolytic activity that was characterized
      as human uPA. The conditioned medium from the cancer cells treated with CSFs
      stimulated the conversion of plasminogen to plasmin, providing a direct
      demonstration of the ability of enhanced uPA to increase plasmin-dependent
      proteolysis. The enhanced invasive behaviour of the cancer cells stimulated by
      CSFs was well correlated with the increase in MMPs and uPA activities. These data
      suggest that the enhanced production of extracellular matrix-degrading
      proteinases by the cancer cells in response to CSF treatment may represent a
      biochemical mechanism which promotes the invasive behaviour of the cancer cells.

PMID- 10408692
TI  - Telomerase activity in melanoma and non-melanoma skin cancer.
AB  - Telomeres are specialized structures consisting of repeat arrays of TTAGGGn
      located at the ends of chromosomes. They are essential for chromosome stability
      and, in the majority of normal somatic cells, telomeres shorten with each cell
      division. Most immortalized cell lines and tumours reactivate telomerase to
      stabilize the shortening chromosomes. Telomerase activation is regarded as a
      central step in carcinogenesis and, here, we demonstrate telomerase activation in
      premalignant skin lesions and also in all forms of skin cancer. Telomerase
      activation in normal skin was a rare event, and among 16 samples of normal skin
      (one with a history of chronic sun exposure) 12.5% (2 out of 16) exhibited
      telomerase activity. One out of 16 (6.25%) benign proliferative lesions,
      including viral and seborrhoeic wart samples, had telomerase activity. In
      premalignant actinic keratoses and Bowen's disease, 42% (11 out of 26) of samples
      exhibited telomerase activity. In the basal cell carcinoma and cutaneous
      malignant melanoma (CMM) lesions, telomerase was activated in 77% (10 out of 13)
      and 69% (22 out of 32) respectively. However, only 25% (3 out of 12) of squamous
      cell carcinomas (SCC) had telomerase activity. With the exception of one SCC
      sample, telomerase activity in a positive control cell line derived from a
      fibrosarcoma (HT1080) was not inhibited when mixed with the telomerase-negative
      SCC or CMM extracts, indicating that, overall, Taq polymerase and telomerase
      inhibitors were not responsible for the negative results. Mean telomere
      hybridizing restriction fragment (TRF) analysis was performed in a number of
      telomerase-positive and -negative samples and, although a broad range of TRF
      sizes ranging from 3.6 to 17 kb was observed, a relationship between telomerase
      status and TRF size was not found.

PMID- 10408693
TI  - Perchloric acid-soluble proteins from goat liver inhibit chemical carcinogenesis
      of Syrian hamster cheek-pouch carcinoma.
AB  - Chemically induced Syrian hamster cheek-pouch squamous cell carcinoma is very
      similar to the corresponding human tumour. This paper describes a blind study in
      which inhibition of dimethylbenzanthracene-induced cheek-pouch tumours by a goat
      liver extract denominated UK101 was investigated. Less than 40% of animals
      treated with UK101 developed tumours compared with 100% of the controls.
      Intermediate results (80%) were noted in a positive control group treated with
      Calmette-Guerin bacillus. Immunocytochemical testing of cheek-pouch mucosa by
      Mib5 showed significantly less proliferating cells in UK101 animals than in the
      controls. The effect of UK101 was completely reversed when dexamethasone was
      added in a third control group. A significant difference in complement-mediated
      cytotoxicity was noted in the sera of UK101-tested and control animals. These
      findings suggest that an immune mechanism is responsible for the inhibition of
      hamster cheek-pouch carcinoma by UK101.

PMID- 10408694
TI  - Activity and regulation by growth factors of calmodulin-dependent protein kinase
      III (elongation factor 2-kinase) in human breast cancer.
AB  - Calmodulin-dependent protein kinase III (CaM kinase III, elongation factor-2
      kinase) is a unique member of the Ca2+/CaM-dependent protein kinase family.
      Activation of CaM kinase III leads to the selective phosphorylation of elongation
      factor 2 (eEF-2) and transient inhibition of protein synthesis. Recent cloning
      and sequencing of CaM kinase III revealed that this enzyme represents a new
      superfamily of protein kinases. The activity of CaM kinase III is selectively
      activated in proliferating cells; inhibition of the kinase blocked cells in G0/G1
      S and decreased viability. To determine the significance of CaM kinase III in
      breast cancer, we measured the activity of the kinase in human breast cancer cell
      lines as well as in fresh surgical specimens. The specific activity of CaM kinase
      III in human breast cancer cell lines was equal to or greater than that seen in a
      variety of cell lines with similar rates of proliferation. The specific activity
      of CaM kinase III was markedly increased in human breast tumour specimens
      compared with that of normal adjacent breast tissue. The activity of this enzyme
      was regulated by breast cancer mitogens. In serum-deprived MDA-MB-231 cells, the
      combination of insulin-like growth factor I (IGF-I) and epidermal growth factor
      (EGF) stimulated cell proliferation and activated CaM kinase III to activities
      observed in the presence of 10% serum. Inhibition of enzyme activity blocked cell
      proliferation induced by growth factors. In MCF-7 cells separated by fluorescence
      activated cell sorting. CaM kinase III was increased in S-phase over that of
      other phases of the cell cycle. In summary, the activity of Ca2+/CaM-dependent
      protein kinase III is controlled by breast cancer mitogens and appears to be
      constitutively activated in human breast cancer. These results suggest that CaM
      kinase III may contribute an important link between growth factor/receptor
      interactions, protein synthesis and the induction of cellular proliferation in
      human breast cancer.

PMID- 10408695
TI  - A new human chromogranin A (CgA) immunoradiometric assay involving monoclonal
      antibodies raised against the unprocessed central domain (145-245).
AB  - Chromogranin A (CgA), a major protein of chromaffin granules, has been described
      as a potential marker for neuroendocrine tumours. Because of an extensive
      proteolysis which leads to a large heterogeneity of circulating fragments, its
      presence in blood has been assessed in most cases either by competitive
      immunoassays or with polyclonal antibodies. In the present study, 24 monoclonal
      antibodies were raised against native or recombinant human CgA. Their mapping
      with proteolytic peptides showed that they defined eight distinct epitopic groups
      which spanned two-thirds of the C-terminal part of human CgA. All monoclonal
      antibodies were tested by pair and compared with a reference radioimmunoassay
      (RIA) involving CGS06, one of the monoclonal antibodies against the 198-245
      sequence. It appears that CgA C-terminal end seems to be highly affected by
      proteolysis and the association of C-terminal and median-part monoclonal
      antibodies is inadequate for total CgA assessment. Our new immunoradiometric
      assay involves two monoclonal antibodies, whose contiguous epitopes lie within
      the median 145-245 sequence. This assay allows a sensitive detection of total
      human CgA and correlates well with RIA because dibasic cleavage sites present in
      the central domain do not seem to be affected by degradation. It has been proved
      to be efficient in measuring CgA levels in patients with neuroendocrine tumours.

PMID- 10408697
TI  - Pharmacodynamics of cisplatin in human head and neck cancer: correlation between
      platinum content, DNA adduct levels and drug sensitivity in vitro and in vivo.
AB  - Total platinum contents and cisplatin-DNA adduct levels were determined in vivo
      in xenografted tumour tissues in mice and in vitro in cultured tumour cells of
      head and neck squamous cell carcinoma (HNSCC), and correlated with sensitivity to
      cisplatin. In vivo, a panel of five HNSCC tumour lines growing as xenografts in
      nude mice was used. In vitro, the panel consisted of five HNSCC cell lines, of
      which four had an in vivo equivalent. Sensitivity to cisplatin varied three- to
      sevenfold among cell lines and tumours respectively. However, the ranking of the
      sensitivities of the tumour lines (in vivo), also after reinjection of the
      cultured tumour cells, did not coincide with that of the corresponding cell
      lines, which showed that cell culture systems are not representative for the in
      vivo situation. Both in vitro and in vivo, however, significant correlations were
      found between total platinum levels, measured by atomic absorption
      spectrophotometry (AAS), and tumour response to cisplatin therapy at all time
      points tested. The levels of the two major cisplatin-DNA adduct types were
      determined by a recently developed and improved 32P post-labelling assay at
      various time points after cisplatin treatment. Evidence is presented that the
      platinum-AG adduct, in which platinum is bound to guanine and an adjacent
      adenine, may be the cytotoxic lesion because a significant correlation was found
      between the platinum-AG levels and the sensitivities in our panel of HNSCC, in
      vitro as well as in vivo. This correlation with the platinum-AG levels was
      established at 1 h (in vitro) and 3 h (in vivo) after the start of the cisplatin
      treatment, which emphasizes the importance of early sampling.

PMID- 10408696
TI  - Different apoptotic pathways are induced from various intracellular sites by
      tetraphenylporphyrins and light.
AB  - The induction of apoptosis from different intracellular sites was studied by
      exposing V79 Chinese hamster fibroblasts to photodynamic therapy (PDT) with
      various porphyrins and light. The effects of two lipophilic, intracellular
      membrane-localized porphyrins, tetra(3-hydroxyphenyl)porphyrin (3THPP) and
      Photofrin, were compared with that of two sulphonated meso-tetraphenylporphines
      (TPPS2a and TPPS4), which are taken up into lysosomes by endocytosis. Apoptotic
      fractions induced by the various dyes and light were quantified by flow cytometry
      using the terminal deoxynucleotidyl transferase (TdT) assay. Cell fragmentation
      was measured in parallel, while the nuclear morphology of apoptotic cells was
      studied by fluorescence microscopy. Different kinetics were found for the
      induction of DNA strand breaks characteristic of apoptotic cells. PDT-induced
      damage to membranes resulted in an increasing number of apoptotic cells for about
      12 h after PDT After damage to lysosomes, apoptotic cells were not detected until
      more than 12 h after PDT. Furthermore, apoptotic bodies were not observed after
      PDT-induced damage to intracellular membranes, whereas apoptosis induced from
      lysosomal sites was characterized by extensive cell fragmentation. Cell
      fragmentation occurred in combination with or in the absence of nuclear
      fragmentation. The results support the idea that the degradation phase of
      apoptosis can consist of a sequence of independent steps rather than a common
      final pathway.

PMID- 10408698
TI  - Effect of intraperitoneally administered recombinant murine granulocyte
      macrophage colony-stimulating factor (rmGM-CSF) on the cytotoxic potential of
      murine peritoneal cells.
AB  - We studied the effect of recombinant murine granulocyte-macrophage colony
      stimulating factor (rmGM-CSF) on the cytotoxic potential of murine peritoneal
      cells. Mice received rmGM-CSF intraperitoneally using different dosages and
      injection schemes. At different time points after the last injection, mice were
      sacrificed, peritoneal cells isolated and their tumour cytotoxicity was
      determined by a cytotoxicity assay using syngeneic [methyl-3H]thymidine-labelled
      colon carcinoma cells. Also, the cytotoxic response to a subsequent in vitro
      stimulation with lipopolysaccharide was determined. Upon daily injection of 6000
      54,000 U rmGM-CSF over a 6-day period, the number of peritoneal cells increased
      over ten fold with the highest rmGM-CSF dose. Increases in cell numbers was
      mainly due to increases in macrophage numbers. Upon injection of three doses of
      3000 U rmGM-CSF per day for 3 consecutive days, the number of macrophages
      remained elevated for minimally 6 days. Although the peritoneal cells from rmGM
      CSF-treated mice were not activated to a tumoricidal state, they could be
      activated to high levels of cytotoxicity with an additional in vitro stimulation
      of lipopolysaccharide. Resident cells isolated from control mice could be
      activated only to low levels of tumour cytotoxicity with lipopolysaccharide.
      Tumour cytotoxicity strongly correlated with nitric oxide secretion. When
      inhibiting nitric oxide synthase, tumour cell lysis decreased. Thus, the expanded
      peritoneal cell population induced by multiple injections of rmGM-CSF has a
      strong tumour cytotoxic potential and might provide a favourable condition for
      immunotherapeutic treatment of peritoneal neoplasms.

PMID- 10408699
TI  - Bcl-2 overexpression blocks caspase activation and downstream apoptotic events
      instigated by photodynamic therapy.
AB  - Treatment with the photosensitizer benzoporphyrin derivative monoacid ring A (BPD
      MA, verteporfin) followed by irradiation with visible light induces apoptosis in
      human acute myelogenous leukaemia HL-60 cells. Photoactivation of BPD-MA induces
      procaspase 3 (CPP32/Yama/apopain) and procaspase 6 (Mch2) cleavage into their
      proteolytically active subunits in these cells. The Bcl-2 proto-oncogene product
      has been shown to protect cells from a number of proapoptotic stimuli. In the
      present study, the influence of Bcl-2 overexpression on cellular resistance to
      photoactivation of BPD-MA was studied. Overexpression of Bcl-2 in HL-60 cells
      prevented apoptosis-related events including caspase 3 and 6 activation, poly(ADP
      ribose) polymerase cleavage and the formation of hypodiploid DNA produced by BPD
      MA (0-200 ng ml(-1)) and light. However, Bcl-2 overexpression was less effective
      at preventing cell death that occurred after photoactivation at high levels (50
      100 ng ml(-1)) compared with lower doses (10-25 ng ml(-1)) of BPD-MA. These
      results indicate that caspase 3 and 6 activation and their regulation by Bcl-2
      may play important roles in photodynamic therapy (PDT)-induced cell killing.

PMID- 10408701
TI  - Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice
      lacking mdr1a P-glycoprotein.
AB  - To gain more insight into the pharmacological role of endogenous P-glycoprotein
      in the metabolism of the widely used substrate drug doxorubicin, we have studied
      the plasma pharmacokinetics, tissue distribution and excretion of this compound
      in mdr1a(-/-) and wild-type mice. Doxorubicin was administered as an i.v. bolus
      injection at a dose level of 5 mg kg(-1). Drug and metabolite concentrations were
      determined in plasma, tissues, urine and faeces by high-performance liquid
      chromatography. In comparison with wild-type mice, the terminal half-life and the
      area under the plasma concentration-time curve of doxorubicin in mdr1a(-/-) mice
      were 1.6- and 1.2-fold higher respectively. The retention of both doxorubicin and
      its metabolite doxorubicinol in the hearts of mdr1a(-/-) mice was substantially
      prolonged. In addition, a significantly increased drug accumulation was observed
      in the brain and the liver of mdr1a(-/-) mice. The relative accumulation in most
      other tissues was not or only slightly increased. The differences in cumulative
      faecal and urinary excretion of doxorubicin and metabolites between both types of
      mice were small. These experiments demonstrate that the absence of mdr1a P
      glycoprotein only slightly alters the plasma pharmacokinetics of doxorubicin.
      Furthermore, the substantially prolonged presence of both doxorubicin and
      doxorubicinol in cardiac tissue of mdr1a(-/-) mice suggests that a blockade of
      endogenous P-glycoprotein in patients, for example by a reversal agent, may
      enhance the risk of cardiotoxicity upon administration of doxorubicin.

PMID- 10408700
TI  - Synergistic inhibition of prostate cancer cell lines by a 19-nor hexafluoride
      vitamin D3 analogue and anti-activator protein 1 retinoid.
AB  - The secosteroid hormones, all-trans- and 9-cis-retinoic acid and vitamin D3, have
      demonstrated significant capacity to control proliferation in vitro of many solid
      tumour cell lines. Cooperative synergistic effects by these two ligands have been
      reported, and it is, therefore, possible that greater therapeutic effects could
      be achieved if these compounds were administered together. The role of retinoid
      dependent anti-activator protein 1 (anti-AP-1) effects in controlling cancer cell
      proliferation appears significant. We have utilized an anti-AP-1 retinoid [2-(4,4
      dimethyl-3,4-dihydro-2H-1 benzopyran-6-yl)carbonyl-2-(4-carboxyphenyl)-1,3,
      dithiane; SR11238], which does not transactivate through a retinoic acid response
      element (RARE), and a potent vitamin D3 analogue [1alpha,25(OH)2-16-ene-23-yne
      26,27-F6-19-nor-D3, code name LH] together at low, physiologically safer doses
      against a panel of prostate cancer cell lines that represent progressively more
      transformed phenotypes. The LNCaP (least transformed) and PC-3 (intermediately
      transformed) cell lines were synergistically inhibited in their clonal growth by
      the combination of LH and SR11238, whereas SR11238 alone was essentially
      inactive. DU-145 cells (most transformed) were completely insensitive to these
      analogues. LNCaP cells, but neither PC-3 nor DU-145, underwent apoptosis in the
      presence of LH and SR11238. Transactivation of the human osteocalcin vitamin D
      response element (VDRE) by LH was not enhanced in the presence of SR11238,
      although the expression of E-cadherin in these cells was additively up-regulated
      in the presence of both compounds. These data suggest the anti-AP-1 retinoid and
      the vitamin D3 analogue may naturally act synergistically to control cell
      proliferation, a process that is interrupted during transformation, and that this
      combination may form the basis for treatment of some androgen-independent
      prostate cancer.

PMID- 10408702
TI  - Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits
      tumour growth in rabbits.
AB  - Neovascularization facilitates tumour growth and metastasis formation. In our
      laboratory, we attempt to identify clinically available oral efficacious drugs
      for antiangiogenic activity. Here, we report which non-steroidal anti
      inflammatory drugs (NSAIDs) can inhibit corneal neovascularization, induced by
      basic fibroblast growth factor (bFGF) or vascular endothelial growth factor
      (VEGF). This antiangiogenic activity may contribute to the known effects of
      NSAIDs on gastric ulcers, polyps and tumours. We found that sulindac was one of
      the most potent antiangiogenic NSAIDs, inhibiting bFGF-induced neovascularization
      by 50% and VEGF-induced neovascularization by 55%. Previously, we reported that
      thalidomide inhibited growth factor-induced corneal neovascularization. When we
      combined sulindac with thalidomide, we found a significantly increased inhibition
      of bFGF- or VEGF-induced corneal neovascularization (by 63% or 74% respectively)
      compared with either agent alone (P < 0.01). Because of this strong
      antiangiogenic effect, we tested the oral combination of thalidomide and sulindac
      for its ability to inhibit the growth of V2 carcinoma in rabbits. Oral treatment
      of thalidomide or sulindac alone inhibited tumour growth by 55% and 35%
      respectively. When given together, the growth of the V2 carcinoma was inhibited
      by 75%. Our results indicated that oral antiangiogenic combination therapy with
      thalidomide and sulindac may be a useful non-toxic treatment for cancer.

PMID- 10408703
TI  - Renal cell carcinoma induces interleukin 10 and prostaglandin E2 production by
      monocytes.
AB  - Immunotherapy with interleukin 2 (IL-2) is not an effective anti-cancer treatment
      in the majority of patients with renal cell carcinoma (RCC), suggesting that the
      activation of cytotoxic T cells or NK cells may be impaired in vivo in these
      patients. The production of immunosuppressive factors by RCC was investigated.
      Using immunohistochemistry, IL-10 was detectable in 10 of 21 tumour samples
      tested. IL-10 was undetectable in the supernatant of cell lines derived from
      these RCCs. However, these cell lines or their conditioned medium (RCC CM), but
      not normal renal epithelial cells adjacent to the RCC or breast carcinoma cell
      lines, were found to induce IL-10, as well as prostaglandin E2 (PGE2) and tumour
      necrosis factor (TNF)alpha production by autologous or allogeneic peripheral
      blood mononuclear cells (PBMCs) and monocytes. IL-10 production induced by RCC CM
      was found to be dependent on TNF-alpha and PGE2 since an anti-TNF-alpha antibody
      (Ab) inhibited 40-70% of IL-10 production by monocytes, and the combination of
      anti-TNF-alpha Ab and indomethacin, an inhibitor of PGE2 production, inhibited 80
      94% of RCC CM-induced IL-10 production by monocytes. The RCC CM of the five cell
      lines tested were found to induce a down-regulation of the expression of HLA-DR
      and CD86, as well as a strong inhibition of mannose receptor-dependent
      endocytosis by monocytes. The blockade of HLA-DR and CD86 expression was
      partially abrogated by indomethacin and anti-IL-10 Ab respectively, and
      completely abrogated by an anti-TNF-alpha Ab. The inhibition of mannose receptor
      dependent endocytosis was partially abrogated by an anti-IL-10 Ab and completely
      abrogated by an anti-TNF-alpha Ab. These results indicate that RCCs induce IL-10,
      PGE2 and TNF-alpha production by monocytes, which down-regulate the expression of
      cell-surface molecules involved in antigen presentation as well as their
      endocytic capacity.

PMID- 10408704
TI  - Deletions of the region 17p11-13 in advanced melanoma revealed by cytogenetic
      analysis and fluorescence in situ hybridization.
AB  - The significance of the p53 tumour-suppressor gene in the oncogenesis of a
      variety of malignant tumours has been demonstrated over recent years. However,
      the role of p53 in human malignant melanoma is still unclear. Therefore, we
      investigated melanoma metastases from 11 patients cytogenetically and with
      fluorescence in situ hybridization (FISH) after short-term culture, employing a
      p53 region-specific probe for 17p13.1 and a probe detecting the centromere of
      chromosome 17. Furthermore, paraffin-embedded tissue samples from nine of these
      patients were investigated immunohistochemically for expression of the p53
      protein. Deletions of the short arm of chromosome 17 were seen in six melanomas
      in cytogenetic analysis. With FISH, three malignant melanomas had clones with
      only one p53-allele and an additional four malignant melanomas showed a reduced
      number of signals at the p53 tumour-suppressor gene locus compared with signals
      for the centromeric region of chromosome 17. This was confirmed by
      immunohistochemistry. Our results suggest that the 17p11-13 region is frequently
      deleted in malignant melanomas and that p53 or other genes located on this band
      might contribute to the malignant potential of advanced melanoma.

PMID- 10408705
TI  - An analysis of first-time enquirers to the CancerBACUP information service:
      variations with cancer site, demographic status and geographical location.
AB  - A retrospective comparison of cancer incidence data and, where relevant,
      population data with 16,955 first-time users (patients, relatives and friends) of
      a national cancer information service (CancerBACUP) during the period April 1995
      to March 1996 is presented. The number of events observed was compared with the
      number of events expected, were the national rates of cancer incidence and
      population demographics apply. Standardized incidence ratios (SIRs) (observed -
      expected ratios) were used to indicate any differences. Statistically significant
      differences (P < 0.001) in the observed and expected sex, age and primary site
      distribution of patients enquired about were found. Statistically significant
      differences (P < 0.001) were also identified for the age, employment status,
      socioeconomic class and geographical location of first-time enquirers (patients,
      relatives and friends). Enquiries about brain, testis and breast cancers and non
      Hodgkin's lymphoma (NHL) were substantially higher than expected; enquiries about
      bladder, lung, stomach and colorectal cancers were much lower than expected. As
      the service is provided via a freephone number, it is available to all, and users
      might be expected to be randomly distributed across the variables listed. The
      underlying reasons for the differences identified need to be investigated, and
      the role of information in the care of cancer patients should be formally
      evaluated.

PMID- 10408707
TI  - Three independently deleted regions at chromosome arm 16q in human prostate
      cancer: allelic loss at 16q24.1-q24.2 is associated with aggressive behaviour of
      the disease, recurrent growth, poor differentiation of the tumour and poor
      prognosis for the patient.
AB  - Loss of heterozygosity at chromosome arm 16q is a frequent event in human
      prostate cancer. In this study, loss of heterozygosity at 16q was studied in 44
      prostate cancer patients exhibiting various clinical features. Fifteen
      polymorphic polymerase chain reaction (PCR) markers were used to identify the
      separately deleted areas and the findings were compared with clinicopathological
      variables and 5-year survival of the patients. The results indicated that there
      are at least three independently deleted regions at 16q. Allelic losses at the
      central and distal areas were associated significantly with aggressive behaviour
      of the disease (16q24.1-q24.2, P < 0.01, and 16q24.3-qter, P < 0.05), and the
      central area of deletion was further significantly associated with poorly
      differentiated tumour cells (P < 0.05) and with recurrent (P < 0.01) growth of
      the tumour. During the follow-up period, 28% of the patients initially with M0
      disease developed distant metastases. Of the patients showing allelic loss at
      16q24.1-q24.2, distant metastasis were found in 45% during the 5-year follow-up
      period, and 31% of the patients showing loss at 16q21.1 also developed distant
      metastases. After the 5-year follow-up period, 14 (32%) of the patients remained
      alive, whereas 19 (43%) had died because of their prostate cancer. The overall
      survival rate of the patients showing allelic loss at 16q21.1 or 16q24.1-q24.2
      was significantly lower than that of the patients with retained heterozygosity.

PMID- 10408706
TI  - Controversies in the management of advanced prostate cancer.
AB  - For advanced prostate cancer, the main hormone treatment against which other
      treatments are assessed is surgical castration. It is simple, safe and effective,
      however it is not acceptable to all patients. Medical castration by means of
      luteinizing hormone-releasing hormone (LH-RH) analogues such as goserelin acetate
      provides an alternative to surgical castration. Diethylstilboestrol, previously
      the only non-surgical alternative to orchidectomy, is no longer routinely used.
      Castration reduces serum testosterone by around 90%, but does not affect androgen
      biosynthesis in the adrenal glands. Addition of an anti-androgen to medical or
      surgical castration blocks the effect of remaining testosterone on prostate cells
      and is termed combined androgen blockade (CAB). CAB has now been compared with
      castration alone (medical and surgical) in numerous clinical trials. Some trials
      show advantage of CAB over castration, whereas others report no significant
      difference. The author favours the view that CAB has an advantage over
      castration. No study has reported that CAB is less effective than castration. Of
      the anti-androgens which are available for use in CAB, bicalutamide may be
      associated with a lower incidence of side-effects compared with the other non
      steroidal anti-androgens and, in common with nilutamide, has the advantage of
      once-daily dosing. Only one study has compared anti-androgens within CAB:
      bicalutamide plus LH-RH analogue and flutamide plus LH-RH analogue. At 160-week
      follow-up, the groups were equivalent in terms of survival and time to
      progression. However, bicalutamide caused significantly less diarrhoea than
      flutamide. Withdrawal and intermittent therapy with anti-androgens extend the
      range of treatment options.

PMID- 10408708
TI  - Comparison of the distribution of non-AIDS Kaposi's sarcoma and non-Hodgkin's
      lymphoma in Europe.
AB  - To evaluate whether some form of mild immunosuppression may influence the
      geographical distribution of non-AIDS Kaposi's sarcoma (KS), we correlated
      incidence rates of KS and non-Hodgkin's lymphoma in individuals aged 60 or more
      in 18 European countries and Israel. Significant positive correlations emerged
      but, within highest risk countries (i.e. Italy and Israel), internal correlations
      were inconsistent.

PMID- 10408709
TI  - Absence of mutation of the p73 gene localized at chromosome 1p36.3 in
      hepatocellular carcinoma.
AB  - Accumulating evidence has demonstrated that aberration of the p53 tumour
      suppressor gene is one of the pivotal genetic events in hepatocellular
      carcinogenesis. Recent reports suggest that the product of hepatitis B virus
      (HBV) interacts with p53 and that the hepatitis C virus (HCV) core protein
      reduces p53 expression. A novel p73 gene, which is related to p53, has recently
      been identified and mapped to chromosome 1p36.3, which is a locus of multiple
      tumour-suppressor genes for many cancers, including hepatocellular carcinoma
      (HCC) and neuroblastoma. Here, we investigated mRNA expression, allelotype and
      mutation of p73 in 48 HCCs obtained from untreated patients. Reverse
      transcriptase polymerase chain reaction (RT-PCR) revealed that p73 mRNA was
      expressed ubiquitously at low levels in all the tumour tissues, as well as in the
      adjacent normal liver tissues. The frequency of p73 loss of heterozygosity was
      observed in 20% of HCCs, but PCR-single strand conformation polymorphism (SSCP)
      analysis showed no mutations in the 48 tumours except for three types of
      polymorphisms. These results suggest that p73 may play a role in hepatocellular
      carcinogenesis in a different manner from a Knudson two-hit model. The regulatory
      mechanism of interaction between p73 and hepatitis viruses remains to be
      determined.

PMID- 10408710
TI  - Microsomal epoxide hydrolase gene polymorphism and susceptibility to colon
      cancer.
AB  - We examined polymorphisms in exons 3 and 4 of microsomal epoxide hydrolase in 101
      patients with colon cancer and compared the results with 203 control samples. The
      frequency of the exon 3 T to C mutation was higher in cancer patients than in
      controls (odds ratio 3.8; 95% confidence intervals 1.8-8.0). This sequence
      alteration changes tyrosine residue 113 to histidine and is associated with lower
      enzyme activity when expressed in vitro. This suggests that putative slow epoxide
      hydrolase activity may be a risk factor for colon cancer. This appears to be true
      for both right- and left-sided tumours, but was more apparent for tumours arising
      distally (odds ratio 4.1; 95% confidence limits 1.9-9.2). By contrast, there was
      no difference in prevalence of exon 4 A to G transition mutation in cancer vs
      controls. This mutation changes histidine residue 139 to arginine and produces
      increased enzyme activity. There was no association between epoxide hydrolase
      genotype and abnormalities of p53 or Ki-Ras.

PMID- 10408711
TI  - Prognostic significance of MIB1-determined proliferative activities in
      intraductal components and invasive foci associated with invasive ductal breast
      carcinoma.
AB  - The prognostic significance of the proliferative activities in intraductal
      components and invasive foci was investigated using 157 cases of invasive ductal
      breast carcinoma in which intraductal components predominated. Proliferative
      activity was expressed as the number of MIB1-positive nuclei per 1000 cancer
      cells in the most active areas of intraductal components (MLI-DCIS) or invasive
      foci (MLI-INV). MLI-DCIS correlated closely with MLI-INV (r = 0.710, 95%
      confidence interval, 0.623-0.780; P < 0.0001). Both MLI-DCIS and MLI-INV were
      related to oestrogen receptor (ER) (P = 0.0006, P = 0.0028 respectively), grade
      of invasive tumour (P < 0.0001, P < 0.0001 respectively) and classification of
      intraductal components (P < 0.0001, P < 0.0001 respectively). In the univariate
      disease-free survival analysis, both MLI-DCIS and MLI-INV were found to be
      significant (P < 0.0001, P = 0.0003 respectively). However, in node-negative
      cases, only MLI-DCIS was significant (P = 0.0416). Multivariate analysis revealed
      that MLI-DCIS was significant not only in all cases, but also in node-negative
      cases (P = 0.0223, P = 0.0426 respectively), whereas MLI-INV was not. These
      findings indicate that MIB1-determined proliferative activity of intraductal
      components is a significant prognostic determinant of invasive ductal breast
      carcinoma in which intraductal components predominate.

PMID- 10408712
TI  - Expression of midkine in the early stage of carcinogenesis in human colorectal
      cancer.
AB  - It has been suggested that a heparin-binding growth factor, midkine (MK), plays
      an important role in carcinogenesis because of its frequent overexpression in
      various malignant tumours. To clarify whether or not MK contributes to the early
      stage of carcinogenesis, we examined the status of MK mRNA in 20 adenomas with
      moderate- and severe-grade dysplasia, 28 carcinomas and 28 corresponding normal
      tissues, by means of Northern blotting. The MK expression level was significantly
      more elevated in adenomas than in normal tissues (P < 0.001, unpaired Student's t
      test). A difference was also observed between carcinomas and the corresponding
      normal tissues (P < 0.04, paired Student's t-test). Moreover, MK immunostaining
      was positive in the adenomas with moderate- and severe-grade dysplasia and in the
      carcinomas, but not in mild-grade dysplasia or in normal tissues. These findings
      were in line with those on Western blotting. In three patients with both adenomas
      with moderate- or severe-grade dysplasia and carcinomas, elevated MK expression
      was observed in the neoplastic lesions. This is the first report of the
      association of elevated MK expression with the early stage of carcinogenesis in
      humans.

PMID- 10408713
TI  - Lesion development in Marburg's type of acute multiple sclerosis: from
      inflammation to demyelination.
AB  - We report a patient who suffered from acute inflammatory CNS demyelination and
      underwent two consecutive diagnostic stereotactic brain biopsies during the early
      disease course. The first lesion was drawn 33 days after the onset of
      disseminated neurological symptoms. Macrophages and T lymphocytes diffusely
      infiltrated small vessel walls and the white matter. mRNA for tumor necrosis
      factor alpha (TNFalpha) and inducible nitric oxide synthase (iNOS) was abundantly
      expressed. Myelin sheaths were entirely preserved. The second biopsy 76 days
      later showed confluent demyelinating lesions with a diffuse infiltration of
      macrophages that were positive for myelin debris, activation markers and TNFalpha
      and iNOS mRNA. IgG and C9neo deposits were found along myelin sheaths. The
      patient had received intravenous immunoglobulins (IVIG) prior to biopsy. Findings
      from this single patient affirm that demyelination follows the migration of
      inflammatory cells from the circulation into the white matter with subsequent
      inflammation and demyelination. Inflammation alone may be sufficient to cause
      significant clinical deficits without demyelination. Inflammatory mediators such
      as TNFalpha and NO are involved at very early stages in the pathogenetic process.
      IVIG treatment may lead to the deposition of immunoglobulins and to the
      activation of the complement cascade, but the clinical relevance of this
      particular finding remains uncertain.

PMID- 10408715
TI  - Reduced visual evoked responses in multiple sclerosis patients with optic
      neuritis: comparison of functional magnetic resonance imaging and visual evoked
      potentials.
AB  - The limited application of functional magnetic resonance imaging (fMRI) for
      investigations of multiple sclerosis (MS) patients has already shown that
      deficits of the motor, cognitive and visual systems may be identified by
      differences in the patterns of activation in response to a suitable stimulus. In
      MS patients with unilateral optic neuritis, the area of activation in the primary
      visual cortex, measured by fMRI techniques, is dramatically reduced in response
      to stimulation of the affected eye. The latency of the major positive component
      of the visual evoked potential (VEP) recorded upon stimulation of the affected
      eye is significantly increased in these patients, as compared to the unaffected
      eye and normal volunteers. We have found a correlation between the neural
      response measured using fMRI and the latency of the VEP. fMRI signal responses
      have the potential to provide more detailed topographic information relating to
      functional deficits in MS.

PMID- 10408714
TI  - Candidate autoantigens in multiple sclerosis.
AB  - Multiple sclerosis is an inflammatory demyelinating CNS disease of putatively
      autoimmune origin. Novel models of experimental autoimmune encephalomyelitis
      (EAE) have demonstrated that T cells specific for various myelin and even
      nonmyelin proteins are potentially encephalitogenic. The encephalitogenic T cell
      response directed against different CNS antigens not only determines the lesional
      topography of CNS inflammation but also the composition of the inflammatory
      infiltrates. The heterogeneity of the lesional distribution seen in EAE might
      therefore be useful for the understanding of the various clinical subtypes seen
      in MS. In this review the possible candidate autoantigens in MS are discussed
      with special regard to the human T cell and B cell responses against various
      myelin and nonmyelin proteins.

PMID- 10408716
TI  - Relationship between tumour necrosis factor-alpha (TNFalpha) production and a
      specific multiple sclerosis (MS) associated TNF gene haplotype.
AB  - OBJECTIVE: To determine if monocyte TNFalpha production from patients homozygous
      for a specific MS associated TNF gene haplotype is different from that produced
      in patients either heterozygous for, or without this haplotype. BACKGROUND: The
      balance between pro- and anti-inflammatory cytokines is important in the clinical
      outcome of inflammatory reactions. Levels of TNFalpha, a pro-inflammatory
      cytokine, is raised in MS as well as being found in acute and chronic MS lesions.
      A previous population based study in Northern Ireland with polymorphisms spanning
      the TNF gene region identified a conserved MS associated haplotype in relation to
      three markers (130: 118: 127 TNF d:a:b) for which 19 MS patients were homozygous.
      METHODS: Venous blood collected in EDTA to give a concentration of 10(-3) M was
      drawn from 16 patients with the conserved MS associated haplotype, 19 patients
      heterozygous for the haplotype and 17 patients without the haplotype. Mononuclear
      cells were separated and cultured by standard techniques and levels of TNFalpha
      and of TNF binding proteins I and II were determined by commercial enzyme-linked
      immunosorbent assays. RESULTS: There were no significant differences in TNFalpha
      production in the 3 h (P = 0.28) or 24 h cultures (P = 0.18) or following
      stimulation with interferon-gamma (P = 0.17) between the group positive for the
      conserved haplotype and the group negative for this haplotype. There was also no
      significant difference when compared to the heterozygote group. No association
      was found between the MS associated haplotype and levels of either TNF binding
      protein. A greater proportion of patients with the conserved haplotype had a
      benign clinical course (P = 0.06). CONCLUSION: We conclude that whilst a trend
      exists, we have found no significant association between peripheral TNFalpha
      production and a specific MS associated TNF haplotype in this population.
      Paradoxically this haplotype may also predict a more favourable clinical course.

PMID- 10408717
TI  - Prognostic factors for survival in multiple sclerosis.
AB  - In a hospital-based study of 119 patients with definite multiple sclerosis,
      demographic and clinical factors were analysed with respect to their validity in
      assessing the long-term prognosis. Over a mean follow-up of 21.7 years, the
      following factors negatively influenced the prognosis by the univariate analysis:
      male sex, age at onset over 25, pyramidal involvement or spasticity at onset, >
      or =3 functional systems affected at onset or after 5 years, incomplete first
      remission, length of the first remission < or =1 year, >5 attacks in the first 10
      years, secondary or primary-progressive disease, time to reach secondary
      progression over 5 years and time to reach EDSS 6 over 7 years. The multivariate
      model showed that in patients with relapsing-remitting disease, 5 years after
      onset, pyramidal involvement at onset and shorter time to reach EDSS 6 predicted
      poor outcome, while after 10 years, higher age at onset and incomplete first
      remission indicated poor prognosis. Ten years after onset, the predictors of poor
      outcome in the secondary-progressive group were shorter time to reach EDSS 6 or
      secondary progression and higher EDSS, while in the primary-progressive group
      those variables were spasticity or higher number of functional systems affected
      at onset, and higher EDSS after 5 and 10 years.

PMID- 10408718
TI  - Sensory symptoms of multiple sclerosis: a hidden reservoir of morbidity.
AB  - OBJECTIVE: To assess the frequency and quality of sensory symptoms in a
      population of patients with Multiple Sclerosis (MS) and compare them with
      controls. DESIGN: Survey to target population and control group evaluating
      demographic data, data on disease course, presence of various symptoms of MS.
      SETTING: Neurological practices affiliated with a tertiary community hospital.
      PARTICIPANTS: 224 patients with MS, 93 controls of similar age and sex. RESULTS:
      Sensory symptoms were more common in MS patients than in controls, and differed
      in severity and quality. Fifty per cent described brief (seconds to hours)
      episodes of neurological dysfunction, significantly more often than in controls
      (P = 0.001). Pain was present at some time in similar percentages in patients and
      controls, but active pain problems were present more often in MS patients (P =
      0.001). The qualitative description of pain in MS patients was more often
      neuropathic, with burning, itching, electric and formicatory pain, as opposed to
      throbbing, sharp or muscular pain. Pain was localized to arms, legs, trunk,
      hands, feet and face more often in the MS group. Lhermitte's phenomenon was
      present in two-thirds of patients at some time in their disease course. Twenty
      per cent of the patients identified themselves as having respiratory problems
      (Controls 7.5%, P = 0.005). Fatigue limited activity in 78% of patients, but only
      in 17% of controls (P = 0.001). Dizziness, memory dysfunction, and restless legs
      symptoms were all more frequent in patients. The self-rated 'worst' symptoms of
      MS was pain in 12%, fatigue in 17% and dizziness in 5%, a total of 34% of 'worst'
      symptoms. Sensory symptoms were present in patients with early disease and
      without disability as often as in disabled patients and in those with longer
      disease duration. There was however a strong correlation between the total number
      of sensory symptoms reported and the presence of disability in the MS patients.
      CONCLUSIONS: Sensory symptoms are common in MS patients. Pain syndromes,
      transient neurologic events, Lhermitte's phenomenon, fatigue, respiratory
      symptoms and vertigo were present significantly more frequently in patients with
      MS than in a control population and contributed to subjective morbidity. Future
      clinical trials assessing therapy in MS might include sensory symptoms as
      secondary endpoints to capture this 'hidden reservoir' of disease morbidity.

PMID- 10408719
TI  - Nasal administration of transforming growth factor-beta1 induces dendritic cells
      and inhibits protracted-relapsing experimental allergic encephalomyelitis.
AB  - Cytokines have a crucial role in initiation and perturbation of EAE that
      represents an animal model of multiple sclerosis (MS). Administration of
      transforming growth factor-beta1 (TGF-beta1) to EAE mice improves clinical EAE
      and prevents relapses by unknown mechanisms. Administering low doses of TGF-beta1
      nasally, we confirmed that TGF-beta1 inhibited development and relapse of
      protracted-relapsing EAE (PR-EAE) in DA rats. Infiltration of CD4+ T-cells and
      macrophages within the central nervous system was clearly reduced, while
      proliferation and IFN-gamma secretion of mononuclear cells (MNC) was augmented in
      TGF-beta1-treated EAE rats compared to PBS-treated control EAE rats. TGF-beta1
      administered nasally also increased nitric oxide production and CD4+ T cell
      apoptosis. TGF-beta1 treated rats showed augmented proliferation of dendritic
      cells (DC) compared to MNC. These data imply that low doses of TGF-beta1 given by
      the nasal route prevent PR-EAE and upregulate DC functions that may be involved
      for disease prevention.

PMID- 10408720
TI  - Treatment adherence and patient retention in the first year of a Phase-III
      clinical trial for the treatment of multiple sclerosis.
AB  - The purpose of this study was to examine the relationship between patient
      management strategies employed by study personnel, and patient retention and
      adherence to treatment in the first year of a Phase III clinical trial of
      interferon beta-1b for treatment of secondary progressive multiple sclerosis
      (MS). Study staff from each of 35 sites were interviewed regarding patient
      management practices. Sites which were rated as more empathetic, as instilling a
      sense of purpose in the patient, and promoting less formal relationships with
      patients had high rates of adherence to treatment. In addressing specific patient
      concerns, attention to patients' emotional status and patients' expectations of
      trial participation were related to better adherence.

PMID- 10408721
TI  - A double-blind, placebo-controlled trial of extracorporeal photopheresis in
      chronic progressive multiple sclerosis.
AB  - Extracorporeal photopheresis is a safe therapy for cutaneous T-cell lymphoma and
      may have efficacy in certain autoimmune disorders. We performed a randomized,
      double-blinded, placebo-controlled trial of monthly photopheresis therapy in 16
      patients with clinically definite multiple sclerosis (MS). All patients had
      progressed during the preceding year with entry Expanded Disability Status Scale
      (EDSS) scores between 3.0 and 7.0. Patients received photopheresis or sham
      therapy for 1 year and were followed for an additional 6 to 12 months. Patients
      were clinically evaluated by three disability scales: (1) EDSS; (2) Ambulation
      index and (3) Scripp's quantitative neurologic assessment. No serious side
      effects occurred in either group. There were no differences between the
      photopheresis and sham therapy groups by the disability measures. Additionally,
      there were no differences in progression of MRI plaque burden or evoked potential
      latencies. In this limited study, photopheresis was found to be safe but did not
      significantly alter the course of chronic progressive MS.

PMID- 10408722
TI  - Aminooxypentane-RANTES, an inhibitor of R5 human immunodeficiency virus type 1,
      increases the interferon gamma to interleukin 10 ratio without impairing cellular
      proliferation.
AB  - Studies have demonstrated that the beta-chemokines RANTES, MIP-1alpha, and MIP
      1beta suppress human immunodeficiency type 1 (HIV-1) replication in vitro.
      Infection with HIV-1 requires expression of CD4 antigen and the chemokine
      receptor CXCR4 (X4) or CCR5 (R5) on the surface of target cells. The engagement
      of these receptors with the viral surface proteins is essential for the membrane
      fusion process. This study investigated the anti-HIV-1 activity of a derivative
      of RANTES, the CCR5 antagonist aminooxypentane (AOP)-RANTES, on R5 HIV-1 isolates
      in peripheral blood mononuclear cells. In drug exposure experiments, AOP-RANTES
      efficiently inhibited viral replication of HIV-1 R5 strains, with a viral
      breakthrough observed after the withdrawal of the compound. The HIV-1-specific
      proliferative capacity was maintained under all conditions when compared with
      controls. An increase in IFN-gamma production accompanied by a parallel decrease
      in the generation of IL-10 was observed following the in vitro exposure of cells
      to AOP-RANTES in the presence of three of four HIV-1 R5 isolates. These
      experiments confirmed that the chemokine receptor antagonist AOP-RANTES was
      effective as an inhibitor of HIV-1 R5 strain infectivity in peripheral blood
      mononuclear cells. The capacity of this compound to maintain HIV-1-specific
      proliferative activity with a shift toward a type 1 cytokine profile makes this
      compound a unique molecule, one adopting an immunological pathway to limit HIV-1
      infection.

PMID- 10408723
TI  - Expression of CCR5 is increased in human monocyte-derived macrophages and
      alveolar macrophages in the course of in vivo and in vitro Mycobacterium
      tuberculosis infection.
AB  - Human immunodeficiency virus (HIV) replicates more efficiently in Mycobacterium
      tuberculosis (MTB)-infected macrophages than in uninfected controls. We
      investigated whether this may be partly explained by changes in expression of
      CCR5 in the course of mycobacterial infection, as this molecule has been shown to
      be a coreceptor for HIV entry. Since the lung is the preferential organ of HIV
      replication in the course of tuberculosis, we preliminarily analyzed beta
      chemokine receptor expression in alveolar macrophages from patients with active
      tuberculosis, using flow cytometry based on an MIP-1alpha ligand-biotin/avidin
      FITC detection system. Increased MIP-1alpha receptor (MIP-1alphaR) expression in
      alveolar macrophages from infected patients was observed whereas no detectable
      expression could be revealed in uninfected controls. Since MIP-la can also bind
      CCR1 and CCR4, the presence of CCR5 mRNA was investigated in bronchoalveolar
      lavage (BAL) cells and detected in alveolar macrophages from tuberculosis
      patients only. The study was then extended to in vitro MTB-infected macrophages.
      Monocyte-derived macrophages (MDMs) were left to differentiate for 7 days before
      MTB H37Rv infection, and CCR5 expression was monitored, by using a specific
      monoclonal antibody, on days 1, 6, and 11 after infection. Increased CCR5
      expression in MTB-infected macrophages was observed, with a peak on day 6 (64% in
      MTB-infected versus 33% in control cultures) and a decrease by day 11 (25% in MTB
      infected versus 13% in control cultures). These results show that CCR5 expression
      is enhanced in the course of in vitro MTB infection and during active pulmonary
      tuberculosis.

PMID- 10408724
TI  - Characterization of mother-infant HIV type 1 gag p17 sequences associated with
      perinatal transmission.
AB  - The gag p17 matrix sequences of human immunodeficiency virus type 1 (HIV-1) from
      seven infected mother-infant pairs were analyzed after perinatal transmission.
      The p17 matrix open reading frame was maintained in 143 of the 166 clones
      analyzed (86.2% frequency of intact p17 open reading frames). The functional
      domains essential for p17 matrix function in HIV-1 replication, including
      targeting of Gag to the plasma membrane, virus assembly and release, envelope
      glycoprotein incorporation into virus particle, virus entry, and localization of
      the virus preintegration complex to the nucleus of nondividing cells, were highly
      conserved in most of the sequences. In addition, examination of the three
      dimensional structure of the p17 matrix protein in mother-infant isolates showed
      a high degree of conservation of amino acids required for correct folding and
      biological activity. Several amino acid motifs common to most of the mother
      infant pairs sequences, including pair-specific signature sequences, were
      observed. There was a low degree of heterogeneity of gag p17 sequences within
      mothers, within infants, and between mother-infant pairs, but the distances were
      greater between epidemiologically unlinked individuals. Phylogenetic analyses of
      166 mother-infant pairs and 181 other p17 sequences available from HIV-1
      databases revealed distinct clusters for each mother-infant pair and for other
      p17 sequences. In conclusion, these findings indicate that an intact and
      functional gag p17 matrix is maintained during maternal-fetal transmission and
      that several motifs in p17 may be associated with perinatal transmission.

PMID- 10408725
TI  - Assay of plasma samples representing different HIV-1 genetic subtypes: an
      evaluation of new versions of the amplicor HIV-1 monitor assay.
AB  - Quantification of plasma HIV-1 RNA levels has rapidly become the main tool for
      monitoring disease progression and treatment. However, some first-generation
      assays do not accurately quantify all HIV-1 subtypes. This study compares the
      first-generation and two newer prototype Amplicor HIV-1 Monitor assays (Roche
      Diagnostic Systems) in terms of their performance in quantifying HIV-1 RNA in
      stored plasma samples from 101 individuals infected with various genetic subtypes
      of HIV-1 (28 subtype A, 18 B, 26 C, 20 D, 2 E, 3 G, 2 H, and 2 J). The HIV-1
      subtype had previously been determined by direct sequencing of the V3 domain of
      the env gene. The results from the three assays agreed for subtypes B and C, as
      well as for most subtype D samples. In contrast, the first-generation assay
      reported significantly lower plasma HIV-1 RNA levels than did the two newer
      versions of the assay for most subtype A, E, G, and H samples. There were no
      differences in mean plasma HIV-1 RNA levels between individuals infected with
      subtypes A, B, C, and D if the results from the two newer test versions were
      used, and if an adjustment was made between subtypes for differences in CD4
      count. Thus, this study confirms that the first-generation assay does not
      accurately quantify HIV-1 RNA levels in many individuals infected with subtype A,
      E, G, and H. These problems appeared to have been greatly reduced in the two new
      prototype versions.

PMID- 10408726
TI  - Exclusion of HIV coreceptors CXCR4, CCR5, and CCR3 from the HIV envelope.
AB  - Both HIV-1 primary isolates and laboratory strains incorporate cell-derived
      molecules into their envelopes depending on the host cell in which they are
      grown. This incorporation is not random and, specifically, HIV-1 has been shown
      to select against the incorporation into its surface of CD4, its main receptor.
      In this study, we have looked at the incorporation of HIV coreceptors CXCR4,
      CCR5, and CCR3 into the HIV envelope. For this purpose, we grew HIV-1 primary
      isolate BZ167 in several cell lines and PBMCs, and the envelope profiles of the
      resulting viruses were determined with a virus-binding ELISA. While the virus
      particle gained several molecules when passed through the different cell lines
      (e.g., ICAM-3, LFA-1, ICAM-1, or MHC class II), BZ167 never incorporated
      significant levels of CXCR4, CCR5, or CCR3 into its envelope even though some or
      all of the cell lines in which it was grown expressed them. These results show
      that HIV-1 selects against the incorporation of these chemokine receptors into
      its envelope molecule, as it does against the incorporation of CD4.

PMID- 10408727
TI  - Immunological responses to envelope glycoprotein 120 from subtypes of human
      immunodeficiency virus type 1.
AB  - The outer envelope glycoprotein (gp120) from subtypes A-E of HIV-1 was purified
      using a specific high mannose-binding lectin, Galanthus nivalis agglutinin. All
      isolates were grown in peripheral blood lymphocyte cells in order to avoid
      selection in cell lines. A comparison of the reactivities of the envelope
      proteins was made using sera from patients infected with the different subtypes.
      In this study, the B and C subtype envelope glycoproteins showed the strongest
      immunological reactivity, when reacted with sera from patients infected with the
      same subtype of virus. On the other hand, sera of patients infected with subtype
      A or C virus had the strongest and broadest reactivities, to envelope
      glycoproteins of many subtypes. The purified gp120 proteins from all five
      subtypes stimulated mononuclear cells from HIV-1 (subtype B)-infected patients,
      indicating conserved T cell-activating epitopes. The immunological reactivities
      indicate that strong antigenicity does not always predict the broadest
      immunogenicity of an envelope glycoprotein. Glycoprotein 120 from foreign
      subtypes may serve to induce strong cross-reactive immune responses.

PMID- 10408728
TI  - Influence of amino acid substitutions on antigenicity of immunodominant regions
      of the HTLV type I envelope surface gylcoprotein: a study using monoclonal
      antibodies raised against relevant peptides.
AB  - By the use of sera of human T cell leukemia virus type I (HTVL-I)-infected
      individuals it was shown that amino acid substitutions at positions 192 (proline
      to serine) and 250 (serine to proline) in major immunodominant regions (175-199
      and 239-261) of the surface envelope glycoprotein (gp46) of the virus may
      influence the humoral response. Since human sera are polyclonal in nature, one
      cannot readily discriminate between an immunoglobulin-specific recognition and
      multiple bindings of diverse antibodies. To overcome this difficulty we generated
      murine monoclonal antibodies to synthetic peptides mimicking all or portions of
      these gp46 regions. The reactivity of some of these antibodies to synthetic
      peptides harboring (or not harboring) the preceding amino acid substitutions at
      position 192 or 250, to denatured gp46 by Western blotting, and to live
      (variously substituted) HTLV-I-infected cells, combined with blocking experiments
      with various peptides, allow us to conclude that the major epitopes (positions
      183-191, 190-197, 190-199, and 246-252) in the two immunodominant regions may
      elicit different antibody responses according to their sequences. It is worth
      noting that in a reporter gene inhibition assay, it was found that a neutralizing
      monoclonal antibody (MF1), the epitope for which is located between residues 190
      and 197, had a high level of activity when cells (2060) harboring a gp46 with
      proline at position 192 were used and had no activity toward cells (1010) with a
      serine at this position. Therefore our results establish that certain amino acid
      substitutions of gp46 may drastically affect the antigenicity of the molecule and
      the biological activity of the antibodies elicited.

PMID- 10408729
TI  - MN and IIIB recombinant glycoprotein 120 vaccine-induced binding antibodies to
      native envelope glycoprotein of human immunodeficiency virus type 1 primary
      isolates. National Institute of Allergy and Infectious Disease Aids Vaccine
      Evaluation Group.
AB  - The ability of antibody induced by MN and IIIB recombinant gp120 (rgp120) human
      immunodeficiency virus type 1 (HIV-1) vaccines to bind to oligomeric native HIV-1
      envelope glycoproteins of primary isolates of HIV-1 was measured by flow
      cytometric indirect immunofluorescence assay (FIFA) in 25 uninfected, healthy
      adults. After three immunizations, MN rgp120 HIV-1 vaccine given alone and
      coadministered with IIIB rgp120 HIV-1 vaccine elicited antibody that bound to
      cells infected with each of a panel of six subtype B strains of HIV-1. Lower
      levels of vaccine-induced binding antibody were detected against envelope subtype
      A, D, and (EA) strains of HIV-1 than against subtype B strains. Priming
      immunization with IIIB rgp120 HIV-1 vaccine alone induced low levels of antibody
      capable of binding to envelope glycoprotein of primary isolate strains of HIV-1,
      and booster immunizations with MN rgp120 HIV-1 vaccine resulted in much higher
      antibody levels. We conclude that MN rgp120 HIV-1 vaccine was an effective
      inducer of antibody to native envelope glycoproteins of antigenically diverse
      primary isolates of HIV-1.

PMID- 10408730
TI  - Mutations in CCR5-coding sequences are not associated with SIV carrier status in
      African nonhuman primates.
AB  - African monkeys can be naturally infected with SIV but do not progress to AIDS.
      Since mutations in the human CCR5 gene have been shown to influence
      susceptibility to HIV infection and disease progression, we have now investigated
      whether mutations in CCR5-coding sequences in African nonhuman primates can
      explain species-specific differences in susceptibility to lentiviral infection.
      The animals studied comprise chronically infected monkeys corresponding to four
      natural hosts of SIV (Cercopithecus aethiops, Cercopithecus pygerythrus,
      Cercopithecus sabaeus, and Cercopithecus tantalus), noninfected animals from
      three species that are known to be susceptible to SIV infection (Cercopithecus
      patas, Cercopithecus Ihoesti, and Pan troglodytes), and monkeys of six species
      that do not carry SIV in the wild (Cercocebus galeritus, Cercocebus aterrimus,
      Cercopithecus ascanius, Cercopithecus nictitans, Cercopithecus neglectus, and
      Cercopithecus cephus). We observed a high degree of genetic divergence among the
      species. The rate of accumulation of amino acid mutations was, however, not
      higher in SIV carriers than in other nonhuman primates. No homozygous premature
      stop codons, deletions, or frameshift mutations were detected. In at least two
      animals, one infected AGM (Cercopithecus tantalus) and one noninfected monkey
      (Cercocebus aterrimus), the CCR5 alleles identified encode functional proteins,
      as they were identical in terms of amino acid sequence to that of functional CCR5
      reported in the literature. We found no other consistent differences in the
      genetic variability of CCR5-coding sequences between the nonhuman primates that
      are carriers of SIV and those that are not.

PMID- 10408731
TI  - Subtypes of HIV type 1 circulating in India: partial envelope sequences.

PMID- 10408732
TI  - Two alleles for rhesus macaque GPR15 (BOB).

PMID- 10408734
TI  - Treating and preventing levodopa-induced dyskinesias: current and future
      strategies.
AB  - Prevention of levodopa-induced dyskinesias is a therapeutic challenge for
      physicians. At present, it seems only possible to delay dyskinesias and motor
      fluctuations. In younger patients (aged <50 years), the strategy is to use a
      dopamine D2 agonist as monotherapy and then to add levodopa treatment when the
      parkinsonian symptoms progress. In older patients, (aged >50 years to <70 years),
      the therapeutic approach is to use early combination therapy of levodopa and a D2
      agonist. The treatment of levodopa-induced dyskinesias must be considered in
      regard to the subtype and the severity of dyskinesias, and the patient. The
      general approach to the treatment of peak dose dyskinesias is to maintain
      dopamine brain stimulation at as stable a level as possible by keeping plasma and
      brain levodopa concentrations in the therapeutic range (above the therapeutic
      threshold but below the dyskinesia threshold). An appropriate strategy is to
      reduce the individual dose of levodopa, to spread out the daily levodopa dose
      and/or to try treatment with the sustained-release form of the drug. Combination
      treatment with the standard and sustained-release levodopa formulations is also
      possible. Stopping selegiline (deprenyl) therapy may reduce dyskinesias; reducing
      the dose of, or stopping treatment with, a dopamine agonist may also be
      beneficial. Anti-dyskinetic drugs such as amantadine, buspirone, fluoxetine,
      propanolol and principally clozapine may be used. In severe dyskinesias,
      apomorphine infusion may be tried. In refractory dyskinesia, surgical procedures
      such as pallidotomy and chronic deep brain stimulation (globus
      pallidus/subthalamic nucleus) may be proposed. Theoretically, treatment of
      diphasic dyskinesias requires the maintenance of plasma levodopa concentrations
      above the dyskinesia threshold. However, this approach leads to constant and
      severe dyskinesia after only a few weeks of treatment. Thus, the strategy used to
      treat diphasic dyskinesia is close to the treatment of peak-dose dyskinesias.
      Apomorphine (or the liquid form of levodopa) may be helpful to prevent diphasic
      dyskinesias. In selected patients, a midday rest in the 'off' phase may decrease
      the duration of dyskinesia. Treatment of early morning dystonia is based on the
      addition to the regimen of the sustained release formulation of levodopa before
      bedtime. Liquid levodopa and apomorphine injection may be used just before the
      appearance of the dystonic posture. Botulinum toxin may be helpful in severe
      dystonia.

PMID- 10408733
TI  - Clinical pharmacology of selective estrogen receptor modulators.
AB  - Observations of the pharmacology of tamoxifen and related compounds have lead to
      the concept of selective estrogen receptor modulators (SERMs). This new class of
      drug displays estrogen agonist or antagonist effects in a tissue-dependent manner
      and appears to offer an alternative to hormone replacement therapy for the
      prevention and treatment of osteoporosis and cardiovascular disease in
      postmenopausal women. Moreover, the estrogen antagonist actions of SERMs on
      breast tissue may also provide a protective effect against breast cancer.
      Although tamoxifen therapy reduces plasma cholesterol levels and maintains bone
      density, it is also associated with an increased risk of endometrial cancer,
      pulmonary embolism and deep vein thrombosis. This has lead to the development of
      newer SERMs which will hopefully lack these adverse effects of tamoxifen. These
      compounds promise a new era of disease prevention in the aging woman and their
      therapeutic potential is currently being evaluated in large-scale clinical
      trials.

PMID- 10408735
TI  - The adverse effects of hormone replacement therapy.
AB  - This article reviews epidemiological data on potential adverse effects of hormone
      replacement therapy (HRT) on the risk of breast, endometrial and ovarian cancer,
      on the risk of stroke, and on the risk of venous and pulmonary thromboembolism.
      As for the potential adverse effects on cancer risk, most information on HRT and
      breast cancer is included in a re-analysis of individual data from 51
      epidemiological studies (including over 90% of the world's data), showing a 2.3%
      increase of the relative risk of breast cancer for each year of use which,
      however, levels off after stopping use. This corresponds to a cumulative excess
      of approximately 2 in 1,000 women who started taking HRT at age 50 and used it
      for 5 years, 6 in 1,000 women who used it for 10 years and 12 in 1,000 women who
      used it for 15 years. Unopposed estrogen use is strongly related to endometrial
      cancer risk mainly in lean women, but the cyclic combined oestrogen-progestin
      treatment appears to largely or totally reduce this effect if progestin is taken
      for more than 10 days per cycle. The data on epithelial ovarian cancer allows
      exclusion of any strong association with HRT, although a moderate positive
      relationship remains open to debate. As for other adverse effects of HRT, the
      relationship between HRT and stroke is still debated, although any strong and
      consistent association can be excluded. Current HRT use, but not past use, is
      associated with venous and pulmonary thromboembolism. Thus, most adverse effects
      of HRT are restricted to current or recent use, and long term HRT use should be
      carefully considered on an individual basis, taking into account any other
      personal risk factors for breast and endometrial cancer and for venous/pulmonary
      thromboembolism, and the potential benefits of HRT on cardiovascular disease and
      osteoporosis.

PMID- 10408737
TI  - Feasibility and outcomes of insulin therapy in elderly patients with diabetes
      mellitus.
AB  - The use of insulin in elderly patients raises special considerations. Most people
      who develop diabetes mellitus late in life have type 2 diabetes mellitus, in
      which there is some residual endogenous insulin secretion. This pancreatic
      insulin secretion, when present, stabilises their metabolic status. However, some
      elderly people lose virtually all their endogenous insulin secretory capacity
      over time, or may even have type 1 (autoimmune) diabetes mellitus with no
      endogenous insulin. Generally, older patients with diabetes mellitus can be
      managed for years, often decades, with nutritional therapy and oral agents. More
      options exist now than did previously. In addition to a variety of sulfonylureas,
      there is metformin, troglitazone, and/or alpha-glucosidase inhibitors, that are
      viable options to be used before turning to insulin. The goals of insulin therapy
      in the elderly must be considered. When hyperglycaemia causes symptoms (polyuria,
      polydypsia and bodyweight loss) blood glucose levels are generally >200 mg/dl,
      and insulin is needed if maximal doses of oral agents have been used. Insulin is
      also indicated when hyperglycaemia puts patients at risk of hyperosmolar states,
      for example, when blood glucose is >300 mg/dl during a normal day. Clinical
      judgement dictates whether to use insulin to control glycaemia in the attempt to
      avoid long term complications such as neuropathy, retinopathy or nephropathy. In
      people with relatively short life expectancy, major comorbities and no sign of
      diabetic complications, the risk may be small. On the other hand, in patients for
      whom neuropathy, in particular, is a major risk, controlling glycaemia (with
      insulin if necessary) does reduce that risk. Most patients with type 2 diabetes
      mellitus can be managed with relatively simple insulin regimens thanks to their
      endogenous insulin secretion. A single bedtime dose of neutral protamine Hagedorn
      (NPH) insulin, with or without continuation of daytime oral agents, may control
      fasting blood glucose. A pre-mix combination of NPH and Regular insulin such as
      70/30 or 50/50 may be used pre-meal. More customised, 'intensive' insulin
      regimens are needed when the glycaemia is unstable. Hypoglycaemia is clearly the
      most significant risk of insulin therapy. If mild and easily treated, it is of no
      real concern. On the other hand, nocturnal hypoglycaemia, and, in particular,
      hypoglycaemia unawareness, are clear signs that the insulin regimen should be
      modified. In summary, insulin therapy may be necessary, and can be used
      effectively, in elderly patients. However, risk:benefit considerations must be
      taken into account when deciding which patients to treat with insulin and what
      insulin regimen to use.

PMID- 10408736
TI  - Recent developments in the drug treatment of Alzheimer's disease.
AB  - Alzheimer's disease (AD) is a chronic neurodegenerative disorder with an impact
      on public health which continues to increase with the increasing longevity of the
      population. The disease is characterised clinically by a progressive loss of
      cognitive and behavioural function. These deficits are thought to result from
      decreased cholinergic transmission; therefore, restoring cholinergic function has
      been the main focus in the development of drugs for AD. Several pharmacological
      approaches to enhancing cholinergic function have been developed for symptomatic
      or palliative therapy of AD. Although these strategies have resulted in modest
      cognitive and behavioural improvements in patients with AD, they do not address
      the underlying progression of the disease. New strategies will be required to
      slow, stop or reverse the effects of neurodegeneration in AD. A number of
      potential therapies are currently under investigation, including estrogen
      replacement, anti-inflammatory agents, free radical scavengers and antioxidants,
      and monoamine oxidase-B (MAO-B) inhibitors. The evidence for a protective effect
      of estrogens or nonsteroidal anti-inflammatory drugs (NSAIDs) is controversial,
      and largely based on retrospective studies. More controlled prospective studies
      are needed to definitively demonstrate the benefits of long term estrogen or
      NSAID use in the prevention of AD. Free radical scavengers/antioxidants such as
      idebenone, and selective prevention MAO-B inhibitors such as lazabemide are well
      tolerated, but require additional studies in order to demonstrate preventative
      effects. In addition, other approaches, such as anti-amyloid treatments that
      affect beta-amylase secretion, aggregation and toxicity, appear promising;
      treatments that hinder neurofibrillary tangle construction and nerve growth
      factor (NGF) induction are in the very early stages of development.

PMID- 10408738
TI  - Prostaglandin analogues in the treatment of glaucoma.
AB  - Prostaglandin (PG) analogues are a new class of ocular hypotensive drugs that
      have been developed for the treatment of open angle glaucoma. Two of these drugs,
      latanoprost and unoprostone, are presently commercially available. Latanoprost
      was introduced in 1996 in the US and Europe. Presently it enjoys the most
      widespread use and is the most well documented drug of this group. It reduces the
      intraocular pressure (IOP) by a mechanism of action different from other drugs;
      namely by increasing the uveoscleral outflow. The aqueous inflow is not affected.
      The optimal dose regimen is one drop of 50 microg/ml once daily, which reduces
      the IOP by approximately 30% in patients with glaucoma. A more pronounced ocular
      hypotensive effect is demonstrated when latanoprost is combined with other
      glaucoma therapies, including beta-blockers, adrenergic and cholinergic agonists
      or carbonic anhydrase inhibitors. Latanoprost is well tolerated. The drug reaches
      a plasma concentration below that needed for stimulation of the FP-receptor,
      which may explain its favourable systemic tolerability profile. The major ocular
      adverse effect is increased iris pigmentation, which is due to increased
      synthesis of melanin in the melanocytes of the iris stroma. It is most frequently
      seen in green-brown eyes and it is probably permanent. A low frequency of cystoid
      macular oedema has also been reported, predominantly in predisposed eyes.
      Unoprostone was launched in Japan in 1994, but there is little experience with
      this drug outside the Japanese market and the documentation is more limited. Its
      main mechanism of action is on outflow, but this is not yet fully elucidated. The
      recommended dosage regimen is 1 drop of 1.2 mg/ml twice daily. No comparative
      studies in humans between the 2 drugs have yet been published.

PMID- 10408739
TI  - Does levodopa accelerate Parkinson's disease?
AB  - Therapeutic options for the treatment of Parkinson's disease (PD) have expanded
      tremendously over the last 5 years, although levodopa remains the gold standard
      of therapy. A major therapeutic controversy has been the question of levodopa's
      potential to cause toxic effects on nigrostriatal cells, thus potentiating the
      progression of the disease. The answer to that question will guide physicians in
      the timing of levodopa initiation and its dosage. The issue of levodopa toxicity
      was initially raised because of its potential to cause long term adverse effects
      (dyskinesias and motor fluctuations), which are not observed in untreated
      patients. Levodopa-induced toxicity can be related to its potential to produce
      free radicals, which are known to be toxic to cells, in the process of its
      conversion to dopamine. In vitro data reveals some evidence of the toxic effect
      of levodopa although recent studies suggest that levodopa toxicity is dependent
      on its concentration and can be ameliorated in the presence of glial cells. In
      vivo data from healthy animals and humans does not convincingly demonstrate
      levodopa toxicity. There is no evidence of levodopa-induced neurotoxicity in
      patients with PD. Despite the absence of toxic effect in patients with PD,
      levodopa can cause long term complications like motor fluctuations and
      dyskinesias and should be used judiciously in the minimal clinically effective
      dose. In this article we review evidence for and against levodopa neurotoxicity
      and the implications of the 'levo-dopa controversy' on clinical practice.

PMID- 10408741
TI  - Thrombolysis versus primary angioplasty in older patients with acute myocardial
      infarction.
AB  - Although it is effective for appropriate older patients with acute myocardial
      infarction (AMI), only about 25% of patients 65 years and older are eligible for
      thrombolytic therapy. Primary percutaneous transluminal coronary angioplasty
      (PTCA) may be a suitable alternative reperfusion therapy, particularly for older
      patients with high risk of intracerebral haemorrhage or cardiogenic shock.
      Randomised trials of primary PTCA versus thrombolytic therapy have demonstrated
      better efficacy for primary PTCA, whereas the 2 therapies produced comparable
      results in observational studies. In subset analyses in 2 randomised trials,
      there were trends toward better outcomes with primary PTCA, although these
      studies had small numbers of older patients. Results from 3 AMI registries (the
      Cooperative Cardiovascular Project, the Myocardial Infarction Triage and
      Intervention Registry, and the National Registry of Myocardial Infarction 2)
      indicated trends toward improved hospital or 30 day death rates in patients 75
      years and older receiving primary PTCA. Older patients who are at high risk of
      bleeding complications may do better with primary PTCA, although for others with
      moderate or minimal risk, the 2 therapies are equivalent. More data about long
      term follow-up and the association between outcomes and hospital and operator
      volumes for primary PTCA in older patients are needed before a definitive
      recommendation can be made.

PMID- 10408740
TI  - Managing alcohol withdrawal in the elderly.
AB  - The alcohol withdrawal syndrome is common in elderly individuals who are alcohol
      dependent and who decrease or stop their alcohol intake. While there have been
      few clinical studies to directly support or refute the hypothesis that withdrawal
      symptom severity, delirium and seizures increase with advancing age, several
      observational studies suggest that adverse functional and cognitive complications
      during alcohol withdrawal do occur more frequently in elderly patients. Most
      elderly patients with alcohol withdrawal symptoms should be considered for
      admission to an inpatient setting for supportive care and management. However,
      elderly patients with adequate social support and without significant withdrawal
      symptoms at presentation, comorbid illness or past history of complicated
      withdrawal may be suitable for outpatient management. Although over 100 drugs
      have been described for alcohol withdrawal treatment, there have been no studies
      assessing the efficacy of these drugs specifically in elderly patients. Studies
      in younger patients support benzodiazepines as the most efficacious therapy for
      reducing withdrawal symptoms and the incidence of delirium and seizure. While
      short-acting benzodiazepines, such as oxazepam and lorazepam, may be appropriate
      for elderly patients given the risk for excessive sedation from long-acting
      benzodiazepines, they may be less effective in preventing seizures and more prone
      to produce discontinuation symptoms if not tapered properly. To ensure
      appropriate benzodiazepine treatment, dose and frequency should be individualised
      with frequent monitoring, and based on validated alcohol withdrawal severity
      measures. Selected patients who have a history of severe or complicated
      withdrawal symptoms may benefit from a fixed schedule of benzodiazepine provided
      that medication is held for sedation. beta-Blockers, clonidine, carbamazepine and
      haloperidol may be used as adjunctive agents to treat symptoms not controlled by
      benzodiazepines. Lastly, the age of the patient should not deter clinicians from
      helping the patient achieve successful alcohol treatment and rehabilitation.

PMID- 10408745
TI  - Increasing government interest in the quality aspects of health care delivery.

PMID- 10408743
TI  - Non-Hodgkin's lymphoma in the elderly: a guide to drug treatment.
AB  - Adverse events are common in the elderly when they undergo potent chemotherapy
      and the reasons for this are various. Therefore, chemotherapy for elderly
      patients with non-Hodgkin's lymphoma (NHL) must differ from that for non-elderly
      patients. Age is one of the poor prognostic factors for NHL and the main reason
      for this is reduced antitumour effect due to decreased dose and increased adverse
      effects. However, many of these elderly patients also die from causes other than
      lymphoma. The usual approach to the treatment of indolent NHL is to use drugs
      with few adverse effects such as nucleoside analogs. Multidrug therapy is used
      for intermediate grade NHL and the most commonly used regimen is CHOP
      (cyclophosphamide, doxorubicin, vincristine and prednisone). In recent years,
      many clinical trials have been performed in elderly patients with NHL. The
      results of these trials indicate that a significantly better prognosis is
      achieved with anthracycline (cytostatic antibiotics) containing regimens. The
      elderly population will continue to grow and so it is necessary to establish more
      effective treatment options for NHL in the elderly.

PMID- 10408744
TI  - Oxaliplatin: a review of its use in the management of metastatic colorectal
      cancer.
AB  - Oxaliplatin is a cytotoxic agent which, like other platinum compounds, acts
      primarily by causing inter- and intra-strand cross-links in DNA, thereby
      inhibiting DNA synthesis. Oxaliplatin has a bulky carrier ligand which is thought
      to enhance cytotoxicity and abolish cross-resistance between oxaliplatin and
      other platinum compounds. Phase II and III clinical trials have found oxaliplatin
      combined with fluorouracil/calcium folinate (leucovorin/folinic acid) to be an
      effective first- and second-line treatment for patients with metastatic
      colorectal cancer. First-line triple therapy with oxaliplatin and
      fluorouracil/calcium folinate achieved significantly higher response rates than
      fluorouracil/calcium folinate alone in 2 phase III studies (objective response
      rates 59 vs 23% and 50.7 vs 22.3%). In addition, median progression-free survival
      was longer with triple therapy in both studies (8.9 vs 5.2 and 8.75 vs 6.0
      months). However, there was no significant difference in median duration of
      survival between treatment groups, although this may be a consequence of the
      subsequent use of oxaliplatin and/or surgery in patients who relapsed during
      therapy with fluorouracil/calcium folinate alone. About 30 to 45% of patients
      (whose disease progressed during or after fluorouracil-based therapy) responded
      to second-line combination therapy with oxaliplatin and fluorouracil/calcium
      folinate. Median progression-free survival ranged from 7 to 10 months and the
      median duration of survival from 10 to 17 months. Objective responses were
      achieved in 20 and 24% of patients in 2 small trials of first-line oxaliplatin
      monotherapy and in about 10% of patients given the drug as a second-line option.
      Peripheral sensory neuropathy is the dose-limiting toxicity associated with
      oxaliplatin. Severe neurotoxicity has been estimated to occur in 10% of patients
      after 6 treatment cycles and in 50% after 9 cycles of an oxaliplatin dosage of
      130 mg/m2 once every 3 weeks. It is cumulative, but reversible on discontinuation
      of therapy. Nausea, vomiting and diarrhoea are common, but are usually mild to
      moderate. Myelosuppression is also observed, but is usually mild. CONCLUSION:
      oxaliplatin is a promising treatment option for patients with metastatic
      colorectal cancer. It appears to be particularly advantageous (in terms of
      response rate and duration of progression-free survival) when used in combination
      with fluorouracil/calcium folinate as both a first- and second-line option,
      although preliminary studies have failed to show any survival advantage over
      fluorouracil/calcium folinate alone. Promising results have been found in studies
      of the drug as monotherapy, and oxaliplatin may also prove useful in the
      neoadjuvant setting in patients with unresectable liver metastases; however, data
      are limited at present.

PMID- 10408742
TI  - The biochemistry of Alzheimer's disease.
AB  - In the course of the biochemical efforts devoted to elucidation of the cause(s)
      and mechanism(s) of neurodegeneration in Alzheimer's disease (AD), much attention
      has been given to the processes by which amyloid is generated from amyloid
      precursor protein, notwithstanding the finding that mutations in 2 other
      proteins, presenilin 1 and 2, are associated with early-onset, familial AD in the
      majority of patients. In addition, the reason why the apolipoprotein E epsilon4
      allele is over-represented in patients with the sporadic form of AD is unknown.
      Furthermore, the degree of dementia is clearly associated more with the degree of
      neurofibrillary pathology than with the amyloid plaque burden. In general,
      amyloid formation may very well be at the end of a pathophysiological cascade,
      set in motion by many different triggers. This cascade could involve excessive
      apoptosis, followed by necrosis and inflammation. In this process, microglia as
      well as astrocytes are involved. Disturbance of I or more critical signal
      transduction processes, especially at the level of the plasma membrane, may be an
      important trigger. The pathogenesis of AD is complicated, but further
      identification of the processes of neurodegeneration will also lead to
      identification of the factors that make specific neurons vulnerable and,
      hopefully, point the way to a means to prevent neuronal degeneration at an early
      stage.

PMID- 10408746
TI  - Addressing adverse events through clinical indicators.
AB  - In an attempt to improve the reporting rate of adverse drug reactions the Adverse
      Drug Reaction Advisory Committee approached the Australian Council on Healthcare
      Standards Care Evaluation Program to develop a set of indicators to improve
      healthcare standards by heightening awareness amongst clinical staff of the
      morbidity, mortality and financial implications of adverse drug reactions. Ten
      clinical indicators addressing: (i) reporting of adverse drug reactions; (ii)
      adherence to treatment protocols for anaphylaxis; (iii) monitoring of warfarin;
      and (iv) monitoring of streptokinase, were field tested in ten Australian health
      care organizations, to determine that the data were available, that the
      indicators were relevant to clinical practice and that the measures were
      achievable. Based on the results of this field test, six adverse drug reaction
      clinical indicators will be introduced into the Australian Council on Healthcare
      Standards Evaluation and Quality Improvement Program from January 1999.

PMID- 10408748
TI  - Patient perceived quality-of-care in hospital in the context of clinical
      pathways: development of an approach.
AB  - Clinical pathways have been introduced in many hospitals with the aims of
      improving efficiency, reducing costs, and improving the quality and outcomes of
      care. However, there is a shortage of research evidence regarding the extent to
      which they do in fact achieve such aims. This paper describes the development and
      testing of a patient-perceived quality-of-care questionnaire for use in relation
      to the assessment of clinical pathways. Issues of validity and reliability are
      addressed and illustrative examples of results for two pilot hospitals are
      presented.

PMID- 10408747
TI  - Beyond evidence-based guidelines to implementation: a model for integrating care
      for people with diabetes.
AB  - There is a growing realization in the health system that integration of effort
      may be the best way of ensuring optimal outcomes of management both for
      clinicians and for people using the health system. It is also hypothesized that
      the impact of diabetes (chronic disease) and its sequelae could be reduced by the
      provision of well-organized care, based on agreed evidence-based guidelines for
      best practice, incorporating patient education and early detection of
      complication. This paper defines the characteristics of an integrated model of
      providing care to people with diabetes.

PMID- 10408749
TI  - Hospital blood pressure measurement: staff and device assessment.
AB  - Evaluation of the ability of clinical staff to measure blood pressure as well as
      the functional state of hospital sphygmomanometers has consistently demonstrated
      marked deficiencies. In this study, the working order of all sphygmomanometers
      (manual and automated) in a teaching hospital was evaluated. Nursing staff were
      tested on their knowledge and use of such devices and were also asked to estimate
      the blood pressure from videotape. The accuracy of a commonly used automated
      device, Dinamap 8100, was also measured. Of 543 manual sphygmomanometers, 14%
      were in perfect working order although portable devices were more likely to be
      functional (47% of 36 units). In contrast, all 135 automated portable devices
      were in perfect working order although service requirements were seldom met. The
      mean time since last service was 18 months. There appeared to be an inverse
      correlation between the availability of automated and manual devices and the
      maintenance of wall-mounted bedside sphygmomanometers. Staff knowledge about
      manual devices was adequate as was their ability to accurately measure blood
      pressure using standardised videotape. Forty-two per cent of 31 nurses who
      completed the test were correct in 9 of 12 blood pressures. A comparison of this
      result with a comparable group of nurses tested in 1990 did not detect a
      significant change in competence. Direct evaluation of the commonly used Dinamap
      8100 in 47 hospital patients demonstrated a poor correlation with a mercury
      sphygmomanometer with a D grade (fail) for systolic and a C grade for diastolic
      pressure. In summary, maintenance of manual sphygmomanometers was very poor,
      probably due to their lack of use by clinical staff. This was particularly true
      for units attached to bedside walls. Nursing staff demonstrated significant
      deficiencies in manual sphygmomanometer use although their skills were similar to
      those measured several years earlier. Because of the demonstrated inaccuracy of
      the Dinamap 8100 automated device, the strong trend towards the use of automated
      devices instead of manual sphygmomanometers within hospitals cannot be supported.

PMID- 10408750
TI  - Functional status and health service planning.
AB  - Functional status indicators have been proposed as instruments to aid health
      service planning for patients. This study examines functional status at three
      points surrounding an acute health episode: admission, discharge and 3 months
      post discharge from a community hospital. The aim of the study is to determine
      the most appropriate time to measure functional status to assist health service
      planning. A longitudinal cohort study was conducted at Manly Hospital, Australia.
      Four hundred patients aged 65 years and over representing a 10% random sample of
      all hospital admissions in a 10-month period were interviewed on admission,
      discharge and 3 months post discharge. Repeated measure multiple analysis of
      variance identified a decline in functional status between admission and
      discharge. At 3 months post discharge functional status had improved to levels
      higher than admission. Functional status assessment at discharge can assist
      consumers, clinicians, health planners and health insurers to make effective
      decisions to maximize health outcomes.

PMID- 10408751
TI  - Towards excellence in quality patient care: a clinical pathway for myocardial
      infarction.
AB  - A major initiative to implement a clinical pathway for myocardial infarction has
      provided a model on which to further develop pathways within our organization.
      Two of the primary objectives were to reduce time to thrombolysis and length of
      stay. Two years after the implementation of the myocardial infarction pathway
      there has been a reduction in the thrombolysis times from 80 to 49 min and in
      length of stay from 7.28 to 6.13 days. These results highlight significant
      improvements in patient and process outcomes. There is heightened awareness about
      best practice for patients who have sustained myocardial infarctions.

PMID- 10408752
TI  - Care co-ordination improves quality-of-care at South Auckland Health.
AB  - Inpatient discharge surveys at Middlemore hospital, a 600 bed hospital in South
      Auckland, New Zealand, consistently rate communication and co-ordination of care
      as parameters in need of improvement. A case management model of care was
      suggested as a means of achieving this. The objective of this study was to
      determine the effectiveness of care co-ordination in an acute general medical
      setting in a pilot study over a 4 week period. A care co-ordinator identified 18
      patients with complex problems among 48 patients admitted to a single medical
      ward under the care of a single multidisciplinary team, with their care being co
      ordinated over the entire episode of illness. A control group of 59 similarly
      complex patients admitted to other wards and teams without care co-ordination
      over the same period was also studied and the outcomes compared. Communication
      and co-ordination, discharge information, involvement in discharge planning and
      information on post-discharge services were rated by the study patients as good
      or very good by 77, 85, 69 and 77%, respectively, compared with 62, 30, 41 and
      45% in the control group. The same parameters were rated as poor or very poor by
      13, 30, 36 and 15% of the control patients, compared with 0% in all these
      measures in the study group. Twenty-one clinical staff involved in the study
      agreed that there was an improvement in care co-ordination with respect to
      efficiency, reduction of workload and better communication, with approval ratings
      being 71, 76 and 76%, respectively. There was no difference in Average Length of
      Stay between the control and study groups, but three of the patients in the
      control group may have had their preventable readmissions within 10 days avoided
      if their care had been co-ordinated during their initial admission.

PMID- 10408753
TI  - Initiation of quality improvement activities in mental health services.
AB  - In the public sector mental health service setting, accountability for quality
      has often been considered the responsibility of the individual clinician. This
      presents a particular challenge for introducing an organization-wide quality
      improvement culture in this setting. The introduction of a systemic view of
      quality may encounter resistance from individual clinicians reluctant to accept
      that some clinical autonomy must be subsumed within more standardized patterns of
      intervention and evaluation. Services must firstly tackle the issue of
      clinicians' readiness to embrace such a culture, which requires strong direction
      from the executive level. The area of recently diagnosed psychosis was selected
      in one public sector mental health service as a starting point for initiating the
      quality improvement culture. The eventual outcome for the organization has been a
      positive commitment to improvement, but the journey was long and hard. This paper
      describes the beginning of this ultimately rewarding journey.

PMID- 10408754
TI  - The characteristics of asthma education programs within New South Wales.
AB  - The aim of the study was to examine the characteristics of asthma education
      programs within NSW. A cross-sectional questionnaire survey concerning the aims
      and characteristics of 42 asthma education programs was administered to members
      of the Asthma Educators Association (AEA) of NSW. While most programs sought to
      improve asthma knowledge (78%), only a small number sought to improve asthma
      management skills (38%), asthma control (33%) and attitudes (10%). Most programs
      performed one-to-one (69%) education. Medical intervention was under-utilized by
      most programs and only 4% gave feedback to the referring doctor. Program
      evaluation was incompletely linked to program aims. There was incomplete
      evaluation of knowledge gain as an outcome. The study reviewed the
      characteristics of education programs within NSW Existing programs appropriately
      employ a variety of educational methods and target a broad range of people with
      asthma. There remains a need to use a combined approach utilizing education and
      medical management, and to employ methods to evaluate programs.

PMID- 10408756
TI  - Cardiac fatty acid metabolism and the induction of apoptosis.
AB  - Fatty acids are the primary source of energy in the adult heart. Recently,
      however, it was discovered that certain saturated fatty acids, such as palmitate
      and stearate, cause cardiac and other types of cells to undergo programmed cell
      death (apoptosis). In cardiac ischemia/reperfusion injury, where blood flow is
      blocked and then restored to the heart, recovery of cardiac cells is inversely
      proportional to the concentration of fatty acids (largely composed of palmitate
      and stearate) in the reperfusate. The aim of this review is to summarize what is
      known about fatty acid induction of heart disease, the role of fatty acids in
      apoptosis, and apoptosis in the heart, including the role that mitochondria play
      in this process.

PMID- 10408755
TI  - Fatty acid oxidation in the reperfused ischemic heart.
AB  - Myocardial ATP production is dependent chiefly on the oxidative decarboxylation
      of glucose and fatty acids. The co-utilization of these and other substrates is
      determined by both the amount of any given substrate supplied to the heart as
      well as by complex intracellular regulatory mechanisms. This regulated balance is
      altered during and after ischemia. During aerobic reperfusion of ischemic
      myocardium, a rapid recovery of energy production is desirable for the complete
      recovery of muscle contractile function. It is now clear that the type of energy
      substrate used by the heart during reperfusion will directly influence this
      contractile recovery. By increasing the relative proportion of glucose oxidized
      to that of fatty acids, the mechanical function of the reperfused heart can be
      improved. However, fatty acid oxidation recovers quickly during reperfusion and
      dominates as a source of oxygen consumption. These high rates of fatty acid
      oxidation occur at the expense of glucose oxidation, resulting in a decreased
      recovery of both cardiac function and efficiency during reperfusion. One
      contributory factor to these high rates of fatty acid oxidation is a decrease in
      myocardial malonyl-coenzyme A (CoA) levels. Malonyl-CoA, which is synthesized by
      acetyl-CoA carboxylase, is an essential metabolic intermediary in the regulation
      of fatty acid oxidation. A decrease in malonyl-CoA level results in an increase
      of carnitine palmitoyl transferase-1 mediated fatty acid uptake into the
      mitochondria. This mechanism seems important in the regulation of fatty acid
      oxidation in the postischemic heart and is discussed in detail in this review,
      with reference to specific clinical scenarios of ischemia and reperfusion and
      options for modulating cardiac energy metabolism.

PMID- 10408757
TI  - Carnitine-acylcarnitine translocase deficiency.
AB  - Carnitine-acylcarnitine translocase deficiency, like other defects of
      mitochondrial fatty acid oxidation, is an autosomal, recessively inherited
      disorder. When the deficiency is near total, it is usually fatal, affects life
      soon after birth, and constitutes one of the causes of skeletal muscle myopathy,
      cardiac and liver abnormalities, and childhood sudden death. The presenting
      features have included neonatal distress, convulsions, hypoglycemia,
      hyperammonemia, hypoketonemia, intermittent dicarboxyluria, hypothermia, apnea,
      neurological deterioration, and hypocarnitinemia with grossly elevated
      acylcarnitines. Two cases of partial translocase deficiency (4-6% residual
      activity) with milder symptoms and without cardiac involvement have also been
      identified. Evidence so far indicates that the translocase protein is the product
      of a single gene. In two cases of translocase deficiency, the accompanying
      mutations have been identified. The benefits of prenatal diagnosis have been
      provided to the affected families by assays of the translocase and/or fatty acid
      oxidation in cultured amniotic/villous cells. In one such case genetic counseling
      was made possible even when the only specimen available from a deceased sibling
      was the Guthrie card.

PMID- 10408758
TI  - The role of the carnitine system in peroxisomal fatty acid oxidation.
AB  - Peroxisomes are small, subcellular organelles that play a major role in lipid
      metabolism. Inherited disorders of peroxisomal structure and metabolism can
      result from defective assembly, missing protein import transporters, or
      individual enzyme deficiencies. Molecular studies helped by the range of
      disorders have now elucidated many of the pathways, including the paths of alpha
      oxidation for phytanic acid and beta-oxidation for very-long-chain and branched
      chain fatty acids and for bile acid synthesis. The mechanism of the transfer of
      substrates, intermediates, and products across the membrane is poorly understood.
      The carnitine system, known to transport activated acyl groups between localized
      coenzyme A pools, is presented. The evidence for the involvement of carnitine in
      the transfer of activated acyl groups to and from the peroxisomes is reviewed.

PMID- 10408759
TI  - Fatty acid utilization in the hypertrophied and failing heart: molecular
      regulatory mechanisms.
AB  - During the development of cardiac hypertrophy and in the failing heart, the chief
      myocardial energy source switches from fatty acid beta-oxidation to glycolysis: a
      reversion to the fetal energy substrate preference pattern. This review describes
      recent molecular studies aimed at delineating the gene regulatory pathway
      involved in the energy metabolic switch in the hypertrophied heart and the
      potential role of the attendant metabolic consequences in the pathogenesis of
      heart failure. Studies have been performed with the 'spontaneous hypertensive and
      heart failure' rat strain and with human cardiomyopathic tissue. These studies
      have demonstrated that expression of the gene that encodes medium-chain acyl
      coenzyme A dehydrogenase (MCAD), a key fatty acid beta-oxidation enzyme, is down
      regulated during the progression from cardiac hypertrophy to ventricular
      dysfunction. A series of studies performed in mice transgenic for the human MCAD
      gene promoter have identified a transcriptional regulatory pathway involved in
      the repression of MCAD gene expression in the hypertrophied mouse heart. Two
      categories of transcription factors, nuclear hormone receptors and Sp factors,
      bind MCAD gene promoter regulatory elements in response to pressure overload to
      reactivate a fetal metabolic gene program. Studies are under way to manipulate
      this transcriptional regulatory pathway in mice using genetic engineering
      strategies to determine whether this energy metabolic derangement plays a primary
      role in the development of cardiac hypertrophy and heart failure.

PMID- 10408760
TI  - Expression and regulation of carnitine palmitoyltransferase-Ialpha and -Ibeta
      genes.
AB  - Two genes control expression of mitochondrial carnitine palmitoyltransferase-I
      (CPT-I), the enzyme that catalyzes the primary rate-controlling step in fatty
      acid oxidation. Two CPT-I isoforms have been found--a "liver" isoform (CPT
      Ialpha) expressed in most tissues, but not in skeletal muscles, and a "muscle"
      isoform (CPT-Ibeta) expressed in muscles and adipocytes. Liver CPT-Ialpha
      increases dramatically at birth, but heart CPT-Ialpha is abundant in the fetus
      and diminishes at birth. Insulin, thyroid hormone, and fatty acids regulate
      expression of CPT-Ialpha in liver, whereas electrical stimulation increases CPT
      Ibeta and decreases CPT-Ialpha in cardiac myocytes. Both genes are TATA-less and
      contain Sp1 transcription factor binding sites upstream of the start site of
      transcription. Multiple transcripts of both CPT-Ialpha and CPT-Ibeta exist, some
      of which may have roles in regulating fatty acid oxidation.

PMID- 10408761
TI  - Effect of dietary vitamin E supplementation on murine nasal allergy.
AB  - BACKGROUND: Although many studies have reported the effects of dietary vitamin E
      on the immune response, none so far has assessed its role in nasal allergy.
      METHODS: Female BALB/c mice were randomized into two groups and fed a 20% casein
      diet (control group, 50 mg vitamin E/kg diet) or this diet supplemented with 535
      mg vitamin E/kg diet (vitamin E group, 585 mg vitamin E/kg diet) for 4 weeks.
      During the fifth week, the mice in each group were divided into two subgroups to
      form a total of four treatment groups: group A (control), group B [control +
      toluene diisocyanate (TDI) sensitization], group C (vitamin E supplementation),
      and group D (vitamin E supplementation + TDI sensitization). Groups B and D were
      treated with two courses of intranasal application of 5% TDI in ethyl acetate,
      whereas groups A and C were treated with ethyl acetate alone. A week after second
      sensitization all groups were provoked by applying 2.5% of TDI in the vehicle and
      nasal allergic responses were observed for 10 minutes. Splenic
      lymphoproliferation, splenic cell cytokines, and the total serum IgE were
      measured. RESULTS: Members of group D had lower (P < 0.01) scores of nasal
      response and sneezed less frequently (P < 0.01) than those of group B. Similarly,
      splenic lymphoproliferation and production of IL-4 and IL-5 as well as the total
      serum IgE levels were lower (P < 0.01) in group D than in group B. CONCLUSIONS:
      The results indicate that higher doses of vitamin E supplementation may suppress
      nasal allergic responses.

PMID- 10408762
TI  - IgA anticardiolipin and anti-beta2-glycoprotein I are the most prevalent isotypes
      in African American patients with systemic lupus erythematosus.
AB  - BACKGROUND: Ethnicity plays a role in the prevalence, isotype distribution, and
      clinical significance of anticardiolipin (aCL) and anti-beta2-glycoprotein I
      (anti-beta2-GPI) antibodies in patients with systemic lupus erythematosus (SLE).
      Few studies have been done in the African American population. METHODS: Serum
      samples from 100 African American patients with SLE were tested for IgG, IgM, and
      IgA aCL and anti-beta2-GPI antibodies by enzyme-linked immunosorbent assay
      (ELISA). Computerized clinical data on these patients were reviewed with a
      specific focus on clinical manifestations of antiphospholipid syndrome (APS).
      RESULTS: Positivity for at least one isotype of aCL antibodies was found in 33%
      of the patients, whereas 28% were positive for at least one isotype of anti-beta2
      GPI antibodies. IgA was the most prevalent isotype for both antibodies; 24% of
      the patients in the aCL ELISA and 19% in the anti-beta2-GPI ELISA were positive
      for IgA. Positivity for both aCL and anti-beta2-GPI in the same patient was seen
      more frequently with the IgA isotype. Fewer than half of the patients positive
      for aCL antibodies had medium-to-high levels of antibodies. A few patients had
      presented thrombotic manifestations, and these patients were positive for aCL (P
      = 0.01) and anti-beta2-GPI antibodies (P = 0.02). No other manifestations of APS
      could be significantly correlated with the presence of these antibodies.
      CONCLUSIONS: Our results show that IgA is the most prevalent isotype among the
      African American patients with SLE studied. The predominance of the IgA isotype
      and the low prevalence of medium-to-high levels of aCL antibodies may account for
      the low frequency of clinical manifestations of APS in these patients.

PMID- 10408764
TI  - Acute hypernatremia and neuroleptic malignant syndrome in Parkinson disease.
AB  - Neuroleptic malignant syndrome is a clinical syndrome characterized by fever,
      muscle rigidity, and mutism. Some patients with neuroleptic syndrome may have
      elevated creatine phosphokinase values and abnormal liver aminotransferase
      values. Precipitating factors are important clues for prompt diagnosis. Typical
      precipitating factors include antipsychotic agents and major tranquilizers. In
      Parkinson disease, drug withdrawal, menstruation, and hyponatremia are
      precipitating factors. We report a case of neuroleptic malignant syndrome in a
      patient with Parkinson disease and hypernatremia. In addition, we hypothesized
      that sudden change of sodium concentrations in the central nervous system could
      trigger neuroleptic malignant syndrome in patients with Parkinson disease.
      According to our experience, neuroleptic malignant syndrome is a clinical
      diagnosis and prompt diagnosis avoids unnecessary, expensive work-ups.

PMID- 10408763
TI  - Effect of calcitriol and pamidronate in multiple myeloma.
AB  - Addition of bisphosphonates to standard treatment of multiple myeloma (MM)
      decreases bone pain and skeletal events without influencing bone healing.
      Calcitriol, besides its established effects on bone remodeling and calcium
      metabolism, has both immunoregulatory and cell differentiating effects in vitro
      and in vivo. Moreover, low serum calcitriol has been reported in MM. We tested
      the effects of supportive treatment with calcitriol and pamidronate on bone
      disease in two stage-III-B MM patients with diffuse bone involvement, normal
      serum calcium, and low serum calcitriol. Complete blood counts, serum calcium,
      creatinine, quantitative serum and urine immunoglobulins, and biochemical indices
      of bone turnover, serum calcidiol, calcitriol, parathyroid hormone, skeletal
      radiographs, and bone mineral density by dual x-ray absorbtiometry were measured
      every 1-6 months for 16 months in the first patient and 7 months in the second
      patient. Both patients showed a dramatic improvement of MM activity and in bone
      disease documented by serial radiographs in the first patient and by increased
      bone mineral density (approximately 15%) in the second. The reduced serum
      calcitriol in both patients and the elevated parathyroid hormone observed in the
      first patient before treatment returned to normal. Supportive treatment with
      pamidronate does not induce bone healing in MM. Therefore, the results observed
      with the addition of calcitriol suggest that this hormone may have contributed to
      the apparent arrest of the progression of MM and caused stimulation of bone
      healing.

PMID- 10408766
TI  - Neural pathways involved in the processing of concrete and abstract words.
AB  - The purpose of this study was to delineate the neural pathways involved in
      processing concrete and abstract words using functional magnetic resonance
      imaging (fMRI). Word and pseudoword stimuli were presented visually, one at a
      time, and the participant was required to make a lexical decision. Lexical
      decision epochs alternated with a resting baseline. In each lexical decision
      epoch, the stimuli were either concrete words and pseudowords, or abstract words
      and pseudowords. Behavioral data indicated that, as with previous research,
      concrete word stimuli were processed more efficiently than abstract word stimuli.
      Analysis of the fMRI data indicated that processing of word stimuli, compared to
      the baseline condition, was associated with neural activation in the bilateral
      fusiform gyrus, anterior cingulate, left middle temporal gyrus, right posterior
      superior temporal gyrus, and left and right inferior frontal gyrus. A direct
      comparison between the abstract and concrete stimuli epochs yielded a significant
      area of activation in the right anterior temporal cortex. The results are
      consistent with recent positron emission tomography work showing right hemisphere
      activation during processing of abstract representations of language. The results
      are interpreted as support for a right hemisphere neural pathway in the
      processing of abstract word representations.

PMID- 10408765
TI  - Hypokalemic periodic paralysis associated with hypophosphatemia in a patient with
      hyperinsulinemia.
AB  - A 34-year-old man was admitted to the hospital because of acute quadriplegia. On
      admission, serum potassium was 2.1 mEq/L and serum inorganic phosphate was 1.4
      mg/dL. Thyroid function was normal. Serum levels of aldosterone, cortisol, and
      intact parathyroid hormone were normal. Fasting plasma glucose was 109 mg/dL, and
      fasting serum insulin was 25.0 U/mL. Shortly after intravenous supplementation of
      potassium, muscle strength was normalized. Oral glucose tolerance test revealed
      impaired glucose tolerance and hyperresponse of insulin. During the oral glucose
      tolerance test, serum potassium and phosphate decreased significantly. These
      findings suggest that hyperinsulinemia and insulin-induced transmembrane shift of
      extracellular potassium and phosphate may have been involved in the abnormalities
      of serum electrolytes and development of hypokalemic periodic paralysis in the
      present patient.

PMID- 10408767
TI  - Learning-related effects and functional neuroimaging.
AB  - A fundamental problem in the study of learning is that learning-related changes
      may be confounded by nonspecific time effects. There are several strategies for
      handling this problem. This problem may be of greater significance in functional
      magnetic resonance imaging (fMRI) compared to positron emission tomography (PET).
      Using the general linear model, we describe, compare, and discuss two approaches
      for separating learning-related from nonspecific time effects. The first approach
      makes assumptions on the general behavior of nonspecific effects and explicitly
      models these effects, i.e., nonspecific time effects are incorporated as a linear
      or nonlinear confounding covariate in the statistical model. The second strategy
      makes no a priori assumption concerning the form of nonspecific time effects, but
      implicitly controls for nonspecific effects using an interaction approach, i.e.,
      learning effects are assessed with an interaction contrast. The two approaches
      depend on specific assumptions and have specific limitations. With certain
      experimental designs, both approaches may be used and the results compared,
      lending particular support to effects that are independent of the method used. A
      third and perhaps better approach that sometimes may be practically unfeasible is
      to use a completely temporally balanced experimental design. The choice of
      approach may be of particular importance when learning-related effects are
      studied with fMRI.

PMID- 10408768
TI  - Brain SPECT imaging and left hemispatial neglect covaried using partial least
      squares: the Sunnybrook Stroke study.
AB  - Hemispatial neglect, characterized as failure to attend to contralesional space,
      is hypothesized by current neuroanatomical models to result from damage to a
      network involving the frontal, parietal, and cingulate cortices, basal ganglia,
      and thalamus. This study investigated this model of neglect in 81 right
      hemisphere-damaged acute stroke patients using 99mTc-HMPAO single photon emission
      computed tomography (SPECT). In order to exploit the inherent collinearity of
      SPECT regional brain ratios, a novel statistical technique, partial least squares
      (PLS), was utilized. It makes use of high correlations to identify biologically
      relevant patterns of brain activity. Averaged ipsilesional cerebellar ratios from
      152 brain segments were covaried with performance on subtests of the Sunnybrook
      Neglect Battery. In this patient sample, the most influential region identified
      by PLS corresponded to the area surrounding the right temporal-parietal-occipital
      (TPO) junction that included the right lateral occipital, temporal, and inferior
      parietal lobes. Hypoperfusion in the medial frontal cortex, including the
      anterior cingulate, also emerged as significantly associated with more severe
      neglect. Thus, hypoperfusion in only two of the five hypothesized network regions
      emerged as significantly associated with hemispatial neglect on SPECT imaging.
      This work converges with structural imaging studies to suggest that damage to the
      TPO junction, not just the parietal lobe, may be the critical region for
      hemispatial neglect. Our study demonstrated the utility of PLS for analyzing
      functional imaging and behavioral data sets in a clinical population in relation
      to current neuroanatomical models of neglect.

PMID- 10408769
TI  - Nonlinear spatial normalization using basis functions.
AB  - We describe a comprehensive framework for performing rapid and automatic nonlabel
      based nonlinear spatial normalizations. The approach adopted minimizes the
      residual squared difference between an image and a template of the same modality.
      In order to reduce the number of parameters to be fitted, the nonlinear warps are
      described by a linear combination of low spatial frequency basis functions. The
      objective is to determine the optimum coefficients for each of the bases by
      minimizing the sum of squared differences between the image and template, while
      simultaneously maximizing the smoothness of the transformation using a maximum a
      posteriori (MAP) approach. Most MAP approaches assume that the variance
      associated with each voxel is already known and that there is no covariance
      between neighboring voxels. The approach described here attempts to estimate this
      variance from the data, and also corrects for the correlations between
      neighboring voxels. This makes the same approach suitable for the spatial
      normalization of both high-quality magnetic resonance images, and low-resolution
      noisy positron emission tomography images. A fast algorithm has been developed
      that utilizes Taylor's theorem and the separable nature of the basis functions,
      meaning that most of the nonlinear spatial variability between images can be
      automatically corrected within a few minutes.

PMID- 10408770
TI  - Reproducibility of BOLD-based functional MRI obtained at 4 T.
AB  - The reproducibility of activation patterns in the whole brain obtained by
      functional magnetic resonance imaging (fMRI) experiments at 4 Tesla was studied
      with a simple finger-opposition task. Six subjects performed three runs in one
      session, and each run was analyzed separately with the t-test as a univariate
      method and Fisher's linear discriminant analysis as a multivariate method.
      Detrending with a first- and third-order polynomial as well as logarithmic
      transformation as preprocessing steps for the t-test were tested for their impact
      on reproducibility. Reproducibility across the whole brain was studied by using
      scatter plots of statistical values and calculating the correlation coefficient
      between pairs of activation maps. In order to compare reproducibility of
      "activated" voxels across runs, subjects and models, 2% of all voxels in the
      brain with the highest statistical values were classified as activated. The
      analysis of reproducible activated voxels was performed for the whole brain and
      within regions of interest. We found considerable variability in reproducibility
      across subjects, regions of interest, and analysis methods. The t-test on the
      linear detrended data yielded better reproducibility than Fisher's linear
      discriminant analysis, and therefore seems to be a robust although conservative
      method. Preliminary data indicate that these modeling results may be reversed by
      preprocessing to reduce respiratory and cardiac physiological noise effects. The
      reproducibility of both the position and number of activated voxels in the
      sensorimotor cortex was highest, while that of the supplementary motor area was
      much lower, with reproducibility of the cerebellum falling in between the other
      two areas.

PMID- 10408771
TI  - Classical galactosemia and mutations at the galactose-1-phosphate uridyl
      transferase (GALT) gene.
AB  - Classical galactosemia is caused by a deficiency in activity of the enzyme
      galactose-1-phosphate uridyl transferase (GALT), which, in turn, is caused by
      mutations at the GALT gene. The disorder exhibits considerable allelic
      heterogeneity and, at the end of 1998, more than 150 different base changes were
      recorded in 24 different populations and ethnic groups in 15 countries worldwide.
      The mutations most frequently cited are Q188R, K285N, S135L, and N314D. Q188R is
      the most common mutation in European populations or in those predominantly of
      European descent. Overall, it accounts for 60-70% of mutant chromosomes, but
      there are significant differences in its relative frequency in individual
      populations. Individuals homoallelic for Q188R tend to have a severe phenotype
      and this is in keeping with the virtually complete loss of enzyme activity
      observed in in vitro expression systems. Globally, K285N is rarer, but in many
      European populations it can be found on 25-40% of mutant chromosomes. It is
      invariably associated with a severe phenotype. S135L is found almost exclusively
      in African Americans. In vitro expression results are discrepant, but some
      individuals carrying S135L appear to exhibit GALT activity in some tissues.
      Duarte 1 (or Los Angeles) and Duarte 2 (or Duarte) variants carry the same amino
      acid substitution, N314D, even though D1 is associated with increased erythrocyte
      GALT activity and D2 with reduced activity. N314D is in linkage disequilibrium
      with other base changes that differ on the D1 and D2 alleles. N314D does not
      impair GALT activity in in vitro expression systems. However, there are
      differences in the abundance of GALT protein in lymphoblastoid cells lines from
      D2 and D1 individuals. It is unclear whether the specific molecular changes that
      distinguish the D1 and D2 alleles account for the different activities. The
      considerable genetic heterogeneity documented to date undoubtedly contributes to
      the phenotypic heterogeneity that is observed in galactosemia. The additional
      effects of nonallelic variation and other constitutional factors on phenotypic
      variability remain to be elucidated.

PMID- 10408772
TI  - Insertion of Alu element responsible for acute intermittent porphyria.
AB  - In this study, we report a large Finnish family in which an Alu element
      interferes with the coding region of the porphobilinogen deaminase (PBGD) gene
      resulting in acute intermittent porphyria (AIP). Polymerase chain reaction (PCR)
      and single-strand conformation polymorphism (SSCP) analysis of exon 5 among
      patients showed an abnormal band around 350 bp apart from the normal bands.
      Subcloning and sequencing of the fragment revealed a 333-bp Alu sequence that was
      directly inserted into exon 5 in antisense orientation. The junction sequences
      included a 13-bp target site duplication. This Alu cassette belongs to a Ya5
      subfamily, one of the youngest and currently most active Alu subfamilies in
      evolution. The Alu insertion resulted in a dramatically decreased steady-state
      level of the allelic transcript, as this Alu sequence could not be demonstrated
      by direct sequencing of the amplified cDNA synthesized from total RNA extracted
      from the patients' lymphoblast cell lines. A stop codon present in the reading
      frame causes premature termination of PBGD synthesis. The predicted polypeptide
      contains 64 of the 361 amino acids of PBGD, followed by 13 amino acids that are
      not identical to the PBGD polypeptide. To further characterize the consequences
      of the insertion, the Alu sequence was inserted into exon 5 of the PBGD cDNA and
      expressed in the eukaryotic COS-1 cell line. The mutated construct expressed no
      enzyme activity comparable to that of the wild-type PBGD; furthermore, no mutant
      protein could be detected by Western blot analysis.

PMID- 10408773
TI  - Three homozygous PTC mutations in the collagen type VII gene of patients affected
      by recessive dystrophic epidermolysis bullosa: analysis of transcript levels in
      dermal fibroblasts.
AB  - The Hallopeau-Siemens variant of recessive dystrophic epidermolysis bullosa (HS
      RDEB) is a severe inherited skin disease characterized by the absence of collagen
      type VII (COLVII) and anchoring fibrils (AF), caused by mutations in collagen
      type VII gene (COL7A1). Mutations leading to the formation of premature
      termination codons (PTCs) of translation are the characteristic genetic lesions
      in HS-RDEB patients; many PTC mutations have been found to be associated with a
      marked reduction or complete absence of COLVII mRNA. In this article, we report
      homozygosity for three different mutations in the COL7A1 of HS-RDEB patients. One
      mutation, the R2685X, falling in exon 109, is a novel mutation, whereas the other
      two, the 425A-->G falling in exon 3 and the 497insA in exon 4, have been
      previously identified in compound heterozygosity with different mutations in
      other unrelated RDEB patients. Haplotype analysis in three Italian families
      carrying the 497insA mutation suggested a common origin of this mutation and
      indicated that this is an ancestral Italian mutation. All these mutations
      generate PTCs and are associated with the absence of COLVII expression, as
      detected by immunofluorescence analysis of the patient's skin. Evaluation of the
      levels of the mutated COLVII mRNAs in cultured skin fibroblasts of the patients
      and of their parents showed that all the mutated transcripts were expressed at
      consistent levels. Therefore, our results indicate that a marked mRNA reduction
      is not a constant feature associated with PTC mutations in COL7A1.

PMID- 10408774
TI  - Four novel mutations in the cystathionine beta-synthase gene: effect of a second
      linked mutation on the severity of the homocystinuric phenotype.
AB  - Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is frequently
      caused by missense mutations. In this article, we report four novel missense
      mutations in the CBS gene: 172C-->T (R58W) linked in cis with A114V; 376A-->G
      (M126V); 904G-->A (E302K); and 1006C-->T (R336C). The CBS activity of the
      corresponding mutant enzymes expressed in Escherichia coli was greatly
      diminished, confirming the pathogenicity of these mutations. Western analysis
      showed that the R58W+A114V and M126V mutant enzymes were unstable in E. coli,
      while the E302K subunits were partially degraded to shorter products. Using site
      directed mutagenesis we found that CBS containing either the R58W or A114V as the
      only mutations demonstrated 18% and 46% of normal activity, respectively. Both
      mutant forms of CBS were stable in E. coli. When these two mutations were
      expressed in cis, the resultant mutant protein exhibited activity 1.3% that of a
      control. All these in vitro results were in good agreement with the clinical
      manifestation in these patients. The Italian patient 2241, an A114V+R58W/M126V
      compound heterozygote, exhibited severe pyridoxine nonresponsive homocystinuria,
      while another Italian patient 2242, with an A114V/E302K genotype, responded to
      pyridoxine treatment and had a much milder phenotype. The third patient 3064, an
      English compound heterozygote for two severe mutations R336C and G307S, was B6
      nonresponsive. This report of a ninth homocystinuric allele carrying two
      mutations in cis raises the possibility that double mutant alleles may be
      underestimated in homocystinuric patients. In this context, a search for
      additional mutations in cis may sometimes be necessary to establish a good
      genotype-phenotype relationship.

PMID- 10408775
TI  - Temperature and pH effects on single-strand conformation polymorphism analysis by
      capillary electrophoresis.
AB  - We investigated the effects of temperature and pH on single strand-conformation
      polymorphism (SSCP) analyzed by capillary electrophoresis (CE) using short-chain
      linear polyacrylamide as the sieving medium. Nine different mutations (in factor
      V, cystathionine beta-synthase, and methylenetetrahydrofolate reductase genes),
      including both transitions and transversions, were investigated. We confirmed
      that low temperature in general increased the number of detectable single-strand
      conformations and thereby the sensitivity of the analysis. The pH effects of the
      separation matrix on the migration pattern, and thus the assay sensitivity,
      varied markedly between the different DNA fragments. Seven of nine single point
      mutations were detected at the ordinary pH of 8.3, whereas the CBS T833C mutation
      was discriminated at the extreme pH values of 9.0 and 6.4, and the CBS G797A
      mutation could not be detected at any pH value within the range 6.4--9.0. These
      data emphasize the importance of the pH of the separation matrix in detecting
      certain mutations by SSCP.

PMID- 10408776
TI  - Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk
      factor for VHL patients to develop an RCC.
AB  - To investigate the nature of somatic von Hippel-Lindau (VHL) mutations, we
      analyzed 173 primary sporadic human renal cell carcinomas for mutations of the
      VHL tumor suppressor gene, using polymerase chain reaction (PCR) and single
      strand conformational polymorphism analysis (SSCP) of DNA. We detected abnormal
      SSCP pattern in 73 samples. After sequencing, we identified microdeletions in 58%
      of cases, microinsertions in 17%, nonsense mutations in 8%, and missense
      mutations in 17%. Among these mutations, 50% correspond to new mutations. VHL
      mutations were found only in the nonpapillary renal cell carcinoma (RCC) subtype,
      as previously reported. To compare somatic and germline mutations, we used the
      VHL database, which includes 507 mutations. The study of mutational events
      revealed a significant difference between somatic and germline mutations with
      mutations leading to truncated proteins observed in 78% of somatic mutations vs
      only 37% in germline mutations (P < 0.001). We postulated that a specific pattern
      of VHL mutations is associated with sporadic RCC. This pattern corresponds to
      mutations leading mainly to truncated proteins with few specific missense
      mutations. We then analyzed the occurrence of RCC in VHL families, based on the
      nature of mutations. We observed RCC in at least one member of the VHL families
      in 77% of cases with mutations leading to truncated proteins versus 55% in cases
      with missense mutations (P < 0.05). Thus, mutations resulting in truncated
      proteins may lead to a higher risk of RCC in VHL patients.

PMID- 10408777
TI  - Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families.
AB  - The Peutz-Jeghers syndrome (PJS) is a rare hereditary disorder in which
      gastrointestinal hamartomatous polyposis, mucocutaneous pigmentation, and a
      predisposition for developing cancer are transmitted in an autosomal dominant
      fashion. The recently identified LKB1/STK11 gene located at chromosome 19p13.3 is
      mutated in a number of PJS pedigrees. We performed mutation analysis in 19,
      predominantly Dutch, PJS families. In 12 of these families, we identified
      LKB1/STK11 mutations, none of which has been described before. These 12 novel
      LKB1/STK11 mutations consist of one nonsense mutation, three frameshift
      deletions, three frameshift insertions, two acceptor splice site mutations, and
      three missense mutations. In addition, we detected four polymorphisms in
      LKB1/STK11. In the remaining seven PJS families, we found no apparent
      abnormalities of the LKB1/STK1I gene, which could reflect the existence of locus
      heterogeneity in PJS. None of the mutations occurred in more than one family, and
      a number were demonstrated to have arisen de novo. The diverse array of mutations
      found, the apparent high mutation rate, as well as the existence of a possible
      second PJS locus, renders diagnostic or predictive genetic testing in individual
      patients difficult, although future identification of additional mutations or
      even gene(s) will help in increasing the yield of direct mutation analysis.

PMID- 10408778
TI  - Steroid 21-hydroxylase deficiency: mutational spectrum in Denmark, three novel
      mutations, and in vitro expression analysis.
AB  - We have investigated 68 unrelated 21-hydroxylase deficient Danish patients,
      representing 136 alleles, and determined the mutational spectrum of the CYP21
      gene. The most frequent mutations detected were deletion of CYP21 and the splice
      mutation in intron 2 (I2-splice). Segregation analysis showed evidence of a de
      novo mutation in each of two patients. Three novel mutations were detected: G64E
      in exon 1, Q262X in exon 7, and A362V in exon 8. G64E and A362V were introduced
      in the CYP21 cDNA by in vitro site-directed mutagenesis, and the two
      corresponding proteins were transiently expressed in COS-7 cells. The activity of
      21-hydroxylase was determined using the two hormone substrates 17
      hydroxyprogesterone and progesterone. The analysis showed no enzyme activity for
      any of the substrates, a result that correlates well with the severity of the
      patients' disease.

PMID- 10408779
TI  - Genomic structure and identification of 11 novel mutations of the PEX6
      (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis
      disorders.
AB  - The PEX6 (peroxisome assembly factor-2, PAF-2) gene encodes a member of the AAA
      protein (ATPases associated with diverse cellular activities) family and restores
      peroxisome assembly in fibroblasts from peroxisome biogenesis disorder patients
      belonging to complementation group C (group 4 in the United States). We have now
      clarified the genomic DNA structure of human PEX6 and identified mutations in
      patients from various ethnic groups. The human PEX6 gene consists of 17 exons and
      16 introns, spanning about 14kb. The largest exon, exon 1, has at least 952 bp
      nucleotides. Eleven novel mutations (18 alleles) were identified by direct
      sequencing of the PEX6 cDNA from 10 patients. All these mutations have been
      confirmed in the corresponding genomic DNA. There was no common mutation, but an
      exon skip was identified in two unrelated Japanese patients. Most of the
      mutations led to premature termination or large deletions of the PEX6 protein and
      resulted in the most severe peroxisome biogenesis disorder phenotype of Zellweger
      syndrome. A patient with an atypical Zellweger syndrome had a missense mutation
      that was shown to disrupt the cell's ability to form peroxisomes. This mutation
      analysis will aid in understanding the functions of the PEX6 protein in
      peroxisomal biogenesis. Hum Mutat 13:487-496, 1999.

PMID- 10408780
TI  - A fast polymerase chain reaction-mediated strategy for introducing repeat
      expansions into CAG-repeat containing genes.
AB  - We describe a simple method for expanding CAG trinucleotides in CAG-repeat
      containing genes which, in contrast to other techniques, leaves the original gene
      sequence intact. Here, we expanded the CAG stretches of a plasmid clone
      containing the cDNA of the SCA3/MJD gene from 22 CAG up to > 130 CAG repeats
      using polymerase chain reaction (PCR)-mediated mutagenesis. The method reported
      in this article requires minimal resources, is very fast, and enables to
      construct recombinant plasmids carrying large CAG expansions.

PMID- 10408781
TI  - Osteogenesis imperfecta: mosaicism and refinement of the genotype-phenotype map
      in OI type III. Mutations in brief no. 242. Online.
AB  - Non-lethal OI III (OMIM 259420) is caused by structural aberrations of collagen
      I. We report four novel glycine substitutions, one in the a1 (I) chain of
      collagen I (G688S) and three in the a2 (I) chain (G241D, G247C, G883V). In each
      of two families (G241D and G883V), we found parental mosaicism for the
      substitution explaining recurrence and intrafamilial variability of OI. The G247C
      and the G883V are the most N-terminally and C-terminally, respectively, placed
      cysteine and valine substitutions reported. The new substitutions add important
      information to the genotype-phenotype map and in particular the importance of a
      chain stoichiometry is underlined. Data regarding the G688S substitution may
      suggest a different effect of the two a-chains in the development of
      dentinogenesis imperfecta (DI).

PMID- 10408782
TI  - Molecular characterization of phenylalanine hydroxylase deficiency in Chile.
      Mutations in brief no. 243. Online.
AB  - Both the haplotype distribution and the mutational spectrum of the phenylalanine
      hydroxylase (PAH) gene has been defined for the Chilean phenylketonuria (PKU)
      population. Mutation analysis was performed using a combined approach of
      screening for common European and Oriental mutations and application of the DGGE
      scanning method in the remaining uncharacterized alleles. A total of 16 different
      mutations have been identified, including two novel ones, Q232X and IVS11nt5. The
      most frequent mutations were IVS10nt-11 and V388M present both in the 13% of the
      mutant chromosomes. The rest of the mutations are rare. The haplotype association
      including VNTR and STR alleles, was examined to investigated the origin and
      distribution of PAH alleles in Chile. Our results are consistent with Southern
      Europeans as the major source of PAH mutations in Latin America. However, we have
      also detected mutations from East and Central Europe, such IVS12nt1, R408W and
      R252W. It is clear that the PKU mutation present in each Latin American country
      varies with the demographic profile and specific mutation scanning is necessary
      in each population both for diagnostic and prognostic purposes. The correlation
      between the genotypes and the phenotypes is consistent with the emerging pattern
      of mutation severity deduced from previous studies in related populations.

PMID- 10408783
TI  - A series of mutations in the dihydropteridine reductase gene resulting in either
      abnormal RNA splicing or DHPR protein defects. Mutations in brief no. 244.
      Online.
AB  - Five novel mutations are described which result in the rare hyperphenylalaninemia
      DHPR-deficiency. Three of these are located at different intron/exon boundaries
      within the DHPR gene, and disrupt the maturation of the DHPR transcript such that
      little full-length mRNA can be detected by RT-PCR. Each mutation alters a
      conserved nucleotide within the splice site consensus sequence, and results in
      the skipping of an exon and, in one case, the activation of an inappropriate
      splicing signal. Two further mutations are missense mutations resulting in a non
      conservative amino acid change within the DHPR protein (L14P and G17V) and are
      associated with a severe phenotype.

PMID- 10408784
TI  - Mutational-screening in the factor VIII gene resulting in the identification of
      three novel mutations, one of which is a donor splice mutation. Mutations in
      brief no. 245. Online.
AB  - Hemophilia A is an X-linked bleeding disease caused by mutations in the
      coagulation factor VIII gene. The identification and characterization of
      pathogenic mutations allows the recognition of new mechanisms of functional
      disturbances of factor VIII. To screen for mutations exons 1-26 of the factor
      VIII gene have been amplified genomically and analyzed by SSCP followed by direct
      sequencing of respective exons showing abnormal electrophoretic mobility on SSCP
      analysis. In the present study we report the detection of four mutations in the
      factor VIII gene, of which three are novel. The mutational analysis of a patient
      with severe hemophilia A has revealed that the ac transversion at position 3 of
      the donor-splice-site of intron 23 results in the skipping of exon 23. A novel
      nonsense mutation Q1778X in exon 16 of factor VIII gene has been identified in a
      second hemophilia A case. Furthermore two missense mutations have been
      ascertained: a novel, S183R, causing a mild phenotype of hemophilia A and R282H,
      previously described in association with severe hemophilia A.

PMID- 10408785
TI  - Different somatic and germline HPRT1 mutations promote use of a common, cryptic
      intron 1 splice site. Mutations in brief no. 246. Online.
AB  - Aberrant hypoxanthine phosphoribosyltransferase (HUGO-approved gene symbol HPRT1;
      MIM# 308000) mRNA splicing, promoted by splice site mutation or loss, is a common
      mechanism for loss of the purine salvage enzyme HPRT1 from human cells. We report
      here two in vivo somatic HPRT1 mutations in human kidney tubular epithelial cells
      that disrupt HPRT1 intron 1 splicing and lead to the inclusion of intron 1
      sequence. We propose an explanation for the use of a common, cryptic intron 1
      splice donor site by these two mutations, and by 14 additional human HPRT1
      mutations that lead to aberrant splicing with the incorporation of intron 1
      sequence into mRNA.

PMID- 10408786
TI  - A rapid screening for steroid 21-hydroxylase mutations in patients with
      congenital adrenal hyperplasia. Mutations in brief no. 247. Online.
AB  - Steroid 21-hydroxylase deficiency is the major cause of congenital adrenal
      hyperplasia (CAH). CAH due to 21-hydroxylase deficiency is divided into three
      classes: salt-wasting (classical), non-classical and simple virilizing,
      reflecting different degrees of clinical severity. Using polymerase chain
      reaction (PCR) and allele-specific oligonucleotide hybridisation (ASO), we
      screened the DNA of 62 Caucasian CAH families (heterozygous parents and children)
      for 14 different and frequently-found CYP21-mutations (HGMD). Of the 62 patients
      (21 males, 41 females), 26 females and 11 males had the classical or salt-wasting
      form, 3 females and 1 male had the non-classical form and 14 females and 7 males
      had simple virilizing CAH. More than 60% of the patients were compound
      heterozygous. We found the mutations on 110 alleles (out of 124 alleles). There
      were 30 CYP21 gene deletions/conversions, 3 substitutions (P30L) in exon 1, 30
      splice mutations (c.93-13A/C>G) in intron 2, 26 point mutations (I172N) in exon
      4, one cluster of mutations (I236N, V237E, M239K) in exon 6, 8 mutations (V281L
      and 1760-1761insT) in exon 7, and 8 nonsense (Q318X) and 4 missense (R356W)
      mutations in exon 8. Our study supports the case for using this rapid technique
      for CAH-family screening as long as alleles from both affected patients and
      parents are screened in parallel.

PMID- 10408788
TI  - Optimizing the APC gene mutation analysis in archival colorectal tumor tissue.
AB  - Critical steps in the methodology of mutation analysis on routinely fixed,
      paraffin-embedded samples have been evaluated, including extraction and
      purification of DNA, amplification of gene fragments in various sizes, and
      screening for mutations. The DNA was extracted from tissue sections with
      proteinase K, using various procedures, and purified. The mutation cluster region
      of the APC gene was amplified with polymerase chain reaction to generate either
      two large or four small overlapping DNA fragments. The GC-clamped fragments were
      screened for mutations with temperature gradient gel electrophoresis, and
      mutations were identified with sequencing. The DNA was easily amplified as large
      fragments from fresh or unfixed-frozen samples. However, DNA amplification of
      large fragments from archival samples was successful in only 40 of the 114 tumor
      specimens analyzed (35%). Prolonged extraction, either at 55 degrees C or at 37
      degrees C, gave no better results. Polymerase chain reaction of smaller
      fragments, with sizes between 200 and 270 base pairs (bp), was successful for 97%
      of the amplification reactions when using DNA that was purified with silica.
      Screening with temperature gradient gel electrophoresis was reproducible and
      sensitive with a detection limit of 5% mutated DNA in the presence of an excess
      of wild-type DNA.

PMID- 10408787
TI  - Comprehensive TP53-denaturing gradient gel electrophoresis mutation detection
      assay also applicable to archival paraffin-embedded tissue.
AB  - A comprehensive mutation detection assay is described for the entire coding
      region and all splice site junctions of TP53. The assay is based on denaturing
      gradient gel electrophoresis, which follows either multiplex polymerase chain
      reaction (PCR) applied to DNA extracted from fresh or frozen tissue samples or
      nested PCR applied to DNA extracted from paraffin-embedded tissue samples. In
      both instances, the analysis can be performed under a single set of conditions.
      When testing the assay on DNA from cultured lung cancer cell lines and from
      paraffin-embedded Dukes C colorectal carcinomas, significant TP53 mutations were
      observed at high frequencies in 15 of 16 lung cancer cell lines (94%) and in 21
      of 30 paraffin-embedded tissue samples of Dukes C colorectal carcinomas (70%). A
      substantial proportion of these significant mutations occurred outside the
      evolutionary conserved region of TP53 in 4 of 16 lung cancer cell lines (25%) and
      in 11 of 30 paraffin-embedded colorectal carcinomas (37%). This underscores the
      importance of a comprehensive TP53 mutation analysis in those instances that TP53
      mutation is taken into account for diagnostic and prognostic purposes.

PMID- 10408789
TI  - Use of the same archival papanicolanou smears for detection of human
      papillomavirus by cytology and polymerase chain reaction.
AB  - An optimal method for the processing of archival cervical Papanicolaou (pap)
      stained smears for the amplification of human papillomavirus (HPV) DNA by
      polymerase chain reaction (PCR) was developed. This methodology was then applied
      to a series of 44 pap smears designated as HPV positive or negative (on the basis
      of both major and minor cytological criteria) or cervical intraepithelial
      neoplasia (CIN)-cancer. For the detection of HPV DNA, each sample was tested with
      the consensus GP5/6 primers, and when negative, with CPI-IIG primers. The HPV DNA
      was detected in 100% (8 of 8) of CIN-cancer smears using the GP5/6 primers. In
      smears with cytological evidence of HPV without CIN. the use of both sets of
      primers yielded positive results in 100% (19 of 19) of the samples. Direct
      sequence analysis of PCR products showed that 16 of the 27 HPV-positive samples
      contained more recently described HPV types. When tested with both primer
      combinations, all 17 cytologically negative smears were positive for beta-globin
      but negative for HPV DNA. The findings show the value of using archival pap
      smears for further investigations to address issues such as latency, but they
      indicate that cytological criteria and DNA technology will be critical factors in
      the reliability of the results.

PMID- 10408790
TI  - Screening for genital human papillomavirus: results from an international
      validation study on human papillomavirus sampling techniques.
AB  - The objective of this study was to determine the validity of human papillomavirus
      (HPV) detection using exfoliated cervical cells compared with cervical biopsy
      specimens in women with normal cervix and to assess whether HPV detection rates
      using exfoliated cells is dependent on the number and order in which cervical
      scrapes are taken. Women undergoing hysterectomy for reasons other than cervical
      cancer were recruited in three hospitals in countries with varying risks of
      cervical cancer. After informed consent and at the time of surgery, three
      consecutive cervical scrapes were taken as well as four biopsy specimens, one in
      each of the quadrants around the cervical os. In this study, 331 women were
      recruited and provided 992 cell samples and 1324 biopsy samples. All scrapes and
      a sample of biopsy specimens (n = 103) were tested by polymerase chain reaction
      enzyme immunoassay using a general primer (GP5+/ bio6+). Type-specific tests were
      performed for 14 HPV types at the subpicogram level in one test and individually.
      Positive samples were verified using Southern blot hybridization. The prevalence
      of HPV DNA was 6.3% in cervical cells. Of 19 HPV positive samples in the scrapes,
      17 were confirmed in the biopsy specimens. The agreement, as measured by the
      Kappa statistic, was 0.90 (P < 0.0001). The concordance in detecting HPV
      infection between scrapes and biopsy specimens was 97.5%, and the concordance in
      categorizing the samples as negatives was 94.4%. These values were unchanged when
      the order in which scrapes were taken was compared. Among women without cervical
      cancer, HPV DNA detection rates do not vary if exfoliated cells or random biopsy
      specimens are taken as the primary testing specimen. Screening programs based on
      highly sensitive HPV DNA detection technology in cell scrapes should expect a
      minimal underdetection.

PMID- 10408791
TI  - Consensus polymerase chain reaction and enzyme-linked immunosorbent assay for
      human papillomavirus detection and typing in cervical specimens.
AB  - Human papillomavirus (HPV) infection is common in cervical intraepithelial
      neoplasia (CIN). This study investigates HPV detection and typing assay based on
      polymerase chain reaction amplification of L1 open reading frame with general
      primers GP5/GP6, followed by enzyme-linked immunosorbent assay detection with
      type-specific DNA probes. To determine the sensitivity of this assay, formalin
      fixed CaSki cells were used as reference cell lines. Fifty copies of viral DNA
      diluted in DNA from 100,000 noninfected cells could be detected. This assay was
      also investigated for HPV detection and typing of 67 cervical specimens diagnosed
      with with CIN III or carcinoma in situ (CIS) and their adjacent squamous
      epithelium. The CIN III lesions were infected in approximately 80% of the
      samples, 81% in the neighboring CIN II, and 68% in CIN I. The HPV infection was
      even detectable in 54% of nondysplastic epithelium located near a CIN III lesion.

PMID- 10408792
TI  - Enteroviral genome in native hearts may influence outcome of patients who undergo
      cardiac transplantation.
AB  - The Enterovirus may be the most common agent responsible for viral myocarditis
      and cardiomyopathy. Very little of the literature is available concerning the
      follow-up of patients who underwent transplantation with enteroviral positivity
      in native hearts. In the present study, 45 explanted hearts from patients who
      underwent orthotopic heart transplant at University of Padova were studied by
      reverse transcriptase (RT)-polymerase chain reaction (PCR): 27 patients had
      dilated cardiomyopathy (DC), 12 had ischemic cardiopathy (IC), 2 had valvular
      disease (VD), 2 had arrhythmogenic right ventricular cardiomyopathy (ARVC), 1 had
      giant cell myocarditis (GCM), and 1 had lymphocytic myocarditis (LM). Two sets of
      PCR primers from the highly conserved region of Enterovirus and Rhinovirus were
      used. Samples of both ventricles and septum were analyzed in every patients. The
      RT-PCR and nucleotide sequencing of amplicons were also performed on all post
      transplantation follow-up biopsies in patients with Enterovirus positivity in the
      native heart. The viral genome was detectable in only 1 of 27 patients with DC
      (3%) and in 1 patient with LM. Nucleotide sequence analysis of the amplified
      product showed differences in nucleotide sequence of PCR samples compared with
      the sequence of the coxsackievirus B3 used in the current study. The patient with
      Enterovirus-positive DC showed a higher index of severe rejection (>3A) in the
      first 6 months, compared with the other patients tested. The patient with
      Enterovirus-positive LM died of disease recurrence 2 months after
      transplantation. The present study reveals a scarce presence of Enterovirus in
      the myocardium of patients with chronic myocardial disease. Because Enterovirus
      infection was predictive of a poor prognosis in these two patients, molecular
      studies are useful in excluding viral involvement in native hearts of
      transplanted patients.

PMID- 10408793
TI  - Cytogenetic aberrations in myelodysplastic syndrome detected by comparative
      genomic hybridization and fluorescence in situ hybridization.
AB  - Conventional cytogenetics (CC) is proven as a diagnostic and prognostic factor in
      myelodysplastic syndrome (MDS). However, CC may be hampered by insufficient
      metaphase preparation and cannot analyze interphase nuclei. These problems are
      solved by using comparative genomic hybridization (CGH). The CGH was applied to
      samples from 45 patients with MDS, and the results were compared with CC and
      fluorescence in situ hybridization (FISH). The CC detected aberrations in 12 of
      45 samples, including chromosomes 3 (n = 1), 5 (n = 9), 7 (n = 2),8(n = 1), 18(n
      = 1),21 (n = 1), X (n = 1), and Y(n = 2). In one patient, loss of B and C group
      chromosomes and a marker chromosome were seen. The CGH revealed chromosomal
      imbalances in 18 of 45 samples, including chromosomes 5 (n = 11), 7 (n = 2), 8 (n
      = 1), 18(n = 1), 20(n = 1), 21 (n = 1), X (n = 1), and Y (n = 2). All unbalanced
      aberrations found by CC were detected by CGH, too. In two patients, the CGH found
      additional aberrations and redefined the aberrations of the chromosomes of the B
      and C group in one sample. The FISH confirmed these aberrations. Additionally
      performed FISH for chromosomes 5, 7, and 8 gave normal findings in all patients
      found to be normal in CC and CGH. The CGH and FISH confirmed the results obtained
      by CC. All three techniques showed changes of chromosomes 5 and 7 as the most
      frequent aberrations, emphasizing the importance of these chromosomes in the
      development of MDS. Furthermore, the CC is proven as the basic technique for
      cytogenetic evaluation of MDS.

PMID- 10408794
TI  - Role of a common mutation in the homocysteine regulatory enzyme
      methylenetetrahydrofolate reductase in ischemic stroke.
AB  - A common mutation in methylenetetrahydrofolate reductase (MTHFR), a homocysteine
      metabolic pathway enzyme, has been associated with increased homocysteine levels
      and increased risk for premature cardiovascular disease. The purpose of this
      study was to assess the association between the prevalence of the MTHFR mutation,
      hyperhomocysteinemia, and subtypes of ischemic stroke in an elderly population
      comprised of three age-balanced groups of patients. The presence of the C677T
      MTHFR mutation was determined by a direct polymerase chain reaction-based assay
      performed on blood samples from 136 patients with acute ischemic stroke, 95
      patients with atherosclerotic risk factors for stroke (including some with a
      history of previous stroke or transient ischemic attack), and 52 healthy control
      subjects. The prevalence of the homozygous C677T mutation was not significantly
      higher in the elderly stroke patients (7%) than in the atherosclerotic risk (8%)
      or healthy elderly control (2%) groups. Plasma homocysteine levels were higher in
      the acute stroke patient group (14.5+/-4.5 micromol/L) and atherosclerotic risk
      patient group (14.6+/-6.2 micromol/L) compared with the control subjects (10.3+/
      3.1 micromol/ L, P < 0.03). Homozygotes for the C677T MTHFR mutation did not have
      significantly higher homocysteine levels than non-homozygotes. Moderate
      hyperhomocysteinemia, though common in older patients with ischemic
      cerebrovascular disease, is not attributable, at least in this patient group, to
      a higher prevalence of the C677T MTHFR mutation.

PMID- 10408795
TI  - T cell response in xenorecognition and xenografts: a review.
AB  - Xenotransplantation has recently become a subject of interest for the
      transplantation community due to the current organ shortage, which could be
      partially or even totally solved by the development of this strategy. The humoral
      response, which arises as a result of species disparities, is the major obstacle
      to the success of xenotransplantation. However, if the use of different
      strategies such as plasmapheresis, immunoadsorption, the utilization of organs
      from transgenic pigs for complement regulatory molecules and new
      immunosuppressive drugs, may allow to overcome or reduce the early antibody
      mediated rejections (hyperacute or acute vascular rejection), delayed responses
      based on cellular activations will still occur. In this review, despite the fact
      that different cell populations have been shown to be implicated in these
      phenomena (NK, granulocytes, macrophages), we will focus on recent published
      information concerning T cell response only, in xenorecognition.

PMID- 10408796
TI  - Differences in IgG subclass do not effect immune complex-enhanced T cell
      activation despite differential binding to antigen presenting cells.
AB  - Ag presentation to CD4 T cells is a critical event in the generation of
      protective immunity. IgG, in the form of IgG-pathogen (Ag) complexes, is capable
      of mediating FcgammaR-dependent Ag presentation, and thereby enhanced T cell
      activation. Therefore, it is important to understand the ability of the
      individual human IgG subclasses to function in enhanced T cell activation. We
      hypothesized that increased delivery of Ag to monocyte FcgammaR by high affinity
      human IgG subclasses, IgG1 and IgG3, would lead to increased Ag presentation, as
      compared to low affinity IgG subclasses, IgG2 and IgG4. To create immune
      complexes, we linked biotinylated IgG subclasses to biotinylated Ag via an avidin
      bridge, and examined T cell responses to them. Although IgG2- and IgG4-Ag
      complexes bound to monocytes at significantly lower levels than those made with
      IgG1 and IgG3, we observed no significant difference in the ability of the four
      human IgG subclasses to mediate enhanced T cell activation. Studies suggest the
      explanation for this dichotomy lies within the first 24 h of Ag processing, and
      that processing efficiency may vary with IgG subclass. They also suggest the
      existence of a highly efficient, and selective processing pathway, which is
      dependent on IgG subclass, and can compensate for low level production and
      FcgammaR binding of IgG2- and IgG4-Ag complexes.

PMID- 10408797
TI  - Clonal characteristics of T cell infiltrates in skin and synovium of patients
      with psoriatic arthritis.
AB  - Psoriasis is a chronic inflammatory skin disease that is often complicated by an
      inflammatory arthritis. Considerable evidence implicates cellular immune
      responses in psoriatic skin lesions, but the pathogenesis of the associated
      arthritis has not been elucidated. We analyzed T cell antigen receptor beta chain
      variable (TCRbetaV) gene repertoires among peripheral blood lymphocytes, skin and
      synovium of nine patients with psoriatic arthritis. RNase protection assays were
      used to quantitate the expression levels of 25 TCRbetaV genes, and CDR3 region
      sequencing was used to further characterize selected expansions. All patients
      exhibited significant TCRbetaV biases in the peripheral blood and moreover, all
      had expansions common to both skin and synovium. CDR3 sequencing demonstrated
      these expansions frequently consisted of oligo- or monoclonal populations.
      Although no ubiquitous CDR3 nucleotide sequences were identified, two patients
      shared identical sequences and several highly homologous amino acid motifs were
      present in skin and synovium among and between individual patients. Findings of
      common TCRbetaV expansions in diverse inflammatory sites, among multiple
      afflicted individuals, suggest that these T cell proliferations are driven by
      engagements with a limited set of conventional antigens. These findings
      demonstrate an important role for cognate T cell responses in the pathogenesis of
      psoriatic arthritis, and further suggest the inciting antigen(s) is identical or
      homologous between afflicted skin and synovium.

PMID- 10408798
TI  - Inhibition of HLA antibody cytotoxicity by intravenous immunoglobulin G F(ab')2
      dimers, monomers, and monovalent F(ab).
AB  - IVIgG preparations are clinically relevant to sensitized transplant candidates
      because they inhibit HLA alloantibody in vitro and in vivo. We hypothesized that
      IVIgG F(ab')2 idiotypic-antiidiotypic dimers may possess a greater
      immunomodulatory capacity when remonomerized than non-dimerizable F(ab')2
      monomers in IVIgG. We reasoned that when 60-75% of potential antiidiotypic IVIgG
      monomers fail to bind to IVIgG molecules in a large pool of plasma donors
      (>10,000), IVIgG monomers may fail to inhibit HLA idiotypic antibodies of
      sensitized transplant candidates. In the first series of AHG T cell crossmatches,
      non-fractionated IVIgG F(ab')2 was found to inhibit titered HLA antibodies in 13
      out of 29 (45%) crossmatch combinations. Crossmatch inhibition was incomplete,
      i.e., a particular titered HLA antibody specificity was not always inhibited by
      IVIgG F(ab')2 in every HLA antigen-matched target cell crossmatch. Next, the
      IVIgG F(ab')2 product was fractionated into F(ab')2 dimers, F(ab')2 monomers and
      Fab monovalent components by size exclusion high pressure liquid chromatography
      (HPLC) and retested in crossmatches which previously demonstrated inhibition. The
      percent of crossmatches that were inhibited by HPLC F(ab')2 IVIgG fractions in
      three separate experiments was statistically similar for pH 4.0 remonomerized
      dimers, 82%; pH 6.0 dimers, 50%; monomers, 64%; and monovalent Fab, 64% (p =
      0.50). Soluble class I HLA antigen was undetectable in IVIgG F(ab')2 by an ELISA
      assay. In conclusion, IVIgG dimers and monomers appear to have similar
      immunomodulatory capacities, and separation of whole IVIgG products into dimer
      and monomer fractions does not appear to be warranted. Further, IVIgG products
      should be tested for optimal HLA antibody inhibition in vitro prior to in vivo
      therapy.

PMID- 10408799
TI  - Implication of soluble and membrane HLA class I and serum IL-10 in liver graft
      acceptance.
AB  - Membrane HLA class-I expression (mHLA-I), soluble HLA class-I antigens (sHLA-I)
      and interleukin (IL)-10 are different factors implicated in the special
      acceptance of liver allograft. In this study, pre- and post-operative levels of
      mHLA-I in peripheral blood lymphocytes (PBL) and serum sHLA-I were analyzed in 86
      liver transplants, immunosuppressed with Cyclosporine-A, methylprednisolone and
      azathioprine, and classified into acute-rejection (AR, n = 28) and non-acute
      rejection (NAR, n = 58) groups. Serum IL-10 was studied in 47 recipients (AR
      group, n = 16 and NAR-group, n = 31). Pre-transplant values of mHLA-I and sHLA-I
      showed a bimodal distribution (high/low) in NAR-recipients, but in AR-patients
      were mainly included in the low expression/secretion zone (mHLA-I, p < 0.02 and
      sHLA-I, p < 0.05). Consequently, average pre-transplant mHLA-I (868 +/- 109
      versus 998 +/- 123, p < 0.05) and sHLA-I (1.3 +/- 0.4 versus 2.02 +/- 0.7
      microg/ml, p < 0.01) was lower in the AR- than in the NAR-group. After transplant
      both parameters decreased in the NAR-group, but increased in AR-recipients
      previous to and on rejection diagnosis day. Additionally, serum IL-10 levels were
      significantly higher (p < 0.01) in the NAR than in the AR-group during the first
      24 h post-transplant. In conclusion, low pre-transplant mHLA-I and sHLA-I levels
      pre-dispose liver recipients to acute rejection, whereas early post-transplant
      increases of serum IL-10 appear to be related to a good liver allograft
      acceptance.

PMID- 10408800
TI  - Antibody immunity to the HER-2/neu oncogenic protein in patients with colorectal
      cancer.
AB  - The HER-2/neu protein is overexpressed in approximately 20% of human
      adenocarcinomas and is a defined tumor antigen in breast cancer. The purpose of
      this study was to evaluate the endogenous HER-2/neu specific antibody response in
      57 patients with colorectal cancer. HER-2/neu specific antibodies, titer > or =
      1:100, were detected in 14% (8/57) of patients with colorectal cancer compared to
      none of the normal control population (0/200). Furthermore, detection of HER
      2/neu specific antibodies in the cancer population correlated significantly with
      HER-2/neu protein overexpression in the patients' tumor (p < 0.01). 46% of
      patients with HER-2/neu overexpressing tumors (6/13) and 5% of HER-2/neu negative
      tumors (2/44) had detectable HER-2/neu specific antibodies. The endogenous HER
      2/neu antibody response in these patients was predominantly IgG or IgA.

PMID- 10408801
TI  - Study of the association between major histocompatibility complex class II genes
      and the response to interferon alpha in patients with chronic hepatitis C
      infection.
AB  - OBJECTIVE: The aim of the study was to determine the influence of HLA class II
      genes on the response to interferon-alpha (IFN-alpha) in patients with chronic
      hepatitis C. METHODS: The distribution of HLA DRB1 and DQB1 alleles was assessed
      in 170 caucasoid patients treated with IFN-alpha for chronic hepatitis C. 50
      patients had a long term sustained response to treatment whereas 120 patients
      were nonresponders. RESULTS: Female sex, non-1 HCV genotype particularly genotype
      2 and pretreatment low serum HCV RNA level were associated with long-term
      sustained response to IFN-alpha. A trend towards a higher prevalence of DRB1*07
      allele in non responders than in patients with sustained response (45% vs. 28%,
      odds ratio 2.1; P < 0.05) on the one hand and of DQB1*06 allele in HCV genotype 1
      patients with sustained response than in HCV genotype 1 nonresponders (75% vs
      27.3%, odds ration 7.9; P < 0.02) on the other hand, were observed. However, none
      of these two differences remained significant after Bonferroni's correction.
      CONCLUSION: Accordingly, we conclude that the response to IFN-alpha therapy is
      more tightly related to virus factors than to host's HLA class II genes.

PMID- 10408802
TI  - Associations of MHC class II alleles with insulin-dependent diabetes mellitus
      (IDDM) in patients from North India.
AB  - Thirty-four insulin-dependent diabetes mellitus (IDDM) patients from North India
      were studied with respect to their HLA class II alleles including those of the
      DRB1, DQA1, DQB1 and DPB1 loci, using the polymerase chain reaction (PCR) and
      hybridization with sequence-specific oligonucleotide probes (SSOP). They were
      compared with the class II alleles of 94 normal adult controls from the same
      ethnic background. The results show a statistically significant increase of
      DRB1*03011 (p < 0.00001), DQB1*0201 (p < 0.007), DQA1*0501 (0.0027) and DPB1*2601
      (p < 0.0042) in patients compared to controls. DR*04 was not significantly
      increased. However, homozygosity for DRB1*03011 was increased more than expected.
      DRB1*1501 and *1502 did not show a significant decrease in the patients. However,
      DRB1*0701 was decreased significantly, but this difference did not remain
      significant when the p value was corrected for the number of alleles tested.
      Similarly, DPB1*2601 was increased significantly in the patients but did not
      remain significant after p was corrected for the number of alleles tested.
      However, DPB1*2601 was increased, and remained significant after correction, in
      patients not having HLA-DR3. We also studied the possible role of aspartic acid
      at codon 57 of the DQ beta chain in protection against development of diabetes,
      and arginine at codon 52 of the DQ alpha chain in susceptibility. We observed an
      increase in non-Asp57 alleles in DQ beta and Arg52 in DQ alpha in the patients,
      however, this effect seems to be due to the fact that the most prevalent
      haplotype in diabetic patients: DRB1*03011-DQA1*0501-DQB1*0201, has DQB1 and DQA1
      alleles which carry non-Asp57 and Arg52, respectively.

PMID- 10408803
TI  - Matching for HLA DPA1 and DPB1 alleles in unrelated bone marrow transplantation.
AB  - The impact of donor-recipient DPA1 and DPB1 matching was examined in 122
      unrelated bone marrow transplant pairs. All pairs were serologically matched at
      the time of transplantation for HLA class I and II and a majority also DRB1
      allele matched. Retrospective A, B, C, DRB1, DQA1, DQB1 in addition to DPA1 and
      DPB1 allele matching was performed by molecular techniques. The percentage of
      pairs that were allele matched was as follows; HLA-A = 91% (n = 80), HLA-B = 94%
      (n = 80), HLA-C = 78% (n = 80), HLA-DRB1 = 96% (n = 122), HLA-DQA1 = 99% (n =
      80), HLA-DQB1 = 92% (n = 122). 92 recipient/donor pairs with informative clinical
      data were available for analysis. DPA1 identity (no incompatibility in either
      direction) was observed in 57% and DPA1 compatibility in 76% of pairs with no
      apparent beneficial effect of matching on patient survival or Graft Versus Host
      Disease (GVHD). DPB1 identity was observed in 11% and compatibility in 27% of
      pairs. A significant improvement in patient survival was observed in DPB1 matched
      compared to one DPB1 mismatch (p < 0.01) and combined one and two DPB1 mismatched
      transplants (p = 0.03). This beneficial effect remained when allele mismatches at
      HLA-A, B, C, DRB1, DQA1, DQB1 were excluded (p = 0.05, p = 0.03, respectively).
      There was a significant association of increased frequency of severe GVHD (grades
      III-IV) compared to mild GVHD (grades I-II) with DPB1 mismatched transplants
      compared to DPB1 matched transplants (p = 0.04). In DPB1 mismatched transplants
      an association between patient survival and matching for individual DPB1
      polymorphic regions was not observed; however in the HLA-A, B, DRB1, DQA1, DQB1
      allele matched transplants a non significant increase in the frequency of Grade
      IV GVHD was observed in recipients who were negative compared to those who were
      positive for DPB1 alleles coding for glutamic acid at position 69.

PMID- 10408804
TI  - Rapid HLA class I DNA typing using microtiter plate-reverse hybridization assay
      (MRHA) by simple thermoregulation: high-resolution subtyping of the HLA-A2 and 
      B40 antigen groups.
AB  - We have established a precise, rapid, simple and economical subtyping method for
      alleles encoding the HLA-A2 and -B40 antigens using microtiter plate-reverse
      hybridization assay (MRHA), which is based on the general principle of HLA
      oligotyping by reverse dot blot hybridization. Amino-modified sequence-specific
      oligonucleotide (SSO) probes were immobilized covalently onto a carboxylate
      modified microtiter plate. In order to perform high-resolution subtyping of the
      HLA-A2 and -B40 antigen groups, the alpha1 and alpha2 domain regions were
      amplified using a pair of group-specific primers composed of an unlabeled sense
      primer and a biotinylated antisense primer. PCR-amplified products were
      hybridized with SSO probes in hybridization buffer containing formamide for 1
      hour at 37 degrees C. After washing with 2 X SSC at room temperature, the bound
      PCR products were detected by alkaline phosphatase-conjugated streptavidine
      followed by color development. All of 8 HLA-B40 suballeles, all of 2 HLA-B47
      suballeles (B40 group-specific primers used in this study allowed also B47
      amplification) and 17 out of 21 HLA-A2 suballeles were discriminated. The
      remaining four HLA-A2 suballeles were determined by analysis after exon 4
      amplification. HLA-DNA typing by this method was easily and exactly performed
      regardless of sample number. The greatest advantages of this technique are strong
      positive signals obtained, reproducibility and the ease of thermoregulation for
      hybridization and washing as compared to previously reported microtiter plate
      hybridization methods.

PMID- 10408805
TI  - The immunobiology of multiple sclerosis: an autoimmune disease of the central
      nervous system.

PMID- 10408806
TI  - Chromosome missegregation and trisomy 21 mosaicism in Alzheimer's disease.
AB  - A connection between Alzheimer's disease (AD) and Down syndrome (trisomy 21) is
      indicated by the fact that all Down syndrome individuals develop Alzheimer's
      disease neuropathology by the 4th decade of life. Previous studies have examined
      the frequency of aneuploidy and other chromosomal defects in cells from familial
      Alzheimer's disease (FAD) patients, with varying results. To investigate the
      possibility that a specific type of aneuploidy--trisomy 21 mosaicism--may
      contribute to Alzheimer's disease, we used quantitative fluorescence in situ
      hybridization to measure the number of trisomy 21 cells in primary fibroblast
      cultures from AD and unaffected subjects. The 27 AD cultures, including 15 that
      were derived from individuals carrying FAD mutations in presenilin 1 or 2,
      exhibited a significant approximately twofold increase in the number of trisomy
      21 cells compared to 13 control cultures. A small double-hybridization experiment
      suggested that the aneuploidy in AD cells was not limited to chromosome 21 but
      extended at least to chromosome 18 as well. In a parallel study, the endogenous
      presenilin proteins in fibroblasts were localized to the centrosomes, the nuclear
      envelope, and its associated interphase kinetochores. Together these results
      indicate that the presenilin proteins may be involved in mitosis and that FAD
      mutations in the presenilin genes may predispose to chromosome missegregation
      (nondisjunction). The data reported here also suggest that trisomy 21 mosaicism
      may contribute to other forms of AD that are not caused by a presenilin mutation.

PMID- 10408807
TI  - Reduction of ischemic damage in NGF-transgenic mice: correlation with enhancement
      of antioxidant enzyme activities.
AB  - If permanent focal ischemia is induced by middle cerebral artery occlusion
      (MCAO), neurons within the infarcted territory die by necrosis and apoptosis (or
      programmed cell death). We have previously shown, using a mouse strain transgenic
      (tg) for the nerve growth factor (NGF) gene, that tg mice have consistently
      smaller infarcted areas than wild-type (wt) animals, correlated with upregulated
      NGF synthesis and impaired apoptotic cell death. We studied, in wt and tg mice
      subjected to MCAO, the activities of several antioxidant enzymes and the
      synthesis of the proteins of the Bcl-2 family. Our results show that the
      antiapoptotic Bcl-2 protein and glutathione peroxidase are recruited after MCAO.
      NGF-tg mice also had an intrinsic resistance to oxidative stress because their
      basal copper zinc superoxide dismutase (SOD) and glutathione transferase
      activities were high. Additionally, manganese SOD activity increased in NGF-tg
      mice after MCAO, correlating strongly with the resistance of these mice to
      apoptosis.

PMID- 10408808
TI  - Receptor-mediated transport of human amyloid beta-protein 1-40 and 1-42 at the
      blood-brain barrier.
AB  - Since amyloid beta-protein (A beta) is the primary component of both vascular and
      parenchymal amyloid deposits in Alzheimer's disease, information regarding its
      permeability at the blood-brain barrier (BBB) will help elucidate the
      contribution of circulating A beta to vascular and parenchymal A beta deposition
      in this disease and in brain aging. The permeability of the D- and L-enantiomers
      of A beta 1-40 and L-A beta 1-42 at the BBB was determined in the normal adult
      rat by quantifying the permeability coefficient-surface area product (PS) for
      each protein after correction for the residual plasma volume (Vp) occupied by the
      protein [labeled with a different isotope of iodine (125I vs 131I)] in blood
      vessels of different brain regions. After a single i.v. bolus injection, the
      plasma pharmacokinetics determined by TCA precipitation, paper chromatography,
      and SDS-PAGE were similar for both 125I-L-A beta 1-40 and 125I-L-A beta 1-42. The
      PS at the BBB for L-A beta 1-42 was significantly (1.4- to 1.8-fold) higher than
      for L-A beta 1-40 and ranged from 17.7 to 26.4 x 10(-6) ml/g/s for different
      brain regions. A comparison of the PS values at the BBB for L-A beta 1-40 showed
      no significant difference when determined at 15 or 30 min after i.v. bolus
      injection, times that reflect different levels of degradation in plasma (37.9% at
      15 min and 65.5% at 30 min). The PS values obtained, therefore, were
      representative of the intact protein rather than degradation products. The PS
      values obtained for the all-D-enantiomer of A beta 1-40 were very low and
      comparable to that of albumin and IgG, whose mechanism of transport is by passive
      diffusion. Taken together, these data imply a stereoisomer-specific, ligand
      receptor interaction at the BBB for the L-A beta proteins. The high PS values
      observed for L-A beta 1-40 and 1-42 compare to insulin, whose uptake is decidedly
      by a receptor-mediated transport process, and suggest a similar mechanism for L-A
      beta entry into the brain.

PMID- 10408809
TI  - Brain IL-1beta increases neutrophil and decreases lymphocyte counts through
      stimulation of neuroimmune pathways.
AB  - Leukocytosis after cerebral injury is well described and may participate in the
      generation of cerebral damage. However, the mechanisms of brain-induced
      leukocytosis are still speculative. Since it is known that proinflammatory
      cytokines are involved in neuroimmunomodulation and since others and we have
      demonstrated high cytokine levels in the cerebrospinal fluid following injury, we
      supposed that brain cytokines may also influence leukocyte counts. In order to
      evaluate this hypothesis, we established an animal model using continuous
      intracerebroventricular (i.c.v.), intrahypothalamic (i.h.), or intravenous
      infusion of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and
      IL-1beta. Controls received vehicle solution. With this experimental paradigm we
      could show that i.c.v. and i.h. infusion of IL-1beta but not TNF-alpha
      dramatically increased neutrophil counts, whereas lymphocytes dropped. Blocking
      the hypothalamic-pituitary-adrenal (HPA) axis by hypophysectomy abolished the
      neutrophilia, whereas the lymphopenia remained unchanged. Furthermore,
      application of the beta2-adrenoreceptor antagonist propranolol prevented the
      decrease of lymphocytes and diminished the neutrophilia. All parameters
      normalized within 48 h after termination of infusion. So, our results demonstrate
      that brain IL-1beta can modify blood leukocyte counts through stimulation of both
      the sympathetic nervous system (SNS) and the HPA axis.

PMID- 10408811
TI  - The role of stress in anaesthetists' health and well-being.
AB  - Stress is an inevitable part of our personal and professional lives. When poorly
      managed, stress will accumulate to levels that become injurious to our health and
      well-being. Burnout is one such consequence. However, because stress is an active
      process, with the proper knowledge and skills, we can learn to better manage and
      control its level of intensity. This paper examines the stress cycle and
      especially those aspects that are unique to the practice of medicine and
      anaesthesia. Sleep deprivation and physical fatigue are analyzed as key
      stressors. The role of the medical marriage and dual-career relationships are
      scrutinized. The importance of retaining the humanistic essence of medicine is
      emphasized. Stress management strategies and coping responses, including self
      care and humor, are discussed.

PMID- 10408810
TI  - Involvement of oxidative stress on the impairment of energy metabolism induced by
      A beta peptides on PC12 cells: protection by antioxidants.
AB  - Alzheimer's disease is widely held to be associated with oxidative stress due, in
      part, to the membrane action of amyloid beta-peptide (A beta) aggregates. In this
      study, the involvement of oxidative stress on A beta-induced energy metabolism
      dysfunction was evaluated on PC12 cells. It was shown that A beta peptides (A
      beta25-35 and A beta1-40) induce a concentration-dependent accumulation of
      reactive oxygen species (ROS), decrease the cellular redox activity, and lead to
      the depletion of ATP levels. The observed inhibition by A beta of mitochondrial
      function and of glycolysis is blocked by the antioxidants vitamin E, idebenone,
      and GSH ethyl ester. Taken together, these data suggest that exposure of PC12
      cells to A beta results in an impairment of energy metabolism, leading to a
      deficit in ATP levels and to the compromise of cellular viability. Furthermore,
      the generation of ROS seems to be a crucial event responsible for the energetic
      metabolic dysfunction induced by A beta.

PMID- 10408812
TI  - Epidural ropivacaine 7.5 mg/ml for elective Caesarean section: a double-blind
      comparison of efficacy and tolerability with bupivacaine 5 mg/ml.
AB  - BACKGROUND: Ropivacaine is a new local anaesthetic drug known to be less
      cardiotoxic than bupivacaine. The aims of this comparative study with bupivacaine
      were to evaluate efficacy, safety and tolerability for the mother and the neonate
      when using ropivacaine 7.5 mg/ml for epidural anaesthesia for elective Caesarean
      section. METHODS: In a double-blind, multicentre trial the patients were
      randomised to receive 20 ml of either ropivacaine 7.5 mg/ml or bupivacaine 5
      mg/ml. The quality of the peroperative analgesia and abdominal muscle relaxation
      as well as tolerability and safety in both the mother and the neonate were
      evaluated. RESULTS: A total of 122 patients were evaluated for efficacy and
      tolerability. There were no significant differences in the onset time and the
      extent of the sensory spread or motor block. The peroperative quality of
      anaesthesia and muscle relaxation was similar in both groups. No significant side
      effects were observed, except for a more profound drop in systolic blood pressure
      in the ropivacaine group. The anaesthetics were well tolerated by the neonate in
      both groups, evaluated by Apgar and NACS scores. CONCLUSION: Ropivacaine 7.5
      mg/ml administered epidurally resulted in equally effective anaesthesia for
      Caesarean section as bupivacaine 5 mg/ml. Because of the lower cardiotoxicity of
      ropivacaine, the new amide has a potential in replacing bupivacaine when used
      epidurally for Caesarean section.

PMID- 10408813
TI  - Block of the brachial plexus branches by the humeral route. A prospective study
      in 503 ambulatory patients. Proposal of a nerve-blocking sequence.
AB  - BACKGROUND: Brachial plexus is usually approached by the supraclavicular or
      axillary route. A technique for selective blockade of the branches of the plexus
      at the humeral canal using electrolocation has recently been proposed. The aim of
      the present study was to assess the feasibility of this technique in the
      ambulatory patient and to determine the optimal sequence of nerve-blocking.
      METHODS: The nerves originating from the brachial plexus were located in the
      humeral canal, at the junction of the proximal and the middle third of the arm,
      with a stimulator and blocked using either lidocaine or a mixture of lidocaine
      and bupivacaine, depending on the anticipated duration of surgery. The minimal
      stimulating intensity eliciting an adequate response, type of local anaesthetic
      and injected volume, and time of onset of surgical anaesthesia were collected.
      RESULTS: The study included 503 consecutive ambulatory patients due to undergo
      surgery of the elbow, wrist or hand in one year. Suitable anaesthesia was
      obtained with the humeral blockade in 82.1% of cases. In the remaining 17.9%, an
      additional block at the elbow was required, mainly for ulnar and median nerves.
      The onset times of sensory blocks were the longest for the median nerve, similar
      for the radial and ulnar nerves, shorter for the musculocutaneous nerve and the
      shortest for the medial brachial and antebrachial cutaneous nerves. The
      difference was more significant with the lidocaine-bupivacaine mixture, than with
      lidocaine alone (P<0.001 vs P<0.05, respectively). The onset times of motor
      blocks were the longest for the median nerve (P<0.05) and the shortest for the
      musculocutaneous nerve (P<0.001). Neither nervous nor vascular complications
      occurred. CONCLUSION: This study shows that the nerve block at the humeral canal
      is an efficient and safe technique. Considering the onset times of nerve blocks,
      the following sequence for blockade can be recommended: median, ulnar, radial,
      musculocutaneous, medial (brachial and antebrachial) cutaneous nerves. The
      selective blockade of the main nerves of the upper limb at the humeral canal can
      be recommended for surgery of the forearm and the hand in the ambulatory patient.

PMID- 10408814
TI  - Errors in the intensive care unit (ICU). Experiences with an anonymous
      registration.
AB  - BACKGROUND: In order to obtain information about the occurrence and severity of
      errors in an ICU, this investigation was conducted in a combined ICU and
      postoperative ward at a Norwegian University Hospital. METHODS: An anonymous
      registration was conducted in order to reveal as many as possible of all errors
      in the unit. A separate registration form was used, recording the type of error,
      date and time, sex and age of the patient, patient condition (unstable/stable)
      and where the error occurred (on the ward or during transport). The registration
      started in October 1995, and reports until November 1996 are included (13
      months). Consequences of the errors were graded using a 6-point scale (0=no
      consequences and 5=fatal). Two experienced intensivists and two experienced ICU
      nurses independently evaluated the errors using a visual analogue scale (VAS)
      with 10 as the worst imaginable error. All four were blinded to consequences of
      the error. RESULTS: A total of 87 errors was reported: 36 (41.3%) were medication
      errors, 17 (19.5%) related to intravenous infusions, 15 (17.2%) were due to
      technical equipment failure, and the rest (19 errors, 21.8%) miscellaneous. No
      consequences could be detected in 55 cases (63%) (grade 0). Six errors were
      graded as 1, and 22 (25%) as grade 2 (therapeutic intervention necessary, no
      damage recorded). Five errors had more serious consequences, and one was fatal.
      The scoring of errors varied a great deal. Mean VAS score was 4.2 (SD 1.7). The
      sum of VAS score (max. 40) on each error followed a normal distribution, and 12
      errors had a score >25. CONCLUSION: Errors happen frequently in the ICU.
      Probably, our data do not represent the true incidence of errors in the period,
      which we believe was higher. Many errors are graded as serious or severe, but
      still have limited consequences for the patient.

PMID- 10408815
TI  - Effects of amide local anaesthetics on eicosanoid formation in burned skin.
AB  - BACKGROUND: Previous studies have demonstrated potent inhibition of burn oedema
      and progressive ischaemia by local anaesthetics. Since eicosanoids have been
      suggested to play an important role in the pathophysiology of burns, we compared
      in the present ex vivo study the effects of topical lidocaine/prilocaine cream
      (EMLA, ASTRA, Sweden) and intravenous lidocaine with that of saline on eicosanoid
      formation by normal and burned rat skin. METHODS: A full-thickness burn trauma
      was induced in the abdominal skin. All the agents were given 5 min postburn until
      2 h after the trauma. The experimental skin was subsequently removed and
      incubated in Krebs solution for 1 h. Eicosanoid concentrations in the solution
      were analysed by radioimmunoassay. RESULTS: EMLA cream induced a significant
      inhibition of TXB2 (P<0.05) and 6-Keto-PGF1alpha (P<0.01) but not of PGE release
      from burned skin as compared to saline treatment. Intravenous lidocaine infusions
      did not significantly influence the release of any of the measured eicosanoids
      versus saline. CONCLUSION: In conclusion, the lack of effect of intravenous
      lidocaine could relate to the severe burn trauma inducing rapid ischaemia which
      may have interfered with the delivery of the agent to the burned tissues or to
      insufficient concentrations achieved in the burn area. Topical treatment of
      burned skin with a local anaesthetic cream significantly reduced the release of
      TXB2 and 6-Keto-PGF1alpha, suggesting a possible mechanism of action in
      progressive burn ischaemia.

PMID- 10408816
TI  - Systemic levels and preportal organ release of tissue-type plasminogen activator
      are enhanced by PEEP in the pig.
AB  - BACKGROUND: Endothelium-derived tissue-type plasminogen activator, t-PA, is the
      key enzyme in the initiation of endogenous thrombolysis. Plasma levels of t-PA
      increase in response to sympatho-adrenergic activation. In the mesenteric
      vascular bed an increased norepinephrine spillover has been observed during
      positive end-expiratory pressure ventilation, PEEP. This experimental study
      examines the effects of PEEP-induced alterations on regional release rates and
      systemic levels of t-PA in vivo. METHODS: The protocol included measurements of
      arterio-venous concentration gradients of t-PA and the respective plasma flow
      across the pulmonary, coronary, hepatic and preportal vascular beds, in pigs,
      during zero-PEEP and at 2, 4 and 10 min after the application of a PEEP of 10 cm
      H2O. Both total plasma t-PA antigen (ELISA with a porcine t-PA standard) and
      active t-PA (spectrophotometric functional assay) were determined. RESULTS:
      During zero-PEEP, a high preportal basal net release and hepatic net uptake of
      total t-PA was observed. With PEEP, the magnitude of the preportal net release of
      t-PA was markedly enhanced (+24+/-5%), as was hepatic net uptake (+21+/-8%),
      simultaneously to a significant decrease in liver plasma flow (-30+/-2%). PEEP
      induced alterations in active t-PA mirrored those observed in total t-PA. No
      significant net fluxes of total or active t-PA were observed across the coronary
      or the pulmonary vascular beds. CONCLUSIONS: Clinically used levels of PEEP
      induce increases in net release of endothelially derived t-PA within preportal
      organs. The application of PEEP is associated with increased systemic levels of
      total and active t-PA, in spite of a simultaneous increase in hepatic net uptake,
      indicating that the preportal vascular bed can not account for the systemic t-PA
      response.

PMID- 10408817
TI  - An alternative method to intubate with laryngeal mask and see-through-bougie.
AB  - BACKGROUND: Different ways of managing the difficult airway is an important issue
      for the anaesthetist. We have investigated a technique with a see-through-bougie
      and laryngeal mask for intubation. METHODS: We report our experience with
      intubation of 30 patients using a see-through-bougie guided through a laryngeal
      mask with a fibreoptic bronchoscope. The bougie is then used as a guidance for a
      tracheal tube. RESULTS: In 29 of the 30 investigated patients, this method could
      be used. In one patient the method had to be abandoned because of a tortuous
      trachea. Seventeen patients were intubated within 2 min, 11 between 2 and 5 min
      and 1 required 10 min. The time was mainly dependent on the endoscopic experience
      of the anaesthetist. No patient sustained arterial desaturation. CONCLUSION: We
      conclude that intubation using a see-through-bougie and a laryngeal mask is a
      valuable method in the difficult intubation situation, when a temporary airway
      can be achieved with laryngeal mask, since it permits continuous ventilation and
      visual control throughout the procedure.

PMID- 10408818
TI  - Prophylactic ondansetron for postoperative emesis. Meta-analysis of its
      effectiveness in patients with previous history of postoperative nausea and
      vomiting.
AB  - BACKGROUND: The objective of this study was to compare, by means of meta
      analysis, the postoperative antiemetic efficacy of ondansetron in patients with
      and without antecedents of postoperative nausea and vomiting. METHODS: MEDLINE
      and EMBASE databases were searched for randomised placebo-controlled trials which
      evaluated the antiemetic effectiveness of 4 mg and 8 mg intravenous doses of
      prophylactic ondansetron in adult patients. A further selection was with respect
      to those studies which noted the patient's previous history of postoperative
      nausea and vomiting (PH-PONV) and, for the meta-analysis, the patients were
      divided into two sub-groups: those with (PH-PONV +) and those without a previous
      history of postoperative nausea and vomiting (PH-PONV -). Absence of vomiting was
      used as the index of effectiveness. RESULTS: Twenty-one trials involving 3984
      patients (2446 in ondansetron groups and 1538 in placebo groups; 1163 PH-PONV(+)
      patients and 2821 PH-PONV(-) patients) met the selection criteria. The
      effectiveness of the 4 mg dose of ondansetron was: OR (95% CI)=2.40 (1.77-3.26)
      vs. 2.71 (2.23-3.30) for the patients of PH-PONV(+) and PH-PONV(-) sub-groups,
      respectively. For the 8 mg dose, the effectiveness of ondansetron was: PH
      PONV(+)=4.21 (2.66-6.66) and PH-PONV(-)=2.61 (1.81-3.59). For neither of the
      doses evaluated was there any significant statistical difference between the sub
      groups. CONCLUSIONS: The effectiveness of ondansetron in the prevention of
      postoperative vomiting is not affected by the patients' PH-PONV.

PMID- 10408819
TI  - Tropisetron or droperidol in the prevention of postoperative nausea and vomiting.
      A comparative, randomised, double-blind study in women undergoing laparoscopic
      cholecystectomy.
AB  - BACKGROUND: Women undergoing laparoscopic cholecystectomy are susceptible to
      postoperative nausea and vomiting (PONV). This study was undertaken to evaluate
      the efficacy of tropisetron or droperidol for preventing PONV after laparoscopic
      cholecystectomy. METHODS: In a prospective, randomised, double-blind trial, 120
      female patients received either tropisetron 5 mg or droperidol 1.25 mg
      intravenously at the beginning of surgery. A standard general anaesthetic
      technique and postoperative analgesia were used. Nausea, emetic episodes and the
      need for rescue medication were recorded for 24 h postoperatively. RESULTS:
      Nausea was experienced by 55% of the patients in the tropisetron group and by 62%
      in the droperidol group (ns). The incidence of emetic episodes was 20% and 52%
      (P=0.001) in the two groups, respectively. Rescue antiemetic medication was
      needed in 42% and 50% (ns) of the patients, respectively. Patients in the
      droperidol group were more drowsy in comparison with patients in the tropisetron
      group, mean sedation score being 6.7 vs 5.7, respectively (P=0.023). No
      difference in other side-effects was observed. CONCLUSION: Tropisetron, when
      compared with droperidol, had no better efficacy on the prevention of
      postoperative nausea but resulted in a significantly lower incidence of vomiting
      after laparoscopic cholecystectomy.

PMID- 10408820
TI  - Pharmacology of G-1-64, a new nondepolarizing neuromuscular blocking agent with
      rapid onset and short duration of action.
AB  - BACKGROUND: Chances are slim that a clinically useful ultra-short-acting
      neuromuscular blocking agent of rapid onset will emerge from the
      benzylisoquinolinium or the aminosteroid series to which all currently popular
      relaxants belong. G-1-64 is a promising prototype of a new series of bis
      quaternary ammonium salt of bistropinyl diester derivatives we have synthesized
      and studied in the laboratory. METHODS: Neuromuscular block (NMB) and autonomic
      and cardiovascular side effects were studied on appropriate preparations of
      anesthetized rats, rabbits, cats, ferrets, pigs and monkeys. Neuromuscular
      blocking characteristics, cumulativeness, and pharmacological reversibility were
      determined. Cardiac vagal block was evaluated by the inhibition of the
      bradycardic response to stimulation of the vagus in the cat, rat, ferret, and
      pig. Sympathetic ganglion block was evaluated on the cat's superior cervical
      ganglion/nictitating membrane preparation. Arterial blood pressure and heart rate
      were determined in all species. RESULTS: G-1-64 produced nondepolarizing NMB with
      train-of-four (TOF) and tetanic fades, and reversible with anticholinesterases.
      Its ED50 ranged between 60 and 800 microg/kg in these species. It showed a
      significantly faster onset (0.9-2.1 min) and/or shorter duration of action (5-12
      min) than either atracurium or mivacurium. It did not show cumulativeness on
      repeated doses or infusion. A varying degree of cardiac vagal block was present,
      dependent on the species at doses exceeding the ED80 for NMB. Cardiovascular
      changes, ganglion block or signs suggesting histamine release were absent.
      CONCLUSION: With favorable neuromuscular blocking characteristics and modest side
      effects, G-1-64 and similar derivatives may have clinical potential.

PMID- 10408822
TI  - Pollution with nitrous oxide using laryngeal mask or face mask.
AB  - BACKGROUND: As environmental pollution by nitrous oxide may influence the health
      of the personnel working in operating theatres, the incidence and magnitude of
      nitrous oxide (N2O) leakage, when using a face mask or a laryngeal mask airway
      (LMA) for controlled ventilation, were studied in 34 patients scheduled for
      elective cystoscopy. METHODS: A semi-closed gas delivery ventilation system with
      active scavenging was used. The N2O concentrations were measured every 8 s at a
      position 30 cm above the patient's mouth with a N2O gas monitor (GD 200, Simrad
      Optronics). RESULTS: When using a face mask, the leakage of N2O resulted in a N2O
      concentration of 157 (85-332) p.p.m. (parts per million) (median concentration
      and 25% and 75% percentiles). With the LMA, a lower median concentration of N2O
      of 60 (28-126) p.p.m. was found (P=0.04). With the face mask, a concentration
      above 100 p.p.m. was found during 51% of the exposure time compared to 24% of the
      time in the LMA group. CONCLUSION: Environmental pollution was less with the LMA
      than the face mask, but under the conditions of the study both modes of airway
      management were associated with levels of N2O peak concentrations in the
      breathing zone of anaesthetists that are deemed to be excessively high by the
      Danish National Institute for Occupational Safety.

PMID- 10408821
TI  - Investigation of fading responses induced by non-depolarising muscle relaxants in
      the evoked EMG of the gastrocnemius muscle of the cat.
AB  - BACKGROUND: During partial neuromuscular blockade indirect repetitive nerve
      stimulation causes fade in the response of the muscle. We studied the intensity
      of the fade induced by intravenous administration of three steroidal muscle
      relaxants, and investigated the mechanism of fade by comparing with results
      obtained during partial blockade with animal toxins and vesamicol. METHODS: In 60
      cats, we measured the fade in the compound action potentials of the gastrocnemius
      muscle evoked by repetitive sciatic nerve stimulation at 100 Hz during partial
      neuromuscular blockade with rocuronium, vecuronium, pancuronium, alpha
      bungarotoxin, mu-conotoxin and vesamicol, respectively. RESULTS: Profound fade
      was induced by all three non-depolarising muscle relaxants
      (rocuronium=vecuronium<pancuronium) and by vesamicol, in contrast to alpha
      bungarotoxin and mu-conotoxin which induced no fading. CONCLUSION: Our results
      suggest that non-depolarising muscle relaxant-induced fade is caused by an
      inhibitory effect on acetylcholine release. Pancuronium seems to have a higher
      potency of presynaptic inhibition of acetylcholine release than both rocuronium
      and vecuronium.

PMID- 10408824
TI  - Anaesthetic management of patients with mucopolysaccharidosis IV presenting for
      major orthopaedic surgery.
AB  - Mucopolysaccharidosis IV, also known as Morquio-Brailsford syndrome, is an
      inherited autosomal recessive disorder of mucopolysaccharide metabolism leading
      to accumulation of keratan sulphate in the connective tissue of multiple organ
      systems. Based on a case report, the anaesthetic implications for the treatment
      of patients with MPS IV presenting for major orthopaedic surgery are discussed.

PMID- 10408823
TI  - Clinical experience using intrathecal (IT) bupivacaine infusion in three patients
      with complex regional pain syndrome type I (CRPS-I).
AB  - BACKGROUND AND AIM: To date, there is no reliable method for treating the severe
      pain and for modifying the natural evolution of CRPS-I. Therefore, we explored
      the effect of long-term IT bupivacaine infusion (with or without buprenorphine)
      on this syndrome. PATIENTS AND METHODS: (a) PATIENTS: two women and one man, 25,
      31 and 42 years old, with CRPS-I of the lower (n=2) or upper (n=1) extremity
      lasting for 4 and 5 months, and 14 years. (b) INTERVENTIONS: insertion of
      externalized IT catheters; IT infusion of buprenorphine 0.015 mg/ml and
      bupivacaine 4.75 mg/ml (n=1), or only bupivacaine 5 mg/ml (n=2) from external
      electronic pumps. RESULTS: The IT treatment lasted for 172, 282 and 668 days. The
      mean/maximal daily doses of the IT bupivacaine were 39/66, 55/80 and 69/125 mg,
      respectively. The pain intensity decreased from VASmean =7+/-1 to VASmean =2+/-2.
      None of the patients had regression of allodynia, edema, and trophic disturbances
      in the affected extremities. In 2 patients, the IT treatment did not prevent
      spread of the disease to the opposite extremity or the occurrence of phantom pain
      and stump allodynia after amputation. The IT catheters were withdrawn as being no
      longer needed: in 2 patients 56 and 458 days after amputation of the involved
      extremity, and in another one before replacement of the IT bupivacaine infusion
      with epidural dorsal column stimulation (EDCS). After termination of the IT
      treatment, the patients were observed for 1437, 1575, and 2689 days (until
      September 1, 1998). At that date, all the patients were alive, and still affected
      by their CRPS-I, either in the amputation stump (n=2), and/or in the opposite or
      remote extremities (n=2); further, two were unemployed and one worked for 75% of
      the time. One of them was taking up to 1500 mg of slow-release morphine to cope
      with pain. CONCLUSION: The IT pain treatment with bupivacaine (with or without
      buprenorphine) alleviated the "refractory" pain, but affected neither the
      associated symptoms and signs of the CRPS-I, nor its natural evolution. Thus, the
      IT treatment cannot be recommended in preference to other pain treatment regimens
      for CRPS-I.

PMID- 10408825
TI  - Slow-resolving pneumonia secondary to bronchiolitis obliterans organizing
      pneumonia.
AB  - We report a case of slow-resolving pneumonia secondary to bronchiolitis
      obliterans organizing pneumonia (BOOP) in a 73-year-old woman. Owing to a delayed
      diagnosis of BOOP, the clinical course was quite long. This syndrome is caused by
      a nonspecific inflammatory pneumonitis, either idiopathic or associated with
      infectious or irritant agents (or drugs). It generally presents as a flu-like
      illness, followed by progressive dyspnea, cough, fever, and bilateral patchy
      alveolar infiltrates, and lasts several weeks. The diagnostic work-up of slow
      resolving pneumonia is discussed.

PMID- 10408826
TI  - High risk of aspiration and difficult intubation in post-esophagectomy patients.

PMID- 10408828
TI  - A new approach to blockade of the posterior tibial nerve.

PMID- 10408827
TI  - Combined spinal and epidural anaesthesia in a parturient with moyamoya disease.

PMID- 10408829
TI  - Isolation and identification of peptidic alpha-glucosidase inhibitors derived
      from sardine muscle hydrolyzate.
AB  - We report here the isolation of alpha-glucosidase (AGH) inhibitory peptides
      derived from sardine muscle hydrolyzate, which was prepared by digestion with
      Bacillus licheniformis alkaline protease. As a result of reversed-phase HPLC
      purification, two AGH inhibitory peptides were isolated from a DEAE-Sephadex A-25
      column eluate. The peptides were identified as follows: Val-Trp (IC50 = 22.6 mM)
      and Try-Tyr-Pro-Leu (IC50 = 3.7 mM). AGH inhibitory studies of Try-Tyr-Pro-Leu
      and its derivatives demonstrated the importance of the tri-peptide chain length
      as well as the hydrophobic aromatic amino acid tyrosine at the N-terminus,
      aliphatic amino acids at the C-terminus, as well as an amide proton from the
      peptide chain at the middle position of the tri-peptide to develop AGH inhibition
      activity.

PMID- 10408830
TI  - Solvent accessibility to aspartyl and succinimidyl residues at positions 7 and 23
      in the amyloid beta 1-28 peptide.
AB  - The water accessibilities to aspartyl residues at positions 7 and 23 in the
      amyloid beta 1-28 peptide associated with Alzheimer's Disease have been
      calculated using different techniques. These accessibilities of water were
      compared to those of the succinimidyl residues (SUC) replacing the aspartyl ones
      (ASP). It has been possible to ascertain that these modifications (ASP--->SUC)
      lead to a significant increase in the water accessibility to the backbone and
      alpha-carbon atom of the SUC7 and SUC23 residues. It is suggested that the
      spontaneous transformation of the ASP--->SUC might lead to an increase of the
      racemization rates due to the higher accessibility of water at these sites. It is
      also proposed that the behavior of the adjacent residues in the selectivity of
      the racemization is to control the water accessibility at the reactive residue.

PMID- 10408831
TI  - Donald A. Pious 1930-1998.

PMID- 10408832
TI  - MMP-2 release and activation in ovarian carcinoma: the role of fibroblasts.
AB  - The matrix metalloproteinase MMP-2 is up-regulated in epithelial cancers and its
      mRNA localizes to stromal fibroblasts. In this paper we show that co-culture of
      ovarian carcinoma cells with fibroblasts resulted in an enhanced release of
      proMMP-2 and TIMP-2 into the culture medium. Cell-cell interaction was a major
      factor in this response and carcinoma cells stimulated proMMP-2 release from
      fibroblasts but not vice versa. Collagen 1, in a dose-dependent fashion, induced
      activation of proMMP-2 by tumour-derived, but not normal, fibroblasts. Antibody
      to beta1 integrin also induced proMMP-2 activation by tumour-derived fibroblasts.
      The activation involved the processing of proMMP-2 by a membrane-bound
      metalloproteinase. We propose that, in the ovarian tumour microenvironment,
      interaction between tumour cells and fibroblasts may enhance fibroblast
      production of the proMMP-2 and TIMP-2. Collagen I, also present in the ovarian
      tumours, then induces these fibroblasts to activate proMMP-2 even in the presence
      of TIMP-2. This active MMP-2 can associate with the cell surface of tumour cells
      and fibroblasts and is used in the processes of tissue remodelling and invasion.

PMID- 10408833
TI  - Abnormal expression and function of the E-cadherin-catenin complex in gastric
      carcinoma cell lines.
AB  - Dysfunction of the cadherin-catenin complex, a key component of adherens
      junctions, is thought to confer invasive potential to cells. The aim of this
      study is to examine the expression and function of the E-cadherin/catenin complex
      in gastric carcinoma cell lines. Expression of E-cadherin, alpha, beta and gamma
      catenin and p120ctn, and of the adenomatous polyposis coli protein (APC),
      together with function of the cadherin-catenin complex was examined in a panel of
      gastric carcinoma cell lines, using immunocytochemistry, Western blotting and a
      cell-cell aggregation assay. Protein interactions were examined by sequential
      immunoprecipitation and immunoblotting with antibodies to E-cadherin, alpha, beta
      and gamma-catenin, p120ctn and APC. Abnormalities of E-cadherin, alpha- and beta
      catenin expression, were associated with disturbance of E-cadherin-catenin
      complex composition, loss of membranous localization and loss of calcium
      dependent aggregation in six gastric carcinoma cell lines. APC protein expression
      and interaction with beta-catenin was preserved in five cell lines. We
      demonstrate frequent abnormalities of expression and function of E-cadherin and
      catenins, and associated disturbance of E-cadherin-mediated intercellular
      adhesion in gastric carcinoma cell lines. These findings support the tumour
      suppressor role of the E-cadherin and its contribution to the development and
      progression of the neoplastic phenotype in gastric carcinoma.

PMID- 10408834
TI  - FMLP- and TNF-stimulated monoclonal Lym-1 antibody-dependent lysis of B
      lymphoblastoid tumour targets by neutrophils.
AB  - Human neutrophils, incubated with Cr51-labelled B lymphoblastoid Raji cells in
      the presence of the anti-target monoclonal antibody (mAb) Lym-1 plus formyl
      methionyl-leucyl-phenylalanine (FMLP) or tumour necrosis factor alpha (TNF
      alpha), were found to induce significant C51 release, i.e. significant cytolysis.
      The lytic process was inhibited by mAb IV.3, specific for the Fcgamma receptor
      (FcgammaR) type II. The mAb 3G8, which reacts with FcgammaR type III, was
      ineffective. Moreover, the lysis was inhibited by the anti-CD18 mAb MEM-48. These
      data suggest that FMLP/Lym-1 as well as TNF-alpha/Lym-1 cytolytic systems
      strictly require FcgammaRII and CD18 integrins. As the lysis induced by TNF
      alpha/Lym-1 was prevented by pertussis toxin (PT), PT-sensitive G-proteins are
      likely to intervene in post-FcgammaRII signal transduction. Both the FMLP- and
      the TNF-alpha-dependent systems were also found to be equally susceptible to
      inhibition by various inhibitors of kinases (genistein, staurosporin, 1-(5
      isoquinolinnylsulphonyl)-2-methylpiperazine and wortmannin). On the contrary, an
      inhibitor of protein kinase C (bis-indolyl-maleimide, BIM) was effective only in
      the FMLP/Lym-1 cytolytic system. Therefore, it appears that signals delivered by
      FMLP or TNF-alpha, BIM-sensitive and insensitive respectively, converge and
      synergize with those from G-protein-coupled FcgammaRII and, probably, CD18
      integrins to promote the expression of the neutrophil cytolytic potential.

PMID- 10408835
TI  - Mismatch repair deficiency is associated with resistance to DNA minor groove
      alkylating agents.
AB  - Mismatch DNA repair deficiency is associated with resistance to certain major
      groove alkylating agents including methylating agents and cisplatin. We have now
      studied the relevance of mismatch repair alterations to the cytotoxicity induced
      by drugs which alkylate N3 adenines in the minor groove of DNA. We have used the
      mismatch repair defective human colocarcinoma cell line HCT-116 which has a
      mutation in the hMLH1 gene, and a subline where hMLH1 expression is restored by
      chromosome 3 transfer (HCT-116+ch3). We have tested three alkylating minor groove
      binders (tallimustine, carzelesin and CC1065) and one non-covalent minor groove
      binder (PNU 151807). The HCT-116+ch3 subline was more sensitive than the parental
      line to the treatment with the three alkylating minor groove binders, while the
      non-alkylating compound had a similar activity in both cell lines. Further
      support for mismatch repair being involved in sensitivity of the minor groove
      alkylators is that two cisplatin-resistant sublines of the human ovarian
      adenocarcinoma cell line A2780 (A2780/CP70 and A2780/MCP-1) are defective in
      hMLH1 expression and are more resistant to these agents than the parental
      mismatch repair proficient cells. Furthermore, the restoration of hMLH1 activity
      in the A2780/CP70 cell line, by introduction of chromosome 3, was associated with
      an increased sensitivity to the three alkylating minor groove binders. Again, the
      non-covalent minor groove binder was equally effective in mismatch repair
      deficient and proficient clones. The data indicate that mismatch repair
      deficiency mediated by loss of hMLH1 expression is associated not only with drug
      resistance to major groove binders, but also to minor groove binders. However,
      loss of mismatch repair does not mediate resistance to the non-covalent minor
      groove binder PNU 151807.

PMID- 10408836
TI  - Transient absorption changes in vivo during photodynamic therapy with pulsed
      laser light.
AB  - High intensity pulsed-laser light can be used to excite absorbing molecules to
      transient states in large proportions. The laser-induced spectral changes can be
      characterized by transient changes in light propagation; through the tissue
      provided the excited states of these molecules have altered absorption spectra.
      Characterization of these transient changes may then be used to exploit new
      mechanisms in photosensitization and/or to optimize photobiological effects. In
      this study, transmittance and reflectance were measured as a function of laser
      pulse energy, from tissue-simulating media as well as in rat muscle and liver
      slices, both with and without the photosensitizer benzoporphyrin derivative
      monoacid (BPD-MA) present. There was a transient decrease in absorption from the
      photosensitizer at peak pulse irradiance in the range of 100-1000 W cm(-2). The
      depth of photodynamic treatment-induced tissue necrosis was measured in a
      subcutaneous prostate cancer model in Copenhagen rats. A comparison between
      continuous wave irradiation and pulsed irradiation with the same average incident
      irradiance showed no statistically significant difference in the depth of
      necrosis at 48 h after irradiation. These results indicate that photosensitizer
      population-state changes are measurable in tissues and may provide a method for
      measuring triplet-state properties of photosensitizer in vivo, but for BPD-MA at
      clinically used concentrations these changes do not significantly affect the
      depth of photodynamically-induced tissue damage.

PMID- 10408837
TI  - Anti-gonadotrophin releasing hormone antibodies inhibit the growth of MCF7 human
      breast cancer xenografts.
AB  - The human breast cancer cell line (MCF7) was established as xenografts in intact
      female nude mice. Xenografts did not require oestrogen supplementation for
      growth, although oestrogen supplementation caused more rapid tumour growth. GnRH
      Pharmaccine is an immunogen composed of gonadotrophin releasing hormone (GnRH)
      linked to diphtheria toxoid. Anti-GnRH antibodies purified from the serum of
      rabbits immunized with GnRH Pharmaccine, were used to passively immunize nude
      mice. In mice treated with anti-GnRH antibodies, xenograft growth was
      significantly inhibited relative to controls (median times of 71 and 29 days
      respectively taken for tumours to attain a predetermined cross-sectional area of
      200 mm2, P < 0.001). The inhibition of tumour growth achieved by anti-GnRH
      antibodies was not significantly different from that produced by the anti
      oestrogen, tamoxifen (59 days). Ovarian/uterine weights were reduced by 61% (P <
      0.001) in anti-GnRH antibody-treated animals compared with controls.
      Histologically there was underdevelopment and atrophy of the reproductive organs.
      Serum levels of both oestrogen and luteinizing hormone were reduced by treatment
      with anti-GnRH antibodies (to 24.9% and 53% respectively of levels in controls,
      both P = 0.04). It is postulated that one of the mechanisms by which anti-GnRH
      antibody treatment inhibits tumour growth is indirectly, by reducing serum
      oestrogen levels.

PMID- 10408838
TI  - Photo-oxidative killing of human colonic cancer cells using indocyanine green and
      infrared light.
AB  - Despite of the approval of Photofrin in various countries, chemically defined
      sensitizers for photodynamic therapy (PDT) are still needed for the absorption of
      light in the infrared spectrum, which provides a maximal penetration of light
      into tissue. Therefore, both the efficacy and the mechanism of action of the
      clinically approved dye indocyanine green (ICG) and laser irradiation were
      investigated in vitro. For the investigation of phototoxic effects, HT-29 cells
      were incubated 24 h prior to irradiation by using different concentrations of ICG
      (10-500 microM). In each experiment, cells were irradiated using a continuous
      wave (cw)-diode laser (lambda(ex) = 805 nm, 30 J cm(-2), 40 mW cm(-2)). After
      laser irradiation, cell viability of dark control and of cells incubated with 500
      microM ICG was 1.27+/-0.11 or 0.28+/-0.05 respectively. Using 100 microM ICG and
      D2O, cell viability was further decreased from 0.46+/-0.03 (H2O) to 0.11+/-0.01
      (D2O). Using D2O and 100 microM ICG, the concentration of malondialdehyde, a
      marker of lipid peroxidation, increased from 0.89+/-0.10 nmol 10(-6) cells to
      11.14+/-0.11 nmol 10(-6) cells. Using 100 microM ICG and laser irradiation sodium
      azide or histidine (50 mM), quenchers of singlet oxygen reduced the cell killing
      significantly. In contrast, when using mannitol, a quencher of superoxide anion
      and hydroxyl radical, cell killing was not inhibited. According to the present
      results, photoactivated ICG seems to kill colonic cancer cells due to the
      generation of singlet oxygen and the subsequent formation of lipid peroxides.
      Therefore, ICG might present a promising photosensitizer for PDT; first clinical
      results confirm these findings.

PMID- 10408839
TI  - CPT-11 converting carboxylesterase and topoisomerase activities in tumour and
      normal colon and liver tissues.
AB  - CPT-11 is a prodrug activated by carboxylesterases to the active metabolite SN-38
      which is a potent inhibitor of topoisomerase I. CPT-11 is of clinical interest in
      the treatment of colorectal cancer. We evaluated the activities of CPT-11
      converting carboxylesterase (CPT-CE) and topoisomerase I (topo I) in 53
      colorectal tumours, in eight liver metastases and in normal tissue adjacent to
      the tumours. Both CPT-CE and topo I activities were widely variable in the
      malignant and the normal tissue of patients with colorectal carcinomas. CPT-CE
      was only two to threefold lower in primary tumours compared to normal liver,
      suggesting that a local conversion to SN-38 might occur in tumour cells. CPT-CE
      was similar in liver and in normal colon tissues. Levels of topo I in tumour
      ranged from 580 to 84 900 U mg protein(-1) and was above 40 000 U mg protein(-1)
      in 11 of 53 patients. Similarly, a very high ratio (> 5) between tumour and
      normal tissues were observed in 12 of 53 patients. An inverse correlation was
      observed between the topo I activity and the clinical stage of disease. Clinical
      studies are in progress in our institution to explore a possible relationship
      between CPT-CE and topo I activities in tumour cells and the response to CPT-11
      based chemotherapy in patients with colorectal cancer.

PMID- 10408841
TI  - Altered expression of exon 6 deleted progesterone receptor variant mRNA between
      normal human breast and breast tumour tissues.
AB  - The progesterone receptor (PR) is an important prognostic marker in breast cancer
      as well as a marker of responsiveness to endocrine therapies. The presence of
      several exon-deleted PR variant mRNAs in both normal and neoplastic breast
      samples has recently been reported. Amongst them, a variant mRNA deleted in exon
      6 (D6-PR mRNA) that if translated would encode a truncated PR-like protein
      missing the hormone binding domain and one of the transactivating domains of the
      wild-type PR protein. In order to determine whether changes in D6-PR variant
      expression could occur during tumorigenesis, its expression was investigated by
      reverse transcription and polymerase chain reaction in ten normal reduction
      mammoplasty samples, nine breast tumours with high PR levels (> 100 fmol mg(-1)
      protein) and eight breast tumours with low PR levels (< 15 fmol mg(-1) protein),
      as determined by ligand binding assay. The relative expression of D6-PR to wild
      type PR mRNA was lower (P< 0.01 ) in normal than in all tumour breast samples.
      Moreover, a trend to lower (P < 0.1) relative D6-PR expression was observed in
      high PR tumours, compared to low PR tumours. These data suggest that increased
      expression of D6-PR occurs during tumorigenesis.

PMID- 10408840
TI  - Camptothecin sensitizes androgen-independent prostate cancer cells to anti-Fas
      induced apoptosis.
AB  - Despite expressing both Fas and Fas ligand, DU145 and LNCaP prostate cancer cells
      were resistant to anti-Fas-induced cell death. Resistance to Fas-mediated
      cytotoxicity could be overcome in DU145, but not in LNCaP, cells by pretreating
      cells with sublethal doses of cytotoxic drugs, such as camptothecin. Activated
      caspases were shown to be required for this cytotoxicity. Indeed, poly(ADP
      Ribose) polymerase was shown to be proteolytically cleaved in cells treated with
      camptothecin plus anti-Fas, but not in cells treated with anti-Fas only.
      Moreover, pretreatment of cells with ZVAD completely blocked camptothecin
      mediated Fas-induced apoptosis. Sensitization of cells to Fas-induced cell death
      did not involve up-regulation of Fas or FasL, and it was independent of
      alterations in the cell cycle. Reactive oxygen intermediates (ROI) have been
      shown to be important mediators of drug-induced apoptosis. Here, we demonstrate
      that treatment of DU145 cells with camptothecin, anti-Fas, or both, did not alter
      the intracellular levels of peroxide or superoxide anion.

PMID- 10408842
TI  - Mutation and deletion analysis of GFR alpha-1, encoding the co-receptor for the
      GDNF/RET complex, in human brain tumours.
AB  - Glial cell line-derived neurotrophic factor (GDNF) plays a key role in the
      control of vertebrate neuron survival and differentiation in both the central and
      peripheral nervous systems. GDNF preferentially binds to GFRalpha-1 which then
      interacts with the receptor tyrosine kinase RET. We investigated a panel of 36
      independent cases of mainly advanced sporadic brain tumours for the presence of
      mutations in GDNF and GFRalpha-1. No mutations were found in the coding region of
      GDNF. We identified six previously described GFRalpha-1 polymorphisms, two of
      which lead to an amino acid change. In 15 of 36 brain tumours, all polymorphic
      variants appeared to be homozygous. Of these 15 tumours, one also had a rare,
      apparently homozygous, sequence variant at codon 361. Because of the rarity of
      the combination of homozygous sequence variants, analysis for hemizygous deletion
      was pursued in the 15 samples and loss of heterozygosity was found in 11 tumours.
      Our data suggest that intragenic point mutations of GDNF or GFRalpha-1 are not a
      common aetiologic event in brain tumours. However, either deletion of GFRalpha-1
      and/or nearby genes may contribute to the pathogenesis of these tumours.

PMID- 10408843
TI  - Prognostic values of proliferating cell nuclear antigen (PCNA) and Ki-67 for
      radiotherapy of oesophageal squamous cell carcinomas.
AB  - The relationship of immunohistochemical indices of proliferating cell nuclear
      antigen (PCNA) and Ki-67 to local control and survival rates for patients with
      oesophageal squamous cell carcinomas treated by definitive radiotherapy (RT) was
      investigated. Biopsy materials before RT were obtained from 65 patients with
      oesophageal cancer. The median PCNA labelling index (LI) and the median Ki-67 LI
      were 52% and 45% respectively. The PCNA LI was independent of known prognostic
      factors on local control for oesophageal cancer, although Ki-67 LI correlated
      with several prognostic factors. In the univariate analysis, patients with the
      PCNA LI of < 52% or the Ki-67 LI of < 45% showed significantly higher local
      recurrence rates than those with higher LIs (both P < 0.05). This difference in
      local control rate according to LIs was prominent for the patients treated with
      conventional fractionation. In the multivariate analysis, T-stage (P = 0.0056)
      and PCNA LI (P = 0.0332) were significant factors for local control in the final
      model using a stepwise regression procedure. In conclusion, PCNA LI and Ki-67 LI
      were significantly correlated with local control probabilities in oesophageal
      squamous cell carcinomas treated by definitive RT.

PMID- 10408844
TI  - Epoetin alpha prevents anaemia and reduces transfusion requirements in patients
      undergoing primarily platinum-based chemotherapy for small cell lung cancer.
AB  - Anaemia commonly occurs in cancer patients receiving chemotherapy, often
      necessitating blood transfusion. This multicentre study was designed to evaluate
      the efficacy and safety of epoetin alpha in preventing the decline in haemoglobin
      (Hb) level, and to determine whether the transfusion requirement could be
      reduced, in patients receiving 4-6 cycles of primarily platinum-based combination
      cyclic chemotherapy for small cell lung cancer (SCLC). A total of 130 non-anaemic
      SCLC patients were randomized to receive no additional treatment (n = 44),
      epoetin alpha 150 IU kg(-1) subcutaneously (s.c.) three times a week (n = 42) or
      300 IU kg(-1) s.c. three times a week (n = 44). Reductions in epoetin alpha
      dosage were made during the study if Hb level increased to >15 g dl(-1). The mean
      weekly dosage was 335 and 612 IU kg(-1), respectively, in the two active
      treatment groups. Significantly fewer (P < 0.05) epoetin alpha-treated patients
      experienced anaemia (Hb < 10 g dl(-1)) during the course of chemotherapy (300 IU
      kg(-1), 39%; 150 IU kg(-1), 48%; untreated, 66%). This was reflected in the
      significantly lower number of treated patients transfused [300 IU kg(-1), 20% (P<
      0.001); 150 IU kg(-1), 45% (P< 0.05); untreated, 59%]. Epoetin alpha was well
      tolerated, and there was no evidence of sustained, clinically significant,
      hypertension. In summary, epoetin alpha is effective and well-tolerated in
      maintaining Hb level and reducing transfusion requirement in patients undergoing
      cyclic chemotherapy for SCLC.

PMID- 10408845
TI  - Conservative treatment followed by chemotherapy with doxorubicin and ifosfamide
      for cervical sarcoma botryoides in young females.
AB  - Sarcoma botryoides of the cervix is an extremely rare tumour and seems to be
      associated with a better prognosis than its vaginal counterpart. Recent studies
      have suggested that it is possible to limit surgery to local excision in stage I
      cases. We report three cases of young subjects treated successfully with
      polypectomy or diathermy loop excision followed by adjuvant chemotherapy. One
      patient had a local recurrence which was treated with further local excision. All
      subjects remain alive without evidence of recurrence and with normal menstrual
      function 36, 38 and 38 months following initial diagnosis. A conservative
      surgical approach to early cervical sarcoma botryoides is possible. The efficacy
      of adjuvant chemotherapy and the regimen of choice still need to be investigated.

PMID- 10408848
TI  - Risk-group discrimination in node-negative breast cancer using invasion and
      proliferation markers: 6-year median follow-up.
AB  - Factors reflecting two major aspects of tumour biology, invasion (urokinase-type
      plasminogen activator (uPA), plasminogen activator inhibiter (PAI-1), cathepsin
      D) and proliferation (S-phase fraction (SPF), Ki-67, p53, HER-2/neu), were
      assessed in 125 node-negative breast cancer patients without adjuvant systemic
      therapy. Median follow-up time was 76 months. Antigen levels of uPA, PAI-1 and
      cathepsin D were immunoenzymatically determined in tumour tissue extracts. SPF
      and ploidy were determined flow-cytometrically, Ki"'-67, p53, and HER-2/neu
      immunohistochemically in adjacent paraffin sections. Their prognostic impact on
      disease-free (DFS) and overall survival (OS) was compared to that of traditional
      factors (tumour size, grading, hormone receptor status). Univariate analysis
      determined PAI-1 (P < 0.001), uPA (P = 0.008), cathepsin D (P = 0.004) and SPF (P
      = 0.023) as significant for DFS. All other factors failed to be of significant
      prognostic value. In a Cox model, only PAI-1 was significant for DFS (P < 0.001,
      relative risk (RR) 6.2). In CART analysis for DFS, the combination of PAI-1 and
      uPA gave the best risk group discrimination. For OS, PAI-1, cathepsin D, tumour
      size and ploidy were statistically significant in univariate, but PAI-1 was the
      only independently significant factor in Cox analysis (P < 0.001, RR 8.9). In
      particular, this analysis shows that PAI-1 is still a strong and independent
      prognostic factor in node-negative breast cancer after extended 6-year median
      follow-up.

PMID- 10408846
TI  - Pretreatment serum markers and lymphocyte response to interleukin-2 therapy.
AB  - Lymphocytosis is a marker of subcutaneous interleukin (IL)-2 therapy efficacy,
      whereas baseline elevated inflammatory indices were noticed in IL-2-resistant
      disease. The aim of this study was to analyse the relationship between
      pretreatment circulating values of IL-6, neopterin, sIL-2R, ESR and the changes
      in lymphocyte number in response to IL-2 administration. Twenty metastatic renal
      cell cancer patients were treated with subcutaneous IL-2 immunotherapy (6 000 000
      IU day(-1) for 6 days per week for 4 weeks); tumour response consisted of partial
      response (PR) in four patients, stable disease (SD) in eight patients and
      progressive disease (PD) in eight patients. Abnormally high pretreatment values
      of each marker were found as follows: IL-6 in seven patients, neopterin in nine
      patients, sIL-2R in 13 patients. In response to IL-2 immunotherapy, a
      significantly higher mean increase in lymphocyte number and a higher percentage
      of patients with tumour response or stable disease were observed when
      pretreatment values of IL-6, neopterin and sIL-2R were within the normal range,
      in comparison to patients with high values for these markers. The pretreatment
      excess of these serum inflammatory markers seems to negatively influence both the
      host and tumour response to IL-2 administration, by preventing the IL-2-induced
      lymphocytosis and resulting in tumour progression. Further studies are requested
      to verify if overall survival and quality of life may depend on pretreatment host
      immune status and/or lymphocyte response after IL-2 administration.

PMID- 10408849
TI  - Improving the letters we write: an exploration of doctor-doctor communication in
      cancer care.
AB  - Referral and reply letters are common means by which doctors exchange information
      pertinent to patient care. Twenty-eight semi-structured interviews were conducted
      exploring the views of oncologists, referring surgeons and general practitioners.
      Twenty-seven categories of information in referral letters and 32 in reply
      letters after a consultation were defined. The letters to and from six medical
      oncologists relating to 20 consecutive new patients were copied, and their
      content analysed. Oncologists, surgeons and general practitioners Australia wide
      were surveyed using questionnaires developed on data obtained above. Only four of
      27 categories of referral information appear regularly (in > 50%) in referral
      letters. Oncologists want most to receive information regarding the patient's
      medical status, the involvement of other doctors, and any special considerations.
      Referring surgeons and family doctors identified delay in receiving the
      consultant's reply letter as of greatest concern, and insufficient detail as
      relatively common problems. Reply letters include more information regarding
      patient history/background than the recipients would like. Referring surgeons and
      family doctors want information regarding the proposed treatment, expected
      outcomes, and any psychosocial concerns, yet these items are often omitted.
      Consultants and referring doctors need to review, and modify their letter writing
      practices.

PMID- 10408847
TI  - Granisetron compared with prednisolone plus metopimazine as anti-emetic
      prophylaxis during multiple cycles of moderately emetogenic chemotherapy.
AB  - This randomized, double-blind, double-dummy parallel study compared the anti
      emetic efficacy and tolerability of the serotonin antagonist granisetron with
      prednisolone plus the dopamine D2 antagonist metopimazine during nine cycles of
      moderately emetogenic chemotherapy. Chemotherapy naive women with stage I or II
      breast cancer scheduled to intravenous cyclophosphamide, fluorouracil and
      methotrexate or cyclophosphamide, epirubicin and fluorouracil every 3 weeks were
      included. Patients received a single intravenous dose of granisetron 3 mg or a 3
      day oral treatment with prednisolone 25 mg once a day plus metopimazine 30 mg
      four times a day. A total of 223 women were enrolled and 218 patients (97.8%)
      were evaluable for efficacy. Granisetron (n = 109) was superior to prednisolone
      plus metopimazine (n = 109) in the prophylaxis of acute nausea and vomiting
      during the first cycle of chemotherapy (P < 0.001) and prednisolone plus
      metopimazine was superior on days 2-5 (P = 0.002). Overall, granisetron was
      superior on days 1-5 (P = 0.009). The median number of cycles completed with
      granisetron was five (95% confidence interval 4-6) compared with two (95%
      confidence interval 2-2) for prednisolone plus metopimazine (P = 0.0019).
      Constipation and rash were reported more frequently with granisetron (P < 0.001
      and P = 0.043 respectively) and palpitations more frequently with prednisolone
      plus metopimazine (P = 0.015). In conclusion, the number of cycles completed with
      granisetron was significantly higher than the number completed with prednisolone
      plus metopimazine, but the anti-emetic efficacy of both treatments declined
      during multiple cycles of moderately emetogenic chemotherapy.

PMID- 10408850
TI  - Phase II study of docetaxel in patients with metastatic pancreatic cancer: a
      Japanese cooperative study. Cooperative Group of Docetaxel for Pancreatic Cancer
      in Japan.
AB  - Docetaxel has been reported to show promising anti-tumour activity in pancreatic
      ductal cancer (PC). This study was conducted to evaluate the activity and
      toxicity of moderate-dose (60 mg m(-2)) docetaxel in Japanese chemo-naive
      patients with measurable metastatic PC. The patients had a performance status of
      0-2. They received docetaxel intravenously over a 1- to 2-h period without any
      premedication for hypersensitivity reactions. This treatment was repeated every 3
      4 weeks with dose adjustments based on the toxic effects observed. Twenty-one
      patients were eligible and treated with docetaxel. The median number of courses
      was 2 (range, 1-4). None of the patients achieved an objective response; seven
      showed no change and 13 showed progressive disease. In one patient, the response
      was not assessable because of early death. The median survival time for all
      patients was 118 days. The main grade 3-4 toxicities by patient were
      leucocytopenia (67%) and neutropenia (86%). Other grade 3-4 toxicities included
      anaemia (10%), thrombocytopenia (5%), nausea/vomiting (29%), anorexia (29%),
      GOT/GPT increase (10%), alkaline phosphatase increase (14%), malaise/fatigue
      (33%) and alopecia (24%). In conclusion, docetaxel, administered on this
      schedule, did not show significant anti-tumour activity in patients with
      metastatic PC.

PMID- 10408851
TI  - An audit of primary surgical treatment for women with ovarian cancer referred to
      a cancer centre.
AB  - Ovarian cancer is the commonest cause of gynaecological cancer death in the UK,
      and guidelines for initial surgery and staging of this disease are widely
      available. We report a retrospective audit of the surgical management of patients
      with newly diagnosed ovarian cancer referred to the Christie Cancer Centre in
      Manchester in 1996. The aim was to assess compliance with surgical guidelines.
      The authors found that the majority of patients (92%) presented via an outpatient
      clinic and for these individuals surgery was therefore elective. This mode of
      presentation should allow management by a small number of dedicated
      gynaecologists at each hospital, but up to seven consultants in each hospital
      performed surgery on a relatively small number of patients. Furthermore, less
      than half the patients underwent the recommended surgical procedure. Although
      some patients may have 'inoperable' disease, these data suggest that a greater
      compliance with national and international guidelines are required to provide an
      optimal level of care.

PMID- 10408852
TI  - Haematogenous cytokeratin 20 mRNA as a predictive marker for recurrence in oral
      cancer patients.
AB  - We examined the expression of cytokeratin 20 (CK20) mRNA in the peripheral blood
      of oral squamous cell carcinoma (SCC) patients by reverse transcriptase
      polymerase chain reaction (RT-PCR). Eleven out of 12 oral SCC patients showed
      positive RT-PCR results. However, there is no clear relationship between the
      haematogenous CK20 mRNA and the metastasis. After initial treatment, all of the
      tumour-free survivors tested showed negative RT-PCR results. CK20 mRNA in
      peripheral blood can be used as a marker for tumour recurrence but not not for
      metastasis in oral SCC patients.

PMID- 10408853
TI  - Associations among telomerase activity, p53 protein overexpression, and genetic
      instability in lung cancer.
AB  - Genomic instability is a driving force for tumorigenesis. p53 and telomerase play
      central roles in maintaining genomic integrity. The purpose of this study was to
      assess the associations among p53 protein overexpression, telomerase activity and
      genetic instability in lung cancer. We found that telomerase activity was
      detectable in 80% of 100 lung tumours, but only 7.7% of 91 paired adjacent normal
      tissues. p53 protein was overexpressed in 63% of the tumours but only 2% of the
      normal tissues. p53 was overexpressed in 56 of the 80 (70%) tumour tissues with
      telomerase activity but only seven of the 20 (35%) without telomerase activity.
      p53 protein overexpression carried a 6.7-fold (95% confidence interval, 1.7-27.7)
      increased risk for positive telomerase activity after adjustment by age, sex,
      ethnicity, smoking status and family history of lung cancer. The mean in vitro
      bleomycin-induced breaks per cell (a marker of cancer susceptibility) was
      significantly higher (0.92) for patients who overexpressed p53 in lung tumour
      tissue than that for patients with no detectable p53 expression in lung tumour
      tissue (0.65). Our data suggest that p53 protein overexpression may be common in
      individuals genetically susceptible to carcinogen exposure. p53 status may be
      related to telomerase expression.

PMID- 10408854
TI  - Alteration of p16 and p15 genes in human uterine tumours.
AB  - The roles of the p16 and p15 inhibitor of cyclin-dependent kinase tumour
      suppressor genes were examined in human uterine cervical and endometrial cancers.
      p16 mRNA, examined by reverse transcription polymerase chain reaction (RT-PCR),
      was significantly reduced in five of 19 (26%) cervical and four of 25 (16%)
      endometrial tumours. Reduced expression of p16 protein, detected by
      immunohistochemistry, occurred even more frequently, in nine of 33 (27%) cervical
      and seven of 37 (19%) endometrial tumours. Hypermethylation of a site within the
      5'-CpG island of the p16 gene was detected in only one of 32 (3%) cervical
      tumours and none of 26 endometrial tumours. Homozygous p16 gene deletion,
      evaluated by differential PCR analysis, was found in four of 40 (10%) cervical
      tumours and one of 38 (3%) endometrial tumours. Homozygous deletion of p15 was
      found in three of 40 (8%) cervical tumours and one of 38 (3%) endometrial
      tumours. PCR-SSCP (single-strand conformation polymorphism) analysis detected
      point mutations in the p16 gene in six (8%) of 78 uterine tumours (four of 40
      (10%) cervical tumours and two of 38 (5%) endometrial tumours). Three were mis
      sense mutations, one in codon 74 (CTG-->ATG) and one in codon 129 (ACC-->ATC),
      both in cervical carcinomas, and the other was in codon 127 (GGG-->GAG) in an
      endometrial carcinoma. There was one non-sense mutation, in codon 50 (CGA-->TGA),
      in an endometrial carcinoma. The remaining two were silent somatic cell
      mutations, both in cervical carcinomas, resulting in no amino acid change. These
      observations suggest that inactivation of the p16 gene, either by homologous
      deletion, mutation or loss of expression, occurs in a subset of uterine tumours.

PMID- 10408855
TI  - Loss of heterozygosity and microsatellite instability in hepatocellular carcinoma
      in Taiwan.
AB  - Elucidation of the basic genetic changes of human hepatocellular carcinoma is
      important for the understanding and treatment of this cancer. We used
      microsatellite polymorphism markers to study 30 cases of hepatocellular carcinoma
      (34 tumours) on all human chromosomes. DNA from 34 pairs of hepatocellular
      carcinomas and corresponding non-tumour parts was prepared. Loss of
      heterozygosity (LOH) and microsatellite instability on 23 chromosomes were
      investigated by 231 sets of microsatellite markers. More than 20% LOH was shown
      for loci on 16q (47.1%), 13q (32.4%), 17p (32.4%), 5q (26.5%), 11p (23.5%) and 9p
      (20.6%). The commonly affected regions were mapped to 16q12.1, 16q12.2, 16q24,
      13q12.1-32, 17p13, 5q32, 5q34, 5q3, 11p15, 11q23-24 and 9p21. Hepatitis B virus
      carriers had a significantly higher frequency of LOH on chromosomes 5q, 11p and
      16q. Furthermore, larger tumour size tended to have higher frequency of LOH at
      D16S409 locus (16q12.1). Microsatellte instability was only found in 12 of 231
      markers and the frequency is very low. These data suggest that the chromosomes
      16q, 13q, 17p, 5q, 11p and 9p might participate in hepatocarcinogenesis. However,
      microsatellite instability might play little role in the development of this
      cancer in Taiwan.

PMID- 10408856
TI  - Alpha-catenin expression has prognostic value in local and locally advanced
      prostate cancer.
AB  - Normally functioning cell-cell adhesion plays an important role in the
      maintenance of tissue architecture and cell cohesion. E-cadherin is an important
      adhesion molecule of epithelial cells. In many types of cancer the expression of
      E-cadherin is reduced leading to increased risk of disease progression. alpha
      Catenin is one of the intracellular elements of the E-cadherin-catenin complex.
      The abnormalities in the expression of alpha-catenin seem to associate with
      malignant cellular features and disease progression in prostate cancer. To
      further analyse the significance of alpha-catenin expression, we studied 215
      cases of prostate cancer by immunohistochemistry and the results were related to
      other known prognostic factors and patient survival during a mean follow-up
      period of 13 years. alpha-Catenin expression was down-regulated in 19% of the
      cases and 3% of the tumours were totally alpha-catenin-negative. The abnormal
      alpha-catenin expression and cytoplasmic signal were significantly linked with
      high T-category, metastatic disease, high Gleason score, perineural growth, high
      mitotic rate, high S phase fraction and DNA aneuploidy (P < 0.05 for all). In the
      survival analysis, reduced alpha-catenin expression (P = 0.06) and cytoplasmic
      signal (P = 0.04) were related to unfavourable patient outcome. In the
      multivariate analysis, including TM-classification and Gleason score, alpha
      catenin expression had independent prognostic value in T1-2 M0 tumors. In the M0
      tumours, abnormal alpha-catenin signal was independently associated with
      recurrence-free survival as well. The results indicate that down-regulation of
      alpha-catenin is related to several malignant cellular features, and it seems to
      have prognostic significance in the early phases of cancer progression. We
      suggest that alpha-catenin expression can provide prognostic information in early
      prostate cancer.

PMID- 10408857
TI  - Serum anti-p53 antibodies in gastric adenocarcinoma patients are associated with
      poor prognosis, lymph node metastasis and poorly differentiated nuclear grade.
AB  - Mutation of the p53 tumour suppressor gene often leads to the accumulation of
      mutant p53 protein in tumour cells. Many cancer patients develop antibodies that
      recognize the overexpressed p53 protein. The presence of these antibodies is, in
      some tumour types, associated with poor prognosis. Gastric cancer is a highly
      prevalent disease associated with a high rate of mortality, there is a need for
      improved clinical and biological markers for disease behaviour. To investigate
      the clinical relevance of serum anti-p53 antibodies in patients with gastric
      adenocarcinoma, we have examined the sera of 501 gastric cancer patients for the
      presence of serum antibodies against the p53 protein. By immunoblotting analysis
      using a cell lysate containing overexpressed p53 protein as well as affinity
      purified recombinant p53 protein as antigens, we have detected anti-p53
      antibodies in 11.2% (61 of 501) of gastric cancer patients, but in none of 46
      cancer-free individuals. The presence of anti-p53 antibodies was tightly
      associated with tumours of higher nuclear grade and lymph node metastasis, and a
      negative association was found between the presence of anti-p53 antibodies and
      survival. These results suggest that a preoperative test of serum anti-p53
      antibodies in gastric cancer patients can be useful to identify subset of
      patients who may need gastrectomy with lymph node dissection and post-operative
      adjuvant therapy.

PMID- 10408858
TI  - Evidence for two candidate tumour suppressor loci on chromosome 9q in
      transitional cell carcinoma (TCC) of the bladder but no homozygous deletions in
      bladder tumour cell lines.
AB  - The most frequent genetic alterations in transitional cell carcinoma (TCC) of the
      bladder involve loss of heterozygosity (LOH) on chromosome 9p and 9q. The LOH on
      chromosome 9p most likely targets the CDKN2 locus, which is inactivated in about
      50% of TCCs. Candidate genes that are the target for LOH on chromosome 9q have
      yet to be identified. To narrow the localization of one or more putative tumour
      suppressor genes on this chromosome that play a role in TCC of the bladder, we
      examined 59 tumours with a panel of microsatellite markers along the chromosome.
      LOH was observed in 26 (44%) tumours. We present evidence for two different loci
      on the long arm of chromosome 9 where potential tumour suppressor genes are
      expected. These loci are delineated by interstitial deletions in two bladder
      tumours. Our results confirm the results of others and contribute to a further
      reduction of the size of these regions, which we called TCC1 and TCC2. These
      regions were examined for homozygous deletions with EST and STS markers. No
      homozygous deletions were observed in 17 different bladder tumour cell lines.

PMID- 10408859
TI  - Quantitation of TIMP-1 in plasma of healthy blood donors and patients with
      advanced cancer.
AB  - A kinetic enzyme-linked immunosorbent assay (ELISA) for plasma tissue inhibitor
      of metalloproteinase (TIMP)-1 was developed in order to examine the potential
      diagnostic and prognostic value of TIMP-1 measurements in cancer patients. The
      ELISA enabled specific detection of total TIMP-1 in EDTA, citrate and heparin
      plasma. The assay was rigorously tested and requirements of sensitivity,
      specificity, stability and good recovery were fulfilled. TIMP-1 levels measured
      in citrate plasma (mean 69.2+/-13.1 microg I(-1)) correlated with TIMP-1 measured
      in EDTA plasma (mean 73.5+/-14.2 microg I(-1)) from the same individuals in a set
      of 100 healthy blood donors (Spearman's rho = 0.62, P< 0.0001). The mean level of
      TIMP-1 in EDTA plasma from 143 patients with Dukes' stage D colorectal cancer was
      240+/-145 microg I(-1) and a Mann-Whitney test demonstrated a highly significant
      difference between TIMP-1 levels in healthy blood donors and colorectal cancer
      patients (P < 0.0001). Similar findings were obtained for 19 patients with
      advanced breast cancer (mean 292+/-331 microg I(-1)). The results show that TIMP
      1 is readily measured in plasma samples by ELISA and that increased levels of
      TIMP-1 are found in patients with advanced cancer. It is proposed that plasma
      measurements of TIMP-1 may have value in the management of cancer patients.

PMID- 10408860
TI  - 'Proteolytic switching': opposite patterns of regulation of gelatinase B and its
      inhibitor TIMP-1 during human melanoma progression and consequences of gelatinase
      B overexpression.
AB  - Although it is generally accepted that proteolytic degradation is an important
      mechanism used by malignant cells in the process of metastasis, comparatively
      little is known about the regulation of molecules responsible for proteolysis and
      how they become de-regulated during human tumour progression. Using a genetically
      related pair of human melanoma cell lines, derived from the same patient at
      different stages of disease, we analysed differences in the cytokine-mediated
      regulation of gelatinase B (MMP-9), an enzyme thought to play an important role
      in cellular invasiveness, and TIMP-1, a physiological inhibitor of this enzyme.
      Whereas the advanced stage (i.e. metastatic) partner of this pair (WM 239) could
      produce gelatinase B upon induction with interleukin (IL)-1beta or tumour
      necrosis factor alpha (TNF-alpha), the early stage (i.e. primary) partner (WM
      115) could not. In sharp contrast, we found that TIMP-1 displayed an opposite
      pattern of induction in these cell lines. Specifically, the early stage cell
      line, WM 115, demonstrated a marked increase in the production of TIMP-1 when
      treated with IL-1beta or TNF-alpha whereas the advanced cell line, WM 239, showed
      no such increase. Treatment with the DNA demethylating agent, 2-deoxy-5
      azacytidine, resulted in a marked up-regulation of both gelatinase B and TIMP-1
      in both cell lines. It was further found that constitutive overexpression of
      gelatinase B in WM 239 cells and an additional melanoma cell line (MeWo), derived
      from a metastatic lesion, was able to greatly enhance lung colonization in an
      experimental metastasis assay while we did not observe differences in
      tumorigenicity. From these results we conclude that an altered responsiveness of
      gelatinase B and TIMP-1 to induction by similar agents is associated with disease
      progression in human melanoma and that this altered responsiveness can have
      consequences to the aggressive nature of the disease.

PMID- 10408862
TI  - c-erbB2/neu gene and chromosome 17 analysis in breast cancer by FISH on archival
      cytological fine-needle aspirates.
AB  - The detection of specific genetic alterations in breast cancer is useful for
      diagnosing, predicting prognosis and planning preoperative treatment. c-erbB2/neu
      overexpression is usually detected by immunocytochemistry (ICC), although this
      technique is neither completely reproducible nor highly reliable, owing to
      specimen and methodologic variability and antibody sensitivity. Here, we combine
      two well-established techniques, fine-needle aspiration (FNA) and fluorescence in
      situ hybridization (FISH), to detect c-erbB2/neu amplification in patients
      candidate to primary chemotherapy and, in part, previously analysed for c
      erbB2/neu overexpression. Sixty smears from FNA were used to simultaneously
      detect c-erbB2/neu and chromosome 17 centromere. FISH was successful in 58 cases
      and detected 24 amplified cases, three of which were negative by
      immunophenotyping, 28 negative cases, with evidence of two normal c
      erbB2/neu/signals, two cases with deletion of c-erbB2/neu, and four cases with
      polysomy, thus providing more reliable and informative results than ICC. This
      study underlines the advantages offered by the FNA and FISH combination which are
      two rapid, reliable, simple and informative techniques, to analyse one of the
      most important genetic markers for predicting prognosis and chemotherapy planning
      for breast carcinoma in particular in the light of the recently proposed trials
      of primary chemotherapy.

PMID- 10408861
TI  - Uncoupling of fatty acid and glucose metabolism in malignant lymphoma: a PET
      study.
AB  - Increased use of glucose through glycolysis is characteristic for neoplastic
      growth while the significance of serum-free fatty acids for regulation of energy
      metabolism in cancer is poorly understood. We studied whether serum-free fatty
      acids (FFA) interfere with glycolytic metabolism of lymphoproliferative neoplasms
      as assessed with 2-F18-fluoro-2-deoxy-D-glucose ([F18]FDG) and positron emission
      tomography (PET). Twelve patients with newly diagnosed non-Hodgkin's lymphoma (n
      = 9) or Hodgkin's disease (n = 3) participated in this study before start of
      oncologic treatment. Each patient underwent two [F18]FDG PET studies within 1
      week after overnight fast: once during high fasting serum FFA concentrations and
      once after reduction of serum FFA by administration of acipimox. Acipimox is a
      nicotinic acid derivative that inhibits lipolysis in peripheral tissues and
      induces a striking reduction in circulating FFA concentration. In all cases,
      dynamic PET imaging over the tumour area was performed for 60 min after injection
      of [F18]FDG. Both graphical analysis (rMR(FDG)) and single scan approach (SUV)
      were used to compare tumour uptake of [F18]FDG under high fasting FFA
      concentrations and after pharmacologically decreased FFA concentrations. Serum
      FFA concentrations were reduced significantly from 0.92+/-0.42 mmol I(-1)at
      baseline to 0.26+/-0.31 mmol I(-1) after acipimox administration (P = 0.0003).
      Plasma glucose, serum insulin and lactate concentrations were similar during both
      approaches. The retention of glucose analogue [F18]FDG in tumour was similar
      between baseline and acipimox studies. Median rMR(FDG) of a total of 12 involved
      lymph nodes in 12 patients was 21.9 micromol 100 g(-1) min(-1) (range 8.7-82.5)
      at baseline and 20.1 micromol 100 g(-1) min(-1)(range 10.7-81.7) after acipimox.
      The respective values for median SUV were 7.8 (range 3.6-18.6) and 6.0 (range 4.1
      20.2). As expected, [F18]FDG uptake in myocardium was clearly enhanced by
      acipimox due to reduction of circulating FFAs. In conclusion, blood fatty acids
      appear to have minor significance for [F18]FDG uptake in lymphoma. This suggests
      that glucose utilization is uncoupled of FFA metabolism and indicates that
      glucose-free fatty acid cycle does not operate in lymphomatous tissue. Glucose
      appears to be the preferred substrate for energy metabolism in tumours, in spite
      of the high supply of FFAs in the fasting state. Although acipimox and other anti
      lipolytic drugs have potential for treatment of catabolic state induced by
      cancer, they are not likely to interfere with tumour energy metabolism which is
      fuelled by glucose.

PMID- 10408863
TI  - Chromosomal gains and losses in primary colorectal carcinomas detected by CGH and
      their associations with tumour DNA ploidy, genotypes and phenotypes.
AB  - Comparative genomic hybridization (CGH) is used to detect amplified and/or
      deleted chromosomal regions in tumours by mapping their locations on normal
      metaphase chromosomes. Forty-five sporadic colorectal carcinomas were screened
      for chromosomal aberrations using direct CGH. The median number of chromosomal
      aberrations per tumour was 7.0 (range 0-19). Gains of 20q (67%) and losses of 18q
      (49%) were the most frequent aberrations. Other recurrent gains of 5p, 6p, 7, 8q,
      13q, 17q, 19, X and losses of 1p, 3p, 4, 5q. 6q, 8p, 9p, 10, 15q, 17p were found
      in > 10% of colorectal tumours. High-level gains (ratio > 1.5) were seen only on
      8q, 13q, 20 and X, and only in DNA aneuploid tumours. DNA aneuploid tumours had
      significantly more chromosomal aberrations (median number per tumour of 9.0)
      compared to diploid tumours (median of 1.0) (P < 0.0001). The median numbers of
      aberrations seen in DNA hyperdiploid and highly aneuploid tumours were not
      significantly different (8.5 and 11.0 respectively; P = 0.58). Four tumours had
      no detectable chromosomal aberrations and these were DNA diploid. A higher
      percentage of tumours from male patients showed Xq gain and 18q loss compared to
      tumours from female patients (P = 0.05 and 0.01 respectively). High tumour S
      phase fractions were associated with gain of 20q13 (P = 0.03), and low tumour
      apoptotic indices were associated with loss of 4q (P = 0.05). Tumours with TP53
      mutations had more aberrations (median of 9.0 per tumour) compared to those
      without (median of 2.0) (P = 0.002), and gain of 8q23-24 and loss of 18qcen-21
      were significantly associated with TP53 mutations (P = 0.04 and 0.02
      respectively). Dukes' C/D stage tumours tended to have a higher number of
      aberrations per tumour (median of 10.0) compared to Dukes' B tumours (median of
      3.0) (P = 0.06). The low number of aberrations observed in DNA diploid tumours
      compared to aneuploid tumours suggests that genomic instability and possible
      growth advantages in diploid tumours do not result from acquisition of gross
      chromosomal aberrations but rather from selection for other types of mutations.
      Our study is consistent with the idea that these two groups of tumours evolve
      along separate genetic pathways and that gross genomic instability is associated
      with TP53 gene aberrations.

PMID- 10408864
TI  - Prognostic value of uPA and p53 accumulation measured by quantitative biochemical
      assays in 1245 primary breast cancer patients: a multicentre study.
AB  - The purpose of this retrospective multicentre study was to assess the prognostic
      value of urokinase plasminogen activator (uPA) and p53 levels in a large series
      of primary breast cancer, using an automatic quantitative luminometric method.
      Samples of 1245 operable breast tumours were collected from seven French
      institutions and patients were followed for a median of 75 months. The median uPA
      and p53 levels assayed in cytosols by means of the immunoluminometric technique
      (LIA) were 0.31 and 0.20 ng mg(-1) of protein respectively. In univariate
      analysis, high levels of uPA and p53 were associated with shorter disease
      specific survival, disease-free interval, and distant recurrence-free interval.
      The 5-year survival rates were 95.5% among patients with uPA values below the
      20th percentile, and 77.5% in those with values above the 80th percentile. The 5
      year survival rates were 91.0% in patients with p53 values below the 20th
      percentile, and 77.6% in those with values above the 80th percentile. In
      multivariate analysis, the risk of disease-related death increased with uPA
      levels after adjustment for tumour size, histological grade, lymph node
      involvement, and estrogen receptor status. A high level of uPA was also related
      to a shorter disease-free interval and distant recurrence-free interval. In node
      negative patients, a high level of uPA remained strongly related to the three
      outcomes. When adjusted for other prognostic factors, p53 was no longer
      significantly related to the outcomes. Given its rapidity and simple application
      to routinely prepared cytosols, this LIA may be useful for evaluating the
      prognostic impact of uPA in primary breast cancer, particularly in node-negative
      patients. According to our results, the prognostic value of p53 accumulation is
      limited when uPA is included in multivariate analysis.

PMID- 10408865
TI  - Proliferation- and apoptosis-associated factors in advanced prostatic carcinomas
      before and after androgen deprivation therapy: prognostic significance of
      p21/WAF1/CIP1 expression.
AB  - The molecular mechanisms leading to androgen-independent growth in prostate
      cancer (PC) are poorly understood. Androgen deprivation therapy (ADT) results
      physiologically in a decrease in proliferation and an increase in programmed cell
      death (PCD)/apoptosis. The aim of our study was to get more insight into these
      processes in prostatic carcinomas before and after ADT. For this purpose,
      immunohistologic staining for the androgen receptor (AR) molecule, the Ki-67
      antigen, the bcl-2 oncoprotein, the p53 protein and its physiologic effector,
      p21/WAF1, was performed on archival material. PCD was visualized by enzymatic
      detection of DNA fragmentation. Specimens from 69 PC patients after ADT were
      studied in correlation to histopathology and prognosis. In 42 cases,
      corresponding tumour tissue from the untreated primary tumours could be analysed
      comparatively. Before ADT, histologic grade was associated with Ki-67 index (P <
      0.0001, Spearman correlation) and PCD rate (P < 0.05, Spearman correlation). Ki
      67 index correlated with PCD rate (P < 0.05, Spearman correlation) and p21/WAF1
      expression (P < 0.01, Fisher's exact test). p21/WAF1 expression was the only
      statistically significant prognostic factor for shorter survival (P < 0.002, log
      rank test). All p21/WAF1-positive cases showed high Ki-67 index and high
      histologic grade. After ADT, loss of AR expression was associated with high Ki-67
      index, whereas histologic signs of regression correlated negatively with Ki-67
      index (P < 0.001, Pearson chi2 test). p21/WAF1 expression increased significantly
      (P < 0.02, McNemar test) and correlated with p53 accumulation (P < 0.0001,
      Pearson chi2 test). Most significant prognostic parameter after conventional ADT
      was high-rate p21/WAF1 expression (> 50% of tumour cells; P < 0.00001, log-rank
      test). This study demonstrates that p21/WAF1 overexpression before and after ADT
      characterizes a subgroup of advanced PC with paradoxically high proliferation
      rate and significantly worse clinical outcome. This finding might be clinically
      useful for planning therapy in these patients.

PMID- 10408866
TI  - Chromosome band 16q24 is frequently deleted in human gastric cancer.
AB  - We have analysed the loss of heterozygosity (LOH) on chromosome bands 16q22-q24
      in 24 primary gastric cancer tissues and found three regions of frequent allelic
      loss (16q22, 16q24.1-q24.3 and 16q24.3). The region for the most frequent allelic
      loss (63%) was in 16q24.1-q24.3. LOH of this region had no relationship with
      histological subtype, but a significant association between LOH and microscopic
      lymphangial invasion was observed. Although not significant, vascular and gastric
      wall invasions are also associated with LOH. The region includes the locus for
      the H-cadherin gene. Therefore we examined the genetic and epigenetic alterations
      of this gene. Markedly reduced expression was observed in gastric cancer cell
      lines compared with that of normal gastric mucosa. However, no mutation was found
      in this gene in any of the gastric cancer tissues or the gastric cancer cell
      lines. Furthermore, we analysed the methylation status of the 5'-flanking region
      of the gene, but no significant association was found. We suggest that some other
      tumour suppressor gene(s) in 16q24.1-q24.3 may be responsible for gastric
      carcinogenesis.

PMID- 10408867
TI  - An audit of breast cancer pathology reporting in Australia in 1995.
AB  - To measure the quality of pathology reporting of breast cancer and establish a
      baseline against which future changes can be measured, we audited item
      completeness in breast cancer reports in Australia in 1995 before the release of
      specific recommendations from the Australian Cancer Network. Tumour type and size
      were given in reports of invasive breast cancer for 93% of women, 70% had, in
      addition, grade and clearance of the margins while only 28% had all recommended
      information. The most complete items in reports were histological type of breast
      cancer (99.6% of cases), tumour size (94%, 95% confidence interval (CI) 92-95)
      and margins of excision (87%, 95% CI 85-89). Histological grade (84%, 95% CI 82
      86 of cases) and presence or absence of ductal carcinoma in situ (DCIS) (79%, 95%
      CI 77-81) were less complete and vessel invasion (61%, 95% CI 58-63) and changes
      in non-neoplastic breast tissue adjacent to the breast cancer (68%, 95% CI 66-71)
      the least complete. Less than half the reports of DCIS reported on tumour size
      (49%, 95% CI 42-57), presence or absence of necrosis (41%, 95% CI 34-49) or
      nuclear grade (39%, 95% CI 31-46). Around 1500 reports were identified as issued
      by 147 laboratories and 392 pathologists; 69% of pathologists issued fewer than
      two reports a month in the audit. We concluded that infrequency of reporting may
      have contributed to incompleteness of reporting. In addition, we found
      significant variation across Australian states with some indication that
      reporting was consistently poor in one state. The audit highlighted areas for
      improvement for breast cancer reporting in Australia. Research evidence suggests
      that multifaceted strategies are needed to assist practitioners with implementing
      more uniform reporting standards.

PMID- 10408868
TI  - Characterization and distribution of an oncofetal antigen (M2A antigen) expressed
      on testicular germ cell tumours.
AB  - M2A antigen is an oncofetal antigen associated with germ cell neoplasia, present
      in testis on fetal gonocytes and re-expressed on carcinoma in situ (CIS) and germ
      cell tumours. We developed a panel of monoclonal antibodies (mAb), M2A (IgG2a),
      D1-26 (IgG2b) and D2-40 (IgG1), to this antigen in order to characterize its
      structure and study its distribution among germ cell tumours. M2A antigen was
      purified by sequential lectin and antibody affinity chromatography and
      characterized as a monomeric M, 40 000 surface sialoglycoprotein, extensively
      glycosylated with O-linked carbohydrate structures, but devoid of N-linked
      sugars. Terminal sialic acid residues were required for reactivity with mAb M2A
      and D1-26, but not D2-40. Sections of 69 testicular germ cell tumours, fixed in
      formalin and embedded in paraffin, were stained with mAb D2-40 to examine the
      distribution of M2A antigen. Uniform membrane staining was observed in seminomas,
      and focal staining in 69% of embryonal carcinomas, 29% of teratomas and 25% of
      yolk sac tumours. CIS in the vicinity of all germ cell tumours also displayed
      uniform membrane staining. The characterization of M2A antigen, and the
      development of mAb which react with it in conventionally preserved archival
      specimens, provide important initiatives to study the origin and progression of
      germ cell neoplasia.

PMID- 10408869
TI  - Expression of interleukin 6 (IL-6) correlates with oestrogen receptor in human
      breast carcinoma.
AB  - Multifunctional cytokines play important and only partially defined roles in
      mammary tumour development and progression. Normal human mammary epithelial cells
      constitutively produce interleukin 6 (IL-6), IL-8 and a non-secreted form of
      tumour necrosis factor. Transformation of mammary epithelial cells by different
      oncogenes is frequently associated with alterations of cytokine/growth factor
      production and responsiveness. In the present study we analysed the expression of
      IL-6 in 149 cases of invasive breast carcinoma and the data have been correlated
      with clinico-pathological variables including tumour size, histological grade,
      nodal status, and oestrogen and progesterone receptors, Ki67 and p53, protein
      expression. Though the majority of breast carcinomas expressed at least low
      levels of immunoreactive IL-6, we found that expression of this cytokine was
      inversely associated with histological tumour grade (P = 0.0017), but not with
      tumour size and nodal status. Ki67 positivity was inversely correlated with IL-6
      expression (P = 0.027). Among biological parameters analysed, a direct
      association was found between the percentage of IL-6-positive cells and that of
      oestrogen (P = 0.00005) and progesterone (P = 0.025) receptor-positive cells. No
      correlation was observed between IL-6 and p53 protein expression. These data
      indicate that down-regulation of IL-6 is associated with highly malignant mammary
      carcinomas. It will be of interest to evaluate whether alterations of cytokines
      that are constitutively produced by mammary cells are also associated with high
      grade tumours.

PMID- 10408871
TI  - Foods, nutrients and prostate cancer: a case-control study in Uruguay.
AB  - A case-control study of diet and prostate cancer was conducted in Montevideo,
      Uruguay involving 175 cases and 233 controls. When the highest quartile of intake
      was compared with the lowest, positive findings were obtained for red meat intake
      (OR 2.0, 95% CI 1.1-3.8), desserts (OR 1.8, 95% CI 0.9-3.3), total energy (OR
      1.9, 95% CI 1.0-3.4) and total fat intake (OR 1.8, 95% CI 0.9-3.4). On the other
      hand, vegetables and fruits (OR 0.5, 95% CI 0.3-0.9), vitamin C (OR 0.4, 95% 0.2
      0.8) and vitamin E (OR 0.6, 95% CI 0.3-1.1) were associated with reduced risks of
      prostate cancer. Possible mechanisms are discussed.

PMID- 10408870
TI  - Association of childhood leukaemia with factors related to the immune system.
AB  - The childhood peak of common acute lymphoblastic leukaemia has been proposed as
      being a rare response to delayed exposure to a common infection. In this context,
      factors related to the child's immune system are of special interest. Information
      on such factors was obtained in a recent German case-control study comprising
      more than 1000 children with acute leukaemia. Neither being the first-born child,
      nor a short duration of breastfeeding, indicators of a deficit in viral contacts
      during infancy or the number of infectious diseases, were significant risk
      factors. We observed a strong association with fewer routine immunizations with a
      3.2-fold increase for those children getting less than four immunizations, but
      this association could partly be explained by reporting bias. While tonsillectomy
      or appendectomy increased the risk of leukaemia in our studies, a protective
      effect of allergies could be seen. In summary, we found only weak support for the
      delayed exposure hypothesis. To some extent this may be due to the chosen
      surrogate markers which reflect, rather indirectly, immunological isolation in
      infancy and delayed exposure to common viruses. However, the significant findings
      for routine immunizations, tonsillectomy and allergies of the child or its
      parents merit further investigation.

PMID- 10408873
TI  - Effect of material deprivation on Epstein-Barr virus infection in Hodgkin's
      disease in the West Midlands.
AB  - We have used Townsend scores from postcode data to compare levels of material
      deprivation and Epstein-Barr virus (EBV)-positivity for 223 patients diagnosed
      with Hodgkin's disease (HD) in the period 1981-1997. The presence of EBV in HD
      tumours was determined using in situ hybridization to target the abundantly
      expressed EBV early RNAs. EBV was detected in the malignant Hodgkin and Reed
      Sternberg cells in 47/223 HD cases (21%). There was found to be a tendency for
      higher Townsend scores (indicative of higher levels of material deprivation) in
      EBV-positive HD patients, but this association was not statistically significant.
      When various subgroups of patients from the study were examined separately the
      indication of higher Townsend scores in EBV-positive patients was found to be
      more marked for patients with mixed cellularity disease (P = 0.09) and for
      females (P = 0.03). The results of this study suggest that differences in the
      level of material deprivation are important in determining the likelihood of EBV
      positive HD in the UK, particularly for certain subgroups of patients. It is not
      known what specific socioeconomic factors are responsible for these differences,
      although alterations in the timing or rate of primary EBV infection, or decline
      in the level of EBV-specific immunity, may be important.

PMID- 10408872
TI  - Cytochrome P450 1A1 genetic polymorphisms and risk of hepatocellular carcinoma
      among chronic hepatitis B carriers.
AB  - Cigarette smoking has been associated with increased risk of hepatocellular
      carcinoma (HCC) in some epidemiological studies. Cytochrome P450 1A1 (CYP1A1) is
      involved in the biotransformation of tobacco-derived polycyclic aromatic
      hydrocarbons (PAHs) into carcinogenic metabolites. The aim of this study was to
      determine whether CYP1A1 polymorphisms were related to HCC risk among chronic
      hepatitis B virus (HBV) carriers. Genotypic variants of CYP1A1 were determined
      using polymerase chain reaction in 81 incident cases of HCC and 409 controls
      nested in a cohort study of 4841 male chronic HBV carriers. No overall
      association between CYP1A1 genotypes and HCC was observed. The presence of the
      Mspl (odds ratio (OR) 3.15, P = 0.0196) or Ile-Val (OR 1.99, P = 0.0855) variant
      allele of CYP1A1 increased HCC risk among smokers, but posed no increased risk
      among non-smokers. The smoking-related HCC risk was most pronounced among those
      who had a susceptible allele of the CYP1A1 and a deficient genotype of
      glutathione S-transferase M1, which detoxifies PAH electrophilic metabolites
      produced by CYP1A1. In the absence of the Ile-Val variant allele, the Mspl
      polymorphism was still associated with smoking-related HCC. This study suggests
      that tobacco-derived PAHs play a role in HCC risk among chronic HBV carriers, and
      CYP1A1 polymorphism is an important modulator of the hepatocarcinogenic effect of
      PAHs. The Mspl and Ile-Val polymorphisms of CYP1A1 may have different mechanisms
      for increasing susceptibility to smoking-related HCC.

PMID- 10408874
TI  - Preterm delivery and risk of breast cancer.
AB  - To explore the risk of breast cancer in relation to the length of a pregnancy we
      tested whether a preterm delivery carries a higher risk of breast cancer than
      does a full-term delivery. Based on information from the Civil Registration
      System, and the National Birth Registry in Denmark, we established a population
      based cohort of 474 156 women born since April 1935, with vital status and
      detailed parity information, including the gestational age of liveborn children
      and stillbirths. Information on spontaneous and induced abortions was obtained
      from the National Hospital Discharge Registry and the National Registry of
      Induced Abortions. Incident cases of breast cancer in the cohort (n = 1363) were
      identified through linkage with the Danish Cancer Registry. The period at risk
      started in 1978 and continued until a breast cancer diagnosis, death, emigration,
      or 31 December, 1992, whichever occurred first. After adjusting for attained age,
      parity, age at first birth and calendar period, we observed the following
      relative risks of breast cancer for different lengths of the pregnancy: < 29
      gestational weeks = 2.11 (95% confidence interval 1.00-4.45); 29-31 weeks = 2.08
      (1.20-3.60); 32-33 weeks = 1.12 (0.62-2.04); 34-35 weeks = 1.08 (0.71-1.66); 36
      37 weeks = 1.04 (0.83-1.32); 38-39 weeks = 1.02 (0.89-1.17); 40 weeks = 1
      (reference). Parous women who had a preterm delivery below 32 weeks gestation had
      a 1.72-fold (1.14-2.59) increased risk of breast cancer compared with other
      parous women. In conclusion, a preterm delivery of 32+ weeks gestation did not
      significantly increase a woman's risk of contracting breast cancer. Only for the
      very small group of women with preterm deliveries of less than 32 weeks gestation
      did we observe an increased risk.

PMID- 10408875
TI  - Food groups, oils and butter, and cancer of the oral cavity and pharynx.
AB  - To elucidate the role of dietary habits, a study was carried out in 1992-1997 in
      the province of Pordenone in Northeastern Italy, and those of Rome and Latina in
      central Italy. Cases were 512 men and 86 women with cancer of the oral cavity and
      pharynx (lip, salivary glands and nasopharynx excluded) and controls were 1008
      men and 483 women who had been admitted to local hospitals for a broad range of
      acute non-neoplastic conditions. The validated dietary section of the
      questionnaire included 78 foods or recipes and ten questions on fat intake
      patterns. After allowance for education, smoking, alcohol and total energy
      intake, significant trends of increasing risk with increasing intake emerged for
      soups, eggs, processed meats, cakes and desserts, and butter. Risk was
      approximately halved in the highest compared to the lowest intake quintile for
      coffee and tea, white bread, poultry, fish, raw and cooked vegetables, citrus
      fruit, and olive oil. The inverse association with oils, especially olive oil,
      was only slightly attenuated by allowance for vegetable intake. Thus, frequent
      consumption of vegetables, citrus fruit, fish and vegetable oils were the major
      features of a low-risk diet for cancer of the oral cavity and pharynx.

PMID- 10408876
TI  - Human papillomavirus infection and other risk factors for cervical
      intraepithelial neoplasia in Japan.
AB  - Various risk factors were investigated in 167 cervical intra-epithelial neoplasia
      (CIN) case and control pairs in Japan. CIN cases showed evidence of nine known
      risk factors including smoking and sexual behaviour. However, after adjustment
      for papillomavirus infection, the highest determinant, the only remaining risk
      factors were: being married, early age at first pregnancy and multiparity.

PMID- 10408877
TI  - Tumor induction by methyl-nitroso-urea following preconceptional paternal
      contamination with plutonium-239.

PMID- 10408878
TI  - Polar lipids of four Listeria species containing L-lysylcardiolipin, a novel
      lipid structure, and other unique phospholipids.
AB  - The membrane lipids of Listeria innocua, Listeria monocytogenes, Listeria
      seeligeri and Listeria welshimeri were fractionated on DEAE-cellulose and
      purified by chromatography on silica gel and/or preparative TLC. The lipid
      structures were elucidated by chemical and chromatographic means. The polar lipid
      composition of the four listeria species was similar. Phospholipids predominated.
      They consisted of phosphatidylglycerol, L-lysylphosphatidylglycerol, cardiolipin
      [bis(phosphatidyl)glycerol] and L-lysylcardiolipin. A phospholipid more polar
      than cardiolipin, possibly two L-lysyl derivatives of it, sn-glycero-1
      phosphoglycolipid, its D-alanyl derivative, and polyprenol phosphate were also
      detected. Towards the end of exponential growth, the relative amounts of
      cardiolipin and L-lysylcardiolipin increased, approaching 47-78% lipid phosphorus
      with a ratio of L-lysylcardiolipin to cardiolipin of 0.25-1.6. As shown by fast
      atom bombardment-mass spectrometry, cardiolipin and L-lysylcardiolipin consisted
      of five molecular species due to various fatty acid combinations. L
      lysylcardiolipin has so far not been found in nature. It belongs to the recently
      discovered class of substituted cardiolipins. Its occurrence in the four listeria
      species tested shows that it is a characteristic lipid component of the L.
      monocytogenes line of descent. Further studies on the lipid pattern of members of
      the other descent line are required to decide whether lysylcardiolipin can serve
      as a genus-specific chemotaxonomic marker for listeriae.

PMID- 10408879
TI  - Reversible inactivation of myosin subfragment-1 activity by mechanical
      immobilization: a reappraisal.

PMID- 10408880
TI  - Selenium as an integral part of factor 3 against dietary necrotic liver
      degeneration. 1951.

PMID- 10408881
TI  - Papers from the 8th annual meeting of the International Working Group on
      Preimplantation Genetics, in association with the 9th International Conference on
      Prenatal Diagnosis and Therapy. Los Angeles, California, USA. June 7, 1998.

PMID- 10408882
TI  - Interference by methyl levulinate in determination of total fat in low-fat, high
      sugar products by gas chromatographic fatty acid methyl ester (GC-FAME) analysis.
AB  - Gas chromatographic fatty acid methyl ester (GC-FAME) analyses of some acid
      hydrolyzed foods revealed a large peak that did not correspond to any FAME
      standards. The unknown peak eluted just after the C12 FAME. If the fatty acid
      response factor and the conversion factor for the nearest calibrated peak (C12
      FAME) were used to determine the total fat, the resulting total fat determination
      was much higher than expected. This peak was present only in acid-hydrolyzed
      samples and was absent in extracts obtained with supercritical CO2 or solvents
      without acid hydrolysis. The compound was isolated, analyzed by mass spectrometry
      and nuclear magnetic resonance spectroscopy, and proved by synthesis to be methyl
      4-oxopentanoate (methyl levulinate). Its source was determined to be sugar in the
      product formula. Levulinic acid is produced by acid hydrolysis of sugar and is
      transesterified by BF3 in methanol to methyl levulinate. Although methyl
      levulinate may appear in the GC analyses of any acid-hydrolyzed products
      containing sugar, if the ratio of fat to sugar is high, the impact of methyl
      levulinate on fat determination would be small. On the other hand, the presence
      of methyl levulinate in analyses of low-fat, high-sugar products is potentially
      problematic if not recognized, although GC analysis can account for the presence
      of this compound.

PMID- 10408883
TI  - [The annual risk of infection with Koch's bacillus--its epidemiological
      importance and the methods for its estimation].

PMID- 10408884
TI  - [A proposed antitobacco law].

PMID- 10408885
TI  - Obesity in childhood and adolescence: assessment, prevention and treatment.
      Proceedings of a conference. Minneapolis, Minnesota, USA. May 1997.

PMID- 10408886
TI  - Physical Activity and Obesity. Satellite Symposium of the 8th International
      Congress of Obesity. Maasricht, The Netherlands, August 1998. Proceedings and
      abstracts.

PMID- 10408887
TI  - Proceedings of the 5th meeting of the American Society for Neural Transplantation
      and Repair. Clearwater, Florida, USA. April 23-25, 1998.

PMID- 10408888
TI  - Differential seizure-induced and developmental changes of neurexin expression.

PMID- 10408889
TI  - Annual meeting of the Hungarian Society for Microbiology. Miskolc, August 24-26,
      1998. Abstracts.

PMID- 10408891
TI  - Spinal cord ischaemia.

PMID- 10408890
TI  - Perforator ligation.

PMID- 10408892
TI  - Compression of false aneurysms.

PMID- 10408893
TI  - Carotid angioplasty.

PMID- 10408894
TI  - From protein sequence to function.
AB  - As genome sequences and protein structures are deciphered, we wish to predict
      their corresponding functions. Many functions cannot be told from from the
      sequence, however, although there has been progress in this quest for an
      impossible Grail. Furthermore, a structure and its corresponding sequence become
      most interesting when one knows the function. Inductive reasoning, based on the
      integration of biological and sequence knowledge, should enable sequence and
      functional data to be combined in a productive way.

PMID- 10408895
TI  - [Can substance P antagonists constitute a new axis for antidepressants?].

PMID- 10408896
TI  - Fee guides.

PMID- 10408897
TI  - Dental care for homebpund and geriatric patients.

PMID- 10408898
TI  - Hypertension--A case for lifestyle modification.

PMID- 10408899
TI  - Profile: Robert S. Fraser.

PMID- 10408900
TI  - Inhibition of DNA synthesis by downregulation of cyclin A but not Skp 2
      overexpression in human hepatocellular carcinoma cells.
AB  - Cyclin A is an S and G2/M phase regulatory protein and associates with Skp 2 in
      many transformed cells. Our previous results showed that 12 (39%) and 17 (55%)
      out of 31 hepatocellular carcinoma (HCC) patients exhibited higher protein
      expression levels of cyclin A and Skp 2, respectively, in their tumorous compared
      to non-tumorous tissues. In the present study, we used Western blot analysis to
      show that 3 out of 6 HCC cell lines, HA59T, HA22T and HCC36, exhibited
      overexpression of cyclin A, among which the HCC36 cell line also expressed a
      higher Skp 2 protein level. Moreover, we used the antisense oligonucleotide
      phosphorothioates to down regulate the overexpression of cyclin A and Skp 2
      proteins to determine whether or not these two proteins are involved in the
      mitogenesis of HCC36 cells. After treatment with antisense oligonucleotide
      phosphorothioates, the gene product of cyclin A or Skp 2 was suppressed dose
      dependently as revealed by Western blot analyses. By [3H]thymidine incorporation
      assay, we found that downregulation of cyclin A but not Skp 2 overexpression
      could inhibit the DNA synthesis ability of HCC36 cells, suggesting that abnormal
      Skp 2 expression is not directly correlated with the HCC proliferation.

PMID- 10408901
TI  - Decrease of metastatic ability after selection for intravasating ability in Lewis
      lung carcinoma (3LL) cell line.
AB  - The release of cancer cells from the primary site and penetration into blood
      vessels are obligatory preliminary steps for metastasis. To investigate the
      mechanism of such steps we isolated variant cells (designated as Int-3LL)
      possessing enhanced intravasating ability from Lewis lung carcinoma (3LL) cells
      by in vivo selection. In spite of the enhanced intravasating ability of Int-3LL,
      the spontaneous and experimental metastatic abilities of Int-3LL decreased
      significantly compared to parent cells. Such a cell line has never been reported
      so far. The matched pair of cell lines described in this report provides a useful
      system for investigating the primary steps of metastasis.

PMID- 10408902
TI  - Presence of the proteinase-activated receptor-2 (PAR-2) in human brain tumor
      cells--trypsin- and SLIGRL-induced calcium response in primary cultured
      meningiomas.
AB  - This study focused on proteinase-activated receptor-2 (PAR-2) in primary cultured
      human meningioma cells. Stimulation of these cells with the serine proteinase
      trypsin resulted in a dose-dependent transient calcium response. Since the
      specific PAR-2 agonist peptide SLIGRL also induced [Ca2+]i mobilization in human
      meningioma cells and successive application of SLIGRL and trypsin elicited no new
      calcium signal we conclude that trypsin-induced calcium signaling is mediated by
      PAR-2 in human meningioma cells. To our knowledge, this is the first report
      describing functional PAR-2-type receptors in human brain tumor cells.

PMID- 10408903
TI  - Anti-psychotic drugs reverse multidrug resistance of tumor cell lines and human
      AML cells ex-vivo.
AB  - Anti-psychotic drugs are used in cancer patients undergoing chemotherapy
      frequently and the concomitantly used drugs may alter the pharmacokinetics of
      each other. One reason for the alteration of pharmacokinetics may be the
      modulation of the function of P-glycoprotein, whose efflux pump occurs in
      resistant cancer cells, in human intestine and in the blood-brain barrier. For
      this reason we tested the effect of several anti-psychotic drugs on the multidrug
      resistant pump, P-glycoprotein. We found that in the MDR gene transfected L121C
      MDR, L5178 MDR and in the KB-V-1 cells selected for resistance some antipsychotic
      drugs block the function of P-glycoprotein. Blood cells of two treatment
      resistant leukemic patients also showed increased uptake of daunorubicin if
      treated ex vivo with the anti-psychotic drugs. Our results suggest that
      pharmacokinetic studies should be performed prior to concomitant clinical use of
      such drugs which block P-glycoprotein function.

PMID- 10408904
TI  - CEA-related proteins on human urothelial cell lines of different transformation
      grades.
AB  - CEA family proteins from human urothelial cell lines of different transformation
      grades were characterized by flow cytometry and Western blotting using monoclonal
      antibodies: 26/3/13, D14HD11, 9A6 and 4/3/17. The following observations were
      made: (i) the urothelial cell lines, representing transformation grade III (TGr
      III, tumorigenic, invasive cells), were characterized by the presence of a
      component with molecular mass 110-135 kDa, most probably representing biliary
      glycoprotein (BGP); (ii) BGP was absent in non-tumorigenic and non-invasive TGr
      II urothelial cell lines; (iii) a protein band with apparent molecular mass 180
      kDa, and migrating as a CEA standard was detected in only one of seven urothelial
      cell lines analyzed; (iv) a broad band of apparent molecular mass migrating at 65
      90 kDa, probably representing NCA-50/90, was found in two tumorigenic and
      invasive cell lines, HCV 29T and Hu 1703He.

PMID- 10408905
TI  - Genotoxic effect of arecoline given either by the peritoneal or oral route in
      murine bone marrow cells and the influence of N-acetylcysteine.
AB  - The carcinogenic potentiality of the major alkaloid of betel nut, arecoline
      (ARC), is well established. This study was undertaken to determine the
      differences in genotoxic effects of ARC when given by two different routes (oral
      administration (OA) and intraperitoneal injection (IP)) in mouse bone marrow
      cells (BMC) since ARC carcinogenicity was observed only when ARC was given
      orally. The data indicate that ARC-OA induced a higher frequency of cancers, a
      greater delay in the cell cycle and greater sister chromatid exchanges than ARC
      IP. The presence of N-acetyl cysteine along with ARC-OA significantly reduced the
      effect of ARC.

PMID- 10408906
TI  - Computerised counting of tumour infiltrating lymphocytes in 90 breast cancer
      specimens.
AB  - Tumour infiltrating lymphocytes (TILs) implicated in immunologic cytotoxicity
      were evaluated by immunohistochemistry and digitally counted in serial sections
      from 90 breast cancers in order to assess their number, the relationships between
      them and to tumour histology. CD3+, CD4+, CD8+, CD20+, CD25+ and CD56+
      lymphocytes were found in 58 (64.4%), 52 (57.7%), 50 (55.5%), 22 (24.4%), 11
      (12.2%) and 21 (23.3%) tumours, respectively. There was no difference in the
      number of TILs between pure infiltrating ductal (NOS) and non-ductal carcinomas,
      and no relationship between TILs and histological grades was found. CD3+ TILs
      directly correlated to age, while lymph node negative patients had tumours
      infiltrated by fewer CD4+ TILs with respect to lymph node positive patients. In
      25/90 patients, randomly chosen, the status of peripheral blood lymphocytes was
      evaluated but no differences with respect to the status found in healthy blood
      donors was obtained; nonetheless while in some patients CD8+ TILs outnumbered
      CD4+ TILs in situ, the CD4/CD8 ratio was normal in their peripheral blood. The
      results show a considerable diversity of TILs among breast tumours, their lack of
      relationship with the status of the peripheral blood cells, and their potential
      important relationship with age (CD3+) and lymph node status (CD4+).

PMID- 10408907
TI  - Higher frequency of DPC4/Smad4 alterations in pancreatic cancer cell lines than
      in primary pancreatic adenocarcinomas.
AB  - The tumor suppressor gene DPC4/Smad4 at 18q21.1 is inactive in about 50% of
      pancreatic carcinoma xenografts and cell lines. However, the role of DPC4 in the
      multistep carcinogenesis of primary pancreatic adenocarcinomas remains uncertain.
      Therefore, we examined 45 primary human pancreatic adenocarcinomas and 12
      pancreatic cancer cell lines for DPC4 alterations by single-strand conformational
      variant (SSCV) analysis and a PCR-based deletion assay. DPC4 was inactivated by
      either homozygous deletion or point mutation in 6 of 12 cell lines (50%). None of
      the primary pancreatic carcinomas carried a DPC4 mutation, although 66% revealed
      LOH of 18q21 sequences. These findings suggest that inactivation of DPC4 occurs
      more frequently in tumor-derived cell lines than in primary pancreatic
      adenocarcinomas. In addition, another, yet unidentified, tumor suppressor gene(s)
      may be linked with the frequent LOH of 18q21 in primary pancreatic
      adenocarcinomas.

PMID- 10408908
TI  - Choice of vincristine or 6-mercaptopurine on the basis of polyamine level in
      tumor-bearing regions of the brain.
AB  - The effects of vincristine (VC) and 6-mercaptopurine (6-MP) on body weight,
      regional weights, and the contents of putrescine, spermidine, and spermine in six
      regions of the brain were examined in rats that had been given these drugs for 5
      consecutive days. VC is recommended for management of tumors in the corpus
      striatum and/or hippocampus, and cortex although its efficacy is dependent on the
      doubling time of the tumor cells, whereas 6-MP is recommended for the management
      of tumors in the cortex, thalamus and/or hypothalamus, and diencephalon. VC and 6
      MI are chosen for treatment of the brain tumors because they reduce polyamines
      which are associated with the reduction of drug-sensitive cells and an inhibition
      of tumor growth.

PMID- 10408910
TI  - In vitro upregulation of carcinoembryonic antigen expression by combinations of
      cytokines.
AB  - Interferons are able to enhance the expression of carcinoembryonic antigen (CEA)
      on tumour cells, allowing improved tumour targeting. In this report the
      hypothesis is tested that combinations of cytokines may further increase the
      tumour antigen expression. The combination of both IFN-gamma and IFN-alpha with
      interleukin-6 demonstrated a significant additive effect on the CEA-expression.
      This was found by quantitatively analysing the CEA-expression on human colorectal
      tumour cells by flow cytometry. It is concluded that combinations of cytokines
      show the potential of inducing tumour antigen expression for improved tumour
      targeting.

PMID- 10408909
TI  - Arecoline-induced changes of poly-ADP-ribosylation of cellular proteins and its
      influence on chromatin organization.
AB  - Arecoline, the major alkaloid of betel nut (Areca catechu L.) and a suspected
      carcinogen, has been implicated in human cancers of various sites. A considerable
      portion of the world's population is constantly exposed to arecoline due to the
      habit of masticating betel nuts. The present work relates to the study of early
      molecular events following chronic arecoline exposure at a dose of 10 microg/ml
      to Swiss albino mice. Poly-ADP-ribosylation of all cellular proteins, histones
      and poly-ADP-ribose polymerase were studied in bone marrow and spleen cells and
      correlated with the organizational status of the chromatin. While most proteins
      showed lowering of their poly-ADP-ribosylation following arecoline treatment,
      only histone protein H1 in spleen cells and H2B in bone marrow cells exhibited an
      increase. The chromatin of both the tissues was progressively relaxed upon
      arecoline exposure. The implications of these changes have been discussed
      regarding the process of initiation of arecoline-induced carcinogenesis.

PMID- 10408911
TI  - Frequent multiplication of chromosomal region 8q24.1 associated with aggressive
      histologic types of breast cancers.
AB  - Carcinogenesis is considered to be a multi-step process that may involve
      cumulative genetic alterations. One such alteration, gain of chromosomal
      material, has the potential for activating genes that promote carcinogenesis in
      breast tissues. Using 14 polymorphic microsatellite markers on the long arm of
      chromosome 8 (8q), we examined 142 sporadic breast cancers for abnormalities in
      the copy-numbers of these loci. At each locus examined, a 2- to 3-fold increase
      in intensities of bands representing single alleles was observed in 57 (40%) of
      the tumors, indicating that 'multiplication' of the DNA sequence had occurred on
      8q. A 16-cM region on 8q24.1 was commonly multiplied among the tumors with
      partial multiplications. Multiplication on 8q24.1 was observed more frequently in
      invasive solid-tubular or scirrhous tumors (48/92, 52%) than in less aggressive
      histologic types (7/25, 28%, P = 0.031). Thus, multiplication of tumor-promoting
      gene(s) located on 8q24.1 may play a role in the development and/or progression
      of a substantial proportion of primary breast cancers, particularly those of the
      invasive histology.

PMID- 10408912
TI  - Incorporation and effect of arachidonic acid on the growth of the human K562 cell
      line.
AB  - Lipoxygenase inhibitors reduce the growth of K562 cells (chronic myelogenous
      human leukaemia blasts) suggesting a role for endogenous lipoxygenase products of
      arachidonic acid (AA) in their proliferation. The objectives of this work are to
      investigate the incorporation of AA into K562 cells and to assess the effects of
      the exogenous addition of AA and lipoxygenase products on their growth. The
      mechanism of acylation of [3H]-AA indicates that K562 cells incorporate AA into
      their membrane phospholipids and triglycerides. PLA2-treatment and base
      hydrolysis experiments confirm that [3H]-AA is incorporated unmodified into K562
      phospholipids and is linked by an ester bond. Prelabelling-chase experiments
      indicate a transfer of labelled AA from phosphatidylcholine to
      phosphatidylethanolamine. The addition of AA and lipoxygenase products of AA
      (leukotriene B4 and C4, lipoxin B4, 12-hydroxyeicosatetraenoic acid (12-HETE) and
      15-HETE) has no effect on K562 cell proliferation assessed by [3H]thymidine
      incorporation into DNA. In conclusion, while K562 cells readily incorporate AA
      into their membrane phospholipids and triglycerides, AA and lipoxygenase products
      are not important modulators of their proliferation.

PMID- 10408913
TI  - Induction of mitochondrial Apo2.7 molecules and generation of reactive oxygen
      intermediates in cultured lymphocytes by the toxic proteins from Viscum album L.
AB  - We analysed mitochondrial alterations in human lymphocytes incubated with toxins
      exerting RNA and/or protein synthesis/transport inhibitory activity. We found
      that all toxins known to affect macromolecule synthesis, such as ricin from
      Ricinus communis, mistletoe lectin I (ML I) from Viscum album, cycloheximide,
      actinomycin D, and brefeldin A but also the thionins from Viscum album
      (viscotoxins; VT) generated reactive oxygen intermediates (ROI) and induced
      expression of newly described mitochondrial membrane proteins Apo2.7, however,
      with different kinetics. Apart from a rapid permeabilisation of cell membranes by
      the VT with swelling of mitochondria, loss of their cristae and ROI generation
      within 2-4 h, the majority of the cells may have received a distinct 'death
      signal' resulting in an induction of Apo2.7 molecules within 24 h. In contrast,
      protein synthesis/transport inhibition may signal for apoptosis within 24 h by
      decreasing distinct 'survival promotors' which remain to be characterised.

PMID- 10408914
TI  - Meta-tetra(hydroxyphenyl)chlorin-sensitized photodynamic damage of cultured tumor
      and normal cells in the presence of high concentrations of alpha-tocopherol.
AB  - Alpha-tocopherol at low concentrations protects biosubstrates from oxidative
      damage, while at high concentrations it may become toxic. Certain lines of tumor
      cells are reported to contain higher levels of vitamin E than normal cells. In
      our study alpha-tocopherol was successfully incorporated by cultured HT29
      adenocarcinoma cells, but not by MRC-5 normal fibroblasts. At high concentrations
      (0.3-1 mM) alpha-tocopherol enhanced meta-tetra(hydroxyphenyl)chlorin (mTHPC)
      sensitized photoinactivation of HT29 cells (415 nm), but not that of normal
      fibroblasts. At none of the concentrations used (0.001-1 mM) did alpha-tocopherol
      protect cells from photokilling, indicating that lipid peroxidation is of minor
      importance in mTHPC photoactivity. Our findings encourage the in vivo testing of
      phenolic antioxidants for selective enhancement of PDT-damage in tumors.

PMID- 10408915
TI  - Inhibition of multidrug resistance-associated protein (MRP) activity by
      rifampicin in human multidrug-resistant lung tumor cells.
AB  - The multidrug resistance-associated protein (MRP) is a drug efflux membrane pump
      conferring multidrug resistance on tumor cells. In order to look for compounds
      that can lead to reversal of such a resistance, the antituberculosis compound
      rifampicin, belonging to the chemical class of rifamycins, was examined for its
      effect on MRP activity in human multidrug resistant lung cancer GLC4/ADR cells.
      Rifampicin was shown to increase accumulation of the MRP substrate calcein in
      GLC4/ADR cells in a dose-dependent manner by inhibiting its MRP-mediated efflux
      from the cells; it also enhanced intracellular retention of another substrate of
      MRP such as the anticancer drug vincristine in the resistant cells. By contrast,
      the antituberculosis drug did not alter cellular levels of accumulation of either
      calcein or vincristine in parental drug-sensitive GLC4 cells. Other rifamycins
      such as rifamycin B and rifamycin SV were also demonstrated to increase
      intracellular accumulation of calcein in GLC4/ADR cells. These results therefore
      indicate that rifamycins, including rifampicin, probably constitute a new
      chemical class of modulators down-regulating MRP-mediated drug transport.

PMID- 10408917
TI  - [Proceedings of the satellite symposium of the XXXIII Congress of IUPS. Molecular
      and Genetic Bases of Adaptive Behavior. St. Petersburg, Russia. July, 1997].

PMID- 10408916
TI  - Trk-neurotrophin receptor-like immunoreactivity in the gut of teleost species.
AB  - Neurotrophins, acting through their high-affinity signal-transducing Trk
      receptors, are involved in the development, differentiation and maintenance of
      discrete neuron populations in the higher vertebrates. Furthermore, the presence
      of Trk receptors in some non-neuronal tissues, including the endocrine cells of
      the gut, could indicate an involvement of neurotrophins also in these tissues.
      Recently, neurotrophins and neurotrophin receptor proteins have been identified
      in the lower vertebrates and invertebrates, whose amino acid sequences are highly
      homologous with those found in mammals. The present study investigates the
      occurrence and distribution of Trk-like proteins in the neurons and gut endocrine
      cells in five species of teleost. Single and double immunolabeling was carried
      out on fresh and paraffin-embedded tissue using commercially available antibodies
      against sequences of the intracytoplasmic domain of the mammalian Trk. Western
      blot analysis, carried out on samples of stomach and intestine of bass,
      identified proteins whose estimated molecular masses (140 kDa, 145 kDa and 143
      145 kDa) were similar to those reported for full-length TrkA, TrkB and TrkC in
      the higher vertebrates. TrkA-like immunoreactivity was found in the enteric
      nervous system plexuses of three fish species. Trk-like immunoreactivity was
      observed in the endocrine cells as follows: sparse TrkA-like immunoreactive
      endocrine cells were detected only in the intestine: TrkB-like immunoreactive
      cells were detected only in the stomach; and TrkC-like immunoreactive cells were
      found both in the intestine of the carp and in the stomach of the bass, where
      they also showed TrkB-like immunoreactivity. These findings confirm the
      occurrence and distribution of Trk-like proteins in teleosts. These proteins are
      closely related to the Trk neurotrophin receptors of mammals. The functional
      significance of Trk-like proteins in both neuronal and non-neuronal cells of
      teleosts is still not clear.

PMID- 10408918
TI  - Molecular flexibility profiling using NMR spectroscopy.
AB  - Molecular flexibility is a factor that is not extensively studied in most
      pharmaceutical research efforts. When it is, the level of effort is high
      involving the preparation of detailed models supported by either molecular
      dynamics simulations and/or Nuclear Magnetic Resonance data. While these studies
      are both powerful and illuminating, they cannot be routinely applied in a drug
      discovery setting as they are time and expertise intensive. Yet there seems to be
      little doubt that at least in some cases, molecular flexibility plays a key role
      in complex formation. A simple, rapid and generally applicable flexibility
      profiling protocol was applied to two model systems and data describing the
      internal mobility of carbon atoms were obtained. The protocol utilizes the Model
      Free approach and NMR data to characterize the internal molecular dynamics of
      these compounds. The first model system consisted of fluorene and diphenylmethane
      where the anticipated flexibility trends were observed in the data providing a
      link between chemical intuition and the experimental results. Data on a second
      model system, which consisted of two Paclitaxel analogs, showed predictable
      patterns including dynamical phenyl and methyl groups and a relatively immobile
      taxane core. Subtle differences in the internal dynamics within the taxane core
      suggest that it cannot be considered as a rigid structure. Key advantages of
      using this approach are that no prior knowledge or supposition of dynamical
      features is required, the protocol can be carried out in most medicinal chemistry
      laboratories and the data obtained provide a common, empirically derived
      reference point to discuss the effects of molecular flexibility on activity.

PMID- 10408919
TI  - Guess what! Cutaneous sarcoidosis, Sjogren's syndrome and autoimmune thyroiditis
      associated with hepatitis C virus infection.

PMID- 10408920
TI  - Guess what! Superficial basal cell carcinoma of the scrotum.

PMID- 10408922
TI  - Synthesis of a monocharged peptide nucleic acid (PNA) analog and its recognition
      as substrate by DNA polymerases.
AB  - The preparation of a novel phosphoramidite monomer based on thyminyl acetic acid
      coupled to the secondary nitrogen of 2-(2-amino-ethylamino)ethanol is described.
      This monomer can be used to attach a deoxynucleotide to the carboxy terminus of a
      PNA oligomer by solid-phase synthesis. The resulting PNA primer is recognized as
      a substrate by various DNA polymerases.

PMID- 10408921
TI  - Guess what! Acute infectious endocarditis with Janeway lesions in a patient with
      atopic dermatitis.

PMID- 10408924
TI  - Microbial fusion.

PMID- 10408923
TI  - Molecular dynamics of labeled oligonucleotide probes used for the detection of
      point mutations in DNA.
AB  - The fluorescent label BODIPY 576-589 linked to the 5-end of an oligonucleotide
      via alkyl chain linkers can be used as a probe to detect point mutations in DNA.
      We have employed fluorescence anisotropy decay and dynamic fluorescence resonance
      energy transfer (FRET) in order to investigate the molecular origin of the
      fluorescence lifetime aberrations of BODIPY in the presence of a mismatched base.
      The results show that both, an increased flexibility of the alcyl chain linker to
      the BODIPY molecule as well as relaxation of the secondary structure of the whole
      complex, contribute to the decreased fluorescence lifetimes reported previously.

PMID- 10408925
TI  - Proteolysis by presenilins and the renaissance of tau.

PMID- 10408926
TI  - Thomas W. Mattingly.

PMID- 10408927
TI  - Comments on: 'Preventive effect of dapsone on renal scarring following mannose
      sensitive piliated bacterial infection' by Mochida et al. (Chemotherapy
      1998;44:36-41)

PMID- 10408928
TI  - Playing with pesticides.

PMID- 10408929
TI  - Not enough spinach?

PMID- 10408931
TI  - Environmental learning 2000.

PMID- 10408930
TI  - Fatal fungus.

PMID- 10408932
TI  - Passive smoke linked to abnormal HDL in children.

PMID- 10408933
TI  - A tradition of focusing on children's health.

PMID- 10408934
TI  - Response to the ACPA's critique.

PMID- 10408935
TI  - EPA releases mercury report. Environmental Protection Agency.

PMID- 10408936
TI  - Fighting disease with disease.

PMID- 10408937
TI  - Is airborne manganese a hazard?

PMID- 10408939
TI  - Big hair news.

PMID- 10408938
TI  - New test speeds detection of E. coli.

PMID- 10408940
TI  - Taking the city to heart in the center of the city.

PMID- 10408941
TI  - Comments on "Trouble in paradise".

PMID- 10408942
TI  - The alpha2u-globulin discussion.

PMID- 10408943
TI  - Re: "A pilot study of urinary estrogen metabolites (16alpha-OHE1 and 2-OHE1) in
      postmenopausal women with and without breast cancer".

PMID- 10408944
TI  - Getting rid of rotavirus.

PMID- 10408945
TI  - Stockpiling safety?

PMID- 10408946
TI  - Gamma groceries.

PMID- 10408947
TI  - Genes and ozone.

PMID- 10408948
TI  - Lower and upper limits of adaptation to energy intake and its principal
      substrates, carbohydrates and lipids. Proceedings of an I/D/E/C/G Workshop. Rome,
      Italy, December 8-11, 1997.

PMID- 10408950
TI  - Strategies for the Chemoprevention of Prostate Cancer. Symposium proceedings.
      Brussels, Belgium. October 29-31, 1998.

PMID- 10408949
TI  - Structural organization and sequence of the homeotic gene Antennapedia of
      Drosophila melanogaster.
AB  - The structure of the Drosophila melanogaster Antennapedia (Antp) gene has been
      investigated by the isolation and sequencing of different cDNAs and genomic
      clones. Northern analysis, S1 mapping and primer extension experiments reveal a
      complex and unusual gene structure. The gene is composed of two promoters, eight
      exons spanning >100 kb, and two termination processing regions. Four major
      polyadenylated transcripts were found, two of them starting at a second internal
      promoter in front of exon 3. All four transcripts have extremely long
      untranslated leader and trailer sequences in the range of 1-2 kb. Despite the
      complex transcriptional organization, the open reading frame is the same in all
      transcripts, and starts in exon 5 giving rise to a protein of mol. wt. 42 800.
      The putative protein is rich in glutamine (18%) and proline (10%). The homeobox,
      a region which previously has been shown to be highly conserved among homeotic
      genes, is contained in the open reading frame and located in the last exon.
      Functional implications of the complex structure with respect to development and
      its relation to the mutant phenotypes are discussed.

PMID- 10408951
TI  - The European Randomized Study of Screening for Prostate Cancer (ERSPC): an
      update. Members of the ERSPC, Section Rotterdam.
AB  - Screening for prostate cancer is controversial. While in some parts of the world
      screening is practised as a healthcare policy, it is strongly rejected in other
      areas, because solid evidence of effectiveness of screening combined with early
      treatment with respect to lowering the mortality of prostate cancer has not been
      shown. It is for this reason that a large European study is installed to
      establish or rule out the value of screening for this frequent disease. The
      present paper presents the goal of the study and elaborates on the value of
      presently available screening tests. Preliminary results with respect to the
      first round of screening in the Rotterdam area relating to 32,000 randomized men
      are presented. Evidence of effectiveness of screening through other studies and
      mechanisms is discussed.

PMID- 10408953
TI  - ESA/NASA Workshop on Cell and Molecular Biology Research in Space.  Leuven,
      Belgium, June 1998. Proceedings.

PMID- 10408952
TI  - Folic acid stimulation of the Galpha4 G protein-mediated signal transduction
      pathway inhibits anterior prestalk cell development in Dictyostelium.
AB  - In Dictyostelium discoideum, several G proteins are known to mediate the
      transduction of signals that direct chemotactic movement and regulate
      developmental morphogenesis. The G protein alpha subunit encoded by the Galpha4
      gene has been previously shown to be required for chemotactic responses to folic
      acid, proper developmental morphogenesis, and spore production. In this study,
      cells overexpressing the wild type Galpha4 gene, due to high copy gene dosage
      (Galpha4HC), were found to be defective in the ability to form the anterior
      prestalk cell region, express prespore- and prestalk-cell specific genes, and
      undergo spore formation. In chimeric organisms, Galpha4HC prespore cell-specific
      gene expression and spore production were rescued by the presence of wild-type
      cells, indicating that prespore cell development in Galpha4HC cells is limited by
      the absence of an intercellular signal. Transplanted wild-type tips were
      sufficient to rescue Galpha4HC prespore cell development, suggesting that the
      rescuing signal originates from the anterior prestalk cells. However, the
      deficiencies in prestalk-specific gene expression were not rescued in the
      chimeric organisms. Furthermore, Galpha4HC cells were localized to the prespore
      region of these chimeric organisms and completely excluded from the anterior
      prestalk region, suggesting that the Galpha4 subunit functions cell-autonomously
      to prevent anterior prestalk cell development. The presence of exogenous folic
      acid during vegetative growth and development delayed anterior prestalk cell
      development in wild-type but not galpha4 null mutant aggregates, indicating that
      folic acid can inhibit cell-type-specific differentiation by stimulation of the
      Galpha4-mediated signal transduction pathway. The results of this study suggest
      that Galpha4-mediated signals can regulate cell-type-specific differentiation by
      promoting prespore cell development and inhibiting anterior prestalk-cell
      development.

PMID- 10408955
TI  - Immune mechanisms in fish skin against monogeneans--a model.
AB  - Host responses against skin inhabiting monogeneans are commonly observed but the
      responsible immune mechanisms in the fish skin are sufficiently described. Based
      on recent knowledge of fish immunity and skin response mechanisms in mammals a
      model for the skin immunity in fish to monogenean infections is proposed.
      Important cellular components of the model are the epithelial cells, the mucous
      cells and leucocytes. The release of cytokines, e.g., IL-1, following mechanical
      or chemical injury of the epithelial cells, initiates a series of events leading
      to decrease of the ectoparasite population. Cytokines (e.g., IL-1, TNF, INF) are
      suggested to affect secretions from mucous cell and attract neutrophils and
      macrophages. Leukotrienes are probably involved in the inflammatory reactions.
      The subsequent production of humoral substances (among others complement factors
      and peptides) could be responsible for the antiparasitic response in the later
      stages of infection. Although non-specific factors dominate the response, the
      involvement of specific antibodies and lymphocytes cannot be excluded.

PMID- 10408956
TI  - Pearle Arnold Capwell (1885-1982), pioneer nurse.

PMID- 10408954
TI  - Synthesis of FinP RNA by plasmids F and pSLT is regulated by DNA adenine
      methylation.
AB  - DNA adenine methylase mutants of Salmonella typhimurium contain reduced amounts
      of FinP, an antisense RNA encoded by the virulence plasmid pSLT. Lowered FinP
      levels are detected in both Dam- FinO+ and Dam- FinO- backgrounds, suggesting
      that Dam methylation regulates FinP production rather than FinP half-life.
      Reduced amounts of F-encoded FinP RNA are likewise found in Dam- mutants of
      Escherichia coli. A consequence of FinP RNA scarcity in the absence of DNA
      adenine methylation is that Dam- mutants of both S. typhimurium and E. coli show
      elevated levels of F plasmid transfer. Inhibition of F fertility by the S.
      typhimurium virulence plasmid is also impaired in a Dam- background.

PMID- 10408957
TI  - Large conjugative vanA plasmids in vancomycin-resistant Enterococcus faecium.

PMID- 10408959
TI  - Histoplasma capsulatum antigen detection: comparison of the performance
      characteristics of a new inhibition immunoassay to those of an established
      antibody sandwich immunoassay.

PMID- 10408958
TI  - Detection and characterization of novel rotavirus strains in the United States.

PMID- 10408960
TI  - Rare case of failure by an automated system to detect extended-spectrum beta
      lactamase in a cephalosporin-resistant Klebsiella pneumoniae isolate.

PMID- 10408961
TI  - Diagnosis and management of Nocardia keratitis.

PMID- 10408962
TI  - Detection of respiratory syncytial virus in samples frozen at -20 degrees C.

PMID- 10408963
TI  - Dominating interleukin-10 mRNA expression induction in cerebrospinal fluid cells
      of dogs with natural canine distemper virus induced demyelinating and non
      demyelinating CNS lesions.
AB  - Canine distemper virus (CDV) infection in dogs is commonly associated with
      demyelinating leukoencephalitis (DL). Although the mechanism of primary
      demyelination in distemper remains undetermined recent studies showed a direct
      virus-induced cytolysis in early non-inflammatory and immune-mediated mechanisms
      in inflammatory lesions. To further investigate the pathogenesis of this
      morbillivirus-induced demyelination the expression of a variety of cytokine mRNA
      species (interleukin (IL)-1beta, IL-2, IL-6, IL-10, IL-12, tumor necrosis factor
      (TNF)-alpha, transforming growth factor (TGF)-beta1, and interferon (IFN)-gamma
      in cerebrospinal fluid cells of 12 dogs with CDV encephalitis was investigated
      employing reverse transcription-polymerase chain reaction (RT-PCR) and these
      findings were correlated to the type of CNS lesions. Neuropathology revealed the
      whole spectrum of distemper DL lesions from acute to chronic alterations,
      however, most plaques lacked active demyelination. Three control animals were
      devoid of any cytokine expression, whereas in distemper animals IL-10 transcripts
      were found in nine dogs with acute and chronic lesions. IL-6, TNF, and TGF mRNA
      was found in six, four, and three animals, respectively. IL-12 and IFN-gamma,
      suggestive of a TH1-like dominated immune response, were detected only in one
      animal with chronic lesions. Summarized, TNF and IL-6, associated with disease
      exacerbation, and IL-10 and TGF, indicative of remission, were often observed
      simultaneously in distemper DL and could not be assigned to a specific disease
      stage. However IL-10 mRNA remained the most frequently detected cytokine
      indicating a stage of inactivity in most animals investigated.

PMID- 10408964
TI  - Contrasting effects of anti-adhesion molecule therapy in experimental allergic
      encephalomyelitis and Theiler's murine encephalomyelitis.
AB  - An augmentation of experimental allergic encephalomyelitis (EAE) was observed
      when monoclonal antibody (mAb) to intercellular adhesion molecule 1 (ICAM-1) was
      administered after adoptive transfer. Clinical disease was more severe in the
      ICAM-1 specific mAb-treated EAE mice and included prominent ataxia compared to
      the PBS-treated controls or Theiler's murine encephalomyelitis virus (TMEV)
      infected mice treated with ICAM-1 specific mAb. Neuropathologic evaluation
      demonstrated a distinctly different distribution of lesions in the anti-ICAM-1
      treated EAE mice which featured prominent demyelination and inflammation in the
      cerebellum, brainstem and cerebrum. These structures were minimally involved in
      the control mice and mAb treatment did not alter the neuropathology in TMEV
      infected mice. These results indicate that anti-ICAM-1 can alter trafficking of
      lymphocytes and mononuclear cells in EAE but not TMEV-induced demyelinating
      disease.

PMID- 10408966
TI  - Hypothalamic beta-endorphin concentrations are decreased in animals models of
      autoimmune disease.
AB  - Complex interactions between the neuroendocrine and the immune systems are
      present in autoimmune diseases. The central opioid peptide beta-endorphin (BE)
      has been shown to modulate peripheral immune responses in normal animals. In the
      present study we analyze the hypothalamic concentrations of this peptide in two
      models of spontaneous autoimmune disease, the MRL [corrected] lpr/lpr mouse, that
      develops a lupus-like autoimmune disease, and the obese strain (OS) chickens
      afflicted with spontaneous autoimmune thyroiditis. In both instances,
      hypothalamic concentrations of BE are significantly lower than normal controls.
      In MRL [corrected] lpr/lpr mice, BE is already lower at 1 month of age, when no
      clinical sign of the disease is yet present. Similarly, low levels of BE are
      observed in OS chickens before the onset of thyroiditis, i.e., already at the
      embryonic stage. Moreover, a further decrease of BE is observed in OS chickens in
      correspondence with the first signs of thyroid mononuclear infiltration.
      Considering the immunosuppressive effects exerted by central BE, these results
      are suggestive of the fact that in autoimmune disease prone animals the low
      hypothalamic concentrations may be one of several factors predisposing for the
      development of autoimmune disease.

PMID- 10408965
TI  - Treatment with BBB022A or rolipram stabilizes the blood-brain barrier in
      experimental autoimmune encephalomyelitis: an additional mechanism for the
      therapeutic effect of type IV phosphodiesterase inhibitors.
AB  - We examined the treatment effects of two structurally distinct phosphodiesterase
      type IV (PDE IV) inhibitors, BBB022 and rolipram, in murine and rat models of
      experimental autoimmune encephalomyelitis (EAE). Based on our data, we propose a
      mechanism of action which may supplement immunomodulatory effects of PDE IV
      inhibitors. In particular, PDE inhibitors promote elevation of intracellular cAMP
      levels, increasing the electrical resistance of endothelial monolayers by
      stabilizing intercellular junctional complexes. Such an effect on central nervous
      system (CNS) vascular endothelium has the potential to reduce disease severity in
      EAE, because both inflammatory cells and humoral factors readily cross a
      disrupted blood-brain barrier (BBB). In this report, we demonstrate the capacity
      of BBB022 and rolipram to decrease clinical severity of EAE. further, PDE IV
      inhibitors significantly reduced BBB permeability in the spinal cords of mice
      with EAE. These results provide evidence that PDE IV-inhibitors may exert
      therapeutic effects in EAE by modifying cerebrovascular endothelial permeability,
      reducing tissue edema as well as entry of inflammatory cells and factors.

PMID- 10408967
TI  - The effect of vesnarinone on TNF alpha production in human peripheral blood
      mononuclear cells and microglia: a preclinical study for the treatment of
      multiple sclerosis.
AB  - Vesnarinone (OPC-8212) is a synthetic quinolinone derivative with inotropic and
      immunomodulatory effects. Vesnarinone has been shown to inhibit tumor necrosis
      factor-alpha (TNF alpha) produced by mitogen stimulated macrophages, and to
      inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNF alpha and
      interferon-gamma (IFNgamma) have been implicated in the pathogenesis of
      autoimmune diseases, and both cytokines are targets for therapeutic intervention.
      IFNgamma can enhance autoimmune disease through direct effects, and indirectly by
      priming macrophages to produce TNF alpha. In this study, we demonstrate that
      while vesnarinone enhances basal TNF alpha levels, it inhibits TNF alpha
      production in peripheral blood mononuclear cells from multiple sclerosis (MS)
      patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed
      with IFNgamma and stimulated with suboptimal doses of LPS. In addition,
      vesnarinone inhibited TNF alpha production in primary adult human microglial
      cultures. However, in contrast to rolipram, another TNF alpha inhibiting agent,
      vesnarinone failed to inhibit TNF alpha production by myelin basic protein
      specific T-cell lines. As oral TNF inhibitors are currently being considered in
      the USA for clinical application in MS, the implications of our findings on the
      development of vesnarinone for treatment of MS are discussed.

PMID- 10408968
TI  - T cell responses to D-penicillamine in drug-induced myasthenia gravis:
      recognition of modified DR1:peptide complexes.
AB  - The anti-rheumatoid drug D-penicillamine (D-pen) has a reactive sulfhydryl group
      capable of modifying self antigens, and can provoke typical autoantibody-mediated
      myasthenia gravis (MG), especially in DR1+ individuals. We have selected T cell
      clones from one such patient that were highly specific for D-pen but not its L
      isomer or D-cysteine. Moreover, they were restricted to HLA-DR1, had a Th1
      phenotype and used TCR V alpha4.1, V beta6.1. They responded well to blood
      mononuclear cells prepulsed with D-pen either in the absence of serum or after
      chloroquine treatment, but not to autologous D-pen-pulsed B cell lines. Thus, D
      pen may directly couple to distinctive peptides resident in surface DR1 molecules
      on circulating macrophages or dendritic cells.

PMID- 10408969
TI  - Overexpression of nerve growth factor and basic fibroblast growth factor in AIDS
      dementia complex.
AB  - Although neurotrophic factors are currently considered as treatment for
      neurodegenerative diseases, little is still known about their presence in the
      central nervous system under pathological conditions. We investigated the
      expression of the neurotrophic molecules NGF, bFGF, BDNF and IGF-1 in brain
      tissue of patients suffering from AIDS dementia complex. In contrast to IGF-1 and
      BDNF, NGF and bFGF mRNA levels were significantly elevated. Strong NGF
      immunoreactivity was found in perivascular areas and was colocalized with
      infiltrating macrophages, whereas intense bFGF staining was found in cells with
      characteristic astrocytic morphology. These data suggest that the induction of
      NGF and bFGF alone appears to be insufficient as a compensatory mechanism to
      prevent ADC.

PMID- 10408970
TI  - Thymulin induces c-fos expression in the spinal cord of rats which is reversed by
      meloxicam and morphine.
AB  - Intraplantar (i.pl.) injections of thymulin have been shown to produce
      hyperalgesia in rats through a prostaglandin E2-dependent mechanism. This study
      aimed at investigating if such injections can produce sustained activation of
      spinal neurons by mapping the fos-like-immunoreactivity (FLI) as a marker for
      this activation. Our results showed that thymulin produces significant and
      sustained FLI in neurons located in spinal laminae known to be involved in
      nociception. Pretreatment with either morphine or meloxicam (a cyclooxygenase
      inhibitor) revealed differential effects on FLI and the hyperalgesia induced by
      thymulin. These findings support the hypothesis that thymulin can affect central
      neurons either directly or through the peripheral nerve terminals.

PMID- 10408972
TI  - Structure-function studies of an anti-asialo GM1 antibody obtained from a phage
      display library.
AB  - Although gangliosides elicit human autoantibodies, they are extremely weak
      immunogens in mice. We obtained a monoclonal antibody Fab fragment (clone 10)
      that is specific for asialo GM1 (GA1), from a phage display library. The Vkappa
      domain of clone 10 could be replaced by two different Vkappa domains without
      changing the specificity of the antibody. Mutagenesis of the third hypervariable
      regions of the heavy and light chains of clone 10 yielded three mutants that
      exhibited a 3 to 4 times increase in avidity for GA1. A molecular model of clone
      10 indicated that the putative antigen-binding site contained a shallow surface
      pocket. These data illustrate the use of recombinant DNA techniques to obtain
      anti-ganglioside antibodies, and to explore the molecular basis of their antigen
      binding activity.

PMID- 10408971
TI  - Characterization of cytokine production, screening of lymphocyte subset patterns
      and in vitro apoptosis in healthy and Alzheimer's Disease (AD) individuals.
AB  - In order to investigate the possibility of whether or not the lymphocytes of
      patients with Alzheimer's Disease (AD) are in an activated state, blood
      mononuclear cells from 45 AD patients and 45 healthy age matched controls were
      immunophenotyped by measuring the expression of CD3, CD4, CD7, CD8, CD25, CD28,
      CD56 and HLA-DR by flow cytometry. Circulating and in-vitro-produced cytokines
      were also measured by ELISA tests. CD7 and CD8 were significantly decreased in AD
      patients (48.3% and 18.2%, respectively) when compared to healthy subjects (63.2%
      and 28.3%, respectively). A significant increase in the CD4, CD25 and CD28
      antigen expression was also observed in the AD group (55.3% 24.8% and 65.1%) with
      respect to healthy subjects (44.5%, 10.3% and 54.3%). In addition there was a
      significant difference in the extent of apoptosis in lymphocyte culture, as
      measured by mean fluorescence intensity (MFI) of Fas antigen (CD95) expression on
      CD4+ T cells in 6 AD patients (MFI = 36% and 43%, by anti-CD3 and hyperthermia
      mediated-apoptosis, respectively) with respect to 6 healthy individuals (MFI =
      24% and 31%, by anti-CD3 and hyperthermia mediated-apoptosis, respectively), as
      well as in T-cell proliferation assay. A decline of Fas antigen expression on
      CD8+ subset was observed in the AD group with both stimuli (19% and 28%)
      comparing to the control group (29% and 39%). No differences were observed on
      circulating cytokines and spontaneous in vitro production of proinflammatory
      interleukin 1beta (IL-1beta), Tumor Necrosis Factor-alpha (TNF-alpha), IL-6 and
      IL-10 cytokines. Lipopolysaccharide (LPS)-stimulated in vitro production of IL
      1beta, TNF-alpha, IL-6 and IL-10 measured by a whole blood culture system was
      significantly higher in AD patients comparing to controls. Furthermore, the
      observed differences were more evident at late stages of disease. These findings
      suggest that immunological tests, based on lymphocyte immunophenotyping combined
      with pro-inflammatory cytokine determinations and measurement of apoptosis in
      peripheral blood might represent a useful tool to obtain more insight into the
      pathogenesis of AD and into the level of immune activation which could
      characterize the pathological state of lymphocytes from individual AD patients.

PMID- 10408973
TI  - The CTLA-4 gene is associated with multiple sclerosis.
AB  - We have investigated whether three intragenic polymorphisms of the CTLA-4 gene, a
      C/T base exchange in the promoter (p.-318), an A/G substitution in exon 1 (p.49)
      and a dinucleotide repeat polymorphism in exon 4 (p.642), were associated with
      genetic susceptibility to multiple sclerosis (MS). We observed a significant
      association (p < 0.05) for homozygosity for the G49 allele in a case-control
      analysis of 378 MS patients and 237 controls, and a transmission disequilibrium
      (p < 0.02) for the G49 allele in 31 MS families. This was further corroborated by
      evidence for linkage by the affected pedigree member (APM) analysis (p < 0.0002)
      and a transmission distortion (p < 0.05) of the exon 4(642) polymorphism.
      Sequencing of the promoter, the first and second exons and the parts of the first
      intron revealed no further polymorphisms. Our results suggest that a
      dysregulation of CTLA-4-driven downregulation of T-cell activation could be
      involved in the pathogenesis of MS.

PMID- 10408974
TI  - Relative amounts of mRNA encoding four subtypes of muscarinic receptors (m2-m5)
      in human peripheral blood mononuclear cells.
AB  - It is known that lymphocytes express functional muscarinic cholinergic receptors.
      In this study, RT-PCR method was applied to study the presence and relative
      levels of mRNA encoding muscarinic receptor subtypes in human peripheral blood
      mononuclear cells (PBMCs). Our results, confirmed by DNA sequencing, demonstrate
      the presence of m2, m3, m4, and m5 receptor subtypes in human PBMCs. The relative
      levels of muscarinic receptor subtypes fit the following pattern: m3 > m5 > m4 >
      m2. Our data provide strong evidence confirming previous pharmacological studies
      that suggested the existence of several subtypes of muscarinic receptors on human
      PBMCs. We cannot exclude the possibility that expression of receptor subtype
      depends on the lineage and/or activation status of the cell.

PMID- 10408976
TI  - Maturation of oligodendrocytes is more sensitive to TNF alpha than is survival of
      precursors and immature oligodendrocytes.
AB  - TNF alpha is a cytokine recently found at high levels in multiple sclerosis
      plaques. The present study addressed the questions whether TNF alpha might affect
      oligodendrocytes at various stages of maturation and whether the effects of
      transient incubation with TNF alpha would last during subsequent differentiation.
      Primary glial-cell cultures were treated with 1000 U/ml of TNF alpha for 48 h,
      beginning on days 1, 2, 6, 8 and 10 days in vitro, and allowed to grow for up to
      3 weeks (total) in vitro. A significant deficit of O4+/MBP+ cells in the TNF
      alpha-treated cultures became obvious during the second week. Moreover, the
      morphology of the O4-positive cells became more complex with time in the control
      cultures, whereas fewer cells in TNF alpha-treated cultures developed into cells
      with sheets of membrane or > four processes. In TNF alpha-treated cultures, the
      numbers of O4-positive cells increased by about four-fold during weeks 2 and 3,
      but the numbers of MBP-positive cells did not and were significantly lower than
      the numbers of MBP-positive cells in control cultures. The effects of TNF alpha
      were apparent 1 to 14 days after treatment, suggesting long-term influences, and
      could be initiated at diverse stages of maturation. Future testing of
      hypothetical mechanisms by which TNF alpha may inhibit oligodendrocyte
      differentiation should impact on our understanding of the apparent limitations on
      remyelination in the mature CNS.

PMID- 10408975
TI  - Mechanisms of recovery from experimental allergic encephalomyelitis induced with
      myelin basic protein peptide 68-86 in Lewis rats: a role for dendritic cells in
      inducing apoptosis of CD4+ T cells.
AB  - Spontaneous remission of experimental allergic encephalomyelitis (EAE) is usually
      associated with prominent apoptosis. The mechanisms behind apoptosis are unknown.
      We examined the functions of dendritic cells (DC) from Lewis rats with EAE
      induced by immunization with myelin basic protein peptide 68-86 (MBP68 - - 86).
      Recovery from EAE was associated with three major functional changes of freshly
      prepared DC: (1) elevated proliferation, (2) increased nitric oxide (NO)
      production, and (3) augmented IFN-gamma secretion. In Freund's complete adjuvant
      (FCA)-immunized control rats, no increase of proliferation, NO production or IFN
      gamma secretion was observed on day 21 post-immunization (p.i.), i.e., recovery
      from EAE. In vitro effects of IFN-gamma, TNF-alpha, TGF-beta1, IL-4 and IL-10 on
      DC were examined. IFN-gamma enhanced proliferation and NO production by DC, while
      TNF-alpha and IL-4 induced only slight DC proliferation. DC from recovering EAE
      rats (day 21 p.i.) suppressed MBP68 - - 86-induced T cell proliferation compared
      to DC obtained at other time points in EAE and FCA-immunized rats. DC-derived NO
      induced apoptosis of CD4+ T cells, thereby inhibiting autoreactive T cell
      responses. Besides IFN-gamma stimulation, NO production by DC was mainly induced
      in an antigen-dependent manner when DC were co-cultured with T cells. The results
      suggest that spontaneous recovery from EAE is associated with augmented DC
      functions. Overproduction of NO by DC results in apoptosis of autoreactive CD4+ T
      cells, thereby decreasing autoreactive T cell reactivities. The existence of such
      a NO negative feedback loop may contribute to remission of EAE.

PMID- 10408977
TI  - Highlights from the Fifth International Congress of the International Society of
      Neuroimmunology.

PMID- 10408978
TI  - Differential modulation of human immunoglobulin isotype production by the
      neuropeptides substance P, NKA and NKB.
AB  - The modifying effects of tachykinins substance P, neurokinin A and neurokinin B
      on immunoglobulin production were analyzed in an in vitro culture system.
      Purified human T- and B-cells were stimulated with TGFbeta2 and IL-5 to induce
      preferential IgA production. Neuropeptides had the following effects. (1) The
      levels of IgA and IgG4 production were enhanced by IL-5 and TGFbeta2; IgA levels
      remained constant or were slightly augmented by neuropeptides, whereas IgG4 was
      further augmented. (2) IL-5 and TGFbeta2 did not alter IgG3 production, but
      neuropeptides stimulated secretion of this subclass. (3) IgG1 and IgM production
      were inhibited by IL-5 and TGFbeta2. This effect was prevented by neuropeptides.
      (4) Other isotypes including IgG2 and IgE remained unaffected. Except for IgM,
      these effects were blocked by specific receptor antagonists indicating
      specificity. The tachykinin receptor NK-1 mRNA was detected in B- and T-cells,
      whereas NK-3 mRNA was only present in T- and B-cell coculture following
      activation. Furthermore, neuropeptide effects depended on cytokine co-stimulation
      and the presence of T-cells. These results suggest that neuropeptides are potent
      modifiers of preferential IgA synthesis.

PMID- 10408979
TI  - Chemokine mRNA expression in the cauda equina of Lewis rats with experimental
      allergic neuritis.
AB  - Chemokines play an important role in the migration of leukocytes to inflammatory
      sites. In this study, using the quantitative competitive reverse transcriptase
      PCR method, we analyzed sequential expression of certain chemokine mRNAs in the
      cauda equina (CE) of rats with experimental allergic neuritis (EAN). Interferon
      gamma-inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, macrophage
      inflammatory protein (MIP)-1alpha, the regulated upon activation normal T cell
      expressed and secreted chemokine (RANTES), and lymphotactin were analyzed on days
      0 (pre-immunization), 7 (preclinical stage), 10 (disease onset), 13 (clinical
      progression), 17 (disease peak), as well as on days 20, 24, and 34 post
      immunization (p.i.) (recovery). MCP-1 message increased at the preclinical stage
      and peaked at day 17 p.i. The increase in the early stage was not detected in
      other tissues, indicating peripheral nerve-specific upregulation. MIP-1alpha and
      IP-10 messages surged at day 13, then returned to low in the recovery stage.
      RANTES message increased at day 13 and peaked at day 17 p.i.; however, unlike
      other chemokines, it showed a second peak of expression on day 24. Lymphotactin
      message was undetectable at any time point. MCP-1 protein was detected
      immunohistologically in endothelial cells at day 7 p.i. The sequential expression
      of these chemokines in relation to the inflammatory process in the nerve leading
      to demyelination is discussed.

PMID- 10408980
TI  - Effects of cyclosporin A treatment on clinical course and inflammatory cell
      apoptosis in experimental autoimmune encephalomyelitis induced in Lewis rats by
      inoculation with myelin basic protein.
AB  - Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by
      inoculation with myelin basic protein (MBP) and adjuvants. Rats were treated with
      second daily injections of saline or cyclosporin A (CsA) from the day of
      inoculation. Saline-treated rats had an acute episode of disease followed by
      clinical recovery. Rats treated with CsA 16 or 32 mg/kg had minimal signs of EAE
      at the usual time after inoculation, but developed signs of disease after
      treatment was ceased. Rats treated with CsA 8 mg/kg had a delayed first episode
      of disease and then developed a relapsing or a chronic persistent course of
      disease. CsA 4 mg/kg delayed the onset of disease. To study the effects of CsA on
      the inflammatory infiltrate, cells were extracted from the spinal cords of rats
      with EAE, 16 h after a single injection of CsA or saline. Extracted cells were
      labelled with antibodies to T cells, CD11b/c (macrophages/microglia), CD95 (Fas)
      and Fas ligand. CsA 4 mg/kg did not alter the composition of the inflammatory
      infiltrate. Treatment with higher single doses of CsA caused a dose-dependent
      decline in the percentage of T cell receptor (TCR) alphabeta+ cells in the
      inflammatory infiltrate. All doses of CsA caused a significant increase in the
      number and percentage of cells that were apoptotic. CsA treatment caused an
      increase in the percentages of CD5+ and TCR alphabeta+ cells that were apoptotic.
      There was a decline in the percentage of apoptotic T cells that were Vbeta8.2+,
      compared to the percentage of non-apoptotic T cells that were Vbeta8.2+, in CsA
      treated rats compared to saline-treated controls. This suggests that, while CsA
      treatment caused a non-specific increase in the overall level of T cell apoptosis
      in the spinal cord, it abrogated the selective apoptosis of Vbeta8.2+
      encephalitogenic T cells that normally occurs during spontaneous recovery from
      acute EAE.

PMID- 10408981
TI  - Intracerebroventricular injection of interleukin-1 stimulates the release of high
      levels of interleukin-6 and interleukin-1 receptor antagonist into peripheral
      blood in the primate.
AB  - Previous studies in the rodent have shown that the cytokine IL-1 can act within
      the brain to influence peripheral IL-6 secretion. In order to determine if such
      an interaction occurs in the primate, we have compared the effects of
      intracerebroventricular vs. intravenous injection of IL-1beta on the release of
      IL-6 into the peripheral circulation of the monkey. The effects of i.c.v. IL
      1beta on the release of the IL-1 receptor antagonist (IL-1ra) were studied in
      parallel. For comparison, we have also measured the release of both IL-6 and IL
      1ra into lumbar CSF after i.c.v. IL-1beta injection. Ten ovariectomized rhesus
      monkeys with indwelling lateral ventricular and peripheral venous cannulae were
      studied. Human rIL-1beta (400 ng) was infused either i.c.v. or i.v. over 30 min
      and blood samples were collected for IL-6 and IL-1ra measurement by monoclonal
      human ELISAs. Although both i.c.v. and i.v. IL-1beta stimulated IL-6 and IL-1ra
      release into peripheral blood, the stimulation was much more profound after
      i.c.v. injection (p < 0.001). Peak IL-6 levels were 2010 +/- 590 pg/ml after
      i.c.v. IL-1beta compared to 243 +/- 60 pg/ml after i.v. IL-1beta. Peak IL-1ra
      levels were 61,310 +/- 16,190 pg/ml after i.c.v. IL-1beta compared to 18,175 +/-
      4270 pg/ml after i.v. IL-1beta. There was no significant effect of an i.c.v.
      saline infusion on peripheral IL-6 or IL-1ra levels. In four animals, lumbar CSF
      was collected 7 h after i.c.v. IL-1beta injection. The mean concentration of IL-6
      in CSF was 103, 570 +/- 13,780 pg/ml after i.c.v. IL-1beta vs. 224 +/- 190 pg/ml
      after i.c.v. saline injection; IL-1ra was 47,460 +/- 6290 pg/ml vs. 1040 +/- 550
      pg/ml. As expected, both i.c.v. and i.v. IL-beta stimulated ACTH and cortisol
      release; the stimulation was significantly greater after i.c.v. compared to i.v.
      administration (p < 0.001). Thus, in the monkey, i.c.v. injection of IL-1beta
      stimulates the release of large amounts of IL-6 and IL-1ra into the CSF and the
      peripheral circulation. Both IL-6 and IL-1ra were released into the peripheral
      circulation to a much greater extent after i.c.v. compared to i.v. IL-1beta
      infusion. These studies provide further support in the primate for a mechanism by
      which inflammation within the brain could induce a variety of systemic responses.

PMID- 10408982
TI  - Activation of microglial cells by the CD40 pathway: relevance to multiple
      sclerosis.
AB  - It is well known that microglial cells perform a key role in mediating
      inflammatory processes, which are associated with neurodegenerative diseases such
      as multiple sclerosis (MS). In this study, we report that CD40 expression on
      microglia is greatly enhanced by a low dose (10 U/ml) of IFN-gamma. We also find
      that ligation of microglial CD40 by CD40L triggers a significant production of
      TNF-alpha. Activation of microglia by ligation of CD40 in the presence of IFN
      gamma results in cultured cortical neuronal injury, which is markedly attenuated
      by blockade of the CD40 pathway or neutralization of TNF-alpha. Finally, we find
      significant levels of IFN-gamma and TNF-alpha in the medium of co-cultured
      activated CD4+ T cells and microglial cells, showing that microglia can supply
      the CD40 receptor to activated CD4+ T cells and suggesting that this cellular
      interaction is a key event in MS pathophysiology.

PMID- 10408983
TI  - Complement-mediated lesion of sympathetic ganglia in vitro with
      acetylcholinesterase antibodies.
AB  - When administered to rats, antibodies against acetylcholinesterase (AChE)
      selectively destroy presynaptic inputs to sympathetic ganglia. To investigate the
      mechanism of this immunolesion, we created an in vitro system in which relevant
      components could be manipulated. Freshly dissected rat superior cervical ganglia
      (SCG) were incubated 15-20 h at 37 degrees C in fresh human serum (a potent
      source of complement) with continuous oxygenation. More than 96% of neurons in
      six control ganglia retained synaptic inputs, as defined by action potentials or
      excitatory postsynaptic potentials (EPSP) upon stimulation of the preganglionic
      trunk. However, when anti-AChE antibodies were present (0.16 mg/ml), none of 61
      neurons from six incubated ganglia showed synaptic responses although membrane
      potential and input resistance remained normal. Staining for AChE and
      synaptophysin (a synaptic vesicle marker) was also disrupted in ganglia exposed
      to AChE antibodies in complement-sufficient serum. When complement was eliminated
      by substituting serum that was heat-inactivated or deficient in C3, synaptic
      input was retained in 60-90% of neurons incubated with AChE antibodies. Choline
      acetyltransferase activity (ChAT), an enzymatic marker of cholinergic cytoplasm
      in sympathetic ganglia, was largely lost after incubation with AChE antibodies
      and serum. However, incubation with AChE antibodies in heat-inactivated serum, or
      serum that was deficient in C3 or C8, caused no measurable loss of ganglionic
      ChAT activity. These findings strongly implicate the complement cascade in the
      destruction of preganglionic sympathetic terminals that follows binding of AChE
      antibodies.

PMID- 10408984
TI  - Epitope specificity of demyelinating monoclonal autoantibodies directed against
      the human myelin oligodendrocyte glycoprotein (MOG).
AB  - We describe the epitope specificity of a panel of ten demyelinating monoclonal
      antibodies (mAb) that recognise the extracellular immunoglobulin-like domain of
      human myelin oligodendrocyte glycoprotein (hMOG(lgd)). All the mAbs bind to the
      surface of MOG-transfected fibroblasts as assessed in vitro by FACS and
      immunocytochemistry but failed to recognise overlapping 15-mer MOG peptides when
      assessed by ELISA. However, increasing peptide length to 25 amino acids revealed
      that four mAbs recognised epitopes within the amino acid sequence 63-100 of human
      MOG. In contrast, a non-demyelinating MOG-specific mAb recognised MOG by both
      ELISA and Western blotting but failed to stain MOG transfected fibroblasts. These
      observations suggest that assays based on the use of MOG-transfected cell lines
      will differentiate between pathogenic and non-pathogenic MOG-specific antibody
      responses in experimental models and human diseases of the nervous system.

PMID- 10408985
TI  - Human immunodeficiency virus glycoproteins 160 and 41 alter sleep and brain
      temperature of rats.
AB  - Sleep is altered during all stages at which it has been recorded during chronic
      human immunodeficiency virus (HIV) infection, including the long latent phase
      before the development of AIDS; the mechanisms for such alterations are not
      known. The HIV envelope glycoprotein (gp) 120 alters sleep of rats in a manner
      somewhat similar to the alterations that occur in humans infected with HIV. To
      further determine which components of the virus may be responsible for altered
      behavior, we administered centrally into rats prior to dark onset recombinant HIV
      gp160 or gp41. Both glycoproteins increased non-rapid eye movements sleep,
      fragmented sleep, altered slow frequency components of the electroencephalogram,
      and induced modest febrile responses. These results complement and extend those
      previously obtained after gp120; HIV envelope glycoproteins are capable of
      altering sleep.

PMID- 10408986
TI  - The role of randomization in clinical studies: myths and beliefs.
AB  - On the basis of a survey of the methodological literature, we analyze widespread
      views on randomization and the advantage of randomized over nonrandomized
      studies. These views follow from theoretical considerations and at least three
      types of empirical investigations into the results of published studies.
      Randomization is often credited with advantages that it does not possess or
      confer. Several popular theoretical arguments in favor of randomization are shown
      to be either incorrect or imprecise. The published empirical comparisons of
      randomized with nonrandomized studies have methodological weaknesses and do not
      give any convincing information about the value of carefully designed and
      conducted nonrandomized studies. Six arguments, most of which are pragmatic
      rather than epistemological, are given to support our belief that randomization
      should not be avoided without compelling need. We conclude that although there
      are good arguments in favor of randomization, these are not the ones usually
      found in the literature. The very negative view on nonrandomized studies
      sometimes encountered in biostatistics and medicine may be comprehensible from a
      historical, pragmatic, or educational viewpoint, but it is not well founded on
      epistemological grounds.

PMID- 10408987
TI  - Positive predictive value of ICD-9th codes for upper gastrointestinal bleeding
      and perforation in the Sistema Informativo Sanitario Regionale database.
AB  - We identified patients whose records in the Sistema Informativo Sanitario
      Regionale database in the Italian region of Friuli-Venezia Giulia showed a code
      of upper gastrointestinal bleeding (UGIB) and perforation according to codes of
      the International Classification of Diseases (ICD)-9th revision. The validity of
      site- and lesion-specific codes (531 to 534) and nonspecific codes (5780, 5781,
      and 5789) was ascertained through manual review of hospital clinical records. The
      initial group was made of 1779 potential cases of UGIB identified with one of
      these codes recorded. First, the positive predictive values (PPV) were calculated
      in a random sample. As a result of the observed high PPV of 531 and 532 codes,
      additional hospital charts were solely requested for all remaining potential
      cases with 533, 534, and 578 ICD-9 codes. The overall PPV reached a high of 97%
      for 531 and 532 site-specific codes, 84% for 534 site-specific codes, and 80% for
      533 lesion-specific codes, and a low of 59% for nonspecific codes. These data
      suggest a considerable research potential for this new computerized health care
      database in Southern Europe.

PMID- 10408988
TI  - The Zelen design may be the best choice for a heroin-provision experiment.
AB  - Recently, the Dutch Parliament agreed upon the conduct of a randomized clinical
      trial on the effects on heroin provision on general health and psychosocial and
      criminal behavior in long-term addicts. Previous studies failed to establish the
      effects beyond reasonable doubt. The main reasons why previous trials failed are
      massive dropout or noncompliance in the control group. Designing a new heroin
      provision trial, we concluded that the Zelen design provides the best guarantee
      for obtaining valid study results. Compared with the traditional design, the
      Zelen design probably reduces noncompliance and dropout considerably, thus
      increasing validity. Depending on the study population, the Zelen design may
      reduce study precision. However, in a trial aimed at badly integrated addicts,
      the Zelen design can be conducted without loss of precision because baseline
      measurements will only weakly correlate with effect measurements. The arguments
      favoring the Zelen design may be generalized to trials in which the experimental
      treatment is highly attractive to the study participants. However, the use of the
      Zelen design precludes blinding of participants who receive the experimental
      treatment. We argue that the conduct of studies that predictably tend to produce
      invalid results is ethically dubious. The ethical problem of studying
      participants without their consent can be solved by a slight modification of the
      Zelen design in which the sampling of a control group is postponed. Both the
      traditional and the Zelen design can imply ethical problems. Both designs can be
      ethically justifiable and should not be rejected on a priori grounds.

PMID- 10408989
TI  - Use of antacids in a general population: the impact of health-related variables,
      lifestyle and sociodemographic characteristics.
AB  - Self-medication with antacids is very common in patients with less severe forms
      of dyspepsia, but we know very little about the users of antacids and their
      incentive to take them. The aim of this study was to analyze the relationship
      between self-reported use of antacids and health-related variables, lifestyle,
      and sociodemographic characteristics in order to characterize the use of antacids
      in a general population. The use of antacids was assessed by a questionnaire
      answered by men and women aged 20-62 years (n = 15,986; response rate 75.9%).
      Logistic regression analysis was used to quantify the relationships between the
      use of antacids and health-related variables, lifestyle, and sociodemographic
      characteristics. Approximately 10% of the population had used antacids during the
      preceding 14 days. There was no overall gender difference. Among those who had no
      dyspeptic symptoms, 1.5% reported use of antacids, whereas among those who had
      all three dyspeptic symptoms (heartburn, epigastric pain, peptic ulcer), 46.5%
      had used antacids. Heartburn was the most important predictor for antacid use in
      both men (odds ratio [OR] = 8.57 [6.65-11.04]) and women (OR = 9.35 [7.16-12.221)
      followed by self-reported epigastric pain and peptic ulcer (both: OR =
      approximately 2). The importance of these self-reported health conditions
      remained unchanged after adjusting for lifestyle and sociodemographic variables.
      There were fewer antacid users among unmarried women than married women, and
      coffee-drinking was inversely associated with antacid use. These findings were
      consistent in both bivariate and multivariate analysis. The present study
      provides population-based information showing that self-medication with antacids
      in Norway appeared to be appropriate. Because dyspeptic symptoms play a major
      role in the consumption of antacids, this study shows the importance of including
      information about specific clinical variables in the analysis and interpretation
      of patterns of drug use.

PMID- 10408990
TI  - Incremental cost-effectiveness analysis: the optimal strategy depends on the
      strategy set.
AB  - Evaluating the incremental cost-effectiveness of a technology is critical to
      understanding the impact of its adoption. The purpose of this study was to
      evaluate, using a particular example, how the specific alternatives selected for
      a cost-effectiveness analysis may influence the results of the analysis. In this
      example, we analyzed the incremental cost-effectiveness of estriol screening for
      Down syndrome. Model assumptions of expected costs and effectiveness were based
      on previously published work involving four clinical strategies, including a "do
      nothing" (no screening) strategy. When the analysis started with all four
      strategies, two of the strategies could not be considered cost-effective because
      of extended dominance. However, when we eliminated the "do nothing" from the
      strategy set because of its clinical irrelevance, all three remaining strategies
      might be considered cost-effective from a policy perspective. We concluded that
      the incremental cost-effectiveness of clinical strategies could be strongly
      affected by the starting point for the analysis.

PMID- 10408991
TI  - Anxiety and depression in breast cancer patients at low risk of recurrence
      compared with the general population: a valid comparison?
AB  - Breast cancer and its treatment have been associated with psychological
      morbidity. In this study our aim was to quantify the excess anxiety and
      depression resulting from breast cancer. We compared 538 newly diagnosed breast
      cancer patients at low risk of recurrence (87.0% responded) to 872 women randomly
      selected from the Danish general population (69.7% responded) using the Hospital
      Anxiety and Depression Scale (HADS). Contrary to expectations, the proportions
      classified as "cases" of anxiety and depression were not significantly different
      in the two groups. The breast cancer patients' mean HADS scores were
      significantly lower than those in the general population sample (anxiety, P =
      0.021; depression, P < 0.001), indicating less anxiety and depression. However,
      we question the validity of this comparison. The HADS may not be suitable for use
      in the general population and there may be methodological problems in comparisons
      of groups whose life situations are very different.

PMID- 10408992
TI  - Development of blood pressure and the incidence of hypertension in men and women
      over an 18-year period: results of the Nijmegen Cohort Study.
AB  - The objective of this study was to determine the factors that influence diastolic
      blood pressure (DBP) and the incidence of hypertension. In 1977, DBP and
      cardiovascular risk factors were measured in 7092 men and women. In 1995, 2335
      subjects participated at a second screening. Those patients already under
      hypertension treatment in 1977 were excluded. The DBP tracking was studied in
      subjects not under hypertension treatment during the study. Hypertension was
      defined on two ways in the analysis: under current hypertension treatment or a
      DBP > 95 mmHg measured at rescreening in 1995. Forty-seven percent of the
      subjects with a DBP < 75 mmHg in 1977 remained in the same category of DBP in
      1995, and 7% had become hypertensive. Of the 75-84 mmHg group in 1977, 40% stayed
      in the same category in 1995 and 15% became hypertensive. Of the 85-94 mmHg
      category, 30% stayed in the same category and 30% became hypertensive in 1995. Of
      the highest category in 1977 (> 95 mmHg), 64% were still in that category in
      1995. Baseline DBP in 1977 had the highest predictive value for future DBP.
      Weight gain over the years increased the risk for future hypertension: in
      contrast, there was no risk at a low DBP without weight gain. There is no need
      for regular check-ups for those patients with a low DBP who experience no weight
      gain. Borderline DBP (85-95 mmHg), together with weight gain, increases the risk
      of development of hypertension. The risk was especially high for men in the lower
      socioeconomic class.

PMID- 10408993
TI  - Detection of antimicrobial activity in urine for epidemiologic studies of
      antibiotic use.
AB  - Antibiotic resistance is the inevitable consequence of the selective pressure of
      antimicrobial drug use and the adaptive plasticity of the microorganisms.
      Excessive and irrational use of antimicrobial drugs is a problem in all
      countries. It is particularly troublesome in developing countries where there is
      a heavy burden of infectious diseases. This study was designed to determine
      whether detection of antimicrobial activity in the urine might be a useful tool
      for epidemiologic studies of the interaction between antibiotic use and
      resistance in developing countries. A laboratory marker is necessary because the
      history of antimicrobial drug use may be unreliable. Serial specimens or
      spontaneously voided urine were obtained from healthy volunteers given a single
      oral dose of commonly used antimicrobial drugs. Urine was also obtained from
      hospitalized patients the morning after the last dose of an antimicrobial drug
      and from untreated controls. Assays were performed with standard American Type
      Culture Collection (Rockville, MD) stains of Bacillus stearothermophilus,
      Escherichia coli, and Streptococcus pyogenes. Antimicrobial activity could not be
      detected in pretreatment urine. After a single oral dose, the beta lactam
      antibiotics and erythromycin could be detected for about 12 to 24 hours, whereas
      clindamycin, tetracycline, trimethoprim/sulfamethoxazole, and ciprofloxacin could
      be detected for 48 or more hours. In hospitalized patients, receiving multiple
      drugs, the following were the sensitivity and specificity for detection of
      antimicrobial activity: for B. stearothermophilus, 100.0% and 85.9%,
      respectively; for S. pyogenes, 94.9% and 94.9%, respectively; and for E. coli,
      71.8% and 98.7%, respectively. The combination of E. coli and Streptococcus
      pyogenes exhibited a sensitivity of 97.4% and specificity of 94.9%. Detection of
      antimicrobial activity in urine is a promising method to determine antimicrobial
      drug use in epidemiologic studies, particularly in populations in which drug use
      history is unreliable.

PMID- 10408994
TI  - An empirical investigation of exposure measurement bias and its components in
      case-control studies.
AB  - This study investigated bias due to misclassification of exposure in case control
      studies. Using a metaanalysis of data from a number of case control studies, in
      which a possibly misclassified exposure was validated against a more reliable
      one, estimates of misclassification indices and bias were obtained. The estimates
      were used to investigate whether misclassification indices, in particular,
      sensitivity and specificity and so-called quality indices, are typically
      nondifferential with respect to cases and controls. It is concluded that quality
      indices do not show any tendency to be either lower or higher in cases than
      controls. On the other hand, sensitivity tends to be higher in cases than
      controls and specificity lower. Estimates of misclassification bias may be either
      positive or negative and are consistent with random variation; there is little to
      suggest that bias is present in the studies analyzed.

PMID- 10408995
TI  - Development of a chronic disease indicator score using a Veterans Affairs Medical
      Center medication database. IMPROVE Investigators.
AB  - OBJECTIVE: Develop a chronic disease index that approximates the number of
      chronic diseases a patient has using a medication database. METHODS: An expert
      panel determined whether specific medication classes could be indicative of a
      chronic disease. Those classes identified were incorporated into a computer
      program and then used to screen the medication records of 246 randomly selected
      patients to estimate the number of chronic diseases present in each patient. This
      number was designated as the chronic disease index (CDI). The CDI was then
      validated against chart review. The CDI and a measure of disease severity, the
      chronic disease score (CDS) also were compared. The sensitivity and specificity
      of the computer program was analyzed for seven common chronic diseases. RESULTS:
      The expert panel designated 54 drug classes containing medications used to treat
      chronic diseases. The CDI correlated moderately with the number of chronic
      diseases found via chart review (r = 0.65; P = 0.001) and highly with the CDS (r
      = 0.81; P = 0.001). The index predicted the presence of three common diseases
      with a sensitivity of > or = 75%, and of six common diseases with a specificity
      of > or = 75%. CONCLUSIONS: The CDI correlates moderately well with the actual
      number of chronic disease states present. This tool may be useful for researchers
      when trying to identify patients with specific diseases and also for risk
      adjustment.

PMID- 10408997
TI  - Age-period-cohort models: a comparative study of available methodologies.
AB  - This article compares the estimates produced by a number of solutions to the
      identifiability problem in age-period-cohort models using a series of disease
      rates with known structure. The results suggest that only those methods that are
      based on the estimable functions such as curvatures can be recommended for use in
      all circumstances. The other common approaches that give parameter estimates that
      are easier to interpret all have induced bias in the estimates. In particular
      methods based on the minimization of a penalty function to achieve
      identifiability are only of use if there is no change in the rates with time. Any
      drift in the rates tends to be expressed as a cohort-based trend. The methods
      based on individual records introduce a bias if there is a strong age effect in
      the direction of a decreasing cohort trend and a compensating increase based on
      period effects. The nonparametric testing method has little power to detect
      trends in the rates in small tables but ascribes a strong drift in the rates to
      both period and cohort trends. With careful interpretation, all methods estimate
      nonlinear components correctly.

PMID- 10408996
TI  - Short- and long-term prediction of clinical and subclinical atherosclerosis by
      traditional risk factors.
AB  - This study compares the cross-sectional and longitudinal associations of
      cardiovascular risk factors with clinical coronary heart disease (CHD) and with
      subclinical carotid atherosclerosis measured by ultrasound. The study population
      were 1410 participants in the Atherosclerotic Risk in Community (ARIC) Study
      (1987-1989) who also participated in a 1974 community health survey. Smoking in
      1974 was associated with increased CHD prevalence in 1987-1989 (adjusted
      prevalence ratio = 2.2), whereas the corresponding cross-sectional association
      was practically absent. For hypercholesterolemia and hypertension, the
      longitudinal associations with CHD were also stronger than the cross-sectional
      associations. In contrast, the strength of the longitudinal and cross-sectional
      associations with carotid atherosclerosis was generally similar. These results
      underscore the advantages of using subclinical measures of atherosclerosis in
      cross-sectional studies. In addition, they suggest that the presence of smoking,
      hypertension, or hypercholesterolemia in mid-adulthood may have some persisting
      effects on the development of atherosclerotic disease in later life.

PMID- 10408998
TI  - Effect of mailed reminders on the response rate in surveys among patients in
      general practice.
AB  - Randomized trials were performed in Denmark and The Netherlands to determine the
      effect of mailed reminders on the response rate in surveys among patients in
      general practice. In both countries, general practitioners handed out
      questionnaires to 200 adult patients who came to visit them. An intervention
      group of 100 patients received reminders at 3 weeks after the visit, whereas a
      control group of the remaining 100 patients did not receive reminders. The
      response rate was significantly higher in the intervention groups than in the
      control group in The Netherlands (86% versus 55%, respectively) but not in
      Denmark (87% versus 81%, respectively). Mailed reminders can improve the response
      rate in surveys related to a general practice, but they are not effective in all
      situations.

PMID- 10408999
TI  - Compliance with fluvastatin treatment characterization of the noncompliant
      population within a population of 3845 patients with hyperlipidemia. CREOLE Study
      Team.
AB  - The objectives of the study were to analyze 1) compliance with an HMG-CoA
      reductase inhibitor, 2) the relationship between treatment compliance and
      sociodemographic, clinical, and psychological criteria, and 3) the effect of
      raising patients' awareness through distribution of an information notice. The
      results analyzed in this article compare the noncompliant and compliant
      population independently of awareness. This open-label study was conducted in two
      randomized parallel groups: a control group that received the information
      normally given by the practitioners, and an awareness group that received
      specific informational brochures on diet and cardiovascular risk factors and the
      reasons for the treatment. Male and female patients (n = 3845) aged 18 to 75
      years with primary hypercholesterolemia (type IIa and IIb), not taking a
      cholesterol-lowering drug or for whom an ongoing treatment was poorly tolerated
      or ineffective, were to be included. Cholesterol levels had to be greater than
      250 mg/dL (or 200 mg/dL if previous coronary history) and triglyceride levels
      less than 350 mg/dL. A total of 2888 subjects (75%) were defined as compliant
      (taking more than 90% of the prescription) and 957 (25%) noncompliant. Both
      populations are identical for age, sex ratio, and different risk factors, with
      the exception of diabetes. The adverse effects in noncompliant subjects were very
      clearly different, with an overrepresentation of gastrointestinal and neurologic
      effects and the noncompliant patients more frequently having more than one
      adverse effect. Noncompliant patients had an identical duration of follow-up, and
      the number of patients claiming to have a symptom related to
      hypercholesterolemia, self-evaluation of cardiovascular risk level, and source of
      knowledge about cholesterol and diet was similar in both groups. In contrast, in
      the noncompliant group, there were a larger number of symptomatic patients who
      thought the drug did not improve the symptoms. In practice, these results show
      that physicians should systematically evaluate compliance by looking for and
      analyzing adverse effects and by reassuring the patient when these effects are
      minor or probably unrelated to the treatment. Diabetics and polymedicated
      patients deserve special attention in this regard.

PMID- 10409000
TI  - [Day surgery for patients with nasal polyps].

PMID- 10409001
TI  - Hypertension.

PMID- 10409002
TI  - Revisiting the Manitoba Centre for Health Policy and Evaluation and its
      population-based health information system.

PMID- 10409003
TI  - A comparative study of the costliness of Manitoba hospitals.
AB  - OBJECTIVES: In light of ongoing discussions about health care policy, this study
      offered a method of calculating costs at Manitoba hospitals that compared
      relative costliness of inpatient care provided in each hospital. RESEARCH DESIGN:
      This methodology also allowed comparisons across types of hospitals-teaching,
      community, major rural, intermediate and small rural, as well as northern
      isolated facilities. MEASURES: Data used in this project include basic hospital
      information, both financial and statistical, for each of the Manitoba hospitals,
      hospital charge information by case from the State of Maryland, and hospital
      discharge abstract information for Manitoba. The data from Maryland were used to
      create relative cost weights (RCWs) for refined diagnostic related groups (RDRGs)
      and were subsequently adjusted for Manitoba length of stay. These case weights
      were then applied to cases in Manitoba hospitals, and several other adjustments
      were made for nontypical cases. This case mix system allows cost comparisons
      across hospitals. RESULTS: In general, hospital case mix costing demonstrated
      variability in hospital costliness, not only across types of hospitals but also
      within hospitals of the same type and size. CONCLUSIONS: Costs at the teaching
      hospitals were found to be considerably higher than the average, even after
      accounting for acuity and case mix.

PMID- 10409004
TI  - The unintended and unexpected impact of downsizing: costly hospitals become more
      costly.
AB  - OBJECTIVES: In this project we assessed the impact of 1992 budget cuts ($50
      million, or approximately 7% of urban hospitals' budgets) on the relative
      costliness of Manitoba's hospitals. The cuts targeted the teaching hospitals,
      those institutions we had found to be particularly costly in a previous Manitoba
      Centre for Health Policy and Evaluation study. RESULTS: Unexpectedly, we found
      that because budget cuts were smaller proportionately than the number of beds
      closed, the care at the teaching hospitals (as well as at several other
      hospitals) became relatively more, not less, costly. Also quite contrary to
      public perceptions, once other expenditures such as new hospital programs and
      expansions were accounted for, the actual change in urban hospital expenditures
      over the years compared was less than 1%. CONCLUSIONS: The study highlighted the
      importance of monitoring program outcomes.

PMID- 10409005
TI  - Monitoring the impact of hospital downsizing on access to care and quality of
      care.
AB  - The most recent data used for monitoring the potential effects of bed closures in
      Winnipeg hospitals since 1992/93 found that despite downsizing, access to care
      was by no means compromised. Just as many patients were cared for in 1995/96 as
      in 1991/92. Changes in patterns of care included more outpatient and fewer
      inpatient surgeries, and a decrease in the number of hospital days. The number of
      high-profile surgical procedures, such as angioplasty, bypass, and cataract
      surgery, performed increased dramatically during downsizing. Quality of care
      delivered to patients, measured by mortality and readmission rates, was
      unaffected by bed closures. Of particular concern was the impact of downsizing on
      the two most vulnerable health groups--the elderly and Manitobans in the lowest
      income group. Access and quality of care for these groups also remained
      unchanged. However, those in the lowest income group spent almost 43% more days
      in hospital than those in the middle income group, and research demonstrates that
      these variations in hospital use across socioeconomic groups reflect real and
      important health differences and are not driven by social reasons for admissions.
      Finally, a large decrease in waiting time for nursing home placement underlines
      the relationship between downsizing and availability of alternatives to
      hospitalization.

PMID- 10409006
TI  - Establishing a population data-based policy unit.
AB  - The Manitoba Centre for Health Policy and Evaluation (MCHPE) developed POPULIS, a
      population-based health information system, as a vehicle for changing the way we
      think about the role of health care as a determinant of health. Serving as a
      bridge between analysts who produce research and politicians and policymakers who
      use it, MCHPE has developed a research infrastructure that can transform
      routinely collected administrative data into policy-relevant information. This
      paper provides a description of Manitoba and its health care system, as well as
      how MCHPE was started and how it functions. It describes how we at the Centre
      work with various databases, from the acquisition process through developing
      concepts and capabilities to the final validity and sensitivity testing of
      results. We detail the role of a population-based conceptual framework in
      challenging those who suggest more spending on medical care is self-evidently
      desirable.

PMID- 10409008
TI  - An assessment of the potential for repatriating care from urban to rural
      Manitoba.
AB  - OBJECTIVES: Following the closure of Manitoba hospital beds, the Manitoba
      government adopted a strategy of shifting hospital care from more expensive urban
      hospitals to less expensive rural facilities. With this project, Manitoba Centre
      for Health Policy and Evaluation (MCHPE) studied the implications of the stated
      policy of "repatriation." RESEARCH DESIGN: The project first involved examining
      population-based patterns of hospital utilization to define hospital service
      areas for 10 large rural hospitals. Three different hospital service area
      definitions were developed for use in sensitivity testing. Rates of overall use
      of hospital services, indicators of need for health care, and patterns of use of
      urban facilities are compared for these hospital service areas. Using a large
      rural hospital as a benchmark, patterns of adult surgical, adult medical,
      pediatric, and obstetric care were examined for the hospital service areas.
      Number and percent of cases provided by the index hospital and by urban hospitals
      were compared, to assess the feasibility and the potential impact of redirection
      of care to the benchmark level. CONCLUSIONS: Although in theory a significant
      percentage of care delivered to rural residents by Winnipeg hospitals might be
      redirected to rural institutions, the project raised issues of feasibility.
      Moreover, it identified that most of the redirected cases could be accommodated
      within existing capacity.

PMID- 10409007
TI  - Assessing the extent to which hospitals are used for acute care purposes.
AB  - OBJECTIVES: The degree to which Manitobans were appropriately hospitalized for
      medical conditions was assessed using a retrospective chart review of a sample of
      patients in 26 hospitals. RESEARCH DESIGN: A standardized set of object-based,
      nondiagnostic criteria (Inter-Qual) was used by trained abstractors to assess the
      patient at admission and for each day of stay. RESULTS: A high percentage of
      admissions and days of care were inappropriate. Overall, 49.5% of medical
      patients were acute at the time of admission, 1.6% required no health care
      services, and 48.9% could have received care through alternate methods or
      facilities. Only 33.4% of the subsequent days of stay were appropriate. For
      patients assessed as acute at the time of admission, by the 8th day of stay, only
      47% were still acute and by day 30, only 27% were acute. Patients aged 75 years
      or older were just as likely to be acute at the time of admission as were younger
      patients; however, they accounted for 54% of the days in the study, and fewer
      than 30% of these days were acute. Our data suggest that despite their high use
      of hospitals, disadvantaged groups (the poor, aboriginal Manitobans), have the
      same levels of appropriateness as others. CONCLUSIONS: We conclude that
      alternatives to hospital care must first be established and made known and
      available before a shift in health care resources can occur.

PMID- 10409009
TI  - Waiting times for surgical procedures.
AB  - OBJECTIVES: Polls show that nearly two thirds of Canadians believe that waiting
      times prior to surgery have increased in recent years. A study was undertaken in
      Manitoba to determine whether public perceptions about long and increasing waits
      were valid. RESEARCH DESIGN: Using administrative data, waiting times for 10
      types of surgery-ranging from coronary artery bypass surgery and mastectomy to
      cataract surgery and hernia repairs-were studied over a 5-year period. RESULTS:
      Using each patient's preoperative visit to the surgeon as the beginning of the
      waiting time, median waiting times for most of the procedures studied were found
      to have, in fact, remained stable or fallen slightly over the period studied.
      CONCLUSIONS: Further, an examination of waiting times for cataract surgery
      demonstrated that allowing surgeons to practice in both public and private arenas
      seems to be counterproductive to providing good public service.

PMID- 10409010
TI  - Needs-based planning for generalist physicians.
AB  - OBJECTIVES: The Manitoba Centre for Health Policy and Evaluation (MCHPE)
      collaborated with a provincially-appointed Physician Resource Committee in an
      assessment of provincial physician resources. RESEARCH DESIGN: Beginning with map
      based analyses of physician supply and contacts across the province, compared
      with the health and socioeconomic characteristics of local populations, the study
      moved to a needs-based, regression-based approach to physician resource planning.
      RESULTS: The results challenged the popular belief that Manitoba suffers from an
      increasing shortage of physicians. A handful of high-need, low-supply and low-use
      areas are identified, as is the expensive surplus of generalist physicians in
      Winnipeg. (Generalist physicians include general and family practitioners as well
      as general internists and pediatricians.) No relationship between physician
      supply and health characteristics of populations, or between high physician
      supply and low hospital use patterns were found. Given the Committee's interest
      in what drives high physician contact rates, analyses of visit patterns of
      hypertensive patients were undertaken. We found that patients who had more
      complex medical conditions made more contacts, but that after controlling for
      this and other key patient characteristics, the patient's primary care
      physician's patient recall rate was a strong influence on how frequently visits
      were made.

PMID- 10409011
TI  - Issues in planning for specialist physicians.
AB  - OBJECTIVES: The Manitoba Centre for Health Policy and Evaluation worked in
      support of a provincial Physician Resource Committee to address questions
      pertinent to assessing Manitoba's supply of specialist physicians. RESEARCH
      DESIGN: Because there was no direct method of determining whether the province's
      supply of specialists was adequate, three types of evidence were reviewed: the
      supply of specialists relative to recommended population/physician ratios; the
      supply of specialists relative to other Canadian provinces; and the level of care
      delivered by specialists in Manitoba relative to other provinces. Four additional
      questions were addressed: is a problem developing from the aging of Manitoba's
      specialist physicians? and will the supply of specialists be sufficient to keep
      up with the aging of the population? How well do specialists serve as a
      provincial resource? and how well do specialists serve high-need populations?

PMID- 10409012
TI  - Using population-based data to enhance clinical practice guideline development.
AB  - OBJECTIVES: Working with the College of Physicians and Surgeons of Manitoba, and
      using tonsillectomies as a basis of inquiry, MCHPE examined surgical rates and
      patterns of practice. This project had three major aims: to review whether
      current patterns of delivery provide optimal care; to enhance the development of
      clinical guidelines; and to inform and influence physician practice. RESEARCH
      DESIGN: Both a population-based method of inquiry (which permits comparisons
      across population groups) and a provider-based approach (which offers insights
      into differences in the nature of care offered by different types of hospitals
      and physicians) were used. MEASURES: Synergies between these two approaches
      offered useful insight into aspects of quality and efficiency of care. RESULTS:
      Consistent with other jurisdictions, there was a high degree of variability
      across regions. However, there were also a number of surprising findings,
      including high rates of surgery in females, in older children, and among
      residents of rural areas. Data analysis raised a number of quality-of-care issues
      related to small caseload volumes, performance of procedures in very young
      children, and patterns of postoperative care in rural hospitals. The analyses
      provided impetus for addressing these issues in the guideline and suggested that
      the target audience for intervention should be rural physicians rather than urban
      specialists. CONCLUSIONS: This project demonstrated that data analysis can
      provide a powerful adjunct to the development and implementation of clinical
      practice guidelines.

PMID- 10409013
TI  - Delivering prevention: the role of public programs in delivering care to high
      risk populations.
AB  - A successful program of prevention or early detection should have a high level of
      population coverage and should ensure that high-risk populations are targeted. In
      practice, relatively little attention has been paid to the tendency toward
      greater use of preventive care by populations at lower risk, in other words, for
      higher use by the wealthy than by the poor. Current delivery patterns of
      preventive care raise questions as to how to organize these services more
      effectively. Physician-based delivery of preventive care in a fee-for-service
      system seems to result in Canadian patterns of use that are fairly similar to
      those found in the United States. Universal free insurance alone does not appear
      to be enough to counteract the failure to target preventive care toward the least
      healthy groups. Appropriately-run Canadian provincial programs may be able both
      to expand coverage and to target high-risk populations. The population coverage
      for three measures directed toward prevention or early detection--childhood
      immunization (which in Manitoba has been offered through a long-standing
      provincial program), screening mammography (a new provincial program), and
      cervical cancer screening (no provincial program)-are compared using longitudinal
      administrative data from Manitoba. The discussion emphasizes the role of
      provincial programs and the possibilities for using population-based data to help
      provide cost-effective care to high-risk populations.

PMID- 10409014
TI  - Managing health services: how the Population Health Information System (POPULIS)
      works for policymakers.
AB  - OBJECTIVES: University-based researchers in Manitoba, Canada, have used
      administrative data routinely collected as part of the national health insurance
      plan to design an integrated database and population-based health information
      system. This information system is proving useful to policymakers for answering
      such questions as: Which populations need more physician services? Which need
      fewer? Are high-risk populations poorly served? or do they have poor health
      outcomes despite being well served? Does high utilization represent overuse? or
      is it related to high need? More specifically, this system provides decision
      makers with the capability to make critical comparisons across regions and
      subregions of residents' health status, socioeconomic risk characteristics and
      use of hospitals, nursing homes, and physicians. The system permits analyses of
      demographic changes, expenditure patterns, and hospital performance in relation
      to the population served. The integrated database has also facilitated outcomes
      research across hospitals and countries, utilization review within a single
      hospital, and longitudinal research on health reform. The discussion highlights
      the strengths of integrated population-based information in analyzing the health
      care system and raising important questions about the relationship between health
      care and health.

PMID- 10409015
TI  - Communicating with the public, communicating with each other.

PMID- 10409016
TI  - From research to policy: what have we learned?
AB  - The Manitoba Centre for Health Policy and Evaluation has now had eight years of
      experience as an academic research unit interfacing with policymakers. Most of
      our research has focused on the determinants of health and on the delivery of
      health care from a population perspective. Each project that we have undertaken
      has made its own contribution and reinforced or built on the contribution of
      others. By communicating closely with policymakers at all levels, while
      maintaining an arm's-length relationship and the right of publication, MCHPE acts
      as a knowledgeable non-stakeholder with a commitment to inform the broader
      public.

PMID- 10409017
TI  - The population's use of pharmaceuticals.
AB  - OBJECTIVES: In this study, population-based analysis is used to study the extent
      to which characteristics such as age, sex, socioeconomic status, and region of
      residence are associated with different patterns of pharmaceutical use. It also
      includes an examination of whether pharmaceutical use is responsive to
      differential health needs across the population. RESEARCH DESIGN: Indicators of
      access, intensity of use, and total expenditures are used to describe Manitobans'
      use of pharmaceutical agents, consistent with the POPULIS framework. MEASURES:
      Several rate-based measures have been developed for this purpose: the number of
      residents who are pharmaceutical users; the number of prescriptions dispensed;
      the number of different drugs dispensed; the total number of defined daily doses
      (DDDs) dispensed; and expenditures for pharmaceuticals. The DDD measurement
      provides a cumulative assessment of total drug use (i.e., across multiple drug
      categories) and is a useful indicator of a population's total drug exposure.
      RESULTS: Patterns of use of pharmaceuticals follow patterns similar to those
      patterns in earlier POPULIS studies on health care access, intensity, and
      expenditures. In areas where health is generally poorer, a greater number of
      prescriptions are dispensed. The highest use of pharmaceuticals also was found in
      the lower-income quintiles and among those at greatest socioeconomic risk,
      traditionally those with the poorest health status. CONCLUSIONS: This kind of
      population-based pharmaceutical information can help monitor the effectiveness of
      policy initiatives, as well as serve to better manage pharmaceutical use within
      the health care system.

PMID- 10409018
TI  - Adding up provincial expenditures on health care for Manitobans: a POPULIS
      project. Population Health Information System.
AB  - OBJECTIVES: Using the POPULIS framework, this project estimated health care
      expenditures across the entire population of Manitoba for inpatient and
      outpatient hospital utilization, physician visits, mental health inpatient, and
      nursing home utilization. RESEARCH DESIGN: This estimated expenditure information
      was then used to compare per capita expenditures relative to premature mortality
      rates across the various areas of Manitoba. RESULTS: Considerable variation in
      health care expenditures was found, with those areas having high premature
      mortality rates also having higher health care expenditures.

PMID- 10409019
TI  - Using the POPULIS framework for interprovincial comparisons of expenditures on
      health care. Population Health Information System.
AB  - OBJECTIVES: Motivated by Manitoba Health's desire to know how health spending in
      Manitoba compared with other provinces, this study is a descriptive project
      designed to inform the health policy process by comparing indicators of need and
      expenditure across Canada. RESEARCH DESIGN: Population characteristics that are
      known to influence the need for health care constitute the comparative data
      categories. FINDINGS: In terms of all five health status indicators and five of
      eight socioeconomic indicators, Manitoba ranked medium (fourth to seventh of 10
      provinces) or average. Demographic characteristics placed Manitoba second to
      Saskatchewan in proportion of both elderly residents and Registered Indians. This
      is notable, because both groups traditionally have high health needs. With
      provincial characteristics established, the second part of the study compares
      provincial per capita health expenditure data with expected need for health care
      services. RESULTS: Overall, the study finds provincial health expenditures are
      not related to health care need indicators. Saskatchewan is a case in point;
      despite having similar population characteristics to Manitoba, Saskatchewan has a
      population with good health status and lower health care expenditures. This
      offers a model that invites further exploration. CONCLUSIONS: At the provincial
      level the amount of health care spending is not positively related to the need
      for health care.

PMID- 10409021
TI  - Blood transfusions in critical care.

PMID- 10409020
TI  - Blood transfusions in critical care.

PMID- 10409022
TI  - Blood transfusions in critical care.

PMID- 10409023
TI  - Blood transfusions in critical care.

PMID- 10409024
TI  - Transfusion medicine.

PMID- 10409025
TI  - Transfusion medicine.

PMID- 10409026
TI  - Transfusion medicine.

PMID- 10409027
TI  - Transfusion medicine.

PMID- 10409028
TI  - Reappearance of hepatitis B 10 years after kidney transplantation.

PMID- 10409029
TI  - Efficacy of superovulation and intrauterine insemination in the treatment of
      infertility.

PMID- 10409030
TI  - Efficacy of superovulation and intrauterine insemination in the treatment of
      infertility.

PMID- 10409031
TI  - Clinical problem-solving: a balancing act.

PMID- 10409032
TI  - Clinical problem-solving: a balancing act.

PMID- 10409033
TI  - Legal action to ensure treatment of tuberculosis.

PMID- 10409034
TI  - Legal action to ensure treatment of tuberculosis.

PMID- 10409035
TI  - False false positive rates.

PMID- 10409036
TI  - Mode of delivery and the risk of vertical transmission of HIV-1.

PMID- 10409037
TI  - Mode of delivery and the risk of vertical transmission of HIV-1.

PMID- 10409038
TI  - Mode of delivery and the risk of vertical transmission of HIV-1.

PMID- 10409039
TI  - Vancomycin resistance in Staphylococcus aureus.

PMID- 10409040
TI  - Exercise electrocardiography with right precordial leads.

PMID- 10409041
TI  - Exercise electrocardiography with right precordial leads.

PMID- 10409042
TI  - Exercise electrocardiography with right precordial leads.

PMID- 10409043
TI  - Exercise electrocardiography with right precordial leads.

PMID- 10409044
TI  - Radial scars and breast cancer.

PMID- 10409045
TI  - Assessment of splenic function in familial asplenia.

PMID- 10409046
TI  - Legalized physician-assisted suicide in Oregon.

PMID- 10409048
TI  - What is rationing?

PMID- 10409047
TI  - Legalized physician-assisted suicide in Oregon.

PMID- 10409049
TI  - "Hibernating myocardium": a confusing term?

PMID- 10409050
TI  - Antibacterial activity of marine-derived fungi.
AB  - A total of 227 marine isolates of ubiquitous fungi were cultivated on different
      media and the secondary metabolite content of the extracts (ethyl
      acetate/chloroform/methanol 3:2:1) characterized by HPLC. The fungi were secured
      from animals, plants and sediments of Venezuelan waters (0-10 m) including
      mangroves and lagoonal areas. The extracts were tested for antibacterial
      activity. A total of 7 were active towards Vibrio parahaemolyticus and 55 towards
      Staphylococcus aureus, representing 18 different fungal species from 8
      ascomycetous genera. For 61 strains of Penicillium citrinum antibacterial
      activity correlated well with content of secondary metabolites as measured by
      HPLC. Thirteen isolates of Penicillium steckii produced very similar profiles of
      secondary metabolites and 6 of these had activity against either V.
      parahaemolyticus or S. aureus or both.

PMID- 10409051
TI  - Executive summary and statement of goals of the report New Zealand Oral Health
      Goals for the New Millennium.

PMID- 10409053
TI  - The electronic plant gene register.

PMID- 10409052
TI  - Treatment of halitosis.

PMID- 10409054
TI  - Varmus defends E-biomed proposal, prepares to push ahead.

PMID- 10409055
TI  - Library-society alliance puts bio journals online.

PMID- 10409056
TI  - Panel discounts implant disease risk.

PMID- 10409057
TI  - RAC nixes plan to treat retinoblastoma.

PMID- 10409058
TI  - Legal fight over patents on life.

PMID- 10409059
TI  - Chimps in the wild show stirrings of culture.

PMID- 10409060
TI  - Are out primate cousins 'conscious'?

PMID- 10409061
TI  - Genomes reveal kin connections for whales and pumas.

PMID- 10409062
TI  - Darwin's more stately mansion.

PMID- 10409063
TI  - Drug development in space?

PMID- 10409065
TI  - Are centrosomes or aneuploidy the key to cancer?

PMID- 10409064
TI  - Mitochondrial recombination?

PMID- 10409066
TI  - A clock for the ages.

PMID- 10409068
TI  - Test tube evolution catches time in a bottle.

PMID- 10409067
TI  - Ecology returns to speciation studies.

PMID- 10409069
TI  - Early life thrived despite earthly travails.

PMID- 10409070
TI  - Going beyond appearances to find life's history.

PMID- 10409071
TI  - FEV1 and PEF in COPD management.

PMID- 10409072
TI  - Health effects of passive smoking.

PMID- 10409073
TI  - Investigation and management of persistent dry cough.

PMID- 10409074
TI  - Targeting DNase in cystic fibrosis.

PMID- 10409075
TI  - [Directives from the commander of the Main Military Medical Administration of the
      Ministry of Defense of the Russian Federation].

PMID- 10409077
TI  - [Dissertations defended at the end of 1998--the start of 1999].

PMID- 10409076
TI  - [The 5th anniversary of the Zashchita All-Russian Center for Catastrophic
      Medicine].

PMID- 10409078
TI  - [2 centuries of our alma mater--half a century with her by one course].

PMID- 10409079
TI  - [The 50th anniversary of the epidemiological health detachment of the Moscow
      Military Air Force and Antiaircraft District].

PMID- 10409080
TI  - [The 5th anniversary of the Morskoi meditsinskii zhurnal].

PMID- 10409081
TI  - Self-management education for adults with asthma improves health outcomes.

PMID- 10409082
TI  - Why futility policies are not the answer.

PMID- 10409083
TI  - Respect for patients should dominate health care decisions.

PMID- 10409084
TI  - A memorable incident: when a shovel should be an agricultural implement.

PMID- 10409085
TI  - Mass Spectrometry in DNA analysis.

PMID- 10409087
TI  - Emergency warning lights and sirens.

PMID- 10409086
TI  - Separation and analysis of peptides and proteins.

PMID- 10409088
TI  - Determination of elevated jugular venous pressure by real-time ultrasound.

PMID- 10409089
TI  - Dangerous form of marijuana.

PMID- 10409090
TI  - Tissue adhesives.

PMID- 10409091
TI  - Routine stress testing at triage for chest pain.

PMID- 10409092
TI  - Routine stress testing at triage for chest pain.

PMID- 10409093
TI  - Managed health care organizations and emergency care. Emergency Medicine Practice
      Committee, American College of Emergency Physicians.

PMID- 10409094
TI  - Ambulance Diversion. EMS Committee, American College of Emergency Physicians.

PMID- 10409095
TI  - Emergency ambulance destination. EMS Committee, American College of Emergency
      Physicians.

PMID- 10409096
TI  - Otolith function in spatial orientation and movement: Symposium in memory of
      Volker Henn. Zurich, Switzerland, May 18-19, 1998. Proceedings.

PMID- 10409097
TI  - Otolith ocular reflex function of the tangential nucleus in teleost fish.
AB  - In teleost fish, the tangential nucleus can be identified as a compact, separate
      cell group lying ventral to the VIIIth nerve near the middle of the vestibular
      complex. Morphological analysis of larval and adult hindbrains utilizing biocytin
      and fluorescent tracers showed the tangential nucleus to be located entirely
      within rhombomeric segment 5 with all axons projecting into the contralateral
      MLF. Combined single-cell electrophysiology and morphology in alert goldfish
      found three classes of neurons whose physiological sensitivity could be readily
      correlated with rotational axes about either the anterior (45 degrees), posterior
      (135 degrees), or horizontal (vertical axis) semicircular canals. Tangential
      neurons could be distinguised from those in semicircular-canal specific subnuclei
      by an irregular, spontaneous background of 10-15 sp/s and sustained static
      sensitivity after +/- 4 degrees head displacements. Each axis-specific tangential
      subtype terminated appropriately onto oculomotor subnuclei responsible for either
      vertical, torsional, or horizontal eye movements and, in a few cases, axon
      collaterals descended in the MLF toward the spinal cord. We hypothesize,
      therefore, that the tangential nucleus consists of 3 axis-specific phenotypes
      that process gravitoinertial signals largely responsible for controlling
      oculomotor function, but that also in part, maintain body posture.

PMID- 10409099
TI  - ["Frontier" products].

PMID- 10409098
TI  - Miniature EPSPs and sensory encoding in the primary afferents of the vestibular
      lagena of the toadfish, Opsanus tau.
AB  - The synaptic activity transmitted from vestibular hair cells of the lagena to
      primary afferent neurons was recorded in vitro using sharp, intracellular
      microelectrodes. At rest, the activity was composed of miniature excitatory
      postsynaptic potentials (mEPSPs) at frequencies from 5 to 20/s and action
      potentials (APs) at frequencies betwen 0 and 10/s. mEPSPs recorded from a single
      fiber displayed a large variability. For mEPSPs not triggering APs, amplitudes
      exhibited an average coefficient of variance (CV) of 0.323 and rise times an
      average CV of 0.516. APs were only triggered by mEPSPs with larger amplitudes
      (estimated 4-6 mV) and/or steeper maximum rate of rise (10.9 mV/ms, +/- 3.7 SD,
      n=4 experiments) compared to (3.50 mV/ms, +/-0.07 SD, n=6 experiments) for
      nontriggering mEPSPs. The smallest mEPSPs showed a fast rise time (0.99 ms
      between 10% and 90% of peak amplitude) and limited variability across fibers
      (CV:0.18) confirming that they were not attenuated signals, but rather
      represented single-transmitter discharges (TDs). The mEPSP amplitude and rise
      time relationship suggests that many mEPSPs represented several, rather than a
      single pulse of secretion of TDs. According to the estimated overall TD
      frequency, the coincidence of TDs contributing to the same mEPSP were not
      statistically independent, indicating a positive interaction between TDs that is
      reminiscent of the way subminiature signals group to form miniature signals at
      the neuromuscular junction. Depending on the duration and intensity of efferent
      stimulation, a complete block of AP initiation occurred either immediately or
      after a delay of a few seconds. Efferent stimulation did not significantly change
      AP threshold level, but abruptly decreased mEPSP frequency to a near-complete
      block that followed the block of APs. Maximum mEPSP rate of rise decreased
      during, and recovered progressively after, efferent stimulation. After
      termination of efferent stimulation, mEPSP amplitude did not recover instantly
      and for a few seconds the amplitude distribution of synaptic events showed fewer
      large-amplitude events than during the control period. This confirms that mEPSP
      amplitude and rate of rise properties, which are critical for triggering afferent
      APs, are modified by efferent activity. The depression of afferent AP firing
      during efferent stimulation corresponded to a decrease in mEPSP frequency and, to
      a lesser extent, a decrease in mEPSP amplitude and rate of rise, suggesting, a
      decrease in the level of interaction among TDs contibuting to a mEPSP.

PMID- 10409100
TI  - Proceedings of the Aortic Surgery Symposium VI. New York, New York, USA. April 30
      May 1, 1998.

PMID- 10409101
TI  - [Surgical treatment of pancreatic cancer--balancing the radicality with the
      quality of life].

PMID- 10409102
TI  - Iodine and disinfection: theoretical study on mode of action, efficiency,
      stability, and analytical aspects in the aqueous system.
AB  - Although they have been in use for nearly 170 years, the mode of action of iodine
      based disinfectants is not yet clearly understood, as is manifested, for example,
      in diverging judgements about the relevance of the individual iodine species.
      Although studies based on calculated equilibrium concentrations in pure iodine
      solutions have already been done, there is a lack of knowledge about iodine
      solutions in the presence of additional iodide which would be of intrinsic
      importance for disinfection practice. Therefore, a re-calculation was undertaken
      considering variations of this parameter in the pH range 0-14. The presented
      calculations concern fresh iodine solutions not affected by disproportionation
      (iodate formation) and provide information about the equilibrium concentrations
      of the species I, I2, I3, I5-, I6(2-), HOI, O1-, HI2O-, IO2- and H2OI+.
      Additional iodide and the pH value have a very pronounced influence on the
      individual equilibrium concentrations (several powers of ten); hence, conditions
      can be indicated where the number of species of virtual importance is drastically
      reduced. In the most common case with iodine in the presence of additional iodide
      at pH < 6, only I-, I2 and I3- play a role. In the absence of additional iodide,
      at pH 8-9 and at high dilution (c(I2) < 10(-5) M), on the other hand, HOI
      accounts for over 90% of the oxidation capacity. At high iodide concentration
      (e.g., Lugol's solution) the species I5- and I6(2-) make up 8.2% of the oxidation
      capacity. The iodine cation H2OI+, frequently quoted as an active agent in
      disinfection, is without any relevance under the conditions occurring in
      practice, as are IO- and HI2O- which become important only at pH > 10. The
      stability problem (i.e. rate of iodate formation) arising at pH > 6 can be
      reduced to hypoiodous acid, as manifested in the simple rate law d[IO3]/dt = 0.25
      [HOI]3/[H+] which allows an estimation of stability under weakly alkaline
      conditions. The results of this study allow us to deduce general qualities of
      aqueous iodine solutions, such as reactivity, stability, and analytical aspects,
      and to estimate major disinfection-orientated properties such as microbicidal
      activity, irritation, and incorporation effects. Though the calculations consider
      primarily preparations devoid of polymeric organic compounds capable of
      complexing iodine species, the results can be largely transferred to iodophoric
      preparations.

PMID- 10409103
TI  - Myofibroblasts. I. Paracrine cells important in health and disease.
AB  - Myofibroblasts are a unique group of smooth-muscle-like fibroblasts that have a
      similar appearance and function regardless of their tissue of residence. Through
      the secretion of inflammatory and anti-inflammatory cytokines, chemokines, growth
      factors, both lipid and gaseous inflammatory mediators, as well as extracellular
      matrix proteins and proteases, they play an important role in organogenesis and
      oncogenesis, inflammation, repair, and fibrosis in most organs and tissues.
      Platelet-derived growth factor (PDGF) and stem cell factor are two secreted
      proteins responsible for differentiating myofibroblasts from embryological stem
      cells. These and other growth factors cause proliferation of myofibroblasts, and
      myofibroblast secretion of extracellular matrix (ECM) molecules and various
      cytokines and growth factors causes mobility, proliferation, and differentiation
      of epithelial or parenchymal cells. Repeated cycles of injury and repair lead to
      organ or tissue fibrosis through secretion of ECM by the myofibroblasts.
      Transforming growth factor-beta and the PDGF family of growth factors are the key
      factors in the fibrotic response. Because of their ubiquitous presence in all
      tissues, myofibroblasts play important roles in various organ diseases and
      perhaps in multisystem diseases as well.

PMID- 10409104
TI  - Peroxide-induced membrane blebbing in endothelial cells associated with
      glutathione oxidation but not apoptosis.
AB  - Cells under oxidative stress induced by peroxides undergo functional and
      morphological changes, which often resemble those observed during apoptosis.
      Peroxides, however, also cause the oxidation of intracellular reduced glutathione
      (GSH). We investigated the relation between these peroxide-induced effects by
      using human umbilical vein endothelial cells (HUVEC) and two HUVEC-derived cell
      lines, ECRF24 and ECV304. With HUVEC, tert-butyl hydroperoxide (tBH) or hydrogen
      peroxide application in the presence of serum induced, in a dose-dependent way,
      reorganization of the actin cytoskeleton, membrane blebbing, and nuclear
      condensation. These processes were accompanied by transient oxidation of GSH.
      With ECRF24 cells, this treatment resulted in less blebbing and a shorter period
      of GSH oxidation. However, repeated tBH addition increased the number of blebbing
      cells and prolonged the period of GSH oxidation. ECV304 cells were even more
      resistant to peroxide-induced bleb formation and GSH oxidation. Inhibition of
      glutathione reductase activity potentiated the peroxide-induced blebbing response
      in HUVEC and ECRF24 cells, but not in ECV304 cells. Neither membrane blebbing nor
      nuclear condensation in any of these cell types was due to apoptosis, as
      evidenced by the absence of surface expression of phosphatidylserine or
      fragmentation of DNA, even after prolonged incubations with tBH, although high
      tBH concentrations lead to nonapoptotic death. We conclude that, in endothelial
      cells, peroxide-induced cytoskeletal reorganization and bleb formation correlate
      with the degree of GSH oxidation but do not represent an early stage of the
      apoptotic process.

PMID- 10409105
TI  - Na(+)-K(+) pump and metabolic activities of trout erythrocytes during anoxia.
AB  - Metabolic activity in the red blood cells of brown trout was monitored under
      conditions of oxygen depletion and chemically induced anoxia. Although metabolic
      activity was reduced during anoxia to one-third of the normoxic value, these
      cells maintained their ATP contents stable and were viable for hours in the
      absence of oxygen. In addition, Na(+)-K(+) pump activity was not down-regulated
      when metabolic activity was reduced during anoxia. The compatibility of this
      finding with energy equilibrium and ion homeostasis was investigated.

PMID- 10409106
TI  - Sex steroids regulate pro- and anti-inflammatory cytokine release by macrophages
      after trauma-hemorrhage.
AB  - Studies indicate that macrophage immune responses in males are depressed after
      trauma-hemorrhage, whereas they are enhanced in females under such conditions.
      Nonetheless, the involvement of male and female sex steroids in this gender
      dependent dimorphic immune response after trauma-hemorrhage remains unclear. To
      study this, male C3H/HeN mice were castrated and treated with pellets containing
      either vehicle, 5alpha-dihydrotestosterone (DHT), 17beta-estradiol, or a
      combination of both steroid hormones for 14 days before soft tissue trauma (i.e.,
      laparotomy) and hemorrhagic shock (35 +/- 5 mmHg for 90 min followed by adequate
      fluid resuscitation) or a sham operation. Twenty-four hours later the animals
      were killed, plasma was obtained, and Kupffer cell and splenic and peritoneal
      macrophage cultures were established. For DHT-treated mice, we observed
      significantly decreased releases of the proinflammatory cytokines interleukin
      1beta (IL-1beta) and IL-6 by splenic macrophage (-50 and -57%, respectively) and
      peritoneal macrophage (-51 and -52%, respectively) cultures after trauma
      hemorrhage compared with releases by cultures of cells from mice subjected to a
      sham operation; in contrast, responses of splenic and peritoneal macrophage
      cultures from other groups subjected to trauma-hemorrhage did not change
      significantly. In addition, only DHT-treated animals exhibited increased Kupffer
      cell IL-6 release (+634%). The release of IL-10 in DHT-treated hemorrhaged
      animals was increased compared with that in sham-operated animals but was
      decreased in estrogen-treated mice under such conditions. These results suggest
      that male and female sex steroids exhibit divergent immunomodulatory properties
      with respect to cell-mediated immune responses after trauma-hemorrhage.

PMID- 10409107
TI  - Calcium dependence of C-type natriuretic peptide-formed fast K(+) channel.
AB  - The lipid bilayer technique was used to characterize the Ca(2+) dependence of a
      fast K(+) channel formed by a synthetic 17-amino acid segment [OaCNP-39-(1-17)]
      of a 39-amino acid C-type natriuretic peptide (OaCNP-39) found in platypus
      (Ornithorhynchus anatinus) venom (OaV). The OaCNP-39-(1-17)-formed K(+) channel
      was reversibly dependent on 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic
      acid-buffered cis (cytoplasmic) Ca(2+) concentration ([Ca(2+)](cis)). The channel
      was fully active when [Ca(2+)](cis) was >10(-4) M and trans (luminal) Ca(2+)
      concentration was 1.0 mM, but not at low [Ca(2+)](cis). The open probability of
      single channels increased from zero at 1 x 10(-6) M cis Ca(2+) to 0.73 +/- 0.17
      (n = 22) at 10(-3) M cis Ca(2+). Channel openings to the maximum conductance of
      38 pS were rapidly and reversibly activated when [Ca(2+)](cis), but not trans
      Ca(2+) concentration (n = 5), was increased to >5 x 10(-4) M (n = 14). Channel
      openings to the submaximal conductance of 10.5 pS were dominant at >/=5 x 10(-4)
      M Ca(2+). K(+) channels did not open when cis Mg(2+) or Sr(2+) concentrations
      were increased from zero to 10(-3) M or when [Ca(2+)](cis) was maintained at 10(
      6) M (n = 3 and 2). The Hill coefficient and the inhibition constant were 1 and
      0.8 x 10(-4) M cis Ca(2+), respectively. This dependence of the channel on high
      [Ca(2+)](cis) suggests that it may become active under 1) physiological
      conditions where Ca(2+) levels are high, e.g., during cardiac and skeletal muscle
      contractions, and 2) pathological conditions that lead to a Ca(2+) overload,
      e.g., ischemic heart and muscle fatigue. The channel could modify a cascade of
      physiological functions that are dependent on the Ca(2+)-activated K(+) channels,
      e.g., vasodilation and salt secretion.

PMID- 10409109
TI  - Long-term effects of Ca(2+) on structure and contractility of vascular smooth
      muscle.
AB  - Culture of dispersed smooth muscle cells is known to cause rapid modulation from
      the contractile to the synthetic cellular phenotype. However, organ culture of
      smooth muscle tissue, with maintained extracellular matrix and cell-cell
      contacts, may facilitate maintenance of the contractile phenotype. To test the
      influence of culture conditions, structural, functional, and biochemical
      properties of rat tail arterial rings were investigated after culture. Rings were
      cultured for 4 days in the absence and presence of 10% FCS and then mounted for
      physiological experiments. Intracellular Ca(2+) concentration ([Ca(2+)](i)) after
      stimulation with norepinephrine was similar in rings cultured with and without
      FCS, whereas force development after FCS was decreased by >50%. The difference
      persisted after permeabilization with beta-escin. These effects were associated
      with the presence of vasoconstrictors in FCS and were dissociated from its growth
      stimulatory action. FCS treatment increased lactate production but did not affect
      ATP, ADP, or AMP contents. The contents of actin and myosin were decreased by
      culture but similar for all culture conditions. There was no effect of FCS on
      calponin contents or myosin SM1/SM2 isoform composition, nor was there any
      appearance of nonmuscle myosin. FCS-stimulated rings showed evidence of cell
      degeneration not found after culture without FCS or with FCS + verapamil (1
      microM) to lower [Ca(2+)](i). The decreased force-generating ability after
      culture with FCS is thus associated with increased [Ca(2+)](i) during culture and
      not primarily caused by growth-associated modulation of cells from the
      contractile to the synthetic phenotype.

PMID- 10409108
TI  - Ca(2+) influx inhibits voltage-dependent and augments Ca(2+)-dependent K(+)
      currents in arterial myocytes.
AB  - These experiments were performed to determine the effects of reducing Ca(2+)
      influx (Ca(in)) on K(+) currents (I(K)) in myocytes from rat small mesenteric
      arteries by 1) adding external Cd(2+) or 2) lowering external Ca(2+) to 0.2 mM.
      When measured from a holding potential (HP) of -20 mV (I(K20)), decreasing Ca(in)
      decreased I(K) at voltages where it was active (>0 mV). When measured from a HP
      of -60 mV (I(K60)), decreasing Ca(in) increased I(K) at voltages between -30 and
      +20 mV but decreased I(K) at voltages above +40 mV. Difference currents
      (DeltaI(K)) were determined by digital subtraction of currents recorded under
      control conditions from those obtained when Ca(in) was decreased. At test
      voltages up to 0 mV, DeltaI(K60) exhibited kinetics similar to control I(K60),
      with rapid activation to a peak followed by slow inactivation. At 0 mV, peak
      DeltaI(K60) averaged 75 +/- 13 pA (n = 8) with Cd(2+) and 120 +/- 20 pA (n = 9)
      with low Ca(2+) concentration. At test voltages from 0 to +60 mV, DeltaI(K60)
      always had an early positive peak phase, but its apparent "inactivation"
      increased with voltage and its steady value became negative above +20 mV. At +60
      mV, the initial peak DeltaI(K60) averaged 115 +/- 18 pA with Cd(2+) and 187 +/-
      34 pA with low Ca(2+). With 10 mM pipette BAPTA, Cd(2+) produced a small
      inhibition of I(K20) but still increased I(K60) between -30 and +10 mV. In Ca(2+)
      free external solution, Cd(2+) only decreased both I(K20) and I(K60). In the
      presence of iberiotoxin (100 nM) to inhibit Ca(2+)-activated K(+) channels
      (K(Ca)), Cd(2+) increased I(K60) at all voltages positive to -30 mV while BAY K
      8644 (1 microM) decreased I(K60). These results suggest that Ca(in), through L
      type Ca(2+) channels and perhaps other pathways, increases K(Ca) (i.e., I(K20))
      and decreases voltage-dependent K(+) currents in this tissue. This effect could
      contribute to membrane depolarization and force maintenance.

PMID- 10409110
TI  - Cholecystokinin induction of mob-1 chemokine expression in pancreatic acinar
      cells requires NF-kappaB activation.
AB  - Inflammatory mediators are involved in the early phase of acute pancreatitis, but
      the cellular mechanisms responsible for their generation within pancreatic cells
      are unknown. We examined the role of nuclear factor-kappaB (NF-kappaB) in
      cholecystokinin octapeptide (CCK-8)-induced mob-1 chemokine expression in
      pancreatic acinar cells in vitro. Supraphysiological, but not physiological,
      concentrations of CCK-8 increased inhibitory kappaB (IkappaB-alpha) degradation,
      NF-kappaB activation, and mob-1 gene expression in isolated pancreatic acinar
      cells. CCK-8-induced IkappaB-alpha degradation was maximal within 1 h. Expression
      of mob-1 was maximal within 2 h. Neither bombesin nor carbachol significantly
      increased mob-1 mRNA or induced IkappaB-alpha degradation. Thus the
      concentration, time, and secretagogue dependence of mob-1 gene expression and
      IkappaB-alpha degradation were similar. Inhibition of NF-kappaB with
      pharmacological agents or by adenovirus-mediated expression of the inhibitory
      protein IkappaB-alpha also inhibited mob-1 gene expression. These data indicate
      that the NF-kappaB signaling pathway is required for CCK-8-mediated induction of
      mob-1 chemokine expression in pancreatic acinar cells. This supports the
      hypothesis that NF-kappaB signaling is of central importance in the initiation of
      acute pancreatitis.

PMID- 10409111
TI  - Membrane phospholipid composition affects function of potassium channels from
      rabbit colon epithelium.
AB  - We tested the effects of membrane phospholipids on the function of high
      conductance, Ca(2+)-activated K(+) channels from the basolateral cell membrane of
      rabbit distal colon epithelium by reconstituting these channels into planar
      bilayers consisting of different 1:1 mixtures of phosphatidylethanolamine (PE),
      phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylinositol (PI).
      At low ambient K(+) concentrations single-channel conductance is higher in PE/PS
      and PE/PI bilayers than in PE/PC bilayers. At high K(+) concentrations this
      difference in channel conductance is abolished. Introducing the negatively
      charged SDS into PE/PC bilayers increases channel conductance, whereas the
      positively charged dodecyltrimethylammonium has the opposite effect. All these
      findings are consistent with modulation of channel current by the charge of the
      lipid membrane surrounding the channel. But the K(+) that permeates the channel
      senses only a small fraction of the full membrane surface potential of the
      charged phospholipid bilayers, equivalent to separation of the conduction pathway
      from the charged phospholipid head groups by 20 A. This distance appears to
      insulate the channel entrance from the bilayer surface potential, suggesting
      large dimensions of the channel-forming protein. In addition, in PE/PC and PE/PI
      bilayers, but not in PE/PS bilayers, the open-state probability of the channel
      decreases with time ("channel rundown"), indicating that phospholipid properties
      other than surface charge are required to maintain channel fluctuations.

PMID- 10409112
TI  - Voltage-dependent outward K(+) current in intermediate cell of stria vascularis
      of gerbil cochlea.
AB  - A voltage-dependent outward K(+) (K(V)) current in the intermediate cell
      (melanocyte) of the cochlear stria vascularis was studied using the whole cell
      patch-clamp technique. The K(V) current had an activation threshold voltage of
      approximately -80 mV, and 50% activation was observed at -42.6 mV. The time
      courses of activation and inactivation were well fitted by two exponential
      functions: the time constants at 0 mV were 7.9 and 58.8 ms for activation and 0.6
      and 4.3 s for inactivation. The half-maximal activation time was 13. 8 ms at 0
      mV. Inactivation of the current was incomplete even after a prolonged
      depolarization of 10 s. This current was independent of intracellular Ca(2+).
      Quinine, verapamil, Ba(2+), and tetraethylammonium inhibited the current in a
      dose-dependent manner, but 4-aminopyridine was ineffective at 50 mM. We conclude
      that the K(V) conductance in the intermediate cell may stabilize the membrane
      potential, which is thought to be closely related to the endocochlear potential,
      and may provide an additional route for K(+) secretion into the intercellular
      space.

PMID- 10409113
TI  - Protein kinase C inhibits Kv1.1 potassium channel function.
AB  - The regulation by protein kinase C (PKC) of recombinant voltage-gated potassium
      (K) channels in frog oocytes was studied. Phorbol 12-myristate 13-acetate (PMA;
      500 nM), an activator of PKC, caused persistent and large (up to 90%) inhibition
      of mouse, rat, and fly Shaker K currents. K current inhibition by PMA was blocked
      by inhibitors of PKC, and inhibition was not observed in control experiments with
      PMA analogs that do not activate PKC. However, site-directed substitution of
      potential PKC phosphorylation sites in the Kv1.1 protein did not prevent current
      inhibition by PMA. Kv1.1 current inhibition was also not accompanied by changes
      in macroscopic activation kinetics or in the conductance-voltage relationship. In
      Western blots, Kv1.1 membrane protein was not significantly reduced by PKC
      activation. The injection of oocytes with botulinum toxin C3 exoenzyme blocked
      the PMA inhibition of Kv1. 1 currents. These data are consistent with the
      hypothesis that PKC-mediated inhibition of Kv1.1 channel function occurs by a
      novel mechanism that requires a C3 exoenzyme substrate but does not alter channel
      activation gating or promote internalization of the channel protein.

PMID- 10409114
TI  - Activation of Ca(2+)- and cAMP-sensitive K(+) channels in murine colonic
      epithelia by 1-ethyl-2-benzimidazolone.
AB  - 1-Ethyl-2-benzimidazolone (EBIO) caused a sustained increase in electrogenic Cl(
      ) secretion in isolated mouse colon mucosae, an effect reduced by blocking
      basolateral K(+) channels. The Ca(2+)-sensitive K(+) channel blocker
      charybdotoxin (ChTX) and the cAMP-sensitive K(+) channel blocker 293B were more
      effective when the other had been added first, suggesting that both types of K(+)
      channel were activated. EBIO did not cause Cl(-) secretion in cystic fibrosis
      (CF) colonic epithelia. In apically permeabilized colonic mucosae, EBIO increased
      the K(+) current when a concentration gradient was imposed, an effect that was
      completely sensitive to ChTX. No current sensitive to trans-6-cyano-4-(N
      ethylsulfonyl-N-methylamino)-3-hydroxy-2, 2-dimethylchromane (293B) was found in
      this condition. However, the presence of basolateral cAMP-sensitive K(+) channels
      was demonstrated by the development of a 293B-sensitive K(+) current after cAMP
      application in permeabilized mucosae. In isolated colonic crypts EBIO increased
      cAMP content but had no effect on intracellular Ca(2+). It is concluded that EBIO
      stimulates Cl(-) secretion by activating Ca(2+)-sensitive and cAMP-sensitive K(+)
      channels, thereby hyperpolarizing the apical membrane, which increases the
      electrical gradient for Cl(-) efflux through the CF transmembrane conductance
      regulator (CFTR). CFTR is also activated by the accumulation of cAMP as well as
      by direct activation.

PMID- 10409115
TI  - Disruption of disulfide bonds exhibits differential effects on trafficking of
      regulated secretory proteins.
AB  - For several secretory proteins, it has been hypothesized that disulfide-bonded
      loop structures are required for sorting to secretory granules. To explore this
      hypothesis, we employed dithiothreitol (DTT) treatment in live pancreatic islets,
      as well as in PC-12 and GH(4)C(1) cells. In islets, disulfide reduction in the
      distal secretory pathway did not increase constitutive or constitutive-like
      secretion of proinsulin (or insulin). In PC-12 cells, DTT treatment caused a
      dramatic increase in unstimulated secretion of newly synthesized chromogranin B
      (CgB), presumably as a consequence of reducing the single conserved chromogranin
      disulfide bond (E. Chanat, U. Weiss, W. B. Huttner, and S. A. Tooze. EMBO J. 12:
      2159-2168, 1993). However, in GH(4)C(1) cells that also synthesize CgB
      endogenously, DTT treatment reduced newly synthesized prolactin and blocked its
      export, whereas newly synthesized CgB was routed normally to secretory granules.
      Moreover, on transient expression in GH(4)C(1) cells, CgA and a CgA mutant
      lacking the conserved disulfide bond showed comparable multimeric aggregation
      properties and targeting to secretory granules, as measured by stimulated
      secretion assays. Thus the conformational perturbation of regulated secretory
      proteins caused by disulfide disruption leads to consequences in protein
      trafficking that are both protein and cell type dependent.

PMID- 10409116
TI  - Characterization of osteoblastic differentiation of stromal cell line ST2 that is
      induced by ascorbic acid.
AB  - The stromal cell line ST2, derived from mouse bone marrow, differentiated into
      osteoblast-like cells in response to ascorbic acid. Ascorbic acid induced
      alkaline phosphatase (ALPase) activity, the expression of mRNAs for proteins that
      are markers of osteoblastic differentiation, the deposition of calcium, and the
      formation of mineralized nodules by ST2 cells. We investigated the mechanism
      whereby ascorbic acid induced the differentiation of ST2 cells. Inhibitors of the
      formation of collagen triple helices completely blocked the effects of ascorbic
      acid on ST2 cells, an indication that matrix formation by type I collagen is
      essential for the induction of osteoblastic differentiation of ST2 cells by
      ascorbic acid. We furthermore examined the effects of bone morphogenetic proteins
      (BMPs) on the differentiation of ST2 cells induced by ascorbic acid. Ascorbic
      acid had no effect on the expression of mRNAs for BMP-4 and the BMP receptors.
      However, a soluble form of BMP receptor IA inhibited the induction of ALPase
      activity by ascorbic acid. These results suggest that ascorbic acid might promote
      the differentiation of ST2 cells into osteoblast-like cells by inducing the
      formation of a matrix of type I collagen, with subsequent activation of the
      signaling pathways that involve BMPs.

PMID- 10409117
TI  - Norepinephrine-induced Ca(2+) waves depend on InsP(3) and ryanodine receptor
      activation in vascular myocytes.
AB  - In rat portal vein myocytes, Ca(2+) signals can be generated by inositol 1,4,5
      trisphosphate (InsP(3))- and ryanodine-sensitive Ca(2+) release channels, which
      are located on the same intracellular store. Using a laser scanning confocal
      microscope associated with the patch-clamp technique, we showed that propagated
      Ca(2+) waves evoked by norepinephrine (in the continuous presence of oxodipine)
      were completely blocked after internal application of an anti-InsP(3) receptor
      antibody. These propagated Ca(2+) waves were also reduced by approximately 50%
      and transformed in homogenous Ca(2+) responses after application of an anti
      ryanodine receptor antibody or ryanodine. All-or-none Ca(2+) waves obtained with
      increasing concentrations of norepinephrine were transformed in a dose-response
      relationship with a Hill coefficient close to unity after ryanodine receptor
      inhibition. Similar effects of the ryanodine receptor inhibition were observed on
      the norepinephrine- and ACh-induced Ca(2+) responses in non-voltage-clamped
      portal vein and duodenal myocytes and on the norepinephrine-induced contraction.
      Taken together, these results show that ryanodine-sensitive Ca(2+) release
      channels are responsible for the fast propagation of Ca(2+) responses evoked by
      various neurotransmitters producing InsP(3) in vascular and visceral myocytes.

PMID- 10409118
TI  - Focal adhesion proteins FAK and paxillin increase in hypertrophied skeletal
      muscle.
AB  - Components of signaling pathways for mechanotransduction during load-induced
      enlargement of skeletal muscle have not been completely defined. We hypothesized
      that loading of skeletal muscle would result in an adaptive increase in the
      expression of two focal adhesion complex (FAC)-related proteins, focal adhesion
      kinase (FAK) and paxillin, as well as increased FAK activity. FAK protein was
      immunolocalized to the sarcolemmal region of rooster anterior latissimus dorsi
      (ALD) myofibers in the middle of the ALD muscle. FAK (77 and 81%) and paxillin
      (206 and 202%) protein concentrations per unit of total protein in Western blots
      increased significantly after 1.5 and 7 days, but not after 13 days, of stretch
      induced hypertrophy-hyperplasia of the ALD muscle. FAK autokinase activity in
      immunoprecipitates was increased after 1.5, 7, and 13 days in stretched ALD
      muscles. To determine whether increased FAK and paxillin protein concentrations
      are associated with hypertrophy and/or new fiber formation, two additional
      experiments were performed. First, during formation of primary chicken myotubes
      (a model of new fiber formation), FAK protein concentration (63%), FAK activity
      (157%), and paxillin protein concentration (97%) increased compared with
      myoblasts. Second, FAK (112% and 611%) and paxillin (87% and 431%) protein
      concentrations per unit of total protein in the soleus muscle increased at 1 and
      8 days after surgical ablation of the synergistic gastrocnemius muscle (a model
      of hypertrophy without hyperplasia). Thus increases in components of the FAC
      occur in hypertrophying muscle of animals and in newly formed muscle fibers in
      culture. Furthermore, increased FAK activity suggests a possible convergence of
      signaling at the FAC in load-induced growth of skeletal muscle.

PMID- 10409119
TI  - Phagocytic and macropinocytic activity in MARCKS-deficient macrophages and
      fibroblasts.
AB  - Macrophages express high levels of the myristoylated, alanine-rich, C kinase
      substrate (MARCKS), an actin cross-linking protein. To investigate a possible
      role of MARCKS in macrophage function, fetal liver-derived macrophages were
      generated from wild-type and MARCKS knockout mouse embryos. No differences
      between the wild-type and MARCKS-deficient macrophages with respect to morphology
      (Wright's stain) or actin distribution (staining with rhodamine-phalloidin, under
      basal conditions or after treatment with phorbol esters, lipopolysaccharide, or
      both) were observed. We then evaluated phagocytosis mediated by different
      receptors: Fc receptors tested with IgG-coated sheep red blood cells, complement
      C3b receptors tested with C3b-coated yeast, mannose receptors tested with
      unopsonized zymosan, and nonspecific phagocytosis tested with latex beads. We
      also studied fluid phase endocytosis in macrophages and mouse embryo fibroblasts
      by using FITC-dextran to quantitate this process. In most cases, there were no
      differences between the cells derived from wild-type and MARCKS-deficient mice.
      However, a minor but significant and reproducible difference in rates of zymosan
      phagocytosis at 45-60 min was observed, with lower rates of phagocytosis in the
      MARCKS-deficient cells. Our data indicate that MARCKS deficiency may lead to
      slightly decreased rates of zymosan phagocytosis.

PMID- 10409120
TI  - Syntaxin 1A inhibits regulated CFTR trafficking in xenopus oocytes.
AB  - The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial
      cell Cl channel, whose gating activity and membrane trafficking are controlled by
      cAMP/protein kinase A (PKA)-mediated phosphorylation. CFTR Cl currents are
      regulated also by syntaxin 1A (A. P. Naren, D. J. Nelson, W. W. Xie, B. Jovov, J.
      Pevsner, M. K. Bennett, D. J. Benos, M. W. Quick, and K. L. Kirk. Nature 390: 302
      305, 1997), a protein best known for its role in membrane trafficking and
      neurosecretion. To examine the mechanism of syntaxin 1A inhibition, we expressed
      these proteins in Xenopus oocytes and monitored agonist-induced changes in plasma
      membrane capacitance and cell surface fluorescence of CFTR that contains an
      external epitope tag. cAMP stimulation elicited large increases in membrane
      capacitance and in cell surface labeling of flag-tagged CFTR. Coexpression of
      CFTR with syntaxin 1A, but not syntaxin 3, inhibited cAMP-induced increases in
      membrane capacitance and plasma membrane CFTR content. Injection of botulinum
      toxin/C1 rapidly reversed syntaxin's effects on current and capacitance,
      indicating that they cannot be explained by an effect on CFTR synthesis.
      Functional expression of other integral membrane proteins, including Na-coupled
      glucose transporter hSGLT1, inwardly rectified K channel hIK1, P2Y2 nucleotide
      receptor, and viral hemagglutinin protein, was not affected by syntaxin 1A
      coexpression. These findings indicate that acute regulation of the number of CFTR
      Cl channels in plasma membrane is one mechanism by which cAMP/PKA regulates Cl
      currents. Inhibition of plasma membrane CFTR content by syntaxin 1A is consistent
      with the concept that syntaxin and other components of the SNARE machinery are
      involved in regulated trafficking of CFTR.

PMID- 10409121
TI  - AMP-activated protein kinase, a metabolic master switch: possible roles in type 2
      diabetes.
AB  - Adenosine 5'-monophosphate-activated protein kinase (AMPK) now appears to be a
      metabolic master switch, phosphorylating key target proteins that control flux
      through metabolic pathways of hepatic ketogenesis, cholesterol synthesis,
      lipogenesis, and triglyceride synthesis, adipocyte lipolysis, and skeletal muscle
      fatty acid oxidation. Recent evidence also implicates AMPK as being responsible
      for mediating the stimulation of glucose uptake induced by muscle contraction. In
      addition, the secretion of insulin by insulin secreting (INS-1) cells in culture
      is modulated by AMPK activation. The net effect of AMPK activation is stimulation
      of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol
      synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte
      lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation
      and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta
      cells. In skeletal muscle, AMPK is activated by contraction. Type 2 diabetes
      mellitus is likely to be a disease of numerous etiologies. However, defects or
      disuse (due to a sedentary lifestyle) of the AMPK signaling system would be
      predicted to result in many of the metabolic perturbations observed in Type 2
      diabetes mellitus. Increased recruitment of the AMPK signaling system, either by
      exercise or pharmaceutical activators, may be effective in correcting insulin
      resistance in patients with forms of impaired glucose tolerance and Type 2
      diabetes resulting from defects in the insulin signaling cascade.

PMID- 10409122
TI  - Glucose metabolism and beta-cell mass in adult offspring of rats protein and/or
      energy restricted during the last week of pregnancy.
AB  - An association between low birth weight and later impaired glucose tolerance was
      recently demonstrated in several human populations. Although fetal malnutrition
      is probably involved, the biological bases of such a relationship are not yet
      clear, and animal studies on the matter are scarce. The present study was aimed
      to identify, in adult (8-wk) female offspring, the effects of reduced protein
      and/or energy intake strictly limited to the last week of pregnancy. Thus we have
      tested three protocols of gestational malnutrition: a low-protein isocaloric diet
      (5 instead of 15%), with pair feeding to the mothers receiving the control diet;
      a restricted diet (50% of the control diet); and a low-protein restricted diet
      (50% of low-protein diet). Only the low-protein diet protocols, independent of
      total energy intake, led to a lower birth weight. The adult offspring female rats
      in the three deprived groups exhibited no decrease in body weight and no major
      impairment in glucose tolerance, glucose utilization, or glucose production
      (basal state and hyperinsulinemic clamp studies). However, pancreatic insulin
      content and beta-cell mass were significantly decreased in the low-protein
      isocaloric diet group compared with the two energy-restricted groups. Such
      impairment of beta-cell mass development induced by protein deficiency limited to
      the last part of intrauterine life could represent a situation predisposing to
      impaired glucose tolerance.

PMID- 10409123
TI  - Effects of dichloroacetate infusion on human skeletal muscle metabolism at the
      onset of exercise.
AB  - This study investigated whether dichloroacetate (DCA) decreases the reliance on
      substrate level phosphorylation during the transition from rest to moderate
      intensity exercise in humans. Nine subjects cycled at approximately 65% of
      maximal oxygen uptake (VO(2 max)) after a saline or DCA (100 mg/kg body wt)
      infusion, with muscle biopsies taken at rest and at 30 s and 2 and 10 min of
      exercise. DCA infusion increased pyruvate dehydrogenase (PDH) activation at rest
      (4.0 +/- 0.3 vs. 0.9 +/- 0.1 mmol. kg wet wt(-1). min(-1)) and at 30 s (3.6 +/-
      0.2 vs. 2.5 +/- 0.4 mmol. kg(-1). min(-1)) of exercise. As a result, acetyl-CoA
      (45.9 +/- 5.9 vs. 11.3 +/- 1.5 micromol/kg dry wt) and acetylcarnitine (13.1 +/-
      1.0 vs. 1.6 +/- 0.3 mmol/kg dry wt) were markedly increased by DCA infusion at
      rest. These differences were maintained at 30 s and 2 min for both acetyl-CoA and
      acetylcarnitine. Resting muscle lactate and phosphocreatine (PCr) were not
      different between trials, but DCA infusion resulted in lower lactate accumulation
      throughout exercise, especially at 2 min (21.6 +/- 3.1 vs. 44.6 +/- 8.0 mmol/kg
      dry wt). PCr utilization in the initial 30 s (16.9 +/- 0.4 vs. 31.7 +/- 2.6
      mmol/kg dry wt) and 2 min (27.8 +/- 4.7 vs. 45.1 +/- 2.6 mmol/kg dry wt) of
      exercise was decreased with DCA. This resulted in a lower accumulation of free
      inorganic phosphate at 30 s (25.4 +/- 2.0 vs. 36.4 +/- 2.8 mmol/kg dry wt) and 2
      min (34.6 +/- 4.7 vs. 50.5 +/- 2.2 mmol/kg dry wt) with DCA and decreased
      glycogenolysis over 10 min. The data from this study support the hypothesis that
      increased provision of substrate by DCA infusion increases oxidative metabolism
      during the rest-to-work transition, resulting in decreased PCr utilization and an
      improved cellular energy state at the onset of exercise. The transitory
      improvement in energy state decreased glycogenolysis and lactate accumulation
      during moderate-intensity exercise.

PMID- 10409124
TI  - Cytochrome c transcriptional activation and mRNA stability during contractile
      activity in skeletal muscle.
AB  - We evaluated contractile activity-induced alterations in cytochrome c
      transcriptional activation and mRNA stability with unilateral chronic stimulation
      (10 Hz, 3 h/day) of the rat tibialis anterior (TA) muscle for 1, 2, 3, 4, 5, and
      7 days (n = 3-11/group). Transcriptional activation was assessed by direct
      plasmid DNA injection into the TA with a chloramphenicol acetyltransferase (CAT)
      reporter gene linked to 326 bp of the cytochrome c promoter. Cytochrome c mRNA in
      stimulated muscles increased by 1.3- to 1. 7-fold above control between 1 and 7
      days. Cytochrome c protein was increased after 5 days of stimulation to reach
      levels that were 1. 9-fold higher than control by 7 days. Cytochrome c mRNA
      stability, determined with an in vitro decay assay, was greater in stimulated TA
      than in control between 2 and 4 days, likely mediated by the induction of a
      cytosolic factor. In contrast, cytochrome c transcriptional activation was
      elevated only after 5 days of stimulation when mRNA stability had returned to
      control levels. Thus the contractile activity-induced increase in cytochrome c
      mRNA was due to an early increase in mRNA stability, followed by an elevation in
      transcriptional activation, leading to an eventual increase in cytochrome c
      protein levels.

PMID- 10409125
TI  - PDH activation by dichloroacetate reduces TCA cycle intermediates at rest but not
      during exercise in humans.
AB  - We hypothesized that dichloroacetate (DCA), which stimulates the pyruvate
      dehydrogenase complex (PDH), would attenuate the increase in muscle tricarboxylic
      acid cycle intermediates (TCAI) during exercise by increasing the oxidative
      disposal of pyruvate and attenuating the flux through anaplerotic pathways. Six
      subjects were infused with either saline (Con) or DCA (100 mg/kg body mass) and
      then performed a moderate leg kicking exercise for 15 min, followed immediately
      by intense exercise until exhaustion (Exh; approximately 4 min). Resting active
      fraction of PDH (PDH(a)) was markedly increased (P </= 0.05) after DCA vs. Con
      (2.65 +/- 0.27 vs. 0.64 +/- 0.07 mmol. min(-1). kg wet wt(-1)); however, there
      were no differences between trials after 1 or 15 min of exercise or at Exh. The
      sum of five measured TCAI (SigmaTCAI; approximately 90% of total TCAI pool) was
      lower (P </= 0.05) after DCA vs. Con at rest (0. 78 +/- 0.11 vs. 1.52 +/- 0.23
      mmol/kg dry wt, respectively). However, the net increase in muscle TCAI during
      the first minute of exercise was higher (P </= 0.05) in the DCA trial vs. Con
      (3.05 +/- 0.45 vs. 2.44 +/- 0.55 mmol. min(-1). kg dry wt(-1), respectively), and
      consequently, the SigmaTCAI was not different between trials during exercise. We
      conclude that DCA reduced TCAI pool size at rest by increasing the flux through
      PDH and diverting pyruvate away from anaplerotic pathways. The reason for the
      similar absolute increase in TCAI during exercise is not clear but may be related
      to 1) an initial mismatch between glycolytic flux and PDH flux that provided
      sufficient pyruvate for anaplerosis in both trials; or 2) a transient inhibition
      of PDH flux during the DCA trial due to an elevated resting acetyl-CoA-to-CoASH
      ratio, which augmented the anaplerotic flux of carbon during the rest-to-work
      transition.

PMID- 10409126
TI  - Initial aerobic power does not alter muscle metabolic adaptations to short-term
      training.
AB  - To investigate the hypothesis that training-induced increases in muscle
      mitochondrial potential are not obligatory to metabolic adaptations observed
      during submaximal exercise, regardless of peak aerobic power (VO(2 peak)) of the
      subjects, a short-term training study was utilized. Two groups of untrained male
      subjects (n = 7/group), one with a high (HI) and the other with a low (LO) VO(2
      peak) (means +/- SE; 51.4 +/- 0.90 vs. 41.0 +/- 1.3 ml. kg(-1). min(-1);P <
      0.05), cycled for 2 h/day at 66-69% of VO(2 peak) for 6 days. Muscle tissue was
      extracted from vastus lateralis at 0, 3, and 30 min of standardized cycle
      exercise before training (0 days) and after 3 and 6 days of training and analyzed
      for metabolic and enzymatic changes. During exercise after 3 days of training in
      the combined HI + LO group, higher (P < 0.05) concentrations (mmol/kg dry wt) of
      phosphocreatine (40.5 +/- 3.4 vs. 52.2 +/- 4.2) and lower (P < 0.05)
      concentrations of P(i) (61.5 +/- 4.4 vs. 53.3 +/- 4.4), inosine monophosphate
      (0.520 +/- 0.19 vs. 0.151 +/- 0.05), and lactate (37.9 +/- 5.5 vs. 22.8 +/- 4.8)
      were observed. These changes were also accompanied by reduced levels of
      calculated free ADP, AMP, and P(i). All adaptations were fully expressed by 3 min
      of exercise and by 3 days of training and were independent of initial VO(2 peak)
      levels. Moreover, maximal activity of citrate synthase, a measure of
      mitochondrial capacity, was only increased with 6 days of training (5.71 +/- 0.29
      vs. 7.18 +/- 0.37 mol. kg protein(-1). h(-1); P < 0. 05). These results
      demonstrate that metabolic adaptations to prolonged exercise occur within the
      first 3 days of training and during the non-steady-state period. Moreover,
      neither time course nor magnitude of metabolic adaptations appears to depend on
      increases in mitochondrial potential or on initial aerobic power.

PMID- 10409127
TI  - Inhibition of salmon calcitonin on secretion of progesterone and GnRH-stimulated
      pituitary luteinizing hormone.
AB  - The effects of salmon calcitonin (sCT) on the production of progesterone and
      secretion of luteinizing hormone (LH) were examined in female rats. Diestrous
      rats were intravenously injected with saline, sCT, human chorionic gonadotropin
      (hCG), or hCG plus sCT. Ovariectomized (Ovx) rats were injected with saline or
      sCT. In the in vitro experiments, granulosa cells and anterior pituitary glands
      (APs) were incubated with the tested drugs. Plasma LH levels of Ovx rats were
      reduced by sCT injection. Administration of sCT decreased the basal and hCG
      stimulated progesterone release in vivo and in vitro. 8-Bromo-cAMP dose
      dependently increased progesterone production but did not alter the inhibitory
      effect of sCT. H-89 did not potentiate the inhibitory effect of sCT. Higher doses
      of 25-hydroxycholesterol and pregnenolone stimulated progesterone production and
      diminished the inhibitory effects of sCT. sCT did not decrease basal release of
      LH by APs, but pretreatment of sCT decreased gonadotropin-releasing hormone
      (GnRH)-stimulated LH secretion. These results suggested that sCT inhibits
      progesterone production in rats by preventing the stimulatory effect of GnRH on
      LH release in rat APs and acting directly on ovarian granulosa cells to decrease
      the activities of post-cAMP pathway and steroidogenic enzymes.

PMID- 10409128
TI  - Characterization of receptors mediating AVP- and OT-induced glucagon release from
      the rat pancreas.
AB  - We characterized the receptors that mediate arginine vasopressin (AVP)- and
      oxytocin (OT)-induced glucagon release by use of a number of antagonists in the
      perfused rat pancreas and the fluorescence imaging of the receptors. AVP and OT
      (3 pM-3 nM) increased glucagon release in a concentration-dependent manner. The
      antagonist with potent V(1b) receptor-blocking activity, CL-4-84 (10 nM),
      abolished AVP (30 pM)-induced glucagon release but did not alter OT (30 pM)
      induced glucagon release. d(CH(2))(5)[Tyr(Me)(2)]AVP (10 nM), a V(1a) receptor
      antagonist, and L-366,948 (10 nM), a highly specific OT-receptor antagonist,
      failed to inhibit AVP-induced glucagon release. In contrast, L-366,948 (10 nM)
      abolished OT (30 pM)-induced glucagon release but did not change the effect of
      AVP. Fluorescent microscopy of rat pancreatic sections showed that fluorescence
      labeled AVP and OT bound to their receptors in the islets of Langerhans and that
      the bindings were inhibited by 1 microM of Cl-4-84 and L-366,948, respectively.
      Because AVP and OT at physiological concentrations (3-30 pM) increased glucagon
      release, we conclude that AVP and OT increase glucagon release under the
      physiological condition through the activation of V(1b) and OT receptors,
      respectively.

PMID- 10409129
TI  - Parenteral amino acid intake alters the anabolic actions of insulin-like growth
      factor I in rats.
AB  - The anabolic properties of insulin-like growth factor (IGF) I are attenuated by
      oral diets that are low in protein. However, it is not known whether parenteral
      nutrition (PN) providing a low amino acid (AA) input will influence IGF-I action.
      With the use of a rat model, this study examined the interaction between AA input
      (1.27 and 0.62 g N. kg body wt(-1). 24 h(-1), AA and 1/2AA groups, respectively)
      and recombinant human IGF-I (rhIGF-I, 2.5 mg. kg body wt(-1). 24 h(-1)) infusion
      on the composition of the carcass and organs and on plasma insulin, IGF-I, IGF
      binding protein 1 (IGFBP-1), and acid-labile subunit (ALS) concentrations.
      Carcass protein deposition only occurred in the AA groups (P < 0.003) and was not
      influenced by administration of rhIGF-I. However, visceral protein loss persisted
      in the AA group but was prevented by rhIGF-I infusion. The changes in water
      content of the carcass and the organs were generally in the expected proportion
      of normal lean tissue. The accumulation of lipid that follows the infusion of the
      AA-deficient PN was prevented by rhIGF-I infusion, which may indicate an improved
      energy utilization. Neither serum insulin nor ALS concentrations were influenced
      by the level of AA infusion but were reduced by rhIGF-I administration. However,
      plasma IGF-I levels were elevated by higher AA infusion and by IGF-I
      administration. Also, IGFBP-1 concentrations were reduced by the higher AA
      infusion and increased with rhIGF-I administration. Interestingly, there was a
      significant interaction effect between both of these influences. It is concluded
      that free IGF-I concentration, which may be regulated by IGFBP-1 through a direct
      effect of AAs on the liver, may have an important role in regulating anabolism in
      visceral and possibly skeletal tissue during PN.

PMID- 10409130
TI  - The sigma-ligand (+)-pentazocine depresses M current and enhances calcium
      conductances in frog melanotrophs.
AB  - Gramicidin-perforated patch clamp experiments and microfluorimetric measurements
      were performed to study the ionic mechanisms involved in the sigma-receptor
      mediated stimulation of frog (Rana ridibunda) pituitary melanotrophs. The sigma
      ligand (+)-pentazocine (50 microM) depressed a sustained outward K(+) current.
      The kinetic properties of this K(+) component, investigated by analyzing tail
      currents, were reminiscent of those of the M current (I(M)), with an activation
      threshold close to -60 mV, a -21-mV half-maximal activation potential, and two
      component exponential deactivation kinetics at -90 mV. (+)-Pentazocine (20
      microM) produced a 12-mV rightward shift of the activation curve and accelerated
      the deactivation rate of the tail current. It is also demonstrated that (+)
      pentazocine (20 microM) reversibly increased both voltage-dependent calcium
      conductances and internal calcium level. Altogether, these results suggest that
      the sigma-receptor-induced modulation of I(M) and calcium currents likely
      underlies the increase of intracellular [Ca(2+)].

PMID- 10409131
TI  - Muscle net glucose uptake and glucose kinetics after endurance training in men.
AB  - We evaluated the hypotheses that alterations in glucose disposal rate (R(d)) due
      to endurance training are the result of changed net glucose uptake by active
      muscle and that blood glucose is shunted to working muscle during exercise
      requiring high relative power output. We studied leg net glucose uptake during 1
      h of cycle ergometry at two intensities before training [45 and 65% of peak rate
      of oxygen consumption (VO(2 peak))] and after training [65% pretraining VO(2
      peak), same absolute workload (ABT), and 65% posttraining VO(2 peak), same
      relative workload (RLT)]. Nine male subjects (178.1 +/- 2.5 cm, 81.8 +/- 3.3 kg,
      27.4 +/- 2.0 yr) were tested before and after 9 wk of cycle ergometer training,
      five times a week at 75% VO(2 peak). The power output that elicited 66.0 +/- 1.1%
      of VO(2 peak) before training elicited 54.0 +/- 1.7% after training. Whole body
      glucose R(d) decreased posttraining at ABT (5.45 +/- 0.31 mg. kg(-1). min(-1) at
      65% pretraining to 4.36 +/- 0.44 mg. kg(-1). min(-1)) but not at RLT (5.94 +/-
      0.47 mg. kg(-1). min(-1)). Net glucose uptake was attenuated posttraining at ABT
      (1.87 +/- 0.42 mmol/min at 65% pretraining and 0.54 +/- 0.33 mmol/min) but not at
      RLT (2.25 +/- 0. 81 mmol/min). The decrease in leg net glucose uptake at ABT was
      of similar magnitude as the drop in glucose R(d) and thus could explain dampened
      glucose flux after training. Glycogen degradation also decreased posttraining at
      ABT but not RLT. Leg net glucose uptake accounted for 61% of blood glucose flux
      before training and 81% after training at the same relative (65% VO(2 peak))
      workload and only 38% after training at ABT. We conclude that 1) alterations in
      active muscle glucose uptake with training determine changes in whole body
      glucose kinetics; 2) muscle glucose uptake decreases for a given, moderate
      intensity task after training; and 3) hard exercise (65% VO(2 peak)) promotes a
      glucose shunt from inactive tissues to active muscle.

PMID- 10409132
TI  - Increased insulin secretion and normalization of glucose tolerance by cholinergic
      agonism in high fat-fed mice.
AB  - Increased insulinotropic activity by the cholinergic agonist carbachol exists in
      insulin-resistant high fat-fed C57BL/6J mice. We examined the efficiency and
      potency of carbachol to potentiate glucose-stimulated insulin secretion and to
      improve glucose tolerance in these animals. Intravenous administration of
      carbachol (at 15 and 50 nmol/kg) markedly potentiated glucose (1 g/kg)-stimulated
      insulin secretion in mice fed both a control and a high-fat diet (for 12 wk),
      with a higher relative potentiation in high fat-fed mice measured as increased (1
      5 min) acute insulin response and area under the 50-min insulin curve.
      Concomitantly, glucose tolerance was improved by carbachol. In fact, carbachol
      normalized glucose-stimulated insulin secretion and glucose tolerance in mice
      subjected to a high-fat diet. Carbachol (>100 nmol/l) also potentiated glucose
      stimulated insulin secretion from isolated islets with higher efficiency in high
      fat-fed mice. In contrast, binding of the muscarinic receptor antagonist [N
      methyl-(3)H]scopolamine to islet muscarinic receptors and the contractile action
      of carbachol on ileum muscle strips were not different between the two groups. We
      conclude that carbachol normalizes glucose tolerance in insulin resistance.

PMID- 10409133
TI  - Aminoacyl-tRNA and tissue free amino acid pools are equilibrated after a flooding
      dose of phenylalanine.
AB  - The flooding dose method, which is used to measure tissue protein synthesis,
      assumes equilibration of the isotopic labeling between the aminoacyl-tRNA pool
      and the tissue and blood free amino acid pools. However, this has not been
      verified for a phenylalanine tracer in an in vivo study. We determined the
      specific radioactivity of [(3)H]phenylalanine in the aminoacyl-tRNA and the
      tissue and blood free amino acid pools of skeletal muscle and liver 30 min after
      administration of a flooding dose of phenylalanine along with
      [(3)H]phenylalanine. Studies were performed in neonatal pigs in the fasted and
      refed states and during hyperinsulinemic-euglycemic-amino acid clamps. The
      results showed that, 30 min after the administration of a flooding dose of
      phenylalanine, there was equilibration of the specific radioactivity of
      phenylalanine among the blood, tissue, and tRNA precursor pools. Equilibration of
      the specific radioactivity of the three precursor pools for protein synthesis
      occurred in both skeletal muscle and liver. Neither feeding nor insulin status
      affected the aminoacyl-tRNA specific radioactivity relative to the tissue free
      amino acid specific radioactivity. The results support the assumption that the
      tissue free amino acid pool specific radioactivity is a valid measure of the
      precursor pool specific radioactivity and thus can be used to calculate protein
      synthesis rates in skeletal muscle and liver when a flooding dose of
      phenylalanine is administered.

PMID- 10409134
TI  - Regulation of the genes for arginase isoforms and related enzymes in mouse
      macrophages by lipopolysaccharide.
AB  - Arginase exists in two isoforms, the hepatic (arginase I) and extrahepatic types
      (arginase II). Arginase I is markedly induced in rat peritoneal macrophages and
      rat tissues in vivo by bacterial lipopolysaccharide (LPS). In contrast, both
      arginase I and arginase II are induced in LPS-activated mouse peritoneal
      macrophages. In the present study, expression of arginase isoforms and related
      enzymes was studied in mouse tissues in vivo and in peritoneal macrophages with
      RNA blot and immunoblot analyses and enzyme assay. When mice were injected
      intraperitoneally with LPS, inducible nitric oxide synthase (iNOS) and arginase
      II were induced early in the lung and spleen. mRNAs for argininosuccinate
      synthase (AS) and ornithine decarboxylase (ODC) were also induced early. In
      comparison, arginase I was induced later in the lung. Early induction of iNOS,
      arginase II, AS, ODC, and cationic amino acid transporter 2 and late induction of
      arginase I were observed in LPS-activated peritoneal macrophages. These results
      indicate that the genes for the two arginase isoforms are regulated
      differentially. Possible roles of the arginase isoforms in the regulation of
      nitric oxide production and in polyamine synthesis are discussed.

PMID- 10409135
TI  - Resistance exercise training increases mixed muscle protein synthesis rate in
      frail women and men >/=76 yr old.
AB  - Muscle atrophy (sarcopenia) in the elderly is associated with a reduced rate of
      muscle protein synthesis. The purpose of this study was to determine if weight
      lifting exercise increases the rate of muscle protein synthesis in physically
      frail 76- to 92-yr-old women and men. Eight women and 4 men with mild to moderate
      physical frailty were enrolled in a 3-mo physical therapy program that was
      followed by 3 mo of supervised weight-lifting exercise. Supervised weight-lifting
      exercise was performed 3 days/wk at 65-100% of initial 1-repetition maximum on
      five upper and three lower body exercises. Compared with before resistance
      training, the in vivo incorporation rate of [(13)C]leucine into vastus lateralis
      muscle protein was increased after resistance training in women and men (P <
      0.01), although it was unchanged in five 82 +/- 2-yr-old control subjects studied
      two times in 3 mo. Maximum voluntary knee extensor muscle torque production
      increased in the supervised resistance exercise group. These findings suggest
      that muscle contractile protein synthetic pathways in physically frail 76- to 92
      yr-old women and men respond and adapt to the increased contractile activity
      associated with progressive resistance exercise training.

PMID- 10409136
TI  - A negative arterial-portal venous glucose gradient increases net hepatic glucose
      uptake in euglycemic dogs.
AB  - We investigated whether a negative arterial-portal venous (a-pv) glucose
      gradient, or "portal signal," can increase net hepatic glucose uptake (NHGU) and
      decrease muscle glucose uptake at euglycemia as it does at hyperglycemia. Twenty
      42-h fasted dogs were studied during a basal and two 120-min euglycemic periods
      (period I and period II). Glucagon was maintained at basal levels, and insulin
      was raised 3-fold (3xIns, n = 10) or 15-fold (15xIns, n = 10). During period I,
      dogs received glucose only peripherally. During period II, one-half of the dogs
      continued the peripheral infusion; the other one-half received glucose
      intraportally (4 mg. kg(-1). min(-1) and reduced peripheral glucose infusion). A
      negative a-pv glucose gradient was present during intraportal glucose infusion.
      All 3xIns and 15xIns dogs had similar NHGU in period I. In period II, it was 2.1
      +/- 0.3 (3xIns) and 2.5 (15xIns) mg. kg(-1). min(-1) greater in the presence than
      in the absence of the portal signal (P < 0.001). The net glucose fractional
      extraction data paralleled NHGU. In 3xIns, but not in 15xIns, whole body
      nonhepatic glucose uptake was lower in the presence of the portal signal than in
      its absence. In conclusion, in hyperinsulinemic, but not hyperglycemic
      conditions, the portal signal is effective in activating NHGU. The inhibition of
      nonhepatic glucose uptake, on the other hand, is minimal under euglycemic as
      opposed to hyperglycemic conditions.

PMID- 10409137
TI  - Insulin-like growth factor I in skeletal muscle after weight-lifting exercise in
      frail elders.
AB  - To assess muscle remodeling and functional adaptation to exercise and diet
      interventions, 26 men and women aged 72-98 yr underwent a vastus lateralis biopsy
      before and after placebo control condition, and progressive resistance training,
      multinutrient supplementation, or both. Type II atrophy, Z band, and myofibril
      damage were present at baseline. Combined weight lifting and nutritional
      supplementation increased strength by 257 +/- 62% (P = 0.0001) and type II fiber
      area by 10.1 +/- 9.0% (P = 0.033), with a similar trend for type I fiber area
      (+12.8 +/- 22.2%). Exercise was associated with a 2. 5-fold increase in neonatal
      myosin staining (P = 0.0009) and an increase of 491 +/- 137% (P < 0.0001) in IGF
      I staining. Ultrastructural damage increased by 141 +/- 59% after exercise
      training (P = 0.034). Strength increases were largest in those with the greatest
      increases in myosin, IGF-I, damage, and caloric intake during the trial. Age
      related sarcopenia appears largely confined to type II muscle fibers. Frail
      elders respond robustly to resistance training with musculoskeletal remodeling,
      and significant increases in muscle area are possible with resistance training in
      combination with adequate energy intakes.

PMID- 10409139
TI  - A critical evaluation of mass isotopomer distribution analysis of gluconeogenesis
      in vivo.
AB  - There are conflicting reports concerning the reliability of mass isotopomer
      distribution analysis (MIDA) for estimating the contribution of gluconeogenesis
      to total glucose production (f) during [(13)C]glycerol infusion. We have
      evaluated substrate-induced effects on rate of appearance (R(a)) of glycerol and
      glucose and f during [2-(13)C]glycerol infusion in vivo. Five groups of mice were
      fasted for 30 h and then infused with [2-(13)C]glycerol at variable rates and
      variable (13)C enrichments (group I: 20 micromol. kg(-1). min(-1), 99% (13)C;
      group II: 60 micromol. kg(-1). min(-1), 60% (13)C; group III: 60 micromol. kg(
      1). min(-1), 99% (13)C; group IV: 120 micromol. kg(-1). min(-1), 40% (13)C; or
      group V: 120 micromol. kg(-1). min(-1), 99% (13)C). The total glycerol R(a)
      increased from approximately 104 to approximately 157 and to approximately 210
      micromol. kg(-1). min(-1) as the infusion of [2-(13)C]glycerol increased from 20
      to 60 and to 120 micromol. kg(- 1). min(-1), respectively. As the amount of 99%
      enriched [2-(13)C]glycerol increased from 20 to 60 and to 120 micromol. kg(-1).
      min(-1) (groups I, III, and V, respectively), plasma glycerol enrichment
      increased from approximately 21 to approximately 42 and to approximately 57% and
      the calculated f increased from approximately 27 to approximately 56 and to
      approximately 87%, respectively. Similar plasma glycerol enrichments were
      observed in groups I, II, and IV (i. e., approximately 21-24%), yet f increased
      from approximately 27 to approximately 57 and to approximately 86% in groups II
      and IV, respectively. Estimates of absolute gluconeogenesis increased from
      approximately 14 to approximately 33 and approximately 86 micromol. kg(-1). min(
      1) as the infusion of [2-(13)C]glycerol increased from 20 to 60 and 120 micromol.
      kg(-1). min(-1). Plausible estimates of f were obtained only under conditions
      that increased total glycerol R(a) approximately 2-fold (P < 0.001) and increased
      glucose R(a) approximately 1.5-fold (P < 0.01) above basal. We conclude that in
      30-h fasted mice, 1) estimates of f by MIDA with low infusion rates of [2
      (13)C]glycerol yield erroneous results and 2) reasonable estimates of f are
      obtained at glycerol infusion rates that perturb glycerol and glucose metabolism.

PMID- 10409138
TI  - Effects of nonsulfur and sulfur amino acids on the regulation of hepatic enzymes
      of cysteine metabolism.
AB  - To determine the role of nonsulfur vs. sulfur amino acids in regulation of
      cysteine metabolism, rats were fed a basal diet or diets supplemented with a
      mixture of nonsulfur amino acids (AA), sulfur amino acids (SAA), or both for 3
      wk. Hepatic cysteine-sulfinate decarboxylase (CSDC), cysteine dioxygenase (CDO),
      and gamma-glutamylcysteine synthetase (GCS) activity, concentration, and mRNA
      abundance were measured. Supplementation with AA alone had no effect on any of
      these measures. Supplementation of the basal diet with SAA, with or without AA,
      resulted in a higher CDO concentration (32-45 times basal), a lower CSDC mRNA
      level (49-64% of basal), and a lower GCS-heavy subunit mRNA level (70-76%). The
      presence of excess SAA and AA together resulted in an additional type of
      regulation: a lower specific activity of all three enzymes was observed in rats
      fed diets with an excess of AA and SAA. Both SAA and AA played a role in
      regulation of these three enzymes of cysteine metabolism, but SAA had the
      dominant effects, and effects of AA were not observed in the absence of SAA.

PMID- 10409140
TI  - Hepatic denervation does not affect plasma vasopressin response to intragastric
      hypertonic saline in conscious rats.
AB  - Peripheral osmoreceptors monitor dietary NaCl and modify central nervous system
      and renal sympathetic nervous system activity accordingly. Experimental evidence
      suggests that these responses are dependent on the hepatic nerves. Peripheral
      osmoreceptors also modify arginine vasopressin (AVP) secretion. However, although
      hepatic denervation reportedly blunts activation of both supraoptic and
      paraventricular hypothalamic neurons after intraportal NaCl infusion, the role of
      the hepatic nerves in the AVP release has not been directly examined. The present
      study tests the hypothesis that the hepatic nerves modify AVP release in response
      to intragastric NaCl infusion. Wistar-Kyoto rats (WKY) received either hepatic
      denervation or a sham operation. Intragastric NaCl infusion significantly
      elevated plasma AVP in both sham-operated WKY and hepatic-denervated WKY, and the
      responses were not different between these groups. Second, previous studies
      suggest that both AVP secretion and baroreflexes are blunted in spontaneously
      hypertensive rats (SHR), deficits that contribute to the observed hypertension in
      SHR. We hypothesized that SHR also have a blunted peripheral osmoreceptor reflex
      and that this contributes to NaCl-sensitive hypertension. In contrast to our
      prediction, in SHR intragastric NaCl infusion induced an increase in plasma AVP
      that was similar to that in the WKY groups. Thus, although hepatic osmoreceptors
      are important for chronic regulation of arterial pressure, renal sympathetic
      nervous system activity, and the activity of hypothalamic neurons, they do not
      appear to influence plasma AVP concentration in response to intragastric NaCl.

PMID- 10409141
TI  - Substrate oxidation by the portal drained viscera of fed piglets.
AB  - Fully fed piglets (28 days old, 7-8 kg) bearing portal, arterial, and gastric
      catheters and a portal flow probe were infused with enteral [U-(13)C]glutamate (n
      = 4), enteral [U-(13)C]glucose (n = 4), intravenous [U-(13)C]glucose (n = 4), or
      intravenous [U-(13)C]glutamine (n = 3). A total of 94% of the enteral [U
      (13)C]glutamate but only 6% of the enteral [U- (13)C]glucose was utilized in
      first pass by the portal-drained viscera (PDV). The PDV extracted 6.5% of the
      arterial flux of [U-(13)C]glucose and 20.4% of the arterial flux of [U
      (13)C]glutamine. The production of (13)CO(2) (percentage of dose) by the PDV from
      enteral glucose (3%), arterial glucose (27%), enteral glutamate (52%), and
      arterial glutamine (70%) varied widely. The substrates contributed 15% (enteral
      glucose), 19% (arterial glutamine), 29% (arterial glucose), and 36% (enteral
      glutamate) of the total production of CO(2) by the PDV. Enteral glucose accounted
      for 18% of the portal alanine and 31% of the portal lactate carbon outflow. We
      conclude that, in vivo, three-fourths of the energy needs of the PDV are
      satisfied by the oxidation of glucose, glutamate, and glutamine, and that dietary
      glutamate is the most important single contributor to mucosal oxidative energy
      generation.

PMID- 10409143
TI  - Lung surfactant kinetics in conscious pigs.
AB  - The primary goal of this study was to determine the contributions of plasma free
      fatty acids (FFA) and de novo synthesized fatty acids (FA) to lung surfactant
      phosphatidylcholine (PC) synthesis. A new stable isotope tracer model was
      developed in which [1, 2-(13)C(2)]acetate and uniformly labeled [U
      (13)C(16)]palmitate were infused in nine normal overnight fasted pigs to quantify
      surfactant kinetics in the basal state and during low-dose glucose infusion (2
      mg. kg(-1). min(-1)). There was no effect of glucose; therefore, all data were
      pooled. The surfactant PC-bound palmitate incorporation rate from plasma
      palmitate was 20.9 +/- 1.9 nmol palmitate. h(-1). g wet lung(-1), compared with
      the rate of 2.1 +/- 0.3 nmol palmitate. h(-1). g wet lung(-1) from de novo
      synthesized palmitate. The PC-bound palmitate secretion rate from the lamellar
      body pool to the alveolar surface pool was 239 +/- 26 nmol palmitate. h(-1). g
      wet lung(-1). Approximately 90% of the secreted PC recycled back to the lamellar
      bodies for reutilization. We conclude that plasma is the primary contributor of
      FA for surfactant PC synthesis under the conditions of this experiment.

PMID- 10409142
TI  - Stimulation of both aerobic glycolysis and Na(+)-K(+)-ATPase activity in skeletal
      muscle by epinephrine or amylin.
AB  - Epinephrine and amylin stimulate glycogenolysis, glycolysis, and Na(+)-K(+)
      ATPase activity in skeletal muscle. However, it is not known whether these
      hormones stimulate glycolytic ATP production that is specifically coupled to ATP
      consumption by the Na(+)-K(+) pump. These studies correlated glycolysis with
      Na(+)-K(+)-ATPase activity in resting rat extensor digitorum longus and soleus
      muscles incubated at 30 degrees C in well-oxygenated medium. Lactate production
      rose three- to fourfold, and the intracellular Na(+)-to-K(+) ratio (Na(+)/K(+))
      fell with increasing concentrations of epinephrine or amylin. In muscles exposed
      to epinephrine at high concentrations (5 x 10(-7) and 5 x 10(-6) M), ouabain
      significantly inhibited glycolysis by approximately 70% in either muscle and
      inhibited glycogenolysis by approximately 40 and approximately 75% in extensor
      digitorum longus and soleus, respectively. In the absence of ouabain, but not in
      its presence, statistically significant inverse correlations were observed
      between lactate production and intracellular Na(+)/K(+) for each hormone.
      Epinephrine had no significant effect on oxygen consumption or ATP content in
      either muscle. These results suggest for the first time that stimulation of
      glycolysis and glycogenolysis in resting skeletal muscle by epinephrine or amylin
      is closely linked to stimulation of active Na(+)-K(+) transport.

PMID- 10409144
TI  - Mucosal immunity and inflammation. III. The mucosal antigen barrier: cross talk
      with mucosal cytokines.
AB  - We have known for many years that mucosal responses to antigens are regulated by
      immune cells and their molecular signals. More recently, it has become clear that
      epithelial cells also synthesize and secrete chemokines and cytokines. A
      sophisticated system of bidirectional cytokine signals is responsible for immune
      activation in the case of enteropathogens vs. immune suppression to food and
      commensal microbial antigens. A key factor in determining antigen handling is the
      route taken by antigens across the epithelial barrier. Cytokines and other
      mucosal messenger molecules play a critical role in the regulation of
      transepithelial antigen transport.

PMID- 10409145
TI  - Lessons from genetically engineered animal models. I. Physiological studies with
      gastrin in transgenic mice.
AB  - The role of gastrin in the regulation of gastrointestinal growth and acid
      secretion has been addressed through recent studies involving transgenic and
      knockout mice. The role of gastrin as a key modulator of parietal cell function
      and gastric acid secretion has been confirmed through studies in mice deficient
      in either gastrin or the gastrin/CCK-B receptor. However, although gastrin
      deficient mice show no changes in gastric proliferation, they do show reduced
      colonic proliferation, and rates of colonic proliferation are increased in
      transgenic mice overexpressing glycine-extended gastrin or progastrin. This
      themes article highlights recent progress in our understanding of the biology of
      gastrin through studies in genetically modified mice.

PMID- 10409146
TI  - Biliary excretion in primary rat hepatocytes cultured in a collagen-sandwich
      configuration.
AB  - The objective of the present investigation was to examine the functional
      reestablishment of polarity in freshly isolated hepatocytes cultured between 2
      layers of gelled collagen (sandwich configuration). Immunoblot analysis
      demonstrated that the canalicular multispecific organic anion transport protein
      (multidrug resistance-associated protein, Mrp2) was partially maintained in day 5
      hepatocytes cultured in a sandwich configuration. Fluorescein-labeled
      taurocholate and carboxydichlorofluorescein were excreted into and concentrated
      in the bile canalicular lumen of day 5 sandwich-cultured hepatocytes, resulting
      in formation of fluorescent networks in standard buffer (intact bile canaliculi).
      Confocal microscopy studies demonstrated that 1) carboxydichlorofluorescein that
      had concentrated in the canalicular lumen was released into the incubation buffer
      in the presence of Ca(2+)-free buffer (disrupted bile canaliculi), and 2)
      rhodamine-dextran, an extracellular space marker, was only able to diffuse into
      the canalicular lumen in the presence of Ca(2+)-free buffer. The cumulative
      uptake of [(3)H]taurocholate in day 5 sandwich-cultured hepatocytes was
      significantly higher in standard buffer compared with Ca(2+)-free buffer, due to
      accumulation of taurocholate in canalicular spaces. When [(3)H]taurocholate was
      preloaded in the day 5 sandwich-cultured hepatocytes, taurocholate efflux was
      greater in Ca(2+)-free compared with standard buffer. The biliary excretion index
      of taurocholate, equivalent to the percentage of retained taurocholate in the
      canalicular networks, increased from approximately 8% at day 0 to approximately
      60% at day 5 in sandwich-cultured hepatocytes. In summary, hepatocytes cultured
      in a collagen-sandwich configuration for up to 5 days establish intact
      canalicular networks, maintain Mrp2, reestablish polarized excretion of organic
      anions and bile acids, and represent a useful in vitro model system to
      investigate the hepatobiliary disposition of substrates.

PMID- 10409147
TI  - Quantification and distribution of Ca(2+)-activated maxi K(+) channels in rabbit
      distal colon.
AB  - The Ca(2+)-activated maxi K(+) channel is an abundant channel type in the distal
      colon epithelium, but nothing is known regarding the actual number and precise
      localization of these channels. The aim of this study has therefore been to
      quantify the maxi K(+) channels in colon epithelium by binding of iberiotoxin
      (IbTX), a selective peptidyl ligand for maxi K(+) channels. In isotope flux
      measurements 75% of the total K(+) channel activity in plasma membranes from
      distal colon epithelium is inhibited by IbTX (K(0.5) = 4.5 pM), indicating that
      the maxi K(+) channel is the predominant channel type in this epithelium.
      Consistent with the functional studies, the radiolabeled double mutant (125)I
      IbTX-D19Y/Y36F binds to the colon epithelium membranes with an equilibrium
      dissociation constant of approximately 10 pM. The maximum receptor concentration
      values (in fmol/mg protein) for (125)I-IbTX-D19Y/Y36F binding to colon epithelium
      are 78 for surface membranes and 8 for crypt membranes, suggesting that the maxi
      K(+) channels are predominantly expressed in the Na(+)-absorbing surface cells,
      as compared with the Cl(-)-secreting crypt cells. However, aldosterone
      stimulation of this tissue induced by a low-Na(+) diet does not change the total
      number of maxi K(+) channels.

PMID- 10409149
TI  - Intestinal plasma membrane calcium pump protein and its induction by
      1,25(OH)(2)D(3) decrease with age.
AB  - The plasma membrane Ca pump of intestinal absorptive cells has been proposed as a
      component in the vitamin D-dependent active transport of Ca. Because intestinal
      Ca transport declines with age, the purpose of this study was to determine if
      changes in Ca pump expression parallel this decline. Intestinal levels of the
      plasma membrane Ca pump protein were measured by Western blotting in Fischer 344
      rats that were 2, 12, and 24 mo of age. Ca pump protein levels declined by 90% in
      the duodenum and 65% in the ileum between 2 and 12 mo of age, the time during
      which active Ca transport declines markedly. The effect of age on the induction
      of the Ca pump by 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the active
      metabolite of vitamin D, was determined. Rats were made deficient in
      1,25(OH)(2)D(3) by feeding a high-strontium diet, and they were then dosed with
      1,25(OH)(2)D(3) or vehicle at 48, 24, and 6 h. In 12-mo-old rats 1,25(OH)(2)D(3)
      induced duodenal Ca pump protein to only 39% and active Ca transport to 33% of
      that seen in 2-mo-old animals. These studies demonstrate that decreased
      expression of the plasma membrane Ca pump protein, along with calbindin protein,
      parallels the decline in intestinal Ca transport and its response to
      1,25(OH)(2)D(3) with age.

PMID- 10409148
TI  - Metabolism of short-chain fatty acids by rat colonic mucosa in vivo.
AB  - To determine the influence of substrate concentration and substrate interactions
      on short-chain fatty acid metabolism in vivo, a surgical procedure was
      established. Rats were surgically operated to cannulate a 5-cm segment of
      proximal colon, isolate the vasculature, and cannulate the right colic vein
      draining this segment. Thus metabolism was restricted to the defined colonic
      segment. The appearance of total (14)C and (14)CO(2) in the mesenteric blood
      stabilized after 30 min of perfusion. Increasing luminal concentrations of
      butyrate from 2 to 40 mmol/l resulted in linear increases in total (14)C, but
      (14)CO(2) production from [(14)C]butyrate increased as a function of
      concentration only up to 10 mmol/l and was stable at higher butyrate
      concentrations. In addition to CO(2), 3-hydroxybutyrate and lactate were major
      metabolites of acetate and butyrate in vivo. The presence of a mixture of
      alternative substrates in the lumen had no influence on the metabolism of
      butyrate to CO(2) but significantly reduced the metabolism of acetate to CO(2).
      When compared with young (4 mo old) animals, transport of butyrate was
      significantly lower for aged (48 mo old) animals, as evidenced by the rate of
      appearance in blood of total (14)C (P = 0.04) and (14)C in butyrate (P = 0.03),
      but metabolism was similar, since differences were not significant for (14)C in
      the major metabolites 3-hydroxybutyrate (P = 0.06) and CO(2) (P = 0.17). These
      results show that important aspects of short-chain fatty acid transport and
      metabolism are not predicted from data using isolated colonocytes but require
      study using an in vivo model.

PMID- 10409150
TI  - Arginine vasopressin inhibits fluid secretion in guinea pig pancreatic duct
      cells.
AB  - The effects of arginine vasopressin (AVP) on pancreatic ductal secretion were
      studied in guinea pigs. In the isolated vascularly perfused pancreas, AVP reduced
      secretin-stimulated fluid secretion and increased the vascular resistance when
      the perfusion rate was held constant. In the isolated interlobular duct segments,
      AVP inhibited secretin-stimulated fluid secretion, indicating the direct
      inhibitory action of AVP on the duct cells. AVP affected neither the basal nor
      the secretin-induced cAMP productions, suggesting that AVP inhibits the fluid
      secretion at a point distal to the production of cAMP. AVP increased
      intracellular Ca(2+) concentration ([Ca(2+)](i)) in the absence of extracellular
      Ca(2+). When [Ca(2+)](i) was elevated by the application of thapsigargin, AVP
      caused a rapid decrease in [Ca(2+)](i). AVP seems to activate both Ca(2+) release
      from intracellular stores and Ca(2+) efflux across the plasma membrane, but its
      relation to the inhibition of fluid secretion remains to be clarified. It is
      concluded that AVP directly inhibits secretin-stimulated ductal fluid secretion
      in the guinea pig pancreas.

PMID- 10409151
TI  - Microcirculatory perfusion deficits are not essential for remote parenchymal
      injury within the liver.
AB  - A normotensive model of hindlimb ischemia-reperfusion in Wistar rats was used to
      test the hypothesis that microvascular perfusion deficits contribute to the
      initiation of remote hepatic injury during a systemic inflammatory response.
      Animals were randomly assigned to one of three groups: 4 h of ischemia with 6 h
      of reperfusion (I/R-6; n = 4), 4 h of ischemia with 3 h of reperfusion (I/R-3; n
      = 5), or no ischemia (naive; n = 5). With intravital fluorescence microscopy,
      propidium iodide (PI; 0.05 mg/100 g body wt) was injected for the in vivo
      labeling of lethally injured hepatocytes (number/10(-1) mm(3)). PI-positive
      hepatocytes increased progressively over the 6-h period (naive 32.9 +/- 7.8 vs.
      I/R-3 92.8 +/- 11.5 vs. I/R-6 232 +/- 39.2), with no difference between
      periportal and pericentral regions of the lobule. Additionally, a significant
      decrease in continuously perfused sinusoids (naive 70.0 +/- 1.5 vs. I/R-3 65.0 +/
      1.0 vs. I/R-6 48.8 +/- 0.9%) was measured. Regional sinusoidal perfusion
      differences were only observed after 3 h of limb reperfusion. Indirect measures
      of hepatocellular injury using alanine transaminase levels support the
      progressive nature of hepatic parenchymal injury (0 h 57.8 +/- 6.5 vs. 3 h 115.3
      +/- 20.7 vs. 6 h 125.6 +/- 19.5 U/l). Evidence from this study suggests that
      remote hepatic parenchymal injury occurs early and progresses after the induction
      of a systemic inflammatory response and that microvascular perfusion deficits are
      not essential for the initiation of such injury.

PMID- 10409152
TI  - Differential changes in ACh-, motilin-, substance P-, and K(+)-induced
      contractility in rabbit colitis.
AB  - To test the hypothesis that the changes in intestinal contractility, which
      accompany inflammation of the gut, are agonist specific, we compared the response
      of inflamed strips to substance P (SP), motilin, ACh, and K(+) as a function of
      time. In parallel experiments, changes in the general mechanical properties
      (passive tension, optimal stretch) of the colitic tissue were evaluated. Colitis
      was induced by trinitrobenzenesulfonic acid, and rabbits were killed after 1, 2,
      3, 5, or 8 days. Passive tension was increased starting from day 2 until day 8,
      and maximal active tension (T(max)) was generated at less stretch from day 5. A
      50% decrease in T(max) was observed for ACh and K(+) between days 2 and 3 and for
      motilin and SP between days 3 and 5. For all compounds, T(max) returned to normal
      after 8 days. The pEC(50) value (negative logarithm of the concentration that
      induces 50% of the maximal contractile activity) for ACh was increased from day 3
      until day 8 and for SP at day 3, whereas for motilin it was decreased at day 1.
      The changes in passive tension and optimal stretch indicate generalized
      structural alterations of smooth muscle tissue. However, the different time
      profiles of the changes in active tension and contractile potency for different
      contractile agents suggest that inflammation specifically affects receptor
      mediated mechanisms.

PMID- 10409153
TI  - Effect of milrinone on small mesenteric artery vasoconstriction: role of K(+)
      channels.
AB  - We examined whether milrinone-mediated attenuation of small mesenteric artery
      vasoconstriction results predominantly from the activation of vascular smooth
      muscle K(+) channels. Resistance arteries (approximately 150 micrometers) were
      dissected from rat mesentery and were mounted on a wire myograph. Isometric force
      development in response to increasing concentrations of norepinephrine (NE) was
      monitored before and after treatment with the type 3 phosphodiesterase inhibitor
      milrinone. Milrinone significantly reduced NE-induced vasoconstriction,
      attenuating both NE sensitivity and maximal tension generation. Inhibition of ATP
      sensitive K(+) channels or voltage-gated K(+) channels did not prevent the
      milrinone-induced attenuation of NE responses. Blockade of inwardly rectifying
      K(+) channels or Ca(2+)-sensitive K(+) channels prevented the milrinone-mediated
      reduction in NE sensitivity, but this effect was apparently due to direct
      enhancement of vasoconstrictor responsiveness rather than interference with the
      mechanism of milrinone action. In addition, milrinone elicited substantial
      relaxation in vessels preconstricted with 100 mM KCl. This effect was mimicked by
      the adenylyl cyclase activator forskolin and was reversed by the Rp diastereomer
      of cAMP, which is a cAMP-dependent protein kinase (PKA) inhibitor. Our results
      indicate that cAMP/PKA-mediated impairment of vasoconstriction may occur without
      the contribution of K(+) channel regulation.

PMID- 10409154
TI  - Stimulation of the paraventricular nucleus modulates the activity of gut
      sensitive neurons in the vagal complex.
AB  - There is good evidence that stimulation of the lateral hypothalamus excites
      neurons in the dorsal vagal complex (DVC), but the data regarding the role of the
      paraventricular nucleus (PVN) in vagal function are less clear. The purpose of
      this study was to clarify the effect of PVN stimulation on the activity of
      neurons in the DVC. We utilized extracellular and intracellular neuronal
      recordings with intracellular injections of a neuronal tracer to label
      individual, physiologically characterized neurons in the DVC of rats anesthetized
      with pentobarbital sodium. Most (80%) of the gut-sensitive dorsal motor nucleus
      of the vagus (DMNV) neurons characterized in this study exhibited a change in
      activity during electrical stimulation of the PVN. Stimulation of the PVN caused
      an increase in the spontaneous activity of 59% of the PVN-sensitive DMNV neurons,
      and the PVN was capable of modulating the response of a small subset of DMNV
      neurons to gastrointestinal stimuli. This study also demonstrated that the PVN
      was capable of influencing the activity of neurons in the nucleus of the solitary
      tract (NST). Electrical stimulation of the PVN decreased the basal activity of
      66% of the NST cells that we characterized and altered the gastrointestinal
      response of a very small subset of NST neurons. It is likely that these
      interactions play a role in the modulation of a number of gut-related homeostatic
      processes. Increased or decreased activity in the descending pathway from the PVN
      to the DVC has the potential to alter ascending satiety signals, modulate vago
      vagal reflexes and the cephalic phase of feeding, and affect the absorption of
      nutrients from the gastrointestinal tract.

PMID- 10409155
TI  - Effects of LPS on transport of indocyanine green and alanine uptake in perfused
      rat liver.
AB  - Lipopolysaccharide (LPS) initiates cholestasis. Whether this process is mediated
      by tumor necrosis factor-alpha (TNF-alpha) and whether the cholestatic response
      to LPS is associated with intrahepatic accumulation of possibly toxic substances
      are under debate. To study these questions the hepatic uptake and biliary
      excretion of indocyanine green (ICG) was examined in the isolated perfused rat
      liver 18 h after intravenous treatment of rats with either saline, 1 mg/kg body
      wt LPS, or LPS and intraperitoneal pentoxifylline (POF) (n = 6 in each group).
      POF inhibits TNF-alpha release after LPS administration. LPS induced a typical
      acute-phase response with increased mRNA for acute-phase proteins, reduced
      albumin mRNA, and increased hepatic uptake of alanine. Intrinsic hepatic
      clearance of ICG in controls (1.01 +/- 0.05 ml. min(-1). g liver(-1)) was
      similarly decreased by LPS alone (0.62 +/- 0.04 ml. min(-1). g(-1); P = 0.002 vs.
      control) or combined with POF (0.66 +/- 0.06 ml. min(-1). g(-1)). A kinetic
      analysis indicated that LPS reduced both uptake and excretion processes in a
      balanced manner, so that intrahepatic ICG content was unaffected or even slightly
      reduced, as confirmed by measurement of ICG contents in the perfused livers. In
      livers from parallel-treated nonperfused rats, mRNA for the organic anion
      transporting protein-1 (Oatp1, which is likely to mediate ICG uptake) was
      unaffected by LPS, whereas the concentration of Oatp1 protein was reduced. Thus
      LPS induced an acute-phase response that included downregulation of ICG uptake by
      reduction of Oatp1 protein concentration, possibly at a posttranscriptional
      level. TNF-alpha appears not to be the mediator because POF did not modify these
      LPS effects.

PMID- 10409156
TI  - Blockade of hepatic nitric oxide synthase causes insulin resistance.
AB  - The hypothesis was tested that insulin sensitivity, previously shown to depend on
      a functional hepatic parasympathetic reflex, was mediated by hepatic production
      of nitric oxide (NO). Insulin sensitivity was measured using the rapid insulin
      sensitivity test. N-nitro-L-arginine methyl ester (L-NAME, 2.5 and 5.0 mg/kg iv)
      and N-monomethyl-L-arginine (L-NMMA, 0.73 mg/kg), nitric oxide synthase (NOS)
      antagonists, caused insulin resistance in rats. Intraportal administration of L
      NAME at a dose of 1.0 mg/kg significantly reduced the response to insulin (54.9
      +/- 5.2%); however, administration of the same dose of L-NAME intravenously did
      not cause a significant decrease in insulin response. Intraportal, but not
      intravenous, administration of 3-morpholinosydnonimine (SIN-1, 5. 0 mg/kg), a NO
      donor, partially reversed the insulin resistance caused by L-NMMA. Intraportal
      administration of SIN-1 (10.0 mg/kg) completely restored insulin sensitivity
      after L-NMMA or surgical denervation of the liver. Insulin resistance produced by
      denervation was not further increased by NOS blockade. These results suggest that
      blockade of NOS causes peripheral insulin resistance secondary to blockade of the
      hepatic parasympathetic reflex release of hepatic insulin-sensitizing substance
      in response to insulin.

PMID- 10409157
TI  - Saturable stimulation of fatty acid transport through model cytoplasm by soluble
      binding protein.
AB  - To better define the role of soluble binding proteins in the cytoplasmic
      transport of amphipathic molecules, we measured the diffusional mobility of a
      fluorescent long-chain fatty acid, 12-N-methyl-(7-nitrobenz-2-oxa-1,3
      diazol)aminostearate (NBD-stearate), through model cytoplasm as a function of
      soluble binding protein concentration. Diffusional mobilities were correlated
      with the partition of the fatty acid between membrane and protein binding sites.
      Cytoplasm was modeled as a dense suspension of liposomes, and albumin was used as
      a model binding protein. Albumin saturably increased NBD-stearate mobility
      through the membrane suspension approximately eightfold. Fatty acid mobility in
      the absence of albumin was identical to the mobility of the membrane vesicles
      (1.99 +/- 0.33 x 10(-8) cm(2)/s), whereas the mobility at saturating
      concentrations was identical to the mobility of albumin (1.65 +/- 0.12 x 10(-7)
      cm(2)/s). The protein concentration producing half-maximal stimulation of NBD
      stearate diffusion (42.8 +/- 0.3 microM) was unexpectedly greater than that
      required to solubilize half of the NBD-stearate (17.9 +/- 3.0 microM). These
      results support a proposed mechanism for cytoplasmic transport of small
      amphipathic molecules in which aqueous diffusion of the protein-bound form of the
      molecule largely determines the transport rate. However, slow interchange of
      fatty acid between the binding protein and membranes also appears to influence
      the transport rate in this model system.

PMID- 10409158
TI  - Part of quercetin absorbed in the small intestine is conjugated and further
      secreted in the intestinal lumen.
AB  - Rutin and quercetin absorption and metabolism were investigated in rats after in
      situ perfusion of jejunum plus ileum (15 nmol/min). In contrast to rutin, a high
      proportion of quercetin (two-thirds) disappeared during perfusion, reflecting
      extensive transfer into the intestinal wall. Net quercetin absorption was not
      complete (2.1 nmol/min), inasmuch as 52% were reexcreted in the lumen as
      conjugated derivatives (7.7 nmol/min). Enterohepatic recycling contribution of
      flavonoids was excluded by catheterization of the biliary duct before perfusion.
      After a 30-min perfusion period, 0.71 microM of quercetin equivalents were
      detected in plasma, reflecting a significant absorption from the small intestine.
      The differential hydrolysis of effluent samples by glucuronidase and/or sulfatase
      indicates that the conjugated forms released in the lumen were 1) glucuronidated
      derivatives of quercetin and of its methoxylated forms (64%) and 2) sulfated form
      of quercetin (36%). In vitro quercetin glucuronides synthetized using jejunal and
      ileal microsomal fractions were similar to those recovered in the effluent of
      perfusion. These data suggest that glucuronidation and sulfatation take place in
      intestinal cells, whereas no glucurono-sulfoconjugates could be detected in the
      effluent. The present work shows that a rapid quercetin absorption in the small
      intestine is very effective together with its active conjugation in intestinal
      cells.

PMID- 10409159
TI  - Molecular diversity of K(V) alpha- and beta-subunit expression in canine
      gastrointestinal smooth muscles.
AB  - Voltage-activated K(+) (K(V)) channels play an important role in regulating the
      membrane potential in excitable cells. In gastrointestinal (GI) smooth muscles,
      these channels are particularly important in modulating spontaneous electrical
      activities. The purpose of this study was to identify the molecular components
      that may be responsible for the K(V) currents found in the canine GI tract. In
      this report, we have examined the qualitative expression of eighteen different
      K(V) channel genes in canine GI smooth muscle cells at the transcriptional level
      using RT-PCR analysis. Our results demonstrate the expression of K(V)1.4,
      K(V)1.5, K(V)1.6, K(V)2.2, and K(V)4.3 transcripts in all regions of the GI tract
      examined. Transcripts encoding K(V)1.2, K(V)beta1.1, and K(V)beta1.2 subunits
      were differentially expressed. K(V)1.1, K(V)1.3, K(V)2.1, K(V)3.1, K(V)3.2,
      K(V)3.4, K(V)4.1, K(V)4.2, and K(V)beta2.1 transcripts were not detected in any
      GI smooth muscle cells. We have also determined the protein expression for a
      subset of these K(V) channel subunits using specific antibodies by immunoblotting
      and immunohistochemistry. Immunoblotting and immunohistochemistry demonstrated
      that K(V)1.2, K(V)1.4, K(V)1.5, and K(V)2.2 are expressed at the protein level in
      GI tissues and smooth muscle cells. K(V)2.1 was not detected in any regions of
      the GI tract examined. These results suggest that the wide array of electrical
      activity found in different regions of the canine GI tract may be due in part to
      the differential expression of K(V) channel subunits.

PMID- 10409160
TI  - Quantitation of rat hepatic stellate cell contraction: stellate cells'
      contribution to sinusoidal resistance.
AB  - Although it has been hypothesized that contraction of hepatic stellate cells
      (HSC) regulates blood flow by modulating sinusoidal resistance, neither HSC
      contraction nor relaxation has been directly quantitated. To test this
      hypothesis, a force transducer was employed to directly measure the magnitude and
      rate of contraction and relaxation by primary rat HSC (4.7 x 10(5) +/- 0.2 x
      10(5) cells) cultured within a collagen gel. Serial exposures to 10% fetal bovine
      serum stimulated 81 +/- 14 and 82 +/- 10 dyn of contractile force, respectively.
      Subsequent stimulation with 2 nM endothelin-1 (ET-1) resulted in the development
      of 185 +/- 25 dyn of force. Contractions began within 10 s of ET-1 stimulation,
      and the half time of maximal force development was <5 min. Removal of agonist
      resulted in complete or nearly complete relaxation within 45 min. These results
      suggest that the magnitude and rate of HSC contraction and relaxation are capable
      of modulating blood flow via sinusoidal constriction.

PMID- 10409161
TI  - A novel nitric oxide scavenger decreases liver injury and improves survival after
      hemorrhagic shock.
AB  - We tested the ability of a nitric oxide (NO) scavenger to reduce tissue injury in
      a rodent model of hemorrhagic shock. Rats were hemorrhaged to a mean arterial
      blood pressure (MAP) of 40 mmHg and then resuscitated when either 30% of their
      shed blood had been returned (group 1) or after 100 min of continuous shock
      (group 2). Selected animals were treated with the NO scavenger NOX (30 mg. kg(
      1). h(-1)) infused over 4 h. Hemorrhaged rats had a lower MAP after resuscitation
      compared with sham-shock control rats. NOX treatment significantly increased MAP
      after resuscitation from hemorrhage. Hemorrhagic shock also increased liver
      injury as reflected by elevated ornithine carbamoyltransferase (OCT) plasma
      levels, and NOX treatment significantly reduced OCT release. In addition, NOX was
      associated with significantly decreased hepatic neutrophil infiltration and
      improved 24-h survival (n = 8 of 9) compared with saline-treated shock animals (n
      = 3 of 9). These data suggest that excess NO mediates shock-induced tissue injury
      and that suppression of NO availability with NO scavengers may reduce the
      pathophysiological sequelae of severe hemorrhage.

PMID- 10409163
TI  - Transcobalamin II synthesized in the intestinal villi facilitates transfer of
      cobalamin to the portal blood.
AB  - This study was designed to identify the cellular component of the intestinal
      villus where transcobalamin II (TCII) is synthesized, because this protein
      provides an essential function in the intestinal absorption of vitamin B(12)
      (cobalamin, Cbl). When a segment of proximal or distal small intestine of the
      guinea pig is cultured in medium containing [(57)Co]Cbl, TCII-[(57)Co]Cbl appears
      within 15 min. Northern blot analysis of RNA from both proximal and distal small
      intestine identified the TCII transcript. In situ hybridization of the distal
      ileum with (35)S-labeled TCII antisense transcript localized grains predominantly
      in crypts and in the lower third and central core of the villi. Grains were also
      evident at the base of the enterocytes in close apposition with the vascular
      network, whereas few grains appeared in the apical region of the columnar cells.
      This study provides evidence that TCII is constitutively expressed in the
      intestinal villi where vascular endothelium is abundant. In the distal ileum,
      where the intrinsic factor (IF) receptor is expressed, after uptake of IF-Cbl and
      the subsequent binding of free Cbl to TCII synthesized in the villi, the TCII-Cbl
      complex enters the microcirculation and passes into the portal blood.

PMID- 10409162
TI  - Mechanism of action of cholera toxin on the opossum internal anal sphincter
      smooth muscle.
AB  - Cholera toxin (CTX), an activator of G(s) protein, is an important
      pharmacological tool in G protein research. The effect and the mechanism of
      action of CTX in the gastrointestinal smooth muscle, including the internal anal
      sphincter (IAS), are not known. The present investigation was carried out to
      examine the effects of CTX on the signal transduction associated with the
      adenylate cyclase (AC) pathway on the basal tone of the IAS smooth muscle. CTX
      caused a prompt and dose-dependent fall in the basal tone of the IAS that was not
      affected by the neurotoxins TTX and omega-conotoxin or the nitric oxide synthase
      inhibitor N(G)-nitro-L-arginine. The cyclooxygenase inhibitor indomethacin, cAMP
      dependent protein kinase inhibitor Rp-8-bromoadenosine 3',5' cyclic
      monophosphorothioate inhibited CTX-induced IAS smooth muscle relaxation.
      Furthermore, CTX caused a concentration-dependent relaxation of the isolated
      smooth muscle cells (SMC) of the IAS, which was blocked by G(s)alpha antibody
      (G(s)alpha-Ab). The IAS smooth muscle relaxation was accompanied with an increase
      in the GTPase activity that was also specifically blocked by G(s)alpha-Ab. We
      conclude that a major part of the inhibitory action of CTX in the IAS is via the
      direct response of the SMC that is linked with G(s) protein to the AC pathway. A
      part of the inhibitory action of CTX on the smooth muscle occurs via the
      activation of cyclooxygenase pathway. The relative contribution of such actions
      of CTX in the smooth muscle in the gastrointestinal motility disturbances
      following cholera infection remains to be determined.

PMID- 10409165
TI  - A thermal injury-induced circulating factor(s) compromises intestinal cell
      morphology, proliferation, and migration.
AB  - The effects of a 60% body surface area thermal injury in rats on the morphology
      and proliferation of the epithelium of the small intestine and the in vitro
      effects of serum collected from scalded rats on intestinal epithelial cells were
      investigated. Scald injury caused significant reductions in duodenal villus width
      and crypt dimensions, villus enterocytes changed in shape from columnar to
      cuboidal, and the number of goblet cells decreased. The proportion of
      bromodeoxyuridine-labeled S phase cells in crypts was also diminished. In vitro,
      incubation of intestinal epithelial cells (IEC-6) with scalded rat serum (SRS)
      collected at either 12 or 24 h after injury caused a disruption in the integrity
      of the confluent culture and induced the appearance of large denuded areas. SRS
      also decreased DNA synthesis and delayed wound closure in an in vitro wound
      healing model. The thermal injury-induced changes in intestinal mucosal
      morphology and epithelial cell growth characteristics described in this study may
      underlie, in part, the mechanism(s) involved in the diminished absorption of
      nutrients, increased intestinal permeability, and sepsis in patients with thermal
      injury.

PMID- 10409166
TI  - Kex2 family endoprotease furin is expressed specifically in pit-region parietal
      cells of the rat gastric mucosa.
AB  - The proprotein-processing endoprotease furin is localized in the gastric
      epithelial cells of the pit region in the rat gastric gland. The gastric pit is
      composed of several cell types, including gastric surface mucosal (GSM) cells and
      parietal cells. Furin converts many growth- or differentiation-related
      proproteins to their active forms. We examined identification of furin-positive
      cells by immunostaining of rat gastric mucosa and regulators of the furin
      expression by measuring the furin promoter activity by luciferase assay. Furin
      positive cells were stained for H(+)-K(+)-ATPase, indicating that they are
      parietal cells. Furin-positive parietal cells were not stained for transforming
      growth factor-alpha (TGF-alpha) but were surrounded by TGF-alpha-positive GSM
      cells. In contrast, parietal cells below the proliferative zone were positive for
      TGF-alpha but not for furin. Furin-positive parietal cells expressed a high level
      of epidermal growth factor receptor (EGFR). TGF-alpha stimulated the furin
      promoter activity highly in a mouse GSM cell line GSM06. Thus we suggest that the
      parietal cells of the pit region have furin-mediated functions that can be
      stimulated by EGFR signaling.

PMID- 10409167
TI  - Selective secretion and replenishment of discrete mucin glycoforms from
      intestinal goblet cells.
AB  - Antibodies against MUC2, MUC3, and MUC5AC peptide epitopes stained the secretory
      contents of all goblet cells in the human colon-derived HT29-18N2 cell line. In
      contrast, four carbohydrate-specific monoclonal antibodies stained mucin
      glycoforms in consistent subsets of goblet cells. Cholinergic agonist-evoked
      decreases in total mucin stores were not always mirrored by proportional changes
      in mucin glycoforms in the same monolayers. Selective secretion of mucin
      glycoforms did not result from differences in receptor distribution, since
      cholinergic stimulation was found to increase intracellular free calcium in all
      cells and selective secretion was also observed when the cells were directly
      stimulated with the protein kinase C activator phorbol myristate acetate. The
      results demonstrate that goblet cells cycle through transient periods in which
      their exocytotic response is unresponsive to cholinergic or protein kinase C
      mediated stimuli. Goblet cells replenished intracellular mucin stores to control
      levels within 1 h, but the relative proportion of mucin glycoforms was not always
      restored until 24 h after stimulation.

PMID- 10409164
TI  - Ion transport across the normal and CF neonatal murine intestine.
AB  - Neonatal mice with cystic fibrosis (CF) exhibit a very high mortality due to
      intestinal obstruction localized primarily to the ileum and colon. It has been
      hypothesized that lack of Cl(-) secretion and possibly elevated Na(+) absorption
      contribute to the gut problems in CF neonates. Therefore, intestines (ileum,
      proximal colon, and distal colon) from normal and CF day-old mouse pups were
      studied on ultra-small-aperture (0.0135 cm(2)) Ussing chambers. All three regions
      of the normal neonatal intestine responded to forskolin with an increase in short
      circuit current, which was completely absent in the CF intestine. The neonatal
      distal colon exhibited a high rate of amiloride-sensitive electrogenic Na(+)
      absorption, which did not differ between the normal and CF preparations. The
      ileum and proximal colon of both genotypes exhibited a small but significant
      electrogenic Na(+) absorption. The neonatal proximal colon and ileum also
      exhibited electrogenic Na(+)-glucose cotransport, which was significantly greater
      in the normal compared with the CF ileum. In addition, all three intestinal
      regions exhibited electrogenic Na(+)-alanine cotransport, which was significantly
      reduced in two of the regions of the CF neonatal intestine. It is speculated
      that: 1) the reduced rate of Na(+)-nutrient cotransport in the CF intestine
      contributes to the lower rate of growth in CF pups, whereas 2) the elevated
      electrogenic Na(+) absorption in the neonatal intestine, coupled with an
      inability to secrete Cl(-), contributes to the intestinal obstruction in the CF
      pups.

PMID- 10409168
TI  - Modulation of host cell membrane fluidity: a novel mechanism for preventing
      bacterial adhesion.
AB  - Adhesion of bacterial enteropathogens to host mucosal surfaces is a critical
      primary step in the pathogenesis of diarrheal disease. We investigated the
      effects of altering the physical properties of eukaryotic cells on bacterial
      adhesion with the use of a series of three structurally dissimilar membrane
      fluidizers and several Escherichia coli as test strains. Lipid fluidity of the
      cell plasma membrane was measured by steady-state fluorescence anisotropy
      employing the probe 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3, 5-hexatriene.
      There was a dose-dependent and reversible inhibition of bacterial adhesion with
      increasing membrane fluidity. Time course experiments indicated that increasing
      membrane fluidity during the early stages of bacterial adhesion was essential for
      inhibition of attachment. None of the fluidizers affected the viability of either
      eukaryotic or prokaryotic cells. These findings demonstrate, for the first time,
      that changes in plasma membrane physical properties of epithelial cells can
      prevent microbial adhesion. This also suggests that altering the membrane
      properties of host cells could form a basis for novel strategies to prevent
      bacterial adhesion during infection in vivo.

PMID- 10409169
TI  - Autoimmune gastritis results in disruption of gastric epithelial cell
      development.
AB  - We have investigated the underlying basis of the lesion in murine autoimmune
      gastritis, a model of the human disease pernicious anemia. The disease is
      mediated by T lymphocytes and characterized by selective depletion of parietal
      and zymogenic cells from the gastric unit (gland) together with gastric
      epithelial cell hyperplasia. The gastric units of gastritic stomachs contained
      2.3-fold more cells than normal and accumulated rapidly dividing, short-lived
      gastric epithelial stem cells and mucous neck cells. Most of these immature cells
      failed to differentiate into end-stage cells but rather appeared to die by
      apoptosis. We also found no correlation between anti-parietal cell autoantibody
      titers and the degree of gastric pathology, providing further evidence that
      autoantibodies do not play a direct role in the pathogenesis of gastritis. Taken
      together, the normal developmental pathways of the gastric mucosa are disrupted
      in autoimmune gastritis, resulting in an amplification of immature cell types.
      The differentiation of these immature cells appears to be blocked, contributing
      to depletion of end-stage cells. This scenario provides an explanation for
      depletion of not only parietal cells but also zymogenic cells even though they
      are not directly targeted by the immune system.

PMID- 10409170
TI  - Cortical activation during human volitional swallowing: an event-related fMRI
      study.
AB  - Functional magnetic resonance imaging (fMRI) provides a safe, noninvasive method
      for studying task-related cortical neuronal activity. Because the cerebral cortex
      is strongly implicated in the control of human swallowing, we sought to identify
      its functional neuroanatomy using fMRI. In 10 healthy volunteers, a swallow event
      related paradigm was performed by injecting 5 ml water bolus into the oral cavity
      every 30 s. Whole brain functional magnetic susceptibility -weighted spiral
      imaging data were simultaneously acquired over 600 s on a 1.5-T magnetic
      resonance scanner, utilizing the blood oxygenation level-dependent technique, and
      correlation maps were generated using both >99% percentile rank and spatial
      extent thresholding. We observed areas of increased signal change consistently in
      caudal sensorimotor cortex, anterior insula, premotor cortex, frontal operculum,
      anterior cingulate and prefrontal cortex, anterolateral and posterior parietal
      cortex, and precuneus and superiomedial temporal cortex. Less consistent
      activations were also seen in posterior cingulate cortex and putamen and caudate
      nuclei. Activations were bilateral, but almost every region, particularly the
      premotor, insular, and frontal opercular cortices, displayed lateralization to
      one or the other hemisphere. Swallow-related cortical activity is
      multidimensional, recruiting brain areas implicated in processing motor, sensory,
      and attention/affective aspects of the task.

PMID- 10409171
TI  - Duodenal neurons provide nicotinic fast synaptic input to sphincter of Oddi
      neurons in guinea pig.
AB  - We have investigated the existence of neural connections between the duodenum and
      the sphincter of Oddi (SO). Stimulation of duodenal myenteric fiber bundles
      elicited synaptic responses in SO neurons, which included nicotinic fast
      excitatory postsynaptic potentials (EPSPs), slow EPSPs, and alpha(2)
      adrenoreceptor-mediated inhibitory postsynaptic potentials. After 48 h in organ
      culture, when extrinsic fibers had diminished, only the fast EPSPs persisted.
      Duodenal mucosal stimulation also elicited nicotinic fast EPSPs in SO neurons.
      There was no association between the SO neurons that received duodenal input and
      their chemical coding. A reciprocal projection also exists from the SO to the
      duodenum. In acute and cultured preparations, duodenal myenteric stimulation
      caused antidromic responses in 20% of SO neurons. Furthermore, 45.6 +/- 10.5
      neurons in SO ganglia were retrogradely labeled from dye application sites in the
      duodenum. It is proposed that bidirectional neural communication occurs between
      the duodenum and the SO and that duodenal neurons provide excitatory fast
      synaptic input to SO neurons through a reflex that can be activated at the
      duodenal mucosa.

PMID- 10409172
TI  - Expression of somatostatin receptor subtypes on guinea pig gastric and colonic
      smooth muscle cells.
AB  - In vivo and in vitro studies have demonstrated that somatostatin can influence
      motility and smooth muscle contractility of the stomach and colon. Recent studies
      have proposed that some of these effects may be mediated by somatostatin
      receptors (sst) directly on the smooth muscle cells. If this is correct, the sst
      receptor subtypes that are present are unknown. This study aimed to resolve these
      points. Because nucleotide sequences of guinea pig sst genes are unknown, we used
      sst subtype-specific primers based on comparisons of human and rat sst subtypes
      and performed RT-PCR of DNase I-treated total RNA from guinea pig total brain.
      PCR products were cloned in pCR II and sequenced and showed 87% (sst(1)), 90%
      (sst(2)), 90% (sst(3)), 99% (sst(4)), and 80% (sst(5)), respectively, nucleotide
      homology to the same region (transmembrane 4-6) of the human sst genes. Homology
      to rat sequences were lower. PCR products were obtained from first-strand cDNA
      derived from DNase I-treated RNA from dispersed guinea pig gastric and colonic
      smooth muscle cells. In gastric and colonic smooth muscle cells, we detected
      sst(1)-sst(3) and sst(5), and all were confirmed by sequencing. The presence of
      sst(4) was shown by Southern blot analysis and hybridization with a guinea pig
      sst(4)-specific primer. RT-PCR from cultured colonic and gastric smooth muscle
      cells devoid of any neural elements gave identical results. These results
      demonstrate that in the guinea pig all five sst subtypes are present directly on
      gastric and colonic smooth muscle cells. Previous studies have suggested that a
      predominant sst(3) subtype on gastric and a sst(5) subtype on colonic muscle
      cells mediated somatostatin's contractile effects, but the finding here that all
      five sst subtypes exist on both of these cells suggests that other sst subtypes
      have only a small or no contractile effect, sst subtypes in guinea pig have a
      different pharmacological profile from rat or human sst, or these other sst
      subtypes have some yet undescribed physiological function in muscle cells.

PMID- 10409173
TI  - Bacterial cell wall polymers promote intestinal fibrosis by direct stimulation of
      myofibroblasts.
AB  - Normal luminal bacteria and bacterial cell wall polymers are implicated in the
      pathogenesis of chronic intestinal inflammation. To determine the direct
      involvement of bacteria and their products on intestinal fibrogenesis, the
      effects of purified bacterial cell wall polymers on collagen and cytokine
      synthesis were evaluated in intestinal myofibroblast cultures established from
      normal fetal and chronically inflamed cecal tissues. In this study, the
      intestines of Lewis rats were intramurally injected with peptidoglycan
      polysaccharide polymers. Collagen and transforming growth factor (TGF)-beta1 mRNA
      levels were measured and correlated with mesenchymal cell accumulation by
      immunohistochemistry. The direct effects of cell wall polymers on fibrogenic
      cytokine and collagen alpha1 (type I) expression were evaluated in intestinal
      myofibroblast cultures. We found that intramural injections of bacterial cell
      wall polymers induced chronic granulomatous enterocolitis with markedly increased
      collagen synthesis and concomitant increased TGF-beta1 and interleukin (IL)-6
      expression. Intestinal myofibroblast cultures were established, which both
      phenotypically and functionally resemble the mesenchymal cells that are involved
      in fibrosis in vivo. Bacterial cell wall polymers directly stimulated collagen
      alpha1 (I), TGF-beta1, IL-1beta, and IL-6 mRNA expression in the intestinal
      myofibroblasts derived from both normal and inflamed cecum. Neutralization of
      endogenous TGF-beta1 inhibited in vitro collagen gene expression. From our
      results, we conclude that increased exposure to luminal bacterial products can
      directly activate intestinal mesenchymal cells, which accumulate in areas of
      chronic intestinal inflammation, thus stimulating intestinal fibrosis in
      genetically susceptible hosts.

PMID- 10409174
TI  - ANG II- and TxA(2)-induced mesenteric vasoconstriction in rats is mediated by
      separate cell signaling pathways.
AB  - Studies in vitro have demonstrated that vasoconstrictor agents increase
      intracellular Ca(2+) and activate protein kinase C (PKC) to elevate vascular
      tone. The aim of the present study was to determine the importance of these
      signaling pathways for angiotensin II (ANG II) and thromboxane A(2) (TxA(2)) in
      regulating mesenteric blood flow (MBF) in vivo. In anesthetized rats increasing
      doses of ANG II or the TxA(2) agonist U-46619 were administered into the superior
      mesenteric artery to reduce MBF. Intra-arterial infusion of inhibitors served to
      examine the contribution of different pathways: 8-(diethylamino)octyl 3,4,5
      trimethoxybenoate hydrochloride (TMB-8) to inhibit intracellular Ca(2+) release,
      nifedipine to block transmembrane Ca(2+) influx through the L-type Ca(2+)
      channel, and staurosporine to inhibit PKC. Each of the inhibitors attenuated ANG
      II-induced reductions in MBF, and all dose-response curves were shifted to the
      right to an approximately threefold higher ANG II dose. Combinations of the
      inhibitors revealed that their effects were additive; together they abolished the
      vasoconstrictor action of ANG II completely. In contrast, the dose-response curve
      for U-46619 was not affected by any of the inhibitors infused either separately
      or together. The results demonstrate that a rise in intracellular Ca(2+) and
      activation of PKC are major mediators of the vasoconstrictor effect of ANG II in
      mesenteric circulation, but they play a subordinate role, if any, for the effects
      of TxA(2). Because TxA(2) plays a major role only under pathological conditions,
      the uncontrolled vasoconstriction appears to be associated with the recruitment
      of novel signal transduction pathways.

PMID- 10409175
TI  - Role of nitric oxide in regulation of renal sympathetic nerve activity during
      hemorrhage in conscious rats.
AB  - The effect of inhibition of nitric oxide (NO) synthesis on the responses of blood
      pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA)
      during hemorrhaging was examined with the use of an NO synthase inhibitor, N(G)
      nitro-L-arginine methyl ester (L-NAME), in conscious rats. In the 0.9% saline
      group, hemorrhage (10 ml/kg body wt) did not alter BP but significantly increased
      HR and RSNA by 88 +/- 12 beats/min and 67 +/- 12%, respectively. Intravenous
      infusion of L-NAME (50 microg. kg(-1). min(-1)) significantly attenuated these
      tachycardic and sympathoexcitatory responses to hemorrhage (14 +/- 7 beats/min
      and 26 +/- 12%, respectively). Pretreatment of L-arginine (87 mg/kg) recovered
      the attenuation of HR and RSNA responses induced by L-NAME (92 +/- 6 beats/min
      and 64 +/- 10%, respectively). L-NAME by itself did not alter the baroreceptor
      reflex control of HR and RSNA. Hemorrhage increased the plasma vasopressin
      concentration, and its increment in the L-NAME-treated group was significantly
      higher than that in the 0.9% saline group. Pretreatment with the vascular
      arginine vasopressin V(1)-receptor antagonist OPC-21268 (5 mg/kg) recovered the
      attenuation of RSNA response induced by L-NAME (54 +/- 7%). These results
      indicate that NO modulated HR and RSNA responses to hemorrhage but did not
      directly affect the baroreceptor reflex arch. It can be assumed that NO modulated
      the baroreflex function by altering the secretion of vasopressin induced by
      hemorrhage.

PMID- 10409176
TI  - Chronic central infusion of ANG II potentiates cardiac sympathetic afferent
      reflex in dogs.
AB  - The aims of this study were to determine whether ANG II is involved in the
      central integration of the cardiac sympathetic afferent reflex (CSAR), and if
      this central effect of ANG II is mediated by the AT(1) receptor. Experiments were
      undertaken in dogs that were anesthetized with alpha-chloralose, sinoaortic
      denervated, and vagotomized. The renal sympathetic nerve activity (RSNA)
      responses to varying frequency and voltage stimulation of cardiac sympathetic
      afferent nerves were used to evaluate the central sensitivity of the CSAR. In two
      groups of dogs, two doses (50 and 100 ng/min icv) of ANG II were acutely infused.
      In a third group of dogs, ANG II was chronically infused for 3 days (100 ng/min,
      1 microliter/h icv). We found that acute infusion into the cerebroventricle of
      two doses of ANG II did not affect the central sensitivity of the CSAR or the
      baseline hemodynamics, but the baseline RSNA increased significantly during the
      infusion of the higher dose of ANG II. However, chronic intracerebroventricular
      infusion of ANG II enhanced the central sensitivity of the CSAR significantly. In
      addition, chronic intracerebrovetricular infusion of ANG II elicited a
      significant increase in water intake and in arterial pressure from the first and
      second day of infusion, respectively. In the group that received chronic
      intracerebroventricular infusion of ANG II, the administration of an AT(1)
      receptor antagonist losartan (0.125 mg/kg icv) abolished ANG II-induced
      augmentation of the CSAR. These results suggest that chronic elevation of central
      ANG II can sensitize the CSAR via central AT(1) receptors.

PMID- 10409177
TI  - Contraction-relaxation coupling: determination of the onset of diastole.
AB  - Left ventricular relaxation is dependent on afterload conditions during systole.
      An abrupt increase in afterload while the ventricle is actively contracting
      prolongs the duration of systole. An increase in afterload during ventricular
      relaxation shortens the duration of systole. Therefore, we hypothesized that the
      point during systole when an abrupt increase in afterload had no effect on the
      duration of systole represented the onset of ventricular relaxation. To determine
      when this point occurs, we performed aortic occlusions progressively throughout
      the duration of systole in six dogs. We determined the change in systolic time
      (t(sys)) after an intervention normalized to t(sys) of a control beat
      (t(sys,i)/t(sys, c)) as a function of systolic occlusion time as a percentage of
      total systolic time (t(occ)/t(sys,c)), where t(sys) is the duration from time of
      left ventricular end-diastolic pressure to the time of minimum first derivative
      of left ventricular pressure. Our results show the onset of left ventricular
      relaxation during normal ejection occurs at 34 +/- 3% of systolic time and
      approximately 16% after the onset of ejection. Thus the beginning of relaxation
      occurs soon after the beginning of ejection, suggesting that relaxation is
      modulated by variable loading conditions during ejection, significantly before
      what has been conventionally been assumed to be the beginning of ventricular
      relaxation.

PMID- 10409178
TI  - Two distinct HCO(-)(3)-dependent H(+) efflux pathways in human vascular
      endothelial cells.
AB  - Intracellular pH (pH(i)) regulation in human umbilical vein endothelial cells
      (HUVEC) was investigated. The pH(i) was recorded using seminaphthorhodafluor-1
      (SNARF-1). Cells were intracellularly acid loaded with NH(4)Cl prepulse. In HEPES
      buffered Tyrode (nominally HCO(-)(3) free), pH(i) recovery from acid load was
      inhibited by 1.5 mM amiloride or Na(+)-free solution. Additionally, in HCO(-)(3)
      buffered Tyrode, a HCO(-)(3)-dependent pH(i) recovery from acidosis was evident
      in the presence of 1.5 mM amiloride, which mediated complete recovery of pH(i)
      (7.26). In Na(+)-free solution, the HCO(-)(3)-dependent acid extruder mediated
      pH(i) recovery after an acid load but only back to 7.09. These results suggest
      that there are two HCO(-)(3)-dependent acid extruders in the HUVEC. One is Na(+)
      dependent, and the other is Na(+) independent. The former was further shown to be
      completely inhibited by 0.5 mM DIDS, whereas the latter was only inhibited by
      24.6%. In Cl(-)-free solution, both of the HCO(-)(3)-dependent pathways were
      inhibited. In conclusion, one HCO(-)(3)-dependent acid extruder in the HUVEC
      resembles the Na(+)-dependent Cl(-)/HCO(-)(3) exchange found in other tissues,
      and the other is Cl(-) dependent but Na(+) independent.

PMID- 10409179
TI  - alpha-adrenergic vasoconstriction in active skeletal muscles during dynamic
      exercise.
AB  - Sympathetic vasoconstriction in working muscles during dynamic exercise has been
      demonstrated by intra-arterial administration of alpha(1)-adrenergic antagonists.
      The purpose of this study was to examine the existence of alpha(1)- and alpha(2)
      adrenergic receptor-mediated vasoconstriction in active skeletal muscles during
      exercise. Six mongrel dogs were instrumented chronically with flow probes on the
      external iliac arteries of both hindlimbs, and a catheter was inserted in one
      femoral artery. All dogs ran on a motorized treadmill at three exercise
      intensities (3 miles/h, 6 miles/h, and 6 miles/h at 10% grade) on separate days.
      After 5 min of exercise, a selective alpha(1)- (prazosin) or a selective alpha(2)
      adrenergic antagonist (rauwolscine) was infused as a bolus into the femoral
      arterial catheter (only one drug per day). The doses of the antagonists were
      adjusted to maintain the same effective concentration at each exercise intensity.
      At the mild, moderate, and heavy workloads prazosin infusion produced immediate
      increases in iliac conductance of 65 +/- 9, 35 +/- 6, and 18 +/- 4% (means +/-
      SE), respectively, and increases in blood flow of 290 +/- 24, 216 +/- 23, and 172
      +/- 18 ml/min, respectively. Rauwolscine infusion produced increases in
      conductance of 52 +/- 5%, 36 +/- 5%, and 26 +/- 3%, respectively, and blood flow
      increases of 250 +/- 34, 244 +/- 39, and 259 +/- 35 ml/min at the three
      workloads. Systemic blood pressure and blood flow in the contralateral iliac
      artery were unaffected by any of the antagonist infusions. These results
      demonstrate that there is ongoing alpha(1)- and alpha(2)-adrenergic receptor
      mediated vasoconstriction in exercising skeletal muscles even at heavy workloads
      and that the magnitude of vasoconstriction decreases as exercise intensity
      increases.

PMID- 10409180
TI  - Changes in sarcolemmal PLC isoenzymes in postinfarct congestive heart failure:
      partial correction by imidapril.
AB  - We have examined the changes in quantity and activity of cardiac sarcolemmal (SL)
      phosphoinositide-phospholipase C (PLC)-beta(1), -gamma(1), and -delta(1) in a
      model of congestive heart failure (CHF) secondary to large transmural myocardial
      infarction (MI). We also instituted a late in vivo monotherapy with imidapril, an
      ANG-converting enzyme (ACE) inhibitor, to test the hypothesis that its
      therapeutic action is associated with the functional correction of PLC
      isoenzymes. SL membranes were purified from the surviving left ventricle of rats
      in a moderate stage of CHF at 8 wk after occlusion of the left anterior
      descending coronary artery. SL PLC isoenzymes were examined in terms of protein
      mass and hydrolytic activity. CHF resulted in a striking reduction (to 6-17% of
      controls) of the mass and activity of gamma(1)- and delta(1)-isoforms in
      combination with a significant increase of both PLC beta(1) parameters. In vivo
      treatment with imidapril (1 mg/kg body wt, daily, initiated 4 wk after coronary
      occlusion) improved the contractile function and induced a partial correction of
      PLCs. The mass of SL phosphatidylinositol 4,5-bisphosphate and the activities of
      the enzymes responsible for its synthesis were significantly reduced in post-MI
      CHF and partially corrected by imidapril. The results indicate that profound
      changes in the profile of heart SL PLC-beta(1), -gamma(1), and -delta(1) occur in
      CHF, which could alter the complex second messenger responses of these isoforms,
      whereas their partial correction by imidapril may be related to the mechanism of
      action of this ACE inhibitor.

PMID- 10409181
TI  - Oxygen delivery does not limit cardiac performance during high work states.
AB  - This study tested the hypothesis that the loss of myocardial high-energy
      phosphates (HEP), which occurs during high cardiac work states [J. Zhang, D. J.
      Duncker, Y. Xu, Y. Zhang, G. Path, H. Merkle, K. Hendrich, A. H. L. From, R.
      Bache, and K. Ugurbil. Am. J. Physiol. 268: (Heart Circ. Physiol. 37): H1891
      H1905, 1995], is not the result of insufficient intracellular O(2) availability.
      To evaluate the state of myocardial oxygenation, the proximal histidine signal of
      deoxymyoglobin (Mb-delta) was determined with (1)H nuclear magnetic resonance
      spectroscopy (MRS), whereas HEP were examined with (31)P MRS. Normal dogs (n =
      11) were studied under basal conditions and during combined infusion of
      dobutamine and dopamine (20 micrograms . kg(-1). min(-1) iv each), which
      increased rate-pressure products to >50,000 mmHg. beats. min(-1). Creatine
      phosphate (CP) was expressed as CP/ATP, and myocardial myoglobin desaturation was
      normalized to the Mb-delta resonance present during total coronary artery
      occlusion. This Mb-delta resonance appeared at 71 parts per million downfield
      from the water resonance. CP/ATP decreased from 2. 22 +/- 0.12 during the basal
      state to 1.83 +/- 0.09 during the high work state (P < 0.01), whereas
      DeltaP(i)/CP increased from 0 to 0.21 +/- 0.04 (P < 0.01). Despite these HEP
      changes, Mb-delta remained undetectable. In contrast, when a coronary stenosis
      was applied to produce a similar decrease in CP/ATP, Mb-delta reached 0.38 +/-
      0.10 of the value present during total coronary occlusion. These data demonstrate
      that Mb-delta is readily detected in vivo during limitation of coronary blood
      flow sufficient to cause a decrease of myocardial CP/ATP. However, similar HEP
      changes that occur at high work states in the absence of coronary occlusion are
      not associated with a detectable Mb-delta resonance. The findings support the
      hypothesis that the myocardial HEP changes observed at high work states are not
      due to inadequate O(2) availability to the mitochondria and emphasize the
      limitations of interpreting HEP alterations in the absence of knowing the level
      of myocyte oxygenation.

PMID- 10409182
TI  - Cotransmission from sympathetic vasoconstrictor neurons to small cutaneous
      arteries in vivo.
AB  - This study has characterized constrictions of small cutaneous arteries in the
      guinea pig ear in response to electrical stimulation of the cervical sympathetic
      nerve (SNS) in vivo. Video microscopy and on-line image analysis were used to
      examine diameter changes of ear arteries (80-140 micrometers resting diameter) in
      anesthetized guinea pigs. Trains of 50-300 impulses, but not single pulses or
      short trains, produced frequency-dependent (2-20 Hz) constrictions. The
      purinoceptor antagonist suramin (30 microM) greatly reduced constrictions
      produced by exogenous ATP but did not affect constrictions produced by SNS at 10
      Hz or exogenous norepinephrine. The alpha(2)-adrenoceptor antagonist yohimbine (1
      microM) enhanced the peak amplitude of sympathetic constrictions at lower
      stimulation frequencies (1-5 Hz). The amplitude of constrictions to SNS at 10 Hz
      was reduced, and the latency of constrictions was increased by the alpha(1)
      adrenoceptor antagonist prazosin (1 microM). Constrictions to SNS at 10 Hz
      remaining after prazosin treatment were reduced in amplitude by dihydroergotamine
      (2 microM) and were attenuated further by the neuropeptide Y Y(1)-receptor
      antagonist 1229U91 (0.3 microM). Thus norepinephrine and neuropeptide Y act as
      cotransmitters to mediate sympathetic constriction of small ear arteries at
      higher stimulation frequencies (10 Hz), but ATP does not seem to contribute
      directly to these constrictions.

PMID- 10409183
TI  - O(2) cost of contractility but not of mechanical energy increases with
      temperature in canine left ventricle.
AB  - We investigated the effects of myocardial temperature on left ventricular (LV)
      mechanoenergetics in the excised, cross-circulated canine heart. We used the
      framework of the LV contractility (E(max))-pressure-volume area (PVA; a measure
      of total mechanical energy)-myocardial oxygen consumption (VO(2)) relationship.
      We have shown this framework to be useful to integrative analysis of the
      mechanoenergetics of a beating heart. In isovolumic contractions at a constant
      pacing rate, increasing myocardial temperature from 30 to 40 degrees C depressed
      E(max) and increased the oxygen cost of E(max), which was enhanced by dobutamine,
      in a linear manner. However, the slope of the VO(2)-PVA relation (reciprocal of
      contractile efficiency) and its VO(2) intercept remained constant. Q(10) values
      of E(max), the oxygen cost of E(max), and the oxygen cost of PVA were 0.4, 2.1
      and 1.0, respectively, around normothermia. We conclude that the temperature
      dependent processes of cross-bridge cycling and Ca(2+) handling integratively
      depress E(max) and augment its oxygen cost without affecting the oxygen cost of
      PVA as myocardial temperature increases by 10 degrees C around normothermia.

PMID- 10409184
TI  - Energy expenditure by Ba(2+) contracture in rat ventricular slices derives from
      cross-bridge cycling.
AB  - To clarify the energy-expenditure mechanism during Ba(2+) contracture of
      mechanically unloaded rat left ventricular (LV) slices, we measured myocardial
      O(2) consumption (VO(2)) of quiescent slices in Ca(2+)-free Tyrode solution and
      VO(2) during Ba(2+) contracture by substituting Ca(2+) with Ba(2+). We then
      investigated the effects of cyclopiazonic acid (CPA) and 2,3-butanedione monoxime
      (BDM) on the Ba(2+) contracture VO(2). The Ca(2+)-free VO(2) corresponds to that
      of basal metabolism (2.32 +/- 0.53 ml O(2). min(-1). 100 g LV(-1)). Ba(2+)
      increased the VO(2) in a dose-dependent manner (from 0.3 to 3.0 mmol/l) from 110
      to 150% of basal metabolic VO(2). Blockade of the sarcoplasmic reticulum (SR)
      Ca(2+) pump by CPA (10 micromol/l) did not at all decrease the Ba(2+)-activated
      VO(2). BDM (5 mmol/l), which specifically inhibits cross-bridge cycling, reduced
      the Ba(2+)activated VO(2) almost to basal metabolic VO(2). These energetic
      results revealed that the Ba(2+)-activated VO(2) was used for the cross-bridge
      cycling but not for the Ca(2+) handling by the SR Ca(2+) pump.

PMID- 10409185
TI  - Cellular basis of ventricular arrhythmias and abnormal automaticity in heart
      failure.
AB  - The high incidence of sudden death in heart failure may reflect an increased
      propensity to abnormal repolarization and long Q-T interval-related arrhythmias.
      If so, cells from failing hearts would logically be expected to exhibit a
      heightened susceptibility to early afterdepolarizations (EAD). We found that
      midmyocardial ventricular cells isolated from dogs with pacing-induced heart
      failure exhibited an increased action potential duration and many more EAD than
      cells from nonpaced controls; this was the case both under basal conditions (P <
      0.01) and after lowering external K(+) concentration ([K(+)](o)) to 2 mM and
      exposing cells to cesium (3 mM; P < 0.05). An unexpected finding was the
      occurrence of spontaneous depolarizations (SD, >5 mV) from the resting potential
      that were not coupled to prior action potentials. These SD were observed in 20%
      of failing cells (n = 5 of 25) under basal ionic conditions but in none of the
      normal cells (n = 0 of 27, P < 0.05). The net inward current that underlies SD is
      not triggered by Ca(2+) oscillations and thus differs fundamentally from the
      currents that underlie delayed afterdepolarizations. We conclude that
      cardiomyopathic canine ventricular cells are intrinsically predisposed to EAD and
      SD. Because EAD have been linked to the pathogenesis of torsade de pointes, our
      results support the hypothesis that sudden death in heart failure often arises
      from abnormalities of repolarization. The frequent occurrence of SD points to a
      novel cellular mechanism for abnormal automaticity in heart failure.

PMID- 10409186
TI  - Detection of a ferrylhemoglobin intermediate in an endothelial cell model after
      hypoxia-reoxygenation.
AB  - A cell culture model of bovine aortic endothelial cells attached to microcarrier
      beads was used to study the interaction of diaspirin cross-linked hemoglobin (an
      oxygen-carrying blood substitute) with hypoxia-reoxygenation. Hemoglobin (200
      microM) and hypoxia-volume restriction (3-5 h), together and separately, caused
      toxicity in this model, as measured by decreased cellular replating efficiency.
      Hemoglobin (60 microM) caused a reduction in hydrogen peroxide concentration and
      an increase in lipid peroxidation above that induced by hypoxia alone. Incubation
      of hemoglobin with endothelial cells caused transient oxidation of hemoglobin to
      its highly reactive and toxic ferryl species after >/=3 h of hypoxia, followed by
      1 h of reoxygenation. Lipid peroxidation, which may occur in the presence of
      ferrylhemoglobin, also occurred after 1 h of reoxygenation. Hemoglobin caused a
      dose-dependent decrease in intracellular glutathione concentration, suggesting
      that it caused an oxidative stress to the cells. However, addition of ascorbate,
      alpha-tocopherol, or trolox did not decrease hemoglobin oxidation in the presence
      of normal or hypoxic cells. It is concluded that diaspirin cross-linked
      hemoglobin forms a ferryl intermediate in the absence of any exogenously added
      oxidant and contributes to the oxidative burden experienced by endothelial cells
      after hypoxia-reoxygenation, a condition that is likely to be encountered during
      trauma and surgery when hemoglobin solutions are used as perfusion agents.

PMID- 10409187
TI  - Alteration of microtubule polymerization modulates arteriolar vasomotor tone.
AB  - Microtubules are important cytoskeletal elements that have been shown to play a
      major role in many cellular processes because of their mechanical properties
      and/or their participation in various cell signaling pathways. We tested the
      hypothesis that depolymerization of microtubules would alter vascular smooth
      muscle (VSM) tone and hence contractile function. In our studies, isolated
      cremaster arterioles exhibited significant vasoconstriction that developed over a
      20- to 40-min period when they were treated with microtubule depolymerizing drugs
      colchicine (10 microM), nocodazole (10 microM), or demecolcine (10 microM).
      Immunofluorescent labeling of microtubules in cultured rat VSM revealed that both
      colchicine and nocodazole caused microtubule depolymerization over a similar time
      course. The vasoconstriction was maintained over a wide range of intraluminal
      pressures (30-170 cmH(2)O). The increased tone was not affected by endothelial
      denudation, suggesting that it was due to an effect on VSM. Microtubule
      depolymerization with demecolcine or colchicine had no effect on VSM
      intracellular Ca(2+) concentration ([Ca(2+)](i)). These data indicate that
      microtubules significantly interact with processes leading to the expression of
      vasomotor tone. The mechanism responsible for the effect of microtubules on
      vasomotor tone appears to be independent of both the endothelium and an increase
      in VSM [Ca(2+)](i).

PMID- 10409188
TI  - Four different components contribute to outward current in rat ventricular
      myocytes.
AB  - In rat ventricle, two Ca(2+)-insensitive components of K(+) current have been
      distinguished kinetically and pharmacologically, the transient, 4-aminopyridine
      (4-AP)-sensitive I(to) and the sustained, tetraethylammonium (TEA)-sensitive
      I(K). However, a much greater diversity of depolarization-activated K(+) channels
      has been reported on the level of mRNA and protein. In the search for
      electrophysiological evidence of further current components, the whole cell
      voltage-clamp technique was used to analyze steady-state inactivation of outward
      currents by conditioning potentials in a wide voltage range. Peak (I(peak)) and
      late (I(late)) currents during the test pulse were analyzed by Boltzmann curve
      fitting, producing three fractions each. Fractions a and b had different
      potentials of half-maximum inactivation (V(0.5)); the third residual fraction, r,
      did not inactivate. Fractions a for I(peak) and I(late) had similar relative
      amplitudes and V(0.5) values, whereas size and V(0.5) of fractions b differed
      significantly between I(peak) and I(late). Only b of I(peak) was transient,
      suggesting a relation with I(to), whereas a, b, and r of I(late) appeared to be
      three different sustained currents. Therefore, four individual outward current
      components were distinguished: I(to) (b of I(peak)), I(K) (a), the steady-state
      current I(ss) (r), and the novel current I(Kx) (b of I(late)). This was further
      supported by differential sensitivity to TEA, 4-AP, clofilium, quinidine,
      dendrotoxin, heteropodatoxin, and hanatoxin. With the exception of I(to), none of
      the currents exhibited a marked transmural gradient. Availability of I(K) was low
      at resting potential; nevertheless, I(K) contributed to action potential
      shortening in hyperpolarized subendocardial myocytes. In conclusion, on the basis
      of electrophysiological and pharmacological evidence, at least four components
      contribute to outward current in rat ventricular myocytes.

PMID- 10409189
TI  - Voltage-dependent K(+) current in capillary endothelial cells isolated from
      guinea pig heart.
AB  - Capillary fragments were isolated from guinea pig hearts, and their electrical
      properties were studied using the perforated-patch and cell-attached mode of the
      patch-clamp technique. A voltage-dependent K(+) current was discovered that was
      activated at potentials positive to -20 mV and showed a sigmoid rising phase. For
      depolarizing voltage steps from -128 to +52 mV, the time to peak was 71 +/- 5 ms
      (mean +/- SE) and the amplitude of the current was 3.7 +/- 0.5 pA/pF in the
      presence of 5 mM external K(+). The time course of inactivation was exponential
      with a time constant of 7.2 +/- 0.5 s at +52 mV. The current was blocked by
      tetraethylammonium (inhibitory constant approximately 3 mM) but was not affected
      by charybdotoxin (1 microM) or apamin (1 microM). In the cell-attached mode,
      depolarization-activated single-channel currents were found that inactivated
      completely within 30 s; the single-channel conductance was 12.3 +/- 2.4 pS. The
      depolarization-activated K(+) current described here may play a role in membrane
      potential oscillations of the endothelium.

PMID- 10409190
TI  - Delayed preconditioning with adenosine is mediated by opening of ATP-sensitive
      K(+) channels in rabbit heart.
AB  - The adenosine agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) induces delayed
      ischemic protection in vivo. We hypothesized that this protection is mediated by
      opening of ATP-sensitive K(+) (K(ATP)) channels and increased synthesis of 72-kDa
      heat shock protein (HSP 72). Six groups (n = 9-13 animals/group) of animals were
      studied: group I, control rabbits that received no treatment; group II, animals
      given glibenclamide (0.3 mg/kg iv) 30 min before ischemia; group III, animals
      given 5-hydroxydecanoate (5-HD; 5 mg/kg iv) 15 min before ischemia; group IV,
      rabbits treated with CCPA (0.1 mg/kg iv) 24 h before ischemia; and groups V and
      VI, CCPA-treated animals that received the K(ATP)-channel blockers glibenclamide
      or 5-HD, respectively, 30 or 15 min before ischemia. All animals were subjected
      to ischemia by 30 min of coronary artery occlusion followed by 3 h of
      reperfusion. Risk area was delineated by injection of 10% Evans blue dye, and
      infarct size was determined by triphenyltetrazolium staining. Action potential
      duration (APD) was measured with an epicardial electrode. HSP 72 was measured by
      Western blotting. CCPA caused a significant reduction in infarct size [12.02 +/-
      1.0 vs. 40.0 +/- 3.8% (%area at risk) in controls, P < 0.01] that was blocked by
      glibenclamide (36.2 +/- 3.1%, P < 0.01) and 5-HD (35.0 +/- 2.9%, P < 0.01).
      Glibenclamide and 5-HD did not change infarct size in control rabbits. These
      blockers significantly suppressed ischemia-induced APD shortening in control and
      CCPA-treated animals. CCPA treatment did not induce HSP 72 in hearts. These data
      suggest that adenosine-initiated delayed protection is mediated via opening of
      K(ATP) channels but does not involve the synthesis of HSP 72.

PMID- 10409191
TI  - Catecholamines and preconditioning: studies of contraction and function in
      isolated rat hearts.
AB  - The aims of this study were to determine whether 1) like ischemic
      preconditioning, transient exposure to norepinephrine before ischemia exacerbates
      contracture during ischemia and 2) protection afforded by norepinephrine is
      stereospecific (receptor mediated). Isolated perfused rat hearts were randomized
      into five groups (n = 6/group): 1) ischemic preconditioning (3 min of ischemia +
      3 min of reperfusion + 5 min of ischemia + 5 min of reperfusion), 2) untreated
      control, 3) vehicle control (ascorbic acid), 4) substitution of preconditioning
      ischemia by perfusion with d-norepinephrine, and 5) substitution of
      preconditioning ischemia by perfusion with l-norepinephrine. This was followed by
      40 min of zero-flow ischemia and 50 min of reperfusion. Ischemic preconditioning
      and l-norepinephrine exacerbated contracture (time to 50% contracture = 9.2 +/-
      1.1 and 9.0 +/- 1.1 vs. 13.3 +/- 0.3, 12.4 +/- 0.5, and 13.2 +/- 0.4 min for
      untreated control, vehicle control, and d-norepinephrine, respectively, P <
      0.05). Postischemic left ventricular developed pressure was poor in untreated
      control (23.0 +/- 2.2%), vehicle control (26.9 +/- 2.3%), and d-norepinephrine
      (19.8 +/- 2.8%) groups but good in preconditioned (52.4 +/- 5.1%) and l
      norepinephrine (52.5 +/- 1.1%) groups (P < 0. 05). Thus norepinephrine
      preconditioning, like ischemic preconditioning, causes a paradoxical exacerbation
      of contracture coupled with enhanced postischemic recovery; both effects are
      stereospecific.

PMID- 10409192
TI  - Myogenic reactivity of rat epineurial arterioles: potential role in local
      vasoregulatory events.
AB  - Local control of neural blood flow is considered to reside in innervation of
      epineurial and endoneurial arterioles rather than in intrinsic autoregulatory
      mechanisms. With the use of an isolated vessel preparation and an in vivo
      approach, the present studies examined intrinsic vasomotor responsiveness of
      epineurial arterioles. Segments of epineurial arterioles, cannulated on glass
      micropipettes (40 micrometers) and pressurized in the absence of intraluminal
      flow, showed sustained pressure-dependent (30-90 mmHg) vasoconstriction and acute
      myogenic reactivity. Myogenic tone was unaffected by phentolamine (10(-6) M).
      Removal of extracellular Ca(2+) resulted in loss of spontaneous tone and passive
      behavior. Concentration-response curves for norepinephrine (10(-9)-3 x 10(-6) M)
      and relaxation to both acetylcholine (10(-8)-10(-5) M) and adenosine (10(-8)-10(
      4) M) were obtained. Acetylcholine dilator responses were inhibited by N(G)-nitro
      L-arginine methyl ester. Epineurial blood flow was measured in vivo using a laser
      Doppler flow probe. Blood flow declined over a 2-h period after surgery, and
      during this time preparations developed responsiveness to the dilator
      acetylcholine. Phentolamine blocked vasoconstrictor responses to exogenous
      norepinephrine but only partially reversed the in vivo baseline tone. The time
      dependent decline in epineurial blood flow was observed despite the presence of
      tetrodotoxin (1 microM), further confirming that tone was predominantly caused by
      myogenic rather than neurogenic mechanisms. It is concluded that because
      epineurial arterioles exhibit intrinsic myogenic reactivity, they have the
      potential to participate in local regulation of neural hemodynamics independently
      of their own innervation.

PMID- 10409193
TI  - Concentration-dependent effects of bradykinin on leukocyte recruitment and
      venular hemodynamics in rat mesentery.
AB  - The results of several recent studies indicate that bradykinin protects tissues
      against the deleterious effects of ischemia-reperfusion (I/R). However, other
      studies indicate that bradykinin can act as a proinflammatory agent, inducing P
      selectin expression, the formation of chemotactic stimuli, and endothelial
      barrier disruption. In the present study, we used intravital microscopic
      techniques to examine the dose-dependent effects of bradykinin on leukocyte
      endothelial cell interactions, the formation of platelet-leukocyte aggregates,
      and venular hemodynamics in rat mesentery in an attempt to explain these
      divergent findings. Superfusion of the mesentery with low concentrations of
      bradykinin (</=10(-7) M) increased venular erythrocyte velocity (V(RBC)) without
      increasing the number of adherent leukocytes, whereas higher concentrations
      (>/=10(-6) M) decreased V(RBC), increased the number of platelet-leukocyte
      aggregates, and induced leukocyte adhesion in single postcapillary venules. The
      formation of platelet-leukocyte aggregates and increased leukocyte adhesion
      induced by high-dose bradykinin were attenuated by administration of a B(2)
      receptor (HOE-140) or a platelet-activating factor (PAF, WEB-2086) antagonist.
      Thus these adhesive interactions induced by high-dose bradykinin appear to be
      mediated by a mechanism that is dependent on B(2)-receptor activation and the
      formation of PAF or PAF-like lipids. The effects of bradykinin on venular V(RBC)
      and blood flow were also concentration dependent, with low doses producing nitric
      oxide-mediated vasodilation, whereas high doses decreased V(RBC) by a mechanism
      that is PAF independent.

PMID- 10409194
TI  - Bradykinin prevents postischemic leukocyte adhesion and emigration and attenuates
      microvascular barrier disruption.
AB  - Although a number of recent reports indicate that bradykinin attenuates ischemia-
      reperfusion (I/R)-induced tissue injury, the mechanisms underlying its protective
      actions are not fully understood. However, because bradykinin induces endothelial
      nitric oxide (NO) production and NO donors have been shown to attenuate
      postischemic leukocyte adhesion, endothelial barrier disruption, and tissue
      injury, we hypothesized that bradykinin may act to reduce I/R-induced tissue
      injury by preventing leukocyte recruitment and preserving microvascular barrier
      function. To address this postulate, we used intravital videomicroscopic
      approaches to quantify leukocyte-endothelial cell interactions and microvascular
      barrier function in single postcapillary venules in the rat mesentery.
      Reperfusion after 20 min of ischemia significantly decreased wall shear rate and
      leukocyte rolling velocity, increased the number of rolling, adherent, and
      emigrated leukocytes, and disrupted the microvascular barrier as evidenced by
      enhanced venular albumin leakage. Superfusion of the mesentery with bradykinin
      (10 nM) during I/R significantly reduced these deleterious effects of I/R.
      Although these inhibitory effects of bradykinin were not affected by
      cyclooxygenase blockade with indomethacin (10 microM), coadministration with NO
      synthase (N(omega)-nitro-L-arginine methyl ester, 10 microM) or bradykinin B(2)
      receptor (HOE-140, 1 microM) antagonists abolished the protective actions of
      bradykinin. Plasma NO concentration was measured in the mesenteric vein and was
      significantly decreased after I/R, an effect that was prevented by bradykinin
      treatment. These results indicate that bradykinin attenuates I/R-induced
      leukocyte recruitment and microvascular dysfunction by a mechanism that involves
      bradykinin B(2)-receptor-dependent NO production.

PMID- 10409195
TI  - A CD18 monoclonal antibody reduces multiple organ injury in a model of ruptured
      abdominal aortic aneurysm.
AB  - The role of CD18 antibody (anti-CD18) in remote and local injury in a model of
      ruptured abdominal aortic aneurysm repair was investigated. Rats were divided
      into sham, shock, clamp, and shock + clamp groups. Shock + clamp animals received
      anti-CD18 or a control monoclonal antibody. One hour of hemorrhagic shock was
      followed by 45 min of supramesenteric aortic clamping. Intestinal and pulmonary
      permeability to (125)I-labeled albumin was determined. Myeloperoxidase (MPO)
      activity, F(2)-isoprostane levels, and transaminases were also measured. Only
      shock + clamp resulted in statistically significant increases in pulmonary and
      intestinal permeability, which were associated with significant increases in MPO
      activity and F(2)-isoprostane levels. Treatment with anti-CD18 significantly
      decreased intestinal and pulmonary permeability in shock + clamp animals. These
      reductions were associated with significantly reduced intestinal and hepatic MPO
      activity and pulmonary F(2)-isoprostane levels and reduced alanine and aspartate
      aminotransferase levels; however, anti-CD18 had no effect on intestinal or
      hepatic F(2)-isoprostane levels or on pulmonary MPO activity. These results
      suggest CD18-dependent and -independent mechanisms of local and remote organ
      injury in this model of ruptured abdominal aortic aneurysm.

PMID- 10409196
TI  - Transmural microcirculatory blood flow distribution in right and left ventricular
      free walls of rabbits.
AB  - Within-layer regional myocardial flows in the left and right ventricles (LV, RV)
      and in LV with increased myocardial workload (beta(1)-adrenoceptor stimulation)
      were studied transmurally in anesthetized rabbits. Myocardial flow distribution
      was visualized with resolutions between 0.1 x 0.1- and 1 x 1-mm(2) pixels, using
      digital radiography combined with the (3)H-labeled desmethylimipramine deposition
      technique. The spatial pattern of flow distribution was quantitated by the
      coefficient of variation of regional flows (CV, related to global flow
      heterogeneity) and the correlation between adjacent regional flows (CA, inversely
      related to local flow randomness). CV was lower in LV than in RV [P < 0.05,
      nonparametric 2-way analysis of variance (NANOVA)]. When resolution was lowered
      from 0.1 x 0.1- to 1 x 1-mm(2) pixels, CV decreased by 70% in both LV and RV. CA
      was higher in LV than in RV (P < 0.05, NANOVA); the interventricular difference
      in CA was large over the resolutions between 0.4 x 0.4- and 1 x 1-mm(2) pixels.
      In LV, both CV and CA increased with depth of myocardium (P < 0.05, NANOVA); in
      subendocardium CV was high comparable with CV in RV (P = 0.47, NANOVA). The
      enhancement of myocardial workload decreased CV and tended to decrease CA in LV
      subendocardium (P < 0.05, P = 0.06, respectively; NANOVA). We conclude that 1)
      microregional flow distribution is less heterogeneous and less random in LV than
      in RV; 2) transmurally, in LV subendocardium global flow heterogeneity was the
      highest whereas local flow randomness was the lowest, so that clusters of low- or
      high-flow regions exist in this LV layer; and 3) global flow heterogeneity
      decreased and local flow randomness tended to increase (flow homogenizing
      occurred) in LV subendocardium with increasing myocardial workload. Thus the
      distributed pattern of myocardial microregional flows may be adaptable to local
      myocardial metabolic change.

PMID- 10409197
TI  - Role of PTP-1B in aortic smooth muscle cell motility and tyrosine phosphorylation
      of focal adhesion proteins.
AB  - Recent studies have focused attention on the role of protein tyrosine kinases in
      vascular smooth muscle cell biology, but similar information regarding protein
      tyrosine phosphatases (PTP) is sparse. PTP-1B is a ubiquitous nonreceptor
      phosphatase with uncertain function and substrates that are mostly unidentified.
      We used antisense oligodeoxynucleotides (ODN) against PTP-1B to investigate the
      role of endogenous PTP-1B in motility of primary cultures of rat aortic smooth
      muscle cells (RASMC). Antisense ODN decreased PTP-1B protein levels and activity
      in a concentration-dependent fashion, whereas sense, scrambled, or three-base
      mismatch antisense ODN had little or no effect. Treatment of cells with antisense
      ODN, but not sense, scrambled, or three-base mismatch antisense ODN, enhanced
      cell motility and increased tyrosine phosphorylation levels of focal adhesion
      proteins paxillin, p130(cas), and focal adhesion kinase. Our findings indicate
      that PTP-1B is a negative regulator of RASMC motility via modulation of
      phosphotyrosine levels in several focal adhesion proteins and suggest the
      involvement of PTP-1B in events such as atherosclerosis and restenosis, which are
      associated with increased vascular smooth muscle cell motility.

PMID- 10409198
TI  - Pathways of HERG inactivation.
AB  - The rapid, repolarizing K(+) current in cardiomyocytes (I(Kr)) has unique
      inwardly rectifying properties that contribute importantly to the downstroke of
      the cardiac action potential. The human ether-a-go-go-related gene (HERG)
      expresses a macroscopic current virtually identical to I(Kr), but a description
      of the single-channel properties that cause rectification is lacking. For this
      reason we measured single-channel and macropatch currents heterologously
      expressed by HERG in Xenopus oocytes. Our experiments had two main findings.
      First, the single-channel current-voltage relation showed inward rectification,
      and conductance was 9.7 pS at -100 mV and 3.9 pS at 100 mV when measured in
      symmetrical 100 mM K(+) solutions. Second, single channels frequently showed no
      openings during depolarization but nevertheless revealed bursts of openings
      during repolarization. This type of gating may explain the inward rectification
      of HERG currents. To test this hypothesis, we used a three-closed state kinetics
      model and obtained rate constants from fits to macropatch data. Results from the
      model are consistent with rapid inactivation from closed states as a significant
      source of HERG rectification.

PMID- 10409200
TI  - Effect of exogenous nitric oxide on baroreflex function in humans.
AB  - Nitric oxide (NO) donors inhibit sympathetic neurotransmission and baroreceptor
      activity and can directly stimulate heart rate (HR) in vitro. To assess whether
      exogenous NO affects cardiovascular autonomic control in humans, we tested the
      baroreceptor-cardiac reflex [baroreflex sensitivity (BRS)] and the arterial blood
      pressure (BP) and HR variability during an infusion of the NO donor sodium
      nitroprusside (SNP, 2 micrograms . kg(-1). min(-1)) or 5% glucose in 16 healthy
      subjects. The hypotensive action of SNP was prevented by phenylephrine (PE, 0.9
      +/- 0.15 micrograms . kg(-1). min(-1)). The SNP + PE infusion did not affect BRS
      or HR variability, but it caused a significant reduction in the diastolic and
      systolic BP low-frequency power. In addition, SNP + PE caused a sustained 12%
      increase in HR in the absence of changes in brachial and aortic BP. In
      conclusion, SNP had no effect on the cardiac-vagal limb of the baroreflex in
      humans but caused a substantial reduction in BP low-frequency power consistent
      with a decreased baroreflex/sympathetic control of peripheral resistance. The
      increase in HR in the absence of baroreceptor downloading confirms our previous
      finding of a direct positive chronotropic effect of NO donors.

PMID- 10409199
TI  - Electrophysiological mechanisms by which hypothyroidism delays repolarization in
      guinea pig hearts.
AB  - Thyroid hormone is known to exert important effects on cardiac repolarization,
      but the underlying mechanisms are poorly understood. We investigated the
      electrophysiological mechanisms of differences in repolarization between control
      guinea pigs and hypothyroid animals (thyroidectomy plus 5-propyl-2-thiouracil).
      Hypothyroidism significantly prolonged the rate-corrected Q-T interval in vivo
      and action potential duration (APD) of isolated ventricular myocytes. Whole cell
      voltage-clamp studies showed no change in current density or kinetics of L-type
      Ca(2+) current, inward rectifier K(+) current, or Na(+) current in hypothyroid
      hearts. Dofetilide-resistant current (I(Ks)) step current densities were smaller
      by approximately 65%, and tail current densities were reduced by 80% in myocytes
      from hypothyroid animals compared with controls. The ratio of delayed rectifier
      step current at +50 mV to tail current at -40 mV was significantly larger in
      hypothyroid cells for test pulses from 60- to 4,200-ms duration, reflecting a
      smaller I(Ks). Dofetilide-sensitive current (I(Kr)) densities were not
      significantly changed. I(Ks) half-activation voltage shifted to more positive
      voltages in hypothyroidism (29.5 +/- 2.2 vs. 21.3 +/- 2.7 mV in control, P <
      0.01), whereas I(Kr) voltage dependence was unchanged. We conclude that
      hypothyroidism delays repolarization in the guinea pig ventricle by decreasing
      I(Ks), a novel and potentially important mechanism for thyroid regulation of
      cardiac electrophysiology.

PMID- 10409201
TI  - Adenosine A(3)-receptor stimulation attenuates postischemic dysfunction through
      K(ATP) channels.
AB  - We tested the hypothesis that selective adenosine A(3)-receptor stimulation
      reduces postischemic contractile dysfunction through activation of ATP-sensitive
      potassium (K(ATP)) channels. Isolated, buffer-perfused rat hearts (n = 8/group)
      were not drug pretreated (control) or were pretreated with adenosine (20 microM),
      2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; A(3)
      agonist, 100 nM), Cl-IB-MECA + 8-(3-noradamantyl)-1,3-dipropylxanthine (KW-3902;
      A(1) antagonist, 5 microM), Cl-IB-MECA + glibenclamide (Glib; K(ATP)-channel
      blocker, 0. 3 microM), or Glib alone for 12 min before 30 min of global
      normothermic ischemia followed by 2 h of reperfusion. After 2 h of reperfusion,
      left ventricular developed pressure (LVDP, %baseline) in control hearts was
      depressed to 34 +/- 2%. In hearts pretreated with Cl-IB-MECA, there was a
      statistically significant increase in LVDP (50 +/- 6%), which was reversed with
      coadministration of Glib (37 +/- 1%). Control hearts also showed similar
      decreases in left ventricular peak positive rate of change in pressure (dP/dt).
      Therefore, the A(3) agonist significantly attenuated postischemic cardiodynamic
      injury compared with the control, which was reversed by Glib. Cumulative creatine
      kinase (CK in U/min) activity was most pronounced in the control group (10.4 +/-
      0.6) and was significantly decreased by Cl-IB-MECA (7.5 +/- 0.4), which was
      reversed by coadministration of Glib (9.4 +/- 0.2). Coronary flow was increased
      during adenosine infusion (160% of baseline) but not during Cl-IB-MECA infusion.
      Effects of Cl-IB-MECA were not reversed by the specific A(1) antagonist KW-3902.
      We conclude that cardioprotection afforded by A(3)-receptor stimulation may be
      mediated in part by K(ATP) channels. Cl-IB-MECA may be an effective pretreatment
      agent that attenuates postischemic cardiodynamic dysfunction and CK release
      without the vasodilator liability of other adenosine agonists.

PMID- 10409202
TI  - Transmural metabolic heterogeneity at high cardiac work states.
AB  - This study compared the transmural distribution of high-energy phosphate (HEP)
      depletion during oxidative stress induced by pacing- and dobutamine-induced
      tachycardia in myocardium perfused by a flow-limiting coronary stenosis.
      Myocardial blood flow (MBF) was measured with radioactive microspheres. Creatine
      phosphate (CrP), ATP, and P(i) were measured with transmurally localized (31)P
      NMR spectroscopy. In normal dogs a hydraulic occluder was used to produce a left
      anterior descending coronary artery stenosis, which maintained constant flow
      measured with a Doppler probe. Tachycardia was induced by rapid pacing (200
      beats/min, n = 11) or by dobutamine infusion (20 micrograms . kg(-1). min(-1) iv,
      n = 13) to produce a similar heart rate. In the presence of stenosis, pacing and
      dobutamine caused similar reductions of subendocardial (Endo)-to-subepicardial
      (Epi) MBF ratios (0.66 +/- 0.06 vs. 0.63 +/- 0.08, respectively). Stenosis plus
      pacing caused a decrease of the CrP-to-ATP ratio (CrP/ATP) in Endo from 2.00 +/-
      0.07 to 1.65 +/- 0. 08 (P < 0.05) with no significant change in Epi. Stenosis
      plus dobutamine caused HEP changes across the left ventricular wall, which were
      most marked in the outer myocardial layer (Epi CrP/ATP decreased from 2.33 +/-
      0.11 to 1.67 +/- 0.12; Endo CrP/ATP decreased from 1.99 +/- 0.09 to 1.64 +/-
      0.12). Thus HEP changes during oxidative stress that are produced by pacing
      parallel the pattern of hypoperfusion and are most severe in the subendocardium.
      In contrast, in response to inotropic stimulation, the transmural metabolic
      changes did not correspond to the pattern of the hypoperfusion.

PMID- 10409203
TI  - Ultrastructural assessment of myocardial necrosis occurring during ischemia and 3
      h reperfusion in the dog.
AB  - To determine whether myocardial necrosis may occur during postischemic
      reperfusion, electron microscopy was used to identify morphological features of
      irreversible injury in myocardial samples taken from anesthetized dogs with 90
      min ischemia and 0-, 5-, 90-, or 180-min reperfusion. In samples without
      detectable collateral blood flow, necrosis was almost complete, whether or not
      the myocardium was reperfused. In samples with collateral flow, necrosis was more
      frequent after 180-min reperfusion than in the absence of reperfusion, despite
      similar collateral flows in the two groups. Excess of necrosis after 180-min
      reperfusion was evident in endocardium (ischemia only: 4 of 13, 180-min reflow:
      14 of 20; P = 0. 03) and midwall (ischemia only: 9 of 25, 180-min reflow: 29 of
      45; P = 0.02). Multiple logistic regression with variables of collateral flow and
      transmural position was used to determine risk of irreversible injury in 111
      samples from ischemic myocardium without reperfusion (model predictive accuracy =
      75%, P < 0.00001) and to predict risk of necrosis in myocardium reperfused for
      180 min. Of 65 samples from endocardium and midwall with detectable collateral
      flow, the model predicted necrosis in 23 samples but necrosis was observed in 43
      samples (P < 0.01). Reperfusion duration was a determinant of frequency of
      irreversible injury. Multiple logistic regression for 186 samples from myocardium
      reperfused for 5, 90, or 180 min showed that reperfusion duration was an
      independent predictor of irreversible injury (P = 0.0003) when collateral flow
      and transmural location were accounted for. These findings are consistent with
      the occurrence of necrosis during reperfusion in myocardium exposed to
      substantial, prolonged ischemia but with sufficient residual perfusion to avoid
      necrosis during the period of flow impairment.

PMID- 10409204
TI  - Activated macrophages decrease rat cardiac myocyte contractility: importance of
      ICAM-1-dependent adhesion.
AB  - Macrophages are found in the heart as part of the inflammatory response. To
      determine whether macrophages could contribute to myocardial dysfunction, rat
      ventricular myocytes were isolated and cocultured with elicited peritoneal
      macrophages in media containing tumor necrosis factor-alpha (TNF-alpha),
      interleukin (IL)-1beta, or endotoxin for 4 h. Cardiac myocytes were electrically
      stimulated, and fractional shortening was determined using videomicroscopy. When
      myocytes alone or myocytes in coculture with macrophages separated by a membrane
      were challenged with TNF-alpha, lipopolysaccharide, or IL-1, fractional
      shortening did not decrease. When macrophages were allowed to contact myocytes,
      fractional shortening decreased from 20. 1 +/- 0.9% in unchallenged macrophage
      myocyte cocultures to 15.5 +/- 0.9, 16.3 +/- 0.8, and 15.8 +/- 0.6% when
      challenged for 4 h with TNF-alpha, endotoxin, or IL-1beta, respectively (P <
      0.05). Myocytes had a mean adherence of 4.2 +/- 0.2 macrophages after TNF-alpha
      challenge compared with 2.6 +/- 0.3 for controls (P < 0.05). The number of
      adherent macrophages was associated with the decrease in fractional shortening.
      Anti-intercellular adhesion molecule-1 (ICAM-1) reduced macrophage adherence and
      prevented the decrease in fractional shortening. This decrease was also prevented
      by desferoxamine, superoxide dismutase, and nitro-L-arginine methyl ester. This
      suggests that activated macrophages adhere to myocytes via ICAM-1, and adherent
      macrophages decrease their contractile function via TNF-alpha, oxygen free
      radicals, and nitric oxide.

PMID- 10409205
TI  - Even slight movements disturb analysis of cardiovascular dynamics.
AB  - We hypothesized that spontaneous movements (postural adjustments and ideomotion)
      disturb analysis of heart rate and blood pressure variability and could explain
      the discrepancy between studies. We measured R-R intervals and systolic blood
      pressure in nine healthy sitting subjects during three protocols: 1) no movement
      allowed, 2) movements allowed but not standing, 3) movements and standing
      allowed. Heart rate and blood pressure were not altered by movements. Movements
      with or without standing produced a twofold or greater increase of the overall
      variability of R-R intervals and of the low-frequency components of spectral
      analysis of heart rate variability. The spectral exponent beta of heart rate
      variability (1. 123 at rest) was changed by movements (1.364), and the percentage
      of fractal noise (79% at rest) was increased by standing (91%, coarse-graining
      spectral analysis). Spontaneous movements could induce a plateau in the
      correlation dimensions of heart rate variability, but they changed its nonlinear
      predictability. We suggest that future studies on short-term cardiovascular
      variability should control spontaneous movements.

PMID- 10409206
TI  - Reduced coronary NO production in conscious dogs after the development of alloxan
      induced diabetes.
AB  - The role of nitric oxide (NO) in the control of coronary blood flow (CBF) during
      the development of diabetes is unknown. To study this, mongrel dogs were
      chronically instrumented using sterile techniques for measurements of systemic
      hemodynamics and CBF. With heart rate controlled (150 beats/min), veratrine (1-10
      micrograms/kg) caused dose-dependent increases in CBF; e.g., 5 mirograms/kg of
      veratrine increased CBF by 57 +/- 7% from 41 +/- 1.3 ml/min (P < 0.05). The dogs
      developed diabetes 4-5 wk after injection of alloxan (40-60 mg/kg iv, blood
      glucose levels were 384 +/- 18 mg/dl). After diabetes the same doses of veratrine
      caused smaller increases in CBF; i.e., 5 micrograms/kg of veratrine increased CBF
      by 32 +/- 2% (P < 0.05 compared with control) from 28 +/- 4 ml/min. ACh- and
      adenosine-induced coronary vasodilation were reduced after diabetes as well. In
      anesthetized dogs after diabetes, vagal stimulation caused smaller increases in
      CBF. ACh and bradykinin caused smaller increases in NO(-)(2) production in
      coronary microvessels from diabetic dogs. Furthermore, despite the fact that mRNA
      for endothelial cell NO synthase from the aorta was increased twofold with the
      use of Northern blotting, the protein for aortic endothelial constitutive NO
      synthase was reduced by 66% after diabetes, as determined by Western blotting.
      Our results indicate that the NO-dependent coronary vasodilation by the Bezold
      Jarisch reflex is impaired in conscious dogs after diabetes. The mechanism
      responsible for the impaired endothelium-dependent coronary vasodilation is most
      likely the decreased release of NO from the endothelium.

PMID- 10409207
TI  - pH regulation of K(+) efflux from myocytes in isolated rat hearts: (87)Rb, (7)Li,
      and (31)P NMR studies.
AB  - This study investigates the effects of intracellular (pH(i)) and extracellular pH
      (pH(e)) on the efflux of Rb(+) and Li(+) in isolated rat hearts. (87)Rb and (7)Li
      NMR were used to measure Rb(+) and Li(+) content, respectively, of hearts, and
      (31)P NMR was used to monitor pH(i), pH(e), and phosphate levels. After 30-min
      equilibration with Rb(+) or Li(+), effluxes were initiated by switching perfusion
      to a Rb(+)- or Li(+)-free, high-K(+) (20.7 mM) Krebs-Henseleit buffer with 15
      microM bumetanide. Monensin (2 microM) increased pH(i) from 7.10 +/- 0.05 to 7.32
      +/- 0.07 and resulted in activation of Rb(+) efflux; the first-order rate
      constant (k x 10(3), in min(-1)) increased from 42 +/- 2 to 116 +/- 16.
      Glibenclamide (4 microM) did not inhibit monensin-activated Rb(+) efflux (k = 110
      +/- 17), whereas quinine (0.2 mM) slightly inhibited it by 19 +/- 9%. Infusion of
      15 mM NH(4)Cl during Rb(+) washout increased k for Rb(+) efflux by 93% (81 +/-
      8), which was glibenclamide and quinine insensitive, and caused a transient
      increase in pH(i) to 7.25 +/- 0.08. Intracellular Li(+) inhibited NH(4)Cl
      stimulated Rb(+) efflux by 55%. Monensin and NH(4)Cl stimulated Li(+) efflux by
      40%, increasing k from 29 +/- 3 to 43 +/- 7 and 41 +/- 3, respectively. The
      stimulation was not sensitive to 10 microM dimethylamiloride. Intracellular
      acidosis that resulted from the washout of NH(4)Cl (pH 6.86 +/- 0.2) slightly
      inhibited Rb(+) efflux (k = 36 +/- 5), whereas NH(4)Cl itself in the absence of
      pH(i) changes did not markedly affect Rb(+) efflux. A moderate increase in pH(i)
      (7.17 +/- 0.06) produced by washout of 15 mM 2, 2-dimethylpropionate (DMP)-Tris
      from hearts preequilibrated with DMP did not markedly affect Rb(+) efflux.
      Neither global alkalosis (pH(i) 7.4, pH(e) 7.55) nor acidosis (pH(i)
      approximately pH(e) 6.8) produced by 3 mM Tris base or 5 mM MES, respectively,
      affected Rb(+) efflux. We suggest that intracellular alkalosis stimulates Rb(+)
      (K(+)) and Li(+) effluxes by activating a nonselective sarcolemmal K(+)
      (Li(+))/cation exchanger or a K(+) (Li(+))-anion symporter.

PMID- 10409208
TI  - Effects of FI(O(2)) on hemodynamic responses and O(2) transport during RSR13
      induced reduction in P(50).
AB  - Reduced Hb-O(2) affinity facilitates O(2) release to tissue but may impair
      pulmonary O(2) uptake, affecting cardiac output and systemic vascular resistance
      (SVR). We studied the effects of shifting the O(2)-dissociation curve (ODC) to
      the right with a continuous infusion of RSR13, an allosteric modifier of Hb, and
      of different inspired O(2) fractions (FI(O(2))) on arterial O(2) saturations
      (Sa(O(2))) in Hb and on hemodynamics in nonanesthetized rats. At an FI(O(2)) of
      0.21, Sa(O(2)) fell during RSR13 from 95 to 81%. Elevation of FI(O(2)) to 0.30
      returned Sa(O(2)) to baseline in the RSR13 group. The decrease in mean arterial
      pressure (MAP) was significantly greater in the control than in the RSR13 group
      at 30% O(2). Cardiac index (CI) increased only during RSR13 at 21% O(2) and
      returned to baseline at 30% O(2). In contrast, SVR decreased after RSR13 was
      infused at 21% O(2) but returned to baseline at 30%O(2), whereas controls showed
      the opposite, a sustained SVR. In the follow-up period, when 21 O(2)% was
      reestablished and mild anemia was present, MAP and SVR fell significantly more in
      controls, whereas CI only increased in controls. Lactate was significantly lower
      in the RSR13 than in the control group during RSR13 and the follow-up period.
      These results demonstrate that 1) continuous infusion of RSR13 produces a
      constant shift in the O(2) tension at which Hb is 50% saturated (P(50)), 2)
      FI(O(2)) of 0.30 compensates for the effects of increased P(50) on pulmonary O(2)
      loading, and 3) right-shifted ODC combined with supplemental O(2) may improve
      tissue O(2) availability.

PMID- 10409209
TI  - NO and prostanoids: age dependence of hypercapniaand histamine-induced dilations
      of pig pial arterioles.
AB  - Responses to hypercapnia and acetylcholine by newborn piglet pial arterioles are
      prostanoid dependent but appear to require both prostanoids and nitric oxide in
      juvenile pigs. We hypothesized that cerebrovascular dilatory responses become
      less prostanoid dependent and more NO dependent with development. Pial arteriolar
      responses to hypercapnia and histamine were recorded from alpha-chloralose
      anesthetized newborn and juvenile pigs with closed cranial windows. Responses
      were recorded during control, after indomethacin or N(omega)-nitro-L-arginine (L
      NNA), and after inhibitor plus iloprost or sodium nitroprusside. Indomethacin
      blocked newborn hypercapnic responses and markedly attenuated histamine
      dilations, but only reduced the dilations to about half in juveniles. Iloprost at
      subdilator concentrations restored newborn responses to hypercapnia and histamine
      but did not alter either response in indomethacin-treated juveniles. L-NNA
      attenuated juvenile, but not newborn, hypercapnia-induced dilations. Sodium
      nitroprusside did not restore the response. L-NNA did not alter responses to
      histamine in either age group. Cerebrovascular dilations to hypercapnia and
      histamine are prostanoid dependent and nitric oxide independent in the newborn
      pig, whereas nitric oxide assumes an increasing role in hypercapnic, but not
      histamine, responses with development.

PMID- 10409210
TI  - Cardiac performance and creatine kinase flux during inhibition of ATP synthesis
      in the perfused rat heart.
AB  - To study the relation among mitochondrial energy supply, cardiac performance, and
      energy transfer through creatine kinase (CK), two acute models of inhibition of
      ATP synthesis were compared in the isovolumic acetate-perfused rat heart. Similar
      impairments of mechanical performance (rate-pressure product, RPP) were achieved
      by various stepwise decreases in O(2) supply (PO(2) down to 20% of control) or by
      infusing CN (0.15-0.25 mM). The forward CK flux measured by saturation-transfer
      (31)P NMR spectroscopy was 6.1 +/- 0. 4 mM/s in control hearts. Only after severe
      hypoxia (PO(2) < 40% of control) did CK flux drop (to 1.9 +/- 0.2 mM/s at PO(2) =
      25% of control) together with impaired systolic activity and a rise in end
      diastolic pressure. In contrast, in mild hypoxia CK flux remained constant and
      similar to control (5.3 +/- 0.5 mM/s, not significant) despite a twofold
      reduction in systolic activity. Similarly in all CN groups, constant CK flux was
      maintained for a threefold reduction in RPP, showing the absence of a relation
      between cardiac performance and global NMR-measured CK flux during mild ATP
      synthesis inhibition.

PMID- 10409211
TI  - Impairment of EDR by a long-term PDGF treatment in organ-cultured rabbit
      mesenteric artery.
AB  - Platelet-derived growth factor (PDGF) has been shown to act chronically on blood
      vessels to regulate not only proliferation but also vascular tone. These effects
      may be at least partly due to the chronic effect of PDGF on vascular endothelium.
      To evaluate this possibility, we examined the effects of PDGF on the endothelium
      dependent relaxation (EDR) and total RNA for endothelial nitric oxide (NO)
      synthase (eNOS) using an organ culture system. In rabbit mesenteric arteries
      cultured in a serum-free medium for 1 wk, amplitude of the substance P-induced
      EDR did not change, whereas dependency of the EDR on NO (approximately 60.0% vs.
      18.9%) and the total amounts of recoverable eNOS mRNA estimated by RT-PCR were
      increased compared with those in freshly isolated arteries. Culture with PDGF for
      1 wk decreased the relaxant effect of substance P and ionomycin (P < 0.01
      compared with the arteries without PDGF), NO production estimated by bioassay (P
      < 0.01), and eNOS mRNA level, whereas the sodium nitroprusside-induced relaxation
      did not change. These results suggest that PDGF has a chronic effect on vascular
      endothelium to decrease eNOS mRNA and NO production and to impair NO-dependent
      EDR.

PMID- 10409212
TI  - Cardiac expression of the Na(+)/Ca(2+) exchanger NCX1 is GATA factor dependent.
AB  - The cardiac sarcolemmal Na(+)/Ca(2+) exchanger plays a primary role in Ca(2+)
      efflux and is important in regulating intracellular Ca(2+) and beat-to-beat
      contractility. Of the three Na(+)/Ca(2+) exchanger genes cloned (NCX1, NCX2, and
      NCX3), only NCX1 is expressed in cardiac myocytes. NCX1 has alternative promoters
      for heart, kidney, and brain tissue-specific transcripts. Analysis of the cardiac
      NCX1 promoter (at -336 bp) identified a cardiac-specific minimum promoter (at 
      137) and two GATA sites (at -75 and -145). In this study, gel shift and
      supershift analyses identified GATA-4 in primary neonatal cardiac myocytes. Site
      directed mutagenesis of the GATA-4 site at -75 abolishes binding and reduces
      activity of the minimum and full-length promoters by >90 and approximately 60%,
      respectively. Mutation of the GATA site at -145 reduces activity of the full
      length promoter by approximately 30%. Mutation of an E-box at -175 does not alter
      promoter activity.

PMID- 10409213
TI  - Cell density and contraction regulate p38 MAP kinase-dependent responses in
      neonatal rat cardiac myocytes.
AB  - In vitro cardiac myocyte hypertrophy is characterized by increased cell size,
      sarcomere organization, and induction of several genes including atrial
      natriuretic factor (ANF). The hypertrophic growth program has been associated
      with activation of various mitogen-activated protein kinase (MAP) kinase family
      members, one of which is a stress kinase, p38. In this study, we found that the
      p38-specific inhibitor SB-203580 failed to inhibit phenylephrine-induced ANF
      driven gene expression in low-density myocyte cultures but did inhibit gene
      expression in higher density cultures. Dense myocyte cultures also had a higher
      metabolic activity and contraction rate than cells plated at low density. We
      found that mimicking this effect by rapid electrical pacing activated ANF-driven
      gene expression and that this expression was inhibited by inactivation of p38.
      However, addition of SB-203580 at time points ranging between 1 and 72 h suggests
      that the effect of p38 on the ANF promoter may be both direct and indirect.
      Electrical pacing induced a small, but consistent, increase in p38
      phosphorylation (phospho-p38) at time points ranging from 30 min to 4 h, but at
      later times phospho-p38 levels were reduced. When myocytes were treated with
      phenylephrine or electrically paced in the presence of the p38 inhibitor, there
      was little discernible change in morphology or rates of protein synthesis from
      DMSO-treated cells at 48 or 72 h. These data indicate that cell density and
      myocyte contraction may modulate p38-dependent pathways for ANF gene expression,
      but these pathways may not be direct and have limited effects on hypertrophic
      morphology.

PMID- 10409214
TI  - ANG II and baroreflex function in rabbits with CHF and lesions of the area
      postrema.
AB  - Blockade of the angiotensin II (ANG II) type 1 receptor (AT(1)) has been shown to
      restore baroreflex sensitivity in rats and rabbits with experimental chronic
      heart failure (CHF). Because the modulation of baroreflex function in response to
      ANG II is mediated in part by AT(1) receptors located in the area postrema, we
      hypothesized that lesions of the area postrema would prevent the enhancement in
      baroreflex function in response to AT(1)-receptor blockade in rabbits with pacing
      induced CHF. Experiments were carried out on 24 male New Zealand White rabbits
      that were divided into sham (n = 12) and lesioned (n = 12) groups further divided
      into normal and CHF subgroups (n = 6 each). All rabbits were identically
      instrumented to measure cardiac external dimensions, central venous pressure,
      arterial pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA).
      After 3-4 wk of pacing, baroreflex sensitivity (infusions of phenylephrine and
      nitroprusside) was evaluated before and after intravenous administration of the
      AT(1)-receptor antagonist L-158,809. Maximum baroreflex sensitivity in nonpaced
      rabbits was 5.4 +/- 0.7 beats. min(-1). mmHg(-1) and 5.2 +/- 0.5% of maximum/mmHg
      for HR and RSNA curves, respectively, and was not altered by L-158,809 in either
      intact or lesioned rabbits. In contrast, L-158,809 enhanced baroreflex
      sensitivity in intact rabbits with CHF (HR from 1.6 +/- 0.3 to 4.1 +/- 0.7 beats.
      min(-1). mmHg(-1), P < 0.001; RSNA from 2.3 +/- 0.2 to 4.9 +/- 0.4% of
      maximum/mmHg, P < 0.001). However, in CHF rabbits with area postrema lesions, L
      158,809 failed to enhance baroreflex sensitivity. Interestingly, area postrema
      lesions did not normalize the baroreflex in CHF rabbits. From these data we
      conclude that the area postrema mediates the normalization of baroreflex
      sensitivity after AT(1) blockade in rabbits with CHF but does not modify resting
      baroreflex function.

PMID- 10409215
TI  - Nonuniform responses of transmembrane potential during electric field stimulation
      of single cardiac cells.
AB  - The response of cellular transmembrane potentials (V(m)) to applied electric
      fields is a critical factor during electrical pacing, cardioversion, and
      defibrillation, yet the coupling relationship of the cellular response to field
      intensity and polarity is not well documented. Isolated guinea pig ventricular
      myocytes were stained with a voltage-sensitive fluorescent dye, di-8-ANEPPS (10
      microM). A green helium-neon laser was used to excite the fluorescent dye with a
      15-micrometers-diameter focused spot, and subcellular V(m) were recorded
      optically during field stimulation directed along the long axis of the cell. The
      membrane response was measured at the cell end with the use of a 30-ms S1-S2
      coupling interval and a 10-ms S2 pulse with strength of up to approximately 500
      mV half-cell length potential (field strength x one-half the cell length). The
      general trends show that 1) the response of V(m) at the cell end occurs in two
      stages, the first being very rapid (<1 ms) and the second much slower in time
      scale, 2) the rapid response consists of hyperpolarization when the cell end
      faces the anode and depolarization when the cell end faces the cathode, 3) the
      rapid response varies nonlinearly with field strengths and polarity, being
      relatively larger for the hyperpolarizing responses, and 4) the slower, time
      dependent response has a time course that varies in slope with field strength.
      Furthermore, the linearity of the dye response was confirmed over a voltage range
      of -280 to +140 mV by simultaneous measurements of optically and electrically
      recorded V(m). These experimental findings could not be reproduced by the
      updated, Luo-Rudy dynamic model but could be explained with the addition of two
      currents that activate outside the physiological range of voltages: a
      hypothetical outward current that activates strongly at positive potentials and a
      second current that represents electroporation of the cell membrane.

PMID- 10409217
TI  - Endothelial nitric oxide synthase gene transfer enhances dilation of newborn
      piglet pulmonary arteries.
AB  - We determined the expression and functional correlate of in vitro transfection
      with a recombinant adenoviral vector encoding the gene for bovine endothelial
      nitric oxide synthase (AdCMVeNOS) or Escherichia coli beta-galactosidase
      (AdCMVLacZ) in pulmonary endothelial cells (EC), vascular smooth muscle cells
      (VSMC), and pulmonary arteries (PA) from newborn piglets. AdCMVeNOS and
      AdCMVeLacZ vectors, grown in 293-cell monolayers, were purified by double-cesium
      gradient ultracentrifugation. Cell cultures and PA were incubated with increasing
      vector titers for 30 or 60 min, followed by incubation in fresh medium for 18 h
      at 37 degrees C. LacZ expression was assessed by histochemical staining; eNOS
      expression was evaluated by Western blot analysis. Functional eNOS expression was
      determined by measurement of cGMP and quantification of the relaxation response
      to bradykinin (BK). In PA, LacZ transgene expression was preferentially localized
      to the adventitia and endothelium. Increased eNOS protein expression was observed
      in EC and VSMC transfected with AdCMVeNOS. Functional studies revealed increased
      cGMP abundance in cultured cells and enhanced relaxation to BK in AdCMVeNOS
      transfected PA. These studies demonstrate that gene transfer with AdCMVeNOS
      results in functional expression and altered vasoactive responses in the neonatal
      pulmonary vasculature. Gene transfer with replication-deficient adenovirus
      vectors is a useful tool for the study of targeted genes in vascular biology.

PMID- 10409216
TI  - Enhanced ET(A)-receptor-mediated inhibition of K(v) channels in hypoxic
      hypertensive rat pulmonary artery myocytes.
AB  - Endothelin (ET)-1 has been implicated as a critical mediator in the pathogenesis
      of hypoxic pulmonary hypertension. We questioned whether, during exposure to
      chronic hypobaric hypoxia, rat pulmonary artery smooth muscle cells (PASMC)
      became sensitized to ET-1. Two effects of ET-1, inhibition of voltage-gated K(+)
      (K(v)) channels and release of intracellular Ca(2+), were studied using whole
      cell patch clamp and single cell indo 1 fluorescence, respectively. In both
      normotensive and chronically hypoxic-hypertensive PASMC, ET-1 caused
      concentration-dependent inhibition of voltage-gated K(+) current [I(K(v))], with
      maximum inhibition of 12-18% seen at a concentration of 0.1-1 nM. Although the
      chronically hypoxic-hypertensive PASMC was no more susceptible to ET-1-mediated
      I(K(v)) inhibition, a switch in coupling between ET-1 and I(K(v)) from ET(B) to
      ET(A) receptors occurred. This switch in receptor coupling, combined with reduced
      I(K(v)) density and increased ET-1 production in the hypoxic rat lung, may help
      explain the ability of ET(A)-receptor blockers to attenuate the development of
      hypoxic pulmonary hypertension in vivo.

PMID- 10409218
TI  - Factors contributing to pressure overload-induced immediate early gene expression
      in adult rat hearts in vivo.
AB  - We determined the contributions of angiotensin II type 1 receptor (AT(1))
      stimulation, adrenergic stimulation, and autonomic activation to pressure
      overload-induced c-fos expression in the adult rat heart in vivo. c-fos
      expression was increased in pressure-overloaded hearts created by aortic banding
      compared with sham-operated rats (458 +/- 100% vs. sham, P < 0.05). GR-138950, a
      selective AT(1) antagonist, did not blunt this expression (banding vs. banding +
      GR-138950: 458 +/- 100% vs. 500 +/- 125%, not significant). Atropine and
      hexamethonium partially decreased c-fos expression (banding vs. banding +
      atropine/hexamethonium: 700 +/- 67% vs. 400 +/- 67%, P < 0.05). Phentolamine had
      no significant effect on c-fos expression; however, propranolol inhibited the
      expression (banding vs. banding + propranolol: 492 +/- 108% vs. 154 +/- 15%, P <
      0.05). The inhibition by propranolol was independent of the decreases in heart
      rate. Thus factors contributing to pressure overload-induced c-fos expression in
      adult rat hearts in vivo are different from those in neonatal myocytes in vitro
      undergoing stretch.

PMID- 10409219
TI  - A novel heart failure model induced by sequential coronary artery occlusions and
      tachycardiac stress in awake pigs.
AB  - A heart failure model was developed using conscious pigs subjected to serial
      myocardial infarctions followed by intermittent rapid ventricular pacing. Aortic
      and atrial catheters, left ventricular (LV) pressure gauge, LV dimension
      crystals, ascending aortic flow probe, pacing leads, and two coronary artery
      occluders were implanted in 15 pigs. The initial distal left circumflex coronary
      artery (LCX) occlusion produced a modest infarct, i.e., 18 +/- 3% of LV, and the
      second proximal LCX occlusion, performed 48 h later, enlarged the infarct to 33
      +/- 2% of the LV with only modest changes in LV function. Thereafter, the pigs
      were subjected to ventricular pacing at 220 beats/min, which was maintained for 7
      days and terminated for 3 days. This pacing cycle was repeated two more times and
      resulted in significantly impaired LV function and systemic hemodynamics. For
      example, after the second cycle of pacing, LV rate of pressure change (dP/dt, -41
      +/- 4% from 2,778 +/- 112 mmHg/s), velocity of circumferential fiber shortening
      (V(cf): -53 +/- 6% from 1.1 +/- 0.1 s(-1)), and cardiac index (CI: -42 +/- 5%
      from 122 +/- 4 ml. min(-1). kg(-1)) were reduced significantly, whereas LV end
      diastolic diameter (EDD: +34 +/- 6% from 39 +/- 2 mm), total peripheral
      resistance (TPR: +75 +/- 16% from 0.79 +/- 0.05 U), and mean left atrial pressure
      (LAP) (+21 +/- 1 mmHg from 5 +/- 1 mmHg) were increased significantly.
      Importantly, 3 wk after cessation of the final pacing cycle, LV dP/dt (-40 +/-
      5%), V(cf) (-48 +/- 9%), and CI (-30 +/- 4%) remained depressed, whereas LV EDD
      (+39 +/- 5%), TPR (+43 +/- 9%), and LAP (+13 +/- 4 mmHg) were still increased. In
      contrast, hemodynamic impairment in six conscious pigs subjected to pacing only
      did not persist when pacing was terminated. Thus this model could provide a
      unique opportunity to study both the effects of preclinical therapeutic
      interventions and the mechanisms involved in the development of heart failure.

PMID- 10409220
TI  - Insulin-induced endothelin release and vasoreactivity in hypertriglyceridemic and
      hypertensive rats.
AB  - Insulin-elicited endothelin release in hypertriglyceridemic, hypertensive,
      hyperinsulinemic (HTG) rats was shown. Weanling male Wistar rats were given 30%
      sucrose in their drinking water for 20-24 wk. In vitro contractions of aorta and
      femoral arteries were elicited with 40 mM KCl. Endothelin release induced with
      KCl plus 50 microU/ml insulin resulted in increases in contractile responses: 41
      +/- 5.9 and 57 +/- 6% for control and 65.5 +/- 6 and 95 +/- 9% for HTG aortas and
      femoral arteries, respectively. The endothelin ET(B)-receptor blocker BQ-788
      decreased responses to KCl + insulin by 39 +/- 8 and 53 +/- 5% in control and 48
      +/- 13 and 79 +/- 3.5% in HTG aortas and femoral arteries, respectively. The
      ET(A)-receptor antagonist PD-151242 inhibited these responses by 12 +/- 10 and 1
      +/- 9% in control and by 51.5 +/- 9 and 58.5 +/- 1% in HTG aortas and femoral
      arteries, respectively. These results suggest that endothelin may contribute to
      the hypertension in this model.

PMID- 10409221
TI  - Potentiation of stretch-induced atrial natriuretic peptide secretion by
      intracellular acidosis.
AB  - We sought to investigate whether atrial myocyte contraction and secretion of the
      atrial natriuretic peptide (ANP) are affected in the same manner by intervention
      in intracellular Ca(2+) handling by acidosis. The effects of propionate (20 mM)
      induced intracellular acidosis on the stretch-induced changes in ANP secretion,
      contraction force, and intracellular Ca(2+) concentration ([Ca(2+)](i)) were
      studied in the isolated rat atrium. The stretch of the atrium was produced by
      increasing the intra-atrial pressure of the paced and superfused preparation.
      Contraction force was estimated from pressure pulses generated by the contraction
      of the atrium. Intracellular Ca(2+) was measured from indo 1-AM-loaded atria, and
      ANP was measured by radioimmunoassay from the perfusate samples collected during
      interventions. Intracellular pH of the atrial myocytes was measured by a
      fluorescent indicator (BCECF)-based imaging system. Intracellular acidification
      caused by 20 mM propionic acid (0.18 pH units) potentiated the stretch-induced
      (intra-atrial pressure from 1 to 4 mmHg) ANP secretion, causing a twofold
      secretion compared with nonacidotic controls. Simultaneously, the responsiveness
      of the atrial contraction to stretch was reduced (P < 0.05, n = 7). Stretch
      augmented the systolic indo 1-AM transients in acidic (P < 0.05, n = 6) and
      nonacidic atria (P < 0.05, n = 6). However, during acidosis this was accompanied
      by an increase of the diastolic indo 1-AM ratio (P < 0.05, n = 6). Cooccurrence
      of stretch and acidosis caused an increase in systolic and diastolic [Ca(2+)](i)
      and potentiated the stretch-induced ANP secretion, whereas the contraction force
      and its stretch sensitivity were decreased. This mechanism may be involved in
      ischemia-induced ANP secretion, suggesting a role for ANP secretion as an
      indicator of contractile dysfunction.

PMID- 10409222
TI  - Separation of cardiomyocytes and coronary endothelial cells for cell-specific RT
      PCR.
AB  - A simple method for analyzing the differential gene expression of coronary
      endothelial cells and cardiac muscle cells was developed. Cells were isolated
      from guinea pig hearts by collagenase digestion. In the diluted cell suspension,
      single cardiomyocytes and capillary fragments containing 6-15 endothelial cells
      could be identified morphologically. A simple "cell picker" was constructed using
      a polyethylene pipette with a tip diameter of approximately 150 micrometers that
      was attached to a micromanipulator and connected to an electric miniature valve.
      Intermittent suction pulses (1- to 2-cm water column) were applied by opening the
      valve for 100-200 ms at 1-s intervals. Cardiomyocytes (800-1,000) or capillary
      fragments (150) were picked under visual control using an inverted microscope.
      The cells were transferred to a reaction tube for RNA extraction, reverse
      transcription (RT), and DNA amplification (RT-PCR) with gene-specific and intron
      spanning primers. All PCR products were verified by sequencing. Troponin T and
      endothelin-1 were found to be specific markers for guinea-pig cardiac muscle
      cells and coronary endothelial cells, respectively.

PMID- 10409223
TI  - Resting myocardial flow in hibernating myocardium: validating animal models of
      human pathophysiology.

PMID- 10409225
TI  - EVE and beyond, retro and prospective insights.
AB  - Our work has focused on the discovery that an endogenous vascular elastase (EVE)
      plays a pivotal role in the vascular changes associated with the development and
      progression of pulmonary hypertension. Recent studies have identified serum
      factors that stimulate transcription of this enzyme and have elucidated a signal
      transduction process involving activation of the mitogen-activated protein kinase
      pathway and nuclear expression of the transcription factor AML1. Proteases
      release and activate growth factors that are bound to the extracellular matrix
      and also induce, in a beta(3)-integrin-dependent manner, the transcription of the
      gene for the matrix glycoprotein tenascin. Tenascin alters smooth muscle cell
      shape and facilitates the proliferative response to growth factors by clustering
      and activating growth factor receptors. In addition, breakdown products of
      elastin, elastin peptides, can upregulate the production of fibronectin, a
      glycoprotein that is critical to smooth muscle cell migration. The mechanisms
      regulating enhanced fibronectin production have recently been successfully
      targeted to prevent the development of intimal lesions.

PMID- 10409226
TI  - Rhinovirus-mediated changes in airway smooth muscle responsiveness: induced
      autocrine role of interleukin-1beta.
AB  - An important interplay exists between specific viral respiratory pathogens, most
      commonly rhinovirus (RV), and altered airway responsiveness in the development
      and exacerbations of asthma. Given that RV infection reportedly induces the
      release of various cytokines in different cell types and that the reported
      effects of RV on airway smooth muscle (ASM) responsiveness are highly comparable
      to those obtained in ASM exposed to the proinflammatory cytokine interleukin (IL)
      1beta, this study examined whether RV (serotype 16)-mediated pertubations in ASM
      responsiveness are mechanistically coupled to altered induced expression and
      action of IL-1beta in RV-exposed isolated rabbit and human ASM tissue and
      cultured cells. Relative to control tissues, ASM inoculated with RV exhibited
      significantly increased maximal isometric contractility to ACh (P < 0.01) and
      attenuated relaxation to isoproterenol (P < 0. 005). In extended studies, we
      found that 1) the RV-induced changes in ASM responsiveness were ablated by
      pretreating the tissues with the IL-1 recombinant human receptor antagonist; 2)
      in contrast to their respective controls, RV-inoculated ASM tissue and cultured
      cells exhibited progressively induced expression of IL-1beta mRNA and elaboration
      of IL-1beta protein at 6 and 24 h after viral exposure; and 3) the latter effect
      of RV was inhibited in the presence of a monoclonal antibody to intercellular
      adhesion molecule-1, the endogenous receptor for most RV. Collectively, these
      observations provide new evidence demonstrating that "pro-asthmatic-like"
      pertubations in agonist responsiveness elicited in RV-exposed ASM are largely
      attributed to the induced autologous expression and autocrine action of IL-1beta
      in the virus-infected ASM.

PMID- 10409227
TI  - alpha-Thrombin stimulates contraction of human bronchial rings by activation of
      protease-activated receptors.
AB  - In a variety of diseases, inflammation causes microvascular leakage and activates
      thrombin. Evidence suggests that thrombin increases cytosolic calcium and
      stimulates human airway smooth muscle (ASM) cell proliferation. The receptor
      subtypes, however, that mediate the effects of thrombin on ASM cell growth or
      calcium mobilization remain unknown. In this study, we postulate that thrombin,
      which activates specific protease-activated receptors (PARs), also stimulates
      contraction of isolated human bronchial rings. With the use of intact human
      bronchial rings, alpha-thrombin (1-20 U/ml) increased bronchial tone to 19 +/- 3%
      of basal tone (P = 0.008; n = 5 experiments) and represents 20 +/- 8% of the
      maximum carbachol response. The EC(50) for thrombin-induced force generation was
      12.2 U/ml (95% confidence interval 9.9-15.3 U/ml) and was not altered in
      bronchial rings that had the epithelium removed. In parallel experiments, a
      specific thrombin receptor-activating peptide (TRAP-14; 0.1-100 micromol/l)
      increased isometric tension to levels (14 +/- 2%; P = 0.0005; n = 5 experiments)
      comparable to those rings stimulated with thrombin. To characterize the receptors
      that mediate thrombin effects on human ASM, the expression of PARs in cultured
      human ASM cells was analyzed by RT-PCR analysis with specific primers for PARs.
      In these cells, PAR1 (thrombin receptor), PAR2, and PAR3 were expressed at
      comparable levels. In other experiments using immunocytochemical staining with
      specific antibodies to PAR1 and PAR2, we showed that ASM in bronchial rings and
      cultured ASM cells express PAR1 and PAR2 proteins. Taken together, these studies
      suggest that alpha-thrombin, in a receptor-specific and dose-dependent manner,
      induces contraction of bronchial rings in vitro. In addition, cultured human ASM
      cells express mRNA of PAR1, PAR2, and PAR3 and express PAR1 and PAR2 protein.
      Further studies are needed to determine whether alpha-thrombin plays a role in
      stimulating bronchoconstriction in inflammatory airway diseases such as asthma
      and bronchiolitis obliterans.

PMID- 10409228
TI  - Intracellular calcium oscillations induced by ATP in airway epithelial cells.
AB  - In airway epithelial cells, extracellular ATP (ATP(o)) stimulates an initial
      transient increase in intracellular Ca(2+) concentration that is followed by
      periodic increases in intracellular Ca(2+) concentration (Ca(2+) oscillations).
      The characteristics and mechanism of these ATP-induced Ca(2+) responses were
      studied in primary cultures of rabbit tracheal cells with digital video
      fluorescence microscopy and the Ca(2+)-indicator dye fura 2. The continual
      presence of ATP(o) at concentrations of 0.1-100 microM stimulated Ca(2+)
      oscillations that persisted for 20 min. The frequency of the Ca(2+) oscillations
      was found to be dependent on both ATP(o) concentration and intrinsic sensitivity
      of each cell to ATP(o). Cells exhibited similar Ca(2+) oscillations to
      extracellular UTP (UTP(o)), but the oscillations typically occurred at lower
      UTP(o) concentrations. The ATP-induced Ca(2+) oscillations were abolished by the
      phospholipase C inhibitor U-73122 and by the endoplasmic reticulum Ca(2+)-pump
      inhibitor thapsigargin but were maintained in Ca(2+)-free medium. These results
      are consistent with the hypothesis that in airway epithelial cells ATP(o) and
      UTP(o) act via P2U purinoceptors to stimulate Ca(2+) oscillations by the
      continuous production of inositol 1,4,5-trisphosphate and the oscillatory release
      of Ca(2+) from internal stores. ATP-induced Ca(2+) oscillations of adjacent
      individual cells occurred independently of each other. By contrast, a
      mechanically induced intercellular Ca(2+) wave propagated through a field of
      Ca(2+)-oscillating cells. Thus Ca(2+) oscillations and propagating Ca(2+) waves
      are two fundamental modes of Ca(2+) signaling that exist and operate
      simultaneously in airway epithelial cells.

PMID- 10409229
TI  - Expression, pharmacological, and functional evidence for PACAP/VIP receptors in
      human lung.
AB  - Pituitary adenylate cyclase-activating peptide (PACAP) type 1 (PAC(1)) and common
      PACAP/vasoactive intestinal peptide (VIP) type 1 and 2 (VPAC(1) and VPAC(2),
      respectively) receptors were detected in the human lung by RT-PCR. The proteins
      were identified by immunoblotting at 72, 67, and 68 kDa, respectively. One class
      of PACAP receptors was defined from (125)I-labeled PACAP-27 binding experiments
      (dissociation constant = 5.2 nM; maximum binding capacity = 5.2 pmol/mg protein)
      with a specificity: PACAP-27 approximately VIP > helodermin approximately peptide
      histidine-methionine (PHM) >> secretin. Two classes of VIP receptors were
      established with (125)I-VIP (dissociation constants of 5.4 and 197 nM) with a
      specificity: VIP approximately helodermin approximately PACAP-27 >> PHM >>
      secretin. PACAP-27 and VIP were equipotent on adenylyl cyclase stimulation
      (EC(50) = 1.6 nM), whereas other peptides showed lower potency (helodermin > PHM
      >> secretin). PACAP/VIP antagonists supported that PACAP-27 acts in the human
      lung through either specific receptors or common PACAP/VIP receptors. The present
      results are the first demonstration of the presence of PAC(1) receptors and
      extend our knowledge of common PACAP/VIP receptors in the human lung.

PMID- 10409230
TI  - Enhancement of tumoricidal activity of alveolar macrophages via CD40-CD40 ligand
      interaction.
AB  - CD40-CD40 ligand (CD40L) interaction was originally defined as important
      molecules for the development of humoral immunity. Thereafter, some
      investigations have focused on its essential roles for the induction of cell
      mediated immunity in host defenses. Here we investigated the antitumor activity
      of murine alveolar macrophages through CD40-CD40L interaction. The CD40L gene was
      transfected into murine lung cancer cells (3LLSA), and CD40L-expressing clones
      (3LLSA-CD40L) were established. Stimulation of CD40 molecules on the surface of
      alveolar macrophages with 3LLSA-CD40L cells induced the production of nitric
      oxide, tumor necrosis factor-alpha, and interleukin-12 and the tumoricidal
      activity of alveolar macrophages in the presence of interferon-gamma, which
      increased the surface expression of CD40 molecules on alveolar macrophages. These
      findings were not observed when alveolar macrophages were obtained from CD40
      deficient mice. On the other hand, interleukin-6 production by alveolar
      macrophages did not depend on CD40-CD40L interaction. We also established a
      murine melanoma cell line expressing CD40L (B16 4A5-CD40L) that could induce
      tumoricidal activity of alveolar macrophages. Furthermore, when spleen cells were
      cocultivated with 3LLSA-CD40L cells, specific cytotoxic T lymphocytes for wild
      type 3LLSA cells could be induced. These results suggest that CD40L gene transfer
      into tumor cells may induce antitumor immunity in a tumor-bearing host and may
      offer a new strategy for cancer gene therapy.

PMID- 10409231
TI  - IL-4 induces ICAM-1 expression in human bronchial epithelial cells and
      potentiates TNF-alpha.
AB  - Interleukin (IL)-4 is thought to contribute to the Th2 type of immune response
      and hence the development of allergic reactions such as asthma. In asthmatic
      patients, the airway epithelium expresses increased amounts of the cell surface
      adhesion molecule intercellular adhesion molecule (ICAM)-1 (CD54). One cytokine
      capable of inducing ICAM-1 in airway epithelial cells, tumor necrosis factor
      alpha (TNF-alpha), is present in asthma. This study evaluated if IL-4 either
      alone or together with TNF-alpha costimulation might modulate CD54 expression by
      human bronchial epithelial cells (HBECs). CD54 positivity increased in response
      to IL-4 (16 +/- 2% positive vs. 3 +/- 1%, P < 0.01); greater induction of CD54
      resulted from TNF-alpha (45 +/- 2%, P < 0.001). Costimulation with TNF-alpha plus
      IL-4 further augmented expression (56 +/- 1%, P < 0.05). Immunoperoxidase results
      were confirmed by flow cytometry. RT-PCR revealed no increase in ICAM-1 mRNA
      expression under control conditions or after stimulation with IL-4 alone. TNF
      alpha increased IL-4 mRNA, and IL-4 potentiated this. Functionally, IL-4
      augmented the adhesion of THP-1 monocyte/macrophage cells to monolayers of HBECs
      both alone and in the presence of TNF-alpha. We conclude that 1) IL-4 augments
      epithelial cell ICAM-1 expression, 2) IL-4 potentiates the adhesion of THP-1
      monocyte/macrophage cells to epithelial cells, and 3) modulation of epithelial
      cell ICAM-1 expression by IL-4 may play a role in the immunopathology of
      bronchial asthma.

PMID- 10409233
TI  - Regulation of mouse SP-B gene promoter by AP-1 family members.
AB  - The regulatory role of activator protein-1 (AP-1) family members in mouse
      surfactant protein (SP) B (mSP-B) promoter function was assessed in the mouse
      lung epithelial cell line MLE-15. Expression of recombinant Jun B and c-Jun
      inhibited mSP-B promoter activity by 50-75%. Although c-Fos expression did not
      alter mSP-B transcription, Jun D enhanced mSP-B promoter activity and reversed
      inhibition of mSP-B by c-Jun or Jun B. A proximal AP-1 binding site (-18 to -10
      bp) was identified that overlaps a thyroid transcription factor-1 binding site.
      Mutation of this proximal AP-1 site blocked both Jun B inhibition and Jun D
      enhancement and partially blocked c-Jun inhibition of promoter activity. Promoter
      deletion mutants were used to identify additional sequences mediating the
      inhibitory effects of c-Jun in the distal region from -397 to -253 bp. The AP-1
      element in this distal site (-370 to -364 bp) is part of a composite binding site
      wherein AP-1, cAMP response element binding protein, thyroid transcription factor
      1, and nuclear factor I interact. Point mutation of the distal AP-1 binding site
      partially blocked c-Jun-mediated inhibition of the SP-B promoter. Both
      stimulatory (Jun D) and inhibitory (c-Jun/Jun B) effects of AP-1 family members
      on mSP-B promoter activity are mediated by distinct cis-acting elements in the
      mSP-B 5'-flanking region.

PMID- 10409232
TI  - Phosphatidylinositol 3-kinase mediates mitogen-induced human airway smooth muscle
      cell proliferation.
AB  - Hypertrophy and hyperplasia of airway smooth muscle (ASM) are important
      pathological features that contribute to airflow obstruction in chronic severe
      asthma. Despite considerable research effort, the cellular mechanisms that
      modulate ASM growth remain unknown. Recent evidence suggests that mitogen-induced
      activation of phosphoinositide (PI)-specific phospholipase C (PLC) and PI
      dependent calcium mobilization are neither sufficient nor necessary to stimulate
      human ASM proliferation. In this study, we identify phosphatidylinositol (PtdIns)
      3-kinase as a key regulator of human ASM proliferation. Pretreatment of human ASM
      with the PtdIns 3-kinase inhibitors wortmannin and LY-294002 significantly
      reduced thrombin- and epidermal growth factor (EGF)-induced DNA synthesis (IC(50)
      approximately 10 nM and approximately 3 microM, respectively). In separate
      experiments, wortmannin and LY-294002 markedly inhibited PtdIns 3-kinase and 70
      kDa S6 protein kinase (pp70(S6k)) activation induced by stimulation of human ASM
      cells with EGF and thrombin but had no effect on EGF- and thrombin-induced
      p42/p44 mitogen-activated protein kinase (MAPK) activation. The specificity of
      wortmannin and LY-294002 was further suggested by the demonstrated inability of
      these compounds to alter thrombin-induced calcium transients, total PI
      hydrolysis, or basal cAMP levels. Transient expression of constitutively active
      PtdIns 3-kinase (p110*) activated pp70(S6k), whereas a dominant-negative PtdIns 3
      kinase (Deltap85) blocked EGF- and thrombin-stimulated pp70(S6k) activity.
      Collectively, these data suggest that activation of PtdIns 3-kinase is required
      for the mitogenic effect of EGF and thrombin in human ASM cells. Further
      investigation of the role of PtdIns 3-kinase may offer new therapeutic approaches
      in the treatment of diseases characterized by smooth muscle cell hyperplasia such
      as asthma and chronic bronchitis.

PMID- 10409235
TI  - Effects of depletion of neutrophils or macrophages on development of cigarette
      smoke-induced emphysema.
AB  - The aim of this study was to ascertain the putative roles of neutrophils or
      macrophages in the pathogenesis of cigarette smoking-induced emphysema on the
      basis of effects of anti-neutrophil (anti-PMN) antibody or anti
      monocyte/macrophage (anti-MoMac) antibody on the development of emphysema in
      cigarette smoke-exposed rats. Rats were treated with rabbit anti-PMN or anti
      MoMac antibody and exposed 7 days/wk for 2 mo to cigarette smoke inhalation; rats
      treated with nonimmunized rabbit IgG (control antibody) and exposed to cigarette
      smoke or normal room air served as controls. Antibody treatments began 24 h
      before the start of smoke or air exposure and was continued with 1 treatment/wk.
      Total and differential cell counts in bronchoalveolar lavage fluid and
      collagenase-dissociated lung and determinations of the elastinolytic activity of
      lung neutrophils or macrophages in [(3)H]elastin-coated wells indicated specific
      suppression of neutrophil accumulation and neutrophil-related elastinolytic
      burden in the lungs of the anti-PMN antibody-treated smoke-exposed rats, in
      contrast to specific suppression of macrophage accumulation and macrophage
      related elastinolytic burden in the lungs of the anti-MoMac antibody-treated
      smoke-exposed rats. Cigarette smoke exposure-induced lung elastin breakdown
      (quantitated by immunologic assay of levels of elastin-derived peptides and
      desmosine in lavage fluid) and emphysema in the lungs (based on morphometric
      analysis of alveolar mean linear intercepts and alveolar tissue density in fixed
      lungs) were not prevented in the lungs of anti-PMN antibody-treated smoke-exposed
      rats but was clearly prevented in lungs of the anti-MoMac antibody-treated smoke
      exposed rats. These findings implicate macrophages rather than neutrophils as the
      critical pathogenic factor in cigarette smoke-induced emphysema.

PMID- 10409234
TI  - Nitric oxide inhibits heterologous CFTR expression in polarized epithelial cells.
AB  - Nitric oxide (. NO) has been implicated in a wide range of autocrine and
      paracrine signaling mechanisms. Herein, we assessed the role of exogenous. NO in
      the modulation of heterologous gene expression in polarized kidney epithelial
      cells (LLC-PK(1)) that were stably transduced with a cDNA encoding human wild
      type cystic fibrosis transmembrane conductance regulator (CFTR) under the control
      of a heavy metal-sensitive metallothionein promoter (LLC-PK(1)-WTCFTR). Exposure
      of these cells to 125 microM DETA NONOate at 37 degrees C for 24 h (a chemical.
      NO donor) diminished Zn(2+)-induced and uninduced CFTR protein levels by 43.3 +/-
      5.1 and 34.4 +/- 17.1% from their corresponding control values, respectively.
      These changes did not occur if red blood cells, effective scavengers of. NO, were
      added to the medium. Exposure to. NO did not alter lactate dehydrogenase release
      in the medium or the extent of apoptosis. Coculturing LLC-PK(1)-WTCFTR cells with
      murine fibroblasts that were stably transduced with the human inducible. NO
      synthase cDNA gene also inhibited CFTR protein expression in a manner that was
      antagonized by 1 mM N(G)-monomethyl-L-arginine in the medium. Pretreatment of LLC
      PK(1)-WTCFTR with ODQ, an inhibitor of guanylyl cyclase, did not affect the
      ability of. NO to inhibit heterologous CFTR expression; furthermore, 8-bromo-cGMP
      had no effect on heterologous CFTR expression. These data indicate that. NO
      impairs the heterologous expression of CFTR in epithelial cells at the protein
      level via cGMP-independent mechanisms.

PMID- 10409236
TI  - Establishment of an immortalized fetal intrapulmonary artery endothelial cell
      line.
AB  - The investigation of fetal pulmonary endothelial cell gene expression and
      function has been limited by the requirement for primary cells. In an effort to
      establish an immortalized cell line, ovine fetal pulmonary artery endothelial
      cells (PAECs; passage 5) were permanently transfected with the E6 and E7 open
      reading frames of human papillomavirus type 16, and phenotypes related to nitric
      oxide (NO) production were evaluated up to passage 28. Acetylated low-density
      lipoprotein uptake, endothelial NO synthase (eNOS) expression, and proliferation
      rates were unaltered by immortalization. Acetylcholine-stimulated eNOS activity
      was 218-255% above basal levels in immortalized cells, and this was comparable to
      the 250% increase seen in primary PAECs (passage 6). eNOS was also acutely
      activated by estradiol to levels 197-309% above basal, paralleling the
      stimulation obtained in primary cells. In addition, the expression of estrogen
      receptor-alpha, which has recently been shown to mediate the acute response in
      primary PAECs, was conserved. Thus fetal PAECs transfected with E6 and E7 show no
      signs of senescence with passage, and mechanisms of NO production, including
      those mediated by estradiol, are conserved. Immortalized PAECs will provide an
      excellent model for further studies of eNOS gene expression and function in fetal
      pulmonary endothelium.

PMID- 10409237
TI  - Abnormal glutathione transport in cystic fibrosis airway epithelia.
AB  - Glutathione (GSH) is a potentially important component of antioxidant defense in
      the epithelial lung lining fluid. Cystic fibrosis (CF) patients have chronic
      inflammation in which oxidative stress can be a factor. To examine the hypothesis
      that the transport of GSH content was defective in CF patients, intracellular and
      extracellular GSH were measured by HPLC. Four cell lines were used: CFT1 cells
      [with defective CF transmembrane conductance regulator (CFTR), DeltaF508
      homozygous, two clones] and one of the CFT1 clones transfected with either normal
      CFTR (CFTR repleted) or beta-galactosidase. GSH content in the apical fluid was
      55% lower in CFTR-deficient cultures than in CFTR-repleted cells (P < 0.001). In
      contrast, intracellular GSH content was similar in CFT1 cells and CFTR-repleted
      cells. gamma-Glutamyl transpeptidase activity, which degrades extracellular GSH,
      did not account for differences in apical GSH. Rather, GSH efflux of CFTR
      deficient cells was lower than that of CFTR-repleted cells. These studies
      suggested that decreased GSH content in the apical fluid in CF resulted from
      abnormal GSH transport associated with a defective CFTR.

PMID- 10409238
TI  - Control of cAMP in lung endothelial cell phenotypes. Implications for control of
      barrier function.
AB  - Pulmonary microvascular endothelial cells (PMVECs) form a more restrictive
      barrier to macromolecular flux than pulmonary arterial endothelial cells (PAECs);
      however, the mechanisms responsible for this intrinsic feature of PMVECs are
      unknown. Because cAMP improves endothelial barrier function, we hypothesized that
      differences in enzyme regulation of cAMP synthesis and/or degradation uniquely
      establish an elevated content in PMVECs. PMVECs possessed 20% higher basal cAMP
      concentrations than did PAECs; however, increased content was accompanied by 93%
      lower ATP-to-cAMP conversion rates. In PMVECs, responsiveness to beta-adrenergic
      agonist (isoproterenol) or direct adenylyl cyclase (forskolin) activation was
      attenuated and responsiveness to phosphodiesterase inhibition (rolipram) was
      increased compared with those in PAECs. Although both types of endothelial cells
      express calcium-inhibited adenylyl cyclase, constitutive PMVEC cAMP accumulation
      was not inhibited by physiological rises in cytosolic calcium, whereas PAEC cAMP
      accumulation was inhibited 30% by calcium. Increasing either PMVEC calcium entry
      by maximal activation of store-operated calcium entry or ATP-to-cAMP conversion
      with rolipram unmasked calcium inhibition of adenylyl cyclase. These data
      indicate that suppressed calcium entry and low ATP-to-cAMP conversion
      intrinsically influence calcium sensitivity. Adenylyl cyclase-to-cAMP
      phosphodiesterase ratios regulate cAMP at elevated levels compared with PAECs,
      which likely contribute to enhanced microvascular barrier function.

PMID- 10409239
TI  - Retrovirus-mediated HO gene transfer into endothelial cells protects against
      oxidant-induced injury.
AB  - Heme oxygenase (HO)-1 is a stress protein that has been implicated in defense
      mechanisms against agents that may induce oxidative injury, such as endotoxins,
      heme, and cytokines. Overexpression of HO-1 in cells might, therefore, protect
      against oxidative stress produced by certain agents, specifically heme, by
      catalyzing its degradation to bilirubin, which by itself has antioxidant
      properties. We report for the first time the successful transduction of human HO
      1 gene into rat lung microvessel endothelium using replication-defective
      retroviral vector. Cells transduced with human HO-1 gene exhibited a 2.1-fold
      increase in HO-1 protein level, which was associated with a 2.3-fold elevation in
      enzyme activity compared with that in nontransduced cells. The cGMP content in
      transduced endothelial cells was increased by 2.9-fold relative to that in
      nontransduced cells. Moreover, human HO-1 gene-transduced endothelial cells
      acquired substantial resistance to toxicity produced by exposure to heme and
      H(2)O(2) compared with that in nontransduced cells. The protective effect of
      enhancement of HO-1 activity against heme and H(2)O(2) was reversed by
      pretreatment with stannic mesoporphyrin, a competitive inhibitor of HO. These
      data demonstrate that the induction of HO-1 in response to injurious stimuli
      represents an important mechanism for moderating the severity of cell damage.
      Regulation of HO activity in this manner may have clinical applications.

PMID- 10409240
TI  - Transcriptional activation and protein binding by two regions of the rat
      surfactant protein A promoter.
AB  - Surfactant protein A (SP-A) is expressed in lung alveolar type II cells and
      bronchiolar Clara cells. We have identified two active regions in the promoter of
      the rat SP-A gene by deletion analysis of a plasmid containing 163 bp before the
      start of transcription (-163 bp), linked to a reporter gene. Constructs were
      transfected into lung cell lines derived from each of the cell types that
      produces SP-A. We found a novel region of promoter activity at approximately 90
      bp before the transcriptional start (SP-A(-90)). Mutation of four nucleotides in
      SP-A(-90) that are highly conserved among species (-92 to -89 bp) decreased
      expression of the SP-A construct by approximately 50% in both cell lines.
      Electrophoretic mobility shift analysis showed specific binding to SP-A(-90) by
      nuclear proteins from the cell lines, as well as from rat lung and liver. The
      electrophoretic mobility of the bands shifted by lung nuclear proteins changed
      late in fetal development. Although in the Clara cell line no reduction of
      promoter activity was seen on deletion of the region upstream of SP-A(-90), in
      the type II cell line, deletion of residues -163 to -133 did reduce activity by
      approximately 50%. This region contains a recognition element for thyroid
      transcription factor-1 (TTF-1). Endogenous TTF-1 binding activity was
      substantially higher in the type II cell line than in the Clara cell line, but
      cotransfection of a TTF-1 expression plasmid enhanced expression of the SP-A
      construct better in the Clara cell line than in the type II cell line. These
      results suggest that the recognition element for TTF-1 has varying activity in
      the lung cell lines of different origin due to the availability of TTF-1.

PMID- 10409241
TI  - Mechanical strain-induced posttranscriptional regulation of fibronectin
      production in fetal lung cells.
AB  - We have shown that intermittent mechanical strain, simulating fetal breathing
      movements, stimulated fetal rat lung cell proliferation. Because normal lung
      growth requires proper coordination between cell proliferation and extracellular
      matrix remodeling, we investigated the effect of strain on fibronectin
      metabolism. Organotypic cultures of fetal rat lung cells, subjected to
      intermittent strain, showed increased fibronectin content in the culture media.
      Fibronectin-degrading activity in media from strained cells was similar to that
      of static cultures. Northern analysis revealed that strain inhibited fibronectin
      mRNA accumulation seen during static culture. Synthesis of fibronectin,
      determined by metabolic labeling, was increased by strain despite lower mRNA
      levels or presence of actinomycin D. This increase was not mediated via a
      rapamycin-sensitive mechanism. Strain stimulated prelabeled fibronectin secretion
      even in the presence of cycloheximide. These results suggest that strain
      differentially regulates fibronectin production of fetal lung cells at the
      transcriptional and posttranscriptional levels. Mechanical strain increases
      soluble fibronectin content by stimulating its synthesis and secretion without
      increasing fibronectin message levels.

PMID- 10409242
TI  - Hydrogen peroxide stimulates tyrosine phosphorylation of focal adhesion kinase in
      vascular endothelial cells.
AB  - Reactive oxygen species (ROS) are implicated in the pathophysiology of several
      vascular disorders including atherosclerosis. Although the mechanism(s) of ROS
      induced vascular damage remains unclear, there is increasing evidence for ROS
      mediated modulation of signal transduction pathways. Exposure of bovine pulmonary
      artery endothelial cells to hydrogen peroxide (H(2)O(2)) enhanced tyrosine
      phosphorylation of 60- to 80- and 110- to 130-kDa cellular proteins, which were
      determined by immunoprecipitation with specific antibodies focal adhesion kinase
      (p125(FAK)) and paxillin (p68). Brief exposure of cells to a relatively high
      concentration of H(2)O(2) (1 mM) resulted in a time- and dose-dependent tyrosine
      phosphorylation of FAK, which reached maximum levels within 10 min (290% of basal
      levels). Cytoskeletal reorganization as evidenced by the appearance of actin
      stress fibers preceded H(2)O(2)-induced tyrosine phosphorylation of FAK, and the
      microfilament disruptor cytochalasin D also attenuated the tyrosine
      phosphorylation of FAK. Treatment of BPAECs with 1,2-bis(2-aminophenoxy)ethane
      N,N,N', N'-tetraacetic acid-AM attenuated H(2)O(2)-induced increases in
      intracellular Ca(2+) but did not show any consistent effect on H(2)O(2)-induced
      tyrosine phosphorylation of FAK. Several tyrosine kinase inhibitors, including
      genistein, herbimycin, and tyrphostin, had no detectable effect on tyrosine
      phosphorylation of FAK but attenuated the H(2)O(2)-induction of mitogen-activated
      protein kinase activity. We conclude that H(2)O(2)-induced increases in FAK
      tyrosine phosphorylation may be important in H(2)O(2)-mediated endothelial cell
      activation.

PMID- 10409243
TI  - ERK activation protects against DNA damage and apoptosis in hyperoxic rat AEC2.
AB  - The survival of type 2 alveolar epithelial cells (AEC2) in the lung after
      hyperoxic injury is regulated by signals from the cellular environment.
      Keratinocyte growth factor and Matrigel can ameliorate the hallmarks of apoptosis
      seen in hyperoxic AEC2 after 24-h culture on plastic [S. Buckley, L. Barsky, B.
      Driscoll, K. Weinberg, K. D. Anderson, and D. Warburton. Am. J. Physiol. 274
      (Lung Cell. Mol. Physiol. 18): L714-L720, 1998]. We used the same model of in
      vivo short-term hyperoxia to characterize the protective effects of substrate
      attachment. Culture of hyperoxic AEC2 on various biological adhesion substrates
      showed reduced DNA end labeling in cells grown on all biological substrates
      compared with growth on plastic. In contrast, the synthetic substrate poly-D
      lysine conferred no protection. Hyperoxic AEC2 cultured on laminin showed an
      increased ratio of expression of Bcl-2 to interleukin-1beta-converting enzyme
      compared with culture on plastic. Laminin also partially restored hyperoxia
      depleted glutathione levels and conferred improved optimal mitochondrial
      viability as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
      bromide (MTT) assay. Conversely, attachment to the nonphysiological substrate
      poly-D-lysine afforded no such protection, suggesting that protection against
      hyperoxia-induced damage may be associated with integrin signaling. Increased
      activation of extracellular signal-regulated kinase (ERK), as detected by
      increased ERK tyrosine phosphorylation, was seen in hyperoxic AEC2 as soon as the
      cells started to attach to laminin and was sustained after 24 h of culture in
      contrast to that in control AEC2. To confirm that protection against DNA strand
      breakage and apoptosis was being conferred by ERK activation, the cells were also
      plated in the presence of 50 microM PD-98059, an inhibitor of the ERK-activating
      mitogen-activating kinase. Culture for 24 h with PD-98059 abolished the
      protective effect of laminin. We speculate that after hyperoxic lung injury,
      signals through the basement membrane confer specific protection against oxygen
      induced DNA strand breakage and apoptosis through an ERK activation-dependent
      pathway.

PMID- 10409244
TI  - Stretch induces cytokine release by alveolar epithelial cells in vitro.
AB  - Mechanical ventilation can injure the lung, causing edema and alveolar
      inflammation. Interleukin-8 (IL-8) plays an important role in this inflammatory
      response. We postulated that cyclic cell stretch upregulates the production and
      release of IL-8 by human alveolar epithelium in the absence of structural cell
      damage or paracrine stimulation. To test this hypothesis, alveolar epithelial
      cells (A549 cells) were cultured on a deformable silicoelastic membrane. When
      stretched by 30% for up to 48 h, the cells released 49 +/- 34% more IL-8 (P <
      0.001) than static controls. Smaller deformations (20% stretch) produced no
      consistent increase in IL-8. Stretch of 4 h duration increased IL-8 gene
      transcription fourfold above baseline. Stretch had no effect on cell
      proliferation, cell viability as assessed by (51)Cr release assay, or the release
      of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor
      alpha. We conclude that deformation per se can trigger inflammatory signaling and
      that alveolar epithelial cells may be active participants in the alveolitis
      associated with ventilator-induced lung injury.

PMID- 10409245
TI  - Regulation of gelatinases in human airway smooth muscle cells: mechanism of
      progelatinase A activation.
AB  - Matrix metalloproteinases (MMPs) play an important role in tumor metastasis and
      invasion, inflammatory tissue destruction and remodeling, wound healing, and
      angiogenesis. The 72-kDa gelatinase A is the most widely distributed of all the
      MMPs, and along with the 92-kDa gelatinase B, both play an important role in the
      turnover of basement membrane. The role of MMPs in chronic airway inflammation
      and remodeling has received scant attention. In this study, we sought to examine
      the release and activation of gelatinases from human airway smooth muscle (ASM)
      cells and the effect of tumor necrosis factor-alpha and phorbol 12-myristate 13
      acetate (PMA) on this release and activation. The role of membrane type 1 MMP
      (MT1-MMP) and tissue inhibitor of MMP (TIMP)-2 in activating progelatinase A has
      been explored. We have demonstrated, using human airway smooth muscle cells in
      culture, that 1) ASM releases gelatinase A constitutively and when stimulated
      with PMA and tumor necrosis factor-alpha releases gelatinase B, and the release
      of gelatinase B is protein kinase C dependent because it is blocked by H-7 and
      staurosporin; 2) treatment of ASM cells with PMA or concanavalin A failed to
      activate progelatinase A despite these agents increasing cell expression of MT1
      MMP; and 3) the inability of ASM cell membranes to activate progelatinase A is
      most likely secondary to the high levels of TIMP-2 on the cell membrane. In
      conclusion, our results demonstrate that human ASM cells constitutively secrete
      progelatinase A and when stimulated with proinflammatory mediators secrete
      gelatinase B. The released gelatinases A and B may be important factors in the
      airway remodeling that occurs in asthma.

PMID- 10409246
TI  - Efficient killing of inhaled bacteria in DeltaF508 mice: role of airway surface
      liquid composition.
AB  - Cystic fibrosis mice have been generated by gene targeting but show little lung
      disease without repeated exposure to bacteria. We asked if murine mucosal
      defenses and airway surface liquid (ASL) Cl(-) were altered by the DeltaF508
      cystic fibrosis transmembrane conductance regulator mutation. Naive DeltaF508 -/-
      and +/- mice showed no pulmonary inflammation and after inhaled Pseudomonas
      aeruginosa had similar inflammatory responses and bacterial clearance rates. We
      therefore investigated components of the innate immune system. Bronchoalveolar
      lavage fluid from mice killed Escherichia coli, and the microbicidal activity was
      inhibited by NaCl. Because beta-defensins are salt-sensitive epithelial products,
      we looked for pulmonary beta-defensin expression. A mouse homolog of human beta
      defensin-1 (termed "MBD-1") was identified; the mRNA was expressed in the lung.
      Using a radiotracer technique, ASL volume and Cl(-) concentration ([Cl(-)]) were
      measured in cultured tracheal epithelia from normal and DeltaF508 -/- mice. The
      estimated ASL volume was similar for both groups. There were no differences in
      ASL [Cl(-)] in DeltaF508 -/- and normal mice (13.8 +/- 2.6 vs. 17.8 +/- 5.6
      meq/l). Because ASL [Cl(-)] is low in normal and mutant mice, salt-sensitive
      antimicrobial factors, including MBD-1, may be normally active.

PMID- 10409247
TI  - Fatty acid translocase/CD36 mediates the uptake of palmitate by type II
      pneumocytes.
AB  - Type II pneumocytes, which synthesize, store, and secrete pulmonary surfactant,
      require exogenous fatty acids, in particular palmitic acid, for maximum
      surfactant synthesis. The uptake of palmitate by type II pneumocytes is thought
      to be protein mediated, but the protein involved has not been characterized. Here
      we show by RT-PCR and Northern blot analysis that rat type II pneumocytes express
      the mRNA for fatty acid translocase (FAT/CD36), a membrane-associated protein
      that is known to facilitate the uptake of fatty acids into adipocytes. The
      deduced amino acid sequence from rat type II pneumocytes reveals 98% identity to
      the FAT/CD36 sequence obtained from rat adipocytes. The uptake of palmitate by
      type II pneumocytes follows Michaelis-Menten kinetics (Michaelis-Menten constant
      = 11.9 +/- 1.8 nM; maximum velocity = 62.7 +/- 5.8 pmol. min(-1). 5 x 10(5)
      pneumocytes(-1)) and decreases reversibly under conditions of ATP depletion to
      35% of control uptake. Incubation of cells at 0 degrees C inhibited the uptake of
      palmitate almost completely, whereas depletion of potassium was without effect.
      Preincubation of the cells with bromobimane or phloretin decreases the uptake of
      palmitate significantly as does preincubation with sulfo-N-succinimidyl oleate,
      the specific inhibitor of FAT/CD36 (C. M. Harmon, P. Luce, A. H. Beth, and N. A.
      Abumrad. J. Membr. Biol. 121: 261-268, 1991). From these data, we conclude that
      FAT/CD36 is expressed in type II pneumocytes and mediates the uptake of palmitate
      in a saturable and energy-dependent manner. The data suggest that the uptake
      process is independent of the formation of coated pits and endocytotic vesicles.

PMID- 10409248
TI  - Na(+)-K(+)-ATPase gene regulation by glucocorticoids in a fetal lung epithelial
      cell line.
AB  - The Na(+) pump, Na(+)-K(+)-ATPase, along with the Na(+) channel is essential for
      the removal of alveolar solute and fluid perinatally. Because Na(+)-pump mRNA and
      activity increase before birth and maternal glucocorticoids (GCs) influence Na(+)
      K(+)-ATPase mRNA expression in fetal rat lung, we hypothesized that GCs increased
      Na(+)-K(+)-ATPase gene expression in a fetal lung epithelial cell line. After 24
      h of exposure, dexamethasone increased the steady-state levels of Na(+)-K(+)
      ATPase alpha(1) and beta(1) mRNA in a fetal rat lung epithelial cell line in a
      dose-dependent fashion (10(-7) to 10(-5) M). The maximal increase in mRNA levels
      was 3. 8-fold for alpha(1) and 2.8-fold for beta(1). The increase in mRNA was
      detected as early as 6 h for the beta(1)-subunit and 18 h for the alpha(1)
      subunit, and both peaked at 24 h. This gene upregulation was not due to increased
      mRNA stability based on mRNA half-life determination after actinomycin D
      inhibition. Transfection experiments with alpha(1) and beta(1) promoter-reporter
      constructs demonstrated 3.2 +/- 0.5- and 2.6 +/- 0.4-fold increases,
      respectively, in promoter activity, consistent with transcriptional activation of
      the promoter-reporter construct. These findings, increased promoter activity with
      no change in stability, indicate that GCs increased Na(+)-K(+)-ATPase
      transcription in a fetal lung epithelial cell line.

PMID- 10409249
TI  - Airway epithelial tight junctions and binding and cytotoxicity of Pseudomonas
      aeruginosa.
AB  - The role of tight junctions in the binding and cytoxicity of Pseudomonas
      aeruginosa to apical or basolateral membranes of lung airway epithelial cells was
      tested with fluorescence microscopy on living cells. Binding of noncytotoxic P.
      aeruginosa strain O1 was assessed with P. aeruginosa that expressed green
      fluorescent protein. Binding of cytotoxic P. aeruginosa strain 6206 was assessed
      with FITC-labeled P. aeruginosa; cytotoxicity was determined from nuclear uptake
      of the impermeant dye propidium iodide. The role of direct contact of P.
      aeruginosa to epithelial cells was tested with filters with small (0.45
      micrometer) or large (2.0-micrometer) pores. High transepithelial resistance
      (R(t)) Calu-3 and cultured bovine tracheal monolayers (R(t) > 1,000 Omega. cm(2))
      bound P. aeruginosa very infrequently (<1 P. aeruginosa/100 cells) at the apical
      membrane, but P. aeruginosa bound frequently to cells near "free edges" at holes,
      wounds, islands, and perimeters; cytotoxicity required direct interaction with
      basolateral membranes. Wounded high R(t) epithelia showed increased P. aeruginosa
      binding and cytotoxicity at the free edges because basolateral membranes were
      accessible to P. aeruginosa, and dead and living cells near the wound bound P.
      aeruginosa similarly. Compared with high R(t) epithelia, low R(t) CFT1 (R(t) =
      100-200 Omega. cm(2)) and EGTA-treated Calu-3 monolayers were 25 times more
      susceptible to P. aeruginosa binding throughout the monolayer. Cytotoxicity to
      CFT1 cells (throughout the confluent monolayer, not only at the free edge)
      occurred after a shorter delay (0.25 vs. 2.0 h) and then five times faster than
      to Calu-3 cells, indicating that the time course of P. aeruginosa cytotoxicity
      may be limited by the rate of gaining access through tight junctions and that
      this occurred faster in low R(t) than in high R(t) airway epithelia. Cytotoxicity
      appeared to occur in a sequential process that led first to a loss of fura 2 and
      a later uptake of propidium iodide. P. aeruginosa bound three times more
      frequently to regions between cells (tight junctions?) than to cell membranes of
      low R(t) CFT1 cells.

PMID- 10409250
TI  - Differential expression of platelet-derived growth factor-alpha receptor by Thy
      1(-) and Thy-1(+) lung fibroblasts.
AB  - Fibroblasts are heterogeneous with respect to surface markers, morphology, and
      participation in fibrotic responses. This study was undertaken to determine
      whether Thy-1(-) and Thy-1(+) rat lung fibroblasts, which have distinct and
      relevant phenotypes, differ in their proliferative responses to platelet-derived
      growth factor (PDGF) isoforms. Homogeneous populations of Thy-1(-) and Thy-1(+)
      fibroblasts were found to proliferate equally in the presence of PDGF-BB, but
      PDGF-AA-mediated proliferation occurred only in Thy-1(-) cells. This differential
      activity correlated with significantly higher expression of PDGF-alpha receptor
      in Thy-1(-) fibroblasts as shown by immunoblotting, immunofluorescence, and
      Northern blotting. There was a rapid increase in c-myc mRNA in Thy-1(-) but not
      in Thy-1(+) fibroblasts on stimulation with PDGF-AA and PDGF-BB. The PDGF-alpha
      receptor, which mediates signaling by all PDGF isoforms, has been implicated in
      numerous clinical and experimental forms of fibrosis and regulates lung
      morphogenesis. Differential expression of the PDGF-alpha receptor supports
      distinct roles for Thy-1(-) and Thy-1(+) fibroblast populations in developmental
      and fibrotic processes in the lung.

PMID- 10409251
TI  - Calcium metabolism before, during, and after a 3-mo spaceflight: kinetic and
      biochemical changes.
AB  - The loss of bone during spaceflight is considered a physiological obstacle for
      the exploration of other planets. This report of calcium metabolism before,
      during, and after long-duration spaceflight extends results from Skylab missions
      in the 1970s. Biochemical and endocrine indexes of calcium and bone metabolism
      were measured together with calcium absorption, excretion, and bone turnover
      using stable isotopes. Studies were conducted before, during, and after flight in
      three male subjects. Subjects varied in physical activity, yet all lost weight
      during flight. During flight, calcium intake and absorption decreased up to 50%,
      urinary calcium excretion increased up to 50%, and bone resorption (determined by
      kinetics or bone markers) increased by over 50%. Osteocalcin and bone-specific
      alkaline phosphatase, markers of bone formation, increased after flight. Subjects
      lost approximately 250 mg bone calcium per day during flight and regained bone
      calcium at a slower rate of approximately 100 mg/day for up to 3 mo after
      landing. Further studies are required to determine the time course of changes in
      calcium homeostasis during flight to develop and assess countermeasures against
      flight-induced bone loss.

PMID- 10409252
TI  - Mitochondrial protein and HSP70 signaling after ischemia in hypothermic-adapted
      hearts augmented with glucose.
AB  - Hypothermia improves resistance to subsequent ischemia in the cardioplegic
      arrested heart (CAH). This adaptive process produces mRNA elevation for heat
      shock protein (HSP) 70-1 and mitochondrial proteins, adenine nucleotide
      translocator (ANT(1)), and beta-F(1)-ATPase. Glucose in cardioplegia also
      enhances myocardial protection. These processes might be linked to reduced ATP
      depletion. To assess for synergism between these protective processes, isolated
      rabbit hearts (n = 91) were perfused at 37 degrees C and exposed to ischemic
      cardioplegic arrest for 2 h. Hearts were in four groups: control (C), hypothermia
      adapted (H) perfused to 31 degrees C 20 min before ischemia, 22 mM glucose (G) in
      cardioplegia, and hypothermic adaptation and glucose (HG). Developed pressure
      (DP), dP/dt(max), and pressure-rate product (PRP) improved (P < 0.05) in G, H,
      and HG compared with C during reperfusion. DP and PRP were elevated in HG over H
      and G. ATP was higher in G, H, and HG, although no additional increase in HG over
      H was found. Lactate and CO(2) production were elevated in G only. The mRNA
      expression for HSP70-1, ANT(1), and beta-F(1)-ATPase was elevated severalfold in
      H and HG, but not G over C during reperfusion. In conclusion, glucose provides
      additional functional improvement in H. Additionally, neither ATP levels nor
      anaerobic metabolism are linked to mRNA expression for HSP70, ANT(1), or beta
      F(1)-ATPase in CAH.

PMID- 10409253
TI  - Hypoxic hypometabolism in the anesthetized turtle, Trachemys scripta.
AB  - A hypometabolic response during acute exposure to hypoxia has been measured in
      both endothermic and ectothermic vertebrates. In the turtle, we determined the
      metabolic response to normocapnic hypoxia and hypercapnic hypoxia. In addition,
      we tested the hypothesis that hypoxic hypometabolism was a regulated response
      that did not depend on O(2) availability. Metabolic, cardiovascular, and blood
      gas measurements were collected in anesthetized turtles under two conditions:
      during normocapnic hypoxia [fractional inspired O(2) FI(O(2)) = 0.1 and 0.05] and
      during hypercapnic hypoxia [FI(O(2)) = 0.1 and 0.05 plus fractional inspired
      CO(2) (FI(CO(2))) = 0.05]. During normoxia, rate of O(2) consumption (VO(2)) was
      0.82 ml. min(-1). kg(-1) and was reduced by nearly 30% at the lowest FI(O(2)).
      Normocapnic hypoxia of FI(O(2)) = 0.1 had no significant effect on VO(2). The
      addition of 5% CO(2) to the inspired air did not enhance the effects of hypoxia.
      Injections of 2,4-dinitrophenol increased VO(2) during hypercapnic hypoxia in
      some animals to levels greater than those measured during normoxia. We conclude
      that hypoxia produces a hypometabolic state in anesthetized turtles, and the
      pharmacological stimulation of VO(2) counteracts the effects of hypoxia on
      metabolism. The hypoxic hypometabolism in turtles most likely represents a
      regulated response and does not reflect limited O(2) availability at the cellular
      level. Finally, we hypothesize that hypoxemia induced by the right-to-left
      cardiac shunt often associated with diving may trigger the development of a
      hypometabolic state and therefore contribute to the prolongation of aerobic dive
      times.

PMID- 10409254
TI  - Heterologous acclimation: a novel approach to the study of thermal acclimation in
      the crab Cancer pagurus.
AB  - The control of the attainment of acclimation in Cancer pagurus has been studied.
      Homologous (8 or 22 degrees C) and heterologous acclimation [central nervous
      system (CNS) and periphery of crabs simultaneously held at 8 or 22 degrees C]
      were used. The dependence of electrophysiological parameters of dactylopodite
      closer muscles of walking legs on nerve stimulation was determined between 6 and
      26 degrees C. Muscle resting potential (RP) hyperpolarized linearly with
      increasing measurement temperatures and showed a 69% compensation between 8 and
      22 degrees C on homologous acclimation. With the CNS temperature constant at 8
      degrees C, the leg muscle RP showed a 72% compensation on heterologous
      acclimation to 8 and 22 degrees C; when CNS temperature was constant at 22
      degrees C, leg muscle RP showed a 48% compensation on heterologous acclimation to
      8 and 22 degrees C. In homologous acclimation, the shape of the excitatory
      junction potential vs. temperature relationship was characteristic of acclimation
      temperature. In heterologous acclimation, the shape of this plot was related to
      the temperature experienced by the leg and not by the CNS. Thus acclimation was
      principally dependent on local tissue temperature and was relatively independent
      of CNS or hormonal influences.

PMID- 10409255
TI  - Hemodynamic responses to electrical stimulation of the aortic depressor nerve in
      awake rats.
AB  - Changes in mean arterial pressure (MAP), heart rate (HR), and vascular resistance
      (hindquarter and mesenteric territories) in response to electrical stimulation
      (ES) of the aortic depressor nerve (ADN) were evaluated in conscious freely
      moving rats. Platinum electrodes were implanted into the ADN of all rats studied,
      and some of these animals were also implanted with miniaturized Doppler probes
      around the superior mesenteric artery and inferior abdominal aorta (hindquarter).
      In both groups, the femoral artery and vein were catheterized one day before the
      experiments. In the first group of rats (n = 7), the control ES of the ADN in the
      range from 0.5 to 3.0 V (50 Hz, 10 ms) produced bradycardia and hypotension in an
      intensity-dependent manner, and treatment with methylatropine (intravenously)
      blocked the bradycardia but produced no significant changes in the hypotensive
      response. In a second group (n = 6), ES of the ADN was performed with the
      intensity fixed at 3 V and the frequency of the stimuli varying from 10 to 50 Hz.
      In this group, the hypotensive response was frequency dependent, whereas the
      bradycardic response was not. In a third group of rats (n = 6), ES of the ADN
      (2.5 V) produced hypotension (-35 +/- 4 mmHg), minor changes in the mesenteric
      (+5 +/- 14%), and vasodilation in hindquarter (-32 +/- 6%) vascular beds. The
      data show that 1) ES of the ADN produces a fall in pressure, bradycardia,
      vasodilation in the hindquarter, and no changes in the mesenteric vascular
      resistance, 2) methylatropine blocked the bradycardia and produced no effect on
      the hypotensive response to ES of the ADN, and 3) the baroreceptor afferent
      fibers involved in the hypotensive response to ES of ADN are sensitive to the
      variation of the frequency of the stimuli, whereas the fibers involved in the
      bradycardic response are not.

PMID- 10409256
TI  - Volume expansion does not activate neuronal projections from the NTS or depressor
      VLM to the RVLM.
AB  - We investigated whether a monosynaptic connection from the nucleus tractus
      solitarius (NTS) or the depressor ventrolateral medulla (VLM) to the pressor
      region of the rostral VLM (RVLM) constituted part of the reflex pathway activated
      by cardiopulmonary baroreceptors. Volume expansion in the conscious rabbit, which
      elicits renal nerve inhibition predominantly via cardiac mechanoreceptors, was
      used as the stimulus. The protein Fos was used as a marker of neuronal
      activation. The retrogradely transported tracer rhodamine-tagged microspheres,
      previously injected into the pressor region of the RVLM, identified medullary
      neurons that projected to that region. Volume expansion significantly increased
      the number of Fos-positive cell nuclei in the NTS and in the depressor VLM.
      Neurons that projected to the RVLM were found throughout the depressor region of
      the VLM and in the NTS but were not activated by volume expansion. Thus, although
      the central reflex pathways activated by volume expansion include the NTS and the
      depressor region of the VLM, we could not find evidence for a monosynaptic
      connection between those regions and the RVLM.

PMID- 10409257
TI  - Heat acclimation and hypohydration: involvement of central angiotensin II
      receptors in thermoregulation.
AB  - This investigation attempted to confirm the involvement of central ANG II-ergic
      signals in thermoregulation. Experiments were conducted on rats undergoing short
      (STHA)- and long (LTHA)-term heat acclimation, with and without superimposed
      hypohydration. Vasodilatation (VTsh) and salivation (STsh) temperature
      thresholds, tail blood flow, and heat endurance were measured in conscious rats
      during heat stress (40 degrees C) before and after losartan (Los), an ANG II
      AT(1)-selective receptor antagonist, administration either to the lateral
      ventricle or intravenously. Heat acclimation alone resulted in decreased VTsh.
      STsh decreased during STHA and resumed the preacclimation value, together with
      markedly increased heat endurance on LTHA. Hypohydration did not affect this
      biphasic response, although STsh was elevated in all groups. The enhanced heat
      endurance attained by LTHA was blunted. Neither Los treatment affected the
      nonacclimated rats. In the heat-acclimated, euhydrated rats,
      intracerebroventricular Los resulted in decreased VTsh, whereas intravenous Los
      resulted in elevated STsh. Both intracerebroventricular and intravenous Los led
      to markedly enhanced heat endurance of the LTHA hypohydrated rats. It is
      concluded that the LTHA group showed a loss of the benefits acquired by
      acclimation on hypohydration, whereas the STHA rats, which show an accelerated
      autonomic excitability in that phase, gained some benefit. It is suggested that
      ANG II modulates thermoregulation in conditions of chronic adjustments. Central
      ANG II signals may lead to VTsh upshift, whereas circumventricular structures,
      activated via circulating ANG II, decrease STsh. On hypohydration these responses
      seem to be desensitized.

PMID- 10409258
TI  - Effects of subfornical organ lesions on acutely induced thirst and salt appetite.
AB  - We examined the role of the subfornical organ (SFO) in stimulating thirst and
      salt appetite using two procedures that initiate water and sodium ingestion
      within 1-2 h of extracellular fluid depletion. The first procedure used
      injections of a diuretic (furosemide, 10 mg/kg sc) and a vasodilator (minoxidil,
      1-3 mg/kg ia) to produce hypotension concurrently with hypovolemia. The resulting
      water and sodium intakes were inhibited by intravenous administration of ANG II
      receptor antagonist (sarthran, 8 micrograms . kg(-1). min(-1)) or angiotensin
      converting enzyme inhibitor (captopril, 2.5 mg/h). The second procedure used
      injections of furosemide (10 mg/kg sc) and a low dose of captopril (5 mg/kg sc)
      to initiate water and sodium ingestion upon formation of ANG II in the brain.
      Electrolytic lesions of the SFO greatly reduced the water intakes, and nearly
      abolished the sodium intakes, produced by these relatively acute treatments.
      These results contrast with earlier findings showing little effect of SFO lesions
      on sodium ingestion after longer-term extracellular fluid depletion.

PMID- 10409259
TI  - Altered daily rhythms of brain and pituitary indolamines and neuropeptides in
      long-term hypoxic rats.
AB  - To determine whether sustained hypoxia alters daily rhythms in brain and
      pituitary neurotransmitters, the daily variations in vasoactive intestinal
      peptide-like immunoreactivity (VIP-LI), neuropeptide Y-like immunoreactivity (NPY
      LI), serotonin (5-HT), and 5-hydroxyindole-3-acetic acid (5-HIAA) content were
      determined in discrete brain regions, pineal gland and anterior pituitary of
      hypoxic (10% O(2); 14 days) and normoxic rats. Hypoxia suppressed daily
      variations in VIP-LI in the suprachiasmatic nuclei (SCN) and the anterior
      pituitary, enhanced the daily rhythmicity in serotonergic elements of the caudal
      part of the dorsomedial medulla oblongata (DMMc), and even induced daily
      variations in NPY-LI in the DMMc as well as in the ventrolateral medulla
      oblongata. In addition, punctual alterations in the rhythmicity of 5-HT and 5
      HIAA in the pineal gland and of plasma corticosterone were observed in hypoxic
      rats. Thus results of this study indicate that a permanent nonphotic stimulus,
      such as sustained hypoxia, may affect the functioning of the internal clock
      located in the SCN and may alter the daily rhythmicity in neurotransmitter
      content of some brain nuclei and the pituitary gland.

PMID- 10409260
TI  - Cardiovascular and neuroendocrine responses to exercise in hypoxia during
      impaired neural feedback from muscle.
AB  - Reflex mechanisms from contracting skeletal muscle have been shown to be
      important for cardiovascular, neuroendocrine, and extramuscular fuel-mobilization
      responses in exercise. Furthermore, because hypoxia results in exaggerated
      metabolic changes in contracting muscle, the present study evaluated whether
      enhancement of cardiovascular and neuroendocrine responses by hypoxia during
      exercise is influenced by neural feedback from contracting muscle. Seven healthy
      males cycled at 46% maximal O(2) uptake for 20 min both during normoxia and at
      11.5% O(2), and both without and with epidural anesthesia (EA; 20 ml 0.25%
      bupivacain, resulting in cutaneous hypesthesia below T10-T12 and 25% reduction in
      maximal leg strength). Exercise to exhaustion was also performed at 7.8% O(2).
      The exercise-induced increases in heart rate; cardiac output; leg blood flow;
      plasma concentrations of growth hormone, adrenocorticotropin, cortisol, and
      catecholamines; renin activity; glucose production and disappearance;
      norepinephrine spillover [2, 190 +/- 341 ng/min (exercise at 11.5% O(2)) vs. 988
      +/- 95 ng/min (exercise during normoxia)]; lactate release from and glucose
      uptake in the leg; and the decreases in plasma insulin and free fatty acids were
      exaggerated in hypoxia (P < 0.05). In muscle, concentrations of lactate,
      creatine, and inosine 5'-monophosphate were higher, and those of phosphocreatine
      were lower after exercise in hypoxia compared with normoxia. The exercise-induced
      increase in mean arterial blood pressure was not affected by hypoxia, but it was
      reduced by EA [108 +/- 4 mmHg (control) vs. 97 +/- 4 mmHg (EA); P < 0.05], and
      the reduction was more pronounced during severe hypoxia compared with normoxia.
      Apart from this, time to exhaustion at extreme hypoxia, circulatory responses,
      concentrations of neuroendocrine hormones, and extramuscular substrate
      mobilization were not diminished by EA. In conclusion, in essence the hypoxia
      induced enhancement of systemic adaptation to exercise is not mediated by neural
      feedback from working muscle in humans.

PMID- 10409261
TI  - Nonlinear, fractal, and spectral analysis of the EEG of lizard, Gallotia galloti.
AB  - Electroencephalogram (EEG) from dorsal cortex of lizard Gallotia galloti was
      analyzed at different temperatures to test the presence of fractal or nonlinear
      structure during open (OE) and closed eyes (CE), with the aim of comparing these
      results with those reported for human slow-wave sleep (SWS). Two nonlinear
      parameters characterizing EEG complexity [correlation dimension (D2)] and
      predictability [largest Lyapunov exponent (lambda(1))] were calculated, and EEG
      spectrum and fractal exponent beta were determined via coarse graining spectral
      analysis. At 25 degrees C, evidence of nonlinear structure was obtained by the
      surrogate data test, with EEG phase space structure suggesting the presence of
      deterministic chaos (D2 approximately 6, lambda(1) approximately 1. 5). Both
      nonlinear parameters were greater in OE than in CE and for the right hemisphere
      in both situations. At 35 degrees C the evidence of nonlinearity was not
      conclusive and differences between states disappeared, whereas interhemispheric
      differences remained for lambda(1). Harmonic power always increased with
      temperature within the band 8-30 Hz, but only with OE within the band 0.3-7.5 Hz.
      Qualitative similarities found between lizard and human SWS EEG support the
      hypothesis that reptilian waking could evolve into mammalian SWS.

PMID- 10409262
TI  - In vivo regulation of plasma platelet-activating factor acetylhydrolase during
      the acute phase response.
AB  - Plasma platelet-activating factor acetylhydrolase (PAF-AH) hydrolyzes PAF and
      oxidized phospholipids and is associated with lipoproteins in the circulation.
      Endotoxin [lipopolysaccharide (LPS)], a potent inducer of the acute phase
      response (APR), produces marked changes in several proteins that play important
      roles in lipoprotein metabolism. We now demonstrate that LPS produces a 2.5- to 3
      fold increase in plasma PAF-AH activity in Syrian hamsters. The plasma PAF-AH
      activity is found in the high-density lipoprotein (HDL) fraction and is increased
      threefold with LPS treatment despite a decrease in plasma HDL levels, indicating
      that plasma PAF-AH activity is increased per HDL particle. LPS markedly increased
      PAF-AH mRNA levels in liver, spleen, lung, and small intestine. The maximal
      increase in plasma PAF-AH activity and mRNA expression in liver and spleen is
      seen 24 h after LPS treatment. Both tumor necrosis factor and interleukin-1
      modestly increased plasma PAF-AH activity and mRNA levels in liver and spleen,
      suggesting that they may partly mediate the effect of LPS on PAF-AH. Surgical
      removal of spleen had no effect on basal or LPS-induced plasma PAF-AH activity,
      suggesting that spleen per se may not contribute to plasma PAF-AH activity.
      Finally, LPS, turpentine and zymosan increased plasma PAF-AH activity in mice
      and/or rats, indicating that multiple APR inducers upregulate plasma PAF-AH and
      this effect is consistent across different rodent species. Taken together, our
      results indicate that plasma PAF-AH activity and mRNA expression is markedly
      upregulated during the host response to infection and inflammation. An increase
      in plasma PAF-AH may enhance the degradation of PAF as well as alter the
      structure and function of HDL during infection and inflammation.

PMID- 10409263
TI  - Role of angiotensin II in modulating the hemodynamic effects of nitric oxide
      synthesis inhibition.
AB  - This study examined the role of ANG II in modulating the increase of hematocrit
      and vascular permeability that follows nitric oxide (NO) synthesis blockade, that
      are contributing to the decrease in cardiac index (CI) in conscious, chronically
      catheterized rats. Pretreatment with losartan attenuated the N(omega)-nitro-L
      arginine methyl ester (L-NAME)-induced increase in total peripheral resistance by
      26% and also blunted the fall in CI (28%) and stroke volume. L-NAME produced an
      increase in hematocrit (4.5%) and in (125)I-labeled albumin content in the heart
      and small intestine in untreated rats, but the increase was prevented in rats
      pretreated with losartan. Furthermore, L-NAME induced a transient increase of
      plasma protein concentration and tissue intestinal blood flow, which was
      abolished in rats given losartan. The results of the present study indicate that
      the systemic hemodynamic responses, the fall in plasma volume, and the increase
      in albumin escape observed after inhibition of NO synthesis are in part the
      consequence of unmasking the actions of endogenous ANG II. These data suggest a
      physiological role for NO by restraint of the vascular actions of the renin
      angiotensin system.

PMID- 10409264
TI  - Renal medullary interstitial infusion of norepinephrine in anesthetized rabbits:
      methodological considerations.
AB  - We tested methods for delivery of drugs to the renal medulla of anesthetized
      rabbits. Outer medullary infusion (OMI) of norepinephrine (300 ng. kg(-1). min(
      1)), using acutely or chronically positioned catheters, reduced both cortical
      (CBF; 15%) and medullary perfusion (MBF; 23-31%). Inner medullary infusion (IMI)
      did not affect renal hemodynamics, whereas intravenous infusion reduced CBF (15%)
      without changes in MBF. During OMI of [(3)H]norepinephrine, much of the
      radiolabel (approximately 40% with chronically positioned catheters) spilled over
      systemically. Nevertheless, autoradiographic analysis showed the concentration of
      radiolabel was about fourfold greater in the infused medulla than the cortex. In
      contrast, during IMI, only approximately 5% of the infused radiolabel spilled
      over into the systemic circulation and approximately 64% was excreted by the
      infused kidney. The resultant intrarenal levels of radiolabel were considerably
      less with IMI compared with OMI. In rabbits, OMI therefore provides a useful
      method for targeting agents to the renal medulla, but given the considerable
      systemic spillover with OMI, its utility is probably limited to substances that
      are rapidly degraded in vivo.

PMID- 10409265
TI  - Chemical composition of saccular endolymph and otolith in fish inner ear: lack of
      spatial uniformity.
AB  - Fish otoliths provide a record of age, growth, and environmental influences. In
      both trout and turbot, spatial chemical investigation of the endolymph
      surrounding the otolith (sagitta) showed a lack of uniformity. Proteins, PO(3
      )(4), and Mg(2+) were significantly more concentrated in the proximal (facing the
      macula) than distal zone, whereas the opposite was observed for K(+) and total
      CO(2) (totCO(2)). Na(+) concentration ([Na(+)]) was 20% higher in the proximal
      zone in trout but not in turbot. Total Ca and Cl(-) contents were uniformly
      distributed in both species. We propose that the endolymphatic gradients of
      protein and totCO(2) concentration within the endolymph are involved in the
      otolithic biocalcification process. Microchemical analyses of otolith sections by
      wavelength dispersive spectrometry showed a lack of spatial uniformity in the
      K/Ca and Na/Ca ratios, whereas the Sr/Ca ratio was uniform. There is a clear
      relationship between endolymph and otolith [K(+)], but the interpretation of the
      results for [Na(+)] needs further investigation. Thus the lack of uniformity in
      the otolith composition must be taken into account when investigating otolith
      microchemistry.

PMID- 10409266
TI  - Transcriptional and posttranscriptional regulation of beta(2)-adrenergic receptor
      gene in rat liver during sepsis.
AB  - Changes in beta(2)-adrenergic receptor (beta(2)-AR) gene expression in the rat
      liver during different phases of sepsis were studied. Sepsis was induced by cecal
      ligation and puncture (CLP). Septic rats exhibit two metabolically distinct
      phases: an initial hyperglycemic (9 h after CLP; early sepsis) followed by a
      hypoglycemic phase (18 h after CLP; late sepsis). The [(3)H]dihydroalprenolol
      binding studies show that the density of beta(2)-AR was decreased by 12 and 35%
      during the early and late phases of sepsis, respectively. Western blot analyses
      depict that the beta(2)-AR protein level was reduced by 37 and 72% during early
      and late sepsis, respectively. The reverse transcription polymerase chain
      reaction and Southern blot analyses reveal that the steady-state level of beta(2)
      AR mRNA was decreased by 37% during early phase and 77% during late phase of
      sepsis. Nuclear run-off assays show that the rate of transcription of beta(2)-AR
      mRNA was reduced by 36% during early sepsis and 64% during late sepsis. The
      stability assays indicate that the half-life of beta(2)-AR mRNA was shortened by
      21 and 50% during the early and late phases of sepsis, respectively, indicating
      that the rate of degradation of beta(2)-AR mRNA was progressively enhanced during
      sepsis. These findings demonstrate that the beta(2)-AR gene was underexpressed in
      the liver during the progression of sepsis, and, furthermore, the underexpression
      of the beta(2)-AR gene was the result of a reduction in the rate of transcription
      coupled with an enhancement in the rate of degradation of beta(2)-AR gene
      transcripts. Thus our findings that the transcriptional and posttranscriptional
      regulation of beta(2)-AR gene associated with decreases in beta(2)-AR number and
      its protein expression may provide a molecular mechanistic explanation for the
      development of hypoglycemia during the late stage of sepsis.

PMID- 10409267
TI  - Neuronal uptake affects dynamic characteristics of heart rate response to
      sympathetic stimulation.
AB  - Recently, studies in our laboratory involving the use of a Gaussian white noise
      technique demonstrated that the transfer function from sympathetic stimulation
      frequency to heart rate (HR) response showed dynamic characteristics of a second
      order low-pass filter. However, determinants for the characteristics remain to be
      established. We examined the effect of an increase in mean sympathetic
      stimulation frequency and that of a blockade of the neuronal uptake mechanism on
      the transfer function in anesthetized rabbits. We found that increasing mean
      sympathetic stimulation frequency from 1 to 4 Hz significantly (P < 0.01)
      decreased the dynamic gain of the transfer function without affecting other
      parameters, such as the natural frequency, lag time, or damping coefficient. In
      contrast, the administration of desipramine (0.3 mg/kg iv), a neuronal uptake
      blocking agent, significantly (P < 0.01) decreased both the dynamic gain and the
      natural frequency and prolonged the lag time. These results suggest that the
      removal rate of norepinephrine at the neuroeffector junction, rather than the
      amount of available norepinephrine, plays an important role in determining the
      low-pass filter characteristics of the HR response to sympathetic stimulation.

PMID- 10409268
TI  - Differential regulation of functional responses by beta-adrenergic receptor
      subtypes in brown adipocytes.
AB  - Brown adipose tissue contains both beta(1)- and beta(3)-adrenergic receptors
      (beta-ARs), and whereas both receptor subtypes can activate adenylyl cyclase,
      recent studies suggest that these subtypes have different pharmacological
      properties and may serve different signaling functions. In this study, primary
      brown adipocyte cultures were used to determine the role of beta-AR subtypes in
      mediating lipolysis and uncoupling protein-1 (UCP1) gene expression, elicited by
      the physiological neurohormone norepinephrine (NE). NE increased both lipolysis
      and UCP1 mRNA levels in brown adipocyte cultures; the beta(1)-receptor-selective
      antagonist CGP-20712A strongly antagonized the increase in UCP1 gene expression
      but had little effect on lipolysis. The beta(3)-receptor-selective agonist CL
      316243 (CL) also increased lipolysis and UCP1 mRNA levels, yet CL was more potent
      in stimulating lipolysis than UCP1 gene expression. NE also increased the
      phosphorylation of cAMP response element-binding protein (CREB) and perilipin
      (PL), both of which are protein kinase A substrates that are differentially
      targeted to the nucleus and lipid droplets, respectively. beta(1)-receptor
      blockade inhibited NE-stimulated phosphorylation of CREB but not PL. The results
      suggest that beta-AR subtypes regulate different physiological responses
      stimulated by NE in brown adipocyte cultures in part by differentially
      transducing signals to subcellular compartments.

PMID- 10409269
TI  - Molecular and functional evidence for Na(+)-K(+)-2Cl(-) cotransporter expression
      in rat skeletal muscle.
AB  - Doubt has been raised about the expression of a functional Na(+)-K(+)-2Cl(-)
      cotransporter in rat skeletal muscle. In this study we present molecular and
      functional evidence for expression of a protein having the characteristics of a
      cotransporter. RT-PCR of RNA isolated from rat soleus muscle with primers to a
      conserved putative membrane-spanning domain resulted in a single product of
      predicted size. Sequencing of the product showed that it bears >90% homology with
      known rodent NKCC1 (BSC2) cotransporters. RNase protection assay of RNA isolated
      from the rat soleus muscle also identified this sequence. Immunologic detection
      of the cotransporter with two different antibodies indicated the presence of
      cotransporter protein, perhaps more than one, in blots of total muscle protein.
      Immunohistochemical detection by confocal microscopy localized the majority of
      expression of the protein to the muscle fibers. Functional studies of cotransport
      activity also indicate the appropriate sensitivity to inhibitors and ion
      dependence. Taken together, these data support the presence and function of Na(+)
      K(+)-2Cl(-) cotransporter activity in the soleus muscle of the rat.

PMID- 10409270
TI  - Intracerebroventricular infusion of angiotensin II increases water and ethanol
      intake in rats.
AB  - The influence of prolonged ingestion of ethanol on stimulation of water or
      ethanol intake by intracerebroventricular infusion of ANG II was evaluated in
      rats. Animals were maintained for 5-6 mo with either 10% ethanol solution or
      water as their only source of fluid. In both groups of rats, infusion of ANG II
      caused a large increase in water intake (7-fold) and a lesser increase in 10%
      ethanol intake (2-fold). The effect of ANG II on the volume of ethanol solution
      ingested, however, was inversely related to the concentration of the ethanol
      solution. As the concentration of ethanol solution was decreased, frequency and
      duration of drinking bouts increased. The intake of sweetened 10% ethanol
      solution or commercially produced wine during infusion of ANG II was similar to
      the intake of 10% ethanol and not related to taste preference. In conclusion,
      chronic consumption of ethanol solution did not appear to adversely effect ANG II
      stimulation of water intake. The intake of ethanol solution during infusion of
      ANG II was inhibited by a direct effect of ingested ethanol and/or by indirect
      effect from metabolized ethanol.

PMID- 10409271
TI  - Myoglobin desaturation with exercise intensity in human gastrocnemius muscle.
AB  - The present study evaluated whether intracellular partial pressure of O(2)
      (PO(2)) modulates the muscle O(2) uptake (VO(2)) as exercise intensity increased.
      Indirect calorimetry followed VO(2), whereas nuclear magnetic resonance (NMR)
      monitored the high-energy phosphate levels, intracellular pH, and intracellular
      PO(2) in the gastrocnemius muscle of four untrained subjects at rest, during
      plantar flexion exercise with a constant load at a repetition rate of 0.75, 0.92,
      and 1.17 Hz, and during postexercise recovery. VO(2) increased linearly with
      exercise intensity and peaked at 1.17 Hz (15. 1 +/- 0.37 watts), when the
      subjects could maintain the exercise for only 3 min. VO(2) reached a peak value
      of 13.0 +/- 1.59 ml O(2). min(-1). 100 ml leg volume(-1). The (31)P spectra
      indicated that phosphocreatine decreased to 32% of its resting value, whereas
      intracellular pH decreased linearly with power output, reaching 6.86. Muscle ATP
      concentration, however, remained constant throughout the exercise protocol. The
      (1)H NMR deoxymyoglobin signal, reflecting the cellular PO(2), decreased in
      proportion to increments in power output and VO(2). At the highest exercise
      intensity and peak VO(2), myoglobin was approximately 50% desaturated. These
      findings, taken together, suggest that the O(2) gradient from hemoglobin to the
      mitochondria can modulate the O(2) flux to meet the increased VO(2) in exercising
      muscle, but declining cellular PO(2) during enhanced mitochondrial respiration
      suggests that O(2) availability is not limiting VO(2) during exercise.

PMID- 10409272
TI  - Nitric oxide differentially attenuates microvessel response to hypoxia and
      hypercapnia in injured lungs.
AB  - The issue of whether the acinar microvessel response to alveolar hypoxia and
      hypercapnia is impaired in injured lungs has not been vigorously addressed,
      despite the importance of knowing whether it is or not when treating patients
      with serious lung injury in terms of permissive hypercapnia. Applying a real-time
      laser confocal luminescence microscope, we studied hypoxia- and hypercapnia
      induced changes in the diameter of the intra-acinar arterioles, venules, and
      capillaries of isolated rat lungs harvested from animals exposed for 48 h to 21%
      O(2) (group N) or 90% O(2) (group H). Measurements were made with and without
      inhibition of nitric oxide (NO) synthase (NOS) by N(omega)-nitro-L-arginine
      methyl ester or of cyclooxygenase (COX) by indomethacin at different basal
      vascular tones evoked by thromboxane A(2) (TXA(2)) analog. Hypoxia in the absence
      of TXA(2) contracted arterioles in group N but not in group H. Attenuated hypoxia
      induced arteriole constriction was restored almost fully by inhibiting NOS and
      partially by inhibiting COX. Hypercapnia induced venule dilation in group N, but
      did not dilate venules in group H, irrespective of TXA(2). NOS inhibition in
      hypercapnia unexpectedly enhanced venule and arteriole dilation in group H. These
      responses no longer occurred when NOS and COX were inhibited simultaneously. In
      conclusion, microvessel reactions to hypoxia and hypercapnia are abnormal in
      hyperoxia-injured acini, in which NO directly attenuates hypoxia-induced
      arteriole constriction, whereas COX inhibited by excessive NO impedes hypercapnia
      induced microvessel dilation.

PMID- 10409274
TI  - Early phase insulin infusion and muscarinic blockade in obese and lean subjects.
AB  - The effect of early phase insulin on postprandial levels of insulin, C-peptide,
      glucose, and glucagon was investigated in lean (n = 10) and obese (n = 12)
      subjects. Subjects underwent four conditions during ingestion of a meal (600
      kcal): 1) saline infusion; 2) 10-min insulin infusion simultaneously with meal
      ingestion (0.24 U bolus, 15 mU. m(-2). min(-1)); 3) atropine infusion (0.4
      mg/m(2) bolus, 0.4 mg. m(-2). h for 4 h); 4) insulin and atropine infusion. Blood
      samples were taken for 3.5 h. Insulin infusion had no effect on postprandial
      insulin levels in either population but significantly reduced postprandial
      glucose in the obese subjects (P < 0.05). Obese subjects with elevated
      postprandial glucose levels in the presence of muscarinic blockade exhibited a
      decline in glucose with insulin supplementation. Atropine reduced postprandial
      insulin levels in both groups, with a greater attenuation in the obese (P <
      0.01), but postprandial glucose levels were also significantly reduced,
      suggesting that atropine inhibited gastric emptying. Thus the effects of
      muscarinic blockade on postprandial insulin levels cannot be evaluated. These
      data suggest that insulin supplementation during the preabsorptive time period
      may contribute to glucoregulation in the obese population.

PMID- 10409273
TI  - Pulmonary artery endothelium-dependent vasodilation is impaired in a chicken
      model of pulmonary hypertension.
AB  - Among chicken strains, broilers are prone to pulmonary hypertension, whereas
      Leghorns are not. Relaxations to endothelium-dependent (ACh, A23187) and
      endothelium-independent [sodium nitroprusside (SNP), papaverine (PPV)]
      vasodilators were compared in preconstricted pulmonary artery (PA) rings from
      these chicken strains. ACh (10(-7), 10(-6), and 10(-5) M)- and A23187 (10(-6) and
      10(-5.5) M)-induced relaxations were smaller (P < 0.05) in broilers than
      Leghorns. N(G)-nitro-L-arginine methyl ester (10(-3.5) M) caused similar
      reductions in ACh-induced relaxations in both strains. L-Arginine (10(-4) M)
      enhanced ACh-induced relaxations more in broilers than Leghorns. Relaxations to
      10(-10)-10(-6) M SNP did not differ between strains, but were greater (P < 0.05)
      in broilers than Leghorns at higher concentrations (10(-5) and 10(-4) M). PPV
      (10(-4) M)- and SNP (10(-4) M)-induced maximal relaxations were greater in
      broilers than in Leghorns (176.2 +/- 14.7 vs. 120.9 +/- 14.7% and 201.3 +/- 7.8
      vs. 171.2 +/- 10.7%, respectively, P < 0.05). Broiler PA rings appear to have
      increased intrinsic tone and reduced endothelium-derived nitric oxide activity,
      both of which may contribute to the susceptibility of broiler chickens to
      pulmonary hypertension.

PMID- 10409275
TI  - Impaired osmoregulatory responses in rats with area postrema lesions.
AB  - Area postrema lesions (APX) in adult male rats produced a robust spontaneous
      intake of 0.5 M NaCl, as reported previously. The largest NaCl intakes (up to 108
      ml/day) were observed when there was little incidental damage in the medial
      subnucleus of the nucleus of the solitary tract adjacent to the caudal and middle
      portions of the area postrema. Rats with discrete APX also drank substantial
      amounts of 0.5 M NaCl when access to saline was restricted to 7 h/day (up to 30
      ml in 1 h, 48 ml in 7 h). Such large NaCl intakes stimulated considerable water
      ingestion and renal sodium excretion, but together these responses usually were
      insufficient for osmoregulation during the 7-h test period. After systemic
      administration of hypertonic NaCl solution, rats with APX excreted less Na(+) in
      urine and secreted less vasopressin and oxytocin than control rats did. The
      prominent salt appetite, insufficient thirst and natriuresis in response to an
      ingested NaCl load, and blunted natriuresis and neurohypophysial hormone
      secretion in response to an injected NaCl load, all indicate that osmoregulatory
      responses are impaired in rats after APX.

PMID- 10409276
TI  - Transmural pressure inhibits prorenin processing in juxtaglomerular cell.
AB  - Pressure control of renin secretion involves a complex integration of shear
      stress, stretch, and transmural pressure (TP). This study was designed to
      delineate TP control of renin secretion with minimal influence of shear stress or
      stretch and to determine its mechanism. Rat juxtaglomerular (JG) cells were
      applied to a TP-loading apparatus for 12 h. In cells conditioned with atmospheric
      pressure or atmospheric pressure + 40 mmHg, renin secretion rate (RSR) averaged
      29.6 +/- 3.7 and 14.5 +/- 3.3% (P < 0.05, n = 8 cultures), respectively, and
      active renin content (ARC) averaged 47.3 +/- 4.6 and 38.4 +/- 3.4 ng of ANG I. h(
      1). million cells(-1) (P < 0.05, n = 10 cultures), respectively. Total renin
      content and renin mRNA levels were unaffected by TP. The TP-induced decrease in
      RSR was prevented by Ca(2+)-free medium and the Ca(2+) channel blocker verapamil
      and was attenuated by thapsigargin and caffeine, which deplete intracellular
      Ca(2+) stores. Thapsigargin and caffeine, but not Ca(2+)-free medium or
      verapamil, prevented TP-induced decreases in ARC. The adenylate cyclase activator
      forskolin did not modulate TP-induced decreases in RSR or ARC. These findings
      suggest that TP not only stimulates Ca(2+) influx but also inhibits prorenin
      processing through an intracellular Ca(2+) store-dependent mechanism and thus
      inhibits active renin secretion by JG cells.

PMID- 10409277
TI  - Mechanisms of inhibition of vasopressin release during moderate antiorthostatic
      posture change in humans.
AB  - The hypothesis was tested that the carotid baroreceptor stimulation caused by a
      posture change from upright seated with legs horizontal (Seat) to supine (Sup)
      participates in the suppression of arginine vasopressin (AVP) release. Ten
      healthy males underwent this posture change for 30 min without or with
      simultaneous application of lower body negative pressure (LBNP) adjusted to
      maintain left atrial diameter (LAD) at the Seat level. Throughout Sup, mean
      arterial pressure and heart rate decreased from 98 +/- 2 to 91 +/- 2 mmHg and
      from 63 +/- 2 to 55 +/- 2 beats/min (P < 0.05), respectively, whereas the
      corresponding decreases during Sup + LBNP were attenuated and of shorter duration
      (98 +/- 2 to 93 +/- 2 mmHg and 62 +/- 2 to 58 +/- 3 beats/min, P < 0.05). During
      Sup, LAD increased from 30 +/- 1 to 33 +/- 1 mm, and arterial pulse pressure (PP)
      increased from 40 +/- 2 to 47 +/- 2 mmHg, whereas plasma AVP decreased from 0.9
      +/- 0.2 to 0.5 +/- 0.1 pg/ml (P < 0.05), and plasma norepinephrine (NE) decreased
      from 176 +/- 20 to 125 +/- 16 pg/ml (P < 0.05). During Sup + LBNP, there were no
      changes in LAD, PP, plasma AVP, or NE. In conclusion, vasopressin secretion is
      suppressed during an antiorthostatic posture change, which increases carotid
      sinus pressure, PP, and LAD. The suppression is absent when PP and LAD are
      prevented from increasing and is thus critically dependent on at least one of
      these stimuli.

PMID- 10409278
TI  - Regulatory response of intramembranous absorption of amniotic fluid to infusion
      of exogenous fluid in sheep.
AB  - Six fetal sheep were operated on at 118 to 121 days of gestation. The pulmonary
      end of the trachea was connected to the gastric end of the esophagus with a
      section of tubing. This left urine as the only source of amniotic fluid and
      intramembranous absorption as sole exit. Multiple indwelling fetal vascular,
      intra-amniotic, allantoic, and a fetal bladder catheter were placed. Beginning 5
      days after surgery, all urine was drained from the bladder and immediately
      reinfused into the amniotic sac to monitor urine production rate. After 4 days of
      urine infusion alone, the urine infusion was augmented for 6 days with an intra
      amniotic infusion of Ringer solution. Amniotic and allantoic fluid volumes were
      measured at autopsy. During the period of Ringer infusion, intramembranous
      absorption of amniotic fluid increased by more than 1,191 +/- 186 (SE) ml/day (P
      < 0.002) and the rates of Na(+) and Cl(-) absorption increased to more than five
      times (P < 0.005) and eight times (P < 0.005) their initial values. Only one of
      six fetuses had polyhydramnios. It is concluded that intramembranous absorption
      of amniotic fluid makes a strong regulatory adjustment in response to an abnormal
      increase in inflow of exogenous fluid.

PMID- 10409279
TI  - Large-magnitude, transient, bradycardic events in rabbits.
AB  - We propose that heart period sequences are organized similarly to sentences, with
      a lexicon of recurrent, similarly shaped words. These words should fulfill four
      criteria: universality, nonrandomness, central statistical tendencies, and
      specific associated physiology. Here we describe a large-magnitude, transient
      bradycardia (LMTB) and assess whether it constitutes a word. LMTBs were seen in
      11 of 12 adult female rabbits. All shape parameters were different than those of
      the beat-randomized and phase-randomized surrogate sequences (P < 0.05-0.001).
      LMTBs were 8. 4 +/- 2.9 beats and 2.64 +/- 0.87 s long and were characterized by
      bradycardia of 77 +/- 49 ms over 1.09 +/- 0.49 s with a recovery to baseline over
      1.56 +/- 0.61 s. The LMTBs had a slower recovery than onset in 9 of 11 rabbits
      and were highly peaked in 10 of 11 rabbits (P < 0.05). Scalar, magnitude, and
      shape parameters had values with central statistical tendencies. About 76% of
      LMTBs were accompanied by hypotension (mean -6.1 +/- 3.9 mmHg) that lagged 2
      beats behind the onset of the bradycardia and that correlated with the
      bradycardia (-10.5 +/- 4.1 ms/mmHg). Thus transient bradycardic events are a
      distinct "word" in the lexicon of heart rate variability.

PMID- 10409280
TI  - Effects of dorsomedial hypothalamic nuclei lesions on intake of an imbalanced
      amino acid diet.
AB  - Within 3 h of ingesting an imbalanced amino acid diet (Imb), rats show attenuated
      intake, which can be ameliorated by prior administration of the serotonin
      receptor antagonist tropisetron (Trop). Earlier work in which the dorsomedial
      hypothalamic nucleus (DMN) was electrolytically lesioned (DMNL) determined that
      this structure plays a role in the early detection of and subsequent adaptation
      to Imb. However, that study did not address whether cell bodies in the DMN,
      fibers of passage, or both were involved in the DMNL response to Imb. In the
      present investigation in experiment 1, rats were given electrolytic DMNL or a
      sham operation (Sham). The rats were injected with saline (Sal) or Trop just
      before introduction of Imb. By 3 h Sal-DMNL rats consumed more Imb than did the
      Sal-Sham rats; intake was normal by 12 h. Trop enhanced Imb intake, with Trop and
      DMNL being additive. By day 4 the DMNL rats were eating and gaining weight less
      than were Sham rats. In experiment 2, DMN cell bodies were destroyed by ibotenic
      acid (Ibo). Sal-injected Ibo-lesioned and Sham rats showed similar food intake
      depression on Imb; Trop similarly increased Imb intake in both groups. By day 4
      both Ibo-L rats were eating and gaining weight less than were Sham rats. In
      experiment 3, groups of rats were given knife cuts posterior, lateral, ventral,
      dorsal, or anterior to the DMN. During the first 3 h of consuming Imb, all cuts
      except posterior enhanced the intake of Imb. Over the next 24 h the anterior cut
      group continued to eat more Imb than did the Sham rats. In experiment 4 DMNL rats
      were given novel diets; the DMNL rats did not display a neophilic response. The
      data suggest that fiber tracts that pass through the DMN may be involved in the
      early detection of Imb. DMN cell bodies, or fibers of passage, are not involved
      in the Trop effect. Finally, DMN cell bodies are necessary for proper long-term
      adaptation to Imb.

PMID- 10409281
TI  - Altered formation and bulk absorption of cerebrospinal fluid in FGF-2-induced
      hydrocephalus.
AB  - Upregulation of certain growth factors in the central nervous system can alter
      brain fluid dynamics. Hydrocephalus was produced in adult Sprague-Dawley rats by
      infusing recombinant basic fibroblast growth factor (FGF-2) at 1 microg/day into
      a lateral ventricle for 2, 3, 5, or 10-12 days. Lateral and third ventricular
      enlargement progressively increased from 2 to 10 days. Ventriculomegaly was also
      induced by a 75% reduced dose of FGF-2. At 10-12 days, there was a 29%
      attenuation in cerebrospinal fluid (CSF) formation rate, from 2. 5 to 1.8
      microliter/min (P < 0.01). Choroid plexus, the main site of CSF secretion, had an
      augmented number of dark epithelial cells, which have previously been associated
      with decreased choroidal fluid formation. The twofold elevated resistance to CSF
      absorption, i.e., 0.8 to 1.7 mmHg. min(-1). microliter(-1), was attributable, at
      least in part, to enhanced fibrosis and collagen deposits in the arachnoid villi,
      a major site for CSF absorption. Normal CSF pressure (2-3 mmHg) was consistent
      with a patent cerebral aqueduct and reduced CSF formation rate. The FGF-2-induced
      ventriculomegaly is interpreted as an ex vacuuo hydrocephalus brought about by an
      altered neuropil and interstitium of the brain.

PMID- 10409282
TI  - Pseudoaffective cardioautonomic responses to gastric distension in rats.
AB  - We examined the heart rate response to gastric distension, the involvement of
      vagal and sympathetic sensory afferents, adrenergic and cholinergic neural
      pathways, and the effects of capsaicin on this response in anesthetized rats.
      Gastric distension volume dependently decreased heart rate by 24.5% (resting rate
      = 219.87 +/- 14.06 beats/min, mean rate during gastric distension with 15 ml =
      165.97 +/- 17.36 beats/min, P < 0.05). The bradycardic response was significantly
      decreased after removal of the celiac plexus (9.71 +/- 1.77 vs. 38.03 +/- 7.06%
      in controls, P < 0.05) or after bilateral subdiaphragmatic vagotomy (6.38 +/-
      2.65%, P = 0.05). The response to gastric distension was largely prevented by
      systemic capsaicin (29.92 +/- 4.93% in controls, 2.58 +/- 4.19% after systemic
      capsaicin, P < 0.05) and decreased by perivagal capsaicin (18.72 +/- 4.75%, P <
      0.05). Atropine almost completely prevented the cardiac response to distension,
      while propranolol and bretylium partially blocked it, implying the response is
      primarily mediated by cholinergic efferents but also involves adrenergic
      pathways. We conclude that unmyelinated, capsaicin-sensitive vagal afferents are
      essential to the pseudoaffective cardioautonomic response to a noxious gastric
      stimulus.

PMID- 10409283
TI  - Reduced sensitivity to the satiation effect of intestinal oleate in rats adapted
      to high-fat diet.
AB  - When rats are maintained on high-fat diets, digestive processes adapt to provide
      for more efficient digestion and absorption of this nutrient. Furthermore, rats
      fed high-fat diets tend to consume more calories and gain more weight than rats
      on a low-fat diet. We hypothesized that, in addition to adaptation of digestive
      processes, high-fat maintenance diets might result in reduction of sensitivity to
      the satiating effects of fat digestion products, which inhibit food intake by
      activating sensory fibers in the small intestine. To test this hypothesis we
      measured food intake after intestinal infusion of oleic acid or the
      oligosaccharide maltotriose in rats maintained on a low-fat diet or one of three
      high-fat diets. We found that rats fed high-fat diets exhibited diminished
      sensitivity to satiation by intestinal infusion of oleic acid. Sensitivity to the
      satiation effect of intestinal maltotriose infusion did not differ between groups
      maintained on the various diets. Reduced sensitivity to oleate infusion was
      specifically dependent on fat content of the diet and was not influenced by the
      dietary fiber or carbohydrate content. These results indicate that diets high in
      fat reduce the ability of fat to inhibit further food intake. Such changes in
      sensitivity to intestinal fats might contribute to the increased food intake and
      obesity that occur with high-fat diet regimens.

PMID- 10409284
TI  - Role of Ca(2+) channels in NE-induced increase in [Ca(2+)](i) and tension in
      fetal and adult cerebral arteries.
AB  - In vascular smooth muscle, elevation of agonist-induced intracellular Ca(2+)
      concentration ([Ca(2+)](i)) occurs via both Ca(2+) release from intracellular
      stores and Ca(2+) influx across the plasma membrane. In the cerebral vasculature
      of the fetus and adult the relative roles of these mechanisms have not been
      defined. To test the hypothesis that plasma membrane L-type and receptor-operated
      Ca(2+) channels play a key role in NE-induced vasoconstriction via alterations in
      plasma membrane Ca(2+) flux and that this may change with developmental age, we
      performed the following study. In main branch middle cerebral arteries (MCA) from
      near-term fetal ( approximately 140 days) and nonpregnant adult sheep, we
      quantified NE-induced responses of vascular tension and [Ca(2+)](i) (by use of
      fura 2) under standard conditions in response to several Ca(2+) channel blockers
      and in response to zero extracellular Ca(2+). In fetal and adult MCA, maximal NE
      induced tensions (g) were 0.91 +/- 0.12 (n = 10) and 1.61 +/- 0.13 (n = 12),
      respectively. The pD(2) values for NE-induced tension were both 6.0 +/- 0.1,
      whereas the fetal and adult maximum responses (%K(max)) were 107 +/- 16 and 119
      +/- 7, respectively. The fetal and adult pD(2) values for NE-induced increase of
      [Ca(2+)](i) were 6.2 +/- 0.1 and 6.4 +/- 0.1, respectively, whereas maximum
      [Ca(2+)](i) responses were 81 +/- 9 and 103 +/- 15% of K(max), respectively.
      After 10(-5) M NE-induced contraction, nifedipine resulted in dose-dependent
      decrease in vessel tone and [Ca(2+)](i) with pIC(50) values for fetal and adult
      tensions of 7.3 +/- 0.1 and 6.6 +/- 0.1, respectively (P < 0.01; n = 4 each),
      whereas pIC(50) for [Ca(2+)](i) responses were 7.2 +/- 0.1 and 6.9 +/- 0.1,
      respectively. The pIC(50) values for tension for diltiazem and verapamil were
      somewhat lower but showed a similar relationship. The receptor-operated Ca(2+)
      channel blocker 2-nitro-4 carboxyphenyl-N,N-diphenyl carbamate showed little
      effect on NE-induced vessel contractility or [Ca(2+)](i). In the absence of
      extracellular Ca(2+) for 2 min, 10(-5) M NE resulted in markedly attenuated
      responses of adult MCA tension and [Ca(2+)](i) to 39 +/- 7 and 73 +/- 8% of
      control values (n = 4). For fetal MCA, exposure to extracellular Ca(2+)
      concentration resulted in essentially no contractile or [Ca(2+)](i) response (n =
      4). Similar blunting of NE-induced tension and [Ca(2+)](i) was seen in response
      to 10(-3) M lanthanum ion. These findings provide evidence to suggest that
      especially in fetal, but also in adult, ovine MCA, Ca(2+) flux via L-type calcium
      channels plays a key role in NE-induced contraction. In contrast, Ca(2+) flux via
      receptor-operated Ca(2+) channels is of less importance. This developmental
      difference in the role of cerebrovascular plasma membrane Ca(2+) channels may be
      an important association with increased Ca(2+) sensitivity of the fetal vessels.

PMID- 10409285
TI  - Muscle IMP accumulation during fatiguing submaximal exercise in endurance trained
      and untrained men.
AB  - To examine the effect of training status on muscle metabolism during exercise,
      seven endurance-trained [peak oxygen uptake (VO(2 peak)) = 65.8 +/- 2.4 ml. kg(
      1). min(-1)] and six untrained (VO(2 peak) = 46. 2 +/- 1.9 ml. kg(-1). min(-1))
      men cycled to fatigue at a work rate calculated to require 70% VO(2 peak). Time
      to exhaustion was 36% longer (P < 0.01) in trained (TR) compared with untrained
      (UT) men (148 +/- 11 vs. 95 +/- 8 min). Although intramuscular glycogen content
      was reduced (P < 0.05) in both TR and UT at fatigue, IMP, a marker of a mismatch
      between ATP supply and demand, was only elevated (P < 0.01) in UT muscle at
      fatigue and was approximately fourfold higher at this point in UT compared with
      TR. These data demonstrate that fatiguing submaximal exercise was associated with
      a similar low level of intramuscular glycogen in both TR and UT men, but a
      mismatch between ATP supply and demand only occurred in UT individuals.

PMID- 10409286
TI  - 2-Mercaptoacetate, an inhibitor of fatty acid oxidation, decreases the membrane
      potential in rat liver in vivo.
AB  - In former work, intraperitoneal injection of 2-mercaptoacetate (MA), an inhibitor
      of fatty acid oxidation, increased food intake in rats, which was attenuated by
      hepatic branch vagotomy, and intraportal injection of MA increased the discharge
      rate in hepatic vagal afferents. In the present study, we investigated, whether
      intraperitoneal injection or intraportal infusion of MA affects the hepatic
      membrane potential in rats in vivo. The liver cell membrane potential was
      measured in anesthetized Sprague-Dawley rats with the microelectrode technique.
      Intraperitoneal injection of MA at a dose of 800 micromol/kg body wt
      significantly decreased the hepatocyte membrane potential by 3.8 mV, whereas at a
      dose of 400 micromol/kg, the depolarization (1.5 mV) of the membrane was not
      significant. In another strain of Sprague-Dawley rats, however, MA (400
      micromol/kg) produced a significant depolarization of the hepatocyte membrane 50
      min (2.6 mV) and 2 h (2.9 mV) after intraperitoneal injection. Intraportal
      infusion of MA (400 micromol/kg) significantly depolarized the membrane 20 and 50
      min after infusion by 3.3 and 4.1 mV, respectively. MA at a dose of 800
      micromol/kg also depolarized the membrane (4.8 mV after 50 min). These findings
      in principle are consistent with the "potentiostatic" hypothesis, postulating a
      link between the hepatic membrane potential, afferent vagal activity, and the
      control of food intake.

PMID- 10409287
TI  - Myocardial blood flow and coronary reserve in chronically anemic fetal lambs.
AB  - Chronic fetal anemia produces large compensatory increases in coronary blood flow
      in the near-term fetal lamb. To determine if increased coronary flow in anemic
      fetuses is associated with decreased coronary flow reserve or, alternatively, an
      increase in coronary conductance, we measured maximal coronary artery conductance
      during adenosine infusion before and during anemia. Isovolemic hemorrhage over 7
      days reduced hematocrit from 30.6 +/- 2. 7 to 15.8 +/- 2.4% (P < 0.02) and the
      oxygen content from 7.3 +/- 1. 4 to 2.6 +/- 0.4 ml/dl (P < 0.001). Coronary blood
      flow increased from control (202 +/- 60) to 664 +/- 208 ml. min(-1). 100 g(-1)
      with adenosine to 726 +/- 169 ml. min(-1). 100 g(-1) during anemia and to 1,162
      +/- 250 ml. min(-1). 100 g(-1) (left ventricle) during anemia with adenosine
      infusion (all P < 0.001). Coronary conductance, determined during maximal
      vasodilation, was 18.2 +/- 7.7 before and 32.8 +/- 11.9 ml. min(-1). 100 g(-1).
      mmHg(-1) during anemia (P < 0. 001). Coronary reserve, the difference between
      resting and maximal myocardial blood flow interpolated at 40 mmHg, was unchanged
      in control and anemic fetuses (368 +/- 142 and 372 +/- 201 ml/min). Because
      hematocrit affects viscosity, anemic fetuses were transfused with blood to
      acutely increase the hematocrit back to control, and conductance was remeasured.
      Coronary blood flow decreased 57.3 +/- 18.9% but was still 42.6 +/- 18.9% greater
      than control. We conclude that in chronically anemic fetal sheep coronary
      conductance is increased and coronary reserve is maintained, and this is
      attributed in part to angiogenesis as well as changes in viscosity.

PMID- 10409288
TI  - Effects on regional brain metabolism of high-altitude hypoxia: a study of six US
      marines.
AB  - Previous studies of brain glucose metabolism in people indigenous to high
      altitude environments uncovered two response patterns: Quechuas native to the
      high Andes of South America sustained modest hypometabolism in most brain regions
      interrogated, whereas Sherpas, native to the Himalayas and considered by many
      biologists to be most effectively high-altitude adapted of all humans, showed
      brain metabolic patterns similar to lowlanders, with no acclimation effects
      noted. In the present study, the database was expanded to include hypoxia
      acclimation effects in lowlanders. Positron emission tomography (PET) and [(18)F]
      2-deoxy-2-fluro-D-glucose (FDG) imaging techniques were used to assess regional
      cerebral glucose metabolic rates (rCMR(glc)) in six US marines (Caucasian
      lineage) before and after a 63-day training program for operations at high
      altitudes ranging from 10,500 to 20,320 ft. Significant changes in rCMR(glc) were
      found for 7 of 25 brain regions examined. Significant decreases in absolute
      cerebral glucose metabolism after high-altitude exposure were found in five
      regions: three frontal, the left occipital lobe, and the right thalamus. In
      contrast, for the right and left cerebellum significant increases in metabolism
      were found. The magnitudes of these differences, in terms of absolute metabolism,
      were large, ranging from 10 to 18%. Although the results may not be solely the
      result of lower oxygen levels at high altitude, these findings suggest that the
      brain of healthy human lowlanders responds to chronic hypoxia exposure with
      precise, region-specific fine tuning of rCMR(glc). The observed short-term
      hypoxia acclimation responses in these lowlanders clearly differ from the long
      term hypoxia adaptations found in brain metabolism of people indigenous to high
      altitude environments.

PMID- 10409289
TI  - Metallothionein response in gills of Oreochromis mossambicus exposed to copper in
      fresh water.
AB  - Freshwater Oreochromis mossambicus (tilapia) were exposed to 3.2 micromol/l
      Cu(NO(3))(2) in the water for up to 80 days, and copper (Cu) and immunoreactive
      metallothionein (irMT) were localized in the branchial epithelium. Cu was
      demonstrated in mucous cells (MC), chloride cells (CC), pavement cells (PC),
      respiratory cells (RC), and basal layer cells (BLC) via autometallography
      combined with alcian blue staining for MC and Na(+)-K(+)-ATPase immunostaining
      for CC and, on the basis of their location in the epithelium of PC, RC, and BLC.
      In control fish (water with Cu concentration </=90 nmol/l) incidentally irMT was
      observed in the area where progenitor cells of the branchial epithelia reside, as
      demonstrated by proliferating cell nuclear antigen staining. This was also the
      area where the first increase irMT expression of the Cu exposure was observed.
      After 2 days of exposure to Cu, irMT was found in CC and PC. From 5 days on, a
      pronounced irMT staining was observed in BLC of branchial epithelium, which then
      appeared to migrate and differentiate into mature CC, PC, and RC. We conclude
      that MT expression in mature CC, PC, and RC requires exposure to Cu in a earlier
      stage of development of these cells. Once expression is initiated in
      undifferentiated cells, MT remains expressed throughout the life cycle of the
      cell.

PMID- 10409290
TI  - ACE inhibition and glucose transport in insulinresistant muscle: roles of
      bradykinin and nitric oxide.
AB  - Acute administration of the angiotensin-converting enzyme (ACE) inhibitor
      captopril enhances insulin-stimulated glucose transport activity in skeletal
      muscle of the insulin-resistant obese Zucker rat. The present study was designed
      to assess whether this effect is mediated by an increase in the nonapeptide
      bradykinin (BK), by a decrease in action of ANG II, or both. Obese Zucker rats (8
      9 wk old) were treated for 2 h with either captopril (50 mg/kg orally),
      bradykinin (200 micrograms/kg ip), or the ANG II receptor (AT(1) subtype)
      antagonist eprosartan (20 mg/kg orally). Captopril treatment enhanced in vitro
      insulin-stimulated (2 mU/ml) 2-deoxyglucose uptake in the epitrochlearis muscle
      by 22% (251 +/- 7 vs. 205 +/- 9 pmol. mg(-1). 20 min(-1); P < 0.05), whereas BK
      treatment enhanced this variable by 18% (249 +/- 15 vs. 215 +/- 7 pmol. mg(-1).
      20 min(-1); P < 0.05). Eprosartan did not significantly modify insulin action.
      The BK-mediated increase in insulin action was completely abolished by
      pretreatment with either the specific BK-B(2) receptor antagonist HOE 140 (200
      micrograms/kg ip) or the nitric oxide synthase inhibitor N(omega)-nitro-L
      arginine methyl ester (50 mg/kg ip). Collectively, these results indicate that
      the modulation of insulin action by BK likely underlies the metabolic effects of
      ACE inhibitors in the insulin-resistant obese Zucker rat. Moreover, this
      modulation of insulin action by BK is likely mediated through B(2) receptors and
      by an increase in nitric oxide production and/or action in skeletal muscle
      tissue.

PMID- 10409291
TI  - Regulation of cyclooxygenase-2 expression in renal medulla by tonicity in vivo
      and in vitro.
AB  - Renal medullary prostaglandins are believed to exert an important functional role
      in antagonizing vasopressin effects in dehydration. Studies were undertaken to
      determine the effect of hyperosmolality on cyclooxygenase (COX) isoform
      expression in the renal medulla. COX-1 and COX-2 mRNA and protein levels were
      determined by RT-PCR or Western blotting in Sprague-Dawley rats on varying water
      intakes, in Brattleboro rats and in Long-Evans controls. Over a wide range of
      urinary tonicity, COX-2 expression correlated closely with urine osmolality
      levels (R = 0.872). COX-1 levels did not vary. Immunolocalization showed that the
      stimulation of COX-2 expression by dehydration occurred predominantly in the
      collecting duct. Hypertonicity caused by addition of NaCl produced a dose- and
      time-dependent stimulation of COX-2 expression in mIMCD-K2 cells as well as in
      MDCK cells. COX-1 was unaffected. In the same cell lines, mannitol, sucrose, and
      raffinose also had a stimulatory effect. The tonicity-stimulated COX-2 expression
      in mIMCD-K2 cells was almost completely blocked by a tyrosine kinase inhibitor,
      genistein at 100 microM. In MDCK cells transfected with a 2.7-kb COX-2 promoter
      and lacZ reporter construct, NaCl induced a twofold increase in beta
      galactosidase activity. Using mIMCD-K2 cells, hypertonic NaCl (600 mosmol/kgH(2)O
      for 24 h) induced a 33-fold increase in PGE(2) release determined by enzyme
      immunoassay, an effect completely blocked by 3 microM indomethacin or the COX-2
      specific blocker N-(2-cyclohexy-4-nitrophenyl)methanesulfonamide (NS-398). We
      conclude that in inner medulla, COX-2 but not COX-1 is upregulated by
      hyperosmolality.

PMID- 10409292
TI  - Differential regulation of COX-2 expression in the kidney by lipopolysaccharide:
      role of CD14.
AB  - Induction of the inducible cyclooxygenase isoform COX-2 is likely to be an
      important mechanism for increased prostaglandin production in renal inflammation.
      We examined the effect of lipopolysaccharide (LPS) on regional renal COX-2
      expression in the rat. In the inner medulla, LPS injection (4 mg/kg ip) induced a
      twofold and 2.5-fold increase in the levels of COX-2 mRNA and COX-2 protein,
      respectively. In contrast, COX-2 expression in the renal cortex was not
      significantly altered. COX-2 promoter transgenic mice were created using the 2.7
      kb flanking region of the rat COX-2 gene. In these animals, LPS injection induced
      reporter gene expression predominately in the inner medulla. The LPS receptor
      CD14, usually regarded as a monocyte/macrophage-specific marker, was found to be
      abundantly expressed in the inner medulla and in dissected inner medullary
      collecting duct (IMCD) cells, suggesting that it may mediate medullary COX-2
      induction. CD14 was present only at low levels in cortex and cortical segments,
      including glomeruli. In cultured cells, it was abundant in mouse IMCD (mIMCD-K2)
      cells and renal medullary interstitial cells, but largely undetectable in
      mesangial cells and M1 cells, a cell line derived from mouse cortical collecting
      ducts. In the mIMCD-K2 cell line, LPS significantly induced COX-2 mRNA
      expression, with concomitant induction of CD14. LPS-stimulated COX-2 expression
      was reduced by the addition of an anti-CD14 monoclonal antibody to the culture
      medium. These results demonstrate that LPS selectively stimulates COX-2
      expression in the renal inner medulla through a CD14-dependent mechanism.

PMID- 10409294
TI  - Role of Fas (CD95) in tubulointerstitial disease induced by unilateral ureteric
      obstruction.
AB  - Murine renal tubular epithelial cells and interstitial fibroblasts may express
      both Fas (CD95) death receptor and Fas ligand and are vulnerable to Fas-mediated
      death in vitro. We therefore hypothesized that an absence of renal Fas may
      protect resident cells from undergoing apoptosis. We performed unilateral
      ureteric ligation [producing unilateral ureteral obstruction (UUO)] in 6-wk-old
      normal control mice and C57Bl6/lpr mice, which express a nonfunctional Fas
      receptor. Obstructed kidneys were removed at days 3, 7, and 14 (n = 6 per group).
      Tubular cell apoptosis at day 7 was significantly reduced in lpr mice [21.8 +/-
      5.8 vs. 45.7 +/- 7.6 cells/10 high-power fields (hpf), P < 0.02]. Importantly,
      there was no difference in tubular cell proliferation between normal and lpr mice
      at any time point studied. Interestingly, double labeling with terminal
      deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and
      the proximal tubule-specific antibody Fx1A indicated that the absence of Fas
      reduced distal but not proximal tubular death at day 7. In addition, there was no
      difference in interstitial cell apoptosis or proliferation, suggesting that Fas
      does not play a significant role in interstitial cell death. Importantly,
      inflammatory macrophage infiltration and ultimate collagen I deposition was
      unchanged in lpr mice. In conclusion, the absence of functional cell surface Fas
      in UUO provides distal tubular cells with partial protection from apoptosis but
      does not affect interstitial cell fate in this model of tubulointerstitial
      injury.

PMID- 10409293
TI  - Polycystin-2 expression is developmentally regulated.
AB  - PKD2 encodes a protein of unknown function that is mutated in 15% of autosomal
      dominant polycystic kidney disease (ADPKD) families. We used polyclonal antisera
      against PKD2 to examine the pattern of Pkd2 expression in staged mouse embryos.
      Staining for Pkd2 was documented as early as the 6th embryonic day (day E6) in
      the embryonic ectoderm and endoderm. Low-intensity staining is seen in
      metanephric ureteric bud at day E12.5. By day E15.5, the adult pattern of
      expression is established with low level staining in proximal tubules and high
      level, basolateral staining in distal tubules. Pkd2 expression is first detected
      in the medullary collecting ducts at postnatal day 14. Outside of the kidney,
      Pkd2 expression is widely distributed in utero and more restricted postnatally.
      The greatest intensity of staining is seen in the fetal but not adult adrenal
      cortex and in red blood cell precursors. Expression also is seen in multiple
      endocrine organs, in cardiac, skeletal, and smooth muscle, and in multiple
      mesenchymal tissues. The diffuse distribution and early expression of Pkd2
      suggest a fundamental developmental role. The persistent strong expression in
      adult kidney is consistent with a more organ-specific function in the maintenance
      of the mature metanephric tubule.

PMID- 10409295
TI  - Nitrotyrosine formation with endotoxin-induced kidney injury detected by
      immunohistochemistry.
AB  - The presence of nitrotyrosine in the kidney has been associated with several
      pathological conditions. In the present study, we investigated nitrotyrosine
      formation in rat kidney after animals received endotoxin for 24 h. With
      lipopolysaccharide (LPS) treatment, immunohistochemical data demonstrated intense
      nitrotyrosine staining throughout the kidney. In spite of marked nitrotyrosine
      formation, the architectural appearance of tubules, glomeruli, and capillaries
      remained intact when examined by reticulin staining. Our data suggested that the
      marked staining of nitrotyrosine in proximal tubular epithelial cells was in the
      subapical compartment where the endocytic lysosomal apparatus is located. Thus a
      large portion of nitrotyrosine may come from the hydrolysis of nitrated proteins
      that are reabsorbed by the proximal tubule during the LPS treatment. We also
      found the colocalization of nitric oxide synthase (NOS-1) and nitrotyrosine
      within the macula densa of LPS-treated rats by using a double fluorescence
      staining method. In renal arterial vessels, vascular endothelial cells were more
      strongly stained for nitrotyrosine than vascular smooth muscle cells. Control
      animals without LPS treatment showed much less renal staining for nitrotyrosine.
      The general distribution of nitrotyrosine staining in control rat renal cortex is
      in the proximal and convoluted tubules, whereas the endothelial cells of vasa
      recta are major areas of nitrotyrosine staining in inner medulla. The renal
      distribution of nitrotyrosine in control and LPS-treated animals suggests that
      protein nitration may participate in renal regulation and injury in ways that are
      yet to be defined.

PMID- 10409296
TI  - Renal cellular response to ureteral obstruction: role of maturation and
      angiotensin II.
AB  - Renal angiotensin II (ANG II) is increased as a result of unilateral ureteral
      obstruction (UUO), and angiotensin AT(2) receptors predominate over AT(1)
      receptors in the early postnatal period. To examine the renal cellular response
      to 3-day UUO in the neonatal and adult rat, AT(1) and AT(2) receptors were
      inhibited by losartan and PD-123319, respectively. Additional rats received
      exogenous ANG II, 0.5 mg. kg(-1). day(-1). Renal cellular proliferation and
      apoptosis were quantitated by proliferating cell nuclear antigen and terminal
      deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling technique,
      respectively. In the neonate, UUO reduced proliferation and increased tubular
      apoptosis. Losartan had no detectable cellular effect, whereas PD-123319
      increased cellular proliferation and suppressed apoptosis, and exogenous ANG II
      stimulated apoptosis. In the adult, UUO increased cellular proliferation as well
      as apoptosis, whereas losartan, PD-123319, and exogenous ANG II did not alter the
      cellular response. In conclusion, UUO impairs renal growth in the neonate by
      reducing proliferation and stimulating apoptosis, at least in part through
      angiotensin AT(2) receptors. UUO stimulates both renal cellular proliferation and
      apoptosis in the adult, but these effects are independent of ANG II. We speculate
      that the unique early responses of the developing kidney to urinary tract
      obstruction are mediated by a highly activated renin-angiotensin system and
      preponderance of AT(2) receptors.

PMID- 10409297
TI  - Plasma and 24-h NO(x) and cGMP during normal pregnancy and preeclampsia in women
      on a reduced NO(x) diet.
AB  - We tested the hypothesis that nitric oxide (NO) biosynthesis increases during
      normal human pregnancy and decreases in preeclampsia. The major metabolites of
      NO, nitrate and nitrite (NO(x)), were measured in both the plasma and 24-h urine
      of women subjected to a reduced NO(x) diet. In this way, the plasma and urinary
      levels mainly reflected endogenous production rather than dietary intake.
      Moreover, we assessed cGMP, a second messenger of NO, in the same samples. Both
      NO(x) and cGMP assays were validated in our laboratory. We first conducted a
      cross-sectional study of nonpregnant women (n = 15), normal pregnant women in the
      first (n = 9), second (n = 17) and third (n = 22) trimesters, as well as women
      with preeclampsia (n = 15) and transient hypertension of pregnancy (n = 7). We
      also performed a serial study in the same women (n = 9) before, during, and after
      pregnancy. Taken together, the results of the two investigations suggested marked
      increases in cGMP production especially during the first trimester when the
      maternal circulation is rapidly vasodilating. In contrast, whole body NO
      production as estimated by the plasma level and urinary excretion of NO(x) was
      not elevated during the first trimester. Finally, unequivocal demonstration of
      reduced NO biosynthesis in preeclampsia was not forthcoming.

PMID- 10409298
TI  - Characterization of acute reversible systemic hypertension in a model of heme
      protein-induced renal injury.
AB  - In the glycerol model of renal injury we describe an acute rise in systemic
      arterial pressure which is attended by a reduced vasodilatory response to
      acetylcholine in vivo; vasodilatory responses to verapamil, however, were not
      impaired. Neither arginine nor sodium nitroprusside diminished this rise in blood
      pressure; N(omega)-nitro-L-arginine methyl ester (L-NAME) elevated basal mean
      arterial pressure and markedly blunted the rise in mean arterial pressure
      following the administration of glycerol. Aortic rings from the glycerol-treated
      rat demonstrate an impaired vasodilatory response to acetylcholine, an effect not
      repaired by arginine; the vasodilatory responses to nitric oxide donors, sodium
      nitroprusside and SIN-1, were also impaired; 8-bromo-cGMP, at higher doses,
      evinced a vasodilatory response comparable to that observed in the control rings.
      This pattern of responses was not a nonspecific effect of aortic injury, since
      aortic rings treated with mercuric chloride, a potent oxidant, displayed an
      impaired vasodilatory response to acetylcholine but not to sodium nitroprusside.
      We conclude that in the glycerol model of heme protein-induced tissue injury,
      there is an acute elevation in mean arterial pressure attended by impaired
      endothelium-dependent vasodilatation in vitro and in vivo. We suggest that the
      acute scavenging of nitric oxide by heme proteins depletes the blood vessel wall
      of its endogenous vasodilator and permeation of heme proteins into the blood
      vessel wall may contribute to such sustained effects as observed in vitro.

PMID- 10409299
TI  - Endopeptidases (kininases) are able to hydrolyze kinins in tubular fluid along
      the rat nephron.
AB  - The activities of serine endopeptidase, prolyl endopeptidase and neutral
      endopeptidase were determined in tubular fluid collected from several portions of
      the rat nephron as well as in urine. The enzyme activities were measured by HPLC
      using bradykinin (BK) as substrate. Free residual peptides of BK obtained by the
      action of these enzymes on the locally produced BK were also determined. The
      endopeptidase activities were found to be present throughout the nephron.
      Equimolar fragments of BK were detected in the early proximal tubule (Arg(1)
      Pro(7), Phe(8)-Arg(9), Arg(1)-Gly(4), Phe(5)-Arg(9), and BK), late proximal
      tubule (Arg(1)-Phe(5), Arg(1)-Pro(7), Gly(4)-Pro(7), Gly(4)-Arg(9), and BK), late
      distal tubule (Arg(1)-Gly(4), Phe(5)-Arg(9), Arg(1)-Phe(5), Ser(6)-Arg(9), Gly(4)
      Arg(9), BK, and [des-Arg(9)]BK) and urine (Phe(8)-Arg(9), Phe(5)-Arg(9), Arg(1)
      Phe(5), Ser(6)-Arg(9), Arg(1)-Pro(7), Gly(4)-Pro(7), Gly(4)-Arg(9), BK, and [des
      Arg(9)]BK). Our data suggest that the endopeptidases and exopeptidases are
      secreted by the nephron. Early proximal tubules secrete angiotensin converting
      enzyme and neutral endopeptidase, differing from late distal tubules that produce
      prolyl endopeptidase, serine endopeptidase, carboxypeptidase, and also neutral
      endopeptidase. All enzymes detected along the rat nephron were found in the
      urine. The existence of endopeptidases and carboxypeptidase in the distal nephron
      may have a potential physiological role in the inactivation of the kinins formed
      by kallikrein in the kidney and also in the inactivation of additional peptides
      other than BK.

PMID- 10409300
TI  - Angiotensin-(1-7) can interact with the rat proximal tubule AT(4) receptor
      system.
AB  - This study was undertaken to identify the non-AT(1), non-AT(2) angiotensin
      receptor that mediates the ANG-(1-7) inhibitory action on rat proximal tubule
      transport processes. ANG-(1-7) inhibited nystatin-stimulated, ouabain
      suppressible O(2) consumption (QO(2)) rates in freshly isolated rat proximal
      tubules (reflecting reduced basolateral Na(+)-K(+)-ATPase activity). Selective
      angiotensin-receptor subtype antagonists revealed that AT(1) and AT(4) receptors
      mediated the response of ANG-(1-7). Receptor autoradiography of the rat kidney
      demonstrated a high density of AT(1) and AT(4) receptors and no specific (125)I
      ANG(1-7) binding sites. Competition assays in rat kidney sections indicated that
      ANG-(1-7) competed predominantly for the AT(1) receptor site, whereas its NH(2)
      terminal-deleted metabolite, ANG-(3-7), competed primarily for the AT(4)-receptor
      site. Metabolism of (125)I-ANG-(1-7) in rat proximal tubules generated peptide
      fragments that included ANG-(3-7), with the pentapeptide producing a
      concentration-dependent inhibition of nystatin-stimulated proximal tubule QO(2)
      that was abolished by AT(4)-receptor blockade. These results suggest that the
      generation of ANG-(3-7) from the NH(2)-terminal metabolism of ANG-(1-7) caused
      the interaction of the parent peptide with the proximal tubule AT(4) receptor,
      which elicited a decrease in energy-dependent solute transport.

PMID- 10409301
TI  - Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells.
AB  - P-glycoprotein (P-gp) on the apical membranes of epithelial cells is known as a
      drug efflux pump. However, unclear is its integral quantitative role in the
      overall epithelial drug transfer, which also involves distinct diffusion
      processes in parallel and sequence. We used a simple three-compartment model to
      obtain kinetic parameters of each drug transfer mechanism, which can
      quantitatively describe the transport time courses of P-gp substrates, digoxin
      and vinblastine, across P-gp-expressing MDCK cell monolayers grown on permeable
      filters. Our results show that the model, which assumes a functionally single
      drug efflux pump in the apical membrane with diffusion across two membranes and
      intercellular junctions, is the least complex model with which to quantitatively
      reproduce the characteristics of the data. Interestingly, the model predicts that
      the MDCK apical membranes are less diffusion permeable than the basolateral
      membrane for both drugs and that the distribution volume of vinblastine is 10
      fold higher than that of digoxin. Additional experiments verified these model
      predictions. The modeling approach is feasible to quantitatively describe overall
      kinetic picture of epithelial drug transport. Further model refinement is
      necessary to incorporate other modes of drug transport such as transcytosis.
      Also, whether P-gp solely accounts for the pump function in this model awaits
      more studies.

PMID- 10409302
TI  - Glucose transporters control gene expression of aldose reductase, PKCalpha, and
      GLUT1 in mesangial cells in vitro.
AB  - The process linking increased glucose utilization and activation of metabolic
      pathways leading to end-organ damage from diabetes is not known. We have
      previously described rat mesangial cells that were transduced to constitutively
      express the facilitative glucose transporter 1 (GLUT1, MCGT1 cells) or bacterial
      beta-galactosidase (MCLacZ, control cells). Glucose transport was rate limiting
      for extracellular matrix production in the MCGT1 cells. In the present work, we
      investigated the effect of GLUT1 overexpression in mesangial cells on aldose
      reductase (AR), protein kinase Calpha (PKCalpha), and native GLUT1 transcript
      levels, to determine whether changes in GLUT1 alone could regulate their
      expression in the absence of high extracellular glucose concentrations. MCGT1
      cells grown in normal (8 mM) or elevated (20 mM) glucose had elevated abundance
      of AR, PKCalpha, and the native GLUT1 transcripts compared with control cells. AR
      protein levels, AR activity, sorbitol production, and PKCalpha protein content
      were also greater in the MCGT1 cells than in control cells grown in the same
      media. This is the first report of the concomitant activation of AR, PKCalpha,
      and GLUT1 genes by enhanced GLUT1 expression. We conclude that increased GLUT1
      expression leads to a positive feedback of greater GLUT1 expression, increased AR
      expression and activity with polyol accumulation, and increased total and active
      PKCalpha protein levels, which leads to detrimental stimulation of matrix protein
      synthesis by diabetic mesangial cells.

PMID- 10409303
TI  - Involvement of PDGF in pressure-induced mesangial cell proliferation through PKC
      and tyrosine kinase pathways.
AB  - In glomerular hypertension, mesangial cells (MC) are subjected to at least two
      physical forces: mechanical stretch and high transmural pressure. Increased
      transmural pressure, as well as mechanical stretch, promotes MC proliferation,
      which may enhance glomerulosclerosis. The exact mechanism of this effect is not
      fully understood. We examined the effects of transmural pressure alone on cell
      proliferation and DNA synthesis and investigated the role of platelet-derived
      growth factor (PDGF) and basic fibroblast growth factor (bFGF), candidates for
      mediation of glomerular diseases, in the pressure-induced events. Pressure was
      applied to cultured MC placed in a sealed chamber using compressed helium gas.
      Application of pressure resulted in a time-dependent ( approximately 2 h) and
      pressure level-dependent (approximately 80 mmHg) increase in cell number (1.4
      fold) and [(3)H]thymidine incorporation (2.7-fold). Pressure-induced DNA
      synthesis was significantly suppressed by inhibitors of phospholipase C (2-nitro
      4-carboxyphenyl-N, N-diphenylcarbamate), protein kinase C [1-(5
      isoquinolinylsulfonyl)-2-methylpiperazine and chelerythrine], or tyrosine kinases
      (genistein). Pressure caused a rapid but transient formation of inositol 1,4,5
      trisphosphate, which was blocked by the phospholipase C inhibitor. Pressure also
      promoted a rapid increase in tyrosine kinase activity. Pressure increased mRNA
      levels of PDGF-B, with a peak at 6 h, but not those of PDGF-A or bFGF. Pressure
      induced DNA synthesis was partially inhibited by a neutralizing anti-PDGF
      antibody but not by an antibody against bFGF or nonimmune IgG. Our results
      indicated that pressure by itself increases DNA synthesis and proliferation of
      cultured rat MC possibly through activation of protein kinase C and tyrosine
      kinases, and PDGF-B could be partially involved in these pathways.

PMID- 10409304
TI  - Neuronal NOS contributes to biphasic autoregulatory response during enhanced TGF
      activity.
AB  - To assess the afferent arteriolar autoregulatory response during increased
      activity of the tubuloglomerular feedback (TGF) mechanism and to delineate the
      contribution of neuronal nitric oxide synthase (nNOS) to this response, afferent
      arteriolar diameter responses to changes in renal perfusion pressure (RPP) were
      monitored in vitro using the blood-perfused rat juxtamedullary nephron
      preparation. At RPP of 100 mmHg, basal afferent arteriolar diameter averaged 21.1
      +/- 1.4 micrometer (n = 9). The initial and sustained constrictor responses of
      afferent arterioles to a 60-mmHg increase in RPP averaged 14.8 +/- 1.4% and 13.3
      +/- 1.3%, respectively. Acetazolamide treatment, which enhances TGF
      responsiveness by increasing distal nephron volume delivery, significantly
      decreased basal afferent arteriolar diameter by 8.2 +/- 0.5% and enhanced the
      initial response (25.5 +/- 2.3%) to a 60-mmHg increase in RPP but did not alter
      the sustained response (14.3 +/- 1.5%). In another series of experiments, nNOS
      inhibition with 10 microM S-methyl-L-thiocitrulline (L-SMTC) significantly
      decreased afferent arteriolar diameter from 20.3 +/- 1.3 to 18.3 +/- 1.1
      micrometer (n = 7) and enhanced both the initial (34.4 +/- 3.5%) and sustained
      constrictor responses (27.6 +/- 2.9%) to a 60-mmHg increase in RPP. Treatment
      with acetazolamide further enhanced both initial (56.4 +/- 3.0%) and sustained
      responses (54.6 +/- 2.7%). Interruption of distal delivery by transection of the
      loops of Henle prevented the enhanced responses to increases in RPP elicited with
      either acetazolamide or L-SMTC. These results indicate that nNOS contributes to
      the counteracting resetting process of biphasic afferent arteriolar constrictor
      responses to increases in RPP through a TGF-dependent mechanism.

PMID- 10409305
TI  - Cloning and functional expression of the mouse epithelial sodium channel.
AB  - The epithelial sodium channel (ENaC) plays a major role in the transepithelial
      reabsorption of sodium in the renal cortical collecting duct, distal colon, and
      lung. ENaCs are formed by three structurally related subunits, termed alpha-,
      beta-, and gammaENaC. We previously isolated and sequenced cDNAs encoding a
      portion of mouse alpha-, beta-, and gammaENaC (alpha-, beta-, and gammamENaC).
      These cDNAs were used to screen an oligo-dT-primed mouse kidney cDNA library.
      Full-length betamENaC and partial-length alpha- and gammamENaC clones were
      isolated. Full-length alpha- and gammamENaC cDNAs were subsequently obtained by
      5'-rapid amplification of cDNA ends (5'-RACE) PCR. Injection of mouse alpha-,
      beta-, and gammaENaC cRNAs into Xenopus oocytes led to expression of amiloride
      sensitive (K(i) = 103 nM), Na(+)-selective currents with a single-channel
      conductance of 4.7 pS. Northern blots revealed that alpha-, beta-, and gammamENaC
      were expressed in lung and kidney. Interestingly, alphamENaC was detected in
      liver, although transcript sizes of 9.8 kb and 3.1 kb differed in size from the
      3.2-kb message observed in other tissues. A partial cDNA clone was isolated from
      mouse liver by 5'-RACE PCR. Its sequence was found to be nearly identical to
      alphamENaC. To begin to identify regions within alphamENaC that might be
      important in assembly of the native heteroligomeric channel, a series of
      functional experiments were performed using a construct of alphamENaC encoding
      the predicted cytoplasmic NH(2) terminus. Coinjection of wild-type alpha-, beta-,
      and gammamENaC with the intracellular NH(2) terminus of alphamENaC abolished
      amiloride-sensitive currents in Xenopus oocytes, suggesting that the NH(2)
      terminus of alphamENaC is involved in subunit assembly, and when present in a 10
      fold excess, plays a dominant negative role in functional ENaC expression.

PMID- 10409306
TI  - Nitric oxide synthase in the JGA of the SHR: expression and role in
      tubuloglomerular feedback.
AB  - The spontaneously hypertensive rat (SHR) has an enhanced tubuloglomerular
      feedback (TGF) and a diminished buffering by juxtaglomerular apparatus (JGA)
      derived NO. We examined the hypothesis that these effects are due to decreases in
      nitric oxide synthase (NOS) expression or limited availability of L-arginine or
      tetrahydrobiopterin (BH(4)). SHR had significantly (P < 0.05) greater mRNA
      abundance (by RT-PCR) or protein (by Western analysis) for neuronal NOS (nNOS, or
      type I) and endothelial cell NOS (ecNOS, or type III) in renal cortex or isolated
      glomeruli, respectively. There was prominent expression of ecNOS in glomerular
      endothelium and nNOS in macula densa. Maximal TGF responses, assessed from
      changes in proximal stop-flow pressure during orthograde loop of Henle (LH)
      perfusion, were greater in SHR [Wistar-Kyoto (WKY), 8.1 +/- 0.3 (n = 46) vs. SHR,
      10.3 +/- 0.3 mmHg (n = 57); P < 0.001]. Unlike WKY, TGF responses of SHR were
      unresponsive to microperfusion of the nNOS inhibitor, 7-nitroindazole (7-NI, 10(
      4) M) [WKY, 9.5 +/- 0.5 to 13.2 +/- 0.7 (n = 13, P < 0.001) vs. SHR, 11.8 +/- 0.7
      to 12.5 +/- 0.6 mmHg (n = 19, not significant)], or to L-arginine (10(-3) M)
      [WKY, 7.7 +/- 0.8 to 6.3 +/- 0.4 (n = 10, P < 0.05) vs. SHR, 10.4 +/- 0.7 to 10.6
      +/- 0.7 mmHg (n = 10, not significant)]. Neither BH(4) (10(-4) M) nor sepiapterin
      (10(-4) M), its stable precursor, modified TGF responses in WKY or in SHR, nor
      did they restore a response to microperfusion of 7-NI in SHR. In conclusion,
      there is a diminished role for NO from nNOS in blunting of TGF in SHR which
      cannot be ascribed to limited NOS expression or availability of substrate or
      BH(4).

PMID- 10409307
TI  - Puromycin aminonucleoside nephrosis results in a marked increase in fractional
      clearance of albumin.
AB  - Puromycin aminonucleoside nephrosis (PAN) results in a marked increase in the
      fractional clearance of albumin. The increase in the fractional clearance of
      [(3)H]albumin to approximately 0.045, as measured both in vivo and in the
      isolated perfused rat kidney (IPK) with PAN, occurs without an accompanying
      equivalent increase in glomerular capillary wall size selectivity as previously
      measured with dextrans. This is very similar to the marked increase in
      albuminuria seen with kidneys treated with inhibitors of endocytosis by the
      tubular epithelium, particularly lysine (T. M. Osicka, L. M. Pratt, and W. D.
      Comper. Nephrology 2: 199-212, 1996). The similarity is further established that,
      like in the presence of lysine, [(3)H]albumin excreted in urine from rats with
      PAN is essentially intact whereas, in both in vivo and IPK control experiments,
      excreted [(3)H]albumin is heavily degraded. The same observations have also been
      made for (3)H-labeled anionic horseradish peroxidase. These observations suggest
      that the significant albuminuria that occurs in PAN is primarily post-glomerular
      basement membrane in origin.

PMID- 10409308
TI  - Immunolocalization of Ksp-cadherin in the adult and developing rabbit kidney.
AB  - The potential for Ksp-cadherin involvement in either the development or
      maintenance of the metanephric kidney was assessed by immunocytochemical
      localization of a monoclonal antibody directed against the rabbit isoform of Ksp
      cadherin in both neonatal and adult rabbit kidneys. In the adult kidney Ksp
      cadherin expression was detected on the basolateral membrane of all cell types in
      both the tubular nephron and the collecting system. Immunoelectron microscopy
      indicated that Ksp-cadherin was expressed at uniform levels along the entire
      length of both the lateral membranes and the basal infoldings of all tubular
      epithelial cell types. In the nephrogenic zone of the neonatal rabbit kidney Ksp
      cadherin expression was detected exclusively on the basolateral membranes of
      epithelial cells in the more highly differentiated regions of the expanding
      ureteric duct. In the highly differentiated corticomedullary and medullary
      regions of the neonatal kidney, distinct basolateral staining was observed in all
      segments of the tubular nephron and the collecting system. The relatively late
      appearance of Ksp-cadherin expression in the developing metanephros indicates
      that Ksp-cadherin probably does not participate in the direction of renal
      morphogenesis. However, the high levels of Ksp-cadherin expression observed in
      all segments of the tubular nephron and the collecting system in the adult kidney
      suggests that it may play a role in the maintenance of the terminally
      differentiated tubular epithelial phenotype.

PMID- 10409309
TI  - Current and novel pharmacologic approaches in advanced heart failure.

PMID- 10409310
TI  - Readmission of patients after coronary artery bypass graft surgery.
AB  - OBJECTIVE: To assess rates, reasons, and predictors of hospital readmission after
      coronary artery bypass grafting (CABG). METHODS: In this prospective,
      descriptive, correlational study, 124 subjects responded to a mailed
      questionnaire 6 weeks after undergoing CABG at Yale New Haven Hospital. RESULTS:
      The sample was 79% male, 94% white, and had a mean age of 66 +/- 10 years and a
      mean length of stay of 5.7 +/- 1.8 days. A total of 14.5% had unplanned cardiac
      related readmissions (44% to their community hospital). Chest pain with or
      without shortness of breath was the primary reason for readmission (33%),
      followed by incisional problems (17%) and analgesic reactions (17%). Logistic
      regression analysis, based on bivariate analyses, revealed that female sex (odds
      ratio 4.7; 95% confidence interval, 1. 5-14.6; P =.007) and obesity (odds ratio
      3.7; 95% confidence interval, 1.2-11.6; P =.026) predicted hospital readmission.
      CONCLUSIONS: Effective follow-up, with particular focus on women and the obese,
      may decrease readmissions. (Heart Lung((R)) 1999;28:243-50).

PMID- 10409311
TI  - Changes in health status and quality of life and the impact of uncertainty in
      patients who survive life-threatening arrhythmias.
AB  - OBJECTIVE: The purpose of this study was to describe the changes in perception of
      health status and quality of life from before treatment to 6 months after and the
      impact of uncertainty on these variables in survivors of life-threatening
      arrhythmia. DESIGN AND SETTING: A descriptive correlational design at a large
      urban teaching hospital. MEASURES: We measured health status, quality of life,
      and uncertainty before treatment and 6 months after a life-threatening
      arrhythmia. RESULTS: Survivors included 66 men and 15 women, 41 of whom received
      pharmacologic therapy and 36 of whom received an implantable cardioverter
      defibrillator (ICD), completed the Medical Outcomes Survey (SF-36), Ferrans and
      Powers Quality of Life Index (QLI), and the Mishel Uncertainty in Illness Scale
      (MUIS-C) before treatment and 6 months after. There were significant improvements
      in the mental and physical health composite summaries as measured by the SF36 (P
      <.01). Conversely, there were significant reductions in the overall score and
      specifically in socioeconomic and psychological/spiritual quality of life domains
      as measured by the QLI (P <.05). An increased perception of uncertainty was
      related to decreased perception of health status and quality of life at both
      measurement times, with higher correlations 6 months later. CONCLUSIONS:
      Survivors demonstrated improvements in perceived health status, although this did
      not appear to translate into improvements in the subjective domains of quality of
      life. The overall quality of life and the domains of psychological/spiritual
      state and socioeconomic status were lower 6 months after a life-threatening
      arrhythmia. Uncertainty had a significant impact on these perceptions,
      identifying an area for nursing interventions.

PMID- 10409312
TI  - How women label and respond to symptoms of acute myocardial infarction: responses
      to hypothetical symptom scenarios.
AB  - OBJECTIVE: To investigate how women label and intend to respond to common and
      less common symptoms of acute myocardial infarction (AMI). DESIGN: Telephone
      interviews were conducted with 862 women older than age 50 years in the state of
      Washington. OUTCOME MEASURES: Intended coping strategies, labeling of
      hypothetical symptoms, perceived risk of AMI, knowledge of AMI symptoms, medical
      and family history of AMI and demographics. RESULTS: Women who labeled common or
      less common symptoms as a heart attack (65% and 36%, respectively) were more
      likely to report they would call 911 or go to a hospital right away than women
      who labeled these symptoms as something else. The results of a multiple logistic
      regression analysis suggests that knowledge of less common AMI symptoms, AMI
      information seeking, and personal risk perceptions were significant predictors of
      labeling less common symptoms as a heart attack. CONCLUSIONS: The findings
      suggest that many women might be in danger of mislabeling their symptoms and not
      taking appropriate action. Women need to be educated about the less common
      symptoms of AMI and need to be encouraged to seek out information regarding AMI.

PMID- 10409314
TI  - Prediction of functional and psychological status after percutaneous transluminal
      coronary angioplasty.
AB  - OBJECTIVE: To examine symptom, functional status, and psychological status
      profiles after percutaneous transluminal coronary angioplasty (PTCA) and
      determine indicators of outcome. DESIGN: Descriptive and correlational with
      repeated measures. SETTING: Hospital or home (2.1 days before PTCA) and home (3.9
      and 10.2 months after discharge). MEASURES: Self-administered questionnaires
      (developed for study) for functional status (personal and instrumental activities
      of daily living), and cardiac symptoms (chest pain and shortness of breath at
      rest and on exertion). General Health Questionnaire(16) for psychological status.
      PATIENTS: One hundred thirty with PTCA (mean age 57 years, 84% male, 15% with
      prior PTCA). RESULTS: Chest pain and shortness of breath at rest and on exertion
      decreased and functional and psychological status improved 3.9 months after PTCA,
      with measures maintained at 10.2 months. At 3.9 months after PTCA, poorer
      psychological status was predicted by having had a longer duration of coronary
      artery disease before PTCA. Post-PTCA indicators of poor psychological status
      were continued chest pain and shortness of breath on exertion and not working.
      The presence of post-PTCA chest pain on exertion and not working were also
      correlated with reduced functional status. CONCLUSIONS: Although pre-PTCA
      variables such as duration of coronary artery disease can predict post-PTCA
      outcome, the use of variables measured after PTCA may also provide clinicians
      with accurate estimates of functional and psychological status after PTCA.

PMID- 10409313
TI  - Changes in cholesterol levels in women after coronary artery bypass surgery.
AB  - OBJECTIVE: To examine the predictors of change in cholesterol levels in a cohort
      of women between the time of surgery and 1 year after coronary artery bypass
      graft surgery (CABG). DESIGN AND SETTING: This study was a prospective,
      descriptive study held at a Mid-Atlantic tertiary care medical center. METHODS:
      Lipid profiles, lifestyle behaviors, and other major coronary risk factors were
      measured at the time of surgery and again 12 months later from a consecutive
      convenience sample of 130 women who underwent first-time, isolated CABG. RESULTS:
      The sample population was 24% black and 76% white and had a mean age of 65 years
      and an average of 11 years of education. Although no statistically significant
      changes in cholesterol levels were observed, a majority (55%) of women had
      increases in total cholesterol level, whereas 45% had decreased total cholesterol
      level between baseline and 1 year of follow-up. After controlling for
      preoperative cholesterol values, a change in cholesterol level was independently
      predicted by ejection fraction, smoking status, and body mass index. At 1 year,
      plasma lipoprotein levels were not optimally managed, with high proportions of
      values exceeding national guidelines for secondary prevention. CONCLUSIONS: Women
      continue to have high cholesterol levels after CABG, putting them at high risk
      for future coronary heart disease events. Effective secondary prevention programs
      targeting multiple lifestyle behaviors and adequate pharmacotherapy are needed.

PMID- 10409315
TI  - Becoming a patient with heart failure.
AB  - OBJECTIVE: The purpose of this study was to gain a better understanding of the
      process of becoming a patient with heart failure, a process of identity
      formation. Are there clues in the patients' stories about heart failure that
      might give us a better idea of how patients adjust to heart failure and what
      heart failure means to them? Meanings that individuals attach to events or
      situations are central to development of identity and subsequent behaviors.
      DESIGN AND SETTING: Qualitative methods involving detailed interviews and
      grounded theory method were used in an outpatient cardiology department of a
      large health care facility in northeast Ohio. PATIENTS: Twenty-one patients with
      a diagnosis of heart failure were conveniently selected and interviewed for this
      research. Patients were selected on the basis of having a left ventricular
      ejection fraction of 35% or less and New York Heart Association class II, III, or
      IV. Other possible selection criteria (eg, VO(2Max ), walk test, or dyspnea) were
      not available for all patients and thus did not constitute consistent selection
      criteria. A broad net was cast for patients with varying characteristics to see
      if common processes and experiences existed regardless of the differences in
      clinical indicators. METHODS: Patients were interviewed in the examining room as
      part of a regularly scheduled visit with their cardiologists. All interviews were
      tape recorded and fully transcribed. Field notes and relevant patient chart data
      (eg, age, sex, race, marital status, cause of heart failure, comorbidities,
      history of hospitalization, New York Heart Association functional class, left
      ventricular ejection fraction) were included in the transcribed interviews. The
      transcribed interview was read and responses were given initial conceptual codes.
      These coded passages were categorized according to more abstract categories or
      concepts and underlying processes that encompass them. This process continues
      until all relevant passages have been categorized and subsumed under higher-order
      (more abstract or general) categories. RESULTS: The process of becoming a patient
      with heart failure involves a gradual process of taking on a new identity. Five
      distinct phases of this process of identity formation emerged from the data: a
      crisis event, the diagnosis, the patient's and family's response to the
      diagnosis, their acceptance and adjustment to life with this condition, and
      making the decision to get on with life. CONCLUSIONS: Most research on heart
      failure has focused on patients or their families farther along in the trajectory
      of this condition. We know little about the psychosocial experience of the early
      phases of this condition. Becoming a patient with heart failure is a process of
      searching for a meaning to this condition (what is it? what does it mean for the
      future?) and a process of taking on a new identity and appropriate role
      behaviors. This process takes place over a period of time. This suggests that the
      formation of individual identities evolve as new information becomes available,
      as meanings are attached to the new circumstances, and as a process of
      negotiating new roles among family members (and among patient, family members,
      and clinicians) takes place. The findings of this study suggest possible
      interventions that may positively affect the patient's condition and the quality
      of family life.

PMID- 10409317
TI  - Nursing strategies for smoking cessation.
AB  - The purpose of this article is to provide the staff nurse with an overview of the
      Agency for Health Care Policy and Research Smoking Cessation guidelines. The
      authors outline the practical components of the guidelines to enable nurses in
      any clinical setting to implement various smoking cessation strategies according
      to individual patient needs. Treatment options, including behavioral modification
      and a comprehensive review of pharmacological therapy, are discussed.

PMID- 10409316
TI  - Serratia marcescens bacteremia after carotid endarterectomy and coronary artery
      bypass grafting.
AB  - Serratia Marcescens is a common, water-borne hospital colonizer. Respiratory
      secretions, wounds, and urine are frequently recognized areas of Serratia
      colonization. Serratia bacteremias usually occur nosocomially and are associated
      with high mortality and morbidity rates. Serratia bacteremias may be primary or
      secondary from an identifiable source. Hospital-acquired S marcescens bacteremias
      have no known source in half of the cases. We present a case of nosocomial
      primary S marcescens bacteremia in a surgical patient successfully treated with
      levofloxacin.

PMID- 10409318
TI  - The use of needle biopsies for radiobiological assessment of oxygen levels in KHT
      C tumors.
AB  - Hypoxia affects the sensitivity of cells to radiation. Hence there is
      considerable interest in the development and assessment of techniques for
      measuring oxygen levels. In the work described here, we explore the use of tumor
      needle biopsies (fine needle aspirates) in an assay that is standard in the field
      of radiation biology: the paired survival assay. We found that needle biopsies
      are a feasible option for estimating cell survival when conducting this assay,
      and that the variability in cell survival between tumors was greater than that
      between different biopsies from the same tumor. Using this technique, we then
      compared measurements of tumor hypoxia using the paired survival assay and the
      growth delay assay in the same individual tumors. We found a significant
      correlation between these two techniques.

PMID- 10409319
TI  - The effects of boron neutron capture irradiation on oral mucosa: evaluation using
      a rat tongue model.
AB  - The ventral surface of the tongue of male Fisher 344 rats was used to evaluate
      the response of oral mucosa to boron neutron capture irradiation. Three hours
      after i.p. injection of 700 mg/kg of the boron delivery agent p
      boronophenylalanine (BPA), the boron concentrations in blood and tongue mucosal
      epithelium were approximately 21 and 23 microgram (10)B/g, respectively. The
      doses required to produce a 50% incidence of ulceration with X rays, the
      Brookhaven Medical Research Reactor thermal neutron beam alone, or the thermal
      neutron beam in the presence of BPA were 13.4 +/- 0.2, 4. 2 +/- 0.1, and 3.0 +/-
      0.1 Gy, respectively. Ulceration of the tongue was evident by 6 to 7 days after
      irradiation, irrespective of the irradiation modality; healing was related to
      dose and was relatively rapid (</=19 days). Compared to 100 kVp X rays, the
      relative biological effectiveness factors were 3.2 for the thermal neutron beam
      and 4.9 for the products of the boron neutron capture reaction,
      (10)B(n,alpha)(7)Li. Oral mucosa is highly sensitive to BPA-mediated BNC
      irradiation and could be a dose-limiting normal tissue in BNCT of brain tumors,
      or if BPA-based BNCT is applied to the treatment of head and neck tumors.

PMID- 10409320
TI  - Adaptive response in embryogenesis: II. Retardation of postnatal development of
      prenatally irradiated mice.
AB  - We previously reported that a priming dose of 0.3 Gy on gestation day 11
      significantly increased the rate of living fetuses and reduced the incidence of
      congenital malformations caused by exposure to 5 Gy X rays on gestation day 12 in
      ICR mice. In the present study, postnatal development of the live offspring was
      investigated using a set of developmental and behavioral parameters. The
      offspring of the mice irradiated with 0.3 Gy generally showed a delay in the
      appearance of most of the physiological markers, impaired acquisition of neonatal
      reflexes, and alteration of adult behavior. However, an increase in body weight
      in the females was observed 4 weeks postnatally. In the offspring primed with 0.3
      Gy followed by a challenging dose of 5 Gy prenatally, a high postnatal mortality
      was found, and all the survivors had various radiation-induced detrimental
      effects. The results indicated that the priming dose was advantageous to survival
      itself, but was disadvantageous to the health of survivor. The results also
      suggested that studying the whole animal can show the extent of the effects of
      radiation, i.e. quality of life, in a way that cellular or molecular studies
      cannot.

PMID- 10409321
TI  - Is repair of DNA strand break damage from ionizing radiation second-order rather
      than first-order? A simpler explanation of apparently multiexponential repair.
AB  - The purpose of this paper is to suggest the hypothesis that repair of radiation
      damage might be largely a second-order process (binary), as well as or instead of
      first-order (monoexponential). Second-order means that the rate of repair is
      proportional to n(2) instead of to n, where n is the number of repairable breaks.
      Integrating this equation gives a linear plot of the reciprocal proportion of
      unrepaired lesions, n(0)/n(t), as a function of repair time. This is in contrast
      to mono- or biexponential processes which give rise to reciprocal plots not
      consistent with such linearity, except with specially selected distributions with
      multiple T((1/2))'s. There is the advantage of only one parameter (the first half
      time) instead of (2n - 1) parameters for n components. At times greater than 2tau
      of the longest exponential component, a larger proportion of damage would be
      incompletely repaired than in a mono- or biexponential model of repair. Data on
      DNA repair from published laboratory experiments were reanalyzed. Results are
      presented as graphs of the reciprocal of the proportion of damage remaining as a
      function of time after irradiation of DNA. If the second-order process is
      correct, these graphs should be straight lines, even though traditional semilog
      plots of the same data are markedly concave upward, showing the well-noted
      slowing down of repair with time after irradiation. All the data sets found in
      the literature showed a good fit to a straight line representing reciprocal
      repair. Repair of single-strand breaks in DNA fitted very well, from 1.0 down to
      1/40 of the initial damage remaining, with tau values of 5-10 min. Repair of DSBs
      fitted almost as well. One set of data showed a strong dependence on temperature
      in the range 10-37 degrees C, with each curve fitting the straight reciprocal
      plot. The tau values for DSBs were 10-100 min, of similar magnitude to those for
      repair of animal tissues. The second-order process with a single time parameter
      could explain the data showing "apparently slowing down" repair previously
      analyzed by multiexponential formulae requiring more parameters. It appears that
      second-order repair may play a larger part in repair processes than has usually
      been assumed. It is suggested that analysis of data on repair of radiation
      induced damage could test the second-order (one-parameter reciprocal) analysis,
      as well as using bi-or multiexponential analyses. If repair in DNA is relevant to
      recovery in mammalian tissues, there may be serious clinical implications, to be
      discussed elsewhere.

PMID- 10409322
TI  - Influence of temperature on radiation-induced inhibition of DNA supercoiling.
AB  - The influence of subnormal temperatures (2, 15 and 28 degrees C) on the effects
      of radiation in MCF-7 cell cultures was studied using the fluorescent (halo)
      nucleoid assay. Increasing the propidium iodide (PI) concentration (0.5-7.5
      microgram/ml PI) resulted in relaxation, i.e. in increasing nucleoid area; higher
      concentrations up to 50 microgram/ml caused rewinding that resulted in nucleoid
      contraction. Rewinding was inhibited by X irradiation (2, 4 and 8 Gy) in a dose
      dependent way. Incubation at subnormal temperature did not influence the nucleoid
      area but did reduce radiation-induced inhibition of rewinding after 4 Gy. The low
      temperature (2 degrees C) during rather than prior to irradiation appeared to
      protect from radiation-induced inhibition of nucleoid rewinding. Decreased
      temperature during irradiation may change the conditions so as to reduce DNA-
      matrix damage induced by radiation.

PMID- 10409324
TI  - No detectable misrejoining in double-minute chromosomes.
AB  - Pulsed-field gel electrophoresis combined with Southern hybridization and rare
      cutting restriction endonuclease digestion has been used recently to quantify
      misrejoining of DNA double-strand breaks (DSBs) resulting from exposure to
      ionizing radiation. Measurements are made 24 h after a high dose of radiation.
      These studies have suggested that a large fraction of DSBs are misrejoined to
      result in gross rearrangements. In the experiments described here, we show that
      elimination of broken DNA also eliminates "misrejoined" DNA. Mouse cells
      resistant to high levels of methotrexate by virtue of 100-fold amplification of
      the dyhydrofolate reductase (Dhfr) gene were treated with 50 and 100 Gy of
      ionizing radiation. The cells were allowed to repair the damage for 24 h. After
      the repair period, the cells were immobilized in agarose. Aliquots of each sample
      were pre-electrophoresed to remove linear DNA molecules smaller than 6 Mbp
      resulting from apoptosis or necrosis. The samples repairing damage from 50 or 100
      Gy that did not receive the pre-electrophoresis showed high levels of label in a
      region of the lane that could be due to misrejoining DNA molecules. However, when
      the DNA from cells undergoing apoptosis or necrosis was removed from these
      samples, the levels of "misrejoined" DNA were reduced to levels far below those
      of unirradiated controls. These results suggest that other radiation-induced
      effects present 24 h after irradiation with 50 or 100 Gy are more significant
      than misrejoining for altering hybridization to regions of the lane outside the
      specific bands. Measurements of misrejoining using PFGE, rare-cutting restriction
      endonucleases, and Southern hybridization are likely to be compromised by
      nonspecific hybridization to broken and difficult-to-digest DNA resulting from
      apoptosis or necrosis.

PMID- 10409323
TI  - Effect of oxygen on radiation-induced DNA damage in isolated nuclei.
AB  - In intact mammalian cells, ionizing radiation causes substantially less damage to
      DNA in the absence of oxygen than in the presence of oxygen. In contrast, when
      DNA is isolated (usually from viruses) and irradiated in solution, the absence of
      oxygen does not lead to a decrease in damage unless low-molecular-weight thiols
      are also present. We investigated an intermediate condition: that of DNA
      irradiated in isolated nuclei. Using an HPLC-based assay of thiols with
      electrochemical detection, we have determined that the nuclear isolation
      procedure leads to the elimination of virtually all low-molecular-weight thiols
      (predominantly glutathione and cysteine). Thus it was our expectation that the
      thiol-depleted state would concurrently eliminate the OER, and thereby mimic the
      isolated DNA system, while retaining structural characteristics of chromosomal
      DNA. We evaluated radiation-induced DNA damage in isolated nuclei by measuring
      single-strand breaks using alkaline elution and by measuring double-strand breaks
      using neutral elution and pulsed-field gel electrophoresis. Despite the removal
      of low-molecular-weight thiol compounds, the oxygen dependence of radiation
      induced damage more closely paralleled that of whole cells than that of DNA in
      solution. Thus damage of DNA irradiated in isolated nuclei is dependent on
      oxygen.

PMID- 10409325
TI  - Irradiation of rat mesangial cells alters the expression of gene products
      associated with the development of renal fibrosis.
AB  - To determine the ability of radiation to modulate mesangial cell expression of
      various molecules involved in promoting extracellular matrix (ECM) accumulation
      [fibronectin, plasminogen activator-inhibitor 1 (Pai1), and tissue inhibitor of
      metalloproteinase-2 (Timp2)] and degradation (Tgfb, plasminogen activators u-PA
      or t-PA, matrix metalloproteinases Mmp2 and Mmp9), 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 (137)Cs gamma rays. After
      irradiation, cells were maintained in serum-free medium for a further 48 h.
      Irradiation of quiescent mesangial cells resulted in significant (P < 0.05) time-
      and dose-dependent increases in Fn and Pai1 mRNA and/or immunoreactive protein.
      Despite an increase in Tgfb1 mRNA, there was little evidence for an increase in
      total Tgfb protein. Indeed, active levels remained unaltered after irradiation.
      Irradiation led to differential changes in MMP expression; active Mmp2 levels
      increased, while Mmp9 levels appeared unaltered. In addition, secretion of
      plasminogen activators into the medium was unchanged after irradiation, while
      secretion of Timp2 increased. We conclude that irradiating mesangial cells leads
      to altered production of various molecules involved in accumulation and
      degradation of extracellular matrix.

PMID- 10409326
TI  - Radiation-induced cytogenetic instability in vivo.
AB  - Radiation-induced cytogenetic instability has been well documented in a number of
      laboratories, and we have hypothesized that such instability is the initiating
      event in the process leading to radiation-induced cancer. To date most studies of
      radiation-induced instability have used systems in which cells are rapidly
      dividing. For this phenomenon to have significance for radiation carcinogenesis,
      it must be established that instability can be induced in vivo in less rapidly
      dividing fully differentiated tissues known to be at risk. In the present study,
      we have examined the kinetics of radiation-induced cytogenetic instability in
      mammary epithelial cells after irradiation in vivo. Having established that
      instability could arise in vivo in intact mammary tissue, we subsequently
      demonstrated a dose-response relationship both in vitro and in vivo and
      demonstrated a lower frequency of instability after fractionated exposures.

PMID- 10409327
TI  - Cooperative inactivation of cells in microcolonies treated with UVA radiation.
AB  - Microcolonies of Madison-Darby canine kidney cells (MDCK II) were exposed to UVA
      radiation, and the number of cells with membrane damage was determined by
      staining with propidium iodide and fluorescence microscopy. The cells were
      clearly damaged in a nonrandom manner: The distribution of damaged cells per
      microcolony was incompatible with the assumption that the cells were damaged
      independently. The data were accurately described by a so-called propagated
      damage model in which a damaged cell can influence its neighbors in a propagating
      manner. These findings do not agree with the common view that optical radiation
      interacts with cells in a way in which damage manifested in a cell is the result
      of absorption of light in the same cell.

PMID- 10409328
TI  - The neoplastic transformation of SCID cells by radiation.
AB  - Severe combined immunodeficiency (SCID) cells are hypersensitive to killing by
      ionizing radiation because of deregulation of DNA-dependent protein kinase (DNA
      PK) and a concomitant deficiency in the repair of DNA double-strand breaks. The
      effect of this condition on the neoplastic transformation of SCID fibroblasts,
      designated SCID 3T1, has been investigated. The spontaneous transformation rate
      was approximately 2 x 10(-5) at early passages and increased up to approximately
      7 x l0(-3) at later passages. The radiation survival curves of transformed cells
      had thresholds and therefore appeared to be qualitatively similar to the survival
      curves of C3H 10T(1/2) mouse fibroblast cells, but the initial slopes were
      steeper. In contrast, per unit dose, SCID cells were more sensitive to
      transformation than 10T(1/2) cells. Eight transformed clones were tested for
      tumorigenicity, and all produced fibrosarcomas in athymic nude mice. Properties
      associated with the tumor suppressor Trp53 (formerly known as p53) were examined
      in three of the clones. In these clones, although Trp53 protein was
      overexpressed, a lower expression of Cdkn1a (formerly known as p21, Cip1) protein
      was observed compared to parental cells. The expression of Trp53 and Cdkn1a and
      the G(1)-phase arrest (one set of data on G(1)-phase delay is included as an
      example) was not induced by ionizing radiation in these transformed clones; each
      clone carried a point mutation in Trp53. This suggests that the deficiency in the
      repair of DNA double-strand breaks increased the tumorigenicity and the genomic
      instability of transformed SCID cells.

PMID- 10409329
TI  - Lenticular opacities in individuals exposed to ionizing radiation in infancy.
AB  - Development of lens opacities and the measures taken to avoid them have clinical
      relevance in the fields of oncology, radiotherapy and radiation protection. The
      aim of this study was to correlate the prevalence of lenticular opacities in
      individuals exposed to ionizing radiation in childhood with radiation dose and
      other possible risk factors. Between 1920 and 1959, about 16,500 children (age
      <18 months) with skin hemangiomas were referred to Radiumhemmet, Karolinska
      University Hospital, 89% of whom were treated with radiotherapy. A total of 484
      exposed individuals and 89 nonexposed controls participated in an
      ophthalmological examination. Lens opacities were found in 357 (37%) of the 953
      lenses examined in the exposed persons. In contrast, lens opacities were observed
      in only 35 (20%) of the 178 lenses examined in the nonexposed control
      individuals. It is concluded that the increased prevalence of cortical and
      posterior subcapsular opacities is related to previous radiotherapy. Age at
      examination was the strongest modifier of risk. Children exposed to a lenticular
      dose of 1 Gy had a 50% increased risk (odds ratio 1.50; 95% confidence interval
      1.10-2.05) of developing a posterior subcapsular opacity and a 35% increased risk
      of a cortical opacity (odds ratio 1.35; 95% confidence interval 1. 07- 1.69).

PMID- 10409331
TI  - Comparison and assessment of electron cross sections for Monte Carlo track
      structure codes.
AB  - The purpose of this study was to make an intercomparison and assessment of cross
      sections for electrons in water used in electron track structure codes. This
      study is intended to shed light on the extent to which the differences between
      the input data and physical and chemical assumptions influence the outcome in
      biophysical modeling of radiation effects. Ionization cross sections and spectra
      of secondary electrons were calculated by various theories. The analyses were
      carried out for water vapor cross sections, as these are more abundant and
      readily available. All suitable published experimental total ionization cross
      sections were fitted by an appropriate function and used for generation of
      electron tracks. Three sets of compiled data were used for comparison of total
      excitation cross sections and mean excitation energy. The tracks generated by a
      Monte Carlo track code, using various combinations of cross sections, were
      compared in terms of radial distributions of interactions and point kernels. The
      spectrum of secondary electrons emitted by the ionization process was found to be
      the factor that has the most influence on these quantities. A different set of
      cross sections for excitation and elastic scattering did not affect the electron
      track structure as much as did ionization cross sections. It is concluded that
      all codes, using different cross sections and in different phase, currently used
      for biophysical modeling exhibit close similarities for energy deposition in
      larger size targets while appreciable differences are observed in B-DNA-size
      targets. We recommend fitted functions to all available suitable experimental
      data for the total ionization and elastic cross sections. We conclude that most
      codes produce tracks in reasonable agreement with the macroscopic quantities such
      as total stopping power and total yield of strand breaks. However, we predict
      differences in frequencies of clustering in tracks from the different models.

PMID- 10409330
TI  - The influence of packing on free radical yields in solid-state DNA: film compared
      to lyophilized frozen solution.
AB  - Radiation-induced free radical damage in solid-state DNA arises from direct-type
      damage mechanisms. In the present study, free radical yields in film and
      lyophilized Na DNA model systems are compared. The free radical yields in
      lyophilized samples are significantly greater than those in films. Since DNA
      conformation cannot account for the differences in free radical yields between
      different DNA preparations, it is proposed that the intermolecular spacing of DNA
      is a critical variable. The differences in the hydration dependence of free
      radical yields between the film and lyophilized DNA model systems are consistent
      with this thesis. The relatively large free radical yields observed in
      lyophilized DNA emphasize the fact that DNA is an extremely effective electron
      and hole scavenger, more so than previously thought.

PMID- 10409332
TI  - Role of DNA-PK subunits in radiosensitization by hyperthermia.
AB  - Thermal radiosensitization is thought to result from inhibition of repair of
      radiation-induced DNA damage, DNA double-strand breaks in particular. Since the
      DNA-dependent protein kinase (DNA-PK) complex plays a major role in the
      nonhomologous end-joining of DSBs, it has been suggested that inactivation of
      this complex as a whole or of its individual subunits by heat might be involved
      in radiosensitization by heat. To test this hypothesis further, the ability of
      heat to enhance the radiosensitivity of cells proficient or deficient in either
      Ku80 or the DNA-PK catalytic subunit (DNA-PKcs) was investigated. In cells of two
      Ku80-deficient and two DNA-PKcs-deficient and double-strand break-deficient cell
      lines, the extent of radiosensitization by heat was not reduced compared to that
      in both their isogenic gene-complemented counterparts as well as to that in their
      parental cells. Thus radiosensitization by hyperthermia can be obtained
      irrespective of the Ku80 or DNA-PKcs status in cells. Therefore, Ku80 or DNA-PKcs
      and hence nonhomologous DSB end-joining do not play a crucial role in the
      enhancement of cellular radiosensitivity by hyperthermia.

PMID- 10409334
TI  - The prince and the butterfly.

PMID- 10409333
TI  - Comments on ICRU report no. 49: stopping powers and ranges for protons and alpha
      particles.
AB  - The International Commission on Radiation Units and Measurements (ICRU) published
      Report No. 49, Stopping Powers and Ranges for Protons and Alpha Particles, in
      1993. Since the report shows only limited comparisons to experimental data, this
      Commentary discusses limits on the accuracy of its tables. Some of the stopping
      tabulations appear to have unusual variations for high energies (>1 MeV/nucleon)
      of the order of 2-4%, while the lower energies have possible errors of 10-20% for
      those targets which were not fitted with new data.

PMID- 10409335
TI  - Lessons from metabolic engineering for functional genomics and drug discovery.

PMID- 10409336
TI  - Target-based discovery of crop protection chemicals.

PMID- 10409337
TI  - An Icelandic saga on a centralized healthcare database and democratic decision
      making.

PMID- 10409338
TI  - Nuffield Council dishes up biotech report.

PMID- 10409339
TI  - BRITECH R&D fund.

PMID- 10409340
TI  - Boning up on gene therapy.

PMID- 10409341
TI  - Library-to-library screening.

PMID- 10409342
TI  - Monarch Bt-corn paper questioned.

PMID- 10409343
TI  - US agbio controversies continue.

PMID- 10409344
TI  - Swiss soiled seed prompts tolerance question.

PMID- 10409345
TI  - UK interest groups take all sides of GM issue.

PMID- 10409346
TI  - EuropaBio unit created to boost agbio defense.

PMID- 10409347
TI  - Was PolyMASC's early demise self-inflicted?

PMID- 10409348
TI  - Genentech relaunched with independence intact.

PMID- 10409349
TI  - Engineering neurons for Parkinson's disease.

PMID- 10409350
TI  - New life for sperm-mediated transgenesis?

PMID- 10409351
TI  - A green light for protein folding.

PMID- 10409352
TI  - Finding Cinderella's slipper--proteins that fit.

PMID- 10409353
TI  - On the wagon--DNA polymerase joins "H-bonds anonymous".

PMID- 10409354
TI  - Metabolic control analysis in biotechnology and medicine.

PMID- 10409355
TI  - Patenting plants: what to claim.

PMID- 10409356
TI  - Recent patents in receptor studies.

PMID- 10409358
TI  - Rewriting biotechnology's story.

PMID- 10409357
TI  - Accurate determination of relative messenger RNA levels by RT-PCR.

PMID- 10409362
TI  - US should rejoin UNESCO.

PMID- 10409361
TI  - Arthritis drug discovery.

PMID- 10409365
TI  - GM roundup.

PMID- 10409364
TI  - Human monoclonal antibodies: the emperor's new clothes?

PMID- 10409366
TI  - US says no to GM labels.

PMID- 10409367
TI  - A yen for biotech.

PMID- 10409368
TI  - Abbott's $335 M HIV buy.

PMID- 10409369
TI  - British Biotech settles up.

PMID- 10409370
TI  - Neuer Markt disappoints.

PMID- 10409372
TI  - Research collaborations.

PMID- 10409371
TI  - New bioengineering institute.

PMID- 10409373
TI  - Cartoon.

PMID- 10409374
TI  - DNA cryptography.

PMID- 10409375
TI  - MMP-2 structure solved.

PMID- 10409376
TI  - Y clone?

PMID- 10409377
TI  - African rice virus overcome?

PMID- 10409378
TI  - Teaching an old reporter new tricks.

PMID- 10409379
TI  - Sugar-free spuds.

PMID- 10409380
TI  - Engineering neurons to treat Parkinson's disease.

PMID- 10409381
TI  - Proteomics get complex.

PMID- 10409383
TI  - Efficient antigen presentation.

PMID- 10409382
TI  - Anti-inflammatory antibodies.

PMID- 10409385
TI  - Illuminating protein folding.

PMID- 10409384
TI  - Weed whacker.

PMID- 10409386
TI  - Peptide mimicry for cancer vaccines?

PMID- 10409392
TI  - In memoriam anthony dipple 

PMID- 10409387
TI  - Different modes of expression of AMPA and NMDA receptors in hippocampal synapses.
AB  - Postembedding immunogold labeling was used to determine the relationship between
      AMPA and NMDA receptor density and size of Schaffer collateral-commissural (SCC)
      synapses of the adult rat. All SCC synapses expressed NMDA receptors. AMPA and
      NMDA receptors were colocalized in at least 75% of SCC synapses; the ratio of
      AMPA to NMDA receptors was a linear function of postsynaptic density (PSD)
      diameter, with AMPA receptor number dropping to zero at a PSD diameter of
      approximately 180 nm. These findings indicate that 'silent' SCC synapses are
      smaller than the majority of SCC synapses at which AMPA and NMDA receptors are
      colocalized. Thus synapse size may determine important properties of SCC
      synapses.

PMID- 10409393
TI  - Design, synthesis, and characterization of 7-methoxy-4-(aminomethyl)coumarin as a
      novel and selective cytochrome P450 2D6 substrate suitable for high-throughput
      screening.
AB  - In this study, a selective substrate for cytochrome P450 2D6 was designed using a
      small molecule model developed by M. J. De Groot et al. [(1997) Chem. Res.
      Toxicol. 10, 41-48]. The substrate, 7-methoxy-4-(aminomethyl)coumarin (MAMC), and
      its putative O-demethylated metabolite 7-hydroxy-4-(aminomethyl)coumarin (HAMC)
      were synthesized, and their respective fluorescence properties were
      characterized. The selectivity of MAMC for P450 2D6 was characterized using
      microsomes containing single human P450 isoenzymes and human liver microsomes.
      Formation of the metabolic product HAMC was easily assessed in real time with
      fluorescence spectroscopy, since MAMC and HAMC excitation and emission
      wavelengths differed significantly. HPLC analysis confirmed that HAMC was the
      single metabolic product of MAMC and that HAMC formation accounts for the total
      increase in fluorescence. It was found that, in microsomes from yeast or
      lymphoblastoid cells selectively expressing P450 isoenzymes, MAMC was selective
      for P450 2D6 at a concentration of 25 microM with only P450 1A2 contributing
      significantly to the formation of HAMC. P450s 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4,
      and 3A5 were shown not to metabolize MAMC at a concentration of 25 microM. K(m)
      and v(max) values of MAMC for P450 2D6 were found to be 26.2 +/- 2.8 microM and
      2.9 +/- 0.07 min(-)(1), respectively. For P450 1A2, MAMC was found to have a K(m)
      value of 29.7 +/- 6.2 microM and a v(max) of 0.57 +/- 0.07 min(-)(1). Formation
      of HAMC in human liver microsomes could be completely inhibited by quinidine, at
      a concentration of 0.5 microM selective for P450 2D6, and furafylline, at a
      concentration of 30 microM selective for P450 1A2. In conclusion, O-demethylation
      of 7-methoxy-4-(aminomethyl)coumarin is a rapid and easily determined parameter
      for P450 2D6 activity and, due to the fluorescent properties of the metabolite
      formed, may be a valuable new tool for high-throughput screening purposes.

PMID- 10409394
TI  - Metabolism of arsenic in primary cultures of human and rat hepatocytes.
AB  - The liver is considered a major site for methylation of inorganic arsenic (iAs).
      However, there is little data on the capacity of human liver to methylate iAs.
      This work examined the metabolism of arsenite (iAs(III)), arsenate (iAs(V)),
      methylarsine oxide (MAs(III)O), methylarsonic acid (MAs(V)), dimethylarsinous
      acid (DMAs(III)), and dimethylarsinic acid (DMAs(V)) in primary cultures of
      normal human hepatocytes. Primary rat hepatocytes were used as methylating
      controls. iAs(III) and MAs(III)O were metabolized more extensively than iAs(V)
      and MAs(V) by either cell type. Neither human nor rat hepatocytes metabolized
      DMAs(III) or DMAs(V). Methylation of iAs(III) by human hepatocytes yielded
      methylarsenic (MAs) and dimethylarsenic (DMAs) species; MAs(III)O was converted
      to DMAs. The total methylation yield (MAs and DMAs) increased over the range of
      0.1 to 4 microM iAs(III). However, DMAs production was inhibited by iAs(III) in a
      concentration-dependent manner, and the DMAs/MAs ratio decreased. iAs(III) (10
      and 20 microM) inhibited both methylation reactions. Inhibition of DMAs synthesis
      resulted in accumulation of iAs and MAs in human hepatocytes, suggesting that
      dimethylation is required for iAs clearance from cells. Methylation capacities of
      human hepatocytes obtained from four donors ranged from 3.1 to 35.7 pmol of
      iAs(III) per 10(6) cells per hour and were substantially lower than the
      methylation capacity of rat hepatocytes (387 pmol of iAs(III) per 10(6) cells per
      hour). The maximal methylation rates for either rat or human hepatocytes were
      attained between 0.4 and 4 microM iAs(III). In summary, (i) human hepatocytes
      methylate iAs, (ii) the capacities for iAs methylation vary among individuals and
      are saturable, and (iii) moderate concentrations of iAs inhibit DMAs synthesis,
      resulting in an accumulation of iAs and MAs in cells.

PMID- 10409395
TI  - Molecular dosimetry of N-7 guanine adduct formation in mice and rats exposed to
      1,3-butadiene.
AB  - 1,3-Butadiene (BD) is a high-volume chemical used in the production of rubber and
      plastic. BD is a potent carcinogen in mice and a much weaker carcinogen in rats,
      and has been classified as a probable human carcinogen. Upon metabolic activation
      in vivo, it forms DNA-reactive metabolites, 1,2-epoxy-3-butene (EB), 1,2:3, 4
      diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBD). The molecular dosimetry
      of N-7 guanine adduct formation by these metabolites of BD in liver, lung, and
      kidney of B6C3F1 mice and F344 rats exposed to 0, 20, 62.5, or 625 ppm BD was
      studied. The adducts, racemic and meso forms of N-7-(2,3,4-trihydroxybut-1
      yl)guanine (THB-Gua), N-7-(2-hydroxy-3-buten-1-yl)guanine (EB-Gua I), and N-7-(1
      hydroxy-3-buten-2-yl)guanine (EB-Gua II), were isolated from DNA by neutral
      thermal hydrolysis, desalted on solid-phase extraction cartridges, and
      quantitated by LC/ESI(+)/MS/MS. The number of adducts per 10(6) normal guanine
      bases for a given adduct was higher in mice than rats exposed to 625 ppm BD, but
      generally similar at lower levels of exposure. The THB-Gua adducts were the most
      abundant (6-27 times higher than EB-Gua) and exhibited a nonlinear exposure
      response relationship. In rats, the exposure-response curves for the formation of
      THB-Gua adducts reached a plateau after 62.5 ppm, suggesting saturation of
      metabolic activation. The number of THB-Gua adducts continued to increase in mice
      between 62.5 and 625 ppm BD. In contrast, the less common EB-Gua adducts had a
      linear exposure-response relationship in both species. Combining the information
      from this study with previous data on BD metabolism, we were able to estimate the
      number of THB-Gua that resulted from DEB and EBD, and conclude that most of the
      THB-Gua is formed from EBD. We hypothesize that most of the EBD arises from the
      immediate conversion of DEB to EBD within the endoplasmic reticulum. This study
      highlights the need for measurements of the levels of EBD in tissues of rats and
      mice and for the development of a unique biomarker for DEB that is available for
      binding to DNA.

PMID- 10409396
TI  - Quantitative particle-induced X-ray emission imaging of rat olfactory epithelium
      applied to the permeability of rat epithelium to inhaled aluminum.
AB  - Neurotoxicity from chronic metal inhalation has been suggested as an underlying
      contributor to late-developing neurodegenerative diseases that have symptoms
      similar to Alzheimer's and Parkinson's syndromes. If inhaled metals contribute to
      pathogenesis of these diseases, identifying, localizing, and quantitating metal
      deposition(s) within specific target regions of the central nervous system will
      be critical to our understanding of the mechanisms. Standard analytical
      techniques used to date require exposure to extremely high concentrations of
      metals to meet analytical detection limits in small tissue areas. The relevance
      to lower-dose environmentally relevant exposures and potential protective
      barriers is therefore questionable. The feasibility of microbeam particle-induced
      X-ray emission is investigated as a method for rapidly scanning tissues to study
      the inhalation of metals, nasal permeability, and central nervous system
      deposition. The optimal beam spot and analysis time used to image the rat
      olfactory epithelium to facilitate the rapid detection of aluminum localizations
      were determined. Measurements of aluminum localizations in rat olfactory bulb and
      brain sections are also presented.

PMID- 10409397
TI  - Inactivation of cytochrome P450 2E1 by benzyl isothiocyanate.
AB  - The cytochrome P450 enzymes constitute a family of phase I enzymes that play a
      prominent role in the metabolism of a great variety of endogenous and xenobiotic
      compounds. In this study, the kinetics for the inactivation of cytochrome P450
      2E1 by benzyl isothiocyanate (BITC) were elucidated. BITC is a naturally
      occurring compound found in cruciferous vegetables such as broccoli. BITC
      inhibited the 7-ethoxy-4-(trifluoromethyl)coumarin (7-EFC) O-deethylation
      activity of purified and reconstituted P450 2E1 in a time- and concentration
      dependent manner. The concentration of inactivator needed for half-maximal
      inactivation (K(I)) was 13 microM, and the maximum rate of inactivation at
      saturation (k(inact)) was 0.09 min-1. The partition ratio for the inactivation of
      P450 2E1 by BITC was found to have an approximate value of 27. Inactivation of
      P450 2E1 by BITC was dependent on the presence of NADPH. Following incubation for
      5 min with BITC, a 65% loss in enzymatic activity was observed, while
      approximately 74% of the spectrally detectable enzyme remained. 7-Ethoxycoumarin
      (7-EC), a substrate of P450 2E1, protected P450 2E1 from BITC inactivation,
      reducing the loss in 7-EFC O-deethylation activity from 50 to 18% when a 1:20
      molar ratio of BITC:7-EC was used. Inactivation of P450 2E1 by BITC was
      irreversible, and no activity was regained after extensive washes to remove BITC.
      Addition of cytochrome b(5) to the reconstituted system did not affect the rate
      of inactivation. Reductase activity was unaffected by BITC. The results reported
      here indicate that BITC is a mechanism-based inactivator of cytochrome P450 2E1
      and that the inactivation was primarily due to a modification of the apoprotein
      by BITC.

PMID- 10409398
TI  - Nuclear targeting and nuclear retention of anthracycline-formaldehyde conjugates
      implicates DNA covalent bonding in the cytotoxic mechanism of anthracyclines.
AB  - The anthracycline, antitumor drugs doxorubicin (DOX), daunorubicin (DAU), and
      epidoxorubicin (EPI) catalyze production of formaldehyde through induction of
      oxidative stress. The formaldehyde then mediates covalent bonding of the drugs to
      DNA. Synthetic formaldehyde conjugates of DOX, DAU, and EPI, denoted Doxoform
      (DOXF), Daunoform (DAUF), and Epidoxoform (EPIF), exhibit enhanced toxicity to
      anthracycline-sensitive and -resistant tumor cells. Uptake and retention of
      parent anthracycline antitumor drugs (DOX, DAU, and EPI) relative to those of
      their formaldehyde conjugates (DOXF, DAUF, and EPIF) were assessed by flow
      cytometry in both drug-sensitive MCF-7 cells and drug-resistant MCF-7/ADR cells.
      The MCF-7 cells took up more than twice as much drug as the MCF-7/ADR cells, and
      both cell lines took up substantially more of the formaldehyde conjugates than
      the parent drugs. Both MCF-7 and MCF-7/ADR cells retained fluorophore from DOXF,
      DAUF, and EPIF hours after drug removal, while both cell lines almost completely
      expelled DOX, DAU, and EPI within 1 h. Longer treatment with DOX, DAU, and EPI
      resulted in modest drug retention in MCF-7 cells following drug removal but poor
      retention of DOX, DAU, and EPI in MCF-7/ADR cells. Fluorescence microscopy showed
      that the formaldehyde conjugates targeted the nuclei of both sensitive and
      resistant cells, and remained in the nucleus hours after drug removal.
      Experiments in which [(3)H]Doxoform was used, synthesized from doxorubicin and
      [(3)H]formaldehyde, also indicated that Doxoform targeted the nucleus. Elevated
      levels of (3)H were observed in DNA isolated from [(3)H]Doxoform-treated MCF-7
      and MCF-7/ADR cells relative to controls. The results implicate drug-DNA covalent
      bonding in the tumor cell toxicity mechanism of these anthracyclines.

PMID- 10409399
TI  - Origins of conformational differences between cis and trans DNA adducts derived
      from enantiomeric anti-benzo[a]pyrene diol epoxides.
AB  - The two enantiomeric metabolites of the carcinogen precursor benzo[a]pyrene, (+)-
      and (-)-anti-BPDE [(7R,8S)-dihydroxy-(9S, 10R)-epoxy-7,8,9,10
      tetrahydrobenzo[a]pyrene and the corresponding 7S,8R,9R,10S enantiomer,
      respectively], bind predominantly to the exocyclic amino groups of dG residues in
      double-stranded DNA by either cis or trans addition to yield four
      stereoisomerically distinct [BP]-N(2)-dG adducts. Both the 10S (+)-trans and 10R
      (-)-transadducts assume minor groove conformations in normal, full duplexes, but
      with opposite 5' or 3' orientations, respectively, relative to the modified
      strand. In contrast, the 10R (+)-cis and 10S (-)-cis adducts assume oppositely
      oriented base-displaced intercalative conformations in normal duplexes, with the
      inserted pyrenyl residues pointing toward the major groove in the (+)-cis isomer
      and toward the minor groove in the (-)-cis isomer. A BPDE-modified nucleoside is
      a small system which can be studied by computational methods with a very thorough
      survey of the potential energy surface. To investigate conformational differences
      between cis and trans adducts, and to elucidate origins governing the opposite
      orientations of these (+)- and (-)-diol epoxide adducts, we have carried out
      extensive investigations of the (+)- and (-)-trans-anti- and (+)- and (-)-cis
      anti-[BP]-N(2)-dG deoxynucleoside adduct pairs. We report results for the (+)-
      and (-)-cis-anti pair, and compare them with the (+)- and (-)-trans-anti adducts.
      We created 373 248 different conformers for each adduct, which uniformly sampled
      at 5 degrees intervals the possible rotamers about three flexible torsion angles
      governing base (chi) and carcinogen (alpha' and beta') orientations, and computed
      each of their energies. The potential energy surface of the molecule was then
      mapped from these results. While four potential energy wells or structural
      domains are found for the (+)-trans adduct and four for the (-)-trans adduct,
      only two of these four domains are favored for each of the two cis adducts. In
      both cis and trans adducts, the (+)/(-) pairs of each structural domain are
      nearly mirror images. The most favored of the domains in both cis and trans
      adducts is observed experimentally in the duplexes containing each of these [BP]
      N(2)-dG lesions. The opposite orientations in both cis and trans adducts stem
      from steric crowding at the benzylic ring, engendered when a (+) stereoisomer is
      rotated into the analogous conformation of its (-) partner, and vice versa.
      Furthermore, the key role of the difference in absolute configuration between
      trans and cis adducts at the hydroxyls of C9 and C8 in governing conformational
      preferences and flexibility is delineated. Cis adducts are less conformationally
      flexible than trans adducts because they are inherently more sterically crowded,
      with C9-OH and C8-OH on the same side of the benzylic ring as guanine and sugar,
      while they are on the opposite side of the benzylic ring in the trans adducts.
      Consequently, the cis adducts inherently favor less the minor groove position
      adopted by trans adducts in DNA duplexes because the C9-OH and C8-OH are directed
      inward into the minor groove in the cis adducts. In the trans adducts, the C9-OH
      and C8-OH are directed outward, away from the interior of the minor groove.
      Observed differential processing of these four adducts by replication, repair,
      and transcription enzymes may well stem from their differing conformational
      preferences.

PMID- 10409400
TI  - Metabolism of genistein by rat and human cytochrome P450s.
AB  - The metabolism of genistein (4',5,7-trihydroxyisoflavone), a phytoestrogen
      derived from soy products, was investigated using rat and human liver microsomes
      and recombinant human cytochrome P450 enzymes. Metabolism of genistein by
      microsomes obtained from rats treated with pyridine, phenobarbital, beta
      naphthoflavone, isosafrole, pregnenolone-16alpha-carbonitrile, or 3
      methylcholanthrene resulted in very different product profiles consisting of five
      different NADPH- and time-dependent metabolites as observed by HPLC reverse-phase
      analysis at 260 nm. The metabolism of genistein was also investigated with
      recombinant human cytochrome P450 1A1, 1A2, 1B1, 2B6, 2C8, 2E1, or 3A4. P450s
      1A1, 1A2, 1B1, and 2E1 metabolized genistein to form predominantly one product
      (peak 3) with smaller amounts of peaks 1 and 2. P450 3A4 produced two different
      products (peaks 4 and 5). Product peaks 1-3 eluted off the HPLC column prior to
      the parent compound genistein, and the UV/vis spectra, GC/MS, and ESI/MS/MS
      analyses support the conclusion that these products result from hydroxylation of
      genistein. The product peak 3 has been identified by tandem mass spectrometry as
      3',4',5, 7-tetrahydroxyisoflavone, also known as orobol, and peaks 1 and 2 appear
      to be hydroxylated at position 6 or 8.

PMID- 10409401
TI  - Detoxification of methylglyoxal by the nucleophilic bidentate,
      phenylacylthiazolium bromide.
AB  - Dicarbonyl-containing compounds such as methylglyoxal (MG) are toxic to cells
      since they can interact with the nucleophilic centers of macromolecules. MG has
      been found to accumulate during hyperglycemia, and it has been suggested that
      this reactive dicarbonyl may contribute to the tissue damage and long-term
      complications of diabetes. A sensitive bacterial assay for investigating the
      ability of nucleophilic agents to interact with and detoxify MG has been
      developed. This assay utilizes the sensitivity of exponential phase cells of an
      Escherichia coli double mutant lacking the KefB and KefC potassium channels
      toward MG. The bidentate nucleophile, phenylacylthiazolium bromide (PTB), was
      found to protect and allow the growth of E. coli cells in the presence of either
      externally added or endogenously produced MG. In the absence of PTB, growth was
      completely inhibited and rapid cell death occurred under these conditions. PTB
      protected E. coli against MG almost as well as aminoguanidine, a compound shown
      previously to be involved in detoxification. The level of protection by PTB
      against MG was much greater than for the endogenous nucleophile, glutathione.
      These data suggested that PTB could interact with and detoxify MG. The mechanism
      of this interaction was characterized by NMR and mass spectroscopy.

PMID- 10409402
TI  - Metabolism of benzo[a]pyrene to trans-7,8-dihydroxy-7, 8-dihydrobenzo[a]pyrene by
      recombinant human cytochrome P450 1B1 and purified liver epoxide hydrolase.
AB  - Recombinant human enzymes expressed in membranes obtained from Escherichia coli
      transformed with cytochrome P450 (P450) and NADPH-P450 reductase cDNAs were used
      to identify the human P450 enzymes that are most active in catalyzing the
      oxidative transformation of benzo[a]pyrene in vitro. Activation of benzo[a]pyrene
      to genotoxic products that cause induction of umu gene expression in Salmonella
      typhimurium NM2009 by P450 1A1 and P450 1B1 enzymes was found to be enhanced by
      inclusion of purified epoxide hydrolase (isolated from rat or human livers) with
      the reaction mixture. High-performance liquid chromatographic analysis showed
      that P450 1B1 catalyzed benzo[a]pyrene to trans-7, 8-dihydroxy-7,8
      dihydrobenzo[a]pyrene at level of approximately 3 nmol min(-)(1) nmol of P450(
      )(1) only when epoxide hydrolase was present and P450 1A1 (with the hydrolase)
      was able to catalyze benzo[a]pyrene at one-tenth of the activity catalyzed by
      P450 1B1. Kinetic analysis showed that ratio of V(max) to K(m) for the formation
      of trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene in this assay system was 3.2
      fold higher in CYP1B1 than in CYP1A1. Other human P450s (including P450s 1A2,
      2E1, and 3A4) were found to have very low or undetectable activities toward the
      formation of trans-7, 8-dihydroxy-7,8-dihydrobenzo[a]pyrene. A reconstituted
      system containing purified P450 1B1, rabbit liver NADPH-P450 reductase, and human
      liver epoxide hydrolase was found to catalyze benzo[a]pyrene to trans-7,8
      dihydroxy-7,8-dihydrobenzo[a]pyrene at a rate of 0.86 nmol min(-)(1) nmol of
      P450(-)(1); the activities were found to be largely dependent on the presence of
      sodium cholate in the system. These results suggest that P450 1B1 is a principal
      enzyme in catalyzing the oxidation of benzo[a]pyrene to trans-7,8-dihydroxy-7, 8
      dihydrobenzo[a]pyrene and that the catalytic functions of P450 1B1 may determine
      the susceptibilities of individuals to benzo[a]pyrene carcinogenesis.

PMID- 10409404
TI  - Characterization of multiple products of cytochrome P450 2A6-catalyzed cotinine
      metabolism.
AB  - The primary metabolite of nicotine in smokers is cotinine. Cotinine is further
      metabolized to trans-3'-hydroxycotinine, the major urinary metabolite of nicotine
      in tobacco users. It was recently reported that cytochrome P450 2A6 catalyzes the
      conversion of cotinine to trans-3'-hydroxycotinine. In this work, we report that
      P450 2A6 metabolizes cotinine not only to trans-3'-hydroxycotinine but also to 5'
      hydroxycotinine, norcotinine, and a fourth as yet unidentified metabolite. The
      products of baculovirus-expressed P450 2A6 [methyl-(3)H]cotinine metabolism were
      analyzed by radioflow HPLC. Three (3)H-labeled metabolites were detected and were
      present in approximately equal amounts. The identities of two of the metabolites
      were confirmed to be 5'-hydroxycotinine and trans-3'-hydroxycotinine by LC/MS/MS
      and LC/MS analysis and comparison to standards. The third product was not
      identified. A fourth product of P450 2A6-catalyzed cotinine metabolism was
      detected by LC/MS. It was identified by cochromatography with a standard and MS
      and MS/MS data to be norcotinine. An attempt was made to further characterize the
      unidentified (3)H-labeled metabolite by comparison to the cotinine metabolites
      generated by hamster liver microsomes. Hamster liver microsomes contain a P450,
      2A8, which is closely related to P450 2A6, and have previously been shown to
      metabolize cotinine to three hydroxylated products, trans-3'-hydroxycotinine, 5'
      hydroxycotinine, and N-(hydroxymethyl)norcotinine. We were unable to confirm that
      N-(hydroxymethyl)norcotinine was the unidentified cotinine metabolite generated
      by P450 2A6.

PMID- 10409403
TI  - Synthesis and biochemical properties of cyanuric acid nucleoside-containing DNA
      oligomers.
AB  - 1-(2-Deoxy-beta-D-erythro-pentofuranosyl)cyanuric acid (cyanuric acid nucleoside,
      dY) (1) has been shown to be formed upon exposure of DNA components to ionizing
      radiation and excited photosensitizers. To investigate the biological and
      structural significance of dY residue in DNA, the latter modified 2'
      deoxynucleoside was chemically prepared and then site-specifically incorporated
      into oligodeoxyribonucleotides (ODNs). This was achieved in good yields using the
      phosphoramidite approach. For this purpose, a convenient glycosylation method
      involving 3,5-protected 2-deoxyribofuranoside chloride and cyanuric acid (2,4,6
      trihydroxy-1,3,5-triazine) was devised. The anomeric mixture of modified 2'
      deoxyribonucleosides (1/2 alpha/beta) was resolved by silica gel purification of
      the 5'-O-dimethoxytritylated derivatives, and then, phosphitylation afforded the
      desired beta-phosphoramidite monomer (5). After solid-phase condensation and
      final deprotection, the purity and the integrity of the modified synthetic DNA
      fragments were checked using different complementary techniques such as HPLC and
      polyacrylamide gel electrophoresis, together with electrospray ionization and
      MALDI-TOF mass spectrometry. The presence of cyanuric acid nucleoside in a 14-mer
      was found to have destabilizing effects on the double-stranded DNA fragment as
      inferred from melting temperature measurements. The piperidine test applied to dY
      containing ODNs supported the high stability of cyanuric acid nucleoside inserted
      into the oligonucleotide chain. Several enzymatic experiments aimed at
      determining the biological features of such a DNA lesion were carried out. Thus,
      processing of dY by nuclease P(1), snake venom phosphodiesterase (SVPDE), calf
      spleen phosphodiesterase (CSPDE), and repair enzymes, including Escherichia coli
      endonuclease III (endo III) and Fapy glycosylase (Fpg), was investigated.
      Finally, a 22-mer ODN bearing a cyanuric acid residue was used as a template to
      study the in vitro nucleotide incorporation opposite the damage by the Klenow
      fragment of E. coli polymerase I.

PMID- 10409405
TI  - Tamoxifen-DNA adducts detected in the endometrium of women treated with
      tamoxifen.
AB  - Women treated for breast cancer with tamoxifen are at increased risk of
      developing endometrial cancer. This carcinogenic effect has been attributed to
      estrogenic stimulation and/or to a genotoxic effect of this drug. To examine
      genotoxicity, we developed a (32)P-postlabeling TLCL/HPLC procedure for
      quantitative analysis of tamoxifen-DNA adducts in endometrial tissue. This assay
      is several orders of magnitude more sensitive than those previously used for this
      purpose; with it, we can detect five tamoxifen-DNA adducts in 10(11) bases.
      Endometrial tissue was obtained from women undergoing tamoxifen therapy and from
      untreated control subjects. DNA adducts, identified as trans and cis epimers of
      alpha-(N(2)-deoxyguanosinyl)tamoxifen, were detected in six of thirteen patients
      in the tamoxifen-treated group. Levels of trans and cis adducts ranged from 0.5
      to 8.3 and from 0.4 to 4.8 adducts/10(8) nucleotides, respectively. Tamoxifen-DNA
      adducts were not detected in endometrial tissue obtained from the control
      subjects. We conclude from this study that one or more tamoxifen metabolites
      react with endometrial DNA to form covalent adducts, establishing the potential
      genotoxicity of this drug for women and suggesting the use of TAM-DNA adducts as
      biomarkers for investigations of tamoxifen-induced endometrial cancer.

PMID- 10409406
TI  - Modification of histidine residues by 4,5-epoxy-2-alkenals.
AB  - The reactions of 4,5(E)-epoxy-2(E)-heptenal with 4-methylimidazole and N(alpha)
      acetyl-L-histidine methyl ester were studied to characterize the adducts produced
      in the modification of histidine residues by epoxyalkenals and to develop a
      methodology for the determination of these adducts in protein hydrolysates. The
      reaction products, which were isolated and characterized, resulted in the Michael
      adducts produced in the addition of one of the imidazolic nitrogens to the carbon
      carbon double bond of the epoxyalkenal. Only some of the theoretical isomers were
      produced. Thus, in the reaction with 4-methylimidazole, the main product was 4, 5
      epoxy-3-(4-methylimidazol-1-yl)heptanol (88%), although the formation of 4,5
      epoxy-3-(5-methylimidazol-1-yl)heptanol (12%) was also observed. On the other
      hand, the reaction with N(alpha)-acetyl-L-histidine methyl ester produced
      exclusively N(alpha)-acetyl-1-[1'-(1' ',2' '-epoxybutyl)-3'-hydroxypropyl]-L
      histidine methyl ester. This last compound was used to develop a procedure for
      the determination of 4, 5(E)-epoxy-2(E)-heptenal-histidine adducts in protein
      hydrolysates. When this procedure was applied to the analysis of bovine serum
      albumin treated with 0.01-10 mM 4,5(E)-epoxy-2(E)-heptenal, the formation of the
      adduct was observed and its concentration increased with the concentration of the
      aldehyde and the incubation time, and was parallel to the histidine losses
      observed in the protein after acid hydrolysis as well as to the formation of
      protein carbonyls. In addition, the number of histidine residues lost in the
      protein was very similar to the number of adduct residues produced, suggesting
      that the addition reaction is the major mechanism for histidine losses suffered
      by proteins following their reaction with epoxyalkenals.

PMID- 10409407
TI  - 32P-Postlabeling of N-(deoxyguanosin-8-yl)arylamine adducts: a comparative study
      of labeling efficiencies.
AB  - 32P-Postlabeling is an extremely powerful technique for the detection of DNA
      adducts. Typically, the quantitation of DNA adducts by (32)P-postlabeling is
      achieved by relative adduct labeling, via comparison of the radioactivity
      incorporated into the adducts to that associated with the normal nucleotides.
      This approach is based on a number of assumptions, the foremost being that normal
      and adducted nucleotide 3'-phosphates are converted to 3', 5'-bisphosphates with
      similar efficiencies. To evaluate labeling efficiencies for specific DNA adducts,
      we conducted a comparative study of the kinetics of phosphorylation by T(4)
      polynucleotide kinase using 2'-deoxyguanosine 3'-phosphate (dG3'p) and a series
      of N-(deoxyguanosin-8-yl)arylamine 3'-phosphate adduct standards (dG3'p-C8-Ar, Ar
      being 4-aminobiphenyl, 3- and 4-methylaniline, and 2,4- and 3,4-dimethylaniline).
      Phosphorylation of dG3'p and the dG3'p-C8-Ar adducts followed Michaelis-Menten
      kinetics. The apparent turnover numbers were 40-240-fold lower when labeling
      dG3'p-C8-Ar adducts compared to that when labeling dG3'p. The apparent
      specificity constant calculated for dG3'p-C8-4-aminobiphenyl (1.4 microM(-)(1)
      min(-)(1)) was approximately 4-fold lower than that (5. 4 microM(-)(1) min(-)(1))
      found for dG3'p. Apparent specificity constants for the monoarylamine adducts
      were even lower (0.043-0.23 microM(-)(1) min(-)(1)) and decreased in the
      following order: 4-methylaniline > 3,4-dimethylaniline > 3-methylaniline > 2, 4
      dimethylaniline. Similar experiments conducted with dG3'p-C8-Ar standards for 2
      methylaniline and 2,3-dimethylaniline produced very poor and irreproducible
      labeling. These results indicate that (32)P-postlabeling of dG3'p-C8-Ar adducts
      is less efficient than that of dG3'p and suggest that normal nucleotides will be
      labeled preferentially to the arylamine adducts under kinetically controlled
      conditions. The data also indicate a further decrease in labeling efficiency upon
      substitution ortho to the amino group (e.g., 2, 4-dimethylaniline). In addition,
      the ATP concentrations required for optimal labeling were found to be
      substantially higher than those used in typical (32)P-postlabeling assays. Since
      the high specific activity of carrier-free [gamma-(32)P]ATP precludes increasing
      the ATP concentration to a significant extent, these data emphasize the need for
      using highly efficient adduct enrichment procedures when conducting (32)P
      postlabeling analyses of DNA adducts.

PMID- 10409408
TI  - Prediction of fathead minnow acute toxicity of organic compounds from molecular
      structure.
AB  - Interest in the prediction of toxicity without the use of experimental data is
      growing, and quantitative structure-activity relationship (QSAR) methods are
      valuable for such predictions. A QSAR study of acute aqueous toxicity of 375
      diverse organic compounds has been developed using only calculated structural
      features as independent variables. Toxicity is expressed as -log(LD(50)) with the
      units -log(millimoles per liter) and ranges from -3 to 6. Multiple linear
      regression and computational neural networks (CNNs) are utilized for model
      building. The best model is a nonlinear CNN model based on eight calculated
      molecular structure descriptors. The root-mean-square log(LD(50)) errors for the
      training, cross-validation, and prediction sets of this CNN model are 0.71, 0.77,
      and 0.74 -log(mmol/L), respectively. These results are compared to a previous
      study with the same data set which included many more descriptors and used
      experimental data in the descriptor pool.

PMID- 10409409
TI  - Mutilations: a necessary evil?

PMID- 10409410
TI  - Musculoskeletal ultrasonography: seeing is believing.

PMID- 10409411
TI  - The role of small ruminants in the epidemiology and transmission of foot-and
      mouth disease.
AB  - Despite representing the largest part of the world's foot-and-mouth disease (FMD)
      susceptible domestic livestock, sheep and goats have generally been neglected
      with regard to their epidemiological role. This is partly due to the often
      inapparent nature of the disease in these hosts. Nevertheless, their ability to
      become carriers represents a reservoir for further infection and spread of
      disease, and so trade of live sheep and goats present a major risk of entry of
      FMD to disease-free countries. Research and epidemiological studies continue to
      be necessary in order both to prevent the entry of the virus and to assist in
      control should the disease reoccur. This review concentrates primarily on more
      recent studies relating to sheep and goats and, in particular, considers the
      importance of these hosts in the overall epidemiology of FMD.

PMID- 10409412
TI  - Behavioural, endocrine and cardiac responses in young calves undergoing dehorning
      without and with use of sedation and analgesia.
AB  - Behaviour, plasma cortisol and heart rate were measured in 4-6-week-old calves
      during and after dehorning with and without the use of sedation and analgesia.
      Six groups of eight Friesian male and female calves were studied; four groups
      were dehorned using an electrical cauterizing dehorner, heated to approximately
      600 degrees C. In group 1, a cornual nerve block was performed and the animals
      were sham-dehorned using a cold dehorner. Group 2 was treated similarly but
      dehorned with the heated dehorner. Group 3 received a mixture of xylazine and
      butorphanol intramuscularly, and were hot dehorned 20 min after the injection.
      Group 4 received the same sedatives-analgesics as group 3, and after 5 min also
      had a cornual nerve block, followed by hot dehorning 15 min later. Group 5 was
      hot dehorned without any form of sedation or analgesia. A sixth group of calves
      without any treatment or handling was used as controls for the behavioural
      observations. Head and leg movements during dehorning were significantly reduced
      when the cornual nerve was blocked. During the 4 h after dehorning, the behaviour
      of calves having a cornual block continued to differ from those in group 5. The
      cornual block prevented short-term increases in plasma cortisol concentrations
      and the long-term increases in heart rate seen in group 5. It was concluded that
      routine field use of local analgesia using a cornual nerve block improved the
      welfare of young calves subjected to dehorning with a hot iron.

PMID- 10409413
TI  - Ultrasonographic examination of the stifle region in cattle--normal appearance.
AB  - The stifle region of 18 healthy cattle (14 cows, four bull calves) and the
      stifles of five bovine cadavers were examined using 7.5 MHz linear or convex and
      5 MHz sector transducers. The normal ultrasonographic appearance of soft tissues
      and bony structures was studied.The homogeneously echogenic patellar and
      collateral ligaments, the combined tendon of the long digital extensor and
      peroneus tertius muscles, the popliteus tendon, the anechoic articular cartilage
      of the femoral trochlea, the echogenic menisci and the hyperechoic bone surfaces
      were imaged successfully in all cattle and cadavers. The boundaries of the joint
      pouches only became partially identifiable, when small amounts of anechoic fluid
      were present in the medial and lateral femorotibial joint pouches. After
      experimental filling in cadavers, the distended synovial cavities were imaged as
      clearly demarcated, anechoic areas. Measurement values of cross-sectional
      diameters of the ligaments, tendons and the popliteal lymph node, the width of
      normal joint pouches, where visible, and articular cartilage thickness are
      presented. The established results should serve as reference data for
      ultrasonography of bovine stifle disorders.

PMID- 10409414
TI  - Genetic clustering of bovine viral diarrhoea viruses in cattle farms: genetic
      identification and analysis of viruses directly from cattle sera.
AB  - The herd-specific genetic clustering of bovine viral diarrhoea virus (BVDV) was
      studied by phylogenetic analysis of 42 sera collected between 1995-97 from
      persistently infected cattle on 16 farms in Sweden. The viruses were typed by
      sequencing a part of the 5' untranslated region of the genome, which had been
      amplified directly from serum by reverse transcription-polymerase chain reaction.
      All of the viruses were of BVDV I, either BVDV Ia (NADL-like) or BVDV Ib (Osloss
      like) genotypes. No relationship was observed between the geographic region of
      origin and the character of clinical signs and the typing of the BVDV isolates.
      However, the phylogenetic analysis revealed a strict herd-specific genetic
      clustering of the virus. In 15 of the 16 herds, animals were infected with a
      single strain of BVDV characteristic for that herd. Direct nucleotide sequence
      analysis from serum can therefore be used as a tool for molecular epizootiology
      of BVDV infections.

PMID- 10409415
TI  - DNA measurement and immunohistochemical characterization of epithelial and
      mesenchymal cells in canine mixed mammary tumours: putative evidence for a common
      histogenesis.
AB  - DNA measurement by image cytometry, and a detailed immunohistochemical study
      using monoclonal antibodies directed against different human cytokeratin types,
      muscle-specific actin, vimentin and S100 protein were carried out on normal
      canine mammary tissue (n =4), benign canine mammary mixed tumours (n =20) and
      malignant canine mammary mixed tumours (n =13). The results showed that ductal
      and alveolar luminal cells in normal and neoplastic tissue were immunoreactive
      with CAM5.2 and AE1/AE3 antibodies recognizing human keratins.Basal/myoepithelial
      cells were clearly differentiated from ductal and alveolar epithelial cells,
      since the latter only expressed cytokeratins, whereas the former also expressed
      vimentin and muscle-specific actin. This immunohistochemical study showed that
      there is loss of expression of muscle-specific actin and cytokeratins in areas of
      myoepithelial proliferation, and enhanced expression of vimentin and S100 protein
      in proliferative areas with osseous and/or chondroid metaplasia. The ploidy
      studies revealed that 20% (4/20) of benign and 54% (7/13) of malignant mixed
      tumours of canine mammary gland were aneuploid and that the epithelial and
      myoepithelial components of the mixed tumours had identical DNA content. Our
      results reinforce the role of myoepithelial cells in mesenchymal metaplasia in
      mixed mammary tumours and suggest the possibility of a common origin of both
      components from a totipotential stem cell with capacity for divergent
      differentiation.

PMID- 10409416
TI  - Near infrared spectroscopy in large animals: optical pathlength and influence of
      hair covering and epidermal pigmentation.
AB  - The effects of epidermal pigmentation and hair covering on the relative
      transparency of various animal tissues to near infrared (NIR) light were
      examined, and the pathlengths of NIR light through tissues at four wavelengths in
      the NIR range were subsequently determined. Black hair covering and black or dark
      coloured hooves prevented NIR light from penetration sufficient for conduction of
      pathlength or NIR spectroscopy measurements. Non-pigmented hair covering of the
      head did not appear to be a barrier to successful NIR light transmission. Tissues
      sufficiently transparent to NIR light had the differential pathlength factor
      (DPF, i.e. the ratio of the observed light pathlength and the geometric light
      source-detector separation) of NIR light determined by intensity modulated
      spectroscopy at the wavelengths 744, 806, 834 and 860 nm. Horse gluteal muscles
      had DPFs of 6.2, 6.2, 6.0, and 5.6, whereas forelimb muscles had DPF of 4.7, 4.4,
      4.5 and 3.9 at the respective wavelengths. Sheep heads had DPF of 7.2 +/- 0.3,
      5.8 +/- 0.5, 5.5 +/- 0.4 and 4.4 +/- 0.6 (+/- SEM) for the above respective
      wavelengths, of which the pathlengths all differed significantly from the other,
      except for between 806 and 834 nm, and 834 and 860 nm. The DPF of horse hooves
      were 4.8 +/- 0.1, 4.8 +/- 0.1, 4.7 +/- 0.1 and 4.4 +/- 0.1 (SEM) for the above
      noted wavelengths, of which the pathlength at 744 and 806 nm differed from the
      pathlength at 860 nm (P>0.05). These results show that NIRS is possible through
      lighter pigmented hair and epidermal tissues, and provide DPFs of horse feet and
      muscle and the sheep head that enables quantitative NIRS in these species

PMID- 10409417
TI  - Fertility in zebu cattle (Bos indicus) after prostaglandin administration and
      artificial insemination.
AB  - A total of 137 cycling zebu cows, each receiving a single dose of prostaglandin
      PGF(2alpha)were used in an oestrus synchronization programme on three different
      farms. Of the cows on the three farms, 60.6 and 90.5% showed overt oestrus and
      luteolysis, respectively. Pregnancy rate to fixed time inseminations following
      single injection of PGF(2alpha)was 61.4% for farm 1, significantly higher than
      the values of 45.7 and 46.9% for farms 2 and 3, respectively. The pregnancy rates
      to second service of rebred cows were 53.3, 50.0 and 50.0% for the three farms,
      respectively, with no significant differences between each. Fertility
      classification of the cows based on progesterone (P(4)) concentration showed that
      6.6% of cows on the three farms were incorrectly diagnosed as having corpora
      lutea; 2.9% of them had incomplete luteolysis and 5.1% may have lost their
      embryos between days 21 and 45 post-insemination. The pregnancy rate was 10%
      higher in the rainy season than in the dry season. Cows with body condition
      scores of 3 and 4 had a higher overall pregnancy rates than those with a body
      condition score of 2. The findings of this study further confirm the luteolytic
      efficacy of prostaglandin in inducing oestrus in zebu cattle and indicate that
      the nutritional status of the cows must be satisfactory before embarking on
      oestrus synchronization programmes.

PMID- 10409418
TI  - Post partum subclinical hypocalcaemia and effects on ovarian function and uterine
      involution in a dairy herd.
AB  - Episodes of subclinical hypocalcaemia occurred in the first 6 weeks after calving
      in 6 out of 12 multiparous Friesian cows calving in the winter period and 7 out
      of 23 calving in the summer in a subtropical environment. In the winter calving
      group, there were significant (P< 0.05) decreases in mean plasma calcium
      concentrations (PTCa) on days 6, 27 and 36 after calving in those animals unable
      to maintain PTCa >2.0 mmol/L in the first 21 days. These cows had a significantly
      higher mean body weight and higher mean milk production than normocalcaemic cows.
      In the summer calving group, the seven cows with episodes of subclinical
      hypocalcaemia had significantly lower mean PTCa over periods of 21 and 60 days.
      Intervals until involution of the uterus were negatively (P< 0.05) correlated
      with mean PTCa over the first 21 and 30 days after calving in the winter and
      summer calving groups (r = -0.62 and -0.42), respectively. The mean size of the
      first ovulated follicles was significantly smaller in cows showing episodes of
      subclinical hypocalcaemia in the winter group and the mean number of ovulatory
      size follicles was less in these cows at 15 days (P< 0.001) (1.2 +/- 0.17 vs 2.3
      +/- 0.21) and at 30 days (P< 0.03) (3.5 +/- 0.43 vs 5.2 +/- 0.54). During the
      first three dioestrus periods, mean plasma progesterone concentration as a
      function of corpus luteum area was significantly lower (P< 0.05) in the cows with
      episodes of subclinical hypocalcaemia in the winter group.

PMID- 10409419
TI  - Fetal haemoglobin in pregnant yaks (Poephagus grunniens L.).

PMID- 10409421
TI  - Announcement 

PMID- 10409422
TI  - Human X inactivation center induces random X chromosome inactivation in male
      transgenic mice.
AB  - X chromosome inactivation is the means to downregulate the transcriptional output
      of X chromosomes in female mammals. Essential DNA from the murine X inactivation
      center (Xic) has been identified by introducing it into male embryonic stem (ES)
      cells. To identify the essential sequences on human X chromosomes, we transfected
      male mouse ES cells with a YAC transgene containing 480 kb of the putative human
      X inactivation center (XIC). Despite little DNA sequence conservation, the human
      transgene is recognized as a second Xic in these XY mouse cells and induces
      random inactivation in chimeric mice derived from these cells. Inactivation is
      extensive on the X chromosome, but more localized on chromosome 11 carrying the
      transgene, demonstrating that initial inactivation and spreading of inactivation
      signals along the chromosome are independent events. Our results show for the
      first time that the DNA included in the human XIC transgene is sufficient to
      initiate random X inactivation, even in cells of another species. Interspecies
      XIC trangenes should facilitate further investigation of this process in humans
      and other mammals.

PMID- 10409423
TI  - Toward the gene catalogue of sea urchin development: the construction and
      analysis of an unfertilized egg cDNA library highly normalized by oligonucleotide
      fingerprinting.
AB  - We describe the use of oligonucleotide fingerprinting for the generation of a
      normalized cDNA library from unfertilized sea urchin eggs and report the
      preliminary analysis of this library, which resulted in the establishment of a
      partial gene catalogue of the sea urchin egg. In an analysis of 21,925 cDNA
      clones by hybridization with 217 oligonucleotide probes, we were able to identify
      6291 clusters corresponding to different transcripts, ranging in size from 1 to
      265 clones. This corresponds to an average 3.5-fold normalization of the starting
      library. The normalized library represents about one-third of all genes expressed
      in the sea urchin egg. To generate sequence information for the transcripts
      represented by the clusters, representative clones selected from 711 clusters
      were sequenced. The construction and preliminary analysis of the normalized
      library are the first steps in the assembly of an increasingly complete
      collection of maternal genes expressed in the sea urchin egg, which will provide
      a number of insights into the early development of this well-characterized model
      organism.

PMID- 10409425
TI  - Fine-mapping of a region of variation in recombination rate on BTA23 to the
      D23S22-D23S23 interval using sperm typing and meiotic breakpoint analysis.
AB  - Meiotic recombination rate (theta) within chromosome segments of similar physical
      size is known to vary widely throughout the genome. This variation has a genetic
      component, occurring between the sexes and among individuals of the same sex. We
      reported previously the existence of variation in theta between males in the DYA
      PRL interval on bovine chromosome 23 (BTA23). This region contains the bovine
      major histocompatibility complex and has been shown to contain recombination
      hotspots in humans and mice. The aim of this study was to map more finely the
      interval(s) on BTA23 where variation in theta occurs using sperm typing and
      meiotic breakpoint analysis. By adding a marker (DRB3) between DYA and PRL, the
      DYA-PRL interval was subdivided into two adjacent intervals, thus permitting
      evaluation and comparison of theta among five bulls. Significant variation in
      theta was found for both intervals; theta(DYA-DRB3) ranged from 13.2 to 28.1%,
      and theta(DRB3-PRL) ranged from 2.4 to 13.0%. The variation in theta was
      individual- and region-specific. A meiotic breakpoint strategy employing PCR
      amplification products from recombinant sperm was then used to refine the
      chromosomal location associated with variation in theta within the DYA-DRB3
      interval. The subinterval D23S22-D23S23 exhibited the greatest degree of
      variation among bulls having high and low theta within the DYA-DRB3 interval. To
      confirm this result, theta(D23S22-D23S23) was directly evaluated in three
      additional randomly chosen bulls using sperm typing. The region showing variation
      in theta was narrowed to the D23S22-D23S23 subinterval, ranging from 4.6 to 9.2%.
      Identification of the molecular basis for variation in theta may be useful for
      map-dependent applications, such as marker-assisted selection and positional
      cloning of genes affecting physiologically important traits.

PMID- 10409424
TI  - A novel retinal degeneration locus identified by linkage and comparative mapping
      of canine early retinal degeneration.
AB  - Early retinal degeneration (erd) is an early onset progressive retinal atrophy, a
      hereditary canine retinal disease phenotypically similar to human retinitis
      pigmentosa (RP). In previous efforts to identify the erd locus, canine homologs
      of genes causally associated with RP in humans, such as opsin (RHO), the beta
      subunit gene for cyclic GMP phosphodiesterase (PDE6B), and RDS/peripherin, were
      excluded. A genome-wide screen was undertaken on canine families segregating the
      erd disease. Analysis of over 150 canine-specific markers has localized erd to a
      single linkage group comprising two previously identified canine linkage groups,
      20 and 26, corresponding to canine radiation hybrid groups RH.34-a and RH.40-a.
      Multipoint analysis places erd in the interval between marker FH2289 (distance
      23.6 cM) and FH2407 (5.9 cM) with a lod score of 12.23. Although the erd linkage
      group has not been assigned to an identified canine chromosome, conserved synteny
      of this linkage group with human 12p13-q13 suggests several candidates for erd
      and identifies a novel retinal degeneration locus. The rapid progress now
      occurring in canine genetics will expedite identification of the genes and
      molecular mechanisms underlying the inherited traits and diseases that make the
      dog a unique asset for study of mammalian traits.

PMID- 10409426
TI  - The cloning and developmental expression of unconventional myosin IXA (MYO9A) a
      gene in the Bardet-Biedl syndrome (BBS4) region at chromosome 15q22-q23.
AB  - Bardet-Biedl Syndrome (BBS) is a heterogeneous, autosomal recessive disorder
      characterized by mental retardation, obesity, retinitis pigmentosa, syndactyly
      and/or polydactyly, short stature, and hypogenitalism and is caused by mutations
      at a number of distinct loci. Using a positional cloning approach for identifying
      the BBS4 (chromosome 15) gene, we identified and cloned an unconventional myosin
      gene, myosin IXA (HGMW-approved symbol MYO9A). Since mutations in unconventional
      myosins are known to cause several human diseases, and since mutations of
      unconventional myosin VIIa cause retinal degeneration, we evaluated myosin IXA as
      a candidate for BBS. We exploited PCR-based techniques to clone a 8473-nt cDNA
      for myosin IXA. A 7644-bp open reading frame predicts a protein with all the
      hallmarks of class IX unconventional myosins. Human Northern blot analysis and in
      situ hybridization of mouse embryos reveal that myosin IXA is expressed in many
      tissues consistent with BBS. Intron/exon boundaries were identified, and myosin
      IXA DNA and RNA from BBS4 patients were evaluated for mutation.

PMID- 10409427
TI  - Identification of a new, unorthodox member of the MAGE gene family.
AB  - Several tumor-associated antigen families, such as MAGE, GAGE/PAGE, PRAME, BAGE,
      and LAGE/NY-ESO-1, exist. These antigens are of particular interest in tumor
      immunology, because their expression, with exception of testis and fetal tissues,
      seems to be restricted to tumor cells only. We have identified a novel member of
      the MAGE gene family, MAGED1. Northern hybridization and RT-PCR demonstrated that
      the expression level of MAGED1 in different normal adult tissues is comparable to
      that in testis and fetal liver. Thus, MAGED1 does not possess an expression
      pattern characteristic of previously identified MAGE family genes, suggesting
      that the biology of the MAGE-family genes is more complex than previously
      thought. Chromosome mapping linked MAGED1 to marker AFM119xd6 (DXS1039) on
      chromosome Xp11.23.

PMID- 10409428
TI  - Gene expression in proliferating human erythroid cells.
AB  - A complete understanding of human erythropoiesis will require a robust
      description of transcriptional activity in hematopoietic cells that proliferate
      and differentiate in response to erythropoietin (EPO). For this purpose, we
      cultured peripheral blood mononuclear cells in the presence or in the absence of
      EPO and examined the transcriptional profile of those cells arising only in
      response to EPO. A distinct population of CD71( +) cells that demonstrated an
      average of six additional doublings in suspension culture and erythroid colony
      formation in methylcellulose was isolated. Suppression subtractive hybridization
      of mRNA isolated from those cells permitted the identification of transcribed
      genes. A summary of 719 expressed sequence tags (ESTs) describing 505 independent
      transcripts is provided here with a full analysis of each EST available at
      http://hembase.niddk.nih.gov. Several transcripts that matched genes previously
      reported in the context of erythroid differentiation including 4 cell surface
      proteins were expressed at this developmental stage. Active chromatin remodeling
      was suggested by the identification of 4 histone proteins, 4 high-mobility group
      proteins, 13 transcription factors, and 6 genes involved in DNA recombination and
      repair. Numerous genes associated with leukemic translocations were also
      recognized including topoisomerases I and II, nucleophosmin, Translin, EGR1, dek,
      pim-1, TFG, and MLL. In addition to known transcripts, 44 novel EST were
      discovered. This transcriptional profile provides the first genomic-scale
      description of gene activity in erythroid progenitor cells.

PMID- 10409429
TI  - Prostate cancer expression profiling by cDNA sequencing analysis.
AB  - Prostate cancer is a frequently diagnosed solid tumor that is originated mostly
      from prostate epithelium. One of the key issues in prostate cancer research is to
      develop molecular markers that can effectively detect and distinguish the
      progression and malignancy of prostate tumors. Automated, single-pass cDNA
      sequencing was utilized to rapidly identify expressed genes in a number of cDNA
      libraries constructed from various normal and tumor prostatic tissues. These
      included cell lines as well as short-term epithelial culture. A total of 6604
      expressed sequence tags (ESTs) were generated and searched against on-line
      nucleotide and protein databases. A relational database centric software system
      was constructed to process, store, and analyze EST data rapidly. cDNA contigs
      were also obtained by assembly of multiple EST sequences. Protein structural
      signatures were annotated using motif analysis tools including BLOCKS and an in
      house-designed neural network. Cross-library comparisons revealed their unique
      gene expression profiles. Several differentially expressed cDNA clones were
      identified, and their expression patterns were confirmed by RNA dot blot and RT
      PCR analyses.

PMID- 10409430
TI  - MLL2: A new mammalian member of the trx/MLL family of genes.
AB  - We have identified a gene at chromosome band 19q13.1, which is closely related to
      MLL. MLL is located in a region of chromosome 11q23 that has partial synteny with
      chromosome 19q. We have named this gene at 19q13.1, MLL2. MLL2 encodes a protein
      that exhibits a high level of similarity to MLL over several important protein
      domains. MLL2 is also ubiquitously expressed among adult human tissues, as is
      MLL. MLL is a homologue of the Drosophila gene trithorax (trx), which encodes a
      regulator of homeotic gene expression. MLL is involved in chromosome
      rearrangements associated with leukemia in mammals. However, no MLL2
      rearrangements associated with leukemia have been recorded.

PMID- 10409431
TI  - Alternative splicing in the murine and human FXR1 genes.
AB  - Fragile X syndrome results from mutations in the X-linked FMR1 gene. The most
      common mutation is expansion and hypermethylation of a CGG repeat in the 5'UTR of
      FMR1, which blocks transcription and results in the loss of FMR1 protein (FMRP).
      Efforts to understand the function of FMRP have led to the identification of two
      autosomal homologs, FXR1P and FXR2P, that may interact with FMRP in some tissues.
      Reported cDNAs for human, murine, and Xenopus FXR1 suggested the potential for
      alternatively spliced isoforms, a feature also found in the FMR1 gene. Using RT
      PCR to characterize FXR1 alternative splicing in different mouse tissues and
      human cell lines, we identified seven isoforms that differ by the presence or
      absence of four DNA regions. These isoforms are found at varying levels in
      different tissues. The structure of the murine Fxr1h gene underlying these
      splicing events has also been determined. Interestingly, the longest FXR1P
      isoform has much greater similarity to FXR2P in the C-terminal region than has
      been previously recognized, and the gene structure of Fxr1h is quite similar to
      those of FMR1 and Fxr2h. However, unlike FMR1 and Fxr2h, there is no (CGG)(n)
      repeat in the 5'UTR region of Fxr1h. Continuing efforts to characterize the
      expression patterns of FMRP family members should aid in our understanding of
      their functions in various cells and tissues.

PMID- 10409432
TI  - Comparative analysis of a novel gene from the Wolf-Hirschhorn/Pitt-Rogers-Danks
      syndrome critical region.
AB  - Wolf-Hirschhorn syndrome (WHS) is a multiple malformation syndrome characterized
      by mental and developmental defects resulting from the absence of a segment of
      one chromosome 4 short arm (4p16.3). Recently, Pitt-Rogers-Danks syndrome (PRDS),
      which is also due to a deletion of chromosome 4p16.3, has been shown to be
      allelic to WHS. Due to the complex and variable expression of these disorders, it
      is thought that WHS/PRDS results from a segmental aneusomy of 4p resulting in
      haploinsufficieny of an undefined number of genes that contribute to the
      phenotype. In an effort to identify genes that contribute to human development
      and whose absence may contribute to the phenotype associated with these
      syndromes, we have generated a transcript map of the 165-kb critical region and
      have identified a number of potential genes. One of these genes, WHSC2, which was
      identified with the IMAGE cDNA clone 53283, has been characterized. Sequence
      analysis defined an open reading frame of 1584 bp (528 amino acids), and
      transcript analysis detected a 2.4-kb transcript in all fetal and adult tissues
      tested. In parallel, the mouse homologue was isolated and characterized. Mouse
      sequence analysis and the pattern of expression are consistent with the clone
      being the murine equivalent of the human WHSC2 gene (designated Whsc2h). The data
      from sequence and transcript analysis of this new human gene in combination with
      the lack of significant similarity to proteins of known function imply that it
      represents a novel gene. Most importantly, its location within the WHSCR suggests
      that this gene may play a role in the phenotype of the Wolf-Hirschhorn/Pitt
      Rogers-Danks syndrome.

PMID- 10409433
TI  - Physical mapping of the CC-chemokine gene cluster on the human 17q11. 2 region.
AB  - Chemokines are a family of small secreted proteins that are involved in the
      trafficking of leukocytes by acting on G-protein-coupled receptors. Specific
      chemokines are also implicated in the regulation of angiogenesis and mobilization
      of hematopoietic cell precursors. Chemokines are subdivided into four groups on
      the basis of the relative positions of their conserved cysteines. For the CC
      chemokine group, in which the first two (of four) conserved cysteines are
      adjacent, 22 members have been described so far. In this work, we have analyzed
      the genomic organization of these genes. We first assigned the genes encoding CC
      chemokines to chromosomal regions and organized their relative positioning by
      using two radiation hybrid panels. Fifteen CC-chemokine genes were shown to be
      clustered within the 17q11.2 region of the human genome. These genes appeared to
      be segregated into two subclusters separated by about 2. 25 Mb (9 cR). Contigs of
      bacterial artificial chromosomes (BAC) covering these two subclusters were
      subsequently isolated and the localizations of the CC-chemokine genes within
      these contigs determined. The relative positioning of the BAC clones was
      determined with the help of fluorescence hybridization on combed genomic DNA. The
      cluster organization of the various CC-chemokine genes in the genome was found to
      be grossly consistent with their structural similarities. This map of the CC
      chemokine gene cluster should facilitate the determination of the full sequence
      of the chromosomal region.

PMID- 10409434
TI  - The novel human HUEL (C4orf1) gene maps to chromosome 4p12-p13 and encodes a
      nuclear protein containing the nuclear receptor interaction motif.
AB  - A 3250-bp novel human cDNA sequence was isolated from the MRC-5 human embryonic
      lung cell line by the rapid amplification of cDNA ends technique. This gene was
      designated HUEL and given the symbol C4orf1 by the HUGO Nomenclature Committee.
      Within HUEL was identified a continuous ORF of 1704 bp encoding a predicted
      hydrophilic protein of 568 amino acids with a calculated molecular mass of 63,410
      Da. The putative protein contains the LXXLL signature motif considered necessary
      and sufficient for binding of certain coactivators to liganded nuclear receptors,
      as well as nuclear localization signals, a nuclear export-like signal, a zinc
      finger-like motif, an acidic region, and two leucine zipper-like domains.
      Northern blot analysis of human fetal tissues revealed 3. 4-kb transcripts, while
      RT-PCR demonstrated HUEL expression in a wide range of human adult tissues and
      cancer cell lines. In the SiHa, HT-1080, and G-401 cancer lines was detected an
      alternative transcript in which a 166-bp segment was excluded by exon skipping,
      which is predicted to culminate in a protein with a modified and truncated C
      terminus. HUEL was localized to chromosome region 4p12-p13 by fluorescence in
      situ hybridization. In Western blots, affinity-purified antibodies raised against
      a HUEL-specific synthetic peptide could recognize a distinct protein band of
      approximately 70 kDa. Immunoblotting of subcellular fractions and indirect
      immunofluorescence of human embryonic lung cells demonstrated the distribution of
      HUEL predominantly in the cytoplasm, with an apparently cytoskeletal association.
      However, in smaller or dividing PLC/PRF/5 and TONG liver carcinoma cells, there
      was a translocation of HUEL from the cytoplasm to the nucleus. Taken together,
      these data suggest that HUEL plays a role in transcriptional regulation.

PMID- 10409435
TI  - Envoplakin, a possible candidate gene for focal NEPPK/esophageal cancer (TOC):
      the integration of genetic and physical maps of the TOC region on 17q25.
AB  - Focal nonepidermolytic palmoplantar keratoderma (NEPPK), or tylosis, is an
      autosomal, dominantly inherited disorder of the skin that manifests as focal
      thickening of the palmar and plantar surfaces. In three families studied, the
      skin disorder cosegregates with esophageal cancer and oral lesions. New haplotype
      analysis, presented here, places the tylosis esophageal cancer (TOC) locus
      between D17S1839 and D17S785. Envoplakin (EVPL) is a protein component of
      desmosomes and the cornified envelope that is expressed in epidermal and
      esophageal keratinocytes and has been localized to the TOC region. Mutation
      analysis of EVPL in the three affected families failed to show tylosis-specific
      mutations, and haplotype analysis of three intragenic sequence polymorphisms of
      the EVPL gene placed it proximal to D17S1839. Confirmation of the exclusion of
      EVPL as the TOC gene by location was obtained by integration of the genetic and
      physical mapping data using radiation hybrid, YAC, BAC, and PAC clones. This new
      physical map will allow further identification of candidate genes underlying
      NEPPK associated with esophageal cancer, which may also be implicated in the
      development of sporadic squamous cell esophageal carcinoma and Barrett's
      adenocarcinoma.

PMID- 10409436
TI  - CAPN11: A calpain with high mRNA levels in testis and located on chromosome 6.
AB  - Calpains are a superfamily of related proteins, some of which have been shown to
      function as calcium-dependent cysteine proteases. In mammals, eight different
      calpains have been identified. We report the identification of a new mammalian
      calpain gene, CAPN11. The predicted protein possesses the features typical of
      calpains including potential protease and calcium-binding domains. The CAPN11
      mRNA exhibits a highly restricted tissue distribution with highest levels present
      in testis. Radiation hybrid mapping localized the gene to human chromosome 6,
      within a region mapped to p12. Phylogenetic analysis suggests that, in mammals,
      the predicted CAPN11 protein is most closely related to CAPN1 and CAPN2. However,
      of the calpain sequences available, the predicted CAPN11 sequence exhibits
      greatest homology to the chicken micro/m calpain. Thus CAPN11 may be the human
      orthologue of micro/m calpain. The discovery of this new calpain emphasizes the
      complexity of the calpain family, with members being distinguished on the basis
      of protease activity, calcium dependence, and tissue expression.

PMID- 10409437
TI  - Genomic structure, chromosomal location, and mutation analysis of the human
      CDC14A gene.
AB  - Human CDC14A is a dual-specificity phosphatase that shares sequence similarity
      with the recently identified tumor suppressor, MMAC1/PTEN/TEP1. By radiation
      hybrid mapping, we localized CDC14A to chromosome band 1p21, a region that has
      been shown to exhibit loss of heterozygosity in highly differentiated breast
      carcinoma and malignant mesothelioma. We have mapped the exon-intron structure of
      CDC14A gene and found an in-frame ATG at 14 codons upstream of the previously
      reported start site (GenBank Accession No. AF000367). In screening a panel of 136
      cDNAs from tumor cell lines for coding mutations, we have identified a 48-bp in
      frame deletion in the cDNA of the breast carcinoma cell line, MDA-MB-436. This
      deletion is the result of an acceptor splice site mutation (AG to AT) in intron
      12 that causes the skipping of exon 13 in the gene. Loss of expression of the
      wildtype allele in the same breast cell line supports the possibility that CDC14A
      may be a tumor suppressor gene that is targeted for inactivation during
      tumorigenesis.

PMID- 10409438
TI  - Cloning and mapping of the XRN2 gene to human chromosome 20p11.1-p11.2.
AB  - The Dhm1 gene is the mouse homologue of the dhp1(+) gene of Schizosaccharomyces
      pombe, which is involved in homologous recombination and RNA metabolism, such as
      RNA synthesis and RNA trafficking, in S. pombe. Complementation analysis showed
      the Dhm1 gene on a multicopy plasmid can rescue the temperature-sensitivity
      mutation of dhp1(ts) and the lethality of the dhp1 null mutation. This finding
      suggests that Dhm1 has a function in mouse similar to that of dhp1(+). The human
      homologue of this gene, XRN2, has been identified. A 3.6-kb transcript of XRN2
      was detected in 16 tissues examined and was more abundant in testis. By radiation
      hybrid panel mapping, the XRN2 gene was localized to chromosome 20p11.1-p11.2
      between markers D20S180 and D20S871.

PMID- 10409439
TI  - Cocaine-induced increase in the permeability function of human vascular
      endothelial cell monolayers.
AB  - The effects of cocaine on endothelial cell macromolecular transport, electrical
      resistance, and morphology were assessed. In confluent endothelial monolayers
      grown on microporus filters, cocaine (0.01 to 1 mmol/L) induced a rapid
      concentration-dependent increase in permeability to peroxidase and low density
      lipoprotein. Along with increased transport, the cocaine effect was paralleled by
      a decrease in transendothelial electrical resistance. Alterations in membrane
      resistance were fully reversible following washout of the drug, providing
      evidence that cocaine does not cause permanent injury to the integrity of the
      monolayer. Cocaines major metabolites, benzoylecgonine and ecgonine methyl ester,
      had minimal effect on electrical resistance properties, whereas monolayer
      impedance was markedly depressed by the novel cocaine/alcohol metabolite, cocaine
      ethyl ester (cocaethylene). Morphologic studies of cocaine-treated endothelial
      cells revealed a marked disruption of F-actin and the formation of intercellular
      gaps; no evidence of cell lysis and/or detachment was noted. Forskolin, a potent
      activator of adenylate cyclase known to promote the endothelial cell barrier
      function, impaired cocaine-induced changes in electrical resistance and
      morphology. Cocaine, however, had no effect on resting levels of intracellular
      adenosine 3',5'-cyclic monophosphate (cAMP) in confluent endothelial monolayers.
      In summary, the results indicate that cocaine directly induces structural defects
      in the endothelial cell barrier which enhance the transport of macromolecular
      tracers, the mechanism does not appear to involve intracellular cAMP.

PMID- 10409440
TI  - Molecular characterization of a novel endonuclease (Xib) and possible involvement
      in lysosomal glycogen storage disorders.
AB  - We cloned and partially characterized a human endonuclease (Xib) which shows
      sequence homologies to pancreatic DNase I but an enzymatic activity closer to
      DNase II. We report on the structural differences found between Xib and other
      recently cloned human DNases. Fluores cence microscopy analysis of transiently
      transfected cells with Xib::pEGFP constructs indicate that the protein is located
      in the cytoplasm and possibly anchored to a membrane, as deduced from a
      hydrophobic amino acid stretch present at the C-terminal end. Xib is
      overexpressed in muscle and cardiac tissues and is alternately spliced in several
      normal and neoplastic cells. In situ hybridization studies using human cardiac
      and muscle biopsies indicate accumulation of Xib transcript in the vacuoles of
      muscle cells from patients affected by vacuolar myopathy as acid maltase
      deficiency; however, no point mutations were detected in their DNA.

PMID- 10409441
TI  - Expression and function of beta(1) and beta(3) integrins of human mesothelial
      cells in vitro.
AB  - Mesothelial cells (MC) and extracellular matrix (ECM) components are thought to
      play a pivotal regulatory role during the inflammatory-reparative response of
      serosal membranes. Integrins are known to serve as cellular ECM receptors, but
      mesothelial integrin expression and its function, particularly its role for
      attachment to different ECM components, remain to be elucidated. The aim of the
      present study was to characterize the integrin expression of human omentum majus
      derived MC (HOMC) in vitro by immunohistochemistry and to investigate their
      functional significance with regard to HOMC adhesion to fibronectin (fn),
      vitronectin (vn), collagen IV (coll IV), and laminin (ln). Mesothelial cells in
      vitro strongly expressed beta(1), beta(3), alpha(2), alpha(3), alpha(5), and
      alpha(v) chains. A weak reactivity was found for alpha(1) and alpha(6), but no
      alpha(4) reactivity was detectable. Compared to the control, fn, vn, coll IV, and
      ln caused a significant 2.6-, 2.2-, 2-, and 1.6-fold increase of HOMC adhesion,
      respectively. Inhibition studies revealed that HOMC attachment to fn is mediated
      by alpha(5)beta(1), alpha(v)beta(1), and alpha(v)beta(3), with a synergistic
      effect of alpha(5)beta(1) and alpha(v)beta(3). Adhesion to vn is mediated by
      alpha(v)beta(1) and alpha(v)beta(3). Integrins alpha(1)beta(1), alpha(2)beta(1),
      and alpha(3)beta(1) mediate adhesion to coll IV and ln. We suggest that the
      integrin expression and function of mesothelial cells described here play an
      important role in the interaction of MC with the ECM, particularly during the
      acute and chronic inflammatory-reparative response of serosal membranes.

PMID- 10409442
TI  - c-myc and chromosome 8 centromere studies of ovarian cancer by interphase FISH.
AB  - Forty tumor specimens from patients with ovarian cancer were studied for
      amplification of the c-myc oncogene relative to chromosome 8 centromere number
      using dual-color FISH. Interphase cytogenetic analysis showed amplification of
      the c-myc oncogene in 40% (16/40) of tumors using the standard
      oncogene:centromere ratio method of analysis. Eleven of these showed moderate
      amplification of c-myc, and 5 samples showed high amplification. Eight of the
      sixteen (50%) amplified tumors were polysomic centromere 8 as were 14 of the 24
      (58%) non-amplified tumors. In previously reported work with these samples, the
      oncogene HER-2/neu, the chromosome 17 centromere, and the tumor suppressor gene
      p53 had been studied. When using the standard oncogene:centromere ratio criteria,
      5 samples had amplification of both the c-myc and the HER-2/neu oncogenes, 5
      samples had HER-2/neu amplification but not c-myc, 11 samples had c-myc
      amplification but not HER-2/neu, and 19 samples had neither oncogene amplified.
      The p53 gene was found to be deleted in 22.5% (9/40) of samples. The loss of the
      p53 gene did not appear to have any clinical correlation. The presence of an
      extra centromere 8 also did not appear to have any clinical correlation. The
      Kaplan-Meier survival curve for those patients who have c-myc amplification,
      while not statistically significant, appears to show a trend toward poorer
      survival. The survival curve for patients whose tumors have HER-2/neu
      amplification shows no clinical significance. It is of great interest, however,
      that the Kaplan-Meier plot of survival for patients whose tumors have
      amplification of both c-myc and HER-2/neu shows a significant difference (P =
      0.047). The median survival times of the doubly amplified patient group and the
      non-doubly amplified groups were 12 and 43 months, respectively. This is the
      first study of the oncogene c-myc using FISH. The results suggest that the
      amplification of c-myc may indicate a poorer patient survival and that the
      amplification of both c-myc and HER-2/neu in combination may be a better
      prognostic indicator of poor patient survival.

PMID- 10409444
TI  - Assessment of chromosome 8 copy number in cervical cancer by fluorescent in situ
      hybridization.
AB  - Cervical carcinoma is a malignancy which typically occurs at the transformation
      zone between squamous and glandular epithelium. The vast majority falls into two
      histologic types, squamous cell and adenocarcinoma. In an effort to identify a
      subset of cervical cancer characterized by chromosome 8 trisomy, a biomarker
      extensively explored by this laboratory, we conducted a study of formalin-fixed,
      paraffin-embedded materials of cervical cancer. A total of 24 cases of cervical
      cancer were identified from the archives of the Rhode Island Hospital.
      Fluorescent in situ hybridization (FISH) using a chromosome 8 centromere
      enumeration probe was conducted to assess the chromosome 8 copy number in these
      specimens. Hybridization signals were scored among tumor cells in a blinded
      fashion. Tumors with >/=15% of cells with three signals were scored as trisomic.
      Of 24 cases studied, 23 were informative. Of the 23 informative cases, 12 (52.2%)
      were found to be trisomic. Eleven cases (47.8%) were disomic. The frequency of
      trisomy in a control chromosome 17 probe was 13.0% (3/23). Selected
      clinicopathologic characteristics of the tumors were also reviewed. The frequency
      of trisomy 8 among cases of invasive squamous cell carcinoma was 44.4% (8 of 18
      tumors) and that of invasive adenocarcinoma was 80% (4 of 5 tumors). The sole
      tumor which was both trisomic 8 and amplified for the HER-2/neu oncogene was
      found to be an invasive adenocarcinoma. While the sample size in this pilot study
      is not large, the data obtained thus far clearly demonstrate that FISH is an
      appropriate technique for detecting chromosomal trisomies and that a subset of
      cervical cancer exists that is characterized by chromosome 8 trisomy. Further
      exploration of this biomarker is warranted.

PMID- 10409443
TI  - Adhesion proteins in the biology of breast cancer: contribution of CD44.
AB  - One of the most important features of tumor cell invasion is the ability to
      establish or modulate adhesion to other cells or to an extracellular matrix, a
      process mediated by a large number of adhesion proteins. This review examines how
      CD44 participates in malignant transformation and progression of the breast
      epithelium. CD44 is a family of cell adhesion glycoproteins generated by
      alternative splicing of up to 10 variant exons. Discrete CD44 isoforms are
      overexpressed in different human cancers, including breast cancer. Recent
      studies, including our own, have shown that CD44 is involved in two of the three
      steps of the invasive cascade: adhesion to the extracellular matrix and motility.
      The overexpression of one of the CD44 variants, CD44v6, is a significant
      component in the malignant transformation of the breast epithelium and its use as
      a prognostic marker is presently investigated.

PMID- 10409445
TI  - HER-2/neu oncogene amplification in stage I and stage III ovarian papillary
      serous carcinoma.
AB  - Oncogene amplification has been implicated in the genesis and progression of many
      cancers. Overexpression of the HER-2/neu proto-oncogene occurs in 20-30% of
      ovarian epithelial cancers, in which it may be of prognostic significance.
      Oncogene overexpression is traditionally studied using immunohistochemistry. In
      this study we used fluorescent in situ hybridization (FISH) to determine HER
      2/neu amplification in ovarian papillary serous carcinoma and compared the
      frequency of amplification in two stages of the disease. Archival tissues from 23
      cases of papillary serous ovarian carcinoma (9 cases of stage I and 14 cases of
      stage III) were analyzed by FISH using a HER-2/neu probe and a chromosome 17
      centromere control probe. Determination of the level of amplification was
      performed according to the standard protocols of the Cytogenetics Laboratory at
      Rhode Island Hospital. Of the 23 cases successfully analyzed, the frequency of
      amplification among stage I tumors was 22% (2/9) and the frequency of
      amplification among stage III tumors was 71% (10/14). These results are
      significant (P = 0.036). The frequency of stage I tumors among amplified cases
      was 17% (27/12) and the frequency of stage III tumors among amplified cases was
      83% (10/12). This study not only confirms the presence of a subset of ovarian
      papillary serous carcinoma with HER-2/neu gene amplification, but it also
      indicates that HER-2/neu oncogene amplification is more likely to be associated
      with a more advanced stage. Thus, the present data are consistent with the
      hypothesis that HER-2/neu amplification, similar to HER-2/neu protein over
      expression, is a prognostic marker of poor outcome.

PMID- 10409446
TI  - Fluorescence in situ hybridization study of HER-2/neu oncogene amplification in
      prostate cancer.
AB  - Prostate cancer is a serious disease affecting men worldwide and treatment
      compromises the quality of life of prostate cancer patients. We conducted a study
      of 88 cases of prostate cancer in an attempt to identify prognostic biomarkers
      that can distinguish aggressive cases that must be treated immediately. HER-2/neu
      oncogene amplification was initially studied because amplification of this gene
      has been reported in many other cancers, including those studied in this
      laboratory. Fluorescence in situ hybridization (FISH) using a HER-2/neu gene
      probe with a chromosome 17 centromere control probe was performed on formalin
      fixed, paraffin-embedded tissues. Of a total of 86 cases successfully analyzed,
      only 8 (9.3%) were found to be amplified. This frequency was lower than the
      frequency of amplification found in other cancers studied. Furthermore, no case
      was found where the level of amplification can be considered high. Only one case
      was found to have moderate amplification. The rest of the positive cases can all
      be classified as low amplification. Thus, while we have demonstrated that FISH is
      a sensitive technique for detecting oncogene amplification, the frequency and
      level of HER-2/neu amplification detected in prostate cancer seem to be lower
      than those in most cancers that we studied. In view of the fact that HER-2/neu
      amplification does not seem to play as significant a role, exploration of other
      biomarkers in prostate cancer is warranted.

PMID- 10409447
TI  - Mid- and Near-Infrared Spectra, Millimeterwave Spectra, and Global Analysis of
      (16)O(12)C(80)Se.
AB  - We have recorded a total of 12 FTIR spectra of monoisotopic OC(80)Se in different
      spectral regions with a resolution (1/maximum optical path difference) between
      2.7 and 13.2 x 10(-3) cm(-1). These spectra spanned the range from 350 to 7800
      cm(-1), many bands being studied with different p x L products in order to also
      detect weak hot bands. Altogether 18 band systems comprising 81 different bands,
      mostly of Sigma type, were observed and analyzed by means of polynomial
      expansions in J(J + 1). New rotational transitions of vibrationally excited
      states as high as 2200 cm(-1) with J" 17-25 in the 140-210 GHz and J" 53-58 in
      the 430-470 GHz millimeterwave regions were measured with the assistance of
      predictions by the global fit. This fit was performed using a weighted least
      squares procedure and employing the whole body of data, and about 100 molecular
      parameters were determined that describe the energy level of (16)O(12)C(80)Se
      with statistical accuracy. Improved highly accurate ground state parameters up to
      sextic centrifugal distortion terms were obtained by a merge of ground state
      combination differences and pure rotational data. The v(1), v(2), v(3) polyad
      interacts anharmonically with the v(1) - 1, v(2) + p, v(3) + q polyads with p +
      2q = 4. Moreover, some local crossings with Coriolis interactions between (v(1),
      v(2), v(3)) and (v(1) - 1, v(2) + 3, v(3) + 1) levels were observed and treated
      perturbationally. Copyright 1999 Academic Press.

PMID- 10409448
TI  - Radio-Frequency, Centimeter-Wave, Millimeter-Wave, and Infrared Spectra of
      SiDF(3) in the v(6) = 1 Excited State.
AB  - This paper deals with the first study of high-resolution radio-frequency,
      centimeter-wave, millimeter-wave, and infrared spectra of the deuterated
      isotopomer of trifluorosilane, SiDF(3), in its lowest degenerate excited v(6) = 1
      state. Following the work of E. I. Lobodenko, O. N. Sulakshina, V. I. Perevalov,
      and Vl. G. Tyuterev, (J. Mol. Spectrosc. 126, 159-170 (1987)) and Harder (J. Mol.
      Spectrosc. 194, 145 (1999)), the data (18 A(1)-A(2) transitions, 229 l-type
      resonance transitions, 189 pure rotational transitions, and 1167 rovibrational
      transitions) have been fitted using three equivalent Q, D, and QD reduction
      schemes enabling the fit of one of the three interaction parameters d, q(12), and
      epsilon, respectively, while the other two are fixed to zero. In addition to
      further higher order constants, either f(K)(22) or tau(K) also had to be
      constrained. By checking the standard deviation of each data set and the
      relations between parameters determined within different constrains, the six
      reduction schemes have been shown to be unitary equivalent. Furthermore, the
      axial rotational ground state constant C(0) has been accurately determined.
      Copyright 1999 Academic Press.

PMID- 10409449
TI  - Microwave Spectrum, Structure, and Nuclear Quadrupole Coupling Constants of 1
      Bromo-1-fluoroethane.
AB  - The microwave spectrum of 1-bromo-1-fluoroethane, CHBrF-CH(3) and CHBrF-CH(2)D
      ((79/81)Br), has been studied for the first time from 8 to 41 GHz. A least
      squares analysis of the observed a- and b-type transition frequencies gave
      rotational and centrifugal distortion constants and components of the bromine
      nuclear quadrupole coupling constant tensor in the principal axes system as
      follows: A = 8979.428(5) MHz, B = 2883.898(3) MHz, C = 2310.535(3) MHz, Delta(J)
      = 0.74(2) kHz, Delta(JK) = 2.49(3) kHz, Delta(K) = 5.3(5) kHz, delta(J) =
      0.146(1) kHz, delta(K) = 2.75(4) kHz, chi(aa) = 493.49(29) MHz, chi(bb) - chi(cc)
      = -38.89(11) MHz, and ||chi(ab) || = 161.8(28) MHz for the CH(79)BrF-CH(3)
      species; A = 8979.257(5) MHz, B = 2859.072(3) MHz, C = 2294.572(3), Delta(J) =
      0.76(2) kHz, Delta(JK) = 2.51(3) kHz, Delta(K) = 4.5(4) kHz, delta(J) = 0.145(1)
      kHz, delta(K) = 2.70(4) kHz, chi(aa) = 412.42(27) MHz, chi(bb) - chi(cc) = -32.56
      (11) MHz, and ||chi(ab) || = 133.3(3) MHz for the CH(81)BrF-CH(3) species. The
      structural parameters are calculated from the 24 observed rotational constants,
      and electronic properties of the carbon-bromine bond in 1-bromo-1-fluoroethane
      are evaluated from the observed nuclear quadrupole coupling constants. These
      molecular properties are compared with those of other related molecules. The
      molecular structure of 1-bromo-1-fluoroethane is found to be very close to that
      of 1,1-difluoroethane except for the C-Br bond. Copyright 1999 Academic Press.

PMID- 10409450
TI  - Rotational Pattern Difference in Resolved Fluorescence Spectra with Different
      Detection Schemes.
AB  - The relative intensities of rotational lines in resolved fluorescence spectra are
      dependent on the detection direction and the choice of the detection scheme when
      a grating monochromator is used. These differences arise from the spatially
      anisotropic distribution of the fluorescence, the rotational branch dependence of
      the fluorescence polarization, and the polarization dependence of the
      monochromator grating efficiency. Both the anisotropy of the emission and the
      rotational branch dependence of the fluorescence polarization are enhanced in
      double-resonance excitation schemes. In the present work, we analyze the relative
      intensities in the (7)Li(2) 1(3)Sigma(-)(g) --> 1(b)(3)Pi(u) and 1(3)Delta(g) -->
      1(b)(3)Pi(u) resolved fluorescence spectra, observed following double-resonance
      excitation, for three different detection schemes. Copyright 1999 Academic Press.

PMID- 10409451
TI  - Millimeter- and Submillimeter-Wave Spectrum of Methylene Fluoride-d(2).
AB  - The millimeter- and submillimeter-wave spectrum of methylene fluoride-d(2)
      (CD(2)F(2)) has been observed in the region between 200 and 415 GHz. The spectrum
      was recorded using a frequency-modulated millimeter- and submillimeter-wave
      spectrometer. More than 400 rotational transitions up to J </= 60 and K(a) </= 21
      in the ground state and more than 200 rotational transitions up to J </= 48 and
      K(a) </= 9 in the v(4) = 1 vibrational state have been assigned. The lines
      assigned are simultaneously least-squares fitted along with the microwave data in
      the Watson's A- and S-reduced Hamiltonian. Improved values have been obtained for
      the rotational constants and quartic centrifugal distortion constants, including
      for the first time, sextic distortion constants of the ground state as well as
      the v(4) = 1 state. Copyright 1999 Academic Press.

PMID- 10409452
TI  - On the Assignment of Optically Pumped Far-Infrared Laser Emission from CH(3)OH.
AB  - Progress in the analysis of the infrared spectrum of CH(3)OH in the 930-1450 cm(
      1) region has led to assignments, confirmations, or new insights for a number of
      far-infrared laser (FIRL) transition systems optically pumped by CO(2) lasers.
      Many of the systems involve FIRL transitions among the CO-stretching, CH(3)
      rocking, OH-bending, and CH(3)-deformation vibrational modes, giving useful
      information on the torsion-rotation structure of the methanol vibrational energy
      manifold. Some anomalies and mysteries concerning the identity of the lasing
      levels have been resolved, but several new ones have arisen. Altogether, 45
      CH(3)OH IR-pump/FIR-laser systems are examined in light of the new spectroscopic
      information; about half of the system assignments are new and half have been
      previously reported in the literature and are here confirmed, extended, or
      revised. Copyright 1999 Academic Press.

PMID- 10409453
TI  - Fourier Transform Emission Spectroscopy of the
AB  - The emission spectrum of ZrCl has been observed in the 1800-12 000 cm(-1) region
      using a Fourier transform spectrometer. The molecules were excited in a microwave
      discharge of a mixture of helium and a trace of ZrCl(4) vapor. In addition to the
      C(4)Delta-X(4)Phi transition reported previously, numerous new bands observed in
      the near infrared have been classified into two electronic transitions,
      [7.3](2)Delta-a(2)Phi and [9.4](2)Phi-a(2)Phi. Five new bands observed in the
      6700-7400 cm(-1) region have been assigned as (2)Delta(3/2)-(2)Phi(5/2) and
      (2)Delta(5/2)-(2)Phi(7/2) subbands of a new electronic transition, [7.3](2)Delta
      a(2)Phi. The two subbands of the [9.4](2)Phi-a(2)Phi transition were previously
      observed by G. Phillips, S. P. Davis, and D. C. Galehouse [Astrophys. J. Suppl.
      43, 417-434 (1980)], who tentatively labeled them as (2)Pi(1/2)-(2)Pi(1/2) and
      (2)Pi(3/2)-(2)Pi(3/2) subbands. A number of new bands involving higher
      vibrational levels have been identified for these two subbands. A rotational
      analysis of a number of bands of both transitions has been obtained and
      spectroscopic constants have been determined. Global perturbations have been
      observed in both spin components of the a(2)Phi state. The assignment of the
      observed electronic states has been discussed in light of recent theoretical
      calculations. Copyright 1999 Academic Press.

PMID- 10409454
TI  - The Electronic Structure of CaCl: Calculation by R Matrix and Generalized Quantum
      Defect Theory.
AB  - The electronic spectrum of CaCl has been calculated using the variational
      eigenchannel R-matrix method combined with generalized multichannel quantum
      defect theory. The motion of the unpaired (Rydberg) electron is represented as a
      double scattering process on the closed-shell Ca(++) and Cl(-) core ions.
      Electron penetration into Ca(++) is taken into account as well as polarization
      effects. The partial saturation of the Cl(-) free-ion polarizability is evaluated
      on the basis of an ab initio calculation of the dipole and quadrupole moments of
      the CaCl(+) ion core. The calculations reproduce the effective principal quantum
      numbers nu of the experimentally known states (including the ground state) to
      within approximately 0.04. States with high-orbital angular momentum up to l = 6
      are predicted. Copyright 1999 Academic Press.

PMID- 10409455
TI  - The 4(3)Pi(g) State of Na(2): Vibrational Numbering and Hyperfine Structure.
AB  - The Na(2) 4(3)Pi(g) state has been studied by continuous-wave (cw) perturbation
      facilitated optical-optical double resonance (PFOODR) fluorescence excitation and
      resolved fluorescence spectroscopy. The absolute vibrational numbering was
      determined by resolved fluorescence to the a(3)Sigma(+)(u) state. The OODR
      excitation lines of the 4(3)Pi(g) (Kv, N) <-- b(3)Pi(u) (Kv(b)('), J')
      approximately A(1)Sigma(+)(u) (Kv(A)('), J') <-- X(1)Sigma(+)(g) (Kv", J")
      transitions show hyperfine splittings, and the hyperfine coupling scheme of the
      upper 4(3)Pi(g) levels is case b(betaS). Although this 4(3)Pi(g) state
      dissociates to the 3p + 3p atomic limit, it is a Rydberg state at a small
      internuclear distance, and the hyperfine splitting is caused mainly by the Fermi
      contact interaction of the varsigma(g)3s valence electron with the nuclei. The
      Fermi contact constant was determined to be b(F) = 218.3 +/- 3.9 MHz. Copyright
      1999 Academic Press.

PMID- 10409456
TI  - High-Resolution Laser Photoacoustic Spectroscopy of OCS in the 12 000-13 000 cm(
      1) Region.
AB  - A spectrum of natural OCS has been recorded in the near-infrared region using the
      laser photoacoustic technique. The source is a titanium-sapphire laser pumped by
      an Ar(+) laser. The tunable 1.5 W beam was sent through the photoacoustic cell.
      This windowless longitudinal resonant cell was designed with two lambda/4 buffer
      volumes at both ends in order to reduce the noise and so to increase the
      sensitivity (alpha(min) approximately 10(-9) cm(-1)). The spectrum of OCS, at a
      pressure of 90 Torr, has been recorded in the regions 11 953-12 084, 12 829-12
      890, and 12 998-13 001 cm(-1). In addition to the 00(0)6-00(0)0 band of
      (16)O(12)C(32)S recently identified by Ch. Hornberger, B. Boor, R. Stuber, W.
      Demtroder, S. Naim, and A. Fayt, J. Mol. Spectrosc. 179, 237-245, 1996, new
      weaker bands have been observed: 04(0)5-00(0)0, 1 10(0)3-00(0)0, 10(0)6-00(0)0,
      14(0)5-00(0)0, 02(0)6-00(0)0, and 01(1)6-01(1)0, and also the 00(0)6-00(0)0 band
      of (16)O(12)C(34)S. Effective state parameters are deduced from the band-by-band
      least-squares fits. The new data have also been introduced in the global analysis
      which takes into account the l-type resonance and the main anharmonic
      interactions and so allows a full understanding of the perturbations and the
      intensity transfers. Copyright 1999 Academic Press.

PMID- 10409457
TI  - The High-Resolution FTIR Far-Infrared Spectrum of Vinylamine.
AB  - The infrared spectrum of vinylamine, generated by pyrolysis of cyclobutylamine,
      has been investigated at low and high resolution. The rovibrational structure of
      the far infrared spectrum (0.002 cm(-1)) has been analyzed, and effective
      rotational and centrifugal distortion constants have been derived for eight
      vibration-rotation bands in the region 250-750 cm(-1). The rovibrational
      structure of two further bands has been assigned using combination differences,
      and some conclusions have been drawn about the vibrational energy levels
      involved. With the large amount of new data it is possible to achieve a
      vibrational analysis of the far infrared region, but not to totally exclude an
      alternative assignment. Copyright 1999 Academic Press.

PMID- 10409458
TI  - Microwave Spectrum and Molecular Conformation of (E)-Benzaldehyde Oxime.
AB  - The microwave spectrum of (E)-benzaldehyde oxime, C(6)H(5)-CH&dbond;NOH and
      C(6)H(5)-CH&dbond;NOD, has been observed in the frequency range from 26.5 to 40.0
      GHz. The spectrum of the ground vibrational state was assigned and fitted to the
      Watson's A-reduced Hamiltonian to obtain these rotational and centrifugal
      distortion constants: A = 5183.13(29) MHz, B = 895.367(3) MHz, C = 763.819(3)
      MHz, Delta(J) = 0.019(3) kHz, and Delta(JK) = 0.204(7) kHz for the normal
      species, and A = 5158.4(23) MHz, B = 869.44(2) MHz, C = 744.34(2) MHz, Delta(J) =
      0.023(2) kHz, and Delta(JK) = 0.193(7) kHz for the deuterated species. The values
      of the DeltaI (=I(c) - I(a) - I(b)) obtained for the normal and deuterated
      species were -0.295(6) and -0.28(5) a.m.u. A(2), respectively. The molecular
      conformation of this molecule was a planar one in which the values of the
      dihedral angles, CCNO and CNOH, were almost 180 degrees and 180 degrees,
      respectively. Copyright 1999 Academic Press.

PMID- 10409459
TI  - Lineshifts in the Fundamental Band of CO: Confirmation of Experimental Results
      for N(2) and Comparison with Theory.
AB  - We have used a three-channel version of a tunable difference frequency laser
      spectrometer to measure the collisionally induced lineshifts at room temperature
      for 26 lines of the fundamental band of CO perturbed by nitrogen. Each lineshift
      was obtained directly by comparing the line center positions of two simultaneous
      recordings, one for a pressure-shifted line, and the other for the same line in
      pure CO line at very low pressure. The experimental results are found to be in
      complete agreement with earlier measurements and confirm that shifts as small as
      3 MHz may be measured in such a system. Our results are compared with theoretical
      calculations. The part of the shifting coefficient antisymmetric with respect to
      a change in sign of the line number m, is in disagreement with the calculations.
      Copyright 1999 Academic Press.

PMID- 10409460
TI  - H(3)Si(37)Cl Revisited with High Resolution: The Ground State and the v(2) = 1;
      v(3) = 1, 2, and 3; v(5) = 1; v(6) = 1 and 2; and v(3) = v(6) = 1 States.
AB  - The infrared spectrum in the range 400-1600 cm(-1) of isotopically pure
      H(3)Si(37)Cl has been recorded at high resolution (2.4-6.6 x 10(-3) cm(-1)) and
      analyzed. Fifteen bands have been studied, namely the four fundamentals nu(3)
      (543.968 cm(-1)), nu(6) (663.738 cm(-1)), nu(2) (947.982 cm(-1)), and nu(5)
      (950.657 cm(-1)), the overtone bands 2nu(3), 2nu(0)(6), and 2nu(-/+2)(6), the
      combination band nu(3) + nu(6), and seven hot bands. Improved ground state
      constant parameters have been obtained, including all four sextic distortion
      constants. As for the J-independent parameters A(0), D(0)(K), and H(0)(K), they
      were determined mainly through the "loop method" involving nu(6), 2nu(-/+2)(6),
      and 2nu(-/+2)(6)-nu(+/-1)(6) and checked through the strong interactions between
      nu(2) and nu(5), producing some "forbidden lines." The nu(2)/nu(5) dyad was
      fitted with success using two different reduced Hamiltonians. Concerning nu(3)
      and nu(6), in spite of their relatively large separation, a Coriolis interaction
      could be evidenced. In both nu(2)/nu(5) and nu(3)/nu(6) interacting systems the
      sign of the interaction was found positive. As for the overtones, 2nu(3) was
      treated as isolated and 2nu(0)(6) and 2nu(-/+2)(6) as linked together by an l(2,
      2) interaction. The data on the v(3) = v(6) = 1 levels were obtained mainly from
      the two hot bands nu(3) + nu(6) - nu(3) and nu(3) + nu(6) - nu(6), and marginally
      from the weak band nu(3) + nu(6), and also fitted as for an isolated level. A
      weak x,y-Coriolis interaction with level crossing between K/(kl - 1) = 21 and 22,
      and a local l(1, -2) resonance at K = 13/kl = -15 between 2nu(3) and nu(5) were
      furthermore detected. Copyright 1999 Academic Press.

PMID- 10409461
TI  - Simultaneous Rovibrational Analysis of the nu(2), nu(3), nu(5), and nu(6) Bands
      of H(3)(12)CF.
AB  - A total of 4892 transition wavenumbers of the nu(2), nu(3), nu(5), and nu(6)
      fundamental bands of H(3)(12)CF and 1469 frequencies of the rotational
      transitions in the v(2) = 1, v(3) = 1, v(5) = 1, and v(6) = 1 vibrational states
      have been fitted simultaneously by taking explicitly into account various
      Coriolis interactions, l-type interactions, and alpha-resonance terms between and
      within the vibrational states. The standard deviation of the fit using 71
      parameters was 8.10 x 10(-5) cm(-1) for the infrared data and 0.198 MHz for the
      rotational data. This study clearly shows that in order to obtain a really
      quantitative fit of the highly precise data of vibration-rotational and
      rotational spectroscopy, it is necessary to fit all the data simultaneously using
      a variational approach. The deperturbed values of the upper state rotational
      constants differ significantly from those obtained previously in fitting the
      nu(3) and nu(6) bands as isolated bands and the nu(2)/nu(5) bands by a
      variational approach. This is important for the precise determination of the
      equilibrium structure of methyl fluoride (J. Demaison, J. Breidung, W. Thiel, and
      D. Papousek, Struct. Chem., in press). Besides this, the results can be used in
      further studies of the reduced Hamiltonians for more complicated systems of
      interacting vibrational levels. Copyright 1999 Academic Press.

PMID- 10409462
TI  - Rotational Analysis of nu(13) of Allyl Radical.
AB  - Transient infrared laser spectroscopy near 3100 cm(-1) has been used to observe
      the nu(13) band of the allyl radical. The rotational structure has been assigned
      and analyzed. Reliable assignments of both asymmetry components have been made
      for the subbands with K(a) = 0-5 and 7-10. Upper state rotational constants have
      been determined. Copyright 1999 Academic Press.

PMID- 10409463
TI  - On the Elimination of Spurious Modes in Algebraic Models of Molecular Vibrations.
AB  - Spurious states arise naturally in the description of molecular vibrational
      excitations. In the harmonic approximation such states can be projected out from
      the physical space exactly. This is in general not the case when anharmonic
      interactions are considered. We show that within the framework of the symmetry,
      adapted vibron models which include anharmonicities from the outset, these states
      can be removed in an exact fashion. Copyright 1999 Academic Press.

PMID- 10409464
TI  - Microwave Spectra of the Methylpolyynes CH(3)(C&tbond;C)(6)H and
      CH(3)(C&tbond;C)(7)H.
AB  - Two new methylpolyynes, CH(3)(C&tbond;C)(6)H (tridecahexayne) and
      CH(3)(C&tbond;C)(7)H (pentadecaheptayne), have been detected in a supersonic
      molecular beam by Fourier transform microwave spectroscopy. A total of 20
      transitions of CH(3)(C&tbond;C)(6)H in the K = 0 and 1 rotational ladders and 8
      transitions of CH(3)(C&tbond;C)(7)H in the K = 0 ladder were observed between 5
      and 11 GHz, allowing for both molecules precise determination of rotational and
      centrifugal distortion constants. Like other long carbon chains of similar
      length, the rotational constants of the two new methylpolyynes are well predicted
      by extrapolation from the shorter members of the sequence; the addition of
      successive C(2) units evidently little perturbs the structure of the rest of the
      molecule. Centrifugal distortion is well described by the same semiclassical
      model that works well for the cyanopolyynes, one which treats a carbon chain as a
      thin elastic rod with a Young's modulus independent of length. Copyright 1999
      Academic Press.

PMID- 10409466
TI  - Curvilinear Coordinate Formulation for Vibration-Rotation-Large Amplitude
      Internal Motion Interactions. III. A Note on the T Transformation for
      Nonprincipal Axis Systems.

PMID- 10409465
TI  - Rotational Spectrum of 1,3-Dioxolane-Argon: A Fourier Transform Investigation.

PMID- 10409467
TI  - Broad-band spectral analysis of 24 h continuous finger blood pressure: comparison
      with intra-arterial recordings.
AB  - The present study compares the spectral characteristics of 24-h blood pressure
      variability estimated invasively at the brachial artery level with those
      estimated by measurement of blood pressure at the finger artery using the non
      invasive Portapres device. Broad-band spectra (from 3x10(-5) to 0.5 Hz) were
      derived from both finger and intra-brachial pressures recorded simultaneously for
      24 h in eight normotensive and twelve hypertensive ambulant subjects. At
      frequencies lower than 0.07 Hz, higher spectral estimates were obtained by
      Portapres than by intra-brachial measurements. The maximum overestimation
      occurred in systolic pressure at around 10(-2) Hz, where the amplitude of the
      oscillations was two times greater when measured by Portapres. A less pronounced
      overestimation was found for diastolic pressures. The maximum overestimation was
      greater during daytime than during night-time. At around 0.1 Hz, invasive and non
      invasive spectra were similar. At the respiratory frequencies (0.15-0.50 Hz), the
      power spectra were overestimated by Portapres during daytime, and underestimated
      at night. These results provide reference information for the correct
      interpretation of Portapres data in the estimation of 24-h blood pressure
      spectral power.

PMID- 10409468
TI  - Basal nitric oxide production is impaired in offspring of patients with essential
      hypertension.
AB  - There is considerable evidence that endothelium-dependent nitric oxide (NO)
      mediated vasodilatation in response to acetylcholine is impaired in essential
      hypertension, whereas the endothelium-independent response to sodium
      nitroprusside is normal. More limited data have suggested that there is also
      reduced vasoconstriction in response to N(G)-monomethyl-L-arginine (L-NMMA), a
      competitive inhibitor of basal NO release. As it is not known whether endothelial
      dysfunction in hypertension, if indeed present, is a cause or consequence of the
      condition, we have studied the normotensive offspring of parents with essential
      hypertension. Both basal and stimulated vascular responses were examined in 12
      normotensive offspring [mean age (+/-S.E.M.) 26.1+/-1.4 years] of parents with
      essential hypertension and compared with those in 12 age-matched offspring (mean
      age 25.6+/-1.1 years) of normotensive subjects. Forearm blood flow was measured
      simultaneously in both arms by venous occlusion plethysmography, both at baseline
      and during intra-arterial brachial infusion of increasing doses of acetylcholine,
      sodium nitroprusside, noradrenaline and L-NMMA. There were no significant
      differences between the groups in the responses to acetylcholine, sodium
      nitroprusside or noradrenaline. In contrast, the vasoconstrictor response to L
      NMMA was significantly blunted in the offspring of hypertensive parents compared
      with that in the offspring of normotensive parents (P=0.005). Thus endothelial
      dysfunction, as demonstrated by impaired basal production of NO, is present in
      subjects at high risk of essential hypertension, and does not occur simply as a
      consequence of the condition.

PMID- 10409469
TI  - Plasma endothelin-1 and total insulin exposure in diabetes mellitus.
AB  - Insulin stimulates endothelin-1 (ET-1) expression in a dose-response
      relationship, and ET-1 effects on vascular wall structure are similar to the long
      term complications of diabetes. We therefore determined whether the plasma ET-1
      concentration in patients with diabetes is associated with their total insulin
      exposure to see if plasma ET-1 might be a link between insulin exposure and long
      term complications of diabetes. We studied 69 patients with Type I and 40
      patients with Type II diabetes mellitus in equally tight glycaemic control for 2
      years in a cross-sectional design. We measured basal and glucagon-stimulated
      plasma C-peptide, abdominal sagittal diameter, skinfold thickness, glomerular
      filtration rate, albumin excretion rate and standard clinical characteristics.
      Mean HbA1c was 6.4% in Type I and 6.3% in Type II diabetes. Patients with an
      albumin excretion rate >300 microg/min were excluded. Adjusted mean plasma ET-1
      was 4.11 (S.E.M. 0.39) pg/ml in 21 normal subjects, 3.47 (0.19) pg/ml in Type I
      diabetes and 4.84 (0.26) pg/ml in Type II diabetes (P=0.0001). In all patients
      with measurable plasma C-peptide, plasma ET-1 was associated with basal plasma C
      peptide (r=0.5018, P<0.0001), with stimulated plasma C-peptide (r=0.5379,
      P<0.0001), and with total daily insulin dose (r=0.2219, P=0.00851). Abdominal
      obesity, metabolic abnormalities, blood pressure and glomerular filtration rate
      were not associated with plasma ET-1, when corrected for C-peptide and daily
      insulin dose. Our study shows that the plasma concentration of ET-1 is closely
      associated with insulin secretion and insulin dose in patients with diabetes.
      Plasma ET-1 is higher in Type II diabetes than in Type I diabetes. Increased
      insulin exposure in patients with diabetes may have long-term effects on vascular
      wall structure through its stimulation of ET-1 expression.

PMID- 10409470
TI  - Changes in calcium homoeostasis in patients undergoing liver transplantation:
      effects of a single infusion of pamidronate administered pre-operatively.
AB  - Bone turnover, bone loss and fracture risk increase after liver transplantation.
      It has been postulated that peri-operative administration of a bisphosphonate
      might prevent bone loss and reduce fracture rate. We studied the effects of a
      single pre-operative dose of pamidronate on biochemical parameters of skeletal
      metabolism in the first month after liver transplantation. In a randomized,
      single-blind study, six of 12 patients with chronic liver disease received 60 mg
      of pamidronate intravenously on a single occasion 1-30 days before
      transplantation. Six other patients undergoing transplantation received no
      pamidronate. We measured serum calcium, phosphate, albumin, bone-specific
      alkaline phosphatase, plasma parathyroid hormone and tartrate-resistant acid
      phosphatase before pamidronate infusion and at frequent intervals during the
      first 30 post-operative days. In treated patients, plasma parathyroid hormone
      increased 12-fold over baseline values and remained elevated in comparison with
      baseline at days 26-30; serum calcium and phosphate fell significantly, returning
      to normal at around day 14 post-operatively. There were no significant changes in
      any parameter in the untreated group. No changes in bone formation or resorption
      markers were observed in either group. The large increase in plasma parathyroid
      hormone concentrations in the treated group is probably secondary to the fall in
      serum calcium. The magnitude of the increase is much greater than that seen after
      pamidronate infusion in other patient groups. The lack of change in, or
      correlation of, serum calcium and plasma parathyroid hormone in the untreated
      group suggests that additional factors release calcium from bone after liver
      transplantation, presumably by increasing bone resorption.

PMID- 10409471
TI  - Enhanced angiotensin-converting enzyme activity and impaired endothelium
      dependent vasodilation in aortae from hypertensive rats: evidence for a causal
      link.
AB  - Endothelial vasomotor function is impaired in a variety of disorders representing
      both early and late stages of atherosclerosis. There is experimental evidence for
      enhanced vascular angiotensin-converting enzyme (ACE) activity in these
      disorders. We explored whether enhanced vascular ACE activity accounts for
      endothelial dysfunction in experimental hypertension. Hypertension was induced in
      rats by coarctation of the aorta. At 2 weeks post-operation, the animals were
      randomly divided into groups receiving the ACE inhibitor quinapril (2.0 mg.kg(
      1).day(-1)), the angiotensin type-1 receptor antagonist losartan (3.0 mg.kg(
      1).day(-1)), the B(2) kinin receptor antagonist icatibant (0.4 mg.kg(-1).day(
      1)), quinapril plus icatibant, losartan plus icatibant, or no drug. Analyses were
      performed 4 weeks post-operation. None of the drug treatments had any significant
      effect on blood pressure. ACE activity was nearly doubled in aortae from
      untreated hypertensive rats as compared with sham-operated rats. Quinapril
      reduced ACE activity in aortae from hypertensive rats by 75%, losartan caused a
      40% decrease, and icatibant had no effect. Endothelium-dependent, nitric oxide
      mediated vasodilator responses studied in vitro were impaired by 40% in aortae
      from untreated hypertensive rats as compared with sham-operated rats. Both
      quinapril and losartan restored endothelial vasomotor function in aortae from
      hypertensive rats. Co-applied icatibant negated the effects of quinapril, but not
      those of losartan. The level of endothelial NO synthase (eNOS) mRNA determined by
      competitive RNA PCR was decreased by half in aortae from untreated hypertensive
      rats as compared with sham-operated rats. Quinapril induced an increase in the
      eNOS mRNA level of 350% in aortae from hypertensive rats, which was negated by co
      applied icatibant. Losartan restored eNOS mRNA expression in aortae from
      hypertensive rats to normal levels, and this effect was not modified by co
      applied icatibant. These findings suggest that enhanced vascular ACE activity
      accounts for endothelial vasomotor dysfunction by impairing the bioavailability
      of endothelium-derived NO. Both enhanced formation of angiotensin II and enhanced
      metabolism of bradykinin might account for a vascular deficiency of bioactive NO.

PMID- 10409472
TI  - Lipoprotein(a), essential fatty acid status and lipoprotein lipids in female
      Australian vegetarians.
AB  - In the present study we investigated serum lipoprotein(a) [Lp(a)] levels, plasma
      lipids, the serum phospholipid polyunsaturated fatty acid profile and correlates
      of serum Lp(a) in healthy free-living female vegetarians (n=50) and omnivores
      (n=24) to assess differences which may have implications for cardiovascular risk.
      Dietary saturated fat and total plasma cholesterol were significantly lower in
      the vegetarians compared with omnivores. The mean serum Lp(a) concentration was
      lower in the vegetarians (171 mg/l) than in the omnivores (247 mg/l). The serum
      Lp(a) concentration was significantly negatively correlated with carbohydrate
      intake (as % of energy), and positively correlated with plasma total cholesterol.
      Compared with the omnivores, the vegetarians had significantly lower
      concentrations of 20:3,n-6, 20:4,n-6, 22:5,n-6, 20:5,n-3, 22:6,n-3 and total n-6
      and n-3 polyunsaturated fatty acids, and a lower n-3/n-6 polyunsaturated fatty
      acid ratio, in serum phospholipids. Lower concentrations of plasma total
      cholesterol, serum phospholipid total fatty acids, total saturated fatty acids
      and arachidonic acid, and a tendency towards a lower serum Lp(a) concentration,
      in vegetarians may have beneficial effects on cardiovascular disease risk.
      However, the decreased concentration of serum phospholipid n-3 polyunsaturated
      fatty acids may potentially promote thrombotic risk. Based on the present data,
      it would seem appropriate for omnivores to reduce their dietary intake of total
      fat and saturated fat in order to decrease their plasma cholesterol, and
      vegetarians should perhaps increase their dietary intake of n-3 polyunsaturated
      fatty acids, and thus improve the balance of n-3/n-6, in order to reduce any
      thrombotic tendency that might increase their generally low risk of
      cardiovascular disease.

PMID- 10409473
TI  - Impaired postprandial clearance of squalene and apolipoprotein B-48 in post
      menopausal women with coronary artery disease.
AB  - It is not known in detail whether postprandial lipaemia is associated with
      coronary artery disease (CAD) in women. To investigate this, we administered an
      oral vitamin A/squalene/fat meal to 24 post-menopausal women with
      angiographically proven CAD who were not taking hormone replacement therapy, and
      to 30 healthy controls (18 without and 12 with hormone replacement therapy) to
      evaluate the effects of CAD on postprandial lipoprotein metabolism. This was done
      by assessing squalene, triacylglycerols, retinyl palmitate and apolipoprotein B
      48 (apoB-48) during the subsequent 24 h. The subjects with CAD had significantly
      higher fasting concentrations of squalene and apoB-48 in triacylglycerol-rich
      lipoproteins (TGRL) compared with the controls. The postprandial areas under the
      incremental curve of TGRL apoB-48, chylomicrons, very-low-density lipoprotein
      (VLDL) and TGRL squalene, and of retinyl palmitate in VLDL only, were
      significantly higher in women with CAD than in controls. Adjustment for fasting
      values did not eliminate the differences in postprandial squalene and apoB-48
      between CAD and controls. The postprandial responses of control subjects were not
      influenced by hormone replacement therapy. The peaks of squalene and retinyl
      palmitate of the controls, but not of the women with CAD, occurred significantly
      earlier (P<0.01 for both) in chylomicrons than in VLDL. The findings suggest that
      lipoproteins that accumulate postprandially are labelled by dietary squalene, and
      that these lipoproteins may be atherogenic in post-menopausal women.

PMID- 10409474
TI  - Prevalence of sleep/wake disorders in persons with blindness.
AB  - Blind individuals are not only handicapped by their loss of vision, but are also
      affected because the loss of sight may have a secondary impact on functioning of
      their biological clock. The objective of the present study was to determine the
      impact of visual loss on sleep/wake disorders. A prospective 48-item
      questionnaire survey was distributed to blind individuals through the French
      Association Valentin Hauy, which serves blind persons. A control group matched by
      age, sex, geographical location and professional activity/non-activity was
      obtained from a panel of 20000 households representative of the French
      population, and this group also completed the questionnaire. From a potential
      blind population of 1500 subjects, 1073 questionnaires (71.5%) were completed and
      usable for analysis, and from a potential 1000 control subjects, 794 (79. 4%) of
      the questionnaires were returned and analysed. Criteria outlined in the
      Diagnostic and Statistical Manual of Mental Disorders, 4th revision, and the
      International Classification of Sleep/Wake Disorders (1990) were used to
      determine pathology. Individuals determined to be 'totally blind' and 'almost
      blind' (i.e. with less than 10% vision left in only one eye) presented a
      significantly higher occurrence of sleep/wake disorders than controls. Nocturnal
      sleep disruption, daytime somnolence, and (to a lesser degree) a 'free-running'
      condition are significantly more common in blind individuals. There is an
      increased use of sleeping pills, and a higher incidence of inappropriate
      involuntary daily naps. In conclusion, individuals with blindness report a
      significant curtailment of total sleep time and hence resulting daytime
      somnolence, which impacts on daytime activities. A 'free-running' condition is
      also a common sleep/wake impairment that may compound the handicap of blindness.

PMID- 10409475
TI  - Pulsatile secretion of atrial natriuretic peptide and brain natriuretic peptide
      in healthy humans.
AB  - Both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are
      involved in sodium and water homoeostasis in healthy humans. The plasma
      concentrations of the natriuretic peptides can be used to differentiate between
      dyspnoea of cardiac and pulmonary origin, and the degree of elevation of the
      peptide levels in the plasma in heart failure is a measure of the severity of the
      disease. However, the patterns of secretion of ANP and BNP are not clear either
      in healthy humans or in patients. The purpose of the present study was to test
      the hypotheses that both ANP and BNP are secreted in pulses in healthy humans,
      and that this phenomenon can be revealed by determination of ANP and BNP in
      peripheral venous blood samples. In 12 healthy subjects, blood samples were drawn
      every 2 min through an intravenously inserted plastic needle over a period of 2
      h. Plasma concentrations of ANP and BNP were determined by RIAs, and the results
      were analysed for pulsatile behaviour by Fourier transformation. Pulsatile
      secretion of ANP was seen in 10 out of 12 subjects [nu=0.028 min(-1) (median;
      range 0.013-0.047 min(-1)), i.e. a pulse of ANP with an interval of 36 min (range
      21-77 min)]. Pulsatile secretion of BNP was seen in nine out of 12 patients
      [nu=0. 021 min(-1) (range 0.013-0.042 min(-1)), i.e. a pulse of BNP with an
      interval of 48 min (range 24-77 min)]. The main conclusion is that the secretion
      patterns of both ANP and BNP are pulsatile in most healthy humans. Consequently,
      it is important to study whether pulsatile secretion also occurs in heart failure
      in order to obtain the most informative predictive values both in the
      differential diagnosis of dyspnoea and in the evaluation of the severity of the
      disease.

PMID- 10409476
TI  - Differential expression of mRNA in human thyroid cells depleted of mitochondrial
      DNA by ethidium bromide treatment.
AB  - A wide variety of human diseases have been associated with defects in
      mitochondrial DNA (mtDNA). The exact mechanism by which specific mtDNA mutations
      cause disease is unknown and, although the disparate phenotypes might be
      explained on the basis of impaired mitochondrial gene function alone, the role of
      altered nuclear gene expression must also be considered. In recent years, the
      experimental technique of depleting cells of mtDNA by culturing them with
      ethidium bromide has become a popular method of studying mitochondrial disorders.
      However, apart from depleting mtDNA, ethidium bromide may have many other
      intracellular and nuclear effects. The aim of the present study was to
      investigate the effects of ethidium bromide treatment on nuclear gene expression.
      A simian-virus-40-transformed human thyroid cell line was depleted of mtDNA by
      culture in ethidium bromide, and differential display reverse transcriptase-PCR
      (DDRT-PCR) was then employed to compare mRNA expression between wild-type, mtDNA
      replete (rho(+)) and ethidium bromide-treated, mtDNA-depleted (rho(0)) cells.
      Expression of the majority of nuclear-encoded genes, including those for subunits
      involved in oxidative phosphorylation, remained unaffected by the treatment.
      Seven clones were found to be underexpressed; three of the clones showed
      significant similarity with sequences of the human genes encoding RNase L
      inhibitor, human tissue factor and ARCN1 (archain vesicle transport protein 1), a
      highly conserved species which is related to vesicle structure and trafficking
      proteins. We conclude that the effects of ethidium bromide treatment on nuclear
      gene expression are not simply limited to changes in pathways directly associated
      with known mitochondrial function. Further studies will be required to elucidate
      which of these changes are due to mtDNA depletion, ATP deficiency or other
      disparate effects of ethidium bromide exposure. Given that most genes appear
      unaffected, the results suggest that depleting cells of mtDNA by ethidium bromide
      treatment is a valuable approach for the study of mitochondrial mutations by
      cybrid techniques.

PMID- 10409477
TI  - Weight loss and low body cell mass in males with lung cancer: relationship with
      systemic inflammation, acute-phase response, resting energy expenditure, and
      catabolic and anabolic hormones.
AB  - The aim of the present study was to investigate, in human lung cancer, the
      relationship between weight loss and the existence of a low body cell mass (BCM)
      on the one hand, and the putative presence of systemic inflammation, an increased
      acute-phase response, anorexia, hypermetabolism and changes in circulating levels
      of several anabolic and catabolic hormones on the other. In 20 male lung cancer
      patients, pre-stratified by weight loss of >/=10% (n=10) or of <10% (n=10), the
      following measurements were performed: BCM (by dual-energy X-ray
      absorptiometry/bromide dilution), circulating levels of sTNF-R55 and sTNF-R75
      (soluble tumour necrosis factor receptors of molecular masses 55 and 75 kDa
      respectively), interleukin-6, lipopolysaccharide-binding protein, albumin,
      appetite (scale of 0-10), resting energy expenditure (by indirect calorimetry)
      and circulating levels of catabolic (cortisol) and anabolic [testosterone,
      insulin-like growth factor-I (IGF-I)] hormones. Compared with the patients with a
      weight loss of <10%, those with a weight loss of >/=10% were characterized by
      higher levels of sTNF-R55 (trend towards significance; P=0.06), and lower levels
      of albumin (27.4 compared with 34.4 mmol/l; P=0.02), testosterone (13.2 compared
      with 21.5 nmol/l; P=0.01) and IGF-I (119 compared with 184 ng/ml; P=0.004). In
      the patient group as a whole, the percentage weight loss was significantly
      correlated with sTNF-R55 (r=0.59, P=0.02), albumin (r=-0.63, P=0.006) and IGF-I
      (r=-0.50, P=0.02) levels. Height-adjusted BCM was significantly correlated with
      sTNF-R55 (r=-0.57, P=0.03), sTNF-R75 (r=-0.50, P=0. 04), lipopolysaccharide
      binding protein (r=-0.50, P=0.04), albumin (r=0.56, P=0.02) and resting energy
      expenditure/BCM (r=-0.54, P=0. 03), and there was a trend towards a correlation
      with IGF-I concentration (r=0.44, P=0.06). We conclude that, in human lung
      cancer, weight loss and the presence of a low BCM are associated with systemic
      inflammation, an increased acute-phase response and decreased levels of IGF-I. In
      addition, a decreased BCM is associated with hypermetabolism.

PMID- 10409478
TI  - Acute administration of 17beta-oestradiol does not improve endothelium-dependent
      vasodilatation in young men.
AB  - Studies have recently demonstrated that long-term oestrogen therapy improves
      endothelium-dependent and endothelium-independent vasodilatation in the
      conductance vessels of biological males. We sought to determine if an acute
      single dose of oestrogen might similarly improve vasodilator function in young
      males. In a randomized, double-blind, placebo-controlled, crossover study, we
      compared the effects of 1 mg of sublingual 17beta-oestradiol (E(2)) and placebo
      on endothelium-dependent and endothelium-independent vasodilatation in the
      brachial artery using a non-invasive ultrasound technique. We recruited 30 young
      males based on a power calculation. Neither acute sublingual oestrogen nor
      placebo affected flow-mediated vasodilatation [5.32+/-0.78% and 5.28+/-0.60%
      respectively (mean+/-S.E.M.), P=0.94]. Responses to nitroglycerine were similar
      after oestrogen or placebo (16.01+/-0.86% and 15.29+/-1. 19%, P=0.47). Basal
      blood flow and flow during reactive hyperaemia did not differ after oestrogen or
      placebo. Heart rate and blood pressure were similar during both treatment phases
      of the study. The absolute change in serum oestradiol levels was greater after
      the oestrogen treatment phase than after placebo (1509+/-87 versus -13+/-4
      pmol/l, P<0.0001). Despite achieving supra-physiological oestradiol levels, the
      acute administration of sublingual E(2) does not appear to improve endothelium
      dependent or endothelium-independent vasodilatation, at least acutely, in the
      brachial artery of young males. In keeping with our previous study, these data
      suggest that a period of oestrogen 'priming' (possibly to induce receptor
      mediated nitric oxide synthesis) may be required to yield an improvement in
      vascular function in males.

PMID- 10409479
TI  - Ramipril prevents basal arterial constriction and enhanced myogenic tone in the
      femoral artery in mildly uraemic normotensive rats.
AB  - Some aspects of vascular reactivity are altered in mild experimental uraemia, as
      shown by increased myogenic tone and a reduced lumen diameter in the femoral
      artery. This study was conducted to investigate the prevention of these uraemia
      induced vascular abnormalities by the angiotensin-converting enzyme inhibitor
      (ACE-I) Ramipril. Ten male Wistar rats were rendered uraemic (U) by 5/6th
      nephrectomy, and 10 control (C) rats were concurrently sham-operated. After 4
      weeks, both groups were given daily subcutaneous injections of 3 microg of
      Ramipril for a further 4 weeks. Tail-cuff systolic blood pressure was then
      recorded and the rat was killed. Isolated femoral arteries were mounted on a
      pressure myograph and pressurized at 40 mmHg for baseline measurements of the
      lumen internal diameter. Myogenic tone was then assessed over a range of
      intravascular pressures from 40 to 160 mmHg. Biochemically, serum urea and
      creatinine were significantly higher in the uraemic (U) group [urea: U, 23+/-3
      mmol/l; C, 6+/-1 mmol/l (P<0.001); creatinine: U, 147+/-17 mmol/l, C, 72+/-11
      mmol/l (P<0.01)]. Systolic blood pressure was the same in both groups (U, 127+/-7
      mmHg; C, 127+/-3 mmHg). The mean baseline internal diameter was the same in both
      groups (U, 756+/-22 microm; C, 721+/-34 microm, not significant), as was mean
      myogenic tone (U, 4.7+/-1%; C, 3.4+/-1%). In conclusion, there were no
      differences in baseline lumen diameter or myogenic tone in uraemic compared with
      control femoral arteries of rats treated with Ramipril, which suggests that
      Ramipril may prevent the development of elevated myogenic tone and decreased
      lumen diameter previously observed in this model of uraemia. These results
      suggest that these specific vascular abnormalities in uraemia may be mediated by
      renin or bradykinin, or by the direct action of angiotensin II on vascular smooth
      muscle.

PMID- 10409480
TI  - Contribution of non-cardiomyocyte apoptosis to cardiac remodelling that occurs in
      the transition from compensated hypertrophy to heart failure in spontaneously
      hypertensive rats.
AB  - Various alterations in molecular and cellular events have been considered as
      possibly contributing to the cardiac remodelling that occurs during the
      transition from compensated hypertrophy to heart failure. The aim of the present
      study is to clarify (1) whether cardiac apoptosis occurs during the transition
      from compensated hypertrophy to decompensated heart failure, and (2) whether
      expression of the genes encoding Bax (an apoptosis inducer) and Bcl-xL and Bcl-2
      (apoptosis inhibitors) is altered during this transition. We used 12-month-old
      and 20-month-old male spontaneously hypertensive rats (SHR(12) and SHR(20)
      respectively) and age-matched Wistar-Kyoto rats (WKY(12) and WKY(20)
      respectively). These rats were killed after measurement of haemodynamic
      parameters by transthoracic echocardiography and use of a tipmanometer via the
      right carotid artery. The expression of bcl-2, bcl-xL and bax was analysed by
      Northern blotting. Samples were also fixed in 4% paraformaldehyde for in situ
      nick end-labelling (TUNEL) methods and immunohistochemistry. SHR(12) had well
      compensated left ventricular hypertrophy with normal fractional shortening and
      normal end-systolic wall stress. In contrast, the hearts of SHR(20) developed
      decompensated dilatation, with a decrease in fractional shortening and an
      increase in end-systolic wall stress. TUNEL-positive cells were seen exclusively
      in the hearts of SHR(20). The major cell types that showed TUNEL-positive nuclei
      were non-cardiomyocytes. The expression of bax remained unchanged during the
      transition to heart failure. However, there was increased expression of bcl-xL in
      the failing stage, whereas the expression of bcl-2 remained unchanged.
      Immunohistochemical studies revealed that Bcl-xL protein was up-regulated in the
      hearts of SHR(20). In conclusion, non-cardiomyocyte apoptosis may play a
      contributory role in the remodelling that occurs in the transition from
      compensatory hypertrophy to decompensated heart failure. In addition, it is
      suggested that enhanced expression of bcl-xL plays an important role in the
      preservation of cardiomyocytes during this transition.

PMID- 10409481
TI  - Adrenomedullin in monocytes and macrophages: possible involvement of macrophage
      derived adrenomedullin in atherogenesis.
AB  - Macrophages secrete a variety of growth factors, cytokines and vasoactive
      peptides, which are related to the progression of atherosclerosis. Adrenomedullin
      (ADM) is a potent vasodilator peptide and inhibits proliferation and migration of
      vascular smooth muscle cells. In this study, we investigated the production and
      secretion of ADM by monocytes and macrophages by Northern blot analysis, RIA and
      immunocytochemistry. Northern blot analysis showed that ADM mRNA was expressed in
      human monocytes obtained from peripheral blood and monocyte-derived macrophages.
      The expression level of ADM mRNA in monocyte-derived macrophages was about five
      times higher than that in monocytes. Treatment with lipopolysaccharide (100
      ng/ml) for 24 h increased ADM mRNA expression levels in both monocytes and
      monocyte-derived macrophages. The levels of immunoreactive ADM in the media of
      monocyte-derived macrophages were about three times higher than that of monocytes
      (0. 718+/-0.046 fmol/24 h/10(5) cells, n=8 compared with 0.259+/-0.018 fmol/24
      h/10(5) cells, n=8; mean+/-S.E.M., P<0.01). The secretion was also increased by
      treatment with lipopolysaccharide. Immunocytochemistry showed positive ADM
      immunostaining in macrophages in atherosclerotic lesions of human aorta obtained
      at autopsy. ADM secreted from activated macrophages may play an inhibitory role
      in atherogenesis.

PMID- 10409482
TI  - Spectral analysis of blood pressure: is it pointing in a useful direction?

PMID- 10409483
TI  - The roles of the sun and the landscape in pigeon homing.
AB  - It seems reasonable to assume that pigeons use visual features in the landscape
      for orientation when they are homing over familiar terrain. Experimental evidence
      to prove or disprove this possibility is, however, difficult to obtain. Here, we
      link the problem with the observation that deflections of initial orientation
      caused by clock-shift are often smaller than predicted on a pure sun compass
      basis. We substantiate the hypothesis that consistently reduced deflections and
      increased angular scatter occur only when pigeons are released in familiar areas
      where a remembered pattern of landscape features can conflict with the position
      of the sun. Repeated releases of the same individuals under clock-shift, or
      elimination of non-visual navigational clues (odours), appear to strengthen the
      conflicting influence of familiar visual landmarks. Accelerated returns of birds
      allowed to preview the surrounding familiar scenery before release also support
      the conclusion that the visual environment is included in the homing system of
      pigeons. The landscape, however, not only helps home-finding, if it is familiar,
      but may also have a distracting influence that contributes to the great
      variability of initial orientation patterns.

PMID- 10409484
TI  - Red muscle activation patterns in yellowfin (Thunnus albacares) and skipjack
      (Katsuwonus pelamis) tunas during steady swimming.
AB  - To learn about muscle function in two species of tuna (yellowfin Thunnus
      albacares and skipjack Katsuwonus pelamis), a series of electromyogram (EMG)
      electrodes was implanted down the length of the body in the internal red
      (aerobic) muscle. Additionally, a buckle force transducer was fitted around the
      deep caudal tendons on the same side of the peduncle as the electrodes.
      Recordings of muscle activity and caudal tendon forces were made while the fish
      swam over a range of steady, sustainable cruising speeds in a large water tunnel
      treadmill. In both species, the onset of red muscle activation proceeds
      sequentially in a rostro-caudal direction, while the offset (or deactivation) is
      nearly simultaneous at all sites, so that EMG burst duration decreases towards
      the tail. Muscle duty cycle at each location remains a constant proportion of the
      tailbeat period (T), independent of swimming speed, and peak force is registered
      in the tail tendons just as all ipsilateral muscle deactivates. Mean duty cycles
      in skipjack are longer than those in yellowfin. In yellowfin red muscle, there is
      complete segregation of contralateral activity, while in skipjack there is slight
      overlap. In both species, all internal red muscle on one side is active
      simultaneously for part of each cycle, lasting 0.18T in yellowfin and 0.11T in
      skipjack. (Across the distance encompassing the majority of the red muscle mass,
      0.35-0.65L, where L is fork length, the duration is 0.25T in both species.) When
      red muscle activation patterns were compared across a variety of fish species, it
      became apparent that the EMG patterns grade in a progression that parallels the
      kinematic spectrum of swimming modes from anguilliform to thunniform. The tuna
      EMG pattern, underlying the thunniform swimming mode, culminates this
      progression, exhibiting an activation pattern at the extreme opposite end of the
      spectrum from the anguilliform mode.

PMID- 10409485
TI  - Muscle dynamics in skipjack tuna: timing of red muscle shortening in relation to
      activation and body curvature during steady swimming.
AB  - Cyclic length changes in the internal red muscle of skipjack tuna (Katsuwonus
      pelamis) were measured using sonomicrometry while the fish swam in a water tunnel
      at steady speeds of 1.1-2.3 L s(-)(1), where L is fork length. These data were
      coupled with simultaneous electromyographic (EMG) recordings. The onset of EMG
      activity occurred at virtually the same phase of the strain cycle for muscle at
      axial locations between approximately 0.4L and 0.74L, where the majority of the
      internal red muscle is located. Furthermore, EMG activity always began during
      muscle lengthening, 40-50  degrees  prior to peak length, suggesting that force
      enhancement by stretching and net positive work probably occur in red muscle all
      along the body. Our results support the idea that positive contractile power is
      derived from all the aerobic swimming muscle in tunas, while force transmission
      is provided primarily by connective tissue structures, such as skin and tendons,
      rather than by muscles performing negative work. We also compared measured muscle
      length changes with midline curvature (as a potential index of muscle strain)
      calculated from synchronised video image analysis. Unlike contraction of the
      superficial red muscle in other fish, the shortening of internal red muscle in
      skipjack tuna substantially lags behind changes in the local midline curvature.
      The temporal separation of red muscle shortening and local curvature is so
      pronounced that, in the mid-body region, muscle shortening at each location is
      synchronous with midline curvature at locations that are 7-8 cm (i.e. 8-10
      vertebral segments) more posterior. These results suggest that contraction of the
      internal red muscle causes deformation of the body at more posterior locations,
      rather than locally. This situation represents a unique departure from the model
      of a homogeneous bending beam, which describes red muscle strain in other fish
      during steady swimming, but is consistent with the idea that tunas produce thrust
      by motion of the caudal fin rather than by undulation of segments along the body.

PMID- 10409486
TI  - The vibrational startle response of the desert locust Schistocerca gregaria.
AB  - Substratum vibrations elicit a fast startle response in unrestrained quiescent
      desert locusts (Schistocerca gregaria). The response is graded with stimulus
      intensity and consists of a small, rapid but conspicuous movement of the legs and
      body, but it does not result in any positional change of the animal. With stimuli
      just above threshold, it begins with a fast twitch of the hindlegs generated by
      movements of the coxa-trochanter and femur-tibia joints. With increasing stimulus
      intensity, a rapid movement of all legs may follow, resulting in an up-down
      movement of the whole body. The magnitude of both the hindleg movement and
      electromyographic recordings from hindleg extensor and flexor tibiae muscles
      increases with stimulus amplitude and reaches a plateau at vibration
      accelerations above 20 m s(-)(2) (peak-to-peak). Hindleg extensor and flexor
      tibiae muscles in unrestrained animals are co-activated with a mean latency of 30
      ms. Behavioural thresholds are as low as 0. 47 m s(-)(2) (peak-to-peak) at
      frequencies below 100 Hz but rise steeply above 200 Hz. The response habituates
      rapidly, and inter-stimulus intervals of 2 min or more are necessary to evoke
      maximal reactions. Intracellular recordings in fixed (upside-down) locusts also
      revealed co-activation of both flexor and extensor motor neurones with latencies
      of approximately 25 ms. This shows that the neuronal network underlying the
      startle movement is functional in a restrained preparation and can therefore be
      studied in great detail at the level of identified neurones.

PMID- 10409487
TI  - Effects of sustained swimming on hepatic glucose production of rainbow trout.
AB  - The rate of hepatic glucose production (R(a)glucose) was measured by continuous
      infusions of 6-[(3)H]glucose in live rainbow trout (Oncorhynchus mykiss) before,
      during and after swimming for 3 h at 1.5 body lengths s(-)(1) in a swim tunnel.
      Contrary to expectation, we found that sustained swimming causes a 33 % decline
      in the R(a),(glucose) of trout (from 7.6+/-2.1 to 5.1+/-1.3 (&mgr;)mol kg(-)(1
      )min(-)(1), means +/- s.e.m., N=7), even though exercise of the same intensity
      elicits a two- to fourfold increase in all the mammalian species investigated to
      date. Measurements of catecholamine levels show that circulating [epinephrine]
      decreases by 30 % during exercise (from 4.7+/-0.3 to 3.3+/-0.4 nmol l(-)(1),
      N=8), suggesting that this hormone is partly responsible for controlling the
      decline in R(a)glucose. The inhibiting effect of swimming on hepatic glucose
      production persists for at least 1 h after the cessation of exercise. In
      addition, rainbow trout can maintain a steady blood glucose concentration
      throughout sustained exercise by closely matching hepatic glucose production with
      peripheral glucose utilization, even though this species is generally considered
      to be a poor glucoregulator. This study provides the first continuous
      measurements of glucose kinetics during the transition from rest to work in an
      ectotherm and it suggests that circulating glucose is not an important fuel for
      aerobic locomotion in trout.

PMID- 10409488
TI  - Lactate transport across sarcolemmal vesicles isolated from rainbow trout white
      muscle.
AB  - Rainbow trout (Oncorhynchus mykiss) retain the majority of lactate produced
      during exhaustive exercise within white muscle. Previous studies have suggested
      that this retention is partially via a re-uptake of released lactate. The purpose
      of this work was to study lactate uptake using trout white muscle sarcolemmal
      vesicles. Lactate uptake by trout white muscle is partially through a low
      affinity, high-capacity carrier (apparent K(m)=55.6 mmol l(-)(1) and V(max)=44.5
      nmol mg(-)(1 )protein min(-)(1)). At high concentrations (20 and 50 mmol l(
      )(1)), pyruvate partially (up to 39 %) inhibited lactate uptake, suggesting the
      involvement of a monocarboxylate carrier. The anion transport inhibitor 4
      acetoamido-4'-isothiocyanstilbene-2,2'-disulphonic acid (SITS) and the
      monocarboxylate transport inhibitor (&agr;)-cyano-4-hydroxycinnamate (CHC)
      stimulated apparent lactate uptake. The model developed suggests that lactate is
      taken up by the vesicles, at least in part by a pyruvate-sensitive
      monocarboxylate carrier, and that its subsequent efflux is inhibited by SITS and
      CHC, suggesting that lactate export from trout white muscle is also carrier
      mediated.

PMID- 10409490
TI  - Increases in tissue free amino acid levels in response to prolonged emersion in
      marine crabs: an ammonia-detoxifying process efficient in the intertidal Carcinus
      maenas but not in the subtidal Necora puber.
AB  - Carcinus maenas and Necora puber were exposed to air for 72 h and 18 h,
      respectively, at 18  degrees C. Changes in the free amino acid (FAA) content of
      their muscle, hepatopancreas and haemolymph were recorded during air-exposure and
      subsequent reimmersion. Muscle and hepatopancreas urate contents and haemolymph
      serum protein levels were also measured during emersion. In air-exposed C.
      maenas, the muscle FAA pool increased significantly within the first 24 h of
      emersion. This increase was due to an increase in the non-essential amino acid
      (NEAA) pool only; the essential amino acid (EAA) pool did not change. In
      haemolymph, the EAA pool decreased during the first 24 h of emersion, whereas the
      FAA and NEAA pools did not change. However, in this compartment, glutamine levels
      increased throughout the air-exposure period. No significant changes in FAA, NEAA
      and EAA contents of the hepatopancreas were observed during the 72 h emersion. In
      air-exposed N. puber, the FAA pools of muscle and hepatopancreas did not change,
      although changes in the levels of some amino acids were observed during the 18 h
      emersion period. In this species, large increases in both the NEAA and EAA pools
      in the haemolymph were recorded. High levels of urate were observed in the muscle
      and hepatopancreas of immersed N. puber, but no significant changes occurred
      during emersion. In contrast, immersed C. maenas exhibited low levels of urate in
      both compartments, and hepatopancreas urate levels increased slightly during
      emersion. Haemolymph protein content did not change in air-exposed N. puber,
      whereas it increased in the haemolymph of 72 h emersed C. maenas. The origin of
      newly formed NEAAs and their role in ammonia detoxification, particularly in C.
      maenas, which is able to regulate its internal ammonia levels during such a
      prolonged emersion, are discussed.

PMID- 10409489
TI  - The control of blood pressure during external hypercapnia in the rainbow trout
      (Oncorhynchus mykiss).
AB  - Adult freshwater rainbow trout (Oncorhynchus mykiss) were exposed acutely
      (approximately 20 min) in a stepwise manner to increasing levels of environmental
      carbon dioxide ranging between 1.7 and 9.0 mmHg (0.23-1.2 kPa). Experiments were
      performed to examine, for the first time, the influence of hypercapnic acidosis
      on aspects of cardiovascular physiology including blood pressure, cardiac output
      and vascular resistance. Fish displayed dose (water CO(2) partial pressure) 
      dependent increases in ventral aortic (13-39 %) and dorsal aortic (17-54 %) blood
      pressures that reflected marked increases in systemic vascular resistance (16-78
      %); branchial vascular resistance was unaffected by hypercapnia. At the highest
      level of hypercapnia (9.0 mmHg), central venous pressure was significantly
      elevated by 54 %. Although cardiac output remained constant, heart rate was
      significantly lowered by 4-7 beats min(-)(1) at the two highest levels of
      hypercapnia. To determine whether the cardiovascular responses to hypercapnia
      were being blunted by the stepwise increase in external P(CO2), a separate group
      of fish was exposed directly to a single step of hypercapnia (water P(CO2) 8.0
      mmHg). The cardiovascular responses were similar to those exhibited by the more
      gradually exposed fish except that central venous pressure did not increase and
      the extent of the bradycardia was greater (13 beats min(-)(1)). After confirming
      the effectiveness of yohimbine in blocking the vasoconstrictory (&agr;)
      adrenoreceptors of the systemic vasculature, this antagonist was used as a tool
      to assess the importance of (&agr;)-adrenoreceptor stimulation in promoting the
      cardiovascular responses during hypercapnia. Prior treatment of fish with
      yohimbine prevented the increased blood pressures and systemic vascular
      resistance during hypercapnia but did not influence the CO(2)-induced
      bradycardia. Plasma levels of catecholamines did not change during hypercapnia,
      and therefore the stimulation of the systemic (&agr;)-adrenoreceptors presumably
      reflected increased sympathetic nerve activity. To determine whether the
      cardiovascular changes elicited by hypercapnia were related to acidosis-induced
      hypoxaemia, fish were exposed to hypoxia in a stepwise manner (water P(O2) 65-151
      mmHg). The cardiovascular responses to hypoxia were markedly different from those
      to hypercapnia and consisted of pronounced increases in systemic and branchial
      vascular resistance, but only at the most severe level of hypoxia; ventral and
      dorsal aortic pressures were unaffected. The differences between the responses to
      hypercapnia and hypoxia, coupled with the smaller reductions in blood oxygen
      content during hypercapnia, support the hypothesis that the cardiovascular
      responses to CO(2) are direct and are unrelated to hypoxaemia.

PMID- 10409491
TI  - Neurochemical control of cricket stridulation revealed by pharmacological
      microinjections into the brain.
AB  - Neuroactive substances were administered into the frontal protocerebrum of
      tethered male Gryllus bimaculatus by pressure injections from microcapillaries.
      All three types of species-specific song pattern (calling song, rivalry song and
      courtship song) could be elicited by injection of acetylcholine and cholinergic
      agonists. Injection of nicotine led to short bouts of calling song that occurred
      after a short latency. In contrast, muscarine elicited long-lasting stridulation
      that took longer to develop. The pharmacologically induced song patterns showed
      transitions from rivalry song to calling song and from calling song to courtship
      song, which also occur during natural behaviour. Stridulation induced by a
      cholinergic agonist could be immediately blocked by microinjection of (&ggr;)
      aminobutyric acid (GABA) into the same neuropile sites. Administration of
      picrotoxin in resting crickets led to enhanced motor activity that incorporated
      the three different song patterns. We propose that, in the brain of the cricket,
      acetylcholine and GABA are putative transmitters involved in the control of
      stridulation. Histological analysis located the stimulation sites to an area
      between the pedunculus and the (&agr;)-lobe of the mushroom body in which the
      command neurons for calling song have dendritic arborizations.

PMID- 10409492
TI  - Expression of membrane transporters in cane toad Bufo marinus oocytes.
AB  - Membrane transport proteins (transporters and ion channels) have been extensively
      expressed in amphibian oocytes. The aims of this study were to determine whether
      oocytes from the cane toad Bufo marinus could be used as an alternative
      expression system to the broadly used Xenopus laevis oocytes. mRNAs encoding
      plasma membrane transporters NaSi-1 and sat-1 (sulphate transporters), NaDC-1
      (dicarboxylate transporter), SGLT-1 (Na(+)/glucose cotransporter) and rBAT and
      4F2 hc (amino acid transporters) were injected into B. marinus oocytes. All led
      to significant induction of their respective transport activities. Uptake rates
      were comparable with those in X. laevis oocytes, with the exception of rBAT,
      which was able to induce amino acid uptake only in X. laevis oocytes, suggesting
      that rBAT may require an endogenous X. laevis oocyte protein that is absent from
      B. marinus oocytes. Transport kinetics were determined for the NaSi-1
      cotransporter in B. marinus oocytes, with identical results to those obtained in
      X. laevis oocytes. NaSi-1 specificity for the Na(+) cation was determined, and
      the anions selenate, molybdate, tungstate, oxalate and thiosulphate could all
      inhibit NaSi-1-induced sulphate transport. This study demonstrates that cane toad
      oocytes can be used successfully to express plasma membrane proteins, making this
      a viable heterologous system for the expression of proteins.

PMID- 10409493
TI  - Migratory directions of free-flying birds versus orientation in registration
      cages.
AB  - Good conditions for migration may promote offshore flights in nocturnal autumn
      migrants at the northern border of the Mediterranean Sea, whereas unfavourable
      conditions may induce flights along the coast. These predictions were tested by
      performing orientation cage experiments and making simultaneous observations of
      free-flying birds using a tracking radar. The flight directions of free-flying
      birds were mainly towards southwest and did not differ between overcast and clear
      sky conditions. The caged birds, however, tended towards southwest under clear
      sky and showed a more scattered distribution in the southwest and southeast
      quadrants under overcast conditions. Similar directional scatter occurred when
      the cage experiments were performed late at night. In contrast, free-flying birds
      shifted their flight direction towards west as night progressed to avoid flights
      across the sea. Flight directions observed by radar shifted slightly towards west
      as the season progressed owing to more frequent southeasterly winds. In
      orientation cages, however, directional preference was scattered towards
      southwest and southeast in the early migratory season and became unimodal
      (southwest) at the peak of the season; this change was not caused by different
      species composition. Consequently, there is a general coincidence of flight
      directions and directional preferences in orientation cages, but interpretations
      of results from orientation cages must allow for the possibility that
      experimental directions are different from migratory directions of free-flying
      birds, particularly under suboptimal migratory conditions.

PMID- 10409494
TI  - Seasonal and temperature effects on the adrenergic responses of Arctic charr
      (Salvelinus alpinus) erythrocytes.
AB  - In the present study, we have examined the adrenergic responses of Arctic charr
      (Salvelinus alpinus) erythrocytes acclimated to different temperatures (2, 8 and
      14 degrees C) during different seasons. We measured the changes in cellular water
      and ion contents after noradrenaline stimulation using different noradrenaline
      concentrations and external pH values. Furthermore, the effects of acute
      temperature changes on the magnitude of the adrenergic response were studied. The
      adrenergic response of Arctic charr erythrocytes showed pronounced seasonal
      variation. The [Na(+)]/[Cl(-)] accumulation ratio after adrenergic stimulation
      was greatest in May, indicating an enhanced activity of the Na(+)/H(+) exchanger.
      The noradrenaline-induced change in [Na(+)](i) was greatest in spring. In
      addition to a seasonal effect, the exchanger seemed to be most active in
      erythrocytes from charr acclimated to low temperature (2 degrees C) early in May:
      the EC(50) value was lower and the calculated maximal increase in [Na(+)](i) was
      greater in the 2 degrees C-acclimated group than in the other acclimation groups.
      In contrast, acclimation to different temperatures did not affect these responses
      (measured at a constant temperature) in February. An acute temperature change has
      a smaller effect on the adrenergic response of Arctic charr erythrocytes than on
      rainbow trout (Oncorhynchus mykiss) erythrocytes.

PMID- 10409495
TI  - Transforming growth factor-beta signalling in extraembryonic mesoderm is required
      for yolk sac vasculogenesis in mice.
AB  - We have analysed the function of transforming growth factor beta (TGF-beta) in
      yolk sac development in mice by generating somatic chimaeras in which the
      extraembryonic mesoderm, which gives rise to the endothelial and haematopoietic
      cells of the yolk sac vasculature, is derived from embryonic stem (ES) cells. The
      ES cells were stably transfected and express either the full-length type II
      binding receptor or a kinase-deficient mutant of this receptor. Examination of
      yolk sacs from chimaeras between E8.5 and 9.5, and analysis of marker expression
      in embryoid bodies from these mutant ES cell lines in prolonged suspension
      culture demonstrated that (1) a major function of TGF-beta in yolk sac mesoderm
      is to regulate production and deposition of fibronectin in the extracellular
      matrix that maintains yolk sac integrity, (2) TGF-beta signalling is not required
      for differentiation of extraembryonic mesoderm into endothelial cells but is
      necessary for their subsequent organisation into robust vessels, and (3) TGF-beta
      signalling must be tightly regulated for the differentiation of primitive
      haematopoietic cells to take place normally. Together, these results show that
      defective TGF-beta signalling in the extraembryonic mesoderm alone is sufficient
      to account for the extraembryonic phenotype reported previously in TGF-beta1(-/-)
      mice (Dickson, M. C., Martin, J. S., Cousins, F. M., Kulkarni, A. B., Karlsson,
      S. and Akhurst, R. J. (1995) Development 121, 1845-1854).

PMID- 10409497
TI  - Wingless, decapentaplegic and EGF receptor signaling pathways interact to specify
      dorso-ventral pattern in the adult abdomen of Drosophila.
AB  - Adult abdominal segments of Drosophila are subdivided along the dorso-ventral
      axis into a dorsal tergite, a ventral sternite and ventro-lateral pleural
      cuticle. We report that this pattern is largely specified during the pupal stage
      by Wingless (Wg), Decapentaplegic (Dpp) and Drosophila EGF Receptor (DER)
      signaling. Expression of wg and dpp is activated at the posterior edge of the
      anterior compartment by Hedgehog signaling. Within this region, wg and dpp are
      expressed in domains that are mutually exclusive along the dorso-ventral axis: wg
      is expressed in the sternite and medio-lateral tergite, whereas dpp expression is
      confined to the pleura and the dorsal midline. Neither gene is expressed in the
      lateral tergite. Shirras and Couso (1996, Dev. Biol. 175, 24-36) have shown that
      tergite and sternite cell fates are specified by Wg signaling. We find that DER
      acts synergistically with Wg to promote tergite and sternite identities, and that
      Wg and DER activities are opposed by Dpp signaling, which promotes pleural
      identity. Wg and Dpp interact antagonistically at two levels. First, their
      expression is confined to complementary domains by mutual transcriptional
      repression. Second, Wg and Dpp compete directly with one another by exerting
      opposite effects on cell fate. DER signaling does not affect the expression of wg
      or dpp, indicating that it interacts with Wg and Dpp at the level of cell fate
      determination. Within the tergite, the requirements for Wg and DER function are
      roughly complementary: Wg is required mainly in the medial region, whereas DER is
      most important laterally. Finally, we show that Dpp signaling at the dorsal
      midline controls dorso-ventral patterning within the tergite by promoting
      pigmentation in the medial region.

PMID- 10409496
TI  - Parathyroid hormone-related protein signaling is necessary for sexual dimorphism
      during embryonic mammary development.
AB  - Male mice lack mammary glands due to the interaction of circulating androgens
      with local epithelial-mesenchymal signaling in the developing mammary bud.
      Mammary epithelial cells induce androgen receptor (AR) within the mammary
      mesenchyme and, in response to androgens, the mesenchyme condenses around the
      epithelial bud, destroying it. We show that this process involves apoptosis and
      that, in the absence of parathyroid hormone-related protein (PTHrP) or its
      receptor, the PTH/PTHrP receptor (PPR1), it fails due to a lack of mesenchymal AR
      expression. In addition, the expression of tenascin C, another marker of the
      mammary mesenchyme, is also dependent on PTHrP. PTHrP expression is initiated on
      E11 and, within the ventral epidermis, is restricted to the forming mammary
      epithelial bud. In contrast, PPR1 expression is not limited to the mammary bud,
      but is found generally within the subepidermal mesenchyme. Finally, transgenic
      overexpression of PTHrP within the basal epidermis induces AR and tenasin C
      expression within the ventral dermis, suggesting that ectopic expression of PTHrP
      can induce the ventral mesenchyme to express mammary mesenchyme markers. We
      propose that PTHrP expression specifically within the developing epithelial bud
      acts as a dominant signal participating in cell fate decisions leading to a
      specialized mammary mesenchyme.

PMID- 10409498
TI  - beta-catenin signaling can initiate feather bud development.
AB  - Intercellular signaling by a subset of Wnts is mediated by stabilization of
      cytoplasmic beta-catenin and its translocation to the nucleus. Immunolocalization
      of beta-catenin in developing chick skin reveals that this signaling pathway is
      active in a dynamic pattern from the earliest stages of feather bud development.
      Forced activation of this pathway by expression of a stabilized beta-catenin in
      the ectoderm results in the ectopic formation of feather buds. This construct is
      sufficient to induce bud formation since it does so both within presumptive
      feather tracts and in normally featherless regions where tract-specific signals
      are absent. It is also insensitive to the lateral inhibition that mediates the
      normal spacing of buds and can induce ectopic buds in interfollicular skin.
      However, additional patterning signals cooperate with this pathway to regulate
      gene expression within domains of stabilized beta-catenin expression. Localized
      activation of this pathway within the bud as it develops is required for normal
      morphogenesis and ectopic activation of the pathway leads to abnormally oriented
      buds and growths on the feather filaments. These results suggest that activation
      of the beta-catenin pathway initiates follicle development in embryonic skin and
      plays important roles in the subsequent morphogenesis of the bud.

PMID- 10409499
TI  - Different contributions of pannier and wingless to the patterning of the dorsal
      mesothorax of Drosophila.
AB  - In Drosophila, the GATA family transcription factor Pannier and the Wnt secreted
      protein Wingless are known to be important for the patterning of the notum, a
      part of the dorsal mesothorax of the fly. Thus, both proteins are necessary for
      the development of the dorsocentral mechanosensory bristles, although their roles
      in this process have not been clarified. Here, we show that Pannier directly
      activates the proneural genes achaete and scute by binding to the enhancer
      responsible for the expression of these genes in the dorsocentral proneural
      cluster. Moreover, the boundary of the expression domain of Pannier appears to
      delimit the proneural cluster laterally, while antagonism of Pannier function by
      the Zn-finger protein U-shaped sets its limit dorsally. So, Pannier and U-shaped
      provide positional information for the patterning of the dorsocentral cluster. In
      contrast and contrary to previous suggestions, Wingless does not play a similar
      role, since the levels and vectorial orientation of its concentration gradient in
      the dorsocentral area can be greatly modified without affecting the position of
      the dorsocentral cluster. Thus, Wingless has only a permissive role on
      dorsocentral achaete-scute expression. We also provide evidence indicating that
      Pannier and U-shaped are main effectors of the regulation of wingless expression
      in the presumptive notum.

PMID- 10409500
TI  - Anterior cephalic neural crest is required for forebrain viability.
AB  - The prosencephalon, or embryonic forebrain, grows within a mesenchymal matrix of
      local paraxial mesoderm and of neural crest cells (NCC) derived from the
      posterior diencephalon and mesencephalon. Part of this NCC population forms the
      outer wall of capillaries within the prosencephalic leptomeninges and
      neuroepithelium itself. The surgical removal of NCC from the anterior head of
      chick embryos leads to massive cell death within the forebrain neuroepithelium
      during an interval that precedes its vascularization by at least 36 hours. During
      this critical period, a mesenchymal layer made up of intermingled mesodermal
      cells and NCC surround the neuroepithelium. This layer is not formed after
      anterior cephalic NCC ablation. The neuroepithelium then undergoes massive
      apoptosis. Cyclopia ensues after forebrain deterioration and absence of
      intervening frontonasal bud derivatives. The deleterious effect of ablation of
      the anterior NC cannot be interpreted as a deficit in vascularization because it
      takes place well before the time when blood vessels start to invade the
      neuroepithelium. Thus the mesenchymal layer itself exerts a trophic effect on the
      prosencephalic neuroepithelium. In an assay to rescue the operated phenotype, we
      found that the rhombencephalic but not the truncal NC can successfully replace
      the diencephalic and mesencephalic NC. Moreover, any region of the paraxial
      cephalic mesoderm can replace NCC in their dual function: in their early trophic
      effect and in providing pericytes to the forebrain meningeal blood vessels. The
      assumption of these roles by the cephalic neural crest may have been instrumental
      in the rostral expansion of the vertebrate forebrain over the course of
      evolution.

PMID- 10409501
TI  - Identification of dividing, determined sensory neuron precursors in the mammalian
      neural crest.
AB  - Sensory and autonomic neurons of the vertebrate peripheral nervous system are
      derived from the neural crest. Here we use the expression of lineage-specific
      transcription factors as a means to identify neuronal subtypes that develop in
      rat neural crest cultures grown in a defined medium. Sensory neurons, identified
      by expression of the POU-domain transcription factor Brn-3.0, develop from
      dividing precursors that differentiate within 2 days following emigration from
      the neural tube. Most of these precursors generate sensory neurons even when
      challenged with BMP2, a factor that induces autonomic neurogenesis in many other
      cells in the explants. Moreover, BMP2 fails to prevent expression of the sensory
      specific basic helix-loop-helix (bHLH) transcription factors neurogenin1,
      neurogenin2 and neuroD, although it induces expression of the autonomic-specific
      bHLH factor MASH1 and the paired homeodomain factor Phox2a in other cells. These
      data suggest that there are mitotically active precursors in the mammalian neural
      crest that can generate sensory neurons even in the presence of a strong
      autonomic-inducing cue. Further characterization of the neurons generated from
      such precursors indicates that, under these culture conditions, they exhibit a
      proprioceptive and/or mechanosensory, but not nociceptive, phenotype. Such
      precursors may therefore correspond to a lineally (Frank, E. and Sanes, J. (1991)
      Development 111, 895-908) and genetically (Ma, Q., Fode, C., Guillemot, F. and
      Anderson, D. J. (1999) Genes Dev. 13, in press) distinct subset of early
      differentiating precursors of large-diameter sensory neurons identified in vivo.

PMID- 10409502
TI  - Gli3 is required for Emx gene expression during dorsal telencephalon development.
AB  - Dentate gyrus and hippocampus as centers for spatial learning, memory and
      emotional behaviour have been the focus of much interest in recent years. The
      molecular information on its development, however, has been relatively poor. To
      date, only Emx genes were known to be required for dorsal telencephalon
      development. Here, we report on forebrain development in the extra toes (Xt(J))
      mouse mutant which carries a null mutation of the Gli3 gene. This defect leads to
      a failure to establish the dorsal di-telencephalic junction and finally results
      in a severe size reduction of the neocortex. In addition, Xt(J)/Xt(J) mice show
      absence of the hippocampus (Ammon's horn plus dentate gyrus) and the choroid
      plexus in the lateral ventricle. The medial wall of the telencephalon, which
      gives rise to these structures, fails to invaginate during embryonic development.
      On a molecular level, disruption of dorsal telencephalon development in
      Xt(J)/Xt(J) embryos correlates with a loss of Emx1 and Emx2 expression.
      Furthermore, the expression of Fgf8 and Bmp4 in the dorsal midline of the
      telencephalon is altered. However, expression of Shh, which is negatively
      regulated by Gli3 in the spinal cord, is not affected in the Xt(J)/Xt(J)
      forebrain. This study therefore implicates Gli3 as a key regulator for the
      development of the dorsal telencephalon and implies Gli3 to be upstream of Emx
      genes in a genetic cascade controlling dorsal telencephalic development.

PMID- 10409503
TI  - Revisiting the Drosophila microchaete lineage: a novel intrinsically asymmetric
      cell division generates a glial cell.
AB  - The bristle mechanosensory organs of the adult fly are composed of four different
      cells that originate from a single precursor cell, pI, via two rounds of
      asymmetric cell division. Here, we have examined the pattern of cell divisions in
      this lineage by time-lapse confocal microscopy using GFP imaging and by
      immunostaining analysis. pI divided within the plane of the epithelium and along
      the anteroposterior axis to give rise to an anterior cell, pIIb, and a posterior
      cell, pIIa. pIIb divided prior to pIIa to generate a small subepithelial cell and
      a larger daughter cell, named pIIIb. This unequal division, oriented
      perpendicularly to the epithelium plane, has not been described previously. pIIa
      divided after pIIb, within the plane of the epithelium and along the AP axis, to
      produce a posterior socket cell and an anterior shaft cell. Then pIIIb divided
      perpendicularly to the epithelium plane to generate a basal neurone and an apical
      sheath cell. The small subepithelial pIIb daughter cell was identified as a sense
      organ glial cell: it expressed glial cell missing, a selector gene for the glial
      fate and migrated away from the sensory cluster along extending axons. We propose
      that mechanosensory organ glial cells, the origin of which was until now unknown,
      are generated by the asymmetric division of pIIb cells. Both Numb and Prospero
      segregated specifically into the basal glial and neuronal cells during the pIIb
      and pIIIb divisions, respectively. This revised description of the sense organ
      lineage provides the basis for future studies on how polarity and fate are
      regulated in asymmetrically dividing cells.

PMID- 10409504
TI  - Role of Pax6 in development of the cerebellar system.
AB  - Post-mitotic neurons generated at the rhombic lip undertake long distance
      migration to widely dispersed destinations, giving rise to cerebellar granule
      cells and the precerebellar nuclei. Here we show that Pax6, a key regulator in
      CNS and eye development, is strongly expressed in rhombic lip and in cells
      migrating away from it. Development of some structures derived from these cells
      is severely affected in Pax6-null Small eye (Pax6(Sey)/Pax6(Sey)) embryos. Cell
      proliferation and initial differentiation seem unaffected, but cell migration and
      neurite extension are disrupted in mutant embryos. Three of the five
      precerebellar nuclei fail to form correctly. In the cerebellum the pre-migratory
      granule cell sub-layer and fissures are absent. Some granule cells are found in
      ectopic positions in the inferior colliculus which may result from the complete
      absence of Unc5h3 expression in Pax6(Sey)/Pax6(Sey) granule cells. Our results
      suggest that Pax6 plays a strong role during hindbrain migration processes and at
      least part of its activity is mediated through regulation of the netrin receptor
      Unc5h3.

PMID- 10409505
TI  - Inactivation of erythropoietin leads to defects in cardiac morphogenesis.
AB  - Erythropoietin is an essential growth factor that promotes survival,
      proliferation, and differentiation of mammalian erythroid progenitor cells.
      Erythropoietin(-/-) and erythropoietin receptor(-/-) mouse embryos die around
      embryonic day 13.5 due, in part, to failure of erythropoiesis in the fetal liver.
      In this study, we demonstrated a novel role of erythropoietin and erythropoietin
      receptor in cardiac development in vivo. We found that erythropoietin receptor is
      expressed in the developing murine heart in a temporal and cell type-specific
      manner: it is initially detected by embryonic day 10.5 and persists until day
      14.5. Both erythropoietin(-/-) and erythropoietin receptor(-/-) embryos suffered
      from ventricular hypoplasia at day 12-13 of gestation. This defect appears to be
      independent from the general state of hypoxia and is likely due to a reduction in
      the number of proliferating cardiac myocytes in the ventricular myocardium. Cell
      proliferation assays revealed that erythropoietin acts as a mitogen in cells
      isolated from erythropoietin(-/-) mice, while it has no effect in hearts from
      erythropoietin receptor(-/-) animals. Erythropoietin(-/-) and erythropoietin
      receptor(-/-) embryos also suffered from epicardium detachment and abnormalities
      in the vascular network. Finally, through a series of chimeric analysis, we
      provided evidence that erythropoietin acts in a manner which is non-cell
      autonomous. Our results elucidate a novel role of erythropoietin in cardiac
      morphogenesis and suggest a combination of anemia and cardiac failure as the
      cause of embryonic lethality in the erythropoietin(-/-) and erythropoietin
      receptor(-/-) animals.

PMID- 10409506
TI  - Mutants of cubitus interruptus that are independent of PKA regulation are
      independent of hedgehog signaling.
AB  - Hedgehog (HH) is an important morphogen involved in pattern formation during
      Drosophila embryogenesis and disc development. cubitus interruptus (ci) encodes a
      transcription factor responsible for transducing the hh signal in the nucleus and
      activating hh target gene expression. Previous studies have shown that CI exists
      in two forms: a 75 kDa proteolytic repressor form and a 155 kDa activator form.
      The ratio of these forms, which is regulated positively by hh signaling and
      negatively by PKA activity, determines the on/off status of hh target gene
      expression. In this paper, we demonstrate that the exogenous expression of CI
      that is mutant for four consensus PKA sites [CI(m1-4)], causes ectopic expression
      of wingless (wg) in vivo and a phenotype consistent with wg overexpression.
      Expression of CI(m1-4), but not CI(wt), can rescue the hh mutant phenotype and
      restore wg expression in hh mutant embryos. When PKA activity is suppressed by
      expressing a dominant negative PKA mutant, the exogenous expression of CI(wt)
      results in overexpression of wg and lethality in embryogenesis, defects that are
      similar to those caused by the exogenous expression of CI(m1-4). In addition, we
      demonstrate that, in cell culture, the mutation of any one of the three serine
      containing PKA sites abolishes the proteolytic processing of CI. We also show
      that PKA directly phosphorylates the four consensus phosphorylation sites in
      vitro. Taken together, our results suggest that positive hh and negative PKA
      regulation of wg gene expression converge on the regulation of CI
      phosphorylation.

PMID- 10409507
TI  - Refined analysis of early symbiotic steps of the Rhizobium-Medicago interaction
      in relationship with microtubular cytoskeleton rearrangements.
AB  - In situ immunolocalization of tubulin revealed that important rearrangements
      occur during all the early symbiotic steps in the Medicago/R. meliloti symbiotic
      interaction. Microtubular cytoskeleton (MtC) reorganizations were observed in
      inner tissues, first in the pericycle and then in the inner cortex where the
      nodule primordium forms. Subsequently, major MtC changes occurred in outer
      tissues, associated with root hair activation and curling, the formation of
      preinfection threads (PITs) and the initiation and the growth of an infection
      network. From the observed sequence of MtC changes, we propose a model which aims
      to better define, at the histological level, the timing of the early symbiotic
      stages. This model suggests the existence of two opposite gradients of cell
      differentiation controlling respectively the formation of division centers in the
      inner cortex and plant preparation for infection. It implies that (i) MtC
      rearrangements occur in pericycle and inner cortex earlier than in the root hair,
      (ii) the infection process proceeds prior to the formation of the nodule
      meristem, (iii) the initial primordium prefigures the future zone II of the
      mature nodule and (iv) the nodule meristem derives from the nodule primordium.
      Finally, our data also strongly suggest that in alfalfa PIT differentiation, a
      stage essential for successful infection, requires complementary signaling
      additional to Nod factors.

PMID- 10409508
TI  - Initiation of shoot apical meristem in rice: characterization of four SHOOTLESS
      genes.
AB  - The regulatory mechanism of shoot apical meristem (SAM) initiation is an
      important subject in developmental plant biology. We characterized nine recessive
      mutations derived from four independent loci (SHL1-SHL4) causing the deletion of
      the SAM. Radicles were produced in these mutant embryos. Concomitant with the
      loss of SAM, two embryo-specific organs, coleoptile and epiblast, were lost, but
      the scutellum was formed normally. Therefore, differentiation of radicle and
      scutellum is regulated independently of SAM, but that of coleoptile and epiblast
      may depend on SAM. Regeneration experiments using adventitious shoots from the
      scutellum-derived calli showed that no adventitious shoots were regenerated in
      any shl mutant. However, small adventitious leaves were observed in both mutant
      and wild-type calli, but they soon became necrotic and showed no extensive
      growth. Thus, leaf primordia can initiate in the absence of SAM, but their
      extensive growth requires the SAM. An in situ hybridization experiment using a
      rice homeobox gene, OSH1, as a probe revealed that shl1 and shl2 modified the
      expression domain of OSH1, but normal expression of OSH1 was observed in shl3 and
      shl4 embryos. Accordingly, SHL1 and SHL2 function upstream of OSH1, and SHL3 and
      SHL4 downstream or independently of OSH1. These shl mutants are useful for
      elucidating the genetic program driving SAM initiation and for unraveling the
      interrelationships among various organs in grass embryos.

PMID- 10409509
TI  - F-spondin and mindin: two structurally and functionally related genes expressed
      in the hippocampus that promote outgrowth of embryonic hippocampal neurons.
AB  - Extracellular matrix (ECM) proteins play an important role in early cortical
      development, specifically in the formation of neural connections and in
      controlling the cyto-architecture of the central nervous system. F-spondin and
      Mindin are a family of matrix-attached adhesion molecules that share structural
      similarities and overlapping domains of expression. Genes for both proteins
      contain a thrombospondin type I repeat(s) at the C terminus and an FS1-FS2
      (spondin) domain. Both the vertebrate F-spondin and the zebrafish mindins are
      expressed on the embryonic floor plate. In the current study we have cloned the
      rat homologue of mindin and studied its expression and activity together with F
      spondin in the developing rodent brain. The two genes are abundantly expressed in
      the developing hippocampus. In vitro studies indicate that both F-spondin and
      Mindin promote adhesion and outgrowth of hippocampal embryonic neurons. We have
      also demonstrated that the two proteins bind to a putative receptor(s) expressed
      on both hippocampal and sensory neurons.

PMID- 10409510
TI  - Ventral midline cells are required for the local control of commissural axon
      guidance in the mouse spinal cord.
AB  - Specialized cells at the midline of the central nervous system have been
      implicated in controlling axon projections in both invertebrates and vertebrates.
      To address the requirement for ventral midline cells in providing cues to
      commissural axons in mice, we have analyzed Gli2 mouse mutants, which lack
      specifically the floor plate and immediately adjacent interneurons. We show that
      a Dbx1 enhancer drives tau-lacZ expression in a subpopulation of commissural
      axons and, using a reporter line generated from this construct, as well as DiI
      tracing, we find that commissural axons projected to the ventral midline in Gli2(
      /-) embryos. Netrin1 mRNA expression was detected in Gli2(-/-) embryos and,
      although much weaker than in wild-type embryos, was found in a dorsally
      decreasing gradient. This result demonstrates that while the floor plate can
      serve as a source of long-range cues for C-axons in vitro, it is not required in
      vivo for the guidance of commissural axons to the ventral midline in the mouse
      spinal cord. After reaching the ventral midline, most commissural axons remained
      clustered in Gli2(-/-) embryos, although some were able to extend longitudinally.
      Interestingly, some of the longitudinally projecting axons in Gli2(-/-) embryos
      extended caudally and others rostrally at the ventral midline, in contrast to
      normal embryos in which virtually all commissural axons turn rostrally after
      crossing the midline. This finding indicates a critical role for ventral midline
      cells in regulating the rostral polarity choice made by commissural axons after
      they cross the midline. In addition, we provide evidence that interactions
      between commissural axons and floor plate cells are required to modulate the
      localization of Nr-CAM and TAG-1 proteins on axons at the midline. Finally, we
      show that the floor plate is not required for the early trajectory of motoneurons
      or axons of the posterior commissure, whose projections are directed away from
      the ventral midline in both WT and Gli2(-/-) embryos, although they are less well
      organized in Gli2(-/-)mutants.

PMID- 10409511
TI  - Regulation of differential growth in the apical hook of Arabidopsis.
AB  - Arabidopsis seedlings develop a hook-like structure at the apical part of the
      hypocotyl when grown in darkness. Differential cell growth processes result in
      the curved hypocotyl hook. Time-dependent analyses of the hypocotyl showed that
      the apical hook is formed during an early phase of seedling growth and is
      maintained in a sequential phase by a distinct process. Based on developmental
      genetic analyses of hook-affected mutants, we show that the hookless mutants
      (hls1, cop2) are involved in an early aspect of hook development. From time
      dependent analyses of ethylene-insensitive mutants, later steps in hook
      maintenance were found to be ethylene sensitive. Regulation of differential
      growth was further studied through examination of the spatial pattern of
      expression of two hormone-regulated genes: an ethylene biosynthetic enzyme and
      the ethylene receptor ETR1. Accumulation of mRNA for AtACO2, a novel ACC (1
      aminocyclopropane-1-carboxylic acid) oxidase gene, occurred within cells
      predominantly located on the outer-side of the hook and was tightly correlated
      with ethylene-induced exaggeration in the curvature of the hook. ETR1 expression
      in the apical hook, however, was reduced by ethylene treatment. Based on the
      expression pattern of ETR1 and AtACO2 in the hook-affected mutants, a model for
      hook development and maintenance is proposed.

PMID- 10409512
TI  - Cubitus interruptus is necessary but not sufficient for direct activation of a
      wing-specific decapentaplegic enhancer.
AB  - In Drosophila, the imaginal discs are the primordia for adult appendages. Their
      proper formation is dependent upon the activation of the decapentaplegic (dpp)
      gene in a stripe of cells just anterior to the compartment boundary. In imaginal
      discs, the dpp gene has been shown to be activated by Hedgehog signal
      transduction. However, an initial analysis of its enhancer region suggests that
      its regulation is complex and depends upon additional factors. In order to
      understand how multiple factors regulate dpp expression, we chose to focus on a
      single dpp enhancer element, the dpp heldout enhancer, from the 3' cis regulatory
      disc region of the dpp locus. In this report, we present a molecular analysis of
      this 358 bp wing- and haltere-specific dpp enhancer, which demonstrates a direct
      transcriptional requirement for the Cubitus interruptus (Ci) protein. The results
      suggest that, in addition to regulation by Ci, expression of the dpp heldout
      enhancer is spatially determined by Drosophila TCF (dTCF) and the
      Vestigial/Scalloped selector system and that temporal control is provided by dpp
      autoregulation. Consistent with the unexpectedly complex regulation of the dpp
      heldout enhancer, analysis of a Ci consensus site reporter construct suggests
      that Ci, a mediator of Hedgehog transcriptional activation, can only
      transactivate in concert with other factors.

PMID- 10409513
TI  - Genes required for axon pathfinding and extension in the C. elegans nerve ring.
AB  - Over half of the neurons in Caenorhabditis elegans send axons to the nerve ring,
      a large neuropil in the head of the animal. Genetic screens in animals that
      express the green fluorescent protein in a subset of sensory neurons identified
      eight new sax genes that affect the morphology of nerve ring axons. sax-3/robo
      mutations disrupt axon guidance in the nerve ring, while sax-5, sax-9 and unc-44
      disrupt both axon guidance and axon extension. Axon extension and guidance
      proceed normally in sax-1, sax-2, sax-6, sax-7 and sax-8 mutants, but these
      animals exhibit later defects in the maintenance of nerve ring structure. The
      functions of existing guidance genes in nerve ring development were also
      examined, revealing that SAX-3/Robo acts in parallel to the VAB-1/Eph receptor
      and the UNC-6/netrin, UNC-40/DCC guidance systems for ventral guidance of axons
      in the amphid commissure, a major route of axon entry into the nerve ring. In
      addition, SAX-3/Robo and the VAB-1/Eph receptor both function to prevent aberrant
      axon crossing at the ventral midline. Together, these genes define pathways
      required for axon growth, guidance and maintenance during nervous system
      development.

PMID- 10409514
TI  - Prostatic growth and development are regulated by FGF10.
AB  - We have examined the role of Fibroblast Growth Factor 10 (FGF10) during the
      growth and development of the rat ventral prostate (VP) and seminal vesicle (SV).
      FGF10 transcripts were abundant at the earliest stages of organ formation and
      during neonatal organ growth, but were low or absent in growth-quiescent adult
      organs. In both the VP and SV, FGF10 transcripts were expressed only in a subset
      of mesenchymal cells and in a pattern consistent with a role as a paracrine
      epithelial regulator. In the neonatal VP, FGF10 mRNA was expressed initially in
      mesenchymal cells peripheral to the peri-urethral mesenchyme and distal to the
      elongating prostatic epithelial buds. At later stages, mesenchymal cells
      surrounding the epithelial buds also expressed FGF10 transcripts. During
      induction of the SV, FGF10 mRNA was present in mesenchyme surrounding the lower
      Wolffian ducts and, at later stages, FGF10 transcripts became restricted to
      mesenchymal cells subadjacent to the serosa. We investigated whether the FGF10
      gene might be regulated by androgens by analysing the levels of FGF10 transcripts
      in SV and VP organs grown in serum-free organ culture. While FGF10 transcript
      levels increased after treatment with testosterone in the SV (but not VP), these
      changes were not sensitive to anti-androgen treatment, and thus it is likely that
      FGF10 mRNA was not directly regulated by testosterone. Also, FGF10 mRNA was
      observed in the embryonic female reproductive tract in a position analogous to
      that of the ventral prostate in males suggesting that FGF10 is not regulated by
      androgens in vivo. Recombinant FGF10 protein specifically stimulated growth of
      Dunning epithelial and BPH1 prostatic epithelial cell lines, but had no effect on
      growth of Dunning stromal cells or primary SV mesenchyme. Furthermore, FGF10
      protein stimulated the development of ventral prostate and seminal vesicle organ
      rudiments in serum-free organ culture. When both FGF10 and testosterone were
      added to organs in vitro, there was no synergistic induction of development.
      Additionally, development induced by FGF10 was not inhibited by the addition of
      the anti-androgen Cyproterone Acetate demonstrating that the effects of FGF10
      were not mediated by the androgen receptor. Taken together, our experiments
      suggest that FGF10 functions as a mesenchymal paracrine regulator of epithelial
      growth in the prostate and seminal vesicle and that the FGF10 gene is not
      regulated by androgens

PMID- 10409515
TI  - Vegetal rotation, a new gastrulation movement involved in the internalization of
      the mesoderm and endoderm in Xenopus.
AB  - A main achievement of gastrulation is the movement of the endoderm and mesoderm
      from the surface of the embryo to the interior. Despite its fundamental
      importance, this internalization process is not well understood in amphibians. We
      show that in Xenopus, an active distortion of the vegetal cell mass, vegetal
      rotation, leads to a dramatic expansion of the blastocoel floor and a concomitant
      turning around of the marginal zone which constitutes the first and major step of
      mesoderm involution. This vigorous inward surging of the vegetal region into the
      blastocoel can be analyzed in explanted slices of the gastrula, and is apparently
      driven by cell rearrangement. Thus, the prospective endoderm, previously thought
      to be moved passively, provides the main driving force for the internalization of
      the mesendoderm during the first half of gastrulation. For further involution,
      and for normal positioning of the involuted mesoderm and its rapid advance toward
      the animal pole, fibronectin-independent interaction with the blastocoel roof is
      required.

PMID- 10409516
TI  - Cardiac surgery in the elderly.

PMID- 10409518
TI  - Cardiac surgery in elderly patients: benefits and resource priorities.

PMID- 10409519
TI  - Cardiac surgery in the elderly: a cardiologist's perspective.

PMID- 10409520
TI  - Cardiac surgery for the elderly: a surgeon's perspective.

PMID- 10409521
TI  - Matching treatment to the genetic basis of (lipid) disorder in patients with
      coronary artery disease.

PMID- 10409522
TI  - High resolution in vivo intra-arterial imaging with optical coherence tomography.
AB  - BACKGROUND: Optical coherence tomography (OCT) is a new method of catheter based
      micron scale imaging. OCT is analogous to ultrasound, measuring the intensity of
      backreflected infrared light rather than sound waves. OBJECTIVE: To demonstrate
      the ability of OCT to perform high resolution imaging of arterial tissue in vivo.
      METHODS: OCT imaging of the abdominal aorta of New Zealand white rabbits was
      performed using a 2.9 F OCT imaging catheter. Using an ultrashort pulse laser as
      a light source for imaging, an axial resolution of 10 micrometer was achieved.
      RESULTS: Imaging was performed at 4 frames/second and data were saved in either
      super VHS or digital format. Saline injections were required during imaging
      because of the signal attenuation caused by blood. Microstructure was sharply
      defined within the arterial wall and correlated with histology. Some motion
      artefacts were noted at 4 frames/second. CONCLUSIONS: In vivo imaging of the
      rabbit aorta was demonstrated at a source resolution of 10 micrometer, but
      required the displacement of blood with saline. The high resolution of OCT allows
      imaging to be performed near the resolution of histopathology, offering the
      potential to have an impact both on the identification of high risk plaques and
      the guidance of interventional procedures.

PMID- 10409523
TI  - The aortic root after Bentall's procedure.

PMID- 10409524
TI  - Good outcomes from cardiac surgery in the over 70s.
AB  - OBJECTIVE: To determine the early mortality and major morbidity associated with
      cardiac surgery in the elderly. DESIGN: Retrospective case record review study of
      575 patients >/= 70 years old who underwent cardiac surgery at the Manchester
      Heart Centre between January 1990 and December 1996. SETTING: Regional
      cardiothoracic centre. SUBJECTS: Patients >/= 70 years old who underwent cardiac
      surgery. MAIN OUTCOME MEASURES: Comparison of 30 day mortality and incidence of
      major morbidity between patients >/= 70 years old and patients < 70 years old.
      RESULTS: Of 4395 cardiac surgical operations, 575 operations (13.1%) were in
      patients aged >/= 70 years (mean (SD) 73.1 (3.2) years). The proportion of
      elderly patients rose progressively from 7.9% in 1990 to 16.5% in 1996. 334
      patients (58.1%) had coronary artery bypass grafting alone, 91 patients (15.8%)
      had valve surgery alone, and 129 patients (22.4%) had combined valve surgery and
      bypass grafting. For isolated coronary artery bypass grafting, 30 day mortality
      in patients >/= 70 years was 3.9% compared with 1.3% in patients < 70 years (p <
      0.001). 30 day mortality for isolated valve surgery in patients >/= 70 years was
      7.7%. Isolated aortic valve replacement was the most common valvar procedure in
      patients >/= 70 years and carried the lowest mortality (4.3%). Additional
      coronary artery bypass grafting increased the mortality rate in patients >/= 70
      years to 9.3% for all valve surgery and to 8.0% for aortic valve replacement.
      Major morbidity in patients >/= 70 years was low for all procedure types (stroke
      1.9%, acute renal failure requiring dialysis 1.6%, perioperative myocardial
      infarction 0.5%). CONCLUSIONS: Early mortality and major morbidity is low for
      cardiac surgery in elderly patients. Concerns over the risk of cardiac surgery in
      the elderly should not prevent referral, and elderly patients usually do well.
      However, unconscious rationing of health care may affect referral patterns, and
      studies that assess the cost effectiveness of cardiac surgery versus conservative
      management in such patients are lacking.

PMID- 10409525
TI  - Surgery for aortic stenosis in severely symptomatic patients older than 80 years:
      experience in a single UK centre.
AB  - OBJECTIVE: To ascertain the surgical risk and long term outcome of patients over
      80 years old undergoing aortic valve replacement (AVR). DESIGN: Consecutive cases
      with respective case note audit and a telephone questionnaire. SETTING: Single UK
      cardiothoracic surgical centre. PATIENTS: 103 (48 male) patients over 80 years
      old undergoing AVR. The median age was 82 years (80-95 years) and 95 of 103
      patients were in New York Heart Association (NYHA) class III or IV. METHOD AND
      RESULTS: Preoperative characteristics, operative course, cost, and outcome
      measures were ascertained. Mean bypass time was 56 minutes and 25 patients had
      simultaneous coronary artery bypass grafting. Overall mortality was 19 of 103.
      Univariate analysis of pertinent variables found that impaired renal function and
      peripheral vascular disease were significantly associated with early
      postoperative death. 10 of 12 patients requiring ventilation for more than 24
      hours died. The 50% actuarial survival was 62 months. Late complications were
      uncommon with 92% of patients in NYHA class I or II at follow up. CONCLUSIONS:
      AVR in patients over 80 years old has a significant risk. However, those patients
      who survive experience significant benefit with good long term prospects for
      general health and social independence.

PMID- 10409526
TI  - To operate or not on elderly patients with aortic stenosis: the decision and its
      consequences.
AB  - OBJECTIVE: To evaluate the application of guidelines in the decision making
      process leading to medical or surgical treatment for aortic stenosis in elderly
      patients. DESIGN: Cohort analysis based on a prospective inclusive registry.
      SETTING: 205 consecutive patients (>/= 70 years) with clinically relevant
      isolated aortic stenosis and without serious comorbidity, seen for the first time
      in the Doppler-echocardiographic laboratories of three university hospitals in
      the Netherlands. RESULTS: The initial choice was surgery in 94 patients and
      medical treatment in 111. Only 59% of the patients who should have had valve
      replacement according to the practice guidelines were actually offered surgical
      treatment. These were mainly symptomatic patients under 80 years of age with a
      high gradient. Operative mortality (30 days) was only 2%. The three year survival
      was 80% in the surgical group (17 deaths among 94 patients) and 49% in the
      medical group (43/111). Multivariate analysis showed that only patients with a
      high baseline risk, mainly determined by impaired left ventricular function, had
      a significantly better three year survival with surgical treatment than with
      medical treatment. CONCLUSIONS: In daily practice, elderly patients with
      clinically relevant symptomatic aortic stenosis are often denied surgical
      treatment. This study indicates that a surgical approach, especially where there
      is impaired systolic left ventricular function, is associated with better
      survival.

PMID- 10409527
TI  - Haemodynamic performance of aortic pericardial bioprostheses and bileaflet
      prostheses at rest and during exercise: implications for the surgical management
      of patients with small aortic roots.
AB  - OBJECTIVE: To determine the haemodynamic behaviour, at rest and during exercise,
      of aortic valve pericardial bioprostheses and different sizes of bileaflet
      prosthesis. DESIGN: Observational study. SETTING: Tertiary medical centre.
      PATIENTS AND INTERVENTIONS: 74 patients (33 women, 41 men; mean age 64 years) in
      whom 40 pericardial bioprostheses and 34 bileaflet prostheses sized 19, 21, or 23
      mm had been implanted to replace aortic valves. MAIN OUTCOME MEASURES: Doppler
      echocardiography at rest and at peak exercise, between 12 and 47 months after
      surgery. RESULTS: All patients achieved a significant increase in heart rate,
      systolic blood pressure, and cardiac output with exercise. Transvalvar pressure
      fall, valve area, and left ventricular systolic and diastolic function indices
      also underwent significant changes with exercise. Reductions in peak and mean
      transvalvar pressure, at rest and at peak exercise, were greater in patients with
      small valves (p < 0.05). Valve areas and effective area index were greater in the
      patients with larger valves (p < 0.001). There were no significant differences
      between patients with mechanical and biological prostheses with regard to
      transvalvar pressure fall and valve areas at rest and at peak exercise.
      CONCLUSIONS: 19 mm and 21 mm aortic prostheses and bioprostheses continue to
      create significant obstruction, particularly with exercise.

PMID- 10409528
TI  - Surgery for postinfarction ventricular tachycardia in the pre-implantable
      cardioverter defibrillator era: early and long term outcomes in 100 consecutive
      patients.
AB  - OBJECTIVE: To report outcome following surgery for postinfarction ventricular
      tachycardia undertaken in patients before the use of implantable defibrillators.
      DESIGN: A retrospective review, with uniform patient selection criteria and
      surgical and mapping strategy throughout. Complete follow up. Long term death
      notification by OPCS (Office of Population Censuses and Statistics) registration.
      SETTING: Tertiary referral centre for arrhythmia management. PATIENTS: 100
      consecutive postinfarction patients who underwent map guided endocardial
      resection at this hospital in the period 1981-91 for drug refractory ventricular
      tachyarrhythmias. RESULTS: Emergency surgery was required for intractable
      arrhythmias in 28 patients, and 32 had surgery within eight weeks of infarction
      ("early"). Surgery comprised endocardial resections in all, aneurysmectomy in 57,
      cryoablations in 26, and antiarrhythmic ventriculotomies in 11. Twenty five
      patients died < 30 days after surgery, 21 of cardiac failure. This high mortality
      reflects the type of patients included in the series. Only 12 received
      antiarrhythmic drugs after surgery. Perioperative mortality was related to
      preoperative left ventricular function and the context of surgery. Mortality
      rates for elective surgery more than eight weeks after infarction, early surgery,
      emergency surgery, and early emergency surgery were 18%, 31%, 46%, and 50%,
      respectively. Actuarial survival rates at one, three, five, and 10 years after
      surgery were 66%, 62%, 57%, and 35%. CONCLUSIONS: Surgery offers arrhythmia
      abolition at a risk proportional to the patient's preoperative risk of death from
      ventricular arrhythmias. The long term follow up results suggest a continuing
      role for surgery in selected patients even in the era of catheter ablation and
      implantable defibrillators.

PMID- 10409529
TI  - Imaging of adenosine bolus transit following intravenous administration: insights
      into antiarrhythmic efficacy.
AB  - OBJECTIVE: To study the effects of the site of intravenous injection of adenosine
      and to assess the site of action of adenosine in the heart by correlating cardiac
      effects with bolus transit. METHODS: Ten patients undergoing routine technetium
      (Tc-99m) gated blood pool ventriculography consented to the coadministration of
      intravenous adenosine. The dose of adenosine required to produce heart block
      during sinus rhythm was determined following antecubital vein administration.
      This dose (6-18 mg) was mixed with Tc-99m and given first into the same
      antecubital vein (proximal injection) and then repeated into a hand vein (distal
      injection). The ECG was recorded and the transit of the bolus was imaged using a
      gamma camera. RESULTS: Heart block occurred in all 10 patients (second degree in
      seven, first degree in three) at (mean (SEM)) 17.5 (1.0) seconds after the
      proximal injection of adenosine. Distal injection produced heart block in six
      patients (second degree in two, first degree in four) at 21.9 (4.4) seconds (p <
      0.01). In eight of 10 patients the electrophysiological effects were less with
      distal injection. The onset of heart block was close to the time of peak bolus Tc
      99m activity in the left ventricle. Peak bolus activity was delayed (by about
      three seconds) and the duration of bolus activity in the left ventricle was
      increased with distal injection compared with proximal injection, at 17.2 (4.2) v
      9.2 (3.1) seconds, p < 0.01. CONCLUSIONS: The lesser electrophysiological effects
      of adenosine following distal intravenous injections were associated with delay
      in transit time and dispersion of the bolus. The correlation of adenosine induced
      heart block with bolus activity in the left heart indicated dependence on
      coronary arterial delivery of adenosine to the atrioventricular node.

PMID- 10409530
TI  - An open label, randomised, crossover study comparing sotalol and atenolol in the
      treatment of symptomatic paroxysmal atrial fibrillation.
AB  - OBJECTIVE: To compare sotalol and atenolol in the treatment of symptomatic
      paroxysmal atrial fibrillation. DESIGN: Prospective, randomised, open label,
      crossover study. SETTING: University hospital. PATIENTS: 47 subjects aged over 50
      years were recruited from the hospital outpatient department following ECG
      documentation of paroxysmal atrial fibrillation that coincided with symptoms. Six
      patients withdrew and 41 completed the trial. INTERVENTIONS: Patients were
      randomised to one month's treatment with sotalol 80 mg twice daily or atenolol 50
      mg once daily. Treatment arms were then crossed over. Patients underwent 72 hour
      Holter monitoring before randomisation and repeat studies were carried out at the
      end of both treatment periods. Symptom assessments were completed using linear
      analogue scales and the Nottingham health profile. MAIN OUTCOME MEASURE:
      Frequency of paroxysmal atrial fibrillation; secondary outcome measures included
      average and total duration of paroxysmal atrial fibrillation, total ectopic
      count, and symptom assessments. RESULTS: A reduction in the number and duration
      of episodes of paroxysmal atrial fibrillation was noted following treatment with
      sotalol and atenolol. There was no difference in frequency of paroxysmal atrial
      fibrillation during treatment with sotalol or atenolol (median difference 0; 95%
      confidence interval (CI) 0 to 1; p = 0.47). There was no difference in total
      duration of paroxysmal atrial fibrillation (median difference 0 min; 95% CI -1 to
      2; p = 0. 51) or in average duration (median difference 0 min; 95% CI 0 to 1; p =
      0.31). No difference was found in total ectopic count between sotalol and
      atenolol (median difference -123; 95% CI -362 to 135; p = 0.14). Treatments were
      equally tolerated with no difference in linear analogue scores for symptoms of
      paroxysmal atrial fibrillation (median difference -5; 95% CI -20 to 5; p = 0.26)
      or in all categories of the Nottingham health profile. CONCLUSIONS: No difference
      was found in terms of ECG or symptomatic control of paroxysmal atrial
      fibrillation between prescribing sotalol 80 mg twice daily and atenolol 50 mg
      once daily. There was an improvement in paroxysmal atrial fibrillation from
      baseline following treatment with either sotalol or atenolol.

PMID- 10409532
TI  - Management of superior vena caval obstruction secondary to a pacing wire with
      percutaneous intravascular stent insertion.

PMID- 10409531
TI  - Electrophysiological effects of flecainide and propafenone on atrial fibrillation
      cycle and relation with arrhythmia termination.
AB  - OBJECTIVES: (1) To investigate the electrophysiological effects of flecainide and
      propafenone during atrial fibrillation, and their relation to arrhythmia
      termination; (2) to investigate the effects of isoprenaline on atrial
      fibrillation in basal conditions and during treatment with class 1C drugs to
      evaluate the role of adrenergic stimulation on proarrhythmic events occurring
      during this treatment. DESIGN: Prospective, single centre study. SETTING:
      University hospital. METHODS: 10 patients with lone paroxysmal atrial
      fibrillation underwent an electrophysiological study. The dynamic behaviour of
      MFF (the mean of 100 consecutive atrial fibrillation intervals) was evaluated at
      two atrial sites after induction of atrial fibrillation either at baseline or
      after class 1C drug administration (flecainide or propafenone 2 mg/kg). The
      effects of isoprenaline on MFF and RR interval were also investigated both under
      basal conditions and during class 1C drug treatment. RESULTS: After induction of
      atrial fibrillation, mean (SD) MFF shortened with time, and was further shortened
      by isoprenaline infusion (177 (22) v 162 (16) v 144 (11) ms, p < 0.05). The
      administration of class 1C drugs reversed this trend and significantly increased
      the MFF to an average of 295 (49) ms, leading to conversion to sinus rhythm
      within 10 minutes in all patients. Atrial fibrillation was then reinduced on
      class 1C drugs: isoprenaline shortened the MFF and RR interval with a trend to AV
      synchronisation (223 (43) v 269 (49) ms for the MFF, 347 (55) v 509 (92) ms for
      the RR, p < 0.05); 1:1 sustained AV conduction occurred in two patients, at 187
      and 222 beats/min respectively. One of these patients underwent electrical
      cardioversion because of haemodynamic collapse. CONCLUSIONS: Class 1C drugs are
      effective at restoring sinus rhythm by increasing the MFF to a much greater
      extent than observed in self terminating atrial fibrillation episodes, and
      reversing the spontaneous atrial fibrillation behaviour (progressive shortening
      of MFF and self perpetuation of atrial fibrillation). MFF prolongation with 1:1
      conduction at fast ventricular rates may lead to synchronisation during
      adrenergic stimulation, with a very short ventricular cycle; hence it is
      advisable to keep the patients at rest after acute class 1C drug loading or to
      consider pharmacological modulation of AV conduction for patients who are prone
      to a fast ventricular response.

PMID- 10409533
TI  - A new physiological method for heart rate correction of the QT interval.
AB  - AIM: To reassess QT interval rate correction. BACKGROUND: The QT interval is
      strongly and inversely related to heart rate. To compare QT intervals between
      different subjects with different heart rates requires the application of a QT
      interval rate correction formula. To date these formulae have inappropriately
      assumed a fixed relation between QT interval and heart rate. An alternative
      method of QT interval rate correction that makes no assumptions about the QT
      interval-heart rate relation is needed. PROPOSAL: A QT heart rate correction
      method should maintain or accentuate biological QT interval variability, should
      totally remove the dependence of the rate corrected QT interval on heart rate,
      and should be applicable over a wide range of conditions with a wide range of
      differing autonomic states. METHODS: QT intervals were obtained at rest and
      during exercise from subjects expected to have different QT intervals and
      different QT interval-heart rate relations. A linear regression line was obtained
      from the exercise test data, and the QT interval at a notional heart rate of 60
      and 0 beats/min, termed the QT(60) interval, and the QT y intercept obtained by
      back calculation. RESULTS: QT(60) and QT y intercept values were prolonged in
      heart failure compared with either left ventricular hypertrophy or controls.
      There was no relation between heart rate and either QT(60) or QT y intercept
      CONCLUSIONS: This new physiologically based method of correcting QT interval for
      heart rate removes the dependence of the corrected QT interval on heart rate, and
      maintains biological differences.

PMID- 10409534
TI  - Risk stratification after acute myocardial infarction by Doppler stroke distance
      measurement.
AB  - OBJECTIVE: To establish the value of Doppler stroke distance measurement as a
      predictor of mortality risk following acute myocardial infarction. DESIGN: Follow
      up study. SETTING: Coronary care unit of a teaching and district general
      hospital. SUBJECTS: 378 patients (mean age 61 years) with acute myocardial
      infarction followed up for a mean of five years (range 2-7 years); 299 (79%)
      patients received thrombolysis. MAIN OUTCOME MEASURES: Stroke distance (the
      systolic velocity integral of blood flow in the aortic arch (percentage of age
      predicted normal value)); presence or absence of left ventricular failure on the
      admission chest radiograph; the codified admission ECG; death during follow up.
      RESULTS: Mean (SD) stroke distance was 81 (19)% and five year survival 76%. For
      patients with stroke distance > 100% (n = 60), 82-100% (n = 134), 63-81% (n =
      122), and < 63% (n = 62), the one month mortality rates were 0%, 1.5%, 4%, and
      18%, respectively; the corresponding estimates for mortality at five years were
      17%, 19%, 24%, and 43%. Survival was independently related to age (p < 0.0001),
      stroke distance (p < 0.0001), and chest radiograph appearance (p = 0.002), but
      not to ECG codes (p = 0.31) or receipt of thrombolysis (p = 0.60). The areas
      under receiver operator characteristic plots for stroke distance measurements
      were 82%, 76%, 71%, and 65% for deaths within one month, six months, one year,
      and two years, respectively. CONCLUSIONS: The bedside measurement of stroke
      distance stratifies mortality risk after acute myocardial infarction. The
      predictive ability of this simple measure of left ventricular systolic function
      compares well with published accounts of the more complex measurement of ejection
      fraction.

PMID- 10409535
TI  - Echocardiographic assessment of ejection fraction in left ventricular
      hypertrophy.
AB  - OBJECTIVE: To investigate the value of Simpson's rule, Teichholz's formula, and
      recording of mitral ring motion in assessing left ventricular ejection fraction
      (EF) in patients with left ventricular hypertrophy. DESIGN: Left ventricular
      ejection fraction calculated by Simpson's rule and by Techholz's formula and
      estimated by mitral ring motion was compared with values obtained by radionuclide
      angiography. SETTING: Secondary referral centre. PATIENTS: 16 patients with left
      ventricular hypertrophy and a clinical diagnosis of hypertrophic cardiomyopathy
      or hypertension. RESULTS: Calculation by Teichholz's formula overestimated left
      ventricular ejection fraction by 10% (p = 0.002) and estimation based on mitral
      ring motion-that is, long axis measurements-underestimated ejection fraction by
      19% (p = 0.002), without significant correlation between ring motion and ejection
      fraction. There was no significant difference between mean values of ejection
      fraction calculated by Simpson's rule and measured by the reference method, but a
      considerable scatter about the regression line with a standard error of the
      estimate of 9.3 EF%. CONCLUSIONS: In patients with left ventricular hypertrophy
      the ejection fraction, calculated by Teichholz's formula or Simpson's rule, is a
      poor measure of left ventricular function. When mitral ring motion is used for
      the assessment in these patients the function should be expressed in ways other
      than by the ejection fraction.

PMID- 10409536
TI  - Prognostic value of symptom limited versus low level exercise stress test before
      discharge in patients with myocardial infarction treated with thrombolytics.
AB  - OBJECTIVE: To evaluate the benefits and risks of symptom limited exercise testing
      versus low level exercise testing soon after a thrombolytic treated acute
      myocardial infarction. DESIGN AND PATIENTS: 98 patients (71 men, 27 women), mean
      (SD) age 64 (9) years (range 45-75 years), were investigated 5-8 days after
      admittance to hospital. An ergometer cycle test was used, starting at 30 W with
      10 W increments per minute. Each exercise test was interpreted at the symptom
      limited end point and a low level end point, which was defined as the point at
      which the patient rated exhaustion as 13 on the 6-20 point Borg scale for rating
      perceived exertion. SETTING: A university hospital. RESULTS: 75 of the 98
      patients were able to perform a predischarge exercise test. Of the remaining 23
      patients who could not perform an early exercise test (because of unstable
      angina, heart failure, or thrombus detected at echocardiography), five died or
      had a myocardial infarction and six underwent bypass surgery or percutaneous
      transluminal coronary angioplasty (PTCA) during a follow up period of one year.
      There were no complications related to the symptom limited exercise tests. The
      test results were positive in 15 patients at the low level end point and in 39
      patients (p < 0.001) at the symptom limited end point. During a follow up period
      of one year, six of the 75 patients died or had a myocardial infarction. Two of
      these six patients had a positive low level exercise test and four had a positive
      symptom limited exercise test. Twenty three of the 75 patients who performed an
      exercise test had a cardiac event within one year (death, myocardial infarction,
      bypass surgery or PTCA); of these, 19 had a positive symptom limited exercise
      test and nine had a positive low level exercise test (p = 0.025). Four of the 36
      patients with a negative symptom limited test suffered cardiac events within a
      year (two patients had a myocardial infarction and two had bypass surgery).
      CONCLUSION: Symptom limited exercise testing soon after thrombolytically treated
      myocardial infarction will identify more patients with exercise induced ST
      depression or chest pain than a low level test, and seems safe. A negative
      symptom limited test has a better negative predictive value (11% risk of an event
      within a year) than a negative low level (25% risk of an event within a year).

PMID- 10409537
TI  - Effect of raised plasma beta endorphin concentrations on peripheral pain and
      angina thresholds in patients with stable angina.
AB  - OBJECTIVE: To determine whether changes in plasma concentrations of beta
      endorphins alter angina threshold and peripheral pain threshold in patients with
      stable angina. DESIGN: Latin square design comparison of angina thresholds by
      exercise treadmill test and peripheral pain thresholds using a radiant heat
      source in eight patients with stable angina under control conditions, after
      stimulation of pituitary beta endorphin release by ketoconazole, after
      suppression of pituitary beta endorphin release by dexamethasone, and after
      blockade of opioid receptors by intravenous naloxone. RESULTS: An approximately
      fivefold increase in circulating concentrations of beta endorphins was found
      after administration of ketoconazole (mean (SEM): 13.9 (1.2) v 73.8 (6.2) pg/ml;
      p < 0.05), which was associated with an increase in peripheral pain threshold to
      a radiant heat source (time to onset of pain perception 72 (19) v 123 (40)
      seconds; p < 0.05), but no significant difference in angina threshold. A
      reduction in circulating concentrations of beta endorphins after pretreatment
      with dexamethasone was statistically non-significant (13.9 (1.2) v 9.0 (1.5)
      pg/ml; NS) and was not associated with any change in either peripheral pain or
      angina thresholds. No effects were seen after blockade of opioid receptors by
      previous administration of intravenous naloxone. CONCLUSIONS: Increased plasma
      concentrations of beta endorphins alter peripheral pain threshold but not angina
      threshold in patients with stable angina pectoris.

PMID- 10409538
TI  - Efficacy of coronary angioplasty for the treatment of hibernating myocardium.
AB  - OBJECTIVES: To determine the efficacy of coronary angioplasty as the sole method
      of revascularisation in patients with coronary artery disease and chronically
      dysfunctional but viable myocardium (hibernating myocardium), and to assess the
      effect of restenosis on functional outcome. DESIGN AND PATIENTS: 24 consecutive
      patients with hibernating myocardium were studied. Positron emission tomography
      was used to assess myocardial viability, blood flow, and flow reserve. One
      patient refused angioplasty, one had bypass surgery, and one died while waiting
      for an elective procedure. The procedure failed in three patients. The remaining
      18 patients had repeat echocardiography, 15 had repeat coronary angiography, and
      nine had repeat assessments of blood flow and flow reserve at mean (SD) 17 (2)
      weeks after angioplasty. In three patients restenosis was documented. RESULTS:
      The wall motion score index in the revascularised territories improved from 1.71
      (0.37) to 1.34 (0.47) (p = 0.008). Thirty of 51 dysfunctional segments improved
      in territories without restenosis compared with three of 14 in restenosed
      territories (p = 0.001). Hibernating and normal segments had comparable flows
      (0.82 (0.26) v 0.89 (0.24) ml/min/g; NS) while flow reserve was lower in
      hibernating segments (1.55 (0.68) v 2.07 (1.08); p = 0.03). In segments without
      restenosis flow reserve improved from 2.03 (1.25) to 2.33 (1.4) (p = 0.03).
      Sensitivity, specificity, and positive and negative predictive accuracy of the
      viability study were 97%, 77%, 82%, and 96%, respectively. After excluding
      patients with restenosis, specificity and positive predictive accuracy improved
      to 90% and 93%. CONCLUSIONS: Angioplasty improves function in hibernating
      myocardium, and restenosis prevents recovery; hibernating myocardium is
      characterised by an impairment of flow reserve; restenosis affects the diagnostic
      accuracy of viability studies.

PMID- 10409539
TI  - Application of a low cost telemedicine link to the diagnosis of neonatal
      congenital heart defects by remote consultation.
AB  - OBJECTIVE: To determine whether accurate remote echocardiographic diagnosis of
      congenital heart disease could be achieved using a low cost telemedicine system.
      DESIGN: Echocardiographic images obtained by a paediatrician from neonates
      suspected of having congenital heart disease were transmitted by a telemedicine
      link across two integrated service digital network (ISDN) lines to a regional
      paediatric cardiology unit for interpretation by a consultant paediatric
      cardiologist. The "tele-echo" diagnosis was verified by the paediatric
      cardiologist on direct consultation and echocardiography. SETTING: Neonatal unit
      of Altnagelvin Hospital, Londonderry (a district general hospital) and the
      regional paediatric cardiology department, Royal Belfast Hospital for Sick
      Children. MAIN OUTCOME MEASURES: Accuracy of the diagnosis made using the
      telemedicine link; impact on patient management. RESULTS: Between September 1995
      and September 1997 echocardiographic images were transmitted on 63 patients. A
      diagnosis was made in 61 (97%) (transmitted images were unsatisfactory in two).
      Congenital heart disease was diagnosed in 42 patients. Fourteen patients with
      major congenital heart disease were accurately diagnosed within 24 hours of
      admission using the telemedicine link and were transferred to the regional
      paediatric cardiology unit. A further 28 with less serious congenital heart
      disease continued to be managed at the district general hospital. Congenital
      heart disease was excluded in 19. Follow up consultation confirmed accurate
      diagnosis or exclusion of congenital heart disease in 57 (93%). There were four
      inaccurate diagnoses (6.3%; three undetected small ventricular septal defects and
      one pulmonary stenosis). CONCLUSIONS: Transmitted images were of sufficient
      quality to allow confirmation or exclusion of major congenital heart disease. The
      telemedicine link facilitated early diagnosis and initiation of appropriate
      management in patients with complex congenital heart disease and avoided the need
      for transfer in those where significant congenital heart disease was excluded.

PMID- 10409540
TI  - Assessment of the quality of neonatal echocardiographic images transmitted by
      ISDN telephone lines.
AB  - OBJECTIVE: To assess the quality of echocardiographic images from neonates
      transmitted over Integrated Service Digital Network 2 (ISDN2) channels. DESIGN:
      Echocardiographic images were viewed live in real time either by a direct video
      link or by transmission over the commercial network, using one, two, or three
      ISDN2 channels. The order of the viewing formats was random and four observers
      marked each view for potential for provision of complete diagnostic information
      and quality. SETTING: Cardiology department of tertiary referral centre for
      paediatric cardiac services. ISDN lines were positioned in two nearby rooms.
      Telephone connection was through the commercial network and video connection by a
      direct video cable. PATIENTS: 10 neonates were studied (weight 2600 to 3900 g).
      In each, nine echocardiographic studies were undertaken to assess imaging (M mode
      and cross sectional) and Doppler (spectral and colour) quality. RESULTS: No
      significant differences were found in diagnostic ability between the different
      formats for M mode, colour, or spectral Doppler studies. For cross sectional
      imaging the diagnostic information and image quality increased with increasing
      numbers of ISDN channels. With six channels there was little difference from the
      directly connected images. CONCLUSIONS: In echocardiographic assessment of the
      newborn, one or two ISDN2 channels will transmit images of satisfactory quality
      in many situations but three or more channels are necessary to ensure minimum
      degradation of the live image.

PMID- 10409541
TI  - Aorto-left ventricular tunnel.

PMID- 10409542
TI  - Clinical outcomes of acute myocarditis in childhood.
AB  - OBJECTIVE: To describe clinical outcomes of a paediatric population with
      histologically confirmed lymphocytic myocarditis. DESIGN: A retrospective review
      between November 1984 and February 1998. SETTING: A major paediatric tertiary
      care hospital. PATIENTS: 36 patients with histologically confirmed lymphocytic
      myocarditis. MAIN OUTCOME MEASURES: Survival, cardiac transplantation, recovery
      of ventricular function, and persistence of dysrhythmias. RESULTS: Freedom from
      death or cardiac transplantation was 86% at one month and 79% after two years.
      Five deaths occurred within 72 hours of admission, and one late death at 1.9
      years. Extracorporeal membrane oxygenation support was used in four patients, and
      three patients underwent heart replacement. 34 patients were treated with
      intravenous corticosteroids. In the survivor/non-cardiac transplantation group (n
      = 29), the median follow up was 19 months (range 1.2-131.6 months), and the
      median period for recovery of a left ventricular ejection fraction to > 55% was
      2.8 months (range 0-28 months). The mean (SD) final left ventricular ejection and
      shortening fractions were 66 (9)% and 34 (8)%, respectively. Two patients had
      residual ventricular dysfunction. No patient required antiarrhythmic treatment.
      All survivors reported no cardiac symptoms or restrictions in physical activity.
      CONCLUSIONS: Our experience documents good outcomes in paediatric patients
      presenting with acute heart failure secondary to acute lymphocytic myocarditis
      treated with immunosuppression. Excellent survival and recovery of ventricular
      function, with the absence of significant arrhythmias, continued cardiac
      medications, or restrictions in physical activity were the normal outcomes.

PMID- 10409543
TI  - Why patients do not attend cardiac rehabilitation: role of intentions and illness
      beliefs.
AB  - OBJECTIVE: Many patients fail to attend cardiac rehabilitation. Attempts to
      identify sociodemographic or clinical predictors of non-attendance have not been
      very successful; therfore, this study aimed to determine whether the illness
      beliefs held during hospitalisation by patients who had suffered acute myocardial
      infarction or who had undergone coronary artery bypass graft surgery could
      predict cardiac rehabilitation attendance. SUBJECTS AND METHODS: 152 patients
      were prospectively studied of whom 41% had attended cardiac rehabilitation at six
      months. RESULTS: In addition to being older, less aware of their cholesterol
      values, and less likely to be employed, non-attenders were less likely to believe
      their condition was controllable and that their lifestyle may have contributed to
      their illness. CONCLUSION: It should now be determined whether interventions
      aimed at optimising certain perceptions could promote cardiac rehabilitation
      uptake among those patients who could benefit the most.

PMID- 10409544
TI  - Children may survive severe myocarditis with prolonged use of biventricular
      assist devices.
AB  - The outcome of acute myocarditis with cardiogenic shock is poor. In some children
      in whom aggressive medical treatment fails, artificial replacement of heart
      function may offer lifesaving support until the myocardium has recovered. Four
      previously healthy children (three boys aged 4, 6, and 1 years; one girl aged 5)
      developed acute myocarditis with ventricular failure and multiorgan dysfunction
      caused by low cardiac output. Biventricular assist devices (BVAD) were implanted
      for prolonged support. In three children cardiac function improved and after up
      to 21 days mechanical support could be withdrawn. They had full recovery of heart
      function. In the fourth patient there was no myocardial recovery after a period
      of 20 days. He underwent orthotopic heart transplantation with an uneventful
      postoperative course. Prolonged circulatory support with BVAD is an effective
      method for bridging until cardiac recovery or transplantation in children.

PMID- 10409545
TI  - Reversal of protein losing enteropathy with prednisone in adults with modified
      fontan operations: long term palliation or bridge to cardiac transplantation?
AB  - Protein losing enteropathy (PLE), defined as severe loss of serum protein into
      the intestine, occurs in 4-13% of patients after the Fontan procedure and carries
      a dismal prognosis with a five year survival between 46% and 59%. Chronically
      raised systemic venous pressure is thought to be responsible for the development
      of PLE in these patients, with perhaps superimposed immunological or inflammatory
      factors. The success rate of contemporary medical, transcatheter, and surgical
      treatments attempting to reduce systemic venous pressure ranges from 19% to 40%.
      Prednisone treatment for PLE has been tried, with variable success rates reported
      in children. The effect of prednisone in adult patients with PLE after the Fontan
      procedure is largely unknown. Two cases of PLE in adults (a 39 year old woman and
      a 25 year old man) after modified Fontan procedure who responded dramatically to
      oral prednisone treatment are reported, suggesting that a trial of this "non
      invasive" treatment should be considered as long term palliation or bridge to
      cardiac transplantation.

PMID- 10409546
TI  - A new ECG sign of an accessory pathway in sinus rhythm: pseudo partial right
      bundle branch block.
AB  - It is clinically important to be able to detect the presence of an accessory
      pathway, as pre-excited atrial fibrillation is a well recognised cause of sudden
      cardiac death, for which there is a potential "cure" in the form of
      radiofrequency ablation of the pathway. The classic manifestations such as a
      shortened PR interval or delta waves may not always be present. In certain
      patients a pseudo partial right bundle block pattern-that is, an rSr' complex in
      lead V1- may be the sole manifestation of a left sided accessory pathway. An
      electrophysiological mechanism is proposed for this pattern and it is suggested
      that this pattern may be used as a new ECG sign for diagnosing an accessory
      pathway in sinus rhythm.

PMID- 10409547
TI  - Recurrent pericardial effusion: the value of polymerase chain reaction in the
      diagnosis of tuberculosis.
AB  - A 23 year old army man presented with progressive dyspnoea and was found to have
      a massive pericardial effusion. Despite extensive investigations the cause
      remained elusive, until samples were sent for polymerase chain reaction (PCR).
      This case was unusual for several reasons and is a reminder of the atypical way
      in which tuberculosis infection can present and how a high index of suspicion
      should be maintained. It shows the importance of molecular biological advances in
      providing simple and rapid methods for arriving at the correct diagnosis, by way
      of nucleic acid probes and polymerase chain reaction.

PMID- 10409548
TI  - Home inotrope treatment for intractable heart failure following heart
      transplantation.
AB  - A 49 year old man developed intractable heart failure three years after
      undergoing heart transplantation. Coronary angiography showed no evidence of
      graft vascular disease. An initial cardiac biopsy identified one episode of
      rejection which responded to augmented immunosuppressive treatment. The patient
      became inotrope dependent and has now survived at home for 22 months using an
      ambulatory delivery system for intravenous adrenaline (epinephrine), without
      significant complications. There has been a noticeable improvement in symptoms
      and left ventricular systolic performance, both clinically and as seen through
      echocardiographic and radiographic examination. This improvement was
      substantiated by the results of cardiac catheterisation, which showed a return to
      normal left ventricular filling pressure and cardiac output. The case is
      noteworthy because this treatment has allowed a patient who otherwise would have
      been hospital bound to return to the community. With the current shortage of
      organs, he would have been unlikely to receive a second transplant. The clinical
      features and outcome, and social, medicolegal, and financial issues are
      discussed.

PMID- 10409549
TI  - Familial fibromuscular dysplasia of bilateral brachial arteries.

PMID- 10409550
TI  - Transition in editorship 

PMID- 10409551
TI  - Influence of brief daily tendon vibration on rat soleus muscle in non-weight
      bearing situation.
AB  - The purpose of this study was to investigate whether tendon vibration could
      prevent soleus muscle atrophy during hindlimb unloading (HU). Mechanical
      vibrations with a constant low amplitude (0.3 mm) were applied (192 s/day) with
      constant frequency (120 Hz) to the Achilles tendon of the unloaded muscle during
      the 14-day HU period. Significant reductions in muscle mass (-41%), fiber size,
      maximal twitch (-54%), and tetanic tensions (-73%) as well as changes in fiber
      type and electrophoretic profiles and twitch-time parameters (-31% in the
      contraction time and -30% in the half relaxation time) were found after 14 days
      of HU when compared with the control soleus. Tendon vibration applied during HU
      significantly attenuated, but did not prevent, 1) the loss of muscle mass (17 vs.
      41%); 2) the decrease in the fiber cross-sectional area of type IIA (-28 vs. 
      50%) and type IIC (-29 vs. -56%) fibers; and 3) the decrease in maximal twitch (
      3 vs. -54%) and maximal tetanic tensions (-29 vs. -73%) and the half relaxation
      time (1 vs. -30%). Changes in the contraction time and in histological and
      electrophoretical parameters associated with HU were not counteracted. These
      findings suggest that tendon vibration can be used as a paradigm to counteract
      the atrophic process observed after HU.

PMID- 10409552
TI  - Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive
      sleep apnea syndrome.
AB  - Obstructive sleep apnea syndrome (OSAS) may be one of the most important risk
      factors of cardiovascular disorders, although the exact mechanism remains to be
      elucidated. In the present study, we hypothesized that OSAS-induced hypoxic
      stress might be involved in the etiology of cardiovascular disorders by
      activating adhesion molecules, including intercellular adhesion molecule 1 (ICAM
      1), vascular cell adhesion molecule 1 (VCAM-1), and L-selectin. To examine this
      hypothesis, we measured circulating ICAM-1, VCAM-1, and L-selectin levels before
      and after sleep in OSAS patients and age-matched controls. The circulating ICAM
      1, VCAM-1, and L-selectin levels increased in the OSAS patients before sleep
      compared with the normal subjects (ICAM-1: 392.9 +/- 48.5 vs. 201.2 +/- 55.0
      ng/ml, P < 0.05; VCAM-1: 811.0 +/- 87.8 vs. 574.2 +/- 42.7 ng/ml, P < 0.05; L
      selectin: 1,386.6 +/- 77.9 vs. 1,038.8 +/- 78.6 ng/ml, P < 0.01, respectively).
      After sleep, significantly greater levels of ICAM-1 and L-selectin, but not VCAM
      1, were observed in the OSAS group. These observations suggest that OSAS-induced
      hypoxia activates adhesion molecules, resulting in the important risk factor of
      cardiovascular disorders. Treatment of OSAS can be, therefore, a potential
      approach to prevention of cardiovascular events.

PMID- 10409553
TI  - Lung mechanics and end-expiratory lung volume during hypoxia in rats.
AB  - We investigated whether an hypoxia-induced increase in airway resistance mediated
      by vagal efferents participates in the increase in end-expiratory lung volume
      (EELV) observed in hypoxia. We also assessed the contribution of the end
      expiratory activity of the diaphragm (DE) to this phenomenon. Therefore, we
      measured EELV, total lung resistance (RL), dynamic lung compliance (Cdyn), DE,
      and minute ventilation (VE) in anesthetized rats during normoxia and hypoxia (10%
      O(2)) before (control) and after administration of atropine or saline. In the
      control group, hypoxia increased EELV, Cdyn, DE, and VE but slightly decreased
      RL. These changes were unaffected by saline or atropine, except that, in the
      atropine-treated rats, hypoxia did not change RL. These results suggest that 1)
      the increase in EELV observed in hypoxia cannot result from an increase in airway
      resistance; 2) the increased and persistent activity of inspiratory muscles
      during expiration is the most likely cause of the increase in EELV during
      hypoxia; and 3) the decrease in RL induced by hypoxia could result from the
      increase in lung volume including EELV.

PMID- 10409554
TI  - Specific strength and voluntary muscle activation in young and elderly women and
      men.
AB  - The extents to which decreased muscle size or activation are responsible for the
      decrease in strength commonly observed with aging remain unclear. Our purpose was
      to compare muscle isometric strength [maximum voluntary contraction (MVC)], cross
      sectional area (CSA), specific strength (MVC/CSA), and voluntary activation in
      the ankle dorsiflexor muscles of 24 young (32 +/- 1 yr) and 24 elderly (72 +/- 1
      yr) healthy men and women of similar physical activity level. Three measures of
      voluntary muscle activation were used: the central activation ratio [MVC/(MVC +
      superimposed force)], the maximal rate of voluntary isometric force development,
      and foot tap speed. Men had higher MVC and CSA than did women. Young men had
      higher MVC compared with elderly men [262 +/- 19 (SE) vs. 197 +/- 22 N,
      respectively], whereas MVC was similar in young and elderly women (136 +/- 15 vs.
      149 +/- 16 N, respectively). CSA was greater in young compared with elderly
      subjects. There was no age-related impairment of specific strength, central
      activation ratio, or the rate of voluntary force development. Foot tap speed was
      reduced in elderly (34 +/- 1 taps/10 s) compared with young subjects (47 +/- 1
      taps/10 s). These results suggest that isometric specific strength and the
      ability to fully and rapidly activate the dorsiflexor muscles during a single
      isometric contraction were unimpaired by aging. However, there was an age-related
      deficit in the ability to perform rapid repetitive dynamic contractions.

PMID- 10409555
TI  - Isoproterenol improves ability of lung to clear edema in rats exposed to
      hyperoxia.
AB  - Exposure of adult rats to 100% O(2) results in lung injury and decreases active
      sodium transport and lung edema clearance. It has been reported that beta
      adrenergic agonists increase lung edema clearance in normal rat lungs by
      upregulating alveolar epithelial Na(+)-K(+)-ATPase function. This study was
      designed to examine whether isoproterenol (Iso) affects lung edema clearance in
      rats exposed to 100% O(2) for 64 h. Active Na(+) transport and lung edema
      clearance decreased by approximately 44% in rats exposed to acute hyperoxia. Iso
      (10(-6) M) increased the ability of the lung to clear edema in room-air-breathing
      rats (from 0.50 +/- 0.02 to 0.99 +/- 0. 05 ml/h) and in rats exposed to 100% O(2)
      (from 0.28 +/- 0.03 to 0. 86 +/- 0.09 ml/h; P < 0.001). Disruption of
      intracellular microtubular transport of ion-transporting proteins by colchicine
      (0. 25 mg/100 g body wt) inhibited the stimulatory effects of Iso in hyperoxia
      injured rat lungs, whereas the isomer beta-lumicolchicine, which does not affect
      microtubular transport, did not inhibit active Na(+) transport stimulated by Iso.
      Accordingly, Iso restored the lung's ability to clear edema after hyperoxic lung
      injury, probably by stimulation of the recruitment of ion-transporting proteins
      (Na(+)-K(+)-ATPase) from intracellular pools to the plasma membrane in rat
      alveolar epithelium.

PMID- 10409556
TI  - Estimation of inspiratory pressure drop in neonatal and pediatric endotracheal
      tubes.
AB  - Endotracheal tubes (ETTs) constitute a resistive extra load for intubated
      patients. The ETT pressure drop (DeltaP(ETT)) is usually described by empirical
      equations that are specific to one ETT only. Our laboratory previously showed
      that, in adult ETTs, DeltaP(ETT) is given by the Blasius formula (F. Lofaso, B.
      Louis, L. Brochard, A. Harf, and D. Isabey. Am. Rev. Respir. Dis. 146: 974-979,
      1992). Here, we also propose a general formulation for neonatal and pediatric
      ETTs on the basis of adimensional analysis of the pressure-flow relationship.
      Pressure and flow were directly measured in seven ETTs (internal diameter: 2.5
      7.0 mm). The measured pressure drop was compared with the predicted drop given by
      general laws for a curved tube. In neonatal ETTs (2.5-3.5 mm) the flow regime is
      laminar. The DeltaP(ETT) can be estimated by the Ito formula, which replaces
      Poiseuille's law for curved tubes. For pediatric ETTs (4.0-7.0 mm), DeltaP(ETT)
      depends on the following flow regime: for laminar flow, it must be calculated by
      the Ito formula, and for turbulent flow, by the Blasius formula. Both formulas
      allow for ETT geometry and gas properties.

PMID- 10409557
TI  - Inhaled NO preadministration modulates local and remote ischemia-reperfusion
      organ injury in a rat model.
AB  - Inhaled nitric oxide (iNO) has been shown to have a protective effect in lung
      ischemia-reperfusion (I/R)-induced injuries. We studied the role of iNO (10
      parts/million for 4 h) administered before I/R. In an isolated perfused lung
      preparation, iNO decreased the extravascular albumin accumulation from 2,059 +/-
      522 to 615 +/- 105 microl and prevented the increase in lung wet-to-dry weight
      ratio. To study the mechanisms of this prevention, we evaluated the role of
      nitric oxide (NO) transport and lung exposure with matched experiments by using
      either lungs or blood of animals exposed to iNO and blood or lungs of naive
      animals. iNO-exposed blood with naive lungs did not limit the extravascular
      albumin accumulation (2,561 +/- 397 microl), but iNO-exposed lungs showed a leak
      not significantly different from the group in which both lungs and blood were iNO
      exposed (855 +/- 224 vs. 615 +/- 105 microl). An improvement in heart I/R left
      ventricular developed pressure in the animals exposed to iNO showed that blood
      transported NO was, however, sufficient to trigger remote organ endothelium and
      reduce the consequences of a delayed injury. In conclusion, preventive iNO
      reduces the consequences of lung I/R injuries by a mechanism based on tissue or
      endothelium triggering.

PMID- 10409558
TI  - The free-convective anomaly.
AB  - Persons exposed to high temperature, or to equivalent environmental factors, have
      quantifiable reactions, such as reducing the resistance to both heat and moisture
      flow in skin tissues and clothing needed to maintain thermal equilibrium. The one
      to-one relationship between this resistance in the walking person and
      temperature, with the other factors neutral, is the basis for the apparent
      temperature scale and the derived heat index. When this approach is taken to
      assess the thermal environment for a still person exposed to heat in still air,
      there is a zone of ambient conditions in which there are three solutions to the
      heat-balance equation. Extraordinary thermal stress occurs, depending slightly on
      other conditions, at ambient temperatures near 41 degrees C, especially at high
      humidity, because of the difficulty in carrying sweat vapor from the person when
      free convection is minimal. This anomaly is examined for a range of ambient vapor
      pressures and extra radiation. The rapid rise in heat stress when ambient
      temperature just exceeds body temperature in still conditions may explain the
      severity of some observed distress.

PMID- 10409559
TI  - Free radical activity, antioxidant enzyme, and glutathione changes with muscle
      stretch injury in rabbits.
AB  - The present study investigated changes in rate of free radical production,
      antioxidant enzyme activity, and glutathione status immediately after and 24 h
      after acute muscle stretch injury in 18 male New Zealand White rabbits. There was
      no change in free radical production in injured muscles, compared with noninjured
      controls, immediately after injury (time 0; P = 0.782). However, at 24 h
      postinjury, there was a 25% increase in free radical production in the injured
      muscles. Overall, there was an interaction (time and treatment) effect (P =
      0.005) for free radical production. Antioxidant enzyme activity demonstrated a
      treatment (injured vs. control) and interaction effect for both glutathione
      peroxidase (P = 0.015) and glutathione reductase (P = 0.041). There was no
      evidence of lipid peroxidation damage, as measured by muscle malondialdehyde
      content. An interaction effect occurred for both reduced glutathione (P = 0.008)
      and total glutathione (P = 0.015). Morphological analysis (hematoxylin and eosin
      staining) showed significant polymorphonuclear cell infiltration of the damaged
      region at 24 h postinjury. We conclude that acute mechanical muscle stretch
      injury results in increased free radical production within 24 h after injury.
      Antioxidant enzyme and glutathione systems also appear to be affected during this
      early postinjury period.

PMID- 10409560
TI  - Distribution of lung density after strenuous, prolonged exercise.
AB  - The postexercise alteration in pulmonary gas exchange in high-aerobically trained
      subjects depends on both the intensity and the duration of exercise (G. Manier,
      J. Moinard, and H. Stoicheff. J. Appl. Physiol. 75: 2580-2585, 1993; G. Manier,
      J. Moinard, P. Techoueyres, N. Varene, and H. Guenard. Respir. Physiol. 83: 143
      154, 1991). In a recent study that used lung computerized tomography (CT),
      evidence was found for accumulation of water within the lungs after exercise (C.
      Caillaud, O. Serre-Cousine, F. Anselme, X. Capdevilla, and C. Prefaut. J. Appl.
      Physiol. 79: 1226-1232, 1995). On representative slices of the lungs, mean lung
      density increased by 0.040 +/- 0.007 g/cm(3) (19%, P < 0.001) in athletes after a
      triathlon. To verify and quantify the mechanism, we determined the change in
      pulmonary density and mass after strenuous and prolonged exercise using another
      exercise protocol and methodology for CT scanning. Nine trained runners (age 30
      46 yr) volunteered to participate in the study. Each subject ran for 2 h on a
      treadmill at a rate corresponding to 75% of maximum O(2) consumption. CT
      measurements were made before and immediately after the exercise test with the
      subject supine and holding his breath at a point close to functional residual
      capacity. The lungs were scanned from the apex to the diaphragm and reconstructed
      in 8-mm-thick slices. Attenuation values of X-rays in each part of the lung were
      expressed in Hounsfield units (HU), which are related to density (D): D = 1 +
      HU/1,000. No significant alteration in pulmonary density (0.37 +/- 0.04 vs. 0.35
      +/- 0.03, not significant) was observed after the 2-h run test. Although lung
      volume slightly increased (change of 166 +/- 205 ml, P < 0.05), lung mass
      remained stable because of a change in density distribution. We failed to detect
      any changes in postexercise lung mass, suggesting that other mechanisms need to
      be considered to explain the observed alterations in pulmonary gas exchange after
      prolonged strenuous exercise.

PMID- 10409561
TI  - mRNA levels for alpha-subunit of prolyl 4-hydroxylase and fibrillar collagens in
      immobilized rat skeletal muscle.
AB  - There is evidence that immobilization causes a decrease in total collagen
      synthesis in skeletal muscle within a few days. In this study, early
      immobilization effects on the expression of prolyl 4-hydroxylase (PH) and the
      main fibrillar collagens at mRNA and protein levels were investigated in rat
      skeletal muscle. The right hindlimb was immobilized in full plantar flexion for
      1, 3, and 7 days. Steady-state mRNAs for alpha- and beta-subunits of PH and type
      I and III procollagen, PH activity, and collagen content were measured in
      gastrocnemius and plantaris muscles. Type I and III procollagen mRNAs were also
      measured in soleus and tibialis anterior muscles. The mRNA level for the PH alpha
      subunit decreased by 49 and 55% (P < 0.01) in gastrocnemius muscle and by 41 and
      39% (P < 0.05) in plantaris muscle after immobilization for 1 and 3 days,
      respectively. PH activity was decreased (P < 0.05-0.01) in both muscles at days 3
      and 7. The mRNA levels for type I and III procollagen were decreased by 26-56% (P
      < 0.05-0.001) in soleus, tibialis anterior, and plantaris muscles at day 3. The
      present results thus suggest that pretranslational downregulation plays a key
      role in fibrillar collagen synthesis in the early phase of immobilization-induced
      muscle atrophy.

PMID- 10409562
TI  - Nitric oxide donors can increase heart rate independent of autonomic activation.
AB  - Administration of nitric oxide (NO) donors in vivo is accompanied by a baroreflex
      mediated increase in heart rate (HR). In vitro, however, NO donors can increase
      HR directly by stimulating a pathway that involves NO, cGMP, and the
      hyperpolarization-activated current (I(f)). The aim of this study was to assess
      the functional significance of this pathway in vivo by testing whether NO donors
      can increase HR in the anesthetized rabbit independent of the autonomic nervous
      system. New Zealand White rabbits were vagotomized, cardiac sympathectomized, and
      treated with propranolol (0.3 mg/kg iv). The NO donor molsidomine (0.2 mg/kg iv)
      caused a progressive increase (Delta) in HR (DeltaHR, 14 +/- 3 beats/min; P <
      0.01). This effect was significantly reduced by the I(f) blocker ZD-7288 (0.2
      mg/kg iv; DeltaHR, 2 +/- 3 beats/min; P = not significant). Similar results were
      seen with sodium nitroprusside. The positive chronotropic effect of sodium
      nitroprusside (50 microM) was confirmed in the isolated working rabbit heart
      preparation (DeltaHR, 17 +/- 3 beats/min; P < 0.01). In conclusion, NO donors
      exert a small, but significant, positive chronotropic effect in vivo that is
      independent of the autonomic nervous system. These results are also consistent
      with data in sinoatrial node cells that show that NO donors increase HR by
      stimulating I(f).

PMID- 10409563
TI  - Role of nitric oxide in hypoxic hypometabolism in rats.
AB  - Because it has been recently suggested that nitric oxide (NO) may mediate the
      effects of hypoxia on body temperature and ventilation, the present study was
      designed to assess more completely the effects of a neuronal NO synthase
      inhibitor (7-nitroindazole, 25 mg/kg ip), at ambient temperature of 26 and 15
      degrees C, on the ventilatory (V), metabolic (O(2) consumption), and thermal
      changes (colonic and tail temperatures) induced by ambient hypoxia (fractional
      inspired O(2) of 11%) or CO hypoxia (fractional inspired CO of 0.07%) in intact,
      unanesthetized adult rats. At both ambient temperatures, 7-nitroindazole
      decreased oxygen consumption, colonic temperature, and V in normoxia. The drug
      reduced ambient or CO hypoxia-induced hypometabolism and ventilatory response,
      but the hypothermia persisted. It is concluded that NO arising from neural NO
      synthase plays an important role in the control of metabolism and V in normoxia.
      As well, it mediates, in part, the hypometabolic and the ventilatory response to
      hypoxia. The results are consistent with the notion that central nervous system
      hypoxia resets the thermoregulatory set point by decreasing brain NO.

PMID- 10409564
TI  - Glucose production during exercise in humans: a-hv balance and isotopic-tracer
      measurements compared.
AB  - The present study compared the arteriohepatic venous (a-hv) balance technique and
      the tracer-dilution method for estimation of hepatic glucose production during
      both moderate and heavy exercise in humans. Eight healthy young men (aged 25 yr;
      range, 23-30 yr) performed semisupine cycling for 40 min at 50.4 +/- 1.5(SE)%
      maximal O(2) consumption, followed by 30 min at 69.0 +/- 2.2% maximal O(2)
      consumption. The splanchnic blood flow was estimated by continuous infusion of
      indocyanine green, and net splanchnic glucose output was calculated as the
      product of splanchnic blood flow and a-hv blood glucose concentration
      differences. Glucose appearance rate was determined by a primed, continuous
      infusion of [3-(3)H]glucose and was calculated by using formulas for a modified
      single compartment in non-steady state. Glucose production was similar whether
      determined by the a-hv balance technique or by the tracer-dilution method, both
      at rest and during moderate and intense exercise (P > 0. 05). It is concluded
      that, during exercise in humans, determination of hepatic glucose production can
      be performed equally well with the two techniques.

PMID- 10409565
TI  - Effects of creatine supplementation on the energy cost of muscle contraction: a
      31P-MRS study.
AB  - Five women and 3 men (29.8 +/- 1.4 yr) performed dynamic knee-extension exercise
      inside a magnetic resonance system (means +/- SE). Two trials were performed 7-14
      days apart, consisting of a 4- to 5-min exhaustive exercise bout. To determine
      quadriceps cost of contraction, brief static and dynamic contractions were
      performed pre- and postexercise. (31)P spectra were used to determine pH and
      relative concentrations of P(i), phosphocreatine (PCr), and betaATP. Subjects
      consumed 0.3 g. kg(-1). day(-1) of a placebo (trial 1) or creatine (trial 2) for
      5 days before each trial. After creatine supplementation, resting DeltaPCr
      increased from 40.7 +/- 1.8 to 46. 6 +/- 1.1 mmol/kg (P = 0.04) and PCr during
      exercise declined from -29.6 +/- 2.4 to -34.1 +/- 2.8 mmol/kg (P = 0.02). Muscle
      static (DeltaATP/N) and dynamic (DeltaATP/J) costs of contraction were unaffected
      by creatine supplementation as well as were ATP, P(i), pH, PCr resynthesis rate,
      and muscle strength and endurance. DeltaATP/J and DeltaATP/N were greatest at the
      onset of the exercise protocol (P < 0.01). In summary, creatine supplementation
      increased muscle PCr concentration, which did not affect muscle ATP cost of
      contraction.

PMID- 10409566
TI  - Hormonal and metabolic responses to maintained hyperglycemia during prolonged
      exercise.
AB  - We studied the effects of maintained hyperglycemia (12 mmol/l) on endurance
      exercise to determine the hormonal and metabolic responses, the maximal rate of
      glucose infusion (i.e., utilization), and the effects on muscle glycogen stores.
      Eight men undertook two trials during which they exercised on a cycle ergometer
      at an intensity of approximately 70% peak O(2) uptake for 120 min. In the first
      trial (trial A), subjects had their blood glucose concentration clamped at 12
      mmol/l 30 min before exercise and throughout exercise. The same rate and volume
      of infusion of saline as had occurred for trial A were used in a placebo trial
      (trial B). Maintained hyperglycemia resulted in significantly lowered plasma
      concentrations of nonesterified fatty acid, glycerol, 3-hydroxybutyrate,
      epinephrine, norepinephrine, and growth hormone (P < 0.001) during exercise,
      whereas concentrations of plasma insulin were significantly elevated (P < 0.001).
      Calculations of the rates of total carbohydrate oxidation showed that trial A
      resulted in significantly higher values when compared with trial B (P < 0.01) and
      that the maximal rates of glucose infusion varied between 1.33 and 2.78 g/min at
      100-120 min. Muscle glycogen concentrations were significantly depleted (P <
      0.01) after both trials (trial A, 170.3 micromol/g dry wt decrease; trial B, 206
      micromol/g dry wt decrease), although this apparent difference may be accounted
      for by storage of 22.6 g glucose during the 30-min prime infusion. The results
      from this study confirm that maintained hyperglycemia attenuates the hormonal
      response and promotes carbohydrate oxidation and utilization and that muscle
      glycogen may not be spared.

PMID- 10409567
TI  - Mechanisms of improvement in pulmonary gas exchange during isovolemic
      hemodilution.
AB  - Severe anemia is associated with remarkable stability of pulmonary gas exchange
      (S. Deem, M. K. Alberts, M. J. Bishop, A. Bidani, and E. R. Swenson. J. Appl.
      Physiol. 83: 240-246, 1997), although the factors that contribute to this
      stability have not been studied in detail. In the present study, 10 Flemish Giant
      rabbits were anesthetized, paralyzed, and mechanically ventilated at a fixed
      minute ventilation. Serial hemodilution was performed in five rabbits by
      simultaneous withdrawal of blood and infusion of an equal volume of 6%
      hetastarch; five rabbits were followed over a comparable time. Ventilation
      perfusion (VA/Q) relationships were studied by using the multiple inert-gas
      elimination technique, and pulmonary blood flow distribution was assessed by
      using fluorescent microspheres. Expired nitric oxide (NO) was measured by
      chemiluminescence. Hemodilution resulted in a linear fall in hematocrit over
      time, from 30 +/- 1.6 to 11 +/- 1%. Anemia was associated with an increase in
      arterial PO(2) in comparison with controls (P < 0.01 between groups). The
      improvement in O(2) exchange was associated with reduced VA/Q heterogeneity, a
      reduction in the fractal dimension of pulmonary blood flow (P = 0.04), and a
      relative increase in the spatial correlation of pulmonary blood flow (P = 0. 04).
      Expired NO increased with anemia, whereas it remained stable in control animals
      (P < 0.0001 between groups). Anemia results in improved gas exchange in the
      normal lung as a result of an improvement in overall VA/Q matching. In turn, this
      may be a result of favorable changes in pulmonary blood flow distribution, as
      assessed by the fractal dimension and spatial correlation of blood flow and as a
      result of increased NO availability.

PMID- 10409568
TI  - Influence of nitric oxide on vascular resistance and muscle mechanics during
      tetanic contractions in situ.
AB  - Studies of the effect of nitric oxide (NO) synthesis inhibition were performed in
      the isometrically contracting blood-perfused canine gastrocnemius-plantaris
      muscle group. Muscle blood flow (Q) was controlled with a pump during continuous
      NO blockade produced with either 1 mM L-argininosuccinic acid (L-ArgSA) or N(G)
      nitro-L-arginine methyl ester (L-NAME) during repetitive tetanic contractions (50
      Hz trains, 200-ms duration, 1/s). Pump Q was set to match maximal spontaneous Q
      (1.3-1.4 ml. min(-1). g(-1)) measured in prior, brief (3-5 min) control
      contraction trials in each muscle. Active tension and oxygen uptake were 500-600
      g/g and 200-230 microl. min(-1). g(-1), respectively, under these conditions.
      Within 3 min of L-ArgSA infusion, vascular resistance across the muscle (R(v))
      increased significantly (from approximately 100 to 300 peripheral resistance
      units; P < 0.05), whereas R(v) increased to a lesser extent with L-NAME (from
      approximately 100 to 175 peripheral resistance units; P < 0.05). The increase in
      R(v) with L-ArgSA was unchanged by simultaneous infusion of 0.5-10 mM L-arginine
      but was reduced with 1-3 microg/ml sodium nitroprusside (41-54%). The increase in
      R(v) with L-NAME was reversed with 1 mM of L-arginine. Increased fatigue occurred
      with infusion of L-ArgSA; active tension and intramuscular pressure decreased by
      62 and 66%, whereas passive tension and baseline intramuscular pressure increased
      by 80 and 30%, respectively. These data indicate a possible role for NO in the
      control of R(v) and contractility within the canine gastrocnemius-plantaris
      muscle during repetitive tetanic contractions.

PMID- 10409569
TI  - Chronic and acute exercise do not alter Ca2+ regulatory systems and
      ectonucleotidase activities in rat heart.
AB  - The purpose of this investigation was to examine the effects of chronic and acute
      exercise on the main components involved in excitation-contraction coupling and
      relaxation in rat heart. Sixty male Wistar rats were divided into a sedentary (S)
      and three 12-wk treadmill-trained groups (T-1, moderate intensity; T-2, high
      intensity; T-3, interval running). After 12-wk, 15 rats from the S group and 15
      rats from the T-2 group were subjected to a single treadmill-exercise session
      until exhaustion before being killed at 0, 24, or 48 h (acute exercise). The
      remaining animals were killed 48 h after the last standard exercise session
      (chronic exercise). The efficacy of the training programs was confirmed by an
      increase in treadmill endurance time and in skeletal muscle citrate synthase
      activity. None of the exercise programs modified heart weight or cardiac
      oxidative capacity. [(3)H]PN200-110 and [(3)H]ryanodine binding to cardiac
      homogenates indicated that the density of L-type and sarcoplasmic reticulum (SR)
      Ca(2+) channels was the same in S and trained rats. The SR Ca(2+)-ATPase activity
      was also unmodified. Finally, the activities of the ectoenzymes Mg(2+)-ATPase and
      5'-nucleotidase, which are involved in degradation of extracellular nucleotides,
      were not affected by either of the running programs. After the acute exercise
      session, no changes were detected in either of the tested parameters in heart
      homogenates of S and T-2 animals. We conclude that neither treadmill-exercise
      training for 12 wk nor exhaustive exercise alters the density of Ca(2+) channels
      involved in excitation-contraction coupling or the SR Ca(2+)-ATPase and the
      ectonucleotidase activities in rat heart.

PMID- 10409570
TI  - A tidal breathing model for the multiple inert gas elimination technique.
AB  - The tidal breathing lung model described for the sine-wave technique (D. J.
      Gavaghan and C. E. W. Hahn. Respir. Physiol. 106: 209-221, 1996) is generalized
      to continuous ventilation-perfusion and ventilation-volume distributions. This
      tidal breathing model is then applied to the multiple inert gas elimination
      technique (P. D. Wagner, H. A. Saltzman, and J. B. West. J. Appl. Physiol. 36:
      588-599, 1974). The conservation of mass equations are solved, and it is shown
      that 1) retentions vary considerably over the course of a breath, 2) the
      retentions are dependent on alveolar volume, and 3) the retentions depend only
      weakly on the width of the ventilation-volume distribution. Simulated
      experimental data with a unimodal ventilation-perfusion distribution are inserted
      into the parameter recovery model for a lung with 1 or 2 alveolar compartments
      and for a lung with 50 compartments. The parameters recovered using both models
      are dependent on the time interval over which the blood sample is taken. For best
      results, the blood sample should be drawn over several breath cycles.

PMID- 10409571
TI  - Role of AVP in mediating the altered core temperature response to a simulated
      open field in pregnant rats.
AB  - Near the term of pregnancy, rats have an attenuated core temperature response on
      exposure to a novel environment (e.g., a simulated open field) compared with that
      observed early in pregnancy or in nonpregnant rats. The present experiments were
      carried out on 26 nonpregnant and 26 pregnant rats to test the hypothesis that
      arginine vasopressin, functioning as an endogenous antipyretic substance in the
      central nervous system, mediates this attenuated core temperature response.
      Exposure to a simulated open field after intracerebroventricular (ICV) vehicle
      produced a significant increase in core temperature in both nonpregnant and
      pregnant animals, the magnitude and duration of which were greater in the
      nonpregnant rats. In nonpregnant rats, exposure to a simulated open field after
      ICV vasopressin V(1)-receptor antagonist altered the pattern of the core
      temperature response but not the core temperature index compared with that
      observed on exposure to a simulated open field after ICV vehicle. In pregnant
      animals, ICV vasopressin V(1)-receptor antagonist did not alter the core
      temperature response to a simulated open field compared with that observed after
      ICV vehicle. Thus our data do not support the hypothesis that a pregnancy-related
      activation of arginine vasopressin attenuates the core temperature response to a
      simulated open field in rats near the term of pregnancy.

PMID- 10409572
TI  - Dexamethasone in resting and exercising men. I. Effects on bioenergetics,
      minerals, and related hormones.
AB  - A placebo and a low and a high dose of dexamethasone (Dex) were administered for
      4.5 days, at 3-wk intervals, to 24 healthy men, following a double-blind, random
      order, crossover procedure. After the last dose the subjects performed a maximal
      cycling exercise, during which respiratory exchanges, electrocardiogram, and
      blood pressures were monitored. Blood was sampled just before and after each
      exercise bout. Dex showed no significant effect on fitness, sleep, exhaustion
      during exercise, maximal O(2) consumption, ventilatory threshold, maximal blood
      lactate, or rest and exercise blood pressures. On the contrary, both doses of Dex
      significantly decreased heart rate at rest and during maximal exercise. Blood
      glucose at rest was higher after both doses of Dex than after placebo; the
      opposite was found during exercise. Blood levels of ACTH, beta-endorphin,
      cortisol, and cortisol-binding globulin were lowered by Dex at rest and after
      exercise. Dex stimulated the increase in atrial natriuretic factor during
      exercise and lowered rest and postexercise aldosterone. Finally, no difference
      between "fit or trained" and "less fit or untrained" subjects could be found with
      respect to Dex effects.

PMID- 10409573
TI  - Dexamethasone in resting and exercising men. II. Effects on adrenocortical
      hormones.
AB  - This study presents the reactions of adrenocorticosteroids (cortisol and
      aldosterone) and sex steroids [testosterone, androstenedione, and
      dehydroepiandrosterone and its sulfate (DHAS)] 1) to a dexamethasone (Dex)
      treatment, which is expected to lower steroid levels via the ACTH blockade, and
      2) to an exercise bout at maximal O(2) consumption, which is expected to increase
      steroid production via ACTH stimulation. Consistent with the decrease in ACTH,
      all steroids except testosterone reacted negatively to Dex, independently of the
      dose (0.5 and 1.5 mg administered twice daily for 4.5 days). After exercise,
      plasma ACTH rose to 600% of basal value, resulting in a significant increase in
      aldosterone and adrenal androgens, but cortisol and DHAS were unaffected. This
      apparently surprising result can be explained by differences in peripheral
      metabolism: a theoretical calculation predicted that after 15 min the increase in
      hormone concentration may only reach 12% for cortisol and 2% for DHAS. For
      cortisol and adrenal androgens, assays were carried out using plasma and saliva.
      The consistent results obtained from the two matrices allow us to consider
      salivary assays as a useful tool for steroid abuse detection.

PMID- 10409574
TI  - Mechanical loading attenuates bone loss due to immobilization and calcium
      deficiency.
AB  - Our purpose was to determine the effects of a mechanical loading intervention on
      mass, geometry, and strength of rat cortical bone during a period of disuse
      concurrent with calcium deficiency (CD). Adult female rats were assigned to
      unilateral hindlimb immobilization, immobilized-loaded, or control (standard
      chow, 1.85% calcium) treatments. Both immobilized groups were fed a CD rat chow
      (0.01% calcium) to induce high bone turnover. Three times weekly, immobilized
      loaded rats were subjected to 36 cycles of 4-point bending of the immobilized
      lower leg. After 6 wk, the immobilized rats exhibited decreased tibial shaft bone
      mineral density (-12%), ultimate load (-19%), and stiffness (-20%; tested in 3
      point bending to failure) vs. control rats. Loading prevented this decline in
      bone density and attenuated decreases in ultimate load and stiffness. Elastic
      modulus was unaffected by disuse or loading. Bone cross-sectional area in the
      immobilized-loaded rats was equivalent to that of control animals, even though
      endocortical resorption continued unabated. On the medial periosteum, percent
      mineralizing surface doubled vs. that in immobilized rats. This loading regimen
      stimulated periosteal mineralization and maintained bone mineral density, thereby
      attenuating the loss in bone strength incurred with disuse and concurrent calcium
      deficiency.

PMID- 10409575
TI  - Fat mass deposition during pregnancy using a four-component model.
AB  - Estimates of body fat mass gained during human pregnancy are necessary to assess
      the composition of gestational weight gained and in studying energy requirements
      of reproduction. However, commonly used methods of measuring body composition are
      not valid during pregnancy. We used measurements of total body water (TBW), body
      density, and bone mineral content (BMC) to apply a four-component model to
      measure body fat gained in nine pregnant women. Measurements were made
      longitudinally from before conception; at 8-10, 24-26, and 34-36 wk gestation;
      and at 4-6 wk postpartum. TBW was measured by deuterium dilution, body density by
      hydrodensitometry, and BMC by dual-energy X-ray absorptiometry. Body protein was
      estimated by subtracting TBW and BMC from fat-free mass. By 36 wk of gestation,
      body weight increased 11.2 +/- 4.4 kg, TBW increased 5.6 +/- 3.3 kg, fat-free
      mass increased 6.5 +/- 3.4 kg, and fat mass increased 4.1 +/- 3.5 kg. The
      estimated energy cost of fat mass gained averaged 44,608 kcal (95% confidence
      interval, -31, 552-120,768 kcal). The large variability in the composition of
      gestational weight gained among the women was not explained by prepregnancy body
      composition or by energy intake. This variability makes it impossible to derive a
      single value for the energy cost of fat deposition to use in estimating the
      energy requirement of pregnancy.

PMID- 10409576
TI  - Failure of autoresuscitation in weanling mice: significance of cardiac glycogen
      and heart rate regulation.
AB  - "Autoresuscitation" (AR) is the spontaneous recovery from hypoxic apnea by
      gasping. We examined aspects of heart function in two situations: 1) the
      maturationally acquired failure of AR that is characteristic of SWR, but not
      BALB/c, weanling mice and 2) AR failure in BALB/c mice induced by repeated
      exposures to anoxia. We determined maturational changes in heart and liver
      glycogen. Unlike liver glycogen levels, heart glycogen levels in SWR mice
      differed from those in BALB/c mice. They were consistently much lower throughout
      maturation and reached a nadir during the brief period when SWR weanling mice are
      vulnerable to AR failure. Also, rate of cardiac glycogen utilization in
      vulnerable SWR mice was lower than that of same-aged BALB/c mice and was nil
      during the latter one-half of the gasping stage when heart function is critical
      for AR success. Therefore, because glycogen utilization reflects cardiac work,
      heart failure could explain AR failure in SWR weanlings. Additionally, the
      increase in hypoxic heart rate that occurs with maturation is developmentally
      delayed in SWR mice, and this may contribute to their AR failure. Cardiac
      glycogen was not fully depleted in BALB/c mice during repeated anoxic exposures,
      indicating other reasons for AR failure. We view these findings as a potential
      model for the age-related peak in incidence of sudden infant death syndrome.

PMID- 10409577
TI  - Wall thickness referenced to myocardial volume: a new noninvasive framework for
      cardiac mechanics.
AB  - Dimensional variables measured for study of left ventricular mechanics are
      subject to errors arising from difficulty in determining zero-stress dimensions
      for use as a reference. Based on a method validated for measurements within
      individuals, we have devised an approach that facilitates comparison between
      individuals while minimizing random scatter. We define an exact mathematical
      index of strain, ln(h(0)/h), using wall thickness (h) referenced to extrapolated
      wall thickness at zero-luminal volume (h(0)). Noninvasive data from rabbits,
      pigs, and humans all yielded highly similar myocardial stress, ln(h(0)/h), and
      work values. The stress-ln(h(0)/h) relationship during afterload variation was
      constant among individual pigs with a twofold variation in ventricular mass.
      Stress-ln(h(0)/h) data from our analysis displayed lower scatter than either
      pressure-volume data normalized to myocardial mass or stress-ln(h(0)/h) data
      referenced to end-diastolic dimensions. A Frank-Starling-like curve with high
      correlation (r(2) = 0.96) was constructed from single points from different pigs,
      suggesting a low level of size and intersubject scatter. This method offers high
      precision for noninvasive characterization of ventricular and myocardial
      mechanics and for comparisons between subjects and between species.

PMID- 10409578
TI  - Effects of endurance exercise training on muscle glycogen accumulation in humans.
AB  - The purpose of this investigation was to determine whether endurance exercise
      training increases the ability of human skeletal muscle to accumulate glycogen
      after exercise. Subjects (4 women and 2 men, 31 +/- 8 yr old) performed high
      intensity stationary cycling 3 days/wk and continuous running 3 days/wk for 10
      wk. Muscle glycogen concentration was measured after a glycogen-depleting
      exercise bout before and after endurance training. Muscle glycogen accumulation
      rate from 15 min to 6 h after exercise was twofold higher (P < 0.05) in the
      trained than in the untrained state: 10.5 +/- 0.2 and 4.5 +/- 1.3 mmol. kg wet
      wt(-1). h(-1), respectively. Muscle glycogen concentration was higher (P < 0.05)
      in the trained than in the untrained state at 15 min, 6 h, and 48 h after
      exercise. Muscle GLUT-4 content after exercise was twofold higher (P < 0.05) in
      the trained than in the untrained state (10.7 +/- 1.2 and 4.7 +/- 0.7 optical
      density units, respectively) and was correlated with muscle glycogen
      concentration 6 h after exercise (r = 0.64, P < 0.05). Total glycogen synthase
      activity and the percentage of glycogen synthase I were not significantly
      different before and after training at 15 min, 6 h, and 48 h after exercise. We
      conclude that endurance exercise training enhances the capacity of human skeletal
      muscle to accumulate glycogen after glycogen-depleting exercise.

PMID- 10409579
TI  - Effect of diet on fat cell size and hormone-sensitive lipase activity.
AB  - This study was designed to examine the relationship between diet-induced insulin
      resistance/hyperinsulinemia, fat cell hypertrophy, and hormone-sensitive lipase
      (HSL) to elucidate whether an attenuated HSL activity leads to obesity. Female
      Fischer 344 rats were fed either a low-fat, complex-carbohydrate diet or a high
      fat, refined-sugar (HFS) diet for 2 wk, 2 mo, or 6 mo. Adipose tissue morphology
      and HSL activity as well as plasma free fatty acid and glycerol levels were
      determined at these times. No differences between groups were seen after 2 wk
      except the previously reported hyperinsulinemia in the HFS animals. At both 2 and
      6 mo, the HFS animals demonstrated adipocyte hypertrophy. Basal and stimulated
      HSL activities and plasma glycerol were significantly elevated in the HFS group.
      There was a positive correlation between adipocyte size and HSL activity for both
      basal and stimulated states. These results demonstrate that an attenuated HSL
      activity is not observed with the onset of insulin resistance/hyperinsulinemia
      and therefore does not play a role in the development of obesity.

PMID- 10409580
TI  - Ventilation and locomotion coupling in varsity male rowers.
AB  - Ventilation and locomotion coupling (entrainment) has been observed and described
      in rowers during incremental exercise protocols but not during simulated race
      conditions. The purpose of this descriptive study was to examine ventilation and
      locomotion entrainment on a breath-by-breath and stroke-by-stroke basis in
      varsity male rowers during a maximal 2,000-m ergometer test. Eight of eleven
      rowers entrained ventilation at integral multiples of stroke rate (1:1, 2:1, or
      3:1) for at least 120 consecutive seconds, with a 2:1 entrainment pattern being
      most common. In all 2:1-entrained subjects, inspiration occurred at catch and
      finish and expiration occurred during the latter portions of drive and recovery.
      In entrained and unentrained breaths from all rowers, peak flow rates and tidal
      volumes varied depending on when the breath was initiated during the stroke
      cycle. Entrained rowers made use of these differences and breathed in a pattern
      by which they avoided initiating breaths that resulted in reduced tidal volumes.
      The present data indicated that ventilation was impaired at stroke finish and not
      at catch, as hypothesized by some previous researchers. Ventilation also appeared
      to be subordinate to consistent locomotive patterns under race conditions.

PMID- 10409581
TI  - Thermoregulatory responses to cold water at different times of day.
AB  - This study examined how time of day affects thermoregulation during cold-water
      immersion (CWI). It was hypothesized that the shivering and vasoconstrictor
      responses to CWI would differ at 0700 vs. 1500 because of lower initial core
      temperatures (T(core)) at 0700. Nine men were immersed (20 degrees C, 2 h) at
      0700 and 1500 on 2 days. No differences (P > 0.05) between times were observed
      for metabolic heat production (M, 150 W. m(-2)), heat flow (250 W. m(-2)), mean
      skin temperature (T(sk), 21 degrees C), and the mean body temperature-change in M
      (DeltaM) relationship. Rectal temperature (T(re)) was higher (P < 0.05) before
      (Delta = 0.4 degrees C) and throughout CWI during 1500. The change in T(re) was
      greater (P < 0. 05) at 1500 (-1.4 degrees C) vs. 0700 (-1.2 degrees C), likely
      because of the higher T(re)-T(sk) gradient (0.3 degrees C) at 1500. These data
      indicate that shivering and vasoconstriction are not affected by time of day.
      These observations raise the possibility that CWI may increase the risk of
      hypothermia in the early morning because of a lower initial T(core).

PMID- 10409582
TI  - Thermoregulation during cold exposure: effects of prior exercise.
AB  - This study examined whether acute exercise would impair the body's capability to
      maintain thermal balance during a subsequent cold exposure. Ten men rested for 2
      h during a standardized cold-air test (4.6 degrees C) after two treatments: 1) 60
      min of cycle exercise (Ex) at 55% peak O(2) uptake and 2) passive heating (Heat).
      Ex was performed during a 35 degrees C water immersion (WI), and Heat was
      conducted during a 38.2 degrees C WI. The duration of Heat was individually
      adjusted (mean = 53 min) so that rectal temperature was similar at the end of WI
      in both Ex (38.2 degrees C) and Heat (38.1 degrees C). During the cold-air test
      after Ex, relative to Heat 1) rectal temperature was lower (P < 0.05) from
      minutes 40-120, 2) mean weighted heat flow was higher (P < 0.05), 3) insulation
      was lower (P < 0.05), and 4) metabolic heat production was not different. These
      results suggest that prior physical exercise may predispose a person to greater
      heat loss and to experience a larger decline in core temperature when
      subsequently exposed to cold air. The combination of exercise intensity and
      duration studied in these experiments did not fatigue the shivering response to
      cold exposure.

PMID- 10409583
TI  - Kinetics of oxygen uptake during supine and upright heavy exercise.
AB  - It is presently unclear how the fast and slow components of pulmonary oxygen
      uptake (VO(2)) kinetics would be altered by body posture during heavy exercise
      [i.e., above the lactate threshold (LT)]. Nine subjects performed transitions
      from unloaded cycling to work rates representing moderate (below the estimated
      LT) and heavy exercise (VO(2) equal to 50% of the difference between LT and peak
      VO(2)) under conditions of upright and supine positions. During moderate
      exercise, the steady-state increase in VO(2) was similar in the two positions,
      but VO(2) kinetics were slower in the supine position. During heavy exercise, the
      rate of adjustment of VO(2) to the 6-min value was also slower in the supine
      position but was characterized by a significant reduction in the amplitude of the
      fast component of VO(2), without a significant slowing of the phase 2 time
      constant. However, the amplitude of the slow component was significantly
      increased, such that the end-exercise VO(2) was the same in the two positions.
      The changes in VO(2) kinetics for the supine vs. upright position were paralleled
      by a blunted response of heart rate at 2 min into exercise during supine compared
      with upright heavy exercise. Thus the supine position was associated with not
      only a greater amplitude of the slow component for VO(2) but also, concomitantly,
      with a reduced amplitude of the fast component; this latter effect may be due, at
      least in part, to an attenuated early rise in heart rate in the supine position.

PMID- 10409584
TI  - Effect of pressure on hydraulic conductivity of endothelial monolayers: role of
      endothelial cleft shear stress.
AB  - Significant changes in transvascular pressure occur in pulmonary hypertension,
      microgravity, and many other physiological and pathophysiological circumstances.
      Using bovine aortic endothelial cells grown on porous, rigid supports, we
      demonstrate that step changes in transmural pressure of 10, 20, and 30 cmH(2)O
      induce significant elevations in endothelial hydraulic conductivity (L(p)) that
      require 5 h to reach new steady-state levels. The increases in L(p) can be
      reversed by addition of a stable cAMP analog (dibutyryl cAMP), and the increases
      in L(p) in response to pressure can be inhibited significantly with nitric oxide
      synthase inhibitors (N(G)-monomethyl-L-arginine and nitro-L-arginine methyl
      ester). The increase in L(p) was not due to pressure-induced stretch because the
      endothelial cell (EC) support was rigid. It is unlikely that the increase in L(p)
      was due to a direct effect of pressure because exposure of the cells to elevated
      pressure (25 cmH(2)O) for 4 h had no effect on the volume flux driven by a
      transmural pressure of 10 cmH(2)O. We hypothesize that elevated endothelial cleft
      shear stress induced by elevated transmural flow in response to elevated pressure
      stimulates the increase in L(p) through a nitric oxide-cAMP-dependent mechanism.
      This is consistent with recent studies of the effects of shear stress on the
      luminal surface of ECs. We provide simple estimates of endothelial cleft shear
      stress, which suggest magnitudes comparable to those imposed by blood flow on the
      luminal surface of ECs.

PMID- 10409585
TI  - Anatomic localization of 24- and 96-h particle retention in canine airways.
AB  - Long-term retention of particles in airways is controversial. However, precise
      anatomic localization of the particles is not possible in people. In this study
      the anatomic location of retained particles after shallow bolus inhalation was
      determined in anesthetized, ventilated beagle dogs. Fifty 30-cm(3) boluses
      containing monodisperse 2.5-micron polystyrene particles (PSL) were delivered to
      a shallow lung depth of 81-129 cm(3). At 96 h before euthanasia, red fluorescent
      PSL were used; at 24 h, green fluorescent PSL and (99m)Tc-labeled PSL were used.
      Clearance of (99m)Tc-PSL was measured during the next 24 h. Sites of particle
      retention were determined in systematic, volume-weighted random samples of
      microwave-fixed lung tissue. Precise particle localization and distribution was
      analyzed by using gamma counting, conventional fluorescence microscopy, and
      confocal microscopy. Within 24 h after shallow bolus inhalation, 50-95% of the
      deposited (99m)Tc-PSL were cleared, but the remaining fraction was cleared slowly
      in all dogs, similar to previous human results. The three-dimensional deposition
      patterns showed particles across the entire cross-sectional plane of the lungs at
      the level of the carina. In these locations, 33 +/- 9.9% of the retained
      particles were found in small, nonrespiratory airways (0.3- to 1-mm diameter) and
      49 +/- 10% of the particles in alveoli; the remaining fraction was found in
      larger airways. After 96 h, a similar pattern was found. These findings suggest
      that long-term retention in airways is at the bronchiolar level.

PMID- 10409587
TI  - Increased extracellular water compartment, relative to intracellular water
      compartment, after weight reduction.
AB  - The hydration of fat free mass (FFM) and extracellular (ECW) and intracellular
      water (ICW) compartments were studied in 30 obese premenopausal women before and
      after a 3-mo weight-reduction program and again after a 9-mo weight-maintenance
      program. Body fat was determined by a four-compartment model. Total body water
      and ECW were determined by deuterium dilution and bromide dilution, respectively.
      After the weight-reduction period, mean weight loss was 12.8 kg, and body fat was
      reduced on average by 10.9 kg. During weight maintenance, changes in body mass
      and body fat were not significant. Before weight reduction, mean ECW/ICW ratio
      was relatively high (0.78 +/- 0.10). During the the study, total body water and
      ICW did not change significantly. ECW did not change significantly after weight
      reduction, but 12 mo after the start ECW was significantly increased by 1 liter.
      The ECW/ICW ratio increased to 0.87 +/- 0.12 (month 12). The hydration of the FFM
      increased from 74 +/- 1 to 77 +/- 2% during the weight reduction and remained
      elevated during weight maintenance. In conclusion, the ECW/ICW ratio and the
      hydration of the FFM, did not normalize during weight reduction and weight
      maintenance.

PMID- 10409586
TI  - Training-induced elevation in FABP(PM) is associated with increased palmitate use
      in contracting muscle.
AB  - To evaluate the effects of endurance training in rats on fatty acid metabolism,
      we measured the uptake and oxidation of palmitate in isolated rat hindquarters as
      well as the content of fatty acid-binding proteins in the plasma membranes
      (FABP(PM)) of red and white muscles from 16 trained (T) and 18 untrained (UT)
      rats. Hindquarters were perfused with 6 mM glucose, 1,800 microM palmitate, and
      [1-(14)C]palmitate at rest and during electrical stimulation (ES) for 25 min.
      FABP(PM) content was 43-226% higher in red than in white muscles and was
      increased by 55% in red muscles after training. A positive correlation was found
      to exist between succinate dehydrogenase activity and FABP(PM) content in muscle.
      Palmitate uptake increased by 64-73% from rest to ES in both T and UT and was 48
      57% higher in T than UT both at rest (39.8 +/- 3.5 vs. 26.9 +/- 4. 4 nmol. min(
      1). g(-1), T and UT, respectively) and during ES (69.0 +/- 6.1 vs. 43.9 +/- 4.4
      nmol. min(-1). g(-1), T and UT, respectively). While the rats were resting,
      palmitate oxidation was not affected by training; palmitate oxidation during ES
      was higher in T than UT rats (14.8 +/- 1.3 vs. 9.3 +/- 1.9 nmol. min(-1). g(-1),
      T and UT, respectively). In conclusion, endurance training increases 1) plasma
      free fatty acid (FFA) uptake in resting and contracting perfused muscle, 2)
      plasma FFA oxidation in contracting perfused muscle, and 3) FABP(PM) content in
      red muscles. These results suggest that an increased number of these putative
      plasma membrane fatty acid transporters may be available in the trained muscle
      and may be implicated in the regulation of plasma FFA metabolism in skeletal
      muscle.

PMID- 10409588
TI  - ICAM-1 and CD11b inhibition worsen outcome in rats with E. coli pneumonia.
AB  - We investigated whether inhibiting an endothelial adhesion molecule
      [intracellular adhesion molecule 1 (ICAM-1)] would alter outcome and lung injury
      in a similar fashion to inhibition of a leukocyte adhesion molecule (integrin
      CD11b) in a rat model of gram-negative pneumonia. Inhibition of ICAM-1 with
      monoclonal antibody (MAb) 1A29 (1 mg/kg sc or 0.2 or 2 mg/kg iv, q 12 h x 3) or
      of CD11b with MAb 1B6 (1 mg/kg sc, q 12 h x 3) were compared against similarly
      administered placebo proteins in rats challenged with intrabronchial Escherichia
      coli. After challenge, all animals were treated with antibiotics. ICAM-1 MAb (6
      mg/kg, iv, total dose) increased mortality vs. control (P = 0.03). CD11b MAb (3
      mg/kg, sc, total dose) did not significantly (P = 0.16) increase mortality rates,
      but this was not in a range of probability to exclude a harmful effect. All other
      doses of MAb had no significant effect on survival rates. ICAM-1 and CD11b MAbs
      had significantly different effects on the time course of lung injury,
      circulating white cells and lymphocytes, and lung lavage white cells and
      neutrophils (P = 0.04-0.003). CD11b MAb decreased, whereas ICAM-1 MAb increased
      these measures compared with control from 6 to 12 h after E. coli. However, from
      144 to 168 h after E. coli both MAbs increased these measures compared with
      control rats but to a greater level with CD11b MAb. Thus both ICAM-1 and CD11b
      appear to be necessary for survival during E. coli pneumonia. Although these
      adhesion molecules may participate differently in early lung injury, with CD11b
      increasing and ICAM-1 decreasing inflammation and injury, both are important for
      the resolution of later injury. During gram-negative pneumonia the protective
      roles of ICAM-1 and CD11b may make their therapeutic inhibition difficult.

PMID- 10409589
TI  - Low doses of melatonin and diurnal effects on thermoregulation and tolerance to
      uncompensable heat stress.
AB  - This study examined whether the reported hypothermic effect of melatonin
      ingestion increased tolerance to exercise at 40 degrees C, for trials conducted
      either in the morning or afternoon, while subjects were wearing protective
      clothing. Nine men performed four randomly ordered trials; two each in the
      morning (0930) and afternoon (1330) after the double-blind ingestion of either
      two placebo capsules or two 1-mg capsules of melatonin. Despite significant
      elevations in plasma melatonin to over 1,000 ng/ml 1 h after the ingestion of the
      first 1-mg dose, rectal temperature (T(re)) was unchanged before or during the
      heat-stress exposure. Also, all other indexes of temperature regulation and the
      heart rate response during the uncompensable heat stress were unaffected by the
      ingestion of melatonin. Initial T(re) was increased during the afternoon (37.1 +/
      0.2 degrees C), compared with the morning (36.8 +/- 0.2 degrees C) exposures,
      and these differences remained throughout the uncompensable heat stress, such
      that final T(re) was also increased for the afternoon (39.2 +/- 0.2 degrees C)
      vs. the morning (39.0 +/- 0.3 degrees C) trials. Tolerance times and heat storage
      were not different among the exposures at approximately 110 min and 16 kJ/kg,
      respectively. It was concluded that this low dose of melatonin had no impact on
      tolerance to uncompensable heat stress and that trials conducted in the early
      afternoon were associated with an increased T(re) tolerated at exhaustion that
      offset the circadian influence on resting T(re) and thus maintained tolerance
      times similar to those of trials conducted in the morning.

PMID- 10409590
TI  - Increased training load and the beta-adrenergic-receptor system on human
      lymphocytes.
AB  - The influence of increased training on the sympathoadrenergic system was
      investigated. Moderately trained male subjects (n = 15) increased their training
      within 10 wk by 60%; eight of the subjects increased their training volume, and
      seven increased their training intensity. Before and after the training, an
      exhaustive treadmill exercise was carried out. Acute treadmill exercise increased
      beta-adrenergic receptor number on mononuclear lymphocytes, isoproternol
      stimulated cAMP production, and plasma catecholamine concentration. The increase
      of receptor number can at least partially be explained by a changed lymphocyte
      composition at rest and after exercise. After training, the exercise-induced
      increase of beta-adrenergic receptor number was significantly blunted, and the
      exercise-induced increase of the isoproternol-stimulated cAMP production per beta
      receptor was enhanced. Subjects who experienced increased symptoms of physical
      discomfort and/or mood changes showed an enhanced cAMP production after training.
      These findings point to an altered regulation of the receptor and postreceptor
      mechanisms as an effect of a 10-wk period of hard training.

PMID- 10409591
TI  - Cellular PO2 as a determinant of maximal mitochondrial O(2) consumption in
      trained human skeletal muscle.
AB  - Previously, by measuring myoglobin-associated PO(2) (P(Mb)O(2)) during maximal
      exercise, we have demonstrated that 1) intracellular PO(2) is 10-fold less than
      calculated mean capillary PO(2) and 2) intracellular PO(2) and maximum O(2)
      uptake (VO(2 max)) fall proportionately in hypoxia. To further elucidate this
      relationship, five trained subjects performed maximum knee-extensor exercise
      under conditions of normoxia (21% O(2)), hypoxia (12% O(2)), and hyperoxia (100%
      O(2)) in balanced order. Quadriceps O(2) uptake (VO(2)) was calculated from
      arterial and venous blood O(2) concentrations and thermodilution blood flow
      measurements. Magnetic resonance spectroscopy was used to determine myoglobin
      desaturation, and an O(2) half-saturation pressure of 3.2 Torr was used to
      calculate P(Mb)O(2) from saturation. Skeletal muscle VO(2 max) at 12, 21, and
      100% O(2) was 0.86 +/- 0.1, 1.08 +/- 0.2, and 1.28 +/- 0.2 ml. min(-1). ml(-1),
      respectively. The 100% O(2) values approached twice that previously reported in
      human skeletal muscle. P(Mb)O(2) values were 2.3 +/- 0.5, 3.0 +/- 0.7, and 4.1 +/
      0.7 Torr while the subjects breathed 12, 21, and 100% O(2), respectively. From
      12 to 21% O(2), VO(2) and P(Mb)O(2) were again proportionately related. However,
      100% O(2) increased VO(2 max) relatively less than P(Mb)O(2), suggesting an
      approach to maximal mitochondrial capacity with 100% O(2). These data 1) again
      demonstrate very low cytoplasmic PO(2) at VO(2 max), 2) are consistent with
      supply limitation of VO(2 max) of trained skeletal muscle, even in hyperoxia, and
      3) reveal a disproportionate increase in intracellular PO(2) in hyperoxia, which
      may be interpreted as evidence that, in trained skeletal muscle, very high
      mitochondrial metabolic limits to muscle VO(2) are being approached.

PMID- 10409592
TI  - Resetting of the carotid arterial baroreflex during dynamic exercise in humans.
AB  - Recent investigations have demonstrated that at the onset of low-to-moderate
      intensity leg cycling exercise (L) the carotid baroreflex (CBR) was classically
      reset in direct relation to the intensity of exercise. On the basis of these
      data, we proposed that the CBR would also be classically reset at the onset of
      moderate- to maximal-intensity L exercise. Therefore, CBR stimulus-response
      relationships were compared in seven male volunteers by using the neck pressure
      neck suction technique during dynamic exercise that ranged in intensity from 50
      to 100% of maximal oxygen uptake (VO(2 max)). L exercise alone was performed at
      50 and 75% VO(2 max), and L exercise combined with arm (A) exercise (L + A) was
      performed at 75 and 100% VO(2 max). O(2) consumption and heart rate (HR)
      increased in direct relation with the increases in exercise intensity. The
      threshold and saturation pressures of the carotid-cardiac reflex at 100% VO(2
      max) were >75% VO(2 max), which were in turn >50% VO(2 max) (P < 0.05), without a
      change in the maximal reflex gain (G(max)). In addition, the HR response value at
      threshold and saturation at 75% VO(2 max) was >50% VO(2 max) (P < 0.05) and 100%
      VO(2 max) was >75% VO(2 max) (P < 0.07). Similar changes were observed for the
      carotid-vasomotor reflex. In addition, as exercise intensity increased, the
      operating point (the prestimulus blood pressure) of the CBR was significantly
      relocated further from the centering point (G(max)) of the stimulus-response
      curve and was at threshold during 100% VO(2 max). These findings identify the
      continuous classic rightward and upward resetting of the CBR, without a change in
      G(max), during increases in dynamic exercise intensity to maximal effort.

PMID- 10409593
TI  - Carotid baroreflex function during prolonged exercise.
AB  - The present investigation was designed to uncouple the hemodynamic physiological
      effects of thermoregulation from the effects of a progressively increasing
      central command activation during prolonged exercise. Subjects performed two 1-h
      bouts of leg cycling exercise with 1) no intervention and 2) continuous infusion
      of a dextran solution to maintain central venous pressure constant at the 10-min
      pressure. Volume infusion resulted in a significant reduction in the decrement in
      mean arterial pressure seen in the control exercise bout (6.7 +/- 1.8 vs. 11.6+/-
      1.3 mmHg, respectively). However, indexes of central command such as heart rate
      and ratings of perceived exertion rose to a similar extent during both exercise
      conditions. In addition, the carotid-cardiac baroreflex stimulus-response
      relationship, as measured by using the neck pressure-neck suction technique, was
      reset from rest to 10 min of exercise and was further reset from 10 to 50 min of
      exercise in both exercise conditions, with the operating point being shifted
      toward the reflex threshold. We conclude that the progressive resetting of the
      carotid baroreflex and the shift of the reflex operating point render the carotid
      cardiac reflex ineffectual in counteracting the continued decrement in mean
      arterial pressure that occurs during the prolonged exercise.

PMID- 10409594
TI  - Blood lactate accumulation and muscle deoxygenation during incremental exercise.
AB  - Near-infrared spectroscopy (NIRS) could allow insights into controversial issues
      related to blood lactate concentration ([La](b)) increases at submaximal
      workloads (). We combined, on five well-trained subjects [mountain climbers; peak
      O(2) consumption (VO(2peak)), 51.0 +/- 4.2 (SD) ml. kg(-1). min(-1)] performing
      incremental exercise on a cycle ergometer (30 W added every 4 min up to voluntary
      exhaustion), measurements of pulmonary gas exchange and earlobe [La](b) with
      determinations of concentration changes of oxygenated Hb (Delta[O(2)Hb]) and
      deoxygenated Hb (Delta[HHb]) in the vastus lateralis muscle, by continuous-wave
      NIRS. A "point of inflection" of [La](b) vs. was arbitrarily identified at the
      lowest [La](b) value which was >0.5 mM lower than that obtained at the following.
      Total Hb volume (Delta[O(2)Hb + HHb]) in the muscle region of interest increased
      as a function of up to 60-65% of VO(2 peak), after which it remained unchanged.
      The oxygenation index (Delta[O(2)Hb - HHb]) showed an accelerated decrease from
      60- 65% of VO(2 peak). In the presence of a constant total Hb volume, the
      observed Delta[O(2)Hb - HHb] decrease indicates muscle deoxygenation (i.e.,
      mainly capillary-venular Hb desaturation). The onset of muscle deoxygenation was
      significantly correlated (r(2) = 0.95; P < 0.01) with the point of inflection of
      [La](b) vs., i.e., with the onset of blood lactate accumulation. Previous studies
      showed relatively constant femoral venous PO(2) levels at higher than
      approximately 60% of maximal O(2) consumption. Thus muscle deoxygenation observed
      in the present study from 60-65% of VO(2 peak) could be attributed to capillary
      venular Hb desaturation in the presence of relatively constant capillary-venular
      PO(2) levels, as a consequence of a rightward shift of the O(2)Hb dissociation
      curve determined by the onset of lactic acidosis.

PMID- 10409595
TI  - Differences in acute hypoxic pulmonary vasoresponsiveness between rat strains:
      role of endothelium.
AB  - Intact Madison (M) rats have greater pulmonary pressor responses to acute hypoxia
      than Hilltop (H) rats. We tested the hypothesis that the difference in pressor
      response is intrinsic to pulmonary arteries and that endothelium contributes to
      the difference. Pulmonary arteries precontracted with phenylephrine (10(-7) M)
      from M rats had greater constrictor responses [hypoxic pulmonary vasoconstriction
      (HPV)] to acute hypoxia (0% O(2)) than those from H rats: 473 +/- 30 vs. 394 +/-
      29 mg (P < 0.05). Removal of the endothelium or inhibition of nitric oxide (NO)
      synthase by N(omega)-nitro-L-arginine (L-NA, 10(-3) M) significantly blunted HPV
      in both strains. Inhibition of cyclooxygenase by meclofenamate (10(-5) M) or
      blockade of endothelin type A and B receptors by BQ-610 (10(-5) M) + BQ-788 (10(
      5) M), respectively, had no effect on HPV. Constrictor responses to
      phenylephrine, endothelin-1, and prostaglandin F(2alpha) were similar in
      pulmonary arteries from both strains. The relaxation response to ACh, an NO
      synthase stimulator, was significantly greater in M than in H rats (80 +/- 3 vs.
      62 +/- 4%, P < 0.01), but there was no difference in response to sodium
      nitroprusside, an NO donor. L-NA potentiated phenylephrine-induced contraction to
      a greater extent in pulmonary arteries from M than from H rats. These findings
      indicate that at least part of the strain-related difference in acute HPV is
      attributable to differences in endothelial function, possibly related to
      differences in NO production.

PMID- 10409596
TI  - Tyrosine kinase inhibitors modulate the ventilatory response to hypoxia in the
      conscious rat.
AB  - Tyrosine kinases (TKs) exert multiple regulatory roles in neuronal activity and
      synaptic plasticity and could be involved in modulation of cardiovascular and
      respiratory control mechanisms within the dorsocaudal brain stem. To study this
      issue, the cardioventilatory responses to 1-microl microinjection within the
      dorsocaudal brain stem of either vehicle (Veh), the inactive TK inhibitor analog
      tyrphostin A1 (A1; 1 mM), or the active TK inhibitors genistein (Gen; 10 mM) and
      tyrphostin A25 (A25; 1 mM) were assessed by whole body plethysmography in
      unrestrained Sprague-Dawley adult rats. No changes in minute ventilation, heart
      rate, or mean arterial pressure occurred with Veh, A1, Gen, or A25 during room
      air breathing (P not significant). However, Gen and A25 attenuated the peak
      hypoxic ventilatory responses (HVR) to 10% O(2) (P < 0.006 vs. Veh), whereas A1
      did not modify HVR (P not significant). HVR reductions by Gen and A25 were
      primarily due to diminished respiratory frequency enhancements (P < 0.002). No
      changes in heart rate or mean arterial pressure responses occurred during hypoxia
      with TK inhibition. In addition, increases in tyrosine phosphorylation of the
      NR2A/B subunits, but not of the NR2C subunit, of the N-methyl-D-aspartate
      receptor occurred at 5, 30, and 60 min of hypoxia in the dorsocaudal brain stem
      and returned to baseline values at 120 min. We conclude that hypoxia induces
      tyrosine phosphorylation of the N-methyl-D-aspartate glutamate receptor, and TK
      inhibition within the dorsocaudal brain stem attenuates components of HVR in
      conscious rats.

PMID- 10409597
TI  - Postnatal hemodynamic changes in very-low-birthweight infants.
AB  - The purpose of this study was to characterize postnatal changes in regional
      Doppler blood flow velocity (BFV) and cardiac function of very-low-birthweight
      infants and to examine factors that might influence these hemodynamic changes.
      Mean and end-diastolic BFV of the middle cerebral and superior mesenteric
      arteries, cardiac output, stroke volume, and fractional shortening were measured
      in 20 infants birthweight 1,002 +/- 173 g, gestational age 28 +/- 2 wk) at 6, 30,
      and 54 h after birth and before and after feedings on days 7 and 14. Postnatal
      increases in cerebral BFV, mesenteric BFV, and cardiac output were observed that
      were not associated with changes in blood pressure, hematocrit, pH, arterial
      PCO(2), or oxygen saturation. The postnatal pattern of relative vascular
      resistance (RVR) differed between the cerebral and mesenteric vasculatures. RVR
      decreased in the middle cerebral but not the superior mesenteric artery.
      Physiological patency of the ductus arteriosus did not alter postnatal
      hemodynamic changes. In response to feeding, mesenteric BFV and stroke volume
      increased, and mesenteric RVR and heart rate decreased. Postprandial responses
      were not affected by postnatal age or the age at which feeding was initiated.
      However, the initiation of enteral nutrition before 3 days of life was associated
      with higher preprandial mesenteric BFV and lower mesenteric RVR than was later
      initiation of feeding. We conclude that in very-low-birthweight infants over the
      first week of life 1) systemic, cerebral, and mesenteric hemodynamics exhibit
      region-specific changes; 2) asymptomatic ductus arteriosus patency and early
      feedings do not significantly influence these postnatal hemodynamic changes; and
      3) cardiac function adapts to increase local mesenteric BFV in response to
      feedings.

PMID- 10409598
TI  - Reflex control of cutaneous vasoconstrictor system is reset by exogenous female
      reproductive hormones.
AB  - To determine whether cardiovascular influences of exogenous female steroid
      hormones include effects on reflex thermoregulatory control of the adrenergic
      cutaneous vasoconstrictor system, we conducted ramp decreases in skin temperature
      (T(sk)) in eight women in both high- and low (placebo)-progesterone/estrogen
      phases of oral contraceptive use. With the use of water-perfused suits, T(sk) was
      held at 36 degrees C for 10 min (to minimize initial vasoconstrictor activity)
      and was then decreased in a ramp, approximately 0.2 degrees C/min for 12-15 min.
      Subjects rested supine for 30-40 min before each experiment, and the protocol was
      terminated before the onset of shivering. Skin blood flow was monitored by laser
      Doppler flowmetry and arterial pressure by finger photoplethysmography. In all
      experiments, cutaneous vasoconstriction began immediately with the onset of
      cooling, and cutaneous vascular conductance (CVC) decreased progressively with
      decreasing T(sk). Regression analysis of the relationship of CVC to T(sk) showed
      no difference in slope between phases (low-hormone phase: 17.67 +/- 5.57; high
      hormone phase: 17.40 +/- 8.00 %baseline/ degrees C; P > 0.05). Additional studies
      involving local blockade confirmed this response as being solely due to the
      adrenergic vasoconstrictor system. Waking oral temperature (T(or)) was
      significantly higher on high-hormone vs. low-hormone days (36.60 +/- 0.11 vs.
      36.37 +/- 0.09 degrees C, respectively; P < 0.02). Integrative analysis of CVC in
      terms of simultaneous values for T(sk) and T(or) showed that the cutaneous
      vasoconstrictor response was shifted in the high-hormone phase such that a higher
      T(or) was maintained throughout cooling (P < 0.05). Thus reflex thermoregulatory
      control of the cutaneous vasoconstrictor system is shifted to higher internal
      temperatures by exogenous female reproductive hormones.

PMID- 10409599
TI  - Intracellular Ca2+ transients in mouse soleus muscle after hindlimb unloading and
      reloading.
AB  - The objective of this study was to determine whether altered intracellular Ca(2+)
      handling contributes to the specific force loss in the soleus muscle after
      unloading and/or subsequent reloading of mouse hindlimbs. Three groups of female
      ICR mice were studied: 1) unloaded mice (n = 11) that were hindlimb suspended for
      14 days, 2) reloaded mice (n = 10) that were returned to their cages for 1 day
      after 14 days of hindlimb suspension, and 3) control mice (n = 10) that had
      normal cage activity. Maximum isometric tetanic force (P(o)) was determined in
      the soleus muscle from the left hindlimb, and resting free cytosolic Ca(2+)
      concentration ([Ca(2+)](i)), tetanic [Ca(2+)](i), and 4-chloro-m-cresol-induced
      [Ca(2+)](i) were measured in the contralateral soleus muscle by confocal laser
      scanning microscopy. Unloading and reloading increased resting [Ca(2+)](i) above
      control by 36% and 24%, respectively. Although unloading reduced P(o) and
      specific force by 58% and 24%, respectively, compared with control mice, there
      was no difference in tetanic [Ca(2+)](i). P(o), specific force, and tetanic
      [Ca(2+)](i) were reduced by 58%, 23%, and 23%, respectively, in the reloaded
      animals compared with control mice; however, tetanic [Ca(2+)](i) was not
      different between unloaded and reloaded mice. These data indicate that although
      hindlimb suspension results in disturbed intracellular Ca(2+) homeostasis,
      changes in tetanic [Ca(2+)](i) do not contribute to force deficits. Compared with
      unloading, 24 h of physiological reloading in the mouse do not result in further
      changes in maximal strength or tetanic [Ca(2+)](i).

PMID- 10409600
TI  - Appetite at "high altitude" [Operation Everest III (Comex-'97)]: a simulated
      ascent of Mount Everest.
AB  - We hypothesized that progressive loss of body mass during high-altitude sojourns
      is largely caused by decreased food intake, possibly due to hypobaric hypoxia.
      Therefore we assessed the effect of long-term hypobaric hypoxia per se on
      appetite in eight men who were exposed to a 31-day simulated stay at several
      altitudes up to the peak of Mt. Everest (8,848 m). Palatable food was provided ad
      libitum, and stresses such as cold exposure and exercise were avoided. At each
      altitude, body mass, energy, and macronutrient intake were measured; attitude
      toward eating and appetite profiles during and between meals were assessed by
      using questionnaires. Body mass reduction of an average of 5 +/- 2 kg was mainly
      due to a reduction in energy intake of 4.2 +/- 2 MJ/day (P < 0.01). At 5,000- and
      6,000-m altitudes, subjects had hardly any acute mountain sickness symptoms and
      meal size reductions (P < 0.01) were related to a more rapid increase in satiety
      (P < 0.01). Meal frequency was increased from 4 +/- 1 to 7 +/- 1 eating occasions
      per day (P < 0. 01). At 7,000 m, when acute mountain sickness symptoms were
      present, uncoupling between hunger and desire to eat occurred and prevented a
      food intake necessary to meet energy balance requirements. On recovery, body mass
      was restored up to 63% after 4 days; this suggests physiological fluid retention
      with the return to sea level. We conclude that exposure to hypobaric hypoxia per
      se appears to be associated with a change in the attitude toward eating and with
      a decreased appetite and food intake.

PMID- 10409602
TI  - Effect of I/E ratio on mean alveolar pressure during high-frequency oscillatory
      ventilation.
AB  - This study investigated factors contributing to differences between mean alveolar
      pressure (PA) and mean pressure at the airway opening (Pao) during high-frequency
      oscillatory ventilation (HFOV). The effect of the inspiratory-to-expiratory time
      (I/E) ratio and amplitude of oscillation on the magnitude of - Pao (Pdiff) was
      examined by using the alveolar capsule technique in normal rabbit lungs (n = 4)
      and an in vitro lung model. The effect of ventilator frequency and endotracheal
      tube (ETT) diameter on Pdiff was further examined in the in vitro lung model at
      an I/E ratio of 1:2. In both lung models, fell below Pao during HFOV when
      inspiratory time was shorter than expiratory time. Under these conditions,
      differences between inspiratory and expiratory flows, combined with the nonlinear
      relationship between resistive pressure drop and flow in the ETT, are the
      principal determinants of Pdiff. In our experiments, the magnitude of Pdiff at
      each combination of I/E, frequency, lung compliance, and ETT resistance could be
      predicted from the difference between the mean squared inspiratory and expiratory
      velocities in the ETT. These observations provide an explanation for the measured
      differences in mean pressure between the airway opening and the alveoli during
      HFOV and will assist in the development of optimal strategies for the clinical
      application of this technique.

PMID- 10409603
TI  - Surfactant effects in model airway closure experiments.
AB  - The capillary instability that occurs on an annular film lining a tube is studied
      as a model of airway closure. Small waves in the film can amplify and form a plug
      across the tube. This dynamical behavior is studied using theoretical models and
      bench-top experiments. Our model predicts the initial growth rate of the
      instability and its dependence on surfactant effects. In experiments, an annular
      film is formed by infusion of water into an initially oil-filled glass capillary
      tube. The thickness of the oil film varies with the infusion flow rate. The
      instability growth rate and closure time are measured for a range of film
      thicknesses. Our theory predicts that a thinner film and higher surfactant
      activity enhance stability; surfactant can decrease the growth rate to 25% of its
      surfactant-free value. In experiments, we find that surfactant can decrease the
      growth rate to 20% and increase the closure time by a factor of 3.8. Functional
      values of a critical film thickness for closure support the theory that it
      increases in the presence of surfactant.

PMID- 10409601
TI  - A technique to measure the ability of the human nose to warm and humidify air.
AB  - To assess the ability of the nose to warm and humidify inhaled air, we developed
      a nasopharyngeal probe and measured the temperature and humidity of air exiting
      the nasal cavity. We delivered cold, dry air (19-1 degrees C, <10% relative
      humidity) or hot, humid air (37 degrees C, >90% relative humidity) to the nose
      via a nasal mask at flow rates of 5, 10, and 20 l/min. We used a water gradient
      across the nose (water content in nasopharynx minus water content of delivered
      air) to assess nasal function. We studied the characteristics of nasal air
      conditioning in 22 asymptomatic, seasonally allergic subjects (out of their
      allergy season) and 11 nonallergic normal subjects. Inhalation of hot, humid air
      at increasingly higher flow rates had little effect on both the relative humidity
      and the temperature of air in the nasopharynx. In both groups, increasing the
      flow of cold, dry air lowered both the temperature and the water content of the
      inspired air measured in the nasopharynx, although the relative humidity remained
      at 100%. Water gradient values obtained during cold dry air challenges on
      separate days showed reproducibility in both allergic and nonallergic subjects.
      After exposure to cold, dry air, the water gradient was significantly lower in
      allergic than in nonallergic subjects (1,430 +/- 45 vs. 1,718 +/- 141 mg; P =
      0.02), suggesting an impairment in their ability to warm and humidify inhaled
      air.

PMID- 10409604
TI  - Physiological effects of alveolar, tracheal, and "standard" pressure supports.
AB  - Pressure support (PS) is characterized by a pressure plateau, which is usually
      generated at the ventilator level (PS(vent)). We have built a PS device in which
      the pressure plateau can be obtained at the upper airway level (PS(aw)) or at the
      alveolar level (PS(A)). The effect of these different PS modes was evaluated in
      seven healthy men during air breathing and 5% CO(2) breathing. Minute ventilation
      during air breathing was higher with PS(A) than with PS(aw) and lower with
      PS(vent) (16 +/- 3, 14 +/- 3, and 11 +/- 2 l/min, respectively). By contrast,
      there were no significant differences in minute ventilation during 5% CO(2)
      breathing (25 +/- 5, 27 +/- 7, and 23 +/- 5 l/min, respectively). The esophageal
      pressure-time product per minute was lower with PS(A) than with PS(aw) and
      PS(vent) during air breathing (29 +/- 26, 44 +/- 44, and 48 +/- 30 cmH(2)O. s,
      respectively) and 5% CO(2) breathing (97 +/- 40, 145 +/- 62, and 220 +/- 41
      cmH(2)O. s, respectively). In conclusion, during PS, moving the inspiratory
      pressure plateau from the ventilator to the alveolar level reduces pressure
      output, particularly at high ventilation levels.

PMID- 10409605
TI  - Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived
      oxidants in cystic fibrosis.
AB  - Cystic fibrosis (CF) is characterized by accumulation of activated neutrophils
      and macrophages on the respiratory epithelial surface (RES); these cells release
      toxic oxidants, which contribute to the marked epithelial derangements seen in
      CF. These deleterious consequences are magnified, since reduced glutathione
      (GSH), an antioxidant present in high concentrations in normal respiratory
      epithelial lining fluid (ELF), is deficient in CF ELF. To evaluate the
      feasibility of increasing ELF GSH levels and enhancing RES antioxidant
      protection, GSH aerosol was delivered (600 mg twice daily for 3 days) to seven
      patients with CF. ELF total, reduced, and oxidized GSH increased (P < 0.05, all
      compared with before GSH therapy), suggesting adequate RES delivery and
      utilization of GSH. Phorbol 12-myristate 13-acetate-stimulated superoxide anion
      (O2-.) release by ELF inflammatory cells decreased after GSH therapy (P < 0.002).
      This paralleled observations that GSH added in vitro to CF ELF inflammatory cells
      suppressed O2-. release (P < 0.001). No adverse effects were noted during
      treatment. Together, these observations demonstrate the feasibility of using GSH
      aerosol to restore RES oxidant-antioxidant balance in CF and support the
      rationale for further clinical evaluation.

PMID- 10409606
TI  - Monitoring respiratory function and sleep in the obese Vietnamese pot-bellied
      pig.
AB  - Development of drug treatments for obstructive sleep-disordered breathing has
      been impeded by the lack of animal models. The obese pig may be a suitable animal
      model, as it has been reported to experience sleep-disordered breathing
      resembling human obstructive sleep apnea. The purpose of this paper is to
      describe in detail techniques for chronic instrumentation of the obese Vietnamese
      pot-bellied pig and to study respiratory function during sleep. Under general
      anesthesia, four obese pigs were instrumented for long-term recording of
      intrapleural and tracheal pressures, genioglossal EMG, and bioelectric signals
      related to sleep. A custom-fitted face mask was used to record respiratory
      variables including airflow, snoring, and expired CO(2). Most chronic
      instrumentation provided robust signals for up to 6 wk after installation. All
      pigs displayed sleep-disordered breathing characterized by increased resistance
      to airflow, snoring, inspiratory flow limitation, and possible sleep disruption.
      Apneas and hypopneas were not a feature of breathing during sleep in these
      animals. Nonetheless, this animal preparation may be useful for exploring
      possible drug treatments for obstructive sleep-disordered breathing.

PMID- 10409607
TI  - Validity of the heart rate deflection point as a predictor of lactate threshold
      during running.
AB  - During an incremental run test, some researchers consistently observe a heart
      rate (HR) deflection at higher speeds, but others do not. The present study was
      designed to investigate whether differences in test protocols could explain the
      discrepancy. Additionally, we sought to determine whether the HR deflection point
      accurately predicts lactate threshold (LT). Eight trained runners performed four
      tests each: 1) a treadmill test for maximal O(2) uptake, 2) a Conconi test on a
      400-m track with speeds increasing approximately 0.5 km/h every 200 m, 3) a
      continuous treadmill run with speeds increasing 0.5 km/h every minute, and 4) a
      continuous LT treadmill test in which 3-min stages were used. All subjects
      demonstrated an HR deflection on the track, but only one-half of the subjects
      showed an HR deflection on the treadmill. On the track the shortening of stages
      with increasing speeds contributed to a loss of linearity in the speed-HR
      relationship. Additionally, the HR deflection point overestimated the LT when a
      continuous treadmill LT protocol was used. In conclusion, the HR deflection point
      was not an accurate predictor of LT in the present study.

PMID- 10409608
TI  - Microdialysis and the measurement of muscle interstitial K+ during rest and
      exercise in humans.
AB  - The purpose of this study was to examine whether microdialysis and the internal
      reference thallium-201 ((201)Tl) could accurately measure muscle interstitial K+
      (Ki+) before, during, and after exercise. The relative loss of (201)Tl and
      simultaneous relative recovery of K+ were measured in vitro for 12 microdialysis
      probes that were bathed in Ringer acetate medium and perfused at various flows (3
      10 microl/min). (201)Tl loss was linearly related to K+ recovery, and their level
      of agreement was not different from zero. Microdialysis and (201)Tl were then
      used to measure Ki+ in the gastrocnemius medialis muscle of four humans during
      rest and static plantar flexion exercise. At rest, Ki+ was 3.9-4.3 mmol/l when
      the perfusate flow was 2 or 5 microl/min. During exercise, Ki+ increased from 6.9
      +/- 0.4 to 7.5 +/- 0.3 mmol/l at low to high intensity and declined to 5.2 +/-
      0.3 mmol/l after exercise. These results suggest that large changes in Ki+ in
      human skeletal muscle can be accurately measured by using microdialysis and
      (201)Tl.

PMID- 10409609
TI  - Aging and acute exercise enhance free radical generation in rat skeletal muscle.
AB  - Reactive oxygen species (ROS) are implicated in the mechanism of biological aging
      and exercise-induced oxidative damage. The present study examined the effect of
      an acute bout of exercise on intracellular ROS production, lipid and protein
      peroxidation, and GSH status in the skeletal muscle of young adult (8 mo, n = 24)
      and old (24 mo, n = 24) female Fischer 344 rats. Young rats ran on a treadmill at
      25 m/min and 5% grade until exhaustion (55.4 +/- 2.7 min), whereas old rats ran
      at 15 m/min and 5% grade until exhaustion (58.0 +/- 2.7 min). Rate of
      dichlorofluorescin (DCFH) oxidation, an indication of ROS and other intracellular
      oxidants production in the homogenate of deep vastus lateralis, was 77% (P <
      0.01) higher in rested old vs. young rats. Exercise increased DCFH oxidation by
      38% (P < 0.09) and 50% (P < 0.01) in the young and old rats, respectively. DCFH
      oxidation in isolated deep vastus lateralis mitochondria with site 1 substrates
      was elevated by 57% (P < 0.01) in old vs. young rats but was unaltered with
      exercise. Significantly higher DCFH oxidation rate was also found in aged-muscle
      mitochondria (P < 0.01), but not in homogenates, when ADP, NADPH, and Fe(3+) were
      included in the assay medium without substrates. Lipid peroxidation in muscle
      measured by malondialdehyde content showed no age effect, but was increased by
      20% (P < 0.05) with exercise in both young and old rats. Muscle protein carbonyl
      formation was unaffected by either age or exercise. Mitochondrial GSH/ GSSG ratio
      was significantly higher in aged vs. young rats (P < 0.05), whereas exercise
      increased GSSG content and decreased GSH/GSSG in both age groups (P < 0.05).
      These data provided direct evidence that oxidant production in skeletal muscle is
      increased in old age and during prolonged exercise, with both mitochondrial
      respiratory chain and NADPH oxidase as potential sources. The alterations of
      muscle lipid peroxidation and mitochondrial GSH status were consistent with these
      conclusions.

PMID- 10409610
TI  - Proteolytic processing in the secretory pathway.

PMID- 10409611
TI  - Base substitution specificity of DNA polymerase beta depends on interactions in
      the DNA minor groove.
AB  - To examine the hypothesis that interactions between a DNA polymerase and the DNA
      minor groove are critical for accurate DNA synthesis, we studied the fidelity of
      DNA polymerase beta mutants at residue Arg(283), where arginine, which interacts
      with the minor groove at the active site, is replaced by alanine or lysine.
      Alanine substitution, removing minor groove interactions, strongly reduces
      polymerase selectivity for all single-base mispairs examined. In contrast, the
      lysine substitution, which retains significant interactions with the minor
      groove, has wild-type-like selectivity for T.dGMP and A.dGMP mispairs but reduced
      selectivity for T.dCMP and A.dCMP mispairs. Examination of DNA crystal structures
      of these four mispairs indicates that the two mispairs excluded by the lysine
      mutant have an atom (N2) in an unfavorable position in the minor groove, while
      the two mispairs permitted by the lysine mutant do not. These results suggest
      that unfavorable interactions between an active site amino acid side chain and
      mispair-specific atoms in the minor groove contribute to DNA polymerase
      specificity.

PMID- 10409612
TI  - Experimental observation of bonding electrons in proteins.
AB  - We demonstrate with two examples the success and potential of recent developments
      in x-ray protein crystallography at ultra high resolution. Our preliminary
      structural analyses using diffraction data collected for the two proteins crambin
      and savinase show meaningful deviations from the conventional independent
      spherical atom approximation. A noise-reduction averaging technique enables
      bonding details of electron distributions in proteins to be revealed
      experimentally for the first time. We move one step closer to imaging directly
      the fine details of the electronic structure on which the biological function of
      a protein is based.

PMID- 10409613
TI  - Interaction of 4,4'-dithiodipyridine with Cys(458) triggers disassembly of GroEL.
AB  - Chaperonin GroEL, consisting of two seven-subunit rings stacked back-to-back, is
      disassembled by interaction of 4, 4'-dithiodipyridine (DTP) with Cys(458) located
      close to the intersubunit contacts within and between the rings. The thiol group
      of Cys(458) is inaccessible to the probe being buried into the pocket locked by
      segment Asn(475)-Asn(487). Flexibility of this segment is proposed to induce the
      "open" state of the pocket and accommodate the bulky probe inside so that the
      consequential irreversible shifts in the pocket constituents disassemble GroEL.
      This scheme is supported by the finding that DTP-induced disassembly of GroEL is
      facilitated by ATP, which specifically stimulates a local shift of the segment
      Asn(475)-Asn(487) into solution.

PMID- 10409614
TI  - Functional interaction of DFF35 and DFF45 with caspase-activated DNA
      fragmentation nuclease DFF40.
AB  - DNA fragmentation factor (DFF) functions downstream of caspase-3 and directly
      triggers DNA fragmentation during apoptosis. Here we described the identification
      and characterization of DFF35, an isoform of DFF45 comprised of 268 amino acids.
      Functional assays have shown that only DFF45, not DFF35, can assist in the
      synthesis of highly active DFF40. Using the deletion mutants, we mapped the
      function domains of DFF35/45 and demonstrated that the intact
      structure/conformation of DFF45 is essential for it to function as a chaperone
      and assist in the synthesis of active DFF40. Whereas the amino acid residues 101
      180 of DFF35/45 mediate its binding to DFF40, the amino acid residues 23-100,
      which is homologous between DFF35/45 and DFF40, may function to inhibit the
      activity of DFF40. In contrast to DFF45, DFF35 cannot work as a chaperone, but it
      can bind to DFF40 more strongly than DFF45 and can inhibit its nuclease activity.
      These findings suggest that DFF35 may function in vivo as an important
      alternative mechanism to inhibit the activity of DFF40 and further, that the
      inhibitory effects of both DFF35 and DFF45 on DFF40 can put the death machinery
      under strict control.

PMID- 10409615
TI  - Sphingolipid depletion increases formation of the scrapie prion protein in
      neuroblastoma cells infected with prions.
AB  - Sphingolipid-rich rafts play an essential role in the posttranslational
      (Borchelt, D. R., Scott, M., Taraboulos, A., Stahl, N., and Prusiner, S. B.
      (1990) J. Cell Biol. 110, 743-752)) formation of the scrapie prion protein
      PrP(Sc) from its normal conformer PrP(C) (Taraboulos, A., Scott, M., Semenov, A.,
      Avrahami, D., Laszlo, L., Prusiner, S. B., and Avraham, D. (1995) J. Cell Biol.
      129, 121-132). We investigated the importance of sphingolipids in the metabolism
      of the PrP isoforms in scrapie-infected ScN2a cells. The ceramide synthase
      inhibitor fumonisin B(1) (FB(1)) reduced both sphingomyelin (SM) and ganglioside
      GM1 in cells by up to 50%, whereas PrP(Sc) increased by 3-4-fold. Whereas FB(1)
      profoundly altered the cell lipid composition, the raft residents PrP(C),
      PrP(Sc), caveolin 1, and GM1 remained insoluble in Triton X-100. Metabolic
      radiolabeling demonstrated that PrP(C) production was either unchanged or
      slightly reduced in FB(1)-treated cells, whereas PrP(Sc) formation was augmented
      by 3-4-fold. To identify the sphingolipid species the decrease of which
      correlates with increased PrP(Sc), we used two other reagents. When cells were
      incubated with sphingomyelinase for 3 days, SM levels decreased, GM1 was
      unaltered, and PrP(Sc) increased by 3-4-fold. In contrast, the glycosphingolipid
      inhibitor PDMP reduced PrP(Sc) while increasing SM. Thus, PrP(Sc) seems to
      correlate inversely with SM levels. The effects of SM depletion contrasted with
      those previously obtained with the cholesterol inhibitor lovastatin, which
      reduced PrP(Sc) and removed it from detergent-insoluble complexes.

PMID- 10409616
TI  - Oxygen exchange between acetate and the catalytic glutamate residue in
      glutaconate CoA-transferase from Acidaminococcus fermentans. Implications for the
      mechanism of CoA-ester hydrolysis.
AB  - The exchange of oxygen atoms between acetate, glutaryl-CoA, and the catalytic
      glutamate residue in glutaconate CoA-transferase from Acidaminococcus fermentans
      was analyzed using [(18)O(2)]acetate together with matrix-assisted laser
      desorption/ionization time of flight mass spectrometry of an appropriate
      undecapeptide. The exchange reaction was shown to be site-specific, reversible,
      and required both glutaryl-CoA and [(18)O(2)]acetate. The observed exchange is in
      agreement with the formation of a mixed anhydride intermediate between the enzyme
      and acetate. In contrast, with a mutant enzyme, which was converted to a thiol
      ester hydrolyase by replacement of the catalytic glutamate residue by aspartate,
      no (18)O uptake from H(2)(18)O into the carboxylate was detectable. This result
      is in accord with a mechanism in which the carboxylate of aspartate acts as a
      general base in activating a water molecule for hydrolysis of the thiol ester
      intermediate. This mechanism is further supported by the finding of a significant
      hydrolyase activity of the wild-type enzyme using acetyl-CoA as substrate,
      whereas glutaryl-CoA is not hydrolyzed. The small acetate molecule in the
      substrate binding pocket may activate a water molecule for hydrolysis of the
      nearby enzyme-CoA thiol ester.

PMID- 10409617
TI  - Are the states that occlude rubidium obligatory intermediates of the Na(+)/K(+)
      ATPase reaction?
AB  - In the Albers-Post model, occlusion of K(+) in the E(2) conformer of the enzyme
      (E) is an obligatory step of Na(+)/K(+)-ATPase reaction. If this were so the
      ratio (Na(+)/K(+)-ATPase activity)/(concentration of occluded species) should be
      equal to the rate constant for deocclusion. We tested this prediction in a
      partially purified Na(+)/K(+)-ATPase from pig kidney by means of rapid filtration
      to measure the occlusion using the K(+) congener Rb(+). Assuming that always two
      Rb(+) are occluded per enzyme, the steady-state levels of occluded forms and the
      kinetics of deocclusion were adequately described by the Albers-Post model over a
      very wide range of [ATP] and [Rb(+)]. The same happened with the kinetics of ATP
      hydrolysis. However, the value of the parameters that gave best fit differed from
      those for occlusion in such a way that the ratio (Na(+)/K(+)-ATPase
      activity)/(concentration of occluded species) became much larger than the rate
      constant for deocclusion when [Rb(+)] <10 mM. This points to the presence of an
      extra ATP hydrolysis that is not Na(+)-ATPase activity and that does not involve
      occlusion. A possible way of explaining this is to posit that the binding of a
      single Rb(+) increases ATP hydrolysis without occlusion.

PMID- 10409618
TI  - Insulin receptor substrate-2 is not necessary for insulin- and exercise
      stimulated glucose transport in skeletal muscle.
AB  - Insulin receptor substrate-2-deficient (IRS2(-/-)) mice develop type 2 diabetes.
      The purpose of this study was to determine whether there is a defect in basal,
      insulin-, and exercise-stimulated glucose transport in the skeletal muscle of
      these animals. IRS2(-/-) and wild-type (WT) mice (male, 8-10 weeks) exercised on
      a treadmill for 1 h or remained sedentary. 2-Deoxyglucose (2DG) uptake was
      measured in isolated soleus muscles incubated in vitro in the presence or absence
      of insulin. Resting blood glucose concentration in IRS2(-/-) mice (10.3 mM) was
      higher than WT animals (4.1 mM), but there was a wide range among the IRS2(-/-)
      mice (3-25 mM). Therefore, IRS2(-/-) mice were divided into two subgroups based
      on blood glucose concentrations (IRS2(-/-)L < 7.2 mM, IRS2(-/-)H > 7.2 mM). Only
      IRS2(-/-)H had lower basal, exercise-, and submaximally insulin-stimulated 2DG
      uptake, while maximal insulin-stimulated 2DG uptake was similar among the three
      groups. The ED(50) for insulin to stimulate 2DG uptake above basal in IRS2(-/-)H
      was higher than WT and IRS2(-/-)L mice, suggesting insulin resistance in the
      skeletal muscle from the IRS2(-/-) mice with high blood glucose concentrations.
      Furthermore, resting blood glucose concentrations from all groups were negatively
      correlated to submaximally insulin-stimulated 2DG uptake (r(2) = 0.33, p < 0.01).
      Muscle GLUT4 content was significantly lower in IRS2(-/-)H mice compared with WT
      and IRS2(-/-)L mice. These results demonstrate that the IRS2 protein in muscle is
      not necessary for insulin- or exercise-stimulated glucose transport, suggesting
      that the onset of diabetes in the IRS2(-/-) mice is not due to a defect in
      skeletal muscle glucose transport; hyperglycemia may cause insulin resistance in
      the muscle of IRS2(-/-) mice.

PMID- 10409619
TI  - Structure and mechanism of formation of human lens fluorophore LM-1. Relationship
      to vesperlysine A and the advanced Maillard reaction in aging, diabetes, and
      cataractogenesis.
AB  - Human lens crystallins become progressively yellow-brown pigmented with age. Both
      fluorescent and non-fluorescent protein adducts and cross-links are formed, many
      of which result from the advanced Maillard reaction. One of them, LM-1, is a blue
      fluorophore that was earlier tentatively identified as a cross-link involving
      lysine residues (1). A two-step chromatographic system was used to unequivocally
      identify and quantitatively prepare a synthetic fluorescent cross-link with
      lysine residues that had identical UV, fluorescent, and chromatographic
      properties with both acetylated and non-acetylated LM-1. Proton, (13)C NMR, and
      molecular mass of the synthetic compound were identical with vesperlysine A, a
      fluorescent cross-link discovered by Nakamura et al. (2). The fragmentation
      patterns of vesperlysine A and LM-1 were identical as determined by NMR/mass
      spectrometry. Lenticular levels of vesperlysine A increase curvilinearly with age
      and reach 20 pmol/mg at 90 years. Levels correlate with degree of lens crystallin
      pigmentation and fluorescence and are increased in diabetes, in contrast to
      N(epsilon)-(carboxymethyl)lysine and pentosidine. Ascorbate, D-pentoses, and D
      threose, but neither D-glucose under oxidative conditions, DL-glyceraldehyde,
      methylglyoxal, glyoxal, nor glycolaldehyde, are precursors. However, addition of
      C-2 compounds greatly catalyzes vesperlysine A formation from ribose. Thus,
      vesperlysine A/LM-1 is a novel product of the advanced Maillard reaction in vivo
      and a specific marker of a diabetic process in the lens that is different from
      glyco- and lipoxidation.

PMID- 10409620
TI  - Protein kinase Cdelta inhibition of S-phase transition in capillary endothelial
      cells involves the cyclin-dependent kinase inhibitor p27(Kip1).
AB  - Distinct protein kinase C (PKC) isoforms differentially regulate cellular
      proliferation in rat microvascular endothelial cells (EC). Overexpression of
      PKCalpha has little effect on proliferation, whereas PKCdelta slows endothelial
      cell proliferation and induces S-phase arrest. Analyses were performed on EC
      overexpressing PKCalpha (PKCalphaEC) or PKCdelta (PKCdeltaEC) to determine the
      role of specific cell cycle regulatory proteins in the PKCdelta-induced cell
      cycle arrest. Serum-induced stimulation of cyclins D1, E, and A-associated kinase
      activity was delayed by 12 h in the PKCdeltaEC line in association with S-phase
      arrest. However, the protein levels for cyclins D1, E, and A were similar.
      Nuclear accumulation of cyclin D1 protein in response to serum was also delayed
      in PKCdeltaEC. In the PKCdeltaEC line, serum induced p27(Kip1) but not p16(Ink4a)
      or p21(Cip1). Serum did not affect p27(Kip1) levels in the control vascular
      endothelial cell line. Immunoprecipitation-Western blotting analysis of p27(Kip1)
      showed serum stimulation of the vascular endothelial cell line resulted in
      increased amounts of cyclin D1 bound to p27(Kip1). In the PKCdeltaEC line, serum
      did not increase the amount of cyclin D1 bound to p27(Kip1). Transfection of full
      length p27(Kip1) antisense into the PCKdeltaEC line reversed the S-phase arrest
      and resulted in normal cell cycle progression, suggesting a critical role for
      p27(Kip1) in the PKCdelta-mediated S-phase arrest.

PMID- 10409621
TI  - Interaction of syntaxins with the amiloride-sensitive epithelial sodium channel.
AB  - Amiloride-sensitive sodium channels mediate sodium entry across the apical
      membrane of epithelial cells in variety of tissues. The rate of Na(+) entry is
      controlled by the regulation of the epithelial sodium channel (ENaC) complex.
      Insertion/retrieval of the ENaC complex into the apical membrane as well as
      direct kinetic effects at the single channel level are recognized mechanisms of
      regulation. Recent data suggest that the syntaxin family of targeting proteins
      interact with and functionally regulate a number of ion channels and pumps. To
      evaluate the role of these proteins in regulating ENaC activity, we co-expressed
      rat ENaC cRNA (alpha, beta, gamma subunits) with syntaxin 1A or 3 cRNAs in
      Xenopus oocytes. Basal ENaC currents were inhibited by syntaxin 1A and stimulated
      by syntaxin 3. Both syntaxin 1A and syntaxin 3 could be co-immunoprecipitated
      with ENaC subunit proteins, suggesting physical interaction. Interestingly,
      immunofluorescence data suggest that with either syntaxin isoform the ENaC
      associated epifluorescence on the oocyte surface is enhanced. These data indicate
      that (i) both syntaxin isoforms increase the net externalization of the ENaC
      channel complex, (ii) that the functional regulation is isoform specific, and
      (iii) suggest that ENaC may be regulated through mechanisms involving protein
      protein interactions.

PMID- 10409622
TI  - Characterization of the cytoplasmic domain of interleukin-13 receptor-alpha.
AB  - Interleukin (IL)-13 and IL-4 are pleiotropic immunoregulatory cytokines that
      share many overlapping biological properties reflecting the fact that both can
      utilize a receptor complex composed of the IL-4 receptor-alpha (IL-4Ralpha) chain
      and the IL-13Ralpha chain. The cytoplasmic domain of the IL-13Ralpha is 60 amino
      acids long and is essential for IL-13-dependent growth. It contains a Pro-rich
      domain in the membrane-proximal region and two Tyr residues. Here we show that a
      truncated IL-13Ralpha, lacking the 38 carboxyl-terminal residues but retaining
      the Pro-rich region, can support IL-13-dependent proliferation, although with
      reduced efficiency. A Y402F mutant of the cytoplasmic domain of IL-13Ralpha
      supported normal IL-13-induced growth. However, tyrosine phosphorylation of
      signal transducer and activator of transcription 3 (STAT3), which we show is
      induced by IL-13 and IL-4 in cells that express the IL-13Ralpha, was
      significantly reduced. The cytoplasmic domain of IL-13Ralpha was constitutively
      associated with STAT3, Tyk2, and Janus kinase 1 (JAK1). IL-13-induced tyrosine
      phosphorylation of IL-13Ralpha in vivo could not be detected using anti-Tyr(P)
      antibodies. A glutathione S-transferase fusion protein of the cytoplasmic domain
      of IL-13Ralpha was phosphorylated on tyrosine in vitro by JAK1, JAK3, and Tyk2,
      although the tyrosine phosphorylation events mediated by Tyk2 and JAK3 were not
      detectable using anti-phosphotyrosine antibodies. These data, together with the
      demonstration that IL-13Ralpha associates constitutively with Tyk2 and that Tyr
      402 is involved in IL-13-induced phosphorylation of STAT3, suggest that the
      latter is mediated by Tyk2. Tyrosine phosphorylation of STAT3, which was not
      necessary for IL-13-induced proliferation, may account for some of the effects of
      IL-4 and IL-13 on the function of their targets.

PMID- 10409623
TI  - Molecular cloning of transferrin receptor 2. A new member of the transferrin
      receptor-like family.
AB  - Transferrin receptor (TfR) plays a major role in cellular iron uptake through
      binding and internalizing a carrier protein transferrin (Tf). We have cloned,
      sequenced, and mapped a human gene homologous to TfR, termed TfR2. Two
      transcripts were expressed from this gene: alpha (approximately 2.9 kilobase
      pairs), and beta (approximately 2.5 kilobase pairs). The predicted amino acid
      sequence revealed that the TfR2-alpha protein was a type II membrane protein and
      shared a 45% identity and 66% similarity in its extracellular domain with TfR.
      The TfR2-beta protein lacked the amino-terminal portion of the TfR2-alpha protein
      including the putative transmembrane domain. Northern blot analysis showed that
      the alpha transcript was predominantly expressed in the liver. In addition, high
      expression occurred in K562, an erythromegakaryocytic cell line. To analyze the
      function of TfR2, Chinese hamster ovary TfR-deficient cells (CHO-TRVb cells) were
      stably transfected with FLAG-tagged TfR2-alpha. These cells showed an increase in
      biotinylated Tf binding to the cell surface, which was competed by nonlabeled Tf,
      but not by lactoferrin. Also, these cells had a marked increase in Tf-bound
      (55)Fe uptake. Taken together, TfR2-alpha may be a second transferrin receptor
      that can mediate cellular iron transport.

PMID- 10409624
TI  - 2'-Deoxycytidine glycols, a missing link in the free radical-mediated oxidation
      of DNA.
AB  - 2'-Deoxycytidine glycols (5,6-dihydroxy-5, 6-dihydro-2'-deoxycytidine) are major
      products of the hydroxyl radical-induced oxidation of 2'-deoxycytidine resulting
      from either a Fenton reaction or exposure to ionizing radiation. Because of their
      instability, however, the glycols have not previously been characterized.
      Instead, the impetus has been placed on the primary decomposition products of 2'
      deoxycytidine glycols, which includes 5-hydroxy-2'-deoxycytidine, 5-hydroxy-2'
      deoxyuridine, and 2'-deoxyuridine glycols. Here, we have identified one of the
      four possible diastereomers of 2'-deoxycytidine glycols by product analyses of
      decomposition products, (1)H NMR, and mass spectrometry. This glycol was observed
      to decompose with a half-life of 50 min at 37 degrees C in buffered neutral
      solutions and preferentially undergo dehydration to 5-hydroxy-2'-deoxycytidine.
      The rate of decomposition was strongly dependent on pH (2-10) and the
      concentration of phosphate ion (10-300 mM). Next, we report on the deamination of
      cytosine glycols to uracil glycols in oxidized DNA using acid hydrolysis and high
      performance liquid chromatography analysis with electrochemical detection to
      monitor 5-hydroxycytosine and 5-hydroxyuracil. The results showed that the
      lifetime of cytosine glycols is greatly enhanced in DNA (34-fold; half-life, 28
      h), and that deamination accounts for at least one-third of the total
      decomposition. The relatively long lifetime of cytosine glycols in DNA suggests
      that this important class of DNA oxidation products will be significantly
      involved in repair and mutagenesis processes.

PMID- 10409625
TI  - Different membrane anchoring positions of tryptophan and lysine in synthetic
      transmembrane alpha-helical peptides.
AB  - Specific interactions of membrane proteins with the membrane interfacial region
      potentially define protein position with respect to the lipid environment. We
      investigated the proposed roles of tryptophan and lysine side chains as
      "anchoring" residues of transmembrane proteins. Model systems were employed,
      consisting of phosphatidylcholine lipids and hydrophobic alpha-helical peptides,
      flanked either by tryptophans or lysines. Peptides were incorporated in bilayers
      of different thickness, and effects on lipid structure were analyzed. Induction
      of nonbilayer phases and also increases in bilayer thickness were observed that
      could be explained by a tendency of Trp as well as Lys residues to maintain
      interactions with the interfacial region. However, effects of the two peptides
      were remarkably different, indicating affinities of Trp and Lys for different
      sites at the interface. Our data support a model in which the Trp side chain has
      a specific affinity for a well defined site near the lipid carbonyl region, while
      the lysine side chain prefers to be located closer to the aqueous phase, near the
      lipid phosphate group. The information obtained in this study may further our
      understanding of the architecture of transmembrane proteins and may prove useful
      for refining prediction methods for transmembrane segments.

PMID- 10409626
TI  - Identification of glutathionyl-3-hydroxykynurenine glucoside as a novel
      fluorophore associated with aging of the human lens.
AB  - A novel fluorophore was isolated from human lenses using high performance liquid
      chromatography (HPLC). The new fluorophore was well separated from 3
      hydroxykynurenine glucoside (3-OHKG) and its deaminated isoform, 4-(2-amino-3
      hydroxyphenyl)-4-oxobutanoic acid O-glucoside, which are known UV filter
      compounds. The new compound exhibited UV absorbance maxima at 260 and 365 nm, was
      fluorescent (Ex(360 nm)/Em(500 nm)), and increased in concentration with age.
      Further analysis of the purified compound by microbore HPLC with in-line
      electrospray ionization mass spectrometry revealed a molecular mass of 676 Da.
      This mass corresponds to that of an adduct of GSH with a deaminated form of 3
      OHKG. This adduct was synthesized using 3-OHKG and GSH as starting materials. The
      synthetic glutathionyl-3-hydroxykynurenine glucoside (GSH-3-OHKG) adduct had the
      same HPLC elution time, thin-layer chromatography R(F) value, UV absorbance
      maxima, fluorescence characteristics, and mass spectrum as the lens-derived
      fluorophore. Furthermore, the (1)H and (13)C NMR spectra of the synthetic adduct
      were entirely consistent with the proposed structure of GSH-3-OHKG. These data
      indicate that GSH-3-OHKG is present as a novel fluorophore in aged human lenses.
      The GSH-3-OHKG adduct was found to be less reactive with beta-glucosidase
      compared with 3-OHKG, and this could be due to a folded conformation of the
      adduct that was suggested by molecular modeling.

PMID- 10409627
TI  - Regulation of apoptotic protease activating factor-1 oligomerization and
      apoptosis by the WD-40 repeat region.
AB  - Apoptotic protease activating factor-1 (Apaf-1) has been identified as a proximal
      activator of caspase-9 in cell death pathways that trigger mitochondrial damage
      and cytochrome c release. The mechanism of Apaf-1 action is unclear but has been
      proposed to involve the clustering of caspase-9 molecules, thereby facilitating
      autoprocessing of adjacent zymogens. Here we show that Apaf-1 can dimerize via
      the CED-4 homologous and linker domains of the molecule providing a means by
      which Apaf-1 can promote the clustering of caspase-9 and facilitate its
      activation. Apaf-1 dimerization was repressed by the C-terminal half of the
      molecule, which contains multiple WD-40 repeats, but this repression was overcome
      in the presence of cytochrome c and dATP. Removal of the WD-40 repeat region
      resulted in a constitutively active Apaf-1 that exhibited greater cytotoxicity in
      transient transfection assays when compared with full-length Apaf-1. These data
      suggest a mechanism for Apaf-1 function and reveal an important regulatory role
      for the WD-40 repeat region.

PMID- 10409628
TI  - Analysis of the role of glutamine 190 in the catalytic mechanism of murine
      leukemia virus reverse transcriptase.
AB  - To determine the catalytic role of Gln(190), a member of the highly conserved
      LPQG motif in Moloney murine leukemia virus reverse transcriptase, we carried out
      site-directed mutagenesis of this residue to generate Q190N and Q190A. Both
      mutant proteins exhibited a significant loss in their polymerase and
      pyrophosphorolysis activities with a more pronounced effect noted with the Gln -
      > Asn substitution. The catalytic efficiencies of the mutants exhibited a 40-70
      fold reduction with poly(rC) and poly(dC) templates in the presence of Mg(2+) and
      a 10-20-fold reduction with poly(rA) template in the presence of Mn(2+).
      Interestingly, the K(m) for NTP exhibited only a moderate 3-10-fold increase
      irrespective of the template-primer and the metal ion. Photoaffinity labeling of
      both the mutant and the WT enzymes exhibited an identical affinity for RNA.DNA
      and DNA.DNA template-primers. However, unlike the WT enzyme, the mutant enzymes
      exhibited a significantly reduced ability to catalyze the nucleotidyltransferase
      reaction on the covalently immobilized template-primer. An examination of the
      rate constants for the first and the second nucleotide for the mutant enzymes
      indicated dissimilar rates, indicating that Gln(190) may be involved in a rate
      limiting, conformational change step both before and after the phosphodiester
      bond formation. Furthermore, the processivity of DNA synthesis by the mutant
      enzymes was decreased severely, which may result from the lower catalytic
      efficiency as well as translocation defect.

PMID- 10409629
TI  - Activation of the promoter of the orphan receptor SHP by orphan receptors that
      bind DNA as monomers.
AB  - Small heterodimer partner (SHP) is an orphan nuclear receptor that lacks a
      conventional DNA binding domain. It interacts with several other members of the
      nuclear receptor superfamily and inhibits receptor transactivation. In order to
      characterize the regulation of SHP expression, a number of receptors and other
      transcription factors were tested for effects on the SHP promoter. Among these,
      the orphan receptor steroidogenic factor-1 (SF-1) was found to potently
      transactivate the SHP promoter. Detailed footprinting studies show that the SHP
      promoter contains at least five SF-1 binding sites, and mutagenesis studies
      demonstrate each of the three strongest binding sites is required for SF-1
      transactivation. SHP is coexpressed with SF-1 in adrenal glands, but is also
      expressed in tissues that lack SF-1, including liver. However, liver expresses a
      close relative of SF-1, the orphan fetoprotein transcription factor (FTF), and
      FTF can also transactivate the SHP promoter. These results suggest that
      alterations in the levels or activities of SF-1 or FTF could modulate SHP
      expression in appropriate tissues and thereby affect a variety of receptor
      dependent signaling pathways.

PMID- 10409630
TI  - A vitamin D analog regulates mesangial cell smooth muscle phenotypes in a
      transforming growth factor-beta type II receptor-mediated manner.
AB  - Mesangial cells share features with contractile smooth muscle cells and
      mechanically support the capillary wall. The role of vitamin D compounds and the
      transforming growth factor-beta (TGF-beta) type II receptor in modulating the
      smooth muscle phenotype of cultured mesangial cells was examined. Cell
      proliferation was significantly inhibited by the vitamin D analog 22-oxa-1,25
      dihydroxyvitamin D(3) (22-oxacalcitriol; OCT) rather than by 1,25
      dihydroxyvitamin D(3) (1, 25(OH)(2)D(3)) in a dose-dependent manner. OCT-treated
      early passage mesangial cells (MC-E cells) had increased expression levels of
      type IV collagen and smooth muscle alpha actin mRNA, but 1, 25(OH)(2)D(3)-treated
      MC-E cells did not. The addition of a TGF-beta(1)-neutralizing antibody to the
      OCT-treated MC-E cells blocked this inhibitory effect for cell proliferation and
      attenuated the up-regulated mRNA levels. However, after exposure to 1,
      25(OH)(2)D(3) or OCT, there was no significant difference in the secretion of
      active TGF-beta. We next investigated whether TGF-beta type II receptor (RII) was
      involved in this regulation. OCT treatment significantly increased the expression
      of the RII mRNA in MC-E cells. These results suggest that the vitamin D analog
      OCT induces smooth muscle phenotypic alterations and that this phenomenon was
      mediated through the induction of RII in cultured mesangial cells.

PMID- 10409631
TI  - Memory and imprinting in multienzyme complexes. Evidence for information transfer
      from glyceraldehyde-3-phosphate dehydrogenase to phosphoribulokinase under
      reduced state in Chlamydomonas reinhardtii.
AB  - The phosphoribulokinase, when it is in a reduced state in a bi-enzyme complex, is
      more active than when it is oxidized. This complex dissociates upon dilution to
      give a metastable reduced form of phosphoribulokinase, which differs from the
      stable form isolated beside the complex. The kinetic parameters of the reduced
      stable phosphoribulokinase and those of the complex are very similar, unlike
      those of the metastable form. Although the kinetic mechanism of the reduced
      stable form is ordered, with ribulose-5-phosphate binding first, ATP binds first
      to the phosphoribulokinase in the complex and to the metastable form. Therefore,
      phosphoribulokinase bears an imprint from glyceraldehyde-3-phosphate
      dehydrogenase after disruption of the complex. Dissociation of
      phosphoribulokinase from the complex also enhances its flexibility. The
      imprinting and greater flexibility result in the catalytic constant of
      dissociated phosphoribulokinase being 10-fold higher than that of the enzyme in
      the complex. Imprinting corresponds to stabilization-destabilization energies
      resulting from conformation changes generated by protein-protein interactions.
      The energy stored within the metastable phosphoribulokinase is mainly used to
      decrease the energy barrier to catalysis.

PMID- 10409632
TI  - Ret-dependent and -independent mechanisms of glial cell line-derived neurotrophic
      factor signaling in neuronal cells.
AB  - Glial cell line-derived neurotrophic factor (GDNF) has been shown to signal
      through a multicomponent receptor complex consisting of the Ret receptor tyrosine
      kinase and a member of the GFRalpha family of glycosylphosphatidylinositol
      anchored receptors. In the current model of GDNF signaling, Ret delivers the
      intracellular signal but cannot bind ligand on its own, while GFRalphas bind
      ligand but are thought not to signal in the absence of Ret. We have compared
      signaling pathways activated by GDNF in two neuronal cell lines expressing
      different complements of GDNF receptors. In a motorneuron-derived cell line
      expressing Ret and GFRalphas, GDNF stimulated sustained activation of the Ras/ERK
      and phosphatidylinositol 3-kinase/Akt pathways, cAMP response element-binding
      protein phosphorylation, and increased c-fos expression. Unexpectedly, GDNF also
      promoted biochemical and biological responses in a line of conditionally
      immortalized neuronal precursors that express high levels of GFRalphas but not
      Ret. GDNF treatment did not activate the Ras/ERK pathway in these cells, but
      stimulated a GFRalpha1-associated Src-like kinase activity in detergent-insoluble
      membrane compartments, rapid phosphorylation of cAMP response element-binding
      protein, up-regulation of c-fos mRNA, and cell survival. Together, these results
      offer new insights into the dynamics of GDNF signaling in neuronal cells, and
      indicate the existence of novel signaling mechanisms directly or indirectly
      mediated by GFRalpha receptors acting in a cell-autonomous manner independently
      of Ret.

PMID- 10409634
TI  - Fibroblast growth factor receptors participate in the control of mitogen
      activated protein kinase activity during nerve growth factor-induced neuronal
      differentiation of PC12 cells.
AB  - The current paradigm for the role of nerve growth factor (NGF) or FGF-2 in the
      differentiation of neuronal cells implies their binding to specific receptors and
      activation of kinase cascades leading to the expression of differentiation
      specific genes. We examined herein the hypothesis that FGF receptors (FGFRs) are
      involved in NGF-induced neuritogenesis of pheochromocytoma-derived PC12 cells. We
      demonstrate that in PC12 cells, FGFR expression and activity are modulated upon
      NGF treatment and that a dominant negative FGFR-2 reduces NGF-induced
      neuritogenesis. Moreover, FGF-2 expression is modulated by NGF, and FGF-2 is
      detected at the cell surface. Oligonucleotides that specifically inhibit FGF-2
      binding to its receptors are able to significantly reduce NGF-induced neurite
      outgrowth. Finally, the duration of mitogen-activated protein kinase (MAPK)
      activity upon FGF or NGF stimulation is shortened in FGFR-2 dominant negative
      cells through inactivation of signaling from the receptor to the Ras/MAPK
      pathway. In conclusion, these results demonstrate that FGFR activation is
      involved in neuritogenesis induced by NGF where it contributes to a sustained
      MAPK activity in response to NGF.

PMID- 10409633
TI  - Targeting expression with light using caged DNA.
AB  - In this report, we describe the inactivation and site-specific light induction of
      plasmid expression using a photosensitive caging compound. Plasmids coding for
      luciferase were caged with 1-(4, 5-dimethoxy-2-nitrophenyl)diazoethane (DMNPE)
      and transfected into approximately 1-cm diameter sites of the skin of rats with
      particle bombardment. Skin sites transfected with caged plasmids did not express
      luciferase. However, subsequent exposure of transfected skin sites to 355-nm
      laser light induced luciferase expression in proportion to the amount of light.
      Liposome transfection of HeLa cells with DMNPE-caged green fluorescent protein
      (GFP) plasmids showed similar results. Caging DNA with DMNPE blocks expression at
      the level of transcription, since in vitro production of mRNA from linearized GFP
      plasmid was also blocked by caging and subsequently restored by exposure to
      light. Under the reaction conditions of these experiments, our absorbance data
      indicate that each DMNPE-caged GFP plasmid contains approximately 270 caging
      groups. In addition to inhibition and subsequent restoration of plasmid
      bioactivity, the presence and photocleavage of this relatively small number of
      cage groups also alters electrophoretic mobility of plasmids and optical
      absorption characteristics. This light-induced expression strategy provides a new
      means to target the expression of genetic material with spatial and temporal
      specificity.

PMID- 10409635
TI  - Cytotoxicity and site-specific DNA damage induced by nitroxyl anion (NO(-)) in
      the presence of hydrogen peroxide. Implications for various pathophysiological
      conditions.
AB  - Nitroxyl anion (NO(-)), the one-electron reduction product of nitric oxide
      (NO(.)), is formed under various physiological conditions. We have used four
      different assays (DNA strand breakage, 8-oxo-deoxyguanosine formation in calf
      thymus DNA, malondialdehyde generation from 2'-deoxyribose, and analysis of site
      specific DNA damage using (32)P-5'-end-labeled DNA fragments of the human p53
      tumor suppressor gene and the c-Ha-ras-1 protooncogene) to study the effects of
      NO(-) generated from Angeli's salt on DNA damage. It was found that strong
      oxidants are generated from NO(-), especially in the presence of H(2)O(2) plus
      Fe(III)-EDTA or Cu(II). NO(.) released from diethylamine-NONOate had no such
      effect. Distinct effects of hydroxyl radical (HO(.)) scavengers and patterns of
      site-specific DNA cleavage caused by Angeli's salt alone or by Angeli's salt,
      H(2)O(2) plus metal ion suggest that NO(-) acts as a reductant to catalyze the
      formation of the HO(.) from H(2)O(2) plus Fe(III) and formation of Cu(I)-peroxide
      complexes with a reactivity similar to HO(.) from H(2)O(2) and Cu(II). Angeli's
      salt and H(2)O(2) exerted synergistically cytotoxic effects to MCF-7 cells,
      determined by lactate dehydrogenase release assay. Thus NO(-) may play an
      important role in the etiology of various pathophysiological conditions such as
      inflammation and neurodegenerative diseases, especially when H(2)O(2) and
      transition metallic ions are present.

PMID- 10409636
TI  - Glycosphingolipid-enriched signaling domain in mouse neuroblastoma Neuro2a cells.
      Mechanism of ganglioside-dependent neuritogenesis.
AB  - Differentiation and neuritogenesis of mouse neuroblastoma Neuro2a cells are
      induced by exogenous ganglioside but are not induced by nerve growth factor
      because its receptor is absent in these cells. In view of the emerging concept of
      the "glycosphingolipid-enriched domain" (GEM), we studied the mechanism of the
      ganglioside effect, focusing on the structure and function of such a domain. GEM
      in Neuro2a cells, separated as a low density membrane fraction, contains
      essentially all glycosphingolipids and sphingomyelin, together with five signal
      transducer molecules (c-Src, Lyn, Csk, Rho A, Ha-Ras). (3)H-Labeled Il(3)NeuAc
      LacCer (GM3), Gb4Cer (globoside), and Il(3)NeuAc-Gg4Cer (GM1) added exogenously
      to cells were incorporated and concentrated in the low density GEM fraction. In
      contrast, more than 50% of glycerophospholipids and 30% of cholesterol were found
      in the high density fraction. (3)H-Labeled phosphatidylcholine added exogenously
      to cells was incorporated exclusively in the high density fraction. c-Src, the
      predominant signal transducer in the microdomain, was coimmunoprecipitated with
      anti-GM3 antibody DH2 or with anti-Csk; reciprocally, Csk was
      coimmunoprecipitated with anti-c-Src, indicating a close association of GM3, c
      Src, and Csk. Brief stimulation of an isolated GEM fraction by the exogenous
      addition of GM3, but not lactosylceramide, caused enhanced c-Src phosphorylation
      with a concomitant decrease of Csk level in GEM. A decreased Csk/c-Src ratio in
      GEM may cause activation of c-Src because Csk is a negative regulator of c-Src.
      The effect of exogenous GM3 on c-Src activity was also observed in intact Neuro2a
      cells. Activation of c-Src was followed by rapid and prolonged (60 min)
      enhancement of mitogen-activated protein kinase activity leading to
      neuritogenesis. Thus, the ganglioside induction of neuritogenesis in Neuro2a
      cells is mediated by GEM structure and function.

PMID- 10409637
TI  - Inactivation of brassinosteroid biological activity by a salicylate-inducible
      steroid sulfotransferase from Brassica napus.
AB  - Recent discoveries from brassinosteroid-deficient mutants led to the recognition
      that plants, like animals, use steroids to regulate their growth and development.
      We describe the characterization of one member of a Brassica napus
      sulfotransferase gene family coding for an enzyme that catalyzes the O
      sulfonation of brassinosteroids and of mammalian estrogenic steroids. The enzyme
      is specific for the hydroxyl group at position 22 of brassinosteroids with a
      preference for 24-epicathasterone, an intermediate in the biosynthesis of 24
      epibrassinolide. Enzymatic sulfonation of 24-epibrassinolide abolishes its
      biological activity in the bean second internode bioassay. This mechanism of
      hormone inactivation by sulfonation is similar to the modulation of estrogen
      biological activity observed in mammals. Furthermore, the expression of the B.
      napus steroid sulfotransferase genes was found to be induced by salicylic acid, a
      signal molecule in the plant defense response. This pattern of expression
      suggests that, in addition to an increased synthesis of proteins having
      antimicrobial properties, plants respond to pathogen infection by modulating
      steroid-dependent growth and developmental processes.

PMID- 10409638
TI  - Mass spectrometric analysis of nitric oxide-modified caspase-3.
AB  - Caspases are a family of cysteine proteases activated during apoptosis.
      Modification of caspases by nitric oxide and its relevance during apoptosis is
      currently a controversial subject. In this study we analyzed the S-nitrosated
      form of caspase-3 at a molecular level. By using electrospray ionization-mass
      spectrometry, we detected poly-S-nitrosation of caspase-3 with an average of
      about 2 molecules of NO bound per enzyme. Although NO treatment completely
      inhibited enzyme activity, S-nitrosation was not restricted to the active site
      cysteine. Rather, we detected multiple relative mass increases of 30 +/- 1 Da in
      both the p12 and p17 subunits of caspase-3, corresponding to single to triple S
      nitrosation. The stability of these S-nitrosations differed in physiologically
      relevant concentrations of 5 mM glutathione. Whereas all S-nitroso bonds in the
      p12 subunit were cleaved with release of NO and partial formation of protein
      mixed disulfides with glutathione, a single S-nitrosation in the p17 subunit
      remained stable. Since this S-nitrosation was not observed in a mutant form of
      caspase-3 lacking the active site cysteine, we conclude that NO nitrosates the
      active site cysteine of caspase-3 and that this modification is notably inert to
      fast trans-nitrosation with glutathione. Furthermore, we provide evidence that
      treatment of caspase-3 with NO can lead to mixed disulfide formation with
      glutathione, demonstrating the oxidative character of NO.

PMID- 10409639
TI  - The DNA helicase, Hmi1p, is transported into mitochondria by a C-terminal
      cleavable targeting signal.
AB  - We have identified a novel mitochondrial targeting signal in the precursor of the
      DNA helicase Hmi1p of Saccharomyces cerevisiae that is located at the C terminus
      of the protein. Similar to classical N-terminal presequences, this C-terminal
      targeting signal consists of a stretch of positively charged amino acids that has
      the potential to form an amphipathic alpha-helix. Deletion of the C-terminal 36
      amino acids of helicase resulted in loss of import into mitochondria, while
      deletion of the N-terminal 40 amino acids had no effect. When C-terminal regions
      of the helicase were placed at the C terminus of a passenger protein,
      dihydrofolate reductase, the resulting fusion proteins were directed into the
      mitochondrial matrix, and the C-terminal region of helicase became
      proteolytically processed. Import of helicase occurs in a C- to N-terminal
      direction; it requires a membrane potential and the TIM17-23 translocase together
      with mitochondrial Hsp70. Helicase is the only mitochondrial matrix protein
      identified thus far with a cleavable targeting signal at its C terminus.

PMID- 10409640
TI  - Requirements for alpha(5)beta(1) integrin-mediated retraction of fibronectin
      fibrin matrices.
AB  - Retraction of the blood clot by nucleated cells contributes both to hemostasis
      and to tissue remodeling. Although plasma fibronectin (FN) is a key component of
      the clot, its role in clot retraction is unclear. In this report, we demonstrate
      that the incorporation of FN into fibrin matrices significantly improves clot
      retraction by nucleated cells expressing the integrin alpha(5)beta(1). Further,
      we show that FN-fibrin clots support increased cell spreading when compared with
      fibrin matrices. To determine the structural requirements for FN in this process,
      recombinant FN monomers deficient in ligand binding or fibrin cross-linking were
      incorporated into fibrin clots. We show that recombinant FN monomers support clot
      retraction by Chinese hamster ovary cells expressing the integrin
      alpha(5)beta(1). This process depends on both the Arg-Gly-Asp (RGD) and the
      synergy cell-binding sites and on covalent FN-fibrin binding, demonstrating that
      cross-linking within the clot is important for cell-FN interactions. These data
      show that alpha(5)beta(1) can bind to FN within a clot to promote clot retraction
      and support cell shape change. This provides strong evidence that alpha(5)beta(1)
      FN interactions may contribute to the cellular events required for wound
      contraction.

PMID- 10409641
TI  - Inhibitor-1 is not required for the activation of glycogen synthase by insulin in
      skeletal muscle.
AB  - Glycogen synthase is an excellent in vitro substrate for protein phosphatase-1
      (PP1), which is potently inhibited by the phosphorylated forms of DARPP-32
      (dopamine- and cAMP-regulated phosphoprotein, M(r) = 32,000) and Inhibitor-1. To
      test the hypothesis that the activation of glycogen synthase by insulin is due to
      a decrease in the inhibition of PP1 by the phosphatase inhibitors, we have
      investigated the effects of insulin on glycogen synthesis in skeletal muscles
      from wild-type mice and mice lacking Inhibitor-1 and DARPP-32 as a result of
      targeted disruption of the genes encoding the two proteins. Insulin increased
      glycogen synthase activity and the synthesis of glycogen to the same extent in
      wild-type and knockout mice, indicating that neither Inhibitor-1 nor DARPP-32 is
      required for the full stimulatory effects of insulin on glycogen synthase and
      glycogen synthesis in skeletal muscle.

PMID- 10409642
TI  - Structural studies of N-glycans of filarial parasites. Conservation of
      phosphorylcholine-substituted glycans among species and discovery of novel chito
      oligomers.
AB  - N-Type glycans containing phosphorylcholine (PC-glycans), unusual structures
      found in the important human pathogens filarial nematodes, represent a novel
      target for chemotherapy. Previous work in our laboratories produced compositional
      information on the PC-glycan of ES-62, a secreted protein of the rodent parasite
      Acanthocheilonema viteae. In particular, we established using fast atom
      bombardment mass spectrometry (MS) analysis that PC was attached to a glycan with
      a trimannosyl core, with and without core fucosylation, carrying between one and
      four additional N-acetylglucosamine residues. In the present study, we
      demonstrate that this structure is conserved among filarial nematodes, including
      the parasite of humans, Onchocerca volvulus, for which new drugs are most
      urgently sought. Furthermore, by employing a variety of procedures, including
      collision-activated dissociation MS-MS analysis and matrix-assisted laser
      desorption MS analysis, we reveal that surprisingly, filarial nematodes also
      contain N-linked glycans, the antennae of which are composed of chito-oligomers.
      To our knowledge, this is the first report of such structures in a eukaryotic
      glycoprotein.

PMID- 10409643
TI  - Activation of human histidine decarboxylase gene promoter activity by gastrin is
      mediated by two distinct nuclear factors.
AB  - The human histidine decarboxylase gene is regulated by gastrin through a cis
      acting element known as the gastrin response element (GAS-RE) that was initially
      localized to a site (+2 to +24) downstream of the transcriptional start site.
      Electrophoretic mobility shift assays using sequentially deleted DNA probes and
      nuclear extracts from AGS-B gastric cancer cells showed that the GAS-RE is
      actually composed of two overlapping binding sites (GAS-RE1, +1 to +19; and GAS
      RE2, +11 to +27) that bind distinct nuclear factors. Reporter gene assays
      demonstrated that each element alone could confer gastrin responsiveness, but the
      presence of both elements was required for complete gastrin response. Stimulation
      of AGS-B cells with gastrin for 10-20 min resulted in a >2-fold increase in
      factor binding. The binding was inhibited by pretreatment of AGS-B cells with
      cycloheximide and the MEK1 inhibitor PD98059, indicating a requirement for
      protein synthesis and also indicating that activation occurs through the
      MEK/mitogen-activated protein kinase pathway. UV cross-linking and Southwestern
      blot analysis showed that GAS-RE1 bound a 52-kDa protein, whereas GAS-RE2 bound a
      35-kDa protein. Hence, activation of histidine decarboxylase gene promoter
      activity by gastrin is most likely mediated by two separate nuclear factors.

PMID- 10409644
TI  - Control of actin filament length and turnover by actin depolymerizing factor
      (ADF/cofilin) in the presence of capping proteins and ARP2/3 complex.
AB  - The effect of Arabidopsis thaliana ADF1 and human ADF on the number of filaments
      in F-actin solutions has been examined using a seeded polymerization assay. ADF
      did not sever filaments in a catalytic fashion, but decreased the steady-state
      length distribution of actin filaments in correlation with its effect on actin
      dynamics. The increase in filament number was modest as compared with the large
      increase in filament turnover. ADF did not decrease the length of filaments
      shorter than 1 micrometer. ADF promoted the rapid turnover of gelsolin-capped
      filaments in a manner dependent on the number of pointed ends. To explain these
      results, we propose that, as a consequence of the cooperative binding of ADF to F
      actin, two populations of energetically different filaments coexist in solution
      pending a flux of subunits from one to the other. The ADF-decorated filaments
      depolymerize rapidly from their pointed ends, while undecorated filaments
      polymerize. ADF also promotes rapid turnover of gelsolin-capped filaments in the
      presence of the pointed end capper Arp2/3 complex. It is shown that the Arp2/3
      complex steadily generates new barbed ends in solutions of gelsolin-capped
      filaments, which represents an important aspect of its function in actin-based
      motility.

PMID- 10409645
TI  - DL-2-Haloacid dehalogenase from Pseudomonas sp. 113 is a new class of
      dehalogenase catalyzing hydrolytic dehalogenation not involving enzyme-substrate
      ester intermediate.
AB  - DL-2-Haloacid dehalogenase from Pseudomonas sp. 113 (DL-DEX 113) catalyzes the
      hydrolytic dehalogenation of D- and L-2-haloalkanoic acids, producing the
      corresponding L- and D-2-hydroxyalkanoic acids, respectively. Every
      halidohydrolase studied so far (L-2-haloacid dehalogenase, haloalkane
      dehalogenase, and 4-chlorobenzoyl-CoA dehalogenase) has an active site
      carboxylate group that attacks the substrate carbon atom bound to the halogen
      atom, leading to the formation of an ester intermediate. This is subsequently
      hydrolyzed, resulting in the incorporation of an oxygen atom of the solvent water
      molecule into the carboxylate group of the enzyme. In the present study, we
      analyzed the reaction mechanism of DL-DEX 113. When a single turnover reaction of
      DL-DEX 113 was carried out with a large excess of the enzyme in H(2)(18)O with a
      10 times smaller amount of the substrate, either D- or L-2-chloropropionate, the
      major product was found to be (18)O-labeled lactate by ionspray mass
      spectrometry. After a multiple turnover reaction in H(2)(18)O, the enzyme was
      digested with trypsin or lysyl endopeptidase, and the molecular masses of the
      peptide fragments were measured with an ionspray mass spectrometer. No peptide
      fragments contained (18)O. These results indicate that the H(2)(18)O of the
      solvent directly attacks the alpha-carbon of 2-haloalkanoic acid to displace the
      halogen atom. This is the first example of an enzymatic hydrolytic dehalogenation
      that proceeds without producing an ester intermediate.

PMID- 10409646
TI  - Opposite regulation of transepithelial electrical resistance and paracellular
      permeability by Rho in Madin-Darby canine kidney cells.
AB  - Small GTPase Rho has been thought to be important for the formation and the
      maintenance of tight junction in epithelial cells, but the role of Rho in the
      regulation of barrier function of tight junction is not well understood. We here
      examined whether Rho was involved in the barrier function of tight junction in
      Madin-Darby canine kidney (MDCK) cells. The activation of prostaglandin EP3beta
      receptor, coupled to a Rho activation pathway, induced the increase in
      transepithelial electrical resistance (TER) but the increase in paracellular flux
      of mannitol in the preformed monolayer of the MDCK cells expressing the EP3beta
      receptor. This effect of the EP3 receptor was mimicked by the expression of
      constitutively active RhoA but not by active Rac1 in MDCK cells, using an
      isopropyl-beta-D-thiogalactoside-inducible expression system. On the other hand,
      the activation of EP3beta receptor suppressed the elevation of TER and the
      decrease in paracellular mannitol flux during Ca(2+) switch-induced tight
      junction formation, whereas the expression of active RhoA or Rac1 did not
      apparently affect the TER development in the Ca(2+) switch. These results
      demonstrate that the EP3 receptor and active RhoA regulate permeabilities of
      ionic and nonionic molecules in opposite directions in the preformed monolayer,
      and the EP3 receptor suppresses the elevation of TER during the tight junction
      formation.

PMID- 10409647
TI  - Distinct calcium-dependent pathways of epidermal growth factor receptor
      transactivation and PYK2 tyrosine phosphorylation in PC12 cells.
AB  - Recently, we have demonstrated that in PC12 cells activation of the
      Ras/extracellular signal-regulated kinase pathway in response to membrane
      depolarization or bradykinin is mediated by calcium-dependent transactivation of
      the epidermal growth factor receptor (EGFR). Here we address the question whether
      Ca(2+)-calmodulin-dependent protein kinase (CaM kinase) has a role in the EGFR
      transactivation signal. Using compounds that selectively interfere with either
      CaM kinase activity or calmodulin function, we show that KCl-mediated membrane
      depolarization-triggered, but not bradykinin-mediated signals involve CaM kinase
      function upstream of the EGFR. Although both depolarization-induced calcium
      influx and bradykinin stimulation of PC12 cells were found to induce c-fos
      transcription through EGFR activation, the former signal is CaM kinase-dependent
      and the latter was shown to be independent. As PYK2 is also activated upon
      elevation of intracellular calcium, we investigated the potential involvement of
      this cytoplasmic tyrosine kinase in EGFR transactivation. Interestingly, we
      observed that inhibition of CaM kinase activity in PC12 cells abrogated tyrosine
      phosphorylation of PYK2 upon KCl but not bradykinin treatment. Nevertheless, PYK2
      activation in response to both stimuli appeared to be mediated by pathways
      parallel to EGFR transactivation. Our data demonstrate the existence of two
      distinct calcium-dependent mechanisms leading either to EGFR-mediated
      extracellular signal-regulated activation or to PYK2 tyrosine phosphorylation.
      Both pathways either in concert or independently might contribute to the
      definition of biological responses in neuronal cell types.

PMID- 10409648
TI  - Auxin induction of cell cycle regulated activity of tobacco telomerase.
AB  - Telomerase activity was measured at each phase of the cell cycle in synchronized
      tobacco (Nicotiana tabacum) BY-2 cells in suspension culture with the use of the
      telomeric repeat amplification protocol assay. The activity was low or
      undetectable at most phases of the cell cycle but showed a marked increase at
      early S phase. The induction of telomerase activity was not affected by the S
      phase blockers aphidicolin (which inhibits DNA polymerase alpha) or hydroxyurea
      (which inhibits ribonucleotide reductase), but it was prevented by olomoucine, an
      inhibitor of Cdc2/Cdk2 kinases that blocks G(1)-S cell cycle transition. These
      results suggest that the induction of telomerase activity is not directly coupled
      to DNA replication by conventional DNA polymerases, but rather is triggered by
      the entry of cells into S phase. Various analogs of the plant hormone auxin,
      including indole-3-acetic acid, alpha-naphthaleneacetic acid, and 2,4
      dichlorophenoxyacetic acid, potentiated the increase in telomerase activity at
      early S phase; the growth-inactive analog 2,3-dichlorophenoxyacetic acid,
      however, had no such effect. Potentiation by indole-3-acetic acid of the
      induction of telomerase activity was dose dependent. Together, these data
      indicate that telomerase activity in tobacco cells is regulated in a cell cycle
      dependent manner, and that the increase in activity at S phase is specifically
      inducible by auxin.

PMID- 10409649
TI  - Fyn and JAK2 mediate Ras activation by reactive oxygen species.
AB  - Reactive oxygen species (ROS) activate Ras and the extracellular signal-regulated
      kinase (ERK) cascade. Because JAK2 is a critical mediator for Ras/Raf/ERK
      activation by several hormones, we examined the role of JAK2 in ROS signal
      events. H(2)O(2) stimulated JAK2 activity in fibroblasts with peak at 2-5 min. To
      determine the specific role of Src and Fyn as mediators of JAK2 activation and
      its downstream events, we used fibroblasts derived from transgenic mice deficient
      in Src (Src-/-) or Fyn (Fyn-/-). H(2)O(2)-stimulated JAK2 activity was completely
      inhibited in Fyn-/- cells. Shc tyrosine phosphorylation and Ras activation by
      H(2)O(2) were also significantly reduced in Fyn-/- cells, but not altered in Src
      /- cells. Activation of JAK2 was restored when Fyn-/- cells were transfected with
      B-Fyn but not with Src. Inhibiting JAK2 activity with the specific inhibitor AG
      490 prevented H(2)O(2) stimulated Shc and Ras activation. H(2)O(2)-mediated
      ERK1/2 activation in Fyn-/- cells and AG-490 treated cells was completely
      inhibited at an early time (5 min), but not at late times (20-40 min) after
      stimulation. These results define a new redox-sensitive pathway for Ras
      activation and rapid ERK1/2 activation, which is mediated by Fyn and JAK2.

PMID- 10409650
TI  - Alternative, non-secretase processing of Alzheimer's beta-amyloid precursor
      protein during apoptosis by caspase-6 and -8.
AB  - Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Although
      the pathogenesis of AD is unknown, it is widely accepted that AD is caused by
      extracellular accumulation of a neurotoxic peptide, known as Abeta. Mutations in
      the beta-amyloid precursor protein (APP), from which Abeta arises by proteolysis,
      are associated with some forms of familial AD (FAD) and result in increased Abeta
      production. Two other FAD genes, presenilin-1 and -2, have also been shown to
      regulate Abeta production; however, studies examining the biological role of
      these FAD genes suggest an alternative theory for the pathogenesis of AD. In
      fact, all three genes have been shown to regulate programmed cell death, hinting
      at the possibility that dysregulation of apoptosis plays a primary role in
      causing neuronal loss in AD. In an attempt to reconcile these two hypotheses, we
      investigated APP processing during apoptosis and found that APP is processed by
      the cell death proteases caspase-6 and -8. APP is cleaved by caspases in the
      intracellular portion of the protein, in a site distinct from those processed by
      secretases. Moreover, it represents a general effect of apoptosis, because it
      occurs during cell death induced by several stimuli both in T cells and in
      neuronal cells.

PMID- 10409651
TI  - Pneumocystis carinii polyamine catabolism.
AB  - DL-alpha-Difluoromethylornithine (DFMO) causes polyamines of the AIDS-associated
      opportunistic pathogen Pneumocystis carinii to diminish 15 times more rapidly
      than mammalian host cells. The proposed mechanism was that, unlike mammalian
      cells, P. carinii is unable to regulate polyamine catabolism when synthesis is
      blocked. To test this, the responses of the polyamine catabolic enzymes
      spermidine/spermine acetyltransferase (SSAT) and polyamine oxidase (PAO) were
      determined using a new high-performance liquid chromatography assay to measure
      the products of these enzymes. The specific activities in untreated Pneumocystis
      carinii were 1.78 +/- 0.5 pmol min(-1) mg protein(-1) for SSAT, similar to
      mammalian cells, and 6.42 +/- 0.8 pmol min(-1) mg protein(-1) for PAO, 19% of
      that of mammalian cells. DFMO treatment for 12 h caused reductions of only 11 and
      4% in SSAT and PAO, respectively, despite polyamine reductions of 94, 96, and 90%
      for putrescine, spermidine, and spermine, respectively. The P. carinii SSAT K(m)
      value of 25 microM spermidine is 20% of that of mammalian cells, and the PAO K(m)
      value of 14 nM N(1)-acetylspermidine is 0.01% of that of mammalian cells.
      Acetylated polyamines continue to be lost from P. carinii even when exposed to
      DFMO. Collectively, these results support the hypothesis that P. carinii is
      unable to regulate polyamine catabolism.

PMID- 10409652
TI  - Molecular and biochemical characterization of the ADP-dependent
      phosphofructokinase from the hyperthermophilic archaeon Pyrococcus furiosus.
AB  - Pyrococcus furiosus uses a modified Embden-Meyerhof pathway involving two ADP
      dependent kinases. Using the N-terminal amino acid sequence of the previously
      purified ADP-dependent glucokinase, the corresponding gene as well as a related
      open reading frame were detected in the genome of P. furiosus. Both genes were
      successfully cloned and expressed in Escherichia coli, yielding highly
      thermoactive ADP-dependent glucokinase and phosphofructokinase. The deduced amino
      acid sequences of both kinases were 21.1% identical but did not reveal
      significant homology with those of other known sugar kinases. The ADP-dependent
      phosphofructokinase was purified and characterized. The oxygen-stable protein had
      a native molecular mass of approximately 180 kDa and was composed of four
      identical 52-kDa subunits. It had a specific activity of 88 units/mg at 50
      degrees C and a pH optimum of 6.5. As phosphoryl group donor, ADP could be
      replaced by GDP, ATP, and GTP to a limited extent. The K(m) values for fructose 6
      phosphate and ADP were 2.3 and 0.11 mM, respectively. The phosphofructokinase did
      not catalyze the reverse reaction, nor was it regulated by any of the known
      allosteric modulators of ATP-dependent phosphofructokinases. ATP and AMP were
      identified as competitive inhibitors of the phosphofructokinase, raising the K(m)
      for ADP to 0.34 and 0.41 mM, respectively.

PMID- 10409653
TI  - Distinct regions of the Swi5 and Ace2 transcription factors are required for
      specific gene activation.
AB  - Swi5 and Ace2 are cell cycle-regulated transcription factors that activate
      expression of early G(1)-specific genes in Saccharomyces cerevisiae. Swi5 and
      Ace2 have zinc finger DNA-binding domains that are highly conserved, and the two
      proteins bind to the same DNA sequences in vitro. Despite this similarity in DNA
      binding, Swi5 and Ace2 activate different genes in vivo, with Swi5 activating the
      HO gene and Ace2 activating CTS1 expression. In this report we have used chimeric
      fusions between Swi5 and Ace2 to determine what regions of these proteins are
      necessary for promoter-specific activation of HO and CTS1. We have identified
      specific regions of Swi5 and Ace2 that are required for activation of HO and
      CTS1, respectively. The Swi5 protein binds HO promoter DNA cooperatively with the
      Pho2 homeodomain protein, and the HO specificity region of Swi5 identified in the
      chimeric analysis coincides with the region of Swi5 previously identified that
      interacts with Pho2 in vitro. Swi5 and Ace2 also activate expression of a number
      of other genes expressed in G(1) phase of the cell cycle, including ASH1, CDC6,
      EGT2, PCL2, PCL9, RME1, and SIC1. Analysis of the Swi5/Ace2 chimeras shows that
      distinct regions of Swi5 and Ace2 contribute to the transcriptional activation of
      some of these other G(1)-regulated genes.

PMID- 10409654
TI  - Sequence requirements of the GPNG beta-turn of the Ecballium elaterium trypsin
      inhibitor II explored by combinatorial library screening.
AB  - The Ecballium elaterium trypsin inhibitor II (EETI-II) contains 28 amino acids
      and three disulfides forming a cystine knot. Reduced EETI-II refolds
      spontaneously and quantitatively in vitro and regains its native structure. Due
      to its high propensity to form a reverse turn, the GPNG sequence of segment 22-25
      comprising a beta-turn in native EETI-II is a possible candidate for a folding
      initiation site. We generated a molecular repertoire of EETI-II variants with
      variegated 22-25 tetrapeptide sequences and presented these proteins on the outer
      membrane of Escherichia coli cells via fusion to the Iga(beta) autotransporter.
      Functional trypsin-binding variants were selected by combination of magnetic and
      fluorescence-activated cell sorting. At least 1-5% of all possible tetrapeptide
      sequences were compatible with formation of the correct three disulfides.
      Occurrence of amino acid residues in functional variants is positively correlated
      with their propensity to be generally found in beta-turns. The folding pathway of
      two selected variants, EETI-beta(NEDE) and EETI-beta(TNNK), was found to be
      indistinguishable from EETI-II and occurs through formation of a stable 2
      disulfide intermediate. Substantial amounts of misfolded byproducts, however,
      were obtained upon refolding of these variants corroborating the importance of
      the wild type EETI-II GPNG sequence to direct quantitative formation of the
      cystine knot architecture.

PMID- 10409655
TI  - A mitochondrial pyruvate dehydrogenase bypass in the yeast Saccharomyces
      cerevisiae.
AB  - Spheroplasts of the yeast Saccharomyces cerevisiae oxidize pyruvate at a high
      respiratory rate, whereas isolated mitochondria do not unless malate is added. We
      show that a cytosolic factor, pyruvate decarboxylase, is required for the non
      malate-dependent oxidation of pyruvate by mitochondria. In pyruvate decarboxylase
      negative mutants, the oxidation of pyruvate by permeabilized spheroplasts was
      abolished. In contrast, deletion of the gene (PDA1) encoding the E1alpha subunit
      of the pyruvate dehydrogenase did not affect the spheroplast respiratory rate on
      pyruvate but abolished the malate-dependent respiration of isolated mitochondria.
      Mutants disrupted for the mitochondrial acetaldehyde dehydrogenase gene (ALD7)
      did not oxidize pyruvate unless malate was added. We therefore propose the
      existence of a mitochondrial pyruvate dehydrogenase bypass different from the
      cytosolic one, where pyruvate is decarboxylated to acetaldehyde in the cytosol by
      pyruvate decarboxylase and then oxidized by mitochondrial acetaldehyde
      dehydrogenase. This pathway can compensate PDA1 gene deletion for lactate or
      respiratory glucose growth. However, the codisruption of PDA1 and ALD7 genes
      prevented the growth on lactate, indicating that each of these pathways
      contributes to the oxidative metabolism of pyruvate.

PMID- 10409656
TI  - Bacterial lipopolysaccharide induces expression of the stress response genes hop
      and H411.
AB  - CD14-transfected Chinese hamster ovary K1 fibroblasts (CHO/CD14) respond to
      lipopolysaccharide (LPS) by metabolizing arachidonic acid and with translocation
      of NF-kappaB to the nucleus. Although previous experiments failed to identify the
      production of tumor necrosis factor-alpha and interleukin (IL)-1beta by CHO/CD14
      cells, LPS did induce the expression of IL-6 mRNA and the subsequent release of
      the IL-6 protein. To identify additional LPS-inducible genes, a cDNA library
      derived from LPS-stimulated CHO/CD14 cells was screened by subtractive
      hybridization. Fourteen genes were found to be expressed differentially, and two
      were analyzed in detail: hop (Hsp70/Hsp90-organizing protein), which is the
      hamster homologue of the stress-inducible yeast gene, STI1, and clone H411, which
      encodes a novel LPS-inducible growth factor. In response to LPS, the expression
      of Hop mRNA was also increased in both the murine macrophage cell line, RAW
      264.7, as well as in primary hamster macrophages. This suggested that the up
      regulation of Hop expression is part of the macrophage stress response to LPS.
      Clone H411 encodes a protein in the epidermal growth factor-like repeat protein
      family. Overexpression of H411 cDNA in the RAW 264.7 macrophage cell line
      promoted an increased growth rate, suggesting that expression of H411 is part of
      the proliferative cell response to LPS. Both Hop and H411 represent novel gene
      products not previously recognized as part of the complex biological response to
      endotoxin.

PMID- 10409658
TI  - Long QT syndrome-associated mutations in the S4-S5 linker of KvLQT1 potassium
      channels modify gating and interaction with minK subunits.
AB  - Long QT syndrome is an inherited disorder of cardiac repolarization caused by
      mutations in cardiac ion channel genes, including KVLQT1. In this study, the
      functional consequences of three long QT-associated missense mutations in KvLQT1
      (R243C, W248R, E261K) were characterized using the Xenopus oocyte heterologous
      expression system and two-microelectrode voltage clamp techniques. These
      mutations are located in or near the intracellular linker between the S4 and S5
      transmembrane domains, a region implicated in activation gating of potassium
      channels. The E261K mutation caused loss of function and did not interact with
      wild-type KvLQT1 subunits. R243C or W248R KvLQT1 subunits formed functional
      channels, but compared with wild-type KvLQT1 current, the rate of activation was
      slower, and the voltage dependence of activation and inactivation was shifted to
      more positive potentials. Co expression of minK and KvLQT1 channel subunits
      induces a slow delayed rectifier K(+) current, I(Ks), characterized by slow
      activation and a markedly increased magnitude compared with current induced by
      KvLQT1 subunits alone. Coexpression of minK with R243C or W248R KvLQT1 subunits
      suppressed current, suggesting that coassembly of mutant subunits with minK
      prevented normal channel gating. The decrease in I(Ks) caused by loss of function
      or altered gating properties explains the prolonged QT interval and increased
      risk of arrhythmia and sudden death associated with these mutations in KVLQT1.

PMID- 10409657
TI  - Tissue inhibitor of matrix metalloproteinase-2 regulates matrix metalloproteinase
      2 activation by modulation of membrane-type 1 matrix metalloproteinase activity
      in high and low invasive melanoma cell lines.
AB  - Activation of pro-matrix metalloproteinase (MMP)-2 on the surface of malignant
      cells by membrane-bound MT1-MMP is believed to play a critical role during tumor
      progression and metastasis. In this study we present evidence that MT1-MMP plays
      a key role for the in vitro invasiveness of malignant melanoma. Melanoma cell
      lines secreted latent MMP-2 when cultured on plastic. However, when cells were
      grown in floating type I collagen lattices, only high invasive melanoma cells
      activated proMMP-2. Activation could be inhibited by antibodies against MT1-MMP,
      by addition of recombinant tissue inhibitor of metalloproteinases (TIMP)-2 and by
      inhibition of MT1-MMP cleavage. MT1-MMP protein was detected as an inactive
      protein in all cell lines cultured as monolayers, whereas in collagen gels,
      active MT1-MMP protein was detected in the membranes of both high and low
      invasive melanoma cells. Production of TIMP-2 was about 10-fold higher in low
      invasive cells as compared with high invasive melanoma cells and was further
      increased in the low invasive cells upon contact to collagen. Thus, in melanoma
      cells TIMP-2 expression levels might regulate MT1-MMP-mediated activation of
      proMMP-2. High invasive melanoma cells displayed increased in vitro invasiveness,
      which was inhibited by TIMP-2. These data indicate the importance of these
      enzymes for the invasion processes and support a role for MT1-MMP as an activator
      of proMMP-2 in malignant melanoma.

PMID- 10409659
TI  - A nuclear encoded and mitochondrial imported dicistronic tRNA precursor in
      Trypanosoma brucei.
AB  - The mitochondrial tRNAs of Trypanosoma brucei are nuclear encoded and imported
      into the mitochondrion. A heterogeneous population of RNAs having characteristics
      of precursor tRNAs have previously been identified within the mitochondrion of T.
      brucei, suggesting that import occurs via a precursor molecule. In order to
      identify nuclear genes encoding tRNAs targeted to the mitochondrion, individual
      mitochondrial tRNAs were separated using two-dimensional gel electrophoresis and
      enzymatically sequenced. A 1.1-kilobase pair genomic DNA fragment was cloned
      containing three tRNA genes, tRNA(1)(Ser), tRNA(Leu), and tRNA(2)(Ser).
      Dicistronic precursors containing the tRNA(1)(Ser) and tRNA(Leu) transcripts with
      a 59-nucleotide intergenic sequence were identified by reverse transcriptase and
      polymerase chain reactions and the 5' end of the precursors determined. The
      dicistronic precursor tRNA is present both in the cytosol and the mitochondrion
      supporting a model for tRNA import involving precursor tRNA transcripts.

PMID- 10409660
TI  - Novel messenger RNA and alternative promoter for murine acetylcholinesterase.
AB  - A portion of the 5'-flanking region of murine acetylcholinesterase was cloned
      from genomic DNA by 5'-rapid amplification of genomic ends, identified in a mouse
      genomic library, and sequenced. Multiple potential binding sites for universal
      and tissue-specific transcription factors were suggestive of a promoter region
      within this DNA sequence. Potential promoter activity was confirmed by coupling
      the new sequence to the open reading frame of a luciferase reporter gene in
      transient expression experiments with nerve and muscle cells. 5'-Rapid
      amplification of cDNA ends with templates from multiple sources revealed a novel
      transcription start site (at position -626, relative to translation start),
      located 32 bases downstream from a TATAA sequence. This start site appeared to
      mark a novel exon (1a) comprising 291 base pairs between positions -335 and -626,
      relative to the translation start. Supporting this conclusion, polymerase chain
      reactions with cDNA from mouse brain, heart, and other tissues, consistently
      amplified a transcript containing the exon 1a sequence fused to the invariant
      sequence beginning at position -22 in exon 2, but lacking exon 1. Northern blot
      analyses confirmed the in vivo expression of exon 1a-containing transcripts,
      especially in heart, brain, liver, and kidney. These results indicate that the
      murine acetylcholinesterase gene has a functioning alternative promoter that may
      influence expression of acetylcholinesterase in certain tissues.

PMID- 10409661
TI  - Abnormal cardiac structure and function in mice expressing nonphosphorylatable
      cardiac regulatory myosin light chain 2.
AB  - A role for myosin phosphorylation in modulating normal cardiac function has long
      been suspected, and we hypothesized that changing the phosphorylation status of a
      cardiac myosin light chain might alter cardiac function in the whole animal. To
      test this directly, transgenic mice were created in which three potentially
      phosphorylatable serines in the ventricular isoform of the regulatory myosin
      light chain were mutated to alanines. Lines were obtained in which replacement of
      the endogenous species in the ventricle with the nonphosphorylatable,
      transgenically encoded protein was essentially complete. The mice show a spectrum
      of cardiovascular changes. As previously observed in skeletal muscle, Ca(2+)
      sensitivity of force development was dependent upon the phosphorylation status of
      the regulatory light chain. Structural abnormalities were detected by both gross
      histology and transmission electron microscopic analyses. Mature animals showed
      both atrial hypertrophy and dilatation. Echocardiographic analysis revealed that
      as a result of chamber enlargement, severe tricuspid valve insufficiency resulted
      in a detectable regurgitation jet. We conclude that regulated phosphorylation of
      the regulatory myosin light chains appears to play an important role in
      maintaining normal cardiac function over the lifetime of the animal.

PMID- 10409662
TI  - The cyclic AMP response element modulator family regulates the insulin gene
      transcription by interacting with transcription factor IID.
AB  - We analyzed a mechanism of transcriptional regulation of the human insulin gene
      by cyclic AMP response element modulator (CREM) through four cyclic AMP response
      elements (CREs). We isolated two novel CREM isoforms (CREMDeltaQ1 and
      CREMDeltaQ2), which lack one of the glutamine-rich domains, Q1 and Q2
      respectively, and six known isoforms (CREMtaualpha, CREMalpha, inducible cyclic
      AMP early repressor (ICER) I, ICER Igamma, CREM-17X, and CREM-17) from rat
      pancreatic islets and the RINm5F pancreatic beta-cell line. CREM isoforms
      functioned as efficient transcriptional activators or repressors to modulate
      insulin promoter activity by binding to all of the insulin CREs. The binding
      activity of repressors is higher than that of activators and suppressed not only
      basal activity but also activator-induced activities. Furthermore, CREM activator
      interacted directly with the transcription factor IID components hTAF(II)130 and
      TATA box-binding protein (TBP). These results suggest that the activation of the
      insulin gene transcription by CREM activator is mediated by not only direct
      binding to the CREs but also by recruiting transcription factor IID to the
      insulin promoter via its interaction with hTAF(II)130 and TBP. On the other hand,
      the CREM repressor ICER competitively interrupts the binding of the activators to
      CREs and does not interact with either TBP or hTAF(II)130; therefore, it might
      fail to stabilize the basal transcriptional machinery and repress
      transactivation.

PMID- 10409663
TI  - Subcellular localization of mannose 6-phosphate glycoproteins in rat brain.
AB  - The intracellular transport of soluble lysosomal enzymes relies on the post
      translational modification of N-linked oligosaccharides to generate mannose 6
      phosphate (Man 6-P) residues. In most cell types the Man 6-P signal is rapidly
      removed after targeting of the precursor proteins from the Golgi to lysosomes via
      interactions with Man 6-phosphate receptors. However, in brain, the steady state
      proportion of lysosomal enzymes containing Man 6-P is considerably higher than in
      other tissues. As a first step toward understanding the mechanism and biological
      significance of this observation, we analyzed the subcellular localization of the
      rat brain Man 6-P glycoproteins by combining biochemical and morphological
      approaches. The brain Man 6-P glycoproteins are predominantly localized in
      neuronal lysosomes with no evidence for a steady state localization in
      nonlysosomal or prelysosomal compartments. This contrasts with the clear endosome
      like localization of the low steady state proportion of mannose-6-phosphorylated
      lysosomal enzymes in liver. It therefore seems likely that the observed high
      percentage of phosphorylated species in brain is a consequence of the
      accumulation of lysosomal enzymes in a neuronal lysosome that does not fully
      dephosphorylate the Man 6-P moieties.

PMID- 10409665
TI  - Induction of endocytic vesicles by exogenous C(6)-ceramide.
AB  - Ceramide is a newly discovered second messenger that has been shown to cause cell
      growth arrest and apoptosis. Here, we present evidence that exogenously added
      C(6)-ceramide induces enlargement of late endosomes and lysosomes. 10 microM C(6)
      ceramide caused the formation of numerous vesicles of varying sizes (2-10
      micrometers) in fibroblasts (3T3-L1 and 3T3-F442A), without toxic effects.
      Vesicle formation induced by C(6)-ceramide was time- and dose-dependent, rapid,
      and reversible. Numerous small vesicles appeared within 8 h of treatment with 10
      microM C(6)-ceramide. They enlarged with time, with large vesicles found in the
      perinuclear region and small ones observed at the cell periphery. Within 24 h of
      treatment, approximately 30% of the cells exhibited these vesicles. Removal of
      ceramide from the culture medium caused disappearance of the vesicles, which
      reappeared upon readdition of ceramide. Confocal immunofluorescence microscopic
      analysis using an anti-lysosome-associated membrane protein antibody identified
      the enlarged vesicles as late endosomes/lysosomes. The fluorescent C(6)-NBD
      ceramide, a vital stain for the Golgi apparatus, did not stain these vesicles.
      The effect on vesicle formation was influenced by ceramide structure; D-erythro
      C(6)-ceramide was the most active ceramide analogue tested. Short chain ceramide
      metabolites, such as sphingosine, sphingosine 1-phosphate, N-hexanoyl
      sphingosylphosphorylcholine, N-acetylpsychosine, and C(2)-ceramide G(M3), (G(M3),
      N-acetylneuraminosyl-alpha(2, 3)-galactosyl-beta(1,4)-glucosylceramide), were
      inactive in causing vesicle formation when added exogenously. Together, these
      studies demonstrate that exogenous C(6)-ceramide induces endocytic vesicle
      formation and causes enlarged late endosomes and lysosomes in mouse fibroblasts.

PMID- 10409664
TI  - Nucleoside hydrolase from Leishmania major. Cloning, expression, catalytic
      properties, transition state inhibitors, and the 2.5-a crystal structure.
AB  - Protozoan parasites lack the pathway of the de novo synthesis of purines and
      depend on host-derived nucleosides and nucleotides to salvage purines for DNA and
      RNA synthesis. Nucleoside hydrolase is a central enzyme in the purine salvage
      pathway and represents a prime target for the development of anti-parasitic
      drugs. The full-length cDNA for nucleoside hydrolase from Leishmania major was
      cloned and sequence analysis revealed that the L. major nucleoside hydrolase
      shares 78% sequence identity with the nonspecific nucleoside hydrolase from
      Crithidia fasciculata. The L. major enzyme was overexpressed in Escherichia coli
      and purified to over 95% homogeneity. The L. major nucleoside hydrolase was
      identified as a nonspecific nucleoside hydrolase since it demonstrates the
      characteristics: 1) efficient utilization of p-nitrophenyl beta-D-ribofuranoside
      as a substrate; 2) recognition of both inosine and uridine nucleosides as favored
      substrates; and 3) significant activity with all of the naturally occurring
      purine and pyrimidine nucleosides. The crystal structure of the L. major
      nucleoside hydrolase revealed a bound Ca(2+) ion in the active site with five
      oxygen ligands from Asp-10, Asp-15 (bidentate), Thr-126 (carbonyl), and Asp-241.
      The structure is similar to the C. fasciculata IU-nucleoside hydrolase apoenzyme.
      Despite the similarities, the catalytic specificities differ substantially.
      Relative values of k(cat) for the L. major enzyme with inosine, adenosine,
      guanosine, uridine, and cytidine as substrates are 100, 0.5, 0.5, 27 and 0.3;
      while those for the enzyme from C. fasciculata are 100, 15, 14, 510, and 36 for
      the same substrates. Iminoribitol analogues of the transition state are nanomolar
      inhibitors. The results provide new information for purine and pyrimidine salvage
      pathways in Leishmania.

PMID- 10409666
TI  - Phosphorylation of cytosolic domain Ser(937) affects both biosynthetic and
      endocytic trafficking of peptidylglycine alpha-amidating monooxygenase.
AB  - Peptidylglycine alpha-amidating monooxygenase (PAM), a bifunctional enzyme,
      catalyzes the COOH-terminal amidation of bioactive peptides. In test tube assays,
      PAM is phosphorylated by protein kinase C at Ser(937). The roles of
      phosphorylation and dephosphorylation of Ser(937) in the biosynthetic and
      endocytic trafficking of integral membrane PAM were examined using an antiserum
      specific for the phosphorylation of Ser(937) and using AtT-20 cells expressing
      membrane PAM in which Ser(937) was mutated to Ala or Asp. Although
      phosphorylation at Ser(937) can occur while PAM is in the endoplasmic reticulum,
      early steps in the biosynthetic trafficking of membrane PAM were not affected by
      Ser(937) phosphorylation. The inability to phosphorylate PAM/S937A increased its
      intracellular degradation and decreased secretion of the soluble monooxygenase
      portion of PAM. In contrast, the biosynthetic trafficking of PAM/S937D was
      indistinguishable from wild-type PAM. Despite the fact that Ser(937) is adjacent
      to the only Tyr-based internalization motif in PAM, internalization and
      trafficking through early endosomes were unaffected by phosphorylation. However,
      PAM antibody internalized by wild-type PAM acquired a perinuclear localization,
      while antibody internalized by PAM/S937A was routed to lysosomes, and antibody
      bound to PAM/S937D maintained a dispersed, punctate pattern. In cells stimulated
      with phorbol ester, phosphorylation of Ser(937) increased and phosphorylated PAM
      accumulated in large vesicular structures. Therefore, phosphorylation of PAM-1 at
      Ser(937) directs newly synthesized and internalized protein away from lysosomes,
      while dephosphorylation is needed for a different step in the late endocytic
      pathway.

PMID- 10409667
TI  - Overexpression of proteins containing tyrosine- or leucine-based sorting signals
      affects transferrin receptor trafficking.
AB  - Targeting of many transmembrane proteins to post-Golgi compartments is dependent
      on cytoplasmically exposed sorting signals. The most widely used signals conform
      to the tyrosine- or the leucine-based motifs. Both types of signals have been
      implicated in protein localization to the same intracellular compartments, but
      previous results from both cell-free experiments and studies of transfected cell
      lines have indicated that the two types of signals interact with separate
      components of the sorting machinery. We have overexpressed several transmembrane
      proteins in stably transfected Madin-Darby canine kidney cells using an inducible
      promoter system. Overexpression of proteins containing tyrosine- or leucine-based
      sorting signals resulted in reduced internalization of the transferrin receptor,
      whereas recycling and polarized distribution was not influenced. Our results
      indicate that proteins with tyrosine- and leucine-based sorting signals can be
      transported along common saturable pathways.

PMID- 10409668
TI  - Interaction of the alpha(1B)-adrenergic receptor with gC1q-R, a multifunctional
      protein.
AB  - gC1q-R, a multifunctional protein, was found to bind with the carboxyl-terminal
      cytoplasmic domain of the alpha(1B)-adrenergic receptor (173 amino acids, amino
      acids 344-516) in a yeast two-hybrid screen of a cDNA library prepared from the
      rat liver. In a series of studies with deletion mutants in this region, the ten
      arginine-rich amino acids (amino acids 369-378) were identified as the site of
      interaction. The interaction was confirmed by specific co-immunoprecipitation of
      gC1q-R with full-length alpha(1B)-adrenergic receptors expressed on transfected
      COS-7 cells, as well as by fluorescence confocal laser scanning microscopy, which
      showed co-localization of these proteins in intact cells. Interestingly, the
      alpha(1B)-adrenergic receptors were exclusively localized to the region of the
      plasma membrane in COS-7 cells that expressed the alpha(1B)-adrenergic receptor
      alone, whereas gC1q-R was localized in the cytoplasm in COS-7 cells that
      expressed gC1q-R alone; however, in cells that co-expressed alpha(1B)-adrenergic
      receptors and gC1q-R, most of the alpha(1B)-adrenergic receptors were co
      localized with gC1q-R in the intracellular region, and a remarkable down
      regulation of receptor expression was observed. These observations suggest a new
      role for the previously identified complement regulatory molecule, gC1q-R, in
      regulating the cellular localization and expression of the alpha(1B)-adrenergic
      receptors.

PMID- 10409669
TI  - Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c.
AB  - Caspases are cysteine proteases that mediate apoptosis by proteolysis of specific
      substrates. Although many caspase substrates have been identified, for most
      substrates the physiologic caspase(s) required for cleavage is unknown. The Bcl-2
      protein, which inhibits apoptosis, is cleaved at Asp-34 by caspases during
      apoptosis and by recombinant caspase-3 in vitro. In the present study, we show
      that endogenous caspase-3 is a physiologic caspase for Bcl-2. Apoptotic extracts
      from 293 cells cleave Bcl-2 but not Bax, even though Bax is cleaved to an 18-kDa
      fragment in SK-NSH cells treated with ionizing radiation. In contrast to Bcl-2,
      cleavage of Bax was only partially blocked by caspase inhibitors. Inhibitor
      profiles indicate that Bax may be cleaved by more than one type of noncaspase
      protease. Immunodepletion of caspase-3 from 293 extracts abolished cleavage of
      Bcl-2 and caspase-7, whereas immunodepletion of caspase-7 had no effect on Bcl-2
      cleavage. Furthermore, MCF-7 cells, which lack caspase-3 expression, do not
      cleave Bcl-2 following staurosporine-induced cell death. However, transient
      transfection of caspase-3 into MCF-7 cells restores Bcl-2 cleavage after
      staurosporine treatment. These results demonstrate that in these models of
      apoptosis, specific cleavage of Bcl-2 requires activation of caspase-3. When the
      pro-apoptotic caspase cleavage fragment of Bcl-2 is transfected into baby hamster
      kidney cells, it localizes to mitochondria and causes the release of cytochrome c
      into the cytosol. Therefore, caspase-3-dependent cleavage of Bcl-2 appears to
      promote further caspase activation as part of a positive feedback loop for
      executing the cell.

PMID- 10409671
TI  - FYN-T-FYB-SLP-76 interactions define a T-cell receptor zeta/CD3-mediated tyrosine
      phosphorylation pathway that up-regulates interleukin 2 transcription in T-cells.
AB  - Protein-tyrosine kinases p56(Lck), SYK, and ZAP-70 and downstream adaptors LAT
      and SLP-76 have been implicated as essential components in T-cell activation.
      Another lymphoid-specific adaptor FYB/SLAP has also been identified as a
      predominant binding partner of SLP-76 and the Src kinase FYN-T, although its role
      in the activation process has been unclear. In this study, we demonstrate that
      FYN-T selectively phosphorylates FYB providing a template for the recruitment of
      FYN-T and SLP-76 SH2 domain binding. This interaction is unusual in its distinct
      cytoplasmic localization and its long term stable kinetics of phosphorylation.
      Furthermore, we demonstrate for the first time that the co-expression of all
      three components of the FYN-T-FYB-SLP-76 matrix can synergistically up-regulate T
      cell receptor-driven interleukin 2 transcription activity. These findings
      document the existence of a T-cell receptor-regulated FYN-T-FYB pathway that
      interfaces with the adaptor SLP-76 and up-regulates lymphokine production in T
      cells.

PMID- 10409670
TI  - Characterization of the murine mafF gene.
AB  - Small Maf proteins are obligatory heterodimeric partner molecules of mammalian
      Cap'n'Collar proteins that together control a wide variety of eukaryotic genes.
      Although both MafK and MafG are expressed in overlapping but distinct tissue
      distribution patterns during embryonic development, the physiological
      consequences of loss-of-function mutations in either gene are modest. This
      suggested that compensation by the third small Maf protein, MafF, might be a
      major reason for such mild phenotypes and that further analysis of MafF might
      therefore provide important insights for understanding small Maf regulatory
      function(s). We therefore cloned, mapped, transcriptionally and developmentally
      characterized, and finally disrupted the mafF gene. We show that murine mafF is
      transcriptionally regulated by three different promoters and is most abundantly
      expressed in the lung. The lacZ gene inserted into the mafF locus revealed
      prominent expression sites in the gut, lung, liver, outflow tract of the heart,
      cartilage, bone membrane, and skin but not in hematopoietic cells at any
      developmental stage. Homozygous mafF null mutant mice were born in a normal
      Mendelian ratio and displayed no obvious functional deficiencies, indicating that
      MafF activity may be dispensable even in tissues where the expression of other
      small Maf proteins is quite low.

PMID- 10409672
TI  - Lung Kruppel-like factor, a zinc finger transcription factor, is essential for
      normal lung development.
AB  - Lung Kruppel-like factor (LKLF) is a member of the Kruppel-like factor family of
      transcription factors and is highly expressed in lung with limited distribution
      in other tissues. Mice lacking LKLF due to inactivation of LKLF by gene targeting
      die in utero at midgestation around day 12.5 due to severe hemorrhage, making it
      difficult to study the role of this transcription factor in lung development and
      function. However, in vitro organ culture of lung buds removed from 11.5-day-old
      LKLF(-/-) embryos show normal tracheobronchial tree formation. To examine later
      stages of lung development, the embryonic lethality due to germ line LKLF null
      mutation was circumvented by constructing LKLF homozygous null mouse embryonic
      stem cells, using a two-step gene targeting procedure, and determining whether
      these cells give rise to lung tissue. The targeted cells were used to produce
      chimeric animals, and the contribution of LKLF-deficient cells to the formation
      of various internal organs was analyzed. In chimeric mice that survived after
      birth, null embryonic stem cells contributed significantly to all of the major
      organs except the lungs. On the other hand, some highly chimeric animals died at
      birth, and histopathological examination of their lungs suggested abnormalities
      in their lung development. These studies show that LKLF plays an important role
      in normal lung development.

PMID- 10409673
TI  - Visual arrestin activity may be regulated by self-association.
AB  - Visual arrestin is the protein responsible for rapid quenching of G-protein
      coupled receptor signaling. Arrestin exists as a latent inhibitor which must be
      'activated' upon contact with a phosphorylated receptor. X-ray crystal structures
      of visual arrestin exhibit a tetrameric arrangement wherein an asymmetric dimer
      with an extensive interface between conformationally different subunits is
      related to a second asymmetric dimer by a local two-fold rotation axis. To test
      the biological relevance of this molecular organization in solution, we carried
      out a sedimentation equilibrium analysis of arrestin at both crystallographic and
      physiological protein concentrations. While the tetrameric form can exist at the
      high concentrations used in crystallography experiments, we find that arrestin
      participates in a monomer/dimer equilibrium at concentrations more likely to be
      physiologically relevant. Solution interaction analysis of a proteolytically
      modified, constitutively active form of arrestin shows diminished dimerization.
      We propose that self-association of arrestin may provide a mechanism for
      regulation of arrestin activity by (i) ensuring an adequate supply for rapid
      quenching of the visual signal and (ii) limiting the availability of active
      monomeric species, thereby preventing inappropriate signal termination.

PMID- 10409674
TI  - Expression of the CYP4F3 gene. tissue-specific splicing and alternative promoters
      generate high and low K(m) forms of leukotriene B(4) omega-hydroxylase.
AB  - Cytochrome P450 4F3 (CYP4F3) catalyzes the inactivation of leukotriene B(4) by
      omega-oxidation in human neutrophils. To understand the regulation of CYP4F3
      expression, we analyzed the CYP4F3 gene and cloned a novel isoform (CYP4F3B) that
      is expressed in fetal and adult liver, but not in neutrophils. The CYP4F3 gene
      contains 14 exons and 13 introns. The cDNAs for CYP4F3A (the neutrophil isoform)
      and CYP4F3B have identical coding regions, except that they contain exons 4 and
      3, respectively. Both exons code for amino acids 66-114 but share only 27%
      identity. When expressed in COS-7 cells, the K(m) of CYP4F3B was determined to be
      26-fold higher than the K(m) of CYP4F3A using leukotriene B(4) as a substrate. 5'
      Rapid amplification of cDNA end studies reveal that the CYP4F3A and CYP4F3B
      transcripts have 5'-termini derived from different parts of the gene and are
      initiated from distinct transcription start sites located 519 and 71 base pairs
      (bp), respectively, from the ATG initiation codon. A consensus TATA box is
      located 27 bp upstream of the CYP4F3B transcription start site, and a TATA box
      like sequence is located 23 bp upstream of the CYP4F3A transcription start site.
      The data indicate that the tissue-specific expression of functionally distinct
      CYP4F3 isoforms is regulated by alternative promoter usage and mutually exclusive
      exon splicing.

PMID- 10409675
TI  - Mutations in the vasopressin prohormone involved in diabetes insipidus impair
      endoplasmic reticulum export but not sorting.
AB  - Familial neurohypophysial diabetes insipidus is characterized by vasopressin
      deficiency caused by heterozygous expression of a mutated vasopressin prohormone
      gene. To elucidate the mechanism of this disease, we stably expressed five
      vasopressin prohormones with a mutation in the neurophysin moiety (NP14G-->R,
      NP47E-->G, NP47DeltaE, NP57G-->S, and NP65G-->V) in the neuroendocrine cell lines
      Neuro-2A and PC12/PC2. Metabolic labeling demonstrated that processing and
      secretion of all five mutants was impaired, albeit to different extents (NP65G-
      >V >/= NP14G-->R > NP47DeltaE >/= NP47E-->G > NP57G-->S). Persisting
      endoglycosidase H sensitivity revealed these defects to be due to retention of
      mutant prohormone in the endoplasmic reticulum. Mutant prohormones that partially
      passed the endoplasmic reticulum were normally targeted to the regulated
      secretory pathway. Surprisingly, this also included mutants with mutations in
      residues involved in binding of vasopressin to neurophysin, a process implicated
      in targeting of the prohormone. To mimick the high expression in vasopressin
      producing neurons, mutant vasopressin prohormones were transiently expressed in
      Neuro-2A cells. Immunofluorescence displayed formation of large accumulations of
      mutant prohormone in the endoplasmic reticulum, accompanied by redistribution of
      an endoplasmic reticulum marker. Our data suggest that prolonged perturbation of
      the endoplasmic reticulum eventually leads to degeneration of neurons expressing
      mutant vasopressin prohormones, explaining the dominant nature of the disease.

PMID- 10409676
TI  - Expression of the H type 1 blood group antigen during enterocytic differentiation
      of Caco-2 cells.
AB  - We made a comparative study of the structures of the oligosaccharides on the
      glycoproteins from Caco-2 human colonic adenocarcinoma cells, before and after
      differentiation. Enterocytic differentiated Caco-2 cells highly express H type 1
      blood group antigen on the cell surface as well as activities of brush border
      membrane hydrolases, such as dipeptidyl peptidase IV and alkaline phosphatase. A
      strong correlation was observed between the amounts of H type 1 blood group
      antigen and the degrees of differentiation. Structural analysis with use of
      lectin affinity high performance liquid chromatography revealed that typical
      mucin-type sugar chains of the glycoproteins from undifferentiated cells have H
      type 2 group, linear polylactosamines, and core 1 structure. On the other hand,
      differentiated cells newly contain H type 1 and Le(b) groups and core 2
      structure. Mucins with H type 1 group make contact with brush border membrane
      enzymes on differentiated cells. Furthermore benzyl 2-acetamide-2-deoxy-alpha-D
      galactopyranoside inhibited both expression of H type 1 group on the cell surface
      and enhancement of brush border membrane enzyme activities even in the presence
      of a differentiating inducer. These results suggest that the mucin-type sugar
      chains with H type 1 group have important functions regarding differentiation of
      Caco-2 cells.

PMID- 10409677
TI  - Differential binding of vascular endothelial growth factor B splice and
      proteolytic isoforms to neuropilin-1.
AB  - Vascular endothelial growth factor B (VEGF-B) is expressed in various tissues,
      especially strongly in the heart, and binds selectively to one of the VEGF
      receptors, VEGFR-1. The two splice isoforms, VEGF-B(167) and VEGF-B(186), have
      identical NH(2)-terminal cystine knot growth factor domains but differ in their
      COOH-terminal domains which give these forms their distinct biochemical
      properties. In this study, we show that both splice isoforms of VEGF-B bind
      specifically to Neuropilin-1 (NRP1), a receptor for collapsins/semaphorins and
      for the VEGF(165) isoform. The NRP1 binding of VEGF-B could be competed by an
      excess of VEGF(165). The binding of VEGF-B(167) was mediated by the heparin
      binding domain, whereas the binding of VEGF-B(186) to NRP1 was regulated by
      exposure of a short COOH-terminal proline-rich peptide upon its proteolytic
      processing. In immunohistochemistry, NRP1 distribution was found to be
      overlapping or adjacent to known sites of VEGF-B expression in several tissues,
      in particular in the developing heart, suggesting the involvement of VEGF-B in
      NRP1-mediated signaling.

PMID- 10409678
TI  - Ku binds telomeric DNA in vitro.
AB  - Ku is a heterodimeric protein with high binding affinity for ends, nicks, and
      gaps in double-stranded DNA. Both in mammalian cells and in budding yeast, Ku
      plays a role in nonhomologous end joining in the double strand break repair
      pathway. However, Ku has a more significant role in DNA repair in mammalian cells
      compared with yeast, in which a homology-dependent pathway is the predominant
      one. Recently Ku has been shown to be a likely component of the telomeric complex
      in yeast, suggesting the possibility of a similar role for Ku at mammalian
      telomeres. However, long single-stranded G-rich overhangs are continuously
      present at mammalian but not at yeast telomeres. These overhangs have the
      potential to fold in vitro into G-G base-paired conformations, such as G
      quartets, that might prevent Ku from recognizing telomeric ends and thus offer a
      mechanism to sequester the telomere from the prevalent double strand break repair
      pathway in mammals. We show here that Ku binds to mammalian telomeric DNA ends in
      vitro and that G-quartet conformations are unable to prevent Ku from binding with
      high affinity to the DNA. Our results indicate that the DNA binding
      characteristics of Ku are consistent with its direct interaction with telomeric
      DNA in mammalian cells and its proposed role as a telomere end factor.

PMID- 10409679
TI  - Human mitochondrial carbonic anhydrase VB. cDNA cloning, mRNA expression,
      subcellular localization, and mapping to chromosome x.
AB  - A cDNA clone for a novel carbonic anhydrase (CA) isozyme was isolated from human
      pancreas and salivary glands. The cDNA sequence of 1182 base pairs encoded a 317
      amino acid protein with a predicted mass of 36.4 kDa. The highest similarity of
      this cDNA and the deduced amino acid sequence is to human CA V (mitochondrial
      CA), hereafter referred to as CA VA. Recombinant protein expressed in COS-7 cells
      transfected with this cDNA clone was enriched in a mitochondrial fraction.
      Confocal fluorescence microscopy showed cytoplasmic granular signals in COS-7
      cells expressing a fusion protein of the novel CA and green fluorescent protein.
      Several lines of evidence suggest that the cDNA clone presented herein encodes a
      novel human mitochondrial CA isozyme, designated CA VB. CA VB has a hydrophobic N
      terminal mitochondrial signal sequence (33 amino acid residues). Western blot
      analysis showed a 36-kDa protein precursor and a 32-kDa mature protein for CA VB.
      Similar to CA VA, CA VB is a "low activity" enzyme with a sensitivity to
      acetazolamide. The CA VB gene is located on Xp22.1. Northern blot analysis in
      normal human tissues demonstrated expression of a 1.3-kilobase transcript in
      heart and skeletal muscle, and reverse transcription-polymerase chain reaction
      analysis showed expression of CA VB in pancreas, kidney, salivary glands, and
      spinal cord but not in liver. CA VA mRNA expression was observed only in liver.
      These findings indicate these are two genetically distinct isoforms of human CA
      V, designated CA VA and CA VB, which have different patterns of tissue-specific
      distribution, suggest different physiological roles for the two mitochondrial
      isozymes.

PMID- 10409680
TI  - A novel mechanism for the regulation of photosynthesis gene expression by the
      TspO outer membrane protein of Rhodobacter sphaeroides 2.4.1.
AB  - A bacterial homolog of the mammalian mitochondrial benzodiazepine receptor, the
      tryptophan-rich sensory protein (TspO) has been previously demonstrated to
      negatively affect the transcriptional expression of several photosynthesis genes
      of Rhodobacter sphaeroides. To identify components of the signal transduction
      pathway from the outer membrane-localized TspO to the DNA-active transcription
      factor(s), we examined the involvement of TspO in the regulation of tetrapyrrole
      metabolism in R. sphaeroides. By analyzing the tetrapyrrole pigments accumulated
      by resting cell suspensions of R. sphaeroides, we demonstrated that TspO
      negatively regulates the activity of coproporphyrinogen III oxidase in this
      bacterium. hemN, encoding one of the isoenzymes of coproporphyrinogen III oxidase
      of R. sphaeroides, provided in trans to the wild type strain, produced a TSPO1
      mutant phenotype by abolishing the negative effect of TspO on the transcription
      of the photosynthesis genes, crtI and puc. It is proposed that TspO, by
      regulating the exit of certain tetrapyrrole intermediates of the
      heme/bacteriochlorophyll biosynthetic pathways in R. sphaeroides in response to
      the availability of molecular oxygen, causes the accumulation of a biosynthetic
      intermediate that serves as a corepressor for both specific pigment gene
      transcription and the puc operon. The relationship between the bacterial TspO and
      the mitochondrial peripheral benzodiazepine receptor is discussed.

PMID- 10409681
TI  - Characterization of NFkappaB activation by detection of green fluorescent protein
      tagged IkappaB degradation in living cells.
AB  - Activation of the transcription factor NFkappaB requires rapid degradation of its
      inhibitor, IkappaBalpha. To facilitate the study of IkappaBalpha degradation, we
      fused IkappaBalpha protein to enhanced green fluorescent protein to construct
      IkappaBalpha-enhanced green fluorescent protein (IG). We demonstrated by both
      flow cytometry and Western blot analysis that the half-life of IG in the presence
      of human tumor necrosis factor (TNF) alpha is approximately 5 min, which is
      similar to the half-life of native IkappaBalpha. The degradation coincided with
      NFkappaB translocation from the cytoplasm to the nucleus and NFkappaB-mediated
      induction of transcription. Phorbol 12-myristate 13-acetate (PMA), but not
      forskolin, also induces degradation of IG fusion protein. The half-life of IG in
      the presence of PMA is approximately 15 min, longer than when induced with
      TNFalpha. Co-treatment with TNFalpha and PMA did not result in a synergistic
      effect on IG degradation, although they stimulate different kinases in two
      different signaling pathways. Degradation of IG was inhibited by mutations at
      serine residues 32 and 36, which are the target sites of the phosphorylation
      modification that initiates degradation of IkappaBalpha. We also demonstrated
      that basal degradation of IG in the presence of cycloheximide is inhibited by
      such mutations, suggesting that basal degradation of IkappaBalpha also requires
      phosphorylation as the signal for degradation. Finally, we showed that the rate
      of TNFalpha-induced degradation of IG remains almost constant throughout the cell
      cycle, except at the mitotic phase, in which IG degrades more slowly.

PMID- 10409682
TI  - On the maximum size of proteins to stay and fold in the cavity of GroEL
      underneath GroES.
AB  - GroEL encapsulates non-native protein in a folding cage underneath GroES (cis
      cavity). Here we report the maximum size of the non-native protein to stay and
      fold in the cis-cavity. Using total soluble proteins of Escherichia coli in
      denatured state as binding substrates and protease resistance as the measure of
      polypeptide held in the cis-cavity, it was estimated that the cis-cavity can
      accommodate up to approximately 57-kDa non-native proteins. To know if a protein
      with nearly the maximum size can complete folding in the cis-cavity, we made a 54
      kDa protein in which green fluorescent protein (GFP) and its blue fluorescent
      variant were fused tandem. This fusion protein was captured in the cis-cavity,
      and folding occurred there. Fluorescence resonance energy transfer proved that
      both GFP and blue fluorescent protein moieties of the same fused protein were
      able to fold into native structures in the cis-cavity. Consistently, simulated
      packing of crystal structures shows that two native GFPs just fit in the cis
      cavity. A fusion protein of three GFPs (82 kDa) was also attempted, but, as
      expected, it was not captured in the cis-cavity.

PMID- 10409683
TI  - A novel serine kinase with specificity for beta3-subunits is tightly associated
      with GABA(A) receptors.
AB  - Tuning of gamma-aminobutyric acid type A (GABA(A)) receptor function via
      phosphorylation of the receptor potentially allows neurons to modulate their
      inhibitory input. Several kinases, both of the serine-threonine kinase and the
      tyrosine kinase families, have been proposed as candidates for such a modulatory
      role in vivo. However, no GABA(A) receptor-phosphorylating kinase physically
      associated with the receptor has been identified so far on a molecular level. In
      this study, we demonstrate a GABA(A) receptor-associated protein serine kinase
      phosphorylating specifically beta3-subunits of native GABA(A) receptors. The
      characteristics of this novel kinase clearly distinguish it from enzymatic
      activities that have been shown so far to phosphorylate the GABA(A) receptor. We
      putatively identify this protein kinase as the previously described GTAP34
      (GABA(A) receptor-tubulin complex-associated protein of molecular mass 34 kDa).
      Using expressed recombinant fusion proteins, we identify serine 408 as a major
      target of the phosphorylation reaction, whereas serine 407 is not phosphorylated.
      This demonstrates the high specificity of the kinase. Phosphorylation of serine
      408 is known to result in a decreased receptor function. The direct association
      of this kinase with the receptor indicates an important physiological role.

PMID- 10409684
TI  - Calpain mediates integrin-induced signaling at a point upstream of Rho family
      members.
AB  - Integrin-induced adhesion leads to cytoskeletal reorganizations, cell migration,
      spreading, proliferation, and differentiation. The details of the signaling
      events that induce these changes in cell behavior are not well understood but
      they appear to involve activation of Rho family members which activate signaling
      molecules such as tyrosine kinases, serine/threonine kinases, and lipid kinases.
      The result is the formation of focal complexes, focal adhesions, and bundles and
      networks of actin filaments that allow the cell to spread. The present study
      shows that mu-calpain is active in adherent cells, that it cleaves proteins known
      to be present in focal complexes and focal adhesions, and that overexpression of
      mu-calpain increased the cleavage of these proteins, induced an overspread
      morphology and induced an increased number of stress fibers and focal adhesions.
      Inhibition of calpain with membrane permeable inhibitors or by expression of a
      dominant negative form of mu-calpain resulted in an inability of cells to spread
      or to form focal adhesions, actin filament networks, or stress fibers. Cells
      expressing constitutively active Rac1 could still form focal complexes and actin
      filament networks (but not focal adhesions or stress fibers) in the presence of
      calpain inhibitors; cells expressing constitutively active RhoA could form focal
      adhesions and stress fibers. Taken together, these data indicate that calpain
      plays an important role in regulating the formation of focal adhesions and Rac-
      and Rho-induced cytoskeletal reorganizations and that it does so by acting at
      sites upstream of both Rac1 and RhoA.

PMID- 10409685
TI  - Crystal structures of zinc-free and -bound heme domain of human inducible nitric
      oxide synthase. Implications for dimer stability and comparison with endothelial
      nitric-oxide synthase.
AB  - The crystal structures of the heme domain of human inducible nitric-oxide
      synthase (NOS-2) in zinc-free and -bound states have been solved. In the zinc
      free structure, two symmetry-related cysteine residues form a disulfide bond. In
      the zinc-bound state, these same two cysteine residues form part of a zinc
      tetrathiolate (ZnS(4)) center indistinguishable from that observed in the
      endothelial isoform (NOS-3). As in NOS-3, ZnS(4) plays a key role in stabilizing
      intersubunit contacts and in maintaining the integrity of the cofactor
      (tetrahydrobiopterin) binding site of NOS-2. A comparison of NOS-2 and NOS-3
      structures illustrates the conservation of quaternary structure, tertiary
      topology, and substrate and cofactor binding sites, in addition to providing
      insights on isoform-specific inhibitor design. The structural comparison also
      reveals that pterin binding does not preferentially stabilize the dimer interface
      of NOS-2 over NOS-3.

PMID- 10409686
TI  - Efficient liver-specific deletion of a floxed human angiotensinogen transgene by
      adenoviral delivery of Cre recombinase in vivo.
AB  - Tissue-specific ablation of gene function is possible in vivo by the Cre-loxP
      recombinase system. We generated transgenic mice containing a human
      angiotensinogen gene flanked by loxP sites (hAGT(flox)). To examine the
      physiologic consequences of tissue-specific loss of angiotensinogen gene function
      in vivo, we constructed an adenovirus expressing Cre recombinase. Studies were
      performed in several independent lines of hAGT(flox) mice before and after
      intravenous administration of either Adcre or AdbetaGal as a control. Systemic
      administration of Adcre caused a significant decrease in circulating human
      angiotensinogen and markedly blunted the pressor response to administration of
      purified recombinant human renin. Southern blot analysis of genomic DNA from
      various organs revealed that the Cre-mediated deletion was liver-specific.
      Further analysis revealed the absence of full-length human angiotensinogen mRNA
      and protein in the liver but not the kidney of Adcre mice, consistent with the
      liver being the target for adenoviruses administered intravenously. These studies
      demonstrate that extra-hepatic sources of angiotensinogen do not contribute
      significantly to the circulating pool of angiotensinogen and provide proof-of
      principle that the Cre-loxP system can be used effectively to examine the
      contribution of the systemic and tissue renin-angiotensin system to normal and
      pathological regulation of blood pressure.

PMID- 10409687
TI  - Cardiac specific overexpression of transglutaminase II (G(h)) results in a unique
      hypertrophy phenotype independent of phospholipase C activation.
AB  - Tissue type transglutaminase (TGII, also known as G(h)) has been considered a
      multifunctional protein, with both transglutaminase and GTPase activity. The role
      of the latter function, which is proposed as a coupling mechanism between
      alpha(1)-adrenergic receptors and phospholipase C (PLC), is not well defined.
      TGII was overexpressed in transgenic mice in a cardiac specific manner to
      delineated relevant signaling pathways and their consequences in the heart.
      Cardiac transglutaminase activity in the highest expressing line was
      approximately 37-fold greater than in nontransgenic lines. However, in vivo
      signaling to PLC, as assessed by inositol phosphate turnover in [(3)H]myoinositol
      organ bath atrial preparations, was not increased in the TGII mice at base line
      or in response to alpha(1)-adrenergic receptor stimulation; nor was protein
      kinase Calpha (PKCalpha) or PKCepsilon activity enhanced in the TGII transgenic
      mice. This is in contrast to mice moderately (approximately 5-fold)
      overexpressing G(alphaq), where inositol phosphate turnover and PKC activity were
      found to be clearly enhanced. TGII overexpression resulted in a remodeling of the
      heart with mild hypertrophy, elevated expression of beta-myosin heavy chain and
      alpha-skeletal actin genes, and diffuse interstitial fibrosis. Resting
      ventricular function was depressed, but responsiveness to beta-agonist was not
      impaired. This set of pathophysiologic findings is distinct from that evoked by
      overexpression of G(alphaq). We conclude that TGII acts in the heart primarily as
      a transglutaminase, and modulation of this function results in unique pathologic
      sequelae. Evidence for TGII acting as a G-protein-like transducer of receptor
      signaling to PLC in the heart is not supported by these studies.

PMID- 10409688
TI  - The Cap-binding protein eIF4E promotes folding of a functional domain of yeast
      translation initiation factor eIF4G1.
AB  - The association of eucaryotic translation initiation factor eIF4G with the cap
      binding protein eIF4E establishes a critical link between the mRNA and the
      ribosome during translation initiation. This association requires a conserved
      seven amino acid peptide within eIF4G that binds to eIF4E. Here we report that a
      98-amino acid fragment of S. cerevisiae eIF4G1 that contains this eIF4E binding
      peptide undergoes an unfolded to folded transition upon binding to eIF4E. The
      folding of the eIF4G1 domain was evidenced by the eIF4E-dependent changes in its
      protease sensitivity and (1)H-(15)N HSQC NMR spectrum. Analysis of a series of
      charge-to-alanine mutations throughout the essential 55.4-kDa core of yeast
      eIF4G1 also revealed substitutions within this 98-amino acid region that led to
      reduced eIF4E binding in vivo and in vitro. These data suggest that the
      association of yeast eIF4E with eIF4G1 leads to the formation of a structured
      domain within eIF4G1 that could serve as a specific site for interactions with
      other components of the translational apparatus. They also suggest that the
      stability of the native eIF4E-eIF4G complex is determined by amino acid residues
      outside of the conserved seven-residue consensus sequence.

PMID- 10409689
TI  - Dominant negative forms of Akt (protein kinase B) and atypical protein kinase
      Clambda do not prevent insulin inhibition of phosphoenolpyruvate carboxykinase
      gene transcription.
AB  - Transcriptional regulation of phosphoenolpyruvate carboxykinase (PEPCK), the rate
      limiting enzyme in hepatic gluconeogenesis, by insulin was investigated with the
      use of adenovirus vectors encoding various mutant signaling proteins. Insulin
      inhibited transcription induced by dexamethasone and cAMP of a chloramphenicol
      acetyltransferase (CAT) reporter gene fused with the PEPCK promoter sequence in
      HL1C cells stably transfected with this construct. A dominant negative mutant of
      phosphoinositide (PI) 3-kinase blocked insulin inhibition of transcription of the
      PEPCK-CAT fusion gene, whereas a constitutively active mutant of PI 3-kinase
      mimicked the effect of insulin. Although a constitutively active mutant of Akt
      (protein kinase B) inhibited PEPCK-CAT gene transcription induced by
      dexamethasone and cAMP, a mutant Akt (Akt-AA) in which the phosphorylation sites
      targeted by insulin are replaced by alanine did not affect the ability of insulin
      to inhibit transcription of the fusion gene. Akt-AA almost completely inhibited
      insulin-induced activation of both endogenous and recombinant Akt in HL1C cells.
      Furthermore, neither a kinase-defective mutant protein kinase Clambda
      (PKClambda), which blocked insulin-induced activation of endogenous PKClambda,
      nor a dominant negative mutant of the small GTPase Rac prevented inhibition of
      PEPCK-CAT gene transcription by insulin. These data suggest that phosphoinositide
      3-kinase is important for insulin-induced inhibition of PEPCK gene transcription
      and that a downstream effector of phosphoinositide 3-kinase distinct from Akt,
      PKClambda, and Rac may exist for mediating the effect of insulin.

PMID- 10409690
TI  - SNAP-25 is targeted to the plasma membrane through a novel membrane-binding
      domain.
AB  - SNAP-25, syntaxin, and synaptobrevin are SNARE proteins that mediate fusion of
      synaptic vesicles with the plasma membrane. Membrane attachment of syntaxin and
      synaptobrevin is achieved through a C-terminal hydrophobic tail, whereas SNAP-25
      association with membranes appears to depend upon palmitoylation of cysteine
      residues located in the center of the molecule. This process requires an intact
      secretory pathway and is inhibited by brefeldin A. Here we show that the minimal
      plasma membrane-targeting domain of SNAP-25 maps to residues 85-120. This
      sequence is both necessary and sufficient to target a heterologous protein to the
      plasma membrane. Palmitoylation of this domain is sensitive to brefeldin A,
      suggesting that it uses the same membrane-targeting mechanism as the full-length
      protein. As expected, the palmitoylated cysteine cluster is present within this
      domain, but surprisingly, membrane anchoring requires an additional five-amino
      acid sequence that is highly conserved among SNAP-25 family members.
      Significantly, the membrane-targeting module coincides with the protease
      sensitive stretch (residues 83-120) that connects the two alpha-helices that SNAP
      25 contributes to the four-helix bundle of the synaptic SNARE complex. Our
      results demonstrate that residues 85-120 of SNAP-25 represent a protein module
      that is physically and functionally separable from the SNARE complex-forming
      domains.

PMID- 10409691
TI  - Heme degradation as catalyzed by a recombinant bacterial heme oxygenase (Hmu O)
      from Corynebacterium diphtheriae.
AB  - Hmu O, a heme degradation enzyme in the pathogen Corynebacterium diphtheriae,
      catalyzes the oxygen-dependent conversion of hemin to biliverdin, carbon
      monoxide, and free iron. A bacterial expression system using a synthetic gene
      coding for the 215-amino acid, full-length Hmu O has been constructed. Expressed
      at very high levels in Escherichia coli BL21, the enzyme binds hemin
      stoichiometrically to form a hexacoordinate high spin hemin-Hmu O complex. When
      ascorbic acid is used as the electron donor, Hmu O converts hemin to biliverdin
      with alpha-hydroxyhemin and verdoheme as intermediates. The overall conversion
      rate to biliverdin is approximately 4-fold slower than that by rat heme oxygenase
      (HO) isoform 1. Reaction of the hemin-Hmu O complex with hydrogen peroxide yields
      a verdoheme species, the recovery of which is much less compared with rat HO-1.
      Reaction of the hemin complex with meta-chloroperbenzoic acid generates a ferryl
      oxo species. Thus, the catalytic intermediate species and the nature of the
      active form in the first oxygenation step of Hmu O appear to be similar to those
      of the mammalian HO. However, the considerably slow catalytic rate and low level
      of verdoheme recovery in the hydrogen peroxide reaction suggest that the active
      site structure of Hmu O is different from that of its mammalian counterpart.

PMID- 10409692
TI  - Phospholipid hydroperoxides are substrates for non-selenium glutathione
      peroxidase.
AB  - This study investigated phospholipid hydroperoxides as substrates for non
      selenium GSH peroxidase (NSGPx), an enzyme also called 1-Cys peroxiredoxin.
      Recombinant human NSGPx expressed in Escherichia coli from a human cDNA clone
      (HA0683) showed GSH peroxidase activity with sn-2-linolenoyl- or sn-2
      arachidonoyl-phosphatidylcholine hydroperoxides as substrate; NADPH or
      thioredoxin could not substitute for GSH. Activity did not saturate with GSH, and
      kinetics were compatible with a ping-pong mechanism; kinetic constants (mM(-1)
      min(-1)) were k(1) = 1-3 x 10(5) and k(2) = 4-11 x 10(4). In the presence of 0.36
      mM GSH, apparent K(m) was 120-130 microM and apparent V(max) was 1.5-1.6
      micromol/min/mg of protein. Assays with H(2)O(2) and organic hydroperoxides as
      substrate indicated activity similar to that with phospholipid hydroperoxides.
      Maximal enzymatic activity was at pH 7-8. Activity with phospholipid
      hydroperoxide substrate was inhibited noncompetitively by mercaptosuccinate with
      K(i) 4 miroM. The enzyme had no GSH S-transferase activity. Bovine cDNA encoding
      NSGPx, isolated from a lung expression library using a polymerase chain reaction
      probe, showed >95% similarity to previously published human, rat, and mouse
      sequences and does not contain the TGA stop codon, which is translated as
      selenocysteine in selenium-containing peroxidases. The molecular mass of bovine
      NSGPx deduced from the cDNA is 25,047 Da. These results identify a new GSH
      peroxidase that is not a selenoenzyme and can reduce phospholipid hydroperoxides.
      Thus, this enzyme may be an important component of cellular antioxidant defense
      systems.

PMID- 10409693
TI  - Phosphatidic acid is a potent and selective inhibitor of protein phosphatase 1
      and an inhibitor of ceramide-mediated responses.
AB  - In the present study, we report that phosphatidic acid (PA) functions as a novel,
      potent, and selective inhibitor of protein phosphatase 1 (PP1). The catalytic
      subunit of PP1alpha was inhibited by PA dose-dependently in a noncompetitive
      manner with a K(i) value of 80 nM. The inhibition by PA was specific to PP1 as PA
      failed to inhibit protein phosphatase 2A (PP2A) or PP2B. Furthermore, PA was the
      most effective and potent inhibitor of PP1 compared with other phospholipids.
      Because we recently showed that ceramides activated PP1, we next examined the
      effects of PA on ceramide stimulation of PP1. PA inhibited both basal and
      ceramide-stimulated PP1 activities, and ceramide showed potent and
      stereoselective activation of PP1 in the presence of PA. Next, the effects of PA
      on ceramide-induced responses were examined. Molt-4 cells took up PA dose- and
      time-dependently such that by 1 and 3 h, uptake of PA was 0.37 and 0. 65% of
      total PA added, respectively. PA at 30 microM and calyculin A at 10 nM (an
      inhibitor of PP1 and PP2A at low concentrations), but not okadaic acid at 10 nM
      (a PP2A inhibitor at low concentrations) prevented poly(ADP-ribose) polymerase
      proteolysis induced by C(6)-ceramide. Moreover, the combination of PA with
      okadaic acid prevented retinoblastoma gene product dephosphorylation induced by
      C(6)-ceramide. These data suggest that PA functions as a specific regulator of
      PP1 and may reverse or counteract those effects of ceramide that are mediated by
      PP1, such as apoptosis and retinoblastoma gene product dephosphorylation.

PMID- 10409694
TI  - Mutational analysis of the hydrolytic activity of yeast RNA polymerase III.
AB  - For 25 mutant alleles of ret1, encoding the second largest subunit of yeast RNA
      polymerase III, we have studied the polymerase III nuclease activity, measuring
      both the total yield and dinucleotide product composition. Mutations affecting
      amino acids 309-325 gave slightly elevated nuclease activity. In region 367-376,
      two mutations gave 12-15-fold increased nuclease activity. Our results do not
      support the catalytic role in nuclease activity proposed for the conserved DDRD
      motif in this region (Shirai, T., and Go, M. (1991) Proc. Natl. Acad. Sci. U. S.
      A. 88, 9056-9060). Mutations centered on a basic region from amino acids 480 to
      490, which aligns with Escherichia coli beta-subunit sequences between Rif(r)
      clusters I and II, produce changes in the relative yields of A- and G-containing
      dinucleotides. Four such mutant polymerases pause during elongation at GPy
      sequences and, in addition, have a reduced frequency of termination at T(5)
      terminator sequences. We propose that the side chains of these mutationally
      altered amino acids are in direct contact with bases in the RNA-DNA hybrid very
      near the growing 3'-end. Two mutations in domain I near the C terminus produced
      very large increases in exonuclease activity and strongly increased termination,
      suggesting that this region also contacts the nascent RNA in the hybrid region.

PMID- 10409695
TI  - Factor VIIa-induced p44/42 mitogen-activated protein kinase activation requires
      the proteolytic activity of factor VIIa and is independent of the tissue factor
      cytoplasmic domain.
AB  - Signal transduction induced by activated factor VII (FVIIa) was studied with baby
      hamster kidney (BHK) cells transfected with human tissue factor (TF). FVIIa
      induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) in
      cells expressing TF, BHK(+TF), but not in wild-type BHK(-TF) cells. BHK(+TF)
      cells responded to FVIIa in a dose-dependent manner, with detectable
      phosphorylation above 10-20 nM FVIIa. BHK cells transfected with a cytoplasmic
      domain-deleted version of TF, (des248-263)TF, or a C245S substitution variant of
      TF also supported FVIIa-induced MAPK activation. Experiments with active site
      inhibited FVIIa, thrombin, factor Xa, and hirudin confirmed that the catalytic
      activity of FVIIa was mandatory for p44/42 MAPK activation. Furthermore, a high
      concentration of FVIIa in complex with soluble TF induced p44/42 MAPK
      phosphorylation in BHK(-TF) cells. These data suggest that TF was not directly
      involved in FVIIa-induced p44/42 MAPK phosphorylation but rather served to
      localize the action of FVIIa to the cell surface, potentially to cleave a cell
      surface receptor. Desensitization experiments with sequential addition of
      proteases suggested that the p44/42 MAPK response induced by FVIIa was distinctly
      different from the thrombin response, possibly involving a novel member of the
      protease-activated receptor family.

PMID- 10409696
TI  - Interaction and specificity of Rel-related proteins in regulating Drosophila
      immunity gene expression.
AB  - NF-kappaB/Rel family proteins regulate genes that are critical for many cellular
      processes including apoptosis, inflammation, immune response, and development. NF
      kappaB/Rel proteins function as homodimers or heterodimers, which recognize
      specific DNA sequences within target promoters. We examined the activity of
      different Drosophila Rel-related proteins in modulating Drosophila immunity genes
      by expressing the Rel proteins in stably transfected cell lines. We also compared
      how different combinations of these transcriptional regulators control the
      activity of various immunity genes. The results show that Rel proteins are
      directly involved in regulating the Drosophila antimicrobial response.
      Furthermore, the drosomycin and defensin expression is best induced by the
      Relish/Dif and the Relish/Dorsal heterodimers, respectively, whereas the attacin
      activity can be efficiently up-regulated by the Relish homodimer and
      heterodimers. These results illustrate how the formation of Rel protein dimers
      differentially regulate target gene expression.

PMID- 10409697
TI  - Biophysical and functional characterization of full-length, recombinant human
      tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherichia coli.
      Comparison of wild type and amino-terminal alanine appended variant with
      implications for the mechanism of TIMP functions.
AB  - Matrix metalloproteinases (MMPs) function in the remodeling of the extracellular
      matrix that is integral for many normal and pathological processes. The tissue
      inhibitor of metalloproteinases family, including tissue inhibitor of
      metalloproteinases-2 (TIMP-2), regulates the activity of these multifunctional
      metalloproteinases. TIMP family members are proteinase inhibitors that contain
      six conserved disulfide bonds, one involving an amino-terminal cysteine residue
      that is critical for MMP inhibitor activity. TIMP-2 has been expressed in
      Escherichia coli, folded from insoluble protein, and functionally characterized.
      The wild type protein inhibited gelatinase A (MMP-2), whereas a variant with an
      alanine appended to the amino terminus (Ala+TIMP-2) was inactive. Removal of
      amino-terminal alanine by exopeptidase digestion restored protease inhibitor
      activity. This confirms the mechanistic importance of the amino-terminal amino
      group in the metalloproteinase inhibitory activity, as originally suggested from
      the x-ray structure of a complex of MMP-3 with TIMP-1 and a complex of TIMP-2
      with MT-1-MMP. The Ala+TIMP-2 variant exhibited conformational, pro-MMP-2 complex
      formation and fibroblast growth modulating properties of the wild type protein.
      These findings demonstrate that Ala+TIMP-2 is an excellent biochemical tool for
      examining the specific role of MMP inhibition in the multiple functions ascribed
      to TIMPs.

PMID- 10409698
TI  - Cholesterol-dependent localization of NAP-22 on a neuronal membrane microdomain
      (raft).
AB  - A membrane microdomain called raft has been under extensive study since the
      assembly of various signal-transducing molecules into this region has been
      envisaged. This domain is isolated as a low buoyant membrane fraction after the
      extraction with a nonionic detergent such as Triton X-100. The characteristic low
      density of this fraction is ascribed to the enrichment of several lipids
      including cholesterol. To clear the molecular mechanism of raft formation,
      several extraction methods were applied to solubilize raft components.
      Cholesterol extraction using methyl-beta-cyclodextrin was found to be effective
      to solubilize NAP-22, a neuron-enriched Ca(2+)-dependent calmodulin-binding
      protein as well as one of the main protein components of brain raft. Purified NAP
      22 bound to the liposomes that were made from phosphatidylcholine and
      cholesterol. This binding was dependent on the amount of cholesterol in
      liposomes. Calmodulin inhibited this binding in a dose-dependent manner. These
      results suggest that the presence of a calcium-dependent regulatory mechanism
      works on the assembly of raft within the neuron.

PMID- 10409699
TI  - Identification, expression, and characterization of a cDNA encoding human
      endoplasmic reticulum mannosidase I, the enzyme that catalyzes the first mannose
      trimming step in mammalian Asn-linked oligosaccharide biosynthesis.
AB  - We have isolated a full-length cDNA clone encoding a human alpha1, 2-mannosidase
      that catalyzes the first mannose trimming step in the processing of mammalian Asn
      linked oligosaccharides. This enzyme has been proposed to regulate the timing of
      quality control glycoprotein degradation in the endoplasmic reticulum (ER) of
      eukaryotic cells. Human expressed sequence tag clones were identified by sequence
      similarity to mammalian and yeast oligosaccharide-processing mannosidases, and
      the full-length coding region of the putative mannosidase homolog was isolated by
      a combination of 5'-rapid amplification of cDNA ends and direct polymerase chain
      reaction from human placental cDNA. The open reading frame predicted a 663-amino
      acid type II transmembrane polypeptide with a short cytoplasmic tail (47 amino
      acids), a single transmembrane domain (22 amino acids), and a large COOH-terminal
      catalytic domain (594 amino acids). Northern blots detected a transcript of
      approximately 2.8 kilobase pairs that was ubiquitously expressed in human
      tissues. Expression of an epitope-tagged full-length form of the human
      mannosidase homolog in normal rat kidney cells resulted in an ER pattern of
      localization. When a recombinant protein, consisting of protein A fused to the
      COOH-terminal luminal domain of the human mannosidase homolog, was expressed in
      COS cells, the fusion protein was found to cleave only a single alpha1,2-mannose
      residue from Man(9)GlcNAc(2) to produce a unique Man(8)GlcNAc(2) isomer (Man8B).
      The mannose cleavage reaction required divalent cations as indicated by
      inhibition with EDTA or EGTA and reversal of the inhibition by the addition of
      Ca(2+). The enzyme was also sensitive to inhibition by deoxymannojirimycin and
      kifunensine, but not swainsonine. The results on the localization, substrate
      specificity, and inhibitor profiles indicate that the cDNA reported here encodes
      an enzyme previously designated ER mannosidase I. Enzyme reactions using a
      combination of human ER mannosidase I and recombinant Golgi mannosidase IA
      indicated that that these two enzymes are complementary in their cleavage of
      Man(9)GlcNAc(2) oligosaccharides to Man(5)GlcNAc(2).

PMID- 10409700
TI  - A comparison of eubacterial and archaeal structure-specific 5'-exonucleases.
AB  - The 5'-exonuclease domains of the DNA polymerase I proteins of Eubacteria and the
      FEN1 proteins of Eukarya and Archaea are members of a family of structure
      specific 5'-exonucleases with similar function but limited sequence similarity.
      Their physiological role is to remove the displaced 5' strands created by DNA
      polymerase during displacement synthesis, thereby creating a substrate for DNA
      ligase. In this paper, we define the substrate requirements for the 5'
      exonuclease enzymes from Thermus aquaticus, Thermus thermophilus, Archaeoglobus
      fulgidus, Pyrococcus furiosus, Methanococcus jannaschii, and Methanobacterium
      thermoautotrophicum. The optimal substrate of these enzymes resembles DNA
      undergoing strand displacement synthesis and consists of a bifurcated downstream
      duplex with a directly abutted upstream duplex that overlaps the downstream
      duplex by one base pair. That single base of overlap causes the enzymes to leave
      a nick after cleavage and to cleave several orders of magnitude faster than a
      substrate that lacks overlap. The downstream duplex needs to be 10 base pairs
      long or greater for most of the enzymes to cut efficiently. The upstream duplex
      needs to be only 2 or 3 base pairs long for most enzymes, and there appears to be
      interaction with the last base of the primer strand. Overall, the enzymes display
      very similar substrate specificities, despite their limited level of sequence
      similarity.

PMID- 10409701
TI  - Transient increases in intracellular calcium result in prolonged site-selective
      increases in Tau phosphorylation through a glycogen synthase kinase 3beta
      dependent pathway.
AB  - Calcium is a universal intracellular signaling molecule. Through variations in
      both the amplitude and frequency of intracellular calcium increases, the same
      calcium ion can elicit different responses. In this report, we investigated the
      effect of a calcium transient, lasting 2-5 min, on alterations in the
      phosphorylation state of the cytoskeletal protein, tau. Transient increases in
      calcium result in a prolonged (1-4 h) approximately 60% increase in tau
      phosphorylation at the Tau-1 epitope. These increases in tau phosphorylation
      appear to be more dependent upon the duration of the increase in intracellular
      calcium and less on the amplitude. The calcium-induced increases in tau
      phosphorylation are not dependent upon protein synthesis, nor are protein kinase
      C or calcium/calmodulin-dependent protein kinase II involved in the response.
      However, the calcium-induced increase in tau phosphorylation was inhibited by
      lithium, a noncompetitive inhibitor of glycogen synthase kinase-3beta (GSK
      3beta), and by the tyrosine kinase inhibitor, genistein. Furthermore, transient
      increases in calcium resulted in a prolonged increase in GSK-3beta tyrosine
      phosphorylation concomitant with the increase in tau phosphorylation. Therefore,
      this study is the first to indicate that transient increases in intracellular
      calcium result in increased tyrosine phosphorylation and activation of GSK-3beta
      which subsequently results in a sustained increase in the phosphorylation state
      of tau.

PMID- 10409702
TI  - Expression of human fibroblast growth factor 2 mRNA is post-transcriptionally
      controlled by a unique destabilizing element present in the 3'-untranslated
      region between alternative polyadenylation sites.
AB  - Fibroblast growth factor 2 (FGF-2) belongs to a family of 18 genes coding for
      either mitogenic differentiating factors or oncogenic proteins, the expression of
      which must be tightly controlled. We looked for regulatory elements in the 5823
      nucleotide-long 3'-untranslated region of the FGF-2 mRNA that contains eight
      potential alternative polyadenylation sites. Quantitative reverse transcription
      polymerase chain reaction revealed that poly(A) site utilization was cell type
      dependent, with the eighth poly(A) site being used (95%) in primary human skin
      fibroblasts, whereas proximal sites were used in the transformed cell lines
      studied here. We used a cell transfection approach with synthetic reporter mRNAs
      to localize a destabilizing element between the first and second poly(A) sites.
      Although AU-rich, the FGF-2-destabilizing element had unique features: it
      involved a 122-nucleotide direct repeat, with both elements of the repeat being
      required for the destabilizing activity. These data show that short stable FGF-2
      mRNAs are present in transformed cells, whereas skin fibroblasts contain mostly
      long unstable mRNAs, suggesting that FGF-2 mRNA stability cannot be regulated in
      transformed cells. The results also provide evidence of a multilevel post
      transcriptional control of FGF-2 expression; such a stringent control prevents
      FGF-2 overexpression and permits its expression to be enhanced only in relevant
      physiological situations.

PMID- 10409703
TI  - p120(ctn) binds to the membrane-proximal region of the E-cadherin cytoplasmic
      domain and is involved in modulation of adhesion activity.
AB  - Cadherins are transmembrane glycoproteins involved in Ca(2+)-dependent cell-cell
      adhesion. Previously, we showed that the conserved membrane-proximal region of
      the E-cadherin cytoplasmic domain negatively regulates adhesion activity. In this
      report, we provide several lines of evidence that p120(ctn) is involved in this
      negative regulation. p120(ctn) binds to the membrane-proximal region of the
      nonfunctional carboxyl-terminally deleted E-cadherin protein. An additional
      internal deletion in this region prevented the association with p120(ctn) and
      activated the protein, as seen in an aggregation assay. Furthermore, the
      nonfunctional E-cadherin can be activated through coexpression of p120(ctn)
      proteins with amino-terminal deletions, which eliminate several potential
      serine/threonine phosphorylation sites but do not affect the ability to bind to
      cadherins. Finally, we show that staurosporine, a kinase inhibitor, induces an
      increased electrophoretic mobility of p120(ctn) bound to E-cadherin polypeptides,
      activates the nonfunctional E-cadherin protein, and converts the wild-type E
      cadherin and an E-cadherin-alpha-catenin chimeric protein from a cytochalasin D
      sensitive to a cytochalasin D-insensitive state. Together, these results indicate
      that p120(ctn) is a modulator of E-cadherin-mediated cell adhesion.

PMID- 10409704
TI  - Subcellular localization and internalization of the four human leptin receptor
      isoforms.
AB  - There are four known isoforms of the human leptin receptor (HLR) with different C
      terminal cytoplasmic domains (designated by the number of unique C-terminal amino
      acids). In cells expressing HLR-5, -15, or -274, 15-25% of the leptin binding
      sites were located at the plasma membrane. In contrast, in cells expressing HLR
      67, only 5% of the total binding sites were at the plasma membrane.
      Immunofluorescent microscopy showed that all four isoforms partially co-localized
      with calnexin and beta-COP, markers of the endoplasmic reticulum and the Golgi,
      respectively. All isoforms were also detected in an unidentified punctate
      compartment. All isoforms were internalized via clathrin-mediated endocytosis,
      but at different rates. After 20 min at 37 degrees C, 45% of a bound cohort of
      labeled ligand had been internalized by HLR-15, 30% by HLR-67, 25% by HLR-274,
      and 15% by HLR-5. Degradation of internalized leptin occurred in lysosomes.
      Overnight exposure to leptin down-regulated all isoforms, but to a variable
      extent. HLR-274 displayed the greatest down-regulation and also appeared to reach
      lysosomes more quickly than the other isoforms. The faster degradation of HLR-274
      may help to terminate leptin signaling.

PMID- 10409705
TI  - Selective association of G protein beta(4) with gamma(5) and gamma(12) subunits
      in bovine tissues.
AB  - The beta and gamma subunits of G proteins are tightly bound under physiological
      conditions, and so far, seven beta and 11 gamma subunit isoforms have been found.
      The relative abilities of the beta and gamma subunits to associate with each
      other have been studied using transfected cell assays, in vitro translation and
      the yeast two-hybrid system, but have not been fully characterized in various
      tissues. In the present study, we demonstrated the selectivity of association of
      the beta with gamma isoforms in bovine tissues. Immunoprecipitation of betagamma
      complexes from tissue extracts with antibodies against various gamma subunits and
      subsequent analyses revealed that beta(4) associated with the gamma subunits with
      the following rank order of selectivity: gamma(5) > gamma(12) > gamma(2) >
      gamma(3), while beta(2) bound to gamma(2), gamma(3), and gamma(12) more
      selectively than to gamma(5). By contrast, beta(1) associated with all gamma
      subunits without significant selectivity. Analyses of purified betagamma
      complexes containing various gamma isoforms revealed beta subunit compositions
      similar to those found in the immunoprecipitates. Particular combinations of beta
      and gamma subunit isoforms may contribute to maintaining efficient and specific
      signal transduction mediated by G proteins.

PMID- 10409706
TI  - Polarized distribution of endogenous Rac1 and RhoA at the cell surface.
AB  - Rac1 and RhoA regulate membrane ruffling and stress fiber formation. Both
      molecules appear to exert their control from the plasma membrane. In fibroblasts
      stimulated with platelet-derived growth factor or lysophosphatidic acid, the
      reorganization of the cytoskeleton begins at specific sites on the cell surface.
      We now report that endogenous Rac1 and RhoA also have a polarized distribution at
      the cell surface. Cell fractionation and immunogold labeling show that in
      quiescent fibroblasts both of these molecules are concentrated in caveolae, which
      are plasma membrane domains that are associated with actin-rich regions of the
      cell. Treatment of these cells with platelet-derived growth factor stimulated the
      recruitment of additional Rac1 and RhoA to caveolae fractions, while
      lysophosphatidic acid only caused the recruitment of RhoA. We could reconstitute
      the recruitment of RhoA using either whole cell lysates or purified caveolae.
      Surprisingly, pretreatment of the lysates with exoenzyme C3 shifted both resident
      and recruited RhoA from caveolae to noncaveolae membranes. The shift in location
      was not caused by inactivation of the RhoA effector domain. Moreover, chimeric
      proteins containing the C-terminal consensus site for Rac1 and RhoA prenylation
      were constitutively targeted to caveolae fractions. These results suggest that
      the polarized distribution of Rho family proteins at the cell surface involves an
      initial targeting of the protein to caveolae and a mechanism for retaining it at
      this site.

PMID- 10409707
TI  - Folding and assembly in rhodopsin. Effect of mutations in the sixth transmembrane
      helix on the conformation of the third cytoplasmic loop.
AB  - Previous studies on bovine opsin folding and assembly have identified an amino
      terminal fragment, EF(1-232), which folds and inserts into a membrane only after
      coexpression with its complementary carboxyl-terminal fragment, EF(233-348). To
      further characterize this interaction, EF(1-232) production was examined upon
      coexpression with carboxyl-terminal fragments of varying length and/or amino acid
      composition. These included fragments with incremental deletions of the third
      cytoplasmic loop (TH(241-348) and EF(249-348)), a fragment composed of the third
      cytoplasmic loop and sixth transmembrane helix (HF(233-280)), a fragment composed
      of the sixth and seventh transmembrane helices (FG(249-312)), and EF(233-348) and
      TH(241-348) fragments with Pro-267 or Trp-265 mutations. Although EF(1-232)
      production was independent of the third cytoplasmic loop and carboxyl-terminal
      tail, both the sixth and seventh transmembrane helices were essential. The
      effects of mutations in the sixth transmembrane helix on EF(1-232) expression
      were dependent on the length of the third cytoplasmic loop. Although Pro-267
      mutations in EF(233-348) failed to stabilize EF(1-232) expression, their
      introduction into TH(241-348) was without discernible effects. However, Trp-265
      substitutions in the EF(233-348) and TH(241-348) fragments conferred significant
      EF(1-232) production. Therefore, key residues in the transmembrane helices may
      exert their effects on opsin folding, assembly, and/or function by influencing
      the conformation of the connecting loops.

PMID- 10409708
TI  - The p75 neurotrophin receptor (p75NTR) alters tumor necrosis factor-mediated NF
      kappaB activity under physiological conditions, but direct p75NTR-mediated NF
      kappaB activation requires cell stress.
AB  - The p75 neurotrophin receptor (p75NTR) has been linked to activation of the NF
      kappaB transcriptional complex in oligodendrocytes, Schwann cells, and PCNA
      cells. In this report, tumor necrosis factor (TNF)- and neurotrophin-mediated NF
      (nuclear factor)-kappaB activation were compared in several cell lines. All cell
      types showed TNF-mediated activation of NF-kappaB, but direct neurotrophin
      dependent activation of NF-kappaB was never observed under normal growth
      conditions. In PCNA cells, a modest nerve growth factor (NGF)-dependent induction
      of NF-kappaB was detected but only after cells were subjected to severe stress.
      Although NGF binding did not directly activate NF-kappaB under normal conditions,
      NGF consistently altered TNF-dependent NF-kappaB activation in each cell type
      examined, and extended exposure to NGF and TNF always increased NF-kappaB
      activation over that achieved with TNF alone. The increase in NF-kappaB activity
      mediated by NGF correlated with reduced levels of IkappaBalpha; NGF added alone
      had no effect on IkappaBalpha levels, but when added with TNF, NGF treatment
      significantly reduced IkappaBalpha levels. We propose that modulation of cytokine
      receptor signaling is a significant physiological function of the p75
      neurotrophin receptor and that previous reports of direct NF-kappaB activation
      through p75NTR reflect this modulatory activity.

PMID- 10409709
TI  - YND1, a homologue of GDA1, encodes membrane-bound apyrase required for Golgi N-
      and O-glycosylation in Saccharomyces cerevisiae.
AB  - The gene for the open reading frame YER005w that is homologous to yeast Golgi
      GDPase encoded by the GDA1 gene was cloned and named YND1. It encodes a 630-amino
      acid protein that contains a single transmembrane region near the carboxyl
      terminus. The overexpression of the YND1 gene in the gda1 null mutant caused a
      significant increase in microsomal membrane-bound nucleoside phosphatase activity
      with a luminal orientation. The activity was equally high toward ADP/ATP,
      GDP/GTP, and UDP/UTP and approximately 50% less toward CDP/CTP and thiamine
      pyrophosphate, but there was no activity toward GMP, indicating that the Ynd1
      protein belongs to the apyrase family. This substrate specificity is different
      from that of yeast GDPase, but similar to that of human Golgi UDPase. The
      Deltaynd1 mutant cells were defective in O- and N-linked glycosylation in the
      Golgi compartments. The overexpression of the YND1 gene complemented some
      glycosylation defects in Deltagda1 disruptants, suggesting a partially redundant
      function of yeast apyrase and GDPase. From these results and the phenotype of the
      Deltaynd1Deltagda1 double deletion showing a synthetic effect, we conclude that
      yeast apyrase is required for Golgi glycosylation and cell wall integrity,
      providing the first direct evidence for the in vivo function of intracellular
      apyrase in eukaryotic cells.

PMID- 10409710
TI  - Serine phosphorylation of the ligand-activated beta-platelet-derived growth
      factor receptor by casein kinase I-gamma2 inhibits the receptor's
      autophosphorylating activity.
AB  - Platelet-derived growth factor (PDGF) receptors (PDGFRs) are membrane protein
      tyrosine kinases that, upon activation, become tyrosine-phosphorylated and
      associate with numerous SH2 domain-containing molecules involved in mediating
      signal transduction. In Rat-2 fibroblasts, we have characterized the
      phosphorylation of the beta-PDGFR following its activation by PDGF. In contrast
      to tyrosine phosphorylation, which was transient and returned to near basal
      levels by 30 min, PDGF-stimulated Ser/Thr phosphorylation of the beta-PDGFR was
      increased by 5 min and remained elevated after 30 min. In vivo, after 5 min of
      PDGF stimulation, serine phosphorylation of the beta-PDGFR was greatly reduced by
      CKI-7, a specific inhibitor of casein kinase I (CKI). In vitro, recombinant CKI
      gamma2 phosphorylated the ligand-activated beta-PDGFR on serine residues in a CKI
      7-sensitive manner and resulted in a marked inhibition of the receptor's
      autophosphorylating activity. Furthermore, in Rat-2 fibroblasts, expression of
      hemagglutinin epitope-tagged active CKI-gamma2 resulted in a dramatic decrease in
      the tyrosine phosphorylation state of the beta-PDGFR in response to PDGF,
      consistent with receptor inactivation. Our data suggest that upon PDGF
      stimulation, CKI-gamma2 is activated and/or translocated in proximity to the beta
      PDGFR, whereby it phosphorylates the beta-PDGFR on serine residues and negatively
      regulates its tyrosine kinase activity, leading to receptor inactivation.

PMID- 10409711
TI  - Characterization of mouse dishevelled (Dvl) proteins in Wnt/Wingless signaling
      pathway.
AB  - The dishevelled (dsh) gene family encodes cytoplasmic proteins that have been
      implicated in Wnt/Wingless (Wg) signaling. To demonstrate functional conservation
      of Dsh family proteins, two mouse homologs of Drosophila Dsh, Dvl-1 and Dvl-2,
      were biochemically characterized in mouse and Drosophila cell culture systems. We
      found that treatment with a soluble Wnt-3A leads to hyperphosphorylation of Dvl
      proteins and a concomitant elevation of the cytoplasmic beta-catenin levels in
      mouse NIH3T3, L, and C57MG cells. This coincides well with our finding in a
      Drosophila wing disc cell line, clone-8, that Wg treatment induced
      hyperphosphorylation of Dsh (Yanagawa, S., van Leeuwen, F., Wodarz, A.,
      Klingensmith, J., and Nusse, R. (1995) Genes Dev. 9, 1087-1097). Furthermore, we
      showed that mouse Dvl proteins affect downstream components of Drosophila Wg
      signaling as Dsh does; overexpression of Dvl proteins in clone-8 cells results in
      elevation of Armadillo (Drosophila homolog of beta-catenin) and Drosophila E
      cadherin levels, hyperphosphorylation of Dvl proteins themselves, and inhibition
      of Zeste-White3 kinase-mediated phosphorylation of a microtubule-binding protein,
      Tau. In addition, casein kinase II was shown to coimmunoprecipitate with Dvl
      proteins, and Dvl proteins were phosphorylated in these immune complexes. These
      results are direct evidence that Dsh family proteins mediate a set of conserved
      biochemical processes in the Wnt/Wg signaling pathway.

PMID- 10409712
TI  - A 36-residue peptide contains all of the information required for 7B2-mediated
      activation of prohormone convertase 2.
AB  - The prohormone convertases (PCs) are serine proteinases responsible for the
      processing of secretory protein precursors. PC2 is the only member of this family
      whose activation requires intracellular interaction with a helper protein, the
      neuroendocrine protein 7B2. In order to gain a better understanding of the
      mechanism of proPC2 activation, we have characterized the structural determinants
      of 7B2 required for proPC2 activation. We had already identified a proline-rich
      binding determinant in the 21-kDa domain, the portion of 7B2 responsible for
      proPC2 activation. We have now investigated the function of the weakly conserved
      amino-terminal portion of 21-kDa 7B2 by sequential deletions. Mutant proteins
      were analyzed in four assays: binding to proPC2, facilitation of proPC2
      maturation, and activation of proPC2 in vivo and in vitro. We found that the
      amino-terminal half of 7B2 is not involved in proPC2 activation, and we
      identified an active 36-residue peptide that contains the previously
      characterized proline-rich sequence as well as an alpha-helix and the only
      disulfide bond of 7B2. Mutation of the alpha-helix and of the cysteines
      demonstrated that these determinants are absolutely required for PC2 activation.
      Thus, the 186-residue full-length 7B2 rat protein can be functionally reduced to
      an internal segment of only 36 residues.

PMID- 10409713
TI  - Fiz1, a novel zinc finger protein interacting with the receptor tyrosine kinase
      Flt3.
AB  - The receptor tyrosine kinase Flt3 has been shown to play a role in proliferation
      and survival of hematopoietic progenitor cells as well as differentiation of
      early B lymphoid progenitors. However, the signaling events that control growth
      or differentiation are not completely understood. In order to identify new
      signaling molecules interacting with the cytoplasmic domain of Flt3, we performed
      a yeast two-hybrid screen. In addition to several SH2 domain-containing proteins,
      we have isolated a novel Flt3 interacting zinc finger protein (Fiz1) with 11
      C(2)H(2)-type zinc fingers. Fiz1 binds to the catalytic domain of Flt3 but not to
      the structurally related receptor tyrosine kinases Kit, Fms, and platelet-derived
      growth factor receptor. This association is independent of kinase activity. The
      interaction between Flt3 and Fiz1 detected in yeast was confirmed by in vitro and
      in vivo coprecipitation assays. Fiz1 mRNA is expressed in all murine cell lines
      and tissues tested. Anti-Fiz1 antibodies recognize a 60-kDa protein, which is
      localized in the nucleus as well as in the cytoplasm. Together, these results
      identified a novel class of interaction between a receptor tyrosine kinase and a
      signaling molecule which is independent of the well established SH2
      domain/phosphotyrosine binding.

PMID- 10409714
TI  - Induction of megakaryocyte differentiation by a novel pregnancy-specific hormone.
AB  - Maturation of megakaryocytes and subsequent platelet release are normally
      regulated by a network of cytokines, including thrombopoietin and various
      interleukins. Because abnormal platelet production and activation have been
      implicated in gestational pathologies, additional pregnancy-specific cytokines
      may play important roles in the regulation of megakaryocytopoiesis. Consistent
      with this hypothesis, we have found that the hormone prolactin-like protein E, a
      placental hormone that we have recently characterized, targets megakaryocytes
      through a specific cell surface receptor and induces megakaryocyte
      differentiation through a gp130-dependent signal transduction pathway.

PMID- 10409715
TI  - Regulation of DNA-dependent activities by the functional motifs of the high
      mobility-group chromosomal proteins.

PMID- 10409716
TI  - Mutations in translation initiation factors lead to increased rates of
      deadenylation and decapping of mRNAs in Saccharomyces cerevisiae.
AB  - The turnover of most mRNAs in Saccharomyces cerevisiae begins with deadenylation
      followed by decapping and 5'-->3' exonucleolytic digestion. An important question
      involves the mechanisms that allow particular mRNAs to exhibit different rates of
      both deadenylation and decapping. Since the cap structure plays a critical role
      in the assembly of translation initiation factors, we hypothesized that the
      status of the cytoplasmic cap binding complex would affect the rate of decapping.
      To test this hypothesis, we examined mRNA decay rates in yeast strains that were
      defective in several translation initiation factors that are part of the cap
      binding complex. These experiments yielded three significant observations. First,
      any mutation known to inhibit translation initiation also increased the rate of
      decapping. Second, decapping still occurred only after deadenylation, suggesting
      that the ability of the poly(A) tail to inhibit decapping does not require
      efficient translation of the transcript. Third, mutants with defects in
      translation initiation factors also showed an increase in the rate of
      deadenylation, suggesting that the rate of deadenylation may be controlled
      primarily by the translation status of the transcript. These results argue that
      the nature of the translation initiation complex is a critical factor in
      determining the mRNA half-life. This view also implies that some cis-acting
      sequences that modulate mRNA decay rate do so by affecting the translation status
      of the transcript.

PMID- 10409717
TI  - Mutations in elongation factor 1beta, a guanine nucleotide exchange factor,
      enhance translational fidelity.
AB  - Translation elongation factor 1beta (EF-1beta) is a member of the family of
      guanine nucleotide exchange factors, proteins whose activities are important for
      the regulation of G proteins critical to many cellular processes. EF-1beta is a
      highly conserved protein that catalyzes the exchange of bound GDP for GTP on EF
      1alpha, a required step to ensure continued protein synthesis. In this work, we
      demonstrate that the highly conserved C-terminal region of Saccharomyces
      cerevisiae EF-1beta is sufficient for normal cell growth. This region of yeast
      and metazoan EF-1beta and the metazoan EF-1beta-like protein EF-1delta is highly
      conserved. Human EF-1beta, but not human EF-1delta, is functional in place of
      yeast EF-1beta, even though both EF-1beta and EF-1delta have previously been
      shown to have guanine nucleotide exchange activity in vitro. Based on the
      sequence and functional homology, mutagenesis of two C-terminal residues
      identical in all EF-1beta protein sequences was performed, resulting in mutants
      with growth defects and sensitivity to translation inhibitors. These mutants also
      enhance translational fidelity at nonsense codons, which correlates with a
      reduction in total protein synthesis. These results indicate the critical
      function of EF-1beta in regulating EF-1alpha activity, cell growth, translation
      rates, and translational fidelity.

PMID- 10409718
TI  - Regulation of transcription at the Saccharomyces cerevisiae start transition by
      Stb1, a Swi6-binding protein.
AB  - In Saccharomyces cerevisiae, gene expression in the late G(1) phase is activated
      by two transcription factors, SBF and MBF. SBF contains the Swi4 and Swi6
      proteins and activates the transcription of G(1) cyclin genes, cell wall
      biosynthesis genes, and the HO gene. MBF is composed of Mbp1 and Swi6 and
      activates the transcription of genes required for DNA synthesis. Mbp1 and Swi4
      are the DNA binding subunits for MBF and SBF, while the common subunit, Swi6, is
      presumed to play a regulatory role in both complexes. We show that Stb1, a
      protein first identified in a two-hybrid screen with the transcriptional
      repressor Sin3, binds Swi6 in vitro. The STB1 transcript was cell cycle periodic
      and peaked in late G(1) phase. In vivo accumulation of Stb1 phosphoforms was
      dependent on CLN1, CLN2, and CLN3, which encode G(1)-specific cyclins for the
      cyclin-dependent kinase Cdc28, and Stb1 was phosphorylated by Cln-Cdc28 kinases
      in vitro. Deletion of STB1 caused an exacerbated delay in G(1) progression and
      the onset of Start transcription in a cln3Delta strain. Our results suggest a
      role for STB1 in controlling the timing of Start transcription that is revealed
      in the absence of the G(1) regulator CLN3, and they implicate Stb1 as an in vivo
      target of G(1)-specific cyclin-dependent kinases.

PMID- 10409719
TI  - Chromatin opening and transactivator potentiation by RAP1 in Saccharomyces
      cerevisiae.
AB  - Transcriptional activators function in vivo via binding sites that may be
      packaged into chromatin. Here we show that whereas the transcriptional activator
      GAL4 is strongly able to perturb chromatin structure via a nucleosomal binding
      site in yeast, GCN4 does so poorly. Correspondingly, GCN4 requires assistance
      from an accessory protein, RAP1, for activation of the HIS4 promoter, whereas
      GAL4 does not. The requirement for RAP1 for GCN4-mediated HIS4 activation is
      dictated by the DNA-binding domain of GCN4 and not the activation domain,
      suggesting that RAP1 assists GCN4 in gaining access to its binding site.
      Consistent with this, overexpression of GCN4 partially alleviates the requirement
      for RAP1, whereas HIS4 activation via a weak GAL4 binding site requires RAP1.
      RAP1 is extremely effective at interfering with positioning of a nucleosome
      containing its binding site, consistent with a role in opening chromatin at the
      HIS4 promoter. Furthermore, increasing the spacing between binding sites for RAP1
      and GCN4 by 5 or 10 bp does not impair HIS4 activation, indicating that
      cooperative protein-protein interactions are not involved in transcriptional
      facilitation by RAP1. We conclude that an important role of RAP1 is to assist
      activator binding by opening chromatin.

PMID- 10409720
TI  - Bradykinin B(2) receptor-mediated mitogen-activated protein kinase activation in
      COS-7 cells requires dual signaling via both protein kinase C pathway and
      epidermal growth factor receptor transactivation.
AB  - The signaling routes linking G-protein-coupled receptors to mitogen-activated
      protein kinase (MAPK) may involve tyrosine kinases, phosphoinositide 3-kinase
      gamma (PI3Kgamma), and protein kinase C (PKC). To characterize the mitogenic
      pathway of bradykinin (BK), COS-7 cells were transiently cotransfected with the
      human bradykinin B(2) receptor and hemagglutinin-tagged MAPK. We demonstrate that
      BK-induced activation of MAPK is mediated via the alpha subunits of a G(q/11)
      protein. Both activation of Raf-1 and activation of MAPK in response to BK were
      blocked by inhibitors of PKC as well as of the epidermal growth factor (EGF)
      receptor. Furthermore, in PKC-depleted COS-7 cells, the effect of BK on MAPK was
      clearly reduced. Inhibition of PI3-Kgamma or Src kinase failed to diminish MAPK
      activation by BK. BK-induced translocation and overexpression of PKC isoforms as
      well as coexpression of inactive or constitutively active mutants of different
      PKC isozymes provided evidence for a role of the diacylglycerol-sensitive PKCs
      alpha and epsilon in BK signaling toward MAPK. In addition to PKC activation, BK
      also induced tyrosine phosphorylation of EGF receptor (transactivation) in COS-7
      cells. Inhibition of PKC did not alter BK-induced transactivation, and blockade
      of EGF receptor did not affect BK-stimulated phosphatidylinositol turnover or BK
      induced PKC translocation, suggesting that PKC acts neither upstream nor
      downstream of the EGF receptor. Comparison of the kinetics of PKC activation and
      EGF receptor transactivation in response to BK also suggests simultaneous rather
      than consecutive signaling. We conclude that in COS-7 cells, BK activates MAPK
      via a permanent dual signaling pathway involving the independent activation of
      the PKC isoforms alpha and epsilon and transactivation of the EGF receptor. The
      two branches of this pathway may converge at the level of the Ras-Raf complex.

PMID- 10409721
TI  - Cer1p functions as a molecular chaperone in the endoplasmic reticulum of
      Saccharomyces cerevisiae.
AB  - Cer1p/Lhs1p/Ssi1p is a novel Hsp70-related protein that is important for the
      translocation of a subset of proteins into the yeast Saccharomyces cerevisiae
      endoplasmic reticulum. Cer1p has very limited amino acid identity to the hsp70
      chaperone family in the N-terminal ATPase domain but lacks homology to the highly
      conserved hsp70 peptide binding domain. The role of Cer1p in protein folding and
      translocation was assessed. Deletion of CER1 slowed the folding of reduced pro
      carboxypeptidase Y (pro-CPY) approximately twofold in yeast. In wild-type yeast
      under reducing conditions, pro-CPY can be found in a complex with Cer1p, while
      partially purified Cer1p is able to bind directly to peptides. Together, this
      suggests that Cer1p has a chaperoning activity required for proper refolding of
      denatured pro-CPY which is mediated by direct interaction with the unfolded
      polypeptide. Cer1p peptide binding and oligomerization could be disrupted by
      addition of ATP, confirming that Cer1p possesses a functional ATP binding site,
      much like Kar2p and other members of the hsp70 family. Interestingly, replacing
      the signal sequence of a CER1-dependent protein with that of a CER1-independent
      protein did not relieve the requirement of CER1 for import. This result suggests
      that an interaction with the mature portion of the protein also is important for
      the translocation role of Cer1p. The CER1 RNA levels increase at lower
      temperatures. In addition, the effects of deletion on folding and translocation
      are more severe at lower temperatures. Therefore, these results suggest that
      Cer1p provides an additional chaperoning activity in processes known to require
      Kar2p. However, there appears to be a greater requirement for Cer1p chaperone
      activity at lower temperatures.

PMID- 10409722
TI  - B-Raf inhibits programmed cell death downstream of cytochrome c release from
      mitochondria by activating the MEK/Erk pathway.
AB  - Growth factor-dependent kinases, such as phosphatidylinositol 3-kinase (PI 3
      kinase) and Raf kinases, have been implicated in the suppression of apoptosis. We
      have recently established Rat-1 fibroblast cell lines overexpressing B-Raf,
      leading to activation of the MEK/Erk mitogen-activated protein kinase pathway.
      Overexpression of B-Raf confers resistance to apoptosis induced by growth factor
      withdrawal or PI 3-kinase inhibition. This is accompanied by constitutive
      activation of Erk without effects on the PI 3-kinase/Akt pathway. The activity of
      MEK is essential for cell survival mediated by B-Raf overexpression, since either
      treatment with the specific MEK inhibitor PD98059 or expression of a dominant
      inhibitory MEK mutant blocks the antiapoptotic activity of B-Raf. Activation of
      MEK is not only necessary but also sufficient for cell survival because
      overexpression of constitutively activated MEK, Ras, or Raf-1, like B-Raf,
      prevents apoptosis after growth factor deprivation. Overexpression of B-Raf did
      not interfere with the release of cytochrome c from mitochondria after growth
      factor deprivation. However, the addition of cytochrome c to cytosols of cells
      overexpressing B-Raf failed to induce caspase activation. It thus appears that
      the B-Raf/MEK/Erk pathway confers protection against apoptosis at the level of
      cytosolic caspase activation, downstream of the release of cytochrome c from
      mitochondria.

PMID- 10409723
TI  - PER and TIM inhibit the DNA binding activity of a Drosophila CLOCK-CYC/dBMAL1
      heterodimer without disrupting formation of the heterodimer: a basis for
      circadian transcription.
AB  - The Drosophila CLOCK (dCLOCK) and CYCLE (CYC) (also referred to as dBMAL1)
      proteins are members of the basic helix-loop-helix PAS (PER-ARNT-SIM) superfamily
      of transcription factors and are required for high-level expression of the
      circadian clock genes period (per) and timeless (tim). Several lines of evidence
      indicate that PER, TIM, or a PER-TIM heterodimer somehow inhibit the
      transcriptional activity of a putative dCLOCK-CYC complex, generating a negative
      feedback loop that is a core element of the Drosophila circadian oscillator. In
      this report we show that PER and/or TIM inhibits the binding of a dCLOCK-CYC
      heterodimer to an E-box-containing DNA fragment that is present in the 5'
      nontranscribed region of per and acts as a circadian enhancer element.
      Surprisingly, inhibition of this DNA binding activity by PER, TIM, or both is not
      accompanied by disruption of the association between dCLOCK and CYC. The results
      suggest that the interaction of PER, TIM, or both with the dCLOCK-CYC heterodimer
      induces a conformational change or masks protein regions in the heterodimer,
      leading to a reduction in DNA binding activity. Together with other findings, our
      results strongly suggest that daily cycles in the association of PER and TIM with
      the dCLOCK-CYC complex probably contribute to rhythmic expression of per and tim.

PMID- 10409724
TI  - Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating
      expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in
      hepatic cells.
AB  - One of the major actions of interleukin-6 (IL-6) is the transcriptional
      activation of acute-phase plasma proteins (APP) genes in liver cells. Signaling
      by the IL-6 receptor is mediated through the signal transducing subunit gp130 and
      involves the activation of Janus-associated kinases (JAKs), signal transducer and
      activator of transcription 3 (STAT3), and mitogen-activated protein (MAP) kinase.
      Functional analysis of gp130 in rat hepatoma cells by using transduced chimeric G
      CSFR-gp130 receptor constructs demonstrates that SHP-2, the Src homology 2 (SH2)
      domain-containing protein tyrosine phosphatase, acts as a negative regulator of
      the JAK/STAT signaling in part by downregulating JAK activity, thereby indirectly
      moderating the induction of STAT3-dependent APP genes. This study shows that in
      hepatoma cells, the recruitment and tyrosine phosphorylation of SHP-2, but not
      SHC, is the primary signaling event associated with the activation of MAP kinases
      (ERK1/2) by gp130. Overexpression of truncated SHP-2 that lacks Grb2-interacting
      sites, but not the full-length catalytically inactive SHP-2, reduces ERK
      activation by IL-6, confirming the signal-mediating role of SHP-2. Activation of
      ERK1/2 is correlated with induction of the immediate-early response genes.
      Stimulation of the c-fos, c-jun, and egr-1 genes is essentially absent in cells
      expressing gp130 with a Y759F mutation, which is unable to recruit SHP-2.
      Interestingly, both JAK/STAT and SHP-2 pathways regulate the induction of the
      junB gene. Moreover, disengagement of SHP-2 from gp130 signaling not only
      enhances APP gene induction but also further reduces cell proliferation, in part
      correlated with the attenuated expression of immediate-early response genes.
      These results suggest that IL-6 regulation of APP genes is affected by SHP-2 in
      two ways: SHP-2 acts as a phosphatase on the JAK/STAT pathway and serves as
      linker to the MAP kinase pathway, which in turn moderates APP production.

PMID- 10409725
TI  - c-Myc overexpression uncouples DNA replication from mitosis.
AB  - c-myc has been shown to regulate G(1)/S transition, but a role for c-myc in other
      phases of the cell cycle has not been identified. Exposure of cells to colcemid
      activates the mitotic spindle checkpoint and arrests cells transiently in
      metaphase. After prolonged colcemid exposure, the cells withdraw from mitosis and
      enter a G(1)-like state. In contrast to cells in G(1), colcemid-arrested cells
      have decreased G(1) cyclin-dependent kinase activity and show hypophosphorylation
      of the retinoblastoma protein. We have found that overexpression of c-myc causes
      colcemid-treated human and rodent cells to become either apoptotic or polyploid
      by replicating DNA without chromosomal segregation. Although c-myc-induced
      polyploidy is not inhibited by wild-type p53 in immortalized murine fibroblasts,
      overexpression of c-myc in primary fibroblasts resulted in massive apoptosis of
      colcemid-treated cells. We surmise that additional genes are altered in
      immortalized cells to suppress the apoptotic pathway and allow c-myc
      overexpressing cells to progress forward in the presence of colcemid. Our results
      also suggest that c-myc induces DNA rereplication in this G(1)-like state by
      activating CDK2 activity. These observations indicate that activation of c-myc
      may contribute to the genomic instability commonly found in human cancers.

PMID- 10409727
TI  - Purification and identification of p68 RNA helicase acting as a transcriptional
      coactivator specific for the activation function 1 of human estrogen receptor
      alpha.
AB  - The estrogen receptor (ER) regulates the expression of target genes in a ligand
      dependent manner. The ligand-dependent activation function AF-2 of the ER is
      located in the ligand binding domain (LBD), while the N-terminal A/B domain (AF
      1) functions in a ligand-independent manner when isolated from the LBD. AF-1 and
      AF-2 exhibit cell type and promoter context specificity. Furthermore, the AF-1
      activity of the human ERalpha (hERalpha) is enhanced through phosphorylation of
      the Ser(118) residue by mitogen-activated protein kinase (MAPK). From MCF-7
      cells, we purified and cloned a 68-kDa protein (p68) which interacted with the
      A/B domain but not with the LBD of hERalpha. Phosphorylation of hERalpha Ser(118)
      potentiated the interaction with p68. We demonstrate that p68 enhanced the
      activity of AF-1 but not AF-2 and the estrogen-induced as well as the anti
      estrogen-induced transcriptional activity of the full-length ERalpha in a cell
      type-specific manner. However, it did not potentiate AF-1 or AF-2 of ERbeta,
      androgen receptor, retinoic acid receptor alpha, or mineralocorticoid receptor.
      We also show that the RNA helicase activity previously ascribed to p68 is
      dispensable for the ERalpha AF-1 coactivator activity and that p68 binds to CBP
      in vitro. Furthermore, the interaction region for p68 in the ERalpha A/B domain
      was essential for the full activity of hERalpha AF-1. Taken together, these
      findings show that p68 acts as a coactivator specific for the ERalpha AF-1 and
      strongly suggest that the interaction between p68 and the hERalpha A/B domain is
      regulated by MAPK-induced phosphorylation of Ser(118).

PMID- 10409726
TI  - Myb-related fission yeast cdc5p is a component of a 40S snRNP-containing complex
      and is essential for pre-mRNA splicing.
AB  - Myb-related cdc5p is required for G(2)/M progression in the yeast
      Schizosaccharomyces pombe. We report here that all detectable cdc5p is stably
      associated with a multiprotein 40S complex. Immunoaffinity purification has
      allowed the identification of 10 cwf (complexed with cdc5p) proteins. Two (cwf6p
      and cwf10p) are members of the U5 snRNP; one (cwf9p) is a core snRNP protein.
      cwf8p is the apparent ortholog of the Saccharomyces cerevisiae splicing factor
      Prp19p. cwf1(+) is allelic to the prp5(+) gene defined by the S. pombe splicing
      mutant, prp5-1, and there is a strong negative genetic interaction between cdc5
      120 and prp5-1. Five cwfs have not been recognized previously as important for
      either pre-mRNA splicing or cell cycle control. Further characterization of
      cwf1p, cwf2p, cwf3p, and cwf4p demonstrates that they are encoded by essential
      genes, cosediment with cdc5p at 40S, and coimmunoprecipitate with cdc5p. We
      further show that cdc5p associates with the U2, U5, and U6 snRNAs and that cells
      lacking cdc5(+) function are defective in pre-mRNA splicing. These data raise the
      possibility that the cdc5p complex is an intermediate in the assembly or
      disassembly of an active S. pombe spliceosome.

PMID- 10409728
TI  - A novel role in DNA metabolism for the binding of Fen1/Rad27 to PCNA and
      implications for genetic risk.
AB  - Fen1/Rad27 nuclease activity, which is important in DNA metabolism, is stimulated
      by proliferating cell nuclear antigen (PCNA) in vitro. The in vivo role of the
      PCNA interaction was investigated in the yeast Rad27. A nuclease-defective rad27
      mutation had a dominant-negative effect that was suppressed by a mutation in the
      PCNA binding site, thereby demonstrating the importance of the Rad27-PCNA
      interaction. The PCNA-binding defect alone had little effect on mutation,
      recombination, and the methyl methanesulfonate (MMS) response in repair-competent
      cells, but it greatly amplified the MMS sensitivity of a rad51 mutant.
      Furthermore, the PCNA binding mutation resulted in lethality when combined with a
      homozygous or even a heterozygous pol3-01 mutation in the 3'-->5' exonuclease
      domain of DNA polymerase delta. These results suggest that phenotypically mild
      polymorphisms in DNA metabolic proteins can have dramatic consequences when
      combined.

PMID- 10409729
TI  - Quantitation of RNA polymerase II and its transcription factors in an HeLa cell:
      little soluble holoenzyme but significant amounts of polymerases attached to the
      nuclear substructure.
AB  - Various complexes that contain the core subunits of RNA polymerase II associated
      with different transcription factors have been isolated from eukaryotes; their
      precise molecular constitution depends on the purification procedure. We
      estimated the numbers of various components of such complexes in an HeLa cell by
      quantitative immunoblotting. The cells were lysed with saponin in a physiological
      buffer; approximately 140,000 unengaged polymerases (mainly of form IIA) were
      released. Only approximately 4,000 of these soluble molecules sedimented in
      glycerol gradients as holoenzyme-sized complexes. About 180,000 molecules of
      polymerases (approximately 110,000 molecules of form IIO) and 10,000 to 30,000
      molecules of each of TFIIB, TFIIEalpha, TFIIEbeta, TFIIF-RAP74, TFIIF-RAP30, and
      TFIIH-MAT1 remained tightly associated with the nuclear substructure. Most
      proteins and run-on activity were retained when approximately 50% of the
      chromatin was detached with a nuclease, but approximately 45,000 molecules of
      bound TATA binding protein (TBP) were detached. Similar results were obtained
      after cross-linking living cells with formaldehyde. The results provide little
      support for the existence of a large pool of soluble holoenzyme; they are
      consistent with TBP-promoter complexes in nuclease-sensitive chromatin being
      assembled into preinitiation complexes attached to the underlying structure.

PMID- 10409730
TI  - Transcriptional elements involved in the repression of ribosomal protein
      synthesis.
AB  - The ribosomal proteins (RPs) of Saccharomyces cerevisiae are encoded by 137 genes
      that are among the most transcriptionally active in the genome. These genes are
      coordinately regulated: a shift up in temperature leads to a rapid, but
      temporary, decline in RP mRNA levels. A defect in any part of the secretory
      pathway leads to greatly reduced ribosome synthesis, including the rapid loss of
      RP mRNA. Here we demonstrate that the loss of RP mRNA is due to the rapid
      transcriptional silencing of the RP genes, coupled to the naturally short
      lifetime of their transcripts. The data suggest further that a global inhibition
      of polymerase II transcription leads to overestimates of the stability of
      individual mRNAs. The transcription of most RP genes is activated by two Rap1p
      binding sites, 250 to 400 bp upstream from the initiation of transcription. Rap1p
      is both an activator and a silencer of transcription. The swapping of promoters
      between RPL30 and ACT1 or GAL1 demonstrated that the Rap1p binding sites of RPL30
      are sufficient to silence the transcription of ACT1 in response to a defect in
      the secretory pathway. Sir3p and Sir4p, implicated in the Rap1p-mediated
      repression of silent mating type genes and of telomere-proximal genes, do not
      influence such silencing of RP genes. Sir2p, implicated in the silencing both of
      the silent mating type genes and of genes within the ribosomal DNA locus, does
      not influence the repression of either RP or rRNA genes. Surprisingly, the 180-bp
      sequence of RPL30 that lies between the Rap1p sites and the transcription
      initiation site is also sufficient to silence the Gal4p-driven transcription in
      response to a defect in the secretory pathway, by a mechanism that requires the
      silencing region of Rap1p. We conclude that for Rap1p to activate the
      transcription of an RP gene it must bind to upstream sequences; yet for Rap1p to
      repress the transcription of an RP gene it need not bind to the gene directly.
      Thus, the cell has evolved a two-pronged approach to effect the rapid extinction
      of RP synthesis in response to the stress imposed by a heat shock or by a failure
      of the secretory pathway. Calculations based on recent transcriptome data and on
      the half-life of the RP mRNAs suggest that in a rapidly growing cell the
      transcription of RP mRNAs accounts for nearly 50% of the total transcriptional
      events initiated by RNA polymerase II. Thus, the sudden silencing of the RP genes
      must have a dramatic effect on the overall transcriptional economy of the cell.

PMID- 10409731
TI  - Ssy1p and Ptr3p are plasma membrane components of a yeast system that senses
      extracellular amino acids.
AB  - Mutations in SSY1 and PTR3 were identified in a genetic selection for components
      required for the proper uptake and compartmentalization of histidine in
      Saccharomyces cerevisiae. Ssy1p is a unique member of the amino acid permease
      gene family, and Ptr3p is predicted to be a hydrophilic protein that lacks known
      functional homologs. Both Ssy1p and Ptr3p have previously been implicated in
      relaying signals regarding the presence of extracellular amino acids. We have
      found that ssy1 and ptr3 mutants belong to the same epistasis group; single and
      ssy1 ptr3 double-mutant strains exhibit indistinguishable phenotypes. Mutations
      in these genes cause the nitrogen-regulated general amino acid permease gene
      (GAP1) to be abnormally expressed and block the nonspecific induction of arginase
      (CAR1) and the peptide transporter (PTR2). ssy1 and ptr3 mutations manifest
      identical differential effects on the functional expression of multiple specific
      amino acid transporters. ssy1 and ptr3 mutants have increased vacuolar pools of
      histidine and arginine and exhibit altered cell growth morphologies accompanied
      by exaggerated invasive growth. Subcellular fractionation experiments reveal that
      both Ssy1p and Ptr3p are localized to the plasma membrane (PM). Ssy1p requires
      the endoplasmic reticulum protein Shr3p, the amino acid permease-specific
      packaging chaperonin, to reach the PM, whereas Ptr3p does not. These findings
      suggest that Ssy1p and Ptr3p function in the PM as components of a sensor of
      extracellular amino acids.

PMID- 10409732
TI  - Hec1p, an evolutionarily conserved coiled-coil protein, modulates chromosome
      segregation through interaction with SMC proteins.
AB  - hsHec1p, a Homo sapiens coiled-coil-enriched protein, plays an important role in
      M-phase progression in mammalian cells. A Saccharomyces cerevisiae protein,
      identical to Tid3p/Ndc80p and here designated scHec1p, has similarities in
      structure and biological function to hsHec1p. Budding yeast cells deleted in the
      scHEC1/NDC80 allele are not viable, but this lethal phenotype can be rescued by
      hsHEC1 under control of the endogenous scHEC1 promoter. At the nonpermissive
      temperature, significant mitotic delay, chromosomal missegregation, and decreased
      viability were observed in yeast cells with temperature-sensitive (ts) alleles of
      hsHEC1. In the hshec1-113 ts mutant, we found a single-point mutation changing
      Trp395 to a stop codon, which resulted in the expression of a C-terminally
      truncated 45-kDa protein. The binding of this mutated protein, hshec1-113p, to
      five identified hsHec1p-associated proteins was unchanged, while its binding to
      human SMC1 protein and yeast Smc1p was ts. Hec1p also interacts with Smc2p, and
      the binding of the mutated hshec1-113p to Smc2p was not ts. Overexpression of
      either hsHEC1 or scHEC1 suppressed the lethal phenotype of smc1-2 and smc2-6 at
      nonpermissive temperatures, suggesting that the interactions between Hec1p and
      Smc1p and -2p are biologically significant. These results suggest that Hec1
      proteins play a critical role in modulating chromosomal segregation, in part,
      through their interactions with SMC proteins.

PMID- 10409734
TI  - Imp3p and Imp4p, two specific components of the U3 small nucleolar
      ribonucleoprotein that are essential for pre-18S rRNA processing.
AB  - The function of the U3 small nucleolar ribonucleoprotein (snoRNP) is central to
      the events surrounding pre-rRNA processing, as evidenced by the severe defects in
      cleavage of pre-18S rRNA precursors observed upon depletion of the U3 RNA and its
      unique protein components. Although the precise function of each component
      remains unclear, since U3 snoRNA levels remain unchanged upon genetic depletion
      of these proteins, it is likely that the proteins themselves have significant
      roles in the cleavage reactions. Here we report the identification of two
      previously undescribed protein components of the U3 snoRNP, representing the
      first snoRNP components identified by using the two-hybrid methodology. By
      screening for proteins that physically associate with the U3 snoRNP-specific
      protein, Mpp10p, we have identified Imp3p (22 kDa) and Imp4p (34 kDa) (named for
      interacting with Mpp10p). The genes encoding both proteins are essential in
      yeast. Genetic depletion reveals that both proteins are critical for U3 snoRNP
      function in pre-18S rRNA processing at the A0, A1, and A2 sites in the pre-rRNA.
      Both Imp proteins associate with Mpp10p in vivo, and both are complexed only with
      the U3 snoRNA. Conservation of RNA binding domains between Imp3p and the S4
      family of ribosomal proteins suggests that it might associate with RNA directly.
      However, as with other U3 snoRNP-specific proteins, neither Imp3p nor Imp4p is
      required for maintenance of U3 snoRNA integrity. Imp3p and Imp4p are therefore
      novel protein components specific to the U3 snoRNP with critical roles in pre
      rRNA cleavage events.

PMID- 10409733
TI  - Differentiation-induced internal translation of c-sis mRNA: analysis of the cis
      elements and their differentiation-linked binding to the hnRNP C protein.
AB  - In previous reports we showed that the long 5' untranslated region (5' UTR) of c
      sis, the gene encoding the B chain of platelet-derived growth factor, has
      translational modulating activity due to its differentiation-activated internal
      ribosomal entry site (D-IRES). Here we show that the 5' UTR contains three
      regions with a computer-predicted Y-shaped structure upstream of an AUG codon,
      each of which can confer some degree of internal translation by itself. In
      nondifferentiated cells, the entire 5' UTR is required for maximal basal IRES
      activity. The elements required for the differentiation-sensing ability (i.e., D
      IRES) were mapped to a 630-nucleotide fragment within the central portion of the
      5' UTR. Even though the region responsible for IRES activation is smaller, the
      full-length 5' UTR is capable of mediating the maximal translation efficiency in
      differentiated cells, since only the entire 5' UTR is able to confer the maximal
      basal IRES activity. Interestingly, a 43-kDa protein, identified as hnRNP C,
      binds in a differentiation-induced manner to the differentiation-sensing region.
      Using UV cross-linking experiments, we show that while hnRNP C is mainly a
      nuclear protein, its binding activity to the D-IRES is mostly nuclear in
      nondifferentiated cells, whereas in differentiated cells such binding activity is
      associated with the ribosomal fraction. Since the c-sis 5' UTR is a translational
      modulator in response to cellular changes, it seems that the large number of
      cross-talking structural entities and the interactions with regulated trans
      acting factors are important for the strength of modulation in response to
      cellular changes. These characteristics may constitute the major difference
      between strong IRESs, such as those seen in some viruses, and IRESs that serve as
      translational modulators in response to developmental signals, such as that of c
      sis.

PMID- 10409735
TI  - The gene for the embryonic stem cell coactivator UTF1 carries a regulatory
      element which selectively interacts with a complex composed of Oct-3/4 and Sox-2.
AB  - UTF1 is a transcriptional coactivator which has recently been isolated and found
      to be expressed mainly in pluripotent embryonic stem (ES) cells (A. Okuda, A.
      Fukushima, M. Nishimoto, et al., EMBO J. 17:2019-2032, 1998). To gain insight
      into the regulatory network of gene expression in ES cells, we have characterized
      the regulatory elements governing UTF1 gene expression. The results indicate that
      the UTF1 gene is one of the target genes of an embryonic octamer binding
      transcription factor, Oct-3/4. UTF1 expression is, like the FGF-4 gene, regulated
      by the synergistic action of Oct-3/4 and another embryonic factor, Sox-2,
      implying that the requirement for Sox-2 by Oct-3/4 is not limited to the FGF-4
      enhancer but is rather a general mechanism of activation for Oct-3/4. Our
      biochemical analyses, however, also reveal one distinct difference between these
      two regulatory elements: unlike the FGF-4 enhancer, the UTF1 regulatory element
      can, by its one-base difference from the canonical octamer-binding sequence,
      selectively recruit the complex comprising Oct-3/4 and Sox-2 and preclude the
      binding of the transcriptionally inactive complex containing Oct-1 or Oct-6.
      Furthermore, our analyses reveal that these properties are dictated by the unique
      ability of the Oct-3/4 POU-homeodomain that recognizes a variant of the Octamer
      motif in the UTF1 regulatory element.

PMID- 10409736
TI  - In vitro analysis of alpha-amanitin-resistant transcription from the rRNA,
      procyclic acidic repetitive protein, and variant surface glycoprotein gene
      promoters in Trypanosoma brucei.
AB  - In Trypanosoma brucei, transcription resistant to the mushroom toxin alpha
      amanitin is not restricted to the rRNA genes (rDNA), as in higher eukaryotes, but
      extends to genes encoding the major cell surface proteins variant surface
      glycoprotein (VSG) and procyclin or procyclic acidic repetitive protein (PARP).
      Here, we report the development of a homologous cell extract from procyclic T.
      brucei cells in which rDNA and PARP A and VSG gene promoters drive efficient,
      accurate, and alpha-amanitin-resistant transcription. A comparative analysis
      revealed that transcription from the three promoters generally required identical
      reaction conditions for maximal efficiency. Nevertheless, PARP promoter
      transcription proved to be exceptional by its high efficiency, its lag phase, a
      high template DNA concentration optimum, and its tolerance to increasing
      concentrations of Mn(2+). Mutational analysis for both the PARP and rDNA
      promoters showed that the proximal and distal core elements were essential for
      efficient transcription in vitro. Deletion of the upstream control regions
      (UCRs), however, had a different effect. Whereas PARP UCR deletion reduced
      transcription efficiency almost 10-fold, deletion of the rDNA UCR had only a
      minor effect on transcription efficiency.

PMID- 10409737
TI  - Osmotic stress-induced gene expression in Saccharomyces cerevisiae requires Msn1p
      and the novel nuclear factor Hot1p.
AB  - After a sudden shift to high osmolarity, Saccharomyces cerevisiae cells respond
      by transiently inducing the expression of stress-protective genes. Msn2p and
      Msn4p have been described as two transcription factors that determine the extent
      of this response. In msn2 msn4 mutants, however, many promoters still show a
      distinct rise in transcriptional activity upon osmotic stress. Here we describe
      two structurally related nuclear factors, Msn1p and a newly identified protein,
      Hot1p (for high-osmolarity-induced transcription), which are also involved in
      osmotic stress-induced transcription. hot1 single mutants are specifically
      compromised in the transient induction of GPD1 and GPP2, which encode enzymes
      involved in glycerol biosynthesis, and exhibit delayed glycerol accumulation
      after stress exposure. Similar to a gpd1 mutation, a hot1 defect can rescue cells
      from inappropriately high HOG pathway activity. In contrast, Hot1p has little
      influence on the osmotic stress induction of CTT1, where Msn1p appears to play a
      more prominent role. Cells lacking Msn1p, Msn2p, Msn4p, and Hot1p are almost
      devoid of the short-term transcriptional response of the genes GPD1, GPP2, CTT1,
      and HSP12 to osmotic stress. Such cells also show a distinct reduction in the
      nuclear residence of the mitogen-activated protein kinase Hog1p upon osmotic
      stress. Thus, Hot1p and Msn1p may define an additional tier of transcriptional
      regulators that control responses to high-osmolarity stress.

PMID- 10409738
TI  - Human TAF(II)55 interacts with the vitamin D(3) and thyroid hormone receptors and
      with derivatives of the retinoid X receptor that have altered transactivation
      properties.
AB  - We have identified novel interactions between the human (h)TATA-binding protein
      associated factor TAF(II)55 and the ligand-binding domains (LBDs) of the nuclear
      receptors for vitamin D(3) (VDR) and thyroid hormone (TRalpha). Following
      expression in Cos cells, hTAF(II)55 interacts with the VDR and TRalpha LBDs in a
      ligand-independent manner whereas no interactions with the retinoid X receptors
      (RXRs) or with other receptors were observed. Deletion mapping indicates that
      hTAF(II)55 interacts with a 40-amino-acid region spanning alpha-helices H3 to H5
      of the VDR and TRalpha LBDs but not with the equivalent highly related region of
      RXRgamma. TAF(II)55 also interacts with chimeric receptors in which the H3-to-H5
      region of RXRgamma has been replaced with that of the VDR or TRalpha.
      Furthermore, replacement of two single amino acids of the RXRgamma LBD with their
      VDR counterparts allows the RXRgamma LBD to interact with hTAF(II)55 while the
      corresponding double substitution allows a much stronger interaction. In
      transfection experiments, the single mutated RXRgamma LBDs activate transcription
      to fivefold higher levels than wild-type RXRgamma while the double mutation
      activates transcription to a level comparable to that observed with the VDR.
      There is therefore a correlation between the ability of the modified RXRs to
      interact with hTAF(II)55 and transactivation. These results strongly suggest that
      the TAF(II)55 interactions with the modified RXR LBDs modulate transcriptional
      activation.

PMID- 10409739
TI  - Regulation of peroxisome proliferator-activated receptor gamma expression by
      adipocyte differentiation and determination factor 1/sterol regulatory element
      binding protein 1: implications for adipocyte differentiation and metabolism.
AB  - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear
      receptor implicated in adipocyte differentiation and insulin sensitivity. We
      investigated whether PPARgamma expression is dependent on the activity of
      adipocyte differentiation and determination factor 1/sterol regulatory element
      binding protein 1 (ADD-1/SREBP-1), another transcription factor associated with
      both adipocyte differentiation and cholesterol homeostasis. Ectopic expression of
      ADD-1/SREBP-1 in 3T3-L1 and HepG2 cells induced endogenous PPARgamma mRNA levels.
      The related transcription factor SREBP-2 likewise induced PPARgamma expression.
      In addition, cholesterol depletion, a condition known to result in proteolytic
      activation of transcription factors of the SREBP family, induced PPARgamma
      expression and improved PPRE-driven transcription. The effect of the SREBPs on
      PPARgamma expression was mediated through the PPARgamma1 and -3 promoters. Both
      promoters contain a consensus E-box motif that mediates the regulation of the
      PPARgamma gene by ADD-1/SREBP-1 and SREBP-2. These results suggest that PPARgamma
      expression can be controlled by the SREBP family of transcription factors and
      demonstrate new interactions between transcription factors that can regulate
      different pathways of lipid metabolism.

PMID- 10409741
TI  - Cdc4, a protein required for the onset of S phase, serves an essential function
      during G(2)/M transition in Saccharomyces cerevisiae.
AB  - Saccharomyces cerevisiae proteins Cdc4 and Cdc20 contain WD40 repeats and
      participate in proteolytic processes. However, they are thought to act at two
      different stages of the cell cycle: Cdc4 is involved in the proteolysis of the
      Cdk inhibitor, Sic1, necessary for G(1)/S transition, while Cdc20 mediates
      anaphase-promoting complex-dependent degradation of anaphase inhibitor Pds1, a
      process necessary for the onset of chromosome segregation. We have isolated three
      mutant alleles of CDC4 (cdc4-10, cdc4-11, and cdc4-16) which suppress the nuclear
      division defect of cdc20-1 cells. However, the previously characterized mutation
      cdc4-1 and a new allele, cdc4-12, do not alleviate the defect of cdc20-1 cells.
      This genetic interaction suggests an additional role for Cdc4 in G(2)/M.
      Reexamination of the cdc4-1 mutant revealed that, in addition to being defective
      in the onset of S phase, it is also defective in G(2)/M transition when released
      from hydroxyurea-induced S-phase arrest. A second function for CDC4 in late S or
      G(2) phase was further confirmed by the observation that cells lacking the CDC4
      gene are arrested both at G(1)/S and at G(2)/M. We subsequently isolated
      additional temperature-sensitive mutations in the CDC4 gene (such as cdc4-12)
      that render the mutant defective in both G(1)/S and G(2)/M transitions at the
      restrictive temperature. While the G(1)/S block in both cdc4-12 and cdc4Delta
      mutants is abolished by the deletion of the SIC1 gene (causing the mutants to be
      arrested predominantly in G(2)/M), the preanaphase arrest in the cdc4-12 mutant
      is relieved by the deletion of PDS1. Collectively, these observations suggest
      that, in addition to its involvement in the initiation of S phase, Cdc4 may also
      be required for the onset of anaphase.

PMID- 10409740
TI  - Histone deacetylase 1 can repress transcription by binding to Sp1.
AB  - The members of the Sp1 transcription factor family can act as both negative and
      positive regulators of gene expression. Here we show that Sp1 can be a target for
      histone deacetylase 1 (HDAC1)-mediated transcriptional repression. The histone
      deacetylase inhibitor trichostatin A activates the chromosomally integrated
      murine thymidine kinase promoter in an Sp1-dependent manner.
      Coimmunoprecipitation experiments with Swiss 3T3 fibroblasts and 293 cells
      demonstrate that Sp1 and HDAC1 can be part of the same complex. The interaction
      between Sp1 and HDAC1 is direct and requires the carboxy-terminal domain of Sp1.
      Previously we have shown that the C terminus of Sp1 is necessary for the
      interaction with the transcription factor E2F1 (J. Karlseder, H. Rotheneder, and
      E. Wintersberger, Mol. Cell. Biol. 16:1659-1667, 1996). Coexpression of E2F1
      interferes with HDAC1 binding to Sp1 and abolishes Sp1-mediated transcriptional
      repression. Our results indicate that one component of Sp1-dependent gene
      regulation involves competition between the transcriptional repressor HDAC1 and
      the transactivating factor E2F1.

PMID- 10409742
TI  - Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK
      localization.
AB  - Genetic screens for modifiers of activated Ras phenotypes have identified a novel
      protein, kinase suppressor of Ras (KSR), which shares significant sequence
      homology with Raf family protein kinases. Studies using Drosophila melanogaster
      and Caenorhabditis elegans predict that KSR positively regulates Ras signaling;
      however, the function of mammalian KSR is not well understood. We show here that
      two predicted kinase-dead mutants of KSR retain the ability to complement ksr-1
      loss-of-function alleles in C. elegans, suggesting that KSR may have
      physiological, kinase-independent functions. Furthermore, we observe that murine
      KSR forms a multimolecular signaling complex in human embryonic kidney 293T cells
      composed of HSP90, HSP70, HSP68, p50(CDC37), MEK1, MEK2, 14-3-3, and several
      other, unidentified proteins. Treatment of cells with geldanamycin, an inhibitor
      of HSP90, decreases the half-life of KSR, suggesting that HSPs may serve to
      stabilize KSR. Both nematode and mammalian KSRs are capable of binding to MEKs,
      and three-point mutants of KSR, corresponding to C. elegans loss-of-function
      alleles, are specifically compromised in MEK binding. KSR did not alter MEK
      activity or activation. However, KSR-MEK binding shifts the apparent molecular
      mass of MEK from 44 to >700 kDa, and this results in the appearance of MEK in
      membrane-associated fractions. Together, these results suggest that KSR may act
      as a scaffolding protein for the Ras-mitogen-activated protein kinase pathway.

PMID- 10409744
TI  - Human transcription factor hTAF(II)150 (CIF150) is involved in transcriptional
      regulation of cell cycle progression.
AB  - Here we present evidence that CIF150 (hTAF(II)150), the human homolog of
      Drosophila TAF(II)150, plays an important and selective role in establishing gene
      expression patterns necessary for progression through the cell cycle. Gel
      filtration experiments demonstrate that CIF150 (hTAF(II)150) seems to be less
      tightly associated with human transcription factor IID than hTAF(II)130 is
      associated with hTAF(II)250. The transient functional knockout of CIF150
      (hTAF(II)150) protein led to cell cycle arrest at the G(2)/M transition in
      mammalian cell lines. PCR display analysis with the RNA derived from CIF150
      depleted cells indicated that CIF150 (hTAF(II)150) is required for the
      transcription of only a subset of RNA polymerase II genes. CIF150 (hTAF(II)150)
      directly stimulated cyclin B1 and cyclin A transcription in cotransfection assays
      and in vitro assays, suggesting that the expression of these genes is dependent
      on CIF150 (hTAF(II)150) function. We defined a CIF150 (hTAF(II)150) consensus
      binding site and demonstrated that a CIF150-responsive cis element is present in
      the cyclin B1 core promoter. These results suggest that one function of CIF150
      (hTAF(II)150) is to select specific RNA polymerase II core promoter elements
      involved in cell cycle progression.

PMID- 10409745
TI  - Eukaryotic translation initiation factors 4G and 4A from Saccharomyces cerevisiae
      interact physically and functionally.
AB  - The initiation of translation in eukaryotes requires several multisubunit
      complexes, including eukaryotic translation initiation factor 4F (eIF4F). In
      higher eukaryotes eIF4F is composed of the cap binding protein eIF4E, the adapter
      protein eIF4G, and the RNA-stimulated ATPase eIF4A. The association of eIF4A with
      Saccharomyces cerevisiae eIF4F has not yet been demonstrated, and therefore the
      degree to which eIF4A's conserved function relies upon this association has
      remained unclear. Here we report an interaction between yeast eIF4G and eIF4A.
      Specifically, we found that the growth arrest phenotype associated with three
      temperature-sensitive alleles of yeast eIF4G2 was suppressed by excess eIF4A and
      that this suppression was allele specific. In addition, in vitro translation
      extracts derived from an eIF4G2 mutant strain could be heat inactivated, and this
      inactivation could be reversed upon the addition of recombinant eIF4A. Finally,
      in vitro binding between yeast eIF4G and eIF4A was demonstrated, as was
      diminished binding between mutant eIF4G2 proteins and eIF4A. In total, these data
      indicate that yeast eIF4G and eIF4A physically associate and that this
      association performs an essential function.

PMID- 10409743
TI  - A fission yeast gene, him1(+)/dfp1(+), encoding a regulatory subunit for Hsk1
      kinase, plays essential roles in S-phase initiation as well as in S-phase
      checkpoint control and recovery from DNA damage.
AB  - Saccharomyces cerevisiae CDC7 encodes a serine/threonine kinase required for
      G(1)/S transition, and its related kinases are present in fission yeast as well
      as in higher eukaryotes, including humans. Kinase activity of Cdc7 protein
      depends on the regulatory subunit, Dbf4, which also interacts with replication
      origins. We have identified him1(+) from two-hybrid screening with Hsk1, a
      fission yeast homologue of Cdc7 kinase, and showed that it encodes a regulatory
      subunit of Hsk1. Him1, identical to Dfp1, previously identified as an associated
      molecule of Hsk1, binds to Hsk1 and stimulates its kinase activity, which
      phosphorylates both catalytic and regulatory subunits as well as recombinant MCM2
      protein in vitro. him1(+) is essential for DNA replication in fission yeast
      cells, and its transcription is cell cycle regulated, increasing at middle M to
      late G(1). The protein level is low at START in G(1), increases at the G(1)/S
      boundary, and is maintained at a high level throughout S phase. Him1 protein is
      hyperphosphorylated at G(1)/S through S during the cell cycle as well as in
      response to early S-phase arrest induced by nucleotide deprivation. Deletion of
      one of the motifs conserved in regulatory subunits for Cdc7-related kinases as
      well as alanine substitution of three serine and threonine residues present in
      the same motif resulted in a defect in checkpoint regulation normally induced by
      hydroxyurea treatment. The alanine mutant also showed growth retardation after UV
      irradiation and the addition of methylmethane sulfonate. In keeping with this
      result, a database search indicates that him1(+) is identical to rad35(+). Our
      results reveal a novel function of the Cdc7/Dbf4-related kinase complex in S
      phase checkpoint control as well as in growth recovery from DNA damage in
      addition to its predicted essential function in S-phase initiation.

PMID- 10409747
TI  - The Wnt/Wg signal transducer beta-catenin controls fibronectin expression.
AB  - beta-Catenin stabilizes the cadherin cell adhesion complex but, as a component of
      the Wnt/Wg signaling pathway, also controls gene expression by forming a
      heterodimer with a transcription factor of the LEF-TCF family. We demonstrate
      that the substrate adhesion molecule fibronectin is a direct target of Wnt/Wg
      signaling. Nuclear depletion of beta-catenin following cadherin transfection in
      Xenopus fibroblasts resulted in downregulation of fibronectin expression which
      was restored by activating the Wnt/Wg signaling cascade via LiCl treatment or
      transfection of either Xwnt-8 or beta-catenin. We isolated the Xenopus
      fibronectin gene (FN) promoter and found four putative LEF-TCF binding sites. By
      comparing the activities of different fibronectin gene reporter constructs in
      fibroblasts and cadherin transfectants, the LEF-TCF site at position -368 was
      identified as a Wnt/Wg response element. LEF-1-related proteins were found in
      nuclei of the fibroblasts but were absent in a kidney epithelial cell line.
      Consistent with the lack of these transcription factors, the FN promoter was
      silent in the epithelial cells but was activated upon transfection of LEF-1. Wild
      type Xenopus Tcf-3 (XTcf-3) was unable to activate FN promoter reporter
      constructs, while a mutant lacking the groucho binding region behaved like LEF-1.
      In contrast to XTcf-3, LEF-1 does not interact with groucho proteins, which turn
      TCFs into activators or repressors (J. Roose, M. Molenaar, J. Hurenkamp, J.
      Peterson, H. Brantjes, P. Moerer, M. van de Wetering, O. Destree, and H. Clevers,
      Nature 395:608-612, 1998). Together these data provide evidence that expressing
      LEF-1 enables fibroblasts, in contrast to epithelial cells, to respond to the
      Wnt/Wg signal via beta-catenin in stimulating fibronectin gene transcription. Our
      findings further promote the idea that due to its dual function, beta-catenin
      regulates the balance between cell-cell and cell-substrate adhesion.

PMID- 10409746
TI  - Enhancement of beta-globin locus control region-mediated transactivation by
      mitogen-activated protein kinases through stochastic and graded mechanisms.
AB  - Activation of the mitogen-activated protein kinase (MAPK) pathway enhances long
      range transactivation by the beta-globin locus control region (LCR) (W. K.
      Versaw, V. Blank, N. M. Andrews, and E. H. Bresnick, Proc. Natl. Acad. Sci. USA
      95:8756-8760, 1998). The enhancement requires tandem recognition sites for the
      hematopoietic transcription factor NF-E2 within the hypersensitive site 2 (HS2)
      subregion of the LCR. To distinguish between mechanisms of induction involving
      the activation of silent promoters or the increased efficacy of active promoters,
      we analyzed basal and MAPK-stimulated HS2 enhancer activity in single, living
      cells. K562 erythroleukemia cells stably transfected with constructs containing
      the human Agamma-globin promoter linked to an enhanced green fluorescent protein
      (EGFP) reporter, with or without HS2, were analyzed for EGFP expression by flow
      cytometry. When most cells in a population expressed EGFP, MAPK augmented the
      activity of active promoters. However, under conditions of silencing, in which
      cells reverted to a state with no measurable EGFP expression, MAPK activated
      silent promoters. Furthermore, studies of populations of EGFP-expressing and non
      EGFP-expressing cells isolated by flow cytometry showed that MAPK activation
      converted nonexpressing cells into expressing cells and increased expression in
      expressing cells. These results support a model in which MAPK elicits both graded
      and stochastic responses to increase HS2-mediated transactivation from single
      chromatin templates.

PMID- 10409748
TI  - Assembly of the cleavage and polyadenylation apparatus requires about 10 seconds
      in vivo and is faster for strong than for weak poly(A) sites.
AB  - We have devised a cis-antisense rescue assay of cleavage and polyadenylation to
      determine how long it takes the simian virus 40 (SV40) early poly(A) signal to
      commit itself to processing in vivo. An inverted copy of the poly(A) signal
      placed immediately downstream of the authentic one inhibited processing by means
      of sense-antisense duplex formation in the RNA. The antisense inhibition was
      gradually relieved when the inverted signal was moved increasing distances
      downstream, presumably because cleavage and polyadenylation occur before the
      polymerase reaches the antisense sequence. Antisense inhibition was unaffected
      when the inverted signal was moved upstream. Based on the known rate of
      transcription, we estimate that the cleavage-polyadenylation process takes
      between 10 and 20 s for the SV40 early poly(A) site to complete in vivo. Relief
      from inhibition occurred earlier for shorter antisense sequences than for longer
      ones. This indicates that a brief period of assembly is sufficient for the
      poly(A) signal to shield itself from a short (50- to 70-nucleotide) antisense
      sequence but that more assembly time is required for the signal to become immune
      to the longer ones (approximately 200 nucleotides). The simplest explanation for
      this target size effect is that the assembly process progressively sequesters
      more and more of the RNA surrounding the poly(A) signal up to a maximum of about
      200 nucleotides, which we infer to be the domain of the mature apparatus. We
      compared strong and weak poly(A) sites. The SV40 late poly(A) site, one of the
      strongest, assembles several times faster than the weaker SV40 early or synthetic
      poly(A) site.

PMID- 10409749
TI  - Role of secondary structure in discrimination between constitutive and inducible
      activators.
AB  - We have examined structural differences between the proto-oncogene c-Myb and the
      cyclic AMP-responsive factor CREB that underlie their constitutive or signal
      dependent activation properties. Both proteins stimulate gene expression via
      activating regions that articulate with a shallow hydrophobic groove in the KIX
      domain of the coactivator CREB-binding protein (CBP). Three hydrophobic residues
      in c-Myb that are conserved in CREB function importantly in cellular gene
      activation and in complex formation with KIX. These hydrophobic residues are
      assembled on one face of an amphipathic helix in both proteins, and mutations
      that disrupt c-Myb or CREB helicity in this region block interaction of either
      factor with KIX. Binding of the helical c-Myb domain to KIX is accompanied by a
      substantial increase in entropy that compensates for the comparatively low
      enthalpy of complex formation. By contrast, binding of CREB to KIX entails a
      large entropy cost due to a random coil-to-helix transition in CREB that
      accompanies complex formation. These results indicate that the constitutive and
      inducible activation properties of c-Myb and CREB reflect secondary structural
      characteristics of their corresponding activating regions that influence the
      thermodynamics of formation of a complex with CBP.

PMID- 10409750
TI  - Pro-B-cell-specific transcription and proapoptotic function of protein kinase
      Ceta.
AB  - Using a subtractive cloning scheme on cDNA prepared from primary pro-B and pre-B
      cells, we identified several genes whose products regulate apoptosis. We further
      characterized one of these genes, encoding protein kinase Ceta (PKCeta). PKCeta
      transcripts were readily detected in pro-B cells but were absent in pre-B cells.
      Although both a full-length and a truncated form of PKCeta were detectable in
      bone marrow pro-B cells, transition to the pre-B-cell stage was associated with
      increased relative levels of truncated PKCeta. We found that PKCeta is
      proteolyzed in apoptotic lymphocytes, generating a kinase-active fragment
      identical to the truncated form which is capable of inducing apoptosis when
      expressed in a pro-B cell line. Caspase-3 can generate an identical PKCeta
      cleavage product in vitro, and caspase inhibitors prevent the generation of this
      product during apoptosis in transfected cell lines. Inducible overexpression of
      either the full-length or truncated form of PKCeta results in cell cycle arrest
      at the G(1)/S transition. These results suggest that the expression and
      proteolytic activation of PKCeta play an important role in the regulation of cell
      division and cell death during early B-cell development.

PMID- 10409751
TI  - Interstrand cross-links induce DNA synthesis in damaged and undamaged plasmids in
      mammalian cell extracts.
AB  - Mammalian cell extracts have been shown to carry out damage-specific DNA repair
      synthesis induced by a variety of lesions, including those created by UV and
      cisplatin. Here, we show that a single psoralen interstrand cross-link induces
      DNA synthesis in both the damaged plasmid and a second homologous unmodified
      plasmid coincubated in the extract. The presence of the second plasmid strongly
      stimulates repair synthesis in the cross-linked plasmid. Heterologous DNAs also
      stimulate repair synthesis to variable extents. Psoralen monoadducts and double
      strand breaks do not induce repair synthesis in the unmodified plasmid,
      indicating that such incorporation is specific to interstrand cross-links. This
      induced repair synthesis is consistent with previous evidence indicating a
      recombinational mode of repair for interstrand cross-links. DNA synthesis is
      compromised in extracts from mutants (deficient in ERCC1, XPF, XRCC2, and XRCC3)
      which are all sensitive to DNA cross-linking agents but is normal in extracts
      from mutants (XP-A, XP-C, and XP-G) which are much less sensitive. Extracts from
      Fanconi anemia cells exhibit an intermediate to wild-type level of activity
      dependent upon the complementation group. The DNA synthesis deficit in ERCC1- and
      XPF-deficient extracts is restored by addition of purified ERCC1-XPF heterodimer.
      This system provides a biochemical assay for investigating mechanisms of
      interstrand cross-link repair and should also facilitate the identification and
      functional characterization of cellular proteins involved in repair of these
      lesions.

PMID- 10409752
TI  - Flanking regulatory sequences of the Tetrahymena R deletion element determine the
      boundaries of DNA rearrangement.
AB  - In the ciliate Tetrahymena thermophila, thousands of DNA segments of variable
      size are eliminated from the developing somatic macronucleus by specific DNA
      rearrangements. It is unclear whether rearrangement of the many different DNA
      elements occurs via a single mechanism or via multiple rearrangement systems. In
      this study, we characterized in vivo cis-acting sequences required for the
      rearrangement of the 1.1-kbp R deletion element. We found that rearrangement
      requires specific sequences flanking each side of the deletion element. The
      required sequences on the left side appear to span roughly a 70-bp region that is
      located at least 30 bp from the rearrangement boundary. When we moved the
      location of the left cis-acting sequences closer to the eliminated region, we
      observed a rightward shift of the rearrangement boundary such that the newly
      formed deletion junction retained its original distance from this flanking
      region. Likewise, when we moved the flanking region as much as 500 bp away from
      the deletion element, the rearrangement boundary shifted to remain in relative
      juxtaposition. Clusters of base substitutions made throughout this critical
      flanking region did not affect rearrangement efficiency or accuracy, which
      suggests a complex nature for this regulatory sequence. We also found that the
      right flanking region effectively replaced the essential sequences identified on
      the left side, and thus, the two flanking regions contain sequences of analogous
      function despite the lack of obvious sequence identity. These data taken together
      indicate that the R-element flanking regions contain sequences that position the
      rearrangement boundaries from a short distance away. Previously, a 10-bp
      polypurine tract flanking the M-deletion element was demonstrated to act from a
      distance to determine its rearrangement boundaries. No apparent sequence
      similarity exists between the M and R elements. The functional similarity between
      these different cis-acting sequences of the two elements is firm support for a
      common mechanism controlling Tetrahymena rearrangement.

PMID- 10409753
TI  - Progressive region-specific de novo methylation of the p16 CpG island in primary
      human mammary epithelial cell strains during escape from M(0) growth arrest.
AB  - CpG island methylation plays an important role in normal cellular processes, such
      as genomic imprinting and X-chromosome inactivation, as well as in abnormal
      processes, such as neoplasia. However, the dynamics of de novo CpG island
      methylation, during which a CpG island is converted from an unmethylated, active
      state to a densely methylated, inactive state, are largely unknown. It is unclear
      whether the development of de novo CpG island methylation is a progressive
      process, in which a subset of CpG sites are initially methylated with a
      subsequent increase in methylation density, or a single event, in which the
      initial methylation event encompasses the entire CpG island. The tumor suppressor
      gene p16/CDKN2a/INK4a (p16) is inactivated by CpG island methylation during
      neoplastic progression in a variety of human cancers. We investigated the
      development of methylation in the p16 CpG island in primary human mammary
      epithelial cell strains during escape from mortality stage 0 (M(0)) growth
      arrest. The methylation status of 47 CpG sites in the p16 CpG island on
      individual DNA molecules was determined by sequencing PCR clones of bisulfite
      treated genomic DNA. The p16 CpG island was initially methylated at a subset of
      sites in three discrete regions in association with p16 transcriptional
      repression and escape from M(0) growth arrest. With continued passage,
      methylation gradually increased in density and methylation expanded to sites in
      adjacent regions. Thus, de novo methylation in the p16 CpG island is a
      progressive process that is neither site specific nor completely random but
      instead is region specific. Our results suggest that early detection of
      methylation in the CpG island of the p16 gene will require methylation analysis
      of the three regions and that the identification of region-specific methylation
      patterns in other genes may be essential for an accurate assessment of
      methylation-mediated transcriptional silencing.

PMID- 10409754
TI  - Transcription factor TFIIH is required for promoter melting in vivo.
AB  - The Rad25 protein in yeast is a DNA helicase and a subunit of the general
      transcription factor TFIIH. While in vitro studies have led to the hypothesis
      that TFIIH helicase activity plays a role in promoter melting, in vivo tests are
      lacking. Using potassium permanganate, which preferentially modifies single
      stranded DNA, we show that a temperature-sensitive rad25(ts) mutant severely
      reduces the normally extensive promoter melting observed in vivo on the highly
      expressed genes TDH2 and PDC1 and on the induced heat shock gene HSP82. Loss of
      promoter melting can be observed in as little as 30 s after a shift to the
      nonpermissive temperature and is accompanied by a dramatic reduction in
      transcription. These effects on the promoter are specific, since the mutation
      does not affect TATA box occupancy or, in the case of HSP82, recruitment of TATA
      binding protein to the TATA element or that of heat shock factor to heat shock
      elements. Additionally, using the technique of formaldehyde cross-linking coupled
      with restriction endonuclease cleavage and ligation-mediated PCR, we were able to
      map the polymerase density on the promoter of HSP82. This high-resolution mapping
      allowed us to determine that the polymerase II (Pol II) density on the promoter
      is also dramatically reduced after inactivation of TFIIH. These data provide
      strong support for the hypothesis that TFIIH functions with Pol II in the
      transcriptionally required step of promoter melting and show, surprisingly, that
      the extent of TFIIH-dependent promoter melting observed in vivo is several times
      larger than that seen in vitro.

PMID- 10409755
TI  - Bcl-2 and Bcl-X(L) block thapsigargin-induced nitric oxide generation, c-Jun
      NH(2)-terminal kinase activity, and apoptosis.
AB  - The proteins Bcl-2 and Bcl-X(L) prevent apoptosis, but their mechanism of action
      is unclear. We examined the role of Bcl-2 and Bcl-X(L) in the regulation of
      cytosolic Ca(2+), nitric oxide production (NO), c-Jun NH(2)-terminal kinase (JNK)
      activation, and apoptosis in Jurkat T cells. Thapsigargin (TG), an inhibitor of
      the endoplasmic reticulum-associated Ca(2+) ATPase, was used to disrupt Ca(2+)
      homeostasis. TG acutely elevated intracellular free Ca(2+) and mitochondrial
      Ca(2+) levels and induced NO production and apoptosis in Jurkat cells transfected
      with vector (JT/Neo). Buffering of this Ca(2+) response with 1, 2-bis(o
      aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA
      AM) or inhibiting NO synthase activity with N(G)-nitro-L-arginine methyl ester
      hydrochloride (L-NAME) blocked TG-induced NO production and apoptosis in JT/Neo
      cells. By contrast, while TG produced comparable early changes in the Ca(2+)
      level (i.e., within 3 h) in Jurkat cells overexpressing Bcl-2 and Bcl-X(L)
      (JT/Bcl-2 or JT/Bcl-X(L)), NO production, late (36-h) Ca(2+) accumulation, and
      apoptosis were dramatically reduced compared to those in JT/Neo cells. Exposure
      of JT/Bcl-2 and JT/Bcl-X(L) cells to the NO donor, S-nitroso-N
      acetylpenacillamine (SNAP) resulted in apoptosis comparable to that seen in
      JT/Neo cells. TG also activated the JNK pathway, which was blocked by L-NAME.
      Transient expression of a dominant negative mutant SEK1 (Lys-->Arg), an upstream
      kinase of JNK, prevented both TG-induced JNK activation and apoptosis. A dominant
      negative c-Jun mutant also reduced TG-induced apoptosis. Overexpression of Bcl-2
      or Bcl-X(L) inhibited TG-induced loss in mitochondrial membrane potential,
      release of cytochrome c, and activation of caspase-3 and JNK. Inhibition of
      caspase-3 activation blocked TG-induced JNK activation, suggesting that JNK
      activation occurred downstream of caspase-3. Thus, TG-induced Ca(2+) release
      leads to NO generation followed by mitochondrial changes including cytochrome c
      release and caspase-3 activation. Caspase-3 activation leads to activation of the
      JNK pathway and apoptosis. In summary, Ca(2+)-dependent activation of NO
      production mediates apoptosis after TG exposure in JT/Neo cells. JT/Bcl-2 and
      JT/Bcl-X(L) cells are susceptible to NO-mediated apoptosis, but Bcl-2 and Bcl
      X(L) protect the cells against TG-induced apoptosis by negatively regulating
      Ca(2+)-sensitive NO synthase activity or expression.

PMID- 10409756
TI  - Stability of the human fragile X (CGG)(n) triplet repeat array in Saccharomyces
      cerevisiae deficient in aspects of DNA metabolism.
AB  - Expanded trinucleotide repeats underlie a growing number of human diseases. The
      human FMR1 (CGG)(n) array can exhibit genetic instability characterized by
      progressive expansion over several generations leading to gene silencing and the
      development of the fragile X syndrome. While expansion is dependent upon the
      length of uninterrupted (CGG)(n), instability occurs in a limited germ line and
      early developmental window, suggesting that lineage-specific expression of other
      factors determines the cellular environment permissive for expansion. To identify
      these factors, we have established normal- and premutation-length human FMR1
      (CGG)(n) arrays in the yeast Saccharomyces cerevisiae and assessed the frequency
      of length changes greater than 5 triplets in cells deficient in various DNA
      repair and replication functions. In contrast to previous studies with
      Escherichia coli, we observed a low frequency of orientation-dependent large
      expansions in arrays carrying long uninterrupted (CGG)(n) arrays in a wild-type
      background. This frequency was unaffected by deletion of several DNA mismatch
      repair genes or deletion of the EXO1 and DIN7 genes and was not enhanced through
      meiosis in a wild-type background. Array contraction occurred in an orientation
      dependent manner in most mutant backgrounds, but loss of the Sgs1p resulted in a
      generalized increase in array stability in both orientations. In contrast, FMR1
      arrays had a 10-fold-elevated frequency of expansion in a rad27 background,
      providing evidence for a role in lagging-strand Okazaki fragment processing in
      (CGG)(n) triplet repeat expansion.

PMID- 10409757
TI  - Activity of the c-myc replicator at an ectopic chromosomal location.
AB  - DNA replication starts at multiple discrete sites across the human chromosomal c
      myc region, including two or more sites within 2.4 kb upstream of the c-myc gene.
      The corresponding 2.4-kb c-myc origin fragment confers autonomously replicating
      sequence (ARS) activity on plasmids, which specifically initiate replication in
      the origin fragment in vitro and in vivo. To test whether the region that
      displays plasmid replicator activity also acts as a chromosomal replicator, HeLa
      cell sublines that each contain a single copy of the Saccharomyces cerevisiae FLP
      recombinase target (FRT) sequence flanked by selectable markers were constructed.
      A clonal line containing a single unrearranged copy of the transduced c-myc
      origin was produced by cotransfecting a donor plasmid containing the 2.4-kb c-myc
      origin fragment and FRT, along with a plasmid expressing the yeast FLP
      recombinase, into cells containing a chromosomal FRT acceptor site. The amount of
      short nascent DNA strands at the chromosomal acceptor site was quantitated before
      and after targeted integration of the origin fragment. Competitive PCR
      quantitation showed that the c-myc origin construct substantially increased the
      amount of nascent DNA relative to that at the unoccupied acceptor site and to
      that after the insertion of non-myc DNA. The abundance of nascent strands was
      greatest close to the c-myc insert of the integrated donor plasmid, and
      significant increases in nascent strand abundance were observed at sites flanking
      the insertion. These results provide biochemical and genetic evidence for the
      existence of chromosomal replicators in metazoan cells and are consistent with
      the presence of chromosomal replicator activity in the 2.4-kb region of c-myc
      origin DNA.

PMID- 10409758
TI  - Neoplastic transformation of RK3E by mutant beta-catenin requires deregulation of
      Tcf/Lef transcription but not activation of c-myc expression.
AB  - Current models predict that beta-catenin (beta-cat) functions in Wnt signaling
      via activation of Tcf/Lef target genes and that its abundance is regulated by the
      adenomatous polyposis coli (APC) and glycogen synthase kinase 3beta (GSK3beta)
      proteins. In colon and other cancers, mutations in APC or presumptive GSK3beta
      phosphorylation sites of beta-cat are associated with constitutive activation of
      Tcf/Lef transcription. In spite of assumptions about its oncogenic potential,
      prior efforts to demonstrate that mutated beta-cat will induce neoplastic
      transformation have yielded equivocal results. We report here that mutated, but
      not wild-type, beta-cat proteins induced neoplastic transformation of RK3E, an
      adenovirus E1A-immortalized epithelial cell line. Analysis of the properties of
      mutant beta-cat proteins and studies with a dominant negative Tcf-4 mutant
      indicated that the ability of beta-cat to bind and activate Tcf/Lef factors is
      crucial for transformation. c-myc has recently been implicated as a critical Tcf
      regulated target gene. However, c-myc was not consistently activated in beta-cat
      transformed RK3E cells, and a dominant negative c-Myc mutant protein failed to
      inhibit beta-cat transformation. Our findings underscore the role of beta-cat
      mutations and Tcf/Lef activation in cancer and illustrate a useful system for
      defining critical factors in beta-cat transformation.

PMID- 10409759
TI  - The cleavage and polyadenylation specificity factor in Xenopus laevis oocytes is
      a cytoplasmic factor involved in regulated polyadenylation.
AB  - During early development, specific mRNAs receive poly(A) in the cytoplasm. This
      cytoplasmic polyadenylation reaction correlates with, and in some cases causes,
      translational stimulation. Previously, it was suggested that a factor similar to
      the multisubunit nuclear cleavage and polyadenylation specificity factor (CPSF)
      played a role in cytoplasmic polyadenylation. A cDNA encoding a cytoplasmic form
      of the 100-kDa subunit of Xenopus laevis CPSF has now been isolated. The protein
      product is 91% identical at the amino acid sequence level to nuclear CPSF
      isolated from Bos taurus thymus. This report provides three lines of evidence
      that implicate the X. laevis homologue of the 100-kDa subunit of CPSF in the
      cytoplasmic polyadenylation reaction. First, the protein is predominantly
      localized to the cytoplasm of X. laevis oocytes. Second, the 100-kDa subunit of
      X. laevis CPSF forms a specific complex with RNAs that contain both a cytoplasmic
      polyadenylation element (CPE) and the polyadenylation element AAUAAA. Third,
      immunodepletion of the 100-kDa subunit of X. laevis CPSF reduces CPE-specific
      polyadenylation in vitro. Further support for a cytoplasmic form of CPSF comes
      from evidence that a putative homologue of the 30-kDa subunit of nuclear CPSF is
      also localized to the cytoplasm of X. laevis oocytes. Overexpression of influenza
      virus NS1 protein, which inhibits nuclear polyadenylation through an interaction
      with the 30-kDa subunit of nuclear CPSF, prevents cytoplasmic polyadenylation,
      suggesting that the cytoplasmic X. laevis form of the 30-kDa subunit of CPSF is
      involved in this reaction. Together, these results indicate that a distinct,
      cytoplasmic form of CPSF is an integral component of the cytoplasmic
      polyadenylation machinery.

PMID- 10409760
TI  - C/EBPbeta (NF-M) is essential for activation of the p20K lipocalin gene in growth
      arrested chicken embryo fibroblasts.
AB  - The p20K gene is induced in conditions of reversible growth arrest in chicken
      embryo fibroblasts (CEF). This expression is dependent on transcriptional
      activation and on a region of the promoter designated the quiescence-responsive
      unit (QRU). In this report, we describe the regulatory elements of the QRU
      responsible for activation in resting cells and characterize the trans-acting
      proteins interacting with these elements. We show that the QRU consists of
      functionally distinct domains including quiescence-specific and weak
      proliferation-responsive elements. The quiescence responsiveness of the QRU was
      mapped to two C/EBP binding sites, and the activity of the p20K promoter and its
      QRU was inhibited by the expression of a dominant negative mutant of C/EBPbeta in
      nondividing cells. The activation of QRU in response to serum starvation and
      contact inhibition correlated with the presence of a growth arrest-specific
      complex in electrophoretic mobility shift assays. This complex was supershifted
      by antibody for C/EBPbeta. C/EBPbeta accumulated in conditions of contact
      inhibition as a result of transcriptional activation. Therefore, C/EBPbeta was
      itself regulated as a growth arrest-specific gene in CEF. Finally, we show that
      the expression of p20K is regulated by linoleic acid, an essential fatty acid
      binding to p20K. The addition of linoleic acid to contact-inhibited CEF markedly
      repressed the synthesis of p20K without inducing mitogenesis. The activity of the
      QRU was inhibited by linoleic acid or the peroxisome proliferator-activated
      receptor PPARgamma2 in transient expression assays. Therefore, we have identified
      C/EBPbeta as a key activator of a growth arrest-specific gene in CEF and
      implicated an essential fatty acid, linoleic acid, in regulation of the QRU and
      the p20K lipocalin gene.

PMID- 10409761
TI  - Dual requirement for the EcR/USP nuclear receptor and the dGATAb factor in an
      ecdysone response in Drosophila melanogaster.
AB  - The EcR/USP nuclear receptor controls Drosophila metamorphosis by activating
      complex cascades of gene transcription in response to pulses of the steroid
      hormone ecdysone at the end of larval development. Ecdysone release provides a
      ubiquitous signal for the activation of the receptor, but a number of its target
      genes are induced in a tissue- and stage-specific manner. Little is known about
      the molecular mechanisms involved in this developmental modulation of the EcR/USP
      mediated pathway. Fbp1 is a good model of primary ecdysone response gene
      expressed in the fat body for addressing this question. We show here that the
      dGATAb factor binds to three target sites flanking an EcR/USP binding site in a
      70-bp enhancer that controls the tissue and stage specificity of Fbp1
      transcription. We demonstrate that one of these sites and proper expression of
      dGATAb are required for specific activation of the enhancer in the fat body. In
      addition, we provide further evidence that EcR/USP plays an essential role as a
      hormonal timer. Our study provides a striking example of the integration of
      molecular pathways at the level of a tissue-specific hormone response unit.

PMID- 10409762
TI  - Notch and wingless regulate expression of cuticle patterning genes.
AB  - The cell surface receptor Notch is required during Drosophila embryogenesis for
      production of epidermal precursor cells. The secreted factor Wingless is required
      for specifying different types of cells during differentiation of tissues from
      these epidermal precursor cells. The results reported here show that the full
      length Notch and a form of Notch truncated in the amino terminus associate with
      Wingless in S2 cells and in embryos. In S2 cells, Wingless and the two different
      forms of Notch regulate expression of Dfrizzled 2, a receptor of Wg; hairy, a
      negative regulator of achaete expression; shaggy, a negative regulator of
      engrailed expression; and patched, a negative regulator of wingless expression.
      Analyses of expression of the same genes in mutant N embryos indicate that the
      pattern of gene regulations observed in vitro reflects regulations in vivo. These
      results suggest that the strong genetic interactions observed between Notch and
      wingless genes during development of Drosophila is at least partly due to
      regulation of expression of cuticle patterning genes by Wingless and the two
      forms of Notch.

PMID- 10409763
TI  - The Epstein-Barr virus oncoprotein latent membrane protein 1 engages the tumor
      necrosis factor receptor-associated proteins TRADD and receptor-interacting
      protein (RIP) but does not induce apoptosis or require RIP for NF-kappaB
      activation.
AB  - A site in the Epstein-Barr virus (EBV) transforming protein LMP1 that
      constitutively associates with the tumor necrosis factor receptor 1 (TNFR1)
      associated death domain protein TRADD to mediate NF-kappaB and c-Jun N-terminal
      kinase activation is critical for long-term lymphoblastoid cell proliferation. We
      now find that LMP1 signaling through TRADD differs from TNFR1 signaling through
      TRADD. LMP1 needs only 11 amino acids to activate NF-kappaB or synergize with
      TRADD in NF-kappaB activation, while TNFR1 requires approximately 70 residues.
      Further, LMP1 does not require TRADD residues 294 to 312 for NF-kappaB
      activation, while TNFR1 requires TRADD residues 296 to 302. LMP1 is partially
      blocked for NF-kappaB activation by a TRADD mutant consisting of residues 122 to
      293. Unlike TNFR1, LMP1 can interact directly with receptor-interacting protein
      (RIP) and stably associates with RIP in EBV-transformed lymphoblastoid cell
      lines. Surprisingly, LMP1 does not require RIP for NF-kappaB activation. Despite
      constitutive association with TRADD or RIP, LMP1 does not induce apoptosis in EBV
      negative Burkitt lymphoma or human embryonic kidney 293 cells. These results add
      a different perspective to the molecular interactions through which LMP1, TRADD,
      and RIP participate in B-lymphocyte activation and growth.

PMID- 10409764
TI  - Nup124p is a nuclear pore factor of Schizosaccharomyces pombe that is important
      for nuclear import and activity of retrotransposon Tf1.
AB  - The long terminal repeat (LTR)-containing retrotransposon Tf1 propagates within
      the fission yeast Schizosaccharomyces pombe as the result of several mechanisms
      that are typical of both retrotransposons and retroviruses. To identify host
      factors that contribute to the transposition process, we mutagenized cultures of
      S. pombe and screened them for strains that were unable to support Tf1
      transposition. One such strain contained a mutation in a gene we named nup124.
      The product of this gene contains 11 FXFG repeats and is a component of the
      nuclear pore complex. In addition to the reduced levels of Tf1 transposition, the
      nup124-1 allele caused a significant reduction in the nuclear localization of Tf1
      Gag. Surprisingly, the mutation in nup124-1 did not cause any reduction in the
      growth rate, the nuclear localization of specific nuclear localization signal
      containing proteins, or the cytoplasmic localization of poly(A) mRNA. A two
      hybrid analysis and an in vitro precipitation assay both identified an
      interaction between Tf1 Gag and the N terminus of Nup124p. These results provide
      evidence for an unusual mechanism of nuclear import that relies on a direct
      interaction between a nuclear pore factor and Tf1 Gag.

PMID- 10409765
TI  - NF-kappaB controls cell growth and differentiation through transcriptional
      regulation of cyclin D1.
AB  - Accumulating evidence implicates the transcription factor NF-kappaB as a positive
      mediator of cell growth, but the molecular mechanism(s) involved in this process
      remains largely unknown. Here we use both a skeletal muscle differentiation model
      and normal diploid fibroblasts to gain insight into how NF-kappaB regulates cell
      growth and differentiation. Results obtained with the C2C12 myoblast cell line
      demonstrate that NF-kappaB functions as an inhibitor of myogenic differentiation.
      Myoblasts generated to lack NF-kappaB activity displayed defects in cellular
      proliferation and cell cycle exit upon differentiation. An analysis of cell cycle
      markers revealed that NF-kappaB activates cyclin D1 expression, and the results
      showed that this regulatory pathway is one mechanism by which NF-kappaB inhibits
      myogenesis. NF-kappaB regulation of cyclin D1 occurs at the transcriptional level
      and is mediated by direct binding of NF-kappaB to multiple sites in the cyclin D1
      promoter. Using diploid fibroblasts, we demonstrate that NF-kappaB is required to
      induce cyclin D1 expression and pRb hyperphosphorylation and promote G(1)-to-S
      progression. Consistent with results obtained with the C2C12 differentiation
      model, we show that NF-kappaB also promotes cell growth in embryonic fibroblasts,
      correlating with its regulation of cyclin D1. These data therefore identify
      cyclin D1 as an important transcriptional target of NF-kappaB and reveal a
      mechanism to explain how NF-kappaB is involved in the early phases of the cell
      cycle to regulate cell growth and differentiation.

PMID- 10409766
TI  - Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome
      c from mitochondria.
AB  - Growth factors signaling through the phosphoinositide 3-kinase/Akt pathway
      promote cell survival. The mechanism by which the serine/threonine kinase Akt
      prevents cell death remains unclear. We have previously shown that Akt inhibits
      the activity of DEVD-targeted caspases without changing the steady-state levels
      of Bcl-2 and Bcl-x(L). Here we show that Akt inhibits apoptosis and the
      processing of procaspases to their active forms by delaying mitochondrial changes
      in a caspase-independent manner. Akt activation is sufficient to inhibit the
      release of cytochrome c from mitochondria and the alterations in the inner
      mitochondrial membrane potential. However, Akt cannot inhibit apoptosis induced
      by microinjection of cytochrome c. We also demonstrated that Akt inhibits
      apoptosis and cytochrome c release induced by several proapoptotic Bcl-2 family
      members. Taken together, our results show that Akt promotes cell survival by
      intervening in the apoptosis cascade before cytochrome c release and caspase
      activation via a mechanism that is distinct from Bad phosphorylation.

PMID- 10409769
TI  - [Emerging diseases and hepatitis C].

PMID- 10409770
TI  - Institutionalizing the evaluation of health programs and policies in France:
      "cuisine internationale" over fast food and "sur mesure" over ready-made.
AB  - The purpose of this article is to describe several chronological milestones in
      institutionalizing the evaluation of public programs and policies in France from
      a governmental perspective and in the health sector, situating such references in
      the international context. The institutional nature of evaluation implies
      integrating it into an action-oriented model, linking analytical activities to
      management, thus constituting the formulation of an evaluation policy for policy
      evaluation. The study focuses on issues related to the structure, practice, and
      utilization of evaluation results as well as other characteristics providing the
      French model with a certain resistance to traditional "fast-food" or "ready-made"
      methodological approaches. The institutionalization of sectorial evaluation
      appears more promising than that of the government's centralized channel, despite
      the work developed by a Scientific Evaluation Council, and suggests avenues for
      reflection and debate pertaining to the Brazilian Unified Health System.

PMID- 10409767
TI  - Multiple roles of ligand in transforming the dioxin receptor to an active basic
      helix-loop-helix/PAS transcription factor complex with the nuclear protein Arnt.
AB  - The dioxin receptor is a ligand-activated transcription factor belonging to an
      emerging class of basic helix-loop-helix/PAS proteins which show interaction with
      the molecular chaperone hsp90 in their latent states and require
      heterodimerization with a general cofactor, Arnt, to form active DNA binding
      complexes. Upon binding of polycyclic aromatic hydrocarbons typified by dioxin,
      the dioxin receptor translocates from the cytoplasm to the nucleus to allow
      interaction with Arnt. Here we have bypassed the nuclear translocation step by
      creating a cell line which expresses a constitutively nuclear dioxin receptor,
      which we find remains in a latent form, demonstrating that ligand has functional
      roles beyond initiating nuclear import of the receptor. Treatment of the nuclear
      receptor with dioxin induces dimerization with Arnt to form an active
      transcription factor complex, while in stark contrast, treatment with the hsp90
      ligand geldanamycin results in rapid degradation of the receptor. Inhibition of
      degradation by a proteasome inhibitor allowed geldanamycin to transform the
      nuclear dioxin receptor to a heterodimer with Arnt (DR-Arnt). Our results
      indicate that unchaperoned dioxin receptor is extremely labile and is consistent
      with a concerted nuclear mechanism for receptor activation whereby hsp90 is
      released from the ligand-bound dioxin receptor concomitant with Arnt
      dimerization. Strikingly, artificial transformation of the receptor by
      geldanamycin provided a DR-Arnt complex capable of binding DNA but incapable of
      stimulating transcription. Limited proteolysis of DR-Arnt heterodimers indicated
      different conformations for dioxin versus geldanamycin-transformed receptors. Our
      studies of intracellular dioxin receptor transformation indicate that ligand
      plays multiple mechanistic roles during receptor activation, being important for
      nuclear translocation, transformation to an Arnt heterodimer, and maintenance of
      a structural integrity key for transcriptional activation.

PMID- 10409768
TI  - A novel 14-base-pair regulatory element is essential for in vivo expression of
      murine beta4-galactosyltransferase-I in late pachytene spermatocytes and round
      spermatids.
AB  - During murine spermatogenesis, beginning in late pachytene spermatocytes, the
      beta4-galactosyltransferase-I (beta4GalT-I) gene is transcribed from a male germ
      cell-specific start site. We had shown previously that a 796-bp genomic fragment
      that flanks the germ cell start site and contains two putative CRE (cyclic AMP
      responsive element)-like motifs directs correct male germ cell expression of the
      beta-galactosidase reporter gene in late pachytene spermatocytes and round
      spermatids of transgenic mice (N. L. Shaper, A. Harduin-Lepers, and J. H. Shaper,
      J. Biol. Chem. 269:25165-25171, 1994). We now report that in vivo expression of
      beta4GalT-I in developing male germ cells requires an essential and previously
      undescribed 14-bp regulatory element (5'-GCCGGTTTCCTAGA-3') that is distinct from
      the two CRE-like sequences. This cis element is located 16 bp upstream of the
      germ cell-specific start site and binds a male germ cell protein that we have
      termed TASS-1 (transcriptional activator in late pachytene spermatocytes and
      round spermatids 1). The presence of the Ets signature binding motif 5'-GGAA-3'
      on the bottom strand of the TASS-1 sequence (underlined sequence) suggests that
      TASS-1 is a novel member of the Ets family of transcription factors. Additional
      transgenic analyses established that an 87-bp genomic fragment containing the
      TASS-1 regulatory element was sufficient for correct germ cell-specific
      expression of the beta-galactosidase reporter gene. Furthermore, when the TASS-1
      motif was mutated by transversion, within the context of the original 796-bp
      fragment, transgene expression was reduced 12- to 35-fold in vivo.

PMID- 10409771
TI  - Debate on the paper by Zulmira M. A. Hartz.

PMID- 10409772
TI  - The field of evaluation and the "sur mesure" strategy.

PMID- 10409773
TI  - Evaluation: the French chefs are still searching for "la nouvelle cuisine".

PMID- 10409774
TI  - "Plus ca change plus c'est la meme chose".

PMID- 10409775
TI  - Can French experience apply to Brazil?

PMID- 10409776
TI  - Is the institutionalization of evaluation sufficient to guarantee its practice?

PMID- 10409777
TI  - Evaluation: from soliloquy to dialogue.

PMID- 10409778
TI  - The author replies - evaluation in health: regulation, research, and culture in
      the challenges of institutionalization

PMID- 10409779
TI  - Social inequalities and health in rural Chiapas, Mexico: agricultural economy,
      nutrition, and child health in La Fraylesca region.
AB  - The objective of this study was to investigate the association between farmers'
      socioeconomic conditions and their children's health in La Fraylesca, Chiapas.
      Data were collected using a cross-sectional survey of 1046 households (5546
      individuals) sampled from locations in two counties situated in the study area.
      The survey included anthropometric measurements, a 24-hour dietary recall, stool
      tests, and childhood mortality data. Children of private farmers and "wealthy
      peasants" displayed better nutritional status, higher quality diet, lower
      prevalence of intestinal parasites, and a lower risk of dying than those whose
      parents were communal farmers, from ejidos, or "poor peasants". The results
      suggest that using volume of maize production as a classification method proved
      more valuable than land tenure to identify agricultural groups with different
      health status. It appears that the main determinants of health differentials are
      structural inequities in resource distribution. Thus, the impact of medical
      interventions on inequalities will be limited unless they are accompanied by
      redistribution of resources.

PMID- 10409780
TI  - [The concept of space in epidemiological research].
AB  - Epidemiology's conceptual and methodological shortcomings have placed constraints
      on the study of health phenomena related to human communities, thus posing a
      challenge to the field. This paper presents some basic principles resulting from
      the observation of the field of geography in defining its object - space - and
      the application of this object to medicine and epidemiology. Such principles
      state the pertinence of a conceptual and methodological strategy focusing on an
      approach to geographic space as expressing the population's living conditions.
      Application of this concept to epidemiological studies is still limited, although
      such proposals have already been developed in other areas of knowledge.
      Ecological studies, whose unit of analysis is the group, and the ecological
      model, based on the idea of an inter-relationship of factors, if improved, could
      become a promising alternative in this direction. The authors emphasize that
      researchers should have wholeness as their scientific reference in order to
      guarantee the non-separation of the complex interactive processes determining
      health phenomena in the population.

PMID- 10409781
TI  - [Variation of anopheles density with deltamethrin-impregnated mosquito nets in an
      endemic malaria area of the Brazilian Amazon].
AB  - In 1992 a survey on the use of deltamethrin-impregnated mosquito nets was
      conducted in the municipality of Costa Marques, Rondonia. In the intradomicile,
      impregnated nets decreased the vector density at rates similar to those for non
      impregnated nets during low-transmission periods; during high anopheline density
      periods, they led to a significant reduction in vector density, while in the non
      impregnated net group there was an increase in the number of anophelines
      captured. There was no change in vector density in the peridomicile. In the
      impregnated net group, the most frequently captured species was Anopheles
      darlingi (63.2%), found mostly in the peridomicile, while Anopheles deaneorum
      (35.3%) was most frequent indoors. The impregnated mosquito nets' excitatory
      repellent effect decreased the intradomiciliary vector density but did not alter
      density in the peridomicile.

PMID- 10409782
TI  - [Public sector and social and health policy reforms. An inventory on the eve of
      the new millennium].
AB  - This study reflects on reforms in health systems and social policies within the
      framework of the so-called public sector reforms. The point of departure is a
      review of various explanations for the crisis in the Welfare State, present in
      the literature from the 1990s. Social policies, at the heart of the crisis, are
      heavily challenged. What we intend to demonstrate is that this argument plays a
      specific role, that of introducing neoliberal changes into economic policy, in
      which the economic tools used generate abstention by the state from the social
      sphere, deregulation of national economies in favor of the free market, and the
      fundamentally oversized role of the international financial market. Within this
      context we analyze the social security and health system reforms. The final part
      of the article deals with current difficulties in social policies, focusing the
      debate on a mapping of possible alternatives for developing social and health
      policies.

PMID- 10409783
TI  - [Arquivos Brasileiros de Nutricao: a review of scientific research on nutrition
      in Brazil from 1944 to 1968].
AB  - This study reviews 209 original articles published in the journal Arquivos
      Brasileiros de Nutricao (1944/1968), a periodical edited by Josue de Castro,
      physician, specialist in nutrition, and founder-director of the Institute of
      Nutrition at the University of Brazil (now the Federal University of Rio de
      Janeiro). Our methodology was based on quantitative and qualitative analyses,
      aimed at summarizing both the topic itself and the authors' backgrounds. Results
      showed that 134 of the articles (64%) adopted a biological perspective to
      nutrition, mostly focusing on laboratory research concerning the chemical
      composition and nutritional value of Brazilian foodstuffs. On the other hand, 75
      articles (36%) took a social perspective, testifying to the first efforts by
      Brazilian nutritional experts to create and improve specific methodological tools
      for investigating our population's nutritional conditions, thereby helping to
      consolidate the field of nutrition in the country.

PMID- 10409784
TI  - [Evaluation of under-reporting of AIDS cases in the city of Rio de Janeiro based
      on data from the hospital information system of the Unified Health System].
AB  - Data from the Hospital Information System (SIH-SUS) were linked to data from the
      AIDS Case Reporting System (Sinan) to assess the level of under-reporting of AIDS
      cases in the city of Rio de Janeiro. A high level of unreported cases(42.7%) was
      observed for patients treated in hospitals under Brazil's Unified Health System
      in the city of Rio. Bivariate analysis showed an association between reporting to
      the Sinan and age, principal diagnosis, and type of hospital.

PMID- 10409786
TI  - [Waist:hips girth ratio as a predictor of arterial hypertension].
AB  - This study aims to define cut-off points for the waist:hips girth ratio (WHR),
      using arterial hypertension as the outcome. The data refer to 3,282 individuals
      over twenty years of age examined in a survey conducted in the municipality of
      Rio de Janeiro in 1995-1996, using a two-stage sample. Sixty census tracts were
      drawn initially; subsequently, 34 households were selected systematically from
      each tract. Stature, weight, waist and hips girths, and blood pressure were
      measured in the households. The criterion for hypertension was a systolic blood
      pressure of ( 140 mmHg or diastolic pressure of ( 90 mmHg, or use of medication
      to reduce blood pressure. The sensitivity and specificity of different cut-off
      points for WHR were calculated in the prediction of arterial hypertension
      according to sex, age, and presence of overweight, classified according to World
      Health Organization guidelines. The best cut-off points for WHR were 0.95 for men
      and 0.80 for women. Compared to the waist:stature ratio and waist circumference,
      the WHR proved more capable of predicting arterial hypertension and less
      correlated with body mass index.

PMID- 10409785
TI  - [Mercury levels in fish consumed by the Sai Cinza indigenous community, Munduruku
      Reservation, Jacareacanga County, State of Para, Brazil].
AB  - This study evaluated fish consumption and mercury levels in fish consumed by an
      indigenous community in the State of Para. Eighty fish samples were collected
      (barbado, surubim, traira, tucunare, piranha, aruana, caratinga, aracu, mandia,
      jandia, and pacu). Mercury analysis was performed using a Mercury Analyzer HG
      3500. Average mercury concentration in carnivorous species was 0.293 (g/g
      (SD=0.104), while in non-carnivorous species it was 0.112 (g/g (SD=0. 036).
      Brazilian legislation establishes a maximum permissible limit of 0.5 (g/g for
      fish consumption. No significant correlation was found between fish length or
      weight and mercury concentration. Types of fish most frequently consumed by the
      community were tucunare, pacu, jaraqui, traira, aracu, matrincha, and caratinga.
      Carnivorous species, especially tucunare and traira, amongst the most frequently
      eaten, had higher mercury levels than non-carnivorous species. Frequency of
      consumption is crucial to assess the risk of mercury contamination in communities
      who lack alternative food sources.

PMID- 10409787
TI  - ["User embracement" and the working process in health: Betim's case, Minas
      Gerais, Brazil].
AB  - The subject of this paper is changes in health care when "user embracement" is
      used as a strategic aim. According to the "user embracement" concept, health care
      clients are the center of the health services' organization, including the
      following: 1) care for everyone seeking it, thus guaranteeing universal
      accessibility; 2) reorganization of the work process, such that its central
      thrust is shifted from the physician to the multiprofessional staff, or "user
      embracement team", in charge of "hearing" users and becoming involved in solving
      their health problems; and 3) solidarity, humanity, and citizenship as parameters
      for the relationship between health care users and providers. The research showed
      improvement of non-medical health care productivity and greater accessibility by
      users. After nine months, the "user embracement team" solved 50% of the health
      problems themselves. The above-mentioned effects were also linked to workers'
      motivation, leading to greater creativity in the work process.

PMID- 10409788
TI  - [Evaluation of orientation and serological support centers in the Brazilian
      Northeast].
AB  - This article presents the results of an evaluation of Orientation and Serological
      Support Centers, or Anonymous HIV Testing Centers, in the Northeast of Brazil.
      Methodological triangulation was used to evaluate these health programs and
      services, including qualitative and quantitative methodology and pointing to the
      insufficiency of single-discipline reasoning to encompass phenomena in social
      organizations. The article also shows results from this triangulation experience,
      seeking to combine Social Sciences and Epidemiology. It describes the structure
      and dynamics of these services, analyzes the relationships, perceptions, and
      representations of the actors, presents a self-evaluation by the professionals,
      expounds on some quantitative results, and discusses some limits and problems, as
      well as proposals to overcome them.

PMID- 10409789
TI  - [Women with AIDS: disclosing risk stories].
AB  - This study approaches the social and cultural profile concerning risk for HIV
      infection in women, describing some epidemiological variables and disclosing
      reports of risk situations, the meaning of living with AIDS, and support
      received. A semi-structured questionnaire was used to interview 25 women from the
      University Hospital of the Federal University of Rio de Janeiro, prior to the
      availability of multi-drug treatment. The majority reported limited schooling,
      were housewives or engaged in under-skilled occupations, and had family incomes
      lower than average for users of this public teaching hospital. The view of AIDS
      as "someone else's disease" was prevalent, and STDs were perceived as male
      infections, although several women reported episodes of STDs prior to HIV. They
      had received their diagnosis and initial medical care only after their partners'
      and/or children's illness or death. The study points to preventive strategies
      reinforcing these silent women's bargaining power, acting on men as potential
      active participants in reproductive health programs that incorporate STD/AIDS
      issues.

PMID- 10409790
TI  - Working conditions of Chagas' disease patients in a large Brazilian city.
AB  - This study evaluated the working conditions of Chagas' disease patients in the
      city of Campinas, Sao Paulo, focusing on two-hundred-fifty patients with steady
      employment and treated at the University Hospital (HC-FCM/Unicamp): 98% were
      working-age and 77.6% were men. The origin of the patients reflected the
      migratory process occurring among this population. Most of the patients had
      limited professional skills, while 63.6% had not finished primary school and
      21.6% were illiterate. However, 63.6% were regularly employed under duly
      processed work contracts. Their jobs were mainly in general services (21.6%) and
      heavy industry (21.2%). Some 55% of the patients reported a monthly income less
      than or equal to U$100.00, and 40.4% reported having been fired at least once
      during the last ten years, in 8.9% of the cases because of a diagnosis of Chagas'
      disease. Of the patients undergoing pre-hiring physical examinations (57.2%),
      9.1% were refused, 92.3% of whom due to positive serology for T. cruzi. Finally,
      78.4% reported not belonging to a labor union. The study demonstrated the
      precarious working conditions and discrimination experienced by workers with
      Chagas' disease.

PMID- 10409791
TI  - [Certificates of live birth: analysis of completion in the city of Ribeirao
      Preto, Sao Paulo, Brazil].
AB  - The study aims to identify the frequency with which certificates of live birth
      are filled out and to analyze the data they provide. To gather the data, the
      authors used a model birth certificate filled out by research assistants based on
      information obtained from the reports on mothers and newborns. This information
      was then compared to data contained in the official birth certificates available
      in the Information Technology Division of the Municipal Health Department. The
      sample consisted of 911 certificates of live birth from July 1996 in the ten
      maternity wards of the city of Ribeirao Preto. Data analysis showed that
      frequency of completion of birth certificates differs by hospital, involving both
      physicians and administrative personnel. The authors identified a high level of
      agreement in the data, i.e., over 90% in 13 of 18 variables compared in the birth
      certificates and in half of the hospitals investigated. The disagreement occurred
      especially with respect to data on the number of children per mother, number of
      prenatal visits, mother's schooling, and father's name.

PMID- 10409792
TI  - [Maternal mortality in the city of Rio de Janeiro, 1993-1996].
AB  - The maternal mortality rate is considered an important indicator of quality of
      care during the gravid-puerperal cycle. To shed light on the maternal mortality
      pattern in the city of Rio de Janeiro, maternal deaths from 1993 to 1996 among
      residents of the city were analyzed, based on data from death certificates. The
      maternal mortality rate was calculated according to cause, age, and schooling.
      High annual mortality rates were detected throughout the period analyzed (74.3,
      47.9, 51.5, and 55.3 per 100,000 live births, respectively). Main causes of death
      were hypertension, hemorrhage, and puerperal complications. Greatest risk of
      death was among the youngest and oldest women and those with less schooling. The
      study discusses strategies to decrease under-recording of deaths and increase
      quality and results of care.

PMID- 10409793
TI  - [Canine heartworm on Sao Luis Island, Northeastern Brazil: a potential zoonosis].
AB  - A survey on the prevalence of canine heartworm was conducted in 1, 495 dogs from
      Maranhao Island, State of Maranhao, Northeastern Brazil, from 1991 to 1994, by
      testing for microfilariae in blood. Of the total, 1,358 (12.8% of which were
      infected) were dogs with no known history; they included 1,265 homeless animals
      (10.3% with microfilariae) and 93 kept by owners at the time the survey was
      conducted (37.8% of which were infected). Prevalence is high among dogs captured
      and/or living along the seashore. Examples of such high coastal prevalence rates
      were found in Olho d'Agua and Calhau (46% and 43%, respectively). The search for
      microfilariae in blood samples of 137 exclusively domiciliary dogs with a known
      history showed that 43% of these animals were infected, confirming transmission
      of heartworm on the island. This was the first survey formally published on
      canine dirofilariasis in Northeastern Brazil. Since D. immitis is infective to
      man and prevalence of the parasite is high, particularly along the coast of
      Maranhao Island, human cases of dirofilariasis may be expected. Local physicians
      should consider this parasite among the possible causes of solitary lesions in
      humans living in this area.

PMID- 10409794
TI  - Anemia and intestinal parasitic infections in primary school students in Aracaju,
      Sergipe, Brazil.
AB  - Anemia is estimated to affect half the school-age children and adolescents in
      developing countries. The main causes are parasitic infections, malaria, and low
      iron intake. This study aimed to describe the prevalence of anemia, parasitic
      infections, and nutritional status of children attending public primary schools
      in Aracaju, Northeast Brazil. Of 360 students, 26.7% were anemic, and prevalence
      was higher in children under 8 and over 15 years of age. Overall prevalence of
      intestinal parasites was 42%, with Ascaris lumbricoides (28.7%), Trichuris
      trichiura (15.6%), and hookworm (1. 7%) most frequently found. There was an
      association between parasitic infections and poor sanitary conditions, but there
      was no association between anemia and presence of intestinal parasites. Height
      for-age Z scores were lower than the NCHS standard, and prevalence of stunting
      was 5.4%. Although intestinal parasites were not associated with anemia, children
      with parasites had lower nutritional indices (weight- and height-for-age Z
      scores) than those without parasites.

PMID- 10409795
TI  - [Public health and behavior modification: a contemporary issue].
AB  - Most cardiovascular disease risk factors can be modified through life-style
      changes. Choices of habits and behavior are in fact heavily influenced by
      concepts of normality and social values. However, social influences fail to fully
      explain these choices, insofar as health-related habits are also shaped by
      personal experience. The main limitations of public health practice can probably
      be found at this subjective level. This article emphasizes the need to consider
      determinants of human behavior at different levels, increasingly important for
      strategies to promote health and prevent disease, or at least delay its onset.
      The primary focus is to influence rules and laws aimed at protecting life. The
      article also discusses possible strategies for translating scientific knowledge
      into public health action, avoiding the restriction to the "healthy life"
      regulatory role. Finally, participation by public health professionals is
      suggested in places where population groups share life experiences, such as
      workplaces, schools, and churches, developing approaches which include those
      experiences as well as fears and hopes related to health. Scientific facts might
      thus be transformed into more familiar elements of everyday life.

PMID- 10409796
TI  - [Cholera epidemic in Southern Brazil].

PMID- 10409797
TI  - A new view on grasping.
AB  - Reaching out for object is often described as consisting of two components that
      are based on different visual information. Information about the object's
      position and orientation guides the hand to the object, while information about
      the object's shape and size determines how the fingers move relative to the thumb
      to grasp it. We propose an alternative description, which consists of determining
      suitable positions on the object - on the basis of its shape, surface roughness,
      and so on - and then moving one's thumb and fingers more or less independently to
      these positions. We modeled this description using a minimum-jerk approach,
      whereby the finger and thumb approach their respective target positions
      approximately orthogonally to the surface. Our model predicts how experimental
      variable such as object size, movement speed, fragility, and required accuracy
      will influence the timing and size of the maximum aperture of the hand. An
      extensive review of experimental studies on grasping showed that the predicted
      influences correspond to human behavior.

PMID- 10409798
TI  - On achieving strong inference in prehension research.
AB  - Smeets and Brenner have suggested that it may be time to abandon Jeannerod's
      "classical approach" to studying human prehension, and have presented a
      mathematical model as an alternative. We argue that this model provides
      insufficient grounds for widespread acceptance, and questions whether or not such
      an approach furthers the science of motor control.

PMID- 10409799
TI  - Computational implications of modeling grasping as a form of (multiple-parallel)
      reaching.
AB  - Although it is true that the specific research on grasping has been dominated in
      recent years by the canonical transport + grip model originally formulated by
      Jeannerod (1984), still one can find in the research on reaching a number of
      links and anticipations to the new view on grasping made explicit by the authors
      of the target article. This paper reviews some of the relevant concepts and
      outlines a modeling framework that aims at biological plausibility.

PMID- 10409800
TI  - Influence of intermittency and synergy on grasping.
AB  - The commentary firstly supports Smeets and Brenner in their choice of a kinematic
      trajectory, submitting that the challenge posed by the rival torque-change
      formulation is resolved by consideration of intermittency in human movement
      control. Second, it examines the choice of optimization criterion for trajectory
      planning, arguing in favor of minimum acceleration rather than minimum jerk.
      Third, using the notion of optimized trajectories in task-dependent coordinate
      space together with synergy generation, it suggests a formulation that reduces
      the processing load entailed in Smeets and Brenner's proposal of individual
      trajectories for each digit.

PMID- 10409801
TI  - On taking the grasping out of prehension.
AB  - Smeets and Brenner provide a very clear and useful statement of the work that has
      been stimulated by Jeannerod's 1984 paper but seem more concerned about the
      viability of model fitting than model assumptions. The theoretical and practical
      limitations of viewing "grasping as nothing more than pointing" are noted. We
      reemphasize the importance in prehension of the union of the hand with the object
      in the act of realizing a task goal.

PMID- 10409803
TI  - Is it pointing to grasping or grasping pointing?
AB  - The Smeets and Brenner view on grasping is simple: grasping is in fact pointing.
      In our comments we examine the model beyond the reach-to-grasp task, namely, by
      grasping (without reaching) of moving objects and eating. The model fits the data
      of both tasks. Although generalization of a model to different tasks usually
      strengthens its acceptance, in the present case it reveals its shortcomings,
      namely, both tasks include a clear grasping component that is hard to accept as
      pointing.

PMID- 10409802
TI  - Approaching grasping from different perspectives.
AB  - The hypothesis introduced by Smeets and Brenner concerning the perpendicular
      approach of the thumb and index finger during grasping has heuristic value, but
      it also has limitations. Among the limitations are the following: (a) the
      approach parameter is not directly testable and it is unclear how the values of
      deceleration at contact and movement time are set theoretically; (b) it is
      questionable that motion of the thumb and index finger are independent; (c)
      reliance on the minimum-jerk account ignores critiques of that account; and (d)
      the model begs the question of how the effectors proximal to the index finger and
      thumb are controlled. We briefly review an alternative model that can handle
      these challenges.

PMID- 10409804
TI  - What can be learned from Smeets and Brenner's model about the control of
      grasping?
AB  - The present reaction on the paper of Smeets and Brenner focuses on two premises
      of their proposed model. The first is that grasping is nothing more than pointing
      with two fingers. It is argued that this assumption cannot be upheld in light of
      the differences between both actions with respect to neuromuscular structures,
      muscular innervation, use of visual feedback, and basic function. The second
      premise of the model is that the velocity profile of the transport component is
      symmetrical and independent of intrinsic object properties. It is shown that the
      symmetrical velocity profile represents a boundary condition and is influenced by
      intrinsic object properties. Given these concerns, it is doubtful that the model
      in its present form will add much to our understanding of the control of
      grasping.

PMID- 10409805
TI  - Temporal and spatial relationship between reaching and grasping. Commentary on "A
      new view on grasping".
AB  - Smeets and Brenner propose a model that attempts to account for the action
      patterns involved in prehensile behaviors. However, the model does not provide a
      full account of the available data on temporal and spatial relationships between
      the transport and grasp components. Predictions from the model in its current
      form appear to correspond only to experimental results in a very general way.

PMID- 10409806
TI  - The reach-to-grasp movement: A new look at an old problem?
AB  - This commentary raises some issues still unresolved in the study of the reach-to
      grasp movement, namely the operational definition of the components of the reach
      to-grasp movement, the independence of these components, and the equivocal
      interpretation of the existing literature. Lastly, this commentary addresses
      issues pertaining to object properties that require both visual and haptic
      determination.

PMID- 10409807
TI  - Grip formation as an emergent property. Response To commentaries on "A new view
      on grasping"
AB  - We begin our response by discussing the commentators' arguments concerning our
      proposal to abandon the classical distinction between transport and grip. In the
      second section, we argue that the minimum-jerk model is not fundamental to our
      approach, but very convenient. In the third section, we discuss how the
      experimental results that the commentators mention fit into our new approach. We
      conclude that the predictive capacity of our model, combined with its simplicity,
      makes it very useful for understanding grasping.

PMID- 10409808
TI  - Transmitter-specific input to OFF-alpha ganglion cells in the cat retina.
AB  - The synaptic input to OFF-center alpha ganglion cells in the cat retina was
      analyzed by electron microscopic reconstruction to quantify the bipolar and
      amacrine cell input and to determine the neurotransmitter content of the
      presynaptic cells. Cone bipolar cells were found to comprise 11% of the total
      input with their dyad synapses distributed across the dendritic tree. The
      remaining contacts were conventional synapses indicative of amacrine cells;
      postembedding immunogold labeling was used to characterize these cells as either
      GABA- or glycine-immunoreactive. Results showed the amacrine input to be equally
      divided between GABA and glycinergic contacts at each order of dendritic
      branching of the alpha cells. Among the GABA-positive neurons were A19 amacrine
      cells, the processes of which are characterized by a dense array of neurotubules.
      A major source of glycinergic input was from lobular appendages of AII amacrine
      cells with lesser contributions from other glycine-positive amacrine cells. The
      physiological role(s) of these amino acids must be interpreted in view of the
      multiple subpopulations of amacrine cells, which provide input to OFF-alpha
      cells, and the diversity in receptors at their synapses.

PMID- 10409809
TI  - Anatomical study of the perforating vessels of the lower leg.
AB  - Difficulty of soft tissue defects of the lower leg demands the development of new
      methods to treat such defects. The aim of this study is the examination of
      perforators and the various ways of blood supply to the skin in the lower leg.
      Provided with certain regularity, we would be able to cure soft-tissue defects
      also in the difficult zone of the distal segment and on the dorsum of the foot
      not harming vessels and not affecting mobility of muscles. Subcutaneous island
      flaps supplied by perforating vessels could replace free flaps. By saving the
      crural fascia of 10 lower legs we flayed layers of skin and fat, marked the
      perforating vessels with pins, and photographed and documented them. Specimens
      were divided into a proximal, an intermediate and a distal segment, each of them
      subdivided into a medial, lateral and dorsal section. The perforators, which can
      be classified as septocutaneous and musculocutaneous vessels, followed a
      reproducible pattern all over the lower leg. All vessels were sufficient in
      number as well as in size. Additionally these perforators can easily be
      identified by colour-coded sonography. The knowledge that perforators in the
      lower leg occur regularly enables the development of a new operative approach in
      therapy of soft-tissue defects in this region with the advantage, that the
      vessels used can be selected preoperatively.

PMID- 10409810
TI  - Histomorphological study on pattern of fluid movement in cortical bone in goats.
AB  - Streaming potential is considered one of the most important mechanisms to
      moderate the function of osteoblasts and osteocytes in bone growth, remodeling
      and fracture repair. The present study was designed to demonstrate the fluid flow
      pattern in the cortical bone matrix in an animal model using undecalcified
      histological techniques. Immediately after injection of ferritin into the tibia
      nutrient artery of four adult goats, the animals were euthanized. Undecalcified
      transverse and longitudinal blocks of cortical bone obtained from the tibial
      diaphysis were immersed in Perl's reagent and embedded in methyl methacrylate.
      Sections were cut and ground to 30-50 microm thickness for histomorphological
      evaluation at different magnifications and focusing levels. A serial grinding
      technique was used to validate the observations made at different focusing
      levels. As expected, ferritin was observed in the interstitial compartment in
      both transverse and longitudinal sections. In osteons sectioned transversely, the
      pattern of centrifugal movement of ferritin marker was demonstrated as single or
      multiple halos around the Haversian canal. The most apparent halo in osteons with
      multiple halos was the one found closest to the Haversian canal. The total number
      of identifiable single or multiple halos increased or was altered when counting
      was made with higher magnification or at different focusing levels, respectively.
      Irregular and incomplete ferritin halos indicated structural complexity of the
      osteons. Overall, the pattern of ferritin movement was consistent with bulk
      interstitial fluid flow influenced by both hydrostatic pressure and transudation.
      This study demonstrated for the first time multiple concentric halos of the fluid
      flow marker ferritin around Haversian canals in the cortical interstitial
      compartment. The results suggest that the undecalcified technique might be a
      useful method for qualitative and quantitative studies on cortical fluid flow.

PMID- 10409811
TI  - External oblique abdominal muscle: a new look on its blood supply and
      innervation.
AB  - Numerous reports have discussed the use of the external oblique abdominal muscle
      as a pedicled or a free flap for defect coverage. A detailed description of the
      supplying vessels and nerves is a prerequisite for successful tissue transfer but
      so far is not available in the literature. A study of the arteries and nerves
      supplying the external oblique abdominal muscle was carried out in 42 cadavers
      after injection of a mixture of latex and bariumsulfate. In seven fresh cadavers
      the motor branches were identified with the Karnovsky technique. Three different
      groups of arteries were identified as the nurturing vessels. The cranial part of
      the muscle is supplied by two branches of the intercostal arteries. While the
      lateral branches run on the outer surface of the muscle together with the nerves,
      the anterior branches enter the muscle from its inner surface. The caudal part of
      the muscle derives its main blood supply from one or two branches of the deep
      circumflex iliac artery (94.7%) or the iliolumbar artery (5.3%). The external
      oblique abdominal muscle is innervated by motor branches of the lateral cutaneous
      branches of the anterior spinal nerves in a segmental pattern. With the exception
      of the subcostal nerve the motor branches enter the outer surface of the muscle
      digitation arising from the rib above. The results show that the cranial half of
      the external oblique abdominal muscle has a strictly segmental blood and nerve
      supply while the caudal half of the muscle derives its main blood supply from one
      artery but still shows a segmental innervation.

PMID- 10409812
TI  - Stereological age-related changes in neurons of the rat dorsal lateral geniculate
      nucleus.
AB  - Quantitative methods were used to compare the changes taking place in the volume
      of the dorsal lateral geniculate nucleus (dLGN) and corresponding neurons of
      young, adult and old rats. The study was carried out on male albino rats aged 3,
      18, 24 and 28 months. In order to estimate the volume of the dLGN, neuronal
      volume density, numerical density and total number of neurons, we used serial
      sections stained according to the Kluver-Barrera technique and stereological
      methods. We found that dorsal lateral geniculate nucleus volume increases between
      3 and 28 months, with a larger increase between 24 and 28 months. Neuronal volume
      density and numerical density of neurons are greater at 3 months and undergo a
      significant decrease between 24 and 28 months. Finally, the total number of
      neurons is shown to be smaller in adult and old animals than in younger ones,
      even though no significant variations are found between 18 and 28 months.
      Furthermore, this study confirms the need to analyze the total number of neurons
      and not just neuronal density if we want to correctly evaluate some of the
      microscopic changes occurring during senescence.

PMID- 10409813
TI  - Comparison of palmar aponeuroses from individuals with diabetes mellitus and
      Dupuytren's contracture.
AB  - It is well known that Dupuytren's contracture is often associated with diabetes
      mellitus. Palmar fascia from individuals with diabetes mellitus and/or
      Dupuytren's contracture as well as controls were subjected to differential
      scanning calorimetry, biomechanical and biochemical analysis. The collagen
      denaturation temperature of the palmar aponeurosis from individuals with diabetes
      mellitus in the presence (71.0 degrees C) or absence of Dupuytren's contracture
      (70. 6 degrees C) was increased as compared with controls (68.5 degrees C), while
      this parameter was significantly reduced (about 3.5 degrees C) in contracture
      bands of Dupuytren's contracture. Stress relaxation experiments revealed that the
      viscous fraction was slightly reduced in diabetes mellitus (6.5%) vs. controls
      (8.3%), whereas in Dupuytren's contracture, irrespective of additional diabetes
      mellitus, a pronounced increase of this parameter was seen (36.5% vs. 24.5%) in
      the presence of diabetes mellitus. The time constants were significantly elevated
      by both disorders, this increase being more pronounced in Dupuytren's
      contracture. Taken together, these changes can be explained by increased cross
      linking in diabetes mellitus, while in Dupuytren's contracture other structural
      changes, such as increased collagen type III content and loss of fascicular
      organization, play an additional role besides the finding of reduced cross
      linking.

PMID- 10409814
TI  - Contribution of the cervical sympathetic ganglia to the innervation of the
      pharyngeal arch arteries and the heart in the chick embryo.
AB  - In the chick heart, sympathetic innervation is derived from the sympathetic
      neural crest (trunk neural crest arising from somite level 10-20). Since the
      trunk neural crest gives rise to sympathetic ganglia of their corresponding
      level, it suggests that the sympathetic neural crest develops into cervical
      ganglia 4-14. We therefore tested the hypothesis that, in addition to the first
      thoracic ganglia, the cervical ganglia might contribute to cardiac innervation as
      well. Putative sympathetic nerve connections between the cervical ganglia and the
      heart were demonstrated using the differentiation markers tyrosine hydroxylase
      and HNK-1. In addition, heterospecific transplantation (quail to chick) of the
      cardiac and trunk neural crest was used to study the relation between the
      sympathetic neural crest and the cervical ganglia. Quail cells were visualized
      using the quail nuclear antibody QCPN. The results by immunohistochemical study
      show that the superior and the middle cervical ganglia and possibly the carotid
      paraganglia contribute to the carotid nerve. This nerve subsequently joins the
      nodose ganglion of the vagal nerve via which it contributes to nerve fibers in
      cardiac vagal branches entering the arterial and venous pole of the heart. In
      addition, the carotid nerve contributes to nerve fibers connected to putative
      baro- and chemoreceptors in and near the wall of pharyngeal arch arteries
      suggesting a role of the superior and middle cervical ganglia and the paraganglia
      of the carotid plexus in sensory afferent innervation. The lower cervical ganglia
      13 and 14 contribute predominantly to nerve branches entering the venous pole via
      the anterior cardinal veins. We did not observe a thoracic contribution.
      Heterospecific transplantation shows that the cervical ganglia 4-14 as well as
      the carotid paraganglia are derived from the sympathetic neural crest. The
      cardiac neural crest does not contribute to the neurons of the cervical ganglia.
      We conclude that the cervical ganglia contribute to cardiac innervation which
      explains the contribution of the sympathetic neural crest to the innervation of
      the chick heart.

PMID- 10409815
TI  - Characterization of olfactory receptor organs in Xenopus laevis Daudin.
AB  - Xenopus laevis is highly suitable for studying the mechanisms of olfactory
      reception for water-soluble odorants and for airborne odorants. However, the
      functional differences of cells and component protein molecules in the olfactory
      receptors of Xenopus have remained obscure. In recent studies, the patterns of
      sugar residues expressed on the cell surface have been utilized to analyze the
      characteristics of neurons, because the sugar chains in neurons play very
      important roles in targeting and cell-to-cell communication. In this study, we
      have determined the distribution of sugar residues and glycoproteins in the
      olfactory receptor organs of Xenopus using lectins as labeling agents, and
      characterized the receptors of water-soluble odorants and of airborne odorants.
      The results of lectin histochemical analysis show distributional differences of
      GlcNAc, GalNAc and mannose between the middle chamber and the lateral chamber of
      the main nasal cavity. Furthermore, a 65 kDa glycoprotein containing mannose,
      GlcNAc and GalNAc was specifically detected in the medial chamber of the main
      cavity epithelium in receptor organs of airborne odorants by SDS-PAGE and lectin
      blotting. The characteristics of the epithelia demonstrated in this study should
      further our understanding of the functional differences between the receptors of
      water-soluble odorants and of airborne odorants at the molecular level.

PMID- 10409816
TI  - Hypothalamopontine projections in the rat: anterograde axonal transport studies
      utilizing light and electron microscopy.
AB  - Projections to the basilar pontine nuclei (BPN) from a variety of hypothalamic
      nuclei were traced in the rat utilizing the anterograde transport of biotinylated
      dextran amine. Light microscopy revealed that the lateral hypothalamic area (LH),
      the posterior hypothalamic area (PH), and the medial and lateral mammillary
      nuclei (MMN and LMN) are the four major hypothalamic nuclei that give rise to
      labeled fibers and terminals reaching the rostral medial and dorsomedial BPN
      subdivisions. Hypothalamopontine fibers extended caudally through the pontine
      tegmentum dorsal to the nucleus reticularis tegmenti pontis and then coursed
      ventrally from the main descending bundle toward the ipsilateral basilar pontine
      gray. Some hypothalamopontine fibers crossed the midline in the tegmental area
      just dorsal to the pontine gray to terminate in the contralateral BPN. Electron
      microscopy revealed that the ultrastructural features of synaptic boutons formed
      by axons arising in the LH, PH, MMN, and LMN are similar to one another. All
      labeled hypothalamopontine axon terminals contained round synaptic vesicles and
      formed asymmetric synaptic junctions with dendritic shafts as well as dendritic
      appendages, and occasionally with neuronal somata. Some labeled boutons formed
      the central axon terminal in a glomerular synaptic complex. In summary, the
      present findings indicate that the hypothalamus projects predominantly to the
      rostral medial and dorsomedial portions of the BPN which, in turn, provide input
      to the paraflocculus and vermis of the cerebellum. Since the hypothalamic
      projection zones in the BPN also receive cerebral cortical input, including
      limbic-related cortex, the hypothalamopontine system might serve to integrate
      autonomic or limbic-related functions with movement or somatic motor-related
      activity. Alternatively, since the cerebellum also receives direct input from the
      hypothalamus, the BPN may function to provide additional somatic and visceral
      inputs that are used by the cerebellum to perform the integrative function.

PMID- 10409818
TI  - Effects of heat shock on the functional morphology of cell organelles observed by
      video-enhanced microscopy.
AB  - In living astrocytes and MDCK cells we observed morphological phenomena during
      and after heat shock (HS) utilizing our new perfusable microchamber system, which
      monitors pH, pO(2), pCO(2), and temperature. By means of electronic light
      microscopy and confocal laser scanning microscopy, mitochondria were demonstrated
      to swell and to reduce their motility. The specific fluorescent probe MitoTracker
      Green revealed that the mitochondrial morphology changed from a rodlike into an
      annular shape with a central vacuole-findings which were corroborated by
      transmission electron microscopy. After HS (shift from 37 degrees C to 45 degrees
      C for 15 min) the mitochondrial membrane potential (DeltaPsi(m)) was depressed in
      most but not all mitochondria as monitored with the fluorescent probe JC-1. The
      dual emission images of JC-1 illustrated a heterogeneous red staining of distinct
      areas of single mitochondria. The shape changes as well as the drop of the
      membrane potential of the mitochondria indicated severe cellular stress and a
      direct intervention on the mitochondrial permeability transition.

PMID- 10409817
TI  - Differential responses to parathyroid hormone-related protein (PTHrP) deficiency
      in the various craniofacial cartilages.
AB  - PTHrP null mutant mice exhibit skeletal abnormalities both in the craniofacial
      region and limbs. In the growth plate cartilage of the null mutant, a diminished
      number of proliferating chondrocytes and accelerated chondrocytic differentiation
      are observed. In order to examine the effect of PTHrP deficiency on the
      craniofacial morphology and highlight the differential feature of the composing
      cartilages, we examined the various cartilages in the craniofacial region of
      neonatal PTHrP deficient mice. The major part of the cartilaginous anterior
      cranial base appeared to be normal in the homozygous PTHrP deficient mice.
      However, acceleration of chondrocytic differentiation and endochondral bone
      formation was observed in the posterior part of the anterior cranial base and in
      the cranial base synchondroses. Ectopic bone formation was observed in the soft
      tissue-running mid-portion of the Meckel's cartilage, where the cartilage
      degenerates and converts to ligament in the course of normal development. The
      zonal structure of the mandibular condylar cartilage was scarcely affected, but
      the whole condyle was reduced in size. These results suggest the effect of PTHrP
      deficiency varies widely between the craniofacial cartilages, according to the
      differential features of each cartilage.

PMID- 10409819
TI  - Lateromedial and dorsoplantar borders among supplying areas of the nerves
      innervating the intrinsic muscles of the foot.
AB  - The branching patterns of nerves supplying the intrinsic muscles of the foot were
      analyzed as a basis to confirm the muscle layer structure. Thirty-eight feet of
      20 Japanese cadavers were examined in detail in this study. The first dorsal
      interosseus was innervated by a branch from the deep peroneal nerve as well as a
      branch of the lateral plantar nerve in 92.1%, the second dorsal interosseus in
      10. 5% and the third dorsal interosseus in 2.6%. In three specimens, branches
      from the deep peroneal nerve innervated the oblique head of the adductor hallucis
      or the lateral head the flexor hallucis brevis. In addition, branches from the
      medial and lateral plantar nerves and the deep peroneal nerve formed
      communication loops in three specimens. The first dorsal interosseus, the oblique
      head of the adductor hallucis and the lateral head of the flexor hallucis and
      their innervating nerve branches are closely related within the first
      intermetatarsal space. Since the tibial part of the first interosseus muscle
      primordium is occupied in the space during development, the variations of
      innervation patterns and formation of the communicating nerve loops may be
      explained by various combinations of the part and the other muscle primordia.

PMID- 10409820
TI  - Review of the fourth Johns Hopkins protein folding meeting.

PMID- 10409822
TI  - X-ray crystallographic studies of the denaturation of ribonuclease S.
AB  - In an attempt to view the onset of urea denaturation in ribonuclease we have
      collected X-ray diffraction data on ribonuclease S crystals soaked in 0, 1.5, 2,
      3, and 5 molar urea. At concentrations above 2 M urea, crystals were stabilized
      by glutaraldehyde crosslinking. We have also collected data on ribonuclease S
      crystals at low pH in an attempt to study the onset of pH denaturation. The
      resolution of the datasets range from 1.9 to 3.0 A. Analysis of the structures
      reveals an increase in disorder with increasing urea concentration. In the 5 M
      urea structure, this increase in disorder is apparent all over the structure but
      is larger in loop and helical regions than in the beta strands. The low pH
      structure shows a very similar pattern of increased disorder. In addition there
      is a major change in the position of the main chain (> 1 A) in the 65-72 turn
      region. This region has previously been shown to be involved in one of the
      initial steps of unfolding in the reduction of ribonuclease A. Crystallographic
      analyses in the presence of denaturant, when combined with controlled
      crosslinking, can thus provide detailed structural information that is related to
      the initial steps of unfolding in solution. Proteins 1999;36:282-294.

PMID- 10409821
TI  - Macromolecular impurities and disorder in protein crystals.
AB  - The mechanisms by which macromolecular impurities degrade the diffraction
      properties of protein crystals have been investigated using X-ray topography,
      high-resolution diffraction line shape measurements, crystallographic data
      collection, chemical analysis, and two-photon excitation fluorescence microscopy.
      Hen egg-white lysozyme crystals grown from solutions containing a structurally
      unrelated protein (ovotransferrin) and a related protein (turkey egg-white
      lysozyme) can exhibit significantly broadened mosaicity due to formation of
      cracks and dislocations but have overall B factors and diffraction resolutions
      comparable to those of crystals grown from uncontaminated lysozyme. Direct
      fluorescence imaging of the three-dimensional impurity distribution shows that
      impurities incorporate with different densities in sectors formed by growth on
      different crystal faces, and that impurity densities in the crystal core and
      along boundaries between growth sectors can be much larger than in other parts of
      the crystal. These nonuniformities create stresses that drive formation of the
      defects responsible for the mosaic broadening. Our results provide a rationale
      for the use of seeding to obtain high-quality crystals from heavily contaminated
      solutions and have implications for the use of crystallization for protein
      purification. Proteins 1999;36:270-281.

PMID- 10409823
TI  - High resolution structure and sequence of T. aurantiacus xylanase I: implications
      for the evolution of thermostability in family 10 xylanases and enzymes with
      (beta)alpha-barrel architecture.
AB  - Xylanase I is a thermostable xylanase from the fungus Thermoascus aurantiacus,
      which belongs to family 10 in the current classification of glycosyl hydrolases.
      We have determined the three-dimensional X-ray structure of this enzyme to near
      atomic resolution (1.14 A) by molecular replacement, and thereby corrected the
      chemically determined sequence previously published. Among the five members of
      family 10 enzymes for which the structure has been determined, Xylanase I from T.
      aurantiacus and Xylanase Z from C. thermocellum are from thermophilic organisms.
      A comparison with the three other available structures of the family 10 xylanases
      from mesophilic organisms suggests that thermostability is effected mainly by
      improvement of the hydrophobic packing, favorable interactions of charged side
      chains with the helix dipoles and introduction of prolines at the N-terminus of
      helices. In contrast to other classes of proteins, there is very little evidence
      for a contribution of salt bridges to thermostability in the family 10 xylanases
      from thermophiles. Further analysis of the structures of other proteins from
      thermophiles with eight-fold (beta)alpha-barrel architecture suggests that
      favorable interactions of charged side chains with the helix dipoles may be a
      common way in which thermophilic proteins with this fold are stabilized. As this
      is the most common type of protein architecture, this finding may provide a
      useful guide for site-directed mutagenesis aimed to improve the thermostability
      of (beta)alpha-barrel proteins. Proteins 1999;36:295-306.

PMID- 10409824
TI  - Examination of shape complementarity in docking of unbound proteins.
AB  - Here we carry out an examination of shape complementarity as a criterion in
      protein-protein docking and binding. Specifically, we examine the quality of
      shape complementarity as a critical determinant not only in the docking of 26
      protein-protein "bound" complexed cases, but in particular, of 19 "unbound"
      protein-protein cases, where the structures have been determined separately. In
      all cases, entire molecular surfaces are utilized in the docking, with no
      consideration of the location of the active site, or of particular residues/atoms
      in either the receptor or the ligand that participate in the binding. To evaluate
      the goodness of the strictly geometry-based shape complementarity in the docking
      process as compared to the main favorable and unfavorable energy components, we
      study systematically a potential correlation between each of these components and
      the root mean square deviation (RMSD) of the "unbound" protein-protein cases.
      Specifically, we examine the non-polar buried surface area, polar buried surface
      area, buried surface area relating to groups bearing unsatisfied buried charges,
      and the number of hydrogen bonds in all docked protein-protein interfaces. For
      these cases, where the two proteins have been crystallized separately, and where
      entire molecular surfaces are considered without a predefinition of the binding
      site, no correlation is observed. None of these parameters appears to
      consistently improve on shape complementarity in the docking of unbound
      molecules. These findings argue that simplicity in the docking process, utilizing
      geometrical shape criteria may capture many of the essential features in protein
      protein docking. In particular, they further reinforce the long held notion of
      the importance of molecular surface shape complementarity in the binding, and
      hence in docking. This is particularly interesting in light of the fact that the
      structures of the docked pairs have been determined separately, allowing side
      chains on the surface of the proteins to move relatively freely. This study has
      been enabled by our efficient, computer vision-based docking algorithms. The fast
      CPU matching times, on the order of minutes on a PC, allow such large-scale
      docking experiments of large molecules, which may not be feasible by other
      techniques. Proteins 1999;36:307-317.

PMID- 10409825
TI  - Methodology for protein-ligand binding studies: application to a model for drug
      resistance, the HIV/FIV protease system.
AB  - A protocol for the rapid energetic analysis of protein-ligand complexes has been
      developed. This protocol involves the generation of protein-ligand complex
      ensembles followed by an analysis of the binding free energy components. We apply
      this methodology toward understanding the origin of binding specificity within
      the human immunodeficiency virus/feline immunodeficiency virus (HIV/FIV) protease
      system, a model system for drug resistance studies. A distinct difference in the
      internal strain of an inhibitor within each protein environment clearly favors
      the HIV protease complex, as observed experimentally. Our analysis also predicts
      that residues within the S2-S3 pockets of the FIV protease active site are
      responsible for this strain. Close examination of the active site residue
      contributions to interaction energy and desolvation energy identifies specific
      amino acids that may also play a role in determining the binding preferences of
      these two enzymes. Proteins 1999;36:318-331.

PMID- 10409826
TI  - Estimates of the loss of main-chain conformational entropy of different residues
      on protein folding.
AB  - The average contribution of conformational entropy for individual amino acid
      residues towards the free energy of protein folding is not well understood. We
      have developed empirical scales for the loss of the main-chain (torsion angles,
      phi and psi) conformational entropy by taking its side-chain into account. The
      analysis shows that the main-chain component of the total conformational entropy
      loss for a residue is significant and reflects intrinsic characteristics
      associated with individual residues. The values have direct correlation with the
      hydrophobicity values and this has important bearing on the folding process.
      Proteins 1999;36:332-339.

PMID- 10409827
TI  - Role of evolutionary information in predicting the disulfide-bonding state of
      cysteine in proteins.
AB  - A neural network-based predictor is trained to distinguish the bonding states of
      cysteine in proteins starting from the residue chain. Training is performed by
      using 2,452 cysteine-containing segments extracted from 641 nonhomologous
      proteins of well-resolved three-dimensional structure. After a cross-validation
      procedure, efficiency of the prediction scores were as high as 72% when the
      predictor is trained by using protein single sequences. The addition of
      evolutionary information in the form of multiple sequence alignment and a jury of
      neural networks increases the prediction efficiency up to 81%. Assessment of the
      goodness of the prediction with a reliability index indicates that more than 60%
      of the predictions have an accuracy level greater than 90%. A comparison with a
      statistical method previously described and tested on the same database shows
      that the neural network-based predictor is performing with the highest
      efficiency. Proteins 1999;36:340-346.

PMID- 10409828
TI  - Evaluation of short-range interactions as secondary structure energies for
      protein fold and sequence recognition.
AB  - Short-range interactions for secondary structures of proteins are evaluated as
      potentials of mean force from the observed frequencies of secondary structures in
      known protein structures which are assumed to have an equilibrium distribution
      with the Boltzmann factor of secondary structure energies. A secondary
      conformation at each residue position in a protein is described by a tripeptide,
      including one nearest neighbor on each side. The secondary structure potentials
      are approximated as additive contributions from neighboring residues along the
      sequence. These are part of an empirical potential to provide a crude estimate of
      protein conformational energy at a residue level. Unlike previous works,
      interactions are decoupled into intrinsic potentials of residues, potentials of
      backbone-backbone interactions, and of side chain-backbone interactions. Also
      interactions are decoupled into one-body, two-body, and higher order interactions
      between peptide backbone and side chain and between backbones. These decouplings
      are essential to correctly evaluate the total secondary structure energy of a
      protein structure without overcounting interactions. Each interaction potential
      is evaluated separately by taking account of the correlation in the amino acid
      order of protein sequences. Interactions among side chains are neglected, because
      of the relatively limited number of protein structures. Proteins 1999;36:347-356.
      Published 1999 Wiley-Liss, Inc.

PMID- 10409829
TI  - An empirical energy potential with a reference state for protein fold and
      sequence recognition.
AB  - We consider modifications of an empirical energy potential for fold and sequence
      recognition to represent approximately the stabilities of proteins in various
      environments. A potential used here includes a secondary structure potential
      representing short-range interactions for secondary structures of proteins, and a
      tertiary structure potential consisting of a long-range, pairwise contact
      potential and a repulsive packing potential. This potential is devised to
      evaluate together the total conformational energy of a protein at the coarse
      grained residue level. It was previously estimated from the observed frequencies
      of secondary structures, from contact frequencies between residues, and from the
      distributions of the number of residues in contact in known protein structures by
      regarding those distributions as the equilibrium distributions with the Boltzmann
      factor of these interaction energies. The stability of native structures is
      assumed as a primary requirement for proteins to fold into their native
      structures. A collapse energy is subtracted from the contact energies to remove
      the protein size dependence and to represent protein stabilities for monomeric
      and multimeric states. The free energy of the whole ensemble of protein
      conformations that is subtracted from the conformational energy to represent
      protein stability is approximated as the average energy expected for a typical
      native structure with the same amino acid composition. This term may be constant
      in fold recognition but essentially varies in sequence recognition. A simple test
      of threading sequences into structures without gaps is employed to demonstrate
      the importance of the present modifications that permit the same potential to be
      utilized for both fold and sequence recognition. Proteins 1999;36:357-369.
      Published 1999 Wiley-Liss, Inc.

PMID- 10409830
TI  - Mechanism of substrate dephosphorylation in low Mr protein tyrosine phosphatase.
AB  - Substrate dephosphorylation by the low molecular weight protein tyrosine
      phosphatases proceeds via nucleophilic substitution at the phosphorous atom
      yielding a cysteinyl phosphate intermediate. However, several questions regarding
      the exact reaction mechanism remain unanswered. Starting from the crystal
      structure of the enzyme we study the energetics of this reaction, using the
      empirical valence bond method in combination with molecular dynamics and free
      energy perturbation simulations. The free energy profiles of two mechanisms
      corresponding to different protonation states of the reacting groups are examined
      along stepwise and concerted pathways. The activation barriers calculated
      relative to the enzyme-substrate complex are very similar for both monoanionic
      and dianionic substrates, but taking the substrate binding step into account
      shows that hydrolysis of monoanionic substrates is strongly favored by the
      enzyme, because a dianionic substrate will not bind when the reacting cysteine is
      ionized. The calculated activation barrier for dephosphorylation of monoanionic
      phenyl phosphate according to this novel mechanism is 14 kcal mol(-1), which is
      in good agreement with experimental data. Proteins 1999;36:370-379.

PMID- 10409831
TI  - Radiology quiz. Paget's disease of bone.

PMID- 10409832
TI  - A career of disease prevention, detection and control: an interview with Dr.
      Denny Donnell, State Epidemiologist of Missouri. Interview by Thomas Eppright,
      Shane Bradley, Maureen A. Allwood, James R. Slaughter.
AB  - Denny Donnell began his tenure as Missouri State Epidemiologist in 1973. Since
      that time, he has been instrumental in the prevention, detection and control of
      disease across the state. In this interview he reflects on the path that led him
      to disease control and he emphasizes the need for further training opportunities
      for physicians who wish to battle disease beyond the realm of one person at a
      time.

PMID- 10409833
TI  - Accurate documentation, correct coding, and compliance: it's your best defense!
AB  - This article focuses on the need for physicians to maintain an awareness of
      regulatory policy and the law impacting the federal government's medical
      insurance programs, and to internalize and apply this knowledge in their
      practices. Basic information concerning selected fraud and abuse statutes and the
      civil monetary penalties and sanctions for noncompliance is discussed. The
      application of accurate documentation and correct coding principles, as well as
      the rationale for implementating an effective compliance plan in order to prevent
      fraud and abuse and/or minimize disciplinary action from government regulatory
      agencies, are emphasized.

PMID- 10409834
TI  - EMTALA. Emergency Medical Treatment and Active Labor Act.

PMID- 10409835
TI  - The effect of a community-based intimate-partner violence advocacy program in the
      emergency department on identification rate of intimate-partner violence.
AB  - A retrospective medical record review assessed identification rate of women
      acutely injured by intimate-partner violence before and after implementation of
      an Emergency Department (ED) intimate-partner violence advocacy program. After
      program implementation, the identification rate of intimate-partner violence
      increased over 40%. Of the 19 physicians in the ED during both time periods, 17
      (89%) identified more cases after the program began (p < 0.003). Implementation
      of a community-based intimate-partner violence advocacy program in the ED
      resulted in an increased identification rate of intimate violence.

PMID- 10409836
TI  - Acting in the best interest of the corporation.

PMID- 10409837
TI  - Apexification & apexogenesis.
AB  - When there is pulpal involvement of permanent teeth with incompletely formed
      roots, techniques for the induction of apical closure should be completed before
      endodontic therapy is begun. Apexification is a method of inducing a calcified
      barrier at the apex of a nonvital tooth with incomplete root formation.
      Apexogenesis refers to a vital pulp therapy procedure performed to encourage
      physiological development and formation of the root end.

PMID- 10409838
TI  - Perforation repairs.
AB  - Management of instrument perforations in the periodontal ligament space during
      endodontic or restorative procedures is an ongoing problem in dentistry. The
      introduction of microscopes, new instruments and materials has resulted in more
      controllable and predictable surgical and nonsurgical outcomes. This paper
      discusses some of the newer techniques and materials used to manage perforations
      effectively.

PMID- 10409839
TI  - Post removal techniques used in nonsurgical endodontic retreatment.
AB  - Removal of posts from root canals is often a tedious and difficult procedure.
      Factors such as type of post, cement used, interradicular relation of post to
      canal walls and accessibility of post affects the eventual success. It is
      necessary, therefore, for the clinician to evaluate his or her ability to remove
      posts when contemplating retreating endodontic cases. This paper discusses and
      evaluates a new technique and instruments used to facilitate post removal in
      nonsurgical endodontics.

PMID- 10409840
TI  - Applications for guided bone regeneration in endodontic surgery.
AB  - Regeneration of apical bony defects remains a significant problem in endodontic
      surgery. When a resorbable membrane is placed over a defect, it acts as a barrier
      between the defect and the overlying gingival tissue. This barrier membrane
      provides sufficient time for bone to regenerate while preventing the faster
      growing connective tissue from invaginating into the area. When new tissue
      replicates the structure and function of the lost tissue, then apical
      regeneration has occurred.

PMID- 10409841
TI  - Configuration of hepatic veins in the right surgical lobe of the human liver with
      special reference to their complementary territorial relationships: morphometric
      analysis of controlled specimens with clearly defined portal segmentation.
AB  - The configurations of hepatic veins, particularly the complementary territorial
      relationships between the veins, in the right surgical lobes of 156 human livers,
      the segments of which were identified clearly according to the portal
      ramification, were studied. In order to assess the functional roles of the
      vessels, we compared the diameter values of the vessels in the upper region of
      the lobe under the assumption that this parameter corresponds very closely to the
      actual blood flow volume through the vessel. The right hepatic vein (RHV)
      sometimes (17%) developed poorly and drained neither segment V (S5) nor VI (S6);
      instead, the inferomedial part of the S6 was often (26%) drained by the middle
      hepatic vein (MHV). However, most thick short hepatic veins (SHVs) did not drain
      S6 specifically instead of a poorly-developed RHV, but usually drained both S6
      and segment VII (S7), irrespective of the configurations of other veins.
      Sometimes (8%), the RHV, rather than the MHV, drained a large part of S5.
      Overall, in the lower region of the lobe, the RHV, SHV and MHV showed
      complementary venous drainage relationships. Furthermore, the RHV usually (75%)
      ran not between S5 and S6 but through S6, corresponding to its usual territory,
      and could not be regarded as the intersectorial landmark in the lower region.
      Although various names have been given to the thick venous tributaries in the
      upper region of the right lobe, we systematically classified these tributaries
      into 5 types of "right superior radicles" (RSR), according to their topographical
      relationships with the right superior portal branches (P7 and P8), RHV, MHV, SHVs
      and their tributaries. When just thick RSRs were considered, the 5 types
      (anterior, posterior, lateral, medial and intersegmental) were observed in 90%,
      88%, 89%, 38% and 34%, respectively. Notably, all but the intersegmntal RSRs
      almost always corresponded to a specific segmental territory (S7 or segment VIII
      (S8) and had specific terminals (at the RHV or MHV), suggesting that these 4 RSRs
      were proper segmental or intrasegmental veins, whereas, the 5th type showed a
      different configuration, i.e., an intersegmental vein that drained both S7 and
      S8, ran along and above the RHV and merged with it. Our morphometric examination
      of the upper region revealed that the sizes of P7 and P8 increased or decreased
      simultaneously, and suggested that the RSRs played limited roles in venous
      return. Rather than the RSRs, the SHVs appeared to drain the overflow in excess
      of the venous return capacity of the RSRs. Despite their limitations and possible
      complementary relationships with some veins, however, all the superior veins
      tended to developed evenly well or poorly. Overall, the venous return did not
      seem to converge into a single particular vein, but was carried away by multiple
      superior veins: the RHV, MHV, SHVs, and 5 RSRs.

PMID- 10409842
TI  - The mouse vertebrae: changes in the morphology of mouse vertebrae exhibit
      specific patterns over limited numbers of vertebral levels.
AB  - The mouse vertebrae from the cervix to the tip of the tail were characterized and
      anatomical features that have been lacking were added to the classical
      description. The vertebrae consist of six long-range and fourteen short-range
      substructures, with the foveal process being a newly identified substructure. The
      caudal transverse process, cranial hemal process and hemal ridge are
      substructures that are clearly defined in the mouse. Each long-range and short
      range substructure has several specific morphological features such as length,
      width, area, shape and angle. These features exibit a crescendo, plateau or
      decrescendo pattern over a limited number of vertebral segments that ranges from
      just a few to twenty. The variety of substructural combinations and the constant
      changes in the morphological features lead to the fact that no single vertebra
      has the same morphology as any other. An analysis of the patterns of changes in
      morphology provides some insight into the genetic plan for the metameric body
      axis.

PMID- 10409843
TI  - FRAP-positive and capsaicin-sensitive terminals in the substantia gelatinosa of
      the mouse spinal trigeminal nucleus caudalis.
AB  - FRAP (fluoride-resistant acid phosphatase)-reactivity in the substantia
      gelatinosa of the mouse spinal trigeminal nucleus caudalis (STNC) was examined by
      light and electron microscopy. Degenerated figures of terminals caused by
      capsaicin were compared with the FRAP-positive terminals. Scalloped (fan-like) or
      indented, sinuous, slender, and cap-like figures with closely packed agranular
      synaptic vesicles of various sizes were common to both FRAP-positive and
      capsaicin-sensitive terminals. These terminals had glomerular or nonglomerular
      endings. Sometimes FRAP-positive and capsaicin-sensitive glomerular terminals
      made presynapses with surrounding dendrites. Frequently, both nonglomerular
      terminals were in direct contact with the neuronal soma. The terminal features of
      FRAP-positive and capsaicin-sensitive ones in the mouse STNC are the same as
      those seen in the superficial dorsal horn of the spinal cord. These findings
      suggest that some of the FRAP-positive terminals are capsaicin-sensitive, thereby
      indicating their nociceptive primary afferent.

PMID- 10409844
TI  - Morphometric dimensions of Syrian golden hamster pancreas of both sexes.
AB  - The morphometric dimensions of the various structures of the pancreas of adult
      Syrian golden hamsters, of both sexes, were evaluated using stereological
      methods. The average body mass of the animals used was 133.8 +/- 2.45 g and 140.6
      +/- 7.98 g for the males and females, respectively, and the pancreatic mass,
      389.9 +/- 14.88 and 409.7 +/- 21.42 mg, respectively. The analysis of variance of
      the obtained data showed that: a) the acini, intercalated ducts and stroma did
      not present statistically significant differences in any of the dimensions
      evaluated, with the exception of the nucleus volume of the acinar cells which was
      8.5% larger in the female (P < 0.05); b) the excretory ducts exhibited surface
      density, total external surface, surface-to-volume ratio, and absolute cell
      number, 18%, 33%, 14%, and 44%, respectively, larger in the females (P < 0.05);
      and c) the pancreatic islets of the females exhibited volume density, total
      volume and absolute cell number, 20%, 27% and 27%, respectively, larger than
      those of the males (P < 0.05).

PMID- 10409845
TI  - Effects of a DNA demethylating agent--5-azacytidine--on testicular morphology
      during mouse embryo development.
AB  - DNA methylation is an epigenetical mechanism that plays crucial roles in cellular
      differentiation and tissue development in embryogenesis. The aim of the present
      study was to determine the effects of a demethylating agent, 5-azacytidine, on
      testicular development during embryonal life in mouse. Ten pregnant mice were
      administered 5-azacytidine (5-azaC) (i.p. 2 mg/kg of agent dissolved in 0.1 mg/ml
      PBS) during 8th (Group 1), 11th (Group 2), 14th (Group 3) and 18th (Group 4) days
      of pregnancy periods and male siblings of these animals were obtained
      (experimental groups) whereas the control group animals received no treatment and
      siblings of this group were also obtained. Testicular tissues from all groups
      were taken 20 days after birth and examined at the light and electron
      microscopical levels. All pregnancies were terminated in Group 1 animals,
      therefore no observations could be done in this group. While Group 2 and 3
      siblings showed distinctive kongenital abnormalities such as; anancephaly, growth
      failure, cleft palate, extremity abnormalities, supernumerary ribs and whirled
      shaped-tails, no such abnormalities were observed in Group 4 when compared to the
      control group. Microscopical examination of testicular tissues in groups 2 and 3
      demonstrated cellular disintegration of spermatocytes in seminiferous tubules. In
      addition, cytoplasmic vacuoles and thickening of the basement membrane were also
      evident in both groups 2 and 3. Apoptotic-like cells were seen especially in
      group 2 and rarely in group 3. There were no structural alterations in group 4
      animals, except a decreased number of spermatocytes in seminiferous tubules when
      compared to the control group, possibly indicating the completion of
      embryogenesis in this group. In conclusion, it could be suggested that the
      demethylating agent 5-azacytidine may trigger an unknown gene reactivation during
      early embryogenesis possibly affecting the cell and tissue differentiation in
      developing mammalian embryos.

PMID- 10409846
TI  - Unusual branching in lumbar plexus: case report.
AB  - This article describes a complex bilateral variation in the formation of lumbar
      plexus in a 32 year old male cadaver. On the left side the plexus was postfixed
      and located posterior to the psoas major muscle. The femoral nerve was formed by
      the union of anterior rami of the second, third, fourth and fifth lumbar spinal
      nerves. On the right side, the lumbar plexus was prefixed. The lateral cutaneous
      nerve of the thigh was formed by the union of the anterior rami of the first and
      second lumbar spinal nerves. The femoral nerve formed by branches from the first,
      second, third and fifth lumbar spinal nerves while the obturator nerve was formed
      by the union of the first, second and third lumbar spinal nerves. The right
      lumbar plexus was located in the substance of the psoas major muscle. In the
      present case, the formation of branches of the lumbar plexus were different from
      the previous data present in the literature.

PMID- 10409847
TI  - Cysts in human thymus: maturational forms of Hassal's corpuscles?
AB  - Presence of extracellular cystic cavities in the thymus of many vertebrates has
      long been known. Various forms of such structures in human thymus were observed
      and examined thoroughly on immunostained and serial semithin sections. We grouped
      these structures into five categories according to their most characteristic
      features. The lympho-epithelial content of the cysts clearly reflected the
      structural features and antigenic profile of thymic cortical parenchyma in both
      elongated and ovo-spherical cysts. Our findings suggest that the various types of
      cystic structures observed in human thymus may represent maturational stages of
      classical Hassal's corpuscles. Presence of cortical lympho-epithelial content and
      its gradual replacement with debris material also suggests a unique mechanism of
      thymocyte disposal.

PMID- 10409848
TI  - Electron microscopic study of the parathyroid gland of Rattus rattus.
AB  - The ultrastructure of the parathyroid glands of Rattus rattus was investigated.
      In the chief cells, the nucleus showed deep indentations, and lysosomal
      inclusions and rod-shaped crystalloids were present. Their ultrastructure is
      described, and the role of the lysosomal inclusions is discussed.

PMID- 10409849
TI  - [Anisocoria after unilateral photorefractive keratectomy. Result of a lesion of
      the pupillary sphincter muscle?].
AB  - BACKGROUND: After unilateral photorefractive keratectomy (PRK) for myopia
      correction, relative mydriasis of the treated eye was noticed. The aim of this
      study was to determine the incidence and possible etiology of this anisocoria.
      PATIENTS AND METHODS: In a prospective clinical study we examined eight
      consecutive patients after PRK of a spherical equivalent of -1.0 to -8.5 D with a
      6.5-7.0 mm optical zone (Schwind-Keratom) for up to 10 months. Measurements of
      the pharmacological uninfluenced pupillary diameter were carried out with a
      Goldmann perimeter under 31.5 asb and under four different room light and
      distance conditions. In five patients a hard contact lens of 0 D power was fitted
      to the treated eye, so that the laser-induced central corneal flattening was
      compensated for by the sublenticular tear film, and the pupillary diameter was
      measured again. The influence of pilocarpine 0.1% eye drops to the pupil was also
      examined. RESULTS: Postoperatively, the pupil of the PRK-treated eye measured up
      to 1.75 mm larger than that of the fellow eye in all patients. The amount of
      anisocoria showed a small negative correlation with the interval between the PRK
      procedure and the day of measurement. It did not correlate significantly with the
      amount of induced refractive change, applied energy, application of pilocarpine
      0.1% eye drops or the contact lens fitting. CONCLUSION: After unilateral PRK,
      anisocoria can regularly be observed. At present its definite pathogenesis is
      unclear, although certain possible optical and neuronal mechanisms have been
      excluded. The most probable etiology is a mild lesion of the pupillary sphincter
      muscle because of its localization in the center of the laser shock wave
      distribution.

PMID- 10409850
TI  - [Experimental external irradiation of corneal neovascularization].
AB  - The clinical effect of ionidizing radiation on ocular neovascularizations is
      controversial not only because of the variety of treatment modalities. The aim of
      our study was to investigate an experimental model which allows to evaluate
      radiation parameters and to study the mechanism of the inhibitory effect on
      neoangiogenesis. METHODS: Corneal angiogenesis was induced by use of a
      micropocket assay in NZW rabbits. Pellets with 500 ng bFGF in 2% methylecellulose
      were implanted into the stroma 2.0 mm from the limbus. Initiation of vessel
      growth occurred on day 3. At this time radiation was performed with different
      doses (single dose of 15 to 30 Gy or fractionated 5 x 5 Gy) using a 6 MeV linear
      accelerator. Vascular growth was quantified. RESULTS: Irradiation with a total
      dose of 25 Gy applied in a fractionated regimen or as single-dose irradiation on
      the day of surgery or on day 6 after surgery did not significantly reduce
      neovascular growth. In contrast, postoperative radiation therapy on day 3 was
      able to reduce the area of ingrowing vessels significantly (P < 0.01). In spite
      of the relatively high dose there were no significant side effects during the
      observation period of 8 weeks. CONCLUSION: Our results show that single-dose
      radiation (> or = 25 Gy) is sufficient to inhibit the growth of corneal
      neovascularizations. With this model it might be possible to investigate
      parameters for therapy of ocular neovascularizations as well as the underlying
      mechanisms.

PMID- 10409851
TI  - [Laser in situ keratomileusis (LASIK). Intraoperative and postoperative
      complications].
AB  - PURPOSE: To quantify the incidence and type of complications after LASIK for the
      correction of myopia with special consideration to the time lapse after surgery
      and the possible consequences regarding high-contrast sensitivity and other
      modalities of visual acuity. MATERIAL AND METHODS: Between January 1995 and April
      1997, 125 eyes of 88 patients with myopia greater than -6.0 D who could not wear
      contact lenses were operated on at our institute. In this prospective study the
      patients were examined consecutively preoperatively as well as postoperatively at
      day 4 and months 1, 3 and 6. The complications were divided into three groups
      (intraoperative, early postoperative and late postoperative). RESULTS: Our
      complication rate was 7.2% (loss of 2 lines of visual acuity)--with cutting
      artifacts related to the microkeratome, wrinkling of the flap and epthelial
      ingrowth. CONCLUSIONS: LASIK is a microsurgical procedure that requires adequate
      experience and the desire by the surgeon for self-evaluation. In spite of the
      good clinical results in the correction of high myopia the complication rates
      seems still to be too high. This should be the objective for further improvement
      primarily related to the microkeratomes.

PMID- 10409852
TI  - [Late dislocation of the capsular bag after phacoemulsification with endocapsular
      IOL in pseudoexfoliation syndrome].
AB  - PES has been associated with weakness of zonular attachments to the ciliary body
      and with late dislocation of the IOL following cataract extraction with in-the
      bag IOL implantation. We evaluated the frequency of PES in patients with IOL
      dislocation following phacoemulsification cataract surgery. PATIENTS AND METHODS:
      We retrospectively reviewed the records of five patients who had undergone
      phacoemulsification, followed by implantation of a posterior chamber IOL in the
      capsular bag during the years 1992 through 1996 and who showed IOL dislocation
      during follow-up. We looked for clinical signs of PES that had been noted prior
      to or after IOL dislocation. RESULTS: Detailed review of the records of these
      patients identified PES as a coexistent condition in all five. The most
      impressive clinical feature was shrinkage of the capsular bag to conform to the
      size and contour of the implanted IOL. CONCLUSIONS: In accordance with many
      histopathological and clinical studies supporting our findings, we suggest that
      shrinkage of the capsular bag can be reduced by not using foldable IOL, by early
      anterior YAG capsulotomy or by the use of an IOL with a larger optic.

PMID- 10409854
TI  - [Ophthalmological screening studies in newborn infants. German Ophthalmological
      Society].

PMID- 10409853
TI  - [Experimental autoimmune uveitis. Characterization of retina infiltrating cells].
AB  - The chronic model of murine EAU induced by interphotoreceptor retinoid binding
      protein represents a disease similar to clinical chorioretinitis. In this study
      we characterized the kinetics of retina infiltrating T-cells, macrophages and
      expression of the adhesion molecules ICAM-1 and ICAM-2. METHODS: B10.A mice were
      immunized subcutaneously with IRBP, and the eyes were analyzed on days 10, 18, 24
      and 28. The infiltrating cells were characterized by mAbs recognizing T-cell
      receptors (TCR) Vss6 and Vss8, T-cell markers, macrophages and ICAM-1 and ICAM-2.
      RESULTS: While CD8+ T-cells and ICAM-2 were detectable from day 10 (retina is
      intact) until day 28, CD4+ T-cells, macrophages and ICAM-1 appear with the onset
      of retinal destruction. Starting at day 10 the dominating TCR was Vss6; Vss8 was
      noticed from day 18 on. CONCLUSION: CD8+ T-cells infiltrating the intact retina
      and stimulating the expression of high endothelial venules (HEVs) could be
      responsible for the onset of uveitis.

PMID- 10409855
TI  - [Arterial occlusion of the eye in infectious endocarditis].
AB  - BACKGROUND: Infectious endocarditis can lead to embolic arterial retinal
      occlusions. Which therapy is indicated? RESULTS: A 33-year-old man suddenly
      became blind in his left eye as the result of a central retinal artery occlusion
      (CRAO). This occurred during high-dosage treatment for infectious endocarditis
      that had been diagnosed 3 weeks earlier. The echocardiogram showed distinct
      vegetation and an abscess on the aortic valve. The CRAO together with the
      ultrasound findings was considered an absolute indication for surgery of the
      aortic valve. During this emergency operation, a 2 cm deep abscess cavity was
      found between the mitral and aortic valves. After removal of the abscess,
      together with the infected valve, a prosthetic valve was inserted. Following the
      operation, the patient made an uneventful recovery. The antibiotic treatment was
      continued for several months. The left eye remained sightless. No recurrence of
      infectious endocarditis occurred during the follow-up of 2 1/4 years. A branch
      retinal arterial occlusion occurred in the right eye of a 35-year-old man who had
      suffered from chronic infectious endocarditis for several months. Insufficiency
      of more than one valve had been diagnosed on several occasions. The patient, a
      drug-addict, had refused surgical treatment on each occasion. After 3 months, the
      right eye became completely blind owing to CRAO. Following high-dosage treatment
      with antibiotics, the infectious endocarditis was healed. The right eye remained
      blind. One year later the patient died. CONCLUSION: Retinal arterial occlusion of
      embolic origin in a patient with infectious endocarditis is an indication for
      immediate medical and/or surgical treatment. This is of particular importance if
      there is ultrasound evidence of an abscess in the valve area.

PMID- 10409856
TI  - [Acute hypopyon uveitis with rifabutin therapy of systemic Mycobacterium avium
      complex (MAC) infection in AIDS].
AB  - BACKGROUND: Hypopyon-uveitis has been identified as a dosage-dependent side
      effect in patients with acquired immunodeficiency syndrome who are treated for
      Mycobacterium avium complex (MAC) infection with systemic rifabutin. PATIENTS AND
      METHODS: We report a 38-year-old female AIDS patient with bilateral hypopyon
      uveitis under therapy with rifabutin in combination with clarithromycin and
      indinavir. RESULTS: At the time of presentation of the bilateral hypopyon uveitis
      the patient was treated with rifabutin (300 mg/day), clarithromycin (1000 mg/day)
      and ethambutol (1000 mg/day) for an M. avium complex infection. Also, the patient
      received the protease inhibitor indinavir. The rifabutin dose was reduced to 150
      mg/day. Hypopyon and inflammation resolved under therapy with steroids.
      CONCLUSIONS: The concomitant use of rifabutin, clarithromycin, and protease
      inhibitors may lead to hypopyon uveitis. Reduction of dosage of rifabutin (150
      mg/day) and treatment with topical steroids are required.

PMID- 10409858
TI  - [Hydrops of the lacrimal sac with epiphora of the right eye. Transitional cell
      carcinoma of the lacrimal sac].

PMID- 10409857
TI  - [E-mail, data security and discussion on the internet].

PMID- 10409859
TI  - [Practical conjunctival cytology].

PMID- 10409860
TI  - Employment of 1996-97 doctoral graduates in physiology.

PMID- 10409861
TI  - [Diagnosis of chronic berylliosis].
AB  - The diagnostic value of the lymphocyte transformation test (BeLT) and the
      intracutaneous skin test with berylliumsulfate was addressed in 13 patients with
      chronic berylliosis, and 15 individuals with occupational exposure. Additionally,
      patients with sarcoidosis (n = 21), tuberculosis (n = 14) and healthy controls (n
      = 25) were tested with BeLT and yielded negative results. In chronic berylliosis
      the BeLT was positive in 10/13. In 3/13 the BeLT was negative, but the skin test
      positive. 6/15 exposed individuals exhibited a positive BeLT. The time course of
      the skin test differed markedly between the individual berylliosis patients.
      Typical granulomas were present in 4/10 cases. In 9 exposed individuals BeLT
      tested negative. Additionally, skin tests were negative in 7 exposed patients,
      however, unspecific skin reactions were observed in 3 cases. The diagnostic value
      of Beryllium IT requires further investigation. At present, BeLT appears to be a
      suitable test to prove beryllium sensitisation.

PMID- 10409862
TI  - [Inpatient treatment costs of exacerbated chronic obstructive lung disease].
AB  - Economic aspects are of increasing importance in health care. However, treatment
      expenditures for most diseases are unknown. We performed a detailed cost analysis
      for the treatment of the exacerbated chronic obstructive pulmonary disease
      (ECOPD) in our department. For one year, all patients admitted because of
      exacerbated chronic obstructive pulmonary disease were included in this study.
      The workload was assessed for each patient by time keeping. Diagnostic and
      therapeutic procedures were considered according to the price list of the German
      hospital association. From 101 patients included into the study, 100 were
      evaluable. The median duration of inpatient hospitalisation amounted to 18 days
      (range: 4 to 210 days). Median total cost was DM 7680.- and mean cost DM 11900.-.
      This consisted of non-medical cost items (36%), personnel expenditures (29%),
      laboratory tests (14%), respiratory and cardiovascular laboratory (7%), radiology
      (5%) and pharmacy cost (7%). Endoscopy, external diagnostics and medical reports
      amounted to 2.8% of the expenditure. Treatment cost correlated with the duration
      of stay, but hardly with lung function and blood gases, these being independent
      of age and sex, but significantly higher in case of bronchiectasis,
      enterobacteriae, cor pulmonale or intensive care. The proportion of the pharmacy
      expenditures was rather small, and hence this is not a primary target for the
      realisation of major savings.

PMID- 10409863
TI  - [Spontaneous course of bilateral sarcoid granulomatosis].

PMID- 10409865
TI  - [Pulmonary aspergillosis in patients without pre-existing pulmonary disease after
      brain edema prevention with dexamethasone].
AB  - Pulmonary aspergillosis (PA) is a well-described complication in severely
      immunocompromised hosts. We report on one case of invasive PA and one case of PA
      following oral dexamethasone prophylaxis for cerebral oedema. Steroids were
      administered in a dosage of 14 mg and 16 mg, daily respectively for 21 and 15
      days. Both patients died despite antifungal treatment. We conclude that PA must
      be considered as a cause for pulmonary complications in non-immunosuppressed, non
      neutropenic patients during oral dexamethasone prophylaxis for neurological
      disease.

PMID- 10409864
TI  - [Established combinations of inhaled corticoids and long-acting beta 2
      symphathomimetics for long-term therapy of bronchial asthma. Position of an
      expert panel study].

PMID- 10409866
TI  - [Thoracic actinomycosis--a case report].
AB  - BACKGROUND: Actinomycosis is caused by a variety of gram-positive anaerobic or
      microaerophilic rods belonging to the genus Actinomyces or Propionibacterium. The
      production of suppurative abscesses or granulomas that eventually develop
      draining sinuses are hallmarks of the disease. We describe the case of a 55 year
      old smoker who presented himself 4 months ago with right thoracic pain and an
      unproductive cough. He developed a warm, red mass in the lower part of the right
      thorax. We performed an ultrasound guided needle aspiration and the pathologic
      examination revealed typical sulfur granules and masses of neutrophils in the
      aspirate. After surgical resection of the abscess and under high-dose therapy
      with penicillin G the further course of disease was uneventful. CONCLUSIONS:
      Although uncommon, thoracic actinomycosis should always taken into account in the
      differential diagnosis of chronic inflammatory processes that involve the
      pulmonary parenchyma or pleural space.

PMID- 10409868
TI  - [Early rehabilitation of patients with COPD in the acute clinic].

PMID- 10409867
TI  - [Prospective lung function determination using an electronic miniature spirometer
      for detection of acute obstructive respiratory changes in diving students during
      occupational diving training].
AB  - BACKGROUND: Changes in lung function have been shown in experienced divers. The
      purpose of this study was to measure the pulmonary function of diving trainees
      who were not exposed to a hyperbaric environment before. METHODS: We measured the
      lung function in a sample of fifteen randomized selected young healthy non
      smoking diving trainees parallel to fourteen open water dives. Five subjects used
      common compressed air diving apparatuses (breathing gas: 21% O2/78% N2) and ten
      subjects used closed circuit diving apparatuses (breathing gas compositions
      depended to the diving depths; 24 m: 60% O2/40% N2, 42 m: 40% O2/60% N2, 54 m:
      32.5% O2/67.5% N2). The values (FVC, FEV1, PEF, MEF 25, MEF 50, MEF 75) were
      obtained by an electronic miniature-spirometer directly before descent, upon
      surfacing, and after one hour and four hours. RESULTS: The lung function values
      of the subjects who used compressed air showed no relevant impairment of lung
      function after the diving exposures. Significant (p < 0.05) post dive lung
      function reductions (FVC, FEV1, PEF, MEF 25, MEF 50, MEF 75), were evident in
      subjects using closed circuit diving apparatuses, after deep dives and shallow
      water dives. CONCLUSIONS: The decreased lung function of the used diving
      apparatuses. The impaired lung functions in subjects using closed circuit diving
      apparatuses may be induced by a subclinical lung edema generated by pressure
      differences between breathing gas and thorax tissues as well as the influences of
      soda-lime dust. Compared to compressed air diving the significantly increased
      oxygen partial pressures (p < 0.001) in closed circuit diving apparatuses may be
      an additional reason for the reversible airway obstructions.

PMID- 10409870
TI  - [Why is physical training in patients with COPD valuable?].

PMID- 10409869
TI  - [Sports and behavior therapy in asthma and chronic obstructive bronchitis. An
      integrated system of patient behavioral training and sports therapy].

PMID- 10409871
TI  - [Training program for patients with COPD].

PMID- 10409872
TI  - [Construction of a questionnaire for assessment of "temperament in infancy" by
      parental judgment--results for the 3- to 4-month old age range].

PMID- 10409873
TI  - [Social therapy of adolescence with social behavior disorders--results and
      catamnesis].
AB  - The therapy program of the social therapeutical ward (STW) at the Pfalzinstitut
      for child and adolescent psychiatry was specially developed for adolescents with
      severe conduct disorders. Each adolescent receives a treatment program (e.g. role
      playing, group therapy, behavioral contracts) according to his individual problem
      behaviors. Essential part of the therapy program is the therapeutic milieu on the
      ward. Since the opening in 1990, 71 adolescents were treated more than 8 weeks at
      the STW. Each adolescent completed after admission and before discharge a
      personality questionnaire (HSPQ). The aggressive behavior during the first weeks
      after admission and the last 4 weeks before discharge respectively was rated by
      staff members on the overt aggression scale (OAS). 1 year posttreatment the
      behavior of these adolescents at home and at school/at work was assessed. 1 year
      follow-up data indicate that about 2/3 of the former patients showed no severe
      behavior problems at home and at school/at work respectively. Positive outcome
      was associated with changes from dissocial to prosocial attitudes, as measured by
      the HSPQ. Decrease in aggressive behavior during therapy, according to the OAS,
      was--contrary to expectations--associated with an increase in behavior problems
      after discharge. Obviously it is more promising to change the attitudes of
      conduct disordered adolescents in the prosocial direction than to change their
      overt aggressive behavior.

PMID- 10409874
TI  - [Attention deficit disorders and memory capacity in children with language delay
      and in normal children].
AB  - In order to investigate the hypothesis that language-impaired children also show
      deficits in memory, 110 language-impaired and 123 children showing no such
      impairments (average age 10;0 yrs.) were tested for verbal memory and selecting
      attention through a matching familiar figures test. As an additional measure,
      teachers assessed the children, using DSM criteria, for both general
      attentivenesse and attention deficit disorder. The results revealed significant
      differences between both groups concerning their ability to memorise word lists
      and difficulties resisting distractions. They also show a significantly
      diminished stability regarding the retention of memories. Furthermore, the
      ability to memorise has proved to be greatly independent of both selective
      attention and the rated attentiveness in class. It is therefore concluded that
      language-impaired children have difficulties in acquiring information as well as
      a limited capacity to memorise. These differences in ability to memorise between
      language-impaired children and children with no impairments are most likely
      attributable to the meta-cognitive competence of the child.

PMID- 10409875
TI  - [Social-emotional and cognitive markers in children of divorce and in children
      from 2-parent families--a cross sectional study].
AB  - Related to the research of the effects of separation and divorce on children
      there is a lack of empirical studies in Germany. The following cross-sectional
      field-study directly investigate 48 children from divorced and 32 children from
      two-parent-families regarding socio-emotional and some cognitive characteristics
      (nonclinical samples). Projective and semi-projective tests were the preferred
      instruments. One of the main questions was related to frustration behavior,
      measured by the Rosenzweig-Picture-Frustration Test (childrens form). This test
      was used for the first time by a population of German children of divorce.
      Children of divorce showed a special frustration behavior, a so called M-profile
      showing many impunitive reactions. They avoid direct conflicts or struggle and
      try to deny the frustration. Also the subtests of the Hamburg-Wechsler
      Intelligence test for children (HAWIK) show clearly that children from divorced
      families obtain much poorer test values in contrast to children from two-parent
      homes.

PMID- 10409876
TI  - [New cytostatic drugs--indications and costs].
AB  - In the last decade six new chemotherapeutic agents including the vinca alcaloid
      vinorelbine, the taxanes paclitaxel and docetaxel, the antimetabolite gemcitabine
      and the two topoisomerase I-inhibitors irinotecan and topotecan were shown to be
      active in several phase II- and randomized phase III-trials. This article reviews
      their mode of action, their efficacy, their side effects and their indications.
      Their state of registration and reimbursement by insurance companies in
      Switzerland are summarized. Finally, their costs and cost-effectiveness in a time
      of increasing financial restraint in health care budgets are analyzed.

PMID- 10409877
TI  - [Low molecular weight heparin--1998 status].
AB  - Extensive review articles and recent comparative clinical studies demonstrate
      that low molecular weight heparins are able to cover successfully the
      prophylactical and therapeutical indications of classical unfractionated heparin.
      Similar antithrombotic mechanisms but better pharmacokinetic properties are the
      reason why low molecular weight heparins are about to become the "better
      heparin". They are the first choice for acute prophylaxis and treatment of venous
      thromboembolism, for clot prevention in hemodialysis and as good or better than
      unfractionated heparin for the management of unstable angina pectoris. In the
      near future studies may prove their antithrombotic efficacy in other parts of the
      arterial circulation.

PMID- 10409878
TI  - [New cardiovascular drugs: expanded therapeutic possibilities in coronary heart
      disease and in heart failure].
AB  - Important novel developments in the pharmacotherapy of cardiovascular diseases
      are briefly summarized. New results with lipid lowering statins in secondary
      prevention of atherosclerosis are mentionned. Atorvastatin, introduced recently,
      is compared to the other statins. The extended possibilities for inhibition of
      platelet-aggregation in coronary disease and after interventional coronary
      therapy with ticlopidine, clopidogrel and specific antagonists of platelet
      integrin IIb/IIIa receptors (abciximab, tirofibrane) as well as fibrinolysis with
      reteplase are covered. Among modern trends in pharmacotherapy of heart failure
      studies with angiotensin-II-receptor inhibition (losartane and related compounds)
      or betablockers (carvedilol) are worth mentioning.

PMID- 10409879
TI  - [Opiates on the upswing--are there really unproblematic?].
AB  - Although morphine is known for almost 200 years as analgesic a considerable
      resistance is encountered regarding its use and prescription. This may only in
      part derive from cultural and political reasons mainly, however, from the
      widespread but usually unfounded fear of side effects. This article tries to put
      these fears in perspective. Morphine is a hardly toxic drug in the hands of the
      clinician aware of the side effects and willing to search for them. Possibilities
      how to avoid side effects and alternatives to morphine are proposed.

PMID- 10409880
TI  - [New psychotropic drugs--is only the price new?].
AB  - In this article a complete overview on all antidepressants and antipsychotics
      available at present is presented. The effects and side effects of the individual
      substance classes are systematically discussed and possible interactions
      stressed. Because of the great variety of available substances an appropriate
      medication may be found for every case.

PMID- 10409882
TI  - [ECG no. 107. What is your diagnosis? Paroxysmal atrial flutter in bradycardia.
      Pacemaker implantation is a good therapeutic option].

PMID- 10409881
TI  - [New drugs in neurology].
AB  - This article reviews new drugs and recent knowledge or indications for old drugs
      for the treatment of neurological disorders. Drugs for disorders such as
      migraine, epilepsy, Parkinson's disease, Alzheimer's disease, ischemic stroke,
      amyotrophic lateral sclerosis and multiple sclerosis are considered.

PMID- 10409883
TI  - [New antiplatelet agents].
AB  - Aspirin has set the gold standard for platelet inhibition in prophylaxis and
      treatment of cardiovascular diseases. Invasive techniques and novel platelet
      inhibitors have fundamentally changed therapeutic approaches to antithrombotic
      treatment and further diversification is to be expected in the future. Three
      trends are essentially obvious: 1) the combination of established inhibitors such
      as aspirin with ticlopidine or clopidogrel, 2) the use of new IIb/IIa antagonists
      in various molecular forms, pharmacologies and doses and 3) the combination of
      established platelet-inhibitors with theses novel IIIb/IIIa antagonists.

PMID- 10409884
TI  - [Autopsy and modern medicine].

PMID- 10409885
TI  - [Routine laboratory studies. A topic with more questions than answers].

PMID- 10409886
TI  - [Drug addict with ptosis. Myasthenia gravis].
AB  - We report a 29 year old female drug addict seen in the emergency room with neck
      abscesses, dysphagia and a symmetric ptosis. Initially misinterpreted as adverse
      effect of illegal drug intake these symptoms were due to myasthenia gravis. This
      case shows an important differential diagnosis of ptosis common in drug addicts.

PMID- 10409887
TI  - [Hymenolepis nana. 45-year-old refugee from the Kosovo region with epigastric
      pain and detection of Hymenolepis nana and Blastocystis hominis in the stool].

PMID- 10409888
TI  - [Cold hands and feet. Raynaud syndrome].

PMID- 10409889
TI  - [Objective value of adenotonsillectomy in the child. A prospective study of
      incidence of tonsillitis, snoring, pulse oximetry and polysomnography and general
      development before and after adenotonsillectomy].
AB  - 65 children were analysed prospectively before and after adeno-tonsillectomy to
      determine the incidence of upper airway infections, snoring and nocturnal
      obstructive symptoms. The weight and height percentiles were also determined
      before and after adeno-tonsillectomy. The Oxygen Desaturation Index (ODI) was
      measured in 27 children suspected of having a sleep apnea syndrome. In six of
      these children polysomnographic studies were carried out. A statistically
      significant reduction (p < 0,005) of upper airway infections could be seen six to
      twelve months after adeno-tonsillectomy. In 25 children (38%), we observed a
      postoperative weight gain and in eight cases (12%) a height gain. The obstructive
      symptoms, especially snoring and respiratory apneas, disappeared or were
      significantly reduced in 90% of the cases after adeno-tonsillectomy. All
      preoperatively pathological ODI and AHI normalised after the operation (p <
      0,005).

PMID- 10409890
TI  - [New treatment concepts in smoking cessation].
AB  - Although the smoking rate in Switzerland had declined during the 1970s and 1980s,
      it has not continued to decrease during the 1990s. About one third of the
      population in Switzerland smoked in 1997. Striking is a sharp increase in young
      female smokers during recent years. The portion of 15- to 25-year-old female
      smokers rose from 26% (1992) to 41% (1997). This undesirable development calls
      for making the most of preventive initiatives to date. Beside primary prevention
      steps, the range of assistance for smokers also needs to be extended. In addition
      to the smoking withdrawal counselling introduced, development of a range of
      programmes should also be expanded to assist smokers who have currently been
      unable to quit. Reduction in the number of cigarettes smoked within the framework
      of intensive specialist care can make sense in this situation. In the near
      future, pharmacological aids (nicotine substitute preparations) are also
      anticipated for this purpose. The most important resources for such smoker
      counselling will be presented. Future studies should focus on optimising
      reduction treatment as a new approach toward treatment.

PMID- 10409891
TI  - [Controversy regarding the sensory niveau after isobaric spinal anesthesia].

PMID- 10409892
TI  - ["I am facing an operation"].

PMID- 10409893
TI  - [Disseminated histoplasmosis within the scope of immune deficiency with suspected
      HIV infection. HIV infection CDC stage C3. Disseminated histoplasmosis].

PMID- 10409895
TI  - [Desire for children--planned children].

PMID- 10409894
TI  - [Abdominal pain with ascites. Hepatorenal syndrome].

PMID- 10409896
TI  - [Desire for children--planned children. Attempt at a historical introduction to
      the medical problem].

PMID- 10409897
TI  - [20 years in vitro fertilization: what follows?].
AB  - During the last two decades in-vitro fertilization (IVF) developed on a worldwide
      scale by increasing numbers of treated couples and by extending the medical
      indications. Existing treatment protocols have been optimized to such an extent
      that pregnancy rates over 30% are reached in many treatment units. Further
      improvements of the pregnancy rate may be achieved with assisted hatching, which
      is now the subject of a large European multicentric prospective study based on
      the University of Lausanne. On the other hand, the occurrence of multiple
      pregnancies, which is the main complication of IVF, may be limited by reducing
      the number of embryos replaced. Further improvements of treatment efficacy may
      result from the introduction of new medications, such as recombinant FSH or GnRH
      antagonists, allowing for the adaptation of the treatment protocol used to the
      individual needs of each patient. A treatment protocol combining a GnRH
      antagonist and gonadotropins may be particularly valuable in young patients for
      the purpose of avoiding the ovarian hyperstimulation syndrome. The major
      disadvantage of these novel medications consists of their increased costs.
      Therefore, a new treatment strategy is currently developed aiming at shortening
      the ovarian stimulation in combination of a prolongation of the laboratory phase.
      The in-vitro maturation of immature oocytes aspirated from small follicles
      previously primed with recombinant FSH has been shown to be a feasible
      alternative to the present treatment modalities. Cryopreservation of unfertilized
      oocytes together with in-vitro maturation may prove to be helpful for women prior
      to chemotherapy or radiation because of malignant diseases or for patients
      suffering from incipient ovarian failure. At present, there seems to be no
      alternative to assisted reproduction although the dominance of this technique may
      impede the development of more cause-related treatment strategies in infertility.

PMID- 10409898
TI  - [Psychosomatic counseling and management of infertile couples].
AB  - Psychosomatic counselling and care of infertile couples has the following
      objectives: Development and implementation of a patient centered communication in
      the consultation itself during diagnostic workup and treatment; detection and
      management of psychosocial problems and difficulties that present barriers to the
      fertility of the couple and may lead to negative consequences of treatment;
      support and help during emotional crisis occurring in the context of the
      treatment and counselling with respect to stress management; therapeutic
      interventions to help couples to cope with the unfulfilled wish for a child and
      to terminate treatment. To fulfill these tasks an integration of psychosomatic
      concepts of thinking and acting in the everyday work in the consultation is
      needed. For this purpose we have developed a model of patient centered
      communication. Furthermore a specialized psychotherapeutic help for couples as
      well as a help and supervision for the infertility team is needed. This 'dual'
      principle of psychosomatic work is the best precondition to assure a high quality
      of personal care for infertile couples.

PMID- 10409899
TI  - [Adoption and/or reproductive medicine].
AB  - Adoption and medically assisted reproduction are alternative options for
      childless parents to fulfill their wish for having a child. In both situations,
      there is a necessity for the future parents to mourn the loss of their imagined
      child, which could have been conceived without a third party (adoption agency or
      medically assisted reproduction). Adoption always represents for the child a loss
      of emotional ties with birthparents and the development of new attachments with
      adoptive parents. Adoption can be considered as a lifetime process of the members
      involved in the adoption triangle, that is birth parents, adoptive parents and
      the child. The article discusses the loss of emotional bonds from primary
      caretakers as a psychological trauma and addresses mourning difficulties in
      adoptees. Problems with the development of new attachments with adoptive parents
      such as loyalty conflicts and the revelation of the adoption are described.
      Family romance fantasy in adoption and aspects of family dynamics as well as the
      specific difficulties adoptive parents encounter are explored.

PMID- 10409900
TI  - [Unfulfilled desire for children--what is the grief for men?].
AB  - The present paper addresses the topic of involuntary childlessness and its
      psychological sequelae for the fathers-to-be. There are at least two different
      psychological stresses men have to cope with: not being able to generate a child,
      and missing a child as one's life fulfillment. A short review of empirical
      research on male coping with infertility illustrates that men suffer from
      involuntary childlessness as do women. Nevertheless, the quality of the
      psychological burden remains open. Results from the Heidelberg Research Project
      on Male Infertility are summarized to assess this quality. Involuntary
      childlessness does not entail psychological sufferings for all patients; indeed,
      it is only a subgroup that remains fixated to the wish to have a child for
      psychological reasons. The project data elucidate the motives behind this
      fixation. They show that the most important psychological burden is not the
      narcissistic wound not to be able to generate a child, but the frustration of
      hope invested into the longed--for child on whom many otherwise unfulfilled
      aspirations are projected.

PMID- 10409902
TI  - [Polycystic ovary syndrome--only relevant in reproductive medicine?].
AB  - The Polycystic Ovary Disease (PCOD) is one of the most common endocrine disorders
      in women with a prevalence of 5%. Affected women often consult a gynecologist
      because of menstrual irregularities, fertility problems or problems of androgen
      excess. However, PCOD is a metabolic disorder affecting multiple organs. Studies
      suggest that those women are at risk for developing several complications such as
      type II diabetes mellitus, hypertension, dyslipidemia and myocardial infarction.
      The risk to develop endometrial carcinoma is also elevated. To give adequate
      treatment to women with PCOD, an interdisciplinary approach of gynecologists
      together with endocrinologists specialized in metabolic and nutritional disorders
      at the University of Basel is presented. The work-up for diagnosis and assessment
      of risk factors is outlined. Goal of this interdisciplinary approach is an
      adequate evaluation of affected patients and their long-term follow-up to test if
      proposed interventions as weight loss, treatment of hyperinsulinemia, regulation
      of menstrual cycle and others can avoid long-term sequelae.

PMID- 10409901
TI  - [Is sterility a genetic burden?].
AB  - Genetic causes of infertility are probably not rare. Today only a fraction of
      genes directly or indirectly involved in reproduction including sex determination
      and differentiation are known. Nevertheless, the list of well-defined genetic
      disorders impairing fertility is impressing already today and growing rapidly.
      Gonosomal aneuploidy and structural rearrangements represent a significant
      portion of the genetic causes of infertility in both sexes. Other chromosomal
      conditions include autosomal balanced structural changes (e.g. translocations),
      probably due to pairing disturbances of the affected chromosomes during meiosis.
      Some fundamental mechanisms in sex determination and differentiation have been
      characterized in recent years. Mutations in some of the genes involved in this
      process may lead to familial infertility. Genetic defects in gametogenesis of
      both sexes are currently being investigated using mouse models. Male specific
      causes of infertility include microdeletion within the AZF region of the
      euchromatic part of the long arm of the Y chromosome and obstructive azoospermia
      due congenital aplasia of the vas deferens in the presence of mutations in the
      CFTR gene.

PMID- 10409903
TI  - [Desire for children in tumor patients].
AB  - After a chemo- and/or radiotherapy not only acute side effects but also longterm
      side effects do occur. The following longterm side effects are observed:
      irregularities in the menstrual cycle, early onset of menopause and infertility.
      They are of special importance to children, teenagers and young adults having
      survived a malignancy. For young women experiencing a premature menopause a
      hormone replacement therapy is indicated. The degree of gonadal failure depends
      on the total dose of cytotoxics, radiation or the combination of both. Alkylating
      substances are responsible for gonadal failure whereas other cytotoxic agents
      lead to reversible gonadal dysfunction. An important risk factor for the
      development of ovarian failure is the woman's age at the time of treatment. A
      pregnancy in patients with a history of malignancy always is a high risk
      pregnancy and needs a close follow up. The offspring of cancer survivors do not
      show a higher rate of chromosomal abnormalities or neoplasms. Before starting a
      chemo- and/or radiotherapy the patient should be informed about acute and late
      effects. Men and adolescent boys should be given the opportunity for sperm
      cryopreservation. It is unclear whether a fertility reserve can be achieved by
      cryopreservation also in women.

PMID- 10409904
TI  - [Quality management in early clinical treatment of severely injured patients].

PMID- 10409905
TI  - [Quality management of early clinical treatment of severely injured patients].
AB  - The early clinical treatment of severely injured patients of today is based on
      modern technical resources as well as on refined therapeutic strategies involving
      a multidisciplinary team. In the meantime the requirements for and expectations
      towards best major trauma care have both increased considerably. In spite of a
      decline in mortality after major trauma during the last two decades still
      clinical deviations from actual treatment guidelines with proven influence on
      negative outcome are to be found. In order to improve the therapeutic process it
      proved effective to introduce the main principles of quality assurance (QA) and
      quality management (QM) that were used successfully in industry into major trauma
      treatment. In QA an analysis of 'process', 'structure' and 'outcome' of the
      clinical treatment is performed. For these components of QA important tools such
      as treatment-guidelines (polytrauma-algorithms), guidelines by the German Society
      of Trauma Surgery for the equipment of a trauma center and score systems for the
      classification of injury severity were elaborated and implemented in major trauma
      care. Further optimization of outcome quality may be achieved by integrating the
      QA- components in a QM-system. QM means introducing relevant feed-back-pathways
      of procedural data for the improvement of the (treatment-) process and of outcome
      data for decisions about structural (and organizational) changements. The
      presented clinical QM-system is based on adequate documentation, analysis and
      assessment of treatment data within a quality committee. The treatment of
      severely injured patients was significantly improved by implementation of the QM
      system in clinical routine with respect to the effectivity of the treatment
      process. Furthermore, by transferring the QM-system to another trauma center, we
      were able to show that the effects of the system in major trauma care are
      reproducible. Besides the internal efforts for quality optimization an external
      quality assessment comparing the own treatment results with other trauma centers
      should take place. For this purpose joining a multicentered trauma registry (i.e.
      the trauma registry of the German Society of Trauma Surgery for the German
      speaking countries) is recommended.

PMID- 10409906
TI  - [Quality of emergency ventilation. A prospective study of trauma patients].
AB  - INTRODUCTION: The prehospitaly initiated endotracheal intubation and controlled
      ventilation, is especially in multi-system-trauma cases, recognized to be the
      "gold standard". Thus especially in view of the increasing demands being placed
      upon the quality of prehospital emergency treatment in general, the quality of
      such prehospital induced ventilation, is becoming of increasing importance.
      Thereby we must take into consideration the limited possabilities, which are
      afflicted with a high degree of uncertainess, which we have at our disposal to
      effectively evaluate the efficiency of emergency ventilation. The purpose of our
      study within a collective of severely traumatized patients, was to determine the
      quality of prehospitaly induced ventilation with regards to the adequacy of
      oxygenation and ventilation and as a result of our findings, to identify areas
      for procedural optimization. RESULTS: The prospective study over an one year
      period involved n = 104 trauma cases (male: 79; female: 25/age: 39.8 +/- 20.8
      years/ISS: 28.1 +/- 15.3) whose prehospital emergency treatment required and
      included endotracheal intubation and controlled ventilation. All patients were
      subject to a prehospital pulse oxymetric monitoring, whereas none were subject to
      an objectivating apparatus monitoring of ventilation: 94.2% of the patients were
      upon admission adequately oxygenated (paO2 > 80 mmHg); only one patient was
      hypoxemic (paO2 < 60 mmHg). 46.2% were adequately ventilated (paCO2: 35-45 mmHg),
      43.2% however were hyperventilated (paCO2 < 35 mmHg), and 10.6% hypoventilated
      (paCO2 > 45 mmHg). A statistical significant relation between hyper
      /hypoventilation and the degree of severity of trauma as well as to the
      individual injury pattern was not evident. However with reference to age: The
      group of > 60 years of age were significantly more frequently hyperventilated
      (paCO2 < 30 mmHg: 31.2%; p < 0.05). A noteworthy accumulation of hypoventilation
      was experienced amongst the group of patients, who during the prehospital
      treatment phase were hemodynamic instable (shock index > 1). CONCLUSION: In
      summary it is evident, that as a rule, even very severe traumatized patients can
      prehospitaly be adequately oxygenated and that such oxygenation can with the
      assistance of pulse oxymetric monitoring be effectively controlled. Remaining
      problem is the emergency physicians ability to evaluate and control ventilation.
      The prehospital determination of minute volume (MV) in accordance with the
      presently valid recommendation: MV = 100-150 ml/kg body weight, in the majority
      of trauma cases results in inadequate ventilation. The introduction of an
      objectifying monitoring method is therefore urgently required.

PMID- 10409907
TI  - [Clinical outcome of arthroscopic posterior cruciate ligament-plasty].
AB  - Twenty-one patients were evaluated with an average follow up of 30 month after
      arthroscopical reconstruction of the posterior cruciate ligament using the IKDC
      Evaluation Document, Lysholm-Score, KT 1000 and X-ray Complex ligament injuries
      and chronic instability of the knee were the indications for operative treatment.
      Semitendinosus--or patella ligament autografts were used. The Lysholm-Score
      significantly improved preoperatively to postoperatively (p < 0.01). The IKDC
      revealed 11 patients for group B, 7 patients for group C and 3 patients for group
      D. The KT 1000 measurement showed a postoperative drawer of 3.6 mm compared with
      the nonoperated side. Thirteen of the 21 patients showed a posterior drawer of
      less than 3 mm. The lateral posterior stress view of the X-ray revealed a 4.1 mm
      (+/- 2.9 mm) side to side difference postoperatively in comparison to 9.5 mm (+/-
      3.5 mm) preoperatively. Three patients possessed radiological signs of
      osteoarthritis grad I by Ahlback. Our results recommend in patients with complex
      PCL-injuries as well as in cases of chronic posterior instability a complex
      reconstruction of the ligaments.

PMID- 10409908
TI  - [Experiences with closed screw placement in intra-articular fractures of the
      calcaneus. Surgical technique and outcome].
AB  - For the closed treatment of an intraarticular fracture of the heel bone it is
      essential to know the 3D shape of the bone, the various types of fractures and to
      get skilled in reduction under an image intensifier. In our hospital we have made
      a comparison of 34 fractures treated with a plate and 94 treated with screws. The
      evaluation was made by the scores based on Merle d'Aubigne and clinical and
      radiological findings. The method of closed reduction and fixation with screws is
      easier, less dangerous for the patient and, compared to the open fixation, the
      results are the same or even better (good and excellent: 79.7%). As a result of
      gentle treatment of the soft tissues and the early reposition, the wound healing
      complications decreased to 2.1% compared to the 14% healing problems connected to
      open plating. Furthermore, cancellous grafting was necessary within the first
      group.

PMID- 10409909
TI  - [Tibial growth after isolated femoral shaft fracture in the growth stage].
AB  - The aim of the present study is to investigate the growth of the tibia after
      femoral shaft fractures in children. We were able to follow up 44 patients (32
      male and 12 female) after a mean of 8 years (range, 5 to 15 years). The age in
      the time of injury was 3 till 13 years (mean 7 years). The length of the femur,
      tibia and leg was measured on X-rays of the entire leg, and the measurements were
      compared with the contralateral side. A statistically significant number of
      tibial elongations were observed in fractures that had healed in considerable
      malalignment (at least 1 cm shortening, dislocation of at least a half of the
      breadth of the femoral shaft, angular deformity of more than 10 degrees) (p =
      0.003) and in fractures that were subjected to manipulation (secondary reduction,
      change of treatment or traction weight) during the healing process (p = 0.007).
      Furthermore, all 7 patients who had infection requiring treatment at the tibial
      plateau extension had more pronounced tibial growth. No significant difference
      was found between tibial growth and the age of the child at the time of injury,
      the type of fracture, the location of fracture and the mode of treatment. The
      following factors were evaluated as being clinically relevant: primary, largely
      anatomic reduction, avoidance of secondary manipulation and prevention of
      infection at the tibial plateau extension.

PMID- 10409910
TI  - [Measuring intraoperative radiation exposure of the trauma surgeon. Measuring
      eye, thyroid gland and hand with highly sensitive thermoluminescent detectors].
AB  - A prospective study of 24 operative procedures involving minimal invasive
      techniques and fluoroscopic guidance was undertaken in order to measure the
      radiation exposure to the primary surgeon. Radiation was monitored with the use
      of high sensitive thermoluminescent dosimeters. At the spots of dosimetry (eyes,
      thyroid gland, hand and genitals under lead apron) the dose was uniformly low and
      ranged from 0.6 muSv at the eyes to 259.3 muSv at the hand. The dose is
      determined by the duration of fluoroscopy and the amount of scattered rays, which
      in turn depends on the volume being x-rayed. On the basis of our results there is
      no likelihood of exceeding the limits of safety regulations even in a very busy
      operative environment, although a statistically increased incidence of thyroid
      cancer or a radiation-induced glaucoma is present. In vitro measurements with
      irradiation of a phantom resulted in the following recommendations: 1)
      fluoroscopy should be performed using the magnification-mechanism of the x-ray
      apparatus, 2) during lateral fluoroscopy the primary surgeon should be positioned
      close to the image intensifier. At least the surgeon should be familiar with the
      technique of closed reduction and instrumentation to reduce the duration of
      fluoroscopy which proved to be the most important factor for the amount of the
      radiation exposure.

PMID- 10409911
TI  - [Preparing a manuscript for publication in a scientific journal].
AB  - Nowadays scientific publishing in peer reviewed international accepted journals
      is not easy. Rejection rates up to 75% occur. The aim of this paper is to provide
      guidance in the preparation of journal papers for the inexperienced scientific
      writer. The traditional paragraphs Abstract, Introduction, Material and Methods,
      Results, and Discussion are described with respect to its contents and basic
      message and how these sections are designed to build a logical flow. Approved
      suggestions for the structural outline of each paragraph are made. The
      significance of reference list, figures, and tables is also explained. The review
      of a manuscript is discussed and the criterias for acceptance of a journal paper
      are indicated.

PMID- 10409912
TI  - [Anterior interosseous nerve syndrome].

PMID- 10409913
TI  - [Locked dorsal shoulder dislocation and contralateral ventral shoulder
      dislocation fracture. A rare combination].
AB  - The posterior luxation of the shoulder joint is a rarely reported and often not
      recognized lesion in the clinical workday. The authors present the first case of
      a posterior luxation of the shoulder joint in combination with an contralateral
      anterior shoulder joint fracture dislocation. In that case the authors stress the
      importance of an exact clinical and radiology diagnostic and the right way to
      reduce a posterior luxation of the shoulder joint. Finally they draw the readers
      attention to operative steps to prevent a reluxation of the shoulder joint.

PMID- 10409914
TI  - [Bilateral traumatic dissection of the carotid artery].
AB  - Bilateral carotid artery dissection is a rare and unusual complication of blunt
      cervicofacial trauma. The diagnosis of a carotid injury is rarely suspected in
      trauma patients with neurological deficits. Neurological symptoms may develop in
      a delayed fashion. Angiography should be considered in trauma patients with
      hemiplegia and a normal mental status and in patients with blunt cervical trauma
      with an abnormal neurological examination. Initial heparinisation can prevent
      arterial thrombosis and neurological deterioration.

PMID- 10409915
TI  - [Focus debridement of chronic sequestered talus osteomyelitis by TCNC
      arthrodesis. A new technique with ring fixateur].
AB  - A technique utilizing the Ilizarov ring fixator to stabilize a tibio-calcaneo
      naviculo-cuboideal arthrodesis following talus resection is introduced. The
      advantages of this method will be demonstrated with the help of a case history.
      The described method permits early weight bearing, while supplying stability and
      compression of the fusion, thereby avoiding further loss of bone stock, while
      reducing the risk of thromboembolic complications. The Ilizarov ring fixator
      construction allows for the combination of the fusion with the correction of a
      preexisting or ensueing leg length discrepancy.

PMID- 10409916
TI  - [Deep venous thrombosis caused by central venous catheter].
AB  - Infections and venous thromboses are the major complications of central venous
      access catheters and ports. The frequency of thrombosis depends on the venous
      access systems used, their material, their diameters and the position of their
      tips. The lowest rate of thrombotic complications is seen with single or double
      lumen Hickman- or port catheters made of silicone with their tips in the lower
      half of the superior vena cava or in the right atrium. Antibiotics given
      preoperatively and heparin for at least 90 days after catheter placement must be
      recommended in oncological patients with a high risk of thrombosis. In case of
      thrombosis-related occlusion of the catheters low-dose urokinase and
      streptokinase can be helpful to restore the catheter's function. Else, therapy is
      identical to that of other types of thrombosis.

PMID- 10409918
TI  - Early and late functional and histopathological perturbations in the rabbit ear
      artery following local cold injury.
AB  - BACKGROUND: These experiments aimed to study the in vivo short and long term
      neurovascular regeneration after frostbite. METHODS: The rabbit central ear
      artery was used as the experimental model. The effects on the noradrenergic
      innervation of the artery were measured in isolated vascular ring segments the
      first day and 2, 3-4, and 8-10 or 10-20 weeks following freezing at -9 degrees C
      or -18 degrees C for 15 min with slow rewarming for 7 min at room temperature.
      RESULTS: Two days after freezing the sympathetic nerves were completely
      degenerated, as observed with glyoxylic acid-induced fluorescence. The vascular
      isometric tension responses to exogenous noradrenaline and endogenously released
      noradrenaline by electrical stimulation in vitro were abolished. A varying degree
      of necrosis of the vascular wall was observed. Two weeks after freezing at -18
      degrees C in vitro responses to exogenous noradrenaline and electrical
      stimulation were still abolished, then gradually approaching control levels after
      10-20 weeks of in vivo regeneration. Eight and 10 weeks after injury at -9
      degrees C increased vascular tension responses to exogenous noradrenaline was
      found. In spite of a long regeneration period the total uptake and the
      spontaneous and K+ (75 mM) evoked releases of [3H]noradrenaline were persistently
      decreased after frostbite at -18 degrees C, but they were regenerated to control
      levels already 10-20 weeks after -9 degrees C. Regeneration of noradrenergic
      nerve function, expressed as [3H]noradrenaline uptake and release and
      responsiveness to electrical stimulation, expressed as vascular contraction, was
      slower than the regeneration of the vascular smooth muscle. Myointimal
      hyperplasia developed in response to -9 degrees C and -18 degrees C frostbite.
      The uptake and the K+ evoked release of [3H]noradrenaline were particularly
      sensitive parameters for autonomic nerve function. CONCLUSIONS: The present
      findings may demonstrate important neurovascular reactions to local frostbite and
      may explain human sequelae following frostbite.

PMID- 10409917
TI  - Dose-dependent increase of transcapillary diffusion of sodium fluorescein after
      histamine microinjections.
AB  - BACKGROUND: To study the dose-dependent effects of histamine on capillary
      permeability in human skin, using the microinjection technique. PATIENTS AND
      METHODS: Eight healthy volunteers (2 w, 6 m; mean age 33 years) were included in
      the study. On two separate occasions, glass microcannulas with a tip diameter of
      7 to 9 microns were inserted into the subepidermal layer of the skin at the
      distal medial tibia surface of each lower limb with a micromanipulator. In each
      subject, 0.5 microliter of 3 different concentrations of histamine solution
      (0.1/1000, 0.01/1000 and 0.001/1000) were injected and compared to the solvent
      (0.9% NaCl). Transcapillary diffusion of intravenously administered Na
      fluorescein was assessed simultaneously using two fluorescence videomicroscopy
      systems. Off-line video densitometry was performed in an area of 0.56 mm2 around
      the injection sites and fluorescence light intensities were measured in arbitrary
      units (AU) at 10, 30, 60, 120 and 600 s after dye appearance. RESULTS: Compared
      to the solvent histamine microinjections resulted in a dose-dependent increase of
      mean fluorescence light intensities (FLI). Whereas mean FLI for the 0.001/1000
      histamine injection was only significantly elevated 10 min after dye appearance
      (p < 0.05) an increase of mean FLI was already observed 10 s after dye appearance
      following the 0.1/1000 histamine injection (p < 0.05), which was more pronounced
      at later time points (p < 0.001). Mean FLI's for the 0.01/1000 histamine solution
      were in between and resulted in significantly elevated values 1 min to 10 min
      after dye appearance (p < 0.05). CONCLUSIONS: We conclude that the microinjection
      technique together with fluorescence videomicroscopy described previously [6] is
      able to document a dose-dependent effect of histamine microinjections on skin
      capillary permeability. The technique may facilitate to determine appropriate
      dosages not only of histamine in order to test the effect of antagonists on human
      skin capillary permeability.

PMID- 10409919
TI  - Alterations of the extracellular matrix of venous walls in varicous veins.
AB  - BACKGROUND: Investigation of changes in normal veins which result in the
      formation of varicosis led to examination of the histological organisation of the
      vessel wall and to histomorphological alterations in the region of the
      extracellular matrix. PATIENTS AND METHODS: The expression pattern of the matrix
      proteins collagen IV, fibronectin, laminin, tenascin, and undulin as well as the
      structure and orientation of elastic fibres were determined by means of
      immunohistochemical staining. RESULTS: All varices exhibited an increased
      expression pattern in comparison to healthy veins. The venous vessel wall was
      often non-homogeneously enlarged. The intima was always more involved than the
      media and showed enhanced accumulation, whereas, the adventitia was not
      influenced by the pathological process. Collagen IV exhibited an early
      accumulation, especially in the subendothelial region. The other matrix proteins
      demonstrated an increase in fibre propagation parallel to the enlargement of the
      vessel wall. Essentially, an augmented de novo synthesis of fibres with an
      irregular arrangement and the formation of local plaques was found. Elastic
      fibres were enhanced by slight involvement of the vessel wall and were reduced
      and fragmented during increased involvement of the venous wall which explained
      the rigidity of varices in contrast to normal veins.

PMID- 10409920
TI  - Expression of tissue-type and urokinase-type plasminogen activator activities in
      chronic venous leg ulcers.
AB  - BACKGROUND: Chronic wounds have been shown to exhibit elevated levels of several
      classes of proteinases. Plasminogen activators (PAs) are proteinases which play a
      major role in the biological processes involved in wound healing and
      abnormalities in PAs may play a role in the pathology associated with chronic
      wounds. Here, we investigated the expression of tPA and uPA activities in chronic
      venous ulcer biopsies. PATIENTS AND METHODS: In 22 patients with chronic venous
      leg ulcers, punch biopsies were taken from the ulcer base, ulcer margin and
      uninvolved skin from the thigh of the affected limb and PA activities were
      assessed using in situ histological zymography. RESULTS: tPA is the main PA
      activity in uninvolved skin but was reduced in ulcer margin skin and venous leg
      ulcer tissue compared to normal skin. uPA activity appeared throughout the ulcer
      margin skin but was at low levels in normal skin. Ulcer base tissue appeared to
      exhibit a plasminogen-independent proteinase activity not seen in normal or ulcer
      margin skin. CONCLUSION: PA activities are altered in and around chronic venous
      leg ulcers and their distribution suggests that blood vessels in CVI may be
      damaged and that the tissue is in an inflamed state.

PMID- 10409921
TI  - Alteration of the fibrinolytic system in patients with peripheral arterial
      occlusive disease.
AB  - BACKGROUND: The fibrinolytic system may play an important role in the development
      and progression of peripheral arterial occlusive disease. PATIENTS AND METHODS:
      The fibrinolytic system of the whole blood and a diseased leg was investigated in
      twenty men with chronic peripheral atherosclerotic occlusive arterial disease
      (PAOD, clinical stage II according to Fontaine), aged from 46 to 66 years (x =
      55.3) [symbol: see text]. The diagnosis of PAOD was established by clinical
      examination and segmental systolic blood pressure measurements using a Doppler
      ultrasound detector. Twenty age-matched (x = 53.4) male volunteers with normal
      arterial circulation of the lower limbs and without risk factors of
      atherosclerosis, served as controls. In both groups fibrinolytic system was
      investigated in basal conditions and during provocation. Release of tissue-type
      plasminogen activator (t-PA) was provoked by 20 min venous occlusion of the arm
      and the leg and by infusion of DDAVP (1-desamino-8-D-arginine-vasopressin, 0.4
      ug/kg of body weight). Blood samples were obtained from the arm and the leg
      before and after each stimulus. The fibrinolytic parameters: euglobulin clot
      lysis time, t-PA activity (amidolytic assay) and antigen (ELISA) and t-PA
      inhibitor (PAI) activity (amidolytic assay) were determined. RESULTS: With the
      exception of a boderline increase in PAI activity in patients, no other
      differences between the two groups were observed in basal conditions. The most
      prominent deterioration of the fibrinolytic system detected in male PAOD patients
      was a significantly higher residual PAI activity registered during venous
      occlusion of the arm and two minutes after combined stimulation. Two minutes
      after combined stimulation (DDAVP and venous occlusion of the arm) significantly
      lower t-PA activity was observed in patients. In patients t-PA antigen response
      to venous occlusion and DDAVP was not significantly different from the response
      observed in healthy volunteers. The fibrinolytic response of the leg to venous
      occlusion was poor and after DDAVP application it was comparable to the arm. The
      fibrinolytic response of the diseased leg in men was not significantly different
      from the healthy leg. CONCLUSION: The results of our study indicate that
      alteration of the fibrinolytic system in atherosclerotic disease is predominantly
      a generalised phenomenon and is not directly related to a local atherosclerotic
      process.

PMID- 10409922
TI  - The arteriovenous impulse system in total hip arthroplasty.
AB  - BACKGROUND: Despite the continuing high incidence of deep vein thrombosis after
      total hip arthroplasty, currently available mechanical thromboprophylactic
      systems are not sufficiently utilised in Germany. PATIENTS AND METHODS: Duplex
      sonographic measurements of the maximum venous flow velocity (V. femoralis) in 10
      healthy individuals performed with a leg orientation synonymous to that during
      total hip arthroplasty were compared to figures obtained during an out-stretched
      leg position. Additionally, duplex-sonography was conducted on 9 patients intra
      operatively during total hip replacement to complete the study. All
      investigations were executed both with and without application of the A-V Impulse
      System (AVIS), a mechanical thromboprophylactic procedure. RESULTS: In contrast
      to the out-stretched leg position, a decreased venous peak flow velocity during
      surgery as well as in the operation-identical leg orientation was demonstrated in
      the absence of AVIS. However, by means of AVIS, a significant increase in the
      venous peak flow velocity (p < 0.01) was achieved for both situations.
      Additionally, an increased vessel diameter of the V. femoralis communis was
      observed in 75% of patients due to the leg orientation stipulated for hip
      replacement surgery. CONCLUSION: The data suggest that the A-V Impulse System can
      effectively accelerate the venous reflux-flow during operations involving hip
      replacements and thus provide an early preventative therapy for deep vein
      thrombosis after a surgical procedure.

PMID- 10409923
TI  - PTA of the subclavian and innominate arteries: long-term results.
AB  - BACKGROUND: To investigate the long-term clinical and duplex sonographic results
      of percutaneous transluminal angioplasty (PTA) of the subclavian and innominate
      arteries, and the potential of a new double balloon technique to avoid
      cerebrovascular thromboembolism. PATIENTS AND METHODS: Forty-three PTAs were
      performed on 38 subclavian, four innominate arteries and one subclavian
      subclavian bypass in 37 patients. In three instances a protective double balloon
      technique was used. Indication for the intervention was: subclavian steal
      syndrome (n = 14 [38%]), upper extremity arterial insufficiency (n = 26 [70%]),
      peripheral thromboembolism (n = 8 [22%]) and PRIND/stroke (n = 3 [8%]). Analysis
      of long-term follow-up (median 15, range 2 to 100 months) was possible of 28
      patients including duplex sonographic assessment in 23 patients. The cumulative
      patency rate was calculated by means of life-table analysis. RESULTS: Technical
      success was achieved in 36 endovascular procedures (84%). Minor peripheral
      catheter complications occurred in three interventions (7%), cerebrovascular
      thromboembolism in four (9%). No cerebrovascular complications were seen using
      the double balloon technique. On final check-up 4 patients (14%) suffered from
      subclavian steal syndrome, 3 (11%) from mild upper extremity arterial
      insufficiency and one (4%) from rest pain. Duplex sonography showed no stenosis
      in 12 of 23 patients (52%) and a stenosis of less than 50% in 8 (35%). The life
      table analysis showed a secondary cumulative patency rate of 72% after 100 months
      with all restenoses occurring within 24 months. CONCLUSIONS: PTA of the
      subclavian and innominate arteries appears to be a useful alternative to surgery
      with a low complication rate. The long-term patency rate of 72% is comparable to
      results of other series. In high risk situations cerebrovascular complications
      may be reduced using the new double balloon technique.

PMID- 10409924
TI  - Ergotamine-induced intermittent claudication.
AB  - We report about a female patient with intermittent claudication caused by
      ergotamine. She used ergotamine as a treatment for migraine headaches for more
      than 4 years. The claudication began 7 month before admission. Colour Doppler
      sonography and angiography showed severe stenosis of the left external iliac and
      superficial femoral artery. The patient was treated with phenprocoumon for one
      year after withdrawal of ergotamine. After that the superficial femoral stenosis
      disappeared completely, but the external iliac stenosis was still present and was
      consequently successfully treated by atherectomy. The histology showed a fibrosis
      of the intima and a hypertrophy of the media.

PMID- 10409925
TI  - Coeliac artery aneurysm: aorto-hepatic artery reconstruction.
AB  - Aneurysms of the coeliac axis are rare. Up to 1997, 137 cases had been reported.
      Here we present a coeliac aneurysm which involved the origin of the splenic, left
      gastric, and common hepatic arteries. After making a midline incision, infra
      diaphragmatic control of the aorta was obtained. The aorta was clamped for 25
      minutes to resect the aneurysm. The defect at the origin of the coeliac axis was
      closed with 1.5 cm PTFE patch. The distal segments of the splenic and left
      gastric arteries were ligated. A 6-mm ringed PTFE graft was interposed between
      the infra-renal aorta and the proper hepatic artery. The control arteriogram
      showed a good arterial flow. The patient recovered uneventfully after surgery
      with normalisation of hepatic function.

PMID- 10409926
TI  - Stenosis-jet can cause a dissection of the superficial femoral artery.
AB  - A dissection of the superficial femoral artery mainly occurs due to trauma or
      manipulation of the artery by means of interventional procedures. In contrast to
      dissections of the carotid arteries which are known to occur spontaneously we
      present the case of a stenosis of the superficial femoral artery that led to a
      dissection caused by the stenosis-jet. The dissection on the other hand caused an
      appositional thrombus which led to the embolic occlusion of the pedal-arteries.
      In case of peripheral embolisms in patients with or without history of peripheral
      arterial occlusion disease it is important to look for a causing arterial
      pathology preferably by duplex sonography.

PMID- 10409927
TI  - Strategies for successful transition from clinician to home care manager.

PMID- 10409928
TI  - Using community resources effectively to plan care.

PMID- 10409929
TI  - Avoiding the pitfalls of hospice continuous care.

PMID- 10409930
TI  - The value of EKG monitoring in the home.

PMID- 10409931
TI  - Have beeper will travel--an after hours program that cuts costs.

PMID- 10409932
TI  - Competencies of effective and efficient home care nurses.
AB  - The abilities of effective and efficient home care nurses include the action
      oriented implementation of knowledge and intellectual skills, including the
      application of psychomotor skills. These abilities have been translated into
      competencies and then quantified into a classification of seven categories of
      practice, with key elements for each category. Since all home care nurses should
      be assessed against valid and reliable competencies, this tool can prove useful
      to managers as they assess and improve competencies of staff RNs.

PMID- 10409934
TI  - Outcome-Based Quality Improvement and the OASIS data set revisited.

PMID- 10409933
TI  - Hiring the home health nursing supervisor: a new focus?

PMID- 10409935
TI  - The importance of research in home care management.

PMID- 10409936
TI  - Suggestions for implementing the OBQI/OASIS data set. Interview by Randa L.
      Sperling.

PMID- 10409937
TI  - Planning effective meetings.

PMID- 10409938
TI  - Electronic clinical records: what do regulators want?

PMID- 10409939
TI  - Grant writing in the home healthcare arena: getting started.

PMID- 10409940
TI  - Structuring for success: a new approach to home care management.

PMID- 10409941
TI  - An innovative approach to reducing home health aide supply costs.

PMID- 10409942
TI  - Surviving the Interim Payment System.

PMID- 10409943
TI  - Making a difference in nursing education: a continuing role for HBCU's.

PMID- 10409944
TI  - Retaining ethnic minority nursing students (REMNS): a multidimensional approach.
AB  - The under-representation of minority nurses in the nation is of critical concern
      for nurse educators. The high attrition rate of minority nursing students, on a
      local and national level, has not been effectively addressed. Project REMNS
      (Retaining Ethnic Minority Nursing Students), an innovative, comprehensive
      project, was designed to increase the retention of minority nursing students at
      Prairie View A&M University. Pre-clinical nursing students were provided
      strategies to improve critical thinking, stress management, and reading
      comprehension skills. This was accomplished by the development and implementation
      of content relevant computer modules on stress management, nutrition, and
      critical thinking. Implementation of Project REMNS resulted in an increased
      number of pre-nursing students admitted and retained in the nursing program.

PMID- 10409945
TI  - Health promoting behaviors of African-American registered nurses.
AB  - The purposes of this study were: (1) to describe the health promoting behaviors
      of African-American nurses, (2) to add to the health promotion data base for
      African-American women, and (3) to pilot test a self-administered questionnaire
      developed by the investigators for use in a larger study of the health-promoting
      behaviors of middle class African-American women. The sample consisted of 49
      African-American registered nurses recruited from members of a nursing sorority.
      Selected criteria for the subjects were female, college graduate, and a middle
      class standard of living. A self-administered questionnaire was used to assess
      the likelihood of engaging in health-promoting behaviors. Descriptive statistics
      were used to describe the findings in terms of frequency and percentage
      distribution. The results indicated that the African-American nurses had high
      percentages of adherence to the following health-promoting behaviors: minimal
      alcohol consumption, avoidance of smoking, cholesterol screening, assessment of
      blood sugar levels, monthly breast self-examination, pap smears, mammogram
      screening and regular measurement of blood pressure. Lower percentages of
      adherence were reported for two health-promoting behaviors: diet and exercise.
      Results of this study support the need for the incorporation of diet and exercise
      into all health promotion intervention programs for African-American women.
      Implications include additional research to validate the findings of this study.

PMID- 10409946
TI  - Computer-based learning: games as an instructional strategy.
AB  - Games are a creative teaching strategy that enhances learning and problem
      solving. Gaming strategies are being used by the authors to make learning
      interesting, stimulating and fun. This article focuses on the development and
      implementation of computer games as an instructional strategy. Positive outcomes
      have resulted from the use of games in the classroom.

PMID- 10409947
TI  - The development and utilization of a computerized student database.
AB  - A computerized student database can provide a comprehensive system for encoding,
      maintaining, and interpreting student data. This paper describes the development
      of a student data base at Prairie View University College of Nursing and explores
      possible uses of the data once collected.

PMID- 10409948
TI  - The nursing wellness center: a win-win situation for faculty.
AB  - This article discusses the community-based wellness center as a solution to
      faculty needs for community-based student clinical practice sites, faculty
      practice and the mission of service to the community. The development of the
      concept at our school is traced, and the benefits of such a program to faculty,
      students, and the University are explored.

PMID- 10409949
TI  - Clearing up the "concept fog".
AB  - This article discusses concept mapping as a useful tool for teaching difficult
      concepts. Definitions, advantages, and further uses of concept mapping are
      provided. Directions for constructing maps and sample maps are included.

PMID- 10409950
TI  - Community partnerships in nursing education.
AB  - A community partnership for a seamless education process is explored. Mechanisms
      for program delivery to a distance education site such as: the use of interactive
      video-conferencing, student support services, and changing faculty roles are
      reviewed. Positive outcomes of the community partnership have developed for both
      the community college and the participating university.

PMID- 10409951
TI  - Meeting the challenge: educating ethnic minority nursing students--a continuing
      role.
AB  - Historically Black Colleges and Universities (HBCU's) traditionally have educated
      large numbers of Black nurses. HBCU programs must not lose the vision from the
      past in attempts to demonstrate diversity in the future. The need for HBCU's as
      providers of Black nurses necessitate an even larger and viable role in changing
      health care environments. The roles must be designed to increase retention,
      reduce barriers, and generate outcomes for HBCU's to remain in the forefront of
      educating nurse leaders for tomorrow.

PMID- 10409952
TI  - Faculty member transitioning into the the advanced practice role.

PMID- 10409953
TI  - Nurses must debate new prescribing proposals.

PMID- 10409954
TI  - The 'Teaching Care Home': new concept, old lessons.

PMID- 10409955
TI  - A guide to the UKCC's professional conduct procedures.
AB  - The primary purpose of the United Kingdom Central Council for Nursing, Midwifery
      and Health Visiting is to protect the public. One of the most visible ways it
      does this is through its professional conduct procedures. This article sets out
      how these procedures work and acts as an introduction to a new series in the
      British Journal of Nursing highlighting examples of professional misconduct case
      studies.

PMID- 10409956
TI  - Case 1: patient abuse. Clients in a residential unit for people with learning
      disabilities.

PMID- 10409957
TI  - Comparison of Rosidal K and SurePress in the treatment of venous leg ulcers.
AB  - Fifty-two patients (26 in each group) were recruited into this randomized,
      comparative, controlled trial of Rosidal K short-stretch compression bandage and
      SurePress long-stretch compression bandage in the treatment of venous leg ulcers.
      Patients were monitored for a maximum of 12 weeks. Each patient was seen weekly
      by a research nurse, who recorded the study variables. The mean percentage
      reduction in the wound bed surface area during the study period was 52% in the
      SurePress group and 73% in the Rosidal K group. Eight patients in each group saw
      their ulcers heal within the study period. The average limb volume reduction,
      based on the first 4 weeks of data collection, was 2.3 cm for those in the
      Rosidal K group and 3.9 cm in the SurePress group. Ulcer size increased in six
      patients allocated to SurePress bandages and in four patients allocated to
      Rosidal K bandages.

PMID- 10409959
TI  - UTI in patients with urethral catheters: an audit tool.
AB  - This article presents an audit tool for the evaluation of practice relating to
      urinary tract infection in hospital patients with indwelling urethral catheters.
      It has been formulated primarily because urinary tract infection is a known
      complication of catheterization, and because studies have shown practitioners'
      knowledge in this area to be poor. Although health professionals have an
      obligation to ensure their practice is evidence based, this requires substantial
      time and skills in critical appraisal. The standard presented here is based on
      evidence from an extensive literature review on how best to minimize urinary
      tract infection during catheter insertion, meatal hygiene and management of the
      drainage system. The audit tool offers the potential for improved practice and
      demonstration of clinical effectiveness through measurable reduction in rates of
      urinary tract infection. Moreover, it provides an ideal opportunity for nurses to
      take the lead in clinical audit activity, which is so often medically led. The
      supplementary information will also provide a useful guide for nurses to
      undertake and initiate clinical audit activity in the future.

PMID- 10409958
TI  - The road to conversion for enrolled nurses: a literature review.
AB  - The literature concerning the plight of the enrolled nurse (EN) is extensive.
      This article examines published material from the last 10-12 years to consider
      the problems that ENs experience in relation to professional development and
      career advancement. For many ENs, conversion to first-level registration is seen
      as the only means of progress and possibly the only means of retaining a career.
      However, does conversion actually achieve progress? The literature on this
      subject is scarce but reports suggest that converted ENs do go on to achieve
      promotion and make use of educational opportunities (Crotty, 1990; MacGregor and
      Hill, 1996). Nevertheless, there is a substantial number of ENs who have no
      desire to convert to first-level registration and their role should be valued.

PMID- 10409960
TI  - Impact of urinary incontinence on the quality of life of women.
AB  - There is a lot of debate among continence specialists as to the impact that
      urinary incontinence (UI) has upon the sufferer's quality of life (QoL).
      Furthermore, healthcare professionals involved in delivering care are examining
      ways to measure the outcomes of their healthcare interventions, in terms of not
      only symptom relief, but also patient-specified improvements to QoL. Healthcare
      professionals have yet to agree upon one standard tool for measuring the effect
      of UI upon sufferers' QoL. This article examines some of the current research on
      UI as experienced by females living in their own homes and its impact on their
      QoL.

PMID- 10409961
TI  - The four-layer bandage system from a nursing perspective.
AB  - This article describes an evaluation that took place in 20 health centres,
      community clinics and hospitals throughout the UK. The aim was to explore nurses'
      opinions of three different four-layer bandage systems: kit A (System 4); kit B
      (Charing Cross); and kit C (Profore). Fifty-seven pairs of nurses were involved;
      within each pair, one was the applier and one the wearer. Each nurse was asked to
      complete a questionnaire which highlighted their opinions relating to ease of
      application, conformability, comfort and preferred bandage length. Responses were
      analysed using simple frequency counts, means, standard errors, Fisher's exact
      test and Kruskal-Wallis' one-way analysis of variance. The nurses involved were
      regular users of either the Charing Cross or Profore systems. Kit A was
      significantly easier to apply than kit B for layer 1 (P < 0.001), layer 2 (P <
      0.05) and layer 3 (P < 0.01). There was no significant difference in relation to
      layer 4. With regard to ease of application there were no statistically
      significant differences between kits A and C or B and C. Layer 1 of kit A was
      significantly more conformable than layer 1 of kit B (P < 0.001). There were no
      significant differences between kits B and C, or A and C or in relation to
      comfort for all bandage kits. Overall preference by the applier was: 25 for kit
      A, nine for kit B and 15 for kit C. Overall preference by the wearer was: 23 for
      kit A, 10 for kit B and 14 for kit C.

PMID- 10409962
TI  - The DIAL-log study 1: Profiling the experience of people with dementia.
AB  - Between July 1996 and December 1997 telephone helpline staff from the Alzheimer's
      Disease Society (ADS) in London, and six participating ADS regions in England and
      one in Northern Ireland, documented calls from people with dementia who contacted
      the service. Each call was recorded as soon as practicable after its completion
      on a Dementia Information and Advice Line (DIAL) log form (DIAL-log). Sixty-four
      calls were recorded in this way and 62 completed DIAL-logs were included in the
      study findings. Analysis of the data was undertaken via SPSS 6.1 for Windows.
      This article, the first of two, introduces the background to the study and notes
      that callers reported memory loss and forgetfulness as the most frequently
      noticed first signs of dementia. The study aims and limitations are also outlined
      in this first article. The second article will detail the main findings and the
      challenges that the DIAL-log study may provide for future dementia care practice
      and research.

PMID- 10409963
TI  - Benefits of nurse teachers returning to clinical practice.
AB  - This article outlines an action research study developed to facilitate nurse
      teachers returning to clinical practice. The article explores how the teachers
      established partnerships with clinicians through which they were able to share
      the experience of returning to an area of nursing that they had previously only
      visited. It discusses four categories: expectations of self and others; entering
      someone else's world; more awareness of student needs; and teaching theory and
      practising nursing. These categories emerged following the analysis of journals,
      focus group interviews and individual interviews and led to a number of
      recommendations concerning the implications for other teachers wishing to return
      to clinical practice.

PMID- 10409964
TI  - We must all press to protect the title 'nurse'.

PMID- 10409965
TI  - International Year of Older Persons 1999.

PMID- 10409968
TI  - Discovery of self: exploring, interconnecting and integrating self (concept) and
      nursing.
AB  - Self concept of individual nurses is still largely unexplored in nursing. While
      the role of self-knowledge and self-actualisation are recognised as integral to
      nursing practice, little has been done to examine their relationships to self
      concept and nursing practice. The aim of this research study was to explore the
      role and significance that self concept plays in women nurses' experience of
      their beginning practice. The exploration examined factors which contribute to
      and impact on self concept within a nursing practice environment. Self concept
      relates to how an individual experiences oneself and is integrally linked to
      one's interactions and relationships with others. This two phase research was
      situated in critical and feminist theory using reflective journalling (phase one)
      and story telling/narrative (phase two) as the research methods. This paper
      discusses the three major themes which arose in phase one of the research. Those
      were: exploring experiences; interconnecting personal and professional worlds;
      and, integrating self 'into' nursing. The paper also explores inter-subjectivity
      in terms of the contribution this concept makes to our understanding of research
      findings.

PMID- 10409967
TI  - Bereavement care: a role for the community nurse.
AB  - Isolation, disability and a socialisation process of days gone by which
      encouraged people to 'keep a stiff upper lip' may prevent elderly people from
      accessing appropriate support in times of grief and/or bereavement. The suffering
      and disorganisation which follows the initial shock of bereavement are health
      hazards in their own right, but more dangerously so in the older spouse or
      partner. The community nurse is well placed to provide bereavement care, given
      that most grief is not pathological in nature, and with some support and use of
      resources available will resolve in time. It is argued that community nurses,
      assisted by inservice education and a protocol in bereavement care, could fulfil
      this role.

PMID- 10409969
TI  - Vaccine know-how. Kimberley immunisation study: community nurses immunisation
      education, knowledge and practice.
AB  - In the remote Kimberley Region of Western Australia, community nurses administer
      almost all childhood vaccines. This paper discusses the immunisation education,
      knowledge and practice of this group of nurses. This research was part of a
      larger Kimberley immunisation study. The first phase investigated the
      immunisation cover and timing of vaccine administration to children in the 0-18
      month age group in the Kimberley Region of Western Australia. Phase two
      investigated immunisation education, knowledge and practice. The study findings
      suggest that community nurses are knowledgeable about vaccine administration, and
      administer vaccines appropriately to children with multiple infections, weight
      loss and failure to thrive. They are also 'active' in following up children due
      and overdue for vaccines. However, a lack of on-going nursing immunisation
      education was reported.

PMID- 10409970
TI  - Evaluating a clinical partnership model for undergraduate nursing students.
AB  - Since the transfer of nurse education to the tertiary sector in Australia there
      have been many challenges associated with the selection, administration and
      facilitation of clinical experiences for undergraduate nursing students. The
      School of Nursing at Australian Catholic University, McAuley Campus, planned and
      implemented a partnership model for clinical practice with the aim of improving
      current methods and overcoming some of the problems previously experienced.
      Evaluation of the model was conducted during the first year of implementation. An
      interpretive approach involving academic staff, clinical affiliates and students
      was used to evaluate the model. Thematic analysis of the data revealed three
      major themes of familiarity, acceptance and trust and supportive learning
      environments. It was found that students had been supported in their learning
      environment through the clinical affiliates commitment to teaching and learning,
      linkage of theory and practice and credibility as practising clinicians.

PMID- 10409972
TI  - Career structures for South Australian nurses: developing a research agenda.
AB  - Career structure models are central to the organisation of the work of
      professionals like nurses, to their remuneration and other forms of recognition,
      and for the organisation of employing institutions. It has been little more than
      a decade since the implementation of a career structure model for nurses in South
      Australia in 1986-7. Since that time a number of changes to the profession, and
      to the health care system more generally, have resulted in ad hoc adaptations to,
      and sometimes an erosion of, the career structure as originally envisioned. As we
      approach the new millennium, an assessment and evaluation of the efficacy of the
      SA career structure in meeting the professional needs of nurses and their
      employing organisations is both timely and necessary. This paper provides the
      historical background to the development of the SA career structure, and
      highlights some of the major issues that have emerged as problematic since
      implementation. The paper then identifies some issues that might contribute
      towards guiding a more systematic approach to the re-appraisal of nurses' career
      structures.

PMID- 10409971
TI  - Nightingalism: haunting nursing history.
AB  - This paper is concerned with determining how 'Florence Nightingale' functions in
      discourse about nurses and nursing. It argues that the nursing profession needs
      to recognise that the name 'Florence Nightingale' serves a political function
      that, even in the 1990s, is still used to construct certain truths about nursing
      praxis. More specifically, it argues that if the nursing profession wants to know
      how history affects its practice then we need to question the whole system of
      knowledge created about nurses and nursing through a reliance on a formation such
      as Nightingalism.

PMID- 10409973
TI  - Varicella zoster virus.

PMID- 10409974
TI  - World Wide Web resources for nurses: IVT and CPR.

PMID- 10409975
TI  - [Nursing practice based on evidence].

PMID- 10409976
TI  - [Quality of life and mortality of patients in intensive care. Indices of quality
      of life].
AB  - INTRODUCTION: At present there is no single practical standardized scale for
      measuring quality of life (QL). Any proposal should include the patient's
      physical impairment, level of independence, and subjective perception of
      happiness. We combined three previously published scales to define a quality of
      life index (QLI) that we propose as a standard quantitative instrument. The
      applicability and usefulness of QLI for the measurement of the level of
      deterioration of patients after admission to an intensive care unit (ICU) was
      examined. We prospectively evaluated QL before patient admission to determine if
      it influences mortality, as well as long-term changes in the QL and the factors
      conditioning te deterioration of patients released from the UCI as evaluated by
      QL indicators. MATERIAL AND METHODS: To calculate QLI, we combined the Karnofsky
      scale, daily life activities index, and the perception of quality of life scale.
      The resulting percentage (QLI) was used to evaluate 536 patients after admission
      to the ICU and 6 and 12 months after release. QLI was compared with the severity
      of disease (Apache II), probability of death (MPM), diagnostic group, and
      socioeconomic variables. RESULTS: Using multivariate methods, four significant
      variables related with mortality were identified: Apache II--MPM, duration of the
      stay in the unit, age, and QLI. Our analysis of long-term deterioration showed
      that advanced age, high QLI before admission, and the patient's diagnostic group
      explained the degree of deterioration. DISCUSSION: QLI was a useful instrument
      for obtaining a quantitative estimate of the QL of critically ill patients.

PMID- 10409977
TI  - [Effect of age on postoperative care in patients following heart surgery under
      extracorporeal circulation].
AB  - The mean age of patients with heart disease who require surgical treatment is
      increasing. In conjunction with the development of surgical and postoperative
      care techniques, the mortality rate of these patients has decreased. In our
      intensive care unit (ICU), we proposed to determine if older patients undergoing
      cardiac surgery had more morbidity and required more care than other patients. An
      evaluation was made of the differences in evolution and nursing requirements of
      patients over 70 and under 70 who had undergone heart surgery with extracorporeal
      circulation by assessing the complications. A retrospective comparative study was
      made of the records of 50 patients > or = 70 years and 50 patients < 70 years who
      had undergone cardiac surgery and were admitted to intensive care for
      postoperative care. An analysis was made of pathology before surgery, operative
      incidents, evolution and postoperative complications of different body systems,
      postoperative care in intensive care by examining nursing records, the duration
      of the ICU stay and the hospital stay. The results indicated that there were no
      significant differences between the two groups in mortality, ICU stay, and severe
      complications. Patients over 70 had more frequent arrhythmias and difficulties in
      maintaining an optimal respiratory function. Such patients require more nursing
      care and a longer hospital stay. However, it is concluded that age per se is not
      a contraindication for heart surgery.

PMID- 10409978
TI  - [Cardiopulmonary resuscitation in pregnant women: peculiarities].
AB  - This review main purpose is to show nursing the present knowledge about
      cardiopulmonary resuscitation (CPR) in pregnant women because of the scarce
      information published by Spanish Nursing Publications. The bibliographical
      research was made using both the Medline (from January 1982 to March 1998) and
      Index de Enfermeria databases. There, we can find 32 references from which only
      23 were selected (all of them belong to the Medline database) in spite of 3
      chapters that had already been selected from other different books. Although
      maternal cardiac arrest rarely happens during pregnancy, it is very important for
      sanitary staff to be familiarized with the specifics thecnics and equipment
      (ultrasound and cardiotocograph monitoring). This review describes the
      physiological changes that take place during pregnancy and have an incidence into
      CPR. The article also includes the conclusions about the checked papers and the
      peculiarities that have to be taken into account in each CPR, such as the fetal
      viability evaluation, right CPR position, airway and breathing, desfibrillation,
      external cardiac compression and use of pharmacologic therapy and intravenous
      fluids. Moreover, there is a special mention of the perimortem cesarean delivery
      features: antecedents, foetus-maternals consequences and managements, due to the
      fact that this surgical operation should be included inside the CPR protocols of
      the pregnant.

PMID- 10409979
TI  - [Doppler transcranial ultrasonography: a means of non-invasive monitoring at the
      patient's bedside].
AB  - A description was made of a new diagnostic technique used in patients with
      neurological disease who require admission to an intensive care unit,
      transcranial Doppler ultrasonography (TCD). TCD is carried out by the physician
      at the patient's bedside for the purpose of monitoring cerebral hemodynamics. A
      bibliographic review of TCD confirmed that little information is available on the
      nursing aspects of the technique. The aim of this article is to describe basic
      TCD concepts, parameters of normality/pathology, and the effects of this
      technique on nursing tasks.

PMID- 10409980
TI  - [Continuing education and self-evaluation: review of the knowledge about
      electrolyte fluids and the care of patients with kidney and urinary tract
      problems].

PMID- 10409981
TI  - The tyrannni of the figure in the research report or "the play's the thing".

PMID- 10409982
TI  - Marginalized women's comparisons of their hospital and freestanding birth center
      experiences: a contrast of inner-city birthing systems.
AB  - The process of birth provides a structure around which social and cultural forces
      guide its expression. These social and cultural forces reflect the organization
      of power in a society while creating the potential for diversity in birth
      beliefs, practices, and experiences. In this article, marginalized women contrast
      their experiences in the cultures of two divergent birth systems: the
      technocratic hospital system and a freestanding midwifery managed birth center
      system. The women in this study come from many different cultures, yet they share
      a common desire to (a) control the birth environment, (b) establish supportive
      interpersonal connections with providers, (c) have a safe birth, and (d) be
      treated with dignity and respect. However, the descriptions in this article
      illustrate the gender, race, and class power inequities experienced when
      technocratic cultural forces conflicted with oppressed women's basic needs for
      respect and control.

PMID- 10409983
TI  - Reasons, health behaviors, and outcomes of no prenatal care: research that
      changed practice.
AB  - Changes in prenatal care practices resulted from a pilot study with 12 urban New
      Mexican women who received no prenatal care. The women were interviewed regarding
      their reasons for not receiving care during pregnancy, health behaviors, and
      perceived neonatal outcomes. Data on actual neonatal outcomes were taken from the
      medical record. Maternal reasons for no prenatal care were socio-demographic,
      system-related, attitudinal, and outside forces of job and childcare. To ensure a
      healthy baby, the women made changes in their nutrition, self-care activities,
      substance use, sleep, and exercise activities. All of the women perceived they
      had a healthy baby. Yet 61% of the neonates had complications and 45% were low
      birth weight. The research findings were used to develop a care management
      program that included case management and utilization management.

PMID- 10409984
TI  - Routine prenatal screening revisited.
AB  - Routine obstetric screening for all prenatal checkups is an important issue. This
      article is an attempt to answer the value of such screening in the case of
      hematocrit. Charts of pregnant women in the Family Medicine Practice Center at
      the American University of Beirut (AUB) over the last eight years were reviewed.
      Demographic data and hematocrit values were collected. The mean value of the
      hematocrit in our sample was 35.87. The prevalence of anemia was 7%; 31% of the
      sample were primigravida. The age group 15 to 19 years had the highest risk for
      developing anemia. Increased parity was associated with increased risk for
      anemia. Intake of iron on presentation was common (17%), and it reached
      statistical significance in the presence of anemia. It is concluded that there is
      need for more critical consideration of iron supplementation. The question of
      routine screening with hematocrit in the first prenatal visit should be
      reevaluated and patients who are at high risk should be screened.

PMID- 10409985
TI  - Nurses' description and evaluation of reproductive health counseling for
      adolescent females.
AB  - Nurses have been providing reproductive health counseling to adolescent females
      for over 20 years. Yet, we found no studies in the nursing literature in which
      the investigator examined the types of reproductive health counseling nurses
      provide to adolescent females. Therefore, the purpose of this study was to
      examine nurses' description and evaluation of the types of reproductive health
      counseling they used for adolescent females. Five registered nurses, with at
      least 10 years experience in providing reproductive health counseling to
      adolescent females, were interviewed using a semi-structured guide. Four areas
      were explored: type of information provided, barriers to providing counseling,
      adolescent female decision-making capacity, and nursing recommendations. Two
      general themes emerged from the respondents' evaluations: frustration and unused
      potential of nurses to affect the reproductive health of adolescent females, and
      the inappropriateness of current reproductive health strategies for adolescent
      females.

PMID- 10409986
TI  - The relationship between physical activity and perimenopause.
AB  - Our purpose in conducting this study was to examine the relationship between
      physical activity and symptoms associated with perimenopause. A group of 214
      perimenopausal women aged 40-55 years (mean = 47 years) completed the Women's
      Health Assessment Scale (assesses symptoms associated with perimenopause:
      vasomotor, psychosomatic, menstrual, and sexual symptoms) and the physical
      activity questionnaire. These women were categorized into three groups based on
      their levels of physical activity: inactive, relatively active, and active.
      Analyses of covariance (ANCOVA) revealed significant differences between groups
      in frequency and distress of overall symptoms associated with perimenopause (F =
      8.86, p = .00, F = 6.25, p = .00, respectively). Further analyses indicated that
      relatively active and active women had significantly fewer and less distressful
      psychosomatic symptoms (F = 8.05, p = .00, F = 5.80, p = .00, respectively), such
      as irritability, forgetfulness, and headache as well as fewer and less
      distressful sexual symptoms (F = 3.42, p = .03, F = 3.73, p = .03, respectively),
      such as vaginal dryness and decreased sexual desire than inactive women. No
      significant differences were found among groups on vasomotor and menstrual
      symptoms. In conclusion, physical activity may be an important
      alternative/adjunct to hormone therapy particularly for psychosomatic and sexual
      symptom management at perimenopause.

PMID- 10409987
TI  - Filipino women living in Canada: constructing meanings of body, food, and health.
AB  - This qualitative study explored the understandings of body size, food and eating,
      and health held by Filipino women living in Canada. Women (n = 11) aged 19 to 30
      years old who were born in the Philippines and living in British Columbia
      participated in individual interviews where they discussed their beliefs and
      practices relating to their body, food, and health. Informants' comments
      reflected contrasting "Canadian" and "Filipino" meanings. Canadian beliefs
      emphasized the desirability of thinness, "watching" intake of fat, rice, and junk
      food, and minimizing disease risk. Filipino beliefs valued fatness, "just eating"
      fat and rice, and maximizing disease resistance. While most informants appeared
      to have adopted the Canadian values, Filipino beliefs continued to be of some
      significance in their lives. These findings demonstrate the socially constructed
      nature of health beliefs and illustrate how members of a minority ethnic group
      negotiate among conflicting cultural beliefs about body size, food and health.

PMID- 10409988
TI  - A pilot study of cancer knowledge and screening behaviors of Vietnamese and
      Cambodian women.
AB  - Breast and cervix cancer screening behaviors, while suboptimal in all Americans,
      are of particular concern in minority females. Little is known about cancer
      knowledge and screening behavior in Southeast Asian populations in the United
      States. We interviewed 38 Southeast Asian women of Cambodian or Vietnamese origin
      living in the Philadelphia, Pennsylvania, area. A telephone interview was
      conducted by bilingual/bicultural interviewers. Seventy-one percent (95%
      confidence interval [CI], 54% to 85%) of women in the study did not know what
      cancer was and 74% were unable to identify a cancer prevention strategy. Greater
      knowledge about cancer and identification of preventive measures were associated
      with employment outside the home, more years of education, and age, but not with
      length of time in the United States. Cancer education programs need to identify
      the patient's level of knowledge about cancer, elicit and respectfully address
      beliefs about causality and prevention, and ensure that health information is
      provided in a language understandable to the patient.

PMID- 10409989
TI  - Nursing's role in racism and African American women's health.
AB  - African American women's health has been neglected in the nursing and other
      health care literature, in spite of evidence that they are among the most
      vulnerable populations in the United States today. In this article, I highlight
      the health disparities between African American and European American women,
      discuss possible reasons for the disparities, and propose that nursing as a
      profession has been complicit in perpetuating the racism of health care and
      society. Although the focus is on nursing research and practice, it is likely
      that other health care disciplines perpetuate racism in similar ways.

PMID- 10409990
TI  - Where is the evidence?

PMID- 10409991
TI  - Family functioning in families providing care for a family member with
      schizophrenia.
AB  - The purpose of this study is to explore the influences of family coping
      behaviors, psychological distress, social support, and patient behavioral
      problems on family functioning in families providing care for a member with
      schizophrenia. Family stress theory provided the theoretical framework for this
      study. A convenience sample of 58 families providing care for a family member
      with schizophrenia was recruited from a metropolitan area in a southeastern
      state. The majority of the caregivers were mothers who were married and college
      educated. The mean age of the caregiver was 59 years, with an average of 17 years
      in providing care for the family member. Findings indicate that family
      psychological distress and patient behavioral problems are important factors in
      family functioning. This knowledge may be useful for mental health nurses in
      assessing families and developing nursing interventions.

PMID- 10409992
TI  - Optimism and its relationship to depression, coping, anger, and life events in
      rural adolescents.
AB  - Optimism is a stable personality trait that has important implications for
      behavior, yet little attention has been given to examining optimism in
      adolescents. This article describes levels of optimism in rural adolescents and
      the relationship of optimism with depression, coping, anger, and life events. The
      identification of optimism may be a vulnerability factor when screening
      adolescent mental health and, as such, has implications for the psychiatric nurse
      clinician.

PMID- 10409993
TI  - Depressed adolescent mothers' perceptions of their own maternal role.
AB  - Although there is a growing body of research in the area of adolescent pregnancy
      and parenting, little is known about the more personal experiences of these
      teens. Ethnographic research methods were used in the present study with the goal
      of narrowing existing gaps in knowledge about the affective component of
      adolescent mothers' role attainment. The sample consisted of 15 voluntary
      informants who reported depressive symptoms during pregnancy or postpartum. The
      findings suggest that for some adolescent mothers the experience of motherhood
      may help them improve their previously self-destructive lives. Many adolescent
      mothers have engaged in impulsive high-risk activities prior to their
      pregnancies. Through the establishment of a maternal identity and simultaneous
      development of a strong sense of maternal protectiveness these young women are
      making realistic, future-oriented decisions that are motivating them to leave
      gang life, finish high school, go to college, and get vocational training.
      However, a subset of adolescent mothers who experience chronic depressive mood
      along with social isolation in the postpartum period may be at increased risk for
      development of problematic maternal behaviors.

PMID- 10409994
TI  - Psychosocial correlates of subjective health in sexagenarians, octogenarians, and
      centenarians.
AB  - The purpose of this study was to determine if a psychosocial model was a
      significant improvement over a demographic or a physical health model in
      predicting subjective health in older adults. Correlates of subjective health in
      sexagenarians, octogenarians, and centenarians were examined with hierarchical
      regression analysis. Data were obtained in the first wave of the Georgia
      Centenarian Study from 1988 to 1992. Psychosocial variables helped explain a
      significant component of subjective health variance above and beyond the effects
      of demographic or physical health variables. For centenarians an apprehensive
      personality and low levels of control over health were additional correlates of
      poor subjective health. Centenarians were the only cohort to have a unique set of
      correlates, indicating a uniqueness in the oldest-old, as compared to the young
      old and old-old. These findings indicate that a multidimensional perspective of
      health in older adults is more appropriate than medical models.

PMID- 10409995
TI  - Ophthalmic foundations.

PMID- 10409997
TI  - Age-related macular degeneration: new treatments show promise.

PMID- 10409996
TI  - Practical ophthalmic microbiology.
AB  - Infection is commonly encountered in everyday ophthalmic practice. It is of great
      importance that all ophthalmic personnel are familiar with the basic etiologies
      of these infections, and the basic techniques which are used in diagnosis. When
      evaluating a patient with possible infection, it is often of great help to be
      familiar with the normal microbial flora of the human body. This normal flora has
      been detailed in the article. The assumption is that knowledge of a patient's
      flora can help guide decisions about the possible etiologies of an infection.
      When presented with an obvious ocular infection, health care personnel should
      review the "usual suspects"--that is, the common etiologies for each type of
      infection. The key to combating ocular infections lies in accurate treatment of
      the presumed infectious agent. Therefore, the techniques and steps used in the
      identification of the etiology of an infection should be known to all ophthalmic
      personnel. The proper sterile techniques of obtaining a specimen from a suspected
      corneal ulcer or conjunctivitis and the plating of the specimen on specific agar
      for identification are essential to everyday practice (Figure 8). Patients who
      will undergo surgery, regardless of the type, are being placed at a special risk
      for infection. These post-operative infections can destroy the work of the most
      careful and exact surgical technique. It is an essential part of the procedure
      that the patient be protected as best they can from subsequent infection. The
      techniques to reduce the risk of post-operative infection have been detailed
      above. Proper preparation of a sterile field, sterile draping, and perioperative
      antibiotics can reduce the chance of a subsequent infection. It is important that
      these basic steps of care be properly provided to help insure successful surgical
      outcomes and excellence in health care.

PMID- 10409998
TI  - Success with low vision patients: realistic prognosis, reasonable goals.

PMID- 10409999
TI  - The role of antioxidants in AMD: ongoing research.

PMID- 10410000
TI  - Researchers explore if drusen lead to the development of wet AMD.

PMID- 10410001
TI  - Dry eyes revisited.

PMID- 10410002
TI  - Integrate everything: the key to collaboration.

PMID- 10410003
TI  - Patient and family education: a nursing basic.

PMID- 10410004
TI  - Reducing patient delay in seeking treatment for acute myocardial infarction.
AB  - Although there have been tremendous strides in therapies for acute myocardial
      infarction (AMI), patients still do not receive these treatments in a timely
      manner, or sometimes not at all. One major reason is inadvertent delays by
      patients and by those with whom they consult about their symptoms. One of the
      National Heart Attack Alert Program's (NHAAP) goals is to reduce the morbidity
      and mortality associated with AMI through the rapid identification and treatment
      of at-risk individuals. Medical-surgical nurses can play a crucial role in
      ensuring that patients and their family members know how to recognize the signs
      and symptoms of a heart attack, what steps to take to get early and appropriate
      evaluation and treatment, and the potentially lifesaving benefits of this
      information.

PMID- 10410005
TI  - Family voices. Emotional roadblocks, misconceptions, keep one patient from
      seeking care.

PMID- 10410006
TI  - Total joint project: acute care to home care.
AB  - The advent of managed care, decreased reimbursement, and competition among
      providers has forced acute care institutions to examine care delivery. Clinical
      paths provide a method that manages patient care toward positive outcomes within
      a cost-effective environment. A collaborative project for total joint patients
      beginning with the office visit and continuing through the entire episode of care
      is described.

PMID- 10410007
TI  - Preparing the patient and family for home mechanical ventilation.
AB  - In the search for patients' improved quality of life and lower health care costs,
      home mechanical ventilation (HMV) has emerged as a method for treating stable
      chronic respiratory failure, particularly restrictive neuromuscular diseases.
      Data suggest that the use of home mechanical ventilation will rise because of the
      documented benefits to patients and the economic pressure to shorten hospital
      stays. The goal of HMV is to help impaired individuals function at their optimal
      levels. The criteria for HMV, the process of preparation for HMV, and the
      activities at discharge are described.

PMID- 10410008
TI  - Clinical update: new drugs for HIV/AIDS.
AB  - Monotherapy to treat the human immunodeficiency virus (HIV) is now a thing of the
      past. Combination drug therapies and several new anti-HIV drugs in clinical
      trials offer new promise for slowing the progress and deleterious effects of this
      disease.

PMID- 10410010
TI  - Home care: a history of caring, a future of challenges.

PMID- 10410009
TI  - Marfan syndrome: identification and management.
AB  - Marfan's syndrome is an autosomal dominant disorder that involves the
      cardiovascular, musculoskeletal, and ocular systems. Displaying a highly variable
      array of symptoms and course, the disease is underdiagnosed and misdiagnosed.
      Since Marfan's syndrome can have fatal consequences, advance practice and other
      adult health nurses need to recognize and manage its symptoms.

PMID- 10410011
TI  - What clinicians need to know about payer and regulatory policies for wound care.

PMID- 10410012
TI  - A model clinical practice program at Northwestern Memorial Hospital.

PMID- 10410013
TI  - Evaluation of undergraduate physical examination: performances by nurse
      practitioner students.

PMID- 10410014
TI  - Cultural awareness lab: first step toward competence.

PMID- 10410016
TI  - Developing students' evaluation skills.

PMID- 10410015
TI  - A stressor identification exercise for the critical care environment.

PMID- 10410017
TI  - Using feminist pedagogical strategies in the research classroom.

PMID- 10410018
TI  - Strengthening clinical reasoning in graduate nursing students.
AB  - Clinical reasoning skills are the cornerstone of successful nursing practice. To
      strengthen the clinical reasoning skills of graduate nursing students, faculty at
      one university developed an innovative course focusing on theoretical knowledge
      about clinical decision making and reflective exercises to foster student
      thinking.

PMID- 10410019
TI  - Substance abuse among nursing students. Establishing a comprehensive policy and
      procedure for faculty intervention.
AB  - Substance abuse among nursing students is a significant problem requiring careful
      and prudent consideration. Studies reveal that many impaired professional nurses
      were addicted as students. This article provides a step-by-step guideline for
      developing comprehensive procedures for faculty who must deal with chemically
      impaired.

PMID- 10410021
TI  - Development of the Texas Textbook Evaluation Tool (T-TET).
AB  - Nurse educators face many challenges in evaluating textbooks to meet the needs of
      their students and preparing professional nurses who will practice in the next
      millennium. Using four phases of development, the Texas Textbook Evaluation Tool
      (T-TET) was created to develop a reliable and valid textbook evaluation
      instrument. The T-TET may be used to evaluate all levels of textbooks, including
      specialty textbooks in nursing.

PMID- 10410022
TI  - Developing and scoring essay tests.
AB  - The need to prepare nursing students for the licensing examination has resulted
      in a predominance of multiple-choice testing in nursing courses. But what about
      evaluating students' ability to present ideas in their own words and develop
      creative responses to questions posed by the teacher? Essay items provide an
      effective means of assessing higher levels of learning and ability to organize
      and present ideas in writing. The author describes how to develop essay items and
      score responses.

PMID- 10410020
TI  - Program closure in a school of nursing.
AB  - Redirection of the academic nursing mission can have significant effects on
      students, faculty, and administrators. The authors discuss the impact of program
      closure within a school of nursing. A recent decision to phase out a longstanding
      associate degree program included nonrenewal of contracts for the program
      faculty. Specific efforts and strategies to facilitate the closure process and
      assist the faculty in transition are delineated.

PMID- 10410023
TI  - Problem-based learning. An outcomes study.
AB  - Problem-based learning (PBL) as a dynamic teaching methodology was detailed in
      the March/April 1998 issue of Nurse Educator. In this article, the second part,
      an outcomes study completed to evaluate PBL as a teaching methodology for
      registered nurse students is described. Two qualitative and two quantitative
      studies were conducted and are reported in this article. The results definitely
      support PBL as an effective teaching strategy for nursing educators.

PMID- 10410024
TI  - On-line interactive evaluation in course and clinical instruction.
AB  - Student evaluations incorporated into feedback for instruction modification are
      an important aspect of any educational program. It is particularly important for
      healthcare programs in which teaching processes are continually dynamic. An
      interactive evaluation was designed and implemented on-line for students.
      Confidentiality was assured and privacy protected through a unique coding system.
      Our experience with the interactive, automated system proved particularly
      successful with respondents and faculty expectations have improved since its
      integration into course and clinical objectives.

PMID- 10410025
TI  - Benchmarking hospital lengths of stay using histograms.
AB  - The authors demonstrated that length of stay histograms can provide considerably
      more benchmark information concerning hospital lengths of stay than numerical
      benchmarks. Examples of histograms described the complete distribution of
      hospital stays, as well as levels of outliers, rather than simple numerical
      averages. Gathering such data led to a clearer understanding of the significant
      LOS impact of certain DRG outliers in the two different hospitals in Syracuse,
      NY. Given that the other two communities represented, Seattle, Washington and San
      Diego, California, were more influenced by extensive managed care penetration,
      variations in histogram data were less in evidence there. Histograms were
      designed with bars to show LOS distributions at the 50th, 75th, and 90th
      percentiles for each of the above DRGs. The greatest variations could be shown
      when comparing the 1997 LOS data on the various DRGs at the two Syracuse
      hospitals. At both hospitals the presence of a large contingent of outliers (for
      different types of mostly medical patients) could be seen as the major factor in
      driving up their overall LOS.

PMID- 10410026
TI  - Perspectives of nursing executives regarding ethical-economic issues.
AB  - The authors grapple with the very real issue of how to allocate scarce health
      care resources while trying to hold down costs, especially in the face of
      changing federal and managed care reimbursement realities. Nurse executives (NEs)
      were surveyed in an attempt to discover their perspectives on a number of related
      ethical-economic issues. The NEs' responses to the entire "ethical-economic"
      survey were contrasted with answers offered to the same tool earlier by staff
      RNs. Among the questions raised was the impact of cost controls on staffing
      patterns. Not surprisingly, the staff nurses reported perceiving that budget cuts
      had a greater negative impact on staff positions and the quality of patient care
      than the nurse executives reported. Both groups were in favor of taxpayers
      covering a greater part of the cost of medically indigent care. When asked if
      they would be willing to pay higher taxes themselves, slightly less than half of
      the nurse executives answered in the affirmative while only 17% of the staff
      nurses indicated a similar willingness.

PMID- 10410027
TI  - Employing new grads: a plan for success.
AB  - The authors describe an elegant goal-driven program designed to prepare new
      nursing graduates to function optimally on a hospital unit by focusing first on
      their security and affiliative needs [belonging], and subsequently on their
      professional skill and knowledge acquisition. This developmental program has both
      a clear timeline and structure as well as well defined role expectations for the
      experienced RN guide/mentor, the orientee, and the unit's nurse manager and
      staff. The guide/mentors are carefully selected and prepared for their new roles
      as well. Shared goal-setting sessions are held weekly, along with three major
      evaluations during the first 90 days, with less frequent updates throughout the
      following year. This frequent feedback, reinforcement, and fine-tuning of goals
      allows the new graduate to gradually take on the full work load by the end of
      week 12 without feeling as overwhelmed or inadequate as those who are less
      carefully developed.

PMID- 10410029
TI  - New signposts and directions: indicators of quality in ambulatory nursing care.

PMID- 10410028
TI  - Direct observation nursing: adverse patient behaviors and functional outcomes.
AB  - The authors describe a study at a rehabilitation facility that was designed to
      enhance understanding of which patient behaviors and cognitive problems were
      predictive of the need for 1:1 or 1:2 full-time staff direct observation (DO).
      The costs associated with such 1:1 monitoring are substantial, having been
      estimated at $6,000 for a typical 3 week LOS, or $78,000 per year for each
      patient so monitored. Traumatic brain injury, stroke, and poor mental status had
      previously been associated with impulsivity, patient falls, and other adverse
      events, and thus such patients were frequently subjected to medical
      immobilization (restraints). Such immobilization has serious negative
      consequences for rehabilitation patients, so nursing assistants would frequently
      be assigned to stay with, observe, and redirect such patients around the clock.
      This study, which was designed to ascertain the significant differences between
      the patients who were placed on physician-ordered direct observation status when
      compared with those not needing DO, encompassed all patients admitted to a 36-bed
      rehabilitation unit between October 1995 and April 1996.

PMID- 10410030
TI  - Working effectively with an executive search consultant.
AB  - It is an exciting time for executives in health care. New opportunities are
      developing and the market-place is constantly changing. Executive search
      consultants can help lead you or your organization to success in the 21st
      century.

PMID- 10410031
TI  - On leadership from mechanical to integrated organizations: the leader's
      challenge.
AB  - The leader in a nursing organization, whether it is the nurse manager or the
      nurse executive, is only as good as the positive synergistic relations that are
      developed with all parts of the organization. The converse is also true that the
      leader of any part of the organization is only as good as the synergistic
      relations she/he develops with the nurses and direct caregivers. Synchronicity is
      the mark of an effective organization and the hallmark of integrated
      organizations.

PMID- 10410032
TI  - Valuing investments in clinical information systems.

PMID- 10410033
TI  - Have license, will travel.

PMID- 10410035
TI  - Management of hypothermias in adults.
AB  - Hypothermia has a high mortality. Mortality will depend on duration and depth of
      cooling. Matching rewarming to these variables may improve survival.

PMID- 10410034
TI  - Developing a culture for empowerment.

PMID- 10410036
TI  - Nursing care of a patient with fever due to sepsis/SIRS.
AB  - The pathophysiology of fever in sepsis/Systemic Inflammatory Response Syndrome
      (SIRS) is outlined. The three phases of fever are explored using a patient case
      study. The conclusion recommends further research is needed on the nursing
      management of critically ill patients with a fever.

PMID- 10410037
TI  - 'I feel a fraud': men and their experiences of acute admission following chest
      pain.
AB  - The meaning of acute chest pain to men and how their masculinity affects the way
      that men respond to the care provided have received little attention in nursing
      research or nursing literature. The data for this paper were collected through
      participant observation whilst clinically working with men who had been admitted
      with acute chest pain. This paper will present a key theme that emerged from this
      study, relating to the dissonance that the men experienced when the initial pain
      that brought them to the hospital was quickly removed leaving them no longer
      feeling 'ill'. This paper will also argue that there is a need to consider the
      theories on masculinity to help in interpreting the reactions of the male patient
      to their condition and also to help direct the care that is being provided.

PMID- 10410038
TI  - Men's experiences during the acute phase of their partners' myocardial
      infarction.
AB  - The men's narratives about the women reveal a disturbance in the balance of their
      daily life, showing how they, the men, perceive powerlessness, and also how they
      passively adapted themselves to what happened. The narratives reveal that the
      women are 'ignoring and withholding' their feelings and that they want to be as
      'responsible and independent' as they used to be. The women are disclosed as 'not
      wanting to face reality': there is an enervating lack of communication.

PMID- 10410039
TI  - The challenge facing critical care nurses in the UK: a personal perspective.
AB  - Wide-reaching professional, organisational and technological changes within
      healthcare have impacted on the role of the critical care nurse over the past
      decade. The major challenge to critical care nurses is to remain focused on
      providing quality care, optimistic about what can be achieved and realistic given
      the finite resources available. Suggestions as to how the future of critical care
      nursing may look are raised. Strategies to ensure that best practice and
      innovation continues within critical care are discussed, ensuring that patient
      and family needs remain a priority.

PMID- 10410040
TI  - Goings-on in a CCU: an ethnomethodological account of things that go on in a
      routine hand-over.
AB  - The transcripts of two hand-overs in a critical care unit are
      ethnomethodologically examined. Specimens of nurses' practices in accomplishing
      forms of social order are identified. The hand-overs show how nurses transfer all
      sorts of taken-for-granted scientific, technological, medical, nursing,
      psychological and sociological material. Doing routine work in nursing is shown
      to be accomplished, with relative ease, during the hand-over when what would
      otherwise be viewed as dramatic features, such as 'professional authority' and
      'telling about dying', are routinely managed by these nurses.

PMID- 10410042
TI  - Managing change--learning to steer, not row

PMID- 10410041
TI  - Supervising Swedish nursing research: conflicts experienced between medical and
      nursing research.
AB  - There still seems to be a limited understanding among practitioners of
      traditional quantitative medical research about the specific characteristics of
      different qualitative approaches which, due to the nature of the specific nursing
      care related problems studied, are often used in nursing research. It is of
      importance for all representatives of nursing and caring sciences to continue
      with ongoing efforts to establish a solid, widely accepted academic basis for
      clinical nursing research. Availability of adequate tutor and scientific
      supervisor competence is crucial for the progress of high-quality nursing
      research. The importance of the nursing and caring sciences in the successful
      development of evidence-based clinical practice is becoming widely acknowledged.
      Therefore, it is expected that in the future more and more responsible health
      care providers will realise the importance for the whole nursing care environment
      of encouraging such research.

PMID- 10410043
TI  - Necrotizing fasciitis: challenging management of a septic wound.
AB  - Bacteria are everywhere. Most are not pathogenic unless the right environment or
      quantity is present. A superficial infection in the medically compromised patient
      can provide a microenvironment conducive to precipitating wound sepsis, local,
      and systemic immune responses. Necrotizing fasciitis (NF) is a subtle yet bold
      infection that presents like cellulitis; however, beneath the surface of the
      integument, the ravaging products of cellular degradation are fulminant. Large
      dermal and subcutaneous involvement, creating significant tissue defects, require
      aggressive assessment and management by all members of the health care team.

PMID- 10410044
TI  - Pediatric leg length discrepancy: causes and treatments.
AB  - Leg length discrepancies have multiple causes with a number of treatment options
      available to accomplish a goal of equal or near equal leg lengths at skeletal
      maturity. The management of a deformity in the lower extremity can be a complex
      undertaking requiring the skill and expertise of a multidisciplinary health care
      team. The purpose of this article is to provide an overview of how a treatment
      plan is formulated after careful evaluation through ongoing assessment,
      diagnosis, treatment, and follow-up. The plan of care needs to fit the needs of
      the child and those of the family through realistic goal setting, ongoing
      teaching, and support.

PMID- 10410045
TI  - The Internet unraveled.
AB  - Although a fairly recent phenomenon in our culture, the Internet and its features
      have enjoyed a meteoric rise in use. E-mail, mailing lists, news groups, and
      forums provide Internet users the ability to network worldwide. The WWW, with its
      ease of use, has made accessing information easy, but has also created a need to
      learn to find and then to evaluate the information that is found. This article
      explores the above facets of the Internet and provides suggestions for using e
      mail, locating mailing lists, searching the WWW, and evaluating the information
      found there. A vocabulary list is provided to assist with unfamiliar terminology.
      Words in the vocabulary are in boldface type the first time they are used.

PMID- 10410046
TI  - NAONline. A valuable Internet resource for orthopaedic nurses.
AB  - NAONline is a valuable Internet resource for obtaining current information about
      topics related to orthopaedic nurses. NAONline provides up-to-date information
      about NAON, upcoming events and registration information, membership information,
      NAON products, continuing education offerings, the Orthopaedic Nursing journal,
      online continuing education offerings, and a forum to exchange information on
      practice topics. This article highlights various aspects of NAONline, how to
      access the site, and a brief discussion on how to connect to the Internet.

PMID- 10410047
TI  - Cooperation and collaboration for clinical nursing research. The Akron-Canton
      Clinical Nursing Research Network.
AB  - Nursing research suffers from an image of being an academic exercise even though
      it is essential for the growth and improvement of professional practice. With the
      current emphasis on redesign and cost containment, nurses need to come to the
      planning table with information and data to assist in decision making and to keep
      the nursing perspective in patient care. There are barriers to conducting nursing
      research, but a group approach, through a regional clinical nursing research
      network, provides the support and resources for an active research program.

PMID- 10410048
TI  - Discharge teaching. Work strategies of patients and families for care in the
      home.
AB  - PURPOSE: To better understand how care givers, and their care receivers who have
      experienced mobility limitations over a period of time, enhance the work of care
      in the home. DESIGN: The qualitative method of grounded theory was used to
      identify work strategies enacted by care dyads consisting of informal (family)
      care givers and their care receivers. SAMPLE: The sample consisted of 60 care
      dyads. METHOD: Data was collected via semi-structured interviews conducted in the
      care receiver's home. After leaving the home, interviewers completed end notes
      describing the care situation. MAIN RESEARCH CLASSIFICATION: Nursing Research,
      Orthopaedic Nursing, Home Health Nursing. FINDINGS: Content analysis revealed
      five interpersonal and informational work strategies, used by both care givers
      and care receivers, to facilitate the work of care: Sharing Ideas and Feelings,
      Delegating, Achieving a Common Goal, Identifying Sources of New Information, and
      Creative Problem Solving. End note data substantiated the benefits of using these
      strategies. CONCLUSION: Although providing care to a family member in the home is
      frequently thought of as "work," few analysts have described the nature of this
      work or considered the care receiver as a worker. This study identified the
      important role of the care receiver in the work of care in the home and
      delineated five specific Work Strategies used by informal care givers and their
      care receivers to facilitate such care. IMPLICATIONS FOR NURSING RESEARCH:
      Ongoing research is needed for further clarification of these strategies and for
      development of innovative ways to teach the strategies to informal care givers
      and their care receivers as they prepare to live with mobility limitations in the
      home setting.

PMID- 10410049
TI  - Cultural aspects of orthopaedic nursing.
AB  - In today's highly mobile and transnational healthcare world, attention to the
      cultural background of orthopaedic patients is no longer a luxury when
      implementing care. Nurses can overcome cultural blindness by developing an
      awareness of their own cultural backgrounds and an understanding about nursing
      values as an expression of cultural norms of the discipline. Developing cultural
      sensitivity without stereotyping patients is a challenge to the professionalism
      of the nurse. However, assessment and care of orthopaedic patients can be
      enhanced by attention to aspects of both the nurse's and the patient's cultural
      backgrounds. Such analysis can lead to some depth of understanding of the patient
      and a genuine desire of the nurse to interact with the patient.

PMID- 10410050
TI  - In search of a standard for pin site care.
AB  - To date, a standard for pin site care has yet to be identified. Pin site care
      recommendations are more often based upon clinician preference rather than
      research findings. Further, there are great variations in recommendations for pin
      care treatments from clinician to clinician. The nursing and medical literature
      were reviewed in an attempt to identify a pin site care standard based upon
      scientific findings. Unfortunately, the research on prophylactic treatment of pin
      sites is limited. The pin site care protocol recommended by this author is based
      on pathophysiologic processes involved in the development of pin site infections,
      as well as information found in the research literature. The recommended protocol
      includes the following: (a) using normal saline as the cleansing agent; (b)
      avoiding ointments for postcleansing care; (c) removing crusts; (d) using sterile
      technique for the hospitalized patient while clean technique is used once the
      patient is discharged from the hospital; (e) applying dressings to pin sites; and
      (f) providing pin care three times a day if drainage is present or once daily in
      the absence of drainage.

PMID- 10410051
TI  - The setup and care of a patient in Buck's traction.
AB  - Buck's traction is certainly one of the more common traction setups seen in
      orthopaedic patient care today. However, just because it is common doesn't mean
      we can take it for granted. Specific setup techniques as well as patient
      evaluation methods must be understood if the traction is to accomplish its task.
      The goal of this article is to go through some of the basics in techniques and
      perhaps explain why this traction is so commonly used.

PMID- 10410052
TI  - Incentives in research: ethical issues.
AB  - The participation of some subjects in research may be association with their
      receiving some compensation for their time and effort. Is the use of monetary or
      other nonmonetary incentives ethical? Do incentives make a study so enticing that
      it is difficult to resist being a participant? The authors discuss some relevant
      ethical questions that a researcher needs to address when providing stipends to
      study subjects. Additionally, there is a discussion of implications for nurses
      such as acquiring knowledge of research and ethics, creating an environment in
      which the patient's questions and any issues can be discussed, advocating for the
      patient who is being asked to participate, and the nurse's responsibilities when
      asked to help with recruitment efforts.

PMID- 10410053
TI  - Preparing the next generation of nurses.

PMID- 10410054
TI  - Transfer rule: boon or bane for rehabilitation providers?

PMID- 10410055
TI  - Implementing practice innovations to improve nurse-client relationships.

PMID- 10410056
TI  - An interdisciplinary approach to the rehabilitation of open-heart surgical
      patients.
AB  - Quite often nurses in environments other than the immediate postoperative setting
      are responsible for the well-being of patients who have had open-heart surgery
      (OHS). These patients may be admitted to rehabilitation or home healthcare
      settings as early as 1 week after surgery. They may be deconditioned because of
      postoperative complications such as a cerebrovascular accident or cardiopulmonary
      compromise. Rehabilitation nurses in inpatient or home health environments are
      key members of the interdisciplinary team in terms of establishing standards of
      care for OHS patients after surgery. Coordinating care within an
      interdisciplinary team reduces fragmentation of care, improves patient outcomes,
      and enhances patient, family, staff, and physician satisfaction. This article
      focuses on empowering rehabilitation nurses as leaders and members of
      interdisciplinary teams as they establish standards for coordinating the
      postoperative care of OHS patients.

PMID- 10410057
TI  - A decentralized admission screening protocol for a geriatric rehabilitation
      program: does it make a difference?
AB  - The purpose of this retrospective evaluation study was to compare outcomes
      related to two distinct processes for screening people referred for admission to
      a geriatric rehabilitation program at a chronic care hospital in southern
      Ontario. Data were collected through chart review and focus group methods. The
      results were unexpected in that the projected outcomes associated with the newer
      referral screening process did not materialize. For both referral screening
      processes, findings are discussed in terms of the percentage of achieved patient
      rehabilitation goals. The average lengths of patient stay associated with both
      screening processes were also compared. No statistically significant differences
      between the two processes were found in terms of either the percentage of goals
      achieved or the length of patient stay. Focus group sessions were held to elicit
      team members' perceptions of the effectiveness of each of the referral processes.
      Participants in the focus groups were supportive of the newer referral screening
      and admission process although the evidence gathered from the chart review did
      not demonstrate improvements in patients' length of stay or an increase in the
      percentage of rehabilitation goals achieved.

PMID- 10410058
TI  - Music therapy as a treatment method for improving respiratory muscle strength in
      patients with advanced multiple sclerosis: a pilot study.
AB  - Respiratory muscle weakness, predominantly of the expiratory muscles, is
      characteristic of individuals with advanced multiple sclerosis and can result in
      difficulty in clearing secretions and repeated episodes of pneumonia. This pilot
      study evaluated the effectiveness of music therapy in strengthening respiratory
      muscles through an emphasis on diaphragmatic breathing and coordination of breath
      and speech. Twenty patients were randomly assigned to one of two groups: one that
      received music therapy or one that attended music appreciation sessions.
      Participants' inspiratory and expiratory muscle strength was measured by testing
      mouth pressure before and after the intervention. The experimental group showed
      some improvement in terms of expiratory muscle strength, in contrast to the
      control group, which showed deterioration. The results were not statistically
      significant, however. Patients in both groups exhibited considerable weakness in
      their expiratory muscles, and results for 79% of the participants were below 30%
      of the predicted values. Variability, a major confounding factor that resulted in
      reduced statistical power, led the investigators to suggest an intercenter
      collaboration to amass sufficient numbers of patients for a future study. Early
      manifestation of respiratory muscle weakness warrants inclusion of respiratory
      muscle testing in examination protocols and early intervention efforts.

PMID- 10410060
TI  - [Welcome at Val de Brenne].

PMID- 10410059
TI  - Poststroke dysphagia: implications for nurses.
AB  - It is important for nurses to increase their understanding of poststroke
      dysphagia because nurses are often the first to observe the signs and symptoms of
      dysphagia. An increased awareness of dysphagia and its complications should help
      prepare nurses to assess high-risk clients, advocate for prompt diagnosis, use
      compensatory interventions, and educate clients and their family members.
      Dysphagia is common after clients have had a stroke, and it places them at risk
      for numerous complications. Prompt assessment and intervention are required and
      may decrease clients' problems. This article presents an overview of the normal
      swallowing reflex to facilitate readers' understanding of dysphagia and discusses
      the assessment, diagnosis, and treatment of dysphagia as well as related nursing
      implications. An individualized plan of care for a dysphagic client requires
      input from the entire interdisciplinary team, and nurses must ensure adherence to
      this plan on a 24-hour-per-day basis.

PMID- 10410061
TI  - [Social emergency services: the number 115].

PMID- 10410062
TI  - [Caring for cases of digestive system cancer treated by combined radiotherapy and
      chemotherapy].

PMID- 10410063
TI  - [Pain (continued)].

PMID- 10410064
TI  - [The use of morphines for children].

PMID- 10410065
TI  - [Treating pain at home].

PMID- 10410066
TI  - [Suffering and abortion].

PMID- 10410067
TI  - [The campaign to fight pain 1998-2000: principal measures].

PMID- 10410069
TI  - [Pain: basic facts].

PMID- 10410068
TI  - [Relieving pain is divine].

PMID- 10410070
TI  - [Nursing care: its application in atopic dermatitis].

PMID- 10410071
TI  - [Topical corticoids for children: how to prescribe?].

PMID- 10410072
TI  - [Antifungal mouthwashes: protocol for care].

PMID- 10410073
TI  - [Home hospitalization: the bed].

PMID- 10410074
TI  - [Nursing schools face their future].

PMID- 10410075
TI  - [In the course of events...] [In Process Citation]

PMID- 10410076
TI  - [Establishing oneself as a private duty nurse in a department].

PMID- 10410077
TI  - [Research and development. A challenge and an asset for nursing].

PMID- 10410078
TI  - [Nursing research: which methods?].

PMID- 10410079
TI  - [Research education for nurses].

PMID- 10410080
TI  - [An example of the formation of knowledge in nursing].

PMID- 10410081
TI  - [Radiation and people].

PMID- 10410082
TI  - [Self-evaluation of nursing practices].

PMID- 10410083
TI  - [What type of research in nursing?].

PMID- 10410084
TI  - [The researcher in a tight space: between patients and nursing personnel].

PMID- 10410085
TI  - [Relaxation at the Institute of Nursing Care Education].

PMID- 10410086
TI  - [Continuing education in schools for nurse-anesthesists].

PMID- 10410087
TI  - [A booklet of possibilities. A tool for the prevention of professional exhaustion
      among nurses].

PMID- 10410089
TI  - [Association and democracy] [In Process Citation]

PMID- 10410088
TI  - [Education of students. What reciprocity for them?].

PMID- 10410090
TI  - [Promoting the importance of our profession all over Europe].

PMID- 10410091
TI  - [A nurse takes the initiative at a health center].

PMID- 10410092
TI  - [Four projects waiting for the ministerial green light] [In Process Citation]

PMID- 10410093
TI  - [Priviledged or survivor?].

PMID- 10410094
TI  - [Organization and execution of transportation for the newborn].

PMID- 10410095
TI  - [The safety of childbirth and the obstetrical-pediatric network].

PMID- 10410096
TI  - [The perinatal network. Experiences from the Bourgogne region].

PMID- 10410098
TI  - [Pediatric patient transports].

PMID- 10410097
TI  - [From one transfer to the next].

PMID- 10410099
TI  - [Handwashing in neonatology].

PMID- 10410100
TI  - [Child abuse. The parents in question ... psychological considerations].

PMID- 10410101
TI  - [The "light eaters"].

PMID- 10410102
TI  - [Accreditation follows dynamic changes. Interview by Marie Hetier].

PMID- 10410103
TI  - [A corner of France...]

PMID- 10410104
TI  - [Stoma therapist, an accomplishment of the art of nursing. Interview by
      Bernadette Fabregas].

PMID- 10410105
TI  - [Who are the enterostomal therapists?].

PMID- 10410107
TI  - [Care of ostomies and specific devices].

PMID- 10410106
TI  - [Who are the patients with ostomies?].

PMID- 10410108
TI  - [Psychology. Towards the restitution of the stoma patient's autonomy].

PMID- 10410109
TI  - [An activity not well known among private duty nurses].

PMID- 10410110
TI  - [Improve our investment in our field of competence].

PMID- 10410111
TI  - [Professional activity. Legal protection of nurses].

PMID- 10410112
TI  - [Psychosomatics, a very special discipline].

PMID- 10410113
TI  - [20 years of support for private practice nurses].

PMID- 10410114
TI  - [School nurses are angry. Interview by Anne Boiteux].

PMID- 10410115
TI  - [Nursing activities in mental health and psychiatry].

PMID- 10410116
TI  - [Education and its demands in psychiatry, a necessary adaptation] [In Process
      Citation]

PMID- 10410117
TI  - [The hospital in search of hospitality].

PMID- 10410118
TI  - Turf battles.

PMID- 10410119
TI  - They just don't get it.

PMID- 10410120
TI  - Floating faux pas. Is there such a thing as 'only giving meds'?

PMID- 10410121
TI  - Medication compliance.

PMID- 10410122
TI  - Herbs' benefits and risks.

PMID- 10410123
TI  - Shake, rattle, or roll?

PMID- 10410124
TI  - Shake, rattle, or roll?

PMID- 10410125
TI  - An internship in Ireland.

PMID- 10410126
TI  - JCAHO on assessing and managing pain.

PMID- 10410127
TI  - We are diminished by one. Just one nurse, with a remarkable dedication.

PMID- 10410128
TI  - A telehealth odyssey.

PMID- 10410129
TI  - Cancer-related spinal cord compression.

PMID- 10410130
TI  - Are you ready for nursing in a developing country?

PMID- 10410131
TI  - Emergency! Ectopic pregnancy.

PMID- 10410132
TI  - MIDCAB. Minimally invasive direct coronary artery bypass.

PMID- 10410133
TI  - Assessing the male genitalia.

PMID- 10410134
TI  - Port Access. Another advance in cardiovascular surgery.

PMID- 10410135
TI  - Nursing supply and demand.

PMID- 10410136
TI  - PTMR. Percutaneous transmyocardial revascularization.

PMID- 10410137
TI  - Working with relapse.

PMID- 10410138
TI  - Is the air in your hospital making you sick?

PMID- 10410139
TI  - Nursing the patient within.

PMID- 10410140
TI  - [Familial cancer: recent advances].
AB  - Familial cancers associated with genetic background are of the most intensively
      investigated diseases in recent years. The phenotype is apparent with most of
      these diseases and can easily be traced through family history. Induction in
      familial cancer appears, on current evidence, to be not different from that
      observed in sporadic cancer. The first suppressor gene Rb gene was cloned from
      retinoblastoma. There are two representative hereditary colorectal cancers:
      familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal
      cancer (HNPCC). The gene responsible for FAP (APC gene) was cloned in 1991. The
      APC gene is a negative regulator of beta-catenin and is considered to play the
      role of gatekeeper in the adenoma carcinoma sequence. Thereafter a group of
      genes, human homologues of mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2,
      hMSH6), have been identified as the genes responsible for HNPCC. These are called
      care taker genes, which serve to maintain genetic stability. Therefore, if one of
      those genes undergoes mutation, the rate of mutation increases significantly. It
      has only been in the last 20 years that familial cancer has become an important
      issue. In association with such advances, predictive testing can now be performed
      on at risk persons. Persons at risk can thus be accurately counseled and screened
      for early detection of disease.

PMID- 10410141
TI  - [Current status of nuclear medicine in Japan].
AB  - Radionuclides have been used for the diagnosis and therapy of cancers. In Japan,
      about 1.8 million studies are performed annually, especially on bone, the heart,
      the brain and cancer. In contrast to anatomical studies with X-ray, US or CT,
      nuclear medicine provides physiological or metabolic images. The characteristics
      of nuclear medicine come from the use of tracer studies employing various
      radiopharmaceuticals. The most commonly used radionuclides for cancer studies are
      67Ga and 201T1. Recently, however, many other radiopharmaceuticals with tumor
      specificity have been developed, such as 99mTc labeled monoclonal antibodies and
      111In labeled octreotide. 18F-FDG, which images glucose metabolism, is very
      useful in the management of lung, colorectal and other cancers. Furthermore,
      radionuclides are also employed in the therapy of cancer, such 131I-labeled anti
      CD20 antibody for the B-cell lymphoma and 89Sr for the palliation of bone pain
      caused by prostate and breast cancer metastases.

PMID- 10410142
TI  - [Tumor imaging using 201Tl chloride and 67Ga citrate in nucleomedical surveys].
AB  - Among nucleomedical examinations for cancer, tumor imaging using 201Tl chloride
      and 67Ga citrate can be easily performed at almost any hospital. However, the
      planar images usually obtained are not sufficient to detect small tumorous
      lesions. For more accurate detection, tomographic images particularly single
      photon emission CT (SPECT) is necessary. SPECT is also indispensable in cancer
      diagnosis. Whether 201Tl SPECT or 67Ga SPECT is chosen depends upon tumor
      localization, histological type, and the final purpose of the study. 201Tl
      accumulates in almost all tumors, but it is not suitable for detection of
      abdominal lesions, because there is much physiological accumulation in the small
      intestine and kidney. In contrast, 67Ga does not always accumulate in
      adenocarcinomas. 201Tl SPECT and 67Ga SPECT are more useful in the functional
      imaging of cancer than is morphological tumor diagnosis. Both methods are useful
      in monitoring treatment effectiveness, detecting recurrent lesions after surgery
      and radiotherapy, and predicting the grade of malignancy of the tumor. Tumor
      SPECT using 201Tl chloride and/or 67Ga citrate provides clinically useful
      information not obtained by morphological tumor diagnosis only.

PMID- 10410143
TI  - [PET evaluation of glucose metabolism in cancer].
AB  - Accelerated glycolysis is one of the biochemical characteristics of cancer cells.
      Based on this fact, positron emission tomography (PET) with 18F
      fluorodeoxyglucose (FDG) has been used in the diagnosis of various cancers. After
      intravenous injection of FDG and PET scans, most cancers are identified by high
      FDG accumulation. This metabolic tumor imaging method has been used successfully
      in the differentiation of benign and malignant tumors, in the diagnosis of
      metastasis or recurrence, in the detection of primary unknown cancers, and in
      cancer screening. Because the degree of FDG accumulation reflects tumor glucose
      consumption, quantification of FDG uptake by PET can be used in predicting
      biological malignancy and in monitoring treatment in both radiation and
      chemotherapy. The potential utility of Glut-1 and hexokinase, reported to be
      responsible for increased glucose metabolism, as biological markers of cancers is
      yet to be determined.

PMID- 10410144
TI  - [Immunoscintigraphy and radioimmunotherapy of cancer using monoclonal
      antibodies].
AB  - Technologies using radiolabeled antibodies have advanced significantly over the
      past decade, although radioimmunotherapy still requires improvements. This paper
      describes the implications of nuclear medicine in the management of cancer in
      terms of detection, staging, and qualification of patients for immunotherapy. The
      results of a clinical trial performed at our institution using 99mTc-labeled anti
      CEA monoclonal antibody are briefly reviewed. Immunoscintigraphy has shown
      particular promise as a means of whole body imaging in patients with colorectal,
      breast, or lung cancer, and the antibodies used for diagnostic imaging are now
      being used for radioimmunotherapy. Radioimmunotherapy of B-cell lymphoma has been
      successfully performed using 131I or 90Y labeled anti-lymphocyte monoclonal
      antibodies, although the treatment of solid tumors is still a major difficulty.
      Elimination of the immune response by generating humanized monoclonal antibodies,
      which are virtually devoid of immunogenicity, is necessary to allow repeated
      administration. This is especially true of patients with solid tumors as compared
      with patients with hematopoietic ones.

PMID- 10410145
TI  - [Internal radiation therapy for malignant neoplasm].
AB  - Internal radiation therapy selectively targets beta- or alpha-emitting
      radionuclides to the area of the tumor tissue, and is therefore capable of
      treating disease regardless of the location and number of foci. The biological
      effect of internal radiation therapy is thought to be different from that of
      conventional external beam radiation. Thyroid cancer: The local recurrence and
      metastatic lesions from differentiated thyroid cancers can be controlled with
      131I administration. Even though the patient does not have macroscopic disease,
      131I is also utilized for thyroid remnant ablation in locally advanced cases.
      Recently, the maximum tolerable dose can be calculated based on the dosimetry of
      each patient, and safely administered. The therapeutic effect of this method is
      superior to the fixed dose method. 131I-MIBG: 131I-MIBG is taken up by
      sympathetic neurons as well as a group of tumors originating in the neural crest,
      especially phecromocytomas and neuroblastomas. The various symptoms caused by the
      hypersecretions of hormone-producing tumors can be improved. Pain palliation of
      bone metastases: Pain palliation using 89Sr is a very promising option in
      treating patients with painful bone metastases. The pain palliation mechanism of
      89Sr is different from other drugs; therefore, complimentary usage is reasonable.
      The symptomatical improvement can last for several months, thus helping to
      maintain the quality of life of the patient.

PMID- 10410146
TI  - [Effects of DAC (doxifluridine, adriamycin, cyclophosphamide) chemotherapy in
      advanced breast cancer patients].
AB  - Effects of DAC (doxifluridine (5'-DFUR), adriamycin (ADM), cyclophosphamide
      (CPA)) chemotherapy were evaluated in seven patients with advanced breast cancer.
      5'-DFUR of 600 mg was orally daily, ADM of 40 mg/m2 was administered
      intravenously (bolus) at day 1 and CPA of 400 mg/m2 was administered
      intravenously (one shot) at day 1 and day 8. These were repeated as one cycle of
      21 days. Two complete responses, three partial responses and two progressive
      diseases were obtained, and the response rate was 71% (95% confidence interval:
      29-96%). The side-effects of more than grade 3 were observed in leucocytopenia
      (4/7), neutrocytopenia (6/7), anorexia (2/7), nausea or vomiting (2/7) and
      alopecia (6/7). These results suggest that DAC chemotherapy is a novel,
      attractive regimen for treatment of advanced breast cancer. The randomized
      clinical trial is required to elucidate the efficacy of 5-fluorouracil (5-FU) or
      its analogues and the significance of methods for their administration in
      management of patients with advanced breast cancer.

PMID- 10410147
TI  - [Docetaxel therapy against anthracycline resistant breast cancer].
AB  - To evaluate the efficacy of docetaxel therapy against anthracycline-resistant
      breast cancer, twenty patients were treated with docetaxel. Of the 20 patients
      pretreated with anthracycline, 17 were clinically anthracycline-resistant and the
      remaining three were refractory to anthracycline on histoculture drug response
      assay. Nine patients had loco-regional recurrence and 11 had distant +/- loco
      regional recurrence. Docetaxel (49-60 mg/m2) was administered every 4 weeks, and
      was infused 1-13 times (median; 3 times). Of the 19 evaluable patients, eight
      (42%) showed partial response with the docetaxel therapy. Durations of the
      response ranged from 1 to 8 months (median; 4 months). Major adverse effects of
      the therapy were alopecia, neutropenia, and leucocytopenia. Hypersensitivity
      reaction was observed in one case. In addition, severe adverse effects such as
      grade 2 pneumonia and grade 4 diarrhea were found in one patient each. In
      conclusion, although the adverse effects are not negligible, docetaxel therapy is
      effective against anthracycline-resistant breast cancer.

PMID- 10410148
TI  - [Combination effect of hyperthermia and MX2 on cultured glioma cell lines].
AB  - MX2, a new lipophilic morpholino anthracycline, has been reported to have
      chemotherapeutic effects superior to those of adriamycin against murine and human
      glioma cells in vitro and in vivo. To assess the combination effect of MX2 and
      hyperthermia in vitro, the thermo-chemosensitivities of cultured human (U251MG
      and KC) and rat (C6 and 9L) glioma cell lines were examined by 3-(4,5
      dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The number of
      viable cells in each cell line was markedly and dose-dependently decreased by MX2
      treatment, but the sensitivity of U251MG to MX2 was less than that of the other
      cell lines. The survival of each cell line was decreased with the hyperthermic
      treatment at 43 degrees C for 60 minutes. Combined treatment with MX2 and
      hyperthermia had an additive effect on cultured glioma cells when MX2 was added
      to the medium at a dose below 50 ng/ml. However, combined treatment indicated
      neither an additive nor a synergistic effect when the dose of MX2 was above 50
      ng/ml. We conclude that MX2 may be clinically useful against malignant gliomas
      when administered alone or in combination with hyperthermia.

PMID- 10410149
TI  - [How should we treat elderly patients with small cell lung cancer?--information
      gathered by questionnaires and analysis of 351 patients aged 70 or over. West
      Japan Thoracic Oncology Group].
AB  - The incidence of elderly patients with small cell lung cancer is increasing in
      Japan. Because of the variation in their physical function and increasing co
      morbid disease, elderly patients are usually excluded from clinical trials.
      Questionnaires were sent to 40 institutes of the "West Japan Thoracic Oncology
      Group", and answers from 33 (83%) institutes were obtained. Eighty-five percent
      of replies recognized the need of trials for limited disease (LD) and 70% for
      extensive disease (ED). We investigated the methods of staging procedures, and
      management of 351 small cell lung cancer patients aged 70 years or older
      diagnosed from 1994 to 1996 in 28 institutes. There were 173 patients aged 70-74,
      120 aged 75-80, and 58 aged 80 years or older. Staging procedures including chest
      CT, abdominal CT, abdominal CT or Echo. Brain CT or MRI and bone scinti scan were
      performed in 333 (95%) patients. One hundred fifty-nine of 178 patients with LD
      and 143 of 168 patients with ED received anticancer therapy. Although 48% of PS 0
      1 patients received 4 courses or more of chemotherapy, among the patients with ED
      24% of patients with PS 2 and 19% of PS 3 patients received adequate
      chemotherapy. The response rate was 79% for LD and 69% for ED. Many elderly
      patients received insufficient courses and/or doses of chemotherapy but achieved
      a good response. Median survival for patients with LD and ED was 12 and 6 months,
      respectively. To determine suitable regimens for elderly patients with lung
      cancer, more clinical trials are definitely needed.

PMID- 10410151
TI  - [Anti-emetic treatment for patients with non-small cell lung cancer after
      chemotherapy, usefulness of preventive combination of anti-emetic agents and
      importance of psychiatric aspect of patients].
AB  - Preventive combined administration of granisetron 3 mg, methylprednisolone 500
      mg, and metoclopramide 40 mg decreased the post-chemotherapy emesis from 56% in
      68 control cases to 16% in 31 administered cases. All cases had non-small cell
      lung cancer and were treated with cisplatin 80 mg/m2, vindesine 3 mg/m2, and
      mitomycin C 8 mg/m2. YG character test in 23 cases revealed that emotional
      unstableness, characterized by the coupled rightward shift of the N (nervous) and
      I (inferior complex) components, was the important cause of emesis in those
      patients who failed to respond to the anti-emetic drugs shown above. Anti-emetic
      agents with different mechanisms and psychiatric counseling are needed in these
      emotionally unstable patients.

PMID- 10410150
TI  - [Period of time patients with advanced non-small cell lung cancer could remain at
      home during CIC--therapy (cisplatin + ifosfamide + CPT-11)].
AB  - Two phase I studies (CIC-therapy) were conducted in advanced non-small cell lung
      cancer (NSCLC) to determine the maximum tolerable dose (MTD) of CPT-11 combined
      with cisplatin and ifosfamide, and MTD of cisplatin combined with CPT-11 and
      ifosfamide with G-CSF support, respectively. Both regimens were repeated every 4
      weeks. G-CSF was administered on days 5 to 18. Eighty-eight patients were
      registered in both studies. The overall response rate was 59.1%, and the median
      survival time was 393 days. In all patients enrolled, we examined retrospectively
      the period of time they could remain at home during chemotherapy. We examined
      this period divided into day 1-18 and day 18-28 until the third course. Although
      myelotoxicity occurring during the third course was the most severe, the mean
      time was 7.1 days (day 1-18 2.2, day 18-28 4.9) for the first course, 10.1 days
      (day 1-18 4.0, day 18-28 6.0) for the second course, and 11.0 days (day 1-18 4.7,
      day 18-28 6.3) for the third course. Only two patients came to the hospital
      because of acute upper respiratory tract infection. Although CIC-therapy was an
      aggressive chemotherapy with G-CSF support, most of the patients were able to
      stay at home during chemotherapy.

PMID- 10410153
TI  - [Giant metastatic neck tumor responding to oral administration of UFT--a case
      report].
AB  - A 63-(correction of 65) year old female with giant neck tumor was admitted to our
      hospital. The pathological diagnosis was metastatic neck carcinoma of unknown
      origin. General and local examinations could not clarify the origin of her neck
      tumor. Computed tomography was performed, and her tumor was diagnosed as
      unresectable. She was treated by oral administration of UFT (400 mg/day). About
      four months later, her neck tumor showed a shrinking tendency and the clinical
      symptoms were improved. This case shows a remarkable response to the oral
      administration of UFT even in a case of terminal neck cancer.

PMID- 10410152
TI  - [Efficacy of combination with granisetron and methylprednisolone for nausea,
      vomiting and appetite loss in remission induction chemotherapy of acute myeloid
      leukemia--a randomized comparative trial between granisetron alone and
      granisetron plus methylprednisolone].
AB  - The prevention of nausea, vomiting and appetite loss induced by remission
      induction chemotherapy for acute myeloid leukemia was compared by randomization
      between granisetron alone and combination with granisetron plus
      methylprednisolone. Granisetron was administered at 40 micrograms/kg during
      chemotherapy, and methylprednisolone was administered concomitantly at 125
      mg/body for 3 days or more in the combination group. The single and combination
      groups comprised 14 and 13 patients, respectively, and there was no significant
      difference between the background of both groups. To evaluate the effect they
      were scored according to 4 grades, and evaluated every 24 hours from the start of
      chemotherapy to 5 days after its completion. The complete inhibition rate of
      vomiting was as high as 71.4% and 92.3% in the single and combination groups,
      respectively, showing no significant difference. The grade of vomiting was mild
      in both groups. Nausea was noted in 71.4% and 46.2%, respectively, and the
      inhibitory effect tended to be higher in the combination group. Appetite loss
      developed in 92.9% and 41.7%, respectively, and the prevention effect was clearly
      higher in the combination group. The prevention effects on nausea 7, 8 and 10
      days after the start of chemotherapy, on appetite loss 2-10 days after it, and 2
      5 days after its completion, were higher in the combination group. Granisetron
      revealed an excellent inhibitory effect on vomiting induced by remission
      induction chemotherapy for acute myeloid leukemia, but combination with
      granisetron and methylprednisolone was considered useful for nausea in the latter
      half of the treatment period and for appetite loss during the whole period.

PMID- 10410154
TI  - [A case of lung cancer with hypercalcemia and renal failure responsive to
      pamidronate].
AB  - A 46-year-old man was diagnosed as Stage IV lung cancer with neck lymph node and
      bilateral adrenal metastases. He was treated with seven courses of combined
      chemotherapy (CDDP + etoposide), until he showed extreme hypercalcemia and acute
      renal failure. The bisphosphonate, pamidronate with elcatonin and prednisolone
      dramatically lowered his serum calcium level and normalized his renal function.
      This is a representative case of humoral hypercalcemia of malignancy whose serum
      calcium could be safely and effectively controlled with pamidronate.

PMID- 10410155
TI  - [A case of gastric carcinoma treated effectively with 5'-DFUR].
AB  - A 79-year-old male was admitted to our hospital for further examination on
      gastric carcinoma (1' type) in the cardia. The histology of biopsied tissue was
      moderately differentiated adenocarcinoma (tub2). The patient refused a
      gastrectomy and received three cycles of local injection therapy with OK-432 +
      Beriplast into the tumor. However, the tumor showed no decrease in size.
      Considering the quality of life, the patient was given out patient treatment with
      5'-DFUR (Furtulon, 800 mg/day). Three months later, the patient showed a partial
      response (PR) on the basis of gastric X-ray and endoscopic findings. No adverse
      reactions to the drug were seen. The patient has been receiving the same drug
      since then, and has continued to show PR for 15 months. Biopsied tissues were
      checked immunohistochemically for expression of thymidine phosphorylase
      (TdRPase), and changes in tissue TdRPase level were examined by ELISA. The
      TdRPase level decreased with shrinking of the tumor. These results suggest that
      the shrinking of tumor following 5'-DFUR therapy is closely related to TdRPase.

PMID- 10410156
TI  - [Cases of refractory testicular cancer treated with all trans-retinoic acid].
AB  - We reported two cases of chemotherapy-refractory testicular cancer treated with
      all trans-retinoic acid (ATRA). Case 1. A 21-year-old male patient underwent
      salvage surgery for lung metastasis which had developed after treatment with
      three different cisplatin-based chemotherapy regimens for malignant teratoma.
      After recovery from surgery, he was treated with oral ATRA at daily dose 80 mg/m2
      for four weeks. Case 2. A-45-year-old patient suffered from lung metastasis after
      orchiectomy for teratocarcinoma. The patient failed to achieve a complete
      response despite two different cisplatin-based chemotherapy and high dose
      chemotherapy regimens with bone marrow rescue. He was treated with oral ATRA for
      five weeks. Both patients showed disease progression with increase in tumor size
      and elevation of tumor marker during ATRA therapy. Side effects were acceptable
      except the headache in Case 2, who needed a dose reduction of ATRA. In
      conclusion, oral ATRA with this dose failed to show clinical antitumor activity
      in patients with refractory testicular cancer.

PMID- 10410158
TI  - [Tumor metastases and adhesion molecules carbohydrates and lectins].
AB  - The expression of carbohydrate antigens has been shown by retrospective
      immunohistochemical analysis to correlate to the progression and metastases of
      human cancers. However, the mechanisms of these changes of carbohydrate
      expression and the role of carbohydrates in the malignant behavior of tumor cells
      are not well known. In this article, we introduce methods to experimentally
      modify carbohydrate expression in tumor cells and to assess the involvement of
      these carbohydrate antigens in the malignant behavior of tumor cells.
      Modifications of the biosynthesis of O- and N-linked carbohydrates, and
      glycolipids are achieved by treating cultured tumor cells with culture media
      containing Benzyl-alpha-GalNAc, swainsonine, or D-PDMP, respectively. Enzymatic
      digestion of cell surface carbohydrates with sialidase, endo-beta-galactosidase
      or other glycosidases can also be performed. These cells can be used for short
      term experiments such as adhesion assays. However, modified carbohydrates may be
      recovered during in vitro and in vivo assays. By transfection of
      glycosyltransferase cDNA, or selection of tumor cells by binding lectins or
      antibodies, stable carbohydrate variant cells can be obtained which are suitable
      for long term experiments such as the experimental formation of metastases in
      vivo. The biological function of tumor cell surface carbohydrates may be diverse.
      These molecules are thought to influence adhesion interaction between tumor cells
      and the endothelial cells of target organs. However, carbohydrate recognition
      molecules, or lectins, are expressed on a variety of cells in the vascular system
      and in the immune system. Therefore, it is essential to design appropriate
      experimental models to study the biological significance of carbohydrate-lectin
      interactions in cancer progression and metastatic dissemination. Adhesion assays
      of tumor cells to selectin-transfected CHO cells were performed. Taking molecules
      other than selectins into consideration, adhesion assays using frozen tissue
      sections were also performed.

PMID- 10410157
TI  - [Trial of combined radiotherapy and chemotherapy (CBDCA) for post-operative non
      small cell lung cancer (N2)].

PMID- 10410159
TI  - Using choice-based conjoint to determine the relative importance of dental
      benefit plan attributes.
AB  - The purpose of this study was to use conjoint analysis to determine the
      importance of specific dental benefit plan features for University of Iowa (UI)
      staff and to build a model to predict enrollment. From a random sample of 2000 UI
      staff, 40 percent responded (N = 773). The survey instrument was developed using
      seven attributes (five dental benefit plan features and two facility
      characteristics) each offered at three levels (e.g., premium = $20, $15,
      $10/month). Pilot testing was used to find a realistic range of plan options.
      Twenty-seven hypothetical dental benefit plans were developed using fractional
      factorial combinations of the three levels for each of the seven attributes. For
      all of the hypothetical plans, dental care was to be provided in the UI
      predoctoral dental clinic. Plan profiles were arranged four per page by combining
      the existing plan with three hypothetical plans, for a total of nine pages.
      Respondents' task was to select one plan from each set of four. A regression-like
      statistical model (Multinomial Logit) was used to estimate importance of each
      attribute and each attribute level. Relative importance (and coefficients) for
      each of the seven attributes are as follows: maximum annual benefit (.98),
      orthodontic coverage (.72), routine restorative (.70), major restorative (.67),
      time to complete treatment (.61), clinic hours of operation (.47), premium (.18).
      For each attribute, relative importance of each of three levels will also be
      presented. These coefficients for each level are used to predict enrollment for
      plans with specific combinations of the dental benefit plan features.

PMID- 10410160
TI  - Acquisition of a touching style.
AB  - A qualitative study investigated dental student perceptions of learning to use
      touch in dental treatment. A focus group design was used to allow volunteer
      participants (students, general dentistry residents, and dental faculty; n = 41)
      to discuss issues related to this question. Each focus group was audiotaped for
      accuracy and transcribed by an independent person. Data gathered were textually
      and thematically analyzed around the specific questions asked. The data indicated
      that learning to touch dental patients was often trial and error and
      uncomfortable for these students. Further, the data suggested that a fine line
      exists preventing students from asking for assistance and faculty in offering
      assistance.

PMID- 10410161
TI  - Student productivity under requirement and comprehensive care systems.
AB  - This retrospective study reviews the educational and patient care effects of
      changing from a numerical requirements-driven clinical curriculum to aa
      comprehensive care model driven by patient needs and led by faculty group
      leaders. In September 1994, the Columbia University School of Dental and Oral
      Surgery implemented a program in which all patient care shifted to a patient care
      completion model. Core assumptions included creating an educational setting where
      students were assigned to groups with continuously assigned faculty as group
      leaders, with intensive case discussion and monitoring of students' progress. All
      patient care took lace under the direction of the group leaders with involvement
      of other attending interdisciplinary faculty and auxiliary staff. Data suggest
      that, over the period of this study (1994-97), a significant increase occurred in
      the number of treatment plans completed by students with no compromise in the
      number of specific procedures completed by individual students. We concluded that
      a carefully structured and monitored comprehensive care/group leader-driven model
      is beneficial for both student education and patient care.

PMID- 10410162
TI  - The effect of an extramural education program on the perceived clinical
      competence of dental hygiene students.
AB  - The purpose of this study is to evaluate the effect of an extramural rotation on
      dental hygiene student self-perceptions of competence in specific clinical areas.
      Dental hygiene students attending one midwestern university from 1992 through
      1998 rated their perceived level of competence on nineteen dimensions of dental
      hygiene practice prior to beginning a four-week extramural rotation and again at
      the completion of the rotation. Results indicated that student perceptions of
      competence improved significantly on six of the nineteen dimensions in each of
      the study years. Study results suggest that an extramural rotation is a valuable
      component of a dental hygiene curriculum to enhance student self-perceptions of
      clinical competence.

PMID- 10410164
TI  - Accuracy of MR imaging in the work-up of suspicious breast lesions: a diagnostic
      meta-analysis.
AB  - RATIONALE AND OBJECTIVES: The authors performed a systematic, critical review of
      the literature on magnetic resonance (MR) imaging for primary breast cancer
      detection in patients with suspicious breast lesions, analyzed MR test
      performance in the articles meeting study criteria, and used this information to
      examine the cost-effectiveness of preoperative MR imaging. MATERIALS AND METHODS:
      A structured, predefined MEDLINE search was conducted to identify potentially
      relevant, peer-reviewed, English-language references from January 1996 through
      August 1997 on the diagnostic accuracy of breast MR imaging. This information was
      supplemented by manually searching bibliographies of the retrieved articles for
      additional potentially relevant references. All studies were independently
      abstracted by two reviewers using a prospectively designed worksheet. Abstraction
      results were analyzed with the summary receiver operating characteristic (ROC)
      method. RESULTS: Of 41 identified studies, 16 met the inclusion criteria. These
      studies reported sensitivities ranging from 63% to 100% and specificities ranging
      from 21% to 100%. Maximum joint sensitivity and specificity of the summary ROC
      curve was 89% (95% confidence interval [CI]: 82%, 93%). At a sensitivity of 95%,
      specificity was 67%. When test performance values were applied to a previous cost
      effectiveness analysis, the cost-effectiveness of preoperative MR imaging
      relative to that of excisional biopsy was confirmed, but its cost-effectiveness
      relative to that of needle core biopsy varied widely. CONCLUSION: For MR imaging
      to be a cost-effective alternative to excisional biopsy for diagnosis of
      suspicious breast lesions, its diagnostic test performance must be equal to or
      better than the best results in recently published studies.

PMID- 10410165
TI  - Straightening the colon with curved cross sections: an approach to CT
      colonography.
AB  - RATIONALE AND OBJECTIVES: The purpose of this study was to straighten digitally
      and consistently the colon with curved cross sections and to compare the results
      with planar cross-section-based processing for computed tomographic (CT)
      colonography. MATERIALS AND METHODS: In electric field-based straightening,
      curved cross sections are formed along electric force lines because of electric
      charges digitally distributed along the colon central path. Four straightening
      experiments were conducted on CT scans of a colonoscopy phantom. Representative
      images were studied for polyp detectability and feature distortion. Two further
      trials involved patient data to demonstrate the clinical feasibility of this
      method. RESULTS: In colon straightening with planar sections, a polyp was counted
      multiple times in both phantom and patient studies where the polyps were in
      central path turns with substantial curvature. Furthermore, opposite the central
      path turns, the colon walls were undersampled with planar sections. Straightening
      with curved sections produced consistent mappings. Image distortion was present
      in straightening with curved sections, but the conspicuity of polyps was
      maintained. In the soft-straightening process, trilinear interpolation greatly
      suppressed the surface- or volume-rendering noise associated with nearest
      neighbor interpolation. CONCLUSION: Straightening with curved sections
      outperforms straightening with planar sections in terms of polyp detectability.
      This approach eliminates the navigation difficulties of current CT colonography
      and may have clinical use.

PMID- 10410166
TI  - Influence of film and monitor display luminance on observer performance and
      visual search.
AB  - RATIONALE AND OBJECTIVES: The purpose of this study was to measure the influence
      of display luminance on detection performance and visual search behavior. The
      results of the study should be helpful in establishing minimally acceptable
      display conditions for viewing radiographs on cathode-ray tube (CRT) monitors.
      MATERIALS AND METHODS: Two groups of six radiologists each viewed 50 pairs of
      mammograms. One group viewed film images on a standard mammographic view box; the
      other viewed images on a high-resolution CRT monitor. Two luminance levels were
      studied for each display type. Observers reported on the presence or absence of
      masses or microcalcification clusters and on their confidence in that decision.
      Confidence data were analyzed by using alternative free-response receiver
      operating characteristic (AFROC) techniques. Eye position also was recorded as
      observers viewed the images. RESULTS: For both the film and monitor studies,
      detection performance (AFROC area under the curve) was not affected significantly
      by display luminance, but search behavior was. Total viewing and decision dwell
      times were shorter with the higher-luminance displays, especially for true
      negative decisions. Significantly more fixation clusters were generated during
      the search of lesion-free than of lesion-containing images with the lower
      luminance displays. CONCLUSION: Display luminance affects visual search
      performance with both film and monitor displays without affecting detection
      performance significantly. Higher-luminance displays yield more efficient search
      performance. The true-negative dwell times and number of clusters are suggestive
      that lower-luminance levels prolong the search and recognition of normal, lesion
      free areas compared with lesion-containing areas.

PMID- 10410167
TI  - Effect of site and rate of contrast material injection on pulmonary vascular
      distention.
AB  - RATIONALE AND OBJECTIVES: The authors performed this study to determine if there
      were differences in vascular caliber measured on angiograms obtained with the
      injection protocol used for spiral computed tomography (CT) versus that used for
      pulmonary angiography. MATERIALS AND METHODS: The authors studied seven juvenile
      anesthetized pigs by using a prospective repeated measures experimental design.
      All pigs received injections of nonionic contrast material via catheters in the
      brachial vein, superior vena cava, main pulmonary artery, and left pulmonary
      artery. Weight-adjusted injection rates and volumes ranged from 0.05 mL/kg/sec
      (3.5 mL/sec, spiral CT protocol) to 0.56 mL/kg/sec (40 mL/sec, pulmonary
      angiography protocol). Heart rate and pulmonary artery and systemic artery
      pressures were recorded. During each injection, identically positioned pulmonary
      angiograms were obtained at full inspiration. Vessel diameters were measured at
      identical locations after each injection by two observers. The relationship
      between vessel diameter and hemodynamic parameters and injection site and rate
      was assessed with analysis of variance. RESULTS: At suspended full inspiration,
      no statistically significant difference (P > .05) in vessel diameter or
      hemodynamic parameters was found between the different injection sites or rates.
      There was no difference in vascular caliber between systole and diastole.
      CONCLUSION: The improved detection of subsegmental pulmonary emboli at pulmonary
      angiography compared with contrast material-enhanced spiral CT is not due to
      differences in vascular distention.

PMID- 10410168
TI  - Iopiperidol: nonionic iodinated contrast medium with promising anticoagulant and
      antiplatelet properties.
AB  - RATIONALE AND OBJECTIVES: The purpose of this study was to determine the
      anticoagulant and antiplatelet characteristics of iopiperidol, a nonionic,
      triiodinated contrast agent. MATERIALS AND METHODS: Anticoagulant effects of
      iopiperidol were assessed both in vitro and in vivo after single or repeated
      intravenous administrations to rats. To this aim, results of prothrombin time,
      activated partial thromboplastin time, thrombin time, and fibrinogen tests were
      evaluated. To define better the mechanism of action of iopiperidol and of the
      contrast media used for comparison, in vitro tests to study the effects on
      thrombin activity and on thrombin generation were performed. In addition, the
      effect of iopiperidol was studied on adenosine diphosphate- and collagen-induced
      platelet aggregation both in vitro and in vivo after single or repeated
      intravenous administrations in the rat. RESULTS: In vitro, iopiperidol showed
      anticoagulant properties similar or superior to those of the ionic ioxaglate.
      Iopiperidol also inhibited collagen-induced platelet aggregation statistically
      significantly more than iodixanol and ioxaglate (P < .05). In vivo, no
      significant differences between iopiperidol and ioxaglate were observed after
      single or repeated administrations. CONCLUSION: The in vitro anticoagulant effect
      of iopiperidol is similar or even superior to that of ioxaglate; the in vivo
      effect is similar to that of reference nonionic contrast media.

PMID- 10410169
TI  - Spectrum of adrenal lesions in children.

PMID- 10410170
TI  - Leadership in radiology.

PMID- 10410171
TI  - Utility of proliferation-associated marker MIB-1 in evaluating lesions of the
      uterine cervix.
AB  - Various cervical lesions at times may be difficult to distinguish from one
      another on routine hematoxylin and eosin stains, and immunostaining for the
      proliferation-associated antigen Ki-67, using monoclonal antibody MIB-1, can aid
      their distinction. The reduced MIB-1 expression in atrophy and increased MIB-1
      expression in dysplasia permits easy distinction between these conditions.
      Presence of MIB-1 in more than 15% of basal cells and/or in surface half of the
      epithelium favor a diagnosis of condyloma over squamous metaplasia or
      inflammatory changes. Normal endocervix shows MIB-1 positivity in less than 10%
      of the cells, but usually in more than 20% of cells in cervical adenocarcinoma.
      With increasing grade of dysplasia, the percentage of MIB-1 positive cells is
      increased, and positive cells are seen in the higher levels of the epithelium.
      Presence of more than 20% MIB-1 positive cells in Pap smears showing atypical
      cells of uncertain significance is associated with a diagnosis of dysplasia on
      subsequent biopsies. Cauterized tissues with dysplasia show MIB-1 expression
      similar to adjacent noncauterized dysplastic areas. MIB-1 expression is,
      therefore, useful in evaluating various cervical lesions.

PMID- 10410172
TI  - Granular cell tumor: a review and update.
AB  - The histogenesis of granular cell tumor (GCT) has been a source of controversy
      since its recognition as an entity by Abrikossoff in 1926. These lesions can
      occur in virtually any location. Benign GCTs are not uncommon, but malignant ones
      are rare and at times difficult to diagnose. The main morphologic feature is the
      granularity of the cytoplasm which is caused by a massive accumulation of
      lysosomes. Early suggestions that GCT may have a myoblastic origin have been
      discounted and use of the term granular cell myoblastoma as a designation for
      this tumor is discouraged. Although most investigators currently favor a Schwann
      cell derivation based on immunohistochemical and electron microscopic findings
      and advocate the designation of granular cell schwannoma, some differences exist
      between schwannomas and GCTs in their ultrastructural characteristics and the
      expression of some immunohistochemical markers. Other investigators believe that
      GCT is not a specific entity but rather a degenerative change that can occur not
      only in Schwann cells but also in a variety of other normal and neoplastic cells.
      Until more information becomes available, particularly that derived from
      cytogenetic studies, this lesion should be considered a separate entity and the
      descriptive designation of granular cell tumor continues to be appropriate.

PMID- 10410173
TI  - Skeletal and extraskeletal myxoid chondrosarcoma: related or distinct tumors?
AB  - Skeletal myxoid chondrosarcoma is a histologic variant of conventional skeletal
      myxoid chondrosarcoma, whereas extraskeletal myxoid chondrosarcoma is a distinct
      entity characterized by a reciprocal t(9;22) translocation resulting in fusion of
      the EWS and CHN genes. Rarely, extraskeletal myxoid chondrosarcoma can occur in
      bone, and it is difficult to describe such tumors, unambiguously, using the
      present nomenclature. Designation as "chordoid sarcoma of bone" would distinguish
      these cases from conventional skeletal myxoid chondrosarcoma.

PMID- 10410174
TI  - The sad NSAID colon.
AB  - The condensed article reports the results of the histopathologic evaluation of
      the colorectal biopsy specimens from 14 patients who developed abdominal pain and
      bloody stools or diarrhea while receiving nonsteroidal anti-inflammatory drugs
      (NSAIDs). All patients had a mixed inflammatory infiltrate (predominantly
      neutrophilic in four patients and lymphocytic in two) and about one-half also had
      minimal crypt disarray. The intestinal symptoms resolved in all patients after
      NSAIDs were discontinued, but there was no histopathologic verification that the
      inflammatory changes had subsided. Nonspecific changes ("focal colitis"), similar
      to those described in this group, are present in most patients who undergo a
      colonoscopy for the investigation of diarrhea. This article calls attention on
      one of the possible and neglected causes for nonspecific colitis. However, larger
      controlled studies are needed to firmly establish a cause-and-effect relationship
      with NSAID intake.

PMID- 10410175
TI  - Myoepithelium in salivary and mammary neoplasms is host-friendly.
AB  - This commentary relates to ameliorative effects of myoepithelial cells in
      carcinomas of salivary glands and the breast as viewed not only by proliferative
      characteristics, but also by laboratory experiments and clinicopathologic
      evidence. The tumor suppressor action of myoepithelium is, in part, associated
      with its matrix-synthesizing and proteinase inhibitor properties. Loss of the
      myoepithelial phenotype yields a more aggressive carcinoma with enhanced invasive
      and metastatic capability.

PMID- 10410176
TI  - Clinical and financial impact of intravenous erythromycin therapy in hospitalized
      patients.
AB  - OBJECTIVE: To determine the economic consequences of intravenous erythromycin use
      in hospital patients in a variety of clinical circumstances. DESIGN:
      Retrospective cohort study of patients with specified primary diagnosis-related
      group discharge diagnoses treated from January 1, 1990, to December 31, 1994, who
      received erythromycin, and a matched cohort group from the same period who did
      not receive erythromycin. SETTING: LDS Hospital, Salt Lake City, UT, a 520-bed
      teaching hospital. PATIENTS: A long-term archive of clinical and financial data
      from a computerized hospital information system was searched for patients meeting
      a strict case definition. This archive contained information on erythromycin
      exposure as well as concurrent drug therapy and adverse drug events that had been
      prospectively evaluated during hospitalization throughout the study and cohort
      periods. Detailed costs were available for each patient. MAIN OUTCOME MEASURE:
      Attributable differences in lengths of stay and total costs determined using
      linear regression modeling. RESULTS: For 797 erythromycin patients and 2771
      cohort patients, we found an attributable increased length of stay of 2.14 days
      and an increased cost of hospitalization of $6061 for erythromycin case patients.
      Case patients also had a significantly increased risk of adverse drug events.
      Linear regression modeling showed that erythromycin use was significantly related
      to increased length of stay and cost of hospitalization. CONCLUSIONS: Intravenous
      erythromycin use has been associated with significant increases in hospital
      length of stay and total hospital cost.

PMID- 10410178
TI  - Diltiazem increases tacrolimus concentrations.
AB  - OBJECTIVE: To describe a patient with increased tacrolimus concentrations due to
      a diltiazem drug interaction. CASE SUMMARY: A 68-year-old white man, four months
      following orthotopic liver transplantation secondary to hepatitis C and Laennec's
      cirrhosis, was admitted to the intensive care unit for diarrhea, dehydration, and
      atrial fibrillation. He was stabilized on oral tacrolimus 8 mg twice daily, with
      a whole blood tacrolimus trough concentration of 12.9 ng/mL on admission. He was
      started on a continuous infusion of diltiazem for one day, followed by 30 mg
      orally every eight hours. Three days after admission, the patient became
      delirious, confused, and agitated; he was found to have a whole blood tacrolimus
      trough concentration of 55 ng/mL. The tacrolimus was withheld and diltiazem was
      discontinued. The tacrolimus concentrations fell over the next three days to 6.7
      ng/mL, with a corresponding improvement in his mental status. The oral tacrolimus
      was restarted at 3 mg twice daily and increased gradually to 5 mg twice daily
      over the next four days; this produced tacrolimus trough concentrations between 9
      and 10 ng/mL. DISCUSSION: Tacrolimus is known to be a substrate for P
      glycoprotein and metabolized by CYP3A. Diltiazem inhibits CYP3A, P-glycoprotein,
      and tacrolimus metabolism in vitro. Although this interaction may have been
      predictable, this is the first detailed case report describing this clinically
      significant drug interaction. CONCLUSIONS: Diltiazem can dramatically increase
      tacrolimus concentrations and result in tacrolimus toxicity. Avoidance of this
      interaction or careful monitoring of tacrolimus concentrations along with
      tacrolimus dose reduction is recommended if diltiazem therapy cannot be avoided.

PMID- 10410177
TI  - Use of nonprescription medications by patients with congestive heart failure.
AB  - OBJECTIVE: To define the utilization pattern of nonprescription therapies in
      patients with congestive heart failure (CHF) and to compare this pattern with
      that of an age- and gender-matched control group without any self-reported heart
      conditions. DESIGN: Survey questionnaire completed by participants at home.
      SETTING: Ambulatory CHF clinic in a tertiary care hospital. SUBJECTS: Patients
      attending the clinic between July 1995 and May 1996 who agreed to participate.
      Control subjects were age- and gender-matched participants identified and
      approached by participating patients. OUTCOME MEASURES: Nonprescription therapies
      used at least once weekly. RESULTS: Completed questionnaires were received from
      180 (75%) of the 239 patients who agreed to participate and from 133 controls.
      Mean age of responding patients was 69 years (63% men). Controls were younger,
      with a mean age of 64 years (63% men). The most commonly used nonprescription
      medication categories for both patients and controls, with no significant
      intergroup differences, were vitamins and minerals (59% patients, 50% controls),
      pain relievers (48% and 43%, respectively), herbal or health food products (38%
      and 38%), antacids (26% and 28%), and laxatives (24% and 21%). Significantly
      fewer patients than controls used cough and cold products (9% vs. 17%; p < 0.05),
      specifically oral decongestants (0.6% vs. 5%; p < 0.01), and more patients than
      controls used nutritional supplements (17% vs. 4%; p < 0.01). CONCLUSIONS:
      Overall, use of nonprescription therapies by our CHF clinic patients is similar
      to that of an age- and gender-matched population without a self-reported heart
      condition. The differences in medication use observed between patients and
      controls included cough and cold products that might be harmful. This likely
      reflects appropriate caution with which CHF patients approach nonprescription
      therapies.

PMID- 10410179
TI  - Hepatotoxicity possibly caused by amphotericin B.
AB  - OBJECTIVE: To report a case of possible amphotericin B-induced hepatotoxicity in
      a patient with pulmonary blastomycosis. SUMMARY: A 26-year-old white man with
      life-threatening pulmonary blastomycosis developed elevation of his liver enzymes
      after the addition of amphotericin B to his initial itraconazole therapy. The
      hepatotoxicity resolved rapidly with discontinuation of the amphotericin B, and
      the blastomycosis was successfully treated with itraconazole alone. DISCUSSION:
      This case illustrates an unusual occurrence of hepatotoxicity associated with a
      short course of amphotericin B. Liver biopsy was compatible with drug-induced
      changes and showed no evidence of blastomycosis. Discontinuation of amphotericin
      B with no other therapeutic changes resulted in a rapid resolution of
      hepatotoxicity. A possible adverse drug interaction with itraconazole and
      amphotericin B is postulated based on the mechanism of action of each drug.
      CONCLUSIONS: Amphotericin B therapy can be associated with many adverse effects,
      but reports of hepatotoxicity are rare. Closer monitoring of liver enzymes in
      patients receiving amphotericin B, especially in combination with potentially
      hepatotoxic agents, including azole antifungal drugs, would be prudent.

PMID- 10410181
TI  - Adverse effects in a newborn infant breast-fed by a mother treated with doxepin.
AB  - OBJECTIVE: To report adverse effects in a newborn infant whose mother had been
      treated with doxepin during pregnancy and while breast-feeding. CASE SUMMARY: The
      nine-day-old white boy was admitted because of poor sucking and swallowing, with
      muscle hypotonia and vomiting. He was drowsy and had lost 150 g. At the time of
      admission, he was breast-fed by his mother who was being treated with doxepin 35
      mg/d. Samples of plasma and breast milk were taken and analyzed by HPLC and
      fluorescence polarization immunoassay. The amount of doxepin and N
      desmethyldoxepin (DDP) ingested via breast-feeding was approximately 10-20
      micrograms/kg/d (i.e., only 2.5% of the weight-adjusted dose of the mother).
      Doxepin was detectable in small amounts in the infant's plasma (approximately 10
      micrograms/L); DDP was below the lower limit of detection of 10 micrograms/L. All
      adverse effects subsided within 48 hours after breast-feeding was stopped.
      DISCUSSION: Despite the small doses of doxepin and its active metabolite ingested
      by breast-fed babies, there is a risk of accumulation and resultant adverse
      effects. In newborns, the metabolic activity is considerably decreased and may be
      further reduced by hyperbilirubinemia. CONCLUSIONS: Available data suggest that
      women treated with doxepin should breast-feed their infants with great caution,
      if at all, although much larger databases are needed to confirm this.

PMID- 10410180
TI  - Treatment of obsessive-compulsive disorder using clomipramine in a very old
      patient.
AB  - OBJECTIVE: To describe the effect of the tricyclic drug clomipramine in a very
      old patient with obsessive-compulsive disorder and Alzheimer dementia. CASE
      SUMMARY: A 93-year-old woman had a history of obsessive-compulsive disorder since
      early adulthood. The obsession consisted of remembering names of famous people
      and the compulsion consisted of excessive list making. With the onset of memory
      loss secondary to Alzheimer disease, she became increasingly anxious and
      compulsive as a result of a failure to remember. After nine weeks on fluoxetine
      she became jittery and more confused. After a two-week wash-out period, she was
      given a nine-week course of clomipramine that was carefully titrated up to a
      therapeutic concentration. RESULTS: At the completion of clomipramine treatment,
      the patient no longer felt driven to recall the names of famous people. Her score
      from the Yale-Brown Obsessive-Compulsive Scale dropped from 29 to 3. Her Folstein
      Mini-Mental State Examination score increased from 21 to 23. CONCLUSIONS:
      Clomipramine appeared much more effective and better tolerated than fluoxetine in
      this very old patient despite its potential anticholinergic effect and the
      coexistence of Alzheimer disease.

PMID- 10410182
TI  - Pyloric channel stricture secondary to high-dose ibuprofen therapy in a patient
      with cystic fibrosis.
AB  - OBJECTIVE: To describe a case of pyloric channel stricture secondary to high-dose
      ibuprofen therapy in a pediatric patient with cystic fibrosis. CASE SUMMARY: A 12
      year-old white girl started taking high-dose ibuprofen to treat the pulmonary
      manifestations of cystic fibrosis. The peak plasma concentration at dose
      initiation was within the accepted therapeutic range. Approximately one month
      later, the patient developed emesis and intolerance of solid foods, which
      persisted for several months and resulted in a weight loss of seven kilograms.
      The patient was referred to a pediatric gastroenterologist, who performed an
      upper endoscopy and subsequently diagnosed a pyloric channel stricture. The
      patient's pyloric channel was successfully dilated with two balloons. It is felt
      that the pyloric stricture developed from healing antral/pyloric channel ulcers.
      Ibuprofen was discontinued and omeprazole therapy was begun. Over the course of
      the following year, the patient was asymptomatic. Follow-up upper
      gastrointestinal barium swallows were normal. DISCUSSION: When used for analgesia
      and fever in the pediatric population, ibuprofen has been shown to be a
      relatively safe drug. While it is known that ibuprofen may cause gastrointestinal
      adverse effects, the pediatric population is at lower risk; however, large doses
      of ibuprofen increase the risk of gastrointestinal adverse effects. The use of
      large doses of ibuprofen in the treatment of cystic fibrosis is a relatively new
      therapy. Limited data thus far in cystic fibrosis patients do not suggest
      increased risk of gastrointestinal complications. CONCLUSIONS: Limited data to
      date indicate that ibuprofen, when used in large doses to treat the pulmonary
      manifestations of cystic fibrosis, is relatively safe. However, because of the
      potential risks to the gastrointestinal tract of high-dose ibuprofen therapy,
      clinicians should be aware of its possible complications.

PMID- 10410183
TI  - Marked elevation of serum creatine kinase associated with olanzapine therapy.
AB  - OBJECTIVE: To report a case of marked elevation of serum creatine kinase (CK)
      associated with olanzapine therapy. CASE SUMMARY: A 39-year-old white Jewish
      schizophrenic man treated with olanzapine developed an elevated serum CK
      concentration with a peak concentration of 4000 IU/L (normal < 230). No other
      diagnostic criteria for neuroleptic malignant syndrome (NMS) were present. On
      discontinuation of the drug, serum CK concentrations returned to normal within
      eight days. DISCUSSION: Olanzapine, like other atypical antipsychotic drugs, may
      cause muscle injury with concomitant elevations of serum CK of muscle origin. We
      suggest that in patients treated with olanzapine, CK concentrations should be
      checked on initiation of therapy, within the first 48 hours, and weekly
      thereafter for at least one month. In addition, patients with clinical signs
      suggestive of NMS should be monitored more carefully. For those patients with a
      history of NMS, or even of isolated serum CK elevation during antipsychotic
      therapy, follow-up should be stricter. CONCLUSIONS: Marked elevation of serum CK
      may be a possible complication of olanzapine therapy.

PMID- 10410184
TI  - Venlafaxine and bupropion combination therapy in a case of treatment-resistant
      depression.
AB  - OBJECTIVE: To report the therapeutic efficacy of venlafaxine and bupropion in a
      patient with treatment-refractory major depression. CASE SUMMARY: A 21-year-old
      white woman with chronic and recurrent major depression presented with lack of
      response to several antidepressants. On examination, the patient exhibited
      neurovegetative signs of depression, guilt feelings, and suicidal ideation. The
      patient was administered venlafaxine 75 mg three times daily. The dose was
      titrated to 150 mg three times daily over the next month. Later bupropion was
      instituted up to 100 mg three times daily over a four-month period. The patient
      responded favorably to combination therapy and has remained free of depression
      for approximately 23 months. DISCUSSION: Venlafaxine and bupropion are
      antidepressant agents with unique pharmacologic profiles, each effective in the
      treatment of depression. Recent data indicate that combinations of selective
      serotonin-reuptake inhibitors and bupropion can convert partial response to full
      response in patients with treatment-resistant depression. We considered whether a
      combination of venlafaxine and bupropion would reduce the depressive symptoms of
      a patient who was unresponsive to various classes of psychotropic agents. Gradual
      administration of venlafaxine and bupropion acted synergistically to
      significantly reduce depressive symptoms (p < 0.002) and significantly increase
      social function (p < 0.002) over a period of eight months. CONCLUSIONS: To our
      knowledge this is the first report of successful combination therapy with
      venlafaxine and bupropion in treatment of chronic recurrent and refractory major
      depression.

PMID- 10410185
TI  - Naratriptan: an alternative for migraine.
AB  - OBJECTIVE: To critically evaluate the literature regarding naratriptan's clinical
      pharmacology, efficacy, safety, and indications. DATA SOURCE: A MEDLINE search
      was conducted for the period from January 1990 to June 1998. Key words used
      included naratriptan, triptan, serotonin agonists, migraine, and migraine
      therapy. In addition, pertinent references cited in articles obtained from
      MEDLINE and product information for triptans were reviewed. STUDY SELECTION AND
      DATA EXTRACTION: All original and review articles and abstracts pertaining to
      naratriptan were reviewed, as were product information extracts. Clinical trials
      of naratriptan were critically reviewed and compared with pertinent clinical
      trials of other oral triptans. DATA SYNTHESIS: The treatment of migraine has been
      dramatically improved with the use of sumatriptan, other triptans, and serotonin
      receptor subtype 1B and 1D agonists. Drawbacks to these medications, however,
      have included poorly tolerated adverse effects and the recurrence of the
      migraine. Naratriptan has been recently approved for acute oral migraine therapy.
      In two Phase III trials of naratriptan compared with placebo, relief at four
      hours was obtained in 60% and 68% of patients using the 2.5-mg dose, with
      recurrence of headache in 24 hours in 27% and 28% of patients. The data on
      migraine recurrence were similar to those of other oral triptans; the efficacy of
      naratriptan at two hours was not specifically analyzed. Adverse effects of
      naratriptan were similar to placebo, and its tolerability seemed superior
      compared with studies of other oral triptans. CONCLUSIONS: Naratriptan is a
      promising new oral therapy for acute migraine; it may successfully treat patients
      who poorly tolerate other triptan therapies or have longer duration migraine
      headaches.

PMID- 10410186
TI  - The evolving role of platelet glycoprotein IIb/IIIa inhibitors in the management
      of acute coronary syndromes.
AB  - OBJECTIVE: To briefly discuss the pathophysiology of acute coronary syndromes
      (ACS) and to present the clinical data currently available regarding the use of
      platelet glycoprotein (GP) IIb/IIIa inhibitors in the management of ACS. DATA
      SOURCES: Literature on antithrombotic therapy in ACS was identified using a
      MEDLINE search (January 1988-September 1998), along with the Agency on Health
      Care Policy and Research guidelines for the management of unstable angina.
      Abstracts from recent scientific meetings were also reviewed. STUDY SELECTION:
      Review articles from the cardiology literature (pathophysiology) and randomized,
      controlled clinical trials of currently approved platelet GP IIb/IIIa inhibitors
      in ACS were evaluated. Ex vivo platelet aggregation studies and pharmacology
      literature were also included. Abstract data were included to illustrate specific
      points when published literature was not available. DATA EXTRACTION: Study data
      were evaluated based on study design, outcome parameters, and adverse drug
      reactions. Clinical information from review articles was evaluated based on
      applicability to the treatment of ACS. DATA SYNTHESIS: Platelet adhesion and
      aggregation are pivotal events in the pathophysiology of ACS. The GP IIb/IIIa
      inhibitors represent a new and unique class of drugs that block fibrinogen and
      von Willebrand factor-mediated platelet aggregation, the common end point of all
      biologic pathways of platelet aggregation. Three agents are currently approved by
      the Food and Drug Administration: abciximab, a monoclonal antibody; eptifibatide,
      a synthetic peptide; and tirofiban, a synthetic nonpeptide. CONCLUSIONS: Clinical
      trial data demonstrate efficacy of all three GP IIb/IIIa inhibitors in reducing
      the combined end point of morbidity and mortality in patients undergoing
      angioplasty. Eptifibatide and tirofiban also reduce the combined end point of
      morbidity and mortality in patients with unstable angina. These data expand the
      present role of platelet GP IIb/IIIa inhibitors by providing evidence for their
      effectiveness in the medical treatment of ACS. However, the specific role that
      these agents will have in the management of ACS is yet to be fully defined.

PMID- 10410187
TI  - Lyme disease prevention and vaccine prophylaxis.
AB  - OBJECTIVE: To provide a comprehensive review of the epidemiology, diagnosis, and
      prevention of Lyme disease with a focus on the Lyme disease vaccine. DATA SOURCE:
      A computerized search of MEDLINE (January 1996-December 1998) was used to
      identify articles regarding Lyme disease, Borrelia burgdorferi, epidemiology,
      prevention, and vaccine. DATA SYNTHESIS: Lyme disease is a condition caused by
      infection with B. burgdorferi. The organism is carried by certain species of
      Ixodes ticks and is the most common tick-borne disease in the US. In patients
      with clinical manifestations of Lyme disease, various pharmacotherapeutic
      approaches have proven effective in treatment of the clinical features.
      Prevention strategies exist; however, their application is sometimes difficult. A
      vaccine for the prevention of Lyme disease is available, and another is being
      considered for approval. The recombinant outer surface protein A (OspA) vaccines
      to prevent Lyme disease are immunogenic and have an acceptable adverse effect
      profile. These vaccines are highly efficacious for the prevention of Lyme
      disease. CONCLUSIONS: Lyme disease is the most common tick-borne disease in the
      US. The infection, caused by B. burgdorferi, results in dermatologic, neurologic,
      cardiovascular, and musculoskeletal manifestations. Until recently, tick bite
      prevention strategies were the only means of decreasing the risk of acquiring the
      infection. The OspA vaccines are efficacious for the prevention of infection.
      Although universal immunization with these vaccines is unlikely, the availability
      of effective vaccines represents an important tool for the prevention of Lyme
      disease in endemic regions of the US.

PMID- 10410188
TI  - Treatment of malignant melanoma.
AB  - OBJECTIVE: To review the current treatments for cutaneous melanoma and discuss
      treatment approaches for each patient population. DATA SOURCES: MEDLINE and IOWA
      database search from January 1990 to December 1998. DATA EXTRACTION: Clinical
      trials and review articles were selected and classified to answer questions
      considered of clinical relevance. RESULTS: Patients with stage I, II, and III
      melanoma should undergo excision after biopsy. In patients with stage IV
      melanoma, surgical excision of metastatic melanoma is not considered curative but
      can provide palliation and improve quality of life. Therapeutic lymph node
      dissection should be performed in patients with melanoma in stages III and IV
      once pathologic confirmation is obtained. Patients at high risk for recurrence or
      metastasis may also be considered for elective node dissection. Adjuvant therapy
      after surgery excision is not a standard of care in patients with stage I and IIa
      melanoma. In patients with stage IIb and III melanoma, the best results have been
      obtained with high doses of interferon alfa-2b, although toxicity is of concern.
      Isolated limb perfusion with melphalan adjuvant to surgery has demonstrated
      clinically significant benefit in patients with locally recurrent melanoma and in
      transit metastases. Studies comparing efficacy and quality of life with this
      technique or with high doses of interferon alfa-2b are needed. The technique
      cannot be recommended for high-risk primary melanoma of an extremity with no
      clinical evidence of metastatic disease. CONCLUSIONS: To date, dacarbazine still
      appears to be the treatment of first choice in metastatic melanoma, outside of a
      clinical trial. The combination of chemotherapy with interferon alfa-2b or
      interferon alfa-2a enhances toxicity without a significant survival advantage.
      Aldesleukin may be an alternative in selected patients when other treatments have
      failed, but the higher toxicity and cost must be considered.

PMID- 10410189
TI  - Treatment of RSV pneumonia in adults--evidence of ribavirin effectiveness?

PMID- 10410190
TI  - Famotidine in the management of schizophrenia.
AB  - OBJECTIVE: To evaluate the use and potential benefit of famotidine in the
      management of schizophrenia. DATA SOURCES: Clinical literature accessed through
      MEDLINE (February 1998-October 1998). Key search terms included famotidine,
      schizophrenia, and histamine. DATA SYNTHESIS: Schizophrenia is a complicated
      disorder associated with high morbidity if left unmanaged. Histamine2 (H2)
      antagonists may be an alternative to conventional treatments. An evaluation of
      studies focusing on famotidine in the management of schizophrenic symptoms was
      conducted. CONCLUSIONS: Famotidine can improve schizophrenic symptoms that were
      otherwise refractory to typical antipsychotic agents. Further studies should be
      conducted to determine if other H2-antagonists are also effective.

PMID- 10410191
TI  - Erythema multiforme possibly due to phenytoin.

PMID- 10410192
TI  - Once- versus twice-daily administration of amikacin in pediatric patients with
      bronchopneumonia: plasma drug concentration and Bayesian pharmacokinetics
      estimation.

PMID- 10410193
TI  - Cyclosporine-induced encephalopathy predisposed by diltiazem in a patient with
      aplastic anemia.

PMID- 10410194
TI  - Automatic autoinjectors hazard: penetration through bone.

PMID- 10410195
TI  - Legal problems concerning the use of fluoxetine in Japan.

PMID- 10410196
TI  - Comment: cidofovir in the treatment of cytomegaloviral disease.

PMID- 10410197
TI  - The relation between sexual orientation and penile size.
AB  - The relation between sexual orientation and penile dimensions in a large sample
      of men was studied. Subjects were 5122 men interviewed by the Kinsey Institute
      for Research in Sex, Gender, and Reproduction from 1938 to 1963. They were
      dichotomously classified as either homosexual (n = 935) or heterosexual (n =
      4187). Penile dimensions were assessed using five measures of penile length and
      circumference from Kinsey's original protocol. On all five measures, homosexual
      men reported larger penises than did heterosexual men. Explanations for these
      differences are discussed, including the possibility that these findings provide
      additional evidence that variations in prenatal hormonal levels (or other
      biological mechanisms affecting reproductive structures) affect sexual
      orientation development.

PMID- 10410198
TI  - Dissimulation in phallometric testing of rapists' sexual preferences.
AB  - Sexual preferences of 38 rapists were assessed phallometrically with and without
      a semantic tracking task in a counterbalanced design. Four categories of
      audiotaped vignettes describing neutral interactions, consenting sex, rape, and
      nonsexual violence were employed as stimuli. In the semantic tracking task,
      participants were instructed to press one button when violent events were
      described in the vignette and another when sexual activities were described.
      Phallometric assessment with the semantic task better discriminated between
      rapists and non-sex-offender participants (from an earlier study) than the same
      assessment without the task. Among four rapists who had previous experience with
      phallometric testing, there was a very strong correlation between deviance scores
      and tracking accuracy. Results suggest that the semantic task may improve
      discriminant validity, particularly among sex offenders who have had previous
      experience with phallometric assessment.

PMID- 10410199
TI  - Estimation of the number of sexual partners for the nonrespondents to a large
      national survey.
AB  - For a random sample of 4548 respondents to the British National Survey of Sexual
      Attitudes and Lifestyles, item nonresponses were assessed by utilizing
      alternating least squares and optimal scaling. Of men who did not answer the
      question on number of lifetime partners, 61% were estimated to have had 10 or
      more partners, whereas 48% of female nonrespondents were estimated to have had no
      partners. Among the latter, the percentage of those with 10 or more partners was
      also elevated to the level almost twice that of respondents. However, the overall
      impact of the estimates on the distribution of lifetime partners was hardly
      noticeable due to the relatively small proportion of incomplete answers to this
      question. Those who did not respond to the question of number of lifetime
      partners were likely to be over 45 years, of lower social class, and poorer
      education in comparison with those who answered the question fully. A larger
      proportion of the former were of Asian extraction and non-Christian in comparison
      to the latter, particularly among women. Not providing a complete answer to the
      question on the number of lifetime partners was associated with the nonresponse
      rate in the range of 90% on the questions of STD clinic attendance and drug
      abuse. Heavy smoking was more prevalent among male nonrespondents in comparison
      to those who provided a full answer to the question on the number of lifetime
      partners.

PMID- 10410200
TI  - Male and female differences in reports of women's heterosexual initiation and
      aggression.
AB  - Previous work that compared male and female reports of women's heterosexual
      initiation and aggression is replicated. It was hypothesized that men's reports
      of women's sexual initiation and aggression would be significantly greater than
      women's self-report of sexual initiation and aggression in the most recent
      sample. Of the 24 questionnaire items, 12 of the 17 specifically designed to
      assess sexual initiation or aggression demonstrated significant reporting
      differences. For every questionnaire item, except "mutually consenting contact,"
      men reported women initiating sexual contact more often than women self-reported.
      In addition, comparisons were made to determine the level of agreement between
      the results of this study and a previous study in which the same comparisons were
      made with a different sample. It was hypothesized that the identical
      questionnaire items would demonstrate significant gender-based reporting
      differences in both samples. This hypothesis was mostly supported with 11 items
      showing a significant difference in both samples. In both samples, males reported
      receiving female initiation and aggression more frequently than females reported
      giving. Logistic regression results supported a difference in perception of
      women's sexual initiation based on gender of respondent. In both samples men see
      women's initiation as less conforming to traditional social norms for women and
      more aggressive than women do. Gender role expectations and social desirability
      may influence male and female perceptions of female heterosexual initiation and
      aggression in a way that contributes to significant differences in reporting.

PMID- 10410201
TI  - Comparing contraceptive use surveys of young people in the United Kingdom.
AB  - Two sets of findings that emerged from a review of surveys assessing young
      people's use of contraception in the U.K. are outlined. First, the paper presents
      estimates of contraceptive use for this population subgroup and, second, it notes
      several limitations of surveys under review. The surveys use a wide range of
      indices in measuring these different aspects of contraceptive (including condom)
      use, which has made accurate cross-study comparisons difficult; hence most
      findings can only be presented as broad estimates (usually depicted within a
      percentage range), rather than as precise values. Nonuse of contraception among
      young people at last intercourse is 20 to 30% and nonuse of the condom lies
      between 40 and 50%. In light of this review process, the paper presents a
      critique of the indices used, labels the importance of using standardized and
      easily understood questions and measures, and highlights the most effective means
      of recording the potential for conception and/or sexually transmitted infection.
      Recommendations for those about to conduct further research in this area are
      added.

PMID- 10410202
TI  - Experiences with sexual aggression within the general population in the Czech
      Republic.
AB  - In a representative survey of the sexual behavior of the inhabitants of the Czech
      Republic (862 men and 825 women older than 15), questions were included
      concerning experience with sexually aggressive behavior: 11.6% of women reported
      this kind of experience (3.4% of them more than once). The average age at the
      time of rape was 21.2 years. Most of these experiences occurred within marriage
      or a stable partnership. In only a tenth of them the perpetrator was a stranger.
      Only 3.4% of the offenses were reported to police. Of Czech men, 4.8% replied
      positively to the question whether they had ever forced a woman to have sexual
      contact. The most common form of these enforced contacts was vaginal coitus.

PMID- 10410203
TI  - [Comparative analysis of guidelines for the treatment of community-acquired
      pneumonias].

PMID- 10410204
TI  - [Adenoid cystic carcinoma of respiratory airways: course and treatment].
AB  - Until recently, adenoid cystic carcinoma (ACC) has been considered to be a
      borderline disease between benign and malignant because of its low level of
      malignancy, slow growth and scarce aggressivity. ACC is now a histologically well
      defined tumor and is currently classified as malignant; it has a prolonged
      natural history, is infiltrative, and tends to recur locally and give rise to
      local-regional metastases or, more rarely, remote metastases. Its incidence in
      the lower airways is low (0.1% of all broncho-pulmonary neoplasms). Eight
      patients (6 women and 2 men) have undergone surgery for ACC since 1969. The
      initial clinical picture included long-term evolution and symptoms were usually
      produced by large caliber obstruction of the airways, mainly affecting the
      trachea and large bronchi. Three cases involved the trachea resection with end-to
      end anastomosis in two cases, right pneumonectomy in two others (one of which
      also involved tracheal carina resection), and two lobectomies. After thoracotomy,
      resection of the tumor was deemed impossible in two cases. Postoperative
      mortality was 12% (1 patient). Complementary radiotherapy was provided in the two
      non-resectable cases, or when there was invasion of resected edges or regional
      metastasis involving ganglia. Total survival was 71.4% after two years, 57.1%
      after five years and 38% after ten years, after excluding postoperative exitus.
      When the trachea was involved, survival was 33.3% after two and five years and
      nil after ten years, with the longest survival 108 months. When bronchi were
      involved, survival was 75% at five and ten years. We conclude that ACC is a rare,
      locally invasive tumor that tends to local recurrence, but that survival after
      surgery is prolonged with or without adjuvant radiotherapy.

PMID- 10410205
TI  - [Role of dyspnea in quality of life of the patient with chronic obstructive
      pulmonary disease].
AB  - OBJECTIVE: To analyze the correlation between quality of life and 1) lung
      function parameters at rest and during exercise, and 2) mean baseline dyspnea
      measured on two scales--Mahler's baseline dyspnea index (BDI/TDI) and the Medical
      Research Council (MRC) scale. We sought to observe the factor or factors having
      the greatest impact on the quality of life of such patients. MATERIAL AND
      METHODS: Fifty-five patients diagnosed of COPD in stable phase of disease
      participated. Al underwent lung function testing at rest and during exercise
      (shuttle walking test with increasing loads and an exercise cycle test). Quality
      of life was assessed on the validated Spanish translation of the Chronic
      Respiratory Disease Questionnaire, which refers specifically to COPD. Baseline
      dyspnea was measured using Mahler's BDI/TDI and the MRC scale. RESULTS: Mean
      patient age was 63 +/- 9.5 years and FEV1 was 40 +/- 16.9%. Overall quality of
      life and each sub-item correlated significantly with mean dyspnea on both scales
      (BDI/TDI and MRC). Effort was weakly correlated and function parameters at rest
      were unrelated. Multiple correlation analysis showed that baseline dyspnea
      (BDI/TDI) was the most important predictor of quality of life. CONCLUSIONS:
      Dyspnea, particularly when expressed as BDI/TDI but also as measured on the MRC
      scale, correlates more highly with quality of life than does any other parameter.
      This indicates that dyspnea has greater impact than other factor on quality of
      life and that BDI/TDI provides a good baseline assessment of dyspnea in COPD
      patients.

PMID- 10410206
TI  - [Results and epidemiological impact of directly observed treatment of
      tuberculosis].
AB  - OBJECTIVES: To analyze the results and epidemiological impact on tuberculosis
      (TB) of directly observed therapy (DOT) for uncooperative patients. METHOD:
      Retrospective study of the case histories of patients admitted to the DOT unit in
      Catalonia (Spain) since its March 1993 inauguration until August 1998. RESULTS:
      Of a total of 470 patients, 102 were cared for during the unit's first phase, in
      which funding resources were insufficient. Of the 368 admitted during the second
      phase beginning January 1996; 176 (47.5%) were cured, 27 (7.3%) died, 72 (19.5%)
      were still at the unit and 93 (25.2%) left the unit before completing treatment.
      Of the last group, 25 were cured, 31 died 19 continued DOT and 18 (4.9% of all
      enrolled in the second phase) were lost to follow-up. Thus, the final outcome
      distribution for the patients was 201 (54.6%) cured, 58 (15.7% died, 91 (24.7%)
      still in DOT and 18 (4.9%) lost to follow-up. The compliance rate during the
      second phase was 91.8%. These results may have contributed significantly to the
      nearly 30% reduction in the incidence of TB in Catalonia between 1992 and 1997, a
      period which saw large decreases in the number of cases among 20-to-44-year-olds
      (33%) and consequently also among under-15-year-olds (55%). Likewise the number
      of cases of TB in high risk groups decreased, 55% on the average with a minimum
      decrease of 40.1% among AIDS patients and a maximum decrease of 85.2% among
      indigents. CONCLUSION: DOT has proven highly effective both for patients and for
      the community, although many other factors must also be considered when
      accounting for the current epidemiological trend.

PMID- 10410207
TI  - [Comparative study of the efficacy of 2 respiratory physiotherapy protocols for
      patients with cystic fibrosis].
AB  - OBJECTIVE: To compare the short-term efficacy of two respiratory physiotherapy
      protocols on sputum clearance, lung function and symptoms in patients with cystic
      fibrosis. Treatment A consisted of diaphragm breathing with incentive spirometry
      and postural drainage. Treatment B consisted of diaphragm breathing with positive
      expiratory pressure (PEP-mask) and postural drainage. METHODS: Twenty-seven
      cystic fibrosis patients in stable condition followed both protocols (A and B) in
      random order on different days separated by at least 48 hours. After each
      treatment session the amount of sputum removed was weighed. Lung function
      variables (FVC, FEV1, FEV1%, MMEFwt-75, MVV and PEF) were measured pre- and
      posttreatment. PEF was measured with a peak flow meter. The patients later
      recorded PEF every hour at home and filled in a questionnaire on frequency and
      intensity of coughing, sputum characteristics, chest discomfort and dyspnea.
      RESULTS: During treatment A with incentive spirometry, 14.6 +/- 13.7 g of sputum
      was removed, whereas 9.8 +/- 10.2 g was eliminated during treatment B (p < 0.05).
      The differences in PEF after treatments A and B in comparison with baseline
      values were +19.3 l/min and -0.2 l/min, respectively (p < 0.01). PEF stayed high
      during the afternoon, in comparison with baseline, with treatment A (p < 0.02).
      After treatment B, no changes in PEF in comparison with baseline were observed (p
      = 0.49). Neither treatment led to significant differences in symptoms reported on
      the clinical questionnaire. CONCLUSIONS: Respiratory physiotherapy with incentive
      spirometry significantly increases sputum clearance in cystic fibrosis patients,
      with no immediate repercussions on lung function or symptoms.

PMID- 10410208
TI  - [Diaphragmatic function during exercise in patients with severe COPD].
AB  - Ventilatory requirements increase during exercise. The respiratory muscles of
      patients with chronic obstructive pulmonary disease (COPD) are at a particular
      disadvantage when dealing with such increased demand. The objective of this study
      was to evaluate the changes in respiratory muscles brought on by exercise in such
      patients. METHODS: Twelve patients with severe CFOPD (FEV1 < 50% ref., 63 +/- 7
      years) were enrolled. Breathing patterns and esophageal (Pes and
      transdiaphragmatic (Pdi) pressures and SaO2 were measured during submaximal
      exercise/Ecsbmax, 60% of the maximum tolerated load). A sniff maneuver was
      performed with the patients breathing ambient air with added oxygen to achieve
      99% SaO2. We also measured level of FRC by inductive plethysmograph in a subgroup
      of five patients. RESULTS: During EXsbmax, SaO2 decreased (from 95.0 +/- 2.1 to
      92.3 +/- 4.0%; p < 0.01); Vt increased (717 +/- 199 to 990 +/- 297 cc, p < 0.01),
      as did respiratory rate (RR, 17 +/- 6 a 28 +/- 9; p < 0.01). Pes and Pdi were
      greater at Vt, changing from -12.4 +/- 4.8 to -27.0 +/- 10.1 and 16.6 +/- 6.1 to
      30.4 +/- 12.4 cmH2O, respectively (p < 0.01 in both cases), whereas no
      significant changes were observed for maximal effort (Pesmax, -61.4 +/- 16.5
      cersus -65.9 +/- 15.2 cmH2O; Pdimac 89.7 +/- 26.1 versus 81.7 +/- 35.7 cmH2O).
      Used as a global measure, Pdi/Pdimax worsened (0.21 +/- 0.12 a 0.42 +/- 0.20; p <
      0.01), as dud the diaphragm tension-time (TTdi; 0.07 +/- 0.04 to 0.15 +/- 0.06, p
      < 0.01). Intrinsic positive end-expiratory pressure (PEEPi) increased an
      estimated 2.7 +/- 2.1 to 9.4 +/- 5.8 cmH2O (p < 0.001), while FRC (delta 357 +/-
      274 ml). Durante el EXsbmax with oxygen supplementation, SaO2 did not decrease.
      However supplementation, though Ti/TTOT and maximal pressures remained unchanged.
      CONCLUSIONS: Respiratory muscle function changes induced by Exsbmax seem to
      relate mainly to a worsening of system mechanics.

PMID- 10410209
TI  - [History of the origin and the first 9 years of life of Archivos de
      Bronconeumologia].

PMID- 10410210
TI  - [Persistent airway leak and residual pleural cavity after lung resection].

PMID- 10410211
TI  - [Resection of bronchogenic carcinoma invading the diaphragm].
AB  - The prognosis for survival when small cell non-anaplastic bronchogenic carcinoma
      (SCN-ABC) invades the diaphragm has not been clearly established because the
      diagnosis is rare. We report a series of eight patients who underwent full
      resection of SCN-ABC with diaphragm invasion. One died during the postoperative
      period. Mean survival was eight months for the remaining seven and no patient
      lived five years. All died as a result of remote metastasis. Given these results,
      we question whether surgery is the most appropriate treatment for these patients.

PMID- 10410212
TI  - [Tracheal and pulmonary papillomatosis].

PMID- 10410213
TI  - [Q fever pneumonia with an unusual form of presentation].

PMID- 10410214
TI  - [Anterior trans-sternal thoracotomy as a surgical approach in bilateral pulmonary
      hydatidosis].

PMID- 10410215
TI  - [Bronchogenic carcinoma and bronchiolitis obliterans organizing pneumonia].

PMID- 10410216
TI  - [Rules for declaring tuberculosis as an occupational disease].

PMID- 10410217
TI  - [Free radicals and their role in inflammation].

PMID- 10410218
TI  - [Drug combinations in the treatment of asthma].

PMID- 10410220
TI  - [The pharmacoeconomics of asthma].

PMID- 10410219
TI  - [The secondary effects of inhaled steroids in asthma. New prospects].

PMID- 10410221
TI  - [Respiratory sleep disorders in COPD].

PMID- 10410223
TI  - [IBERPOC: an evaluation of the results. The Scientific Committee of the IBERPOC
      Study].

PMID- 10410224
TI  - [Counselling and the prescription of physical activity and their relation to the
      mountains].

PMID- 10410222
TI  - [Assessing exertion capacity in COPD. A critical review of walking tests].

PMID- 10410225
TI  - [Maximum respiratory flow on an expedition to the Himalaya].

PMID- 10410226
TI  - [Spirometry and arterial oxygen saturation on the ascent to Aneto].

PMID- 10410227
TI  - [Re-evaluation of the etiology of community-acquired pneumonia: the impact of the
      age of comorbidity and of the severity of the pneumonia and of other additional
      factors].

PMID- 10410228
TI  - [Severe community-acquired pneumonia. An update].

PMID- 10410229
TI  - [New quinolones].

PMID- 10410230
TI  - [The place of the new quinolones in the guidelines on the treatment of community
      acquired pneumonia].

PMID- 10410231
TI  - [The impact of molecular biology on pneumonology].

PMID- 10410232
TI  - [Practical guides for stopping the tobacco habit: what are they, why and how to
      use them?].

PMID- 10410233
TI  - [Practical guides for stopping the tobacco habit: a cost-effectiveness
      analysis?].

PMID- 10410234
TI  - [Home oxygen therapy. What future awaits it?].

PMID- 10410235
TI  - [Methods for the diagnosis of atopy in asthma].

PMID- 10410236
TI  - Total reactive antioxidant potential in human saliva of smokers and non-smokers.
AB  - Uric acid is the most important non-enzymatic antioxidant present in human
      saliva. There is a great variability among individuals, both in salivary uric
      acid content and saliva total reactive antioxidant potential (TRAP). The uric
      acid present in saliva correlates with plasma uric acid, suggesting that the
      former is imported from plasma. There are not statistical differences between
      uric acid or TRAP values in saliva of smokers and non-smokers. Also, smoking a
      cigarette does not modify the levels of antioxidants present in saliva.

PMID- 10410237
TI  - The lysine and methionine rich basic subunit of buckwheat grain legumin: some
      results of a structural study.
AB  - The 26 kD basic subunit of 280 kD buckwheat grain legumin has been partially
      characterized by measurement of its fluorescence and CD spectra. The protein has
      22% alpha-helix, 36% beta-sheet, 12% beta-turn and 30% random coil secondary
      structure. In comparison with the basic subunits of other legumin-type proteins,
      the buckwheat legumin subunit has a high content of lysine and methionine. The
      protein also has higher ratios of lysine to arginine and methionine to arginine.

PMID- 10410238
TI  - Activation of bradykinin B2 receptors increases calcium entry and intracellular
      mobilization in C9 liver cells.
AB  - In C9 rat liver cells bradykinin and kallidin increased (approximately 2-fold)
      the intracellular concentration of calcium, but the B1 agonist, des-Arg9
      bradykinin did not. The effect of bradykinin was inhibited by the B2 antagonists,
      Hoe 140 and N-alpha-adamantaneacetyl-D-Arg-[Hyp3, Thi5,8, D-Phe7]-bradykinin, but
      not by the B1 antagonist, des-Arg9-[Leu8]-bradykinin. The action of bradykinin
      was diminished, but not abolished, in medium without calcium. The peptide was
      able to increase intracellular calcium concentration in cells treated with
      thapsigargin. Bradykinin action was not observed in cells previously stimulated
      with this local mediator: however, under the same conditions, angiotensin II
      induced a clear increase in intracellular calcium concentration. Our data
      indicate that activation of bradykinin B2 receptors increase intracellular
      calcium concentrations by inducing both gating of the cation and intracellular
      mobilization in C9 liver cells. In addition, homologous desensitization was
      observed.

PMID- 10410239
TI  - RAPD profile based genetic characterization of chemotypic variants of Artemisia
      annua L.
AB  - The annual herbaceous plant, Artemisia annua L., belonging to family Asteraceae,
      is the natural source of the highly potent antimalarial compound, artemisinin,
      besides producing valuable essential oil. The plant is at present the sole
      commercial source for artemisinin production since all the chemical syntheses are
      non-viable. Therefore, economic and practical considerations dictate that plants
      with maximum content of artemisinin be found and/or ways to increase their
      artemisinin content be sought. The key to this selection and breeding is a
      comprehension of chemical and genetic variability and suitable selection(s) of
      elites from within the available population. In the present study, RAPD analyses
      of selected chemotypes from a decade old introduced population in India were
      carried out using arbitrary primers. The RAPD data clearly indicate the
      distinction amongst these plants. Further, the detection of highly polymorphic
      profiles (97 polymorphic markers out of a total of 101 markers) suggests the
      existence of very high levels of genetic variation in the Indian population
      despite geographical isolation and opens out a strong possibility of further
      genetic improvement for superior artemisinin content. UPGMA analyses of RAPD and
      phytochemical trait data indicate that the wide phytochemical diversity is
      included within the genetic diversity. These results further support the
      prospects for selection and breeding of superior artemisinin containing lines.

PMID- 10410241
TI  - Synthetic insulin fragment with insulin-like biological activity.
AB  - An insulin fragment, representing the C-terminal functionally important site of
      its molecule and responsible for receptor binding, was synthesized. The fragment
      consists of two peptides: a dipeptide (A 20-21) and an octapeptide (B 19-26),
      linked with a disulfide bond (A20-B19). The biological activity of the newly
      synthesized fragment relative to insulin was assayed for the influence on
      glycogenesis and for the ability to stimulate glucose uptake. Comparative tests
      for the biological activity of the synthesized fragment and of the intact hormone
      allowed us to conclude that the fragment has insulin-like properties.

PMID- 10410240
TI  - Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its
      interaction with the active site(s) of the enzyme.
AB  - Porphyrinogen carboxy-lyase is an enzyme that sequentially decarboxylates
      uroporphyrinogen III (8-COOH) to yield coproporphyrinogen III (4-COOH). In
      mammals this enzyme activity is impaired by hexachlorobenzene treatment, through
      generation of an enzyme inhibitor. The interaction of porphyrinogen carboxy-lyase
      inhibitor, extracted from the liver of hexachlorobenzene-treated rats, with
      substrate decarboxylation sites on the enzyme, was studied using four different
      carboxylated substrates belonging to the isomeric III series of naturally-formed
      porphyrinogens containing 8-,7-,6- and 5-COOH. Similar inhibitor effects were
      elicited against all the substrates assayed, with the exception of
      pentacarboxyporphyrinogen III in which decarboxylation was not inhibited to same
      extent. Enzyme protection assays in the presence of the different substrates,
      indicated that each porphyrinogen protects its own decarboxylation from inhibitor
      action. Preincubation of the inhibitor with normal enzyme increased its
      inhibitory effect. On the other hand, preincubation of both enzyme and inhibitor
      with superoxide dismutase or mannitol, did not alter inhibitory activity.
      Preincubation of the inhibitor with a number of amino acids showed that only
      arginine and its derivative N alpha-Benzoyl-L-Arginine ethyl ester interact with
      the inhibitor, noticeably reducing its ability to inhibit porphyrinogen carboxy
      lyase. Albumin, histidine, serine, cysteine and imidazol, were unable to quench
      inhibitor activity. The present results indicate that the inhibitor acts at the
      binding site of each porphyrinogen. Taking into account that arginine is related
      to enzyme activity, and that histidine is found at the binding site of the
      substrates, the results suggest that the inhibitor could bind to arginine
      residues, blocking the access of substrates to histidine and altering the
      adequate orientation for decarboxylation by masking the positively charged active
      site necessary for porphyrinogen binding to the enzyme. In addition an indirect
      effect of the inhibitor mediated through free radicals could be discarded.

PMID- 10410242
TI  - Evidence of carbamoylphosphate induced conformational changes upon binding to
      human ornithine carbamoyltransferase.
AB  - Human liver ornithine carbamoyltransferase undergoes absorbance changes in the UV
      region upon formation of the carbamoylphosphate-norvaline-enzyme ternary complex.
      The UV changes are similar in the presence of carbamoylphosphate alone, whilst
      they are lower in the presence of ornithine or norvaline alone. The extent of the
      UV changes correlates with the enzyme susceptibility to proteolytic degradation.
      The free native enzyme is completely and rapidly hydrolyzed by trypsin, whilst it
      is partially protected upon carbamoylphosphate binding. The extent of protection
      increases for the carbamoylphosphate-norvaline-enzyme ternary complex. These
      results strongly suggest that the binding of the first substrate, i.e.
      carbamoylphosphate, to human ornithine carbamoyltransferase induces a large
      protein isomerization, which regards the polar domain plus a part of equatorial
      domain of each subunit.

PMID- 10410243
TI  - Expression of the divergent transcription unit containing the yeast PET122 and
      OXA1 genes.
AB  - The nuclear PET122 gene of S. cerevisiae encodes a mitochondrial-localized
      protein that activates initiation of translation of the mitochondrial mRNA from
      the COX3 gene, which encodes subunit III of cytochrome c oxidase. The PET122
      locus contains two divergent transcription units: one is involved in expression
      of PET122 mRNA and the mRNA for an adjacent gene OXA1, which is also required for
      cytochrome c oxidase biogenesis, and the other is involved in expression of an
      antisense RNA that is complementary to about two thirds of the PET122 mRNA and an
      adjacent gene YER152C of unknown function. Steady state levels of OXA1, PET122
      sense and PET122 antisense RNAs were measured after growth of yeast cells under
      catabolite repressing or derepressing conditions, or after deletion of portions
      of the 5' flanking DNA of the genes. The results reported here indicate that the
      PET122 and OXA1 genes are unconventional in terms of the control of their
      transcription. Neither possesses a canonical TATA element and they exhibit no
      apparent need for native upstream DNA. These results raise the interesting
      possibility that PET122 and OXA1 transcription is controlled by downstream DNA,
      perhaps located within the coding regions of the respective genes.

PMID- 10410244
TI  - Superoxide anion and hydroxyl radical scavenging activities of vegetable extracts
      measured using electron spin resonance.
AB  - Radical scavenging by reconstituted lyophilized powders of water extracts from 16
      common vegetables was measured using electron spin resonance (ESR) with 5,5
      dimethyl-1-pyrroline-N-oxide (DMPO), hydroxyl radicals, (.OH) or superoxide anion
      radicals (O2.-), as DMPO-OH or DMPO-OOH spin adducts. On a dry weight basis,
      eggplant, and red, yellow and green bell pepper extracts showed potent superoxide
      anion radical scavenging activities (SOD-like activities). Ascorbate oxidase- or
      heat-treatments, decreased SOD-like activities in bell pepper extracts suggesting
      that ascorbate accounts for much of their free radical scavenging activity.
      Eggplant epidermis extract exhibited the most potent hydroxyl radical scavenging
      and SOD-like activities. Eggplant SOD-like activity did not decrease after
      ascorbate oxidase treatment, but decreased following ultrafiltration
      demonstrating that SOD-like activity is partially due to high molecular weight
      substances. Nasunin, an anthocyanin in eggplant epidermis, showed markedly potent
      superoxide anion radical scavenging activity, while it inhibited hydroxyl radical
      generation probably by chelating ferrous ion.

PMID- 10410245
TI  - Stabilization of the T-state of human hemoglobin by proflavine, an antiseptic
      drug.
AB  - The effect of proflavine (3,6-diaminoacridine), an antiseptic drug, on the
      spectroscopic and oxygen binding properties of ferrous human adult hemoglobin
      (Hb) has been investigated. Upon binding of proflavine to the nitric oxide
      derivative of ferrous human adult hemoglobin (HbNO), the X-band EPR spectrum
      displays the characteristics which have been attributed to the T-state of the
      ligated tetramer. In parallel, oxygen affinity for the deoxygenated derivative of
      ferrous human adult Hb decreases in the presence of proflavine. The effect of
      proflavine on the spectroscopic and ligand binding properties of ferrous human
      adult Hb is reminiscent that of 2,3-D-glycerate bisphosphate, the physiological
      modulator of Hb action.

PMID- 10410246
TI  - The amino acid sequence of ovocleidin 17, a major protein of the avian eggshell
      calcified layer.
AB  - The amino acid sequence of ovocleidin 17, a major protein of the chicken eggshell
      calcified layer, contains 142 amino acids including 2 phosphorylated serines.
      Data base searches show that ovocleidin belongs to a heterogeneous group of
      proteins consisting of a single C-type lectin domain (CTL). The most similar
      sequences with an average of 30% identical amino acids were those of pancreatic
      stone protein (lithostathine) and lectins and anticoagulant proteins from snake
      venom.

PMID- 10410247
TI  - Overexpression of human testis antigens in Escherichia coli host cells is
      influenced by site of expression and the induction temperature.
AB  - A panel of twenty human testis cDNA clones were expressed in an Escherichia coli
      expression system and six clones were found to express identifiable fusion
      polypeptides. Expression was found to be influenced not only by the site of
      localization of the polypeptide in the host cells, but also by the temperature
      used for induction. This emphasized the need for cytoplasmic and periplasmic
      expression of new antigens of unknown properties, as well as the use of
      temperatures of 30 degrees C or lower. A majority of the expressed polypeptides
      were mainly in an insoluble form. By reducing the induction temperature to 30
      degrees C production of the soluble fraction was further improved.

PMID- 10410248
TI  - The antioxidant status of patients subjected to total body irradiation.
AB  - BACKGROUND AND PURPOSE: Total body irradiation (TBI) is a routine preconditioning
      procedure for the treatment of leukemia and aplastic anemia, prior to bone marrow
      transplantation (BMT). Ionizing radiation generates reactive oxygen derived
      species (ROS) that can be removed by antioxidants. Our purpose is to determine
      the antioxidant status of patients undergoing TBI by evaluating the oxidant
      stress and their antioxidant capacity. MATERIAL AND METHODS: We evaluated by
      cyclic voltammetry (CV) the total antioxidant capacity (TAC) in plasma of 14
      patients undergoing TBI prior to BMT. The levels of the antioxidants, ascorbic
      acid (AA) and uric acid (UA) were determined by HPLC-ECD. The oxidant stress
      level was calculated by the ratio [dehydro ascorbic acid]/total ascorbic acid].
      RESULTS: TAC was reduced by 36% (p < 0.02) but after 4 months recovered to a
      level 22% higher than before the treatment (p < 0.05). Both, AA and UA, decreased
      following irradiation by 84% (p < 0.02) and 24% (p < 0.05) respectively, but
      returned to a level of 21% and 320% after 4 months compared to baseline values.
      The changes in [UA] were affected by Allopurinol (xanthine oxidase inhibitor),
      given as a routine pretransplant therapy until day -1. The [dehydroascorcbic
      acid]/[total ascorbic acid] (%) was 45% (range of normal controls = 13.2 +/-
      1.5%) and increased by 69% following TBI. In order to obtain a decrease in the
      TAC of plasma in vitro, comparable to that in vivo, a 1000 fold higher dose of
      irradiation was required. CONCLUSIONS: TBI caused a pronounced decrease in
      antioxidant capacity and an excessive increase in oxidant stress. We assume that
      TBI alters antioxidant homeostasis greatly enhancing the stress damage. CV
      measurements may lead to a better understanding of the balance between oxidant
      stress and antioxidant utilization, and to a reconsideration of the routine use
      of Allopurinol as pretreatment for TBI, and antioxidant support before and/or
      after TBI.

PMID- 10410249
TI  - Noncompetitive, Ca(2+)-independent inhibition of pyruvate dehydrogenase
      phosphatase by fluphenazine.
AB  - The effects of two different classes of calmodulin antagonists on the catalytic
      activities of purified pyruvate dehydrogenase (PDH) phosphatase and PDH complex
      (PDC) were studied. In general, PDH phosphatase was more strongly inhibited than
      PDC by the calmodulin antagonists with the following potency order: fluphenazine
      > chlorpromazine > thioridazine > triflupromazine. Promazine and two sulfonamides
      (W-5 and W-7) did not suppress PDH phosphatase activity at 1 mM concentrations,
      while about 20% of PDC activity was inhibited by these antagonists. Fluphenazine
      mediated inhibition of PDH phosphatase was observed with the purified PDC as well
      as intact mitochondria. Although Ca2+ stimulates PDH phosphatase activity, the
      addition of exogenous Ca2+ did not overcome the inhibition by calmodulin
      antagonists. These results suggest that the suppression of PDH phosphatase
      activity is dependent upon the structure of the individual calmodulin antagonist
      and appears to be Ca(2+)-independent. Kinetic analysis showed a noncompetitive
      inhibition of PDH phosphatase by fluphenazine, indicating that it binds to
      different site(s) from the catalytic site of the enzyme.

PMID- 10410250
TI  - Preparation and characterization of beta 1-bungarotoxin bispecific monoclonal
      antibody.
AB  - A hybrid hybridoma (tetradoma) that produces bispecific monoclonal antibodies
      (mAbs)2, which recognize two different epitopes on the A chain of beta 1
      bungarotoxin (beta 1-bgt) at peptide sequences 46-51 and 100-106, has been
      obtained by fusing two hybridoma cell lines. The bispecific mAb were observed to
      inhibit 98% of the enzymatic activity of beta 1-bgt and neutralize its lethal
      toxicity completely. The avidity between the bispecific mAb and beta 1-bgt was
      noted to be 4.5 x 10(10) (liter/nmol), which is about 45-150 folds higher than
      the avidity of its two parental mAbs. All the soluble complexes, obtained from
      bispecific mAb and beta 1-bgt with different molar ratios, emerged in the void
      volume of size exclusion chromatography column, indicating multiple complexes of
      beta 1-bgt and bispecific mAb were formed. Based on these results, it indicated
      that the binding of bispecific mAb with its two epitopes on beta 1-bgt, which
      facilitates the immuno-complex formation and enhances the avidity, also highly
      neutralizes the biological activity of beta 1-bgt.

PMID- 10410251
TI  - Changes of nuclear membrane fluidity during rat liver regeneration.
AB  - We have previously shown that the nuclear membrane fluidity is affected by lipid
      composition changes and that is very high, particularly in the hydrophobic core.
      The aim of this work is to study the modifications of nuclear membrane fluidity
      in relation to the cell cycle. Since compensatory hepatic growth is an
      informative and well characterised model for natural cell proliferation, the
      nuclear membrane fluidity, detected by two fluorescent probes, was studied at
      various regenerating times, ranging from 0 to 30 hours after partial hepatectomy.
      At 18 hours after partial hepatectomy the nuclear membrane fluidity increased and
      at 30 hours the higher values of hydrophobic core fluidity were observed. The
      behaviour of fluidity was related to the nuclear membrane neutral
      sphingomyelinase activity and, then, to the content of sphingomyelin. Therefore,
      the significant changes of the nuclear membrane fluidity and of the neutral
      sphingomyelinase activity found during rat liver regeneration suggested a their
      likely role in signal transduction pathways implying cell regeneration.

PMID- 10410252
TI  - Denitration of peroxynitrite-treated proteins by "protein nitratases" from dog
      prostate.
AB  - Putative "protein nitratases," which catalyze denitration of peroxynitrite (PN)
      treated, proteins, were detected in the crude extract of dog prostate. Nitratase
      activity was monitored by the decreased intensity of nitrotyrosine immunoreactive
      bands in Western blot and increased nitrate level in dialysate of incubation
      mixture, which contained prostate crude extract, protease inhibitors and a PN
      treated substrate, such as treated histone (III-S), BSA, invertase, or
      polylysine. Nitratases were activated by preincubation with m-calpain/Ca2+.
      Furthermore, after denitration, the activity of PN/DTT-treated invertase
      decreased to the similar activity level of DTT-treated invertase. At least two
      different types of nitratases may occur: type I, reductant-dependent, and type
      II, reductant-independent.

PMID- 10410253
TI  - Purification and partial characterization of a new proteolytic enzyme from the
      venom of Bothrops moojeni (CAISSACA).
AB  - A basic serine protease which is active on casein and fibrinogen was purified
      from Bothrops moojeni venom using a single step chromatography on a CM-Sepharose
      fast flow column. The enzyme, MOO3, was not hemorrhagic and presented only a
      trace of blood-clotting activity. Synthetic chromogenic substrates (azoacasein
      and azoalbumin) where not hydrolyzed by MOO3. Using polyacrylamide gel
      electrophoresis at pH 4.3, MOO3 showed as a single protein band. Using sodium
      dodecyl sulfate-polyacrylamide electrophoresis, MOO3 behaved as a single-chain
      protein with an approximate mol. weight of 27,000, both in the presence and
      absence of beta-mercaptoethanol. Its pI was 7.8 by electrofocusing. The enzyme
      did not contain neutral carbohydrates and its N-terminal amino acid was alanine.
      The amino acid composition showed 249 residues/mole, a high content of
      hydrophilic amino acids and 14 half-cystine residues, which should account for 7
      disulfide bonds. The protease cleaved the A-alpha chain faster than the B-beta of
      bovine fibrinogen and showed no effect on the delta-chain. Specific esterolytic
      activity of MOO3 on alpha-N-tosyl-l-arginine methyl ester was 29.64 mumol min-1 x
      mg-1. MOO3 represented 1.42% (w/w) of the initial desiccated venom. Its
      proteolytic activity was inhibited by beta-mercaptoethanol, leupeptin,
      phenylmethylsulphonyl fluoride and ethylenediamine tetraacetate.

PMID- 10410254
TI  - Purification and characterization of tripeptidyl peptidase I from Dictyostelium
      discoideum.
AB  - A tripeptidyl peptidase I from Dictyostelium discoideum was purified 744-fold to
      near homogeneity. The enzyme is 214 kDa in size and is composed of two monomers
      with a M(r) of 107 kDa. It has two pH optima at pH 4.5 and 5.9 and is a serine
      peptidase with no aminopeptidase or dipeptidyl peptidase activity. The enzyme was
      relatively specific showing activity on ala-ala-phe-p-nitroaniline but also acted
      on substrates with proline in the P1 position in contrast to mammalian TPP I. The
      K(m) values of the enzyme at pH 4.5 for ala-ala-phe-, ala-phe-pro- and ala-ala
      pro-p-nitroanilines were 27 microM, 437 microM and 888 microM, respectively. The
      enzyme is most abundant during the amoeba stage of the life cycle but is present
      in the early stages of development and may therefore have a dual role in the
      organism in mobilizing amino acids or in processing specific peptides or
      proteins.

PMID- 10410255
TI  - Resveratrol inhibits copper ion-induced and azo compound-initiated oxidative
      modification of human low density lipoprotein.
AB  - To investigate whether resveratrol, a polyphenolic compound in red wine, affects
      the oxidation of human low density lipoprotein (LDL), LDL purified from
      normolipidemic subjects was subjected to Cu(2+)-induce and azo compound-initiated
      oxidative modification, with and without the addition of varying concentrations
      of resveratrol. Modification of LDL was assessed by the formation of
      thiobarbituric acid reactive substances (TBARS) and changes in the relative
      electrophoretic mobility (REM) of LDL on agarose gels. Resveratrol (50 microM)
      reduced TBARS and REM of LDL during Cu(2+)-induced oxidation by 70.5% and 42.3%,
      respectively (p < 0.01), and prolonged the lag phase associated with the
      oxidative modification of LDL by copper ion or azo compound. These in vitro
      results suggest that resveratrol may afford protection of LDL against oxidative
      damage resulting from exposure to various environmental challenges, possibly by
      acting as a free radical scavenger.

PMID- 10410257
TI  - Diagnostic approach in a patient presenting with polymyalgia.

PMID- 10410256
TI  - Mechanisms of lupus: the role of estrogens.

PMID- 10410258
TI  - Radiological deterioration worsens despite clinical improvement in rheumatoid
      arthritis.

PMID- 10410259
TI  - Radiographic damage occurs early in rheumatoid arthritis and is predicted by some
      radiological, clinical and humoral features.

PMID- 10410260
TI  - Tissue distribution and persistence of arthritogenic and non-arthritogenic
      Eubacterium cell walls.
AB  - OBJECTIVE: To study the tissue distribution and persistence of arthritogenic and
      non-arthritogenic Eubacterium cell walls (CWs), using arthritogenic Eubacterium
      aerofaciens and non-arthritogenic Eubacterium limosum. METHODS: Eubacterium
      aerofaciens or Eubacterium limosum CW was injected into Lewis rats
      intraperitoneally. Inflammatory changes in the synovium and periarticular tissues
      were graded histologically. On days 14, 28 and 56 after the injection, the
      presence of CW in the liver, spleen, mesenteric lymph nodes and synovium was
      studied by indirect immunofluorescence. In parallel, CW-derived muramic acid in
      the liver and spleen was measured by gas chromatography-mass spectrometry. In
      addition, serum TNF-alpha, IL-1 beta and IL-10 concentrations were determined by
      ELISA. RESULTS: Systemic injection of Eubacterium aerofaciens CW, but not of
      Eubacterium limosum CW, resulted in chronic arthritis. Both E. aerofaciens and E.
      limosum CWs were observed in the liver and spleen at all of the time points
      studied. In addition, Eubacterium limosum CW was present in non-arthritic
      synovium on day 14. It was not, however, detected in the synovium or lymph nodes
      on days 28 and 56, in clear contrast to the rats injected with E. aerofaciens CW.
      According to the analysis by gas chromatography-mass spectrometry, non
      arthritogenic E. limosum CW had accumulated in the liver cells on days 14 and 28
      after the injection to a greater extent than arthritogenic E. aerofaciens CW,
      leading to a lesser distribution in the other organs. A weak trend was observed
      suggesting that the production of TNF-alpha and IL-1 beta, but not of IL-10, is
      stimulated better by arthritogenic CW than by non-arthritogenic CW. CONCLUSION:
      Our results indicate that non-arthritogenic CWs are handled by the rat's defence
      mechanisms in a different way than arthritogenic CWs. The tissue distribution and
      persistence of CWs play a role in arthritogenicity, but additional factors must
      exist to determine why the CWs of certain bacteria are arthritogenic and those of
      others are not.

PMID- 10410262
TI  - Evidence of disordered symptom appraisal in fibromyalgia: increased rates of
      reported comorbidity and comorbidity severity.
AB  - OBJECTIVE: Using a large series of unselected consecutive patients, to
      investigate whether patients with fibromyalgia differ from those with rheumatoid
      arthritis (RA) or osteoarthritis (OA) in the number of reported comorbid
      conditions and in their perceived importance, and thereby to investigate
      differences in symptom appraisal and somatization. METHOD: In a clinical care
      setting, 1,298 patients with fibromyalgia and 2,396 with RA or OA participating
      in longitudinal data bank research as part of their routine medical care
      completed questionnaires concerning the presence or absence of 23 comorbid
      conditions, and then rated the current importance of each condition to them.
      Additional information concerning psychological factors and disease severity was
      also obtained. RESULTS: In analyses adjusted for age and sex, patients with
      fibromyalgia reported more conditions (4.5 vs. 3.1) than those with RA or OA. In
      17 of 23 conditions, the condition was more commonly reported in fibromyalgia
      than in RA or OA. In 20 of the 23 conditions, the importance attached to the
      conditions by fibromyalgia patients exceeded that of the importance attributed by
      RA/OA patients. After adjustment for anxiety, statistical differences between the
      groups for importance was lost for 6 conditions. CONCLUSIONS: Fibromyalgia
      patients report more medical conditions and report that they are more important
      to them than do patients with RA or OA. These differences extend to conditions
      that might be expected to cause symptoms, as well as to those that are usually
      symptom free. These data suggest that, on average, patients with fibromyalgia
      appraise medical symptoms and their importance differently from patients with
      other rheumatic conditions.

PMID- 10410261
TI  - Mycobacterium tuberculosis infection in patients with systemic rheumatic
      diseases. A case-series.
AB  - OBJECTIVE: To describe the clinical characteristics of patients with systemic
      rheumatic diseases and tuberculosis. A retrospective case series from 1987 to
      1994, drawn from a tertiary-care hospital in Mexico City, was studied. RESULTS:
      Thirty patients were included (20 women, 10 men), with mean age of 39.8 years
      (range 14-66), and a mean duration of the systemic rheumatic disease of 44 months
      (1-372). The rheumatic diseases included systemic lupus erythematosus (SLE) (n =
      13), rheumatoid arthritis (7), polymyositis or dermatomyositis (5), and other
      diseases (5). During the six months previous to the diagnosis of tuberculosis, 22
      patients had received corticosteroids, and 13 others immunosuppressants.
      Mycobacterium tuberculosis was isolated from 18 patients. Pulmonary tuberculosis
      was found in 10 patients, and extrapulmonary tuberculosis in 20, seven of these
      with miliary disease. SLE was seen in 6 of the patients with miliary
      tuberculosis. The clinical manifestations were: fever (67%), weight loss (67%),
      diaphoresis (60%), cough and sputum (53%), lymph node enlargement (43%), and
      dyspnea (33%). Sixteen patients had an abnormal chest film. Of 18 patients tested
      by PPD RT-2, 8 had an induration > 10 mm. Patients were initially treated with 3
      or 4 anti-tuberculosis drugs for 15 days to 6 months, followed by 6 to 10 months
      of isoniazid plus rifampicin. Three relapsed, and 2 died of respiratory failure.
      CONCLUSIONS: This case series showed a particular pattern of tuberculosis in
      patients with systemic rheumatic diseases.

PMID- 10410263
TI  - Relation of plasma dexamethasone to clinical response.
AB  - OBJECTIVE: The clinical effects of high dosage pulse glucocorticosteroid (GS)
      infusion as a treatment for rheumatoid arthritis (RA) differ considerably between
      patients. The aim of the present study was to gain more insight into these
      differences in clinical response. METHODS: Twenty-three RA patients (6 M/17 F)
      with treatment-resistant active erosive disease were treated with GS pulse
      therapy, consisting of 3 infusions of 200 mg dexamethasone at 3-day intervals.
      Plasma dexamethasone and plasma cortisol levels, as well as the mononuclear cell
      glucocorticosteroid receptor density, were determined on days 0, 2, 6, 12 and 40
      after the start of therapy. Clinical evaluation consisted of the Thompson
      articular index, the erythrocyte sedimentation rate (ESR), and the serum
      concentration of C reactive protein (CRP). RESULTS: Plasma dexamethasone levels
      in RA patients determined during pulse therapy revealed the existence of two
      groups. One group reached significantly (p < 0.05) higher plasma levels than
      another group comparable for age and sex. The CRP, ESR and Thompson joint score
      prior to the start of pulse therapy were all higher (p < 0.05) for the high
      plasma dexamethasone group. The decrease in ESR, CRP and the Thompson joint score
      was also significantly greater (all p < 0.05) for the high plasma dexamethasone
      group. Plasma cortisol, as well as the GS receptor density at the start of
      treatment, did not differ between the two groups; both decreased after the first
      pulse in both groups and returned to pre-treatment values shortly after the last
      infusion. CONCLUSION: The treatment of refractory RA with dexamethasone pulse
      therapy is, on average, beneficial. The high plasma dexamethasone levels reached
      might depend on the greater severity of the disease in these patients prior to
      the start of the treatment, and result in greater changes in the disease
      parameters. Glucocorticosteroid receptor density measurements made during and
      directly after high dose pulse dexamethasone treatment proved to be unreliable
      because of the high plasma dexamethasone levels.

PMID- 10410264
TI  - Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs
      correlate with clinical efficacy in rheumatoid arthritis.
AB  - OBJECTIVES: To measure MTX polyglutamates in circulating erythrocytes (E-MTX),
      mononuclear cells (MNC-MTX) and polymorphs (PMN-MTX) in rheumatoid arthritis (RA)
      patients and to see whether these correlated with clinical efficacy and side
      effects. METHODS: Sixty-five patients (40F, 25M; mean age 57 yrs.) with RA (ARA
      revised criteria) who had been on weekly pulse MTX (2.5-37.5 mg) for at least 2
      months were entered into this study. The patients were classified as responders
      (R), partial responders (PR) or non-responders (NR) when blood was sampled for
      the MTX determination. Side effects since the initiation of MTX were also
      recorded. MTX-polyglutamates were measured (blinded to clinical details) using an
      enzymatic assay. RESULTS: E-MTX in responders and partial responders were
      significantly higher (p < 0.001) than in non-responders. Similarly, PMN-MTX were
      also higher, but the difference was only significant for the R group (p =
      0.0019). The differences in concentrations could not be explained on the basis of
      the dose, which tended to be higher in NR than in R (p = 0.085). The concommitant
      prednisolone dose was significantly lower in R than in NR (p = 0.001), as were
      the ESR and CRP (p = 0.007, and p = 0.05 respectively), but the MCV was higher (p
      = 0.047). E-MTX tended to be higher in patients with side effects, but this
      difference did not reach statistical significance (p = 0.15). CONCLUSION: The
      results suggest that circulating intracellular levels of MTX polyglutamates in
      RBC and PMN correlate with clinical efficacy but not with toxicity in patients
      with RA.

PMID- 10410265
TI  - The best approach to the problem of whiplash? One ticket to Lithuania, please.
AB  - The Quebec Task Force (QTF) on Whiplash Associated Disorders (WAD)--1995--sent a
      clear message that we need to re-evaluate the basis for our treatment strategies,
      and in particular place more emphasis on research to better define these
      strategies. Judging by many of the clinical strategies currently in use, the Task
      Force recommendations seem to have been largely ignored three years later. A
      further compelling reason to re-evaluate our current practices at this time is
      the finding of much more rapid recovery rates in some cultures, even with little
      or no therapy. This commentary is a frank consideration of the therapeutic
      community's responsibility to not only help solve the dilemma of whiplash, but
      also avoid contributing to the problem. We thus explore a new biopsychosocial
      model of whiplash, considering the effects of symptom expectation, amplification,
      and attribution in chronic pain reporting. Based on that model we propose a
      treatment strategy, and conclude that such strategies provide the only viable
      approach to this medicolegal and social dilemma.

PMID- 10410267
TI  - Decrease of respiratory burst in neutrophils of patients with ankylosing
      spondylitis by combined radon-hyperthermia treatment.
AB  - OBJECTIVE: To define the respiratory burst activity of neutrophils, the total
      anti-oxidative status of plasma, and the parameters of systemic inflammation in
      patients with ankylosing spondylitis (AS) before and after a combined radon
      hyperthermia treatment in the thermal tunnels of Bockstein-Bad Gastein in
      Austria. METHODS: In 20 patients with AS the effects of a total of 15 hours of
      radon-hyperthermia-treatment spread over a period of three weeks were studied.
      The respiratory burst activity of neutrophils was measured fluorometrically using
      dichlorofluorescein diacetate, the total anti-oxidant status was measured using
      azinodiethyl-benzthiazoline-sulphonate, and inflammation parameters were
      determined by routine laboratory assays. RESULTS: Before treatment, the basal
      neutrophil respiratory burst in patients (n = 20) was 409 +/- 62 fluorescence
      arbitrary units (AU; mean +/- SEM) and 359 +/- 37 AU in controls (n = 9; p >
      0.5); the stimulated respiratory burst (fMet-Leu-Phe, 10(-6) M) was 1,027 +/- 133
      AU in patients and 1,152 +/- 218 AU in controls (p > 0.5). After treatment, the
      basal neutrophil respiratory burst in patients (n = 19) was 137 +/- 16 and in
      controls it was 174 +/- 35 AU (n = 8; p > 0.1); the stimulated respiratory burst
      was 670 +/- 66 and 1,305 +/- 82 AU, in patients and controls respectively (p <
      0.001). No effects of treatment on the total anti-oxidant status of the plasma or
      on the parameters of inflammation were detected. CONCLUSION: Combined radon
      hyperthermia treatment reduces the respiratory burst activity of the blood
      circulating neutrophils in patients with AS. If respiratory burst activity from
      the neutrophils plays a role in the pathophysiology of ankylosing spondylitis,
      the observed reduction may be related to the beneficial effects of radon
      hyperthermia treatment.

PMID- 10410266
TI  - Osteoblast behaviour in the presence of bisphosphonates: ultrastructural and
      biochemical in vitro studies.
AB  - OBJECTIVE: A positive balance in bone remodelling is an important goal of bone
      metabolism both in the presence of the osteoporotic processes characteristic of
      ageing and, especially, of prosthetic implants. The aim of the present work was
      to obtain new information about the initial steps of osteoblastic growth in an in
      vitro osteoblastic model in the presence of two bisphosphonates. METHODS:
      Experiments were performed with Alendronate and Neridronate, two molecules used
      in the therapy of osteoporosis. Since differentiating features into osteoblastic
      cells are known to parallel the presence in the cytoplasm of alkaline phosphatase
      and osteocalcin, we also carried out immunohistochemical typing. RESULTS: Good
      differentiation and osteoblastic activity were generally observed in the cells in
      contact with these compounds, except for 10(-4) Neridronate, where biochemical
      data clearly indicated its toxic effect on the cells. CONCLUSION: The detection
      of osteoblastic markers associated with an ultrastructural picture of correct
      organellar morphology in our cultures further supports the hypothesis of a
      metabolically positive action of these molecules on osteoblasts.

PMID- 10410268
TI  - Lack of Fas and Fas-L mutations in patients with lymphoproliferative disorders
      associated with Sjogren's syndrome and type II mixed cryoglobulinemia.
AB  - OBJECTIVE: Murine models (MRL/gld/gld mice) and recent evidence in humans suggest
      a possible role of Fas and Fas ligand (Fas-L) germline mutations in the
      pathogenesis of autoimmune-related lymphoproliferation, including adult cases. In
      this study, the presence of Fas and Fas-L germline mutations was investigated in
      a consecutive series of adult patients with lymphoproliferative disorders
      occurring in the context of Sjogren's syndrome (SS) and type II mixed
      cryoglobulinemia (MC). METHODS: 11 patients (8 primary SS and 3 type II MC; F/M:
      10/1; mean age 64 yrs.) were investigated. All patients were suffering from
      atypical lymphoproliferative disorders or MALT lymphoproliferative lesions (mean
      duration 3.5 yrs.). Four patients later developed a malignant lymphoma. DNA from
      peripheral blood mononuclear cells from 11 patients and 10 controls was tested
      for germline mutations in the Fas gene (exons 4, 8 and 9) and Fas-L gene (exon 4)
      by the polymerase chain reaction-single strand conformation polymorphism (SSCP)
      method. RESULTS: All DNA samples from both patients and controls showed
      amplification of Fas and Fas-L specific fragments. Identical SSCP migration
      patterns were observed in all the cases, indicating the lack of mutations in the
      whole series. CONCLUSION: Although it cannot be excluded that Fas and Fas-L
      mutations might be present in exons different from those analyzed, our data do
      not support the hypothesis that germline mutations in these genes are responsible
      for a major subset of lymphoproliferative syndromes in adult patients with SS and
      type II MC. Additional studies would be worthwhile in SLE-related
      lymphoproliferation, which is, however, a subset of limited clinical relevance
      when considering all cases with autoimmune-related lymphoproliferation.

PMID- 10410269
TI  - Nitrite production in mouse 3T3 fibroblasts by bleomycin-stimulated peripheral
      blood mononuclear cell factors.
AB  - OBJECTIVE: It is well known that bleomycin induces tissue fibrosis, including
      pulmonary fibrosis or scleroderma-like conditions. However, the pathogenesis has
      not been completely elucidated. We recently observed that peripheral blood
      mononuclear cells (PBMCs) stimulated by bleomycin show growth stimulatory
      activity for fibroblasts. Nitric oxide (NO) is an important mediator of immune
      and inflammatory responses, and has recently been suggested to play a role in the
      pathogenesis of autoimmune disorders. In this study, we have examined whether
      bleomycin-stimulated PBMCs induce nitrite production in mouse 3T3 fibroblasts in
      vitro. METHODS: PBMCs were obtained from 6 patients with systemic sclerosis (SSc)
      and 6 normal volunteers, and stimulated by bleomycin; the culture supernatants
      were collected as conditioned medium (CM). The release of nitrite from 3T3
      fibroblasts after incubation with CM was determined by Griess reagents. Induction
      of inducible NO synthase (iNOS) mRNA expression in 3T3 fibroblasts after
      incubation with CM was examined by the reverse transcriptase-polymerase chain
      reaction (RT-PCR) method. RESULTS: Bleomycin induced significant nitrite release
      from PBMCs in a time-dependent manner. Stimulation with CM increased nitrite
      production in 3T3 fibroblasts, which was significantly inhibited by antibodies
      against interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha),
      and iNOS inhibitor, L-NMMA. CM from SSc patients induced higher amounts of
      nitrite from 3T3 fibroblasts, compared with that from normal subjects, although
      the difference was not significant. CM induced iNOS mRNA expression in 3T3
      fibroblasts in a time-dependent manner. CONCLUSION: These results suggest that
      bleomycin, as well as IL-1 beta and TNF-alpha, induce NO release from mononuclear
      cells, and that these cytokines furthermore stimulate fibroblasts to produce NO,
      which raises the possibility of the involvement of NO in the development of
      tissue fibrosis induced by bleomycin.

PMID- 10410270
TI  - Disease patterns of patients with Behcet's disease demonstrated by factor
      analysis.
AB  - OBJECTIVE: To explore the main patterns of Behcet's disease (BD) expression,
      applying factor analysis. METHODS: Sixty-eight BD patients were studied. The
      following disease manifestations were used for the factor analysis: genital
      ulcerations, typical skin lesions (erythema nodosum, folliculitis or papulo
      pustular rash), uveitis, CNS involvement, joint disease, deep vein and
      superficial vein thrombosis, and gastrointestinal manifestations. The results
      were further analyzed according to sex, HLA typing, and childhood vs. adult-onset
      disease. RESULTS: Five factors were derived, which accounted for 69% of the
      variance of the matrix. Factor 1 represented the association between folliculitis
      and genital ulceration. Factor 2 represented the association between papulo
      pustular rash and gastrointestinal symptoms. Factor 3 represented the inverse
      association between superficial vein thrombosis and erythema nodosum. Factor 4
      represented the correlation between deep vein thrombosis and neuro-Behcet. Factor
      5 represented joint disease. No difference was found between males and females in
      relation to factors 1, 2 or 5, but factors 3 and 4 had higher scores in male
      patients (p = 0.1 and p = 0.07, respectively). Factor 3 was significantly higher
      in patients with HLA-B5, compared to HLA-B5-negative BD patients (p < 0.001).
      Factors 1 and 3 were higher in patients with adult onset of the disease (p =
      0.07, and p = 0.003, respectively), while factor 2 was higher in patients with
      childhood-onset BD (p = 0.07). CONCLUSIONS: The application of factor analysis
      revealed possible associations between distinct types of skin lesions, or venous
      thrombosis, and other disease manifestations of Behcet's syndrome, some of which
      were sex, age at onset, or HLA-related.

PMID- 10410271
TI  - A 47-year-old woman with persistent watery diarrhea, proteinuria, proximal
      weakness and monoclonal gammopathy.

PMID- 10410272
TI  - Rheumatoid arthritis associated with methotrexate-induced pneumonitis:
      improvement with i.v. cyclophosphamide therapy.
AB  - Pneumonitis is one of the most serious adverse effects associated with low-dose
      weekly methotrexate (MTX) therapy. Immediate cessation of MTX, and the
      introduction of oxygen therapy and glucocorticoids usually results in a dramatic
      improvement in the pulmonary toxicity. We report here a case of MTX-induced
      pneumonitis in a patient with rheumatoid arthritis (RA). Severe hypoxemia and
      interstitial infiltration in both lung fields did not respond to the withdrawal
      of MTX and the administration of oxygen and steroid pulse therapy. When
      intravenous cyclophosphamide (CYC) pulse therapy was initiated, however, rapid
      physiologic and radiographic improvement was seen. Our case suggests that CYC
      treatment may have a beneficial effect on MTX-induced pneumonitis that is
      resistant to steroid therapy.

PMID- 10410273
TI  - Hepatotoxicity of parenteral gold therapy in rheumatoid arthritis: a case report
      and review of the literature.
AB  - We report a case of severe hepatotoxic reaction during gold therapy for
      rheumatoid arthritis. The previous literature on this condition is reviewed and
      the possible mechanisms of gold-induced hepatotoxicity are discussed.

PMID- 10410274
TI  - Takayasu's arteritis overlapping with systemic sclerosis.
AB  - We describe an unusual case of overlap between Takayasu's arteritis (TA) and
      systemic sclerosis (SSc). TA has been found in association with several diseases,
      but not with SSc. To our knowledge this is the first case report of TA associated
      with SSc in the literature. It is possible that the expression of the two
      diseases in our patient was influenced by the presence of genetic factors
      predisposing to both TA and SSc.

PMID- 10410275
TI  - Juvenile arthritis--who gets it, where and when? A review of current data on
      incidence and prevalence.
AB  - Epidemiological studies of chronic arthritis in childhood can provide clues to
      genetic determinants of disease manifestations and environmental triggers.
      Available data are difficult to compare, however, because of the heterogeneity of
      the disease, differences in the classification criteria used for definition and
      inclusion, and differences in source populations and case ascertainment.
      Nevertheless, when the data are interpreted according to the methodologies used,
      geographical and ethnic differences can be found with regard to occurrence rates,
      age at onset, subgroup distribution and immunological markers. Seasonal
      variations have been detected in systemic disease. Variations in the incidence of
      childhood arthritis over time have also been observed, indicating environmental
      influences on disease frequency, while familial aggregations suggest the presence
      of genetic factors. These epidemiological data from a challenging puzzle which we
      hope will provide clues to future understanding of etiologies and cures, with the
      help of basic scientific research.

PMID- 10410276
TI  - Clinical significance of anticardiolipin antibodies in juvenile idiopathic
      arthritis.
AB  - OBJECTIVE: Anticardiolipin antibodies (aCL) have been demonstrated in a large
      spectrum of autoimmune diseases. However, its occurrence in childhood, in
      particular in juvenile idiopathic arthritis (JIA), is not well established. The
      present study addressed the frequency and clinical significance of aCL in a group
      of JIA patients. METHODS: aCL (IgG and IgM isotypes), antinuclear antibodies
      (ANA), and rheumatoid factor (RF) were determined in 86 children with JIA (33
      systemic, 31 polyarticular and 22 oligoarticular onset type). Thirty-two juvenile
      systemic erythematosus lupus patients (JSLE) and 52 healthy children formed the
      control groups. The disease activity and functional status of the JIA patients
      were scored to study their possible associations with the presence of aCL.
      RESULTS: Serum aCL levels above the normal range were detected in 28/86 JIA
      patients (32.5%), 12/32 JSLE patients (37.5%), and 3/52 healthy children (6%).
      Positive aCL levels were slightly or moderately elevated (usually below 30 GPL
      and 20 MPL). The presence of aCL was not associated with the presence of ANA or
      RF. Associations between aCL and clinical parameters, such as disease onset,
      duration, activity or severity could not be established. No JIA patient had
      vascular thrombosis, thrombocytopenia or "livedo reticularis". CONCLUSION: aCL
      occurred in low titers in JIA children, in a similar frequency to that observed
      in JSLE. No association with JIA clinical parameters or the clinical features
      classically linked to the antiphospholipid antibody syndrome were observed.

PMID- 10410277
TI  - Primary Sjogren's syndrome in children and adolescents: proposal for diagnostic
      criteria.
AB  - OBJECTIVE: Primary Sjogren's syndrome (pSS) in childhood is a rare disease.
      Diagnostic criteria are available for adult patients only. In order to establish
      diagnostic criteria for juvenile pSS an analysis of 7 girls and one boy suffering
      from pSS with early onset is reported. Due to the rarity of the disease, data on
      patients with pSS reported in the literature are included in the proposal for
      modified diagnostic criteria. METHODS: The diagnosis of pSS was established
      according to the criteria for adulthood pSS, duly modified, which include
      clinical symptoms and laboratory immunological evaluation. RESULTS: The average
      age of our patients at clinical onset was 13.5 years (range: 10-17 yrs.).
      Clinical signs included systemic (fever, fatigue) as well as local (parotitis,
      vulvovaginitis, conjunctivitis) symptoms. Paralysis due to hypokalemia linked to
      renal tubular acidosis and central nervous system (CNS) involvement was seen in
      one patient. Asymptomatic renal tubular acidosis was diagnosed in another 2
      patients. Autoimmune hepatitis was present in 2 patients. All patients had
      laboratory abnormalities: hyperimmunoglobulinemia IgG, high titers of antinuclear
      antibodies (anti-SS-A and/or anti-SS-B) and elevated serum amylases. Sicca
      syndrome was never seen during childhood, although it developed later in 3
      patients, after 7 to 10 years of follow-up. CONCLUSIONS: It has been stressed
      that the classical diagnostic criteria for adult Sjogren's syndrome, especially
      sicca syndrome, are not applicable to a pediatric onset of the disease. On the
      other hand, the presence of typical laboratory abnormalities can allow the
      diagnosis of these patients in the early stages. Both laboratory and clinical
      symptoms typical for childhood are included in our proposal for diagnostic
      criteria applicable to juvenile pSS. Life-threatening conditions such as
      hypokalemic paralysis, CNS involvement and hepatitis may also occur in children.
      Sicca syndrome tends to develop much later in pediatric patients.

PMID- 10410278
TI  - Outcome of Keller resection arthroplasty in the rheumatoid foot. A radiographic
      follow-up study of 4 to 11 years.

PMID- 10410279
TI  - Familial Mediterranean fever with HLA B-27 positive ankylosing spondylitis in a
      young Armenian man.

PMID- 10410280
TI  - Soluble CD30 in primary Sjogren's syndrome.

PMID- 10410281
TI  - Remitting seronegative symmetrical synovitis with pitting edema syndrome
      associated with cryptogenic hepatocellular carcinoma.

PMID- 10410282
TI  - Treatment of thrombophlebitis of Behcet's disease with low dose cyclosporin A.

PMID- 10410283
TI  - Hormones, sex ratios and juvenile rheumatoid arthritis.

PMID- 10410284
TI  - Treatment of recurrent oro-genital ulceration with low doses of thalidomide.

PMID- 10410285
TI  - Multiple coronary occlusions associated with ST-segment elevation.

PMID- 10410286
TI  - Why do patients with hypertrophic cardiomyopathy have heart failure symptoms?

PMID- 10410287
TI  - Diagnosis and management of cardiac tamponade in the era of echocardiography.
AB  - Cardiac tamponade is a life-threatening condition. Accurate diagnosis and prompt
      intervention are necessary. Classically, clinical features of tamponade include
      pulsus paradoxus, tachycardia, increased jugular venous pressure, and
      hypotension. With the advent of echocardiography, confirmation of an effusion and
      accurate assessment of its hemodynamic impact can be achieved, frequently in the
      absence of overt clinical manifestations. The decision regarding treatment and
      timing of intervention must take into account the clinical presentation and
      echocardiographic findings, along with careful weighing of risks and benefits to
      the individual patient. Echocardiographically guided pericardiocentesis is the
      best available therapy for initial management of cardiac tamponade. It is simple,
      safe, and effective for removing pericardial fluid and reversing hemodynamic
      instability, and the use of a pericardial catheter for extended drainage has been
      associated with significant reduction in recurrence of fluid accumulation.

PMID- 10410288
TI  - Predicting mitral regurgitation following percutaneous mitral valvotomy with the
      Inoue balloon: comparison of two echocardiographic scoring systems.
AB  - BACKGROUND: Percutaneous balloon mitral valvotomy (PBMV) has become the procedure
      of choice for many patients with symptomatic mitral stenosis. However, the
      development of significant mitral regurgitation (MR) remains an infrequent but
      very important complication. The echocardiographic scoring system described by
      Padial et al. has been successful in predicting the development of severe MR
      following PBMV using the double balloon technique. HYPOTHESIS: We aimed to assess
      the applicability of this new scoring system in predicting a significant increase
      in MR with the Inoue balloon and to compare it with the established Wilkins
      score. METHODS: The echocardiograms of 23 patients who had undergone PBMV for
      symptomatic mitral stenosis were analyzed retrospectively using both scoring
      systems, and the severity of MR was determined from pre- and postprocedural
      studies. RESULTS: Post PBMV, significant MR occurred in four patients (17%) while
      severe MR occurred in two patients (9%). Padial scores [mean (standard error of
      the mean)] in the group of patients with and without significant MR were [9.1
      (0.8)] and [6.0 (0.3)], respectively (p = 0.002), while the Wilkins score was
      [7.5 (1.0)] and [6.4 (0.5)], respectively (p = 0.3). Using 8 as a cutoff point,
      the sensitivity and specificity of the newer scoring system was 83 and 100%,
      respectively, while the sensitivity and specificity of the Wilkins score was 50
      and 50%, respectively. The positive predictive value > 8 was 100% (4/4) for the
      Padial and 25% (1/4) for the Wilkins system. Accordingly, the negative predictive
      value < 8 was 89% (17/19) for the Padial and 73% (14/19) for the Wilkins system.
      CONCLUSION: The newer scoring system is better at reliably identifying patients
      at risk of developing significant MR from PBMV with the Inoue balloon.

PMID- 10410289
TI  - Surgical repair of tetralogy of Fallot in adults today.
AB  - BACKGROUND: Today, corrective surgery of native tetralogy of Fallot beyond
      childhood is a rare exception. In the years following the fall of the Berlin
      wall, 22 adults with uncorrected tetralogy presented to our center, mostly from
      former Eastern Block countries. HYPOTHESIS: Our aim was to examine whether adults
      with tetralogy of Fallot benefit from late surgical repair. Nineteen patients
      underwent corrective surgery; hospital mortality was 16%. Follow-up examination
      3.5 (0.3-9.7) years postoperatively consisted of chart review and a written
      questionnaire. Incidence of ventricular arrhythmias was 32% before surgery and
      increased to 50% 3.5 years after surgery. Clinical status and New York Heart
      Association classification were clearly improved. This was not reflected in an
      improvement of the patients' socioeconomic status, as none of the 9 patients in
      our group of 19, who were jobless before the surgery, experienced a change in
      employment status. Marital status did not change in any patient and, in
      particular, the number of single male patients remains high. Except for one
      nearly asymptomatic younger woman who had delivered four children, only one of
      the seven married women had delivered a child before and one of the younger women
      after cardiac repair, which we consider to be a positive effect of this surgery.
      Surgical correction of adult patients with tetralogy of Fallot carries a higher
      risk compared with correction in childhood. It improves quality of life but does
      not change socioeconomic habits.

PMID- 10410290
TI  - Comparison of coronary collateral circulation in diabetic and nondiabetic
      patients suffering from coronary artery disease.
AB  - BACKGROUND AND HYPOTHESIS: Although it is well established that diabetes mellitus
      (DM) induces more severe coronary artery disease (CAD), it is not known whether
      it contributes to the development of coronary collateral circulation. The present
      study examines coronary collateral circulation in diabetic and nondiabetic
      patients with angiographically verified CAD. METHODS: The study group consisted
      of 463 diabetic patients (382 men, 81 women) with a mean age of 60.3 +/- 8.8
      years, and 227 nondiabetic subjects (159 men, 68 women) with a mean age of 59.2
      +/- 9 years. The extension and functional capacity of coronary collateral
      circulation was assessed according to the Cohen and Rentrop grading system of 0
      to III. RESULTS: We found that diabetic patients had grade III collateral
      circulation more frequently than nondiabetic subjects (13.2 vs. 8.5%, p < 0.01).
      This finding was even more pronounced in diabetic men aged < 55 years compared
      with both nondiabetic men (20 vs. 3.4%, p < 0.001) and diabetic women (20 vs.
      2.2%, p < 0.001). Grade III collateral circulation was found to develop mainly at
      the left anterior descending (LAD) coronary artery and the right coronary artery
      (RCA), where complete occlusions of coronary arteries usually occur. CONCLUSIONS:
      Diabetic patients with CAD develop more extensive coronary collateral circulation
      than nondiabetic subjects, especially men aged < 55 years. The collateral
      circulation mainly develops at the LAD and RCA.

PMID- 10410291
TI  - Left ventricular filling in the hypertensive patient: long-term course and
      influence of treatment.
AB  - BACKGROUND: Hypertension is accompanied by abnormalities in left ventricular
      filling; however, there is a lack of agreement on the extent of the influence of
      antihypertensive treatment on them. HYPOTHESIS: The present study was designed to
      evaluate the long-term course of these abnormalities in both treated and
      untreated hypertensive patients. METHODS: Left ventricular filling assessed by
      pulsed Doppler echocardiography of mitral flow was studied over a long follow-up
      period in both untreated and treated hypertensive patients. This retrospective
      study included 73 hypertensive patients who had not received any treatment. They
      had been followed up for at least 3 years and were divided a posteriori into two
      groups: Group 1 comprised the untreated patients, while Group 2 included the
      patients who had received antihypertensive treatment throughout the follow-up
      period. RESULTS: In the overall population, age and heart rate measured during
      the Doppler examination were the only parameters that correlated significantly
      with mitral flow. No significant changes in blood pressure or left ventricular
      mass were observed in Group 1 (14 patients) over the study period. There was a
      slight but nonsignificant decrease in E/A ratio of mitral flow. In the treated
      patients, there was a drop in heart rate-adjusted E/A ratio, despite a reduction
      in blood pressure and left ventricular mass, at mean follow-up of 5 years.
      CONCLUSION: Antihypertensive therapy did not arrest the long-term reduction in
      E/A ratio in hypertensive patients despite reduction in blood pressure and left
      ventricular mass.

PMID- 10410292
TI  - Influence of thrombolytic therapy on the incidence of left ventricular thrombi
      after acute anterior myocardial infarction: role of successful reperfusion.
AB  - BACKGROUND: Previous studies have reported controversial results regarding the
      effectiveness of systemic thrombolysis in preventing left ventricular (LV)
      thrombus after acute myocardial infarction (MI). HYPOTHESIS: This study was
      performed to evaluate the influences of thrombolysis, and particularly successful
      reperfusion, on the incidence of LV thrombus formation after acute anterior MI.
      METHODS: In all, 191 patients suffering from a first attack of acute anterior MI
      were prospectively evaluated by two-dimensional echocardiography and coronary
      angiography, performed at the end of the first week and within the first two
      weeks of MI, respectively. Of these, 98 who presented within 12 h of onset of
      symptoms received intravenous streptokinase (1.5 million IU), while the remaining
      93 patients who, either because of contraindications or late admission, did not
      receive thrombolytic treatment served as control group. All patients received
      aspirin and full-dose anticoagulation with intravenous heparin. Successful
      reperfusion in the streptokinase group was assessed by enzymatic and
      electrocardiographic evidence. RESULTS: The overall incidence of LV thrombi was
      24.6% (47/191). When all patients were evaluated, no statistically significant
      difference was found between the frequency of LV thrombi in the patients who had
      thrombolysis (22.4%) and those who did not (26.8%), despite a trend toward the
      formation of fewer thrombi in the initial group (p > 0.05). However, the patients
      who had successful reperfusion with streptokinase (n = 64) had significantly
      reduced incidence of LV thrombi compared with those who did not receive
      thrombolytic therapy (20 vs. 26.8%, p < 0.05). Stepwise multivariate analysis
      suggested that LV abnormal wall motion score (p = 0.01) and presence of LV
      aneurysm were independent predictors of LV thrombus formation in patients with
      acute anterior MI. CONCLUSION: Not all patients who received streptokinase for
      acute anterior MI, but only those with successful reperfusion had reduced
      incidence of LV thrombi. The favorable effects of thrombolysis on LV thrombus
      formation are probably due to the preservation of global LV systolic function.

PMID- 10410293
TI  - Examining the psychosocial impact of implantable cardioverter defibrillators: a
      literature review.
AB  - BACKGROUND: The implantable cardioverter defibrillator (ICD) has proven to be
      superior to medications in treating potentially life-threatening ventricular
      arrhythmias, resulting in reduced mortality rates. Despite the number of patients
      receiving this therapy, its psychosocial impact is not well understood.
      HYPOTHESIS: The purposes of this paper are (1) to review the available literature
      documenting the psychosocial impact of the ICD on patients, (2) to hypothesize
      possible mechanisms for this psychosocial impact, and (3) to suggest clinical
      risk profiles and indications for psychological consultation. METHODS: Electronic
      and library searches (e.g., MEDLINE, PsychLit) were used to gather studies
      examining the psychosocial impact of the ICD. Only studies investigating
      psychosocial outcomes (e.g., psychological distress, quality of life, social and
      role functioning), either prospectively or cross-sectionally, were admitted into
      the review. No literature reviews or secondary sources were included. RESULTS AND
      CONCLUSIONS: Current research suggests that ICD-specific fears and symptoms of
      anxiety (e.g., excessive worry, physiological arousal) are the most common
      psychological symptoms experienced by ICD recipients, with approximately 13-38%
      of recipients experiencing diagnosable levels of anxiety. Depressive symptoms are
      reported at rates that are generally consistent with other cardiac populations.
      Although the incidence of psychological disorders appears to be similar to that
      found in general cardiac populations, specific ICD-related concerns such as fear
      of shock, fear of device malfunction, fear of death, and fear of embarrassment
      have been identified. Selected psychological theories such as classical
      conditioning, learned helplessness, and a cognitive appraisal model help to
      explain the occurrence of psychological symptoms post implantation. Psychosocial
      adjustment risk profiles indicate that young ICD recipients and those with high
      discharge rates may experience the most adjustment difficulties.

PMID- 10410294
TI  - Apparent bigeminy and pulsus alternans in intermittent left bundle-branch block.

PMID- 10410295
TI  - Mitral stenosis with left atrial thrombi.

PMID- 10410296
TI  - Pocket infection complicating inadvertent transarterial permanent pacing.
      Successful percutaneous explantation.
AB  - This report describes a patient admitted for the treatment of a pocket infection
      occurring 5 months after a dual chamber pacemaker implantation. The ventricular
      lead had been inadvertently placed into the left ventricle through the arterial
      system. After careful examination using transesophageal echocardiography and left
      heart angiogram, successful percutaneous extraction was performed without
      complication.

PMID- 10410297
TI  - The "Lone Eagle's" contribution to cardiology.

PMID- 10410298
TI  - Nonpharmacologic therapies that reduce blood pressure: a fresh perspective.
AB  - Traditional approaches to control the epidemic of blood pressure-related
      atherosclerotic cardiovascular disease (ASCVD) have largely focused on drug
      therapy in persons with hypertension. Still, nonpharmacologic therapy, also
      termed lifestyle modification, has an important and expanding role that
      complements drug therapy. Specifically, nonpharmacologic therapies can serve as
      initial therapy in Stage 1 hypertensive patients, facilitate medication step down
      or withdrawal in patients with well-controlled hypertension, prevent hypertension
      in high-risk populations, and reduce blood pressure in normotensive individuals
      and thereby lower their risk of ASCVD. Traditional lifestyle modifications that
      reduce blood pressure include sodium reduction, weight loss, moderation of
      alcohol intake, and increased physical activity. Such strategies have been
      prominently advocated in the Fifth Report of the Joint National Committee on
      Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
      Recommendations to increase potassium, magnesium, and calcium intake were based
      primarily on general health considerations, not for control of high blood
      pressure. In its sixth and most recent report (JNC VI) published in 1997, the
      Joint National Committee has extended its recommendations. In addition to the
      traditional lifestyle recommendations, the JNC VI advocates increased potassium
      intake for control of high blood pressure. Furthermore, this policy-making body
      now recommends a healthy dietary pattern, that is, one that is rich in fruits,
      vegetables, and low-fat dairy products, and reduced in saturated fat, total fat,
      and cholesterol. This diet, which was rigorously evaluated in the Dietary
      Approaches to Stop Hypertension (DASH) clinical trial, substantially lowered
      blood pressure in normotensive and hypertensive individuals. These recent
      developments reinforce the hypothesis that multiple dietary factors influence
      blood pressure. Nonpharmacologic approaches have enormous potential as a means to
      reduce blood pressure and control hypertension, thereby preventing the occurrence
      of ASCVD. The current challenge to health care providers, government officials,
      and the general public is to develop and implement effective clinical and public
      health strategies that lead to desirable lifestyle modifications.

PMID- 10410299
TI  - A dietary approach to prevent hypertension: a review of the Dietary Approaches to
      Stop Hypertension (DASH) Study.
AB  - BACKGROUND: Populations eating mainly vegetarian diets have lower blood pressure
      levels than those eating omnivorous diets. Epidemiologic findings suggest that
      eating fruits and vegetables lowers blood pressure. HYPOTHESIS: Two hypotheses
      were tested: (1) that high intake of fruits and vegetables lowers blood pressure,
      and (2) that an overall dietary pattern (known as the DASH diet, or DASH
      combination diet) that is high in fruits, vegetables, nuts, and low-fat dairy
      products, emphasizes fish and chicken rather than red meat, and is low in
      saturated fat, cholesterol, sugar, and refined carbohydrate lowers blood
      pressure. METHODS: Participants were 459 adults with untreated systolic blood
      pressure < 160 mmHg and diastolic blood pressure 80-95 mmHg. After a 3-week run
      in on a control diet typical of Americans, they were randomized to 8 weeks
      receiving either the control diet, or a diet rich in fruits and vegetables, or
      the DASH diet. The participants were given all of their foods to eat, and body
      weight and sodium intake were held constant. Blood pressure was measured at the
      clinic and by 24-h ambulatory monitoring. RESULTS: The DASH diet lowered systolic
      blood pressure significantly in the total group by 5.5/3.0 mmHg, in African
      Americans by 6.9/3.7 mmHg, in Caucasians by 3.3/2.4 mmHg, in hypertensives by
      11.6/5.3 mmHg, and in nonhypertensives by 3.5/2.2 mmHg. The fruits and vegetables
      diet also reduced blood pressure in the same subgroups, but to a lesser extent.
      The DASH diet lowered blood pressure similarly throughout the day and night.
      CONCLUSIONS: The DASH diet may offer an alternative to drug therapy in
      hypertensives and, as a population approach, may prevent hypertension,
      particularly in African Americans.

PMID- 10410300
TI  - Nut consumption, lipids, and risk of a coronary event.
AB  - In the past, many have avoided nuts because of their high fat content. The
      Dietary Approaches to Stop Hypertension (DASH) diet, however, recommends regular
      consumption of this food along with seeds and dried beans (4-5 servings per week)
      as part of a diet to control hypertension. Nuts are nutrient-dense and most of
      their fat is unsaturated. They are also perhaps the best natural source of
      vitamin E and are relatively concentrated repositories of dietary fiber,
      magnesium, potassium, and arginine, the dietary precursor of nitric oxide. Human
      feeding studies have demonstrated reductions of 8-12% in low-density lipoprotein
      (LDL) cholesterol when almonds and walnuts are substituted for more traditional
      fats. Other studies show that macadamias and hazelnuts appear at least as
      beneficial as fats in commonly recommended diets. Whether consuming modest
      quantities of nuts daily may promote weight gain is not known with certainty, but
      preliminary data suggest that this is unlikely. Four of the best and largest
      cohort studies in nutritional epidemiology have now reported that eating nuts
      frequently is associated with a decreased risk of coronary heart disease of the
      order of 30-50%. The findings are very consistent in subgroup analyses and
      unlikely to be due to confounding. Possible mechanisms include reduction in LDL
      cholesterol, the antioxidant actions of vitamin E, and the effects on the
      endothelium and platelet function of higher levels of nitric oxide. Although nuts
      may account for a relatively small percentage of dietary calories, the potential
      interacting effects of these factors on disease risk may be considerable.

PMID- 10410301
TI  - Dietary Approaches to Stop Hypertension (DASH) in clinical practice: a primary
      care experience.
AB  - BACKGROUND: The Sixth Report of the Joint National Committee on Prevention,
      Detection, Evaluation, and Treatment of High Blood Pressure placed increased
      emphasis on lifestyle modification for the prevention and management of
      hypertension. The Dietary Approaches to Stop Hypertension (DASH) diet, rich in
      fruits, vegetables, nuts, and low-fat dairy foods, with reduced saturated and
      total fats, was found in clinical trials to lower blood pressure substantially
      and significantly. The DASH diet appears appropriate for use in the primary care
      setting, although it is unknown whether results will mirror those found in
      clinical trial. METHODS: A review of the literature of successful physician-based
      dietary interventions and of the Stages of Change model as it applies to dietary
      behavior was completed. Some changes needed to adapt the DASH diet to the
      outpatient family practice setting were identified and implemented among a
      predominantly non-Caucasian (56%), female (61%) population. The most common
      concerns and diagnoses among this population are essential hypertension,
      diabetes, and general medical examination. RESULTS: Under study conditions, DASH
      reported that patients experienced an average reduction of 6 mmHg systolic and 3
      mmHg diastolic blood pressure. Results were better in those with high blood
      pressure--systolic dropped by 11 mmHg and diastolic dropped by 6 mmHg. This
      reduction occurred within 2 weeks of starting the plan. Our clinical experience
      matches these published results.

PMID- 10410302
TI  - Redox signaling: hydrogen peroxide as intracellular messenger.
AB  - Although superoxide anions (O2.-) and H2O2 are generally considered to be toxic
      by-products of respiration, recent evidence suggests that the production of these
      reactive oxygen species (ROS) might be an integral component of membrane receptor
      signaling. In mammalian cells, a variety of extracellular stimuli have recently
      been shown to induce a transient increase in the intracellular concentration of
      ROS, and specific inhibition of the ROS generation resulted in a complete
      blockage of stimulant-dependent signaling. In the next few years, therefore, a
      flurry of research activity is expected in relation to the elucidation of ROS
      production in response to receptor stimulation, identification of ROS target
      molecules, and investigation of ROS elimination. The goal of this report is to
      review our current knowledge of ROS-regulated signal transduction and propose
      future directions.

PMID- 10410303
TI  - Change of plasma lipoproteins by heparin-released lipoprotein lipase.
AB  - Lipoprotein lipase (LPL) is known to be attached to the luminal surface of
      vascular endothelial cells in a complex with membrane-bound heparan sulfate, and
      released into blood stream by heparin. LPL that catalyzes hydrolysis of
      triglyceride (TGL) on chylomicron and VLDL into two fatty acids and
      monoacylglycerol, is also implicated to participate in an enhancement of
      cholesterol uptake by arterial endothelial cells in vitro. But little is known
      about the LPL-mediated cholesterol uptake in physiological state. In this study,
      changes in blood lipid composition and levels of lipoproteins were determined
      after the injection of heparin in human. The level of LPL in plasma was increased
      from 0 to 11 mU/ml within 30-40 min post-heparin administration and decreased to
      the basal level within 2 h. The level of TGL in plasma decreased from 70 mg/dl to
      20 mg/dl within 1 h and gradually increased to 80 mg/dl within 4 h. However the
      level of total cholesterol in plasma remained at 140 mg/dl during an experimental
      period of 4 h. Analysis of Lipoproteins in plasma by NaBr density gradient
      ultracentrifugation showed that the level of VLDL decreased from 50 mg/dl to 10
      mg/dl within 1-2 h and returned to normal plasm level at 4 h. However there were
      no significant changes in the level of LDL and HDL. These results suggest that,
      at least, in normo-lipidemic subjects, increased free plasm LPL acts primarily on
      VLDL and failed to show any significant uptake of cholesterol-rich lipoproteins
      in human.

PMID- 10410304
TI  - Asp 280 residue is important in the activity of the Escherichia coli leader
      peptidase.
AB  - Leader peptidase is a novel serine protease in Escherichia coli, which catalyzes
      the cleavage of amino-terminal signal sequences from exported proteins. It is an
      integral membrane protein containing two transmembrane segments with its carboxy
      terminal catalytic domain residing in the periplasmic space. Recently, the x-ray
      crystal structure of signal peptidase-inhibitor complex showed that Asp 280, a
      highly conserved consensus sequence of E. coli leader peptidase is the closest
      charged residue in the vicinity of two catalytic dyad, Ser 90 and Lys 145, and it
      is likely held in place by a salt bridge to Arg 282. Possible roles of Asp 280
      and Arg 282 in the structure-catalytic function relationship were investigated by
      the site-directed mutagenesis of Asp 280 substituted with alanine, glutamic acid,
      glycine, or asparagine and of Arg 282 with methionine. All of mutants purified
      with nickel affinity chromatography were inactive using in vitro assay. It is
      surprising to find complete lose of activity by an extension of one carbon units
      in the mutant where Asp 280 is substituted with glutamic acid. These results
      suggest that Asp 280 and Arg 282 are in a sequence which constitutes catalytic
      crevice of leader peptidase and are essential for maintaining the conformation of
      catalytic pocket.

PMID- 10410305
TI  - Induction of fibronectin gene expression by inhibitors of protein phosphatase
      type 2B in normal and transformed fibroblasts.
AB  - Two intracellular signal pathways mediated by cAMP and protein kinase C (PKC)
      were involved in the regulation of FN gene expression (Lee et al., Exp. Mol. Med.
      30: 240, 1998). In this study, a possible involvement of protein phosphatase
      dependent pathways in the regulation of FN gene expression was investigated by
      using protein phosphatase type 2B (PP2B) inhibitors, cyclosporin A and ascomycin.
      Both cyclosporin A and ascomycin increased the levels of FN mRNA in WI-38 human
      lung fibroblasts and the SV40-transformed WI-38 cells but not in MC3T3-E1
      osteoblasts. The expression of FN appears to increase from six hours up to 48
      hours after treatment suggesting that it is not an immediate effect. In addition,
      this effect required a new protein synthesis. Neither cyclosporin A nor ascomycin
      affects the phorbol myristate acetate (PMA)-induced stimulation of FN gene
      expression and the same result occurred in vice versa suggesting the mechanism of
      PMA and cyclosporin A/ascomycin in the regulation of FN gene expression may share
      a common downstream pathway. Taken together, this study suggests that PP2B is
      involved in the regulation of FN gene expression in normal and transformed
      fibroblasts but not in osteoblasts.

PMID- 10410306
TI  - Role of Ras/ERK-dependent pathway in the erythroid differentiation of K562 cells.
AB  - The chronic myelogenous leukemic K562 cell line carrying Bcr-Abl tyrosine kinase
      is considered as pluripotent hematopoietic progenitor cells expressing markers
      for erythroid, granulocytic, monocytic, and megakaryocytic lineages. Here we
      investigated the signaling modulations required for induction of erythroid
      differentiation of K562 cells. When the K562 cells were treated with herbimycin A
      (an inhibitor of protein tyrosine kinase), ras antisense oligonucleotide, and
      PD98059 (a specific inhibitor of MEK), inhibition of ERK/MAPK activity and cell
      growth, and induction of erythroid differentiation were observed. The ras mutant,
      pZIPRas61leu-transfected cells, K562-Ras61leu, have shown a markedly decreased
      cell proliferation rate with approximately 2-fold doubling time, compared with
      the parental K562 cells, and about 60% of these cells have shown the phenotype of
      erythroid differentiation. In addition, herbimycin A inhibited the growth rate
      and increased the erythroid differentiation, but did not affect the elevated
      activity of ERK/MAPK in the K562-Ras61leu cells. On the other hand, effects of
      PD98059 on the growth and differentiation of K562-Ras61leu cells were biphasic.
      At low concentration of PD98059, which inhibited the elevated activity of
      ERK/MAPK to the level of parental cells, the growth rate increased and the
      erythroid differentiation decreased slightly, and at high concentration of
      PD98059, which inhibited the elevated activity of ERK/MAPK below that of the
      parental cells, the growth rate turned down and the erythroid differentiation was
      restored to the untreated control level. Taken together, these results suggest
      that an appropriate activity of ERK/MAPK is required to maintain the rapid growth
      and transformed phenotype of K562 cells.

PMID- 10410307
TI  - Hydrogen peroxide mediates doxorubicin-induced transglutaminase 2 expression in
      PC-14 human lung cancer cell line.
AB  - Increased expression of Transglutaminases 2 (TGase 2, TGase C) was observed in PC
      14 human lung cancer cells in association with doxorubicin resistance and the
      reduction of the enzyme expression was correlated with the increasing
      cytotoxicity of the drug (Han and Park, 1999). Hydrogen peroxide was suggested to
      be a key mediator for doxorubicin-induced DNA fragmentation leading to apoptosis.
      A possible role of hydrogen peroxide as a putative mediator of TGase 2 expression
      in the doxorubicin sensitive PC-14 cells was examined. TGase 2 expression was
      increased in PC-14 cells treated with doxorubicin in a dose-dependent manner
      resulting in the concomitant increase of reactive oxygen species. The rise of
      TGase 2 expression by doxorubicin treatment was inhibited by N-acetylcysteine or
      glutathione treatment, while direct addition of hydrogen peroxide to PC-14 cells
      induced TGase 2 expression. These results suggest that generation of hydrogen
      peroxide induced by doxorubicin treatment is one of the key factors in an
      enhancement of TGase 2 expression in PC-14 cells.

PMID- 10410308
TI  - Cholera toxin mediated regulation of the expression of Gq alpha and G11 alpha GTP
      binding proteins.
AB  - Previously it has been shown that persistent activation of the stimulatory
      adenylyl cyclase pathway with cholera toxin (CT) downregulates the Gs alpha
      polypeptide (80%) in a cAMP-independent manner in C6 glioma cells (Shah, 1997).
      This study was conducted to examine the short and long term effects of CT on the
      regulation of pertussis toxin-sensitive and -insensitive G proteins and their
      transcripts in C6 glioma cells. Treatment of C6 cells with CT (100 ng/ml) up to
      16 h had no effect on either Gi or Gq/11 alpha proteins. However, prolonged
      exposure (24-48 h) caused increased expression of Gi (20-30%) and Gq/11 alpha
      proteins (40%). Urea gradient gels, which can separate Gq alpha and G11 alpha
      proteins, revealed that prolonged CT treatment increased the expression of both
      of these G proteins. The CT-mediated enhanced expression of Gq alpha and G11
      alpha proteins was accompanied by increased mRNA levels of these proteins as
      determined by RT/PCR. Cyclic-AMP elevating agents like forskolin (10 microM) and
      db-cAMP (1 mM) mimicked the effect of CT on Gi but not Gq/11 alpha proteins.
      These studies show long term cAMP-dependent regulation of Gi and cAMP-independent
      expression of Gq/11 alpha proteins in C6 glioma cells.

PMID- 10410309
TI  - Synthesis of recombinant blood coagulation factor VIII (FVIII) heavy and light
      chains and reconstitution of active form of FVIII.
AB  - FVIII is synthesized as a single chain precursor of approximately 280 kD with the
      domain structure of A1-A2-B-A3-C1-C2 and it circulates as a series of metal ion
      linked heterodimers that result from cleavages at B-A3 junction as well as
      additional cleavages within B domain. Factor VIII is converted to its active
      form, factor VIIIa, upon proteolytic cleavages by thrombin and is a heterotrimer
      composed of the A1, A2, and A3-C1-C2 subunits. A1 subunits of factor VIIIa
      terminates with 36 residue segment (Met337-Arg372) rich in acidic residues. This
      segment is removed after cleavages at Arg336 by activated protein C, which
      results in inactivation of the cofactor. In the present study, site-directed
      mutagenesis of FVIII at Arg336 to Gln336 was performed in order to produce an
      inactivation resistant mutant rFVIII (rFVIIIm) with an extended physiological
      stability. A recombinant mutant heavy chain of FVIII (rFVIII-Hm; Arg336 to
      Gln336) and wild-type light chain of FVIII (rFVIII-L) were expressed in
      Baculovirus-insect cell (Sf9) system, and a biologically active recombinant
      mutant FVIII (rFVIIIm) was reconstituted from rFVIII-Hm and rFVIII-L in the FVIII
      depleted human plasma containing 40 mM CaCl2. The rFVIIIm exhibited cofactor
      activity of FVIIIa (2.85 x 10(-2) units/mg protein) that sustained the high level
      activity during in vitro incubation at 37 degrees C for 24 h, while the cofactor
      activity of normal plasma was declined steadily for the period. These results
      indicate that rFVIIIm (Arg336 to Gln336) expressed in Baculovirus-insect cell
      system is inactivation resistant in the plasma coagulation milieu and may be
      useful for the treatment of hemophilia A.

PMID- 10410310
TI  - Development of two novel nontoxic mutants of Escherichia coli heat-labile
      enterotoxin.
AB  - Escherichia coli heat-labile enterotoxin (LT) is composed of catalytic A and non
      catalytic homo-pentameric B subunits and causes diarrheal disease in human and
      animals. In order to produce a nontoxic LT for vaccine and adjuvant development,
      two novel derivatives of LT were constructed by a site-directed mutagenesis of A
      subunit; Ser63 to Tyr63 in LTS63Y and Glu110, Glu112 were deleted in LT delta
      110/112. The purified mutant LTs (mLTs) showed a similar molecular structural
      complex as AB5 to that of wild LT. In contrast to wild-type LT, mLTs failed to
      induce either elongation activity, ADP-ribosyltransferase activity, cAMP
      synthesis in CHO cells or fluid accumulation in mouse small intestine in vivo.
      Mice immunized with mLTs either intragastrically or intranasally elicited high
      titers of LT-specific serum and mucosal antibodies comparable to those induced by
      wild-type LT. These results indicate that substitution of Ser63 to Tyr63 or
      deletion of Glu110 and Glu112 eliminate the toxicity of LT without a change of
      AB5 conformation, and both mutants are immunogenic to LT itself. Therefore, both
      mLTs may be used to develop novel anti-diarrheal vaccines against enterotoxigenic
      E. coli.

PMID- 10410311
TI  - Characterization of regulatory elements on the promoter region of human ATP
      citrate lyase.
AB  - ATP-citrate lyase (ACL), an enzyme catalyzing the first step in biosynthesis of
      fatty acids, is induced during the lipogenesis and cholesterologenesis. We
      demonstrate that the region -213 to -128 of human ACL promoter is responsible for
      conferring glucose-mediated transcription. This region in the ACL promoter
      contains Sp1 binding sites determined by DNase I foot-printing assay. Gel
      retardation assay using oligonucleotides from -179 to -141 and -140 to -110
      showed two specific DNA-protein complexes postulated to be formed by
      transcription factor Sp1. Competition gel shift and supershift assays have
      confirmed that these DNA-protein complexes were the result of induced Sp1 as well
      as another Sp1-related proteins. Western blot analysis also demonstrated that
      transcription factor Sp1 was slightly increased in the nuclear proteins extracted
      from Alexander cells following supplementation of glucose. In addition,
      expression of 110 kDa protein reacting with antibody against Sp3 was dramatically
      increased by glucose supplementation, while isoforms of Sp3, about 80 kDa in size
      was decreased in its amounts. Our results suggest that changes in the expression
      of Sp1 family proteins play an important role in activation of the ACL promoter
      by glucose.

PMID- 10410312
TI  - [Issues in genitourinary tract infections].

PMID- 10410313
TI  - Clinical study on recurrence in bladder cancer patients undergoing total
      cystectomy--statistical analysis of factors related to recurrence.
AB  - A clinico-pathological study was performed retrospectively for 77 patients
      undergoing total cystectomy for primary transitional cell carcinoma of the
      urinary bladder between 1981 and 1995 to clarify the mode of recurrence, the risk
      factors which may affect recurrence following cystectomy and prognostic factors.
      Postoperative recurrence was recognized in 27 (35.1%) out of 77 patients and the
      one-, two- and three-year non-recurrent rates by the Kaplan-Meier method were
      75.3, 64.9% and 63.3%, respectively. The duration from cystectomy to recurrence
      was 1 to 102 months with a mean of 12.1 months, and approximately 92.6% of
      recurrence occurred within two years. Among 27 patients with recurrence, pelvic
      recurrence, distant metastasis, both of them and urethral recurrence were
      recognized in 6 (22.2%), 18 (66.7%), 1 (3.7%) and 2 (7.4%), respectively as the
      first site of recurrence. The overall one-, three- and five-year cause-specific
      survival rates of the 77 patients were 84.7, 71.1% and 65.6%, respectively. Of
      the 27 patients with recurrence, 25 (92.6%) died of bladder cancer. Of the
      factors related to recurrence or prognosis, pathological stage, lymphatic
      invasion, venous invasion, type of infiltration and lymph node metastasis but not
      pathological grade or adjunctive chemotherapy were significant risk factors for
      recurrence and prognostic factors in univariate analysis. However, lymphatic
      invasion was the only significant risk factor for recurrence and prognosis in
      multivariate analysis using Cox's proportional hazard model.

PMID- 10410314
TI  - [A clinical study of recurrence and progression of grade 3 superficial bladder
      tumor].
AB  - Forty-one patients who had grade 3, superficial, transitional cell carcinoma of
      the bladder were treated with transurethral resection of bladder tumor between
      January, 1986 and April, 1998. The clinicopathological studies were conducted on
      intravesical recurrence, disease progression, and prognosis using multivariate
      analyses. Intravesical recurrence was found in 18 patients (43.9%), and the
      recurrence-free rate was 77.0% for 1 year. The 3- and 5-year recurrence-free
      rates were 57.7% and 38.5% for patients with stage pTa disease, and 36.3% and
      36.3% for patients with stawe pT1-disease. There was a significant difference
      between the recurrence-free rates in the patients with stage pTa disease and
      those with stage pT1 disease (p < 0.01). Disease progression was observed after a
      mean period of 14.2 months after treatment in 6 patients (14.6%) with pT1 tumors.
      Three of these patients died of cancer. In the multivariate analyses with
      clinical and pathological factors, bladder irritability, urine cytology after
      initial treatment, and tumor multiplicity were the factors contributing to a high
      risk for recurrence. Intravesical instillation with Calmette-Guerin bacillus was
      found to prevent recurrence. These results suggest that radical surgery should be
      performed in a timely manner in patients with G3-stage pT1 tumors because they
      have a higher risk of recurrence and progression as compared to patients with G3
      stage pTa tumors.

PMID- 10410316
TI  - [A case of renal cell carcinoma associated with tuberous sclerosis].
AB  - Tuberous sclerosis is associated commonly with renal angiomyolipoma. On the other
      hand, the relation between tuberous sclerosis and renal cell carcinoma is not
      widely recognized. We report a case of renal cell carcinoma of the right kidney
      associated with tuberous sclerosis.

PMID- 10410315
TI  - [A case of pheochromocytoma detected by hypertensive crisis immediately after
      drip infusion urography].
AB  - We report a rare case of a 60-year-old man with a pheochromocytoma detected by a
      hypertensive crisis immediately after drip infusion urography. The patient
      initially consulted our hospital complaining of dysuria. He underwent a drip
      infusion urography and experienced a hypertensive crisis. The next day he was
      diagnosed with paralytic ileus. An endocrinological examination, abdominal
      computed tomography and 123I-metaiodobenzyl-guanidine scintigraphy revealed a
      pheochromocytoma. The tumor mass was removed, and immediately his blood pressure
      became normal and the paralytic ileus improved; however, temporary postoperative
      hypoglycemia was seen. Frequent monitoring of his blood glucose and the
      administration of an appropriate solution of dextrose, both during and after the
      operation, were recommended.

PMID- 10410318
TI  - [Three cases of metastatic renal tumor].
AB  - Since solitary metastatic renal tumors are not commonly diagnosed before death,
      the conclusive treatment of the metastatic renal tumor has not been established.
      We report three cases of metastatic renal tumors and discuss the indication of
      surgical therapy for metastatic renal tumors. The first case was in a 64-year-old
      male who underwent esophagectomy for squamous cell carcinoma. Seven months after
      the operation, a right renal tumor was found. The second case was in a 63-year
      old male who underwent right upper pneumonectomy for adenocarcinoma with a right
      renal tumor, which seemed to be a solitary metastasis. The third case was in a 69
      year-old male who underwent right pneumonectomy for adenocarcinoma. One month
      after the initial operation, a left renal cystic tumor was found. Since, in all
      cases, the tumors seemed to be solitary metastatic renal tumors without any other
      metastatic lesions, nephrectomy was performed. Unfortunately, however, the
      nephrectomy did not improve prognosis and all three patients did within 10 months
      after the nephrectomy. Nephrectomy may not be recommended in cases of metastatic
      renal tumors even if no other metastatic lesions can be found by various image
      examinations.

PMID- 10410317
TI  - [Cystic renal cell carcinoma diagnosed as a simple cyst preoperatively with
      incidental renal tumor: a case report].
AB  - A 54-year-old man visited our hospital with right incidentally-found renal tumor
      detected by ultrasonography. Computed tomography, magnetic resonance imaging and
      angiography showed a small tumor, 1.5 cm in size, at the upper portion and a
      simple cyst, 4 cm in size, at the lower pole of the right kidney. We enucleated
      the small tumor and aspirated the cyst with outer part resection of the cyst
      wall. Pathological findings of the tumor showed renal cell carcinoma, alveolar
      type, common type, clear cell subtype, G1, pT1, INF-alpha. Microscopic appearance
      of the excised cyst wall also revealed sheets of renal cell carcinoma inside the
      wall. Therefore, two weeks after the first operation, we performed right radical
      nephrectomy. The resected specimen had severe inflammation without any evidence
      of residual tumor. Eight months after the nephrectomy, no recurrence has
      occurred.

PMID- 10410320
TI  - [A case of spontaneous pyeloduodenal fistula].
AB  - A 61-year-old woman visited our hospital complaining of right flank pain and
      fever. The radiograph demonstrated multiple renal calculi. Radio renography
      showed no uptake in the right kidney. Therefore, we diagnosed her with
      pyonephrosis, and recommended open nephrectomy. However, she selected the
      conservative treatment with extra corporeal shockwave lithotripsy (ESWL). In
      spite of disappearance of multiple calculi, pyuria continued for 3 months after
      ESWL. Retrograde pyelography showed a fistula from the right pelvis into the
      duodenum. The patient was successfully treated by nephrectomy and duodeno
      fistelectomy.

PMID- 10410319
TI  - [A case of subclinical IgA nephropathy and cyclosporin associated arteriolopathy
      diagnosed by non-episode biopsy of graft kidney after renal transplantation].
AB  - We report a case of subclinical immunoglobulin A (IgA) nephropathy and
      cyclosporin associated arteriolopathy following renal transplantation. A 39-year
      old male with chronic glomerulonephritis received kidney transplantation from a
      two- human leukocyte antigen (HLA) mismatched cadaveric donor. The initial
      immunosuppressive therapy was triple-drug therapy with cyclosporin, prednisolone
      and mizoribine. Four months after transplantation, he had an acute rejection
      episode, and the renal function was recovered by steroid pulse and 15
      deoxyspergualin therapy. Eight years after transplantation, we conducted a non
      episode biopsy of the renal allograft to examine subclinical lesions. The
      histopathological findings showed cyclosporin associate arteriolopathy (CAA) and
      IgA nephropathy. There was no sign of acute or chronic rejection. At the present
      time, the renal function of the allograft is good. In conclusion, the non-episode
      biopsy of renal allograft is useful for examination of subclinical lesions.

PMID- 10410321
TI  - [Primary intestinal type adenocarcinoma of the urinary bladder: a case report].
AB  - A 43-year-old man was referred to our hospital with complaints of macroscopic
      hematuria, micturition pain, and pollakisuria. Cystoscopy revealed a papillary
      broad-based tumor of 4 cm in diameter at the posterior wall and trigone of the
      urinary bladder. A punch biopsy specimen was diagnosed histopathologically as
      adenocarcinoma mimicking colorectal cancer. Computed tomographic (CT) scan
      demonstrated a large tumor involving both the urinary bladder and the rectum.
      Total cystoprostatectomy and low anterior resection following colorectal
      anastomosis, double barreled colostomy, and ileal conduit urinary diversion were
      performed. The tumor was diagnosed histopathologically as primary intestinal type
      adenocarcinoma of the urinary bladder infiltrating the sigmoid colon and the
      small intestine. The patient died 12 months after the operation due to
      peritonitis carcinomatosa.

PMID- 10410322
TI  - [Augmentation ileocystoplasty as a treatment of vesicoureteral injury following
      rectal amputation: a case report].
AB  - A 65-year-old man underwent transperineal drainage of pelvic abscess after rectal
      amputation for rectal cancer. The bladder wall and right ureter were injured
      during this operation, which led to vesicoperineal fistula and contracted
      bladder. We performed partial resection of the bladder (fistulectomy),
      augmentation ileocystoplasty (Cup-patch technique), and bilateral ureteral
      reimplantation (LeDuc-Camey technique). After surgery, the patient was able to
      void without any residual urine or incontinence. There was no hydronephrosis or
      resicoureteral reflux postoperatively. Augmentation cystoplasty is usually
      performed to treat a contracted bladder, but it can also be applied for the
      reconstruction of complicated lower urinary tract injury, and may improve the
      quality of life (QOL) dramatically.

PMID- 10410323
TI  - [Intravesical instillation of Maalox for the treatment of bladder hemorrhage due
      to prostate cancer invasion: report of two cases].
AB  - Two cases treated by intravesical instillation of Maalox for bladder hemorrhage
      are reported. A 79-year-old man and an 81-year-old man were admitted because of
      macroscopic hematuria and bladder tamponade. In both cases, bladder hemorrhage
      caused by bladder invasion of prostate cancer had not improved after bladder
      lavage, intravenous drip infusion and medication of hemostatics. In the first
      case, bladder hemorrhage had decreased 4 days after the intravesical instillation
      of 50-100 ml Maalox for an hour per day. In the second case, irrigation of Maalox
      was performed because of the difficulty of intravesical instillation of Maalox
      due to irritable bladder. The bladder hemorrhage had not completely disappeared
      but improved 5 days after the bladder irrigation of 100 ml of Maalox with 100 ml
      of 0.9% NaCl for an hour per day. This method is easy and can be performed
      without complications. This method might be useful as first-line therapy in the
      case of severe bladder hemorrhage.

PMID- 10410324
TI  - [A case of prostate cancer associated with osteolytic bone metastases].
AB  - It is well known that prostate cancer metastasizes bone with osteoblastic change
      and that osteolytic change is rare. We report a case of prostate cancer that had
      bone metastases which were all osteolytic. A 62-year-old man was referred to our
      department because of abnormal prostatic acid phosphatase and pain in his right
      upper arm. Digital examination revealed an enlarged and hard prostate. A computed
      tomographic scan revealed multiple osteolytic changes and a bone scintigraphy was
      positive at these sites. Histopathology of both prostate and humerus showed
      poorly differentiated adenocarcinoma. He received castration and antiandrogen as
      hormonal therapy, but the patient's prostate specific antigen did not normalize.
      Therefore this case was suspected to be hormone-refractory prostate cancer.

PMID- 10410325
TI  - [Giant prostatic hypertrophy: a case report].
AB  - Benign prostate hypertrophy weighing more than 200 g is defined as giant
      prostatic hypertrophy. An 81-year-old man presented with urinary retention and
      underwent retropubic prostatectomy. Blood loss was 1,850 ml and he received 800
      ml of autologous blood. The removed specimen weighed 267 g and pathology revealed
      benign hyperplasia of the prostate. We collected 32 such cases from the Japanese
      literature.

PMID- 10410326
TI  - [A case of intrascrotal extratesticular schwannoma].
AB  - A 71-year-old man visited our hospital with a complaint of a right intrascrotal
      mass. An elastic hard mass was palpable in the right intrascrotal extratesticular
      space. Ultrasonography, computed tomographic scan and magnetic resonance imaging
      showed a left intrascrotal extratesticular tumor. However, preoperative diagnosis
      was not decided. Tumor resection was performed, and the histological diagnosis
      was schwannoma. Intrascrotal extratesticular schwannoma is very rare, and this
      case was considered as the second report in Japan.

PMID- 10410327
TI  - Partial purification of acetylcholine receptor binding components from the
      Duvernoy's secretions of blanding's tree snake (Boiga blandingi) and the mangrove
      snake (Boiga dendrophila).
AB  - Acetylcholine receptor (AChR) binding activity was detected in Duvernoy's
      secretions from B. blandingi and B. dendrophila as they competitively inhibited
      formation of 3[H]bungarotoxin-acetylcholine receptor complexes (3[H]Bgt-AChR) in
      a concentration-dependent manner. Secretions contained two types of toxin: low
      affinity and high affinity. Reversed-phase HPLC of B. blandingi and B.
      dendrophila secretions afforded 20 and 14 peaks, respectively. AChR binding
      components, as revealed by SDS-PAGE, had apparent molecular weights of 10 and 11
      kDa (B. blandingi) or 11 and 12 kDa (B. dendrophila). Periodic acid-Schiff
      staining indicated these were not glycoproteins. Alkylation with 4-vinylpyridine
      significantly decreased their ability to inhibit 3[H]Bgt-AChR binding, indicating
      disulphide bridges were necessary for receptor-binding activity. Attempts to
      sequence the B. blandingi peptides were negative as these components seemed to be
      N-terminally blocked.

PMID- 10410328
TI  - Examination of psoralens-induced photodermatitis in Wistar rats under scanning
      electron microscopy.
AB  - The psoralens are photoactivated plant biosynthetic compounds which are found in
      several plant families, including common fruits and vegetables. Synthetic forms
      of the psoralens bergapten (5-methoxypsoralen) and xanthotoxin (8
      methoxypsoralen) are extensively used in skin chemotherapy in combination with
      long-wave ultraviolet radiation (PUVA). Side effects of PUVA therapy are not,
      however, desirable, and this therapy has been linked with increased incidence of
      skin cancer in humans. The psoralens are known to be carcinogenic, mutagenic and
      teratogenic, and to cause photodermatitis. The main objective of this study was
      to document the effect of PUVA on the epidermis of rats. Female Wistar rats were
      administered dietary bergapten and/or xanthotoxin (0-200 mg/kg body) and exposed
      to UVA radiation (45 min./day) for four weeks. At the end of the four-week period
      the rats were sacrificed; skin samples were taken from the ears and the top part
      of the tail and fixed for examination by Scanning Electron Microscopy. The
      animals subjected to PUVA had significantly smaller scales on the tail epidermis
      (mean scale size for the control 926 mu vs. 725 to 805 mu for the psoralen
      treatment groups. The rats that received dietary psoralens also had significantly
      less hair on the ears compared with the control animals (mean number of hairs per
      millimeter over the ear edge for the control 54.9 vs. 2.00 to 10.7 for the
      treatment groups). The two compounds were synergistic in their ability to reduce
      scale size on the tail epidermis.

PMID- 10410329
TI  - The hind paw edema produced by staphylococcal enterotoxin B in female mice is
      modulated by sex hormones.
AB  - This paper describes the involvement of sex hormones in the edematogenic response
      produced by staphylococcal enterotoxin B (SEB) in the mouse hindpaw. Both the paw
      weight variation and the protein exudate produced by the intraplantar
      administration of SEB (12.5 micrograms/paw) to intact, randomly cycling female
      (IRCF) mice were significantly attenuated when the animals were ovariectomized
      (OVX). The attenuation of SEB-induced paw swelling produced by OVX was not
      reversed by estradiol (OE2) reposition. Thus, 4 h after the injection of SEB the
      increase in paw weight in OVX-mice treated with OE2 (10 micrograms/kg in corn
      oil) was 15.0 +/- 0.9 mg, while the exudation corresponded to 2.1 +/- 0.3
      micrograms of Evans blue dye/g of tissue. Neither of these values differed
      significantly from those obtained 4 h after the intraplantar injection of SEB
      (12.5 micrograms/paw) in non-treated OVX-mice (paw swelling, 14.0 +/- 0.8 mg; dye
      exudation, 2.0 +/- 0.3 micrograms/g, N = 6). Pretreating IRCF mice once a day for
      three days with human chorionic gonadotrophin (40 IU/kg, i.m.) reduced the paw
      edema produced by the toxin, thus indicating an involvement of gonadotrophins in
      this event. A pronounced decrease in paw weight variation (about 45%) and dye
      exudation (61%) was detected when IRCF mice were previously treated every 72 h
      with three injections of OE2 (10 micrograms/kg in corn oil, i.m.). Similar
      situations were also seen when the animals were pretreated at 72 h intervals with
      three injections of testosterone (10 mg/kg in corn oil, i.m.). We conclude that
      the paw edema induced by SEB in female mice is hormonally regulated. Our results
      also indicate that the HPA-immune axis is involved in this phenomenon.

PMID- 10410330
TI  - Partial amino acid sequence and biological characterization of elegatoxin,
      hemorrhagic toxin from Trimeresurus elegans (Sakishimahabu) venom.
AB  - A hemorrhagic toxin, designated Elegatoxin, was isolated from the venom of
      Trimeresurus elegans using HW-55, DEAE-Sephacel, CM-Cellulose and Mono S column
      chromatographies. The purified toxin was shown to be homogeneous by sodium
      dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, isoelectric
      electrophoresis, and Ouchterlony immunodiffusion. Elegatoxin has a molecular
      weight of 26,000 with an isoelectric point of 8.6. The toxin demonstrated both
      hemorrhagic and proteolytic activities. Hemorrhagic activity was inhibited by
      ethylenediaminetetraacetic acid (EDTA), ethyleneglycol-bis-(2-amino
      ethylether)N,N'-tetraacetic acid (EGTA), o-phenanthroline, and N
      bromosuccinimide, but not by amidinophenylmethanesulfonyl fluoride hydrochloride
      (APMSF). The minimum hemorrhagic dose was found to be 0.8 microgram/mouse.
      Elegatoxin possesses proteolytic activity as evidenced by hydrolyzing type IV
      collagen, actin and the A alpha, B beta, and gamma chains of bovine fibrinogen.
      This purified toxin contains 1 mol of zinc and 2 mols of calcium per mol of
      protein and a partial amino acid sequence was determined. The pathological and
      biochemical properties of Elegatoxin were investigated, and these results are
      reported in this paper.

PMID- 10410331
TI  - Hyperglycemic effect of a neurotoxic fraction (F3) from Naja haje venom: role of
      hypothalamo-pituitary adrenal axis (HPA).
AB  - The effect of bolus intravenous injection of sub-LD50 (35 micrograms Kg-1) of the
      neurotoxic fraction (F3) of the Egyptian cobra Naja haje on the plasma level of
      ACTH and serum levels of cortisol, insulin, glucose, total lipids,
      triacylglycerols, free fatty acids, total cholesterol, HDL and LDL-cholesterol,
      and glycogen content of liver and kidneys were studied in rabbit pretreated with
      cyproteron acetate (CA) or saline solution and propylene glycol (PG) to elucidate
      the possible role of the hypothalamo-pituitary adrenal (HPA) axis in the venom
      fraction-induced hyperglycemia. F3 increased cortisol and insulin level in both
      groups, whereas ACTH was found to decrease subsequent to the treatment. Serum
      glucose level was elevated by F3 treatment and this effect was substantiated in
      CA-treated rabbits. This hyperglycemia was concomitant with a decline in glycogen
      content of the liver and kidneys. A decline in serum total lipids,
      triacylglycerols, and free fatty acids was observed following F3 treatment, and
      this effect was intensified by CA-pretreatment. These data suggest that F3
      stimulates glucocorticoid release from adrenocortical cells which, in turn, may
      modulate both insulin and glucose turnover to maintain hyperglycemia during
      stress period. The possible underlying mechanisms were discussed.

PMID- 10410332
TI  - Development of reversed passive latex agglutination for detection of Thai cobra
      (Naja kaouthia) venom.
AB  - A simple, rapid, and sensitive diagnostic kit for detecting Thai cobra (Naja
      kaouthia) venom was developed using latex particles sensitized with venom
      specific immunoglobulin. The kit is capable of detecting 25-50 ng/ml of Thai
      cobra venom. The capability was not affected by human plasma. Specificity of the
      kit was proven using snake venoms from Vipera russelli, Calloselasma rhodostoma,
      Trimeresurus albolabris, Naja siamensis, Ophiophagus hannah, and Bungarus
      fasciatus. The diagnostic kit does not lose its capability under refrigeration
      for two months and by lyophilization.

PMID- 10410333
TI  - Cobrotoxin: structure and function.
AB  - Cobrotoxin is the main neurotoxic protein isolated from the venom of Taiwan cobra
      Naja naja atra. It is a small, basic protein consisting of a single polypeptide
      chain of 62 amino acids, cross-linked by four disulfide bonds. The disulfide
      bonds and Tyr-25 which is buried in the molecule form a central core to maintain
      and stabilize the active conformation of the toxin. Selective and stepwise
      chemical modifications of cobrotoxin indicate that at least two cationic groups,
      an epsilon-amino group of Lys-47 and a guanidino group of Arg-33, both of which
      are common to all known postsynaptic neurotoxins, held at a certain critical
      distance in the molecule, are functionally important for its neuromuscular
      blocking activity. The cDNA encoding cobrotoxin was constructed from the cellular
      RNA isolated from the venom glands of Naja naja atra by reverse transcription
      polymerase chain reaction. Sequencing several clones containing about 0.5 Kb DNA
      inserts contained a complete and full-length reading frame of 249 base pairs
      covering a precursor of cobrotoxin gene with a deduced mature protein sequence of
      62 amino acids which are identical to the amino acid sequence of cobrotoxin and a
      21 amino acid segment of signal peptide. Expression of cobrotoxin in E. coli
      vector generated a polypeptide which can cross-react with the antisera against
      the native cobrotoxin.

PMID- 10410334
TI  - Toxins from sea cucumbers (holothuroids): chemical structures, properties,
      taxonomic distribution, biosynthesis and evolution.
AB  - Studies on structures, biological activities, chemical properties, taxonomic
      distribution, biosynthesis, and evolution of toxins from sea cucumbers (the
      phylum Echinodermata, the class Holothurioidea) were reviewed with special
      emphasis on recent results from our laboratory. These toxins are triterpene
      oligoglycosides having very often one or several sulfate groups in carbohydrate
      moieties. Their aglycones belong to lanostane derivatives and sometimes contain
      shortened side chains. Many aglycones are labile in the acid medium. There is a
      relationship between structures of the glycosides and taxonomic positions of
      corresponding animals, producers of these toxins. Toxins from sea cucumbers act
      on delta 5-sterol-containing biological membranes with the formation of glycoside
      sterol complexes followed by the disturbance of membrane permeability and
      inhibition of activities of some membrane enzymes. The presence of the toxins
      causes the alterations in membrane sterol compositions of toxic sea cucumbers in
      comparison with non-toxic species. These alterations include the change of delta
      5-sterols for those having 7(8)- and 9(11)-double bonds as well as
      biotransformation of a part of free sterol fractions into sterol sulfates and
      sterol xylosides.

PMID- 10410335
TI  - Marine spongean cytotoxins.
AB  - Elucidation of naturally occurring toxins is very important from various points
      of view. Of these toxin studies, search for cytotoxins which show selective
      toxicity against tumor cells is a challenging subject of study. In search of new
      bioactive substances from marine organisms, we have been investigating cytotoxic
      constituents in marine sponges. Through bioassay-guided separation of marine
      spongean extracts by use of L1210 and KB cell lines, we isolated several potent
      cytotoxins. This article reviews our recent investigations of three spongean
      cytotoxins: 1) altohyrtin A and its allied compounds (macrolides, IC50 0.01-0.4
      ng/ml (KB cells)) from Hyrtios altum, 2) arenastatin A (a depsipeptide, IC50 5
      pg/ml (KB)) from Dysidea arenaria, and 3) callystatin A (a polyketide, IC50 10
      pg/ml (KB)) from Callyspongia truncata.

PMID- 10410336
TI  - Protein toxins produced by pathogenic vibrios.
AB  - Genus Vibrio includes some pathogenic species which are classified into two
      groups: a gastrointestinal infection group and an extraintestinal infection
      group. The vibrios produce various toxic proteins. Cholera toxin (CT) produced by
      V. cholerae O1 and O139 is a factor causing diarrhea with severe dehydration by
      ADP-ribosylation of the alpha subunit of the GTP-binding protein which stimulates
      adenylate cyclase activity. CT-like toxins are found in some strains of V.
      cholerae non-O1 or V. mimicus, but not in V. parahaemolyticus, another major
      diarrheagenic vibrio species. A thermostable direct hemolysin (TDH) is thought to
      be the pathogenic factor causing diarrhea in the vibrio. Hemolysin is the most
      widely distributed toxin in the pathogenic vibrios and plays various roles in the
      infection process. Protease activity is also common in the vibrios. Many of the
      proteases produced by the vibrios are a metalloprotease having a zinc atom
      immunologically cross reactive to each other. The proteases act not only for
      processing and activation of protein toxins but also direct toxic factors causing
      edematous or hemorrhagic skin lesions or disturbance of host defense system.

PMID- 10410337
TI  - Nephrotoxicity in snake envenomation.
AB  - There is a broad spectrum of renal involvement following snake envenomation. At
      the clinical level the renal manifestation may be absent or minimal. Mild
      proteinuria with abnormal urinary sediment may be observed. Significant
      proteinuria is uncommon. Hematuria and hemoglobinuria are seen in envenomation by
      vipers or crotalids, while myoglobinuria follows envenomation of sea snakes or
      elapids. Acute renal failure can occur in these snake bites. All renal structures
      can be involved. Mesangial proliferative glomerulonephritis is common. Tubular
      necrosis is the important pathological counterpart of acute renal failure. Three
      mechanisms including hemodynamic alterations, immunologic reactions, and direct
      nephrotoxicity are incriminated in the pathogenesis of renal lesions.

PMID- 10410338
TI  - Scientific aspects of traditional usage of bioresources.
AB  - Research on natural products provides not only knowledge and understanding of
      living organisms but chemical entities obtained from bioresources can also be
      used as structural models for further development in the various fields, notably
      in the agricultural and pharmaceutical sciences. Selected examples on the
      scientific aspects of traditional usage of bioresources are described.

PMID- 10410340
TI  - Otolaryngology research in Canada.

PMID- 10410339
TI  - Acetylcholinesterase from snake venom as a model for its nerve and muscle
      counterpart.
AB  - Acetylcholinesterase (AChE) plays a key role in cholinergic transmission. At the
      neuromuscular junction of vertebrates, for example, it allows a fine temporal
      control of muscle contraction. The presence of AChE in tissues devoid of
      cholinergic function is also well known and raises the question of its role. In
      particular, AChE is abundant in the venoms of Elapid snakes, except mambas. AChE
      purified from snake venom consists of soluble, hydrophilic monomers. Cloning of
      cDNA of the AChE from Bungarus fasciatus venom showed that its C-terminal peptide
      is very different from those of other AChEs. The partial sequence of the Bungarus
      fasciatus AChE gene shows that this peptide is encoded by a new alternative exon,
      called S for soluble and snake. It is a short very basic peptide of 15 residues.
      Analysis of the venom enzyme and in vitro expression experiments showed that the
      last eight residues are removed in the mature protein. AChEs from snake venoms
      vary in their sensitivity to peripheral site inhibitors, notably to fasciculins
      from mamba venoms. While Ophiophagus AChE is as sensitive as Torpedo enzyme (IC50
      around 10(-10) M), Naja and Heamacatus AChEs are insensitive to the toxin up to a
      concentration of 10(-6) M Bungarus AChE has an intermediate IC50 of 10(-8) M.
      Analysis of its sequence reveals two major differences in the peripheral site
      region, compared to Torpedo or mammalian AChEs: at position 70 it contains a
      methionine instead of a tyrosine, and at position 285 it contains a lysine
      instead of an acidic residue (glutamic or aspartic acid). Modification of these
      residues by site-directed mutagenesis, and enzymatic analysis of modified
      recombinant enzymes, confirmed that these two residues are implicated in the
      properties of the Bungarus AChE peripheral site. The presence of an alternative
      exon, which generates a soluble form of AChE in venoms, raises interesting
      evolutionary questions: Does it exist in snakes whose venom does not contain
      AChE, e.g., mambas? Did this exon pre-exist, for expression in other contexts?
      Snake venom AChEs offer an exceptional system for analyzing the mechanism of
      peripheral site inhibition, because of their wide range of activities.

PMID- 10410341
TI  - Middle ear instillation of gentamicin and streptomycin in chinchillas:
      morphologic appraisal of selective ototoxicity.
AB  - OBJECTIVE: To determine selective cochlear and vestibular ototoxicity of two
      aminoglycoside antibiotics (gentamicin and streptomycin) in the chinchilla model.
      Middle ear application of these agents mirrors the clinical practice of chemical
      vestibular ablation used in Meniere's disease. BACKGROUND: Middle ear
      instillation of gentamicin or streptomycin has become a popular form of
      vestibular ablative treatment for disabling Meniere's disease. The vestibular
      selectivity of these two drugs applied in this fashion has clinical support but
      is not fully established in humans. Our understanding in this regard has largely
      been limited to animal models exposed to systemic infusion of aminoglycosides.
      METHOD: Ten chinchillas underwent left middle ear instillation of one of three
      agents using variable dosing schedules: gentamicin (n = 6), streptomycin (n = 2),
      and saline (n = 2) as control. Animals were sacrificed for temporal bone studies
      using scanning electron microscopy. Morphologic changes in the cochlear and
      vestibular neuroepithelia were identified. RESULTS: Widespread cochlear and
      vestibular neuroepithelial injuries were observed with both gentamicin and
      streptomycin. Contralateral ototoxicity was variable and not related to the total
      dose of drug delivered. The effect of these two aminoglycosides on the dark cells
      of the vestibular system appeared negligible. CONCLUSION: We were unable to
      confirm the selective damage of vestibular end-organ in the chinchilla by either
      gentamicin or streptomycin, a phenomenon that is generally perceived to occur in
      humans. Chinchillas, like other small mammals, may not be an ideal model for the
      study of human ototoxicity.

PMID- 10410342
TI  - Endoscopic repair of cerebrospinal fluid rhinorrhea: is it the treatment of
      choice?
AB  - Between 1991 and 1998, 12 patients with cerebrospinal fluid rhinorrhea were
      operated on using the intranasal endoscopic approach. The procedure was
      successful in 10 cases. The endoscopic approach failed in two patients who had
      larger bony defects and herniating meningoencephaloceles. This paper analyzes the
      case material with respect to the etiology and site of leakage. The value of
      computed tomography and magnetic resonance imaging for preoperative localization
      of the leak is discussed. The technique of underlay fascia graft is described and
      discussion ensues regarding potential pitfalls that may lead to failure of leak
      closure.

PMID- 10410343
TI  - Retropharyngeal abscesses: a clinical and radiologic correlation.
AB  - OBJECTIVE: This study evaluates the efficacy at our centre of the lateral neck x
      ray and the computed tomography (CT) scan in differentiating retropharyngeal
      cellulitis from abscess in retropharyngeal space inflammatory process. METHOD: We
      reviewed the medical records of 37 patients with the diagnosis of retropharyngeal
      abscess or cellulitis hospitalized at the Centre Universitaire de Sante de
      l'Estrie in Sherbrooke between 1986 and 1997. Patients with a positive drainage
      at surgery were considered as retropharyngeal abscess and the rest as cellulitis.
      We measured the sensitivity, specificity, and positive and negative predictive
      values for the lateral neck x-ray and CT scan. Demographic and clinical data were
      also extracted for each patient. RESULTS: Twenty-five patients were classified as
      retropharyngeal cellulitis and only six patients as retropharyngeal abscess,
      although 13 patients went to the operating room for drainage. Results for the
      sensitivity and specificity were 80% and 100% for the lateral neck x-ray and 100%
      and 45% for the CT scan. Positive and negative predictive values for lateral neck
      x-ray were 100% and 94%, respectively. Forty percent and 100% were the values
      calculated for the CT scan. Clinical data were consistent with what has been
      reported in the literature. CONCLUSION: CT scan is helpful in the management of
      retropharyngeal abscess but has limits in differentiating cellulitis and abscess.
      Lateral neck x-ray was found to be very specific when the air sign was present.

PMID- 10410344
TI  - Colour Doppler ultrasonography of retropharyngeal abscess.
AB  - OBJECTIVE: This study was conducted to determine the capability of colour Doppler
      ultrasonography (CDU) in evaluating retropharyngeal abscess in children.
      MATERIALS AND METHODS: From July 1996 to February 1998, five children with
      clinical suspicion of retropharyngeal abscess were evaluated by CDU. The distance
      from internal carotid artery (ICA) to cervical vertebra (CV) (DICA-CV) at the
      upper cervical level was measured by longitudinal ultrasonography. Fifty healthy
      children, aged from 1 to 15 years, were recruited in the study to measure DICA-CV
      as control. Colour Doppler ultrasonography was used to differentiate abscess from
      other pathology and to detect carotid sheath invasion. Computed tomography was
      performed to confirm the sonographic diagnosis. Measurements of the DICA-CV at
      regular intervals were performed to monitor the progression of retropharyngeal
      abscess. RESULTS: Retropharyngeal abscess was highly suspected in all cases under
      sonographic studies. A patient was found to have carotid sheath invasion.
      Computed tomography confirmed the diagnosis of retropharyngeal abscess in all
      cases. Retropharyngeal abscess can be evaluated by the measured DICA-CV. The DICA
      CV decreased as the retropharyngeal abscess gradually resolved. CONCLUSION:
      Colour Doppler ultrasonography offers a sensitive method to evaluate
      retropharyngeal abscess in children. It can also be used to monitor the
      progression of retropharyngeal abscess and avoid unnecessary radiologic
      examinations.

PMID- 10410345
TI  - Effect of nasal continuous positive airway pressure on esophageal function.
AB  - OBJECTIVE: The purpose of this study was to conduct a prospective investigation
      of the mechanism(s) of nasal continuous positive airway pressure (CPAP) upon the
      reduction of recumbent gastroesophageal reflux. DESIGN: Prospective assessment.
      SETTING: Health Sciences Center and St. Boniface General Hospital, Winnipeg,
      Manitoba. METHODS: An esophageal motility examination was conducted on 16
      patients during the application of nasal CPAP set at 0 cm, 4 cm, and 8 cm water
      pressure. Esophageal parameters studied were wave amplitude and velocity,
      midesophageal resting pressure, and upper and lower esophageal sphincter resting
      pressure. RESULTS: The midesophageal resting pressure increased significantly
      from a baseline of -3.5 +/- 1.4 mm Hg to -1.6 +/- 1.8 mm Hg at 4 cm CPAP (p <
      .01) and -0.9 +/- 1.2 mm Hg at 8 cm CPAP (p < .01). CONCLUSIONS: The known
      reduction of nocturnal reflux that occurs when patients use an application of
      nasal CPAP appears to be related to direct mechanical compression of the
      esophagus. Results of an earlier report suggesting a reflex response by the lower
      sphincter were not reproduced.

PMID- 10410346
TI  - Juvenile nasopharyngeal angiofibroma.
AB  - This is a retrospective study of 17 patients with juvenile nasopharyngeal
      angiofibroma treated from 1983 to 1996. Patients with Stage I or II disease
      according to the Fisch classification system were treated surgically by a
      transpalatal approach. One patient underwent a Le Fort I osteotomy and down
      fracture approach for access. Three patients underwent combined transpalatal and
      lateral rhinotomy for access, whereas one underwent a transcervical double
      mandibular osteotomy to facilitate the exposure. A patient with Stage IV disease
      underwent a combined subcranial frontonasal osteotomy plus a Le Fort I osteotomy
      for access to a massive angiofibroma. Initial surgical management prevented
      recurrence in 79% of patients. Two patients with intracranial extension were
      treated with primary irradiation therapy; their tumours became asymptomatic.
      Preoperative angiography and embolization were used to treat all surgical
      candidates. The use of newer craniofacial or subcranial techniques and
      infratemporal fossa approaches with osteotomies can provide access to large
      angiofibromas even when there is skull base or intracranial involvement. Surgical
      exposure may also be enhanced by the use of the Le Fort I osteotomy and down
      fracture approaches.

PMID- 10410348
TI  - Intracranial facial nerve reconstruction.
AB  - Surgery for tumours of the cerebellopontine angle (CPA) or the internal auditory
      canal (IAC) is sometimes complicated by the severing of the seventh nerve. Many
      procedures are available for facial reanimation. Among these, primary
      intracranial VII-VII reanastomosis is considered as the method of choice. This
      series reviews all the cases of primary intracranial facial nerve reconstruction
      that we have performed either directly or with the use of a nerve graft
      interposition. Functional results are analyzed according to the House-Brackmann
      grading scale. The advantages and benefits of this technique are discussed as
      compared with other methods of facial reanimation, namely, the hypoglossal-facial
      anastomosis.

PMID- 10410347
TI  - Effect of diameter of microvascular interposition vein grafts on vessel patency
      and free flap survival in the rat model.
AB  - Interposition vein grafting is an important technique in microvascular free
      tissue transfer. Studies in rats have demonstrated that the patency rate of
      vessels is not affected by interposition grafting when the vein grafts and
      receipt vessels are of similar diameter. Size discrepancy between vein grafts and
      recipient vessels is frequently encountered in clinical practice and may
      potentially be an important factor in anastomotic patency. This study was,
      therefore, designed to assess the effect of vein graft diameter on the patency of
      arterial repair and survival of a groin free flap in the rat model. Forty-nine
      Sprague-Dawley rats were used. The inferior epigastric and femoral veins were
      used to reconstruct the femoral artery in situ (12 rats, 24 anastomoses) and in
      groin free flaps (30 rats). The vessel patency with inferior epigastric (1:1 size
      match) and femoral (2:1 size match) veins was 100% in the non free flap model. In
      the free flap model, flap survival was 30% in the femoral (2:1 size match) vein
      graft group. This was significantly less than both the free flap epigastric vein
      graft group (90% survival) and primary anastomoses group (100% survival). The
      results of this study suggest that size-matched interposition vein grafts can
      provide a high degree of reliability, but with size mismatch vein grafts are
      prone to thrombus formation and subsequent free flap failure.

PMID- 10410349
TI  - Subjective visual vertical in patients with benign paroxysmal positional vertigo.
AB  - The ocular tilt reaction leads to an alteration in the subjective visual vertical
      (SVV). Nonsurgical peripheral vestibular dysfunction only rarely leads to changes
      in the SVV. To our knowledge, no studies have examined the effects on the SVV in
      patients with benign positional paroxysmal vertigo (BPPV) post Hallpike and
      Semont maneuvers. Sixteen patients with posterior canal BPPV were assessed in the
      vestibular clinic in Winnipeg, Manitoba. These patients had assessment of their
      SVV at baseline, post Hallpike and Semont maneuvers, and at follow-up 2 weeks
      later. These patients were also compared to a control group (n = 9). Ten of 16
      patients showed a statistically significant change in SVV post Hallpike maneuver.
      An even larger number of patients, 14 of 16, showed a significant difference when
      compared to the control group post Hallpike. These findings suggest that the
      inferior vestibular nerve may to some degree influence the ocular tilt reaction.

PMID- 10410351
TI  - Primary laryngeal amyloidosis in a child.

PMID- 10410350
TI  - Cutaneous metastasis from a parotid adenoid cystic carcinoma arising in a
      pleomorphic adenoma.

PMID- 10410352
TI  - Optimizing calvarial bone graft harvesting with the SIM/Plant software system.

PMID- 10410353
TI  - Smoke and TMJ?

PMID- 10410355
TI  - Practice guidelines for the assessment of children with sickle cell pain.
AB  - ISSUES AND PURPOSE: Pain is the most frequent and important problem for children
      with sickle cell disease (SCD), but it has been undertreated and understudied. A
      multidisciplinary group of healthcare providers, academics, and people with SCD
      and their families met to (1) examine the pain of vaso-occlusive events (VOE) in
      children and adults with SCD and (2) reach consensus about necessary improvements
      in care. CONCLUSIONS: Accurate assessment of pain is at the crux of effective
      care for children with VOE. This requires a trusting interactive relationship
      among patient, family, and healthcare team. Comprehensive pain assessment is a
      lifelong process in need of continued updating. PRACTICE IMPLICATIONS: Children
      with SCD seek treatment from nurses in many settings. Traditional care has been
      frustrating to both families and care providers. Children and adolescents with
      SCD pain would benefit from nursing care that considers patients' perspectives
      about pain and comfort as key determinants for treatment. A unified approach to
      pain assessment may be a significant factor in improving pain control.

PMID- 10410354
TI  - Examination of gavage tube placement in children.
AB  - ISSUES AND PURPOSE: A primary issue in ensuring safe and effective enteral
      feeding by tube is achieving and maintaining correct tube position. This study
      was conducted to determine the prevalence of tube placement errors, risk factors
      associated with these errors, and accuracy of commonly used bedside placement
      screening methods. DESIGN AND METHODS: In this descriptive study, 39 hospitalized
      children having one or more types of enteral tubes were studied prospectively.
      Tube placement was assessed across time, using three common placement-screening
      methods compared to radiographs. RESULTS: Tube placement error occurred in 43.5%
      of tubes at least once during the observation period. Children who were comatose
      or semicomatose, were inactive, had swallowing problems, or had Argyle tubes were
      more likely to have tube placement errors. PRACTICE IMPLICATIONS: Findings
      suggest that radiographs to document tube placement may be needed, at least on
      initial enteral tube insertion.

PMID- 10410357
TI  - Outcomes research: practice counts!

PMID- 10410356
TI  - Face to face with Sturge-Weber syndrome.
AB  - ISSUES AND PURPOSE: Chronic illness is a way of life for parents of children with
      Sturge-Weber syndrome (SWS), a rare progressive congenital disease that has as
      its defining feature a port wine stain. This case study describes the experience
      of one family living with a child with SWS. CONCLUSIONS: This family's struggle
      with a devastating syndrome and the ways in which they coped and maintained hope
      inform all those who care for families living with a chronically ill, disabled
      child. PRACTICE IMPLICATIONS: Social support is critical for families facing
      overwhelming care needs. Families also need anticipatory guidance about child
      rearing, developmental milestones, decision making, and coping strategies.
      Additionally, families may need help in mobilizing professional and family
      resources and in effectively using available services.

PMID- 10410358
TI  - Caring for children in adult settings.

PMID- 10410359
TI  - [The eosinophil: doctor Jekyll or mister Hyde?].

PMID- 10410360
TI  - [Cytokines: soluble factors in intercellular communication].
AB  - Cytokines (cyto:cell; kine:factor) are produced by cells and serve as chemical
      messengers for one type of intracellular communication. Cytokines play a central
      role in host defense mechanisms. Defense against infectious and tumoral disease
      depends on nonspecific myelomonocyte defenses in conjunction with specific immune
      processes. Both systems are regulated by various leukocytes in the blood and
      tissue. All these cell components are produced in the bone marrow from
      hematopoietic stem cells. Cytokines are soluble messengers allowing deployment
      and coordination of all cell systems. Despite the complexity of the cytokine
      network, we now have a better understanding of the interactions between the
      different components determining secretion and activity of these mediators. This
      knowledge may hold the promise of better control of immune and inflammatory
      responses. Experimental data shows that the cytokine balance can be modulated in
      auto-immune, immune deficiency, and malignant diseases, opening up new
      perspectives for therapy and perhaps vaccination.

PMID- 10410361
TI  - [Eosinophils: receptors, mediators, functions].
AB  - Eosinophils have been studied using various models. Resulting data indicate that
      these polynuclear cells may have good and bad effects on the host. Eosinophils
      have been shown to destroy parasites in vitro but also to contribute to
      inflammation especially in association with bronchial asthma. These findings
      illustrate the functional versatility of a cell with the ability to interpret
      messages from its environment including chemokines, cytokines, growth factors,
      lipid mediators, and neuropeptides. In succession, these signals can stimulate
      eosinophils to express a range of regulated (homeostasis) or unregulated
      (pathogenesis) activity. Some signals cause selective migration into target
      tissues, especially submucosa in contact with the environment. Other signals
      determine local function. Understanding these mechanisms will be crucial to
      development of effective management of persistent hypereosinophilia syndromes.

PMID- 10410362
TI  - [Eosinophilia and interleukin-5: role in pulmonary atopic processes].
AB  - Infiltration of some tissues including the lung by activated eosinophil
      leukocytes is a characteristic feature of allergic disorders. In asthma patients,
      eosinophils have been shown to promote and prolong inflammation of bronchial
      mucosa. This effect is due to the release by eosinophils of numerous inflammation
      stimulating mediators and cytokines as well as cationic proteins known to damage
      lung epithelium. Differentiation of eosinophils from their hematopoietic
      precursors as well as subsequent processes including maturation, chemotaxis, and
      activation are controlled mainly by interleukin-5 (IL-5). This cytokine is
      produced not only by a subpopulation of T-lymphocyte helpers, named Th2, but also
      by mastocytes and eosinophils themselves. A massive increase in IL-5
      concentrations as well as in mRNA for IL-5 synthesis has been detected in serum,
      broncho-alveolar lavage fluid, and bronchial mucosa of asthmatic patients. In
      animal models mimicking clinical manifestations of lung allergy, neutralization
      of IL-5 using specific antibodies inhibits eosinophilic infiltration into the
      airways and improves respiratory function. These findings suggest that release of
      IL-5 during atopic disorders is a cardinal step in the development of
      inflammation and lesions in asthmatic patients. Treatment with drugs that
      selectively inhibit the synthesis and/or effects of IL-5 could represent a new
      therapeutic strategy not only for allergic disorders but also for other diseases
      associated with blood and tissue eosinophilia.

PMID- 10410363
TI  - [Role of eosinophilia in atopic pathology].
AB  - Atopy corresponds to a heightened predisposition to develop an IgE-mediated
      reaction to allergens in the environment. Symptomatic manifestations of atopy
      include skin disorders, rhinitis, and allergic asthma. Tissue infiltration by
      polynuclear eosinophils is a shared feature of all atopic diseases. In asthma,
      eosinophilic infiltration is considered as a pathognomonic finding, proportional
      to severity. Eosinophils have been linked directly to epithelial damage
      responsible for asthma symptoms as a result of massive production of basic
      proteins which are toxic for the mucosa. Eosinophils also produce fibrosis
      inducing cytokines and contribute to remodeling of the airway. Activation of Th2
      lymphocytes accounts for the influx of eosinophils into the airway via production
      not only of IL-5 but also of chemokines such as RANTES, MCP-3, and, above all,
      eotaxine. Resolution of airway inflammation in asthma is related to eosinophil
      apoptosis occurring spontaneously or therapeutically in response to anti
      inflammatory agents. Based on current data, eosinophils can be considered as a
      pivotal factor in the occurrence of atopic manifestations and thus constitute a
      prime target for future immunotherapies.

PMID- 10410364
TI  - [The eosinophilic lung].
AB  - Eosinophilic lung disease comprises a diverse group of disorders characterized by
      eosinophilic pulmonary infiltration in association with other inflammatory cells.
      In patients with respiratory symptoms, usually associated with radiographically
      documented infiltrates, blood eosinophilia is a helpful but inconsistent
      diagnostic finding. Currently diagnosis is confirmed more often by
      bronchoalveolar lavage than by lung biopsy. Possible etiologies include
      parasites, mycotic agents, drugs, and angeitis. Remaining cases are classified as
      idiopathic eosinophilic lung disease including Carrington's disease, idiopathic
      hypereosinophilic syndrome, acute eosinophilic pneumonia, and Loeffler's
      syndrome. Mild eosinophilia is also a possible finding of bronchoalveolar lavage
      in several other disorders but the role of eosinophils is less important. The
      prognosis and treatment of eosinophilic lung disease varies depending on
      etiology. Corticosteroids are frequently used but treatment modalities also
      depend on etiology.

PMID- 10410365
TI  - [Idiopathic chronic eosinophilic pneumonia].
AB  - Idiopathic chronic eosinophilic pneumonia is a rare disease first described by
      Carrington 30 years ago. The cause is unknown. As illustrated by the case
      described in this report, most cases occur in asthmatic patients in the fifth
      decade of life. Cardinal features are respiratory symptoms, altered general
      status, laboratory evidence of inflammation, blood eosinophilia in most cases,
      and x-ray images showing the presence of infiltrates in both lungs. Diagnosis can
      be confirmed by detection of eosinophils in broncho-alveolar lavage fluid.
      Extrapulmonary involvement is uncommon and is suggestive of Churg and Strauss
      syndrome. In atypical cases, diagnosis requires histological study demonstrating
      infiltration of interstitial tissue and alveolar spaces. Differential diagnosis
      can be difficult since several disorders identified within the last 10 years are
      nosologically similar, e.g. acute eosinophilic pneumonia. In many cases,
      diagnosis is based on response to corticosteroid treatment which is highly
      effective on idiopathic chronic eosinophilic pneumonia. Frequent recurrence leads
      to corticosteroid dependence in 20 to 30% of cases.

PMID- 10410366
TI  - [The heart and the eosinophil].
AB  - The beneficial effects of polynuclear eosinophils (PE) are well known. However,
      under certain circumstances, PE can be harmful. The heart is a prime target for
      PE toxicity which is due to release of basic proteins by eosinophils including
      major basic protein, cationic protein, and peroxidase. The most common
      manifestation of PE toxicity is chronic parietal endocarditis (CPE) which
      regroups two entities: Loeffler's fibroplastic endocarditis and Davies'
      endomyocardial fibrosis. Loeffler's fibroplastic endocarditis occurs mainly in
      temperate climates. Patients present high, persistent eosinophil levels similar
      to those observed in essential hypereosinophilic syndrome (EHS) or Chusid
      syndrome. Davies' endomyocardial fibrosis occurs in tropical countries where
      eosinophilic helminthiasis are endemic. The incidence of eosinophilic myocarditis
      (EM) is low but probably underestimated. EM can be observed in any case involving
      PE and has been described in many cases of drug-induced atopy, in Churg and
      Strauss syndrome, and in EHS. The most common cause of death is short-term
      occurrence of cardiogenic shock or dilated hypokinetic cardiomyopathy. Some
      patients have been successfully treated by early, intensive corticosteroid
      therapy and/or heart transplantation. The nosological classification of EM and
      CPE remains controversial. The two disorders may form a continuum with CPE as the
      second phase. Other authors have suggested that EM and CPE result from the action
      of PE on two distinct targets, i.e. endothelial cells for EM and myocytes for
      CPE. In the future, it may be possible to identify subjects with a predisposition
      to PE-induced heart disease by studying of genes coding for interleukins (IL-5,
      IL-4, IL-3) and GM-CSF in the 5q31-q33 region of chromosome 5.

PMID- 10410367
TI  - [Acute eosinophilic myocarditis: a diagnostic and therapeutic emergency].
AB  - This report describes three histologically documented cases of acute eosinophilic
      myocarditis. These three cases illustrate the different clinical and therapeutic
      outcomes of this disease which can range from full recovery under prolonged
      corticosteroid treatment to requirement for emergency heart transplantation or
      death due to intractable cardiac insufficiency. In absence of specific clinical
      or laboratory data, diagnosis must be established in vivo by endomyocardial
      biopsy demonstrating eosinophil-rich inflammatory infiltration and necrotic
      lesions. Rapid decision-making is necessary to allow early initiation of
      intensive corticosteroid treatment without which the most likely outcome is
      death. Clinicopathological and experimental evidence suggests that acute
      eosinophilic myocarditis is caused by the cytotoxic effects of granule components
      (mainly major basic protein) released by activated polynuclear eosinophils.

PMID- 10410368
TI  - [Neuromuscular diseases with eosinophilia].
AB  - Neuromuscular diseases with eosinophilia include a number of disorders associated
      with variable degrees of muscle, peripheral nerve, and connective tissue
      involvement. Eosinophilic infiltration in blood and/or tissue is a consistent
      finding. In addition to the neurologic manifestations of systemic vascularitis,
      in particular Churg and Strauss syndrome, there are three main forms of
      neuromuscular disease. Diffuse fasciitis or Shulman syndrome which can be limited
      to the fascia or associated with perimyositis is sensitive to corticosteroids.
      Eosinophilic myositis corresponds to focal muscle involvement and is also
      sensitive to corticosteroids. Eosinophilic polymyositis is a manifestation of
      essential hypereosinophilic syndrome and is life-threatening. Eosinophilia
      myalgia syndrome and toxic oil syndrome are separate entities that occur in
      outbreaks and involve poisoning by ingestion of L-tryptophan and adulterated oil
      containing aniline respectively. The key to diagnosis of these neuromuscular
      diseases is muscle biopsy to detect the presence of polynuclear eosinophils.

PMID- 10410369
TI  - [Eosinophilia and renal pathology].
AB  - Although rare, renal involvement during hypereosinophilic syndromes can lead to
      life-threatening situations. Since eosinophilic renal lesions can occur in a wide
      range of primary or secondary diseases, diagnosis can pose difficult clinical
      dilemmas. In some settings, renal lesions may be a predictable complication as in
      essential hypereosinophilic syndrome or angiolymphoid hyperplasia with
      eosinophilia. In other cases, renal lesions may be a highly unusual event
      secondary to cholesterol embolization, drug-induced reactions, immunoallergic
      responses, eosinophilic helminthic infection, or maintenance hemodialysis. The
      mechanisms of renal involvement are complex. In hypereosinophilic syndromes,
      renal involvement has been attributed to the deleterious effects of eosinophil
      granules and possibly to micro-emboli from the heart in patients presenting
      fibroplastic endocarditis or eosinophilic myocarditis. Most secondary forms are
      usually due to an immuno-allergic process leading to deposit of immune complexes
      in glomeruli. The effects of polynuclear eosinophils could also be due to release
      of cytokines and other mediators such as leukotriens. Cholesterol embolization
      involves a different mechanism in which hypereosinophilia is often moderate and
      accessory to arteriolar lesions. Eosinophiluria may be observed in any setting
      but the prognostic value of this finding as well as the mechanism underlying
      remain unclear.

PMID- 10410370
TI  - [Soft tissue eosinophilic granuloma or Kimura's disease: a case report].
AB  - Soft tissue eosinophilic granuloma or Kimura's disease is a chronic inflammatory
      disorder of unknown etiology. It is endemic in the Far East but can occur
      sporadically in other populations especially Middle Eastern peoples as
      illustrated by the present case involving a 55-year-old man. Examination 8 years
      after an initial episode revealed masses in the cheek and submaxillary regions
      with hypereosinophilia and characteristic histological findings. The usual
      clinical presentation of Kimura's disease includes subcutaneous nodules with
      lymph node involvement or presence of tumor in the salivary glands. These
      clinicopathological findings require differential diagnosis with Hodgkin's
      lymphoma, dermopathic lymphoma, or Castelman's disease. However, the most
      difficult distinction involves angiolymphoid hyperplasia with eosinophilia. Final
      diagnosis requires anatomopathological study. The most frequently encountered
      histological criteria are preservation of node structure, highly developed
      germinal centers, eosinophilic infiltration, and presence of numerous
      postcapillary veinlets. Prognosis is favorable but multiple relapses are
      possible. Corticosteroid therapy is usually effective but radiation treatment may
      be necessary in patients with recurrent disease.

PMID- 10410371
TI  - [Eosinophilic gastroenteritis: an example of gastrointestinal toxicity of
      eosinophils].
AB  - Toxicity of polynuclear eosinophils in the digestive tract results from a cascade
      of immune responses involving various mediators including mastocytes and T
      lymphocyte helpers. Polynuclear eosinophils may be implicated in many digestive
      disorders. This involvement is well established in eosinophilic gastroenteritis
      which has become the model for study of eosinophil toxicity on the digestive
      tract. Considered to be of uncertain etiology up until 1998, this mechanism is
      well illustrated by the case described in this report involving infiltration of
      all layers of the small intestinal mucosa in a 23-year-old patients who responded
      well to corticosteroid treatment. This case provides the opportunity to update
      physiopathologic and therapeutic data concerning this unpredictable syndrome.
      Current evidence of transition forms from idiopathic hypereosinophilic syndrome
      casts doubt on the conventional classification of eosinophilic gastroenteritis
      and underlines the need for careful diagnostic work-up and prolonged follow-up.

PMID- 10410372
TI  - [Diagnostic approach to hypereosinophilia].
AB  - Blood hypereosinophilia is a common finding in medical practice requiring further
      investigation. There are a wide range of potential causes including atopic
      disorder, drug allergy, parasitic infection, certain forms of immune deficiency,
      inflammatory process, hemopathy, and malignant disease. Diagnosis of persistent
      hypereosinophilia not associated with parasitic infection is one of the major
      diagnostic dilemmas in medicine. If through investigation fails to achieve
      diagnosis, idiopathic hypereosinophilia may be suspected including the
      possibility of essential hypereosinophilic syndrome or Chusid syndrome. The
      primary determination for diagnosis of hypereosinophilia involves the presence or
      absence of parasitic infection. If parasitic infection is ruled out, it is often
      difficult to distinguish benign, self-limiting forms from severe forms requiring
      careful surveillance and subsequent treatment. From a pathophysiological
      standpoint, one may ask if some eosinophilic conditions are not due to
      deregulation of immunologic mechanisms that normally protect the organism against
      parasitic infection.

PMID- 10410374
TI  - [Diagnostic and treatment of hypereosinophilia upon return from the tropics: 102
      patients].
AB  - Management of blood eosinophilia in travelers returning from the tropics is
      controversial. In this prospective study, 102 asymptomatic tropical travelers
      underwent investigation and treatment for hypereosinophilia. In contrast with
      direct tests for parasitic infection which were positive in only 15% of cases,
      immunological tests were suggestive of helminthic infection is 77%. The most
      common diagnoses were toxocarosis (49%), strongyloidiasis (30%), and filariasis
      (19%). Anti-parasite treatment was undertaken based on laboratory findings (12
      cases) or on presumptive diagnosis using two-agent therapy (ivermectin and
      praziquantel) in 13 cases or three-agent therapy (ivermectin, praziquantel,
      flubendazole) in 77 cases. As a result of treatment, eosinophil count returned to
      normal in 61% of cases and decreased in 30%. These findings suggest that
      presumptive treatment of blood eosinophilia can be undertaken in tropical
      travelers using three anti-parasitic drugs: ivermectin (1 x 0.4 mg/kg),
      flubendazole (2 x 100 mg per day for 3 days), and praziquantel (1 x 40 mg). As a
      precaution before using ivermectin, tests should be performed to detect loiasis
      which can lead to adverse reactions.

PMID- 10410373
TI  - [Value of laboratory findings in the diagnosis of hypereosinophilia].
AB  - The investigation of hypereosinophilias (HE) is a long and complicated process
      requiring a close collaboration between biologist and clinician physicians. The
      latter especially will have to provide information on symptoms (association with
      a fever; a hepatitis) and on the epidemiological history (patient's occupation
      and country of origin, and/or time and place of the travels or stays out of the
      European Union). The first step of laboratory investigations consists of making a
      check blood count, then measuring the sedimentation rate. At the time of the
      second step, the measurement of total IgE (a concentration greater than 500 IU/ml
      is often linked to a helminthiasis), that of specific IgE for common inhalant
      allergens, and three stool examinations using Baermann's technique will be
      carried out. The request for parasitic serodiagnoses only will be done if the
      above-cited investigations are negative, and if HE persists after a therapeutic
      test. A panel of serological tests often needs to be performed. If a helminthic
      infection is suspected but the immunodiagnostic methods fail, these tests may be
      required again after a time of a few weeks. At this stage, the measurement of
      eosinophil cationic protein is useful, since a high level of eosinophil cationic
      protein is suggestive of non allergic HE.

PMID- 10410375
TI  - [Methods and criteria for studying polynuclear eosinophil activation].
AB  - The deleterious effects of eosinophilis in many disease associated with
      hypereosinophilia are due mainly to the ability of eosinophils to degranulate and
      release inflammatory substances into host tissues (e.g. proteins, lipid
      mediators, cytokines). Prior to degranulation, which may occur either after
      stimulation or for unexplained reasons, eosinophils undergo an activation
      process. This process comprises functional, metabolic, and structural changes
      that potentiate the stimulatory and/or regulatory activities of eosinophils. The
      present article describes methods that can be used for in vitro or ex vivo
      evaluation of polynuclear eosinophil activation. In vivo and ex vivo assessment
      of the activation status of eosinophils is a crucial step to a better
      understanding of the role played by these cells in various diseases. Up to now,
      the most widespread technique for evaluation of eosinophil activation consisted
      of studying cell density by centrifugation through discontinuous gradients. This
      method is both complex and time-consuming. Recently discovered surface molecules
      associated with eosinophil activation and technological advances allowing rapid
      and accurate sample analysis (whole blood flow cytometry) have opened the way to
      new methods for the study of eosinophils. A combination of ex vivo (flow
      cytometry, in situ hybridization) and in vivo (cell density analysis, titration)
      techniques will provide new insights into the physiology and heterogeneity of
      eosinophil function.

PMID- 10410377
TI  - [Hypereosinophilia: what is important to the clinician?].

PMID- 10410376
TI  - [Genetic control of hypereosinophilias].
AB  - Polynuclear eosinophils play a major role in host defense against infectious
      diseases and especially helminthiasis. Onset of hypereosinophilia can be
      attributed to two mechanisms which can occur separately or in combination. The
      first mechanism involves enhancement of medullary production and differentiation
      of eosinophils. The second is prolonged life span of eosinophils. Response to
      eosinophils depends on various cytokines including IL-5, IL-4, IL-3 and GM-CSF.
      Since it contains the genes coding for these cytokines, the 5q31-q33 region of
      chromosome 5 is the focus of study on genetic control of human hypereosinophilia.
      The goal of these studies is to allow screening of subjects predisposed to
      helminthic infection and to deregulation of immune responses that may lead to
      atopy and various types systemic inflammatory diseases.

PMID- 10410379
TI  - Prostaglandin E2 regulates vitamin D receptor expression, vitamin D-24
      hydroxylase activity and cell proliferation in an adherent human myeloid leukemia
      cell line (Ad-HL60).
AB  - The effects of prostaglandin E2, forskolin, and phorbol 12-myristate 13-acetate
      on cell proliferation, cell surface antigen expression, vitamin D-24-hydroxylase
      activity and vitamin D receptor (VDR) expression have been studied in an adherent
      variant (Ad-HL60) of the human HL60 promyelomonocytic leukemia cell line. Ad-HL60
      cells have a more differentiated phenotype than the nonadherent HL60 cells from
      which they were derived and, unlike the parent cell line, constitutively express
      vitamin D-24-hydroxylase activity. Treatment of Ad-HL60 cells with 1 microM PGE2
      resulted in a decrease in the rate of cell proliferation (cell numbers were
      approximately 23% of control values after 72 h treatment), a change in expression
      of leukocyte surface antigens (decreased CD13 and CD14, increased CD11b and CD49d
      expression), an increase in the synthesis of 24,25-dihydroxyvitamin D3 from
      substrate 25-hydroxyvitamin D3 (control 5.76 +/- 0.17, 72 h PGE2-treated cells
      12.10 +/- 1.90 pmol/h/10(6) cells), and an increase in receptors for the active
      metabolite of vitamin D, 1 alpha,25-dihydroxyvitamin D3, from 3910 to 11285
      receptors per cell in control and 7-day treated cells, respectively.
      Prostaglandin E2 may be acting via a mechanism involving cyclic AMP in these
      cells, as we have also demonstrated that 10 microM forskolin, an adenylate
      cyclase activator, has similar effects. Phorbol 12-myristate 13-acetate had
      little effect on any of the parameters measured in this cell line.

PMID- 10410378
TI  - Existence of acyl-CoA hydrolase-mediated pathway supplying arachidonic acid for
      prostaglandin synthesis in microsomes from rabbit kidney medulla.
AB  - We have previously shown that acyl-coenzyme A (CoA) hydrolase that hydrolyzes
      arachidonoyl-CoA (AA-CoA) to arachidonic acid (AA) and CoA is present in the
      cytosol of rabbit kidney medulla and that this enzyme can supply AA for
      prostaglandin (PG) synthesis in this region. In the present study, the existence
      of the acyl-CoA hydrolase-mediated pathway that supplies AA available for PG
      synthesis in microsomes from the kidney medulla was examined. AA-CoA (20 microM)
      was preincubated with the 105,000 g pellet (microsomes, 0.5 mg of protein) from
      the medulla for 5 min at 37 degrees C followed by incubation with the medulla
      microsomes (0.5 mg of protein) (the source of PG synthesizing enzymes) in the
      presence of hydroquinone and reduced glutathione for 5 min at 37 degrees C. The
      PGs formed were measured by high-pressure liquid chromatography using 9
      anthryldiazomethane for derivatization. The addition of the microsomal fraction
      from the medulla in the preincubation mixture increased total PG formation from
      3.86 to 8.70 nmol, and this stimulatory effect was somewhat weaker than that of
      the cytosolic fraction. On the other hand, the microsomal fraction in the kidney
      cortex has an extremely lower capacity to supply AA for PG synthesis than do
      medulla microsomes. These results suggest that, in kidney medulla, the microsomes
      as well as the cytosol have the potential route that supplies AA from AA-CoA for
      PG synthesis and that this pathway is mediated by acyl-CoA hydrolase.

PMID- 10410380
TI  - Urinary platelet-activating factor excretion is elevated in non-insulin dependent
      diabetes mellitus.
AB  - Proteinuria is currently considered a very sensitive predictor of diabetic
      nephropathy, but 20-25% of all diabetic patients with negative Albustix reaction
      excrete higher than normal (< 20 mg/24 h) amounts of albumin in their urine. It
      is our hypothesis that platelet-activating factor (PAF), a potent
      glycerophospholipid that acts as a chemical mediator for a wide spectrum of
      biological activities, including increased vascular permeability, may be produced
      in significant amounts during periods preceding microalbuminuria. In this study,
      we compared urinary PAF excretion in Mexican-American subjects who were diagnosed
      with non-insulin dependent diabetes mellitus (NIDDM) with their healthy control
      counterparts. The age of the NIDDM subjects (45.9 +/- 2.1 years) was not
      significantly different from the healthy control group, which was 39.4 +/- 2.7
      years (P < 0.0672). The NIDDM subjects (body mass index, 29.9 +/- 1.1 compared to
      26.1 +/- 0.9 kg/m2 in healthy controls) were characterized by significantly
      increased (P < 0.05) fasting plasma glucose (192 +/- 11 vs. 97 +/- 4 mg/dl in
      healthy controls), fasting insulin (20.9 +/- 2.4 vs. 12.3 +/- 1.6 microU/ml),
      fasting C-peptide (2.93 +/- 1.26 vs. 1.48 +/- 0.51 ng/ml), and hemoglobin A1c
      (10.3 +/- 0.7 vs. 5.6 +/- 0.3%), respectively. The urine output for the NIDDM and
      control subjects were 1942 +/- 191 ml/24 h and 1032 +/- 94 ml/24 h, respectively,
      and urinary albumin excretion (UAE) rates were estimated to be 38 +/- 7
      micrograms/min and 11 +/- 1 micrograms/min, respectively. The NIDDM subjects
      produced significantly increased levels of urinary PAF (2606.3 +/- 513.1 ng/24 h
      compared with 77.9 +/- 14.1 ng/24 h in controls (or 1706.3 +/- 420.8 ng/ml
      compared with 85.4 +/- 17.8 pg/ml of urine, in NIDDM and control subjects,
      respectively). We found that urinary PAF excretion was significantly correlated
      with microalbumin excretion (r = 0.7) especially at UAE rates greater than 30
      mg/day and more importantly, some NIDDM patients with negative Albustix reaction
      (i.e. normal UAE) produced significantly more PAF, suggesting that PAF excretion
      may precede microalbuminuria and that subtle injury to the kidneys are present in
      NIDDM long before overt albuminuria ensues, urinary PAF measurements could
      potentially therefore serve as a sensitive indicator of renal injury in diabetes
      mellitus. These results lend further credence to our hypothesis that PAF may be
      the biochemical compound linking the various members of the insulin resistance
      syndrome.

PMID- 10410381
TI  - The role of vitamin E on the anti-atherosclerotic effect of fish oil in diet
      induced hypercholesterolemic rabbits.
AB  - The role of vitamin E on the anti-atherosclerotic effect of fish oil in diet
      induced hypercholesterolemic rabbits was studied in male New Zealand white
      rabbits. The animals were randomly divided into six groups of 14 each according
      to the chow given them. Group I, control, rabbits were fed regular laboratory
      rabbit chow. In addition to the regular chow, Group II rabbits were fed a high
      (1%) cholesterol-enriched diet. Group III had the same diet as Group II plus 450
      mg vitamin E/1000 g chow. Group IV also had the same diet as Group II plus 10%
      fish oil, but without vitamin E. Group V's diet contained 1% cholesterol, 10%
      fish oil, and 450 mg vitamin E/1000 g chow. Group VI had the same diet as Group
      V, but with 150 mg vitamin E/1000 g chow. At the end of a 6-week feeding, the
      ascending aorta from seven rabbits from each group was harvested for the analysis
      of prostanoid production, thiobarbituric acid reactive substances (TBARS),
      superoxide dismutase activity, and cholesterol and vitamin E levels; the same
      tissue from the other seven rabbits from each group was obtained for the
      delineation of atherosclerotic lesions by planimetry after the Sudan IV stain.
      The high cholesterol diet-treated rabbits had worse prostanoid synthesis and
      higher TBARS levels, which paralleled the severity of the atherosclerosis.
      Vitamin E or fish oil supplementation in a high cholesterol diet had beneficial
      prostanoid production, reduced aortic TBARS levels, and attenuated
      atherosclerotic lesions; these effects were potentiated when vitamin E and fish
      oil were combined together. The atherosclerotic lesion reduction in rabbits
      treated with high cholesterol plus fish oil and 450 mg vitamin E/1000 g chow
      reached statistical significance (P < 0.05) compared to high cholesterol and the
      same dose of vitamin E-treated rabbits. The rabbits treated with high cholesterol
      plus fish oil, but without vitamin E or with 150 mg vitamin E/1000 g chow showed
      an increased plasma creatine kinase activity at 4 (P < 0.01 and 0.05,
      respectively) and 6 (P < 0.001 and 0.01, respectively) week of feeding. These
      results suggest that vitamin E and/or fish oil attenuate atherosclerosis in high
      cholesterol-fed rabbits; vitamin E and fish oil potentiated the effect of each
      other. Furthermore, without sufficient vitamin E supplementation, rabbits treated
      with high cholesterol plus fish oil will show an elevation of plasma creatine
      kinase activity.

PMID- 10410382
TI  - Effects of misoprostol on bone loss in ovariectomized rats.
AB  - This study was performed to investigate whether misoprostol (prostaglandin E1
      analogue) (Cytotec, Searle, England) is effective for restoration of bone loss.
      Four-month-old parous female Sprague-Dawley rats (n = 30) were subjected either
      to bilateral ovariectomy (OVX, 24 rats) or to sham surgery (sham, 6 rats). The
      OVX rats were divided into four groups 60 days after the surgery. Six of them
      were killed, and dual-energy X-ray absorption (Norland xr-36, Norland
      Corporation, Fort Atkinson, WI, USA) measurements were performed, called
      pretreatment OVX group. The remaining groups (each had 6 rats) treated orally
      with 0 (control), 100, 200 micrograms/kg/day misoprostol for 60 days. All rats
      were killed 60 days after having treatment, and bone loss of the lumbar spine was
      measured by dual-energy X-ray absorption. The bone mineral density was decreased
      by 25.4% in control group and 23.6% in pretreatment group compared to sham group,
      but restored by 86% and 96% in groups treated with 100 and 200 micrograms/kg/day
      misoprostol, respectively. These results suggest that misoprostol restores bone
      loss in the lumbar spine of OVX rats in a dose-dependent manner.

PMID- 10410383
TI  - Role of prostaglandin H synthase isoforms in murine ear edema induced by phorbol
      ester application on skin.
AB  - Topical application of TPA to a murine ear induced an edema that was accompanied
      by eicosanoid biosynthesis and an early enhancement of prostaglandin H synthase 2
      (PGHS-2) expression. PGHS-2 induction may be correlated with the time-course of
      TPA-induced edema formation. Treatment with drugs that inhibit AA mobilization
      such as dexamethasone or manoalide or inhibitors of leukotriene formation such as
      zileuton or baicalein, reduced TPA-induced edema development and PGHS-2 levels.
      On the other hand, arachidonic acid (AA) application on the murine ear induced
      rapid expression of PGHS-2. This effect was not reproduced by other fatty acids
      such as oleic, linoleic, eicosatetraynoic or eicosapentaenoic acids. PGHS-2
      expression induced by AA application was independent of PGHS and lipoxygenase
      metabolite synthesis. However, topical application of PGE2 on skin induced PGHS-2
      overexpression. This study suggests that AA release and/or subsequent metabolism
      by PGHS may be involved in the induction of PGHS-2 expression in murine TPA- and
      AA-induced ear oedema.

PMID- 10410384
TI  - Molecular cloning and characterization of the canine prostaglandin E receptor EP2
      subtype.
AB  - Prostaglandin E2 (PGE2) binds to four G-protein coupled cell surface receptors
      (EP1-EP4) and has been implicated as a local mediator of bone anabolism via a
      cyclic AMP mediated pathway following activation of the EP2 and/or EP4 receptor
      subtype. A canine kidney cDNA library was screened using a human EP2 probe, and a
      clone with an open reading frame of 1083 bp, potentially encoding a protein of
      361 amino acids, was characterized. This open reading frame has 89% identity to
      the human EP2 cDNA at the nucleotide level and 87% identity at the predicted
      protein level. Scatchard analysis of a CHO cell line stably transfected with
      canine EP2 yielded a dissociation constant of 22 nM for PGE2. Competition binding
      studies, using 3H-PGE2 as ligand, demonstrated specific displacement by PGE2,
      Prostaglandin E1, Prostaglandin A3, and butaprost (an EP2 selective ligand), but
      not by ligands with selectivity for the related DP, FP, IP, or TP receptors.
      Specific ligand binding also resulted in increased levels of cAMP in EP2
      transfected cells with no evidence of short-term, ligand-induced desensitization.
      Northern blot analysis revealed two transcripts of 3300 and 2400 bp in canine
      lung, and reverse-transcription polymerase chain reaction showed expression in
      all tissues examined. Southern blot analysis suggests the presence of a single
      copy gene for EP2 in the dog.

PMID- 10410385
TI  - Analyses of prostaglandin D2 metabolites in urine: comparison between enzyme
      immunoassay and negative ion chemical ionisation gas chromatography-mass
      spectrometry.
AB  - Measurements of the prostaglandin (PGD2) metabolite 9 alpha, 11 beta-PGF2 in
      unextracted urine performed by enzyme immunoassay (EIA) were compared with values
      obtained by negative chemical ionisation gas chromatography-mass spectrometry
      (NCI GC-MS). Values determined by NCI GC-MS were in the same range but
      consistently lower than those obtained by EIA, suggesting that other endogenous
      compounds could be contributing to the immunoreactivity. Isoprostanes were
      generated by autoxidation of arachidonic acid and the 9 alpha, 11 beta-PGF2
      antibody demonstrated less than 0.7% crossreactivity to the mix, making it
      unlikely that isoprostanes in urine interfere with quantification of 9 alpha, 11
      beta-PGF2 by EIA. This was further supported by the 70% reduction in
      immunoreactive material measured in urine after three days treatment in a healthy
      volunteer with the cyclooxygenase inhibitor ibuprofen. Purification of urine
      samples by reverse phase high-performance liquid chromatography (HPLC) revealed
      the presence of two immunoreactive compounds in addition to 9 alpha, 11 beta
      PGF2. The compounds were identified as dinor compounds by NCI GC-MS. One of the
      compounds was identical to 9 alpha, 11 beta-2,3-dinor-PGF2 which was generated by
      beta-oxidation of 9 alpha, 11 beta-PGF2 and identified by electron impact (EI)-GC
      MS. In conclusion, urinary 9 alpha, 11 beta-PGF2 concentrations measured by EIA
      represent the sum of 9 alpha, 11 beta-PGF2 and two isomers of its dinor
      metabolite. Thus, the direct EIA is fast, sensitive and sufficiently specific to
      monitor activation of the PGD2 pathway, thereby providing a valuable clinical
      tool to assess the status of mast cell activation in vivo.

PMID- 10410386
TI  - Maize meal, non-esterified linoleic acid, and endemic cancer of the esophagus-
      preliminary findings.
AB  - Endemic cancer of the esophagus has shown a positive association with the
      consumption of maize meal. It has been postulated that this association is due to
      the conversion, in the stomach mucosa, of the linoleic acid contained in maize
      meal to prostaglandin E2. The proportion of non-esterified linoleic acid
      available in the stomach may therefore be an important factor. Samples of
      commercially prepared maize flour, cooked and uncooked, and other maize-based
      foods were analysed for total and free content of various fatty acids using gas
      liquid chromatography. High levels of non-esterified fatty acids (11 to 42% of
      contained fatty acids) were found both in maize meal and in foods prepared from
      it. In food prepared from maize meal, 49 mg to 363 mg non-esterified linoleic
      acid per 100-g sample was found. High levels of non-esterified linoleic acid in
      the diet, causing raised intragastric production of prostaglandin E2 and
      profoundly affecting the normal pH and fluid content of the esophagus, may create
      a predisposition to esophageal carcinogenesis.

PMID- 10410387
TI  - Left atrial endocardium and prostacyclin.
AB  - In patients with rheumatic mitral stenosis, intracardiac thrombi are found
      mostly, for reasons still unknown, in the left atrium. We compared the release of
      PGI2 from the endocardium of the left atrium with that of the right ventricle and
      from the endothelium of the pulmonary arteries. Endocardial endothelial cells
      (EECs) were isolated from right ventricles (RV) and left atrial appendages (LAA)
      of porcine hearts, and vascular endothelial cells (VECs) from pulmonary arteries
      (PA) were obtained from the same animals. Cultured EEC and PA-VEC monolayers were
      placed in a pressure loading apparatus and incubated for 30 min under various
      pressures. After incubation, the supernatants were sampled and the 6-keto-PGF1
      alpha contents measured. PGI2 release from LAA-EEC was much less than from RV-EEC
      or from PA-VEC. Moreover, transmural pressure did not enhance PGI2 release from
      LAA-EEC, although it did from RV-EEC and PA-EEC in a pressure-dependent manner.
      These results may explain why the left atrium is a common site for intracardiac
      thrombus formation in patients with mitral valve disease.

PMID- 10410388
TI  - [International comparison of occupational health related laws and occupational
      health systems on ethics].
AB  - We compared occupational health related laws and occupational health systems on
      ethics in Germany, France, USA, UK, and Japan, and reviewed them. The duties of
      appointment of occupational physicians, competence of occupational physicians,
      responsibility for maintaining the confidentiality of the medical records,
      professional independence of occupational physicians, employment and dismissal of
      occupational physicians, etc. were discussed. Concerning maintaining the medical
      privacy of workers, the Japanese law and system are thought to be different from
      those of other countries. Concerning the professional independence of
      occupational physicians, the Japanese law does not have this point of view. We
      hope that Japanese occupational physicians express their opinions on these
      issues.

PMID- 10410389
TI  - [Evaluation of Japanese school lunch cooks' work by foreign researchers: an
      attempt to promote an effective discussion by presenting a video tape record].
AB  - The aim of this study was to collect and examine foreign researchers' evaluations
      of Japanese school lunch cooks' workload, risk of musculoskeletal disorders, and
      some related issues by means of video tape discussion method at international
      conferences. The author reported work-related musculoskeletal disorders of
      Japanese school lunch cooks' at three international conferences. Together with
      the presentation a video tape recorded at one school kitchen during working hours
      was shown and the participants at the conferences were asked to evaluate the
      workload and risks of the Japanese school lunch cooks in the form of a
      questionnaire. Out of 151 participants from 21 countries at three conferences, 86
      participants from 18 countries answered the questionnaire. The median of the
      values for Japanese school cooks' workload, derived by the Visual Analogue Scale
      method ranging from 0 (easy) to 10 (severe), was 8.5. Concerning the possibility
      of occurrence of musculoskeletal problems, 83% of the respondents pointed out
      that the occurrence of musculoskeletal disorders was certain, and 17% of them
      estimated that it was probable. Out of 18 countries from which participants came
      from, 12 countries were serving meals at school, and school lunch cooks in these
      12 countries had similar occupational problems to those in Japan, such as
      musculoskeletal disorders, skin disorders and injuries, etc. The participants
      also pointed out that Japanese school lunch cooks were exposed to various
      problems, i.e., excessive workloads for women, and too few replacements of manual
      work by machinery. On the other hand, the cleanliness of the school kitchen,
      quality of meals, and conscientious cooking work were evaluated as very high.
      There were 36 researchers who asked for a copy of the video tape in order to use
      it in the education of industrial health personnel, medical students, and so on.
      These results showed the same tendency as Japanese researchers have found over
      the past 16 years. The video tape discussion method is proved to be useful in
      deepening mutual understanding at international conferences.

PMID- 10410390
TI  - [The effects of low intensity aerobic training on the physiological indexes and
      the quality of life in middle-aged white collar workers].
AB  - The effects of short-term low intensity aerobic training on the physiological
      indexes and the Quality of Life were examined in 43 middle-aged White Collar
      Workers. Training was carried out for 205 +/- 117 minutes/week, at least 2-3
      times/week for 2 months on a cycle ergometer or walking with intensity level set
      at the 50% VO2max. Following this training protocol, thirty-six men (exercise
      group) completed the 2-month training program and 7 men dropped out (the dropout
      group). In the exercise group, both the VO2max (l/min) and VO2max/wt increased
      significantly (VO2max (l/min): P < 0.05. VO2max/wt: P < 0.01), whereas the
      weight, body mass index, %fat, fat (kg) and the waist hip ratio (WHR) decreased
      significantly (WHR: P < 0.05, others: P < 0.01) after 2 months. In addition, the
      DBP and serum TC, LDL-c/HDL-c decreased significantly (LDL-c/HDL-c: P < 0.01,
      others: P < 0.05) whereas the HDL-c increased significantly (P < 0.05). A
      modified Croog questionnaire was used to assess the subject's Quality of Life.
      The questionnaire consisted of 59 questions and the overall assessment was based
      on eight components. Regarding the Quality of Life, physical symptoms, work
      performance and satisfaction, total Quality of Life all improved significantly
      (physical symptoms, P < 0.05; others: P < 0.01) and social participation also
      tended to improve (P < 0.08). There was a significantly negative correlation
      between the initial Quality of Life and the changes in the Quality of Life (6 of
      the 8 components). In the all subjects, there was a significantly positive
      correlation between the changes in physical symptoms and the changes in VO2max/wt
      (r = 0.36, P < 0.05). In the dropout group, the FBS increased significantly (P <
      0.05) but no other variables regarding the Quality of Life significantly changed
      after 2 months. In conclusion the above results suggest that short-term low
      intensity aerobic training in the present study can help improve the
      physiological indexes, VO2max and Quality of Life in middle-aged White Collar
      Workers and the observed improvement in the Quality of Life was also found to be
      greater in the subjects with a low Quality of Life than in those with a high
      Quality of Life.

PMID- 10410391
TI  - ["Tonoko" pneumoconiosis in household industries].

PMID- 10410392
TI  - [Structural changes in platelets in alloxan diabetes as parameters of their
      activation in the vascular bed and morphologic features].
AB  - The present study shows that a stable level of blood platelet number persists in
      diabetic rats (following 15 and 60 days after experimental alloxan injection)
      Unusual platelet megaforms are seen accumulating (up to 36%), having no size
      analogs in control animals. A quantitative electron-microscopic analysis
      demonstrated that the enlargements of diabetic platelets was accompanied by their
      rounding in shape and by a more frequent (by 2.0-2.6 times) generation of surface
      pseudopodia. The share of platelets increased in two independent fractions, with
      considerable deflexion over the normal range limit variations in the number, size
      and general volume of their alpha-granules (cutting down) or dense (increase)
      bodies. At the same time a common decrease in these indexes for different types
      of grains in platelets of various dimensions occurred. The integral picture of
      the platelet granular apparatus (image of granular apparatus), that demonstrates
      quantitative proportions between the number and size indexes of different grain
      types, is found distorted in diabetic rats.

PMID- 10410393
TI  - [Dynamics of various integral characteristics of individual changes in ethanol
      resistance in isolated muscles of grass frog].
AB  - A study was made of the dynamics of the mean level of toxic ethyl alcohol (EA)
      (3.5 M) resistance, of the correlation between the initial individual level of
      this resistance and the value and shifting direction of the level, and of the
      pattern of correlation between levels of resistance in the pair sartoria muscles
      and variability of resistance level in muscles, kept in EA subtoxic solutions
      (0.87 and 1.09 M) for 240 min. Two-phase changes in the mean level of resistance
      in muscles were revealed that involved its increase by 20% within 60 min of
      maintenance in both EA concentrations, and followed by a decrease of this level
      by the end of observation. On the first steps of muscle maintenance in EA
      subtoxic solutions, a negative correlation was noticed between the initial level
      of resistance and the value and direction of its shifting, in addition to
      narrowing the range of variability of this level in muscles. All these events
      were accompanied by a decrease or fluctuations in the correlation coefficient
      between levels of resistance in the pair muscles. By the end of the experiment,
      the range of variability of the level of resistance was seen to increase, and the
      earlier negative correlation between the initial individual level of resistance
      and the value and direction of its shifting appeared to change for a positive
      one. Both processes preceded the decrease in the mean level of muscle resistance.

PMID- 10410395
TI  - [Defect of preferential repair of gamma-ray-induced single-strand breaks in
      transcribed DNA in ataxia-telangiectasia cells].
AB  - Transcriptionally activity-dependent heterogeneity of gamma-induced DNA single
      strand break repair in ataxia-telangiectasia cells has been investigated. It is
      found that in AT cells no increased induction of damage in the c-myc gene
      compares with normal human fibroblasts. At the same time an evident defect of
      preferential accelerated repair of single-strand breaks in the c-myc gene was
      observed. DNA single-strand breaks repair in human satellite III and total DNA
      single-strand breaks in c-myc gene in AT cells correlate with increased
      radiosensitivity of cells.

PMID- 10410394
TI  - [Generation of reactive forms of oxygen by polymorphonuclear leukocytes during
      hepatoma growth in the peritoneal cavity of animals].
AB  - In the present work, an attempt was made to analyse generation of reactive oxygen
      species (ROS) by polymorphonuclear leucocytes (PMN) in the course of tumour
      growth, using chemiluminescence (CL). A multiple increase in the capacity of
      polymorphonuclear leucocytes of generating active forms of oxygen in the course
      of tumor growth was discovered. Two causes of this process were found. 1) the
      increase in specific activity of leucocytes; 2) the increase in the total
      quantity of PMN circulating in the blood. Leucocytes were also found in the
      ascite liquid. PMN leucocytes were shown to participate in the antitumor defence
      of the organism.

PMID- 10410396
TI  - [ANS fluorescence. I. Effect of self-association on the spectral properties of
      the probe].
AB  - The dependence of spectral properties of Mg2+ and NH4+ salt of 8-anilino-1
      naphthalenesulfonic acid (Mg-(ANS)2 and NH4-ANS, respectively) on the dye
      concentration and solvent composition was investigated by means of steady-state
      and time-resolved fluorescence spectroscopy. We have shown that the increase in
      ANS concentrations leads to changes in the shape of absorption and fluorescence
      spectra of the dye, accompanied by the decrease in its fluorescence decay time
      values. Such changes, observed in aqueous and organic solvents for both salts of
      ANS, reflect the existence of self-association of the dye molecules. The decrease
      in fluorescence intensity induced by self-association of the probe molecules is
      too small to explain a weak fluorescence of ANS in water. At the same time, it
      expounds the difference between the decay times of protein-embedded ANS molecules
      upon interaction of this probe with native and molten globule proteins.

PMID- 10410397
TI  - [ANS fluorescence. II. Use of the method of fluorescent probe decay for studying
      the structural transformations in globular proteins].
AB  - Changes in ANS fluorescence decay parameters induced by the interaction of the
      probe with proteins have been investigated. The existence of at least two
      different modes of interactions between the ANS and protein was established. The
      interactions of the first type are connected with binding of an ANS molecule with
      the surface of a protein molecule. In this case ANS molecules are well acceptable
      for a solvent. The interactions of the second type are characteristic of the
      protein-embedded ANS molecules. The decay time values of the second type
      complexes change considerably (> 1.5-fold) during the protein molecule
      transformation into the molten globule-like conformation. The molecular model
      explaining such a behaviour is suggested.

PMID- 10410398
TI  - [Pleiotropic changes in karyotype structure of Chinese hamster fibroblast cell
      lint CHL V-79 RJK in relation to their acquisition of resistance to etoposide, an
      inducer of apoptosis].
AB  - Chinese hamster fibroblasts CHL V-79 RJK were subjected to multistep selection in
      the presence of etoposide, known as an inhibitor of topoisomerase II and inductor
      of apoptosis. The karyotype of cells stably resistant to etoposide was analysed
      at progressive stages of selection using G-type staining of metaphase
      chromosomes. Multiple changes in the karyotype of resistant cells were observed
      at an early stage of selection (0.2 mg/ml of etoposide) and included: random
      chromosome breaks leading to formation of new chromosome markers, high frequency
      of aneuploid and polyploid cells, morphological instability and extracopy of q
      shoulder of chromosome 1. On advanced stages of selection we observed an
      increased frequency of specific minute chromosome and the appearance of
      chromosomes with homogeneously or differentially stained regions (HSR and DSR).
      These data suggest that different mechanisms may be involved in developing
      cellular resistance to etoposide at progressive stages of selection.

PMID- 10410399
TI  - Assessment through the dialectic: the necessary forgotten link.
AB  - Traditional assessment procedures focus on diagnosing psychopathology, thereby
      implicitly endorsing the medical model. It is equally vital to assess the
      nonpathological side of the person, the part that strives for increased personal
      satisfaction and impels the individual to seek psychotherapy. A dialectically
      based assessment would evaluate both the healthy and unhealthy forces in the
      person. Such an evaluation would address the nature and extent of participants'
      experienced pain, the degree to which participants are open to external
      assistance, and the style of assistance best suited for each individual.

PMID- 10410400
TI  - Optimism as an indicator of psychological health: using psychological assessment
      wisely.
AB  - Healthy aspects of psychological functioning are often overlooked in traditional
      psychological assessment. When this happens, the client may become discouraged
      with his or her testing results, or perhaps worse, may feel that the assessor was
      not interested in obtaining a complete picture of who he or she is. Assessing
      healthy aspects of psychological functioning can be problematic, however; adding
      new instruments that only speak to one aspect of psychological functioning is not
      practical. A system is proposed in which one aspect of healthy psychological
      functioning--optimism--can be assessed using a standard projective test. Use of
      this scale can aid the assessor in conceptualizing the client's functioning and
      can also be a helpful tool to draw on in the course of treatment.

PMID- 10410401
TI  - Predicting outcome of military basic training for individuals referred for
      psychological evaluation.
AB  - We examined outcome data for 632 U.S. Air Force personnel who were referred for
      psychological evaluation during Basic Military Training (BMT) but who were
      subsequently returned to BMT to determine what proportion graduated. We analyzed
      motivational, biographical, and psychological testing variables, using logistic
      regression to develop a model predictive of training outcome. The results
      demonstrated that a relatively small number of variables could predict outcome
      with close to 70% accuracy. Level of optimism regarding training, history of
      physical abuse, and frequency of visits to the trainee health clinic were major
      contributors to the model. MMPI-2 (Hathaway & McKinley, 1989) Scales D and Sc
      also remained in the model but added little to its power. The findings are
      generally consistent with prior research on normal military populations, except
      that some factors previously linked to adjustment, such as sex and ethnicity,
      were found to be unrelated to training outcome in this population.

PMID- 10410402
TI  - An impression after the annual meeting of American Society of Regional
      Anesthesia: is regional block an ideal technique for anesthesia and postoperative
      pain management?

PMID- 10410403
TI  - Prevention of hypotension after spinal anesthesia for cesarean section: dextran
      40 versus lactated Ringer's solution.
AB  - BACKGROUND: This study was designed to compare the efficacy of 10% dextran 40
      with lactated Ringer's (LR) solution in reducing the incidence and severity of
      hypotension after spinal anesthesia for Cesarean section. METHODS: Sixty ASA
      grade I patients scheduled for Cesarean section were randomized into two groups
      in a double-blind fashion to receive either 500 ml of dextran 40 or 1000 ml of LR
      solution prior to induction of spinal anesthesia. RESULTS: The incidence of
      hypotension was 16 in 30 (53.3%) in the LR solution group and 8 in 30 (26.7%) in
      the dextran group (P < 0.05). The required dose of ephedrine for treatment of
      hypotension was significantly greater in the LR solution group than in the
      dextran group (15.5 mg versus 3.2 mg, P < 0.05). Neonatal outcome, as determined
      by Apgar score, was good and similar in both groups. CONCLUSIONS: We concluded
      that 500 ml of dextran 40 is more effective than 1000 ml of lactated Ringer's
      solution in reducing the incidence of hypotension induced by spinal anesthesia.

PMID- 10410404
TI  - Spinal anesthesia for cesarean section: isobaric versus hyperbaric solution.
AB  - BACKGROUND: The present study was undertaken to compare the outcomes of
      hyperbaric versus isobaric spinal anesthesia in Cesarean delivery. METHODS: The
      anesthetic solution was administered in sitting position as this posture is
      commonly used in this clinical setting. Except for the baricity of the anesthetic
      solution, identical technique was employed for every parturient in the study.
      Following administration of anesthetic solution the parturient immediately
      resumed horizontal supine position. The solutions used were 2.0 mL of 0.5%
      tetracaine in 5% dextrose (hyperbaric) for Group H (n = 30) and in cerebrospinal
      fluid (isobaric) for Group I (n = 30). RESULTS: Both hyperbaric and isobaric
      tetracaine given in sitting position provided adequate analgesic levels. However,
      hyperbaric tetracaine solution produced a slightly higher median peak level of
      wilder range, and caused a higher incidence of hemodynamic changes and subjective
      sensation of "feeling sick" than isobaric tetracaine. Additionally, the duration
      of surgical anesthesia was shorter and the sacral block was longer for hyperbaric
      tetracaine solution than for isobaric tetracaine solution at same dose and
      concentration. Only one mother in Group H needed supplemental inhalation
      anesthesia for a subsequent hysterectomy due to uncontrollable bleeding. There
      were no complications, including postpuncture headache in either group.
      CONCLUSIONS: Our results indicated that numerous variables must be taken into
      consideration in predicting the outcome of a spinal anesthesia. Alternation in
      the technique and individual patient factor may individually or collectively
      produce different results.

PMID- 10410405
TI  - The construction of a pain intensity verbal rating scale in Chinese.
AB  - BACKGROUND: Despite the growing interest of developing multidimensional scales,
      the use of unidimensional scales in assessing clinical pain is popular for its
      simplicity, efficiency and ease of administration. The purposes of this study
      were: first, to explore the pain intensity descriptors used among Chinese.
      Second, it was to construct a verbal rating scale for pain assessment. METHODS:
      It consisted of two stages. Stage One was a cross-sectional descriptive survey to
      explore the pain intensity descriptors used among adult Chinese in Hong Kong.
      Stage Two was a Q-sorting technique to array the pain intensity descriptors
      obtained in Stage One. This was to construct a verbal rating scale (VRS) for pain
      assessment. RESULTS: Nine hundred and eighty six healthy Chinese adults
      participated in Stage One. The ten pain intensity descriptors obtained were
      bearable ([symbol: see text]), crushing the heart and lungs ([symbol: see text]),
      crucifying pain ([symbol: see text]), excruciating pain ([symbol: see text]),
      indescribable ([symbol: see text]), quite painful ([symbol: see text]), painful
      ([symbol: see text]), slight pain ([symbol: see text]), unbearable ([symbol: see
      text]) and very painful ([symbol: see text]). In Stage Two, fifty-four
      baccalaureate-nursing students participated in the Q-sorting procedure. They were
      asked to rank the pain intensity descriptors according to a set of psychometric
      criteria. A vertical VRS was constructed with the least pain at the bottom and
      the most pain on the top. A 'no pain' was added to the bottom of the scale.
      CONCLUSIONS: The order of the rank was no pain, slight pain, quite painful,
      painful, very painful, bearable, indescribable, excruciating pain, unbearable,
      crushing the heart and lungs and crucifying pain. It is anticipated that a VRS of
      this kind has its value in the measurement of pain intensity with cultural
      relevancy.

PMID- 10410406
TI  - Anesthesia for ankylosing spondylitis patients undergoing transpedicle
      vertebrectomy.
AB  - BACKGROUND: Ankylosing Spondylitis (AS) patients present specific challenges to
      the anesthesiologists. Airway management, central venous access, positioning,
      neuraxial monitoring and protection as well as management of massive blood loss
      may prove to be difficult. We retrospectively reviewed the anesthetic management
      of consecutive AS patients who underwent transpedicle vertebrectomy (TPV).
      METHODS: To secure airway and administer anesthesia, we used awake fiberoptic
      endotracheal intubation. The central venous access was attempted through the
      infraclavicular approach. The positioning was made possible with modification of
      the operation table and padding. The neuraxial monitoring was done with both
      somatosensory evoked potentials (SSEPs) and the modified transcranial magnetic
      evoked potential (tcMMEP). The spinal cord protection was attempted with
      deliberate hypothermia. To prevent massive blood loss we did controlled
      hypotension, and autotransfusion. RESULTS: Fiberoptic endotracheal intubation was
      done smoothly in all cases except two. In one of these two cases, endotracheal
      intubation was successful only after cricothyroidectomy and retrograde
      intubation. In the other case antegrade stiff catheter guided intubation was
      attempted to overcome the acute angulation cause by fixed cervical flexion.
      Central venous access through infraclavicular approach was agreeable except one
      case of pneumothorax. Massive rapid blood loss during vertebral osteotomy,
      occurred in one patient with fall of the mean blood pressure to 20 mmHg and
      ventricular tachycardia for 10 min, during which all the SSEPs and tcMMEP
      activities disappeared. The patient recovered without sequelae. CONCLUSIONS:
      Although it is extremely challenging, with proper planning, anticipation of
      difficulties and meticulous work in airway management, central venous
      catheterization and positioning as well as prevention of neurological injury and
      massive bleeding, we successfully accomplished fine job of anesthesia for the AS
      patients presented for correction of severe kyphosis.

PMID- 10410407
TI  - Epidural catheter placement in the rabbit--a novel approach.
AB  - BACKGROUND: Using a pediatric epidural set and through caudal approach, we
      studied a relatively non-invasive technique for epidural percutaneous cannulation
      in rabbit for chronic laboratory investigations. METHODS: Ten rabbits weighing
      over 3 kg were chosen and anesthetized with intravenous pentothal. A #19
      pediatric Touhy needle and 23-gauge catheter were used for cannulation. Via the
      caudal approach, the epidural space could be located either by a "give" or with a
      technique of loss of resistance. Under fluoroscopy the catheter was tested with
      the injection of contrast medium for the confirmation of the proper position. The
      catheter was then tunneled under the skin and secured. The rabbits were kept in
      standard care for 4 weeks and then sacrificed by intraperitoneal pentothal
      overdose. A pathologist blinded to the study carefully examined the whole spine
      by laminectomy from cervical to coccyx and the findings were recorded. RESULTS:
      With the injection of contrast medium, the final position of the catheter was
      validated by fluoroscopy in all rabbits. Two rabbits sustained immediate
      complications from the contrast medium and/or technique, of which one died
      shortly after the contrast medium injection and the other had weakness of the
      hind legs for a week. At sacrifice, all the catheters were found in good
      position. Two had hematoma associated with signs of trauma. One developed
      subcutaneous abscess. One had stitch infection of skin. CONCLUSIONS: Percutaneous
      cannulation of epidural catheter is possible in the rabbit. Complications could
      be ameliorated by prudent approach in a skillful hand. It can be a reasonable
      model for the study of centrally administered medicines and their neurotoxicity.

PMID- 10410408
TI  - Anesthetic management for pheochromocytoma resection using spinal cord
      stimulation and intravenous nicardipine--a case report.
AB  - We have used spinal cord stimulation (SCS), diazepam and nitrous oxide for
      maintenance of general anesthesia. Blood pressure was maintained by bolus
      administration of nicardipine for the removal of pheochromocytoma. Both SCS and
      nicardipine reduced systemic vascular resistance and SCS increased cardiac
      output. However, neither SCS nor nicardipine could inhibit the release of
      norepinephrine. SCS proved to be useful as one of anesthetic technique during the
      removal of pheochromocytoma, and also in the management of postoperative pain and
      the prevention of complications.

PMID- 10410409
TI  - The anesthetic management of a preterm infant weighing 500 grams undergoing
      ligation of patent ductus arteriosus--a case report.
AB  - PDA (patent ductus arteriosus) is a common congenital heart disease. Usually
      surgical intervention through left thoracotomy or recently through video assisted
      thoracoscopy will be recommended if the preceding or intent medical treatment
      fails or is contraindicated. However, once surgical intervention is decided,
      various complications are still a real fear in the mind of the surgeon and the
      anesthesiologist, particularly if the infant is premature or very sick. Here we
      report an anesthetic management in a female preterm infant weighing 500 grams,
      who underwent PDA ligation. She was born at gestation age of 28 weeks at our
      hospital, and since her birth she was noted to have infant respiratory distress
      syndrome associated with renal dysfunction. She was admitted to the neonatal
      intensive care unit (NICU) straightaway. After thorough examination, a severe PDA
      was disclosed. The possibility of pulmonary hemorrhage and heart failure could be
      predicted in view of the large left to right shunt. Worst of all was that her
      poor renal function contradicted a medical treatment. So we decided to carry out
      the ligation procedure at once although she was premature and only 5 days old.
      The NICU was chosen as the operation theater for transferring concerns. General
      anesthesia was induced and maintained by atropine 0.01 mg, pancuronium 0.1 mg,
      fentanyl 2 micrograms, and ketamine 0.15 mg intravenously. Supplemental oxygen
      was given throughout the operation. The PDA was ligated through left thoracotomy
      and blood loss was minimal. The peri-operative course was uneventful. The patient
      recovered well following surgery and anesthesia.

PMID- 10410410
TI  - Children with mucopolysaccharidoses--three cases report.
AB  - The mucopolysaccharidoses (MPS) are a group of inherited disorders of metabolism,
      with widespread, progressive involvement and derangement of many organs and
      tissues. Because of their disabling nature, frequent surgical intervention for
      the abnormality entailed is common, and is associated with a high degree of
      anesthetic risks perioperatively. One of the major hazards which we find
      clinically is airway difficulty. Multiple factors are present in the
      mucopolysaccharidoses to make airway management and trachael intubation
      potentially hazardous. Aside from generalized infiltration and thickening of the
      soft tissues, the oropharynx may be obstructed by a large tongue with tonsillar
      hypertrophy. Also, the friable mucosa covering the nasal and oral pharynx renders
      these structures easily to bleed and edematous. The neck is typically short and
      immobile, and the cervical spine and tempromandibular joint may have a limited
      range of movement. From our experience, we have learned not to overlook the
      propensity of airway difficulty. The uniqueness of their anatomy and extremely
      sensitive airway often result in failed intubation and bronchospasm even after
      successful intubation. Recently, in Mackay Memorial Hospital we have encountered
      in series three pediatric cases with mucopolysaccharidoses (one Hurler and two
      Hunter syndromes). In this report we would like to share our experiences and to
      discuss the anesthetic risks and management of the MPS patients.

PMID- 10410411
TI  - Intubation of newborn during delivery with intact umbilical cord--a case report.
AB  - A 24-year-old gravida 2, para 1 woman at 38th week gestation was scheduled for
      elective Cesarean section (C/S) because of a previous C/S and prenatal diagnosis
      of congenital diaphragmatic hernia. We decided to intubate the newborn during
      delivery before the umbilical cord was cut. After delivery of the fetal head and
      part of the shoulders, the mouth of the fetus was cleared and the trachea was
      intubated orally with a 2.5 mm internal diameter (I.D.) endotracheal tube under
      sterile conditions while the uteroplacental circulation was still intact. The
      patient had to be repeatedly resuscitated due to bradycardia in intensive care
      unit. No surgical correction of the hernia was attempted because of the poor
      condition of the baby, which died 3.5 hours after birth. Although our case ended
      up in mortality despite successful perinatal intubation, we recommend that in
      case where airway or ventilatory problems are anticipated, tracheal intubation is
      done during delivery before the umbilical cord is clamped. When the fetus is
      sharing the maternal circulation, it will allow physicians to have more time and
      safety to perform corrective measures.

PMID- 10410412
TI  - Common peroneal nerve palsy following a surgical procedure--a case report.
AB  - Common peroneal nerve injury may occur during surgery, particularly when patients
      are placed in lithotomy position. We report a case of common peroneal nerve palsy
      following a surgical procedure. Incorrect posture of a surgical assistant which
      made him lean his body against the patient's knee support might possibly be the
      cause of this injury. The patient reported that she had a left drop foot and a
      numbness of her left lower extremity following surgery. Electromyographic and
      nerve conduction studies revealed a left common peroneal nerve palsy. Physical
      therapy was started immediately. Patient's neurologic function of the leg totally
      recovered 3 months later.

PMID- 10410414
TI  - [Neonatal screening: should the number of diseases to be detected be increased?].

PMID- 10410413
TI  - Unexpected transurethral resection of prostate syndrome complicated with acute
      myocardial infarction during transurethral incision procedure--a case report.
AB  - Transurethral incision (TUI) is a simple and safe procedure. We, herein, present
      a case undergoing transurethral incision procedure during which he developed
      transurethral resection of prostate syndrome (TURP syndrome) and hypothermia
      precipitating an acute perioperative myocardial infarction attack. The potential
      risk of development of TURP syndrome in settings other than TURP surgery as well
      as its prevention are reviewed and discussed.

PMID- 10410415
TI  - [English words with a misleading translation in pediatrics].

PMID- 10410416
TI  - [A comparative study of the weight-height development of the long-term survivors
      of acute leukemia and solid tumors].
AB  - OBJECTIVE: Our objectives were to analyze the final height and nutritional status
      in survivors of childhood cancer, their evolution since diagnosis and to identify
      neoplasm- and/or therapy-related differences. PATIENTS AND METHODS: A survey of
      long-term survivors of childhood cancer (acute leukemia, Wilms' tumor,
      sympathetic nervous system tumors) diagnosed before 15 years of age and between
      1971 and 1985 in a single tertiary care center was performed. Final height,
      target height and body mass index were measured at evaluation. Height and body
      mass index, at diagnosis and at the end of treatment, was retrieved from their
      clinical records. All parameters are expressed as standard deviation scores of
      the mean of the population reference. Survivors were grouped according to
      diagnosis and type of treatment. Comparisons between groups and within each group
      were made at the time of diagnosis, at the end of treatment and at the time of
      evaluation. RESULTS: Sixty-one survivors of acute leukemia and 62 of solid tumors
      were included (32 Wilms' tumors, 20 neuroblastomas, 4 ganglioneuroblastomas and 6
      ganglioneuromas). Eighty survivors had attained final height at the time of
      evaluation and their target height was available. Fourteen had at least one
      relapse. The mean height standard deviation score was positive at diagnosis and
      negative at the time of evaluation in all groups. Mean height loss ranged from 
      0.84 for the non-irradiated acute leukemia group to -1.34 for the non-irradiated
      solid tumor group. Adjusted final height for target height showed stature loss
      only in irradiated groups. Height loss was equivalent in cranially irradiated
      survivors (-0.32 after 18 Gy, -0.34 after 24-25.5 Gy). The age at menarche
      correlated negatively with the dose of cranial radiotherapy (r = -0.6, p = 0.002)
      and positively with stature loss (r = 0.5, p = 0.006). The mean body mass index
      standard deviation score was negative at diagnosis and positive at the time of
      evaluation in all groups. Twenty percent of solid tumor survivors and 12.5% of
      acute leukemia survivors were malnourished at diagnosis. Nutritional status
      improved in all groups at the time of evaluation. Obesity was more frequent in
      those who received cranial radiotherapy (14%) or intensified therapy (21%)
      compared with those non-cranially irradiated (none) or whose therapy was less
      intense (9%). CONCLUSIONS: Most survivors of childhood cancer attained their
      target height. Stature loss was related to cranial radiotherapy in acute leukemia
      survivors and to spinal irradiation in solid tumor survivors. At diagnosis,
      malnourishment was more frequent in solid tumor patients, while at the time of
      evaluation obesity was associated with a more intensified therapy.

PMID- 10410417
TI  - [Headache in a short-stay unit. A retrospective study of 140 cases].
AB  - OBJECTIVE: Our objective was to study those patients that warranted admission to
      our Short-Stay Unit (Observation Unit) with an incoming diagnosis of headache so
      as to determine the characteristics of the headache, analyze complementary
      explorations and their use and to establish the causes of the problem. PATIENTS
      AND METHODS: A retrospective review of the clinical history of patients admitted
      for headache between 1992 and 1997 was done, recording specific data according to
      pre-set objectives. RESULTS: One hundred forty patients were admitted with
      headache (2% of total admittance to the Unit. Sixty-one percent were males.
      Seventy cases were between 11 and 15 years old. The most frequent accompanying
      symptoms were vomiting (61%), fever (31%) and various concurrent infections
      (21%). Seventy-two cases (51%) presented an evolution of less than 24 hours
      before admittance. Frontal headache was the most common localization, 30.6% of
      the patients were awaken by the pain and 32% calmed with analgesics. CAT
      scan/70%) and skull X-ray (59%) were the most used complementary explorations.
      Ten CAT scans and 3 X-rays showed anomalies. Evolution was favorable in most
      cases. The most frequent diagnoses were headache associated with infections
      (31%), tension headaches (29%) and migraine (21%). Fourteen percent were non
      specific headaches. A central nervous system tumor was diagnosed in 6 patients,
      where 5 showed papilledema on initial exploration. CONCLUSIONS: Headache,
      especially in adolescents, is a common cause of consultations to the emergency
      room. When not accompanied by other symptoms it is not usually precluding a
      severe disease. In an emergency room exploration, a complete neurological exam
      must be undergone, including retinal exam, leaving further complementary exams
      for those cases where the patient history suggests an organic alteration.

PMID- 10410419
TI  - [The teaching of basic pediatric cardiopulmonary resuscitation in the degree
      course in medicine and surgery].
AB  - OBJECTIVE: The aim of this study was to analyze the effectiveness of pediatric
      cardiopulmonary resuscitation training of medical students in pediatric basic
      life support (PBLS) courses. PATIENTS AND METHODS: Between 1995 and 1998, four
      theoretical and practical PBLS courses were given to 304 fifth and sixth-year
      medical students. The theoretical classes provided conceptual information about
      cardiorespiratory arrest and prevention, basic cardiopulmonary resuscitation
      maneuvers and practice sessions in basic cardiopulmonary resuscitation of infants
      and older children to groups of 6 to 8 students. At the beginning of the course,
      students took a theoretical test that consisted of 10 or 20 multiple-choice
      questions. At the end of the course, the theoretical test was repeated and a
      practical test of basic cardiopulmonary resuscitation skills for infants and
      children was given. Students evaluated the course by completion of an anonymous
      written questionnaire. RESULTS: The mean initial score (out of a maximum of 10)
      was 6.4 and the mean score on the final theoretical test was 9.6 (p < 0.001). The
      practical evaluation showed that 95% of the students mastered the skills of the
      basic pediatric cardiopulmonary resuscitation maneuvers. The student evaluation
      of the course yielded scores (on a scale of 5 points) of 4.4 for the theoretical
      classes, 4.4 for presentation, 4.7 for practical classes and 4.8 for professors'
      teaching skills. CONCLUSIONS: The pediatric basic life support courses were a
      useful method for providing theoretical-practical training to students of
      medicine and should be an essential part of the pediatric curricula in medical
      studies.

PMID- 10410418
TI  - [Changes in the epidemiology of the acute respiratory distress syndrome (ARDS) in
      children].
AB  - OBJECTIVE: Our aim was to analyze, in a retrospective study, changes in acute
      respiratory distress syndrome (ARDS) within the same pediatric intensive care
      unit by using the same diagnostic criteria as published in 1982. PATIENTS AND
      METHODS: Fifteen patients (mean age 5.1 years, range 16 days-15 years) admitted
      between 1988 and 1994 fulfilling our former criteria for ARDS were included in
      the study. RESULTS: The incidence of ARDS after the age of 7 days was 0.45% of
      all admissions between the age of 1 week and 16 years vs 1.79% in the former
      series of patients (p < 0.001). Thus, the yearly rate of ARDS decreased from 5.7
      to 2.1 cases per year. Six patients suffered a chronic underlying disease vs none
      in 1982 (p < 0.01). Triggering of ARDS by infection/inflammation was present in
      14/15 patients vs 7/20 in the first series (p < 0.001). Except for the nadir
      PaO2/FiO2 ratio (54 mmHg vs 97 mmHg, p < 0.01), and duration of FiO2 > or = 0.5
      (204 h vs 39 h, p < 0.01) there was no statistically significant difference with
      regard to respiratory data. Incidence of multiple organ/system failure and
      numbers of failing organs/systems remained unchanged. Eight of 15 patients died
      in the actual series vs 8/20 in 1982 (not significant). CONCLUSIONS: Compared to
      our former data, the incidence of ARDS has decreased. Although the number of
      patients with severe chronic disease has increased, mortality remains
      statistically unchanged. Infection/inflammation is currently the predominant
      event triggering ARDS. Judging by the PaO2/FiO2 ratio and duration of FiO2 > or =
      0.5, pulmonary involvement is more severe. The number of failing organs/systems
      remains nearly twice as frequent in non-survivors compared to survivors.

PMID- 10410420
TI  - [The benefits and risks of following dietary guidelines aimed at decreasing
      cardiovascular risk from childhood].
AB  - OBJECTIVE: In recent years much attention has been given to the possibility of
      establishing precocious dietary recommendations which might help reduce the risk
      of cardiovascular disease later in life. The aim of the present review is to
      analyze the possible risks associated with such practices. RESULTS: Some authors
      suggest that restriction of total fat, saturated fat and cholesterol intake might
      lead to nutritional imbalances and deficiencies in minerals and vitamins,
      especially fat-soluble vitamins, pyridoxine, riboflavin, calcium, zinc, iron,
      iodine and magnesium. It might also be associated with changes in the growth and
      development of children, increased risk of cardiovascular disease and mortality
      due to other causes. All authors and organizations agree that in children, the
      principle objective should be that the diet provides the correct quantities of
      energy and nutrients in order for them to achieve optimum growth and development.
      With respect to the prevention of cardiovascular disease, it would seem best that
      a slow transition occur from the high fat intake of early infancy to those
      recommended in adult life (less than 30% of energy from fats, less than 10% from
      saturated fat and less than 300 mg/day cholesterol). CONCLUSIONS: In general, a
      transition stage should be respected with a gradual decrease in the amount of fat
      consumed between the age of two years and the end of the growth period. When
      restriction diets are absolutely necessary, their criteria should be carefully
      considered. The nutritional status of children following such diets should be
      monitored so that the fight against cardiovascular disease does not condition
      nutritional deficiencies with repercussions similar to, or even more serious
      than, the condition they intend to avoid.

PMID- 10410422
TI  - [Growth and the assessment of body composition in children treated with the
      growth hormone].
AB  - OBJECTIVE: The objective of the present work was to analyze the variations in
      corporal composition of children treated with growth hormone. PATIENTS AND
      METHODS: Nineteen patients, 8 girls and 11 boys, with growth retardation were
      studied. The mean age of these children was 8.6 years with a range of 4 to 13
      years. Growth hormone (GH) secretion was evaluated by using clonidine and insulin
      stimulation to evaluate the presence of classic and partial deficits of GH. The
      integrated 24-hour GH concentration was evaluated in the children with
      neurosecretory dysfunction of GH and with biologically inactive GH. IGF-I and
      IGFBP3 levels were also studied. Bio-electric impedance was measured with a
      corporal composition analyzer (Maltron BF 905). The software used, taking into
      account the weight and height of the children and employing Lukaski's equation,
      give the following information: impedance in Ohms, Lean mass and fat mass in
      percentage and Kg, corporal water in liters and percentage, basal metabolism,
      ideal water and ideal fat. The auxological data were obtained with precision
      instruments. Analysis of variance (ANOVA) was used to determine if differences
      existed between the parameters studied at baseline and at 3, 6, 9 and 12 months
      of treatment. The correlation between the resistance index and total corporal
      water was calculated, as well as between tricipital skinfold thickness and
      corporal fat. RESULTS: The patients experienced an increase in lean mass (not
      significant = NS), an increase in corporal water (p < 0.01), a decrease in the
      percentage of fat (NS), a decrease in tricipital and subscapular skinfolds (p <
      0.05 and NS, respectively), an increase in the perimeter of the arm muscle (NS),
      an increase in basic metabolism (NS) and a decrease in electrical impedance (NS).
      The resistance index had a linear relationship with total body water (r = 0.9)
      and tricipital skinfold with corporal fat (r = 0.8).

PMID- 10410421
TI  - [The first national program of pediatric lung transplantation: the experience in
      pediatric intensive care].
AB  - OBJECTIVE: The aim of this study was to analyze the postoperative progress and
      medical management in the Pediatric Intensive Care Unit (PICU) of patients that
      underwent bilateral lung transplant. PATIENTS AND METHODS: From April 1997 to
      June 1998, 10 pediatric lung transplants were performed at the Hospital Reina
      Sofia (Cordoba, Spain). There were 4 males and 6 females (mean age 11.5 years,
      range 5 to 15 years). Indications for transplantation were cystic fibrosis (n =
      9) and one pulmonary fibrosis secondary to viral infection. Before the
      transplant, two patients required mechanical ventilation for acute respiratory
      decompensation and one patient was ventilator-dependent. Immunosuppression
      consisted of corticosteroids, azathioprine and cyclosporine or tacrolimus. Post
      transplantation management included early extubation, when possible, optimal
      fluid balance to prevent lung edema, low aggressive mechanical ventilation and
      adequate treatment of complications, such as rejection and infection. RESULTS:
      There were no peri-operative mortalities. The mean stay in the PICU was 28 days
      (median: 17 days) and the mean time on mechanical ventilation was 19 days
      (median: 5.5 days). The most frequent complications were rejection (n = 8),
      hyperglycemia (n = 6), renal failure (n = 4), arterial hypertension (n = 4) and
      respiratory infections (n = 3). There were no airway complications. CONCLUSIONS:
      Even if the post-operative period in pediatric lung transplant patients is
      difficult, the results have been good with an important improvement in the
      quality of life of these patients has been achieved.

PMID- 10410423
TI  - [Neonatal viability and resuscitation in preterm newborns with an extremely low
      birth weight].

PMID- 10410424
TI  - [Anonymous serological screening for HIV infection in umbilical cord blood by the
      pooled-batch system].
AB  - OBJECTIVE: The aim of this study was to estimate the sero-prevalence of HIV
      infections in pregnant women of the health area of Zamora, Spain by unlinked
      anonymous screening and to estimate the percentage of non-diagnosed cases by non
      systematic screening. PATIENTS AND METHODS: Umbilical cord blood samples of 2,695
      newborns at "Virgen de la Concha" hospital of Zamora collected between January
      1994 and December 1996 were stored with a code number and with no personal
      identification. HIV antibody testing in the serum from the umbilical cord blood
      was performed with an enzyme-immunoassay using pooled sera and verified with
      Western blot. All children born to HIV-infected women during the same period were
      registered. RESULTS: Four of 2,695 samples were seropositive. HIV prevalence was
      0.15% (CI 95%, 0.04-0.37). During the same period only 3 children born to HIV
      infected women were recognized. We estimate that at least 25% of seropositive
      women were undetected. CONCLUSIONS: We conclude that routine HIV screening should
      be offered to all pregnant women.

PMID- 10410425
TI  - [Calcification of the intervertebral disks in childhood as the cause of acute
      torticollis].

PMID- 10410427
TI  - [Myopericarditis simulating a myocardial infarct in a child].

PMID- 10410426
TI  - [Acute encephalopathy and a pericerebral fluid collection in the battered child
      syndrome].

PMID- 10410428
TI  - [Anomalies of Mullerian duct fusion. A report of 3 cases of uterus didelphys
      associated with a double vagina and ipsilateral renal agenesis].

PMID- 10410430
TI  - [Fever and purpuric lesions in a previously health adolescent. Infectious
      endocarditis].

PMID- 10410429
TI  - [Congenital chloridorrhea: adjuvant therapy with ibuprofen and ranitidine].

PMID- 10410431
TI  - [A protocol for the diagnosis and follow-up of cystic fibrosis patients. Sociedad
      Espanola de Neumologia Pediatrica. The Cystic Fibrosis Working Group].

PMID- 10410432
TI  - [Pseudohypoparathyroidism in a pediatric patient].

PMID- 10410433
TI  - [Acute gastric dilatation in a maltreated child].

PMID- 10410434
TI  - [Syncope due to hair grooming].

PMID- 10410435
TI  - [Late neonatal sepsis with meningitis due to meningococcus serogroup C].

PMID- 10410436
TI  - Should hypercholesterolemia be treated in patients older than 65?

PMID- 10410437
TI  - Transplantation without immunosuppression: what the future may hold.
AB  - Research in noncompliant allograft recipients and in a murine model has led us to
      hypothesize that it may be possible to exploit the phenomenon of linked antigen
      recognition in human organ transplantation. If this approach proves successful,
      it may ultimately allow transplant recipients to avoid taking immunosuppressive
      drugs long-term.

PMID- 10410438
TI  - Treatment of Helicobacter pylori in nonulcer dyspepsia: should we or shouldn't
      we?
AB  - Two recent trials of treatment to eradicate Helicobacter pylori in infected
      patients with nonulcer dyspepsia seemingly came to opposite conclusions: one
      found such treatment to be beneficial but the other did not. My interpretation:
      If a patient has unexplained dyspepsia and no abnormal findings on endoscopy,
      blood chemistry, or the blood count, it is reasonable to test for H pylori and to
      give antibiotics if he or she tests positive. However, in no more than
      approximately one fourth of such patients will the problem respond to therapy.
      Furthermore, one should never give anti-H pylori treatment without first
      obtaining proof of infection.

PMID- 10410439
TI  - The role of the maternal-fetal medicine specialist.
AB  - The maternal-fetal medicine specialist is trained to manage high-risk pregnancies
      and obstetric complications. This paper describes the role of the maternal-fetal
      medicine specialist on the obstetric health care team and conditions in which he
      or she may enhance the outcome of pregnancy.

PMID- 10410440
TI  - Late-stage emphysema: when medical therapy fails.
AB  - Although most patients with emphysema are managed medically, a small subset of
      severely disabled patients may become candidates for surgery. This paper
      discusses for the internist who works with emphysema patients the risks,
      benefits, patient selection criteria, and outcome data for three procedures in
      current use: bullectomy, lung transplantation, and a new procedure which provides
      an alternative to transplantation--lung volume reduction.

PMID- 10410441
TI  - Aneurysms and hypermobility in a 45-year-old woman.
AB  - EDS type IV presents a diagnostic and therapeutic challenge to the primary care
      physician, surgeon, and rheumatologist. In patients for whom the diagnosis is
      known, avoidance of trauma, contact sports, or strenuous activities, joint
      bracing and protection, and counseling on contraception are helpful preventive
      strategies. In patients presenting with vascular, gastrointestinal, or obstetric
      complications, a history of hypermobility and skin fragility (easy bruising,
      abnormal scarring, poor wound healing) should lead to a suspicion of this
      diagnosis, and to caution in the use of certain invasive diagnostic and operative
      techniques. Efforts should be made to examine family members. Most importantly,
      when caring for such patients, the acute onset of headaches, chest pain,
      shortness of breath, and abdominal pain should arouse suspicion of a potentially
      catastrophic vascular or visceral event.

PMID- 10410442
TI  - Intracoronary stenting: an overview for the clinician.
AB  - Intracoronary stenting reduces restenosis rates and effectively treats abrupt
      vessel closure, two frequent complications following percutaneous coronary
      angioplasty (PTCA). But it has drawbacks, such as in-stent restenosis, high cost,
      and lack of long-term follow-up data. This paper discusses current indications
      and the future role of stenting.

PMID- 10410443
TI  - Subacute care: which patients benefit?
AB  - The decision about appropriate referral of patients to a subacute care unit is
      the key to both continuity of care and the financial viability of a hospital's
      subacute care unit. Patient selection, subacute care admission criteria, patient
      education, and financial concerns are discussed.

PMID- 10410444
TI  - [The heterogeneity of paracetamol metabolism in Gilbert's disease].
AB  - BACKGROUND: Gilbert's syndrome (GS) is a hereditary deficiency of bilirubin UDP
      glucuronosyltransferase (UGT). The aim of this study was to analyze changes in
      the metabolism of paracetamol, which is primarily eliminated by liver
      glucuronidation, through urine concentrations of its four principal hepatic
      metabolites, in persons with GS. MATERIAL AND METHODS: Thirty-two healthy
      volunteers and 18 persons with GS were studied. Subjects were given 1.5 g of oral
      paracetamol. Elimination of free paracetamol, as well as derivatives of its
      conjugation (glucuronide, sulfate) and of its oxidation (cysteine, mercapturic
      acid), was determined in 24-hour urine by high performance liquid chromatography
      (HPLC). Results were expressed as a percentage of the total quantity of
      paracetamol eliminated. Patients with GS were divided in two subgroups (GS-I and
      GS-II) according to whether glucuronidation was greater than or less than 50%.
      RESULTS: Patients with GS showed no significant differences in the urinary
      elimination of metabolites compared with controls. However, the subgroup GS-II
      showed decreased glucuronidation (p = 0.0012) and increased oxidation (p =
      0.0051) compared with the other two groups. Moreover, there was an inverse
      correlation between the glucuronide conjugate and oxidation derivatives (r =
      0.08718; p < 0.005). CONCLUSIONS: Persons with GS form a heterogeneous group as
      far as paracetamol metabolism is concerned. In one subgroup metabolism was normal
      and in the other glucuronication was clearly decreased and oxidation was
      increased. These alterations could make these subjects more susceptible to liver
      damage after paracetamol overdose.

PMID- 10410445
TI  - [The evaluation of a new immunoenzyme analysis for the detection of Helicobacter
      pylori infection in stool samples].
AB  - BACKGROUND: Detection of bacterial antigen in stool specimens (HpSAT) is a new
      promising tool for diagnosing Helicobacter pylori infection. OBJECTIVE: To
      evaluate diagnostic accuracy of HpSAT in the diagnosis of Helicobacter pylori
      infection. PATIENTS AND METHODS: We evaluate the presence of Helicobacter pylori
      infection by the rapid urease test and the 13C-urea breath test in endoscopic
      biopsies. Patients who were positive for both tests were considered to have
      Helicobacter pylori infection. Patients negative for both tests were considered
      free of infection. The presence of Helicobacter pylori infection was also
      determined in stool specimens by means of HpSAT. RESULTS: The sensitivity of
      HpSAT was 92.8%, the specificity 92.3%, the positive predictive value 98.1% and
      the negative predictive value 75%. CONCLUSIONS: HpSAT is a reliable tool for
      diagnosing Helicobacter pylori infection.

PMID- 10410446
TI  - [The assessment of colonic polyps found via colonoscopy].
AB  - AIM: To evaluate the histopathological characteristics of colonic polyps, found
      during colonoscopy examination and endoscopic polypectomy, and their relation to
      age, tumor location, sex, histological type and degree of epithelial dysplasia.
      MATERIAL AND METHODS: Between 1996 and 1997, 2,465 total colonoscopies were
      performed at the Gastroenterology Department of the Virgin Macarena University
      Hospital in Seville. Different size polyps were found in 318 patients who had
      been referred because of several symptoms/by several centers. The mean age was
      59.2 years in men and 61.5 years in women. RESULTS: 446 polyps were removed by
      endoscopic polypectomy, 32 (7.2%) were hyperplastic polyps, 402 were adenomas
      (90.2%) and 12 (2.6%) were adenomas with adenocarcinoma. Seventy-five percent of
      adenomas were located in the left colon and rectum and 25% in right colon.
      Hyperplastic polyps were found in left colon. Of the polyps removed, 55.1% were
      smaller than 1 cm, 26.5% were between 1 and 2 cm and 18.4% were between 2 and 7
      cm. Histopathologic study of adenomas revealed that 17% were villous adenoma, 80%
      were tubular adenomas and 3% were tubulovillous adenomas. Adenocarcinomas were
      found in 12 (2.8%) adenomas. Of the adenomatous polyps, 87.4% had low-grade
      dysplasia and 12.6% high-grade dysplasia. Statistical analysis showed a strong
      correlation between size of adenoma and degree of dysplasia (p < 0.05). Similar
      significant relation was found between histological type and size (p < 0.05) but
      there were no statistically significant differences between location, sex or age,
      and degree of dysplasia (p < 0.05). CONCLUSIONS: Size of colonic polyps is
      related to epithelial dysplasia and histological type (p < 0.05). No correlation
      was found between location, sex or age and degree of dysplasia.

PMID- 10410447
TI  - [Acute recurrent pancreatitis in a patient with Oddi's sphincter dysfunction].
AB  - Alcohol consumption and gallstones are the most common causes of acute
      pancreatitis in developed countries. However, some episodes of acute pancreatitis
      have being regarded "idiopathic" once blood samples have been analyzed and
      diagnostic procedures (abdominal ultrasonography, CT and ERCP) have been
      performed. Sphincter of Oddi (SO) dysfunction is a rare entity that may be
      involved in the development of recurrent acute pancreatitis. SO manometry is the
      first option to investigate SO dysfunction. A recurrent idiopathic pancreatitis
      case in a young patient is presented. The manometric study revealed SO
      dysfunction, and oral nidefipine 10 mg was started. After a 12-months follow-up
      undergoing this therapy, the patient remains asymptomatic.

PMID- 10410448
TI  - [Recurrent digestive hemorrhage as a complication of an intraduodenal
      diverticulum].
AB  - Intraluminal duodenal diverticulum (IDD) is a rare congenital anomaly, which
      usually causes symptoms in adulthood. We report a 39-year-old woman, who
      presented several episodes of upper gastrointestinal bleeding and who was
      successfully treated with surgery. The clinical presentation, diagnosis and
      treatment of the 56 cases published in the English and Spanish literature from
      1975 to 1998 are reviewed.

PMID- 10410449
TI  - [Amebic liver abscesses with bacterial superinfection in a nonendemic area].
AB  - A 26-year-old man was admitted to hospital with asthenia, weight loss, right
      upper quadrant abdominal pain, diarrhea without blood, and fever. Abdominal
      ultrasonography showed multiple hypoechoic areas in the left hepatic lobe. On
      abdominal CT, multiple hypodense areas without contrast capture were consistent
      with hepatic abscesses. Cultures were obtained and the patient was placed
      empirically on metronidazole, gentamicin and ampicillin, without improvement in
      the first 72 hours, and a drain was placed in the largest lesion collecting a
      purulent material. The abscess culture was positive for group C beta-hemolytic
      Streptococcus. Entamoeba histolytica serology was positive and colon biopsies
      revealed trophozoites. Multiple left hepatic lobe abscesses secondary to E.
      histolytica, with bacterial superinfection, is an unusual presentation of amoebic
      infection, considering that Spain is not an endemic area.

PMID- 10410450
TI  - [Primary sclerosing cholangitis].

PMID- 10410451
TI  - [Infectious esophagitis].

PMID- 10410452
TI  - [Oxidative stress and gastrointestinal damage].

PMID- 10410453
TI  - [Pneumatosis intestinalis: an accidental finding in a patient after kidney
      transplantation].

PMID- 10410454
TI  - [Systemic mastocytosis and fever of unknown origin].

PMID- 10410455
TI  - [Caustic lesions due to dishwasher liquid for industrial use].

PMID- 10410457
TI  - Activation of enzymatic catalysis.
AB  - Modulation of enzyme activity by inhibition and activation plays an important
      physiological role in regulation of cellular metabolism. Compared to the wealth
      of information available regarding inhibition of metabolic pathways, little is
      known about activation. Limited proteolysis of zymogens exemplifies irreversible
      activation. Reversible activation may involve post-translational modifications or
      dissociable binding of small molecules. Sometimes, chemical modification may also
      activate enzymes. The influence of small molecules on the reversible binding and
      activation of enzymes is summarized.

PMID- 10410456
TI  - [An aortoesophageal fistula as the initial manifestation of esophageal
      carcinoma].

PMID- 10410458
TI  - Channeling of TCA cycle intermediates in Saccharomyces cerevisiae.
AB  - Metabolism of 13C labeled substrates viz. glucose and pyruvate in S. cerevisiae
      has been studied by 13C Nuclear Magnetic Resonance Spectroscopy. C3-Pyruvate,
      alanine and lactate, and C2-acetate are produced from [1-13C]glucose. The
      pyruvate, entering TCA cycle, leads to preferential labeling of C2-glutamate. [2
      13C]Glucose results in labeling of C2-pyruvate, alanine and lactate. Some C3
      pyruvate is also produced, indicating the routing of the label from glucose
      through pentose phosphate pathway (PPP). In TCA cycle the C2-pyruvate
      preferentially labels the C3-glutamate. The NMR spectra, obtained with [2
      13C]pyruvate as substrate, confirm the above observations. These results suggest
      that the intermediates of TCA cycle are transferred from one enzyme active site
      to another in a manner that allows only restricted rotation of the intermediates.
      That is, the intermediates are partially channeled.

PMID- 10410459
TI  - Chemical modification of 3-HBA-6-hydroxylase by phenylglyoxal: kinetic and
      physicochemical studies on the modified enzyme.
AB  - The inactivation of 3-HBA-6-hydroxylase isolated from Micrococcus species by
      phenylglyoxal and protection offered by 3-HBA against inactivation indicate the
      presence of arginine residue at or near the substrate binding site. The loss of
      enzyme activity was time and concentration dependent and displayed pseudo-first
      order kinetics. A 'n' value of 0.9 was obtained thus suggesting the modification
      of a single arginine residue per active site which led to the loss of enzyme
      activity. The enzyme activity could be restored by extensive dialysis at neutral
      pH. Quenching of the intrinsic fluorescence and reduction in the ellipticity
      value at 280 nm in the near-UV CD spectrum of the enzyme was noticed after its
      treatment with phenylglyoxal. These observations probably imply distinct
      perturbations in the environment of adjacent aromatic amino acid residues such as
      tryptophan as a consequence of arginine modification.

PMID- 10410460
TI  - Conformational flexibility of voltage gated dihydropyridine sensitive calcium
      channel in hydrated DMPC bilayer.
AB  - We have built a model for Ca2+ channel using amino acid sequence from S3 helix of
      the fourth internal repeat of alpha 1 subunit of dihydropyridine sensitive
      calcium channel from rabbit skeletal muscle, on the basis of X-ray
      crystallographic data on four helix bundle. The assembling of the geometry of the
      pore was achieved using a sixteen residues peptide fragment from short SSI/II
      loop (residues 1010-1025) which had F1013 and E1014 residues, considered to be
      important for the drug induced activity of the channel. This had hairpin bend
      between F1013 to W1016. The drug 2,6-dimethyl 3,5-dicarbomethoxy-4 (2
      nitrobenzyl) 1,4 dihydropyridine (DHP) (nifedipine), which is a calcium channel
      inhibitor used in the treatment of cardiovascular diseases, was introduced,
      interacting with these two residues via Ca2+ ion. Two more Ca2+ ions were
      introduced in the pore. The model was incorporated in the bilayer of 36
      dimyristoyl phosphatidyl choline (DMPC) molecules with 1201 water molecules and
      simulated for 200 picoseconds (ps) after equilibration for 120 ps. We also
      simulated the channel model in vacuum and in aqueous environment for comparison.
      The latter was unstable after 120 ps. The geometric parameters of the pore are
      analysed by MOLMOL, PCURVE 3.1 and a special program ANHELIX developed by us.
      Stability of the pore dimensions during simulations is discussed in this paper.

PMID- 10410461
TI  - Cell surface alterations induced by methylene blue and direct electric current in
      Escherichia coli.
AB  - Cell surface properties, including hydrophobicity, zeta potential, carbohydrate
      and fatty acid components, were altered on treatment of E. coli K12 with
      methylene blue (MB) and direct electric current (DC). The treatment of fimbriated
      E. coli cells with MB greatly increased the agglutination of yeast cells when
      compared to untreated bacteria. However, this increased agglutination was
      markedly reduced when the bacteria were treated with MB plus DC. These results
      suggest that MB modifies cell surface components in the absence of light and
      these alterations are more pronounced when cells are treated simultaneously with
      MB and DC.

PMID- 10410462
TI  - Spectral studies on the interaction of iodine and anthracene sulfonate with
      bacterial phospholipids from different mutants of Salmonella minnesota.
AB  - Using spectrophotometric and spectrofluorometric techniques, the interaction of
      iodine and 2-anthracene sulfonate (ANS) with the phospholipids (PL) isolated from
      four genetically correlated Salmonella minnesota isolates viz., a smooth form
      (S), a deeply rough mutant (Rc) and two intermediate forms (Ra and Rb) were
      studied. Appearance of an isosbestic point and a new band in absorption spectra
      indicated charge-transfer (C-T) interaction of iodine with the PL through the
      formation of 1:1 complex. Stern-Volmer type fluorescence quenching of PL was
      observed with the addition of iodine to PL, while PL enhanced the fluorescence of
      anionic dye ANS. The values of the binding constants between iodine/PL and
      ANS/PL, measured by using suitable equations, showed a systematic gradation in
      the molecular properties of the PL in the membrane structure in smooth (S) and
      rough (Ra, Rb and Rc) mutants of Salmonella minnesota.

PMID- 10410463
TI  - Role of fatty acid binding protein in the modulation of inhibitory effect of
      fatty acids on fatty acid synthase and ATP-citrate lyase in developing human
      brain.
AB  - Inhibition of the activities of fatty acid synthase and ATP-citrate lyase (ATP
      CL) by fatty acids and their CoA esters has been studied. Purified fatty acid
      binding protein from human fetal brain reverses this inhibition. This protein
      also activates the enzyme when added alone. ATP-citrate lyase and fatty acid
      synthase activity gradually increased with the advancement of gestation showing a
      relationship between high demand of fatty acid synthesis in developing brain and
      supply of its precursors.

PMID- 10410464
TI  - Atherogenic diet alters folate enzymes in mice: implications of folate deficient
      homocysteinemia.
AB  - The two key enzymes, methylenetetrahydrofolate reductase and methionine synthase
      involved in methionine synthesis from homocysteine were studied in atherogenic
      diet fed mice. Methylenetetrahydrofolate reductase activity was elevated while
      methionine synthase was impaired in atherogenic diet fed group. Impaired
      methionine synthase activity would adversely affect the methionine synthesis from
      homocysteine, resulting in a rise in the homocysteine levels, which are
      atherogenic. This is reflected by the increased levels of very low density and
      low density lipoprotein cholesterol values and a higher ratio for total
      cholesterol to high density lipoprotein cholesterol.

PMID- 10410465
TI  - Identification and estimation of endogenous digoxin in biological fluids and
      tissues by TLC and HPLC.
AB  - A procedure for estimation of digoxin in biological samples after adding a known
      quantity of digoxin followed by extraction, separation by TLC and HPLC is
      described. The identity of digoxin thus extracted from rat brain has been
      established by reaction with digoxin antibody and by its inhibition of Na(+)-K+
      ATPase activity. The method could be a better substitute to the routine
      radioimmunoassay as interfering substances are removed by TLC and HPLC.

PMID- 10410466
TI  - Comparison of the antioxidant action of the alcoholic extract of Rubia cordifolia
      with rubiadin.
AB  - The inhibition of FeSO4 induced lipid peroxidation in rat liver by alcoholic
      extract of Rubia cordifolia and by one of its constituent rubiadin (1, 3
      dihydroxy-2-methyl anthraquinone) (pure form) has been compared. Both have been
      found to inhibit lipid peroxidation in a dose dependent manner. Whereas the
      former shows both oxidising and reducing properties with Fe2+ and Fe3+, the
      latter shows oxidising property only by converting Fe2+ to Fe3+. The former
      inhibits the oxidation of reduced glutathione while the latter does not.

PMID- 10410467
TI  - Assay of matrix metalloproteinases in substrate impregnated gels in multiwells.
AB  - A zymographic method for the assay of matrix metalloproteinases in substrate
      impregnated gels in multiwells has been developed for the analysis of a large
      number of samples at a time. Enzyme was copolymerized with 300 microliters of 10%
      acrylamide impregnated with gelatin substrate and incubated for 16 hr. The gels
      were stained with coomassie blue, destained with water and the intensity measured
      in a densitometer. This method was tested with pure bacterial collagenase and
      three different gelatinases purified from rat mammary gland. The characteristics
      of these enzymes such as cation dependence, inhibition and concentration
      dependence have been examined by this method.

PMID- 10410468
TI  - [Complications of percutaneous nephrostomy. Apropos of 481 procedures: the value
      of puncture of the median calices].
AB  - The authors report on a series of 481 percutaneous nephrostomy procedures, and
      describe the complications encountered. 163 percutaneous nephrostomies for
      drainage and 318 percutaneous stone removals, were performed between 1985 and
      1995 in the Radiology Department of Hotel-Dieu de France Hospital under
      fluoroscopy. One tract was needed for PN but more than one was sometimes
      necessary for percutaneous stone removal. Complication rate was identical to the
      results reported in the literature. Complications were more frequently
      encountered when the upper calyx was punctured (intercostal approach), mostly
      pleural lesions. Puncture of the middle and inferior calyx were associated with
      the same rate of complications, but with different degrees of severity. Major
      complications (80% of cases of hemorrhage, including all arteriovenous fistulae
      and pseudoaneurysms) were encountered with the puncture of the lower calyx while
      those associated with the puncture of the middle calyx were minimal. Thus,
      puncture of the middle calyx is the least morbid. It is recommended by the
      authors, whenever possible.

PMID- 10410469
TI  - The standardization of the Denver Developmental Screening Test on Arab children
      from the Middle East and north Africa.
AB  - A total of 936 children of Arab ethnic origin and culture were tested for the
      purpose of the standardization of the Denver Developmental Screening Test (DDST)
      on children from the Middle East and North Africa. There were 457 males and 479
      females included in the study, with a race distribution of 216 white, 96 black,
      and 624 of mixed racial origin. The sample was divided into three age groups,
      with the age-range all-inclusive being from birth to six years. Five social
      classes were included. Accordingly, a new DDST screening form was designed and
      presented for the population studied. Age norms of developmental milestones on
      the personal-social, fine motor-adaptive, language, and gross motor skills are
      presented here.

PMID- 10410471
TI  - [Immunogenetics and new therapies in type I diabetes mellitus].

PMID- 10410472
TI  - [Cockayne syndrome in Lebanon. Description of 3 cases and review of the
      literature].
AB  - Cockayne syndrome is a rare autosomal recessive progressive neurological disorder
      characterized by a nanism, a major cachexy, a characteristic facial appearance of
      premature ageing, a sun-sensitivity, a retinopathy, and a mental retardation. We
      report three observations of Cockayne syndrome. The diagnostic criteria, notably
      clinical, found in these patients are discussed in comparison to the literature.

PMID- 10410473
TI  - Clinical study of 457 cholecystectomy cases in a private hospital.
AB  - This is a retrospective study of 457 cases of cholecystectomized patients, who
      were admitted to Vichaiyut Hospital from 1970 to 1996. The ratio of male to
      female was 1:1.6 and the most common age range was 51-60 years, 45.3 per cent of
      patients were older than 60 years. Associated or underlying diseases were highly
      prevalent (81.6%). Diabetes mellitus, cardiovascular disease and liver disease
      were the three most common associated diseases. In acute cholecystitis the
      pathological findings were in accordance with clinical feature in only 46.2 per
      cent but in chronic or subsided cholecystitis pathology confirmed in 97.5 per
      cent. Carcinoma of the gallbladder was found in 0.9 per cent. Clinical diagnosis
      of cholecystitis was incorrect in 1.1 per cent. Multiple gallstones were found in
      67.3 per cent, single stone in 23.5 per cent, sand stones in 2.1 per cent and
      acalculous cholecystitis in 7.1 per cent. Combined gallstones and CBD stones were
      found in 9.8 per cent. Enteric bacteria were isolated from the bile in 32.5 per
      cent and in acute cholecystitis similar organisms were isolated from both bile
      and blood cultures in 12.8 per cent. Morbidity rate of cholecystectomy was 7.6
      per cent, the most common complication was perioperative infection in 3.5 per
      cent. It is interesting to find that atelectasis was recognized only in 2 out of
      57 laparoscopic cholecystectomy. Mortality rate was low (0.66%).

PMID- 10410474
TI  - The association of age, sex and the number of sides of carpal tunnel syndrome.
AB  - The association of age, sex and the number of sides of carpal tunnel syndrome
      were studied in 250 patients. The mean age of the patients with bilateral
      involvement was more than unilateral involvement (t = 2.48, p < 0.05). A
      statistically significant association was found between age and the number of
      sides of carpal tunnel syndrome (chi-square = 16.707, p < 0.05). There was also
      statistical significance in association of sex and the number of sides of carpal
      tunnel syndrome (chi-square = 10.2398, p < 0.01). The association of age, sex and
      the number of sides of carpal tunnel syndrome found in the study may help the
      prediction of diagnosis and natural history of the disease.

PMID- 10410475
TI  - External cephalic version: first report from Thailand.
AB  - This prospective study was to preliminary report the safety and success rate of
      external cephalic version (ECV) in patients with breech presentation or
      transverse lie at 36 weeks of gestation or more. The aim of this procedure was to
      reduce the cesarean section rate from indication of breech presentation and
      transverse lie. This procedure was first started in the Obstetrics and Gynecology
      Department, Ramathibodi Hospital in June 1998. Thirty two patients were enrolled
      in this study. ECV was 65 per cent successful with the reversion rate of five per
      cent. There was no maternal or fetal complication related to this procedure.
      Factors associated with successful outcome in this study were the location of
      placenta, the position of fetal spine and the amount of amniotic fluid. A larger
      study is needed before the true success rate and the efficacy of this procedure
      can be apparent.

PMID- 10410476
TI  - A comparative study of membrane stripping and nonstripping for induction of labor
      in uncomplicated term pregnancy.
AB  - A prospective, randomized controlled trial was undertaken at the Department of
      Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn Hospital to
      determine whether stripping of the fetal membranes is a safe and effective method
      for induction of labor in uncomplicated term pregnancy. Ninety-six women were
      included in this study; 16 were excluded; 41 were randomized to a study group and
      39 to a control group. Both groups had pelvic examination performed under sterile
      technique and a Bishop score was assessed. In the study group, membrane stripping
      was performed. Gentle pelvic examination for Bishop scoring was continued weekly
      in both groups. Thirty five of 41 women (85.4%) in the study group delivered
      within 7 days as compared to 22 of 39 women (56.4%) in the control group, a
      statistically significant difference (P = 0.004). A statistically significant
      difference was also observed with respect to the mean number of days to delivery
      (5.3 +/- 4.9 versus 9.5 +/- 5.9 days, respectively; P = 0.002). No statistically
      significant differences were observed in both maternal and fetal complications.
      In conclusion, membrane stripping is a safe and effective method for induction of
      labor in uncomplicated term pregnancy.

PMID- 10410477
TI  - A result of sublabial transnasomaxillary approach for nasopharyngeal angiofibroma
      -retrospective study.
AB  - To evaluate the result of sublabial transnasomaxillary approach (STA) as a route
      for removal of juvenile nasopharyngeal angiofibroma (JNA). Eleven young male
      patients with angiofibroma underwent removal via the sublabial transnasomaxillary
      approach. This technique is described in detail. There was neither major
      operative nor postoperative complication. One patient developed dacryocystitis.
      Long term follow-up longer than 18 months in 5 patients, showed no recurrence.
      This technique is useful for removal of angiofibroma because it enables the
      surgeon to gain extensive exposure of maxillary, ethmoid and sphenoid sinuses and
      to control sphenopalatine and internal maxillary arteries, without risk of
      palatal dysfunction or of oronasal fistula. Other advantages comprise the lack of
      a facial scar, nasal septal scar and bilateral premaxillar numbness, and good
      postoperative assessment.

PMID- 10410478
TI  - Scintimammography (SMM) in breast cancer patients.
AB  - The author retrospectively reviewed the scintimammography (SMM) using 201Tl
      and/or 99mTc-MIBI in 45 breast cancer patients. 36 cases with 37 intact breast
      masses and another 9 cases with previous excision of the masses were studied. The
      sensitivity for the detection of the primary breast cancer was 92 per cent and
      that of ipsilateral axillary lymph node metastasis was only 48 per cent. SMM is
      helpful for the diagnosis of breast cancer and differentiating malignant from
      benign masses, thus improving the accuracy of routine mammography. In
      postoperative cases SMM is helpful to detect palpable local tumor recurrence and
      axillary node metastasis but it is not accurate enough for assessing the extent
      of microscopic tumor involvement locally and also distant metastasis. Thus, it is
      not recommended to use SMM alone for staging of breast cancer.

PMID- 10410479
TI  - p53 gene mutations in non-small cell lung cancer from Thai patients.
AB  - Paraffin embedded tissues from twenty-two Thai patients with non-small cell lung
      cancer were studied for p53 gene mutations in exon 5 to 8 using polymerase chain
      reaction and single-stranded conformation polymorphism (PCR-SSCP) followed by
      thermal cycle sequencing. Results showed that point mutations in this region of
      p53 gene were present in 3 cases. One harboured the base change from GAC to AAC
      at codon 281, changing amino acid from aspartic acid to asparagine, whilst the
      other cases were transversion of AAA (lysine) to ACA (threonine) at codon 292.
      All subjects with p53 mutation had a past history of tobacco smoking.

PMID- 10410480
TI  - Improved detection of radiofrequency current-induced minor myocardial injury by
      cardiac troponin T measurement.
AB  - Transcatheter radiofrequency current application in patients with cardiac
      arrhythmias was reported to be associated with a low rate of an increase in the
      activity of enzyme creatine kinase (CK) and CK-MB isoenzyme. As the novel heart
      specific protein troponin T (cTnT) was shown to be superior to CK and CK-MB in
      detecting small damage to myocardial tissue in various clinical situations
      including unstable angina, a comparison of the diagnostic efficiency of these
      marker proteins to detect myocardial damage was made in 34 patients (mean age
      38.3 +/- 15.6 years) undergoing radiofrequency (RF) catheter ablation of
      accessory pathways (n = 17) and atrioventricular nodal reentrant tachycardia (n =
      17). Serial measurements of total CK and CK-MB activity before and every 8 hours
      for 24 hours after ablative procedure were performed with enzymatic and
      immunoinhibition method, respectively, using automated chemical analyzer Hitachi
      717. Serum concentration of cTnT was determined by one-step sandwich ELISA
      performed on ES 300 analyzer (Boehringer Mannheim). With a median of 7.0 (range 1
      39) RF current pulses only 12 (35%) and 10 (29%) of 34 patients showed an
      increase above the upper limit of normal CK and CK-MB activity, respectively. The
      peak activity of CK (mean peak = 285.8 +/- 517.7 IU/L) occurred at a variable
      time that infrequently coincided with those of peak CK-MB activity (23.1 +/- 8.0
      IU/L). By contrast, all except 4 (88%) of 34 patients exhibited a distinct
      elevation of cTnT concentration (mean peak = 0.56 +/- 0.63 ng/ml), with almost
      all (33) of these 34 patients showed an early peak value at 8 hours
      postprocedural. There was, on the average, a small but distinct higher relative
      increase (5.6 times) in cTnT concentration from the upper limit of reference
      range compared with those of CK (1.5 times) and CK-MB peak activity (0.9 time).
      In conclusion, cTnT exhibited a minor but distinct elevation in its concentration
      and demonstrated a higher rate and magnitude of increase following radiofrequency
      current application than the conventional CK and CK-MB isoenzyme. Measurements of
      cTnT serum concentration may thus provide a useful test method for assessing the
      effect of the new transcatheter ablation procedures on myocardial tissue.

PMID- 10410481
TI  - Prevalence of type specific Epstein-Barr virus in the genital tract of genital
      herpes suspected patients.
AB  - A total of 62 clinical specimens from the genital tract of patients who were
      suspected of contracting genital herpes were investigated for HSV infection by
      the virus isolation method, and also investigated for the co-infection with EBV
      infection by detecting EBV DNA using nested PCR. HSV infection was diagnosed in
      30 (48.4%) of the study cases, and so was EBV. EBV DNA was present in 17 (56.7%)
      of the 30 HSV positive samples. No correlation was found between the co-existence
      of these two viruses together. EBV DNA was detected in genital specimens of
      cervical, vaginal, urethral, and anal swabs. Ninety per cent of EBV belonged to
      type 1, and the remainder belonged to type 2 and mixed types. The role of EBV in
      genital tract infection needs to be further investigated.

PMID- 10410482
TI  - Percutaneous transthoracic needle aspiration biopsy of localized lung lesions
      under fluoroscopic or ultrasound guidance.
AB  - Diagnostic percutaneous transthoracic needle aspiration biopsy (TNAB) under
      fluoroscopic or ultrasound guidance was performed in 195 patients with peripheral
      lung lesions. Final diagnosis was confirmed in 178 cases. These consisted of 150
      cases of malignant and 28 cases of non-malignant lung lesions. Most cases of the
      latter belonged to the infectious group. Sensitivity of TNAB in the diagnosis of
      malignancy and lung infections were 92.0 per cent and 62.5 per cent respectively.
      Needles with different sizes were used and the needle number 18G was found to
      obtain both cytological and histological samples and showed the highest
      sensitivity. Among cases that TNAB provided both types of samples, histology
      alone showed higher sensitivity in diagnosis than cytology alone. However, by
      cytological examination, malignant tumors could be interpreted for definite cell
      type in more cases than by histology. To reach the highest diagnostic yield, the
      results of both samples should be combined. We also found that the aspirated
      samples with solid or semisolid features were more diagnostic than those with
      other features. Pneumothorax, the most common complication of the TNAB procedure,
      was found in only 2.0 per cent of our series.

PMID- 10410483
TI  - Serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding
      protein-3 (IGFBP-3) in healthy Thai children and adolescents: relation to age,
      sex, and stage of puberty.
AB  - The authors studied the serum concentrations of insulin-like growth factor-1 (IGF
      1) and IGF-binding protein-3 (IGFBP-3) in 260 healthy children and adolescents
      (115 males, 145 females) aged 5-20 years. The subjects were divided into 12
      groups according to age and sex. The serum IGF-1 and IGFBP-3 concentrations
      increased with age and peaked at age 13-15 years in males, and 11-13 years in
      females. After the peak concentration, IGF-1 and IGFBP-3 levels declined
      significantly in males, but were still high in females. Comparing between sexes,
      the concentrations of IGF-1 and IGFBP-3 were greater in females than males in all
      age groups. However, when subjects were divided according to the stage of
      puberty, the different concentrations between sexes were not significant, except
      for children within Tanner stage V where concentrations of IGF-1 and IGFBP-3 were
      significantly greater in females than males. Multiple regression analysis
      demonstrated the age, sex, and stage of puberty-dependent of IGF-1 concentration,
      and only the age and sex-dependent of IGFBP-3 concentration.

PMID- 10410484
TI  - Urinary iodine excretion as a predictor of the iodine content of breast milk.
AB  - Endemic goitre has re-emerged in Thailand. This is particularly dangerous for
      children since iodine deficiency disorders (IDDs) might negatively influence
      their intellectual and mental development. In order to assess the situation, the
      iodine content of breast milk was determined and a method is proposed on how to
      monitor IDDs in lactating mothers later on. Seventy-five lactating women aged
      from 15 to 45 years, from 12 villages of 3 districts, namely Chumpae. Srichompu
      and Pupaman within the mountainous areas of Khon Kaen province, Northeast of
      Thailand were investigated. The breast milk from 46.7 per cent of mothers was
      found to be below recommended standards. In addition, 52.0 per cent of the women
      investigated had low urinary iodine excretion. The risk of women with low iodine
      excretion was 15 fold higher in comparison to women with sufficient iodine
      excretion to provide breast milk for their babies with insufficient iodine
      content. It is concluded that urinary iodine excretion can be used to monitor the
      IDDs in lactating mothers.

PMID- 10410485
TI  - Transcatheter coil occlusion of patent ductus arteriosus.
AB  - Between May 1995 and October 1997, 17 cases of small patent ductus arteriosus
      (PDA) underwent percutaneous coil occlusion at the Department of Pediatrics,
      Chulalongkorn Hospital. The mean age was 5.3 +/- 3.6 years (range, 1 year 4
      months to 12.0 years); mean weight was 18.9 +/- 11.7 kg (range, 9 to 48 kg). The
      mean minimum diameter of the PDA was 2.8 +/- 0.6 mm (range, 1.7 to 4.0 mm). PDA
      occlusion was achieved with one coil in 9 patients and two coils in 8 patients.
      One patient required the second coil occlusion procedure to occlude the residual
      PDA leakage. Of the 17 patients, coils were successfully implanted in 15
      patients: complete closure of PDA was obtained in 14 patients, confirmed by
      aortography or by color flow echo imaging or both. In the two unsuccessful coil
      implantation cases, coils migrated to the distal left pulmonary artery (1 case)
      and the distal right pulmonary artery (1 case). They could not be retrieved. Both
      patients had surgical closure of PDA on the following day after the failed
      procedure. No clinical and chest X-ray showed any evidence of pulmonary
      complication from the migrated coils up to 1-year follow-up. PDA coil occlusion
      provides an alternative to surgical closure. The procedure is safe and has a good
      result.

PMID- 10410486
TI  - Caffeine clearance study in hepatocellular carcinoma.
AB  - The purpose of this study was to evaluate hepatic metabolic capacity in cirrhotic
      patients with hepatocellular carcinoma (HCC). We compared plasma caffeine
      clearance, calculated by two point analysis, between patients with cirrhosis
      alone and cirrhosis complicated with HCC. These two groups were comparable with
      regards to age, sex, and the severity of liver disease, graded by Child-Pugh
      score as compensated and decompensated cases. From our result, caffeine clearance
      in compensated cases was clearly higher than that of decompensated cases in both
      groups studied, particularly in the HCC group (p = 0.001). The mean value of
      caffeine clearance in HCC patients correlated well with the tumor staging as
      classified by Okuda's criteria. There was also a reversal correlation between
      tumor size and the clearance tested in compensated cases of HCC (p = 0.046), but
      this finding was not detected in decompensated cases (p > 0.05). We conclude that
      the determination of caffeine clearance can serve as a useful parameter for the
      assessment of hepatic functional reserve in cirrhotic patients complicated with
      HCC, and may be a useful predictor for survival outcome.

PMID- 10410487
TI  - Hematological parameters, ferritin and vitamin B12 in vegetarians.
AB  - Hematological parameters and serum ferritin were compared between 179 vegetarians
      and 58 control subjects using Hematology analyzer H3 and microparticle enzyme
      immunoassay, respectively. Serum Vitamin B12 was also compared between 68
      vegetarians and 30 control subjects using microparticle enzyme immunoassay. It
      was found that hemoglobin, hematocrit, mean corpuscular hemoglobin, mean
      corpuscular hemoglobin concentration, white blood cells, neutrophils, serum
      ferritin and serum vitamin B12 in vegetarian were significantly lower than
      control subjects (P < 0.05). In addition, red cell distribution width and
      lymphocytes in vegetarians were significantly higher than control subjects (P <
      0.05). There were 34 cases of iron deficiency in 179 vegetarians (19.%) which can
      be classified to iron depletion (4 cases), iron deficient erythropoiesis (12
      cases) and iron deficiency anemia (18 cases). Vitamin B12 deficiency was found in
      27 cases of 68 vegetarians (40%).

PMID- 10410488
TI  - Hughes-Stovin syndrome: a case report and review of the literature.
AB  - A young man presented with prolonged pyrexia, recurrent optic neuritis,
      thrombophlebitis and bilateral pulmonary artery aneurysms with thrombus
      formation. The life-threatening hemoptysis necessitated mechanical ventilatory
      support and emergency left lower lobectomy. Systemic corticosteroids conferred
      clinical improvement and reduction of the remaining right pulmonary artery
      aneurysm. The patient eventually succumbed to sudden massive hemoptysis. This
      report underscores the unpredictable nature of this syndrome and emphasises the
      need for aggressive surgical intervention of pulmonary artery aneurysms in Hughes
      Stovin syndrome.

PMID- 10410489
TI  - Physicians and the death penalty.

PMID- 10410490
TI  - Neonatal and maternal complications among pregnant women delivered by vacuum
      extraction or forceps extraction.
AB  - A historical cohort study was used to analyse the maternal and neonatal
      complications among pregnant women delivered by vacuum or forceps extraction at
      Rajavithi Hospital, 1994. The maternal complications (third and fourth degree of
      perineal tear and postpartum hemorrhage) were statistically significant more
      often in the forceps group than in the vacuum extraction group. But fetal
      complications (neonatal hyperbilirubinemia, low Apgar scores (< 7) at 1 and 5
      minutes and the transfer to NICU) were statistically significant more often in
      the vacuum extraction group than in the forceps group.

PMID- 10410491
TI  - Growth patterns of low-birth-weight infants: 2-year longitudinal study.
AB  - A 2 year longitudinal study of the growth of 147 low birthweight (LBW) < 2,500 g
      infants who had no known factors disturbing growth was conducted. The infants
      were divided into 6 groups according to birthweight and maturity: group 1-
      appropriate for gestational age (AGA) with birthweight < 1,500 g (n = 18); group
      2--AGA 1,500-1,999 g (n = 41); group 3--AGA 2,000-2,499 g (n = 26); group 4-
      small for gestational age (SGA) < 1,500 g (n = 5); group 5--SGA 1,500-1,999 g (n
      = 20); group 6--SGA 2,000-2,499 g (n = 37). The control group consisted of 149
      normal birthweight (> 2,500 g) infants. Weight, height, and head circumference
      were measured at birth, 2, 4, 6, 9, 12, 18, and 24 months postnatally and
      recorded in standard deviation score (SDS). All groups showed catch-up growth in
      the first 6 months. At 2 years old, all infants were above -2 SDS. However, the
      SGA infants with birthweight < 1,500 g were significantly lighter (-0.9 SDS, p =
      0.003), shorter (-0.6 SDS, p = 0.001) and had smaller head size (-0.65 SDS, p =
      0.027) whereas, the other groups were not different compared to the control
      group. We also compared those LBW infants who, at 2 years of age, weighed below 
      1 SDS to those who weighed above -1 SDS and found no significant difference in
      familial income, parental education, nursing care or parental height. We
      concluded that with adequate nutritional intake and nursing care, LBW infants
      have the potential for good catch-up growth. For the SGA infants with birthweight
      < 1,500 g, although they showed good catch-up growth, they still remained smaller
      than their peers at 2 years of age.

PMID- 10410492
TI  - Intraoperative intracranial aneurysm rupture.
AB  - 119 patients with surgically treated intracranial aneurysm between December 18,
      1984 and October 1997 were analyzed resulting in nine patients with
      intraoperative aneurysm rupture. These nine cases formed the basis of this study.
      The incidence of intraoperative aneurysm rupture was 7.6 per cent. The mortality
      was 33.3 per cent. In our institution, maneuvers used to control profuse
      hemorrhage include induced hypotension, suction dissection, and temporary clips
      at the parent vessels. Some controversies exist regarding the effect of timing of
      surgery on intraoperative aneurysm rupture and ischemic consequence from induced
      hypotension. The argument is whether early surgery, within 72 hours, increases
      the incidence of intraoperative aneurysm rupture.

PMID- 10410493
TI  - Survival in patients with advanced non-small-cell lung cancer receiving
      supportive care.
AB  - AIMS: To fully describe the survival duration among Thai patients with advanced
      non-small-cell lung cancer (NSCLC) receiving supportive care. SETTING: A 500-bed
      referral cardiothoracic centre. METHODS: Follow-up study in patients with
      advanced NSCLC, diagnosed from January to December 1996, who, for a variety of
      reasons, did not receive chemotherapy or radiation therapy. All patients were
      followed-up until death or defaulted. Kaplan-Meier survival analysis and log rank
      test were employed. RESULTS: A total of 130 patients with histologically proven
      NSCLC receiving supportive care were followed. 98 patients were males and 32 were
      females. The mean age was 61 years (SD 13.5). 82 patients were in stage 3B and 48
      patients in stage 4. In stage 3B, the median survival was 13 weeks (range: 1-94,
      75th centile = 7, 25th centile = 18 weeks). For stage 4, the median survival was
      8 weeks (range: 0.5-31, 75th centile = 4, 25th centile = 10 weeks). For pooled
      data of stage 3B and 4, median survival was 11 weeks (range: 0.5-94, 75th centile
      = 6, 25th centile = 16 weeks). CONCLUSIONS: Survival among patients with advanced
      non-small-cell lung cancer is uniformly short. Considering this poor prognosis,
      implementation of resources and strategies to diagnose an early stage of lung
      cancer should be one of the highest priorities in the national health plans.

PMID- 10410494
TI  - Comparison of the efficacy and acceptability of atypical antipsychotic drugs: a
      meta-analysis of randomized, placebo-controlled trials.
AB  - Knowing the clinical differences of olanzapine, quetiapine, and risperidone would
      be of benefit for choosing an atypical antipsychotic drug. In order to compare
      their efficacy and acceptability, we conducted a meta-analysis of published,
      randomized, placebo-controlled trials by comparing the response and dropout rates
      of an atypical antipsychotic drug group and those of a placebo group. After a
      comprehensive search of study reports, the response and dropout rates of patients
      treated with an atypical antipsychotic drug and those treated with placebo were
      extracted on the intention-to-treat basis. The effect size with 95 per cent
      confidence interval (CI) of pooled data comparing the response and dropout rates
      of an atypical antipsychotic drug group and those of a placebo group were
      calculated by using the Peto method. The response-rate effect sizes (95% CIs) of
      olanzapine, quetiapine, and risperidone were 1.75 (1.06 to 2.89), 1.71 (1.20 to
      2.42), and 3.28 (1.98 to 5.44), respectively. The dropout-rate effect sizes (95%
      CIs) of olanzapine, quetiapine, and risperidone were 0.55 (0.35 to 0.88), 0.65
      (0.46 to 0.91), and 0.39 (0.24 to 0.62), respectively. In conclusion, olanzapine,
      quetiapine, and risperidone are more effective and more acceptable than placebo
      in treating schizophrenic patients. However, they are not different from each
      other in the respect of efficacy and acceptability. The cost of these agents
      should play an important role in choosing an atypical antipsychotic drug.

PMID- 10410495
TI  - The predictive value of skin thickness in the diagnosis of osteopenia.
AB  - Skin and bone share a similar organic constituent (type I collagen) which
      decreases with time after menopause due to hypoestrogenism. The interdependence
      of skin and bone atrophy has been reported. This study was conducted to assess
      the predictive value of an ultrasonographic measurement of skin thickness in the
      diagnosis of osteopenia (BMD below -1.5 SD.) in perimenopausal and early
      postmenopausal women. All patients had skin thickness measured by the same
      radiologist and had a dual-energy X-ray absorptiometry (DEXA) scan of the lumbar
      spine and the femoral neck. Of the 77 women studied, the mean age was 50.9 +/-
      3.0 years. Thirty patients were in perimenopause and 47 in early postmenopause.
      Mean skin thickness was 2.1 +/- 0.4 mm. Women with a skin thickness of < or = 1.7
      mm carried a higher risk for developing osteopenia at the lumbar spine (odds
      ratio 8.41, 95% confidence interval 2.19-32.35) and the femoral neck (odds ratio
      3.88, 95% CI 1.14-13.17). Patients with a skin thickness of > or = 2.4 mm had a
      lower probability of osteopenia at the lumbar spines (odds ratio 0.17, 95% CI
      0.035-0.845) and the femoral neck (odds ratio 0.22, 95% CI 0.055-0.899). In
      conclusion, a low skin thickness measurement by ultrasonography may be used as an
      indicator for osteopenia in perimenopausal and early postmenopausal women.

PMID- 10410497
TI  - Maternal mortality in Ramathibodi Hospital: a 28-year comparative study.
AB  - A comparative review of maternal mortality rates at Ramathibodi Hospital from
      1969 through 1996 including 176, 161 live births is presented. The data are
      divided into two time periods, both of 14 years, for comparison. A significant
      decrease in direct obstetric deaths secondary to infection and toxemia (P <
      0.05). The rate of deaths due to indirect causes in unchanged. Deaths due to
      malignancies have increased. This study of maternal mortality demonstrates the
      need for increased contraceptive services, voluntary sterilization, patient
      education and preconceptional identification of high-risk patients for further
      reduction of the maternal mortality rate.

PMID- 10410498
TI  - Combined use of fine needle aspiration cytology and polymerase chain reaction in
      the diagnosis of cervical tuberculous lymphadenitis.
AB  - Although fine needle aspiration cytology (FNAC) is an effective mean for the
      diagnosis of cervical tuberculous lymphadenitis (CTL), it still poses a certain
      degree of false negative and false positive. The objective of this study was to
      determine the efficiency of polymerase chain reaction (PCR) in combination with
      fine needle aspiration cytology in the diagnosis of CTL. Thirty three patients
      who presented with enlarged cervical lymph nodes, and were clinically suggestive
      of CTL were included in the study. Fine needle aspiration or surgical biopsy of
      lymph nodes was performed, the specimens were studied for cytology, acid fast
      bacilli stain, culture for mycobacteria and PCR technique. The sensitivity and
      specificity of FNAC was 48 per cent and 87.5 per cent respectively, while that of
      PCR was 84 per cent and 75 per cent respectively. When FNAC and PCR were
      combined, the sensitivity and specificity increased to 84 per cent and 100 per
      cent respectively. We concluded that FNAC in combination with the PCR technique
      is a fast and effective clinical diagnostic approach for CTL.

PMID- 10410499
TI  - Screening for asymptomatic bacteriuria in pregnant women: urinalysis versus urine
      culture.
AB  - A diagnostic test study was conducted to evaluate the diagnostic performance of a
      simple urinalysis as a screening test for asymptomatic bacteriuria (ABU) in
      pregnant women. Seven hundred and seventy four asymptomatic pregnant women
      attending their first antenatal care at Srinagarind Hospital from June 1, 1994 to
      January 31, 1995 were studied. Simple urinalysis and urine culture were performed
      on all 774 subjects. The presence of > or = 5 WBC/HPF of centrifuged urine
      indicated a positive test. ABU was defined as the presence of > or = 10(5) colony
      forming units of single bacteria per milliliter of urine. Sensitivity,
      specificity, positive predictive value, negative predictive value and accuracy of
      simple urinalysis in detecting ABU, using urine culture as a gold standard were
      calculated. Simple urinalysis had a 18.4 per cent sensitivity, 97.2 per cent
      specificity, 45.7 per cent positive predictive value, 90.4 per cent negative
      predictive value and 88.4 per cent accuracy in detecting ABU. Because of its low
      sensitivity and the possible consequences of ABU, simple urinalysis should not be
      used as a screening test for ABU.

PMID- 10410500
TI  - Comparative studies on iodine levels in gallstones and bile of Japanese and Thais
      (Chiang Mai and Bangkok).
AB  - We measured the iodine content of gallstones and bile from patients in three
      areas (Kawasaki in Japan, and Chiang Mai and Bangkok in Thailand) by means of
      neutron activation analysis. The mean values for iodine content in three types of
      gallstones (cholesterol, pigment and rare stones) and bile from patients living
      in Chiang Mai were clearly smaller than those from patients living in Kawasaki
      and Bangkok. The low iodine intake by Chiang Mai patients continued from the
      start of gallstone formation until the time when the stones were excised, and the
      iodine intake was low when bile was collected. The PBI levels in the sera of
      Chiang Mai residents with low iodine intake over a long period were clearly lower
      than those of Bangkok patients with normal intake, and the levels in goiter
      patients were similar to those in healthy people and patients with gallstones
      among Chiang Mai residents.

PMID- 10410496
TI  - Skin thickness in different menopausal status.
AB  - It is well known that skin thickness will decrease in the years after menopause.
      Women may have climacteric symptoms including those associated with skin
      alterations as early as during the perimenopausal period. This study was
      performed to compare the skin thickness of women in their premenopause (N = 31),
      perimenopause (N = 35) and early postmenopause (N = 46). The mean skin thickness
      in each group was 2.28 +/- 0.39 mm., 2.18 +/- 0.35 mm. and 2.02 +/- 0.36 mm.
      respectively. The skin thickness of women in the early postmenopausal group was
      significantly lower than those in the premenopausal group, but no difference was
      found between premenopausal and perimenopausal group nor between perimenopausal
      and early postmenopausal group. Furthermore, we found no correlation between skin
      thickness and chronological age. In conclusion, the decline in skin thickness of
      women entering menopause requires a period of time to undergo significant
      alterations and the study revealed a significant reduction of skin thickness as
      early as in the course of the early postmenopausal period.

PMID- 10410501
TI  - Fetal metabolism.
AB  - Normal reference ranges for apolipoprotein A-I, apolipoprotein A-II,
      apolipoprotein B, total triglyceride, total cholesterol, HDL-cholesterol, LDL
      cholesterol, VLDL-cholesterol + chylomicron, plasma glucose, total protein,
      albumin and globulin were determined from 25 fetal plasma samples between 21-39
      weeks' gestation. Pure fetal blood was obtained by cordocentesis under continuous
      ultrasound guidance. They were referred to us for advanced maternal age and a
      previous chromosomal aneuploidy baby. All these biochemical parameters excepts
      total protein and albumin showed no change with gestational age. These normal
      values of fetal metabolism will improve our knowledge of physiology and help to
      determine the specific values of a test in fetal pathology.

PMID- 10410502
TI  - Umbilical artery blood gas and lactate in healthy newborns.
AB  - This study aimed to establish the normal range of umbilical artery pH, pCO2, base
      deficit and lactate in normal term and preterm newborn. Umbilical artery pH,
      pCO2, base deficit and lactate was measured in 637 newborn babies. The study
      included 555 babies at term with Apgar score equal to or more than 7 at 5
      minutes, not requiring assisted ventilation and not admitted to the neonatal unit
      (NNU), as well as 47 preterm babies with Apgar score equal to or more than 7 at 5
      minutes who were admitted to the NNU for observation only because of prematurity.
      Data was presented as mean and SD. Statistical analysis was done by t-test and
      simple linear regression analysis. In the newborn at term mean umbilical artery
      blood gas and lactate were as follows; pH = 7.25 (+/- 0.08), pCO2 = 45.66 (+/-
      1.88) mmHg, base deficit = 7.69 (+/- 3.88) mEq/L, lactate = 2.96 (+/- 1.8)
      mMol/L. In preterm newborn the values were; pH = 7.25 (+/- 0.04), pCO2 = 51.78
      (+/- 13.00) mmHg, base deficit = 5.29 (+/- 1.87) mEq/L, lactate = 2.55 (+/- 1.87)
      mMol/L. The range of umbilical artery blood gas and lactate parameters in term
      and preterm fetuses with good neonatal outcome were derived. There was a
      statistically significant difference in pCO2 and base deficit between term and
      preterm newborn. There was no linear correlation between lactate, pH, pCO2, base
      deficit and fetal glucose respectively in term or preterm infants.

PMID- 10410503
TI  - Tumor angiogenesis.
AB  - Tumor angiogenesis is the growth of new blood vessels which is required for tumor
      growth and progression. Vascularization of the tumor occurs through a series of
      sequential steps before or during the multistep progression to neoplasia. Several
      events occur during the formation of new vessels including production of protease
      enzymes, unregulation of positive regulators of angiogenesis, and down regulation
      of negative regulators. In addition, tumor associated macrophage also influence
      angiogenesis by secreting enzymes, enzymes inhibitors and cytokines. Recent
      knowledge in tumor angiogenesis may have clinical implications in diagnosis and
      treatment. Quantification of microvessel density in tumor specimen correlates
      either metastasis or recurrence in many malignancies such as breast cancer and
      lung cancer. Therefore, assessment of tumor angiogenesis may serve as prognostic
      factors. Therapeutic applications include the development of new agents with
      antiangiogenic properties, vascular targeting drugs, antibody-based therapy, and
      gene therapy. Combination of antiangiogenic therapy with cytotoxic drugs may
      enhance antitumor activity. Moreover, the role of antiangiogenic therapy in
      adjuvant setting may provide and alternative approach to better cancer treatment
      in the near future.

PMID- 10410504
TI  - Radial scar with microcalcification mammographic-pathologic correlation: case
      report.
AB  - Radial scar, a descriptive term for a pathologic lesion, is composed of central
      area of fibroelastosis and distorted ducts, and peripheral zone of intraductal
      hyperplasia. This lesion often presents as a spiculated lesion, sometimes with
      microcalcifications, on mammography which may mimic malignancy such as tubular
      carcinoma. We report a case of radial scar with clustered microcalcifications
      incidentally found in the screened mammogram.

PMID- 10410505
TI  - Superior branch palsy of the oculomotor nerve caused by acute sphenoid sinusitis.
AB  - A 52-year-old man presented with unilateral headache for 6 days. Physical
      examination revealed an ipsilateral paresis of the superior division of the
      oculomotor nerve with chemosis. CT scan of the paranasal sinuses showed
      ipsilateral sphenoid sinusitis with cavernous sinus involvement. The symptoms
      were completely improved by medical treatment only.

PMID- 10410506
TI  - Advance medical directives (living wills).

PMID- 10410507
TI  - [Infection in burn patients: the problems of pathogenesis, prevention and
      treatment].
AB  - Urgent issues of pathogenesis, prophylaxis and treatment of infection in patients
      with thermal injuries are considered. Analysis of the results of multifactorial
      dynamic examinations of immunological reactivity and nonspecific resistance of
      198 burnet patients is presented. For the first time a substantial decrease of B
      lymphocytes count in normal or elevated level of immunoglobulins of the main
      classes is shown as well as a decrease in plasma fibronectin content. Lowering of
      T-lymphocytes content and polymorphonuclear leucocytes function disturbances,
      dominant role of St. aureus and P. aeruginosa in etiology of infections in burnt
      patients and high antibiotic resistance of these microorganisms are demonstrated.
      Pathogenetic substantiation of combined therapeutic usage of thymus and
      interferon preparations and when indicated--immunoglobulines is recorded.
      Positive experience in application of recombinant interleukine-2 (Ronkoleukine)
      is outlined. The data are provided on advisability of application of new
      cephalosporines and fluorine-quinolones for antibiotic therapy and prophylaxis in
      the burnet. In complicated forms of gram-negative infections the combination of
      aminoglycosides with ureidopenicillines or cyprofloxacine is recommended, in
      infections provoked by polyresistant strains of S. aureus vancomycin is
      indicated. With prophylactic aim in case of early surgical treatment it is
      recommended to apply modern antibacterial preparations with broad spectrum of
      action. Prophylaxis of hospital infections inpatients of specialised clinics for
      the burnt is discussed.

PMID- 10410508
TI  - [The surgical procedure in hemorrhages from acute ulcers and erosions in the
      gastroduodenal area].
AB  - The experience obtained in treatment of 132 patients with acute ulcers and
      erosions of gastroduodenal area (GDA) is presented. Based on the analysis of
      surgical treatment in 38 patients with acute ulcers of the stomach and the
      duodenum, complicated with bleeding, the necessary scope of diagnostic modalities
      was suggested and substantiated, the terms and extent of surgical intervention
      were determined. The criteria for determining surgical policy in bleeding from
      acute ulcers and erosions of GDA were based on the intensity of blood loss and
      the endoscopical characteristics of acute ulcers (size, multiplicity, location).
      The necessity of computer pH-metry for optimization of the extent and method of
      surgical option in patients with acute ulcers and erosions of GDA is emphasized.
      In early postoperative period the authors have applied the method of external
      decompression of the stomach and the duodenum with enteral probe feeding. The
      results of treatment in all operated patients have been studied. Postoperative
      lethality made up 5.3%.

PMID- 10410509
TI  - [Debatable problems in the surgical treatment of perforated gastroduodenal
      ulcers].
AB  - The experience in surgical treatment of 1027 patients with perforated
      gastroduodenal ulcer was assessed. Particular attention was paid to the most
      arguable problems of surgical treatment of this disease. The records evidence
      that at present there are no reliable objective criteria which enable to
      differentiate acute perforated ulcers from chronic ones before or during the
      operation. It has been convincingly proved, that in spite of all known risk
      factors (age of patients above 60 years, accompanying diseases, preoperative
      shock and duration of the perforation over 24 hours, disseminated peritonitis,
      etc.), truncal vagotomy with excision of the ulcer and pyloroplasty provides
      lower lethality rate in comparison with any other surgical operation. The
      operation is recommended not only for saving of patients life, but for receiving
      in great majority of cases favourable long-term results in patients of young as
      well as old age irrespective of the presence of ulcer in the anamnesis.

PMID- 10410510
TI  - [The surgical procedure in ulcerous duodenal hemorrhages].
AB  - Available are the results of treatment of 493 patients with duodenal ulcer
      complicated by bleeding in the center of gastro-intestinal bleedings at N. I.
      Pirogov City Hospital No. 1 in 1995-1996 years. 74 patients were operated.
      Overall lethality made up 1.8%, postoperative lethality rate--8.1%. In ulcer of
      posterior wall of the duodenum, 10 mm and more in diameter with blood loss of
      medium and high degree, the number of relapses made up 57.1%. In cases of urgent
      operations (n = 30); carried out on the first day of admittance to the hospital,
      1 patient died. Expectant policy in treatment of patients with ulcer of posterior
      wall of the duodenum results in poor effect of the treatment and complications
      (4.1%). The advantages of active individual approach in treatment of patients
      with acute duodenal bleeding are outlined.

PMID- 10410511
TI  - [The bleeding ulcer of the duodenum: the procedure in unreliable hemostasis].
AB  - The treatment of patients with bleeding duodenal ulcers is still one of the most
      complicated and discussable problems in surgery. The aim of this study was an
      attempt to predict the relapse of bleeding from ulcer of the duodenum on the
      basis of the experience in the treatment of 539 patients with this disease, 101
      of whom underwent surgery. Diagnostic criteria for prognosis of repeated bleeding
      have been developed and the role of each of them in reliability of hemostasis in
      ecores was determined. It was established that indication for urgent operations
      for unreliable hemostasis is determined by the sum of 11 scores and more, as
      probability of bleeding recurrence in this situation in 90.2%.

PMID- 10410513
TI  - [The surgical correction of the disordered sphincteric function of the cardia].
AB  - For comparative assessment of some methods of surgical correction of the cardia
      the results of surgical treatment of 180 patients were analyzed. In 33 patients
      hiatal diaphragmatic hernia (HDH) was detected, in 84--duodenal ulcer was
      combined with HDH and in 63--duodenal ulcer was detected. In 15 patients
      operation by Hill was performed for correction of cardial function, in 9-
      operation by Dor was carried out, in 3--valvular gastroplication by N.N. Kanshin,
      in 23--esophagofundorrhaphy and in 130--modified by N. N. Kanshin and A. F.
      Chernousov fundoplication was performed. In 49 patients fundoplication by
      improved method was carried out with the use of intraoperative esophagomanometric
      control for adequacy of the procedure. The effectiveness of the treatment was
      evaluated according to the short-term and long-term results. It was thus
      established, that the best procedure of surgical correction of the cardia was
      fundoplication. Introduction of esophagomanometry during fundoplication valve
      formation is the most important factor contributing to adequate restoration of
      the cardia.

PMID- 10410512
TI  - [Helicobacter pylori in patients with complicated peptic ulcer].
AB  - The results of examination of 167 patients suffering from gastric and duodenal
      ulcers complicated by bleeding and perforation in a rehabilitation period are
      presented. High contamination by HP bacteria was established in gastroduodenal
      bleeding especially in duodenal ulcer (94.45%), as well as direct correlation
      between the contamination range and blood loss degree. The presence of HP
      infection during a control check-up examination suggests that the course of anti
      ulcer therapy should last not less than 4-6 weeks. In treating patients suffering
      from ulcer bleeding conservative therapy is preferable. Stomach resection is
      considered as a method of choice. Lethality makes up 0.94 and 6.25%,
      respectively.

PMID- 10410514
TI  - [The prevention and treatment of the incompetence of esophageal anastomoses].
AB  - The main cause of lethal outcomes after operations on the oesophagus and cardia
      remains failure of esophageal anastomosis. The lack of substantial positive
      changes in prophylaxis and especially in treatment of this complication is
      explained by etiological approach to this problem. Pathogenesis of the failure is
      determined by the only trigger--penetration of infection into the tissues of
      anastomotic area. The authors have developed and introduced into practice the
      method and the device to influence the basic link of the pathogenesis. The
      application of the method of permanent irrigation and sealing of the esophageal
      anastomosis line in treatment of 917 patients made it possible to cut down lethal
      outcomes from insufficiency of esophageal anastomosis to 0.1%.

PMID- 10410515
TI  - [The surgical treatment of echinococcosis of the diaphragmatic surface of the
      liver].
AB  - The results of surgical treatment of 628 patients aged 15-76 years operated on
      for echinococcosis of diaphragmatic surface of the liver have been analysed for
      period from 1976 to 1996. 333 patients had complicated echinococcosis, 124
      combined pathology of other organs. Methods which have been applied for diagnosis
      of echinococcosis of the liver and its complications are described. Details of
      surgical treatment of the echinococcosis of the diaphragmatic surface of the
      liver are elucidated in time course aspects, as a staged treatment, during which
      various factors were used for antiparasitic treatment of cystic cavity as well as
      various methods of elimination of the residual cavity. Problems concerning
      application of laser and plasmatic scalpel during various stages of the
      operation, as well as low-intensity lasers and low-frequency ultrasound during
      the operation and in postoperative period are considered. Postoperative
      complications were detected in 99 (15.8%) patients, lethal outcomes were in 5
      (0.8%) cases.

PMID- 10410516
TI  - [Conservative surgery in injuries and focal formations of the spleen].
AB  - Clinical records of 128 operations on the spleen including 102 organ-saving
      procedures are surveyed [correction of servieved]. Basing on his rich experience
      of organ-saving operations the author suggests classification of injuries of the
      spleen resting on the criteria dictating certain surgical policy. Diagnostic
      algorithm is proposed which provides early and correct diagnosis. The techniques
      are described including original approach which save the spleen or its part in
      lesions of various locations and sizes. Saving policy is based on peculiarities
      of intraorganic circulation and is justified by functional importance of the
      spleen in the body.

PMID- 10410517
TI  - [Laparoscopic operations in emergency surgery].
AB  - 582 laparoscopic operations for various urgent diseases of the organs of
      abdominal cavity were made. 190 of them were performed for acute appendicitis,
      266--for acute cholecystitis and its complications, 33--for pancreonecrosis, 39-
      for perforated gastro-duodenal ulcers, 32--for acute bowel obstruction and 22-
      for other pathological conditions. The necessity of conversion to conventional
      open surgery has arose in 41 (7.0%) patients. Intraoperative complications were
      detected in 7 (1.3%) patients. Postoperative complications developed in 18 (3.3%)
      patients. 2 patients (0.4%) died. The obtained results of treatment made it
      possible to recommend laparoscopic operations in acute abdominal diseases.

PMID- 10410518
TI  - [The technical aspects of vertical gastroplasty in Mason's modification for the
      treatment of morbid obesity].
AB  - Vertical gastroplasty is one of the most well-known abroad surgical methods for
      treatment of complicated forms of obesity. However, the results of the operation
      in many respects depend on technical peculiarities of its performance. The most
      important features in performance of the operation in modification of E. Mason
      are ensuring of an adequate exposition, formation of small part of the stomach in
      cylinder shape with the volume not more than 20 ml and intraoperative measurement
      of its volume, one-stage 4-row vertical suturing strictly in direction to Hiss
      angle and strengthening of outlet from the small volume of the stomach with the
      cuff from polypropylene with perimeter 5 cm. Some other details of the operation
      technique are also outlined.

PMID- 10410519
TI  - [Combined operations in abdominal surgery].
AB  - Out of 20,890 operations on the organs of abdominal cavity 405 operations were
      combined. 146 patients underwent elective surgery and 259 were operated urgently.
      In 88 patients who underwent elective operations the extent of surgical
      intervention was determined beforehand, in 58 patients it was unexpected.
      Simultaneous stage of the operation usually does not influence the course of post
      operative period.

PMID- 10410520
TI  - [The role of chronic colitis in the pathogenesis of Hirschsprung 's disease in
      children].
AB  - The role of chronic colitis in pathogenesis of Hirschsprung's disease was studied
      ultrastructurally and morphometrically. Morphological features of chronic colitis
      were revealed by examination of full-layers biopsies and excised fragments of the
      colon in 26 children aged from 2 to 14 years with Hirschsprung's disease.
      Atrophic-sclerotic form of colitis develops in various disturbances of colo
      rectal innervation. In this condition diffuse sclerosis of bowel wall could be
      considered as pathognomonic symptom of Hirschsprung's disease. As a result of
      development of sclerosis insufficiency of the bowel motor function increases.

PMID- 10410521
TI  - [Postoperative venous thromboembolic complications: a fatal inevitability or a
      controllable danger?].

PMID- 10410522
TI  - [Tuberculous ileotyphlitis].

PMID- 10410523
TI  - [The surgical treatment of an esophageal-bronchial fistula of many years'
      duration].

PMID- 10410525
TI  - [The late results of extensive liver resection].

PMID- 10410524
TI  - [Thoracoscopic resection of the esophagus for cancer of its inferior pars
      thoracica].

PMID- 10410526
TI  - [The 125th anniversary of the Society of Surgeons of Moscow and Moscow Province].

PMID- 10410527
TI  - Efficacy of aquatic exercises for patients with low-back pain.
AB  - We have studied 35 patients (25 female and 10 male) with low-back pain who were
      managed with aquatic exercises after an appropriate period of treatment for their
      condition in the medical institution. The exercises employed consisted of
      strengthening exercises for the abdominal, gluteal, and leg muscles, stretching
      of the back, hip, hamstrings, and calf muscles, walking in water, and swimming.
      All the patients had been participating in the exercise program for more than 6
      months. The frequency of performing exercises was once a week for 7 patients,
      twice a week for 19, and 3 or more times a week for the remaining patients. The
      method used in this study was a survey questionnaire which was composed of
      questions about the patient's physical and psychological condition. Those
      patients who had performed exercises twice or more in a week showed a more
      significant improvement in the physical score than those who performed exercises
      only once a week. More than 90% of the patients felt they had improved after 6
      months of participation in the program. The improvement in physical score was
      independent of the initial ability in swimming. The results obtained suggested
      that exercises in water may be one of the most useful modes of exercise for a
      patient with low-back pain.

PMID- 10410528
TI  - Outbreak of aseptic meningitis due to ECHO-9 in northern Kyushu island in the
      summer of 1997.
AB  - An outbreak of aseptic meningitis caused by echovirus type 9 (ECHO-9) occurred
      between June and August 1997 in the Chikugo area, Fukuoka, Japan. Clinical
      manifestations and laboratory data of 317 children with aseptic meningitis were
      analyzed. The age of the patients ranged from 1 month to 12 years with the
      highest incidence in 4 years old children. The male: female ratio was 2.0:1.0.
      Symptoms of the meningitis included fever (100%), headache (89.5%) and nausea
      and/or vomiting (85.6%). Skin rash was not frequent (2.2%) in contrast to
      previous reports of ECHO 9 infections. The number of white blood cells (WBC) in
      cerebrospinal fluid (CSF) ranged from 10 to 3,493 cells/microliter (median; 412
      cells/microliter). The neutrophils were more than 50% of the WBC in CSF in one
      fourth of the patients at diagnosis. Enteroviruses were identified from CSF
      utilizing virus culture and enterovirus-specific RT-PCR, and ECHO-9 infection was
      determined by antibody titer of paired sera. Finally 44 patients were diagnosed
      virologically or serologically as aseptic meningitis caused by ECHO-9. Sequence
      analysis revealed that two strains of ECHO-9 isolated from CSF in this epidemic
      were closely related to ECHO-9 virulent strain Barty.

PMID- 10410529
TI  - Endocrine tumor of the pancreas--an evaluation of eighteen patients who underwent
      resection followed by long-term survival.
AB  - Tumors arising from the pancreatic endocrine (islet) cells represent a
      heterogeneous group of lesions. Some tumors present with well characterized
      syndromes, while others appear to be nonfunctioning. Eighteen patients with
      pancreatic endocrine tumors who received surgical treatment at Kurume University
      Hospital during a 24-year period were reviewed. There were 10 patients with
      nonfunctioning tumors including 3 patients with benign tumors, and 8 patients
      with insulinomas. No patients had multiple endocrine neoplasms. Location of the
      pancreatic tumor was determined preoperatively in 83.3% of the patients.
      Immunohistochemical analysis of the resected specimens showed multi
      immunoreactivity to gut hormones among benign lesions and one malignant lesion,
      whereas malignant lesions showed no or mono immunoreactivity except in one case.
      In this series, there were no characteristic immunohistochemical findings in the
      tumors. Both patients with malignant and benign lesions have good prognoses if
      the main tumors and metastatic lesions are removed.

PMID- 10410530
TI  - Phase I study of a combination of irinotecan and ifosfamide in advanced primary
      lung cancer.
AB  - We sought to investigate cisplatin-free chemotherapy for patients with primary
      lung cancer. We therefore conducted a Phase II study to identify; a) the maximum
      tolerated dose (MTD) of irinotecan (CPT-11) given with a fixed dose of ifosfamide
      (IFM), and b) the principal toxic effects associated with this regimen in a Phase
      I study. A total of 27 patients with previously treated or untreated primary lung
      cancer received CPT-11 on days 1, 8 and 15 in combination with a fixed dose of
      IFM, 1.5 g/m2/day, on days 1 through 3, given every 4 weeks. The starting dose of
      CPT-11 was 30 mg/m2, which was increased by amounts of 10 mg/m2. Four patients
      were assigned to different dosage levels, and drug toxicity was evaluated for the
      first 2 cycles. The MTD of CPT-11 was 90 mg/m2, with leukopenia being the dose
      limiting effect. The response rate was 43% (6/14; 1 complete response) in non
      small cell lung cancer, and 78% (7/9; no complete response) in small cell lung
      cancer. The recommended dose of CPT-11 for a Phase II study is thus 80 mg/m2 on
      days 1, 8 and 15 with IFM 1.5 g/m2 given on days 1 through 3. This regimen
      appears particularly encouraging, because of its low toxicity. Phase II trials of
      the combination are indicated.

PMID- 10410531
TI  - Improvement of dysgeusia after thymectomy with thymoma.
AB  - We present a case of 39-year-old woman with thymoma complaining of dysgeusia.
      This patient had suffered from dysgeusia for the previous 6 months. Thymectomy
      with the thymoma was performed, and her dysgeusia was improved within 6 months
      after the operation. The anti-acetylcholine-receptor antibody was reduced from
      0.9 nmol/l to 0.4 nmol/l (normal: below 0.6 nmol/l) by the surgical intervention.
      This case suggested that symptoms of dysgeusia can be associated with myasthenic
      status.

PMID- 10410533
TI  - Asymptomatic hyponaturemia in a patient with mild head injury due to syndrome of
      inappropriate diuretic hormone--a case report.
AB  - Hyponatremia is commonly seen in patients with severe and moderate head injury,
      but it is rarely reported in those with mild head injury. The authors report a
      patient with mild head injury who presented with data typical of inappropriate
      secretion of antidiuretic hormone (SIADH), but showed no clinical deterioration.
      Though the clinical significance of this condition is unclear, the true incidence
      of this pathology might well be found to be higher than expected, should it
      receive more clinical and/or serological attention. Continuing clinical
      assessment will be needed to determine the significance of this condition in
      relation to that in patients with SIADH following the various causes reported
      previously.

PMID- 10410532
TI  - A resected case of pancreatic metastasis from primary renal cell carcinoma.
AB  - A 71-year-old man, who had received a right nephrectomy for a primary renal cell
      carcinoma 8 years earlier, and had two years later received a distal gastrectomy
      for duodenal ulcer, was admitted. In the subsequent clinical course, a solitary
      low echographical tumor was found in the pancreas. Abdominal computed tomography
      revealed a tumor of low density area, and celiac angiography revealed a
      hypervascular tumor stain of the pancreas. From the above findings, a diagnosis
      of pancreatic tumor was made, and a distal pancreatectomy was performed.
      Examination of the resected tissues confirmed the presence of a solitary tumor in
      the pancreatic tail. Histologically, the tumor corresponded to the initial renal
      cell carcinoma and pancreatic metastasis of renal cell carcinoma was diagnosed.
      We report a resected case of such a metastasis and review the literature.

PMID- 10410534
TI  - Angiomyolipoma of the liver--a case report and review of 48 cases reported in
      Japan.
AB  - Hepatic angiomyolipoma was considered to be a rare benign tumor, but the number
      of cases has been increasing recently as imaging techniques improve. We describe
      a case of hepatic angiomyolipoma for which a definitive diagnosis could not be
      made on imagings and in which resection was performed. The patient had anti-HCV
      antibody and slight dysfunction of the liver. The tumor showed a heterogeneous
      high echo on ultrasonography and a low attenuation value of +32.6 Housfield
      Units, which was much higher than fat density, on plain computed tomography.
      Discrimination from hepatocellular carcinoma with fatty change was difficult
      preoperatively. Microscopically, the tumor consisted of spindle-shaped and
      epithelioid smooth muscles, adipose tissues and proliferating blood vessels and
      these histological findings confirmed the diagnosis of hepatic angiomyolipoma.
      The appearance of hepatic angiomyolipoma on imaging diagnosis varies widely due
      to the fact that the relative proportion of vessels, muscles and fats varies
      widely from tumor to tumor. The tumor in our case had relatively few fat
      components. We review 48 cases reported in Japan and discuss imaging diagnosis
      and surgical indications for tumors.

PMID- 10410535
TI  - Serous adenocarcinofibroma of the ovary--report of two cases and review of the
      literature.
AB  - We investigated the clinical and histologic characteristics of patients with
      ovarian serous adenocarcinofibroma. Because the tumors in both cases contained
      fibroma components; they were hard and clinically indistinguishable from uterine
      myoma, even by computed tomography. Both patients experienced relapses associated
      with tumors that originated outside the abdominal cavity (the subcutaneous
      abdominal wall in case 1, and the inguinal lymph nodes in case 2). The serum
      level of CA125 was normal or only moderately elevated at the first onset and
      relapse. The present cases suggest that the diagnostic features and clinical
      course differ between ovarian serous adenocarcinoma and serous
      adenocarcinofibroma.

PMID- 10410536
TI  - Deaths: final data for 1997.
AB  - OBJECTIVES: This report presents final 1997 data on U.S. deaths and death rates
      according to demographic and medical characteristics such as age, sex, race,
      Hispanic origin, marital status, educational attainment, injury at work, State of
      residence, and cause of death. Trends and patterns in general mortality, life
      expectancy, and infant and maternal mortality are also described. A previous
      report presented preliminary mortality data for 1997. METHODS: In 1997 a total of
      2,314,245 deaths were reported in the United States. This report presents
      descriptive tabulations of information reported on the death certificates. Death
      certificates are completed by funeral directors, attending physicians, medical
      examiners, and coroners. Original records are filed in the State registration
      offices. Statistical information is compiled into a national data base through
      the Vital Statistics Cooperative Program of the National Center for Health
      Statistics (NCHS), Centers for Disease Control and Prevention. RESULTS: The 1997
      age-adjusted death rate for the United States decreased to an all-time low of
      479.1 deaths per 100,000 standard population, and life expectancy at birth
      increased to a record high of 76.5 years. The 15 leading causes of death remained
      the same as in 1996, although Human immunodeficiency virus (HIV) infection
      plummeted from the 8th leading cause of death to the 14th leading cause. Some of
      the 8th-14th leading causes of death shifted positions. HIV infection remained
      the leading cause of death for black persons aged 25-44 years. The largest
      decline in age-adjusted death rates among the leading causes of death was for HIV
      infection, which dropped 47.7 percent between 1996 and 1997. Mortality declined
      for all age groups, except for persons aged 85 and over. The infant mortality
      rate reached a record low of 7.2 infant deaths per 1,000 live births in 1997
      although the decline in the rate from 1996 was not statistically significant.
      CONCLUSIONS: The overall improvements in general mortality and life expectancy in
      1997 continue the long-term downward trend in U.S. mortality. The trend in U.S.
      infant mortality is of steady declines over the past four decades.

PMID- 10410537
TI  - [Effects of female hormones on respiratory and cardiovascular regulation].
AB  - The influences of sex steroids on ventilation, ventilatory control, and pulmonary
      vascular response are briefly reviewed. This review focuses on the ventilatory
      and cardiovascular effects of endogenous and exogenous female and male steroids.
      Understanding the influences of sex steroids on respiratory and cardiovascular
      control is important in view of the gender differences in susceptibility to
      various respiratory diseases, and the changes in ventilation that occur at
      various phases of the life cycle, including pregnancy, menstrual cycle, and
      menopause. We summarize evidence concerning the importance of hormonal influences
      on pulmonary vascular control in selected pathophysiological and physiological
      states. The detailed information we acquired concerning the effects of sex
      steroids on ventilatory control is important for understanding the sites and
      integrated modes of action by which ventilation is regulated in health and
      disease.

PMID- 10410538
TI  - [Evaluation of sleep fragmentation by EEG spectrography in patients with
      obstructive sleep apnea syndrome].
AB  - Sleep fragmentation is considered to have a central role in the pathophysiology
      of sleep-disordered breathing. However, the evaluation of sleep fragmentation can
      be very troublesome work. We sought to evaluate sleep fragmentation in 10
      patients with obstructive sleep apnea syndrome by utilizing fast-fourier
      transforms to render their sleep encephalograms as spectrograms (horizontal axis:
      time, vertical axis: frequency, color: power). Detailed 5-minute spectrograms
      revealed relatively uniform patterns of change in EEG spectra during and after
      apnea episodes. In non-REM sleep, delta activity during apnea was followed by
      alpha and beta activity during resumed breathing. In REM sleep, flat and low
      power spectral patterns during apnea were followed by relatively weak alpha and
      beta activity during resumed breathing. In compressed, 1-hour views of the
      spectrograms, repeated apnea events appeared as vertical striped patterns of
      spectral change. These patterns were thought to be representative of sleep
      fragmentation. The spectrographic display of EEGs may be a very simple and easy
      method for the evaluation of sleep-fragmentation in sleep disordered breathing.

PMID- 10410539
TI  - [Adenosine deaminase activity in bronchoalveolar lavage fluid of sarcoidosis
      patients].
AB  - We studied adenosine deaminase (ADA) activity in bronchoalveolar lavage fluid
      (BALF) specimens from 24 patients with sarcoidosis. Mean BALF-ADA activity was
      significantly (p < 0.0001) elevated in patients with sarcoidosis (1.02 +/- 1.01
      IU/L, mean +/- SD) compared to the subjects in a healthy control group (0.08 +/-
      0.29 IU/L). In the sarcoidosis patients with high BALF-ADA activity (> or = 1.0
      IU/L), AaDO2 was significantly (p < 0.0001) elevated compared to its level in
      patients with normal BALF-ADA activity (< 1.0 IU/L). BALF-ADA activity was
      significantly (p < 0.01) higher in patients who exhibited lung-field
      accumulations on 67Ga scintigrams compared to those with no accumulations, and
      significantly (p < 0.001) higher in patients undergoing corticosteroid treatment
      compared to in those patients who did not receive such treatment. These findings
      were similar to the results of studies using data on BALF-ADA/albumin ratios.
      Furthermore, they suggest that the localized production of ADA may increase in
      sarcoidosis patients displaying 67Ga scintigram lung-field accumulations with
      increased AaDO2, and that BALF-ADA activity may be a useful indicator of disease
      activity and the need for treatment.

PMID- 10410540
TI  - [Utilization of NIH image for quantification of emphysema by computed
      tomography].
AB  - The percentage of the low attenuation area (LAA%) is understood to be the most
      accurate index in quantifying emphysema by computed tomography (CT). To date, CT
      scanners with enhanced post-processing programs have been used for measurements
      of LAA%. In this study, we sought develop a method of LAA% determination using a
      conventional density mapping program for CTs and NIH Image, an image-analysis
      software package for personal computers. Our results for overall LAA%, together
      with the correlations between overall LAA% and pulmonary function tests, agreed
      well with the findings of earlier reports. In reproducibility trials utilizing
      our method interoperator error for LAA% was within +/- 2%. A phantom experiment
      indicated that there was little difference between LAA% values obtained by this
      method and the values obtained by direct CT measurements. Therefore, we concluded
      that this method is sufficiently reliable for clinical use and capable of
      facilitating LAA% measurements with CT scanners that are not equipped with
      enhanced post-processing software.

PMID- 10410541
TI  - [Comparative study of clinical features of typical and atypical pneumonias].
AB  - We prospectively analyzed the clinical and laboratory features of 74 patients
      with community-acquired pneumonia who required hospitalization between May 1996
      and October 1997. Typical pathogens were identified in 47, and atypical pathogens
      in 27. The average age was higher in patients affected by typical pathogens (73.9
      years), than in patients affected by atypical pathogens (50.9 years). Univariable
      analysis found that atypical pneumonias were more frequent in healthy patients
      than typical pneumonias. Moreover, the presence of relatives with symptoms of
      airway infection, headache, and earache was more common among the patients with
      atypical pneumonias, while leukocytosis and elevated C-reactive protein levels
      were more frequent among patients with typical pneumonias. Typical pathogens
      accounted for up to 79.6% of the cases of pneumonia with in older patients (aged
      60 years or more), whereas atypical pathogens accounted for up to 80% of the
      cases of pneumonia in younger patients (aged under 60 years). This difference was
      statistically significant. Of all 74 patients, 39 (52.7%) were afflicted by
      severe community-acquired pneumonia, as categorized by American Thoracic Society
      guidelines. The most common pathogen among these patients was Streptococcus
      pneumoniae. Legionella was one of the top four. Selection of the initial
      antimicrobial treatment is an important clinical decision that should be made on
      the basis of clinical features at admission, age, and severity of the patient's
      illness.

PMID- 10410542
TI  - [Pneumonitis induced by the drug ougon].
AB  - We report a case of drug-induced pneumonitis associated with the herbal
      medications Sho-saiko-to and Ouren-gedoku-to. A 62-year-old man experienced fever
      and dry cough after using Ouren-gedoku-to for 2 months. He was admitted to our
      hospital because a subsequent 5-day course of Sho-saiko-to for suspected
      bronchitis aggravated these symptoms and caused exertional dyspnea. Chest X-ray
      films revealed a ground-glass appearance in both lower lung fields. Cessation of
      these medications improved the patient's clinical and X-ray findings.
      Bronchoalveolar lavage showed an increase in lymphocytes with a decreased CD 4/CD
      8 ratio. While drug-induced lymphocyte stimulation tests gave negative results,
      challenge tests for Ouren-gedoku-to and Sho-saiko-to were both positive. A
      diagnosis of drug-induced pneumonitis was made. Our findings suggested the
      involvement of Ougon, the only common ingredient in the two medications.

PMID- 10410543
TI  - [Pranoprofen-induced lung injury manifesting as acute eosinophilic pneumonia].
AB  - A 48-year-old man was admitted to our hospital complaining of fever, dyspnea, and
      cough. He had been treated with pranoprofen and antibiotics by an outpatient
      clinic for the preceding 4 days. Chest X-ray films revealed Kerley B lines,
      perivascular cuffing, and hilar haze with pleural effusion in both lungs. Chest
      computed tomographic films showed non-segmental patchy infiltrates, and
      thickening of bronchovascular bundles and interlobular septa. Laboratory data
      showed eosinophilia in peripheral blood (28%) and severe hypoxemia (PaO2:60
      torr). Bronchoalveolar lavage fluid disclosed an increased total cell count,
      eosinophils (39%), and CD 4/CD 8 ratio (2.1). Microscopic examination of
      transbronchial lung biopsy specimens showed infiltration of eosinophils and
      mononuclear cells into alveolar wall's and spaces. Acute eosinophilic pneumonia
      was suspected on the basis of Allen's diagnostic criteria (N Engl J Med: 1989).
      After discontinuation of pranoprofen, the patient's clinical symptoms, laboratory
      data, and chest X-ray findings improved rapidly without steroid therapy. A
      leukocyte migration test (LMT) for pranoprofen was positive and a challenge test
      for smoking was negative. An environmental provocation test in the patient's home
      gave negative results. A challenge test for pranoprofen was not performed due to
      the lack of informed consent. Based on these findings, our diagnosis was
      pranoprofen-induced lung injury manifesting as acute eosinophilic pneumonia.

PMID- 10410544
TI  - [Sarcoidosis synchronously detected in identical twins].
AB  - We report on the synchronous detection of sarcoidosis in identical 22-year-old
      male twins. The patients visited a nearby physician because of fever and cough,
      were found to have abnormal chest shadows and thus admitted to our hospital. Both
      had swollen cervical and hilar nodes and lesions in both left and right lung
      fields, and also presented similar clinical symptoms. However, bilateral uveitis
      was observed only in the elder twin. Because epithelioid cell granulomas without
      caseous necrosis were histopathologically observed in tissue specimens from their
      cervical lymph nodes, the patients were given a diagnosis of sarcoidosis.
      Although they were positive for the HLA-D antigens DR 2 and DR 12, they were
      negative for DRw 52. an antigen that is considered to be quite common in Japanese
      sarcoidosis patients. Genetic factors were thought to be involved in the onset of
      sarcoidosis in these twins.

PMID- 10410545
TI  - [Recurrent pulmonary infarction associated with familial protein S deficiency
      type III].
AB  - A 38-year-old woman was admitted to our hospital because of recurrent chest pain
      and fever. Chest X-ray films and computed tomograms showed subpleural
      consolidation containing small cavity-like opacities. Open lung biopsy revealed
      non-infectious abscess and vessels with organizing thrombus. The patient was
      given a diagnosis of pulmonary infarction due to the existence of deep venous
      thrombosis. Coagulation studies demonstrated that she had decreased plasma
      protein S activity, whereas her free and total protein S antigen levels were
      normal. Because her mother and maternal uncle and aunt also demonstrated
      decreased protein S activity with normal plasma protein S antigen levels, the
      patient was considered to be affected by familial protein S deficiency type III.

PMID- 10410547
TI  - [Benign clear cell tumor of the lung diagnosed by transbronchial biopsy].
AB  - A 26-year-old woman had an abnormal shadow on chest X-ray films during a general
      medical examination. A chest roentgenogram showed a nodular shadow 8 mm in
      diameter in the middle field of the right lung. Transbronchial biopsy specimens
      revealed that the coin lesion was a benign clear cell tumor. Benign clear cell
      tumors of the lung are rare; only 21 cases, including the present case, have been
      reported in Japan. Although the diagnosis in most of the cases reported required
      an open thoracotomy, for our patient the diagnosis was based solely on the
      findings of a transbronchial biopsy.

PMID- 10410546
TI  - [Acute myelocytic leukemia and plasmacytoma secondary to chemotherapy and
      radiotherapy in a long-term survivor of small cell lung cancer].
AB  - A 68-year-old man was given a diagnosis of lung cancer of the right upper lobe
      (small cell carcinoma, T 4 N 2 M 0, stage IIIB) in February 1991. The tumor
      diminished after chemotherapy and radiotherapy. In February 1992, a partial
      resection of the lower lobe of the right lung was performed because of the
      appearance of a metastatic tumor. In September 1994, squamous cell carcinoma
      developed in the lower part of the esophagus, but disappeared after radiotherapy.
      In February 1998, a diagnosis of myelodysplastic syndrome was made. Two months
      later, the patient had an attack of acute myelocytic leukemia and died of cardiac
      tamponade. An autopsy determined that both the lung cancer and esophageal cancer
      had disappeared. Acute myelocytic leukemia and plasmacytoma of lymph nodes in the
      irradiated area were confirmed. These were regarded as secondary malignancies
      induced by chemotherapy and radiotherapy.

PMID- 10410548
TI  - [Positive response to smoking challenge test in a case of acute eosinophilic
      pneumonia].
AB  - A 19-year-old man presented with an acute febrile illness and progressive
      dyspnea. He had begun smoking two weeks before admission. A chest X-ray film
      revealed Kerley B lines and diffuse infiltration in both lungs. Analysis of
      bronchoalveolar lavage fluid showed 21% eosinophils. The patient had no history
      of hypersensitivity to drugs, nor was there any evidence of infectious disease.
      Acute eosinophilic pneumonia was diagnosed, and his condition improved without
      steroid treatment. A smoking challenge test was performed. After the test, the
      patient's body temperature rose to 38.0 degrees C, computed tomograms of the
      chest showed increased density, and elevated eosinophil levels were again
      detected in bronchoalveolar lavage fluid. These findings supported the view that
      beginning to smoke can be a cause of acute eosinophilic pneumonia.

PMID- 10410549
TI  - [Severe adult-type Williams-Campbell syndrome (Williams-Campbell-type
      bronchiectasis)].
AB  - A 70-year-old man was admitted to our hospital because of dyspnea. Arterial blood
      gas analysis indicated severe type-II respiratory failure. Williams-Campbell-type
      bronchiectasis was suspected because chest radiographs disclosed multiple cystic
      shadows in both lungs. Although inspiratory chest radiographs and computed
      tomographic (CT) scans showed cystic bronchiectasis, expiratory chest radiographs
      and CT scans demonstrated characteristic collapse of the ectatic bronchi.
      Continuous fluoroscopic visualization of the respiratory phase demonstrated
      bronchial dilatation during inhalation and collapse during exhalation. Williams
      Campbell-type bronchiectasis was diagnosed on the basis of the radiological
      findings. Compared with previous cases of Williams-Campbell syndrome reported in
      Japan, this case was interesting because the patient exhibited severe respiratory
      failure and because the dilatating and collapsing bronchi were demonstrated by
      fluoroscopy.

PMID- 10410550
TI  - [Intralobar pulmonary sequestration presenting increased serum CEA, CA 19-9, and
      CA 125, and associated with asymptomatic pulmonary aspergillosis].
AB  - A 44-year-old woman was admitted to our hospital for further evaluation of a
      consolidated shadow in the left lower lobe and the evaluation of serum tumor
      markers (CEA 46.3 ng/ml, CA 19-9 1911 U/ml, and CA 125 103 U/ml). Chest computed
      tomography revealed an irregular shaped, low density mass shadow in the left S10
      region, suggesting the diagnosis of pulmonary sequestration or bronchial atresia.
      However digital subtraction angiography failed to demonstrate an anomalous
      feeding artery. We could not rule out the possibility that a malignant lesion was
      included in the consolidated shadow. A left thoracotomy revealed an intralobar
      pulmonary sequestration of the left lower lobe. Hyphae of aspergillus were found
      in the lumen of the cystic bronchus of the resected lung. Immunohistochemical
      studies showed strong expression of CEA, CA 19-9, and CA 125 by bronchial
      epithelia in the pulmonary sequenstration. The serum values of tumor markers
      returned to their normal ranges after surgery.

PMID- 10410551
TI  - [Kirisawa type uveitis (acute retinal necrosis syndrome)].

PMID- 10410552
TI  - [Vascular endothelial growth factor promotes experimental choroidal
      neovascularization in monkey eyes].
AB  - PURPOSE: To evaluate the effect of vascular endothelial growth factor (VEGF) on
      experimental choroidal neovascularization (CNV) in monkey eyes through clinical,
      morphometric, and histological observations. METHOD: CNV was induced in both eyes
      of 6 rhesus monkeys by intense photocoagulation by red krypton laser. Immediately
      after photocoagulation, 2.5 micrograms of exogenous human VEGF was injected into
      the vitreous of the left eye in each animal. The right eyes served as controls.
      The eyes were enucleated 3 days to 12 weeks after photocoagulation and were
      examined by light and electron microscopy. RESULTS: VEGF-treated eyes developed
      remarkable serous retinal detachment around the sites of photocoagulation with
      manifest CNV one week after photocoagulation. Although there was no difference in
      the incidence of CNV between the treated and control eyes, the treated eyes
      showed more intense leakage of fluorescein from the CNVs for up to 4 weeks after
      treatment. Morphometrically, the CNVs were significantly larger and continued to
      grow longer in the treated than in the control eyes after one week of
      photocoagulation. Histologically, newly formed vessels with a distinct lumen were
      present in the treated eyes after 3 days of photocoagulation. CONCLUSION:
      Intravitreal injection of human VEGF promotes experimental choroidal
      neovascularization in monkey eyes.

PMID- 10410554
TI  - [Extracellular matrix influencees proliferation of cultured porcine lens
      epithelial cells].
AB  - PURPOSE: To investigate whether extracellular matrix (ECM) influences the
      proliferation of cultured lens epithelial cells (LECs). MATERIAL AND METHODS:
      Porcine LECs were cultured in F-12 nutrient mixture supplemented with 5% fetal
      bovine serum (FBS) for 24 or 96 hours on the dishes coated with laminin,
      fibronectin, type I collagen, or type IV collagen. As a control, LECs were
      cultured on uncoated dishes. Twenty-four or ninety-six hours later, the number of
      cells was determined. We determined the proliferation ratio of the number of
      cells 96 hours after plating to the number of cells 24 hours after plating. This
      ratio was used to assess the cell proliferation. RESULTS: The ratio of the LECs
      on the uncoated dishes was 2.3. Dish coating with type I or type IV collagen, and
      fibronectin significantly increased this ratio (4.0, 3.5, and 3.0, respectively),
      whereas coating with laminin did not affect this ratio (2.5). CONCLUSION: These
      findings suggest that ECM influences cultured porcine LEC proliferation.

PMID- 10410553
TI  - [Histochemical studies of glycosaminoglycans in the developing eyelids of
      experimental microphthalmic (Cts) mice].
AB  - PURPOSE: The Cts mouse is a mutant strain which induces congenital cataract and
      small eyes in homozygotes. The process of eyelid development in Cts mice was
      examined histochemically. MATERIALS AND METHODS: Prenatal (from day 14 of
      gestation) and postnatal (to day 14) animals of unaffected and homozygous mice
      were examined. Sensitized high iron diamine staining was done after
      chondroitinase B/testicular hyaluronidase double digestion, and sensitized low
      iron diamine staining was done after Streptomyces hyaluronidase digestion.
      RESULTS: The main chondroitin sulfate isomer in the dermis of the eyelid changed
      from chondroitin sulfate A/C to chondroitin sulfate B at birth in the unaffected
      mice. In the homozygotes, the same change took place 4 days after birth. In the
      dermis of the eyelid, hyaluronic acid was first detected on day 14 of gestation
      and gradually increased until birth in both unaffected and homozygous mice. There
      was slightly more hyaluronic acid in homozygous mice until 4 days after birth.
      CONCLUSION: The present study showed that the maturation of glycosaminoglycan
      molecular species in the eyelid was retarded in Cts homozygotes.

PMID- 10410555
TI  - [Effects of corticosteroid on porcine retinal pigment epithelial cells in culture
      -1. Inhibitory effect on cell proliferation].
AB  - PURPOSE: Proliferation is an important function of the retinal pigment epithelial
      (RPE) cells. The effect of a corticosteroid on the proliferation of cultured
      porcine RPE cells was investigated. METHODS: After administration of various
      concentrations (10-1,000 nM) of betamethasone sodium phosphate (betamethasone),
      we counted RPE cell numbers at 1, 3, 6, 9, and 14 days. RESULTS: Betamethasone
      administration resulted in a dose-dependent decrease in RPE cell proliferation.
      The proliferation of the cultured RPE cells was significantly inhibited by
      betamethasone, at a dose of 300 nM in 9 days. Ten-nM betamethasone neither
      inhibited nor promoted the RPE cell proliferation in culture. CONCLUSIONS: These
      results suggest that corticosteroids inhibit proliferation of cultured porcine
      RPE cells.

PMID- 10410556
TI  - [Cerebrospinal fluid analysis in Kirisawa-Urayama type uveitis].
AB  - PURPOSE: We investigated whether viral encephalitis could occur in patients with
      Kirisawa-Urayama type uveitis by analysing the cerebrospinal fluid (CSF).
      METHODS: CSF samples were aspirated from nine patients with Kirisawa-Urayama type
      uveitis and assayed for local antibody production and the presence of herpesvirus
      DNA. RESULTS: Seven cases had mild CSF pleocytosis. In six of seven cases who
      underwent CSF antibody analysis, we found intrathecal antibody production against
      herpes simplex virus or varicella-zoster virus which were the causative viruses
      diagnosed from intraocular fluid in each patients. Polymerase chain reaction
      (PCR) assay was used to search for virus DNA in the CSF of six patients, but all
      were negative. CONCLUSIONS: The results of this study suggest that Kirisawa
      Urayama type uveitis is often accompanied with optic nerve involvement and
      intrathecal antibody production against causative viruses, but we could not find
      any viral encephalitis.

PMID- 10410557
TI  - [Analysis of the long-term prognosis for conjunctival malignant melanomas in
      Japan].
AB  - PURPOSE: To investigate the long-term prognosis for primary conjunctival
      malignant melanomas in Japan. MATERIALS & METHODS: We conducted a survey of 61
      cases which had been reported in a 38-year period (1959 to 1996). We gathered
      information regarding the survival of patients, the post-operative follow-up
      period, the causes of death, and recurrences. Answers were obtained segarding 51
      cases (84%). Detailed progress was identified in 23 of these cases. The survival
      rates were calculated using the Kaplan-Meier method. RESULTS: The survival rates
      were 95.1% after 1 year, 72.9% after 3 years, and 53.4% after 5 years. These
      values are relatively low compared with those reported in Europe and the United
      States.

PMID- 10410558
TI  - [Radiation therapy for small choroidal neovascularization in age-related macular
      degeneration].
AB  - OBJECTIVE: To evaluate radiation therapy for age-related macular degeneration
      with subfoveal or juxtafoveal choroidal neovascularization smaller than or equal
      to 1 disc area. DESIGN: Nonrandomized comparative clinical trial. PARTICIPANTS:
      Fourteen eyes received a total radiation dose of 10-20 Gy in 5-10 fractions. The
      mean follow-up time was 22 months. Ten eyes in a control group were followed for
      an average of 16 months without any treatment. RESULTS: At a 12-month follow-up
      examination, funduscopic and angiographic findings had improved in 7 eyes (50%),
      were unchanged in 1 eye (7%) and, had deteriorated in 6 eyes (43%) among the
      treated patients. The same findings had improved in 1 eye (10%), were unchanged
      in 2 eyes (20%), and had deteriorated in 7 eyes (70%) among the control patients.
      There was a statistically significant difference by Mann-Whitney U test between
      the two groups. Visual acuity had improved in 4 eyes (29%), was unchanged in 6
      eyes (43%), and had declined in 4 eyes (29%) among the treated patients. Among
      the control patients visual acuity had improved in none of the eyes (0%), was
      unchanged in 6 eyes (60%), and had declined in 4 eyes (40%). The difference
      between the two groups was not statistically significant. Of the 7 cases whose
      fundus had improved by 12 months, 4 cases maintained a favorable status through
      the following 2 years. CONCLUSION: Radiation therapy had an inhibitory effect on
      small choroidal neovascularization when viewed by funduscopy and angiography,
      but, the efficacy for visual prognosis was not always identified.

PMID- 10410559
TI  - [Use of the multifocal electroretinogram to evaluate retinal function after pars
      plana vitrectomy for diabetic macular edema].
AB  - PURPOSE: Multifocal electroretinograms (multifocal ERGs) were performed to
      evaluate retinal function in patients with diabetic macular edema. MATERIALS &
      METHODS: Eight eyes of 5 patients underwent pars plana vitrectomy for diabetic
      macular edema. Multifocal ERGs, fundus examinations, and fluorescent
      angiographies were done both before and after the operation. RESULTS: Post
      operative visual acuity was improved by two or more lines in 3 eyes. In
      multifocal ERGs, the amplitude of the positive wave (P1) from the macular area
      decreased transiently after surgery (p < 0.05), but it improved with the passage
      of time. The P1 amplitude from the peripheral area was decreased throughout the
      observation period of six months (p < 0.05). For both areas, the P1 latency was
      increased significantly (p < 0.05) at one month post-operatively, and then
      decreased. CONCLUSION: These findings are consistent with the possibility that
      the surgical method, especially removal of the posterior cortical vitreous, can
      cause retinal damage.

PMID- 10410560
TI  - [Accuracy of intraocular power calculation formulas].
AB  - PURPOSE: We examined the accuracy of intraocular lens power calculation formulas,
      with special emphasis on the prediction of refraction in different axial lengths.
      MATERIAL AND METHODS: 786 cases were subdivided into four groups based on the
      axial length (short axial length < 22.0 mm, normal axial length = 22-24.4 mm, mid
      range axial length = 24.5-26.9 mm and long axial length > 27 mm). Seven different
      formulas (Holladay, SRK, SRK II, SRK/T, S-SRK, M-SRK, L-SRK) were tested for
      their accuracy in predicting post-operative refraction. RESULT: The best results
      were obtained using the S-SRK formula in the short axial length group (n = 114),
      The SRK and Holladay formulas in the normal axial length group (n = 278). The
      Holladay and SRK/T formulas in the mid-range axial length group (n = 135), and
      the SRK/T and L-SRK in the long axial length group (n = 259). CONCLUSION: Our
      results emphasize the importance of using an intraocular lens formula specific
      for each range of axial length when calculating the predicted refraction.

PMID- 10410561
TI  - [Acute retinal necrosis with varicella zoster dermatitis in the fellow eyelid].
AB  - BACKGROUND: We report a case of acute retinal necrosis with contralateral
      varicella zoster dermatitis. CASE: The patient, a 61-year-old man, developed
      acute retinal necrosis in the right eye 1 month after varicella zoster dermatitis
      in the left eyelid. PROGRESS: Intravenous acyclovir, corticosteroids, and laser
      photocoagulation were effective without any surgical treatment. CONCLUSION: We
      suggest that ophthalmoscopic examination of both eyes is needed in cases with
      varicella zoster dermatitis.

PMID- 10410562
TI  - [Centenarian study: present status and perspectives].

PMID- 10410563
TI  - [Genetic factors in the development of atherosclerosis].

PMID- 10410564
TI  - [DNA polymorphisms of the age-related gene in geriatric diseases].

PMID- 10410565
TI  - [Gene polymorphisms in atherosclerotic diseases and lipoprotein metabolism
      disorders].
AB  - Atherosclerosis results from complex inflammatory-fibroproliferative responses.
      Among the factors that could affect atherogenesis, the genes involved in
      regulation of the plasma lipoprotein levels are believed to play central roles.
      This paper focuses on the genes regulating the metabolism of the three major
      atherogenic lipoproteins, i.e. LDL, remnants, and Lp (a), and discusses the
      clinical significance of studying their polymorphism.

PMID- 10410566
TI  - [Gene polymorphisms and cardiovascular diseases in the elderly].

PMID- 10410567
TI  - [Osteoporosis and genetic polymorphism].

PMID- 10410568
TI  - [Genetic risk factors in senile dementia].
AB  - Alzheimer's disease (AD) and vascular dementia (VD) are two major dementing
      disorders in Japan. It has been well established that apolipoprotein E4 (ApoE4)
      increases the incidence of AD and lower the onset of AD in a dose-dependent
      manner. ApoE genotyping should not be used alone in the diagnosis of AD due to
      its limited sensitivity to detect AD. In VD, at the present time, no genetic risk
      factors that are directly linked to VD have been established. However,
      methylenetetrahydrofolate reductase gene polymorphism may be a candidate
      conferring a risk to develop vascular diseases.

PMID- 10410570
TI  - [Clinical characteristics of polycythemia vera in the elderly].
AB  - Of 43 elderly patients who were suspected to have polycythemia between October
      1990 and July 1998, 12 patients showed an increased red cell volume measured by
      51Cr-labeled red blood cells. We analyzed the clinical characteristics of the 12
      patients consisted of 7 men and 5 women, with a median age of 71 (range: 57-92).
      Chief complaints were headaches and dizziness (3 cases), symptoms of other
      conditions than polycythemia (4 cases). Five patients had no symptoms. Five of 6
      patients over 70 years old had no symptoms due to polycythemia. Seven cases (58%)
      showed splenomegaly and three cases (25%) showed hepatomegaly. Laboratory
      findings were as follows: WBC 9.7 +/- 3.9 x 10(3)/microliter (mean +/- SD, p <
      0.02 vs normal control), Hb 17.9 +/- 4.2 g/dl (p < 0.001), Plt 39.7 +/- 26.0 x
      10(4)/microliter, EPO 13.8 +/- 5.2 mU/ml (p < 0.0001), NAP score 258 +/- 114,
      Vit. B12 1,686 +/- 2,156 pg/ml, arterial O2 saturation more than 92% in all
      cases. The diagnosis of all cases was polycythemia vera according to the
      diagnostic criteria of Polycythemia Vera Study Group. Associated conditions
      included 8 cases of thrombosis (cerebral thrombosis 4, thrombophrebitis 2,
      myocardial infarction 1, ischemic colitis 1) and 3 cases of malignancy
      (esophageal cancer 1, breast cancer 1, renal cancer 1), none of which was therapy
      related cancer. Six patients (50%) had only phlebotomy, three (25%) only
      chemotherapy, and three (25%) both phlebotomy and chemotherapy. Patients over 80
      years old needed neither intensive nor continuous treatment. Only one patient
      died due to esophageal cancer at age 89.

PMID- 10410569
TI  - [Alterations in neurotransmitter, amino acid and free radical related substances
      in cerebrospinal fluid in patients with cerebrovascular diseases].
AB  - Acetylcholinesterase (AChE), choline, monoamine and its metabolite, amino acid
      and superoxide dismutase (SOD) levels were measured in cerebrospinal fluid (CSF)
      in patients with cerebrovascular diseases. Patients were classified into the
      following four groups; controls: normal subjects without neurological disease,
      group A: cerebral hemorrhage, group B: cerebral infarction, group C: patients
      with mental impairment, including those in groups A and B, and a low score on
      Hasegawa's Dementia Rating Scale. CSF AChE level of groups A, B and C was
      decreased significantly, while choline concentration from patients showed a
      increase compared with that of control cases. CSF alanine concentration showed a
      tendency to increase, while glycine and glutamate tended to decrease. CSF
      epinephrine, norepinephrine or 3-methoxy-4-hydroxyphenylethylen glycol
      concentrations of groups A, B and C did not exhibit a significant difference from
      that in control cases. Some cases with cerebrovascular diseases showed low
      concentrations of both CSF 5-hydroxyindole acetic acid and homovanillic acid.
      However, dihydroxyphenyl acetic acid concentration was higher than in control
      cases. The CSF SOD level was not significantly from that in control cases. The
      changes in neurochemical substances in the CSF support their use as markers of
      cerebrovascular disease-related change.

PMID- 10410571
TI  - [Compliance concerning external protectors for hip fractures among the
      institutionalized elderly in Japan].
AB  - An external protector (EHP) which was developed in Europe to protect the femoral
      neck from direct impact on falling is available but has not been examined
      sufficiently in Japan. In order to explore the compliance of use of the EHP among
      the institutionalized elderly with in case of hip fracture who are at high risk
      of falling, we conducted the four-week intervention study using two types of a
      EHP. The subjects of a study consisted of 10 elderly people (2 men, 8 women) with
      a mean age 85.7 living in nursing home in a village. Informed consent was
      obtained from all participants. At the end of the study, rate of subjects who
      wore EHP was relatively high for the Finnish EHP (Safety Pants) group compared to
      the Danish EHP (Hip Protector) group. There were no significant differences
      between variables in age, sex, fall experience during the previous year, history
      of diseases etc. The reasons for dropout were first: difficult in wearing EHP and
      accompanying delay in toilet, secondly: taking much time to wear, thirdly: a
      sense of incongruity, too small or too tight'. If the EHP is redesigned to suit
      Japanese elderly, the compliance might increase. Thorough explanation to
      institutionalized elderly who may have cognitive impairment, physical problems,
      or both, is required.

PMID- 10410573
TI  - [An elderly case of juvenile muscular atrophy in the unilateral upper extremity
      with tremor in both hands].
AB  - A 75-year-old man had noticed muscle atrophy and weakness of his right hand and
      forearm at the age of 25. The symptoms slowly progressed and then stopped. Right
      hand tremor appeared at about age 40. There was no symptom in his left upper
      extremity, and his gait was normal. He now shows severe muscle atrophy in his
      right hand and forearm. There was distally dominant weakness of the right upper
      extremity and his hand grip was 0 kg on the right and 25 kg on the left. On
      admission there was no weakness in the bilateral lower extremities. He had
      postural tremor in both hands and fingers. The tendon reflexes were hypoactive in
      the upper extremities and normal in the lower extremities. Abnormalities in the
      superficial sensation were unremarkable, whereas vibration sensation in both the
      upper and lower extremities was mildly disturbed. Electromyography revealed
      chronic denervation, especially in the right upper extremity. The sensory nerve
      conduction study results and somatosensory evoked potentials in the upper
      extremities were normal. Cervical MRI demonstrated spondylotic changes, canal
      stenosis from the C5 to C7 levels, and compression of the spinal cord. His hand
      tremor was dominant on the right with a peak frequency of about 7 Hz. Tremor
      frequency and power were decreased by mechanical load. Hirayama's disease
      (juvenile muscular atrophy of unilateral upper extremity) was the most probable
      diagnosis, although aging might have produced various additional abnormalities.
      The tremor seen in this patient showed characteristics of enhanced physiological
      tremor.

PMID- 10410572
TI  - [Aspergillosis following influenza A infection].
AB  - An 83-year-old man had an influenza-like upper respiratory infection that
      progressed to pneumonia and respiratory insufficiency during a period two weeks.
      After admission, anti-influenza A antibody increased 32-fold and antibiotic
      treatment had little effect on the pneumonia. Aspergillus antigen was detected
      from his serum and pleural effusion, however, culture of sputum was negative for
      aspergillus. Administration of amphotericin B reduced the serum level of
      aspergillus antigen, however he died due to the progression of respiratory
      insufficiency and bloody sputum. Aspergillus infection is generally thought to
      occur in immunocompromised hosts, but this patient had no apparent
      immunosuppressive conditions except for his age before the influenza A infection.
      His WBC and lymphocyte count temporally decreased to 2,000 x 10(6)/L (lymphocytes
      160 x 10(6)/L) followed by aspergillus infection. This temporally reduction of
      lymphocytes is thought to have been responsible for the aspergillus infection.
      Complications of influenza infection are sometimes fatal and vaccination against
      influenza seems necessary in high risk individuals such as elderly people.

PMID- 10410574
TI  - [Soluble cell adhesion molecules in chronic renal graft rejection].
AB  - Cell-bound adhesion molecules are involved in immune and inflammatory responses.
      Soluble forms of adhesion molecules (s.a.m.) can be detected in the blood. The
      elevated blood levels of s.a.m. were found as a response to variety disease
      processes (e.g. septic shock, acute graft rejection, atherosclerosis). The
      objective of the present study was to measure the serum levels of s.a.m. in
      patients with chronic renal allograft rejection and in recipients with a stable
      graft function. Evaluated was also the effect of activity of graft rejection (ch.
      g. r.) and risk factors of graft lesion on the levels of the investigated s.a.m.
      34 patients with ch.g.r. were examined (Group I), 50 patients with a stable
      allograft function (Group II), and 25 healthy subjects (control). Group I
      patients were 76 +/- 34 months and Group II patients were 59 +/- 36 months after
      transplantation. Both groups of patients were treated with immunosuppressive
      drugs (CsA, azathioprine and prednisone) Group I patients had a higher plasma
      levels of creatinine and uric acid, increased arterial blood pressure and
      triglycerides concentrations, and lower plasma levels of HDL cholesterol, as
      compared to Group II patients. In all the examined subjects, serum concentrations
      of s.a.m. from the immunoglobulin and selectin families (s.ICAM-1, s.VCAM-1, s.E
      selectin) were measured by the immunoenzymatic method. The investigations of
      s.a.m. in ch.g.r. patients revealed a statistically significant increase the
      serum levels of s.ICAM-1, s.VCAM-1 and s.E-selectin. Some disorders of the
      release of s.a.m. into blood were also found in patients without graft
      disfunction. In this patients were observed: increased levels of s.VCAM-1 and s.E
      selectin. S.ICAM-1, s.VCAM-1 and s.E-selectin serum levels showed a correlation
      with plasma uric acid concentration and arterial pressure, whereas the other two
      molecules with the plasma level of triglycerides. Each of the three molecules had
      a negative correlation with the HDL cholesterol level. The regression analysis
      revealed a correlation of s.ICAM-1 and s.VCAM-1 with IL-6. The correlation of the
      molecules with chemokines (s.VCAM-1 and s. E-selectin with IL-8, and s. E
      selectin with MCP-1) may results from their release in the course of the
      inflammatory process. The increased levels of circulating s.VCAM-1 and s.E
      selectin found in renal allograft patients suggest a chronic stimulation and
      activation of the endothelium. Non-immunological mechanisms (such as arterial
      hypertension or metabolic disorders) contributed to the generation of the s.a.m.
      in patients with ch.g.r. and in those with stable graft function. The negative
      correlation of HDL with s.a.m. (s.ICAM-1, s.VCAM-1) suggests a protective role of
      HDL on the vascular endothelium by inhibiting the generation of these mediators.

PMID- 10410575
TI  - Glucosamine levels in people with ischaemic heart disease with and without type
      II diabetes.
AB  - Glucosamine has a major influence on the impairment of some metabolic mechanisms
      in the human body. As shown in vitro experiments, it takes part in inducing
      mechanisms of insulin resistance. Therefore, the purpose of our study was to
      evaluate glucosamine levels in the serum of patients who suffered myocardial
      infarction (MI) and who either had or didn't have diagnosed type II diabetes in
      relation to healthy people. The levels of glucosamine, immunoreactive insulin, C
      peptide, glucose and lipid indexes were measured in venous blood in investigated
      patients. In patients with MI without diabetes the highest concentrations of
      glucosamine, insulin and C-peptide were noted as compared to the results obtained
      from other groups of patients. In patients with diabetes, on the other hand, the
      highest glucose levels were noted as compared to the results of other patients.
      There were no statistically differences of lipid indexes between two groups of
      patients following MI. A negative correlation between glucosamine levels and
      glucose concentrations in patients without diabetes may suggest that glucose does
      not directly determine glucosamine levels. The returning of insulin levels to
      normal in patients with hyperinsulinemia (antidiabetic drugs) may play a role in
      the lowering of glucosamine induced peripheral insulin resistance.

PMID- 10410576
TI  - [Evaluation of the correlation between the level of IgG antibodies against
      mycobacterial A60-antigen and tuberculin reactivity in persons without a history
      of tuberculosis and in active pulmonary tuberculosis patients].
AB  - A measurement of antimycobacterial antibodies levels provides important
      informations about infection with tubercle bacilli and the development of
      tuberculosis. A tuberculin test as a manifestation of cellular immunity, has lost
      in diagnostic value. The aim of the present study was to assess the correlation
      between the level of IgG antibodies against A60 antigen of Mycobacterium bovis
      BCG and tuberculin reactivity. 213 persons were involved into the study: 104
      subjects without history of tuberculosis in the past (Group I) and 109 active
      pulmonary tuberculosis patients (Group II)--56 culture positive patients and 53
      culture negative patients. In all subjects the A60-ELISA test with the use of
      Immune kit was performed. All subjects were also tuberculin tested by the Mantoux
      technique using 2 units of tuberculin Rt23. We found that the levels of anti-60
      antibodies in patients with active pulmonary tuberculosis were significantly
      higher than in controls (median value 43 U/ml and 237.5 U/ml respectively; p =
      0.0001). We observed 47.1% and 74.3% tuberculin positive subjects in Group I and
      Group II respectively. We did not find relationship between the level of IgG anti
      A60 antibodies and tuberculin reactivity in tuberculin-positive and tuberculin
      negative subjects both in controls and active pulmonary tuberculosis patients. We
      conclude: 1. There is no correlation between A60-ELISA results and tuberculin
      reaction status. 2. The serological test can better than tuberculin test
      differentiate subjects with non-active tuberculous infection from active disease.

PMID- 10410577
TI  - [The effect of nasal and skin colonization on the development of exit site and
      peritoneal catheter tunnel infections in patients on peritoneal dialysis].
AB  - ESI remain a major problem in patients undergoing peritoneal dialysis and are
      frequently the reason for catheter removal. The treatment is often costly and not
      effective and the need for routine prophylactics has to be clarified. In this
      study 38 peritoneal dialysis patients (15 F & 23 M, age: 18-73) were analysed
      prospectively for ESI and TI in respect to skin (exit site and inguinal area) and
      nostrils colonisation. There were 14 diabetics and 24 non-diabetics. All had
      standard double-cuff Tenckhoff catheter and none presented with ESI prior to the
      study. No treatment was applied on the basis of positive culture only. In 27
      patients swab were repeated after 6-11 months. Eight episodes of ESI and three TI
      were recorded. Following pathogens were cultured: S.aureus in 4 Klebsiella
      pneumoniae in 2, Corynebacterium sp. in 1, negative in 1 and with TI S.aureus in
      3. Positive nasal cultures (S.aureus, Klebs.pn.) were observed in 5 patients
      subsequently developing ESI (p < 0.01) and in 2 with TI. In 2 cases exit site was
      also colonized by pathogens responsible for ESI (p = NS). Inguinal area was
      colonized by various pathogens in 7 patients, but only one of these developed ESI
      (p = NS) and no one TI. There was no difference between diabetic and non
      diabetics neither in the frequency of ESI, TI nor in nasal carriage of pathogens.
      In the majority of patients nostrils and inguinal area were colonized by
      S.epidermidis. When the second culture was analyzed it appeared that
      significantly more patients had exit site colonized by S.epidermidis (2 and 11
      patients in 2 consecutive cultures respectively (p < 0.01). In conclusion, it
      appears that nasal carriers of pathogens like S.aureus and Klebsiella pneumoniae
      are more prone to ESI. Inguinal area and exit site colonization does not seem to
      precede ESI or TI. We would suggest that nasal carriage status should be
      routinely identified in all patients entering peritoneal dialysis programme and
      the carriers properly treated.

PMID- 10410578
TI  - [Antibacterial treatment in patients after extended bowel resection with ileo
      cecal valve removal--personal experience].
AB  - Small bowel infection in patients that underwent extensional bowel resection is
      one of causal mechanisms of massive diarrhoea in postoperative period. The aim of
      this study was to investigate clinical importance of ciprofloxacin efficacy in
      treatment of massive diarrhoea in patients after extensional bowel resection with
      removing of ileo-coecal valve (EBR + ICVR). From group of 21 patients that
      underwent EBR + ICVR the postoperative period survived only 11. In 9 cases
      massive diarrhoea and sepsis was observed. Routinely applied three-drugs
      antibacterial therapy based on penicillin or first-generation cephalosporin,
      aminoglycoside and metronidazole was efficient in 18% of patients only. The
      ciprofloxacin was used as a second-shot therapy in patients which did not realt
      on routine three-drugs antibacterial management. In all cases the clinical
      efficacy was observed as recessing of diarrhoea and septic symptoms. On the basis
      of our experience we suggest that in patients with massive diarrhea due to
      ascending contamination of small bowel after extensive resection with removal of
      ileo-coecal valve, ciprofloxacine is the treatment of choice.

PMID- 10410579
TI  - [Ischemic heart disease as a factor for hindering diagnosis of idiopathic
      pulmonary fibrosis].
AB  - The aim of the study was to find factors that may influence diagnostic process of
      idiopathic pulmonary fibrosis (IPF). Clinical presentation, lung function data
      and radiological changes were assessed in 57 patients with diagnosis of IPF.
      There were 25 females and 32 males in the study group; mean age was 61.4 +/- 10.9
      years. Mean duration of symptoms in the whole group was 18.4 +/- 16.0 months. The
      most common symptoms were dyspnea on exertion (96.5% of cases) and cough (84.2%
      of cases). 56 out of 57 patients (98.2% of cases) had crackles on ausculation of
      the lungs. In one third of the patients clubbing of the fingers was found. Mean
      FVC% of predicted was 77.2 +/- 19.8%, and mean DLCO% of predicted was 61.6 +/-
      16.8%. The most common associated disease was ischemic heart disease, found in
      43.9% of patients. Duration of symptoms in patients with ischemic heart disease
      was 25.7 +/- 18.8 months and was as twice long as in the rest of the patients,
      12.8 +/- 10.5 months (p < 0.005). CONCLUSIONS: 1: Associated ischemic heart
      disease may cause delay in establishing the diagnosis of IPF; 2. Crackles on
      ausculation are characteristic for IPF and together with disseminated changes on
      chest radiograms indicate correct diagnosis in patients with associated ischemic
      heart disease.

PMID- 10410580
TI  - [Pulmonary microlithiasis--difference between radiology results and pulmonary
      function tests].
AB  - The case od 22-years old woman with pulmonary microlithiasis is described. The
      diagnosis was confirmed by histopathological examination of lung tissue. In
      electron microscopy lung fibrosis was seen. High resolution computed tomography
      (HRCT) and pulmonary function tests (lung compliance, diffusion capacity,
      exercise test) were done. The role of bronchoalveolar lavage (BAL) and lung
      scintigraphy with technetium in the diagnostic procedure of this disease is
      discussed.

PMID- 10410581
TI  - [Arterial hypertension due to perirenal hematoma after renal percutaneous
      biopsy].
AB  - We report three cases in which arterial hypertension occurred after percutaneous
      renal biopsy due to perirenal hematoma. Perirenal hematoma is common complication
      of renal biopsy. The mechanism of hypertension depends on renal ischemia.
      Compressive ischemia decrease the renal blood flow, increase mechanism RAA, the
      amount of urine is decreased, with low sodium concentration and finally the
      arterial hypertension appears.

PMID- 10410582
TI  - [Cyclosporine: properties, mechanism of action and application in therapy of
      rheumatoid arthritis].

PMID- 10410584
TI  - [Cardiac complications of antineoplastic chemotherapy].

PMID- 10410583
TI  - [Antithrombotic treatment in atrial fibrillation].

PMID- 10410586
TI  - [Neonatal hemochromatosis. Report of 3 autopsy cases].
AB  - INTRODUCTION: Neonatal hemochromatosis is a disease that starts in utero,
      characterized by severe fibrosis or cirrhosis and siderosis of the liver and
      other organs without affecting the mononuclear fagocytic system. The most
      important clinical features are severe hepatic failure at birth and hypoglycemia.
      The diagnosis is made excluding other diseases more frequently seen in the
      neonatal period and with at least two of the clinicopathologic criteria
      delineated by Knisely. METHODS: A retrospective analysis of the autopsies of
      newborn done at the Department of Pathology of the Hospital de Pediatria, C.M.N.
      SXXI, IMSS, a tertiary care facility in the period 1989 from 1997. Those cases
      with primarily hepatic disease as the main diagnosis were chosen. The degree of
      siderosis was determined cualitatively. The amount of Fe and copper in the liver
      and spleen in samples fixed in formalin was obtained using X ray fluorescence in
      the Instituto Nacional de Investigaciones Nucleares, two control cases were also
      tested. RESULTS: Only four out of 210 autopsies of newborn babies were found to
      have hepatic disease as a main diagnosis but without an etiology determined. In
      three of such cases the diagnosis of neonatal hemochromatosis was made. All
      patients were male with ages six, 29 and 36 days, one with Down's syndrome. The
      ratio of iron deposits in liver/spleen in hemochromatosis' cases was higher to
      1.5 in the liver in contrast to the two control cases. CONCLUSIONS: These cases
      showed the utility of the autopsy in establishing the adequate diagnosis in three
      cases of neonatal hemochromatosis. The importance of establishing an accurate
      diagnosis is to recognize it as an entity with a lethal course, that can be
      potentially managed with liver transplant as well as genetic counseling to the
      family. A remarkable finding in the study of these cases was the ratio of iron
      concentration in the liver and spleen that allowed to discard other causes of
      siderosis. To our knowledge this finding has never been recorded.

PMID- 10410587
TI  - [Reasons for fresh frozen plasma transfusion in a general hospital].
AB  - OBJECTIVE: To assess the fresh-frozen plasma (FFP) transfusion indications in a
      Mexican hospital. SETTING: A general hospital for federal government employees
      located in the city of Morelia, State of Michoacan, Mexico. MATERIAL AND METHODS:
      We evaluated all FFP transfusions between February and August, 1998 classifying
      them as appropriate or inappropriate according to the recent FFP-transfusion
      guidelines: correction of known coagulation factor deficiencies with bleeding and
      correction of microvascular bleeding when prothrombin and activated partial
      thromboplastin time are > 1.6 times normal (coagulation index o CI), urgent
      reversal of warfarin therapy, antithrombin III deficiency, thrombotic
      thrombocytopenic purpura treatment, liver transplant and acute disseminated
      intravascular coagulation. RESULTS: 78 patients with 292 FFP units transfused
      were analyzed: in 20 patients the indication was clotting support, 16 with CI <
      1.5 and four with CI > 1.6, one with blood loss and one with surgical procedure;
      hypoalbuminemia in 10; hypovolemia in eight; unidentified reason in 33 and others
      in seven patients. Eleven units (3.76%) were considered properly transfused
      whereas 281 (96.23%) were inadequately indicated.

PMID- 10410585
TI  - Neutrophil recovery time and adverse side effects in acute leukemia patients
      treated with intensive chemotherapy and concomitant G or GM-CSF.
AB  - OBJECTIVE: Compare the speed of neutrophil recovery and the unwanted secondary
      effects in two groups of acute leukemia patients treated with intensive
      chemotherapy and G or GM-CSF. PATIENTS AND METHODS: Patients were randomly
      assigned to receive subcutaneous G-CSF at a daily dose of 300 micrograms for
      adults and 150 micrograms for children or GM-CSF at 400 and 200 micrograms
      respectively, starting With chemotherapy and stopping when the absolute
      neutrophil count (ANC) reached 500/microL. Secondary effects were attributed to
      growth factors only when not coincidental with infection, chemotherapy or
      hemoderivative transfusion. RESULTS: 34 patients were included in the G-CSF arm
      and 37 in the GM-CSF arm. Distribution by sex, age, type of acute leukemia,
      induction or post-induction therapy, as well as initial neutrophil count were
      comparable among the two groups. Mean time for ANC > 500/microL was 19 days for G
      CSF group and 16 days for GM-CSF group (p = 0.08). There were no statistically
      significant differences in secondary unwanted side effects between the two
      groups. There were two cases of growth factor-related-fever in the G-CSF group
      and five in the GM-CSF group (p = 0.25). There was a case of systemic reaction in
      the G-CSF group. Twenty-nine patients in each group presented febrile neutropenia
      episodes (p = 0.45). The only factor that showed significance on neutrophil
      recovery speed was type of leukemia (p = 0.04). CONCLUSIONS: We found no clear
      advantage of one growth factor over the other for this indication.

PMID- 10410588
TI  - [Clinical competence of the family doctor in systemic arterial hypertension].
AB  - OBJECTIVE: To establish clinical competence of family physicians to diagnose
      systemic arterial hypertension and to analyze it's associations with some
      variables related to working conditions and prior training. METHODS: The clinical
      competence was established in a non probabilistic sample of 165 family physicians
      working in 12 units of the Instituto Mexicano del Seguro Social (IMSS) in Mexico
      City. We used questionnaire of 160 items (true/false/don't know) to evaluate
      clinical competence. Association of the scores were explored for work shift
      (morning/afternoon), working conditions (very favorable/favorable/little
      favorable/unfavorable) and having been trained in a familiar medicine residency
      of the IMSS (yes/no). RESULTS: There were a general low competence to diagnose
      systemic arterial hypertension (median score of 36 of a possible 160). There were
      associations of competence with more favorable working conditions (p = 0.005
      Kruskal-Wallis test) and with having been trained previously (p = 0.0123 U Mann
      Whitney test). CONCLUSIONS: Our results support the need to continue in this area
      of research to improve measuring instruments and to identify the modifiers of
      clinical competence to overcome the deficiencies detected in the present study.

PMID- 10410589
TI  - Effect of nutritional rehabilitation of undernourished rats on serum insulin-like
      growth factor (IGF)-I and IGF-binding proteins.
AB  - The aim of the present work was to study the effect of nutritional rehabilitation
      with different concentration of dietary protein (6, 18 or 50%) of previously
      undernourished rats on serum Insulin-like growth factor-I (IGF-I) and Insulin
      like growth factor binding proteins levels (IGFBPs). Undernutrition was induced
      by feeding rats with 0.5% casein diet for 5 weeks. Over this period, growth,
      serum total proteins, IGF-I levels and IGFBP-3/IGFBP-2 ratio were significantly
      decreased compared to the group fed ad libitum 18% casein diet. Nutritional
      rehabilitation for 21 days with 6% casein diet did not change any of these
      parameters. Nutritional rehabilitation with 18 or 50% casein diet for one day did
      not initiate the restoration of serum IGF-I levels and IGFBP-3/IGFBP-2 ratio.
      However, after 10 days with 18 or 50% casein diets, there was an increase of 12
      fold in IGF-I levels and 7 fold in the IGFBP-3/IGFBP-2 ratio. Finally,
      rehabilitation for 21 days with 18 or 50% casein diet produced an increase of 21
      and 26 fold in IGF-I levels, and 6.1 and 14.5 fold in the IGFBP-3/IGFBP-2 ratio
      respectively. These results suggest that nutritional rehabilitation with 18%
      casein and above were more effective than 6% casein diets to reestablish body
      weight. Serum IGF-I and IGFBP-3 concentrations were sensitive indicators of the
      evolution of the nutritional status of the rats depending of the protein
      concentration in the diet in previously undernourished rats.

PMID- 10410590
TI  - [Stem cell factor (SCF) supports granulocyte progenitor survival in mouse bone
      marrow cultures].
AB  - The regulation of cell differentiation and cell death in crucial to the
      generation of hematopoietic cells both in vitro and in vivo. The biologic role of
      stem cell factor (SCF) in hematopoietic cell development is not well known. We
      monitored the survival, proliferation and differentiation of mouse hematopoietic
      cells in culture in the presence of SCF. Examination of colony formation, MTT and
      thymidine killing of mouse bone marrow indicated that SCF is mainly a survival
      factor. Our results show that SCF maintains cells in a "undifferentiated" state.
      Committed granulocytic and monocytic progenitors (CFU-GM) survive for seven days
      in the presence of SCF alone, under conditions where no maturing granulocytic
      monocytic cells could be recovered. On transfer to GM-CSF containing cultures,
      these cells proliferate and differentiate terminally. Together, our data indicate
      that SCF induces survival in hematopoietic progenitors. Furthermore, SCF favors
      the survival of granulocytic progenitors over that of monocytic progenitors. In
      the absence of later acting factors such as GM-CSF, cells that progress beyond
      the CFU-GM stage lose c-kit expression and die by default. Hence, lack of cell
      expansion in the presence of SCF by itself is due to constant cell proliferation
      and survival, which is counterbalanced by cell death. In contrast, the presence
      of both SCF and GM-CSF allows for the continuous survival and expansion of
      hematopoietic progenitor cells in culture, as well as favoring their terminal
      differentiation along granulocytic and monocytic pathways. Furthermore, GM-CSF
      induces colonies of macrophages that produce G-CSF and IL-6, two molecules
      involved in granulopoiesis, and these in turn stimulate granulocyte colony
      formation. Finally, our data suggest that survival signals by SCF are crucial
      during the differentiative process of granulocytes, giving strength to
      deterministic model.

PMID- 10410591
TI  - Bronchoaspiration as a possible cause in a case of tetanus. A reminder on the
      importance of adulthood immunizations.
AB  - Although preventable by immunization tetanus still takes a large death toll,
      mostly in developing countries, where adult population is often unprotected and
      opportune medical care unavailable. We present a case of tetanus in an elderly
      patient with bronchoaspiration pneumonia after a near-drowning incident, in which
      no objective entry site could be suspected with as much temporal relation as the
      bronchoaspiration incident. Bronchoaspiration of organic matter and feces
      provides both a source of the causative agent and an adequate polymicrobial
      environment for the development of the disease. It is under such conditions that
      we propose this unusual entry site as the cause of tetanus in our patient.
      Special emphasis is made on the importance of adulthood immunization programs and
      how incidents like this one should be taken into account in the overall care
      provided to the elderly population.

PMID- 10410592
TI  - [The other genome: the clinical concept of mitochondrial cytopathies or disorders
      of pxidative phosphorylation].
AB  - The investigations of mitochondrial DNA abnormalities and its relationship with
      derangements of oxidative phosphorylation and electron transport system, has
      yielded description a myriad of syndromes called mitochondrial diseases or
      cytopathies. The objective of this paper is to review the clinical relevant
      features of this heterogeneous group of diseases, to understand the board
      spectrum of signs and symptoms and suggest an algorithm for the diagnosis.

PMID- 10410593
TI  - [International COnference on Nutritional Morbidity in Children with Cancer].

PMID- 10410594
TI  - [The EMECAM study on the effects of air pollution. Estudio Multicentrico Espanol
      sobre la Contaminacion Atmosferica y la Mortalidad].

PMID- 10410595
TI  - [The effects of air pollution on health: an introduction].
AB  - In recent years, major progress has been made as regards the knowledge and
      understanding which has been gained of the impact of air pollution. In this
      study, the basic concepts are set out regarding this subject, and the different
      possible approaches as far as methodologies are concerned are reviewed. Among the
      epidemiological studies, the time series studies are those most often used for
      assessing the short-term impact of air pollution. The most important factors
      leading to confusion in this type of study are the seasonal and weekly changes,
      the tendency, the weather variables and the serious illnesses of a seasonal
      pattern, such as the flu. The main short-term impact of air pollution on human
      health range from a rise in the overall death rate resulting from respiratory and
      cardiovascular diseases to the worsening of lung function and other symptoms,
      including a rise in the number of doctor visits and hospital admissions. Despite
      a widespread consensus existing with regard to the harmful impact of air
      pollution, there are a number of questions currently in the need of further
      research.

PMID- 10410596
TI  - [Air pollutants and their monitoring].
AB  - Some basic concepts regarding air pollution are set out. Although, from a health
      care standpoint, our interest revolves around the impact which pollution has on
      human health, it being important to ascertain the main pollutants, the sources of
      emissions, the physiochemical properties thereof, the sampling and analysis
      methods which are used at the air pollution control stations, the limits set by
      the laws currently in impact and the World Health Organization recommendations
      with regard to the levels of immission. This study reviews these concepts with
      regard to the pollutants which have been analyzed in the Spanish Multicenter
      Study of Air Pollution and Mortality (EMECAM): particles, sulfur dioxide (SO2),
      nitrogen dioxide (NO2), carbon monoxide (CO) and ozone (O3). For this purpose,
      the most recent publications on this subject have been used, including part of
      what is going to be the line around which all of the measures aimed at combating
      air pollution are going to be revolving in the very near future, that is, the new
      set of European Union Directives (some currently in the proposal stage) and the
      latest recommendations (not as yet published) of the World Health Organization.
      Lastly, a wide range of aspects are set out which involve Public Health in the
      field of air pollution, despite the monitoring and control thereof falling to the
      environmental affairs authorities in terms of government organization.

PMID- 10410597
TI  - [Time series methods in epidemiological studies on air pollution].
AB  - The time series methods in the epidemiological studies on air pollution are
      reviewed, illustrated by means of an autoregressive Poisson regression which was
      employed in the APHEA and EMECAM Projects. A listing is provided of the
      variations in the daily number of deaths of people over age 70 (all causes, CIE
      9:001-799) in Barcelona, 1991-1995, with the average variations in the daily smog
      pollution levels. A Poisson regression is used insofar as the dependent random
      variable presumably follows such a probability distribution. As variable possibly
      leading to confusion, the impact of weather variables (daily temperature and
      relative humidity averages), seasonal, tendency-related behaviours and day of the
      year on the death rate are taken into account (all estimated on a determinist
      basis), in addition to any other variable which behaves in a way that it can be
      related to the dependent variable (i.e. flu epidemics). The relationship between
      the death rate and the confusing-causing variables is modelled on a non-linear
      basis, and the foreseeable lag times are also taken into account (i.e. by using
      explicative variable time lags). However, due to control not being perfect, it
      has been decided to opt for estimating an autoregressive Poisson model (adding in
      some different explicative variables time giving rise to a lag in the death rate)
      offsetting the residual autocorrelation. The main advantage of the method of
      analysis described above is that of making it possible to control confusing
      variables from a determinist standpoint with a software to which all of the
      groups taking part in this Project had access. This also affords the possibility
      of using this method in a set, standardized manner, facilitating the comparison
      of results and making an objective point analysis possible.

PMID- 10410598
TI  - [A review of original papers that analyze the effects of air pollution on
      mortality, 1994-1998].
AB  - The different studies published and indexed in Medline and in the Spanish Medical
      Index (IME) from 1984 up to 1998 (IME: 1971-1996) are reviewed. To start with, an
      assessment was made of the number of publications put out which have to do with
      the impact of pollution on human health as well as the percentage thereof which
      analyze the mortality as a health indicator. Afterward, the original works
      published within the January 1994-June 1998 period were reviewed in detail. Most
      of the original articles are combined time series studies which analyze, on a
      single-day basis, the relationship between the levels of pollution and the
      mortality for non-accidental causes. Other original articles were also summarized
      based on an approach other than the time series one, highlighting different
      cohort studies which relate the levels of pollution to the mortality on an
      individual level and which confirm the findings of prior ecological studies. The
      pollutants analyzed most often are the different types of particles, although
      studies are also common regarding the impact of sulfur dioxide, nitrogen dioxide,
      ozone and carbon monoxide. The method of analysis most used is the Poisson
      regression, into which different confusion variables bearing an impact thereon
      such as seasonality and tendency, temperature and relative humidity and day of
      the year are basically added. In the studies reviewed, the positive significant
      findings prevail, being consistent especially for particles, which is the
      pollutant most analyzed. The articles studying other pollutants, although fewer
      in number, also indicate a significant relationship between pollution levels and
      the mortality.

PMID- 10410599
TI  - [The EMECAM project: the Spanish Multicenter Study on the Relationship between
      Air Pollution and Mortality. The background, participants, objectives and
      methodology].
AB  - In recent years, a growing number of studies suggests that increases in air
      pollution levels may have short-term impact on human health, even at pollution
      levels similar to or lower than those which have been considered to be safe to
      date. The different methodological approaches and the varying analysis techniques
      employed have made it difficult to make a direct comparison among all of the
      findings, preventing any clear conclusions from being drawn. This has led to
      multicenter projects such as the APHEA (Short-Term Impact of Air Pollution on
      Health. A European Approach) within a European Scope. The EMECAM Project falls
      within the context of the aforesaid multicenter studies and has a wide-ranging
      projection nationwide within Spain. Fourteen (14) cities throughout Spain were
      included in this Project (Barcelona, Metropolitan Area of Bilbao, Cartagena,
      Castellon, Gijon, Huelva, Madrid, Pamplona, Seville, Oviedo, Valencia, Vigo,
      Vitoria and Saragossa) representing different sociodemographic, climate and
      environmental situations, adding up to a total of nearly nine million
      inhabitants. The objective of the EMECAM project is that to asses the short-term
      impact of air pollution throughout all of the participating cities on the
      mortality for all causes, on the population and on individuals over age 70, for
      respiratory and cardiovascular design causes. For this purpose, with an
      ecological, the time series data analyzed taking the daily deaths, pollutants,
      temperature data and other factors taken from records kept by public
      institutions. The period of time throughout which this study was conducted,
      although not exactly the same for all of the cities involved, runs in all cases
      from 1990 to 1996. The degree of relationship measured by means of an
      autoregressive Poisson regression. In the future, the results of each city will
      be combined by means of a meta-analysis.

PMID- 10410600
TI  - [The EMECAM protocol: an analysis of the short-term effect of air pollution on
      mortality. Estudio Multicentrico Espanol sobre la Relacion entre la Contaminacion
      Atmosferica u la Mortalidad].
AB  - The aim of this study is to Mortality show the protocol of analysis which was set
      out as part of the EMECAM Project, illustrating the application thereof to the
      effect of pollution has on the mortality in the city of Valencia. The response
      variables considered will be the daily deaths rate resulting from all causes,
      except external ones. The explicative variables are the daily series of different
      pollutants (black smoke, SO2, NO2, CO, O3). As possible confusion variables,
      weather factors, structural factors and weekly cases of flu are taken into
      account. A Poisson regression model is built up for each one of the four deaths
      series in two stages. In the first stage, a baseline model is fitted using the
      possible confusion variables. In the second stage, the pollution variables or the
      time legs thereof are included, controlling the residual autocorrelation by
      including mortality time lags. The process of fitting the baseline model is as
      follows: 1) Include the significant sinusoidal terms up to the sixth order. 2)
      Include the significant temperature or temperature squared terms with the time
      lags thereof up to the 7th order. 3) Repeat this process with the relative
      humidity. 4) Add in the significant terms of calendar years, daily tendency and
      tendency squared. 5) The days of the week as dummy variables are always included
      in the model. 6) Include the holidays and the significant time lags of up to two
      weeks of flu. Following the reassessment of the model, each one of the pollutants
      and the time lags thereof up to the fifth order are proven out. The impact is
      analyzed by six-month periods, including interaction terms.

PMID- 10410601
TI  - [The short-term effects of air pollution on mortality: the results of the EMECAM
      project in 2 cities of Asturias. Estudio Multicentrico Espanol sobre la Relacion
      entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: The studies conducted to date regarding the possibility that air
      pollutants, at levels considered safe to date, are capable of having impact are
      capable of having impact on human health have not led to homogeneous findings.
      This study is aimed at estimating the degrees of relationship between the daily
      levels of the pollutants and the death rate on a short-terms basis in the two
      most populated cities in Austria (Gijon and Oviedo), as well as contributing to
      increasing the statistical importance and the representative nature of the EMECAM
      Project, within which this study is comprised. METHODS: Ecological time series
      study, Estimate of degrees of group exposure based on the readings taken at the
      pollution control stations. Modeling of the death rate series, including control
      variables, by means of Poisson regression. Estimating risks related to each
      pollutant for the death rate, controlling the series-based autocorrelation.
      RESULTS: Throughout the 1993-1996 period, the pollution by means of particles in
      suspension and CO was greater in Gijon, that involving SO2 and NO2 having been
      greater in Oviedo. In these two cities, the levels can be considered to be low
      and to fall within what is considered admissible under the laws currently in
      impact. Most of the relative risk forecasts neared the zero impact point,
      although significant positive (especially for NO2) as well as negative
      relationships have been found to exist. The significant relationships found were
      not proven to be consistent in these two cities for the periods studied.
      CONCLUSIONS: Based on the findings of this study, the conclusion cannot be drawn
      that a clear-cut relationship exists between the pollutants studied (particles,
      SO2, NO2, CO) and the death rate on a short-term basis, at least at the levels
      detected in Gijon and Oviedo.

PMID- 10410602
TI  - [The short-term effects of air pollution on mortality. The results of the EMECAM
      project in the city of Barcelona, 1991-1995. Estudio Multicentrico Espanol sobre
      la Relacion entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: Most of the studies which demonstrate the existence of a short-term
      relationship between air pollution and morbidity and the Mortality analyze the
      impact of "classic" pollutants which are by-products of combustion. However, the
      changes in the sources of these emissions, shifting basically toward road
      traffic, has made a change in air pollution, heightening the importance of the
      photochemical components, such as ozone (O3) and nitrogen dioxide (NO2).
      Barcelona is a city located in a mild climate zone, and its air pollution comes
      mainly from vehicle emissions. The main objective of this article is that of
      analyzing the relationship between the photochemical pollutants, NO2 and O3 and
      the death rate for different causes in the city of Barcelona throughout the 1991
      1995 period, using the procedure for analysis set out as part of the EMECAM
      Project. METHODS: Daily changes in the number of deaths resulting from all
      causes, of the number of deaths for all causes of those over age 70, of the
      number of deaths resulting from cardiovascular diseases, and of the number of
      deaths resulting from respiratory-related causes are related to the daily changes
      in the photochemical pollutants using autoregressive Poisson models, controlling
      confusion-causing variables such as the temperature, the relative humidity, the
      systematic time structure and the autoregressive structure. RESULTS: Except for
      the relationship between O3 and the mortality for causes involving respiratory
      diseases, the relationships between photochemical pollutants and the mortality
      for all the causes considered were statistically significant. The risks related
      to dying as a result of rises in O3 were greater than as a result of rises in
      NO2, almost triple among cardiovascular diseases. The risks related to dying for
      all the causes are lower than for specific causes and than for those individuals
      over age 70. The results of the analysis by six-month periods are quite similar
      to the overall results, revealing, in any event, relative risks somewhat greater
      during the warm months (May to October). CONCLUSIONS: Photochemical pollution,
      especially that which is caused by O3, comprises a health risk. In the case of
      NO2, this might not be more than an indicators of the suspended particles or of
      other pollutants stemming from city traffic. There may be a certain adjustment
      between six-month periods of the impact of O3 on the mortality for causes of the
      circulatory system.

PMID- 10410603
TI  - [The short-term effects of air pollution on mortality: the results of the EMECAM
      project in greater Bilbao. Estudio Multicentrico Espanol sobre la Relacion entre
      la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: The objective of this study was to assess the short-term impact of
      air pollution with sulfur dioxide (SO2), total suspended particles (TSP),
      nitrogen dioxide (NO2) and black smoke (BS) on the daily number of deaths in the
      metropolitan area of Bilbao. METHODS: The EMECAM project protocol was followed.
      RESULTS: Increases in TSP, in both maximum hourly figures and daily averages, are
      significantly associated with increases in the daily number of deaths from all
      causes, from circulatory causes and from all causes among those older than 70. No
      differences between six-month periods were found. NO2 average levels were
      associated with daily mortality from respiratory causes in the entire period and
      during the warm season, and from all causes among those older than 70 in the cool
      months. CONCLUSIONS: TSP levels are associated with daily mortality in the
      metropolitan area of Bilbao. The relationship between NO2 and the number of
      deaths from respiratory causes, very high in the warm season, needs further
      research to assess its independence.

PMID- 10410604
TI  - [The short-term results of air pollution on mortality: the results of the EMECAM
      project in Cartagena, 1992-96. Estudio Multicentrico Espanol sobre la Relacion
      entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: The problems of air pollution became noticeable in Cartagena in the
      seventies, high SO2 and particle levels having been reached from time to time.
      Our aim is to assess, using the EMECAM methodology, the acute impact of SO2 and
      particle air pollution on the daily death rate of the city of Cartagena in the
      1992-1996 period. METHODS: A daily listing is provided of the total number of non
      accidental deaths within the population as a whole and for those over age 70, the
      cardiovascular and the respiratory deaths due to dioxide and particle air
      pollution for the 1992-1996 period using autoregressive Poisson models which
      control seasonality, weather, time of year, flu, special events, and time lags.
      RESULTS: In the period under study, there has been a drop in the SO2 air
      pollution as compared to previous years, which was not as marked for the
      particles. The analyses reveal significant relationships in the total non
      accidental deaths in those over age 69, with the average particle count and those
      particles with cardiovascular deaths for the months of May to October. In the six
      month period of the year, when the weather is cold, we found a positive
      statistically significant relationship to exist in the maximum daily hourly value
      of the particles and the deaths due to cardiocirculatory and respiratory
      diseases. However, there is no consistency in the between on assessing the
      reliability of the models.

PMID- 10410605
TI  - [The short-term effects of air pollution on mortality: the results of the EMECAM
      project in Castellon, 1991-95. Estudio Multicentrico Espanol sobre la Relacion
      entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: In the last decade several studies have found out an association
      between air pollution and mortality in levels below the standards allowed by
      regulations. Castellon is a small city (134,000 inhabitants) with low air
      pollution levels. This work aims to identify if there is a short term relation
      between these both variables in this city. METHODS: We used mortality data and
      air pollution data (black smoke and sulphur dioxide), from 1.991 to 1.995, doing
      an ecological study using a time series analysis with the day as unit of the
      analysis. Poisson regression allow us to get the relative risk adjusted by others
      variables (meteorological, trend, influenza, day of the week, season) in
      autoregresive models. RESULTS: Black smoke and SO2 daily means were respectively
      34.6 and 15.7 micrograms/m3. Results showed a 3.6% (IC95 0.3-7.0) of SO2 and 3.5%
      (IC95% 0.5-6.5) increment of cardiovascular mortality for an increment of 10
      micrograms/m3 of SO2 and black smoke respectively. Sulphur dioxide was positively
      associated with all four groups of mortality causes but only in cold season.
      CONCLUSION: Even in a small city with low air pollution levels, we found an
      association between air pollution and immediate mortality. In some cases, the
      analysis by periods (warm and cold) show an strong effect modification.

PMID- 10410606
TI  - [The short-term effects of air pollution on mortality: the results of the EMECAM
      project in the city of Huelva, 1993-96. Estudio Multicentrico Espanol sobre la
      Relacion entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: The objective of this study was to estimate the relationship between
      the levels of air pollution and the daily mortality in the city of Huelva for the
      1993-1996 period using the EMECAM methodology. METHODS: The number of daily
      deaths for all causes except external ones, the death rate of those over age 69,
      due to diseases of the circulatory system and for respiratory diseases were used
      as rate indicators. Four pollutants--SO2, PM10, NO2 and CO--were analyzed, the
      daily levels of which were furnished by the air pollution monitoring network in
      Huelva. Autoregressive Poisson regression models were constructed controlling by
      tendency, seasonality, temperature, humidity, flue and events out of the
      ordinary. RESULTS: For the mortality rate for all causes, a significant
      association impact was found to exist for the NO2 for the entire period (RR10
      microgram/m3: 1.0414; CI95%: 1.0047-1.0794) and for the particles (PM10) for the
      cold half of the year (RR10 microgram/m3: 1.0358; CI95%: 1.007-1.0722). For the
      mortality in people over age 69, a significant relationship was found to exist
      for SO2 throughout the entire period (RR10 microgram/m3: 1.0606; CI95%: 1.0020
      1.1227). A significant relationship to the mortality from respiratory disease
      particles (PM10) was found to exist for the cold half of the year (RR10
      microgram/m3: 1.1412; IC95%: 1.0300-1.2644). There was no association of
      contaminants with cardiovascular mortality; also there was no association between
      levels of CO and mortality indicators. CONCLUSIONS: In Huelva, significant
      relationships have been found to exist between the current levels of air
      pollution resulting from particles, SO2 and NO2 and the daily mortality. The
      impact of these pollutants on the mortality is coherent with scientific
      literature, although in the case of Huelva, the extremely small number of daily
      deaths due to its small population and other factors limit the consistency
      thereof.

PMID- 10410607
TI  - [The short-term effects of air pollution on mortality: the results of the EMECAM
      project in the municipality of Madrid, 1992-1995. Estudio Multicentrico Espanol
      sobre la Relacion entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: Despite the changes which have taken place in the sources of
      emissions, the levels of particles, SO2 and CO continue to be high in the
      municipality of Madrid. Apart from this, photochemical pollutants, such as NO2
      and O3 are taking on growing importance due to the increased number of cars and
      trucks on the road and the major degrees of sunlight in this city. The objective
      of this article is to set out the short-term relationship between the major
      pollutants and the daily death rate in the city of Madrid for the 1992-1995
      period, using the standardized procedure of the EMECAM Projects (Spanish
      Multicenter Study of Air Pollution and Death Rate). METHODS: The daily
      fluctuations in the death rate for all causes except external ones for all ages
      and for those individuals over age 69, in addition to those of the circulatory
      system and respiratory apparatus are related to the daily fluctuations in
      particles (PM10), SO2, NO2, CO and O3, by means of autoregressive Poisson
      regression models. The seasonality, tendency, temperature, relative humidity,
      flu, day of the week, holidays and events out of the ordinary are controlled.
      RESULTS: Statistically significant positive relationships were found to exist
      between SO2 and all of the death rate series analyzed, between CO and the death
      rate of individuals over age 69, as well as with cardiovascular and respiratory
      deaths and of the particles to the death rate as the result of cardiovascular
      disease. A statistically significant relationship was also found to exist between
      NO2 and the cardiovascular death rate. These impact are immediate, that is to
      say, they occur with the pollutants of the same day. No significant positive
      relationships were found to exist for O3. CONCLUSIONS: These findings suggest
      that, for a broad spectrum of major pollutants, the current levels of air
      pollution in Madrid are related to a rise in the death rate.

PMID- 10410608
TI  - [The short-term effects of air pollution on mortality: the results of the EMECAM
      project in the city of Pamplona, 1991-95. Estudio Multicentrico Espanol sobre la
      Relacion entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: To assess the short-term impact of air pollution on the daily death
      rate in the city of Pamplona. METHOD: Ecological study with a population of
      212,000 inhabitants. A time series data analysis is conducted by means of
      multiple linear regression and Poisson regression, with the daily death rate
      data, air pollution levels for Particles and SO2, weather parameters of average
      relative humidity and temperature daily and number of cases weekly of flu for the
      1991-1995 period. RESULTS: The average number of deaths daily for non-external
      causes is that of 4.15 deaths, with a range from zero to 13 deaths. The city of
      Pamplona has a mean annual temperature of 12.7 degrees C (-2.3 degrees C to 31.6
      degrees C) and a relative humidity of 68.5%. In the model, the temperature (with
      a one-day time lag and a six-day time lag temperature squared) and the humidity
      (with a one-day time lag) is related to the death rate for all causes. But the
      death rate for non-external causes is only related in the model with the
      temperature (one-day time lag, P: 0.035) and five-day time lag with temperature
      squared (p: 0.028). The timely estimates of the relative particle-related risk
      show that the highest risk of dying stems from respiratory causes with a relative
      risk of 1.13. However, none of these relationships is statistically significant.
      In the case of Sulfur Dioxide, the estimates closely near the zero figure, and
      none of them is significant. CONCLUSIONS: The Temperature has an impact of the
      death rate for all causes, both external and non-external, and the relative
      humidity solely has an impact on the death rate for non-external causes. It has
      not been possible to prove any influence of the daily environmental pollution
      levels on the daily death rate.

PMID- 10410609
TI  - [The short-term effects of air pollution on mortality. The results of the EMCAM
      project in the city of Seville, 1992-1996. Estudio Multicentrico Espanol sobre la
      Relacion entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: As part of the EMECAM Project, the objective of this study is that of
      assessing the impact of air pollution on the daily mortality in Seville
      throughout the 1992-1996 period. METHODS: During the 1992-1996 period, readings
      were taken daily of the amounts of SO2, particles in suspension (PM10) and NO2
      present in the air in the city of Seville, in addition to the number of deaths
      daily due to different causes. For analyzing this data, a multivariable Poisson
      regression model was used for modeling each one of the causes of death in terms
      of the air immission readings, controlling other confusion-causing variables.
      RESULTS: A relationship was found to exist between the rises in the NO2 levels
      and the daily death rate throughout the months of May to October. For each 10
      micrograms/m3 rise, the risk of death or all causes showed a 2% rise, the same
      rise in the NO2 levels leading to a 3% rise in the risk of death resulting from
      cardiovascular diseases. CONCLUSIONS: A relationship exists between the levels of
      NO2 air pollution and the daily death rate in Seville. The findings provide
      scientific knowledge and information which can be of use for preventing the
      impact of air pollution on human health.

PMID- 10410611
TI  - [The short-term effects of air pollution on mortality. The results of the EMECAM
      project in the city of Vigo, 1991-94. Estudio Multicentrico Espanol sobre la
      Relacion entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: In the Autonomous Region of Galicia, no study has been made of the
      impacts of air pollution on human health, despite the fact that several of its
      major cities have moderate levels of pollution. Therefore, we have considered the
      need of making this study in the city of Vigo. The main objective of this
      analysis is that of analyzing the short-term impact of air pollution on the daily
      death rate for all reasons in the city of Vigo throughout the 1991-1994 period,
      by using the procedure for analysis set out as part of the EMECAM Project.
      METHOD: The daily fluctuations in the number of deaths for all causes with the
      exception of the external ones are listed with the daily fluctuations of sulfur
      dioxide and particles using Poisson regression models. A non-parametric model is
      also used in order to better control the confusion variables. RESULTS: Using the
      Poisson regression model, no significant relationships have been found to exist
      between the pollutants and the death rate. In the non-parametric model, a
      relationship was found between the concentration of particles on the day
      immediately prior to the date of death and the death rate, an effect which
      remains unchanged on including the autoregressive terms. CONCLUSIONS: Particle
      based air pollution is a health risk despite the average levels of this pollutant
      falling within the air quality guideline levels in the city of Vigo.

PMID- 10410610
TI  - [The short-term effects of air pollution on mortality. The results of the EMECAM
      project in the city of Valencia, 1994-96. Estudio Multcentrico Espanol sobre la
      Relacion entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: To determine the short-term impact of air pollution on mortality in
      the city of Valencia throughout the 1994-1996 period by employing the analysis
      method of the Spanish multicenter study with regard to the relationship between
      air pollution and the mortality (EMECAM Project). METHODS: The daily levels of
      black smoke, sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO)
      and ozone (O3) were obtained from the Valencia air pollution monitoring network.
      The death rate indicators analyzed were the daily number of death due to all
      causes, except the external ones, the deaths of those over age 70, and the deaths
      resulting from respiratory and cardiovascular diseases. Following the methods of
      the EMECAM Project, autoregressive Poison regression models were built up,
      controlling the different confounding factors (seasonality, trend, calendar,
      weather variables and flu impact). RESULTS: For total mortality except the
      external ones, a significant impact of black smoke (RR 10 micrograms/m3: 1.013;
      CI95% 1.003 to 1.023) and for CO 24 la (RR 1 mg/m3: 1.024; CI95% 1.003 to 1.046)
      was found. For the mortality of those individuals over 70, the estimated impact
      was somewhat greater than for black smoke (RR 10 micrograms/m3: 1.017; CI95%
      1.005-1.029), as well as for CO2 1 h (RR 10 micrograms/m3: 1.007; CI95% 1.001
      1.013). No significant relationship was found with the mortality due to
      respiratory or cardiovascular diseases for the entire period. CONCLUSIONS: The
      current levels of pollution in the city of Valencia show a significant impact on
      daily mortality. These findings are consistent with the previous research and are
      coherent with those obtained on analyzing the relationship between air pollution
      and morbidity indicators.

PMID- 10410612
TI  - [The short-term effects of air pollution on mortality. The results of the EMECAM
      project in Vitoria-Gasteiz, 1990-94. Estudio Multicentrico Espanol sobre la
      Relacion entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: The objective of this article is that of assessing the short-term
      relationship between the black smoke (SM) and SO2 levels and the mortality in
      Vitoria-Gasteiz over a five-year period by means of employing the procedure for
      analysis standardized in the EMECAM Project. METHODS: Ecological time series
      study aimed at estimating the relationship between the daily fluctuations in the
      mortality (total mortality of all ages and total death rate for those over age
      70) and air pollution (sulfur dioxide-SO2 and black smoke), employing the Poisson
      regression models. The EMECAM methodology was followed. RESULTS: The median of
      daily deaths was three for the entire population and two for the elderly. The
      mean black smoke level was 51.15 micrograms/m3 and that of SO2 18.04
      micrograms/m3. A statistically significant relationship was found to exist
      between black smoke and the mortality for the elderly through the cold half of
      the year, with an RR of 1.014 (CI95%: 1.002-1.026), pertinent to a 10
      micrograms/m3 rise in the pollutant. A threshold at 80-90 micrograms/m3 seemed to
      be detected for black smoke. The relationship with SO2 was not significant.
      CONCLUSIONS: The black smoke levels for the period studied are related to a rise
      in the mortality among the elderly, tallying with the results of other studies.

PMID- 10410613
TI  - [The short-term effects of air pollution on mortality. The results of the EMECAM
      project in Saragossa, 1991-1995. Estudio Multicentrico Espanol sobre la Relacion
      entre la Contaminacion Atmosferica y la Mortalidad].
AB  - BACKGROUND: To assess the short-term impact of pollution on the respiratory death
      rate in the city of Saragossa throughout the 1991-1995 period and to pinpoint
      whether any differences exists in terms of age and time of the year. METHODS: The
      relationship of daily concentrations of smog and SO2 to the daily deaths due to
      respiratory diseases (CIE-9 460-486) and chronic lung blockage disease and
      similar EPOC-EA (490-496) was analyzed using Poisson models in keeping with the
      EMECAM procedure. Possible differences in the impact on those below and over age
      70 and according to the six-month period in question were researched. Relative
      risks (RR) and 95% confidence, intervals (CI95%) WERE CALCULATED FOR 10
      micrograms/m3 rises in pollutant. RESULTS: A relationship was found to exist
      between the respiratory and smog death rate (RR 1.028 CI95% 1.006-1051), the
      highest risk being during the six-months period of warm weather. For those
      individuals over age 70, the relationship remained the same throughout this six
      month period and was negative for those individuals under age 70. The RR's for
      the death rate based on EPOC-EA were, overall, 1.038 (CI95% 1.002-1075) and of
      1.068 (CI95%: 1.004-1.137) for the six-month period of warm weather. The SO2
      pollution showed a positive relationship to the respiratory death rate for the
      warm period for all ages, RR 1.093 (CI95%: 1.006-1.187) and for those under age
      70 (RR 1.240 CI95%: 1.028-1.496). The impact was not conclusive for the cases of
      pneumonia. CONCLUSIONS: Low levels of air pollution can have a significant impact
      on the respiratory death rate, especially among the elderly and during the six
      month period of warm weather.

PMID- 10410614
TI  - [The EMECAM project: a discussion of the results in the participating cities.
      Estudio Multicentrico Espanol sobre la Relacion entre la Contaminacion
      Atmosferica y la Mortalidad].
AB  - This article draws a comparison and provides a discussion of the findings
      resulting from the local analyses of the 14 cities participating in the EMECAM
      Project. An analysis is made of the time series related to mortality, pollutants
      (particles in suspension, SO2, NO2, O3 and CO), temperature and other factors
      taken from records of public institutions. By using Poisson autoregressive
      regression, an estimate has been made of the short-term relationship between the
      number of deaths and the air pollution indicators in each one of the following
      cities: Barcelona, metropolitan area of Bilbao, Cartagena, Castellon, Gijon,
      Huelva, Madrid, Pamplona, Seville, Oviedo, Valencia, Vigo, Vitoria and Saragossa.
      The findings reveal the air pollution figures in our country to be similar to
      those of other European cities. The levels of the different pollutants point
      toward road traffic as being the main source of most of this pollution. A
      relationship has been found between the mortality and different pollutants in
      most cities, although the results are not homogeneous among the cities and show
      variability in the different causes under study. In some cities, especially in
      those having smaller populations, there have been no findings providing any
      evidence of a relationship, or the findings themselves are not highly consistent.
      The meta-analysis will provide estimates for all of the cities as a whole and
      will allow the possibility of making a more clear-cut assessment of the time lag
      impact of air pollution on the mortality. Worthy of special mention is the
      participation in this project of public health officers as actively involved
      researchers.

PMID- 10410615
TI  - The effect of waitresses' touch on alcohol consumption in dyads.
AB  - A total of 96 men and 48 women participated in a study on the effect of touch in
      the natural setting of public taverns in the United States. Participants in the
      same-gender (men-men) or mixed-gender dyads were either touched or not touched by
      waitress confederates. Regardless of dyad type, participants who were touched
      consumed more alcohol than participants who were not touched. Men in the mixed
      gender dyads consumed more alcohol when the women was touched. Same-gender (men
      men) dyads aggregately consumed more alcohol than mixed-gender dyads. The results
      are interpreted in terms of the environmental cues and the dynamics of the group.

PMID- 10410616
TI  - The effects of mood on managerial risk perceptions: exploring affect and the
      dimensions of risk.
AB  - The effects of managerial mood on situational risk perceptions were tested among
      85 managers from a variety of organizations, industries, and positions in
      Singapore. A risk-assessment scenario was developed that systematically varied
      the risk dimensions of outcome uncertainty, potential gains and losses,
      situational framing, and personal expectations. Negative, neutral, and positive
      moods were induced by having managers recall and describe work events. As
      affective state became more positive, managers perceived situational framing as
      more positive, and their beliefs that they could influence risky outcomes
      increased. Additionally, positive affect increased the likelihood that people who
      perceived situations as risky would select riskier courses of action.

PMID- 10410617
TI  - Ethnic identity and its relation to personal self-esteem: a comparison of
      Canadian-born and foreign-born Chinese adolescents.
AB  - Ethnic identity and its relation to personal self-esteem were examined by
      comparing 31 Chinese adolescents who immigrated to Canada and 31 Chinese
      adolescents who were Canadian born. The foreign-born adolescents were more likely
      to identify themselves as Chinese (rather than Chinese Canadian) and to include
      references to their ethnicity in response to an open-ended Who Am I
      Questionnaire, a variation of the Twenty Statements Test (M. H. Kuhn & T. S.
      McPartland, 1954). For the foreign-born group only, aspects of collective self
      esteem were positively related to personal self-esteem. The differences between
      the groups supported a contextual emphasis for associating collective self-esteem
      with personal self-esteem. The data were consistent with an interpretation
      involving collectivistic-individualistic distinctions, with the foreign-born
      sample being more collectivistic.

PMID- 10410618
TI  - Victim-blaming tendency toward people with AIDS among college students.
AB  - The victim-blaming tendency toward people with AIDS was examined in relation to
      gender, fraternity-sorority affiliation, classification (freshmen vs. others),
      religion (Catholic vs. others), and academic major (business college vs. others)
      in a survey of 818 students at a midwestern state university in the United
      States. Desired social distance from gay men and lesbians, the intervening
      variable in these relations, significantly mediated the indirect effect of
      fraternity-sorority affiliation, classification, and gender on the victim-blaming
      tendency. Gender and desired social distance were found to be significant direct
      determinants of the victim-blaming tendency toward people with AIDS. The study
      suggests that attitudes toward gay men and lesbians must change if attitudes
      toward people with AIDS are to change.

PMID- 10410619
TI  - Covert discrimination against gay men by U.S. college students.
AB  - This study examined the use of sexual orientation as a meaningful social category
      and the consequences of using this category. The sample consisted of 260 U.S.
      college students who viewed a video and completed a 29-item scale (L. L. Thompson
      & J. Crocker, 1990) and the 7-item Homophobia Scale (R. A. Bouton et al., 1987).
      Results showed that participants' adjective ratings of targets favored gay men.
      Participants did not exhibit greater bias toward gay men when provided with
      justification. However, there was a pattern of bias in which participants showed
      favoritism toward heterosexual male targets when provided with no justification
      for bias.

PMID- 10410620
TI  - Dispositional and situational goal orientations as discriminators among
      recreational and competitive league athletes.
AB  - The present study examined the relationship between individual goal orientation,
      motivational team climate, perceived sport competence, and league structure among
      216 youth soccer players. It was predicted that competitive league teams would
      report higher ego-involvement and performance-oriented team climate and lower
      sport competence than recreational teams. Discriminant analyses indicated that
      only the mastery-oriented team climate variable differentiated competitive and
      recreational teams. Athletes who participated in recreational teams reported a
      greater degree of mastery-oriented climate than competitive league players. The
      results suggest that athletes' perceptions of situational rather than
      dispositional aspects of achievement goals are more highly affected by the
      playing structure present in youth sport teams. The possible psychological
      benefits derived from the development of a mastery-oriented team climate in
      sports are discussed.

PMID- 10410621
TI  - The effects of women's age and physical appearance on evaluations of
      attractiveness and social desirability.
AB  - Younger people are perceived as possessing a host of socially desirable
      attributes, some of which are the same traits attributed to attractive people. In
      the present study, 160 younger and older White Canadians rated the attractiveness
      and personality traits of 1 of 4 target women. The results indicated an
      interaction between the participant's age and gender and the age and
      attractiveness of the target person. Both younger and older judges showed an
      attractiveness bias and downrated the social desirability of younger unattractive
      targets. Younger judges rated younger and older attractive targets as equal in
      social desirability. Older male judges rated older attractive targets as less
      socially desirable than younger attractive targets. Results are discussed in
      terms of cultural expectations of beauty.

PMID- 10410622
TI  - The effects of gender and music video imagery on sexual attitudes.
AB  - This study examined the influence of gender and exposure to gender-stereo-typed
      music video imagery on sexual attitudes (adversarial sexual beliefs, acceptance
      of rape myths, acceptance of interpersonal violence, and gender role
      stereotyping). A group of 44 U.S. college students were randomly assigned to 1 of
      2 groups that viewed either a video portraying stereotyped sexual imagery or a
      video that excluded all sexual images. Exposure to traditional sexual imagery had
      a significant main effect on attitudes about adversarial sexual relationships,
      and gender had main effects on 3 of 4 sexual attitudes. There was some evidence
      of an interaction between gender and exposure to traditional sexual imagery on
      the acceptance of interpersonal violence.

PMID- 10410623
TI  - Effects of parenting on the peer relations of Australian adolescents.

PMID- 10410624
TI  - Some psychological correlates of population density in east Africa.

PMID- 10410625
TI  - The role of neuroticism in test and social anxiety.

PMID- 10410626
TI  - Antibiotic resistance: the agricultural connection.

PMID- 10410627
TI  - Update on the new virus in Malaysia.

PMID- 10410628
TI  - New method for prostate exam.

PMID- 10410629
TI  - Alternative views on alternative therapies.

PMID- 10410630
TI  - Saskatchewan physicians' attitudes and knowledge regarding assessment of medical
      fitness to drive.
AB  - BACKGROUND: Although legislation has been introduced in Saskatchewan for
      mandatory reporting by physicians of patients considered medically unfit to
      drive, little is known about physicians' attitudes, knowledge or resources with
      regard to evaluating medical fitness to drive. METHODS: The objective of this
      study was to determine Saskatchewan physicians' attitudes, knowledge, training,
      resources and current educational needs with regard to evaluating medical fitness
      to drive. A questionnaire survey of all physicians in the province who were
      identified as likely to be involved in determining medical fitness to drive was
      conducted between October and December 1996. RESULTS: Of the 1102 physicians who
      received a questionnaire, 690 (62.6%) responded, of whom 167 were excluded
      because they were not involved in assessing fitness to drive. Thus, 523 (55.9%)
      of the 935 eligible physicians surveyed completed the questionnaire. Most (57.6%
      [298/517]) of the respondents indicated that they do not hesitate to report
      patients medically unfit to drive; however, 59.5% (307/516) felt that the
      physician-patient relationship is negatively affected by reporting. Overall,
      85.5% (444/519) of the respondents felt that restricted licensing is a fair
      alternative for people who might otherwise be denied a full licence. The
      availability of restricted licensing positively influenced the decision to report
      for 60.3% (313/519) of the respondents. Significantly more rural physicians than
      urban physicians believed that the need to drive was greater for rural residents
      than for urban dwellers (81.2% [95/117] v. 64.2% [257/400], p < 0.001). Physician
      knowledge regarding specific medical conditions and fitness to drive was
      generally poor. The resource most commonly used in determining medical fitness to
      drive was the Physicians' Guide to Driver Examination (71.1% [361/508] of
      respondents). The most useful continuing medical education methods indicated by
      physicians for assessing medical fitness to drive included conference
      presentations, workshops and journal articles. INTERPRETATION: Most of the
      Saskatchewan physicians surveyed supported restricted licensing, and the
      availability of restricted licensing made them more likely to report patients
      considered medically unfit to drive. The physician-patient relationship was felt
      to be negatively affected by reporting.

PMID- 10410632
TI  - Physicians' perceptions of the effect on clinical services of an alternative
      funding plan at an academic health sciences centre.
AB  - BACKGROUND: In July 1994 an alternative funding plan for clinical services
      (global funding instead of fee-for-service payment) was established at the
      Southeastern Ontario Health Sciences Centre, Kingston, Ont. This study describes
      the perceptions of the referring physicians and consultants of the effects of the
      alternative funding plan 2.5 years after it was initiated. METHODS: A
      questionnaire was mailed to all physicians in the Kingston area in November 1996.
      Information was collected on demographics, referring physicians' perceptions of
      the funding plan's impact on their practices, consultants' perceptions of its
      impact on their activities, perceptions of referring and consultant physicians of
      its impact on services provided by consultants, and attitudes toward alternative
      funding in the context of the Ontario health care system. RESULTS: Of the 772
      physicians 531 (68.8%) returned a completed questionnaire (323 referring
      physicians and 208 consultants). A sizeable proportion of the referring
      physicians (126 [39.0%]) indicated that they were referring fewer patients to
      consultants at the study centre. They did not think that their practice volume
      had increased, but they did report spending more time on complex cases and on
      patient care after referral or hospital stay, and more time coordinating
      community care after hospital stay. Of the consultants 81 (38.9%) believed that
      their time spent on patient care had increased. No consistent impact on time
      spent on research or teaching activities was perceived. A total of 54 (26.0%) of
      the consultants were concerned about the impact of the alternative funding plan
      on quality of care. A significant proportion of the respondents (399 [75.1%])
      believed that outpatient waiting times had increased, and 116 (35.9%) of the
      referring physicians believed that consultants were not as available by
      telephone. Most (220 [68.1%]) of the referring physicians believed that the
      funding change had had a negative effect on health care services in the region,
      and 87 (41.8%) of the consultants agreed. Nevertheless, the respondents believed
      that other factors such as funding cuts, hospital bed closures and staff layoffs
      were much more responsible than the alternative funding plan for their negative
      perceptions. INTERPRETATION: The alternative funding plan appears to have had an
      impact on the practices of individual physicians. However, it was not the focus
      for significant opposition or support from either consultants participating in
      the funding plan or referring physicians.

PMID- 10410631
TI  - Decision-making for long-term tube-feeding in cognitively impaired elderly
      people.
AB  - BACKGROUND: The decision to start long-term tube-feeding in elderly people is
      complex. The process by which such decisions are made is not well understood. The
      authors examined the factors involved in the decision to start long-term tube
      feeding in cognitively impaired older people from the perspective of the
      substitute decision-maker. METHODS: A telephone survey was administered to the
      substitute decision-makers of tube-fed patients over 65 years old in chronic care
      facilities in Ottawa. Subjects were recruited from September 1997 to March 1998.
      Patients were incapable of making their own decisions about tube-feeding. Data
      were collected on sociodemographic factors, patients' health status, advance
      directives, communication between the substitute decision-maker and the health
      care team, and the decision-maker's perceived goals of tube-feeding and
      satisfaction with the decision regarding tube-feeding. RESULTS: Among the 57
      cases in which the patient was eligible for inclusion in the study, 46 substitute
      decision-makers agreed to participate. Most of the patients had not given advance
      directives, and only 26 substitute decision-makers (56.5%) were confident that
      the patient would want to be tube-fed. A physician spoke with the substitute
      decision-maker about tube-feeding for 15 minutes or less in 17 cases (37.0%) and
      not at all in 13 cases (28.3%). Most of the substitute decision-makers (39
      [84.8%]) felt that they understood the benefits of tube-feeding, but less than
      half (21 [45.7%]) felt that they understood the risks. The prevention of
      aspiration and the prolongation of life were the medical benefits most often
      cited as reasons for tube-feeding. Just over half (24 [52.2%]) of the substitute
      decision-makers felt that they had received adequate support from the health care
      team in making the decision. Substitute decision-makers of patients less than 75
      years old were more likely than those of older patients to feel supported (odds
      ratio [OR] 4.2, 95% confidence interval [CI] 1.0-17.9). Compared with the
      physician's making the decision independently, substitute decision-makers felt
      more supported if they primarily made the decision (OR 16.5, 95% CI 2.7-101.4) or
      if they made the decision together with the physician (OR 5.3, 95% CI 1.0-27.9).
      Most (20 [43.5%]) of the substitute decision-makers did not feel that tube
      feeding improved the patient's quality of life, and less than half (21 [45.7%])
      indicated that they would choose the intervention for themselves. INTERPRETATION:
      The substitute decision-making process for tube-feeding in cognitively impaired
      elderly people is limited by a need for advance directives, lack of confidence in
      substituted judgement and poor communication of information to the substitute
      decision-maker by the health care team.

PMID- 10410633
TI  - [Identifying the requirements for formulating medical ethics: a methodology with
      clinical emphasis].

PMID- 10410634
TI  - Fetal exposure to oral isotretinoin: failure to comply with the Pregnancy
      Prevention Program.

PMID- 10410635
TI  - Substitute decision-making for cognitively impaired older people.

PMID- 10410636
TI  - Oral isotretinoin: prescribers beware.

PMID- 10410637
TI  - Tuberculosis: 7. Laboratory aspects of diagnosis.

PMID- 10410638
TI  - Canadian health expenditures: where do we really stand internationally?
AB  - There are different ways to measure how much Canada spends on health care and the
      quality of these measurements may vary. This paper examines Organization for
      Economic Cooperation and Development data for 3 common standards of measure:
      health expenditures as a proportion of gross domestic product (GDP), nominal
      spending per capita (US dollars) and spending per capita in purchasing power
      parities (PPP) equivalents. In 1994, the most recent year for which there were
      firm data. Canada spent 9.9% of its GDP on health care (rank 3 of 29), and $1999
      PPPs per capita (rank 3). However, actual spending was only US$1824 per capita
      (rank 14). In the same year Japan spent 7% of GDP on health care (rank 22), $1478
      in PPPs per capita (rank 16), but actually spent US$2614 per capita (rank 3).
      Although each measure is suitable for some policy purposes, Canadian spending
      remains modest by international standards.

PMID- 10410639
TI  - A physician-centred intervention to shorten hospital stay: a pilot study.
AB  - BACKGROUND: Studies of length of stay (LOS) in hospital usually focus on
      physician-independent factors. In this study, the authors identified physician
      dependent factors and tested an intervention aimed at them to determine its
      effect on LOS. METHODS: A prospective comparison of LOS on 2 general medical
      wards in a tertiary care teaching hospital before and after the intervention. The
      pre-intervention (control) period and the intervention period were each 4 weeks.
      The intervention consisted of a checklist for planning management and discharge.
      RESULTS: Overall, the mean LOS was shorter during the intervention period than
      during the control period, but the difference was not statistically significant
      (12.0 and 14.4 days respectively, p = 0.13). The difference was significant on
      ward A (11.0 v. 14.7 days respectively, p = 0.02) but not on ward B (13.0 and
      14.0 days respectively, p = 0.90). INTERPRETATION: An intervention at the level
      of the admitting physician may help to shorten LOS on a general medical ward.

PMID- 10410640
TI  - Canadian Consensus Conference on Dementia: a physician's guide to using the
      recommendations.

PMID- 10410641
TI  - Mapping your way through MEDLINE.

PMID- 10410642
TI  - The Canada Health Act goes on trial.

PMID- 10410643
TI  - Easier-to-use fitness-to-drive guide on way from CMA.

PMID- 10410644
TI  - Fear of black market means no RU-486 for Canada until US approves drug.
AB  - Mifepristone, the "abortion pill" that is better known as RU-486, is no closer to
      arriving in Canada than it was 8 years ago. But that fact hasn't slowed debate
      about the product.

PMID- 10410645
TI  - The recognition, assessment and management of dementing disorders: conclusions
      from the Canadian Consensus Conference on Dementia.
AB  - OBJECTIVE: To develop evidence based consensus statements on which to build
      clinical practice guidelines for primary care physicians toward the recognition,
      assessment and management of dementing disorders and to disseminate and evaluate
      the impact of these statements and guidelines built on these statements. OPTIONS:
      Structured approach to assessment, including recommended laboratory tests,
      choices for neuroimaging and referral, management of complications (especially
      behavioural problems and depression) and use of cognitive enhancing agents.
      POTENTIAL OUTCOMES: Consistent and improved clinical care of persons with
      dementia; cost containment by more selective use of laboratory investigations;
      neuroimaging and referrals; and appropriate use of cognitive enhancing agents.
      EVIDENCE: Authors of each background paper were entrusted to perform a literature
      search, discover additional relevant material, including references cited in
      retrieved articles, consult with other experts in the field and then synthesize
      information. Standard rules of evidence were applied. Based on this evidence,
      consensus statements were developed by a group of experts, guided by a steering
      committee of 8 individuals, from the areas of Neurology, Geriatric Medicine,
      Psychiatry, Family Medicine, Preventive Health Care and Health Care Systems.
      VALUES: Recommendations have been developed with particular attention to the
      context of primary care, and are intended to support family physicians in their
      ongoing assessment and care of patients with dementia. BENEFITS HARM AND COSTS:
      Potential for improved clinical care of people with dementia. A dissemination and
      evaluation strategy will attempt to measure the impact of the recommendations.
      RECOMMENDATIONS: Forty-eight recommendations are offered that address the
      following aspects of dementia care: early recognition; importance of careful
      history and examination in making a positive diagnosis; essential laboratory
      tests; rules for neuroimaging and referral; disclosure of diagnosis; importance
      of monitoring and providing support to caregivers; cultural aspects; detection
      and treatment of depression; observation and management of behavioural
      disturbances; detection and reporting of unsafe motor vehicle driving; genetic
      factors and opportunities for preventing dementia; pharmacological treatment with
      particular emphasis on cognitive enhancing agents. VALIDATION: Four other sets of
      consensus statement or guidelines have been published recently. These
      recommendations are generally congruent with our own consensus statements. The
      consensus statements have been endorsed by relevant bodies in Canada.

PMID- 10410646
TI  - Management of pancreatic injuries.

PMID- 10410647
TI  - [Infection therapy in neutropenia].

PMID- 10410648
TI  - [Antimicrobial therapy for fever of unknown origin in neutropenia. Standard
      recommendations of the Work Group of Infections in Hematology and Oncology of the
      German Association of Hematology and Oncology].

PMID- 10410649
TI  - [Interventional antimicrobial therapy for febrile complications after high-dose
      chemotherapy and autologous stem cell transplantation. Standard recommendations
      of the Work Group of Infections in Hematology and Oncology of the German
      Association of Hematology and Oncology].

PMID- 10410650
TI  - [Sepsis in neutropenia. Standard recommendations of the Work Group of Infections
      in Hematology and Oncology of the German Association for Hematology and
      Oncology].

PMID- 10410651
TI  - [Diagnosis and therapy of lung infiltrates in febrile neutropenic patients.
      Standard recommendations of the Work Group of Infections in Hematology and
      Oncology of the German Association of Hematology and Oncology].

PMID- 10410652
TI  - [Diagnosis of systemic fungal infections in hematology. Standard recommendations
      of the Working Group for Infections in Hematology and Oncology of the German
      Association for Hematology and Oncology].

PMID- 10410653
TI  - [Advances in cancer research. Cancer research and clinical oncology in the 21st
      century].
AB  - It is my great pleasure to congradulate the Japanese Journal of Cancer and
      Chemotherapy on its 25 th anniversary. During this period, great progress has
      been made in cancer research, mainly owing to the advances in technology in
      molecular biology. Recently, not only researchers, but lay people as well have
      come to understand that cancer is mainly a genetic disease. Advances in the human
      genome project, DNA chip technology and gene technology; including gene targeting
      and cloning techniques, will enable us to accelerate progress forward the final
      goal of cancer research in the coming century. Major changes are coming in both
      cancer research and clinical oncology, which will completely transform the human
      social environment.

PMID- 10410654
TI  - [Trends in surgical treatment in various malignancies].
AB  - Broad resections, both more extensive and en bloc, have come to be the standard
      surgical treatment for malignant tumors. However, because there is a fair
      incidence of postoperative complication and sequela, and the application selected
      is not always appropriate in all cases, the prognosis with such treatment has not
      improved as much as was expected. In the 1980 s, as the biological
      characteristics of tumors came to be better understood, advances in treatments
      other than surgery and a greater awareness of the patient's QOL brought increased
      use of minimally invasive surgery techniques such as function preserving reduced
      operations and microscopic surgery. Optimum surgical techniques with no excess or
      insufficiency are sought--the major requisite being an undiminished prognosis-
      but more time is required before such treatments can be established.

PMID- 10410655
TI  - [History of radiotherapy for cancer].
AB  - The basic principle of radiotherapy for cancer patients is to establish a course
      of therapy which offers good prospects for a cure, has tolerable adverse effects,
      and promises a comfortable life for the patient thereafter. There have been two
      paths in the development of radiotherapy. One is physical, in which efforts have
      been made to improve the dose concentration on the tumor while avoiding healthy
      tissue, and the order is biological efforts to increase radiation susceptibility
      of tumors. Recently, computer medicine has improved radiation planning and made
      high quality radiotherapy possible. Elderly patients with cancer need to be
      treated with minimally invasive organ-preserving therapy techniques. Radiotherapy
      is an important tool for cancer treatment in the past, present and future.

PMID- 10410656
TI  - [Advance in cancer chemotherapy].
AB  - From the middle of the 20th Century, many anticancer drugs have been developed,
      and about 40 kinds of anticancer drugs are currently have been used for cancer
      treatment. From the past pre-clinical and clinical studies, it was found that
      combination of two or more drugs was sometimes more effective than the single
      use, resulting the increase of cure-rates in some-type of human malignancies.
      Recently, new treatment regimens based on the concept of biochemical modulation
      have been used for the treatment of cancer of the digestive organs. Also,
      currently, supportive therapies against the adverse-drug reactions (side effects)
      became available, and sometimes improvement of QOL of the cancer patients has
      been expected with the use of these therapies. In facing to the 21st Century,
      studies of new type of drugs such as those to novel molecular targets have been
      progressing.

PMID- 10410657
TI  - [Recent progress in biological therapies for cancer].
AB  - After approval of national health insurance for non-specific immunomodulation
      such as OK-432 (1978) and PSK (1980), lentinan, SPG, bestatin and dried BCG
      vaccine have been tried. Including cytokines such as IL-2, IL-12, IFN, TNF or
      monoclonal antibodies, they have been widely used as biological response
      modifiers (BRM). Progress in BRM therapy may be broken down into the first 10
      years as development, the next 10 years as disappointment and the most recent 5
      years as dream-like progress owing to molecular biological techniques. An
      interdisciplinary approach has been taken by the Japanese Research Society for
      Surgical Cancer Immunology, founded in 1980, and the Japanese Society of BRM
      founded in 1988. Many investigations have been performed on issues such as the
      clinical evaluation or criteria for responder cases, host immunocompetency, post
      operative adjuvant immuno-chemotherapy, locoregional immunotherapy, cytokine
      therapy, adoptive immunotherapy, and tumor specific immunotherapy. Attention has
      also focused on malignant tumor injury, surgical stress, the advantages or
      disadvantages of splenectomy, and discussions of the current status and future
      prospects in the next century for new BRM therapy.

PMID- 10410658
TI  - [Advances in endoscopic therapies for cancers of the digestive tract].
AB  - Endoscopic therapies for the treatment of cancers of the digestive tract have
      been improved. Today, some early cancers can be curatively treated by endoscopy
      (endoscopic polypectomy, endoscopic mucosal resection, heatprobe method, etc.).
      In addition, endoscopic local injection chemotherapy is performed for some
      advanced cancers as an adjuvant therapy. Recent progress in endoscopic therapies
      for cancer is reviewed in this paper, including their historical background.
      Improvements in these endoscopic treatment methods are expected to provide
      increased advantages for the treatment of patients with cancer in the near
      future.

PMID- 10410659
TI  - [The advances of gene therapy in this quarter century].
AB  - Progress of molecular biological technology has brought about great advances in
      gene therapy. The establishment of DNA recombination and transfection techniques
      in 1980s allowed us to utilize gene as therapeutics. Since the initial clinical
      trial of gene therapy in 1990, over 250 of clinical protocols have been undergone
      in United States and over two thousand patients have been enrolled in gene
      therapy in worldwide. First gene therapy protocol was carried out in 1995 and
      cancer gene therapy was just started last year in our country. The overview of
      gene therapy in this quarter century was described and also the development of
      gene therapy related technologies was mentioned in this review.

PMID- 10410660
TI  - [Recent advances of supportive therapy for cancer patients].
AB  - Over 25 years ago survival was the sole aim in the management of cancer patients.
      However, over the past 25 years quality of life (QOL) as well as survival has
      become increasingly important in the treatment of cancer. In other words,
      treatment modalities without good QOL are no longer accepted. Thus, supportive
      therapies for cancer patients are very important. These supportive therapies fall
      into two categories. One is the management of adverse events induced by cancer
      therapies such as surgery, radiotherapy or chemotherapy. Adverse events induced
      by the administration of anti-cancer drugs in particular must be managed to
      maintain QOL. The second category is the management of pain, cachexia, metabolic
      disorders or mental depression induced by the existence of cancer. Over these 25
      years major advances have been observed in the supportive therapy for cancer
      patients. These include the development of colony-stimulating factor (CSF) agents
      and the anti emetic agents such as serotonin-receptor inhibitors. These two
      agents have contributed to the relief of drug-induced adverse events. Opioids
      have been frequently used to relieve cancer pain. Hypercalcemia accompanying
      cancer are very easily treated with bisphosphonate agents. In the present paper,
      the advances in supportive therapy for cancer patients that have been made during
      these 25 years will be reviewed.

PMID- 10410662
TI  - [Brain tumors].
AB  - The outcome of brain tumor treatment has greatly improved through the development
      of imaging diagnosis techniques such as CT scan or MRI, and microsurgical
      techniques. During the past 25 years, an efficient therapeutic modality for
      benign brain tumors, which constitute approximately half of all brain tumors, has
      been well established through early diagnosis an precise surgical manipulation.
      The outcome of malignant brain tumors has also improved with radiotherapy
      together with chemotherapy or an adjuvant treatment with biological response
      modifiers such as interferon. Although a complete therapeutic strategy for
      medulloblastoma or germ cell tumors is expected in near future, the ideal
      therapeutic modalities for other malignant brain tumors remain further off. On
      the other hand, focal radiotherapeutic equipment such as the gamma knife or
      photonradiosurgical system have been introduced for the treatment of brain tumors
      and the efficacy has been clinically proved. Even though much progress in brain
      tumor treatment has been made, the prognosis of malignant brain tumors in general
      is still poor and the lives of those patients are quite limited. The development
      of gene therapy or immunotherapy for brain tumors is, thus, looked forward to in
      the 21 st century.

PMID- 10410661
TI  - [Progress in palliative medicine].
AB  - The major factors in the progress in palliative medicine in Japan are the hospice
      movement, as represented by the activities of the Japanese Association for
      Clinical Research on Death and Dying, and interdisciplinary research on the
      quality of life (QOL), particularly in the field of clinical oncology. Palliative
      medicine as a new paradigm today encompasses the fields of biology, psychology,
      sociology, and ethics, all of which are making steady progress under the banner
      of evidence-based medicine. In recent years, the problems of euthanasia and
      physician-assisted suicide, subjects of great debate and public concern,
      especially in America and European countries, have been studied in the field of
      psycho-oncology and continue to attract considerable attention. The relationship
      between depression and social supports is said to be of particular importance.
      The American Society of Clinical Oncology (ASCO) has made a positive statement to
      the effect that it would not hesitate in confronting the so-called "end-of-life"
      issue. All of these global trends point to the increasing importance of
      palliative medicine.

PMID- 10410663
TI  - [Development of treatments for head and neck squamous cell carcinomas].
AB  - Histopathologically, about 90% of head and neck carcinomas are squamous cell
      carcinomas. In this paper, the changes and the recent developments in treatment
      modalities for squamous cell carcinomas in the head and neck are reviewed. The
      curative treatments for head and neck carcinomas are radiation and/or surgical
      resection. The development of diagnostic techniques and the introduction of these
      curative treatments have contributed to an improvement in the long-term outcome.
      In terms of surgical procedures, reconstructive surgeries such as free cutaneous
      and/or muscle flap procedures have been developed and led to extended radical
      resection, while with curative radiotherapy, the increase in total dose and
      improvements in radiation field have been made possible. However, there has been
      a limit regarding significant improvements in prognosis with these curative
      therapies alone, excluding laryngeal cancer, because of the difficulty of early
      detection. Since the 1980 s, multi-drug chemotherapy including cisplatin (CDDP)
      has been administered in advanced cases. First, this chemotherapy was applied as
      neo-adjuvant chemotherapy (NAC) for previously untreated cases followed by
      curative surgery or radiotherapy. As a result, chemotherapy including CDDP and 5
      fluorouracil has been shown to be the most efficacious with a high complete
      response (CR) rate. Furthermore, cases with CR have shown better outcomes than
      those without CR. Curative treatment modalities including impact chemotherapy
      have been invented and trials have begun with the aim of organ preservation.
      These include NAC followed by curative radiotherapy, curative radiotherapy with
      chemotherapy with almost the same anti-tumor effect as NAC and potential a
      radiation sensitizer (concomitant chemoradiotherapy), and NAC followed by
      concomitant chemoradiotherapy. These treatment modalities, including impact
      chemotherapy, are recommendable for the preservation of functions, e. g.,
      swallowing and/or articulation, without worsening the prognosis. Furthermore,
      maintenance chemotherapy subsequent to curative treatment is advisable for
      advanced head and neck carcinomas. Besides the future development of the above
      mentioned treatment modalities, new treatment modalities taking QOL into
      consideration for the elder are necessary, and improvements in poor prognoses of
      cases with complications and those with double cancer which are common in
      patients with head and neck squamous cell carcinomas is indispensable.

PMID- 10410664
TI  - [Progress in breast cancer treatment over a quarter of a century].
AB  - The treatment of breast cancer has changed greatly over the last 25 years in
      Japan. The use of Halsted's surgical procedure has been reduced in breast
      conserving treatment, and even the ommision of axillary dissection has been
      argued recently. On the other hand, endocrine therapy has progressed remarkably
      with acceptance of tamoxifen in the clinic. Approval of LH-RH analogs and
      aromatase inhibitors has brought a new era in breast cancer treatment. The
      introduction of adriamycin, a powerful anticancer drug brought about a rapid
      increase in response rate and the development of oral type 5-fluorouracil (5-FU)
      derivatives made new treatments possible. S-1 and capecitabine, newly licensed 5
      FU derivatives developed in Japan, have attracted notice worldwide. In 1992 the
      Japan Breast Cancer Society was founded and the level of breast cancer research
      in Japan has improved remarkably. Treatment results are now camparable to those
      of western countries.

PMID- 10410665
TI  - [Short history of the clinical developments in lung cancer treatment].
AB  - Through the 1980's and the early part of the 1990's several new anti-cancer drugs
      to fight lung cancer were clinically introduced, bringing cytotoxic chemotherapy
      to play an important role as a mainstay in the combined modality therapy for both
      small cell and non-small cell lung cancer. This is different from the state prior
      to the introduction of these drugs. There is no need to say that these advances
      were supported by the unceasing efforts of oncologists and their patience in
      performing the many randomized controlled trials. This review attempts to
      summarize the history of the clinical developments in lung cancer treatment since
      the beginning of the 20th century.

PMID- 10410666
TI  - [Twenty-five years of progress in the treatment of esophageal and gastric
      cancers].
AB  - As we approach the year 2000, it seems useful to look back at the progress that
      has been made in medicine. The author has had 25 years' experience in
      gastrointestinal surgery for esophageal and gastric cancers. Twenty-five years
      ago in the field of gastrointestinal cancer diagnosis, double-contrast
      radiography was the leading technology and the development of fiberscopes led to
      an increasing number of early cancers being detected by endoscopy combined with
      biopsy. The treatment of advanced cancers relied heavily on the surgical knife,
      with the aim of complete removal of cancer cells by through and extended combined
      resection. Today, greater importance is placed on limited resection that allows
      for the preservation of function. The combined use of chemotherapy and
      radiotherapy is also regarded as important in some areas, reflecting a great
      change in therapeutic trends. This paper examines the author's 25 years of
      experience as a clinical surgeon, and, in doing so, provides an outline of the
      changes in the treatment of esophageal and gastric cancers during the last
      quarter of this century. Based on this, and with a view to the 21st century, the
      author hopes to contribute to new developments in the treatment of esophageal and
      gastric cancers.

PMID- 10410667
TI  - [Progress in the treatment of colorectal cancer].
AB  - The chemotherapeutic management of advanced colorectal cancer has been a
      challenge to oncologists for the last 30 years, with 5-fluorouracil (5-FU) being
      used as the core drug. However, its effectiveness is far from satisfactory, and
      there has been no evidence of improved survival. Recently, a method of
      biochemical modulation was used to enhance the effect of 5-FU. In colorectal
      cancer patients with recurrent or metastatic sites, survival was significantly
      prolonged for a group receiving LV.5-FU therapy, based on biochemical modulation,
      compared with a group receiving no chemotherapy (best supportive care). Still
      more, LV.5-FU therapy was proved to be beneficial for survival when it was used
      as a postoperative adjuvant. In this way, the most recent chemotherapy for
      colorectal cancer was proved to be effective.

PMID- 10410668
TI  - [Cancer of the liver, pancreas, gallbladder, and bile duct].
AB  - In cancer of the liver, pancreas, gallbladder, and bile duct, symptoms and signs
      are non-specific compared with benign conditions. Early detection is difficult
      and long term survivors are extremely low. The role of systemic chemotherapy in
      patients with these malignancies is only palliative. Prolongation of survival has
      not been demonstrated with any single agent or with any combination chemotherapy.
      However, in some instances, useful symptomatic palliation may occur even without
      an objective partial response. Quality of life is an important parallel endpoint
      in these malignancies. In advanced cancer of the liver, numerous alternative
      therapies have been investigated. These include pharmacologically based
      chemotherapeutic delivery methods, percutaneous alcohol injection, TAE, TACE,
      etc. However, further rigorous investigations will be warranted. It is hoped that
      successful chemotherapeutic agents or other modalities can be developed and
      combined with limited efficacy of surgery and radiotherapy. In this respect,
      newer, more active chemotherapy regimens are clearly needed.

PMID- 10410669
TI  - [Trends in comprehensive treatment for gynecologic malignancies].
AB  - Advances in many areas, including oncology-epidemiology, chemotherapy, diagnosis,
      surgery, radiology, and clinical research have all had a positive impact on the
      treatment of gynecologic malignancies, so that today we have achieved an improved
      quality of life concomitant with increased survival rates in patients. The
      improvements in therapy for gynecologic malignancies have been in diagnostic
      procedures, such as tumor markers, molecular biologic methods, and image
      analysis. Considerable progress has been made in surgical management, from focal
      excision of primary lesions to minimal debulking surgery after the initial
      chemotherapy for advanced cancer. Chemotherapy has advanced markedly after the
      introduction of cisplatin, and various regimens or anticancer drug-analogs of
      cisplatin, camptotesin, and paclitaxel have been introduced. In recent years, the
      quality of life of patients with malignancies has been one of the most important
      factors in treatment. Intensive and combination therapies will be put to greater
      use for gynecologic malignancy in the future.

PMID- 10410670
TI  - [Recent advancement of the treatment of urological malignancies].
AB  - The treatment strategies for urological malignancies including prostate cancer,
      urotherial cancers, renal cell cancer and testicular cancer, have shown steady
      improvements over the past 25 years. These improvements have been greatly
      enhanced by progress in basic medicine. Not only improvements in surgical
      techniques but improvements in the fields of cancer chemotherapy, immunology, and
      diagnostic methods have contributed to the development of modern clinical
      medicine. On the other hand, it is true that the treatment outcome by cancer
      stage has not improved as much as expected. In next 25 years, cancer treatment
      strategies will be established on the basis of patient-oriented or disease
      oriented treatment plans, making full use of newly developed treatment
      modalities, and giving consideration to improving the QOL of patients.

PMID- 10410671
TI  - [Hematologic tumors].
AB  - Hematologic tumors are commonly systemic on diagnosis, and chemotherapy is
      therefore the sole method by which to obtain a prolongation of survival or cure.
      Based upon results from a prospective randomized trial compared to a combination
      regimen consisting of daunorubicin and cytarabine, the first line
      chemotherapeutic regimen for acute myelogenous leukemia is considered to be a
      combination regimen consisting of idarubicin and cytarabine. The standard
      chemotherapeutic regimen for advanced Hodgkin's disease would seem to be an ABVD
      regimen, judging from results reported from a prospective randomized trial which
      compared MOPP, ABVD and MOPP-ABVD. The first generation combination CHOP is
      recognized as a standard regimen for advanced non-Hodgkin lymphoma due to results
      of a prospective randomized trial compared with intensive chemotherapeutic
      regimens.

PMID- 10410672
TI  - [Skin cancer melanoma].
AB  - The most common dermal malignancies are basal cell carcinoma, spinous cell
      carcinoma, and malignant melanoma, of which the latter two carry a poor
      prognosis. This communication deals with therapies for spinous cell carcinoma and
      malignant melanoma. Therapies for these malignancies have made huge strides,
      helping to formulate the policy and strategy for treatment and doing much to
      improve their prognoses. Chemotherapy, in particular, has become firmly
      established, contributing a great deal to the improvement of their prognoses.
      PEP, combination therapy with PEP plus MMC and CPT-11 are used for the treatment
      of spinous cell carcinoma, while CAV therapy is given to patients with advanced
      spinous cell carcinoma. In the treatment of malignant melanoma that is considered
      resistant to chemotherapy, DAV and PAV therapies have been attempted, and CDV and
      DACTam therapies have been tried on patients with advanced spinous cell
      carcinoma. Adoptive immunotherapy has also been used in the battle with this
      malignancy. Furthermore, excellent results have been observed with intratumor
      administration of IFN-beta. IFN-beta plus DAV has served well adjuvant therapy to
      improve the prognosis of Stage II or III malignant melanoma.

PMID- 10410673
TI  - [Recent advances in management of musculoskeletal tumors].
AB  - Neoadjuvant chemotherapy plays a significant role in improving the prognosis of
      malignant bone tumors such as osteosarcoma and Ewing's sarcoma. Doxorubicin,
      cisplatin and high-dose methotrexate are key drugs in the chemotherapy for
      osteosarcoma. Intraarterial administration of the drugs is very effective in
      local control, so that wide resection of the tumor may be performed safely. The
      efficacy of preoperative chemotherapy is evaluated by the histological necrosis
      rate of the resected tumor after which postoperative drugs will be chosen. Limb
      salvage is becoming more and more common, and an excellent limb can be
      reconstructed using an artificial joint. In soft tissue sarcomas, brachytherapy
      can make the surgical resection margin narrower, resulting in good function of
      the extremities. Fragility of bone caused by metastatic bone diseases is reversed
      by surgical intervention.

PMID- 10410674
TI  - [Malignant tumors in childhood].
AB  - With the consistent use of effective multimodal treatment, including combination
      chemotherapy, surgery and radiotherapy, the prognosis for all types of childhood
      cancer has dramatically improved over the last 25 years and the current 5-year
      survival rate is about 60-98%. Concurrently, developments in the laboratory have
      improved our understanding of the biology of childhood malignancies. The
      availability of new imaging techniques, particularly advances in magnetic
      resonance imaging, have enabled more accurate assessments of tumor extent and
      staging. Such imaging techniques are now routinely used in radiotherapy planning
      to maximize treatment to tumor sites, while minimizing the exposure of normal
      tissues. Progress in surgery has allowed for better reconstructive techniques to
      repair defects created by tumor resections. The availability of blood component
      transfusions and hematopoietic cytokines, and advances in supportive care such as
      isolation techniques and preventive high-dose antibiotic therapy for infections,
      have allowed for the administration of increasingly intensive chemotherapies.
      Advances in our understanding of hematopoietic stem cells have enabled for
      significant extension of the techniques of bone marrow transplantation. Many of
      the advances in diagnosis, treatment, and our understanding of the biology of
      childhood cancers have emerged from studies conducted at centers with the
      required expertise, where multidisciplinary teams are available to coordinate the
      diagnosis, treatment, supportive care, and follow-up of children with cancer. The
      increasing population of children who survive into adulthood has renewed concern
      for the long-term consequences of therapy. Current studies focus on "risk
      adapted" therapy, where the most intensive treatment is reserved for patients at
      highest risk of treatment failure, whereas treatment of children with a more
      favorable prognosis is designed to minimize the acute and late toxicities of
      therapy.

PMID- 10410675
TI  - A role for RNA processing in regulating expression from transfected genes.
AB  - We have examined the expression of cloned genes following their stable
      integration into the genome of pluripotent embryonal carcinoma stem cells.
      Transfected genes integrate into the genome as tandem arrays. Expression of
      reporter genes from these tandem arrays in embryonal carcinoma cells is
      inefficient probably because genes are subject to repeat-induced gene silencing.
      We found that expression of reporter genes was significantly enhanced if co
      transfected with cloned fragments derived from the murine Pgk-1 gene. The
      enhanced expression required (a) that the Pgk-1 fragment carries an active
      promoter, (b) that the promoter drives transcription through a region of more
      than 12 kbp, and (c) that this transcribed region contains both introns and
      exons. Reporter gene activity did not require specific Pgk-1 DNA sequences
      suggesting that the coupled processes of transcription and RNA processing
      conferred activity on neighboring genes probably by influencing local chromatin
      structure. Consistent with this idea, the effect of the Pgk-1 gene could be
      mimicked by exposing cells to butyrate or trichostatin A, inhibitors of histone
      deacetylase. Thus, the effect of the co-transfected Pgk-1 gene is to inhibit the
      process of gene inactivation possibly by functioning like an insulator or
      boundary element in the chromatin.

PMID- 10410676
TI  - Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment
      of normal polyglutamine proteins.
AB  - Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat
      encoding a tract of consecutive glutamines near the amino terminus of huntingtin,
      a large protein of unknown function. It has been proposed that the expanded
      polyglutamine stretch confers a new property on huntingtin and thereby causes
      cell and region-specific neurodegeneration. Genotype-phenotype correlations
      predict that this novel property appears above a threshold length (approximately
      38 glutamines), becomes progressively more evident with increasing polyglutamine
      length, is completely dominant over normal huntingtin and is not appreciably
      worsened by a double genetic dose in HD homozygotes. Recently, an amino terminal
      fragment of mutant huntingtin has been found to form self-initiated fibrillar
      aggregates in vitro. We have tested the capacity for aggregation to assess
      whether this property matches the criteria expected for a fundamental role in HD
      pathogenesis. We find that that in vitro aggregation displays a threshold and
      progressivity for polyglutamine length remarkably similar to the HD disease
      process. Moreover, the mutant huntingtin amino terminus is capable of recruiting
      into aggregates normal glutamine tract proteins, such as the amino terminal
      segments of both normal huntingtin and of TATA-binding protein (TBP). Our
      examination of in vivo aggregates from HD post-mortem brains indicates that they
      contain an amino terminal segment of huntingtin of between 179 and 595 residues.
      They also contain non-huntingtin protein, as evidenced by immunostaining for TBP.
      Interestingly, like the in vitro aggregates, aggregates from HD brain display
      Congo red staining with green birefringence characteristic of amyloid. Our data
      support the view that the expanded polyglutamine segment confers on huntingtin a
      new property that plays a determining role in HD pathogenesis and could be a
      target for treatment. Moreover, the new property might have its toxic
      consequences by interaction with one or more normal polyglutamine-containing
      proteins essential for the survival of target neurons.

PMID- 10410677
TI  - Characterization of a human genomic DNA fragment which rescues defective lipid
      linked oligosaccharide synthesis in a mutant G258 cell line isolated from the
      FM3A mouse mammary carcinoma cell line.
AB  - The G258 mutant cell line, isolated from the FM3A mouse mammary carcinoma cell
      line, is temperature-sensitive for both cell growth and asparagine-linked
      glycosylation due to mutation at a single location. The biochemical defect in the
      G258 mutant resides in the formation of lipid-linked oligosaccharide, presumably
      in one of the steps of GDP-mannose-dependent mannosylation (Y. Nishikawa, J.
      Cell. Physiol. 119, 260-266, 1984; Y. Nishikawa, Biochim. Biophys. Acta 1091, 135
      140, 1991). In the present study, we transfected human genomic DNA fragments into
      the G258 mutant by the radiation hybrid method and isolated transformants (KK-1, 
      3 and -4) which showed recovery from both temperature-sensitive cell growth and
      asparagine-linked glycosylation. These transformants contained a common Alu
      containing human DNA fragment (1.3 kb) which will be used as a marker for
      isolating the gene that complements the defect of lipid-liked oligosaccharide
      synthesis in the G258 mutant.

PMID- 10410678
TI  - PAC and cosmid contig spanning the HOXA cluster on human chromosome 7p15.
AB  - To construct the PAC and cosmid contig map spanning the HOXA cluster on human
      chromosome 7, we used 9 DNA markers (D7S2243, D7S3010, HOXA1, EVX1, 750, pBH8,
      p60, p8.0, and HOXA11), among which the final 4 were generated in this study by
      shotgun cloning strategy. From the libraries, 5 PAC and 35 cosmid clones were
      screened and as a result, an overlapping continuous array of cosmid and PAC
      clones covering the genomic region (about 200 kb) spanning the entire cluster
      were constructed. The isolated cosmids contained several consecutive HOX genes of
      regional group, probably sharing the regulatory processes such as alternative
      splicing or polyadenylation, and thus could be used as useful materials for
      elucidating the molecular mechanism of HOX gene expression in the future.

PMID- 10410679
TI  - Cointegration of DNA molecules introduced into mammalian cells by
      electroporation.
AB  - Electroporation was used to introduce a mixture of two plasmid-cloned genes into
      Chinese hamster ovary (CHO) cells, and the location of the two genes was
      subsequently determined by fluorescence in situ hybridization (FISH). The 25 kb
      Chinese hamster gene for dihydrofolate reductase (dhfr) in the form of a cosmid
      derived 40 kb BglI fragment and the SV40 promoter-driven E. coli gene for guanine
      phosphoribosyltransferase (gpt) were co-electroporated and gpt + transfectants
      selected. Clones that had also integrated a single copy of the dhfr gene were
      studied by 2-color fluorescence in situ hybridization (FISH) to localize the
      integration site(s) of the exogenous DNA in metaphase chromosomes. All 9 clones
      examined showed co-localization of the two transgenes. The chromosomal site of
      integration was different in each clone. Co-integration was confirmed by co
      amplification experiments. We conclude that, even when provided at low
      concentrations, separate soluble DNA molecules become linked upon gene transfer
      by electroporation, either by intracellular ligation prior to integration, or by
      co-integration at a common site in a given recipient cell.

PMID- 10410680
TI  - A new efficient method for transfection of neonatal cardiomyocytes using histone
      H1 in combination with DOSPER liposomal transfection reagent.
AB  - Although cationic lipids are successfully used for gene transfer in vitro,
      primary cells such as neonatal cardiomyocytes frequently resist efficient
      transfection. We show here that the polycationic lipid DOSPER in combination with
      histone H1 was much more efficient in transfection of neonatal cardiomyocytes
      than DOSPER alone or other cationic lipids. This has been shown for transfection
      with the reporter plasmids pSV beta-gal and pCMV luc. If viral transfections are
      not possible, this mild method is an alternative to transfect cardiomyocytes.

PMID- 10410681
TI  - New imaging techniques in endovascular surgery.
AB  - Imaging requirements for endovascular surgery are quite different from imaging
      requirements for open surgical procedures. As with the entire field of
      endovascular surgery, imaging techniques and recommendations are changing
      rapidly. Preoperative imaging is crucial--once deployed, an endograft cannot be
      retrieved without conversion to open surgical repair. As with any surgical
      procedure, patient selection and preoperative planning are at least as important
      as technical skills and at least as difficult to learn. Nonetheless, good imaging
      technology is no substitute for good judgement. Endovascular procedures are also
      unique because intraoperative and postoperative imaging are also keys to the
      success of the procedure. Postoperative imaging techniques are evolving more
      slowly as long-term data are gathered but seem to be vitally important.

PMID- 10410682
TI  - The new operating room environment.
AB  - As endovascular procedures become more complex, the need for a suitably equipped
      endovascular suite is recognized. This specialized theater combines the features
      of the traditional operating room and the interventional radiology suite. The
      availability of high-resolution digital fluoroscopy facilitates the precise
      deployment of endovascular grafts and stents. In addition, combined open and
      endovascular procedures can be performed simultaneously. In this new environment,
      vascular surgeons are able to select the most appropriate operation without
      hindrance.

PMID- 10410683
TI  - Use of digital cine-fluoroscopy and catheter-directed techniques to improve and
      simplify standard vascular procedures.
AB  - Digital cine-fluoroscopy and catheter-directed treatments have become
      indispensable tools in the armamentarium of surgeons performing vascular
      procedures. These new technologies not only improve and simplify the performance
      of standard vascular operations but also allow surgeons to perform a wide range
      of interventions previously unavailable in the operating room.

PMID- 10410684
TI  - Devices for aortic aneurysm repair.
AB  - Although the technical success and short-term efficacy of endovascular grafts
      have now been demonstrated, the long-term durability of grafts used in the aorta
      remains to be proven. No long-term data are yet available regarding device
      durability or patient outcome beyond the initial few years. Recent evidence shows
      that the ability of endovascular grafts to cause shrinkage and regression of
      aortic aneurysms may have a paradoxic effect of distorting the endograft itself,
      thus causing geometric changes within the supporting metallic framework and,
      ultimately, device failure (Fig. 9). Thus, the desired positive effect of the
      device may, ironically, lead to its eventual failure.

PMID- 10410685
TI  - Early clinical results and studies of aortic aneurysm morphology after
      endovascular repair.
AB  - Endovascular repair is a feasible treatment alternative with favorable short-term
      results compared with standard operations. Nonrandomized, multicenter trials
      already in progress should help to define the role of endovascular grafting in
      the treatment of patients who are otherwise candidates for conventional repair.
      Long-term follow-up studies will test the durability of the procedure, including
      clinical repercussions of late endoleaks and migration related to slow
      alterations in aortic morphology, such as neck dilation and aortic shortening.
      More research is needed into long-term aortic morphologic changes; further
      insights into these changes may allow subclinical prediction of clinical events
      and permit intervention before a catastrophic failure. How great an advantage
      this procedure has over observation in high-risk patients for whom no open
      surgical alternative is available is also unknown because the overall mortality
      of this patient cohort may mitigate any treatment benefits. In today's cost
      conscious world, the viability of this new technology may be dependent on
      balancing the short-term benefits of this procedure against its associated
      requirements for monitoring and subsequent reinterventions.

PMID- 10410686
TI  - Laparoscopically assisted abdominal aortic aneurysm repair.
AB  - Since the first description of abdominal aortic aneurysms by sixteenth-century
      anatomist Vesalius, the history of this disease has reflected the remarkable
      progress of vascular surgery. From initial attempts of ligation and sclerosis to
      the recent advances of endovascular and laparoscopic repair, present-day vascular
      surgeons are supplied with a technically evolving choice of therapeutics. None of
      these procedures is mutually exclusive; currently, great interest lies in the use
      of laparoscopy to provide extraluminal control at the neck of aneurysms, to work
      with endoluminal grafts, and to control collateral vessel endoleaks. Laparoscopic
      vascular surgery must not be introduced into the clinical arena based only on the
      assumption that it is feasible. Clearly, it is a technically challenging
      procedure with a steep learning curve that requires specialized instrumentation
      and sophisticated laparoscopic suturing capability; however, with continued
      investigation, including prospective randomized trials, laparoscopic treatment of
      aortic aneurysms may become a standard option for high-risk patients.

PMID- 10410687
TI  - Endovascular treatment of descending thoracic aortic aneurysms and dissections.
AB  - Various endovascular techniques have become viable therapeutic alternatives in
      the treatment of patients with many types of descending thoracic aortic pathology
      and aortic dissections. Descending thoracic aortic aneurysms can be successfully
      treated using stent grafts. This technique is less invasive and is associated
      with acceptable morbidity and mortality rates. Patients who are particularly
      likely to benefit include the very elderly population; those with markedly
      compromised cardiac, pulmonary, or renal status; and individuals who have
      previously undergone complex operations on the thoracic aorta. Other endovascular
      methods, such as aortic flap fenestration, stent, or covering of the primary
      intimal tear in the descending thoracic aorta with a stent graft, have also been
      effectively employed in the treatment of peripheral arterial complications of
      aortic dissection. Despite the reported early success of these endovascular
      percutaneous methods, true assessment of the effectiveness of these various
      techniques awaits long-term follow-up evaluation in large patient populations.

PMID- 10410688
TI  - Percutaneous transluminal angioplasty and stenting for iliac artery occlusive
      disease.
AB  - Atherosclerotic iliac artery stenoses respond well to simple balloon angioplasty
      and have the best results of all of the peripheral vessels. Nonetheless, initial
      technical failures occur in as many as 20% of patients, most of which can be
      salvaged with intravascular stenting, as can many of the potential complications;
      however, even though the initial technical success rates for stenting approach
      100%, stenotic recurrences within stents are not infrequent. Whether promising
      new concepts, such as brachytherapy, gene therapy, and endoluminal grafting, will
      have a durable impact on the results of iliac angioplasty is yet to be seen.
      Meanwhile, the excellent results of endoluminal treatment of patients with iliac
      artery occlusive disease, combined with the relatively low risk for complications
      compared with surgical revascularization, ensure an enduring role for this
      modality of treatment and a diminution in the fraction of patients requiring
      surgery to correct their iliac artery occlusive disease.

PMID- 10410689
TI  - Stent grafts in occlusive arterial disease.
AB  - The use of endovascular grafts for the treatment of occlusive arterial disease
      continues to evolve as the sophistication of currently available devices improves
      with regard to device composition and delivery systems. Endovascular grafting for
      occlusive arterial disease is particularly useful in high-risk patients with
      medical comorbidities who are otherwise unfit for a major operation and
      conventional open repair. The early term and midterm results on the treatment of
      occlusive, iliac, and femoropopliteal disease have been encouraging. Further
      refinements in catheter technology, stent grafts, and delivery systems will
      further extend the use of these devices. Increasing experience from centers using
      different devices and long-term follow-up with regard to durability and
      complication will establish the role of endovascular grafts as alternatives to
      conventional repair.

PMID- 10410690
TI  - Endarterectomy of the superficial femoral artery.
AB  - Semiclosed endarterectomy of the SFA belongs in the armamentarium of the vascular
      surgeon. New technology offers the possibility of performing this less invasive
      operation so that only a single incision is needed to obtain access to the artery
      and perform remote disobliteration. Strong indications show that the anticipated
      restenosis of long, segmental, closed endarterectomies can be reduced remarkably
      by expanded PTFE endolining.

PMID- 10410691
TI  - Less-invasive saphenous harvest.
AB  - Vascular and cardiovascular surgeons, having only recently been introduced to
      less-invasive techniques of saphenous vein harvest and in situ preparation, are
      embracing these new technologies with cautious enthusiasm. Although the available
      data are limited, with few prospective randomized trials, less-invasive methods
      of saphenous vein harvest seem to result in reduced wound complications, improved
      patient satisfaction, and decreased hospital LOS. The most important but least
      well defined variable is the effect of harvesting technique on graft patency.
      Concerns that excess traction and manipulation of the vein during less-invasive
      harvesting techniques may compromise patency have limited the wide adoption of
      these techniques. Although an increase in the need for vein repair with 7-0
      sutures was reported in one series, limited histologic studies have not shown
      injury at the cellular level. Patency data for endovascular-assisted, less
      invasive, in situ bypass procedures have demonstrated equivalent intermediate
      results, but less-invasive saphenous vein harvest has limited follow-up data
      available. Before these less-invasive techniques can be fully embraced,
      intermediate and long-term patency data must be critically analyzed. If the
      preliminary impressions of decreased morbidity and hospital LOS are supported by
      future trials, these savings will certainly eclipse the costs associated with
      prolonged operating room use and disposable instrumentation. The variety of
      instruments available and the preponderance of disposables in the market attest
      to the newness of the field. Although mechanical retraction devices predominate,
      carbon dioxide insufflation has been used successfully. As the techniques and
      instrumentation for saphenous harvest are refined, reusable instrumentation will
      likely play a more prominent role and result in additional cost savings.

PMID- 10410692
TI  - Minimally invasive in situ bypass.
AB  - Since the report of a successful femoropopliteal in situ saphenous vein bypass in
      1962, surgeons have attempted to make this bypass a less invasive operation and
      simplify the two principal technical components of the operation: (1) rendering
      the saphenous vein valves incompetent and (2) occluding the venous side branches.
      To accomplish this bypass, however, a long incision that is the length of the leg
      over the course of the saphenous vein is often necessary, which can be fraught
      with hazard, especially in patients with diabetes in whom wound complications can
      be devastating. An angioscopically assisted technique that allows the surgeon to
      perform valvulotomy and occlude venous side branches from within the saphenous
      vein--a minimally invasive in situ vein bypass--has been developed. This article
      discusses preclinical, fluoroscopic clinical, and angioscopic clinical studies of
      minimally invasive in situ bypass.

PMID- 10410693
TI  - Endovascular treatment of vascular injuries.
AB  - The endovascular management of hemodynamically stable patients with traumatic
      vascular lesions is an appealing concept. In principle, many of the injuries
      detected at the time of diagnostic angiography can be treated at the same
      setting. Moreover, lesions that occur at the base of the skull or at
      infraclavicular and pelvic locations pose far less difficulty when managed by
      transcatheter techniques than by traditional surgical exposure. Even among more
      accessible injuries, standard surgical dissection is often complicated by the
      presence of hematoma or pseudoaneurysm, which causes obliteration of natural
      tissue planes, or arteriovenous fistulas that may complicate dissection because
      of associated regional venous hypertension. Thus, endovascular approaches may
      provide easier access to the target lesion, limit the morbidity often associated
      with surgical exploration, and reduce transfusion requirements. Nonetheless, the
      long-term consequence of placing an intravascular foreign body in a young patient
      is undefined, and the potential risk for a device infection cannot be ignored.
      Definitive answers to these issues await the outcome of longitudinal follow-up
      studies. Until that time, a prudent approach in the use of this new technology is
      appropriate.

PMID- 10410694
TI  - Endoscopic perforating vein surgery.
AB  - Perforator incompetence, caused by primary valvular incompetence or by previous
      deep venous thrombosis, contributes to ambulatory venous hypertension and the
      development of chronic venous disease. Although the exact role and contribution
      of perforators to the development of ulcers are still debated, poor results of
      nonoperative management to prevent ulcer recurrence justify surgical attempts at
      perforator ligation, in addition to ablation of superficial reflux. The
      endoscopic technique of perforator interruption has significantly fewer wound
      complications than the open technique and is the preferred method for ablation of
      medial perforating veins. Interruption of incompetent perforators with ablation
      of the superficial reflux, if present, effectively and durably decreases symptoms
      of CVI and rapidly heals ulcers. Ulcer recurrence following correction of
      perforator and superficial reflux in patients with post-thrombotic syndrome is
      much higher than in patients with primary valvular incompetence. A prospective
      randomized trial is needed to define the long-term benefits of interrupting
      incompetent perforators in all patients with advanced chronic venous disease and
      which patients with post-thrombotic syndrome should undergo perforator
      interruption.

PMID- 10410695
TI  - Superior vena cava syndrome. Experience with endovascular stents and surgical
      therapy.
AB  - Superior vena cava (SVC) syndrome is a serious complication of benign and
      malignant diseases. Benign causes may be increasing because of the increased use
      of central venous cannulation. Modern surgical therapy is durable with a few
      complications. Traditional treatment for SVC obstruction from malignant causes
      has consisted of anticoagulation, radiation, chemotherapy, and occasionally
      surgery. Endovascular techniques present a new treatment option for these
      patients, and uses a combination of thrombolysis, angioplasty, and intravascular
      stents. Short-term results are excellent with relatively rapid patient recovery.
      Further research is needed to elucidate the long-term results of endovascular
      treatment and to find its role in benign and malignant disease.

PMID- 10410696
TI  - Glia: a curtain raiser.

PMID- 10410697
TI  - Glial cell participation in the degeneration of dopaminergic neurons in
      Parkinson's disease.

PMID- 10410698
TI  - Neurotrophins in the pathogenesis and potential treatment of Parkinson's disease.

PMID- 10410699
TI  - Pathophysiology of the motor cortex in patients with Parkinson's disease.

PMID- 10410700
TI  - The role of cortico-striatal circuits in learning sequential information.

PMID- 10410701
TI  - Motor skills in motor disorders: measuring performance changes in tracking and
      other perceptual-motor tasks.

PMID- 10410702
TI  - The cognitive neuropsychology of Parkinson's disease: a functional neuroimaging
      perspective.

PMID- 10410703
TI  - Neurophysiological tests for the assessment of tremors.

PMID- 10410704
TI  - Functional consequences of dopaminergic degeneration in Parkinson's disease.

PMID- 10410705
TI  - Advances in understanding the neural mechanisms underlying L-DOPA-induced
      dyskinesia.

PMID- 10410706
TI  - The metabolic landscape of Parkinson's disease.

PMID- 10410707
TI  - Nonisotopic surrogates for technetium as ligands for monoamine transporters.

PMID- 10410708
TI  - Localization of adenosine A2A receptors in brain: therapeutic implications.

PMID- 10410709
TI  - Adenosine receptor antagonists and Parkinson's disease: actions of the A2A
      receptor in the striatum.

PMID- 10410710
TI  - Antiparkinsonian activity of adenosine A2A antagonists in experimental models.

PMID- 10410711
TI  - Metabolism of adenosine increase in the striatum in common marmoset parkinsonism
      induced by MPTP.

PMID- 10410712
TI  - Glutamate receptor-mediated mechanisms in levodopa-induced motor fluctuations in
      an experimental model of parkinsonism.

PMID- 10410713
TI  - Neurotrophins and cytokines in Parkinson's disease.

PMID- 10410714
TI  - Is Parkinson's disease an inherited condition?

PMID- 10410715
TI  - Epidemiology of Parkinson's disease.

PMID- 10410716
TI  - Genetic and environmental factors in Parkinson's disease.

PMID- 10410717
TI  - The Contursi kindred, a large family with autosomal dominant Parkinson's disease:
      implications of clinical and molecular studies.

PMID- 10410718
TI  - Genetic and environmental factors in the pathogenesis of Parkinson's disease.

PMID- 10410719
TI  - Clinical genetic study of familial Parkinson's disease in Italy.

PMID- 10410720
TI  - Dopamine cell death by a single genetic mechanism: phenotypic analysis and
      linkage study of autosomal recessive juvenile parkinsonism.

PMID- 10410721
TI  - Molecular genetics of DOPA-responsive dystonia.

PMID- 10410722
TI  - Toxins, genetics, and Parkinson's disease: the role of N-acetyltransferase 2.

PMID- 10410723
TI  - Mechanisms of neuronal death in idiopathic parkinsonism.

PMID- 10410724
TI  - Idiopathic Parkinson's disease: a genetic and environmental model.

PMID- 10410725
TI  - Time sequences of dopaminergic cell death in Parkinson's disease: indications for
      neuroprotective studies.

PMID- 10410726
TI  - Etiology of Parkinson's disease: contributions from 18F-DOPA positron emission
      tomography.

PMID- 10410727
TI  - Mitochondrial DNA in Parkinson's disease.

PMID- 10410728
TI  - Nitric oxide in the pathogenesis of Parkinson's disease.

PMID- 10410729
TI  - Nitric oxide and basal ganglia degeneration.

PMID- 10410730
TI  - N-methyl(R)salsolinol, a dopamine neurotoxin, in Parkinson's disease.

PMID- 10410731
TI  - Oxidative stress and neuroprotection in Parkinson's disease: implications from
      studies on dopamine-induced apoptosis.

PMID- 10410733
TI  - Role of iron in 6-hydroxydopamine neurotoxicity.

PMID- 10410732
TI  - P450 and heme oxygenase enzymes in the basal ganglia and their roles in
      Parkinson's disease.

PMID- 10410734
TI  - Apomorphine, a dopamine receptor agonist with remarkable antioxidant and
      cytoprotective properties.

PMID- 10410735
TI  - Movement disorders with tau protein cytoskeletal pathology.

PMID- 10410736
TI  - Pathobiology of the Lewy body.

PMID- 10410737
TI  - Preclinical diagnosis of Parkinson's disease.

PMID- 10410738
TI  - Parkinsonian and essential tremors: different entities or different
      manifestations of the same disorder?

PMID- 10410739
TI  - Progressive supranuclear palsy.

PMID- 10410740
TI  - Urinary and anorectal function evaluation in Parkinson's disease.

PMID- 10410741
TI  - Separating the primary autonomic failure syndromes, multiple system atrophy, and
      pure autonomic failure from Parkinson's disease.

PMID- 10410742
TI  - Apomorphine test in the assessment of parkinsonian patients: a meta-analysis.

PMID- 10410743
TI  - Rare and unusual parkinsonian syndromes.

PMID- 10410744
TI  - Saccades and antisaccades in parkinsonian syndromes.

PMID- 10410745
TI  - Visual and visual cognitive dysfunction in Parkinson's disease: spatial and
      chromatic vision.

PMID- 10410747
TI  - Psychosis and hallucinations in Parkinson's disease.

PMID- 10410746
TI  - DOPA-responsive dystonic parkinsonism--pathophysiologic considerations.

PMID- 10410748
TI  - The place of dementia in Parkinson's disease: a methodologic saga.

PMID- 10410749
TI  - Clinicopathological heterogeneity and non-dopaminergic influences on behavior in
      Parkinson's disease.

PMID- 10410750
TI  - Hallucinations in Parkinson's disease: the clinical syndrome.

PMID- 10410751
TI  - Dopamine, serotonin, and schizophrenia.

PMID- 10410753
TI  - Standardized quantitative measurements in Parkinson's disease.

PMID- 10410752
TI  - Evaluating community-based Parkinson's disease nurse specialists: rationale,
      methodology, and representativeness of patient sample in a large randomized
      controlled trial.

PMID- 10410754
TI  - Theoretical basis and problems of quantification of movement disorders.

PMID- 10410755
TI  - Objective assessment in Parkinson's disease: optoelectronic movement and force
      analysis in clinical routine and research.

PMID- 10410756
TI  - Adolf Hitler's cognitive disorder and how it affected his conduct of World War
      II.

PMID- 10410757
TI  - Notable Europeans with Parkinson's disease.

PMID- 10410758
TI  - Art and Parkinson's disease.

PMID- 10410759
TI  - Do we need more drugs to treat Parkinson's disease?

PMID- 10410760
TI  - Clinical pharmacology of levodopa-induced dyskinesia in parkinsonian patients.

PMID- 10410761
TI  - COMT inhibition with entacapone in the treatment of Parkinson's disease.

PMID- 10410763
TI  - Evidence suggesting the role of norepinephrine deficiency in late stages of
      Parkinson's disease.

PMID- 10410762
TI  - Pharmacology of rasagiline (N-propargyl-1R-aminoindan).

PMID- 10410764
TI  - Combined and selective monoamine oxidase inhibition in the treatment of
      depression in Parkinson's disease.

PMID- 10410766
TI  - Lazabemide for the treatment of Alzheimer's disease: rationale and therapeutic
      perspectives.

PMID- 10410765
TI  - Moclobemide in patients with dementia and depression.
AB  - Moclobemide, the first reversible inhibitor of MAOA (so-called RIMA) to become
      widely available for clinical use, is an effective and well-tolerated
      antidepressant. Preclinical experiments, as well as studies in human volunteers
      and patients, provide evidence for the cognition enhancing effects of
      moclobemide. This cognition improvement, taken together with moclobemide's
      absence of anticholinergic effects, lack of sedation, and similarity in
      pharmacokinetics in young and elderly individuals, makes this drug especially
      appropriate for use in treatment of the elderly depressed patient.

PMID- 10410767
TI  - Use of apomorphine in clinical practice.

PMID- 10410768
TI  - Future delivery systems for apomorphine in patients with Parkinson's disease.

PMID- 10410771
TI  - Interdisciplinary rehabilitation in Parkinson's disease.
AB  - The use of a multidisciplinary team in managing end-stage PD was described,
      emphasizing the use of a specifically designed rehabilitation program based on
      current concepts of basal ganglia function and malfunction in PD as a means of
      unifying the team members, providing them with a common knowledge base and
      enabling the team members to speak to the patients with a common language. This
      approach has enabled the multidisciplinary team to function in an
      interdisciplinary and intradisciplinary manner.

PMID- 10410769
TI  - Effects of long-term, continuous subcutaneous apomorphine infusions on motor
      complications in advanced Parkinson's disease.

PMID- 10410772
TI  - Pragmatic physical therapy in Parkinson's disease: any scientific basis?

PMID- 10410770
TI  - New delivery systems for antiparkinsonian drugs.

PMID- 10410773
TI  - Traditional and complementary therapies in Parkinson's disease.
AB  - Parkinson's disease has existed in different parts of the world since ancient
      times. The first clear description is found in the ancient Indian medical system
      of Ayurveda under the name Kampavata. Traditional therapies in the form of herbal
      preparations containing anticholinergics, levodopa, and monoamine oxidase
      inhibitors were used in the treatment of PD in India, China, and the Amazon
      basin. Scientific reevaluation of these therapies may be valuable, as shown in
      the case of Mucuna pruriens and Banisteria caapi. Complementary therapies such as
      massage therapy, biofeedback, and acupuncture may have beneficial effects for
      patients and deserve further study.

PMID- 10410774
TI  - Posteroventral medial pallidotomy in advanced Parkinson's disease.

PMID- 10410775
TI  - Image-guided electrophysiologically controlled posteroventral pallidotomy for the
      treatment of Parkinson's disease: a 28-case analysis.

PMID- 10410776
TI  - Current controversies in pallidal surgery.

PMID- 10410777
TI  - Surgical treatment of levodopa-induced dyskinesias.

PMID- 10410778
TI  - New aspects in the pathophysiology of dyskinesia. Salpetriere Deep Brain
      Stimulation Group.

PMID- 10410779
TI  - Reversal of levodopa failure syndrome by posteroventral-ansa pallidotomy.

PMID- 10410780
TI  - Long-term electrostimulation of the ventroposterolateral pallidum in the
      treatment of Parkinson's disease.

PMID- 10410782
TI  - Long-term ventralis intermedius thalamic stimulation for parkinsonian tremor.
      Italian Registry for Neuromodulation in Movement Disorders.

PMID- 10410781
TI  - Effect of long-term stimulation of the ventral intermediate thalamic nucleus on
      gait in Parkinson's disease.

PMID- 10410783
TI  - Neural transplantation: can we improve the symptomatic relief?

PMID- 10410784
TI  - The case for neural tissue transplantation as a treatment for Parkinson's
      disease.
AB  - Neural tissue grafting can be highly effective and constitutes a potentially
      curative approach for progressive neurodegenerative disorders such as PD.
      Virtually all signs and symptoms of PD have been shown to improve after grafting
      but not necessarily simultaneously in one patient. Several technical aspects
      require improvement before widespread use of neural tissue implants can be
      recommended. These include better definition of donor tissue in terms of
      infectious risks, the need and duration of immunosuppressive treatment, and the
      minimal amount of tissue needed for definite benefit. Somatotropism within the
      basal ganglia system (with specific targeted grafts) aimed at relieving certain
      symptoms need to be elucidated experimentally. Interaction with the underlying
      disease process is also important to consider, and the role of intracerebral
      grafts in differing patterns of parkinsonism needs to be addressed. Grafting is
      potentially a very powerful therapeutic approach that may evolve to be the ideal
      treatment for patients with young-onset disease who, when starting to experience
      fluctuations, may have a life expectancy of 25 years with the disease. For these
      patients, grafting is likely to be both effective and long-lasting. For these
      patients, it is likely to become an efficient and also economically sound
      treatment for the patients and society. Provided that the transplantation
      procedure is performed judiciously and with strict adherence to basic principles
      defined from animal and human experimentation, more patients are likely to
      benefit from the procedure.

PMID- 10410785
TI  - The need for phase III studies in experimental surgical treatments of Parkinson's
      disease.

PMID- 10410786
TI  - Developmental alterations in the alpha-fetoprotein sugar chain in maternal serum
      analyzed by lectin affinity electrophoresis.
AB  - Our purpose was to investigate developmental alterations of human alpha
      fetoprotein (AFP) oligosaccharides in maternal serum by lectin affinity
      electrophoresis and to compare the AFP glycoforms in maternal serum with those in
      umbilical cord serum and amniotic fluid. AFP glycoforms were separated by
      affinity electrophoresis with concanavalin A (Con A), lentil lectin (LCA),
      erythroagglutinating phytohemagglutinin (E-PHA) and Allomyrina dichotoma lectin
      (allo A) and detected by sensitive antibody affinity blotting. In maternal serum,
      increased proportions of Con A-nonreactive AFP (AFP-C1), LCA strongly-reactive
      AFP (AFP-L3) and E-PHA-reactive AFP (AFP-P4 and AFP-P5) decreased gradually
      during the early gestational weeks. Allo A-nonreactive AFP (AFP-A1 and asialo
      AFP) were found only in amniotic fluids during early gestational weeks. The
      percentages of these glycoforms at full term were almost the same among those
      body fluids. Since the glycoforms of maternal serum AFP were close to those of
      umbilical cord serum AFP, lectin-affinity electrophoretic analysis of maternal
      serum AFP may be useful for evaluating the developmental state of fetus by
      examining the nature of AFP sugar chain.

PMID- 10410787
TI  - A new experimental system for irradiating tumors in mice using a linear
      accelerator under specific pathogen-free conditions.
AB  - We developed a reliable system for the irradiation of xenografted tumors in mice
      which allows for accurate local irradiation under specific pathogen-free
      conditions. The system presented here consists of acrylic supports for mice and
      an acrylic box connected to a pump through 0.22 microns pore-sized filters. Mice
      with xenotransplanted tumors growing on their right hind legs were set on the
      supports and put into the box in a laminar flow hood. The tumors of 7 mice were
      irradiated simultaneously with X-rays of 6 and 10 MV generated by a linear
      accelerator at a dose rate of 3.1-4.7 Gy/min. The air was ventilated through
      filters during irradiation in the closed box. Microorganism tests confirmed that
      no bacteria entered or left the box. One of the significant characteristics of
      this setup is that it allows for irradiation under conditions of acute hypoxia,
      which is obtained using an integrated tourniquet. The dose variation among 7
      tumors was less than 1%. The rest of the mouse's body was shielded effectively by
      a half-field technique and a lead block. As a result, the whole body dose for the
      mice was 0-4% of the total dose absorbed by the tumor. Due to the high dose rate
      and the ability to irradiate 7 mice simultaneously under specific pathogen-free
      conditions, this new system can be considered a time-saving and valuable tool for
      radiation oncology research.

PMID- 10410788
TI  - Preferential salivary-type hypoamylasemia in obese children.
AB  - Serum levels of total amylase, pancreatic type (P-type) isoamylase, and salivary
      type (S-type) isoamylase were measured in obese children (153 subjects; mean age,
      10.1 years old; 86 boys and 67 girls) before and after weight reduction therapy.
      Serum amylase activities were determined using p-nitrophenylmaltoheptaoside as a
      substrate, with or without an antibody added to inhibit the S-type isoamylase.
      Serum levels of total amylase, P-type isoamylase and S-type isoamylase activities
      were significantly decreased in obese children with an obesity index more than
      50%. S-type and P-type isoamylases showed negative correlation with the obesity
      index, the correlation coefficient being slightly larger in S-type than in P-type
      isoamylase. Analysis of the serum amylase activities in obese children who
      underwent weight reduction treatments showed a negative correlation only between
      the differences in S-type isoamylase activity and the differences in the obesity
      index. It may be concluded that the S-type isoamylase activity in serum of obese
      children is decreased and that it can be increased by reducing their body weight.

PMID- 10410789
TI  - Efficacy of lodoxamide eye drops on tear fluid cytology of patients with vernal
      conjunctivitis.
AB  - A double-masked, randomized, placebo-controlled study was conducted to evaluate
      the effectiveness of lodoxamide tromethamine 0.1% eyedrops in preventing
      inflammatory cell accumulation in the tear fluid of patients with vernal
      conjunctivitis. A 1-week baseline period was followed by 4 weeks of treatment
      with either lodoxamide tromethamine 0.1% ophthalmic solution or placebo in 30
      symptomatic subjects with vernal conjunctivitis. Cytological evaluation of tear
      fluid was performed before and after the treatment. In the lodoxamide-treated
      group, but not in the placebo-treated group, the number of neutrophils (P =
      0.051) and eosinophils (P = 0.020) in the tears significantly decreased at the
      end of 4 weeks when compared with baseline (Wilcoxon-signed rank test). It was
      concluded that lodoxamide treatment was significantly more effective than the
      placebo in terms of reducing inflammatory cells in the tear fluid in vernal
      conjunctivitis. This objective inhibition of inflammatory cells may be associated
      with clinical relief.

PMID- 10410790
TI  - The role of electromyography in the diagnosis of velopharyngeal insufficiency:
      our experiences.
AB  - The subject of this study is the electromyographic investigation of the
      velopharyngeal sphincter structures. Seventy-five patients underwent examination,
      both patients with symptoms of velopharyngeal insufficiency and patients who were
      thought to have latent pathological sphincter changes based on local findings. A
      control group of 10 healthy examinees was also investigated. On the basis of
      electromyographic findings we divided patients into 2 groups: 57 patients without
      neuromuscular disorders and 18 patients with neuromuscular disorders of the
      velopharyngeal sphincter. Twelve patients from the latter group had acute, and 6
      had chronic lesions of the velopharyngeal sphincter. Particular cases of illness
      within these 2 groups were investigated further. This study shows the usefulness
      of electromyography for diagnosing the exact causes of velopharyngeal
      insufficiency and for choosing the best approach to treatment.

PMID- 10410792
TI  - Medical students' perception of inpatients' anxiety, self-esteem, purpose-in-life
      and health locus of control as compared with nursing practitioners'.
AB  - Medical students (fourth-year: n = 67; fifth-year: n = 63) estimated inpatients'
      feelings of anxiety, self-esteem, purpose-in-life, and multidimensional health
      locus of control. Their ratings were compared both with the ratings given by the
      121 inpatients themselves and with those given by nursing practitioners (nurses
      and nursing students). Findings showed that the medical students overestimated
      inpatients' anxiety, while they underestimated the inpatients' purpose-in-life
      and internal health locus of control. Hence they underestimated, as did the
      nursing practitioners, the inpatients' positive emotional states and their
      positive attitude toward their own lives. Fifth-year medical students, with
      clinical experience, rated the inpatients' score of chance health locus of
      control higher than did the fourth-year medical students, who had no clinical
      experience. These findings indicate that medical students, like nursing
      practitioners, are inclined to pay more attention to inpatients' weaknesses than
      to their strengths.

PMID- 10410791
TI  - Urinary excretion of type I collagen cross-linked N-telopeptides, bone mass and
      related lifestyle in middle-aged women.
AB  - The relationship between past and present lifestyle and urinary excretion of type
      I collagen cross-linked N-telopeptides (NTx) was studied in 61 Japanese females
      aged 34-59, with a view toward using NTx excretion rates as a predictor of future
      osteoporosis. Bone mineral density (BMD) of the lumbar spine, the speed of sound
      (SOS) and broadband ultrasound attenuation (BUA) of the os calcis, urinary NTx,
      serum osteocalcin (BGP) and bone-specific alkaline phosphatase (BAP) were
      measured. Stiffness index (stiffness) was calculated from SOS and BUA. The
      subjects were asked whether they took regular exercise in their childhood and
      teen years (in elementary, junior-high, senior-high school and college), the past
      (20-40 years of age) and present adulthood. Regular calcium intake, smoking
      habits, alcohol and other beverage consumption and milk consumption were also
      covered in the questionnaire. The mean NTx values of premenopausal and
      postmenopausal group were 22.2 and 56.0 nM bone collagen equivalents (BCE)/mM
      urinary creatinine (Cr), respectively. The group which did not exercise regularly
      between the ages of 20 and 40 had a higher mean NTx value (40.9 nMBCE/mMCr) than
      the group which did exercise regularly (22.7 nMBCE/mMCr). In multiple regression
      analyses, age, stiffness and exercise in past adulthood could explain 43.5% of
      the NTx variance. For prevention of bone metabolic increases around menopause,
      habitual exercise in early adulthood seems to be effective.

PMID- 10410793
TI  - Raman spectroscopy of protein and nucleic acid assemblies.
AB  - The Raman spectrum of a protein or nucleic acid consists of numerous discrete
      bands representing molecular normal modes of vibration and serves as a sensitive
      and selective fingerprint of three-dimensional structure, intermolecular
      interactions, and dynamics. Recent improvements in instrumentation, coupled with
      innovative approaches in experimental design, dramatically increase the power and
      scope of the method, particularly for investigations of large supramolecular
      assemblies. Applications are considered that involve the use of (a) time-resolved
      Raman spectroscopy to elucidate assembly pathways in icosahedral viruses, (b)
      polarized Raman microspectroscopy to determine detailed structural parameters in
      filamentous viruses, (c) ultraviolet-resonance Raman spectroscopy to probe
      selective DNA and protein residues in nucleoprotein complexes, and (d) difference
      Raman methods to understand mechanisms of protein/DNA recognition in gene
      regulatory and chromosomal complexes.

PMID- 10410794
TI  - Multiprotein-DNA complexes in transcriptional regulation.
AB  - Transcription in eukaryotes is frequently regulated by a mechanism termed
      combinatorial control, whereby several different proteins must bind DNA in
      concert to achieve appropriate regulation of the downstream gene. X-ray
      crystallographic studies of multiprotein complexes bound to DNA have been carried
      out to investigate the molecular determinants of complex assembly and DNA
      binding. This work has provided important insights into the specific protein
      protein and protein-DNA interactions that govern the assembly of multiprotein
      regulatory complexes. The results of these studies are reviewed here, and the
      general insights into the mechanism of combinatorial gene regulation are
      discussed.

PMID- 10410795
TI  - RNA folds: insights from recent crystal structures.
AB  - An RNA fold is the result of packing together two or more coaxial helical stacks.
      To date, four RNA folds have been determined at near-atomic resolution by X-ray
      crystallography: transfer RNA, the hammerhead ribozyme, the P4-P6 domain of the
      Tetrahymena group I intron, and the hepatitis delta virus ribozyme. All four
      folds result in RNAs that are considerably more compact than isolated A-form
      duplexes. These structures illustrate, to varying degrees, three modes of fold
      stabilization: association of complementary molecular surfaces, stabilization of
      close RNA packing by binding of cations, and stabilization through
      pseudoknotting.

PMID- 10410796
TI  - Modern applications of analytical ultracentrifugation.
AB  - Analytical ultracentrifugation is a classical method of biochemistry and
      molecular biology. Because it is a primary technique, sedimentation can provide
      first-principle hydrodynamic and first-principle thermodynamic information for
      nearly any molecule, in a wide range of solvents and over a wide range of solute
      concentrations. For many questions, it is the technique of choice. This review
      stresses what information is available from analytical ultracentrifugation and
      how that information is being extracted and used in contemporary applications.

PMID- 10410797
TI  - DNA repair mechanisms for the recognition and removal of damaged DNA bases.
AB  - Recent structural and biochemical studies have begun to illuminate how cells
      solve the problems of recognizing and removing damaged DNA bases. Bases damaged
      by environmental, chemical, or enzymatic mechanisms must be efficiently found
      within a large excess of undamaged DNA. Structural studies suggest that a rapid
      damage-scanning mechanism probes for both conformational deviations and local
      deformability of the DNA base stack. At susceptible lesions, enzyme-induced
      conformational changes lead to direct interactions with specific damaged bases.
      The diverse array of damaged DNA bases are processed through a two-stage pathway
      in which damage-specific enzymes recognize and remove the base lesion, creating a
      common abasic site intermediate that is processed by damage-general repair
      enzymes to restore the correct DNA sequence.

PMID- 10410798
TI  - Nitroxide spin-spin interactions: applications to protein structure and dynamics.
AB  - Measurement of the distance between two spin label probes in proteins permits the
      spatial orientation of elements of defined secondary structure. By using site
      directed spin labeling, it is possible to determine multiple distance constraints
      and thereby build tertiary and quaternary structural models as well as measure
      the kinetics of structural changes. New analytical methods for determining
      interprobe distances and relative orientations for uniquely oriented spin labels
      have been developed using global analysis of multifrequency electron paramagnetic
      resonance data. New methods have also been developed for determining interprobe
      distances for randomly oriented spin labels. These methods are being applied to a
      wide range of structural problems, including peptides, soluble proteins, and
      membrane proteins, that are not readily characterized by other structural
      techniques.

PMID- 10410799
TI  - Molecular dynamics simulations of biomolecules: long-range electrostatic effects.
AB  - Current computer simulations of biomolecules typically make use of classical
      molecular dynamics methods, as a very large number (tens to hundreds of
      thousands) of atoms are involved over timescales of many nanoseconds. The
      methodology for treating short-range bonded and van der Waals interactions has
      matured. However, long-range electrostatic interactions still represent a
      bottleneck in simulations. In this article, we introduce the basic issues for an
      accurate representation of the relevant electrostatic interactions. In spite of
      the huge computational time demanded by most biomolecular systems, it is no
      longer necessary to resort to uncontrolled approximations such as the use of
      cutoffs. In particular, we discuss the Ewald summation methods, the fast particle
      mesh methods, and the fast multipole methods. We also review recent efforts to
      understand the role of boundary conditions in systems with long-range
      interactions, and conclude with a short perspective on future trends.

PMID- 10410800
TI  - The lysosomal cysteine proteases.
AB  - A significant number of exciting papain-like cysteine protease structures have
      been determined by crystallographic methods over the last several years. This
      trove of data allows for an analysis of the structural features that empower
      these molecules as they efficiently carry out their specialized tasks. Although
      the structure of the paradigm for the family, papain, has been known for twenty
      years, recent efforts have reaped several structures of specialized mammalian
      enzymes. This review first covers the commonalities of architecture and purpose
      of the papain-like cysteine proteases. From that broad platform, each of the
      lysosomal enzymes for which there is an X-ray structure (or structures) is then
      examined to gain an understanding of what structural features are used to
      customize specificity and activity. Structure-based design of inhibitors to
      control pathological cysteine protease activity will also be addressed.

PMID- 10410801
TI  - Rotational coupling in the F0F1 ATP synthase.
AB  - The F0F1 ATP synthase is a large multisubunit complex that couples translocation
      of protons down an electrochemical gradient to the synthesis of ATP. Recent
      advances in structural analyses have led to the demonstration that the enzyme
      utilizes a rotational catalytic mechanism. Kinetic and biochemical evidence is
      consistent with the expected equal participation of the three catalytic sites in
      the alpha 3 beta 3 hexamer, which operate in sequential, cooperative reaction
      pathways. The rotation of the core gamma subunit plays critical roles in
      establishing the conformation of the sites and the cooperative interactions.
      Mutational analyses have shown that the rotor subunits are responsible for
      coupling and in doing so transmit specific conformational information between
      transport and catalysis.

PMID- 10410802
TI  - Solid-state nuclear magnetic resonance investigation of protein and polypeptide
      structure.
AB  - Solid-state nuclear magnetic resonance (NMR) is rapidly emerging as a successful
      and important technique for protein and peptide structural elucidation from
      samples in anisotropic environments. Because of the diversity of nuclei and
      nuclear spin interactions that can be observed, and because of the broad range of
      sample conditions that can be studied by solid-state NMR, the potential for
      gaining structural constraints is great. Structural constraints in the form of
      orientational, distance, and torsional constraints can be obtained on proteins in
      crystalline, liquid-crystalline, or amorphous preparations. Great progress in the
      past few years has been made in developing techniques for obtaining these
      constraints, and now it has also been clearly demonstrated that these constraints
      can be assembled into uniquely defined three-dimensional structures at high
      resolution. Although much progress toward the development of solid-state NMR as a
      routine structural tool has been documented, the future is even brighter with the
      continued development of the experiments, of NMR hardware, and of the molecular
      biological methods for the preparation of labeled samples.

PMID- 10410803
TI  - Structure and conformation of complex carbohydrates of glycoproteins,
      glycolipids, and bacterial polysaccharides.
AB  - For nuclear magnetic resonance determinations of the conformation of
      oligosaccharides in solution, simple molecular mechanics calculations and nuclear
      Overhauser enhancement measurements are adequate for small oligosaccharides that
      adopt single, relatively rigid conformations. Polysaccharides and larger or more
      flexible oligosaccharides generally require additional types of data, such as
      scalar and dipolar coupling constants, which are most conveniently measured in
      13C-enriched samples. Nuclear magnetic resonance relaxation data provide
      information on the dynamics of oligosaccharides, which involves several different
      types of internal motion. Oligosaccharides complexed with lectins and antibodies
      have been successfully studied both by X-ray crystallography and by nuclear
      magnetic resonance spectroscopy. The complexes have been shown to be stabilized
      by a combination of polar hydrogen bonding interactions and van der Waals
      attractions. Although theoretical calculations of the conformation and stability
      of free oligosaccharides and of complexes with proteins can be carried out by
      molecular mechanics methods, the role of solvent water for these highly polar
      molecules continues to present computational problems.

PMID- 10410804
TI  - The proteasome.
AB  - Proteasomes are large multisubunit proteases that are found in the cytosol, both
      free and attached to the endoplasmic reticulum, and in the nucleus of eukaryotic
      cells. Their ubiquitous presence and high abundance in these compartments
      reflects their central role in cellular protein turnover. Proteasomes recognize,
      unfold, and digest protein substrates that have been marked for degradation by
      the attachment of a ubiquitin moiety. Individual subcomplexes of the complete 26S
      proteasome are involved in these different tasks: The ATP-dependent 19S caps are
      believed to unfold substrates and feed them to the actual protease, the 20S
      proteasome. This core particle appears to be more ancient than the ubiquitin
      system. Both prokaryotic and archaebacterial ancestors have been identified.
      Crystal structures are now available for the E. coli proteasome homologue and the
      T. acidophilum and S. cerevisiae 20S proteasomes. All three enzymes are
      cylindrical particles that have their active sites on the inner walls of a large
      central cavity. They share the fold and a novel catalytic mechanism with an N
      terminal nucleophilic threonine, which places them in the family of Ntn (N
      terminal nucleophile) hydrolases. Evolution has added complexity to the
      comparatively simple prokaryotic prototype. This minimal proteasome is a
      homododecamer made from two hexameric rings stacked head to head. Its heptameric
      version is the catalytic core of archaebacterial proteasomes, where it is
      sandwiched between two inactive antichambers that are made up from a different
      subunit. In eukaryotes, both subunits have diverged into seven different subunits
      each, which are present in the particle in unique locations such that a complex
      dimer is formed that has six active sites with three major specificities that can
      be attributed to individual subunits. Genetic, biochemical, and high-resolution
      electron microscopy data, but no crystal structures, are available for the 19S
      caps. A first step toward a mechanistic understanding of proteasome activation
      and regulation has been made with the elucidation of the X-ray structure of the
      alternative, mammalian proteasome activator PA28.

PMID- 10410805
TI  - Membrane protein folding and stability: physical principles.
AB  - Stably folded membrane proteins reside in a free energy minimum determined by the
      interactions of the peptide chains with each other, the lipid bilayer hydrocarbon
      core, the bilayer interface, and with water. The prediction of three-dimensional
      structure from sequence requires a detailed understanding of these interactions.
      Progress toward this objective is summarized in this review by means of a
      thermodynamic framework for describing membrane protein folding and stability.
      The framework includes a coherent thermodynamic formalism for determining and
      describing the energetics of peptide-bilayer interactions and a review of the
      properties of the environment of membrane proteins--the bilayer milieu. Using a
      four-step thermodynamic cycle as a guide, advances in three main aspects of
      membrane protein folding energetics are discussed: protein binding and folding in
      bilayer interfaces, transmembrane helix insertion, and helix-helix interactions.
      The concepts of membrane protein stability that emerge provide insights to
      fundamental issues of protein folding.

PMID- 10410806
TI  - Closing in on bacteriorhodopsin: progress in understanding the molecule.
AB  - Bacteriorhodopsin is the best understood ion transport protein and has become a
      paradigm for membrane proteins in general and transporters in particular. Models
      up to 2.5 A resolution of bacteriorhodopsin's structure have been published
      during the last three years and are basic for understanding its function. Thus
      one focus of this review is to summarize and to compare these models in detail.
      Another focus is to follow the protein through its catalytic cycle in summarizing
      more recent developments. We focus on literature published since 1995; a
      comprehensive series of reviews was published in 1995 (112).

PMID- 10410807
TI  - [Plea for rational use of perfusion methods in the acute stage of myocardial
      infarct].

PMID- 10410808
TI  - [Effect of resection of the anterior chordae on cardiac function after surgical
      correction of mitral valve insufficiency].
AB  - The preservation of cardiac function in surgical correction of mitral
      regurgitation implies partially or totally preserving the subvalvular apparatus.
      However, the conservation of the whole subvalvular apparatus during mitral valve
      replacement is technically difficult as the anatomical conditions are not always
      favourable. In order to determine the consequences of isolated resection of the
      anterior chordae, the authors studied global and segmental cardiac function by
      isotopic angiocardiography after mitral valve repair (n = 23) or replacement with
      conservation of the posterior chordae (n = 16) in 39 patients with isolated, non
      ischaemic mitral regurgitation. The left ventricular ejection fraction decreased
      after valve replacement (64.1 +/- 8.5% to 57.4 +/- 10%, p = 0.01) but not after
      mitral valve repair (65 +/- 11.3% to 62.1 +/- 12.2%, p = NS). The ejection
      fractions of segments 4 and 5, corresponding to the zones of insertion of the
      anterior papillary muscle, decreased after valve replacement compared with repair
      (segment 4: -9 +/- 13.7 versus +2 +/- 11.3, p = 0.01) (segment 5: -15 +/- 13.2
      versus 2 +/- 11.7, p = 0.003). The right ventricular ejection fraction improved
      after valve repair (40.9 +/- 9.1% to 46.4 +/- 10.1%, p = 0.03), whereas it
      remained unchanged after valve replacement (42.9 +/- 10.3% to 42.8 +/- 8.6%, p =
      NS). These results indicate a deleterious effect of isolated resection of the
      anterior chordae on cardiac function during mitral valve replacement with
      localised abnormalities of left ventricular function. This study supports the
      rationale of mitral valve repair or conservation of the anterior and posterior
      chordae during valve replacement for isolated mitral regurgitation.

PMID- 10410809
TI  - [Paradoxal lowering of parasympathetic indices in myasthenic patients].
AB  - Myasthenia gravis is an autoimmune disease presenting antibodies developed
      against the nicotinic receptors of acetylcholine. The aim of this study was to
      evaluate heart rate variability in these patients. Heart rate variability was
      studied with 24 hour Holter recordings. Eighteen myasthenic patients, 7 men and
      11 women, under pyridostigmine treatment, with an average age of 40 years (25 to
      63 years) were aged and gender matched to a control group of 18 healthy subjects.
      All patients exhibited normal cardiac status and Doppler echocardiography. The
      following parameters were collected over 24 hours and the data further
      differentiated between night and day: for the temporal domain: heart rate, SDNN,
      pNN50, rMSSD; and for the spectral domain: total power, high frequency (HF) and
      low frequency (LF) power. The mean heart rate was slightly higher in the
      myasthenic group (non significant), due to a less marked nocturnal bradycardia.
      There was a decrease in the observed absolute values of SDNN as well as temporal
      and spectral parasympathetic indices (pNN50, rMSSD, HF) (p < 0.01) over the 24
      hour period. The results were more significant during the night. Cardiac
      parasympathetic modulation is significantly modified in myasthenic patients.
      Considering that lack of bradycardia argues against an over active vagal tone,
      three hypothesis are discussed that favor of a low vagal tone: antibodies effects
      on the nicotinic receptors of the autonomic nervous system, respiratory
      impairment and a desensitization of the acetylcholine receptors.

PMID- 10410810
TI  - [A new diagnostic concept in cardiac pacing for the evaluation of the incidence
      of atrial arrhythmias. Results of the AIDA study].
AB  - An international, prospective, multicentre trial (AIDA) was undertaken from
      October 1995 to March 1997. The object was to compare the diagnosis of atrial
      arrhythmias (AA) by the automatic interpretation of the memory functions of dual
      chamber pacemakers with that of 24 hour Holter monitoring at day 1. The second
      objective was to assess the incidence and symptomatology of the AA during follow
      up at Day 28. In France, 226 patients implanted with Chorus, Chorus II and Chorus
      RM pacemakers were included in the study (148 men, 70.5 +/- 10.8 years) for the
      following indications: AVB (atrioventricular block)/bundle branch block (47.3%),
      sinus mode dysfunction (10.2%), bradycardia-tachycardia syndrome (10.2%), AVB +
      sinus node dysfunction + cardia-tachycardia syndrome (19.5%), other (2.2%). AA
      were documented in 34.5% of patients before implantation. Of the 226 patients
      analysed at Day 1, 23 (10.2%) had at least one episode of AA diagnosed
      simultaneously by Holter monitoring and the automatic interpretation (AIDA).
      These AA were atrial fibrillation (15 patients), atrial flutter (2 patients) and
      atrial tachycardia (6 patients). The sensitivity of the AIDA programme for
      detecting AA was 92% and the specificity 97%. Of the 156 patients evaluated at
      Day 28, the programme diagnosed AA in 78 patients (50%), 34 of which (21.8%) were
      asymptomatic and without previously documented AA. The results of the AIDA study
      confirmed the excellent sensitivity and specificity of the memory functions of
      these cardiac pacemakers for analysis of AA. They seem to be very common during
      the follow-up of pacemaker-equipped patients. This new diagnostic concept will
      facilitate the programming and study of the efficacy of anti-arrhythmic therapy
      prescribed during long-term follow-up.

PMID- 10410811
TI  - [Treatment of cardiac insufficiency: does treatment depend on whether its cause
      is ischemic or idiopathic?].
AB  - Angiotensin converting enzyme (ACE) inhibitors are associated with a greater
      reduction in mortality in non-ischaemic cardiomyopathy than in ischaemic
      cardiomyopathy after the results of the V-HeFT-II and SOLVD trials in symptomatic
      patients. However, a recent analysis of the global, symptomatic and therapeutic,
      results of the SOLVD trials, demonstrated a similar reduction in mortality with
      ACE inhibitors in ischaemic and non-ischaemic cardiomyopathies. Moreover, after
      myocardial infarction, the beneficial effects of ACE inhibitors have been well
      established in patients with left ventricular dysfunction. Betablockers,
      especially bisoprolol in the CIBIS-I trial, also seem to be more effective in non
      ischaemic cardiomyopathy. However, CIBIS-II and the US Carvedilol Heart Failure
      Trial Program clearly showed that the benefits of betablockade were identical
      whether ischaemic or not. The beneficial effects of betablockers in the post
      infarction period are more marked when left ventricular dysfunction is severe.
      The PROVED and RADIANCE trials suggest that digitalis is more effective in non
      ischaemic cardiomyopathy. These results were not confirmed by the DIG trial which
      showed a significant reduction in the combined criterion, mortality and hospital
      admission for aggravation of cardiac failure, both in ischaemic and in non
      ischaemic cardiomyopathy. However, the use of digitalis should be prudent during
      ischaemic cardiomyopathy, the neutral effect on global mortality in the DIG trial
      masking divergent results with a tendency to reducing mortality due to
      aggravation of cardiac failure and a significant increase of other causes of
      cardiac death, especially from myocardial infarction and arrhythmias. Amiodarone
      could also be useful in non-ischaemic cardiomyopathy. The reduction in risk of
      death in the GESICA study, which comprised 60% of patients with non-ischaemic
      cardiomyopathy, contrasting with the absence of an effect with this molecule in
      the STAT-CHF trial which only comprised 29% of patients with non-ischaemic
      cardiomyopathy. The new generation of calcium antagonists could also be more
      effective in non-ischaemic cardiomyopathy. Although amlodipine significantly
      reduced mortality in the PRAISE trial in non-ischaemic cardiomyopathy, there was
      no favourable effect with felodipine in the V-HeFT-III tria. Finally, if in the
      earlier studies oral anticoagulants were more effective in non-ischaemic
      cardiomyopathy, the recent results of the SOLVD trial showed that warfarin
      decreased the mortality in both ischaemic and non-ischaemic cardiomyopathy. The
      value of anti-aggregant therapy is not questioned in coronary artery disease, but
      its role in dilated cardiomyopathy has not yet been established. In conclusion,
      apart from the use of digitalis which must be prudent in post-infarction
      cardiomyopathy or in patients with ventricular arrhythmias, the treatment of
      cardiac failure differs little with respect to its ischaemic or non-ischaemic
      aetiology, and should be based on the NYHA (New York Heart Association)
      classification.

PMID- 10410812
TI  - [Combined blockade of the renin-angiotensin system].
AB  - In view of the internal counter-regulation mechanisms of the renin-angiotensin
      system (RAS), complete blockade would not seem to be possible if only one of its
      components is targeted. Instead of increasing the dosage of an angiotensin
      converting enzyme (ACE) inhibitor or that of an angiotensin II antagonist (AA),
      blockade of the system at two different levels by neutralising the internal
      counter-regulation mechanism could provide more effective blockade and,
      therefore, more pronounced biological effects. For this reason, the authors
      undertook two studies in a model of mild salt depletion of a normotensive
      subject, which showed additive effects on the lowering of the blood pressure and
      renin secretion during combined administration of captopril and losartan, then
      enalapril and losartan. There was no additive effect on plasma aldosterone
      levels. The administration of the ACE inhibitor neutralised the expected
      increases in plasma Angiotensin II values due to the losartan. All combinations
      of ACE inhibitor and AA were tested in spontaneous hypertensive rats using a
      dosage scale from 1 to 30, the results of which showed the beneficial effects of
      combined blockade on left ventricular mass and the deleterious effects on renal
      function when blockade of the RAS is too complete. Based on the results obtained
      in normotensive subjects and homogeneous groups of hypertensive animals, the
      authors conclude that low doses of an AA and of an ACE inhibitor is more
      effective in lowering the blood pressure than higher doses of each drug
      administered separately. How can these results be applied clinically in
      hypertension and cardiac failure? The choice between increasing the dose of each
      of the two drugs or the association of low doses of both drugs will depend more
      on the tolerance of each therapeutic strategy than on the efficacy. The choice
      between the two strategies will also depend on the demonstration of consequences
      specific to each modality of inhibition of the system, especially with respect to
      the effects of accumulation of bradykinin and to stimulation of type 2 receptors.
      The additive effects of a combined treatment should be validated by repeated
      administration in hypertensive patients.

PMID- 10410813
TI  - [Coronary microcirculation. Physiologic and pathologic aspects].
AB  - The coronary circulation has a protective regulation system which, in extreme
      haemodynamic conditions, compensates increased myocardial oxygen demand. The
      coronary reserve, based on this concept defines the capacity of the system to
      increase flow temporally, and, thereby, myocardial oxygen supply. The
      introduction of new methods of investigating the coronary microcirculation has
      enabled the study of this phenomenon in several cardiovascular pathologies. Two
      types of investigation are used currently for studying the coronary
      microcirculation: 1) invasive methods, especially the recently developed
      intracoronary Doppler and pressure guide, 2) non-invasive methods, and, in
      particular, contrast echocardiography, position emission tomography and magnetic
      nuclear resonance. These investigations allow measurement of the coronary reserve
      or the assessment of the myocardial consequences of abnormalities of the
      microcirculation. Some workers use these methods to investigate pathological
      coronary microcirculation in different cardiomyopathies, in the presence of
      different cardiovascular risk factors (hypertension, diabetes, smoking,
      hypercholesterolaemia) and after cardiac transplantation.

PMID- 10410814
TI  - [Hereditary resistance to vitamin K antagonists. Apropos of a case].
AB  - Resistance to vitamin K antagonists is a rare phenomenon. In general, it is the
      result of poor patient compliance, malabsorption, a diet rich in vitamin K, or
      the use of enzyme inducers. Occasionally, the diagnosis of resistance is made
      when plasma levels are high. The authors report a case of hereditary resistance
      to vitamin K antagonists in a 43 year old man admitted for atrial fibrillation.
      The precise prevalence of this anomaly is unknown. However, the existence should
      be known to clinicians who often use this important family of drugs.

PMID- 10410815
TI  - [Transthoracic echocardiography].

PMID- 10410816
TI  - [Transesophageal echocardiography].

PMID- 10410817
TI  - [Stress echocardioography].

PMID- 10410818
TI  - [Informed consent for implantation of automatic defibrillator].

PMID- 10410819
TI  - CCBs and cancer.

PMID- 10410820
TI  - Calcium antagonists and cancer: causation or association?

PMID- 10410821
TI  - Angina: who needs it? Cardioprotection in the preconditioning era.
AB  - Over the past two decades, it has been demonstrated in various animal species
      that the myocardium possesses innate adaptive mechanisms that may render it more
      resistant to ischemic injury. Ischemic preconditioning, defined as the protection
      conferred to ischemic myocardium by prior episodes of brief sublethal ischemia,
      is one of the most potent of such adaptive phenomena. Extensive research over the
      past decade has alluded to the cellular mechanisms underlying this powerful means
      of reducing myocardial ischemia-reperfusion injury. Moreover, the possibility
      that such adaptive mechanisms might be inducible in the human heart has generated
      considerable excitement and enthusiastic research, which has significantly
      enhanced our understanding of the pathogenesis of ischemia-reperfusion injury. An
      insight into the mechanisms underlying the cardioprotective properties of
      ischemic preconditioning has, on the one hand, directed research aimed at
      identification of novel therapeutic agents for the treatment of ischemic heart
      disease, and on the other, questioned the use of potentially deleterious agents
      that may abolish the cardioprotective actions of ischemic preconditioning in
      patients with angina. Current studies are under way to evaluate the potential
      protection afforded by these "preconditioning" agents in patients with acute
      coronary syndromes, and some early reports provide some basis for optimism that a
      beneficial and clinically detectable improvement in myocardial protection may be
      possible. This article reviews our current knowledge of the cellular mechanisms
      responsible for mediation of ischemic preconditioning, the evidence for the
      existence of this phenomenon in humans, and its potential therapeutic
      applications.

PMID- 10410822
TI  - Meeting report: Hatter Institute workshop on myocardial preconditioning.

PMID- 10410823
TI  - Nisoldipine selectively induces coronary vasodilation and improves mild
      myocardial ischemia in dogs: a potential role of cellular acidosis.
AB  - We examined whether nisoldipine, a calcium (Ca) channel blocker, increases
      coronary blood flow (CBF) without decreasing aortic blood pressure (AoP) with
      ischemic and nonischemic hearts, and whether the presence of cellular acidosis in
      ischemic myocardium contributes to the augmentation of coronary vasodilation due
      to nisoldipine. In 42 dogs, coronary perfusion pressure (CPP) was reduced so that
      CBF decreased to 60% of the baseline, and CPP was maintained constant thereafter.
      First, we administered nisoldipine into a systemic vein in the ischemic and
      nonischemic hearts. Second, nisoldipine was administered into the canine coronary
      artery of the ischemic myocardium, with and without administration of either
      sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), or amiloride. Nisoldipine
      (0.25-4.0 mg/kg, i.v.) increased CBF by 59% in the ischemic myocardium more than
      the nonischemic myocardium (by 34%) without reducing AoP. The infusion of
      nisoldipine (40 ng/kg/min, IC) increased CBF markedly by about 55% in the
      ischemic myocardium with increases in fractional shortening (FS; 11 +/- 2% to 21
      +/- 2%) and lactate extraction ratio (LER; -19 +/- 4% to 15 +/- 2%). Increases in
      CBF, FS, and LER were markedly attenuated during administration of nisoldipine
      with concomitant administration of either NaHCO3 or NaOH. Furthermore, the extent
      of increases in CBF (54 +/- 2 mL/100 g/min), FS (13 +/- 2%), and LER (-17 +/- 4%)
      were also markedly attenuated due to the concomitant treatment with amiloride. We
      conclude that myocardial cellular acidosis plays an important role in mediating
      coronary vasodilation affected by nisoldipine in the ischemic myocardium. H+ may
      modulate the property of voltage-dependent Ca channels via Na(+)-H+ exchange.

PMID- 10410824
TI  - Effects of trimetazidine on metabolic and functional recovery of postischemic rat
      hearts.
AB  - The objective of this study was to test the hypothesis that the beneficial effect
      of trimetazidine during reflow of ischemic hearts is mediated by energy sparing
      and ATP pool preservation during ischemia. Isolated rat hearts (controls and rats
      treated with 10(-6) M trimetazidine, n = 17 per group) underwent the following
      protocol: baseline perfusion at normal coronary flow (20 minutes), low-flow
      ischemia at 10% flow (60 minutes), and reflow (20 minutes). We measured
      contractile function, O2 uptake, lactate release, venous pH and PCO2, and the
      tissue content of high-energy phosphates and their metabolites. During baseline,
      trimetazidine induced higher venous pH and lower PCO2 without influencing
      performance and metabolism. During low-flow ischemia, trimetazidine reduced
      myocardial performance (P = 0.04) and ATP turnover (P = 0.02). During reflow,
      trimetazidine improved performance (91 +/- 6% versus. 55 +/- 6% of baseline),
      prevented the development of diastolic contracture and coronary resistance, and
      reduced myocardial depletion of adenine nucleotides and purines. ATP turnover
      during low-flow ischemia was inversely related to recovery of the rate-pressure
      product (P = 0.002), end-diastolic pressure (P = 0.007), and perfusion pressure
      (P = 0.05). We conclude that trimetazidine-induced protection of ischemic
      reperfused hearts is also mediated by energy sparing during ischemia, which
      presumably preserves the ATP pool during reflow.

PMID- 10410825
TI  - Beta-adrenergic blockade decreases coronary collateral blood flow in patients
      with coronary artery disease.
AB  - The effect of beta-adrenergic blockade on coronary collateral blood flow has not
      been clarified. We examined the acute effects of beta-adrenergic blockade on
      coronary collateral blood flow. Fifteen patients (Part A) with stable angina were
      studied while undergoing coronary angioplasty. According to the protocol, all
      patients underwent a minimum of three balloon inflations. Collateral flow
      velocity was determined during balloon inflations using the Doppler flow
      guidewire positioned distally to the lesion. The two tested balloon inflations,
      the second and third, were maintained for the same length of time. Between the
      second and third balloon inflations, 1 mg of propranolol was administered IC into
      the treated artery. Ten controls were studied following saline infusion. In 10
      other patients (Part B), the effect of 1 mg IC propranolol on the coronary artery
      area distal to the lesion was studied, and five patients served as controls. In
      the treated group, in Part A blood pressure remained stable during the balloon
      inflations tested. Heart rate decreased from 79 +/- 11 to 73 +/- 12 beats/min (P
      < .05), velocity time integral from 9.6 +/- 8.2 to 6.6 +/- 4.1 cm (P < .05), and
      ST elevation from 1.3 +/- .9 to .9 +/- 1.0 mV (P < .05) between the second and
      third balloon inflations. In the controls the variables examined did not change
      during the balloon inflations tested. In Part B, neither propranolol nor normal
      saline had any significant effect on coronary artery lumen area. Thus, IC
      administration of beta-adrenergic blockade decreases coronary collateral blood
      flow, and this potentially worsens the ischemic zone. However, beta-adrenergic
      blockade ameliorates myocardial ischemia during coronary angioplasty.

PMID- 10410826
TI  - Disproportional response between refractory period and blood flow to alpha 1- and
      beta-adrenoceptor blockade in canine ischemic myocardium.
AB  - We investigated the response of refractory periods and blood flow to blockade of
      alpha 1- and beta-adrenoceptors alone, or in combination on endocardium and
      epicardium, during myocardial ischemia. Dogs were anesthetized with alpha
      chloralose and divided into bunazosin (an alpha 1-blocking agent)-treated (0.1
      0.2 mg/kg, i.v., n = 14), propranolol-treated (0.2 mg/kg, i.v., n = 12), and
      vehicle-control (n = 10) groups. The diagonal branches of the left anterior
      descending artery were ligated. The refractory period (ERP) and blood flow (RMBF)
      were determined by an S1-S2 extrastimulus method and a nonradioactive microsphere
      technique, respectively. The duration of regional electrograms (DRE) was measured
      in the endocardial and epicardial sites. Bunazosin alone reversed the ischemia
      related shortening of ERPs at both the endocardial and epicardial sites, with a
      greater effect seen epicardially (P < .05). Subsequent administration of
      propranolol further prolonged ERPs in both sites, although the effect was greater
      in the epicardial surface (P < .05). Bunazosin reduced RMBF to a greater degree
      at the endocardial site than at the epicardial site in the ischemic zone (P < .01
      and P < .05, respectively), but the magnitude of the reduction in RMBF and the
      difference in RMBF between sites were similar to the control group (P < .01).
      Propranolol alone and subsequent administration of bunazosin prolonged the ERP
      more at the epicardial site (P < .01) than at the endocardial sites in the
      ischemic zone. Propranolol produced no significant difference in RMBF between
      both sites. DREs in animals treated with bunazosin and propranolol alone, or in
      combination, were similar to those in animals treated with vehicle. These results
      suggest that differences in ERPs between endocardium and epicardium with blockade
      of alpha 1- and/or beta-adrenoceptor are not due to concomitant alterations in
      RMBF, but to differences in electrophysiological properties of the endocardial
      and epicardial cells during the acute phase of myocardial ischemia.

PMID- 10410827
TI  - Differential rate and potassium-dependent effects of the class III agents d
      sotalol and dofetilide on guinea pig papillary muscle.
AB  - The class III agents d-sotalol and dofetilide have been shown to exhibit
      differential effects in large controlled clinical trials. The aim of this study
      was to investigate the basic electrophysiological properties of these two
      antiarrhythmia agents in an in vitro experimental model with regard to potential
      antiarrhythmic and proarrhythmic action. Using standard microelectrode
      techniques, we evaluated the electrophysiological effects of d-sotalol and
      dofetilide on action potential parameters recorded from guinea pig papillary
      muscle at 2.5 mM, 3.5 mM, and 5.6 mM extracellular potassium concentrations. The
      following parameters were recorded: resting membrane potential (RMP), action
      potential amplitude (APA), action potential duration at 90% repolarization (APD
      90), and maximum upstroke velocity (Vmax). Under all conditions studied, both d
      sotalol and dofetilide exhibited highly selective reverse rate-dependent class
      III action. In contrast to dofetilide, the class III activity of d-sotalol was
      markedly influenced by changes in extracellular potassium concentrations,
      predominantly at low pacing rates. Hypokalemia enhanced the action potential
      prolonging effects of d-sotalol, whereas hyperkalemia diminished this effect. In
      addition, reverse rate dependence associated with dofetilide was significantly
      more pronounced than reverse rate dependence associated with d-sotalol. Our
      observations provide a potential electrophysiological basis for differential
      antiarrhythmic and proarrhythmic mechanisms associated with these two drugs.

PMID- 10410828
TI  - Mechanism underlying the strong positive inotropic effects of LND-623: specific
      inhibition of Na, K-ATPase isoforms and exclusion of cellular sites of
      contractile control.
AB  - LND-623 is a new aminosteroid analog of ouabain, with a greater separation
      between efficacy and toxicity than ouabain. To determine its mechanism of action,
      we studied its biochemical and physiological effects on human red blood cell
      sodium transports on different cellular structures regarded as sites of
      contractile control, and we compared its relative efficacy to ouabain in rat
      heart preparations and membrane-bound Na, K-ATPase isoenzymes. The response to
      ouabain was evaluated in Langendorff-perfused hearts and on purified membrane
      bound Na, K-ATPase. LND-623 is 6.8-fold more efficient than ouabain in inhibiting
      the human Na+ pump (IC50 = 0.098 +/- 0.001 microM vs. 0.67 +/- 0.02 microM); (P <
      0.0001). LND-623 had no effect on the following cellular functions: Na-Ca
      exchange, Na-K cotransport, Ca-ATPase, slow calcium channels, adenylate cyclase
      system, phosphodiesterase, and calcium sensitivity of the contractile protein
      system. The dose-response curve for the positive inotropic and inhibitory effects
      on rat cardiac isoenzymes produced by LND-623 were clearly biphasic. The
      amplitude of the maximum inotropic effect, without any toxic effect, was up to
      three-fold higher with LND-623 than with the same maximum dose of ouabain used.
      The strong positive inotropic effect of LND-623 in rats could be related to a
      specific inhibition of the two rat cardiac isoforms of the Na, K-ATPase.

PMID- 10410829
TI  - Pimobendan has a potent venodilating action in patients with congestive heart
      failure.

PMID- 10410830
TI  - Echocardiographic findings of the heart resembling dilated cardiomyopathy during
      hypokalemic myopathy due to licorice-induced pseudoaldosteronism.

PMID- 10410831
TI  - The roles of receptor abnormalities in the pathogenesis and chronic complications
      of type 2 diabetes mellitus.
AB  - Type 2 diabetes mellitus is a polygenic disorder with complicated biochemical
      alterations. Numerous investigators have examined the implication of receptor
      abnormalities in the pathogenesis of the disorder. The authors review the
      potential roles of some important receptors, such as the insulin receptor, beta 3
      adrenergic receptor, leptin receptor and peroxisome proliferator-activated
      receptor gamma, in the pathogenesis of human type 2 diabetes. They emphasize the
      significance of effective glycemic control by examining the evidence that
      strongly suggests the association of chronic complications of type 2 diabetes
      with abnormalities of receptors for the advanced glycation end products,
      transforming growth factor-beta and platelet-derived growth factor. The molecular
      understanding of receptor abnormalities and alterations in postreceptor
      signalling pathways may not only clarify the pathogenesis of human type 2
      diabetes and the development of chronic complications in the disorder but also
      provide insight into more efficacious drug regimens that target these receptors.

PMID- 10410832
TI  - Prevalence and severity of nausea and vomiting of pregnancy and effect of vitamin
      supplementation.
AB  - OBJECTIVE: Although nausea and vomiting of pregnancy is the most common medical
      condition during pregnancy, there are many unanswered questions regarding its
      cause, epidemiologic features and optimal management. The objectives of this
      study were to ascertain the prevalence of nausea and vomiting in a sample of
      Canadian women, to characterize the distribution of their severity and to
      investigate the role of vitamin B6 deficiency in their etiology. DESIGN:
      Prospective study. SETTING: Antenatal counselling service for pregnant women.
      PATIENTS: Three cohorts of women: a prospective, population-based cohort of 193
      women, to estimate the rate and severity of nausea and vomiting (cohort A); a
      cohort of 555 women who sought advice for nausea with or without vomiting, to
      study the correlation between the maximal daily number of episodes of vomiting
      and maximal weight loss (cohort B); and a prospective cohort of 301 women who
      reported vomiting, to correlate vitamin supplementation with vomiting (cohort C).
      INTERVENTIONS: All 3 cohorts were interviewed during the counselling session, and
      cohort B was followed up prospectively. OUTCOME MEASURES: Frequency of nausea and
      vomiting, weight loss, maximal number of daily episodes of vomiting, rate of
      multivitamin supplementation. RESULTS: Overall, 67% of the women in cohort A
      reported experiencing nausea or vomiting, or both; 22% reported vomiting, and 9%
      experienced weight loss. In cohort B there was a significant correlation between
      the maximal number of daily episodes of vomiting and maximal weight loss,
      although there was wide variation (r2 = 0.25, p < 0.001). There was a highly
      significant correlation between the number of daily vomiting episodes and mean
      weight loss (r2 = 0.99). In cohort C, vomiting was significantly associated with
      lack of supplementation with multivitamins before 6 weeks' gestation (p = 0.002).
      CONCLUSIONS: The relation between number of daily vomiting episodes and mean
      weight loss may serve as a clinical tool to assess the severity of nausea and
      vomiting in pregnancy and the success of anti-emetics and rehydration regimens.
      Further study is needed to elucidate the biologic basis of the observed
      association between vomiting and lack of multivitamin supplementation in early
      pregnancy.

PMID- 10410833
TI  - Testing for HIV among patients with tuberculosis in Montreal.
AB  - OBJECTIVE: To determine the rate of HIV testing among patients with tuberculosis
      (TB) in Montreal, and to identify patient characteristics associated with
      physician screening patterns. Knowledge of local patterns of HIV testing among
      patients with TB could be used to facilitate the development of strategies to
      improve compliance with recommendations that all patients with TB be screened for
      HIV. DESIGN: Retrospective chart review. PATIENTS: All patients with TB reported
      to the Montreal Public Health Unit from 1992 to 1994 (ages 19 to 50) and from
      1992 to 1995 (ages 18 and under) and for whom a chart could be reviewed. OUTCOME
      MEASURES: Patients with TB screened versus not screened for HIV infection,
      analyzed to determine which variables independently predict the likelihood of
      screening for HIV infection. RESULTS: Of the 376 patients with TB for whom data
      were available, 192 (51%) were screened for HIV. Of those, 33 (17%) had been
      tested before having received the diagnosis of TB. Multivariate analysis revealed
      that patients with TB who were male, aged 30 to 39, had a positive sputum smear,
      displayed at least 1 clinical symptom, received the TB diagnosis from a
      microbiologist or infectious disease specialist, or reported 1 or more HIV risk
      factors were more likely to be screened for HIV. CONCLUSIONS: HIV screening of
      patients with TB is selective, depending on both patient and physician
      characteristics. Physicians' awareness of recommendations needs to be increased
      to improve the diagnosis and treatment of TB/HIV co-infection.

PMID- 10410834
TI  - Reshaping health research in Canada: an initiative whose time has come.

PMID- 10410835
TI  - Role of carbohydrate in physical activity.
AB  - Carbohydrate is an essential fuel for prolonged, strenuous exercise, although the
      carbohydrate stores of the body are limited. Research studies have provided
      evidence that carbohydrate depletion is associated with fatigue, decrease in
      exercise intensity, and even exercise cessation. With the appropriate diet and
      exercise protocol, however, the carbohydrate stores of the body can be
      substantially increased and exercise performance improved by carbohydrate
      supplementation before and during exercise. In this article, the role of
      carbohydrate supplementation for increasing carbohydrate stores before exercise,
      maintaining blood glucose during exercise, and the rapid replenishment of the
      carbohydrate stores after exercise are discussed. Considered in the discussion
      are the types, amounts and forms of carbohydrate supplements that are most
      effective, and the most appropriate times for their ingestion.

PMID- 10410836
TI  - Role of fats in exercise. Types and quality.
AB  - Plasma TGs, FFAs, and muscle TG are oxidizable lipid fuel sources for skeletal
      muscle metabolism during prolonged exercise. Plasma FFAs are a major fuel
      oxidized by skeletal muscle, and their rate of use by muscle depends on several
      factors, including plasma FFA availability, transport from plasma to the
      mitochondria, and intracellular metabolism. Mobilization of FFAs from adipose
      tissue is the first committed step in FFA metabolism, and it depends on the rate
      of adipose tissue lipolysis. Adipose tissue lipolysis increases with exercise
      duration and exercise intensity up to intensities of approximately 60% to 65%.
      Evidence suggests that FFAs are transported from plasma to the mitochondria by
      FFA transporter proteins that include the plasma membrane and cytosolic FABPPM
      and FABPC. Plasma FFA use can also be regulated at the mitochondrial transport
      step by changing the activity of carnitine palmitoyltransferase (CPT-1). Although
      results from biopsy and tracer studies indicate that muscle TG contribute to
      skeletal muscle oxidative metabolism during exercise, their exact contribution is
      difficult to ascertain. Evidence shows that muscle TG use depends on exercise
      intensity, duration, and mode. The contribution of plasma TG to skeletal muscle
      metabolism is small. The rate of use of plasma TG is dependent on lipoprotein
      lipase activity, which is correlated with the oxidative capacity of the muscle
      fibers. Dietary manipulations can modulate substrate use during exercise and can
      potentially affect exercise performance. High carbohydrate availability before
      exercise is associated with an increase in blood glucose and plasma insulin
      concentrations, which can ultimately decrease the rate of adipose tissue
      lipolysis and the availability of plasma FFAs. Increased glucose flux has also
      been shown to decrease lipid oxidation by directly inhibiting the transport of
      FFAs across the mitochondrial membranes. High lipid availability can be changed
      by short-term or long-term exposure to high-fat diets. Because carbohydrate
      reserves are diminished with exposure to high-fat diets, improvements in exercise
      performance have been difficult to measure under these conditions.

PMID- 10410837
TI  - Role of protein in exercise.
AB  - Most research confirms that the body's increased use of protein, as a "fuel" and
      for repair, increases with aerobic exercise, especially during high intensity and
      long duration activity. Protein intake higher than the United States Food and
      Drug Administration's Recommended Dietary Allowance (RDA), with additional energy
      and resistance training, results in optimal protein status for participants in
      strength training. Although many active individuals interpret this research to
      mean that they need to consume extra protein foods or supplements to perform
      optimally, most people in the United States already consume protein at a level
      well above the RDA. Physicians should be aware that low energy consuming
      individuals (e.g., women, those dieting for weight loss, the elderly) may be at
      risk for low protein intake, and thus protein status, if they are active.

PMID- 10410838
TI  - Water and electrolyte requirements for exercise.
AB  - Exercise performance can be compromised by a body water deficit, particularly
      when exercise is performed in hot climates. It is recommended that individuals
      begin exercise when adequately hydrated. This can be facilitated by drinking 400
      mL to 600 mL of fluid 2 hours before beginning exercise and drinking sufficient
      fluid during exercise to prevent dehydration from exceeding 2% body weight. A
      practical recommendation is to drink small amounts of fluid (150-300 mL) every 15
      to 20 minutes of exercise, varying the volume depending on sweating rate. Core
      temperature, heart rate, and perceived effort remain lowest when fluid
      replacement comes closest to matching the rate of sweat loss. During exercise
      lasting less than 90 minutes, water alone is sufficient for fluid replacement.
      During prolonged exercise lasting longer than 90 minutes, commercially available
      carbohydrate electrolyte beverages should be considered to provide an exogenous
      carbohydrate source to sustain carbohydrate oxidation and endurance performance.
      Electrolyte supplementation is generally not necessary because dietary intake is
      adequate to offset electrolytes lost in sweat and urine; however, during initial
      days of hot-weather training or when meals are not calorically adequate,
      supplemental salt intake may be indicated to sustain sodium balance.

PMID- 10410839
TI  - Antioxidants and exercise.
AB  - Muscular exercise results in an increased production of radicals and other forms
      of reactive oxygen species. Further more, growing evidence implicates cytotoxic
      ROS as an underlying cause in exercise-induced disturbances in muscle redox
      status that could result in muscle fatigue or injury. Muscle cells contain
      complex cellular defense mechanisms to minimize the risk for oxidative injury.
      Two major classes of endogenous protective mechanisms work together to reduce the
      harmful effects of oxidants in the cell: (1) enzymatic and (2) nonenzymatic
      antioxidants. Key antioxidant enzymes include superoxide dismutase, glutathione
      peroxidase, and catalase. These enzymes are responsible for removing superoxide
      radicals, hydrogen peroxide or organic hydroperoxides, and hydrogen peroxide,
      respectively. Important nonenzymatic antioxidants include vitamins E and C, beta
      carotene, GSH, uric acid, ubiquinone, and bilirubin. Vitamin E, beta-carotene,
      and ubiquinone are located in lipid regions of the cell, whereas uric acid, GSH,
      and bilirubin are in aqueous compartments of the cell. Although numerous animal
      experiments have demonstrated that the addition of antioxidants can improve
      muscular performance, to date, limited evidence shows that dietary
      supplementation with antioxidants improves human performance. This is an
      important area for future research.

PMID- 10410840
TI  - Nutrition, exercise, and immune system function.
AB  - Many components of the immune system exhibit adverse change after prolonged,
      intense exertion. During this "open window" of impaired immunity (which may last
      3-72 h, depending on the immune measure), viruses and bacteria may gain a
      foothold, increasing the risk for subclinical and clinical infection. The
      influence of nutritional supplements, primarily zinc, vitamin C, glutamine, and
      carbohydrate, on the acute immune response to prolonged exercise has been
      measured in endurance athletes. Vitamin C and glutamine have received much
      attention, but the data thus far are inconclusive. The most impressive results
      have been reported with carbohydrate supplementation. Carbohydrate beverage
      ingestion has been associated with increased plasma glucose levels, an attenuated
      cortisol and growth hormone response, fewer perturbations in blood immune cell
      counts, decreased granulocyte and monocyte phagocytosis and oxidative burst
      activity, and a diminished pro-inflammatory and anti-inflammatory cytokine
      response. Overall these data indicate that the physiologic stress to the immune
      system is reduced when endurance athletes use carbohydrate beverages before,
      during, and after prolonged and intense exertion. The clinical significance of
      these carbohydrate-induced effects on the endocrine and immune systems awaits
      further research.

PMID- 10410841
TI  - Nutritional needs of the female athlete.
AB  - US women, including female athletes, are under ever increasing pressure to be
      thin ar thinner. this pressure to achieve and maintain a low body weight leads to
      potentially harmful patterns of long-term dieting or disordered eating, which can
      affect long-term health. Some of the health consequences of long-term energy
      restriction in female athletes may include poor energy and nutrient intakes, poor
      nutritional status, decreased RMR and total daily energy expenditure, increased
      psychological stress and risk for a clinical eating disorder, and increased risk
      for exercise-induced amenorrhea and osteoporosis. Female athletes participating
      in thin-build sports may be at risk for the disorders of the female athlete
      triad: disordered eating, amenorrhea, and osteoporosis. This triad of disorders
      can also produce severe health consequences that can influence present and future
      health. Strategies for helping active women get off the dieting "bandwagon"
      requires the identification of an appropriate and healthy body weight, good
      eating and exercise habits, and techniques for maintaining these habits
      throughout life.

PMID- 10410842
TI  - Nutrition in the exercising elderly.
AB  - When making nutrition recommendations to the exercising elderly population, four
      important areas should be taken into consideration: (1) the changing needs that
      occur with age; (2) the changing needs that occur with exercise; (3) the presence
      of any chronic illnesses or diseases; and (4) whether one is exercising for
      fitness, recreation, or competition. For the most part, these four areas have
      been researched separately, and recommendations for elderly athletes need to be
      synthesized from this information. The nutrients for which food consumption is
      often inadequate and has the largest impact on the exercising elderly population
      include vitamin B6, vitamin B12, calcium, and vitamin D. The exercising elderly
      population needs to be aware of their bodies changing needs with exercise and
      should focus on maintaining energy balance while selecting a wide variety of
      foods high in complex carbohydrates. When adequate dietary intakes cannot be
      obtained, supplementation with a multivitamin of no more than 100% of the RDA is
      recommended.

PMID- 10410843
TI  - Nutrition and exercise in individuals with diabetes.
AB  - Individuals with type 1 (insulin-dependent diabetes mellitus [IDDM]) and type 2
      (non-insulin-dependent diabetes mellitus [NIDDM]) diabetes should be encouraged
      to exercise. Although there is an absence of consistent evidence that adaptations
      to routine exercise improve glucose control in type 1 diabetes, there is evidence
      that shows improved glucose control in individuals with type 2 diabetes. Although
      both groups benefit from exercise, the merit and suitability of routine exercise
      is measured by the extent to which the advantageous adaptive effects of regular
      exercise surpass the risks of a sole bout of exercise. In addition, when
      considering acute versus routine exercise, special considerations must be given
      to children with diabetes and older adults at risk for insulin resistance.
      Finally, a greater research focus is needed on engaging in competitive and
      recreational sports so that children and adults with diabetes may participate
      safely in activities such as baseball, swimming, basketball, soccer, and hockey.

PMID- 10410844
TI  - Nutrient requirements at high altitude.
AB  - Travel to terrestrial altitudes greater than 2500 m, for more than 2 to 3 days,
      results in acute and long-term physiologic adaptations with the potential to
      profoundly affect the requirements for some nutrients. This article discusses the
      evidence for these increased requirements and makes recommendations regarding
      appropriate intakes at high altitude. Discussion of nutrients includes energy and
      the food components that supply it (i.e., protein, carbohydrate, and fat), water,
      vitamins, and minerals. Because the anorexia associated with high altitude
      exposure may limit the intake of adequate nutrients, a food and water regimen, or
      "doctrine," is proposed and described.

PMID- 10410845
TI  - Nutritional requirements to increase lean mass.
AB  - If a physician determines that an athlete has the potential to increase lean body
      mass, the following components are necessary for success: appropriate progressive
      resistance-training program. Adequate rest and sleep. Adequate energy intake.
      Five to nine eating occasions a day. Increased amount of food if possible. High
      energy supplements. Adequate protein intake. [table: see text]

PMID- 10410846
TI  - Facts and fallacies of purported ergogenic amino acid supplements.
AB  - Although current research suggests that individuals involved in either high
      intensity resistance or endurance exercise may have an increased need for dietary
      protein, the available research is either equivocal or negative relative to the
      ergogenic effects of supplementation with individual amino acids. Although some
      research suggests that the induction of hyperaminoacidemia via intravenous
      infusion of a balanced amino acid mixture may induce an increased muscle protein
      synthesis after exercise, no data support the finding that oral supplementation
      with amino acids, in contrast to dietary protein, as the source of amino acids is
      more effective. Some well-controlled studies suggest that aspartate salt
      supplementation may enhance endurance performance, but other studies do not,
      meriting additional research. Current data, including results for several well
      controlled studies, indicated that supplementation with arginine, ornithine, or
      lysine, either separately or in combination, does not enhance the effect of
      exercise stimulation on either hGH or various measures of muscular strength or
      power in experienced weightlifters. Plasma levels of BCAA and tryptophan may play
      important roles in the cause of central fatigue during exercise, but the effects
      of BCAA or tryptophan supplementation do not seem to be effective ergogenics for
      endurance exercise performance, particularly when compared with carbohydrate
      supplementation, a more natural choice. Although glutamine supplementation may
      increase plasma glutamine levels, its effect on enhancement of the immune system
      and prevention of adverse effects of the overtraining syndrome are equivocal.
      Glycine, a precursor for creatine, does not seem to possess the ergogenic
      potential of creatine supplementation. Research with metabolic by-products of
      amino acid metabolism is in its infancy, and current research findings are
      equivocal relative to ergogenic applications. In general, physically active
      individuals are advised to obtain necessary amino acids through consumption of
      natural, high-quality protein foods.

PMID- 10410847
TI  - Creatine supplementation. Its role in human performance.
AB  - Creatine supplementation is the most popular nutritional supplement today.
      Although many questions remain regarding the use and benefits of creatine
      supplementation, a fast-growing body of literature is starting to define both its
      acute and chronic effects on human and physiologic performance. The initial data
      indicate that this energetic boost of the phosphagen energy system also helps to
      enhance strength and power training. Few documented side effects have been
      demonstrated in the medical and scientific literature, but further investigation
      is still required as to long-term use (i.e., beyond several months).

PMID- 10410848
TI  - Steroids and steroid-like compounds.
AB  - Athletes have been searching for an "edge" in competition as long as there has
      been a reward for success. Anabolic-androgenic steroids have been the most
      popular of these ergogenic aids when winning is the only goal. The authors
      present a concise review of these substances, their prevalence, efficacy, adverse
      effects, and legality. This article also presents a steroid user profile and
      discusses physician perception and management of a patient who uses these drugs.
      The popular precursors of testosterone, dehydroepiandrosterone, and
      androstenedione are discussed with a review of the limited available data on
      these substances.

PMID- 10410849
TI  - Popular weight loss diets. Health and exercise implications.
AB  - Obesity is a serious problem in the United States. More than 50% of adult
      Americans have body mass indices equal to or greater than 25--the new criteria
      for being overweight. US Government health organizations have recently issued
      clinical guidelines for the identification, evaluation, and treatment of obesity,
      and criteria for evaluating weight loss programs. Despite all this, overweight
      individuals often turn for guidance to weight loss books and programs promoted in
      the popular press rather than healthcare professionals. A review of some of the
      most popular diet programs reveals that they fall along a continuum from
      "anticarbohydrate" to "anti-fat." Several of these diets are discussed and
      evaluated based on the criteria proposed by obesity experts.

PMID- 10410850
TI  - Dietary examples. A practical approach to feeding athletes.
AB  - This article provides practitioners with meal plan samples at four calorie levels
      as a guide for planning athletes' food choices. Many good and practical
      publications are available for trainers and dietitians who assist athletes in
      their nutritional plans. The two primary needs of people with increased physical
      activity are increased energy and fluid intakes. As illustrated in this article,
      these energy needs can be met fairly easily at various calorie levels with a meal
      plan. For individual requirements, athletes should consult with health care
      professionals for calorie and fluid requirements.

PMID- 10410851
TI  - Pediatric echocardiography: applications and limitations.
AB  - Echocardiography is an extraordinarily useful imaging technique in fetuses,
      infants, children, and adolescents. Recent technologic innovations have expanded
      its versatility in the pediatric population. However, limited societal resources,
      limitations inherent to ultrasound imaging, and numerous imaging options even
      within the field of pediatric echocardiography necessitate the discriminate and
      thoughtful use of echocardiography in children. The clinical assessment remains a
      critical prelude to echocardiographic examination of the pediatric cardiovascular
      system.

PMID- 10410852
TI  - Update on the cutaneous manifestations of HIV infection. Clinical and pathologic
      features.
AB  - Skin is the most commonly affected organ in patients with HIV. As such, cutaneous
      manifestations of HIV infection have been the subject of intense scrutiny as well
      as the topic of many articles. A broad range of infectious and noninfectious skin
      lesions may develop during the course of the disease. This article discusses the
      clinical and pathological cutaneous manifestations of HIV infection.

PMID- 10410853
TI  - Update on inherited bullous dermatoses.
AB  - Bullous diseases are becoming increasingly better understood owing to the active
      research which has taken place in this field over the past decade. Advances in
      understanding of bullous disease pathophysiology is translating into clinical
      applications for diagnosis and therapy that will greatly enhance the quality of
      care bullous disease patients may receive now and in the future. This review
      focuses on the progress which has been achieved in inherited bullous dermatoses.

PMID- 10410854
TI  - Histopathologic and immunohistochemical diagnosis of benign and malignant fibrous
      and fibrohistiocytic tumors of the skin.
AB  - This article describes the histopathology and immunohistochemistry of benign and
      malignant fibrous and fibrohistiocytic tumors. Some of the benign
      fibrohistiocytic proliferation's have atypical variants which could be
      misinterpreted as malignant processes. Key points for the diagnosis of these
      entities based on routine histology and immunohistochemistry are presented.

PMID- 10410855
TI  - Selected cutaneous vascular neoplasms. A review.
AB  - This article reviews the pathology of benign, borderline, and malignant vascular
      neoplasms of the skin. The classification of vascular lesions of childhood is
      presented. Defined variants of hemangioma (including sinusoidal, microvenular,
      glomeruloid, epithelioid, and targetoid hemosideric hemangioma, as well as
      acquired tufted hemangioma and angiofibroma) are discussed. Borderline
      hemangioendotheliomas are classified. Kaposi sarcoma is reviewed with an update
      on the role of human herpesvirus type 8 in its pathogenesis. Angiosarcoma and
      acquired progressive lymph-angioma are also discussed.

PMID- 10410856
TI  - Clinical, histopathologic, and molecular aspects of cutaneous human
      papillomavirus infections.
AB  - Human papillomaviruses comprise a large family of double stranded DNA viruses
      that are the etiologic agents of benign warts and anogenital cancers. At least 82
      different human papillomavirus types have been identified and many remain yet
      uncharacterized. The development of new molecular techniques in recent years has
      led to an increased understanding of human papillomaviruses and their roles in
      carcinogenesis. Several clinicopathologic entities arising from human
      papillomavirus infection encountered by the dermatologist are the subject of the
      article. The epidemiology, molecular biology, clinical presentation, histologic
      findings, and treatment of each disorder, where applicable, is discussed.

PMID- 10410857
TI  - Recent advances in the pathology of cutaneous drug eruptions.
AB  - Cutaneous reactions to drug therapy may be of either immunologic or
      nonimmunologic etiology. It is important that the dermatologist and pathologist
      be familiar with these types of cutaneous reactions. This article discusses the
      clinical features, pathogenesis, and histopathology of various cutaneous drug
      eruptions.

PMID- 10410858
TI  - Immunopathology of the human hair follicle.
AB  - Although patients are told that, in many instances, their hair loss is
      precipitated by stress, they are certainly stressed and saddened by their
      alopecia. They would be elated with the ability to regrow their hair. Ideally,
      therapy would be specific and targeted at the cascade of inflammatory, cytokine
      mediated, and mesenchymal events which lead to hair loss. Such is the case with
      infectious folliculitides: Pityrosporum folliculitis is cleared with antifungal
      agents, bacterial folliculitis is cleared with antibiotics, and herpetic
      folliculitis is treated with antiviral agents. Future studies of the hair
      follicle will perhaps unlock the mechanisms that drive and maintain normal hair
      growth. Until that time scientists will, no doubt, continue to be fascinated by
      the intricate developmental and immunologic mechanisms that drive this micro
      organ of the skin.

PMID- 10410859
TI  - Cutaneous lymphoma. Understanding the new classification schemes.
AB  - Both the REAL and EORTC classification schemes classify lymphomas according to
      their cell of origin. These schemata also incorporate clinical features that
      allow for the distinction of some of these disorders. The EORTC classification
      scheme for primary cutaneous tumors uses terminology similar to that of the REAL
      classification and should allow for the recognition of teleologically similar
      tumors in cutaneous and extracutaneous sites. Future investigations will no doubt
      yield information regarding the true nature of the low-grade B-cell lymphomas of
      the skin and sort out the ever-increasing number of tumors found to express CD30.
      Most important, the continued expansion of knowledge regarding cutaneous
      lymphomas should enhance the ability of physicians to predict prognosis and to
      arrive at the most effective therapy for patients with these diseases.

PMID- 10410860
TI  - Morphologic spectrum of cutaneous B-cell lymphomas.
AB  - Cutaneous B-cell lymphomas represent a heterogeneous group of entities which show
      variation in histology, immunophenotype, and in prognosis. In the current review
      the morphologic spectrum of cutaneous B-cell lymphomas comprising primary and
      secondary cutaneous B-cell lymphomas is discussed according to the REAL
      classification scheme.

PMID- 10410861
TI  - Cutaneous T-cell lymphoma. Refinement in the application of controversial
      histologic criteria.
AB  - The term cutaneous T-cell lymphoma was originally coined to encompass the
      spectrum of mycosis fungoides and Sezary syndrome. It has become increasingly
      evident that the histopathologic diagnosis of CTCL can be exceedingly
      challenging. A series of recent studies, however, have helped clarify the nature
      of the histologic findings in CTCL. Recently reported histologic data on mycosis
      fungoides, Sezary syndrome, and their variants is emphasized in this article,
      with special focus given to the findings in early lesions. A brief summary of
      lymphocyte immunophenotyping and the role of T-cell reception gene rearrangements
      in CTCL is included.

PMID- 10410862
TI  - Recent developments in the pathology of melanocytic neoplasia.
AB  - This article selectively discusses clinically relevant aspects of the pathology
      of cutaneous melanocytic neoplasms, from the literature of the past recent years.
      Topics include the changing role of immunohistochemistry in diagnosis, the
      controversies over dysplastic nevi, description of other specialized variants of
      melanocytic nevi, diagnosis of melanocytic neoplasms of acral skin, and melanoma
      occurring in childhood. Several variants of melanoma including desmoplastic and
      spindle-cell types, verrucous melanoma, epidermotropic melanoma, and melanoma of
      the female genitalia are reviewed. The issue of appropriate margins of resection
      for melanoma and the use of Mohs Micrographic surgery for this tumor are
      considered. Finally, a review of the sentinel node biopsy technique and of nodal
      nevi is presented.

PMID- 10410863
TI  - Update of diagnostic and prognostic markers in cutaneous malignant melanoma.
AB  - The biomolecules described in this article generally have been studied as
      possible diagnostic or clinically prognostic markers in the context of melanoma
      disease progression as measured by the gold standards of tumor thickness and
      development of metastasis. Most of the markers showed variations in expression
      phenotype only during the deeply invasive or metastatic stage of tumor
      progression and were thus predictive of clinical outcome only for these subgroups
      of patients. Some of the markers may have utility in identifying patients with
      deeply invasive primary tumors who are likely to develop metastasis and thus
      should receive earlier, more aggressive treatments. In addition, some of the
      markers may identify patients likely to respond better to a new type of therapy
      (e.g., anti-angiogenic therapy in a patient whose tumor is overexpressing VEGF or
      immunotherapy for a patient whose tumor is expressing high levels of MART-1). In
      the future, it will probably be possible to employ new techniques, such as laser
      guided microdissection of tissues, to isolate individual melanocytes in order to
      identify the earliest stage-specific defects that contribute to an aggressive
      biological behavior. Identifying the subset of patients with superficially
      invasive melanomas who will develop metastatic disease will continue to provide a
      challenge.

PMID- 10410864
TI  - Sentinel lymphadenectomy in the management of primary cutaneous malignant
      melanoma. An update.
AB  - The management of lymph nodes in melanoma patients who have no clinical evidence
      of nodal disease has changed dramatically with the development of selective lymph
      node biopsy. This procedure localizes the node in a regional basin most likely to
      contain a metastasis (the sentinel node) and averts the morbidity of unnecessary
      elective node dissection. This update reviews the rationale for this procedure
      and describes the methodology used by the surgeon and the pathologist. A progress
      report highlights the promise and limitation of this procedure. Sentinel node
      biopsy is currently the standard for staging select groups of melanoma patients,
      but the field is rapidly evolving and may eventually be surpassed by even newer
      molecular diagnostic techniques.

PMID- 10410865
TI  - Use of the polymerase chain reaction in the evaluation of cutaneous T-cell
      infiltrates.
AB  - Histologic evaluation of suspected cutaneous T-cell neoplasia is challenging.
      There is significant overlap with features of benign condition, and neoplastic
      cells often occur in a reactive background. Recently, molecular techniques using
      paraffin-embedded tissue have been applied to the diagnosis of cutaneous T-cell
      infiltrates. These methods are useful for determining whether a clonal population
      of T-cells is present. The advantages and limitation of molecular diagnostic
      methods in the diagnosis of cutaneous T-cell infiltrates are discussed.

PMID- 10410866
TI  - Immunohistochemistry in diagnostic dermatopathology.
AB  - This article briefly reviews many immunohistochemical stains that have been in
      use for years, emphasizing their diagnostic use and potential pitfalls. Several
      newer immunostains are described in a more comprehensive fashion, including brief
      summaries from recently published studies.

PMID- 10410867
TI  - Update on immunoelectron microscopy in diagnostic dermatopathology and cutaneous
      biology.
AB  - Immunoelectron microscopy for diagnostic dermatopathology is hardly ever
      necessary. Immunoelectron microscopy, however, is very helpful in the work-up of
      interesting cases, for the study of genetic and autoimmune bullous diseases and
      for basic science studies, particularly in conjunction with molecular biology
      techniques. It is also very helpful for investigators requiring double labeling.

PMID- 10410868
TI  - A sherlockian approach to contact dermatitis.
AB  - Identifying the etiology of allergic contact dermatitis requires detective work.
      Not all allergic reactions are eczematous in appearance. The most reliable
      clinical clue to the allergic nature of the dermatitis is its geographic
      distribution. Patch testing provides the list of culprit allergens. The mystery
      is solved when the suspected allergen is found to be relevant and the patient has
      been adequately instructed in allergen avoidance.

PMID- 10410869
TI  - Tear lysozyme activity in frozen Schirmer strips and salivary gland biopsy as
      parameters of lacrimal gland function.
AB  - PURPOSE: The lysozyme concentration in human tears is an important parameter for
      tear gland function. The decline of lysozyme in tears reflects lacrimal gland
      destruction. In Sjogren's patients, lacrimal gland destruction parallels labial
      salivary gland destruction. The objective of this study was to determine whether
      human tear lysozyme that was frozen on Schirmer strips at -20 degrees C for
      several years maintained activity and whether there was a linear relation with
      inflammatory changes in labial salivary glands. METHODS: A total of 200 frozen
      Schirmer strips were processed. They were collected from 20 randomly selected
      patients each year of five consecutive years, all attending the UCSF Sjogren's
      Clinic. The tear lysozyme in the Schirmer strips was measured by a colorimetric
      assay. The average lysozyme concentration each year was calculated and compared.
      One third of the patients underwent labial salivary gland biopsy. The correlation
      was calculated between the tear lysozyme concentration and the lymphocytic focus
      scores in biopsy specimens. RESULTS: No significant difference of average
      lysozyme concentration in the Schirmer strips was found when the five different
      years of collection were compared. The linear relation between the tear lysozyme
      concentrations and the focus score in labial salivary gland biopsies showed a
      coefficient of r = -0.41. The linear relation between other diagnostic
      measurements, like Schirmer test, tear breakup time, or rose bengal staining
      pattern, and the focus score was lower. CONCLUSIONS: Human tear lysozyme in
      Schirmer strips can be stored at -20 degrees C for at least five years. There is
      little difference in lysozyme activity of frozen compared to unfrozen specimens.
      The lysozyme concentration in tears correlates better with the lymphocytic focus
      score in labial salivary gland biopsy than does clinical assessment and is
      therefore a parameter for the actual degree of tear gland destruction.

PMID- 10410870
TI  - Clinical application of a homogeneous colorimetric assay for tear lysozyme.
AB  - PURPOSE: Tear lysozyme and tear lactoferrin are enzymes synthesized by the
      lacrimal gland. Their concentration in human tears reflects tear gland function.
      Tear gland dysfunction can lead to ocular surface disease. We developed a
      colorimetric lysozyme assay. The objective of this study was to determine the
      diagnostic power and the clinical application of this assay that allows rapid and
      precise quantification of tear lysozyme. METHODS: Tear specimens of 120 eyes (30
      Sjogren's patients and 30 controls) were collected using standardized filter
      paper discs. Tear lysozyme concentration was determined using p-nitrophenyl penta
      N-acetyl-beta-chitopentaoside as substrate in the colorimetric assay. The results
      were compared to clinical findings and to two commonly used tests, the
      Micrococcus agar diffusion assay for tear lysozyme and the tear lactoferrin
      immunodiffusion assay. RESULTS: The colorimetric assay showed a good dose
      response relationship. The use of the assay as a method of diagnosing aqueous
      tear deficiency, using the clinical findings and the medical history as gold
      standard, demonstrated 85% sensitivity and 92% specificity. The results of the
      colorimetric assay when compared with the Micrococcus agar diffusion assay showed
      a linear relationship of r=0.77; when compared with the lactoferrin immunoassay
      r=0.73. CONCLUSIONS: The colorimetric assay is simple to perform and does not
      require sophisticated laboratory equipment and personnel. Results can be
      precisely quantified within one hour after tear collection. The diagnostic power
      of the test is comparable to previously reported assays for lysozyme and
      lactoferrin and will be useful in the diagnosis of ocular surface disease.

PMID- 10410871
TI  - Experimental ocular toxoplasmosis induced in naive and preinfected mice by
      intracameral inoculation.
AB  - We have developed a murine model to investigate the pathogenesis of acquired
      ocular toxoplasmosis. Tachyzoites of PLK strain of Toxoplasma gondii were
      intracamerally inoculated under anesthesia into the right eyes of naive or
      perorally preinfected C57BL/6 and MRL-MpJ mice. Clinical and histopathological
      observations of responses to intraocular infection were analyzed. Ocular
      inflammation from Toxoplasma gondii is dose-dependent in both strains of mice.
      After inoculation of fifty parasites, no evidence of inflammation was observed in
      the eyes of naive mice. The eyes of naive mice that received 500 or 5,000
      parasites developed inflammatory changes by day 6 post challenge. By day 8, the
      changes progressed to moderate to severe intraocular inflammation. Histologic
      analysis of the ocular lesions demonstrated mononuclear cell infiltration and
      necrosis predominantly in the anterior segment of the eyes of the naive mice.
      Inoculation of 50,000 tachyzoites induced a destructive ocular inflammatory
      response and was uniformly lethal to the mice by approximately one week after
      challenge. In contrast, eyes from mice previously orally infected with Toxoplasma
      gondii and that received a 50 or 500 parasite intracameral challenge revealed no
      inflammation, but the eyes receiving 5,000 parasites demonstrated necrotic focal
      retinochoroiditis with vitreitis by day 8 after challenge. The murine model
      reproduces some features of ocular toxoplasmosis in humans and may be suitable
      for large-scale controlled studies of the pathogenesis and therapeutics of
      acquired ocular toxoplasmosis as well as for study of the mechanisms of immune
      privilege in the eye.

PMID- 10410872
TI  - Differential regulation of nitric oxide synthase-II mRNA by growth factors in
      rat, bovine, and human retinal pigmented epithelial cells.
AB  - Retinal pigmented epithelial cells (RPE cells) express the inducible isoform of
      NO synthase (NOS-II) after stimulation by cytokines and endotoxin. We have
      attempted to describe and compare the effect of fibroblast growth factor (FGF)
      and transforming growth factor beta (TGFbeta) on NOS-II mRNA level in three
      different cell species: rat, bovine, and human. Northern blot analysis
      demonstrated that, in the rat RPE cells, FGF upregulates and TGFbeta inhibits NOS
      II mRNA accumulation, whereas in the bovine cells, the opposite effect appears.
      For the human RPE cells, RT-PCR analysis demonstrated that FGF upregulates and
      TGFbeta inhibits NOS-II mRNA accumulation, as in rat cells, even though the
      effect of TGFbeta was weaker. Thus, this study demonstrates that marked
      differences in growth factors regulating NOS-II occur between species, suggesting
      fundamental signal transduction differences at some level between rat, human, and
      cow.

PMID- 10410873
TI  - Role of tear inflammatory mediators in contact lens-associated giant papillary
      conjunctivitis in soft contact lens wearers.
AB  - Contact lens-associated giant papillary conjunctivitis (CL-GPC) caused by
      mechanical and immune mechanisms is a significant problem resulting in contact
      lens intolerance and discontinuation of contact lens wear. In the present study,
      tear fluid leukotriene C4 (LTC4) level was evaluated in soft contact lens wearers
      with and without CL-GPC using ELISA. Statistical analysis showed no significant
      difference in tear fluid LTC4 between contact lens wearers without GPC and normal
      controls (p>0.05), but a significant increase in tear LTC4 level in CL-GPC
      patients (p<0.05). On the basis of this finding, it might be possible to explain
      redness, conjunctival edema, increased mucoid secretion, and papillary changes by
      the effect of LTC4 on eye tissues. Effective treatment of CL-GPC might be
      possible in the future by employing inhibitors of leukotriene synthesis and
      action.

PMID- 10410874
TI  - Bovine iris-sphincter muscle lacks FP receptor binding sites.
AB  - PURPOSE: To determine the affinity, density, and specificity of the binding sites
      of tritium-labeled prostaglandin F2alpha in membrane preparations of bovine iris
      sphincter muscle and corpus luteum. METHODS: Membrane preparations were incubated
      with 0.312-40.0 nM 3H-prostaglandin F2alpha in saturation experiments, or 8 nM 3H
      prostaglandin F2alpha in competition studies, in the presence or absence of
      varying concentrations of unlabeled prostaglandin F2alpha or other prostaglandin
      receptor agonists. The affinity (Kd) and the density of the binding sites (Bmax)
      of 3H-prostaglandin F2alpha in the bovine iris-sphincter muscle were determined
      by Scatchard analysis. Reverse transcription polymerase chain reaction was
      performed with bovine iris-sphincter muscle and corpus luteum total RNA and the
      PCR products were hybridized with specific 32P-labeled probe for further
      confirmation of FP receptor expression. RESULTS: Specific binding sites of 3H
      prostaglandin F2alpha in the membranes of bovine iris-sphincter muscle are
      saturable with an affinity of 9.5 nM and a density of 596 fmoles/mg of protein.
      Prostaglandin E2, 17-phenyl trinor prostaglandin E2, and GR63799 (EP, EP1, and
      EP3 receptor agonists, respectively) inhibited 3H-prostaglandin F2alpha binding
      with an IC50 of 0.0048 microM, 0.0038 microM, and 0.044 microM, respectively.
      Fluprostenol, a specific FP receptor agonist did not inhibit 3H-prostaglandin
      F2alpha binding. In contrast, prostaglandin F2alpha and fluprostenol effectively
      inhibited 3H-prostaglandin F2alpha binding in the bovine corpus luteum with an
      IC50 of 0.031 microM and 0.037 microM, respectively. CONCLUSIONS: Our results
      demonstrate that in the bovine iris-sphincter muscle, FP receptors are not
      expressed and 3H-prostaglandin F2alpha binds to EP1 and EP3 receptor sites. RT
      PCR results demonstrated that FP receptor mRNA, which is present in bovine corpus
      luteum, is probably absent in iris-sphincter muscle.

PMID- 10410875
TI  - Efficacy of low-dose and long-term oral acyclovir therapy after penetrating
      keratoplasty for herpes simplex heratitis.
AB  - PURPOSE: To evaluate the efficacy of long-term and low-dose prophylactic oral
      acyclovir therapy in preventing the recurrence of herpetic infection and
      increasing graft survival in patients who undergo penetrating keratoplasty (PK)
      for herpes simplex keratitis (HSK). PATIENTS AND METHODS: Nineteen patients were
      included in the study, who underwent PK for herpes keratitis from July 1993 to
      November 1995, received oral acyclovir, and were followed at least 12 months.
      Group 1 included 12 patients with corneal scarring without perforation. These
      patients were free of inflammation for a mean of 4.1+/-2.2 months preoperatively,
      and received oral acyclovir 400 mg/day postoperatively for one year. Seven
      patients (Group 2) who developed corneal perforation due to necrotizing keratitis
      were treated with tissue adhesives, therapeutic contact lenses, and topical
      antiviral and oral acyclovir therapy for the resolution of active inflammation
      followed by PK after a mean of 3.8+/-2.1 months follow-up. They received oral
      acyclovir 400 mg/day postoperatively for one year in addition to standard
      postoperative therapy. The control group consisted of 16 patients (Groups 3 and
      4) who underwent PK for herpes simplex keratitis and did not receive oral
      acyclovir. The indication for PK was corneal opacity and impaired visual acuity
      in 12 patients (Group 3) and corneal perforation in four (Group 4). RESULTS:
      After an average of 25 months follow-up, there was only one recurrence (8.3%) in
      Group 1 and two cases (28.6%) of herpetic recurrence in Group 2. Recurrence
      occurred at two months in one patient while he was taking oral acyclovir. Two of
      these recurrences followed the withdrawal of oral acyclovir therapy after one
      year of therapy. In contrast, in control groups there were four cases of herpetic
      recurrence (33.3%) in Group 3 and two (50%) in Group 4 after a mean of 30.5
      months postoperative follow-up. In the study groups, a rejection episode was seen
      in three patients (15.8%) which was successfully treated with medical therapy.
      One patient from Group 2 developed bacterial keratitis which subsequently
      resulted in graft failure. All grafts remained clear in the other patients
      (94.7%). In the control groups, rejection developed in seven patients. Three
      rejection episodes were treated successfully. The other four developed graft
      failure in spite of intensive medical therapy. CONCLUSIONS: Our results suggest
      that postoperative oral acyclovir therapy is effective in preventing the
      recurrence of herpetic infection. However, the recurrence may develop after
      cessation of oral acyclovir therapy, especially in patients who underwent PK for
      corneal perforation due necrotizing HSK.

PMID- 10410877
TI  - Surgical treatment of recurrent primary ovarian leiomyosarcoma. A case report.

PMID- 10410876
TI  - Human papillomavirus 18 oncoproteins E6 and E7 enhance irradiation- and
      chemotherapeutic agent-induced apoptosis in p53 and Rb mutated cervical cancer
      cell lines.
AB  - Tumor suppressor genes p53 and Rb are important in cell cycle control. Necessity
      of wild type p53 is implicated in irradiation-induced apoptosis. Numerous tumor
      cells carry p53 mutations and yet are sensitive to irradiation or
      chemotherapeutic agents. Therefore p53-and Rb-independent pathways must exist to
      account for irradiation-induced apoptosis. We evaluated the apoptotic response of
      a p53- and Rb-mutated, Human Papilloma Virus (HPV) negative cervical cancer cell
      line (C33a), and C33a cell lines infected with HPV 18 oncoproteins E6, E7, and
      E6&7 using recombinant retrovirus to various apoptosis-inducing agents including
      gamma irradiation, mitomycin C (MMC), and staurosporine (SSP). Apoptosis was
      measured by avidinebiotin tunnel staining method. Our results showed significant
      apoptosis in C33a cell lines in response to gamma-irradiation, MMC, and SSP.
      Moreover, apoptosis was enhanced when HPV 18 E6, and E6&7 infected C33a cell
      lines were treated with irradiation, MMC, and SSP. HPV 18 E7 infected C33a cell
      lines enhanced the apoptotic response to irradiation and to MMC, but not to SSP.
      In conclusion, our results imply the presence of a p53- and Rb-independent
      pathway in irradiation-induced apoptosis in cervical cancer cell lines: this
      effect is even more evident in HPV oncoprotein infected cell lines. The
      radiosensitizing effects of HPV oncoproteins may lead to new perspectives in the
      treatment of cervical cancer.

PMID- 10410878
TI  - Multiple primary tumors in a woman exposed to the excess radiation of the
      Chernobyl nuclear disaster.

PMID- 10410880
TI  - Malignant melanoma of the vulva: report of six cases and review of the
      literature.
AB  - Six patients with vulvar malignant melanoma are reported. They accounted for 5.2%
      of all females with vulvar malignancies diagnosed in the south of Israel between
      1961 and 1997. Age ranged from 25 to 66 years. Presenting symptoms were pruritus,
      bleeding and ulcer. Lesion originated in the labia minora in four patients and
      the labia majora in two, and lesion size ranged from I to 8 cm. Five patients had
      nodular melanoma, and one had superficial spreading melanoma. Breslow depth
      ranged from 2.5 to 8 mm, Clark level was IV in four patients and III in two, and
      Chung level was IV in all patients. Two patients had radical vulvectomy and
      bilateral groin lymphadenectomy, one had wide local excision, and one refused
      surgery. The two patients who had radical hemivulvectomy and bilateral groin
      lymphadenectomy were given adjuvant active specific immunotherapy with allogeneic
      vaccine and have survived disease-free, whereas the remaining four patients died
      of disease. It is concluded that vulvar malignant melanoma is a rare and
      aggressive tumor. For patients who present with deep lesions (Breslow depth >
      0.76 mm, Clark level > II, Chung level > II) the recommended treatment is wide
      radical local excision (or at the most, radical hemivulvectomy) and bilateral
      groin lymphadenectomy.

PMID- 10410879
TI  - Secretion of vascular endothelial growth factor in ovarian cancer.
AB  - Vascular endothelial growth factor (VEGF) is an important regulator of vascular
      endothelial cell function during vasculogenesis and tumor growth and is believed
      to play a major role in peritoneal fluid accumulation in ascites tumors. High
      VEGF production from primary tumors has been reported to correlate with increased
      metastatic spreading and worse prognosis compared to low VEGF secreting tumors.
      In addition, VEGF secretion has recently been proposed as one of the major
      factors responsible for defective immune function in cancer patients. In order to
      evaluate whether ovarian carcinomas actively secrete VEGF, in this study we have
      analyzed and quantified VEGF secretion in several fresh and established human
      ovarian carcinoma cell lines in vitro using a sensitive enzyme-linked
      immunosorbent assay (ELISA). In addition, VEGF levels were also evaluated in the
      ascitic fluids and plasma of six ovarian cancer patients. All fresh tumors
      secreted high levels of VEGF (mean = 5,046, range between 1,760 and 7,780
      pg/ml/10(5) cells/48 hr) when compared to established ovarian carcinoma cell
      lines (mean = 493, range between 160 to 1,120 pg/ml/10(5) cells/48 hr) (p <0.02).
      Importantly, high grade malignancies were found to secrete larger amounts of VEGF
      (mean = 6,660 pg/ml) when compared to lower grade tumors (mean = 1,820 pg/ml) (p
      <0.01). Ascitic fluids from all patients were rich in VEGF (mean = 5,483, range
      between 1,300 and 11,200 pg/ml) and plasma levels of VEGF in ovarian cancer
      patients were significantly higher (mean = 408, range between 160 and 810 pg/ml)
      when compared with healthy individuals (mean = 46, range between 35 and 60 pg/ml)
      (p <0.01). Taken together, these data demonstrate that ovarian cancers secrete
      large amounts of VEGF in vitro and in vivo. This findings therefore suggest that
      this factor may play a crucial role in the genesis of ascitic fluid accumulation,
      angiogenesis and tumor induced immunosuppression in ovarian cancer patients. The
      design of anti-angiogenic treatment directed at blocking the action of VEGF may
      be a reasonable novel therapeutic approach in the treatment of ovarian cancer.

PMID- 10410881
TI  - Glioblastoma multiforme in a dermoid cyst of the ovary. A case report.
AB  - Malignant change to glioblastoma multiforme in a mature cystic teratoma (dermoid
      cyst) is exceptionally rare. Besides a report on such a case we give a brief
      review of the literature on this subject and a comment on treatment. The reported
      case is about a 41-year-old woman with a mature cystic teratoma of the ovary with
      transformation to glioblastoma multiform. The tumor was limited to the ovary and
      completely excised by salpingo-oophorectomy. Three and a half years after surgery
      the patient is alive without evidence of recurrent disease. For limited stage Ia
      tumors we found support in the literature for expectant management after surgery,
      without adjuvant chemotherapy.

PMID- 10410882
TI  - Ovarian carcinoma metastatic to bilateral axillary lymph nodes. A case report.
AB  - BACKGROUND: Ovarian cancer is a major cause of cancer deaths in women and usually
      presents with diffuse abdominal disease. Lymph node metastases are common, but
      axillary lymph nodes are rarely involved. CASE: A 63-year-old woman, initially
      presenting with abdominal symptoms and massive ascites, underwent optimal
      cytoreduction followed by intravenous chemotherapy with paclitaxel and
      carboplatin. The patient subsequently underwent a second-look surgery revealing
      only microscopically positive disease and then received intraperitoneal
      chemotherapy with cisplatin. At a follow-up visit, she was found to have
      bilateral axillary lymph node enlargement. Mammography revealed no lesions in
      either breast. Fine needle aspiration dissection confirmed the diagnosis of
      metastatic, recurrent ovarian adenocarcinoma and subsequently axillary lymph node
      dissection was undertaken. CONCLUSION: Ovarian carcinoma, which usually follows
      typical patterns of metastatic involvement, can appear in unusual areas.

PMID- 10410883
TI  - Vulvar carcinoma in young patients and its relationship with genital warts.
AB  - We report the occurrence of aggressive vulvar carcinoma associated with condyloma
      acuminata in three patients under 33 years old. Discussion of the role of the
      human papilloma virus (HPV) in the development of vulvar cancer is also
      presented. Three patients with condyloma associated with aggressive vulvar
      squamous cell carcinoma, in situ (1 case) and invasive (2 cases), documented by
      biopsy and/or vulvectomy are presented. In situ hybridization (ISH) was used to
      characterize the subtypes of HPV. One patient with erythematous systemic lupus
      developed in situ carcinoma after 5 years. The other two cases also developed
      aggressive multicentric, invasive squamous cell carcinoma after 10 years of
      diagnosis of condyloma. In all cases HPV cytological abnormalities were seen
      throughout the pathological examination. HPV 16 and 18 were present in cells of
      invasive squamous cell carcinoma in cases 2 and 3. HPV 6 and 11 were detected
      only in the condyloma area in case 2. HPV 30 was seen only in the condyloma area
      in case 3. This report emphasizes the need for biopsies of all unusually
      persistent or treatment-resistant condylomas, particularly in young and/or
      immunosuppressed patients.

PMID- 10410884
TI  - Extrarenal Wilms' tumor of the uterus.
AB  - Wilms' tumor (nephroblastoma) is rare in adults. Its occurrence as a primary
      tumor outside the kidney is exceptional. Only 4 cases [1-4] have occurred in the
      uterus. This report adds the fifth instance of primary uterine Wilms' tumor. The
      patient, a 77-year-old woman (G2P2), is the oldest ever described with a Wilms'
      tumor.

PMID- 10410886
TI  - Laparoscopic prophylactic oophorectomy in women with inherited risk of ovarian
      cancer.
AB  - The aim of this study was to specify the surgical procedure most adapted for
      prophylactic laparoscopic oophorectomy in patients with an inherited risk of
      ovarian cancer. This prospective study was based on a series of 27 patients who
      underwent prophylactic bilateral laparoscopic oophorectomy between September 1995
      and January 1998. Nine patients underwent an oophorectomy (33%) and 18 patients
      an adnexectomy (67%). The laparoscopic procedure was converted into a laparotomy
      in one patient in whom an ovarian adenocarcinoma was detected during the surgical
      procedure. During final histologic examination of the ovaries, 23 patients were
      found to have benign atypical histologic alterations, one patient had an ovarian
      adenocarcinoma and only three patients (11%) had normal ovaries. In women with an
      inherited risk of ovarian cancer, during the laparoscopic procedure for
      prophylactic oophorectomy, the abdomino-pelvic cavity should be thoroughly
      explored with peritoneal cytology and systematic peritoneal biopsies. The
      laparoscopic procedure could be converted into a laparotomy if an ovarian cancer
      is discovered.

PMID- 10410887
TI  - Invasive micropapillary carcinoma. Distinct features of a poorly recognized
      variant of breast carcinoma.
AB  - INTRODUCTION: Invasive micropapillary carcinoma (IMC) is a histological variant
      of breast cancer with a poor prognosis. MATERIAL AND METHODS: Pathological
      findings of 15 cases of IMC are compared with those of 144 invasive duct
      carcinoma (IDC) and 10 invasive papillary carcinoma (IPC). RESULTS: Only 33% of
      cases were diagnosed in stage I. Mean tumor size was 2.3 cm. Nuclear grade 3 was
      found in 60% of cases, aneuploidy in 78%, and 92% had hormone receptors. Nine
      patients showed lymph node metastasis. Tumor size, nuclear grade, mitotic rate
      and lymph node involvement were higher in IMC when compared with IDC grade I and
      IPC, but not when compared with IDC grade II and III. Four cases of IMC (27%)
      recurred before two years. Recurrences and lymph node metastases showed the same
      architectural pattern as the primary tumor. DISCUSSION: IMC shows a high
      incidence of lymph node involvement and a high early recurrence rate.

PMID- 10410885
TI  - Long-term results of sequential chemotherapy-radiotherapy-chemotherapy in locally
      advanced squamous cell carcinoma of the uterine cervix.
AB  - PURPOSE OF INVESTIGATION: In order to evaluate the impact of sequential
      chemotherapy-radiotherapy-chemotherapy on local control and survival, a follow-up
      study was carried out 12 years after the treatment of 22 patients with FIGO stage
      IIB-III squamous cell cervical cancer. METHODS: Patients were submitted to three
      cycles of induction chemotherapy (cisplatin and bleomycin) followed by whole
      pelvis irradiation and central boost with endocavitary brachytherapy. Ten
      patients underwent three further cycles of chemotherapy after radiotherapy. All
      patients were maintained by regular follow-up. Only one patient was lost 48
      months after treatment. RESULTS: At the end of treatment complete response was
      obtained in 14 patients (63.5%). Four of these recurred locally, and one at also
      distance. Eight patients failed to obtain a complete response. Twelve patients
      died from disease and one patient died from other causes. Nine of 22 (41%)
      patients are alive without evidence of disease with a median follow-up of 134
      months. Acute toxicity was mild, while two severe late complications were
      observed. CONCLUSIONS: The achievement of complete remission at the end of
      treatment is important in terms of life expectancy. Further chemotherapy appears
      useful for patients who do not reach complete local remission after radiotherapy.

PMID- 10410888
TI  - Colposcopy and microcolpohysteroscopy qualification for large loop excision of
      the transformation zone (LLETZ) in the management of cervical intraepithelial
      neoplasia.
AB  - OBJECTIVE: Large loop excision of the transformation zone is more and more often
      used as a treatment for cervical intraepithelial neoplasia. There is still debate
      as to whether this method should be performed in cases when the lesion extends
      into the cervical canal. Some colposcopists consider loop excision equal to cone
      biopsy, while others confine its application to satisfactory colposcopy findings.
      The purpose of the study was to compare the effectiveness and morbidity of LLETZ
      performed due to CIN in patients with and without extension of the lesion into
      the cervical canal. DESIGN: Prospective study of 143 women treated by LLETZ due
      to cervical intraepithelial neoplasia. METHODS: A series of 143 patients
      cytologically and colposcopically suspected of cervical intraepithelial neoplasia
      received outpatient treatment by large loop excision of the transformation zone
      (LLETZ). Microcolpohysteroscopy examinations of the cervix were performed on all
      patients. Depending on the involvement of the endocervix the material was divided
      into two groups. Group A comprised 83 women with a colposcopically visible upper
      margin of the lesion. Group B consisted of 60 patients with the lesion ranging in
      the endocervix, but not exceeding 10 mm from the external os. Chi square analyses
      of indication, morbidity and recurrence of the lesions in the two groups were
      done. Results were considered significant at p less than 0.05. RESULTS: Minimal
      thermal damage of excised tissue did not interfere with histological examination
      in either group. In 139 cases (97.20%) histology examination confirmed the
      presence of CIN. There were no significant differences between the two treatment
      groups with respect to mean age, mean parity and indications for LLETZ. The women
      in the group with an entirely visible lesion experienced less perioperative blood
      loss. There was no significant difference in secondary haemorrhage, infection,
      stenosis, incomplete excision of the lesion, visibility of neosquamocolumnar
      junction and residual disease between the two groups. CONCLUSIONS: On the basis
      of the results obtained it can be stated that LLETZ performed with colposcopic
      guidance complemented by microcolpohysteroscopy constitutes a valuable method in
      the treatment of CIN and it may in selected cases replace cone biopsy.

PMID- 10410889
TI  - Distant cutaneous metastasis from carcinoma of the uterus. A case report.
AB  - Cutaneous metastasis from intraabdominal carcinoma is relatively rare. When it is
      present it is usually located in the skin overlying the neoplasm [1]. Carcinoma
      of the uterus metastatic to the skin accounts for 9% of all cutaneous metastases.
      Distant metastasis is extremely rare. Such a metastasis to the skin of the big
      toe of the lower limb is presented.

PMID- 10410890
TI  - Hypersensitivity reaction to carboplatin. Results of skin tests.
AB  - Four patients with hypersensitivity reaction to carboplatin of variable severity,
      after previous uneventful cisplatin and carboplatin treatment, are described.
      Skin testing performed in two of the patients suggests a cross-reaction with
      cisplatin but was negative with carboplatin in one of them. The mechanism of
      hypersensitivity reaction to carboplatin is poorly understood and the issue of
      retreatment with carboplatin is controversial. Physicians should be aware of the
      possible hypersensitivity reaction to carboplatin and appropriate precautions
      should be taken.

PMID- 10410891
TI  - Use of hysterosonography in women with abnormal postmenopausal bleeding.
AB  - PURPOSE OF INVESTIGATION: Hysterosonography (HS) allows evaluation of the
      endometrial cavity by endouterine administration of sterile physiologic solution.
      We aimed to identify the role of HS and transvaginal ultrasonography (TU) in
      postmenopausal women with unexplained bleeding in order to avoid further invasive
      investigation for patients with atrophic endometrium, and to obtain significant
      information on intracavitary focal lesions. METHODS: Eighty postmenopausal women
      with unexplained metrorrhage underwent both TU and HS. They were subsequently
      referred for hysteroscopy or dilatation and curettage, and histology was
      obtained. RESULTS: The sensibility of TU was comparable with that of HS (90% vs
      93%). However, the specificity of TU was only 30%. Combined use of TU and HS
      raised sensibility and specificity to 95.9% and 96.7%, respectively. CONCLUSION:
      HS is superior to TU in the diagnosis of focal lesions because the uterine
      cavity, lesion volume and margins, and associated diffuse endometrial alterations
      are adequately depicted. HS is particularly valuable with benign focal lesions
      associated with atrophic endometrium, as in patients under tamoxifen in whom TU
      fails to detect the uterine cavity.

PMID- 10410892
TI  - Metastasis of a breast carcinoma in a mature teratoma of the ovary.
AB  - Metastatic tumors in ovaries from breast carcinoma are well known. Breast
      carcinoma metastases in primary ovarian tumors are much more uncommon. The
      authors present a case of a primary breast carcinoma, with a lobular component
      (signet ring cells), which metastasized into a mature cystic teratoma of the
      ovary. The problem of differential diagnosis with other primary ovarian tumors or
      metastatic tumors and the problem of particular behavior of metastatic lobular
      components are discussed.

PMID- 10410893
TI  - Mature teratoma of the ovary with predominant benign anlage component. Report of
      a case.

PMID- 10410894
TI  - Correlation between cervical intraepithelial neoplasia and human papillomavirus
      male infections: a longitudinal study.
AB  - BACKGROUND: Genital HPV infection is one of the most common sexually-transmitted
      diseases. The aim of the study was to evaluate the correlation between HPV
      associated lesions in male partners of women affected by CIN. METHODS: 210 male
      partners of women affected by CIN were examined in a long-term follow-up (from 5
      to 13 years). The diagnosis in females was performed by cytology, colposcopy and
      histology. Male partners were submitted to clinical examination, peniscopy and
      biopsy. RESULTS: 111/210 (53%) females had CIN I, 53/210 (25%) and 46/210 (22%)
      had CIN III. Subclinical lesions were associated with 18%, 28% and 24% of male
      partners of women with CIN I, CIN II and CIN III, respectively. Clinical lesions
      were observed in 7% and 10% of sexual partners of women with CIN I and CIN II,
      respectively. Mixed lesions affected only 3% of sexual partners of women with CIN
      I. CONCLUSIONS: Our data show that the transmissibility of HPV infection to the
      male partners of women affected by CIN was easier when there was a lower grade of
      CIN. In fact, male partners of women with CIN III had a lower percentage (26%) of
      clinical or subclinical HPV skin lesions.

PMID- 10410895
TI  - Cis-platinum combination chemotherapy during pregnancy for mucinous
      cystadenocarcinoma of the ovary. Case report.

PMID- 10410896
TI  - Urothelial carcinoma of the vagina six years following cystectomy for invasive
      cancer. A case report.
AB  - A 74-year-old woman presented with vaginal spotting secondary to transitional
      cell carcinoma six years following cystectomy for invasive, yet localized,
      transitional cell carcinoma of the bladder. This represents primary, not
      metastatic, tumor of the vagina.

PMID- 10410897
TI  - Primary squamous cell carcinoma of the endometrium. Immunopathological study of a
      case.

PMID- 10410898
TI  - Papillary serous carcinoma of the ovary following prolonged tamoxifen treatment.
AB  - We present a patient with breast cancer who developed papillary serous
      adenocarcinoma of the ovary after 13 years of tamoxifen use. The possible
      association is explored and the literature is reviewed.

PMID- 10410899
TI  - Distinct roles for visceral endoderm during embryonic mouse development.
AB  - The murine visceral endoderm is an extraembryonic cell layer that appears prior
      to gastrulation and performs critical functions during embryogenesis. The
      traditional role ascribed to the visceral endoderm entails nutrient uptake and
      transport. Besides synthesizing a number of specialized proteins that facilitate
      uptake, digestion, and secretion of nutrients, the extraembryonic visceral
      endoderm coordinates blood cell differentiation and vessel formation in the
      adjoining mesoderm, thereby facilitating efficient exchange of nutrients and
      gases between the mother and embryo. Recent studies suggest that in addition to
      this nutrient exchange function the visceral endoderm overlying the egg cylinder
      stage embryo plays an active role in guiding early development. Cells in the
      anterior visceral endoderm function as an early organizer. Prior to formation of
      the primitive streak, these cells express specific gene products that specify the
      fate of underlying embryonic tissues. In this review we highlight recent
      investigations demonstrating this dual role for visceral endoderm as a provider
      of both nutrients and developmental cues for the early embryo.

PMID- 10410900
TI  - Requirement of Drosophila I(2)gl function for survival of the germline cells and
      organization of the follicle cells in a columnar epithelium during oogenesis.
AB  - The lethal(2)giant larvae gene, or 1(2)gl, encodes a widely expressed
      cytoskeletal protein which acts in numerous biological processes during
      embryogenesis and oogenesis, including cell proliferation, and morphogenetic
      movements. Having identified the nucleotide change occurring in the l(2)gl(ts3)
      sequence, we produced by site-directed mutagenesis the identical change leading
      to the substitution of a serine by a phenylalanine at position 311 of p127l(2)gl
      and introduced the modified l(2)glF311 gene into l(2)gl flies. The transgene can
      fully rescue the development of l(2)gl flies raised at 22 degrees C but causes
      drastic effects on their development at 29 degrees C confirming the temperature
      sensitivity of the phenylalanine substitution at position 311. Fertility of
      females, albeit not of males, was strongly affected. Temperature-shift
      experiments and microscopic examination of ovaries showed that the mutation
      blocked egg chamber development at the onset of vitellogenesis (stages 8-9) with
      growth arrest of the oocyte, incomplete follicle cell migration over the oocyte
      associated with abnormal organization of the follicular epithelium, and apoptosis
      of the germline cells, as measured by TUNEL assays. By comparison to wildtype, we
      found that p127F311 is already reduced in amount at 22 degrees C and delocalized
      from the cytoskeletal matrix, albeit without affecting the apical localization of
      myosin II, a major partner of p127. At 29 degrees C, the level of p127F311 is
      even more reduced and the distribution of myosin-II becomes markedly altered at
      the apices of the follicle cells. These data indicate that during oogenesis p127
      plays a critical function at the onset of vitellogenesis and regulates growth of
      the oocyte, follicle cell migration over the oocyte and their organization in a
      palisadic epithelium, as well as viability of the germline cells.

PMID- 10410901
TI  - In vitro binding and expression studies demonstrate a role for the mouse Sry Q
      rich domain in sex determination.
AB  - The Q-rich domain of the mouse sex determining gene, Sry, is encoded by an in
      frame insertion of a repetitive sequence composed of mostly CAG repeats. The
      exact function of this Q-rich domain is unknown. Studies on the polymorphisms
      within this Q-rich domain among different domesticus and musculus mouse strains
      suggest a possible role for this domain in sex determination. Using the
      farwestern protein-blotting technique and recombinant fusion proteins containing
      the Sry Q-rich domain as probes, three Sry interactive proteins of 94, 32 and 28
      kDa apparent molecular weight (Sip-1, -2 and -3 respectively) were consistently
      detected in adult testis. Sip expression was detected in somatic cells and was
      associated with the spermatogenic activity of the testis. During embryogenesis,
      Sips were readily detected in total tissue extracts of embryos as early as E8.5
      day. In fetal gonads of both sexes, their expression peaked around E11.5-13.5
      day, at the time of sex determination and differentiation, and decreased
      drastically towards late stages of gestation. These observations support the
      hypothesis that the Q-rich domain may contribute to the biological function(s) of
      mouse Sry through a protein-protein interactive role(s).

PMID- 10410902
TI  - Expression of galectin-7 during epithelial development coincides with the onset
      of stratification.
AB  - Galectin-7 is a 14 KDa member of the galectin family that we have cloned from
      human, rat and mouse. Our previous studies have shown that in the adult, galectin
      7 is expressed in all cell layers of epidermis and of other stratified epithelia
      such asthe cornea and the lining of the oesophagus. This suggested that galectin
      7 expression might be induced at a particular stage in the embryonic development
      of stratified epithelia. In the present study we have investigated this
      hypothesis by in situ hybridization of galectin-7 mRNA in mouse embryos. Starting
      from E13.5, weak expression of galectin-7 was detected in bilayered ectoderm, and
      stronger expression was found in areas of embryonic epidermis where
      stratification was more advanced. Galectin-7 expression was maintained in all
      living layers after epidermal development was completed. Galectin-7 was also
      strongly and specifically expressed in stratified regions of ectodermally-derived
      non-epidermal epithelia such as the lining of the buccal cavity, the oesophagus
      and the ano-rectal region. In contrast, no expression of galectin-7 was found in
      epithelia derived from endoderm, such as lining of the intestine, kidney and
      lung. Our results demonstrate that galectin-7 is expressed in all stratified
      epithelia examined so far, and that the onset of its expression coincides with
      the first visible signs of stratification. These results establish galectin-7 as
      the first region-independent marker of epithelial stratification.

PMID- 10410903
TI  - Midline fusion in the formation of the secondary palate anticipated by
      upregulation of keratin K5/6 and localized expression of vimentin mRNA in medial
      edge epithelium.
AB  - Secondary palatal fusion is dependent on targeted removal of the epithelium
      between the palatal shelves. Aseptically delivered rat embryos 15 through 18 days
      post coitum (dpc) were probed with DIG-labeled antisense and sense ssDNA probes
      for spliced exon sequences flanking intron E of cytokeratins K5/6 and spliced
      exon sequences flanking intron F of vimentin. Cytokeratin K5/6 expression was
      upregulated in the medial edge epithelium (MEE) prior to rotation of the palatal
      shelves and in the vomerine epithelium in the region of fusion with the palate.
      K5/6 expression continued in the medial epithelial seam (MES) and in epithelial
      islands during breakdown of the MES. Vimentin expression was not detected in the
      MEE prior to rotation but was specifically upregulated in the MEE following
      rotation and prior to midline contact and continued in the MES and in epithelial
      cells identifiable during the breakdown of the MES. Initiation of vimentin
      upregulation in the MEE prior to contact of the palatal shelves was tested by
      serum-free organ culture of palates from embryos at 15.5 dpc with the shelves
      separated by a biocompatible membrane. Vimentin upregulation occurred in the
      epithelium specifically in the region of anticipated contact. These results are
      interpreted as indicating that i) cytokeratin K5/6 expression may play a critical
      role in the integration of the epithelial layers of the MES to ensure subsequent
      merging of the mesenchyme and ii) epithelial cells in the MEE are specifically
      'primed' to upregulate expression of mesenchymal genes prior to integration into
      and breakdown of the MES.

PMID- 10410904
TI  - Initial features of the inner dental epithelium histo-morphogenesis in the first
      lower molar in mouse.
AB  - First lower molar development in the mouse was investigated from the cap to early
      bell stage using histology, morphometry, TEM and 3D reconstructions. This period
      was characterized by the histogenesis of the enamel organ (EO), folding of the
      epithelio-mesenchymal junction and growth of the tooth. The histogenesis of the
      EO and appearance of the enamel knot (EK) were initiated at the early cap stage
      (ED14). From ED14 to ED15, the anterior and posterior extension of the EK was
      very prominent whilst the length of the enamel organ did not substantially
      change. The EK appeared as a dynamic and transitory histological structure
      including dying and replacement cells. At ED16, the folding of the IDE, which
      extended over the anterior two thirds of the molar, was the first sign of
      cuspidogenesis. It was accompanied by a local remodeling of the basement membrane
      (BM): IDE cells involved in this folding transitorily lost contact with the BM
      which formed a loop in the mesenchyme. During this period, the growth of the
      lower M1 along the antero-posterior axis was restricted to the posterior part of
      the molar. Histogenesis occurred in the whole EO, whilst initial cuspidogenesis
      was limited to the anterior part of the tooth. Distinct cell populations were
      thus involved in different contemporary processes leading to changes in the cell
      density in the mesenchyme, in the mitotic activity, in cell-shape, and cell
      matrix interactions in the IDE, and remodeling of the BM where both epithelium
      and mesenchyme might participate.

PMID- 10410905
TI  - Mouse odontogenesis in vitro: the cap-stage mesenchyme controls individual molar
      crown morphogenesis.
AB  - Day 14 ICR mouse first lower (M1) and upper molars (M1) as well as heterotopic
      recombinations of M1 epithelium/M1 mesenchyme and M1 epithelium/M1 mesenchyme
      were cultured for 6, 8 and 10 days on semi-solid medium. Computer-assisted 3D
      reconstructions were performed to follow the in vitro development of these
      explants. In vitro culture of cap-stage molars allowed for the emergence of
      unequivocal morphological features distinctive for M1 versus M1 including the
      cusp pattern, cusp inclination and tooth specific chronology for odontoblast and
      ameloblast terminal differentiations. Both M1 epithelium/M1 mesenchyme and M1
      epithelium/M1 mesenchyme recombinations developed according to the known
      developmental fate of the mesenchyme. Our data demonstrate that the cap-stage
      dental ecto-mesenchyme not only directs tooth class specific morphogenesis, but
      also individual molar crown features. Furthermore, the mesenchyme apparently also
      controls the typical mirror symmetry of right and left handed teeth.

PMID- 10410906
TI  - Aspects of cell proliferation kinetics of the inner dental epithelium during
      mouse molar and incisor morphogenesis: a reappraisal of the role of the enamel
      knot area.
AB  - First lower E-14 and E-16 mouse molars and E-13 lower incisors were cultured in
      vitro and either sequentially or continuously labelled with BrdU (5-bromo-2'
      deoxyuridine). The behaviour of the non-cycling inner dental epithelial cells
      emerging from the enamel knot area of the molars was analysed by 3D (three
      dimensional) reconstructions of serial sections. These cells, as well as slow
      cycling cells underwent a coordinated temporo-spatial patterning leading to their
      patchy segregation at the tips of the forming cusps. In incisors (in vitro and in
      vivo), non-cycling cells were also present in the inner dental epithelium of the
      enamel knot area. However, these cells were not redistributed during incisor
      morphogenesis. These non-dividing inner dental epithelium cells of the enamel
      knot area which are either redistributed or not according to the tooth type
      specific morphogenesis might represent the organizers of morphogenetic units
      (OMU), the cusps.

PMID- 10410907
TI  - The cardiac neural crest in Ambystoma mexicanum.
AB  - To establish whether a region of the cranial neural crest contributes cells to
      the developing heart of Ambystoma mexicanum (axolotl), as it does in many other
      vertebrates, we constructed a fate map for the neural crest in late neurula stage
      (stage 19-20) embryos. The fluorescent vital dye, Dil, was used as the lineage
      label. The various regions of the cranial neural folds were identified in
      relation to such landmarks as the developing forebrain, midbrain and hindbrain,
      and the appearance and extent of emerging somites. Labelled cells originating in
      the rhombencephalic region were found in the aortic arches and in the truncus
      arteriosus, and occasionally in the walls of the conus arteriosus. Cells were
      also found in the third and fourth branchial arches. Labelled neural crest from
      the adjacent anterior trunk region appeared neither in the heart nor the visceral
      skeleton, whereas those from the mesencephalic region contributed to the first
      hypobranchial cartilage and to the first three branchial arches, but not to the
      heart. No labelled cells from any of the regions were seen in the ventricle or
      auricle.

PMID- 10410908
TI  - The 35UZ transposon of Drosophila melanogaster reveals differences in maintenance
      of transcriptional control between embryonic and larval stages.
AB  - The D. melanogaster transposon P[35UZ] contains a lacZ reporter gene fused to 35
      kb of Ubx upstream sequences which drive a Ubx-like expression in embryos and in
      metathoracic imaginal discs. Transposition of P[35UZ] followed by analysis of
      different lines in wild-type and mutant backgrounds allowed us to analyze the
      interplay between Ubx regulatory elements, including the Polycomb response
      element (PRE), located inside the transposon and cis-acting regulatory elements,
      located outside. We found that all lines show a Ubx-like beta-galactosidase
      expression pattern in the embryo, but proximity to strong imaginal enhancers can
      change this pattern drastically. These data illustrate how maintenance of gene
      expression depends on the chromosomal environment and on dynamic interactions
      between all developmentally regulated enhancers located close to a promoter under
      PcG control.

PMID- 10410909
TI  - Characterisation of developmentally regulated chromatin structure in the coding
      region of the proto-oncogene, c-fos, in the male laboratory mouse.
AB  - In mouse, tissue-specific developmental de novo methylation of the proto-oncogene
      c-fos, which is abundantly expressed during embryonic stages, occurs perinatally
      (between the day of birth to 20 dpp) and is maintained in the adult. In liver,
      where c-fos is only active up to the day of birth, the gene has more sites
      methylated than in brain, where it is expressed until about day 5 post-partum. We
      have studied chromatin organisation of c-fos and compared thisto DNA methylation
      in the fetal and adult brain and liver. Purified nuclei of these tissues from
      fetus as well as adult were digested with the restriction enzyme Mspl. DNA was
      extracted from the Mspl digested chromatin and probed with two DNA segments
      covering the major part of the body of the gene (from distal part of second exon
      to major part of fourth exon). Southern hybridisation studies revealed that in
      the fetus, in both liver and brain, the chromatin in the coding region was
      sensitive to Mspl digestion and the extent of sensitivity was nearly the same
      between the two. In the adult tissues, however, chromatin from brain was almost
      as sensitive as in the fetus, but in the liver it was highly resistant to Mspl.
      We suggest that a shift from the undermethylated state in the fetus to the heavy
      methylated state in the adult causes a corresponding change in the organisation
      of chromatin of c-fos in the coding region. Furthermore, the difference in the
      tissue-specificity in the methylation induced chromatin compaction could be due
      to differences in the transcription levels of c-fos and de novo methylation
      during early neonatal development.

PMID- 10410910
TI  - Allergy--a public health issue: when should governments act?

PMID- 10410911
TI  - Presenting graphical information.
AB  - This article outlines the mistakes that are commonly made when data are presented
      graphically. Common errors when displaying data are highlighted, and preferred
      solutions for avoiding these mistakes are described. The preferred approaches
      form the requirements that authors should meet when submitting papers to the
      journal of Pediatric Allergy and Immunology.

PMID- 10410912
TI  - Peanut allergy: a major public health issue.

PMID- 10410913
TI  - Peanut oil in vitamin A and D preparations: reactions to skin test and
      manifestation of symptoms.
AB  - The aim of this study was to establish whether there is a link between
      sensitisation to peanut and exposure to peanut oil in vitamin A and D
      preparations. Forty-one children with a positive in vivo or in vitro test towards
      peanut were included. Twenty-one children had consumed vitamins A and D in oil
      solution, 14 in water solution, and 6 both types. Refined and unrefined peanut
      oils were obtained and skin prick test extracts were prepared. None of the
      children exhibited a positive SPT in response to the refined peanut extract. In
      contrast, 15 children exhibited a positive SPT to the unrefined extract. There
      was no significant difference in the number of children reacting clinically to
      peanut exposure who had received vitamins A and D in oil-based or water-based
      formulations. However, children with clinical allergy to peanut and who had
      exclusively consumed vitamin A and D in peanut oil, exhibited a greater number of
      different allergic symptoms upon consumption of peanut compared with clinical
      allergic children who had consumed the vitamins in water solution or both types
      (p<0.01). This study indicates that sensitisation to peanut during childhood
      through consumption of vitamins A and D in oil-based solution seems unlikely, but
      its consumption may contribute to the development of a wider range of clinical
      symptoms due to peanut exposure.

PMID- 10410914
TI  - Exposure to peanuts in utero and in infancy and the development of sensitization
      to peanut allergens in young children.
AB  - This study attempted to determine the underlying factors that may influence the
      development of peanut sensitization in young children in South Africa. One of our
      objectives was to ascertain whether the consumption of peanuts or peanut
      containing foods during pregnancy and lactation by mothers from atopic families
      impacted upon the development of an allergic response to peanuts in the child.
      Forty-three children between the ages of 0 and 3 yr participated in this study.
      There were 25 peanut-sensitized subjects and 18 control subjects (children
      sensitized to milk and/or egg, but not to peanuts). A significant association was
      found between peanut sensitization and sensitivity to soya (p=0.0002), wheat
      (p=0.03), and cod fish. We found that mothers who consumed peanuts more than once
      a week during pregnancy were more likely to have a peanut-allergic child than
      mothers who consumed peanuts less than once a week (odds ratio=3.97, 98%
      confidence interval 0.73-24). Peanuts or peanut butter was introduced into the
      child's diet from a significantly younger age in the peanut-allergic subjects
      (p<0.03). There was a positive correlation in the peanut-allergic subjects
      between age of introduction of peanuts and age at the onset of symptoms (r=0.63).
      Exclusive breast feeding did not protect against the development of peanut
      sensitization. Peanut allergy is associated with an increased risk of
      sensitization to other foods. It is more likely to occur if mothers eat peanuts
      more frequently during pregnancy and introduce it early to the infant's diet.
      These features highlight potentially avoidable factors that might prevent
      sensitization.

PMID- 10410915
TI  - Food hypersensitivity in children: clinical aspects and distribution of
      allergens.
AB  - The aims of this work were to investigate, in children and adolescents, the
      clinical aspects of food hypersensitivity and the distribution of allergens, in a
      prospective and descriptive study. Five hundred and forty-four pediatric cases
      from a series of 703 patients with food allergies, confirmed by food challenge,
      were studied. Their clinical characteristics and the distribution according to
      allergen were investigated. There was a family history of atopic disease in 70.5%
      of patients. Atopic dermatitis was the main symptom (275/544; 50.5% of patients),
      followed by urticaria and angio-edema (165/544; 30%). There was asthma in 8.6% of
      patients (47 children) and anaphylaxis in 4.5% (27 patients). The rarest signs
      were rhinitis (n=2; 0.3%), oral allergy syndrome (n=8; 1.4%), and
      gastrointestinal signs (n=11; 2%). Five allergens accounted for 78% of food
      hypersensitivity. These allergens were: eggs (36%), peanuts (24%), cow's milk
      (8%), mustard (6%), and cod (4%). Peanut was the most common allergen for
      children over the age of 3 yr. In this selected population, sensitivity of
      individuals to more than three foods was unusual (5%). Atopic dermatitis was the
      main symptom of food allergy in children. The symptoms changed over time, with
      respiratory disorders, oral allergy syndrome and ocular problems occuring later.
      Anaphylaxis also occured mostly in older children. Five allergens were
      responsible for more than three-quarters of food allergies in children. However,
      the number of allergens implicated was higher for the group of children over the
      age of 6 yr than for younger children.

PMID- 10410916
TI  - Macrophage inflammatory protein-1alpha and RANTES are present in nasal secretions
      during ongoing upper respiratory tract infection.
AB  - Macrophage inflammatory protein-1alpha (MIP-1alpha) and RANTES (regulated upon
      activation, normal T-cell expressed and secreted) were measured by enzyme-linked
      immunosorbent assay (ELISA) from virus-infected respiratory cell culture
      supernatants and from 100 nasal wash samples obtained from patients aged 8 d to
      10 yr. The results of the nasal wash samples were analyzed in relation to the
      etiology of the viral infection. In vitro, respiratory syncytial virus (RSV)
      induced the production of MIP-1alpha, while both RSV and adenovirus were
      associated with the production of RANTES. Both MIP-1alpha and RANTES were
      detected in nasopharyngeal secretions from pediatric patients with acute upper
      respiratory tract RSV, adenovirus, influenza, and parainfluenza virus infection
      (p<0.001 by Fisher's exact test). As both of these chemokines have potent effects
      on the recruitment and degranulation of eosinophils and basophils, further
      understanding of their role in upper respiratory tract infections may provide
      valuable insights into the immunopathogenesis of respiratory viral infections.

PMID- 10410917
TI  - Markers of inflammation and bronchial reactivity in children with asthma, exposed
      to animal dander in school dust.
AB  - Several studies have confirmed the presence of animal dander allergens in school
      dust but the effect of this indirect animal exposure on health has not been
      evaluated. In this study we investigated bronchial reactivity and markers of
      eosinophil activity and inflammation during two separate weeks of school in 10
      children with mild asthma and a positive skin prick test to cat and dog. At the
      beginning and the end of the first week the children underwent bronchial
      challenges with methacholine, and at the beginning and the end of the second week
      they underwent nasal lavages (NAL) and induced sputum samplings. Blood and urine
      samples for analysis of inflammatory markers were obtained before and after both
      school weeks. Peak expiratory flow (PEF) and symptoms of asthma and allergy were
      recorded daily, and spirometry was performed on each visit. The exposure to
      animal dander allergens was estimated from dust samples obtained in the subjects'
      schools and homes. Bronchial sensitivity to methacholine increased in the week
      when this was measured. The proportion of eosinophils in peripheral blood, and
      urinary eosinophil protein X (EPX), decreased in both weeks. There was a trend
      towards an increase of eosinophil peroxidase (EPO) and myeloperoxidase (MPO) in
      sputum in the week when these proteins were measured. The concentrations of cat
      (Fel d1) and dog (Can f1) allergens were higher in dust collected in schools than
      in homes. Our results show that in children with mild asthma and animal dander
      allergy, there is a significantly increased bronchial sensitivity to methacholine
      after one school week. There is also a significant decrease in the number of
      circulating eosinophils and a trend towards an increase of sputum EPO, which
      could correlate with the early phase of eosinophil recruitment to the lungs.
      These effects may be related to the continuous exposure to animal allergens in
      school dust.

PMID- 10410918
TI  - In vivo histamine release during the first minutes after deliberate sting
      challenges correlates with the severity of allergic symptoms.
AB  - In this study, deliberate sting challenge was investigated as a method for
      estimating the severity of anaphylactic reactions in bee venom-sensitized
      subjects. Twenty-one patients with previous anaphylactic reactions to field bee
      sting were subjected to a deliberate sting challenge (n = 32). To document
      anaphylactic reactions, plasma histamine levels were measured before, and then 1
      and 2 min after, bee sting challenge. Eleven patients were re-challenged after 3
      5 weeks. On 18 occasions, sting challenges caused no systemic reactions, in seven
      cases reactions were mild, in five moderate and in two severe. In all children
      showing systemic reactions, significant increases of plasma histamine were
      measured after 2 min. The results correlated significantly with clinical scores
      but not with skin prick test or with specific immunoglobulin E (IgE) and
      immunoglobulin G (IgG) antibodies against bee venom. In patients developing local
      reactions only, no increase of plasma histamine was detected. The relative amount
      of released histamine correlated significantly with the severity of clinical
      symptoms. Significant histamine release occured during the first 2 min after
      sting challenge in children with subsequent systemic reactions and the severity
      of these subsequent anaphylactic reactions correlated with plasma histamine
      concentrations. The measurement of plasma histamine levels in the first minutes
      after challenge test may therefore be used as an objective marker of a potential
      systemic reaction.

PMID- 10410919
TI  - Wheezing in school children is not always asthma.
AB  - Our objective was to study whether children with reported asthma differed from
      children with wheeze but without asthma, and from children with neither asthma
      nor wheeze, regarding lung function, bronchial hyper-responsiveness (BHR) using
      methacholine inhalation, exercise-induced bronchoconstriction (EIB), and skin
      prick test (SPT) reactivity. School children (n=2188), enrolled in a survey of
      asthma, were classified into three mutually exclusive groups by parental report
      of: asthma, wheeze, and no asthma/no wheeze. A random sample of 80 children in
      each group was tested (n=240). Among asthmatics, 68% (95% confidence interval
      (CI), 57-79) had a BHR (measured as PD20 forced expiratory volume in 1 s (FEV1) <
      or = 8.16 micromol using methacholine) compared to 31% (CI 20-42%) and 30% (CI 19
      40%) in the wheeze and no asthma/no wheeze groups. The dose-response slope (DRS)
      confirmed the PD20 data and distinguished equally between groups. EIB (> or =10%
      fall in FEV1) was more frequent (40%, CI 29-52%) among asthmatics than among
      children with wheeze (12%, CI 4-19%) and no asthma/no wheeze (7%, CI 1-13%). The
      prevalence of at least one positive SPT was twice as high in the asthma group
      (58%, CI 47-69%) than in the wheeze (27%, CI 16-37%) and the no asthma/no wheeze
      (25%, CI 15-35%) groups. These results indicate that children with asthma differ
      from children with wheeze and children with no asthma/no wheeze regarding lung
      function, BHR, EIB, and SPT reactivity. Children with wheeze are more similar to
      children with no asthma/no wheeze with respect to these parameters.

PMID- 10410920
TI  - Application and efficacy of the multi-dose powder inhaler, Easyhaler, in children
      with asthma.
AB  - With powder inhalers, optimal performance is dependent on the inspiratory flow
      produced by the patient through the devices. The objective of this open, non
      randomized study was to evaluate the suitability of a new, multidose, dry powder
      inhaler, the Easyhaler, for children with asthma. The peak inspiratory flow (PIF)
      through the Easyhaler (PIF(EH)) was measured with a pneumotachograph in 120
      asthmatic children aged 4-16 yr. The bronchodilatory effect of 0.2 mg salbutamol
      through the Easyhaler was compared with that of 0.2 mg salbutamol through a
      metered dose inhaler (MDI) with a spacer, in 15 children with obstruction. The
      mean PIF(EH) was 56 l/min (range 22-83 l/min). The PIF(EH) correlated
      significantly with age, height, and absolute peak expiratory flow (PEF), but not
      with the level of obstruction (PEF percentage of predicted, range 45-146%). Only
      four children (aged 5, 6, 10, and 16 yr) had PIF(EH) values below 28 l/min, which
      has been shown in in vitro studies to be the threshold for effective use of the
      Easyhaler. In 15 children with PEF, < 85% of predicted bronchodilatory effects of
      0.2 mg salbutamol through the Easyhaler and from an MDI-cum-spacer were equal.
      Most children aged 6-16 yr produce PIF values sufficient for the use of the
      Easyhaler. The gain of 0.2 mg salbutamol from the Easyhaler was equal to that
      from a new, unprimed, MDI with a spacer in children with asthma.

PMID- 10410921
TI  - Development of latex allergy in children up to 5 years--a retrospective analysis
      of risk factors.

PMID- 10410923
TI  - Determination of fenoprofen in serum by capillary isotachophoresis.
AB  - A isotachophoretic method with conductivity detection was developed and validated
      to directly determine fenoprofen in human serum. The leading electrolyte
      contained hydrochloric acid (10 mmol/l), 6-aminocaproic acid (pH 4.8) and
      polyvinylpyrrolidone (0.1%). The terminating electrolyte was 4
      morpholineethanesulfonic acid (5 mmol/l). The calibration curve was linear over
      the concentration range 0.02-0.40 mmol/l. Within-day standard deviation ranged
      from 0.001 to 0.004 and between-day standard deviation ranged from 0.001 to
      0.004. The limit of determination was 0.02 mmol/l. The assay was employed to
      determine serum concentration of fenoprofen in patients.

PMID- 10410922
TI  - Improvement in assay sensitivity for plasma dolastatin-10 using capillary
      electrophoresis at elevated temperatures.
AB  - The very potent antimitotic and anticancer agent, dolastatin-10 (DOL-10),
      currently undergoing testing in a phase II clinical trial, has been quantitated
      previously in human plasma by high-performance capillary electrophoresis (HPCE).
      This method provides a lower limit of detection of 25 ng/ml DOL-10 from extracted
      patient samples. Without changes in preconcentration techniques, we report a
      significant improvement in the sensitivity of this method using elevated
      temperatures with conventional UV absorbance detection and liquid-liquid
      extraction which lowers the detection limit to 3 ng/ml of the drug. An elevated
      separation temperature of 50 degrees C was critical in achieving this 8x
      improvement in the detection limit. Partial validation of the method at this
      temperature gave excellent linearity (0-100 ng/ml; y=0.018x+0.085, r=0.993),
      limit of quantitation (5 ng/ml), and good overall recovery of the drug (>85%). We
      have applied this improved method towards the in vivo quantitation of DOL-10 in
      mice and in a patient receiving the drug in a phase I clinical study. From these
      analyses we conclude that this method is suitable for clinical studies where
      plasma levels of DOL-10 are > or = 5 ng/ml.

PMID- 10410924
TI  - Novel high-performance liquid chromatographic and solid-phase extraction methods
      for quantitating methadone and its metabolite in spiked human urine.
AB  - A novel solid-phase extraction (SPE) method and HPLC method were developed for
      the determination of methadone and its metabolite from spiked human urine. For
      sample cleanup, a spiked urine sample was pretreated with phosphoric acid
      followed by a well-thought-out SPE method using a 10-mg Oasis HLB 96-well
      extraction plate. In this SPE method, the concentration of methanol as well as
      the pH are optimized to preferentially isolate the analytes of interest from the
      sample matrix. Low elution volumes (200 microl) are achieved; this eliminates
      evaporation and reconstitution of the sample solution. Recoveries from human
      urine matrix were greater than 91% with RSD values less than 4.5%. For the HPLC
      analysis, the separation was obtained using a SymmetryShield RP18 column with a
      mobile phase of 0.1% TFA-methanol (60:40, v/v). Good peak shapes were obtained
      without the need of addition of any competing reagent to the mobile phase.
      Additionally, significant signal-to-noise enrichment was achieved by diluting the
      final SPE eluates four-fold with water.

PMID- 10410925
TI  - Achiral and chiral determination of ciprofibrate and its glucuronide in human
      urine by capillary electrophoresis.
AB  - A method for achiral separation of the racemic hypolipidaemic agent ciprofibrate
      and its main metabolite ciprofibrate glucuronide by capillary electrophoresis
      (CE) was developed. The glucuronide was isolated from urine by chromatographic
      procedures and characterized by alkaline as well as enzymatic hydrolysis and mass
      spectrometric and nuclear magnetic resonance experiments. Chiral discrimination
      of the ciprofibrate enantiomers and their diastereomeric glucuronides by CE was
      achieved by the use of gamma-cyclodextrin as buffer additive. The fractionated
      crystallization of ciprofibrate yielded the R-(+)-enantiomer as less soluble
      diastereomeric salt with (+)-1-phenylethylamine. This allowed the identification
      of the enantiomers of ciprofibrate as well as the diastereomeric glucuronides of
      ciprofibrate by CE. In a study with three volunteers inter- and intra-individual
      differences of ratios of both ciprofibrate glucuronides in urine were observed.
      After oral administration of a single dose of the racemate the S-ciprofibrate
      glucuronide was mainly excreted in the first time intervals, in the last time
      intervals the R-glucuronide dominated.

PMID- 10410926
TI  - Bioanalysis of aplidine, a new marine antitumoral depsipeptide, in plasma by high
      performance liquid chromatography after derivatization with trans-4-hydrazino-2
      stilbazole.
AB  - A sensitive bio-analytical assay in plasma of the depsipeptide aplidine is
      reported, based on reversed-phase liquid chromatography and fluorescence
      detection of the trans-4'-hydrazino-2-stilbazole (4'H2S) derivative of the
      analyte. At ambient temperature, two conformations of the depsipeptide are
      observed in solution due to cis-trans isomerism at the proline-pyruvoyl peptide
      bond. Aplidine is isolated from the matrix by solid-phase extraction on an
      octadecyl modified silica stationary phase. After evaporation of the acetone
      eluate, a derivatization with 4'H2S is performed in a water-acetonitrile mixture
      at pH 4. The reaction mixture is injected directly into the chromatograph and the
      analyte is quantified by fluorescence detection at 410 and 560 nm for excitation
      and emission, respectively. The method has been validated in the 2-100 ng/ml
      range, 2 ng/ml being the lower limit of quantification. Precision and accuracy
      both meet the current requirements for a bioanalytical assay. The identity of the
      4'H2S reaction products of aplidine have been confirmed by mass spectrometric
      analysis. Finally, the method has been employed for a pilot pharmacokinetic study
      of aplidine in mice which demonstrated its usefulness for pharmacological
      research.

PMID- 10410927
TI  - Non-covalent labeling of human serum albumin with indocyanine green: a study by
      capillary electrophoresis with diode laser-induced fluorescence detection.
AB  - Indocyanine green (ICG) is a negatively charged, water-soluble, tricarbocyanine
      dye used primarily for medical imaging. ICG is only weakly fluorescent in the
      near-infrared region in its free (unbound) state in dilute aqueous solution.
      However, when non-covalently bound to protein, its fluorescence is greatly
      enhanced, making it a candidate for diode laser-induced fluorescence (diode-LIF)
      detection of proteins in capillary electrophoresis (CE). This paper investigates
      the suitability of ICG as a fluorescent label for the separation and detection of
      human serum albumin (HSA) by CE with diode-LIF detection. Specifically, we have
      considered the separation conditions necessary to resolve free ICG from ICG-HSA
      complexes; the limits of detection for free and HSA-bound ICG; the stability of
      aqueous ICG and ICG-HSA solutions over time; and the stoichiometry of the ICG-HSA
      complex.

PMID- 10410929
TI  - Variation in volatile organic compounds in the breath of normal humans.
AB  - We studied the variation in volatile organic compounds (VOCs) in the breath of 50
      normal humans, using gas chromatography and mass spectroscopy. An average breath
      sample contained 204.2 VOCs (SD=19.8, range 157-241). The alveolar gradient of
      each VOC (abundance in breath minus abundance in air) varied with rate of
      synthesis minus rate of clearance. A total of 3481 different VOCs were observed:
      1753 with positive alveolar gradients, 1728 with negative alveolar gradients.
      Twenty-seven VOCs were observed in all fifty subjects. This study confirmed
      previous reports of wide inter-individual variations. Two new findings were the
      comparatively small variation in total number of breath VOCs, and the presence of
      a 'common core' of breath VOCs in all subjects.

PMID- 10410928
TI  - Capillary zone electrophoresis and MALDI-mass spectrometry for the monitoring of
      in vitro O-glycosylation of a threonine/serine-rich MUC5AC hexadecapeptide.
AB  - The in vitro N-acetylgalactosaminylation by human gastric UDP-GalNAc:polypeptide
      N-acetylgalactosaminyltransferases was assessed using the peptide motif
      GTTPSPVPTTSTTSAP, which is found naturally in the tandem repeat domains of the
      apomucin encoded by the gene MUC5AC. This peptide appeared to be an excellent
      tool for obtaining an insight into the extensive O-glycosylation processes of
      apomucins. Up to six N-acetylgalactosamines were added and the given glycopeptide
      species were well separated by capillary zone electrophoresis. Moreover, the
      degree of glycosylation (number of monosaccharide O-linked attachments) could be
      determined by MALDI-mass spectrometry without prior separation. Using different
      incubation times, we evidenced the accumulation of various glycopeptides,
      suggesting that the total glycosylation of an apomucin-peptide requires orderly N
      acetylgalactosaminylation processing. This information was completed by
      experimental data showing that N-acetylgalactosaminylated octapeptides (the
      peptide backbones of which are part of GTTPSPVPTTSTTSAP) were able to selectively
      inhibit some N-acetylgalactosaminyltransferases. Our results suggest that this
      inhibition may influence the quality of the intermediate products appearing
      during the in vitro O-glycosylation process.

PMID- 10410930
TI  - Determination of angiotensin metabolites in human plasma by fluorimetric high
      performance liquid chromatography using a heart-cut column-switching technique.
AB  - Fluorimetric column-switching HPLC method with naphthalene-2,3-dialdehyde (NDA)
      was developed for the determination of endogenous angiotensin (ANG) metabolites
      in human plasma. After one-step extraction to clean up the ultrafiltered plasma
      sample on the reversed HPLC system, the zone of the retention time of each ANG
      analyte was subjected to the NDA-derivatization. After putting into a first Phe
      ODS (for ANG (3-4) and (5-8) determinations) or ODS column (for ANG I and II
      determinations), the heart-cut of the retention time of the NDA-ANG was separated
      on a second ODS column with a mobile phase containing 5 mM ion-pair reagent.
      Complete separation and good detection were accomplished within 2 h. Good
      linearity of the regression equation for all ANG analytes with the correlation
      coefficient of >0.993 as well as good reproducibility (C.V.<4.0%). Good agreement
      of the range of ANG II plasma level between the present (25-47 fmol/ml in plasma)
      and the radioimmunoassay methods (28-52 fmol/ml in plasma) indicated that the
      column-switching method could be applicable for the determination of endogenous
      smaller ANGs as well as for ANG I or II in plasma.

PMID- 10410931
TI  - Direct determination of methamphetamine enantiomers in urine by liquid
      chromatography with a strong cation-exchange precolumn and phenyl-beta
      cyclodextrin-bonded semi-microcolumn.
AB  - Methamphetamine enantiomers in drug abusers' urine were clearly separated by semi
      microcolumn liquid chromatography using a column-switching system. The system
      consists of two separation processes: firstly, a strong cation-exchange precolumn
      removes neutral and anionic substances in urine, and then methamphetamine
      enantiomers trapped in the column are transferred to and separated in a phenyl
      beta-cyclodextrin-bonded semi-microcolumn (Chiral Drug, 150 mm x 1.5 mm I.D.).
      (S)-(+)-Methamphetamine was baseline separated from (R)-(-)-methamphetamine
      within 25 min, directly from urine samples. The detection limit for both
      enantiomers was 0.1 microg/ml.

PMID- 10410932
TI  - Liquid chromatographic determination of ethyl alcohol in body fluids.
AB  - A high-performance liquid chromatographic technique for ethyl alcohol
      determination in body fluids is proposed. Ethyl alcohol is quantitatively
      converted into acetaldehyde-phenylhydrazone by oxidation in the presence of
      alcohol dehydrogenase, nicotinamide-adenine dinucleotide and phenylhydrazine. The
      derivative is suitable for reversed-phase liquid chromatography and ultraviolet
      detection at 276 nm. The limits of linearity, detection and quantification as
      well as accuracy and reproducibility were investigated in water, serum and whole
      blood. Analytical responses were linear within the 0.008 to 5 g/l range, and the
      limit of quantification was 0.02 g/l both in aqueous standard and in biological
      matrix assays. Mean analytical recovery of ethyl alcohol in blood serum averaged
      98.2+/-4.2%, imprecision (CV%) at 0.80 g/l was 2.2%, and the limit of
      quantification was 0.02 g/l. Serum concentrations of persons that avoided
      alcoholic beverages for a week were less than the limit of quantification. Ethyl
      alcohol concentrations in serum and whole blood compared well with those obtained
      by headspace gas chromatography. This simple and reliable procedure, which was
      also used for a urine assay, could be suitable for validation of the screening
      procedures used to monitor ethanol abuse.

PMID- 10410933
TI  - Trace analysis of ethosuximide in human plasma with a chemically removable
      derivatizing reagent and high-performance liquid chromatography.
AB  - A simple and sensitive liquid chromatographic method is described for the
      determination of ethosuximide in human plasma, as a highly sensitive derivative.
      Ethosuximide spiked in plasma was extracted with toluene and derivatized with a
      chemically removable derivatizing reagent, 2-(2-naphthoxy)ethyl 2-[1-(4
      benzyl)piperazyl]ethanesulfonate, in a homogeneous system, using magnesium oxide
      as base catalyst. The resulting derivative was separated on a LiChrospher diol
      column with 1.2% isopropanol in n-hexane as the mobile phase and using coumarin
      as the internal standard. Several parameters affecting the
      extraction/derivatization of ethosuximide from spiked plasma were investigated.
      The linear range for the determination of ethosuximide in spiked plasma was over
      30-700 nmol/ml. For ethosuximide in plasma, the detection limit (signal-to-noise
      ratio=3; sample size, 10 microl) was about 9 pmol; the relative standard
      deviation was 6.4% for intra-day assay (n=6) and 9.2% for inter-day assay (n=6)
      and the relative recovery was found greater than 94%.

PMID- 10410934
TI  - Measurement of unbound caffeic acid in rat blood by on-line microdialysis coupled
      with liquid chromatography and its application to pharmacokinetic study.
AB  - To monitor the levels of caffeic acid in rat blood, an on-line microdialysis
      system coupled with liquid chromatography was developed. The microdialysis probe
      was inserted into the jugular vein/right atrium of male Sprague-Dawley rats.
      Caffeic acid (100 mg/kg, i.v.) was then administered via the femoral vein.
      Dialysates were automatically injected onto a liquid chromatographic system via
      an on-line injector. Samples were eluted with a mobile phase containing methanol
      100 mM monosodium phosphoric acid (35:65, v/v, pH 2.5). The UV detector
      wavelength was set at 320 nm. The detection limit of caffeic acid was 20 ng/ml.
      The in vivo recoveries of the microdialysis probe for caffeic acid at 0.5 and 1
      microg/ml were 48.34+/-2.68 and 47.64+/-3.43%, respectively (n=6). Intra- and
      inter-assay accuracy and precision of the analyses were < or = 10% in the range
      of 0.05 to 10 microg/ml. Pharmacokinetics analysis of results obtained using such
      a microdialysis-chromatographic method indicated that unbound caffeic acid in the
      rat fitted best to a biexponential decay model.

PMID- 10410935
TI  - Screening of sulphonamides in egg using gas chromatography-mass-selective
      detection and liquid chromatography-mass spectrometry.
AB  - A rapid extraction and clean-up procedure for sulphonamide antibiotics in eggs
      suitable for both GC-MSD and LC-MS end determinations has been developed. The
      drugs were extracted using acetonitrile, acidified using acetic acid and cleaned
      up using cation- and anion-exchange. For determination by GC-MSD, extracts were
      derivatised with diazomethane followed by pentafluoropropionic acid anhydride.
      For LC-MS extracts were taken up in water and used directly. The methodology
      developed was validated at the 100 and 25 microg kg(-1) levels, equivalent to the
      MRL and one quarter of the MRL. Results for the GC-MS procedure were quantitated
      against deuterated sulphadiazine with relative recoveries ranging from 54% for
      sulphachloropyridazine to 135.5% for sulphamethazine. Recoveries for the LC-MS
      procedure ranged from 33% for sulphaguanidine to 92% for sulphamethazine and
      sulphadimethoxine.

PMID- 10410936
TI  - Study of the solid-phase extraction of diclofenac sodium, indomethacin and
      phenylbutazone for their analysis in human urine by liquid chromatography.
AB  - A selective semi-automated solid-phase extraction (SPE) of the non-steroidal anti
      inflammatory drugs diclofenac sodium, indomethacin and phenylbutazone from urine
      prior to high-performance liquid chromatography was investigated. The drugs were
      recovered from urine buffered at pH 5.0 using C18 Bond-Elut cartridges as solid
      sorbent material and mixtures of methanol-aqueous buffer or acetonitrile-aqueous
      buffer as washing and elution solvents. The extracts were chromatographed on a
      reversed-phase ODS column using 10 mM acetate buffer (pH 4.0)-acetonitrile
      (58:42, v/v) as the mobile phase, and the effluent from the column was monitored
      at 210 nm with ultraviolet detection. Absolute recoveries of the anti
      inflammatory drugs within the range 0.02-1.0 microg/ml were about 85% for
      diclofenac and indomethacin, and 50% for phenylbutazone without any interference
      from endogenous compounds of the urine. The within-day and between-day
      repeatabilities were in all cases less than 5% and 10%, respectively. Limits of
      detection were 0.007 microg/ml for diclofenac sodium and indomethacin and 0.035
      microg/ml for phenylbutazone, whereas limits of quantitation were 0.02 microg/ml
      for diclofenac and indomethacin and 0.1 microg/ml for phenylbutazone.

PMID- 10410937
TI  - Simultaneous determination of donepezil (aricept) enantiomers in human plasma by
      liquid chromatography-electrospray tandem mass spectrometry.
AB  - A rapid, sensitive and enantioselective LC-MS-MS method using deuterium-labeled
      internal standard was developed and evaluated for the simultaneous quantitative
      determination of donepezil enantiomers in human plasma without interconversion
      during clean-up process and measurement. The use of an avidin column allowed the
      separation of donepezil enantiomers, which were specifically detected by MS-MS
      without interference from its metabolites and plasma constituents. Evaluation of
      this assay method shows that samples can be assayed with acceptable accuracy and
      precision within the range from 0.0206 ng/ml to 51.6 ng/ml for both R-donepezil
      and S-donepezil. This analytical method was applied to the simultaneous
      quantitation of donepezil enantiomers in human plasma.

PMID- 10410938
TI  - Determination of marbofloxacin in plasma samples by high-performance liquid
      chromatography using fluorescence detection.
AB  - A simple and sensitive HPLC method has been developed for the determination of
      marbofloxacin (MAR) in plasma. Sample preparations were carried out by adding
      phosphate buffer (pH 7.4, 0.1 M), followed by extraction with trichloromethane.
      MAR and the internal standard, enrofloxacin (ENR), were separated on a reversed
      phase column and eluted with aqueous solution-acetonitrile (80:20). The
      fluorescence of the column effluent was monitored at lambda(ex) = 338 and
      lambda(em) = 425 nm. The retention times were 2.20 and 3.30 min for MAR and ENR,
      respectively. The method was shown to be linear from 15 to 1500 ng/ml (r2 =
      0.999). The detection limit was 15 ng/ml. Mean recovery was determined as 90% by
      the analysis of plasma standards containing 150, 750, and 1500 ng/ml. Inter- and
      intra-assay precisions were 3.3% and 2.7%, respectively.

PMID- 10410939
TI  - Sensitive and selective gas chromatographic methods for the quantitation of
      camphor, menthol and methyl salicylate from human plasma.
AB  - Analytical methods using gas chromatography-flame ionization detection (GC-FID)
      for the quantitation of camphor and menthol and GC-MS for the quantitation of
      methyl salicylate have been developed for measurement of low concentrations from
      human plasma. Anethole serves as the internal standard for camphor and menthol
      and ethyl salicylate serves as the internal standard for methyl salicylate.
      Plasma samples undergo multiple, sequential extractions with hexane in order to
      provide optimal recovery. For menthol and camphor, the extracting solvent is
      reduced in volume and directly injected onto a capillary column (Simplicity-WAX).
      Extracted methyl salicylate is derivatized with BSTFA prior to injection onto a
      capillary column (Simplicity-5). Between-day variation (% RSD) at 5 ng/ml varies
      from 6.2% for methyl salicylate to 13.5% for camphor. The limit of detection for
      each analyte is 1 ng/ml and the limit of quantitation is 5 ng/ml. These
      analytical methods have been used in a clinical study to assess exposure from
      dermally applied patches containing the three compounds.

PMID- 10410940
TI  - Quantitation of levorphanol in human plasma at subnanogram per milliliter levels
      using capillary gas chromatography with electron-capture detection.
AB  - A gas chromatographic method for the determination of levorphanol in human plasma
      is described. The method utilizes extractive alkylation with tetrabutylammonium
      cation as the phase-transfer catalyst and pentafluorobenzyl bromide as the
      alkylating agent, and employs a structural analog, d-3-hydroxy-N-ethylmorphinan,
      as the internal standard. The pentafluorobenzyl ethers formed are separated by
      capillary gas chromatography and detected by electron capture. The method has
      good precision and accuracy for concentrations ranging from 0.25 ng/ml to 100
      ng/ml and has been used to measure plasma concentrations as part of a study to
      evaluate the management of chronic neuropathic pain with levorphanol.

PMID- 10410941
TI  - High-performance liquid chromatographic determination with amperometric detection
      of piroxicam in human plasma and tissues.
AB  - After repeated topical application of a piroxicam gel preparation to the knee,
      piroxicam was quantified in plasma, subcutaneous tissue, synovial capsule and
      synovial fluid, using specimens obtained during knee surgery. Electrochemical
      detection was used and the limit of quantification (LOQ) was 0.72 ng/ml in plasma
      at a signal-to-noise ratio of 10:1. The chromatographic method was optimised to
      determine piroxicam in all four matrices, and the analyte was quantified using a
      calibration line constructed from plasma calibration standards. Levels in
      subcutaneous tissue, synovial capsule and synovial fluid were compared to plasma
      steady-state levels and expressed as a ratio, in order to ascertain
      bioavailability.

PMID- 10410943
TI  - Evaluation of the programmed temperature vaporiser for large-volume injection of
      biological samples in gas chromatography.
AB  - The use of a programmed temperature vaporiser (PTV) with a packed liner was
      evaluated for the injection of large volumes (up to 100 microl) of plasma
      extracts in a gas chromatograph. Solvent purity, which is essential when large
      volumes are injected into the GC system, was determined. Special attention was
      paid to the purity of the solvents used for the solid-phase extraction (SPE)
      procedure. For this SPE method, ethyl acetate was used as the extraction and
      reconstitution solvent, and thus the purity of the ethyl acetate was critical,
      especially when a non-selective GC detector was applied. The liquid capacity and
      inertness of different packed liners were investigated. The liner packed with
      ATAS "A" (modified Chromosorb-based material with special treatment) was found to
      be the most suitable for the analysis of the tested drugs. Good linearity in
      response for variations in volume and concentration was observed. A comparison
      was made between the applicability of flame ionisation detection (FID) and mass
      selective detection (MSD). When 50-microl volumes of plasma extracts were
      injected with the PTV, the detection limits for secobarbital, lidocaine,
      phenobarbital and diazepam were about 50-times lower than when 1-microl volumes
      were injected. The detection limits of the tested compounds in plasma for
      injection of 50-100 microl plasma extract are 5-10 ng/ml for GC-FID whereas
      plasma concentrations of 250 pg/ml can be detected using the selected ion
      monitoring (SIM) mode of a MSD. For non-selective GC-FID, the background from a
      50-microl injection was substantially larger than with 1-microl injection as a
      result of co-injected plasma matrix components and solvent impurities. These
      background effects were less with GC-MSD in the total ion current mode and
      virtually absent with GC-MSD in the SIM mode.

PMID- 10410942
TI  - Stability of individual carotenoids, retinol and tocopherols in human plasma
      during exposure to light and after extraction.
AB  - We have modified gradient HPLC procedures for simultaneous quantification of
      retinol, gamma-tocopherol, alpha-tocopherol, lutein/zeaxanthin, beta
      cryptoxanthin, trans-lycopene, cis-lycopene, alpha-carotene and beta-carotene in
      200-microl aliquots of human plasma. The photosensitivity of these analytes in
      plasma exposed to fluorescent lighting for up to 72 h was investigated and most
      were stable under these conditions. The stability of these analytes held in
      darkness at -20 degrees C, 4 degrees C or room temperature for up to 48 h after
      extraction from plasma was also investigated. Variability in measurement of most
      analytes was greater at room temperature than at 4 degrees C or -20 degrees C.
      There were statistically significant variations in the measured concentrations of
      some analytes in samples kept cold. However, the magnitude of these variations
      was small and of little biological significance, particularly over the first 24
      h.

PMID- 10410944
TI  - Determination of extracellular and intracellular enrichments of [1-(13)C]-alpha
      ketoisovalerate using enzymatically converted [1-(13)C]-valine standardization
      curves and gas chromatography-mass spectrometry.
AB  - We report a validated method for the determination of extra- and intracellular [1
      (13)C]-alpha-ketoisovalerate ([1-(13)C]-KIV) enrichments by gas chromatography
      mass spectrometry. Standardization curves were prepared by enzymatic oxidation of
      [1-(13)C]-valine enriched standards of known composition. Slopes of [1-(13)C]
      valine standardization curves (mean+/-SD: 0.99+/-0.02, n=5) and [1-(13)C]-KIV
      standardization curves (mean+/-SD: 0.98+/-0.01, n=7) were not significantly
      different. The method was applied for the determination of [1-(13)C]-KIV
      enrichments in plasma and tissues during [1-(13)C]-valine infusion in a piglet.
      [1-(13)C]-KIV enrichment could be determined+/-0.1 MPE (C.V. 1%), and
      extracellular [1-(13)C]-KIV enrichment was a reliable estimate of intracellular
      (skeletal muscle, bone growth plate) [1-(13)C]-KIV enrichment.

PMID- 10410945
TI  - Sensitive and selective liquid chromatographic assay of memantine in plasma with
      fluorescence detection after pre-column derivatization.
AB  - A procedure was developed for the determination of memantine in plasma using
      liquid chromatography with fluorescence detection. Following a liquid-liquid
      extraction from 1 ml of plasma containing the internal standard amantadine, the
      extract was derivatized at room temperature with dansyl chloride, and the highly
      fluorescent derivatives were chromatographed with a reversed-phase C18 column and
      a mobile phase of phosphate buffer and acetonitrile. Dansylated memantine and
      amantadine were eluted in less than 13 min with no interference from endogenous
      material. The calibration curve was linear over the concentration range of 3-400
      ng/ml with inter- and intra-assay imprecision (C.V.) of less than 10%. The limit
      of quantitation was 3 ng/ml, and no major antidepressant, neuroleptic or their
      respective metabolites interfered with the quantitation of memantine. This method
      could also be applied to the quantitation of amantadine.

PMID- 10410946
TI  - Rapid chiral high-performance liquid chromatographic assay for salmeterol and
      alpha-hydroxysalmeterol. Application to in vitro metabolism studies.
AB  - A rapid and sensitive chiral high-performance liquid chromatographic (HPLC) assay
      for the simultaneous determination of salmeterol and its principal human
      metabolite alpha-hydroxysalmeterol is described. The two pairs of enantiomers
      were resolved on a chiral-cellobiohydrolase column and detected by
      electrochemical detection at +700 mV. Standard curves were linear over the
      concentration range 0.1 to 4.0 microM for alpha-hydroxysalmeterol enantiomers and
      2.5 to 40.0 microM for salmeterol enantiomers. Intra- and inter-day coefficients
      of variation were < 10%. The method was applied to a study of human hepatic
      metabolism in vitro which showed that microsomal metabolism of salmeterol to
      alpha-hydroxysalmeterol is not stereoselective.

PMID- 10410947
TI  - Simultaneous high-performance liquid chromatographic determination of retinol by
      fluorometry and of tocopherol by ultraviolet absorbance in the serum of newborns.
AB  - The simultaneous determination of retinol and tocopherol by isocratic HPLC in 100
      microl serum from preterm newborns is described. Retinol (tR 2.02+/-0.04 min) and
      retinyl acetate were detected fluorometrically, and were baseline-resolved in 4
      min. Tocopherol (tR 8.4+/-0.16 min) and tocopheryl acetate were detected by UV
      absorbance. Intra- and inter-assay RSD were: retinol, 5.6 and 8.1, and
      tocopherol, 3.6 and 6.7, respectively. This method is fast, selective and highly
      sensitive for retinol. It permits the measurement of serum concentrations of
      retinol and tocopherol with good accuracy and precision.

PMID- 10410948
TI  - Measurement of 4,5-dioxovaleric acid by high-performance liquid chromatography
      and fluorescence detection.
AB  - In this work we describe a sensitive method for the detection of 4,5-dioxovaleric
      acid (DOVA). 4,5-Dioxovaleric acid is derivatized with 2,3-diaminonaphthalene to
      form 3-(benzoquinoxalinyl-2)propionic acid (BZQ), a product with favorable UV
      absorbance and fluorescence properties. The high-performance liquid
      chromatographic method with UV absorbance and fluorescence detection is simple
      and its detection limit is approximately 100 fmol. This method was used to detect
      4,5-dioxovaleric acid formation during metal-catalyzed 5-aminolevulinic acid
      (ALA) oxidation. Iron and ferritin were active in the formation of 4,5
      dioxovaleric acid in the presence of 5-aminolevulinic acid. In addition, HPLC-MS
      MS assay was used to characterize BZQ. The determination of 4,5-dioxovaleric acid
      is of great interest for the study of the mechanism of the metal-catalyzed damage
      of biomolecules by 5-aminolevulinic acid. This reaction may play a role in
      carcinogenesis after lead intoxication. The high frequency of liver cancer in
      acute intermittent porphyria patients may also be due to this reaction.

PMID- 10410949
TI  - Measurement of the novel decapeptide cetrorelix in human plasma and urine by
      liquid chromatography-electrospray ionization mass spectrometry.
AB  - A sensitive LC-MS quantitation method of cetrorelix, a novel gonadotropin
      releasing hormone (GnRH) antagonist, was developed. Plasma and urine samples to
      which brominated cetrorelix was added as an internal standard (I.S.) were
      purified by solid-phase extraction with C8 cartridges. The chromatographic
      separation was achieved on a C18 reversed-phase column using acetonitrile-water
      trifluoroacetic acid (35:65:0.1, v/v/v) as mobile phase. The mass spectrometric
      analysis was performed by electrospray ionization mode with negative ion
      detection, and the adduct ions of cetrorelix and I.S. with trifluoroacetic acid
      were monitored in extremely high mass region of m/z 1543 and 1700, respectively.
      The lower limit of quantitation was 1.00 ng per 1 ml of plasma and 2.09 ng per 2
      ml of urine, and the present method was applied to the analysis of
      pharmacokinetics of cetrorelix in human during phase 1 clinical trial.

PMID- 10410950
TI  - Analysis of ergovaline in milk using high-performance liquid chromatography with
      fluorimetric detection.
AB  - A high-performance liquid chromatographic method for the determination of the
      mycotoxin ergovaline in goat's milk is described here. Ergotamine was used as an
      internal standard. For a sample size of 5.0 ml, the cleanup method included
      precipitation of milk protein with acetone. Then, ergovaline was extracted twice
      with chloroform and purified by elution on an Ergosil column. HPLC separation of
      the extract was accomplished on a C18 column: an isocratic elution, using
      acetonitrile-ammonium carbonate, was performed, and the analyte was detected by
      fluorimetry. The method was found to be linear between 0.7 and 8 ng ml(-1), a
      mean recovery rate of 99.8% was obtained, and the described assay appeared both
      repeatable and reproducible. The limit of detection and the limit of quantitation
      of ergovaline in milk were 0.2 ng ml(-1) and 0.7 ng ml(-1), respectively. In
      order to apply the proposed method, four lactating goats were administered the
      toxin intravenously at a dose of 32 mg kg(-1) body weight. The concentrations of
      the drug in plasma and milk were then determined at standardized intervals.
      Ergovaline (unequivocally identified by LC-MS-MS) could not be detected in the
      milk beyond eight hours post-dosing. Therefore, in goats, milk does not appear to
      be a major excretion route for the unmetabolized toxin.

PMID- 10410951
TI  - Sensitive high-performance liquid chromatographic determination of nifedipine in
      cat plasma following improved sample treatment.
AB  - A simple, easy and accurate reversed-phase high-performance liquid
      chromatographic method is described for the determination of nifedipine in cat
      plasma. The procedure involves extraction of nifedipine from plasma using a Sep
      Pak C18 cartridge and ultraviolet detection at 350 nm. The present method
      provides the required reproducibility and sensitivity for the determination of
      low concentrations of nifedipine without interference from plasma components or
      photodegradation products. The method was validated over the range 1-50 ng/ml
      nifedipine. Accuracy and precision were, respectively, 97% or more and 5% or less
      over the concentration range examined. The minimum quantifiable concentration of
      nifedipine was found to be 1 ng/ml.

PMID- 10410952
TI  - Sensitive high-performance liquid chromatography method for the simultaneous
      determination of low levels of dichloroacetic acid and its metabolites in blood
      and urine.
AB  - Dichloroacetic acid (DCA) is a contaminant found in treated drinking water due to
      chlorination. DCA has been shown to be a complete hepatocarcinogen in both mice
      and rats. In this study we developed a rapid and sensitive high-performance
      liquid chromatography (HPLC) method to simultaneously detect DCA and its
      metabolites, oxalic acid, glyoxylic acid and glycolic acid in blood and urine
      samples of animals sub-chronically administered with DCA (2 g/l) in drinking
      water. Both urine and plasma samples were treated minimally before HPLC analysis.
      Separation and detection of DCA and its metabolites were achieved using an anion
      exchange column and a conductivity detector. The mobile phase consisted of an
      initial concentration of 0.01 mM sodium hydroxide in 40% methanol followed by a
      linear gradient from 0.01 mM to 60 mM sodium hydroxide in 40% methanol for 30
      min. The lower detection limit for DCA and each of its three major metabolites
      was 0.05 microg/ml. DCA and its metabolites gave a linear response range from
      0.05 to 100 microg/ml. Plasma DCA was also analyzed by gas chromatography (GC),
      and the results obtained correlated with those from the HPLC method (correlation
      coefficient=0.999). While available HPLC techniques offer sensitive procedures to
      detect either glycolic acid or oxalic acid, the described HPLC method has the
      unique advantage of determining simultaneously the parent compound (DCA) and its
      three major metabolites (oxalic acid, glyoxylic acid and glycolic acid) in
      biological samples, without complex sample preparation.

PMID- 10410953
TI  - Determination of leukotriene E4 in human urine using liquid chromatography-tandem
      mass spectrometry.
AB  - A liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method was
      developed for the quantitation of urinary leukotriene E4 (LTE4). LTE4 and its
      internal standard were extracted by solid-phase extraction and analysed using LC
      MS-MS in the selected reaction monitoring (SRM) mode. A good linear response over
      the range of 10 pg to 10 ng was demonstrated. The accuracy of added LTE4 ranged
      from 97.0% to 108.0% with a mean and SD of 100.6+/-2.4%. We detected LTE4 (63.1+/
      18.7 pg/mg creatinine, n=10) in healthy human urine. This method can be used to
      determine LTE4 in biological samples.

PMID- 10410954
TI  - Development and validation of a sensitive solid-phase extraction and high
      performance liquid chromatographic assay for the novel bio-reductive anti-tumor
      agent RH1 in human and mouse plasma.
AB  - A HPLC assay and solid-phase extraction technique from human plasma has been
      developed and validated for the experimental anticancer agent, RH1 (2,5
      diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone) which is currently being
      evaluated by the CRC phase I/II committee. A 500 mg amino propyl solid-phase
      extraction cartridge was used to isolate RH1 from human plasma. Analysis was
      performed on a reversed-phase chromatography system using a 15 cm cyanopropyl
      column and isocratic elution with a 10% methanol-90% water (double distilled)
      solution. The lower limit of quantitation for RH1 was found to be 0.00375
      microg/ml (3.75 ng/ml+/-8.3%) in water and following extraction from plasma.
      Recovery of >80%(+/-11.9%) was achieved over a five-day validation study. This
      method was used to carry out pre-clinical studies in BDF mice (standard strain of
      hybrid mice) at three dose levels (2, 5 and 10 mg/kg of RH1 in 0.9% (w/v) saline
      via an intraperotoneal injection). Standard Version of PC Winnonlin
      pharmacokinetic modelling software was used to model the data. A none
      compartmental model was used to describe the disposition of RH1 in mice plasma.
      RH1 was rapidly eliminated from plasma with a mean plasma clearance of 23.4
      ml/min, mean volume of distribution of 321.6 ml and mean t(1/2) alpha and beta
      decays of 4.8 and 9.6 min, respectively. RH1 in human and mouse whole blood and
      plasma was found to be stable up to 2 h.

PMID- 10410955
TI  - Determination of cyclophosphamide and its metabolites in human plasma by high
      performance liquid chromatography-mass spectrometry.
AB  - A sensitive HPLC-MS method was developed for the simultaneous determination of
      cyclophosphamide and its metabolites 4-hydroxycyclophosphamide
      (aldocyclophosphamide), 4-ketocyclophosphamide, caboxyphosphamide and 3
      dechloroethylifosfamide in human plasma. 4-Hydroxycyclophosphamide was converted
      with methylhydroxylamine to the stable methyloxime form. We used a solid-phase
      extraction with C18 cartridges followed by HPLC-MS with the single mass
      spectrometer SSQ 7000 of Finnigan. The limits of detection were 15 ng/ml for
      cyclophosphamide, 3-dechloroethylifosfamide and ketocyclophosphamide in each case
      and 30 ng/ml for carboxyphosphamide and 4-hydroxycyclophosphamide, respectively.
      First results of pharmacokinetics are shown.

PMID- 10410956
TI  - Radiochemical assay for determination of dihydropyrimidinase activity using
      reversed-phase high-performance liquid chromatography.
AB  - A radiochemical assay was developed to measure the activity of
      dihydropyrimidinase (DHP) in human liver homogenates. The method is based on the
      separation of radiolabeled dihydrouracil from N-carbamyl-beta-alanine by HPLC
      with on-line detection of radioactivity combined with detection of 14CO2 by
      liquid scintillation counting. The assay was linear with time and protein
      concentration. The minimum amount of radiolabeled products which could be
      determined proved to be 12 pmol using a purified stock solution of [2-(14)C]-5,6
      dihydrouracil. This highly sensitive assay is especially suitable to identify
      patients with a dihydropyrimidinase deficiency.

PMID- 10410957
TI  - Assay for levormeloxifene, a selective estrogen receptor modulator, in human and
      monkey plasma employing high-performance liquid chromatography and solid-phase
      extraction.
AB  - Assays for levormeloxifene, a new selective estrogen receptor modulator, and its
      7-desmethyl metabolite in human and cynomolgus monkey plasma are described.
      Plasma was extracted on mixed-mode bonded sorbent material (C8/SCX) and the
      extracts were analysed by high-performance liquid chromatography with
      fluorescence detection. Recoveries of levormeloxifene and the metabolite exceeded
      70%. Within and total assay precision calculated as a coefficient of variation
      (C.V.) were <8% for both compounds at all concentration levels, except at the
      limit of quantitation (LOQ) where the C.V. was 15%. Within and total-assay
      accuracy calculated as a percentage of the nominal value were between 90 and 114%
      for both analytes. The LOQ was for levormeloxifene and 7
      desmethyllevormeloxifene, respectively, 1.5 and 2.5 ng/ml (man) and 5.2 and 6.9
      ng/ml (monkey). In the monkey plasma assay, human plasma could substitute monkey
      plasma as blank plasma.

PMID- 10410958
TI  - High-performance liquid chromatographic assay of the X-ray contrast agent
      iopiperidol in plasma and urine of rats and humans.
AB  - Iopiperidol is a non ionic iodinated compound currently under evaluation as a
      potential contrast medium with anticoagulant property for radiological
      examinations. An HPLC method for assaying iopiperidol in plasma and urine of rats
      and humans is described. The analysis is based on the reversed-phase
      chromatographic separation of iopiperidol and the internal standard (iopamidol)
      from the endogenous components of the biological fluids, and their detection by
      UV absorption at 244 nm. The selectivity of the method was satisfactory. The mean
      absolute recovery was greater than 80%. The precision and accuracy of the
      analytical methods were in the range 0.3 to 3.3 and -8.5 to +11%, respectively.
      The detection limits of iopiperidol in plasma (0.1 ml) and urine (0.25 ml) were
      0.2 and 0.4 microg/ml, respectively.

PMID- 10410959
TI  - Gas chromatographic-mass spectrometric determination of total homocysteine in
      human plasma by stable isotope dilution: method and clinical applications.
AB  - The detection and quantitation of slight increases of plasma homocysteine levels
      is of growing interest. This has prompted us to develop a highly sensitive and
      accurate capillary gas chromatography-mass spectrometry (GC-MS) method. The
      method proved to be highly sensitive (DL=0.17 micromol/l) with between- and
      within-run precision less than 6% and 7%, respectively. Reference values of
      plasma total homocysteine have been determined for men (n=39) and women (n=36),
      showing a significant difference (P=0.003) between gender. Preliminary results in
      cerebrovascular accidents and in venous thrombosis are presented.

PMID- 10410960
TI  - Detection and identification of morphine in urine extracts using thin-layer
      chromatography and tandem mass spectrometry.
AB  - The application of tandem mass spectrometry to the analysis and identification of
      morphine following thin-layer chromatography is described. FAB-mass spectrometry
      and mass spectrometry-mass spectrometry were performed following chromatography
      on silica gel high-performance thin-layer chromatography plates. The successful
      application of this simple methodology to a urine extract suggests that this
      approach has practical utility for confirming the identity of abused drugs
      detected by thin-layer chromatography.

PMID- 10410961
TI  - Determination of differential activities of soluble and membrane-bound catechol-O
      methyltransferase in tissues and erythrocytes.
AB  - Catechol-O-methyltransferase (COMT) exists as two isoenzymes, a membrane-bound
      form (MB-COMT) and a soluble form (S-COMT), with different roles in the
      metabolism of catecholamines and other catechol compounds. This report documents
      an HPLC assay for separate estimation of S-COMT and MB-COMT activity and examines
      activities of the two isoenzymes among different rat tissues and in human and rat
      erythrocytes. Activities of MB-COMT and S-COMT varied widely among tissues. There
      were higher activities of S-COMT than MB-COMT in all tissues except the adrenal
      medulla where MB-COMT was the predominant isoenzyme, consistent with the
      importance of this tissue and MB-COMT for the O-methylation of catecholamines. MB
      COMT and S-COMT in rat and human erythrocytes showed divergent levels and
      patterns of activity. The assay represents a rapid and accurate method for
      quantifying MB-COMT and S-COMT in various tissues and examining the relative
      roles of COMT isoenzymes in the metabolism of catechol compounds in health and
      disease.

PMID- 10410962
TI  - Effect of salt concentration on separation patterns in static capillary
      isoelectric focusing with imaging detection.
AB  - Salts introduced into protein samples have an impact on the pH gradient in free
      solution in isoelectric focusing (IEF), which is reflected by the separation
      pattern. In this study, samples containing different concentrations of phosphate
      buffered saline (PBS) were focused in capillary format and detected in a real
      time mode using an imaged capillary isoelectric focusing (CIEF) system at 280 nm.
      It was observed that salt compressed the pH gradient with a degree of 4.3% at a
      PBS concentration interval of 10 mM. As a result, the same sample components,
      therefore, were focused at different positions inside the capillary. Using two pI
      markers as the internal standards, the separation patterns in the presence of
      salts were corrected to the salt-free matrix by simply stretching the
      electropherograms. The stretched electropherograms of model samples, pI markers
      and myoglobin, demonstrated the feasibility of this correction. This simple
      method is promising for identifying proteins, which may exhibit different pI
      values after their mutation and stability process, when salt is present in the
      sample.

PMID- 10410964
TI  - High-performance liquid chromatographic purification and capillary
      electrophoresis quantification of the chemokine stromal cell-derived factor-1.
AB  - Chemokines are members of the chemotactic cytokines family implicated in various
      immunoregulatory functions. The CXC-chemokine stromal cell derived factor-1 (SDF
      1alpha) was purified from the culture medium of murine bone marrow stromal cell
      line (MS-5) by affinity and reversed-phase liquid chromatography. Yield and
      purity were assessed by capillary electrophoresis (CE) with reference to the
      human SDF-1alpha from recombinant DNA technology. CE technique was useful to
      evaluate the purity of human SDF-1alpha from chemical synthesis and to resolve
      murine and human SDF-1alpha, differing by only one amino acid. Chemotactic
      activity of the murine SDF-1alpha was tested on the basis of CE quantification.

PMID- 10410963
TI  - Qualitative and quantitative determination of sesquiterpenoids in Achillea
      species by reversed-phase high-performance liquid chromatography, mass
      spectrometry and thin-layer chromatography.
AB  - A reversed-phase high-performance liquid chromatographic method was developed as
      a universal analysis system in order to determine and quantify antiphlogistic
      sesquiterpenoids in different Achillea species. Identification was performed by
      HPLC and diode array detection as well as by monitoring the HPLC fractions by TLC
      and MS. Using santonin as internal standard, HPLC separations were achieved with
      a methanol-water gradient system using RP 8 LiChrospher 100 (5 microm) as
      stationary phase. For validation, sample analyses were performed, using the two
      tetraploid species A. collina and A. pratensis. The method allows the
      identification and quantification of the main compounds achillicin, 8alpha
      tigloxy-artabsin, 8alpha-angeloxy-artabsin, arglanin and santamarin with
      variation coefficients between 3.4 and 4.7% (total content) using santonin as
      internal standard. For the different compounds recovery was found between 81 and
      107% performing multiple analyses of A. collina and A. pratensis.

PMID- 10410965
TI  - Interference by S-nitroso compounds with the measurement of nitrate in methods
      requiring reduction of nitrate to nitrite by cadmium.
AB  - Various methods suited for the measurement of nitrate require its reduction to
      nitrite by cadmium under acidic or alkaline conditions. N(G)-Nitroarginine
      analogs have been shown to interfere with the measurement of nitrate by such
      assays. In the present work we show by gas chromatography-mass spectrometry that
      under alkaline reduction conditions the S-nitroso compounds S-nitrosoglutathione
      and S-nitrosohomocysteine but not S-nitroso-N-acetylcysteine and S-nitroso-N
      acetylpenicillamine can considerably contribute to nitrate and thus interfere
      with its measurement. Our results suggest that S-nitroso compounds may interfere
      with the measurement of nitrate in methods requiring cadmium-catalyzed reduction
      of nitrate to nitrite.

PMID- 10410966
TI  - Affinity-purification of a TMV-specific recombinant full-size antibody from a
      transgenic tobacco suspension culture.
AB  - A TMV-specific full-size murine IgG-2b/K antibody (mAb24) was expressed in a
      Nicotiana tabacum cv. Petite Havana SR1 suspension culture (P9s), which was
      derived from a stably transformed transgenic plant (P9). The integration of an N
      terminal murine leader peptide directed the assembled immunoglobulin for
      secretion. However, in suspension culture, the full-size recombinant antibody,
      rAb24, was retained by the plant cell wall and was not present in the culture
      medium. rAb24 expression reached a basal level of 15 microg per gram wet cell
      weight, corresponding to 0.3% of the total soluble plant cell protein. The level
      of rAb24 could be increased three-fold by amino acid supplementation of the
      culture medium. For purification of the recombinant antibody from batch-cultured
      tobacco suspension cells, the primary plant cell wall was partially digested by
      enzymatic treatment. This resulted in a total release of recombinant full-size
      rAb24 into the extraction buffer. A three-step procedure was used to purify the
      immunoglobulins, starting with cross-flow filtration (step 1) followed by protein
      A affinity chromatography (step 2) and gel filtration as a final purification
      step (step 3). This procedure gave a recovery of more than 80% of the expressed
      rAb24 from plant cell extracts. SDS-PAGE, IEF and immunoblot analyses
      demonstrated a high degree of homogeneity for the affinity-purified rAb24. An
      ELISA procedure demonstrated that the specificity and affinity of the protein A
      affinity purified antibody was indistinguishable from its murine counterpart,
      indicating the potential of plant cell suspension cultures as bio-reactors for
      the production of recombinant antibodies.

PMID- 10410967
TI  - Heparin in plasma samples causes nonspecific binding to histones on Western
      blots.
AB  - We observed an artifactual reactivity on Western blots when heparin was used as
      the anticoagulant in collected blood specimens. This nonspecific interaction was
      found to be due to immunoglobulin aggregates that bound to cellular proteins, in
      particular histones. Nonspecific interaction was not observed in fresh
      heparinized samples, but was present in samples frozen for long-term storage.
      Other anticoagulants such as EDTA, oxaloacetate and sodium citrate did not cause
      this nonspecific reactivity. Although adding heparin to serum could reproduce the
      nonspecific reactivity on Western blots, other immunological tests such as ELISA
      or indirect immunofluorescence were not affected by the use of heparinized
      plasma. Enzymatic digestion of heparinized samples with Heparinase I removed the
      artifactual reactivity, leaving specific antigen-antibody interactions
      unaffected. Therefore, we advise caution in the interpretation of Western
      blotting experiments when blood or other tissue fluid specimens are collected in
      heparin.

PMID- 10410968
TI  - Follicular dendritic cells mediated maintenance of primary lymphocyte cultures
      for long-term analysis of a functional in vitro immune system.
AB  - Primary lymphocyte cultures are important for analysis of cellular and molecular
      events occurring during immune responses. However, the lymphoid cells (especially
      B cells) typically only survive for a few days in vitro which limits studies.
      Establishment of long-term primary lymphocyte cultures where a functioning
      humoral immune responses can be maintained and regulated is still a challenge.
      Follicular dendritic cells (FDC) are immune accessory cells that reside in the
      follicles of secondary lymphoid organs and are known to protect lymphocytes from
      apoptosis. We hypothesized that addition of FDC to primary lymphocyte cultures
      may help maintain humoral immune responses in vitro as they do in vivo. To test
      the hypothesis, freshly isolated lymphocytes were cultured with or without FDC.
      The B cells in cultures were labeled using B220 and apoptotic cells were labeled
      using the TUNEL assay. Antibody production was monitored in supernatant fluids
      using ELISA. The results showed that FDC reduced apoptosis and helped sustain
      primary lymphocyte cultures and antibody production was maintained throughout the
      entire period (e.g., 8 weeks). This FDC dependent system should be useful for
      analysis of cellular and molecular events over extended periods in vitro.

PMID- 10410969
TI  - A novel cytolysis assay using fluorescent labeling and quantitative fluorescent
      scanning technology.
AB  - A novel cellular cytotoxicity assay using Calcein acetoxymethyl (Calcein-AM), a
      cytoplasmic fluorescent label, has been developed as an alternative to the
      standard 51Chromium (Cr)-release. Target cells were loaded with Calcein-AM and
      then co-incubated with effector cells. An additional reagent, FluoroQuench, is
      added to extinguish fluorescence of dying target cells and of the culture media.
      Assay plates are read on a quantitative fluorescent scanner for determination of
      viable target cells. Percent lysis is calculated as one minus the percent viable
      cells as compared to fluorescent-labeled targets-only wells. The assay was tested
      to demonstrate the lytic activity of cytotoxic T lymphocyte (CTL) cultures,
      lymphokine-activated killer (LAK), and natural killer (NK) cell line effectors
      against peptide-pulsed and melanoma targets. In addition to the acquisition of
      results comparable to the 51Cr-release assay, the Calcein assay reliably measures
      cell-mediated cytotoxicity with little variance among replicates. The fluorescent
      assay represents a simple and useful alternative to the use of radioactive
      materials and adds the additional benefit of digital images and analysis.

PMID- 10410970
TI  - Application of a fluorometric assay to detect caspase activity in thymus tissue
      undergoing apoptosis in vivo.
AB  - To date, in vivo apoptosis within the thymus has been assessed using
      morphological criteria and/or detection of a DNA ladder indicative of
      oligonucleosomal fragmentation of the DNA. Here, we have used a fluorometric
      method to investigate activation of the caspase protease family in the thymus
      following in vivo induction of apoptosis by injection of the synthetic
      glucocorticoid hydrocortisone. Cleavage of DEVD-MCA by caspase-3 and other group
      II caspases releases free MCA which can be detected fluorimetrically. We
      demonstrate a time-dependent increase in DEVD-MCA cleavage activity within this
      tissue indicating the activation of caspase-3 like enzymes. This activity was
      inhibited by the specific group II caspase inhibitor DEVD-CHO. The interpretation
      of increased caspase activity was confirmed by immunoblot analysis to reveal
      cleavage of the caspase-3 substrate, fodrin. In addition, agarose gel
      electrophoresis of the DNA yielded a ladder pattern, confirming the occurrence of
      apoptosis. This study demonstrates that DEVD-MCA cleavage activity may be a
      useful quantitative method for the analysis of apoptosis in thymus tissue. It is
      a relatively rapid procedure not requiring thymocyte isolation or gel
      electrophoresis and detects fairly early biochemical changes occurring during
      apoptosis. In the present study we have used this method to demonstrate the
      involvement of caspases in thymocyte apoptotic death induced in vivo by
      glucocorticoids. Thus, measurement of caspase activity in thymus tissue may have
      applications for studying the in vivo effects of immunotoxicants.

PMID- 10410971
TI  - Endotoxin potency in the A549 lung epithelial cell bioassay and the limulus
      amebocyte lysate assay.
AB  - The purpose of this study was to elucidate to what extent the potency of
      endotoxins measured by the limulus amebocyte lysate (LAL) assay is reflected in
      the potency in an in vitro assay based on release of interleukin-8 (IL-8) from a
      lung epithelial cell line, A549. Lipopolysaccharides (LPS) from Escherichia coli,
      Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella enteritidis and
      detoxified LPS from E. coli were applied in serial dilutions in the LAL assay and
      in the A549 bioassay. Also 19 organic dust samples from waste recycling plants
      were tested. The A549 cells were incubated for 24 h with LPS or dust, and the IL
      8 secretion was determined by ELISA. The method for evaluation of the LAL assay
      showed linearity for the four endotoxins. Using the slope as a measure of the
      potency factor (PF), LPS from E. coli and S. enteritidis was about four times
      more potent than that for LPS from K. pneumoniae and P. aeruginosa. In the A549
      bioassay each of the different types of endotoxin had characteristic and very
      different dose-response curves. The potency of the LPS, in the A549 bioassay,
      ranked as follows K. pneumoniae > P. aeruginosa > E. coli > or = S. enteritidis.
      The content of endotoxin in the dust samples did not correlate with their potency
      in the A549 bioassay. The present study indicates a poor correlation between the
      potency of endotoxin in the LAL assay compared with the A549 bioassay. The lack
      of correlation when organic dust samples are tested may reflect the fact that
      these samples contain biological active compounds, which are non-reactive in the
      LAL-assay but stimulate IL-8 secretion from epithelial cells.

PMID- 10410972
TI  - Discrimination of damaged/dead cells by propidium iodide uptake in
      immunofluorescently labeled populations analyzed by phase-sensitive flow
      cytometry.
AB  - We report a flow cytometric fluorescence lifetime-based method to discriminate
      damaged/dead from viable cells in immunofluorescently labeled populations using
      propidium iodide as a dye-exclusion viability probe. Fluorescence signals from
      propidium iodide and the anti-thymus cell-surface immunofluorescence marker
      fluorochromes, phycoerythrin and phycoerythrin/Texas Red (tandem conjugate),
      which have overlapping emission spectra with propidium iodide, are resolved based
      on differences in their fluorescence emission lifetimes using phase-sensitive
      detection. Mouse thymus cell samples were first labeled separately with anti-Thy
      1.2 antibody directly conjugated to phycoerythrin and to phycoerythrin/Texas Red
      and propidium iodide. Labeled cells were then analyzed to determine the lifetimes
      of the immunofluorescence markers and propidium iodide. Based on these results,
      rat and mouse thymocytes labeled with anti-Thy 1.1 conjugated to phycoerythrin
      and anti-Thy 1.2 conjugated to phycoerythrin/Texas Red, respectively, were
      suspended in phosphate buffered saline containing propidium iodide, and were
      analyzed as they passed through a flow chamber and crossed a high-frequency,
      intensity-modulated (sinusoidal) laser excitation beam. The resulting
      immunofluorescence and propidium iodide signals were resolved based on
      differences in fluorescence lifetimes expressed as phase shifts using phase
      sensitive detection and displayed as frequency distribution histograms and
      bivariate contour diagrams. This technology provides a new method to resolve
      immunofluorescence and propidium iodide signals from overlapping fluorescence
      emission spectra and a flow cytometric lifetime-based technique to quantify
      damaged/dead cells in immunofluorescence studies.

PMID- 10410974
TI  - Identification of unacceptable background caused by non-specific protein
      adsorption to the plastic surface of 96-well immunoassay plates using a
      standardized enzyme-linked immunosorbent assay procedure.
AB  - A standardized enzyme-linked immunosorbent assay (ELISA) was used to examine the
      capacity of immunoassay plates to prevent non-specific protein binding under
      blocking conditions. Data from 16 types of 96-well microtitre plate from seven
      commercial sources, are described. Plates were evaluated with respect to their
      capacity to adsorb a conjugated antibody in diluent buffer containing non-ionic
      detergent Tween 20 (0.05%) and skimmed milk proteins (5%). Plates with an
      absorbance value of > or = 0.05, in not more than one well, were defined as
      within acceptable limits. Major problems were seen in high binding gamma
      irradiated polystyrene plates, from all sources, where only < or = 30% of plates
      were acceptable. These showed high, randomly distributed, non-specific binding,
      with some wells showing absorbance values > 2.0. Similar results were obtained
      when high binding plates were repeatedly gamma-irradiated, and after gamma
      irradiation of low binding polystyrene plates. For high binding, non- gamma
      irradiated polystyrene plates, approximately 70% of plates were acceptable.
      Better results (86-100% acceptability) were observed for all low binding
      polystyrene plates. Only one source in three provided acceptable, low binding,
      polyvinylchloride plates. This paper confirms a widely held view that non
      specific binding to certain plates could be a serious factor in both the
      development and application of ELISAs. Therefore, the test protocol described is
      proposed as an additional quality control method for certifying ELISA plates by
      commercial companies.

PMID- 10410973
TI  - Isolation of bovine neutrophils with biomagnetic beads: comparison with standard
      Percoll density gradient isolation methods.
AB  - A prerequisite for studies on bovine neutrophils is a reliable method of
      neutrophil isolation from blood to obtain highly purified cell populations that
      are functionally active. Since current techniques of neutrophil isolation fall
      short of these requirements, we have developed a newer and more effective
      technique for isolation of bovine neutrophils that utilizes biomagnetic beads
      coated with a monoclonal antibody that recognizes an abundant surface antigen on
      bovine neutrophils to purify these cells. Comparison of the purity and viability
      of bovine neutrophils isolated by a conventional method (continuous Percoll
      density gradient) with this new method showed that neutrophils isolated with
      biomagnetic beads were higher in purity and had an increased yield. In addition,
      cells isolated with biomagnetic beads demonstrated normal or even improved
      function in assays of chemotaxis, phagocytosis, degranulation, and respiratory
      burst activity. Finally, bovine neutrophils isolated using this method showed an
      overall lower level of spontaneous apoptosis, which correlates well with the high
      level of viability observed in the purified cell preparations. Thus, this method
      represents a significant advance over current methods for isolating bovine
      neutrophils and would be widely applicable to labs studying the biochemistry and
      signal transduction pathways in these cells.

PMID- 10410976
TI  - Flow cytometric detection of antigen-specific cytokine responses in lung T cells
      in a murine model of pulmonary inflammation.
AB  - Multiparameter flow cytometry was used to examine the cytokine responses of
      antigen-specific T lymphocytes isolated from the lungs of antigen-sensitized mice
      which developed pulmonary inflammation after aerosol challenge with ovalbumin
      (OA) (OA/OA). Lung T cells were stimulated in vitro with OA and anti-CD28
      monoclonal antibody (mAb) in the presence of the secretion inhibitor, brefeldin
      A. T cell subsets were examined for intracellular cytokine expression using
      fluorochrome-labeled cell-surface specific and anti-cytokine antibodies. Antigen
      specific responses resulted in significant numbers of CD4+ lung cells expressing
      cytoplasmic interleukin (IL)-2 (6%), IL-4 (1.5%), IL-5 (4%), and tumor necrosis
      factor (TNF)-alpha (11%), but not interferon (IFN)-gamma. Dual cytokine analyses
      demonstrated antigen-specific responses resulted in CD4+ T cells being positive
      for IL-2 and IL-4 or IL-2 and IL-5. TNF-alpha was the only antigen-specific
      cytokine response detected in CD8+ lung T cells after in vitro activation with
      OA. Cytokines in the supernatants of cultures activated with OA and anti-CD28
      were measured by ELISA and the results confirmed the antigen-specific responses
      measured by flow cytometry. Polyclonal activation of lung T cells from OA/OA mice
      with 12-myristate 13-acetate (PMA), ionomycin, anti-CD3 mAb, and anti-CD28 mAb
      resulted in higher percentages of IL-2+ (43%) and IL-5+ (7%) CD4 cells when
      compared to CD4+ T cells from non-OA sensitized, challenged mice. CD8+ cells from
      OA/OA mice demonstrated intracellular staining for IL-2 (26%), TNF-alpha (55%),
      and IFN-gamma (37%), but not IL-4 or IL-5, after polyclonal activation. There is
      less agreement between intracellular cytokine staining of CD4+ T cells and
      cytokines released into the culture medium after polyclonal activation. Dual
      cytokine analyses of polyclonal-activated CD4+ cells demonstrated co-expression
      of IFN-gamma with IL-2, IL-4, or IL-5. T cells co-expressing IL-2 with IL-4 or IL
      5 were also detected. These results demonstrate the utility of multiparameter
      flow cytometry to directly measure antigen-specific cytokine responses in subsets
      of T lymphocytes isolated from inflammatory sites.

PMID- 10410975
TI  - Simultaneous analysis of eosinophil and neutrophil adhesion to plasma and tissue
      fibronectin, fibrinogen, and albumin.
AB  - A simple and convenient assay for the simultaneous measurement of eosinophil and
      neutrophil adhesion is described. Incubations were performed in microtitre plates
      coated with different proteins. Adhesion of eosinophils and neutrophils was
      determined by the use of specific radioimmunoassays for eosinophil cationic
      protein (ECP) and myeloperoxidase (MPO). Using this assay, Mn2+ induced a
      significant increase of the adhesion of eosinophils to plasma fibronectin and
      fibrinogen in a time-dependent fashion, while a small increase of the adhesion of
      neutrophils to these two proteins was observed. In contrast, a time-dependent
      potent increment of the adhesion of both eosinophils and neutrophils to tissue
      fibronectin and albumin was found. Tissue fibronectin preferentially supported
      eosinophil adhesion compared with that of neutrophils in the presence of Mn2+.
      PMA (10(-9) mol/l) induced a significant increase in the adhesion of eosinophils
      and neutrophils of the same pattern to all four proteins. However, when
      granulocytes were stimulated by Mn2+ in combination with PMA, eosinophils and
      neutrophils showed different patterns of response to plasma fibronectin and
      fibrinogen, respectively, but the same pattern of response to tissue fibronectin.
      f-MLP stimulated an early increase of the adhesion of neutrophils to fibrinogen,
      while a weak stimulation of the adhesion of eosinophils to plasma fibronectin and
      fibrinogen and of neutrophils to plasma fibronectin was observed. Co-stimulation
      with f-MLP and Mn2+ did not induce any additive effects on granulocyte adhesion.
      In conclusion, the assay allows rapid quantification of eosinophil and neutrophil
      adhesion and can be used to directly compare the response of neutrophils and
      eosinophils. The assay is thus suitable for studies aimed at identifying agents
      with a selective effect on either of the cells.

PMID- 10410977
TI  - Detection of biomolecules in the near-infrared spectral region via a fiber-optic
      immunosensor.
AB  - The design, development, and application of a fluorescent fiber-optic
      immunosensor (FFOI) procedure for the detection of antibody/antigen binding
      within the near-infrared (NIR) spectral region is reported. The technique was
      developed through the combined use of fiber-optics, semiconductor laser
      excitation, fluorescence detection, NIR dye, and immunochemical techniques. The
      antibody is immobilized on the FFOI's sensing tip and utilized as a recognition
      component for trace amounts of specific antigen. The FFOI is constructed to
      utilize antibody sandwich technique. Three individual immunoassays are reported.
      The first two assays utilize the FFOI and NN382, a commercial NIR dye, for the
      detection of human immunoglobulin G (IgG). In these assays, goat anti-human IgG
      antibody (GAHG) is immobilized on the sensitive terminal of the FFOI followed by
      the exposure of the antibody-coated terminal to human IgG. The probe is then
      introduced to GAHG labeled with NN382, generating a signal. The third assay
      utilizes the FFOI for the detection of trace amounts of Legionella pneumophila
      serogroup 1 (LPS1). In this assay, rabbit anti-LPS1 antibody is immobilized on
      the sensitive terminal of the FFOI followed by exposure to LPS1. The antigen
      coated probe is then treated with monoclonal anti-LPS1 antibody followed by
      incubation with GAHG labeled with NN382. The assays are optimized to detect the
      corresponding antigen via the NIR-FFOI. Typical measurements are performed in 10
      15 min. A 780-nm semiconductor laser provides the excitation of the immune
      complex and the resulting emission is detected by a 820-nm silicon photodiode
      detector. The intensity of the resulting fluorescence is directly proportional to
      the concentration of the antigen. Solutions of IgG and LPS1 with concentrations
      as low as 10(-11) M and 0.5 ng/ml, respectively, have been detected with a
      minimum interference.

PMID- 10410978
TI  - Purification of morphologically and functionally intact human basophils to near
      homogeneity.
AB  - Certain studies on basophils require highly purified functionally intact cell
      preparations. Here, a three-step procedure is described that meets these
      requirements. The procedure consists of a Ficoll density gradient step,
      counterflow elutriation and negative selection by magnetic cell sorting (MACS).
      The mean purity of basophils obtained from 30 donors was 97.6+/-3.96% with a
      viability of 99.6+/-0.83%. The recovery rate was 49.7+/-15.6%. The cells had a
      normal morphological appearance as assessed by May-Grunwald-stained cytospins and
      were functionally intact as shown by their unaltered capacity to release
      histamine and interleukin 4 (IL-4) following immunological activation. This
      procedure is a clear improvement over currently available techniques and should
      facilitate future investigations on basophils.

PMID- 10410979
TI  - Specific detection by flow cytometry of histidine-tagged ligands bound to their
      receptors using a tag-specific monoclonal antibody.
AB  - Engineering proteins to contain a histidine (His)-tag has proved to be very
      useful for the purification and analyses of these molecules. In the present
      study, we demonstrate that the binding of His-tagged ligands to their receptors
      may be visualised by flow cytometry making use of a selected monoclonal antibody
      (mAb) against the His-tag. Employing this method, a recombinant C3a (rC3a)
      anaphylatoxin with a His-tag at its N-terminus could be shown to bind to C3a
      receptor (C3aR)-expressing RBL-2H3 transfectants with a half-maximal effective
      concentration (EC50) of about 3 nM which is well within the range of published
      affinity constants. Binding of a recombinant interleukin-8 (rIL-8) molecule with
      a C-terminal His-tag to RBL-2H3 cells which stably express the IL-8 receptors
      CXCR1 or CXCR2 could also be demonstrated using the tag-specific mAb.
      Furthermore, aminoterminally tagged C5a molecules of rat or human origin could be
      shown to bind to the human C5a receptor (C5aR). However, the fluorescence signal
      of the binding of rat rC5a to the human C5aR was distinctly higher over a wide
      range of ligand concentrations than the signal of human rC5a binding although
      both ligands were equally potent in the induction of chemotaxis in C5aR
      expressing cells. Thus, the tag-specific mAb was able to interfere with the
      binding of human but not rat rC5a to the human C5aR. This observation is in
      agreement with the hypothesis of a two binding site model for the interaction of
      human C5a with its receptor whereas a different binding mode may apply for rat
      C5a. Our data demonstrate that the selected His-tag specific mAb may be a
      valuable tool for the visualisation of the binding of recombinant ligands to
      their receptors and may also provide useful information on the specific binding
      properties of the ligands.

PMID- 10410980
TI  - Reverse transcriptase in situ polymerase chain reaction for gene expression in
      rat mast cells and macrophages.
AB  - Direct reverse transcriptase in situ polymerase chain reaction (RT-in situ PCR)
      of selected mRNA expression in rat mast cells (MC) and alveolar macrophages (AM)
      was optimized. Rat peritoneal mast cells (PMC), rat cultured mast cells (RCMC),
      rat bronchoalveolar lavage cells (BALC) or rat cultured alveolar macrophages
      (NR8383) were studied for the detection of mRNA for beta-actin, TNF-alpha and/or
      CD8alpha. Each type of cell has unique optimal conditions for RT-in situ PCR. The
      following parameters were carefully evaluated for optimization: protease
      digestion, DNAse digestion, heparinase digestion, RT, PCR cycle number and signal
      development with chromagen. Heparinase digestion was required for PMC mRNA
      detection because they contain large amounts of heparin proteoglycan, which is a
      potent inhibitor of RT and Taq polymerase enzymes. Only a few PCR cycles were
      needed to produce a cytoplasmic signal for mRNA transcripts in RCMC, whereas
      other types of cells (PMC, BALC and NR8383) needed at least 20 cycles for mRNA
      detection. The mRNA signal in PMC was localized to the perinuclear region,
      whereas mRNA in other cell types (RCMC, BALC and NR8383) were detected throughout
      the cytoplasm. Furthermore, modified Southern blot analysis for TNF-alpha in RCMC
      treated with RT-in situ PCR demonstrated the specificity of amplification
      product. The modified and optimized protocols for this procedure were
      successfully applied to detect and localize several mRNA transcripts in rat MC
      and AM. The approach is valuable and can be used to further study selected gene
      expression in these and other cell types.

PMID- 10410981
TI  - Development of a sensitive enzyme-linked immunosorbent assay for eotaxin and
      measurement of its levels in human blood.
AB  - The CC chemokine eotaxin is potent eosinophil-selective chemoattractant, and it
      is thought that the function of eotaxin is closely related to the recruitment of
      eosinophils in certain inflammatory reactions. In order to learn more about the
      biological role of this molecule, we have developed a new sandwich ELISA method
      to measure human eotaxin using two monoclonal anitibodies and purified
      recombinant eotaxin as a standard. The minimal detectable concentration of
      eotaxin in this assay was 1.5 pg/ml, and the working range was 3.1--200 pg/ml
      with low CVs (< 10%). Both within- and between-run precision levels were less
      than 6.7% of the CVs. The dilution curves of two serum and two spiked plasma
      samples showed good linearity and the recovery range was 92.8--103.3%. No cross
      reactivity was found with other similar chemokines. MCP-1, MCP-2, MCP-3, MCP-4,
      eotaxin-2 and RANTES. This assay was sensitive enough to measure the circulating
      eotaxin levels of healthy volunteers. However, the eotaxin levels in serum
      samples (mean+/-SD; 68.6+/-13.4 pg/ml, n=15) were significantly higher than those
      in matched plasma samples (19.2+/-5.4 pg/ml) separated from blood collected in
      tubes containing EDTA. Kinetic studies revealed that the eotaxin levels in serum
      markedly increased depending on the elapsed time before separation from blood
      cells, but such changes in EDTA-plasma were negligible up to 4 h at 25 degrees C.
      Our new ELISA is an accurate and useful method for quantifying human eotaxin in
      blood and demonstrates that the process of preparing blood samples affects the
      measurement of the eotaxin levels.

PMID- 10410982
TI  - Detection and quantification of complexed and free soluble human vascular
      endothelial growth factor receptor-1 (sVEGFR-1) by ELISA.
AB  - Vascular endothelial growth factor (VEGF) is an important factor for endothelial
      cell proliferation and a key regulator of blood vessel development in embryos and
      angiogenesis in adult tissues. Its biological activity is mediated by two
      receptor tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (KDR). In contrast to
      VEGFR-2, a naturally occurring soluble form of the VEGFR-1 (sVEGFR-1) is produced
      by endothelial cells by differential splicing of the flt-1 gene, and it is a
      secreted gene product. In order to develop a specific enzyme-linked immunosorbent
      assay (ELISA) for the measurement of sVEGFR-1, we established five anti-human
      receptor antibodies and characterized them in detail. These antibodies recognize
      different epitopes located within the seven Ig-like domains of the extracellular
      receptor protein but have no neutralizing activity in ligand binding assays.
      Together with a polyclonal antiserum, a specific human sVEGFR-1 ELISA was
      developed using the mAb #190.11. The ELISA can detect human sVEGFR-1 with a
      minimum detection limit of 1 ng/ml. The ELISA does not show any cross-reactivity
      with other related soluble receptors. Using this assay, human sVEGFR-1 was
      measured in the supernatant of different VEGFR-1 expressing cell types. No sVEGFR
      1 protein was detectable after heparin Sepharose treatment or size-exclusion
      filtration (< 30 kDa). The ELISA assay for sVEGFR-1 was also used to measure the
      amount of the soluble receptor in amniotic fluid samples of patients undergoing
      amniocentesis during the course of normal pregnancies. The concentration of the
      samples was in the range of 5-35 ng/ml. This ELISA could be useful powerful tool
      for investigations concerning the physiological function of the soluble receptor
      under normal and pathophysiological conditions.Furthermore, it may facilitate
      studies of the mechanisms of receptor production.

PMID- 10410983
TI  - Intracellular and cell surface displayed single-chain diabodies.
AB  - Intracellularly expressed antibody fragments have found various applications in
      therapy by virtue of their ability to inhibit the function of cellular proteins
      or interfere with subcellular trafficking. Bivalent antibody fragments might
      further improve this inhibitory potential by increasing the functional affinity
      and bispecific antibody fragments may also be useful for the intracellular
      retargeting of molecules. Here, we have evaluated the functional expression of
      intracellular diabodies. A previously constructed secreted bispecific single
      chain diabody directed against carcinoembryonic antigen and Escherichia coli beta
      galactosidase was modified for subcellular targeting to the cell surface
      membrane, endoplasmic reticulum, mitochondria, cytoplasm, and nucleus.
      Subcellular localisation was analysed by immunofluorescence, and the assembly of
      functional antibodies was analysed by binding of beta-galactosidase to the
      antibody fragment and subsequent substrate conversion. Bispecific single-chain
      diabodies could be directed to all subcellular compartments analysed. However,
      functional assembly was only observed for single-chain diabodies retained in the
      endoplasmic reticulum or displayed in the cell membrane while no antigen binding
      activity was seen with diabodies directed to the cytoplasm, nucleus, or
      mitochondria. The results demonstrate the functional expression of bispecific
      recombinant antibody fragments in the secretory pathway and integration into the
      plasma membrane of mammalian cells.

PMID- 10410984
TI  - The role of chemokines in the regulation of dendritic cell trafficking.
AB  - The immunobiology of dendritic cells (DC) involves localization in tissues and
      trafficking via the lymph or blood to lymphoid organs. Appropriate assays
      representative of different steps of DC trafficking (e.g., reverse
      transmigration) provide the tools to dissect the migratory properties of these
      cells. Chemokines have emerged as important regulators of DC migration. DC are
      both the target and the source of chemokines. DC express receptors for and
      respond to a set of chemoattractants that overlap with, but are distinct from,
      those active on other leukocytes. Differential expression of the CCR6 receptor
      reveals heterogeneity among DC populations. Functional maturation is associated
      with loss of responsiveness to chemokines present at sites of inflammation and
      acquisition of a receptor repertoire that renders these cells responsive to
      signals that guide their localization in lymphoid organs. A better understanding
      of the molecular basis of DC trafficking may provide molecular and conceptual
      tools to direct and modulate DC traffic as a strategy to up-regulate and orient
      specific immunity.

PMID- 10410985
TI  - Neutrophil migration during endotoxemia.
AB  - Endotoxemia is marked by a global activation of inflammatory responses, which can
      lead to shock, multiple organ failure, and the suppression of immune and wound
      healing processes. Neutrophils (PMNs) play a central role in some of these
      responses by accumulating in tissues and releasing reactive oxygen species and
      proteases that injure host structures. This review focuses on altered PMN
      migratory responses that occur during endotoxemia and their consequences in the
      development of pulmonary infection. The inflammatory mediators that might be
      responsible for these altered responses are discussed. The oxidant potential of
      PMNs is increased after exposure to endotoxin both in vitro and during clinical
      and experimental endotoxemia. However, other functions such as chemotaxis and
      phagocytosis are often depressed in these same cells. Endotoxin exposure renders
      PMNs hyperadhesive to endothelium. The sum of these effects produces activated
      inflammatory cells that are incapable of leaving the vasculature. As such, the
      endotoxic PMN is more likely to promote tissue injury from within microvascular
      beds than to clear pathogens from extravascular sites. Moreover, the functional
      characteristics of endotoxic PMNs are similar to those observed during trauma,
      burn injury, sepsis, surgery, and other inflammatory conditions. Accordingly,
      several clinical conditions might have a common effector in the activated, yet
      migratorially dysfunctional, PMN. Direct effects of endotoxin on PMNs as well as
      effects of endogenous mediators released during endotoxemia are discussed.
      Understanding PMN behavior during endotoxemia may provide basic and critical
      insights that can be applied to a number of inflammatory scenarios.

PMID- 10410986
TI  - Adhesion and homing of blood-borne cells in bone marrow microvessels.
AB  - After birth, the bone marrow (BM) is the principal site of hematopoiesis in
      mammals. Thus, a large number of newly formed blood cells must penetrate the wall
      of BM microvessels to enter the circulation. In addition, the BM appears to
      function as a lymphoid organ and is also part of the macrophagal system. Subsets
      of circulating lymphocytes and other cells of the immune system continuously home
      to the BM. However, neither the mechanisms of blood cell migration to and from
      the BM nor its precise role in the immune system are well understood. One reason
      for the relative paucity of data on BM physiology is the fact that normal BM is
      surrounded by thick cortical bone that impedes direct observation and
      experimental manipulation. One notable exception is the calvaria of the murine
      skull where hematopoietically active BM is only covered by a thin lamella of bone
      that is sufficiently translucent to allow a detailed in situ analysis of the BM
      microcirculation by epi-fluorescence microscopy. Here, we review our current
      knowledge of the anatomic, hemodynamic, and endothelial properties of the
      specialized microvascular bed within murine skull BM. In addition, we summarize
      recent studies on the molecular mechanisms that mediate the homing of circulating
      hematopoietic progenitor cells to the BM, an event that is critical for the
      success of BM transplantations.

PMID- 10410987
TI  - Role of cytokines in epidermal Langerhans cell migration.
AB  - In the epidermal compartment of skin, keratinocytes (KC), Langerhans cells (LC),
      and their soluble products, i.e. cytokines, constitute a unique immunologic
      microenvironment. KC participate in cutaneous immune responses by producing
      various cytokines. LC, a member of the dendritic cell (DC) family, represent the
      professional antigen-presenting cells in the epidermis. Although it has been
      demonstrated that migration of LC from skin to lymph nodes is a critical step for
      the antigen presentation, molecular mechanisms for such an event remain unclear.
      Recent studies suggest that cytokines are able to modulate LC/DC migration. There
      is accumulating evidence that proinflammatory cytokines including interleukin
      (IL)-1 and tumor necrosis factor alpha promote LC emigration from the skin,
      whereas the anti-inflammatory cytokine IL-10 is a counter-regulator. LC/DC
      express chemokine receptors. Chemokines generated from lymphatic endothelial
      cells and lymph node cells play a role in the directional migration of LC/DC into
      lymph nodes. This article reviews current studies on the role of cytokines in
      LC/DC migration.

PMID- 10410988
TI  - Urokinase plasminogen activator receptor (CD87) expression of tumor-associated
      macrophages in ductal carcinoma in situ, breast cancer, and resident macrophages
      of normal breast tissue.
AB  - Macrophages concentrate urokinase-type plasminogen activator (uPA) at the cell
      surface by expressing urokinase receptors (uPAR) in order to focus the
      pericellular space plasminogen-dependent proteolysis important in matrix
      remodeling and cell movement. This study examines the uPAR levels of tumor
      associated macrophages (TAM) of invasive breast carcinomas, of TAMs from ductal
      carcinoma in situ (DCIS) and of macrophages derived from normal (non-tumor)
      breast tissue. TAMs from invasive breast carcinomas (n = 30), from DCIS (n = 12),
      and macrophages from normal breast tissue (n = 30) were cultured and
      immunocytochemically phenotyped by using a panel of antibodies. Urokinase
      receptor levels were determined by Western blot analysis and in cell-free
      supernatants by enzyme-linked immunosorbent assay. Urokinase receptor cell
      surface fluorescence intensity was determined by FACS and by confocal laser scan
      microscopy. Urokinase-receptor mRNA was detected by in situ hybridization. TAMs
      of invasive breast carcinomas and of DCIS possess significantly elevated uPAR
      levels compared with macrophages derived from normal breast tissue. CONCLUSIONS:
      activated macrophages with elevated uPAR levels belong to inflammatory areas in
      close vicinity of infiltrating and non-infiltrating (DCIS) tumor cells. Blood
      monocytes that possess elevated uPAR-levels may be selectively recruited from the
      bloodstream to inflammatory sites close to carcinoma cells, and/or breast cancer
      and precursor lesions may induce elevated uPAR-levels in TAMs by paracrine
      interactions.

PMID- 10410989
TI  - Involvement of caveolae in the uptake of respiratory syncytial virus antigen by
      dendritic cells.
AB  - The uptake of respiratory syncytial virus (RSV) antigen by cattle dendritic cells
      was investigated. Pathways of antigen uptake were monitored by flow cytometry
      using specific tracers and by proliferation assays, which were used to measure
      the presentation of RSV antigen and ovalbumin. Inhibitors that differentially
      affected pathways were used to distinguish them. Presentation of RSV antigen, but
      not ovalbumin, was inhibited by phorbol myristate acetate and filipin, which have
      been reported to inhibit caveolae, but not by cytochalasin D, amiloride, or
      mannose. These inhibitors have been reported to block macropinocytosis and other
      actin-dependent uptake mechanisms, endocytic pathways involving clathrin-coated
      pits, and the mannose receptor. Furthermore, co-localization of RSV antigen and
      caveolae was observed by confocal microscopy. Thus, the major route for uptake of
      RSV antigen by cattle dendritic cells is one mediated by caveolae, adding a
      pathway of antigen uptake by dendritic cells to those established.

PMID- 10410990
TI  - Reperfusion-induced oxidative stress in diabetes: cellular and enzymatic sources.
AB  - Reactive oxygen metabolites (ROMs) have been implicated in the pathogenesis of
      the inflammatory response to ischemia/reperfusion (I/R), which is exacerbated in
      diabetes. This study revealed an increased (P < 0.01) ROMs production in
      mesenteric tissue (measured using the oxidant-sensitive fluorochrome
      dihydrorhodamine 123) after I/R in control and diabetic rats, with larger
      increments (P <0.0001) observed in the latter group, that was associated with an
      increased inflammatory response measured by intravital microscopy. Either
      xanthine oxidase inhibition, superoxide scavenging, ICAM-1 immunoneutralization,
      or blockade of platelet-activating factor or leukotrienes effectively reduced
      leukocyte recruitment and ROMs production in control and diabetic rats. Moreover,
      neutrophils from diabetic rats showed an enhanced production of ROMs in vitro in
      basal and stimulated conditions. We conclude that the oxidative stress during
      reperfusion is markedly enhanced in diabetes and this appears to result from
      increased leukocyte recruitment and a higher capacity of diabetic leukocytes to
      generate ROMs in response to stimulation.

PMID- 10410992
TI  - Mechanisms of ozone-induced inhibitory effect of bronchoalveolar lavage fluid on
      alveolar macrophage-mediated immunosuppressive activity in rats.
AB  - Resident alveolar macrophages (AM) play an important immunomodulatory role via
      suppression of lymphocyte proliferation, and nitric oxide (NO) plays a crucial
      role in this immunosuppression of AM. Our previous report suggested that during
      ozone (O3)-induced lung inflammation, bronchoalveolar lavage fluid (BALF)
      inhibited AM-mediated immunosuppression and concanavalin A (Con A)-induced
      proliferation of lymph node cells (LNC) [E. Koike et al. (1998) Toxicol. Sci. 41,
      217-223]. In these studies, we investigated the mechanisms of the inhibition of
      BALF from O3-exposed rats (O3-BALF). We investigated whether BALF might affect
      (1) the interferon-gamma (IFN-gamma) production by Con A-stimulated LNC and IFN
      gamma-induced NO production by AM, and (2) the interleukin (IL)-2 production by
      Con A-stimulated LNC and IL-2-induced LNC proliferation. These results
      demonstrated that O3-BALF inhibited IFN-gamma production by Con A-stimulated LNC,
      IFN-gamma-induced NO production by AM, and IL-2-induced LNC proliferation. In
      addition, the major inhibitory factor against AM-mediated immunosuppression in O3
      BALF may be a protein of greater than 10 kDa.

PMID- 10410991
TI  - Intestinal inflammation in adhesion molecule-deficient mice: an assessment of P
      selectin alone and in combination with ICAM-1 or E-selectin.
AB  - Biopsy specimens from patients with inflammatory bowel disease have demonstrated
      an up-regulation of P-selectin, suggesting a role for P-selectin in intestinal
      inflammation. We examined the role of P-selectin in experimental intestinal
      inflammation using mice deficient in P-selectin alone or in combination with
      either ICAM-1 or E-selectin. Colitis was induced using acetic acid or
      trinitrobenzene sulfonic acid (TNBS). Damage scores and neutrophil infiltration
      24 h post acetic acid were not different between wild-type and P-selectin- or P
      selectin/ICAM-1-deficient mice, whereas P/E-selectin-deficient mice had enhanced
      leukocyte recruitment and damage. At 72 h an attenuation in damage scores and a
      slight decrease in neutrophil infiltration was observed in the P- and P/ICAM
      deficient animals. The P/E-selectin-deficient mice maintained enhanced leukocyte
      recruitment and damage. In wild-type mice P-selectin expression was elevated 48
      and 72 h post acetic acid-induced inflammation. Surprisingly, P-selectin or P
      selectin/ICAM-1 deficiency did not improve the inflammation induced by TNBS over
      7 days. In fact, increased mortality was observed. Anti-adhesion therapy may play
      only a limited, beneficial role and often a detrimental role in intestinal
      inflammation.

PMID- 10410993
TI  - Suppression of cytokine-mediated beta2-integrin activation on circulating
      neutrophils in critically ill patients.
AB  - The beta2 integrin CD11b plays a central role in inflammation and the systemic
      inflammatory response syndrome (SIRS). The CD11b molecule activates in two ways:
      the density of membrane-bound CD11b up-regulates and the molecule undergoes a
      conformational change that confers adhesiveness to counter-receptors. We studied
      the kinetics of CD11b activation in patients with SIRS. We found a significantly
      diminished CD11b activation in response to tumor necrosis factor alpha (TNF
      alpha). This affected all circulating polymorphonuclear neutrophils (PMN) and was
      an intrinsic property of the cells and not due to antagonism by soluble TNF-alpha
      receptors or loss of cellular receptors for TNF-alpha. Diminished responsiveness
      correlated with the severity of organ failure and lasted for months in some
      patients but had no impact on mortality. We speculate that reduced CD11b
      responsiveness in SIRS contributes to the high risk of recurrent infection, but
      that it may also be protective against excessive PMN activation within the
      vascular space.

PMID- 10410994
TI  - The initiation of the neutrophil chemotactic response in filters.
AB  - The fluid gradient chamber was used to study the migration of human neutrophils
      in preformed gradients of N-formyl-methionyl-leucyl-phenylalanine. After 60 min,
      the chemotactic gradient was replaced by a new one of identical steepness but
      opposite direction. In a control group of experiments, the first gradient was
      retained. Migration was assessed from cell distributions in filter sandwiches
      after 30, 60, and 90 min. Filters obtained after 5, 15, and 30 min of migration
      were stained with fluorescent phalloidin for microscopic evaluations of cell
      polarity. At 30 min most cells had polarized in vertical directions and invaded
      the filters. The distance of chemotactic migration was similar during the second
      and the third 30-min periods (although the direction of migration was reversed in
      the new gradient) and significantly greater than during the first 30 min. In
      conclusion, the initial slow response to the chemotactic gradient represents an
      adaptation of the cells that later respond promptly to changes in gradient
      direction.

PMID- 10410995
TI  - Decreased availability of GDP-L-fucose in a patient with LAD II with normal GDP-D
      mannose dehydratase and FX protein activities.
AB  - Leukocyte adhesion deficiency type II (LAD II) is caused by a disorder in the
      metabolism of GDP-L-fucose, which causes hypofucosylation of glycoconjugates.
      This study analyzes a newly identified LAD II patient who shows the same severe
      hypofucosylation of glycoconjugates as the other described patients. However, in
      vitro assays of cytosolic extracts from leukocytes and fibroblasts of the patient
      demonstrated a normal GDP-L-fucose biosynthesis from GDP-D-mannose. Analysis of
      the two enzymes involved in the pathway, GDP-D-mannose 4,6-dehydratase and FX
      protein, revealed normal numbers of transcripts without any detectable mutations
      within the coding regions of either gene. In contrast to previously published
      observations [Sturla et al. (1998) FEBS Lett. 429, 274-278], the major pathway of
      GDP-L-fucose synthesis can be normal in LAD II.

PMID- 10410996
TI  - Respiratory syncytial virus infection of human respiratory epithelial cells
      enhances inducible nitric oxide synthase gene expression.
AB  - The induction kinetics of the mRNA of interferon regulatory factor 1 (IRF-1),
      inducible nitric oxide synthase (iNOS), and proinflammatory cytokines in
      respiratory syncytial virus (RSV)-infected human type 2 alveolar epithelial cells
      (A549 cells) were analyzed semiquantitatively by RT-PCR. RSV enhanced IRF-1 and
      iNOS mRNA expression as early as 4 h after RSV infection and this enhancement
      lasted several hours. No IFN-gamma gene expression was observed during the whole
      course of the infection. Expression of IFN-beta, IL-1beta, and TNF-alpha genes
      was observed slightly at 4 h and became marked 7 h after infection. Addition of
      neutralizing antibodies to these cytokines to the culture had no effect on the
      induction of iNOS mRNA. The iNOS transcriptional activity in RSV-infected cells
      was significantly enhanced by an exogenous cytokine mixture (IL-1beta, TNF-alpha,
      and IFN-gamma). An apparent nitric oxide (NO) production was identified only when
      cytokines were added together with RSV infection. A significant increase of iNOS
      gene expression was observed in nasopharyngeal exudate cells obtained from
      infants during the acute phase of RSV bronchiolitis. These observations suggest
      that RSV infection of human respiratory epithelial cells induces the iNOS gene
      both in vitro and in vivo; this induction may occur rather promptly and involves
      transcriptional activator IRF-1 induced by the RSV infection itself. The iNOS
      gene, which is initially induced by RSV infection, may be further enhanced in a
      paracrine fashion by proinflammatory cytokines released by infection-activated
      inflammatory cells.

PMID- 10410997
TI  - MHC class II-dependent activation of CD4+ T cell hybridomas by human mast cells
      through superantigen presentation.
AB  - Human mast cells (MC) were examined for expression of MHC class II antigens and
      for their ability to activate CD4+ T cell hybridomas through presentation of
      superantigen (SAg). HMC-1, a leukemic immature MC line expressing class II Ags,
      was shown to efficiently present the staphylococcal enterotoxin B (SEB) SAg to
      responding T cell hybridoma on treatment with interferon-gamma (IFN-gamma), which
      up-regulated class II molecules. The study was then extended to human normal MC.
      Almost pure (>99%) cord blood-derived MC (CBMC) were shown to express class II
      Ags (HLA-DR and HLA-DQ) and CD80, which were up-regulated by IFN-gamma treatment
      and, to a lesser extent, by interleukin-4 (IL-4) and granulocyte-macrophage
      colony-stimulating factor (GM-CSF). CBMC directly activated CD4+ T cell
      hybridomas through presentation of SEB and TSST1 SAgs. The production of IL-2
      required a cell-to-cell contact between T cells and CBMC and it was inhibited by
      anti-class II antibodies. Furthermore, an additional pretreatment of CBMC by IFN
      gamma or GM-CSF or IL-4 had no effect on their presenting efficiency. This
      previously unknown function of human MC, i.e., MHC class II-dependent activation
      of CD4+ T cells, may be critical in subsequent cellular activation events because
      colocalization of mast and T cells is frequently observed at sites of antigen
      entry.

PMID- 10410998
TI  - Differential iron transport into phagosomes isolated from the RAW264.7 macrophage
      cell lines transfected with Nramp1Gly169 or Nramp1Asp169.
AB  - The transport of iron by RAW264.7 macrophage cell lines transfected with either
      Nramp1Gly169 (resistant) or Nramp1ASp169 (susceptible) alleles was assessed. We
      found no difference between resistant and susceptible cells in the rate of Fe
      import or export when Fe transport was measured in intact cells. In contrast, the
      rate of Fe import by latex-bead phagosomes isolated from resistant cells was more
      than double the rate by latex-bead phagosomes from susceptible cells. Similarly,
      phagosomes isolated from resistant cells that had been pre-labeled with 55Fe
      citrate before phagocytosis contained up to four times as much Fe as the
      corresponding phagosomes from susceptible cells. Phagocytosis of Mycobacterium
      avium was accompanied by an increase in the production of hydroxyl radicals by
      Nramp1cGly169-transfected macrophages but not by macrophages transfected with the
      susceptible allele. These results are consistent with the hypothesis that Nramp1
      functions to transport Fe into the bacterium-containing phagosome where it serves
      as a catalyst for the Haber-Weiss reaction, which accounts for the increased
      capacity of these cells to limit mycobacterial growth.

PMID- 10410999
TI  - An autologous self-antigen differentially regulates expression of I-A
      glycoproteins and B7 costimulatory molecules on CD4- CD8- T helper cells.
AB  - During inflammation, T helper cells transiently express class II major
      histocompatibility complex (MHC) glycoproteins and present antigens to other T
      cells. To assess involvement of self-antigens in the generation of T cell antigen
      presenting cell (T-APC) activity, rat (R) myelin basic protein (MBP) was used to
      stimulate a rat CD4-CD8- T cell clone. RMBP induced T cell surface expression of
      class II MHC glycoproteins and T-APC activity, although RMBP did not elicit
      interleukin (IL-2) production or proliferation. When added to culture with the
      strong agonist guinea pig (GP) MBP, RMBP acted as a partial antagonist and
      inhibited responses of IL-2 production, proliferation, and T cell expression of
      B7.1. RMBP did not, however, efficiently antagonize GPMBP-induced I-A expression
      on T cells. These findings indicate that the self-antigen RMBP specifically
      induces accumulation of I-A/peptide complexes at signaling thresholds that
      inhibit pathogenic autoimmune responses. Overall, this study suggests a role for
      self-antigens in the generation of B7-deficient T-APC activity as a mechanism of
      tolerance in experimental autoimmune encephalomyelitis.

PMID- 10411000
TI  - No detectable NO synthesis from L-arginine or N(G)-hydroxy-L-arginine in fMLP
      stimulated human blood neutrophils despite production of nitrite, nitrate, and
      citrulline from N(G)-hydroxy-L-arginine.
AB  - Nitric oxide (NO) is a well-documented effector molecule in rodent phagocytes but
      its synthesis in human neutrophils has been controversial. In this study, NO
      production in human neutrophils activated by chemotactic peptide N-formyl
      methionyl-leucyl-phenylalanine (fMLP) was measured in the presence of L-arginine
      (L-Arg) and N(G)-hydroxy-L-arginine (OH-L-Arg), the precursor and intermediate
      amino acids in NO synthesis, respectively. Incubation of fMLP-activated
      neutrophils with OH-L-Arg resulted in a production of nitrite, nitrate, and
      citrulline that was greater than with unstimulated neutrophils but was not
      inhibited by the NOS inhibitors L-NMMA and L-NIO or the cytochrome P450 inhibitor
      troleandomycin and was not seen when OH-L-Arg was replaced with L-Arg. This
      nitrite, nitrate, and citrulline production was not associated with any
      detectable NO synthesis because no increases in cyclic GMP were observed in the
      presence of phosphodiesterase inhibitors and in the presence or absence of
      superoxide dismutase. Moreover, no increases in the formation of the reaction
      product of NO with superoxide, peroxynitrite, were observed on addition of either
      OH-L-Arg or L-Arg to activated neutrophils, as assessed either by
      dihydrorhodamine oxidation or protein nitration. This suggests that, in spite of
      the production of nitrite, nitrate, and citrulline, commonly used indicators of
      NO formation, normal human blood neutrophils, are not producing detectable
      amounts of either NO or peroxynitrite when stimulated with fMLP in the presence
      of OH-L-Arg.

PMID- 10411001
TI  - Modulation of CXCR4 expression and SDF-1alpha functional activity during
      differentiation of human monocytes and macrophages.
AB  - Chemoattraction of monocytes by the CXC chemokine stromal cell-derived factor
      1alpha (SDF-1alpha) and its receptor CXCR4 may be involved in vascular diseases
      like atherosclerosis. We studied the regulation of CXCR4 transcription and SDF-1
      induced functional responses in human monocytes during their differentiation in
      the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF),
      oxidized low-density lipoprotein (Ox-LDL), and unmodified LDL. Our results reveal
      that the rapid decline of SDF-1-mediated [Ca2+]i influx after monocyte isolation
      is followed by a gradual functional restoration and a concomitant reexpression of
      CXCR4 mRNA over time. A further three- to fourfold induction of CXCR4 mRNA
      occurred in macrophage-derived foam cells on treatment with Ox-LDL. HL-60 cells
      induced with phorbol myristate acetate (PMA) showed a rapid fourfold stimulation
      of CXCR4 mRNA within 1 h, declining to barely detectable levels at 3 h, with
      eventual restoration over time, mirroring the expression pattern in monocytes.
      Surface expression of CXCR4 is maintained in HL-60 cells during PMA-induced
      differentiation, as demonstrated by flow cytometry. GM-CSF had no effect on CXCR4
      mRNA in HL-60 cells and does not cause its down-regulation in human macrophages.

PMID- 10411002
TI  - Mucosal and systemic candidiasis in IL-8Rh-/- BALB/c mice.
AB  - Germ-free BALB/c mice, genetically engineered to be deficient for interleukin-8
      (IL-8) receptor homolog (IL-8Rh-/-), were more susceptible to gastric candidiasis
      after oral challenge and to acute systemic candidiasis after intravenous
      challenge than IL-8Rh+/+ controls. In comparison to IL-8Rh+/+ mice, the IL-8Rh-/-
      mice had slower influx of polymorphonuclear neutrophils (PMN) into Candida
      albicans-infected tissues and a lower percentage of PMN in peritoneal exudate
      cells (PEC) elicited with heat-killed C. albicans. PEC from IL-8Rh-/- mice
      exhibited less luminol-dependent chemiluminescence in response to C. albicans and
      did not kill C. albicans hyphae as well as PEC from IL-8Rh+/+ mice. C. albicans
      colonized IL-8Rh-/- mice showed no histological evidence of systemic candidiasis.
      These results suggest a role for the IL-8Rh in murine resistance to gastric and
      acute systemic candidiasis, but not in resistance to systemic candidiasis of
      endogenous origin.

PMID- 10411003
TI  - Regulatory effects of interleukin-11 during acute lung inflammatory injury.
AB  - The role of interleukin-11 (IL-11) was evaluated in the IgG immune complex model
      of acute lung injury in rats. IL-11 mRNA and protein were both up-regulated
      during the course of this inflammatory response. Exogenously administered IL-11
      substantially reduced, in a dose-dependent manner, the intrapulmonary
      accumulation of neutrophils and the lung vascular leak of albumin. These in vivo
      anti-inflammatory effects of IL-11 were associated with reduced NF-kappaB
      activation in lung, reduced levels of tumor necrosis factor alpha (TNF-alpha) in
      bronchoalveolar lavage (BAL) fluids, and diminished up-regulation of lung
      vascular ICAM-1. It is interesting that IL-11 did not affect BAL fluid content of
      the CXC chemokines, macrophage inflammatory protein-2 (MIP-2) and cytokine
      inducible neutrophil chemoattractant (CINC); the presence of IL-11 did not affect
      these chemokines. However, BAL content of C5a was reduced by IL-11. These data
      indicate that IL-11 is a regulatory cytokine in the lung and that, like other
      members of this family, its anti-inflammatory properties appear to be linked to
      its suppression of NF-kappaB activation, diminished production of TNF-alpha, and
      reduced up-regulation of lung vascular ICAM-1.

PMID- 10411004
TI  - Induction of CC chemokines in human peripheral blood mononuclear cells by
      staphylococcal exotoxins and its prevention by pentoxifylline.
AB  - We investigated the inflammatory processes that might be associated with the
      arthrogenic activity of Staphylococcus aureus, the principal causative agent of
      bacterial arthritis. Human peripheral blood mononuclear cells (PBMC) were
      stimulated with the staphylococcal toxic shock syndrome toxin-1 (TSST-1) or
      enterotoxin B (SEB) and the production of chemokines was examined. Both TSST-1
      and SEB induced high levels (ng/mL) of MIP-1alpha, MIP-1beta, and MCP-1. The
      induction of these chemokines occurred mostly by direct stimulation of PBMC with
      staphylococcal exotoxins (SE), without requiring the intervention of IL-1 and TNF
      alpha. The production of SE-induced chemokines was blocked partially by anti-DR
      and anti-CD2 antibodies. Cell separation revealed monocytes as the cell source of
      these chemokines. However, addition of purified T cells amplified the levels of
      chemokine produced, suggesting that cognate interaction of SE bound on antigen
      presenting cells with T cells also contributes to chemokine production. The
      activation and recruitment of leukocytes by these chemokines may contribute to
      the pathophysiology of septic arthritis caused by staphylococci in humans through
      tissue injury and the recruitment of T lymphocytes, perhaps also initiating
      autoimmune responses. Pentoxifylline, an anti-inflammatory agent, completely
      inhibited the production of these chemokines.

PMID- 10411005
TI  - Induction of DAP12 phosphorylation, calcium mobilization, and cytokine secretion
      by Ly49H.
AB  - The ability of several Ly49 family members to inhibit natural killer (NK) cell
      functions through recruitment of SHP-1 phosphatase has been reported. In
      contrast, the mechanisms underlying the activating signal generated by Ly49D are
      poorly understood. A homodimeric phosphoprotein (pp16) that physically and
      functionally associates with Ly49D has been described. In this study, a rabbit
      anti-mouse pp16 antiserum was generated and used to demonstrate that pp16
      corresponds to the recently described DAP12 molecule. In addition, we show that a
      second Ly49 family member that lacks an immunoreceptor tyrosine-based inhibitory
      motif and contains a charged residue in the transmembrane domain, Ly49H, also
      associates with DAP12. Furthermore, we show that engagement of the Ly49H/DAP12
      complex results in phosphorylation of DAP12, intracellular calcium mobilization,
      and tumor necrosis factor secretion in transfected cells. These results thus
      provide evidence that Ly49H is an activating receptor that associates with DAP12,
      previously described as a pp16 component of the Ly49D receptor complex.

PMID- 10411006
TI  - Regulation of the plasminogen activator inhibitor-2 (PAI-2) gene in murine
      macrophages. Demonstration of a novel pattern of responsiveness to bacterial
      endotoxin.
AB  - We investigate the regulation of plasminogen activator inhibitor-2 (PAI-2) in
      murine macrophages. PAI-2 mRNA was inducible by bacterial lipopolysaccharide
      (LPS) in primary cells and macrophage-like cell lines. Evidence is presented for
      a role for autocrine factors, including cyclooxygenase products but not the
      cytokines tumor necrosis factor alpha or interferon-beta (IFN-beta). PAI-2 mRNA
      levels generally varied inversely from those of its target, urokinase-type
      plasminogen activator (uPA), and the macrophage growth factor CSF-1, which
      induces uPA, inhibited PAI-2 expression in cells treated subsequently with LPS.
      Expression of PAI-2 was distinct from that of other LPS-inducible genes in terms
      of induction time course, LPS dose response, and sensitivity to co-stimulation
      with IFN-gamma. Induction of PAI-2 mRNA in subclones of the cell line RAW 264 was
      not uniform, reflecting heterogeneous expression in the parent line. The
      expression pattern of PAI-2 is discussed in terms of a possible role in LPS
      induced pathology such as septicemia.

PMID- 10411007
TI  - ETS transcription factors regulate an enhancer activity in the third intron of
      TNF-alpha.
AB  - We describe an enhancer site in the third intron of tumor necrosis factor alpha
      (TNF-alpha). A reporter construct containing the 5'-flanking region of the mouse
      TNF-alpha gene displayed weak activity when transfected into RAW264.7 macrophage
      like cells. The addition of the third intron of TNF-alpha to this construct
      resulted in an enhancement of CAT protein. This enhancement was eliminated if a
      conserved 20-bp sequence was removed from the intron or if a dominant-negative
      ets-binding factor was co-transfected with the reporter gene. Mutations of this
      site that destroyed potential ets transcription factor binding sites had reduced
      transcriptional activity. The major transcription factor that bound to the
      oligonucleotide was confirmed to be GABP by supershift and competition analysis.
      In RAW264.7 cells, the binding was constitutive, however, in bone marrow-derived
      macrophages binding activity was shown to be interferon-gamma inducible. This may
      imply a role for ets transcription factors in the production of TNF-alpha.

PMID- 10411008
TI  - Interrelations of age, sensory functions, and human brain signal processing.
AB  - Disturbances of sensory functions may additionally impair cognitive functions in
      elderly persons. To delineate the impact of visual sensory functions on brain
      signal processing during normal aging from an electrophysiological perspective,
      we investigated 289 fit community-dwelling subjects (162 men [56%] and 127 women
      [44%]; age range, 18-98 years) by means of visual event-related P300 potentials.
      By taking age, visual acuity, and stimulus-dependent components of visual-evoked
      potentials (PVEPs) into account, we found age to be the single most important
      factor for P300 variability (partial F > 10.0, p < .0001 for all P300 parameters;
      stepwise regression analysis). Furthermore, both the N75 (partial F = 12.415) and
      P100 latencies (partial F = 4.850) of the PVEPs were independently correlated
      with the P300 latencies, whereas the P300 amplitudes revealed additional
      correlations with the P100 amplitudes (partial F = 8.576; p < .0001, for all).
      Sex, however, did not influence these age-related P300 changes. Aging itself
      accounts for the largest proportion of variability in human brain signal
      processing as reflected by P300 potentials. Visual sensory functions, however,
      also provide an independent, but minor, contribution to P300 variability.
      Therefore, it seems prudent to take parameters of sensory functions into account
      especially for clinical P300 applications in the elderly population.

PMID- 10411009
TI  - Neural mechanisms of delirium: current hypotheses and evolving concepts.
AB  - The purpose of this article is to review current knowledge regarding potential
      neural mechanisms of delirium. A MEDLINE search for relevant English language
      articles was undertaken using various combinations of delirium (including
      cognitive disorders, encephalopathy, and confusion) with pathogenesis and
      pathophysiology. These articles were scanned for content related to hypotheses
      concerning the neurobiology of delirium. Additional references were obtained from
      a manual search of the bibliography of these articles. A secondary MEDLINE search
      of delirium with the mechanism in question (i.e., serotonin, acetylcholine, etc.)
      was then undertaken. Literature review was last updated as of April 1998. Despite
      being a common problem among elderly patients, the mechanisms of delirium are
      poorly understood. Delirium is a syndrome that may occur as the result of
      multiple complex interacting neurotransmitter systems and pathologic processes.
      The neurotransmitters acetylcholine and serotonin may play particularly important
      roles in common medical and surgical delirium. Other neurotransmitters such as
      dopamine and gamma-aminobutyric acid each may be involved in the development of
      delirium under special conditions. Other neurobiologic factors such as cytokines,
      cortisol abnormalities, and oxygen free radicals will require further study to
      define their role in delirium. Distinct neuropathologic processes leading to
      delirium are beginning to be defined. Such mechanisms may differ in various
      clinical settings. There is probably no final common pathway to delirium, but
      rather, delirium is the final common symptom of multiple neurotransmitter
      abnormalities. Further situation-specific studies of delirium pathophysiology
      should lead to more effective prevention and treatment strategies.

PMID- 10411010
TI  - Dynamic paradigms for human mortality and aging.
AB  - Hazard models are often applied to mortality data of humans and other species so
      that the parameter estimates made for those models can be used to make inferences
      about the biology, and comparative biology, of aging processes. Enough
      longitudinal data on physiological and functional changes in humans now exist to
      know that the age trajectory of the physiological state of individuals is
      multidimensional, stochastic, and plastic. Thus, to fully assess the biological
      significance of existing longitudinal data on human aging and mortality
      processes, multivariate stochastic process models must be developed that are
      biologically detailed and valid. This requires assessing genetic mechanisms
      controlling human longevity and rates of aging, developing models of how those
      traits may have evolved, and developing statistical methods for identifying gene
      environment interactions. This article examines the theoretical basis for such
      models and the biological rationale of their parametric structure. Several
      examples are given.

PMID- 10411011
TI  - A view of the aging-disease relationship from age 85.

PMID- 10411012
TI  - Emerging issues in antibiotic resistant infections in long-term care facilities.
AB  - Managing patients infected with antibiotic resistant bacteria is becoming one of
      the major clinical obstacles facing physicians who treat patients in long-term
      care facilities (LTCFs). Penicillin-resistant pneumococci (PRP), vancomycin
      resistant enterococci (VRE), gram-negative bacteria that produce extended
      spectrum and ampC-type beta-lactamase enzymes, and quinolone-resistant gram
      positive and gram-negative bacteria are the major resistant pathogens that are
      emerging in these settings. The mechanisms responsible for the evolution of these
      antibiotic resistant organisms (molecular rearrangement of penicillin binding
      protein genes, acquisition of a mobile genetic element, and point mutation that
      alter the active site) are reviewed. Vancomycin intermediate Staphylococcus
      aureus (VISA) and multidrug efflux pumps in gram-negative bacteria are also
      threatening our most potent antimicrobials. Aggressive screening, education,
      antibiotic-control measures, and immunization are advocated as important
      preventive measures. The combined efforts of the medical directors, infection
      control personnel, and administrators are needed to stem this problem.

PMID- 10411013
TI  - Efficacy of calcium supplements on bone mass in postmenopausal women.

PMID- 10411014
TI  - Effect of facilitation of sensation from plantar foot-surface boundaries on
      postural stabilization in young and older adults.
AB  - BACKGROUND: One of the more pervasive effects of aging is loss of cutaneous
      sensation, which appears to correlate with impaired postural control and
      increased risk of falling. This study examined the potential for compensating for
      the destabilizing effects of reduced cutaneous sensitivity by placing a raised
      edge underneath the perimeter of the plantar foot surface, so as to facilitate
      sensation from the stability boundaries of the base of support. METHODS: The main
      experiment involved 14 healthy older adults (aged 65-73) selected because they
      were known, from a previous study, to have moderate plantar cutaneous
      insensitivity. We also report results of an initial experiment involving 7
      healthy young adults (aged 23-31). In both experiments, we studied effects of the
      plantar facilitation on control of rapid stepping reactions evoked by
      unpredictable postural perturbation, applied via sudden platform movement in
      forward, backward, and lateral directions. We also studied effects on "feet-in
      place" responses evoked by continuous pseudorandom platform motion in
      mediolateral and anteroposterior directions. Subjects were blindfolded in all
      tests. RESULTS: Plantar facilitation reduced the incidence of "extra" limb
      movements, beyond the initial step, during forward-step reactions in the older
      adults. There also appeared to be an improved ability to control feet-in-place
      reactions: young subjects were better able to recover balance without stepping
      when falling backward (given instructions to "try not to step"), and both young
      and older subjects reduced the extent to which the center of foot pressure
      approached the posterior foot boundary during continuous anteroposterior platform
      motion. CONCLUSIONS: This study provides evidence that mechanical facilitation of
      sensation from the boundaries of the plantar surface of the foot can improve the
      efficacy of certain types of stabilizing reactions evoked by unpredictable
      postural perturbation. The results may be directly transferable to the design of
      special footwear insoles to reduce instability and risk of falling in older
      adults.

PMID- 10411016
TI  - Past and current smoking in relation to body fat distribution in older men and
      women.
AB  - BACKGROUND: Smoking is reported to be positively related to abdominal fat in
      young and middle-aged persons; however, it is unclear whether this relationship
      exists in elderly persons. Behavioral influence on fat distribution is of
      importance because of the accumulation of abdominal fat with age and its
      associated health risks. METHODS: The relationship was investigated in a
      population-based sample of 1,178 men and 1,163 women aged 55-85 years,
      representative of the Dutch older population in 1992-1993. Waist and hip
      circumference and their ratio were used as indices of fat distribution. Past and
      current smoking habits were obtained by questionnaire. RESULTS: Smoking was
      associated with waist/hip-ratio (WHR) in men, with current smokers having the
      highest WHR and never smokers the lowest. A dose-response relationship between
      the daily number of cigarettes smoked and WHR was observed in men. These
      associations remained significant after adjustment for confounding due to age,
      education, body mass index, health status, alcohol intake, and sports activity.
      The dose-response relationship did not change after additional adjustment for
      duration of smoking. Among former male smokers, recent quitters had a higher WHR
      compared to long-term quitters. Additional analysis showed that smoking was more
      strongly associated with waist than with hip circumference. In women the
      relationship between smoking and fat distribution was not clear. CONCLUSIONS:
      Past and current smoking habits are positively associated with abdominal fat in
      older men, but not in older women.

PMID- 10411015
TI  - A cross-cultural comparison of neuromuscular performance, functional status, and
      falls between Japanese and white women.
AB  - BACKGROUND: Previous studies have reported that the incidence of falls among
      Japanese women is about half that of white women. The difference in incidence
      might result from differences in neuromuscular performance, such as muscle
      strength, mobility, and balance. This hypothesis was tested by comparing two
      community-dwelling populations: Japanese women in the Hawaii Osteoporosis Study,
      and Caucasian women in the Study of Osteoporotic Fractures. METHODS:
      Neuromuscular performance was assessed for women in the two cohorts using
      standardized procedures. Falls were monitored longitudinally, using surveys
      mailed at 4-month intervals. RESULTS: The Japanese and white women differed
      substantially in their neuromuscular performance. The Japanese women had faster
      walking speeds and chair stands, and performed better on a series of balance
      tests. The white women had greater strength, particularly at the quadriceps, and
      faster hand and foot reaction times. The white women also reported fewer
      functional disabilities, including fewer difficulties in climbing steps, doing
      heavy housework, and shopping for groceries. In age-adjusted analyses, the risk
      of falls was greater for the white women [odds ratio (OR) = 1.8; 95% confidence
      interval (CI) = 1.6, 2.0]. After adjusting for the neuromuscular test results and
      the number of functional disabilities, the odds ratio for the risk of falls
      remained essentially the same (OR = 1.8; 95% CI = 1.5, 2.1). CONCLUSIONS: The
      Japanese and white women had different advantages and limitations in
      neuromuscular performance. These differences, however, did not explain the lower
      risk of falls among Japanese women.

PMID- 10411017
TI  - Prevalence and severity of urinary incontinence in older African American and
      Caucasian women.
AB  - BACKGROUND: Few studies have investigated the prevalence and severity of urinary
      incontinence in older African American women. Comparisons of findings with those
      for older Caucasian women could provide important clues to the etiology of
      urinary incontinence and be used in planning screening programs and treatment
      services. METHODS: Data are from the first wave of the Asset and Health Dynamics
      Among the Oldest Old (AHEAD) study. A nationally representative sample of
      noninstitutionalized adults 70 years of age and older was interviewed. African
      Americans were oversampled to ensure that there would be enough minority
      respondents to compare findings across racial groups. RESULTS: A statistically
      significant relationship was found between race and urinary incontinence in the
      previous year: 23.02% of the Caucasian women reported incontinence, compared with
      16.17% of the African American women. Other factors that appear to increase the
      likelihood of incontinence include education, age, functional impairment, sensory
      impairment, stroke, body mass, and reporting by a proxy. Race was not related to
      the severity (as measured by frequency) of urine loss among incontinent older
      women. CONCLUSION: This study identifies or confirms important risk factors for
      self-reported urinary incontinence in a national context, and suggests factors
      leading to protection from incontinence. Race is found to relate to incontinence,
      with older African American women reporting a lower prevalence.

PMID- 10411018
TI  - Preserved blood pressure and heart rate circadian rhythm in early stage
      Alzheimer's disease.
AB  - BACKGROUND: This study investigated the blood pressure (BP) values over the day
      night period in 11 noninstitutionalized patients affected by probable Alzheimer's
      disease (AD) in its early stage. The scientific aim was to detect whether the BP
      circadian rhythm (CR) was preserved, given the fact that CR disruption was
      observed in advanced or institutionalized AD patients. METHODS: The BP within-day
      values were gathered via noninvasive ambulatory monitoring. The BP time series
      were analyzed according to the chronobiological procedure, called Cosinor method
      with three harmonic components. RESULTS: The biometric analysis was able to
      document that BP changes over the 24-h scale in AD patients as a function of a
      significant CR. Such a preserved circadian regulation is, however, compromised in
      the second and third harmonic component, suggesting that the BP within-day
      variability is desynchronized by the environmental clues that act as
      synchronizers during the diurnal part of the day. CONCLUSIONS: The preservation
      of the BP CR in the early stage of AD suggests using such a finding as a clinical
      tool for confirming the recent onset of the disease. As a matter of fact, it is
      presumed that the disease is not evolved enough to reach the suprachiasmatic
      nuclei, wherein is located the BP circadian pacemaker. The abolition of the
      ultradian components is another precocious sign that, in turn, indicates early
      stage AD patients to be particularly compromised in their synchronization to
      diurnal cues, such as social routines, meal timing schedule, psycho-physical
      activity, and occupational schemes.

PMID- 10411019
TI  - Commentary: Chronomes: time structures within the physiological range identify
      early disease risk aiming at primary prevention.

PMID- 10411020
TI  - A neuropathological study of dementia in nursing homes in Shimane prefecture,
      Japan: evaluation of the age and gender effect.
AB  - BACKGROUND: Vascular dementia (VD) has been held responsible for the majority of
      all dementia cases in both epidemiological and neuropathological studies in
      Japan. The aim of this study was to clarify relative frequencies of dementia
      neuropathologically in Japanese nursing home residents over a 17-year period and
      to clarify the gender and age effect on the relative frequencies. METHODS: Three
      hundred ten aged nursing home residents (146 men and 164 women), including
      dementia cases in Shimane prefecture, Japan, were evaluated clinically and
      neuropathologically over a period of 17 years. RESULTS: One hundred twenty-two
      (48 men and 74 women) of the 310 autopsied (39%) had shown signs of dementia
      during their lives. In classifying dementia type, Alzheimer's disease (AD)
      accounted for 34% (41); VD 35% (42); mixed dementia 11% (14); and "other"
      dementia 20% (25) of all samples. As to the gender and age effect, the most
      characteristic findings were as follows: (a) There were only VD cases in the 57
      69-year-old group; (b) the 70-79 male age group lacked any cases with only AD;
      (c) more AD than VD was found in elderly men; and (d) in women, AD was the major
      cause of dementia in total. CONCLUSIONS: VD is responsible for the major cause of
      dementia in the younger women and the men under 90 years of age; AD is the
      leading cause of dementia in the elderly men and the women over 79 years of age
      in nursing homes, Shimane prefecture, Japan.

PMID- 10411021
TI  - Description of a mixed ethnic, elderly population. I. Demography, nutrient/energy
      intakes, and income status.
AB  - BACKGROUND: Elderly participants in the Title III-C Nutrition Program, 60-103
      years of age, were assessed for nutrient/energy intakes, relationship of income
      status to intakes, and comparison with data from the National Evaluation of the
      Elderly Nutrition Program (ENP). METHOD: Nonrandomized volunteers were
      interviewed in senior centers or in their homes. Chi-square, t test, and ANOVA
      were used to test for differences in dietary intakes with regard to ethnicity,
      gender, age, type of meal (congregate dining or home delivered), socialization
      factor (lived alone or with others), and income status. A new method of looking
      at diet quality, which conjoins nutrients and energy, was developed for this
      study. RESULTS: Six percent of the sample had adequate energy and nutrient
      intakes over a 3-day period; 53% were rated tenuous or marginal, and 41%
      submarginal or inadequate. The Title III-C noon meal provided 38%-44% of the
      average daily energy intake and 33%-65% of the average intake of selected
      nutrients. Diets of men were better than those of women (p < .05). Calcium (p <
      .01) and potassium (p < .05) were higher in diets of female elders above the
      poverty line than those below. Black women were most affected by poverty, with
      92% below the poverty line. A trend was observed for higher intakes of fatty
      components (total fat, cholesterol, % fat calories) for both men and women in the
      below-poverty than in above-poverty groups. DeKalb Community Council on Aging
      subjects had higher intakes of Vitamin A than those in the ENP, but overall most
      nutrients were higher in both congregate and home delivery clients of ENP.
      CONCLUSIONS: Title III-C Nutrition Programs have been implemented since 1973, and
      nutrition education is an obligatory component. The high incidence of
      nutrient/energy inadequacy in this study was surprising, but consistent with
      previous reports. New ways of implementing better food intakes of senior citizens
      are needed. In addition, research is needed to establish differences in nutrient
      profiles of elderly clients below and above the poverty level.

PMID- 10411022
TI  - Description of a mixed ethnic, elderly population. II. Food group behavior and
      related nonfood characteristics.
AB  - BACKGROUND: Elderly persons 60-103 years of age, who were participants in a Title
      III-C Nutrition Program, provided information regarding weekly frequencies of
      food group consumption, weekend meals and snack patterns, and several nonfood
      items that may affect food intakes. METHODS: Nonrandomized volunteers were
      interviewed in senior centers or in their homes. Chi-square, t test, and
      Pearson's product moment correlations were used to assess differences in the
      population sample with regard to six independent variables: ethnicity, gender,
      type meal (congregate or home delivered), age, proportion of noon meal usually
      eaten, and socialization factor (lived alone or with others). RESULTS: White
      subjects ate more fruits, dairy products, and weekend snacks than black subjects.
      White elders also consumed more caffeine, had larger incomes, and more often had
      sufficient money to buy food. Black subjects ate more pasta and desserts, and in
      sickness more often had help available. Men consumed more meats, dairy products,
      eggs, and starchy foods than women. There were no gender differences in income,
      but men ate more weekend meals in restaurants, spent more money weekly for food,
      more often were able to shop for food and leave home without assistance, and
      reported greater pleasure associated with eating. Home delivery clients ate more
      desserts and Sunday snacks and more frequently ate breakfast on the weekend than
      congregate clients. Congregate clients had more money to buy food, were better
      able to shop for and prepare food, and more frequently had help available in
      sickness. Young-old (<75 yr) and old-old (> r =75 yr) clients showed no
      difference in consumption of any of the food groups. Persons who usually ate all
      or most of the noon meal more frequently experienced pleasurability in eating,
      reported less anorexia, and had larger intakes of the vegetable and pasta groups.
      Persons living with others ate more meats, pasta, and desserts, spent more weekly
      for food, and ate more weekend meals in restaurants. CONCLUSION: The need for
      focus of the elderly nutrition program is greater in home delivery than
      congregate clients. The average home delivery client is older, has more chronic
      health problems and less physical prowess, less income, less frequently has help
      available in sickness, and has greater need for services other than the noon
      meal.

PMID- 10411023
TI  - Description of a mixed ethnic, elderly population. III. Special diets, food
      preferences, and medicinal intakes.
AB  - BACKGROUND: The objective was to assess the use of physician-prescribed special
      diets, food preferences, and daily and occasional drug use by elderly
      participants in a Title III-C Nutrition Program. METHODS: Data were collected by
      nonrandom interviews of congregate and meals-on-wheels clients. Chi-square was
      used to assess whether food and drug behaviors were related to six population
      variables: ethnicity, age, gender, congregate versus meals-on-wheels clients,
      proportion of noon meal usually eaten, and whether clients lived alone or with
      others. RESULTS: Special diets and daily and occasional medications showed no
      significant differences with regard to the six variables. Broccoli was the food
      disliked most frequently. Suggestions that certain foods be served more
      frequently were greater among white than black clients (p < .001) and among home
      delivery than among congregate clients (p < .005). Persons who regularly ate half
      or less of the noon meal made more suggestions for cooking foods differently (p <
      .005) and had longer lists of favorite foods (p < .001) than those who usually
      ate most of or all of the meal. Persons who lived alone had more suggestions for
      cooking foods differently (p < .005) and serving certain items more often (p <
      .05) than those who lived with other persons. Favorite foods, changes in cooking
      methods, and frequency of offering certain foods were not related significantly
      to age or to gender. CONCLUSIONS: Certain suggested changes in food choices and
      preparation can be implemented within Title III guidelines and may improve food
      intakes. While medicinal intakes were similar to those reported previously for
      the elderly cohort, there is reason for concern with regard to drug-induced
      illness.

PMID- 10411024
TI  - This month in investigative urology. Kidney cancer: novel model for cancer
      genetics and therapy.

PMID- 10411025
TI  - Prostate specific antigen: a decade of discovery--what we have learned and where
      we are going.
AB  - PURPOSE: Many advances have occurred during the last decade in the clinical use
      of prostate specific antigen (PSA) for detecting, staging and monitoring prostate
      cancer. We review the clinical usefulness and limitations of serum PSA as a tumor
      marker of prostate cancer. MATERIALS AND METHODS: The English language literature
      was reviewed with respect to the major contributions and limitations of PSA in
      present clinical practice. RESULTS: Although controversial, age specific PSA
      reference ranges can improve the sensitivity for prostate cancer detection in
      young men and the specificity in older men. Percent free PSA improves the
      specificity for prostate cancer detection in men with PSA values between 4 and 10
      ng./ml., and a PSA density of greater than 0.15 may better distinguish benign
      prostatic hyperplasia from prostate cancer. PSA velocity can improve the ability
      to detect prostate cancer when 3 serial PSA values are measured during a 2-year
      period. For prostate cancer staging PSA is most useful combined with clinical
      stage and Gleason score in multivariate analysis. Percent free PSA may prove
      useful for staging prostate cancer but further clinical trials are needed to
      determine its clinical usefulness. PSA is the most clinically useful means to
      monitor disease recurrence after treatment of prostate cancer. With
      ultrasensitive PSA assays it is now possible to increase the lead time for
      detection of disease recurrence by several months. CONCLUSIONS: During the last
      decade much of the focus has been on improving the ability of this tumor marker
      to detect prostate cancer. PSA remains the best and most widely used tumor marker
      in urology today.

PMID- 10411026
TI  - Clinical and molecular followup after radical retropubic prostatectomy.
AB  - PURPOSE: We previously reported evidence of hematogenous dissemination of
      prostate cells during radical retropubic prostatectomy, and we now provide
      clinical and molecular reverse transcriptase-polymerase chain reaction (RT-PCR)
      followup of that patient cohort. MATERIALS AND METHODS: A total of 101 men with
      clinically localized prostate cancer were prospectively enrolled in the study.
      The prostate specific antigen (PSA) RT-PCR assay was performed on peripheral
      venous blood samples preoperatively in 101, during surgery in 29, during and up
      to 12 weeks after surgery in 50 and at least 1 year postoperatively in 65
      patients. Correlation with clinical (PSA) indicators of recurrence was performed.
      RESULTS: Of the 101 patients 9 demonstrated biochemical evidence of prostate
      cancer progression (median followup 22 months). Of the 50 men with perioperative
      molecular results the RT-PCR positive rate increased from 22% preoperatively in
      11 to 48% in 24 (p = 0.02) and then decreased to 10% in 4 of 40 men at 1 year
      postoperatively (p = 0.07). Molecular followup at a minimum of 1 year after
      radical retropubic prostatectomy was obtained in 65 men, of whom the RT-PCR
      positive rate decreased from 23% preoperatively in 14 to 9.2% in 6 (p = 0.05). No
      significant correlation was observed between a persistently positive RT-PCR
      result and biochemical failure. CONCLUSIONS: Although a significant proportion of
      men have molecular evidence of hematogenous prostate cell dissemination
      intraoperatively, longitudinal molecular and clinical followup demonstrates
      reconversion to a negative status as the predominant trend. At relatively short
      followup no significant correlation was identified between the RT-PCR result and
      the PSA progression-free survival.

PMID- 10411027
TI  - Unenhanced computerized axial tomography to detect retained calculi after
      percutaneous ultrasonic lithotripsy.
AB  - PURPOSE: We report our experience with unenhanced computerized axial tomography
      (CT) after percutaneous ultrasonic lithotripsy in patients thought to be at high
      risk for retained calculi. MATERIALS AND METHODS: CT was obtained in 121 patients
      (124 kidneys) within 12 to 36 hours of percutaneous ultrasonic lithotripsy for
      staghorn or large nonstaghorn renal calculi. Cases were grouped according to the
      CT findings as no retained calculi, insignificant retained calculi (fragments 1
      to 3 mm.), retained calculi amenable to shock wave lithotripsy and retained
      fragments requiring second look percutaneous ultrasonic lithotripsy or flexible
      nephroscopy. RESULTS: No calculi were seen in 73 kidneys (59%) and retained
      calculi were identified in 51 (41%). Shock wave lithotripsy was used to treat 8
      patients and another percutaneous ultrasonic lithotripsy or flexible nephroscopy
      was performed in 23 to remove retained stones. Insignificant calculi were noted
      in the remaining 21 patients. CONCLUSIONS: We believe that postoperative
      unenhanced CT is superior to plain renal tomography and is the best method to
      determine if a patient is stone-free after percutaneous ultrasonic lithotripsy.
      It helps to locate precisely those stones requiring a second percutaneous
      ultrasonic lithotripsy or nephroscopic extraction. An unenhanced renal CT devoid
      of calculi obviates routine postoperative second look flexible nephroscopy. We
      encourage others to consider this technique to define more accurately kidney
      stone status after percutaneous ultrasonic lithotripsy for large staghorn calculi
      or in any patient at high risk for retained calculi after percutaneous ultrasonic
      lithotripsy.

PMID- 10411028
TI  - Computerized tomography nephroscopic images of renal pelvic carcinoma.
AB  - PURPOSE: Computerized tomography (CT) endoscopy is an interactive 3-dimensional
      image acquired by helical CT. We assess the usefulness of CT nephroscopy in the
      diagnosis of renal pelvic cancers. MATERIALS AND METHODS: Surface rendering CT
      nephroscopy was performed after intravenous administration of contrast agent and
      furosemide in 32 patients with suspected renal pelvic carcinoma. Retrospective
      review revealed that 23 patients later underwent nephroureterectomy. Two
      observers blinded to the pathology results independently reviewed the CT
      nephroscopic and axial CT images of the 23 patients to localize pelvic tumors and
      to determine the extent of the disease. The CT nephroscopic and axial CT images
      were correlated with the pathological findings. RESULTS: Pathological examination
      revealed 4 polypoid, 6 pedunculated, 7 sessile, 1 sessile with ulceration and 6
      infiltrating renal pelvic carcinomas in the 23 patients. CT nephroscopy revealed
      22 carcinomas (92%) and CT demonstrated 20 (83%). CT nephroscopy was superior to
      axial CT in detecting 4 pedunculated and 3 infiltrating carcinomas but failed to
      detect 1 sessile carcinoma which completely replaced the upper portion of a
      double renal pelvis and 1 polypoid tumor associated with infiltrating carcinoma.
      The CT nephroscopic images correlated well with pathological findings.
      CONCLUSIONS: CT nephroscopy is useful to visualize the complex morphology of
      renal pelvic carcinomas noninvasively and is superior to axial CT for the
      detection of infiltrating and pedunculated carcinomas.

PMID- 10411029
TI  - Use of self-expanding permanent endoluminal stents for benign ureteral
      strictures: mid-term results.
AB  - PURPOSE: Benign ureteral strictures constitute a therapeutic dilemma, especially
      in patients unable to undergo an open operative procedure. We report on 13
      patients with benign ureteral strictures treated with endoscopic implantation of
      self-expanding permanent endoluminal stents. MATERIALS AND METHODS: Endoscopic
      implantation was done using the Wallstent in 4 patients, the Memotherm stent in 5
      and the Sinus stent in 4. The technique of implantation followed the standardized
      procedure that we described in 1995. RESULTS: Mean followup was 41.6 months.
      Primary patency (ureters patent since implantation) was achieved in 7 patients
      and assisted patency (additional intervention) was noted in 5. In 1 case the
      kidney had to be removed because of progressive malfunction. CONCLUSIONS:
      Implantation of self-expanding permanent endoluminal stents for benign ureteral
      strictures is safe, effective and minimally invasive in select cases. Additional
      studies and long-term results are needed to make definitive conclusions about
      this method.

PMID- 10411030
TI  - Ileal ureteral substitution in reconstructive urological surgery: is an
      antireflux procedure necessary?
AB  - PURPOSE: Whether antireflux implantation techniques are necessary in adults who
      undergo ileal ureteral substitution is controversial. We prospectively evaluated
      the correlation between reflux and renal function in 19 patients who underwent
      ileal ureteral substitution with no antireflux implantation technique. MATERIALS
      AND METHODS: Followup included clinical evaluation, serum creatinine, blood
      gasses, excretory urogram, cystogram and dynamic selective renographic clearance
      on technetium mercaptotriglycine renal scans. All patients were followed for a
      minimum of 4 years except 2 who died 26 and 43 months postoperatively. Mean
      followup was 57 months (range 48 to 72). RESULTS: Despite reflux, renal scans
      indicated a significant increase in renal function in all patients. Vesico-ileal
      reflux was present in 9 cases and reflux in the renal pelvis occurred in only 3.
      Reflux occurred in only 3 of 10 patients with ileal segments longer than 15 cm.,
      and did not reach the renal pelvis. CONCLUSIONS: Reflux appears to have no
      detrimental effect on renal function in adults with ileal ureters and, therefore,
      an antireflux procedure is unnecessary. In addition, an ileal segment longer than
      15 cm. appears to safeguard the renal pelvis against visible reflux stemming from
      pro-grade intestinal peristalsis.

PMID- 10411031
TI  - Nitric oxide: a useful gas in the detection of lower urinary tract inflammation.
AB  - PURPOSE: Luminal nitric oxide has been shown to be elevated in the bladder of
      patients with cystitis of various etiologies. We determine whether luminal nitric
      oxide can be used as a marker to differentiate inflammation, that is interstitial
      cystitis, from urgency, frequency, nocturia and pain due to noninflammatory
      disorders, such as outflow obstruction and neurogenic dysfunction. MATERIALS AND
      METHODS: We measured luminal nitric oxide in the bladder of patients with urgency
      due to detrusor instability (6), outflow obstruction (7), sensory urge (19) and
      interstitial cystitis (8), and controls without urgency symptoms (11). Nitric
      oxide-free air was incubated in the bladder for 5 minutes and analyzed in a
      chemiluminescence nitric oxide analyzer. RESULTS: There was a nearly 20-fold
      increase in mean bladder nitric oxide concentration in patients with interstitial
      cystitis (234+/-67 parts per billion) compared to those with detrusor instability
      (11+/-1), outflow obstruction (9+/-1) and sensory urgency (10+/-1), and controls
      (13+/-2). CONCLUSIONS: Measurement of nitric oxide in air from the bladder is a
      simple, safe and fast method to differentiate urgency due to inflammation from
      neurogenic disorders or outflow obstruction. The simplicity of this method makes
      it potentially useful as a screening method for office use.

PMID- 10411032
TI  - Comparison of bladder blood flow in patients with and without interstitial
      cystitis.
AB  - PURPOSE: We compared bladder blood flow during filling and emptying in patients
      with and without interstitial cystitis, and correlated blood flow with symptoms
      in those with interstitial cystitis. MATERIALS AND METHODS: Bladder perfusion was
      measured using a dual channel endoscopic laser Doppler flow probe. Measurements
      were obtained in superficial and deeper vascular beds from the bladder mucosa at
      the trigone and back wall at baseline, at the volume of awake capacity, during 80
      cm. water hydrodistention and after bladder drainage. American Urological
      Association symptom score was obtained preoperatively in interstitial cystitis
      patients. RESULTS: In all areas bladder perfusion decreased with filling in
      interstitial cystitis patients and increased in those without interstitial
      cystitis. There were no significant differences in response to emptying the
      bladder, as perfusion tended to increase in both groups. There was no correlation
      between bladder perfusion at baseline, or in response to filling or emptying with
      overall symptom score. CONCLUSIONS: Bladder perfusion decreases with bladder
      filling in patients with but increases in those without interstitial cystitis.
      The inability of the interstitial cystitis bladder to increase bladder blood flow
      with filling may be a reflection of other pathological processes in the bladder
      mucosa. The lack of correlation between blood flow and symptoms suggests that
      bladder ischemia alone cannot account for the symptoms in interstitial cystitis.

PMID- 10411033
TI  - Endoscopic treatment of bladder outlet obstruction in men after pancreas
      transplantation.
AB  - PURPOSE: Diabetic cystopathy comprises a spectrum of voiding dysfunction. The
      usual clinical manifestations are impaired bladder sensation and detrusor
      contractility. Diabetic cystopathy is present in as many as 43 to 85% of patients
      undergoing pancreas transplantation. We evaluated endoscopic management of
      bladder outlet obstruction for adjuvant treatment of urological complications
      after pancreas transplantation. MATERIALS AND METHODS: We evaluated 10 men with
      recurrent urological complications, including bladder leak, urinary tract
      infection, the dysuria/urethritis syndrome and reflux nephropathy, after pancreas
      transplantation. Evaluation consisted of peak flow rate, post-void residual and
      written questionnaires in all cases, and preoperative urodynamics in 2. All
      patients had signs and symptoms of bladder outlet obstruction at post-transplant
      presentation and underwent bladder neck incision, direct visual internal
      urethrotomy, limited transurethral resection of the bladder neck or transurethral
      resection of the prostate. Hospital costs, including operating room, laboratory,
      pharmacy, hospital room occupancy, anesthesia and radiology fees, were obtained
      from the University of Washington. RESULTS: Mean peak flow rate plus or minus
      standard deviation increased from 10.1+/-3.2 to 21.0+/-5.1 cc per second and post
      void residual decreased from 259.2+/-38.6 to 43.6+/-36.8 cc after endoscopic
      intervention. Of the patients 4 presented early (mean 4.3 months) after
      transplantation with bladder leak or reflux nephropathy, while late presentation
      (mean 43 months) was associated with recurrent urinary tract infection, the
      urethritis/dysuria syndrome and more obstructive symptoms. Complications resolved
      in all cases after surgery and enteric conversion, which costs 5-fold more than
      endoscopic intervention, was avoided. CONCLUSIONS: Recurrent urological
      complications warrant early evaluation for occult bladder dysfunction. Endoscopic
      procedures to relieve outlet obstruction are beneficial in alleviating recurrent
      urological complications in men after pancreas transplantation. This cost
      effective and low morbidity procedure may obviate the need for enteric conversion
      in some male transplant recipients.

PMID- 10411034
TI  - Sequential bacillus Calmette-Guerin and epirubicin versus bacillus Calmette
      Guerin alone for superficial bladder tumors: a randomized prospective study.
AB  - PURPOSE: This study was designed to find a new therapeutic modality that may have
      the same efficacy and lower toxicity than bacillus Calmette-Guerin (BCG) for the
      treatment of superficial transitional cell carcinoma of the bladder. MATERIALS
      AND METHODS: Between January 1993 and July 1997 a prospective randomized trial
      was conducted on 139 patients with stages pTa and pT1 bladder transitional cell
      carcinoma to compare the prophylactic efficacy and toxicity of sequential BCG and
      epirubicin (group 1) versus BCG alone (group 2). Group 1 comprised 69 patients
      who received alternating doses of 150 mg. BCG and 50 mg. epirubicin (1 drug at a
      time), while 70 patients in group 2 received 150 mg. BCG at each instillation.
      Treatment was continued for 6 weeks followed by 10 monthly instillations.
      RESULTS: Therapy was discontinued permanently in 3 group 1 and 12 group 2
      patients due to severe side effects, and they were excluded from the study. Among
      the 124 evaluable patients (96 men and 28 women, mean age 58.2 years) mean
      followup was 30.4 months (range 12 to 50). Recurrence and progression rates were
      statistically comparable in both groups. Interval to first recurrence with or
      without progression was longer in group 1 than in group 2 (log rank p = 0.05).
      Toxicity and complications were significantly lower with sequential treatment
      than with BCG alone at rates of 27.3% (18 patients) and 70.7% (41), respectively
      (p = 0.001). CONCLUSIONS: Sequential BCG and epirubicin are comparable to BCG
      alone in efficacy and superior in terms of toxicity.

PMID- 10411035
TI  - Assessment of patients with metastatic transitional cell carcinoma of the urinary
      tract.
AB  - PURPOSE: We propose an appropriate assessment of patients with disseminated
      transitional cell carcinoma of the urothelial tract, and investigate the pattern
      of metastases relative to pathological features and primary tumor treatment.
      MATERIALS AND METHODS: A total of 156 consecutive patients with recurrent locally
      advanced (nonresectable, radioresistant) and/or metastatic transitional cell
      carcinoma of the urothelial tract were evaluated with blood tests, chest x-ray,
      bone scintigraphy, bone marrow biopsy, and abdominal and brain computerized
      tomography. RESULTS: Distant metastases were evident in 86% of the patients, with
      lymph nodes and bones being the most frequent sites. Bone metastases were mostly
      in the pelvis or lower spine and were asymptomatic in 19% of patients. Bone
      marrow metastases were noted in 14% of these patients. However, most of them also
      had radiological bone metastases and bone marrow biopsy is not recommended for
      routine evaluation. Approximately 2% of patients had brain metastases without
      symptoms at recurrence. Elevated lactate dehydrogenase was predictive of
      disseminated disease. Patients receiving radical radiotherapy as primary
      treatment had an increased rate of recurrent locally advanced disease but the
      same frequency of distant metastases compared to those undergoing cystectomy.
      Primary tumor features did not relate to the pattern of metastases. CONCLUSIONS:
      We recommend chest x-ray, whole abdominal computerized tomography and routine
      blood tests, including lactate dehydrogenase, for patients with recurrent locally
      advanced or metastatic disease. Skeletal symptoms should be examined
      radiologically, while asymptomatic patients with recurrence in sites other than
      bone should be evaluated with bone scintigraphy.

PMID- 10411036
TI  - The significance of the open bladder neck associated with pelvic fracture
      urethral distraction defects.
AB  - PURPOSE: As a result of pelvic fracture urethral distraction defects, urinary
      continence relies predominantly on intact bladder neck function. Hence, when
      cystoscopy and/or cystography reveals an open bladder neck before urethroplasty,
      the probability of postoperative urinary incontinence may be significant.
      Unresolved issues are the necessity, the timing and the type of bladder neck
      repair. We report the outcome of various therapeutic options in patients with
      pelvic fracture urethral distraction defects and open bladder neck. We also
      attempt to identify prognostic factors of incontinence before urethroplasty.
      MATERIALS AND METHODS: We retrospectively reviewed the records of 15 patients
      with a mean age of 30 years in whom an open bladder neck was identified before
      posterior urethroplasty between January 1981 and October 1997. RESULTS: Of the 15
      patients 6 were continent and 8 were incontinent postoperatively. One patient
      underwent artificial urethral sphincter implantation simultaneously with pelvic
      fracture urethral distraction defect repair and was dry postoperatively without
      sphincter activation. Average bladder neck and prostatic urethral opening on the
      cystourethrogram before urethroplasty was significantly longer in incontinent
      (1.68 cm.) than in continent (0.9 cm.) patients. Of the 8 patients who were
      incontinent 6 underwent bladder neck reconstruction, 1 artificial urinary
      sphincter and 1 periurethral collagen implant. Five patients with bladder neck
      reconstruction are totally continent and 1 requires 1 pad daily. The patient who
      underwent collagen implant requires 2 pads daily and the patient who received an
      artificial urethral sphincter has minor urge leakage. CONCLUSIONS: Open bladder
      neck before urethroplasty may herald postoperative incontinence which may be
      predicted by radiographic and cystoscopic features. Evaluation of the risk of
      postoperative incontinence may be valuable, and eventually guide the necessity
      and timing of anti-incontinence surgery, although our preference remains to
      manage the pelvic fracture urethral distraction defects and bladder neck problem
      sequentially. Bladder neck reconstruction provides good postoperative continence
      rates and is our technique of choice.

PMID- 10411037
TI  - Sacral nerve stimulation for treatment of refractory urinary urge incontinence.
      Sacral Nerve Stimulation Study Group.
AB  - PURPOSE: A prospective, randomized study was performed to evaluate sacral nerve
      stimulation for the treatment of refractory urinary urge incontinence. MATERIALS
      AND METHODS: Primary outcome variables were obtained from voiding diaries. After
      baseline evaluation candidates who satisfied inclusion criteria were enrolled
      into the study. Test stimulation results determined eligibility for randomization
      into a stimulation (treatment) or delay (control) group. The stimulation group
      included 34 patients who underwent implantation and were followed for 6 months.
      The delay group comprised 42 patients who received standard medical therapy for 6
      months and then were offered implantation. The stimulation group completed a
      therapy evaluation test (on versus off) after 6 months. RESULTS: At 6 months the
      number of daily incontinence episodes, severity of episodes and absorbent pads or
      diapers replaced daily due to incontinence were significantly reduced in the
      stimulation compared to the delay group (all p<0.0001). Of the 34 stimulation
      group patients 16 (47%) were completely dry and an additional 10 (29%)
      demonstrated a greater than 50% reduction in incontinence episodes 6 months after
      implantation. Efficacy appeared to be sustained for 18 months. During the therapy
      evaluation test the group returned to baseline levels of incontinence when
      stimulation was inactivated. Urodynamic testing confirmed that sacral nerve
      stimulation did not adversely affect voiding function. Complications included
      implantable pulse generator site pain in 15.9% of the patients, implant site pain
      in 19.1% and lead migration in 7.0%. Surgical revision was required in 32.5% of
      patients with implants to resolve a complication. There were no reports of
      permanent injury or nerve damage. CONCLUSIONS: Sacral nerve stimulation is safe
      and effective in treating refractory urinary urge incontinence.

PMID- 10411038
TI  - Study of cavernosal arterial anatomy using color and power Doppler sonography:
      impact on hemodynamic parameter measurement.
AB  - PURPOSE: We report on color and power Doppler ultrasound to study cavernosal
      arterial anatomy, and evaluate the impact of vascular anatomy on the measurement
      of hemodynamic parameters. MATERIALS AND METHODS: Cavernosal arterial anatomy of
      42 patients with erectile dysfunction was evaluated using color and power Doppler
      ultrasound. A computerized waveform analysis was used to measure peak systolic
      velocity, end diastolic velocity and resistive indexes at various sites,
      including the penile crura, and proximal mid and distal penile shaft. Hemodynamic
      parameters were measured in each artery in cases of bifurcated or multiple
      cavernosal arteries. RESULTS: A total of 80 corpora were adequately evaluated. We
      observed a single artery without major proximal branches in 37 corpora, a single
      artery with major proximal branches in 17, bifurcated arteries in 15, 2
      cavernosal arteries in 4 and marked arterial tortuosity in 1. In 6 corpora the
      main cavernosal artery arose from the superficial dorsal artery. The peak
      systolic velocity was highest at the proximal and decreased progressively at the
      distal site. The peak systolic velocity plus or minus standard deviation at the
      mid shaft averaged 69.3+/-30.0% of that at the proximal penile shaft. Of the 15
      corpora with bifurcated arteries 67% had a 40% or greater difference in peak
      systolic velocity between the branches. Complete or partial occlusion of the
      cavernosal artery was identified in 3 corpora, and a dramatic difference in peak
      systolic velocity proximal and distal to the stenotic area was demonstrated.
      CONCLUSIONS: Cavernosal arterial anatomy is variable and hemodynamic parameters
      differ at various sites of measurement. Parameters should be measured at a
      consistent proximal site to obtain a reliable assessment. Variations in vascular
      anatomy and cavernosal artery pathology should be considered when interpreting
      color Doppler sonography and before penile vascular surgery.

PMID- 10411039
TI  - Rising risk of testicular cancer by birth cohort in the United States from 1973
      to 1995.
AB  - PURPOSE: Recent epidemiological studies have demonstrated an increasing incidence
      of testicular cancer in white men which appears to be correlated with the period
      of birth. Because this birth cohort phenomenon can explain etiological factors in
      testicular cancer, we determine whether this trend is present throughout the
      United States based on an analysis of testicular cancer incidence by birth
      cohort. MATERIALS AND METHODS: Testicular cancer incidence was obtained from the
      National Cancer Institute Surveillance, Epidemiology and End Results database
      from 1973 to 1995. Numbers of cases were extracted and grouped by 5-year birth
      cohorts for all testicular germ cell neoplasms. Poisson regression analysis with
      variables of age, time of diagnosis and birth cohort were used to determine
      relative risk. Poisson models were compared using computer log linear model
      software. RESULTS: Between 1973 and 1995 the incidence of testicular cancer in
      the United States increased 51% (3.61 to 5.44/100,000). Analysis of Poisson
      models revealed that birth cohort was strongly associated with relative risk of
      testicular cancer (p = 0.001). In addition, peak age at diagnosis decreased for
      each successive birth cohort. CONCLUSIONS: The overall incidence of testicular
      cancer in white men and the relative risk of testicular cancer have been
      increasing in the United States. This trend is strongly associated with birth
      cohort in concordance with previously reported European data. Moreover,
      testicular cancer is being diagnosed at a younger age as evidenced by a shift to
      the left in the age of peak incidence. These unique epidemiological patterns
      offer a basis for analysis of potential etiological factors.

PMID- 10411040
TI  - False-negative biopsies for testicular intraepithelial neoplasia.
AB  - PURPOSE: Testicular intraepithelial neoplasia, also called carcinoma in situ of
      the testis, is diagnosed by conventional surgical biopsy based on the assumption
      that testicular intraepithelial neoplasia is randomly distributed throughout the
      testis. We evaluate the frequency of and possible reasons for false-negative
      biopsies. MATERIALS AND METHODS: Contralateral testicular biopsy was performed in
      1,954 consecutive patients with testicular germ cell tumor. Of the patients 1,859
      with a negative biopsy for testicular intraepithelial neoplasia were followed for
      a median of 6 years. Patients with a second testicular tumor despite previous
      negative biopsy were evaluated clinically and biopsy specimens were reexamined
      immunohistologically. RESULTS: Despite negative biopsy 5 patients had a second
      testis tumor. Testicular intraepithelial neoplasia was detected on reexamination
      in 2 of the specimens, and mechanical damage to the specimen and technical
      problems with immunohistochemical staining accounted for the diagnostic failures.
      The proportion of false-negative biopsies was 0.3% (95% confidence intervals [CI]
      0.087 to 0.627). The sensitivity of testicular biopsies to detect testicular
      intraepithelial neoplasia was 0.95 (95% CI 0.887 to 0.984) and the overall
      accuracy of the biopsy was 0.997 (95% CI 0.994 to 0.999). To our knowledge 14
      cases have been previously reported in the literature, including 2 treated with
      chemotherapy before testicular biopsy. CONCLUSIONS: The overall proportion of
      false-negative biopsies for testicular intraepithelial neoplasia is as low as
      0.3%. The main reason for diagnostic failure is probably the nonrandom
      distribution of testicular intraepithelial neoplasia within the testis. Previous
      chemotherapy and rare technical failures, in particular mechanical damage to the
      biopsy specimen, may also account for diagnostic failures. Surgical biopsy
      remains the gold standard for the diagnosis of testicular intraepithelial
      neoplasia.

PMID- 10411041
TI  - The National Institutes of Health chronic prostatitis symptom index: development
      and validation of a new outcome measure. Chronic Prostatitis Collaborative
      Research Network.
AB  - PURPOSE: Chronic abacterial prostatitis is a syndrome characterized by pelvic
      pain and voiding symptoms, which is poorly defined, poorly understood, poorly
      treated and bothersome. Research and clinical efforts to help men with this
      syndrome have been hampered by the absence of a widely accepted, reliable and
      valid instrument to measure symptoms and quality of life impact. We developed a
      psychometrically valid index of symptoms and quality of life impact for men with
      chronic prostatitis. MATERIALS AND METHODS: We conducted a structured literature
      review of previous work to provide a foundation for the new instrument. We then
      conducted a series of focus groups comprising chronic prostatitis patients at 4
      centers in North America, in which we identified the most important symptoms and
      effects of the condition. The results were used to create an initial draft of 55
      questions that were used for formal cognitive testing on chronic prostatitis
      patients at the same centers. After expert panel review formal validation testing
      of a revised 21-item draft was performed in a diverse group of chronic
      prostatitis patients and 2 control groups of benign prostatic hyperplasia
      patients and healthy men. Based on this validation study, the index was
      finalized. RESULTS: Analysis yielded an index of 9 items that address 3 different
      aspects of the chronic prostatitis experience. The primary component was pain,
      which we captured in 4 items focused on location, severity and frequency. Urinary
      function, another important component of symptoms, was captured in 2 items (1
      irritative and 1 obstructive). Quality of life impact was captured with 3 items
      about the effect of symptoms on daily activities. The 9 items had high test
      retest reliability (r = 0.83 to 0.93) and internal consistency (alpha = 0.86 to
      0.91). All but the urinary items discriminated well between men with and without
      chronic prostatitis. CONCLUSIONS: The National Institutes of Health chronic
      prostatitis symptom index provides a valid outcome measure for men with chronic
      prostatitis. The index is psychometrically robust, easily self-administered and
      highly discriminative. It was formally developed and psychometrically validated,
      and may be useful in clinical practice as well as research protocols.

PMID- 10411042
TI  - Incidence rates and risk factors for acute urinary retention: the health
      professionals followup study.
AB  - PURPOSE: We define incidence rates and risk factors for acute urinary retention.
      MATERIALS AND METHODS: In 1992, 41,276 United States male health professionals 45
      to 83 years old self-reported baseline health data and American Urological
      Association symptom index scores. In 1995 a subset reported the year of any
      episode of acute urinary retention requiring catheterization. Of 8,418
      respondents 6,100 without a history of prostate cancer, prostatectomy or acute
      urinary retention before 1992 provided data. Incidence rates from 1992 to 1995
      were calculated and risk factors were assessed using logistic regression.
      RESULTS: During 15,851 person-years of followup 82 men reported an episode of
      acute urinary retention (sampling weighted incidence 4.5/1,000 person-years, 95%
      confidence intervals 3.1 to 6.2). Rates increased with age and baseline symptom
      severity. In men with symptom score 0 to 7 (none or mild lower urinary tract
      symptoms) the incidence of acute urinary retention increased from 0.4/1,000
      person-years for those 45 to 49 years old to 7.9/1,000 person-years for those 70
      to 83 years old. In men with symptom score 8 to 35 (moderate or severe lower
      urinary tract symptoms) rates increased from 3.3/1,000 person-years for those 45
      to 49 years old to 11.3/1,000 person-years for those 70 to 83 years old. Men with
      a clinical diagnosis of benign prostatic hyperplasia and a symptom score 8 or
      greater had the highest rates (age adjusted incidence 13.7/1,000 person-years).
      All 7 lower urinary tract symptoms comprising the American Urological Association
      symptom index individually predicted acute urinary retention (age adjusted odds
      ratio 1.8 to 2.9 for symptoms occurring more than 25% of the time during the last
      month). The sensation of incomplete bladder emptying, having to void again after
      less than 2 hours and a weak urinary stream were the best independent symptom
      predictors. Use of medications with adrenergic or anticholinergic side effects
      also predicted acute urinary retention. CONCLUSIONS: Acute urinary retention
      occurred relatively infrequently but older age, moderate or severe lower urinary
      tract symptoms, a diagnosis of benign prostatic hyperplasia and specific drug
      therapies significantly increased the risk of occurrence.

PMID- 10411043
TI  - Ethanol injection therapy of the prostate for benign prostatic hyperplasia:
      preliminary report on application of a new technique.
AB  - PURPOSE: We evaluate the efficacy of a new technique of minimally invasive
      treatment for benign prostatic hyperplasia involving direct injection of
      dehydrated ethanol. MATERIALS AND METHODS: Dehydrated ethanol was injected
      transurethrally with lumbar or sacral and urethral anesthesia in 10 patients with
      prostatic hyperplasia. Endoscopic injection was performed at 4 to 8 sites in the
      prostate and 3.5 to 12.0 ml. ethanol were used. RESULTS: There were no
      intraoperative complications but postoperative urinary retention occurred
      transiently in all patients which required catheterization for a mean of 8.8
      days. Mean symptom score plus or minus standard deviation was 12.2+/-5.8 at 3
      months postoperatively, which was significantly improved from 23.1+/-7.0
      preoperatively (p<0.01). Mean quality of life score also improved significantly
      from 5.1+/-0.6 preoperatively to 3.2+/-1.5 at 3 months postoperatively (p<0.01),
      mean peak urinary flow rate increased from 8.0+/-2.2 (9 patients) to 13.1+/-3.6
      ml. per second (p<0.05) and mean residual urine volume decreased from 129.1+/
      55.3 (9 patients) to 49.3+/-34.7 ml. (p<0.05). There was no significant change in
      prostate volume. Acute epididymitis and chronic prostatitis occurred in 1 patient
      each. CONCLUSIONS: This technique can be performed as an outpatient procedure and
      appears to be safe and cost-effective. Retrograde ejaculation can be avoided.

PMID- 10411044
TI  - Transurethral thermotherapy for benign prostatic hyperplasia significantly
      decreases infravesical obstruction: results in 134 patients after 1 year.
AB  - PURPOSE: We prospectively evaluated a decrease in outflow obstruction caused by
      benign prostatic hyperplasia (BPH) with second generation thermotherapy.
      MATERIALS AND METHODS: Transurethral microwave therapy was given with local
      anesthesia to 134 patients with urodynamically and cystoscopically documented
      obstruction by BPH and preserved detrusor function. Of 134 patients 67 (50%) had
      a general health score of 3 or greater. RESULTS: Urgency was the main complaint
      during thermotherapy. After a median followup of 24 months (minimum 12) 100
      patients were evaluable at 6 and 12 months. Of the initial 134 patients 17 (13%)
      who required additional treatment (repeat thermotherapy, transurethral prostatic
      resection, permanent cystostomy), 7 who died during followup for treatment
      unrelated reasons and 10 who were lost to followup or refused evaluation were
      excluded from further analysis. Mean International Prostate Symptom Score
      decreased from 22.5 before to 3.6 at 6 months after treatment and remained stable
      at 12 months. Mean Quality of Life Index improved from 4.3 before to 1 at 12
      months after treatment. Mean maximum flow increased from 7.3 ml. per second
      before to 14.5 at 6 months and 13.9 at 12 months after treatment. Mean post-void
      residual decreased from 199 to 34.8 and 37.2 ml. at 6 and 12 months,
      respectively. Urodynamic evaluation of 84 patients after 6 months revealed a
      decrease in mean detrusor opening pressure from 96.8 to 53 cm. water and mean
      detrusor pressure at maximum flow from 99.8 to 59.7 cm. water. Mean
      ultrasonographic prostate volume decreased from 57.6 to 42.4 cc and a cavity in
      the prostate was documented in 65 of the 84 cases (77%). All changes between the
      pretreatment and posttreatment values at 6 and 12 months, respectively, were
      statistically significant (paired t test p<0.00001). CONCLUSIONS: Targeted
      transurethral thermotherapy with second generation microwave equipment is
      minimally invasive, easy to apply and generally well tolerated with local
      anesthesia. Infravesical outlet obstruction and voiding pressures as assessed by
      pressure flow studies significantly decreased 6 months after treatment.
      Subjective voiding symptoms as well as post-void residual urine were
      significantly decreased, and urinary flow was improved 6 and 12 months after
      treatment of documented BPH.

PMID- 10411045
TI  - Racial differences in tumor volume and prostate specific antigen among radical
      prostatectomy patients.
AB  - PURPOSE: Black men with and without prostate cancer in general have higher
      prostate specific antigen (PSA) before screening and treatment than other racial
      groups. A preliminary study suggested that higher PSA levels may be primarily due
      to greater tumor burden. We compared PSA and 3-dimensional (D) tumor volume in a
      consecutive cohort of black and white radical prostatectomy patients in an equal
      access military health care setting to determine racial differences in these
      parameters. MATERIALS AND METHODS: Prospective data collection, 2.25 mm. step
      section whole mount specimen processing and 3-D tumor volume assessment were
      performed in 226 patients with clinical stage T1-T3 prostate cancer undergoing
      radical prostatectomy at our center between April 1993 and March 1997. Of the
      patients 25 were excluded from further analysis because of neoadjuvant hormone
      treatment, T3 disease or Asian race. A total of 155 white and 46 black patients
      were compared. RESULTS: There was no significant racial difference in the
      distribution of patients by age, clinical stage, pathological stage, Gleason sum
      or benign prostate gland volume. A significant racial difference was noted for
      pretreatment PSA and 3-D tumor volume. PSA values were higher in black men than
      in white men, and the racial difference remained statistically significant in
      multivariate analysis adjusting for 3-D tumor volume, benign gland volume, age,
      stage and Gleason sum. CONCLUSIONS: Racial difference in PSA persists, despite
      rigorous covariate adjustment, and further study is needed to explain this PSA
      difference.

PMID- 10411046
TI  - Quality of life after salvage cryotherapy: the impact of treatment parameters.
AB  - PURPOSE: Cryotherapy has emerged as a promising salvage therapy option for
      treatment of locally recurrent prostate cancer after initial therapy. In this
      retrospective study we evaluate patient quality of life after salvage cryotherapy
      and correlate complications impairing quality of life with specific cryotherapy
      treatment parameters. MATERIALS AND METHODS: A modified UCLA Prostate Cancer
      Index measuring health related quality of life was sent to 150 patients who
      underwent salvage cryotherapy between July 1992 and April 1995. We evaluated the
      relationships among incontinence, pain, impotence, sloughing of tissue and
      problematic voiding symptoms, and cryotherapy treatment parameters, including use
      of a urethral warming catheter, number of cryotherapy probes and number of freeze
      thaw cycles. We also evaluated patient overall degree of satisfaction with the
      procedure. RESULTS: Of 150 surveys 112 (74%) were returned. Mean followup was
      16.7 months (range 0.5 to 31.5). Treatment without an effective urethral warming
      catheter was highly associated with urinary incontinence (p<0.003), perineal pain
      (p<0.001), tissue sloughing (p<0.003) and American Urological Association symptom
      score greater than 20 (p<0.004). Impotence was higher in the double freeze-thaw
      cycle group (p<0.05). Overall satisfaction with cryotherapy was 33%. CONCLUSIONS:
      Quality of life may be compromised by urinary incontinence, impotence, tissue
      sloughing, problematic voiding symptoms and/or perineal pain in a substantial
      number of patients following salvage cryotherapy. Effective urethral warming is
      essential in reducing complications and maximizing quality of life. Salvage
      cryotherapy does not appear to offer any quality of life advantages compared to
      salvage prostatectomy.

PMID- 10411047
TI  - Early quality of life assessment in men treated with permanent source
      interstitial brachytherapy for clinically localized prostate cancer.
AB  - PURPOSE: We prospectively assessed quality of life changes with time using
      validated instruments in men with clinically localized prostate cancer treated
      with permanent source interstitial brachytherapy. MATERIALS AND METHODS: A total
      of 46 men consecutively treated with permanent source interstitial brachytherapy
      between September 1997 and June 1998 completed quality of life (Functional
      Assessment of Cancer Therapy-Prostate [FACT-P]) and urinary symptom
      (International Prostate Symptom Score [I-PSS]) questionnaires before (T0), and 1
      (T1) and 3 (T3) months after treatment. All participants were treated with
      125iodine alone. Repeated measures analyses of variance were conducted on all
      quality of life and urinary outcome measures for 44 patients with data at all 3
      time points. RESULTS: Median patient age was 68 years (range 51 to 80). All men
      had clinical T1c to T2b prostate cancer, Gleason score was 6 or less in 36 (78%)
      and median pretreatment prostate specific antigen was 7 ng./ml. (range 1.1 to
      20.6). Mean score (and standard deviation) at T0, T1 and T3 for each
      questionnaire was FACT-P 138.9 (14.4), 128.6 (19.4) and 136.7 (17.4), TO versus
      T1 p = 0.0005 and T0 versus T3 p = 0.6612, and I-PSS 8.3 (5.4), 19.7 (9.0) and
      15.7 (7.2), T0 versus T1 p = 0.0001 and T0 versus T3 p = 0.0001. For the global
      test across time statistically significant differences were observed for the
      cumulative scores of FACT-P, I-PSS, physical well-being and prostate cancer
      subscales of the FACT-P and the Trial Outcome Index. By 3 months all quality of
      life measures had returned to baseline. Urinary symptoms as measured by I-PSS
      persisted for at least 3 months. CONCLUSIONS: Clinically meaningful decreases in
      quality of life, as measured by the FACT-P instrument, were evident within weeks
      after permanent source interstitial brachytherapy. However, by 3 months FACT-P
      scores returned to near baseline levels. A validated instrument designed to
      measure urinary symptoms (I-PSS) demonstrated that moderate to severe urinary
      symptoms persisted for at least 3 months following permanent source interstitial
      brachytherapy. An instrument specifically designed to measure urinary symptoms
      can provide additional clinical information when combined with FACT-P.

PMID- 10411048
TI  - Quality of life and prostate cancer treatment.

PMID- 10411049
TI  - Willet F. Whitore, Jr. Lecture: back to the future--the role of complementary
      medicine in urology.

PMID- 10411050
TI  - Prostate brachytherapy: treatment strategies.
AB  - PURPOSE: Patients who present with localized and locally advanced prostate cancer
      may be candidates for prostate brachytherapy. We evaluated the treatment outcomes
      in a diverse group of prostate cancer patients who presented with low, moderate
      and high risk features. MATERIALS AND METHODS: A total of 301 patients who
      presented with T1 to T3 prostate cancer were treated with brachytherapy alone or
      combined with hormonal therapy and/or external beam irradiation. Of these
      patients 109 at low risk with prostate specific antigen (PSA) 10 ng./ml. or less,
      Gleason score 6 or less and clinical stage T2a or less were treated with
      125iodine alone, 152 at moderate risk with PSA greater than 10 ng./ml., Gleason
      score greater than 6 or stage T2b or greater were treated with 125iodine or
      103palladium or combined implant alone with 5 months of hormonal therapy, and 40
      at high risk with PSA greater than 15 ng./ml., Gleason 8 or greater, clinical
      stage T2c to T3 or positive seminal vesicle biopsy (20) were treated with
      combination brachytherapy, external beam irradiation and 9 months of hormonal
      therapy. Patients with a positive seminal vesicle biopsy (T3c disease) and
      negative pelvic lymph nodes were included in the high risk group, and the walls
      of the seminal vesicles were also treated with implantation. Followup was
      performed every 6 months with digital rectal examination and ultrasound
      evaluation. Prostate biopsy was routinely recommended 2 years after completion of
      the radiation. Failure was defined as PSA increase on 2 consecutive
      determinations above 1 ng./ml. or evidence of local recurrence on digital rectal
      examination, transrectal ultrasound or biopsy. Kaplan-Meier projections were used
      to calculate progression-free survival rates. RESULTS: Of the 109 patients at low
      risk followed from 1 to 7 years (median 18 months) 91% were free of PSA failure
      at 4 years. No patient experienced urinary incontinence following implantation,
      although grade 1 to 2 radiation proctitis occurred in 5 (4.5%). Of the 152
      patients at moderate risk 73 received implantation and 79 received implantation
      combined with hormonal therapy. The 4-year biochemical freedom from failure rate
      for the hormone group was 85% versus 58% for the no hormone group (p = 0.08). The
      difference was more significant for those with Gleason score 7 or greater (90
      versus 43%, p = 0.01) and for those with PSA greater than 10 ng./ml. (87 versus
      59%, p = 0.04). Grade 1 to 2 radiation proctitis occurred in 1 of the 79 patients
      (1.3%) receiving hormonal therapy and in 3 (4%) treated with implantation only.
      There were no cases of urinary incontinence. Of the 40 patients at high risk 71%
      were free of biochemical failure at 3 years. Of the 4 patients with failure (10%)
      3 (75%) originally had positive seminal vesicle biopsies. Five patients
      experienced gastrointestinal complications, although none was grade 3 or 4. The
      actuarial freedom from grade 2 proctitis was 82%. No patient experienced urinary
      incontinence. Prostate biopsies were negative in 87% of the low risk, 96.8
      (hormone group) versus 68.6% (no hormone group) of the moderate risk (p = 0.0023)
      and 86% of the high risk patients. CONCLUSIONS: Brachytherapy appears to offer
      comparable results to external beam irradiation and radical prostatectomy when
      patients are stratified by disease extent. Adopting a strategy of implant alone,
      implant with hormonal therapy or implant with hormonal therapy and external beam
      irradiation in patients who present with low to high risk features can improve
      the overall results in the more advanced cases.

PMID- 10411051
TI  - The efficacy of cryosurgical ablation of prostate cancer: the University of
      California, San Francisco experience.
AB  - PURPOSE: We analyze biopsy and prostate specific antigen (PSA) results following
      cryosurgery for patients with clinically localized prostate cancer. MATERIALS AND
      METHODS: A total of 176 patients underwent 207 cryosurgical procedures for
      clinically localized (stages T1 to T4) prostate cancer using a multiprobe
      cryosurgical device. Cancer stage was T1 in 8.7%, T2 in 30%, T3 in 59% and T4 in
      2.3% of the 176 patients. Neoadjuvant androgen deprivation was delivered to 101
      patients (57%). End points used to determine efficacy of the procedure included
      analysis of posttreatment serum PSA characteristics (nadir and nonrising status)
      and biopsy results (absence of cancer). Cryosurgery was considered successful if
      PSA reached a nadir of less than 0.5 ng./ml. and did not increase by more than
      0.2 ng./ml. on 2 consecutive occasions. Mean followup for the entire group was
      30.8 months, with 122 patients (60%) followed for 24 or more months and 75 (36%)
      followed for 36 or more months. RESULTS: Serial PSA data was available after 181
      initial and repeat procedures. Nadir PSA was undetectable in 88 patients (49%),
      between 0.1 and 0.4 ng./ml. in 39 (21%) and 0.5 ng./ml. or greater in 54 (30%)
      following cryosurgery. After 78 of these procedures (43%) serum PSA reached a
      nadir of less than 0.5 ng./ml. and failed to increase greater than 0.2 ng./ml. on
      at least 2 occasions. Prostate biopsy was performed following 167 procedures and
      was positive after 64 (38%). CONCLUSIONS: Cryosurgery was associated with
      favorable serum PSA characteristics in 49% of patients 3 years after treatment.
      Undetectable PSA nadir and pretreatment PSA 10 ng./ml. or less were associated
      with a favorable outcome, with a biochemical disease-free survival of 77% and 61%
      3 years after treatment, respectively.

PMID- 10411052
TI  - Potency, continence and complication rates in 1,870 consecutive radical
      retropubic prostatectomies.
AB  - PURPOSE: We update results in a series of consecutive patients treated with
      anatomic radical retropubic prostatectomy regarding recovery of erections,
      urinary continence and postoperative complications. MATERIALS AND METHODS: One
      surgeon performed anatomic radical retropubic prostatectomy on 1,870 men, using
      the nerve sparing modification when feasible. We evaluated recovery of erections
      and urinary continence in men followed for a minimum of 18 months. Patients who
      were not reliably potent before surgery, did not undergo a nerve sparing
      procedure, or received hormonal therapy or postoperative adjuvant radiotherapy
      were excluded from the analysis of potency rates but not of continence rates.
      Other postoperative complications were evaluated for the entire patient
      population. RESULTS: Recovery of erections occurred in 68% of preoperatively
      potent men treated with bilateral (543 of 798) and 47% treated with unilateral
      (28 of 60) nerve sparing surgery. Recovery of erections was more likely with
      bilateral than with unilateral nerve sparing surgery in patients less than 70
      years old (71 versus 48%, p<0.001) compared with patients with age 70 years old
      or older (48 versus 40%, p = 0.6). Recovery of urinary continence occurred in 92%
      (1,223 of 1,325 men) and was associated with younger age (p<0.0001) but not with
      tumor stage (p = 0.2) or nerve sparing surgery (p = 0.3). Postoperative
      complications occurred in 10% of patients overall and were associated with older
      age (p<0.002) but the incidence declined significantly with increasing experience
      of the surgeon (p<0.0001). There was no operative mortality. CONCLUSIONS:
      Anatomic radical retropubic prostatectomy with the nerve sparing modification can
      be performed with favorable results in preserving potency and urinary continence.
      Better results are achieved in young men with organ confined cancer. Other
      complications can be reduced with increasing surgeon experience.

PMID- 10411053
TI  - Statistical considerations when assessing outcomes following treatment for
      prostate cancer.
AB  - PURPOSE: We explore the impact of study designs, biases, outcome variables and
      statistical techniques when interpreting studies concerning prostate cancer
      management. MATERIALS AND METHODS: Examples from the current literature and a
      recently assembled population based sample of patients 55 to 75 years old at
      diagnosis identified by the Connecticut Tumor Registry as having newly diagnosed
      localized prostate cancer between 1971 and 1984 are provided to assist the reader
      to understand the principles discussed. RESULTS: Most reports concerning prostate
      cancer outcomes suffer from obvious and subtle biases that confound the reader's
      understanding of the impact of different treatment alternatives. CONCLUSIONS: By
      remaining vigilant to these confounding issues, clinicians and patients can gain
      greater insights into the medical literature and can make individual
      interpretations concerning the potential impact of treatment interventions on men
      with prostate cancer.

PMID- 10411054
TI  - An update of combined modality therapy for patients with muscle invading bladder
      cancer using selective bladder preservation or cystectomy.
AB  - PURPOSE: We update the results of tri-modality treatment for patients with muscle
      invading bladder tumors with selection for bladder preservation based on tumor
      response to induction therapy. MATERIAL AND METHODS: We reviewed the literature
      on modern tri-modality bladder preserving approaches using transurethral
      resection, radiation and concurrent chemotherapy followed by either bladder
      conservation with careful surveillance for complete responding patients or prompt
      cystectomy in those whose tumors persist after induction therapy. RESULTS: The
      published experiences from 3 centers and 2 prospective trials done by the
      Radiation Therapy Oncology Group were evaluated for 5-year overall survival of
      patients selected for bladder preservation or prompt cystectomy (49 to 63%) and
      for those with a conserved bladder (38 to 43%). The overall 5-year survival rates
      were comparable to other series of immediate cystectomy based approaches in
      patients of similar age and presenting with tumors of similar clinical stage. Of
      patients treated with the bladder preserving approach 20 to 30% cured of muscle
      invading cancer will subsequently have a new superficial tumor. The superficial
      tumors have responded well to intravesical drug therapy. Modern bladder
      preserving treatments usually result in a well functioning bladder without
      incontinence or significant hematuria. However, concurrent systemic chemotherapy
      and radiation have the potential for acute morbidity. Presently the ideal
      candidate for bladder preservation has primary clinical stage T2 tumor, no
      associated ureteral obstruction, visibly complete transurethral resection and
      complete response after induction chemoradiation based on endoscopic evaluation
      including re-biopsy and cytology. CONCLUSIONS: It is recommended that tri
      modality treatment be administered by dedicated multimodality teams. In this
      country this approach to treatment is available at many of the institutions
      participating in the Radiation Therapy Oncology Group study. This treatment may
      be considered a reasonable alternative in patients who are deemed medically unfit
      for cystectomy and for those who are seeking an alternative to radical
      cystectomy.

PMID- 10411055
TI  - Against bladder sparing: surgery.
AB  - PURPOSE: The efficacy of bladder preservation strategies for invasive cancer of
      the bladder are evaluated. MATERIALS AND METHODS: The literature was reviewed
      specifically regarding the relative success of bladder preservation therapy
      compared with total cystectomy. RESULTS: Bladder preservation strategies
      currently available are substantially inferior to cystectomy for elimination of
      the existing cancer and prevention of pelvic recurrence (soft tissue after
      cystectomy or in the bladder after bladder preservation). The best bladder
      preservation protocols eliminate cancer from the bladder at first evaluation in
      10 to 20% and 50 to 80% of patients with T3b and T2 cancers, respectively, while
      later recurrences in the bladder are seen in 40 to 60%. Cystectomy provides a
      local failure rate of 10 to 25% for T2 and T3b disease, respectively. In
      addition, bladder reconstruction with a neobladder after cystectomy minimizes
      deterioration of quality of life which is the motivating rationale for bladder
      preservation. CONCLUSIONS: While continuing clinical trials of new strategies for
      bladder preservation are necessary and laudable, clinical practice currently
      affirms cystectomy, possibly with neobladder formation, as optimal therapy in
      appropriate patients.

PMID- 10411056
TI  - Hemostatic control with flexible compression tape used during partial nephrectomy
      and organ salvage.
AB  - PURPOSE: A secure method of achieving hemostasis during partial nephrectomy to
      accomplish guillotine polar amputation is described. MATERIALS AND METHODS: A
      common hardware item, the so-called cable tie, proved to be useful during removal
      of a block of neoplastic renal tissue from the lower central pole of a unilateral
      kidney. RESULTS: Complete hemostasis and resection of the renal parenchyma were
      obtained with ease and minimal expense. CONCLUSIONS: The use of a flexible
      plastic compression tape has proved valuable to adhere to organ contours closely,
      maximally control bleeding and marking a line of incision during amputation of a
      portion of the renal substance. This device may prove useful for analogous
      surgical purposes with other vascular organs.

PMID- 10411057
TI  - The supine stress test: a simple method to detect intrinsic urethral sphincter
      dysfunction.
AB  - PURPOSE: A new clinical test for intrinsic urethral sphincter dysfunction is
      proposed and compared to abdominal leak point pressure determination by video
      urodynamics. MATERIALS AND METHODS: Patients were prospectively included in the
      study if they had stress urinary incontinence symptoms and were to undergo video
      urodynamic testing. Patients with urinary tract infection, cystocele, rectocele
      and vaginal vault prolapse were excluded from study. A supine stress test using
      cough and Valsalva's maneuvers was performed after bladder filling to 200 ml.
      with sterile normal saline solution by gravity. Efflux of the bladder solution
      from the meatus coinciding with the cough or Valsalva maneuver indicated a
      positive clinical test. A video urodynamic study, including abdominal leak point
      pressure, was performed. Intrinsic urethral sphincter dysfunction was diagnosed
      if abdominal leak point pressure was less than 100 cm. water. Test indexes were
      calculated based on the results of the supine stress test and the abdominal leak
      point pressure measurements. RESULTS: Results were positive in 30 of 41
      consecutive patients and negative in 11. Using abdominal leak point pressure
      measurement, the supine stress test had 93.5% sensitivity, 90.0% specificity,
      96.7% positive predictive value and 81.8% negative predictive value for detecting
      intrinsic urethral sphincter dysfunction. CONCLUSIONS: The supine stress test is
      easy, quick and inexpensive, and a positive test is a reliable predictor of
      intrinsic urethral sphincter dysfunction. A negative test is highly correlated
      with the absence of intrinsic urethral sphincter dysfunction during video
      urodynamic testing. This test is more reliable in diagnosing intrinsic urethral
      sphincter dysfunction than other nonurodynamic tests reported in the literature.
      The supine stress test can be a useful supplement to cotton swab testing for
      urethral hypermobility in determining the appropriate management for stress
      urinary incontinence.

PMID- 10411058
TI  - Efficacy and user acceptability of the urethral occlusive device in women with
      urinary incontinence.
AB  - PURPOSE: We determine the efficacy and user acceptability of the urethral
      occlusive device (FemAssist) for incontinence for 1 month and identify factors
      that may predict successful use of the device. MATERIALS AND METHODS: Baseline
      and posttreatment outcome measures included a 1-hour pad test, frequency volume
      chart (leakage, voiding and number of pads per 24 hour), visual analog scale for
      incontinence impact and quality of life (Urogenital Distress Inventory). The last
      36 consecutive women also completed a linear analog scale about attitudes toward
      touching the genitalia. RESULTS: The device was offered to 100 consecutive
      incontinent women of whom 3 did not enroll in the study and 57 (57%) completed
      the 1-month trial. Age, incontinence type or severity and attitudes about
      touching the genitalia were not significantly different between dropouts and
      participants. Only 13% of recruits were disinclined to place the device on the
      urethra. Significant reduction of incontinence was observed for all outcome
      measures with the device in situ. Pad testing revealed that 47% of the patients
      became continent and 33% had more than 50% benefit, while 9% had worse leakage.
      Those with severe baseline leakage were equally likely to respond as those with
      mild or moderate pad test loss. Women with stress, urge or mixed incontinence
      appeared to respond equally well. CONCLUSIONS: The urethral occlusive device
      provides a further nonsurgical treatment option which is useful for a range of
      incontinence types.

PMID- 10411059
TI  - Dynamic suburethral suspension with pedicled external oblique aponeurosis in the
      management of female urinary incontinence.
AB  - PURPOSE: Despite excellent postoperative continence with pubovaginal sling
      procedures, the resultant morbidities of de novo urgency and urinary obstruction
      due to sling tension remain valid concerns. The feasibility and outcome of
      dynamic suburethral suspension using bilateral strips of external oblique
      aponeurosis left attached medially to the anterior rectus sheath and joined
      beneath the urethra under no tension were determined. MATERIALS AND METHODS:
      Between May 1995 and April 1998, 25 women with stress urinary incontinence were
      evaluated and underwent a dynamic suburethral suspension procedure. All patients
      were followed annually with a 10-point questionnaire by an independent registered
      nurse who analyzed the results, complications and satisfaction outcome. RESULTS:
      At a mean followup of 26 months all patients (100%) were cured of stress
      incontinence. Associated urge incontinence due to detrusor overactivity persisted
      in 3 patients postoperatively and, thus, the overall postoperative cure/dry rate
      was 88% for the study group. Of the 18 patients with preoperative urgency 12
      (66%) were cured postoperatively. De novo urgency developed in 1 patient after
      surgery. No patient had prolonged urinary retention. Overall 92% of the patients
      were satisfied with the outcome of surgery. CONCLUSIONS: This dynamic suburethral
      suspension procedure cured stress incontinence in the majority of patients with
      no resultant urinary obstruction. The mechanism of action is believed to work by
      providing a viable suburethral "backboard" of support and by dynamic lifting of
      the proximal urethra cradled by the fascial loop precisely at the time of
      abdominal strain. Pronounced urge incontinence due to detrusor overactivity is
      unlikely to benefit from suspension procedures.

PMID- 10411060
TI  - Repeat noninvasive bladder pressure measurements with an external catheter.
AB  - PURPOSE: Previously it has been shown that an objective diagnosis of infravesical
      obstruction can be made by combining the maximum flow rate and isovolumetric
      bladder pressure. We evaluate a noninvasive method to measure isovolumetric
      bladder pressure to help develop a noninvasive modality for diagnosing
      obstruction. MATERIALS AND METHODS: An external catheter consisting of an
      incontinence condom, tube and pressure transducer was used. Flow rate through the
      catheter was remotely interrupted to measure the bladder pressure in the condom.
      Two series of measurements were done in 11 healthy male volunteers. In the first
      series we determined whether voiding was affected after flow rate interruption.
      In the second series we analyzed repeat pressure measurements of 1 voiding to
      determine whether maximum isovolumetric pressure depended on bladder volume.
      RESULTS: Flow rate was unaffected after interruption for pressure measurement.
      Repeat measurements of isovolumetric bladder pressure demonstrated that the
      pressure depended significantly on bladder volume. Average maximum isovolumetric
      pressure was 12.2 kPa. at a bladder volume of 251 ml. CONCLUSIONS: As no
      inhibition of voiding was noted after a single pressure measurement, repeat
      noninvasive measurements can be made on voiding. With repeat measurements the
      dependence of isovolumetric bladder pressure on bladder volume can be considered
      to obtain a reliable estimate of pressure as a basis for a noninvasive diagnosis
      of obstruction.

PMID- 10411061
TI  - Successful living related kidney transplantation despite renal angiomyolipoma in
      situ.

PMID- 10411062
TI  - An unusual case of multilocular cystic nephroma with prominent renal pelvis
      involvement treated with nephron sparing techniques.

PMID- 10411063
TI  - Simultaneous bilateral perirenal hematomas developing spontaneously in a patient
      with polyarteritis nodosa.

PMID- 10411064
TI  - Renal lymphangioma.

PMID- 10411065
TI  - Port site metastasis after laparoscopic nephrectomy: unsuspected transitional
      cell carcinoma within a tuberculous atrophic kidney.

PMID- 10411066
TI  - Scrotal herniation of the bladder secondary to prostate enlargement.

PMID- 10411067
TI  - Adenocarcinoma of an augmented bladder 25 years after ileocecocystoplasty and 6
      years after renal transplantation.

PMID- 10411068
TI  - Phaeohyphomycosis of the epididymis caused by Exophiala jeanselmei.

PMID- 10411069
TI  - Flutamide photosensitivity.

PMID- 10411071
TI  - Primary lymphoma of the prostate with features of low grade B-cell lymphoma of
      mucosa associated lymphoid tissue: a rare cause of urinary obstruction.

PMID- 10411070
TI  - CAG repeats in the androgen receptor: a case of spinal and bulbar muscular
      atrophy associated with prostate cancer.

PMID- 10411072
TI  - Laparoscopic excision of seminal vesicle cysts.

PMID- 10411073
TI  - Re: Is stenting following ureteroscopy for removal of distal ureteral calculi
      necessary?

PMID- 10411074
TI  - Re: Epidemiology of interstitial cystitis: a population based study.

PMID- 10411075
TI  - Re: NMP22 is a sensitive, cost-effective test in patients at risk for bladder
      cancer.

PMID- 10411076
TI  - Re: Cytokeratin 20: a new marker for early detection of bladder cell carcinoma.

PMID- 10411077
TI  - Re: Free and complexed prostate specific antigen in the differentiation of benign
      prostatic hyperplasia and prostate cancer: studies in serum and plasma samples.

PMID- 10411078
TI  - Neural innervation of the newborn exstrophic bladder: an immunohistochemical
      study.
AB  - PURPOSE: Continence in bladder exstrophy is not always easy to attain. Some
      patients have a small noncontractile bladder while in others an adequate capacity
      bladder may not contract normally. Innervation of the detrusor determines its
      ability to contract. The exstrophic bladder during organogenesis does not store
      urine. Therefore, its requirements for contraction are limited and its
      innervation would potentially reflect this difference in function. The
      availability of specific immunostains allows better differentiation of the neural
      elements in tissue specimens. Our study focuses on myelinated nerves innervating
      the newborn exstrophic detrusor. MATERIALS AND METHODS: Biopsies were obtained
      from the anterior wall of 10 newborn exstrophic bladders at the time of initial
      closure and compared to 10 newborn controls. Patient age at bladder closure
      ranged from 1 to 90 days (mean 22). Specimens were formalin fixed and paraffin
      embedded. Then 4 micro. thick sections were stained with S100, an immunostain
      that stains neural crest elements including Schwann's elements (myelinated nerve
      fibers). The entire tissue section was examined. Microscopic fields were
      sequentially examined with a morphometric system comprising a microscope, video
      camera and personal computer with a video frame grabber. The output image was
      displayed on a second monitor and the nerves in each field and numbers of fields
      in each section were counted. To be considered, fields had to have greater than
      75% tissue coverage. The average number of nerves per field was compared between
      the exstrophic bladders and normal controls. RESULTS: The average number of
      myelinated nerves per field in the newborn exstrophic bladders (0.13 per field)
      was significantly reduced compared to normal controls (1.25 per field) and
      statistically significant (p<0.001). This reduction in nerve fibers appeared to
      be due to lack of smaller fibers with preservation of larger fibers. There was no
      difference in innervation in cases closed at birth compared to those closed after
      month 1 of life. CONCLUSIONS: The newborn exstrophic bladder has fewer myelinated
      nerve fibers than normal controls primarily due to reduction in the smaller
      fibers which may represent a maturational delay in the development of the
      exstrophic bladder. Another possible explanation may be degeneration of the
      fibers due to lack of bladder contraction but no indication of nerve degeneration
      was evident in our study. Followup studies of patients at various stages of
      reconstruction will determine the evolution of neural innervation in the
      exstrophic bladder.

PMID- 10411080
TI  - Rectovaginoplasty for vaginal atresia with anorectal malformation.

PMID- 10411079
TI  - Immunohistochemical localization of transforming growth factor-alpha and
      transforming growth factor-beta during early human fetal prostate development.
AB  - PURPOSE: We investigated the role of peptide growth factors and androgens in the
      developing human prostate. MATERIALS AND METHODS: We performed
      immunohistochemical staining of prostate tissue sections from human fetuses 9.5,
      11.5, 13, 16.5, 18 and 20 weeks in gestation. RESULTS: The temporal and spatial
      expression of these growth factors was related to the gestational androgen surge.
      Before the androgen surge (9.5 to 11.5 weeks) transforming growth factor (TGF)
      alpha, TGF-beta1 and TGF-beta3 but not TGF-beta2 were present in the mesenchyme.
      The epithelium exhibited no detectable staining for any of the growth factors.
      During the androgen peak (13 to 16.5 weeks) TGF-beta1 decreased and TGF-beta2
      increased in the mesenchyme, and TGF-alpha, TGF-beta1 and TGF-beta3 increased in
      the epithelium. With declining androgen levels TGF-alpha, TGF-beta2 and TGF-beta3
      remained unchanged but TGF-beta1 increased in the mesenchyme with no change in
      the tested peptide growth factor levels in the epithelium. CONCLUSIONS: These
      data suggest that androgens regulate the differential expression of TGF-alpha and
      TGF-beta, and support a role for peptide growth factors as the direct mediators
      of androgen action on the mesenchymal and epithelial interactions responsible for
      prostate development.

PMID- 10411081
TI  - Child sexual abuse: what the urologist needs to know.
AB  - PURPOSE: We define what the urologist needs to know regarding child sexual abuse.
      MATERIALS AND METHODS: Based on our experience in treating numerous child victims
      of sexual assault and a review of the contemporary literature, the data
      concerning child sexual abuse incidence, risk factors, clinical presentation,
      child interview, physical examination and management were analyzed. RESULTS: It
      is estimated that at least 1 in 4 girls and 1 in 10 boys will suffer
      victimization by age 18 years. There are no predicting socioeconomic factors. In
      legally proved cases of child sexual abuse the majority of victims have no
      diagnostic physical findings. Examination findings change depending on the
      position of the child, degree of relaxation, amount of labial traction and time
      to perform the evaluation. Findings that are consistent but not independently
      diagnostic of abuse include chafing, abrasions or bruising of inner thighs or
      genitalia, scarring, tears or distortion of the hymen, a decreased amount of or
      absent hymenal tissue, scarring of the fossa navicularis, injury to or scarring
      of the posterior fourchette/posterior commissure and scarring or tears of the
      labia minora. In all 50 states physicians are mandated by law to report to child
      protection services whenever they suspect that a child has been sexually abused.
      CONCLUSIONS: The urologist must routinely examine the anogenital area of children
      during routine urethral evaluation and include child sexual abuse as part of the
      routine urological history.

PMID- 10411082
TI  - Fetal genital anatomy reconstructive implications.
AB  - PURPOSE: Genital anomalies are not typically diagnosed and/or treated in utero.
      Recent reports have focused on the prenatal treatment of congenital adrenal
      hyperplasia. The normal male and female genitalia anatomy is reviewed with an
      emphasis on reconstructive implications. MATERIALS AND METHODS: Normal fetal
      genital anatomy was analyzed by serial immunohistochemical staining and 3
      dimensional computer reconstruction. RESULTS: The neuroanatomy was analogous in
      male and female patients, revealing an extensive network of nerves not only at
      the 11 and 1 o'clock position, but completely surrounding the ventral aspect of
      erectile bodies. The 12 o'clock position was notable for a lack of nerves which
      has implications in the design of penile straightening procedures. Ultrastructure
      of the female corporeal bodies is similar to the male counterpart. Evaluation of
      a fetal specimen with hypospadias revealed a similar anatomy to the normal penis
      except at the area of deficient urethral spongiosum. CONCLUSIONS: Attention to
      anatomical detail will improve surgical techniques for reconstruction in patients
      with penile curvature and masculinization of the external genitalia.

PMID- 10411083
TI  - The sonographic appearance of normal and abnormal fetal genitalia.
AB  - PURPOSE: Prenatal sonography has evolved through advancements in imaging
      technology and observer experience. This review focuses on our current knowledge
      of the sonographic appearance of normal and abnormal fetal genitalia. MATERIALS
      AND METHODS: A MEDLINE computerized reference and manual bibliography reviews
      were performed to find pertinent peer-reviewed articles on the sonographic
      appearance of normal and abnormal fetal genitalia. RESULTS: The sonographic
      appearance of the normal fetal genitalia has been defined. The male phallus can
      be visualized as early as 10 to 11 weeks of gestation, while testicular descent
      is not seen before 26 weeks. Hydroceles are commonly detected. In the female
      subject the labia majora and labia minora are visible by 15 weeks.
      Hydrometrocolpos due to uterovaginal anomalies can be seen as early as 26 weeks.
      CONCLUSIONS: Advances in prenatal sonography enable one to diagnose late first
      trimester gender. Sonography of the fetal genitalia complements fetal sex
      determination in cases of intersex, X-linked disorders or gender specific fetal
      anomalies, and is an important tool with increasing indications in prenatal
      medicine.

PMID- 10411084
TI  - Prenatal treatment of congenital adrenal hyperplasia.
AB  - PURPOSE: The relevant aspects of congenital adrenal hyperplasia due to 21
      hydroxylase deficiency (CAH-21), the single most common cause of female
      pseudohermaphroditism, are reviewed to understand the benefits and risks of
      prenatal intervention. Timely diagnosis is important, since infants with this
      condition may suffer adrenal insufficiency which carries a high mortality rate.
      MATERIALS AND METHODS: Infants suspected of having CAH-21 should undergo
      radioimmunoassay of serum 17-hydroxyprogesterone, karyotype and pelvic/abdominal
      ultrasound at a minimum. Treatment with glucocorticoid and mineralocorticoid
      supplements should be instituted immediately. Surgical correction of
      genitourinary tract anomalies should be performed by a pediatric urologist
      experienced in this area. RESULTS: Proper postnatal medical and surgical
      management of CAH-21 will allow the patient to thrive. Many women with classic
      CAH-21 have now conceived and delivered healthy children. Prenatal diagnosis, now
      most often done by molecular genetic techniques, is feasible and often done in
      conjunction with prenatal treatment of the at risk mother. CONCLUSIONS: CAH-21
      has been well characterized. The benefit of prenatal therapy is to ameliorate
      potentially genital ambiguity in affected female subjects. The risks of
      unnecessarily treating unaffected pregnancies, which now seem small, may not be
      fully elucidated for many years. Prenatal treatment must be done under careful,
      centralized and ideally long-term medical supervision.

PMID- 10411085
TI  - Dexamethasone treatment of congenital adrenal hyperplasia in utero: an
      experimental therapy of unproven safety.
AB  - Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is
      a common cause of genital virilization in female infants resulting from
      inappropriate fetal adrenal androgen secretion. Some investigators have advocated
      treating pregnant women who are at risk for carrying a CAH fetus with
      dexamethasone to suppress fetal adrenal androgen synthesis. Experience to date
      shows that this treatment can be effective in ameliorating the genital
      virilization in female fetuses. However, the doses used are supraphysiological,
      the mechanism of dexamethasone action in the fetus is unclear and no long-term
      followup studies have been done. To be effective the treatment would need to be
      started by week 6 of gestation but the genetic diagnosis cannot be made until
      week 12. If the mother has had a previous CAH child, only 1 in 4 pregnancies will
      be affected and only the female fetuses stand to benefit from treatment, thus, 7
      of 8 fetuses will be treated needlessly. In view of these and other concerns, the
      prenatal treatment of CAH remains an experimental therapy and, hence, must only
      be done with fully informed consent in controlled prospective trials approved by
      human experimentation committees at centers that see enough of these patients to
      collect meaningful data.

PMID- 10411086
TI  - Optimisation of the formation and distribution of protoporphyrin IX in the
      urothelium: an in vitro approach.
AB  - PURPOSE: To optimize conditions for photodynamic detection (PDD) and photodynamic
      therapy (PDT) of bladder carcinoma, urothelial accumulation of protoporphyrin IX
      (PpIX) and conditions leading to cell photodestruction were studied. MATERIALS
      AND METHODS: Porcine and human bladder mucosae were superfused with derivatives
      of 5-aminolevulinic acid (ALA). PpIX accumulation and distribution across the
      mucosa was studied by microspectrofluorometry. Cell viability and structural
      integrity were assessed by using vital dyes and microscopy. RESULTS: ALA esters,
      especially hexyl-ALA, accelerated and regularized urothelial PpIX accumulation
      and allowed for necrosis upon illumination. CONCLUSIONS: hexyl-ALA used at
      micromolar concentrations is the most efficient PpIX precursor for PDD and PDT.

PMID- 10411087
TI  - In situ detection of lipid peroxidation by-products as markers of renal ischemia
      injuries in rat kidneys.
AB  - PURPOSE: Lipid peroxidation is an autocatalytic mechanism leading to oxidative
      destruction of cellular membranes. In renal transplantation, this mechanism is
      triggered by ischemia/reperfusion and may be of relevance in graft failure.
      MATERIALS AND METHODS: Using specific antibodies directed against malondialdehyde
      (MDA) and 4-hydroxynonenal (HNE) adducts, major aldehydic metabolites of lipid
      peroxidation, we investigated, in situ, by means of an immunohistochemical
      procedure, the occurrence of lipid peroxidation during different warm ischemic
      periods of 0, 15, 30, 45 and 60 minutes in rat kidneys prior to reperfusion. The
      same experiments included followup of the rats after nephrectomy and reperfusion
      for 10 days. RESULTS: We observed superficial and deep cortex immunostaining with
      both antibodies against MDA and HNE after 30 minutes of warm ischemia. This
      immunostaining was observed in the absence of any histological lesions, as
      assessed by routine staining. After 45 and 60 minutes of warm ischemia, lipid
      peroxidation byproducts were detected both in the cortex and in the medulla,
      which is associated with 33% and 66% of rat deaths respectively. CONCLUSIONS:
      This study confirms the involvement of the lipid peroxidation process in kidney
      damage during anoxia before reperfusion, and its extension to the whole organ.
      Lipid peroxidation byproducts were detectable in warm ischemic kidney, and the
      presence of medulla immunostaining was associated with the animals' death. Lipid
      peroxidation immunostaining might thus be useful as a sensitive tool to detect
      ischemic damage after warm ischemia prior to reperfusion, as well as in the
      decision to carry out kidney transplantation in humans.

PMID- 10411088
TI  - Alterations in the nitric oxide synthase binding sites and non-adrenergic, non
      cholinergic mediated smooth muscle relaxation in the diabetic rabbit bladder
      outlet: possible relevance to the pathogenesis of diabetic cystopathy.
AB  - PURPOSE: To investigate the effect of diabetes mellitus (DM) on the density and
      distribution of nitric oxide synthase (NOS) and the smooth muscle responses to
      non-adrenergic, non-cholinergic (NANC) nerve stimulation and exogenous nitric
      oxide (NO) in the rabbit lower urinary tract. MATERIALS AND METHODS: Transverse
      sections of detrusor, bladder neck and urethra, from control and six months
      alloxan-induced DM New Zealand White rabbits were incubated with a radioligand
      for NOS ([3H]-L-N(G)-nitroarginine). Densitometric analysis was performed on the
      autoradiographs. NADPH diaphorase histochemistry was also used as a marker for
      NOS activity. Responses to NANC nerve stimulation (5 to 20 Hz) and to NO (10(-6)
      to 3x10(-4) M.) on smooth muscle strips from detrusor, bladder neck and urethra
      were measured in organ baths. RESULTS: NOS binding sites were significantly
      (p<0.03) more dense in the bladder neck than in the detrusor in both DM and
      control groups. In DM bladder neck, NOS binding sites were significantly (p<0.04)
      increased compared with the controls. NADPH diaphorase activity appeared markedly
      increased in the detrusor, bladder neck and urethra of DM animals compared with
      controls. The mean IC50 for exogenous NO in control versus DM were not
      statistically different in the bladder neck (1.03x10(-4) M versus 9.8x10(-5) M)
      and urethra (8.1x10(-5) M versus 8.8x10(-5) M), but the relaxations to 5x10(-6) M
      of NO were significantly impaired (p<0.04) in the DM urethral smooth muscle. NANC
      nerve-mediated relaxations were significantly impaired (p<0.001) in the DM
      urethral smooth muscle. CONCLUSIONS: Alterations of both the NOS binding sites
      and functional responses to NANC nerve stimulation suggest that NO may have a
      pathophysiological role in the urinary bladder dysfunction associated with DM.

PMID- 10411089
TI  - In vivo description of dendritic cells in human renal cell carcinoma.
AB  - PURPOSE: Dendritic cells (DCs) are efficient and effective antigen-presenting
      cells that play a major role in initiating the primary immune response. They are
      the most potent stimulators of T-cell activation and would thus be expected to be
      of great importance in the antitumoral immune response. Although DC phenotype and
      function have been described under in vitro conditions, their in vivo
      characteristics are less well detailed. Human renal cell carcinoma (RCC) is an
      excellent model to explore tumor infiltrating dendritic cells (TiDCs) because of
      rare clinical spontaneous regressions and the association of high numbers of
      tumor infiltrating lymphocytes (TiLs), suggesting a strong immune response.
      MATERIALS AND METHODS: We determined the in situ phenotype of mature CD83+ TiDCs
      using monoclonal antibodies to known activation molecules (CD86 [B7.2], CD80
      [B7.1], CD40, CD54, CD1a and HLA-DR). Seventeen primary RCCs, representing four
      distinct histologies, were evaluated using double-staining immunohistochemical
      techniques and light microscopy. RESULTS: CD83+ TiDCs were found in all tumors.
      Expression of CD40 correlated with expression of CD1a on CD83+ TiDCs. Expression
      of CD54 (ICAM-1) correlated with a lower expression of CD86 (B7.2) as well as a
      decrease in CD3+ and CD8+ TiLs. CONCLUSIONS: These data suggest a de novo lipid
      or sugar-based immunogenic antigen presentation by TiDCs. Also, the data support
      an impaired antigen-presenting capability for CD54+ TiDCs based on the decreased
      coexpression of CD86 (B7.2) and the decrease of associated CD8+ TiLs.

PMID- 10411091
TI  - Contractions in human detrusor smooth muscle induced by hypo-osmolar solutions.
AB  - PURPOSE: The aim of this study was to investigate stretch activated channels in
      human detrusor using hypo-osmolar solutions to produce cell deformation. Stretch
      activated channels could provide another mechanism by which detrusor myocytes may
      be coupled. MATERIALS AND METHODS: Human detrusor removed at surgery was
      dissected into strips and also enzymatically digested and cultured. Strips (5x1x1
      mm.) were mounted in an organ bath and perfused with gassed Tyrode's. Hypo
      osmolar solutions were made by removal of NaCl. Gadolinium (Gd3+), a blocker of
      stretch activated channels (SACs), and diltiazem, an L-type Ca2+ channel
      antagonist were used at 10 microM concentrations. Mean data +/- S.E.M. are
      expressed as a percentage of maximal tension produced by 1 microM carbachol for
      each patient. Enzymatically disaggregated, human detrusor was cultured in flasks,
      passaged and placed on glass coverslips. Once confluent the cells were incubated
      with the Ca2+ sensitive fluorochrome Fura-2AM. Coverslips were placed in a bath
      on the stage of EPI-fluorescence microscope and solutions were perfused through
      the bath (5 ml. per minute, 35C, pH 7.4). Changes in fluorescence emission ratio
      (proportional to changes in cytosolic Ca2+) were measured. RESULTS: Hypo-osmolar
      solutions produced a tension increase in the strips and a Ca2+ influx in the
      cells. In the strips in paired experiments Gd3+ and diltiazem significantly
      reduced the response to hypo-osmolar solution (87%+/-16% v. 51%+/-12.5%, p =
      0.003, n = 10 for Gd3+), and (69%+/-11% v. 37%+/-9%, p = 0.001, n = 9 for
      diltiazem). In Ca2+ free solution responses were significantly reduced (65%+/-10%
      v. 21%+/-8%, p = 0.001, n = 9). In the cells in paired experiments, 10 microM
      Gd3+ significantly reduced the elevation of cytosolic Ca2+ in response to hypo
      osmolar solutions (median 0 v. 0.38 (62 cells, n = 7 bladders)), as did Ca2+ free
      hypo-osmolar solution (median 0 v. 0.44 (46 cells, n = 7)). 10 microM diltiazem
      (L-type Ca2+ channel antagonist) did not influence the response to hypo-osmolar
      solution (p = 0.14, median 0.5 v. 0.54 (31 cells, n = 4)). CONCLUSIONS: Hypo
      osmolar solutions produced a tension increase in human detrusor that appears to
      be dependent on upon influx of Ca2+ through stretch activated channels (SACs),
      influx of Ca2+ through L-type Ca2+ channels and also on release of intracellular
      Ca2+.

PMID- 10411090
TI  - Reduced expression of beta-subunit of Na,K-ATPase in human clear-cell renal cell
      carcinoma.
AB  - PURPOSE: Multiple subtypes of renal cancer have been identified. Clear-cell renal
      cell carcinoma (RCC) is the most common subtype of RCC and one of the more
      aggressive. The goal of this study was to investigate in RCC the levels of Na,K
      ATPase, an abundant enzyme in the kidney which is crucial for various kidney
      functions. Na,K-ATPase is a heterodimer consisting of a catalytic a-subunit and a
      glycosylated beta-subunit whose function is still not well-defined. MATERIALS AND
      METHODS: Fourteen clear-cell RCC specimens were studied. The levels of the Na,K
      ATPase alpha and beta-subunits in normal kidney and RCC tissues were determined
      by immunoblot analysis. The localization of the alpha and beta-subunits was
      studied by immunofluorescence and laser scanning confocal microscopy. Na,K-ATPase
      activity was determined using a coupled-enzyme spectrophotometric assay. RESULTS:
      In normal kidney, the cells demonstrate an epithelial morphology with distinct
      basolateral plasma membrane localization of the alpha and beta-subunits.
      Conversely, the cells of the clear-cell RCC have lost their epithelial phenotype
      and the alpha and beta-subunits show a diffuse intracellular staining. Clear-cell
      RCC tumor cell lysates showed a consistent 95.6+/-2.8% (mean +/- SD) reduction in
      protein levels of beta-subunit relative to the levels in normal kidney. The alpha
      subunit level in RCC lysates was generally near or above the levels relative to
      normal kidney. The reduced beta-subunit expression was accompanied by a
      significant reduction in the Na,K-ATPase activity in RCC membranes. CONCLUSIONS:
      These results suggest that the beta-subunit may regulate the Na,K-ATPase activity
      in vivo. Diminished Na,K-ATPase activity in conjunction with the reduced beta
      subunit level is associated with the clear-cell RCC phenotype.

PMID- 10411092
TI  - Chromosome 16 allelic loss analysis of a large set of microdissected prostate
      carcinomas.
AB  - PURPOSE: To perform loss of heterozygosity (LOH) analysis on chromosome 16 in 102
      highly purified DNA samples isolated from one or more adenocarcinomas, prostatic
      intraepithelial neoplasia (PIN), and matched benign prostatic epithelium from 95
      radical prostatectomy patients. MATERIALS AND METHODS: Specimens were procured by
      microdissection of frozen tissue samples, thus ensuring that highly select pure
      populations of cells were obtained for DNA extraction and LOH analysis. Multiple
      microsatellite markers were used to determine allelic loss on chromosome 16q.
      RESULTS: Overall loss on 16q was seen in 31% of the cancers, and occurred more
      frequently in high stage cancers than low stage cancers. In contrast, allelic
      loss in PIN failed to exceed 6% at any of the loci that were examined.
      CONCLUSIONS: These results suggest that inactivation of a putative tumor
      suppressor gene on 16q may be involved in the progression of some prostate
      cancers.

PMID- 10411093
TI  - FGF7 and FGF2 are increased in benign prostatic hyperplasia and are associated
      with increased proliferation.
AB  - PURPOSE: To determine if overexpression of FGF7 and FGF2 occurs in benign
      prostatic hyperplasia (BPH) and if so, whether such overexpression is correlated
      with increased proliferation of epithelial and/or stromal cells. MATERIALS AND
      METHODS: The FGF7 and FGF2 content of protein extracts of normal peripheral zone,
      normal transition zone and hyperplastic prostatic tissues were determined by
      enzyme-linked immunoabsorption assay. Proliferation of epithelial and stromal
      cells was assessed by immunohistochemistry with anti-Ki67 antibodies on frozen
      sections of the same tissues used for protein extraction. The in vitro effects of
      FGF7 and FGF2 on proliferation were assessed by addition of recombinant growth
      factor to primary cultures of prostatic epithelial and stromal cells. RESULTS: We
      have found that both FGF7 and FGF2 are overexpressed in hyperplastic prostate in
      comparison to normal peripheral and transition zone tissue. FGF7 is a potent
      mitogen for epithelial cells in culture. Consistent with these in vitro effects,
      quantitative analysis of cellular proliferation by Ki67 immunohistochemistry
      revealed a strong correlation of epithelial proliferation with FGF7 content in
      BPH tissue, consistent with a key role for this growth factor in driving the
      abnormal epithelial proliferation in BPH. FGF2 is mitogenic for stromal cells in
      culture and there was a weaker correlation of FGF2 content with increased stromal
      proliferation. CONCLUSION: Overexpression of FGF7 and FGF2 may play an important
      role in the abnormal cellular proliferation seen in benign prostatic hyperplasia.

PMID- 10411094
TI  - Bacillus-Calmette-Guerin (BCG) and 3D tumors: an in vitro model for the study of
      adhesion and invasion.
AB  - PURPOSE: To study adhesion, penetration and internalization of BCG and effector
      cells to and into three-dimensional in vitro cell aggregates from benign and
      malignant urothelial origin mimicking small in vitro tumors. MATERIALS AND
      METHODS: Multicellular spheroids (MCS) were generated by "liquid-overlay"
      technique. Adhesion and penetration of viable FITC-labelled BCG into MCS from
      urothelial cancer cell lines and normal urothelial cells was studied by electron
      microscopy (TEM) and fluorescence microscopy. Spheroid growth during BCG-co
      incubation was determined by light microscopy. Peripheral blood mononuclear cells
      (PBMC) were stimulated with BCG to generate BCG-activated-killer (BAK) cells. The
      infiltration of these effectors and of lymphokine-activated killer (LAK) cells
      into MCS was examined at different intervals by means of immunohistochemistry.
      The resulting cytotoxicity was judged in a 3H-l-methionine release assay.
      RESULTS: BCG adhered to MCS from tumor cells but not to benign cell MCS.
      Intracellular internalization of the bacteria was detectable in superficial tumor
      cell-layers (1-5) whereas BCG was not found in deeper layers. Proliferation of
      malignant MCS was reduced in the presence of BCG. Benign MCS showed contact
      inhibition growth arrest, which was not altered by BCG. BAK and LAK effector
      cells both infiltrated tumor cell MCS as opposed to unstimulated PBMC. In
      contrast to LAK cells, BAK cells did not infiltrate into benign cell MCS and were
      not cytotoxic towards them. CONCLUSION: With regard to the clinical situation the
      selective adhesion and internalization of BCG to malignant cells might explain
      why BCG has been rarely found in follow-up biopsies in tumor free patients. More
      interestingly, the selective adhesion of BCG to and infiltration of BAK effector
      cells into malignant cell spheroids suggests a selective mode of action of BCG.

PMID- 10411095
TI  - Consequences of lithotripter shockwave interaction with gas body contrast agent
      in mouse intestine.
AB  - PURPOSE: Shockwave lithotripsy can involve complications associated with
      hemorrhage and internal bleeding which appear to be due to acoustic cavitation.
      Gas-body-based contrast agents recently developed for diagnostic ultrasound can
      enhance cavitational bioeffects under some conditions. This study examined the
      occurrence and progression of vascular damage in mouse intestine when a contrast
      agent was present during shockwave treatment. MATERIALS AND METHODS: Anesthetized
      hairless mice were injected with Albunex contrast agent or a gas-body-free blank,
      and exposed to sham, 200 or 800 lithotripter shockwaves. RESULTS: Exposure of the
      mouse abdomen to lithotripter shockwaves produced petechiae in the intestinal
      wall and hemorrhage into the lumen. Contrast-agent gas bodies greatly enhanced
      the numbers of petechiae (but not the hemorrhages), relative to the blank agent.
      When evaluation of these effects was delayed for one day, both effects decreased,
      and the gas-body-associated petechiae seemed to disappear. However, survival
      significantly decreased for mice with added gas bodies and shockwave treatment.
      CONCLUSIONS: The presence of a gas-body-based ultrasound contrast agent enhances
      vascular side effects of shockwave lithotripsy. Although there are great
      uncertainties in relating these observations to human clinical conditions, a
      delay in planned treatment might be prudent for patients scheduled for shockwave
      lithotripsy soon after receiving gas-body-based ultrasound contrast agents.

PMID- 10411097
TI  - Characteristic loss of heterozygosity in chromosome 3P and low frequency of
      replication errors in sporadic renal cell carcinoma.
AB  - PURPOSE: A high frequency of genetic loss at 4 loci on chromosome 3p has been
      shown in human sporadic renal cell carcinomas (RCCs), but the relative
      contribution of each locus is not well known, and the involvement of DNA
      replication errors (RERs) in carcinogenesis of RCCs remains unclear. We report
      the simultaneous comparison of genetic loss at the 4 chromosome 3p loci and RERs
      in sporadic RCCs. MATERIALS AND METHODS: DNA was extracted from 33 Japanese
      sporadic RCC samples, and examined for loss of heterozygosity (LOH) and RERs by
      amplification of 14 microsatellite regions. LOH of the von Hippel Lindau (VHL)
      gene was analyzed by a polymerase chain reaction (PCR)-restriction fragment
      length polymorphism (RFLP) method. The target sequences of RER, transforming
      growth factor beta type II receptor (TGFbetaRII) and Bcl-2-associated X protein
      (BAX) genes were amplified and analyzed for mutations by sequencing. RESULTS: LOH
      of the VHL gene was observed in 53.3% of RCCs, a higher frequency than that of
      the 4 regions 3p12-p13 (18.8%), 3p14.2 (17.4%), 3p21 (21.2%) and 3p25-p26 except
      for VHL (31.3%). There were no RERs in 14 microsatellite regions, including the
      mononucleotide (A)10 repeats of the TGFbetaRII gene and (G)8 repeats of the BAX
      gene. CONCLUSION: Japanese sporadic RCCs were characterized by predominant loss
      of VHL gene and low contribution of the other 3 candidate RCC tumor suppressor
      genes. RERs, mostly caused by a defect of DNA mismatch repair, might only rarely
      be involved in the carcinogenesis of sporadic RCCs.

PMID- 10411096
TI  - Immunohistochemical analysis of BCL-2 protein expression in renal cell carcinoma.
AB  - PURPOSE: To investigate the incidence, extent, and distribution of bcl-2 protein
      expression in human renal cell carcinomas. MATERIALS AND METHODS: Using
      immunohistochemical tissue staining techniques, bcl-2 protein expression was
      analyzed in archival nephrectomy specimens removed for renal cell carcinoma or
      trauma and in 3 renal cell carcinoma cell lines. RESULTS: Normal kidneys
      demonstrated bcl-2 immunopositivity primarily within the cytoplasm of distal
      tubule cells. Only rare and minor staining of the proximal tubular cells, thought
      to be the origin of renal cell carcinoma, was noted in histologically normal
      controls and areas adjacent to tumor. In contrast, bcl-2 protein expression was
      demonstrated in 70% of renal cell carcinomas and in all 3 experimental cell
      lines. CONCLUSIONS: Bcl-2 is a proto-oncogene known to regulate apoptosis
      (programmed cell death). Bcl-2 protein is overexpressed in the majority of renal
      cell carcinomas examined. Bcl-2 overexpression may have a role in tumorigenesis
      and may explain the relative resistance of renal cell carcinoma to
      chemotherapeutic agents and to radiation therapy.

PMID- 10411098
TI  - Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder
      cancer treated with selective bladder preservation by combined radiation therapy
      and chemotherapy: initial results of radiation therapy oncology group 89-03.

PMID- 10411099
TI  - Characterization of urinary calculi: in vitro study of "twinkling artifact"
      revealed by color-flow sonography.

PMID- 10411100
TI  - Malignant and other properties of human colon carcinoma cells after suppression
      of sulfomucin production in vitro.
AB  - Although the loss of sulfomucins was known as an indicator of carcinogenesis and
      malignant progression of colonic epithelia, it was not known whether the loss was
      directly related to the malignant behavior of colon carcinoma cells. We have
      studied the biological properties of LS174T human colon carcinoma cells before
      and after suppression of sulfomucin production. Incorporation of [35S]-sulfate
      into high molecular weight mucins decreased after carcinoma cell treatment with
      1.5% dimethylsulfoxide (DMSO) for 8 days. The amounts of sulfomucin determined
      using a sulfomucin-specific monoclonal antibody (mAb 91.9H), in Western blot and
      flowcytometric analyses, also decreased. In addition, the levels of MUC2 and
      MUC5B mucin gene expression measured by RT-PCR were reduced after DMSO-treatment,
      whereas the levels of MUC1, MUC5AC, and MUC6 mucin gene expression were not. The
      DMSO-treated cells were tested in vitro and in vivo for their properties.
      Differences were not detected in their anchorage-independent growth, anchorage
      dependent growth, E-selectin-dependent cell adhesion or sensitivity to
      interleukin (IL)-2-activated lymphocyte cytolysis. When untreated or DMSO-treated
      LS174T cells were injected intrasplenically into nude mice, the treated cells
      lacking certain cell surface sulfomucins formed fewer metastatic colonies in the
      liver. These results suggest that the loss of sulfomucins by colonic epithelial
      cells during progression is not directly related to the enhanced malignant
      behavior.

PMID- 10411101
TI  - Overexpression of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in
      metastatic MDCK cells transformed by v-src.
AB  - This article discusses the transformation of epithelial Madin-Durby canine kidney
      (MDCK) cells with v-src induced expression of membrane-type 1-matrix
      metalloproteinase (MT1-MMP) and metastatic growth in nude mice (Kadono Y et al.,
      Cancer Res 1998; 58: 2240-44). To analyze genes associated with invasive
      phenotype of v-src MDCK cells, mRNA differential display was performed between
      control and the transformed cells. A clone 12', the expression of which was
      clearly up-regulated in the transformed cells, encoded a protein 81% homologous
      to human tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Northern
      hybridization showed that only MT1-MMP expression was enhanced and other matrix
      metalloproteinases (MMPs) were undetectable or rather repressed in the
      transformed cells. Proteolytic activity against type I gelatin was observed in v
      src MDCK cells, which was inhibited only by TIMP-2 but not by TIMP-1. MDCK cells
      stably transfected with the MT1-MMP gene also degraded gelatin, which was
      selectively inhibited by TIMP-2. These results suggest that MT1-MMP, the
      expression of which is induced in v-src MDCK cells, degrades extracellullar
      matrix by itself rather than through the activation of progelatinase A, which in
      turn contributes to the metastasis of the transformed cells.

PMID- 10411102
TI  - The matrix metalloproteinase inhibitor batimastat inhibits angiogenesis in liver
      metastases of B16F1 melanoma cells.
AB  - Matrix metalloproteinases (MMPs) have been shown to contribute functionally to
      tumor metastasis. MMP inhibitors are thus being assessed for clinical utility as
      anti-metastatic therapeutics. Batimastat (BB-94) is a synthetic MMP inhibitor
      that has been shown to inhibit tumor growth and metastasis in mice. Here we
      assessed the ability of batimastat to inhibit liver metastases of murine B16F1
      cells, after injection of cells in mice via mesenteric vein to target the liver.
      We then determined which of the sequential steps in metastasis were affected by
      batimastat, in order to identify its mechanism of action in vivo. Intravital
      videomicroscopy was used to assess the effect on extravasation, and a 'cell
      accounting' procedure was used to determine the effect on initial survival of
      cells. Stereological quantification of functional blood vessels was used to
      determine the effect on tumor vascularity, thereby avoiding problems associated
      with immunohistochemical detection of liver sinusoidal endothelial cells. We
      found that batimastat (50 mg/kg i.p. 5 h prior to and after cell injection, daily
      thereafter) resulted in a 23% reduction in mean diameter of liver metastases
      (equivalent to a 54% reduction in tumor volume), while not reducing the number of
      metastases. Extravasation of cells from the liver circulation was not affected:
      at 8, 24 and 48 h after injection of cells, the same proportion of cells had
      extravasated from treated vs. control mice. Batimastat also did not inhibit early
      survival of cells. However, batimastat-treated mice had a significantly reduced
      percentage vascular volume within liver metastases, indicating inhibition of
      angiogenesis. This study demonstrates in vivo that the mechanism by which
      batimastat limits growth of B16F1 metastases in liver is not by affecting
      extravasation, but by inhibiting angiogenesis within metastases. This finding
      suggests that MMP inhibitors may be appropriate for use in patients with
      metastatic cells that have already extravasated in secondary sites.

PMID- 10411103
TI  - Inhibitory effects of roxithromycin on tumor angiogenesis, growth and metastasis
      of mouse B16 melanoma cells.
AB  - We examined the effects of roxithromycin, a 14-membered ring macrolide
      antibiotic, on tumor angiogenesis, tumor growth and metastasis of mouse B16BL6
      melanoma cells. The inhibitory effect of roxithromycin on angiogenesis using
      mouse dorsal air sac model was dose-dependent, and 100 mg/kg of roxithromycin
      administered intraperitoneally twice a day reduced the dense capillary network
      area to about 20% of the control. Administration of roxithromycin histologically
      reduced the development of microvessels and mononuclear cell infiltration. In
      vivo tumor growth studies demonstrated that intraperitoneal administration of
      roxithromycin at 20 mg/kg/day and 50 mg/kg/day reduced tumor size of B16BL6
      melanoma to about 56% and 33% (experiment 1), 71% and 48% (experiment 2) of that
      in the respective controls. Roxithromycin also significantly inhibited pulmonary
      metastasis of B16BL6 cells in a spontaneous system. The inhibitory activities of
      roxithromycin on angiogenesis, tumor growth and metastasis were compared with
      those of a potent angiogenesis inhibitor, TNP-470. These data demonstrated that
      roxithromycin has potent antiangiogenic and antitumor effects and might have
      possible therapeutic applications.

PMID- 10411104
TI  - Effects of immunization with tumor cells double transfected with interleukin-2
      (IL-2) and interleukin-12 (IL-12) genes on artificial metastasis of colon26 cells
      in BALB/c mice.
AB  - In order to induce tumor specific cytotoxicity, the poorly immunogenic murine
      colon cancer cell colon26 was transfected with murine IL-2 cDNA and/or IL-12 cDNA
      and their anti-tumor effects were investigated. Double transfectants produced
      murine IL-2 and murine IL-12, the same as single transfectants. Intraperitoneal
      administration of double transfectants inhibited pulmonary metastasis of colon26
      inoculated intravenously to a stronger degree than that of single transfectants.
      Splenocytes from mice administered double transfectants intraperitonealy showed
      higher cytolytic activity against colon26 than those from mice administered
      single transfectants, and also showed cytolytic activity against murine B16-BL6
      melanoma. In the NK cell-depleted mice, double transfectants inhibited pulmonary
      metastasis from the control markedly, but could not do completely, the same as in
      the NK cell-reserved mice. The difference of the metastatic colonies between NK
      cell-depleted mice and the control was much greater than that between NK cell
      depleted mice and NK cell-reserved mice. These results suggested that cytotoxic T
      lymphocytes might participate in this anti-tumor effect.

PMID- 10411105
TI  - Matrix-degrading proteinases are shed in membrane vesicles by ovarian cancer
      cells in vivo and in vitro.
AB  - The in vitro release of matrix-degrading proteinases from breast cancer cells is
      associated in part with shed membrane vesicles. To determine whether shed
      vesicles might play a similar role in ovarian cancer cells, we analyzed the
      shedding phenomenon in vivo and in vitro as well as the enzymatic content of
      their vesicles. This is the first time that an immunoelectron microscopical
      analysis revealed membrane vesicles carrying tumor-associated antigen alpha
      Folate Receptor (alpha-FR), circulating in biological fluids (ascites and serum)
      of an ovarian carcinoma patient. These vesicles were trapped in a fiber network
      with characteristic fibrin periodicity. An ovarian cancer cell line (CABA I)
      established from ascitic fluid cells of this patient, grew in Matrigel and formed
      tubular structures suggesting invasive capability. Immunofluorescence analysis
      demonstrated strong cytoplasmic staining of CABA I cells with anti-matrix
      metalloproteinase-9 (MMP-9) and anti-urokinase-type plasminogen activator (uPA)
      antibodies. CABA I cells shed membrane vesicles, which were morphologically
      similar to those identified in vivo, as determined by electron microscopy.
      Gelatin zymography of vesicles isolated both in vivo and in vitro revealed major
      gelatinolytic bands of the MMP family, identified as the zymogen and active forms
      of gelatinase B (MMP-9) and gelatinase A (MMP-2). By casein-plasminogen
      zymography we observed high-molecular weight (HMW)-uPA and plasmin bands.
      Incubation of purified vesicles from CABA I cells with Matrigel led to cleavage
      of Matrigel components. Taken together, our results point to a possible role of
      shed vesicles, both in vivo and in vitro, in proteolysis that mediates invasion
      and spread of ovarian epithelial carcinoma cells.

PMID- 10411106
TI  - Involvement of small GTPases Rho and Rac in the invasion of rat ascites hepatoma
      cells.
AB  - Lysophosphatidic acid (LPA) triggers the invasion of a mesothelial cell monolayer
      by rat ascites hepatoma (MM1) cells. LPA also induces rapid morphological changes
      of MM1 cells, cell surface blebbing and pseudopodia formation. Pseudopodia
      formation is tightly correlated with cellular invasiveness. Clostridium Botulinum
      C3 exoenzyme and genistein abrogated the formation of blebs and pseudopodia
      together with the inhibition of invasion, indicating that GTPase Rho and certain
      tyrosine kinases are involved in both processes. MM1 cells expressing
      constitutively active Rho exhibited the invasion and the formation of blebs and
      pseudopodia in the absence of LPA. In contrast, MM1 cells expressing
      constitutively active Rac were not invasive in the absence of LPA, but were
      invasive in the presence of LPA. Their morphological response to LPA was almost
      the same as that of parental MM1 cells. Expression of dominant negative Rac
      suppressed the invasiveness to approximately 3% of that of parental MM1 cells,
      together with the inhibition of pseudopodia formation. Thus, Rho and Rac are
      cooperatively involved in both the invasion and the related morphological changes
      of MM1 cells. Rho activation is sufficient both for the induction of invasion and
      the morphological changes leading to the invasion, whereas Rac activation is
      necessary but not sufficient by itself. We propose that Rho activation is not
      mediated by Rac but the cooperation of both GTPases is essential to trigger the
      invasive behavior of MM1 cells.

PMID- 10411107
TI  - Murine hepatic microvascular adhesion molecule expression is inducible and has a
      zonal distribution.
AB  - The structural and functional heterogeneity of hepatocytes and non-parenchymal
      cells across the liver lobule or acinus has been well documented. The geographic
      distribution and potential for induced expression of adhesion molecules on murine
      hepatic microvascular cells has not been reported, although these molecules are
      able to influence the metastatic outcome of intravascular cancer cells. We have
      postulated that the expression of adhesion molecules on these cells is
      susceptible to regulation by environmental factors and that these molecules have
      a zonal distribution across the acinus. To test this hypothesis, we injected
      C57BL/6 mice with bacterial lipopolysaccharide, 1 microg/g body weight, i.p. At
      various time points (0-48 h) after stimulation, liver tissue sections were
      prepared for immunohistochemistry. Confocal microscopy was used to detect the
      expression of vascular cell adhesion molecule-1 (VCAM-1), E-selectin,
      intercellular adhesion molecule-1 (ICAM-1) and alpha v integrin. The expression
      patterns were quantitatively measured by histomorphometry. Under basal
      conditions, ICAM-1 was weakly expressed in terminal portal veins while minimal
      VCAM-1 and no E-selectin were detected. Following stimulation with
      lipopolysaccharide, VCAM-1 and E-selectin were expressed on the endothelium of
      terminal portal veins and on sinusoidal lining cells with significantly stronger
      expression in the periportal zone than midzone. VCAM-1 expression peaked at 4 h
      and decreased gradually by 48 h. E-selectin peaked at 2 h and disappeared by 12 h
      after stimulation. ICAM-1 expression showed a much stronger and more uniform
      expression across the acinus with the peak reached by 4 h and sustained for
      longer than 48 h after lipopolysaccharide administration. The alpha v integrin
      was not detected under basal conditions or after lipopolysaccharide stimulation.
      Expression of all these adhesion molecules (ICAM-1, VCAM-1, E-selectin and alpha
      v integrin) was induced by growth of B16F1 melanoma cells in the peritoneal
      cavity of the mouse. These results support the hypotheses that expression of
      microvascular adhesion molecules in the mouse liver is susceptible to regulation
      by environmental stimuli and has a zonal heterogeneity across the acinus.

PMID- 10411108
TI  - Characterization of a highly metastatic, orthotopic lung cancer model in the nude
      rat.
AB  - The prevailing subcutaneous nude rodent tumor xenograft models used for
      biological and preclinical studies do not optimally reflect some important
      biological properties of cancer, especially invasion and metastasis. Orthotopic
      models have been developed to address this need. However, for lung cancer none of
      the available models are optimal, in that none originate from an orthotopic
      (bronchial) primary site and exhibit extensive extrathoracic metastasis. Our goal
      was to develop a consistent rodent model of non-small cell lung cancer with both
      of these properties. Groups of male Rowett nude rats were given 500 rads of gamma
      radiation and then endobronchially implanted in the right caudal lobe airway with
      50 mg of small NCI-H460 tumor fragments taken from an orthotopic donor tumor.
      They were then sacrificed at selected post-implantation times and evaluated
      grossly and histologically for animal weight, primary tumor take and size, and
      metastatic tumor incidence at multiple sites. At a late time point (32-35 days),
      consistency of primary tumor size and metastasis was estimated by comparing
      results from four groups of rats implanted on different occasions. The results
      showed that the primary tumors grew steadily, reaching four grams by days 32-35.
      Rats gained weight until days 14 to 21, but then began to show cachexia. High
      metastatic rates (>60%) were seen for mediastinal lymph nodes (by 21 days), and
      kidney, bone and brain (by 28 days). Mean primary tumor size and the incidences
      of both regional and systemic metastasis were consistent at 32-35 days in four
      different groups of six animals. In conclusion, this orthotopic lung cancer model
      is highly metastatic and consistent in terms of both primary tumor growth and
      metastatic behavior. It is the only available rodent model of human lung cancer
      emanating from an endobronchial site and metastasizing to multiple extrapulmonary
      sites, and should be very useful for both biological and preclinical studies of
      lung cancer, particularly where studies of antimetastatic activity are of
      interest, and/or where survival studies are desired.

PMID- 10411109
TI  - A novel orthotopic model of breast cancer metastasis to bone.
AB  - Breast cancer affects approximately one woman in twelve and kills more women than
      any other cancer. If detected early, patients have a five year survival rate of
      66%, but once metastatic disease has developed, there is no effective treatment.
      About 70% of patients with metastatic disease have bone involvement, while lungs
      and liver are the other common targets. Bone metastases cause severe pain,
      pathological fractures and hypercalcaemia and thus are a significant clinical
      problem. The development of new therapies for metastatic breast carcinoma depends
      on a better understanding of the mechanism of homing of the tumour cells to bone,
      liver and lungs and the factors required for their growth in these organs.
      Research on mechanisms of breast cancer metastasis, particularly to bone, has
      relied on in vitro studies or on tumour models in which the inoculation route is
      designed to promote delivery of tumour cells to a specific organ. Metastases in
      bone are achieved by inoculation into the right ventricle of the heart. To our
      knowledge there has been no report of a model of metastatic spread from the
      mammary gland to distant sites which reliably includes bone. In this paper, we
      describe our recent development of a novel murine model of metastatic breast
      carcinoma. The new model is unique in that the pattern of metastatic spread
      closely resembles that observed in human breast cancer. In particular, these
      murine breast tumours metastasise to bone from the primary breast site and cause
      hypercalcaemia, characteristics not normally found in murine tumours, but common
      in human disease. Furthermore, in a preliminary characterisation of this model,
      we show that secretion of parathyroid hormone-related protein, a role for which
      has been implicated in breast cancer spread to bone, correlates with metastasis
      to bone. This model therefore provides an excellent experimental system in which
      to investigate the factors that control metastatic spread of breast cancer to
      specific sites, particularly bone. The special advantage of this system is that
      it involves the whole metastasis process, beginning from the primary site.
      Existing models consider mechanisms that pertain to growth of tumour once the
      site has been reached. An understanding of the regulation of these factors by
      potential therapeutic agents could lead to improvement in therapies designed to
      combat metastatic disease. For the first time, this development will allow
      exploration of the molecular basis of site-specific metastasis of breast cancer
      to bone in a clinically relevant model.

PMID- 10411110
TI  - Low E-cadherin and beta-catenin expression correlates with increased spontaneous
      and artificial lung metastases of murine carcinomas.
AB  - This study examined the relationship between the expression of E-cadherin or beta
      catenin in murine adenocarcinomas and their hematogenous metastatic propensity,
      assessed by both spontaneous and artificial lung metastasis. Seven different
      carcinomas, syngeneic to C3Hf/Kam mice were used: 4 mammary carcinomas (MCa-4,
      MCa-29, MCa-35, and MCa-K), ovarian carcinoma OCa-I, hepatocarcinoma HCa-I, and
      adenosquamous carcinoma ACa-SG. These tumors vary widely in their ability to
      spontaneously metastasize to the lung (from 0 to 100% metastatic incidence), and
      their cells greatly differ in their ability to form artificial lung nodules when
      injected i.v. Primary tumors in the leg were assessed for E-cadherin and beta
      catenin expression by western blotting. The expression of both proteins showed
      wide variation among the tumors; however, the expression of E-cadherin correlated
      well with that of beta-catenin. There was significant inverse correlation between
      the expression of E-cadherin, as well as beta-catenin, and the incidence of both
      spontaneous and artificial lung metastases from these tumors. Spontaneous
      metastases of highly metastatic HCa-I and moderately metastatic MCa-35 were
      significantly lower in E-cadherin and beta-catenin expression than their
      corresponding primary tumors were. Thus, the propensity of murine carcinomas for
      hematogenous spread is highly related to E-cadherin and beta-catenin levels in
      primary tumors. The inverse correlation between the expression of these molecules
      and spontaneous and artificial metastases implies that tumor cells with low E
      cadherin and beta-catenin content have increased ability to enter the vascular
      circulation at the primary tumor site and to colonize distant tissues.

PMID- 10411112
TI  - The thyrotropin receptor mutation database.

PMID- 10411111
TI  - Experimental metastasis is suppressed in MMP-9-deficient mice.
AB  - Matrix metalloproteinases (MMPs) are thought to play a key role in tumor invasion
      and metastasis. The role of MMP-9 (gelatinase B) in tumor metastasis was examined
      in MMP-9-deficient mice produced by gene targeting using embryonic stem cells.
      MMP-9-deficient mice develop normally and are fertile. In these mice, the number
      of metastatic colonies of B16-BL6 melanoma cells or Lewis lung carcinoma cells
      that were implanted intravenously fell by 45% for B16-BL6 melanoma and 59% for
      Lewis lung carcinoma (p = 0.03 and p = 0.0043, respectively). Gelatin zymography
      showed that both tumor cell lines did not secrete MMP-9 by themselves but the
      host cells surrounding the tumor cells secrete MMP-9 in vivo. These results
      indicated that host-derived MMP-9 plays an important role in the process of tumor
      metastasis.

PMID- 10411113
TI  - Structural analysis of the thyrotropin receptor in four patients with congenital
      hypothyroidism due to thyroid hypoplasia.
AB  - Sporadic congenital hypothyroidism is most commonly caused by developmental
      abnormalities of the thyroid gland. More rarely, it is due to defects in gene
      products involved in the regulation of the hypothalamic-pituitary-thyroid axis or
      thyroid hormone synthesis. Loss of function mutations in the thyrotropin (TSH)
      receptor have been shown to result in resistance to biologically active TSH. In
      complete resistance to TSH, the thyroid gland is hypoplastic and unable to
      synthesize and secrete sufficient amounts of thyroid hormones. In partial
      resistance, referred to as euthyroid hyperthyrotropinemia, the size of the gland
      and the thyroid hormone levels are normal at the expense of an elevated TSH. Four
      patients with sporadic congenital hypothyroidism and properly located hypoplastic
      thyroid glands were included in this study. Serum TSH concentrations were 150
      mU/L or higher, serum thyroglobulin levels were within normal limits (6.1 to 8.2
      ng/mL; normal range: 2.1 to 32 ng/mL), and thyroid autoantibodies were absent.
      The coding region of the TSHbeta subunit gene, the TSH receptor gene, and exons 8
      and 9 of Gsalpha were analyzed by direct sequencing and found to be normal in all
      patients. One patient was heterozygous for a G to A transition in the TSHbeta
      gene resulting in a substitution of alanine by threonine at position -7 of the
      signal peptide. This substitution was also found in her euthyroid father. In
      addition, Southern analysis of the TSH receptor gene excluded major structural
      alterations. These findings support previous reports that indicate that TSH
      resistance is genetically heterogeneous. In addition to mutations in the TSH
      receptor or the Gsalpha genes, other genetic defects can lead to an identical
      phenotype. These observations also suggest that TSH receptor mutations might be a
      relatively rare cause of congenital thyroid hypoplasia.

PMID- 10411114
TI  - Epitope heterogeneity of thyrotropin receptor-blocking antibodies in Graves'
      patients as detected with wild-type versus chimeric thyrotropin receptors.
AB  - The stable transfectants of wild-type (W25) and mutant thyrotropin-receptor (TSH
      R) allow detection of the bioactivities of TSH-R antibodies in Graves' patients.
      A mutant Chinese hamster ovary (CHO) cell line (Mc1+2) transfected with a
      chimeric construct, where residues 8 to 165 of the TSH-R are replaced with
      residues 10 to 166 of the lutropin/choriogonadotropin (LH/CGR) receptor, lacks
      the cyclic adenosine monophosphate (cAMP) response to most thyrotropin
      stimulating antibodies (TSAb), yet retains the response to TSH and acquires the
      response to LH/CG. We compared Mc1+2 cells with wild-type W25 cells for their
      ability to detect TSAb as well as thyrotropin-blocking antibodies (TBAb) in
      Graves' sera. Eighteen normal and 39 Graves' sera were tested for TSAb and TBAb
      levels by in vitro bioassays using W25 and Mc1+2 cells. In addition, these sera
      were also tested for thyrotropin-binding inhibitory activity (TBII) by a
      radioreceptor assay. Eighteen (47%) Graves' sera had TBAb activity measured with
      W25 cells but not with Mc1+2 cells. These TBAbs were, therefore, a population of
      antibodies with functional epitopes on the N-terminus of the extracellular
      domain. This TBAb activity by W25 cells exhibited a high degree of correlation
      with TBII levels by a radioreceptor assay (r = 0.70, p = 0.001). Ten (25.6%)
      Graves' sera had positive TBAb activity in both W25 and Mc1+2 cells; moreover,
      their activity in both assays was similar (r = 0.83, p < 0.001). The TBAb
      activity in these sera, however, did not correlate with TBII activity. Eleven
      (28%) Graves' sera had no TBAb activity. Overall, thyroid-stimulating antibodies
      were detected in 87% and 28% of the 39 Graves' sera by W25 and Mc1 +2 cells,
      respectively. Thus, using the 2 cell lines, at least 2 distinct populations of
      TBAbs were detected. One is detected in a similar fashion by both W25 and Mc1+2
      cell lines and likely interacts with the epitopes residing in the unaltered C
      terminus of the TSH-R. The other is reactive in W25 cells only, indicating the
      loss of TBAb epitope in the chimeric receptor located in the N-terminus of the
      TSH-R. Furthermore, our results indicate that the TBAb binding epitope in 8-165
      residues of the native TSH-R is highly associated with TBII activity in Graves'
      disease. These results indicate that patients with Graves' disease harbor TBAbs
      with epitope heterogeneity and favor the notion that there are different sites
      and mechanisms by which TBAbs act in Graves' patients. It remains to be
      determined whether or not TBAb subtyping will have a useful predictive role in
      the management of patients with Graves' disease.

PMID- 10411116
TI  - Risks of iodine-induced hyperthyroidism after correction of iodine deficiency by
      iodized salt.
AB  - Biochemical signs of hyperthyroidism, or even overt and possibly lethal clinical
      hyperthyroidism were reported in 2 severely iodine-deficient African countries
      (Zimbabwe and Democratic Republic of Congo, RDC) soon after the introduction of
      iodized salt. The 2 countries had access to iodized salt produced in Botswana, as
      well as 5 other countries in the region, namely Cameroon, Nigeria, Kenya,
      Tanzania, and Zambia. Therefore, a multicenter study was conducted in these 7
      countries to evaluate whether the occurrence of iodine-induced hyperthyroidism
      (IIH) after the introduction of iodized salt was a general phenomenon or
      corresponded to specific local situations in the 2 affected countries. Two or 3
      areas with a past history of severe iodine deficiency that had recently been
      supplemented with iodized salt were selected in each of the 7 countries. The
      prevalence of goiter was determined in 4423 schoolchildren in these areas and the
      concentration of urinary iodine in 2258. Salt factories and health structures
      were visited for the evaluation of the quality of iodized salt and the possible
      occurrence of IIH. The study showed that iodine deficiency had been eliminated in
      all areas investigated, and that the prevalence of goiter had markedly decreased
      since the introduction of iodized salt. This is a remarkable achievement in terms
      of public health. However, some areas were now exposed to iodine excess due
      mostly to a poor monitoring of the quality of the iodized salt and of the iodine
      intake of the population. In these areas or countries, IIH occurred only when the
      introduction of iodized salt had been of recent onset (<2 years), namely in
      Zimbabwe and RDC. In conclusion, the risk of IIH after correction of iodine
      deficiency is closely related to a recent excessive increment of iodine supply.

PMID- 10411115
TI  - Effect of endogenous subclinical hyperthyroidism on bone metabolism and bone
      mineral density in premenopausal women.
AB  - In this cross-sectional study, we evaluated 15 premenopausal women to elucidate
      whether bone turnover is increased and bone mineral density is reduced due to
      endogenous subclinical hyperthyroidism. Each patient had normal free thyroxine
      (FT4) and free triiodothyronine (FT3) levels associated with a stable suppression
      (<0.1 mU/L) of serum thyrotropin (TSH) levels during a period ranging between 6
      and 11 months. Metabolic parameters of bone turnover (serum osteocalcin, bone
      specific alkaline phosphatase, procollagen I C-terminal peptide reflecting bone
      formation; urinary deoxypyridinoline and calcium excretion reflecting bone
      resorption) were assessed. Bone mineral density was measured at lumbar 1-4
      vertebrae, femoral neck, and the forearm (midshaft radius and distal radius) by
      dual energy x-ray absorptiometry. All measurements were compared with 15 healthy
      age-, height-, and weight-matched premenopausal women who served as control
      group. Our findings suggest that endogenous subclinical hyperthyroidism is not
      associated with increased bone turnover, and bone mineral density is not reduced
      in premenopausal women, at least in the short term.

PMID- 10411117
TI  - Possible role of genetic factors in thyroid growth rate and in the assessment of
      upper limit of normal thyroid volume in iodine-replete adolescents.
AB  - The objective of this study was to answer the question whether thyroid volume in
      adolescent siblings of similar age and a life-long sufficient iodine intake is
      uniform. If different, it would indicate that genetic or environmental factors
      unrelated to iodine intake can influence thyroid growth. We measured thyroid
      volume by ultrasound in: (1) 251 sibling pairs (SP) and 19 sibling triads 10 to
      18 years of age. The age range of each SP was less than 24 months and of each
      triad less than 42 months; (2) 28 monozygotic and 13 dizygotic sets of twins 7 to
      18 years of age. The sibling pairs were retrospectively divided into 3 groups
      irrespective of age (thyroid volume as means+/-S.E. mL/m2). Group 1: 159 pairs
      with low thyroid volume in both siblings; mean thyroid volume of each pair less
      than 5.00 mL/m2 (3.96+/-0.05, median 4.08, range 2.07-4.98); group 2: 69 pairs
      with high thyroid volume in both siblings; mean thyroid volume greater than 5.00
      mL/m2 (5.85+/-0.12, median 5.57, range 5.03-11.02); group 3: 23 pairs with low
      thyroid volume in 1 sibling (3.53+/-0.15, median 3.53, range 1.71-4.91) and high
      thyroid volume in another (7.36+/-0.23, median 7.18, range 5.96-10.30). The
      majority of triads, monozygotic, and dizygotic twins resembled group 1, a few
      resembled group 2, and only 3 triads and 1 set of dizygotic twins resembled group
      3. Among monozygotic twins, there was no pair with a strikingly discordant
      thyroid volume and only 1 such pair was found among dizygotic twins. In
      monozygotic twins, the thyroid volume was almost identical (mean difference
      0.34+/-0.06 mL/m2) and significantly less (p < 0.012) than in dizygotic twins
      (0.9+/-0.25 mL/m2). Among 502 children of 251 sibling pairs the frequency of high
      thyroid volume (>5.00 mL/m2) was greater in girls (103/279, 36.9%, p < 0.01) than
      in boys (49/223, 22.0%). The same was true for the frequency of hypoechogenicity
      (42/279 or 15.0% in girls vs. 12/223 or 5.4% in boys; p < 0.01). The frequency of
      hypoechogenicity in both sexes of the combined groups 2 and 3 (40/186, 21.5%) was
      higher (p < 0.001) than in group 1 (14/316, 4.4%). All siblings examined lived in
      a common household with their parents, eating the same daily meals at home and
      school. Our results suggest that the observed differences in thyroid volume of
      siblings were not related to iodine intake, but to other factors, eg, genetic and
      environmental. It is not clear whether the children with high thyroid volume and
      increased frequency of hypoechogenicity should be included into the recently
      recommended range of normal thyroid volume for adolescents.

PMID- 10411118
TI  - Expression of the Axl receptor tyrosine kinase in human thyroid carcinoma.
AB  - Protein tyrosine kinases (PTKs) play a crucial role in regulating thyroid cell
      growth and differentiation. The Axl protein is a member of a new family of
      receptor tyrosine kinases, of which the ligand, Gas6, a protein S-related
      molecule, recently was proved to be a mitogenic factor for human thyroid cells.
      To further investigate the involvement of Axl in human thyroid carcinoma, we
      examined tissues obtained from 81 patients with thyroid carcinomas, 18 with
      adenomas, and 13 with adenomatous goiters by immunohistochemistry and in situ
      hybridization. In addition, among the thyroid carcinomas, we compared Axl
      expression levels with the grade of differentiation and lymph node metastasis of
      the carcinoma. Axl was expressed faintly in adenomatous goiter and adenomas, but
      not in normal thyroid tissues. Among the 81 cases of thyroid carcinoma, 70
      (86.4%) showed a positive staining for the Axl protein. Immunopositive (+ +) was
      detected in papillary carcinomas and anaplastic carcinomas. The level of Axl
      expression, however, had no correlation with the presence of lymph node
      metastasis in thyroid carcinomas. In situ hybridization also confirmed the
      presence of axl mRNA in thyroid carcinoma tissues. These findings suggest that
      Axl expression may be closely involved in human thyroid tumorigenesis.

PMID- 10411119
TI  - Cathepsin B activity and protein levels in thyroid carcinoma, Graves' disease,
      and multinodular goiters.
AB  - Cathepsin B (CB) is involved in the hydrolysis of thyroglobulin (Tg) and thought
      to be regulated by thyroid stimulating hormone (TSH) in the normal thyroid. Our
      analyses of 91 thyroid tissues from 71 patients with Graves' disease (GD),
      multinodular goiter (MNG), papillary carcinoma (PC), or follicular carcinoma
      (FC), demonstrated a 2-fold increase in expression of CB in GD and an average
      increase of 1.5-fold in MNG (varying from 10-fold below normal to 6-fold above
      normal in MNG nodules), as might be predicted by the altered functional status of
      thyroid follicular cells in those diseases. However, CB activity was not
      downregulated in conjunction with the known "blocking effect" of malignancy on
      many thyroid functions, but rather increased on average 9-fold in papillary
      carcinomas (n = 33), and also showed a marked increase in 2 follicular
      carcinomas. Activity measurements were confirmed by CB protein detection on
      Western blot with moderately increased CB protein levels demonstrated in GD,
      variable expression in nodules of MNG, and markedly increased protein expression
      in carcinomas. In all diseased states, increased protein was detected primarily
      as overexpression of the 27 kd heavy chain of 2-chain mature CB and less
      frequently as overexpression of 31 kd single-chain mature CB. However, an
      additional 35 kd protein form was noted in 3 of 9 PCs, 1 of 2 FCs, and 1 of 4 GD
      cases but in none of 10 MNG cases. In conjunction with elevated CB activity plus
      additional protein bands on Western blots, altered patterns of CB
      immunohistochemical staining were observed, irrespective of the type of thyroid
      disease, suggesting certain common changes in CB expression, posttranslational
      processing, and vesicular trafficking. In summary, GD and MNG thyroid tissues
      demonstrated altered CB expression in keeping with predicted functional changes
      in thyroid follicular cells, while increased CB expression in carcinomas
      indicated a more pathological role for CB in thyroid cancers, possibly related to
      the processes of invasion or metastasis.

PMID- 10411120
TI  - Evaluation of routine basal serum calcitonin measurement for early diagnosis of
      medullary thyroid carcinoma in seven hundred seventy-three patients with nodular
      goiter.
AB  - The aims of the study were to identify medullary thyroid cancer (MTC) in its
      earliest stages by screening patients with basal calcitonin measurements and to
      determine whether basal serum calcitonin measurements should be a part of the
      routine evaluation of a nodular goiter. Basal serum calcitonin levels were
      obtained from 75 patients (female:male 57:18, mean age 42.8 years, range with 18
      76 years) with nonnodular thyroid disease as controls. Their mean basal
      calcitonin level was 7.8+/-0.4 pg/mL with a range of 5-27 pg/mL. Seven hundred
      seventy-three patients with nodular goiter were included in the study
      (female:male 586:187) with the mean age of 46.1 years (range 17-78). Four
      patients had elevated basal serum calcitonin levels ranging between 150-1000
      pg/mL. These 4 patients underwent surgery. MTC was confirmed by histopathology in
      all 4. One patient's mother and brother were also diagnosed as MTC as a result of
      family screening. Basal serum calcitonin levels were higher than 150 pg/mL in
      these patients. Fine needle aspiration biopsy (FNAB) of 2 of 4 MTC patients were
      incorrectly diagnosed as papillary carcinoma; another had malignant cytology and
      the fourth had benign cytology. None were diagnosed as MTC on the basis of FNAB.
      In conclusion, calcitonin measurement is an effective method for the diagnosis of
      MTC. Measurement of basal calcitonin levels in patients with malignant or
      suspicious FNAB may be a cost-effective approach to screen for MTC. High basal
      serum calcitonin levels increase the chance of curative therapy by diagnosing MTC
      in the early stages. It is superior to FNAB for diagnosis of MTC.

PMID- 10411121
TI  - Evaluation of indium-111 pentetreotide somatostatin receptor scintigraphy to
      detect recurrent thyroid carcinoma in patients with negative radioiodine
      scintigraphy.
AB  - The follow-up of patients who underwent thyroidectomy for differentiated thyroid
      carcinoma is based on the combination of serum thyroglobulin (Tg) measurement and
      radioiodine total-body scan (ITBS). The diagnostic strategy to be used in
      patients with elevated serum Tg level but negative ITBS remains debatable.
      Somatostatin receptor scintigraphy (SRS) has been proposed. Our objective was to
      compare the results of SRS and conventional radiological imaging (CRI) for the
      diagnosis of recurrent disease and/or metastases in 15 patients who had had
      thyroidectomy for differentiated carcinoma (14 papillary, 1 Hurthle cell
      carcinoma) and who displayed elevated Tg levels (10 to 65000 ng/mL) together with
      negative ITBS performed after 100 mCi. All patients underwent SRS and CRI within
      3 months, allowing comparison of the 2 approaches for the identification of
      thyroid carcinoma metastases. CRI first included a chest x-ray and
      ultrasonography of the neck. It was followed by computed tomography (CT) scanning
      and/or magnetic resonance imaging (MRI) of the neck, chest and occasionally
      abdomen, and 99mTc bone scintigraphy in case of negative results. In 6 patients
      with Tg levels ranging from 65 to 65000 ng/mL, CRI detected 12 histologically
      proven metastases among 9 organs. Among these patients, SRS identified only 6
      metastases. SRS identified 1 case of mediastinal recurrence that was not detected
      by CRI. In another patient with a Tg level of 51 ng/mL, a cervical node was
      identified using both SRS and CRI but proved to be a false-positive (inflammatory
      cervical node). In the other 8 patients with Tg levels ranging from 10 to 580
      ng/mL, SRS and CRI were negative, and the source of Tg secretion remains unknown.
      The results of SRS did not correlate with serum Tg level. In conclusion, the
      diagnostic accuracy of SRS in this study was disappointing and clearly lower than
      that of CRI. Our results do not support the use of SRS as a guide conventional
      imaging modalities in patients operated on for differentiated thyroid carcinoma
      who display elevated Tg levels together with negative ITBS.

PMID- 10411122
TI  - Cervicomediastinal magnetic resonance imaging in persistent or recurrent
      papillary thyroid carcinoma: clinical use and limits.
AB  - Cervicomediastinal magnetic resonance imaging (MRI) was evaluated in 13
      consecutive persistent or recurrent papillary thyroid carcinoma (PTC) patients,
      previously treated by total thyroidectomy and radioiodine ablation. All had
      elevated thyroglobulin (Tg) levels and were therefore submitted to a new
      therapeutic radioiodine dose followed by a posttherapeutic whole-body scan (131I
      WBS) and subsequent MRI. Patients with known distant metastases were excluded
      from the study. Group 1 included 7 patients with a negative 131I-WBS, whereas
      cervical and/or mediastinal 131I-uptake was evidenced in the other 6 patients
      (group 2). MRI was thus compared to 131I-WBS, and additionally in 8 reoperated
      cases, to histology. MRI was positive in 11 of 13 (85%) patients, corresponding
      to 23 of 55 (41.8%) histologically confirmed sites. In group 1, MRI was positive
      in 5 of 7 patients, with a sensitivity of 47% (15/32 histologically positive
      sites), allowing appropriate indication of surgery: 4 neck surgery, and 1
      mediastinal dissection because of too distant lymph node foci. In group 2, MRI
      always showed more localization than 131I-WBS; histology was obtained in 3.
      Because all the foci located in the mediastinal area (0.8 to 1.8 cm) were
      histologically confirmed (7/7 sites), MRI avoided underestimation of surgery in
      the 8 reoperated patients. However, additional images were also observed
      corresponding to a normal thymus, a small neuroma or inflammatory lymph nodes,
      but pretracheal and very small nodes (less than 0.5 cm) were missed. In
      conclusion, although less specific than radioiodine scintigraphy, MRI can detect
      local persistent or recurrent PTC, and seems particularly effective for
      evaluation of mediastinal involvement.

PMID- 10411123
TI  - Hypercalcitoninemia, nodular goiter, and pancreatic tumor.

PMID- 10411124
TI  - Hormone-dependent regulation of intercellular adhesion molecule-1 gene
      expression: cloning and analysis of 5'-regulatory region of rat intercellular
      adhesion molecule-1 gene in FRTL-5 rat thyroid cells.
AB  - Intercellular adhesion molecule-1 (ICAM-1) has been suggested to play an
      important role in the perpetuation of autoimmune thyroid disease. To clarify the
      regulation of ICAM-1 gene in thyroid cells, we investigated ICAM-1 expression in
      the FRTL-5 thyroid cell model and defined several elements in the 5'-regulatory
      region that are important for transcriptional regulation of the rat ICAM-1 gene.
      Cells maintained in medium with 5% serum but without hydrocortisone, insulin, and
      thyrotropin (TSH) express the highest levels of ICAM-1 RNA. TSH/forskolin
      downregulate ICAM-1 RNA levels independent of the presence or absence of
      hydrocortisone or insulin. Moreover, TSH/forskolin decrease ICAM-1 RNA levels
      that are maximally induced by two cytokines: 100 ng/mL tumor necrosis factor
      alpha (TNF-alpha) or 100 U/ml interferon-gamma (IFN-gamma). The effect of
      TSH/forskolin, as well as TNF-alpha and IFN-gamma, on ICAM-1 RNA levels is
      transcriptional. Thus, we cloned a 1.8-kb fragment of the 5'-flanking region of
      the rat ICAM-1 gene, upstream of the translational start site, and showed that
      TNF-alpha or IFN-gamma caused a 3.5- and greater than 12-fold increase
      respectively, in its promoter activity, when linked to a luciferase reporter gene
      and stably transfected into FRTL-5 cells. TSH or forskolin, in contrast, halved
      the activity of the full length chimera within 24 hours and significantly
      suppressed the TNF-alpha and IFN-gamma-induced increase (>50%; p < 0.02). Using
      5'-deletion mutants, we located the element important for the TNF-alpha effect
      between -431 and -175 bp; we additionally show that deletion of a NF-kappaB core
      element within this region, TTGGAAATTC (-240 to -230 bp), causes the loss of TNF
      alpha inducibility. The effect of IFN-gamma could be localized between -175 bp
      and -97 bp from the start of translation. This region contains 2 regulatory
      elements known to be involved in IFN-gamma action in other eukaryotic cells, an
      IFN-gamma activated site (GAS), -138 to -128 bp, and Spl site, -112 to -108 bp.
      Deletion of the 10 bp GAS sequence resulted in the complete loss of IFN-gamma
      induction of pCAM-175 promoter activity. TSH and forskolin action was also mapped
      between -175 bp and -97 bp from the start of translation. The mutant construct,
      pCAM-175delGAS mutl, which has no GAS sequence, exhibited no TSH-mediated
      suppression of promoter activity. We thus show that TSH/cAMP can downregulate
      ICAM-1 gene expression and inhibit the activity of cytokines (TNF-alpha and IFN
      gamma) to increase ICAM-1 gene expression in FRTL-5 thyroid cells. We also
      localized elements on the 5'-flanking region of ICAM-1 important for these
      actions. We propose that this TSH/cyclic adenosine monophosphate (cAMP) action is
      a component of the mechanism to preserve self-tolerance of the thyroid during
      hormone-induced growth and function of the gland, and it may attenuate cytokine
      action during inflammatory reactions.

PMID- 10411125
TI  - Effects of thyrotropin on the proliferation and differentiation of cultured rat
      preadipocytes.
AB  - Thyrotropin receptor (TSHR) is expressed during the differentiation of rat
      preadipocytes and is highly abundant in mature fat adipocytes, but its
      physiological role is unknown. In this article, long-term effects of thyrotropin
      (TSH) on the proliferation and the differentiation were investigated using
      cultured rat preadipocytes. When TSH was added at the beginning of
      differentiation, TSH increased the number of preadipocytes and 3H-thymidine
      uptake. Apoptosis of the cells was not influenced by TSH. Preadipocytes incubated
      in the presence of TSH had fewer fat droplets, decreased level of mRNA for
      lipoprotein lipase (LPL), a marker of adipocyte differentiation. Histochemical
      study showed that the cells that increased their number and expressed lower level
      of LPL in response to TSH were preadipocytes, and not contaminating fibroblasts.
      In conclusion, TSH causes the proliferation and inhibits the differentiation of
      rat preadipocytes. Results suggest that TSH may be a potent regulator of
      preadipocyte proliferation and differentiation in vivo.

PMID- 10411127
TI  - The interleukin-1 receptor antagonist gene shows no allelic association with
      three autoimmune diseases.

PMID- 10411126
TI  - The effects of lysophosphatidate on thyrotropin-mediated differentiated thyroid
      function in FRTL-5 thyroid cells.
AB  - Lysophosphatidate (LPA; 1-acyl-sn-glycero-3-phosphate) is a novel lipid mediator
      with diverse biological activity. The intracellular mechanisms that mediate the
      actions of LPA include activation of phospholipase C and protein kinase C (PKC),
      increases in intracellular Ca2+, inhibition of adenylyl cyclase, and activation
      of phospholipase D (PLD). We have shown that thyrotropin (TSH) mediated PLD
      activation involves both the cyclic adenosine monophosphate (cAMP) and PKC
      pathways. We determined the effects of LPA (10 or 50 microM; 30 minutes) on TSH-
      and forskolin-mediated cAMP production in FRTL-5 thyroid cells. Basal cAMP was
      unaffected by LPA. However, both 10 microM and 50 microM LPA inhibited TSH
      mediated cAMP production by 66% and 64%, respectively (p < 0.01, ANOVA). A
      similar inhibition of forskolin-mediated cAMP production was observed following
      LPA (p < 0.01, ANOVA). After 30-minutes exposure to 50 microM LPA, TSH-mediated
      iodide uptake (IU) was unaffected. However, 50 microM LPA enhanced TSH-IU after
      24-hour exposure by 23%+/-8% (p < 0.03, ANOVA) and inhibited TSH-IU following 72
      hour exposure by 43%+/-10% (p < 0.02, ANOVA). There was no effect of LPA on basal
      IU. To determine whether PLD activation mediated the effects of LPA, PLD activity
      was examined in FRTL-5 thyroid cells 30 minutes after LPA exposure. While PLD was
      increased 3.5-fold compared to control values following 50 microM LPA (p < 0.05,
      ANOVA), no increase in PLD activation was seen following treatment with 10 microM
      LPA. Preliminary evidence revealed no effect of a protein kinase C inhibitor on
      LPA inhibition of cAMP generation. To examine the products of PLD activation, we
      measured the production of phosphatidate (PA) and diacylglycerol (DAG) in FRTL-5
      thyroid cells following treatment with 50 microM LPA or 100 microU/mL TSH. Within
      1 minute following LPA, a rapid spike of DAG production was observed (1.5- +/-
      0.2-fold above basal, p < 0.05, ANOVA). No similar increases in PA or bisPA were
      demonstrated. However, TSH caused a steady increase in PA and DAG that reached a
      maximum after 30 minutes. In summary, the effects of LPA on differentiated
      thyroid function in FRTL-5 thyroid cells are complex. LPA inhibits TSH- and
      forskolin-mediated cAMP generation most likely via a direct inhibition of
      adenylyl cyclase, whereas its effects on TSH-IU involve other mechanisms,
      possibly including PLD activation.

PMID- 10411128
TI  - Directed hydroxyl radical probing of 16S rRNA in the ribosome: spatial proximity
      of RNA elements of the 3' and 5' domains.
AB  - We have shown previously that directed hydroxyl radical probing of 16S rRNA from
      Fe(II) tethered to specific sites within the RNA gives valuable information about
      RNA-RNA proximities in 70S ribosomes. Here, we extend that study and present
      probing data from nt 424 in 16S rRNA. To tether an Fe(II) to position 424 in the
      rRNA we created a specific discontinuity in the RNA by in vitro transcription of
      the RNA as two separate fragments corresponding to nt 1-423 and 424-1542. An
      Fe(II)-BABE was covalently attached to a 5'-guanosine-alpha-phosphorothioate at
      position 424 and 30S subunits were reconstituted from the two pieces of rRNA and
      the small subunit proteins. Reconstituted 30S subunits capable of associating
      with 50S subunits were selected by isolation of 70S ribosomes. Hydroxyl radicals,
      generated in situ from the tethered Fe(II), cleaved positions in the RNA backbone
      that were close in three-dimensional space to the Fe(II), and the sites of
      cleavage were identified using primer extension. Fe(II) tethered to position 424
      induces cleavage around nt 424, 513, and 531 in the 5'-domain of 16S rRNA and
      around nt 1008, 1029, 1044, and 1208 in the 3'-domain of 16S ribosomal RNA. These
      data constrain the positions of the 420, 1015, 1030 and 1000/1040 helices, for
      which there is little structural information. Since the 5'- and 3'-domains of 16S
      rRNA constitute the body and head, respectively, of 30S subunits, these findings
      provide direct evidence for proximity of RNA elements in the body and head of
      30S.

PMID- 10411129
TI  - Positions in the 30S ribosomal subunit proximal to the 790 loop as determined by
      phenanthroline cleavage.
AB  - Positioning rRNA within the ribosome remains a challenging problem. Such
      positioning is critical to understanding ribosome function, as various rRNA
      regions interact to form suitable binding sites for ligands, such as tRNA and
      mRNA. We have used phenanthroline, a chemical nuclease, as a proximity probe, to
      help elucidate the regions of rRNA that are near neighbors of the stem-loop
      structure centering at nt 790 in the 16S rRNA of the Escherichia coli 30S
      ribosomal subunit. Using phenanthroline covalently attached to a DNA oligomer
      complementary to nt 787-795, we found that nt 582-584, 693-694, 787-790, and 795
      797 were cleaved robustly and must lie within about 15 A of the tethered site at
      the 5' end of the DNA oligomer, which is adjacent to nt 795 of 16S rRNA.

PMID- 10411130
TI  - Inosine and N1-methylinosine within a synthetic oligomer mimicking the anticodon
      loop of human tRNA(Ala) are major epitopes for anti-PL-12 myositis
      autoantibodies.
AB  - Sera of some patients afflicted with the inflammatory disease myositis contain
      antibodies of the anti-PL-12 type. A fraction of these polyclonal autoantibodies
      specifically precipitates the fully matured human tRNA(Ala) bearing the anticodon
      IGC (PL-12 antigen). Earlier work (Bunn & Mathews, 1987, Science 238:116-119) had
      shown that the epitopes are located entirely within the anticodon stem-loop of
      the tRNA(Ala). Here we demonstrate that human anti-tRNA(Ala) autoantibodies
      immunoprecipitate a synthetic polyribonucleotide containing inosine (I) and N1
      methylinosine (m1I) separated by 2 nt as in the anticodon stem-loop of human
      tRNA(Ala). The shortest polyribonucleotide that can be immunoprecipitated
      corresponds to the pentanucleotide IpGpCpm1IpUp, which corresponds to part of the
      anticodon loop of human tRNA(Ala) and lacks the stem-loop structure. The
      efficiency of immunoprecipitation was about four times greater with longer
      polyribonucleotides capable of forming a stem-loop structure, and was abolished
      by altering the relative positions of I and m1I within the synthetic
      polynucleotide. Synthetic oligodeoxyribonucleotide analogs of the tRNA(Ala) stem
      loop, containing the sequence dIpdGdCdm1Ip, are not antigenic. Our results show
      that human anti-tRNA(Ala) autoantibodies selectively recognize chemical details
      of modified nucleotides (the 6-keto group of inosine-34 and the 6-keto group and
      the N1-methyl groups of N1-methylinosine-37) within an anticodon loop structure
      of a tRNA molecule. We also describe the chemical synthesis of the
      phosphoramidite derivatives corresponding to N1-methylinosine and N1-methyl-2'
      deoxyinosine for use in the automatic chemical synthesis of oligonucleotides
      containing N1-methylinosine and N1-methyl-2'-deoxyinosine.

PMID- 10411131
TI  - Trans-complementation of the second step of pre-mRNA splicing by exogenous 5'
      exons.
AB  - During splicing of nuclear pre-mRNAs, the first step liberates the 5' exon (exon
      1) and yields a lariat intron-3'exon (intron-exon 2) intermediate. The second
      step results in exon ligation. Previous results indicated that severe truncations
      of the 5' exon of the actin pre-mRNA result in a block to the second splicing
      step in vitro in yeast extracts, leading to an accumulation of intron-exon 2
      lariat intermediates. We show that exogenous exon 1 RNA oligonucleotides can
      chase these stalled intermediates into lariat intron and spliced exons. This
      reaction requires some of the cis elements and trans-acting factors that are
      required for a normal second step. There is no strong sequence requirement for
      the exon 1 added in trans, but oligonucleotides with complementarity to the U5
      snRNA conserved loop perform the chase more efficiently. Using a dominant
      negative mutant of the DEAH-box ATPase Prp16p and ATP depletion, we show that the
      stalled intermediate is blocked after the Prp16p-dependent step. These results
      show that exogenous RNAs with various sequences but containing no splicing
      signals can be incorporated into spliceosomes and undergo RNA recombination and
      exon shuffling during the second step of pre-mRNA splicing.

PMID- 10411132
TI  - Kinetoplastid RNA editing does not require the terminal 3' hydroxyl of guide RNA,
      but modifications to the guide RNA terminus can inhibit in vitro U insertion.
AB  - During RNA editing in kinetoplastid parasites, trans-acting guide RNAs (gRNAs)
      direct the insertion and deletion of U residues at precise sites in mitochondrial
      pre-mRNAs. We show here that some modifications to the 3' terminal ribose of gRNA
      inhibit its ability to direct in vitro U insertion. However, we found that gRNAs
      lacking this moiety in some circumstances support in vitro editing. Thus, the 3'
      OH is not required. Inhibition resulting from gRNA modification can be overcome
      by increasing the gRNA-pre-mRNA base-pairing potential upstream of the editing
      site, suggesting an importance for this interaction to productive processing.

PMID- 10411134
TI  - Yeast Rnt1p is required for cleavage of the pre-ribosomal RNA in the 3' ETS but
      not the 5' ETS.
AB  - We have reexamined the role of yeast RNase III (Rnt1p) in ribosome synthesis.
      Analysis of pre-rRNA processing in a strain carrying a complete deletion of the
      RNT1 gene demonstrated that the absence of Rnt1p does not block cleavage at site
      A0 in the 5' external transcribed spacers (ETS), although the early pre-rRNA
      cleavages at sites A0, A1, and A2 are kinetically delayed. In contrast, cleavage
      in the 3' ETS is completely inhibited in the absence of Rnt1p, leading to the
      synthesis of a reduced level of a 3' extended form of the 25S rRNA. The 3'
      extended forms of the pre-rRNAs are consistent with the major termination at site
      T2 (+210). We conclude that Rnt1p is required for cleavage in the 3' ETS but not
      for cleavage at site A0. The sites of in vivo cleavage in the 3' ETS were mapped
      by primer extension. Two sites of Rnt1p-dependent cleavage were identified that
      lie on opposite sides of a predicted stem loop structure, at +14 and +49. These
      are in good agreement with the consensus Rnt1p cleavage site. Processing of the
      3' end of the mature 25S rRNA sequence in wild-type cells was found to occur
      concomitantly with processing of the 5' end of the 5.8S rRNA, supporting previous
      proposals that processing in ITS1 and the 3' ETS is coupled.

PMID- 10411133
TI  - The human Prp8 protein is a component of both U2- and U12-dependent spliceosomes.
AB  - This study reports the cloning, sequencing, and development of antisera against
      the human U5 snRNP 220-kDa protein or hPrp8p. Prp8p is the most highly conserved
      large nuclear protein known to date, but it is not related to any other protein.
      Southern, Northern, and expressed sequence tag analyses indicate that hPrp8p is
      encoded by a single gene. Prp8p is a core component of U5 snRNP and the U4/U6.U5
      tri-snRNP, and antibodies raised against it immunoprecipitate both the major, U2
      dependent and minor, U12-dependent spliceosomes. These spliceosomes, which excise
      different classes of introns, contain distinct sets of snRNAs overlapping only
      with U5 snRNA. Other than the core Sm proteins, hPrp8p is the first splicing
      factor shown to be common to both spliceosomes.

PMID- 10411135
TI  - SR proteins are required for nematode trans-splicing in vitro.
AB  - SR (ser/arg) proteins have been shown to play roles in numerous aspects of pre
      mRNA splicing, including modulation of alternative splicing, commitment of
      substrates to the splicing pathway, and splice site communication. The last of
      these, splice site communication, is particularly relevant to trans-splicing in
      which the 5' and 3' exons originate on separate molecules. The participation of
      SR proteins in naturally occurring, spliced leader RNA-dependent transsplicing
      has not been examined. Here, we have isolated SR proteins from an organism that
      performs both trans- and cis-splicing, the nematode Ascaris lumbricoides. To
      examine their activity in in vitro splicing reactions, we have also developed and
      characterized an SR protein-depleted whole-cell extract. When tested in this
      extract, the nematode SR proteins are required for both trans- and cis-splicing.
      In addition, the state of phosphorylation of the nematode SR proteins is critical
      to their activity in vitro. Interestingly, mammalian (HeLa) and A. lumbricoides
      SR proteins exhibit equivalent activities in cis-splicing, while the nematode SR
      proteins are much more active in trans-splicing. Thus, it appears that SR
      proteins purified from an organism that naturally trans-splices its pre-mRNAs
      promote this reaction to a greater extent than do their mammalian counterparts.

PMID- 10411136
TI  - The yeast retrotransposon Ty5 uses the anticodon stem-loop of the initiator
      methionine tRNA as a primer for reverse transcription.
AB  - Retrotransposons and retroviruses replicate by reverse transcription of an mRNA
      intermediate. Most retroelements initiate reverse transcription from a host
      encoded tRNA primer. DNA synthesis typically extends from the 3'-OH of the
      acceptor stem, which is complementary to sequences on the retroelement mRNA (the
      primer binding site, PBS). However, for some retrotransposons, including the
      yeast Ty5 elements, sequences in the anticodon stem-loop of the initiator
      methionine tRNA (IMT) are complementary to the PBS. We took advantage of the
      genetic tractability of the yeast system to investigate the mechanism of Ty5
      priming. We found that transposition frequencies decreased at least 800-fold for
      mutations in the Ty5 PBS that disrupt complementarity with the IMT. Similarly,
      transposition was reduced at least 200-fold for IMT mutations in the anticodon
      stem-loop. Base pairing between the Ty5 PBS and IMT is essential for
      transposition, as compensatory changes that restored base pairing between the two
      mutant RNAs restored transposition significantly. An analysis of 12 imt mutants
      with base changes outside of the region of complementarity failed to identify
      other tRNA residues important for transposition. In addition, assays carried out
      with heterologous IMTs from Schizosaccharomyces pombe and Arabidopsis thaliana
      indicated that residues outside of the anticodon stem-loop have at most a
      fivefold effect on transposition. Our genetic system should make it possible to
      further define the components required for priming and to understand the
      mechanism by which Ty5's novel primer is generated.

PMID- 10411137
TI  - Ribosomal RNA is the target for oxazolidinones, a novel class of translational
      inhibitors.
AB  - Oxazolidinones are antibacterial agents that act primarily against gram-positive
      bacteria by inhibiting protein synthesis. The binding of oxazolidinones to 70S
      ribosomes from Escherichia coli was studied by both UV-induced cross-linking
      using an azido derivative of oxazolidinone and chemical footprinting using
      dimethyl sulphate. Oxazolidinone binding sites were found on both 30S and 50S
      subunits, rRNA being the only target. On 16S rRNA, an oxazolidinone footprint was
      found at A864 in the central domain. 23S rRNA residues involved in oxazolidinone
      binding were U2113, A2114, U2118, A2119, and C2153, all in domain V. This region
      is close to the binding site of protein L1 and of the 3' end of tRNA in the E
      site. The mechanism of action of oxazolidinones in vitro was examined in a
      purified translation system from E. coli using natural mRNA. The rate of
      elongation reaction of translation was decreased, most probably because of an
      inhibition of tRNA translocation, and the length of nascent peptide chains was
      strongly reduced. Both binding sites and mode of action of oxazolidinones are
      unique among the antibiotics known to act on the ribosome.

PMID- 10411138
TI  - Influence of specific mutations on the thermal stability of the td group I intron
      in vitro and on its splicing efficiency in vivo: a comparative study.
AB  - Group I introns constitute excellent systems for analyzing the relationship
      between RNA tertiary folding and catalysis. Within a hierarchical framework
      interpretation of RNA folding, secondary structure motifs subtend RNA three
      dimensional (3D) architecture. Thus, mutations in two-dimensional motifs are
      expected to have effects different from those disrupting 3D contacts. Using UV
      spectroscopy, we have studied the influence of nucleotide substitutions, in both
      secondary and tertiary structure elements, on the thermal stability of the
      tertiary folding of the bacteriophage T4 td group I intron. Further, we present a
      quantitative analysis of the relationship between the splicing efficiency in vivo
      and the stability of the intron structure as monitored by UV melting curves. We
      conclude that the stability of the tertiary structure of a group I intron as
      measured by UV melting is generally a good indication of its ability to splice in
      vivo.

PMID- 10411141
TI  - Mutational analysis of three tumor suppressor genes in two models of rat
      hepatocarcinogenesis.
AB  - An albumin-simian virus 40 (SV40) large T-antigen (T-Ag) transgenic model and a
      chemically induced model of multistage hepatocarcinogenesis were created in our
      laboratory to study the molecular mechanisms involved in the genesis and
      progression of neoplasia in the rat liver. In the study presented here, these two
      models of rat hepatocarcinogenesis were used to perform a comparative mutational
      analysis of three tumor suppressor genes involved in hepatic neoplastic growth.
      By using polymerase chain reaction-single strand conformation polymorphism
      analysis and sequencing, exons 5-8 of the p53 tumor suppressor gene and a region
      between nt 4325 and 4479 of the rat mannose 6-phosphate/insulin-like growth
      factor 2 receptor (M6p/Igf2r) coding sequence were screened. The latter is
      homologous to the human M6P/IGF2r coding sequence which is mutated in human
      hepatocellular carcinoma. A complete single strand conformation polymorphism
      analysis of the entire coding region of the rat adenomatous polyposis coli (Apc)
      gene was also performed for the first time in rat tumorigenic samples. Twenty-six
      chemically induced rat hepatocellular carcinomas, 21 neoplasms from the livers of
      SV40 T-Ag animals, and five immortalized hepatic cell lines from the transgenic
      rats were evaluated. None of the hepatic tumors exhibited mutations in the
      regions analyzed. The albumin-SV40 T-Ag transgenic cell line L-60, derived from
      normal hepatic tissue, had two mutations in contiguous codons of exon 5 of the
      p53 gene: a GGT --> GTT missense transversion in codon 183 and a silent mutation
      in codon 184. The transversion, which may affect the DNA binding domain of the
      p53 protein, probably originated during cell culture and may have been positively
      selected because it gave a growth advantage to the mutated cells. The studied
      region of the M6p/Igf2r gene was not found to be mutated in these two models of
      rat hepatocarcinogenesis. Although M6p/Igf2r, Apc, and p53 have been shown to be
      mutated in a variety of human hepatic proliferative diseases, our results
      indicate that aberrations in these genes may not be necessary for liver
      carcinogenesis in the rat.

PMID- 10411140
TI  - Roles of polyadenylation and nucleolytic cleavage in the filamentous phage mRNA
      processing and decay pathways in Escherichia coli.
AB  - To define basic features of mRNA processing and decay in Escherichia coli, we
      have examined a set of mRNAs encoded by the filamentous phage f1 that have
      structures typical of bacterial mRNAs. They bear a stable hairpin stem-loop on
      the 3' end left from rho-independent termination and are known to undergo
      processing by RNase E. A small percentage of the f1 mRNAs were found to bear
      poly(A) tails that were attached to heterogeneous positions near the common 3'
      end. In a poly(A) polymerase-deficient host, the later-appearing processed mRNAs
      were stabilized, and a novel small RNA accumulated. This approximately 125-nt RNA
      proved to arise via RNase E cleavage from the 3'-terminal region of the mRNAs
      bearing the terminator. Normally ribosomes translating gene VIII appear to
      protect this cleavage site from RNase E, so that release of the fragment from the
      mRNAs occurs very slowly. The data presented define additional steps in the f1
      mRNA processing and decay pathways and clarify how features of the pathways are
      used in establishing and maintaining the persistent filamentous phage infection.
      Although the primary mode of decay is endonucleolytic cleavage generating a
      characteristic 5' --> 3' wave of products, polyadenylation is involved in part in
      degradation of the processed mRNAs and is required for turnover of the 125-nt
      mRNA fragment. The results place polyadenylation at a later rather than an
      initiating step of decay. They also provide a clear illustration of how stably
      structured RNA 3' ends act as barriers to 3' --> 5' exonucleolytic mRNA decay.

PMID- 10411139
TI  - The first ATPase domain of the yeast 246-kDa protein is required for in vivo
      unwinding of the U4/U6 duplex.
AB  - The yeast PRP44 gene, alternatively named as BRR2, SLT22, RSS1, or SNU246,
      encodes a 246-kDa protein with putative RNA helicase function during pre-mRNA
      splicing. The protein is a typical DEAD/H family member, but unlike most other
      members of this family, it contains two putative RNA helicase domains, each with
      a highly conserved ATPase motif. Prior to this study little was known about
      functional roles for these two domains. We present genetic and biochemical
      evidence that ATPase motifs of only the first helicase domain are required for
      cell viability and pre-mRNA splicing. Overexpression of mutations in the first
      domain results in a dominant negative phenotype, and extracts from these mutant
      strains inhibit in vitro pre-mRNA splicing. In vitro analyses of affinity
      purified proteins revealed that only the first helicase domain possesses poly (U)
      dependent ATPase activity. Overexpression of a dominant negative protein in vivo
      reduces the relative abundance of free U4 and U6 snRNA with a concomitant
      accumulation of the U4/U6 duplex. Accumulation of the U4/U6 duplex was relieved
      by overexpression of wild-type Prp44p. Three DEAD/H box proteins, Prp16p, Prp22p
      and Prp44p, have previously been shown to affect U4/U6 unwinding activity in
      vitro. The possible role of these proteins in mediating this reaction in vivo was
      explored following induced expression of ATPase domain mutants in each of these.
      Although overexpression of the mutant form of either Prp16p, Prp22p, or Prp44p
      was lethal, only expression of the mutant Prp44p resulted in accumulation of the
      U4/U6 helix. Our results, when combined with previously published in vitro
      results, support a direct role for Prp44p in unwinding of the U4/U6 helix.

PMID- 10411142
TI  - Telomerase activation and cell proliferation during 7,12
      dimethylbenz[a]anthracene-induced hamster cheek pouch carcinogenesis.
AB  - Telomerase is a ribonucleoprotein complex intimately involved in cell
      immortalization and carcinogenesis. This enzyme is activated and stabilizes
      telomere length in almost all types of cancer. Telomerase may be necessary for
      continuous cell proliferation. In this study, we analyzed telomerase activity in
      hamster experimental oral lesions (starting from epithelial hyperplasia through
      dysplasia, carcinoma in situ, and invasive carcinoma) evoked by 7,12
      dimethylbenz[a]anthracene, and in normal mucosa. We also analyzed proliferative
      activity in these lesions by using immunohistochemical analysis and flow
      cytometry. Histologically normal epithelium expressed weak telomerase activity.
      The telomerase activity count increased rapidly in the early stage of
      carcinogenesis and gradually in the late stage. Cell-proliferative activity
      closely correlated with progression of disease. These findings indicate that
      telomerase activation is an early event and that increases in telomerase activity
      upregulate cell proliferation in chemically induced hamster oral carcinogenesis.

PMID- 10411143
TI  - Expression and regulation of the meprin beta gene in human cancer cells.
AB  - A novel mRNA isoform (meprin beta') of the cell-surface protease subunit meprin
      beta was previously identified in human colon cancer cells. The study reported
      here revealed that this mRNA isoform was identical within the protein coding
      region and at the 3' end to the beta isoform of normal intestine but that it
      contained an extended 5' untranslated region. Meprin beta' mRNA was expressed in
      the human breast cancer cell lines MCF-7 and SK-BR-3, in the human osteosarcoma
      cell line U2 Os, and in the human pancreatic cancer cell line BxPC-3. Meprin beta
      mRNA, but not beta' mRNA, was expressed in human fetal kidney cells. We cloned
      and sequenced genomic DNA encoding portions of the promoter region of the meprin
      beta gene. The unique sequences present in the beta' mRNA were present in the
      human genomic DNA immediately upstream of the transcription start site for the
      beta mRNA. The human meprin promoter sequence was searched for potential
      transcription-factor binding sites, and putative activator protein-1, polyoma
      enhancer activator 3 (PEA3), CCAAT enhancer-binding protein beta, and estrogen
      receptor binding sites were identified along with binding sites for the intestine
      specific cdx-2 transcription factor. The activity of meprin promoter/luciferase
      reporter gene constructs transfected into U2 Os cells was highest with constructs
      containing 83 and 639 bp of promoter DNA. These regions of the promoter each
      contain a putative PEA3 element. Treatment of the human colon adenocarcinoma cell
      line HT29-18C1 with 50 or 100 ng/mL phorbol myristal acetate for 8 h increased
      meprin beta' mRNA levels. Likewise, U2 Os cells transfected with the 
      639/luciferase or -1800/luciferase constructs showed a phorbol myristal acetate
      inducible increase in reporter gene activity, indicating that the PEA3 element
      within the -639 construct or other elements further upstream respond to phorbol
      ester.

PMID- 10411145
TI  - In vivo association of pp60v-src and the gap-junction protein connexin 43 in v
      src-transformed fibroblasts.
AB  - v-src-transformed fibroblasts have significantly reduced levels of gap junction
      mediated intercellular communication. This observed downregulation of cellular
      communication has been associated with tyrosine phosphorylation of the gap
      junction protein connexin 43 (Cx43). Previously, we demonstrated that purified,
      kinase-active pp60src phosphorylates Cx43 in vitro (J Biol Chem 1995; 270:12751
      12761). More recently, we reported that this association is mediated by the SH2
      and SH3 domains of pp60v-src (J Biol Chem 1997;272:22824-22831). In this report,
      we present in vivo evidence supporting the hypothesis that Cx43 is an endogenous
      substrate of pp60v-src in v-src-transformed fibroblasts. Cytological localization
      studies with confocal microscopy demonstrated that pp60v-src and Cx43 were
      partially co-localized in regions of the plasma membrane. Cx43 and pp60v-src co
      immunoprecipitated from v-src-transformed fibroblasts, indicating that the two
      proteins were associated, and form a stable complex. Furthermore, pp60v-src could
      phosphorylate co-immunoprecipitated Cx43 in an immune-complex kinase assay. Two
      dimensional phosphopeptide mapping of the immune-complexed Cx43 phosphorylated in
      vitro demonstrated that the sites of tyrosine phosphorylation were consistent
      with previously identified sites of pp60v-src phosphorylation. These results
      provide additional in vivo evidence that Cx43 is a direct substrate of pp60v-src
      in v-src-transformed fibroblasts. The ability of pp60v-src to alter gap junction
      mediated cellular communication may serve as one mechanism by which pp60v-src
      initiates and/or maintains aspects of cellular transformation.

PMID- 10411144
TI  - Multiple pathways of prostate carcinogenesis analyzed by using cultured cells
      isolated from rats treated with N-methyl-N-nitrosourea and testosterone.
AB  - Treatment of rats with N-methyl-N-nitrosourea (MNU) and testosterone results in a
      high incidence of metastasizing dorsolateral prostate tumors. In previous
      studies, a high frequency (> or = 70%) of a G35 --> A transition mutation at the
      second position of codon 12 of the Ki-ras oncogene was found in these tumors.
      This was confirmed in the study reported here, and the frequency of this mutation
      appeared similar in tumors induced in four different rat strains, regardless of
      differences in sensitivity among these strains to the induction of prostate
      cancers by MNU and testosterone: Wistar Furth (62% incidence of grossly visible
      prostate tumors) > Lobund Wistar (55%) > Fisher 344 (40%) > Copenhagen (37%). A
      method was developed to isolate and separately culture epithelial and stromal
      cells from these rat prostate carcinomas. Of 20 primary cell cultures established
      from histologically confirmed rat prostate carcinomas, 19 (95%) displayed one or
      more of the following characteristics: the Ki-ras mutation (17 of 20; 85%),
      anchorage-independent growth in soft agar at early passage (12 of 20; 60%), or
      tumorigenicity at later passage (eight of eight; 100%). One epithelial cell
      culture and all five stromal cell cultures established from prostate tumors had
      none of these characteristics. Epithelial cultures that had the Ki-ras mutation
      and grew in soft agar constitute the predominant genotype/phenotype (55%),
      cultures with the mutation that did not grow in soft agar were less frequent
      (30%), 10% of the cultures had neither characteristic, and only one grew in soft
      agar but did not have the mutation. These findings suggest that there are at
      least two and perhaps more different molecular pathways of prostate
      carcinogenesis in rats treated with MNU plus testosterone. Furthermore, these
      data suggest that these pathways and the mechanisms determining strain
      differences in sensitivity to prostate cancer induction are unrelated.

PMID- 10411146
TI  - Peroxyacetyl nitrate-induced apoptosis through generation of reactive oxygen
      species in HL-60 cells.
AB  - Peroxyacetyl nitrate (PAN), an ubiquitous air pollutant, induced apoptosis in
      human leukemia HL-60, human chronic myelogenous leukemia K-562, and mouse
      monocyte-macrophage RAW 264.7 cell lines. In the HL 60 cells, characteristic
      apoptosis morphology could be observed 4 h after the cells were treated with 50
      microM PAN. Exposure of HL-60 cells to increasing concentrations of PAN (from 1
      microM to 100 microM) confirmed the concentration dependence of apoptosis as
      evidenced by DNA fragmentation in HL-60 cells, chromatin condensation by acridine
      orange staining, and the appearance of the DNA apoptotic peak in flow cytometry.
      During apoptosis in HL-60 cells, 3-nitrotyrosine and 3,5-dinitrotyrosine were
      detected by high-performance liquid chromatography and liquid chromatography-mass
      spectrometry-mass spectrometry. We hypothesized that PAN might induce cell death
      in human leukemia cells by releasing peroxynitrite and other reactive oxygen
      species (ROS) such as superoxide and hydrogen peroxide. Moreover, exogenous
      superoxide dismutase promoted PAN-induced apoptosis, and in contrast, a
      combination of superoxide dismutase and catalase suppressed this apoptosis. We
      also hypothesize that the generation of ROS during PAN-induced apoptosis in HL-60
      cells could activate stress-activated protein kinase/jun N-terminal kinase
      activity. The formation of H2O2 produced from the dismutation of PAN-elicited
      superoxide anion contributed to the apoptotic mechanism in HL-60 cells through
      ROS pathways. These findings suggested that induction of apoptosis by the air
      pollutant PAN might occur as a result of the release of ROS.

PMID- 10411147
TI  - Nuclear localization of beta-catenin in normal and carcinogenic endometrium.
AB  - We have previously shown that the connexin (Cx) 26 and 32 genes are expressed
      during the secretory phase of the human endometrium and that their expression is
      downregulated during the proliferative phase, suggesting a role for intercellular
      transduction in cell growth control in human endometrium. To further study the
      possible role of cell-to-cell interaction in growth regulation, we
      immunohistochemically analyzed 80 endometrial samples (30 of normal endometrium,
      20 of endometrial hyperplasia, and 30 of endometrial cancer) for the expression
      of E-cadherin; alpha-, beta-, and gamma-catenin; adenomatous polyposis coli (APC)
      protein, and sex-steroid hormone receptors at three points in the cells: the cell
      to-cell border, the cytoplasm, and the nucleus. In this study, moderate or strong
      staining of beta-catenin in the nuclei was observed in 60.0% of endometrial
      hyperplasia samples and 30.0% of endometrial cancer samples, although the beta
      catenin gene was mutated in only two of the nine samples that showed the
      intensive nuclear staining. Western blotting analysis showed that the samples
      that had intense nuclear staining of beta-catenin had much higher expression of
      beta-catenin than the samples that did not have nuclear staining. Furthermore,
      normal endometrium showed nuclear localization, especially in the mid- and late
      proliferative and early-secreting phases of the menstrual cycle. The results
      suggest that the nuclear localization of beta-catenin observed in endometrial
      hyperplasia and endometrial cancer, as in other tumors, implies that beta
      catenin/Wnt-1 signal transduction is highly activated in carcinogenesis of the
      endometrium as well as in normal physiological conditions.

PMID- 10411149
TI  - There is nothing wrong with dermatologists selling products to patients!

PMID- 10411150
TI  - Magnetic resonance angiography in the diagnosis of a case of giant cell arteritis
      manifesting as scalp necrosis.

PMID- 10411148
TI  - Differential effects of arsenic(III) and chromium(VI) on nuclear transcription
      factor binding.
AB  - The toxic metals arsenic(III) and chromium(VI) are considered human carcinogens,
      although they may act through different mechanisms. We previously showed that
      when administered at single low, non-overtly toxic doses, chromium, arsenic, and
      several other chemical carcinogens preferentially alter expression of several
      model inducible genes in both whole-animal and cell-culture systems. In this
      study, we assessed whether chromium and arsenic target specific signaling
      pathways within cells to selectively modulate gene expression. We examined the
      effects of non-cytotoxic and cytotoxic doses of arsenic(III) and chromium(VI) on
      nuclear binding of the transcription factors AP-1, NF-kappaB, Sp1, and YB-1 in
      human MDA-MB-435 breast cancer and rat H4IIE hepatoma cells. These transcription
      factors were chosen because they may regulate many inducible genes, including
      those previously shown to be altered by metal treatments. We report that both
      arsenic and chromium significantly altered nuclear binding levels of these
      factors to their respective cis-acting elements. However, there were qualitative
      and quantitative differences in these effects that were dependent on the metal,
      time, dose, transcription factor, and cell line. These effects may play a
      significant role in metal-induced alterations in gene expression.

PMID- 10411151
TI  - Dermatologic manifestations of Hermansky-Pudlak syndrome in patients with and
      without a 16-base pair duplication in the HPS1 gene.
AB  - BACKGROUND: Hermansky-Pudlak syndrome (HPS) consists of oculocutaneous albinism,
      a platelet storage pool deficiency, and lysosomal accumulation of ceroid
      lipofuscin. Patients with HPS from northwest Puerto Rico are homozygous for a 16
      base pair (bp) duplication in exon 15 of HPS1, a gene on chromosome 10q23 known
      to cause the disorder. OBJECTIVE: To determine the dermatologic findings of
      patients with HPS. DESIGN: Survey of inpatients with HPS by physical examination.
      SETTING: National Institutes of Health Clinical Center, Bethesda, Md (a tertiary
      referral hospital). PATIENTS: Sixty-five patients aged 3 to 54 years were
      diagnosed on the basis of the absence of platelet dense bodies in individuals
      with albinism and a bleeding diathesis. The presence of a 16-bp duplication in
      HPS1 was determined by polymerase chain reaction amplification; 40 patients were
      homozygous for the duplication and 25 lacked the duplication. All patients with
      the duplication were from northwest Puerto Rico; all patients without the
      duplication were non-Puerto Rican except 4 from central Puerto Rico. RESULTS:
      Both patients homozygous for the 16-bp duplication and patients without the
      duplication displayed skin color ranging from white to light brown. Patients with
      the duplication, as well as those lacking the duplication, had hair color ranging
      from white to brown and eye color ranging from blue to brown. New findings in
      both groups of patients with HPS were melanocytic nevi with dysplastic features,
      acanthosis nigricans-like lesions in the axilla and neck, and trichomegaly.
      Eighty percent of patients with the duplication exhibited features of solar
      damage, including multiple freckles, stellate lentigines, actinic keratoses, and,
      occasionally, basal cell or squamous cell carcinomas. Only 8% of patients lacking
      the 16-bp duplication displayed these findings. As a group, the patients with the
      duplication lived closer to the equator than those without the duplication.
      CONCLUSION: Patients with HPS exhibit wide variation in pigmentation and
      dermatologic findings.

PMID- 10411152
TI  - Basal cell skin carcinoma and other nonmelanoma skin cancers in Finland from 1956
      through 1995.
AB  - OBJECTIVE: To study trends of nonmelanoma skin cancer in Finland. DESIGN:
      Descriptive analysis of incidence and mortality rates for basal cell skin
      carcinoma (BCC) and other non-melanoma skin cancers (NMSCs) from 1966 and 1956,
      respectively, through 1995 in relation to sex, age, anatomical distribution,
      place of residence, and occupation. SETTING: Data were obtained from the
      nationwide Finnish Cancer Registry, to which reporting of skin cancer is
      compulsory. PATIENTS: Inhabitants of Finland (5.1 million in 1998). MAIN OUTCOME
      MEASURES: Age- and sex-specific incidence and mortality rates and overall rates
      adjusted for age to the world standard population; occupation-specific
      standardized incidence ratios, with the total Finnish population as reference.
      RESULTS: The age-adjusted incidence rate in 1991 through 1995 for BCC was 49 per
      100,000 person-years in men and 45 in women. For NMSC it was 8.7 in men and 5.3
      in women. Both cancer types showed an increasing trend in incidence rates. The
      proportion of tumors in the face, scalp, and neck was 59% for BCC and 67% for
      NMSC. The incidence rate of NMSC increased from north to south, while there was
      no great urban-rural or occupational variation in the occurrence of NMSC. The
      incidence rate for BCC was higher in urban than in rural regions. Farmers,
      forestry workers, and fishermen showed low incidence of BCC, whereas occupations
      with a high level of education or compulsory health checkups and medical care
      occupations appeared to have an increased incidence of BCC. The mortality rate
      for BCC in 1991 through 1995 was 0.08 per 100,000 person-years in men and 0.05 in
      women, and for NMSC, it was 0.38 in men and 0.23 in women. The mortality trend
      was decreasing for both cancer types. CONCLUSIONS: The incidence of NMSC is
      fairly low in Finland, accounting for 3.5% of all new cancer cases. Conversely,
      BCC is the most common cancer type. The incidence trend is increasing for both
      skin cancer types, but mortality remains low.

PMID- 10411153
TI  - Bowen disease and risk of subsequent malignant neoplasms: a population-based
      cohort study of 1147 patients.
AB  - OBJECTIVE: To address the long-standing question of whether patients with Bowen
      disease are at increased risk of internal malignant neoplasms. PATIENTS: A total
      of 1147 Danish patients diagnosed between 1978 and 1993 as having Bowen disease
      at nongenital sites were followed up for 6463 person-years for cancer occurrence
      up to 16 years after the skin lesion. MAIN OUTCOME MEASURE: Standardized
      incidence ratios (SIRs)--the ratios of observed-to-expected numbers of cancer-
      served as measures of relative risk. RESULTS: The observed number of noncutaneous
      cancers occurring in the cohort (n = 115) was close to expected (n = 103.0) (SIR
      = 1.1; 95% confidence interval, [CI], 0.9-1.3). However, nonmelanoma skin cancer
      (SIR = 4.3; 95% CI, 3.5-5.4; n = 83), lip cancer (SIR = 8.2; 95% CI, 2.6-19.1; n
      = 5), and, among men, leukemia (SIR = 3.2; 95% CI, 1.04-7.5; n = 5) occurred in
      excess. CONCLUSIONS: Patients with Bowen disease do not appear to
      constitutionally be at any unusually high general cancer risk. The increased risk
      of invasive skin and lip cancers is likely due to the common risk factor of UV
      light.

PMID- 10411154
TI  - Asymmetric periflexural exanthem of childhood: a clinical, pathologic, and
      epidemiologic prospective study.
AB  - OBJECTIVE: To assess the clinical, pathologic, and epidemiologic features of
      asymmetric periflexural exanthem of childhood (APEC), a clinically distinctive
      eruption, especially its link with pityriasis rosea and pattern of transmission.
      DESIGN: A prospective case series, including an analysis of epidemiologic
      triggering factors and mode of transmission. Pathologic study, including
      immunohistochemistry of the inflammatory infiltrate. SETTING: A mixed, community
      based referral center. PATIENTS: A total of 37 girls and 30 boys with typical
      APEC referred from April 1994 to December 1996 were included in the study; 82%
      came from the greater Bordeaux area in France. INTERVENTION: None. MAIN OUTCOME
      MEASURE: Possible interhuman transmission of APEC. RESULTS: [corrected] No
      triggering factor was identified; no interhuman transmission occurred; and no
      demonstrable link with pityriasis rosea was apparent. Several new clinical
      variants were recognized or confirmed (high fever, facial and peripheral
      involvement, prolonged course). Distinctive perisudoral interface CD8+ infiltrate
      was suggestive of diagnosis. CONCLUSIONS: Interhuman transmission was doubtful,
      but inoculation disorder was still possible. Histopathologic findings seem more
      specific than previously thought.

PMID- 10411155
TI  - Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy.
AB  - OBJECTIVE: To characterize the epidemiological, clinical, and histopathological
      features of patients with cancer who develop widespread polymorphic and pruritic
      skin lesions following radiotherapy. PATIENTS, DESIGN, AND INTERVENTIONS: During
      phase 1, epidemiological and clinical features of 103 patients with cancer, 83
      treated with radiotherapy (71 women and 12 men) and 20 controls who did not
      undergo radiotherapy (16 women and 4 men), were explored during 3 months (October
      1995 to January 1996). During phase 2, in 30 additional patients with cancer who
      were treated with telecobalt or linear accelerator, 18 with skin lesions (15
      women and 3 men) and 12 without lesions (10 women and 2 men), the following were
      investigated: (1) hematoxylin-eosin-stained sections for routine
      histopathological examination and direct immunofluorescence, and lymphocytic
      markers; (2) blood, skin, and primary tumor eosinophilia; and (3) the presence of
      antiepidermal autoantibodies. Patients were examined during 5 months (February
      1996 to June 1996). SETTING: A dermatology department at a university hospital.
      RESULTS: During phase 1, 14 (17%) of the 83 patients undergoing radiotherapy
      developed an eruption. Acral excoriations, erythematous papules, vesicles, and
      bullae were the most frequent lesions. During phase 2, in 18 patients, a
      superficial and deep lymphocytic perivascular infiltrate with numerous
      eosinophils, intraepidermal and interstitial eosinophilic infiltrates,
      eosinophilic panniculitis, IgM and C3 perivascular deposits, and slightly
      predominant CD4+ cells were observed. No antiepidermal autoantibodies were found.
      CONCLUSIONS: The clinical, histopathological, and immunopathologic features in
      patients with cancer undergoing radiotherapy are described. To our knowledge,
      this condition has not been well characterized. Because of its unique
      presentation, the denomination "eosinophilic, polymorphic, and pruritic eruption
      associated with radiotherapy" is suggested.

PMID- 10411156
TI  - Urinary adenosine and aminoimidazolecarboxamide excretion in methotrexate-treated
      patients with psoriasis.
AB  - BACKGROUND: We hypothesized that low-dose methotrexate treatment for patients
      with psoriasis would block purine biosynthesis at the step catalyzed by
      aminoimidazolecarboxamide (AICA) ribotide transformylase and would inhibit
      adenosine metabolism as evidenced by increased urinary levels of AICA and
      adenosine, respectively. Eight patients collected a 24-hour urine specimen on the
      day before their methotrexate dose and the next day during their methotrexate
      dose. Eight age- and sex-matched controls also collected a 24-hour urine sample.
      Urinary AICA and adenosine were assayed by spectrophotometric and radioimmune
      assays, respectively; means are reported as micromole per millimole of creatinine
      and were compared by the paired t test (1-tailed). OBSERVATIONS: Mean AICA
      excretion increased from 1.30 micromol/mmol on the day before to 1.85
      micromol/mmol on the day during methotrexate dosing (P<.01). Mean adenosine
      values increased from 0.68 to 1.07 micromol/mmol, (P<.03). Controls had mean AICA
      and adenosine levels of 1.29 and 0.50 micromol/mmol, respectively. During the day
      of methotrexate dosing, patients had higher mean AICA and adenosine levels when
      compared with controls (P<.01). Mean AICA levels increased from 1.36 to 2.06
      micromol/mmol (P<.025), and mean adenosine levels increased from 0.72 to 1.25
      micromol/mmol (P<.025) in 5 patients showing improvement in clinical disease
      activity. In contrast, 3 patients with no change or worsening in clinical disease
      activity had smaller increases. CONCLUSIONS: Methotrexate treatment of patients
      with psoriasis inhibits AICA ribotide transformylase and adenosine metabolism.
      Since adenosine is a T-lymphocyte toxin, it may be partially responsible for the
      immunosuppressive effect.

PMID- 10411157
TI  - Leg ulcers and hydroxyurea: forty-one cases.
AB  - BACKGROUND: Hydroxyurea is an antitumor agent used to treat chronic
      myeloproliferative disorders. Leg ulcerations have been reported in patients
      undergoing long-term hydroxyurea therapy for myeloproliferative diseases. To
      better define this dermatological adverse effect of hydroxyurea therapy and to
      try to understand the pathophysiological process of this disease, we collected
      medical information for such patients in a multicenter retrospective study.
      OBSERVATIONS: Forty-one patients (mean age, 67 years) developed leg ulcerations
      while undergoing hydroxyurea therapy (mean therapy duration, 5 years). The sex
      ratio was 1, and there was no underlying vascular disease. Hematologic
      abnormalities were identified. Complete recovery from the ulcerations occurred
      quickly after withdrawal of treatment in 33 (80%) of the cases. CONCLUSIONS: This
      longest-reported series of patients confirms the role of hydroxyurea therapy in
      the onset of leg ulcerations. Healing or improvement requires cessation of
      treatment. Cutaneous atrophy and impaired wound healing may explain the
      relationship between hydroxyurea and leg ulcers. In addition, the megaloblastic
      erythrocytes resulting from the presence of hydroxyurea may circulate poorly
      through the capillary network. A prospective study in hematologic centers would
      be valuable.

PMID- 10411158
TI  - Altered lamellar body secretion and stratum corneum membrane structure in
      Netherton syndrome: differentiation from other infantile erythrodermas and
      pathogenic implications.
AB  - BACKGROUND: The infant with Netherton syndrome (NS) typically displays a
      generalized erythroderma covered by fine, translucent scales, which can be
      difficult to distinguish clinically from erythrodermic psoriasis, nonbullous
      congenital ichthyosiform erythroderma, or other infantile erythrodermas. Some
      infants with NS develop progressive hypernatremic dehydration, failure to thrive,
      and enteropathy. Such complications can be fatal. Diagnosis is typically delayed
      until the appearance of a pathognomonic hair shaft anomaly, trichorrhexis
      invaginata (bamboo hair). To facilitate the early diagnosis of NS, we obtained
      biopsy specimens from 7 patients with erythrodermic NS and compared their
      morphologic findings to those of 3 patients with erythrodermic psoriasis and 2
      with congenital ichthyosiform erythroderma. Biopsy specimens were processed for
      light and electron microscopy using postfixation with osmium tetroxide and
      ruthenium tetroxide. OBSERVATION: In NS, and often in congenital ichthyosiform
      erythroderma and erythrodermic psoriasis, the stratum corneum layer was largely
      replaced by parakeratotic cells. A distinctive feature--premature secretion of
      lamellar body contents--occurred only in NS. Furthermore, lamellar body-derived
      extracellular lamellae and stratum corneum lipid membranes were separated
      extensively by foci of electron-dense material. Finally, transformation of
      lamellar body-derived lamellae into mature lamellar membrane structures was
      disturbed in NS. CONCLUSIONS: Premature lamellar body secretion and foci of
      electron-dense material in the intercellular spaces of stratum corneum, features
      not observed in other erythrodermic disorders, appear to be frequent and
      relatively specific markers for NS. These ultrastructural features could permit
      the early diagnosis of NS before the appearance of the hair shaft abnormality.
      These abnormalities could explain the impaired permeability barrier in NS, and
      account for hypernatremia and dehydration in infants with NS.

PMID- 10411159
TI  - Treatment with UV-B for psoriasis and nonmelanoma skin cancer: a systematic
      review of the literature.
AB  - BACKGROUND: In a cost-effectiveness study currently being conducted of short
      contact anthralin treatment for psoriasis in an outpatient setting as compared
      with the standard treatment with UV-B radiation, the excess incidence (IDD) of
      skin cancer due to exposure to UV-B could not be ascertained because the study
      did not last long enough. A meta-analysis of published data was deemed
      appropriate. OBJECTIVE: To quantify the IDD of nonmelanoma skin cancer as a
      function of the total dose of UV-B and specific for time since first exposure,
      age at first treatment, and other treatments received. METHODS: Systematic review
      of the literature with meta-analysis of all available evidence published in
      English, French, German, or Dutch between 1980 and 1996. RESULTS: Four articles
      contained information that enabled us to calculate an overall IDD of nonmelanoma
      skin cancer. The estimates varied between -0.6 and 2 extra skin cancers per 100
      patients with psoriasis treated with UV-B phototherapy per year. However, these
      estimates were calculated under several assumptions, and do not allow for the
      construction of a dose-response model specific for time since exposure or age at
      first treatment. A model based on animal data suggests that a total of 5 excess
      skin cancers can be expected per 100 treated in the 60 years after the start of
      treatment with 500 minimum effective doses of UV-B per year from age 25 years.
      CONCLUSIONS: The available evidence is insufficient for quantifying the IDD of
      nonmelanoma skin cancer in patients with psoriasis treated with UV-B radiation.
      However, it seems unlikely that the excess risk exceeds 2% per year. As yet, it
      is not possible to assess at what level of exposure this IDD occurs, or how long
      after exposure excess risk is present.

PMID- 10411160
TI  - The mysteries of geographic variability in nonmelanoma skin cancer incidence.

PMID- 10411161
TI  - Penile erythematous eruption in a man with diabetes.

PMID- 10411162
TI  - Palmar ulceration.

PMID- 10411163
TI  - An asymptomatic penile plaque with regional lymphadenopathy.

PMID- 10411164
TI  - Discoid lupus erythematosus-like lesions and stomatitis.

PMID- 10411165
TI  - The sale of products benefits patients and doctors alike.

PMID- 10411166
TI  - The ethical dispensing of nonprescription skin care medications is useful as we
      approach the new millennium.

PMID- 10411167
TI  - A full "cure" for onychomycosis is not always possible.

PMID- 10411168
TI  - The role of mycophenolate mofetil in the management of pemphigus.

PMID- 10411169
TI  - Is mycophenolic acid effective for the treatment of pemphigus?

PMID- 10411171
TI  - Topical amphotericin B for cutaneous leishmaniasis.

PMID- 10411170
TI  - EMLA cream-induced eye injury.

PMID- 10411172
TI  - A histopathologic evaluation of vulvar melanosis.

PMID- 10411173
TI  - Genital Bowen disease associated with an unusual human papillomavirus type 57b.

PMID- 10411174
TI  - Poliosis associated with a giant congenital nevus.

PMID- 10411175
TI  - Treatment of psoriasis with calcipotriene plus psoralen-UV-A-bath therapy.

PMID- 10411176
TI  - A piece of my mind. To whom shall I tell my grief?

PMID- 10411177
TI  - Prescribing for seniors: neither too much nor too little.

PMID- 10411178
TI  - Experts debate drugs for healthy women with breast cancer risk.

PMID- 10411180
TI  - Report on Australian research ups funding.

PMID- 10411179
TI  - Opinions divided on high-dose chemotherapy for breast cancer.

PMID- 10411181
TI  - Animal feed antibiotic use raises drug resistance fear.

PMID- 10411182
TI  - From the Centers for Disease Control and Prevention. Patients' reports of
      counseling on mammography screening by health-care providers--North Carolina,
      1997.

PMID- 10411183
TI  - From the Centers for Disease Control and Prevention. Illnesses associated with
      occupational use of flea-control products--California, Texas, and Washington,
      1989-1997.

PMID- 10411184
TI  - Effect of lifestyle changes on coronary heart disease.

PMID- 10411185
TI  - Effect of lifestyle changes on coronary heart disease.

PMID- 10411186
TI  - Effect of lifestyle changes on coronary heart disease.

PMID- 10411187
TI  - Exploring the ethics of clinical role conflicts.

PMID- 10411188
TI  - Exploring the ethics of clinical role conflicts.

PMID- 10411189
TI  - Gabapentin for painful diabetic neuropathy.

PMID- 10411190
TI  - Gabapentin for painful diabetic neuropathy.

PMID- 10411191
TI  - Gabapentin for postherpetic neuralgia.

PMID- 10411192
TI  - A close look at standards for therapeutic touch.

PMID- 10411193
TI  - Risks and benefits of gun ownership.

PMID- 10411194
TI  - Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy,
      working adults: a randomized controlled trial.
AB  - CONTEXT: Influenza virus is a major cause of illness, disruption to daily life,
      and increased use of health care in all age groups. OBJECTIVE: To assess the
      safety and effectiveness of intranasally administered trivalent, live, attenuated
      influenza virus (LAIV) vaccine for reducing illness, absenteeism, and health care
      use among healthy, working adults. DESIGN: Randomized, double-blind, placebo
      controlled trial conducted from September 1997 through March 1998. SETTING:
      Thirteen centers across the United States. PARTICIPANTS: A total of 4561 healthy,
      working adults aged 18 to 64 years recruited through health insurance plans, at
      work sites, and from the general population. INTERVENTION: Participants were
      randomized 2:1 to receive intranasally administered trivalent LAIV vaccine (n =
      3041) or placebo (n = 1520) in the fall of 1997. MAIN OUTCOME MEASURES: Episodes
      of febrile illness, severe febrile illness, febrile upper respiratory tract
      illness, work loss, and health care use during the peak and total influenza
      outbreak periods, and adverse events. RESULTS: Recipients of LAIV vaccine were as
      likely to experience 1 or more febrile illnesses as placebo recipients during
      peak outbreak periods (13.2% for vaccine vs 14.6% for placebo; P=.19). However,
      vaccination significantly reduced the numbers of severe febrile illnesses (18.8%
      reduction; 95% confidence interval [CI], 7.4%-28.8%) and febrile upper
      respiratory tract illnesses (23.6% reduction; 95% CI, 12.7%-33.2%). Vaccination
      also led to fewer days of illness across all illness syndromes (22.9% reduction
      for febrile illnesses; 27.3% reduction for severe febrile illnesses), fewer days
      of work lost (17.9% reduction for severe febrile illnesses; 28.4% reduction for
      febrile upper respiratory tract illnesses), and fewer days with health care
      provider visits (24.8% reduction for severe febrile illnesses; 40.9% reduction
      for febrile upper respiratory tract illnesses). Use of prescription antibiotics
      and over-the-counter medications was also reduced across all illness syndromes.
      Vaccine recipients were more likely to experience runny nose or sore throat
      during the first 7 days after vaccination, but serious adverse events between the
      groups were not significantly different. The match between the type A(H3N2)
      vaccine strain and the predominant circulating virus strain
      (A/Sydney/05/97[H3N2]) for the 1997-1998 season was poor, suggesting that LAIV
      provided substantial cross-protection against this variant influenza A virus
      strain. CONCLUSION: Intranasal trivalent LAIV vaccine was safe and effective in
      healthy, working adults in a year in which a drifted influenza A virus
      predominated.

PMID- 10411195
TI  - Queuing for coronary angiography during severe supply-demand mismatch in a US
      public hospital: analysis of a waiting list registry.
AB  - CONTEXT: Adverse cardiac events have been reported in patients waiting for either
      coronary surgery or angioplasty. However, data on the risk of adverse events
      while awaiting coronary angiography are limited, and none are available from a US
      population. OBJECTIVE: To quantify cardiac outcomes in patients waiting for
      elective coronary angiography. DESIGN, SETTING, AND PARTICIPANTS: Observational
      cohort study of 381 adult outpatients (mean [SD] age, 55 [12] years; 64% male;
      61% white) on a waiting list for coronary angiography at a US tertiary care
      public teaching hospital during 1993-1994. MAIN OUTCOME MEASURES: Rates of
      cardiac death, nonfatal myocardial infarction, and hospitalizations for unstable
      angina or heart failure as a function of amount of time spent on a waiting list.
      RESULTS: Sixty-six patients were dropped from the waiting list but were included
      in the study analysis. During a mean (SD) follow-up of 8.4 (6.5) months, cardiac
      death, myocardial infarction, and hospitalization occurred in 6 (1.6%), 4 (1.0%),
      and 26 (6.8%) patients, respectively. The probability of events was minimal in
      the first 2 weeks and increased steadily between 3 and 13 weeks. By Cox
      multivariate analysis, 2 variables independently identified an increased risk of
      adverse events: a strongly positive treadmill exercise electrocardiogram or
      positive stress imaging result at referral (odds ratio [OR], 2.32; 95% confidence
      interval [CI], 1.22-4.16; P=.01) and the use of 2 to 3 anti-ischemic medications
      (OR, 1.98; 95% CI, 1.19-3.96; P=.04). Among 311 patients who ultimately underwent
      angiography, those with adverse events had a higher prevalence of coronary
      disease (96% vs 60%; P<.001), more frequently required revascularization (93% vs
      53%; P<.001), and had longer hospital stays (mean [SD], 6.2 [4.3] vs 1.3 [0.7]
      days; P=.001). CONCLUSION: Our data suggest that in a cohort referred for
      coronary angiography, delaying the procedure places some patients at risk for
      death, myocardial infarction, unplanned hospitalization, a longer hospital stay,
      and, potentially, a poorer prognosis. Waits longer than 2 weeks should be
      avoided, and patients with strongly positive stress test results and those who
      require 2 to 3 anti-ischemic medications should be prioritized for early
      intervention.

PMID- 10411196
TI  - Prevalence of carpal tunnel syndrome in a general population.
AB  - CONTEXT: Carpal tunnel syndrome (CTS) is a cause of pain, numbness, and tingling
      in the hands and is an important cause of work disability. Although high
      prevalence rates of CTS in certain occupations have been reported, little is
      known about its prevalence in the general population. OBJECTIVE: To estimate the
      prevalence of CTS in a general population. DESIGN: General health mail survey
      sent in February 1997, inquiring about symptoms of pain, numbness, and tingling
      in any part of the body, followed 2 months later by clinical examination and
      nerve conduction testing of responders reporting symptoms in the median nerve
      distribution in the hands, as well as of a sample of those not reporting these
      symptoms (controls). SETTING: A region in southern Sweden with a population of
      170000. PARTICIPANTS: A sex- and age-stratified sample of 3000 subjects (age
      range, 25-74 years) was randomly selected from the general population register
      and sent the survey, with a response rate of 83% (n = 2466; 46% men). Of the
      symptomatic responders, 81% underwent clinical examination. MAIN OUTCOME
      MEASURES: Population prevalence rates, calculated as the number of symptomatic
      responders diagnosed on examination as having clinically certain CTS and/or
      electrophysiological median neuropathy divided by the total number of responders.
      RESULTS: Of the 2466 responders, 354 reported pain, numbness, and/or tingling in
      the median nerve distribution in the hands (prevalence, 14.4%; 95% confidence
      interval [CI], 13.0%-15.8%). On clinical examination, 94 symptomatic subjects
      were diagnosed as having clinically certain CTS (prevalence, 3.8%; 95% CI, 3.1%
      4.6%). Nerve conduction testing showed median neuropathy at the carpal tunnel in
      120 symptomatic subjects (prevalence, 4.9%; 95% CI, 4.1%-5.8%). Sixty-six
      symptomatic subjects had clinically and electrophysiologically confirmed CTS
      (prevalence, 2.7%; 95% CI, 2.1%-3.4%). Of 125 control subjects clinically
      examined, electrophysiological median neuropathy was found in 23 (18.4%; 95% CI,
      12.0%-26.3%). CONCLUSION: Symptoms of pain, numbness, and tingling in the hands
      are common in the general population. Based on our data, 1 in 5 symptomatic
      subjects would be expected to have CTS based on clinical examination and
      electrophysiologic testing.

PMID- 10411198
TI  - Mandatory reporting of diseases and conditions by health care professionals and
      laboratories.
AB  - CONTEXT: Surveillance is a key component of the core public health function of
      health assessment. Systematic reporting by health care professionals and
      laboratories, which may vary by state law, statute, or regulation, continues to
      provide essential data for assessing public health. OBJECTIVE: To describe the
      state and territorial reporting requirements for diseases and conditions
      recommended for national public health surveillance. DESIGN, SETTING, AND
      PARTICIPANTS: Between May and August 1997, the state and territorial
      epidemiologists from all 50 states, in addition to New York City, Puerto Rico,
      and Guam, completed questionnaires indicating which diseases and conditions were
      reportable by health care professionals and laboratories in their jurisdictions.
      The surveys were subsequently updated to reflect reporting requirements current
      as of January 1, 1999. The overall response rate for the survey was 100% for US
      states and 90% overall, including the territories. MAIN OUTCOME MEASURE: State
      and territorial reporting requirements for diseases and conditions of public
      health concern. RESULTS: Of the 58 diseases and conditions recommended for
      national reporting, 35 (60%) were reportable in greater than 90% of the states
      and territories, 15 (26%) were reportable in 75% to 90%, and 8 (14%) were
      reportable in less than 75%. Nineteen of the infectious diseases were reportable
      in all of the states and territories that responded. CONCLUSIONS: Required
      reporting varies substantially by state or territory. Health care professionals
      are integral to public health efforts at the local, state, and national levels.

PMID- 10411197
TI  - Quality of care in investor-owned vs not-for-profit HMOs.
AB  - CONTEXT: The proportion of health maintenance organization (HMO) members enrolled
      in investor-owned plans has increased sharply, yet little is known about the
      quality of these plans compared with not-for-profit HMOs. OBJECTIVE: To compare
      quality-of-care measures for investor-owned and not-for-profit HMOs. DESIGN,
      SETTING, AND PARTICIPANTS: Analysis of the Health Plan Employer Data and
      Information Set (HEDIS) Version 3.0 from the National Committee for Quality
      Assurance's Quality Compass 1997, which included 1996 quality-of-care data for
      329 HMO plans (248 investor-owned and 81 not-for-profit), representing 56% of the
      total HMO enrollment in the United States. MAIN OUTCOME MEASURES: Rates for 14
      HEDIS quality-of-care indicators. RESULTS: Compared with not-for-profit HMOs,
      investor-owned plans had lower rates for all 14 quality-of-care indicators. Among
      patients discharged from the hospital after myocardial infarction, 59.2% of
      members in investor-owned HMOs vs 70.6% in not-for-profit plans received a beta
      blocker (P<.001); 35.1% of patients with diabetes mellitus in investor-owned
      plans vs 47.9% in not-for-profit plans had annual eye examinations (P<.001).
      Investor-owned plans had lower rates than not-for-profit plans of immunization
      (63.9% vs 72.3%; P<.001), mammography (69.4% vs 75.1%; P<.001), Papanicolaou
      tests (69.2% vs 77.1%; P<.001), and psychiatric hospitalization (70.5% vs 77.1%;
      P<.001). Quality scores were highest for staff- and group-model HMOs. In
      multivariate analyses, investor ownership was consistently associated with lower
      quality after controlling for model type, geographic region, and the method each
      HMO used to collect data. CONCLUSIONS: Investor-owned HMOs deliver lower quality
      of care than not-for-profit plans.

PMID- 10411199
TI  - A new doctor in the house: ethical issues in hospitalist systems.
AB  - The traditional patient-primary care physician (PCP) relationship provides many
      ethical protections for patients, including confidentiality, shared medical
      decision making, and respect for patient autonomy. Hospitalist models, which
      introduce a purposeful discontinuity of care, threaten these protections and
      raise certain ethical concerns. We analyze 2 cases that explore ethical issues
      arising in hospitalist systems and suggest ways to ensure ethical protection for
      patients. The first case examines how hospitalization can disrupt the patient-PCP
      relationship and raise ethical issues regarding confidentiality. In the second
      case, we discuss decision making when the patient's goals and preferences for
      care change as a result of hospitalization. Effective hospitalist systems provide
      a model for a trusting patient-physician relationship. Although the hospitalist
      must take responsibility for inpatient management, the PCP has a key role in
      addressing important issues in the hospital and providing care after discharge.
      As hospitalists assume control of inpatient care, they must also provide ethical
      protections to patients to supplement those currently vested in the patient-PCP
      relationship. An approach that keeps the patient's best interests foremost,
      defines a clear role for the PCP, and takes advantage of the expertise and
      availability of hospitalists will best serve patients and physicians.

PMID- 10411200
TI  - The rational clinical examination. Does this adult patient have acute meningitis?
AB  - CONTEXT: Early clinical recognition of meningitis is imperative to allow
      clinicians to efficiently complete further tests and initiate appropriate
      therapy. OBJECTIVE: To review the accuracy and precision of the clinical
      examination in the diagnosis of adult meningitis. DATA SOURCES: A comprehensive
      review of English- and French-language literature was conducted by searching
      MEDLINE for 1966 to July 1997, using a structured search strategy. Additional
      references were identified by reviewing reference lists of pertinent articles.
      STUDY SELECTION: The search yielded 139 potentially relevant studies, which were
      reviewed by the first author. Studies were included if they described the
      clinical examination in the diagnosis of objectively confirmed bacterial or viral
      meningitis. Studies were excluded if they enrolled predominantly children or
      immunocompromised adults or focused only on metastatic meningitis or meningitis
      of a single microbial origin. A total of 10 studies met the criteria and were
      included in the analysis. DATA EXTRACTION: Validity of the studies was assessed
      by a critical appraisal of several components of the study design. These
      components included an assessment of the reference standard used to diagnose
      meningitis (lumbar puncture or autopsy), the completeness of patient
      ascertainment, and whether the clinical examination was described in sufficient
      detail to be reproducible. DATA SYNTHESIS: Individual items of the clinical
      history have low accuracy for the diagnosis of meningitis in adults (pooled
      sensitivity for headache, 50% [95% confidence interval [CI], 32%-68%]; for
      nausea/vomiting, 30% [95% CI, 22%-38%]). On physical examination, the absence of
      fever, neck stiffness, and altered mental status effectively eliminates
      meningitis (sensitivity, 99%-100% for the presence of 1 of these findings). Of
      the classic signs of meningeal irritation, only 1 study has assessed Kernig sign;
      no studies subsequent to the original report have evaluated Brudzinski sign.
      Among patients with fever and headache, jolt accentuation of headache is a useful
      adjunctive maneuver, with a sensitivity of 100%, specificity of 54%, positive
      likelihood ratio of 2.2, and negative likelihood ratio of 0 for the diagnosis of
      meningitis. CONCLUSIONS: Among adults with a clinical presentation that is low
      risk for meningitis, the clinical examination aids in excluding the diagnosis.
      However, given the seriousness of this infection, clinicians frequently need to
      proceed directly to lumbar puncture in high-risk patients. Many of the signs and
      symptoms of meningitis have been inadequately studied, and further prospective
      research is needed.

PMID- 10411201
TI  - Intranasal influenza vaccine: adding to the armamentarium for influenza control.

PMID- 10411202
TI  - Coronary angiography: a long look at a short queue.

PMID- 10411203
TI  - What is carpal tunnel syndrome?

PMID- 10411204
TI  - Voters and health care in the 1998 election.

PMID- 10411205
TI  - JAMA Patient Page: carpal tunnel syndrome.

PMID- 10411206
TI  - Natural product research at the British Pharmaceutical Conference.

PMID- 10411207
TI  - Radioligand-receptor binding assays in the search for bioactive principles from
      plants.

PMID- 10411209
TI  - Hypericum perforatum extracts as potential antidepressants.
AB  - Extracts of Hypericum perforatum have been used in the treatment of mild to
      moderate depression for many years in Europe. More recently, these extracts have
      become available in the USA as dietary supplements and have been popularly used
      to improve mood. In support of this practice, data from several controlled
      clinical studies suggest that Hypericum perforatum is better than placebo and as
      effective as established antidepressant drugs. These data have, however, several
      limitations that should temper our enthusiasm and argue for more research before
      accepting Hypericum perforatum extracts into our pharmacopoeia of established
      antidepressants. Extant data on the possible effects of Hypericum perforatum
      extracts in depression are here critically reviewed and plans for further
      research presented.

PMID- 10411208
TI  - The scientific basis for the reputed activity of Valerian.
AB  - The underground organs of members of the genus Valeriana (Valerianaceae), as well
      as related genera such as Nardostachys, are used in the traditional medicine of
      many cultures as mild sedatives and tranquillizers and to aid the induction of
      sleep. V. officinalis is the species most commonly used in northern Europe and
      still retains its official pharmacopoeial status although it is most commonly
      encountered as an ingredient of herbal medicines. This plant is still the subject
      of considerable research aimed at establishing the chemical and pharmacological
      basis of the activity which has been clearly shown in a number of animal and
      clinical studies. The constituents of the volatile oil are very variable due to
      population differences in genetics and to environmental factors. The major
      constituents include the monoterpene bornyl acetate and the sesquiterpene
      valerenic acid, which is characteristic of the species, in addition to other
      types of sesquiterpene. Some of these have been shown to have a direct action on
      the amygdaloid body of the brain and valerenic acid has been shown to inhibit
      enzyme-induced breakdown of GABA in the brain resulting in sedation. The non
      volatile monoterpenes known as valepotriates were first isolated in 1966 and
      contribute to the overall activity by possessing sedative activity based on the
      CNS although the mode of action is not clearly known. The valepotriates
      themselves act as prodrugs which are transformed into homobaldrinal which has
      been shown to reduce the spontaneous motility of mice. More recent studies have
      shown that aqueous extracts of the roots contain appreciable amounts of GABA
      which could directly cause sedation but there is some controversy surrounding the
      bioavailability of this compound. Another recent finding is the presence of a
      lignan, hydroxypinoresinol, and its ability to bind to benzodiazepine receptors.
      Valerian is a good example of both the negative and positive aspects of herbal
      drugs. The considerable variation in its composition and content as well as the
      instability of some of its constituents pose serious problems for standardization
      but the range of components which contribute to its overall activity suggest that
      it may correct a variety of underlying causes of conditions which necessitate a
      general sedative or tranquilizing effect.

PMID- 10411210
TI  - Flavonoids and the central nervous system: from forgotten factors to potent
      anxiolytic compounds.
AB  - The list of activities of plant flavonoids did not include effects on the central
      nervous system (CNS) up to 1990, when our laboratory described the existence of
      natural anxiolytic flavonoids. The first of these was chrysin (5,7
      dihydroxyflavone), followed by apigenin (5,7,4'-trihydroxyflavone) and flavone
      itself. Semisynthetic derivatives of flavone obtained by introducing halogens,
      nitro groups or both in its molecule, give rise to high affinity ligands for the
      benzodiazepine receptor, active in-vivo; 6,3'-dinitroflavone, for example, is an
      anxiolytic drug 30 times more potent than diazepam. The data collected in this
      paper make clear that some natural flavonoids are CNS-active molecules and that
      the chemical modification of the flavone nucleus dramatically increases their
      anxiolytic potency.

PMID- 10411211
TI  - Medicinal plants and Alzheimer's disease: from ethnobotany to phytotherapy.
AB  - The use of complementary medicines, such as plant extracts, in dementia therapy
      varies according to the different cultural traditions. In orthodox Western
      medicine, contrasting with that in China and the Far East for example,
      pharmacological properties of traditional cognitive- or memory-enhancing plants
      have not been widely investigated in the context of current models of Alzheimer's
      disease. An exception is Gingko biloba in which the gingkolides have antioxidant,
      neuroprotective and cholinergic activities relevant to Alzheimer's disease
      mechanisms. The therapeutic efficacy of Ginkgo extracts in Alzheimer's disease in
      placebo controlled clinical trials is reportedly similar to currently prescribed
      drugs such as tacrine or donepezil and, importantly, undesirable side effects of
      Gingko are minimal. Old European reference books, such as those on medicinal
      herbs, document a variety of other plants such as Salvia officinalis (sage) and
      Melissa officinalis (balm) with memory-improving properties, and cholinergic
      activities have recently been identified in extracts of these plants. Precedents
      for modern discovery of clinically relevant pharmacological activity in plants
      with long-established medicinal use include, for example, the interaction of
      alkaloid opioids in Papaver somniferum (opium poppy) with endogenous opiate
      receptors in the brain. With recent major advances in understanding the
      neurobiology of Alzheimer's disease, and as yet limited efficacy of so-called
      rationally designed therapies, it may be timely to re-explore historical archives
      for new directions in drug development. This article considers not only the value
      of an integrative traditional and modern scientific approach to developing new
      treatments for dementia, but also in the understanding of disease mechanisms.
      Long before the current biologically-based hypothesis of cholinergic derangement
      in Alzheimer' s disease emerged, plants now known to contain cholinergic
      antagonists were recorded for their amnesia- and dementia-inducing properties.

PMID- 10411212
TI  - Therapeutic value of Ginkgo biloba in reducing symptoms of decline in mental
      function.
AB  - The Chinese tree Ginkgo biloba or "maiden hair tree" is extensively cultivated
      for the exploitation of the medicinal properties of its leaves. From these, a
      well-defined extract designated "EGb 761" has been developed, which was
      commercialized initially as Tanakan, Tebonin and Rokin; a similar product, Kaveri
      (LI 3170), also exists. The major therapeutic applications for these products are
      "cerebral insufficiency", other cerebral disorders, neurosensory problems and
      peripheral circulatory disturbances. Four primary concepts of action have been
      proposed to explain the pharmacotherapeutic benefits of EGb761; these are:
      vasoregulatory, cognition-enhancing, stress-alleviating, and gene-regulatory.
      These actions are believed to be realized through the principal active
      ingredients, flavonoids and the terpenoids ginkgolides and bilobalide acting
      simultaneously in concert, combination and synergy, so-called polyvalent action.
      It has been proposed that EGb761 may improve the memory of healthy volunteers,
      and in an assessment of [corrected] forty clinical studies, it was reported that
      Ginkgo was able to improve the twelve different symptoms comprising 'cerebral
      insufficiency', all of which are manifest in the elderly. These were supported in
      a second major study, using LI1370. However, in both instances, the evidence was
      largely based upon the results of self-assessment questionnaires. Latterly, in a
      large double blind study of men and women with the diagnosis of uncomplicated
      dementia who were administered Ginkgo for a year, a further positive outcome was
      claimed. In this study, patients were tested using ADAS-cog, GERRI and CGIC. It
      is suggested that whilst these different outcomes are compatible with (but do not
      affirm) a clinical benefit resulting from the use of Ginkgo, the application of a
      more objective system of assessment would be able to provide firm proof. It is
      proposed, therefore, that an objective, computer-based testing system for
      assessment of clinical improvement in volunteers and patients administered Ginkgo
      (such as CANTAB) would provide the convincing evidence currently being sought by
      patients, carers, physicians, legislators and the pharmaceutical industry.

PMID- 10411213
TI  - Synthesis and cytotoxicity evaluation of some 8-hydroxyquinoline derivatives.
AB  - Interest in Mannich bases of 8-hydroxyquinoline stems from reports of their high
      potency against human cancer cells. In the search for potential anticancer drug
      candidates, Mannich bases of 8-hydroxyquinoline (7-pyrrolidinomethyl-8
      hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline, 7-piperidinomethyl-8
      hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline) were synthesised by
      reaction with various secondary amines and formaldehyde. They were prepared as
      hydrochlorides. The cytotoxic activity of 7-pyrrolidinomethyl-8-hydroxyquinoline,
      7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline
      compounds in the National Cancer Institute in-vitro cancer cell line panel was
      determined. It was found that they exhibited substantial cytotoxic activity
      against leukaemia. The log concentration of 7-pyrrolidinomethyl-8
      hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl
      8-hydroxyquinoline that inhibited 50% of 60 cell lines' growth were -4.81 M, 
      5.09 M and -5.35 M, respectively. Compound 7-pyrrolidinomethyl-8-hydroxyquinoline
      was selected for further in-vivo testing. The electrophysiological effect of 7
      pyrrolidinomethyl-8-hydroxyquinoline also was tested in human myeloma cells (RPMI
      8226). The outward current was voltage dependent, activating at -40 mV and
      believed to be the voltage-activated K+ current I(K(V)). 7-Pyrrolidinomethyl-8
      hydroxyquinoline (1-30 microM) caused the inhibition of I(K(V)) in a
      concentration-dependent manner. The IC50 value of 7-pyrrolidinomethyl-8
      hydroxyquinoline-induced inhibition of I(K(V)) is 23 microM. The GI50 value of 7
      pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of cell growth is 14
      microM. The results suggest that at least part of the cytotoxicity effect of 7
      pyrrolidinomethyl-8-hydroxyquinoline on myeloma cells could be related to
      blockade of voltage-activated K+ channels.

PMID- 10411214
TI  - Synthesis and anticonvulsant activity of N-benzyloxycarbonyl-amino acid prodrugs
      of phenytoin.
AB  - Glycine, which has weak anticonvulsant properties, has been shown to potentiate
      the activity of several antiepileptic drugs but not phenytoin. Recently, studies
      have shown that N-(benzyloxycarbonyl)glycine (Z-glycine) antagonized seizures
      more than glycine in addition to possessing activity in the maximal electroshock
      test, a convulsive model in which glycine is inactive. In the present study
      esters of 3-hydroxymethylphenytoin, a phenytoin prodrug, and Z-glycine as well as
      the homologous N-(benzyloxycarbonyl)-omega-amino acids, Z-beta-alanine and Z
      gamma-aminobutyric acid (Z-GABA), were prepared and tested for their
      anticonvulsant and acute neurotoxic activities. The phenytoin prodrugs were
      obtained by esterification of bis(2-oxo-3-oxazolidinyl)-phosphinic acid chloride
      mediated esterification of 3-hydroxymethylphenytoin with the respective N
      benzyloxycarbonyl-protected amino acid. The Z-glycine-phenytoin ester was the
      most active anticonvulsant derivative. Compared with phenytoin the compound
      exhibited a decreased median effective dose (ED50) in the MES test and an
      increased median toxic dose (TD50), resulting in an significantly improved
      protective index expressed as the ratio between TD50 and ED50. The present data
      suggest that covalent binding of phenytoin to Z-glycine results in an improved
      pharmacological profile of the drug.

PMID- 10411216
TI  - Characterization and in-vivo ocular absorption of liposome-encapsulated
      acyclovir.
AB  - The potential of liposomes as an in-vivo ophthalmic drug delivery system for
      acyclovir was investigated. The drug-membrane interaction was evaluated by means
      of differential scanning calorimetry analysis. These experiments showed that
      acyclovir is able to interact with both positively and negatively charged
      membranes via electrostatic or hydrogen bonds. No interaction was observed with
      neutral membranes made up of dipalmitoylphosphatidylcholine. Different liposome
      preparation procedures were carried out to encapsulate acyclovir. The drug
      encapsulation mainly depends on the amount of water which the liposome system is
      able to entrap. In the case of multilamellar vesicles, charged systems showed the
      highest encapsulation efficiency. No particular difference in the encapsulation
      efficiency was observed for oligolamellar vesicles prepared with the reverse
      phase evaporation technique. Oligolamellar liposomes showed the highest acyclovir
      encapsulation parameters and had release profiles similar to those of
      multilamellar liposomes. In-vivo experiments using male New Zealand albino
      rabbits were carried out to evaluate the aqueous humour concentration of
      acyclovir bioavailability. The most suitable ophthalmic drug delivery system was
      oligolamellar systems made up of dipalmitoylphosphatidylcholine-cholesterol
      dimethyldioctadecyl glycerole bromide (7:4:1 molar ratio), which presented the
      highest encapsulation capacity and were able to deliver greater amounts of the
      drug into the aqueous humour than a saline acyclovir solution or a physical
      liposome/drug blend.

PMID- 10411215
TI  - Synthesis, physicochemical properties and biological evaluation of aromatic ester
      prodrugs of 1-(2'-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP102): orally
      active iron chelators with clinical potential.
AB  - The synthesis of seven aromatic ester derivatives of 1-(2'-hydroxyethyl)-2-ethyl
      3-hydroxypyridin-4-one is described. These ester prodrugs have been designed to
      target iron chelators to the liver, the major iron storage organ. In principle
      this should improve chelation efficacy and minimize toxicity. The distribution
      coefficients of these ester prodrugs between 1-octanol and MOPS buffer pH 7.4
      were measured together with their rates of hydrolysis at pH 2 and pH 7.4, in rat
      blood and liver homogenate. Esters with heteroaromatic acid moieties were found
      to be less stable than benzoyl analogues. The in-vivo iron mobilisation efficacy
      of these ester prodrugs has been compared with that of the parent drug using a
      59Fe-ferritin loaded rat model. Many prodrugs were found to enhance the ability
      of the parent hydroxypyridinone to facilitate 59Fe excretion. However, not all
      prodrugs provided increased efficacy, demonstrating that lipophilicity is not the
      only factor which influences drug efficacy. Furthermore, no clear correlation
      between efficacy and susceptibility to hydrolysis was detected. The picolinic and
      nicotinic ester derivatives appear to offer the best potential as prodrugs as
      they have a relatively low LogP value and yet lead to enhanced efficacy over the
      parent hydroxypyridinone.

PMID- 10411217
TI  - Control of the dispersing process and pharmacokinetics in rats for lipid A
      analogue, E5531.
AB  - E5531 is a synthetic disaccharide analogue of lipid A which has a low toxicity
      but retains the ability to reduce production of tumour necrosis factor. This
      analogue has potential for use in the treatment of septic shock. An injectable
      formulation of E5531 would be useful, but dispersion in aqueous solution is a
      problem. In the present study the dispersing process for E5531 was evaluated
      using the pH-jump method (pH 11.0-->7.3). The size of the aggregates was
      decreased (reaching 20 nm) with increasing dispersing time in 0.003 M NaOH (pH
      11.0). The membrane fluidity of the aggregates increased with increasing
      dispersing time. When prepared by the normal dilution method (pH 7.3-->7.3), the
      size of the aggregates remained constant at 140 nm and the membrane fluidity was
      smaller than that of samples prepared by the pH-jump method. This indicates that
      during dispersing at basic pH, the hydration proceeded in a normal manner, but
      then stopped, just after adjustment of the pH to 7.3. This suggests that the
      degree of hydration of the membrane is dependent on the dispersing time at pH
      11.0. Using samples with different degrees of hydration and different membrane
      fluidity prepared by the pH-jump method, the pharmacokinetics and stability of
      the aggregates were evaluated after intravenous injection into rats. The data
      thus obtained confirmed that the membrane fluidity was correlated with the
      pharmacokinetics and stability in rat plasma. It was concluded that the
      pharmacokinetics of E5531 in rats can be controlled by changing the degree of
      hydration and membrane fluidity by means of using different dispersing times in
      alkaline solution (pH 11.0).

PMID- 10411218
TI  - Effect of pentobarbital anaesthesia on intestinal absorption and hepatic first
      pass metabolism of oxacillin in rats, evaluated by portal-systemic concentration
      difference.
AB  - The effects of anaesthesia on intestinal drug absorption and hepatic first-pass
      metabolism in rats were investigated by observing the difference in the drug
      concentration between portal and systemic bloods. Oxacillin and pentobarbital
      were selected as a model drug and as an anaesthetic, respectively. Rats were
      divided into a conscious control group and an anaesthetized group. All rats were
      cannulated simultaneously in the portal vein and in the femoral artery, and
      oxacillin was orally administered after its intra-arterial injection (double
      dosing). For the anaesthetized group, pentobarbital was intrasubcutaneously
      administered twice, first before intra-arterial injection and again before oral
      administration of oxacillin. The arterial blood alone was sampled from the
      cannula in the femoral artery before oral administration, whereas the arterial
      and portal bloods were simultaneously sampled from both cannulated sites after
      oral administration. Oxacillin concentrations in plasma were assayed by HPLC. The
      anaesthesia increased the absolute bioavailability (F), the mean absorption time
      (MAT) and the hepatic recovery ratio (F(H)), but caused little change in the
      local absorption ratio into the portal system (Fa) and the total clearance (CL).
      The hepatic clearance (CL(H)) was significantly decreased, resulting in an
      apparent small change in CL-CL(H) which is considered to be renal clearance. By
      this method, it was shown directly that an increase in F due to pentobarbital
      anaesthesia was attributable to the significant increase in F(H). It is expected
      that the method is useful not only to evaluate the effect of anaesthesia on the
      first-pass effect, but also to assess the effect of co-administration of drugs on
      first-pass metabolism.

PMID- 10411219
TI  - Molecular basis of indomethacin-human serum albumin interaction.
AB  - Studies on the strength and extent of binding of the non-steroidal anti
      inflammatory drug indomethacin to human serum albumin (HSA) have provided
      conflicting results. In the present work, the serum-binding of indomethacin was
      studied in 55 mM sodium phosphate buffer (pH 7.0) at 28 degrees C, by using a
      fluorescence quench titration technique. The interaction of indomethacin with
      human serum albumin has been studied as a function of temperature, ionic strength
      and pH. The results suggest that electrostatic interaction plays a major role in
      the binding. The possible role of lysine residues in this interaction was studied
      by modifying exposed and buried lysine residues of HSA with potassium cyanate and
      studying indomethacin binding with the modified HSA. The data suggest that the
      interaction takes place via a salt bridge formation between the carboxylate group
      of indomethacin and a buried lysine residue of HSA. A technique involving
      fluorescence enhancement of bilirubin upon its interaction with HSA was used to
      study its displacement by indomethacin. The displacement, although apparently
      competitive in nature, was not strong suggesting that the primary sites of
      interaction of bilirubin and indomethacin are different.

PMID- 10411220
TI  - Pharmacokinetics of buspirone following oral administration to rhesus monkeys.
AB  - Pharmacokinetics of buspirone and its active metabolite, 1-pyrimidinyl piperazine
      (1-PP) following oral administration were assessed in rhesus monkeys at doses
      used in chronic toxicology studies. The study was conducted over four periods in
      three male and three female rhesus monkeys. In the first three periods, buspirone
      hydrochloride solution was administered in a randomized manner by oral gavage at
      doses (expressed as buspirone free base) of 12.5, 25 and 50 mg kg(-1) once a day
      on days 1 and 7 and twice a day on days 2-6. In the last period, all monkeys
      received 25 mg kg(-1) buspirone as a single daily dose for 7 days. Serial plasma
      samples were collected for analysis of buspirone and 1-PP on days 1 and 7 in the
      first three periods and on day 7 in the last period for assessment of single dose
      and steady-state pharmacokinetics. Inter-animal variability in the
      pharmacokinetics of buspirone was high. Examination of Cmin vs time plots
      revealed that the steady state was attained by day 7 except for one monkey who
      demonstrated much higher Cmin values. For buspirone, dose proportionality was
      concluded for both Cmax and AUC on day 1 but not on day 7. The accumulation
      factor on day 7 for buspirone was nearly 5 for Cmax and 7 for AUC when compared
      with day 1. For 1-PP, dose proportionality was concluded except for Cmax in male
      monkeys on day 7. In contrast to buspirone, 1-PP showed less than 2-fold
      accumulation in Cmax and AUC values on day 7 compared with those on day 1.
      Exposure at a dose of 25 mg kg(-1) once daily was in between the 125 mg kg(-1)
      and 25 mg kg(-1) twice-a-day regimens. These results document dose-dependency in
      the steady-state pharmacokinetics of buspirone in rhesus monkeys.

PMID- 10411221
TI  - Distribution of ciprofloxacin into the central nervous system in rats with acute
      renal or hepatic failure.
AB  - Pharmacokinetic changes of various drugs have been reported in renal or hepatic
      failure. The present study employed ciprofloxacin, a quinolone antibiotic having
      neurotoxic side effects, to assess the influence of these diseases on
      distribution of ciprofloxacin into the central nervous system (CNS). After
      intravenous dosing of ciprofloxacin (10-30 mg kg(-1)), ciprofloxacin levels in
      plasma and brain were measured in normal rats (Wistar, male, 10-week-old) and
      those with acute renal and hepatic injuries which were induced by uranyl nitrate
      and carbon tetrachloride (CCl4), respectively. In the uranyl nitrate-treated
      rats, the plasma elimination half-life of ciprofloxacin was prolonged and the
      total body clearance was reduced when compared with those in the normal rats.
      Similar but smaller changes were observed in the CCl4-treated group. Brain levels
      of ciprofloxacin were significantly increased by both uranyl nitrate and CCl4
      treatments. A proportional correlation between serum unbound levels and brain
      levels of ciprofloxacin was observed in the normal group. However, brain-to-serum
      unbound concentration ratios of ciprofloxacin were reduced in the rats with renal
      or hepatic failure. These results suggest that renal failure as well as hepatic
      failure retards elimination of ciprofloxacin from the blood, leading to elevation
      of the CNS level, and also that ciprofloxacin distribution in the brain is
      reduced in these disease states.

PMID- 10411222
TI  - Effects of mebudipine and dibudipine, two new calcium-channel blockers, on rat
      left atrium, rat blood pressure and human internal mammary artery.
AB  - Mebudipine and dibudipine are two new dihydropyridine calcium-channel blockers
      that have been synthesized in our laboratory. In a previous study, they showed
      considerable relaxant effect on vascular and ileal smooth muscle. Here, the
      pharmacological effects of mebudipine and dibudipine on isolated rat left atrium,
      rat blood pressure and isolated human internal mammary artery are described.
      Results are compared with those obtained for nifedipine. Mebudipine and
      dibudipine reduced contraction force of rat left atrium (pIC30 values: 5.37+/
      0.13 and 5.49+/-0.15, respectively) but their negative inotropic effects were
      significantly weaker than that of nifedipine (pIC30 value: 6.63+/-0.11).
      Mebudipine and dibudipine lowered rat blood pressure. The hypotensive effect of
      mebudipine was similar to that of nifedipine while dibudipine was weaker than
      nifedipine. It was found that the half-life of the hypotensive action of
      dibudipine (41.91+/-3.77 min, 31.13+/-2.26 min and 28.20+/-4.37 min at 2, 4 and 8
      mg kg(-1) orally administered doses, respectively) was longer than that of
      nifedipine (11.85+/-2.88 min, 16.65+/-2.42 min and 14.03+/-0.10 min at the same
      doses, respectively). Also, it appeared that mebudipine had a slower rate of
      absorption compared with nifedipine (the time to reach peak hypotensive action at
      2, 4 and 8 mg kg(-1) orally administered doses were, respectively, 24.00+/-6.96
      min, 23.75+/-2.39 min and 15.00+/-2.04 min for mebudipine and 7.80+/-0.86 min,
      13.75+/-3.15 min and 833+/-0.88 min for nifedipine). The two new compounds, as
      well as nifedipine, relaxed KCl-treated isolated human internal mammary artery
      (pEC50 values; 7.87+/-0.12, 7.22+/-0.24 and 7.67+/-0.12 for mebudipine,
      dibudipine and nifedipine, respectively). The relaxant effects of mebudipine and
      dibudipine did not show any significant difference compared with that of
      nifedipine. It is concluded that these new compounds are weak cardiodepressants
      and, with due attention to its significant vasorelaxant action, mebudipine is a
      vasoselective compound. In addition, these two compounds have potent blood
      pressure lowering effects. Also, their vasorelaxant action can be reproduced in
      human vascular preparations.

PMID- 10411223
TI  - Paradoxical cholinergic and purinergic vascular reactivity of rabbit thoracic
      aorta cold-stored in University of Wisconsin solution.
AB  - Endothelial dysfunction has been reported in donor blood vessels destined for
      organ transplantation following cold-storage preservation with University of
      Wisconsin solution (UW). This was investigated in the present work. Segments of
      rabbit thoracic aorta were mounted on isometric fine-wire myographs at 37 degrees
      C and gassed with 95% O2/5% CO2. Concentration-dependent vasodilatations to
      acetylcholine and adenosine-5'-triphosphate (ATP) were obtained in freshly
      harvested rabbit aortic rings, with and without the endothelium, and after 8 days
      of cold-storage, at 4 degrees C, in either UW, Krebs-Bulbring buffer (KBB) or
      saline. The action of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine
      methyl ester (L-NAME) (100 microM) was evaluated upon the concentration-response
      curves to determine whether nitric oxide (NO) exerted any modulatory actions.
      Endothelium-dependent, NO-mediated responses to acetylcholine were unaltered
      after eight days of storage in UW, reduced after storage in KBB and absent after
      removal of the vascular endothelium, saline storage or after testing in the
      presence of L-NAME, suggesting improved NO-mediated endothelial function with the
      use of UW. Structural preservation was also confirmed using scanning electron
      microscopy. In contrast, endothelium-dependent responses to ATP were unchanged
      after eight days of storage in KBB but were reduced after storage in UW and
      saline, suggesting purinergic (ATP) endothelial dysfunction after storage in UW.
      L-NAME markedly reduced vasodilatation to ATP in freshly harvested rings and
      after eight days of storage in KBB. This reduction was statistically significant
      (P < 0.05, Student's two tailed, unpaired t-test) at -log (M) ATP concentrations
      of 5.5, 5.0, 4.5, 4.0 and 3.5. NO-dependent vasodilatation to ATP was not
      attenuated by L-NAME in UW-stored rings. Eight days' UW-storage of rabbit
      thoracic aortic rings appeared to have differential and paradoxical effects upon
      NO-dependent vasodilatation to acetylcholine and ATP. Morphological observations
      using electron microscopy suggested that UW preserved the vascular endothelium
      and this was verified by retained vascular reactivity of endothelium-dependent
      vasodilatations to acetylcholine. UW-storage however, significantly reduced
      endothelium-dependent relaxation to ATP thereby suggesting that P2Y
      purinoceptors, which are located on the vascular endothelium, may be more
      susceptible to biodegradation than cholinergic receptors and may be responsible
      for endothelial dysfunction following transplantation.

PMID- 10411224
TI  - Effects of tetraethylammonium, 4-aminopyridine and bretylium on cardiovascular
      tissues from normo- and hypertensive rats.
AB  - Our objective was to test whether potassium-channel blockade is a potential
      positive inotropic mechanism for heart failure. Thus we studied the effects of
      tetraethylammonium, 4-aminopyridine and bretylium on left ventricular action
      potentials, left ventricular contractility in the absence and presence of
      hypertrophy, and on isolated blood vessels from Wistar Kyoto normotensive rats
      (WKY) and spontaneously hypertensive rats (SHRs). Tetraethylammonium at 10(-3)
      10(-2) M, 4-aminopyridine at 10(-4)-10(-3) M and bretylium at 10(-6)-10(-4) M
      prolonged the action potentials of the WKY left ventricular strip. Similar
      concentrations of tetraethylammonium, 4-aminopyridine and bretylium augmented the
      peak force, prolonged the contractions, and did not cause arrhythmias in the
      absence or presence of isoprenaline on left ventricular strips from 12-month-old
      WKY. The 12-month-old SHR has hypertrophy of the left ventricle with reduced
      contractility and prolongation of relaxation. The effects of tetraethylammonium
      and bretylium were similar on WKY and SHR, whereas the effects of 4-aminopyridine
      were reduced on SHR left ventricular contractility, which suggests that the
      function of the transient outward-blocking potassium channel may be impaired in
      hypertrophy. Bretylium at < or = 10(-4) M had no effect on the portal vein,
      intralobar or mesenteric arteries. Tetraethylammonium and 4-aminopyridine at > or
      = 10(-5) M increased the duration or amplitude, or both, of the portal vein
      contractions. Tetraethylammonium at > or = 10(-2) M and 4-aminopyridine at > or =
      3 x 10(-4) M contracted the mesenteric artery, and 4-aminopyridine also
      contracted the intralobar pulmonary artery. In summary, we have demonstrated that
      the action potential prolonging effects of potassium-channel blockade is
      associated with a positive inotropic effect on the rat left ventricle. The non
      specific blockers, tetraethylammonium and 4-aminopyridine, do not have potential
      as positive inotropes in heart failure because of their widespread effects,
      including vasoconstriction. The potential of bretylium and some of the newer
      selective potassium-channel blockers as positive inotropes requires further
      evaluation.

PMID- 10411225
TI  - Phycocyanin extract reduces leukotriene B4 levels in arachidonic acid-induced
      mouse-ear inflammation test.

PMID- 10411226
TI  - Maintenance programmes after weight reduction--how useful are they?
AB  - Maintenance programmes lasting one or two years or even longer are generally
      recommended to improve long-term outcome after weight reduction. They may not be
      practical for several reasons: it is not known whether they really improve long
      term outcome or only delay relapse; they may lessen patients' motivation to take
      full responsibility for their life-style changes; and they need extra resources.
      Some series on treatment of obesity and experience with successful maintainers
      suggest that satisfactory long-term outcome can also be achieved without long
      maintenance programmes. We believe that weight reduction programmes lasting 4-6
      months can be developed to ensure better maintenance. The programmes should adopt
      a patient centred approach, support patients' full responsibility for life-style
      changes, and use principles and methods acceptable for most obese people.

PMID- 10411227
TI  - Distribution of waist-to-hip ratio, other indices of body fat distribution and
      obesity and associations with HDL cholesterol in children and young adults aged 4
      19 years: The Third National Health and Nutrition Examination Survey.
AB  - BACKGROUND: Little data has been published on the association of indices of body
      fat distribution and HDL cholesterol (HDL), a risk factor for cardiovascular
      morbidity, in representative samples of total populations of children and
      adolescents including blacks and Hispanics. OBJECTIVE: To describe the
      distribution of waist-to-hip ratio (WHR) in US children and adolescents and to
      assess the association with HDL. DESIGN: Cross-sectional survey of a large
      national sample, the Third National Health and Nutrition Examination Survey.
      PARTICIPANTS: People aged 4-19 y. MEASUREMENTS: Body circumferences, skinfold
      thickness, body mass index (BMI), and serum total and HDL cholesterol
      concentrations. RESULTS: Mean WHR varied consistently with age, gender, and
      ethnic group. Levels were highest in Mexican Americans. WHR showed significant
      negative associations with HDL cholesterol concentration and positive
      associations with the ratio of total serum cholesterol to HDL in pre- and
      postpubertal girls independent of age and BMI. However, associations were often
      not as strong as those with BMI. Other indices of body fat distribution were not
      superior to WHR. CONCLUSION: Further research is needed on the association of
      WHR, other indices of body fat distribution and HDL measured in childhood with
      subsequent risk of atherosclerosis.

PMID- 10411228
TI  - Abdominal obesity reduction in indigenous men.
AB  - OBJECTIVES: To assess the effectiveness of a men's 'waist loss' program over one
      year in Indigenous men. DESIGN: Pre-and post-test measurements of 47 Indigenous
      men on four island groups in the Torres Strait region of Northern Australia
      involved in a version of the 'GutBuster' program, modified by and for Indigenous
      men. RESULTS: Weight, waist and hip size of 47 men, and body fat estimated from
      electrical impedence measures of 27 men, were compared at baseline, after approx
      2 months, approx 6 months and approx one year. Average weight loss was 3.3 kg
      (3.5%), and waist loss 4.0 cm (3.5%). The average percentage decrease in fat mass
      (FM) was 10.8%. An environmental audit technique highlighted modifications needed
      to the environment to assist behaviour change. CONCLUSIONS: Education-behaviour
      change interventions of this kind may offer opportunities for health improvements
      in Indigenous men.

PMID- 10411229
TI  - Nicotine induces uncoupling protein 1 in white adipose tissue of obese mice.
AB  - OBJECTIVE: To test the hypothesis that nicotine not only activates uncoupling
      protein1 (UCP1) in brown adipose tissue (BAT), but also induces UCP1 in white
      adipose tissue (WAT), which contributes to the mitigation of obesity in obese
      mice. DESIGN: Weights of the whole body, the gastrocnemius muscle, interscapular
      BAT and subcutaneous and retroperitoneal WAT, food intake and the mRNA and
      protein of UCP1 in these tissues were measured and immunohistochemistry using
      antiserum against UCP1 was also performed in obese yellow KK mice treated with
      nicotine for 6 months and control mice treated with physiological saline.
      RESULTS: Obese mice treated with nicotine for 6 months, compared with those
      injected with saline, weighed significantly less (P < 0.01) and had smaller
      subcutaneous and retroperitoneal WAT pads (P < 0.01), while obese mice that
      received nicotine ate less (P < 0.05) than those injected with saline. In mice
      treated with nicotine, the mRNA and protein of UCP1 was detected not only in BAT,
      but also in subcutaneous and retroperitoneal WATs. Immunohistochemically, the BAT
      of obese mice contained large lipid droplets and appeared rather WAT-like, but
      changed to typical brown adipocytes after nicotine treatment. The fat pads of
      nicotine-treated mice contained many multilocular cells that were positive for
      UCP1. CONCLUSION: Nicotine not only activates UCP1 in BAT, but also induces UCP1
      in WAT and decreases food intake, which contributes to the mitigation of obesity.

PMID- 10411230
TI  - Prevalence and correlates of binge eating in a nonclinical sample of women
      enrolled in a weight gain prevention program.
AB  - OBJECTIVES: The aims of the present study were to examine the prevalence and
      correlates of binge eating in a nonclinical sample of women and to examine
      whether associations differed by overweight status. DESIGN: Cross-sectional
      comparison of women based on self-reported binge eating status (large amount of
      food eaten and feelings of lack of control during these eating episodes) and
      overweight status (measured body weight: overweight defined as body mass index
      (BMI) > or = 27.3 kg/m2). PARTICIPANTS: Subjects were 817 women aged 20-45y from
      the community who enrolled in a three year prospective intervention study to
      examine methods for preventing age-related weight gain. MEASURES: Body weight was
      measured at baseline and three-year follow-up. Self-report measures of binge
      eating, dieting practices, eating and exercise behaviours, depression, self
      esteem and stressful life events were collected at the three-year follow-up.
      RESULTS: The prevalence of binge eating in the past six months was 9% among
      normal weight women and 21% among overweight women. The frequency of binge eating
      was low (> 50% of binge eaters binged less than once per week) and did not
      significantly differ by body weight status. Compared to non-binge eaters, binge
      eaters reported more dieting practices, more extreme attitudes about weight and
      shape, and higher levels of depression and stressful life events. Binge eating
      was not related to habitual eating and exercise behaviours. In multivariate
      models, weight/shape importance (odds ratio (OR) = 3.33; 95% confidence intervals
      (95% CI) = 2.10, 5.29), depression (OR = 1.73; 95% CI = 1.07, 2.79) and history
      of intentional weight loss episodes (OR = 1.68; 95% CI = 1.03, 1.13) were
      independently associated with increased odds of binge eating. CONCLUSIONS: Binge
      eating is about twice as prevalent among overweight women, compared to normal
      weight women, in a nonclinical sample, but has similar correlates (that is,
      dieting, depression, weight/shape preoccupation). Prospective research is needed
      to determine whether there are causal associations between binge eating,
      depression, dieting and weight gain.

PMID- 10411231
TI  - Fat storage capacity in growth-selected and control mouse lines is associated
      with line-specific gene expression and plasma hormone levels.
AB  - OBJECTIVE: For a detailed understanding of the complex traits growth and fat
      storage, a dissection into single genetic entities is mandatory. Therefore, blood
      plasma concentrations of hormones and the expression of selected genes were
      measured in extremely differentiated mouse lines. Genes were selected as
      candidates which might influence the complex traits body weight and fat
      accumulation, and which are located in chromosomal regions recently identified to
      affect trait differences between the lines. SUBJECTS AND MEASUREMENTS: The mouse
      lines were selected for high body weight (DU6), high carcass protein content
      (DU6P) and unselected controls (DUKs). In the selected lines DU6 and DU6P, mean
      body weights at the age of six weeks were about twice as high as the DUKs,
      whereas total fat weight was increased 2.2-fold in DU6 mice compared to DU6P and
      3.2-fold in comparison to DUKs. Blood plasma concentrations of insulin-like
      growth factor 1 (IGF-1), growth hormone (GH), insulin and leptin, were measured
      in all lines at three weeks and at six weeks of age. Expression patterns of the
      genes encoding growth hormone (Gh), insulin-like growth factor 1 (Igf1),
      lipoprotein lipase (Lpl), glycerolphosphate dehydrogenase 1 (GDC-1), and
      adipocyte protein 2 (Ap2) were analyzed by Northern blot hybridization. RESULTS:
      In line DU6, highly significant increased concentrations of insulin and leptin
      were observed at six weeks of age; at this stage, IGF-1 concentrations were
      elevated in the two selected lines compared to controls with maximal
      concentrations of IGF-1 and GH in DU6P. The amount of mRNA for GH in the
      pituitary gland, for Igf1 in the liver and for LPL in epididymal fat tissue was
      significantly elevated in the two selected lines compared to controls at the age
      of three weeks, but not at six weeks. IGF-1 and GDC-1 mRNA concentrations were
      significantly higher in the DU6 mice than in the DU6P (P < 0.01) and the DUKs (P
      < 0.001) mice examined at both ages. CONCLUSIONS: The results prove line-specific
      concentrations of the analyzed hormones and the transcription amounts of Gh,
      Igf1, GDC-1 and Lpl. The measured differences are either direct genetic effects
      or secondary changes, resulting from different food consumption.

PMID- 10411232
TI  - Dehydroepiandrosterone alters the growth of stromal vascular cells from human
      adipose tissue.
AB  - OBJECTIVE: The purpose of this study was to determine if the antiobesity actions
      of dehydroepiandrosterone (DHEA) observed in vivo are due to an influence on the
      proliferation and differentiation of primary cultures of stromal-vascular (SV)
      cells isolated from human adipose tissue. DESIGN: SV cells were isolated from
      subcutaneous adipose tissue obtained from a young adult female undergoing
      elective liposuction. For the proliferation assay (Experiment 1), cultures were
      fed proliferation media containing 0, 5, 25 or 100 microM DHEA for 3d. At the end
      of this treatment period, cultures were either prepared for counting or for
      determining their metabolic activity using the Alamar Blue staining procedure.
      For the differentiation assays (Experiment 2), cultures were fed differentiation
      media containing 0, 25 or 50 microM DHEA for 20 d. At the end of this treatment
      period, cultures were either prepared for lipid staining using Oil Red O or for
      marker enzyme analysis (glycerol-3-phosphate dehydrogenase activity; GPDH). To
      determine if the stimulatory effects of DHEA on SV cell differentiation were
      dependent on the presence of thiazolidinediones (Experiment 3), cultures of
      differentiating SV cells were incubated in the presence and absence of BRL 49653
      and either 0, 25 or 50 microM DHEA. RESULTS: In Experiment 1, cultures treated
      with 25 and 100 microM DHEA had fewer cells than cultures treated with either 0
      or 5 microM DHEA. Alamar Blue staining decreased as the level of DHEA in the
      cultures increased. In Experiment 2, cultures treated with DHEA had more lipid
      and GPDH activity than control cultures. In Experiment 3, cultures treated with
      BRL 49653 had more triglyceride than cultures treated without BRL 49653.
      Likewise, cultures treated with DHEA had more triglyceride than their non-DHEA
      controls. Regardless of the BRL status, cultures supplemented with DHEA had more
      triglyceride than control cultures. CONCLUSION: These data suggest that in
      cultures of SV cells from human adipose tissue, DHEA supplementation attenuates
      proliferation and enhances differentiation. These data support the hypothesis
      that DHEA directly attenuates preadipocyte proliferation in humans as we
      previously demonstrated in primary cultures of pig and rat SV cells and in
      cultures of 3T3-L1 preadipocytes. In contrast, DHEA stimulated the
      differentiation of human preadipocytes, which is contrary to its actions in
      differentiating cultures of preadipocytes from animals.

PMID- 10411233
TI  - Weight loss increases and fat loss decreases all-cause mortality rate: results
      from two independent cohort studies.
AB  - OBJECTIVE: In epidemiological studies, weight loss is usually associated with
      increased mortality rate. Contrarily, among obese people, weight loss reduces
      other risk factors for disease and death. We hypothesised that this paradox could
      exist because weight is used as an implicit adiposity index. No study has
      considered the independent effects of weight loss and fat loss on mortality rate.
      We studied mortality rate as a function of weight loss and fat loss. DESIGN:
      Analysis of 'time to death' in two prospective population-based cohort studies,
      the Tecumseh Community Health Study (1890 subjects; 321 deaths within 16y of
      follow-up) and the Framingham Heart Study (2731 subjects; 507 deaths within 8y of
      follow-up), in which weight and fat (via skinfolds) loss were assessable.
      RESULTS: In both studies, regardless of the statistical approach, weight loss was
      associated with an increased, and fat loss with a decreased, mortality rate (P <
      0.05). Each standard deviation (s.d.) of weight loss (4.6 kg in Tecumseh, 6.7 kg
      in Framingham) was estimated to increase the hazard rate by 29% (95% confidence
      interval CI), (14%, 47%, respectively) and 39% (95% CI, 25%, 54% respectively),
      in the two samples. Contrarily, each s.d. of fat loss (10.0 mm in Tecumseh, 4.8
      mm in Framingham) was estimated to reduce the hazard rate 15% (95% CI, 4%, 25%)
      and 17% (95% CI, 8%, 25%) in Tecumseh and Framingham, respectively.
      Generalisability of these results to severely (that is, body mass index BMI) > or
      = 34) obese individuals is unclear. CONCLUSIONS: Among individuals that are not
      severely obese, weight loss is associated with increased mortality rate and fat
      loss with decreased mortality rate.

PMID- 10411234
TI  - Relationships between IGF-I and age, gender, body mass, fat distribution,
      metabolic and hormonal variables in obese patients.
AB  - OBJECTIVE: To compare insulin-like growth factor-I (IGF-I) concentrations in
      obese and normal subjects, and evaluate the possible relationships between IGF-I
      concentrations and demographic, anthropometric, metabolic and hormonal variables
      in obese patients. SUBJECTS AND METHODS: 286 obese outpatients (OB, 234 female
      and 52 male; age 18-71 y, body mass index (BMI) > 27 kg/m2) were recruited.
      MEASUREMENTS: BMI, waist-to-hip ratio (WHR), serum basal and oral glucose
      tolerance test (OGTT)-stimulated glucose and insulin concentrations, IGF-I, basal
      growth hormone (GH), prolactin (PRL), androgens, thyrotropin (TSH), free
      triiodothyronine (fT3), free thyroxine (fT4), free fatty acids (FFA),
      triglycerides, total and high density lipoprotein (HDL)-cholesterol, 24h-urinary
      cortisol levels and blood pressure (BP) values were measured. IGF-I
      concentrations were also evaluated in a large population of 326 age-matched
      controls (controls, 228 women, 98 men; age 20-86 y, BMI < 25 kg/m2). RESULTS: IGF
      I concentrations were lower in OB than in controls (age-adjusted mean: 21.6 vs
      23.6 nmol/L, P < 0.03). However, individual IGF-I concentrations in OB were
      within the age-adjusted normal range. In both groups, IGF-I concentrations were
      gender-independent, and showed a simple negative correlation with age (r = 
      0.47). In OB, univariate analysis also shows that IGF-I concentrations were
      negatively correlated with BMI (r = -0.33), but not WHR, with both basal (r = 
      0.16) and OGTT-stimulated glucose levels (r = -0.17), as well as FFA levels (r = 
      0.19), and with both diastolic and systolic BP (both r = -0.17). In OB women, IGF
      I concentrations positively correlated with PRL (r = 0.31), testosterone (r =
      0.30), androstenedione (r = 0.30), and dehydroepiandrosterone-sulfate (DHEAS)
      concentrations (r = 0.41). No correlation was found with other variables. The
      multiple regression analysis showed that IGF-I concentrations were inversely and
      independently related to age and BMI only. CONCLUSIONS: In obesity, IGF-I
      concentrations are slightly reduced, but generally within the age-adjusted normal
      range. IGF-I concentrations in obesity show independent and negative
      relationships with age and BMI, but are not associated with fat distribution,
      insulin secretion, glucose tolerance, BP or risk indices for cardiovascular
      disease (CVD).

PMID- 10411235
TI  - Sick leave and disability pension before and after treatment for obesity: a
      report from the Swedish Obese Subjects (SOS) study.
AB  - OBJECTIVES: To analyse sick leave and disability pension among surgically and
      conventionally treated obese patients. DESIGN: A prospective study over five
      years. Differences in sick leave and disability pension were analysed using
      multiple and logistic regressions. Possible confounding factors were analysed and
      controlled for. SETTING: Nine counties in Sweden. SUBJECTS: 369 surgically
      treated patients and 371 matched obese controls, included in the Swedish Obese
      Subjects (SOS) study. At baseline, mean body mass index (BMI) was 42 kg/m2 in
      surgical patients and 41 kg/m2 in controls. After four years of treatment, weight
      reduction was 20% among surgical patients while the control patients kept their
      initial weight. INTERVENTION: Gastric bariatric surgery. MEASUREMENTS: Days of
      sick leave plus disability pension, and days of disability pension. RESULTS: In
      the year prior to treatment, adjusted average number of days of sickness due to
      sick leave plus disability pension was similar in surgical patients and controls.
      Compared with controls, the surgical group had 35% more days of sickness during
      the first year after initiation of treatment, but 10-14% fewer days during years
      2-3. During year four, days of sickness tended to be lower in the surgical group
      (P = 0.07). In the sub-group, aged above the median, surgical patients had 14-18%
      fewer days of sickness than controls, during years 2-3 after initiation of
      treatment This difference did not occur in the group below median age.
      CONCLUSION: Surgical treatment of obesity results in a reduction of sick leave
      and disability pension, compared to controls, particularly in subjects aged 47-60
      y.

PMID- 10411236
TI  - Leptin concentrations during oral glucose tolerance test (OGTT) in obese and
      normal weight women.
AB  - OBJECTIVE: To examine possible changes of leptin concentrations after the acute
      administration of glucose orally (OGTT). DESIGN: Seventy-five grams of glucose
      were administered per os in one group of obese and normal weight individuals and
      concentrations of glucose, insulin and leptin were measured at 0, 30, 60, 90 and
      120 min. In an age matched control group of individuals with similar BMI water
      was given and leptin concentrations were measured before and after 30, 60, 90 and
      120 min. SUBJECTS: Twenty-seven obese women aged 34+/-1.57 y with BMI 37.1+/-0.8
      kg/m2 and 16 normal weight women, aged 32+/-1.13 y with BMI 23.6+/-0.3 kg/m2
      formed the experimental group, while 10 obese and 10 normal weight females with
      similar age and BMI were used as controls. MEASUREMENTS: Weight, height, BMI,
      body fat, glucose, insulin and leptin at baseline and during OGTT. Variations of
      the above parameters were calculated from the area under the curve (AUC).
      RESULTS: Fasting leptin concentrations and AUC were higher in obese than in
      normal weight women. In obese women, leptin increased significantly in comparison
      to its basal concentrations 30 and 60 min after the glucose loading. Insulin was
      also increased, as expected. No correlation was found between insulin and leptin
      concentrations after glucose loading. Basal concentrations of leptin did not
      correlate with those of glucose and insulin. No changes in leptin concentrations
      were found in normal weight women after OGTT. However, a significant positive
      correlation was found between insulin and basal leptin. Finally, leptin
      concentrations did not change in obese and normal weight controls after water
      administration. CONCLUSION: A significant increase in leptin concentrations was
      found 30 and 60 min after glucose loading in obese individuals. No such increase
      was found in normal-weight women.

PMID- 10411237
TI  - The impact of increased dietary lipid on the regulation of glucose uptake and
      oxidation by insulin in brown- and a range of white-adipose-tissue depots in
      vivo.
AB  - OBJECTIVE: To determine: (a) whether active pyruvate dehydrogenase (PDHa)
      activity in interscapular brown adipose tissue (IBAT) is acutely regulated by
      altered insulin status at euglycaemia; (b) the relationship between glucose
      uptake/phosphorylation and PDHa activities in IBAT in vivo; and (c) the impact of
      increased dietary lipid on the regulation of glucose uptake and oxidation by
      insulin in IBAT in comparison with that exerted on various white adipose tissue
      depots. DESIGN: Rats were provided with either a standard diet (8% fat, 72%
      carbohydrate, by energy) or a diet moderately high in saturated fat (47%, by
      energy) and low in carbohydrate (33%, by energy) for four weeks. Rats were
      studied in the absorptive state, in the post-absorptive state or after 2.5 h
      euglycaemic hyperinsulinaemia. Tissues sampled included IBAT and four white
      adipose tissue depots, two abdominal (parametrial (PM) and perirenal (PR)) and
      two superficial (subcutaneous (SC) and interscapular (IS)). MEASUREMENTS: Whole
      body glucose disposal was estimated using [3-3H]glucose. Glucose
      uptake/phosphorylation in vivo was estimated using 2-deoxy[1-3H]-D-glucose.
      Insulin action was evaluated using the euglycaemic-hyperinsulinaemic clamp
      technique. PDHa activity was assayed spectrophotometrically in freeze-clamped
      tissue extracts. PDH kinase (PDK) activities were assayed in mitochondrial
      extracts by rates of ATP-dependent PDHa inactivation. RESULTS: Whole-body glucose
      disposal was decreased by high-fat-feeding in the post-absorptive state (P <
      0.05) and during euglycaemic hyperinsulinaemia (P < 0.01). Glucose
      transport/phosphorylation in IBAT was decreased by high-fat feeding in the
      absorptive (P < 0.001) and post-absorptive states (by 84%, P < 0.05) and during
      steady-state euglycaemic hyperinsulinaemia (by 73%, P < 0.001). IBAT PDHa
      activities were suppressed by high-fat feeding. Euglycaemic hyperinsulinaemia in
      post-absorptive control rats increased PDHa activities in IBAT (P < 0.001) to
      values comparable to those found in the absorptive state. Although IBAT PDHa
      activities were increased by euglycaemic hyperinsulinaemia in post-absorptive
      high-fat-fed rats, they remained lower (by 55%; P < 0.01) than those of controls.
      The failure of hyperinsulinaemia to normalise IBAT pyruvate dehydrogenase complex
      (PDHC) activities in high-fat-fed rats was associated with a stable 1.4-fold
      increase in IBAT PDK activity. High-fat feeding decreased glucose utilisation
      rates in the post-absorptive state in IS, but not in SC, PM or PR white adipose
      tissue depots. Euglycaemic hyperinsulinaemia significantly increased glucose
      utilisation in three out of the four depots of the control rats, but did not
      elicit statistically-significant changes in high-fat-fed rats. High-fat feeding
      influenced PDHa activity in PR, but was without significant effect on PDHa
      activity in PM, SC and IS. CONCLUSIONS: The results demonstrate that PDHa
      activity in the IBAT of rats maintained on standard diet responds to changes in
      insulin concentrations over the low physiological range, and that inactivation of
      PDHa in IBAT after feeding a diet moderately high in saturated fat is a
      consequence of the induction of tissue insulin resistance. Effects of this
      dietary regime on PDHa activity are paralleled by changes in insulin-stimulated
      glucose uptake/phosphorylation by IBAT in vivo, and IBAT is specifically
      targeted, with only moderate effects in white adipose tissue. The finding of
      impaired activation of BAT glucose transport/phosphorylation and PDHa activity in
      response to insulin may contribute to impaired thermogenesis in rats maintained
      on diets containing a relatively high proportion of saturated fat.

PMID- 10411238
TI  - Relationship between stature, overweight and central obesity in the adult
      population in Sao Paulo, Brazil.
AB  - OBJECTIVE: To test association between overweight, central obesity and stature.
      DESIGN: Cross-sectional study carried-out between 1990-1991. SUBJECTS: 951 adults
      (387 male and 564 female) aged 20-64 y, resident in the metropolitan area of Sao
      Paulo, Brazil. MEASUREMENTS: Anthropometry, blood lipid concentrations (total,
      high density lipoprotein (HDL) and low density lipoprotein (LDL)-cholesterol,
      triglycerides (TGs) and blood glucose. Body mass index (BMI), waist-to-hip ratio
      (WHR) and waist circumference were used to identify overweight (BMI > 25 kg/m2),
      abdominal obesity (WHR tertile 3 and waist circumference tertile 3),
      respectively. The subjects were categorised as those of short stature (women <
      150 cm, men < 162cm) and those of normal stature (women > or = 150 cm, men > or =
      162 cm). RESULTS: Prevalence of short stature was 19.6% and 15.4% in men and
      women, respectively. Short stature women had higher serum concentrations of total
      cholesterol, LDL-cholesterol, TGs and glucose than those of normal stature. Among
      men, this difference was not observed, except for glucose concentrations. Short
      stature women had high BMI and WHR means in some age categories, compared with
      those of normal stature. Both overweight and high WHR frequencies were greater in
      short stature women than in those of normal ones. In multivariate analysis,
      adjusted by age, income, marital status, education, physical activity and tobacco
      use, only women group with short stature compared with normal stature had
      significantly risk of overweight an high WHR. In the same group there was no
      association with waist circumference. Among the men there was significant
      opposite association with waist circumference. CONCLUSION: Short stature in women
      can potentially be an independent risk factor for overweight and high WHR.

PMID- 10411239
TI  - Effect of weight loss and regional fat distribution on plasma leptin
      concentration in obese women.
AB  - OBJECTIVES: To investigate how circulating leptin concentrations are related to
      regional fat distribution and whether moderate weight loss alters these
      relationships. DESIGN: A 6 month, clinical weight reduction trial with
      measurements before and after weight loss. SUBJECTS: 38 healthy, obese women
      (age: 44.3+/-9.9 y, BMI: 34.0+/-4.0 kg/m2). MEASUREMENTS: The following
      measurements were made. 1. indices of obesity and fat distribution: weight, body
      mass index (BMI), hip circumference (peripheral fat), waist circumference, total
      body fat (bioelectrical impedance), abdominal fat distribution: visceral fat and
      abdominal subcutaneous fat (ultrasonography); and 2. Biochemical measurements:
      plasma leptin and serum insulin. RESULTS: Baseline plasma leptin concentrations
      were three-fold higher in obese women than in normal weight controls. After
      weight loss averaging 8.4 kg (9.0%), plasma leptin decreased by a mean of 22.3%
      (P < 0.001), corresponding to body fat decrease of 16.6% (P < 0.001), abdominal
      subcutaneous fat decrease of 17.4% (P < 0.001) and visceral fat decrease of 18.7%
      (P < 0.001). The total amount of body fat correlated with plasma (serum) leptin
      before (r = 0.64, P < 0.001) and after (r = 0.75, P < 0.001) weight loss. Plasma
      leptin concentrations expressed per kg of body fat did not change significantly
      during weight loss. After controlling for body fat, baseline leptin
      concentrations were significantly associated with hip circumference (r = 0.57, P
      < 0.001) but not with any indices of abdominal fat distribution. After weight
      loss the associations became significant for hip and waist circumference as well
      as for visceral and abdominal subcutaneous fat. Changes in leptin correlated with
      changes in all indices of obesity except visceral fat. CONCLUSIONS: Plasma leptin
      concentrations reflect not only total fat mass but also adipose tissue
      distribution, especially peripheral fat. Plasma leptin values per kilogram of fat
      mass do not change significantly with modest weight loss.

PMID- 10411240
TI  - Stimulation of uncoupling protein 1 expression in brown adipocytes by naturally
      occurring carotenoids.
AB  - OBJECTIVE: To assess the effect of naturally occurring carotenoids on brown
      adipocyte proliferation and differentiation. The rationale behind is that certain
      carotenoids have provitamin A activity in mammals, and that one of the active
      forms of vitamin A, (retinoic acid) is known to behave as a transcriptional
      activator of the key gene for brown fat thermogenesis, the one encoding the
      uncoupling protein thermogenin (UCP1). DESIGN: Confluent primary cultures of mice
      brown adipocytes were treated with various concentrations of carotenoids. Cell
      morphology, total culture protein content, the DNA synthesis rate, and the levels
      of UCP1, retinoic acid receptor alpha (RARalpha) and retinoid X receptor alpha
      (RXRalpha) were analysed. RESULTS: Treatment with beta-carotene, alpha-carotene
      and lutein promoted UCP1 expression in a dose-dependent manner, with an
      effectiveness that was related to their potency as vitamin A precursors. Cell
      morphology, total culture protein content at confluence and DNA synthesis rate
      were unaffected after carotenoid treatment up to 10 microM. CONCLUSION: The
      results indicate that carotenoids can positively affect the expression of UCP1
      without altering brown adipocyte proliferation.

PMID- 10411241
TI  - Relative weight gain and obesity as a child predict metabolic syndrome as an
      adult.
AB  - OBJECTIVE: To examine whether birth weight, weight gain from birth to the age of
      seven or body-mass index at the age of seven have any association with metabolic
      syndrome as an adult. DESIGN: A population study. SUBJECTS: 210 men and 218 women
      out of a total 712 subjects aged 36, 41 or 46 years in Pieksamaki town, Finland.
      MAIN OUTCOME MEASURES: Weight at birth and weight and height at the age of seven
      and metabolic syndrome defined as a clustering of hypertension, dyslipidemia
      (hypertriglyceridaemia or low high-density-lipoprotein cholesterol), and insulin
      resistance (inferred by abnormal glucose tolerance or hyperinsulinaemia).
      RESULTS: No association was found between birth weight and the metabolic syndrome
      as an adult. Among obese children at the age of seven (body-mass index in the
      highest quartile), the odds ratio (OR) for the metabolic syndrome in adulthood
      was 4.4 (95% CI 2.1-9.5) as compared to the other children (the three other
      quartiles combined). After adjustment for age, sex and current obesity, the risk
      of the syndrome still was 2.4 (95% CI 2.1-9.5). CONCLUSION: We could not
      replicate the close association between low birth weight and the metabolic
      syndrome in adulthood as has been shown in some earlier studies. Obesity at the
      age of seven predicts the metabolic syndrome in adulthood.

PMID- 10411242
TI  - Leptin increases circulating glucose, insulin and glucagon via sympathetic neural
      activation in fasted mice.
AB  - OBJECTIVE: A number of recent studies suggest that leptin has effects on glucose
      metabolism and pancreatic hormone secretion. Therefore, the effect of leptin
      administration on circulating glucose, insulin and glucagon in fed and fasted
      mice was investigated. The potential contribution of the sympathetic nervous
      system to the effects of leptin was also examined. DESIGN: Recombinant human or
      murine leptin was administered intraperitoneally (300 microg/mouse per 12 h over
      24 h) to fed or fasted, normal or chemically sympathectomized NMRI mice. Blood
      samples were collected at baseline and after 24 h. MEASUREMENTS: Plasma
      concentrations of glucose, insulin and glucagon. RESULTS: In the fed state (n =
      24), leptin administration did not affect glucose, insulin or glucagon
      concentrations after 24 h. Fasting (n = 24) reduced body weight by 2.2+/-0.4 g,
      plasma glucose by 3.7+/-0.4 mmol/l, plasma insulin by 138+/-35 pmol/l, and plasma
      glucagon by 32+/-7 pg/ml. In fasted mice, human leptin (n = 24) increased plasma
      glucose by 1.5+/-0.2 mmol/l (P = 0.041), plasma insulin by 95+/-22 pmol/l (P =
      0.018), and plasma glucagon by 16+/-3 pg/ml (P = 0.025), relative to saline
      injected control animals. Murine leptin exerted similar stimulating effects on
      circulating glucose (+1.0+/-0.2 mmol/l, P = 0.046), insulin (+58+/-17 pmol/l, P =
      0.038) and glucagon (+24+/-9 pg/ml, P = 0.018) as human leptin in fasted mice (n
      = 12) with no significant effect in fed mice (n = 12). Human leptin did not
      affect circulating glucose, insulin or glucagon in fasted mice after chemical
      sympathectomy with 6-hydroxydopamine (40 mg/kg iv 48 h prior to fasting; n = 12).
      CONCLUSION: Leptin increases circulating glucose, insulin and glucagon in 24 h
      fasted mice by a mechanism requiring intact sympathetic nerves.

PMID- 10411243
TI  - A mitochondrial DNA D-loop polymorphism and obesity in three cohorts of women.
AB  - OBJECTIVE: To examine the hypothesis of an association between a mtDNA D-loop Kpn
      I restriction site polymorphism (RSP) at base pair (bp) 16,133 (morph-1) and
      obesity in women. DESIGN: Comparisons of carriers and noncarriers of the mutation
      for BMI (Body Mass Index) levels and of the frequency of the mutation in obese
      and normal weight women. SUBJECTS: 567 unrelated adult Caucasian non-diabetic
      women from the HERITAGE Family Study (n = 63; BMI: 15-47 kg/m2), Quebec Family
      Study (QFS; 77 controls, BMI: 19-26 kg/m2 and 38 obese, BMI: 27-56 kg/m2) and
      Swedish Obese Subjects (SOS) Study (81 controls, BMI: 18-26 kg/m2 and 308 obese,
      BMI: 33-58 kg/m2). MEASUREMENTS: BMI was calculated from weight and height
      (kg/m2). mtDNA was amplified between base pair 15,928 and 16,500 by polymerase
      chain reaction (PCR) and digested with the restriction endonuclease Kpn I.
      RESULTS: No significant differences in the age-adjusted BMI for the mtDNA D-loop
      Kpn I RSP at base pair (bp) 16,133 (morph-1) between carriers and non-carriers in
      the HERITAGE cohort. No significant association was found between BMI and the Kpn
      I RSP carrier status in the SOS and QFS cohorts. The observed frequencies for the
      Kpn I RSP were not significantly (P > 0.05) different between the SOS controls
      and SOS obese irrespective of the degree of severity of obesity (BMI > 40, > 45
      or > 50 kg/m2). CONCLUSION: We conclude that the mtDNA D-loop Kpn I RSP at bp
      16,133 (morph-1) is not a determinant of human obesity.

PMID- 10411244
TI  - The European Board of Cardiovascular Perfusion pre-bypass checklist.

PMID- 10411245
TI  - Albumin in the cardiopulmonary bypass prime: how little is enough?
AB  - Previous studies have demonstrated high transoxygenator pressures with noncoated
      hollow-fiber membrane oxygenators. These reports have been associated with
      dramatic platelet count drops during cardiopulmonary bypass (CPB). It has also
      been shown that adding human albumin to the prime of the bypass circuit reduces,
      if not eliminates, these problems. This study was conducted to determine what is
      the smallest amount of albumin added to the prime that will still display its
      protective effects. Eighty patients undergoing nonemergency open-heart surgery
      were randomly divided into four groups. Groups I and II received the Sarns Turbo
      440 oxygenator with 0.0375 g of albumin/100 ml of prime and 0.125 g of
      albumin/100 ml of prime, respectively, added to the pump prime. Groups III and IV
      received the Medtronic Maxima-PRF oxygenator with 0.0375 g of albumin/100 ml of
      prime and 0.125 g of albumin/100 ml of prime, respectively, added to the pump
      prime. Pre-CPB, on CPB (15-20 min after the initiation of bypass) and warming
      hemoglobin, hematocrit and platelet counts were drawn on all patients. Net
      platelet count drop, which accounted for hemodilutional effects, was calculated
      for all specimens and compared to previous results obtained from the test
      oxygenators without albumin in the prime. The net platelet count drops for the
      study groups were as follows: Sarns oxygenator with no albumin in the prime =
      11.8+/-12.5%; Sarns oxygenator with 0.0375 g of albumin/100 ml prime = -3.7+/
      10.8%; Sarns oxygenator with 0.125 g of albumin/100 ml prime = -2.0+/-12.6%;
      Medtronic oxygenator with no albumin in the prime = 20.1+/-14.5%; Medtronic
      oxygenator with 0.0375 g albumin/100 ml prime = -6.9+/-8.7%; and Medtronic
      oxygenator with 0.125 g albumin/100 ml prime = -14.0+/-12.4%. Our results
      illustrate that adding as little as 0.0375 g albumin/100 ml prime (3 ml of 25%
      solution/2000 ml of prime) to the pump prime illicits the beneficial effects of
      surface coating on platelet loss during CPB.

PMID- 10411246
TI  - Nucleated red blood cells after cardiopulmonary bypass in infants and children:
      is there a relationship to the systemic inflammatory response syndrome?
AB  - In a retrospective case control study we aimed to evaluate whether infants and
      children with nucleated red blood cells (NRBCs) in their peripheral blood smears
      after cardiopulmonary bypass (CPB) had longer bypass times than controls without
      NRBCs. On review of a 3-year period, 58 children with NRBCs after CPB (and
      without NRBCs prior to CPB) were identified (cases). A random sample of 100
      children without NRBCs after CPB over the same period served as controls. The
      median age (range) of the children with NRBCs and without NRBCs was 0.6 years (2
      days to 20 years) and 1.4 years (2 days to 16 years), respectively (p = 0.03).
      The children with NRBCs had a significantly longer bypass time than the controls
      (mean, standard deviation (SD): 114 min, 50 vs 79 min, 46 min; p < 0.0001). For
      the patients with postoperative polychromasia alone, the mean CPB time (111 min,
      SD 46 min) was also significantly longer than the respective time in the controls
      (p < 0.001). Markers of organ dysfunction (renal failure, use of inotropic
      support, time of endotracheal intubation, stay in intensive care unit and stay in
      hospital) were significantly more frequent/longer in the NRBC group. Post-CPB
      release of NRBCs is associated with longer CPB time. This alteration may be part
      of the CPB-related systemic inflammatory response syndrome.

PMID- 10411247
TI  - Assessing heparin neutralization following cardiac surgery: sensitivity of
      thrombin time-based assays versus protamine titration methods.
AB  - Adequate assessment of heparin neutralization following cardiac surgery is
      critical in reducing the patient's exposure to protamine. Both excessive
      protamine and residual heparin have been associated with postoperative bleeding
      and poor patient recovery. The activated clotting time (ACT) is the preferred
      intraoperative heparin monitor, while both protamine titration (i.e. a protamine
      containing ACT) and thrombin time methods have been used to detect circulating
      residual heparin after protamine administration. Following initial protamine
      dosing using the protamine response test (PRT), postoperative monitoring was
      employed in the operating room prior to transport of the patient to intensive
      care. Two point-of-care assays, the thrombin time (TT) and the protamine dose
      assay (PDA), were evaluated to determine their relative heparin sensitivity and
      their usefulness to quantitate protamine dose. The PDA, which is based on the
      ACT, was shown in laboratory and clinical studies to detect residual heparin
      above 0.25 units/ml and to quantify additional minidoses of protamine (as low as
      25 mg) required to obtain complete heparin neutralization. Differential
      evaluation of the TT and heparin neutralized thrombin time (HNTT) was shown in
      laboratory studies to be more sensitive to small amounts of residual heparin than
      the ACT. Clinical evaluations confirmed that additional protamine is required in
      approximately 12% of cardiac surgical cases managed using the PRT system. Both
      the PDA and TT/HNTT provided useful postoperative assessment of the adequacy of
      heparin neutralization. The TT/HNTT had slightly improved heparin sensitivity
      even in the presence of significant fibrinogen loss. These point-of-care assays
      provide the opportunity to optimize heparin and protamine management in the
      cardiac surgery patient.

PMID- 10411248
TI  - Retrospective analysis of effect of low-dose aprotinin priming on allogeneic
      blood transfusion in repeated cardiac operations.
AB  - The objective of this retrospective study was to investigate efficacy of low-dose
      aprotinin priming therapy on the requirement of allogeneic transfusion and to
      identify risk factors for allogeneic transfusion in patients undergoing repeated
      cardiac operations. The present study includes a critical review of 124
      consecutive charts of patients undergoing elective repeat cardiac surgery. We
      examined the effect of low-dose aprotinin priming therapy on blood loss, amounts
      of mediastinal drainage following intensive care unit (ICU) administration and
      the number of units of blood products given during the perioperative period. The
      rate of nonallogeneic transfusion was not affected by low-dose aprotinin priming
      therapy, although aprotinin reduced the amount of allogeneic transfusion and the
      amount of mediastinal drainage 12 h following ICU admission. In conclusion, low
      dose aprotinin priming therapy is effective in reducing blood loss and the amount
      of allogeneic transfusion. However, it failed to improve the rate of cardiac
      reoperations without allogeneic blood transfusion.

PMID- 10411249
TI  - Effect of surface coating on platelet count drop during cardiopulmonary bypass.
AB  - This study was designed to investigate the effect of surface coating on platelet
      count drop during cardiopulmonary bypass (CPB). Sixty patients undergoing open
      heart surgery were randomly divided into three groups each receiving a different
      type of coated hollow-fiber membrane oxygenator. The patients were given either
      an uncoated oxygenator (noncoated group), an oxygenator coated with Carmeda
      (Carmeda group) or an uncoated oxygenator with albumin in the priming solution
      (albumin group). Comparisons were made in platelet count pre-CPB, on bypass (15
      25 min) and during the warming period. Calculations were used to account for the
      effect of hemodilution. The albumin group had significantly lower platelet count
      drops (-4.8+/-7.1%) than the Carmeda group (11.0+/-8.3%) and the noncoated group
      (20.3+/-14.5%). Carmeda surface coating demonstrated some beneficial effects, but
      to a lesser degree than the albumin.

PMID- 10411250
TI  - Effect of low-dose methyl prednisolone on serum cytokine levels following
      extracorporeal circulation.
AB  - The systemic inflammatory response to cardiopulmonary bypass (CPB) is associated
      with increased production of cytokines. This systemic inflammatory response
      characterized by the activation of interleukin-6 (IL-6) and interleukin-8 (IL-8)
      during and after CPB is well documented. A prospective, randomized, double-blind
      study was performed so as to understand the effects of low-dose methyl
      prednisolone sodium succinate (MPSS) on the circulating levels of serum cytokines
      and clinical outcome. Twenty patients were randomly divided into two groups on
      the basis of the administration of low-dose (1 mg/kg) MPSS (n = 10) and placebo
      (n = 10) into the pump prime solution. All patients were scheduled to undergo a
      primary elective coronary artery bypass grafting operation. Patients receiving
      concurrent corticosteroids, salicylates, dipyridamol or anticoagulants were
      excluded from the study. Other exclusion criteria were concurrent chronic
      obstructive pulmonary disease, chronic renal failure, insulin-dependent diabetes,
      congestive cardiac failure, peptic ulcer history, prior cardiac operations,
      recent (in a one-month period) myocardial infarction and steroid dependency. Mild
      systemic hypothermia (30-32 degrees C, rectal) was assured during the CPB. Four
      blood samples were drawn from the radial artery catheter immediately before
      starting CPB (T1), following protamine administration (T2) and at 24 (T3) and 48
      h (T4) after completion of CPB. In each sample, creatine kinase-myocardial band
      (CK-MB), white blood cell (WBC), IL-6 and IL-8 levels were measured. IL-6 and IL
      8 concentrations were measured by enzyme immunoassay and enzyme-linked
      immunoabsorbant assay methods. Serum IL-6 T2 and serum IL-6 T3 levels were
      significantly higher than IL-6 T1 levels in both groups (p < 0.001) and (p <
      0.01), and there was no significant elevation in serum IL-8 levels in either
      group. Serum IL-6 levels were significantly higher in the placebo group than in
      the MPSS group at T3 (p < 0.009). There was no significant difference in CK-MB T1
      levels between the groups. Although there was no significant difference between
      CK-MB T1 and T2 levels in the MPSS group, the CK-MB T2 and CK-MB T3 levels were
      significantly higher than T1 levels in the placebo group (p < 0.001) and (p <
      0.05). There was significant elevation of WBC levels at T2 and T3 in both groups
      without notable difference between the groups (p < 0.05). This study has shown
      that low-dose MPSS suppresses CPB-induced inflammatory response. Further clinical
      studies (on larger and higher risk groups) may reveal more information on
      relations between morbidity and cytokine levels which may have some predictive
      value on clinical outcome following CPB.

PMID- 10411251
TI  - The incidence and cause of emergency oxygenator changeovers.
AB  - Emergency oxygenator changeover presents as an important potential hazard during
      cardiopulmonary bypass. In order to assess the frequency and possible causes of
      this event a retrospective survey was conducted of cardiothoracic units in the UK
      and Ireland. The survey was sent to these units in 1993 to cover the period from
      1990 to 1992 inclusive and again in 1997 to cover the period from 1994 to 1996
      inclusive. The total number of procedures reported in 1993 was 68937 (response of
      63%), among which there were 17 emergency oxygenator changeovers representing an
      incidence of one for every 4055 cases. The use of aprotinin was associated with
      nine of these incidents. Two other incidents occurred due to leaking oxygenators.
      The total number of procedures reported in 1997 was 97313 (response of 70%),
      among which there were 21 emergency oxygenator changeovers, representing an
      incidence of one for every 4634 cases. The use of aprotinin was only associated
      with two of these incidents while seven were due to the development of a high
      trans-oxygenator pressure gradient and six occurred due to leaking oxygenators.

PMID- 10411252
TI  - Patient outcome as a selection criterion in determining treatment mode.
AB  - The climate of health care reform encourages scrutiny of traditional and new
      forms of medical and surgical therapy. With the emergence of technologically
      innovative cardiac procedures, therapy advocates must weigh cost versus patient
      outcomes. Therapies range from purely medical management, through staged
      interventions, to median sternotomy and cardiopulmonary bypass. Outcomes will
      necessarily be related to quality of life. A literature search was performed to
      determine types of medical and surgical therapies associated with patient
      outcomes as they define quality of life. Medical treatment may include the use of
      anti-platelet therapy, beta-blockers and diuretics to treat the cardiac patient
      at low risk who can maintain an acceptable quality of life. Improvements in
      medical therapies may extend the life of the low-risk patient, eliminating the
      need to consider bypass surgery. Some patients at high risk, or with left
      ventricular hypertrophy combined with an impaired ejection fraction, may require
      coronary artery bypass surgery. Studies indicate that patients undergoing open
      heart surgery demonstrate significant improvement in functional classification,
      increased activity and reduction in anti-anginal medications. Proponents of
      minimally invasive surgery claim potential benefits of lower surgical trauma,
      shorter hospital stays and shorter recovery times. Quality of life is defined by
      outcomes. Only by comparing outcomes of all available therapies can a physician
      or patient make an informed decision regarding treatment.

PMID- 10411253
TI  - Cardiopulmonary bypass on a patient with malaria.
AB  - There are special considerations when performing cardiopulmonary bypass (CPB) on
      a patient with malaria. A 70-year-old female with a recent history of severe
      aortic stenosis was scheduled to undergo elective aortic valve replacement. One
      week prior to surgery, the patient developed shaking chills and fever, with a
      positive malaria smear. An extensive literature search was undertaken to
      determine the effect of CPB on a patient with active malaria, but no prior
      reference was found. One major concern was the lysis of red blood cells while on
      bypass. The surgery was performed uneventfully, following 2 weeks of treatment
      with primaquine phosphate.

PMID- 10411254
TI  - A subfamily of MalT-related ATP-dependent regulators in the LuxR family.

PMID- 10411255
TI  - A novel tRNA-associated locus (trl) from Helicobacter pylori is co-transcribed
      with tRNA(Gly) and reveals genetic diversity.
AB  - To date several genes have been identified in Helicobacter pylori that are
      expressed in only a proportion of strains, some of which are correlated with the
      pathogenicity of the bacterium. With this in mind, the present study was
      undertaken to identify other genes that are not expressed in all clinical
      isolates of H. pylori. Using arbitrarily primed PCR of RNA, a cDNA fragment of
      187 bp (designated trl for transfer RNA-associated locus) was identified that was
      expressed in only one of two clinical isolates being tested. The fragment was
      purified, cloned and sequenced. A search of public databases prior to the release
      of the complete genome sequence of H. pylori strain 26695 showed no similarity
      with any other known genes or gene products. Inverse PCR was used to obtain
      further nucleotide sequence information surrounding the trl locus. A DNA probe
      derived from the trl locus hybridized with 32 (50%) of 64 clinical H. pylori
      isolates tested. Comparison of the nucleotide sequences of a trl-positive and trl
      negative isolate showed that the locus is situated between two tRNA genes,
      tRNA(Gly) and tRNA(Leu), in H. pylori. Primer extension analysis showed that the
      trl locus is co-transcribed with tRNA(Gly). Analysis of the region between
      tRNA(Gly) and tRNA(Leu) in trl-negative isolates revealed additional genetic
      diversity among these isolates.

PMID- 10411256
TI  - Genetic suppression analysis of an asgA missense mutation in Myxococcus xanthus.
AB  - The asgA gene is required for generation of extracellular A signal, which serves
      as a cell-density signal for fruiting body development in Myxococcus xanthus. The
      AsgA protein is a histidine protein kinase and consists of a receiver domain that
      is conserved among response regulators of two-component signal transduction
      systems, followed by a histidine protein kinase domain that is conserved among
      sensor proteins of two-component systems. AsgA is thought to function in a signal
      transduction pathway that leads to expression of genes required for A-signal
      generation. A genetic suppression analysis of an asgA missense mutation was
      undertaken in order to identify genes that may provide information regarding the
      role of AsgA in A-signal generation and fruiting body formation. Twenty-two
      independent strains containing mutations that suppress asgA473 were isolated by
      selecting for production of heat-resistant spores under conditions that promote
      fruiting body development in wild-type cells. Ten of the 22 suppressor strains
      contained bypass suppressors. All the suppressor strains had direct spore counts
      at least three to four times greater than the original asgA473 mutant, and three
      strains had viable counts that exceeded wild-type by more than one order of
      magnitude. Surprisingly, none of the suppressor strains produced wild-type levels
      of extracellular A-signal.

PMID- 10411257
TI  - Constructs for insertional mutagenesis, transcriptional signal localization and
      gene regulation studies in root nodule and other bacteria.
AB  - Cassettes have been developed that contain an antibiotic resistance marker with
      and without a promoterless gusA reporter gene. The nptII (encoding kanamycin
      resistance) or aacCI (encoding gentamicin resistance) genes were equipped with
      the tac promoter (Ptac) and the trpA terminator (TtrpA) and then cloned between
      NotI sites to construct the CAS-Nm (Ptac-nptII-TtrpA) and CAS-Gm (Ptac/PaacCI
      aacCI-TtrpA) cassettes. The markers were also cloned downstream to a modified
      promoterless Escherichia coli gusA gene (containing TGA stop codons in all three
      reading frames prior to its RBS and start codon) to construct the CAS-GNm (gusA
      Ptac-nptII-TtrpA) or CAS-GGm (gusA-Ptac/PaacCI-aacCI-TtrpA) cassettes. Cassettes
      containing the promoterless gusA create type I fusions with a target DNA sequence
      to detect transcriptional activity. The promoterless gusA gene has also been
      cloned into a broad-host-range IncP1 plasmid. This construct will enable
      transcriptional activity to be monitored in different genetic backgrounds. Each
      cassette was cloned as a NotI fragment into the NotI site of a pUT derivative to
      construct four minitransposons. The mTn5-Nm (containing Ptac-nptII-TtrpA) and
      mTn5-Gm (containing Ptac/PaacCI-aacCI-TtrpA) minitransposons have been
      constructed specifically for insertional inactivation studies. The
      minitransposons mTn5-GNm (containing gusA-Ptac-nptII-TtrpA) and mTn5-GGm
      (containing gusA-Ptac/PaacCI-aacCI-TtrpA) can be used for transcription signal
      localization or insertional inactivation. The TAC-31R and TAC-105F primers can be
      used to sequence DNA flanking both sides of CAS-Nm, CAS-Gm, mTn5-Nm and mTn5-Gm.
      The WIL3 and TAC-105F primers can be used to sequence DNA flanking both sides of
      CAS-GNm, CAS-GGm, mTn5-GNm and mTn5-GGm. The specific application of these
      constructs to generate acid- or nodule-inducible fusions is presented. The new
      constructs provide useful tools for insertional mutagenesis, transcriptional
      signal localization and gene regulation studies in the root nodule bacteria and
      possibly other gram-negative bacteria.

PMID- 10411258
TI  - Colony morphotypes on Congo red agar segregate along species and drug
      susceptibility lines in the Mycobacterium avium-intracellulare complex.
AB  - Isolates of the Mycobacterium avium-intracellulare complex (MAC) have long been
      known to segregate into transparent opaque and rough colony morphotypes that
      differ from each other in clinically important parameters including drug
      susceptibility and virulence. Here the authors report additional morphotypic
      variation that occurs on two levels: interspecific (between M. avium and M.
      intracellulare) and intraspecific (within individual M. avium isolates). Clinical
      isolates of M. avium grown on Congo red (CR) plates formed red, pink or mixed
      (red and white) opaque colonies, while M. intracellulare isolates formed purely
      white opaque colonies. A quantitative CR binding assay showed that this
      interspecific differential applies to transparent as well as opaque colony
      variants; however, it was less pronounced among laboratory reference strains than
      among recent clinical isolates. Opaque colonies of M. avium isolates with 'mixed'
      phenotypes segregated into stable opaque red and white variants with shared
      IS1245 banding patterns (intraspecific segregation). White segregants of M. avium
      were more flocculent and significantly more resistant to ciprofloxacin and
      rifamycin drugs than were red segregants. Thus, cultivation on CR agar revealed a
      previously unknown multidrug resistant colony morphotype of M. avium.

PMID- 10411259
TI  - Flow cytometry and other techniques show that Staphylococcus aureus undergoes
      significant physiological changes in the early stages of surface-attached
      culture.
AB  - The techniques of flow cytometry, scanning and transmission electron microscopy,
      and confocal scanning laser microscopy were used to study the physiology of
      Staphylococcus aureus in the early stages of surface-attached culture, and to
      make direct comparisons with planktonic bacteria grown under the same conditions.
      Attached bacteria growing in nutrient-rich batch culture were found to go through
      the same growth phases as equivalent planktonic cultures, but with an exponential
      growth rate of about half that of the planktonic bacteria. Viability of attached
      bacteria was very high (around 100%) throughout the first 24 h of growth. The
      size and protein content of attached bacteria varied with growth phase, and both
      measurements were always smaller than in planktonic bacteria at equivalent growth
      phases. Respiratory activity per bacterium, as measured by flow cytofluorimetry,
      and corrected for cell volume, peaked very early in attached cultures (before the
      first cell division) and declined from then on, whereas in planktonic bacteria it
      peaked in late exponential phase. Attached and planktonic bacteria showed thicker
      cell walls in stationary phase than in exponential phase. Membrane potentials of
      planktonic and attached bacteria were similar in stationary phase, but were much
      lower in exponential-phase attached cells than in the equivalent planktonic
      cells. It is apparent that a range of significant physiological adaptations occur
      during the early phases of attached growth.

PMID- 10411260
TI  - Phenotypic variation in Actinobacillus actinomycetemcomitans during laboratory
      growth: implications for virulence.
AB  - This study examined alteration of specific virulence traits associated with
      phenotypic changes seen when a low-passage disease-associated and well maintained
      parent strain of Actinobacillus actinomycetemcomitans was compared to a
      laboratory-grown spontaneous variant/mutant. Clinical isolates of A.
      actinomycetemcomitans recovered from periodontitis patients typically grow as
      rough, adherent colonies on primary culture but undergo transformation to smooth,
      non-adherent colonies following repeated passage in vitro. The relationship of
      these phenotypic changes to the virulence of the organism or to the processes
      that underlie this transformation are not understood. A fresh clinical isolate,
      designated strain CU1000, was obtained from the first molar site of a patient
      with classical signs of localized juvenile periodontitis and used as the parent
      strain to study virulence-related phenotypes. Following several passages of
      CU1000 on selective agar, a spontaneous variant that demonstrated smooth, opaque,
      non-adherent colonies was isolated and designated strain CU1060. This study
      compared the properties of these two strains with respect to colony morphology,
      autoaggregation, surface appendages, adherence to saliva-coated hydroxyapatite
      (SHA), LPS chemotype and activity, induction of fibroblast proteinase activity
      and antigenic properties. CU1000 demonstrated rough, raised, star-positive
      colonies which upon electron microscopic examination revealed the presence of
      large, flexible, bundled fibrils. In addition, CU1000 showed adherence to SHA,
      several unique protein antigens and elevated endotoxin and fibroblast proteinase
      activity. CU1060, on the other hand, showed minimal adherence to SHA and fewer
      reactive proteins compared to the fresh clinical isolates. This strain formed
      smooth, opaque colonies on agar, showed minimal fibril formation and limited
      endotoxin and fibroblast-proteinase-inducing activity. These findings demonstrate
      that clinical isolates of A. actinomycetemcomitans undergo significant virulence
      reducing phenotypic alterations during in vitro passage and support the need to
      study this organism in its clinical form.

PMID- 10411261
TI  - Mucoid conversion of Pseudomonas aeruginosa by hydrogen peroxide: a mechanism for
      virulence activation in the cystic fibrosis lung.
AB  - The leading cause of mortality in patients with cystic fibrosis (CF) is
      respiratory failure due in large part to chronic lung infection with Pseudomonas
      aeruginosa strains that undergo mucoid conversion, display a biofilm mode of
      growth in vivo and resist the infiltration of polymorphonuclear leukocytes
      (PMNs), which release free oxygen radicals such as H2O2. The mucoid phenotype
      among the strains infecting CF patients indicates overproduction of a linear
      polysaccharide called alginate. To mimic the inflammatory environment of the CF
      lung, P. aeruginosa PAO1, a typical non-mucoid strain, was grown in a biofilm.
      This was treated with low levels of H2O2, as if released by the PMNs, and the
      formation of mucoid variants was observed. These mucoid variants had mutations in
      mucA, which encodes an anti-sigma factor; this leads to the deregulation of an
      alternative sigma factor (sigma22, AlgT or AlgU) required for expression of the
      alginate biosynthetic operon. All of the mucoid variants tested showed the same
      mutation, the mucA22 allele, a common allele seen in CF isolates. The mucoid
      mucA22 variants, when compared to the smooth parent strain PA01, (i) produced 2-6
      fold higher levels of alginate, (ii) exhibited no detectable differences in
      growth rate, (iii) showed an unaltered LPS profile, (iv) were approximately 72%
      reduced in the amount of inducible-beta-lactamase and (v) secreted little or no
      LasA protease and only showed 44% elastase activity. A characteristic
      approximately 54 kDa protein associated with alginate overproducing strains was
      identified as AlgE (Alg76) by N-terminal sequence analysis. Thus, the common
      phenotype of the mucoid variants, which included a genetically engineered mucA22
      mutant, suggested that the only mutation incurred as a result of H2O2 treatment
      was in mucA. When a P. aeruginosa biofilm was repeatedly exposed to activated
      PMNs in vitro, mucoid variants were also observed, mimicking in vivo
      observations. Thus, PMNs and their oxygen by-products may cause P. aeruginosa to
      undergo the typical adaptation to the intractable mu- coid form in the CF lung.
      These findings indicate that gene activation in bacteria by toxic oxygen
      radicals, similar to that found in plants and mammalian cells, may serve as a
      defence mechanism for the bacteria. This suggests that mucoid conversion is a
      response to oxygen radical exposure and that this response is a mechanism of
      defence by the bacteria. This is the first report to show that PMNs and their
      oxygen radicals can cause this phenotypic and genotypic change which is so
      typical of the intractable form of P. aeruginosa in the CF lung. These findings
      may provide a basis for the development of anti-oxidant and anti-inflammatory
      therapy for the early stages of infection in CF patients.

PMID- 10411262
TI  - Mechanisms of pyrazinamide resistance in mycobacteria: importance of lack of
      uptake in addition to lack of pyrazinamidase activity.
AB  - Mycobacteria are known to acquire resistance to the antituberculous drug
      pyrazinamide (PZA) through mutations in the gene encoding pyrazinamidase (PZase),
      an enzyme that converts PZA into pyrazinoic acid, the presumed active form of PZA
      against bacteria. Additional mechanisms of resistance to the drug are known to
      exist but have not been fully investigated. Among these is the non-uptake of the
      pro-drug, a possibility investigated in the present study. The uptake mechanism
      of PZA, a requisite step for the activation of the pro-drug, was studied in
      Mycobacterium tuberculosis. The incorporation of [14C]PZA by the bacilli was
      followed in both neutral and acidic environments since PZA activity is known to
      be optimal at acidic pH. By using a protonophore (carbonyl cyanide m
      chlorophenylhydrazone; CCCP), valinomycin, arsenate and low temperature, it was
      shown that an ATP-dependent transport system is involved in the uptake of PZA.
      Whilst the structurally analogous compound nicotinamide inhibited the transport
      system of PZA, other structurally related compounds such as pyrazinoic acid,
      isoniazid and cytosine did not. Acidic conditions were also without effect. Based
      on diffusion experiments in liposomes, it was found that PZA diffuses rapidly
      through membrane bilayers, faster than glycerol, whilst the presence of OmpATb,
      the porin-like protein of M. tuberculosis, in proteoliposomes slightly increased
      the diffusion of the drug. This finding may explain why the cell wall mycolate
      hydrophobic layer does not represent the limiting step in the diffusion of PZA,
      as judged from comparative experiments using a M. tuberculosis strain and its
      isogenic mutant elaborating 40% less covalently linked mycolates. PZase activity,
      and PZA uptake and susceptibility in different mycobacterial species were
      compared. M. tuberculosis, a naturally PZA-susceptible species, was the only
      species that exhibited both PZase activity and PZA uptake; no such correlation
      was observed with the four naturally resistant species examined. Mycobacterium
      smegmatis possessed a functional PZase but did not take up PZA; the reverse was
      true for the PZase-negative strain of Mycobacterium avium used, with PZA uptake
      comparable to that of M. tuberculosis. Mycobacterium bovis BCG and Mycobacterium
      kansasii exhibited neither a PZase activity nor PZA uptake. These data clearly
      demonstrate that one of the mechanisms of resistance to PZA resides in the
      failure of strains to take up the drug, indicating that susceptibility to PZA in
      mycobacteria requires both the presence of a functional PZase and a PZA transport
      system. No correlation was observed between the occurrence and cellular location
      of PZase and of nicotinamidase in the strains examined, suggesting that one or
      both amides can be hydrolysed by other mycobacterial amidases.

PMID- 10411263
TI  - A novel protein of Erysipelothrix rhusiopathiae that confers haemolytic activity
      on Escherichia coli.
AB  - Erysipelothrix rhusiopathiae, the cause of swine erysipelas and human
      erysipeloid, produces a haemolysin. A recombinant plasmid, pHLY, conferring
      haemolytic activity on Escherichia coli was isolated from a genomic library of
      Ery. rhusiopathiae strain Tama-96. This plasmid was stable in RecA- E. coli, but
      unstable in a RecA+ strain. A spontaneous deletion plasmid, pMini-HLY, also
      conferring haemolytic activity was derived from pHLY. Two ORFs were detected in
      pHLY. Analysis of pMini-HLY and other deletion clones established that ORF2 was
      associated with haemolytic activity. The sequence of ORF1 was highly homologous
      to those of transposases in the IS30 family. The deletion which generated pMini
      HLY was between two short direct repeat (DR) sequences flanking the ORF1
      sequence, and there were inverted repeat sequences inside the two DR sequences,
      suggesting an insertion element. No sequence homology to the deduced amino acid
      sequence of ORF2 was detected in the databases, but its sequence was
      characteristic of a surface lipoprotein. Western blot analysis, using antiserum
      against the 16 kDa protein produced from ORF2, found the protein to be commonly
      distributed in all Erysipelothrix species.

PMID- 10411264
TI  - Lactococcus lactis contains only one glutamate decarboxylase gene.
AB  - Glutamate decarboxylase, which is associated with a glutamate-dependent acid
      resistance mechanism, was purified from Lactococcus lactis subsp. lactis by a
      three-step procedure. The specific activity was increased about 114-fold with a
      yield of 16%. The N-terminal amino acid sequence of the enzyme was determined.
      The gene encoding this enzyme was cloned in Escherichia coli, and its nucleotide
      sequence was determined. The deduced amino acid sequence suggests that the enzyme
      is produced as a mature form (466 amino acid residues), not as a precursor
      protein. The subunit molecular mass of L. lactis glutamate decarboxylase was
      calculated to be 53 926 Da. The enzyme was maximally active at pH 4.7 and reacted
      only with L-glutamate among 20 alpha-amino acids. The apparent Km value was
      calculated to be 0.51 mM. The activity was stable at acidic pH values; there was
      no activity in the neutral pH range. At pH 4.1 the enzyme activity was retained
      at temperatures up to 70 degrees C in 10 min incubations. L. lactis glutamate
      decarboxylase behaved as a single protein when the enzyme was purified. A single
      band corresponding to the glutamate decarboxylase gene was detected on Southern
      blot analysis. These data suggest that there is one glutamate decarboxylase gene
      in L. lactis.

PMID- 10411265
TI  - The prpE gene of Salmonella typhimurium LT2 encodes propionyl-CoA synthetase.
AB  - Biochemical and genetic evidence is presented to demonstrate that the prpE gene
      of Salmonella typhimurium encodes propionyl-CoA synthetase, an enzyme required
      for the catabolism of propionate in this bacterium. While prpE mutants used
      propionate as carbon and energy source, prpE mutants that lacked acetyl-CoA
      synthetase (encoded by acs) did not, indicating that Acs can compensate for the
      lack of PrpE in prpE mutants. Cell-free extracts enriched for PrpE catalysed the
      formation of propionyl-CoA in a propionate-, ATP-, Mg2+- and HS-CoA dependent
      manner. Acetate substituted for propionate in the reaction at 48% the rate of
      propionate; butyrate was not a substrate for PrpE. The propionyl-CoA synthetase
      activity of PrpE was specific for ATP. GTP, ITP, CTP and TTP were not used as
      substrates by the enzyme. UV-visible spectrophotometry, HPLC and MS data
      demonstrated that propionyl-CoA was the product of the reaction catalysed by
      PrpE.

PMID- 10411266
TI  - Structure and expression of the fliA operon of Salmonella typhimurium.
AB  - The fliA gene encodes the flagellum-specific sigma factor sigma28 In Salmonella
      typhimurium. The transcription in vivo and in vitro of this gene was analysed and
      it was found that there are two promoters for the expression of this gene. One is
      a class 2 promoter which is recognized by sigma70-RNA polymerase in the presence
      of the FlhD and FlhC activator proteins. The other is a class 3 promoter which is
      recognized by sigma28-RNA polymerase. Therefore, the fliA operon is under dual
      positive control from FlhD/FlhC and from FliA itself. The nucleotide sequence
      downstream of the fliA gene was determined. The sequence contains two ORFs
      following the fliA gene. On the basis of their sequence homology, it is concluded
      that these two correspond to the fliZ and fliY genes of Escherichia coil.
      Northern blot analysis revealed that the fliZ gene is transcribed from the fliA
      promoters, whereas the fliY gene is transcribed from both the fliA promoters and
      its own FlhD/FlhC-independent promoter. A fliZ-disruption mutant was constructed
      by inserting a kanamycin-resistance gene cassette into the fliZ gene on the
      chromosome. The mutant showed poor motility, and introduction of a fliZ+ plasmid
      into this mutant restored the wildtype level of motility. These results suggest
      that the fliZ gene may be required for expression of maximal motility.

PMID- 10411267
TI  - Agrobacterium tumefaciens possesses a fourth flagelin gene located in a large
      gene cluster concerned with flagellar structure, assembly and motility.
AB  - The authors have identified a fourth flagellin gene in a 21850 bp region of the
      Agrobacterium tumefaciens C58C1 chromosome containing at least 20 genes concerned
      with flagellar structure, assembly and function. Three flagellin genes, flaA,
      flaB and flaC, orientated rightward, are positioned in a tandem array at the
      right end, with the fourth, substantially larger gene, flaD, in the opposite
      orientation, at the left end. Between these lie four apparent operons, two
      transcribed in each direction (motA, flhB leftward; flgF, flgB rightward) from a
      divergent position approx 7.5 kb from the left end. This unifies the previously
      published motA, flgB and flaABC sequences into a single region, also containing
      the homologues of flhB, flgF and fliI. Site-specific mutagenesis of fliI results
      in a non-flagellate phenotype, while a Tn5-induced flhB mutant possesses abnormal
      flagella. Mutagenesis and protein profiling demonstrate that all four flagellins
      contribute to flagellar structure: FlaA is the major protein, FlaB and FlaC are
      present in lesser amounts, and FlaD is a minor component. FlaA has anomolous
      electrophoretic mobility, possibly due to glycosylation.

PMID- 10411268
TI  - Mutational analysis of the dimethylsulfoxide respiratory (dor) operon of
      Rhodobacter capsulatus.
AB  - Four genes, dorC, dorD, dorB and dorR of the DMSO respiratory gene cluster of
      Rhodobacter capsulatus have been identified and sequenced. dorC encodes a
      pentahaem c-type cytochrome of the NirT class and the derived DorC protein
      sequence shows highest similarity to TorC from the Escherichia coli
      trimethylamine-N-oxide (TMAO) respiratory system. Mutagenesis of dorC resulted in
      the loss of a 46 kDa haem-staining polypeptide from membranes of R. capsulatus.
      dorD encodes a protein with highest sequence similarity to TorD from the E. coli
      TMAO respiratory system. DMSO reductase polypeptide (DorA) could not be detected
      in cell-free extracts of a dorD mutant and it is suggested that DorD has a role
      in stabilizing the DorA apo-protein prior to insertion of the pterin molybdenum
      cofactor. dorB encodes a protein with highest sequence similarity to NapD of
      Paracoccus denitrificans. Mutagenesis of dorB reduced the activity of DMSO
      reductase and led to the accumulation of a larger form of the enzyme that is
      presumed to represent a cytoplasmic precursor polypeptide. It is suggested that
      DorB has a role in the biogenesis of DMSO reductase prior to its secretion into
      the periplasm. dorR is transcribed in the opposite direction to dorC. The derived
      amino acid sequence of DorR indicates that it is a response regulator and
      mutation of dorR shows that it is essential for expression of the dorCDA operon.
      Expression of a chromosomal dorA::lacZ fusion was also dependent on the
      transcriptional regulator Fnr. The intergenic region between dorR and dorC
      contains four putative binding sites for DorR but no binding site for Fnr was
      identified.

PMID- 10411269
TI  - Characterization of a molybdenum cofactor biosynthetic gene cluster in
      Rhodobacter capsulatus which is specific for the biogenesis of dimethylsulfoxide
      reductase.
AB  - The DMSO reductase of Rhodobacter capsulatus contains a pterin molybdenum
      cofactor (Moco) and is located in the periplasm. DNA sequence analysis identified
      four genes involved in the biosynthesis of the Moco (moaA, moaD, moeB and moaC)
      immediately downstream of the dor (DMSO respiratory) gene cluster. Rhodobacter
      capsulatus MoaA was expressed in Escherichia coli as a His6-tagged protein.
      Although, the expressed protein formed inclusion bodies, EPR spectroscopy showed
      that MoaA contains a [3Fe-4S] cluster. A moaA mutant was constructed and its
      phenotype indicates that the Moco biosynthetic gene cluster downstream of the dor
      operon is specific for the biogenesis of DMSO reductase. Two forms of DMSO
      reductase were purified by immunoaffinity chromatography from the moaA mutant. A
      mature form of DMSO reductase was located in the periplasm and a precursor form
      was found in the cytoplasm.

PMID- 10411270
TI  - Flocculation of hyphae is associated with a deletion in the putative CaHK1 two
      component histidine kinase gene from Candida albicans.
AB  - In Candida albicans, three putative histidine kinase genes have been described
      thus far, including CaSLN1, CaNIK1/COS1 and CaHK1. The encoded proteins for C.
      albicans, CaSln1p and CaNik1p, which are similar to Sln1p from Saccharomyces
      cerevisiae and Nik-1 from Neurospora crassa, seem to function in osmoregulation
      and morphogenesis, respectively. Recently, the isolation of CaHK1, a putative
      histidine kinase gene from C. albicans has been reported. In addition to the
      histidine and aspartyl domains located at its C-terminus as previously described,
      it is shown here that the N-terminal domain of Cahk1p contains a P-loop motif and
      a sequence which shows significant homology with the seven C-terminal domains of
      serine/threonine kinases. The Ser/Thr-homologous domains of Cahk1p could, in
      fact, correspond to its sensor sequence. CaHK1 has been mapped to chromosome 2
      and gene deletion studies were undertaken to understand its function. Deltacahk1
      mutants are phenotypically different from any other histidine kinase mutants thus
      far described either in C. albicans or in any other yeast or filamentous fungus.
      This study demonstrates that deltacahk1 mutants flocculate extensively in a gene
      dosage-dependent manner under conditions which induce germ-tube formation, such
      as growth in medium 199 (pH 7.5). The flocculation occurs by an interaction along
      the hyphal surfaces, probably because of the altered expression of one or more
      hyphal-cell-surface components in the deltacahk1 mutants. These results indicate
      that CaHK1 could be involved in regulating their expression.

PMID- 10411271
TI  - The erg-3 (sterol delta14,15-reductase) gene of Neurospora crassa: generation of
      null mutants by repeat-induced point mutation and complementation by proteins
      chimeric for human lamin B receptor sequences.
AB  - Null mutations were generated in the erg-3 gene of Neurospora crassa by repeat
      induced point mutation (RIP). The mutants were viable, lacked ergosterol, were
      resistant to the steroidal glycoside alpha-tomatine and were sensitive to the
      phytoalexins pisatin and biochanin A. RIP was frequently associated with
      silencing of the hph gene located adjacent to the duplicated erg-3 sequence. The
      silencing of hph was reversible in the two cases examined and appeared to be due
      to the spread of cytosine methylation associated with RIP. The erg-3 mutant could
      be complemented by transformation with recombinant genes that encode proteins
      chimeric for amino acid sequences from the transmembrane (TM) domain of human
      lamin B receptor (LBR). This indicates that the LBR TM domain possesses
      delta14,15-reductase activity.

PMID- 10411272
TI  - Geminivirus-related extrachromosomal DNAs of the X-clade phytoplasmas share high
      sequence similarity.
AB  - Southern blot hybridization analysis revealed that the extrachromosomal DNAs (EC
      DNAs) associated with Vaccinium witches' broom (VAC) and walnut witches' broom
      phytoplasmas and various strains of the Italian clover phyllody phytoplasma
      (ICPh) were highly homologous among themselves but distinct from EC-DNAs of aster
      yellows related phytoplasmas occurring in the same insect and plant hosts and
      collected at the same site as the ICPh strains. The EC-DNAs of various strains of
      the ICPh differed significantly in number and size, more markedly among samples
      from different host plant species than among samples from the same host plant
      species. However, experiments on insect-mediated transmission suggested that the
      size variation is not associated with plant host specificity. Sequence analysis
      of cloned fragments revealed the presence of highly conserved ORFs (with
      substantially invariant putative translation products) but also the presence of
      regions rich in short direct and inverted repeats, which may be the cause of the
      size variations. The partial sequence of an EC-DNA associated with VAC encoding a
      putative replication-associated protein indicated their close phylogenetic
      relationship with geminiviruses.

PMID- 10411273
TI  - The genes controlling sucrose utilization in Clostridium beijerinckii NCIMB 8052
      constitute an operon.
AB  - The sucrose operon of Clostridium beijerinckii NCIMB 8052 comprises four genes,
      which encode a sucrose-specific enzyme IIBC(Scr) protein of the
      phosphotransferase system (ScrA), a transcriptional repressor (ScrR), a sucrose
      hydrolase (ScrB) and an ATP-dependent fructokinase (ScrK). The scrARBK operon was
      cloned in Escherichia coli in three stages. Initial isolation was achieved by
      screening a C. beijerinckii genomic library in E. coli for clones able to utilize
      sucrose, while the remainder of the operon was isolated by inverse PCR and by
      plasmid rescue of flanking regions from a scrB mutant constructed by targeted
      gene disruption. Substrate specificity assays confirmed that the sucrose
      hydrolase was a beta-fructofuranosidase, able to hydrolyse sucrose and raffinose
      but not inulin or levans, and that the scrK gene encoded an ATP/Mg2+-dependent
      fructokinase. Both enzyme activities were induced by sucrose in C. beijerinckii.
      Disruption of the scr operon of C. beijerinckii by targeted plasmid integration
      into either the scrR or the scrB gene resulted in strains unable to utilize
      sucrose, indicating that this was the only inducible sucrose catabolic pathway in
      this organism. RNA analysis confirmed that the genes of the scr operon were co
      transcribed on a 5 kb mRNA transcript and that transcription was induced by
      sucrose, but not by glucose, fructose, maltose or xylose. Primer extension
      experiments identified the transcriptional start site as lying 44 bp upstream of
      the scrA ATG start codon, immediately adjacent to the imperfect pelindrome
      sequence proposed to be a repressor binding site. Disruption of the scrR gene
      resulted in constitutive transcription of the upstream scrA gene, suggesting that
      ScrR encodes a transcriptional repressor which acts at the scrA operator
      sequence. The scrR gene is therefore itself negatively autoregulated as part of
      the polycistronic scrARBK mRNA

PMID- 10411274
TI  - Molecular characterization of idiA and adjacent genes in the cyanobacteria
      Synechococcus sp. strains PCC 6301 and PCC 7942.
AB  - IdiA (iron-deficiency-induced protein A) is a protein expressed at highly
      elevated levels in Synechococcus sp. strains PCC 6301 and PCC 7942 under Fe- or
      Mn-limiting growth conditions. Besides being similar to two bacterial Fe-binding
      proteins, SfuA and FbpA, IdiA shows similarity to two ORFs (slr0513 and sir1295)
      of Synechocystis sp. PCC 6803. Northern blot analysis detected one transcript of
      about 1300 nt in RNA extracted from Synechococcus sp. PCC 6301 and PCC 7942 grown
      under Fe deficiency. The intensity of this transcript was considerably reduced in
      Fe-sufficient culture. It could be further shown that the regulation of IdiA
      expression is at the transcriptional level and that transcription and translation
      of IdiA are closely linked. Primer extension analysis indicated a single
      transcriptional start site 193 nt upstream of the first presumed translational
      start codon. Moreover, molecular characterization of the entire 5.8 kb
      chromosomal HindIII DNA fragment carrying the idiA gene from Synechococcus sp.
      PCC 6301 led to the identification of six long ORFs in addition to idiA. The two
      genes adjacent to idiA, and dpsA located 2018 nt downstream of idiA, were
      insertionally inactivated in Synechococcus sp. PCC 7942 and the corresponding
      mutants were partially characterized. These experiments provide evidence that the
      gene products of idiB, located immediately downstream of idiA, and of dpsA are
      involved in the activation of IdiA expression, since the absence of each of these
      two gene products prevents the greatly elevated expression of IdiA under nutrient
      deficiency.

PMID- 10411275
TI  - Two-hybrid assay: construction of an Escherichia coli system to quantify
      homodimerization ability in vivo.
AB  - A hybrid system which takes advantage of the properties of the lambda repressor
      allows detection of protein-protein interactions. Fusion of the cI N-terminal
      domain to a heterologous protein will result in a functional lambda repressor,
      able to strongly bind to its operator and conferring immunity to lambda infection
      only when the heterologous protein dimerizes efficiently. In this paper,
      construction of a recombinant plasmid which allows detection of the activity of
      the lambda chimeric repressor formed by the N-terminal part of cI fused with a
      heterologous protein is reported. This construct is interesting due to its
      potential to be integrated in any target gene of the bacterial host, thus
      permitting this hybrid assay to be performed, not only in Escherichia coli
      strains, but in every bacterial genus where the reporter gene can be expressed.
      In addition, because of its modular construction, this plasmid can be easily
      modified to be exploitable in many experimental situations, such as in the
      detection of promoter region activity.

PMID- 10411276
TI  - Chemical and structural characterization of exopolymers produced by Pseudomonas
      sp. NCIMB 2021 in continuous culture.
AB  - The growth of marine Pseudomonas sp. NCIMB 2021 as continuous cultures in the
      presence of surfaces of AISI 316 stainless steel allowed the isolation and
      partial chemical characterization of exopolymers released into the culture medium
      (free exopolymers), as well as capsular and biofilm exopolymers. Fourier
      transform infrared (FTIR) spectroscopy demonstrated the presence of O- and N
      acetylation within the carbohydrate moieties and a predominant 310-helical
      structure of the protein component, highly resistant to hydrogen/deuterium
      exchange. Differences between the exopolymers were apparent. Relatively less
      uronic acid residues were detected in the capsular exopolymers compared to either
      the biofilm or free exopolymers. O- and N-acetylation were greatest in the
      biofilm exopolymer. SDS-PAGE protein profiles confirmed differences between
      exopolymers. The secondary structures of proteins determined using FTIR
      spectroscopy indicated that the capsular exopolymer had reduced helical content
      and an increased aggregated strand content compared to the biofilm exopolymer.
      However, the free exopolymer had an increased beta-sheet component and a reduced
      unordered component when compared to the biofilm and capsular exopolymers. These
      data suggest that exopolymer chemistry varies with cellular mode of growth.

PMID- 10411277
TI  - Generation of a novel polysaccharide by inactivation of the aceP gene from the
      acetan biosynthetic pathway in Acetobacter xylinum.
AB  - The acetan biosynthetic pathway in Acetobacter xylinum is an ideal model system
      for engineering novel bacterial polysaccharides. To genetically manipulate this
      pathway, an Acetobacter strain (CKE5), more susceptible to gene-transfer
      methodologies, was developed. A new gene, aceP, involved in acetan biosynthesis
      was identified, sequenced and shown to have homology at the amino acid level with
      beta-D-glucosyl transferases from a number of different organisms. Disruption of
      aceP in strain CKE5 confirmed the function assigned above and was used to
      engineer a novel polysaccharide with a pentasaccharide repeat unit.

PMID- 10411278
TI  - Imiquimod applied topically: a novel immune response modifier and new class of
      drug.
AB  - Imiquimod (S-26308, R-837) (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4
      amine), an immune response modifier, demonstrates potent antiviral and antitumor
      activity in animal models (see structure in Fig. 1). The drug exhibits no direct
      antiviral or antiproliferative activity when tested in a number of cell culture
      systems. Imiquimod's activity was discovered while screening for anti-herpes
      virus activity. One of the first analogs in the series, S-25059 was tested in the
      early 1980's and due to slight toxicity, caused slightly reduced herpes
      cytopathology in Vero cell cultures. Follow-up testing in herpes infected guinea
      pigs showed complete protection toward lesion development. Activity of these
      drugs results primarily from interferon alpha (IFN-alpha) induction and other
      cytokine induction. At least part of the cytokine induction is mediated through
      NF-kappaB activation. These cytokines stimulate several other aspects of the
      innate immune response. In addition, imiquimod stimulates acquired immunity, in
      particular the cellular arm which is important for control of viral infections
      and various tumors. This effect is mediated by drug induced IFN-alpha and
      Interleukin-12 (IL-12) and IFN-gamma induced by these cytokines. Imiquimod is
      expected to be effective where exogenous IFN-alpha has shown utility and where
      enhancement of cell-mediated immunity is needed. The following is a brief review
      of the preclinical pharmacology of imiquimod and the clinical results of genital
      wart trials. The mechanism of action of topically applied imiquimod will likely
      lead to benefits in several other chronic virus infections and tumors of the
      skin. Two other reviews on imiquimod that focus mainly on the clinical results
      have been published (Beutner & Geisse, 1997; Slade, Owens, Tomai & Miller, 1998).

PMID- 10411279
TI  - Thymosin-alpha1 stimulates maturation of CD34+ stem cells into CD3+4+ cells in an
      in vitro thymic epithelia organ coculture model.
AB  - The effect of thymosin-alpha1 on thymopoiesis is largely unknown. Thymosin is
      found in the cortical and medullary thymic epithelia, as well as in nurse cells;
      thus, it is hypothesized that thymosin may affect both early and late stage of
      thymocyte maturation. In this study, the effect of thymosin-alpha1 on
      thymopoiesis was determined by coculturing in vitro CD34+ stem cells (SC) with
      allogeneic cultured thymic epithelia fragments (CTEF) for 1-4 weeks and analyzing
      T-cell maturation by flow cytometry. Thymosin-alpha1 significantly enhanced the
      cell number (e.g., proliferation) of mononuclear cells obtained at 2 and 4 weeks
      of the SC-CTEF cocultures (P < 0.01 and < 0.05, respectively). In particular,
      thymosin-alpha1 stimulated expression of CD3+ cells at 3 and 4 weeks (P < 0.05).
      The predominant subpopulation increased by thymosin stimulation was single
      positive mature CD4+ cells, which was confirmed to occur within the SC-CTEF
      thymic organ tissue by laser confocal immunofluorescence microscopy. Thymosin
      stimulation tended to enhance IL-7 synthesis, critical cytokine in the maturation
      of thymocytes. In summary, this is the first study to demonstrate that thymosin
      alpha1 enhanced thymopoiesis of CD34+ stem cells in humans using an in vitro
      model of differentiation using stem cells and cultured thymic epithelial
      fragments cocultures. Furthermore, the thymosin significantly increased
      expression of CD3+4+ T cells.

PMID- 10411280
TI  - Melatonin administration in tumor-bearing mice (intact and pinealectomized) in
      relation to stress, zinc, thymulin and IL-2.
AB  - Melatonin (MEL) may counteract tumors through a direct oncostatic role. MEL is
      also an antistress agent with immunoenhancing properties against tumors due to a
      suppressive role of MEL on corticosterone release. Rotational stress (RS)
      (spatial disorientation) facilitates metastasis progression in mice. Also, MEL
      counteracts tumors because of its influence on immune responses via the metabolic
      zinc pool, which, is reduced in tumors and stress. Zinc is required for normal
      thymic endocrine activity (i.e. thymulin) and interleukin-2 (IL-2) production.
      Because in vivo data is still controversial, exogenous MEL treatment (22 days in
      drinking water) in both intact and pinealectomized (px) mice bearing Lewis lung
      carcinoma leads to significant decrements of metastasis volume, restoration of
      the negative crude zinc balance, recovery of thymulin activity and increment of
      IL-2 exclusively in intact and px tumor bearing mice subjected to RS. Significant
      inverse correlations are found in both stressed intact and px tumor bearing mice
      after MEL treatment between zinc and corticosterone (r = 0.78, P < 0.01; r =
      0.80, P < 0.01, respectively). Positive correlations between zinc and IL-2 (r =
      0.75, P < 0.01; r = 0.73, P < 0.01, respectively) or thymulin (r = 0.75, P <
      0.01; r = 0.82, P < 0.01, respectively) are observed in same models of mice.
      These findings suggest a MEL action to decrease metastasis mediated by a possible
      interplay between zinc and MEL, via corticosterone, with consequent restoration
      of thymic efficiency and IL-2 production. MEL as an antistress agent with
      immunoenhancing properties in cancer deserves further consideration.nuclear
      factor-kb; POMC, proopiomelanocortin; Px, pinealectomized mice; RIA,
      radioimmunoassay; RS, rotational stress; SDI, stressed intact mice; SDPx,
      stressed pinealectomized mice; TNF-alpha, tumor necrosis factor-alpha; ZnFTS,
      active zinc-bound thymulin; ZnFTS + FTS, total thymulin.

PMID- 10411281
TI  - Inhibition of various functions in murine peritoneal macrophages by aflatoxin B1
      exposure in vivo.
AB  - Aflatoxin B1 (AFB1) has been known to impair specific and nonspecific immunity.
      In the present study, we tested various functions of murine peritoneal
      macrophages that were isolated and stimulated with LPS after AFB1 (400 microg/5
      ml/kg) was administered every other day for 2 weeks. AFB1 decreased phagocytosis
      and the production of superoxide anion (O2-) and hydrogen peroxide (H2O2),
      compared to those of corn oil-treated control group. In addition, the production
      of NO and TNF-alpha was decreased in macrophages of AFB1-treated mice. In vitro
      antitumor activity of in vivo AFB1-treated macrophages was reduced against target
      cell, L929. Taken together, these results suggested that AFBI might have the
      immunosuppressive effect on macrophages after in vivo exposure, which was related
      to the antitumor activity reduction.

PMID- 10411282
TI  - Immunomodulating activity of seaweed extract on human lymphocytes in vitro.
AB  - Effect of eight kinds of seaweed extract (SWE) on human lymphocytes was studied
      in vitro. The extracts of Hizikiafusiformis and Meristotheca papulosa (green)
      markedly stimulated human lymphocytes to proliferate, whereas Eucheuma muricatum
      and Meristotheca papulosa (red) weakly stimulated proliferation. The responder
      cells are T cells, because T cells purified by sheep red blood cell (SRBC)
      rosette-formation were significantly stimulated with SWE, but B cells were not.
      These extracts enhanced the induction of cytotoxic T lymphocyte (CTL) activity,
      but failed to enhance natural killer (NK) cell activity. These extracts had a
      stimulatory effect on immunoglobulin (Ig) production by B cells and tumor
      necrosis factor (TNF) production by monocytes. The activity of Hizikia fusiformis
      associated with polysaccharides which were extracted with ethanol and purified by
      ion-exchange and gel filtration chromatography, whose molecular weight was about
      100 kDa. These results suggest that SWE has an immunomodulating activity on human
      lymphocytes and this ability might be useful for clinical application to treat
      several diseases such as tumors.

PMID- 10411283
TI  - Motivation for improvement in quality: personal and international perspectives.

PMID- 10411284
TI  - Using antecedents of medical care to develop valid quality of care measures.
AB  - OBJECTIVE: To present a new model for using the antecedents of medical care in
      outcomes assessment to develop valid quality of care measures. METHODS: The
      pertinent literature describing the history of outcomes assessment and the
      influence of patient and environmental risk factors on health status were
      reviewed. RESULTS: Past outcomes assessment studies have not consistently
      demonstrated a correlation between the processes and the outcomes of care. The
      use of the model described in this article indicates that the lack of correlation
      between process and outcome is probably because past outcomes assessment studies
      lacked the inclusion of medical care antecedents (primarily patient and
      environmental risk factors) that had a significant influence on the outcomes
      measured. Included is a description of a study that tests the utility of
      incorporating the antecedents of medical care into outcomes assessment to develop
      valid quality of care measures. CONCLUSION: The model presented in this article
      advances quality of care measure development by using: (i) qualitative research
      to characterize the pertinent antecedents of medical care; and (ii) as many of
      the pertinent antecedents of medical care as possible to develop risk adjustment
      models for measuring outcomes that are more likely to identify the true linkages
      between the processes and outcomes of care. Knowing the linkages between the
      processes and outcomes of care would provide the information needed to develop
      valid quality of care measures, so that quality can be measured accurately and
      the groundwork for its improvement can be laid.

PMID- 10411285
TI  - An experience of utilization review in Europe: sequel to a BIOMED project.
AB  - OBJECTIVE: To develop and test a utilization review screening tool for use in
      European hospitals. SETTING: In 1993 a group of researchers financed by a
      European Union grant reviewed the use of utilization review in Europe. They
      quickly noticed a lack of specifically designed instruments able to take into
      account the health care and cultural differences across Europe, and available for
      use in different health care systems. Hence, they embarked upon the task of
      developing and testing a utilization review screening tool for use in European
      hospitals. RESULTS: The European Union-Appropriateness Evaluation Protocol's list
      of reasons was developed and assessed. This is a common taxonomy that classifies
      days identified as unnecessary and provides a list of levels of care to identify
      patients' needs. This new protocol not only substitutes for the multiple previous
      local versions of the Appropriateness Evaluation Protocol, but will also
      facilitate comparisons of the varying experiences in European countries. MAIN
      FINDINGS: Development of utilization review in Europe has been carried out mostly
      on a voluntary basis and the main objective was not control. The experience
      varies widely: from France, where utilization review is still developing and
      research has been implemented by local teams, to Portugal, where utilization
      review programmes have been initiated by government authorities. At this point
      different initiatives in quality improvement, and more specifically in
      utilization review, are being developed within the European context.

PMID- 10411286
TI  - Development and application of a generic methodology to assess the quality of
      clinical guidelines.
AB  - BACKGROUND: Despite clinical guidelines penetrating every aspect of clinical
      practice and health policy, doubts persist over their ability to improve patient
      care. We have designed and tested a generic critical appraisal instrument, that
      assesses whether developers have minimized the biases inherent in creating
      guidelines, and addressed the requirements for effective implementation. DESIGN:
      Thirty-seven items describing suggested predictors of guideline quality were
      grouped into three dimensions covering the rigour of development, clarity of
      presentation (including the context and content) and implementation issues. The
      ease of use, reliability and validity of the instrument was tested on a national
      sample of guidelines for the management of asthma, breast cancer, depression and
      coronary heart disease, with 120 appraisers. A numerical score was derived to
      allow comparison of guidelines within and between diseases. RESULTS: The
      instrument has acceptable reliability (Cronbach's alpha coefficient, 0.68-0.84;
      intra-class correlation coefficient, (0.82-0.90)). The results provided some
      evidence of validity (Pearson's correlation coefficient between appraisers'
      dimension scores and their global assessment was 0.49 for dimension one, 0.63 for
      dimension two and 0.40 for dimension three). The instrument could differentiate
      between national and local guidelines and was easy to apply. There was variation
      in the performance of guidelines with most not achieving a majority of criteria
      in each dimension. CONCLUSIONS: Use of this instrument should encourage
      developers to create guidelines that reflect relevant research evidence more
      accurately. Potential users or groups adapting guidelines for local use could
      apply the instrument to help decide which one to follow. The National Health
      Service Executive is using the instrument to assist in deciding which guidelines
      to recommend to the UK National Health Service. This methodology forms the basis
      of a common approach to assessing guideline quality in Europe.

PMID- 10411287
TI  - Inter-hospital comparison of mortality rates.
AB  - OBJECTIVE: To compare crude and adjusted in-hospital mortality rates after
      prostatectomy between hospitals using routinely collected hospital discharge data
      and to illustrate the value and limitations of using comparative mortality rates
      as a surrogate measure of quality of care. METHODS: Mortality rates for non
      teaching hospitals (n = 21) were compared to a single notional group of teaching
      hospitals. Patients age, disease (comorbidity), length of stay, emergency
      admission, and hospital location were identified using ICD-9-CM coded Victorian
      hospital morbidity data from public hospitals collected between 1987/88 and
      1994/95. Comparisons between hospitals were based on crude and adjusted odds
      ratios (OR) and 95% confidence intervals (CI) derived using univariate and
      multivariate logistic regression. Model fit was evaluated using receiver
      operating characteristic curve i.e. statistic, Somer's D, Tau-a, and R2. RESULTS:
      The overall crude mortality rates between hospitals achieved borderline
      significance (alpha2=31.31; d.f.=21; P=0.06); these differences were no longer
      significant after adjustment (chi2=25.68; P=0.21). On crude analysis of mortality
      rates, four hospitals were initially identified as 'low' outlier hospitals; after
      adjustment, none of these remained outside the 95% CI, whereas a new hospital
      emerged as a 'high' outlier (OR=4.56; P= 0.05). The adjusted ORs between
      hospitals compared to the reference varied from 0.21 to 5.54, ratio = 26.38. The
      model provided a good fit to the data (c=0.89; Somer's D= (0.78; Tau-a = 0.013;
      R2= 0.24). CONCLUSIONS: Regression adjustment of routinely collected data on
      prostatectomy from the Victorian Inpatient Minimum Database reduced variance
      associated with age and correlates of illness severity. Reduction of confounding
      in this way is a move in the direction of exploring differences in quality of
      care between hospitals. Collection of such information over time, together with
      refinement of data collection would provide indicators of change in quality of
      care that could be explored in more detail as appropriate in the clinical
      setting.

PMID- 10411288
TI  - Functional status outcomes for assessment of quality in long-term care.
AB  - OBJECTIVE: Although decline in functional status has been recommended as a
      quality indicator in long-term care, studies examining its use provide no
      consensus on which definition of functional status outcome is the most
      appropriate to use for quality assessment. We examined whether different
      definitions of decline in functional status affect judgments of quality of care
      provided in Department of Veterans Affairs (VA) long-term care facilities.
      METHODS: Six measures of functional status outcome that are prominent in the
      literature were considered. The sample consisted of 15 409 individuals who
      resided in VA long-term care facilities at any time from 4/1/95 to 10/1/95.
      Activities of daily living variables were used to generate measures of functional
      status. Differences between residents' baseline and semi-annual assessments were
      considered and facility performance using the various definitions of functional
      status were described. RESULTS: The percentage of residents seen as declining in
      functional status ranged from 7.7% to 31.5%, depending upon the definition
      applied. The definition of functional status also affected rankings, z-scores,
      and 'outlier' status for facilities. CONCLUSION: Judgments of facility
      performance are sensitive to how outcome measures are defined. Careful selection
      of an appropriate definition of functional status outcome is needed when
      assessing quality in long-term care.

PMID- 10411289
TI  - Waiting for elective surgery: effects on health-related quality of life.
AB  - OBJECTIVE: To describe the experiences of people required to wait for admission
      to a New Zealand regional hospital to receive elective surgery. DESIGN: Cross
      sectional. SETTING: Eligible people were invited to participate in a face-to-face
      interview with one of us in their own home or in a private office at the
      University of Otago. STUDY PARTICIPANTS: The study population comprised all
      people on the waiting list for prostatectomy or hip or knee joint replacement. Of
      those who were eligible and contacted, 89% of men (n=102) on the prostatectomy
      waiting list and 92%. of people (n = 47) on the hip/knee joint replacement
      waiting list were interviewed. Main outcome measures. Participants completed the
      SF-36 health survey to measure general health-related quality of life and
      condition-specific instruments to measure the severity of each participant's
      condition. Participants were also asked questions concerning acceptable waiting
      times. RESULTS: The majority of participants reported severe symptoms and
      significantly poorer health-related quality of life on most dimensions than a
      general sample of the New Zealand population. Neither general quality of life nor
      condition-specific health appeared to worsen with the duration of wait, but this
      may have been an effect of the study design. People with more severe symptoms
      desire surgery more quickly than people with less severe symptoms. The lengthy
      wait for surgery experienced by many participants represents a burden in terms of
      living with the unrelieved severe symptoms and poor health-related quality of
      life.

PMID- 10411290
TI  - Perceptions on the influence of cost issues on quality improvement initiatives: a
      survey of Saudi health care managers.
AB  - OBJECTIVE: To determine (i) the cost issues which Saudi health care managers
      perceive to influence overall quality improvement initiatives, and (ii) the
      relationship between health care managers' satisfaction with such initiatives and
      their perceptions regarding the influence of different cost issues on the overall
      quality improvement initiatives. DESIGN: Data were collected through a self
      administered questionnaire in August and September 1996 in the Western Region of
      the Kingdom of Saudi Arabia. The participants were 236 health care managers of
      private hospitals. Data was analysed using the chi2 test. RESULTS: Less than one
      half of the health care managers surveyed were satisfied with their hospitals'
      overall quality improvement initiatives. The issue that was rated to have the
      most influence on such initiatives was the 'cost of malpractice lawsuits'
      followed by the budget for the quality assurance programme'. The issue that was
      perceived to have the least influence on overall quality improvement initiatives
      was 'data on cost allocation'. Of the 17 cost issues included in the study, eight
      had statistically significant influence on the health care managers' satisfaction
      with their hospitals' overall quality improvement initiatives. The most
      statistically significant was the 'measurement of the costs of quality-related
      actions'.

PMID- 10411291
TI  - Training for quality management: report on a nationwide distance learning
      initiative for physicians in Spain.
AB  - Under the sponsorship of a pharmaceutical firm, a distance-learning course on
      Quality Management methods was developed at the University of Murcia (Spain) and
      offered nationwide to primary health care physicians working in the public
      system. A total of 7104 physicians (47.7% of the census) signed up (at least one
      in 92.2% of the health centres). The course content follows the author's model of
      quality improvement, monitoring and design trilogy, but focuses mainly on methods
      for a quality improvement cycle using a learning-by-doing and problem-solving
      approach. The unexpected success of this initiative has led us to reflect on the
      interest in learning about quality improvement methods shown by physicians, the
      usefulness of the distance-learning approach, and also to continue the project
      with new initiatives such as: a summary poster, software containing all the
      necessary tools and data analysis for quality improvement, and a manual.

PMID- 10411292
TI  - Quality of care in rehabilitation medicine.
AB  - This paper discusses the generally accepted approaches to the study of the
      quality of care in medical rehabilitation. It reviews clements of structure,
      process and outcome of rehabilitation care that are relevant during various
      phases of rehabilitation and suggests drawing criteria and standards for
      assessment of quality from these elements of care.

PMID- 10411293
TI  - Attitudes to audit.

PMID- 10411294
TI  - Actions of bFGF on mitogenic activity and lineage expression in rat
      osteoprogenitor cells: effect of age.
AB  - Rat osteoprogenitor cells were used to examine the effects of bFGF on DNA
      synthesis and the expression of osteoblast (OB)-related genes. bFGF, as low as
      0.1 ng/ml, stimulated DNA synthesis. bFGF also increased the mRNA level of
      osteopontin (OP) and decreased that of type I collagen (COL I). When cultures
      were grown in dexamethasone (DEX) to induce OB lineage commitment, the expression
      of COL I, alkaline phosphatase (AP) and OP was greatly enhanced. Subsequent
      incubation with bFGF partially negated the stimulatory effect of DEX on AP and
      COL I mRNAs. bFGF also inhibited the expression of osteocalcin mRNA in cells
      grown in 1,25(OH)2D3 and DEX. Combined effects of bFGF with IGF-I or PDGF on DNA
      synthesis and OP expression were examined. bFGF + IGF-I, but not bFGF + PDGF, was
      more effective than PDGF alone. By comparing cells from adult and old animals, we
      found that bFGF-induced mitogenic activity was reduced significantly with age. In
      contrast, the effect of bFGF on the expression of OB genes was not significantly
      altered by age. These findings suggest that bFGF plays a dual role as a local
      positive and negative regulator on proliferation and osteogenic lineage
      expression, respectively, in osteoprogenitor cells, and that the mitogenic
      activity in response to bFGF was impaired in aging.

PMID- 10411295
TI  - Estrogen and aryl hydrocarbon responsiveness of ECC-1 endometrial cancer cells.
AB  - ECC-1 endometrial cancer cells express estrogen receptor alpha (ER(alpha)), and
      17beta-estradiol (E2) induces cell proliferation, cathepsin D mRNA levels, and
      reporter gene activity in cells transiently transfected with constructs derived
      from the human cathepsin D and creatine kinase B (pCD and pCKB, respectively)
      gene promoters. The comparative antiestrogenic activity of aryl hydrocarbon
      receptor (AhR) agonists and ER(alpha) antagonists were also determined in these
      endometrial cancer cells. A functional AhR was expressed in ECC-1 cells and AhR
      agonists including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibited E2
      induced cell proliferation and transactivation. This was comparable to inhibitory
      AhR-ER crosstalk in breast cancer cell lines. The pure ER antagonist ICI 182,780
      also exhibited antiestrogenic activity in ECC-1 cells; however, the results
      obtained for 4'-hydroxytamoxifen were response-specific. 4'-Hydroxytamoxifen
      alone did not induce ECC-1 cell proliferation but completely inhibited E2-induced
      cell proliferation. 4'-Hydroxytamoxifen primarily exhibited ER antagonist
      activities in transactivation assays and this contrasted to the predominant ER
      agonist responses observed in other endometrial cancer cell lines. The unique
      cellular context of ECC-1 cells was confirmed using pCKB and constructs
      expressing wild-type ER or ER variants expressing activation function 1 (AF1) or
      AF2 (ER-AF1 and ER-AF2, respectively). 4'-Hydroxytamoxifen did not induce
      reporter gene activity in cells cotransfected with pCKB and ER-AF1 or ER-AF2;
      however, in cotreatment studies (4'-hydroxytamoxifen plus E2), 4'
      hydroxytamoxifen inhibited E2-induced transcriptional activation by ER-AF1 or ER
      AF2. Thus, the primarily antiestrogenic activity observed for 4'-hydroxytamoxifen
      in ECC-1 cells may be related to the inability to activate gene expression
      through AF1-dependent pathways.

PMID- 10411297
TI  - Effects of equine oestrogens on markers of vasoactive function in human coronary
      artery endothelial cells.
AB  - A large proportion of the beneficial effects that oestrogens demonstrate on the
      vasculature are believed to be mediated via direct effects on the vascular wall.
      In this study we compared a number of oestrogenic compounds isolated from
      pregnant mare's urine including 17beta-oestradiol and oestrone, in terms of their
      abilities to inhibit stimulated endothelin-1 release from normal human coronary
      artery endothelial cells (CAEC). We also examined their ability to stimulate
      expression of constitutive endothelial nitric oxide synthase (eNOS) and explored
      their effects on cellular angiotensin converting enzyme (ACE). All the oestrogens
      tested were able to inhibit serum-stimulated ET-1 release. Oestrone and 17alpha
      dihydroequilenin failed to significantly affect cellular eNOS levels. 17Beta
      oestradiol and oestrone significantly increased cellular ACE levels while
      17beta,delta(8,9)-dehydroestradiol decreased cellular ACE. We discuss these
      observations in terms of their potential clinical relevance and use as a means of
      screening novel oestrogen-like compounds.

PMID- 10411296
TI  - COX-2 compensation in the uterus of COX-1 deficient mice during the pre
      implantation period.
AB  - Prostaglandins (PGs) produced by cyclooxygenase (COX) participate in many aspects
      of female reproduction. The two isoforms of cyclooxygenase, COX-1 and COX-2, have
      distinct expression patterns in the mouse uterus during the peri-implantation
      period and suggest their independent contribution to uterine PGs. Using wild type
      and COX-1(-/-) mice, we examined the role of COX-1-derived PGs on day 4 of
      pregnancy, when its expression is maximal. Uterine vascular permeability was
      measured by 125I-labeled bovine serum albumin (BSA) uptake, and PG content was
      measured by gas chromatography-mass spectrometry. Vascular permeability and PG
      concentrations were reduced in COX-1(-/-) mice, but by less than the expected
      amount. After ovariectomy, uterine vascular permeability declined in both groups,
      but returned to baseline in wild type and was exaggerated in COX-1(-/-) females
      after treatment with ovarian steroids. Most importantly, COX-1(-/-) uteri
      displayed COX-2 expression on the morning of day 4, when COX-2 is normally
      absent. This hybridization pattern resembles the native expression of COX-1, and
      may partially offset the loss of COX-1-derived PGs. These data indicate that COX
      1-derived PGs are important during uterine preparation for implantation, and that
      COX-2 compensation occurs in the absence of COX-1.

PMID- 10411298
TI  - Inhibitory effects of TNF alpha on mouse tumor Leydig cells: possible role of
      ceramide in the mechanism of action.
AB  - TNF alpha is reported to inhibit steroidogenesis in mouse Leydig cells. In
      primary cells this inhibition resulted mainly from a reduced expression of Cyp-17
      gene. Mouse tumor Leydig cells, MA-10, being free of macrophages and lacking Cyp
      17, appear to be an excellent model to investigate those effects of TNF alpha
      which are independent of either macrophages or Cyp-17. We report here that TNF
      alpha receptors are expressed in this cell line. Treatment of the cells with TNF
      alpha had no effect on basal progesterone production. In contrast, LH-, 8Br-cAMP
      and forskolin-stimulated progesterone production was inhibited by TNF alpha.
      Neither enzymes involved in the conversion of cholesterol to pregnenolone nor
      hormone-induced hydrolysis of [14C] cholesterol-ester were affected by TNF alpha.
      The hormone-induced expression of StAR protein was diminished in mitochondrial
      fractions from TNF alpha-treated cells. Also cell permeable ceramides markedly
      inhibited StAR protein levels. We show further that TNF alpha was able to induce
      [14C]-ceramide accumulation in MA-10 cells and suggest that this sphingolipid may
      be considered as a transmitter of TNF alpha signals to the StAR protein.

PMID- 10411299
TI  - Role of amino acid residues at the interface of alpha52asparginyl-N-glycosyl
      chain of human choriogonadotropin.
AB  - Of all the four N-glycosyl chains present in hCG, only one of them at alpha52Asn
      is located at the alpha/beta subunit interface and is crucial for the biological
      function of the hormone. The other three are exposed on the surface of the
      molecule and play only a minor role in the function of the hormone. The
      alpha52Asn oligosaccharide interacts with five amino acid residues in the beta
      subunit, Tyr59, Val62, Phe64, Ala83, and Thr97. The present studies were
      undertaken to determine the role of the residues at the alpha52Asn
      oligosaccharide and the beta-subunit interface in the mechanism of subunit
      association and downstream signaling events. Ten mutants, two of the alpha
      subunit by the replacement of Asn52 and Thr80 with Gln and eight of the beta
      subunit by multiple or single amino acid mutations, were prepared. These mutants
      included, hCGbeta59,62,64,97Ala, hCGbeta59,62,64Ala, hCGbeta62,64Ala,
      hCGbeta59Phe, hCGbeta62Ala or Thr, hCGbeta83Ile and hCGbeta97Ala. The mutation of
      the Asn52 to Gln resulted in a drastic change in its conformation and as a
      consequence in its weak affinity with the wild type beta as compared with that of
      the wild type hCGalpha and hCGalpha80Gln. The mutants with mutations in the four
      or three amino acids as well as both mutants of hCGbeta62Val almost failed to
      combine with hCGalpha again as a result of conformational changes shown by
      circular dichroism (CD) analysis and not due to their direct involvement in the
      subunit association. The double mutant combined with hCGalpha and the heterodimer
      behaved more like the wild type hCG. The mutation of Tyr to Phe resulted in a
      drop of 20% in the receptor binding and cAMP stimulation although Tyr is
      considered to be involved directly in subunit association. HCGbeta with mutations
      in the other amino acids, Phe64, Ala83, and Thr97, combined with the alpha
      subunit forming heterodimers with biological activity comparable to that of the
      wild type hCG. Thus, it appears that among the five amino acids in the vicinity
      of alpha52Asn carbohydrate, only beta59Tyr and beta62Val may be involved directly
      or indirectly in the alpha/beta beta dimer formation.

PMID- 10411300
TI  - Progenitor cells in the embryonic anterior pituitary abruptly and concurrently
      depress mitotic rate before progressing to terminal differentiation.
AB  - The control of progenitor cell proliferation in concert with terminal
      differentiation during embryonic development is poorly understood. The present
      paper examines this issue in the different cell lineages of the fetal mouse
      pituitary. Mouse fetuses were pulse-exposed to 3H-thymidine (3H-T) on a single
      day between embryonic day (E) 10 and E16 (prior to the onset of hormone phenotype
      expression) and the 3H-T labeling index of each cell type determined 3 or 4 days
      later (E13-19), when hormone phenotypes were detectable. In the pars tuberalis
      primordium, TSHbeta appeared from E13. Of these cells 75.5% were labeled when 3H
      T had been administered on E10. Label decreased to 40.8% when it had been
      incorporated on E11 and was negligible (4.2%) when it had been taken up on E12.
      In the pars distalis, ACTH appeared on E13, TSHbeta, and PRL on E14,
      LHbeta/FSHbeta on E15 and GH on E16. When examined on E16, all these cell types
      were labeled for 50-60% if 3H-T had been injected on E12, but this number dropped
      to about 15% when 3H-T had been given on E13. Only 5-10% of the hormonal cells
      had taken up label when E14, 15, and 16 were the days of 3H-T administration. The
      decline in overall labeling index (LI) within both parts of the pituitary was
      significantly smaller than that in the hormone expressing cells. It is concluded
      that an outspoken decline in proliferation of the cells destined to become
      hormone-expressing cell types occurs one to several days before these hormones
      come to expression. In the pars distalis, this decline occurs at a common time
      point i.e. between E12 and E13 for each cell type. Pars tuberalis and pars
      distalis TSHbeta cells show distinct 3H-T labeling profiles, suggesting distinct
      cell lineage sources for each.

PMID- 10411301
TI  - Bioassay for growth hormone releasing hormone (GHRH) using a recombinant receptor
      and cAMP-responsive reporter system.
AB  - Growth hormone releasing hormone (GHRH) receptors are members of the G-protein
      receptor family that use cAMP as a second messenger. A human fetal kidney 293
      derived cell line stably expressing the porcine GHRH receptor (pGHRHr/293 cells)
      and a cAMP-responsive reporter system were used to develop a bioassay for human
      GHRH. The reporter system (ph alpha180SEAP) was constructed by subcloning the
      tandem cAMP response elements from the human glycoprotein hormone alpha subunit
      gene promoter (h alpha180) upstream from the secreted alkaline phosphatase cDNA
      of reporter plasmid pSEAP-Basic. To generate a stable cell line expressing both
      the GHRH receptor and SEAP reporter system, a DNA fragment from pPUR that confers
      puromycin resistance was subcloned downstream from the reporter construct of ph
      alpha180SEAP. Tranfection of ph alpha180SEAPpur into pGHRHr/293 cells yielded
      pGHRHr/SEAP/293 cell lines that responded to recombinant GHRH with dose-dependent
      increases in SEAP activity. The GHRH receptor-SEAP reporter bioassay was compared
      to a conventional bioassay using cultured rat anterior pituitary cells. Synthetic
      and recombinant GHRH induced a 3.1-fold increase in growth hormone release by rat
      pituitary cells with ED50's of 3.6 and 2.2 x 10(-10) M, respectively. Recombinant
      GHRH was 1.7 +/- 0.7 times more potent than synthetic GHRH in the pituitary cell
      bioassay. In an analogous experiment, pGHRHr/SEAP/293 cells responded to
      synthetic and recombinant GHRH with a 9.1-fold increase in SEAP activity. The
      ED50's were 7.8 and 4.3 x 10(-11) M, respectively, with recombinant GHRH being
      1.8 +/- 0.1 times more potent than the synthetic preparation. Thus, the GHRH
      receptor-SEAP reporter bioassay is a sensitive, accurate, precise and efficient
      method for measuring GHRH biological activity.

PMID- 10411302
TI  - E75 expression in mosquito ovary and fat body suggests reiterative use of
      ecdysone-regulated hierarchies in development and reproduction.
AB  - The steroid hormone ecdysone controls genetic regulatory hierarchies underlying
      insect molting, metamorphosis and, in some insects, reproduction. Cytogenetic and
      molecular analysis of ecdysone response in Drosophila larval salivary glands has
      revealed regulatory hierarchies including early genes which encode transcription
      factors controlling late ecdysone response. In order to determine whether similar
      hierarchies control reproductive ecdysone response, we have investigated ecdysone
      regulated gene expression in vitellogenic mosquito ovaries and fat bodies. Here,
      we identify the homologue of the Drosophila E75 early ecdysone inducible gene in
      the yellow fever mosquito Aedes aegypti, and show that, as in Drosophila, the
      mosquito homologue, AaE75, consists of three overlapping transcription units with
      three mRNA isoforms, AaE75A, AaE75B, and AaE75C, originating as a result of
      alternative splicing. All three AaE75 isoforms are induced at the onset of
      vitellogenesis by a blood meal-activated hormonal cascade, and highly expressed
      in the mosquito ovary and fat body, suggesting their involvement in the
      regulation of oogenesis and vitellogenesis, respectively. Furthermore, in vitro
      fat body culture experiments demonstrate that AaE75 isoforms are induced by 20
      hydroxyecdysone, an active ecdysteroid in the mosquito. These findings suggest
      that related ecdysone-triggered regulatory hierarchies may be used reiteratively
      during developmental and reproductive ecdysone responses.

PMID- 10411303
TI  - Transforming growth factor-beta (TGF-beta) type I and type II receptors are both
      required for TGF-beta-mediated extracellular matrix production in lung
      fibroblasts.
AB  - Transforming growth factor-beta (TGF-beta) regulates a variety of cellular
      activities including cell growth, differentiation and extracellular matrix
      production. The TGF-beta type I and type II serine/threonine kinase receptors
      (TbetaRI and TbetaRII) have been identified as signal-transducing TGF-beta
      receptors. This study was undertaken to examine the role of the type I and type
      II receptors in TGF-beta-induced extracellular matrix production of lung
      fibroblasts. We constructed expression plasmids containing truncated derivatives
      of TbetaRI and TbetaRII that lacked the cytoplasmic serine/threonine kinase
      domain (TbetaRI deltaK and TbetaRII deltaK), and transfected them into lung
      fibroblasts. TbetaRII deltaK expressed by lung fibroblasts was able to bind 125I
      TGF-beta1, whereas TbetaRI deltaK was unable to bind ligand when expressed alone.
      Co-expression with TbetaRII was required for binding and cross-linking of TGF
      beta1 to TbetaRI deltaK. Lung fibroblasts upregulate tenascin and fibronectin
      production when treated with TGF-beta1. The kinase-defective deletions of both
      TbetaRI and TbetaRII were dominant-acting inhibitors of TGF-beta signal
      transduction. Expression of either TbetaRI deltaK or TbetaRII deltaK alone was
      sufficient to block TGF-beta-induced tenascin and fibronectin production of lung
      fibroblasts. The results indicate that both TbetaRI and TbetaRII were required
      for TGF-beta signaling in regulation of extracellular matrix production by lung
      fibroblasts.

PMID- 10411304
TI  - Estrogen receptor binding to estrogen response elements slows ligand dissociation
      and synergistically activates reporter gene expression.
AB  - Estradiol (E2)-liganded estrogen receptor (ER) bound to three or four tandem
      copies of a consensus ERE (EREc38) in a cooperative manner. E2-ER binding to one
      or two EREs was non-cooperative. When ER was liganded by the antiestrogen 4
      hydroxytamoxifen (4-OHT), ER-ERE binding was not cooperative, regardless of the
      number of EREs. Here we evaluated how binding to EREc38 affects ER conformation
      in the ligand binding domain (LBD) as reflected in the dissociation kinetics of
      [3H]ligand from the ER. Binding of ER to EREc38 slowed the rate of dissociation
      of either E2 or 4-OHT, indicating that DNA allosterically modulates the LBD
      conformation creating a tighter fit between the ligand and the ER. Conformational
      differences in ER induced by E2 versus antiestrogen were not reflected in
      differences in E2 or 4-OHT dissociation parameters under these conditions. No
      difference in the association rate of E2- versus 4-OHT-liganded ER binding to
      EREc38 was detected in electrophoretic mobility shift assay (EMSA). Synergistic,
      E2-dependent activation of a reporter gene was detected from three and four, but
      not one or two, tandem copies of EREc38. These observations suggest that
      cooperative binding of E2-ER to multiple copies of EREc38 is likely responsible
      for transcriptional synergy and that cooperativity may not involve direct
      interaction between the LBDs of ERE-bound ER. Since the number of copies of
      EREc38 did not alter E2 dissociation kinetics, functional synergy must involve
      cellular factors in addition to the ER ligand.

PMID- 10411305
TI  - The shed thyrotropin receptor is primarily a carboxyl terminal truncated form of
      the A subunit, not the entire A subunit.
AB  - The TSH receptor (TSHR) sheds its A subunit, particularly when cells are cultured
      in serum-poor medium. This shed A subunit is reported to be smaller than the cell
      associated receptor because of the loss of glycan without change in its
      polypeptide core. Contrary to previous deductions, we now find that the 'small'
      shed A subunit has lost a glycan moiety because of the proteolytic clipping of a
      small C-terminal fragment containing an Asn-linked glycan. Moreover, this lost
      peptide fragment contains cysteine residues likely involved in A subunit linkage
      to the membrane-associated B subunit. Progressive lowering of the serum
      concentration in culture medium accentuates the process. Therefore, 'small' A
      subunit shedding does not appear related to a physiological mechanism involving
      disulfide bond reduction. On the other hand, we detected, for the first time,
      shedding of a lesser amount of normal-sized, in addition to small, A subunits,
      especially by cells cultured in standard serum concentrations.

PMID- 10411306
TI  - Canine mammary growth hormone gene transcription initiates at the pituitary
      specific start site in the absence of Pit-1.
AB  - Growth hormone (GH) gene expression has been reported in the mammary glands of
      various mammalian species. The mechanism by which the GH gene becomes activated
      in extrapituitary tissues is currently unclear. We have characterized the canine
      mammary and pituitary GH gene transcripts by Northern blot, 5'- and 3'-RACE
      (rapid amplification of cDNA ends), and DNA sequence analysis. Northern blot
      analysis detected GH gene transcripts in mammary glands of dogs which were
      exposed to high levels of progestins. The mammary and pituitary GH cDNAs were
      shown to be identical in both the coding region and untranslated regions.
      Pituitary GH gene expression is highly dependent upon the transcription factor
      Pit-1. Analysis of Pit-1 gene expression using RT-PCR followed by Southern
      hybridization revealed a strong pituitary signal but faint, weak or no
      hybridization signals in mammary gland samples. Among the negative samples were
      progestin-treated dogs with high mammary GH gene expression. These findings
      indicate that mammary and pituitary GH gene transcripts originate from the same
      transcription start site but are regulated differentially.

PMID- 10411307
TI  - Targeted ablation of gonadotrophs in transgenic mice affects embryonic
      development of lactotrophs.
AB  - Ablation of pituitary gonadotrophs was obtained in transgenic mice expressing
      diphtheria toxin A (DTA) under control of the -313/+48 bovine glycoprotein
      hormone alpha-subunit (alphaSU) promoter, previously shown to be active in mouse
      gonadotrophs but not in thyrotrophs. Development of hormone-producing cell types
      was assessed on the day of birth by computer-assisted image analysis on paraffin
      embedded, immunostained pituitary sections. Six out of 50 transgenic F0
      ('founder') mice (3 males and 3 females) showed a nearly complete disappearance
      of gonadotrophs but not of thyrotrophs. The number of lactotrophs and the
      relative area occupied by PRL-immunoreactivity were significantly reduced in the
      gonadotroph-depleted mice. The size of lactotroph clusters was smaller in the
      absence of gonadotrophs. The number and immunoreactive area of corticotrophs and
      somatotrophs, on the other hand, were not significantly affected by gonadotroph
      ablation. Based on the reported evidence that fetal ovaries do not produce
      steroid hormones as a result of lack of expression of at least three of the
      steroidogenic enzymes, P450scc, P450c17, and P450arom, the present observations
      can hardly be explained by a decline in estrogen levels due to gonadotroph
      ablation. Rather, the present data indicate that gonadotrophs directly stimulate
      the development of lactotrophs during fetal and early postnatal life, consistent
      with previous in vitro observations, and/or that gonadotrophs may share a cell
      lineage relationship with a subpopulation of lactotrophs.

PMID- 10411308
TI  - Loss of several cell functions including okadaic acid-induced apoptosis after
      multiple passages in FRTL-5 cells.
AB  - In FRTL-5 cells, cultured over a period of more than 3 years, different
      properties of the cells have been observed to undergo spontaneous changes in the
      course of aging, i.e. after an increase in the number of passages. This consists
      mainly in alterations in their morphological phenotype and in some of their
      functional properties. The morphology of the cells displayed a progressive
      disruption of the monolayer organization with a loss of cell-cell contacts and a
      marked rounding-up of the cells. The uptake of iodide was not modified nor was
      the expression of thyroglobulin (Tg) mRNA as determined at various time intervals
      in the course of the cells culturing. Estimation of the proliferation by counting
      the frequency of [3H]thymidine labeled nuclei revealed an age-related decline in
      the sensitivity to TSH mitogenic action associated with a reciprocal increase in
      the insulin synergistic effect. Aged cells (+/- 40 passages) lost their apoptosis
      sensitivity to the phosphatase inhibitor, okadaic acid (OA) but not to
      cycloheximide (CHX) and/or actinomycin D (act. D) exposure. Altogether these
      observations favor the existence of a shift towards transformed properties with
      only partial loss of differentiated functions.

PMID- 10411309
TI  - Definition of a high affinity growth hormone DNA response element.
AB  - Rat liver contains a growth hormone inducible nuclear factor complex, GHINF, that
      binds to the growth hormone response element (GHRE) of the serine protease
      inhibitor (Spi) 2.1 gene. GHINF contains Stat5 and binds to paired gamma
      activated sites (GAS) within the GHRE, but poorly to either one alone. By
      analysis of the sequence of various GAS sites that bind the GHINF complex (based
      on the GHRE 3' GAS motif), we demonstrate that a 13 nucleotide high affinity DNA
      recognition sequence (haGHRE) for GHINF complex binding is
      (ANTTC)C/T(N)A/G(GAA)A/T(A)/T. One copy of the haGHRE will replace the
      requirement for two GAS elements present in the wild type promoter in supporting
      a GH response in primary hepatocyte culture. Mutation of the native Spi 2.1 from
      a paired GAS site to a single haGHRE does not appreciably change its affinity for
      binding to the GHINF complex, nor does it alter its sensitivity to GH
      concentration.

PMID- 10411311
TI  - Adrenergic regulation of translocation of protein kinase C isozymes in rat
      pinealocytes.
AB  - Protein kinase C (PKC) is involved in the alpha1-adrenergic-potentiation of beta
      adrenergic stimulated cyclic nucleotide responses in rat pinealocytes. In the
      present study, the PKC isozymes expressed in rat pinealocytes and their
      regulation by norepinephrine (NE) were investigated. Western blot analysis
      identified PKC alpha (a classical PKC isozyme), PKC delta and epsilon (novel PKC
      isozymes), and PKC zeta: (atypical PKC isozymes). NE caused an increase in PKC
      alpha, delta, and epsilon, but not PKC zeta, in the particulate fraction. BAPTA
      AM, which clamps intracellular Ca2+, reduced NE mediated translocation of PKC
      alpha, delta, and epsilon. Subjecting the animals to stimulus deprivation, which
      altered adrenergic-stimulated cyclic nucleotide responses, had no effect on the
      expression of PKC alpha, delta, epsilon, and zeta. Overnight treatment with 4beta
      phorbol 12-myristate 13-acetate, an activator of PKC, down-regulated PKC alpha,
      delta, and epsilon, but not PKC zeta. Our results indicate that all three classes
      of PKC isozymes (PKC alpha, delta, epsilon, and zeta are expressed in the rat
      pineal gland. However, selective activation of these PKC isozymes does not appear
      to account for the differences in the pineal cAMP and cGMP responses to
      stimulation.

PMID- 10411310
TI  - Estrogen stimulates expression of adenine nucleotide translocator ANT1 messenger
      RNA in female rat hearts.
AB  - The identification of estrogen-responsive genes in the heart, is necessary to
      understand estrogen-induced changes in cardiac function. Using Delta RNA
      fingerprinting, we demonstrate that a single injection of estradiol benzoate (50
      microg, s.c.) revealed mRNA species that were elevated, down-regulated, or were
      unaffected in the heart tissue of ovariectomized female rats. One of the
      upregulated genes was identified, by cloning and sequencing, to have 95.8%
      (230/240) identity with the 3' end of the rat ant1 gene encoding the
      mitochondrial adenine nucleotide translocator, ANT1. Using the isolated ANT1 cDNA
      (280 bp) as a probe in Northern analysis, estrogen was shown to upregulate the
      expression of cardiac ANT1, by at least 3-fold in female rats, from as early as 1
      h to as long as 24 h. In contrast, estrogen treatment had no effect on ANT1
      expression in heart tissue from male rats. RNA yields were low in rat atria and
      no transcript was detectable by Northern analysis. Using primers specific to the
      known rat ANT1 gene, the estrogen upregulation of the cardiac ANT1 transcript in
      female rat was confirmed by reverse transcriptase-polymerase chain reaction (RT
      PCR); a predicted product of 249 bp was obtained and this was stimulated by at
      least 3-fold upon estrogen treatment for 24 h.

PMID- 10411312
TI  - Estrogenicity of bisphenol A in a human endometrial carcinoma cell line.
AB  - The ability of bisphenol A (BPA) to affect human estrogen receptor (ER) binding,
      expression of progesterone receptor (PR) mRNA and protein, and cell proliferation
      has been measured in the human endometrial cell line, ECC-1. Although less potent
      than 17beta-estradiol, BPA was able to bind to the human uterine ER. BPA also
      induced both mRNA and protein to levels similar to E2. BPA-mediated PR mRNA
      induction was antagonized by ICI, suggesting an ER-mediated pathway. Finally, E2
      produced a 2-fold increase in cell number, while BPA showed no difference
      compared with vehicle control. The increase by E2 was inhibited by treatment with
      the either ICI 182,780 (ICI) or BPA, suggesting similar binding sites. Although
      ER binding is similar, E2 affected both proliferation and PR expression, while
      BPA only affected PR gene expression. The results of this study provide evidence
      that two ER agonists can act differentially in vitro to affect the expression of
      genes involved in regulating cellular growth and development, though the human
      risk potential remains to be determined.

PMID- 10411314
TI  - Aldosterone action: new answers, new questions.

PMID- 10411313
TI  - Human A-type ANP receptor upregulation by PACAP and carbachol in neuroblastoma
      cells.
AB  - Pituitary adenylyl cyclase activating polypeptide (PACAP-27), forskoline and
      carbachol increased type A atrial natriuretic peptide receptor (NPR-A) density,
      as well as NPR-A mRNA level, in the human neuroblastoma NB-OK-1 cell line. TPA
      did not have any effect per se, but blunted the effect of PACAP-27 on both NPR-A
      density and NPR-A mRNA. The half-life of the NPR-A mRNA was not modified by any
      of the agents tested. Our data support an original transcriptional upregulation
      of human NPR-A in response to cAMP-induced agents, and in response to carbachol.

PMID- 10411315
TI  - The ubiquitin system in gametogenesis.
AB  - Ubiquitin is a ubiquitous and highly conserved protein of 76 amino acid residues,
      that can be covalently attached to cellular acceptor proteins. The attachment of
      ubiquitin to target proteins is achieved through a multi-step enzymatic pathway,
      which involves activities of ubiquitin-activating E1 enzymes, ubiquitin
      conjugating E2 enzymes, and ligating E3 enzymes. Mono- or poly-ubiquitination of
      proteins can lead to protein degradation or modification of protein activity.
      Many components of the complex ubiquitin system show remarkable evolutionary
      conservation, from yeast to mammalian species. The ubiquitin system is essential
      to all eukaryotic cells. Among others, several signal transduction cascades show
      involvement of the ubiquitin system, but there are currently little data
      supporting a specific role of the ubiquitin system in hormonal control of
      reproduction. Interestingly, during gametogenesis, many specialized and important
      aspects of the ubiquitin system become apparent. Components of the ubiquitin
      system appear to be involved in different steps and processes during
      gametogenesis, including control of meiosis, and reorganization of chromatin
      structure.

PMID- 10411316
TI  - Clusterin in the male reproductive system: localization and possible function.
AB  - Clusterin is a glycoprotein that was initially isolated from the male
      reproductive system. Subsequently, clusterin has been found to be widely
      distributed in a variety of tissues in mammals. One characteristic of the
      expression of clusterin is that it is induced as a result of cellular injury,
      death, or pathology. Despite the efforts of many laboratories working in diverse
      biological systems, the function of clusterin remains unknown. Recent studies
      have revealed a 'heat-shock element' in the promoter of the gene that may account
      for the inducible nature of the clusterin gene. Overall, the evidence suggests
      that function of clusterin is to protect surviving cells after damage. This
      protection may result from a detergent-like action of the protein.

PMID- 10411317
TI  - Signal transduction involving cyclic AMP-dependent and cyclic AMP-independent
      mechanisms in the control of steroidogenesis.
AB  - The control of steroidogenesis via signal transduction mechanisms involving cAMP
      dependent and cAMP-independent mechanisms is reviewed. Several structurally
      unrelated factors that are potent stimulators of steroidogenesis whose actions do
      not require cAMP and/or synthesis of proteins have been identified. These include
      various interleukins, a lipophilic factor from macrophages, a steroidogenic
      inducing protein from follicular fluid and an imidazole compound, calmidazolium.
      All of these factors are capable of inducing maximum steroidogenesis. Calcium is
      required for steroidogenesis in all steroidogenic cells. With the exception of
      the effects of angiotensin II, there is little evidence for a role of IP3 in the
      stimulation of the release of calcium from intracellular stores in steroidogenic
      cells under physiological conditions. There may however, be a cAMP-mediated
      activation of a plasma membrane calcium channel. Chloride channels that can be
      regulated by cAMP-dependent and -independent mechanisms, are present in
      steroidogenic cells. Chloride ions exert a negative effect on steroidogenesis
      because exclusion of chloride from the extracellular medium markedly enhances
      cAMP-stimulated steroidogenesis. Arachidonic acid and its lipoxygenase products
      are involved in the control of steroidogenesis via cAMP mediated processes. An
      arachidonic acid related thioesterase has been isolated that is activated by ACTH
      and which may be involved in the release of arachidonic acid. It is concluded
      that while cAMP is a second messenger for LH/ACTH in the control of
      steroidogenesis, other signalling systems exist which are potentially equally
      effective in controlling steroidogenesis. In addition, the action of cAMP
      requires other signalling pathways involving calcium and chloride ions, as well
      as arachidonic acid and its lipoxygenase products.

PMID- 10411318
TI  - Regulation of thyroid hormone metabolism during fetal development.
AB  - Compared with adults, plasma T3 concentrations in the human fetus are decreased,
      whereas levels of rT3 and the different iodothyronine sulfates, T4S, T3S, rT3S
      and 3,3'-T2S, are increased. The low T3 and high rT3 concentrations reflect the
      preponderance of inner ring versus outer ring deiodinase activity due to high
      type III iodothyronine deiodinase (D3) expression in fetal tissues, such as liver
      and brain, the placenta, and perhaps also the uterus, in combination with still
      incomplete expression of hepatic type I iodothyronine deiodinase (D1) expression.
      In contrast to humans, D3 is hardly expressed in the fetal rat liver. However,
      high D3 expression is observed in the embryonic chicken liver which decreases
      dramatically towards the end of incubation, resulting in a marked increase in
      plasma T3. Thyroid hormone is essential for the development of the brain, in
      which local conversion of the prohormone T4 to the active hormone T3 by the type
      II iodothyronine deiodinase (D2) plays a very important role. In contrast to the
      rat, however, little is known about the ontogeny of D2 in different human brain
      areas. The cause of the high concentrations of sulfated iodothyronines in fetal
      plasma is unknown. In adults, the liver is an important site for the clearance of
      these conjugates, where they are rapidly degraded by D1. Although fetal human
      liver expresses significant D1 activity, clearance of iodothyronine sulfates may
      be defective due to the lack of transporters mediating their hepatic uptake.
      However, production of iodothyronine sulfates may also be increased in the human
      fetus, although the responsible sulfotransferases and their location remain to be
      identified. Sulfation may be a reversible pathway of thyroid hormone
      inactivation, depending on the recovery of free hormone by sulfatases. However,
      little is known at present about the characteristics and regulation of these
      enzymes in fetal human tissues. Further studies are required to increase our
      understanding of the tissue-specific and stage-dependent regulation of thyroid
      hormone bioactivity during human development.

PMID- 10411319
TI  - After chromatin is SWItched-on can it be RUSHed?
AB  - Repressive chromatin must be remodeled to allow for transcriptional activation of
      genes in eukaryotic cells. Factors that alter chromatin structure to permit
      access of transcriptional activators, RNA polymerase II and the polymerase
      associated general transcription factors to nucleosomal promoter sequences are as
      highly conserved as the basic mechanism of transcription. One group of promoter
      restructuring factors that perturbs chromatin in an ATP-dependent manner includes
      NURF, CHRAC, ACF, the SWI/SNF complex, and SWI/SNF-related proteins. Each member
      of this group contains a subunit homologous to the DNA-dependent ATPase; however,
      their individual mechanisms of action are unique. The small amount of SWI/SNF
      complex (100-200 copies/cell), its affiliation with a select number of inducible
      genes, and its interaction with the glucocorticoid and estrogen receptors,
      suggests the SWI/SNF complex might be preferentially targeted to active
      promoters. The SWI/SNF-related family of RUSH proteins which includes RUSH-1alpha
      and beta, hHLTF, HIP116, Zbu1, P113, and the transcription factor RUSH-1alpha
      isolog has been implicated as a highly conserved DNA binding site-specific
      ATPase.

PMID- 10411320
TI  - The role of estrogen in folliculogenesis.
AB  - Gonadotrophins are fundamental to the mechanisms regulating follicle status and
      development. Follicles in the ovary are either quiescent or committed to one of
      two pathways: growth or atresia. The requirement for gonadotrophins by the
      follicles varies with development: committed follicles grow independently of
      gonadotrophins (primarily FSH) until the late preantral stage when antrum
      formation is contingent upon FSH. The involvement of estrogen in regulating
      gonadotrophin secretion is well documented and while evidence for a local
      regulatory role of estrogen in the ovary mounts, an obligatory role for estrogen
      in the folliculogenic process has not been established. The availability of a
      wide range of gene-disrupted mice termed 'knockouts', is providing information
      relevant to the study of folliculogenesis. Mice deficient in either estrogen or
      estrogen receptors, are infertile primarily due to either a block in
      folliculogenesis prior to antrum formation or as a consequence of failing to
      ovulate. Blocking estrogen stimulated, post-receptor molecules such as cyclin D2,
      severely retards granulosa cell proliferation and leads to infertility, although
      the contribution of estrogen in this model is not so clear given that FSH also
      stimulates cyclin D2. Similar problems dissociating the roles of FSH and estrogen
      are evident with the FSH deficient animal models. Nevertheless, estrogen is
      clearly an important and probably obligatory regulator of folliculogenesis,
      especially in the post antral stage. The exact points in the folliculogenic
      process where estrogen exerts its principal effects remains to be elucidated.

PMID- 10411321
TI  - Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction.
AB  - Extracellular signals activate mitogen-activated protein kinase (MAPK) cascades
      to execute complex cellular programs, like proliferation, differentiation and
      apoptosis. In mammalian cells, three MAPK families have been characterized:
      extracellular signal-regulated kinase (ERK), which is activated by growth
      factors, peptide hormones and neurotransmitters, and Jun kinase (JNK) and p38
      MAPK, which are activated by cellular stress stimulus as well as growth factors.
      This review describes the family of 90 kDa ribosomal S6 kinases (RSK; also known
      as p90rsk or MAPK-activated protein kinase-1, MAPKAP-K1), which were among the
      first substrates of ERK to be discovered and which has proven to be a ubiquitous
      and versatile mediator of ERK signal transduction. RSK is composed of two
      functional kinase domains that are activated in a sequential manner by a series
      of phosphorylations. Recently, a family of RSK-related kinases that are activated
      by ERK as well as p38 MAPK were discovered and named mitogen- and stress
      activated protein kinases (MSK). A number of cellular functions of RSK have been
      proposed. (1) Regulation of gene expression via association and phosphorylation
      of transcriptional regulators including c-Fos, estrogen receptor,
      NFkappaB/IkappaB alpha, cAMP-response element-binding protein (CREB) and CREB
      binding protein; (2) RSK is implicated in cell cycle regulation in Xenopus laevis
      oocytes by inactivation of the Myt1 protein kinase leading to activation of the
      cyclin-dependent kinase p34cdc2; (3) RSK may regulate protein synthesis by
      phosphorylation of polyribosomal proteins and glycogen synthase kinase-3; and (4)
      RSK phosphorylates the Ras GTP/GDP-exchange factor, Sos leading to feedback
      inhibition of the Ras-ERK pathway.

PMID- 10411322
TI  - Should prolactin be reconsidered as a therapeutic target in human breast cancer?
AB  - Although prolactin (PRL) has been long suspected to be involved in the
      progression of human breast cancer, the failure of clinical improvement by
      treatment with dopamine agonists, which lower circulating levels of PRL, rapidly
      reduced the interest of oncologists concerning a potential role of this pituitary
      hormone in the development of breast cancer. Within the last few years, however,
      several studies reported first, that PRL is also synthesized in the mammary
      gland, and second that it exerts its proliferative action in an
      autocrine/paracrine manner. These observations have led to a reconsideration of
      the role of PRL as an active participant in breast cancer and are an impetus to
      search for alternative strategies aimed at inhibiting the proliferative effects
      of PRL on tumor mammary cells. In this report, we discuss the three possible
      levels that can be targeted for this purpose: the mammary synthesis of PRL, the
      interaction of the hormone with its receptor at the surface of mammary cells, and
      the intracellular signaling cascades triggered by the activated receptor. For
      each of these steps, we discuss the molecular event(s) that can be targeted, our
      understanding of the mechanisms involving these putative targets as well as the
      tools currently available for their inhibition. Besides its proliferative effect,
      PRL is also involved in the control of angiogenesis through one of its cleaved
      fragments, named PRL 16K, which has been shown to inhibit the angiogenic process.
      In view of this biological activity, we discuss first the cleavage of PRL with
      respect to the human mammary gland and, second, the hypothesis speculating that a
      balance between the proliferative effect of intact PRL and the anti-angiogenic
      activity of its 16K-like fragments might be physiologically relevant in the
      evolution of mammary tumors. If true, our hypothesis would suggest that the
      enzymatic cleavage of PRL could represent a new molecular target in the search
      for alternative strategies in the treatment of breast cancer.

PMID- 10411323
TI  - Mutations and polymorphisms in gonadotropin genes.
AB  - Mutations in gonadotropin genes are extremely rare. Only one case of inactivating
      human luteinizing hormone (LH) beta mutation exists in the literature, a male
      with absence of Leydig cells, lack of spontaneous puberty and infertility. A
      total of four cases of inactivating mutation of the follicle-stimulating hormone
      beta (FSHbeta) gene (two female and two male) are known. The phenotype of the
      women was primary amenorrhea and absence of follicular maturation, the men were
      azoospermic. In addition, a common genetic variant (v) of LH was recently
      discovered. It is caused by two point mutations in the LH beta-subunit gene,
      resulting in amino acid alterations: Trp8 --> Arg and Ile15 --> Thr. In addition,
      the latter change introduces an extra glycosylation signal for oligosaccharide
      attachment to Asn13. The v-LHbeta allele has a carrier frequency ranging from 0
      to > 50% in various populations. The variant LH molecule has increased intrinsic
      bioactivity in vitro, but decreased circulatory half-life in vivo, and the v
      LHbeta promoter is about 50% more active in cell line transfections than that of
      wild-type (wt) LH. These differences in LH synthesis and action in individuals
      homo- or heterozygous for the v-LH allele are reflected by altered disposition to
      pathologies of pituitary-gonadal function, such as delayed puberty, polycystic
      ovarian syndrome and infertility.

PMID- 10411324
TI  - The role of sex steroids in the oxytocin hormone system.
AB  - The sex steroids and the peptide hormone oxytocin are both ancient modulators of
      the reproductive system of most metazoan species responsible for tissue
      differentiation and acute events respectively. In vivo experimentation implies
      estrogenic control of both the oxytocin (OT) gene and that for its receptor
      (OTR). Yet neither gene promoter appears able to bind classic estrogen-dependent
      nuclear receptors (ER) in vitro. The literature is confused by some transfected
      cell culture experiments which suggest that the human and rat OT gene promoter
      can be regulated by both ER alpha and ER beta through a major hormone response
      element at -160 bp upstream of the transcription start site. These findings
      depended, however, upon the presence of a high molar excess of the nuclear
      estrogen receptor. The current consensus suggests that the sex steroids are
      acting indirectly on both the OT and OTR genes, possibly involving intermediate
      transcription factors or cofactors. They may also act upon the OTR at the cell
      membrane, though more study is needed before the few current observations can be
      generalized. Due to the OT system being so ancient and fundamental to all aspects
      of reproduction, it is likely that the mechanisms by which the sex steroids
      influence this system are going to be of general importance to many other basic
      aspects of reproductive control.

PMID- 10411325
TI  - Local activation and inactivation of thyroid hormones: the deiodinase family.
AB  - Tissue-specific activation and inactivation of ligands of nuclear receptors which
      belong to the steroid retinoid-thyroid hormone superfamily of transcription
      factors represents an important principle of development- and tissue-specific
      local modulation of hormone action. Recently, several enzyme families have been
      identified which act as 'guardians of the gate' of ligand-activated transcription
      modulation. Three monodeiodinase isoenzymes which are involved in activation the
      'prohormone' L-thyroxine (T4), the main secretory product of the thyroid gland,
      have been identified, characterized, and cloned. Both, type I and type II 5'
      deiodinase generate the thyromimetically active hormone 3,3',5-triiodothyronine
      (T3) by reductive deiodination of the phenolic ring of T4. Inactivation of T4 and
      its product T3 occurs by deiodination of iodothyronines at the tyrosyl ring. This
      reaction is catalyzed both the type III 5-deiodinase and also by the type I
      enzyme, which has a broader substrate specificity. The three deiodinases appear
      to constitute a newly discovered family of selenocysteine-containing proteins and
      the presence of selenocysteine in the protein is critical for enzyme activity.
      Whereas the selenoenzyme characteristics of the type I and type III deiodinases
      are definitively established some controversy still exists for the type II 5'
      deiodinase in mammals. The mRNA probably encoding the type II 5'-deiodinase
      subunit is markedly longer than those of the two other deiodinases and its
      selenocysteine-insertion element is located more than 5 kB downstream of the UGA
      codon in the 3'-untranslated region. The three deiodinase isoenzymes show a
      distinct development- and tissue-specific pattern of expression, operate at
      individual optimal substrate levels, are differently regulated and modulated by
      hormones, cytokines, signaling pathways, natural factors, and pharmaceuticals.
      Whereas circulating T3 mainly originates from hepatic production via the type I
      5'-deiodinase, the local cellular thyroid hormone concentration in various
      tissues including the central nervous system is controlled by complex para-, auto
      , and intracrine interactions of all three deiodinases. Local thyroid hormone
      availability is further modulated by conjugation reactions of the phenolic 4'-OH
      group of iodothyronines, which also inactivate the thyroid hormones.

PMID- 10411326
TI  - The 11beta-hydroxysteroid dehydrogenases: functions and physiological effects.
AB  - The 11beta-hydroxysteroid dehydrogenase enzymes (11beta-HSD) interconvert
      cortisol and cortisone in man, and corticosterone and 11-dehydrocorticosterone in
      rodents. Two distantly related congeners have been isolated and conserved domains
      identified by multiple alignment and hydrophobic cluster analysis. 11Beta-HSD1 in
      the liver acts mainly as an oxoreductase maintaining circulating glucocorticoid
      levels. Gene deletion studies suggest it plays an important role in providing
      elevated local concentrations of hormone. In contrast, 11beta-HSD2 inactivates
      glucocorticoids and is pivotal in the distal tubule where it protects the
      mineralocorticoid receptor from occupation, thus endowing specificity on a non
      selective receptor. Mutations in 11beta-HSD2 result in sodium retention and
      severe hypertension, account for the syndrome of apparent mineralocorticoid
      excess and may be responsible for other forms of hypertension. 11Beta-HSD2 is
      also present in the placenta where it protects the fetus from high circulating
      levels of maternal glucocorticoids. Attenuated placental 11beta-HSD2 activity has
      recently been shown to be associated with intrauterine growth retardation. 11Beta
      HSD2 may also play important roles in pulmonary physiology and breast cancer.
      This review focuses on recent developments.

PMID- 10411327
TI  - The tail of the gonadotrophin-releasing hormone receptor: desensitization at, and
      distal to, G protein-coupled receptors.
AB  - In recent years a general scheme for the rapid desensitization and cycling of G
      protein-coupled receptors (GPCRs) has emerged. In this scheme agonist-induced
      phosphorylation (most often in the receptors' C-terminal tail) causes association
      with beta-arrestin which not only reduces the efficiency of G-protein activation,
      but also targets these desensitized receptors for internalization, after which
      they may be either proteolytically degraded or resensitized and recycled back to
      the cell surface. Although sustained stimulation of pituitary gonadotrophs with
      gonadotrophin-releasing hormone (GnRH) is known to cause a pronounced
      desensitization of GnRH-stimulated gonadotrophin secretion, the discovery that
      mammalian GnRH receptors do not possess C-terminal tails raised the question of
      whether receptor desensitization is involved. This review outlines data
      demonstrating that tail-less mammalian GnRH receptors can be considered as
      natural desensitization and internalization deficient 'mutants'. This is in stark
      contrast to non-mammalian GnRH receptors which do possess tails and conform to
      the general scheme. In the absence of receptor desensitization, post receptor
      mechanisms take on increasing importance for desensitization of GnRH action via
      mammalian GnRH receptors. The down regulation of Ins(1,4,5)P3 receptors and
      consequent desensitization of GnRH effects on cytosolic Ca2+ are discussed as a
      novel mechanism for such desensitization.

PMID- 10411328
TI  - Use of two-hybrid methodology for identifying proteins of interest in
      endocrinology.
AB  - During the last 10 years, much progress has been made in understanding signal
      transduction. However, the function of many newly identified proteins remains
      unknown. The protein/protein interactions have emerged as a major biochemical
      mechanism of signal transduction. They are of major interest to elucidate the
      role of a protein in one or another cellular process. The two-hybrid system is
      especially well designed for such investigation. Here we show that the
      contribution of this technique already is and will be essential in dissecting the
      molecular mechanism of transduction pathways in many cell types.

PMID- 10411329
TI  - Nutrient-induced insulin resistance.
AB  - Impaired function of the hormone insulin (insulin resistance) is a major feature
      of type 2 diabetes, a condition that is expected to afflict over 200 million
      people by early next century. Intensive investigation has failed to find a
      genetic basis for insulin resistance in the majority of cases. In this brief
      review the evidence that insulin resistance may be caused by excess nutrient
      supply will be presented. Both excess glucose and excess fat can cause insulin
      resistance in muscle and fat tissue, while excess fat can cause impaired
      suppression of endogenous glucose production. Each nutrient may impair insulin
      action by several mechanisms, at least one of which may be common to both.

PMID- 10411330
TI  - Adrenal zonation: clues from 11beta-hydroxylase and aldosterone synthase.
AB  - Aldosterone and cortisol are the major mineralocorticoid and glucocorticoid
      produced by the human adrenal. Circulating levels of angiotensin II and potassium
      control the adrenal production of aldosterone, while the production of cortisol
      is controlled mainly by adrenocorticotropin. The capacity of the adrenal cortex
      to differentially produce aldosterone and cortisol relies to a large degree on
      the expression of aldosterone synthase (CYP11B2) and 11beta-hydroxylase
      (CYP11B1). CYP11B2 catalyzes the final steps in the biosynthesis of aldosterone
      and is expressed solely in the glomerulosa of the adrenal cortex, while CYP11B1
      catalyzes the final steps in the biosynthesis of cortisol and is expressed in the
      fasciculata/reticularis. The zonal expression of these two isozymes appears to
      result from transcriptional regulation of the two genes. Herein, the recent
      progress in defining the cellular mechanisms that regulate transcription of these
      two isozymes and thus the capacity of the adrenal gland to differentially produce
      aldosterone and cortisol is discussed.

PMID- 10411331
TI  - Transcriptional regulation of the StAR gene.
AB  - The steroidogenic acute regulatory (StAR) protein regulates the rate-limiting
      step of steroidogenesis. In steroidogenic tissues, the StAR gene is regulated
      acutely by trophic hormone through a cAMP second messenger pathway. Thus, the
      gene encoding StAR must be finely regulated so that it is expressed in
      steroidogenic tissues at the proper time in development, and must be rapidly
      induced in response to cAMP stimulation. We have summarized the available
      information concerning the regulation of StAR mRNA levels including promoter
      mapping and transactivation studies. We also discuss the various transcription
      factors which have been implicated in the regulation of the StAR gene thus far,
      and propose models of how StAR transcription may be regulated.

PMID- 10411332
TI  - Development of the ovarian follicular epithelium.
AB  - A lot is known about the endocrine control of the development of ovarian
      follicles, but a key question now facing researchers is which molecular and
      cellular processes take part in control of follicular growth and development. The
      growth and development of ovarian follicles occurs postnatally and throughout
      adult life. In this review, we focus on the follicular epithelium (membrana
      granulosa) and its basal lamina. We discuss a model of how granulosa cells arise
      from a population of stem cells and then enter different lineages before
      differentiation. The structure of the epithelium at the antral stage of
      development is presented, and the effects that follicle growth has on the
      behavior of the granulosa cells are discussed. Finally, we discuss the evidence
      that during follicle development the follicular basal lamina changes in
      composition. This would be expected if the behavior of the granulosa cells
      changes, or if the permeability of the basal lamina changes. It will be evident
      that the follicular epithelium has similarities to other epithelia in the body,
      but that it is more dynamic, as gross changes occur during the course of follicle
      development. This basic information will be important for the development of
      future reproductive technologies in both humans and animals, and possibly for
      understanding polycystic ovarian syndrome in women.

PMID- 10411333
TI  - Structural basis of G protein-coupled receptor function.
AB  - The vast majority of extracellular signaling molecules, like hormones and
      neurotransmitters, interact with a class of membranous receptors characterized by
      a uniform molecular architecture of seven transmembrane alpha-helices linked by
      extra- and intracelluar peptide loops. In a reversible manner, binding of diverse
      agonists to heptahelical receptors leads to activation of a limited repertoire of
      heterotrimeric guanine nucleotide-binding proteins (G proteins) forwarding the
      signal to intracellular effectors such as enzymes and ion channels. Proper
      functioning of a G protein-coupled receptor is based on a complex interplay of
      structural determinants which are ultimately responsible for receptor folding,
      trafficking and transmembrane signaling. Applying novel biochemical and molecular
      biological methods interesting insights into receptor structure/function
      relationships became available. These studies have a significant impact on our
      understanding of the molecular basis of human diseases and may eventually lead to
      novel therapeutic strategies.

PMID- 10411334
TI  - Hormone regulation of chondrocyte differentiation and endochondral bone
      formation.
AB  - Endochondral bone formation, the formation of calcified bone on a cartilage
      scaffold, occurs during skeletal development, post natal growth and during bone
      remodelling and fracture repair. The epiphyseal growth plates represent classical
      tissues in which to study the ossification process, which requires two co
      ordinated components; progressive chondrocyte differentiation and cartilage
      neovascularisation. Many gene knockout studies have produced new insights
      regarding how chondrocyte differentiation and angiogenesis are controlled at the
      molecular level. Additional genetic studies have produced new information
      regarding the role of hormones in the regulation of endochondral bone formation.
      The new challenge for the future is to determine how bone formation and turnover
      is physiologically regulated and co-ordinated to ensure that skeletal development
      and growth progresses correctly. This study reviews the emerging data in this
      quickly growing field which should ultimately provide fundamental insights into
      the normal control of endochondral ossification.

PMID- 10411335
TI  - Indirect mechanisms and cascades of androgen action.
AB  - Androgens are the main hormones responsible for the induction of the male
      phenotype. This process involves a complex combination of reversible and
      irreversible effects. As for other steroid hormones, many of the effects of
      androgens are mediated by a specific intracellular receptor that interacts with
      cis-acting regulatory regions (AREs) in the affected genes. Apart from these
      direct effects, however, androgens may indirectly affect the expression of a
      variety of genes that do not necessarily contain AREs. Indirect effects may be
      related to androgen-induced changes in the concentration or activity of secondary
      transcription factors, autocrine and paracrine mediators, and circulating
      hormones. Such indirect effects may induce cascade-like actions and may play an
      important role in more complex effects of androgens involving coordinated
      responses of genes, cells and organs.

PMID- 10411336
TI  - The renal function of 25-hydroxyvitamin D3-1alpha-hydroxylase.
AB  - The active, hormonal form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)
      has numerous pleiotropic actions including the regulation of calcium homeostasis,
      control of bone cell differentiation and modification of immune responses.
      Synthesis of 1,25(OH)2D3 from the major circulating metabolite, 25-hydroxyvitamin
      D3 (25(OH)D3), is catalysed by the mitochondrial cytochrome P450 enzyme 25
      hydroxyvitamin D-1alpha-hydroxylase (1alpha-HYD). Although 1alpha-HYD activity
      has been demonstrated at several ectopic sites, circulating levels of 1,25(OH)2D3
      appear to reflect the expression of this enzyme in the kidney. The tight
      regulation of 1alpha-HYD in both renal and ectopic tissues has made studies of
      the expression and regulation of this enzyme remarkably difficult. However, the
      recent cloning of mouse, rat and human cDNAs for 1alpha-HYD has stimulated
      renewed interest in the molecular endocrinology of 1,25(OH)2D3 production.
      Analysis of the 1alpha-HYD sequence has revealed homology with the liver enzyme
      vitamin D-25-hydroxylase, and the ubiquitously expressed vitamin D-24
      hydroxylase. Furthermore, mutations causing the inherited disorder vitamin D
      dependent rickets type 1, also known as pseudo-vitamin D deficiency rickets have
      been described for the 1alpha-HYD gene and these have been mapped to chromosome
      12q14 by linkage analysis. The availability of sequence information for the
      1alpha-HYD gene has also facilitated the development of new molecular tools which
      will help to clarify key functions of the enzyme. Specific issues such as tissue
      distribution and regulatory pathways are discussed in this review, with
      particular emphasis on the role of 1alpha-HYD in renal calcium/phosphate
      homeostasis.

PMID- 10411337
TI  - The neuropathology of schizophrenia.
AB  - This review of brain changes in schizophrenia provides the neuropathologist with
      a conceptual framework to understand this disease. Numerous conflicting reports
      describe structural, functional, neurochemical, and neuropathological alterations
      in brains of schizophrenic patients. A core clinical manifestation of
      schizophrenia is disruption of thought; a mental process that is poorly localized
      in the brain and influenced by multiple neural systems. Schizophrenia has
      variable clinical presentations, natural history, and response to medication that
      imply a pathologically heterogenous group of diseases. Recent studies suggest
      that schizophrenia may involve cortical, limbic, and subcortical structures as
      well as multiple neurotransmitter systems. Schizophrenia may result from a
      perinatal insult in a genetically predisposed individual that produces neuronal
      alterations that manifest during final synaptic reorganization and myelination of
      early adulthood.

PMID- 10411338
TI  - Proteasome-dependent degradation of p27/kip1 in gliomas.
AB  - p27/kip1 regulates the G1-S transition of the cell cycle by inhibiting cyclin D
      CDK4, cyclin E-CDK2, and cyclin A-CDK2. Modulation of p27 cellular abundance
      occurs mainly at post-translational level by the ubiquitin-proteasome
      proteolysis. Although rearrangements and mutations of p27/kip1 are extremely rare
      events, p27 levels are reduced and associated with a poor prognosis in many human
      carcinomas. In astrocytic tumors, p27 decreases with advancing anaplasia and is
      almost absent in glioblastomas. To verify whether the degradation of p27 protein
      was responsible for its reduced levels in malignant gliomas, p27 degradation
      activity was tested in 22 tissue extracts that represented high, low, and absent
      p27 protein levels. p27 protein expression was detected by immunohistochemistry
      and immunoblot analysis and comparable results between the 2 methods were
      obtained. Low or undetectable p27 degradation activity was found in samples that
      displayed high levels of p27, i.e. all 4 normal brain biopsies, and 4 out of 6
      grade II astrocytomas. Enhanced degradation activity resulted in malignant
      gliomas with low or absent p27 protein levels. The proteasome inhibitor LLnL
      abolished p27 degradation, demonstrating that it occurs in a proteasome-dependent
      manner. These data suggest that proteasome degradation of p27 may be instrumental
      in the deregulation of the cell cycle and to the malignant transformation of
      gliomas.

PMID- 10411339
TI  - Acquired rearrangement of an amplified epidermal growth factor receptor (EGFR)
      gene in a human glioblastoma xenograft.
AB  - Amplification of the epidermal growth factor receptor (EGFR) occurs in about 40%
      of human glioblastomas. In half of these cases, rearrangements of the amplified
      gene result in aberrant transcripts and proteins. The most frequent rearrangement
      affects the external domain of the receptor and results in nonbinding of ligand
      and constitutive activity. Less frequent rearrangements involve changes resulting
      in the loss of cytoplasmic amino acid sequences necessary for downregulation of
      the receptor following ligand binding. Here we report the development and
      selection for a rearranged amplified EGF receptor, which lacks cytoplasmic amino
      acid sequences in a human glioblastoma xenograft. An identical aberration has
      previously been reported in glioblastoma tissue. The patient tumor material, as
      well as the first passages of the xenograft showed amplification of the EGFR
      gene, but no evidence of gene rearrangement or an aberrant transcript. Interphase
      FISH data show the amplified gene on double minutes. Between passages 3 and 16,
      the growth rate of the xenograft almost doubled, the rearranged amplicon became
      dominant, as did the aberrant transcript, indicating selection under these
      conditions.

PMID- 10411340
TI  - Studies in transgenic mice indicate a loss of connexin32 function in X-linked
      Charcot-Marie-Tooth disease.
AB  - X-linked Charcot-Marie-Tooth disease (CMTX) is an inherited demyelinating
      neuropathy caused by mutations in the gene encoding the gap junction protein
      connexin32 (Cx32). Despite the identification of over 160 different mutations in
      the Cx32 coding sequence, it is not known whether the mutations cause the disease
      manifestations through a loss of Cx32 function or through toxic effects on
      peripheral nerve. We created transgenic mice with a frameshift mutation at codon
      175 (175fs), identified in a large CMTX pedigree. Light microscopic examination
      of the peripheral nerves from adult transgenic animals showed no pathological
      features. Western blotting did not show transgenic Cx32 protein in any of the 26
      lines, although expression of transgenic messenger RNA was detected by reverse
      transcriptase polymerase chain reaction and by ribonuclease protection assay. Our
      findings indicate that the 175fs mutation results in a loss of Cx32 function,
      without additional toxic effects.

PMID- 10411341
TI  - The apolipoprotein E epsilon2 allele and the pathological features in cerebral
      amyloid angiopathy-related hemorrhage.
AB  - Cerebral amyloid angiopathy (CAA) is associated with apolipoprotein E (APOE gene,
      apoE protein) polymorphism: current evidence suggests that the epsilon4 allele is
      a risk factor for the development of CAA and the epsilon2 allele predisposes to
      hemorrhage. We sought to determine the relationship between the APOE epsilon2
      allele and both the immunoreactivity profiles and vascular complications of CAA.
      We performed immunohistochemistry for amyloid beta-protein (A beta), apoE,
      cystatin C, and activated microglia, and examined the morphology of cortical and
      leptomeningeal vessels in 37 CAA-related hemorrhage (CAAH), 26 Alzheimer disease
      (AD) patients, and 20 controls. The extent of immunostaining of vessels for A
      beta, apoE, cystatin C, and perivascular activated microglia increased from
      controls through AD to a maximum in CAAH patients. Among cases with CAA (37 CAAH,
      19 AD, and 6 controls, n = 62) vascular apoE (p < 5 x 10(-4)), cystatin C (p <
      10(-4)), activated microglia (p < 10(-4)), vessels with a high ratio of wall
      thickness to lumen diameter (p < 0.003) as well as dilated/microaneurysmal
      vessels (p < 0.01) were present more frequently in patients with hemorrhage than
      without; however, these features were not associated with the APOE epsilon2
      allele. Fibrinoid necrosis alone was associated with the APOE epsilon2 allele (p
      < 0.04) and we suggest that over-representation of APOE epsilon2 in CAAH may
      result from its association with fibrinoid necrosis.

PMID- 10411342
TI  - Pigment epithelium-derived factor (PEDF) protects motor neurons from chronic
      glutamate-mediated neurodegeneration.
AB  - Although pigment epithelium-derived factor (PEDF) is a neurotrophic factor that
      may aid the development, differentiation, and survival of adjacent neural
      retinae, the wider distribution of PEDF mRNA in the central nervous system
      suggested to us that this factor could have pleiotropic neurotrophic and
      neuroprotective effects on nonretinal neurons. We examined the distribution of
      PEDF mRNA and its transcript in the spinal cord. By immunohistochemistry and
      western blot analysis using an antihuman PEDF antiserum of known specificity, we
      found that PEDF protein is present in spinal cord, cerebrospinal fluid, and
      skeletal muscle and that its mRNA appears concentrated in motor neurons of the
      human spinal cord. These observations indicate that PEDF could have potential
      autocrine and paracrine effects on motor neurons, as well as being target
      derived. We analyzed the pharmacologic utility of PEDF in a postnatal organotypic
      culture model of motor neuron degeneration and proved it is highly
      neuroprotective. The effect was biologically important, significantly sparing the
      spinal cord's gross organotypic morphological appearance and preserving motor
      neuron choline acetyltransferase (ChAT). PEDF alone did not increase ChAT,
      indicating that the observed effect is neuroprotective, not merely an
      upregulation of motor neuron ChAT. Further, PEDF preserved motor neuron number,
      proving a survival effect. We hypothesize that PEDF may play important roles in
      the survival and maintenance of spinal motor neurons in their neuroprotection
      against acquired insults in postnatal life. It should be developed further as a
      therapeutic strategy for motor neuron diseases such as amyotrophic lateral
      sclerosis (ALS).

PMID- 10411343
TI  - BDNF and full-length and truncated TrkB expression in Alzheimer disease.
      Implications in therapeutic strategies.
AB  - Brain-derived neurotrophic factor (BDNF), and full-length and truncated tyrosin
      kinase B receptor (TrkB) protein expression were examined by Western blotting and
      immunohistochemistry in the frontal cortex and hippocampus of individuals
      affected by long-lasting severe Alzheimer disease (AD) and age-matched controls.
      Since preliminary processing studies in the brains of rats have shown loss of
      immunoreactivity depending on the postmortem delay in tissue processing and on
      the type, duration, and temperature of the fixative solution, only human samples
      obtained up to 6 hours (h) after death for biochemical and morphological studies
      and fixed by immersion in 4% paraformaldehyde for 24 h for morphological studies
      were included in the present series. Decreased BDNF and full-length TrkB
      expression accompanied by increased truncated TrkB expression, as revealed by
      Western blotting, was observed in the frontal cortex of patients with AD.
      Immunohistochemistry disclosed reduced BDNF and full-length TrkB immunoreactivity
      in neurons. BDNF decrease was equally observed in tangle-bearing and non-tangle
      bearing neurons, as revealed with double-labeling immunohistochemistry to BDNF
      and phosphorylated tau or phosphorylated neurofilament epitopes. Full-length TrkB
      immunoreactivity was largely decreased in tangle-bearing neurons, whereas only
      moderate decreases occurred in neurons with granulovacuolar degeneration. Strong
      BDNF immunoreactivity was observed in dystrophic neurites surrounding senile
      plaques, whereas strong TrkB expression occurred in reactive glial cells,
      including those surrounding senile plaques. Finally, truncated TrkB
      immunoreactivity was observed in individual neurons and in reactive glial cells
      in the cerebral cortex and white matter in AD. These results show decay in the
      expression of BDNF and TrkB in AD neurons, accompanied by altered BDNF, and full
      length and truncated TrkB expression in dystrophic neurites and reactive glial
      cells, respectively, in this disease. The present results demonstrate selective
      decline of the BDNF/TrkB neurotrophic signaling pathway in the frontal cortex and
      hippocampus in AD and provide supplemental data that may be relevant in
      discussing the suitability of the use of BDNF as a therapeutic agent in patients
      with AD.

PMID- 10411344
TI  - Decrease and structural modifications of phosphatidylethanolamine plasmalogen in
      the brain with Alzheimer disease.
AB  - Several lipid modifications, some of which were attributed to oxidative stress,
      have been reported in the brains of patients with Alzheimer disease (AD). To
      evaluate this possibility, all phospholipids and their ether subclasses from the
      frontal cortex, hippocampus, and the white matter of AD brain were analyzed by
      high performance liquid chromatography and gas chromatography. The total
      phospholipid in the frontal cortex and hippocampus decreased on a DNA basis by
      about 20% and this change was essentially explained by a selective decrease in
      phosphatidylethanolamine and phosphatidylcholine. The lower content of
      phosphatidylethanolamine was due to a specific decrease in the plasmalogen
      subclass. Phosphatidylethanolamine plasmalogen was also the only lipid exhibiting
      major structural modifications: a significant decrease in polyunsaturated fatty
      acids and oleic acid as well as a shift of the aldehyde pattern from 18:1 to
      18:0. The only modification observed in the other phospholipids was a decrease in
      oleic acid in diacyl-phosphatidylethanolamine and diacyl-phosphatidylcholine.
      None of these changes were observed in the white matter. Both the vinyl ether
      bond of phosphatidylethanolamine plasmalogen and polyunsaturated fatty acids are
      major targets in oxidative stress; thus, these specific lipid modifications
      strongly support the involvement of free radicals in the pathogenesis of AD.

PMID- 10411345
TI  - Synapses in the hereditary ataxias.
AB  - The goal of this investigation was the systematic assessment of synapses in the
      hereditary ataxias by the immunocytochemical and immunofluorescent visualization
      of SNAP-25, a protein of the presynaptic membrane. Sections were prepared from
      the cerebellar cortex, dentate nucleus, basis pontis, inferior olivary nuclei,
      and the spinal cord in 57 cases of autosomal dominant and recessive ataxia. The
      neuropathological phenotype included 18 cases of olivopontocerebellar atrophy
      (OPCA), 14 cases of familial cortical cerebellar atrophy (FCCA), 4 cases of
      Machado-Joseph disease (MJD), and 21 cases of Friedreich's ataxia (FA). Among the
      autosomal dominant ataxias, spinocerebellar ataxia type 1 (SCA-1), SCA-2, MJD/SCA
      3, and SCA-6 were represented. Expanded guanine-adenine-adenine trinucleotide
      repeats were confirmed in 7 patients with FA. The abundance of SNAP-25 was
      estimated by comparing the fluorescence of the regions of interest to that of the
      frontal cortex, which was considered unaffected by the disease process. Despite
      severe Purkinje cell loss, abundant SNAP-25 reaction product remained in the
      molecular layer of FCCA and OPCA. Among the cases of OPCA, those identified as
      SCA-2 showed the most severe overall synaptic destruction in cerebellum and brain
      stem. In SCA-1, which caused either OPCA or FCCA, significant synaptic loss was
      restricted to the inferior olivary nuclei. Sparing of cerebellar cortex and
      inferior olivary nuclei was the rule for MJD/SCA-3 and FA, though the dentate
      nucleus showed reduced SNAP-25 immunoreactivity in both ataxias. In FA,
      preservation of SNAP-25 in the dentate nucleus was characteristic of long
      survival. Severe cases with short survival revealed synaptic depletion of the
      dentate nucleus. At the level of the spinal cord, synaptic loss in the dorsal
      nuclei of Clarke characterized FA and MJD/SCA-3. The inexorable clinical
      progression of the hereditary ataxias could not be attributed to synaptic loss in
      a single anatomic structure of cerebellum, brain stem, or spinal cord.
      Nevertheless, synaptic loss in dentate and inferior olivary nuclei correlated
      more precisely with the severity of the ataxia than the changes in the cerebellar
      cortex.

PMID- 10411346
TI  - Increased brain-derived neurotrophic factor-containing axons in the basal ganglia
      of patients with multiple system atrophy.
AB  - Brain-derived neurotrophic factor (BDNF) has a neurotrophic effect not only on
      mesencephalic dopaminergic neurons, but also on striatal neurons. To investigate
      whether the abnormal expression of BDNF occurs in the basal ganglia of patients
      with Parkinson disease (PD) and multiple system atrophy (MSA), we compared the
      BDNF levels in the striatum and globus pallidus of patients with PD or MSA to
      controls using immunohistochemistry. Furthermore, to quantitatively evaluate the
      immunohistochemical changes in the striatum, image analysis of the putamen was
      performed. BDNF-positive nerve fiber bundles and fine granular structures were
      scattered throughout the striatum and globus pallidus of all samples. Most of
      these granular structures were observed in glial fibrillary acidic protein
      positive astrocytes. In addition, BDNF-positive neurites were abundant in the
      striatum of all MSA patients, and numerous BDNF-positive varicose fibers were
      found in the globus pallidus of some MSA cases with particularly severe striatal
      involvement. These observations suggest that the upregulated expression of BDNF
      may occur as a protective mechanism in the striatum of MSA patients, and that
      severe striatal degeneration may cause the aberrant accumulation of BDNF in the
      striatal projection areas of the globus pallidus of MSA patients.

PMID- 10411347
TI  - Increased mast cell degranulation within thalamus in early pre-lesion stages of
      an experimental model of Wernicke's encephalopathy.
AB  - A large increase in the number and percentage of degranulating mast cells was
      observed within thalamus of rats after 6-7 days of thiamine deficiency (TD). No
      mast cells were detected in the inferior olivary and lateral vestibular nuclei,
      which are also severely damaged by TD. After 11-12 days of TD, the number of ED2
      immunopositive macrophages increased in thalamus. In the brainstem nuclei, an
      increase in the number of macrophages occurred much earlier in treatment (i.e.
      day 6). An increase in GFAP-positive astrocytes within thalamus occurred after
      the changes in mast cells and prior to the increase in macrophages. In brainstem,
      reactive astrocytes appeared along with the increase in macrophages. These data
      suggest that mast cell degranulation is a very early response induced by TD, and
      the resultant release of cytokines and other chemical mediators may play critical
      roles in both the early vascular damage and eventual tissue destruction within
      thalamus, but not within brainstem. These results also suggest that macrophages
      and reactive astrocytes may play more direct roles in the pathogenesis of
      brainstem lesions.

PMID- 10411348
TI  - Human T-cell lymphotropic virus type I and systemic lupus erythematosus.

PMID- 10411349
TI  - Efficacy and changes of the nonstructural 5A GENE by prolonged interferon therapy
      for patients with hepatitis C virus genotype 1b and a high level of serum HCV
      RNA.
AB  - OBJECT: The aim of this study was to examine the efficacy and the changes of
      amino acid sequences of the interferon sensitivity-determining region (ISDR) by
      prolonged interferon (IFN) treatment in patients who have serum hepatitis C virus
      (HCV)-genotype 1b and a high level of serum HCV-RNA. METHODS: Inclusion criteria
      were biopsy-proven chronic hepatitis, positive HCV-RNA, and an abnormal serum
      aminotransferase level. Twenty-five patients received 6 MU of natural IFN-alpha
      daily for 8 weeks, followed by three times weekly for 40 weeks (1,056 MU). One
      patient was withdrawn from the study due to IFN side effects. Therefore, the
      remaining 24 patients (group 1) were studied the efficacy of IFN administration
      and changes of ISDR. As a control, 22 patients (group 2) treated with natural IFN
      alpha for 24 weeks for the same period were studied retrospectively. Patients
      were defined as complete responders (CR) if serum HCV-RNA levels were negative
      for 6 months after IFN therapy. RESULTS: According to this criterion, CR was 25%
      (6/24) in group 1 and 9.1% (2/22) in group 2. The normalization rates of alanine
      aminotransferease (ALT) for six months after termination of IFN was 41% (10/24)
      in group 1 and 18.2% (4/22) in group 2. Regarding the changes of ISDR in patients
      with no CR, the change rates of ISDR were 16.7% (3/18) in group 1 and 10% (2/20)
      in group 2. CONCLUSION: We concluded that prolonged IFN therapy was effective for
      patients with HCV-genotype 1b and a high level of serum HCV-RNA.

PMID- 10411350
TI  - Relationship between insulin and blood pressure in Japanese obese subjects.
AB  - OBJECT: The association of obesity and hypertension is well recognized. However,
      the nature of the relationship between increased body weight and blood pressure
      (BP) elevation has remained obscure. PATIENTS AND METHODS: We evaluated BP,
      insulin sensitivity, insulin clearance and fasting plasma insulin concentration
      in 19 younger (over 40 years) and in 15 older (more than 40 years) obese subjects
      to determine the relationships between BP and other factors. Insulin sensitivity
      and clearance were determined with the euglycemic clamp technique. RESULTS: BP
      was not associated with insulin sensitivity although most of the subjects showed
      insulin resistance. In the younger obese group, a positive correlation between
      diastolic BP and body mass index (kg/m2) was found (r=0.740; p=0.043). In the
      older obese group, systolic and diastolic BP were correlated with fasting plasma
      insulin levels (r=0.705; p=0.003; r=0.574; p=0.025, respectively), and systolic
      BP was inversely correlated with insulin clearance (r=-0.715, p=0.003).
      CONCLUSION: These results suggest that insulin is an important factor in BP
      elevation in older obese subjects, but not in younger obese subjects.

PMID- 10411351
TI  - Intravenous methylcobalamin treatment for uremic and diabetic neuropathy in
      chronic hemodialysis patients.
AB  - OBJECT: To study the effects of the intravenous administration of
      methylcobalamin, an analogue of vitamin B12, for uremic or uremic-diabetic
      polyneuropathy in patients who are receiving maintenance hemodialysis. An ultra
      high dose of vitamin B12 has been reported to promote peripheral nerve
      regeneration in experimental neuropathy. METHODS: Nine patients received a 500
      microg methylcobalamin injection 3 times a week for 6 months. The effects were
      evaluated using neuropathic pain grading and a nerve conduction study. RESULTS:
      Serum concentrations of vitamin B12 were ultra-high during treatment due to the
      lack of urinary excretion. After 6 months of treatment, the patients' pain or
      paresthesia had lessened, and the ulnar motor and median sensory nerve conduction
      velocities showed significant improvement. There were no side effects.
      CONCLUSION: Intravenous methycobalamin treatment is a safe and potentially
      beneficial therapy for neuropathy in chronic hemodialysis patients.

PMID- 10411352
TI  - Fifteen-year follow-up of a heterozygous Fabry's disease patient associated with
      pre-excitation syndrome.
AB  - A 47-year-old woman with heterozygous Fabry's disease with pre-excitation
      syndrome has been followed up for 15 years. Diagnosis was confirmed by the
      typical electron microscopic feature of the endomyocardial specimen and a
      decreased plasma alpha-galactosidase activity. As the disease progressed, the
      interventricular septum thickened from 11 to 17 mm as measured by
      echocardiography, while the AH interval was prolonged from 80 to 140 msec. In
      Fabry's disease, the PR interval has been reported to be variable from short PR
      to AV block. Therefore, this case may be helpful to understand the time course in
      the AV conduction abnormalities with the progression of Fabry's disease.

PMID- 10411353
TI  - Remission of insulin autoimmune syndrome in a patient with Grave's disease by
      treatment with methimazole.
AB  - The patient, a 24-year-old man, had suffered from hunger, sweating, tachycardia
      and palpitation for three years. He was diagnosed as having Graves' disease (GD)
      and treated with methimazole (MMI) for 3 months. He noted that palpitation and
      perspiration seemed to particularly occur when he was hungry, and thus he was
      examined to determine whether these symptoms were caused by hypoglycemia. As a
      markedly elevated immunoreactive insulin level and the presence of insulin
      antibody in serum were found, he was diagnosed as having insulin autoimmune
      syndrome (IAS). HLA typing revealed the patient to be positive for group
      Bw62/Cw4/DR4, which is reportedly a specific HLA type in MMI-treated euthyoroid
      GD patients with IAS. In spite of the continuation of MMI treatment, the %
      binding of IRI decreased and the hypoglycemic episode disappeared. In contrast to
      the previously reported MMI induced IAS in GD cases, MMI is unlikely to have
      exacerbated IAS in the present case, although his HLA combination is identical to
      that of the previous cases.

PMID- 10411354
TI  - Hypercalcemia accompanied by hypothalamic hypopituitarism, central diabetes
      inspidus and hyperthyroidism.
AB  - We present here a case of prominent hypercalcemia accompanied by hypothalamic
      tumor and Graves' disease. A 24-year-old man with hypothalamic tumor showed
      hypopituitarism, central diabetes inspidus (DI) and hyperthyroidism. Nausea, loss
      of thirst and appetite, and general fatigue were found with the unveiling of
      hypercalcemia and hypernatremia. Parathyroid hormone (PTH) and 1alpha
      dihydroxyvitamin D levels were suppressed with a normal range of PTH-related
      protein values. One-desamino-(8-D-arginine)-vasopressin (DDAVP) and half-saline
      administration normalized hypernatremia, while hypercalcemia was still sustained.
      Administration of cortisone acetate and thiamazole reduced the elevated serum Ca
      level. In the present case, concurrent hyperthyroidism was assumed to accelerate
      skeletal mobilization of calcium into the circulation. Hypocortisolism and
      central DI was also considered to contribute, to some extent, to the
      hypercalcemia through renal handling of Ca.

PMID- 10411355
TI  - Hyperimmunoglobulin E syndrome associated with nephrotic syndrome.
AB  - A 21-year-old man was admitted to Kure National Hospital with nephrotic syndrome
      in September 1996. He had suffered from an intractable pruritic skin rash and
      recurrent subcutaneous abscesses caused by the hyperimmunoglobulin E syndrome
      since the age of 18 months. Renal biopsy gave a diagnosis of
      membranoproliferative glomerulonephritis. Steroid therapy decreased urinary
      protein loss and hypoproteinemia, and his pruritic skin rash was improved.
      Patients with hyperimmunoglobulin E syndrome have a defective immune response,
      especially to Staphylococcus aureus infection. Continuous antigen stimulation may
      have caused this patient's renal histological damage as in immune complex
      glomerulonephritis.

PMID- 10411356
TI  - Hemolytic uremic syndrome associated with immunoglobulin A nephropathy: a case
      report and review of cases of hemolytic uremic syndrome with glomerular disease.
AB  - A 35-year-old man with immunoglobulin A (IgA) nephropathy who developed hemolytic
      uremic syndrome (HUS) presented with transient elevation of serum creatinine,
      thrombocytopenia, and hemolytic anemia with fragmented red cells with nephrotic
      syndrome. Hemolytic anemia and the temporarily deteriorated renal function were
      improved after hemodialysis and plasma exchange. Histological findings were
      consistent with HUS and IgA nephropathy. Including this case, we reviewed the
      cases of HUS accompanied by glomerular diseases reported from 1969 to 1996.
      Surprisingly, most cases showed nephrotic syndrome at the onset of HUS. Several
      possible relationships between HUS and nephrotic syndrome are discussed.

PMID- 10411357
TI  - Biclonal lymphoplasmacytic immunocytoma associated with Crohn's disease.
AB  - A 33-year-old man with a 4-year history of Crohn's disease presented with marked
      ascites and an abdominal tumor. Two M-protein peaks, immunoglobulin (Ig) G-kappa
      and IgA-kappa, were detected in the serum. Neoplastic lymphoplasmacytic cells
      were infiltrated in the bone marrow and ascites. Histological examination of the
      abdominal tumor showed marked proliferation of lymphoplasmacytic cells that were
      positive for either IgG or IgA. Moreover, DNA sequences of the expressed IgG and
      IgA genes were different in the complementarity-determining region 3. These
      results suggest that chronic inflammation in Crohn's disease contributes to the
      simultaneous development of biclonal lymphoplasmacytic immunocytoma of the small
      intestine.

PMID- 10411358
TI  - Myotonic dystrophy associated with insulinoma.
AB  - We describe a 51-year-old man with myotonic dystrophy (MyD) associated with
      insulinoma. In addition to the typical symptoms of MyD, he showed hypoglycemic
      attacks after meals. The radiological examination and selective blood sampling
      revealed an insulinoma in the head of the pancreas. The tumor was resected and
      histopathologically diagnosed as an insulinoma. In Southern blot analysis, CTG
      repeat of the myotonin protein kinase gene in the insulinoma showed the longest
      expansion, followed by normal tissue of the pancreas, muscle and white blood
      cells. Therefore, microsatellite instability was the most prominent in the tumor
      cells.

PMID- 10411359
TI  - T-cell lymphoma showing a non-enhancing diffuse white matter lesion with marked
      brain atrophy.
AB  - We report an autopsy case of T-cell lymphoma with diffuse white matter
      infiltration. Cranial magnetic resonance (MR) images showed atrophy of the brain
      with a diffuse, non-enhancing, T2-high signal intensity lesion in the cerebral
      white matter. Intra-axial infiltration of T-cell lymphoma should be considered a
      differential diagnosis in patients with these MRI findings.

PMID- 10411360
TI  - Human T cell leukemia virus type I-associated myelopathy in a patient with
      systemic lupus erythematosus.
AB  - A case of human T cell leukemia virus type I (HTLV-1) associated myelopathy
      (HAM)/tropical spastic paraparesis (TSP) with 14-year history of systemic lupus
      erythematosus (SLE) is reported. For 9 years, the numbness of the feet and sacral
      region progressed with occasional urinary incontinence and constipation. She was
      admitted to hospital due to gait disturbance and aggravation of SLE and the
      diagnosis of HAM/TSP was confirmed, indicating that HTLV-1 infection is
      associated with the development of not only HAM/TSP but also SLE.

PMID- 10411361
TI  - Calcinosis cutis and intestinal pseudoobstruction in a patient with adult onset
      Still's disease associated with recurrent relapses of disordered coagulopathy.
AB  - Adult onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown
      origin, characterized by a typical spiking fever, evanescent salmon-colored rash,
      polyarthralgia, and myalgia. Calcinosis cutis and gastrointestinal involvement
      have rarely been noted in AOSD. We herein describe a 54-year-old woman who
      demonstrated repeated disseminated intravascular coagulation (DIC), and adult
      respiratory distress syndrome (ARDS), associated with AOSD. The patient also
      revealed a remarkable degree of digital calcinosis cutis and intestinal
      pseudoobstruction. A connective tissue disease, such as systemic sclerosis, might
      have been the underlying factor in the latter two symptoms.

PMID- 10411362
TI  - Fenoldopam: a new parenteral antihypertensive: consensus roundtable on the
      management of perioperative hypertension and hypertensive crises.
AB  - A panel of clinicians from anesthesiology, surgery, nephrology, hypertension,
      cardiology, and pharmacology was convened to discuss pharmacologic therapeutics
      in the management of hypertensive crisis and perioperative hypertension. The
      panel discussed the advantages and limitations of currently available parenteral
      drugs, and assessed the potential use of fenoldopam mesylate, a drug in clinical
      development since 1981, and recently approved by the U.S. Food and Drug
      Administration (FDA). Fenoldopam is a dopamine receptor (DA1 selective) agonist
      that is a systemic and renal vasodilator. It was concluded that fenoldopam offers
      significant advantages as a parenterally administered agent for the management of
      blood pressure in both hypertensive emergencies and in the perioperative setting.

PMID- 10411364
TI  - Effect of hypertension and its treatment on lipid, lipoprotein(a), fibrinogen,
      and bilirubin levels in patients referred for dyslipidemia.
AB  - We measured the serum lipid profile, together with plasma fibrinogen and serum
      lipoprotein(a) (Lp[a]), glucose, bilirubin, and albumin levels in 491 patients
      (310 men) who were referred for the management of primary dyslipidemia. All these
      variables have been shown to predict vascular events. The patients were not
      taking lipid-lowering drugs; hypertension was present in 156 (31.7%) of them. Of
      the hypertensive patients, 52 (33%) were not receiving any treatment to control
      their blood pressure. This omission was not due to a lower prevalence of
      established vascular disease. The treated hypertensives were divided into three
      groups according to their treatment: 62 were taking lipid-hostile
      antihypertensives (beta-blockers, thiazides), 37 were taking lipid-neutral
      antihypertensives (angiotensin converting enzyme inhibitors, Ca-channel blockers,
      angiotensin II receptor blockers, indapamide sustained release), and five were
      taking lipid-friendly antihypertensives (doxazosin). Lipid-hostile
      antihypertensive drugs were associated with a significantly higher fibrinogen
      concentration when compared with untreated hypertensives or those taking lipid
      neutral/lipid-friendly drugs (median values: 383, 353, and 336 mg/dL,
      respectively; P < .01). Lipid-neutral/lipid-friendly antihypertensive drugs were
      associated with lower Lp(a) levels when compared with untreated hypertensives
      (median values: 22 and 45 mg/dL, respectively; P < .05). The serum bilirubin
      level was significantly lower in the untreated hypertensives when compared with
      normotensives or the treated hypertensives. There were no significant differences
      in lipids, glucose, or albumin among the groups of hypertensives or
      normotensives. The influence of antihypertensive drugs on additional
      cardiovascular risk factors should be considered when selecting medication to
      reduce blood pressure.

PMID- 10411363
TI  - Effects of the administration of an angiotensin-converting enzyme inhibitor
      during the acute phase of myocardial infarction in patients with arterial
      hypertension. SMILE Study Investigators. Survival of Myocardial Infarction Long
      term Evaluation.
AB  - A positive history of arterial hypertension (HBP) is present in as many as 30% of
      patients with acute myocardial infarction (AMI) and their clinical outcome could
      be greatly improved by drugs enhancing blood pressure control and preserving
      ventricular function. The aim of the present study was to evaluate the importance
      of a history of HBP on the clinical efficacy of early treatment with the
      angiotensin-converting enzyme (ACE) inhibitor zofenopril in patients with
      anterior AMI. We summarize the results of a post-hoc analysis of data from the
      Survival of Myocardial Infarction Long-term Evaluation (SMILE) study, which
      randomly evaluated the efficacy of zofenopril given within 24 h of symptom onset
      to patients with anterior AMI not undergoing thrombolysis. Of 1441 patients who
      entered the study, 565 (39.2%) had a history of HBP. The mean follow-up time was
      12 months and the main outcome measures were 6-week combined occurrence of death
      and severe congestive heart failure (CHF) and 1-year mortality. After 6-week of
      treatment with zofenopril the relative risk of death or severe CHF was 0.60 (95%
      confidence interval [CI]: 0.45-0.81; 2P < .05) in the hypertensive group and 0.89
      (0.74-1.08; 2P = .62) for normotensive patients, whereas the 1-year risk of death
      was 0.61 (95% CI: 0.23,0.89; 2P < .05) and 0.77 (95% CI: 0.52-1.17; 2P = .22),
      respectively. The 6-week prevalence of mild-to-moderate CHF was also
      significantly reduced by zofenopril in the hypertensive population (14.1% v 9.4%;
      2P < .05). The present data suggest that treatment with zofenopril started within
      24 h of the onset of anterior AMI could be highly beneficial in patients with a
      history of HBP.

PMID- 10411365
TI  - A weight reduction and weight maintenance program with long-lasting improvement
      in left ventricular mass and blood pressure.
AB  - Obesity is a major risk factor for cardiovascular disease and is associated with
      hypertension and increased left ventricular mass (LVM). Maintenance of reduced
      weight has been a matter of recent concerns in the treatment of obese subjects.
      This study was conducted to confirm the effect of the addition of exercise to
      diet on maintenance of body weight in a weight reduction program. In addition,
      this study was conducted to estimate whether LVM changes in parallel with a
      change in body weight during a long-term follow-up after a weight-reduction
      program. Twenty-two normotensive (NT) obese subjects and 14 mild hypertensive
      (HT) obese subjects ranging in age from 22 to 51 years participated in a 12-week
      supervised weight-reduction program involving mild exercise and a mild
      hypocaloric diet. After this 12-week intervention, they were advised to maintain
      their modified lifestyle during a 1-year follow-up period. After the 12-week
      intervention, the mean reductions in body weight (BW) in the NT and HT groups
      were 4.1 kg (P < .0001) and 5.8 kg (P < .0001), respectively. LVM in the NT and
      HT groups was significantly reduced from 154 g to 136 g (P < .005) and from 169 g
      to 152 g (P < .002), respectively. One year after intervention, the mean gains in
      BW in the NT and HT groups were 2.3 kg (not significant, NS) and 0.4 kg (NS),
      respectively. The mean gains in LVM in the NT and HT groups were 8 g (NS) and 7 g
      (NS), respectively. It was also shown that blood pressures in the HT group were
      significantly decreased after the 12-week intervention and there was no
      significant change in blood pressure in the HT group 1 year after intervention.
      In conclusion, reduced body weight was maintained for 1 year after a 12-week
      supervised weight-reduction program in both normotensive and mild hypertensive
      obese subjects. Reduced left ventricular mass was maintained for a long period in
      both normotensive and mild hypertensive obese subjects and lowered blood pressure
      was maintained in the mild hypertensive obese subjects.

PMID- 10411366
TI  - Comparison of two strategies for intensifying antihypertensive treatment: low
      dose combination (enalapril + felodipine ER) versus increased dose of monotherapy
      (enalapril). LEVEL (Lexxel vs Enalapril) Study Group.
AB  - To compare two popular strategies for intensifying treatment for hypertension, a
      double-blind, randomized, prospective, parallel-group, and partial crossover
      study was done. After 2 weeks of placebo run-in (baseline) and 3 weeks of 5 mg
      enalapril once daily, 217 patients were randomized to 6 weeks of treatment with
      either a low-dose combination therapy (5 mg enalapril + 5 mg felodipine ER once
      daily, Lexxel, Astra Merck, Inc.), or a higher dose of monotherapy (10 mg
      enalapril once daily, Vasotec, Merck & Co., Inc.). The group randomized to the
      combination had significantly greater reductions in sitting systolic/diastolic
      blood pressure (BP)--14.2/10.6 mm Hg compared with baseline versus 9.6/7.4 mm Hg
      (P < .05/.01)--as well as a greater percentage of patients having achieved either
      diastolic BP < 90 mm Hg or a decline of at least 10 mm Hg (responders), 59% v 41%
      (P < .01). When patients originally taking 10 mg enalapril were crossed over to
      the combination therapy for a further 6 weeks, there was a further BP reduction
      and increase in response rate, with loss of significant differences compared with
      those treated continuously with the combination for the entire 12 weeks. The
      greater BP-lowering efficacy of the combination was independent of age, gender,
      and race. There were no significant differences in tolerability between the
      regimens. These data support the hypothesis that in patients who do not achieve
      goal BP reduction with a low dose of an antihypertensive agent, a combination of
      two drugs with complementary mechanisms of action is more effective than
      increasing the dose of the first agent.

PMID- 10411367
TI  - Prevalence of the angiotensin I converting enzyme insertion/deletion
      polymorphism, plasma angiotensin converting enzyme activity, and left ventricular
      mass in a normotensive Chilean population.
AB  - The aim of this study was to estimate the prevalence of the different alleles of
      the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D)
      polymorphism and associated plasma ACE activity, as well as cardiac
      echocardiographic structure, in a healthy Chilean population. We selected 117
      healthy normotensive subjects (aged 45 to 60 years, middle socioeconomic status,
      nonobese, and nondiabetic) from a population-based study concerning the
      prevalence of risk factors for chronic diseases (Conjunto de Acciones Para la
      Reduccion Multifactorial de las Enfermedades no Transmisibles [CARMEN]). The
      frequencies of the I and D alleles were 0.57 and 0.43, respectively. Mean plasma
      ACE activity was 15.3 +/- 3.9 U/mL. Compared with subjects with the II genotype,
      plasma ACE activity was significantly higher in subjects with the ID and DD
      genotypes with no difference between them. No correlation was observed between
      blood pressure and plasma ACE activity. Among the three different genotypes there
      was no difference in left ventricular (LV) dimensions or in LV mass. No
      correlation between plasma ACE activity and LV mass was observed for either
      gender or different genotypes. Multivariate linear regression analysis using LV
      mass and LV mass index as dependent variables showed independent effects (P <
      .05) for gender (higher LV mass in men) and diastolic blood pressure, but not for
      the DD genotype. In conclusion, in this population, the presence of the D allele
      on the ACE gene determined higher circulating ACE activity. However, in this
      normotensive healthy population, male gender and diastolic blood pressure, but
      not the presence of the D allele, were associated with increased LV mass.

PMID- 10411368
TI  - Chronic captopril administration decreases vasodilator responses in skeletal
      muscle arterioles.
AB  - Changes in arteriolar reactivity to dilator agonists were assessed in the
      cremaster muscle of Sprague-Dawley rats fed normal rat chow with captopril (100
      mg/kg/day) in the drinking water for 8 weeks and in nontreated controls. The in
      situ cremaster muscle was prepared, superfused with physiologic salt solution,
      and arteriolar diameter was measured using television microscopy. Changes in the
      diameter of distal arterioles in response to topical application of iloprost,
      forskolin, cholera toxin, acetylcholine, and nitroprusside were measured with a
      video micrometer. Arteriolar responses to each of the vasodilator agonists used
      in this study were significantly reduced in the captopril-treated rats, relative
      to the untreated controls. The maximum dilation of the arterioles, determined
      during superfusion with Ca2+-free physiologic salt solution containing 10(-4)
      mol/L adenosine, was also reduced in the captopril-treated rats, suggesting
      structural remodeling of the arteriolar wall. These observations indicate that
      chronic angiotensin converting enzyme inhibition with captopril leads to
      significant alterations in arteriolar structure and reactivity, and that
      angiotensin II may play a protective role in maintaining normal vascular
      structure and vasodilator reactivity in the microcirculation.

PMID- 10411369
TI  - Altered angiotensin II-induced small artery contraction during the development of
      hypertension in spontaneously hypertensive rats.
AB  - This study assessed whether the angiotensin-II (Ang II)-induced contractile
      responsiveness of resistance arteries is altered during the development of
      hypertension in spontaneously hypertensive rats (SHR). Structural parameters and
      Ang II-stimulated contraction were determined in small mesenteric arteries from 6
      week-old (phase of developing hypertension) and 21-week-old SHR (phase of
      established hypertension), compared with age-matched Wistar-Kyoto rats (WKY). To
      ascertain whether effects were specific for Ang II, contractile responses to
      another vasoactive agonist, vasopressin (AVP), were also determined. Systolic
      blood pressure was measured in conscious rats by the tail-cuff method. Segments
      of third-order mesenteric arteries (approximately 200 microm in diameter and 2 mm
      in length) were mounted in a pressurized system with the intraluminal pressure
      maintained at 45 mm Hg. Blood pressure was significantly increased in SHR (P <
      .001) and was higher in adult than in young SHR (P < .001). Ang II dose
      dependently increased contraction, with responses significantly greater (P < .05)
      in SHR than in age-matched WKY. SHR, in the early phase of hypertension,
      exhibited significantly augmented contractile responses (Emax = 70 +/- 5%),
      compared with SHR with established hypertension (Emax = 33 +/- 5%). These effects
      were not generalized, as responses to AVP were not significantly different
      between young and adult SHR. Functional Ang II-elicited alterations were
      associated with structural modifications: 6-week-old SHR had smaller media to
      lumen ratio compared with 21-week-old SHR (8.1% +/- 0.17% v 10.6% +/- 0.20%, P <
      .01). In young SHR vessels the media cross-sectional area was unchanged relative
      to age-matched WKY rats, suggesting eutrophic remodeling (remodeling index 101.4%
      v 93.3% young v adult), whereas the cross-sectional area of adult vessels was
      increased in comparison to WKY rats, suggesting mild hypertrophic remodeling
      (growth index -1.0% v 15.2%, young v adult). In conclusion, the present study
      demonstrates that in SHR with early hypertension and slight medial thickening,
      Ang II-mediated vascular contractile responsiveness is significantly augmented
      compared with SHR with established hypertension and more severe vascular
      structural changes. These findings indicate attenuation, as hypertension
      progresses, of the initially enhanced vascular reactivity to Ang II that is
      present during the development of hypertension in SHR.

PMID- 10411370
TI  - Different effects of antihypertensive agents on cardiac and vascular hypertrophy
      in the transgenic rat line TGR(mRen2)27.
AB  - The hypertensive transgenic rat model TGR(mRen2)27 has been used to investigate
      the development of cardiac and vascular hypertrophy in response to two different
      drug regimes. Cardiac hypertrophy was shown to be related to age and gender with
      the copy number of mouse renin transgenes having an additive effect. A similar
      observation was noted for hypertrophy in the vasculature, which was assessed
      using flow cytometry cell cycle DNA analysis of aortic vascular smooth muscle
      cells. Chronic treatment from weaning with equihypotensive doses of perindopril
      (2 mg/kg/day) or hydralazine and hydrochlorothiazide (4 mg/day of each) prevented
      the development of cardiac hypertrophy. Perindopril treatment also effectively
      prevented the development of vascular hypertrophy; however, treatment with
      hydralazine and hydrochlorothiazide was not as effective despite equivalent blood
      pressure reduction. These studies have demonstrated the presence of marked
      vascular and cardiac hypertrophy in the hypertensive transgenic TGR(mRen2)27
      model of hypertension. Furthermore, these results provide new evidence to support
      the role of a locally activated renin angiotensin system in the blood vessel
      wall, which is involved in the pathogenesis of vascular hypertrophy in this
      transgenic rat model.

PMID- 10411372
TI  - Effect of hematocrit on blood pressure via hyperviscosity.
AB  - Increase in blood viscosity, defined as resistance to flow, is one factor in
      hypertension and atherosclerosis that contributes to the morbidity and mortality
      associated with tissue ischemia. In this research we evaluated the effect of
      hematocrit on increasing viscosity, and possible related changes in blood
      pressure, flow rate, and the equivalent physiologic compensation ratios. Blood
      samples were taken from 32 healthy individuals and centrifuged for 5 min at 3000
      rpm to obtain 2.5 mL of erythrocyte mass from each. Then, at each step 0.5 mL of
      plasma was consecutively added in a total of 17 steps. The resultant hematocrit
      and viscosity changes were measured. Viscosity measurement was performed by
      capillary viscometer. The results were evaluated by the Student t test. It was
      observed that in the range of 60.16% and 25.32%, a 10.99% increase of hematocrit
      produced an increase of 1 unit relative viscosity, which means approximately a
      20% increase in blood viscosity for a healthy individual. According to
      Poiseuille's equation, with a constant vessel length, if viscosity is increased
      by 20%, the decrease in blood flow rate will be 16.67% (100/120 = 83.33%; 100 -
      83.33 = 16.67%). For the physiologic compensation of 20% increased viscosity,
      blood pressure increase will be 20% or vasodilation will be 4.66% in radius.
      Atherosclerotic and some healthy vessels with little vasodilatory capacities
      might benefit from treatment modalities to decrease the viscosity by
      hemodilution.

PMID- 10411371
TI  - Arterial structural changes with verapamil in spontaneously hypertensive rats.
AB  - Reducing pulse pressure might be more powerful than reducing mean arterial
      pressure to obtain regression of vascular hypertrophy. However, this hypothesis
      has never been investigated in the conduit arteries of intact hypertensive
      animals. A group of 4-week-old spontaneously hypertensive rats (SHR) was treated
      with the calcium-entry blocker verapamil (50 mg/kg) for 16 weeks and compared
      with untreated SHR and control Wistar Kyoto (WKY) normotensive rats of the same
      age. At the end of the experiment, intraarterial thoracic aorta blood pressure
      was measured both in the conscious and anesthetized animals. Carotid artery
      diameter and stiffness (echo-tracking techniques) and aortic histomorphometry
      were determined in parallel. With verapamil, pulse pressure, but not mean
      arterial pressure, was significantly decreased but did not reach the normotensive
      values. Carotid internal diameter, medial thickness, and collagen content were
      significantly reduced by comparison with SHR and did not differ from the values
      of the WKY group. A significant positive and independent correlation was observed
      between pulse pressure and medial thickness in the overall population. The study
      shows that, in SHR chronically treated with verapamil, structural changes may be
      completely prevented without any change in mean arterial pressure. The parallel
      change in pulse pressure might suggest that mechanosensitive elements within the
      vascular wall may be selectively sensitive to the dynamic aspects of physical
      forces and are able to convert frequency and amplitude information into cellular
      responses that lead to vascular remodeling.

PMID- 10411373
TI  - Masoprocol lowers blood pressure in rats with fructose-induced hypertension.
AB  - Rats with fructose-induced hypertension were treated by oral gavage with either
      masoprocol (nordihydroguaiaretic acid) or vehicle. Masoprocol treatment resulted
      in significantly (P < .05 to .001) lower values for systolic blood pressure (120
      +/- 3 v 164 +/- 5 mm Hg), as well as plasma insulin (30 +/- 5 v 44 +/- 4
      microU/mL), free fatty acid (551 +/- 20 v 692 +/- 22 microEq/L), and triglyceride
      (79 +/- 5 v 219 +/- 32 mg/dL) concentrations. These results indicate that
      masoprocol, a lipoxygenase inhibitor, is able to lower blood pressure, as well as
      improve the metabolic abnormalities present in a rodent model of hypertension
      that simulates the characteristic of many patients with essential hypertension.

PMID- 10411374
TI  - Spondyloarthropathies.

PMID- 10411375
TI  - Clinical aspects, outcome assessment, disease course, and extra-articular
      features of spondyloarthropathies.
AB  - Much has been written over the years regarding the clinical aspects and disease
      course of the spondyloarthropathies, but publications relating to outcome
      assessment that attempt to relate measures of process with outcome are few. Extra
      articular features of the spondyloarthropathies, eg, uveitis, colitis, and
      aortitis, are well described, but in the past few years there has been an
      increasing interest in the incidence of osteoporosis in this group of patients,
      particularly those with ankylosing spondylitis. In rheumatoid arthritis
      functional indices have been developed, such as the Health Assessment
      Questionnaire score, which has been shown to be robust in monitoring response to
      therapy, but the situation is quite different in a condition such as ankylosing
      spondylitis. In the last few years a number of functional indices have been
      developed that are now beginning to be applied to monitor response to treatment
      in the spondyloarthropathies. The impact of ankylosing spondylitis in women is an
      area that has been neglected in the past, and a recent review addresses the
      effects of the disease on the reproductive capacity in women. This overall review
      of the past year's publications from the clinical aspects of ankylosing
      spondylitis confirms that clinical research still has much to contribute to this
      fascinating group of disorders.

PMID- 10411376
TI  - Reactive arthritis.

PMID- 10411377
TI  - Enthesitis in spondyloarthropathy.
AB  - Inflammation at the insertions of ligaments, tendons, or joint capsules to bone,
      which is termed enthesitis, is a characteristic feature of spondyloarthropathy.
      Because of the relative inaccessibility of the enthesis, the inflammatory,
      microbiologic, and immunologic events at that site have been poorly defined.
      Recent magnetic resonance imaging studies have drawn attention to the ubiquitous
      nature of enthesitis in spondyloarthropathies, especially adjacent to synovial
      joints. This may have implications for the mechanisms of synovitis in
      spondyloarthropathies. Magnetic resonance imaging studies also suggest that
      enthesitis lesions may be extensive, which could explain the diffuse nature of
      bone changes seen in some patients with spondyloarthropathies. The importance of
      enthesitis as a skeletal phenomenon in spondyloarthropathies has gained further
      support from transgenic models in which either tumor necrosis factor-alpha or
      bone morphogenetic protein-6 overexpression result in entheseal-associated
      polyarthropathy.

PMID- 10411378
TI  - Psoriatic arthritis and the spectrum of syndromes related to the SAPHO
      (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome.
AB  - During the past year, the increasing use of nuclear magnetic resonance imaging
      techniques, with their ability to delineate cartilage and ligamentous structures
      and to identify edema, are providing a radical improvement in ascertainment of
      musculoskeletal abnormalities, although their significance remains incompletely
      delineated. A second theme has come from the study of spondyloarthropathies in
      different ethnic groups and societal environments, revealing that the Northern
      European and North American form of the disease, with its powerful association
      with HLA-B27, is little evident in the rest of the world's population and that
      different susceptibility genes and environmental factors operate in other regions
      and peoples. Related to this theme is the compelling evidence of the marked
      influence of HIV infection on the development of spondyloarthropathies in Africa.
      Two areas of immune recognition are discussed as examples of emerging fields that
      may provide useful paradigms for the experimental approach to mechanisms in
      psoriatic arthritis. One of these is the three-cell model of CD8 T-cell
      interaction, in which a dendritic cell presents a peptide from an immunogenic
      protein to both a CD4 and CD8 T-cell clone, providing a cognitive interaction
      that disrupts tolerance and results in the expansion of the cytotoxic T-cell
      clone. In this respect, the combination of an activated dendritic cell, together
      with enhanced availability of arthritogenic microbial antigens caused by
      microbial persistence, are interesting candidates to explore as the basis of the
      HIV-associated rheumatic diseases. The second area of immune recognition is the
      growing understanding of the outline of the solution to the problem of the
      association of a spondyloarthropathy with several

PMID- 10411379
TI  - Immunogenetics, HLA-B27 and spondyloarthropathies.
AB  - HLA-B27 is the strongest HLA molecule associated with a disease. However, the
      reason only a small fraction of HLA-B27 positive individuals develop
      spondyloarthropathies is still unknown. Recent advances in genetics support the
      fact that additional genetic factors influence the disease and that the
      environmental factors may be ubiquitous. The mechanism of association of HLA-B27
      and disease remains unknown, but recent studies reveal some peculiar properties
      of accessory molecules in antigen presentation of B27. Furthermore, research has
      focused on the analysis of HLA-B27-restricted processing and presentation of a
      bacteria-derived peptide as playing a key role in the development of
      spondyloarthropathy. Other studies support a more complex interaction between
      bacteria and HLA-B27 and suggest that other roles unrelated to antigen
      presentation might contribute to the development of SpA.

PMID- 10411380
TI  - Elevation of serum IgA in spondyloarthropathies and IgA nephropathy and its
      pathogenic role.
AB  - Ankylosing spondylitis and IgA nephropathy share some immunologic features, eg,
      elevated serum IgA and IgA-immune complex levels. These entities are frequently
      found as being associated. IgA and IgA immune complex catabolism involves
      asialoglycoprotein receptors and specific IgA Fc receptors (FcalphaR or CD89) on
      tissue and blood cells. Recent studies revealed impaired CD89 expression in both
      diseases. These abnormalities, which are associated with receptor saturation,
      might generate the increase in serum IgA and IgA immune complex levels by either
      altered recycling or failure of degradation. This article reviews the literature
      on IgA abnormalities and discusses the potential role of FcalphaR in IgA
      nephropathy and AS and the consequences of its similar defect in the two
      diseases.

PMID- 10411381
TI  - Viral arthritis.
AB  - Identifying viral infections related to rheumatic syndromes and understanding the
      pathophysiologic mechanisms by which they cause disease are crucial steps to
      furthering our understanding of the pathogenesis of rheumatic disease. Many
      common viral infections can induce autoantibody formation. Parvovirus B19 (B19)
      can cause acute arthritis, and occasionally chronic arthropathy, in infected
      adults. Persistent B19 infection can be found in synovium of some patients.
      Antibodies reactive with B19 epitopes can cross react with some autoantigens.
      Studies of rheumatic syndromes associated with other viral infections, including
      alphaviruses, rubella, hepatitis C, and retroviruses, suggest differing
      mechanisms of host interaction with the infectious agents to cause disease.

PMID- 10411382
TI  - Lyme disease.
AB  - Lyme disease (LD) is the most common tick-borne disease in the United States. The
      overall trend has been an average annual increase in reported cases since
      surveillance was initiated by the Centers for Disease Control and Prevention in
      1982. Ixodes ticks often carry more than one potential pathogen, and co-infection
      with Borrelia burgdorferi and other organisms has been reported. The impact of
      dual infection upon the clinical course of LD is not known. Further studies of
      erythema migrans-like rashes in the Southern United States have indicated that it
      is likely caused by a related spirochetal organism. Case reports of unusual
      presentations have broadened our understanding of the clinical spectrum of LD.
      Studies in patients with chronic Lyme arthritis have indicated that an autoimmune
      process may be responsible for such cases. Results of two large, placebo
      controlled trials of a recombinant Lyme vaccine have been reported and results
      indicate that the vaccine is safe and effective in preventing LD in adults.

PMID- 10411383
TI  - The evolving role of direct amplification tests in diagnosing osteoarticular
      infections caused by mycobacteria and fungi.
AB  - Polymerase chain reaction-based direct amplification tests have been developed
      for many species of mycobacteria and fungi. Their applications in clinical
      medicine are evolving rapidly but are still not fully defined. Uncritical use of
      direct amplification tests for individual patients without a clear understanding
      of their limitations and how to integrate their results with other clinical and
      laboratory data may lead to incorrect patient management. Although presently
      available tests seem to be clinically useful when properly applied, further
      technical development and clinical studies are needed before these powerful
      diagnostic tools achieve their full value.

PMID- 10411384
TI  - Metabolic bone disease.

PMID- 10411385
TI  - Genetic aspects of osteoporosis.
AB  - At a given age, bone mass represents the difference between the maximal amount of
      bone mineral mass gained during growth (peak bone mass) and post-menopausal
      and/or senile bone loss. Twins and parents-offspring models have shown a strong
      inheritance of peak bone mass and it is now known that familial resemblance in
      various bone mass constituents is detectable well before the pubertal growth
      spurt. Recent developments in the molecular epidemiology of osteoporosis have
      focused on the association between areal bone mineral density and common
      polymorphisms in several candidate genes. Among them, vitamin D receptor (VDR),
      estrogen receptor and collagen-1 -alpha-1 (COL1A1) genes have been the most
      extensively investigated. Although controversial results have been reported and
      osteoporosis cannot be predicted by any single polymorphic gene marker, recent
      advances in this field have emphasized the complexity of bone mineral mass
      determination, because of gene-gene and gene-environment interactions.

PMID- 10411386
TI  - Selective estrogen receptor modulators.
AB  - Selective estrogen receptor modulators are a growing class of nonsteroidal
      compounds with estrogen-like actions in bone, lipid metabolism, and
      antiestrogenic actions in the breast. Tamoxifen and its derivatives have a weak
      estrogenic action in the uterus and are responsible for endometrial hyperplasia.
      Raloxifene does not stimulate endometrial growth but is less effective than
      tamoxifen for the treatment of patients with breast cancer. The duality of
      selective estrogen receptor modulators and 1 7B-estradiol actions is explained by
      several hypotheses referring to the molecular biology of estrogen receptor.
      Clinical trials are conducted with raloxifene in post-menopausal women. The
      results show a significant decrease in vertebral fracture risk and a decrease of
      low-density lipoprotein cholesterol, with no change in triglyceride levels.
      Endometrial thickness does not change. Interestingly, the risk for newly
      diagnosed breast cancer decreases significantly with no change in risk for
      estrogen receptor-negative tumors. Selective estrogen receptor modulators might
      change the way we manage hormone replacement therapy of postmenopausal women.

PMID- 10411387
TI  - Body mass and bone mineral quality.
AB  - During adulthood, the amount and quality of muscle and bone mineral decreases,
      whereas fat increases. Persons with low muscle mass and bone quality may not have
      the physical or structural strength to support the body. The dual-energy x-ray
      absorptiometer is used to measure the amount of muscle, fat, and the quality of
      bone mineral. Men have larger average amounts of muscle and bone, and greater
      average bone density than women. In women, the normal decrease of body mass and
      bone quality is accentuated by menopause. On average, blacks have a larger amount
      of muscle and more dense bones than whites. A person with a high peak bone mass
      can lose bone normally with age and still maintain good bone quality. Lifestyle,
      diet, and exercise are important to maintaining a healthy body and good bone
      quality. Physically active persons have increased levels of muscle and bone
      density. Age, sex, race, and lifestyle affect the level of, and changes in, body
      mass and bone mineral density.

PMID- 10411389
TI  - Bibliography of the current world literature. Spondyloarthropathies.

PMID- 10411388
TI  - Bone markers in clinical practice.
AB  - Although biologic indices of bone turnover are widely accepted as research tools
      in population-based studies, their clinical utility in the management of the
      individual patient remains controversial. Their main limitation for a routine
      clinical use is related to an important biologic variability, which means that
      large variations (ie, in response to therapy) are needed to consider a difference
      between two measurements as reflecting a significant biologic change. To date,
      the most valuable bone markers are serum osteocalcin, bone-specific alkaline
      phosphatase, and the N-terminal propeptide of type 1 procollagen for bone
      formation and urinary measurements of the phenazopyridine crosslinks and related
      telopeptides for bone resorption. New serum assays for both C-telopeptide and N
      telopeptide of type 1 collagen seem promising but need extensive validation.
      Although bone markers provide little information in the diagnosis of
      osteoporosis, strong evidence now shows that they can predict, albeit
      imperfectly, the rate of bone loss in menopausal women and the response to some
      antiresorptive therapies. In some populations, increased bone turnover has been
      shown to be a strong predictor of fracture risk, independently and to the same
      extent as low bone density. Whether bone markers are used to monitor the efficacy
      of (or compliance with) a specific treatment or to identify patients at risk for
      osteoporosis and thus to target preventive therapy, cost-benefit analysis, and
      evaluation of the potential improvement in patient outcome are clearly needed
      before these parameters may be universally accepted as tools to optimize patient
      care.

PMID- 10411390
TI  - Bibliography of the current world literature. Infectious arthritis and immune
      dysfunction.

PMID- 10411391
TI  - Bibliography of the current world literature. Metabolic bone disease.

PMID- 10411394
TI  - Ultrastructural changes in the chick thymus following unilateral vagotomy.
AB  - The ultrastructure of the thymus in the chick (Gallus domesticus) was studied
      after unilateral vagotomy at survival times of 3, 7 and 10 days. Ultrastructural
      changes in the ipsilateral thymus were observed in axon boutons as well as in
      myoid and cystic cells in the medulla, especially those situated near the
      corticomedullary junction. Structural changes in axon boutons ranged from
      granular degeneration of the axonal cytoskeleton to vacuolation of the axoplasm.
      Myelin figures of different sizes and configurations and clumping of small
      agranular vesicles were commonly observed in the axon terminals. Degeneration of
      myoid cells appeared to peak at 7 days post-vagotomy. Changes ranged from
      oedematous appearance and intense vacuolation of the peripheral cytoplasm to
      disorganisation and clumping of myofibrils. In some myoid cells the sarcomeres
      showed granular degeneration at the I-bands and in others, the myofibrils were
      completely degenerated such that amorphous material and partially degenerated
      organelles filled the entire cell. The majority of cystic cells at 3 days post
      vagotomy showed a uniform increase in electron density. Numerous electron dense
      bodies, some displaying concentric lamellation, were observed throughout the
      expanse of the cytoplasm. At 7 days post-vagotomy, the cytoplasm of some cells
      gave a "moth-eaten" appearance. Dying cystic cells were encountered at 10 days
      after vagotomy. Degeneration in the myoid and cystic cells suggests that these
      cellular components may be the putative targets of the vagal fibres in the chick
      thymus. The changes in these cells reflect a disturbance in the cell metabolism
      presumably brought about by the removal of vagal influence.

PMID- 10411393
TI  - Innervation of the mitral valve is strikingly depleted with age.
AB  - Previous reports demonstrated that mammalian atrioventricular (AV) valves possess
      a dense nerve plexus, consisting of nerve subpopulations which differ from each
      other in densities and patterns of distribution in the valves, and which may have
      sensory or motor roles in valve function. Although there is extensive evidence
      that age-related changes occur in autonomic nerves of animals and humans (Daly et
      al. J. Pharm. Exp. Ther., 1988;245(3):798-803; Ingall et al. Aust. NZ J. Med.,
      1990;20:570-577; Tumer et al. Exp. Gerontol., 1992;27:301-307), and that these
      changes contribute to changes in cardiac function (Klausner and Schwartz Clin.
      Geriat. Med., 1985;1(1):119-114), there is little information about age-related
      changes in heart valve innervation. In this study, we used acetylcholinesterase
      (AChE) histochemistry to localize and compare qualitative and quantitative
      changes in the innervation of the mitral valves in young adult and aged animals
      of three species. Young adult and aged guinea pigs, mice, and Wistar and Fischer
      344 rats were anesthetized with Nembutal, the hearts removed, and the mitral
      valves dissected out and processed for AChE localization. Camera lucida drawings
      of the AChE-positive nerves in representative segments of valve cusps were made
      directly from slides; these drawings were digitized and subjected to computer
      assisted image analysis to obtain quantitative information about nerve plexus
      density in the valves. All three animal species showed profuse AChE-positive
      innervation in the mitral valves of young adult animals, and decreases in the
      density of this innervation in aged animals. The most striking loss of
      innervation, compared to the young adult, occurred in the mitral valves of aged
      Fischer 344 rats, in which large regions of the valves appeared virtually devoid
      of nerves. Further studies are needed to investigate whether and to what extent
      age-related losses in heart valve innervation affect valvular structure and
      function.

PMID- 10411392
TI  - Ultrastructural studies of glycan changes in the apical surface of the uterine
      epithelium during pre-ovulatory and and pre-implantation stages in the marmoset
      monkey.
AB  - It has been postulated that carbohydrates are involved in a variety of cell-cell
      interactions including blastocyst implantation. In primates, there are only
      limited investigations on the ultrastructural localisation of the cyclic changes
      in uterine epithelial surface carbohydrates. Our aim was to investigate such
      changes during the pre-ovulatory and pre-implantation stages of the reproductive
      cycle in the marmoset monkey. After fixation of endometrial tissues, avidin
      ferritin lectin cytochemistry was employed for apical surface glycan detection at
      the ultrastructural level. Five lectins were used including Canavalia ensiformis
      (Con A), Lotus tetragonolobus (LTA), Glycine max (SBA), Phytolacca americana
      (PWM) and Triticum vulgaris (WGA). Morphometry was used to quantitate changes in
      the intensity of lectin staining by determining the total number of ferritin
      particles per unit length of membrane. Surface and intra-cytoplasmic vesicles,
      stained by the lectins, were also examined. Quantitative ferritin assessment
      showed that 1 day before presumed implantation (days 11 to 12 after ovulation in
      the marmoset monkey) there was a significant increase in Con A, LTA and SBA
      staining on the apical uterine epithelial plasma membrane compared to the pre
      ovulatory phase and earlier stages of pregnancy (days 4-8 after ovulation). A
      significant increase in PWM was also detected from early pregnancy to pre
      implantation stages. All lectins except WGA produced reproducible staining within
      reproductive cycle groups. The greatest variation and intensity of epithelial
      surface staining was observed with WGA and the weakest with LTA. The patchy
      staining with LTA compared with thick coverage by WGA indicated the complexity of
      the carbohydrate arrangement in the glycocalyx of the uterine surface plasma
      membrane. Reduction of WGA reactivity after neuraminidase treatment suggested
      that the lectin binding might be related to the presence of heavily sialylated
      apical uterine membrane glycoconjugates. This is the first high-resolution study
      in primates to report quantitative cyclic changes in fucosyl, galactosyl,
      glucosyl, and mannosyl sugar residues of the apical uterine epithelial
      glycocalyx. The findings support the concept that uterine epithelial glycocalyx
      surface carbohydrates play a role in preparing a receptive uterine surface.

PMID- 10411395
TI  - Anatomical study of the neural ganglionated plexus in the canine right atrium:
      implications for selective denervation and electrophysiology of the sinoatrial
      node in dog.
AB  - The aim of the present study was to elucidate the topography and architecture of
      the intrinsic neural plexus (INP) in the canine right atrium because of its
      importance for selective denervation of the sinoatrial node (SAN). The morphology
      of the intrinsic INP was revealed by a histochemical method for
      acetylcholinesterase in whole hearts of 36 mongrel dogs and examined by
      stereoscopic, contact, and electron microscopes. At the hilum of the heart,
      nerves forming a right atrial INP were detected in five sites adjacent to the
      right superior pulmonary veins and superior vena cava (SVC). Nerves entered the
      epicardium and formed a INP, the ganglia of which, as a wide ganglionated field,
      were continuously distributed on the sides of the root of the SVC (RSVC). The
      epicardiac ganglia located on the RSVC were differentially involved in the
      innervation of the sinoatrial node, as revealed by epicardiac nerves emanating
      from its lower ganglia that proceed also into the atrial walls and right auricle.
      The INP on the RSVC (INP-RSVC) varied from animal to animal and in relation to
      the age of the animal. The INP-RSVC of juvenile dogs contained more small ganglia
      than that of adult animals. Generally, the canine INP-RSVC included 434+/-29
      small, 17+/-4 medium-sized, and 3+/-1 large epicardiac ganglia that contained an
      estimated 44,700, 6,400, and 2,800 neurons, respectively. Therefore, the canine
      right atrium, including the SAN, may be innervated by more than 54,000
      intracardiac neurons residing mostly in the INP-RSVC. In conclusion, the present
      study indicates that epicardiac ganglia that project to the SA-node are
      distributed more widely and are more abundant than was previously thought.
      Therefore, both selective and total denervation of the canine SAN should involve
      the whole region of the RSVC containing the INP-RSVC.

PMID- 10411396
TI  - Comparison of cholinergic and histaminergic axons in the lateral geniculate
      complex of the macaque monkey.
AB  - The cholinergic and histaminergic projections have important neuromodulatory
      functions in the ascending visual pathways, so we compared the pattern and mode
      of innervation of the two projections in the lateral geniculate complex (dorsal
      lateral geniculate nucleus and pregeniculate nucleus) of the macaque monkey.
      Brain tissue from macaques was immunoreacted by means of antibodies to choline
      acetyltransferase (ChAT) or to histamine and processed for light and electron
      microscopy. A dense plexus of thin, highly branched ChAT-immunoreactive axons
      laden with varicosities was found in all layers of the dLGN including the
      koniocellular laminae and in the pregeniculate nucleus. ChAT label was more dense
      in magnocellular layers 1 and 2 than in parvocellular layers 3-6 and relatively
      sparse in the interlaminar zones. Varicosities associated with the cholinergic
      axons had an average of three conventional asymmetric synapses per varicosity,
      and these appeared to contact dendrites of both thalamocortical cells and
      interneurons. Histamine-immunoreactive axons were distributed homogeneously
      throughout all laminar and interlaminar zones of the dLGN, but were denser in the
      pregeniculate nucleus than in the dLGN. Histaminergic axons branched infrequently
      and were typically larger in caliber than cholinergic axons. The overwhelming
      majority of varicosities were found en passant and rarely displayed conventional
      synapses, despite the abundance of synaptic vesicles, and were not associated
      preferentially with specific cellular structures. The innervation of the macaque
      dLGN complex by cholinergic and histaminergic systems is consistent with their
      proposed role in state dependent modulation of thalamic activity. The dense and
      highly synaptic innervation by cholinergic axons supports the proposal of
      additional involvement of these axons in functions related to eye movements.

PMID- 10411397
TI  - Effect of androgens on the cranial suspensory ligament and ovarian position.
AB  - Androgens have been postulated to have a major role in testicular descent via
      regression of the cranial suspensory ligament, which in normal rodents anchors
      the ovary to the retroperitoneum near the lower pole of the kidney. This study
      aimed to quantitate the degree of descent of the foetal ovary in androgen-treated
      female mice to determine the role of androgens in regression of the cranial
      suspensory ligament and descent of the testis. Time-pregnant mice were injected
      with testosterone propionate or methyl testosterone (2.5-3.0 mg) in vehicle on
      day 13 or 14. Control animals received vehicle only. Newborn mice were
      anaesthetised and dissected for macroscopic anatomy of the ovary, which was
      quantified by measuring the vertical distance from the lower pole of the kidney
      to the lower pole of the ovary. Histological analysis was also performed. The
      external genitalia were masculinised in all females exposed to prenatal
      androgens. The ovaries of treated animals were mobile, with no cranial suspensory
      ligament, and located slightly caudal to the kidney. Wolffian duct structures
      were identifiable, but the gubernaculum was qualitatively unchanged compared with
      control females. The ovary was displaced caudally (P< 0.001), but only 15-25% of
      the distance to the lower abdomen. Exogenous androgens induce regression of the
      cranial suspensory ligament, causing the ovary to be more mobile and lower in the
      abdominal cavity. However, since the testicular position at birth is at or below
      the bladder neck, androgen-mediated regression of the cranial suspensory ligament
      is only an adjunct to the control of transabdominal testicular descent.

PMID- 10411398
TI  - Sexual dimorphism of proximal straight tubular cells in mouse kidney.
AB  - The proximal straight tubular epithelium of the mouse kidney exhibited sexual
      dimorphism in conventional paraffin sections stained with periodic acid Schiff
      (PAS) in our preliminary observation. The purpose of this study was to clarify
      the sex-dependent structural features in the proximal straight tubular cells of
      the mouse kidney, and to clarify the effects of sex hormones on this portion of
      the renal tissue. The mice used in this study were divided into intact,
      orchiectomized, ovariectomized, testosterone-treated and estradiol-treated
      groups. The kidneys of these animals were examined by histological, cytological
      and cytochemical (for acid phosphatase reaction) procedures. In the proximal
      straight tubular epithelium of intact adult mice, PAS staining of the brush
      border in females was more intense than that in males. Furthermore, PAS-positive
      granules were observed in the cytoplasm of females only. Orchiectomy changed the
      male-specific features to that of the females, and treatment with testosterone
      induced the male-specific features. Ovariectomy and estradiol treatment showed no
      effects. Ultrastructurally, PAS-positive granules were observed as electron-dense
      myelinoid bodies, and these contained acid phosphatase-positive matrix. The
      present study demonstrated apparent sexual dimorphism and effects of testosterone
      on PAS staining and PAS-positive granules in the proximal straight tubule cells
      in normal mice. In addition, the association of PAS-positive granules and
      lysosomes was suggested by cytological and cytochemical examination.

PMID- 10411399
TI  - Quantitative study of the effects of denervation and castration on the levator
      ani muscle of the rat.
AB  - The levator ani muscle (LA) of the rat is highly androgen-sensitive and, like all
      skeletal muscles, deteriorates structurally and functionally when denervated. In
      order to elucidate the interplay of neural and endocrine influences, the separate
      and combined effects of denervation and castration on myofiber cross-sectional
      area and nuclear populations were quantitatively studied. In one group of 4-month
      old male rats (A), the LA was denervated. Another group (B) was surgically
      castrated and a third group (C) was both denervated and castrated. The control
      rats (D) remained both gonad- and nerve-intact. After two months, the LA was
      obtained for myofiber and nuclear enumeration, cross-sectional area and satellite
      cell frequency determination. In the denervated muscle of gonad-intact rats
      (Group A), myofiber cross-sectional area was markedly diminished (265.84+/-11.38
      microm2; compared with controls [Group D]: 1519.98+/-79.41 microm2; P < 0.05).
      Satellite cell nuclei, as a percentage of total sublaminar nuclei (i.e.,
      satellite cell ratio), increased significantly (4.26%, from a control value of
      1.91%). Castration alone (Group B) resulted in pronounced myofiber atrophy (mean
      cross-sectional area: 754.03+/-89.63 microm2) but had no significant effect on
      satellite cell ratio (2.36%). The combination of castration and denervation
      (Group C) elicited the same degree of myofiber atrophy as denervation alone
      (Group A) but had no significant impact on satellite cell ratio. Instead, the
      nuclear count per myofiber declined to about a third of the control level
      (300.5+/-38.49 compared with 861.7+/-24.8; P < 0.05). The results indicate that
      the atrophic effects of denervation and castration on the LA are non-synergistic
      and mechanistically similar. They also show that the inability of satellite cells
      to respond mitotically to the withdrawal of neural input under disandrogenized
      conditions is a factor in the myonuclear depletion of the denervated muscle of
      castrated rats.

PMID- 10411400
TI  - Central and peripheral benzodiazepine ligands prevent mitochondrial damage
      induced by noise exposure in the rat myocardium: an ultrastructural study.
AB  - Noise represents an environmental stress factor affecting several organs and
      apparatuses, including the cardiovascular system. In experimental animals
      undergoing noise exposure, subcellular myocardial changes have been reported,
      especially at the mitochondrial level. In previous studies we found that
      diazepam, acting at both central and peripheral benzodiazepine receptors,
      prevented the onset of this myocardial damage. In the present study, we
      investigated the specific role played by central and/or peripheral benzodiazepine
      receptors in preventing noise-induced myocardial alterations. In particular, the
      effect of clonazepam as a selective ligand for central sites, in comparison with
      the efficacy of ligands selective for peripheral sites, such as Ro 5-4864 and PK
      11195, was evaluated. Rats were pretreated with the test drugs 30 min before
      exposure to noise for 6 or 12 hr and then sacrificed. After fixing, samples of
      right atrium and ventricle were taken and processed for either transmission or
      scanning electron microscopy. After 6 hr of noise exposure, only the atrium
      exhibited significant mitochondrial alterations, whereas after 12 hr both atrium
      and ventricle were damaged. As expected, diazepam prevented noise-induced
      mitochondrial injury at both 6 and 12 hr. By contrast, clonazepam was effective
      only after 6 hr. The peripheral ligand PK-11195 attenuated mitochondrial damage
      at both 6 and 12 hr, whereas Ro 5-4864 was effective only after 12 hr. In the
      present study, we confirm that noise exposure induces mitochondrial damage in the
      rat myocardium. Drugs acting at both central and peripheral benzodiazepine
      receptors significantly prevent this damage. Differences in the amount and in the
      duration of the protective effect might depend on variability in the potency and
      in the pharmacokinetics of the specific drugs.

PMID- 10411401
TI  - Development of the actin and the cytokeratin cytoskeletons of parietal cells
      during differentiation of the rat gastric mucosa.
AB  - Available evidence strongly suggests that microfilaments and cytokeratin
      intermediate filaments (IF) play a role in the reorganization of the luminal pole
      required for the secretion of acid by parietal cells. To correlate the
      organization of both cytoskeletal systems with the differentiation of the
      secretory membranes of parietal cells, the distribution of F-actin and
      cytokeratin was studied during the ontogenic development of the rat. Primitive
      parietal cells were detected with parietal cells autoantibodies and
      ultrastructurally by transmission electron microscopy (TEM). The distribution of
      IF and of F-actin in differentiating parietal cells was determined using
      anticytokeratin antibodies and FITC-phalloidin, respectively. Development of both
      cytoskeletal systems was followed by TEM. Ultrastructurally, parietal cells are
      identified from day 19 on, by the presence of an incipient canaliculus, which
      later enlarges and fills with microvilli. No intracellular tubulovesicular system
      is observed. Using parietal cells autoantibodies these cells are detected from
      day 20 on. Immunocytochemistry and TEM demonstrate that parietal cells possess
      organized cytokeratin and actin cytoskeletons, which develop further as
      differentiation proceeds. At birth, parietal cells show an ultrastructure and a
      distribution of IF and microfilaments similar to that of differentiated cells. In
      newly born rats, the F-actin cytoskeleton redistributes after suckling. This
      reorganization results from an enlargement of the canalicular lumen, filled with
      microvilli rich in actin. Thus, functional maturation of parietal cells is
      paralleled by the development of organized IF and F-actin cytoskeletons
      associated to the secretory surface.

PMID- 10411402
TI  - Abnormal skeletogenesis occurs coincident with increased apoptosis in the Splotch
      (Sp2H) mutant: putative roles for Pax3 and PDGFRalpha in rib patterning.
AB  - Although the importance of the transcription factor Pax3 has been identified in
      many embryological processes including neural crest cell migration, neural tube
      closure, and limb muscle formation, its role in proper formation of the ribs has
      not been well characterized. We have used the Splotch mouse which has a mutation
      in the Pax3 gene to determine what role Pax3 may play in rib morphogenesis.
      Homozygous Splotch embryos collected from days 13.5 to 16.5 of gestation
      displayed severe rib abnormalities including fusions at both the proximal and
      distal regions. Given its expression in the dermomyotome, we sought to determine
      when Pax3 expression in the Splotch mutant initially becomes abnormal and which
      rib segment progenitors may be affected. Prior to somite differentiation at 9.5
      dpc (days post coitum), Pax3 is normally expressed in the somites; after
      differentiation, however, Pax3 expression is diminished in Splotch embryos. We
      also determined that significantly increased levels of apoptosis occur in the
      thoracic region by 11.0 dpc relative to wild-type littermates. Because Patch
      mouse mutants which fail to express PDGF alpha-receptor also have rib
      abnormalities, we sought to determine whether Pax3 may influence the expression
      of this receptor. By in situ hybridization, we determined that initially the
      expression of PDGFRalpha is normal in Splotch mutants at 10.0 dpc, but decreases
      by 12.5 dpc in the thoracic somite region, suggesting that Pax3 may act upstream
      of PDGFRalpha. Taken together, our results show that Pax3 expression is important
      for normal rib development and that increased apoptosis occurs in the thoracic
      muscles. We suggest that Pax3 may influence the expression of PDGFRalpha, and
      that the reduced and/or deficient thoracic muscles may contribute to the
      resulting rib abnormalities.

PMID- 10411403
TI  - Varicella zoster virus.
AB  - Because of its ability to produce two clinically distinct disease entities
      (chickenpox and shingles), varicella zoster virus (VZV) is an unusual etiologic
      agent. Although in the past viral exanthems were mostly only of academic interest
      to the practitioner, the development of antiviral agents and the newly approved
      varicella (OKA) vaccine have increased the clinical significance. Also, with the
      increasing seroprevalence of HIV infection, more patients will be stricken with
      zoster (at a younger age) and disseminated varicella. In this review, the
      history, incidence, pathogenesis, clinical manifestations, and treatment options
      (of VZV infection and postherpetic neuralgia) will be discussed.

PMID- 10411404
TI  - Longitudinal melanonychia in children: a clinical and histopathologic study of 40
      cases.
AB  - OBJECTIVE: Very little has been published on longitudinal melanonychia in
      children. Our objective was to determine the nature of melanocytic lesions in
      pediatric patients with longitudinal or total melanonychia and to look for
      correlations between clinical and histologic features. METHODS: All patients
      younger than 16 years of age with longitudinal or total melanonychia who were
      evaluated at our nail disorder outpatient clinic between September 1993 and
      September 1996 were included. The clinical and histologic features of the nail
      condition were determined in each case. RESULTS: Forty patients were included.
      The final diagnosis was nevus in 19 cases (junctional in 17 cases and compound in
      2), lentigo in 12 cases, and functional longitudinal melanonychia in 9. The
      latter corresponded to a hyperpigmentation caused by melanocytic activation with
      no increase in the number of melanocytes. None of the patients had melanoma.
      Appearance within the first year of life, periungual pigmentation, and total
      melanonychia were consistent features in patients with melanocytic hyperplasia
      (lentigo or nevus). Early onset of a dark broad lesion in a white patient was
      typical of melanocytic hyperplasia, although none of these features were
      pathognomonic. CONCLUSION: Benign melanocytic hyperplasia (lentigo or nevus) was
      the cause of 77.5% of cases of longitudinal melanonychia in our overall pediatric
      population and of 85% of cases in the subset of white patients. All the remaining
      cases of longitudinal melanonychia were the result of melanocytic activation.

PMID- 10411405
TI  - Cigarette smoking-associated elastotic changes in the skin.
AB  - BACKGROUND: Clinical features of the skin in persons who smoke include increased
      wrinkling, gauntness, and discoloration that has been termed smoker's face. The
      histologic changes in the sun-exposed skin of these patients have not been
      previously elucidated. OBJECTIVE: The purpose of this study was to assess the
      amount of elastosis in the sun-exposed skin of smokers and nonsmokers. METHODS:
      We evaluated the skin from the forehead and cheeks of 17 smokers and 14
      nonsmokers for the presence of elastosis. With the use of a computer-generated
      analysis of tissue sections at 4 different levels, the amount of elastotic
      material was expressed as an average percent of the field staining for elastic
      tissue. Patients were also evaluated for the presence of other malignancies,
      arsenic and radiation exposure, and previous skin cancers. RESULTS: There was a
      significantly greater amount of elastosis (P < .05) in the skin of patients who
      smoked compared with those patients who did not. No significant differences were
      found between the 2 groups with regard to the other parameters evaluated.
      CONCLUSION: Cigarette smoking is associated with an increase in elastosis, which
      may contribute to the clinical features of "smoker's face."

PMID- 10411406
TI  - Public knowledge, awareness, and perceptions of the association between skin
      aging and smoking.
AB  - BACKGROUND: Although the tobacco industry promotes images of glamour, 2 decades
      of epidemiologic research have concluded the opposite: smokers have enhanced
      facial aging and skin wrinkling compared with nonsmokers. OBJECTIVE: The purpose
      of this study was to obtain information on the public's awareness of the
      association between cigarette smoking and skin aging. METHODS: In the spring of
      1994, the Maine-wide Cooperative Telephone Survey conducted telephone interviews
      in 678 randomly selected, nonseasonal dwelling units in Maine. From each dwelling
      unit, one randomly selected adult resident was interviewed to assess awareness of
      the association of skin aging with smoking. RESULTS: Fifty-eight percent of those
      persons interviewed had smoked at least 100 cigarettes, and among them, 24% were
      current smokers (28% men, 21% women). After adjusting for sex, age, and
      education, current smokers remained less likely to be aware of this association
      compared with former (prevalence ratio, 0.78; 95% confidence interval, 0.64-0.95)
      and never smokers (prevalence ratio, 0.87; 95% confidence interval, 0.70-1.07).
      However, nearly one fourth of smokers in this study believed that most or some
      smokers would consider this information in their decision to quit, with slightly
      higher findings in young smokers. CONCLUSION: These findings are of public health
      importance. While strategies for framing messages about the association between
      smoking and facial aging await further study, this association deserves to be
      considered in all tobacco control and counter-advertising campaigns.

PMID- 10411407
TI  - Porphyria cutanea tarda and hepatitis C virus: a case-control study and meta
      analysis of the literature.
AB  - BACKGROUND: Porphyria cutanea tarda (PCT) and hepatitis C virus (HCV) infection
      have been associated in several reports with the prevalence of HCV exhibiting
      considerable regional variation. However, most reports were confounded by
      selection bias and a regional prevalence of HCV in the populations studied. In
      the United States, only a few cases of this association have been reported to
      date. OBJECTIVE: We concluded a study to evaluate the association between PCT and
      HCV in a US population. We used a case-control study design to control the
      systemic error that may occur during a selecting process or sampling procedure.
      METHODS: We reviewed the medical records of Wishard Memorial Hospital, a county
      hospital serving metropolitan Indianapolis, Indiana, to perform a retrospective
      case-control study of 26 patients with PCT (as case) against 149,756 regional
      volunteer blood donors (as control-1) and 51 patients receiving methotrexate for
      psoriasis (as control-2). HCV antibody titers and other liver abnormalities were
      our main outcome measures. We then performed a weighted meta-analysis of 17
      reports that had at least 17 patients in their study populations. RESULTS:
      Sixteen (94%) of 17 PCT patients tested for HCV were antibody positive. Among
      blood donors, only 255 or 0.17% were HCV antibody positive (P < 10(-5), two-sided
      chi-square test). Of 5 psoriasis patients tested for HCV, none were HCV antibody
      positive (P = .0002, two-sided Fisher's exact test). For geographic comparison,
      meta-analysis of the literature demonstrated a varying regional prevalence of HCV
      in PCT patients as follows: Northern Europe 17%, Australia/New Zealand 20%, and
      Southern Europe 65%. CONCLUSION: Although a marked geographic variation was found
      in the worldwide prevalence of HCV in PCT patients, a very large percentage of US
      patients with PCT had HCV infection. Our results emphasize the need for
      clinicians to actively look for HCV in patients with PCT.

PMID- 10411408
TI  - Follow-up and evaluation of skin cancer screening in British Columbia.
AB  - BACKGROUND: Skin cancer screening is thought to be a useful public health tool
      for the early detection of skin cancers. However, few studies have reported on
      follow-up and outcome of subjects who have a positive screen. OBJECTIVE: The aims
      of this study were to evaluate attendance at skin cancer screening clinics in
      British Columbia for the period 1994 and 1995 and to assess follow-up outcome
      among participants who were identified to have a potentially serious skin lesion
      that warranted further medical review. METHODS: A self-administered questionnaire
      was sent to participants screening positive for skin cancer and to their
      attending physicians. RESULTS: Five hundred twenty people were screened. Of
      these, 105 were referred for evaluation of a potential malignancy or precursor
      lesion. One melanoma, 3 basal cell carcinomas, 4 atypical nevi, and 1 actinic
      keratosis were histologically confirmed in 76 referred participants for whom
      follow-up information was available. The positive predictive values ranged from
      17% to 89% depending on the screening diagnosis. Several false-positive results
      and one false-negative result were observed. Reasons for not seeking recommended
      follow-up were addressed. CONCLUSIONS: Our yield and positive predictive values
      for different screening diagnoses were virtually identical to those previously
      reported in larger US studies. Improved communication between screening
      physicians and screening participants may improve follow-up rates in those people
      who would benefit from further medical care.

PMID- 10411409
TI  - Immunohistochemical evaluation of androgen receptors in genital and extragenital
      lichen sclerosus: evidence for loss of androgen receptors in lesional epidermis.
AB  - BACKGROUND: Reduction of lichen sclerosus has been seen with topical
      testosterone, and spontaneous resolution has been attributed to increasing
      androgen levels. OBJECTIVE: Our purpose was to investigate the role of androgens
      in lichen sclerosus by studying lesional skin and site-specific normal skin for
      the presence of androgen receptors. METHODS: Immunoperoxidase staining for
      androgen receptors was performed on lesional tissue from 31 patients and
      microscopically compared with site-specific normal skin. RESULTS: Androgen
      receptors were present in normal genital and extragenital skin. Lesional genital
      and extragenital areas showed decreased staining compared with site-specific
      controls. Finally staining was decreased in histologically well-developed lesions
      compared with early lesions. CONCLUSION: This study provides evidence for the
      loss of androgen receptors with disease progression in both genital and
      extragenital skin affected by lichen sclerosus. These findings support a hormonal
      pathogenesis of lichen sclerosus and may be significant in the treatment of the
      disease.

PMID- 10411410
TI  - Ultraviolet A1 (340-400 nm) phototherapy for cutaneous T-cell lymphoma.
AB  - BACKGROUND: The results of a recent study suggested that ultraviolet A1 radiation
      (UVA1R; 340-400 nm) phototherapy for atopic dermatitis works through induction of
      apoptosis in skin-infiltrating helper T cells, indicating the possibility that
      other helper T cell-mediated skin diseases may respond to UVA1R as well.
      OBJECTIVE: The purpose of this open pilot study was to assess the therapeutic
      effectiveness of UVA1 phototherapy for cutaneous T-cell lymphoma (CTCL). METHODS:
      UVA1 phototherapy was used as monotherapy in patients (n = 3) with histologically
      proven CTCL (stages IA and IB). For daily whole body UVA1 irradiations, either a
      high-dose (n = 2; 130 J/cm2 UVA1 per exposure) or medium-dose (n = 1; 60 J/cm2
      UVA1) regimen was used. Therapeutic effectiveness was assessed clinically and
      histologically. RESULTS: In each of the 3 patients, skin lesions began to resolve
      after only a few UVA1 radiation exposures. Complete clearance was observed
      between 16 and 20 exposures, regardless of whether the high- or medium-dose
      regimen had been employed. CONCLUSION: These studies suggest that patients with
      CTCL stages IA and IB can be treated effectively with UVA1 phototherapy.

PMID- 10411411
TI  - Duration of remission of psoriasis therapies.
AB  - The armamentarium of therapies for psoriasis continues to expand with drugs such
      as tazarotene, calcipotriene, and acitretin approved in recent years. New forms
      of old treatments such as cyclosporine and anthralin have also been introduced.
      Frequently, inadequate attention is devoted to duration of remission. The purpose
      of this article is to examine the duration of remission reported with many
      therapies currently used for psoriasis. Studies examining duration of remission
      are included. Among our conclusions were the following: the definitions of
      remission/relapse used in various studies differ, duration of remission is
      influenced by the natural history of each patient's disease, among topical
      monotherapies anthralin and tazarotene appear to induce longer remissions than
      calcipotriene and corticosteroids, among systemic agents longer remissions occur
      with etretinate than cyclosporine or methotrexate but compared with the remission
      rate of phototherapeutic modalities, especially Goeckerman and PUVA therapy, the
      remission rates are much less.

PMID- 10411412
TI  - An open study of tinea capitis in 50 children treated with a 2-week course of
      oral terbinafine.
AB  - BACKGROUND: Terbinafine is used in the treatment of dermatophyte infections.
      There have been several studies suggesting a good response to terbinafine in
      treating tinea capitis, specifically with dermatophytes of the Trichophyton
      species. METHODS: We enrolled 50 consecutive children with a clinical diagnosis
      of tinea capitis into an open study using terbinafine for 2 weeks. RESULTS:
      Clinical and mycologic cure occurred in more than 86% of patients with no side
      effects and good compliance. CONCLUSION: In this study terbinafine was a safe and
      effective treatment of tinea capitis in children, particularly when caused by the
      Trichophyton species.

PMID- 10411413
TI  - Recurrence rate of hirsutism after 3 different antiandrogen therapies.
AB  - BACKGROUND: Although antiandrogens are frequently and successfully used to treat
      hirsutism, little attention has been paid to optimal duration of treatment and
      recurrence rate after cessation of therapy. OBJECTIVE: Our purpose was to
      determine the recurrence rate of hirsutism after 3 different antiandrogen
      therapies. METHODS: Eighty-one hirsute women referred to a tertiary hirsutism
      clinic were assigned to one of three regimens: spironolactone 100 mg/day with an
      oral contraceptive, cyproterone acetate 50 mg/day on days 1 to 10 with an oral
      contraceptive, or flutamide 250 mg twice a day. Hirsutism scores according to the
      Ferriman-Gallwey scoring system and endocrine parameters were evaluated before,
      during, and 1 year after withdrawal of treatment regimens. RESULTS: Hirsutism
      scores decreased significantly and similarly in spironolactone, flutamide, and
      cyproterone acetate treatment groups. However, 1 year after withdrawal of
      treatment in all antiandrogen therapy groups, hirsutism returned. CONCLUSION:
      Antiandrogens are effective in the treatment of hirsutism. However, cessation of
      antiandrogen therapy is followed by recurrence.

PMID- 10411414
TI  - Basal cell carcinoma: a comparison of shave biopsy versus punch biopsy techniques
      in subtype diagnosis.
AB  - BACKGROUND: There are two standard ways to obtain tissue for histologic
      classification of a clinically suspected basal cell carcinoma: shave and punch
      biopsy. However, information on the value of each method is limited. OBJECTIVE:
      The purpose of this study was to identify accuracy rates of two standard biopsy
      techniques in diagnosing subtypes of basal cell carcinoma. METHODS: A total of 86
      cases were identified that had received either a punch or a shave biopsy with
      subsequent total excision of tumor. The biopsy specimens and excisions were
      compared for histologic correlation. RESULTS: Analysis of specimens from punch
      and shave biopsies produced equivalent diagnostic accuracy rates: 80.7% and
      75.9%, respectively. There was no statistically significant tendency to overcall
      or undercall any particular tumor subtype on the basis of the type of biopsy
      procedure used. CONCLUSION: For histologic classification of basal cell
      carcinoma, there is an approximately 80% accuracy rate with both the shave and
      the punch biopsy. Therefore either biopsy technique is appropriate.

PMID- 10411415
TI  - Biochemical and immunologic mechanisms in atopic dermatitis: new targets for
      emerging therapies.
AB  - The immunologic and pharmacophysiologic features of atopic dermatitis have
      stimulated research seeking to identify relevant effector cells and mediators
      that characterize chronic skin inflammation. The theory that unifies the various
      abnormalities associated with atopic dermatitis suggests that hematopoietic cells
      carrying abnormal genetic expressions of atopy cause clinical disease once they
      infiltrate the skin and mucosa. The proposed underlying mechanism may be either
      abnormalities in cyclic nucleotide regulation of marrow-derived cells or
      allergenic overstimulation that causes secondary abnormalities. The primacy of
      one mechanism over the other remains unresolved, but this does not obviate their
      value in identifying two novel therapeutic targets: phosphodiesterase inhibition
      and immune-intervention alternatives to corticosteroids. New type IV
      phosphodiesterase inhibitors are proving promising in topical formulations, as
      are inhibitors of calcineurin, such as FK506 and SDZ ASM 981, an ascomycin
      macrolactam derivative that in early clinical research appears to offer the
      potency of a corticosteroid without its adverse side effects. The promising
      clinical trial profiles of these new topical agents may result in alternative
      therapies providing potent anti-inflammatory activity without the adverse effects
      that limit corticosteroid use.

PMID- 10411416
TI  - Surgical pearl: the Red Rubber Robinson bolster in cutaneous surgery.

PMID- 10411417
TI  - The health impact of solar radiation and prevention strategies: Report of the
      Environment Council, American Academy of Dermatology.
AB  - It is well recognized that exposure to solar radiation is a major risk factor for
      the development of skin cancer, photoaged skin, and immune system alterations.
      However, major questions remain regarding the specific wavelengths and type of
      exposure that incur risk. The purpose of this article is to critically examine,
      on the basis of current knowledge, the impact of stratospheric ozone depletions,
      tanning bed skin cancer risk, the safety of sunscreens as an important element of
      our solar protection strategies, the wavelengths of solar radiation responsible
      for melanoma, and the incidence of melanoma. Recommendations are made on
      prevention strategies and public health messages.

PMID- 10411418
TI  - Atrophie blanche-like scarring after pulsed dye laser treatment.
AB  - Pulsed dye laser treatment is well established for the treatment of port-wine
      stains and other vascular skin lesions. Although hyperpigmentation is quite
      common, other side effects such as hypopigmentation and atrophic scarring occur
      infrequently, and hypertrophic scarring is rare.

PMID- 10411419
TI  - Drug-induced linear IgA bullous dermatosis probably induced by furosemide.
AB  - Linear IgA bullous dermatosis (LABD) is an autoimmune disease, characterized by
      linear deposition of IgA along the basement membrane zone. Drug-induced LABD is
      rare but increasing in frequency. A new case of drug-induced LABD associated with
      the administration of furosemide is described.

PMID- 10411420
TI  - Development of Peyronie's and Dupuytren's diseases in an individual after single
      episodes of trauma: a case report and review of the literature.
AB  - A case is presented in which a patient experienced the development of both
      Dupuytren's disease and Peyronie's disease after single episodes of sports
      related trauma. These disorders and other fibromatoses are linked not only by
      similar pathologic features but by increased frequency of simultaneous
      occurrence. Some genetically predisposed individuals experience the development
      of the disorders after trauma or after some other factor unmasks that
      predisposition. A review of the literature with emphasis on the relationship
      between these fibromatoses and the varied nonsurgical attempts at treatment is
      presented.

PMID- 10411421
TI  - Eccrine angiomatous hamartoma: report of a case and literature review.
AB  - Eccrine angiomatous hamartoma is a rare condition characterized histologically by
      increased numbers of eccrine structures and numerous capillary channels. Patients
      characteristically have a solitary, congenital nodule that may be painful and
      that may show hyperhidrosis. It is important to recognize this condition because
      it is a benign lesion for which aggressive treatment is not indicated. We report
      the case of a congenital eccrine angiomatous hamartoma that had a firm nodule
      studded with blue papules.

PMID- 10411422
TI  - Tufted hair folliculitis: a pattern of scarring alopecia?
AB  - We present a patient with pemphigus vulgaris who, over the years, experienced the
      development of tufted hair folliculitis as a result of scalp involvement.
      Multiple hairs emerged from widely dilated follicular ostia surrounded by
      indurated, scarred skin. Histopathologic findings were typical for tufted hair
      folliculitis. We believe that because a specific host response to scalp injury
      might be crucial to the development of this rare disorder, it should be regarded
      as a type of scarring alopecia.

PMID- 10411423
TI  - Ectopic hidradenoma papilliferum: a case report and review of the literature.
AB  - Hidradenoma papilliferum is a benign, cystic, papillary tumor that occurs almost
      exclusively in women on the skin of the anogenital region. Nonanogenital
      (ectopic) hidradenoma papilliferum are rare. We describe a 72-year-old white man
      with an enlarging nodule in the region of the right triceps muscle; microscopic
      examination showed a hidradenoma papilliferum. The median age of patients with
      ectopic hidradenoma papilliferum is between 1 to 2 decades older than the average
      age range of lesion onset in patients with anogenital hidradenoma papilliferum.
      In contrast to anogenital hidradenoma papilliferum, nearly one half of the
      patients with ectopic hidradenoma papilliferum are men. Ectopic hidradenoma
      papilliferum occurs most frequently (60%) in the head and neck region. Eighty
      five percent of cases are 1.5 cm in the greatest diameter or smaller. The race,
      clinical features, pathologic features, treatment, and prognosis for hidradenoma
      papilliferum occurring in anogenital and ectopic locations are similar.

PMID- 10411424
TI  - Acute varicella zoster with postherpetic hyperhidrosis as the initial
      presentation of HIV infection.
AB  - A 31-year-old man presented with acute pain in his left arm and hemorrhagic
      vesicles that followed his left 8th cervical nerve. A diagnosis of herpes zoster
      was made, and the patient was treated with valacyclovir. He refused testing for
      antibodies to HIV because he denied being at risk. Two months later he returned
      with postherpetic neuralgia and postherpetic hyperhidrosis in the distribution of
      the vesicles, which had since resolved. Serology for HIV at this visit was
      positive, and the patient admitted to having sexual relations with prostitutes.
      Six months later the patient was being treated with triple antiretroviral
      therapy, and all signs and symptoms of postherpetic zoster had resolved. This
      case report documents the need for HIV testing in patients with unusual
      presentations of herpes zoster even if they initially deny being at risk.

PMID- 10411425
TI  - Photosensitivity in the Smith-Lemli-Opitz syndrome: the US experience of a new
      congenital photosensitivity syndrome.
AB  - Photosensitivity has been briefly mentioned in several publications on the Smith
      Lemli-Opitz (SLO) syndrome, an autosomal recessive mental retardation syndrome.
      We conducted a questionnaire-based survey to determine the incidence and main
      features of photosensitivity in SLO. We confirmed a high incidence, and initial
      evidence suggests that SLO may be the first example of an inherited
      photosensitivity disorder in which sensitivity to UVA is common.

PMID- 10411426
TI  - Cimetidine therapy for recalcitrant warts in adults: is it any better than
      placebo?
AB  - Three open-label, uncontrolled studies have documented successful treatment of
      warts with cimetidine, whereas two placebo-controlled, double-blind studies and
      two open-label comparative trials have failed to demonstrate efficacy. This
      double-blind, placebo-controlled study was designed with stringent enrollment and
      outcome criteria to minimize the confounding issue of spontaneous remission.
      Efficacy was not statistically superior to that of placebo, but a trend toward
      efficacy was suggested for younger subjects.

PMID- 10411427
TI  - Expression of basic fibroblast growth factor and its receptor in angiosarcoma.
AB  - Angiosarcoma, a rare aggressive malignant tumor thought to be of vascular origin
      with high potential for metastasis, frequently occurs on the scalp of elderly
      people. Recent findings have shown that overexpression of basic fibroblast growth
      factor and its receptor is associated with neoplasia, which suggests that basic
      fibroblast growth factor promotes tumor vascularization and subsequent growth. In
      this study, we examined the immunohistologic localization of basic fibroblast
      growth factor and its receptor in angiosarcoma. Our results suggest that basic
      fibroblast growth factor synthesized in the tumor endothelial cells plays an
      important role in the growth and progression in angiosarcoma and that serum basic
      fibroblast growth factor levels are elevated in patients with nodular type
      angiosarcoma.

PMID- 10411429
TI  - Risk of melanoma in medium-sized congenital melanocytic nevi.

PMID- 10411428
TI  - Cost analysis studies of Mohs micrographic surgery.

PMID- 10411430
TI  - Perioperative care of the colorectal patient.

PMID- 10411432
TI  - In vivo real-time analysis of intraperitoneal radiolabeled tumor cell movement
      during laparoscopy.
AB  - PURPOSE: A porcine model has been developed to allow the real-time imaging of
      radiolabeled tumor cell movement throughout the peritoneal cavity, both at rest
      and during carbon dioxide insufflation. METHODS: Fifteen 30-kg domestic white
      female pigs were used. Under anesthesia, 15 to 20 million radiolabeled human
      colorectal tumor cells (LIM1215) were introduced into the peritoneal cavity under
      laparoscopic vision into the pelvis. Radiolabeled tumor cell movement was
      examined by using a 25-cm-diameter, low-energy mobile gamma camera with high
      resolution collimator. Tumor cell movement and distribution during two hours
      without insufflation was examined in four pigs. Then tumor cell movement and
      distribution during two hours with CO2 insufflation was examined in four pigs. In
      a further four pigs, tumor cells were then mixed with blood and injected into the
      peritoneal cavity and the effect of no insufflation vs. insufflation was noted. A
      further three pigs were examined with manipulation of the intra-abdominal
      contents after injection of LIM1215 cells into the peritoneal cavity. Venting
      insufflating CO2 was filtered for tumor cells. RESULTS: Widespread
      intraperitoneal distribution of tumor cells from the pelvis was identified both
      with CO2 insufflation of the peritoneal cavity and without insufflation. Tumor
      cells dispersed throughout the peritoneal cavity at a slower rate without carbon
      dioxide insufflation. There was a differential rate of tumor cell movement to the
      left upper quadrant and right upper quadrant with insufflation and without
      insufflation. Blood within the peritoneal cavity and an extended contact of the
      laparoscopic trocars with the peritoneal cavity in this setting increased
      contamination of the trocars and trocar sites with tumor cells. Tumor cells were
      identified on laparoscopic instruments in all experiments. No evidence of
      aerosolization of tumor cells was found. CONCLUSION: Tumor cells move throughout
      the peritoneal cavity both at rest and during CO2 insufflation. The pattern of
      tumor cell dispersion differs with CO2 insufflation. The presence of blood and
      extended contact of trocars with peritoneal contents are a major factor in trocar
      and trocar site tumor cell contamination.

PMID- 10411431
TI  - Long-term cost of fecal incontinence secondary to obstetric injuries.
AB  - INTRODUCTION: Anal incontinence is eight times more frequent in females than in
      males because of injuries sustained at childbirth. The aim of the present study
      was to determine the long-term costs associated with anal incontinence related to
      obstetric injuries. METHODS: Sixty-three patients with anal incontinence caused
      by obstetric sphincter injuries answered questionnaires regarding previous
      treatments, symptoms, and use of protective products. Of the patients, 31 were
      treated surgically, 11 with biofeedback, 6 with a combination of surgery and
      biofeedback, and 15 conservatively. Treatments and their respective costs were
      obtained from patient records, patient questionnaires, billing database, and
      Health Care Financing Administration's 1996 inpatient database. Costs were
      expressed in 1996 dollars. RESULTS: The mean incontinence score changed from 26
      at evaluation to 16 at follow-up (P < 0.001). The average cost per patient was
      $17,166. Evaluation and follow-up charges totaled $65,412, and physiologic
      assessment accounted for 64 percent of these costs. Treatment charges totaled
      $559,341, and physician charges accounted for 18 percent of these charges.
      CONCLUSIONS: Fecal incontinence after childbirth results in substantial economic
      costs, and treatment is not always successful. New treatment modalities, such as
      artificial bowel sphincter or dynamic graciloplasty, should be assessed to
      determine their cost-effectiveness.

PMID- 10411433
TI  - Colorectal cancer after surveillance colonoscopy: false-negative examination or
      fast growth?
AB  - PURPOSE: Colonoscopy is the preferred method for colorectal cancer surveillance
      of high-risk patients. Despite its high sensitivity, polyps or cancers may be
      undetected by colonoscopy and later attributed to an accelerated adenoma
      carcinoma sequence. This study assesses how the characteristics of colorectal
      cancers found at intervals between surveillance relate to the adenoma-carcinoma
      sequence and its prevention. METHODS: The records of 557 patients with colorectal
      cancer that were diagnosed from January 1, 1990, to December 31, 1996, were
      reviewed to identify those patients who had prior colonoscopic surveillance
      within 60 months of their diagnosis. RESULTS: There were 29 (5.2 percent)
      patients who had one or more colonoscopies before diagnosis of their colorectal
      cancer. Mean interval between diagnosis and prior colonoscopy was 23 (range, 4
      59) months. The distribution of cancers included nine cecum, two ascending, three
      hepatic flexure, five transverse, one splenic flexure, three descending, two
      sigmoid, three rectum, and one anal canal. The mean tumor size was 4.4 cm for the
      cecum and 2.4 cm for all other locations. There were 7 Tis, 6 T1, 4 T2, and 12 T3
      lesions. Six patients with T3 lesions had prior colonoscopies within 24 months of
      the diagnosis. Three of four patients with lymphatic metastases had tumors in the
      cecum. Twenty tumors (69 percent) were well or moderately differentiated. Mean
      follow-up was 41 (range, 7-95) months with two local recurrences and two
      unrelated deaths. CONCLUSIONS: Size, differentiation, and stage of colorectal
      cancer in addition to the interval to diagnosis suggest that the majority of
      cancers found during surveillance colonoscopy followed prior false-negative
      examinations. Because cecal landmarks are most constant, prior photographic
      documentation may help to prove or disprove fast growth of cancers found in the
      cecum during surveillance colonoscopy.

PMID- 10411434
TI  - All patients with small intramural rectal cancers are at risk for lymph node
      metastasis.
AB  - PURPOSE: Although local excision can be curative in patients with early-stage
      rectal cancer, approximately 20 percent of patients will develop local
      recurrence, many as a result of unrecognized and unresected regional lymph node
      metastases. Our objective was to determine if standard pathologic factors can
      predict lymph node metastases in small intramural rectal cancers and provide a
      basis for patient selection for nonradical surgery. METHODS: Between June 1986
      and September 1996, 318 patients with T1 or T2 rectal cancers underwent radical
      resection at our institution. Of these, 159 patients (48 T1 and 111 T2) were
      potentially eligible for curative local excision (< or =4 cm in size, < or =10 cm
      from the anal verge, no synchronous metastases), and the prevalence of lymph node
      metastases based on T stage and other pathologic factors was analyzed in this
      group. RESULTS: The overall frequency of lymph node metastasis was 15 percent
      (24/159 patients). T stage (T1, 10 percent; T2, 17 percent), differentiation
      (well-differentiated or moderately differentiated, 14 percent and poorly
      differentiated, 30 percent), and lymphatic vessel invasion (lymphatic vessel
      invasion-negative, 14 percent and lymphatic vessel invasion-positive, 33 percent)
      influenced the risk of lymph node metastasis. However, only blood vessel invasion
      (blood vessel invasion-negative, 13 percent and blood vessel invasion-positive,
      33 percent) reached statistical significance as a single predictive factor
      (P=0.04). Tumors with no adverse pathologic features (low-risk group) had a lower
      overall frequency of lymph node metastasis (11 percent) compared with the
      remaining tumors (high-risk group, 31 percent; P=0.008). However, even in the
      most favorable group (T1 cancers with no adverse pathologic features) lymph node
      metastases were present in 7 percent of patients. CONCLUSION: In rectal cancer
      patients potentially eligible for local excision, the overall risk of undetected
      and untreated lymph node metastases is considerable (15 percent). The use of
      pathologic factors alone after local excision does not reliably assure the
      absence of lymph node metastases.

PMID- 10411435
TI  - Intraoperative irradiation after surgery for locally recurrent rectal cancer.
AB  - PURPOSE: This study retrospectively evaluated the effects of intraoperative
      electron beam irradiation on patients with locally recurrent (pelvic) rectal
      cancer. METHODS: From November 1, 1975, to December 31, 1997, 51 patients
      underwent surgery for locally recurrent rectal or rectosigmoid cancer, and 27
      patients received intraoperative electron beam irradiation. The intraoperative
      electron beam irradiation dose was 15 to 30 Gy. Kaplan-Meier survival estimates
      at three and five years were analyzed for the 47 patients who recovered
      postoperatively. RESULTS: Statistically significant factors related to survival
      included intraoperative electron beam irradiation vs. no intraoperative electron
      beam irradiation (P=0.0007), amount of residual tumor (slight vs. gross;
      P=0.0022), and symptom status (P=0.0024). Factors not associated with survival
      included distant metastases at reoperation, type of surgery for the recurrent
      tumor, external beam irradiation, pathologic grade, age, and gender. Surgical
      resection without intraoperative electron beam irradiation resulted in three-year
      and five-year survival rates of 5 and 0 percent, respectively. For patients who
      received intraoperative electron beam irradiation, the three-year survival rate
      was 43 percent and five-year survival rate was 21 percent. Intraoperative
      electron beam irradiation was a statistically significant factor related to
      survival in patients with and without distant metastasis (P=0.04 and P=0.0035,
      respectively), with slight residual tumor (P=0.0003), or with palliative surgery
      (P=0.0276). CONCLUSION: The trends seen in resection with intraoperative electron
      beam irradiation are encouraging with regard to improvements in survival as
      compared with studies not using intraoperative electron beam irradiation
      treatment.

PMID- 10411436
TI  - Colonic pouch vs. side-to-end anastomosis in low anterior resection.
AB  - PURPOSE: Colonic pouches have gained increasing popularity in reconstruction
      after low anterior resection. In this prospective, randomized trial colonic pouch
      reconstruction is compared with side-to-end anastomosis for functional outcome.
      METHODS: From October 1995 to October 1996, 29 patients had colonic pouch and 30
      patients had side-to-end anastomosis reconstruction after low anterior resection.
      Patients were matched for age, gender, and tumor stage and localization. All
      patients underwent functional evaluation preoperatively and at three and six
      months postoperatively. RESULTS: There was no difference in preoperative
      anorectal function. The operating time was higher in the colonic pouch group (167
      vs. 149 minutes). Twenty-three patients (79.3 percent) with colonic pouch had a
      protective stoma compared with 21 patients (70 percent) with side-to-end
      anastomosis. Postoperative complications were 10.3 and 13.3 percent,
      respectively. There was no difference in manometric pressure of the anus, in
      anorectal angle, and in continence status after three and six months. Stool
      frequency was higher in the side-to-end anastomosis group, with 2.2 vs. 5.4 per
      day at three months and 2.3 vs. 3.1 per day at six months. Constipation was noted
      in two patients with colonic pouch (7 percent) and none in the side-to-end
      anastomosis group at three months and two vs. none at six months. Maximum
      tolerated volume and threshold volume was higher in the colonic pouch group at
      three and at six months. CONCLUSION: Both forms of reconstruction have similar
      satisfactory long-term functional results. The major advantage of colonic pouch
      was seen in the immediate postoperative phase.

PMID- 10411437
TI  - Functional outcome of conversion of ileorectal anastomosis to ileal pouch-anal
      anastomosis in patients with familial adenomatous polyposis and ulcerative
      colitis.
AB  - PURPOSE: The aim of this study was to review the functional outcome in 20
      patients with familial adenomatous polyposis and ulcerative colitis who were
      converted from ileorectal anastomosis to ileal pouch-anal anastomosis. METHODS:
      From 1985 to 1997, 12 patients with familial adenomatous polyposis (5 males; mean
      age, 39.1 years) and 8 patients with ulcerative colitis (5 males; mean age, 36.7
      years) underwent conversion from ileorectal anastomosis to ileal pouch-anal
      anastomosis. Clinical and operative data were analyzed retrospectively.
      Functional results were obtained by telephone interview in 16 patients (94
      percent) after pouch construction. Four patients were not interviewed (2 were
      deceased, 1 was lost to follow-up, and 1 was not reachable). RESULTS: Indications
      for conversion were uncontrollable rectal polyps (10 patients) and colonic cancer
      found in the pathology specimen after ileorectal anastomosis in patients with
      familial adenomatous polyposis (2 patients), intractable proctitis (5 patients),
      colonic cancer found in the pathology specimen of patients with ulcerative
      colitis after ileorectal anastomosis (2 patients), and rectal dysplasia (1
      patients). Mean follow-up time was 5 (range, 1-11) years. Ileal pouch-anal
      anastomosis was handsewn in 14 patients, and the remaining cases were double
      stapled in 4 patients with ulcerative colitis. No intraoperative difficulties
      were reported in 13 cases; technical problems were related to adhesions (3
      cases), difficult rectal dissection (2 cases), and stapler-related difficulties
      (2 cases). Postoperative complications after ileal pouch-anal anastomosis
      included small-bowel obstruction (4 patients) and ileal pouch-anal anastomosis
      leak (1 patient). Patients with ileorectal anastomosis vs. those with ileal pouch
      anal anastomosis had a better functional outcome with regard to nighttime
      continence (14 (88 percent) vs. 6 (38 percent) patients) and average bowel
      movements (<6/day; 12 (75 percent) vs. 4 (25 percent) patients). Complete daytime
      continence, 15 (94 percent) vs. 10 (62 percent) patients, was similar in the two
      groups. Physical and emotional well-being were similarly rated as very good to
      excellent. CONCLUSIONS: In patients with familial adenomatous polyposis and
      ulcerative colitis with ileorectal anastomosis, conversion to ileal pouch-anal
      anastomosis may be required. In view of the risk of rectal cancer or intractable
      proctitis, patients seem to accept the conversion in spite of poorer bowel
      function.

PMID- 10411438
TI  - Limited hemorrhoidectomy: results and long-term follow-up.
AB  - PURPOSE: Three-column excision has traditionally been the preferred treatment for
      symptomatic hemorrhoidal disease in patients failing nonoperative treatments.
      There are few data evaluating focused surgical management of only the symptomatic
      hemorrhoidal complexes by limited hemorrhoidectomy. The purpose of this study was
      to evaluate patient outcome after one-quadrant or two-quadrant hemorrhoidectomy
      for symptomatic hemorrhoids. METHODS: We retrospectively studied patients
      undergoing a one-quadrant or two-quadrant hemorrhoidectomy as initial surgical
      treatment of symptomatic columns from April 1987 to July 1993. Patients
      undergoing a traditional three-quadrant hemorrhoidectomy during the same time
      period were used as controls. Statistical analysis was used to determine
      significance. RESULTS: There were 115 evaluable patients who had undergone a one
      quadrant or two-quadrant hemorrhoidectomy. One hundred thirty-three three
      quadrant patients were studied as the control group. The mean follow-up was 8.1
      years and 7.2 years for the limited and three-quadrant hemorrhoidectomy group,
      respectively. The majority of patients (96 percent limited and 98 percent three
      quadrant) experienced initial relief of symptoms after surgery. There was no
      significant difference between the two groups in the development of recurrent
      anorectal symptoms (34 percent limited and 29 percent three-quadrant), in the
      need for additional medical therapy (11.3 percent limited and 15.8 percent three
      quadrant), or in the need for additional interventional therapy (2.9 percent
      limited and 0.8 percent three-quadrant). No patients in either group required
      additional surgical hemorrhoidectomy. CONCLUSIONS: The majority of patients with
      hemorrhoidal disease requiring excision can be managed effectively by focused
      treatment of the problematic columns. With this approach fewer than 2 percent of
      patients will require further procedural intervention of their hemorrhoidal
      disease.

PMID- 10411439
TI  - Lloyd-Davies position with Trendelenburg--a disaster waiting to happen?
AB  - PURPOSE: Lower limb compartment syndrome has been reported to occur after
      colorectal, urological, and gynecological procedures during which the patient's
      lower limbs are elevated for prolonged periods of time. METHOD: We investigated
      lower limb perfusion in a group of patients undergoing prolonged pelvic surgery
      both during and immediately after surgery, using intra-arterial blood pressure
      monitoring, laser doppler flowmetry, and pulse oximetry. RESULTS: Use of the
      modified lithotomy position was not associated with any demonstrable decrease in
      lower limb perfusion. The addition of 15 degrees head-down tilt, however, during
      pelvic dissection, led to an immediate and significant drop in lower limb
      perfusion (P < 0.05; Mann-Whitney U test). The subgroup of patients analyzed
      postoperatively showed a ten-fold increase (P < 0.01) in perfusion that was
      confined to the muscle compartment with no demonstrable increase in skin
      perfusion or intra-arterial pedal blood pressure. CONCLUSION: The use of the
      modified lithotomy position during pelvic surgery is not associated with lower
      limb ischemia. Addition of Trendelenburg position, however, causes profound
      ischemia of the lower limbs, and this is followed during the recovery period by
      hyperperfusion that is confined to the muscle compartments, which may put
      patients at risk of developing lower limb compartment syndrome.

PMID- 10411440
TI  - Should carcinoembryonic antigen be used in the management of patients with
      colorectal cancer?
AB  - The contribution of carcinoembryonic antigen carcinoembryionic antigen for the
      effective management of colorectal cancer patients remains a controversial issue.
      The aim of this study is to attempt to get some valid answers to its function in
      the diagnosis, prognosis, and overall management of colorectal cancer patients.
      METHODS: A retrospective review of colorectal cancer patients managed and
      prospectively registered by the authors between 1985 and 1998 was performed.
      Serum carcinoembryionic antigen levels were determined preoperatively in 209
      patients with primary colorectal cancer and postoperatively in 196 patients who
      had undergone curative resection of their tumors, according to a fixed schedule.
      A maximum value of 5 ng/ml was accepted as being normal. With the exception of
      endoscopy, all other diagnostic techniques were only used after an abnormal
      carcinoembryionic antigen result (a raised value found twice consecutively).
      RESULTS: carcinoembryionic antigen preoperative values were raised only in 40
      percent of patients and were related to disease stage, with the highest values
      found in patients with Stage IV disease. However, an elevated preoperative
      carcinoembryionic antigen value had a very marked prognostic importance, with a
      statistically significant difference in survival curves (Kaplan-Meier); the same
      was valid for curatively resected patients (Stages I, II, and III) and for Stages
      II and III patients considered separately. Multivariate analysis using the Cox
      proportional hazards technique confirmed these results, showing preoperative
      carcinoembryionic antigen to have an independent prognostic value, with a
      relative risk of recurrence of 3.74 for patients with raised preoperative
      carcinoembryonic antigen levels. In postoperative follow-up, carcinoembryionic
      antigen elevation was found to be a very accurate marker of recurrence
      (sensitivity, 77 percent; specificity, 98 percent), mainly in liver metastasis
      (sensitivity, 100 percent), and the best marker of asymptomatic recurrence (63
      percent of cases). However, carcinoembryionic antigen's impact on overall
      survival was negligible because of the poor results of surgical treatment of
      recurrences. CONCLUSIONS: Preoperative carcinoembryionic antigen is a very
      important prognostic indicator and should be considered in future trials.
      Postoperative carcinoembryionic antigen elevation is a very sensitive marker of
      recurrence and even of asymptomatic recurrence, but its impact on overall
      survival does not seem to be relevant. Nevertheless, carcinoembryionic antigen
      should continue to be used in colorectal cancer patients until better methods of
      diagnosis and treatment of recurrence are developed.

PMID- 10411441
TI  - Laparoscopic vs. open abdominoperineal resection for cancer.
AB  - PURPOSE: The aim of this study was to compare the safety and efficacy of
      laparoscopic abdominoperineal resection and open abdominoperineal resection for
      cancer. METHODS: Records of 194 patients who underwent laparoscopic
      abdominoperineal resection (42 patients) or open abdominoperineal resection (152
      patients) at three institutions between 1991 and 1997 were reviewed. Follow-up
      was through office charts, American College of Surgeons cancer registry, or
      telephone contact. Tumors included (laparoscopic abdominoperineal resection and
      open abdominoperineal resection, respectively) adenocarcinoma (86 and 92
      percent), squamous (12 and 7 percent), and gastrointestinal stromal (2 and 1.4
      percent) types; Stages I (17 and 26 percent), II (24 and 33 percent), III (43 and
      32 percent), and IV (14 and 9 percent); and those with invasion of pelvic
      structures (14 and 16 percent). RESULTS: Laparoscopic abdominoperineal resection
      was converted to open abdominoperineal resection in 21 percent because of vessel
      injury (33 percent), poor exposure (22 percent), adhesions (22 percent), inguinal
      hernia (11 percent), or radiation fibrosis (11 percent). Perineal infections
      occurred more often in the laparoscopic abdominoperineal resection group (24 vs.
      8 percent; P=0.02). Late stoma complications were similar. Mean hospital stay was
      shorter after laparoscopic abdominoperineal resection (7 vs. 12 days). Radial
      margins were positive in 12 percent of laparoscopic abdominoperineal resection
      and 12.5 percent of open abdominoperineal resection specimens. Tumor recurrence
      was similar for both local (19 and 14 percent) and distant (38 and 26 percent)
      recurrence. Survival rates were similar by Kaplan-Meier curves, with median
      follow-up of 19 and 24 months, respectively (P=0.22; log rank). CONCLUSION:
      Laparoscopic abdominoperineal resection can be performed safely and results in a
      shorter hospital stay. A randomized, prospective trial is needed to determine the
      long-term outcome of cancer treatment.

PMID- 10411442
TI  - Treatment of enterocele by obliteration of the pelvic inlet.
AB  - PURPOSE: Enterocele is defined as a herniation of the peritoneal sac between the
      vagina and the rectum. This hernial sac contains either sigmoid colon or small
      bowel. It is well known that enteroceles are associated with symptoms of pelvic
      discomfort. It is unclear whether enteroceles contribute to evacuation
      difficulties. Controversies also exist regarding their treatment of choice. The
      aim of the present prospective study was to evaluate the impact of obliteration
      of the pelvic inlet on evacuation difficulties and on symptoms of pelvic
      discomfort. METHODS: From October 1994 to August 1996 20 females (median age, 53;
      range, 41-73 years) with symptomatic enterocele diagnosed on evacuation
      proctography underwent obliteration of the pelvic inlet with a nonabsorbable
      Mersilene mesh. All patients presented with pelvic discomfort, characterized by
      feelings of prolapse (n=20), pelvic pressure (n=16), lower abdominal pain (n=13),
      and false urge to defecate (n=15). Symptoms of obstructed defecation were noted
      in 15 patients. Six months after repair, evacuation proctography with
      opacification of the small bowel and the vagina was repeated. RESULTS: The median
      duration of follow-up was 25 (range, 10-34) months. A persistent or recurrent
      enterocele was observed in none of the patients. All symptoms of pelvic
      discomfort disappeared except feelings of a false urge to defecate, which
      persisted in 27 percent of cases. Symptoms of obstructed defecation persisted in
      all patients with evacuation difficulties. CONCLUSIONS: In patients with pelvic
      discomfort enterocele should be considered as a possible causative factor. It is
      unlikely that this abnormality contributes to the problem of obstructed
      defecation. In patients with a symptomatic enterocele, obliteration of the pelvic
      inlet with a Mersilene mesh is an adequate treatment.

PMID- 10411443
TI  - Perianal Bowen's disease and anal intraepithelial neoplasia: review of the
      literature.
AB  - PURPOSE: The aim of this study was to review the literature with regard to
      perianal Bowen's disease and anal intraepithelial neoplasia. METHODS: A
      literature review was conducted from 1960 to 1999 using MEDLINE. RESULTS:
      Perianal Bowen's disease and anal intraepithelial neoplasia are precursors to
      squamous carcinoma of the anus. They are analogous to and are associated with
      cervical and vulvar intraepithelial neoplasia, and have human papillomavirus as a
      common cause. Biopsy and histopathologic examination is required for diagnosis
      and to distinguish other perianal dermatoses. Treatment options range from
      aggressive wide local excision of all disease with negative margins to
      observation alone for microscopic lesions not visible to the naked eye. The
      disease has a proclivity for recurrence and recalcitrance. CONCLUSIONS: Most
      surgeons caring for patients with perianal Bowen's disease and high-grade anal
      epithelial neoplasia use wide local excision, with an effort to obtain disease
      free margins. Some authors have reported the advantages of ablative procedures
      such as laser ablation and cryotherapy. Microscopic disease found serendipitously
      in hemorrhoidectomy specimens can probably be treated conservatively with serial
      examinations alone. There is a lack of controlled data supporting an optimal
      treatment strategy. A multicenter controlled study comparing wide local excision
      with ablative procedures may be warranted.

PMID- 10411444
TI  - Perianal lymphoma in a heterosexual and nonimmunocompromised patient: report of a
      case and review of the literature.
AB  - PURPOSE: This study was conducted to report a rare case of anorectal pathology.
      METHODS: We report a case of perianal lymphoma in a nonimmunocompromised,
      heterosexual patient and review the literature. RESULTS: A 67-year-old white male
      was found to have an ulcerated posterior anal mass. Biopsy revealed large cell
      lymphoma, B cell type, immunoblastic. There was no disseminated disease. The
      patient denied any homosexual activity and was HIV negative. There was complete
      resolution with chemotherapy (cyclophosphamide, doxorubicin, vincristine, and
      prednisone), and he remained disease free for six years. CONCLUSIONS: Rare
      anorectal pathology may mimic common conditions. Biopsies should be taken to rule
      out malignancy.

PMID- 10411445
TI  - Transverse colon diverticulitis: successful nonoperative management in four
      patients. Report of four cases.
AB  - PURPOSE: Diverticulitis of the transverse colon is a rare disorder and is often
      confused with other conditions. Previously reported cases of transverse colon
      diverticulitis were diagnosed and treated by surgical exploration. Four cases are
      presented that were successfully managed with a nonsurgical approach. METHODS AND
      RESULTS: Review of the literature in English disclosed 31 cases of transverse
      colon diverticulitis. The clinical characteristics and management of these
      patients are reviewed and compared with the current series of patients. The
      utility of computerized tomography in the diagnosis of diverticulitis is
      discussed. CONCLUSIONS: Medical therapy with bowel rest and antibiotics is
      appropriate for transverse colon diverticulitis when free perforation and
      peritoneal signs are absent and the inflammation is contained, as shown by
      computerized tomography. Operative exploration should be reserved for patients
      with diffuse peritonitis or those where perforated colon cancer cannot be
      excluded.

PMID- 10411446
TI  - Rectal injury caused by a personal watercraft accident: report of a case.
AB  - PURPOSE: An original case of rectal injury after a personal watercraft accident
      is reported. Principles of rectal trauma management are discussed. METHODS: We
      present a case of a rectal injury after a fall from a personal watercraft. Rigid
      sigmoidoscopy and a water-soluble contrast enema documented a posterior rectal
      tear. The patient was managed by diversion, drainage, and administration of
      antibiotics. RESULTS: The patient's rectal tear healed without complication.
      CONCLUSION: To our knowledge, this is the first reported case of an injury to the
      rectum as a result of a personal watercraft accident. A high suspicion of rectal
      injury must be maintained in victims who have fallen from the back of a personal
      watercraft. Treatment of a rectal injury should follow the basic principles of
      drainage, diversion, and administration of antibiotics, but variations in
      traditional management may be appropriate. Finally, preventative methods
      including wearing protective clothing, and possible modification to the
      watercraft to reduce risk of injury should be considered.

PMID- 10411447
TI  - Perineal reconstruction for severe sequela of ecthyma gangrenosum: report of a
      case.
AB  - Ecthyma gangrenosum is a cutaneous gangrenous disorder which usually follows
      Pseudomona aeruginosa infection and is found mainly in immunosuppressed children.
      We describe a case of a five-year-old female with leukemia with a severe perineal
      ecthyma gangrenosum resulting in a cloaca-like deformity. One year later a
      perineoplasty with puborectalis interposition and overlapping external anal
      sphincteroplasty was successfully performed, achieving satisfactory continence.

PMID- 10411448
TI  - Urinary retention after anorectal operations.

PMID- 10411449
TI  - Surgery for obstructed defecation: deja vu all over again?

PMID- 10411450
TI  - Enzymatic cleavage of peptide-linked radiolabels from immunoconjugates.
AB  - We have incorporated peptides selected by combinatorial library [Peterson, J. J.,
      and Meares, C. F. (1998) Bioconjugate Chem. 9, 618-626) into peptide-linked
      radiolabeled immunoconjugates of the form DOTA-peptide-antibody. Decapeptide
      linkers -GFQGVQFAGF- and -GFGSVQFAGF-, selected for cleavage by human liver
      cathepsin B, were rapidly digested in vitro when compared to the simple model
      tetrapeptide motif of the prototype -GGGF- [Li, M., and Meares, C. F. (1993)
      Bioconjugate Chem. 4, 275-283]. Cleavage properties of these library-selected
      substrates for cathepsin B compared favorably with decapeptide linkers 
      GLVGGAGAGF- and -GGFLGLGAGF-, which incorporate two of the most labile extended
      cathepsin B substrates from the literature. The decapeptide linker -GFGSTFFAGF-,
      selected from the library for cleavage by human liver cathepsin D, was rapidly
      digested by cathepsin D while the others were not.

PMID- 10411451
TI  - Size reduction of galactosylated PEI/DNA complexes improves lectin-mediated gene
      transfer into hepatocytes.
AB  - Hepatocytes are interesting targets for gene therapy applications. Several
      hepatocyte-directed gene delivery vectors have been described. For example,
      simple galactosyl residues coupled to polyethylenimine (PEI) gave an efficient
      vector which selectively transfected hepatocytes via the asialoglycoprotein
      receptor-mediated endocytosis [Zanta, M. A., et al. (1997) Bioconjugate Chem. 8,
      839-844]. However, the large size of these galactosylated PEI/DNA complexes
      prevented their use in vivo. We have investigated the role of the saccharide
      length on the size of glycosylated-PEI/DNA particles. When 5% of the PEI
      nitrogens were grafted with a linear tetragalactose structure (lGal4), small and
      stable particles were formed upon complexation with plasmid DNA. These particles
      were essentially toroids having a size of 50-80 nm and a zeta-potential close to
      neutrality. Moreover, these slightly charged PEI-lGal4/DNA complexes were as
      selective as the previously described galactosylated-PEI vector to transfect
      hepatocytes, but in addition, they were more efficient. It is expected that the
      properties of the PEI-lGal4/DNA complexes may increase their diffusion into the
      liver and their efficiency to transfect hepatocytes.

PMID- 10411453
TI  - A psoralen-conjugated triplex-forming oligodeoxyribonucleotide containing
      alternating methylphosphonate-phosphodiester linkages: synthesis and interactions
      with DNA.
AB  - A psoralen-conjugated oligodeoxyribopyrimidine (1443), PS-pTTTTCTTTTCTTCTT, where
      PS is trimethylpsoralen and C is 5-methyl-2'-deoxycytidine, that contains
      alternating methylphosphonate-phosphodiester internucleotide linkages was
      synthesized. The ability of 1443 to form triple-stranded complexes with a purine
      tract in a synthetic DNA duplex was studied. Irradiation of solutions containing
      the DNA target and 10 microM 1443 or 0.25 microM of a similar psoralen-conjugated
      oligodeoxyribonucleotide that contained all phosphodiester linkages, (1193), with
      long-wavelength UV light resulted in approximately 80% formation of interstrand
      cross-links at pH 7.0, 37 degrees C, in the presence of 20 mM magnesium chloride.
      The extent of triplex formation as monitored by photo-cross-linking decreased
      over the pH range 5.5-8.0, and the apparent pK of the 5-methylcytosines (C) in
      1443 was approximately one-half of a pH unit less than that of the 5
      methylcytosines in 1193. Oligomer 1443 formed triplexes in the absence of
      magnesium, and maximum triplex formation was observed in solutions containing 2.5
      mM magnesium, whereas maximal triplex formation by the fully charged 1193 was not
      observed until the magnesium concentration was 10 mM or higher. Unlike the all
      phosphodiester backbone of 1193, the alternating methylphosphonate-phosphodiester
      backbone of 1193 is resistant to hydrolysis by exonucleases in fetal calf serum.
      The nuclease resistance of 1443 and its ability to form triplexes at very low
      magnesium concentrations suggests that triplex-forming oligomers with alternating
      methylphosphonate-phosphodiester backbones may be good candidates for use as
      antigene reagents in cell culture.

PMID- 10411452
TI  - Grafting protein ligand monolayers onto the surface of microparticles for probing
      the accessibility of cell surface receptors.
AB  - Coupling of a specific ligand to vaccines or drugs can be a powerful aid to route
      these compounds to a certain target cell population. However, if the targeted
      receptor is buried in a glycocalyx, binding of the ligand may be sterically
      hindered or even abolished, especially when the ligand is attached to bulky
      payloads. The antigen-transporting M cells that cover the gut-associated lymphoid
      tissue have a less pronounced glycocalyx than neighboring enterocytes. Such
      architectural differences might provide a possibility for targeting micro- or
      nanoparticulate vaccines to the mucosal immune system. To investigate the
      influence of the glycocalyx on the accessibility of cell surface receptors, we
      developed a system where a monolayer of ligand molecules is coupled in spatially
      aligned manner onto the surface of microparticles. On the basis of fluorescent
      carboxylate-modified particles of 1 micron diameter, different synthetic
      strategies were tested. Particles were first modified to display aldehyde
      functions on their surface, then protein ligands were coupled via Schiff base
      formation. The performance of the particles was tested on cultured mouse
      fibroblasts using the B subunit of cholera toxin as ligand and the plasma
      membrane glycolipid ganglioside G(M1) as receptor. Cholera toxin B subunit-coated
      microparticles generated by one of our synthetic pathways exhibited specific
      binding to fibroblasts which could be blocked with soluble cholera toxin B
      subunit. As particles as small as 50 nm and any proteinaceous ligand may be used,
      this system provides a versatile means for monitoring receptor accessibilities in
      vitro and in vivo.

PMID- 10411454
TI  - Synthesis and application of novel bifunctional spin labels.
AB  - The synthesis of new bifunctional spin-labeled cross-linking reagents is
      described. Covalent attachment to papain was achieved via a thiol-specific
      thiosulfonate residue and, for the second anchor point, via a nonspecific
      photoreactive azido function. The thiosulfonate formed a reversible disulfide
      linkage, which could be cleaved again reductively by dithiothreitol. The spin
      label, a pyrroline-1-oxyl radical, was highly immobilized after attachment to
      papain by both functional groups and showed little if any relative motion with
      respect to the protein.

PMID- 10411455
TI  - Molecular modeling of hapten structure and relevance to broad specificity
      immunoassay of sulfonamide antibiotics.
AB  - Molecular modeling of hapten structure was used to predict and influence, through
      appropriate synthetic work, the outcome of an immunization program. Examination
      of the structures of sulfonamide antibiotics led to the development of a
      hypothesis and the consequent synthesis of a sulfacetamide-protein immunogen
      aimed at the generation of broad specificity anti-sulfonamide antibodies. The
      antisera generated, alongside anti-sulfachlorpyradizine antisera generated at the
      same time, were characterized for cross-reactions against a range of sulfonamide
      drugs, and were found to exhibit good but not the desired broad specificity.
      Discussion is presented as to the reasons for the failure of the hypothesis.
      Further hypotheses are developed and speculation is made as to the future of
      molecular modeling in immunochemical research.

PMID- 10411456
TI  - Structure-activity relationships of water-soluble cationic
      methacrylate/methacrylamide polymers for nonviral gene delivery.
AB  - A number of water-soluble cationic carriers was evaluated as transfectant. Almost
      all studied cationic methacrylate/methacrylamide polymers were able to condense
      the structure of plasmid DNA, yielding polymer/plasmid complexes (polyplexes)
      with a size of 0.1-0.3 micron and a slightly positive zeta-potential, which can
      be taken up by cells, e.g., via endocytosis. However, the transfection efficiency
      and the cytotoxicity of the polymers differed widely: the highest transfection
      efficiency and cytotoxicity were observed for poly[2-(dimethylamino)ethyl
      methacrylate], p(DMAEMA). Assuming that polyplexes enter cells via endocytosis,
      p(DMAEMA) apparently has advantageous properties to escape the endosome. A
      possible explanation is that, due to its average pK(a) value of 7.5, p(DMAEMA) is
      partially protonated at physiological pH and might behave as a proton sponge.
      This might cause a disruption of the endosome, which results in the release of
      both the polyplexes and cytotoxic endosomal/lysosomal enzymes into the cytosol.
      On the other hand, the analogues of p(DMAEMA) studied here have a higher average
      pKa value and have, consequently, a higher degree of protonation and a lower
      buffering capacity. This might be associated with a lower tendency to destabilize
      the endosome, resulting in both a lower transfection efficiency and a lower
      cytotoxicity. Furthermore, molecular modeling showed that, of all studied
      polymers, p(DMAEMA) has the lowest number of interactions with DNA. We therefore
      hypothesized that the superior transfection efficiency of p(DMAEMA) containing
      polyplexes can be ascribed to an intrinsic property of p(DMAEMA) to destabilize
      endosomes combined with an easy dissociation of the polyplex once present in the
      cytosol and/or the nucleus.

PMID- 10411457
TI  - Peptide-oligonucleotide phosphorothioate conjugates with membrane translocation
      and nuclear localization properties.
AB  - Eighteen peptide-oligonucleotide phosphorothioate conjugates were prepared in
      good yield and thoroughly characterized with electrospray ionization mass
      spectra. When applied to the living cells, conjugates exhibiting membrane
      translocation and nuclear localization properties displayed efficient
      intracellular penetration but failed to show any serious antisense effect.
      Studies on the intracellular distribution of the fluorescein-labeled conjugates
      revealed their trapping in endosomes.

PMID- 10411458
TI  - Use of heavy-metal clusters in the design of N-succinimidyl ester acylation
      reagents for side-chain-specific labeling of proteins.
AB  - New heavy transition metal carbonyl markers for protein labeling, containing an
      "Mn(CO)11" (M = Ru, Os, n = 3; M = Ir, n = 4) moiety, were prepared by reaction
      of "lightly stabilized" clusters with an N-succinimidyl ester functionalized
      phosphine, namely N-succinimidyl 3-diphenylphosphine-propionate (DPPS). The
      reaction of Os3(CO)11(DPPS) with the model amino acid beta-alanine was performed
      and led to the expected amide. From the reaction of Mn(CO)11(DPPS) with bovine
      serum albumin (BSA) in mixed organic/aqueous medium, conjugates bearing a fairly
      high number of metal carbonyl fragments were obtained, thus demonstrating the
      usefulness of this class of reagents for the selective and covalent graft of
      heavy metal clusters to side chain of proteins.

PMID- 10411459
TI  - Conjugation, immunoreactivity, and immunogenicity of calix[4]arenes; model study
      to potential calix[4]arene-based Ac3+ chelators.
AB  - For the development of calix[4]arene-based radiotherapeutic agents, the
      conjugation to biomolecules and immunogenicity in mice of potential 225Ac3+
      chelating calix[4]arenes were studied. A calix[4]arene triethyl ester
      isothiocyanate and a bis(calix[4]arene) hexacarboxylic acid, containing a masked
      thiol functionality, were used in conjugation experiments to a mouse monoclonal
      antibody and serum albumins. All characterization techniques indicate that only
      the calix[4]arene carboxylic acid is successfully conjugated to the biomolecules.
      The immunoreactivity of the conjugates is not impaired when up to 6 equiv of
      calixarene are bound to the monoclonal antibody. Animal tests indicated that the
      immunogenicity toward the calix[4]arene is strongly influenced by the nature of
      the carrier, the dosage, and the injection method. No immune response occurred
      when a homologous carrier was used or when a heterologous carrier was applied at
      a dosage of 10 microg per immunization via intravenous injection. Under all other
      conditions, the presence of antibodies directed against the calix[4]arene was
      demonstrated. Thus, for the application in radioimmunotherapy, the conjugation of
      a calix[4]arene to a humanized antibody will probably not lead to an immune
      response, and the immunoreactivity will not be disturbed.

PMID- 10411460
TI  - Caged DNA does not aggregate in high ionic strength solutions.
AB  - The assembly of DNA into compact particles that do not aggregate in physiologic
      salt solution occurs naturally in chromatin and viral particles but has been
      challenging to duplicate using artificial constructs. Cross-linking amino
      containing polycations in the presence of DNA with bisimidoester cross-linker
      leads to the formation of caged DNA particles that are stable in salt solutions.
      This first demonstration of caged DNA provides insight into how natural
      condensation processes avoid aggregation and a promising avenue for developing
      nonviral gene therapy vectors.

PMID- 10411461
TI  - Novel biotinylated phenylarsonous acids as bifunctional reagents for spatially
      close thiols: studies on reduced antibodies and the agonist binding site of
      reduced Torpedo nicotinic receptors.
AB  - We synthesized three novel organoarsenicals as prototype bifunctional reagents
      for spatially close thiols, N-(4-arsenosophenyl) hexahydro-2-oxo-(3aS,4S,6aR)-1H
      thieno[3, 4-d]imidazole-4-pentamide (1), 2-[4-[(4-arsenosophenyl)amino]-1, 4
      dioxobutyl] hydrazide, (3aS,4S,6aR)-hexahydro-2-oxo- 1H-thieno[3, 4-d] imidazole
      4-pentanoic acid (2), and [4-[[12-[[5-[(3aS,4S, 6aR)-hexahydro-2-oxo-1H-thieno[3,
      4-d]imidazol-4-yl]-1-oxopentyl]amino]-1-oxododecyl]amino]phe nyl]-arso nous acid
      (3) containing both biotin and arsenic with intervening varying length spacers
      extending from 2 to 15 A beyond biotin bound to streptavidin. Conceptually, the
      arsenical group can form a stable, covalent ring structure with appropriately
      spaced thiols and thereby anchor the reagent to a macromolecule, while biotin
      allows for the detection of the reagent-macromolecule complex via avidin binding.
      Because the alpha-subunits of all characterized nicotinic receptors contain an
      easily reducible disulfide bond between adjacent cysteine residues, the reduced
      alpha-subunit is an attractive site for labeling. Compounds 1-3 all
      simultaneously bound streptavidin and dithiols, and all three decreased the
      number of [125I]alpha-bungarotoxin-binding sites in reduced Torpedo nicotinic
      receptors (IC50s 10-300 nM). Moreover, arsenylation of the receptors prevented
      their reoxidation with dithio-bis(nitrobenzoic acid), was reversible with 2,3
      dimercaptopropanesulfonic acid, and protected the receptor from irreversible
      alkylation by bromoacetylcholine. However, in no case did 1-3 allow simultaneous
      binding to reduced nicotinic receptors and to [125I]streptavidin, although 3
      alone allowed simultaneous labeling of a spatially close dithiol located in
      reduced antibodies.

PMID- 10411462
TI  - Biopharmaceutical properties of uricase conjugated to neutral and amphiphilic
      polymers.
AB  - A comparative pharmacokinetic and biodistribution investigation of polymer
      protein conjugates prepared with various amphiphilic polymers was carried out
      using uricase as a model. Four polymer-uricase derivatives have been obtained by
      covalent binding of a similar number of polymer chains of (a) linear
      poly(ethylene glycol) (Mw 5000 Da); (b) branched poly(ethylene glycol) (Mw 10 000
      Da); (c) poly(N-vinylpyrrolidone) (Mw 6000 Da); (d) poly(N-acryloilmorpholine)
      (Mw 6000 Da). By intravenous administration to Balb/c mice, the conjugates
      displayed different pharmacokinetic and organ distribution behaviors. (1) The
      unmodified enzyme and the poly(N-vinylpyrrolidone) conjugate were the enzyme
      forms with the shortest and the longest permanence in blood respectively (mean
      residence time 45 and 4378 min). (2) Native uricase was found to localize soon
      after administration significantly in heart, lungs, and liver from where it was
      also rapidly cleared. (3) The poly(N-acryloilmorpholine) derivative showed the
      highest concentration levels in liver (up to 25.5% of the dose) and considerable
      accumulation took also place in the other considered organs. (4) Poly(N
      vinylpyrrolidone)-uricase displayed a relevant tropism for liver but low uptake
      indexes were found for the other organs. (5) The branched poly(ethylene glycol)
      derivative accumulated preferentially in liver and spleen. (6) The linear
      poly(ethylene glycol) conjugate was, among the various uricase forms, the species
      with the lowest distribution levels in all the examined organs. (7) Finally, all
      the enzyme forms slowly disposed in kidneys with higher levels for the poly(N
      acryloilmorpholine) derivative (15% after 2880 min) and unmodified uricase (14%
      after 1440 min).

PMID- 10411463
TI  - Bifunctional phosphoramidite reagents for the introduction of histidyl and
      dihistidyl residues into oligonucleotides.
AB  - The synthesis and characterization of reagents for the incorporation of histidyl
      residues into oligonucleotides by automated chemical synthesis is described.
      Automated oligonucleotide synthesis utilizing a bifunctional reagent for the
      incorporation of a dihistidyl residue into oligonucleotides is described.
      Oligonucleotides incorporating one to three dihistidyl residues were prepared and
      characterized. The interaction of these oligonucleotides with a metal chelating
      IMAC matrix was explored.

PMID- 10411464
TI  - Application of oligo-(14-amino-3,6,9,12-tetraoxatetradecanoic acid) lipid
      conjugates as steric barrier molecules in liposomal formulations.
AB  - Lipid conjugates of oligo-(14-amino-3,6,9,12-tetraoxatetradecanoic acid) (ATTAn)
      were synthesized as monodisperse analogues of poly(ethylene glycol) (PEG)
      derivatives used in liposomal drug delivery systems. The new lipids were shown to
      be at least equivalent to MePEGA-2000-DSPE in assays designed to evaluate the
      effectiveness of polymers as steric barrier molecules in liposomes. Liposomes
      containing 1-5% of ATTA8-DSPE (octamer) showed comparable long circulation
      behavior relative to PEG-2000-DSPE analogues. Surprisingly, the shorter ATTA4
      DSPE (tetramer) appeared to be quite effective in reducing clearance. Liver
      enzyme levels and systemic single dose tolerability of ATTA8-DSPE liposomes were
      comparable to controls, suggesting that the new materials are nontoxic. Prolonged
      exposure of ATTA8-DSPE liposomes to splenocytes in vitro showed no evidence of
      mitogenicity relative to controls or MePEGA-2000-DSPE liposomes. ATTA8-DSPE was
      as effective as MePEGC-2000-DSPE in preventing complement activation by cationic
      liposome systems. Repeat dosage in vivo regimes in ICR mice using
      DSPC/cholesterol liposomes, with and without 5% ATTA8-DSPE and MePEGC-2000-DSPE,
      showed no evidence of enhanced clearance on successive doses. Splenocytes
      recovered after repeat doses showed no significant evidence of mitogenicity on
      restimulation with liposomes. Cellular differentiation and activation marker
      levels in splenocytes recovered after the fourth in vivo administration were at
      normal levels. These results suggest that ATTAn oligomers do not induce an immune
      response in isolation. It was demonstrated that ATTA8-DSPE could be used to
      replace PEG-lipids in the formulation of doxorubicin, plasmid DNA and
      oligonucleotides using a variety of formulation techniques. The study
      demonstrates that ATTAn oligomers can be safely and effectively used in place of
      poly(ethylene glycol) as well-defined biomaterials in liposomal applications
      where reproducible behavior is critical.

PMID- 10411465
TI  - Functionalized congeners of 1,4-dihydropyridines as antagonist molecular probes
      for A3 adenosine receptors.
AB  - 4-Phenylethynyl-6-phenyl-1,4-dihydropyridine derivatives are selective
      antagonists at human A3 adenosine receptors, with Ki values in a radioligand
      binding assay vs [125I]AB-MECA [N(6)-(4-amino-3-iodobenzyl)-5'-N-methylcarbamoyl
      adenosine] in the submicromolar range. In this study, functionalized congeners of
      1,4-dihydropyridines were designed as chemically reactive adenosine A3
      antagonists, for the purpose of synthesizing molecular probes for this receptor
      subtype. Selectivity of the new analogues for cloned human A3 adenosine receptors
      was determined in radioligand binding in comparison to binding at rat brain A1
      and A2A receptors. Benzyl ester groups at the 3- and/or 5-positions and phenyl
      groups at the 2- and/or 6-positions were introduced as potential sites for chain
      attachment. Structure-activity analysis at A3 adenosine receptors indicated that
      3,5-dibenzyl esters, but not 2,6-diphenyl groups, are tolerated in binding. Ring
      substitution of the 5-benzyl ester with a 4-fluorosulfonyl group provided
      enhanced A3 receptor affinity resulting in a Ki value of 2.42 nM; however, a long
      chain derivative containing terminal amine functionalization at the 4-position of
      the 5-benzyl ester showed only moderate affinity. This sulfonyl fluoride
      derivative appeared to bind irreversibly to the human A3 receptor (1 h incubation
      at 100 nM resulting in the loss of 56% of the specific radioligand binding
      sites), while the binding of other potent dihydropyridines and other antagonists
      was generally reversible. At the 3-position of the dihydropyridine ring, an amine
      functionalized chain attached at the 4-position of a benzyl ester provided higher
      A3 receptor affinity than the corresponding 5-position isomer. This amine
      congener was also used as an intermediate in the synthesis of a biotin conjugate,
      which bound to A3 receptors with a Ki value of 0.60 microM.

PMID- 10411466
TI  - Bioactive surfaces via immobilization of self-assembling polymers onto
      hydrophobic materials.
AB  - Conjugation of proteins to copolymers from poly(acrylic acid) grafted onto PEO
      PPO-PEO backbone (Pluronic-PAA) following adsorption of the conjugates onto
      hydrophobic surfaces is reported. Insulin-Pluronic-PAA conjugates show negligible
      internalization of insulin into human uterine smooth muscle cells as well as
      enhancement of mitogenic activity. Glucose-induced release of glycated albumin
      complexed with a Pluronic-PAA-concanavalin conjugate and adsorbed onto
      polystyrene nanospheres may provide a model for a glucose-responsive protein
      delivery system or a heterogeneous diagnostic device.

PMID- 10411467
TI  - A versatile method for the conjugation of proteins and peptides to poly[2
      (dimethylamino)ethyl methacrylate].
AB  - Random copolymers of 2-(dimethylamino) ethyl methacrylate (DMAEMA) with
      aminoethyl methacrylate (AEMA) were synthesized by radical polymerization. The
      amount of incorporated primary amino groups could be controlled by the feed ratio
      of AEMA to DMAEMA, and was varied from 2 to 6 mol %. Subsequently, protected
      thiol groups were introduced in a derivatization step with N-succinimidyl 3-(2
      pyridyldithio)propionate (SPDP) and subsequent treatment with dithiothreitol
      (DTT). The obtained thiolated p(DMAEMA-co-AEMA) was conjugated to transferrin
      (Tf) or the F(ab') fragment of mAb 323/A3 via a disulfide linkage. Moreover, the
      maleimide derivative of the nuclear localization signal (NLS) decapeptide Gly-Pro
      Lys-Lys-Lys-Arg-Lys-Val-Glu-Asp-NH(2) was coupled to the thiolated polymer via a
      thioether linkage. The coupling efficiency, as determined by GPC (Tf), SDS-PAGE
      [F(ab')], or (1)H NMR (NLS peptide) was 90-95% for the Tf conjugate, and more
      than 95% for the F(ab') conjugate and the NLS conjugate. The synthetic strategy
      described in this paper is a universal method for the preparation of conjugates
      of proteins and peptides with pDMAEMA in particular. This method can possibly be
      used to synthesize protein-polymethacrylate conjugates in general.

PMID- 10411468
TI  - Characterization of lysozyme-estrone glucuronide conjugates. The effect of the
      coupling reagent on the substitution level and sites of acylation.
AB  - Estrone glucuronide conjugates of hen egg white lysozyme were prepared by the
      mixed anhydride and active ester coupling procedures. Both methods gave good
      yields of conjugates, but the active ester procedure gave a more diverse range of
      products, making it less suitable for preparing conjugates for homogeneous enzyme
      immunoassay. Conjugation of lysozyme with estrone glucuronide by the mixed
      anhydride procedure gave one major derivative exclusively acylated at lysine
      residue 33 whereas conjugation by the active ester method gave six derivatives
      which were acylated at one or more of lysine residues 33, 97, and 116. None of
      the lysine residues 1, 13, and 96, or the N-terminal alpha-amino group, were
      acylated in any of the conjugates isolated. The correlation of the conjugate
      structures with the protein environments of the amino groups in the crystal
      structure of lysozyme suggested that the sites of acylation were determined not
      only by the chemical nature of the acylating reagent but also by the surface
      accessibility and nucleophilicity of the individual lysine residues.

PMID- 10411469
TI  - NOVEL PARAMAGNETIC MACROMOLECULAR COMPLEXES DERIVED FROM THE LINKAGE OF A
      MACROCYCLIC Gd(III) COMPLEX TO POLYAMINO ACIDS THROUGH A SQUARIC ACID MOIETY 

PMID- 10411470
TI  - Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major
      groove.
AB  - The ecteinascidins (Ets), which are natural products derived from marine
      tunicates, exhibit potent antitumor activity. Of the numerous Ets isolated, Et
      743 is presently being evaluated in phase II clinical trials. Et 743 binds in the
      minor groove of DNA and alkylates N2 of guanine. Although structurally similar to
      saframycin, which exhibits poor activity in cellular assays, Et 743 has shown
      good efficacy as an antitumor agent. In this study, DNA structural distortions
      induced by Et 743 were examined to provide insight into the molecular basis for
      the antitumor activity of Et 743. Electrophoretic mobility shifts of ligated
      oligomers containing site-directed adducts were used to examine the extent and
      direction of the Et 743-induced bend. Surprisingly, we find that Et 743 bends DNA
      toward the major groove, which is a unique feature among DNA-interactive agents
      that occupy the minor groove.

PMID- 10411471
TI  - Evaluation of PMF scoring in docking weak ligands to the FK506 binding protein.
AB  - A new knowledge-based scoring function (PMF-score), implemented into the DOCK4
      program, was used to screen a database of 3247 small molecules for binding to the
      FK506 binding protein (FKBP). The computational ranking of these compounds was
      compared to the binding affinities measured by NMR. It was demonstrated that
      small, weakly binding molecules have, on average, higher computational scores
      than nonbinders and are enriched in the upper ranks of the computational scoring
      lists. In addition, the results obtained with the PMF scoring function were
      superior (by 30-120% larger enrichment factors) to those obtained with the
      standard force field score of DOCK4. The reliable ranking of small, weakly
      binding molecules offers new ways of designing building blocks in combinatorial
      libraries as well as SAR by NMR libraries with the increased chance of
      identifying suitable lead compounds for drug design.

PMID- 10411472
TI  - Synthesis and serotonergic activity of substituted 2, N-benzylcarboxamido-5-(2
      ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives: novel
      antagonists for the vascular 5-HT(1B)-like receptor.
AB  - The synthesis and vascular 5-HT(1B)-like receptor activity of a novel series of
      substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N
      dimethyltryptamine derivatives are described. Modifications to the 5-ethylene
      linked heterocycle and to substituents on the 2-benzylamide side chain have been
      explored. Several compounds were identified which exhibited affinity at the
      vascular 5-HT(1B)-like receptor of pK(B) > 7.0, up to 100-fold selectivity over
      alpha(1)-adrenoceptor affinity and 5-HT(2A) receptor affinity, and which
      exhibited a favorable pharmacokinetic profile. N-Benzyl-3-[2
      (dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2, 5-dioxo-1-imidazolidinyl)ethyl]-1H
      indole-2-carboxamide (23) was identified as a highly potent, silent (as judged by
      the inability of angiotensin II to unmask 5-HT(1B)-like receptor-mediated agonist
      activity in the rabbit femoral artery), and competitive vascular 5-HT(1B)-like
      receptor antagonist with a plasma elimination half-life of approximately 4 h in
      dog plasma and with good oral bioavailability. The selectivity of compounds from
      this series for the vascular 5-HT(1B)-like receptors over other receptor subtypes
      is discussed as well as a proposed mode of binding to the receptor pharmacophore.
      It has been proposed that the aromatic ring of the 2, N-benzylcarboxamide group
      can occupy an aromatic binding site rather than the indole ring. The resulting
      conformation allows an amine-binding site to be occupied by the ethylamine
      nitrogen and a hydrogen-bonding site to be occupied by one of the hydantoin
      carbonyls. The electronic nature of the 2,N-benzylcarboxamide aromatic group as
      well as the size of substituents on this aromatic group is crucial for producing
      potent and selective antagonists. The structural requirement on the 3-ethylamine
      side chain incorporating the protonatable nitrogen is achieved by the bulky 2, N
      benzylcarboxamide group and its close proximity to the 3-side chain.

PMID- 10411473
TI  - Potentiation of cADPR-induced Ca(2+)-release by methylxanthine analogues.
AB  - Caffeine and other methylxanthines are known to induce Ca(2+)-release from
      intracellular stores via the ryanodine receptor. In the present work, a range of
      caffeine analogues, in which methyl groups at the 1 and 7 positions were replaced
      with alkyl chains containing different functional groups (oxo, hydroxyl,
      propargyl, ester, and acids), were synthesized. These compounds were then
      screened for their ability to potentiate Ca(2+)-release induced by cADPR (an
      endogenous modulator of ryanodine receptors) in sea urchin egg homogenates. Two
      of the synthesized methylxanthines, 1, 3-dimethyl-7-(7-hydroxyoctyl)xanthine (37)
      and 3-methyl-7-(7-oxooctyl)-1-propargylxanthine (66), were shown to be more
      potent than caffeine in potentiating cADPR-induced Ca(2+)-release, while 1,3
      dimethyl-7-(5-ethylcarboxypentyl)xanthine (14) was shown to be more efficacious.
      The development of new methylxanthine analogues may lead to a better
      understanding of ryanodine receptor function and could possibly provide novel
      therapeutic agents.

PMID- 10411474
TI  - 2,3-Dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione derivatives, a class of
      cytotoxic agents active on multidrug-resistant cell lines: synthesis, biological
      evaluation, and structure-activity relationships.
AB  - A series of DNA-intercalating potential antitumor agents, (amino)alkyl
      substituted 2,3-dihydro-1H,7H-pyrimido[5,6, 1-de]acridine-1,3,7-triones, has been
      prepared by aminolysis of the corresponding 6-chloro derivative with a suitable
      omega-aminoalkylamine. The noncovalent DNA-binding properties of these compounds
      have been examined using a fluorometric technique. In vitro cytotoxic potencies
      of these derivatives toward eight tumor cell lines, including human colon
      adenocarcinoma (HT29, LoVo sensitive and LoVo/Dx (doxorubicin-resistant)) and
      human ovarian carcinoma (A2780 sensitive, A2780cisR (cisplatin-resistant), CH1,
      CH1cisR (cisplatin-resistant), and SKOV-3) cells, are described and compared to
      that of reference drugs. The cytotoxic activity often parallels the observed DNA
      affinities, for almost all the target compounds. Interesting structure-activity
      relationships have been found. The octanol/water partition coefficients have also
      been calculated, but there was no correlation either with cytotoxicity values or
      with resistance index. Three highly DNA-affinic analogues, 9 and 15f,15h, have
      been identified with a useful broad spectrum of cytotoxic activity.

PMID- 10411475
TI  - Chemical stability and fate of the cytostatic drug ifosfamide and its N
      dechloroethylated metabolites in acidic aqueous solutions.
AB  - 31P NMR spectroscopy was used to study the products of the decomposition of the
      antitumor drug ifosfamide (IF, 1d) and its N-dechloroethylated metabolites,
      namely, 2,3-didechloroethylIF (1a) and 2- (1b) and 3-dechloroethylIF (1c), in
      buffered solutions at acidic pH. The first stage of acid hydrolysis of these four
      oxazaphosphorines is a P-N bond cleavage of the six-membered ring leading to the
      phosphoramidic acid monoesters (2a-d) of type R'HN(CH(2))(3)OP(O)(OH)NHR, with R
      and/or R' = H or (CH(2))(2)Cl. The electron-withdrawing chloroethyl group at the
      endocyclic and/or exocyclic nitrogens counteracts the endocyclic P-N bond
      hydrolysis. This effect is even more marked when the N-chloroethyl group is in
      the exocyclic position since the order of stability is 1d > 1c > 1b > 1a. In the
      second stage of hydrolysis, the remaining P-N bond is cleaved together with an
      intramolecular attack at the phosphorus atom by the non-P-linked nitrogen of the
      compounds 2a-d. This leads to the formation of a 2-hydroxyoxazaphosphorine ring
      with R = H (3a coming from compounds 2a,c) or (CH(2))(2)Cl (3b coming from
      compounds 2b,d) and to the release of ammonia or chloroethylamine. The third step
      is the P-N ring opening of the oxazaphosphorines 3a,b leading to the phosphoric
      acid monoesters, H(2)N(CH(2))(3)OP(O)(OH)(2) (4a) and
      Cl(CH(2))(2)HN(CH(2))(3)OP(O)(OH)(2) (4b-1), respectively. For the latter
      compound, the chloroethyl group is partially (at pH 5.5) or totally (at pH 7.0)
      cyclized into aziridine (4b-2), which is then progressively hydrolyzed into an N
      hydroxyethyl group (4b-3). Compounds 3a,b are transient intermediates, which in
      strongly acidic medium are not observed with (31)P NMR. In this case, cleavage of
      the P-N bond of the type 2 phosphoramidic acid monoesters leads directly to the
      type 4 phosphoric acid monoesters. The phosphate anion, derived from P-O bond
      cleavage of these latter compounds, is only observed at low levels after a long
      period of hydrolysis. Compounds 1a-c and some of their hydrolytic degradation
      products (4b-1, 4b-2, diphosphoric diester
      [Cl(CH(2))(2)NH(CH(2))(3)OP(O)(OH)](2)O (5), and chloroethylamine) did not
      exhibit, as expected, any antitumor efficacy in vivo against P388 leukemia. (31)P
      NMR determination of the N-dechloroethylated metabolites of IF or its structural
      isomer, cyclophosphamide (CP), and their degradation compounds could provide an
      indirect and accurate estimation of chloroacetaldehyde amounts formed from CP or
      IF.

PMID- 10411476
TI  - Derivatives of the new ring system indolo[1,2-c]benzo[1,2,3]triazine with potent
      antitumor and antimicrobial activity.
AB  - Derivatives of the new ring system indolo[1,2-c]benzo[1,2,3]triazine 5 were
      synthesized by diazotization of substituted 2-(2-aminophenyl)indoles followed by
      an intramolecular coupling reaction of the diazonium group with the indole
      nitrogen. To obtain the indolobenzotriazine system it was necessary to protect
      the 3 position of the indole nucleus to avoid cyclization into the indolo[3,2
      c]cinnoline system 4. Indolobenzotriazines 5a-g were evaluated in vitro for
      antitumor activity against a panel of leukemia-, lymphoma-, carcinoma-, and
      neuroblastoma-derived cell lines. Some compounds inhibited the proliferation of T
      and B cell lines at submicromolar concentrations, whereas their activity against
      solid tumor cell lines was in the micromolar range. When evaluated for their
      antifungal potential 5a,d inhibited some of the fungi tested, although at
      concentrations very close to those inhibiting the proliferation of human cells.
      On the contrary, all indolobenzotriazines proved fairly potent and selective
      inhibitors of Streptococcus and Staphylococcus. In particular 5b,c,g were up to
      80 times more potent than the reference drug streptomycin and inhibited the
      growth of the above Gram-positive bacteria at concentrations far lower than those
      cytotoxic for animal cells.

PMID- 10411477
TI  - Novel euglycemic and hypolipidemic agents. 4. Pyridyl- and quinolinyl-containing
      thiazolidinediones.
AB  - A series of substituted pyridyl- and quinolinyl-containing 2, 4
      thiazolidinediones having interesting cyclic amine as a linker have been
      synthesized. Both unsaturated thiazolidinediones 5 and saturated
      thiazolidinediones 6 and their various salts were evaluated in db/db mice for
      euglycemic and hypolipidemic effects and compared with BRL compound 11 and BRL
      49653, respectively. Some of the potent compounds were converted to various salts
      in order to obtain improved activities. Among all the salts evaluated, the
      maleate salt of unsaturated TZD 5a was found to be a very potent euglycemic and
      hypolipidemic compound. Some of the more interesting compounds have also been
      evaluated in ob/ob mice and compared with rosiglitazone (maleate salt of BRL
      49653). Oral glucose tolerance tests were performed in both db/db and ob/ob mice.
      Pharmacokinetic studies of 5a maleate are also reported. Receptor binding studies
      of PPARgamma by 5a/5a maleate did not show any significant transactivation of
      PPARalpha or PPARgamma.

PMID- 10411478
TI  - Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H
      dibenz[b,f]azepine-5-carboxamide derivatives.
AB  - A series of esters of the major metabolite of oxcarbazepine (2), 10, 11-dihydro
      10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated
      for their anticonvulsant and brain sodium channel-blocking properties. The
      compounds were assayed intraperitoneally and per os in rats against seizures
      induced by maximal electroshock (MES). Neurologic deficit was evaluated by the
      rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of
      the series against MES-induced seizures with oral ED(50) values at t(max) of 10.9
      +/- 2.3 and 4.7 +/- 0.9 mg/kg, respectively. After intraperitoneal
      administration, carbamazepine (1) behaved more potently than 2 and all other new
      dibenz[b, f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12
      were equally potent. In the rotarod test, low doses of 1 produced considerable
      motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6, (R)-7,
      and racemic alcohol 8, or racemic acetate 10 or (R)-11. The potencies of the
      racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in
      the MES and rotarod test were found to be similar between them, and consequently
      they exhibit similar protective index values. All three forms of the alcohol and
      their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to
      differ in the MES or rotarod tests; the ED(50) value for (S)-6 against MES
      induced seizures was nearly 3-fold that for (S)-12. The protective index also
      differed markedly between all stereoisomers of the alcohol and their
      corresponding acetates, most pronouncedly for compound (S)-12 which attained the
      highest value (12.5) among all compounds tested. Blockade of voltage-sensitive
      sodium channels was studied by investigating [(3)H]batrachotoxinin A 20-alpha
      benzoate ([(3)H]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than
      the standards 1 and 2 at inhibiting the binding of [(3)H]BTX to sodium channels
      and the influx of (22)Na(+) into rat brain synaptosomes. It is concluded that
      acetates (R)-11 and (S)-12 are not simple metabolic precursors of alcohols (R)-7
      and (S)-6 in rodents but that they possess anticonvulsant and sodium channel
      blocking properties in their own right.

PMID- 10411479
TI  - Novel cryptophycin antitumor agents: synthesis and cytotoxicity of fragment "B"
      analogues.
AB  - A general synthetic approach to novel cryptophycin analogues 6 is described. N
      Hydroxysuccinimide active ester 15, a key common intermediate, was converted to
      beta-epoxide 6 in three steps, via initial coupling with unprotected amino acid
      9, followed by deprotection/macrolactamization of acyclic precursor 16, and final
      oxidation of styrene 7 to install the C7-C8 beta-epoxide. Cryptophycin styrenes 7
      and beta-epoxides 6, bearing diverse side chains in fragment "B", were evaluated
      for cytotoxic activity. beta-Epoxides 6, in general, were significantly more
      potent than the corresponding alpha-epoxides 17 and styrenes 7. A benzyl side
      chain was required for potent activity, with beta-epoxide 6u, possessing a 3-Cl,4
      (dimethylamino)benzyl moiety, as the most potent cytotoxic agent prepared, with
      an IC(50) = 54 pM, only 2-fold less than that of Cryptophycin-52 (3).

PMID- 10411480
TI  - Synthesis and antimalarial activity of cyclic peroxides, 1,2,4,5, 7-pentoxocanes
      and 1,2,4,5-tetroxanes.
AB  - A variety of 1,2,4,5,7-pentoxocane and 1,2,4,5-tetroxane derivatives were
      prepared as potential peroxide antimalarial agents. In both series of cyclic
      peroxides, the steric and electronic effects of the substituents attached to the
      peroxide ring exert a remarkable influence on the antimalarial activity. For some
      cyclic peroxides, which were found to be highly effective in vitro, the study in
      vivo has been also conducted.

PMID- 10411481
TI  - Phosphinic pseudo-tripeptides as potent inhibitors of matrix metalloproteinases:
      a structure-activity study.
AB  - Several phosphinic pseudo-tripeptides of general formula R-XaaPsi(PO(2)
      CH(2))Xaa'-Yaa'-NH(2) were synthesized and evaluated for their in vitro
      activities to inhibit stromelysin-3, gelatinases A and B, membrane type-1 matrix
      metalloproteinase, collagenases 1 and 2, and matrilysin. With the exception of
      collagenase-1 and matrilysin, phosphinic pseudo-tripeptides behave as highly
      potent inhibitors of matrix metalloproteinases, provided they contain in P(1)'
      position an unusual long aryl-alkyl substituent. Study of structure-activity
      relationships regarding the influence of the R and Xaa' substituents in this
      series may contribute to the design of inhibitors able to block only a few
      members of the matrix metalloproteinase family.

PMID- 10411482
TI  - 1,3-Disubstituted benzazepines as novel, potent, selective neuropeptide Y Y1
      receptor antagonists.
AB  - A novel series of potent and selective non-peptide neuropeptide Y (NPY) Y1
      receptor antagonists, having benzazepine nuclei, have been designed, synthesized,
      and evaluated for activity. Chemical modification of the R(1) and R(3)
      substituents in structure 1 (Chart 1) yields several compounds that show high
      affinity for the Y1 receptor (K(i) values of less than 10 nM). SAR studies
      revealed that introduction of an isopropylurea group at R(1) and a 3-(benzo
      condensed-urea) group, 3-(fluorophenylurea) group, or a 3-(N-(4
      hydroxyphenyl)guanidine) group at R(3) in structure 1 afforded potent and subtype
      selective NPY Y1 receptor antagonists. 3-(3-(Benzothiazol-6-yl)ureido)-1-N-(3-(N'
      (3-isopropylureido++ +))benzyl )-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (21),
      which was one of the most potent derivatives, competitively inhibited specific
      [(125)I]peptide YY (PYY) binding to Y1 receptors in human neuroblastoma SK-N-MC
      cells (K(i) = 5.1 nM). 21 not only inhibited the Y1 receptor-mediated increase in
      cytosolic free Ca(2+) concentration in SK-N-MC cells but also antagonized the Y1
      receptor-mediated inhibitory effect of peptide YY on gastrin-induced histamine
      release in rat enterochromaffin-like cells. 21 showed no significant affinity in
      17 receptor binding assays including Y2, Y4, and Y5 receptors.

PMID- 10411483
TI  - alpha-Functionalized phosphonylphosphinates: synthesis and evaluation as
      transcarbamoylase inhibitors.
AB  - Diverse alpha-methyl-substituted phosphonylphosphinates (P-C-P-C-X) are
      accessible from a protected, pentafluorophenylsulfonated phosphonylphosphinate
      via nucleophilic displacement. The utility of this route is demonstrated with
      several nitrogen nucleophiles. The resulting amine and amino acid
      phosphonylphosphinate derivatives were evaluated as inhibitors of Streptococcus
      faecalis ornithine transcarbamoylase (OTC). Compared with the structurally
      related phosphonoacetyl-L-ornithine (L-PALO), a known inhibitor of OTCs from
      various sources, the phosphonylphosphinates are surprisingly poor inhibitors,
      binding several orders of magnitude less tightly to the enzyme. These results
      suggest that the tetrahedral intermediate formed in the normal transcarbamoylase
      reaction is poorly mimicked by a tetrahedral and anionic phosphonate, either
      because of directly unfavorable interactions with a hydrogen-bond acceptor within
      the active site or because transition-state analogues are unable to induce the
      protein conformation changes that normally accompany reaction.

PMID- 10411484
TI  - Carbonic anhydrase inhibitors. Synthesis of water-soluble, topically effective,
      intraocular pressure-lowering aromatic/heterocyclic sulfonamides containing
      cationic or anionic moieties: is the tail more important than the ring?
AB  - Reaction of several aromatic/heterocyclic sulfonamides containing a free amino,
      imino, hydrazino, or hydroxyl group, with 2, 3-pyridinedicarboxylic anhydride or
      2,6-pyridinedicarboxylic acid in the presence of carbodiimide derivatives,
      afforded two series of water-soluble (as hydrochloride, triflate, or carboxylate
      salts) compounds. The new derivatives were assayed as inhibitors of the zinc
      enzyme carbonic anhydrase (CA) and more precisely of three of its isozymes, CA I,
      II (cytosolic forms), and IV (membrane-bound form), involved in important
      physiological processes. Efficient inhibition was observed against all three
      isozymes, but especially against CA II and IV (in nanomolar range), the two
      isozymes known to play a critical role in aqueous humor secretion within the
      ciliary processes of the eye. Some of the best inhibitors synthesized were
      applied as 2% water solutions directly into the eye of normotensive and
      glaucomatous albino rabbits. Very strong and long-lasting intraocular pressure
      (IOP) lowering was observed with many of them. This result prompted us to
      reanalyze the synthetic work done by other groups for the design of water
      soluble, topically effective antiglaucoma sulfonamides. According to these
      researchers, the IOP-lowering effect is due to the intrinsic nature of the
      specific heterocyclic sulfonamide considered, among which the thienothiopyran-2
      sulfonamide derivatives represent the best-studied case. Indeed, the first agents
      developed for topical application, such as dorzolamide, are derivatives of this
      ring system. To prove that the tail (in this case the pyridinecarboxylic
      moieties) conferring water solubility to a sulfonamide CA inhibitor is more
      important than the ring to which the sulfonamido group is grafted, we also
      prepared dorzolamide derivatives incorporating such moieties. These new compounds
      possess good water solubility as hydrochloride or carboxylate salts, balanced by
      a relatively modest lipid solubility. They are strong CA II inhibitors and are
      able to lower IOP in experimental animals more than the parent derivatives. Our
      conclusion is that the tail conferring water solubility to such an enzyme
      inhibitor is more important for topical activity as an antiglaucoma drug, than
      the heterocyclic/aromatic ring to which the sulfonamido moiety is grafted.

PMID- 10411486
TI  - Anti-AIDS agents. 37. Synthesis and structure-activity relationships of (3'R,4'R)
      (+)-cis-khellactone derivatives as novel potent anti-HIV agents.
AB  - To explore the structural requirements of (+)-cis-khellactone derivatives as
      novel anti-HIV agents, 24 monosubstituted 3', 4'-di-O-(S)-camphanoyl-(+)-cis
      khellactone (DCK) derivatives were synthesized asymmetrically. These compounds
      included 4 isomeric monomethoxy analogues (3-6), 4 isomeric monomethyl analogues
      (7-10), 4 4-alkyl/aryl-substituted analogues (11-14), and 12 4-methyl-(+)-cis
      khellactone derivatives (15-26) with varying 3', 4'-substituents. These (+)-cis
      khellactone derivatives were screened against HIV-1 replication in acutely
      infected H9 lymphocytes. The results demonstrated that the (3'R,4'R)-(+)-cis
      khellactone skeleton, two (S)-(-)-camphanoyl groups at the 3'- and 4'-positions,
      and a methyl group on the coumarin ring, except at the 6-position, were optimal
      structural moieties for anti-HIV activity. 3-Methyl- (7), 4-methyl- (8), and 5
      methyl- (9) 3',4'-di-O-(S)-camphanoyl-(3'R, 4'R)-(+)-cis-khellactone showed
      EC(50) and therapeutic index values of <5.25 x 10(-5) microM and >2.15 x 10(6),
      respectively, in H9 lymphocytes, which are much better than those of DCK and AZT
      in the same assay. Furthermore, 8 and 9 also showed potent inhibitory activity
      against HIV-1 replication in the CEM-SS cell line, and most monosubstituted DCK
      analogues were less toxic than DCK in both assays.

PMID- 10411485
TI  - Identification of pharmacokinetically stable 3, 10-dibromo-8
      chlorobenzocycloheptapyridine farnesyl protein transferase inhibitors with potent
      enzyme and cellular activities.
AB  - Farnesyl protein transferase (FPT) is a promising target for the development of
      cancer chemotherapeutics because it is responsible for the farnesylation of
      oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and
      necessary for cellular development and growth. The recent discovery and
      progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch
      66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have
      spawned extensive structure-activity relationship studies (SAR) of this class of
      compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have
      identified several which inhibit FPT and cellular proliferation at single-digit
      nanomolar concentrations and which have good pharmacokinetic properties in mice.

PMID- 10411487
TI  - Novel pyrimidine and purine derivatives of L-ascorbic acid: synthesis and
      biological evaluation.
AB  - The novel pyrimidine derivatives 1-6 of 2,3-dibenzyl-4,5-didehydro-5, 6-dideoxy-L
      ascorbic acid were synthesized by the condensation of pyrimidine bases with 5,6
      diacetyl-2,3-dibenzyl-L-ascorbic acid (DDA). Both N-9 (7) and N-7 (8)
      regioisomers were obtained in the reaction of 6-chloropurine with 5-acetyl-6
      bromo-2, 3-dibenzyl-L-ascorbic acid (ABDA), while the reaction of 6-(N
      pyrrolyl)purine with ABDA afforded exclusively the N-9 isomer 9. Structures of
      all newly prepared compounds were deduced from the chemical shifts in (1)H and
      (13)C NMR spectra, as well as connectivities in 2D homo- and heteronuclear
      correlation spectra. An unambiguous proof of the structure and conformation of 7
      was obtained by X-ray crystallographic analysis. Compounds 1-9 were found to
      exert cytostatic activities against malignant cell lines: pancreatic carcinoma
      (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal
      carcinoma (Hep2), murine leukemia (L1210/0), murine mammary carcinoma (FM3A), and
      human T-lymphocytes (Molt4/C8 and CEM/0), as well as antiviral activities against
      varicella-zoster virus (TK(+)VZV and TK(-)VZV) and cytomegalovirus (CMV). The
      compound 6 containing a trifluoromethyl-substituted uracil ring exhibited marked
      antitumor activity. The N-7-substituted purine regioisomer 8 had greater
      inhibitory effects on the murine L1210/0 and human CEM/0 cell lines than the N-9
      isomer 7. Compound 9 with the 6-purine-substituted pyrrolo moiety had a more
      pronounced selective cytostatic activity against human (Molt4/C8 and CEM/0) cell
      lines than murine (L1210/0 and FM3A/0) and human (MiaPaCa2, MCF7, HeLa, and Hep2)
      tumor cell lines and normal fibroblasts (Hef522). The compound 6 exhibited the
      most potent antiviral activities against TK(+)VZV, TK(-)VZV, and CMV, albeit at
      concentrations that were only slightly lower than the cytotoxic concentrations.

PMID- 10411488
TI  - 2,7-Disubstituted amidofluorenone derivatives as inhibitors of human telomerase.
AB  - Telomerase is a major new target for the rational design of novel anticancer
      agents. We have previously identified anthraquinone-based molecules capable of
      inhibiting telomerase by stabilizing G-quadruplex structures formed by the
      folding of telomeric DNA. In the present study we describe the synthesis and
      biological evaluation of a series of analogous fluorenone-based compounds with
      the specific aims of, first, determining if the anthraquinone chromophore is a
      prerequisite for activity and, second, whether the conventional cytotoxicity
      inherent to anthraquinone-based molecules may be reduced by rational design. This
      fluorenone series of compounds exhibits a broad range of telomerase inhibitory
      activity, with the most potent inhibitors displaying levels of activity (8-12
      microM) comparable with other classes of G-quadruplex-interactive agents.
      Comparisons with analogous anthraquinone-based compounds reveal a general
      reduction in the level of cellular cytotoxicity. Molecular modeling techniques
      have been used to compare the interaction of fluorenone- and analogous
      anthraquinone-based inhibitors with a human G-quadruplex structure and to
      rationalize their observed biological activities.

PMID- 10411489
TI  - Characterization of "mini-nucleotides" as P2X receptor agonists in rat
      cardiomyocyte cultures. An integrated synthetic, biochemical, and theoretical
      study.
AB  - The design and synthesis of "mini-nucleotides", based on a xanthine-alkyl
      phosphate scaffold, are described. The physiological effects of the new compounds
      were evaluated in rat cardiac cell culture regarding Ca(2+) elevation and
      contractility. The results indicate biochemical and physiological profiles
      similar to those of ATP, although at higher concentrations. The biological target
      molecules of these "mini-nucleotides" were identified by using selective P2-R and
      A(1)-R antagonists and P2-R subtype selective agonists. On the basis of these
      results and of experiments in Ca(2+) free medium, in which [Ca(2+)](i) elevation
      was not observed, we concluded that interaction of the analogues is likely with
      P2X receptor subtypes, which causes Ca(2+) influx. Theoretical calculations
      analyzing electronic effects within the series of xanthine-alkyl phosphates were
      performed on reduced models at quantum mechanical levels. Calculated dipole
      moment vectors, electrostatic potential maps, and volume parameters suggest an
      explanation for the activity or inactivity of the synthesized derivatives and
      predict a putative binding site environment for the active agonists. Xanthine
      alkyl phosphate analogues proved to be selective agents for activation of P2X-R
      subtypes, whereas ATP activated all P2-R subtypes in cardiac cells. Therefore,
      these analogues may serve as prototypes of selective drugs aiming at cardiac
      disorders mediated through P2X receptors.

PMID- 10411490
TI  - Effect of aromatic short-chain analogues of ceramide on axonal growth in
      hippocampal neurons.
AB  - A series of D-erythro- and L-threo-ceramide analogues was synthesized and
      investigated for their ability to reverse the inhibitory effects of fumonisin
      B(1) (FB(1)) on axonal growth in hippocampal neurons. The analogues contained
      either a C(7) side chain or a phenyl group substituted for the C(13) residue
      present in naturally occurring ceramides, while the N-acyl chain length was
      reduced from C(16)-C(24) to C(2)-C(8). D-erythro-Ceramide 18a with a C(7) side
      chain and an N-acetyl residue and D-erythro-ceramide 20c with an aromatic side
      chain and an N-hexanoyl residue were most active in reversing the inhibitory
      effects of FB(1) on axonal growth, although the mechanism remains unclear.

PMID- 10411491
TI  - 1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1, 3-dihydroimidazol-2-one: a
      selective high-affinity antagonist for the human dopamine D(4) receptor with
      excellent selectivity over ion channels.
AB  - After the requirement of pseudocycle formation in the ureas 3 and 7 for hD(4)
      binding and selectivity was confirmed, structural hybridization with the known
      hD(4) ligand 2 led to the design and identification of the lead 4-(2-oxo-1, 3
      dihydroimidazol-2-yl)piperidine 8. Optimization studies were carried out on 8
      with the aim of achieving 1000-fold selectivity for hD(4) over all other
      receptors while retaining the good pharmacokinetic properties of the lead. After
      initial preparation of 8 as a minor component in a low-yielding reaction, a novel
      and regioselective "four-step/one-pot" procedure was developed which proved to be
      applicable to rapid investigation of the SAR of the 1, 3-dihydroimidazol-2-one
      ring. Various changes to substituents attached to the 3-, 4-, or 5-position of
      the 1, 3-dihydroimidazol-2-one core of 8 did not significantly improve
      selectivity for hD(4) over hD(2) and hD(3). Greater selectivity (>1000-fold) was
      ultimately achieved by meta substitution of the benzyl group of 8 with various
      substituents. Compounds 28, 31, and 32 all possess the required selectivity for
      hD(4) over the other dopamine subtypes, but only 32 has >1000-fold selectivity
      over all the key counterscreens we tested against. Compound 32 is an antagonist
      at hD(4) and has a good pharmacokinetic profile in the rat, with excellent
      estimated in vivo receptor occupancy, thus making it a potentially useful
      pharmacological tool to investigate the role of the D(4) receptor.

PMID- 10411492
TI  - (2R,1'S,2'R,3'S)-2-(2'-Carboxy-3'-phenylcyclopropyl)glycine (PCCG-13), the first
      potent and selective competitive antagonist of phospholipase D-coupled
      metabotropic glutamate receptors: asymmetric synthesis and preliminary biological
      properties.
AB  - The asymmetric synthesis of (2R,1'S,2'R, 3'S)-2-(2'-carboxy-3'
      phenylcyclopropyl)glycine (PCCG-13), a trisubstituted carboxycyclopropylglycine
      endowed with unusual stereochemical features, is described. Preliminary
      biological evaluation demonstrates PCCG-13 as a very potent and selective
      competitive antagonist for the novel class of metabotropic glutamate (mGlu)
      receptors coupled to the activity of phospholipase D (PLD). PCCG-13 is therefore
      a useful tool for the exploration of the physiopathological role of this novel
      class of receptors.

PMID- 10411493
TI  - Gene discovery and product development for grain quality traits.
AB  - The composition of oils, proteins, and carbohydrates in seeds of corn, soybean,
      and other crops has been modified to produce grains with enhanced value. Both
      plant breeding and molecular technologies have been used to produce plants
      carrying the desired traits. Genomics-based strategies for gene discovery,
      coupled with high-throughput transformation processes and miniaturized, automated
      analytical and functionality assays, have accelerated the identification of
      product candidates. Molecular marker-based breeding strategies have been used to
      accelerate the process of moving trait genes into high-yielding germplasm for
      commercialization. These products are being tested for applications in food,
      feed, and industrial markets.

PMID- 10411494
TI  - Nutritional genomics: manipulating plant micronutrients to improve human health.
AB  - The nutritional health and well-being of humans are entirely dependent on plant
      foods either directly or indirectly when plants are consumed by animals. Plant
      foods provide almost all essential vitamins and minerals and a number of other
      health-promoting phytochemicals. Because micronutrient concentrations are often
      low in staple crops, research is under way to understand and manipulate synthesis
      of micronutrients in order to improve crop nutritional quality. Genome sequencing
      projects are providing novel approaches for identifying plant biosynthetic genes
      of nutritional importance. The term "nutritional genomics" is used to describe
      work at the interface of plant biochemistry, genomics, and human nutrition.

PMID- 10411495
TI  - Plant functional genomics.
AB  - Nucleotide sequencing of the Arabidopsis genome is nearing completion, sequencing
      of the rice genome has begun, and large amounts of expressed sequence tag
      information are being obtained for many other plants. There are many
      opportunities to use this wealth of sequence information to accelerate progress
      toward a comprehensive understanding of the genetic mechanisms that control plant
      growth and development and responses to the environment.

PMID- 10411496
TI  - Worlds apart? The reception of genetically modified foods in Europe and the U.S.
AB  - Recent controversies about genetically modified foods in the United Kingdom and
      several other European countries highlight the apparent differences that exist in
      public opinion on this subject across the Atlantic. Why are people in the United
      States seemingly untroubled by a technology that causes Europeans so many
      difficulties? The results of survey research on public perceptions of
      biotechnology in Europe and the United States during 1996-1997, together with an
      analysis of press coverage and policy formation from 1984 to 1996, can help to
      answer this question.

PMID- 10411497
TI  - Biotechnology and food security in the 21st century.
AB  - Biotechnology can contribute to future food security if it benefits sustainable
      small-farm agriculture in developing countries. Presently, agrobiotechnology
      research cites ethical, safety, and intellectual property rights issues.
      Protection of intellectual property rights encourages private sector investment
      in agrobiotechnology, but in developing countries the needs of smallholder
      farmers and environmental conservation are unlikely to attract private funds.
      Public investment will be needed, and new and imaginative public-private
      collaboration can make the gene revolution beneficial to developing countries.
      This is crucial for the well-being of today's hungry people and future
      generations.

PMID- 10411498
TI  - Electronically configurable molecular-based logic gates 
AB  - Logic gates were fabricated from an array of configurable switches, each
      consisting of a monolayer of redox-active rotaxanes sandwiched between metal
      electrodes. The switches were read by monitoring current flow at reducing
      voltages. In the "closed" state, current flow was dominated by resonant tunneling
      through the electronic states of the molecules. The switches were irreversibly
      opened by applying an oxidizing voltage across the device. Several devices were
      configured together to produce AND and OR logic gates. The high and low current
      levels of those gates were separated by factors of 15 and 30, respectively, which
      is a significant enhancement over that expected for wired-logic gates.

PMID- 10411499
TI  - Electrostatic repulsion of positively charged vesicles and negatively charged
      objects 
AB  - A positively charged, mixed bilayer vesicle in the presence of negatively charged
      surfaces (for example, colloidal particles) can spontaneously partition into an
      adhesion zone of definite area and another zone that repels additional negative
      objects. Although the membrane itself has nonnegative charge in the repulsive
      zone, negative counterions on the interior of the vesicle spontaneously aggregate
      there and present a net negative charge to the exterior. Beyond the fundamental
      result that oppositely charged objects can repel, this mechanism helps to explain
      recent experiments on surfactant vesicles.

PMID- 10411500
TI  - Climate and satellite indicators to forecast Rift Valley fever epidemics in
      Kenya.
AB  - All known Rift Valley fever virus outbreaks in East Africa from 1950 to May 1998,
      and probably earlier, followed periods of abnormally high rainfall. Analysis of
      this record and Pacific and Indian Ocean sea surface temperature anomalies,
      coupled with satellite normalized difference vegetation index data, shows that
      prediction of Rift Valley fever outbreaks may be made up to 5 months in advance
      of outbreaks in East Africa. Concurrent near-real-time monitoring with satellite
      normalized difference vegetation data may identify actual affected areas.

PMID- 10411501
TI  - Unraveling the electronic structure of individual photosynthetic pigment-protein
      complexes 
AB  - Low-temperature single-molecule spectroscopic techniques were applied to a light
      harvesting pigment-protein complex (LH2) from purple photosynthetic bacteria. The
      properties of the electronically excited states of the two circular assemblies
      (B800 and B850) of bacteriochlorophyll a (BChl a) pigment molecules in the
      individual complexes were revealed, without ensemble averaging. The results show
      that the excited states of the B800 ring of pigments are mainly localized on
      individual BChl a molecules. In contrast, the absorption of a photon by the B850
      ring can be consistently described in terms of an excitation that is completely
      delocalized over the ring. This property may contribute to the high efficiency of
      energy transfer in these photosynthetic complexes.

PMID- 10411502
TI  - Differences in left-right axis pathways in mouse and chick: functions of FGF8 and
      SHH.
AB  - A molecular pathway leading to left-right asymmetry in the chick embryo has been
      described, in which FGF8 is a right determinant and Sonic Hedgehog a left
      determinant. Here evidence is presented that the Fgf8 and Sonic Hedgehog genes
      are required for left-right axis determination in the mouse embryo, but that they
      have different functions from those previously reported in the chick. In the
      mouse FGF8 is a left determinant and Sonic Hedgehog is required to prevent left
      determinants from being expressed on the right.

PMID- 10411503
TI  - Bacterial photoreceptor with similarity to photoactive yellow protein and plant
      phytochromes.
AB  - A phytochrome-like protein called Ppr was discovered in the purple photosynthetic
      bacterium Rhodospirillum centenum. Ppr has a photoactive yellow protein (PYP)
      amino-terminal domain, a central domain with similarity to phytochrome, and a
      carboxyl-terminal histidine kinase domain. Reconstitution experiments demonstrate
      that Ppr covalently attaches the blue light-absorbing chromophore p
      hydroxycinnamic acid and that it has a photocycle that is spectrally similar to,
      but kinetically slower than, that of PYP. Ppr also regulates chalcone synthase
      gene expression in response to blue light with autophosphorylation inhibited in
      vitro by blue light. Phylogenetic analysis demonstrates that R. centenum Ppr may
      be ancestral to cyanobacterial and plant phytochromes.

PMID- 10411504
TI  - An allele of COL9A2 associated with intervertebral disc disease.
AB  - Intervertebral disc disease is one of the most common musculoskeletal disorders.
      A number of environmental and anthropometric risk factors may contribute to it,
      and recent reports have suggested the importance of genetic factors as well. The
      COL9A2 gene, which codes for one of the polypeptide chains of collagen IX that is
      expressed in the intervertebral disc, was screened for sequence variations in
      individuals with intervertebral disc disease. The analysis identified a putative
      disease-causing sequence variation that converted a codon for glutamine to one
      for tryptophan in six out of the 157 individuals but in none of 174 controls. The
      tryptophan allele cosegregated with the disease phenotype in the four families
      studied, giving a lod score (logarithm of odds ratio) for linkage of 4.5, and
      subsequent linkage disequilibrium analysis conditional on linkage gave an
      additional lod score of 7.1.

PMID- 10411505
TI  - Prevention of graft versus host disease by inactivation of host antigen
      presenting cells.
AB  - Graft versus host disease, an alloimmune attack on host tissues mounted by donor
      T cells, is the most important toxicity of allogeneic bone marrow
      transplantation. The mechanism by which allogeneic T cells are initially
      stimulated is unknown. In a murine allogeneic bone marrow transplantation model
      it was found that, despite the presence of numerous donor antigen-presenting
      cells, only host-derived antigen-presenting cells initiated graft versus host
      disease. Thus, strategies for preventing graft versus host disease could be
      developed that are based on inactivating host antigen-presenting cells. Such
      strategies could expand the safety and application of allogeneic bone marrow
      transplantation in treatment of common genetic and neoplastic diseases.

PMID- 10411506
TI  - Generation of a widespread Drosophila inversion by a transposable element.
AB  - Although polymorphic inversions in Drosophila are very common, the origin of
      these chromosomal rearrangements is unclear. The breakpoints of the cosmopolitan
      inversion 2j of D. buzzatii were cloned and sequenced. Both breakpoints contain
      large insertions corresponding to a transposable element. It appears that the two
      pairs of target site duplications generated upon insertion were exchanged during
      the inversion event, and that the inversion arose by ectopic recombination
      between two copies of the transposon that were in opposite orientations. This is
      apparently the mechanism by which transposable elements generate natural
      inversions in Drosophila.

PMID- 10411507
TI  - Identification of a vertebrate sister-chromatid separation inhibitor involved in
      transformation and tumorigenesis.
AB  - A vertebrate securin (vSecurin) was identified on the basis of its biochemical
      analogy to the Pds1p protein of budding yeast and the Cut2p protein of fission
      yeast. The vSecurin protein bound to a vertebrate homolog of yeast separins Esp1p
      and Cut1p and was degraded by proteolysis mediated by an anaphase-promoting
      complex in a manner dependent on a destruction motif. Furthermore, expression of
      a stable Xenopus securin mutant protein blocked sister-chromatid separation but
      did not block the embryonic cell cycle. The vSecurin proteins share extensive
      sequence similarity with each other but show no sequence similarity to either of
      their yeast counterparts. Human securin is identical to the product of the gene
      called pituitary tumor-transforming gene (PTTG), which is overexpressed in some
      tumors and exhibits transforming activity in NIH 3T3 cells. The oncogenic nature
      of increased expression of vSecurin may result from chromosome gain or loss,
      produced by errors in chromatid separation.

PMID- 10411508
TI  - Different trajectories of parallel evolution during viral adaptation.
AB  - The molecular basis of adaptation is a major focus of evolutionary biology, yet
      the dynamic process of adaptation has been explored only piecemeal. Experimental
      evolution of two bacteriophage lines under strong selection led to over a dozen
      nucleotide changes genomewide in each replicate. At least 96 percent of the amino
      acid substitutions appeared to be adaptive, and half the changes in one line also
      occurred in the other. However, the order of these changes differed between
      replicates, and parallel substitutions did not reflect the changes with the
      largest beneficial effects or indicate a common trajectory of adaptation.

PMID- 10411509
TI  - Conservation and function of a bovine sperm A-kinase anchor protein homologous to
      mouse AKAP82.
AB  - Protein kinase A regulates sperm motility through the cAMP-dependent
      phosphorylation of proteins. One mechanism to direct the activity of the kinase
      is to localize it near its protein substrates through the use of anchoring
      proteins. A-Kinase anchoring proteins (AKAPs) act by binding the type II
      regulatory subunit of protein kinase A and tethering it to a cellular organelle
      or cytoskeletal element. We showed previously that mAKAP82, the major protein of
      the fibrous sheath of the mouse sperm flagellum, is an AKAP. The available
      evidence indicates that protein kinase A is compartmentalized to the fibrous
      sheath by binding mAKAP82. To characterize AKAP82 in bovine sperm, a testicular
      cDNA library was constructed and used to isolate a clone encoding bAKAP82, the
      bovine homologue. Sequence analysis showed that the primary structure of bAKAP82
      was highly conserved. In particular, the amino acid sequence corresponding to the
      region of mAKAP82 responsible for binding the regulatory subunit of protein
      kinase A was identical in the bull. Bovine AKAP82 was present in both epididymal
      and ejaculated sperm and was localized to the entire principal piece of the
      flagellum, the region in which the fibrous sheath is located. Finally, bAKAP82
      bound the regulatory subunit of protein kinase A. These data support the idea
      that bAKAP82 functions as an anchoring protein for the subcellular localization
      of protein kinase A in the flagellum.

PMID- 10411510
TI  - Acute effects of adenosine triphosphates, cyclic 3',5'-adenosine monophosphates,
      and follicle-stimulating hormone on cytosolic calcium level in cultured immature
      rat Ssertoli cells.
AB  - The ability of ATP and FSH to induce intracellular calcium [Ca(2+)](i) changes in
      Sertoli cells is imperfectly understood and reports are conflicting. We have
      applied the single-cell microfluorometry technique with the calcium probe indo-1
      to investigate [Ca(2+)](i) in individual cultured Sertoli cells. When cells were
      exposed to ATP, cAMP, and FSH, a fast and biphasic increase in [Ca(2+)](i) was
      obtained in 100%, 70%, and 56% of cells, respectively. Caffeine did not activate
      Ca(2+) mobilization, while thapsigargin suppressed the peak response. External
      calcium free-EGTA buffer suppressed the plateau phase, while blockers of voltage
      operated Ca(2+) channels did not abolish the response to cAMP and ATP. We
      conclude that the three messengers mobilized Ca(2+) from intracellular
      thapsigargin-sensitive stores, which induced a subsequent Ca(2+) influx from the
      extracellular medium by a voltage-independent Ca(2+) entry. The well-documented
      mechanisms by which these messengers act on cells support the idea that they
      release Ca(2+) from smooth endoplasmic reticulum by two different pathways, or
      that FSH and cAMP first release ATP, which then acts on cells. Among the cells,
      77% and 80% responded, respectively, to FSH and cAMP by a delayed long-lasting
      decrease in [Ca(2+)](i) that was never recorded in the presence of ATP. This
      suggests that FSH and cAMP also promote a slow redistribution of [Ca(2+)](i) from
      the exchangeable pool to the bound nonexchangeable pools. Involvement of voltage
      operated and voltage-independent calcium channels in the response of Sertoli
      cells to ATP, FSH, and cAMP is discussed.

PMID- 10411511
TI  - Androgens promote oocyte insulin-like growth factor I expression and initiation
      of follicle development in the primate ovary.
AB  - In the study reported here, we investigated the effect of androgens on
      recruitment of resting, primordial follicles into the actively growing pool.
      Healthy, random-cycling female rhesus monkeys were treated with testosterone,
      dihydrotestosterone (DHT), or vehicle for 3-10 days, after which ovaries were
      collected for histological analysis. The first stage of follicle growth is the
      formation of the primary follicle, consisting of an oocyte surrounded by a single
      layer of cuboidal granulosa cells. The number of primary follicles was
      significantly increased over time in testosterone-treated animals. In situ
      hybridization showed that androgen treatment resulted in an increase to 3-fold in
      insulin-like growth factor I (IGF-I) and to 5-fold in IGF-I receptor mRNA in
      primordial follicle oocytes. DHT effects were comparable to those of
      testosterone, showing that these are androgen receptor-mediated phenomena. These
      data show that androgens promote initiation of primordial follicle growth and
      implicate oocyte-derived IGF-I in this activation process.

PMID- 10411512
TI  - Evidence for ovarian granulosa stem cells: telomerase activity and localization
      of the telomerase ribonucleic acid component in bovine ovarian follicles.
AB  - We have previously postulated that granulosa cells of developing follicles arise
      from a population of stem cells. Stem cells and cancer cells can divide
      indefinitely partly because they express telomerase. Telomerase is a
      ribonucleoprotein enzyme that repairs the ends of telomeres that otherwise
      shorten progressively upon each successive cell division. In this study we
      carried out cell cycle analyses and examined telomerase expression to examine our
      hypothesis. Preantral (60-100 microm) and small (1 mm) follicles, as well as
      granulosa cells from medium-sized (3 mm) and large (6-8 mm) follicles, were
      isolated. Cell cycle analyses and expression of Ki-67, a cell cycle-related
      protein, were undertaken on follicles of each size (n = 3) by flow cytometry; 12%
      to 16% of granulosa cells in all follicles were in the S phase, and less than 2%
      were in the G(2)/M phase. Telomerase activity (n = 3) was highest in the small
      preantral follicles, declining at the 1-mm stage and even further at the 3-mm
      stage. In situ hybridization histochemistry was carried out on bovine ovaries,
      and telomerase RNA was detected in the granulosa cells of growing follicles but
      not primordial follicles. Two major patterns of staining were observed in the
      membrana granulosa of antral follicles: staining in the middle and antral layers,
      and staining in the middle and basal layers. No staining was detected in oocytes.
      Our results strongly support our hypothesis that granulosa cells arise from a
      population of stem cells.

PMID- 10411513
TI  - Participation of embryonic genotype in the pregnancy block phenomenon in mice.
AB  - Pregnancy block by male pheromones in mice differs in incidence depending on the
      combination of strains. Female mice of BALB/cA strain mated with BALB/cA males
      show a 100% pregnancy block when exposed to males of inbred strain DDK shortly
      after copulation (Chung et al., Biol Reprod 1997; 57:312-319). In the present
      study, BALB/cA females mated with the males of other strains--CBA/J, C3H/HeN,
      C57BL/6Cr, and IXBL--showed higher pregnancy rates (66.6-87. 5%) even when they
      were exposed to DDK males. In the pharmacological induction of pregnancy block
      with dopamine agonist (bromocriptine, 4 mg/kg BW), BALB/cA females mated with
      BALB/cA males showed a 100% pregnancy block. In contrast, BALB/cA females mated
      with CBA/J, C3H/HeN, and C57BL/6Cr males showed higher pregnancy rates (40-70%).
      These results suggest that the better pregnancy rate of BALB/cA females mated
      with alien males may be due to the stronger viability of F(1) embryos. This
      interpretation was confirmed by an embryo transfer experiment in which a higher
      implantation rate was observed when BALB/cA embryos grown in BALB/cA females
      exposed to BALB/cA males were transferred into recipient BALB/cA females exposed
      to DDK males. These results suggest that the embryonic genotype or viability of
      the embryo is one factor contributing to the occurrence of pregnancy block by
      male pheromones in mice.

PMID- 10411514
TI  - Isolation of complementary deoxyribonucleic acids encoding putative secreted and
      membrane-bound folate binding proteins from endometrium of swine.
AB  - Two distinct forms of endometrial folate binding protein (FBP) cDNAs were
      isolated using reverse transcription-polymerase chain reaction and 3' and 5'
      rapid amplification of cDNA ends (RACE) procedures. On the basis of the absence
      or presence of an intact glycophosphatidylinositol linkage site in the C terminus
      of the predicted amino acid sequences, the two forms appear to encode secreted
      and membrane-bound forms of FBP. The cDNAs for the putative secreted and membrane
      forms encoded 252- and 249-amino acid proteins, respectively, that were 73%
      identical with each other and were 66-82% identical with other known FBPs.
      However, the nucleotide sequences within the 5' untranslated region and from
      codons 224 and 223 of the secreted and membrane forms, respectively, to the 3'
      ends of each RNA, were divergent. The divergence in the 3' ends of the two cDNAs
      was exploited to determine changes in concentrations of each mRNA in the
      endometrium during the estrous cycle and early pregnancy. Northern blots of
      endometrial total RNA probed with a putative secreted FBP specific probe
      indicated that mRNA concentrations do not change during early pregnancy. In
      contrast, blots probed with a putative membrane FBP specific probe indicated that
      mRNA concentrations increase dramatically from Day 15 to Day 24 of pregnancy.
      Finally, N-terminal amino acid sequencing of FBP purified from Day 15 pregnant
      uterine flushings matched the secreted form of FBP mRNA. These data are
      consistent with a role for putative secreted and membrane-bound forms of FBPs in
      the transport of folate to the developing swine conceptus during early pregnancy.

PMID- 10411515
TI  - Uterine-associated serine protease inhibitors stimulate deoxyribonucleic acid
      synthesis in porcine endometrial glandular epithelial cells of pregnancy.
AB  - Protease inhibitors are major secretory components of the mammalian uterus that
      are thought to mediate pregnancy-associated events primarily by regulating the
      activity of proteolytic enzymes. In the present study, we examined the mitogenic
      potentials of two serine protease inhibitors, namely secretory leukocyte protease
      inhibitor (SLPI) and uterine plasmin/trypsin inhibitor (UPTI) in primary cultures
      of glandular epithelial (GE) cells isolated from early pregnant (Day 12) pig
      endometrium, using the [(3)H]thymidine incorporation assay. Purified porcine SLPI
      (pSPLI), porcine UPTI (pUPTI), or recombinant human SLPI (rhSLPI), all of which
      exhibited anti-trypsin activity, increased (p < 0.05) labeled thymidine
      incorporation into DNA of serum-deprived GE cells when tested at a range of 10
      1000-ng/ml concentrations. Polyclonal antibodies directed against either hSLPI or
      pSLPI abrogated the effect of SLPI. Co-addition of pSLPI and pUPTI increased DNA
      synthesis in these cells to a level higher (p < 0.05) than that observed with
      either protease inhibitor. The glycosaminoglycan heparin, which has been
      previously shown to increase the anti-protease activity of SLPI, exhibited a
      tendency (p = 0.08) to enhance SLPI and UPTI induction of cellular DNA synthesis.
      Reverse transcription-polymerase chain reaction indicated that the messenger RNAs
      for both protease inhibitors were present in the endometrium throughout pregnancy
      and, within this tissue, in GE cells to a greater extent (p < 0.05) than in
      stromal fibroblastic cells. Results demonstrate that, in addition to their well
      documented anti-protease activities, SLPI and UPTI may constitute autocrine
      growth promotants for the uterine epithelium. These data suggest a novel
      mechanism whereby locally produced protease inhibitors may modulate
      periimplantation events and embryo-maternal communication.

PMID- 10411516
TI  - Mitogenic and antioxidant mechanisms of estradiol action in preovulatory ovine
      follicles: relevance to luteal function.
AB  - The objectives of this investigation were to determine the intrafollicular
      mechanisms and physiological consequences of estradiol actions in preovulatory
      ovine follicles. Acute suppression of estradiol production in proestrous ewes by
      an aromatase inhibitor (Arimidex) was associated with follicular lipid
      peroxidation, testosterone accumulation, and a granulosa cell deficiency
      (decreased proliferation/increased apoptosis). Estradiol-17beta stimulated
      granulosa proliferating cell nuclear antigen (PCNA) and protected cells from
      oxidative (H(2)O(2)) stress-induced apoptosis in vitro; the PCNA, but not the
      antiapoptotic response, was negated by the transcriptional inhibitor actinomycin
      D. Thus, it appears that genomic/mitotic and cytoprotective (oxygen-scavenging)
      modes of estradiol action operate in preovulatory follicles. Luteal (large
      steroidogenic cell) function was diminished following ovulation induction of
      estradiol-deficient follicles. It is suggested that inadequate exposure of the
      preovulatory follicle to estradiol caused the granulosa lutein insufficiency.

PMID- 10411517
TI  - Role of radical oxygen species in rat testicular germ cell apoptosis induced by
      heat stress.
AB  - The present study was designed to clarify the role of radical oxygen species in
      testicular germ cell apoptosis induced by heat stress. Testicular cells isolated
      from immature rats were cultured with or without elevated temperature, and
      occurrence of apoptosis in these cells was defined by the appearance of DNA
      fragmentation following agarose gel electrophoresis and by flow cytometric
      quantification of apoptotic cells. At 32.5 degrees C, < 1% of cells showed signs
      of apoptosis throughout the culture period, whereas under heat stress, the
      proportion of apoptotic cells increased to 5% at 37 degrees C after 24 h of
      culture, or to 14% after 1-h exposure at 43 degrees C followed by 23-h culture at
      32.5 degrees C. Similar to the effect of heat stress, exogenously supplied oxygen
      free radicals also induced apoptosis. In contrast, treatment with catalase
      significantly attenuated heat stress-induced apoptosis. Furthermore, heat stress
      of testicular cells was associated with an increased intracellular peroxide level
      as measured by a fluorescent probe, 2', 7'-dichlorofluorescin diacetate. In
      conclusion, our data indicate the involvement of radical oxygen species during
      testicular germ cell apoptosis induced by heat stress. This study provides a
      useful in vitro model for the study of testicular germ cell apoptosis.

PMID- 10411518
TI  - Sperm mobility: A primary determinant of fertility in the domestic fowl (Gallus
      domesticus).
AB  - Previous research demonstrated that sperm mobility is a quantitative trait of the
      domestic fowl. The trait is quantified by measuring the absorbance of an Accudenz
      solution after overlay with a sperm suspension and brief incubation at body
      temperature. In the present work, average and high sperm mobility phenotypes (n =
      30 males per phenotype) were selected from a base population. Differences were
      found between sperm oxygen consumption (p < 0.0001), acylcarnitine content (p <
      0.05), linear velocity (p < 0.001), and straightness (p < 0.001), a trajectory
      variable measured with the Hobson SpermTracker. Oxygen consumption and
      stearoylcarnitine content of sperm from the high-mobility phenotype were twice
      those observed with sperm from average males, implying a pivotal role for
      mitochondria. On the basis of these results, a graded relationship was predicted
      between fertility and sperm mobility. Males (n = 48) were chosen at random from
      another base population, sperm mobility was measured per male, and each ejaculate
      was used to inseminate 8-12 hens (8 x 10(7) viable sperm per hen). When fertility
      was plotted as a function of sperm mobility, data points approximated a skewed
      logistic function. The hypothesis that vaginal immunoglobulins constitute an
      immunological barrier to sperm transport was tested and rejected. Therefore, we
      concluded that sperm mobility is a primary determinant of fertility in the fowl.

PMID- 10411519
TI  - Analysis of in vitro migration patterns of human spermatozoa by a petri dish
      based horizontal column.
AB  - Spermatozoa are required to travel a considerable distance in vivo to meet the
      oocyte at the fertilization site. However, none of the existing in vitro tests
      critically evaluates migration of sperm to assess their potential of reaching the
      oocyte. On the other hand, an in vivo model is not suitable for this type of
      study because of ethical and technical constraints. In the present study we
      utilized a horizontal column technique to analyze sperm migration. Migratory
      characteristics of fresh, unwashed semen sperm and sperm undergoing various
      treatments were examined in vitro using a Petri dish-based horizontal fluid
      column. The procedure involved loading a sperm sample into the column and
      determining sperm concentration, motility, and viability at different column
      segments for different migration durations (6, 12, 24, 48, and 72 h). All sperm
      samples produced an exponential migration pattern in all durations of migration.
      Propagation along the column edge, tendency to exit from the column, and hiding
      in the blind pouches were some of the important characteristic features exhibited
      by the migratory sperm. Variations in migration patterns were documented among
      semen donors, between fresh and frozen semen, and between washed and unwashed
      sperm. Prolonged postejaculation time diminished migratory potential. The
      recovery of sperm in the column end was independent of seminal variables with the
      exception of oligozoospermia. These observations suggest that the Petri dish
      based horizontal column is effective for analyzing sperm migration
      characteristics for prolonged periods. The potential of this migration assay in
      predicting the in vivo potential of spermatozoa to reach the fertilization site
      will be worth exploring.

PMID- 10411520
TI  - Pulsatile output of prostaglandin F(2alpha) does not increase around the time of
      luteolysis in the pregnant goat.
AB  - Prostaglandin (PG) F(2alpha) secreted from the uterus is the luteolysin of the
      estrous cycle and is also believed to be responsible for luteolysis in the
      pregnant doe at term. We have reported that basal progesterone concentrations
      decrease before basal PGF(2alpha) concentrations increase, which is inconsistent
      with this view. In this study we investigated whether luteolysis is associated
      with increased frequency or amplitude of pulsatile PGF(2alpha) secretion in does
      over the last 2 wk of gestation. Progesterone concentrations decreased
      approximately 1 wk before parturition. There was no accompanying increase in
      PGF(2alpha) concentrations or pulse frequency, and those pulses that were
      observed were of lesser amplitude and duration than those that have been
      associated with luteolysis in cycling ewes. A small increase in PGF(2alpha) pulse
      frequency was identified during the 3 days before parturition, but this was not
      associated with any change in progesterone concentrations. The biological
      significance of these small changes in PGF(2alpha) pulse frequency is obscure,
      although the high concentration of this eicosanoid at labor may have been related
      to the final, precipitous decline in plasma progesterone concentrations. These
      findings do not support the notion that PGF(2alpha) is the principal luteolysin
      in the pregnant doe at term.

PMID- 10411521
TI  - Glucocorticoids stimulate the accumulation of lipids in the rat corpus luteum.
AB  - We investigated the physiological basis for the trophic effect of glucocorticoids
      in rat corpora lutea in the absence of pituitary gonadotropins. Immature (Day 29)
      Sprague-Dawley rats were given eCG and hCG to induce the development of corpora
      lutea and were hypophysectomized on Day 32. Beginning on Day 40, rats received
      twice-daily s.c. injections of either dexamethasone (dex; 200 microg/rat/day) or
      vehicle (controls) and then were killed on Day 44. Plasma 20alpha
      dihydroprogesterone, a major steroid produced by the corpora lutea, was higher (p
      </= 0.01) in dex-treated than in control rats (44.5 +/- 2.3 vs. 23.0 +/- 5.6
      ng/ml). Dexamethasone treatment increased lipid droplets and lipid in the corpora
      lutea as revealed by electron microscopy and oil red O staining. Cholesterol
      esters were higher in corpora lutea of dex-treated rats compared to controls
      (14.8 +/- 1.1 vs. 2.2 +/- 0.5 microg/mg corpora lutea wet tissue, respectively; p
      </= 0.05). Another group of hypophysectomized rats was treated with either a high
      or a lower dosage of corticosterone, both of which caused an elevation to > 2
      fold of plasma 20alpha-dihydroprogesterone concentration compared to controls.
      Glucocorticoid receptor protein (about 92 kDa) was detected in both luteal and
      nonluteal ovarian tissues in this animal model. These effects of glucocorticoids
      and the presence of the glucocorticoid receptor raise the possibility of a
      physiological role for glucocorticoids in the rat corpus luteum.

PMID- 10411522
TI  - Turkey sperm mobility influences paternity in the context of competitive
      fertilization.
AB  - We have devised a novel means of investigating competitive fertilization in
      turkeys, using microsatellite genotyping to identify male parentage. Our results
      demonstrate that sperm mobility is a mechanism responsible in part for paternity
      efficiency in turkeys. Sperm mobility is composed of several parameters in which
      sperm motility is a component. Differences between ejaculates in the number of
      sperm penetrating into a dense, insert, nontoxic solution were measured and used
      to classify males into high, average, or low sperm mobility phenotypes.
      Microsatellite genotyping was used to determine parentage of poults after equal
      numbers of sperm from 10 males (either high or average phenotype, n = 5, mixed
      with low phenotype, n = 5) were inseminated simultaneously. In a separate study,
      the numbers of sperm hydrolyzing the perivitelline layer of eggs were compared
      between hens inseminated with sperm from high-, average-, or low-phenotype males.
      Overall, heterospermic inseminations resulted in consistently fewer offspring
      produced by low-mobility phenotype males. This correlated with physiological data
      in which semen from the low-mobility males had reduced numbers of sperm at the
      fertilization site as determined by sperm hole counts in the perivitelline layer
      of eggs. This is the first illustration of a measurable sperm trait predictive of
      paternity success in a competitive fertilization trial in turkeys, a species that
      is predominately reproduced by artificial insemination of multiple-sire pools.

PMID- 10411523
TI  - Sperm mitochondria-associated cysteine-rich protein (SMCP) is an autoantigen in
      Lewis rats.
AB  - A common repertoire of rat sperm antigens have previously been identified by
      Western blotting of sperm proteins with sera obtained after vasectomy or
      isoimmunization with sperm. Aside from a determination of their apparent masses,
      however, the biochemical characteristics of these antigens have remained unknown.
      In this study, a rat testis cDNA expression library was screened with polyclonal
      antibodies obtained from rats immunized with isologous spermatozoa to identify
      and sequence a full-length clone encoding rat sperm mitochondria-associated
      cysteine-rich protein (SMCP). The open reading frame of SMCP was expressed in the
      pET22b vector, and recombinant SMCP (rec-SMCP) was purified. Sera from rats that
      had been vasectomized or hyperimmunized with isologous sperm specifically
      recognized rec-SMCP whereas preimmune sera from these experimental groups did not
      react. Rabbit antiserum produced to rec-SMCP recognized rec-SMCP on Western blots
      and precisely immunolocalized SMCP to the mid-piece of rat sperm. On Western
      blots against sperm extracts, the rabbit antibody recognized a major protein band
      of approximately 22-25 kDa that co-migrated with bands of identical mass that
      were recognized by sera from hyperimmune or vasectomized rats. These findings
      demonstrate that SMCP is a sperm autoantigen, recognized following vasectomy, and
      an isoantigen, recognized by antibodies generated through isologous immunization
      with sperm.

PMID- 10411524
TI  - Inter-alpha-inhibitor binding to hyaluronan in the cumulus extracellular matrix
      is required for optimal ovulation and development of mouse oocytes.
AB  - This report characterizes the effects of excess hyaluronan (HA) upon the
      expansion of the cumulus oocyte complex (COC) within intact follicles and upon
      ovulation and oocyte viability in mice. Covalent linkage between heavy chains of
      the inter-alpha-inhibitor (IalphaI) family of serum glycoproteins and HA is
      necessary for optimal cumulus extracellular matrix (cECM) stabilization and
      cumulus expansion. Intravenous administration of HA oligosaccharides inhibited
      the binding of IalphaI to endogenous HA, disrupting the process of expansion and
      resulting in a reduction in the size of the cumulus mass. Western blot and
      immunocytochemical analyses of COCs from HA-treated animals demonstrated a
      reduction of IalphaI heavy chains within the cECM. Additionally, HA-treated
      immature animals ovulated 56.3% fewer COCs compared to control animals. The
      developmental potential of COCs in HA-treated animals was also tested. Extended
      periods of oviductal storage of COCs ovulated by HA-injected adult mice resulted
      in a reduction of normal embryos and a significant increase in the proportion of
      fragmented oocytes/embryos. These observations support the view that covalent
      binding of IalphaI heavy chains to HA is required for optimal cumulus expansion,
      extrusion of the COCs from the follicle at ovulation, and maintenance of oocyte
      viability within the oviduct.

PMID- 10411525
TI  - A plasma membrane-associated hyaluronidase is localized to the posterior
      acrosomal region of stallion sperm and is associated with spermatozoal function.
AB  - Sperm hyaluronidase has been implicated in sperm penetration of the extracellular
      matrix of the cumulus oophorus and may play a crucial role in gamete interaction
      and fertility in mammals. The objectives of this study were to characterize the
      enzyme activity of equine sperm hyaluronidase and to investigate its cellular
      distribution. Zymography of stallion sperm plasma membrane extracts was used to
      identify hyaluronidase activity in protein bands. Affinity-purified polyclonal
      IgG raised against equine sperm hyaluronidase was used to label fresh and
      capacitated stallion sperm, followed by indirect immunofluorescence. Equine sperm
      plasma membrane extracts displayed 3 major protein bands with potent
      hyaluronidase activity of approximately 54, 59, and 83 kDa. Under reducing
      conditions, a single protein band was observed at 62 kDa, although the reduced
      sample exhibited no enzyme activity. The polyclonal IgG labeled the postacrosomal
      region of stallion sperm and was redistributed over the acrosomal region during
      in vitro capacitation in a significant percentage of sperm cells. These studies
      suggest that a specific protein localized to the equine sperm head displays
      hyaluronidase activity, gets redistributed over the acrosomal region during
      capacitation, and may be important in fertility in this species.

PMID- 10411526
TI  - Bicarbonate/chloride exchange regulates intracellular pH of embryos but not
      oocytes of the hamster.
AB  - The ability to regulate intracellular pH (pH(i)) is essential for normal cell
      development and differentiation. This study was an investigation of the
      regulatory system used by the hamster oocyte and preimplantation embryo to
      regulate pH(i) in the alkaline range. Recovery from alkalosis by late 1-cell and
      2-cell embryos was rapid, and physiological pH(i) levels could be restored within
      10 min. Recovery from an induced alkaline load was dependent on the chloride
      concentration in the external medium and sensitive to a stilbene derivative 4,4'
      diisothiocyanatostilbene-2,2'-di-sulfonic acid that inhibits bicarbonate and
      chloride exchange. Therefore the recovery from alkalosis by hamster embryos
      appears to be via activity of the HCO(3)(-)/Cl(-) exchanger that was activated
      above a pH(i) set point of 7.24. In contrast, hamster oocytes and early 1-cell
      embryos (collected 3-4 h post-egg activation) could not recover from an
      intracellular alkalosis, and pH(i) remained elevated. Therefore, the hamster
      oocyte and the early 1-cell embryo still undergoing pronuclear formation lack an
      active HCO(3)(-)/Cl(-) exchanger for the restoration of pH(i). Inability to
      restore pH(i) from an alkali challenge resulted in a reduced ability of embryos
      to develop to the morula/blastocyst stages in culture, indicating that HCO(3)(
      )/Cl(-) exchange is involved in physiological regulation of pH(i).

PMID- 10411527
TI  - Apoptosis in human term placenta is not increased during labor but can be
      massively induced in vitro.
AB  - Apoptosis in human placental villi is reported to increase until close to
      delivery. However, the involvement of the apoptotic process in the initiation of
      labor, and more particularly in relation to the decrease in placental perfusion
      during uterine contractions, remains unknown. The purpose of the study was to
      examine the reactivity of the apoptotic machinery in term placentae obtained
      before or after the onset of labor and after in vitro incubations. The incidence
      of apoptotic nuclei (< 1%) as evidenced by the terminal deoxynucleotidyl
      transferase-mediated dUTP nick end-labeling (TUNEL) method, and the histological
      distribution of immunoreactive Bcl-2, Bax, and Bcl-x proteins, were similar in
      placentae collected after delivery and before the onset of labor and in placental
      explants maintained overnight at 4 degrees C in a minimal salt-Hepes medium. By
      contrast, 28% of nuclei contained fragmented DNA when placental explants were
      incubated overnight at 37 degrees C. This marked increase was associated with a
      decrease in the intensity of the Bcl-2 immunostaining and an increase in the
      intensity of Bax and Bcl-x immunostaining. In conclusion, the present study
      clearly evidences the presence of an active apoptotic machinery in term placental
      cells that is not involved in normal parturition.

PMID- 10411529
TI  - Virilization of the male pouch young of the tammar wallaby does not appear to be
      mediated by plasma testosterone or dihydrotestosterone.
AB  - Virilization of the male urogenital tract of all mammals, including marsupials,
      is mediated by androgenic hormones secreted by the testes. We have previously
      demonstrated profound sexual dimorphism in the concentrations of gonadal
      androgens in pouch young of the tammar wallaby Macropus eugenii during the
      interval when the urogenital sinus virilizes. To provide insight into the
      mechanisms by which androgens are transported from the testes to the target
      tissues, we measured testosterone and dihydrotestosterone in plasma pools from
      tammar pouch young from the day of birth to Day 150. Plasma testosterone levels
      were measurable (0.5-2 ng/ml) at all times studied, but there were no differences
      between males and females. These low concentrations of plasma testosterone appear
      to be derived from the adrenal glands and not the testes. Plasma
      dihydrotestosterone levels in plasma pools from these animals were also low and
      not sexually dimorphic. We conclude that virilization of the male urogenital
      tract cannot be explained by the usual transport of testosterone or
      dihydrotestosterone in plasma but may be mediated by the direct delivery of
      androgens to the urogenital tract via the Wolffian ducts. Alternatively,
      circulating prohormones may be converted to androgens in target tissues.

PMID- 10411528
TI  - Differential effects of intrauterine and subcutaneous administration of
      recombinant ovine interferon tau on the endometrium of cyclic ewes.
AB  - Interferon tau (IFNtau) is the antiluteolytic signal produced by the conceptus of
      ruminants. Intrauterine administration of recombinant ovine IFNtau suppresses
      expression of endometrial estrogen receptor (ER) and oxytocin receptor (OTR) in
      the luminal and superficial glandular epithelia to abrogate the production of
      luteolytic prostaglandin F(2alpha) (PGF(2alpha)) pulses. Subcutaneous (s.c.)
      injections of recombinant ovine (o) IFNtau appear to extend the interestrous
      interval by altering uterine PGF(2alpha) response to oxytocin. The present study
      tested the hypothesis that antiluteolytic effects of roIFNtau injected into the
      uterine lumen (paracrine) or s.c. (endocrine) are equivalent in suppressing
      expression of endometrial ER and OTR and inducing uterine expression of type I
      IFN-regulated Mx and ubiquitin cross-reactive proteins (UCRP). Sixteen cyclic
      ewes were fitted with uterine catheters on Day 5 (Day 0 = estrus), were assigned
      randomly to receive treatment with control proteins or roIFNtau (2 x 10(7)
      antiviral units/day) by either intrauterine or s.c. injections from Days 11 to
      15, and were ovariohysterectomized on Day 16. Results indicated that expression
      of ER and OTR mRNAs in endometrial epithelium was suppressed by intrauterine but
      not by s.c. injections of roIFNtau. Intrauterine injections of roIFNtau increased
      expression of Mx and UCRP mRNA in the endometrium. Subcutaneous injections of
      roIFNtau increased endometrial Mx mRNA levels but not UCRP mRNA. Unexpectedly,
      intrauterine and s.c. injections of roIFNtau were equally effective in inducing
      expression of Mx and UCRP mRNA in the corpus luteum. Although s.c. injections of
      roIFNtau induced Mx mRNA in the endometrial epithelium, s.c. injections of
      roIFNtau did not abrogate activation of the uterine luteolytic mechanism by
      suppressing epithelial ER and OTR expression. Therefore, results of this study
      failed to support the assumption that endocrine roIFNtau mimics antiluteolytic
      effects of paracrine IFNtau to improve pregnancy rates in sheep.

PMID- 10411530
TI  - Expression and hormonal regulation of the Sox4 gene in mouse female reproductive
      tissues.
AB  - The SOX genes define a family of transcriptional regulators whose diverse
      patterns and tightly controlled temporal profiles of expression suggest that they
      play key roles in determination of cell fate during development. One of the
      family members, Sox4, is expressed in the gonads of adult mice, but expression in
      the reproductive tissues has not been studied. As previous studies in this
      laboratory had shown that the SOX4 gene was regulated by ovarian hormones in
      breast cancer cells, murine Sox4 expression was analyzed in the reproductive
      tissues of mice by Northern blot analysis and ribonuclease protection assays.
      Sox4 mRNA expression was detected in the uterus and, at a lower level, in the
      mammary glands of pubertal and adult mice. Expression was modulated in the uterus
      of intact mice at various stages of the estrous cycle and was reduced by
      estradiol treatment of ovariectomized mice. Progesterone treatment partially
      reversed the estradiol effect. Although no modulation of Sox4 expression in the
      mammary glands was detected by Northern blot analysis, further evaluation of Sox4
      protein expression at a cellular level is required. No modulation of Sox4 levels
      was observed in the thymus. The results presented here suggest that expression of
      the Sox4 gene is under ovarian hormone control in the uterus and implicate Sox4
      in the complex effects controlled by ovarian hormones in the female reproductive
      system.

PMID- 10411531
TI  - Comparison of protein synthesis patterns in mouse cumulus cells and mural
      granulosa cells: effects of follicle-stimulating hormone and insulin on granulosa
      cell differentiation in vitro.
AB  - Successful development of mammalian oocytes requires correct interactions between
      developing oocytes and associated granulosa cells. Development of oocyte
      granulosa cell complexes from preantral follicles in vitro does not produce
      oocytes competent to develop to blastocysts at the same frequency as for oocytes
      that develop in vivo. Addition of either FSH or insulin to cultures of oocyte
      granulosa cell complexes does not improve the frequency of blastocyst
      development, and the combination of both insulin and FSH is deleterious. Here,
      high-resolution 2-dimensional PAGE (2D-PAGE) and computerized gel image analysis
      were used to compare patterns of protein synthesis in cumulus cells and mural
      granulosa cells of small antral follicles, and then to assess effects of FSH and
      insulin on the differentiation of oocyte-associated granulosa cells (OAGCs) in
      vitro. Culture of OAGCs without FSH or insulin resulted in failure to synthesize
      many proteins at rates characteristic of cumulus cells. Either hormone used alone
      caused many cumulus cell proteins that were decreased in control cultures to be
      synthesized at nearly normal cumulus cell rates, and also caused the synthesis of
      other proteins to be increased or decreased. The two hormones added together
      produced the greatest change in protein synthetic pattern, including
      overexpression or underexpression of many proteins not affected by either hormone
      alone. Addition of these hormones to culture media thus appeared insufficient to
      elicit a normal cumulus cell phenotype in OAGCs and could lead to complex changes
      in protein synthesis that may be deleterious to oocyte development. The high
      resolution 2D-PAGE approach described here should be a valuable tool in studies
      on oocyte and granulosa cell development in vitro, since phenotype can be
      evaluated globally through the display of over 1000 newly synthesized proteins
      rather than relying upon the expression of just a few genes.

PMID- 10411532
TI  - Interferon-gamma contributes to the normalcy of murine pregnancy.
AB  - Uterine natural killer (uNK) cells are transient, large, heavily granulated,
      maternal lymphocytes present on the mesometrial side of the pregnant mouse
      uterus. These cells contribute to normal implantation site development. Cytokine
      production, particularly interferon (IFN)-gamma, is a major function of most NK
      cell subsets. In this study, uNK cells were assessed for IFN-gamma production.
      Local concentrations of IFN-gamma were measured in the mesometrial regions of
      murine implantation sites between Days 6 and 16 of gestation. IFN-gamma was
      detected by ELISA at all days studied in a random-bred (CD1) and an inbred
      (BALB/c) strain of immune-competent mouse and in two immune-deficient strains,
      SCID (NK(+), T(-), B(-)) and tgepsilon26 (NK(-), T(-), B(+)). Concentrations of
      IFN-gamma per implantation site peaked at Day 10 of gestation in NK(+) strains
      but were low and relatively constant in NK(-) mice. To evaluate the functions of
      IFN-gamma at murine implantation sites, pregnancy was studied in homozygously
      mated IFN-gamma(-/-) and IFN-gammaRalpha(-/-) mice and their congenic controls.
      Primiparous but not multiparous IFN-gamma(-/-) mice experienced significant fetal
      loss. Primiparous IFN-gammaRalpha(-/-) carried full litters to term. Implantation
      site pathology was demonstrated in both strains of gene-deleted mice by light
      microscopy and ultrastructurally. This included elevated numbers of uNK cells
      that contained fewer and smaller granules and, after Day 10 of gestation,
      progressive necrosis and loss of decidua. The presence of a fetus able to produce
      IFN-gamma did not modify the phenotype of pregnant IFN-gamma(-/-) mice. This
      study indicates that during murine pregnancy, uNK cells are the main source of
      IFN-gamma on the mesometrial side of the uterus and that IFN-gamma contributes to
      normal health of the midgestational decidua. Furthermore, evidence is presented
      that IFN-gamma-producing cells exist in mesometrial regions of implantation sites
      that are neither NK nor T cells.

PMID- 10411533
TI  - Development and characterization of an in vitro ovulation model using mouse
      ovarian follicles.
AB  - To investigate ovulation, an in vitro model with cultured mouse follicles was
      developed and compared with an in vivo ovulation model. In this model, secondary
      follicles were grown in vitro with immature mouse serum (5%) and recombinant
      human FSH. Addition of ascorbic acid and selenium to the medium increased
      follicular survival (from 29% to 86%) and resulted in the development of healthy
      preovulatory follicles (> 400 microm) producing estradiol. Depending on the
      starting size of the follicles, the preovulatory stage was reached after 4-6
      days. The ovulatory response to hCG was maximal in follicles exceeding a diameter
      of 400 microm. The in vitro-ovulated oocytes could be fertilized and were able to
      develop to the blastocyst stage. Ovulation induced by hCG was dose dependent,
      reaching a maximum of 80% at 1 IU/ml. Concomitantly, progesterone production
      increased from 3.6 +/- 0.5 to 29 +/- 2 ng/ml. Both in vivo and in vitro, hCG
      induced expression of the progesterone receptor and the prostaglandin
      endoperoxide synthase-2 (PGS-2) gene within 3 h. Ovulation could be completely
      blocked with the anti-progestogen Org-31710 and partially (50%) with the PGS
      inhibitor indomethacin in vitro and in vivo. Org-31710 and indomethacin did not
      affect progesterone production. In summary, a physiologically relevant in vitro
      ovulation model of cultured mouse follicles that can be used to study the process
      of follicular rupture has been developed.

PMID- 10411534
TI  - Relaxin in the marmoset monkey: secretion pattern in the ovarian cycle and early
      pregnancy.
AB  - Relaxin is a peptide hormone with a broad range of biological activities, related
      not only to parturition and lactation but possibly also to decidualization,
      implantation, and early pregnancy. The present study was designed to investigate
      the secretion pattern of relaxin throughout the cycle and early pregnancy in the
      common marmoset monkey in relation to ovarian function and the systemic hormone
      milieu. First, a novel relaxin ELISA was developed and validated to confirm the
      pattern of relaxin secretion during pregnancy. Secondly, serum relaxin profiles
      were determined through nonconceptive and conceptive cycles and analyzed in
      relation to the concentration of other hormones and to the development of ovarian
      follicles and corpora lutea (CL). Blood samples were collected 2-3 times per week
      from the experimental animals and analyzed for relaxin, progesterone, and LH. The
      animals from the conceptive cycles were also ultrascanned at these time points to
      determine the ovarian status up to Day 25 of pregnancy. During early pregnancy,
      the relaxin levels in serum were approximately 1 ng/ml, increasing up to 15 ng/ml
      in the second trimester, at a time when progesterone levels had declined. In the
      third trimester, when progesterone levels were increasing again, the levels of
      relaxin decreased, returning to basal levels by term of pregnancy. In early
      pregnancy there was a parallel increase in both relaxin and LH/hCG, with the
      relaxin rise in the conceptive cycle appearing sooner than in the nonconceptive
      cycle, suggesting that, like chorionic gonadotropin (CG), relaxin may be a useful
      and early marker for pregnancy. Unlike the situation in the human, there was no
      correlation between the levels of either hormone and the number of CL detected,
      infants born, mother's age, or parity. Relaxin levels increased in early
      pregnancy before bioactive LH/CG, implying that relaxin is not directly regulated
      by this gonadotropin. Furthermore, hCG applied to nonconceptive females during
      the expected time of implantation caused an increase in progesterone but not in
      relaxin concentrations. In summary, the results obtained indicate that relaxin
      may be a reliable indicator of early pregnancy status in the common marmoset, but
      it is independent of direct CG influence.

PMID- 10411535
TI  - Development of cellular polarity of hamster embryos during compaction.
AB  - Development of cellular polarity is an important event during early mammalian
      embryo development and differentiation. Blastomeres of hamster embryos at various
      stages were examined by scanning electron microscopy (SEM) and immunocytochemical
      staining. SEM observations revealed that 1- to 7-cell-stage embryos showed a
      uniform distribution of microvilli throughout the cell surface. Microvillous
      polarization was initially noted in the blastomeres (10-35%) of 8-cell-stage
      embryos. The polarized microvilli were observed mostly in the basal region of
      cell-cell contact and occasionally at the apical, outward-facing surface of the
      blastomere. Fluorescein-isothiocyanate-conjugated concanavalin A failed to reveal
      any polarity in the blastomeres regardless of the stages of the embryos. Actin
      staining showed that microfilaments were present beneath the cell surface, and in
      addition, areas of cell contact were more heavily stained, indicating a thick
      microfilament domain. Microtubules were located throughout the cytoplasm and were
      heavily concentrated near the nucleus during interphase, although they became
      redistributed in the region of the mitotic spindle during karyokinesis. The
      position of nucleus changed from the cell center to the apical, outward-facing
      surface of the cell, and it distanced itself from the basal microvillous pole. It
      is suggested that the changes in the cell surface and nuclear position are the
      first manifestations of cell polarity in peri-compacted hamster embryos, which
      appear as early as the 8-cell stage; furthermore, the outward migration of the
      nuclei may parallel the redistribution of microtubules in the cytoplasm.

PMID- 10411536
TI  - B-chain sequence and in situ hybridization of the rabbit placental relaxin-like
      gene product.
AB  - We reported that the nucleotide sequence of a cDNA generated from rabbit
      placental poly(A)(+) RNA using porcine preprorelaxin primers was identical to
      SQ10, a product of squamous differentiated tracheal epithelial cells. However,
      these results did not confirm that SQ10 was the biologically active rabbit
      relaxin that had been isolated previously yet not sequenced. In this study, a 7
      kDa protein isolated from rabbit placentas exhibited relaxin bioactivity and
      cross-reacted with a porcine relaxin antiserum. A partial amino acid sequence of
      this protein revealed a sequence identical to that of SQ10. Although the amino
      acid sequence of the putative relaxin receptor-binding domain found in the B
      chain of relaxin was modified in SQ10 from CGRDYVR to CRNDFVR, the placental
      protein was bioactive. These results suggest that SQ10 is the rabbit relaxin. In
      situ hybridization, using an SQ10 riboprobe, indicated radiolabeling in the
      syncytiotrophoblast cells of the rabbit placenta. The pattern of labeling
      corresponded with the immunohistochemical staining for relaxin observed with use
      of a porcine relaxin antiserum. These results indicate that the
      syncytiotrophoblast cells are a site of synthesis for SQ10 and that the
      immunostaining is not solely the result of sequestering SQ10 through receptor
      mediated endocytosis. A potential role for relaxin in implantation is discussed.

PMID- 10411537
TI  - Effects of fetuin on zona pellucida hardening and fertilizability of equine
      oocytes matured in vitro.
AB  - In vitro fertilization (IVF) has had poor success in the horse, a situation
      related to low rates of sperm penetration through the zona pellucida (ZP). Zona
      pellucida hardening (ZPH) is seen in mouse and rat oocytes cultured in serum-free
      medium. The hardened ZP is refractory to sperm penetration. Fetuin, a component
      of fetal calf serum, inhibits ZPH and allows normal fertilization rates in
      oocytes cultured in the absence of serum. We evaluated whether fetuin is present
      in horse serum and follicular fluid (FF) and whether fetuin could inhibit ZPH in
      equine oocytes matured in vitro, thus increasing sperm penetration during IVF.
      The presence of fetuin in equine serum and FF was confirmed by immunoblotting.
      Oocytes submitted to in vitro maturation (IVM) in medium containing fetuin were
      used for ZPH assay or IVF. Intracytoplasmic sperm injection (ICSI) was carried
      out as a control procedure. The presence of fetuin during IVM did not affect the
      rate of maturation to metaphase II. Maturation of oocytes in the presence of
      fetuin reduced ZPH in a dose-dependent manner. After both IVF and ICSI, there was
      no significant difference in oocyte fertilization between fetuin-treated and
      untreated oocytes. The fertilization rate was significantly higher after ICSI
      than after IVF, both in fetuin-treated and in untreated oocytes. In conclusion,
      fetuin reduced ZPH in equine oocytes but did not improve sperm penetration during
      IVF. This implies that, in the horse, "spontaneous" ZPH is unlikely to be the
      major factor responsible for inhibiting sperm penetration in vitro.

PMID- 10411538
TI  - Coenzyme Q(10) in submicron-sized dispersion improves development, hatching, cell
      proliferation, and adenosine triphosphate content of in vitro-produced bovine
      embryos.
AB  - Coenzyme Q(10) (CoQ(10)) is an essential component of the plasma membrane ion
      transporter (PMIT) system and of the electron transport chain in the inner
      mitochondrial membrane. Because of its intrinsic functions in cell growth and
      energy metabolism (ATP synthesis), and its protective effects against oxidative
      stress, CoQ(10) is a good candidate for supporting growth of cells in culture.
      However, because of its quinone structure, CoQ(10) is extremely lipophilic and
      practically insoluble in water. We used a specific technology to prepare a
      submicron-sized dispersion of CoQ(10), inhibiting re-crystallization by a
      stabilizer. This dispersion, which exhibits a very large specific surface area
      for drug dissolution, was tested as a supplement for the in vitro culture of
      bovine embryos in a chemically defined system. The rate of early cleavage of
      embryos (5- to 8-cell stages) was evaluated 66 h postinsemination (hpi) and was
      highest in medium supplemented with 30 or 100 microM CoQ(10) (66.5 +/- 0.8% and
      68.7 +/- 1.1%, respectively) and lowest in 10 microM CoQ(10) (55.3 +/- 0.8%). The
      proportions of oocytes developing to blastocysts by 186 hpi were 19.0 +/- 0.6%
      and 25.2 +/- 0.3% in medium supplemented with 10 microM and 30 microM CoQ(10),
      respectively, and were significantly (p < 0.001) higher than those obtained with
      the equivalent amounts of stabilizer (9.9 +/- 0.4% and 11.3 +/- 0.4%). In the
      presence of 30 microM CoQ(10), significantly (p < 0.001) more blastocysts hatched
      by 210 hpi than in the equivalent amount of stabilizer (31.8 +/- 1.3 vs. 8.4 +/-
      2.2). Expanded blastocysts produced in the presence of 30 microM CoQ(10) had
      significantly (p < 0.01) more inner cell mass cells and trophectoderm cells, and
      a significantly (p < 0.001) increased ATP content as compared to expanded
      blastocysts produced in the presence of the corresponding amount of stabilizer.
      Our results show that noncrystalline CoQ(10) in submicron-sized dispersion
      supports the development and viability of bovine embryos produced in a chemically
      defined culture system.

PMID- 10411539
TI  - Regulation of monocyte chemotactic protein-1 expression in human endometrial
      stromal cells by integrin-dependent cell adhesion.
AB  - Shed menstrual endometrium is viable and has the ability to implant and grow in
      women, who eventually develop endometriosis. Many of the cell-to-cell or cell-to
      extracellular matrix (ECM) connections are mediated by integrins. Monocyte
      chemotactic protein (MCP)-1, a potent chemotactic factor produced in many cell
      types, is elevated in the peritoneal fluid of women with endometriosis. In this
      study, we investigated whether endometrial stromal cell (ESC) adhesion itself
      induces the expression of MCP-1 and whether this process is integrin mediated.
      ESC were plated on Petri dishes and 24-well plates coated with fibronectin,
      laminin, collagen IV, poly-L-lysine, or mouse anti-human integrin beta(1) and
      beta(2) monoclonal antibodies. Adherence of ESC to various ECM substrates, except
      for poly-L-lysine, a non-integrin-dependent adhesion matrix, induced the
      expression of MCP-1 at both mRNA and protein levels. Engagement of beta(1)
      containing integrins was associated with ESC adhesion and resulted in up
      regulation of MCP-1 gene expression and protein secretion. Disruption of the
      actin cytoskeleton by treating ESC with cytochalasin D completely blocked the
      increase of MCP-1 induced in response to integrin activation. These findings
      indicate a novel mechanism of MCP-1 regulation. Cell adhesion to ECM is an
      important event that leads to stimulation of MCP-1 expression, and this process
      is mediated by integrins.

PMID- 10411540
TI  - Morphometric analysis of primordial follicle number in pigtailed monkey ovaries:
      symmetry and relationship with age.
AB  - We previously described a modern, three-dimensional counting method for
      determining primordial follicle (PF) numbers in primate ovaries using a
      combination of fractionator and physical dissector techniques. The purposes of
      our current study were 1) to apply our method to describe intraindividual
      differences in PF numbers between ovaries and 2) perform a linear regression
      analysis of age versus mean PF number per ovary. Ovaries from 16 pigtailed
      monkeys (Macaca nemestrina) age 0.85-12.5 yr were examined. Both ovaries were
      available from 11 subjects. The difference between ovaries ranged from 2% to 22%
      (mean +/- SD, 10 +/- 7%) and was not statistically significant. Regression
      analysis of data from all 16 subjects displayed a log-linear relationship
      according to the equation log N(a) = 4.8542 - 0.0714(age) where N(a) is the
      number of PF at a given chronological age. The fit for this model was highly
      significant (r(2) = 0.73, p </= 0.0001). Extrapolation of the model suggests that
      there are 71 483 PF in each ovary at the time of birth. We conclude that right
      and left ovaries differ little and that PF numbers follow a log-linear rate of
      decline during the reproductive years in this species.

PMID- 10411541
TI  - Is lipid peroxidation relevant to atherogenesis?

PMID- 10411542
TI  - Suppression of arthritic bone destruction by adenovirus-mediated csk gene
      transfer to synoviocytes and osteoclasts.
AB  - Rheumatoid arthritis (RA) is characterized by a chronic inflammation of the
      synovial joints resulting from hyperplasia of synovial fibroblasts and
      infiltration of lymphocytes, macrophages, and plasma cells, all of which manifest
      signs of activation. Recent studies have revealed the essential role of
      osteoclasts in joint destruction in RA. Src family tyrosine kinases are
      implicated in various intracellular signaling pathways, including mitogenic
      response to growth factors in fibroblasts, activation of lymphocytes, and
      osteoclastic bone resorption. Therefore, inhibiting Src activity can be a good
      therapeutic strategy to prevent joint inflammation and destruction in RA. We
      constructed an adenovirus vector carrying the csk gene, which negatively
      regulates Src family tyrosine kinases. Csk overexpression in cultured rheumatoid
      synoviocytes remarkably suppressed Src kinase activity and reduced their
      proliferation rate and IL-6 production. Bone-resorbing activity of osteoclasts
      was strongly inhibited by Csk overexpression. Furthermore, local injection of the
      virus into rat ankle joints with adjuvant arthritis not only ameliorated
      inflammation but suppressed bone destruction. In conclusion, adenovirus-mediated
      direct transfer of the csk gene is useful in repressing bone destruction and
      inflammatory reactions, suggesting the involvement of Src family tyrosine kinases
      in arthritic joint breakdown and demonstrating the feasibility of intervention in
      the kinases for gene therapy in RA. off

PMID- 10411543
TI  - The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin.
AB  - Recent data point to the contribution of P-glycoprotein (P-gp) to digoxin
      elimination. On the basis of clinical observations of patients in whom digoxin
      levels decreased considerably when treated with rifampin, we hypothesized that
      concomitant rifampin therapy may affect digoxin disposition in humans by
      induction of P-gp. We compared single-dose (1 mg oral and 1 mg intravenous)
      pharmacokinetics of digoxin before and after coadministration of rifampin (600
      mg/d for 10 days) in 8 healthy volunteers. Duodenal biopsies were obtained from
      each volunteer before and after administration of rifampin. The area under the
      plasma concentration time curve (AUC) of oral digoxin was significantly lower
      during rifampin treatment; the effect was less pronounced after intravenous
      administration of digoxin. Renal clearance and half-life of digoxin were not
      altered by rifampin. Rifampin treatment increased intestinal P-gp content 3.5 +/-
      2.1-fold, which correlated with the AUC after oral digoxin but not after
      intravenous digoxin. P-gp is a determinant of the disposition of digoxin.
      Concomitant administration of rifampin reduced digoxin plasma concentrations
      substantially after oral administration but to a lesser extent after intravenous
      administration. The rifampin-digoxin interaction appears to occur largely at the
      level of the intestine. Therefore, induction of intestinal P-gp could explain
      this new type of drug-drug interaction.

PMID- 10411544
TI  - Safety and antitumor activity of recombinant soluble Apo2 ligand.
AB  - TNF and Fas ligand induce apoptosis in tumor cells; however, their severe
      toxicity toward normal tissues hampers their application to cancer therapy. Apo2
      ligand (Apo2L, or TRAIL) is a related molecule that triggers tumor cell
      apoptosis. Apo2L mRNA is expressed in many tissues, suggesting that the ligand
      may be nontoxic to normal cells. To investigate Apo2L's therapeutic potential, we
      generated in bacteria a potently active soluble version of the native human
      protein. Several normal cell types were resistant in vitro to apoptosis induction
      by Apo2L. Repeated intravenous injections of Apo2L in nonhuman primates did not
      cause detectable toxicity to tissues and organs examined. Apo2L exerted
      cytostatic or cytotoxic effects in vitro on 32 of 39 cell lines from colon, lung,
      breast, kidney, brain, and skin cancer. Treatment of athymic mice with Apo2L
      shortly after tumor xenograft injection markedly reduced tumor incidence. Apo2L
      treatment of mice bearing solid tumors induced tumor cell apoptosis, suppressed
      tumor progression, and improved survival. Apo2L cooperated synergistically with
      the chemotherapeutic drugs 5-fluorouracil or CPT-11, causing substantial tumor
      regression or complete tumor ablation. Thus, Apo2L may have potent anticancer
      activity without significant toxicity toward normal tissues.

PMID- 10411545
TI  - Increased frequency of antigen-specific CD8(+) cytotoxic T lymphocytes
      infiltrating an Epstein-Barr virus-associated gastric carcinoma.
AB  - Gastric adenocarcinomas carrying Epstein-Barr virus (EBV) are known to be
      accompanied by massive lymphocyte infiltration. To characterize the tumor
      infiltrating lymphocytes (TILs), we isolated and cultured such cells from a
      surgically resected EBV-associated gastric carcinoma. They were found to be
      positive for CD3, CD8, T-cell receptor beta chain, and cytotoxic molecules. The
      isolated TILs consisted of human leukocyte antigen (HLA) class I-restricted
      CD8(+) cytotoxic T lymphocytes (CTLs), which killed autologous EBV-transformed
      cells (but not phytohemagglutinin blast cells) and recognized HLA-A24 as
      restriction molecules. However, the TILs did not recognize known EBV antigenic
      peptides presented by HLA-A24 molecules, nor HLA-A24(+) fibroblasts infected with
      vaccinia recombinant virus expressing each of the EBV latent proteins. EBV(+)
      gastric carcinomas do not express conventional target proteins of EBV-specific
      CTLs, and the data suggest that some cellular proteins may be involved in the
      strong T-cell response to EBV-associated gastric carcinoma. In addition, our data
      suggest that class I-restricted, antigen-specific CD8(+) CTLs are specifically
      expanded within EBV(+) gastric carcinoma tissue.

PMID- 10411546
TI  - Rapid generation of broad T-cell immunity in humans after a single injection of
      mature dendritic cells.
AB  - Dendritic cells (DCs) are potent antigen-presenting cells that initiate
      protective T-cell immunity in mice. To study the immunogenicity of DCs in humans,
      we injected 9 healthy subjects subcutaneously with a control injection of
      autologous monocyte-derived, mature DCs, followed 4-6 weeks later by DCs pulsed
      with keyhole limpet hemocyanin (KLH), HLA-A*0201-positive restricted influenza
      matrix peptide (MP), and tetanus toxoid (TT). Four more subjects received these
      antigens without DCs. Injection of unpulsed DCs, or antigens alone, failed to
      immunize. Priming of CD4(+) T cells to KLH was observed in all 9 subjects
      injected with KLH-pulsed DCs, and boosting of TT-specific T-cell immunity was
      seen in 5 of 6 subjects injected with TT-pulsed DCs. Injection of antigen-pulsed
      DCs led to a severalfold increase in freshly isolated MP-specific, IFN-gamma
      secreting CD8(+) T cells in all 6 HLA-A*0201-positive subjects, as early as 7
      days after injection. When T cells were boosted in culture, there was an increase
      in MHC tetramer-binding cells and cytotoxic T cells after DC vaccination. These
      data provide the first controlled evidence of the immunogenicity of DCs in
      humans, and demonstrate that a single injection of mature DCs rapidly expands T
      cell immunity.

PMID- 10411547
TI  - Increased renal vasodilator prostanoids prevent hypertension in mice lacking the
      angiotensin subtype-2 receptor.
AB  - The angiotensin subtype-1 (AT(1)) receptor mediates renal prostaglandin E(2)
      (PGE(2)) production, and pharmacological blockade of the angiotensin subtype-2
      (AT(2)) receptor potentiates the action of angiotensin II (Ang II) to increase
      PGE(2) levels. We investigated the role of the AT(2) receptor in prostaglandin
      metabolism in mice with targeted deletion of the AT(2) receptor gene. Mice
      lacking the AT(2) receptor (AT(2)-null) had normal blood pressure that was
      slightly elevated compared with that of wild-type (WT) control mice. AT(2)-null
      mice had higher renal interstitial fluid (RIF) 6-keto-PGF(1alpha) (a stable
      hydrolysis product of prostacyclin [PGI(2)]) and PGE(2) levels than did WT mice,
      and had similar increases in PGE(2) and 6-keto-PGF(1alpha) in response to dietary
      sodium restriction and Ang II infusion. In contrast, AT(2)-null mice had lower
      PGF(2alpha) levels compared with WT mice during basal conditions and in response
      to dietary sodium restriction or infusion of Ang II. RIF cAMP was markedly higher
      in AT(2)-null mice than in WT mice, both during basal conditions and during
      sodium restriction or Ang II infusion. AT(1) receptor blockade with losartan
      decreased PGE(2), PGI(2), and cAMP to levels observed in WT mice. To determine
      whether increased vasodilator prostanoids prevented hypertension in AT(2)-null
      mice, we treated AT(2)-null and WT mice with indomethacin for 14 days. PGI(2),
      PGE(2), and cAMP were markedly decreased in both WT and AT(2)-null mice. Blood
      pressure increased to hypertensive levels in AT(2)-null mice but was unchanged in
      WT. These results demonstrate that in the absence of the AT(2) receptor,
      increased vasodilator prostanoids protect against the development of
      hypertension.

PMID- 10411548
TI  - DNA immunization to prevent autoimmune diabetes.
AB  - Mice expressing lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a
      transgene in their beta cells develop insulin-dependent diabetes mellitus (IDDM)
      only after LCMV infection. Inoculation of plasmid DNA encoding the insulin B
      chain reduced the incidence of IDDM by 50% in this model. The insulin B-chain DNA
      vaccination was effective through induction of regulatory CD4 lymphocytes that
      react with the insulin B chain, secrete IL-4, and locally reduce activity of LCMV
      NP-autoreactive cytotoxic T lymphocytes in the pancreatic draining lymph node. In
      contrast, similar vaccination with plasmids expressing the LCMV viral ("self")
      protein did not prevent IDDM, because no such regulatory cells were induced.
      Thus, DNA immunization with plasmids expressing self-antigens might constitute a
      novel and attractive therapeutic approach to prevent autoimmune diseases, if the
      antigens are carefully preelected for an ability to induce regulatory lymphocytes
      in vivo.

PMID- 10411549
TI  - Basolateral Na(+)/HCO(3)(-) cotransport activity is regulated by the dissociable
      Na(+)/H(+) exchanger regulatory factor.
AB  - In the renal proximal tubule, the activities of the basolateral Na(+)/HCO(3)(-)
      cotransporter (NBC) and the apical Na(+)/H(+) exchanger (NHE3) uniformly vary in
      parallel, suggesting that they are coordinately regulated. PKA-mediated
      inhibition of NHE3 is mediated by a PDZ motif-containing protein, the Na(+)/H(+)
      exchanger regulatory factor (NHE-RF). Given the common inhibition of these
      transporters after protein kinase A (PKA) activation, we sought to determine
      whether NHE-RF also plays a role in PKA-regulated NBC activity. Renal cortex
      immunoblot analysis using anti-peptide antibodies directed against rabbit NHE-RF
      demonstrated the presence of this regulatory factor in both brush-border
      membranes (BBMs) and basolateral membranes (BLMs). Using a reconstitution assay,
      we found that limited trypsin digestion of detergent solubilized rabbit renal BLM
      preparations resulted in NBC activity that was unaffected by PKA activation. Co
      reconstitution of these trypsinized preparations with a recombinant protein
      corresponding to wild-type rabbit NHE-RF restored the inhibitory effect of PKA on
      NBC activity in a concentration-dependent manner. NBC activity was inhibited 60%
      by 10(-8)M NHE-RF; this effect was not observed in the absence of PKA.
      Reconstitution with heat-denatured NHE-RF also failed to attenuate NBC activity.
      To establish further a physiologic role for NHE-RF in NBC regulation, the renal
      epithelial cell line B-SC-1, which lacks detectable endogenous NHE-RF expression,
      was engineered to express stably an NHE-RF transgene. NHE-RF-expressing B-SC-1
      cells (B-SC-RF) exhibited markedly lower basal levels of NBC activity than did
      wild-type controls. Inhibition of NBC activity in B-SC-RF cells was enhanced
      after 10 microM of forskolin treatment, consistent with a postulated role for NHE
      RF in mediating the inhibition of NBC activity by PKA. These findings not only
      suggest NHE-RF involvement in PKA-regulated NBC activity, but also provide a
      unique molecular mechanism whereby basolateral NBC and apical NHE3 activities may
      be coordinately regulated in renal proximal tubule cells.

PMID- 10411550
TI  - Persistence of infectious hepadnavirus in the offspring of woodchuck mothers
      recovered from viral hepatitis.
AB  - Mother-to-child transmission is an important route for hepatitis B virus (HBV)
      dissemination. It has been established that HBV traces persist for years after
      complete clinical recovery from hepatitis B. Similarly, resolution of hepatitis
      caused by HBV-related woodchuck hepatitis virus (WHV) is followed by occult
      lifelong carriage of pathogenic virus. In this study, we documented that WHV
      persisting after termination of acute hepatitis is transmittable to newborns as
      an asymptomatic long-term infection. All 11 offspring from 4 dams studied carried
      transcriptionally active WHV genomes for 3.5 years after birth without
      immunovirological markers of infection. WHV genomes and mRNA were detected both
      in the liver and lymphoid tissue in the majority of offspring; WHV covalently
      closed circular DNA was detected in some samples. In 4 offspring, however, the
      virus was restricted to the lymphatic system. In the circulation, WHV DNA
      reactive particles were DNase resistant and of comparable size and density to
      complete virions. Importantly, the virus in offspring with or without hepatic WHV
      DNA expression was infectious to WHV-naive woodchucks. Finally, offspring
      challenged with WHV were not protected against reinfection. These findings show
      that mothers with occult hepadnaviral carriage transmit pathogenic virus to their
      offspring, inducing a persistent infection invariably within the lymphatic system
      but not always in the liver.

PMID- 10411551
TI  - Dissociation of atherogenesis from aortic accumulation of lipid hydro(pero)xides
      in Watanabe heritable hyperlipidemic rabbits.
AB  - Antioxidants can inhibit atherosclerosis, but it is unclear how inhibition of
      intimal lipid oxidation relates to atherogenesis. Here we tested the effect of
      probucol and its metabolite bisphenol on aortic lipid (per)oxidation and
      atherogenesis in Watanabe heritable hyperlipidemic (WHHL) rabbits. LDL and aortas
      from rabbits fed probucol contained bisphenol at concentrations comparable to
      those in bisphenol-treated animals. Bisphenol treatment increased plasma
      cholesterol slightly, and plasma and aortic alpha-tocopherol more substantially;
      these parameters were unaffected by probucol. Bisphenol and probucol treatment
      both enhanced the resistance of circulating LDL to peroxyl radical-induced lipid
      peroxidation; this was due to bisphenol, not probucol. Only probucol enhanced
      LDL's resistance to Cu(2+)-induced oxidation. Both bisphenol and probucol
      treatment strongly inhibited aortic accumulation of hydroperoxides and hydroxides
      of cholesteryl esters and triglycerides [LO(O)H]. Despite this, however, probucol
      had a modestly significant effect on the extent of lesion formation; bisphenol
      had no inhibitory effect. In addition, the extent of atherosclerosis did not
      correlate with amounts of aortic LO(O)H present, but, as expected, it did
      correlate with aortic alpha-tocopherol and cholesterol. Together, these results
      suggest that aortic accumulation of LO(O)H is not required for, nor is alpha
      tocopherol depleted during, the initiation and progression of atherogenesis in
      WHHL rabbits.

PMID- 10411552
TI  - NPS R-568: a type II calcimimetic compound that acts on parathyroid cell calcium
      receptor of rats to reduce plasma levels of parathyroid hormone and calcium.
AB  - Calcimimetics like N-(3-[2-chlorophenyl]propyl)-(R)-alpha-methyl-3
      methoxybenzylamine (NPS R-568) potentiate the effects of extracellular Ca(2+) on
      parathyroid Ca(2+) receptors and inhibit parathyroid hormone (PTH) secretion in
      vitro. When administered by gavage to normal rats in this study, NPS R-568 caused
      a rapid, dose-dependent (ED(50), 1.1 +/- 0.7 mg/kg) decrease in PTH levels that
      was paralleled by a subsequent decrease in plasma Ca(2+) (ED(50), 10.4 +/- 3.7
      mg/kg). At higher doses (>/=3.3 mg/kg), PTH was reduced to a minimum level within
      15 min, the duration of which was dose dependent. With doses of 10 to 100 mg/kg,
      the hypocalcemia was rapid in onset (<30 min) and, at 33 to 100 mg/kg, persisted
      for >24 h. Neither the magnitude nor the kinetics of the hypocalcemic response
      was affected by total nephrectomy, demonstrating that NPS R-568 does not induce
      hypocalcemia by acting on renal Ca(2+) receptors to increase Ca(2+) excretion. In
      contrast, parathyroidectomy (intact thyroid) abolished the hypocalcemic response
      to NPS R-568, regardless of whether the rats were hypocalcemic or rendered
      acutely normo- or hypercalcemic by calcium infusion before dosing. These data
      show that the parathyroid Ca(2+) receptor can be selectively activated in vivo
      with a small organic compound to decrease plasma levels of PTH and Ca(2+) and
      thus define the mechanism of action of this compound in vivo. Moreover, the data
      add pharmacological support to the view that the Ca(2+) receptor is the primary
      molecular entity regulating systemic Ca(2+) homeostasis.

PMID- 10411553
TI  - Calcimimetic compound NPS R-568 stimulates calcitonin secretion but selectively
      targets parathyroid gland Ca(2+) receptor in rats.
AB  - N-(3-[2-Chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine (NPS R-568) is
      an orally active compound that activates Ca(2+) receptors on parathyroid cells
      and rapidly suppresses plasma levels of parathyroid hormone (PTH) and Ca(2+)
      (ED(50), 1 and 10 mg/kg, respectively). We now show that increased calcitonin
      secretion contributes to NPS R-568-induced hypocalcemia. In parathyroidectomized
      thyroid-intact rats in which normocalcemia was restored by PTH infusion, NPS R
      568 rapidly reduced plasma Ca(2+) levels, indicating that decreased PTH secretion
      was not solely responsible for the hypocalcemia seen in normal animals. NPS R-568
      decreased plasma Ca(2+) levels in thyroidectomized parathyroid-intact rats, but
      the rate of onset of hypocalcemia was slower than in controls. In contrast, NPS R
      568 had no effect on plasma Ca(2+) levels in PTH-infused,
      thyroparathyroidectomized rats, providing evidence that increased calcitonin
      secretion caused the hypocalcemia in PTH-infused parathyroidectomized rats. NPS R
      568 rapidly increased plasma calcitonin levels to a peak at 10 to 20 min after
      oral dosing (ED(50) 40 mg/kg). NPS R-568 did not affect the rate of disappearance
      of (45)Ca from blood, indicating that hypocalcemia resulted from decreased influx
      of Ca(2+) into the circulation and not from increased efflux. This suggests that
      NPS R-568-induced hypocalcemia resulted solely from reduced efflux of Ca(2+) from
      bone after increased calcitonin and reduced PTH secretion. Thus, NPS R-568 causes
      hypocalcemia by activating Ca(2+) receptors on C cells and parathyroid cells;
      however, NPS R-568 is about 40 times more potent in reducing PTH levels than in
      increasing calcitonin levels.

PMID- 10411554
TI  - Relevance of aromatic residues in transmembrane segments V to VII for binding of
      peptide and nonpeptide antagonists to the human tachykinin NK(2) receptor.
AB  - We used membranes from Chinese hamster ovary cells stably transfected with the
      human tachykinin NK(2) receptor, either wild-type or mutated, at four aromatic
      residues (His(198), Tyr(266), Phe(270), Tyr(289)) located in transmembrane
      segments V to VII, to assess the role of these residues in the binding of natural
      tachykinins and peptide and nonpeptide antagonists. Three radioligands, the
      agonist [(125)I]neurokinin A (NKA), the peptide antagonist [(3)H]MEN 11420, and
      the nonpeptide antagonist [(3)H]SR 48968 bound to the wild-type receptor with
      high affinity (K(d) = 2.4 nM, 0.3 nM, and 4.0 nM, respectively). Four of the six
      mutant receptors tested retained high affinity for at least one of the
      radioligands. H(198)A mutation abrogated the binding of NKA but not that of MEN
      11420 or SR 48968 (K(d) = 4.8 and 11.5 nM, respectively); Y(266)F mutation
      abrogated the binding of MEN 11420 but not that of NKA or SR 48968 (K(d) = 2.8 nM
      and 1.2 nM, respectively); F(270)A mutation abrogated the binding of both NKA and
      MEN 11420 but not that of SR 48968 (K(d) = 1.6 nM); Y(289)F mutation abrogated
      the binding of SR 48968 but not that of NKA and MEN 11420 (K(d) = 2.0 and 2.9 nM,
      respectively). Y(266)A and Y(289)A mutations abrogated the binding of all
      radioligands. Among the unlabeled antagonists, the affinity of the nonpeptide GR
      159897, at variance with SR 48968, resulted heavily compromised by H(198)A and
      Y(266)F mutations; the peptide antagonists R396 and MEN 10376 essentially
      followed the binding profile of NKA, but R396 showed markedly increased affinity
      for the Y(289)F mutant receptor. Taken together, these results indicate that
      different, partially overlapping sets of sites may be involved in the binding of
      agonists and diverse antagonists to the human tachykinin NK(2) receptor.

PMID- 10411555
TI  - In vivo analysis of amantadine renal clearance in the uninephrectomized rat:
      functional significance of in vitro bicarbonate-dependent amantadine renal tubule
      transport.
AB  - Amantadine transport into renal proximal and distal tubules is bicarbonate
      dependent. In the present study, we addressed the effects of bicarbonate on renal
      clearance and urinary excretion of amantadine. Renal clearance of kynurenic acid
      was also studied to determine whether bicarbonate effects are specific for
      organic base transport by the kidney. After a moderate diuresis was established,
      animals received i.v. [(3)H]amantadine or [(3)H]kynurenic acid followed by an
      acute dose of sodium bicarbonate or physiological saline. Urine and blood samples
      were analyzed for [(3)H]amantadine or [(3)H]kynurenic acid, blood gases, and pH.
      Amantadine and kynurenic acid were excreted by the kidneys, and both compounds
      underwent renal tubular secretion. Amantadine metabolism occurred, and one
      metabolite was detected in the urine. In the bicarbonate-treated rats, the total
      amount of amantadine excreted in the urine was decreased, whereas the amount of
      metabolite recovered was similar in both groups. Bicarbonate treatment caused a
      sustained increase in blood bicarbonate levels, a mild increase in blood pH, and
      a decrease in amantadine renal clearance and in the amantadine/creatinine
      clearance ratio. Only a transient decrease in the renal clearance of kynurenic
      acid and the kynurenic acid/creatinine clearance ratio was observed. This study
      demonstrates that short-term changes in bicarbonate concentration may have
      significant effects on renal organic cation elimination. Coupled with our
      previous in vitro demonstration of bicarbonate-dependent organic cation
      transport, the present study suggests that bicarbonate inhibition of renal tubule
      organic cation secretion may explain the previous observation that bicarbonate
      dosing decreases amantadine excretion by the kidney.

PMID- 10411556
TI  - Levosimendan: effects of a calcium sensitizer on function and arrhythmias and
      cyclic nucleotide levels during ischemia/reperfusion in the Langendorff-perfused
      guinea pig heart.
AB  - The majority of clinically used inotropes act by increasing cytosolic calcium
      levels, which may hypothetically worsen reperfusion stunning and provoke
      arrhythmias. We tested the hypothesis that the calcium sensitizer levosimendan
      (levo) given during ischemia alone or ischemia and reperfusion would improve
      reperfusion function without promoting arrhythmias. The Langendorff-perfused
      guinea pig heart, subjected to 40-min low-flow ischemia (0.4 ml/min) with or
      without levo (10-300 nM) given during ischemia or ischemia/reperfusion was used.
      Left ventricular developed pressure (LVDP) was used as an index of mechanical
      function. The effect of levo (300 nM) or dobutamine (0.1 microM) on the incidence
      of ischemia/reperfusion arrhythmias was also investigated. Control hearts
      (vehicle-perfused) had LVDPs of 69.4 +/- 2.1 mm Hg whereas hearts treated with
      levo during ischemia and reperfusion (300 nM) had LVDPs of 104.5 +/- 2.7 mm Hg (p
      <.05). Hearts treated with levo during ischemia alone (10 nM) had reperfusion
      LVDPs of 95.8 +/- 4.2 mm Hg (p <.05) after 30-min reperfusion. Hearts treated
      with both levo and 10 microM glibenclamide (K(ATP) channel blocker) during
      ischemia had reperfusion LVDPs of 73.4 +/- 4.3 mm Hg after 30-min reperfusion. Of
      control hearts, 25% developed reperfusion ventricular tachycardia but not
      ventricular fibrillation. Levo-treated hearts had no ischemia/reperfusion
      arrhythmias whereas 83% (p <.05 versus control) of dobutamine-treated hearts
      developed ventricular tachycardia and 33% (p <.05 versus levo) developed
      reperfusion ventricular fibrillation. Levo improved reperfusion function without
      promoting arrhythmias in this model. This was possibly achieved by opening the
      K(ATP) channels during ischemia and sensitizing myocardial contractile apparatus
      instead of elevating cytosolic calcium levels in reperfused hearts.

PMID- 10411557
TI  - Mechanism of transient outward K(+) channel block by disopyramide.
AB  - The block of the transient outward K(+) current (I(to)) by disopyramide was
      studied in isolated rat right ventricular myocytes using whole cell patch-clamp
      techniques. Disopyramide at a concentration of 10 to 1000 microM reduced peak
      I(to) and accelerated the apparent rate of current inactivation. The onset of
      block was assessed using a double pulse protocol with steps from -70 to +50 mV.
      As the duration of the first (conditioning) pulse was increased from 1 to 50 ms,
      block was increased. Further prolongation of the conditioning pulse resulted in
      relief of block, which was nearly complete with a 1-s conditioning pulse. In the
      absence of drug, the recovery from inactivation of I(to) at -70 mV was fast and
      best fit with a single exponential function having a time constant of 33 +/- 13
      ms. In contrast, in the presence of 100 microM disopyramide, recovery from
      apparent inactivation was biexponential with time constants of 35 +/- 13 ms and
      7.16 +/- 1.5 s. The time course of the slow component was used to estimate
      recovery of channels from block by disopyramide. Recovery from block was voltage
      dependent, suggesting that disopyramide was trapped by the open channel. Taken
      together, these results suggest that disopyramide rapidly blocks channels in the
      open state and that unblock occurs from the inactivated state.

PMID- 10411558
TI  - Enhancement of collagen-induced arthritis in mice by diesel exhaust particles.
AB  - The present study was undertaken to investigate the effect of diesel exhaust
      particles (DEP) on collagen-induced arthritis (CIA), which is an experimental
      model of autoimmune disease, in mice. CIA was induced by s.c. injection of type
      II collagen (CII) emulsified with complete Freund's adjuvant into the base of the
      tail (day 0) followed by a booster injection on day 21. Varying doses of DEP were
      intranasally administered every 2 days from days 0 to 20. The results showed that
      administration of DEP enhanced both the incidence and the severity of CIA. The
      enhancement of the disease was associated with pronounced production of anti-CII
      IgG and IgG2a antibodies. Treatment with DEP also augmented proliferative
      responses of spleen cells to CII. There was marked secretion of interferon-gamma,
      interleukin (IL)-2, and IL-4 from the lymphoid cells in DEP-treated mice.
      Administration of DEP after onset of CIA was also effective in enhancing the
      severity of the disease as well as production of anti-CII IgG and IgG2a
      antibodies and secretion of interferon-gamma, IL-2, and IL-4. These results
      suggest that exposure to DEP may influence autoimmune disease.

PMID- 10411559
TI  - Omeprazole has a dual mechanism of action: it inhibits both H(+)K(+)ATPase and
      gastric mucosa carbonic anhydrase enzyme in humans (in vitro and in vivo
      experiments).
AB  - In this study our experiments followed in vitro and in vivo the effect of
      omeprazole on purified and erythrocyte carbonic anhydrase (CA) I and II isozymes,
      as well as on gastric mucosa CA IV in humans. Our in vitro results show that
      omeprazole-induced inhibition of purified CA I and CA II and gastric mucosa CA IV
      is dose- and pH-dependent. In vivo, the i.v. administration of omeprazole in
      humans in therapeutic doses produced a decrease in erythrocyte CA I and CA II
      activity, as well as in gastric mucosa CA I, II, and IV. Regarding CA IV, the
      results lead to the conclusion that omeprazole selectively inhibits gastric
      mucosa CA IV and does not modify the activity of the same isozyme from the kidney
      and lung, indicating organ specificity. Our results strongly suggest that
      omeprazole has a dual mechanism of action: H(+)K(+)ATPase inhibition and gastric
      mucosa CA inhibition, and that these enzymes may be functionally coupled. This 2
      fold mechanism of action could explain the greater effectiveness of substituted
      benzimidazoles as compared with other therapies.

PMID- 10411560
TI  - Caffeine, acting on adenosine A(1) receptors, prevents the extinction of cocaine
      seeking behavior in mice.
AB  - Drug-naive DBA/2 mice were trained to self-administer cocaine (40
      microgram/kg/infusion) i.v. by nose poking. The number of nose-poke responses was
      higher in mice receiving response-contingent injections of cocaine (active group)
      than in yoked controls or in animals receiving response-contingent saline
      injections. Twenty-four hours after the training session (cocaine or saline self
      administration), mice were injected i.p. with saline, cocaine, caffeine, 1,3
      dipropyl-8-cyclopentyl xanthine (DPCPX), 8-cyclopentyl theophylline (8-CPT), 5
      amino-7-(2-phenylethyl)2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo[1,5
      c]pyrimidine (SCH 58261), or 9-chloro-2(2-furyl)[1,2, 4]triazolo[1,5-c]quinazolin
      5-amine (CGS 15943) and placed again in exactly the same operant boxes as during
      the training session but without response-contingent i.v. infusions. Saline
      injection elicited similar responding in animals from the active group and from
      the yoked control group. A low dose of cocaine (5 mg/kg) or caffeine (3 mg/kg),
      but not higher doses, produced greater responding in the active group than in the
      yoked control group during a single extinction trial. The adenosine A(1)-receptor
      antagonists DPCPX and 8-CPT and the nonselective antagonist CGS 15943 partially
      reproduced the effect of a low dose of caffeine on the cocaine-associated
      behavior in a dose-dependent manner and did not alter the nose-poke activity of
      yoked control mice in the extinction experiment. In contrast, the adenosine A(2A)
      antagonist SCH 58261, in doses above 1 mg/kg, reduced nose-poke activity equally
      in active and yoked control animals. This confirms that a drug from a different
      pharmacological class (adenosine-receptor antagonist) can induce behavior changes
      similar to the effects of the original self-administered drug (indirect dopamine
      receptor agonist). The data also suggest that the effects of caffeine on cocaine
      seeking behavior might be related to interaction with adenosine A(1) receptors,
      but not A(2A) receptors.

PMID- 10411561
TI  - The role of probenecid-sensitive organic acid transport in the pharmacokinetics
      of N-methyl-D-aspartate receptor antagonists acting at the glycine(B)-site:
      microdialysis and maximum electroshock seizures studies.
AB  - The purpose of the present study was to determine whether the probenecid
      sensitive organic acid transporter is responsible for the short duration of
      action of a new group of N-methyl-D-aspartate receptor glycine(B)-site
      antagonists, MRZ 2/570, 2/571, and 2/576. A prolongation of their anticonvulsant
      activity from 60 to 180 to 240 min, was found in mice after pretreatment with
      probenecid (200 mg/kg i.p.). Microdialysis studies in rats showed that this is
      likely due to a change in central nervous system concentrations of these drugs
      because cotreatment with probenecid caused an increase in the brain extracellular
      fluid half-life (0.5- to 4-fold) and the brain area under the curve (1.8- to 3.6
      fold). In serum the half-life of MRZ 2/576 (30 mg/kg) was also increased by
      coadministration of probenecid from 15.6 +/- 1.3 to 40.6 +/- 6.0 min. At steady
      state (MRZ 2/576, 20 mg/kg/h i.v.), brain extracellular fluid concentration was
      elevated 2.5-fold by concomitant administration of probenecid. These results
      clearly show that these glycine(B)-site antagonists are rapidly cleared from the
      systemic circulation and the central nervous system by the probenecid-sensitive
      organic acid transport system. Moreover, the present data show that MRZ 2/570,
      2/571, and 2/576 reach the brain in concentrations (1.34-2.32 microM) above the
      range of their in vitro potencies at the glycine site of the N-methyl-D-aspartate
      receptor (0.1-1.0 microM).

PMID- 10411562
TI  - Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]:
      a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and
      biochemical profiles.
AB  - The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved
      in inflammation and that COX-1 is the major isoform responsible for the
      production of prostaglandins (PGs) in the gastrointestinal tract have provided a
      rationale for the development of specific COX-2 inhibitors as a new class of anti
      inflammatory agents with improved gastrointestinal tolerability. In the present
      study, the preclinical pharmacological and biochemical profiles of rofecoxib
      [Vioxx, also known as MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)
      furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent
      inhibitor of the COX-2-dependent production of PGE(2) in human osteosarcoma cells
      (IC(50) = 26 +/- 10 nM) and Chinese hamster ovary cells expressing human COX-2
      (IC(50) = 18 +/- 7 nM) with a 1000-fold selectivity for the inhibition of COX-2
      compared with the inhibition of COX-1 activity (IC(50) > 50 microM in U937 cells
      and IC(50) > 15 microM in Chinese hamster ovary cells expressing human COX-1).
      Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2
      (IC(50) = 0.34 microM) but caused inhibition of purified human COX-1 in a non
      time-dependent manner that could only be observed at a very low substrate
      concentration (IC(50) = 26 microM at 0.1 microM arachidonic acid concentration).
      In an in vitro human whole blood assay, rofecoxib selectively inhibited
      lipopolysaccharide-induced, COX-2-derived PGE(2) synthesis with an IC(50) value
      of 0.53 +/- 0.02 microM compared with an IC(50) value of 18.8 +/- 0.9 microM for
      the inhibition of COX-1-derived thromboxane B(2) synthesis after blood
      coagulation. Using the ratio of the COX-1 IC(50) values over the COX-2 IC(50)
      values in the human whole blood assay, selectivity ratios for the inhibition of
      COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib,
      meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent
      models, rofecoxib is a potent inhibitor of carrageenan-induced paw edema (ID(50)
      = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID(50) = 1.0 mg/kg),
      lipopolysaccharide-induced pyresis (ID(50) = 0.24 mg/kg), and adjuvant-induced
      arthritis (ID(50) = 0.74 mg/kg/day). Rofecoxib also has a protective effect on
      adjuvant-induced destruction of cartilage and bone structures in rats. In a
      (51)Cr excretion assay for detection of gastrointestinal integrity in either rats
      or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5
      days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological
      profile clearly distinct from that of current nonsteroidal anti-inflammatory
      drugs and represents a new therapeutic class of anti-inflammatory agents for the
      treatment of the symptoms of osteoarthritis and rheumatoid arthritis with
      improved gastrointestinal tolerability.

PMID- 10411563
TI  - In vivo and in vitro evidence of blood-brain barrier transport of a novel
      cationic arginine-vasopressin fragment 4-9 analog.
AB  - The blood-brain barrier (BBB) transport and metabolism of a novel arginine
      vasopressin fragment 4-9 [AVP(4-9), isoelectric point; (pI) = 9.2] analog, that
      is, cationic AVP(4-9) (C-AVP(4-9), PI = 9.8), were examined in vivo and in vitro.
      At 45 min after an i.v. administration to mice, the cerebrum-to-plasma
      concentration ratios of (35)S-labeled AVP(4-9) and (125)I-labeled C-AVP(4-9) were
      0.103 and 0.330 ml/g cerebrum, respectively, and the BBB permeation clearances
      were 1.47 x 10(-4) and 3.10 x 10(-4) ml/min/g cerebrum, respectively. In the in
      vitro study using mouse brain capillary endothelial cells immortalized by SV40
      infection (MBEC4), the acid-resistant binding values of (35)S-labeled AVP(4-9)
      and (125)I-labeled C-AVP(4-9) to MBEC4 at 120 min were 0.93 and 1.95
      microliter/mg protein (as the cell/medium ratios), respectively. (35)S-labeled
      AVP(4-9) showed two-phase saturable acid-resistant binding, and its half
      saturation constants (K(D)) were 3.8 nM (high affinity) and 45.7 microM (low
      affinity). (125)I-labeled C-AVP(4-9) showed single-phase saturable acid-resistant
      binding, with a K(D) value of 16.4 microM. The acid-resistant binding of (125)I
      labeled C-AVP(4-9) was significantly dependent on temperature and medium
      osmolarity. The acid-resistant binding of (125)I-labeled C-AVP(4-9) was inhibited
      by dancylcadaverine, phenylarsine oxide (endocytosis inhibitors), 2,4
      dinitrophenol (a metabolic inhibitor), and AVP(4-9), poly(L-lysine), and
      protamine (cationic substances), but not by poly(L-glutamic acid) (an anionic
      peptide) and the V(1) and V(2) vasopressin receptor antagonists. In addition, the
      conversion of C-AVP(4-9) to AVP(4-9) in the cerebral homogenate was confirmed by
      HPLC and mass spectrometry. The present results demonstrate that C-AVP(4-9) is
      transported through the BBB more effectively than AVP(4-9), via absorptive
      mediated endocytosis, and that C-AVP(4-9) is converted to the neuroactive parent
      peptide, AVP(4-9), in the cerebrum.

PMID- 10411564
TI  - Different state dependencies of 4-aminopyridine binding to rKv1.4 and rKv4.2:
      role of the cytoplasmic halves of the fifth and sixth transmembrane segments.
AB  - 4-Aminopyridine (4AP) binding to rKv1.4 occurs preferentially in the activated
      state, whereas binding to rKv4.2 occurs in the rested state. To explore
      structural basis for the different state dependencies of 4AP binding, regions of
      rKv1.4 that are likely to form the 4AP-binding site and/or the activation gate
      were replaced by the corresponding rKv4.2 sequences one at a time, and the
      resulting effects on channel gating and 4AP binding were examined. Replacing the
      amino acid sequence of rKv1.4 in the intracellular loop between the fourth and
      fifth transmembrane segments (S4 and S5) with that of rKv4.2 did not alter
      channels' gating properties or the state dependence of 4AP binding. On the other
      hand, replacing the rKv1.4 sequence in the cytoplasmic half of S5 (N-S5) or S6 (C
      S6) with that of rKv4.2 markedly altered the voltage dependence and kinetics of
      activation gate function. Importantly, these mutations transferred the rested
      state 4AP-binding preference from the donor to the host channel. These data can
      be explained by a scheme in which the function of the activation gate determines
      the state dependence of 4AP binding, although the relationship between the
      binding site and the gate may be similar between rKv1.4 and rKv4.2. The amino
      acid sequences in the N-S5 and C-S6 domains contribute to this activation gate
      function.

PMID- 10411565
TI  - Sarcoplasmic reticulum Ca(2+) release by 4-chloro-m-cresol (4-CmC) in intact and
      chemically skinned ferret cardiac ventricular fibers.
AB  - The purpose of this study was to determine whether 4-chloro-m-cresol (4-CmC)
      could generate caffeine-like responses in ferret cardiac muscle. The
      concentration dependence of 4-CmC-mediated release of Ca(2+) from the
      sarcoplasmic reticulum was studied in intact cardiac trabeculae and saponin
      skinned fibers in which the sarcoplasmic reticulum was loaded with Ca(2+). In
      intact and saponin-skinned preparations isolated from right ventricle, the effect
      of 4-CmC on sarcoplasmic reticulum Ca(2+) content was estimated by analysis of
      caffeine contracture after application of chlorocresol. In addition, the effects
      of 4-CmC on maximal Ca(2+)-activated tension and the Ca(2+) sensitivity of
      myofibrils were analyzed by using Triton-skinned cardiac fibers. The results show
      that 4-CmC generates a contractile response in saponin-skinned but not intact
      fibers. The sarcoplasmic reticulum is implicated in the 4-CmC response; more
      precisely, in Ca(2+) release via the ryanodine receptor. Moreover, 4-CmC, like
      caffeine, has effects on maximal Ca(2+)-activated tension and the Ca(2+)
      sensitivity of myofibrils.

PMID- 10411566
TI  - Inhibition of interleukin-1-induced proteoglycan degradation and nitric oxide
      production in bovine articular cartilage/chondrocyte cultures by the natural
      product, hymenialdisine.
AB  - The effects of hymenialdisine (SK&F 108752) were evaluated on interleukin-1 (IL
      1)-induced proteoglycan (PG) degradation, PG synthesis, nitric oxide (NO)
      production, and inducible nitric oxide synthase (iNOS) gene expression in bovine
      articular cartilage (BAC) and/or cartilage-derived chondrocytes. Cartilage disks
      from 0- to 3-month-old calves were treated with IL-1alpha or retinoic acid. PG
      release was determined by measuring glycosaminoglycan release, and nitrite
      production was measured as a readout for NO. Inhibition of iNOS gene expression
      was measured by Northern blot analysis in IL-1alpha-stimulated, cartilage-derived
      chondrocytes. To measure PG synthesis, chondrocytes were established in alginate
      beads and treated with hymenialdisine, and then [(35)S]sulfate incorporation into
      PGs was determined. Hymenialdisine inhibited IL-1alpha-stimulated PG breakdown in
      BAC in a dose-related manner with an IC(50) of approximately 0.6 microM.
      Herbimycin, a protein tyrosine kinase inhibitor, also inhibited PG breakdown,
      whereas RO 32-0432, a protein kinase C inhibitor, had no effect. Both
      hymenialdisine and herbimycin also were able to inhibit retinoic acid-stimulated
      PG release. IL-1alpha-stimulated NO production in BAC was inhibited by
      hymenialdisine and herbimycin at similar concentrations. The effect on iNOS gene
      expression was determined by Northern blot analysis in chondrocytes grown in
      monolayer, and inhibition by hymenialdisine was observed with an IC(50) of
      approximately 0.8 microM. In chondrocytes cultured in alginate beads, IL-1alpha
      inhibited PG synthesis, whereas hymenialdisine stimulated synthesis at low
      concentrations (0.6 and 1.25 microM), and higher doses (2.5 microM) were not
      stimulatory. Compounds with this profile may have utility in the treatment of
      osteoarthritis.

PMID- 10411568
TI  - Inhibition of beta(2)-adrenergic and muscarinic cholinergic receptor endocytosis
      after depletion of phosphatidylinositol bisphosphate.
AB  - Recent evidence supporting a role for phosphoinositides in the endocytosis of
      phospholipase C-coupled receptors has prompted an investigation of whether there
      exists a similar requirement for the internalization of adenylyl cyclase-linked
      receptors. When 1321N1 astrocytoma cells, which possess both muscarinic
      cholinergic receptors (mAChRs) that couple to phospholipase C and beta-adrenergic
      receptors (beta(2)-ARs) linked to adenylyl cyclase, were pretreated with
      wortmannin (WT) at a concentration known to inhibit phosphatidylinositol 4-kinase
      activity, the labeling of both phosphatidylinositol 4-phosphate and
      phosphatidylinositol 4, 5-bisphosphate (PIP(2)) was reduced. Stimulation of
      phosphoinositide breakdown by activation of mAChRs in WT-pretreated cells led to
      a further depletion of PIP(2). As previously demonstrated for SH-SY5Y
      neuroblastoma, inclusion of WT inhibited the endocytosis of mAChRs in 1321N1
      cells by >85%. In contrast, the internalization of beta(2)-ARs was only partially
      ( approximately 30%) prevented. However, when the concentration of PIP(2) was
      further reduced by exposure of WT-pretreated 1321N1 cells to a muscarinic
      agonist, the endocytosis of beta(2)-ARs was substantially inhibited (>70%). Lower
      concentrations of WT (100 nM) that were sufficient to fully inhibit
      phosphatidylinositol 3-kinase activity had no effect on either phosphoinositide
      synthesis or receptor endocytosis. The results indicate that the agonist-induced
      endocytosis of an adenylyl cyclase-linked receptor such as the beta(2)-AR, like
      that of the phospholipase C-coupled mAChR, is dependent on the synthesis of
      phosphoinositides and, in particular, that of PIP(2).

PMID- 10411567
TI  - Use of the steroid derivative RPR 106541 in combination with site-directed
      mutagenesis for enhanced cytochrome P-450 3A4 structure/function analysis.
AB  - RPR 106541 (20R-16alpha,17alpha-[butylidenebis(oxy)]-6al pha, 9alpha-difluoro
      11beta-hydroxy-17beta-(methylthio)androst a-4-en-3-one) is an airway-selective
      steroid developed for the treatment of asthma. Two metabolites produced by human
      liver microsomes were identified as R- and S-sulfoxide diastereomers based on
      liquid chromatography/mass spectrometry analysis, proton nuclear magnetic
      resonance, and cochromatography with standards. Sulfoxide formation was
      determined to be cytochrome P-450 (CYP) 3A4-dependent by correlation with CYP3A4
      marker nifedipine oxidase activity, inhibition by cyclosporin A and
      troleandomycin, and inhibition of R- (70%) and S- (64%) sulfoxide formation by
      anti-3A antibody. Expressed CYP2C forms catalyzed RPR 106541 sulfoxidation;
      however, other phenotyping approaches failed to confirm the involvement of CYP2C
      forms in these reactions in human liver microsomes. Expressed CYP3A4 catalyzed
      the formation of the sulfoxide diastereomers in a 1:1 ratio, whereas CYP3A5
      displayed stereoselectivity for formation of the S-diastereomer. The high rate of
      sulfoxidation by CYP3A4 and the blockage of oxidative metabolism at the
      electronically favored 6beta-position provided advantages for RPR 106541 over
      other substrates as an active site probe of CYP3A4. Therefore, oxidation of RPR
      106541 by various CYP3A4 substrate recognition site (SRS) mutants was assessed.
      In SRS-4, A305V and F304A showed dramatically reduced rates of R-diastereomer
      formation (83 and 64% decreases, respectively), but S-diastereomer formation was
      affected to a lesser extent. A370V (SRS-5) showed decreased formation of the R
      sulfoxide (52%) but increased formation of the S-diastereomer. In the SRS-2
      region, the most dramatic change in sulfoxide ratios was observed for L210A. In
      conclusion, the structure of RPR 106541 imposes specific constraints on enzyme
      binding and activity and thus represents an improved CYP3A4 probe substrate.

PMID- 10411569
TI  - Binge drinking disturbs hepatic microcirculation after transplantation:
      prevention with free radical scavengers.
AB  - Disturbances in hepatic microcirculation increase graft injury and failure;
      therefore, this study evaluates the effects of ethanol on microcirculation after
      liver transplantation. Donor rats were given one dose of ethanol (5 g/kg) by
      gavage 20 h before explantation, and grafts were stored in University of
      Wisconsin solution for 24 h before implantation. Acute ethanol treatment
      decreased 7-day survival of grafts from about 90 to 30%, increased transaminase
      release nearly 4-fold, and decreased bile production by 60%. Moreover, portal
      pressure increased significantly and liver surface oxygen tension decreased about
      50%, indicating that ethanol disturbs hepatic microcirculation. Pimonidazole, a 2
      nitroimidazole hypoxia marker, was given i.v. to recipients 30 min after
      implantation, and grafts were harvested 1 h later. Ethanol increased hepatic
      pimonidazole binding about 3-fold, indicating that ethanol led to hypoxia in
      fatty grafts. Ethanol also significantly increased free radicals in bile.
      Catechin (30 mg/kg i.v. upon reperfusion), a free radical scavenger, and Carolina
      Rinse solution, which contains several agents that inhibit free radical
      formation, minimized disturbances in microcirculation and prevented pimonidazole
      adduct formation significantly. These treatments also blunted increases in
      transaminase release and improved survival of fatty grafts. Destruction of
      Kupffer cells with GdCl(3) (20 mg/kg i.v. 24 h before explantation) or inhibition
      of formation of leukotrienes with MK-886 (50 microM in University of Wisconsin or
      rinse solution) also minimized hypoxia and improved survival after
      transplantation. Taken together, these results demonstrate that ethanol disturbs
      hepatic microcirculation, leading to graft hypoxia after transplantation, most
      likely by activating Kupffer cells and increasing free radical production.

PMID- 10411570
TI  - SB 203580, an inhibitor of p38 mitogen-activated protein kinase, enhances
      constitutive apoptosis of cytokine-deprived human eosinophils.
AB  - The role of p38 mitogen-activated protein (MAP) kinase, and extracellular
      regulated protein kinase -1 and -2 in regulating constitutive apoptosis and
      interleukin (IL)-5-induced survival of human eosinophils have been investigated.
      Two populations of donors were identified whose eosinophils, in the absence of
      exogenous cytokines, underwent apoptosis at different rates. Eosinophils were
      thus arbitrarily classified as either "fast"- or "slow"-dying cells, where
      greater or less than 15% of the cells were apoptotic at 2 days, respectively. The
      selective p38 MAP kinase inhibitor, SB 203580, increased constitutive eosinophil
      apoptosis in both populations (EC(50) approximately 2 microM) as evinced from
      morphological analysis, flow cytometry, and DNA laddering. The ability of SB
      203580 to kill eosinophils was not due to nonspecific toxicity or through the
      inhibition of prostanoid or leukotriene production. Exposure of eosinophils to IL
      5, at a concentration (10 pM) that enhanced survival maximally, abolished SB
      203580-induced apoptosis. In contrast PD 098059, which selectively blocks MAP
      kinase kinase (MEK) 1, did not affect apoptosis of fast- or slow-dying
      eosinophils, or the enhanced survival of cells effected by IL-5. Collectively,
      these results suggest that: 1) the basal activity of p38 MAP kinase may regulate
      the survival of cytokine-deprived eosinophils through inhibition of apoptosis, 2)
      the enhancement of eosinophil survival effected by IL-5 is mediated by a
      mechanism(s) divorced from the activation of p38 MAP kinase, and 3) neither
      spontaneous eosinophil apoptosis nor their enhanced survival by IL-5 involves the
      activation of MEK-1.

PMID- 10411571
TI  - Peripheral injection of a new corticotropin-releasing factor (CRF) antagonist,
      astressin, blocks peripheral CRF- and abdominal surgery-induced delayed gastric
      emptying in rats.
AB  - The effect of the corticotropin-releasing factor (CRF) receptor antagonists
      astressin and D-Phe CRF(12-41) injected i.v. on CRF-induced delayed gastric
      emptying (GE) was investigated in conscious rats. Gastric transit was assessed by
      the recovery of methyl cellulose/phenol red solution 20 min after its
      intragastric administration. The 55% inhibition of GE induced by CRF (0.6
      microgram i.v.) was antagonized by 87 and 100% by i.v. astressin at 3 and 10
      microgram, respectively, and by 68 and 64% by i.v. D-Phe CRF(12-41) at 10 and 20
      microgram, respectively. CRF (0.6 microgram)-injected intracisternally (i.c.)
      induced 68% reduction of GE was not modified by i.v. astressin (10 microgram)
      whereas i.c. astressin (3 or 10 microgram) blocked by 58 and 100%, respectively,
      i.v. CRF inhibitory action. Abdominal surgery with cecal manipulation reduced GE
      to 7.1 +/- 3.1 and 27.5 +/- 3.3% at 30 and 180 min postsurgery, respectively,
      compared with 40.3 +/- 4.3 and 59.5 +/- 2.9% at similar times after anesthesia
      alone. Astressin (3 microgram i.v.) completely and D-Phe CRF(12-41) (20 microgram
      i.v.) partially (60%) blocked surgery-induced gastric stasis observed at 30 or
      180 min. The CRF antagonists alone (i.v. or i.c.) had no effect on basal GE.
      These data indicate that CRF acts in the brain and periphery to inhibit GE
      through receptor-mediated interaction and that peripheral CRF is involved in
      acute postoperative gastric ileus; astressin is a potent peripheral antagonist of
      CRF when injected i.v. whereas i.c. doses >/=3 microgram exert dual central and
      peripheral blockade of CRF action on gastric transit.

PMID- 10411572
TI  - A novel transversion in the intron 5 donor splice junction of CYP2C19 and a
      sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for
      the anticonvulsant drug S-mephenytoin.
AB  - Cytochrome P-450 (CYP) 2C19 is responsible for the metabolism of a number of
      therapeutic agents such as S-mephenytoin, omeprazole, proguanil, certain
      barbiturates, diazepam, propranolol, citalopram and imipramine. Genetic
      polymorphisms in this enzyme are responsible for the poor metabolizers (PM) of
      mephenytoin, which represent approximately 13-23% of Asians and 3-5% of
      Caucasians. Several polymorphisms contribute to this phenotype. We have isolated
      two new allelic variants that contribute to the PM phenotype in Caucasians.
      CYP2C19*7 contained a single T --> A nucleotide transversion in the invariant GT
      at the 5' donor splice site of intron 5. The second PM allele, CYP2C19*8,
      consisted of a T358C nucleotide transition in exon 3 that results in a Trp120Arg
      substitution. In a bacterial expression system, CYP2C198 protein exhibited a
      dramatic (approximately 90% and 70%) reduction in the metabolism of S-mephenytoin
      and tolbutamide, respectively, when compared with the wild-type CYP2C191B
      protein. Restriction fragment length polymerase chain reaction tests were
      developed to identify the new allelic variants.

PMID- 10411573
TI  - Lack of effect of McN-A-343 on membrane current and contraction in guinea pig
      ventricular myocytes.
AB  - We asked whether agonist occupancy of M(1) muscarinic receptor (mAChR) causes
      increased L-type Ca(2+) [I(Ca(L))] and contractions in ventricular myocytes.
      Voltage-clamp pulses evoked I(Ca(L)) in guinea pig ventricular myocytes
      superfused with Tyrode's solution (22-24 degrees C). The mAChR agonists carbachol
      (Cch, nonselective), McN-A-343 (McN, M(1)-selective), and oxotremorine (Oxo, M(2)
      selective) were tested at 0.1 mM. None of these agonists affected basal I(Ca(L)).
      McN did not change isoproterenol-stimulated I(Ca(L)) in 13 of 15 cells. The
      slight decrease in two cells was not muscarinic because atropine (1 microM) did
      not antagonize it. Carbachol or Oxo decreased isoproterenol-stimulated I(Ca(L))
      by 87 +/- 6.7 (n = 8 cells) and 49 +/- 9.0% (n = 4 cells), respectively. Atropine
      blocked inhibition by Cch or Oxo. External stimulation evoked contractions of
      single myocytes (35 degrees C). McN increased contraction in 1 of 22 cells
      stimulated at 0.2 Hz and in 0 of 16 cells stimulated at 1.0 Hz. Carbachol
      significantly increased contraction in 10 of 15 cells at 0.2 Hz and in 8 of 10
      cells at 1.0 Hz stimulus frequency. Summarily, the M(1)-selective agonist McN had
      a negligible role to regulate I(Ca(L)). The antiadrenergic effect of mAChR
      agonists is attributable to M(2) receptor occupancy. That Cch, but not McN,
      increased cell shortening excludes participation of M(1) mAChR in the stimulant
      effect of Cch on guinea pig ventricular myocyte contractions.

PMID- 10411574
TI  - Potent and selective human beta(3)-adrenergic receptor antagonists.
AB  - Although the functional presence of beta(3)-adrenergic receptors (beta(3)-AR) in
      rodents is well established, its significance in human adipose tissue has been
      controversial. One of the issues confounding the experimental data has been the
      lack of potent and selective human beta(3)-AR ligands analogous to the rodent
      specific agonist BRL37344. Recently, we described a new class of
      aryloxypropanolamine beta(3)-AR agonists that potently and selectively activate
      lipolysis in rhesus isolated adipocytes and stimulate the metabolic rate in
      rhesus monkeys in vivo. In this article, we describe novel and selective beta(3)
      AR antagonists with high affinity for the human receptor. L-748,328 and L-748,337
      bind the human cloned beta(3)-AR expressed in Chinese hamster ovary (CHO) cells
      with an affinity of 3.7 +/- 1.4 and 4.0 +/- 0.4 nM, respectively. They display an
      affinity of 467 +/- 89 and 390 +/- 154 nM for the human beta(1)-AR. Their
      selectivity for human beta(3)-AR versus beta(2)-AR is greater than 20-fold (99 +/
      43 nM) and 45-fold (204 +/- 75 nM), respectively. These compounds are
      competitive antagonists capable of inhibiting the functional activation of
      agonists in a dose-dependent manner in cells expressing human cloned beta(3)-AR.
      Moreover, both L-748,328 and L-748,337 inhibit the lipolytic response elicited by
      the beta(3)-AR agonist L-742,791 in isolated nonhuman primate adipocytes. The
      aryloxypropanolamine benzenesulfonamide ligands illustrated here and elsewhere
      demonstrate high-affinity human beta(3)-AR binding. In addition, we describe
      specific 3'-phenoxy substitutions that transform these compounds from potent
      agonists into selective antagonists.

PMID- 10411575
TI  - Bradykinin activates a cross-signaling pathway between sensory and adrenergic
      nerve endings in the heart: a novel mechanism of ischemic norepinephrine release?
AB  - We had shown that bradykinin (BK) generated by cardiac sympathetic nerve endings
      (i.e., synaptosomes) promotes exocytotic norepinephrine (NE) release in an
      autocrine mode. Because the synaptosomal preparation may include sensory C-fiber
      endings, which BK is known to stimulate, sensory nerves could contribute to the
      proadrenergic effects of BK in the heart. We report that BK is a potent releaser
      of NE from guinea pig heart synaptosomes (EC(50) approximately 20 nM), an effect
      mediated by B(2) receptors, and almost completely abolished by prior C-fiber
      destruction or blockade of calcitonin gene-related peptide and neurokinin-1
      receptors. C-fiber destruction also greatly decreased BK-induced NE release from
      the intact heart, whereas tyramine-induced NE release was unaffected.
      Furthermore, C-fiber stimulation with capsaicin and activation of calcitonin gene
      related peptide and neurokinin-1 receptors initiated NE release from cardiac
      synaptosomes, indicating that stimulation of sensory neurons in turn activates
      sympathetic nerve terminals. Thus, BK is likely to release NE in the heart in
      part by first liberating calcitonin gene-related peptide and Substance P from
      sensory nerve endings; these neuropeptides then stimulate specific receptors on
      sympathetic terminals. This action of BK is positively modulated by
      cyclooxygenase products, attenuated by activation of histamine H(3) receptors,
      and potentiated at a lower pH. The NE-releasing action of BK is likely to be
      enhanced in myocardial ischemia, when protons accumulate, C fibers become
      activated, and the production of prostaglandins and BK increases. Because NE is a
      major arrhythmogenic agent, the activation of this interneuronal signaling system
      between sensory and adrenergic neurons may contribute to ischemic dysrhythmias
      and sudden cardiac death.

PMID- 10411576
TI  - Mechanism-based modeling of rebound tachycardia after chronic l-propranolol
      infusion in spontaneous hypertensive rats.
AB  - The aims of the study were to characterize the rate and extent of the rebound
      effect after abrupt cessation of a chronic exposure of l-propranolol in
      spontaneous hypertensive rats, using exercise-induced tachycardia as a
      pharmacodynamic endpoint. Thirty-two spontaneous hypertensive rats were
      randomized to receive either placebo or 4 or 8 mg/kg/day s.c. infusion of l
      propranolol for 11 days using osmotic minipumps. The heart rate was measured
      after standardized physical exercise before and during drug exposure and over 12
      days after cessation, using a computerized tail-cuff method. Blood samples were
      collected after each effect measurement during the infusion. A similar reduction
      in exercise tachycardia was registered for the two doses. No apparent tolerance
      development was found, but both doses showed a clear rebound effect of similar
      extent and intensity. The maximal rebound effect was observed on the second day
      after cessation and was found to have a duration of about 6 days. A mechanism
      based model was developed to describe the rate and extent of changes in beta
      adrenoceptor up- and down-regulation with increased sensitivity of the transducer
      complex. The half-life of disappearance of up-regulated beta-adrenoceptors was
      estimated to be 2.0 days (1.0-3.9 days). The effect-versus-time data was analyzed
      by nonlinear mixed-effect modeling with the program NONMEM. A dose-dependent
      reduction in the growth of body weight was observed during drug treatment, which
      was reversible. A dose- and time-dependent increase in the alpha(1)-acid
      glycoprotein concentration was also observed.

PMID- 10411577
TI  - The interaction and transport of beta-lactam antibiotics with the cloned rat
      renal organic anion transporter 1.
AB  - In the present study, we investigated the interactions between antibiotics,
      especially beta-lactam antibiotics, and rat renal organic anion transporter 1
      (OAT1). [(14)C]p-Aminohippurate (PAH) uptake via OAT1 expressed in Xenopus laevis
      oocytes was inhibited by all of the penicillins and cephalosporins tested.
      Penicillin G, carbenicillin, cephaloridine, cephalothin, cefazolin, and
      cephalexin inhibited [(14)C]PAH uptake via OAT1 in a competitive manner (K(i) =
      0.29-2.33 mM). Cinoxacin, a quinolone gyrase inhibitor, also inhibited PAH uptake
      via OAT1. Other antibiotics, such as gentamicin, streptomycin, and vancomycin,
      which do not contain anionic moieties, did not interact with OAT1.
      [(3)H]Penicillin G and [(14)C]cephaloridine were demonstrated to be transported
      via OAT1. Using the cells that stably expressed OAT1, we analyzed the
      cytotoxicity of several beta-lactam antibiotics. Cells expressing OAT1 showed
      higher susceptibility to cephaloridine (a potentially nephrotoxic beta-lactam
      antibiotic) toxicity than did control cells. The present study suggests that OAT1
      is the major organic anion transporter in the kidney that is responsible for the
      renal secretion of antibiotics, especially that of beta-lactam antibiotics.
      Furthermore, the culture cell system expressing OAT1 was revealed to be useful
      for the prediction of the nephrotoxicity of beta-lactam antibiotics.

PMID- 10411579
TI  - Interspecies differences in the cardiac negative inotropic effects of beta(3)
      adrenoceptor agonists.
AB  - The aim of the present study was to compare the effects of three preferential
      (BRL 37344, SR 58611, CL 316 243) and a partial (CGP 12177) beta-adrenoceptor
      (beta(3)-AR) agonists on the contractility of ventricular strips sampled from
      various mammalian species including humans. In the human heart, all beta(3)-AR
      agonists tested decreased contractility by 40 to 60% below control with an order
      of potency: BRL 37344 > CL 316 243 = SR 58611 >> CGP 12177. In the dog, the
      negative inotropic effects produced by beta(3)-AR stimulation were less
      pronounced than in humans, approximately 30% below control. The order of potency
      of beta(3)-AR agonists was CGP 12177 > BRL 37344 = SR 58611 >> CL 316 243; i.e.,
      very different from that observed in humans. In rat, only BRL 37344 was efficient
      to decrease contractility. In guinea pig, only CL 316 243 significantly reduced
      peak tension. In both species, the reduction in peak tension did not exceed 20 to
      30%. Finally, in the ferret, none of the agonists tested induced a negative
      inotropic effect. In dog, the negative inotropic effects of CGP 12177 were not
      modified by nadolol, but were abolished by bupranolol, a beta(1-3)-AR. beta(3)-AR
      transcripts were detected in the dog but not in the rat ventricle by using a
      reverse transcription-polymerase chain reaction assay. We conclude that cardiac
      negative inotropic effects related to beta(3)-AR agonist stimulation vary
      markedly depending on the species. A comparable interspecies variation previously
      has been reported concerning the lipolytic effects of beta(3)-AR agonist
      stimulation. Our study demonstrates that the pharmacological profile of a beta(3)
      AR agonist on the human myocardium cannot be extrapolated from usual animal
      models.

PMID- 10411578
TI  - Effects of systemically administered dynorphin A(1-17) in rhesus monkeys.
AB  - The effects of i.v. dynorphin A(1-17) and its main nonopioid biotransformation
      fragment, dynorphin A(2-17), were compared in rhesus monkeys with those of the
      selective kappa-opioid agonist, U69, 593, in assays of operant behavior, thermal
      antinociception, and neuroendocrine function (prolactin release). Dynorphin A(1
      17) (0. 1-3.2 mg/kg i.v.) and U69,593 (0.001-0.032 mg/kg s.c.) decreased rates of
      schedule-controlled (fixed ratio 20) food-reinforced responding, whereas
      dynorphin A(2-17) (1-3.2 mg/kg i.v.) was ineffective. Pretreatment studies with
      the opioid antagonist quadazocine (0.32 mg/kg s.c.) revealed that the operant
      effects of dynorphin A(1-17) were not mediated by kappa- or micro-opioid
      receptors. A different profile was observed in the warm water tail withdrawal
      assay of thermal antinociception, where both dynorphin A(1-17) and A(2-17) (0.032
      3.2 mg/kg i.v., n = 4) were modestly effective in 50 degrees C water, and both
      were ineffective in 55 degrees C water. By comparison, U69,593 (0.032-0.18 mg/kg
      s.c.) was maximally effective in 50 degrees C water and partially effective in 55
      degrees C. kappa-opioid agonists increase serum levels of prolactin in animals
      and humans. Dynorphin A(1-17) (ED(50) = 0.0011 mg/kg i.v.), similar to U69,593
      (ED(50) = 0.0030 mg/kg i.v.), was very potent in increasing serum prolactin
      levels in follicular phase female rhesus monkeys, whereas dynorphin A(2-17) (0.32
      mg/kg i.v.) was ineffective. The effects of dynorphin A(1-17) and U69,593 on
      serum prolactin were both antagonized by quadazocine (0.32 mg/kg s.c.) in a
      surmountable manner, consistent with opioid receptor mediation. The present
      studies show that serum prolactin levels are a sensitive quantitative endpoint to
      study the systemic effects of the endogenous opioid peptide, dynorphin A(1-17),
      in primates.

PMID- 10411580
TI  - The relationship between the myocardial kinetics of meperidine and its effect on
      myocardial contractility: model-independent analysis and optimal regional model.
AB  - The myocardial kinetics of meperidine and the relationship between these kinetics
      and the effect of meperidine on myocardial contractility (maximum positive rate
      of change of left ventricular pressure) were examined by analysis of previously
      published data collected in sheep after the i.v. injection of 100 mg of
      meperidine over 1 s. There was significant hysteresis between reductions in
      myocardial contractility and the arterial concentrations of meperidine, but not
      the coronary sinus blood (effluent from the heart) or calculated myocardial
      concentrations. The peak reduction in contractility occurred after the peak
      arterial concentration, at the time of the peak myocardial concentration, but
      before the peak coronary sinus concentration, suggesting that the site of drug
      action in the heart was not in equilibrium with either arterial blood or effluent
      blood from the heart. The most appropriate form of a dynamic model (a linear
      model with a threshold) was determined, without the need to assume a kinetic
      model, by directly fitting the observed reductions in myocardial contractility to
      the calculated myocardial concentrations. To determine the optimal kinetic and
      combined kinetic-dynamic models, a variety of one-, two-, and three-compartment
      models of the myocardium were fitted to the coronary sinus concentrations by
      using hybrid modeling. These included "tank in series" models that accounted well
      for drug dispersion and "peripheral compartment" models that accounted well for
      deep distribution. The most appropriate model was a "compilation" model, which
      incorporated features of both these extremes and was a better fit to the observed
      data than either a traditional single flow-limited compartment or a traditional
      membrane-limited model.

PMID- 10411581
TI  - Mechanism-based pharmacokinetic-pharmacodynamic modeling of antilipolytic effects
      of adenosine A(1) receptor agonists in rats: prediction of tissue-dependent
      efficacy in vivo.
AB  - In this study, we analyzed the antilipolytic effects of six N(6)
      cyclopentyladenosine analogs in rats and developed a mechanistic pharmacokinetic
      pharmacodynamic model to quantify and predict the tissue-selective action of
      adenosine A(1) receptor agonists in vivo. Freely moving rats received an i.v.
      infusion of vehicle or compound over 15 min. Arterial blood samples were taken at
      regular time intervals for the determination of concentrations of drugs using
      HPLC analysis and of nonesterified fatty acids (NEFAs). All N(6)
      cyclopentyladenosine analogs that were investigated produced a significant
      decrease in the NEFA plasma concentration after i.v. infusion. The
      pharmacokinetic behavior of each ligand was described by a standard two
      compartment model. The pharmacokinetic parameter estimates then were used to
      simultaneously fit the individual (n = 6-8) time-NEFA concentration profiles for
      each agonist to a physiological indirect response model in combination with the
      Hill equation to obtain estimates of the NEFA elimination rate constant (k(e))
      and upper asymptote (fractional inhibition), midpoint location, and midpoint
      slope parameter (alpha, pEC(50), and n(H), respectively) of the concentration
      effect relationship. Subsequently, the data were analyzed with the operational
      model of agonism to obtain estimates of in vivo affinity and efficacy. It was
      estimated that the in vivo density and/or coupling of adenosine A(1) receptors
      mediating antilipolytic effects is approximately 38 times higher compared with
      the receptors mediating bradycardia. The model predicts that it is possible to
      design ligands that produce significant inhibition of lipolysis and are
      completely devoid of cardiovascular effects in vivo.

PMID- 10411582
TI  - Evidence for differential regulation of renal proximal tubular p-aminohippurate
      and sodium-dependent dicarboxylate transport.
AB  - In renal proximal tubules, the basolateral organic anion [p-aminohippurate (PAH)]
      transporter is functionally coupled to the sodium-dependent dicarboxylate
      transporter. This study was undertaken to elucidate whether protein kinases
      differentially modulate the activities of these transporters. In isolated S(2)
      segments of proximal tubules microdissected from rabbit kidneys, we investigated
      whether the transporters are regulated by tyrosine kinases, phosphatidylinositol
      3-kinase (PI3K), and mitogen-activated protein kinase (MAPK). The tubules were
      collapsed; hence, tubular uptake of the marker substances [(3)H]PAH and
      [(14)C]glutarate reflects transport across the basolateral cell membrane.
      Genistein, a selective inhibitor of tyrosine kinase, diminished PAH uptake at 10(
      7) M by 15.6 +/- 11.7% and at 10(-6) M by 25.6 +/- 9.1%. An inactive analog of
      genistein, diadzein, was without effect even at a concentration 100-fold higher
      than the lowest concentration of genistein, which produced significant reduction
      of PAH uptake. At 10(-7) M, wortmannin, a selective inhibitor of PI3K, reduced
      PAH uptake by 24.1 +/- 11.3% and, at 10(-6) M, it reduced it by 32.9 +/- 11.8%.
      The selective inhibitor of MAPK, PD98059, diminished PAH uptake at 5 x 10(-5) M
      by 23.2 +/- 6.8% and at 10(-4) M by 18.3 +/- 5.2%. Glutarate uptake was not
      reduced by any of these protein kinase inhibitors. Insulin had no effect on PAH
      uptake. These findings indicate that, in addition to protein kinase A, protein
      kinase C and calcium/calmodulin-dependent protein kinase II (former studies from
      this laboratory), as well as tyrosine kinases, PI3K, and MAPK, modulate renal
      basolateral PAH transport, whereas none of these protein kinases affects
      basolateral glutarate transport. Thus, the results provide evidence for
      differential regulation of basolateral transporters for PAH and dicarboxylates.

PMID- 10411583
TI  - Effects of LU-111995 in three models of disrupted prepulse inhibition in rats.
AB  - LU-111995 is a novel antipsychotic drug in clinical development. It has a
      clozapine-like receptor profile and affinities for dopamine D(4) and 5
      hydroxytryptamine(2A) receptors. The effects of LU-111995 were examined in three
      models of disrupted prepulse inhibition (PPI) in rats. The first model tested the
      hypothesis that LU-111995 would normalize the deficit in PPI exhibited by rats
      treated with the dopamine agonist apomorphine. LU-111995 significantly reduced
      the effect of apomorphine on PPI but also slightly increased PPI by itself. Thus,
      the increases in PPI were not specific to the animals treated with apomorphine
      but reflected an effect of LU-111995 on PPI. LU-111995 also attenuated the
      apomorphine-induced increase in startle reactivity. The second model tested the
      hypothesis that LU-111995 would normalize the deficit in PPI exhibited by rats
      treated with the psychotomimetic phencyclidine (PCP). LU-111995 significantly
      blocked the PCP-induced increase in startle reactivity but did not alter the PPI
      disruptive effects of PCP. The third model tested the hypothesis that LU-111995
      would normalize the deficit in PPI exhibited by isolation-reared rats tested as
      adults. Isolation rearing of rats produced deficits in PPI. LU-111995 reversed
      the isolation rearing-induced deficit in PPI without having any significant
      effect on PPI in socially reared rats. In summary, LU-111995 exhibits potential
      antipsychotic-like activity in two models of disrupted PPI. It remains to be
      elucidated whether its effects on PPI can be attributed to a blockade of single
      dopamine and 5-hydroxytryptamine receptor subtypes, especially D(4) and 5
      hydroxytryptamine(2A), or a combination of both.

PMID- 10411584
TI  - Studies on maitotoxin-induced intracellular Ca(2+) elevation in chinese hamster
      ovary cells stably transfected with cDNAs encoding for L-type Ca(2+) channel
      subunits.
AB  - The aim of the present study was to characterize the role played by different L
      type Ca(2+) channel subunits in [Ca(2+)](i) increase induced by maitotoxin (MTX).
      In the presence of 5 mM extracellular K(+), MTX (0.01-0.5 ng/ml) induced a
      significant concentration-dependent increase in Fura-2-monitored [Ca(2+)](i) in
      single Chinese hamster ovary (CHO) cells expressing the alpha(1c) (CHOCalpha9
      cells) or the alpha(1c)beta(3)alpha(2)delta (CHOCalpha9beta3alpha2/delta4 cells)
      subunits of voltage-gated Ca(2+) channels (VGCCs), whereas the effect was much
      reduced in wild-type CHO cells lacking VGCCs. In addition, MTX effect on
      CHOCalpha9, CHOCalpha9beta3alpha2/delta4, and GH(3) cells (0.01-0.1 ng/ml) was
      inhibited by the selective L-type Ca(2+) channel entry-blocker nimodipine (10
      microM); a nimodipine-insensitive component was still present, particularly at
      high (>1 ng/ml) toxin concentrations. In CHOCalpha9beta3alpha2/delta4 cells,
      depolarizing concentrations of extracellular K(+) (55 mM) reinforced the
      [Ca(2+)](i) increase induced by MTX (0.1 ng/ml), and this effect was prevented by
      nimodipine (10 microM). Finally, patch-clamp experiments in
      CHOCalpha9beta3alpha2/delta4 cells showed that low MTX concentrations (0.03
      ng/ml) induced the occurrence of an inward current at -60 mV, which was
      completely prevented by Cd(2+) (100 microM) and by nimodipine (10 microM),
      whereas the same dihydropyridine concentration (10 microM) failed to prevent the
      electrophysiological effects of a higher toxin concentration (3 ng/ml). In
      conclusion, the results of the present study showed that MTX-induced [Ca(2+)](i)
      elevation involves two components: 1) an action on L-type VGCCs at the pore
      forming alpha(1c) subunit level, which is responsible for the greatest rise of
      [Ca(2+)](i); and 2) a VGCC-independent mechanism that is present both in
      excitable and in nonexcitable cells and is responsible for a lower elevation of
      [Ca(2+)](i).

PMID- 10411585
TI  - Nicotinic acetylcholine receptor agonist SIB-1508Y improves cognitive functioning
      in chronic low-dose MPTP-treated monkeys.
AB  - Monkeys that receive chronic low-dose 1-methyl-4-phenyl-1,2,3, 6
      tetrahydropyridine (MPTP) administration have difficulty performing numerous
      cognitive tasks. This study further examines the extent to which chronic low-dose
      MPTP exposure affects performance of a visual memory task [variable delayed
      response (VDR)] with both attentional and short-term memory components and
      assesses the effects of the novel neuronal nicotinic acetylcholine receptor
      agonist SIB-1508Y and levodopa on cognitive task performance. Before MPTP
      treatment, these monkeys displayed a delay-dependent decrement in performance on
      the VDR task and performed well on delayed matching-to-sample and visual pattern
      discrimination tasks. Chronic low-dose MPTP treatment caused a shift to a delay
      independent pattern of responding on the VDR task, such that short-delay trials
      were performed as poorly as long-delay trials. There were also deficits in
      performing the delayed matching-to-sample task, whereas visual discrimination
      performance remained intact. SIB-1508Y normalized the pattern of response on the
      VDR task by significantly improving performance on short-delay trials and on the
      delayed matching-to-sample task. These effects lasted up to 24 to 48 h after SIB
      1508Y administration. Neither levodopa nor nicotine significantly improved task
      performance. These results suggest that chronic low-dose MPTP exposure results in
      a cognitive disturbance that can be corrected by the nicotinic acetylcholine
      receptor agonist SIB-1508Y but not by levodopa. Thus, SIB-1508Y may be useful in
      the treatment of the cognitive deficits in Parkinson's disease.

PMID- 10411586
TI  - Synthetic estrogen 17alpha-ethinyl estradiol induces pattern of uterine gene
      expression similar to endogenous estrogen 17beta-estradiol.
AB  - 17alpha-Ethinyl estradiol is one of most widely prescribed estrogens. We compared
      the effects of this synthetic estrogen to those of the endogenous ovarian hormone
      17beta-estradiol on the expression of four estrogen-inducible genes in the rat
      uterus. The genes examined include c-fos, c-jun, vascular endothelial growth
      factor, and creatine kinase B, which are all known to be primary responses to
      estrogen administration. Both estrogens induced the four target genes with
      similar time courses and produced the same pattern of cell-specific expression of
      c-fos and vascular endothelial growth factor in the uterine epithelium and
      stroma, respectively. Dose-response studies established that the potency and
      efficacy of both estrogens in the uterus were the same for all four hormone
      regulated genes. These studies suggest that 17alpha-ethinyl and 17beta-estradiol
      produce similar if not identical patterns of gene expression in the uterus.

PMID- 10411588
TI  - Proteinase-activated receptor 2 (PAR(2)): development of a ligand-binding assay
      correlating with activation of PAR(2) by PAR(1)- and PAR(2)-derived peptide
      ligands.
AB  - A cloned rat proteinase-activated receptor (PAR)(2)-expressing cell line (KNRK
      rPAR(2)) was used to study the structure-activity relationships (elevated
      intracellular Ca(2+)) for a series of: 1) PAR(1)-derived receptor-activating
      ligands (PAR(1)-APs) [SFLLR (P5), SFLLR-NH(2) (P5-NH(2)), SFLLRNP (P7), SFLLRNP
      NH(2) (P7-NH(2)), and TFLLR-NH(2) (TF-NH(2))] and 2) PAR(2)-derived-activating
      peptides (PAR(2)-APs) [SLIGRL-NH(2) (SL-NH(2)), SLIGR-NH(2) (GR-NH(2)), and
      SLIGKV-NH(2) (KV-NH(2))]. The activities of the PAR-APs were compared with the
      PAR(2)-AP analog trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-Orn-NH(2) tc-NH(2)), which
      as a [(3)H]propionyl derivative ([(3)H]propionyl-tc-NH(2)) was used to develop a
      radioligand-binding assay for PAR(2). The relative potencies of the PAR-APs in
      the Ca(2+)-signaling assay were tc-NH(2) = SL-NH(2) > KV-NH(2) congruent with P5
      NH(2) > GR-NH(2) > P7-NH(2) > P7 > P5 > TF-NH(2). The reverse sequence PAR-APs,
      LSIGRL-NH(2) (LS-NH(2)), LRGILS-NH(2) (LR-NH(2)), FSLLRY-NH(2) (FSY-NH(2)), and
      FSLLR-NH(2) (FS-NH(2)), as well as the Xenopus PAR(1)-AP TFRIFD-NH(2), were
      inactive. The relative biological potencies of the peptides were in accord with
      their ability to compete for the binding of [(3)H]propionyl-tc-NH(2) (tc-NH(2) =
      SL-NH(2) > GR-NH(2) congruent with P5-NH(2) > P5) to KNRK-rPAR(2) cells, whereas
      inactive peptides (FS-NH(2); LR-NH(2)) showed no appreciable binding competition.
      Our data therefore validate a ligand-binding assay for the use in studies of
      PAR(2) and indicate that the relative biological potencies of the PAR(1)-APs for
      activating rat PAR(2) parallel their ability to activate human PAR(1). The
      relative receptor-binding activities of the PAR-APs, although in general
      agreement with their relative biological activities, point to differences in the
      intrinsic receptor-activating activities between the several PAR-APs. The binding
      assay we have developed should prove of use for the further study of PAR(2)
      ligand interactions.

PMID- 10411587
TI  - Improvement of mortality by long-term E4010 treatment in monocrotaline-induced
      pulmonary hypertensive rats.
AB  - We investigated the effects of long-term treatment with a selective
      phosphodiesterase 5 inhibitor E4010, 4-(3-chloro-4methoxybenzyl)amino-1-(4
      hydroxypiperidino)-6-phth alazin ecarbonitrile monohydrochloride, on the survival
      rate of rats with pulmonary hypertension induced by monocrotaline (MCT). After an
      s.c. injection of 40 mg/kg MCT (day 0), male Wistar rats of 4 weeks of age were
      divided into four groups. Vehicle-treated rats (control, n = 8) and MCT-treated
      rats (n = 32) were fed a commercial diet. E4010-treated rats were given a
      commercial diet containing 0.01% (E4010 0.01%, n = 32) and 0.1% (E4010 0.1%, n =
      32) of E4010, respectively. At day 23, all rats in the control group and 28.1% of
      those in the MCT group (P <.01 versus control) were alive. Although the survival
      rate of E4010 0.01%-treated rats was not improved (50%) compared with MCT, those
      at 0.1% showed a significant difference (84. 4%, P <.01 versus MCT). For MCT rats
      (n = 9), right ventricle weight and the levels of plasma atrial natriuretic
      peptide (ANP), brain natriuretic peptide (BNP), cGMP, and cyclic AMP were higher
      compared with control (n = 8). In E4010 0.1%-treated rats (n = 27), the right
      ventricular hypertrophy was suppressed, and the increase in plasma cGMP level was
      amplified compared with MCT without any effects on plasma ANP, BNP, and cyclic
      AMP levels. Accordingly, we consider that the mechanism of action of E4010 may be
      related to the decreased pulmonary arterial pressure caused by the augmentation
      of pulmonary arterial relaxation through an ANP and/or BNP-cGMP system. These
      results suggest that E4010 will be useful for the treatment of pulmonary
      hypertension.

PMID- 10411589
TI  - Comparison of the pharmacological properties of cloned rat, human, and bovine
      norepinephrine transporters.
AB  - The aims of this study were to characterize the recently cloned rat
      norepinephrine transporter (NET) in more detail and in particular to study
      possible species differences in its pharmacological properties compared with the
      human and bovine NETs. The study was carried out by measuring the uptake of
      [(3)H]norepinephrine in COS-7 cells expressing the NET after transient
      transfection with rat, human, or bovine NET cDNA. There were small but
      significant differences between the rat NET and the human or bovine NETs with
      respect to the affinities of sodium ions (greater for rat than for bovine) of the
      substrates norepinephrine, epinephrine, and 1-methyl-4-phenylpyridinium (greater
      for human than for rat), and of the inhibitor cocaine (greater for human and
      bovine than for rat), whereas the affinities of dopamine and of most inhibitors,
      including tricyclic antidepressants, showed no species differences. The fact that
      the affinities for some substrates, cocaine and sodium ions exhibited small but
      significant interspecies differences among the rat, human, and bovine NETs
      suggests that ligand recognition, the translocation process, and sodium ion
      dependence are influenced differentially by just a few amino acid exchanges in
      the primary sequences of the transporters. On the other hand, the lack of any
      major differences in the pharmacological properties of the rat, human, and bovine
      NETs in this study suggests that data obtained in previous studies on rat tissues
      and bovine cells can be extrapolated, in all except the most quantitative
      analyses, to the properties of the human NET.

PMID- 10411590
TI  - Depletion and restoration of the putative photosensitive materials store yielding
      nitric oxide in the isolated mouse gastric fundus.
AB  - We investigated the possibility of there being any photosensitive materials
      stores yielding nitric oxide (NO), and combined for the first time electrical
      field stimulation (EFS)- and UV light-induced relaxations in mouse gastric
      fundus. The tissue responded with relaxation to long wave UV light (366 nm).
      Repeated exposure to light decreased the fundic photorelaxation in that the
      initial photorelaxation was 31.5 +/- 6.9% whereas the last (10th) photorelaxation
      was 2.3 +/- 0.8%. There were no significant differences between EFS (30 V, 0.5
      ms, 1 Hz, 15 s)-induced relaxations obtained before (39.7 +/- 7.7%) and after
      (33.4 +/- 9.1%) UV irradiation, which were completely blocked by 10(-4) M L-N(G)
      nitro-arginine methyl ester. Treatment of the tissue with NaNO(2), L-N(G)-nitro
      arginine, S-nitrosoglutathione, or sodium nitroprusside for 30 min followed by
      prolonged washout restored the photorelaxation, whereas glyceryl trinitrate or L
      arginine did not produce any improvement. EFS (30 V, 0.5 ms, 3 Hz) applied for 60
      min significantly recovered the reduction of the photorelaxation. L-N
      (delta)iminoethyl-L-ornithine, which does not contain NO(2) moiety, abolished
      electrically induced relaxation; however, it did not change photorelaxations. UV
      irradiation caused relaxation only when the adventitial surface of the
      preparation was oriented to the source of UV light. These results indicate that
      there could be a photosensitive relaxant materials store yielding NO in the
      smooth muscle layer of the gastric fundus from mouse. This putative store can be
      refilled by NaNO(2), L-N(G)-nitro-arginine, sodium nitroprusside, S
      nitrosoglutathione, or long-term EFS but not glyceryl trinitrate or L-arginine.
      Possible candidates for NO-yielding substances might not be an organic nitrate
      but an intracellular nitrite, nitrosylated substances, and unknown nitro
      containing compounds, which could be all sensitive to UV light.

PMID- 10411591
TI  - S-Adenosylmethionine protects against cyclosporin A-induced alterations in rat
      liver plasma membrane fluidity and functions.
AB  - We studied the effect of cyclosporin A (CyA) on liver plasma membrane (LPM)
      composition, fluidity, and functions and on hepatic glutathione (GS) and
      oxidative status. We also evaluated the ability of S-adenosylmethionine (SAMe) to
      antagonize the CyA-induced disturbances in rats. The animals were randomly
      divided into four groups and treated daily with saline, CyA vehicle, CyA, and
      SAMe plus CyA, respectively, for 1 week. Bile, blood, and liver samples and LPM
      vesicles were obtained at the end of the treatments. CyA-induced cholestasis was
      associated with alterations in LPM composition and fluidity. The contents of
      total phospholipids, phosphatidylcholine, and proteins were decreased and
      cholesterol and the cholesterol/phospholipid molar ratio increased. Na(+), K(+)
      ATPase activity was decreased, whereas those of 5'-nucleotidase, Mg(2+)-ATPase,
      and gamma-glutamyltransferase increased. The hepatic contents of proteins and GS
      and the reduced/oxidized glutathione molar ratio were decreased and hepatic
      malondialdehyde increased. SAMe cotreatment 1) significantly improved or
      abolished the CyA-induced changes in LPM fluidity and composition and the changes
      in the activity of the carrier and enzymes tested, 2) counteracted the hepatic
      depletion of GS and proteins caused by CyA and normalized the reduced/oxidized
      glutathione ratio, and, as expected, 3) prevented cholestasis and the inhibitory
      effect of CyA on hepatobiliary transport of the major bile components. We
      conclude that CyA-induced cholestasis and hepatotoxicity in the rat is associated
      with changes in LPM composition and fluidity, liver GS depletion, and oxidative
      stress. SAMe cotreatment significantly improves or totally protects against these
      hepatotoxic effects.

PMID- 10411592
TI  - Inhibition of neutrophil proteinases by recombinant serpin Lex032 reduces
      capillary no-reflow in ischemia/reperfusion-induced acute pancreatitis.
AB  - Because neutrophil proteinases such as elastase and cathepsin G are considered to
      play a major role in inflammatory tissue damage, the microcirculatory effect of
      the serine proteinase inhibitor (serpin) Lex032 after ischemia/reperfusion (I/R)
      induced pancreatitis was investigated. Lex032 inhibits these proteinases by
      recombinant combination of alpha(1)-antitrypsin and alpha(1)-antichymotrypsin.
      Twenty-eight anesthetized rats received either Lex032 or NaCl 0.9% as a control
      solution during baseline conditions or after 1 h of complete reversible ischemia
      induced by microclip occlusion of the pancreatic arteries. The number of
      erythrocyte-perfused capillaries (functional capillary density) and the leukocyte
      adherence in postcapillary venules were assessed by intravital microscopy 45, 90,
      and 120 min after administration. In the baseline group, Lex032 increased
      leukocyte adherence compared with the NaCl 0.9% baseline group, without changing
      any other parameter. I/R without Lex-032 treatment resulted in a 50% reduction in
      functional capillary density, a 2-fold increase in leukocyte adherence, an
      increase in interleukin-6 serum concentration, and a significant fall in blood
      pressure during reperfusion time compared with baseline animals. Treatment with
      Lex032 in I/R resulted in significant preservation of capillary perfusion, an
      absence of interleukin-6 increase, and preservation of mean arterial pressure
      during reperfusion time, without changing the leukocyte adherence, compared with
      the NaCl 0.9% I/R group. Because of its considerable amelioration of
      microcirculatory perfusion, Lex032 might be useful in the treatment of pancreatic
      I/R tissue damage (e.g., cardiac bypass surgery, pancreas transplantation, and
      hemorrhagic shock) by prevention of capillary perfusion failure.

PMID- 10411593
TI  - Association of heparin with basic fibroblast growth factor, epidermal growth
      factor, and constitutive nitric oxide synthase on healing of gastric ulcer in
      rats.
AB  - The healing effect of heparin on gastric ulcer and its underlying mechanisms were
      studied. The influences of protamine on these effects were also investigated.
      Gastric ulcer was induced by acetic acid in rats. Heparin (100-1000 U/kg i.v.)
      was given once daily for 4 or 7 days. Ulcer area was measured; gastric mucosal
      regeneration, proliferation, and angiogenesis were determined by histological or
      immunohistochemical methods. Gastric mucosal basic fibroblast growth factor
      (bFGF) level was assessed by an enzyme-linked immunosorbent assay, and the
      mucosal epidermal growth factor (EGF) level and nitric oxide synthase (NOS)
      activity were measured by radioimmunoassay. The anticoagulant action of heparin
      was determined by the duration of bleeding time. The results showed that heparin
      given for 4 or 7 days significantly accelerated gastric ulcer healing in a dose
      dependent manner. The three doses of heparin significantly stimulated mucosal
      regeneration and proliferation as well as angiogenesis but not the contraction of
      ulcer base. Similar effects were observed in gastric mucosal bFGF and EGF levels
      and constitutive NOS activity. Protamine not only abolished the anticoagulant
      action of heparin but also significantly potentiated its effects on ulcer
      healing, gastric mucosal proliferation, angiogenesis, and constitutive NOS
      activity. These findings indicate that heparin can accelerate gastric ulcer
      healing, which is associated with mucosal regeneration, proliferation, and
      angiogenesis. These actions are likely to be stimulated by bFGF, EGF, and
      constitutive NOS activity in the gastric mucosa. Protamine potentiates the ulcer
      healing effect of heparin, which is probably acting through constitutive NOS
      activation.

PMID- 10411594
TI  - The irreversible gamma-aminobutyric acid (GABA) transaminase inhibitor gamma
      vinyl-GABA blocks cocaine self-administration in rats.
AB  - gamma-Vinyl gamma-aminobutyric acid (GABA) (GVG) is an irreversible inhibitor of
      GABA transaminase, the primary enzyme involved in GABA metabolism. Acute
      administration of GVG increases brain GABA levels and blocks cocaine-induced
      locomotor activity, cocaine-induced lowering of brain stimulation reward
      thresholds, and cocaine-induced conditioned place preference. To further evaluate
      the effects of GVG on cocaine-induced reward, we examined its effects on cocaine
      self-administration in male Wistar rats on fixed ratio 5 and progressive ratio
      schedules of reinforcement. Additionally, the effects of GVG on operant
      responding for a food reward were examined on the same two schedules to determine
      whether the effects of GVG were specific to cocaine reward or generalized to
      other types of reward. GVG dose dependently decreased responding for cocaine on
      both schedules of reinforcement, suggesting that GVG attenuated the reward value
      of the cocaine. Responding for food was also decreased by GVG, suggesting that
      the effects of increased GABA levels induced by GVG may have a general effect on
      central reward systems. Data from this and other studies indicate that GVG does
      not induce motor impairment, decrease spontaneous locomotor activity, or induce
      catalepsy. Taken together, these data suggest that increases in GABAergic
      activity induced by GVG have an attenuating effect on centrally mediated reward
      systems and that the GABA system may be a useful target in the development of new
      therapeutic strategies for cocaine addiction.

PMID- 10411596
TI  - Attenuation of cortical neuronal apoptosis by gangliosides.
AB  - Addition of the natural gangliosides monosialoganglioside (GM1),
      disialoganglioside, trisialoganglioside, or tetrasialoganglioside in the range of
      10 to 100 microM, but not asialoganglioside lacking the sialic acid moiety,
      attenuated cortical neuronal apoptosis induced by serum deprivation, ionomycin,
      or cyclosporin A but not by protein kinase inhibitors (staurosporine, genistein,
      lavendustin A, or herbimycin A). Coaddition of 100 nM wortmannin, a selective
      inhibitor of phosphatidylinositol 3-kinase, but not 1 microM Go6976, a selective
      protein kinase C inhibitor, blocked the neuroprotective effect of GM1. In
      contrast to its antiapoptotic effect, GM1 at up to 200 microM did not attenuate
      cortical neuronal necrosis induced by exposure to the excitotoxins N-methyl-D
      aspartate or kainate. Furthermore, GM1 increased the necrosis induced by
      oxidative stress (addition of Fe(2+) or buthionine sulfoximine). These data
      suggest that neuroprotective effects of natural gangliosides may preferentially
      reflect reduction of neuronal apoptosis rather than necrosis, and be mediated
      through mechanisms involving activation of phosphatidylinositol 3-kinase.

PMID- 10411595
TI  - Synaptic activation and properties of 5-hydroxytryptamine(3) receptors in
      myenteric neurons of guinea pig intestine.
AB  - The contribution of 5-hydroxytryptamine (serotonin; 5-HT) acting at 5-HT(3)
      receptors to fast excitatory postsynaptic potentials (fEPSPs) and the properties
      of 5-HT(3) receptors in the guinea pig small intestinal myenteric plexus were
      investigated using electrophysiological methods. In 11% of neurons studied in the
      acutely isolated myenteric plexus, ondansetron (1 microM) inhibited hexamethonium
      (100 microM)-resistant fEPSPs. 5-HT elicited an inward current in neurons
      maintained in primary culture. The peak current reached maximum in <150 ms and
      desensitized with a double exponential time course (tau1 = 1.1 +/- 0.1 s; tau2 =
      6.9 +/- 0.9 s). The whole-cell current/voltage relationship was linear, with a
      reversal potential of 2.7 +/- 1.5 mV. The rapidly activating and desensitizing
      current was completely blocked by ondansetron (1 microM) and partly inhibited by
      d-tubocurare (1 microM). The 5-HT(3)-receptor agonist, 2-methyl-5-HT (100
      microM), caused a peak current that was 18% of the peak current caused by 5-HT in
      the same cells; 2-methyl-5-HT (1 microM) inhibited currents caused by 5-HT. 5-HT
      activated single-channel currents in outside-out patches; this response was
      blocked by ondansetron. The single-channel conductance was 17 +/- 1 pS. The
      single-channel current/voltage relationship was linear between -110 and 70 mV and
      had a reversal potential near 0 mV. These data indicate that 5-HT contributes to
      fEPSPs in the myenteric plexus. The 5-HT(3) receptor expressed by guinea pig
      myenteric neurons has pharmacological and electrophysiological properties that
      distinguish it from 5-HT(3) receptors expressed by other autonomic neurons and
      neurons in the central nervous system.

PMID- 10411597
TI  - Amplification of the cyclic AMP response to forskolin in pheochromocytoma PC12
      cells through adenosine A(2A) purinoceptors.
AB  - In this study, we present evidence on the ability of endogenous adenosine to
      modulate adenylyl cyclase activity in intact PC12 cells. The adenosine receptor
      antagonists PD 115199, xanthine amine congener, 8-cyclopentyl-1,3
      dipropylxanthine, 8-(p-sulfophenyl)theophylline, and 3,7-dimethyl-1
      propargylxanthine inhibited 10 microM forskolin-induced cyclic AMP (cAMP)
      accumulation, with IC(50) values of 2.76 +/- 1.16 nM, 17.4 +/- 1.08 nM, 443 +/-
      1. 03 nM, 2.00 +/- 1.01 microM, and 2.25 +/- 1.05 microM, respectively.
      Inhibition by 2.5 nM PD 115199 was only partially reversed by increasing
      forskolin concentrations up to 100 microM. The addition of PD 115199 with or 60
      min after forskolin caused a comparable inhibition of forskolin effect over the
      next hour. Both exogenous adenosine (0.1 microM) and its precursor, AMP (10 and
      100 microM), significantly enhanced forskolin-induced cAMP accumulation, whereas
      inosine was ineffective. Forskolin activity was also potentiated by the
      hydrolysis-resistant adenosine receptor agonists 5'-N-ethylcarboxamido adenosine
      and CGS 21680 (8.9- and 12.2-fold increase, respectively). Adenosine deaminase (1
      U/ml) and 8-SPT (25 microM), which nearly abolished the response to 1 microM
      adenosine, also reduced cAMP accumulation caused by AMP (-78 and -54%,
      respectively). These results demonstrate that in PC12 cells, activation of
      adenylyl cyclase by forskolin is highly dependent on the occupancy of A(2A)
      adenosine receptors and that AMP potentially contributes to the amplification of
      forskolin response.

PMID- 10411598
TI  - Effects of ZD6169, a K(ATP) channel opener, on the micturition reflex in the rat.
AB  - The effects of ZD6169, a new ATP-sensitive potassium channel opener, on reflex
      urinary bladder activity were evaluated in urethane-anesthetized female Wistar
      rats. Continuous transvesical slow infusion cystometrograms (0.04 ml/min) were
      performed in untreated, capsaicin-pretreated (125 mg/kg s.c., 4 days before
      experiments) and capsaicin vehicle-pretreated rats. Intravesical infusion of
      ZD6169 in concentrations of 6, 15, 30, and 300 nM for 2 h at each concentration
      increased the intercontraction interval and pressure threshold for voiding in a
      concentration-dependent manner in untreated and vehicle-pretreated rats but not
      in capsaicin-pretreated animals. The effects appeared within 30 min after
      administration. ZD6169 did not alter baseline bladder pressure, duration of
      contractions, or the peak pressure during voiding. Glibenclamide (20 mg/kg i.v.)
      reversed the effects of ZD6169 (30 nM). During transvesical cystometrograms
      performed at a fast rate (0.21 ml/min), ZD6169 in concentrations between 6 and
      300 nM did not alter the intercontraction interval or pressure threshold for
      voiding. ZD6169 produced smaller and more variable effects during slow
      transurethral cystometrograms. Capsaicin, a C-fiber afferent neurotoxin,
      administered s.c. 4 days before the experiment, produced similar changes and also
      eliminated the effect of ZD6169. These data suggest that ZD6169 raises the
      threshold for activation of C-fiber mechanoreceptors in the bladder wall and
      thereby increases the bladder volume for inducing reflex voiding.

PMID- 10411599
TI  - Heterogeneity of endothelium-dependent vasodilation in pressurized cerebral and
      small mesenteric resistance arteries of the rat.
AB  - We compared endothelial responses to calcium-mobilizing agents in mesenteric and
      cerebral resistance arteries of the rat. Middle cerebral and small mesenteric
      arteries were mounted in a pressure myograph, and myogenic responses were
      recorded. The effects of acetylcholine (ACh), bradykinin, substance P, histamine,
      A23187, cyclopiazonic acid (CPA), and sodium nitroprusside were investigated in
      both arteries with myogenic tone in the absence and presence of nitric oxide
      synthase and cyclooxygenase inhibitors. The effects of raised potassium, K(+)
      channel blockers, and arachidonic metabolism inhibition were examined on the
      nitric oxide (NO) synthase/cyclooxygenase inhibitor-resistant dilation induced by
      ACh and CPA. Cerebral arteries display a high level of myogenic reactivity
      compared with mesenteric arteries. In cerebral arteries, only bradykinin and
      substance P induced endothelium-dependent dilation. The observed dilation was
      solely related to the activation of the NO pathway. However, in mesenteric
      arteries, all of the vasoactive agents induced endothelium-dependent dilation. A
      combination of NO, cyclooxygenase-derived prostanoids, and a factor with
      endothelium-derived hyperpolarizing factor-like properties was responsible for
      the observed vasodilation. NO and cyclooxygenase derivatives were able to
      compensate for each other in the CPA-induced endothelium-dependent vasodilation
      when one of the two pathways was blocked. Moreover, small Ca(2+)-activated K(+)
      channels and a combination of both large and small Ca(2+)-activated K(+) channels
      were implicated in the endothelium-derived hyperpolarizing factor-like component
      of dilation to ACh and CPA, respectively. Finally, the results suggest that the
      pathway by which agonists raise intracellular calcium concentration may determine
      the nature of the endothelial secretory product.

PMID- 10411600
TI  - Pharmacology of tezosentan, new endothelin receptor antagonist designed for
      parenteral use.
AB  - Tezosentan (Ro 61-0612) [5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy
      ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)-pyrimidin
      4-ylamide] is a new endothelin (ET) receptor antagonist specifically designed for
      parenteral use. Tezosentan competitively antagonizes the specific binding of
      (125)I-labeled ET-1 and of the selective ET(B) receptor ligands (125)I-labeled ET
      3 and (125)I-labeled sarafotoxin S6c on cells and tissues carrying ET(A) and
      ET(B) receptors, with inhibitory constants in the nanomolar range, and has high
      water solubility. Tezosentan exhibits high functional inhibitory potency for
      inhibiting contraction induced by ET-1 on isolated rat aorta (ET(A) receptors;
      pA(2) = 9.5) and by sarafotoxin S6c on rat trachea (ET(B) receptors; pA(2) =
      7.7). In vivo, tezosentan inhibits the pressor effect of big ET-1 in pithed rats
      and increases ET-1 plasma concentrations in conscious rats in a dose-dependent
      fashion. In spontaneously hypertensive rats, i.v. injection of tezosentan has
      acute hemodynamic effects and decreases blood pressure. Tezosentan is also able
      to prevent the acute renal failure that complicates rhabdomyolysis in a rat model
      of myoglobinuric nephropathy. Finally, tezosentan exhibits an apparent
      elimination half-life of less than 1 h in rabbits and primates and of 2 h in
      rats. In conclusion, tezosentan, a potent mixed ET receptor antagonist with a
      short half-life, may offer a novel medical approach for the i.v. treatment of
      acute pathological conditions.

PMID- 10411601
TI  - N-Type Ca(2+) channels trigger release of excitatory and inhibitory
      neurotransmitter from nerve endings in canine bronchi.
AB  - We set out to characterize the types of Ca(2+) channels that mediate release of
      the predominant excitatory (acetylcholine) and inhibitory (norepinephrine)
      neurotransmitters in canine bronchi, using electrically evoked contractions and
      relaxations, respectively, as indicators of this release. We found that the
      selective N-type Ca(2+) channel blocker (omega-conotoxin GVIA) eliminated
      electrically evoked contractions in a dose-dependent fashion (half-maximal
      inhibition in the presence of 1-5 nM) but had no significant effect on those
      evoked by exogenously added acetylcholine. Selective blockers of P-type Ca(2+)
      channels (omega-agatoxin TK; 10(-8) to 10(-7) M) or of L-type Ca(2+) channels
      (nifedipine; 10(-8) to 10(-6) M) had no significant effect on the responses to
      neurally released or exogenously added acetylcholine. Likewise, electrically
      evoked relaxations were blocked by omega-conotoxin GVIA (10(-7) M) but not by
      omega-agatoxin TK (10(-7) M) or nifedipine (10(-7) M); none of these Ca(2+)
      channel blockers had a significant inhibitory effect on isoproterenol-triggered
      relaxations. We conclude that excitatory and inhibitory neurotransmission in
      canine bronchi is mediated predominantly by N-type Ca(2+) channels, with little
      or no contribution from L-, P-, Q-, or T-type channels.

PMID- 10411602
TI  - Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein
      and effect on cytochrome P-450 activities.
AB  - Overexpression of ATP-dependent drug efflux pumps, P-glycoprotein (Pgp) or
      multidrug resistance-associated protein (MRP), confers multidrug resistance to
      tumor cells. Modulators of multidrug resistance block the action of these pumps,
      thereby sensitizing cells to oncolytics. A potent Pgp modulator is LY335979,
      which fully sensitizes Pgp-expressing cells at 0.1 microM in cytotoxicity assays
      and for which Pgp has an affinity of 59 nM. The present study examines its effect
      on MRP1-mediated drug resistance and cytochrome P-450 (CYP) activity and its
      ability to serve as a Pgp substrate. Drug resistance was examined with HL60/ADR
      and MRP1-transfected HeLa-T5 cells. Drug cytotoxicity was unaffected by 1 microM
      LY335979; leukotriene C4 uptake into HeLa-T5 membrane vesicles was unaffected.
      Because the substrate specificity of Pgp and CYP3A overlap, the effect of
      LY335979 on the 1'-hydroxylation of midazolam by CYP3A in human liver microsomes
      was examined. The apparent K(i) was 3.8 microM, approximately 60-fold higher than
      the affinity of Pgp for LY335979. The modulator's effect on Pgp was evaluated
      with Pgp-overexpressing CEM/vinblastine (VLB)(100) and parental CCRF-CEM cells.
      Both cell lines accumulated [(3)H]LY335979 equally well and did not efflux
      [(3)H]LY335979 during a 3-h incubation, indicating that it is not a substrate of
      Pgp. Equilibrium-binding studies with CEM/VLB(100) plasma membranes and
      [(3)H]LY335979 showed that Pgp had a K(d) of 73 nM, which is in good agreement
      with the previously determined K(i) value. Thus, LY335979 is an extremely potent
      Pgp, and not MRP1 or MRP2, modulator and has a significantly lower affinity for
      CYP3A than for Pgp.

PMID- 10411603
TI  - Differential kappa-opioid receptor expression on mouse lymphocytes at varying
      stages of maturation and on mouse macrophages after selective elicitation.
AB  - The combination of indirect immunofluorescent labeling and flow cytometry has
      proven to be a sensitive method for labeling of the kappa-opioid receptor on
      mouse thymocytes. In the present study, this labeling procedure was applied,
      along with phenotypic analysis, to mature immune cell populations to determine
      whether kappa-opioid receptor expression is present after immune cell maturation.
      Unfixed primary splenocytes from 6- to 8-week-old C57BL/6ByJ male mice were
      incubated with the fluorescein-containing, kappa-selective ligand fluorescein
      conjugated 2-(3, 4-dichlorophenyl)-N-methyl-N-[1-(3-aminophenyl)-2-(1
      pyrrolidinyl)eth yl]acetamide (FITC-AA). Amplification of FITC-AA binding to the
      kappa-opioid receptor was attained by adding a biotin-conjugated antifluorescein
      antibody, followed by extravidin-R-phycoerythrin. It has been shown previously
      that greater than 60% of immature thymocytes (CD4(+)/CD8(+)) demonstrated
      specific kappa-opioid receptor labeling. However, the present report shows that
      less than 25% of either T-helper or T-cytotoxic splenic lymphocytes expressed the
      kappa-opioid receptor. Likewise, only 16% of all splenic B lymphocytes were
      labeled for the kappa-opioid receptor. These findings demonstrate a decrease in
      kappa-opioid receptor expression on maturation of mouse lymphocytes.
      Interestingly, resident peritoneal macrophages showed a greater magnitude of
      specific receptor labeling, compared with either thymocytes or splenocytes, and
      approximately 50% of the resting Mphi expressed the kappa-opioid receptor.
      However, elicitation of Mphi with thioglycollate resulted in the complete loss of
      the expression of this receptor. Taken together, these findings demonstrate the
      diversity in the expression of the kappa-opioid receptor on immune cells at
      varying stages of differentiation, with preferential expression demonstrated by
      resident, peritoneal macrophages.

PMID- 10411604
TI  - Determinants of paclitaxel penetration and accumulation in human solid tumor.
AB  - The present study examined the determinants of the penetration and accumulation
      of [(3)H]paclitaxel (12-12,000 nM) in three-dimensional histocultures of patient
      tumors and of a human xenograft tumor in mice. The results showed 1) significant
      and saturable drug accumulation in tumors, 2) extensive drug retention in tumors,
      and 3) a slower penetration but a more extensive accumulation in the xenograft
      tumor compared with patient tumors. Drug penetration was not rate-limited by drug
      diffusion from medium through the matrix supporting the histocultures. The
      difference in the expression of the mdr1 P-glycoprotein did not fully account for
      the difference in the drug accumulation in xenograft and patient tumors.
      Autoradiography and imaging were used to evaluate the spatial relationship
      between tumor architecture, tumor cell distribution, and drug distribution as a
      function of time and initial drug concentration in culture medium. The tumor cell
      density and the kinetics of drug-induced apoptosis were also evaluated. The
      results indicate that a high tumor cell density is a barrier to paclitaxel
      penetration and that the apoptotic effect of paclitaxel enhances its penetration
      in solid tumor. These factors are responsible for the time- and concentration
      dependent drug penetration rate, with drug penetration confined to the periphery
      until apoptosis and reduction of epithelial cell density occurred at 24 h, after
      which time paclitaxel penetrated the inner parts of the tumor.

PMID- 10411605
TI  - Total neurochemical lesion of noradrenergic neurons of the locus ceruleus does
      not alter either naloxone-precipitated or spontaneous opiate withdrawal nor does
      it influence ability of clonidine to reverse opiate withdrawal.
AB  - It has been suggested that an increase firing rate of noradrenergic neurons of
      the locus ceruleus is responsible for the opiate withdrawal syndrome. However,
      lesion studies have indicated that the noradrenergic neurons of the locus
      ceruleus are not essential for either the expression or suppression by clonidine
      of opiate withdrawal. The present study was designed to determine the effect of
      the almost complete 6-hydroxydopamine lesion of noradrenergic neurons (94%) of
      the locus ceruleus on various components of the opiate withdrawal syndrome and on
      its protection by clonidine. Morphine dependence was induced by s.c. implantation
      of morphine pellets (2 x 75 mg base). The following paradigms were used: 1)
      naloxone-induced conditioned place aversion, 2) naloxone-precipitated acute
      opiate withdrawal syndrome, 3) nycthemeral locomotor activity as a measure of
      spontaneous opiate withdrawal. The results showed that quasi-total lesion of
      noradrenergic neurons of the locus ceruleus did not modify opiate dependence as
      revealed by naloxone-induced conditioned place aversion and the expression of an
      acute morphine withdrawal syndrome. Moreover, clonidine prevented the opiate
      withdrawal syndrome in both lesioned and sham-operated rats, suggesting that the
      action of clonidine is certainly mediated through postsynaptic alpha(2)
      adrenoceptor stimulation. Finally, the nycthemeral locomotor activity during
      spontaneous morphine withdrawal did not differ between the lesioned and the sham
      operated rats.

PMID- 10411606
TI  - Characterization of prejunctional and postjunctional muscarinic receptors of the
      ascending reflex contraction in rat ileum.
AB  - The ascending reflex contraction of the small intestine involves predominantly
      cholinergic neurotransmission. The orally projecting neural excitatory pathway of
      the myenteric reflex was studied in an in vitro model of rat ileal segments. The
      contractile response elicited by aboral field stimulation was significantly
      inhibited by a range of muscarinic receptor antagonists. Methoctramine and
      tripitramine (both M(2) selective, pIC(50) = 9.3 and 8.8, respectively),
      darifenacin and hexahydrosiladifenidol (both M(3) selective, pIC(50) = 7.3 and
      7.7, respectively), and pirenzepine (M(1) selective, pIC(50) = 7.0). In
      radioligand binding experiments on synaptosomal and smooth muscle plasma membrane
      fractions, we examined whether prejunctional or postjunctional muscarinic
      receptors exist that could potentially contribute to the reflex contraction. In
      the synaptosomal fraction, the muscarinic ligand [(3)H]N-methylscopolamine
      labeled a homogeneous population of receptors (Hill coefficient = 1) with a K(d)
      value of 0.31 +/- 0.09 nM and a B(max) value of 185 +/- 16.6 fmol/mg protein. The
      ratio of potency of subtype-selective muscarinic receptor antagonists in
      competition studies was tripitramine (pK(i) = 8.7 +/- 0.3) > 1/6 x methoctramine
      (pK(i) = 7.9 +/- 0.02) > 1/25 x darifenacin (pK(i) = 7. 3 +/- 0.2) > 1/316 x
      hexahydrosiladifenidol (pK(i) = 6.2 +/- 0.1) > 1/2511 x pirenzepine (pK(i) = 5.3
      +/- 0.1). In the smooth muscle plasma membrane fraction, the K(d) value was 0.29
      +/- 0.05 nM and the B(max) value was 770 +/- 29 fmol/mg. The competition studies
      revealed a similar ratio of potency of the respective antagonists. These data
      suggest that muscarinic M(2) receptors, located at prejunctional and
      postjunctional sites, are predominantly involved in the ascending reflex
      contraction.

PMID- 10411607
TI  - Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics,
      inhibit conditioned avoidance response in rats.
AB  - The purpose of our studies was to determine the effects of muscarinic receptor
      agonists on conditioned avoidance responding in the rat. Rats were trained to
      avoid or escape an electric shock delivered to the feet in a discrete trial
      procedure. The muscarinic receptor agonists pilocarpine and [2-ethyl-8-methyl-2,8
      diazaspiro(4. 5)decane-1,3-dione] hydrochloride (RS86) and the cholinesterase
      inhibitor physostigmine all decreased the percentage of avoidance responses at
      doses that produced less than approximately 30% response failures. Similar
      results were obtained with the antipsychotic drugs haloperidol, trifluoperazine,
      chlorpromazine, and clozapine. However, the benzodiazepine anxiolytic diazepam
      did not decrease avoidance responding up to doses that produced ataxia. On the
      other hand, oxotremorine and arecoline decreased avoidance responding only by
      producing response failures, whereas aceclidine produced intermediate changes.
      The muscarinic receptor antagonists scopolamine, trihexyphenidyl, and benztropine
      were without effect when administered alone but antagonized the decreases in
      avoidance responding produced by pilocarpine and RS86. Scopolamine had little
      effect on the decreases in avoidance responding produced by haloperidol. The
      newer muscarinic receptor partial agonists or agonist/antagonists [R-(Z)-(+)
      alpha-(methoxyimino)-1-azabicyclo[2.2. 2]octane-3-acetonitrile] hydrochloride,
      talsaclidine, milameline, and xanomeline also produced dose-related decreases in
      avoidance responding. Our results demonstrate that muscarinic receptor agonists
      can decrease avoidance responding in a manner similar to dopamine-receptor
      antipsychotic drugs, suggesting that muscarinic receptor agonists may provide an
      alternative approach to the treatment of psychosis.

PMID- 10411609
TI  - Quantitative autoradiography with short-lived positron emission tomography
      tracers: a study on muscarinic acetylcholine receptors with N-[(11)C]methyl-4
      piperidylbenzilate.
AB  - The present work demonstrates quantitative autoradiography by using positron
      emission tomography tracers and storage phosphorimaging plates. The uptake and
      association of [(11)C]N-methyl-4-piperidylbenzilate was measured in rat brain
      tissue cryosections of various thicknesses. The signal increased with increasing
      section thickness, but only in 10-micrometer-thick sections did the binding reach
      the steady state during a 50-min observation time. This violation of the
      equilibrium condition, potentially combined with perfusion limitations, leads to
      erroneous increased binding-site density and decreased affinity in the 25- and 50
      micrometer-thick sections. For better imaging of receptor distribution it is
      reasonable to use thicker sections. For quantitative analysis of receptor-binding
      parameters, the specific properties of ligands at different thicknesses of
      cryosections need to be considered. Evidence is provided that the nonselective
      muscarinic antagonist N-methyl-4-piperidylbenzilate binds preferentially to the
      M(4) subtype of muscarinic acetylcholine receptors.

PMID- 10411608
TI  - Comparison of the ligand binding and signaling properties of human dopamine D(2)
      and D(3) receptors in Chinese hamster ovary cells.
AB  - Human dopamine D(2) (hD(2)) and D(3) (hD(3)) receptors were expressed at similar,
      high expression levels in Chinese hamster ovary (CHO) cells, and their coupling
      to G proteins and further signal transduction pathways were compared. In
      competition radioligand-binding experiments, guanosine-5'-O-(3-thio)triphosphate
      (GTPgammaS) treatment of hD(2S)- or hD(3)-CHO cell membranes induced a rightward
      shift and steeping of the dopamine inhibition curve. This effect was pronounced
      for hD(2) receptors and small for hD(3) receptors. Activation of G proteins was
      investigated in [(35)S]GTPgammaS-binding assays. Dopamine stimulated
      [(35)S]GTPgammaS binding 330 and 70% over basal levels on hD(2)-CHO and hD(3)-CHO
      cell membranes, respectively. (+)-7-(Dipropylamino)-5, 6,7,8-tetrahydro-2
      naphthalenol and PD128907 were partial agonists for both receptors. Haloperidol,
      risperidone, raclopride, and nemonapride inhibited dopamine-stimulated
      [(35)S]GTPgammaS binding with potencies comparable to their binding affinities
      for hD(2) and hD(3) receptors in CHO cell membranes; inverse agonism could not be
      detected with this assay. Receptor stimulation by dopamine inhibited forskolin
      induced cyclic AMP formation in hD(2)-CHO and hD(3)-CHO cells by 70%.
      Furthermore, the extracellular acidification rate increased when hD(2)-CHO and
      hD(3)-CHO cells were stimulated by dopamine; this effect was abolished by
      pertussis toxin pretreatment. In this study, we could demonstrate clear
      functional effects at different levels of the signaling cascade of hD(2) and
      hD(3) receptors in CHO cells when expressed at high levels. High-affinity agonist
      binding to hD(2) and hD(3) receptors was still present, but effects of receptor-G
      protein uncoupling at hD(3) receptors were small, indicating that hD(3) receptors
      maintain relatively high-affinity agonist binding in the absence of G proteins.

PMID- 10411610
TI  - Zinc stimulates DNA synthesis during its antiapoptotic action independently with
      increments of an antiapoptotic protein, Bcl-2, in porcine kidney LLC-PK(1) cells.
AB  - Cadmium, an environmental pollutant, caused nephroptosis that was inhibitable by
      zinc. The mechanism of the antiapoptotic action of zinc is poorly understood. In
      this study, we found the stimulation of DNA synthesis, as assessed by
      bromodeoxyuridine incorporation, during prevention by zinc of apoptosis,
      suggesting that the proliferactive nature of zinc contributes to its inhibition
      of apoptosis. This finding was consistent with the result that the cells driven
      by dialyzed fetal bovine serum were resistant to apoptotic stimuli of cadmium.
      Furthermore, zinc activated the expression of endogenous Bcl-2 proteins. However,
      overexpression of Bcl-2 proteins by transfection did not facilitate zinc-mediated
      DNA synthesis. Thus, one possible role of zinc in the prevention of apoptosis is
      to promote DNA synthesis independently with activation of antiapoptotic proteins
      Bcl-2.

PMID- 10411611
TI  - Cerebral blood flow responses to somatosensory stimulation are unaffected by
      scopolamine in unanesthetized rat.
AB  - Studies with positron-emission tomography have indicated that muscarinic
      acetylcholine receptors may be involved in the mechanism of enhancement of
      cerebral blood flow (CBF) by neuronal functional activation. We examined the
      effects of muscarinic receptor blockade by scopolamine on the local CBF responses
      to vibrissal stimulation in the whisker-to-barrel cortex sensory pathway in
      unanesthetized rats. Local CBF was measured by the quantitative autoradiographic
      [(14)C]iodoantipyrine method. Scopolamine (0.4 or 0.8 mg/kg) was injected i.v. 30
      min before measurement of local CBF; control rats received equivalent volumes of
      physiological saline. Vibrissae on the left side of the face were stroked
      continuously throughout the 1-min period of measurement of CBF. Local CBF was
      determined bilaterally in four structures of the pathway, i.e., spinal and
      principal sensory trigeminal nuclei, ventral posteromedial thalamic nucleus, and
      barrel field of the sensory cortex, as well as in four representative structures
      unrelated to the pathway. The higher dose of scopolamine raised baseline CBF in
      the two trigeminal nuclei, but neither dose diminished the percentage of
      increases in local CBF because of vibrissal stimulation in any of the stations of
      the pathway. These results do not support involvement of muscarinic receptors in
      the mechanism of enhancement of local CBF by functional neuronal activation, at
      least not in the whisker-barrel cortex sensory pathway in the unanesthetized rat.

PMID- 10411612
TI  - Escalating crisis in Canada's health workforce.

PMID- 10411613
TI  - That which is timeles.

PMID- 10411614
TI  - Beta3 integrin--a promiscuous integrin involved in vascular pathology.
AB  - OBJECTIVE: To determine whether beta3 integrin is present in blood vessels
      involved by atherosclerosis, Monckeberg's medial calcinosis, vein graft
      atherosclerosis, transplant graft vascular disease and arterial restenosis.
      DESIGN: Retrospective histological and immunohistochemistry examination of
      tissues obtained from autopsy and surgery. SETTING: Tertiary care hospital.
      PATIENTS: The patients had surgical excisions of limbs, grafts, veins and
      arteries for the treatment of ischemic heart disease and peripheral vascular
      disease. Other tissues were derived from autopsies of the same patient
      populations. MAIN RESULTS: Beta3 integrin was found in the blood vessels involved
      in all of the vascular diseases examined. The location of the integrin varied
      among the diseases. Osteopontin, a bone sialoprotein involved in atherosclerosis
      and vascular repair, was also commonly detected. CONCLUSIONS: Beta3 integrin
      expression noted in the present study confirms the presence of this integrin in
      arteries with restenosis and atherosclerosis, which expands its involvement to
      the processes of transplant graft vascular disease, peripheral vascular disease
      and vein graft disease. The integrin may influence cell migration and adhesion by
      its interaction with noncollagenous matrix proteins, including osteopontin.

PMID- 10411616
TI  - Impact and inequity of inpatient waiting times for advanced cardiovascular
      services in community hospitals across the greater Toronto area.
AB  - OBJECTIVE: To assess waiting times for inpatients requiring urgent transfer for
      advanced cardiovascular procedures from community hospitals; the magnitude of
      adverse events while waiting; and possible inequity among community hospitals in
      access to these services. SETTING: Seven representative community hospitals in
      the Greater Toronto Area (GTA). DESIGN: Prospective data collection over 12
      months (May 1997 to April 1998). PATIENTS: One thousand, two hundred and three
      inpatients who waited a total of 7261 hospital days for advanced cardiovascular
      procedures. MAIN RESULTS: The average (+/- SD) inpatient waiting time, in days,
      for catheterization was 5.7+/-1.3, angioplasty 5.8+/-2.1, bypass surgery 7.0+/
      2.1 and pacemakers 4.2+/-1.6. During this time there were 14 deaths (1.2%) and 12
      (1.0%) morbid events in-hospital. Extrapolation of these data to all 21 community
      hospitals in the GTA suggests that annually 21,783 bed days are used by
      inpatients awaiting transfer for advanced cardiovascular procedures, during which
      time 42 fatal and 36 morbid events can be expected to occur. Of the seven
      hospitals, one had a catheterization laboratory (group 1), two had no laboratory
      but had catheterizing cardiologists (group 2), and four had no laboratory and no
      catheterizing cardiologists (group 3). None of these hospitals had on-site
      revascularization facilities. The average number of days spent waiting for
      catheterization in group 1 (3.1+/-0.4) was significantly less than that in group
      2 (5. 4+/-1.3, P<0.001) and group 3 (6.5+/-1.3, P<0.0001). The catheterization
      wait in group 2 was significantly less than that in group 3 (P<0.02). There were
      no significant differences among the three groups in the number of days spent
      waiting for angioplasty or bypass surgery. CONCLUSION: Waiting times for
      inpatients requiring advanced cardiovascular procedures in GTA community
      hospitals are long, and are associated with substantial morbidity and mortality.
      These waiting times also promote inefficient bed use and increased health care
      costs. Furthermore, these data suggest that access to inpatient coronary
      angiography in the GTA is inequitable and appears to depend more on the presence
      of on-site catheterization laboratories or catheterizing cardiologists than on
      illness severity.

PMID- 10411615
TI  - Incidence and risk factors for delirium and other adverse outcomes in older
      adults after coronary artery bypass graft surgery.
AB  - OBJECTIVE: To determine the incidence and risk factors for delirium after
      coronary artery bypass graft (CABG) surgery. DESIGN: Prospective cohort. SETTING:
      Cardiac surgery units of a tertiary care hospital. PARTICIPANTS: Consecutive
      patients over age 65 years undergoing elective CABG surgery. Exclusion criteria
      included preoperative sensory or language barriers. INTERVENTIONS: Each patient
      was assessed within 24 h before surgery for baseline demographic, medical and
      functional data. Incident delirium (within four postoperative days) was diagnosed
      by a study physician. Nine potential risk factors for delirium were subjected to
      univariate and multivariate analysis. MAIN RESULTS: Of 75 consenting patients,
      three died during or soon after surgery and one was still comatose at follow-up.
      Of the remaining 71 participants, 23 (32%) experienced delirium. Those with
      delirium were more likely than those without delirium to have a history of a
      stroke (21% versus 4%, respectively, P=0.032) and to have had a longer duration
      of cardiopulmonary bypass (CPB) (113 mins versus 95 mins, respectively, P=0.025).
      A tendency to have experienced low cardiac output (83% versus 58%, respectively,
      P=0.061) postoperatively was also noted. Multivariate analysis confirmed past
      stroke and duration of cardiopulmonary bypass as risk factors. CONCLUSIONS:
      Delirium in the elderly after CABG surgery is common. Its occurrence may be
      predisposed by a history of a stroke and precipitated by a longer duration of
      CPB.

PMID- 10411617
TI  - Optimizing disease management at a health care system level: the rationale and
      methods of the improving cardiovascular outcomes in Nova Scotia (ICONS) study.
AB  - Improving Cardiovascular Outcomes in Nova Scotia (ICONS) is a five-year project
      that aims to determine whether the management of patients with an acute coronary
      syndrome, congestive heart failure or atrial fibrillation can be improved through
      a multilateral health care stakeholder effort using a disease management
      strategy. It is a large prospective cohort study with two major phases. The first
      involves passive baseline measurement of process of care and outcomes as these
      relate to all hospitalized Nova Scotians with a disease of interest as well as
      high risk persons from the community. The second comprises a series of
      interventions, developed on the basis of insights gained from the analysis of
      baseline, that are aimed at optimizing care. Process of care and outcomes during
      and after these interventions are compared with those measured at baseline. There
      is no control population. The hypothesis is that a population-based disease
      management approach will lead primarily to an optimization in health care
      delivery, as reflected by a 25% absolute increase in the utilization of evidence
      based marker therapies over the course of the study, and that this will
      secondarily result in improved health outcomes. Approximately 1000 patients in
      each of the three disease groups are required to test the primary hypothesis.
      However, about 10,000 Nova Scotians annually are study eligible and are targeted
      for enrolment. Outcomes evaluated are all-cause and cardiovascular mortality,
      major cardiovascular morbidity, hospitalization, revascularization, health care
      resource use, patient quality of life and satisfaction with their care, and
      employment and workplace productivity issues.

PMID- 10411618
TI  - Transmyocardial laser revascularization: experimental and clinical results.
AB  - BACKGROUND: Transmyocardial laser revascularization (TMR) is an emerging therapy
      for the treatment of coronary artery disease not amenable to percutaneous
      transluminal coronary angioplasty (PTCA) or coronary artery bypass surgery
      (CABG). OBJECTIVE: To summarize the experimental and clinical experience to date
      with TMR. Specifically, the history of the technique, preclinical and clinical
      data, patient selection and perioperative management, as well as future
      applications of TMR are discussed. DATA SOURCES: All English language articles
      pertaining to TMR published through March 1999. MEDLINE was searched with the key
      words 'myocardial revascularization', 'lasers' and 'laser surgery', as well as
      the text terms 'transmyocardial laser revascularization', 'TMR' and 'TMLR'.
      Reference lists of articles obtained from MEDLINE were studied for additional
      references not discovered in computer searches. Pertinent abstracts published
      within the past two years were reviewed as well. STUDY SELECTION: Studies that
      produced original experimental or clinical data were selected. DATA SYNTHESIS:
      Experimental studies demonstrate that TMR channels become occluded in the early
      postoperative period. However, experimental data indicate that laser injury
      appears to promote neovascularization with secondary improvements in perfusion in
      treated regions. Human clinical studies confirm the efficacy of the procedure,
      with significant improvements in anginal class up to at least one year
      postoperatively, although documented improvements in myocardial perfusion have
      been less consistent. Perioperative morbidity and mortality appear to be
      increased in patients with unstable angina or reduced left ventricular function.
      CONCLUSIONS: With careful patient selection and peri- operative management, TMR
      is a safe and effective therapy for severe angina pectoris secondary to end-stage
      coronary artery disease. Additional studies are required to define the role of
      TMR in combination with PTCA, CABG and angiogenic growth factors, as well as the
      safety and efficacy of catheter-based TMR.

PMID- 10411620
TI  - A look back at 1998 

PMID- 10411619
TI  - A case of thyrotoxicosis and reversible systolic cardiac dysfunction.
AB  - A woman with congestive heart failure and reduced left ventricular ejection
      fraction associated with hyperthyroidism is reported. Congestive heart failure
      resolved and left ventricular ejection fraction normalized within three weeks of
      treatment of her hyperthyroidism. The literature on previously reported cases of
      reversible systolic heart failure associated with hyperthyroidism is reviewed and
      the possible mechanisms leading to systolic dysfunction and congestive heart
      failure in thyrotoxicosis are discussed. One such mechanism may be the action of
      thyroid hormone on altering gene expression in cardiac cells; another could be
      the chronic tachycardia associated with thyrotoxicosis. Although it is a not a
      common cause of systolic heart failure, thyrotoxicosis should be considered in
      the differential diagnosis of cardiomyopathies because it is a potentially
      reversible cause.

PMID- 10411621
TI  - Sequencing and characterization of the citrus weevil, Diaprepes abbreviatus,
      trypsin cDNA. Effect of Aedes trypsin modulating oostatic factor on trypsin
      biosynthesis.
AB  - Trypsin mRNA from the citrus weevil, Diaprepes abbreviatus, was reverse
      transcribed and amplified by PCR. A cDNA species of 513 bp was cloned and
      sequenced. The 3' and 5' ends of the gene (262 bp and 237 bp, respectively) were
      amplified by rapid amplification of cDNA ends, cloned and sequenced. The deduced
      sequence of the trypsin cDNA (860 bp) encodes for 250 amino acids including 11
      amino acids of activation and signal peptides and exhibited 16.8% identity to
      trypsin genes of selected Lepidoptera and Diptera. A three-dimensional model of
      Diaprepes trypsin contained two domains of beta-barrel sheets as has been found
      in Drosophila and Neobellieria. The catalytic active site is composed of the
      canonical triad of His41, Asp92 and Ser185 and a specificity pocket occupied by
      Asp179 with maximal activity at pH 10.4. Southern blot analysis indicated that at
      least two copies of the gene are encoded by Diaprepes midgut. Northern blot
      analysis detected a single RNA band below 1.35 kb at different larval ages (28
      100 days old). The message increased with age and was most abundant at 100 days.
      Trypsin activity, on the other hand, reached a peak at 50 days and fell rapidly
      afterwards indicating that the trypsin message is probably regulated
      translationally. Feeding of soybean trypsin inhibitor and Aedes aegypti trypsin
      modulating oostatic factor affected trypsin activity and trypsin biosynthesis,
      respectively. These results indicate that Diaprepes regulates trypsin
      biosynthesis with a trypsin modulating oostatic factor-like signal.

PMID- 10411622
TI  - Widely different off rates of two closely related cellulose-binding domains from
      Trichoderma reesei.
AB  - The filamentous fungus Trichoderma reesei produces two cellobiohydrolases (CBHI
      and CBHII). These, like most other cellulose-degrading enzymes, have a modular
      structure consisting of a catalytic domain linked to a cellulose-binding domain
      (CBD). The isolated catalytic domains bind poorly to cellulose and have a much
      lower activity towards cellulose than the intact enzymes. For the CBDs, no
      function other than binding to cellulose has been found. We have previously
      described the reversibility and exchange rate for the binding of the CBD of CBHI
      to cellulose. In this work, we studied the binding of the CBD of CBHII and showed
      that it differs markedly from the behaviour of that of CBHI. The apparent binding
      affinities were similar, but the CBD of CBHII could not be dissociated from
      cellulose by buffer dilution and did not show a measurable exchange rate.
      However, desorption could be triggered by shifting the temperature. The CBD of
      CBHII bound reversibly to chitin. Two variants of the CBHII CBD were made, in
      which point mutations increased its similarity to the CBD of CBHI. Both variants
      were found to bind reversibly to cellulose.

PMID- 10411623
TI  - Site-directed removal of N-glycosylation sites in human gastric lipase.
AB  - Human gastric lipase (HGL) is a highly glycosylated protein, as glycan chains
      account for about 15% of the molecular mass of the native HGL. Four potential N
      glycosylation consensus sites (Asn15, 80, 252 and 308) can be identified from the
      HGL amino acid sequence. We studied the functional role of the individual N
      linked oligosaccharide chains by removing one by one all the N-glycosylation
      sites, via Ala residue replacement by site-directed mutagenesis of Ser and Thr
      residues from the consensus sequences Asn-X-Ser/Thr. Mutagenized cDNA constructs
      were heterologously expressed in the baculovirus/insect cell system. Removal of
      oligosaccharides either at Asn15, 80 or 252 was found to have no significant
      influence on the enzymatic activity measured in vitro. However, the absence of
      glycosylation at Asn308, as well as a total deglycosylation, reduced the specific
      enzymatic activity of recombinant HGL (r-HGL), measured on short- and long-chain
      triglycerides, to about 50% of normal values. Furthermore, biosynthesis and
      secretion of r-HGL markedly dropped when all four potential glycosylation sites
      were mutated. The kinetics of the interfacial adsorption of r-HGL and the
      completely deglycosylated r-HGL (four-site mutant) were found to be identical
      when recording the changes with time of the surface pressure either at the air
      water interface or in the presence of an egg phosphatidylcholine (PtdCho)
      monomolecular film spread at various initial surface pressures. This indicates
      that both recombinant HGLs are identical, as far as recognition of phospholipid
      film and adsorption on PtdCho are concerned. The N-glycosylation of HGL may
      contribute to the enzyme stability in the stomach, as under acidic conditions the
      degradation by pepsin of the unglycosylated r-HGL is increased.

PMID- 10411624
TI  - Identification of AtPIS, a phosphatidylinositol synthase from Arabidopsis.
AB  - Phosphatidylinositol synthase is the enzyme responsible for the synthesis of
      phosphatidylinositol, a key phospholipid component of all eukaryotic membranes
      and the precursor of messenger molecules involved in signal transduction pathways
      for calcium-dependent responses in the cell. Using the amino acid sequence of the
      yeast enzyme as a probe, we identified an Arabidopsis expressed sequence tag
      potentially encoding the plant enzyme. Sequencing the entire cDNA confirmed the
      homology between the two proteins. Functional assays, performed by overexpression
      of the plant cDNA in Escherichia coli, a bacteria which lacks
      phosphatidylinositol and phosphatidylinositol synthase activity, showed that the
      plant protein induced the accumulation of phosphatidylinositol in the bacterial
      cells. Analysis of the enzymatic activity in vitro showed that synthesis of
      phosphatidylinositol occurs when CDP-diacylglycerol and myo-inositol only are
      provided as substrates, that it requires manganese or magnesium ions for
      activity, and that it is at least in part located to the bacterial membrane
      fraction. These data allowed us to conclude that the Arabidopsis cDNA codes for a
      phosphatidylinositol synthase. A single AtPIS genetic locus was found, which we
      mapped to Arabidopsis chromosome 1.

PMID- 10411625
TI  - Preferential uptake and accumulation of oxidized vitamin C by THP-1 monocytic
      cells.
AB  - THP-1 cells preferentially accumulate vitamin C in its oxidized form. The uptake
      displays first-order kinetics and leads to a build-up of an outward concentration
      gradient which is stable in the absence of extracellular vitamin. The transport
      is faster than reduction by extracellular glutathione or by added cytosolic
      extract, and glutathione-depleted cells show the same uptake rates as control
      cells. In addition, energy depletion or oxidation of intracellular sulfhydryls
      does not inhibit accumulation of ascorbate. The accumulation, however, always
      occurs in the reduced form. The affinity for dehydroascorbate is lower (Km 450
      microM vs 60 microM) than for reduced ascorbate, but the maximal rate is more
      than 30 times higher (581 compared to 19 pmol.min-1 per 106 cells), and it is
      independent of sodium, whereas the uptake of ascorbate is not. The sodium
      gradient also allows accumulation of reduced ascorbate. Inhibitors of glucose
      transport by the GLUT-1 transporter also inhibit uptake of dehydroascorbate
      (DHA), but there are some inconsistencies, because the Ki-values are higher than
      reported for the isolated transporter and one inhibitor (deoxyglucose) is
      noncompetitive. The preferential uptake of the dehydro-form of the vitamin may be
      useful for situations where this short-lived metabolite is formed by oxidation in
      the environment.

PMID- 10411626
TI  - Characterization of specific binding sites for a mitogenic sulfated peptide,
      phytosulfokine-alpha, in the plasma-membrane fraction derived from Oryza sativa
      L.
AB  - Treatment of rice cells with an endogenous mitogenic peptide, phytosulfokine
      alpha (PSK-alpha), results in cell proliferation. In the present study, [3H]PSK
      alpha prepared by catalytic reduction of a PSK-alpha analog containing
      tetradehydroisoleucine was employed to identify putative PSK-alpha target
      molecules on rice plasma membranes. Membrane binding of the ligand was found to
      be saturable, reversible and pH dependent. Scatchard analysis demonstrated the
      existence of both high- and low-affinity binding sites with Kd values of 1.4 nM
      and 27 nM, respectively. Competition studies with [3H]PSK-alpha and several PSK
      alpha analogs showed that displacing activity closely corresponds to the ability
      to induce cell proliferation. The properties of the binding sites distributed on
      plasma membranes are consistent with the function of PSK-alpha receptors in
      activating a cascade of molecular events involved in plant cell proliferation.

PMID- 10411627
TI  - The structural basis for the regulation of tissue transglutaminase by calcium
      ions.
AB  - The role of calcium ions in the regulation of tissue transglutaminase is
      investigated by experimental approaches and computer modeling. A three
      dimensional model of the transglutaminase is computed by homology building on
      crystallized human factor XIII and is used to interpret structural and functional
      results. The molecule is a prolate ellipsoid (6.2 x 4.2 x 11 nm) and comprises
      four domains, assembled pairwise into N-terminal and C-terminal regions. The
      active site is hidden in a cleft between these regions and is inaccessible to
      macromolecular substrates in the calcium-free form. Protein dynamics simulation
      indicates that these regions move apart upon addition of calcium ions, revealing
      the active site for catalysis. The protein dimensions are consistent with results
      obtained with small-angle neutron and X-ray scattering. The gyration radius of
      the protein (3 nm) increases in the presence of calcium ions (3.9 nm), but it is
      virtually unaffected in the presence of GTP, suggesting that only calcium ions
      can promote major structural changes in the native protein. Proteolysis of an
      exposed loop connecting the N-terminal and C-terminal regions is linearly
      correlated with enzyme inactivation and prevents the calcium-induced
      conformational changes.

PMID- 10411628
TI  - Primary structure and properties of the cathepsin G/chymotrypsin inhibitor from
      the larval hemolymph of Apis mellifera.
AB  - A member of the Ascaris inhibitor family exhibiting anti-cathepsin G and anti
      chymotrypsin activity was purified from the larval hemolymph of the honey bee
      (Apis mellifera). Three forms of the inhibitor, designated AMCI 1-3, were
      isolated using gel filtration and anion-exchange chromatographies followed by
      reverse-phase HPLC. The amino-acid analyses indicated that AMCI-1 and AMCI-2 have
      an identical composition whereas AMCI-3 is shorter by two residues (Thr, Arg).
      All three forms contain as many as 10 cysteine residues and lack tryptophan,
      tyrosine, and histidine. The sequence of the isoinhibitors showed that the major
      form (AMCI-1) consisting of 56 amino-acid residues was a single-chain protein of
      molecular mass 5972 Da, whereas the other two forms were two-chain proteins with
      a very high residue identity. The AMCI-2 appeared to be derived from AMCI-1, as a
      result of the Lys24-Thr25 peptide bond splitting, while AMCI-3 was truncated at
      its N-terminus by the dipeptide Thr25-Arg26. The association constants for the
      binding of bovine alpha-chymotrypsin to all purified forms of the inhibitor were
      high and nearly identical, ranging from 4.8 x 10(10) M-1 for AMCI-1 to 2.7 x
      10(9) M-1 for AMCI-3. The sensitivity of cathepsin G to inhibition by each
      inhibitor was different. Only the association constant for the interaction of
      this enzyme with AMCI-1 was high (2 x 10(8) M-1) whereas those for AMCI-2 and
      AMCI-3 were significantly lower, and appeared to be 3.7 x 10(7) M-1 and 4.5 x
      10(6) M-1, respectively. The reactive site of the inhibitor, as identified by
      cathepsin G degradation and chemical modification, was found to be at Met30
      Gln31. A search in the Protein Sequence Swiss-Prot databank revealed a
      significant degree of identity (44%) between the primary structure of AMCI and
      the trypsin isoinhibitor from Ascaris sp (ATI). On the basis of the cysteine
      residues alignment, the position of the reactive site as well as some sequence
      homology, the cathepsin G/chymotrypsin inhibitor from larval hemolymph of the
      honey bee may be considered to be a member of the Ascaris inhibitor family.

PMID- 10411629
TI  - Cell wall teichoic acids of Actinomadura viridis VKM Ac-1315T.
AB  - The cell walls of Actinomadura viridis contain poly(glycosylglycerol phosphate)
      chains of complex structure. On the basis of NMR spectroscopy of the polymer and
      glycosides thereof the following structural units were found: beta-D-Galp3Me-(1-
      >4)[beta-D-Glcp-(1-->6)]-beta-D-Galp-(1-->1)-++ +snGro (G1); beta-D-Galp-(1-->4)
      beta-D-Galp-(1-->1)-snGro (G2); beta-D-Galp3Me-(1-->4)-beta-D-Galp-(1-->1)-snGro
      (G2a); beta-D-Galp-(1-->1)-snGro (G3); beta-D-Galp-(1-->1)[beta-D-Galp-(1-->2)]
      snGro (G4); beta-D-Glcp-(1-->2)-snGro (G5). Glycosides G1, G2 and G3 were the
      predominant components of the teichoic acid: they formed the polymer chain via
      phosphodiester bonds involving C-3 of the glycerol residue and C-3 of the
      galactosyl residue which in turn glycosylates C-1 of the glycerol residue.
      Whether the different glycosides make up the one chain or whether there are
      several poly(glycosylglycerol phosphate) chains in the cell wall remains to be
      determined. It was suggested that the minor component G5 is located at the
      nonterminal end of the chains. Compound G4 which contains disubstituted glycerol
      residues (unusual for the teichoic acid) was also found as a minor component;
      this may be the glycoside of a new type of teichoic acid, or a glycoside on the
      terminal end of the above mentioned chains. In addition, small amounts of 1,3
      poly(glycerol phosphate) chains were found in the cell wall.

PMID- 10411630
TI  - An endogenous activator of renal glutamic acid decarboxylase effects of adenosine
      triphosphate, phosphate and chloride on the activity of this enzyme.
AB  - The renal glutamic acid decarboxylase (GAD) differs from the brain and pancreatic
      enzyme by its strong binding to membranes that is not influenced by detergents.
      After centrifugation of freshly prepared homogenate of the rat renal cortex, only
      10-15% of GAD activity was found in supernatants and 15-30% in pellets. The
      majority of the GAD activity was lost. The bound GAD was found in the pellet. A
      thermolabile activator was present in the supernatant, which was not lost on
      dialysis. Approximately 55% of the total GAD activity was solubilized in
      homogenates stored for 24 h at 4 degrees C without detergent, whereas in
      homogenates stored with Triton X-100, the solubilized GAD increased to 80%. This
      solubilization was decreased by inhibitors of thioproteases such as leupeptin,
      antipain and trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane (E-64).
      Solubilized GAD was applied to DEAE Toyopearl resin and the GAD activator was
      eluted with 35 mM Pi. GAD was eluted with 250 mM Pi. The effect of ATP on the
      activity of renal GAD was also different to its effect on brain GAD. ATP is a
      strong inhibitor of the brain enzyme at physiological concentrations. ATP (and
      Pi), together with chlorides (another brain GAD inhibitor), stabilize the renal
      GAD. However, renal GAD was inhibited by ATP in the presence of leupeptin in
      freshly prepared homogenates. Similarly, ATP inhibits solubilized GAD from
      homogenates stored without Triton X-100 for 24 h at 4 degrees C, but Pi retains
      its stabilizing effect in this preparation. A significant finding of the work
      presented here is the obligatory requirement of an endogenous activator for renal
      GAD activity. Whether this activator is an enzyme converting the inactive GAD to
      active enzyme (as hypothesized for brain GAD), or whether it is a protein
      affecting the activity of renal GAD by binding (as observed for GAD in some
      plants) remains to be established.

PMID- 10411631
TI  - Mechanism of inhibition of aldehyde dehydrogenase by citral, a retinoid
      antagonist.
AB  - Low concentrations of citral (3,7-dimethyl-2,6-octadienal), an inhibitor of
      retinoic acid biosynthesis, inhibited E1, E2 and E3 isozymes of human aldehyde
      dehydrogenase (EC1.2.1.3). The inhibition was reversible on dilution and upon
      long incubation in the presence of NAD+; it occurred with simultaneous formation
      of NADH and of geranic acid. Thus, citral is an inhibitor and also a substrate.
      Km values for citral were 4 microM for E1, 1 microM for E2 and 0.1 microM for E3;
      Vmax values were highest for E1 (73 nmol x min-1 x mg-1), intermediate for E2 (17
      nmol x min-1 x mg-1) and lowest (0.07 nmol x min-1 x mg-1) for the E3 isozyme.
      Citral is a 1 : 2 mixture of isomers: cis isomer neral and trans isomer,
      geranial; the latter structurally resembles physiologically important retinoids.
      Both were utilized by all three isozymes; a preference for the trans isomer,
      geranial, was observed by HPLC and by enzyme kinetics. With the E1 isozyme, both
      geranial and neral, and with the E2 isozyme, only neral obeyed Michaelis-Menten
      kinetics. With the E2 isozyme and geranial sigmoidal saturation curves were
      observed with S0.5 of approximately 50 nM; the n-values of 2-2.5 indicated
      positive cooperativity. Geranial was a better substrate and a better inhibitor
      than neral. The low Vmax, which appeared to be controlled by either the slow
      formation, or decomposition via the hydride transfer, of the thiohemiacetal
      reaction intermediate, makes citral an excellent inhibitor whose selectivity is
      enhanced by low Km values. The Vmax for citral with the E1 isozyme was higher
      than those of the E2 and E3 isozymes which explains its fast recovery following
      inhibition by citral and suggests that E1 may be the enzyme involved in vivo
      citral metabolism.

PMID- 10411632
TI  - In vivo post-translational processing and subunit reconstitution of cephalosporin
      acylase from Pseudomonas sp. 130.
AB  - Cephalosporin acylases are a group of enzymes that hydrolyze cephalosporin C
      (CPC) and/or glutaryl 7-amino cephalosporanic acid (GL-7ACA) to produce 7-amino
      cephalosporanic acid (7-ACA). The acylase from Pseudomonas sp. 130 (CA-130) is
      highly active on GL-7ACA and glutaryl 7-aminodesacetoxycephalosporanic acid (GL
      7ADCA), but much less active on CPC and penicillin G. The gene encoding the
      enzyme is expressed as a precursor polypeptide consisting of a signal peptide
      followed by alpha- and beta-subunits, which are separated by a spacer peptide.
      Removing the signal peptide has little effect on precursor processing or enzyme
      activity. Substitution of the first residue of the beta-subunit, Ser, results in
      a complete loss of enzyme activity, and substitution of the last residue of the
      spacer, Gly, leads to an inactive and unprocessed precursor. The precursor is
      supposed to be processed autocatalytically, probably intramolecularly. The two
      subunits of the acylase, which separately are inactive, can generate enzyme
      activity when coexpressed in Escherichia coli. Data on this and other related
      acylases indicate that the cephalosporin acylases may belong to a novel class of
      enzymes (N-terminal nucleophile hydrolases) described recently.

PMID- 10411633
TI  - Interaction of CYP11B1 (cytochrome P-45011 beta) with CYP11A1 (cytochrome P
      450scc) in COS-1 cells.
AB  - The interactions of CYP11B1 (cytochrome P-45011beta), CYP11B2 (cytochrome P
      450aldo) and CYP11A1 (cytochrome P-450scc) were investigated by cotransfection of
      their cDNA into COS-1 cells. The effect of CYP11A1 on CYP11B isozymes was
      examined by studying the conversion of 11-deoxycorticosterone to corticosterone,
      18-hydroxycorticosterone and aldosterone. It was shown that when human or bovine
      CYP11B1 and CYP11A1 were cotransfected they competed for the reducing equivalents
      from the limiting source contained in COS-1 cells; this resulted in a decrease of
      the CYP11B activities without changes in the product formation patterns. The
      competition of human CYP11A1 with human CYP11B1 and CYP11B2 could be diminished
      with excess expression of bovine adrenodoxin. However, the coexpression of bovine
      CYP11B1 and CYP11A1 in the presence of adrenodoxin resulted in a stimulation of
      11beta-hydroxylation activity of CYP11B1 and in a decrease of the 18
      hydroxycorticosterone and aldosterone formation. These results suggest that the
      interactions of CYP11A1 with CYP11B1 and CYP11B2 do not have an identical
      regulatory function in human and in bovine adrenal tissue.

PMID- 10411634
TI  - The structure of a glycosylated protein hormone responsible for sex determination
      in the isopod, Armadillidium vulgare.
AB  - Two glycoforms (AH1 and AH2) of androgenic hormone, and its corresponding hormone
      precursor derived from HPLC-purified androgenic gland extract from the woodlouse
      Armadillidium vulgare were fully characterized by microsequencing and mass
      spectrometry. The amino-acid sequences of the two glycoforms were identical; they
      consist of two peptide chains, A and B, of 29 and 44 amino acids, respectively,
      with chain A carrying one N-glycosylated moiety on Asn18. The two chains are
      linked by two disulfide bridges. Glycoforms were only differentiated by the size
      and heterogeneity of the glycan chain. The androgenic hormone precursor (16.5
      kDa) was shown to contain the sequence of chains A and B from the androgenic
      hormone, connected by a C-peptide (50 amino acids). These results were confirmed
      by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF)
      analysis performed on a single hypertrophied androgenic gland. When injected into
      young females, both glycoforms of the androgenic hormone were able to override
      genetic sex-determination. In invertebrates, there is no other example where sex
      differentiation is controlled by a protein hormone that is not synthesized by the
      gonads but by a special gland. A functional comparison with two other hormones
      which are believed to play a role in sex determination, i.e. ecdysone in insects
      and anti-Mullerian hormone in mammals, is presented. Work is in progress to clone
      and characterize the gene encoding androgenic hormone, moreover special attention
      is devoted to its regulatory regions, putative targets for the Wolbachia action.

PMID- 10411635
TI  - Molecular cloning and functional properties of two early-stage encapsulation
      relating proteins from the coleopteran insect, Tenebrio molitor larvae.
AB  - Encapsulation is a major defensive reaction against foreign materials that are
      too large to be phagocytosed by individual hemocytes; however, the biochemical
      process of encapsulation is still obscure. To isolate and characterize the early
      stage encapsulation-relating protein (ERP), we used the coleopteran insect,
      Tenebrio molitor larvae, injecting three differing kinds of bead or inserting
      pieces of surgical suture into the abdomen of T. molitor larvae. The resulting
      proteins from the injected beads or the inserted pieces of surgical suture were
      recovered 10 min after injection or insertion, and were analyzed on SDS/PAGE
      under reducing conditions. Four different proteins (86, 78, 56 and 48 kDa) were
      enriched compared with the crude hemolymph. Among them, we purified 56-kDa and 48
      kDa ERPs to homogeneity and raised polyclonal antibodies against each protein.
      Immunoblotting analysis showed that the affinity-purified antibodies of the 56
      kDa and 48-kDa ERPs cross-reacted with the 48-kDa and 56-kDa ERPs, respectively.
      Analysis of the cDNA of 56-kDa ERP consisted of 579 amino acid residues and
      showed a novel glutamine-rich protein. Positive clones of the 48-kDa ERP showed
      the same DNA sequence as 56-kDa ERP. Interestingly, the chemically determined N
      terminal amino acid sequence and the three partial amino acid sequences of the 48
      kDa protein were found in the 56-kDa ERP, suggesting that the 48 kDa ERP was
      produced by the cleavage of Arg101-Gly102 of the 56-kDa ERP by a limited
      proteolysis. Western blotting analysis showed that these ERPs were detected
      exclusively on membrane fractions of hemocytes. Also, when the early-stage
      encapsulated beads were coated with both the 56-kDa and 48-kDa ERP antibodies and
      re-injected into larvae, no further encapsulation reaction was observed. However,
      when the early-stage encapsulated beads were incubated with 56-kDa ERP antibody,
      48-kDa ERP antibody or nonimmunized rabbit IgG and re-injected into larvae,
      further encapsulation did occur.

PMID- 10411636
TI  - Purification, structural characterization, cloning and immunocytochemical
      localization of chemoreception proteins from Schistocerca gregaria.
AB  - Soluble low-molecular-mass protein isoforms were purified from chemosensory
      organs (antennae, tarsi and labrum) of the desert locust Schistocerca gregaria.
      Five genes encoding proteins of this group were amplified by PCR from cDNAs of
      tarsi and sequenced. Their expression products are polypeptide chains of 109
      amino acids showing 40-50% sequence identity with putative olfactory proteins
      from Drosophila melanogaster and Cactoblastis cactorum. Direct structural
      investigation on isoforms purified from chemosensory organs revealed the presence
      in the expression products of two of the genes cloned. Two additional protein
      isoforms were detected and their molecular structure exhaustively characterized.
      MS analysis of all isoforms demonstrated that the four cysteine residues
      conserved in the polypeptide chain were involved in disulfide bridges (Cys29
      Cys38 and Cys57-Cys60) and indicated the absence of any additional post
      translational modifications. Immunocytochemistry experiments, performed with
      rabbit antiserum raised against the protein isoform mixture, showed selective
      labelling of the outer lymph in contact sensilla of tarsi, maxillary palps and
      antennae. Other types of sensilla were not labelled, nor were the cuticle and
      dendrites of the sensory cells. No binding of radioactively labelled glucose or
      bicarbonate was detected, in disagreement with the hypothesis that this class of
      proteins is involved in the CO2-sensing cascade. Our experimental data suggest
      that the proteins described here could be involved in contact chemoreception in
      Orthoptera.

PMID- 10411637
TI  - Complete nucleotide sequence, origin of isoform and functional characterization
      of the mouse hepsin gene.
AB  - Hepsin, a type-II membrane-associated serine protease, has been implicated in
      cell growth and development as well as possible initiation of blood coagulation.
      Here, we report on the complete nucleotide sequence, functional characterization
      of key structural features and the promoter of the mouse hepsin gene. The gene
      has a size of approximately 17 kb, and is composed of 12, 13, or 14 exons
      depending on alternative intron splicings - one in the 5'-UTR and the other two
      in the second intron. The latter two, which occur in approximately half of the
      hepsin transcripts, generate a hepsin mRNA species with an extra exon, which is
      responsible for producing a hepsin isoform with a unique 20-residue sequence
      inserted in the cytoplasmic portion of hepsin. Most hepsin transcripts have the
      5'-UTR intron spliced, and its splicing can occur independently of the other
      alternative splicings. The transcriptional initiation site was determined to be
      636 bp upstream of the first ATG site in a cytidine-rich region. The 5'-flanking
      region of hepsin up to nucleotide 274 showed a substantial promoter activity in
      HepG2 cells, with its expression activity sevenfold higher in the presence of the
      5'-UTR intron sequence in comparison to that without the intron sequence. The
      basal promoter region contains potential binding sites for several transcription
      factors including SP1, AP2, C/EBP, LF-A1, and E box, which may be responsible for
      ubiquitous, but liver- and kidney-preferred tissue expression of the hepsin gene.

PMID- 10411638
TI  - Purification of a serine and histidine phosphorylated mitochondrial nucleoside
      diphosphate kinase from Pisum sativum.
AB  - For the first time, to our knowledge, a nucleoside diphosphate kinase (NDPK) has
      been purified from plant mitochondria (Pisum sativum L.). In intact pea leaf
      mitochondria, a 17.4-kDa soluble protein was phosphorylated in the presence of
      EDTA when [gamma-32P]ATP was used as the phosphate donor. Cell fractionation
      demonstrated that the 17.4-kDa protein is a true mitochondrial protein, and the
      lack of accessibility to EDTA of the matrix compartment in intact mitochondria
      suggested it may have an intermembrane space localization. The 17.4-kDa protein
      was purified from mitochondrial soluble proteins using ATP-agarose and anion
      exchange chromatography. Amino-acid sequencing of two peptides, resulting from a
      trypsin digestion, revealed high similarity with the conserved catalytic
      phosphohistidine site and with the C-terminal of NDPKs. Acid and alkali
      treatments of [32P]-labelled pea mitochondrial NDPK indicated the presence of
      acid-stable as well as alkali-stable phosphogroups. Thin-layer chromatography
      experiments revealed serine as the acid-stable phosphogroup. The alkali-stable
      labelling probably reflects phosphorylation of the conserved catalytic histidine
      residue. In phosphorylation experiments, the purified pea mitochondrial NDPK was
      labelled more heavily on serine than histidine residues. Furthermore, kinetic
      studies showed a faster phosphorylation rate for serine compared to histidine.
      Both ATP and GTP could be used as phosphate donor for histidine as well as serine
      labelling of the pea mitochondrial NDPK.

PMID- 10411639
TI  - New inhibitors of Helicobacter pylori urease holoenzyme selected from phage
      displayed peptide libraries.
AB  - Urease is an important virulence factor for Helicobacter pylori and is critical
      for bacterial colonization of the human gastric mucosa. Specific inhibition of
      urease activity has been proposed as a possible strategy to fight this bacteria
      which infects billions of individual throughout the world and can lead to severe
      pathological conditions in a limited number of cases. We have selected peptides
      which specifically bind and inhibit H. pylori urease from libraries of random
      peptides displayed on filamentous phage in the context of pIII coat protein.
      Screening of a highly diverse 25-mer combinatorial library and two newly
      constructed random 6-mer peptide libraries on solid phase H. pylori urease
      holoenzyme allowed the identification of two peptides, 24-mer
      TFLPQPRCSALLRYLSEDGVIVPS and 6-mer YDFYWW that can bind and inhibit the activity
      of urease purified from H. pylori. These two peptides were chemically synthesized
      and their inhibition constants (Ki) were found to be 47 microM for the 24-mer and
      30 microM for the 6-mer peptide. Both peptides specifically inhibited the
      activity of H. pylori urease but not that of Bacillus pasteurii.

PMID- 10411640
TI  - Enzymatic action of human glandular kallikrein 2 (hK2). Substrate specificity and
      regulation by Zn2+ and extracellular protease inhibitors.
AB  - Human glandular kallikrein 2 (hK2) is a serine protease expressed by the prostate
      gland with 80% identity in primary structure to prostate-specific antigen (PSA).
      Recently, hK2 was shown to activate the zymogen form of PSA (proPSA) in vitro and
      is likely to be the physiological activator of PSA in the prostate. hK2 is also
      able to activate urokinase and effectively cleave fibronectin. We studied the
      substrate specificity of hK2 and regulation of its activity by zinc and
      extracellular protease inhibitors present in the prostate and seminal plasma. The
      enzymatic activity and substrate specificity was studied by determining hK2
      cleavage sites in the major gel proteins in semen, semenogelin I and II, and by
      measuring hydrolysis of various tripeptide aminomethylcoumarin substrates. HK2
      cleaves substrates C-terminal of single or double arginines. Basic amino acids
      were also occasionally found at several other positions N-terminal of the
      cleavage site. Therefore, the substrate specificity of hK2 fits in well with that
      of a processor of protein precursors. Possible regulation mechanisms were studied
      by testing the ability of Zn2+ and different protease inhibitors to inhibit hK2
      by kinetic measurements. Inhibitory constants were determined for the most
      effective inhibitors PCI and Zn2+. The high affinity of PCI for hK2 (kass = 2.0 x
      10(5) M-1 x s-1) and the high concentrations of PCI (4 microM) and hK2 (0.2
      microM) in seminal plasma make hK2 a very likely physiological target protease
      for PCI. hK2 is inhibited by Zn2+ at micromolar concentrations well below the 9
      mM zinc concentration found in the prostate. The enzymatic activity of hK2 is
      likely to be reversibly regulated by Zn2+ in prostatic fluid. This regulation may
      be impaired in CAP and advanced metastatic cancer resulting in lack of control of
      the hK2 activity and a need for other means of control.

PMID- 10411642
TI  - Glutamine synthetase expression in perinatal spiny mouse liver.
AB  - The pronounced increase in the protein/mRNA ratio of ammonia-metabolising enzymes
      in rat liver in the last prenatal week represents a clear example of a post
      transcriptional level of control of gene expression. Both the underlying
      mechanism, namely an increase in translational efficiency of the mRNA and/or
      enhanced stability of the protein, and its importance for perinatal adaptation
      are unknown. We investigated this process in spiny mouse liver, because the
      comparison of rat and spiny mouse can discriminate adaptively from
      developmentally regulated processes in the perinatal period. We focused on
      glutamine synthetase (GS) because of the conveniently small size of its mRNA.
      Prenatally, GS enzyme activity slowly accumulated to approximately 1.3 U x g-1
      liver at birth and postnatally more rapidly to 5.5 U x g-1 at 2 weeks. Both
      phases of enzyme accumulation obeyed exponential functions. Western-blot analysis
      showed that changes in GS activity reflected changes in GS protein content. GS
      mRNA content of the liver was 45 fmol x g-1 at 2 weeks before birth and slowly
      declined to approximately 25 fmol x g-1 at 2 weeks after birth. The GS
      protein/mRNA ratio increased 2.5-fold prenatally and sixfold postnatally.
      Analysis of prenatal and postnatal polysome profiles revealed no evidence of GS
      mRNA-containing ribonucleoprotein particles. Instead, GS mRNAs were (fully)
      occupied by 12 ribosomes, indicating regulation at the level of elongation. The
      kinetics of GS protein accumulation, in conjunction with GS mRNA content, are
      consistent with an approximately sixfold increase in its rate of synthesis at
      birth as the result of a corresponding stimulation of the rate of elongation.

PMID- 10411641
TI  - Tyrosine phosphorylation modulates the interaction of calmodulin with its target
      proteins.
AB  - The activation of six target enzymes by calmodulin phosphorylated on Tyr99 (PCaM)
      and the binding affinities of their respective calmodulin binding domains were
      tested. The six enzymes were: myosin light chain kinase (MLCK), 3'-5'-cyclic
      nucleotide phosphodiesterase (PDE), plasma membrane (PM) Ca2+-ATPase, Ca2+-CaM
      dependent protein phosphatase 2B (calcineurin), neuronal nitric oxide synthase
      (NOS) and type II Ca2+-calmodulin dependent protein kinase (CaM kinase II). In
      general, tyrosine phosphorylation led to an increase in the activatory properties
      of calmodulin (CaM). For plasma membrane (PM) Ca2+-ATPase, PDE and CaM kinase II,
      the primary effect was a decrease in the concentration at which half maximal
      velocity was attained (Kact). In contrast, for calcineurin and NOS
      phosphorylation of CaM significantly increased the Vmax. For MLCK, however,
      neither Vmax nor Kact were affected by tyrosine phosphorylation. Direct
      determination by fluorescence techniques of the dissociation constants with
      synthetic peptides corresponding to the CaM-binding domain of the six analysed
      enzymes revealed that phosphorylation of Tyr99 on CaM generally increased its
      affinity for the peptides.

PMID- 10411643
TI  - Expression and characterization of bispecific single-chain Fv fragments produced
      in transgenic plants.
AB  - We describe the expression of the bispecific antibody biscFv2429 in transgenic
      suspension culture cells and tobacco plants. biscFv2429 consists of two single
      chain antibodies, scFv24 and scFv29, connected by the Trichoderma reesi
      cellobiohydrolase I linker. biscFv2429 binds two epitopes of tobacco mosaic virus
      (TMV): the scFv24 domain recognizes neotopes of intact virions, and the scFv29
      domain recognizes a cryptotope of the TMV coat protein monomer. biscFv2429 was
      functionally expressed either in the cytosol (biscFv2429-cyt) or targeted to the
      apoplast using a murine leader peptide sequence (biscFv2429-apoplast). A third
      construct contained the C-terminal KDEL sequence for retention in the ER
      (biscFv2429-KDEL). Levels of cytoplasmic biscFv2429 expression levels were low.
      The highest levels of antibody expression were for apoplast-targeted biscFv2429
      apoplast and ER-retained biscFv2429-KDEL that reached a maximum expression level
      of 1.65% total soluble protein in transgenic plants. Plant-expressed biscFv2429
      retained both epitope specificities, and bispecificity and bivalency were
      confirmed by ELISA and surface plasmon resonance analysis. This study establishes
      plant cells as an expression system for bispecific single-chain antibodies for
      use in medical and biological applications.

PMID- 10411644
TI  - Spectroscopic characterization of the spinach Lhcb4 protein (CP29), a minor light
      harvesting complex of photosystem II.
AB  - A spectroscopic characterization is presented of the minor photosystem II
      chlorophyll a/b-binding protein CP29 (or the Lhcb4 protein) from spinach,
      prepared by a modified form of a published protocol [Henrysson, T., Schroder, W.
      P., Spangfort, M. & Akerlund, H.-E. (1989) Biochim. Biophys. Acta 977, 301-308].
      The isolation procedure represents a quicker, cheaper means of isolating this
      minor antenna protein to an equally high level of purity to that published
      previously. The pigment-binding protein shows similarities to other related light
      harvesting complexes (LHCs), including the bulk complex LHCIIb but more
      particularly another minor antenna protein CP26 (Lhcb5). It is also, in the main,
      similar to other preparations of CP29, although some significant differences are
      discussed. In common with CP26, the protein binds about six chlorophyll a and two
      chlorophyll b molecules. Two chlorophyll b absorption bands are present at 638
      and 650 nm and they are somewhat more pronounced than in a recent report
      [Giuffra, E., Zucchelli, G., Sandona, D., Croce, R., Cugini, D., Garlaschi, F.M.,
      Bassi, R. & Jennings, R.C. (1997) Biochem. 36, 12984-12993]. The bands give rise
      to positive and negative linear dichroism, respectively; both show negative CD
      bands (cf. bands with similar properties at 637 and 650 nm in CP26). Chlorophyll
      a absorption is dominated by a large contribution at 674 nm which also shows
      similarities to the major band in LHCIIb and CP26, while (as for CP26) a
      reduction in absorption around 670 nm is observed relative to the bulk complex.
      Principal differences from LHCIIb and CP26, and from other CP29 preparations,
      occur in the carotenoid region.

PMID- 10411645
TI  - O-linked N-acetylglucosamine levels in cerebellar neurons respond reciprocally to
      pertubations of phosphorylation.
AB  - The novel intracellular carbohydrate O-linked N-acetylglucosamine (O-GlcNAc) is
      present on proteins ranging from those of viruses to those of humans and include
      cytosolic, nuclear and plasma-membrane proteins. In this report we have examined
      the effect of manipulation of phosphorylation on the levels of O-GlcNAc in
      cerebellar neurons from early postnatal mice. Our results indicate a reciprocal
      response of O-GlcNAc levels to phosphorylation. Activation of protein kinase A or
      C, for example, results in reduced levels of O-GlcNAc specifically in the
      fraction of cytoskeletal and cytoskeleton-associated proteins, while inhibition
      of the same kinases results in increased levels of O-GlcNAc. These data are in
      keeping with a reciprocal action of O-GlcNAc with respect to phosphorylation and
      suggest that this modification may have a role in signal transduction.

PMID- 10411646
TI  - Eukaryotic precursor proteins are processed by Escherichia coli outer membrane
      protein OmpP.
AB  - A new specific endopeptidase that cleaves eukaryotic precursor proteins has been
      found in Escherichia coli K but not in E. coli B strains. After purification,
      protein sequencing and Western blotting, the endopeptidase was shown to be
      identical with E. coli outer membrane protein OmpP [Kaufmann, A., Stierhof, Y.-D.
      & Henning, U. (1994) J. Bacteriol. 176, 359-367]. Further characterization of
      enzymatic properties of the new peptidase was performed. Comparison of the
      cleavage specificities of the newly found endopeptidase and that of rat
      mitochondrial processing peptidase (MPP) showed that patterns of proteolytic
      cleavage on the investigated precursor proteins by both enzymes are similar. By
      using three mitochondrial precursor proteins, the specificity assigned to OmpP
      previously, a cleavage position between two basic amino-acid residues, was
      extended to a three amino-acid recognition sequence. Positions +1 to +3 of this
      extended recognition site consist of an amino-acid residue with a small aliphatic
      side chain such as alanine or serine, a large hydrophobic residue such as leucine
      or valine followed by an arginine residue. Additionally, structural motifs of the
      substrate seem to be required for OmpP cleavage.

PMID- 10411647
TI  - Tyrosine hydroxylase binds tetrahydrobiopterin cofactor with negative
      cooperativity, as shown by kinetic analyses and surface plasmon resonance
      detection.
AB  - Kinetic studies of tetrameric recombinant human tyrosine hydroxylase isoform 1
      (hTH1) have revealed properties so far not reported for this enzyme. Firstly,
      with the natural cofactor (6R)-Lerythro-5,6,7, 8-tetrahydrobiopterin
      (H4biopterin) a time-dependent change (burst) in enzyme activity was observed,
      with a half-time of about 20 s for the kinetic transient. Secondly, nonhyperbolic
      saturation behaviour was found for H4biopterin with a pronounced negative
      cooperativity (0.39 < h < 0.58; [S]0.5 = 24 +/- 4 microM). On phosphorylation of
      Ser40 by protein kinase A, the affinity for H4biopterin increased ([S]0.5 = 11 +/
      2 microM) and the negative cooperativity was amplified (h = 0.27 +/- 0.03). The
      dimeric C-terminal deletion mutant (Delta473-528) of hTH1 also showed negative
      cooperativity of H4biopterin binding (h = 0.4). Cooperativity was not observed
      with the cofactor analogues 6-methyl-5,6,7,8-tetrahydropterin (h = 0.9 +/- 0.1;
      Km = 62.7 +/- 5.7 microM) and 3-methyl-5,6,7, 8-tetrahydropterin (H43-methyl
      pterin)(h = 1.0 +/- 0.1; Km = 687 +/- 50 microM). In the presence of 1 mM H43
      methyl-pterin, used as a competitive cofactor analogue to BH4, hyperbolic
      saturation curves were also found for H4biopterin (h = 1.0), thus confirming the
      genuine nature of the kinetic negative cooperativity. This cooperativity was
      confirmed by real-time biospecific interaction analysis by surface plasmon
      resonance detection. The equilibrium binding of H4biopterin to the immobilized
      iron-free apoenzyme results in a saturable positive resonance unit (DeltaRU)
      response with negative cooperativity (h = 0.52-0.56). Infrared spectroscopic
      studies revealed a reduced thermal stability both of the apo-and the holo-hTH1 on
      binding of H4biopterin and Lerythro-dihydrobiopterin (H2biopterin). Moreover, the
      ligand-bound forms of the enzyme also showed a decreased resistance to limited
      tryptic proteolysis. These findings indicate that the binding of H4biopterin at
      the active site induces a destabilizing conformational change in the enzyme which
      could be related to the observed negative cooperativity. Thus, our studies
      provide new insight into the regulation of TH by the concentration of H4biopterin
      which may have significant implications for the physiological regulation of
      catecholamine biosynthesis in neuroendocrine cells.

PMID- 10411648
TI  - Purification and cDNA cloning of a protein derived from Flammulina velutipes that
      increases the permeability of the intestinal Caco-2 cell monolayer.
AB  - A new protein that decreases transepithelial electrical resistance (TEER) in the
      human intestinal Caco-2 cell monolayer was found in a water-soluble fraction of
      the mushroom Flammulina velutipes. This protein, termed TEER-decreasing protein
      (TDP), is not cytotoxic and does not induce cell detachment, but rapidly
      increases the tight junctional permeability for water-soluble marker substances
      such as Lucifer Yellow CH (Mr 457) through the paracellular pathway. TDP was
      isolated and purified from the aqueous extract of F. velutipes by chromatographic
      means. Purified TDP was found to be a simple, nonglycosylated protein without
      intermolecular disulfide bonds, and the apparent molecular mass as estimated by
      SDS/PAGE and gel filtration is 30 kDa. It was revealed that the N-terminal amino
      acid sequence of purified TDP is identical to the recently reported N-terminal
      sequence of flammutoxin, a membrane-perturbing hemolytic protein, for which the
      complete primary structure has not yet been reported [Tomita, T., Ishikawa, D.,
      Noguchi, T., Katayama, E., and Hashimoto, Y. (1998) Biochem. J. 333, 24794
      24799]. The cDNA coding for TDP was cloned by 5' and 3' rapid amplification of
      cDNA ends. The ORF encodes a protein with 272 amino-acid residues showing no
      homology to known proteins. Relevant studies using TDP cDNA will provide insight
      into the structure-function relationships of membrane pore-forming toxins.

PMID- 10411649
TI  - Biochemical and structural characterization of recombinant copper-metallothionein
      from Saccharomyces cerevisiae.
AB  - Methods were developed for large-scale purification of recombinant Cu
      metallothionein (Cu-MT) for structural investigations and the determination of Cu
      binding stoichiometry. Cu-MT of Saccharomyces cerevisiae overexpressed in
      Escherichia coli was purified using a procedure based on ion exchange and gel
      filtration chromatography followed by reversed-phase HPLC. The purified protein
      was fully characterized by electrophoresis, amino acid analysis, atomic
      absorption spectroscopy and elemental analysis, and was shown to contain 10 +/- 2
      Cu(I) per molecule of protein. Small angle X-ray scattering measurements yielded
      a radius of gyration of 1.2 nm for the recombinant protein, indicating a more
      extended structure in solution than that derived from the recent NMR data
      [Peterson, C.W., Narula, S.S. & Armitage, I.A. (1996) FEBS Lett. 379, 85-93].

PMID- 10411650
TI  - Genomic origin and transcriptional regulation of two variants of cGMP-binding
      cGMP-specific phosphodiesterases.
AB  - We have reported alternative splice variants of cGMP-binding cGMP-specific
      phosphodiesterases (PDE5A), i.e. rat PDE5A2, human PDE5A1, canine PDE5A1 and
      PDE5A2, which possess distinct N-terminal sequences. In this study, the DNA
      sequences corresponding to the unique N-terminal portions of PDE5A1 and PDE5A2
      were shown to be tandemly located upstream of exons encoding the common region of
      PDE5A in both human and rat PDE5A genes. The presence of human PDE5A2 and rat
      PDE5A1 transcripts in lung was confirmed by reverse transcriptase-PCR. These
      results indicated that two variant forms of PDE5A exist in humans, canines and
      rats. We examined the tissue distribution of the two variants of human PDE5A in
      adult and fetal humans. The patterns of expression of the two alternatively
      spliced transcripts of human PDE5A in human tissues differed. Many putative
      regulatory elements including cAMP response elements were observed in the 5'
      untranslated region and intron of the PDE5A gene. The levels of the PDE5A
      transcripts, especially the PDE5A2 transcripts, were increased by a cAMP analogue
      in cultured rat vascular smooth muscle cells, indicating that the PDE5A2 is an
      inducible variant of PDE5A in rats.

PMID- 10411651
TI  - Cysteine control over glutathione homeostasis in Chinese hamster fibroblasts
      overexpressing a gamma-glutamylcysteine synthetase activity.
AB  - Gamma-glutamylcysteine synthetase (GCS) catalyses the first step of glutathione
      (GSH) biosynthesis and is considered to be the rate-limiting step of this
      pathway. In several experimental systems, GCS overexpression has been associated
      with GSH pool expansion and drug resistance. In this report, we describe a mutant
      line of Chinese hamster fibroblasts that overexpress this activity by 4-5 times,
      due to the amplification of the gene encoding the catalytic subunit of GCS. These
      mutant cells contained a wild-type steady-state level of GSH and, after
      depletion, synthesized GSH at the same rate as wild-type cells because their rate
      of endogenous production of cysteine was limiting. An exogenous supply of
      cysteine expanded the pool of GSH in mutant cells by 80% but did not increase
      that of wild-type cells, and, in GSH-depleted cells, increased the rate of GSH
      biosynthesis by eight and 35-times in wild-type and mutant cells, respectively.
      These experiments indicated that GCS overexpression had no consequence on the
      metabolism of GSH, unless a supply of cysteine was provided. Mutant cells were
      not resistant to cisplatin or nitrogen mustard.

PMID- 10411652
TI  - Phosphoinositide-dependent activation of Rho A involves partial opening of the
      RhoA/Rho-GDI complex.
AB  - Rho GTPases have two interconvertible forms and two cellular localizations. In
      their GTP-bound conformation, they bind to the cell membrane and are activated.
      In the inactive GDP-bound conformation, they associate with a cytosolic protein
      called GDP dissociation inhibitor (GDI). We previously reported that the RhoA
      component of the RhoA/Rho-GDI complex was not accessible to the Clostridium
      botulinum C3 ADP-ribosyl transferase, unless the complex had been incubated with
      phosphoinositides. We show here that PtdIns, PtdIns4P, PtdIns3,4P2, PtdIns4,5P2
      and PtdInsP3 enhance not only the C3-dependent ADP-ribosylation, but also the
      GDP/GTP exchange in the RhoA component of the prenylated RhoA/Rho-GDI complex. In
      contrast, in the nonprenylated RhoA/Rho-GDI complex, the levels of ADP
      ribosylation and GDP/GTP exchange are of the same order as those measured on free
      RhoA and are not modified by phosphoinositides. In both cases, phosphoinositides
      partially opened, but did not fully dissociate the complex. Upon treatment of the
      prenylated RhoA/Rho-GDI complex with phosphoinositides, a GTP-dependent transfer
      to neutrophil membranes was evidenced. Using an overlay assay with the prenylated
      RhoA/Rho-GDI complex pretreated with PtdIns4P and labeled with [alpha32P]GTP,
      three membrane proteins with molecular masses between 26 and 32 kDa were
      radiolabeled. We conclude that in the presence of phosphoinositides, the
      prenylated RhoA/Rho-GDI complex partially opens, which allows RhoA to exchange
      GDP for GTP. The opened GTP-RhoA/Rho-GDI complex acquires the capacity to target
      specific membrane proteins.

PMID- 10411654
TI  - Effect of high hydrostatic pressures on 20S proteasome activity.
AB  - The 20S proteasome is the catalytic core of the ubiquitin proteolytic pathway,
      which is implicated in many cellular processes. The cylindrical structure of this
      complex consists of four stacked rings of seven subunits each. The central cavity
      is formed by two beta catalytic subunit rings in which protein substrates are
      progressively degraded. The 20S proteasome is isolated in a latent form which can
      be activated in vitro by various chemical and physical treatments. In this study,
      the effects of high hydrostatic pressures on 20S proteasome enzymatic activity
      were investigated. When proteasomes were subjected to increasing hydrostatic
      pressures, a progressive loss of peptidase activities was observed between 75 and
      150 MPa. The inactivation also occurred when proteasomes were pressurized in the
      presence of synthetic peptide substrates; this may be the result of the
      dissociation of the 20S particle into its subunits under pressure, as was shown
      by PAGE. Pressurized proteasomes also lost their caseinolytic activity. In
      contrast, in the presence of casein, the pressure-induced inactivation and the
      dissociation of the 20S particles were prevented. In addition, in comparison to
      that observed at atmospheric pressure, their caseinolytic activity was increased
      under pressure. Following depressurization, the caseinolytic activity returned to
      basal levels but was further enhanced following an additional pressurization
      treatment. Thus, the structure of the 20S particle exhibits a certain degree of
      plasticity. This pressure-induced activation of the 20S proteasome is discussed
      in relation to its hollow structure, its currently accepted proteolytic mechanism
      and the general effect of high pressures on the biochemical reactions and
      structures of biopolymers.

PMID- 10411653
TI  - Relationship of membrane sidedness to the effects of the lipophosphoglycan of
      Leishmania donovani on the fusion of influenza virus.
AB  - Cells expressing the influenza hemagglutinin protein were fused to planar lipid
      bilayers containing the viral receptor GD1a at pH 5.0. An amphiphile known to
      alter membrane properties is lipophosphoglycan (LPG). This glycoconjugate was
      added from aqueous solution to either the cis or the trans monolayer to examine
      its effects on the fusion process. LPG markedly inhibited the formation of fusion
      pores when present in the cis monolayer but LPG in the trans monolayer had no
      effect on the parameters of pore formation or on the properties of the pores. The
      N-terminal segment of the HA2 subunit of the influenza hemagglutinin protein is
      important for membrane fusion. The effect of LPG on the conformation and membrane
      insertion of a synthetic 20-amino-acid peptide, corresponding to the influenza
      fusion peptide, was examined at pH 5.0 by attenuated total reflection Fourier
      transform infrared spectroscopy and by the fluorescence properties of the Trp
      residues of this peptide. It was found that cis LPG did not prevent insertion of
      the peptide into the membrane but it did alter the conformation of the membrane
      inserted peptide from alpha-helix to beta-structure. The beta-structure was
      oriented along the bilayer normal. The effect of cis LPG on the conformation of
      the fusion peptide probably contributes to the observed inhibition of pore
      formation and lipid mixing. In contrast, trans LPG has no effect on the
      conformation or angle of membrane insertion of the peptide, nor does it affect
      pore formation by HA-expressing cells. The ineffectiveness of trans LPG, despite
      it having strong positive curvature-promoting properties, may be a consequence of
      the size of this amphiphile being too large to enter a fusion pore.

PMID- 10411655
TI  - Characterization of a truncated recombinant form of human membrane type 3 matrix
      metalloproteinase.
AB  - Membrane type 3 matrix metalloproteinase (MT3-MMP), an activator for the zymogen
      of MMP-2 (proMMP-2, or progelatinase A), is known to be expressed in human
      placenta, brain, lung and rat vascular smooth muscle cells, but information about
      its biochemical properties is limited. In the present study, we expressed and
      purified a truncated form of MT3-MMP lacking the transmembrane and
      intracytoplasmic domain (DeltaMT3) and characterized the enzyme biochemically.
      DeltaMT3 digested type III collagen into characteristic 3/4- and 1/4-fragments by
      cleaving the Gly781-Ile782 and Gly784-Ile785 bonds of alpha1(III) chains.
      Although DeltaMT3 did not have such an activity against type I collagen, it
      attacked the Gly4-Ile5 bond of the triple helical portion of alpha2(I) chains,
      leading to removal of the crosslink containing N-terminal telopeptides. By
      quantitative analyses of the activities of DeltaMT3 and a similar deletion mutant
      of MT1-MMP (DeltaMT1), DeltaMT3 was approximately fivefold more efficient at
      cleaving type III collagen. DeltaMT3 also digested cartilage proteoglycan,
      gelatin, fibronectin, vitronectin, laminin-1, alpha1-proteinase inhibitor and
      alpha2-macroglobulin into almost identical fragments to those given by DeltaMT1,
      although carboxymethylated transferrin digestion by DeltaMT3 generated some extra
      fragments. The activity of DeltaMT3 was inhibited by tissue inhibitor of
      metalloproteinases-2 (TIMP-2) and TIMP-3 in a 1 : 1 stoichiometry, but not by
      TIMP-1. ProMMP-2 was partially activated by DeltaMT3 to give the intermediate
      form. These results indicate that, like MT1-MMP, MT3-MMP exhibits proteolytic
      activities against a wide range of extracellular matrix molecules. However,
      differences in the proMMP-2 activation and tissue distribution suggest that MT3
      MMP and MT1-MMP play different roles in the pathophysiological digestion of
      extracellular matrix.

PMID- 10411656
TI  - The inhibitory properties and primary structure of a novel serine proteinase
      inhibitor from the fruiting body of the basidiomycete, Lentinus edodes.
AB  - A novel proteinase inhibitor, Lentinus proteinase inhibitor, has been purified
      from the fruiting bodies of the edible mushroom, Lentinus edodes, by buffer
      extraction and affinity chromatography on immobilized anhydrotrypsin. The protein
      simultaneously inhibits bovine beta-trypsin and alpha-chymotrypsin at independent
      sites, with apparent dissociation constants of 3.5 x 10(-10) M and 4 x 10(-8) M,
      respectively. The purified protein is eluted as two well-separated peaks on
      reversed-phase HPLC, one of which is inhibitory-active and the other inactive,
      and they are interconvertible under folding/unfolding conditions. Among the
      mammalian and microbial serine proteinases examined, including human enzymes of
      blood coagulation and fibrinolysis, activated factor XI was inhibited by the
      Lentinus proteinase inhibitor. Chemical modification studies suggest involvement
      of one or more arginine residues in the inhibition of trypsin. The complete
      primary structure composed of 142 amino acids with an acetylated N-terminus was
      determined by protein analysis. The theoretical molecular mass (15999.2) from the
      sequence is close to the experimental value of 15999.61 +/- 0.61 determined by
      mass spectrometry. Although there are no apparently homologous proteinase
      inhibitors in the protein database, there is a rather striking similarity to the
      propeptide segment of a microbial serine proteinase, as well as to the N-terminal
      region of the mature enzyme.

PMID- 10411658
TI  - NMR investigation and secondary structure of domains I and II of rat brain
      calbindin D28k (1-93).
AB  - Calbindin D28k, a member of the troponin C superfamily of calcium-binding
      proteins, contains six putative EF hand domains but binds only four calcium
      atoms: one at a binding site of very high affinity and three calcium-atoms at
      binding sites of lower affinity. The high-affinity site could be located within
      domain I while domains III, IV, and V bind calcium less tightly. The recombinant
      protein construct calb I-II (residues 1-93) comprising the first two EF hands
      affords a unique opportunity to study a pair of EF hands with one site binding
      calcium tightly and the second site empty. A series of heteronuclear 2D, 3D and
      4D high-resolution NMR experiments were applied to calb I-II, and led to the
      complete assignment of the 1H, 13C and 15N resonances. The secondary structure of
      the protein was deduced from the size of the 3JHN-Halpha coupling constants, the
      chemical shift indices of 1Etaalpha, 13Calpha, 13C' and 13Cbeta nuclei and from
      an analysis of backbone NOEs observed in 3D and 4D NOESY spectra. Four major
      alpha-helices are identified: Ala13-Phe23, Gly33-Ala50, Leu54-Asp63, Val76-Leu90,
      while residues Ala2-Leu6 form a fifth, flexible helical segment. Two short beta
      strands (Tyr30-Glu32, Lys72-Gly74) are found preceding helices B and D and are
      arranged in an anti-parallel interaction. Based on these data a structural model
      of calb I-II was constructed that shows that the construct adopts a tertiary
      structure related to other well-described calcium-binding proteins of the EF-hand
      family. Surprisingly, the protein forms a homodimer in solution, as was shown by
      its NMR characterization, size-exclusion chromatography and analytical ultra
      centrifugation studies.

PMID- 10411657
TI  - Association of 5' CpG demethylation and altered chromatin structure in the
      promoter region with transcriptional activation of the multidrug resistance 1
      gene in human cancer cells.
AB  - Selection of human cells for resistance to vincristine or doxorubicin often
      induces overexpression of the multidrug resistance 1 gene (MDR1), which encodes
      the cell surface P-glycoprotein, as a result of gene amplification or
      transcriptional activation. However, the precise mechanism underlying such
      transcriptional activation of MDR1 remains unclear. The relation between
      methylation status of CpG sites in the MDR1 promoter region and transcriptional
      activation of MDR1 has now been investigated. The P-glycoprotein-overexpressing,
      multidrug-resistant KB/VJ300 and KB-C1 cells, which were established from human
      cancer KB3-1 cells, were examined; MDR1 is transcriptionally activated but not
      amplified in KB/VJ300 cells, whereas it is amplified in KB-C1 cells.
      Determination of the methylation status revealed that the MDR1 promoter region
      was hypomethylated in KB/VJ300 and KB-C1 cells, but hypermethylated in KB3-1
      cells. Prior treatment of KB3-1 cells with the DNA methyltransferase inhibitor 5
      aza-2'-deoxycytidine resulted in a 90-fold increase in the frequency of
      vincristine-resistance. Of three lines, KB/CdR-1, KB/CdR-2, and KB/CdR-3,
      established from KB3-1 cells after exposure to 5-aza-2'-deoxycytidine, MspI/HpaII
      sites in the MDR1 promoter region were hypomethylated in KB/CdR-1 and KB/CdR-2
      cells, but not in KB/CdR-3 cells. MDR1 mRNA expression was detected in KB/CdR-1
      and KB/CdR-2 cells, but not in KB/CdR-3 cells. The binding of YB-1 and Sp1,
      transcription factors implicated in MDR1 expression, in the MDR1 promoter was not
      affected by the methylation status of a neighboring CpG sites. The MDR1 promoter
      region in KB/VJ300 cells showed an increased sensitivity to DNase I compared with
      that in KB3-1 cells, suggesting an altered chromatin structure. The methylation
      status of the promoter region may plays an important role in MDR1 overexpression
      and in acquisition of the P-glycoprotein-mediated multidrug resistance phenotype.

PMID- 10411659
TI  - The effect of interleukin 1 beta on the biosynthesis of cholesterol,
      phosphatidylcholine, and sphingomyelin in fibroblasts, and on their efflux from
      cells to lipid-free apolipoprotein A-I.
AB  - In this study we have investigated the effect of interleukin 1beta (IL-1beta) on
      the metabolism of cholesterol and choline-phospholipids in cultured fibroblasts,
      and also measured efflux of these lipids to lipid-free apo A-I as a function of
      IL-1beta treatment. Long-term exposure (up to 48 h) of cells to IL-1beta (1 ng.mL
      1) markedly increased the rate of cholesterol esterification, as determined by
      the incorporation of [3H]oleic acid into cholesteryl esters. This treatment also
      led to a substantially increased mass of cholesteryl esters in the cells. The
      accumulation of cholesteryl esters in IL-1beta-treated cells could be blocked
      using compound 58-035 to inhibit the activity of acyl-CoA cholesterol acyl
      transferase. The activation of cholesterol esterification by IL-1beta was evident
      within a few hours after initiation of the IL-1beta treatment. Cholesterol
      biosynthesis was inhibited by 25% by IL-1beta (after 48 h exposure), and this
      eventually led to a 20% decrease in cell cholesterol mass. Treatment of cells
      with IL-1beta for 48 h also reduced the synthesis of sphingomyelin and caused a
      30% decrease in cell sphingomyelin mass (after 48 h at 1 ng.mL-1 of IL-1beta). IL
      1beta did not stimulate an acute (within a few minutes up to an hour) degradation
      of cell [3H]sphingomyelin. This suggests that IL-1beta did not activate an
      endogenous sphingomyelinase in these cells, but only affected rates of synthesis.
      The rate of phosphatidylcholine synthesis was barely affected, but mass was
      moderately reduced by a 48-h treatment of cells with IL-1beta. Finally, the
      efflux of cell [3H]cholesterol, [3H]sphingomyelin, and [3H]phosphatidylcholine to
      lipid-free apolipoprotein A-I was markedly increased from cells treated with IL
      1beta for 24 and 48 h. We conclude that long-term exposure of cells to IL-1beta
      had marked effects on the cellular homeostasis of cholesterol and choline
      containing phospholipids.

PMID- 10411660
TI  - Mounting evidence for the involvement of zinc and copper in Alzheimer's disease.

PMID- 10411661
TI  - Myocardial bradykinin production during coronary balloon angioplasty in humans.
AB  - BACKGROUND: Recent studies have implicated the peptide bradykinin as a potential
      trigger of ischaemic preconditioning, the phenomenon whereby a brief episode of
      myocardial ischaemia induces an increased tolerance to subsequent more prolonged
      ischaemia. Brief myocardial ischaemia occurring during percutaneous transluminal
      coronary balloon angioplasty in humans is reported to be capable of inducing
      preconditioning. DESIGN: We studied the intracardiac production of bradykinin in
      eight patients (seven men, mean age 53.5 years) undergoing elective percutaneous
      transluminal coronary angioplasty for a single left anterior descending coronary
      artery stenosis. Paired blood samples were obtained from the coronary sinus and
      the proximal aorta at baseline, immediately before balloon deflation after a 2
      min inflation, and at 1, 3 and 5 min post deflation. Bradykinin levels were
      measured by radioimmunoassay. RESULTS: There was no significant change either in
      aortic or coronary sinus bradykinin levels at any time point. CONCLUSIONS:
      Intracardiac production of bradykinin is unlikely to be a trigger for ischaemic
      preconditioning after brief myocardial ischaemia in humans.

PMID- 10411663
TI  - Perioperative catecholamine changes in cardiac risk patients.
AB  - BACKGROUND: It has previously been found that in cardiac risk patients undergoing
      non-cardiac surgery post-operative cardiac complications are correlated with high
      post-operative serum levels of troponin T (TNT) and troponin I (TNI). We
      investigated whether perioperative changes in the release of free (fCAs) and
      conjugated catecholamines (cCAs) correlate with the increased serum level of TN
      (TN upward arrow). MATERIALS AND METHODS: Plasma levels of CAs were determined in
      28 patients at risk for or with definite coronary artery disease. Blood sampling
      was performed in the morning on the day before surgery, on the day of surgery
      before induction of anaesthesia and until the fifth post-operative day for
      measurement of CAs by high-performance liquid chromatography. RESULTS: The plasma
      concentrations of free and conjugated noradrenaline (fNA and cNA) as well as of
      free and conjugated adrenaline (fA and cA) were increased significantly in TN
      upward arrow patients post-operatively. The plasma levels of free as well as of
      conjugated NA and A in TN upward arrow patients were significantly higher than in
      TN0 patients over the whole post-operative period. CONCLUSION: This study
      demonstrates that increased post-operative release of fNA and fA as well as of
      cNA and cA correlates with high post-operative serum levels of troponins in
      cardiac risk patients undergoing non-cardiac surgery.

PMID- 10411662
TI  - Endothelial activation and response in patients with hand arm vibration syndrome.
AB  - BACKGROUND: Hand-arm vibration syndrome (HAVS) is a form of secondary Raynaud's
      phenomenon (RP) of occupational origin. In other forms of RP, blood and blood
      vessel wall interaction is one factor in the pathophysiology. Cytokines and cell
      adhesion molecules both play an important role in this interaction, and basal
      vascular tone and vasodilatation are regulated by nitric oxide. METHODS: Blood
      flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) and levels
      of soluble intercellular adhesion molecule-1 (sICAM-1) and the inflammatory
      cytokine interleukin 8 (IL-8) were measured in eight male patients with vibration
      white finger disease, which is part of HAVS, and in eight healthy matched male
      control subjects. RESULTS: sICAM-1 levels were statistically higher (P = 0.02,
      Mann-Whitney U-test) and IL-8 levels (P < 0.01, Mann-Whitney) were significantly
      lower in the patient group. The patients with HAVS had significantly reduced
      vascular responses to SNP (P < 0.05, ANOVA). CONCLUSIONS: In this study, we
      reveal differences in vascular responses to SNP that suggest there may be an
      impairment of the smooth muscle response to nitric oxide in patients with HAVS.
      The increase in sICAM-1 that occurs in patients with HAVS suggests that leucocyte
      adhesion is increased and that adherent neutrophils may contribute to the
      microvascular damage seen in this disease. The impeded flow of blood cells
      through the microcirculation may result in the low levels of circulating IL-8 due
      to the cytokine binding to erythrocytes. The possible role of NO activity in HAVS
      warrants further investigation.

PMID- 10411664
TI  - Skin perfusion in patients with erythromelalgia.
AB  - BACKGROUND: Erythromelalgia (EM) is a chronic disorder characterized by
      intermittent pain, warmth and erythema of the extremities. Symptoms can be
      precipitated by increasing the temperature of the affected limb and can be
      partially relieved by direct cooling. MATERIALS AND METHODS: Microvascular
      assessment was conducted under 'hot' (28 degrees C) environmental conditions in
      61 EM (EMI) patients and 30 control subjects. Twenty patients with many of the
      symptoms of EM were enrolled as an active control group (EMII). Using laser
      Doppler flowmetry, basal skin erythrocyte flux (SkEF) and the hyperaemic response
      to local heating (44 degrees C) were measured. RESULTS: Compared with control
      subjects, basal SkEF was reduced at the toe (P < 0.001), index finger (P < 0.05),
      dorsal and plantar aspects of the foot (P < 0.01) in both patient groups and at
      the medial mid-calf (P < 0.05) in EMI patients. Both EM groups also had a
      significantly reduced maximum SkEF at the dorsum of foot and medial mid-calf (all
      P < 0.001) compared with control values. In a subset of patients and control
      subjects, transcutaneous carbon dioxide levels were raised in EMI patients (P <
      0.02) compared with levels in control subjects. Toe temperature was significantly
      reduced in both EM groups compared with control subjects (both P < 0. 001).
      CONCLUSION: Our study indicates for the first time that there is a
      vasoconstrictor tendency in patients with EM, which may be related to functional
      or structural changes in skin microvessels. Thus, the previous hypothesis that
      the pathophysiology of EM relates to vasodilatation is not supported in our
      patients. We believe that, in EM, vasoconstriction precedes reactive hyperaemia,
      similar to that seen in Raynaud's phenomenon.

PMID- 10411665
TI  - Hypertensive left ventricular hypertrophy is linked to an enhanced catecholamine
      response to submaximal exercise.
AB  - BACKGROUND: The serial plasma catecholamine response to exercise has not been
      studied fully in relation to left ventricular hypertrophy (LVH) in patients with
      hypertension (HT). This study determined whether plasma catecholamine responses
      to exercise are altered in essential HT in the presence or absence of LVH.
      MATERIALS AND METHODS: Plasma noradrenaline (NA) and plasma adrenaline (A) were
      measured at rest, during and after treadmill exercise in 59 hypertensive subjects
      and 22 age-matched control subjects. Patients were divided into LVH(-) (n = 20)
      and LVH(+) (n = 39) stratified by left ventricular mass index [LVMI: control
      subjects, LVH(-), LVH(+): 114 +/- 4, 105 +/- 3, 151 +/- 3 g m-2]. RESULTS:
      Exercise time (9.9 +/- 0.6, 7.6 +/- 0.7, 7.3 +/- 0.6 min) was shorter in patients
      with HT. Both systolic and diastolic blood pressures were higher in patients with
      HT, and no difference was observed between LVH(-) and LVH(+) patients. Resting
      plasma NA was not different (157 +/- 16, 173 +/- 17, 167 +/- 14 pg mL-1), but
      plasma NA at stage I (300 +/- 30, 342 +/- 40, 469 +/- 40 pg mL-1) was higher in
      LVH(+) patients than in LVH(-) patients or control subjects. Plasma A response to
      exercise was similar among the three groups. There was a positive correlation (r
      = 0.38, P < 0.001) between LVMI and Deltaplasma NA at stage I in all subjects.
      CONCLUSIONS: Patients with essential HT with LVH had augmented plasma NA response
      during submaximal exercise, whereas patients without LVH did not exhibit this
      augmentation. The positive correlation between LVMI and Deltaplasma NA suggested
      a possible association between the degree of cardiac hypertrophy and sympathetic
      activation during exercise.

PMID- 10411666
TI  - Comparison of bolus versus fractionated oral applications of [13C]-linoleic acid
      in humans.
AB  - BACKGROUND: The endogenous conversion of linoleic acid into long-chain
      polyunsaturated fatty acids is of potential importance for meeting substrate
      requirements, particularly in young infants. After application of [13C]-linoleic
      acid, we estimated its conversion to dihomo-gamma-linolenic and arachidonic acids
      from only two blood samples. DESIGN: Oral tracer doses were given to five healthy
      adults as a single bolus. In four subjects the tracer was given in nine equal
      portions over 3 days. Concentration and 13C content of fatty acids from serum
      phospholipids were analysed by gas chromatography combustion isotope ratio-mass
      spectrometry. Areas under the tracer-concentration curves were calculated, and
      fractional transfer and turnover rates estimated from compartmental models.
      RESULTS: The median fractional turnover of linoleic acid was 93.7% per day
      (interquartile range 25.3) in the bolus group and 80. 0% per day (6.3) in the
      fraction group (NS). Fractional conversion of linoleic to dihomo-gamma-linolenic
      acid was 1.5% (0.9) vs. 2.1% (0.7) (bolus vs. fraction, P < 0.05), and fractional
      conversion of linoleic to arachidonic acid was 0.3% (0.3) vs. 0.6% (0.3) (bolus
      vs. fraction, NS). In the fraction group conversion was significantly higher
      based on areas under the curve. The ratio of tracer concentration in conversion
      products to linoleic acid 48 h after dosing correlated very well (r >/= 0.94, P <
      0.05) with the ratio of areas under the curve. CONCLUSIONS: Using areas under the
      curve overestimates the conversion, because different residence times are not
      considered. Estimation of conversion intensity appears possible with only one
      blood sample obtained after tracer application.

PMID- 10411667
TI  - Comparison of the effect of native glucagon-like peptide 1 and dipeptidyl
      peptidase IV-resistant analogues on insulin release from rat pancreatic islets.
AB  - BACKGROUND: Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and may
      improve glycaemic control in type 2 diabetes. Therapeutic use is limited by its
      rapid degradation, primarily by dipeptidyl peptidase IV. MATERIALS AND METHODS:
      Five GLP-1 analogues with alterations at cleavage positions were synthesized
      according to the Fmoc strategy and tested for metabolic stability by incubation
      with rat kidney membranes containing dipeptidyl peptidase IV activity. Their
      insulinotropic effect was compared in isolated rat pancreatic islets after 24 h
      maintenance in tissue culture. Ten islets per vial were incubated for 30 min;
      insulin was measured radioimmunologically. Each analogue was compared with GLP-1
      in the same experiment. RESULTS: All analogues were biologically active in
      isolated islets in the potency order da2d8 = da2 > d2d9 > da2ds8 > desamino. At
      16.7 mmol L-1 glucose, GLP-1 and GLP-1 analogues altered as position 2, or 2 and
      8 significantly (P < 0.05) increased insulin release at 10(-9) mol L-1. N
      terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV
      degradation in rat kidney membranes in vitro. CONCLUSIONS: The analogues tested
      are biologically active and resistant to degradation by dipeptidyl peptidase IV.
      Their greater metabolic stability may help to realize the potential of GLP-1
      analogues in diabetes therapy.

PMID- 10411668
TI  - Antroduodenal motility and small bowel transit during continuous intraduodenal or
      intragastric administration of enteral nutrition.
AB  - BACKGROUND: Gastrointestinal intolerance is observed more frequently during
      intraduodenal (ID) tube feeding than during intragastric (IG) feeding, possibly
      because it evokes a stronger gastrointestinal response and accelerates small
      bowel transit. We have investigated whether the accelerated small bowel transit
      during ID feeding results from alterations in antroduodenal motility pattern.
      DESIGN: The effect of IG and ID infusion of a polymeric diet (Nutrison, 125 kcal
      h-1) on antroduodenal motility, small bowel transit time (SBTT) and
      gastrointestinal hormone release was studied in nine healthy subjects. These
      subjects were studied on three occasions for 6 h during fasting, continuous IG or
      ID feeding. RESULTS: Phase III recurrence time was significantly prolonged during
      IG feeding compared with fasting (240 +/- 51 vs. 136 +/- 24 min; P < 0.05). None
      of the subjects had recurrence of phase III during ID feeding; the fed motor
      pattern remained present. Parameters of fed motility (mean amplitude and motility
      index) were not significantly different between IG and ID feeding, although the
      frequency of antral and duodenal contractions was lower during ID than during IG
      feeding. SBTT was significantly accelerated during ID compared with IG feeding
      and with fasting (58 +/- 8 vs. 73 +/- 9 and 83 +/- 10 min respectively; P <
      0.05). Plasma cholecystokinin (CCK) and pancreatic polypeptide (PP) levels were
      significantly higher during ID than during IG feeding. Peptide YY (PYY) levels
      were significantly higher during ID than during fasting, but not during IG
      feeding CONCLUSIONS: During intraduodenal feeding, a fed motility pattern is
      preserved, whereas during intragastric feeding transition from a fed to a fasting
      motor pattern is observed in over 50% of the subjects. These differences may be
      related to augmented hormone release during intraduodenal feeding.

PMID- 10411669
TI  - [13C]-Galactose breath test: correlation with liver fibrosis in chronic hepatitis
      C.
AB  - BACKGROUND: The galactose elimination capacity test is a quantitative liver
      function test that has been shown to be a potential surrogate marker for death in
      advanced chronic liver diseases. However, this test lacks sensitivity in early
      liver disease. The goal of this study was to evaluate a [13C]-galactose breath
      test (GBT) in a population of patients with chronic hepatitis C. DESIGN: The GBT
      was performed in 10 control subjects and 50 patients with chronic hepatitis C;
      the results were compared with the METAVIR pathological scoring of liver biopsy
      specimens and with standard biochemical liver function tests. RESULTS: In 10
      patients, oral vs. intravenous administration of galactose yielded similar
      results for the GBT (3.01% +/- 0.12% dose h-1 for oral galactose vs. 2.98 +/-
      0.21 for intravenous). The GBT was then performed orally in the remaining 40
      patients and 10 control subjects. A significant difference was observed between
      control subjects and patients (4.51% +/- 0.18% vs. 2.97% +/- 0.14% dose h-1, P <
      0.0001). A significant difference for GBT results was observed between each
      fibrosis stage, but not with regard to the activity score. CONCLUSIONS: The GBT
      results are dependent on the severity of liver fibrosis in chronic hepatitis C.
      Further studies are needed to evaluate the usefulness of the GBT for the follow
      up of chronic hepatitis C.

PMID- 10411670
TI  - Immunohistochemical localization of somatostatin receptor sst2A in sarcoid
      granulomas.
AB  - BACKGROUND: In a previous study, we demonstrated the presence of receptors for
      somatostatin, a neuropeptide with immunoregulatory properties, in the
      inflammatory lesions of patients suffering from sarcoidosis and other
      granulomatous diseases by in vivo somatostatin receptor scintigraphy and in vitro
      autoradiography. However, it was not possible to identify exactly which cell
      types expressed the somatostatin receptors and which subtype was expressed. In
      this study we used a polyclonal antiserum directed against the sst2A receptor to
      identify more accurately the sst2A-expressing cells in sarcoidosis and other
      granulomatous diseases. DESIGN: Tissue biopsies from 12 patients with
      sarcoidosis, one patient with giant cell arteritis and one patient with Wegener's
      granulomatosis were studied by immunohistochemistry with the sst2A-specific
      antiserum. Two of the sarcoidosis patients were treated with the somatostatin
      analogue octreotide (100 microg t.i.d.). RESULTS: Epithelioid cells,
      multinucleated giant cells and a subset of CD68+ macrophages stained positive for
      sst2A in 9 out of 12 of the sarcoid biopsies and in both non-sarcoid granuloma
      biopsies. Treatment with octreotide resulted in clinical improvement in one out
      of two treated patients. CONCLUSION: The identification of somatostatin receptors
      on granuloma macrophages, epithelioid cells and giant cells, and the successful
      treatment of one patient with sarcoidosis with a somatostatin analogue, may offer
      new possibilities for treatment of granulomatous diseases.

PMID- 10411671
TI  - Serum zinc, copper, insulin and lipids in Alzheimer's disease epsilon 4
      apolipoprotein E allele carriers.
AB  - BACKGROUND: Copper (Cu) and zinc (Zn) have been implicated in the development of
      Alzheimer's disease (AD) and, in this regard, Cu and Zn serum concentrations have
      been analysed but with inconclusive results. Serum insulin, glucose and
      cholesterol concentrations have been related to the apolipoprotein E genotype in
      non-AD populations. DESIGN: In this study, we have analysed the relationship
      between serum Cu, Zn, insulin, glucose and lipid parameters (cholesterol,
      triglycerides, apoA and apoB apolipoproteins) in AD and AD epsilon 4
      apolipoprotein E carriers by multivariate analysis using logistic regression,
      including the variables that showed a significance of P < 0.05 in the bivariate
      analysis. RESULTS: The results obtained show that epsilon 4 apoE allele is an
      independent AD risk factor (OR = 6. 67, 95% CI = 2.59-17.16). In AD epsilon 4
      apoE allele carriers, we found significantly higher Zn, Cu and insulin serum
      concentrations. Non-demented control subjects with at least one epsilon 4 apoE
      allele had the lowest serum insulin concentrations. There was no significant
      association between epsilon 4 apolipoprotein E allele and lipid parameters in the
      sample studied. CONCLUSIONS: In AD we have found a significant association
      between higher serum Zn, Cu and insulin concentrations and the presence of an
      epsilon 4 apoE allele, but only greater serum Zn concentration appears to be an
      independent risk factor associated with the development of AD.

PMID- 10411673
TI  - Tetrahydropapaveroline, a dopamine-derived isoquinoline alkaloid, undergoes
      oxidation: implications for DNA damage and neuronal cell death.

PMID- 10411672
TI  - Peripheral markers of oxidative stress in probable Alzheimer patients.
AB  - BACKGROUND: The current research on Alzheimer's disease is mainly focused in the
      post-mortem characterization of pathological and biochemical alterations in the
      brain. The finding of peripheral markers that could be associated with the
      changes observed in the Alzheimer's brain would be of interest in this field. The
      aim of the present study was to evaluate the state of different peripheral
      markers of oxidative stress in probable Alzheimer patients and compare them with
      a group of healthy individuals. DESIGN: The determinations made include the
      plasma total antioxidant capacity (TRAP) and tert-butyl hydroperoxide-initiated
      chemiluminescence and catalase activity in erythrocytes from 18 patients with
      probable Alzheimer's disease and 18 matched control subjects with normal
      cognitive function. RESULTS: TRAP was decreased in Alzheimer patients by 24%
      (control group 308 micromol L-1 Trolox, SEM 34, n = 18). tert-Butyl hydroperoxide
      initiated chemiluminescence and catalase activity showed an increase in
      erythrocytes from Alzheimer patients by 52% (control group 116 700 cps mg-1
      haemoglobin, SEM 6690) and 75% (control group 2.55 pmol mg-1 protein, SEM 0.39, n
      = 18) respectively. CONCLUSION: Oxidative stress in the blood of probable
      Alzheimer patients could be a reflection of the brain condition and suggests that
      oxygen free radicals could be partially responsible of the damage observed in
      this disease.

PMID- 10411674
TI  - The hemodialysis catheter conundrum: hate living with them, but can't live
      without them.
AB  - BACKGROUND: Hemodialysis requires reliable recurrent access to the circulation.
      On a chronic basis, this has been best provided by the use of arteriovenous
      fistulae and arteriovenous grafts. In recent years, hemodialysis catheters have
      come to play an increasingly important role in the delivery of hemodialysis. The
      use of both temporary as well as cuffed hemodialysis catheters has emerged as a
      significant boon for both patients and practicing nephrologists. The
      complications, however, associated with each of these hemodialysis catheters,
      both in terms of anatomic, thrombotic, and infectious issues, have emerged as a
      major problem with their continued use. This significant morbidity and
      complication rate has forced many nephrologists to face a basic conundrum: they
      have come to hate having to deal with the problems inherent in catheter usage,
      but the enormous utility of these devices have forced physicians to accept the
      fact they cannot live without them in their current practice. METHODS: We used a
      comprehensive literature review to describe the types, use and dilemmas of
      hemodialysis catheters. RESULTS: This article provides a comprehensive review of
      both the benefits inherent with the use of these hemodialysis catheters while
      cataloging their complications and offering some possible solutions. CONCLUSION:
      Hemodialysis vascular access catheters are essential in the maintenance of
      hemodialysis vascular access. However, they have a significant infectious,
      thrombotic, anatomic complication rate that are detailed with proposed problem
      solving guidelines.

PMID- 10411675
TI  - Gene targeting: applications in transplantation research.
AB  - Gene targeting, the manipulation of gene in the mouse genome using homologous
      recombination in embryonic stem cells, is a powerful experimental tool that has
      been widely utilized in a number of disciplines. The ability to precisely alter
      genes in this way provides an avenue for investigating the role of a gene product
      in normal and pathological processes in the intact animal, with a precision and
      efficacy not possible using pharmacological agents, antibodies or engineered
      proteins. In transplant research, gene targeting provides a unique tool for
      discriminating the contributions of gene expression in donor versus recipient
      tissues. This review focuses on several areas in transplantation research where
      gene targeting has made useful contributions. These include studies of the role
      of donor and recipient multiple histocompatibility complex antigens in regulating
      rejection responses, the role of CD4+ T cell in mediating acute rejection, and
      the functions of cytokines during rejection and tolerance induction. These
      studies highlight the unique advantages of gene targeting in studies of complex
      processes in whole animals and illustrate the contributions of this technique to
      understanding the pathogenesis of allograft rejection.

PMID- 10411676
TI  - Seven novel mutations of the PKD2 gene in families with autosomal dominant
      polycystic kidney disease.
AB  - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is genetically
      heterogeneous, with at least three chromosomal loci accounting for the disease.
      Mutations in the PKD2 gene on the long arm of chromosome 4 are expected to be
      responsible for approximately 15% of cases of ADPKD. METHODS: We report a
      systematic screening for mutations covering the 15 exons of the PKD2 gene in
      eight unrelated families with ADPKD type 2, using the heteroduplex technique.
      RESULTS: Seven novel mutations were identified and characterized that, together
      with the previously described changes, amount to a detection rate of 85% in the
      population studied. The newly described mutations are two nonsense mutations, a 1
      bp deletion, a 1 bp insertion, a mutation that involves both a substitution and a
      deletion (2511AG-->C), a complex mutation in exon 6 consisting of a simultaneous
      7 bp inversion and a 4 bp deletion, and the last one is a G-->C transversion that
      may be a missense mutation. Most of these mutations are expected to lead to the
      formation of shorter truncated proteins lacking the carboxyl terminus of PKD2. We
      have also characterized a frequent polymorphism, Arg-Pro, at codon 28 in this
      gene. The clinical features of these PKD2 patients are similar to the previously
      described, with the mean age of end-stage renal disease being 75.5 years (SE +/-
      3.8 years). CONCLUSIONS: Our results confirm that many different mutations are
      likely to be responsible for the disease and that most pathogenic defects
      probably are point or small changes in the coding region of the gene.

PMID- 10411677
TI  - Familial phenotype differences in PKD11.
AB  - Familial phenotype differences in PKD1. BACKGROUND: Mutations within the PKD1
      gene are responsible for the most common and most severe form of autosomal
      dominant polycystic kidney disease (ADPKD). Although it is known that there is a
      wide range of disease severity within PKD1 families, it is uncertain whether
      differences in clinical severity also occur among PKD1 families. METHODS: Ten
      large South Wales ADPKD families with at least 12 affected members were included
      in the study. From affected members, clinical information was obtained, including
      survival data and the presence of ADPKD-associated complications. Family members
      who were at risk of having inherited ADPKD but were proven to be non-affected
      were included as controls. Linkage and haplotype analysis were performed with
      highly polymorphic microsatellite markers closely linked to the PKD1 gene.
      Survival data were analyzed by the Kaplan-Meier method and the log rank test.
      Logistic regression analysis was used to test for differences in complication
      rates between families. RESULTS: Haplotype analysis revealed that each family had
      PKD1-linked disease with a unique disease-associated haplotype. Interfamily
      differences were observed in overall survival (P = 0.0004), renal survival (P =
      0.0001), hypertension prevalence (P = 0.013), and hernia (P = 0.048). Individuals
      with hypertension had significantly worse overall (P = 0.0085) and renal (P =
      0.03) survival compared with those without hypertension. No statistically
      significant differences in the prevalence of hypertension and hernia were
      observed among controls. CONCLUSION: We conclude that phenotype differences exist
      between PKD1 families, which, on the basis of having unique disease-associated
      haplotypes, are likely to be associated with a heterogeneous range of underlying
      PKD1 mutations.

PMID- 10411678
TI  - Synergistic effect of interleukin-1 and CD40L on the activation of human renal
      tubular epithelial cells.
AB  - BACKGROUND: Renal tubular epithelial cells are a central cell type in
      tubulointerstitial inflammation because they can produce inflammatory mediators
      such as cytokines and chemokines. Several signals derived from either monocytes
      or activated T cells have been reported to regulate the activation of tubular
      epithelial cells. We studied this regulation in more detail by combined treatment
      with CD40 ligand and the proinflammatory cytokine interleukin-1 (IL-1) in vitro.
      METHODS: The regulation of cytokine and chemokine production was studied in
      primary cultures of human proximal tubular epithelial cells (PTECs). PTECs were
      activated by coculture with CD40L-transfected murine fibroblasts in combination
      with recombinant human cytokines. The production of IL-6, IL-8, monocyte
      chemoattractant protein-1 (MCP-1), and RANTES were measured by specific enzyme
      linked immunosorbent assay. RESULTS: The combined activation of PTECs with CD40L
      and IL-1 resulted in strong synergistic effects on the production of IL-6, IL-8,
      and RANTES, whereas only an additive stimulation of MCP-1 production was
      observed. The effects were specific for IL-1 and could be neutralized by the
      addition of the IL-1R antagonist. Both IL-1alpha and IL-1beta showed similar
      effects on cytokine production by PTECs. The effects of IL-1 were dose dependent,
      and kinetic experiments showed that synergistic effects were observed after 24
      hours of activation and remained present for at least five days. Reverse
      transcription-polymerase chain reaction analysis showed that human PTECs could
      express both IL-1alpha and IL-1beta. The activation of PTECs with IL-1 resulted
      in an up-regulation of CD40 expression on these cells. CONCLUSIONS: A complex
      network of regulation exists for the production of cytokines and chemokines by
      PTECs. The combined treatment results in strong synergistic effects on IL-6, IL
      8, and RANTES production. This strengthens the potential role of tubular
      epithelial cells in inflammatory responses within the kidney.

PMID- 10411679
TI  - Expression of the C-C chemokine receptor 5 in human kidney diseases.
AB  - BACKGROUND: Chemokines are proteins that contribute to the migration of
      leukocytes to sites of tissue injury. CCR5 is a receptor for the C-C chemokine
      RANTES, which is expressed in inflammatory kidney diseases and transplant
      rejection. METHODS: In order to study the distribution of CCR5, we developed a
      series of monoclonal antibodies against human CCR5. These antibodies were then
      evaluated by flow cytometry, Western blot, and immunohistochemistry on formalin
      fixed, paraffin-embedded tonsils. Eighty biopsies from patients with membranous
      glomerulonephritis (N = 9), IgA nephropathy (N = 10), lupus nephritis (N = 10),
      membranoproliferative glomerulonephritis (N = 10), acute interstitial nephritis
      (N = 13), chronic interstitial nephritis (N = 10), acute transplant rejection (N
      = 9), and chronic transplant rejection (N = 9) were stained for CCR5 and CD3
      expression in parallel sections. RESULTS: One monoclonal antibody (MC-5) showed a
      single protein band of approximately 38 kD corresponding to CCR5 in Western blot.
      By indirect immunohistochemistry, a cell membrane signal was detected exclusively
      on mononuclear inflammatory cells. All control stainings with an isotype-matched
      mouse IgG2a were negative. CCR5-positive cells were identified in areas of
      interstitial infiltration in biopsies of chronic glomerulonephritis, interstitial
      nephritis, and transplant rejection. The staining of CCR5 showed the same
      distribution as CD3-positive T cells. In patients with impaired renal function, a
      significantly higher number of CCR5-positive cells were found as compared with
      patients with normal renal function. In contrast to the prominence of CCR5
      positive cells in the interstitial infiltrate, the number of CCR5-positive cells
      within the glomeruli was low, even in cases with proliferative
      glomerulonephritis. No CCR5 expression could be detected on intrinsic cells of
      glomerular, tubular, or vascular structures. CONCLUSIONS: The pattern of CCR5 and
      CD3 cell infiltration suggests that CCR5-positive T cells may play a role in
      interstitial processes leading to fibrosis. Further studies are required to
      define the pathophysiological relevance of these cells in progressive renal
      diseases.

PMID- 10411680
TI  - Subcellular localization of glucocorticoid receptor protein in the human kidney
      glomerulus.
AB  - BACKGROUND: The detailed mechanisms of glucocorticoid action in idiopathic
      nephrotic syndrome and progressive glomerulonephritides have not been clearly
      elucidated. The pharmacological actions of glucocorticoids are mediated by their
      binding to an intracellular protein, the glucocorticoid receptor (GR). The
      determination of GR localization in normal glomerular cells is essential to
      elucidate the mechanisms of glucocorticoid action in various glomerular diseases.
      METHODS: We carried out an immunoblot examination using antihuman GR-specific
      antibody and homogenates of isolated normal human glomeruli and mesangial cells
      in culture. Immunohistochemical examinations were also performed on normal human
      kidney specimens at light and electron microscopic levels. The nuclear
      translocation of GRs elicited by ligand binding was further investigated by
      confocal laser-scanning microscopic inspection of freshly isolated glomeruli and
      mesangial cells cultured with dexamethasone. RESULTS: An immunoblot examination
      demonstrated the presence of a 94 kDa protein, a molecular weight consistent with
      that of GRs, in the homogenates of glomeruli and cultured mesangial cells. By
      light microscopic examination, GRs were strongly detected in the nucleus and
      moderately in the cytoplasm of all glomerular cells, parietal and visceral
      epithelial cells, endothelial cells, and mesangial cells. By electron microscopic
      examination, the nuclear GRs of all glomerular cells were found to be diffusely
      distributed in the euchromatin. Additionally, the immunofluorescence intensities
      of nuclear GRs in isolated glomeruli and mesangial cells in culture became more
      intense by the addition of dexamethasone. CONCLUSIONS: Our findings suggest that
      all subsets of human glomerular cells definitely express the GR protein, which
      potentially undergoes translocation by glucocorticoids.

PMID- 10411681
TI  - Reduced tolerance to acute renal ischemia in mice with a targeted disruption of
      the osteopontin gene.
AB  - BACKGROUND: Mice with a targeted disruption of the osteopontin gene through
      homologous recombination in embryonic stem cells have recently been generated and
      shown to be characterized by unaltered fertility and normal embryonic and
      postnatal development, including renal development, but altered
      osteoclastogenesis from spleen progenitors. The lack of detectable pathological
      manifestations in kidneys of mice with the targeted disruption of the osteopontin
      gene (opn -/-) makes them an excellent model for studies of pathophysiological
      processes that are thought to be accompanied by changes in renal osteopontin
      expression. It has previously been suggested that osteopontin may play an
      important role in the pathophysiology of acute renal failure, thus prompting this
      study. METHODS: Wild-type and opn -/- mice were subjected to 30 minutes of renal
      ischemia and were studied 24 hours later. RESULTS: Control opn +/+ mice showed a
      significant retention of blood urea nitrogen and creatinine, which is indicative
      of the development of ischemic acute renal dysfunction. This was accompanied by a
      2.7-fold increase in the immunodetectable osteopontin compared with sham-operated
      control. Animals with the disrupted osteopontin gene exhibited ischemia-induced
      renal dysfunction, which was twice as pronounced as that observed in mice with
      the intact osteopontin response to stress. In addition, the structural damage to
      the ischemic kidneys obtained from opn -/- mice was more pronounced than that
      observed in similarly treated wild-type mice. This was associated with the
      augmented expression of inducible nitric oxide synthase and the prevalence of
      nitrotyrosine residues in kidneys from opn -/- mice versus wild-type
      counterparts. In vitro studies with proximal tubular cells subjected to hypoxia
      in the presence of OPN, but not OPN with deleted arginine-glycine-aspartic acid
      (RGD) domain, resulted in cytoprotection. CONCLUSIONS: The comparative analysis
      of functional and morphological sequelae of acute renal ischemia in opn +/+ and
      opn -/- mice provides strong evidence of renoprotective action of osteopontin in
      acute ischemia.

PMID- 10411682
TI  - TGF-beta1 stimulates the release of pre-formed bFGF from renal proximal tubular
      cells.
AB  - BACKGROUND: It is now clear that the progression of renal disease is closely
      correlated to the degree of renal interstitial fibrosis. We have previously
      demonstrated that the renal proximal tubular epithelial cell may contribute to
      the fibrotic response by the generation of profibrotic cytokines. Transforming
      growth factor-beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF) are two
      of a group of profibrotic cytokines that have been associated with the
      development of renal interstitial fibrosis. In this study, we have examined the
      influence of TGF-beta1 on the generation of bFGF by renal tubular epithelial
      cells. METHODS: HK2 cells were grown to confluence and were serum deprived and
      stimulated with recombinant TGF-beta1 under serum-free conditions. Subsequently,
      supernatant, cell-associated, intracellular, and matrix-associated bFGF
      concentrations were determined by enzyme-linked immunosorbent assay (ELISA). bFGF
      mRNA expression was examined by reverse transcription-polymerase chain reaction
      (RT-PCR). RESULTS: The exposure of confluent serum-deprived HK2 cells to TGF
      beta1 led to a significant increase in bFGF concentration in the cell culture
      supernatant. Twenty-four hours following the addition of 10 ng/ml TGF-beta1, this
      represented a twofold increase in bFGF concentration (control, 102 pg/ml, N = 24,
      vs. 202 pg/ml, N = 19, P = 0.0001). Despite the increase in bFGF concentration in
      the supernatant, there was no change in the expression of bFGF mRNA following the
      addition of TGF-beta1. The addition of 10 ng/ml of TGF-beta1 led to a 30%
      decrease in the total cell-associated bFGF concentration (control, 8.51 ng/ml, N
      = 16, TGF-beta1, 6.01 ng/ml, N = 13, P = 0.0042). This decrease in intracellular
      bFGF was associated with a 15% reduction in anti-bFGF antibody binding to fixed
      permeabilized cells, following the addition of 10 ng/ml of recombinant TGF-beta1
      (N = 9, P = 0.0007), suggesting that the mechanism of stimulation of bFGF by TGF
      beta1 involved the release of preformed bFGF from within the cells. In addition,
      following the addition of TGF-beta1, there was a significant dose-dependent
      decrease in the amount of bFGF sequestered in the extracellular matrix. At a dose
      of 10 ng/ml TGF-beta, this represented a greater than sevenfold decrease (N = 9,
      P = 0.0007) in matrix-bound bFGF, although this represented less than 3% of the
      total bFGF released into the supernatant. CONCLUSION: The data presented suggest
      that the main mechanism by which TGF-beta1 stimulates bFGF generation by proximal
      tubular epithelial cells is by stimulation of the secretion of preformed cytokine
      from within the cells.

PMID- 10411683
TI  - Role of fibronectin deposition in cystogenesis of Madin-Darby canine kidney
      cells.
AB  - BACKGROUND: Madin-Darby canine kidney (MDCK) cells cultured within collagen I gel
      exhibit clonal growth and form spherical multicellular cysts. The cyst-lining
      epithelial cells are polarized with the basolateral surface in contact with the
      collagen gel and the apical surface facing the lumen. To understand whether MDCK
      cysts construct the basal lamina, we characterized the composition of the
      extracellular matrix deposited by MDCK cysts. The cyst-lining cells produced an
      apparently incomplete basal lamina containing a discontinuous laminin substratum.
      In addition, the basal cell surface of the cyst was surrounded by a thick layer
      of fibronectin. This study was conducted to delineate the role of fibronectin
      deposition in cystogenesis. METHODS: MDCK cells cultured in collagen gel were
      employed. We first used Arg-Gly-Asp (RGD) peptides containing disintegrin
      rhodostomin to disturb the interaction between fibronectin and the cell surface
      integrin. We then established several stable transfectants expressing the
      fibronectin antisense RNA and with which to directly examine the role of
      fibronectin in cystogenesis. RESULTS: Rhodostomin markedly decreased the growth
      rates of the MDCK cyst, suggesting the importance of a normal interaction between
      fibronectin and integrins. The stable transfectants overexpressing the
      fibronectin antisense RNA exhibited relatively lower levels of fibronectin and
      markedly lower cyst growth rates than the control clone. The lower growth rate
      was correlated with an increase in collagen gel-induced apoptosis. CONCLUSIONS:
      The results indicate that the deposition of fibronectin underlying the cyst
      lining epithelium serves to prevent apoptosis induced by three-dimensional
      collagen gel cultures, and hence facilitates cyst growth of MDCK cells.

PMID- 10411684
TI  - Plasma membrane phospholipid integrity and orientation during hypoxic and toxic
      proximal tubular attack.
AB  - BACKGROUND: Acute cell injury can activate intracellular phospholipase A2 (PLA2)
      and can inhibit plasma membrane aminophospholipid translocase(s). The latter
      maintains inner/outer plasma membrane phospholipid (PL) asymmetry. The
      mechanistic importance of PLA2-mediated PL breakdown and possible PL
      redistribution ("flip flop") to lethal tubule injury has not been well defined.
      This study was performed to help clarify these issues. METHODS: Proximal tubule
      segments (PTS) from normal CD-1 mice were subjected to either 30 minutes of
      hypoxia, Ca2+ ionophore (50 microM A23187), or oxidant attack (50 microM Fe).
      Lethal cell injury [the percentage of lactate dehydrogenase (LDH) release],
      plasma membrane PL expression [two-dimensional thin layer chromatography (TLC)],
      and free fatty acid (FFA) levels were then assessed. "Flip flop" was gauged by
      preferential decrements in phosphatidylserine (PS) versus phosphatidylcholine
      (PC; PS/PC ratios) in response to extracellular (Naja) PLA2 exposure. RESULTS:
      Hypoxia induced approximately 60% LDH release, but no PL losses were observed.
      FFA increments suggested, at most 3% or less PL hydrolysis. Naja PLA2 reduced PLs
      in hypoxic tubules, but paradoxically, mild cytoprotection resulted. In contrast
      to hypoxia, Ca2+ ionophore and Fe each induced significant PL losses (6 to 15%)
      despite minimal FFA accumulation or cell death (26 to 27% LDH release).
      Arachidonic acid markedly inhibited PLA2 activity, potentially explaining an
      inverse correlation (r = -0.91) between tubule FFA accumulation and PL
      decrements. No evidence for plasma membrane "flip flop" was observed. In vivo
      ischemia reperfusion and oxidant injury (myohemoglobinuria) induced 0 and 24%
      cortical PL depletion, respectively, validating these in vitro data. CONCLUSIONS:
      (a) Plasma membrane PLs are well preserved during acute hypoxic/ischemic injury,
      possibly because FFA accumulation (caused by mitochondrial inhibition) creates a
      negative feedback loop, inhibiting intracellular PLA2. (b) Exogenous PLA2 induces
      PL losses during hypoxia, but decreased cell injury can result. Together these
      findings suggest that PL loss may not be essential to hypoxic cell death. (c)
      Oxidant/Ca2+ overload injury induces early PL losses, perhaps facilitated by
      ongoing mitochondrial FFA metabolism, and (d) membrane "flip flop" does not
      appear to be an immediate mediator of acute necrotic tubular cell death.

PMID- 10411685
TI  - Inhibition of nuclear factor-kappaB activation reduces cortical
      tubulointerstitial injury in proteinuric rats.
AB  - BACKGROUND: Protein-induced chemokine expression in proximal tubular cells is
      mediated by the transcription factor nuclear factor-kappa B (NF-kappaB). We
      hypothesized that in vivo inhibition of renal NF-kappaB activation would reduce
      interstitial monocyte infiltration in a rat model of nonimmune proteinuric
      tubulointerstitial inflammation. METHODS: Male Wistar rats received a single
      intravenous injection of doxorubicin hydrochloride [adriamycin (ADR), 7.5 mg/kg]
      and were studied 7, 14, 21, and 28 days later. In a second study, inhibitors of
      NF-kappaB [N-acetylcysteine (NAC; 150 mg/kg, b.i.d., i.p.), pyrrolidine
      dithiocarbamate (PDTC, 50 mg/kg, b. i.d., i.p.)] or vehicle were commenced on day
      14 after the onset of proteinuria and were continued until day 30. RESULTS: Rats
      injected with ADR had increased proteinuria (UpV, day 28, 474 +/- 57; control, 18
      +/- 2 mg/day; P < 0.01) and cortical tubulointerstitial injury [tubule cell
      atrophy, interstitial volume, and monocyte/macrophage (ED-1) infiltration].
      Electrophoretic mobility shift assay of nuclear extracts from whole cortex of ADR
      rats demonstrated that NF-kappaB activation (p50/65, p50/c-Rel) increased from
      day 7 (4.7 +/- 0.2 fold-increase above control; P < 0.01) was maximal at day 28
      (6.2 +/- 0.7; P < 0.01) and correlated with UpV (r = 0.63; P < 0.05) and
      interstitial ED-1 infiltration (r = 0.67; P < 0.01). Chronic treatment of ADR
      rats with PDTC suppressed NF-kappaB activation (by 73%; P < 0.05) without any
      effect on UpV. NF-kappaB inhibition with PDTC was accompanied by a reduction in
      tubule cell atrophy (59%; P < 0.01), interstitial volume (49%; P < 0.05) and ED-1
      infiltration (48%; P < 0.01), and cortical lipid peroxidation (41%; P < 0.05)
      compared with vehicle-treated ADR rats. In contrast NAC had no effect on NF
      kappaB activation, tubulointerstitial injury, or UpV in ADR rats. CONCLUSION: The
      activation of NF-kappaB may have an important role in mediating cortical
      interstitial monocyte infiltration and tubular injury in nonimmune proteinuric
      tubulointerstitial inflammation.

PMID- 10411686
TI  - Monocyte chemoattractant protein-1 mediates collagen deposition in experimental
      glomerulonephritis by transforming growth factor-beta.
AB  - BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) plays a significant role
      in the recruitment of monocytes/macrophages in experimental glomerulonephritis
      (GN). Because recent evidence points to possible profibrogenic effects of
      leukocyte-derived factors in GN, this study was designed to evaluate the role of
      the chemokine MCP-1 in the fibrogenesis of experimental GN. METHODS: Rats with an
      anti-thy-1-induced GN were treated with a neutralizing antiserum against MCP-1.
      Glomerular collagen type IV, as a marker of glomerular matrix deposition, was
      assessed by Northern and Western blotting and immunohistology. Transforming
      growth factor-beta (TGF-beta), an important mediator of this matrix expansion,
      was studied by Northern and Western blotting. RESULTS: The induction of GN
      resulted in a significant increase of glomerular collagen type IV deposition and
      TGF-beta synthesis. The neutralization of MCP-1 significantly reduced the
      enhanced collagen type IV protein synthesis and deposition without affecting
      collagen mRNA expression. However, both the enhanced transcription and protein
      synthesis of TGF-beta were inhibited by anti-MCP-1 antiserum in nephritic
      animals. CONCLUSIONS: In this model of GN, MCP-1 has a fibrogenic effect through
      the stimulation of TGF-beta. MCP-1 is thus not only important for the recruitment
      of inflammatory cells, but also mediates glomerular matrix accumulation.

PMID- 10411687
TI  - Changes in collagenases and TGF-beta precede structural alterations in a model of
      chronic renal fibrosis.
AB  - BACKGROUND: To study the role of collagenases and transforming growth factor-beta
      (TGF-beta) in the genesis of interstitial fibrosis, we used the model of
      bromoethylamine (BEA)-induced papillary necrosis, which is known to lead over a
      period of 1 to 12 months to interstitial fibrosis and renal insufficiency.
      METHODS: Rats were injected with BEA, and urine and kidney tissue (cortex and
      medulla) were collected after 1, 2, 3, 7, and 30 days. One kidney was perfused
      and fixed for morphological studies and immunostained for collagen type I, III,
      and IV. The other kidney was used to prepare cortex and medulla extracts for
      gelatinases (by fluorometric and zymographic techniques), tissue inhibitors of
      metalloproteinase-1 (TIMP-1), and TIMP-2 (by enzyme-linked immunosorbent assay,
      ELISA) and TGF-beta1 (by ELISA). RESULTS: Albuminuria and interstitial fibrosis
      were present in BEA rats by day 7, which continued until day 30.
      Immunocytochemical staining for collagen types showed that collagen III and IV
      increased in the interstitium by day 30, but collagen I remained unchanged.
      Gelatinase activity in the medulla decreased by 57% compared with control by day
      2 and remained low until day 30. In the cortex, gelatinase activity remained
      unchanged between 0 and 7 days after BEA but decreased by 72% by day 30. TIMP-1
      and TIMP-2 were decreased by 80% compared with day 0 in both the medulla (by day
      1) and cortex (by day 2) and remained low up to day 30. TGF-beta1
      immunoreactivity increased progressively until day 2 in the medulla (16-fold
      higher than control) and day 3 in the cortex (8-fold higher than control) and
      returned to control level by day 3 in the medulla and by day 30 in the cortex.
      Two days after BEA injection, the mRNA for TGF-beta1 was increased eightfold in
      the cortex and 12-fold in the medulla, and it remained high for up to 30 days.
      CONCLUSIONS: The fibrosis that follows papillary necrosis is associated with both
      high TGF-beta1 expression and depressed gelatinolytic activity.

PMID- 10411688
TI  - Removal of digoxin and doxorubicin by multidrug resistance protein-overexpressed
      cell culture in hollow fiber.
AB  - BACKGROUND: Drug removal by hemoperfusion is not effective because of its lower
      capacity and nonspecificity. We invented a new hybrid type of hemodialysis
      system. METHODS: An immortalized proximal tubular cell line (PCTL) overexpressing
      human multidrug resistance protein-1 (MDR-1) was cultured either on polus filter
      membranes or on hollow fiber modules. The modules were incubated in an incubator
      conditioned with 95% O2/5% CO2 that was kept at 37 degrees C. At 10 days on
      culture, the drug-transporting capacity of these systems was examined. RESULTS:
      MDR was successfully expressed in the PCTL as evaluated by Western blot.
      Basolateral to apical transport of 3H-digoxin, a substrate of MDR, was examined
      by using the cells cultured on a microporous membrane. PCTL-MDR showed a 10-fold
      increase in MDR protein and a 12-fold increase of 3H-digoxin transport through a
      cell layer on a microporous membrane. The increase of the transport was abolished
      by the addition of 5 microM verapamil, an inhibitor of MDR, to the apical side.
      When digoxin or doxorubicin was infused in the capillary side of the hollow fiber
      modules after 10 days on culture, the largest portion of the drugs was
      transported to the pericapillary side (P < 0.001). This transport was also
      abolished by an addition of verapamil to the pericapillary side. Transport of
      para-aminohippurate was not different between two cells, and inulin was not
      transported in this system. CONCLUSION: The hybrid hollow fiber system can
      selectively remove a significant amount of drugs that have an affinity to MDR
      from the medium, and perfuse them to the capillary side in vitro.

PMID- 10411689
TI  - Effects of missense mutations on rat aquaporin-2 in LLC-PK1 porcine kidney cells.
AB  - BACKGROUND: Mutations in the aquaporin-2 (AQP2) gene have been found in families
      with nephrogenic diabetes insipidus (NDI), but the pathophysiological mechanisms
      of how mutant AQP2 causes the disease are still not clear. METHODS: Wild-type
      (WT) AQP2 and four mutants-T126M, A147T, R187C, and S216P-were transiently
      expressed in LLC-PK1 cells. The osmotic water permeability of LLC-PK1 cells
      expressing AQP2 mutants was determined by stopped-flow light-scattering
      microphotometry. Cell surface expression, subcellular localization, and effects
      of vasopressin stimulation were examined by surface biotin labeling and confocal
      immunohistochemistry. RESULTS: The osmotic water permeability (Pf) of cells
      expressing WT increased significantly after vasopressin treatment, whereas the Pf
      of cells expressing T126M A147T, R187C, and S216P was not significantly different
      from that of the control even after vasopressin stimulation. Confocal
      immunohistochemistry demonstrated distribution of WT and A147T in early/recycling
      endosomal compartments and vasopressin-responsive translocation and surface
      expression. In contrast, stainings of T126M, R187C, and S216P were similar to
      that of Grp78, indicating that these mutants were misassembled and retarded in
      the endoplasmic reticulum. CONCLUSION: Our results indicated that the
      intracellular distribution and vasopressin-regulated trafficking of A147T is
      intact, in contrast to the other three mutants, of which both were impaired.
      Thus, it is conceivable that the disruption of the AQP2 channel function accounts
      for the pathogenesis of A147T NDI, whereas trafficking defects account for that
      of the other types, suggesting that the pathophysiology of AQP2-related NDI is
      heterogeneous.

PMID- 10411690
TI  - Regulation of the Na+/H+ antiporter in patients with mild chronic renal failure:
      effect of glucose.
AB  - BACKGROUND: The aim of this study was to determine the glucose-dependent
      regulation of the sodium-proton-antiporter (Na+/H+ antiporter) in patients with
      mild chronic renal failure (CRF). METHODS: We measured plasma glucose
      concentrations, plasma insulin concentrations, plasma C peptide concentrations,
      arterial blood pressure, cytosolic pH (pHi), cellular Na+/H+ antiporter activity,
      and cytosolic sodium concentration ([Na+]i) in 19 patients with CRF and 41 age
      matched healthy control subjects (control) during a standardized oral glucose
      tolerance test. Intracellular pHi, [Na+]i, and Na+/H+ antiporter activity was
      measured in lymphocytes using fluorescent dye techniques. RESULTS: Under resting
      conditions, the pHi was significantly lower, whereas the Na+/H+ antiporter
      activity was significantly higher in CRF patients compared with controls (each P
      < 0.0001). The oral administration of 100 g glucose significantly increased the
      Na+/H+ antiporter activity in CRF patients from 13.35 +/- 1.26 x 10-3 pHi/second
      to 16.44 +/- 1.37 x 10-3 pHi/second after one hour and to 14.06 +/- 1.36 x 10-3
      pHi/second after two hours (mean +/- SEM, P = 0.008 by Friedmans's two-way
      analysis of variance). In controls, the administration of 100 g glucose
      significantly increased the Na+/H+ antiporter activity from 4.23 +/- 0.20 x 10-3
      pHi/second to 6.00 +/- 0.56 x 10-3 pHi/second after one hour and to 6.65 +/- 0.64
      x 10-3 pHi/second after two hours (P = 0.0003). The glucose-induced enhancement
      of the Na+/H+ antiporter activity was more pronounced in CRF patients compared
      with controls (P = 0.011). Resting [Na+]i was not significantly different between
      the two groups. CONCLUSIONS: CRF patients show an intracellular acidosis leading
      to an increased Na+/H+ antiporter activity. In addition, high glucose levels
      exaggerate the differences in Na+/H+ antiporter activity already present between
      cells from patients with mild CRF and those from control subjects.

PMID- 10411691
TI  - Hydrogen peroxide activates ion currents in rat mesangial cells.
AB  - BACKGROUND: Hydrogen peroxide (H2O2) is an important mediator of glomerular
      injury, which induces proliferation and cell contraction in mesangial cells. The
      aim of this study was to investigate whether and which ion currents are activated
      during the early cellular responses to H2O2, and to study possible mechanisms of
      their activation. METHODS: The effect of H2O2 on membrane voltage of mesangial
      cells in short-term culture was investigated with the patch clamp technique in
      the fast whole cell configuration. RESULTS: H2O2 contracted mesangial cells and
      induced a concentration-dependent biphasic membrane voltage response. One hundred
      micromol/liter H2O2 led to a hyperpolarization of mesangial cells from -45 +/- 1
      to -55 +/- 1 mV, which was followed by a sustained depolarization to -20 +/- 3
      mV. The hyperpolarization induced by H2O2 was completely blocked by the K+
      channel blocker Ba2+. In the presence of a low extracellular Cl- concentration
      (32 mmol/liter), the depolarization induced by H2O2 was significantly increased.
      The H2O2-induced depolarization was inhibited by 100 micromol/liter of the
      disulfide-reducing agent dithiothreitol, whereas higher concentrations of
      dithiothreitol (1 mmol/liter) were required to partially inhibit the
      hyperpolarization. Protein kinase C inhibitors blocked the H2O2-induced
      depolarization, but not the hyperpolarization. CONCLUSIONS: The data indicate
      that H2O2 leads to a biphasic membrane voltage response in mesangial cells: an
      initial transient hyperpolarization, which is due to the activation of a K+
      conductance, and a subsequent depolarization, which is, at least in part, due to
      the activation of a Cl- conductance. The oxidation of thiol groups by H2O2 is
      involved in the membrane voltage response, and the depolarization may be
      regulated by protein kinase C.

PMID- 10411692
TI  - Erythrocyte voltage-dependent calcium influx is reduced in hemodialyzed patients.
AB  - BACKGROUND: Uremia displays increased cytosolic free calcium ([Ca2+]i) in many
      different cell types, supporting the hypothesis of an altered Ca2+ transport
      modifying the functional activity of calcium signaling pathway. METHODS: Thirty
      five hemodialyzed patients and 20 age-matched subjects were studied. Erythrocyte
      resting [Ca2+]i and Ca2+ influx were measured by the fluorescent Ca2+-sensitive
      dye fura-2. RESULTS: We found an increase of resting [Ca2+]i in erythrocytes from
      uremic hemodialyzed patients compared with matched healthy controls (103 +/- 2.5
      nM, N = 20, vs. 90 +/- 4, N = 20, P < 0.01). Moreover, we found an altered
      voltage-dependent Ca2+ influx showing a reduced transport rate (0.42 +/- 0.03
      nM/second vs. 0.74 +/- 0.08, P < 0.01). High levels of plasma parathyroid hormone
      (PTH) were related to augmented Ca2+ entry (r = 0.511, P < 0.05), contributing to
      maintain a high level of [Ca2+]i. Hemodialysis had no effect on cell calcium
      level and Ca2+ influx indices. The therapy with Ca2+ antagonists did not modify
      the values of resting [Ca2+]i or Ca2+ influx indices, but the correlation between
      PTH and influx indices was lost. CONCLUSIONS: In conclusion, we found evidence
      for an alteration of erythrocyte Ca2+ influx caused by uremic toxicity that could
      be related to some organ disorders in uremia. The chronic increase of cellular
      calcium may contribute to influx derangement.

PMID- 10411693
TI  - Hyperkalemia in patients infected with the human immunodeficiency virus:
      involvement of a systemic mechanism.
AB  - BACKGROUND: The appearance of hyperkalemia has been described in human
      immunodeficiency virus (HIV)-positive patients treated with drugs with amiloride
      like properties. Recent in vitro data suggest that individuals infected with HIV
      have alterations in transcellular K+ transport. METHODS: With the objective of
      examining the presence of alterations in transmembrane K+ equilibrium in HIV
      positive patients, we designed a prospective, interventional study involving 10
      HIV-positive individuals and 10 healthy controls, all with normal renal function.
      An infusion of L-arginine (6%, intravenously, in four 30-min periods at 50, 100,
      200, and 300 ml/hr) was administered, and plasma and urine electrolytes,
      creatinine, pH and osmolality, total and fractional sodium and potassium
      excretion, transtubular potassium gradient, plasma insulin, renin, aldosterone,
      and cortisol were measured. RESULTS: A primary disturbance consisting of a
      significant rise in plasma [K+] induced by L-arginine was detected in only the
      HIV patients but not in the controls (P < 0.001 between groups). A K+
      redistribution origin of the hyperkalemia was supported by its rapid development
      (within 60 min) and the lack of significant differences between HIV-positive
      individuals and controls in the amount of K+ excreted in the urine. The fact that
      the HIV-positive individuals had an inhibited aldosterone response to the
      increase in plasma K+ suggested a putative mechanism for the deranged K+
      response. CONCLUSIONS: These results reveal that HIV-infected individuals have a
      significant abnormality in systemic K+ equilibrium. This abnormality, which leads
      to the development of hyperkalemia after the L-arginine challenge, may be
      related, in part, to a failure in the aldosterone response to hyperkalemia. These
      results provide a new basis for understanding the pathogenesis of hyperkalemia in
      HIV individuals, and demonstrate that the risk of HIV-associated hyperkalemia
      exists even in the absence of amiloride-mimicking drugs or overt hyporeninemic
      hypoaldosteronism.

PMID- 10411694
TI  - Renal hemodynamics in radiocontrast medium-induced renal dysfunction: A role for
      dopamine-1 receptors.
AB  - BACKGROUND: Radiocontrast medium (RCM) administration induces a transient
      increase in renal blood flow (RBF), followed by a prolonged vasoconstriction.
      This vasoconstrictor phase in RBF is accompanied by a decrement in glomerular
      filtration rate (GFR). Nonselective dopamine (DA) receptor stimulation is known
      to increase RBF and GFR. Clinical studies, however, fail to demonstrate a
      renoprotective effect of DA following RCM administration. This lack of
      renoprotection may relate to nonspecific adrenergic stimulation by DA. The effect
      of select DA-1 receptor stimulation on renal hemodynamics following RCM
      administration has not been evaluated. METHODS: This study tests the hypothesis
      that selective DA-1 receptor stimulation blunts the declines in RBF and GFR that
      follow RCM injections, independent of changes in baseline RBF and GFR.
      Experiments were performed in six anesthetized, volume-depleted dogs. RBF was
      measured by an electromagnetic flow probe around the renal artery and GFR by
      inulin clearance. After a 60-minute equilibration period, baseline values of RBF,
      GFR, and arterial pressure were determined. Two separate intrarenal bolus
      injections of the ionic RCM Renograffin were then given in the presence of saline
      infusion. After a 60-minute recovery period, intra-arterial infusions of either
      the selective DA-1 receptor agonist fenoldopam or the selective DA-1 receptor
      antagonist Schering 23390 were started in random order, and experiments were
      repeated. RESULTS: Neither agent significantly altered baseline values of
      arterial pressure, RBF, or GFR rate. Fenoldopam prevented reductions in GFR (-17
      +/- 2 Deltaml/min, control vs. 2 +/- 1 Deltaml/min, fenoldopam, P < 0.001).
      Conversely, GFR was further reduced in the presence of Schering 23390 (-15 +/- 2
      Deltaml/min, control vs. -23 +/- 1 Deltaml/min, Schering 23390, P < 0.05).
      Similarly, the maximal reduction in RBF was blunted with fenoldopam (-71 +/- 12
      Deltaml/min, control vs. -3 +/- 2 Deltaml/min, fenoldopam, P < 0. 01), whereas
      Schering 23390 potentiated maximal RBF reductions following the RCM injection (
      85 +/- 11 Deltaml/min, control vs. -119 +/- 14 Deltaml/min, Schering 23390, P <
      0.05). The duration of recovery from vasoconstriction was also prolonged in the
      presence of Schering 23390 (342 +/- 35 seconds, control vs. 762 +/- 56 seconds,
      Schering 23390, P < 0.0001). CONCLUSION: We conclude that selective DA-1 receptor
      stimulation protects against RCM-mediated decrements in renal hemodynamics,
      independent of changes in baseline GFR and RBF. Clinical trials are required to
      examine whether selective DA-1 receptor stimulation may have a role in
      prophylaxis against nephropathy development in high-risk patients undergoing
      procedures that require RCM.

PMID- 10411695
TI  - Increased bradykinin and "normal" angiotensin peptide levels in diabetic Sprague
      Dawley and transgenic (mRen-2)27 rats.
AB  - BACKGROUND: The transgenic (mRen-2)27 rat (TGR) is a high tissue renin, high
      angiotensin (Ang) II model of hypertension. When administered streptozotocin
      (STZ), TGRs develop a rapidly progressive diabetic nephropathy with renal failure
      over 12 weeks. Bradykinin (BK) and Ang II are potent vasoactive peptides that may
      participate in the vascular and metabolic abnormalities of diabetes. METHODS: TGR
      and Sprague-Dawley (SD) rats were administered STZ (diabetic) or citrate buffer
      (nondiabetic) at six weeks of age. Diabetic rats received daily ultralente
      insulin to maintain moderate hyperglycemia ( approximately 18 mM). Rats were
      sacrificed four- and eight-weeks post-STZ or vehicle. RESULTS: Diabetes did not
      modify the blood pressure of either SD rats or TGRs. Diabetes increased levels of
      BK-(1-9) and its metabolite BK-(1-7) in kidney, aorta, and heart of both SD rats
      and TGRs. Diabetes did not influence Ang II levels in plasma, kidney, aorta,
      heart, or adrenal gland of SD rats, but reduced to normal the elevated Ang II
      levels in plasma, kidney, aorta, and adrenal gland of TGRs. CONCLUSIONS: STZ
      induced diabetes was associated with elevated tissue levels of BK-(1-9) and
      "normal" circulating and tissue levels of Ang II. The increased BK-(1-9) levels
      were consistent with the participation of this peptide in the vascular and
      metabolic abnormalities of diabetes. However, the rapidly progressive nephropathy
      of diabetic TGRs was not associated with BK-(1-9) and Ang II levels in target
      organs that differed from those of diabetic SD rats.

PMID- 10411697
TI  - Uremic autonomic neuropathy studied by spectral analysis of heart rate.
AB  - BACKGROUND: There is good evidence that power spectral analysis (PSA) of heart
      rate variability may provide an insight into the understanding of autonomic
      disorders. METHODS: We investigated 30 chronic uremic patients who were on
      periodic bicarbonate hemodialysis by a battery of six cardiovascular autonomic
      tests (beat-to-beat variations during quiet breathing and deep breathing, heart
      rate responses to the Valsalva maneuver and standing, blood pressure responses to
      standing and sustained handgrip) and PSA of heart rate variations. RESULTS:
      Eleven patients (37%) had an abnormal response to only one parasympathetic test.
      Twelve patients (40%) had a definite parasympathetic damage, as indicated by at
      least two abnormal heart rate tests, whereas four (13%) had combined
      parasympathetic and sympathetic damage. Multivariate analysis of the
      cardiovascular tests revealed that 19 patients (63%) had moderate-to-severe
      autonomic neuropathy (AN), and 11 patients exhibited normal autonomic function.
      Among the symptoms suggestive of autonomic dysfunction, only impotence in males
      was significantly associated with test-proven AN. The PSA of the heart rate
      variability demonstrated a good discrimination of low-frequency (LF) and high
      frequency (HF) bands (LF, 0.03 to 0.15 Hz; HF, 0.15 to 0.33 Hz) among controls,
      uremic patients without test-proven AN, and uremic patients with test-proven AN.
      A significant reduction of the LF value on supine uremic patients without AN
      suggests that an early sympathetic involvement exists that traditional autonomic
      tests were unable to detect. CONCLUSIONS: Our study indicates that the current
      opinion of a major parasympathetic damage in chronic uremic patients on
      hemodialysis has to be modified in favor of a more widespread autonomic
      dysfunction involving both the sympathetic and parasympathetic pathways.

PMID- 10411696
TI  - Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve
      increased renal angiotensin II concentrations.
AB  - BACKGROUND: Chronic nitric oxide synthase (NOS) inhibition results in
      hypertension, proteinuria, and renal morphological changes. Continuous
      angiotensin II (Ang II) blockade prevents these effects, suggesting an essential
      role of Ang II. However, it is not known whether renal Ang II concentrations are
      primarily increased or whether the scarcity of NO allows normal concentrations of
      Ang II to cause these detrimental effects. Therefore, we measured renal Ang II
      concentrations before and during the development of renal damage. METHODS: Group
      1 served as controls. Groups 2 through 5 received the NOS inhibitor Nomega-nitro
      L-arginine (L-NNA; 40 mg/kg/day) for 4, 7, 14, and 21 days, respectively.
      Systolic blood pressure (SBP), proteinuria, glomerular filtration rate (GFR), and
      renal and blood Ang II were measured. In a separate experiment, rats were treated
      with L-NNA + the Ang II AT1 receptor blocker losartan to determine the functional
      effects of endogenous Ang II during chronic NOS inhibition. RESULTS: L-NNA
      treatment resulted in an increase in SBP from day 4 (161 +/- 4 vs. 135 +/- 4 mm
      Hg in control, P < 0.05) to day 21 (230 +/- 9 mm Hg). GFR was decreased from day
      4 (1.9 +/- 0.2 vs. 2.5 +/- 0.2 ml/min in control, P < 0.05) to day 21 (1.2 +/-
      0.2 ml/min). Proteinuria was increased from day 14 (85 +/- 14 vs. 6 +/- 1 mg/day
      in control, P < 0.05) to day 21 (226 +/- 30 mg/day). L-NNA treatment during four
      days resulted in a significant decrease in renal Ang II (183 +/- 32 vs. 454 +/-
      40 fmol/g in control, P < 0.05). On day 7, 14, and 21, renal Ang II was not
      significantly different from the control. Blood Ang II was not significantly
      different from the control on days 4, 7, and 14 but was significantly increased
      after 21 days of L-NNA treatment (215 +/- 35 vs. 78 +/- 13 fmol/ml in control, P
      < 0.05). Ang II type-1 (AT1) receptor blockade prevented the severe renal injury
      and hypertension induced by chronic NOS inhibition. CONCLUSIONS: Losartan
      sensitive renal damage caused by chronic NOS inhibition does not involve
      increased renal Ang II concentrations. This suggests that the detrimental effects
      of endogenous Ang II are increased during chronic NOS inhibition. Thus, when NO
      levels are low, normal Ang II concentrations can cause renal injury and
      hypertension.

PMID- 10411698
TI  - Acute renal failure in the cardiac care unit: etiologies, outcomes, and
      prognostic factors.
AB  - BACKGROUND: Heart disease is a leading cause of hospitalizations, and its
      prevalence is expected to grow rapidly over the next few decades. The purpose of
      this study was to examine the incidence, etiologies, outcomes, and risk factors
      for mortality of acute renal failure (ARF) in cardiac care unit (CCU) patients.
      METHODS: A retrospective, cohort study examining all patients who developed ARF
      while in the CCU at Barnes-Jewish Hospital over a 17-month time period was
      performed. Charts were reviewed to determine etiologies, hospital mortality
      rates, and risk factors for mortality. RESULTS: Four percent of admissions to the
      CCU met criteria for ARF while in the unit. The etiologies of ARF were congestive
      heart failure (CHF; 35%), multifactorial (usually involving CHF; 26%),
      arrest/arrhythmia (13%), contrast (11%), volume depletion (6%), sepsis (6%) and
      obstruction (3%). The mortality rate was 50%. Oliguria, mechanical ventilation,
      and decreased cardiac function were statistically significant risk factors for
      mortality by univariate but not multivariate analysis. Thirty percent of patients
      with a cardiac index of less than 2.0 liter/min/m2 survived to discharge.
      CONCLUSIONS: ARF occurs commonly in CCU patients and is associated with a high
      mortality rate. However, there are a significant number of survivors even among
      patients with severely depressed cardiac function.

PMID- 10411699
TI  - Total body water data for white adults 18 to 64 years of age: the Fels
      Longitudinal Study.
AB  - BACKGROUND: Total body water (TBW) volume is reported to decrease with age, but
      much of the published data are 20 to almost 50 years old and are cross-sectional.
      Proper interpretation of clinical levels of TBW and trends with age necessitates
      the availability of current longitudinal data from healthy individuals. METHODS:
      Mixed longitudinal data for TBW of 274 white men and 292 white women (18 to 64
      years of age) in the Fels Longitudinal Study were collected on a regular schedule
      over a recent eight-year period. The concentration of deuterium was measured by
      deuterium nuclear magnetic resonance spectroscopy. Body composition estimates
      were made with dual-energy x-ray absorptiometry, and random effect models were
      used to determine the patterns of change over time with and without covariates.
      RESULTS: The mean TBW data for the Fels men are either similar to or
      approximately 2 to as much as 6 liters greater than that reported by most other
      investigators 20 to 50 years ago. For Fels women, the mean TBW ranges from
      approximately 2 to as much as 5 liters less than that reported previously. These
      comparisons with much earlier studies reflect cohort effects and the secular
      changes in overall body size that have occurred during the past 60 to 70 years.
      These findings are reinforced by the fact that some early data sets included
      individuals born almost 140 years ago. After adjusting for the covariate effects
      of total body fat (TBF) and fat-free mass (FFM) with age, there were no
      significant age or age-squared effects on TBW in the men. In the women, after
      adjusting for the covariate associations of TBF and FFM with age, there was a
      small, but significant, negative linear association of TBW with age. In the men
      and women, the mean ratio of TBW to weight declined with age as a function of an
      increase in body fatness and more so for the men than the women. CONCLUSION: The
      findings from these mixed longitudinal data indicate that TBW volume, on average,
      maintains a reasonable degree of stability in men and women through a large
      portion of adulthood. These TBW data are recommended as current reference data
      for healthy adults.

PMID- 10411700
TI  - Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated
      hemodialysis patients with cardiac disease.
AB  - BACKGROUND: Hypertension is a recognized complication of partial correction of
      anemia with recombinant human erythropoietin (epoetin) in hemodialysis patients.
      We used interdialytic ambulatory blood pressure (ABP) monitoring to study the
      effects of partially corrected anemia versus normal hematocrit (hct) on BP in
      hemodialysis patients. METHODS: Repeated interdialytic ABP monitoring was
      performed for up to one year in 28 chronic hemodialysis patients with cardiac
      disease who were randomized to achieve and maintain normal hct levels (42 +/- 3%,
      group A) or anemic hct levels (30 +/- 3%, group B) with epoetin. Routine BP
      measurements obtained at dialysis treatments were also evaluated. RESULTS: Mean
      hct levels were 30.7 +/- 0.7% in group A and 30.6 +/- 0.7% in group B at
      baseline, then 39.3 +/- 1.2% (group A) and 33.5 +/- 0.6% (group B) at four
      months, and 42.0 +/- 1.1% (group A) and 30.4 +/- 1.0% (group B) at 12 months.
      Baseline ABP and routine dialysis unit BP levels were not different between the
      groups. At 2, 4, 8, and 12 months of follow-up, there were no statistically
      significant differences in any BP parameters between groups or increases in any
      BP parameters in either group A or group B patients compared with baseline. At 12
      months, the mean nighttime diastolic BP (DBP) in group A patients was slightly
      but significantly lower than the mean daytime DBP (daytime DBP 76.6 +/- 1.9 mm Hg
      vs. nighttime DBP 72.9 +/- 2.1 mm Hg, P < 0.05). The mean daytime and nighttime
      BPs were not different from each other at two, four, and eight months in group A
      or at any time in group B, and in both groups, most patients had little diurnal
      change in BP. CONCLUSION: Correction of hct to normal with epoetin in chronic
      hemodialysis patients with cardiac disease did not cause increased BP as assessed
      by interdialytic ABP monitoring or by the measurement of routine predialysis and
      postdialysis BP. There was little diurnal change in systolic or diastolic BP at
      baseline or after correction of anemia to normal levels, and although mean
      nighttime DBP was lower than mean daytime DBP at 12 months in group A, the
      maintenance of normal hct levels did not affect the abnormal diurnal BP pattern
      seen at moderately anemic hct levels in most patients.

PMID- 10411701
TI  - MK-591 acutely restores glomerular size selectivity and reduces proteinuria in
      human glomerulonephritis.
AB  - BACKGROUND: Leukotrienes are 5-lipoxygenated (5-LO) metabolites of arachidonic
      acid that mediate some of the glomerular hemodynamic and structural changes in
      experimental and human glomerulonephritis. METHODS: We conducted an open-label,
      pilot study of the short-term effects of leukotriene biosynthesis inhibition
      using an orally active 5-LO activating protein (FLAP) antagonist (MK-591) on
      glomerular function in patients with glomerulonephritis. Eleven adult patients
      (seven women, median age 38 years) with glomerulonephritis (5 lupus nephritis, 2
      IgA nephropathy, 1 membranoproliferative, 1 membranous, 1 C1q-deficiency, and 1
      idiopathic crescentic) and moderate renal insufficiency [glomerular filtration
      rate (GFR) 62 +/- 9 ml/min/1.73 m2] were given MK-591 at a dose of 100 mg orally
      twice a day for four days. RESULTS: MK-591 reduced proteinuria (albumin and IgG
      excretion rates) from 3233 +/- 1074 to 1702 +/- 555 microg/min and from 196 +/-
      78 to 148 +/- 55 microg/min for albumin and IgG, respectively (P < 0.05 for
      both). This was not accompanied by a reduction in systemic arterial pressure,
      GFR, or renal plasma flow. By analysis of the fractional clearance of
      polydisperse dextrans, baseline proteinuria resulted from a loss of size
      selectivity with enhanced passage of large (>52 A) dextrans as compared with
      healthy controls. Treatment with MK-591 caused a selective improvement in the
      enhanced passage of large (>58 A) dextrans without affecting the handling of
      smaller dextrans, indicating an improvement in glomerular size selectivity. MK
      591 was well tolerated, and no adverse effects were observed. CONCLUSIONS: Short
      term therapy with MK-591 reduces proteinuria by restoring glomerular size
      selectivity and thus reduces transglomerular protein trafficking. These benefits
      may result from glomerular leukotriene biosynthesis inhibition, but other MK-591
      specific actions cannot be excluded.

PMID- 10411702
TI  - Plasma calcium oxalate supersaturation in children with primary hyperoxaluria and
      end-stage renal failure.
AB  - BACKGROUND: Children with primary hyperoxaluria type 1 (PH 1) are at great risk
      to develop systemic oxalosis in end-stage renal disease (ESRD), as endogenous
      oxalate production exceeds oxalate removal by dialytic therapy. As oxalate
      accumulates, calcium oxalate (CaOx) tissue deposition occurs. Children with other
      causes of ESRD, however, are not prone to CaOx deposition despite elevated plasma
      oxalate (POx) levels. METHODS: Our study objective was to examine the potential
      mechanisms for these observations. We measured POx, sulfate, citrate, and
      calculated CaOx saturation (betaCaOx) in 7 children with ESRD caused by PH 1 and
      in 33 children with non-PH-related ESRD. Maintenance hemodialysis (HD) was
      performed in 6 PH 1 and 22 non-PH patients: Pre- and post-HD levels were analyzed
      at this point and were repeated twice within 12 months in 5 PH 1 and 14 non-PH
      patients. Samples were obtained only once in 12 patients (one PH 1) on peritoneal
      dialysis (PD). After liver-kidney or kidney transplantation, plasma levels were
      measured repetitively. RESULTS: The mean POx was higher in PH 1 (125.7 +/- 17.9
      micromol/liter) than in non-PH patients (44.2 +/- 3.3 micromol/liter, P < 10(
      4)). All other determined anions did not differ between the two groups. betaCaOx
      was higher in PH 1 (4.71 +/- 0.69 relative units) compared with non-PH children
      (1.56 +/- 0.12 units, P < 10(-4)). POx and betaCaOx were correlated in both the
      PH 1 (r = 0.98, P < 2 x 10(-4)) and the non-PH group (r = 0.98, P < 10(-4)). POx
      and betaCaOx remained stable over time in the non-PH children, whereas an
      insignificant decline was observed in PH 1 patients after six months of more
      aggressive dialysis. betaCaOx was supersaturated (more than 1) in all PH 1 and in
      25 out of 33 non-PH patients. Post-HD betaCaOx remained more than 1 in all PH 1,
      but in only 2 out of 22 non-PH patients. In non-PH children, POx and betaCaOx
      decreased to normal within three weeks after successful kidney transplantation,
      whereas the levels still remained elevated seven months after combined liver
      kidney transplantation in two PH 1 patients. CONCLUSION: Systemic oxalosis in PH
      1 children with ESRD is due to higher POx and betaCaOx levels. As betaCaOx
      remained supersaturated in PH 1 even after aggressive HD, oxalate accumulation
      increases, and CaOx tissue deposition occurs. Therefore, sufficient reduction of
      POx and betaCaOx is crucial in PH 1 and might only be achieved by early,
      preemptive, combined liver-kidney transplantation or liver transplantation alone.

PMID- 10411703
TI  - Predictors of adequacy of arteriovenous fistulas in hemodialysis patients.
AB  - BACKGROUND: Dialysis access procedures and complications represent a major cause
      of morbidity, hospitalization, and cost for chronic dialysis patients. To improve
      the outcomes of hemodialysis access procedures, recent clinical guidelines have
      encouraged attempts to place an arteriovenous (A-V) fistula, rather than an A-V
      graft, whenever possible in hemodialysis patients. There is little information,
      however, about the success rate of following such an aggressive strategy in the
      prevalent dialysis population. METHODS: We evaluated the adequacy of all A-V
      fistulas placed in University of Alabama at Birmingham dialysis patients during a
      two-year period. A fistula was considered adequate if it supported a blood flow
      of >/=350 ml/min on at least six dialysis sessions in one month. Fistula adequacy
      was correlated with clinical and demographic factors. RESULTS: The adequacy could
      be determined for 101 fistulas; only 47 fistulas (46.5%) developed sufficiently
      to be used for dialysis. The adequacy rate was lower in older (age >/= 65) versus
      younger (age < 65) patients (30.0 vs. 53.5%, P = 0.03). It was also marginally
      lower in diabetics versus nondiabetics (35.0 vs. 54.1%, P = 0.061) and in
      overweight (BMI >/= 27 kg/m2) versus nonoverweight patients (34.5 vs. 55.2%, P =
      0.07). The adequacy rate was not affected by patient race, smoking status,
      surgeon, serum albumin, or serum parathyroid hormone. The adequacy rate was
      substantially lower for forearm versus upper arm fistulas (34.0 vs. 58.9%, P =
      0.012). The adequacy of forearm fistulas was particularly poor in women (7%),
      patients age 65 or older (12%), and diabetics (21%). In contrast, upper arm
      fistulas were adequate in 56% of women, 54% of older patients, and 48% of
      diabetics. CONCLUSIONS: An aggressive approach to the placement of fistulas in
      dialysis patients results in a less than 50% early adequacy rate, which is
      considerably lower than that reported in the past. Moreover, the success rate of
      fistulas is even lower for certain patient subsets. To achieve an optimal outcome
      with A-V fistulas, we recommend that they be constructed preferentially in the
      upper arm in female, diabetic, and older hemodialysis patients.

PMID- 10411704
TI  - Cytokine gene polymorphisms predict acute graft rejection following renal
      transplantation.
AB  - BACKGROUND: The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha)
      has been implicated in the pathogenesis of acute rejection, while animal models
      suggest a role for interleukin-10 (IL-10) in promoting graft survival. It has
      also been shown that polymorphisms in the TNFA gene promoter (position -308) and
      in the IL-10 gene promoter (position -1082) correlate with differential
      production of these cytokines in vitro. The aim of this study was to determine
      whether TNF-alpha and IL-10 gene polymorphisms influence the incidence and
      severity of acute rejection in the first six months following renal
      transplantation. METHODS: The cytokine genotypes of 115 consecutive first
      cadaveric kidney allograft recipients and their donors were screened. The
      rejection episodes (REs) were defined clinically and confirmed histologically
      where possible and further classified according to severity (RS), namely steroid
      resistant or responsive REs. The genotypes were then correlated with the REs and
      RS. RESULTS: The recipient TNF-alpha high producer genotype and IL-10 high
      producer genotype were significantly associated with multiple REs (>/=2) in human
      leukocyte antigen (HLA)-DR mismatched transplants (P = 0.0047 and P = 0.045,
      respectively), whereas only the TNF-alpha high producer genotype was associated
      with steroid-resistant REs (P = 0.025). When recipient cytokines were analyzed
      together, the TNF-alpha high/IL-10 high producer genotype had the worst
      prognosis, whereas TNF-alpha low/IL-10 low producer genotype was protective.
      CONCLUSIONS: We conclude that recipient TNF-alpha and IL-10 gene polymorphisms
      are determinants of REs and RS following kidney transplantation. Routine
      screening of these gene polymorphisms may have a clinical role in identifying
      patients at risk of multiple REs and severe rejections.

PMID- 10411705
TI  - Paraoxonase polymorphisms are not associated with cardiovascular risk in renal
      transplant recipients.
AB  - BACKGROUND: Paraoxonase (PON1) gene variants have been identified as risk factors
      for cardiovascular disease (CVD). There are two common PON1 polymorphisms at
      position 55 (Leu-Met change) and 192 (Gln-Arg change) of the amino acid chain.
      Leucine at position 55 and arginine at position 192 have been associated with
      increased cardiovascular risk. The increased prevalence of CVD in renal
      transplant recipients can be only partly explained by the increased prevalence of
      conventional risk factors. METHODS: We therefore investigated PON1 polymorphisms
      in renal transplant recipients (N = 491) with (N = 103) and without CVD (N = 388)
      using polymerase chain reaction-restriction fragment length analysis. PON1
      polymorphisms and their associated PON1/arylesterase activities were also
      assessed in a subgroup of patients (N = 165). RESULTS: The genotype distribution
      and allele frequencies for both polymorphisms were similar in both groups. The
      frequencies for LL, LM, and MM genotypes for the 55 position in patients with CVD
      were 0.39, 0.51, and 0.10, respectively, compared with 0.43, 0.43, and 0.14 in
      patients without CVD (P = 0.31). The distribution for the QQ, QR, and RR
      genotypes at the 192 position were 0.48, 0.43, and 0.09, respectively, in
      patients with CVD compared with 0.46, 0.46, and 0.08 in patients without CVD (P =
      0.8). There were highly significant differences in serum activities of
      PON1/arylesterase between genotypes defined by 55 and 192 polymorphisms. Leucine
      at position 55 and arginine at position 192 were associated with higher
      activities. CONCLUSION: These data indicate that there is no association between
      the PON1 gene variants, conferring higher enzyme activity, and the increased
      cardiovascular risk in renal transplant recipients.

PMID- 10411706
TI  - Fibrinogen fragments and platelet dysfunction in uremia.
AB  - BACKGROUND: The uremic state is characterized by subnormal platelet aggregation.
      Fibrinogen fragments, usually absent in normal human blood, but present in uremic
      plasma, may play a role in uremic platelet dysfunction. METHODS: To examine this
      hypothesis, we investigated the availability and function of fibrinogen receptors
      [glycoprotein (GP) IIb-IIIa] on uremic and normal platelets, as well as the
      effect of fragments obtained from chymotrypsin digestion of human fibrinogen on
      normal platelets. The availability of fibrinogen receptors was examined using
      anti-GP IIb-IIIa antibodies and flow cytometry, whereas receptor function was
      assessed by the receptor's ability to mediate fibrinogen binding and platelet
      aggregation. RESULTS: Platelet aggregation and the availability of GP IIb-IIIa
      were lower in uremic patients when compared with normal controls. Flow cytometric
      analysis showed that fibrinogen fragments decreased the binding of anti-CD61, an
      activation-independent anti-GP IIIa monoclonal antibody, to resting normal
      platelets. These fragments also reduced the binding of PAC-1, an activation
      dependent anti-GP IIb-IIIa monoclonal antibody, to adenosine diphosphate (ADP)
      activated normal platelets. In addition, the binding of radiolabeled fibrinogen
      to activated normal platelets and platelet aggregation in response to ADP were
      both decreased by fibrinogen fragments. CONCLUSIONS: These findings suggest that
      fibrinogen fragments impair platelet function by occupying fibrinogen receptors
      prior to cell activation, thus preventing the binding of intact fibrinogen to
      platelets after subsequent stimulation. These observations also suggest a
      plausible mechanism by which endogenous fibrinogen fragments present in uremic
      plasma may contribute to platelet dysfunction.

PMID- 10411707
TI  - Parathyroid function as a determinant of the response to calcitriol treatment in
      the hemodialysis patient.
AB  - BACKGROUND: Bolus calcitriol (CTR) is used for the treatment of secondary
      hyperparathyroidism in dialysis patients. Although CTR treatment reduces
      parathyroid hormone (PTH) levels in many dialysis patients, a significant number
      fail to respond. METHODS: To learn whether or not an analysis of parathyroid
      function could further illuminate the response to CTR, a PTH-calcium curve was
      performed before and after at least two months of CTR treatment in 50
      hemodialysis patients with a predialysis intact PTH of greater than 300 pg/ml.
      RESULTS: For the entire group (N = 50), CTR treatment resulted in a 24% reduction
      in predialysis (basal) PTH from 773 +/- 54 to 583 +/- 71 pg/ml (P < 0.001),
      whereas ionized calcium increased from 1.10 +/- 0.02 to 1.22 +/- 0.02 mM (P <
      0.001); however, maximal and minimal PTH did not change from pre-CTR values.
      Based on whether or not the basal PTH decreased by 40% or more during CTR
      treatment, patients were divided into responders (Rs, N = 25) and nonresponders
      (NRs, N = 25). Before CTR, the NR group was characterized by a greater basal (959
      +/- 80 vs. 586 +/- 51 pg/ml, P < 0.001) and maximal (1899 +/- 170 vs. 1172 +/-
      108 pg/ml, P < 0. 001) PTH and serum phosphorus (6.14 +/- 0.25 vs. 5.14 +/- 0.34
      mg/dl, P < 0.01). Logistical regression analysis showed that the pre-CTR basal
      PTH was the most important predictor of the post-CTR basal PTH, and a pre-CTR
      basal PTH of 750 pg/ml represented a 50% probability of a response. Basal PTH
      correlated with the ionized calcium in the NR group (r = 0.59, P = 0.002) but not
      in the R group (r = 0.06, P = NS). In the R group, an inverse correlation was
      present between ionized calcium and the basal/maximal PTH ratio, an indicator of
      whether calcium is suppressing basal PTH secretion relative to the maximal
      secretory capacity (maximal PTH) r = -0.55, P = 0.004; in the NR group, this
      correlation approached significance but was positive (r = 0.34, P = 0.09). After
      CTR treatment, serum calcium increased in both groups, and despite marked
      differences in basal PTH (Rs, 197 +/- 25 vs. NRs, 969 +/- 85 pg/ml), an inverse
      correlation between ionized calcium and basal/maximal PTH was present in both
      groups (Rs, r = -0.61, P = 0.001, and NRs, r = -0.60, P = 0.001). CONCLUSIONS:
      (a) Dynamic testing of parathyroid function provided insights into the
      pathophysiology of PTH secretion in hemodialysis patients. (b) The magnitude of
      hyperparathyroidism was the most important predictor of the response to CTR. (c)
      Before CTR treatment, PTH was sensitive to calcium in Rs, and serum calcium was
      PTH driven in NRs, and (d) after the CTR-induced increase in serum calcium,
      calcium suppressed basal PTH relative to maximal PTH in both groups.

PMID- 10411708
TI  - Improvement in specific aspects of neurocognitive performance in children after
      renal transplantation.
AB  - BACKGROUND: Chronic renal failure in childhood is considered to affect
      neurocognitive function adversely, and kidney transplantation may ameliorate the
      deficits. However, previous studies have suffered from the use of poorly matched
      control groups, comparison of transplant with uncorrected uremia, lack of
      standardization of dialysis, and insufficiently sensitive neuropsychological
      tests. METHODS: We studied nine medically stable children and adolescents age
      14.2 +/- 3.5 years with end-stage renal disease prior to and again one year after
      successful renal transplant. At baseline, the Wechsler Intelligence Scale for
      Children-III (WISC-III) or the Wechsler Adult Intelligence Scale-Revised (WAIS-R)
      was performed. Repeatable tests used before and after transplant included the
      Paced Auditory Serial Addition Test (PASAT) or the Children's Paced Auditory
      Serial Addition Test (CHIPASAT), the Stroop Color-Word Naming Test, the Buschke
      Selective Reminding Test, the Meier Visual Discrimination Test, the Grooved
      Pegboard Test, the WISC-III or the WAIS-R Coding subtests and the Trailmaking
      Test. Computer-based measures of mental processing speed, reaction time, and
      discrimination sensitivity included the Cognitive Abilities Test (CAT) and the
      Connors Continuous Performance Test (CPT). Formal kinetic modeling of dialysis
      delivery ensured adequate renal replacement therapy. Transplant function was good
      on stable doses of immunosuppressives, without recent rejections at the time of
      testing. RESULTS: Within-subject comparison showed statistically significant
      improvement in mental processing speed by CAT, reaction time and discrimination
      sensitivity by CPT, and working memory by PASAT/CHIPASAT after renal transplant.
      Other measures were unchanged. CONCLUSION: Mental processing speed and sustained
      attention improved in children after renal transplantation in a carefully
      controlled prospective cross-over study.

PMID- 10411709
TI  - Long-term outcome of dialysis patients in the United States with coronary
      revascularization procedures.
AB  - BACKGROUND: The optimal method of coronary revascularization in dialysis patients
      is controversial, as previous small retrospective studies have reported increased
      cardiac events after percutaneous transluminal coronary angioplasty (PTCA)
      compared with coronary artery bypass (CAB) surgery. The purpose of this study was
      to compare the long-term survival of chronic dialysis patients in the United
      States following PTCA or CAB surgery. METHODS: Dialysis patients hospitalized
      from 1978 to 1995 for first coronary revascularization procedure after initiation
      of renal replacement therapy were retrospectively identified from the United
      States Renal Data System database. Survival for the endpoints of all-cause death,
      cardiac death, myocardial infarction, and cardiac death or myocardial infarction
      was estimated by the life-table method and was compared by the log-rank test. The
      impact of independent predictors on survival was examined in a Cox regression
      model with comorbidity adjustment. RESULTS: The in-hospital mortality was 5.4%
      for 6887 PTCA patients and 12.5% for 7419 CAB patients. The two-year event-free
      survival (+/-SE) of PTCA patients was 52.9 +/- 0.7% for all-cause death, 72.5 +/-
      0.7% for cardiac death, and 62.0 +/- 0.7% for cardiac death or myocardial
      infarction. In CAB patients, the comparable survivals were 56.9 +/- 0.6, 75.8 +/-
      0.6, and 71.3 +/- 0. 6%, respectively (P < 0.02 for PTCA vs. CAB surgery for all
      endpoints). After comorbidity adjustment, the relative risk of CAB surgery (vs.
      PTCA) performed 1990 to 1995 for all-cause death was 0. 91 (95% CI, 0.86 to
      0.97); cardiac death, 0.85 (95% CI, 0.78 to 0. 92); myocardial infarction, 0.37
      (95% CI, 0.32 to 0.43); and cardiac death or myocardial infarction 0.69 (95% CI,
      0.64 to 0.74). CONCLUSIONS: In this retrospective study, dialysis patients in the
      United States had better survival after CAB surgery compared with PTCA, but our
      study does not exclude the possibility of more unfavorable coronary anatomy in
      the PTCA patients at baseline. Our data support the need for prospective trials
      of newer percutaneous coronary revascularization procedures in dialysis patients.

PMID- 10411710
TI  - The course of the remnant kidney model in mice.
AB  - The remnant kidney model was produced in mice by unilateral nephrectomy and
      partial infarction of the remaining kidney. Control mice underwent laparotomy
      only. The mice were studied for up to 44 weeks. No quantitative differences were
      noted in systolic arterial pressure, proteinuria, or histopathology between
      control mice and those with a remnant kidney. Glomerular enlargement occurred in
      the remnant kidney.

PMID- 10411712
TI  - Phenotypic variability in PKD1: the family as a starting point.

PMID- 10411711
TI  - An automated technique for the simultaneous determination of cations in nanoliter
      volumes.
AB  - BACKGROUND: The study of ion transport along the renal tubule in vivo or in vitro
      requires a technique capable of analyzing ion concentrations in sample volumes of
      only a few nanoliters. This article describes a method for the analysis of
      cations at physiological concentrations in samples of tubular fluid taken from
      single renal tubules in vivo. Method. A background electrolyte composed of 2-[N
      Morpholino] ethane-sulfonic acid (MES) (50 mmol/liter) and L-histidine (50
      mmol/liter; pH congruent with 6.2), with the additives 18-crown-6 (1 mmol/liter)
      and methanol (30%) was used for the cation separation combined with conductivity
      detection. RESULTS: Capillary zone electrophoresis was used to separate NH4, K,
      Na, Ca, Li, Mg, and Ba in six minutes. Simultaneous quantitative analysis was
      performed for sodium and potassium, providing detection limits of 0.2 pmol for
      sodium and 30 fmol for potassium. The calibration plots were linear over three
      orders of magnitude, including the range of interest to clinical analysis. Data
      on the reproducibility and repeatability of peak areas and of the repeatability
      of migration times are reported. CONCLUSION: The results for sodium and potassium
      are in close agreement with those obtained by atomic absorption spectrometry,
      indicating that this is a suitable technique for the routine measurement of these
      cations in tubule fluid samples.

PMID- 10411714
TI  - Long-term evolution of cardiomyopathy in dialysis patients.

PMID- 10411713
TI  - Chemokines, chemokine receptors and renal disease.

PMID- 10411715
TI  - High serum IgE levels are associated with selective proteinuria in
      glomerulonephritis.

PMID- 10411716
TI  - Dialysis and protein malnutrition.

PMID- 10411717
TI  - Paraneoplastic glomerulopathies: new insights into an old entity.

PMID- 10411718
TI  - Genetics of Methanococcus: possibilities for functional genomics in Archaea.
AB  - Although the genomic sequences of a number of Archaea have been completed in the
      last three years, genetic systems in the sequenced organisms are absent. In
      contrast, genetic studies of the mesophiles in the archaeal genus Methanococcus
      have become commonplace following the recent developments of antibiotic
      resistance markers, DNA transformation methods, reporter genes, shuttle vectors
      and expression vectors. These developments have led to investigations of the
      transcription of the genes for hydrogen metabolism, nitrogen fixation and
      flagellin assembly. These genetic systems can potentially be used to analyse the
      genomic sequence of the hyperthermophile Methanococcus jannaschii, addressing
      questions of its physiology and the function of its many uncharacterized open
      reading frames. Thus, the sequence of M. jannaschii can serve as a starting point
      for gene isolation, while in vivo genetics in the mesophilic methanococci can
      provide the experimental systems to test the predictions from genomics.

PMID- 10411719
TI  - Bacterial transcription factors involved in global regulation.
AB  - The presence of intricate global cell regulation mechanisms may be one reason for
      the exceptional environmental and evolutionary success of microbes. Promoters,
      the cis-acting signals, are responsive to several stimuli related to growth,
      stress and substrate specificity. Their response is mediated by a wide variety of
      trans-acting regulators that sense the environment and the physiological state of
      the cell and adjust the transcription of specific genes. One of the main
      transcriptional regulation webs operates in the transition from affluent to
      barren conditions, with sigmaS being the chief actor in a company of players that
      stage a competition for the sparsely available RNA polymerase molecules. In this
      role, sigmaS may be assisted by several factors, including nucleoid-related
      proteins and metabolites. In addition, the levels of sigmaS itself are regulated
      by mechanisms that include inactivation and degradation. Several transcription
      factors, belonging to different regulatory pathways, may operate in the same
      promoter. In such a case, the final transcriptional output depends both on the
      interplay of effectors and on the properties of the recruitment of the effector
      RNA polymerase complex to the promoter. RNA polymerase itself is also capable of
      establishing selective interactions with activators and specific promoter regions
      through the carboxy-terminal domain of its alpha subunit (alphaCTD).
      Transcriptional regulation controls pervade such crucial events in the life of
      bacterial cells as Escherichia coli cell division, Bacillus subtilis sporulation
      and Caulobacter crescentus differentiation. These examples suggest that bacteria
      have been particularly inventive in adapting gene expression regulation to
      survive under a diversity of environments and have done so by exploiting the
      malleable molecular mechanisms involved in transcription, developing complexities
      that may match those found in eukaryotic cells.

PMID- 10411720
TI  - Differential fiu-lacZ fusion regulation linked to Escherichia coli colony
      development.
AB  - Colonies of strains carrying a stable lambdaplacMu15 translational fusion
      displayed sharply defined intense staining at the centre on Xgal medium. The
      fusion was in fiu (ferric ion uptake), encoding an iron-regulated outer membrane
      protein (IROMP) controlled via four overlapping ferric uptake regulator (Fur)
      boxes in the sigma70 promoter region. Fiu-LacZ was synthesized in low amounts (<
      1% of a transcriptional fiu:lacZ+ fusion), localized to membranes, and underwent
      processing from a large protein to one that co-migrated with native beta
      galactosidase. Intact cells synthesizing Fiu-LacZ often displayed greater
      enzymatic activity than permeabilized cells. The colony centre was insensitive to
      iron regulation observed in liquid cultures and at the colony edge. Within
      colonies grown on 36 microM iron citrate medium, fiu'-'lacZ protein fusion
      strains displayed 60-fold higher beta-galactosidase activity in the centre, and
      transcriptional fiu:lacZ+ fusion strains displayed a 10-fold centre/edge
      difference. On medium without added iron citrate, the centre/edge difference
      collapsed to < 2.2-fold for both translational and transcriptional fusions
      because activity at the edge was derepressed. Iron-insensitive fiu'-'lacZ
      expression in the colony centre occurred during a 6-18 h time window at the start
      of colony morphogenesis, corresponding to the initiation of multilayer
      microcolony development. A simple model for differential fiu'-'lacZ regulation is
      proposed whereby iron accessibility changes during colony morphogenesis.

PMID- 10411721
TI  - Co-ordinating DNA replication with cell division in bacteria: a link between the
      early stages of a round of replication and mid-cell Z ring assembly.
AB  - Spores of a thymine-requiring strain of Bacillus subtilis 168, which is also
      temperature sensitive for the initiation of chromosome replication, were
      germinated and allowed to grow out at the permissive temperature in a minimal
      medium containing no added thymine. Under these conditions, there was no or very
      limited progression into the elongation phase of the first round of replication.
      In a significant proportion of the outgrown cells, a Z ring formed precisely at
      mid-cell and over the centrally positioned nucleoid, leading eventually to the
      formation of a mature division septum. When initiation of the first round of
      replication was blocked through a temperature shift and with thymine present, the
      Z ring was positioned acentrally. The central Z ring that formed in the absence
      of thymine was blocked by the presence of a DNA polymerase III inhibitor. It is
      concluded that the very early stages of a round of replication (initiation plus
      possibly limited progression into the elongation phase) play a key role in the
      precise positioning of the Z ring at mid-cell and between replicating daughter
      chromosomes.

PMID- 10411723
TI  - The prepropeptide of vacuolar aminopeptidase I is necessary and sufficient to
      target the fluorescent reporter protein GFP to the vacuole of yeast by the Ccvt
      pathway.
AB  - We have studied the capacity of the prepro amino extension of vacuolar protease
      leucine aminopeptidase I (API) to target the fluorescent reporter protein GFP to
      the vacuole of yeast. The preproGFP chimera constructed by extending the amino
      end of GFP with the prepro-part of API is rapidly degraded in both wild-type WCG
      cells and WCG 11/21a cells deficient in the proteasome. In contrast, the chimera
      expressed in WCG-PP cells deficient in both proteasome activity and vacuolar
      proteinase A accumulates in the vacuole, where it remains stable. Replacement of
      Gly by Ile-7, a substitution that prevents folding of the pre-part into an
      amphipathic helix and inhibits the targeting of the API precursor to the vacuole,
      inhibits the targeting of preproGFP to the vacuole. The separated pre- and pro
      parts of the API precursor do not target GFP to the vacuole. Targeting of
      preproGFP to the vacuole is independent of its levels of expression, as the
      fluorescent protein localizes to the vacuole in cells expressing the protein
      under the control of both the GAL 1/10 or the API promoter. The preproGFP
      expressed under both promoters is recovered as monomers from cytosolic cell
      extracts. PreproGFP expressed under the API promoter is packed into cytoplasmic
      bodies that penetrate into the vacuolar lumen to release the protein. Altogether
      our results show that the prepro-part of the API precursor is necessary and
      sufficient to target the green fluorescent reporter protein to the vacuole.

PMID- 10411722
TI  - The extended promoters for two outer membrane lipoprotein genes of Borrelia spp.
      uniquely include a T-rich region.
AB  - OspA and B proteins of Borrelia burgdorferi and Vmp proteins of Borrelia hermsii
      are abundant outer membrane lipoproteins, whose expression varies with the
      environment. The genes for these proteins have the '-35' and '-10' elements of a
      sigma70-type promoter. Deletions of the promoters for these genes were analysed
      with a chloramphenicol acetyltransferase (CAT) reporter gene and plasmid
      constructs that were stably maintained in Escherichia coli or transiently
      transfected into B. burgdorferi. Reporter expression was measured as
      susceptibility of transformed E. coli cells to chloramphenicol and the CAT
      activity of E. coli and B. burgdorferi lysates in vitro. Presence of the '-10'
      element was essential for full activity in both B. burgdorferi and E. coli.
      Upstream of the '-35' elements of the ospAB and vmp promoters were tracts with Ts
      in 16 of 20 positions for B. burgdorferi and 18 of 20 positions for B. hermsii.
      Deletion of the T-rich region from the ospAB or vmp promoter caused a greater
      reduction of CAT activity in B. burgdorferi than in E. coli. The findings
      indicate that ospAB and vmp promoters are extended promoters with two parts: (i)
      a core region containing typical '-35' and '-10' elements and (ii) a unique T
      rich region.

PMID- 10411724
TI  - The aerobactin iron transport system genes in Shigella flexneri are present
      within a pathogenicity island.
AB  - Genes encoding the synthesis and transport of aerobactin, a hydroxamate
      siderophore associated with increased virulence of enteric bacteria, were mapped
      within a pathogenicity island in Shigella flexneri. The island, designated SHI-2
      for Shigella pathogenicity island 2, was located downstream of selC, the site of
      insertion of pathogenicity islands in several other enteric pathogens. DNA
      sequence analysis revealed the presence of multiple insertion sequences upstream
      and downstream of the aerobactin genes and an integrase gene that was nearly
      identical to an int gene found in Escherichia coli O157:H7. SHI-2 sequences
      adjacent to selC were similar to sequences at the junction between selC and
      pathogenicity islands found in E. coli O157:H7 and in enteropathogenic E. coli,
      but the junctions between the island and downstream yic genes were variable. SHI
      2 also encoded immunity to the normally plasmid-encoded colicins I and V,
      suggesting a common origin for the aerobactin genes in both S. flexneri and E.
      coli pColV. Polymerase chain reaction and Southern hybridization data indicate
      that SHI-2 is present in the same location in Shigella sonnei, but the aerobactin
      genes are not located within SHI-2 in Shigella boydii or enteroinvasive E. coli.
      Shigella dysenteriae type 1 strains do not produce aerobactin but do contain
      sequences downstream of selC that are homologous to SHI-2. The presence of the
      aerobactin genes on plasmids in E. coli pColV and Salmonella, on a pathogenicity
      island in S. flexneri and S. sonnei and in a different chromosomal location in S.
      boydii and some E. coli suggests that these virulence-enhancing genes are mobile,
      and they may constitute an island within an island in S. flexneri.

PMID- 10411725
TI  - The selC-associated SHI-2 pathogenicity island of Shigella flexneri.
AB  - Pathogenicity islands are chromosomal gene clusters, often located adjacent to
      tRNA genes, that encode virulence factors present in pathogenic organisms but
      absent or sporadically found in related non-pathogenic species. The selC tRNA
      locus is the site of integration of different pathogenicity islands in
      uropathogenic Escherichia coli, enterohaemorrhagic E. coli and Salmonella
      enterica. We show here that the selC locus of Shigella flexneri, the aetiological
      agent of bacterial dysentery, also contains a pathogenicity island. This
      pathogenicity island, designated SHI-2 (Shigella island 2), occupies 23.8 kb
      downstream of selC and contains genes encoding the aerobactin iron acquisition
      siderophore system, colicin V immunity and several novel proteins. Remnants of
      multiple mobile genetic elements are present in SHI-2. SHI-2-hybridizing
      sequences were detected in all S. flexneri strains tested and parts of the island
      were also found in other Shigella species. SHI-2 may allow Shigella survival in
      stressful environments, such as those encountered during infection.

PMID- 10411726
TI  - Selection of the midcell division site in Bacillus subtilis through MinD
      dependent polar localization and activation of MinC.
AB  - Bacterial cell division commences with the assembly of the tubulin-like protein,
      FtsZ, at midcell to form a ring. Division site selection in rod-shaped bacteria
      is mediated by MinC and MinD, which form a division inhibitor. Bacillus subtilis
      DivIVA protein ensures that MinCD specifically inhibits division close to the
      cell poles, while allowing division at midcell. We have examined the localization
      of MinC protein and show that it is targeted to midcell and retained at the
      mature cell poles. This localization is reminiscent of the pattern previously
      described for MinD. Localization of MinC requires both early (FtsZ) and late
      (PbpB) division proteins, and it is completely dependent on MinD. The effects of
      a divIVA mutation on localization of MinC now suggest that the main role of
      DivIVA is to retain MinCD at the cell poles after division, rather than
      recruitment to nascent division sites. By overexpressing minC or minD, we show
      that both proteins are required to block division, but that only MinD needs to be
      in excess of wild-type levels. The results suggest a mechanism whereby MinD is
      required both to pilot MinC to the cell poles and to constitute a functional
      division inhibitor.

PMID- 10411727
TI  - A putative two-component signal transduction system regulates sigmaE, a sigma
      factor required for normal cell wall integrity in Streptomyces coelicolor A3(2).
AB  - The extracytoplasmic function (ECF) sigma factor, sigmaE, is required for normal
      cell wall integrity in Streptomyces coelicolor. We have investigated the
      regulation of sigmaE through a transcriptional and mutational analysis of sigE
      and the surrounding genes. Nucleotide sequencing identified three genes located
      downstream of sigE; orf202, cseB and cseC (cse, control of sigE ). cseB and cseC
      encode a putative response regulator and a putative transmembrane sensor
      histidine protein kinase respectively. Although most sigE transcription appeared
      to be monocistronic, sigE was also transcribed as part of a larger operon,
      including at least orf202. sigE null mutants are sensitive to cell wall lytic
      enzymes, have an altered peptidoglycan muropeptide profile, and on medium
      deficient in Mg2+ they overproduce actinorhodin, sporulate poorly and form
      crenellated colonies. A constructed cseB null mutant appeared to have the same
      phenotype as a sigE null mutant, which was accounted for by the observed absolute
      dependence of the sigE promoter on cseB. It is likely that the major role of cseB
      is to regulate sigE transcription because expression of sigE alone from a
      heterologous promoter suppressed the cseB mutation. Mg2+ suppresses the CseB/SigE
      phenotype, probably by stabilizing the cell envelope, and sigE transcript levels
      were consistently higher in Mg2+-deficient cultures than in high Mg2+-grown
      cultures. We propose a model in which the CseB/CseC two-component system
      modulates activity of the sigE promoter in response to signals from the cell
      envelope.

PMID- 10411728
TI  - The 5' region of cnf1 harbours a translational regulatory mechanism for CNF1
      synthesis and encodes the cell-binding domain of the toxin.
AB  - The Escherichia coli cytotoxic necrotizing factor 1 (CNF1) is organized into
      three functional domains: the N-terminal part containing the cell-binding domain,
      a putative central membrane-spanning region, and a C-terminal catalytic region.
      On the basis of competition assays between CNF1 and GST-recombinant proteins
      containing different N-terminal fragments, and point mutations, we restricted the
      binding region to the first 190 amino acids. Hydrophilic amino acids 53-75 are
      strictly necessary to cell receptor recognition. Using different cnf1-lacZ
      translational fusions, we demonstrated that the mRNA corresponding to the first
      48 codons of cnf1 is involved in the translational regulation of CNF1 synthesis.
      This regulation consists of both a positive and a negative control. The positive
      control is exerted by codons 6-20, including a putative downstream box that
      enhances the translational expression of cnf1. The negative control depends on
      codons 45-48. In this region, an anti-Shine-Dalgarno sequence, highly homologous
      to the core of the internal complementary sequence already reported for growth
      rate-regulated metabolic genes, has been detected. To some extent, the inner
      structural organization of CNF1 would thus suggest the compiling of several
      functions in a single mRNA protein system.

PMID- 10411729
TI  - Intracistronic transcription termination in polysialyltransferase gene (siaD )
      affects phase variation in Neisseria meningitidis.
AB  - Expression of serogroup B meningococcal capsular polysaccharide is subject to
      frequent phase variation. A reversible +1/-1 frameshift mutation within a
      poly(dC) repeat altering the reading frame of the polysialyltransferase gene
      (siaD ), thereby causing premature arrest of translation, is responsible for loss
      of capsule expression. After analysis of transcription of the siaD gene from an
      encapsulated strain and from two unencapsulated derivatives, we have found that
      the siaD mRNA in the unencapsulated strains is reduced in size as a result of
      premature transcription termination at a cryptic Rho-dependent site within the
      proximal region of the siaD cistron. Termination is sensitive to bicyclomycin, a
      natural inhibitor of Rho activity. Bicyclomycin decreased the rates of capsule re
      expression (off-on) without affecting the rates of loss of capsule expression (on
      off). This finding suggested the existence of a novel mechanism linking
      transcription elongation termination and mutation frequency. A genetic system was
      therefore developed to measure phase variation of siaD-ermC' gene fusions in wild
      type and Rho-defective Escherichia coli strains. These studies demonstrated that
      in the Rho-defective E. coli strain readthrough transcription of the mutated siaD
      gene caused a fourfold lower off-on phase variation rate than in the congenic
      Rho+ strain. Analysis of phase variation of siaD-ermC' gene fusions in a DNA
      mismatch-defective E. coli strain suggests that the effect of transcription on
      mutation rates required a functional mismatch repair system.

PMID- 10411730
TI  - The molecular characterization of the first autolytic lysozyme of Streptococcus
      pneumoniae reveals evolutionary mobile domains.
AB  - A biochemical approach to identify proteins with high affinity for choline
      containing pneumococcal cell walls has allowed the localization, cloning and
      sequencing of a gene (lytC ) coding for a protein that degrades the cell walls of
      Streptococcus pneumoniae. The lytC gene is 1506 bp long and encodes a protein
      (LytC) of 501 amino acid residues with a predicted M r of 58 682. LytC has a
      cleavable signal peptide, as demonstrated when the mature protein (about 55 kDa)
      was purified from S. pneumoniae. Biochemical analyses of the pure, mature protein
      proved that LytC is a lysozyme. Combined cell fractionation and Western blot
      analysis showed that the unprocessed, primary product of the lytC gene is located
      in the pneumococcal cytoplasm whereas the processed, active form of LytC is
      tightly bound to the cell envelope. In vivo experiments demonstrated that this
      lysozyme behaves as a pneumococcal autolytic enzyme at 30 degrees C. The DNA
      region encoding the 253 C-terminal amino acid residues of LytC has been cloned
      and expressed in Escherichia coli. The truncated protein exhibits a low, but
      significant, choline-independent lysozyme activity, which suggests that this
      polypeptide adopts an active conformation. Self-alignment of the N-terminal part
      of the deduced amino acid sequence of LytC revealed the presence of 11 repeated
      motifs. These results strongly suggest that the lysozyme reported here has
      changed the general building plan characteristic of the choline-binding proteins
      of S. pneumoniae and its bacteriophages, i.e. the choline-binding domain and the
      catalytic domain are located, respectively, at the N-terminal and the C-terminal
      moieties of LytC. This work illustrates the natural versatility exhibited by the
      pneumococcal genes coding for choline-binding proteins to fuse separated
      catalytic and substrate-binding domains and create new and functional mature
      proteins.

PMID- 10411731
TI  - Characterization of SprA, an AraC-like transcriptional regulator encoded within
      the Salmonella typhimurium pathogenicity island 1.
AB  - Pathogenicity island 1 (SPI-1) located at centisome 63 of the Salmonella
      chromosome encodes a type III protein secretion system that is essential for its
      pathogenicity. The translocation of effector proteins through this system results
      in the stimulation of signalling events, leading to actin cytoskeletal
      rearrangements and nuclear responses. These cellular responses ultimately lead to
      bacterial uptake, production of proinflammatory cytokines in non-phagocytic cells
      and the initiation of programmed cell death in macrophages. The regulation of
      expression of components and substrates of this type III secretion system is
      complex and involves the activity of several specific transcriptional regulatory
      proteins encoded within SPI-1. Here, we describe two additional regulatory
      proteins, SprA and SprB, which are encoded within SPI-1. SprA and SprB exhibit
      significant sequence similarity to the AraC/XylS and the LuxR/UhaP family of
      transcriptional regulatory proteins respectively. Insertion mutations in sprA and
      sprB did not significantly affect the transcription of invasion-associated genes
      and, consequently, did not affect the ability of Salmonella typhimurium to gain
      access into host cells. However, expression of sprA from an inducible
      heterologous promoter resulted in increased expression of genes associated with
      the centisome 63 type III secretion system and increased the ability of S.
      typhimurium to enter into host cells. Further analysis demonstrated that SprA
      acts either upstream or at the same level as HilA in the SPI-1 transcriptional
      regulatory cascade.

PMID- 10411732
TI  - Autoactivation and environmental regulation of bfpT expression, the gene coding
      for the transcriptional activator of bfpA in enteropathogenic Escherichia coli.
AB  - Expression of bfpA, the gene coding for the structural subunit of the bundle
      forming pili (BFP) in enteropathogenic Escherichia coli (EPEC), requires the
      product of bfpT (also called perA), a member of the AraC family of
      transcriptional regulators. Here, we show that bfpT-cat fusions were not
      expressed in a bfpT - or in a non-EPEC strain, unless a functional bfpT was
      present, indicating that an autoregulatory mechanism is involved in expression.
      Further experiments with bfpT-cat fusions and primer extension analysis showed
      that bfpT is transcribed from a conventional sigma-70 promoter and that it is
      expressed throughout the growth curve. It is regulated in response to the
      ammonium concentration, temperature and growth media, in the same proportions as
      those described previously for bfpA. In addition, bfpT and bfpA expression was
      also modulated by osmolarity, but was not affected by pH, iron excess or
      limitation. Deletion analysis of the bfpT upstream region revealed that a DNA
      segment of 81 bp, extending upstream from the transcriptional start site,
      contained all the sequence elements required for maximal expression of bfpT.
      Furthermore, it shares significant homology with a bfpA upstream AT-rich region,
      which has been shown to be involved in the BfpT-dependent regulation of bfpA.
      Interestingly, ammonium repression was observed only when bfpT-cat or bfpA-cat
      expression was complemented in an EPEC background, whereas low-temperature
      regulation was observed in both EPEC and non-EPEC strains. This suggests that
      specific regulatory elements are present in EPEC, while others are shared with
      non-pathogenic E. coli.

PMID- 10411733
TI  - Inducible prophages contribute to Salmonella virulence in mice.
AB  - We show that Salmonella typhimurium harbours two fully functional prophages,
      Gifsy-1 and Gifsy-2, that can be induced by standard treatments or, more
      effectively, by exposing bacteria to hydrogen peroxide. Curing bacteria for the
      Gifsy-2 prophage significantly reduces Salmonella's ability to establish a
      systemic infection in mice. Cured strains recover their virulence properties upon
      relysogenization. Phage Gifsy-2 carries the sodC gene for a periplasmic [Cu,Zn]
      superoxide dismutase previously implicated in the bacterial defences against
      killing by macrophages. The contribution of the Gifsy-1 prophage to virulence -
      undetectable in the presence of Gifsy-2 as prophage - becomes significant in
      cells that lack Gifsy-2 but carry the sodC gene integrated in the chromosome.
      This confirms the involvement of Gifsy-2-encoded SodC protein in Salmonella
      pathogenicity and suggests that the Gifsy-1 prophage carries one or more
      additional virulence genes that have a functional equivalent on the Gifsy-2
      genome.

PMID- 10411734
TI  - Glucose metabolism in Chlamydia trachomatis: the 'energy parasite' hypothesis
      revisited.
AB  - Chlamydia trachomatis is an obligate intracellular eubacteria that is dependent
      on a eukaryotic host cell for a variety of metabolites. For years, it has been
      speculated that chlamydiae are energy parasites, totally dependent on their host
      cell for ATP and other high-energy intermediates. To determine whether C.
      trachomatis contains functional enzymes that produce energy or reducing power,
      four enzymes involved in glycolysis or the pentose phosphate pathway,
      specifically pyruvate kinase, phosphoglycerate kinase, glyceraldehyde-3-phosphate
      dehydrogenase and glucose-6-phosphate dehydrogenase, were cloned, sequenced and
      expressed as recombinant proteins in Escherichia coli. The deduced amino acid
      sequences obtained show high homology to other pyruvate kinase, phosphoglycerate
      kinase, glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate
      dehydrogenase enzymes. In contrast to numerous other bacterial species,
      chlamydial glycolytic genes are not arranged in an operon, but are dispersed
      throughout the genome. Results from reverse transcriptase-polymerase chain
      reaction (RT-PCR) analysis indicate that all four genes are maximally expressed
      in the middle of the chlamydial developmental cycle. The chlamydial genes are
      capable of complementing mutant E. coli strains lacking the respective enzyme
      activities. In vitro enzyme analysis indicates that recombinant chlamydial
      enzymes expressed in E. coli are active and, interestingly, recombinant
      chlamydial pyruvate kinase is not regulated allosterically by fructose 1,6
      bisphosphate or AMP, as found with other bacterial pyruvate kinases. In summary,
      identification and characterization of these glucose-catabolizing enzymes
      indicate that chlamydia contains the functional capacity to produce its own ATP
      and reducing power.

PMID- 10411735
TI  - The C-terminal half of RNase E, which organizes the Escherichia coli degradosome,
      participates in mRNA degradation but not rRNA processing in vivo.
AB  - RNase E is an essential Escherichia coli endonuclease, which controls both 5S
      rRNA maturation and bulk mRNA decay. While the C-terminal half of this 1061
      residue protein associates with polynucleotide phosphorylase (PNPase) and several
      other enzymes into a 'degradosome', only the N-terminal half, which carries the
      catalytic activity, is required for growth. We characterize here a mutation
      (rne131 ) that yields a metabolically stable polypeptide lacking the last 477
      residues of RNAse E. This mutation resembles the N-terminal conditional mutation
      rne1 in stabilizing mRNAs, both in bulk and individually, but differs from it in
      leaving rRNA processing and cell growth unaffected. Another mutation (rne105 )
      removing the last 469 residues behaves similarly. Thus, the C-terminal half of
      RNase E is instrumental in degrading mRNAs, but dispensable for processing rRNA.
      A plausible interpretation is that the former activity requires that RNase E
      associates with other degradosome proteins; however, PNPase is not essential, as
      RNase E remains fully active towards mRNAs in rne+pnp mutants. All mRNAs are not
      stabilized equally by the rne131 mutation: the greater their susceptibility to
      RNase E, the larger the stabilization. Artificial mRNAs generated by E. coli
      expression systems based on T7 RNA polymerase can be genuinely unstable, and we
      show that the mutation can improve the yield of such systems without compromising
      cell growth.

PMID- 10411736
TI  - ZntR is an autoregulatory protein and negatively regulates the chromosomal zinc
      resistance operon znt of Staphylococcus aureus.
AB  - A chromosomally encoded znt operon of Staphylococcus aureus consists of two
      consecutive putative genes designated zntR and zntA. The zntA gene encodes a
      transmembrane protein that facilitates extrusion of Zn2+ and Co2+, whereas the
      zntR gene encodes a putative regulatory protein that controls the expression of
      the znt operon. The zntR gene was amplified using the polymerase chain reaction,
      cloned into Escherichia coli for overexpression as His-tagged ZntR and purified
      by Ni2+-affinity column. His-tag-free ZntR was purified to near homogeneity after
      digestion with enterokinase. Electrophoretic mobility shift assays (EMSAs)
      indicated that the ZntR bound to a fragment of DNA corresponding to the
      chromosomal znt promoter region with an affinity of about 8.0 x 10-12 M. The
      addition of 25 microM Zn2+ or Co2+ in the binding reaction completely or
      significantly inhibited association of ZntR with the znt promoter. DNase I
      footprinting assays identified a ZntR binding site encompassing 49 nucleotides in
      the znt promoter region that contained repeated TGAA sequences. These sequences
      have been proposed to be the binding sites for SmtB, a metallorepressor protein
      from the cyanobacterium Synechococcus, to its corresponding operator/promoter. In
      vitro transcription assays, using S. aureus RNA polymerase, revealed that ZntR
      represses transcription from the znt promoter in a concentration-dependent
      fashion. The EMSAs, DNase I footprinting and in vitro transcription assays
      indicate that ZntR is a trans-acting repressor protein that binds to the znt
      promoter region and regulates its own transcription together with that of zntA.

PMID- 10411737
TI  - The R28 protein of Streptococcus pyogenes is related to several group B
      streptococcal surface proteins, confers protective immunity and promotes binding
      to human epithelial cells.
AB  - The R28 protein is a surface molecule expressed by some strains of Streptococcus
      pyogenes (group A streptococcus). Here, we present evidence that R28 may play an
      important role in virulence. Sequence analysis demonstrated that R28 has an
      extremely repetitive sequence and can be viewed as a chimera derived from the
      three surface proteins Rib, alpha and beta of the group B streptococcus (GBS).
      Thus, the gene encoding R28 may have originated in GBS. The R28 protein promotes
      adhesion to human epithelial cells, as shown by experiments with an R28-negative
      mutant and by the demonstration that antibodies to highly purified R28 inhibited
      adhesion. In a mouse model of lethal intraperitoneal S. pyogenes infection,
      antibodies to R28 conferred protective immunity. However, the virulence of an R28
      negative mutant was similar to that of the parental strain in the intraperitoneal
      infection model. Together, these data indicate that R28 represents a novel type
      of adhesin expressed by S. pyogenes and that R28 may also act as a target for
      protective antibodies at later stages of an infection. We consider the hypothesis
      that R28 played a pathogenetic role in the well-known epidemics of childbed fever
      (puerperal fever), which were caused by S. pyogenes. A role for R28 in these
      epidemics is suggested by epidemiological data.

PMID- 10411739
TI  - A conserved motif in the hexosyltransferases.

PMID- 10411738
TI  - MutK may be a 32 kDa protein and be widespread among proteobacteria.

PMID- 10411740
TI  - Intramolecular transposition of insertion sequence IS91 results in second-site
      simple insertions.
AB  - A series of plasmids carrying an IRL-kan-IRR transposable cassette, in which IRL
      and IRR are the left- and right-terminal sequences of IS91, have been
      constructed. These cassettes could be complemented for transposition with similar
      efficiency when IS91 transposase was provided either in cis or in trans. A total
      of 87% of IS91 transposition products were simple insertions of the element,
      while the remaining 13% were plasmid fusions and co-integrates. When transposase
      expression was induced from an upstream lac promoter, transposition frequency
      increased approximately 100-fold. An open reading frame (ORF) present upstream of
      the transposase gene, ORF121, could be involved in target selection, as mutations
      affecting this ORF were altered in their insertion specificity. Intramolecular
      rearrangements were analysed by looking at transposition events disrupting a
      chloramphenicol resistance gene (cat ) located outside the transposable cassette.
      Plasmid instability resulting from insertion of an extra copy of IRL-kan-IRR
      within the cat gene was observed; transposition products contained a second copy
      of the cassette inserted either as a direct or as an inverted repeat. No deletion
      or inversion of the intervening DNA was observed. These results could be
      explained as a consequence of intramolecular transposition of IS91 according to a
      model of rolling-circle transposition.

PMID- 10411741
TI  - A novel mutation in the KH domain of polynucleotide phosphorylase affects
      autoregulation and mRNA decay in Escherichia coli.
AB  - Polynucleotide phosphorylase (PNPase) is a key 3'-5' exonuclease for mRNA decay
      in bacteria. Here, we report the isolation of a novel mutant of Escherichia coli
      PNPase that affects autogenous control and mRNA decay. We show that the
      inactivation of PNPase by a transposon insertion increases the half-life of
      galactokinase mRNA encoded by a plasmid. When the bacteriophage lambda int gene
      retroregulator (sib/tI ) is placed between pgal and galK, it severely diminishes
      galactokinase expression because of transcription termination. The expression of
      galK from this construct is increased by a single base mutation, sib1, which
      causes a partial readthrough of transcription at tI. We have used this plasmid
      system with sib1 to select E. coli mutants that depress galK expression. Genetic
      and molecular analysis of one such mutant revealed that it contains a mutation in
      the pnp gene, which encodes the PNPase catalytic subunit alpha. The mutation
      responsible (pnp-71 ) has substituted a highly conserved glycine residue in the
      KH domain of PNPase with aspartate. We show that this G-570D substitution causes
      a higher accumulation of the alpha-subunit as a result of defective
      autoregulation, thereby increasing the PNPase activity in the cell. The purified
      mutant alpha-subunit shows the same electrophoretic mobility in denaturing gels
      as the wild-type subunit, as expected. However, the mutant protein present in
      crude extracts displays an altered electrophoretic mobility in non-denaturing
      gels that is indicative of a novel enzyme complex. We present a model for how the
      pnp-71 mutation might affect autoregulation and mRNA decay based on the
      postulated role of the KH domain in RNA-protein and protein-protein interactions.

PMID- 10411742
TI  - Membrane cyclopropane fatty acid content is a major factor in acid resistance of
      Escherichia coli.
AB  - Cyclopropane fatty acid (CFA) formation is a post-synthetic modification of the
      lipid bilayer that occurs as cultures of Escherichia coli and many other bacteria
      enter stationary phase. We report the first distinct phenotype for this membrane
      modification; early stationary phase cultures of strains lacking CFA (as a result
      of a null mutation in the cfa gene) are abnormally sensitive to killing by a
      rapid shift from neutral pH to pH 3. This sensitivity to acid shock is dependent
      on CFA itself because resistance to acid shock is restored to cfa mutant strains
      by incorporation of CFAs from the growth medium or by introduction of a
      functional cfa gene on a plasmid. The synthesis of CFA depends in part on the
      RpoS sigma factor, but the role of RpoS in resistance to acid shock involves
      additional factors because strains with null mutations in both cfa and rpoS are
      more sensitive to acid shock than either single mutant strain. Exponential phase
      cultures of E. coli are much more sensitive to acid shock than stationary phase
      cultures, but survival is greatly increased if the exponential phase cultures are
      exposed to moderately acid conditions (pH 5) before shift to pH 3. We show that
      exposure to moderately acid conditions gives a marked increase in cfa
      transcription. The efficiency of the survival of acid shock is extremely strain
      dependent, even among putative wild-type strains. Much, but not all, of this
      variability can be explained by the partially or totally defective RpoS alleles
      carried by many strains.

PMID- 10411743
TI  - Expression of the phosphotransferase system both mediates and is mediated by Mlc
      regulation in Escherichia coli.
AB  - The ptsHIcrr operon encodes the cytoplasmic components of the phosphotransferase
      system (PTS). It is expressed from two major promoters, of which the upstream
      promoter has previously been shown to be induced by glucose and to be dependent
      upon cAMP/CAP. This promoter is now shown to be repressed by Mlc. Mlc is a
      transcriptional regulator controlling, among others, the gene ptsG, encoding
      EIICBGlc, the glucose-specific transporter of the PTS. Transcription of ptsH p0
      and ptsG are subject to the same regulatory pattern. In addition to induction by
      glucose and repression by Mlc, mutations in ptsHIcrr, which interrupt the PEP
      dependent phosphate transfer through the soluble components of the PTS, lead to
      high expression of both ptsH and ptsG, while mutations inactivating EIIBCGlc are
      non-inducible. Mutations in mlc lead to high constitutive expression and are
      dominant, implying that Mlc is the ultimate regulator of ptsHI and ptsG
      expression. Growth on other PTS sugars, besides glucose, also induces ptsH and
      ptsG expression, suggesting that the target of Mlc regulation is the PTS.
      However, induction by these other sugars is only observed in the presence of
      ptsG+, thus confirming the importance of glucose and EIICBGlc in the regulation
      of the PTS. The ptsG22 mutation, although negative for glucose transport, shows a
      weak positive regulatory phenotype. The mutation has been sequenced and its
      effect on regulation investigated.

PMID- 10411744
TI  - The heat shock response in yeast: differential regulations and contributions of
      the Msn2p/Msn4p and Hsf1p regulons.
AB  - The heat shock transcription factor Hsf1p and the stress-responsive transcription
      factors Msn2p and Msn4p are activated by heat shock in the yeast Saccharomyces
      cerevisiae. Their respective contributions to heat shock protein induction have
      been analysed by comparison of mutants and wild-type strains using [35S]
      methionine labelling and two-dimensional gel electrophoresis. Among 52 proteins
      induced by a shift from 25 degrees C to 38 degrees C, half of them were found to
      be dependent upon Msn2p and/or Msn4p (including mostly antioxidants and enzymes
      involved in carbon metabolism), while the other half (including mostly chaperones
      and associated proteins) were dependent upon Hsf1p. The two sets of proteins
      overlapped only slightly. Three proteins were induced independently of these
      transcription factors, suggesting the involvement of other transcription
      factor(s). The Ras/cAMP/PKA signalling pathway cAMP had a negative effect on the
      induction of the Msn2p/Msn4p regulon, but did not affect the Hsf1p regulon. Thus,
      the two types of transcription factor are regulated differently and control two
      sets of functionally distinct proteins, suggesting two different physiological
      roles in the heat shock cellular response.

PMID- 10411745
TI  - TorC apocytochrome negatively autoregulates the trimethylamine N-oxide (TMAO)
      reductase operon in Escherichia coli.
AB  - The trimethylamine N-oxide (TMAO) anaerobic respiratory system of Escherichia
      coli comprises a periplasmic terminal TMAO reductase (TorA) and a pentahaem c
      type cytochrome (TorC), which is involved in electron transfer to TorA. The
      structural proteins are encoded by the torCAD operon whose expression is induced
      in the presence of TMAO through the TorS/TorR two-component system. By using a
      genomic library cloned into a multicopy plasmid, we identified TorC as a possible
      negative regulator of the tor operon. Interestingly, in trans overexpression of
      torC not only decreased the activity of a torA'-'lacZ fusion, but also
      dramatically reduced the amount of mature TorC cytochrome. This led us to propose
      that, after translocation, TorC apocytochrome downregulates the tor operon unless
      it is properly matured. In agreement with this hypothesis, we have shown that
      mini-Tn10 insertions within genes involved in the c-type cytochrome maturation
      pathway or haem biosynthesis decreased tor operon expression. Dithiothreitol
      (DTT), which reduces disulphide bonds and thus prevents the first step in c-type
      cytochrome formation, also strongly decreases the tor promoter activity. The DTT
      effect is TorC dependent, as it is abolished when torC is disrupted. In contrast,
      overexpression of the c-type cytochrome maturation (ccm ) genes relieved the tor
      operon of the negative control and allowed the bacteria to produce a higher
      amount of TorC holocytochrome. Therefore, the TorC negative autoregulation
      probably means that maturation of the c-type cytochrome is a limiting step for
      Tor system biogenesis. Genetic experiments have provided evidence that TorC
      control is mediated by the TorS/TorR two-component system and different from the
      tor anaerobic control. In our working model, TMAO and apoTorC bind to the
      periplasmic side of TorS, but TMAO activates TorS autophosphorylation, whereas
      apoTorC inhibits the TorS kinase activity.

PMID- 10411746
TI  - The Per regulon of enteropathogenic Escherichia coli : identification of a
      regulatory cascade and a novel transcriptional activator, the locus of enterocyte
      effacement (LEE)-encoded regulator (Ler).
AB  - Enteropathogenic Escherichia coli (EPEC) is the prototype organism of a group of
      pathogenic Gram-negative bacteria that cause attaching and effacing (AE)
      intestinal lesions. All EPEC genes necessary for the AE phenotype are encoded
      within a 35.6 kb pathogenicity island termed the locus of enterocyte effacement
      (LEE). The LEE encodes 41 predicted open reading frames (ORFs), including
      components of a type III secretion apparatus and secreted molecules involved in
      the disruption of the host cell cytoskeleton. To initiate our studies on
      regulation of genes within the LEE, we determined the genetic organization of the
      LEE, defining transcriptional units and mapping transcriptional start points. We
      found that components of the type III secretion system are transcribed from three
      polycistronic operons designated LEE1, LEE2 and LEE3. The secreted Esp molecules
      are part of a fourth polycistronic operon designated LEE4. Using reporter gene
      fusion assays, we found that the previously described plasmid-encoded regulator
      (Per) activated operons LEE1, LEE2 and LEE3, and modestly increased the
      expression of LEE4 in EPEC. Using single-copy lacZ fusions in K-12-derived
      strains, we determined that Per only directly activated the LEE1:lacZ fusion, and
      did not directly activate the other operons. Orf1 of the LEE1 operon activated
      the expression of single-copy LEE2:lacZ and LEE3:lacZ fusions in trans and
      modestly increased the expression of LEE4:lacZ in K-12 strains. Orf1 was
      therefore designated Ler, for LEE-encoded regulator. Thus, the four polycistronic
      operons of the LEE that encode type III secretion components and secreted
      molecules are now included in the Per regulon, where Ler participates in this
      novel regulatory cascade in EPEC.

PMID- 10411747
TI  - Characterization of the SarA virulence gene regulator of Staphylococcus aureus.
AB  - Staphylococcus aureus is a potent human pathogen that expresses a large number of
      virulence factors in a temporally regulated fashion. Two pleiotropically acting
      regulatory loci were identified in previous mutational studies. The agr locus
      comprises two operons that express a quorum-sensing system from the P2 promoter
      and a regulatory RNA molecule from the P3 promoter. The sar locus encodes a DNA
      binding protein that activates the expression of both agr operons. We have cloned
      the sarA gene, expressed SarA in Escherichia coli and purified the recombinant
      protein to apparent homogeneity. The purified protein was found to be dimeric in
      the presence and absence of DNA and to consist mostly of alpha-helices. DNase I
      footprinting of SarA on the putative regulatory region cis to the agr promoters
      revealed three high-affinity binding sites composed of two half-sites each.
      Quantitative electrophoretic mobility shift assays (EMSAs) were used to derive
      equilibrium binding constants (KD) for the interaction of SarA with these binding
      sites. An unusual ladder banding pattern was observed in EMSA with a large DNA
      fragment including all three binding sites. Our data indicate that SarA
      regulation of the agr operons involves binding to multiple half-sites and may
      involve other sites located downstream of the promoters.

PMID- 10411749
TI  - Antisense inhibition of expression of the light subunit (35 kDa) of the
      Gal/GalNac lectin complex inhibits Entamoeba histolytica virulence.
AB  - One of the under-represented genes identified by cDNA representational difference
      analysis (RDA) between avirulent Entamoeba histolytica strain Rahman and virulent
      strain HM-1:IMSS was the amoebic light (35 kDa) subunit of the Gal/GalNac lectin
      complex. This lectin complex, which mediates the adhesion of the parasite to the
      target cell, also contains a heavy (170 kDa) subunit, which has the carbohydrate
      binding domain. Stable transfectants of the virulent strain in which the
      expression of the 35 kDa subunit was inhibited by antisense RNA were not
      significantly affected in their adhesion activity to mammalian or bacterial cells
      but were strongly inhibited in their cytopathic activity, cytotoxic activity and
      in their ability to induce the formation of liver lesions in hamsters. These
      findings suggest that the 35 kDa subunit may have a specific function in the
      pathogenic pathway and provides a new insight into the role of this component of
      the Gal/GalNac lectin complex in amoebic virulence.

PMID- 10411748
TI  - The Staphylococcal accessory regulator (sar) represses transcription of the
      Staphylococcus aureus collagen adhesin gene (cna) in an agr-independent manner.
AB  - Comparison of Staphylococcus aureus strains carrying mutations inactivating the
      staphylococcal accessory regulator (sar ) and/or the accessory gene regulator
      (agr ) suggests that sar is the primary regulatory element controlling
      transcription of the collagen adhesin gene (cna ) and that the regulatory effect
      of sar is independent of the interaction between SarA and agr. To test this
      hypothesis, we cloned the regions encoding each of the overlapping sar
      transcripts, all of which include the sarA open reading frame (ORF), and
      introduced each clone into cna-positive sar and agr mutants. The introduction of
      each clone restored the expected sar transcripts and the temporal pattern of sar
      transcription. The introduction of each clone also complemented the defect in cna
      transcription and restored collagen binding to wild-type levels. This was true
      even when the clones were introduced into a sar/agr double mutant. These results
      confirm the hypothesis that the sar-mediated regulation of cna transcription
      occurs via an agr-independent pathway. Direct evidence supporting this hypothesis
      comes from electrophoretic mobility shift assays demonstrating that SarA exhibits
      high-affinity binding to cis elements upstream of the cna structural gene. We
      also examined the correlation between sar transcription and the production of
      SarA. Western blot analysis of two wild-type strains indicated that SarA was
      produced in indistinguishable amounts during both the exponential and the post
      exponential growth phases.

PMID- 10411750
TI  - Heterotrimerization of PII-like signalling proteins: implications for PII
      mediated signal transduction systems.
AB  - PII-like signalling molecules are trimeric proteins composed of 12-13 kDa
      polypeptides encoded by the glnB gene family. Heterologous expression of a
      cyanobacterial glnB gene in Escherichia coli leads to an inactivation of E.
      coli's own PII signalling system. In the present work, we show that this effect
      is caused by the formation of functionally inactive heterotrimers between the
      cyanobacterial glnB gene product and the E. coli PII paralogues GlnB and GlnK.
      This led to the discovery that GlnK and GlnB of E. coli also form heterotrimers
      with each other. The influence of the oligomerization partner on the function of
      the single subunit was studied using heterotrimerization with the Synechococcus
      PII protein. Uridylylation of GlnB and GlnK was less efficient but still possible
      within these heterotrimers. In contrast, the ability of GlnB-UMP to stimulate the
      adenylyl-removing activity of GlnE (glutamine synthetase
      adenylyltransferase/removase) was almost completely abolished, confirming that
      rapid deadenylylation of glutamine synthetase upon nitrogen stepdown requires
      functional homotrimeric GlnB protein. Remarkably, however, rapid adenylylation of
      glutamine synthetase upon exposing nitrogen-starved cells to ammonium was shown
      to occur in the absence of a functional GlnB/GlnK signalling system as
      efficiently as in its presence.

PMID- 10411751
TI  - Cloning and allelic exchange mutagenesis of two flagellin genes of Helicobacter
      felis.
AB  - Helicobacter felis has been used extensively in animal model studies of gastric
      Helicobacter infections. Attempts to manipulate H. felis genetically have,
      however, been unsuccessful and, consequently, little is known about the
      pathogenic mechanisms of this bacterium. In common with other Helicobacter spp.,
      H. felis is a highly motile organism. To characterize the flagellar structures
      responsible for this motility, we cloned and sequenced the two flagellin-encoding
      genes, flaA and flaB, from H. felis. These genes encode two flagellin proteins
      that are expressed simultaneously under the control of putative sigma28 and
      sigma54 promoters respectively. Isogenic mutants of H. felis in flaA and flaB
      were generated by electroporation-mediated allelic disruption and replacement,
      showing for the first time that H. felis could be manipulated genetically. Both
      types of H. felis flagellin mutants exhibited truncated flagella and were poorly
      motile. H. felis flaA mutants were unable to colonize the gastric mucosa in a
      mouse infection model.

PMID- 10411752
TI  - A mutation in Saccharomyces cerevisiae adenylate cyclase, Cyr1K1876M,
      specifically affects glucose- and acidification-induced cAMP signalling and not
      the basal cAMP level.
AB  - In the yeast Saccharomyces cerevisiae, the addition of glucose to derepressed
      cells and intracellular acidification trigger a rapid increase in the cAMP level
      within 1 min. We have identified a mutation in the genetic background of several
      related 'wild-type' laboratory yeast strains (e.g. ENY.cat80-7A, CEN.PK2-1C) that
      largely prevents both cAMP responses, and we have called it lcr1 (for lack of
      cAMP responses). Subsequent analysis showed that lcr1 was allelic to CYR1/CDC35,
      encoding adenylate cyclase, and that it contained an A to T substitution at
      position 5627. This corresponds to a K1876M substitution near the end of the
      catalytic domain in adenylate cyclase. Introduction of the A5627T mutation into
      the CYR1 gene of a W303-1A wild-type strain largely eliminated glucose- and
      acidification-induced cAMP signalling and also the transient cAMP increase that
      occurs in the lag phase of growth. Hence, lysine1876 of adenylate cyclase is
      essential for cAMP responses in vivo. Lysine1876 is conserved in
      Schizosaccharomyces pombe adenylate cyclase. Mn2+-dependent adenylate cyclase
      activity in isolated plasma membranes of the cyr1met1876 (lcr1) strain was
      similar to that in the isogenic wild-type strain, but GTP/Mg2+-dependent activity
      was strongly reduced, consistent with the absence of signalling through adenylate
      cyclase in vivo. Glucose-induced activation of trehalase was reduced and
      mobilization of trehalose and glycogen and loss of stress resistance were delayed
      in the cyr1met1876 (lcr1) mutant. During exponential growth on glucose, there was
      little effect on these protein kinase A (PKA) targets, indicating that the
      importance of glucose-induced cAMP signalling is restricted to the transition
      from gluconeogenic/respiratory to fermentative growth. Inhibition of growth by
      weak acids was reduced, consistent with prevention of the intracellular
      acidification effect on cAMP by the cyr1met1876 (lcr1) mutation. The mutation
      partially suppressed the effect of RAS2val19 and GPA2val132 on several PKA
      targets. These results demonstrate the usefulness of the cyr1met1876 (lcr1)
      mutation for epistasis studies on the signalling function of the cAMP pathway.

PMID- 10411753
TI  - Identification and characterization of a stress-responsive promoter in the
      macromolecular synthesis operon of Bacillus subtilis.
AB  - Bacillus subtilis DB1005 is a temperature-sensitive (Ts) sigA mutant. Induction
      of sigmaA has been observed exclusively in this mutant harbouring extra copies of
      the plasmid-borne Ts sigA gene transcriptionally controlled by the P1P2 promoters
      of the B. subtilis macromolecular synthesis (MMS; rpoD or sigA) operon.
      Investigation of the mechanisms leading to the induction has allowed us to
      identify a sigmaB-type promoter, P7, in the MMS operon for the first time.
      Therefore, at least seven promoters in total are responsible for the regulation
      of the B. subtilis MMS operon, including the four known sigmaA- and sigmaH-type
      promoters, as well as two incompletely defined promoters. The P7 promoter was
      activated in B. subtilis after the imposition of heat, ethanol and salt stresses,
      indicating that the MMS operon of B. subtilis is subjected to the control of
      general stress. The significant heat induction of P7 in B. subtilis DB1005
      harbouring a plasmid-borne Ts sigA gene can be explained by a model of
      competition between sigmaA and sigmaB for core binding; very probably, the sigmaB
      factor binds more efficiently to core RNA polymerase under heat shock. This
      mechanism may provide a means for the expression of the B. subtilis MMS operon
      when sigmaA becomes defective in core binding.

PMID- 10411754
TI  - Alanine mutants of the Spo0F response regulator modifying specificity for sensor
      kinases in sporulation initiation.
AB  - Five single alanine substitution mutations in the Spo0F response regulator gave
      rise to mutant strains of Bacillus subtilis with seemingly normal sporulation
      that nevertheless rapidly segregated variants blocked in sporulation. The basis
      for this deregulated phenotype was postulated to be increased phosphorylation of
      the Spo0A transcription factor, resulting from enhanced phosphate input or
      decreased dephosphorylation of the phosphorelay. Strains bearing two of these
      Spo0F mutant proteins, Y13A and I17A, retained a requirement for KinA and KinB
      kinases in sporulation, whereas the remaining three, L66A, I90A and H101A, gave
      strains that sporulated well in the absence of both KinA and KinB. Sporulation of
      strains bearing L66A and H101A mutations was decreased in a mutant lacking KinA,
      KinB and KinC, but the strain bearing the I90A mutation required the further
      deletion of KinD to lower its sporulation frequency. The affected residues, L-66,
      I-90 and H-101, are involved in crucial hydrophobic contacts stabilizing the
      orientation of helix alpha4 of Spo0F. The data are consistent with the notion
      that these three mutations alter the conformation of the beta4-alpha4 loop of
      Spo0F that is known to contain residues critical for KinA:Spo0F recognition. As
      this loop has a propensity for multiple conformations, the spatial arrangement of
      this loop may play a critical role in kinase selection by Spo0F and might be
      altered by regulatory molecules interacting with Spo0F.

PMID- 10411755
TI  - Dynamics of multigene expression during catabolic adaptation of Ralstonia
      eutropha JMP134 (pJP4) to the herbicide 2, 4-dichlorophenoxyacetate.
AB  - Ralstonia eutropha JMP134 carries a 22 kb DNA region on plasmid pJP4 necessary
      for the degradation of 2,4-D (2,4-dichlorophenoxyacetate). In this study,
      expression of the 2,4-D pathway genes (designated tfd ) upon exposure to
      different concentrations of 2,4-D was measured at a detailed timescale in
      chemostat-grown R. eutropha cultures. A sharp increase in mRNA levels for tfdA,
      tfdCDEF-B, tfdDIICIIEIIFII-BII and tfdK was detected between 2 and 13 min after
      exposure to 2,4-D. This response time was not dependent on the 2,4-D
      concentration. The genes tfdA, tfdCD and tfdDIICII were expressed immediately
      upon induction, whereas tfdB, tfdBII and tfdK mRNAs could be detected only around
      10 min later. The number of tfd mRNA transcripts per cell was estimated to be
      around 200-500 during maximal expression, after which they decreased to between 1
      and 30 depending on the 2,4-D concentration used for induction. Unlike the mRNAs,
      the specific activity of the 2,4-D pathway enzyme chlorocatechol 1,2-dioxygenase
      did not increase sharply but accumulated to a steady-state plateau, which was
      dependent on the 2, 4-D concentration in the medium. At 1 mM 2,4-D, several
      oscillations in mRNA levels were observed before steady-state expression was
      reached, which was caused by transient accumulation of the first pathway
      intermediate, 2,4-dichlorophenol, to toxic concentrations. Expression of tfdR and
      tfdS, the (identical) regulatory genes for the tfd pathway remained low and
      essentially unchanged during the entire adaptation phase.

PMID- 10411756
TI  - Identification and characterization of a germination operon on the virulence
      plasmid pXO1 of Bacillus anthracis.
AB  - The spores of Bacillus anthracis, the agent of anthrax disease, germinate within
      professional phagocytes, such as murine macrophage-like RAW264.7 cells and
      alveolar macrophages. We identified a cluster of germination genes extending for
      3608 nucleotides between the pag and atxA genes on the B. anthracis virulence
      plasmid pXO1. The three predicted proteins (40, 55 and 37 kDa in size) have
      significant sequence similarities to B. subtilis, B. cereus and B. megaterium
      germination proteins. Northern blot analysis of total RNA from sporulating cells
      indicated that the gerX locus was organized as a tricistronic operon (gerXB,
      gerXA and gerXC). Primer extension analysis identified a major potential
      transcriptional start site 31 bp upstream from the translation initiation codon
      of gerXB. Expression of the gerX operon was studied using a gerXB-lacZ
      transcriptional fusion. Expression began 2.5-3 h after the initiation of
      sporulation and was detected exclusively in the forespore compartment. A gerX
      null mutant was constructed. It was less virulent than the parental strain and
      did not germinate efficiently in vivo or in vitro within phagocytic cells. These
      data strongly suggest that gerX-encoded proteins are involved in the virulence of
      B. anthracis.

PMID- 10411757
TI  - Role of lon and ClpX in the post-translational regulation of a sigma subunit of
      RNA polymerase required for cellular differentiation in Bacillus subtilis.
AB  - The RNA polymerase sigma subunit, sigmaH (Spo0H) of Bacillus subtilis, is
      essential for the transcription of genes that function in sporulation and genetic
      competence. Although spo0H is transcriptionally regulated by the key regulatory
      device that controls sporulation initiation, the Spo0 phosphorelay, there is
      considerable evidence implicating a mechanism of post-translational control that
      governs the activity and concentration of sigmaH. Post-translational control of
      spo0H is responsible for the reduced expression of genes requiring sigmaH under
      conditions of low environmental pH. It is also responsible for heightened sigmaH
      activity upon relief of acid stress and during nutritional depletion. In this
      study, the ATP-dependent proteases LonA and B and the regulatory ATPase ClpX were
      found to function in the post-translational control of sigmaH. Mutations in lonA
      and lonB result in elevated sigmaH protein concentrations in low-pH cultures.
      However, this is not sufficient to increase sigmaH-dependent transcription.
      Activation of sigmaH-dependent transcription upon raising medium pH and in cells
      undergoing sporulation requires clpX, as shown by measuring the expression of
      lacZ fusions that require sigmaH for transcription and by complementation of a
      clpX null mutation. A hypothesis is presented that low environmental pH results
      in the Lon-dependent degradation of sigmaH, but the activity of sigmaH in
      sporulating cells and in cultures at neutral pH is stimulated by a ClpX-dependent
      mechanism in response to nutritional stress.

PMID- 10411758
TI  - In vitro activation and repression of photosynthesis gene transcription in
      Rhodobacter capsulatus.
AB  - It has been known for over half a century that anoxygenic photosynthetic bacteria
      maximally synthesize their photosystems in the absence of oxygen. During the last
      decade, it has become clear that this regulation is largely at the
      transcriptional level, with photosynthesis genes expressed only under anaerobic
      conditions. We describe here in vitro reconstitution of activation and repression
      of three photosynthesis promoters, bch (bacteriochlorophyll biosynthesis), puc
      (light-harvesting II apoproteins) and puf (reaction centre and light-harvesting I
      apoproteins) using purified transcription factors and RNA polymerase from
      Rhodobacter capsulatus. Previous genetic results have indicated that each of
      these three promoters is differentially regulated by three key regulators: CrtJ
      acting as a repressor of bch and puc and the two-component regulators RegA/RegB,
      which are activators of puc and puf. These regulators are distinct from those
      that mediate oxygen control in enteric bacteria. Our in vitro studies show that
      these purified regulators directly control the expression of the housekeeping RNA
      polymerase at these promoters. High-level basal expression of the bch promoter is
      shown to be repressed by CrtJ. The puc promoter is activated by the RegB
      phosphorylated RegA protein and additionally repressed by CrtJ. At the puc
      promoter, CrtJ effectively competes for promoter binding with RegA, while at the
      bch promoter, repression appears to be by competition for the RNA polymerase
      binding site. In contrast to what has been suggested previously, the RegA
      activated puf promoter is demonstrated as being recognized by the housekeeping
      RNA polymerase. We also discuss evidence that RegA approximately P activation of
      the puc and puf promoters involves recruitment of RNA polymerase by different
      modes of protein-protein interaction.

PMID- 10411759
TI  - DB or not DB in translation?

PMID- 10411760
TI  - Misled by sequence complementarity: does the DB-anti-DB interaction withstand
      scientific scrutiny?

PMID- 10411761
TI  - Changing aspects of sevoflurane in paediatric anaesthesia: 1975-99.

PMID- 10411762
TI  - Organ donation.

PMID- 10411763
TI  - Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia.
AB  - A prospective, randomized and double blind study was undertaken to determine the
      incidence and a possible dose- or age-dependence of hiccups in children
      premedicated with rectal midazolam and to investigate the treatment of hiccups by
      intranasal ethyl chloride spray application. Two hundred ASA physical status 1
      and 2 children, weighing 3.0 to 15.0 kg, scheduled for minor surgery, were
      randomly assigned to be given either 0.5 mg.kg-1 midazolam(n=100) or 1.0 mg. kg-1
      midazolam (n=100) administered rectally. If hiccups were observed during a period
      of 20 min after premedication with midazolam, these children were treated after 3
      min of hiccups with two short intranasal applications of ethyl chloride spray.
      Hiccups occurred in 22% of children in the 0.5 mg.kg-1 group and 26% in the 1.0
      mg.kg-1 group (n.s.). The intranasal application with ethyl chloride was
      successful in 100% in both groups. The mean age levels between children with or
      without hiccups were 5+/-9 months vs 21+/-19 months (P<0.01) in the 0.5 mg.kg-1
      group and 6+/-7 months vs 20+/-14 months (P<0.01) in the 1.0 mg.kg-1 group.
      Intranasal application of ethyl chloride spray seems to be an effective therapy
      for midazolam induced hiccups in paediatric anaesthesia. The incidence of these
      hiccups is highly age significant, but not dose dependent.

PMID- 10411764
TI  - Effects of sevoflurane anaesthesia on recovery in children: a comparison with
      halothane.
AB  - We prospectively studied one hundred ASA physical status I-II children, ages six
      months to six years, undergoing myringotomy surgery. Children were randomly
      assigned to one of four anaesthetic groups receiving either halothane or
      sevoflurane for anaesthesia and oral midazolam premedication or no premedication.
      We found that children anaesthetized with sevoflurane had significantly faster
      recovery times and discharge home times than those who received halothane.
      Patients given oral midazolam premedication had significantly longer recovery
      times, but no delay in discharge home compared with those not premedicated.
      However, children anaesthetized with sevoflurane and no premedication had an
      unacceptably high incidence (67%) of postoperative agitation. The use of oral
      midazolam preoperatively did decrease the amount of postoperative agitation seen
      with sevoflurane. We conclude that although sevoflurane does shorten recovery
      times, the degree of associated postoperative agitation makes it unacceptable as
      a sole anaesthetic for myringotomy surgery.

PMID- 10411765
TI  - Relative effectiveness of lignocaine-prilocaine emulsion and nitrous oxide
      inhalation for routine preoperative laboratory testing.
AB  - We studied the impact of age-related factors and the benefits of 50% nitrous
      oxide or EMLA cream in 108 children undergoing preoperative laboratory testing.
      Procedural pain was assessed by behavioural scores (CHEOPS) and pain intensity
      ratings. Age, preexisting behavioural distress and difficulty of venous access
      were significant predictors of outcome in univariate analysis. Nitrous oxide and
      EMLA cream were both effective in lowering pain related behaviour and pain
      ratings generated by the different adult observers and the children where
      applicable. EMLA cream was more effective than 50% nitrous oxide in children 1-4
      years old. Although EMLA cream was responsible for a 28+/-5 min prolongation of
      waiting time at the clinic, the present results suggest that it should remain the
      first line intervention to alleviate pain from venepuncture in paediatric
      outpatients.

PMID- 10411766
TI  - Postal survey of the anaesthetic techniques used for paediatric tonsillectomy
      surgery.
AB  - A postal survey of anaesthetic techniques used for tonsillectomy surgery in
      children (age 3-16 years) was performed with particular reference to the use of
      the reinforced laryngeal mask airway and the use of suxamethonium. From 110
      questionnaires despatched, replies were obtained from 88 consultant anaesthetists
      with commitments to otolaryngologic (ENT) anaesthesia (response rate 80%). In
      paediatric practice, the reinforced laryngeal mask airway was routinely used by
      14 (16%) respondents from the 88 who replied. Thirteen (33%) respondents out of
      39 respondents who replied saying that they had used the reinforced laryngeal
      mask airway at some point, reported problems with its use. Suxamethonium was used
      routinely by 40 consultants (45%) for tonsillectomy surgery. Severe problems with
      its use had been encountered by 26 (30%) respondents

PMID- 10411767
TI  - A comparison of two concentrations of bupivacaine and adrenaline with and without
      fentanyl in paediatric inguinal herniorrhaphy.
AB  - This study was designed to determine whether administration of caudal bupivacaine
      with fentanyl would have any effect on analgesia in paediatric patients
      undergoing inguinal herniorrhaphy repair. Fifty-six outpatient paediatric
      patients undergoing inguinal hernia repair were evaluated. Patients received, in
      a randomized manner, 1 ml.kg-1 of either bupivacaine 0.25% or 0.125% with or
      without fentanyl 1 microg.kg-1. There was no difference in pain scores in the
      hospital, the night of surgery, or 24 h postoperatively nor was there a
      difference in the oral analgesics administered between any of the groups. There
      was a higher incidence of vomiting at home in both 0.25% bupivacaine groups
      irrespective of the use of fentanyl. The 0.125% bupivacaine group had
      significantly more patients who received intravenous fentanyl in the PACU than
      did the other three groups (P<0.001). Increasing the concentration of bupivacaine
      from 0. 125% to 0.25% increased the incidence of postoperative vomiting. We
      recommend that clinicians utilize bupivacaine 0.125% with 1 microg. kg-1 fentanyl
      as the caudal injectate in paediatric patients undergoing inguinal hernia repair.

PMID- 10411768
TI  - Efficacy and complications of morphine infusions in postoperative paediatric
      patients.
AB  - The aim of the study was to evaluate the efficacy and the incidence of clinically
      significant adverse drug reactions (ADRs) in paediatric patients receiving
      continuous intravenous morphine infusions for acute postoperative pain.
      Definitions were established for ADRs and data were collected in an immediately
      retrospective fashion for a maximum of 72 h in 110 patients >/=5 three months of
      age (0.3-16.7 years) receiving morphine infusions and admitted to a general ward
      over a three month convenience sampling period. Inadequate analgesia occurred in
      65.5% of patients during the first 24 h of therapy and occurred most frequently
      in patients with infusion rates of 20 microg.kg-1.h-1 or less. Nausea/vomiting
      was the most commonly experienced ADR (42.5%). The incidence of respiratory
      depression was 0% (95% CI=0-3.3%). Other ADRs included: urinary retention
      (13.5%), pruritus (12.7%), dysphoria (7.3%), hypoxaemia (4.5%), discontinuation
      of morphine for treatment of an ADR (3.6%), and difficulty in arousal (0.9%). The
      most common ADRs associated with morphine infusions were inadequate analgesia (in
      the first 24 h) and nausea/vomiting. There were no cases of respiratory
      depression. Methods of avoiding initial inadequate analgesia and treating nausea
      and vomiting associated with morphine infusions are needed.

PMID- 10411769
TI  - Combination of granisetron and droperidol for the prevention of vomiting after
      paediatric strabismus surgery.
AB  - This study was undertaken to compare the efficacy of granisetron plus droperidol
      with each antiemetic alone for the prevention of vomiting after paediatric
      strabismus surgery. In a prospective, randomized, double-blinded trial, 120 ASA
      physical status I children, aged 4-10 years, received granisetron 40 microg.kg-
      1, droperidol 50 microg.kg- 1, granisetron 40 microg.kg- 1 plus droperidol 50
      microg.kg- 1 (n=40 of each) intravenously after an inhalation induction of
      anaesthesia. A complete response, defined as no vomiting, no retching and no need
      for another rescue antiemetic medication, during 0-3 h after anaesthesia was 80%
      with granisetron, 45% with droperidol and 98% with granisetron plus droperidol,
      respectively; the corresponding incidence during 3-24 h after anaesthesia was
      78%, 38% and 98% (P< 0.05; overall chi-squared test with Yates continuity
      correction). No clinically important adverse events were observed in any of the
      groups. In conclusion, a combination of granisetron and droperidol was more
      effective than granisetron or droperidol as a sole antiemetic for the prevention
      of postoperative vomiting in children undergoing strabismus repair.

PMID- 10411770
TI  - The effect of syringe size on the performance of an infusion pump.
AB  - This study investigated the effect of using three different sized syringes on the
      accuracy of fluid delivery when using an infusion pump at low infusion rates (1
      ml.h-1). The study also measured the influence of the syringe size on the time to
      occlusion alarm, and on the size of the subsequent bolus dose that might be
      infused after relief of the occlusion which triggered the alarm. The use of a
      larger size syringe was found not to affect the accuracy of infusate delivery,
      but delayed the time to occlusion alarm and increased the size of the
      postocclusion bolus dose.

PMID- 10411771
TI  - Novel use of neonatal cuffed tracheal tube to occlude tracheo-oesophageal
      fistula.
AB  - The use of a cuffed tracheal tube is described to occlude the leak through a
      tracheo-oesophageal fistula (TOF) in a neonate and prevent gastric dilatation
      during positive-pressure lung ventilation.

PMID- 10411772
TI  - Accidental hypothermia in a child.
AB  - We report a case of severe accidental hypothermia (24.8 degrees C) in a seven
      year-old child due to prolonged exposure to low temperatures and temporary
      contact with river water. When the patient was seen in hospital, bradycardia
      (30.min-1), bradypnoea (5. min-1), scarcely reacting pupils, and Glasgow Coma
      Scale=3 were noted. For rewarming minimally invasive techniques (humidified
      warmed gases and intravenous solutions at 40 degrees C) were employed with a very
      successful outcome.

PMID- 10411773
TI  - Fatal pulmonary haemorrhage during anaesthesia for bronchial artery embolization
      in cystic fibrosis.
AB  - Three children with cystic fibrosis (CF) had significant pulmonary haemorrhage
      during anaesthetic induction prior to bronchial artery embolization (BAE).
      Haemorrhage was associated with rapid clinical deterioration and subsequent early
      death. We believe that the stresses associated with intermittent positive
      pressure ventilation (IPPV) were the most likely precipitant to rebleeding and
      that the inability to clear blood through coughing was also an important factor
      leading to deterioration. Intermittent positive pressure ventilation should be
      avoided when possible in children with CF with recent significant pulmonary
      haemorrhage.

PMID- 10411774
TI  - Heart block following propofol in a child.
AB  - We present the case of a nine-year-old boy afflicted with Ondine's curse, who
      developed complete atrioventricular heart block after a single bolus of propofol
      for induction of anaesthesia for strabismus surgery. Ondine's curse, the other
      name for congenital central hypoventilation syndrome, is characterized by a
      generalized disorder of autonomic function. Propofol has no effect on the normal
      atrioventricular conduction system in humans but it reduces sympathetic activity
      and can highly potentiate other vagal stimulation factors. Heart block has been
      documented after propofol bolus use in adults but, to our knowledge, not in
      children. It would appear that propofol is not a good choice for anaesthesia in
      congenital central hypoventilation syndrome.

PMID- 10411775
TI  - Anaesthetic implications of rigid spine syndrome.
AB  - The perioperative management of a 14-year-old girl, suffering from the muscular
      disorder rigid spine syndrome, is presented. The anaesthetic implications with
      regard to possible difficult intubation, cardiac involvement, malignant
      hyperthermia, neuromuscular blocking agents, and postoperative recovery are
      discussed.

PMID- 10411776
TI  - Anaesthetic management of a patient with erythropoietic protoporphyria for
      ventricular septal defect closure.
AB  - Erythropoietic protoporphyria (EPP) is due to a deficiency in ferrochelatase
      required for haem synthesis. We describe the anaesthetic management of a seven
      year-old with EPP undergoing closure of a haemodynamically significant
      ventricular septal defect. Photosensitivity in EPP patients is triggered at
      wavelengths near 400 nm and light-excited porphyrins generate free radicals and
      singlet oxygen that lead to erythrocyte deformity and haemolysis. Stimuli that
      could trigger a porphyric crisis during anaesthesia and surgery were reduced by
      avoiding exposure to the sensitive 400 nm spectrum and using light sources
      covered with yellow acrylate filters in the operating room. Anaesthetic agents
      not previously associated with porphyric crisis were chosen. Whole blood priming
      of the extracorporeal circuit was performed to ensure adequate haemoglobin
      concentrations during the perioperative period.

PMID- 10411777
TI  - Unexpected difficult intubation in the patient with Morning Glory syndrome.
AB  - Morning Glory syndrome is an uncommon congenital optic disc anomaly with
      occasional systemic associations. A case of unsuspected difficult intubation in a
      three-year old patient is described in this case report.

PMID- 10411778
TI  - Extrapyramidal side-effects from droperidol mixed with morphine for patient
      controlled analgesia in two children.
AB  - We report two cases of extrapyramidal reactions occurring in children following
      the use of droperidol in combination with morphine for patient-controlled
      analgesia (PCA). Symptoms appeared 38 and 27 h, respectively, after commencement
      and after a total dose of 0.14 mg.kg-1 and 0.17 mg.kg-1, respectively. Although
      effective and safe in adult patients, we recommend caution with the use of
      droperidol-morphine mixtures for PCA in paediatric patients.

PMID- 10411779
TI  - Historical abstract. The Hyderabad Chloroform Commission.

PMID- 10411780
TI  - What we should know about paracetamol.

PMID- 10411781
TI  - The intrauterine contraceptive device: an often-forgotten and maligned method of
      contraception.
AB  - Although 90% of women at risk for unintended pregnancy in the United States use
      contraception, <1% of these women use the intrauterine contraceptive device. The
      mechanism of action of intrauterine contraceptive devices has been controversial,
      but several studies suggest that interference with sperm migration or function
      and with fertilization may be the most likely mechanisms. More important, there
      is lack of compelling evidence that the intrauterine contraceptive device acts as
      an abortifacient. The risk for pelvic inflammatory disease among users now
      appears to be extremely low, primarily as a result of better selection of
      candidates. A levonorgestrel-releasing intrauterine contraceptive device may
      offer some new therapeutic approaches for the treatment of certain gynecologic
      disorders. Although women who are not at risk for pelvic inflammatory disease or
      sexually transmitted diseases are appropriate candidates for the intrauterine
      contraceptive device, it appears that use can be expanded to selected nulliparous
      women and women with certain medical conditions.

PMID- 10411782
TI  - Neurobehavioral effects of low-level lead exposure in human neonates.
AB  - In a clinically healthy sample of 103 African American neonates maternal blood
      lead levels <10 micrograms/dL were related to discrete aspects of neonatal
      behavior but not to a priori cluster scores of the Brazelton Neonatal Behavior
      Assessment Scale. In statistical tests modest detrimental effects on motor
      control and attention were found for neonatal subjects whose mothers had slightly
      higher blood lead levels in the sixth and seventh prenatal months. Correlation
      and dose-effect trends reveal slightly poorer attention and motor control
      performance among neonatal offspring of mothers with higher maternal blood lead
      levels. These results are in agreement with those of previous studies, which have
      consistently reported modest statistical relationships between low-level prenatal
      lead exposure and neonatal behavior.

PMID- 10411783
TI  - Pelvic organ prolapse: anterior, superior, and posterior vaginal segment defects.
AB  - Pelvic organ prolapse is a complex entity that potentially involves not only poor
      support for multiple sites in the vagina but also the function of the urethra,
      bladder, and anorectum, as well as sexual function. We must provide a
      comprehensive approach to the evaluation and management of women with pelvic
      organ prolapse and must critically review the assessment of surgical management.

PMID- 10411784
TI  - A review of the effects of hazardous waste on reproductive health.
AB  - Approximately 1 in 4 Americans lives within 4 miles of a hazardous waste site
      according to the Environmental Protection Agency. In light of this large
      proportion and the public's high level of concern that hazardous waste causes
      health problems, it is important for primary care physicians and other health
      care providers to know that residential proximity to some kinds of hazardous
      waste sites is associated with adverse reproductive effects. Findings from both
      state-based surveillance programs and studies of individual hazardous waste sites
      have shown increased risk of congenital malformations and reductions in birth
      weight among infants born to parents living near hazardous waste sites. This
      article summarizes salient literature on human health effects of hazardous waste
      and suggests actions for primary care providers to consider.

PMID- 10411785
TI  - Domestic violence and physical abuse of women: the Grady Memorial Hospital
      experience.
AB  - OBJECTIVES: This study was undertaken to determine the prevalence of self
      reported physical abuse among women seeking gynecologic and obstetric emergency
      care services. STUDY DESIGN: A voluntary self-administered anonymous
      questionnaire was given to all women seeking treatment at the Gynecologic and
      Obstetric Emergency Clinic at Grady Memorial Hospital during the month of April
      1991. The survey respondents were divided into 4 abuse categories. RESULTS: Among
      the 452 respondents to the survey, 181 women (40.1%) gave a history of abuse.
      Among these, 93 women (51.3%) were currently in an abusive relationship, 45 women
      (24.9%) were currently in an abusive relationship and had a history of abuse, and
      43 women (23.8%) had a history of abuse. The most common injuries described were
      fractures. Men were more likely not to have received counseling. CONCLUSIONS: The
      topic of domestic violence must be incorporated into the medical education
      curriculum and should be taught through a multidisciplinary approach.

PMID- 10411786
TI  - Adnexal masses in pregnancy: a review of 130 cases undergoing surgical
      management.
AB  - OBJECTIVE: Our purpose was to determine maternal and fetal outcome in patients
      undergoing surgery for pelvic mass in pregnancy. STUDY DESIGN: Maternal and fetal
      records of 130 cases of adnexal masses associated with intrauterine pregnancy
      that required laparotomy or aspiration or that were diagnosed incidentally at the
      time of cesarean section were reviewed. The chi(2) and Fisher's exact tests were
      used for statistical analysis. A P value of </=.05 was considered significant.
      RESULTS: The incidence of adnexal masses in pregnant women who required surgical
      management was 1 in 1312 live births. A malignant tumor or a tumor of low
      malignant potential was found in 6.1% of cases. In 10 patients the only finding
      at the time of laparotomy was leiomyomas. Ultrasonography was not helpful in
      distinguishing tumors of low malignant potential from benign neoplasms or in
      identifying the source of the pelvic mass in patients found to have only
      leiomyomas. There were 2 intrauterine fetal deaths and 1 neonatal death in this
      cohort of patients. Patients who underwent laparotomy after 23 weeks' gestation
      had a significantly higher adverse pregnancy outcome compared with those who
      underwent laparotomy earlier in pregnancy (P =.005). CONCLUSION: The incidence of
      an adnexal mass during pregnancy in our population was consistent with what has
      been reported in the literature. However, the percentage of malignant tumors or
      tumors of low malignant potential was 2-fold greater than previously reported.
      Preoperative ultrasonography was not helpful in differentiating tumors of low
      malignant potential from benign neoplasms.

PMID- 10411787
TI  - Racial patterns in the effects of tobacco use on fetal growth.
AB  - OBJECTIVE: The aim of this study was to characterize the interaction between the
      effects on fetal growth of maternal smoking and race by means of race-specific
      growth normograms. STUDY DESIGN: A case-control study was performed on white and
      African American mothers who were delivered at 2 hospitals in metropolitan
      Atlanta between February 1993 and December 1994. The study population consisted
      of 621 small for gestational age infants and their mothers and 324 appropriate
      for gestational age infants and their mothers. Face-to-face interviews with
      mothers and detailed anthropometric measurements of neonates were performed.
      Relationships among tobacco use, race, and fetal growth were evaluated by means
      of multiple logistic regression. The chi(2) test of trend was performed to assess
      a dose-response relationship between smoking and fetal growth. RESULTS: Mothers
      of small for gestational age neonates were significantly more likely than control
      mothers to be single (52% versus 40%), to be primiparous (47% versus 37%), to
      have a low body mass index (26% versus 17%), to have hypertension (22% versus
      15%), and to use alcohol (15% versus 9%). Mothers of small for gestational age
      infants were significantly more likely than control mothers to smoke (26% versus
      12%) and to smoke more cigarettes (P <.05). After controlling for potential
      confounders cigarette smoking in the second trimester was significantly
      associated with small for gestational age infants in both races (whites <1 pack/d
      adjusted odds ratio 3.82, 1-2 packs/d adjusted odds ratio 4.86, >2 packs/d crude
      odds ratio; African Americans <1 pack/d adjusted odds ratio 2. 35, 1-2 packs/d
      adjusted odds ratio 2.52). The chi(2) test of trend results were consistent with
      a dose-response relationship between smoking and small for gestational age
      infants (whites chi(2) = 14.06, P <.0001, African Americans chi(2) = 7.99).
      Comparison between the 2 races of the adverse effects of smoking on fetal growth
      showed no significant difference. CONCLUSION: Self-reported maternal smoking
      during the second trimester is associated with fetal growth restriction in a dose
      response manner. According to race-specific growth normograms no significant
      difference in the effects of tobacco use on fetal growth was found between white
      and African American women.

PMID- 10411789
TI  - Threatened pregnancy: environment and reproduction at risk. Keynote address:
      taming the tempest of teen pregnancy.

PMID- 10411790
TI  - Significance of true surgical pathologic staging: a Gynecologic Oncology Group
      Study.
AB  - OBJECTIVE: The object of the study was to determine the true surgical pathologic
      disease extent in patients with clinical stage II adenocarcinoma of the
      endometrium. STUDY DESIGN: As part of a Gynecologic Oncology Group surgical
      pathologic protocol of patients with adenocarcinoma of the endometrium, patients
      with clinical stage II cancers were evaluated. Among >1000 patients with early
      stage disease entered into this protocol group study, 148 were in clinical stage
      II. All patients underwent abdominal hysterectomy, bilateral salpingo
      oophorectomy, and selective pelvic and para-aortic lymphadenectomy as the primary
      therapy. Surgical pathologic material was evaluated to determine true extent of
      disease. RESULTS: Only 66 of 148 (45%) of patients in clinical stage II had
      cancer in the cervix. Fifty-seven patients had disease limited to the upper
      fundus and 25 had disease extending into the lower uterine segment but not into
      the cervix. Among the 66 patients with disease in the cervix, only 35 had disease
      limited to the uterus whereas 31 patients had extrauterine disease (lymph nodes,
      adnexa, etc). Thus among 148 patients with diagnoses of clinical stage II disease
      only 35 (24%) in fact had true surgical stage II cancer. CONCLUSION: Clinical
      diagnosis of stage II adenocarcinoma of the uterus is a poor reflection of true
      surgical stage II cancer. Only when true extent of disease is known can optimally
      definitive therapy be determined.

PMID- 10411788
TI  - Decreasing estrogen in nonpregnant women lowers uterine myometrial type I nitric
      oxide synthase protein expression.
AB  - OBJECTIVE: Our purpose was to study the effect of estrogen on myometrial nitric
      oxide synthase. STUDY DESIGN: Twenty-four women were randomly assigned to
      treatment with gonadotropin-releasing hormone agonist or placebo for 8 weeks
      before hysterectomy, at which time samples of myometrium were collected and the
      serum levels of estrogen, nitrate, and nitrite measured. Myometrial nitric oxide
      synthase was measured with the arginine-citrulline assay. The levels of
      endothelial nitric oxide synthase and neuronal nitric oxide synthase were
      determined by Western blot analysis. RESULTS: Myometrial nitric oxide synthase
      was 88% calcium dependent but only partially calmodulin dependent. Women treated
      with gonadotropin-releasing hormone agonist had postmenopausal levels of
      estradiol and had significantly lower levels of myometrial neuronal nitric oxide
      synthase than those in the control group. Total, endothelial, and inducible
      nitric oxide synthase levels in the myometrium were unchanged, as were serum
      nitrite and nitrate levels. CONCLUSION: Neuronal nitric oxide synthase is
      regulated in the myometrium by estrogen. Myometrial nitric oxide synthase is not
      all calmodulin dependent; this may represent the activity of a novel nitric oxide
      synthase isoform.

PMID- 10411791
TI  - Threatened pregnancy: environment and reproduction at risk. Teen pregnancy
      problems and approaches: panel presentations.

PMID- 10411792
TI  - Lower urinary tract injury during the Burch procedure: is there a role for
      routine cystoscopy?
AB  - OBJECTIVE: This study was undertaken to evaluate the use of intraoperative
      cystoscopy for the detection of incidental bladder or ureteral injuries during
      abdominal urethropexy procedures and to determine whether the incidence of
      injuries warrants the routine use of cystoscopy. METHODS: We reviewed the medical
      records of 109 consecutive patients who underwent abdominal urethropexy
      procedures between November 1990 and February 1996 at a teaching institution.
      Each underwent intraoperative cystoscopy. We determined the incidence of
      cystotomy and ureteral obstruction and attempted to determine surgical factors
      that might be associated with an increased risk of injury. RESULTS: Ten of 109
      patients (9%) had bladder or ureteral injury, including 1 cystotomy during
      retropubic dissection, 6 cases of a transvesical suture noted during cystoscopy,
      1 cystotomy recognized before closure, 1 case of ureteral obstruction found
      during cystoscopy, and 1 case of ureteral obstruction not recognized at
      cystoscopy. Cystoscopy allowed detection of 7 of 9 (78%) otherwise unrecognized
      events. The only injury that resulted in significant postoperative morbidity was
      the unrecognized ureteral obstruction. There was no association between incidence
      of lower urinary tract injuries and surgical risk factors. CONCLUSION:
      Intraoperative bladder or ureteral injuries during urethropexy procedures are not
      uncommon, with an incidence of 9% in our series. There is minimal morbidity if
      these injuries are detected and corrected during the operation, whereas morbidity
      may be significant if they remain unrecognized. With a potential for unrecognized
      injury in 8% of Burch procedures without the use of cystoscopy, routine use of
      cystoscopy during urethropexy procedures appears to be warranted.

PMID- 10411793
TI  - The infrequent use of office-based diagnostic tests for vaginitis.
AB  - OBJECTIVE: This study was undertaken to determine physician use of simple office
      based tests in the evaluation of women with vulvovaginal symptoms. STUDY DESIGN:
      A medical record review of 52 women seeking care at a referral-based vaginitis
      clinic was performed. The evaluation performed and the care management were
      recorded for 150 previous physician-provided office visits. RESULTS: A
      microscopic assessment of vaginal fluid was not performed in 37% of office
      visits, and 42% of physicians did not perform microscopy as part of any
      evaluation of vaginitis. Whiff amine tests and measurement of vaginal pH were
      rarely performed (3% of office visits). Treatment without adequate evaluation of
      the etiology of the symptoms occurred in 54% of visits in which medication was
      prescribed. CONCLUSIONS: In our study population the evaluation and care provided
      to women presenting for evaluation of vulvovaginal symptoms were suboptimal. The
      use of simple inexpensive office-based tests can optimize the assessment of
      vaginal infections and should be encouraged.

PMID- 10411794
TI  - Oxytocin activates mitogen-activated protein kinase and up-regulates
      cyclooxygenase-2 and prostaglandin production in human myometrial cells.
AB  - OBJECTIVE: The objective of our study was to test the hypothesis that oxytocin
      promotes prostaglandin production by up-regulating cyclooxygenase-2 via
      activation of mitogen-activated protein kinase cascade in human myometrial cells.
      STUDY DESIGN: Confluent cultures of human myometrial cells obtained from uterine
      specimens of premenopausal women undergoing hysterectomy were serum starved for
      48 hours before oxytocin stimulation. Prostacyclin levels, as 6-keto
      prostaglandin F(1) (alpha), were measured by radioimmunoassay, and the cellular
      cyclooxygenase-2 protein content was determined by Western blot. Mitogen
      activated protein kinase activity was assessed by measuring the phosphorylation
      of myelin basic protein. RESULTS: In a time- and dose-dependent manner oxytocin
      promoted prostacyclin production in human myometrial cells. Maximal responses
      were observed after 8 hours of stimulation at a dose of 100 nmol/L. This effect
      was mainly due to the expression of cyclooxygenase-2 protein. Within 5 minutes
      oxytocin significantly stimulated mitogen-activated protein kinase, as compared
      with the expression in untreated controls. The maximal increase in enzyme
      activity (2.5-fold) was obtained at 45 minutes. A selective inhibitor of mitogen
      activated protein kinase activation (PD98059), as well as herbimycin, a tyrosine
      kinase inhibitor, and the transcriptional blocker actinomycin D, suppressed
      oxytocin-induced cyclooxygenase-2 expression and prostacyclin production. The
      stimulatory action of oxytocin was also sensitive to inhibition by pertussis
      toxin but appeared to be independent of protein kinase C activation. CONCLUSION:
      Our data indicate a largely unrecognized signal transduction mechanism for
      oxytocin, involving G-protein-coupled activation of mitogen-activated protein
      kinase and cyclooxygenase-2 gene expression, leading to increased prostaglandin
      production in human myometrial cells. This signaling pathway complements the
      rapid activation of the phosphoinositide cycle and may be responsible for
      sustained release of prostaglandins in uterine tissues, promoting labor and
      parturition.

PMID- 10411795
TI  - Localization and expression of oxytocin receptor and its messenger ribonucleic
      acid in peri-implantation phase human endometrium during control and clomiphene
      treated cycles.
AB  - OBJECTIVES: This study was undertaken to determine expression levels of oxytocin
      receptor and its gene in peri-implantation phase human endometrium during
      clomiphene-treated cycles compared with control cycles. STUDY DESIGN: Oxytocin
      receptor and its messenger ribonucleic acid in peri-implantation phase
      endometrium during control and clomiphene-treated (50 mg days 5 to 9) cycles of 5
      healthy fertile women were determined by immunohistochemical methods, Western
      blot analysis with monoclonal antibody against amino acids 20 through 40 of the
      extracellular N-terminal human oxytocin receptor, and reverse transcription
      polymerase chain reaction with oligonucleotide primers to amplify the 391-base
      pair fragment of the oxytocin receptor gene. RESULTS: Oxytocin receptor and its
      messenger ribonucleic acid were expressed in human peri-implantation phase
      endometrial samples from both control and clomiphene-treated cycles. The receptor
      was localized predominantly in the epithelial cells and glands, with little or
      none detected in the stroma. Oxytocin receptor protein was separated out as a
      single 70-kd band by Western blot analysis; its relative abundance was
      significantly reduced during clomiphene-treated cycles. The messenger ribonucleic
      acid was detected in all endometrium during control and clomiphene-treated
      cycles, with greater expression during control cycles. CONCLUSIONS: The
      expressions of oxytocin receptor and its gene in luteal phase human endometrium
      suggest a functional relevance in modulation of biochemical changes for
      implantation.

PMID- 10411796
TI  - A comparison of methods for preoperative discrimination between malignant and
      benign adnexal masses: the development of a new logistic regression model.
AB  - OBJECTIVE: The aim of this study was to assess the complementary use of
      ultrasonographic end points with the level of circulating CA 125 antigen by
      multivariate logistic regression analysis algorithms to distinguish malignant
      from benign adnexal masses before operation. STUDY DESIGN: One hundred ninety-one
      patients aged 18 to 93 years with overt adnexal masses were examined by
      transvaginal ultrasonography with color Doppler imaging and 31 variables were
      recorded. The end points were the histologic classification of the tumor and the
      areas under the receiver-operator characteristic curves of alternative
      algorithms. RESULTS: One hundred forty patients had benign tumors and 51 (26.7%)
      had malignant tumors: 31 primary invasive tumors (37% International Federation of
      Gynecology and Obstetrics stage I), 5 tumors of borderline malignancy (100%
      International Federation of Gynecology and Obstetrics stage I), and 15 tumors
      were metastatic and invasive. The most useful variables for the logistic
      regression analysis were the menopausal status, the serum CA 125 level, the
      presence of >/=1 papillary growth (>3 mm in length), and a color score indicative
      of tumor vascularity and blood flow. The optimized procedure had a sensitivity of
      95.9% and a specificity of 87.1%. The area under the receiver-operator
      characteristic curve was significantly higher (P <.01) than the corresponding
      values from the independent use of serum CA 125 levels or indexes of tumor form
      or vascularity. CONCLUSION: Regression analysis of a few complementary variables
      can be used to accurately discriminate between malignant and benign adnexal
      masses before operation.

PMID- 10411797
TI  - Reduced thermoregulatory null zone in postmenopausal women with hot flashes.
AB  - OBJECTIVE: Most menopausal hot flashes are preceded by small elevations in core
      body temperature. If the thermoneutral zone between the thresholds for sweating
      and shivering is reduced in women with symptoms, the triggering mechanism for hot
      flashes could be explained. STUDY DESIGN: We studied 12 postmenopausal women with
      symptoms and 8 without symptoms. We measured body temperatures with a rectal
      probe, an ingested telemetry pill, and a weighted average of rectal and skin
      temperatures. Each woman underwent 3 experimental sessions: determination of the
      sweating threshold by body heating, determination of the shivering threshold by
      body cooling, and replication of the sweating threshold with exercise. RESULTS:
      The women with symptoms had significantly smaller interthreshold zones than did
      the symptom-free women for all 3 measures of body temperature: rectal
      temperature, 0.0 degrees C +/- 0.06 degrees C versus 0.4 degrees C +/- 0.18
      degrees C (P <.005); telemetry pill temperature, 0.0 degrees C +/- 0.11 degrees C
      versus 0.4 degrees C +/- 0.18 degrees C (P <.005); and mean body temperature, 0.8
      degrees C +/- 0.09 degrees C versus 1.5 degrees C +/- 0.20 degrees C (P <. 0006).
      Sweat rates were significantly higher among the women with symptoms (0.06 +/-
      0.002 mg. cm(-2). min(-1)) than among the women without symptoms (0.03 +/- 0.001
      mg. cm(-2). min(-1), P <.05). Sweating thresholds during exercise did not
      significantly differ from those during body heating. During exercise all the
      women with symptoms and none of the women without symptoms had hot flashes.
      CONCLUSIONS: Menopausal hot flashes in women with symptoms may be triggered by
      small elevations in body temperature acting within a reduced thermoneutral zone.

PMID- 10411798
TI  - Efficacy and safety of low, standard, and high dosages of an estradiol
      transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly
      symptomatic menopausal patients. The Esclim Study Group.
AB  - OBJECTIVE: Our purpose was to evaluate the efficacy and safety of 3 dosages of
      Esclim, delivering 0.025 mg, 0.050 mg, or 0.100 mg 17beta-estradiol per 24 hours,
      in the treatment of moderate to severe vasomotor symptoms. STUDY DESIGN: In this
      double-blind, placebo-controlled, parallel-group, multicenter trial, 196 highly
      symptomatic menopausal women received 12 weeks of continuous unopposed treatment
      with 1 of the 3 dosages of Esclim or a matching placebo patch. RESULTS: The
      reduction in frequency of moderate to severe vasomotor symptoms was statistically
      significant compared with placebo (P <.05) from week 2 onward in the Esclim 50
      and 100 groups and from week 3 onward in the Esclim 25 group. Symptom severity
      was also reduced. Estrogen-related adverse events, particularly metrorrhagia and
      endometrial hyperplasia, were less frequent in the Esclim 25 group than in the
      higher-dosage groups. CONCLUSION: All 3 dosages of Esclim were effective in the
      treatment of vasomotor symptoms. The efficacy and safety of Esclim 25 indicate a
      good risk-benefit ratio.

PMID- 10411799
TI  - Transplantation of CD34 human cells into mice with severe combined
      immunodeficiency results in functional T cells 4 weeks after transplantation.
AB  - OBJECTIVE: Our purpose was to determine whether transplantation of fetal human
      CD34(+) cells into mice with severe combined immunodeficiency results in
      functional T cells. STUDY DESIGN: The cells used in this study were isolated from
      fetal human liver tissue obtained after elective termination of normal 18- to 24
      week pregnancies. Women with medical conditions that could confound the outcome
      were excluded. Cells were labeled with fluorochrome-conjugated antibodies that
      recognized CD34 or other cell surface antigens. The cells were then sorted with
      the use of a fluorescein-activated cell sorter. The human sorted cells were
      injected intraperitoneally in mice with severe combined immunodeficiency. Four
      groups of mice were studied: group 1, injected with 10(5) CD34(+) cells (n = 17);
      group 2, injected with 10(5) CD34(-) cells (n = 14); group 3, injected with 10(6)
      unsorted cells (n = 19); and group 4, sham-injected with phosphate-buffered
      saline solution as controls (n = 14). At 1, 2, and 4 weeks after transplantation,
      the peripheral blood monocytes of the study mice were analyzed for functional T
      cells. Aliquots of cells (10(5)) were incubated for 48 hours with 0, 5, 10, and
      20 micrograms of phytohemagglutinin. Thereafter the cells were treated with 1
      microCi of tritiated thymidine. Subsequently the incorporation of tritiated
      thymidine was determined by liquid scintillation counting. RESULTS: Cells from
      mice transplanted with either unsorted cells, sorted CD34(+) cells, or CD34(-)
      cells showed a response to phytohemagglutinin that varied with time and with the
      mitogen concentration. Even though unsorted fetal human liver cells had a maximal
      response at 2 weeks, this posttransplantation response was not statistically
      significant. CD34(+) cell response to phytohemagglutinin was significant at 4
      weeks after transplantation. CD34(-) cells also had a peripheral blood cell
      response at 4 weeks after transplantation; however, this response was not
      statistically significant. In addition, all mice transplanted with fetal human
      liver cells had some functional T cells at 4 weeks; however, this response was
      statistically significant only for CD34(+) cells. CONCLUSION: Transplantation of
      either sorted CD34 (positive or negative) cells or unsorted fetal human liver
      cell preparations into mice with severe combined immunodeficiency results in
      functional T cells. However, only the mice with transplanted CD34(+) cells
      demonstrated a statistically significant response.

PMID- 10411800
TI  - Accuracy of clinical assessment of paravaginal defects in women with anterior
      vaginal wall prolapse.
AB  - OBJECTIVE: The objective of this study was to determine the accuracy of clinical
      assessment of paravaginal defects in women with anterior vaginal wall prolapse.
      STUDY DESIGN: A retrospective chart review of all women undergoing surgery for
      anterior vaginal wall prolapse during the years of 1994 to 1996 identified
      operative notes that described the surgical assessment of paravaginal support.
      These surgical findings were compared with the preoperative clinical assessment.
      Clinical parameters that predicted poor correlation were identified. Statistical
      analysis used the chi(2) test. RESULTS: One hundred seventeen patients had
      surgery for anterior vaginal prolapse. Seventy had documentation of an
      intraoperative paravaginal support evaluation. Of these, 44 patients had vaginal
      procedures, and 26 had abdominal procedures. All patients had at least stage 2
      prolapse before surgery, and all were noted to have excellent pelvic support 4 to
      6 weeks after surgery. The prevalence of paravaginal defects at surgery was 47%
      on the right and 41% on the left. The sensitivity and negative predictive value
      for the clinical assessment for paravaginal defects were good on both the right
      and left sides, whereas the specificity and positive predictive values were poor.
      Stage of prolapse, previous hysterectomy, or previous anterior colporrhaphy did
      not significantly affect the accuracy of the clinical examination in predicting
      fascial defects. However, previous retropubic urethropexy did significantly
      decrease the accuracy of the clinical examination in predicting right paravaginal
      defects (P <.01) but not left. CONCLUSION: Although preoperative clinical
      assessment for paravaginal defects is useful, it does not substitute for careful
      intraoperative evaluation for endopelvic fascial defects.

PMID- 10411801
TI  - Interstitial brachytherapy in the treatment of advanced and recurrent vulvar
      cancer.
AB  - OBJECTIVE: Our purpose was to evaluate the role of interstitial brachytherapy in
      vulvar cancer management. STUDY DESIGN: From 1985-1992 we performed a
      retrospective study of patients treated at the University of California, Irvine
      Medical Center, and Long Beach Memorial Medical Center. RESULTS: Eleven patients
      received interstitial brachytherapy, with (n = 5) or without (n = 6) external
      beam radiotherapy, for locally advanced (n = 5) or recurrent (n = 6) vulvar
      cancer. Local control was achieved in all patients. Ten patients have died of
      disease at a mean interval of 33 months from the time of treatment, with 9
      patients having maintenance of local control at death. One patient is alive
      without disease after 77 months of follow-up. There were 2 cases of local
      necrosis (18%) and 1 case of rectovaginal fistula (9%). CONCLUSION: Local control
      of advanced vulvar cancer can be achieved with interstitial brachytherapy, with
      or without external beam radiotherapy. With improved systemic therapy this
      treatment modality may be used to salvage women with bulky, symptomatic tumors.

PMID- 10411802
TI  - Assessment of response to treatment in vulvar vestibulitis syndrome by means of
      the vulvar algesiometer.
AB  - OBJECTIVE: A pilot study was undertaken to investigate the utility of the vulvar
      algesiometer in correlating symptom improvement with treatment response. STUDY
      DESIGN: Women with a diagnosis of vulvar vestibulitis syndrome attending a
      specialist vulvar clinic were assessed with the vulvar algesiometer before and
      after treatment. RESULTS: The conditions of 25 patients had improved to the point
      of discharge, and readings from before and after treatment were compared. There
      was a statistically significant difference in the vulvar algesiometer readings
      before and after treatment and this improvement was reflected in patient
      response. Nine patients had no response to treatment and also no significant
      improvement in vulvar algesiometer score. CONCLUSION: The vulvar algesiometer
      provides an easy noninvasive means of assessing vestibular tenderness in vulvar
      vestibulitis syndrome that is well tolerated by the patients and provides a
      degree of biofeedback for them.

PMID- 10411803
TI  - Severe immune hemolytic anemia associated with prophylactic use of cefotetan in
      obstetric and gynecologic procedures.
AB  - Second- and third-generation cephalosporins, especially cefotetan, are
      increasingly associated with severe, sometimes fatal immune hemolytic anemia. We
      noticed that 10 of our 35 cases of cefotetan-induced hemolytic anemias were in
      patients who had received cefotetan prophylactically for obstetric and
      gynecologic procedures. Eight of these cases of severe immune hemolytic anemia
      are described.

PMID- 10411804
TI  - Effects of acute and chronic hypoxia on nitric oxide-mediated relaxation of fetal
      guinea pig arteries.
AB  - OBJECTIVE: These studies tested whether fetal artery reactivity is sensitive to
      both acute changes in oxygen levels (in vitro) and chronic changes (in utero).
      STUDY DESIGN: Pregnant guinea pigs near term were exposed to either normoxia or
      hypoxia (12% oxygen) for 4 or 7 days. The effect of decreasing PO (2 ) in vitro
      (acute hypoxia) on relaxation in response to acetylcholine, A23187, sodium
      nitroprusside, and 8-bromo-cyclic guanosine monophosphate was measured in
      isolated carotid arteries from normoxic fetuses. In separate experiments
      relaxation in response to acetylcholine and sodium nitroprusside of endothelially
      intact and denuded fetal arteries from fetuses exposed to normoxic conditions and
      long-term (4 and 7 days) hypoxic conditions was measured in the presence and
      absence of nitro-L -arginine (10(-4) mol/L). RESULTS: Acute hypoxia inhibited
      endothelium-dependent relaxation in response to acetylcholine and A23187,
      increased sensitivity to sodium nitroprusside, but had no effect on relaxation in
      response to 8-bromo-cyclic guanosine monophosphate. Chronic hypoxia (4 but not 7
      days) inhibited maximal relaxation of arteries in response to acetylcholine but
      not relaxation of arteries in response to sodium nitroprusside with respect to
      relaxation seen in arteries from normoxic fetuses. Nitro-L -arginine attenuated
      the differences between normoxic and hypoxic fetuses in acetylcholine response.
      CONCLUSION: Hypoxia may alter relaxation of fetal arteries by decreasing the
      availability of oxygen for nitric oxide production and causing vascular
      adaptations related to altered nitric oxide release.

PMID- 10411805
TI  - Misleading authors' inferences in obstetric diagnostic test literature.
AB  - OBJECTIVE: Our goal was to determine the validity of authors' inferences about
      the value of the cervico-vaginal fetal fibronectin test in the prediction of
      preterm birth and the utility of uterine artery Doppler waveform analysis in the
      prediction of preeclampsia. STUDY DESIGN: We evaluated all 35 diagnostic test
      studies (14 on fetal fibronectin and 21 on uterine artery Doppler) included in 2
      meta-analyses. The information on authors' conclusions regarding the value of a
      positive or negative test result was independently abstracted from each article
      by 2 reviewers, and it was classified as definitely useful, moderately useful,
      slightly useful, or not at all useful. For the "gold" standard, likelihood ratios
      of >10 and <0. 1 were regarded as definitely useful, 5 to 10 and 0.1 to 0.2 were
      regarded as moderately useful, 2 to 5 and 0.2 to 0.5 were regarded as slightly
      useful, and 1 to 2 and 0.5 to 1 were regarded as not at all useful. The agreement
      between the authors and the reference standard was computed by simple percentage
      agreement and weighted kappa statistic. RESULTS: Among articles assessing the
      diagnostic value of fetal fibronectin the simple agreement between the authors
      and the "gold" standard was 26% (7/26) with a kappa of 0.05 (P =.83), and authors
      overestimated the value of the test result in 66% (17/26) of instances.
      Similarly, among articles assessing uterine artery Doppler the simple agreement
      between the authors and the "gold" standard was 31% (13/42) with a kappa of 0.28
      (P =.31), and authors overestimated the value of the test result in 48% (20/42)
      of instances. CONCLUSION: Authors claimed more positive conclusions than could be
      supported by their data. When studies are reported in a misleading manner, the
      chance of misinterpretation on the part of the clinical reader is increased. The
      use of explicit criteria that are based on likelihood ratios may reduce the risk
      of erroneous inferences.

PMID- 10411806
TI  - Functional and molecular characterization of nitric oxide synthase in the
      endometrium and myometrium of pregnant sheep during the last third of gestation.
AB  - OBJECTIVE: This study was undertaken to characterize the biochemical and
      expression profiles of the nitric oxide synthase isoforms present in the sheep
      uterus during late gestation. STUDY DESIGN: Myometrium and endometrium were
      obtained from 28 time-mated pregnant sheep that were under halothane general
      anesthesia. Tissues were kept frozen at -80 degrees C until they were homogenized
      for the measurement of (1) nitric oxide synthase activity according to the carbon
      14-labeled arginine-citrulline conversion assay, (2) nitric oxide synthase
      protein mass according to Western blot analysis, and (3) nitric oxide synthase
      messenger ribonucleic acid according to the ribonuclease protection assay. The
      nitric oxide synthase activity assay included 8 parallel treatments for
      biochemical characterization, in particular with the arginase inhibitors
      ornithine and (+)-S-2-amino-5-iodoacetamidopentanoic acid. RESULTS: The
      biochemical characterization of nitric oxide synthase indicated that the
      predominant form of nitric oxide synthase in endometrium and myometrium (80%-90%)
      was calcium-calmodulin dependent. In endometrium 50% of reduced nicotinamide
      adenine dinucleotide-dependent arginine metabolism was accounted for by the
      presence of alternative arginine metabolic pathways. Expressions of type 1 and
      type 3 nitric oxide synthase were demonstrated in endometrium and myometrium by
      Western blot and ribonuclease protection assay. Although no significant decrease
      in nitric oxide synthase activity or protein mass was observed, a significant
      decrease in myometrial type 1 nitric oxide synthase messenger ribonucleic acid
      occurred in sheep not in labor at 140 days' gestation (P <.05 by analysis of
      variance; term is 144 +/- 5 days). CONCLUSION: In the gravid sheep uterus the
      predominant nitric oxide synthase isoforms are type 1 in myometrium and type 3 in
      endometrium. Despite a decrease in type 1 nitric oxide synthase messenger
      ribonucleic acid, enzymatic activity and type 1 nitric oxide synthase protein
      mass do not decrease before parturition.

PMID- 10411807
TI  - Polymorphism for mutation of cytosine to thymine at location 677 in the
      methylenetetrahydrofolate reductase gene is associated with recurrent early fetal
      loss.
AB  - OBJECTIVE: This study was undertaken to determine whether a cytosine to thymine
      mutation at nucleotide 677 in the gene encoding for methylenetetrahydrofolate
      reductase is associated with particular subtypes of recurrent unexplained
      spontaneous abortion. STUDY DESIGN: The prevalences of cytosine to thymine
      mutation at nucleotide 677 in the gene encoding for methylenetetrahydrofolate
      reductase among 41 patients with recurrent unexplained spontaneous abortions and
      among 18 healthy control subjects were determined with polymerase chain reaction.
      RESULTS: Homozygosity and heterozygosity for the cytosine to thymine mutation at
      nucleotide 677 in the gene encoding for methylenetetrahydrofolate reductase were
      observed at nonsignificantly different rates among patients and control subjects
      (9% and 48% versus 22% and 38%, respectively, P <.95). Among patients with
      recurrent unexplained spontaneous abortions both homozygosity and heterozygosity
      were associated with significantly increased prevalence of recurrent early fetal
      loss rather than with repeated anembryonic gestations (P <.0001). CONCLUSION: The
      observation that polymorphism for the cytosine to thymine mutation at nucleotide
      677 in the gene encoding for methylenetetrahydrofolate reductase is associated
      with repeated early fetal losses rather than with anembryonic gestations
      strengthens the argument for the role of hypercoagulability and abnormal
      uteroplacental vasculature in recurrent spontaneous abortion.

PMID- 10411808
TI  - Second-trimester maternal serum inhibin A concentration as an early marker for
      preeclampsia.
AB  - OBJECTIVE: Maternal serum inhibin A concentration is elevated in established
      preeclampsia. The aim of this study was to investigate whether this relationship
      antedates the appearance of the classic signs of preeclampsia. STUDY DESIGN: A
      retrospective analysis was performed on trisomy 21 screening data from 685 women
      at between 15 and 19 weeks' gestation. The main outcome measures were
      preeclampsia and small for gestational age (<5th percentile) infants. RESULTS:
      Preeclampsia developed in 35 women (5.5%). Women with inhibin A concentration
      >2.0 multiples of the median were significantly more likely to acquire
      preeclampsia (P <.00001) and to be delivered of a small for gestational age
      infant (<5th percentile, P <.00001) than were women with inhibin A concentration
      </=2.0 multiples of the median. The odds ratios were 9.4 (95% confidence interval
      4.6-19.3) for development of preeclampsia and 18.2 (95% confidence interval 6. 0
      54.8) for preeclampsia necessitating delivery at <37 weeks' gestation. The
      association remained statistically significant for nulliparous women. CONCLUSION:
      Elevated maternal inhibin A concentration in the second trimester was strongly
      associated with a subsequent risk of preeclampsia. The potential role of second
      trimester inhibin A measurement in a screening strategy for preeclampsia needs to
      be investigated further.

PMID- 10411809
TI  - The location of chronic pregnancy hypertension on the vasoconstriction-volume
      spectrum: working hypothesis.
AB  - OBJECTIVE: The purpose of this study was to examine whether volume loading is a
      factor in chronic pregnancy hypertension. STUDY DESIGN: Five patients with
      chronic hypertension performed home self-monitoring daily with a noninvasive
      pressure transducer from a fingertip. Determinants of mean arterial pressure were
      computed from the pressure data and a concurrent electrocardiogram. For this
      study blood pressure and rapid ejection time, which is an empiric indicator of
      arterial compliance, were evaluated during antihypertensive therapy. Data were
      transmitted by facsimile to the hospital. RESULTS: One patient with hypertension
      who was admitted to the study at 10 weeks' gestation became normotensive with a
      diuretic (furosemide) alone. Medication was discontinued at 23 weeks' gestation.
      This patient remained normotensive until delivery at 41 weeks' gestation. Blood
      pressure was controlled with furosemide combined with nifedipine and labetolol in
      the other 4 cases. Three patients were studied with concurrent blood pressure and
      rapid ejection time measurements made before and after antihypertensive
      medication. All 3 showed decreases in these measurements with medication.
      CONCLUSION: Both volume excess and vasoconstriction should be considered in the
      pathogenesis of chronic pregnancy hypertension.

PMID- 10411810
TI  - Puerperal septic pelvic thrombophlebitis: incidence and response to heparin
      therapy.
AB  - OBJECTIVE: Before the availability of modern imaging studies the diagnosis of
      septic pelvic thrombophlebitis causing prolonged puerperal fever was difficult to
      confirm without surgical exploration. With the use of computed tomography
      infection-related pelvic phlebitis can now be confirmed, and this study was
      designed to determine its incidence after delivery. We also designed a randomized
      clinical trial to evaluate the efficacy of heparin added to antimicrobial therapy
      for treatment of women with septic phlebitis. STUDY DESIGN: We studied women who
      had pelvic infection and fever that persisted after 5 days despite adequate
      antimicrobial therapy with clindamycin, gentamicin, and ampicillin. After giving
      consent study participants underwent abdominopelvic computed tomographic imaging.
      Women with pelvic thrombophlebitis were randomly assigned to 1 of 2 management
      schemes that included continuation of antimicrobial therapy, either alone or with
      the addition of heparin, until the temperature was </=37.5 degrees C for 48
      hours. RESULTS: During the 3-year study period 44,922 women were delivered at
      Parkland Hospital; among these 8535 (19%) were delivered by the cesarean route.
      There were 69 women who met criteria for prolonged infection, and 15 (22%) of
      these were found to have septic pelvic thrombophlebitis. Four had infection after
      vaginal delivery and 11 had been delivered by the cesarean route. Of 14 women
      randomly assigned to therapy, 8 were assigned to receive continued antimicrobial
      therapy without the addition of heparin and the other 6 were assigned to receive
      heparin therapy in addition to the antimicrobial agents. According to an intent
      to-treat analysis there was no significant difference between the responses of
      women with pelvic infection who were and were not given heparin therapy.
      Specifically, women not given heparin were febrile for 140 +/- 39 hours compared
      with 134 +/- 65 hours for women who received heparin (P =.83). Duration of
      hospitalization was also similar between the 2 groups at 10.6 +/- 1.9 days for
      those with thrombosis who were given antimicrobial agents alone and 11.3 +/- 1.2
      days for women who also received heparin (P >.5). The 54 women with persistent
      fever but without computed tomographic evidence of septic pelvic thrombophlebitis
      were hospitalized for a mean of 12.0 +/- 4.1 days, compared with 10.9 +/- 2.9
      days for women in whom thrombosis was diagnosed (P =.14). These women were
      followed up for >/=3 months post partum and none showed evidence of reinfection,
      embolic episodes, or postphlebitic syndrome. CONCLUSIONS: The overall incidence
      of septic pelvic thrombophlebitis was 1:3000 deliveries. The incidence was about
      1:9000 after vaginal delivery and 1:800 after cesarean section. Women given
      heparin in addition to antimicrobial therapy for septic thrombophlebitis did not
      have better outcomes than did those for whom antimicrobial therapy alone was
      continued. These results also do not support the common empiric practice of
      heparin treatment for women with persistent postpartum infection.

PMID- 10411811
TI  - Oral methotrexate compared with injected methotrexate when used with misoprostol
      for abortion.
AB  - OBJECTIVE: This study was undertaken to compare oral to injected methotrexate
      with respect to effectiveness, side effects, and acceptability. STUDY DESIGN: One
      hundred women in an urban primary care practice were randomly assigned in phase 1
      to receive 50 mg/m(2) methotrexate by either the oral or the injected route. In
      phase 2 another 87 women were allowed to choose between the oral and injected
      routes. In both phases and in all groups the methotrexate was followed 5 to 7
      days later by misoprostol administered vaginally by the patient. The main outcome
      was the success rate (the number whose pregnancies aborted without surgery);
      other outcomes included side effects and acceptability. RESULTS: There were no
      differences in rates of success, side effects, or acceptability between groups
      receiving oral and injected methotrexate. Among the women in phase 2 the oral
      form was chosen by 57.5%. CONCLUSION: This study indicates that for medical
      abortions induced with methotrexate and misoprostol it is possible to offer both
      the oral and injected routes of methotrexate without sacrificing efficacy and
      that about half of the women offered a choice will choose the oral route.

PMID- 10411812
TI  - Collagenolysis in the lower uterine segment during parturition at term:
      correlations with stage of cervical dilatation and duration of labor.
AB  - OBJECTIVE: The objective of this study was to quantify the extent of neutrophil
      infiltration and the concentrations of enzymes involved in collagenolysis in the
      lower uterine segment in relation to the degree of cervical dilatation and the
      duration of labor. STUDY DESIGN: Biopsy specimens of the lower uterine segment
      were obtained from 62 women undergoing cesarean section at term. The number of
      extravascular neutrophils was assessed with enzyme histochemical evaluation, and
      the concentrations of matrix metalloproteinase-8, matrix metalloproteinase-9, and
      tissue inhibitor of metalloproteinases-1 by were assessed by enzyme-linked
      immunosorbent assay. RESULTS: The neutrophil count and the concentrations of
      matrix metalloproteinase-8, matrix metalloproteinase-9, and tissue inhibitor of
      metalloproteinases-1 increased with increasing cervical dilatation. At >6 cm the
      neutrophil count and the concentrations of matrix metalloproteinase-8, matrix
      metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 were
      significantly higher than at <2 cm. An association with the duration of labor was
      found for the neutrophil count and the concentrations of matrix metalloproteinase
      9 and tissue inhibitor of metalloproteinases-1. Multiple linear regression
      analysis showed that the degree of cervical dilatation is more closely related to
      the 4 laboratory parameters investigated than to the duration of labor.
      CONCLUSION: The findings support the hypothesis that local changes (ie,
      collagenolysis) in the lower uterine segment unrelated to uterine activity play a
      crucial role in cervical dilatation at term.

PMID- 10411813
TI  - The effect of chronic nitric oxide synthase inhibition on blood pressure and
      heart rate in unrestrained pregnant rats as recorded by radiotelemetry.
AB  - OBJECTIVES: The objective of this study was to determine the effect of chronic
      nitric oxide synthase inhibition on heart rate and intravascular blood pressure
      in unrestrained pregnant rats as recorded by radiotelemetry. STUDY DESIGN: Heart
      rate and systolic and diastolic blood pressures were monitored beginning with day
      6 of pregnancy and until 1 week post partum with a radiotelemetric device. On day
      10 of pregnancy osmotic minipumps were implanted subcutaneously and loaded to
      continuously deliver N(G)-nitro-L -arginine methyl ester (50 mg/d per rat, n = 6
      animals) or vehicle (control group, n = 6 animals). RESULTS: Blood pressure in
      the animals treated with N(G)-nitro-L -arginine methyl ester significantly
      increased compared with that in the control group and heart rate significantly
      decreased immediately after nitric oxide synthase blockade. Blood pressure then
      trended downward as gestation progressed, until the difference between the
      control group and the group treated with N(G)-nitro-L -arginine methyl ester
      became nonsignificant after day 17. Refractoriness to nitric oxide synthase
      blockade was especially evident in the diastolic pressure. Systolic, diastolic,
      and mean blood pressures in the rats treated with N(G)-nitro-L -arginine methyl
      ester were again significantly higher than those in the control group immediately
      after delivery and remained so despite a lower heart rate until the experiment
      was ended on postpartum day 6. CONCLUSIONS: Radiotelemetry can be used to monitor
      heart rate and intra-arterial blood pressure in unstressed, unrestrained animals.
      Chronic inhibition of nitric oxide does not cause sustained hypertension
      throughout pregnancy. Nitric oxide does not appear to be the only factor
      responsible for the vascular changes in pregnancy. The factors responsible for
      the refractoriness to nitric oxide synthase blockade are specific to pregnancy
      and disappear immediately after delivery.

PMID- 10411814
TI  - Incorrect recall of residual risk three years after carrier screening for cystic
      fibrosis: a comparison of two-step and couple screening.
AB  - OBJECTIVE: This study was undertaken to compare long-term recall of the meaning
      of test results after a negative result of 2-step or couple antenatal screening.
      STUDY DESIGN: In a randomized controlled trial a subject-completed questionnaire
      was sent to 275 women who had undergone couple testing 3 years earlier and 83
      women who had undergone 2-step testing 3 years earlier (n = 263/358 for a
      response rate of 73%). The main outcome measure was understanding of test
      results. RESULTS: Three years after testing women who had undergone couple
      testing were 4.5 times (95% confidence interval 2.4-8.4 times) more likely than
      those who had undergone 2-step testing to accurately recall that the test result
      meant that they were unlikely to be carriers for cystic fibrosis (80%, 95%
      confidence interval 74%-86%, versus 49%, 95% confidence interval 36%-61%).
      Anxiety level, plans to have more children, and age were unrelated to recall.
      CONCLUSION: The results of this study, together with those from other
      evaluations, suggest that not only does couple testing avoid the high levels of
      anxiety associated with 2-step testing but it also results in greater awareness
      of the residual risk inherent in a negative screening test result.

PMID- 10411815
TI  - Neopterin concentrations in fetal and maternal blood: a marker of cell-mediated
      immune activation.
AB  - OBJECTIVE: Neopterin is generated by macrophages and monocytes in response to
      cytokine and endotoxin stimulation and is a sensitive marker of the severity of
      infectious-, autoimmune-, and alloimmune-mediated inflammatory disorders. This
      study was designed to evaluate fetal and maternal neopterin concentrations during
      the second half of pregnancy. STUDY DESIGN: We conducted a cross-sectional
      analysis of serum neopterin values with a sensitive radioimmunoassay in 35 paired
      fetal and maternal and 8 neonatal samples. The fetal and maternal samples were
      obtained between 20 and 38 weeks' gestation at the time of diagnostic
      cordocentesis. All maternal, fetal, and neonatal samples were derived from
      uncomplicated pregnancies resulting in term delivery of appropriately grown
      fetuses. RESULTS: Fetal neopterin concentrations increased across gestation (r =
      0.64, P <.001), and mean values were significantly higher than paired maternal
      values (6.28 [+/-2.44] ng/mL vs 2.05 [+/-0.87] ng/mL, P <.001]. In contrast,
      maternal neopterin concentrations did not correlate with gestational age (r =
      0.22, P =.24). No significant correlation was found between fetal and maternal
      values (r = 0.34, P =.07). CONCLUSION: Fetal neopterin values rise significantly
      across gestation. They are substantially greater than maternal levels and are not
      correlated significantly with paired maternal levels. These findings are the
      first report of a physiologically normal range for fetal neopterin concentrations
      in a sample of uncomplicated pregnancies. The values suggest progressive
      increases in fetal cell-mediated immunity and macrophage-monocyte activation as
      gestation progresses.

PMID- 10411816
TI  - Relationship of umbilical vein blood flow to growth parameters in the human
      fetus.
AB  - OBJECTIVE: Our purposes were to determine the relationship of the growth of
      umbilical blood flow to growth in body measurements of human fetuses in
      uncomplicated pregnancies. The study also aimed to assess the relative
      contributions of growth in umbilical vein diameter and of increased velocity to
      the increase in umbilical blood flow. STUDY DESIGN: An animal study was conducted
      to assess the accuracy of umbilical vein blood flow measurements obtained by
      triplex mode ultrasonography. Seven pregnant ewes underwent triplex mode
      umbilical vein flow determination. These results were compared with historical
      flow data obtained by a steady-state diffusion technique in 34 ewes matched for
      gestational age and weight. In a separate study performed on human beings,
      reproducibility and precision of triplex mode flow determination were assessed,
      as were the relationships between umbilical vein flow and gestational age and
      head and abdominal circumferences. This cross-sectional study was performed with
      70 healthy fetuses ranging from 20 weeks' gestation to term. Best-fit
      interpolating equations and confidence limits were calculated for blood flow
      measurements versus gestational age and head and abdominal circumferences.
      RESULTS: In the validation study performed on sheep there were no significant
      differences between triplex mode and steady-state measurement groups with respect
      to gestational age or weight. The umbilical vein flows were similar between
      triplex mode and steady-state measurement groups (P =.881). In the human study
      the intraobserver and interobserver coefficients of variation for the vein
      diameter, mean velocity, and absolute umbilical vein blood flow varied from 2.9%
      to 12.7%. The mean duration of examination was 3 +/- 1 minutes. The umbilical
      vein diameter and mean velocity increased throughout pregnancy. The absolute
      umbilical vein flow increased exponentially from 97.3 mL/min at midgestation to
      529.1 mL/min at 38 weeks' gestation, whereas umbilical vein flow per kilogram of
      fetal weight did not change significantly with gestational age. There was a
      strong correlation between absolute umbilical vein flow and the fetal head and
      abdominal circumferences. CONCLUSIONS: The triplex mode ultrasonographic
      technique can play an innovative role in obtaining quick and reproducible
      measurements of umbilical vein blood flow. The approach was validated with a
      sheep model. Umbilical vein blood normalized for fetal weight (milliliters per
      minute per kilogram of fetal weight) and absolute flow (in milliliters per
      minute) are consistent with previous human studies. We have established new
      reference values of umbilical vein blood flow relative to head and abdominal
      circumferences. The growth of umbilical venous diameter accounted for most of the
      growth in umbilical vein flow.

PMID- 10411817
TI  - Normal expression of tissue factor, thrombomodulin, and annexin V in placentas
      from women with antiphospholipid syndrome.
AB  - OBJECTIVE: Placentas from pregnancies complicated by antiphospholipid syndrome
      often show thromboses and infarction, which may result from aberrations in
      placental coagulant pathways. We tested the hypothesis that alterations in tissue
      factor, thrombomodulin, and annexin V expressions contribute to poor pregnancy
      outcome associated with antiphospholipid syndrome. STUDY DESIGN: Frozen sections
      from random biopsy samples of the basal plates of placentas from patients with
      primary antiphospholipid syndrome (n = 9), patients with secondary
      antiphospholipid syndrome (n = 3), and gestational age-matched control subjects
      (n = 10) were immunostained for tissue factor, thrombomodulin, and annexin V.
      Intensity of immunostaining was assessed by means of quantitative image analysis.
      Annexin V protein expression was evaluated with Western blotting techniques.
      RESULTS: Tissue factor was expressed in the perivascular cells of the villous
      vasculature. Thrombomodulin and annexin V immunostaining was localized to the
      syncytiotrophoblast. There were no differences in the intensity of immunostaining
      for tissue factor, thrombomodulin, and annexin V between placentas from women
      with antiphospholipid syndrome and those from control subjects. Western blot
      analysis of annexin V expression showed no differences between study patients and
      control subjects. CONCLUSION: Alterations in placental coagulant pathways
      involving tissue factor, thrombomodulin, and annexin V do not contribute to poor
      pregnancy outcome associated with antiphospholipid syndrome.

PMID- 10411818
TI  - Neonatal nucleated red blood cell counts in growth-restricted fetuses:
      relationship to arterial and venous Doppler studies.
AB  - OBJECTIVE: Elevated nucleated red blood cell count in neonatal blood and Doppler
      detected circulatory decompensation in fetuses with intrauterine growth
      restriction are associated with hypoxemia. We sought to determine the
      relationship between the nucleated red blood cell count at birth and the
      circulatory status of fetuses with intrauterine growth restriction. STUDY DESIGN:
      Eighty-four fetuses with elevated umbilical artery pulsatility index values >2 SD
      above the gestational age mean and a subsequent birth weight <10th percentile
      were examined serially. Umbilical and middle cerebral artery pulsatility index,
      inferior vena cava and ductus venosus peak velocity index, and flow pattern in
      the umbilical vein (umbilical vein constant vs pulsatile) were recorded. Fetuses
      were grouped as follows, on the basis of the last examination before delivery: 1,
      elevated umbilical artery pulsatility index only; 2, middle cerebral artery
      pulsatility index >2 SD below the gestational age mean in addition to abnormal
      umbilical artery pulsatility index; 3, either peak velocity index >2 SD above the
      gestational age mean in the inferior vena cava and ductus venosus or pulsatile
      flow in the umbilical vein, or both. Nucleated red blood cells per 100 white
      blood cells were ascertained in a peripheral blood sample obtained within 1 hour
      of delivery with daily follow-up samples until the nucleated red blood cell count
      was <5/100 white blood cells. RESULTS: Groups 2 (median 38.5, range 1-273) and 3
      (median 145, range 2-3180) had higher nucleated red blood cell counts than group
      1 (median 8.5, range 1-270) (P <.05 and P <.005, respectively). The persistence
      of the nucleated red blood cell count elevation was also longer in groups 3
      (median 4 days, range 1-19 days) and 2 (median 2. 5 days, range 1-7 days) than in
      group 1 (median 1 day, range 1-8 days). Neonates in group 3 also had lower
      platelet count, hemoglobin value, hematocrit value, and white blood cell count.
      The umbilical cord artery bicarbonate level was the strongest independent
      determinant of the peak nucleated red blood cell count and persistence of
      nucleated red blood cell elevation (r (2) = 0.27, P <. 001 and r (2) = 0.47, P
      <.0001). CONCLUSION: Increasing abnormality of arterial and venous flows in
      fetuses with intrauterine growth restriction is associated with increasing
      nucleated red blood cell count at birth. Metabolic acidemia rather than altered
      PO (2 ) associated with this circulatory state appears to be the main determinant
      of the rise in nucleated red blood cells.

PMID- 10411819
TI  - Nucleated red blood cells as a marker of acidemia in term neonates.
AB  - OBJECTIVES: Nucleated red blood cells are produced in increased numbers under
      hypoxic conditions. We sought to examine the relationship between nucleated red
      blood cell count in the circulations of term neonates and other possible markers
      of fetal hypoxia. STUDY DESIGN: We prospectively collected umbilical blood from
      all live-born neonates delivered at our institution. Arterial blood was analyzed
      for pH and blood gas values. Venous blood was analyzed for nucleated red blood
      cell count. We reviewed the medical records for maternal data and neonatal
      outcomes of gestations of >/=37 weeks' duration. RESULTS: We evaluated 1561
      cases. The mean nucleated red blood cell count per 100 white blood cells was 9.2
      +/- 18.1 (range, 0-327). Nucleated red blood cell counts were higher in infants
      with pH <7.20 (P =.001). Both patients with respiratory acidemia and patients
      with uncompensated metabolic acidemia had elevated nucleated red blood cell
      counts (P =.013 and P =.014, respectively). As umbilical artery pH and base
      excess decreased, nucleated red blood cells became more prevalent. Elevated
      nucleated red blood cell counts were associated with presence of meconium (P =.
      020) and neonatal intensive care unit admission (P =.024). CONCLUSIONS: We found
      that nucleated red blood cell counts vary widely in the circulation of term
      neonates. Elevated nucleated red blood cell counts are associated with fetal
      acidemia, meconium, and neonatal intensive care unit admission.

PMID- 10411820
TI  - The effects of first-trimester diabetes control on the incidence of macrosomia.
AB  - OBJECTIVE: The aim of this study was to explore the association between
      glycosylated hemoglobin concentrations during pregnancy and macrosomia. STUDY
      DESIGN: One hundred thirty-six pregnancies in 120 women with type 1 or type 2
      diabetes were studied longitudinally between January 1, 1991, and December 31,
      1996. Glycosylated hemoglobin concentration and several maternal variables of
      mothers of neonates who were large for gestational age were compared with those
      of neonates who were appropriate for gestational age. Receiver-operator
      characteristic curves and regression analyses were used to determine a threshold
      related to macrosomia and to assess its predictive value. RESULTS: Glycosylated
      hemoglobin concentrations throughout pregnancy were higher in mothers of neonates
      who were large for gestational age (n = 65) than in mothers of neonates who were
      appropriate for gestational age (n = 71, P <. 001). A first-trimester
      glycosylated hemoglobin concentration of >/=5.5% (3 SD above the normal mean) was
      established by receiver-operator characteristic curves as the strongest predictor
      of macrosomia and yielded an odds ratio of 24 in multiple logistic regression
      analysis. CONCLUSION: Macrosomia is determined mainly by first-trimester diabetes
      control.

PMID- 10411821
TI  - Predicting risk of preterm delivery by second-trimester measurement of maternal
      plasma corticotropin-releasing hormone and alpha-fetoprotein concentrations.
AB  - OBJECTIVE: Many women who have preterm labor have abnormally high plasma
      concentrations of the placental peptide corticotropin-releasing hormone and the
      fetal product alpha-fetoprotein in early pregnancy. This study was designed to
      evaluate the ability of these biochemical tests and a clinical risk factor score
      to prospectively discriminate pregnancies at high risk for preterm delivery.
      STUDY DESIGN: Eight hundred sixty women were studied prospectively from the early
      second trimester until delivery. A risk factor score for preterm delivery was
      calculated from the clinical history and maternal plasma corticotropin-releasing
      hormone and alpha-fetoprotein concentrations were measured by radioimmunoassay
      between 17 and 30 weeks' gestation. The risk factor score, corticotropin
      releasing hormone concentration, and alpha-fetoprotein concentration for each
      woman were expressed as individual odds or likelihood ratios for preterm delivery
      and as a combined risk estimate derived from the 3 tests. RESULTS: Sixty women
      had preterm deliveries (n = 37 spontaneous labor, n = 23 planned deliveries), and
      these women had significantly higher concentrations of corticotropin-releasing
      hormone (median 1.92 multiples of the median) and alpha-fetoprotein (median 1.32
      multiples of the median) than did women with term deliveries (median 1.00
      multiples of the median, P <.001 for both tests), with these abnormalities being
      evident from early in the second trimester. The risk factor score was >/=10 in
      28% of women with preterm delivery and 7% of women with term delivery. The
      combination of all 3 markers resulted in a higher detection rate and a higher
      positive predictive value than the risk factor score, corticotropin-releasing
      hormone concentration, or alpha-fetoprotein concentration alone, correctly
      discriminating 37% of women who would have preterm deliveries with a false
      positive rate of 5%. The positive predictive value was also 37% (odds of being
      affected given a positive result were 1:1.7). CONCLUSIONS: The combination of
      measurement of maternal plasma corticotropin-releasing hormone and alpha
      fetoprotein concentrations in the second trimester with risk factor scoring
      provides a more accurate indicator of the risk of preterm delivery than does risk
      factor scoring alone. This method of risk assessment may therefore be of use in
      targeting prevention strategies.

PMID- 10411822
TI  - Doppler ultrasonographic evidence of intrapartum brain-sparing effect in fetuses
      with low oxygen saturation according to pulse oximetry.
AB  - OBJECTIVE: This study was undertaken to verify by means of Doppler
      ultrasonography and simultaneous fetal pulse oximetry the redistribution of fetal
      blood flow in favor of the brain during intrapartum hypoxemia. STUDY DESIGN:
      During labor 11 term fetuses with abnormal heart rate patterns and arterial
      oxygen saturation <30% and 14 control term fetuses with normal oxygen saturation
      were simultaneously monitored by pulse oximetry and Doppler ultrasonography. The
      results were compared with the Student t test. RESULTS: The blood flow velocity
      in the middle cerebral artery was significantly higher in the presence of reduced
      oxygen saturation, implying lower pulsatility and resistance indices (P <.001).
      The reduction of blood flow in the umbilical artery was not significant (P =.61).
      CONCLUSION: Simultaneous intrapartum pulse oximetry and Doppler ultrasonography
      proved that reduced arterial oxygen saturation (<30%) is associated with profound
      changes in fetal hemodynamics and could be tolerated for only a limited period,
      which should be the subject of further studies.

PMID- 10411823
TI  - New opportunities for researchers in obstetrics and gynecology through programs
      supported by the National Institute of Child Health and Human Development.
AB  - The organization of the National Institute of Child Health and Human Development
      and its funding procedures are reviewed from the perspective of the specialty of
      obstetrics and gynecology. The opportunities for research training and career
      development recently made available by the National Institute of Child Health and
      Human Development are described. Active and productive use of these opportunities
      by the academic community is important.

PMID- 10411824
TI  - Obstetric management in 219 cases of infants with hypoplastic left heart
      syndrome.

PMID- 10411825
TI  - A trial of vaginal route for hysterectomy.

PMID- 10411830
TI  - Preparation, (99m)Tc-labeling, and in vitro characterization of hynic and N(3)S
      modified RC-160 and

PMID- 10411827
TI  - Comment on reduced consumption of maternal red blood cells in alloimmunized fetus
      compared with that of volunteers is still questionable.

PMID- 10411831
TI  - Cystinuria subtype and nephrolithiasis.

PMID- 10411832
TI  - Halothane, children and original sources.

PMID- 10411833
TI  - The use of NSAIDs in asthmatic children: a questionnaire survey.

PMID- 10411835
TI  - Marshall-Marchetti-Krantz urethropexy and Burch colposuspension for stress
      urinary incontinence in women with low pressure and hypermobility of the urethra:
      early results of a prospective randomized clinical trial.
AB  - OBJECTIVE: The aim of the study was to compare the effects of Burch
      colposuspension and Marshall-Marchetti-Krantz urethropexy with videourethroscopic
      control in the correction of stress urinary incontinence in patients with low
      pressure and hypermobility of the urethra. STUDY DESIGN: Thirty women were
      randomly assigned to undergo 1 of the 2 surgical procedures from November 1993 to
      May 1996 (15 Burch colposuspensions and 15 Marshall-Marchetti-Krantz
      urethropexies) and were evaluated subjectively and objectively for stress urinary
      incontinence at 2 and 12 months. Data obtained were analyzed with the Student t
      test, the Fisher exact test, and the Wilcoxon signed rank test. RESULTS: At 1
      year of follow-up 15 women in the Marshall-Marchetti-Krantz urethropexy group
      (100%) and 10 women in the Burch colposuspension group (66%) were subjectively
      considered cured (P =.02, 2-tailed Fisher exact test), and stress test results
      were negative in 14 women (93%) and 8 women (53%), respectively (P =.017, 2
      tailed Fisher exact test). The resumption of spontaneous voiding was attained
      after 6.5 +/- 3.3 days in the Burch colposuspension group and in 20.5 +/- 13.4
      days in the Marshall-Marchetti-Krantz urethropexy group (P <.001, 2-tailed
      Wilcoxon rank sum test). CONCLUSION: The high cure rate and low associated
      morbidity mark the Marshall-Marchetti-Krantz procedure with videourethroscopic
      control as more effective than Burch colposuspension in repairing stress urinary
      incontinence associated with low pressure and hypermobility of the urethra.

PMID- 10411837
TI  - May-Hegglin anomaly and uncomplicated vaginal delivery: a report of 41 cases.

PMID- 10411838
TI  - A novel correction of inverted nipples during pregnancy.

PMID- 10411839
TI  - Pregnancy after radical vaginal trachelectomy.

PMID- 10411840
TI  - They should have reviewed the obstetric literature.

PMID- 10411841
TI  - Increased superoxide in heart failure: a biochemical baroreflex gone awry.

PMID- 10411843
TI  - Muscle and skin sympathetic nerve traffic during the "white-coat" effect.
AB  - BACKGROUND: Sphygmomanometric blood pressure measurements induce an alerting
      reaction and thus an increase in the patient's blood pressure and heart rate.
      Whether and to what extent this "white-coat" effect is accompanied by detectable
      changes in sympathetic nerve traffic has never been investigated. METHODS AND
      RESULTS: In 10 mild untreated essential hypertensives (age 37.9+/-3. 8 years,
      mean+/-SEM), we measured arterial blood pressure (by Finapres), heart rate (by
      ECG), and postganglionic muscle and skin sympathetic nerve activity via
      microneurography. Measurements were performed with the subject supine during (1)
      a 15-minute control period, (2) a 10-minute visit by a doctor unfamiliar to the
      patient who was in charge of measuring his or her blood pressure by
      sphygmomanometry, and (3) a 15-minute recovery period after the doctor's
      departure. The entire procedure was performed twice at a 45-minute interval to
      obtain, in separate periods, muscle or skin sympathetic nerve traffic recordings,
      whose sequence was randomized. The doctor's visit induced a sudden, marked, and
      prolonged pressor and tachycardic response, accompanied by a significant increase
      in skin sympathetic nerve traffic (+38.6+/-6.7%, P<0.01). In contrast, muscle
      sympathetic nerve traffic was significantly inhibited (-25. 5+/-4.1%, P<0.01).
      All changes persisted throughout the doctor's visit and, with the exception of
      skin sympathetic nerve traffic, showed a slow rate of disappearance after the
      doctor's departure. CONCLUSIONS: Thus, the pressor and tachycardic responses to
      the alerting reaction that accompanies sphygmomanometric blood pressure
      measurement is characterized by a behavior of the adrenergic nervous system that
      causes muscle sympathoinhibition and skin sympathoexcitation.

PMID- 10411842
TI  - Plasma alpha-tocopherol and coronary endothelium-dependent vasodilator function.
AB  - BACKGROUND: In the presence of atherosclerosis, the coronary endothelial
      vasomotor response to acetylcholine is frequently abnormal but is variable
      between patients. We tested the hypothesis that the plasma concentration of alpha
      tocopherol is associated with the preservation of nitric oxide-mediated
      endothelium-dependent vasomotion. METHODS AND RESULTS: We studied 15 men and 6
      women (mean age 61+/-10 years) at coronary angiography who were not taking
      vitamin supplements. Coronary endothelium-dependent and -independent vasomotion
      was assessed by intracoronary infusions of acetylcholine and nitroglycerin. The
      vasomotor responses were compared with the plasma concentration of alpha
      tocopherol and the plasma alpha-tocopherol concentration relative to total lipid
      (total cholesterol plus triglycerides). The mean plasma alpha-tocopherol was
      25.6+/-6.1 micromol/L, total cholesterol 193+/-27 mg/dL, triglycerides 115+/-66
      mg/dL, and alpha-tocopherol to total lipid 4. 2+/-0.9 micromol. L(-1). (mmol/L)(
      1). The mean vasomotor response to acetylcholine was -1% (range -33% to 28%) and
      to nitroglycerin 22% (range 0% to 54%). Plasma alpha-tocopherol was significantly
      correlated with the acetylcholine response (r=0.49, P<0.05) but not the
      nitroglycerin response (r=0.13, P>0.05). The acetylcholine response remained
      significant after adjustment for other potential sources of oxidant stress (total
      cholesterol, diabetes mellitus, smoking, angina class) (P<0.01). The relative
      concentration of alpha-tocopherol to total lipid was not related to endothelial
      function (r=0.24, P=0.3, n=20). CONCLUSIONS: alpha-Tocopherol may preserve
      endothelial vasomotor function in patients with coronary atherosclerosis. This
      effect may be related primarily to the action of alpha-tocopherol in the vascular
      wall. Further studies that assess the impact of alpha-tocopherol supplementation
      as therapy of endothelial dysfunction are justified.

PMID- 10411844
TI  - Reversal by vasopressin of intractable hypotension in the late phase of
      hemorrhagic shock.
AB  - BACKGROUND: Hypovolemic shock of marked severity and duration may progress to
      cardiovascular collapse unresponsive to volume replacement and drug intervention.
      On the basis of clinical observations, we investigated the action of vasopressin
      in an animal model of this condition. METHODS AND RESULTS: In 7 dogs, prolonged
      hemorrhagic shock (mean arterial pressure [MAP] of approximately 40 mm Hg) was
      induced by exsanguination into a reservoir. After approximately 30 minutes,
      progressive reinfusion was needed to maintain MAP at approximately 40 mm Hg, and
      by approximately 1 hour, despite complete restoration of blood volume, the
      administration of norepinephrine approximately 3 micrograms . kg(-1). min(-1) was
      required to maintain this pressure. At this moment, administration of vasopressin
      1 to 4 mU. kg(-1). min(-1) increased MAP from 39+/-6 to 128+/-9 mm Hg (P<0.001),
      primarily because of peripheral vasoconstriction. In 3 dogs subjected to similar
      prolonged hemorrhagic shock, angiotensin II 180 ng. kg(-1). min(-1) had only a
      marginal effect on MAP (45+/-12 to 49+/-15 mm Hg). Plasma vasopressin was
      markedly elevated during acute hemorrhage but fell from 319+/-66 to 29+/-9 pg/mL
      before administration of vasopressin (P<0.01). CONCLUSIONS: Vasopressin is a
      uniquely effective pressor in the irreversible phase of hemorrhagic shock
      unresponsive to volume replacement and catecholamine vasopressors. Vasopressin
      deficiency may contribute to the pathogenesis of this condition.

PMID- 10411846
TI  - Primary stenting versus balloon angioplasty in occluded coronary arteries: the
      Total Occlusion Study of Canada (TOSCA).
AB  - BACKGROUND: Balloon angioplasty (PTCA) of occluded coronary arteries is limited
      by high rates of restenosis and reocclusion. Although stenting improves results
      in anatomically simple occlusions, its effect on patency and clinical outcome in
      a broadly selected population with occluded coronary arteries is unknown. METHODS
      AND RESULTS: Eighteen centers randomized 410 patients with nonacute native
      coronary occlusions to PTCA or primary stenting with the heparin-coated Palmaz
      Schatz stent. The primary end point, failure of sustained patency, was determined
      at 6-month angiography. Repeat target-vessel revascularization, adverse
      cardiovascular events, and angiographic restenosis (>50% diameter stenosis)
      constituted secondary end points. Sixty percent of patients had occlusions of >6
      weeks' duration, baseline flow was TIMI grade 0 in 64%, and median treated
      segment length was 30.5 mm. With 95.6% angiographic follow-up, primary stenting
      resulted in a 44% reduction in failed patency (10.9% versus 19.5%, P=0.024) and a
      45% reduction in clinically driven target-vessel revascularization at 6 months
      (15.4% versus 8.4%, P=0.03). The incidence of adverse cardiovascular events was
      similar for both strategies (PTCA, 23.6%; stent, 23.3%; P=NS). Stenting resulted
      in a larger mean 6-month minimum lumen dimension (1.48 versus 1.23 mm, P<0.01)
      and a reduced binary restenosis rate (55% versus 70%, P<0.01). CONCLUSIONS:
      Primary stenting of broadly selected nonacute coronary occlusions is superior to
      PTCA alone, improving late patency and reducing restenosis and target-vessel
      revascularization.

PMID- 10411845
TI  - Long-term effects of pravastatin on plasma concentration of C-reactive protein.
      The Cholesterol and Recurrent Events (CARE) Investigators.
AB  - BACKGROUND: Elevated plasma concentrations of C-reactive protein (CRP) are
      associated with increased cardiovascular risk. We evaluated whether long-term
      therapy with pravastatin, an agent that reduces cardiovascular risk, might alter
      levels of this inflammatory parameter. METHODS AND RESULTS: CRP levels were
      measured at baseline and at 5 years in 472 randomly selected participants in the
      Cholesterol and Recurrent Events (CARE) trial who remained free of recurrent
      coronary events during follow-up. Overall, CRP levels at baseline and at 5 years
      were highly correlated (r=0.60, P<0.001). However, among those allocated to
      placebo, median CRP levels and the mean change in CRP tended to increase over
      time (median change, +4. 2%; P=0.2 and mean change, +0.07 mg/dL; P=0.04). By
      contrast, median CRP levels and the mean change in CRP decreased over time among
      those allocated to pravastatin (median change, -17.4%; P=0.004 and mean change, 
      0.07 mg/dL; P=0.002). Thus, statistically significant differences were observed
      at 5 years between the pravastatin and placebo groups in terms of median CRP
      levels (difference, -21.6%; P=0.007), mean CRP levels (difference, -37.8%;
      P=0.002), and absolute mean change in CRP (difference, -0.137 mg/dL; P=0.003).
      These effects persisted in analyses stratified by age, body mass index, smoking
      status, blood pressure, and baseline lipid levels. Attempts to relate the
      magnitude of change in CRP to the magnitude of change in lipids in both the
      pravastatin and placebo groups did not reveal any obvious relationships.
      CONCLUSIONS: Among survivors of myocardial infarction on standard therapy plus
      placebo, CRP levels tended to increase over 5 years of follow-up. In contrast,
      randomization to pravastatin resulted in significant reductions in this
      inflammatory marker that were not related to the magnitude of lipid alterations
      observed. Thus, these data further support the potential for nonlipid effects of
      this agent.

PMID- 10411847
TI  - Effects of dobutamine on coronary stenosis physiology and morphology: comparison
      with intracoronary adenosine.
AB  - BACKGROUND: The mechanisms leading to dobutamine-induced ischemia are not fully
      understood. In the present study, we investigated the effects of high-dose
      intravenous dobutamine on morphological and physiological indexes of coronary
      stenoses. METHODS AND RESULTS: Twenty-two patients with normal left ventricular
      function and isolated coronary stenoses were studied. At catheterization, mean
      aortic pressure (P(a)), mean distal coronary pressure (P(d)), and P(d)/P(a) as an
      index of myocardial resistance were recorded at rest, after intracoronary
      adenosine, and during intravenous infusion of dobutamine (10 to 40 micrograms .
      kg(-1). min(-1)). Reference vessel diameter and minimal luminal diameter, as
      assessed by coronary angiography, did not change during dobutamine infusion
      compared with baseline (2.84+/-0.49 versus 2.77+/-0.41 mm and 1.35+/-0.38 versus
      1. 27+/-0.31 mm, respectively; both P=NS). During peak dobutamine infusion, P(d)
      and P(d)/P(a) reached similar levels as during adenosine infusion (60+/-18 versus
      59+/-18 mm Hg and 0.68+/-0.18 versus 0.68+/-0.17, respectively; all P=NS). In 9
      patients, an additional bolus of intracoronary adenosine given at the peak dose
      of dobutamine failed to further decrease P(d)/P(a). Furthermore, in patients with
      dobutamine-induced wall motion abnormalities, the maximal decrease in P(d)/P(a)
      was similar during dobutamine and adenosine infusions. CONCLUSIONS: High-dose
      intravenous infusion of dobutamine does not modify the dimensions of the
      epicardial coronary stenosis. However, much like the direct coronary vasodilator
      adenosine, dobutamine fully exhausts myocardial resistance regardless of the
      presence of mechanical dysfunction.

PMID- 10411848
TI  - Clinical potential of intravascular ultrasound for physiological assessment of
      coronary stenosis: relationship between quantitative ultrasound tomography and
      pressure-derived fractional flow reserve.
AB  - BACKGROUND: Little is known regarding intravascular ultrasound (IVUS) criteria to
      determine the functional severity of coronary stenosis. Recently, fractional flow
      reserve (FFR) has emerged as a lesion-specific index of the functional severity
      of a coronary stenosis that is independent of systemic hemodynamic variability.
      The present study was undertaken to determine the IVUS parameters for the
      physiological severity of coronary stenosis. METHODS AND RESULTS: Fifty-one
      lesions in 42 patients were evaluated by means of quantitative coronary
      angiogram, IVUS, and intracoronary pressure measurements. The FFR was calculated
      as the ratio of the distal coronary pressure divided by the proximal coronary
      pressure under hyperemia. We considered a value of the FFR <0.75 as significant
      in determining inducible ischemia, according to the previous studies. The minimal
      luminal area (MLA) and the area stenosis were measured by IVUS. By regression
      analysis, the MLA showed a positive correlation with the FFR value (r(2)=0.62,
      P<0.0001). The area stenosis had a significant inverse correlation with the value
      of FFR (r(2)=0.60, P<0.0001). The IVUS thresholds that maximized the sensitivity
      and specificity were MLA <3.0 mm(2) (sensitivity, 83.0%; specificity, 92.3%) and
      area stenosis >0.6 (sensitivity, 92.0%; specificity, 88.5%). The combination of
      both criteria (MLA <3.0 mm(2) and area stenosis <0.6) without exception met a
      value of the FFR <0.75. CONCLUSIONS: Anatomic parameters obtained by IVUS showed
      a significant correlation to the FFR values. The present study demonstrated that
      the combination of the MLA and area stenosis measured by IVUS can be an anatomic
      predictor for the physiological impact of coronary epicardial stenosis.

PMID- 10411849
TI  - Long-term follow-up after percutaneous transluminal coronary angioplasty was not
      performed based on intravascular ultrasound findings: importance of lumen
      dimensions.
AB  - BACKGROUND: Angiography is limited in determining the anatomic severity of
      coronary artery stenoses. Clinical decision-making in patients with symptoms and
      intermediate lesions remains challenging. METHODS AND RESULTS: The current
      analysis included 300 patients (357 intermediate native artery lesions) in whom
      intervention was deferred based on intravascular ultrasound (IVUS) findings.
      Standard clinical, angiographic, and IVUS parameters were collected. Patients
      were followed for >1 year. Events occurred in 24 patients (8%). They included 2
      cardiac deaths, 4 myocardial infarctions, and 18 target-lesion revascularizations
      (TLR; 12 percutaneous transluminal coronary angiographies and 6 coronary artery
      bypass grafts; only 3 TLRs occurred within 6 months after the IVUS study). All
      significant univariate clinical, angiographic, and IVUS parameters (P<0.05) were
      tested in multivariate models. These included diabetes mellitus, IVUS lesion
      lumen area, maximum lumen diameter, minimum lumen diameter, plaque area, plaque
      burden, and area stenosis (AS). No angiographic measurement was significant at
      P<0.05. The only independent predictors of an event (death, myocardial
      infarction, or TLR) were IVUS minimum lumen area and AS. The only independent
      predictors of TLR were diabetes mellitus, IVUS minimum lumen area, and AS. In 248
      lesions with a minimum lumen area >/=4.0 mm(2), the event rate was only 4.4% and
      the TLR rate 2.8%. CONCLUSIONS: Long-term follow-up after IVUS-guided deferred
      interventions in patients with de novo intermediate native artery lesions showed
      a low event rate. In patients with a minimum lumen area >/=4.0 mm(2), the event
      rate was especially low. IVUS imaging is an acceptable alternative to
      physiological assessment in these patients.

PMID- 10411850
TI  - Enhanced sympathetic and ventilatory responses to central chemoreflex activation
      in heart failure.
AB  - BACKGROUND: Sympathetic activation and respiratory abnormalities may each be
      implicated in the pathophysiology of congestive heart failure (CHF).
      Chemoreflexes are an important mechanism regulating both sympathetic drive and
      breathing. We therefore tested the hypothesis that chemoreflex function is
      altered in CHF. METHODS AND RESULTS: We compared ventilatory, sympathetic, heart
      rate, and blood pressure responses to hypoxia, hypercapnia, and the cold pressor
      test in 9 patients with CHF and 9 control subjects matched for age and body mass
      index. Baseline muscle sympathetic nerve activity (MSNA) was higher in the
      patients with CHF compared with control subjects (47+/-8 versus 23+/-3 bursts per
      minute, P<0.01). During hypercapnia, patients with CHF had greater increases in
      minute ventilation (6.7+/-1.4 versus 2.7+/-0.9 L/min, P=0.03) and heart rate
      (7.0+/-2.1 versus 0.6+/-1.2 bpm, P=0.02). Despite higher ventilation, which
      inhibits sympathetic activity, the MSNA increase in patients with CHF was also
      greater than that in control subjects (58+/-12% versus 21+/-9%, P=0.03).
      Ventilatory, autonomic, and blood pressure responses to hypoxia and the cold
      pressor test in CHF patients were not different from those in control subjects.
      CONCLUSIONS: Chronic heart failure is characterized by a selective potentiation
      of ventilatory and sympathetic responses to central chemoreceptor activation by
      hypercapnia.

PMID- 10411851
TI  - Role of bradykinin in the vasodilator effects of losartan and enalapril in
      patients with heart failure.
AB  - BACKGROUND: ACE inhibitors have been shown to potentiate the effects of exogenous
      bradykinin by inhibition of its breakdown. Despite this, there is little evidence
      that inhibition of endogenous bradykinin breakdown actually contributes to the
      effects of ACE inhibitors, or indeed, other inhibitors of the renin-angiotensin
      system, such as angiotensin II type I receptor (AT(1)) antagonists, and no
      evidence at all that it does so in patients with heart failure. METHODS AND
      RESULTS: Twelve patients with heart failure (11 male, 1 female, ages 59 to 81
      years) were randomized to double-blind crossover treatment with enalapril 10 mg
      BID followed by losartan 25 mg BID, or the reverse, each for 5 weeks. At the end
      of each treatment period, forearm blood flow was measured by venous occlusion
      plethysmography during an intrabrachial infusion of bradykinin before and after
      an intrabrachial infusion of Hoe-140 (a potent, selective, and long-acting
      bradykinin antagonist). Bradykinin caused profound vasodilatation after enalapril
      (peak, 357+/-67%) and less after losartan (peak, 230+/-46%). Despite this, Hoe
      140 had no discernible effects after enalapril or losartan. Similarly, this was
      despite the finding that Hoe-140 significantly reduced vasodilatation to
      bradykinin after enalapril (peak, 192+/-35%) and losartan (peak, 66+/-13%).
      CONCLUSIONS: Inhibition of endogenous bradykinin breakdown does not appear to
      contribute to the effects of ACE inhibition or AT(1) antagonism in the forearm of
      patients with heart failure at rest, despite the very obvious effects of ACE
      inhibition compared with AT(1) antagonism on exogenous bradykinin.

PMID- 10411852
TI  - Parasympathetic control of cardiac sympathetic activity: normal ventricular
      function versus congestive heart failure.
AB  - BACKGROUND: Muscarinic receptors on adrenergic nerve terminals attenuate
      norepinephrine release. The role of these receptors in the modulation of cardiac
      norepinephrine release in humans remains uncertain. METHODS AND RESULTS: Twelve
      patients with normal left ventricular (LV) function and 18 with congestive heart
      failure (CHF) were studied. A radiotracer technique was used to measure cardiac
      norepinephrine spillover (CANESP) in response to intracoronary acetylcholine
      (ACh, 5x10(-5) Mol), and in response to intracoronary atropine (12
      micrograms/min). ACh did not affect CANESP in the group of subjects with normal
      LV function, but it caused a significant reduction in those with CHF [197 (150 to
      302) versus 168 (87 to 288) pmol/min, P<0.05]. Atropine caused a significant
      increase in CANESP in those with normal LV function [47 (27 to 51) versus 64 (38
      to 139) pmol/min, P<0.05], but no change was observed in the CHF group.
      CONCLUSIONS: Therefore, in the setting of heart failure and sympathetic
      activation, muscarinic receptor stimulation decreases CANESP, an effect not
      observed in patients with preserved LV function. Blockade of muscarinic receptors
      with atropine increased CANESP in patients with normal LV function, suggesting
      that cardiac parasympathetic tone has inhibitory effects on cardiac sympathetic
      activity. This basal inhibition was not observed in CHF patients in response to
      atropine. The lack of basal parasympathetic inhibition of cardiac sympathetic
      activity may play a role in the pathogenesis of cardiac sympathetic activation in
      heart failure.

PMID- 10411853
TI  - Seasonal variation in chronic heart failure hospitalizations and mortality in
      France.
AB  - BACKGROUND: Circannual variation in blood pressure and in the incidence of acute
      myocardial infarction is well known but has not been investigated in chronic
      heart failure. This report describes and compares the seasonal variation of
      chronic heart failure hospitalizations and mortality in the French population.
      METHODS AND RESULTS: All deaths that occurred among French adults over the period
      1992 to 1996 (n=138 602) and all discharges by adults in French public hospitals
      for chronic heart failure over the period 1995 to 1997 (n=324 013) were examined
      retrospectively. First, chronic heart failure deaths in France occurred with a
      striking annual periodicity and peaked in winter (December through January), both
      in the overall population and in subgroups defined by age (>44 years old) and
      sex. The distribution of cumulative monthly deaths differed by nearly 35%,
      ranging from a peak of 20% above average in January to 15% below average in
      August (Roger's test: P<0.001). Second, hospitalizations for chronic heart
      failure in French public hospitals followed a similar seasonal pattern (P<0.001),
      with a winter-spring predominance (+7% to +10% from December through April).
      Third, for persons >/=85 years old, excess hospitalizations occurred earlier in
      the year, with marked synchronized peaks in January for both mortality and
      hospitalizations (P<0.001). CONCLUSIONS: Clear seasonal variations in adult
      chronic heart failure hospitalizations and deaths were identified. The
      considerable economic impact on health care services warrants further
      epidemiological investigations and a more comprehensive approach to disease
      management.

PMID- 10411854
TI  - Discoordinate modulation of natriuretic peptides during acute cardiac allograft
      rejection in humans.
AB  - BACKGROUND: Increased circulating levels of the cardiac polypeptide hormones
      atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) may be
      observed after orthotopic cardiac transplantation. Both the hypertrophic and
      inflammatory processes in the allograft may contribute to this increase, but no
      mechanistic explanation has been suggested for this observation. METHODS AND
      RESULTS: Plasma immunoreactive ANF and BNP determinations were performed in 10
      consecutive transplant patients. These were correlated with degree of rejection
      as reflected by histopathological findings at serial endomyocardial biopsies.
      Three patients had associated hemodynamic measurements and blood samples 24 hours
      before and after transplantation. All rejection episodes that received treatment
      were accompanied by a marked increase in BNP plasma levels to > approximately 400
      pg/mL. Steadily increasing BNP levels preceded overt rejection as assessed by
      histopathological criteria. The increase in plasma BNP was not always accompanied
      by an increase in ANF, which suggests the specific upregulation of BNP gene
      expression during acute rejection episodes. Treatment of the acute rejection
      episodes led to a substantial decrease of BNP plasma levels. CONCLUSIONS: The
      significant selective increase in plasma BNP levels found in the present study
      has not been previously described. This finding provides a new insight into the
      mechanism of allograft rejection and the modulation of natriuretic peptide
      synthesis and release. Furthermore, although preliminary, the data suggest that
      BNP plasma levels could form the basis for a new, noninvasive screening test to
      predict acute cardiac allograft rejection. Because treatment with the
      antilymphocyte monoclonal antibody OKT3 (murine monoclonal antibody to the CD3
      antigen of the human T-cell) decreased BNP plasma levels, cytokine production by
      T-cells may mediate the selective increase in circulating BNP.

PMID- 10411855
TI  - Endothelial dysfunction in chronic myocardial infarction despite increased
      vascular endothelial nitric oxide synthase and soluble guanylate cyclase
      expression: role of enhanced vascular superoxide production.
AB  - BACKGROUND: Endothelial dysfunction of the peripheral vasculature is a well-known
      phenomenon in congestive heart failure that contributes to the elevated
      peripheral resistance; however, the underlying mechanisms have not yet been
      clarified. METHODS AND RESULTS: Dilator responses, the expression of protein and
      mRNA of the endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and
      soluble guanylate cyclase (sGC), and superoxide anion (O(2)(-)) and peroxynitrite
      production were determined in aortic rings from Wistar rats 8 weeks after
      myocardial infarction and compared with those in sham-operated animals. In rats
      with heart failure, the concentration-response curve of the endothelium-dependent
      vasodilator acetylcholine (after preconstriction with phenylephrine) was
      significantly shifted to the right, and the maximum relaxation was attenuated.
      Determination of expression levels of the 2 key enzymes for NO-mediated
      dilations, eNOS and sGC, revealed a marked upregulation of both enzymes in aortas
      from rats with heart failure, whereas iNOS expression was not changed.
      Pretreatment with exogenous superoxide dismutase partially restored the
      acetylcholine-induced relaxation in aortas from rats with heart failure. Aortic
      basal and NADH-stimulated O(2)(-) production assessed by use of lucigenin
      enhanced chemiluminescence was significantly elevated in rats with chronic
      myocardial infarction. Peroxynitrite-mediated nitration of protein tyrosine
      residues was not different between the 2 groups of rats. CONCLUSIONS: These
      results demonstrate that endothelial dysfunction in ischemic heart failure occurs
      despite an enhanced vascular eNOS and sGC expression and can be attributed to an
      increase in vascular O(2)(-) production by an NADH-dependent oxidase. By
      inactivation of NO, O(2)(-) production appears to be an essential mechanism for
      the endothelial dysfunction observed in heart failure.

PMID- 10411856
TI  - Novel therapeutic strategy against central baroreflex failure: a bionic
      baroreflex system.
AB  - BACKGROUND: Central baroreflex failure in Shy-Drager syndrome and traumatic
      spinal cord injuries results in severe orthostatic hypotension and often confines
      the patient to the bed. We proposed a novel therapeutic strategy against central
      baroreflex failure: implementation of an artificial feedback control system able
      automatically to regulate sympathetic vasomotor tone, that is, a bionic
      baroreflex system (BBS). With the use of a rat model of central baroreflex
      failure, we developed the BBS and tested its efficacy. METHODS AND RESULTS: Our
      prototype BBS for the rat consisted of a pressure sensor placed into the aortic
      arch, stimulation electrodes implanted into the greater splanchnic nerve, and a
      computer-driven neural stimulator. By a white noise approach for system
      identification, we first estimated the dynamic properties underlying the normal
      baroreflex control of systemic arterial pressure (SAP) and then determined how
      the BBS computer should operate in real time as the artificial vasomotor center
      to mimic the dynamic properties of the native baroreflex. The open-loop transfer
      function of the artificial vasomotor center was identified as a high-pass filter
      with a corner frequency of 0.1 Hz. We evaluated the performance of the BBS in
      response to rapid-progressive hypotension secondary to sudden sympathetic
      withdrawal evoked by the local imposition of a pressure step on carotid sinus
      baroreceptors in 16 anesthetized rats. Without the BBS, SAP rapidly fell by 49+/
      8 mm Hg in 10 seconds. With the BBS placed on-line with real-time execution, the
      SAP fall was suppressed by 22+/-6 mm Hg at the nadir and by 16+/-5 mm Hg at the
      plateau. These effects were statistically indistinguishable from those of the
      native baroreflex system. CONCLUSIONS: These results suggest the feasibility of a
      BBS approach for central baroreflex failure.

PMID- 10411857
TI  - alpha- and beta-adrenergic pathways differentially regulate cell type-specific
      apoptosis in rat cardiac myocytes.
AB  - BACKGROUND: The apoptosis of cardiac myocytes may play a role in the development
      of heart failure. Norepinephrine is one of the factors activated in heart failure
      and can induce myocardial cell apoptosis in culture. However, it is unknown if
      alpha- and beta-adrenergic pathways coordinately or differentially regulate
      apoptosis and if this apoptotic pathway uses common or cell type-specific
      apoptotic signals. METHODS AND RESULTS: We stimulated cultured neonatal rat
      cardiac myocytes with an alpha(1)-adrenergic agonist (PE, phenylephrine), a beta
      adrenergic agonist (isoproterenol [Iso]) or a membrane-permeable cAMP analogue (8
      Br-cAMP) in serum-free conditions for 48 hours. Iso and 8-Br-cAMP markedly
      increased the number of TUNEL-positive cells (%TUNEL-positive nuclei >40%)
      compared with saline stimulation (<10%). DNA fragmentation was also confirmed by
      ladder formation in agarose gels. Apoptotic myocytes were characterized by cell
      shrinkage and nuclear condensation, consistent with morphological features of
      apoptosis. The Iso-induced apoptosis was almost completely inhibited by the
      protein kinase A-specific inhibitor KT5720. In contrast, PE inhibited 8-Br-cAMP
      induced myocardial cell apoptosis. The apoptosis-inhibitory effect by PE was
      negated by the alpha(1)-adrenergic receptor antagonist prazosin and the MEK-1
      specific inhibitor PD098059. Interestingly, although 8-Br-cAMP markedly induced
      apoptosis in cardiac myocytes, it completely blocked serum depletion-induced
      apoptosis in PC12 cells, a rat pheochromocytoma cell line. CONCLUSIONS: These
      findings indicate that alpha- and beta-adrenergic pathways differentially
      regulate myocardial cell apoptosis. The results also suggest that a cAMP- protein
      kinase A pathway is necessary and sufficient for beta-adrenergic agonist-induced
      apoptosis and that this apoptotic pathway is not functional in other cell types,
      for example, PC12 cells.

PMID- 10411858
TI  - Simultaneous multisite mapping of the right and the left atrial septum in the
      canine intact beating heart.
AB  - BACKGROUND: The spread of activation between the right atrium (RA) and left
      atrium (LA), particularly along the right and left aspects of the interatrial
      septum, is not clear. METHODS AND RESULTS: Basket-shaped catheters carrying 64
      electrodes were deployed into both the RA and LA of 10 dogs. Position and
      orientation of the baskets were determined by fluoroscopy and echocardiography.
      Basket unipolar electrograms were simultaneously recorded in each dog during
      sinus rhythm, right ventricular pacing, and pacing of the right septum through
      the basket in the superior and inferior regions. Isochrone maps depicting all
      aspects of the atria, including the septum, were compared. During sinus rhythm
      and superior right septal pacing, wave fronts propagated predominantly from
      superior to inferior regions on both the right and left septum. However,
      activation of the left septum was delayed compared with the right septum. During
      right ventricular pacing and inferior right septal pacing, activation of the
      septum was discordant; 1 wave front propagated rapidly on the right septum from
      inferior to superior regions, whereas 2 opposing wave fronts originated on the
      left septum in both the superior and inferior regions. The left septum was
      activated predominantly by the superior wave front. Activation of the left septum
      was completed in a significantly shorter time during pacing of the right septum
      in the inferior region compared with the superior region. CONCLUSIONS: In dogs,
      activation of the right and left aspects of the interatrial septum is discordant.
      Electrical connections are present between the RA and LA in regions superior as
      well as inferior to the septum.

PMID- 10411859
TI  - New device for closure of muscular ventricular septal defects in a canine model.
AB  - BACKGROUND: Repair of muscular ventricular septal defects (MVSDs) has always been
      challenging to the surgeon. Long-term morbidity and mortality are significantly
      increased if the defects are closed via left ventriculotomy or if they are
      associated with other complex congenital anomalies. The purpose of this study was
      to close MVSDs with the Amplatz ventricular septal defect device. This device is
      constructed from 0.004-in nitinol wire mesh filled with polyester fibers. It is
      retrievable, repositionable, self-centering, and of low profile. METHODS AND
      RESULTS: MVSDs were created with the help of a sharp punch in 10 dogs. The
      location of the defects was anterior muscular (n=3), midmuscular (n=3), apical
      (n=3), and inlet muscular (n=1). The diameter of the defects ranged from 6 to 14
      mm. All defects were closed in the catheterization laboratory. The device was
      placed with the help of transesophageal echocardiography and fluoroscopy. A 7F
      sheath was used to deploy the device from the right ventricular side in 8 and the
      left ventricular side in 2 dogs. Placement was successful in all animals. The
      complete closure rate was 30% (3/10) immediately after placement and 100% at 1
      week follow-up. Pathological examination of the heart revealed complete
      endothelialization of the device in dogs killed after 3 months. CONCLUSIONS: The
      Amplatz ventricular septal defect device appears highly efficacious in closing
      MVSDs. The advantages include a small delivery sheath, complete retrievability
      before release, and the fact that it is self-centering and self-expanding,
      thereby making it an attractive option in smaller children.

PMID- 10411861
TI  - Correction 

PMID- 10411860
TI  - Leaking left ventricular pseudoaneurysm.

PMID- 10411862
TI  - Effects of lovastatin and warfarin on early carotid atherosclerosis: sex-specific
      analyses. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.
AB  - BACKGROUND: Few clinical trials have documented the efficacy of preventive
      treatment in asymptomatic women. METHODS AND RESULTS: Lovastatin and minidose
      warfarin were evaluated in a factorially designed, placebo-controlled, randomized
      trial. The primary outcome was 3-year change in the mean maximum intimal-medial
      thickness of the carotid arteries as measured by B-mode ultrasonography.
      Participants (n=919) were randomized to 1 of 4 treatment groups: lovastatin
      alone, warfarin alone, lovastatin+warfarin combination, or a double-placebo
      group. Eligible participants were asymptomatic for cardiovascular disease, with
      evidence of early carotid atherosclerosis and moderately elevated LDL cholesterol
      level. Almost half (n=445) of the participants were women. To avoid confounding,
      117 women taking estrogen were excluded from analysis. Both sexes experienced
      reductions in disease progression with lovastatin; there was no evidence of an
      overall sex x treatment interaction (P=0.72). When estimates of the sex-specific
      results were examined post hoc, women experienced disease regression to the
      greatest extent with the lovastatin + warfarin combination (P=0.02), although the
      women on lovastatin alone also had a reduction in progression (P=0.09). Men
      experienced the greatest reduction with lovastatin alone (P=0.02), although there
      is a suggestion that warfarin may also reduce progression to some extent.
      CONCLUSIONS: Lovastatin is beneficial in reducing disease progression in women
      and men. Warfarin has no effect in women, although it may reduce progression in
      men. In men, warfarin does not add to the benefit of lovastatin and has no
      advantage over lovastatin alone.

PMID- 10411863
TI  - Nail gun penetrating injury of the left ventricle and descending aorta.

PMID- 10411864
TI  - On the mechanism of silencing in Escherichia coli.

PMID- 10411865
TI  - How to induce involuntary suicide: the need for dipeptidyl peptidase I.

PMID- 10411866
TI  - A paradigm for finding genes for a complex human trait: polycystic ovary syndrome
      and follistatin.

PMID- 10411867
TI  - Here's the hook: similar substrate binding sites in the chaperone domains of Clp
      and Lon.

PMID- 10411868
TI  - Gene therapy in plants.

PMID- 10411870
TI  - Introduction to German-American Frontiers of Science.

PMID- 10411869
TI  - Tat as one key to HIV-induced immune pathogenesis and Tat (correction of Pat)
      toxoid as an important component of a vaccine.

PMID- 10411872
TI  - Smart materials and structures.

PMID- 10411871
TI  - Ultrafast detection and control of molecular dynamics.
AB  - Many elementary chemical and physical processes such as the breaking of a
      chemical bond or the vibrational motion of atoms within a molecule take place on
      a femtosecond (fs = 10(-15)s) or picosecond (ps = 10(-12)s) time scale. It is now
      possible to monitor these events as a function of time with temporal resolution
      well below 100 fs. This capability is based on the pump-probe technique where one
      optical pulse triggers a reaction and a second delayed optical pulse probes the
      changes that ensue. To illustrate this capability, the dynamics of ligand motion
      within a protein are presented. Moving beyond casual observation of a reaction to
      active control of its outcome requires additional experimental and theoretical
      effort. To illustrate the concept of control, the effect of optical pulse
      duration on the vibrational dynamics of a tri-atomic molecule are discussed. The
      experimental and theoretical resources currently available are poised to make the
      dream of reaction control a reality for certain molecular systems.

PMID- 10411873
TI  - The mathematics of microstructure and the design of new materials.

PMID- 10411874
TI  - The past and the future fate of the universe and the formation of structure in
      it.
AB  - The history and the ultimate future fate of the universe as a whole depend on how
      much the expansion of the universe is decelerated by its own mass. In particular,
      whether the expansion of the universe will ever come to a halt can be determined
      from the past expansion. However, the mass density in the universe does not only
      govern the expansion history and the curvature of space, but in parallel also
      regulates the growth of hierarchical structure, including the collapse of
      material into the dense, virialized regions that we identify with galaxies.
      Hence, the formation of galaxies and their clustered distribution in space depend
      not only on the detailed physics of how stars are formed but also on the overall
      structure of the universe. Recent observational efforts, fueled by new large,
      ground-based telescopes and the Hubble Space Telescope, combined with theoretical
      progress, have brought us to the verge of determining the expansion history of
      the universe and space curvature from direct observation and to linking this to
      the formation history of galaxies.

PMID- 10411875
TI  - Emerging fluorescence sensing technologies: from photophysical principles to
      cellular applications.

PMID- 10411876
TI  - Resolution of concerted versus sequential mechanisms in photo-induced double
      proton transfer reaction in 7-azaindole H-bonded dimer.
AB  - The experimental and theoretical bases for a synchronous or concerted double
      proton transfer in centro-symmetric H-bonded electronically excited molecular
      dimers are presented. The prototype model is the 7-azaindole dimer. New research
      offers confirmation of a concerted mechanism for excited-state biprotonic
      transfer. Recent femtosecond photoionization and coulombic explosion techniques
      have given rise to time-of-flight MS observations suggesting sequential two-step
      biprotonic transfer for the same dimer. We interpret the overall species observed
      in the time-of-flight experiments as explicable without conflict with the
      concerted mechanism of proton transfer.

PMID- 10411877
TI  - Guest exchange in an encapsulation complex: a supramolecular substitution
      reaction.
AB  - Encapsulation complexes are reversibly formed assemblies in which small molecule
      guests are completely surrounded by large molecule hosts. The assemblies are held
      together by weak intermolecular forces and are dynamic: they form and dissipate
      on time scales ranging from milliseconds to days-long enough for many
      interactions, even reactions, to take place within them. Little information is
      available on the exchange process, how guests get in and out of these complexes.
      Here we report that these events can be slow enough for conventional kinetic
      studies, and reactive intermediates can be detected. Guest exchange has much in
      common with familiar chemical substitution reactions, but differs in some
      respects: no covalent bonds are made or broken, the substrate is an assembly
      rather than a single molecule, and at least four molecules are involved in
      multiple rate-determining steps.

PMID- 10411878
TI  - Potent selective nonpeptidic inhibitors of human lung tryptase.
AB  - Human lung tryptase, a homotetrameric serine protease unique to mast cell
      secretory granules, has been implicated in the pathogenesis of asthma. A
      hypothesis that tethered symmetrical inhibitors might bridge two adjacent active
      sites was explored via a rationally designed series of bisbenzamidines. These
      compounds demonstrated a remarkable distanced-defined structure-activity
      relationship against human tryptase with one series possessing subnanomolar
      potencies. Additional evidence supporting the concept of active-site bridging is
      also presented.

PMID- 10411880
TI  - Dynamics of Helicobacter pylori colonization in relation to the host response.
AB  - The dynamics of Helicobacter pylori colonization from its acquisition through the
      development of steady-state are examined through a mathematical model that
      includes the host response. The model encompasses both host and microbiological
      variation. The individual capacity of the host response is shown to be a key
      model parameter, leading to either transient or persistent colonization, whereas
      the growth rate of that response has little effect. Analyses of competing strains
      indicate that each must occupy a specific niche, otherwise exclusion occurs. The
      model implies that there exists a lower bound on the host response to the
      indigenous microflora that is consistent with current biological views of H.
      pylori. Parallel models may be useful in understanding other persistent host
      microbial interactions.

PMID- 10411879
TI  - Long-distance charge transport in duplex DNA: the phonon-assisted polaron-like
      hopping mechanism.
AB  - An anthraquinone-linked duplex DNA oligomer containing 60 base pairs was
      synthesized by PCR. The strand complementary to the quinone-containing strand has
      four isolated GG steps, which serve as traps for a migrating radical cation.
      Irradiation of the quinone leads to electron transfer from the DNA to the quinone
      forming the anthraquinone radical anion and a base radical cation. The radical
      cation migrates through the DNA, causing reaction at GG steps revealed as strand
      breaks. The efficiency of strand cleavage falls off exponentially with distance
      from the quinone (slope = -0.02 A(-1)). This finding necessitates
      reinterpretation of mechanisms proposed for radical cation migration in DNA. We
      propose that radical cations form self-trapped polarons that migrate by thermally
      activated hopping.

PMID- 10411881
TI  - A "midinfrared" scenario for cuprate superconductivity.
AB  - I conjecture that the mechanism of superconductivity in the cuprates is a saving,
      due to the improved screening resulting from Cooper pair formation, of the part
      of the Coulomb energy associated with long wavelengths and midinfrared
      frequencies. This scenario is shown to provide a plausible explanation of the
      trend of transition temperature with layering structure in the Ca-spaced
      compounds and to predict a spectacularly large decrease in the electron-energy
      loss spectroscopy cross-section in the midinfrared region on transition to the
      superconducting state, as well as less spectacular but still surprisingly large
      changes in the optical behavior. Existing experimental results appear to be
      consistent with this picture.

PMID- 10411882
TI  - Genetic mapping of resistance to Bacillus thuringiensis toxins in diamondback
      moth using biphasic linkage analysis.
AB  - Transgenic plants producing environmentally benign Bacillus thuringiensis (Bt)
      toxins are deployed increasingly for insect control, but their efficacy will be
      short-lived if pests adapt quickly. The diamondback moth (Plutella xylostella), a
      worldwide pest of vegetables, is the first insect to evolve resistance to Bt
      toxins in open-field populations. A recessive autosomal gene confers resistance
      to at least four Bt toxins and enables survival without adverse effects on
      transgenic plants. Allelic variants of this gene confer resistance in strains
      from Hawaii, Pennsylvania, and the Philippines. Here we exploited the biphasic
      nature of Lepidopteran genetic linkage to map this gene in diamondback moth with
      207 amplified fragment length polymorphisms as DNA markers. We also cloned and
      sequenced an amplified fragment length polymorphism marker for the chromosome
      containing the Bt resistance gene. The results provide a powerful tool for
      facilitating progress in understanding, monitoring, and managing resistance to
      Bt.

PMID- 10411883
TI  - Crystal structure of the pleckstrin homology-phosphotyrosine binding (PH-PTB)
      targeting region of insulin receptor substrate 1.
AB  - We have determined the crystal structure at 2.3-A resolution of an amino-terminal
      segment of human insulin receptor substrate 1 that encompasses its pleckstrin
      homology (PH) and phosphotyrosine binding (PTB) domains. Both domains adopt the
      canonical seven-stranded beta-sandwich PH domain fold. The domains are closely
      associated, with a 720-A(2) contact surface buried between them that appears to
      be stabilized by ionic, hydrophobic, and hydrogen bonding interactions. The
      nonconserved 46-residue linker between the domains is disordered. The PTB domain
      peptide binding site is fully exposed on the molecular surface, as is a large
      cationic patch at the base of the PH domain that is a likely binding site for the
      head groups of phosphatidylinositol phosphates. Binding assays confirm that
      phosphatidylinositol phosphates bind the PH domain, but not the PTB domain.
      Ligand binding to the PH domain does not alter PTB domain interactions, and vice
      versa. The structural and accompanying functional data illustrate how the two
      binding domains might act cooperatively to effectively increase local insulin
      receptor substrate 1 concentration at the membrane and transiently fix the
      receptor and substrate, to allow multiple phosphorylation reactions to occur
      during each union.

PMID- 10411884
TI  - A structural snapshot of an intermediate on the streptavidin-biotin dissociation
      pathway.
AB  - It is currently unclear whether small molecules dissociate from a protein binding
      site along a defined pathway or through a collection of dissociation pathways. We
      report herein a joint crystallographic, computational, and biophysical study that
      suggests the Asp-128 --> Ala (D128A) streptavidin mutant closely mimics an
      intermediate on a well-defined dissociation pathway. Asp-128 is hydrogen bonded
      to a ureido nitrogen of biotin and also networks with the important aromatic
      binding contacts Trp-92 and Trp-108. The Asn-23 hydrogen bond to the ureido
      oxygen of biotin is lengthened to 3.8 A in the D128A structure, and a water
      molecule has moved into the pocket to replace the missing carboxylate
      interaction. These alterations are accompanied by the coupled movement of biotin,
      the flexible binding loop containing Ser-45, and the loop containing the Ser-27
      hydrogen bonding contact. This structure closely parallels a key intermediate
      observed in a potential of mean force-simulated dissociation pathway of native
      streptavidin, where the Asn-23 hydrogen bond breaks first, accompanied by the
      replacement of the Asp-128 hydrogen bond by an entering water molecule.
      Furthermore, both biotin and the flexible loop move in a concerted conformational
      change that closely approximates the D128A structural changes. The activation and
      thermodynamic parameters for the D128A mutant were measured and are consistent
      with an intermediate that has traversed the early portion of the dissociation
      reaction coordinate through endothermic bond breaking and concomitant gain in
      configurational entropy. These composite results suggest that the D128A mutant
      provides a structural "snapshot" of an early intermediate on a relatively well
      defined dissociation pathway for biotin.

PMID- 10411885
TI  - Interactions of Escherichia coli sigma(70) within the transcription elongation
      complex.
AB  - A functional transcription elongation complex can be formed without passing
      through a promoter by adding a complementary RNA primer and core Escherichia coli
      RNA polymerase in trans to an RNA-primed synthetic bubble-duplex DNA framework.
      This framework consists of a double-stranded DNA sequence with an internal
      noncomplementary DNA "bubble" containing a hybridized RNA primer. On addition of
      core polymerase and the requisite NTPs, the RNA primer is extended in a process
      that manifests most of the properties of in vitro transcription elongation. This
      synthetic elongation complex can also be assembled by using holo rather than core
      RNA polymerase, and in this study we examine the interactions and fate of the
      sigma(70) specificity subunit of the holopolymerase in the assembly process. We
      show that the addition of holopolymerase to the bubble-duplex construct triggers
      the dissociation of the sigma factor from some complexes, whereas in others the
      RNA oligomer is released into solution instead. These results are consistent with
      an allosteric competition between sigma(70) and the nascent RNA strand within the
      elongation complex and suggest that both cannot be bound to the core polymerase
      simultaneously. However, the dissociation of sigma(70) from the complex can also
      be stimulated by binding of the holopolymerase to the DNA bubble duplex in the
      absence of a hybridized RNA primer, suggesting that the binding of the core
      polymerase to the bubble-duplex construct also triggers a conformational change
      that additionally weakens the sigma-core interaction.

PMID- 10411886
TI  - Crystal structure of ERA: a GTPase-dependent cell cycle regulator containing an
      RNA binding motif.
AB  - ERA forms a unique family of GTPase. It is widely conserved and essential in
      bacteria. ERA functions in cell cycle control by coupling cell division with
      growth rate. ERA homologues also are found in eukaryotes. Here we report the
      crystal structure of ERA from Escherichia coli. The structure has been determined
      at 2.4-A resolution. It reveals a two-domain arrangement of the molecule: an N
      terminal domain that resembles p21 Ras and a C-terminal domain that is unique.
      Structure-based topological search of the C domain fails to reveal any meaningful
      match, although sequence analysis suggests that it contains a KH domain. KH
      domains are RNA binding motifs that usually occur in tandem repeats and exhibit
      low sequence similarity except for the well-conserved segment VIGxxGxxIK. We have
      identified a betaalphaalphabeta fold that contains the VIGxxGxxIK sequence and is
      shared by the C domain of ERA and the KH domain. We propose that this
      betaalphaalphabeta fold is the RNA binding motif, the minimum structural
      requirement for RNA binding. ERA dimerizes in crystal. The dimer formation
      involves a significantly distorted switch II region, which may shed light on how
      ERA protein regulates downstream events.

PMID- 10411887
TI  - A novel function for transglutaminase 1: attachment of long-chain omega
      hydroxyceramides to involucrin by ester bond formation.
AB  - Transglutaminases (TGases) are defined as enzymes capable of forming isopeptide
      bonds by transfer of an amine onto glutaminyl residues of a protein. Here we show
      that the membrane-bound form of the TGase 1 enzyme can also form ester bonds
      between specific glutaminyl residues of human involucrin and a synthetic analog
      of epidermal specific omega-hydroxyceramides. The formation of a approximately 5
      nm-thick lipid envelope on the surface of epidermal keratinocytes is an important
      component of normal barrier function. The lipid envelope consists of omega
      hydroxyceramides covalently linked by ester bonds to cornified envelope proteins,
      most abundantly to involucrin. We synthesized an analog of natural omega
      hydroxyceramides N-[16-(16-hydroxyhexadecyl)oxypalmitoyl]sphingosine (lipid Z).
      When recombinant human TGase 1 and involucrin were reacted on the surface of
      synthetic lipid vesicles containing lipid Z, lipid Z was attached to involucrin
      and formed saponifiable protein-lipid adducts. By mass spectroscopy and
      sequencing of tryptic lipopeptides, the ester linkage formation used involucrin
      glutamine residues 107, 118, 122, 133, and 496 by converting the gamma
      carboxamido groups to lipid esters. Several of these residues have been found
      previously to be attached to ceramides in vivo. Mass spectrometric analysis after
      acetonide derivatization also revealed that ester formation involved primarily
      the omega-hydroxyl group of lipid Z. Our data reveal a dual role for TGase 1 in
      epidermal barrier formation and provide insights into the pathophysiology of
      lamellar ichthyosis resulting from defects of TGase 1 enzyme.

PMID- 10411888
TI  - Crystallographic analysis of CD40 recognition and signaling by human TRAF2.
AB  - Tumor necrosis factor receptor superfamily members convey signals that promote
      diverse cellular responses. Receptor trimerization by extracellular ligands
      initiates signaling by recruiting members of the tumor necrosis factor receptor
      associated factor (TRAF) family of adapter proteins to the receptor cytoplasmic
      domains. We report the 2.4-A crystal structure of a 22-kDa, receptor-binding
      fragment of TRAF2 complexed with a functionally defined peptide from the
      cytoplasmic domain of the CD40 receptor. TRAF2 forms a mushroom-shaped trimer
      consisting of a coiled coil and a unique beta-sandwich domain. Both domains
      mediate trimerization. The CD40 peptide binds in an extended conformation with
      every side chain in contact with a complementary groove on the rim of each TRAF
      monomer. The spacing between the CD40 binding sites on TRAF2 supports an elegant
      signaling mechanism in which trimeric, extracellular ligands preorganize the
      receptors to simultaneously recognize three sites on the TRAF trimer.

PMID- 10411890
TI  - Three-dimensional structure of low density lipoproteins by electron
      cryomicroscopy.
AB  - Human low density lipoproteins (LDL) are the major cholesterol carriers in the
      blood. Elevated concentration of LDL is a major risk factor for atherosclerotic
      disease. Purified LDL particles appear heterogeneous in images obtained with a
      400-kV electron cryomicroscope. Using multivariate statistical and cluster
      analyses, an ensemble of randomly oriented particle images has been subdivided
      into homogeneous subpopulations, and the largest subset was used for three
      dimensional reconstruction. In contrast to the general belief that below the
      lipid phase-transition temperature (30 degrees C) LDL are quasi-spherical
      microemulsion particles with a radially layered core-shell organization, our
      three-dimensional map shows that LDL have a well-defined and stable organization.
      Particles consist of a higher-density outer shell and lower-density inner
      lamellae-like layers that divide the core into compartments. The outer shell
      consists of apolipoprotein B-100, phospholipids, and some free cholesterol.

PMID- 10411889
TI  - A model for the mechanism of strand passage by DNA gyrase.
AB  - The mechanism of type II DNA topoisomerases involves the formation of an enzyme
      operated gate in one double-stranded DNA segment and the passage of another
      segment through this gate. DNA gyrase is the only type II topoisomerase able to
      introduce negative supercoils into DNA, a feature that requires the enzyme to
      dictate the directionality of strand passage. Although it is known that this is a
      consequence of the characteristic wrapping of DNA by gyrase, the detailed
      mechanism by which the transported DNA segment is captured and directed through
      the DNA gate is largely unknown. We have addressed this mechanism by probing the
      topology of the bound DNA segment at distinct steps of the catalytic cycle. We
      propose a model in which gyrase captures a contiguous DNA segment with high
      probability, irrespective of the superhelical density of the DNA substrate,
      setting up an equilibrium of the transported segment across the DNA gate. The
      overall efficiency of strand passage is determined by the position of this
      equilibrium, which depends on the superhelical density of the DNA substrate. This
      mechanism is concerted, in that capture of the transported segment by the ATP
      operated clamp induces opening of the DNA gate, which in turn stimulates ATP
      hydrolysis.

PMID- 10411891
TI  - Protein preservation and DNA retrieval from ancient tissues.
AB  - The retrieval of DNA from fossils remains controversial. To substantiate claims
      of DNA recovery, one needs additional information on the preservation of other
      molecules within the same sample. Flash pyrolysis with GC and MS was used to
      assess the quality of protein preservation in 11 archaeological and
      paleontological remains, some of which have yielded ancient DNA sequences
      authenticated via a number of criteria and some of which have consistently failed
      to yield any meaningful DNA. Several samples, including the Neanderthal-type
      specimen from which DNA sequences were recently reported, yielded abundant
      pyrolysis products assigned to 2,5-diketopiperazines of proline-containing
      dipeptides. The relative amounts of these products provide a good index of the
      amount of peptide hydrolysis and DNA preservation. Of these samples, four stem
      from arctic or subarctic regions, emphasizing the importance of cooler
      temperatures for the preservation of macromolecules. Flash pyrolysis with GC and
      MS offers a rapid and effective method for assessing fossils for the possibility
      of DNA preservation.

PMID- 10411892
TI  - A role for coenzyme M (2-mercaptoethanesulfonic acid) in a bacterial pathway of
      aliphatic epoxide carboxylation.
AB  - The bacterial metabolism of short-chain aliphatic alkenes occurs via oxidation to
      epoxyalkanes followed by carboxylation to beta-ketoacids. Epoxyalkane
      carboxylation requires four enzymes (components I-IV), NADPH, NAD(+), and a
      previously unidentified nucleophilic thiol. In the present work, coenzyme M (2
      mercaptoethanesulfonic acid), a compound previously found only in the
      methanogenic Archaea where it serves as a methyl group carrier and activator, has
      been identified as the thiol and central cofactor of aliphatic epoxide
      carboxylation in the Gram-negative bacterium Xanthobacter strain Py2. Component I
      catalyzed the addition of coenzyme M to epoxypropane to form a beta
      hydroxythioether, 2-(2-hydroxypropylthio)ethanesulfonate. Components III and IV
      catalyzed the NAD(+)-dependent stereoselective dehydrogenation of R- and S
      enantiomers of 2-(2-hydroxypropylthio)ethanesulfonate to form 2-(2
      ketopropylthio)ethanesulfonate. Component II catalyzed the NADPH-dependent
      cleavage and carboxylation of the beta-ketothioether to form acetoacetate and
      coenzyme M. These findings evince a newfound versatility for coenzyme M as a
      carrier and activator of alkyl groups longer in chain-length than methane, a
      function for coenzyme M in a catabolic pathway of hydrocarbon oxidation, and the
      presence of coenzyme M in the bacterial domain of the phylogenetic tree. These
      results serve to unify bacterial and Archaeal metabolism further and showcase
      diverse biological functions for an elegantly simple organic molecule.

PMID- 10411893
TI  - Hot-spot mutants of p53 core domain evince characteristic local structural
      changes.
AB  - Most of the oncogenic mutations in the tumor suppressor p53 map to its DNA
      binding (core) domain. It is thus a potential target in cancer therapy for rescue
      by drugs. To begin to understand how mutation inactivates p53 and hence to
      provide a structural basis for drug design, we have compared structures of wild
      type and mutant p53 core domains in solution by NMR spectroscopy. Structural
      changes introduced by five hot-spot mutations (V143A, G245S, R248Q, R249S, and
      R273H) were monitored by chemical-shift changes. Only localized changes are
      observed for G245S, R248Q, R249S, and R273H, suggesting that the overall tertiary
      folds of these mutant proteins are similar to that of wild type. Structural
      changes in R273H are found mainly in the loop-sheet-helix motif and the loop L3
      of the core domain. Mutations in L3 (G245S, R248Q, and R249S) introduce
      structural changes in the loop L2 and L3 as well as terminal residues of strands
      4, 9, and 10. It is noteworthy that R248Q, which is often regarded as a contact
      mutant that affects only interactions with DNA, introduces structural changes as
      extensive as the other loop L3 mutations (G245S and R249S). These changes suggest
      that R248Q is also a structural mutant that perturbs the structure of loop L2-L3
      regions of the p53 core domain. In contrast to other mutants, replacement of the
      core residue valine 143 to alanine causes chemical-shift changes in almost all
      residues in the beta-sandwich and the DNA-binding surface. Long-range effects of
      V143A mutation may affect the specificity of DNA binding.

PMID- 10411894
TI  - Cell cycle regulation of Dfp1, an activator of the Hsk1 protein kinase.
AB  - In fission yeast, the Hsk1 protein kinase is essential for the initiation of DNA
      replication. We have shown previously that Hsk1 forms a heterodimeric complex
      with the regulatory subunit, Dfp1. In this report we describe the further
      characterization of Dfp1. Reconstitution experiments with purified proteins
      indicate that Dfp1 is necessary and sufficient to activate Hsk1 phosphorylation
      of exogenous substrates, such as the Schizosaccharomyces pombe minichromosome
      maintenance protein Cdc19. The dfp1(+) gene is essential for viability of S.
      pombe, and depletion of the Dfp1 protein significantly delays the onset of S
      phase. Dfp1 is a phosphoprotein in vivo and becomes hyperphosphorylated when
      cells are blocked in S phase by treatment with the DNA synthesis inhibitor
      hydroxyurea. Hyperphosphorylation in S phase depends on the checkpoint kinase
      Cds1. The abundance of Dfp1 varies during progression through the cell cycle. The
      protein is absent when cells are arrested in G(1) phase. When cells are released
      into the cell cycle, Dfp1 appears suddenly at the G(1)/S transition, coincident
      with the initiation of DNA replication. The absence of Dfp1 before S phase is due
      largely, but not exclusively, to posttranscriptional regulation. We propose that
      cell cycle-regulated activation of Dfp1 expression at the G(1)/S transition
      results in activation of the Hsk1 protein kinase, which, in turn, leads to the
      initiation of DNA replication.

PMID- 10411895
TI  - Human papillomavirus type 31 oncoproteins E6 and E7 are required for the
      maintenance of episomes during the viral life cycle in normal human
      keratinocytes.
AB  - The E6 and E7 oncoproteins of the high-risk human papillomavirus (HPV) types are
      able to immortalize human keratinocytes in vitro and likely contribute to the
      development of anogenital malignancies in vivo. The role of these oncoproteins in
      the productive viral life cycle, however, is not known. To begin to examine these
      possible roles, mutations in E6 were introduced in the context of the complete
      HPV 31 genome. Although transfected wild-type HPV 31 genomes, as well as genomes
      containing an E6 translation termination linker, an E6 frameshift mutation, and a
      point mutation in the p53 interacting domain were able to replicate in transient
      assays, only the wild-type genome was stably maintained as an episome.
      Interestingly, mutant genomes in either the E6 splice-donor site or splice
      acceptor site were reduced in replication ability in transient assays; however,
      cotransfection of E1 and E2 expression vectors restored this function. In a
      similar fashion, genomes containing mutant HPV 31 E7 genes, including a
      translation termination mutant, two Rb-binding site mutants, a casein kinase II
      phosphorylation site mutant, and a transformation deficient mutant, were
      constructed. Although transient replication was similar to wild type in all of
      the E7 mutants, only the casein kinase II mutant had the ability to maintain high
      copies of episomal genomes. These findings suggest a role for E6 and E7 in the
      viral life cycle beyond their ability to extend the life span of infected cells.

PMID- 10411896
TI  - The kinetoplast structure-specific endonuclease I is related to the 5'
      exo/endonuclease domain of bacterial DNA polymerase I and colocalizes with the
      kinetoplast topoisomerase II and DNA polymerase beta during replication.
AB  - The mitochondrial DNA (kinetoplast DNA) of the trypanosomatid Crithidia
      fasciculata has an unusual structure composed of minicircles and maxicircles
      topologically interlocked into a single network and organized in a disc-shaped
      structure at the base of the flagellum. We previously purified a structure
      specific endonuclease (SSE1), based on its RNase H activity, that is enriched in
      isolated kinetoplasts. The endonuclease gene has now been cloned, sequenced, and
      found to be closely related to the 5' exonuclease domain of bacterial DNA
      polymerase I proteins. Although the protein does not contain a typical
      mitochondrial leader sequence, the enzyme is shown to colocalize with a type II
      DNA topoisomerase and a DNA polymerase beta at antipodal sites flanking the
      kinetoplast disc. Cell synchronization studies with an epitope-tagged construct
      show that the localization of the endonuclease to the antipodal sites varies in a
      cell cycle-dependent manner similar to that of the DNA polymerase beta [Johnson,
      C. E. & Englund, P. T. (1998) J. Cell Biol. 143, 911-919]. Immunofluorescent
      localization of SSE1 to the antipodal sites is only observed during kinetoplast
      replication. Together, these results suggest a point of control for kinetoplast
      DNA replication through the regulation of the availability of DNA replication
      proteins and a possible role for the antipodal sites in removal of RNA primers
      and the repair of gaps in newly replicated minicircles.

PMID- 10411897
TI  - Characterization of lipid bilayer phases by confocal microscopy and fluorescence
      correlation spectroscopy.
AB  - We report the application of confocal imaging and fluorescence correlation
      spectroscopy (FCS) to characterize chemically well-defined lipid bilayer models
      for biomembranes. Giant unilamellar vesicles of dilauroyl
      phosphatidylcholine/dipalmitoyl phosphatidylcholine (DLPC/DPPC)/cholesterol were
      imaged by confocal fluorescence microscopy with two fluorescent probes, 1, 1'
      dieicosanyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI-C(20)) and 2
      (4,4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza-s-indacene-3-pentanoyl)-1
      hexadecanoyl-sn-glycero-3 -phosphoc holine (Bodipy-PC). Phase separation was
      visualized by differential probe partition into the coexisting phases. Three
      dimensional image reconstructions of confocal z-scans through giant unilamellar
      vesicles reveal the anisotropic morphology of coexisting phase domains on the
      surface of these vesicles with full two-dimensional resolution. This method
      demonstrates by direct visualization the exact superposition of like phase
      domains in apposing monolayers, thus answering a long-standing open question.
      Cholesterol was found to induce a marked change in the phase boundary shapes of
      the coexisting phase domains. To further characterize the phases, the
      translational diffusion coefficient, D(T), of the DiI-C(20) was measured by FCS.
      D(T) values at approximately 25 degrees C ranged from approximately 3 x 10(-8)
      cm(2)/s in the fluid phase, to approximately 2 x 10(-9) cm(2)/s in high
      cholesterol-content phases, to approximately 2 x 10(-10) cm(2)/s in the spatially
      ordered phases that coexist with fluid phases. In favorable cases, FCS could
      distinguish two different values of D(T) in a region of two-phase coexistence on
      a single vesicle.

PMID- 10411898
TI  - Translocation of the catalytic domain of diphtheria toxin across planar
      phospholipid bilayers by its own T domain.
AB  - The T domain of diphtheria toxin is known to participate in the pH-dependent
      translocation of the catalytic C domain of the toxin across the endosomal
      membrane, but how it does so, and whether cellular proteins are also required for
      this process, remain unknown. Here, we report results showing that the T domain
      alone is capable of translocating the entire C domain across model, planar
      phospholipid bilayers in the absence of other proteins. The T domain therefore
      contains the entire molecular machinery for mediating transfer of the catalytic
      domain of diphtheria toxin across membranes.

PMID- 10411899
TI  - Mapping the sensitivity of T cells with an optical trap: polarity and minimal
      number of receptors for Ca(2+) signaling.
AB  - Contact with antigen-presenting cells (APCs) initiates an activation cascade
      within T lymphocytes, including a rise in cytosolic calcium, lymphokine
      production, and cell division. Although T cell-APC physical contact is required
      for an immune response, little is known about the patterns of cellular
      interactions and their relation to activation. Calcium imaging combined with an
      optical trap enabled the T cell contact requirements and polarity to be
      investigated at the single-cell level. APCs or anti-CD3 mAb-coated beads were
      trapped with a laser and placed at different locations along the T cell, which
      has a polarized appearance defined by the shape and direction of crawling. T
      cells were 3-fold more sensitive to APC contact made at the leading edge of the T
      cell than with contact made at the tail. Anti-CD3 mAb-coated 6-micrometer beads
      induced calcium signaling with approximately 10-fold higher frequency and
      approximately 4-fold shorter latency on contact with the leading edge of the T
      cell than on contact with the trailing edge. Alterations in antibody density (2
      to 500 per micrometer(2)) and bead size (1 to 6 micrometer in diameter) were used
      to determine the spatial requirements and the minimal number of receptors which
      must be engaged to transmit a positive signal. T cell response percentage,
      latency, and calcium-signaling pattern (transient vs. sustained or oscillatory)
      depended on antibody density on the bead. The presence of approximately 170 anti
      CD3 mAb within the contact area elicited a detectable T cell calcium response. We
      propose here that engagement of no more than 340 T cell receptors (approximately
      1% of the total on the cell) is sufficient to initiate Ca(2+) signaling. The
      minimal contact area was approximately 3 micrometer(2).

PMID- 10411900
TI  - A systematic study of low-resolution recognition in protein--protein complexes.
AB  - A comprehensive nonredundant database of 475 cocrystallized protein-protein
      complexes was used to study low-resolution recognition, which was reported in
      earlier docking experiments with a small number of proteins. The docking program
      GRAMM was used to delete the atom-size structural details and systematically dock
      the resulting molecular images. The results reveal the existence of the low
      resolution recognition in 52% of all complexes in the database and in 76% of the
      113 complexes with an interface area >4,000 A(2). Limitations of the docking and
      analysis tools used in this study suggest that the actual number of complexes
      with the low-resolution recognition is higher. However, the results already prove
      the existence of the low-resolution recognition on a broad scale.

PMID- 10411901
TI  - Development of gene-switch transgenic mice that inducibly express transforming
      growth factor beta1 in the epidermis.
AB  - Previous attempts to establish transgenic mouse models to study the functions of
      transforming growth factor beta1 (TGFbeta1) in the skin revealed controversial
      roles for TGFbeta1 in epidermal growth (inhibition vs. stimulation) and resulted
      in neonatal lethality in one instance. To establish a viable transgenic model for
      studying functions of TGFbeta1 in the skin, we have now developed transgenic
      mice, which allow focal induction of the TGFbeta1 transgene in the epidermis at
      different expression levels and at different developmental stages. This system,
      termed "gene-switch," consists of two transgenic lines. The mouse loricrin vector
      targets the GLVPc transactivator (a fusion molecule of the truncated progesterone
      receptor and the GAL4 DNA binding domain), and a thymidine kinase promoter drives
      the TGFbeta1 target gene with GAL4 binding sites upstream of the promoter. These
      two transgenic lines were mated to generate bigenic mice, and TGFbeta1 transgene
      expression was controlled by topical application of an antiprogestin. On
      epidermal-specific induction of the TGFbeta1 transgene, the BrdUrd labeling index
      in the transgenic epidermis decreased 6-fold compared with controls. Induction of
      the TGFbeta1 transgene expression also caused epidermal resistance to phorbol 12
      myristate 13-acetate-induced hyperplasia, with a reduction in both epidermal
      thickness and BrdUrd labeling compared with those in controls. In addition,
      TGFbeta1 transgene expression induced an increase in angiogenesis in the dermis.
      Given that the TGFbeta1 transgene can affect both the epidermis and dermis, this
      transgenic model will provide a useful tool for studying roles of TGFbeta1 in
      wound-healing and skin carcinogenesis in the future.

PMID- 10411902
TI  - The tumor-suppressor gene FHIT is involved in the regulation of apoptosis and in
      cell cycle control.
AB  - Alteration of the FHIT (fragile histidine triad) gene occurs as an early and
      frequent event in lung carcinogenesis. FHIT gene transfer into lung cancer cell
      line H460 lacking Fhit protein expression resulted in reversion of
      tumorigenicity. To gain insight into the biological function of FHIT, we compared
      the H460 cell line with its Fhit transfectants (H460/FHIT). A significant
      inhibition of cell growth was observed in H460/FHIT cells. The analysis of
      apoptosis by in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end
      labeling revealed a high rate of apoptosis-induced DNA strand breaks in stable
      clones. In situ results were confirmed by FACScan analysis that showed an
      apoptotic rate of 44-47% compared with a 15% level in the control H460 cells.
      Analysis of cell cycle-phase distribution indicated a significant G(0)/G(1)
      arrest and the presence of a sub-G(1) peak in the stable clones. No significant
      changes in Bcl2, BclX, and Bax protein expression level were observed in the
      transfected clones as compared with the control H460 cells whereas a 2-fold
      increase in Bak protein levels was noticed. An increased level of p21(waf)
      protein paralleled by an up-regulation of p21(waf) transcripts also was found in
      Fhit-expressing clones compared with the H460 cell line. No differences in p53
      levels were observed in the same cells, suggesting a p53-independent effect.
      These data suggest that the observed growth-inhibitory effect in FHIT
      reexpressing cells could be related to apoptosis and cell cycle arrest and link
      the tumor-suppressor activity of FHIT to its proapoptotic function.

PMID- 10411903
TI  - Retention of the BUB3 checkpoint protein on lagging chromosomes.
AB  - Accurate chromosome segregation at mitosis is ensured both by the intrinsic
      fidelity of the mitotic machinery and by the operation of checkpoints that
      monitor chromosome-microtubule attachment. When unattached kinetochores are
      present, anaphase is delayed and the time available for chromosome-microtubule
      capture increases. Genes required for this delay first were identified in budding
      yeast (the MAD and BUB genes), but it is not yet known how the checkpoint senses
      unattached chromosomes or how it signals cell-cycle arrest. We report the
      isolation and analysis of a murine homologue of BUB3, a gene whose deletion
      abolishes mitotic checkpoint function in Saccharomyces cerevisiae. mBub3 belongs
      to a small gene family that has been highly conserved through evolution. By
      expressing recombinant proteins in insect cells, we show that mBub3, like yeast
      Bub3p, binds to Bub1 to form a complex with protein kinase activity. During
      prophase and prometaphase, preceding kinetochore-microtubule attachment, Bub3
      localizes to kinetochores. High levels of mBub3 remain associated with lagging
      chromosomes but not with correctly aligned chromosomes during metaphase,
      consistent with a role for Bub3 in sensing microtubule attachment. Intriguingly,
      the number of lagging chromosomes with high Bub3 staining increases dramatically
      in cells treated with low (and pharmacologically relevant) concentrations of the
      chemotherapeutic taxol and the microtubule poison nocodazole.

PMID- 10411904
TI  - TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two
      mitochondrial modulators of apoptosis with opposing functions.
AB  - Mitochondria have emerged as central regulators of apoptosis. Here, we show that
      TID1, a human homolog of the Drosophila tumor suppressor lethal (2) tumorous
      imaginal discs, l(2)tid, encodes two mitochondrial matrix proteins, designated
      hTid-1(L) and hTid-1(S). These splice variants are both highly conserved members
      of the DnaJ family of proteins, which regulate the activity of and confer
      substrate specificity to Hsp70 proteins. Both hTid-1(L) and hTid-1(S)
      coimmunoprecipitate with mitochondrial Hsp70. Expression of hTid-1(L) or hTid
      1(S) have no apparent capacity to induce apoptosis but have opposing effects on
      apoptosis induced by exogenous stimuli. Expression of hTid-1(L) increases
      apoptosis induced by both the DNA-damaging agent mitomycin c and tumor necrosis
      factor alpha. This activity is J domain-dependent, because a J domain mutant of
      hTid-1(L) can dominantly suppress apoptosis. In sharp contrast, expression of
      hTid-1(S) suppresses apoptosis, whereas expression of a J domain mutant of hTid
      1(S) increases apoptosis. Hence, we propose that TID1 gene products act to
      positively and negatively modulate apoptotic signal transduction or effector
      structures within the mitochondrial matrix.

PMID- 10411905
TI  - Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle
      progression.
AB  - Alterations in normal protein biogenesis and the resulting accumulation of
      improperly folded proteins in the endoplasmic reticulum (ER) trigger a stress
      response that up-regulates the expression of ER chaperones, while coordinately
      repressing overall protein synthesis and causing cell-cycle arrest. Activation of
      this unfolded protein response (UPR) in mouse NIH 3T3 fibroblasts with the
      glycosylation inhibitor tunicamycin led to a decline in cyclin D- and E-dependent
      kinase activities and to G(1) phase arrest. Cyclin D1 protein synthesis was
      rapidly inhibited by tunicamycin treatment. However, the drug did not
      significantly affect the mitogen-dependent activities of the extracellular signal
      activated protein kinases ERK1 and ERK2 or the level of cyclin D1 mRNA until much
      later in the response. Therefore, the UPR triggers a signaling pathway that
      blocks cyclin D1 translation despite continuous mitogenic stimulation. Enforced
      overexpression of cyclin D1 in tunicamycin-treated cells maintained cyclin D- and
      E-dependent kinase activities and kept cells in cycle in the face of a fully
      activated UPR. Translational regulation of cyclin D1 in response to ER stress is
      a mechanism for checkpoint control that prevents cell-cycle progression until
      homeostasis is restored.

PMID- 10411906
TI  - Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3
      proteins.
AB  - Apoptosis signal-regulating kinase 1 (ASK1) is a pivotal component of a signaling
      pathway induced by many death stimuli, including tumor necrosis factor alpha,
      Fas, and the anticancer drugs cisplatin and paclitaxel. Here we report that ASK1
      proapoptotic activity is antagonized by association with 14-3-3 proteins. We
      found that ASK1 specifically bound 14-3-3 proteins via a site involving Ser-967
      of ASK1. Interestingly, overexpression of 14-3-3 in HeLa cells blocked ASK1
      induced apoptosis whereas disruption of the ASK1/14-3-3 interaction dramatically
      accelerated ASK1-induced cell death. Targeting of ASK1 by a 14-3-3-mediated
      survival pathway may provide a novel mechanism for the suppression of apoptosis.

PMID- 10411907
TI  - The cytosolic tail of class I MHC heavy chain is required for its dislocation by
      the human cytomegalovirus US2 and US11 gene products.
AB  - The US2 and US11 glycoproteins of human cytomegalovirus facilitate destruction of
      MHC class I heavy chains by proteasomal proteolysis through acceleration of
      endoplasmic reticulum-to-cytosol dislocation. Modification of the class I heavy
      chain was used to probe the structural requirements for this sequence of
      reactions. The cytosolic domain of the class I heavy chain is required for
      dislocation to the cytosol and for its subsequent destruction. However,
      interactions between US2 or US11 and the heavy chain are maintained in the
      absence of the class I cytosolic domain, as shown by chemical crosslinking in
      vivo and coprecipitation when translated in vitro. Thus, substrate recognition
      and accelerated destruction of the heavy chain, as facilitated by US2 or US11,
      are separable events.

PMID- 10411908
TI  - Hsl7p, a negative regulator of Ste20p protein kinase in the Saccharomyces
      cerevisiae filamentous growth-signaling pathway.
AB  - In the budding yeast, Saccharomyces cerevisiae, protein kinases Ste20p
      (p21(Cdc42p/Rac)-activated kinase), Ste11p [mitogen-activated protein kinase
      (MAPK) kinase kinase], Ste7p (MAPK kinase), Fus3p, and Kss1p (MAPKs) are utilized
      for haploid mating, invasive growth, and diploid filamentous growth. Members of
      the highly conserved Ste20p/p65(PAK) protein kinase family regulate MAPK signal
      transduction pathways from yeast to man. We describe here a potent negative
      regulator of Ste20p in the yeast filamentous growth-signaling pathway. We
      identified a mutant, hsl7, that exhibits filamentous growth on rich medium. Hsl7p
      belongs to a highly conserved protein family in eukaryotes. Hsl7p associates with
      the noncatalytic region within the amino-terminal half of Ste20p as well as
      Cdc42p. Deletions of HSL7 in haploid and diploid strains led to cell elongation
      and enhancement of both haploid invasive growth and diploid pseudohyphal growth.
      However, deletions of STE20 in haploid and diploid greatly diminished these hsl7
      associated phenotypes. In addition, overexpression of HSL7 inhibited pseudohyphal
      growth. Thus, Hsl7p may inhibit the activity of Ste20p in the S. cerevisiae
      filamentous growth-signaling pathway. Our genetic analyses suggest the
      possibility that Cdc42p and Hsl7p compete for binding to Ste20p for pseudohyphal
      development when starved for nitrogen.

PMID- 10411910
TI  - Natural (13)C abundance reveals trophic status of fungi and host-origin of carbon
      in mycorrhizal fungi in mixed forests.
AB  - Fungi play crucial roles in the biogeochemistry of terrestrial ecosystems, most
      notably as saprophytes decomposing organic matter and as mycorrhizal fungi
      enhancing plant nutrient uptake. However, a recurrent problem in fungal ecology
      is to establish the trophic status of species in the field. Our interpretations
      and conclusions are too often based on extrapolations from laboratory microcosm
      experiments or on anecdotal field evidence. Here, we used natural variations in
      stable carbon isotope ratios (delta(13)C) as an approach to distinguish between
      fungal decomposers and symbiotic mycorrhizal fungal species in the rich sporocarp
      flora (our sample contains 135 species) of temperate forests. We also
      demonstrated that host-specific mycorrhizal fungi that receive C from overstorey
      or understorey tree species differ in their delta(13)C. The many promiscuous
      mycorrhizal fungi, associated with and connecting several tree hosts, were
      calculated to receive 57-100% of their C from overstorey trees. Thus, overstorey
      trees also support, partly or wholly, the nutrient-absorbing mycelia of their
      alleged competitors, the understorey trees.

PMID- 10411909
TI  - Genetic evidence that Shp-2 tyrosine phosphatase is a signal enhancer of the
      epidermal growth factor receptor in mammals.
AB  - By using both genetic and biochemical approaches, we have investigated the
      physiological role of Shp-2, a cytoplasmic tyrosine phosphatase with two Src
      homology 2 domains, in signaling pathways downstream of epidermal growth factor
      receptor (EGF-R). In previous studies, a targeted deletion mutation in the SH2-N
      domain of Shp-2 was introduced into the murine Shp-2 locus, which resulted in
      embryonic lethality of homozygous mutant (Shp-2(-/-)) mice at midgestation. By
      aggregating Shp-2(-/-) embryonic stem cells with wild-type embryos, we created
      Shp-2(-/-)/wild-type chimeric animals. Most chimeras had open eyelids at birth
      and abnormal skin development, a phenotype characteristic of mice with mutations
      in EGF-R signaling components. In genetic crosses, a heterozygous Shp-2 mutation
      dominantly enhanced the phenotype of a weak mutant allele of EGF-R (wa-2),
      resulting in distinctive growth retardation, developmental defects in the skin,
      lung, and intestine, and perinatal mortality that are reminiscent of EGF-R
      knockout mice. Biochemical analysis revealed that signal propagation proximal to
      the EGF-R upon EGF stimulation was significantly attenuated in wa-2 fibroblast
      cells, which was exacerbated by the additional Shp-2 mutation. Thus, we provide
      biological evidence here that protein-tyrosine phosphatase Shp-2 acts to enhance
      information flow from the EGF-R in mouse growth and development.

PMID- 10411911
TI  - Divergent evolution of membrane protein topology: the Escherichia coli RnfA and
      RnfE homologues.
AB  - Although the molecular evolution of protein tertiary structure and enzymatic
      activity has been studied for decades, little attention has been paid to the
      evolution of membrane protein topology. Here, we show that two closely related
      polytopic inner membrane proteins from Escherichia coli have evolved opposite
      orientations in the membrane, which apparently has been achieved by the selective
      redistribution of positively charged amino acids between the polar segments
      flanking the transmembrane stretches. This example of divergent evolution of
      membrane protein topology suggests that a complete inversion of membrane topology
      is possible with relatively few mutational changes even for proteins with
      multiple transmembrane segments.

PMID- 10411914
TI  - Gene silencing via protein-mediated subcellular localization of DNA.
AB  - We previously reported that overexpression of SopB, an Escherichia coli F plasmid
      encoded partition protein, led to silencing of genes linked to, but well
      separated from, a cluster of SopB-binding sites termed sopC. We show here that in
      this SopB-mediated repression of sopC-linked genes, all but the N-terminal 82
      amino acids of SopB can be replaced by the DNA-binding domain of a sequence
      specific DNA-binding protein, provided that the sopC locus is also replaced by
      the recognition sequence of the DNA-binding domain. These results, together with
      our previous finding that the N-terminal fragment of SopB is responsible for its
      polar localization in cells, suggest a mechanism of gene silencing: patches of
      closely packed DNA-binding domains are formed if a sequence-specific DNA-binding
      protein is localized to specific cellular sites; such a patch can capture a DNA
      carrying the recognition site of the DNA-binding domain and sequestrate genes
      adjacent to the recognition site through nonspecific binding of DNA. The
      generalization of this model to gene silencing in eukaryotes is discussed.

PMID- 10411912
TI  - Transcription in archaea.
AB  - Using the sequences of all the known transcription-associated proteins from
      Bacteria and Eucarya (a total of 4,147), we have identified their homologous
      counterparts in the four complete archaeal genomes. Through extensive sequence
      comparisons, we establish the presence of 280 predicted transcription factors or
      transcription-associated proteins in the four archaeal genomes, of which 168 have
      homologs only in Bacteria, 51 have homologs only in Eucarya, and the remaining 61
      have homologs in both phylogenetic domains. Although bacterial and eukaryotic
      transcription have very few factors in common, each exclusively shares a
      significantly greater number with the Archaea, especially the Bacteria. This last
      fact contrasts with the obvious close relationship between the archaeal and
      eukaryotic transcription mechanisms per se, and in particular, basic
      transcription initiation. We interpret these results to mean that the archaeal
      transcription system has retained more ancestral characteristics than have the
      transcription mechanisms in either of the other two domains.

PMID- 10411913
TI  - The magical touch: genome targeting in epidermal stem cells induced by tamoxifen
      application to mouse skin.
AB  - Gene knockout technology has provided a powerful tool for functional analyses of
      genes expressed preferentially in a particular tissue. Given marked similarities
      between human and mouse skin, such studies with epidermally expressed genes have
      often provided valuable insights into human genetic skin disorders. Efficient
      silencing of a specified gene in a temporally regulated and epidermal-specific
      fashion could extend functional analyses to broadly expressed genes and increase
      the categories of human skin disorders to which parallels could be drawn. We have
      generated transgenic mice expressing Cre and a fusion protein between Cre
      recombinase and the tamoxifen responsive hormone-binding domain of the estrogen
      receptor (CreER(tam)) under the control of the human keratin 14 (K14) promoter.
      This promoter is strongly active in dividing cells of epidermis and some other
      stratified squamous epithelia. With K14-Cre, transgenic embryos recombine
      genetically introduced loxP sequences efficiently and selectively in the genomes
      of keratinocytes that reside in embryonic day 14.5 skin, tongue, and esophagus.
      With K14-CreER(tam), postnatal transgenic mice show no Cre activity until
      tamoxifen is administered. If orally administered, tamoxifen activates
      keratinocyte-specific CreER(tam), allowing recombination of loxP sequences in
      epidermis, tongue, and esophagus. If topically administered, tamoxifen allows
      recombination in the area of skin where tamoxifen was applied. Finally, we show
      that epidermal cells harboring a Cre-dependent rearranged genome persist for many
      months after tamoxifen application, indicating that the epidermal stem cell
      population has been targeted efficiently. These tools now pave the way for
      testing the functional role of different somatic mutations that may exist in
      mosaic disorders of the skin, including squamous and basal cell carcinomas.

PMID- 10411915
TI  - Mucolipidosis IV consists of one complementation group.
AB  - Mucolipidosis IV (MLIV) is an autosomal recessive disorder of unknown etiology
      characterized by severe visual impairment and psychomotor retardation. Recently,
      there has been considerable interest in positional cloning of the MLIV gene. It
      is unknown whether MLIV is a genetically homogenous disorder. In this paper, we
      present experiments that determined whether the MLIV phenotype in fibroblasts
      could be corrected by fusing normal cells to MLIV cells and fusing fibroblasts
      from pairs of patients. All of our MLIV patients fulfilled several diagnostic
      criteria that we developed. In addition, we found high sensitivity to chloroquine
      in cultured fibroblasts from MLIV patients. We found that normal cells corrected
      the MLIV phenotype. Fusion products of normal and MLIV fibroblasts, but not MLIV
      fibroblasts themselves, were relatively protected against chloroquine selection.
      In addition, 74% of the normal-to-patient fusion products had reduced levels or
      total loss of MLIV characteristic autofluorescence. However, there was no
      complementation of the phenotype in fibroblast cultures from any of our MLIV
      patients, including those of non-Jewish ancestry. In fusion products of MLIV
      cultures from 24 patients, 90-100% of the cells remained autofluorescent. These
      results indicate that all of our known MLIV patients, regardless of ancestry or
      severity of the developmental defect, have a single mutated gene.

PMID- 10411916
TI  - "Mutagenesis" by peptide aptamers identifies genetic network members and pathway
      connections.
AB  - We selected peptide aptamers from combinatorial libraries that disrupted cell
      cycle arrest caused by mating pheromone in yeast. We used these aptamers as baits
      in two-hybrid hunts to identify genes involved in cell-cycle arrest. These
      experiments identified genes known to function in the pathway, as well as a
      protein kinase, the CBK1 product, whose function was not known. We used a
      modified two-hybrid system to identify specific interactions disrupted by these
      aptamers. These experiments demonstrate a means to perform "genetics" on the
      protein complement of a cell without altering its genetic material. Peptide
      aptamers can be identified that disrupt a process. These aptamers can then be
      used as affinity reagents to identify individual proteins and protein
      interactions needed for the process. Forward genetic analysis with peptide
      aptamer "mutagens" should be particularly useful in elucidating genetic networks
      in organisms and processes for which classical genetics is not feasible.

PMID- 10411917
TI  - Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence
      for linkage is with follistatin.
AB  - Polycystic ovary syndrome (PCOS) is a common endocrine disorder of women,
      characterized by hyperandrogenism and chronic anovulation. It is a leading cause
      of female infertility and is associated with polycystic ovaries, hirsutism,
      obesity, and insulin resistance. We tested a carefully chosen collection of 37
      candidate genes for linkage and association with PCOS or hyperandrogenemia in
      data from 150 families. The strongest evidence for linkage was with the
      follistatin gene, for which affected sisters showed increased identity by descent
      (72%; chi(2) = 12.97; nominal P = 3.2 x 10(-4)). After correction for multiple
      testing (33 tests), the follistatin findings were still highly significant (P(c)
      = 0.01). Although the linkage results for CYP11A were also nominally significant
      (P = 0.02), they were no longer significant after correction. In 11 candidate
      gene regions, at least one allele showed nominally significant evidence for
      population association with PCOS in the transmission/disequilibrium test (chi(2)
      >/= 3.84; nominal P < 0.05). The strongest effect in the
      transmission/disequilibrium test was observed in the INSR region (D19S884; allele
      5; chi(2) = 8.53) but was not significant after correction. Our study shows how a
      systematic screen of candidate genes can provide strong evidence for genetic
      linkage in complex diseases and can identify those genes that should have high
      (or low) priority for further study.

PMID- 10411918
TI  - An agouti mutation lacking the basic domain induces yellow pigmentation but not
      obesity in transgenic mice.
AB  - Chronic antagonism of melanocortin receptors by the paracrine-acting agouti gene
      product induces both yellow fur and a maturity-onset obesity syndrome in mice
      that ubiquitously express wild-type agouti. Functional analysis of agouti
      mutations in transgenic mice indicate that the cysteine-rich C terminus, signal
      peptide, and glycosylation site are required for agouti activity in vivo. In
      contrast, no biological activity has been ascribed to the conserved basic domain.
      To examine the functional significance of the agouti basic domain, the entire 29
      aa region was deleted from the agouti cDNA, and the resulting mutation
      (agoutiDeltabasic) was expressed in transgenic mice under the control of the beta
      actin promoter (BAPaDeltabasic). Three independent lines of BAPaDeltabasic
      transgenic mice all developed some degree of yellow pigment in the fur,
      indicating that the agoutiDeltabasic protein was functional in vivo. However,
      none of the BAPaDeltabasic transgenic mice developed completely yellow fur,
      obesity, hyperinsulinemia, or hyperglycemia. High levels of agoutiDeltabasic
      expression in relevant tissues exceeded the level of agouti expression in obese
      viable yellow mice, suggesting that suboptimal activity or synthesis of the
      agoutiDeltabasic protein, rather than insufficient RNA synthesis, accounts for
      the phenotype of the BAPaDeltabasic transgenic mice. These findings implicate a
      functional role for the agouti basic domain in vivo, possibly influencing the
      biogenesis of secreted agouti protein or modulating protein-protein interactions
      that contribute to effective antagonism of melanocortin receptors.

PMID- 10411919
TI  - Stromal cell-derived factor 1 (SDF-1) and antenatal human B cell lymphopoiesis:
      expression of SDF-1 by mesothelial cells and biliary ductal plate epithelial
      cells.
AB  - The chemokine stromal cell-derived factor 1 (SDF-1) stimulates the growth of pre
      B cells in vitro, and mice with a disrupted SDF-1 gene have abnormal fetal liver
      B cell lymphopoiesis. The origin of SDF-1 production has not been determined yet.
      Using an anti-SDF-1 mAb, we performed immunohistochemical studies in four human
      embryos and five fetuses to define which cells express the SDF-1 protein at sites
      of antenatal B cell lymphopoiesis. All mesothelial cells contained SDF-1 at all
      stages of development, including in the intraembryonic splanchnopleuric mesoderm
      early into gestation. In fetal lungs and kidneys, SDF-1 was expressed by
      epithelial cells, and a few B lymphoid precursors, expressing V pre-B chains,
      were also detected. In the fetal liver, in addition to mesothelial cells, biliary
      epithelial cells were the only cells to contain SDF-1. Pre-B cells expressing V
      chains were abundant and exclusively located around the edge of portal spaces, in
      close contact with biliary ductal plate epithelial cells. They did not colocalize
      with biliary collecting ducts. Biliary ductal plate epithelial cells and liver B
      cell lymphopoiesis display a parallel development and disappearance during fetal
      life. These results indicate that early B cell lymphopoiesis in the
      splanchnopleura may be triggered by mesothelial cells producing SDF-1. Later into
      gestation, biliary ductal plate epithelial cells may support B cell
      lymphopoiesis, thus playing a role similar to that of epithelial cells in the
      avian bursa of Fabricius, and of thymic epithelial cells for T cell
      lymphopoiesis.

PMID- 10411920
TI  - Tumor-targeted IL-2 amplifies T cell-mediated immune response induced by gene
      therapy with single-chain IL-12.
AB  - Induction, maintenance, and amplification of tumor-protective immunity after
      cytokine gene therapy is essential for the clinical success of immunotherapeutic
      approaches. We investigated whether this could be achieved by single-chain IL-12
      (scIL-12) gene therapy followed by tumor-targeted IL-2 using a fusion protein
      containing a tumor-specific recombinant anti-ganglioside GD(2) antibody and IL-2
      (ch14.18-IL-2) in a poorly immunogenic murine neuroblastoma model. Herein, we
      demonstrate the absence of liver and bone marrow metastases after a lethal
      challenge with NXS2 wild-type cells only in mice (five of six animals) vaccinated
      with scIL-12-producing NXS2 cells and given a booster injection of low-dose
      ch14.18-IL-2 fusion protein. This tumor-protective immunity was effective 3
      months after initial vaccination, in contrast to control animals treated with a
      nonspecific fusion protein or an equivalent mixture of antibody and IL-2. Only
      vaccinated mice receiving the tumor-specific ch14.18-IL-2 fusion protein revealed
      a reactivation of CD8(+) T cells and subsequent MHC class I-restricted tumor
      target cell lysis in vitro. The sequential increase in the usage of TCR chains
      Vbeta11 and -13 in mouse CD8(+) T cells after vaccination and amplification with
      ch14.18-IL-2 suggests that the initial polyclonal CD8(+) T cell response is
      effectively boosted by targeted IL-2. In conclusion, we demonstrate that a
      successful boost of a partially protective memory T cell immune response that is
      induced by scIL-12 gene therapy could be generated by tumor-specific targeting of
      IL-2 with a ch14.18-IL-2 fusion protein. This approach could increase success
      rates of clinical cancer vaccine trials.

PMID- 10411921
TI  - In vivo proliferation of naive and memory influenza-specific CD8(+) T cells.
AB  - The virus-specific CD8(+) T cell response has been analyzed through the
      development, effector, and recovery phases of primary and secondary influenza
      pneumonia. Apparently, most, if not all, memory T cells expressing clonotypic
      receptors that bind a tetrameric complex of influenza nucleoprotein (NP)(366-374)
      peptide+H-2D(b) (NPP) are induced to divide during the course of this localized
      respiratory infection. The replicative phase of the recall response ends about
      the time that virus can no longer be recovered from the lung, whereas some
      primary CD8(+)NPP(+) T cells may proliferate for a few more days. The greatly
      expanded population of CD8(+)NPP(+) memory T cells in the lymphoid tissue of
      secondarily challenged mice declines progressively in mean prevalence over the
      ensuing 100 days, despite the fact that at least some of these lymphocytes
      continue to cycle. The recall of cell-mediated immunity thus is characterized by
      massive proliferation of the antigen-specific CD8(+) set, whereas the extent of
      lymphocyte turnover in the absence of cognate peptide is variable, at a low
      level, and can be influenced by intercurrent infection.

PMID- 10411922
TI  - Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide
      specific CD4(+) T cell responses.
AB  - CTLA-4-deficient mice develop a fatal lymphoproliferative disorder, characterized
      by polyclonal expansion of peripheral lymphocytes. To examine the effect of
      restricting the CD4(+) TCR repertoire on the phenotype of CTLA-4-deficient mice
      and to assess the influence of CTLA-4 on peptide-specific CD4(+) T cell responses
      in vitro, an MHC class II-restricted T cell receptor (AND TCR) transgene was
      introduced into the CTLA-4(-/-) animals. The expression of the AND TCR transgene
      by CD4(+) T cells delays but does not prevent the lymphoproliferation in the CTLA
      4(-/-) mice. The CD4(+) T cells become preferentially activated and expand.
      Interestingly, young AND TCR(+) CTLA-4(-/-) mice carrying a null mutation in the
      rag-1 gene remain healthy and the T cells maintain a naive phenotype until later
      in life. We demonstrate that CTLA-4 regulates the peptide-specific proliferative
      response generated by naive and previously activated AND TCR(+) RAG(-/-) T cells
      in vitro. The absence of CTLA-4 also augments the responder frequency of cytokine
      secreting AND TCR(+) RAG(-/-) T cells. These results demonstrate that CTLA-4 is a
      key regulator of peptide-specific CD4(+) T cell responses and support the model
      that CTLA-4 plays a differential role in maintaining T cell homeostasis of CD4(+)
      vs. CD8(+) T cells.

PMID- 10411924
TI  - One lyn molecule is sufficient to initiate phosphorylation of aggregated high
      affinity IgE receptors.
AB  - In response to antigenic stimuli, the multisubunit immune recognition receptors
      become aggregated and then phosphorylated on their cytoplasmic tyrosines. For the
      clonotypic receptors of B and T cells and for Fc receptors such as the high
      affinity receptor for IgE (FcepsilonRI), a Src family kinase initiates this
      phosphorylation. We ask whether aggregation of the initiating kinase itself is
      required for signal transduction or whether, alternatively, a single associated
      kinase molecule can phosphorylate the receptors in an aggregate. We formulate the
      alternative molecular mechanisms mathematically and compare predictions with
      experimental findings on FcepsilonRI-bearing cells expressing varying amounts of
      the transfected Src family kinase Lyn. The data are consistent with the
      requirement of only a single Lyn molecule per FcepsilonRI aggregate to initiate
      signaling and are inconsistent with a mechanism requiring more than one Lyn
      molecule.

PMID- 10411923
TI  - Induction of hyporesponsiveness to intact foreign protein via retroviral-mediated
      gene expression: the IgG scaffold is important for induction and maintenance of
      immune hyporesponsiveness.
AB  - IgG molecules can be highly tolerogenic carriers for associated antigens.
      Previously, we reported that recipients of bone marrow or lipopolysaccharide
      stimulated B-cell blasts, both of which were retrovirally gene-transferred with
      an immunodominant peptide in-frame with the variable region of a murine IgG heavy
      chain, were rendered profoundly unresponsive to that epitope. To further
      investigate whether tolerance to larger molecules can be achieved via this
      approach and whether the IgG scaffold is important for induction and maintenance
      of immunological tolerance, we engineered two retroviral constructs encoding the
      cI lambda repressor (MBAE-1-102 and MBAE-1-102-IgG) for gene transfer. Our
      results show that recipients of bone marrow or peripheral B cells, transduced
      with the MBAE-1-102-IgG recombinant, are hyporesponsive to p1-102. In addition,
      the self-IgG scaffold enhanced the induction and maintenance of such an immune
      hyporesponsiveness. Thus, our studies demonstrate that in vivo-expressed IgG
      heavy chain fusion protein can be processed and presented on the appropriate MHC
      class II, resulting in hyporesponsiveness to that antigen and offering an
      additional therapeutic approach to autoimmune diseases.

PMID- 10411925
TI  - The lack of consensus for I-A(g7)-peptide binding motifs: is there a requirement
      for anchor amino acid side chains?
AB  - We discuss here the problems in identifying sequence motifs of peptides that bind
      to I-A(g7), the class II histocompatibility molecule of NOD diabetic mice. We
      present studies that indicate a minor contribution of amino acid side chains for
      binding. A peptide from the Ealpha chain binds to I-A(g7) molecules and is
      recognized by CD4 T cells. By producing single-residue mutations we identified
      four residues that were considered to contact the T cell receptor. No residue was
      found to be essential for binding to I-A(g7): a peptide that contained the T cell
      contact residues, on a backbone of alanines, bound to I-A(g7) and stimulated the
      T cells. We conclude that peptides can bind to I-A(g7) without the requirement
      for residues with prominent side chains to anchor them.

PMID- 10411926
TI  - Dipeptidyl peptidase I is required for the processing and activation of granzymes
      A and B in vivo.
AB  - Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease that has been
      implicated in the processing of granzymes, which are neutral serine proteases
      exclusively expressed in the granules of activated cytotoxic lymphocytes. In this
      report, we show that cytotoxic lymphocytes derived from DPPI-/- mice contain
      normal amounts of granzymes A and B, but these molecules retain their
      prodipeptide domains and are inactive. Cytotoxic assays with DPPI-/- effector
      cells reveal severe defects in the induction of target cell apoptosis (as
      measured by [(125)I]UdR release) at both early and late time points; this defect
      is comparable to that detected in perforin-/- or granzyme A-/- x B-/- cytotoxic
      lymphocytes. DPPI therefore plays an essential role in the in vivo processing and
      activation of granzymes A and B, which are required for cytotoxic lymphocyte
      granule-mediated apoptosis.

PMID- 10411927
TI  - CD4(+) T cells eliminate MHC class II-negative cancer cells in vivo by indirect
      effects of IFN-gamma.
AB  - CD4(+) T cells can eliminate tumor cells in vivo in the absence of CD8(+) T
      cells. We have CD4(+) T cells specific for a MHC class II-restricted, tumor
      specific peptide derived from a mutant ribosomal protein expressed by the UV
      light-induced tumor 6132A-PRO. By using neutralizing mAb specific for murine IFN
      gamma and adoptive transfer of CD4(+) T cells into severe combined
      immunodeficient mice, we show that anti-IFN-gamma treatment abolishes the CD4(+)
      T cell-mediated rejection of the tumor cells in vivo. The tumor cells were MHC
      class II negative, and IFN-gamma did not induce MHC class II expression in vitro.
      Therefore, the tumor-specific antigenic peptide must be presented by host cells
      and not the tumor cells. Tumor cells transduced to secrete IFN-gamma had a
      markedly reduced growth rate in severe combined immunodeficient mice, but IFN
      gamma did not inhibit the growth of the tumor cells in vitro. Furthermore, tumor
      cells stably expressing a dominant-negative truncated form of the murine IFN
      gamma receptor alpha chain, and therefore insensitive to IFN-gamma, nevertheless
      were rejected by the adoptively transferred CD4(+) T cells. Thus, host cells, and
      not tumor cells, seem to be the target of IFN-gamma. Together, these results show
      that CD4(+) T cells can eliminate IFN-gamma-insensitive, MHC class II-negative
      cancer cells by an indirect mechanism that depends on IFN-gamma.

PMID- 10411928
TI  - CD8(+) minor histocompatibility antigen-specific cytotoxic T lymphocyte clones
      eliminate human acute myeloid leukemia stem cells.
AB  - Effective immunotherapy for human leukemia based on infusions of T lymphocytes
      requires the identification of effector T cells that target the leukemic stem
      cell. The transplantation of human acute myeloid leukemia into nonobese
      diabetic/severe combined immune deficient (SCID) mice has identified a rare
      leukemic progenitor termed the SCID leukemia-initiating cell, which is present in
      low frequency in the leukemic population and is essential for establishing
      leukemic hematopoiesis. Thus, this transplant model may be ideally suited to
      identify effector T cells with antileukemic activity. We report that CD8(+)
      cytotoxic T lymphocyte (CTL) clones specific for minor histocompatibility
      antigens inhibit the engraftment of human acute myeloid leukemia cells in
      nonobese diabetic/SCID mice and demonstrate that this inhibition is mediated by
      direct CTL recognition of SCID leukemia-initiating cells. These results indicate
      that CD8(+) minor histocompatibility antigen-specific CTL may be mediators of the
      graft-versus-leukemia effect associated with allogeneic hematopoietic cell
      transplantation and provide an experimental model to identify and select T cell
      clones for immunotherapy to prevent or treat relapse after allogeneic
      hematopoietic cell transplantation.

PMID- 10411929
TI  - Defective CTLA-4 cycling pathway in Chediak-Higashi syndrome: a possible
      mechanism for deregulation of T lymphocyte activation.
AB  - Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, also known as CD152) has
      been shown to play a major role in the regulation of T cell activation. Its
      membrane expression is highly regulated by endocytosis and trafficking through
      the secretory lysosome pathway. Chediak-Higashi syndrome (CHS) is an inherited
      disorder caused by mutations in the lysosomal trafficking regulator gene, LYST.
      It results in defective membrane targeting of the proteins present in secretory
      lysosomes, and it is associated with a variety of features, including a
      lymphoproliferative syndrome with hemophagocytosis. The murine equivalent of CHS,
      beige mice, present similar characteristics but do not develop the
      lymphoproliferative syndrome. We show herein that CTLA-4 is present in enlarged,
      abnormal vesicles in CHS T cells and is not properly expressed at the cell
      surface after T cell activation, whereas its surface expression is not impaired.
      It is therefore proposed that the defective surface expression of CTLA-4 by CHS T
      cells is involved in the generation of lymphoproliferative disease. This
      observation may provide insight into the role of CTLA-4 in humans.

PMID- 10411930
TI  - Elevated retinoic acid receptor beta(4) protein in human breast tumor cells with
      nuclear and cytoplasmic localization.
AB  - The transcription factor retinoic acid receptor beta(2) (RARbeta(2)) is a potent
      inhibitor of breast cancer cells in vitro, and studies suggest that RARbeta
      expression is lost in primary breast cancer. Although RARbeta(2) is selectively
      down-regulated at the mRNA level in breast tumor cells, we show that expression
      of an RARbeta protein is elevated in five of five breast tumor cell lines
      relative to normal human mammary epithelial cells. Subsequent analysis identified
      this protein as the translation product of the human RARbeta(4) transcript.
      Unlike the previously characterized mouse RARbeta(4) isoform, the human
      RARbeta(4) retains only half of a DNA-binding domain and lacks a ligand
      independent transactivation domain at its N terminus. The RARbeta(4) protein
      localizes to the cytoplasm and to subnuclear compartments that resemble nuclear
      bodies. The structure and preliminary characterizations of human RARbeta(4),
      coupled with the observation that its expression is greatly elevated in breast
      tumor cell lines, support the hypothesis that RARbeta(4) functions as a dominant
      negative repressor of RAR-mediated growth suppression.

PMID- 10411931
TI  - Long-term regulated expression of growth hormone in mice after intramuscular gene
      transfer.
AB  - Effective delivery of secreted proteins by gene therapy will require a vector
      that directs stable delivery of a transgene and a regulatory system that permits
      pharmacologic control over the level and kinetics of therapeutic protein
      expression. We previously described a regulatory system that enables
      transcription of a target gene to be controlled by rapamycin, an orally
      bioavailable drug. Here we demonstrate in vivo regulation of gene expression
      after intramuscular injection of two separate adenovirus or adeno-associated
      virus (AAV) vectors, one encoding an inducible human growth hormone (hGH) target
      gene, and the other a bipartite rapamycin-regulated transcription factor. Upon
      delivery of either vector system into immunodeficient mice, basal plasma hGH
      expression was undetectable and was induced to high levels after administration
      of rapamycin. The precise level and duration of hGH expression could be
      controlled by the rapamycin dosing regimen. Equivalent profiles of induction were
      observed after repeated administration of single doses of rapamycin over many
      months. AAV conferred stable expression of regulated hGH in both immunocompetent
      and immunodeficient mice, whereas adenovirus-directed hGH expression quickly
      extinguished in immunocompetent animals. These studies demonstrate that the
      rapamycin-based regulatory system, delivered intramuscularly by AAV, fulfills
      many of the conditions necessary for the safe and effective delivery of
      therapeutic proteins by gene therapy.

PMID- 10411932
TI  - Regulation of vascular endothelial growth factor production and angiogenesis by
      the cytoplasmic tail of tissue factor.
AB  - Tissue factor (TF), a transmembrane receptor for coagulation factor VII/VIIa, is
      aberrantly expressed in human cancers. We demonstrated a significant correlation
      between TF and vascular endothelial growth factor (VEGF) production in 13 human
      malignant melanoma cell lines (r(2) = 0.869, P < 0.0001). Two of these cell
      lines, RPMI-7951, a high TF and VEGF producer, and WM-115, a low TF and VEGF
      producer, were grown s.c. in severe combined immunodeficient mice. The high
      producer cell line generated solid tumors characterized by intense vascularity,
      whereas the low producer generated relatively avascular tumors, as determined by
      immunohistologic staining of tumor vascular endothelial cells with anti-von
      Willebrand factor antibody. To investigate the structure-function relationship of
      TF and VEGF, a low-producer melanoma cell line (HT144) was transfected with a TF
      cDNA containing the full-length sequence, a cytoplasmic deletion mutant lacking
      the coding sequence for the distal three serine residues (potential substrates
      for protein kinase C), or an extracellular domain mutant, which has markedly
      diminished function for activation of factor X. Cells transfected with the full
      length sequence produced increased levels of both TF and VEGF. Transfectants with
      the full-length sequence and the extracellular domain mutant produced
      approximately equal levels of VEGF mRNA. However, cells transfected with the
      cytoplasmic deletion mutant construct produced increased levels of TF, but little
      or no VEGF. Thus, the cytoplasmic tail of TF plays a role in the regulation of
      VEGF expression in some tumor cells.

PMID- 10411933
TI  - Medin: an integral fragment of aortic smooth muscle cell-produced lactadherin
      forms the most common human amyloid.
AB  - Aortic medial amyloid is a form of localized amyloid that occurs in virtually all
      individuals older than 60 years. The importance and impact of the amyloid
      deposits are unknown. In this study we have purified a 5.5-kDa aortic medial
      amyloid component, by size-exclusion chromatography and RP-HPLC, from three
      individuals, and we have shown by amino acid sequence analysis that the amyloid
      is derived from an integral proteolytic fragment of lactadherin. Lactadherin is a
      364-aa glycoprotein, previously known to be expressed by mammary epithelial cells
      as a cell surface protein and secreted as part of the milk fat globule membrane.
      The multidomain protein has a C-terminal domain showing homology to blood
      coagulation factors V and VIII. We found that the main constituent of aortic
      medial amyloid is a 50-aa-long peptide, here called medin, that is positioned
      within the coagulation factor-like domain of lactadherin. Our result is supported
      by the specific labeling of aortic medial amyloid in light and electron
      microscopy with two rabbit antisera raised against two synthetic peptides
      corresponding to different parts of medin. By using in situ hybridization we have
      shown that lactadherin is expressed by aortic medial smooth muscle cells.
      Furthermore, one of the synthetic peptides forms amyloid-like fibrils in vitro.
      Lactadherin was not previously known to be an amyloid precursor protein or to be
      expressed in aortic tissue. The structure of lactadherin may implicate an
      important regulatory function in the aorta.

PMID- 10411935
TI  - CpG island methylator phenotype in colorectal cancer.
AB  - Aberrant methylation of promoter region CpG islands is associated with
      transcriptional inactivation of tumor-suppressor genes in neoplasia. To
      understand global patterns of CpG island methylation in colorectal cancer, we
      have used a recently developed technique called methylated CpG island
      amplification to examine 30 newly cloned differentially methylated DNA sequences.
      Of these 30 clones, 19 (63%) were progressively methylated in an age-dependent
      manner in normal colon, 7 (23%) were methylated in a cancer-specific manner, and
      4 (13%) were methylated only in cell lines. Thus, a majority of CpG islands
      methylated in colon cancer are also methylated in a subset of normal colonic
      cells during the process of aging. In contrast, methylation of the cancer
      specific clones was found exclusively in a subset of colorectal cancers, which
      appear to display a CpG island methylator phenotype (CIMP). CIMP+ tumors also
      have a high incidence of p16 and THBS1 methylation, and they include the majority
      of sporadic colorectal cancers with microsatellite instability related to hMLH1
      methylation. We thus define a pathway in colorectal cancer that appears to be
      responsible for the majority of sporadic tumors with mismatch repair deficiency.

PMID- 10411934
TI  - JE-2147: a dipeptide protease inhibitor (PI) that potently inhibits multi-PI
      resistant HIV-1.
AB  - We designed, synthesized, and identified JE-2147, an allophenylnorstatine
      containing dipeptide HIV protease inhibitor (PI), which is potent against a wide
      spectrum of HIV-1, HIV-2, simian immunodeficiency virus, and various clinical HIV
      1 strains in vitro. Drug-resistant clinical HIV-1 strains, isolated from seven
      patients who had failed 9-11 different anti-HIV therapeutics after 32-83 months,
      had a variety of drug-resistance-related amino acid substitutions and were highly
      and invariably resistant to all of the currently available anti-HIV agents. JE
      2147 was, however, extremely potent against all such drug-resistant strains, with
      IC(50) values ranging from 13-41 nM (<2-fold changes in IC(50) compared with that
      of wild-type HIV-1). The emergence of JE-2147-resistant HIV-1 variants in vitro
      was substantially delayed compared with that of HIV-1 resistant to another
      allophenylnorstatine-containing compound, KNI-272, and other related PIs.
      Structural analysis revealed that the presence of a flexible P2' moiety is
      important for the potency of JE-2147 toward wild-type and mutant viruses. These
      data suggest that the use of flexible components may open a new avenue for
      designing PIs that resist the emergence of PI-resistant HIV-1. Further
      development of JE-2147 for treating patients harboring multi-PI-resistant HIV-1
      is warranted.

PMID- 10411936
TI  - Transient expression of DNA and RNA in parasitic helminths by using particle
      bombardment.
AB  - Parasitic helminths (worms belonging to several metazoan phyla) cause
      considerable morbidity and mortality in humans. They are an important veterinary
      problem, and they result in significant economic losses in animal grazing and
      agriculture. Experimental studies on parasitic helminths have been limited by a
      lack of parasite cell lines and methods for molecular genetic analyses. We
      evaluated particle bombardment (biolistics) as a strategy to introduce and
      express nucleic acids in these multicellular parasites. By using embryos of the
      parasitic nematode Ascaris as a model, we developed methods to introduce and
      express both DNA and RNA during several stages of Ascaris embryogenesis.
      Biolistic transfection will facilitate experimental strategies in Ascaris embryos
      complementing other biochemical tools available (e.g., in vitro whole-cell embryo
      extracts for transcription, RNA processing, and translation). Transfection
      experiments with adult schistosomes further suggest that the biolistic strategy
      should be applicable to a variety of other parasitic helminths. The development
      of these methods provides molecular genetic tools to study gene expression and
      the biology of a variety of types and developmental stages of important helminth
      parasites.

PMID- 10411937
TI  - A heterozygous mutation of beta-actin associated with neutrophil dysfunction and
      recurrent infection.
AB  - A human disorder caused by mutation in nonmuscle actin has not been reported. We
      report here a variant of nonmuscle actin in a female patient with recurrent
      infections, photosensitivity, and mental retardation. She also had abnormalities
      in neutrophil chemotaxis, superoxide production, and membrane potential response.
      Two-dimensional PAGE analysis of proteins from neutrophils and other cell types
      from this patient demonstrated a unique protein spot migrating at 42 kDa with pI
      shifted slightly to neutral relative to normal beta- and gamma-actin. Digestion
      peptide mapping and Western blotting showed this spot to be an abnormal actin. A
      full-length cDNA library was constructed by using mRNA from patient's cells and
      cDNA encoding the mutant beta-actin molecule was identified by an in vitro
      translation method. Sequencing of the clones demonstrated a G-1174 to A
      substitution, predicting a glutamic acid-364 to lysine substitution in beta-actin
      and eliminating a HinfI DNase restriction site found in normal beta-actin
      sequence. By HinfI digestion and by sequencing, the mutation in one allele of
      patient's genomic DNA was confirmed. Though no defect in cell-free polymerization
      of actin was detected, this defect lies in a domain important for binding to
      profilin and other actin-regulatory molecules. In fact, the mutant actin bound to
      profilin less efficiently than normal actin did. Heterozygous expression of
      mutant beta-actin in neutrophils and other cells of this patient may act in a
      dominant-negative fashion to adversely affect cellular activities dependent on
      the function of nonmuscle actin.

PMID- 10411938
TI  - Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves
      ligand-independent death receptor aggregation and activation of caspases.
AB  - Suicide gene therapy systems such as the herpes simplex thymidine
      kinase/ganciclovir system (TK/GCV) may kill cancer cells by apoptosis through as
      yet undefined mechanisms. Here we show that TK/GCV treatment induces p53
      accumulation and increases cell surface expression of CD95 and tumor necrosis
      factor receptor, which is likely to involve p53-mediated translocation of CD95 to
      the cell surface. TK/GCV-induced apoptosis involves CD95-L-independent CD95
      aggregation leading to the formation of a Fas-associated death domain protein
      (FADD) and caspase-8-containing, death-inducing signaling complex. Dominant
      negative FADD, the caspase-8 inhibitor zIETD-fmk [Z-Ile-Glu(OMe)-Thr-Asp(OMe)
      fluoromethylketone], and zVAD-fmk (Z-Val-Ala-Asp-fluoromethylketone) partially
      abrogate TK/GCV-induced apoptosis. In addition to apoptosis induction, TK/GCV
      treatment strongly sensitizes for CD95-L-, TNF-, and TNF-related, apoptosis
      inducing, ligand (TRAIL)-induced cell death in constitutively resistant cells.
      These findings may be used to increase the efficacy of TK/GCV and other suicide
      gene therapy systems for the treatment of cancer.

PMID- 10411939
TI  - Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1.
AB  - The process through which multipotential hematopoietic cells commit to distinct
      lineages involves the induction of specific transcription factors. PU.1 (also
      known as Spi-1) and GATA-1 are transcription factors essential for the
      development of myeloid and erythroid lineages, respectively. Overexpression of
      PU.1 and GATA-1 can block differentiation in lineages in which they normally are
      down-regulated, indicating that not only positive but negative regulation of
      these factors plays a role in normal hematopoietic lineage development. Here we
      demonstrate that a region of the PU.1 Ets domain (the winged helix-turn-helix
      wing) interacts with the conserved carboxyl-terminal zinc finger of GATA-1 and
      GATA-2 and that GATA proteins inhibit PU.1 transactivation of critical myeloid
      target genes. We demonstrate further that GATA inhibits binding of PU.1 to c-Jun,
      a critical coactivator of PU.1 transactivation of myeloid promoters. Finally,
      PU.1 protein can inhibit both GATA-1 and GATA-2 transactivation function. Our
      results suggest that interactions between PU.1 and GATA proteins play a critical
      role in the decision of stem cells to commit to erythroid vs. myeloid lineages.

PMID- 10411940
TI  - Cancer dormancy and cell signaling: induction of p21(waf1) initiated by membrane
      IgM engagement increases survival of B lymphoma cells.
AB  - The p21(WAF1) (p21) cyclin-dependent kinase inhibitor plays a major role in
      regulating cell cycle arrest. It was recently reported that the p53-independent
      elevation of p21 protein levels is essential in mediating the G(1) arrest
      resulting from signal transduction events initiated by the crosslinking of
      membrane IgM on Daudi Burkitt lymphoma cells. Although the role of p21 in cell
      cycle regulation is well documented, there is little information concerning its
      role in antibody-mediated apoptosis. In the present study, we examined the
      involvement of p21 in the regulation of apoptosis by suppressing its induction in
      anti-IgM-treated Daudi cells through a p21 antisense expression construct
      approach. Reduction in induced p21 protein levels resulted in diminished G(1)
      arrest and increased apoptosis. The increased susceptibility to anti-IgM-mediated
      apoptosis was associated with increased caspase-3-like activity and poly
      (ADP)ribose polymerase cleavage. These data suggest that p21 may directly
      interfere with the caspase cascade, thus playing a dual role in regulating both
      cell cycle progression and apoptosis.

PMID- 10411941
TI  - A set of independent selectable markers for transfection of the human malaria
      parasite Plasmodium falciparum.
AB  - Genomic information is rapidly accumulating for the human malaria pathogen,
      Plasmodium falciparum. Our ability to perform genetic manipulations to understand
      Plasmodium gene function is limited. Dihydrofolate reductase is the only
      selectable marker presently available for transfection of P. falciparum.
      Additional markers are needed for complementation and for expression of mutated
      forms of essential genes. We tested parasite sensitivity to different drugs for
      which selectable markers are available. Two of these drugs that were very
      effective as antiplasmodial inhibitors in culture, blasticidin and geneticin
      (G418), were selected for further study. The genes BSD, encoding blasticidin S
      deaminase of Aspergillus terreus, and NEO, encoding neomycin phosphotransferase
      II from transposon Tn 5, were expressed under the histidine-rich protein III
      (HRPIII) gene promoter and tested for their ability to confer resistance to
      blasticidin or G418, respectively. After transfection, blasticidin and G418
      resistant parasites tested positive for plasmid replication and BSD or NEO
      expression. Cross-resistance assays indicate that these markers are independent.
      The plasmid copy number and the enzymatic activity depended directly on the
      concentration of the drug used for selection. These markers set the stage for new
      methods of functional analysis of the P. falciparum genome.

PMID- 10411942
TI  - Differential acute and chronic responses of tumor necrosis factor-deficient mice
      to experimental brain injury.
AB  - The present study evaluated behavioral and histopathological outcome after
      controlled cortical impact (CCI) brain injury in mice deficient in tumor necrosis
      factor [TNF(-/-)] and their wild-type (wt) littermates. Mice were subjected to
      CCI brain injury [TNF(-/-), n = 10; wt, n = 10] or served as uninjured controls
      [TNF(-/-), n = 10; wt, n = 10] and were evaluated for deficits in memory
      retention at 7 days postinjury. Although both brain-injured wt and TNF(-/-) mice
      exhibited significant memory dysfunction compared to uninjured controls (P <
      0.02), the deficits in memory retention in injured TNF(-/-) mice were
      significantly less severe than in injured wt mice (P < 0.02). A second group of
      mice was subjected to CCI brain injury [TNF(-/-), n = 20; wt, n = 20] or served
      as uninjured controls [TNF(-/-), n = 15; wt, n = 15] and were evaluated over a 4
      week period for neurological motor function. In the acute posttraumatic period
      (48 h postinjury), brain-injured TNF(-/-) mice were significantly less impaired
      than injured wt mice on composite neuroscore (P < 0.001), rotarod (P < 0.05), and
      beam balance (P < 0. 02) tests. However, wt mice recovered from brain injury by 2
      3 weeks postinjury, whereas TNF(-/-) mice continued to demonstrate persistent
      motor deficits up to 4 weeks postinjury. Histopathological analysis at 2 and 4
      weeks postinjury revealed that brain-injured TNF(-/-) mice had significantly more
      cortical tissue loss than wt mice (P < 0.02). Our results suggest that although
      the presence of TNF in the acute posttraumatic period may be deleterious, this
      cytokine may play a role in facilitating long-term behavioral recovery and
      histological repair after brain injury.

PMID- 10411943
TI  - Transgenic mice expressing a Huntington's disease mutation are resistant to
      quinolinic acid-induced striatal excitotoxicity.
AB  - Huntington's disease (HD) is a hereditary neurodegenerative disorder presenting
      with chorea, dementia, and extensive striatal neuronal death. The mechanism
      through which the widely expressed mutant HD gene mediates a slowly progressing
      striatal neurotoxicity is unknown. Glutamate receptor-mediated excitotoxicity has
      been hypothesized to contribute to the pathogenesis of HD. Here we show that
      transgenic HD mice expressing exon 1 of a human HD gene with an expanded number
      of CAG repeats (line R6/1) are strongly protected from acute striatal excitotoxic
      lesions. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor
      agonist quinolinic acid caused massive striatal neuronal death in wild-type mice,
      but no damage in transgenic HD littermates. The remarkable neuroprotection in
      transgenic HD mice occurred at a stage when they had not developed any
      neurological symptoms caused by the mutant HD gene. At this stage there was no
      change in the number of striatal neurons and astrocytes in untreated R6/1 mice,
      although the striatal volume was decreased by 17%. Moreover, transgenic HD mice
      had normal striatal levels of NMDA receptors, calbindin D28k (calcium buffer),
      superoxide dismutase activity (antioxidant enzyme), Bcl-2 (anti-apoptotic
      protein), heat shock protein 70 (stress-induced anti-apoptotic protein), and
      citrate synthase activity (mitochondrial enzyme). We propose that the presence of
      exon 1 of the mutant HD gene induces profound changes in striatal neurons that
      render these cells resistant to excessive NMDA receptor activation.

PMID- 10411944
TI  - Inhibition of uptake unmasks rapid extracellular turnover of glutamate of
      nonvesicular origin.
AB  - Maintaining glutamate at low extracellular concentrations in the central nervous
      system is necessary to protect neurons from excitotoxic injury and to ensure a
      high signal-to-noise ratio for glutamatergic synaptic transmission. We have used
      DL-threo-beta-benzyloxyaspartate (TBOA), an inhibitor of glutamate uptake, to
      determine the role of glutamate transporters in the regulation of extracellular
      glutamate concentration. By using the N-methyl-D-aspartate receptors of patched
      CA3 hippocampal neurons as "glutamate sensors," we observed that application of
      TBOA onto organotypic hippocampal slices led to a rapid increase in extracellular
      glutamate concentration. This increase was Ca(2+)-independent and was observed in
      the presence of tetrodotoxin. Moreover, prevention of vesicular glutamate release
      with clostridial toxins did not affect the accumulation of glutamate when uptake
      was inhibited. Inhibition of glutamine synthase, however, increased the rate of
      accumulation of extracellular glutamate, indicating that glial glutamate stores
      can serve as a source in this process. TBOA blocked synaptically evoked
      transporter currents in astrocytes without inducing a current mediated by the
      glutamate transporter. This indicates that this inhibitor is not transportable
      and does not release glutamate by heteroexchange. These results show that under
      basal conditions, the activity of glutamate transporters compensates for the
      continuous, nonvesicular release of glutamate from the intracellular compartment.
      As a consequence, acute disruption of transporter activity immediately results in
      significant accumulation of extracellular glutamate.

PMID- 10411945
TI  - Novelty acquisition is associated with induction of hippocampal long-term
      depression.
AB  - Homosynaptic long-term depression (LTD) consists of a persistent nonpathological
      decrease in synaptic transmission, which is induced by low-frequency stimulation.
      In vivo, low-frequency stimulation (1 Hz, 900 pulses) induces LTD in Wistar but
      not Hooded Lister rats. In this study, we investigated the influence of
      behavioral learning and behavioral state on the expression of LTD in both rat
      strains. Recordings were taken from freely moving animals that had undergone
      chronic implantation of a recording electrode in the hippocampal CA1 region and a
      bipolar stimulating electrode in the ipsilateral Schaffer collateral-commissural
      pathway. Exposure of the rat strains to stress induced a significant elevation in
      serum corticosterone levels but did not facilitate LTD expression. However, LFS
      given during exploration of a novel environment resulted in LTD expression in
      Hooded Lister, and LTD enhancement in Wistar, rats. Reexposure to the same
      environment did not result in new expression of LTD. Behavioral comparison
      between the first and second environmental exposure confirmed that the animals
      had habituated to the novel environment. These observations strongly implicate an
      association between novelty acquisition and LTD.

PMID- 10411946
TI  - Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate
      induced inhibition of Akt-1 activity in neurons.
AB  - This report describes a modulatory action of lithium and glutamate on the
      activity of serine/threonine kinase Akt-1. Lithium is most commonly used to treat
      bipolar disorder, but the mechanism of its therapeutic action remains unknown. We
      have recently demonstrated that lithium protects against glutamate-induced
      excitotoxicity in cultured brain neurons and in an animal model of cerebral
      ischemia. This study was undertaken to investigate the role of Akt-1, activated
      by the phosphatidylinositol 3-kinase (PI 3-K) signaling pathway, in mediating
      glutamate excitotoxicity and lithium protection in cerebellar granule cells. High
      levels of phosphorylation and activity of Akt-1 were detected in cerebellar
      neurons cultured in the presence of serum. Protracted treatment with selective PI
      3-K inhibitors, wortmannin and LY294002, abolished Akt-1 activity and induced
      neuronal death that could be reduced by long-term lithium pretreatment. Exposure
      of cells to glutamate induced a rapid and reversible loss of Akt-1
      phosphorylation and kinase activity. These effects were closely correlated with
      excitotoxicity and caspase 3 activation and were prevented by phosphatase
      inhibitors, okadaic acid and caliculin A. Long-term lithium pretreatment
      suppressed glutamate-induced loss of Akt-1 activity and accelerated its recovery
      toward the control levels. Lithium treatment alone induced rapid increase in PI 3
      K activity, and Akt-1 phosphorylation with accompanying kinase activation, which
      was blocked by PI 3-K inhibitors. Lithium also increased the phosphorylation of
      glycogen synthase kinase-3 (GSK-3), a downstream physiological target of Akt.
      Thus, modulation of Akt-1 activity appears to play a key role in the mechanism of
      glutamate excitotoxicity and lithium neuroprotection.

PMID- 10411947
TI  - Cross-modal reorganization of callosal connectivity without altering
      thalamocortical projections.
AB  - Mammalian cerebral cortex is composed of a multitude of different areas that are
      each specialized for a unique purpose. It is unclear whether the activity pattern
      and modality of sensory inputs to cortex play an important role in the
      development of cortical regionalization. The modality of sensory inputs to
      cerebral cortex can be altered experimentally. Neonatal diversion of retinal
      axons to the auditory thalamus (cross-modal rewiring) results in a primary
      auditory cortex (AI) that resembles the primary visual cortex in its visual
      response properties and topography. Functional reorganization could occur because
      the visual inputs use existing circuitry in AI, or because the early visual
      inputs promote changes in AI's circuitry that make it capable of constructing
      visual receptive field properties. The present study begins to distinguish
      between these possibilities by exploring whether the callosal connectivity of AI
      is altered by early visual experience. Here we show that early visual inputs to
      auditory thalamus can reorganize callosal connections in auditory cortex, causing
      both a reduction in their extent and a reorganization of the pattern. This result
      is distinctly different from that in deafened animals, which have widespread
      callosal connections, as in early postnatal development. Thus, profound changes
      in cortical circuitry can result simply from a change in the modality of afferent
      input. Similar changes may underlie cortical compensatory processes in deaf and
      blind humans.

PMID- 10411948
TI  - Intravascular flow decreases erythrocyte consumption of nitric oxide.
AB  - Nitric oxide (NO) produced by the endothelium diffuses both into the lumen and to
      the smooth muscle cells according to the concentration gradient in each
      direction. The extremely high reaction rate between NO and hemoglobin (Hb),
      k(Hb)= 3-5 x 10(7) M(-1).s(-1), suggests that most of the NO produced would be
      consumed by Hb in the red blood cells (RBCs), which then would block the
      biological effect of NO. Therefore, specific mechanisms must exist under
      physiological conditions to reduce the NO consumption by RBCs, in which the Hb
      concentration is very high (24 mM heme). By using isolated microvessels as a
      bioassay, here we show that physiological concentrations of RBCs in the presence
      of intravascular flow does not inhibit NO-mediated vessel dilation, suggesting
      that RBCs under this condition are not an NO scavenger. On the other hand, RBCs
      (50% hematocrit) without intravascular flow reduce NO-mediated dilation to
      serotonin by 30%. In contrast, free Hb (10 microM) completely inhibits NO
      mediated dilation with or without intravascular flow. The effect of flow on NO
      consumption by RBCs may be attributed to the formation of an RBC-free zone near
      the vessel wall, which is caused by hydrodynamic forces on particles.
      Intravascular flow does not affect the reaction rate between NO and free Hb in
      the lumen, because the latter forms a homogeneous solution and is not subject to
      the hydrodynamic separation. However, intravascular flow only partially
      contributes to the reduced consumption of NO by RBCs, because without the flow,
      the NO consumption by RBCs is already about 3 orders of magnitude slower than
      free Hb.

PMID- 10411949
TI  - The violaxanthin cycle protects plants from photooxidative damage by more than
      one mechanism.
AB  - When light energy absorbed by plants becomes excessive relative to the capacity
      of photosynthesis, the xanthophyll violaxanthin is reversibly deepoxidized to
      zeaxanthin (violaxanthin cycle). The protective function of this phenomenon was
      investigated in a mutant of Arabidopsis thaliana, npq1, that has no functional
      violaxanthin deepoxidase. Two major consequences of the npq1 mutation are the
      absence of zeaxanthin formation in strong light and the partial inhibition of the
      quenching of singlet excited chlorophylls in the photosystem II light-harvesting
      complexes. Prolonged exposure of whole plants to bright light resulted in a
      limited photoinhibition of photosystem II in both npq1 and wild-type leaves,
      although CO(2) fixation and the linear electron transport in npq1 plants were
      reduced substantially. Lipid peroxidation was more pronounced in npq1 compared
      with the wild type, as measured by chlorophyll thermoluminescence, ethane
      production, and the total hydroperoxy fatty acids content. Lipid peroxidation was
      amplified markedly under chilling stress, and photooxidative damage ultimately
      resulted in leaf bleaching and tissue necrosis in npq1. The npq4 mutant, which
      possesses a normal violaxanthin cycle but has a limited capacity of quenching
      singlet excited chlorophylls, was rather tolerant to lipid peroxidation. The
      double mutant, npq4 npq1, which differs from npq4 only by the absence of the
      violaxanthin cycle, exhibited an increased susceptibility to photooxidative
      damage, similar to that of npq1. Our results demonstrate that the violaxanthin
      cycle specifically protects thylakoid membrane lipids against photooxidation.
      Part of this protection involves a mechanism other than quenching of singlet
      excited chlorophylls.

PMID- 10411950
TI  - Targeted manipulation of maize genes in vivo using chimeric RNA/DNA
      oligonucleotides.
AB  - Site-specific heritable mutations in maize genes were engineered by introducing
      chimeric RNA/DNA oligonucleotides. Two independent targets within the endogenous
      maize acetohydroxyacid synthase gene sequence were modified in a site-specific
      fashion, thereby conferring resistance to either imidazolinone or sulfonylurea
      herbicides. Similarly, an engineered green fluorescence protein transgene was
      site-specifically modified in vivo. Expression of the introduced inactive green
      fluorescence protein was restored, and plants containing the modified transgene
      were regenerated. Progeny analysis indicated Mendelian transmission of the
      converted transgene. The efficiency of gene conversion mediated by chimeric
      oligonucleotides in maize was estimated as 10(-4), which is 1-3 orders of
      magnitude higher than frequencies reported for gene targeting by homologous
      recombination in plants. The heritable changes in maize genes engineered by this
      approach create opportunities for basic studies of plant gene function and
      agricultural trait manipulation and also provide a system for studying mismatch
      repair mechanisms in maize.

PMID- 10411951
TI  - A tool for functional plant genomics: chimeric RNA/DNA oligonucleotides cause in
      vivo gene-specific mutations.
AB  - Self-complementary chimeric oligonucleotides (COs) composed of DNA and modified
      RNA residues were evaluated as a means to (i) create stable, site-specific base
      substitutions in a nuclear gene and (ii) introduce a frameshift in a nuclear
      transgene in plant cells. To demonstrate the creation of allele-specific
      mutations in a member of a gene family, COs were designed to target the codon for
      Pro-196 of SuRA, a tobacco acetolactate synthase (ALS) gene. An amino acid
      substitution at Pro-196 of ALS confers a herbicide-resistance phenotype that can
      be used as a selectable marker in plant cells. COs were designed to contain a 25
      nt homology domain comprised of a five-deoxyribonucleotide region (harboring a
      single base mismatch to the native ALS sequence) flanked by regions each composed
      of 10 ribonucleotides. After recovery of herbicide-resistant tobacco cells on
      selective medium, DNA sequence analyses identified base conversions in the ALS
      gene at the codon for Pro-196. To demonstrate a site-specific insertion of a
      single base into a targeted gene, COs were used to restore expression of an
      inactive green fluorescent protein transgene that had been designed to contain a
      single base deletion. Recovery of fluorescent cells confirmed the deletion
      correction. Our results demonstrate the application of a technology to modify
      individual genetic loci by catalyzing either a base substitution or a base
      addition to specific nuclear genes; this approach should have great utility in
      the area of plant functional genomics.

PMID- 10411953
TI  - Algae displaying the diadinoxanthin cycle also possess the violaxanthin cycle.
AB  - According to general agreement, all photosynthetic organisms using xanthophyll
      cycling for photoprotection contain either the violaxanthin (Vx) cycle or the
      diadinoxanthin (Ddx) cycle instead. Here, we report the temporal accumulation of
      substantial amounts of pigments of the Vx cycle under prolonged high-light stress
      in several microalgae thought to possess only the Ddx cycle. In the diatom
      Phaeodactylum tricornutum, used as a model organism, these pigments also
      participate in xanthophyll cycling, and their accumulation depends on de novo
      synthesis of carotenoids and on deepoxidase activity. Furthermore, our data
      strongly suggest a biosynthetic sequence from Vx via Ddx to fucoxanthin in P.
      tricornutum. This gives experimental support to the long-stated hypothesis that
      Vx is a common precursor of all carotenoids with an allenic or acetylenic group,
      including the main light-harvesting carotenoids in most chlorophyll a/c
      containing algae. Thus, another important function for xanthophyll cycling may be
      to optimize the biosynthesis of light-harvesting xanthophylls under fluctuating
      light conditions.

PMID- 10411952
TI  - LOV (light, oxygen, or voltage) domains of the blue-light photoreceptor
      phototropin (nph1): binding sites for the chromophore flavin mononucleotide.
AB  - Phototropism, the bending response of plant organs to or away from a directional
      light source, is one of the best studied blue light responses in plants. Although
      phototropism has been studied for more than a century, recent advances have
      improved our understanding of the underlying signaling mechanisms involved. The
      NPH1 gene of Arabidopsis thaliana encodes a blue light-dependent
      autophosphorylating protein kinase with the properties of a photoreceptor for
      phototropism. NPH1 apoprotein noncovalently binds FMN to form the holoprotein
      nph1. The N-terminal region of the protein contains two LOV (light, oxygen, or
      voltage) domains that share homology with sensor proteins from a diverse group of
      organisms. These include the bacterial proteins NIFL and AER, both of which bind
      FAD, and the phy3 photoreceptor from Adiantium capillus-veneris. The LOV domain
      has therefore been proposed to reflect a flavin-binding site, regulating nph1
      kinase activity in response to blue light-induced redox changes. Herein we
      demonstrate that the LOV domains of two nph1 proteins and phy3 bind
      stoichiometric amounts of FMN when expressed in Escherichia coli. The spectral
      properties of the chromopeptides are similar to the action spectrum for
      phototropism, implying that the LOV domain binds FMN to function as a light
      sensor. Thus, our findings support the earlier model that nph1 is a dual
      chromophoric flavoprotein photoreceptor regulating phototropic responses in
      higher plants. We therefore propose the name phototropin to designate the nph1
      holoprotein.

PMID- 10411954
TI  - How can we boost IQs of "dull children"?: A late adoption study.
AB  - From 5,003 files of adopted children, 65 deprived children, defined as abused
      and/or neglected during infancy, were strictly selected with particular reference
      to two criteria: (i) They were adopted between 4 and 6 years of age, and (ii)
      they had an IQ <86 (mean = 77, SD = 6.3) before adoption. The average IQs of
      adopted children in lower and higher socioeconomic status (SES) families were 85
      (SD = 17) and 98 (SD = 14.6), respectively, at adolescence (mean age = 13.5
      years). The results show (i) a significant gain in IQ dependent on the SES of the
      adoptive families (mean = 7.7 and mean = 19.5 IQ points in low and high SES,
      respectively), (ii) IQs after adoption are significantly correlated with IQs
      before adoption, and (iii) during adolescence, verbal IQs are significantly lower
      than performance IQs.

PMID- 10411955
TI  - Oreopithecus was a bipedal ape after all: evidence from the iliac cancellous
      architecture.
AB  - Textural properties and functional morphology of the hip bone cancellous network
      of Oreopithecus bambolii, a 9- to 7-million-year-old Late Miocene hominoid from
      Italy, provide insights into the postural and locomotor behavior of this fossil
      ape. Digital image processing of calibrated hip bone radiographs reveals the
      occurrence of trabecular features, which, in humans and fossil hominids, are
      related to vertical support of the body weight, i.e., to bipedality.

PMID- 10411956
TI  - Cloning and embryonic stem cells: a new era in human biology and medicine.
AB  - The cloning of mammals using adult cells as nuclear donors has been achieved and
      the same procedure can be, at least theoretically, used to clone humans. Another
      recent technological advance, the derivation of human embryonic stem cells, opens
      up new possibilities in cell and tissue replacement therapy and heralds
      significant improvements in gene therapy. Besides suggesting new and potentially
      valuable medical applications, the insights gained through the use of these
      techniques could significantly enrich our understanding of basic mechanisms
      regulating human development. On the other hand, these preliminary results are
      viewed by many as the opening of the Pandora's box and there are loud voices
      clamoring that research in these areas be forbidden in perpetuity. I suggest in
      the following article that at present we do not know enough to make anything but
      an entirely emotional decision about future applications of these techniques. I
      try to summarize the current state of the kn owledge in the field and indicate
      how much further research is necessary if benefits and drawbacks are to be
      properly understood.

PMID- 10411957
TI  - Computing for the next millennium.
AB  - Computer technology has changed our lives, even that of physicians. In a few
      years time, a physician can expect to have a new tool by the bedside: a hand-held
      computer small enough to put into a pocket and powerful enough for all everyday
      activities, including highly specialized and sophisticated activities such as
      prevention of adverse drug reactions. The Croatian Academic and Research Network
      (CARNet) was crucial in bringing the benefits of the information technology to
      the Croatian scientists. At the Split University School of Medicine, we started
      the Virtual Medical School project, which now also includes the Mostar University
      School of Medicine in neighboring Bosnia and Herzegovina. Virtual Medical School
      aims to promote free dissemination of medical knowledge by creating medical
      education network as a gateway to the Internet for health care professionals.

PMID- 10411958
TI  - Ethical aspects of neural tissue transplantation.
AB  - The method of neural grafting is considered to be a very promising therapeutic
      strategy for the treatment of certain neurodegenerative disorders such as
      Parkinson's disease or Huntington's disease. During the last 15 years, clinical
      transplantation studies have been carried out worldwide in several hundreds of
      patients with Parkinson's disease. In these studies, primarily fetal
      mesencephalic tissue derived from aborted human fetuses has been used for
      implantation. Neural tissue transplantation gives rise to ethical issues in two
      different areas that need careful examination: the first, ethical problems linked
      to the use of tissue from aborted human fetuses; and the second, ethical issues
      concerning the graft recipients in clinical trials, i.e., his or her well-being,
      personality, and personal identity.

PMID- 10411959
TI  - Computer-assisted morphometry of cell-substratum contacts.
AB  - AIM: Quantitative analysis of size and shape of the cell-substratum contacts in
      Dictyostelium and comparison of these parameters between wild-type cells and the
      cells bearing cytoskeletal protein mutations. METHODS: Reflection interference
      contrast microscopy (RICM) was used to image the areas of contact between
      aggregation-competent Dictyostelium cells and weakly adhesive mica surfaces. The
      cell-substratum contact areas were automatically identified in RICM micrographs
      by digital image processing. Information about the size and shape of the contact
      areas was obtained by using the shape descriptors based on two-dimensional
      geometrical moment invariants. RESULTS: Lack of either of the two actin
      crosslinking proteins, a-actinin and 120 kDa gelation factor, similarly affects
      the cell-substratum interactions of Dictyostelium cells. The shape descriptors,
      elongation and dispersion, of the contact areas were reduced by 10% to 30% in
      mutant cells when compared to the wild type, but the size of the contacts was not
      affected. CONCLUSION: Video microscopy combined with digital image processing and
      quantitative image analysis is capable of revealing small phenotypic effects of
      cytoskeletal protein mutations on the level of single cells. Such automated
      microscopic methods are expected to gain importance and find a widespread use in
      biomedicine.

PMID- 10411960
TI  - "Uncaging" using optical fibers to deliver UV light directly to the sample.
AB  - Photolysis or "uncaging" of caged compounds represents a significant tool in cell
      biology and chemistry. It provides a means for quantitative control of compound
      delivery with temporal and spatial resolution while observing their consequences
      for cellular signaling. We discuss the use of ultraviolet-transmitting optical
      fibers to directly deliver UV energy to the sample, combined with a nitrogen
      pulsed laser as a source of UV light. In this approach the size of the photolysis
      area is regulated by the exit aperture of the fiber tip which is controlled by
      pulling the optical fibers to desirable diameters. A diode (red) laser that is
      also coupled to the optical fiber aids the location of UV energy delivery through
      the fiber. We used this method to quantitatively uncage norepinephrine and
      calcium. The major advantage of this photolysis approach is its independence of
      microscope objectives and traditional optical pathways. Because the optical
      pathway of the microscope needs no modification to accommodate this photolysis
      system, integration with other experimental methods, such as electrochemistry,
      electrophysiology, confocal microscopy, and wide-field epifluorescence
      microscopy, is relatively simple.

PMID- 10411961
TI  - Confocal microscopy in biomedical research.
AB  - Confocal microscopy has allowed a major advance in biological imaging, since it
      represents a rapid, cost effective means of ecamining thick tissue specimens. In
      most cases, this involves fluorescence imaging and it is increasingly being used
      as a basic tool in biomedical research. Confocal microscopy allows the collection
      of thin optical sections, without the need for physical sectioning of the tissue.
      Additionally, confocal microscopes can usually produce images with greater
      sensitivity, contrast and resolution than those produced with normal light
      microscopes. We attempt to explain how this technology might be better used as a
      routine research tool. Since high quality, in-focus optical sections of thick
      tissue preparations can be generated quickly, confocal microscopy, in combination
      with immunofluorescence histochemistry, can now be used to examine complex three
      dimensional distributions of distinct structures within tissues such as nerves
      within airways. Additionally, ultraviolet confocal microscopy allows the
      assessment of both dynamic and static phenomena in living cells and tissues.
      Thus, in addition to the imaging of fluorescence associated with structural
      elements, confocal microscopes can be used to quantitatively evaluate the
      distribution and fluxes of intracellular ions like calcium. Rapid, line-scanning
      confocal microscopes can be used in the assessment of dynamic events. For
      example, the in vivo imaging of microvascular permeability in airways becomes
      possible for the first time. By providing examples of some of our uses for
      confocal microscopy, we might encourage others to explore this relatively new and
      important texhnology for examining events and structures in single cells, tissue
      samples and in intact animals.

PMID- 10411962
TI  - Toxicity of major histocompatibility complex class II specific monoclonal
      antibodies: audietur et altera pars.
AB  - AIM: To investigate whether in vivo toxicity of class II major histocompatibility
      complex (MHC) specific monoclonal antibodies (mAb) is contributed by mAb's
      constant region binding to Fc receptor (FcR). METHODS: Laboratory mice were
      injected intravenously (i.v.) with class II MHC-specific mAb of various isotypes
      and respective antigen-binding fragments, and their clinical status was observed
      subsequently. RESULTS: All anti-class II mAb of the IgG2a isotype exhibit acute
      toxicity, manifested in severe lethargy and a frequent death. No adverse effects
      were observed after the FcR-binding capability of the toxic mAb was eliminated
      via deletion or mutation of its Fc segment. CONCLUSION: In vivo toxicity of anti
      class II mAb appears to be the consequence of the crosslinking of class II+ cells
      with cells expressing FcR.

PMID- 10411963
TI  - Drug interactions of H2-receptor antagonists involving cytochrome P450 (CYPs)
      enzymes: from the laboratory to the clinic.
AB  - This paper reviews the main steps in the research of the interactions of H2
      receptor antagonist drugs with cytochrome P450 (CYP) enzymes. Cimetidine,
      ranitidine, and related compounds are used as examples. The results from in vitro
      studies are related to the observed clinically significant in vivo drug-drug and
      drug-chemical interactions. Uses of the in vitro results are discussed for the
      interpretation and possible prediction of drug-drug interactions, which may be
      important in developing new drugs. Other approach in the use of the in vitro data
      is to prevent undesirable and toxic actions of drugs related to the catalytic
      activity of CYP enzymes. In the case of H2-receptor antagonists, the inhibition
      of the metabolic reactions due to the binding of the drugs with the enzymes was
      used to avoid side effects of co-administered drugs. The in vitro metabolic
      studies using recombinant human as well as animal CYP enzymes are now widely used
      as model syste ms for designing new drugs with improved therapeutic properties.

PMID- 10411964
TI  - Manipulating mammalian genome by gene targeting.
AB  - The development of strategies which allow the inactivation of specific murine
      genes by homologous recombination in embryonic cells has revolutionized
      biological science in the last 10 years. A large number of mice carrying genetic
      lesions, generated by gene targeting technology, has tremendously increased our
      knowledge in many areas of biology, culminating in the identification of mouse
      models for human genetic disorders. These findings have been recently
      complemented by "conditional" gene targeting technology, allowing gene
      inactivation in a defined tissue and at a specific time point during development
      or adulthood, thereby extending the sophistication and potential of this
      technology.

PMID- 10411965
TI  - Early effects of hypoxia on brain cell function.
AB  - This article reviews the changes in neuronal function produced by oxygen lack,
      especially as observed in hippocampal slices in vitro. An early cessation of
      electrical activity ("firing"), caused by a K+ conductance-mediated neuronal
      hyperpolarization and disappearance of excitatory synaptic potentials (EPSPs),
      can be seen as a protective mechanism that prevents the cellular damage resulting
      from severe mismatch between energy needs and supplies. These changes are
      triggered by such hypoxia-induced signals as a rise in cytoplasmic free calcium,
      fall in adenosine triphosphate (ATP), and extracellular accumulation of adenosine
      (produced by ATP breakdown). Upon reoxygenation, the suppression of
      neuronal/synaptic activity is quite reversible, as long as hypoxic nerve cells
      have an adequate supply of glucose. But if sufficient ATP cannot be obtained by
      anerobic glycolysis to maintain essential Na-K pump activity and protein
      synthesis, long-term cell functi on and survival are compromised. Thus, when both
      oxygen and glucose are deficient, as in strokes, the cellular protective
      mechanisms cannot prevent the lethal effects of excessive Ca2+ influx.

PMID- 10411966
TI  - The pharmacology of gene therapy.
AB  - The objective for human gene therapy is to express exogenous DNA at a site in
      vivo for long enough, and at sufficient levels to produce a therapeutic response.
      The obstacles to this objective are numerous and include the formulation or
      packaging of the DNA, in vivo delivery, penetration of biological barriers, DNA
      elimination within the cell and from the tissue compartments of the whole body,
      control of product expression and overt toxicity. The current challenge is to
      resolve each of these obstacles to produce a practical and efficient gene
      therapy. In doing so, it is vital to understand the disposition of DNA vectors in
      vivo, and to know how conventional medicines may be used to modulate this
      disposition and to enhance the therapeutic effect of these vectors. Many of the
      general concepts of human gene therapy have been reviewed extensively in the
      literature. This review discusses some of the pharmacological aspects of gene
      delivery and the fate of vectors in vivo, and then highlights how drugs are being
      used to modulate gene therapy.

PMID- 10411967
TI  - Histological analysis and ancient DNA amplification of human bone remains found
      in caius iulius polybius house in pompeii.
AB  - Thirteen skeletons found in the Caius Iulius Polybius house, which has been the
      object of intensive study since its discovery in Pompeii 250 years ago, have
      provided an opportunity to study either bone diagenesis by histological
      investigation or ancient DNA by polymerase chain reaction analysis. DNA analysis
      was done by amplifying both X- and Y-chromosomes amelogenin loci and Y-specific
      alphoid repeat locus. The von Willebrand factor (vWF) microsatellite locus on
      chromosome 12 was also analyzed for personal identification in two individuals
      showing alleles with 10/11 and 12/12 TCTA repeats, respectively. Technical
      problems were the scarcity of DNA content from osteocytes, DNA molecule
      fragmentation, microbial contamination which change bone structure, contaminating
      human DNA which results from mishandling, and frequent presence of Taq DNA
      polymerase inhibiting molecules like polyphenols and heavy metals. The results
      suggest that the remains contain endogenous human DNA that can be amplified and
      analyzed. The amplifiability of DNA corresponds to the bone preservation and
      dynamics of the burial conditions subsequent to the 79 A.D. eruption.

PMID- 10411968
TI  - Laser-assisted hatching in assisted reproduction.
AB  - AIM: The use of a 1.48 um diode laser for assisted hatching was investigated in
      animal experimentation. Laser assisted hatching was offered to patients with
      advanced maternal age to evaluate a possible benefit. METHODS: Using the
      Fertilase(r) system we investigated the impact of openings with different size in
      the zona of mouse embryos on the hatching process, as well as that of two
      openings. Laser-drilling was performed at the blastocyst stage to look for
      differences in timing and efficacy of hatching. The possible benefit of assisted
      hatching was studied in 24 couples with advanced maternal age (38.8+2.1 years)
      and compared to a control group (37.8+2.5 years) treated in the same time period
      but without assisted hatching. RESULTS: A certain diameter of a laser drilled
      opening in the zona pellucida is necessary for efficient hatching. When two
      openings are present in the zona, the embryo will use both openings for hatching
      and subsequently become trapped. Laser-drilling at th e expanded blastocyst stage
      causes an immediate collapse of treated blastocysts and the onset of hatching is
      retarded. Assisted hatching in 24 patients with advanced maternal age resulted in
      a significant increase (p<0.01) in the implantation rate when compared to 24
      untreated patients. CONCLUSION: The use of a 1.48 microm diode laser to drill an
      opening into the zona pellucida provides a good alternate to conventionally
      applied techniques. The procedure is efficient and safe as long as it is applied
      properly. In a human in vitro fertilization program, selected patients will have
      a benefit form assisted hatching.

PMID- 10411969
TI  - Quantity and origin of transplanted autologous blood cells are independent
      factors associated with speed of postransplant hematological reconstitution.
AB  - AIM: Multivariate analysis of the prognostic significance of clinical and
      laboratory parameters on hematological recovery after autologous hematopoietic
      stem cell transplantation. METHODS: Sixty-two patients suffering from
      hematological and non-hematological malignancies entered the study. After
      conditioning therapy, 28 patients received bone marrow stem cells, 21 received
      peripheral blood stem cells, and 13 received both. The dynamic of hematological
      engraftment was calculated as recovery probability of leukocytes and neutrophils.
      Statistics was done using Kaplan-Meier method and multivariate Cox's proportional
      regression. RESULTS: Numerous clinical and laboratory parameters correlated with
      hematological recovery, but only two variables were found to be independently
      associated. Faster reconstitution correlated with greater number of progenitors
      and patients who received bone marrow cells recovered significantly later than
      others. Faster recovery could be expected in patient s receiving >13x10(4) CFU
      GM/kg body weight, and significantly slower in those receiving <8.5x10(4) CFU
      GM/kg. CONCLUSION: The quantity of progenitor cells and transplant type are
      variables significantly associated with the speed of postransplant engraftment,
      but these two parameters are mutually independent. The number of stem cells
      estimated by CFU-GM assay is a good and reliable routine test for predicting
      hematopoietic recovery.

PMID- 10411970
TI  - Voice-controlled robotic arm in laparoscopic surgery.
AB  - AIM: To report on our experience with a voice-directed robotic arm for scope
      management in different procedures for "solo-surgery" and in complex laparoscopic
      operations. METHODS: A chip card with orders for the robotic arm is individually
      manufactured for every user. A surgeon gives order through a microphone and the
      optic field is thus under direct command of the surgeon. RESULTS: We analyzed 200
      cases of laparoscopic procedures (gallbladder, stomach, colon, and hernia repair)
      done with the robotic arm. In each procedure the robotic arm worked precisely;
      voice understanding was exact and functioned flawlessly. A hundred "solo-surgery"
      operations were performed by a single surgeon. Another 96 complex videoscopic
      procedures were performed by a surgeon and one assistant. In comparison to other
      surgical procedures, operative time was not prolonged, and the number of used
      ports remained unchanged. CONCLUSION: Using the robotic arm in some procedures
      abolishes the need for assist ance. Further benefit accrued by the use of robotic
      assistance includes greater stability of view, less inadvertent smearing of the
      lens, and the absence of fatigue. The robotic arm can be used successfully in
      every operating theater by all surgeons using laparoscopy.

PMID- 10411971
TI  - Three dimensional ultrasound and power doppler in assessment of uterine and
      ovarian angiogenesis: a prospective study.
AB  - AIM: To determine whether three-dimensional power Doppler can improve the
      recognition of pelvic tumor morphology and angiogenesis. METHODS: Using this
      technique we analyzed 180 adnexal masses and 110 uterine lesions. Tumor volume,
      morphology, and vascularity were evaluated in each patient. Irregular and
      randomly dispersed vessels with complex branching depicted by comprehensive three
      dimensional display were suggestive of pelvic malignancy, while linear-like
      vascular morphology, single vessel arrangement and regular branching were typical
      for benign structures. RESULTS: Addition of qualitative analysis of vascular
      architecture of adnexal tumor to morphological parameters reached 96.15%
      sensitivity and 98.73% specificity. When endometrial lesions were prospectively
      analyzed, sensitivity and specificity were 91.67% and 98.49%, respectively.
      Because the lowest positive predictive value of 16.67% was obtained for
      myometrial lesions, this method should not be advised for their eva luation.
      CONCLUSION: Good results achieved by three dimensional ultrasound can be
      explained by improved recognition of the pelvic lesion anatomy, characterization
      of the surface features, detection of the tumor infiltration, and precise
      depiction of the size and volume. Three dimensional power Doppler imaging can
      detect structural abnormalities of the malignant tumor vessels, such as
      arteriovenous shunts, microaneurysms, tumoral lakes, disproportional calibration,
      coiling, and dichotomous branching. Therefore it enhances and facilitates the
      morphologic and functional evaluation of both benign and malignant pelvic tumors.

PMID- 10411972
TI  - Telepathology and pathology at distance: an overview.
AB  - Telepathology is probably the latest addition to the world of pathology. The
      costs of pathologic tests have increased, the requirements for shortened
      turnaround time are omnipresent and we are all aware of the current litigious
      environment. Telepathology is one of the answers to at least some of these
      requests. Here we review the current status of telepathology in the world of
      telemedicine; compare differences, similarities and applications of static and
      dynamic telepathology; and give a short introduction to the basic setup of a
      telepathology laboratory.

PMID- 10411973
TI  - Computer-based teaching of pathology at the Zagreb University School of Medicine.
AB  - AIM: To review the experience gained in transferring USA computer-based teaching
      system of medical school pathology to Croatia. METHODS: Computer-based teaching
      program of pathology developed at the University of Kansas School of Medicine,
      Kansas City, Kansas, USA, was transferred to the University of Zagreb School of
      Medicine, Zagreb, Croatia. The experimental group of 49 students was enrolled
      into this computer-based program. Their performance was compared with that of 195
      classmates enrolled in the standard course. Objective (performance on the
      examinations) and subjective data (students' interviews and written evaluations
      of the course) were analyzed. RESULTS: The computer program was operational 5
      months from the inception of the transfer. It was well received by the students,
      even though many initially complained that it required more effort and a
      continuous commitment. The major problems concerned scheduling, reflecting
      various requirements i mposed on students by other departments teaching in
      parallel with the Pathology course. Objective data gathered so far indicate that
      the students enrolled in the computer-based program took the first midterm
      examination at a significantly higher rate than the rest of the class (p<0.001),
      and passed the examination with significantly better grades (p<0.001).
      CONCLUSION: Computer-based teaching programs can be readily transferred to other
      countries. Full implementation of the program, however, may require significant
      changes in the existing curriculum in the medical school to which such a program
      has been transferred or considerable modifications in the program adopted for
      transfer. It appears that the students enrolled in the computer-based program
      perform better than students in the standard pathology course.

PMID- 10411974
TI  - Percutaneous autologous bone marrow grafting on the site of tibial delayed union.
AB  - Six months after injury, 150 mL of autogenous bone marrow was applied
      percutaneously at the site of delayed union to stimulate the healing of a tibial
      delayed union fracture in a 44 year-old man. Five months following the procedure,
      the fracture gaps and bone defects were completely filled with callus, the
      external fixator was removed, and the patient started using normal leg loading.

PMID- 10411975
TI  - Prenatal diagnosis of spinal muscular atrophy type I (Werdnig- hoffmann) by DNA
      deletion analysis of cultivated amniocytes.
AB  - AIM: Presentation of a prenatally diagnosed case of Werdnig-Hoffmann disease, the
      most severe type of spinal muscular atrophy. METHODS: DNA obtained from
      cultivated amniocytes was analyzed for deletions in the survival motor neuron
      gene and neuronal apoptosis inhibitory protein gene. RESULTS: The fetus was
      diagnosed as an affected homozygote for deletions in exon 7 and exon 8 of the
      survival motor neuron gene. No deletions of exon 5 in the neuronal apoptosis
      inhibitory protein gene were found. CONCLUSION: Direct DNA deletion analysis of
      the survival motor neuron gene and neuronal apoptosis inhibitory protein gene in
      affected families represents a highly reliable and fast method for prenatal
      diagnosis of Werdnig-Hoffmann disease.

PMID- 10411976
TI  - Challenge of Goodness II: new humanitarian technology, developed in croatia and
      bosnia and Herzegovina in 1991-1995, and applied and evaluated in Kosovo 1999.
AB  - This paper presents improvements of the humanitarian proposals of the Challenge
      of Goodness project published earlier (1). In 1999 Kosovo crisis, these proposals
      were checked in practice. The priority was again on the practical intervention -
      helping people directly - to prevent, stop, and ease suffering. Kosovo experience
      also prompted us to modify the concept of the Challenge of Goodness. It should
      include research and education (1. redefinition of health, 2. confronting
      genocide, 3. university studies and education, and 4. collecting experience);
      evaluation (1. Red Cross forum, 2. organization and technology assessment, 3.
      Open Hand - Experience of Good People); activities in different stages of war or
      conflict in: 1. prevention (right to a home, Hate Watch, early warning), 2.
      duration (refugee camps, prisoners-of-war camps, global hospital, minorities), 3.
      end of conflict (planned, organized, and evaluated protection), 4. post conflict
      (remaini ng and abandoned populations, prisoners of war and missing persons,
      civilian participation, return, and renewal). Effectiveness of humanitarian
      intervention may be performed by politicians, soldiers, humanitarian workers, and
      volunteers, but the responsibility lies on science. Science must objectively
      collect data, develop hypotheses, check them in practice, allow education, and be
      the force of good, upon which everybody can rely. Never since the World War II
      has anybody in Europe suffered in war and conflict so much as peoples in Croatia,
      Bosnia and Herzegovina, and Kosovo. We should search for the meaning of their
      suffering, and develop new knowledge and technology of peace.

PMID- 10411977
TI  - Building peace from scratch: some theoretical and technological aspects.
AB  - A peace-building process is based on activity, acceptance, understanding of
      political reality, communication, and empowerment. Acceptance means accepting
      everybody as he or she is and let each know it. This is at the heart of peace
      work, it is the prerequisite for effective communication, and includes accepting
      other even in cases of severe disagreement. Peace work requires both an
      understanding of political reality and the expression of one's own political
      opinion. Acceptance and the expression of political opinion are not at variance
      but complementary. Combining acceptance and understanding of the political
      context provides hope for real communication in which messages are both sent and
      received, with appreciation and interest. Empowerment implies overcoming of the
      feeling of powerlessness, often present in conflict by all sides and in all
      social groups. It includes recovery of self-respect and respect for others.
      Education and economic independence are important facets of the empowerment
      concept. Essential principles of peace-building process are responsibility,
      solidarity, cooperation, and nonviolence. Responsibility encompasses caring for
      human rights, the suffering of others, and for consequences of our own intended
      and unintended actions. Solidarity allows learning through listening and
      understanding. Even with the best intentions on both sides, cooperation may be
      difficult and painful. Nonviolence is a way of life.

PMID- 10411978
TI  - In vitro analysis of a mammalian retinal progenitor that gives rise to neurons
      and glia.
AB  - In vivo lineage studies have shown that retinal cells arise from multipotential
      progenitors whose fates are regulated by cell-cell interactions. To understand
      the mechanism underlying their maintenance and differentiation, we have analyzed
      the differentiation potential of progenitors derived from embryonic rat retina in
      vitro. These progenitors proliferate and remain undifferentiated in vitro in the
      presence of epidermal growth factor (EGF) and display properties similar to stem
      cells. In addition to expressing nestin, the neuroectodermal stem cell marker,
      retinal progenitors are multipotential. Upon withdrawal of EGF and addition of
      serum, the progenitors downregulate the expression of nestin and express cell
      type specific markers corresponding to neurons and glia. In addition to
      expressing cell-type specific markers, retinal progenitors and their progeny
      could be distinguished on the basis of their distinct voltage gated current
      profile. A proportion of progenitors is lineage restricted and the fate of these
      cells can be influenced by the microenvironment, suggesting that stage-specific
      interactions mediated by the local environment influence the progression of
      progenitors towards acquisition of differentiated phenotypes.

PMID- 10411980
TI  - Neonatal ventral hippocampal lesions attenuate the nucleus accumbens dopamine
      response to stress: an electrochemical study in the adult rat.
AB  - Neonatal damage to the ventral hippocampus (VH) can lead, during adulthood, to
      behaviours that are believed to reflect enhanced mesocorticolimbic dopamine (DA)
      transmission. In the present study, the effects of neonatal excitotoxic lesions
      to the VH on spontaneous locomotor activity and stress-elicited increases in
      extracellular nucleus accumbens (NAcc) DA levels were examined in adult rats.
      Male pups received, on postnatal day 7, bilateral injections of either an
      ibotenic acid solution (lesioned) or vehicle (sham-lesioned) into the VH. At 3-4
      months of age, animals were assessed during five daily sessions for changes in
      spontaneous locomotor activity associated with habituation to a novel
      environment. Voltammetry was used in separate groups of sham- and VH-lesioned
      animals to monitor the NAcc DA response to each of five once-daily exposures to
      tail-pinch stress. The results indicate that while VH-lesioned animals seem to
      habituate to novelty, they remain hyperactive relative to sham-lesioned controls.
      In contrast, however, stress consistently elicited in VH-lesioned animals smaller
      and shorter-lasting increases in NAcc DA than in sham-lesioned controls. These
      data suggest that neonatal excitotoxic damage to VH leads to changes in DA
      function that persist into adulthood. The blunted response to stress seen in VH
      lesioned animals indicates that one consequence of such damage is a functional
      hyporeactivity in meso-NAcc DA neurons. The fact that these animals are
      spontaneously more active suggests compensatory changes in DA function that are
      efferent to DA terminals in NAcc.

PMID- 10411979
TI  - Organization of the secretory machinery in the rodent brain: distribution of the
      t-SNAREs, SNAP-25 and SNAP-23.
AB  - Vesicular transport events appear to be facilitated by the VAMP/synaptobrevin
      family of membrane proteins in the vesicle (v-SNAREs) and a heterodimeric complex
      of syntaxin and SNAP-23/25 family members in the target membrane (t-SNAREs). In
      this manuscript we examine the tissue distribution and composition of the
      heterodimeric t-SNARE complexes in adult rodent brain. Analysis of protein
      extracts from brain regions shows that SNAP-25, syntaxin 1, and 4 are broadly
      distributed, while SNAP-23, syntaxin 3, and 7 show distinct patterns of
      expression. Further immunohistochemistry and fractionation studies show that
      while SNAP-25 is enriched in axons and nerve terminals, SNAP-23 is concentrated
      in cell bodies. Both SNAP-23 and SNAP-25 associate with the plasma membrane and
      can be metabolically labeled with [(3)H] palmitate in AtT-20 cells. Anti-SNAP-25
      antibodies co-immunoprecipitate t-SNARE heterodimers from brain extracts that
      predominantly contain syntaxin 1 and 2. Contrary to results from in vitro binding
      assays, SNAP-23 was found predominantly associated with syntaxin 3. These
      observations suggest that t-SNARE, heterodimer composition is governed more by
      SNARE expression and localization than by simple protein-protein affinity.

PMID- 10411981
TI  - Centrally administered galanin blocks morphine place preference in the mouse.
AB  - Galanin is a neuropeptide with appetitive, antinociceptive and neuroendocrine
      functions. Galanin and galanin binding sites are present in brain areas that
      mediate reinforcement, such as nucleus accumbens and ventral tegmental area, as
      well as locus coeruleus, an area known to be involved in development of drug
      dependence and withdrawal. This localization, coupled with the observation that
      there is a strong interaction between morphine and galanin in spinal cord, made
      it of interest to study whether galanin might have effects on morphine
      reinforcement. Using the place preference paradigm we found that galanin (1
      microg i.c.v.) alone does not possess reinforcing or aversive properties but
      attenuates the preference conditioned by peripheral administration of morphine (5
      mg/kg s.c.). Quantitative receptor autoradiography showed that morphine treatment
      that could condition a place preference decreased galanin binding in the nucleus
      accumbens and increased galanin binding in the locus coeruleus. In contrast,
      acute naltrexone administration increased galanin binding in the nucleus
      accumbens, suggesting that levels of galanin binding are tonically regulated by
      opioid receptors in that area. Contrary to what is seen in the spinal cord, these
      results indicate that galanin and morphine have an antagonistic interaction in
      the brain that results in attenuation of morphine reinforcement by activation of
      the galaninergic system.

PMID- 10411982
TI  - Inactivation gating and 4-AP sensitivity in human brain Kv1.4 potassium channel.
AB  - Voltage-gated K(+) channels vary in sensitivity to block by 4-aminopyridine (4
      AP) over a 1000-fold range. Most K(+) channel phenotypes with leucine at the
      fourth position (L4) in the leucine heptad repeat region, spanning the S4-S5
      linker, exhibit low 4-AP sensitivity, while channels with phenylalanine exhibit
      high sensitivity. Mutational analysis on delayed rectifier type K(+) channels
      demonstrate increased 4-AP sensitivity upon mutation of the L4 heptad leucine to
      phenylalanine. This mutation can also influence inactivation gating, which is
      known to compete with 4-AP in rapidly inactivating A-type K(+) channels. Here, in
      a rapidly inactivating human brain Kv1.4 channel, we demonstrate a 400-fold
      increase in 4-AP sensitivity following substitution of L4 with phenylalanine.
      Accompanying this mutation is a slowing of inactivation, an acceleration of
      deactivation, and depolarizing shifts in the voltage dependence of activation and
      steady-state inactivation. To test the relative role of fast inactivation in
      modulating 4-AP block, N-terminal deletions of the fast inactivation gate were
      carried out in both channels. These deletions produced no change in 4-AP
      sensitivity in the mutant channel and approximately a six-fold increase in the
      wild type channel. These results support the view that changes at L4 which
      increase 4-AP sensitivity are largely due to 4-AP binding and may, in part, arise
      from alterations in channel conformation. Primarily, this study demonstrates that
      the fast inactivation gate is not a critical determinant of 4-AP sensitivity in
      Kv1.4 channels.

PMID- 10411983
TI  - Loss of antiallodynic and antinociceptive spinal/supraspinal morphine synergy in
      nerve-injured rats: restoration by MK-801 or dynorphin antiserum.
AB  - The co-administration of morphine at spinal (i.th.) and supraspinal (i.c.v.)
      sites to the same rat produces antinociceptive synergy, a phenomenon which may
      underlie the clinical analgesic utility of this drug. In animals with peripheral
      nerve injury, however, the antinociceptive potency and efficacy of i.th. morphine
      is significantly decreased. Here, the possible loss of spinal/supraspinal
      morphine antinociceptive synergy and relationship to elevation of spinal
      dynorphin content was studied. Ligation of lumbar spinal nerves resulted in
      elevated dynorphin in the ipsilateral lumbar and sacral spinal cord. In sham
      operated rats supraspinal/spinal co-administration of morphine produced
      synergistic antinociception which was unaffected by i.th. MK-801 or dynorphin
      A((1-17)) antiserum. In nerve-injured rats, i.th. morphine was inactive against
      tactile allodynia and showed diminished in potency against acute nociception
      without supraspinal/spinal antinociceptive synergy. Antiserum to dynorphin A((1
      17)) or the non-competitive NMDA antagonist MK-801 increased the antinociceptive
      potency of i.th. morphine, restored supraspinal/spinal morphine antinociceptive
      synergy and elicited a dose-related i.th. morphine antiallodynic action. These
      agents did not demonstrate antinociceptive or antiallodynic activity alone and
      did not alter morphine actions in sham-operated animals. The loss of
      spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of
      spinal morphine appear to be due to the elevation across multiple spinal segments
      of dynorphin following nerve injury. Pathological actions of elevated dynorphin
      may directly or indirectly modulate the NMDA receptor, result in a loss of
      supraspinal/spinal morphine synergy and may thus account for the decreased
      clinical analgesic efficacy of morphine in peripheral neuropathies.

PMID- 10411984
TI  - Methyl isobutyl amiloride alters regional brain reperfusion after resuscitation
      from cardiac arrest in rats.
AB  - In a rat model of cardiac arrest and resuscitation, [(14)C]-iodoantipyrene (IAP)
      autoradiography was used to measure the regional variations in cerebral blood
      flow 15 and 60 min after reperfusion. The purpose of this study was to
      investigate the hypothesis that the inhibition of the Na+/H+ antiporter with
      methyl isobutyl amiloride (MIA) would decrease postischemic pericapillary
      cytotoxic edema and, therefore, improve vascular perfusion dynamics. Vehicle
      treated rats responded to cardiac arrest and resuscitation as expected with
      initial hyperemia after 15 min of reperfusion, except for thalamic and midbrain
      structures which were hypoperfused. All brain structures were perfused at half
      the baseline blood flow at 60 min after resuscitation, and the residual blood
      flow in each region was proportional to the baseline flow of each region. MIA
      treatment was associated with decreased blood flow in every region examined at
      both 15 min and 60 min of reperfusion. No hyperemia was observed at 15 min in any
      region after MIA treatment. Sixty minutes after resuscitation in MIA-treated
      rats, all structures were hypoperfused (to 25+/-7% of baseline, 48+/-8% of
      vehicle-treated rats). These effects are unlikely to be due to prevention of
      cytotoxic edema, but may be due to MIA protection of capillary endothelium by
      prevention of neutrophil activation.

PMID- 10411985
TI  - The relative roles of phenylalanine and tyrosine as substrates for DOPA synthesis
      in PC12 cells.
AB  - The relative contributions of tyrosine (TYR) and phenylalanine (PHE) to the
      synthesis of dihydroxyphenylalanine (DOPA) were studied in PC12 cells following
      inhibition of aromatic L-amino acid decarboxylase with m-hydroxybenzylhydrazine
      (NSD-1015). Cells were incubated with varying concentrations of unlabeled L-TYR
      and L-PHE, and either L-(3)H-TYR or L-(3)H-PHE. Following incubation, labeled and
      unlabeled TYR, PHE, and DOPA were quantitated following HPLC separation. PC12
      cells synthesized DOPA from both TYR and PHE. Raising the concentration of one
      amino acid relative to that of the other increased the proportion of DOPA
      synthesized from that amino acid. TYR suppressed DOPA synthesis from (3)H-PHE at
      concentrations lower than that observed for a similar inhibition by PHE of DOPA
      synthesis from (3)H-TYR. Inhibition of total DOPA synthesis occurred only at high
      concentrations of either amino acid. The results suggest that in the PC12 cell,
      TYR and PHE can be used interchangeably as substrates for TYR hydroxylation, and
      that the proportion of catecholamine synthesized will depend on the relative
      proportions of each substrate available to the cell. However, TYR is clearly the
      preferred substrate for tyrosine hydroxylase.

PMID- 10411986
TI  - Volatile anesthetic inhibition of neuronal Ca channel currents expressed in
      Xenopus oocytes.
AB  - The genes encoding the alpha(1A), alpha(1B), alpha(1C) and alpha(1E) subunits of
      neuronal high voltage-gated Ca channels (HVGCCs) were separately expressed with
      beta(1B) and alpha(2)/delta subunits in Xenopus oocytes to determine the effects
      of volatile anesthetics (VAs) on currents through each specific channel. VA
      effects were determined on currents carried by Ba(2+) (I(Ba)) using the two
      electrode voltage clamp technique. Although time to peak was unaffected, both
      halothane (0.59 mM) and isoflurane (0.70 mM) reversibly inhibited peak I(Ba) by
      25-35% and late current (at 830 ms) by 50-60%. A hyperpolarizing shift in steady
      state inactivation of alpha(1E)-current was found which could contribute up to
      one third of observed decrease in the peak current. The rate of inactivation of
      I(Ba) seen with alpha(1A), alpha(1B) and alpha(1E)-type Ca channels was
      consistently increased by halothane and isoflurane. To more clearly quantify
      these effects, I(Ba) inactivation was fit by a single exponential function. The
      anesthetics depressed both the inactivating and non-inactivating residual
      components of I(Ba) and decreased the time constant of inactivation. In the case
      of I(Ba) through alpha(1C)-type channels, inactivation was minimal; however, the
      average current was inhibited by VAs. Similar inhibition of all these HVGCCs by
      halothane and isoflurane suggests that a common structural component may be
      involved. Furthermore, the inhibition of such neuronal HVGCCs in situ could alter
      synaptic neurotransmitter release and contribute to the anesthetic state.

PMID- 10411987
TI  - Dopamine modulates carotid nerve responses induced by acetylcholine on the cat
      petrosal ganglion in vitro.
AB  - We have recently reported that application of acetylcholine (ACh) or nicotine to
      the petrosal ganglion-the sensory ganglion of the glossopharyngeal nerve-elicits
      a burst of discharges in the carotid nerve branch, innervating the carotid body
      and sinus, but not in the glossopharyngeal branch, innervating the tongue and
      pharynx. Thus, the perikarya of sensory neurons for the carotid bifurcation
      exhibit selective cholinosensitivity. Since dopamine (DA) modulates carotid nerve
      chemosensory activity, we searched for the presence of DA sensitivity at the
      perikarya of these neurons in the cat petrosal ganglion superfused in vitro.
      Applications of DA in doses of up to 5 mg to the ganglion did not modify the rate
      of spontaneous discharges in the carotid nerve. However, if DA was applied 30 s
      before ACh injections, ACh-evoked reactions were modified: low doses of DA
      enhanced the subsequent responses to ACh, while high doses of DA depressed the
      responses to ACh. This depressant effect of DA on ACh responses was partially
      antagonized by adding spiroperone to the superfusate. Our results show that the
      response to ACh of petrosal ganglion neurons projecting through the carotid nerve
      is modulated by DA acting on D(2) receptors located in the somata of these
      neurons. Thus, dopaminergic modulation of cholinosensitivity could be shared also
      by the membranes of peripheral endings and perikarya of primary sensory neurons
      involved in arterial chemoreception.

PMID- 10411988
TI  - Postmortem elevation in extracellular glutamate in the rat hippocampus when brain
      temperature is maintained at physiological levels: implications for the use of
      human brain autopsy tissues.
AB  - Postmortem alterations in the neuronal cytoskeleton resemble some aspects of the
      cytoskeletal disruption associated with neurodegenerative disorders, and are also
      similar to those observed following ischemia and produced by excitotoxins in vivo
      and in vitro. This suggests the involvement of excitotoxic mechanisms during the
      postmortem interval. The purpose of this study was to determine if extracellular
      levels of glutamate are elevated postmortem. Extracellular levels of GABA and
      taurine were also monitored using in vivo microdialysis. These three amino acids
      were analyzed using high-performance liquid chromatography. When postmortem rat
      brain temperature cooled rapidly to near room temperature, dialysate
      concentrations of glutamate were not increased in the hippocampal CA1 region
      during a 2-h postmortem interval, although increased extracellular levels of GABA
      and taurine were observed. In contrast, maintenance of brain temperature at 37
      degrees C resulted in a 12-to-40 fold elevation in extracellular glutamate levels
      20-120 min postmortem. In addition, the elevation in dialysate taurine
      concentration was greater than that observed in rats in which postmortem brain
      temperature was not maintained. Excitatory amino acid antagonists, NBQX (2, 3
      dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) and MK-801 (dizocilpine, (+)-5
      methyl-10,11-dihydro-5H-dibenzo[a,d]cylohepten-5, 10-imine hydrogen maleate
      blocked the additional elevation in taurine associated with maintaining brain at
      37 degrees C, but had less robust effects against glutamate and GABA release. The
      results indicate that extracellular concentrations of glutamate, taurine and GABA
      increase in postmortem rat brain when physiologic temperatures are maintained,
      but that these increases are blunted when brain temperature decreases. After
      death, the human brain cools much more slowly than does the rat brain. Therefore,
      extracellular glutamate levels are likely to increase in the postmortem human
      brain and may contribute to excitotoxic neuronal damage occurring in the interval
      between death and autopsy.

PMID- 10411989
TI  - Weak effect of neuromodulators on climbing fiber-activated [Ca(2+)](i) increases
      in rat cerebellar Purkinje neurons.
AB  - The effect of several neuromodulators (carbachol (CCh), serotonin (5-HT),
      noradrenaline (NE), and dopamine (DA)) on the climbing fiber (CF)-induced
      [Ca(2+)](i) increase in the dendrites of cerebellar Purkinje cells was examined
      in slices from the rat cerebellum. Purkinje cells were filled with the Ca(2+)
      indicator bis-fura-2 with patch electrodes on the soma. [Ca(2+)](i) changes were
      measured from regions of interest in the dendrites with a high speed camera.
      Changes evoked by one or three responses were measured in control conditions and
      with neuromodulators added to the bath. None of these four classic modulators
      caused a significant change in the CF-induced [Ca(2+)](i) amplitude. Buspirone, a
      partial 5-HT(1A) agonist and a weak DA receptor antagonist caused a small (10
      15%) reduction in the response.

PMID- 10411990
TI  - Convulsant actions of the neurosteroid pregnenolone sulfate in mice.
AB  - Pregnenolone sulfate (PS) is an endogenous neurosteroid known to antagonize
      GABA(A) receptor-mediated inhibitory responses and potentiate NMDA receptor
      mediated excitatory responses in vitro. To assess the actions of the steroid as a
      modulator of seizure susceptibility in vivo, PS (30-300 nmol) was administered
      intracerebroventricularly in mice. At doses of 50 to 150 nmol, PS elicited
      seizures characterized by head jerks, rearing and falling, severe forelimb and
      hindlimb clonus, opisthotonos and explosive running. The seizures increased in
      severity and frequency with time and eventually progressed to status epilepticus,
      tonic hindlimb extension and death. The doses producing convulsions in 50%
      (CD(50)) and 97% (CD(97)) of animals were 92 and 205 nmol, respectively. A
      subconvulsant dose of PS (50 nmol) significantly increased the convulsant
      potencies of systemically administered pentylenetetrazol (30-50 mg/kg) and NMDA
      (50-100 mg/kg). Systemically administered PS at doses as high as 100 mg/kg failed
      to induce seizures or alter the convulsant potencies of pentylenetetrazol and
      NMDA. Protection against PS (205 nmol)-induced seizures and lethality was
      conferred by the GABA(A) receptor positive allosteric modulators clonazepam and
      allopregnanolone, and by the NMDA receptor antagonists dizocilpine and (R)-CPP.
      The overall pharmacological profile suggests that the convulsant actions of PS
      are mediated predominantly via its effects on GABA(A) receptors, and also
      possibly by effects on NMDA receptors.

PMID- 10411991
TI  - Selective oxidation and externalization of membrane phosphatidylserine: Bcl-2
      induced potentiation of the final common pathway for apoptosis.
AB  - The induction of apoptosis in PC12 cells by the enediyne neocarzinostatin (NCS)
      is paradoxically potentiated by overexpression of bcl-2. The enhanced activation
      of NCS seen in bcl-2-overexpressing cells cannot by itself be responsible for the
      potentiation of apoptosis, since Bcl-2 would be expected to block apoptosis at a
      point distal to NCS activation (e.g., in the apoptosis final common pathway). We
      now report that overexpression of bcl-2 in PC12 cells does not protect the cells
      from NCS-induced oxidation of membrane phosphatidylserine (PS), and results in
      potentiation of NCS-induced externalization of membrane PS, two events associated
      with the apoptosis final common pathway. The mechanism of potentiation of
      apoptosis by Bcl-2 is related to the enhanced reducing potential of bcl-2
      overexpressing PC12 cells.

PMID- 10411992
TI  - Forebrain ischemia: effect on pharmacologically induced seizure thresholds in the
      rat.
AB  - Seizures are common after severe cerebral ischemia. To examine the mechanisms
      underlying these seizures, we determined the impact of prior forebrain ischemia
      on the seizure thresholds of four convulsants with differing modes of action:
      lidocaine, pentylenetetrazol (PTZ), N-methyl-D-aspartate (NMDA), and picrotoxin.
      Anesthetized Sprague-Dawley rats were chronically instrumented with screw
      electrodes and vascular catheters, and then subjected to 10 min of forebrain
      ischemia, produced by carotid occlusion and hypotension (mean arterial pressure
      to 30 mmHg). Animals were then awakened. 6, 24 or 48 h later, groups of awake
      animals received intravenous infusions of the four drugs. The total dose of drug
      infused prior to either electrical seizures (lidocaine, PTZ, and picrotoxin) or
      tonic-clonic convulsions (all drugs) were noted. For each drug, a group of Sham
      animals (no ischemia) served as controls. There were markedly different patterns
      of changes in the convulsant thresholds for the drugs. For example, at 6 h post
      ischemia, rats treated with lidocaine died before convulsing, while the threshold
      for PTZ increased by 86%. There was no change in the picrotoxin threshold at 6 h,
      but the dose of NMDA needed to induce tonic-clonic seizure activity was reduced
      by 70%. By 48 h, lidocaine and PTZ thresholds had returned to values similar to
      those in Shams, but the NMDA threshold had now increased to a value 62% greater
      than Sham. Ten minutes of cerebral ischemia is followed by a complex and changing
      pattern of susceptibility to chemical convulsants. Finding suggests that early
      post-ischemic seizures may be related to increased NMDA receptor sensitivity.

PMID- 10411993
TI  - Sodium-dependent glutamate transport in Muller glial cells: regulation by phorbol
      esters.
AB  - The regulation of the Na(+)-dependent high affinity glutamate/aspartate
      transporter system expressed in cultured Muller glia cells from chick retina was
      studied. Treatment of the cells with the Ca(2+)/diacylglycerol dependent protein
      kinase C (PKC) activator, phorbol 12-tetradecanoil-13-acetate (TPA) produced a
      decrease in [(3)H]D-aspartate uptake which was reversed by staurosporine and
      partially by H7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochoride],
      two PKC inhibitors. Long-term treatment with TPA resulted in a drastic decrease
      in the uptake activity, correlated with a substantial fall in the expression of
      the transporter protein. These findings suggest that PKC is involved in transport
      modulation at two different levels: phosphorylation and transporter expression in
      retinal Muller glial cells.

PMID- 10411994
TI  - Estrous cycle modulation of extracellular serotonin in mediobasal hypothalamus:
      role of the serotonin transporter and terminal autoreceptors.
AB  - In vivo microdialysis was used to examine extracellular serotonin (5-HT) in the
      mediobasal hypothalamus (MBH) of male and female Fischer (CDF-344) rats. Females
      from the stages of diestrus, proestrus, and estrus were used. Additionally,
      ovariectomized rats, primed subcutaneously (s.c.) with estradiol benzoate or
      estradiol benzoate plus progesterone were examined. Extracellular 5-HT in the MBH
      varied with stage of the estrous cycle and with the light/dark cycle. Proestrous
      females had the highest microdialysate concentrations of 5-HT during the light
      portion of the light/dark cycle and lowest concentrations during the dark portion
      of the cycle. Diestrous females had the highest levels during the dark portion of
      the cycle, while males and estrous females showed little change between light and
      dark portions of the cycle. In ovariectomized rats, there was no effect of 2.5
      microg or 25 microg estradiol benzoate (s.c.) on extracellular 5-HT; but the
      addition of 500 microg progesterone, 48 h after estrogen priming, reduced
      microdialysate 5-HT near the threshold for detection. In intact females and in
      males, reverse perfusion with 3 microM fluoxetine, a selective serotonin reuptake
      inhibitor (SSRI), or 2 microM methiothepin, a 5-HT receptor antagonist, increased
      microdialysate concentrations of 5-HT. Estrous females and males showed nearly a
      4-fold increase in microdialysate 5-HT in response to fluoxetine while smaller
      responses were seen in diestrous and proestrous rats. In contrast, proestrous
      rats showed the largest response to methiothepin. Estrous females showed a
      delayed response to methiothepin, but there was no methiothepin-induced increase
      in extracellular 5-HT in males. These findings are discussed in reference to the
      suggestion that extracellular 5-HT in the MBH is regulated in a manner that is
      gender and estrous cycle dependent. The 5-HT terminal autoreceptor may exert a
      greater role in proestrous females; the serotonin transporter appears to play a
      more active role in the regulation of extracellular 5-HT in estrous females and
      in males.

PMID- 10411995
TI  - 8-OH-DPAT-sensitive neurons in the nucleus raphe magnus modulate thermoregulatory
      output in rats.
AB  - The nucleus raphe magnus (NRM) is purported to be a relay through which
      peripheral thermoafferent information is transmitted to thermointegrative centers
      located in the preoptic/anterior hypothalamus (POAH). Therefore, suppression of
      neural activity in the NRM should reduce thermoregulatory responses to peripheral
      thermal challenges, but not affect responses elicited by manipulation of POAH
      temperature. At low ambient temperatures lidocaine injections into the NRM of
      nonanesthetized rats resulted in decreases in POAH temperature, oxygen
      consumption, and electromyographic activity. At a warm ambient temperature,
      lidocaine injections into the NRM decreased the elevations in oxygen consumption
      and electromyographic activity elicited by cooling the POAH. The effects of
      lidocaine injections were duplicated by injection of a 5-HT(1A) agonist 8-hydroxy
      dipropylaminotetralin (8-OH-DPAT) into the NRM. The effect of 8-OH-DPAT was
      eliminated by pre-treatment with a selective autoreceptor antagonist. These
      results suggest that NRM 5-HT neurons are modulating the relationship between
      output of thermointegrative centers and thermoregulatory effector responses
      rather than processing thermoafferent information.

PMID- 10411996
TI  - Priming threshold: a novel quantitative measure of the reinstatement of cocaine
      self-administration.
AB  - The intravenous injection of cocaine has been reported to reliably reinstate
      (prime) the self-administration of cocaine in animals. We report herein that
      there is a cocaine priming threshold in rats trained to self-administer cocaine.
      The cocaine priming threshold is defined as the minimum level of cocaine in the
      body that will reinstate maintained cocaine self-administration. The mean cocaine
      priming threshold in rats was calculated to be approximately 186 to 212 microg
      kg(-1). Therefore, any injection, series of injections or continuous infusion
      that result in a level of cocaine equivalent to that produced by a single
      intravenous injection of this range of doses, will reinstate cocaine self
      administration. The priming threshold was significantly increased by the D(1)
      dopamine receptor antagonist SCH23390 (10 microg kg(-1), i.v.), indicating a role
      for dopaminergic neurotransmission. The priming threshold, but not the inter
      injection interval of maintained self-administration, was increased following
      withdrawal from a 7-day infusion of D-amphetamine. In addition, there was no
      correlation between the cocaine priming threshold and the inter-injection
      intervals of maintained cocaine self-administration. Therefore, the mechanisms
      underlying the reinstatement of cocaine self-administration are distinct from the
      mechanisms underlying the maintenance of cocaine self-administration and they are
      differentially regulated. It is possible that the priming threshold may represent
      a distinct target for medications development.

PMID- 10411997
TI  - Effects of T-588, a newly synthesized cognitive enhancer, on hippocampal CA1
      neurons in rat brain tissue slices.
AB  - The effects of a newly synthesized cognitive enhancer, (-)-R-alpha-[[2
      (diethylamino) ethoxy] methyl] benzo [b] thiophene-5-methanol hydrochloride (T
      588), on the membrane properties of hippocampal CA1 neurons were investigated in
      a rat brain slice preparation. T-588 produced a slow and long-lasting
      depolarization of CA1 neurons with an increase in membrane resistance; this
      action showed close similarity to that of acetylcholine (ACh). However, the
      action of T-588 was not affected by atropine, tetrodotoxin or DL-2-amino-5
      phosphonovalerate, while the action of ACh was blocked by atropine. The estimated
      reversal potential of this T-588 effect was near -90 mV which is the reversal
      potential of potassium ions in CA1 neurons. In the whole-cell voltage-clamp
      study, T-588 produced a reversible block of the outward potassium current in CA1
      neurons. T-588 did not block the afterhyperpolarization evoked by an
      intracellular current injection, while ACh suppressed it. These results suggest
      that T-588 has a direct effect on CA1 neurons independent of its cholinergic
      activity, resulting from blockade of a conductance carried predominantly by
      potassium ions.

PMID- 10411998
TI  - Functional mapping of transsynaptic effects of local manipulation of inhibition
      in gerbil auditory cortex.
AB  - Cortical networks are under the tonic influence of inhibition which is mainly
      mediated by GABA. The state of inhibition of small neuronal populations in the
      auditory cortex (AC) field AI of gerbils was altered by local microinjection of
      GABA, of the GABA(A)-receptor agonist 4-piperidine-sulfonic acid (P4S) and the
      GABA(A)-receptor antagonists bicuculline methiodide (BMI) and SR-95531. In order
      to elucidate direct and transsynaptic effects of the alterations of inhibition
      produced by these substances we used the 2-fluoro-2-deoxy-D-[(14)C(U)] glucose
      (FDG) mapping method. The injection of GABA (10 mM) caused no significant changes
      in FDG labeling but P4S caused a marked decrease of local FDG uptake in a small
      region surrounding the injection site but in no other region. The injection of
      the GABA(A)-receptor antagonists caused massive increases of FDG uptake within
      the entire ipsilateral AC, whereas the contralateral AC was not significantly
      affected in spite of prominent callosal connections. However, disinhibited
      excitatory output from the ipsilateral AC is suggested by a strong increase in
      FDG labeling of the corticothalamic fiber tract and ipsilateral structures like
      medial geniculate nucleus, caudal striatum, and lateral amygdaloid nucleus and a
      structure at the caudoventral margin of the thalamic reticular nucleus,
      presumably the subgeniculate nucleus, a structure with hitherto unknown
      connections and function. No alteration of FDG uptake could be detected in the
      inferior colliculus, another main descending target structure of the AC. In
      summary, the effects resulting from microinjection of GABA(A)-receptor
      antagonists reflect a differential influence of the AC on its anatomically
      connected target regions. The findings demonstrate the potential of the method of
      focal application of neuroactive substances in combination with the FDG technique
      for mapping their transsynaptic influences which are hard to derive from
      anatomical tracing studies alone.

PMID- 10411999
TI  - The demonstration of immunoreactive dystrophin and its developmental expression
      in perivascular astrocytes.
AB  - Immunoreactivity of dystrophin family proteins was observed in the astrocytes of
      the adult and immature rat hippocampus and cerebral cortex by using Dys2, a
      monoclonal antibody recognizing both 427 kDa and short dystrophin isoforms. As
      revealed by light and electron microscopy, immunostaining of the ribosomal
      apparatus and of pericapillary endfeet was particularly pronounced in the adult.
      In the pericapillary astrocyte processes immunostaining appeared between
      postnatal days 10 and 20, and reached the intensity seen in the adult by
      postnatal day 30. In the pericapillary astrocyte process, the membrane facing the
      endothelial basal lamina was the earliest structure to show the immunoreaction.
      At later stages, the pericapillary astrocyte process was gradually filled up with
      immunoprecipitate. Findings suggest that dystrophins are expressed coinciding
      with the development of the blood-brain barrier, and it is assumed that they
      contribute to the formation of this system.

PMID- 10412000
TI  - The network-selective actions of quinoxalines on the neurocircuitry operations of
      the rabbit retina.
AB  - We examined the contribution of N-methyl-D-aspartate (NMDA) and alpha-amino-3
      hydroxy-5-methyl-4-isoxalole-4-propionic acid (AMPA)/kainate (KA) receptors to
      the light-responses of rabbit retinal neurons. In the outer retina, bath
      application of the AMPA/KA receptor antagonists 6,7-dinitro-quinoxaline-2,3-dione
      (DNQX) and 2,3,dihydroxy-6-nitro-7-sulfamoyl-benzo-f-quinoxaline (NBQX) blocked
      the light-responses of horizontal cells. Application of quinoxalines enhanced ON
      bipolar cell light-responses, and was associated with a hyperpolarization of
      their resting potentials. In the inner retina, application of both AMPA/KA and
      NMDA antagonists to AII amacrine-like cells only partially blocked their light
      responses. Their residual responses may reflect electrical coupling to
      neighboring ON-center cone bipolar cells, and can inhibit OFF-center ganglion
      cells. ON-sustained ganglion cells were highly sensitive to the quinoxalines,
      which reduced their light-evoked firing, while the firing of ON-transient cells
      remained as NMDA-mediated light-responses. Quinoxalines had differential effects
      on the firing rates of ON- and OFF-center ganglion cells: ON-cells were reduced,
      while OFF-cells were increased. In contrast, firing rates of ON-OFF ganglion
      cells were not excited by NBQX, and showed a recovered light-response mediated by
      NMDA receptors. The receptive field surround was lost in ganglion cells. For
      comparison, NMDA antagonists had only moderate effects on all ganglion cell light
      responses. Our results indicate that NMDA and AMPA/KA receptors both contribute
      to ganglion cell light-responses. However, AMPA/KA receptors also significantly
      effect the light-response of neurons presynaptic to retinal ganglion cells,
      altering the observed pharmacology at the ganglion cell level.

PMID- 10412001
TI  - Transport mechanisms for the antidepressant citalopram in brain microvessel
      endothelium.
AB  - Blood-brain barrier transport of the selective serotonin reuptake inhibitor and
      antidepressant, citalopram, was studied using monolayers of bovine brain
      microvessel endothelial cells (BMECs). This study provides for the first time,
      evidence of a transport mechanism for a selective serotonin reuptake inhibitor
      (SSRI). Carrier-mediated transport, efflux mechanisms, as well as inhibition of
      metabolizing enzymes of citalopram were investigated. Citalopram transport was
      saturable and temperature-dependent suggesting that passage of the drug across
      BMECs was mediated by a carrier mechanism. Since the apical to basolateral and
      basolateral to apical permeability coefficients were similar and cyclosporin A, a
      P-glycoprotein inhibitor, does not modify the transport of citalopram, it
      appeared that no active efflux systems were involved in this transport.
      Citalopram is only available as a racemic drug and its pharmacological effect
      resides mainly in the S-(+)-enantiomer. However, the passage of citalopram
      enantiomers across BMEC monolayers was not stereoselective. Finally, inhibition
      of the metabolizing enzymes of citalopram and monoamine oxidases did not modify
      the permeation of citalopram across BMECs. Collectively, our results suggested
      that citalopram crosses the blood-brain barrier via a non-stereoselective,
      bidirectional and symmetrical carrier-mediated mechanism without influences of
      active efflux mechanisms or monoamine oxidases.

PMID- 10412002
TI  - Short and long term plasticity after lesioning of the cell body or terminal field
      area of the dopaminergic mesocorticolimbic system in the rat.
AB  - To investigate within one study regenerative capacities of dopaminergic axons and
      cell bodies, short and long term recovery of behavioral and biochemical
      impairments following a bilateral 6-hydroxydopamine (6-OHDA) lesion of the
      ventral tegmental area (VTA)-nucleus accumbens (NAc) pathway was investigated in
      rats. Novelty-induced motility, presynaptic functions and the levels of dopamine
      (DA) and its metabolites were reduced when cell bodies in the VTA or axons in the
      NAc were lesioned. Spontaneous recovery of the behavioral deficit was observed 4
      weeks after a lesion of the NAc. Subsequently presynaptic functions recovered as
      shown by the reappearance of low dose apomorphine (50 mg/kg)-induced
      hypomotility, normalization of [(3)H]dopamine uptake, reinnervation of the NAc
      and normalization of levels of DA and its metabolites within 24 weeks. In
      contrast, after a VTA lesion no recovery was observed during 48 weeks, neither
      from hypomotility and loss of the low dose apomorphine response nor from
      decreased [(3)H]dopamine uptake and levels of DA in the NAc. Short term
      postsynaptic supersensitivity (hypermotility upon a higher dose of apomorphine
      (125 mg/kg)) was present 1 and 4 weeks after the lesion but not thereafter. A
      near total absence of dopaminergic neurons in the VTA and axons in the NAc were
      found 24 weeks postlesion. Treatment with the ACTH-(4-9) analog ORG 2766 (10
      mg/kg s.c., 6 days once daily) facilitated recurrence of presynaptic functions
      after a lesion of axons but had no short or long term effect when cell bodies
      were lesioned. These findings substantiate the postulate that the peptide
      facilitates recovery processes.

PMID- 10412003
TI  - Cardiovascular regulatory actions of the hypocretins in brain.
AB  - The hypocretins, also known as the orexins, are alternate translation products of
      a single gene. The recognition of their production in neurons of the rostral
      diencephalon, and their axonal localization in brain sites known to be important
      in the control of appetite, led to the demonstration of their orexogenic actions.
      However, these peptides are not as potent as other appetite stimulating
      neuropeptides and they have been localized in areas of brain more related to
      cardiovascular function. We verified the orexogenic actions of hypocretin-1 (Hcrt
      1) and hypocretin-2 (Hcrt-2) in an ad libitum feeding model and identified the
      threshold dose to be 1 nmol when given into the lateral cerebroventricle (i.c.
      v.). Even at threshold doses for feeding, both Hcrt-1 and Hcrt-2 given i.c.v.
      into conscious, unrestrained rats stimulated significant elevations in mean
      arterial blood pressure, that appeared dose related. These elevations were
      relatively long lasting, mirroring the time course of a pressor dose of
      angiotensin II (0.1 nmol i.c.v.); however, the magnitude of blood pressure
      elevation to hypocretin did not equal that of A II. These data suggest an
      additional, non-appetitive action of the hypocretins and indicate that the
      peptide and receptor mapping studies may have predicted important roles for the
      peptides in the central nervous system control of cardiovascular function.

PMID- 10412004
TI  - Increase in glucose transporter densities of Glut3 and decrease of glucose
      utilization in rat brain after one week of hypoglycemia.
AB  - The present study addresses the question whether a chronic decrease of plasma
      glucose concentration for 1 week induces a global or local increase in glucose
      transporter densities Glut1 and Glut3 in the brain. To induce chronic
      hypoglycemia insulin was infused into rats by osmotic minipumps for 1 week
      resulting in a mean plasma glucose concentration of 3.1+/-0.5 mmol/l (control
      group: 8.1+/-0.5 mmol/l). Global and local densities of Glut1 and Glut3 glucose
      transporters were measured by immunoautoradiographic methods. The mean density of
      glucose transporters Glut1 remained unchanged, whereas the mean density of Glut3
      increased slightly, although significantly. To determine whether the increased
      density of Glut3 is related to a change in glucose metabolism, the local cerebral
      metabolic rate of glucose (lCMR(glc)) was quantified by the 2-deoxyglucose
      method. Mean glucose utilization was decreased by 15%. Local analysis of
      transporter densities (Glut1 and Glut3) and glucose utilization showed a
      significant correlation between local glucose transporter densities (Glut1 and
      Glut3) and lCMR(glc) during hypoglycemia as already previously observed during
      normoglycemia. It is concluded that 1 week of hypoglycemia is a stimulus for the
      induction of additional glucose transporters Glut3 in the brain. These additional
      neuronal glucose transporters may support the maintenance of glucose utilization
      which is not completely maintained under these conditions.

PMID- 10412005
TI  - Visualization of mitochondrial oxygen fixation in brain slices by gas-tissue
      autoradiography.
AB  - We have developed a novel autoradiographic method of visualizing oxygen fixation
      with sufficient delivery of [(15)O]O(2)/O(2). Brain slices (400 microm) were
      preincubated in Krebs-Ringer phosphate buffer and exposed to [(15)O]O(2) in a
      chamber. Fixation of [(15)O]O(2) correlated with the polarographically measured
      oxygen consumption among tissue slices from various organs (r=0.84). The fixation
      of [(15)O]O(2) by brain slices was significantly reduced (7. 2% of the control)
      by heat-treatment or dose dependently by NaCN (18. 2% of the control on 50 mM
      NaCN pretreatment). The (15)O radioactivity in the brain slices prepared from
      rotenone injected rats was also reduced compared to the control (56.8% of the
      control side). In an autoradiographic study, (15)O radioactivity showed a
      heterogeneous distribution both in coronal and sagittal sections. Autoradiography
      of young and senescent rat brain sections showed reduction of oxygen uptake with
      aging in the cerebrum, the senescent being 77.4% of the young. This method
      provides information regarding basic oxygen consumption of tissue slices under
      condition of sufficient O(2) delivery, which reflects mitochondrial electron
      transport.

PMID- 10412006
TI  - Transient in vivo membrane depolarization and glutamate release before anoxic
      depolarization in rat striatum.
AB  - Increased extracellular glutamate ([GLU]e), under the condition of cerebral
      ischemia, anoxia or hypoxia, has been recognized as being associated with
      neuronal cell damage and death. We performed real-time monitoring of [GLU]e
      dynamics in vivo in the rat striatum during systemic acute anoxia or hypoxia, as
      well as monitoring the direct current potential (DC) and cerebral blood flow
      (CBF). Adult Wistar rats were orotracheally intubated and artificially ventilated
      with room air. A microdialysis electrode, temperature sensor probe, DC
      microelectrode and laser Doppler probe were then implanted. The inspired gas was
      changed to 100% N(2) (anoxia), or to 3, 5 or 8% O(2) (remainder N(2)) (hypoxia).
      With 100% N(2), distinct biphasic [GLU]e elevations were observed. With 3% O(2),
      a transient [GLU]e increase was seen before anoxic depolarization (AD). With 5%
      O(2), however, the start of the transient [GLU]e increase was significantly
      delayed. Anoxia-induced depolarization started at about 100 s. The 3% O(2)
      induced transient depolarization and AD began at nearly the same time as the
      transient and AD-induced increase in [GLU]e. Similarly, the responses to 5% O(2)
      showed significant delays in the transient depolarization and AD-induced increase
      in [GLU]e. CBF during 3 or 5% O(2) hypoxic insult was consistently maintained
      above the control level, i.e., prior to cardiac arrest. Our new dialysis
      electrode method employing both GOX and ferrocene-conjugated bovine serum albumin
      allowed evaluation of transient [GLU]e dynamics in the early phase of severe
      hypoxia in vivo.

PMID- 10412007
TI  - Proliferation of neuronal precursor cells in the dentate gyrus is accelerated
      after transient forebrain ischemia in mice.
AB  - We investigated the proliferation of neuronal progenitor cells by labeling
      dividing cells by systemic application of the thymidine analog 5
      bromodeoxyuridine (BrdU) during transient forebrain ischemia in mice. At 3 (n=6),
      7 (n=6), 10 (n=6), and 17 days (n=6) after reperfusion, BrdU-labeled cells were
      detected in the dentate gyrus and paraventricle lesion. After ischemia
      reperfusion, BrdU-labeled cells in the dentate gyrus significantly increased in
      number but not in the paraventricle lesion. These observations may help to
      clarify the mechanism of functional recovery after stroke.

PMID- 10412008
TI  - Morphological relationship between serotonergic neurons and nitrergic neurons for
      electrolytes secretion in the submucous plexus of the guinea pig distal colon.
AB  - In the submucous plexus, double immunocytochemistry revealed that nitric oxide
      synthase (NOS)-immunoreactivity was found in both numerous nerve fibers and some
      nerve cell bodies, while 5-hydroxytryptamine (5-HT)-immunoreactivity was limited
      to many nerve fibers, but not any nerve cell bodies. About 30% of the total NOS
      positive neurons (978) had close or some contact with 5-HT positive nerve fiber,
      suggesting that NO may participate in the 5-HT-evoked chloride secretion.

PMID- 10412009
TI  - Age-related changes in number of phosphorylated tau-immunopositive particles in
      neurons of facial and lateral cerebellar nuclei of normal and groggy mutant rats.
AB  - The numbers of cytoplasmic particles immunopositive to an anti-phosphorylated tau
      antibody (AT8) were counted in the neurons of facial and lateral cerebellar
      nuclei of Slc:Wistar and groggy mutant rats aged from 20 to 360 days. These
      particles greatly increased in number from 20 to 30 days of age in the Slc:Wistar
      rats, whereas in the groggy rats, they increased at such a slower rate than in
      the Slc:Wistar rats as to reach the peak at 60 days of age. The particles
      decreased to lower levels at 120 days of age in both rat strains, and increased
      again from 180 days of age. The results indicate that the numbers of AT8
      immunopositive particles in neuronal cytoplasm change dynamically according to
      the physiological state associated with the growing and aging processes.

PMID- 10412010
TI  - PhTx4, a new class of toxins from Phoneutria nigriventer spider venom, inhibits
      the glutamate uptake in rat brain synaptosomes.
AB  - We report the characterization of a new class of glutamate uptake inhibitors
      isolated from Phoneutria nigriventer venom. Glutamate transport activity was
      assayed in rat cerebrocortical synaptosomes by using [(3)H]-L-glutamate. PhTx4
      inhibited glutamate uptake in a dose dependent manner. The IC(50) value obtained
      was 2.35+/-0.9 microg/ml which is in the observed range reported for glutamate
      uptake blockers. Tx4-7, one of PhTx4 toxins, showed the strongest inhibitory
      activity (50.3+/-0.69%, n=3).

PMID- 10412011
TI  - Tangled areas of Alzheimer brain have upregulated levels of exon 10 containing
      tau mRNA.
AB  - We measured the relative levels of exon 10 containing and exon 10 deleted tau
      mRNAs in multiple areas of Alzheimer disease (AD) and normal brain. Compared with
      normal brain, we found a 3.4-fold upregulation of exon 10 plus and a 1.9-fold
      downregulation of exon 10 minus mRNAs in areas of AD brain with a heavy burden of
      neurofibrillary tangles. These data suggest that tangle formation in AD is
      initially determined by transcriptional factors and is not exclusively caused by
      post-translational events.

PMID- 10412012
TI  - Evidence for medullary projections of the intercostal nerve-elicited inspiratory
      termination.
AB  - This study hypothesized that the ICN-elicited inspiratory termination reflex
      required synaptic activation in two distinct regions of the ventral respiratory
      group (VRG): (1) transitional (tVRG), and (2) pre-Botzinger complex (pre-BotC).
      Data from adult cats indicate that axons of passage associated with the ICN
      elicited termination reflex traverse tVRG, but that relevant synaptic processing
      does not occur in this region. Furthermore, data indicate that neither synaptic
      nor axonal transmission within the pre-BotC is required for the SLN- or ICN
      elicited termination reflex.

PMID- 10412013
TI  - Golfalpha is expressed in primary sensory neurons outside of the olfactory
      neuroepithelium.
AB  - Golfalpha is the alpha chain of a trimolecular stimulatory G protein originally
      described as the G protein responsible for signal transduction in odourant
      recognition within neurons of the olfactory neuroepithelium. While applying the
      technique of mRNA differential display to herpes simplex virus infected tissue, a
      partial cDNA clone corresponding to the mouse homologue of Golfalpha was isolated
      from sensory dorsal root ganglia. Levels of this transcript were reduced
      following viral infection and this reduction was enhanced in CD8(+) depleted
      mice. The presence of this G protein within sensory ganglia was confirmed with
      Northern blotting and PCR and in situ hybridization studies localised Golfalpha
      expression exclusively to neurons within this tissue.

PMID- 10412014
TI  - The intrastratial injection of an adenosine A(2) receptor antagonist prevents
      frontal cortex EEG abnormalities in a rat model of Huntington's disease.
AB  - The influence of 3,7-dimethyl-1-propargylxanthine (DMPX) an adenosine A(2)
      receptor antagonist, was studied in the quinolinic acid (QA) model of
      Huntington's disease. Male Wistar rats received bilateral intrastriatal
      injections of QA (300 nmol) alone or plus DMPX (0.02, 0.2 and 2 microg). At the
      dose of 0.2 microg, DMPX completely prevented QA-induced EEG abnormalities at the
      level of frontal cortex. The results support the hypothesis of a neuroprotective
      role of adenosine A(2) receptor antagonists.

PMID- 10412015
TI  - Beta(1-40) amyloid peptide injection into the nucleus basalis of rats induces
      microglia reaction and enhances cortical gamma-aminobutyric acid release in vivo.
AB  - The nucleus basalis of adult rats was injected with beta(1-40) amyloid peptide. A
      marked increase in basal and K(+)-evoked GABA release in the ipsilateral cortex
      and a significant decrease in GAD activity in the injected NB were found 30 days
      after injection. An intense activation of microglial cells that surrounded and
      infiltrated the deposit was observed. These data demonstrate that a local
      injection of beta(1-40) peptide into the NB induces glia activation and affects
      GABAergic neurons.

PMID- 10412016
TI  - Septal cholinergic deafferentation of the dentate gyrus results in a loss of a
      subset of neuropeptide Y somata and an increase in synaptic area on remaining
      neuropeptide Y dendrites.
AB  - Removal of cholinergic septal inputs using the immunotoxin 192 IgG-saporin
      reduces the number of interneurons containing neuropeptide Y (NPY)
      immunoreactivity in the rat dentate gyrus by approximately 30% [Milner et al., J.
      Comp. Neurol. 386 (1997) 48-59]. The goal of the present study was to determine
      if NPY-containing neurons that survive deafferentation have any distinguishing
      morphological and/or microenvironmental features. For this, 2 or 24 weeks after
      intracerebroventricular injections of 192 IgG-saporin, NPY-immunolabeled neurons
      in the hilus of the dentate gyrus were examined by electron microscopy. Neither
      the size nor morphological traits of NPY-labeled perikaryal or dendritic profiles
      from lesioned compared to control rats at either time-point differed
      significantly. However, at both time-points, NPY-containing somatal profiles from
      immunolesioned rats compared to controls had a reduced percentage of their
      plasmalemmal surface apposed to unmyelinated axon profiles and an increased
      percentage of their surface occupied by astrocytic profiles. At the 24 week time
      point, these differences were statistically significant. The primary contributing
      factor for these changes was the absence of a subgroup of NPY-labeled somatal
      profiles in lesioned rats compared to controls which was: (a) distinguished by
      frequent appositions of unmyelinated axons (from 15 to 35%) to the plasmalemmal
      surface; and (b) located primarily in the central hilar region. Unlike NPY
      containing somata, changes associated with NPY-labeled dendritic profiles were
      exclusively related to associated presynaptic profiles at the 24 week time-point.
      In lesioned rats compared to controls at this time-point, NPY-containing
      dendritic profiles had a concurrent increase in the percentage of the
      plasmalemmal surface occupied by active zones and the size of terminals
      contacting them. The present results combined with those of our earlier study
      suggest that septal cholinergic deafferentation results in: (a) the loss of a
      distinct subpopulation of hippocampal NPY-containing neurons; and (b) an increase
      in total active zone area suggesting a strengthening of synaptic connections to
      the surviving population of NPY-containing neurons in the long term.

PMID- 10412017
TI  - Functional absence of extraocular photoreception in hamster circadian rhythm
      entrainment.
AB  - The mammalian circadian pacemaker is entrainable by light via the retina. The
      putative role of extraocular light perception was investigated in blinded
      hamsters. These animals were shaved and exposed to a light-emitting pad for
      either 30 min or 3 h. The absence of any phase-shifting effects on wheel running
      activity rhythms indicates that extraocular light perception plays no functional
      role in photic entrainment of the circadian pacemaker in the hamster.

PMID- 10412020
TI  - Regional distribution of cyclooxygenase-2 in the hippocampal formation in
      Alzheimer's disease.
AB  - Cyclooxygenase-2 (COX-2), a key enzyme in prostanoid biosynthesis, may represent
      an important therapeutic target in Alzheimer's disease (AD). In the present
      study, we explored the regulation of COX-2 in the hippocampal formation in
      sporadic AD. Using semiquantitative immunocytochemical techniques, we found that
      in AD cases (vs. age-matched controls) neurons of the CA1-CA4 subdivisions of the
      hippocampal pyramidal layer showed elevation of COX-2 signal; COX-2 levels
      correlated with amyloid plaque density. In contrast, the level of COX-2
      immunostaining in the dentate gyrus granule neurons was not elevated in AD. No
      expression of COX-2 in cells with glial morphology was found in any case
      examined. In parallel, in vitro studies found that neurons derived from
      transgenic mice with neuronal overexpression of COX-2 are more susceptible to
      beta-amyloid (Abeta) toxicity, with potentiation of redox impairment. The results
      indicate elevated expression of neuronal COX-2 in subregions of the hippocampal
      formation in AD and that such elevation may potentiate Abeta-mediated oxidative
      stress.

PMID- 10412021
TI  - Fractionation and enrichment of oligodendrocytes from developing human brain.
AB  - Enriched cultures of human oligodendrocytes were obtained from fetal brain
      specimens between 16 and 21 gestational weeks. Brain cells were separated over a
      Percoll density gradient and collected as two fractions with initial relative
      densities of approximately 1.035 g/ml and 1.102 g/ml, for fractions 1 and 2,
      respectively. After separation, 58.3 and 67.7% of the cells in fractions 1 and 2,
      respectively, were labeled by the antibody O4 that recognizes immature
      oligodendrocytes. A total of 15.5 and 29.4% of the cells in fractions 1 and 2,
      respectively, were positive for tubulin-beta(III), a marker for neurons but none
      of the freshly isolated cells were positive for glial fibrillary acidic protein
      (GFAP), a protein associated with astrocytes in the central nervous system. When
      the fractionated cells were cultured on poly-ornithine coated coverslips for 3
      days and processed for immunocytochemistry, the percentage of O4+
      oligodendrocytes decreased to less than 4% whereas GFAP+ cells increased to 1.8
      and 12.4% for fractions 1 and 2 respectively. The percentage of tubulin-betaIII+
      cells increased to 46 and 61% in cultures from the two Percoll fractions. This
      increase is probably due to the decrease in the number of oligodendrocytes. To
      avoid the loss of oligodendrocytes, cells were cultured as free-floating
      aggregates in the presence of 20 ng/ml of fibroblast growth factor-2 for 2 weeks.
      The resultant cultures became enriched for oligodendrocytes as demonstrated by
      cellular morphology and by positive O4 labeling. The method described here
      provides a means of obtaining enriched cultures of immature human
      oligodendrocytes for developmental and transplantation studies.

PMID- 10412022
TI  - Evidence for caspase-mediated cleavage of AMPA receptor subunits in neuronal
      apoptosis and Alzheimer's disease.
AB  - In Alzheimer's disease (AD) synapses degenerate and neurons die in brain regions
      involved in learning and memory processes. Although the cellular and molecular
      mechanisms underlying the neurodegenerative process in AD are unclear, increasing
      evidence suggests roles for amyloid beta-peptide (Abeta) and biochemical cascades
      associated with a form of programmed cell death called apoptosis. Cysteine
      proteases of the caspase family are activated in neurons undergoing apoptosis and
      apparently play a major role in the cell death process by cleaving yet-to-be
      identified substrates. We now report that caspase activity is increased in brain
      tissue and neurons from AD patients, and in cultured hippocampal neurons
      undergoing apoptosis after exposure to amyloid beta-peptide (Abeta). Western blot
      analyses using antibodies against different subunits of 2-amino-3-hydroxy-5
      methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) types of
      ionotropic glutamate receptors indicate that AMPA receptor subunits (GluR1,
      GluR2/3, and GluR4), but not NMDA receptor subunits (NR1 and NR2A), are
      proteolytically cleaved after exposure of hippocampal neurons to apoptotic
      insults, including Abeta, and that the caspase inhibitor zVAD-fmk suppresses such
      cleavage. Western blot analysis of brain tissue from AD patients and age-matched
      controls revealed evidence for increased proteolysis of AMPA receptor subunits in
      AD. Our data suggest roles for caspase-mediated cleavage of AMPA receptor
      subunits in modifying neuronal responsivity to glutamate and in the
      neurodegenerative process in AD.

PMID- 10412024
TI  - Phosphatidylinositol 3-kinase and Akt protein kinase mediate IGF-I- and
      prosaptide-induced survival in Schwann cells.
AB  - Withdrawal of trophic factors necessary for Schwann cell survival regulates
      Schwann cell number during development and after nerve injury. In the present
      study, we identified signaling pathways involved in Schwann cell survival by
      prosaposin, prosaptides (peptides incorporating the neurotrophic sequence of
      prosaposin), and insulinlike growth factor-I (IGF-I). When postnatal Schwann
      cells were placed in low serum medium, cells underwent abrupt shrinkage,
      condensation of nuclei occurred, and smooth rounded apoptotic bodies appeared.
      Dose-response studies of cell death, measured by lactate dehydrogenase (LDH)
      release, demonstrated that both prosaptide TX14(A) and IGF-I dose dependently
      reduced cell death in primary Schwann cells. Histone-associated DNA fragmentation
      enzyme-linked immunosorbent assay, showed a 10- and 14-fold increase in apoptosis
      after 4 and 24 hr in low serum medium, respectively, that was reduced by
      prosaposin, TX14(A), or IGF-I. Phosphatidylinositol 3-kinase (PI3K) inhibitors,
      wortmannin or LY294002, blocked the survival effects of both TX14(A) and IGF-I.
      In contrast, only TX14(A) anti-apoptotic activity was blocked by the MEK
      inhbitor, PD98059, although TX14(A) and IGF-I are potent activators of
      extracellular regulated kinases in Schwann cells. Phosphorylation of the PI3K
      signaling target, Akt, was measured; TX14(A) and IGF-I increased Akt activity by
      12-fold and 22-fold, respectively, that was inhibited by LY294002. These findings
      indicate that prosaposin and IGF-I use the PI3K/Akt pathway to induce survival of
      Schwann cells.

PMID- 10412023
TI  - GABA induces norepinephrine exocytosis from hippocampal noradrenergic axon
      terminals by a dual mechanism involving different voltage-sensitive calcium
      channels.
AB  - GABA can evoke norepinephrine (NE) release by activating GABAA receptors or GABA
      transporters on noradrenergic terminals. The heterocarrier-induced release occurs
      by conventional exocytosis. We here characterized the mechanism of the GABAA
      receptor-induced release and investigated what type(s) of voltage-sensitive Ca2+
      channels (VSCCs) are involved in the GABA heterocarrier and GABA(A) receptor
      evoked release. The effect of GABA in superfused rat hippocampal synaptosomes
      prelabeled with [(3)H]-NE was partially prevented by bicuculline or the GABA
      uptake inhibitor SKF 89976A and abolished by blocking both GABAA receptors and
      GABA transporters. The release elicited through GABAA receptors was Ca2+
      dependent, prevented by Cd2+ or by botulinum toxin C, and modulated through
      alpha2 autoreceptors. The GABAA receptor-evoked release was insensitive to
      nifedipine and to omega-conotoxin MVIIC, but was inhibited ( approximately 50%)
      by omega-conotoxin GVIA. The heterocarrier-evoked release, nifedipine
      insensitive, was inhibited approximately 30% either by omega-conotoxin GVIA or by
      omega-conotoxin MVIIC; the combined toxins produced approximately 60% inhibition.
      To conclude: a) the releases of NE evoked by activation of GABA(A) receptors and
      GABA heterocarriers are additive, although they both occur by conventional
      exocytosis; b) the heterocarrier-induced release requires activation of N and P/Q
      type channels, whereas the GABAA receptor-induced release only involves channels
      of the N type.

PMID- 10412025
TI  - Synthesis of vesicular GABA from glutamine involves TCA cycle metabolism in
      neocortical neurons.
AB  - In contrast to the classic concept of direct conversion of glutamine to gamma
      aminobutyric acid (GABA; via glutamate), this process may involve alpha
      ketoglutarate as an intermediary metabolite and tricarboxylic acid (TCA) cycle
      activity. To obtain information about a possible differential role of these
      pathways for the synthesis of cytosolic and vesicular GABA, cultured neocortical
      neurons were incubated in medium containing [U-(13)C]glucose (0.5 mM) and in some
      cases unlabeled glutamine (0.5 mM). Subsequently, the cells were "superfused" for
      investigation of the effect of depolarization by 55 mM K+. To make sure that
      depolarization by 55 mM K+ released only vesicular GABA, tiagabin, a
      nontransportable inhibitor of the plasma membrane GABA carriers, was included in
      the medium to prevent GABA release from the cytoplasmic pool by reversal of the
      carriers. The importance of the TCA cycle for conversion of the carbon skeleton
      of glutamine to GABA was evident from the effect of glutamine on the labeling
      pattern of GABA. Percentage of labeling by GABA released into the depolarizing
      medium was the same as that in the corresponding cell extracts and was unaffected
      by the presence of glutamine during incubation. Despite the existence of multiple
      forms of glutamate decarboxylase, compartmentation of glutamate pools, and
      functionally different compartments within neurons, there appears to be full
      equilibration between the vesicular and cytosolic pools of GABA. However, during
      depolarization, the newly synthesized pool of GABA from glutamine does not
      rapidly equilibrate with the vesicular pool.

PMID- 10412026
TI  - Influence of CA2+ on K+ efflux during regulatory volume decrease in cultured
      astrocytes.
AB  - The calcium (Ca2+) dependence of potassium (K+) efflux activated by hyposmolarity
      in cultured cerebellar astrocytes was investigated, measuring in parallel
      experiments (86)Rb release and changes in cytosolic Ca2+ ([Ca2+]i). Hyposmotic
      (50%) medium increased [Ca2+]i from 117 to 386 nM, with contributions of
      extracellular Ca2+ and Ca2+ from the endoplasmic reticulum. Hyposmotic medium
      increased (86)Rb efflux rate from 0.015 min(-1) to a maximal of 0. 049 min(-1)
      and a net release of 30%. This osmosensitive efflux was inhibited by Ba(2+)
      (0.028 min(-1)), quinidine (0.024 min(-1)), and charybdotoxin (0.040 min(-1)),
      but was unaffected by TEA, 4-AP, or apamin. Removal of external Ca2+ from the
      hyposmotic medium increased (86)Rb efflux to a maximal rate constant of 0.056
      min(-1) and a net release of 38% and caused a delay of inactivation. These
      changes were due to the overlaping of an efflux activated by Ca2+ removal in
      isosmotic medium. This isosmotic 86Rb efflux was unaffected by TEA or 4-AP,
      reduced by verapamil, and abolished by Ba2+, nitrendipine, and Mg2+. With the
      swelling-induced [Ca2+]i rise suppressed by ethyleneglycoltetraacetic acid
      acetoxy-methyl ester (EGTA-AM), hyposmotic (86)Rb was 30% reduced. The Ca2+ entry
      blockers Cd2+, Ni2+, La3+, and Gd3+ did not affect (86)Rb efflux. A 40% decrease
      observed with verapamil and nitrendipine was found unrelated to Ca2+, because
      these agents did not affect the [Ca2+]i rise and the inhibition persisted in the
      absence of external Ca2+. The phospholipase C blocker U-73122 did not affect
      [Ca2+]i nor (86)Rb efflux. Blockers of Ca2+/calmodulin W7 and KN-93 decreased
      (86)Rb efflux to the same extent as EGTA-AM. Ionomycin markedly potentiated
      (86)Rb release in hyposmotic conditions only when [Ca2+]i was raised to about 1
      microM, suggesting the implication of maxi-K+ channels at this [Ca2+]i threshold,
      which nonetheless, was not attained during hyposmotic swelling. It is concluded
      that (86)Rb efflux in cerebellar astrocytes is largely (70%) Ca2+-independent and
      the Ca2+-dependent fraction is sustained essentially by Ca2+ released from the
      endoplasmic reticulum and mediated by a mechanism involving Ca2+/calmodulin.

PMID- 10412027
TI  - Cortical NADH during pharmacological manipulations of the respiratory chain and
      spreading depression in vivo.
AB  - The nicotinamide adenine dinucleotide (NADH) is one of the main means for energy
      transfer in the mitochondrial respiratory chain and is an important parameter of
      cellular metabolism. NADH can be measured by its fluorescence and various
      fluorometric methods have been developed. In this study, a pulsed nitrogen laser
      combined with a fibreoptic set-up and photomultipliers was used to induce and
      measure NADH fluorescence on the cortical surface. The aim of the study was to
      assess the suitability of the laser induced spectroscopy for in vivo and on-line
      measurement of NADH in neuroscience and particularly for the assessment of
      neuronal metabolism. Changes in cerebral blood flow may affect fluorescence
      measurement. To assess the consequences of alterations in blood flow, the
      vasodilators glyceryl trinitrate and nimodipine and the vasoconstrictor
      endothelin-1 were applied. The induced hemodynamic changes were verified by
      colour Doppler sonography. The tests using the vasodilators showed that an
      increased blood flow in the brain increased not only NADH fluorescence but also
      the scattered light measured. The vasoconstrictor caused opposite effects.
      Insertion of a compensation method (subtraction of the scattered light) allowed
      the exclusion of hemodynamic artifacts. Effects of changes in the cellular
      metabolism were induced by sodium cyanide, an inhibitor of the mitochondrial
      respiratory chain, or by 2,4-dinitrophenol (2,4-DNP), an uncoupler of the
      oxidative phosphorylation. Sodium cyanide induced a transient increase of NADH
      fluorescence and 2,4-DNP decreased intracellular NADH fluorescence. Furthermore,
      the repercussions of cortical spreading depressions (CSD), a response of the
      brain to noxious stimuli, on cortical NADH fluorescence were determined. A single
      CSD decreased cortical NADH fluorescence for about 1 min, followed by a 5- to 10
      min increase. The changes in NADH levels seem to correspond with the excitation
      and inhibition of neuronal metabolism, respectively. In summary, the measurement
      of NADH fluorescence using the laser technique allows the determination of
      changes in oxidative phosphorylation with high regional selectivity and time
      resolution.

PMID- 10412028
TI  - GT3 and its O-acetylated derivative are the principal A2B5-reactive gangliosides
      in cultured O2A lineage cells and are down-regulated along with O-acetyl GD3
      during differentiation to oligodendrocytes.
AB  - Among the developmentally regulated antigens expressed on the surface of
      bipotential glial precursors isolated from neonatal rat brain are the
      gangliosides recognized by the monoclonal antibody A2B5. Immunostaining of thin
      layer chromatograms showed that oligodendrocyte-type 2 astrocyte (O2A)
      progenitors in culture express two ganglioside antigens that react strongly with
      the A2B5 antibody. Both ganglioside antigens are down-regulated as the cells
      differentiate to oligodendrocytes, corresponding to the disappearance of cell
      surface immunostaining by A2B5 in mature oligodendrocytes. By contrast, both
      gangliosides continue to be expressed when the cells differentiate to type-2
      astrocytes. These two A2B5-reactive gangliosides in O2A lineage cells were
      identified as GT3 and O-acetyl GT3 by using the monoclonal antibody 18B8 that
      recognizes GT3 and an influenza C virus esterase that specifically removes O
      acetyl moieties from sialic acids. Thin-layer chromatographic immunostaining with
      the JONES monoclonal antibody demonstrated that the progenitor cells in culture
      also express O-acetyl GD3, which is similarly down-regulated in oligodendrocytes,
      but retained in type-2 astrocytes. The 18B8 and JONES antibodies also
      immunostained the surface of O2A progenitors. Therefore, expression of GT3 and O
      acetylation of GT3 and GD3 occur during the proliferative and migratory stages of
      glial cell development. Published 1999 Wiley-Liss, Inc.

PMID- 10412029
TI  - Nerve growth factor increases the synthesis and release of acetylcholine and the
      expression of vesicular acetylcholine transporter in primary cultured rat
      embryonic septal cells.
AB  - Acetylcholine (ACh) is synthesized by choline acetyltransferase (ChAT) in the
      cytoplasm of cholinergic nerve terminals and transported into synaptic vesicles
      by vesicular ACh transporter (VAChT). The genes encoding ChAT and VAChT are
      colocalized within the genome, and their products are known to be coregulated by
      various neurotrophic factors. In the present study, nerve growth factor (NGF; 100
      ng/ml) was shown to enhance expression of VAChT and ChAT mRNA in primary cultured
      rat embryonic septal cells. By using a radioimmunoassay, we also found that NGF
      increased both neuronal content and spontaneous release of ACh, which were first
      detected on day 2 of culture and time-dependently increased up to day 10.
      Stimulated release of ACh elicited by high K+ (50 mM KCl) was also significantly
      greater in NGF-treated cells than in control cells. NGF enhanced immunoreactivity
      to antiserum against VAChT, indicating that the augmented responses were due to,
      at least in part, increased expression of VAChT protein. In contrast, the numbers
      of immunocytochemically positive cells were unaffected. Thus, NGF appears to
      augment ACh synthesis, its transport into synaptic vesicles, and its subsequent
      release. The data also suggest that NGF facilitates growth and development of
      cholinergic neurons, but not their survival.

PMID- 10412030
TI  - Interleukin-1beta, inducible nitric oxide synthase, and nuclear factor-kappaB are
      induced in morphologically distinct microglia after rat hippocampal
      lipopolysaccharide/interferon-gamma injection.
AB  - In a number of pathological states of the brain, the activation of the inducible
      nitric oxide synthase (iNOS) plays a major role. Interleukin (IL)-1beta is
      believed to be an essential factor in the induction of iNOS. However, little is
      known about the cascade of events culminating in iNOS expression in vivo. To
      identify the morphological as well as temporal relationship of lipopolysaccharide
      (LPS)/interferon-gamma (IFN-gamma) -induced microglial iNOS- and IL-1beta
      expression, a mixture of LPS and IFN-gamma was injected into the rat hippocampus.
      IL-1beta immunoreactivity was detected as early as 3 hr following surgery in
      ramified microglia in the lesioned hippocampus and in distal cortical layers
      adjacent to the pia mater. By 12 hr post-injection, IL-1beta immunoreactive,
      ramified microglia with swollen processes were widely distributed throughout
      hippocampal and neocortical areas, and staining was observed up to 48 hr after
      treatment. In contrast, iNOS immunostaining was seen in activated amoeboid
      microglia/macrophages in the ipsilateral hippocampus and around blood vessels but
      not earlier than 12 hr post-surgery. The temporal pattern of iNOS and IL-1beta
      expression corresponded to newly induced transcriptional activity as revealed by
      RT-PCR. Activation of NF-kappaB was restricted to brain regions in which IL-1beta
      was expressed and was detected both in microglia and astrocytes. A number of
      LPS/IFN-gamma-stimulated, IL-1beta-expressing microglia exhibited co-staining for
      activated NF-kappaB. The finding that IL-1beta precedes iNOS expression is
      consistant with a role of IL-1beta in the intercellular signaling events leading
      to microglial iNOS-induction. Co-localization of IL-1beta and NF-kappaB suggests
      an association between IL-1beta and NF-kappaB induction.

PMID- 10412031
TI  - Phytoestrogen kaempferol (3,4',5,7-tetrahydroxyflavone) protects PC12 and T47D
      cells from beta-amyloid-induced toxicity.
AB  - In clinical studies, it has been shown that estrogen replacement therapy in
      menopause is strongly correlated with a reduced risk of the development of
      Alzheimer's disease (AD). In in vitro experiments, it was demonstrated that
      estradiol protects cells against the toxic effects of beta-amyloid, the major
      component of plaques in brains of AD patients. Therefore, estrogens have become
      interesting candidates for a possible treatment of neurodegeneration. In plants,
      a class of compounds has been identified that bind to human estrogen receptor, so
      called phytoestrogens, which are part of our daily diet. Here, we compared the
      effects of alpha- and beta-estradiol with plant-derived kaempferol on beta
      amyloid peptide-induced toxicity in PC12 neuroblastoma and T47D human breast
      cancer cells. The present results demonstrate a protective effect of kaempferol
      comparable to that observed with estradiol. The effects of the weak estrogen
      receptor agonists alpha-estradiol and kaempferol were found to be similar to the
      effects of the strong estrogen receptor agonist beta-estradiol, suggesting a mode
      of action independent from the nuclear estrogen receptor.

PMID- 10412033
TI  - Inducible nitric oxide synthase expression in cultures enriched for mature
      oligodendrocytes is due to microglia 
AB  - Hewett JA, Hewett SJ, Winkler S, Pfeiffer SE. 1999. Inducible nitric oxide
      synthase expression in cultures enriched for mature oligodendrocytes is due to
      microglia. J Neurosci Res 56:189-198. In the article referenced above, the LPS
      concentration employed in all studies was 1 &mgr;g/ml, not 1 mg/ml as published.
      This correction appears: in the Materials and Methods section on page 190, column
      1, line 47; in the Results section on page 191, column 2, legend to Figure 1,
      line 3; on page 192, column 2, legend to Figure 2, line 3; on page 194, column 2,
      legend to Figure 5, line 4; on page 195, column 1, legend to Figure 6, line 3;
      and in the Discussion section on page 196, column 1, line 9. The publisher
      regrets this error.

PMID- 10412032
TI  - Role of zinc released by stimulation in rat amygdala.
AB  - The movement and role of actively functioning zinc, i.e., vesicular zinc, in the
      amygdala was studied, based on the data that 65Zn is localized in the limbic
      system, which may correspond to the regions with high densities of zinc
      containing neuron terminals. When release of 65Zn into the extracellular space
      was examined 2 hr or 25 hr after injection of 65ZnCl2 into the amygdala, 65Zn
      release was facilitated by stimulation with high K+ 2 hr after injection, but not
      25 hr after injection. Even 25 hr after 65Zn injection into the amygdala,
      approximately 95% of total 65Zn in the brain was detected in the injected area.
      These results suggest that zinc released into the extracellular space in the
      amygdala is not readily restored to the presynaptic vesicles. Moreover, to
      chelate zinc in the extracellular space (and in the synaptic vesicles) in the
      amygdala, the amygdalae were perfused with 10 microM diethyldithiocarbamate
      during behavioral tests for odor recognition. The olfactory sensation was
      temporarily disturbed by the perfusion. These results suggest that vesicular zinc
      is essential to the function of the amygdala, e.g., olfactory function.

PMID- 10412034
TI  - Induction of apoptosis and differentiation in neuroblastoma and astrocytoma cells
      by the overexpression of Bin1, a novel Myc interacting protein.
AB  - Bin1 is a novel protein that specifically binds Myc and inhibits, at least in
      part, Myc transactivation. Bin1 seems to play a role in cell cycle control,
      acting as a tumor suppressor gene. Since MYC family genes play a regulatory role
      in the proliferation, differentiation, and apoptosis of the nervous system, we
      studied the effects of the overexpression of the Myc-interacting protein, Bin1,
      in neuroblastoma and astrocytoma cell lines, which were chosen as neural cell
      system models. The major effects of BIN1 overexpression observed in
      undifferentiated neuroblastoma and astrocytoma cells were a significant reduction
      of cell growth, an increase in the G(0)/G(1) cell population and the induction of
      apoptosis. The trigger of programmed cell death by Bin1 is described for the
      first time. Bin1 overexpression in undifferentiated cells did not induce any
      maturation process as neither neuronal nor astrocyte differentiation markers were
      upregulated in neuroblastoma and astrocytoma cells, respectively. On the other
      side, the effects of Bin1 overproduction in neuroblastoma and astrocytoma cells
      committed towards neuronal and astrocyte differentiation, respectively, were
      different from those observed in undifferentiated cells. Although we did not
      evidence any triggering of programmed cell death, we did notice a further
      induction towards more differentiated phenotypes. Our studies suggest that Bin1
      overexpression in neuroblastoma and astrocytoma cells can result in one of the
      following pathways: (1) suppressed cell proliferation, (2) induced
      differentiation, or (3) apoptosis. Thus, it appears that Bin1 operates through
      different pathways that involve activation of different genes: the chosen pathway
      however will depend on the proliferating or differentiated state of the cell.

PMID- 10412035
TI  - Three-dimensional model of the ligand binding domain of the nuclear receptor for
      1alpha,25-dihydroxy-vitamin D(3).
AB  - A three-dimensional model for residues 142-427 of the ligand binding domain (LBD)
      of the human nuclear receptor for 1alpha, 25-dihydroxy-vitamin D(3) [VDR] has
      been generated based on the X-ray crystallographic atomic coordinates of the LBD
      of the rat alpha1 thyroid receptor (TR). The VDR LBD model is an elongated
      globular shape comprised of an antiparallel alpha-helical triple sandwich
      topology, made up of 12 alpha-helical elements linked by short loop structures;
      collectively these structural features are similar to the characteristic
      secondary and tertiary structures for six nuclear receptors with known X-ray
      structures. The model has been used to describe the interaction of the
      conformationally flexible natural hormone, 1alpha,25-dihydroxy-vitamin D(3)
      [1alpha, 25(OH)(2)D(3)], and a number of related analogs with the VDR LBD. The
      optimal orientation of the 1alpha,25(OH)(2)D(3) in the LBD is with its A-ring
      directed towards the interior and its flexible side chain pointing towards and
      interacting with helix-12, site of the activation function-2 domain (AF-2) of the
      VDR. Mapping of four natural and one experimental point mutations of the VDR LBD,
      which result in ligand-related receptor dysfunction, indicates the close
      proximity of these amino acids to the bound ligand.

PMID- 10412036
TI  - Self-association of Puralpha is mediated by RNA.
AB  - The 322 amino acid cellular protein, Puralpha, is a sequence-specific single
      stranded DNA-binding protein implicated in control of transcription and
      replication. Previous studies have demonstrated that the interaction between
      Puralpha and its target DNA sequence results in the formation of multimeric
      complexes. In this study, we demonstrate that Puralpha can self-associate in the
      absence of DNA. This self-association, while independent of DNA, is mediated by
      RNA. Through in vitro studies with bacterially expressed glutathione S
      transferase fusion proteins, and the synthetic peptides corresponding to various
      central regions of Puralpha, the domain which is important for the self
      association of Puralpha is localized to acidic leucine-rich repeats.
      Interestingly, these repeats have previously been shown to interact with the
      human immunodeficiency virus 1 (HIV-1) Tat protein and in this study we
      demonstrate that Tat is able to disrupt the self- association of Puralpha. We
      have recently cloned a Puralpha associated-RNA, PU-RNA, and here we show that PU
      RNA can specifically reconstitute the self-association of Puralpha. RNA not only
      mediates the self-association of Puralpha, but also modulates the ability of
      Puralpha to interact with its target DNA sequence. Electrophoretic mobility shift
      assays performed with and without RNase treatment demonstrate that RNA inhibits
      the interaction between Puralpha and its target DNA sequence. Moreover, we
      demonstrate that the self-association of Puralpha can be reconstituted by a
      specific oligonucleotide encompassing the Puralpha binding site. The implications
      of these findings with respect to Puralpha's role in transcription and
      replication are discussed.

PMID- 10412037
TI  - Regulation of cell-cell communication in rat bone cells: the effect of phorbol
      esters.
AB  - The skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent
      inhibitor of gap junctional intercellular communication. In the present study,
      the inhibition of cell-cell communication by TPA has been investigated in primary
      bone cells from newborn rat calvaria, with an emphasis on the involvement of
      intracellular pH (pH(i)) and cytosolic calcium ([Ca(+2)](i)) in this process. The
      results show that TPA (5 x 10(-)(8) M) caused a complete inhibition of
      intercellular communication within 40-60 min. The intercellular communication was
      fully restored after overnight incubation in the presence of TPA. This effect was
      found to be associated with an elevation of pH(i). However, neither an increase
      of pH(i) alone nor exposure to TPA, under conditions preventing pH(i)-shift, were
      found to affect intercellular communication. It is suggested that the inhibition
      of intercellular communication, in the presence of TPA, depends on the pH(i)
      shift itself rather than on the absolute value of pH(i). In addition, elevation
      of cytosolic calcium by ionomycin led to the termination of intercellular
      communication after 30 min. This inhibitory effect was abolished when the cells
      were incubated for overnight with TPA and then intracellular calcium was elevated
      by the addition of ionomycin. These results indicate that shift of pH(i) and the
      increase of intracellular calcium are involved in repression of intercellular
      communication by TPA.

PMID- 10412038
TI  - Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by
      PPARgamma2.
AB  - Cells of the bone marrow stroma can reversibly convert among different
      phenotypes. Based on this and on evidence for a reciprocal relationship between
      osteoblastogenesis and adipogenesis, we have isolated several murine bone marrow
      derived clonal cell lines with phenotypic characteristics of osteoblasts or
      adipocytes, or both. Consistent with a state of plasticity, cell lines with a
      mixed phenotype synthesized osteoblast markers like type I collagen, alkaline
      phosphatase, osteocalcin, as well as the adipocyte marker lipoprotein lipase,
      under basal conditions. In the presence of ascorbic acid and beta
      glycerophosphate-agents that promote osteoblast differentiation-they formed a
      mineralized matrix. In the presence of isobutylmethylxanthine, hydrocortisone,
      and indomethacin-agents that promote adipocyte differentiation-they accumulated
      fat droplets, but failed to express adipsin and aP2, markers of terminally
      differentiated adipocytes. Furthermore, they were converted back to matrix
      mineralizing cells when the adipogenic stimuli were replaced with the
      osteoblastogenic ones. A prototypic cell line with mixed phenotype (UAMS-33)
      expressed Osf2/Cbfa1-a transcription factor required for osteoblast
      differentiation, but not PPARgamma2-a transcription factor required for terminal
      adipocyte differentiation. Stable transfection with a PPARgamma2 expression
      construct and activation with the thiazolidinedione BRL49653 stimulated aP2 and
      adipsin synthesis and fat accumulation, and simultaneously suppressed Osf2/Cbfa1,
      alpha1(I) procollagen, and osteocalcin synthesis. Moreover, it rendered the cells
      incapable of forming a mineralized matrix. These results strongly suggest that
      PPARgamma2 negatively regulates stromal cell plasticity by suppressing Osf2/Cbfa1
      and osteoblast-like biosynthetic activity, while promoting terminal
      differentiation to adipocytes.

PMID- 10412039
TI  - Effects of interferon alpha on human osteoprogenitor cell growth and
      differentiation in vitro.
AB  - The specific effects of interferon alpha (IFNalpha), on the differentiation
      pathways of human osteogenic cells are not known. The aim of this study was to
      investigate possible effects of IFNalpha on osteogenic development by
      investigating cell differentiation, colony formation (colony forming unit
      fibroblastic, CFU-F), cell proliferation, and gene expression, in particular bone
      morphogenetic protein (BMP) expression, of human bone marrow osteoprogenitor
      cells. Human bone marrow fibroblasts were cultured with or without the addition
      of IFNalpha (5-1,000 IU/ml) in the presence and absence of dexamethasone (10 nM)
      and ascorbate (100 microM), which are agents known to affect osteogenic
      differentiation. IFNalpha produced a significant dose-dependent inhibition of
      cell proliferation and alkaline phosphatase specific activity at concentrations
      as low as 50 IU/ml. IFNalpha (50-1,000 IU/ml) inhibited the stimulation of
      alkaline phosphatase specific activity induced by ascorbate and dexamethasone.
      Examination of CFU-F showed dose- and time-dependent inhibitions of colony
      formation and reductions in both colony size and alkaline phosphatase-positive
      CFU-F colonies particularly at earlier times. Reactivity with an antibody
      specific for osteoprogenitors (HOP-26), was reduced in IFNalpha-treated cultures.
      Northern blot analysis showed a significant dose-dependent up-regulation of BMP-2
      mRNA, estrogen receptor alpha mRNA and osteocalcin mRNA expression in
      ascorbate/dexamethasone cultures. In contrast, IFNalpha significantly inhibited
      BMP-2 mRNA expression in the absence of ascorbate and dexamethasone. In
      conclusion, IFNalpha inhibits human osteoprogenitor cell proliferation, CFU- F
      formation, HOP-26 expression, and alkaline phosphatase specific activity and
      modulates BMP-2 gene expression. These results suggest a role for IFNalpha in
      local bone turnover through the specific and direct modulation of osteoprogenitor
      proliferation and differentiation.

PMID- 10412040
TI  - Inhibitory effect of uremic solutions on protein-DNA-complex formation of the
      vitamin D receptor and other members of the nuclear receptor superfamily.
AB  - Chronic renal failure is often associated with a resistance to the biologically
      active form of vitamin D(3), the nuclear hormone 1alpha, 25-dihydroxyvitamin D(3)
      (VD). The actions of VD are mediated by the vitamin D receptor (VDR), a ligand
      dependent transcription factor that binds as a dimeric complex with the retinoid
      X receptor (RXR) to specific DNA binding sites in the promoter regions of primary
      VD responding genes, referred to as VD response elements (VDREs). It could be
      shown in this study that uremic solutions derived from ultrafiltrate from
      hemodialysis patients and dialysate from peritoneal dialysis patients had an
      inhibitory effect on the complex formation and ligand inducibility of VDR-RXR
      heterodimers on different VDRE types. This inhibition was attributed to the
      formation of Schiff bases between "reactive aldehydes" and lysine residues of the
      DNA binding domain (DBD) of the VDR, but point mutagenesis data of different
      lysine residues in this study could not confirm this idea. However, the
      inhibitory effect of uremic solutions could also be observed for the complex
      formation of other homo- or heterodimer forming nuclear receptors, whereas an as
      a monomer binding nuclear receptor did not appear to be affected. These results
      indicate that VDR is a target of substances in uremic solutions in vitro, but
      also to some extent other nuclear receptors (i.e., other endocrine signaling
      systems) may be affected by renal failure.

PMID- 10412041
TI  - Cloning and characterization of the prostate-specific membrane antigen promoter.
AB  - Prostate-specific membrane antigen (PSMA) is a protein that is expressed
      predominantly in normal prostate epithelial cells and in most adenocarcinomas of
      the prostate (Cap) and in virtually all Cap metastases. In this article we
      describe the cloning of a 2-kb human genomic DNA fragment containing the 5'
      upstream untranslated region of the PSMA gene and present evidence that it
      provides promoter activity. When the DNA fragment was cloned into transient
      expression vectors to examine promoter activity, the vectors were functional in
      promoting expression in several prostate and nonprostate cell lines in transient
      transfection assays. A 614-bp fragment derived from the 3' end of the 2-kb
      fragment may represent the minimal PSMA promoter as determined by deletion
      mutagenesis. The 2-kb fragment compared with the 614-bp fragment provided higher
      expression levels when using prostate-derived cell lines (DU 145 and LNCaP). The
      increased transcription using the 2-kb fragment was not as great in non-prostate
      cell lines. Little or no transcription over basal levels was seen with a 232-bp
      promoter fragment. When the concentration of dihydrotestosterone was depleted or
      supplemented in the growth medium, no significant effect was seen on PSMA
      promoted transient expression in LNCaP cells, a prostate cell line. J. Cell.
      Biochem. 74:395-405, 1999. Published 1999 Wiley-Liss, Inc.

PMID- 10412042
TI  - Differential expression of PSP94 in rat prostate lobes as demonstrated by an
      antibody against recombinant GST-PSP94.
AB  - Prostate secretory protein (PSP94, 94 amino acids) is one of the most abundant
      proteins secreted from the prostate. Its biological role is unknown and still
      controversial, although it is assumed to have the potential to be a biomarker and
      a suppressor of prostate cancer. In order to establish an animal model to further
      elucidate its biological role, we expressed the mature form of rat PSP94 in
      Escherichia coli, using a glutathione S-transferase (GST) fusion expression
      vector; we generated a polyclonal rabbit antibody against the recombinant
      protein. The antibody specifically recognized recombinant rat PSP94 and cross
      reacted only very weakly with its human homologue. Using the characterized anti
      rat PSP94 antibody, we found that PSP94 was located primarily in rat prostate.
      Furthermore, PSP94 is present at different levels in different lobes of rat
      prostate, with significant levels detectable only in the lateral lobe (LP). In
      addition, the most abundant PSP94 expression was found in the prostate lobe
      secretions, and PSP94 levels in LP secretions were at least seven times higher
      than in secretions from the dorsal prostate (DP). The rat ventral prostate (VP)
      and other regions of the male accessory glands were found to be almost completely
      devoid of PSP94. Since most rat prostate dysplasia induced by steroid hormone
      treatment occurs only in dorsolateral prostate, prostate tissue-specific
      expression and the expression of PSP94 in dorsolateral, but not other, lobes of
      the prostate suggest a potential role in prostate targeting and prostate cancer
      development.

PMID- 10412043
TI  - Multiple glucocorticoid receptor transcripts in membrane glucocorticoid receptor
      enriched S-49 mouse lymphoma cells.
AB  - A cDNA library from plasma membrane glucocorticoid receptor-enriched (mGR(++)) S-
      49 mouse T lymphoma cells was screened with full-length rat intracellular GR
      (iGR) cDNA, BUGR-2 antibody, and PCR amplimers to portions of the mouse GR cDNA.
      One or two single-base substitutions resulting in amino acid changes (which do
      not incapacitate the receptor) were found in all but one clone: Val437 --> Gly
      (located in the first zinc finger), and Glu546 --> Gly (in the steroid-binding
      domain). Two previously unidentified exon 1 variants (1D and 1E), and two of
      three previously reported variants (1A, 1B) were found to be spliced onto the
      common exon 2. Exon 1D- and 1E-containing transcripts were confirmed by direct
      sequencing of amplimers from reverse transcriptase-coupled PCR. RNase protection
      studies revealed that one of these transcripts was expressed in mGR(++) cells
      only, but not in two mGR-less (mGR(--) S-49, and AtT-20 mouse pituitary) cell
      lines. These studies suggest that at least four promoters may be responsible for
      the control of GR (iGR and mGR) types in mouse lymphoma cells.

PMID- 10412044
TI  - Association of the glucocorticoid receptor alternatively-spliced transcript 1A
      with the presence of the high molecular weight membrane glucocorticoid receptor
      in mouse lymphoma cells.
AB  - Using the combination of a cDNA library prepared from membrane glucocorticoid
      (mGR)-enriched S-49 cells and a mouse leukocyte genomic library, we have cloned a
      7.3 kb full-length glucocorticoid receptor 1A cDNA. Primer extension, 5'RACE, and
      long distance PCR identified the transcription start site as being located at
      1026 bp from the ATG codon. The first 1,013 nucleotides (nts) of the full length
      sequence constitute 5' UTR sequence (exon 1), the next 2349 bp, the coding
      region, and the last 3,907 bp, the 3'UTR. The entire 5'UTR sequence is unique to
      transcript 1A. The 3'UTR sequence is approximately 88.5 % conserved with the rat
      3'UTR. Western blot analysis compared the molecular weight of in vitro
      translation products from the cloned 1A cDNA with partially purified cellular
      mGR. Both preparations contained the novel 150 KD and the 94 KD classical GR
      peptides, suggesting that transcript 1A encodes both receptor forms. Transfection
      of mGR-less and glucocorticoid lysis-resistant AtT-20 and HL-60 cells with full
      length GR 1A cDNA imparted both mGR expression and glucocorticoid lysis
      sensitivity to these cells.

PMID- 10412046
TI  - Only a small portion of the cytoplasmic progesterone receptor is associated with
      Hsp90 in vivo.
AB  - In cell extracts all of the nonliganded steroid receptor molecules are found as
      an oligomeric complex with Hsp90 and other proteins. In previous studies we have
      shown that Wild-type Hsp90 and progesterone receptor (PR) are located in
      different cell compartments (Tuohimaa et al. [1993] Proc. Natl. Acad. Sci. USA
      90:5848-5852). In the present work we studied whether PR and Hsp90 can
      efficiently associate provided they are present in the same cell compartment. The
      association of Hsp90 with PR in vivo was studied by nuclear cotranslocation and
      immunohistochemistry with an antibody (alphaD) which can distinguish between the
      oligomeric and dissociated form. Upon expression of a cytoplasmic mutant of PR
      with Wild-type (cytoplasmic) Hsp90 and Wild-type (nuclear) PR with NLS-Hsp90 (a
      Hsp90 with a nuclear localization signal), we noted that the epitope of alphaD in
      PR was exposed in both cases. Also, in vivo crosslinking and treatment of cells
      with substances which stabilize the oligomeric complex in vitro were inefficient
      in demonstrating or inducing a similar oligomeric receptor form detectable in
      vitro in cell homogenates. However, when the cytoplasmic PR mutant (DeltaPR) was
      coexpressed with a nuclear form of Hsp90 (NLS-Hsp90), a portion of PR was
      cotranslocated into the nucleus. This would indicate that steroid receptors are
      indeed associated with Hsp90 in intact cells, but the Hsp90-associated receptor
      pool represents only a small portion of the receptors. This suggests that the
      majority of oligomeric complexes seen in cell extracts are formed during cell
      fractionation.

PMID- 10412045
TI  - Detection of dendritic cells in the non-obese diabetic (NOD) mouse islet pancreas
      infiltrate is correlated with Th2-cytokine production.
AB  - We investigate the role played by dendritic cells (DCs) in the non-obese diabetic
      (NOD) mouse pancreas. The early peri-islet, nondestructive infiltration phase,
      and intra-islet, destructive infiltration phase, which immediately precedes overt
      diabetes, are studied. Results show that infiltrating cells are Ia-b, ICAM-1,
      and, mainly, MIDC-8 immunoreactive (ir). These data from silica-treated animals
      and ultrastructural observations strongly support the hypothesis that DCs are
      both Ia-b-ir and ICAM-1-ir and that they exert a pivotal role during the period
      of early infiltration. This is a novel finding for NOD mice and increases the
      interest for this protective cell type during the rather complex islet
      infiltration process. Moreover, the cytokine profile demonstrates that Th2
      protective cytokines are specific for peri-islet infiltrate. Disappearance of DCs
      from the infiltrate is concomitant with both the formation of intra-islet
      infiltration and the increase in proinflammatory Th1 cytokine levels. This
      further supports the hypothesis that DCs may exert a protective role against
      diabetes development.

PMID- 10412047
TI  - In vivo and in vitro iron deficiency reduces protein kinase C activity and
      translocation in murine splenic and purified T cells.
AB  - We investigated the effects of iron deficiency anemia, iron repletion, and iron
      chelation by deferoxamine on protein kinase C (PKC) activity, an enzyme that
      plays a crucial role on T lymphocyte proliferation. The study involved 23 control
      (C), 18 pairfed (PF), and 24 iron deficient (ID) mice or ID mice that were
      repleted for 3 (n = 14), 7 (n = 17), or 14 (n = 14) days. The low iron (0.09 mmol
      iron/kg) and iron-supplemented (0.9 mmol iron/kg) diets were fed to mice for 53
      days. Mean hemoglobin, hematocrit, and liver iron stores of ID mice were one
      third of those of C mice. Lymphocyte proliferation was reduced (P < 0.05) in
      spleen and purified T cells in ID but not PF mice. In concanavalin A,
      phytohemagglutinin, and anti-CD3 antibody-treated and untreated cells that were
      incubated in serum-free and serum-containing medium, PKC activity was
      significantly (P < 0.05) reduced in ID but not PF mice and returned to normal
      before correction of anemia. In mitogen-treated cells, while the ratios of
      membrane-bound to cytosol activity increased nearly seven-fold (from 0.4-0.63 in
      resting cells to 1.43-7.23) in spleen cells from C, PF, and repleted mice and 11
      fold in T cells (P < 0.005), they remained below 1 in ID mice suggesting reduced
      translocation. In vitro iron chelation by deferoxamine for 120 min prior to cell
      activation reduced (P < 0.05) PKC activity by 46-60% in C and PF and 28-53% in ID
      mice. The data suggest that: 1) it is iron-deficiency but not anemia or
      differences in the proportion of immunocompetent T cells that reduced PKC
      activity in cells from ID mice; 2) reduced PKC translocation may play an
      important role on altered lymphocyte proliferation and associated functions in
      iron-deficient individuals.

PMID- 10412048
TI  - Involvement of p38 mitogen-activated protein kinase in basic fibroblast growth
      factor-induced interleukin-6 synthesis in osteoblasts.
AB  - We previously showed that basic fibroblast growth factor (bFGF)-induced
      activation of protein kinase C (PKC) via phosphatidylinositol-hydrolyzing
      phospholipase C and phosphatidylcholine-hydrolyzing phospholipase D suppresses
      interleukin-6 (IL-6) synthesis by bFGF itself in osteoblast-like MC3T3-E1 cells.
      In the present study, we further investigated the mechanism underlying the bFGF
      induced IL-6 synthesis in MC3T3-E1 cells. bFGF time-dependently induced the
      phosphorylation of p38 mitogen-activated protein (MAP) kinase. SB203580, a
      specific inhibitor of p38 MAP kinase, suppressed the bFGF-induced IL-6 synthesis
      dose-dependently. The phosphorylation of p38 MAP kinase by bFGF was suppressed by
      TMB-8, an inhibitor of intracellular Ca(2+) mobilization, or the depletion of
      extracellular Ca(2+) with EGTA. A23187, a Ca-ionophore, stimulated the
      phosphorylation of p38 MAP kinase. SB203580 inhibited the A23187-induced
      synthesis of IL-6. 1-Oleoyl-2-acetyl-sn-glycerol, a synthetic diacylglycerol
      activating PKC, reduced the bFGF-induced IL-6 synthesis. 12-O
      Tetradecanoylphorbol-13-acetate, an activator of PKC, attenuated the
      phosphorylation of p38 MAP kinase by bFGF, but did not affect the A23187-induced
      phosphorylation. These results strongly suggest that bFGF-induced IL-6 synthesis
      is mediated via p38 MAP kinase activation in osteoblasts, and that PKC acts at a
      point upstream from p38 MAP kinase.

PMID- 10412050
TI  - A hard sell for stem cells.

PMID- 10412051
TI  - Making holes in the visual world.

PMID- 10412049
TI  - Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human
      breast carcinoma cells.
AB  - Lactoferrin inhibits cell proliferation and suppresses tumor growth in vivo.
      However, the molecular mechanisms underlying these effects remain unknown. In
      this in vitro study, we demonstrate that treatment of breast carcinoma cells MDA
      MB-231 with human lactoferrin induces growth arrest at the G1 to S transition of
      the cell cycle. This G1 arrest is associated with a dramatic decrease in the
      protein levels of Cdk2 and cyclin E correlated with an inhibition of the Cdk2
      kinase activity. Cdk4 activity is also significantly decreased in the treated
      cells and is accompanied by an increased expression of the Cdk inhibitor
      p21(CIP1). Furthermore, we show that lactoferrin maintains the cell cycle
      progression regulator retinoblastoma protein pRb in a hypophosphorylated form.
      Additional experiments with synchronized cells by serum depletion confirm the
      anti-proliferative activity of human lactoferrin. These effects of lactoferrin
      occur through a p53-independent mechanism both in MDA-MB-231 cells and other
      epithelial cell lines such as HBL-100, MCF-7, and HT-29. These findings
      demonstrate that lactoferrin induces growth arrest by modulating the expression
      and the activity of key G1 regulatory proteins.

PMID- 10412052
TI  - Digging for gold in the human genome.

PMID- 10412053
TI  - Pointing the way toward target selection.

PMID- 10412055
TI  - Signaling myopia.

PMID- 10412054
TI  - Sorting the wheat from the chaff in visual perception.

PMID- 10412056
TI  - P is for phenomenology 

PMID- 10412057
TI  - Amyloid production and deposition in mutant amyloid precursor protein and
      presenilin-1 yeast artificial chromosome transgenic mice.

PMID- 10412059
TI  - Light- and focus-dependent expression of the transcription factor ZENK in the
      chick retina.
AB  - Ocular growth and refraction are regulated by visual processing in the retina. We
      identified candidate regulatory neurons by immunocytochemistry for immediate
      early gene products, ZENK (zif268, Egr-1) and Fos, after appropriate visual
      stimulation. ZENK synthesis was enhanced by conditions that suppress ocular
      elongation (plus defocus, termination of form deprivation) and suppressed by
      conditions that enhance ocular elongation (minus defocus, form deprivation),
      particularly in glucagon-containing amacrine cells. Fos synthesis was enhanced by
      termination of visual deprivation, but not by defocus and not in glucagon
      containing amacrine cells. We conclude that glucagon-containing amacrine cells
      respond differentially to the sign of defocus and may mediate lens-induced
      changes in ocular growth and refraction.

PMID- 10412058
TI  - The p75 neurotrophin receptor influences NT-3 responsiveness of sympathetic
      neurons in vivo.
AB  - To determine the role of the p75 neurotrophin receptor (p75NTR) in sympathetic
      neuron development, we crossed transgenic mice with mutations in p75NTR, nerve
      growth factor (NGF) and neurotrophin-3 (NT-3). Neuron number is normal in
      sympathetic ganglia of adult p75NTR-/- mice. Mice heterozygous for a NGF deletion
      (NGF+/-) have 50% fewer sympathetic neurons. In the absence of p75NTR (p75NTR-/-
      NGF+/-), however, neuron number is restored to wild-type levels. When NT-3 levels
      are reduced (p75NTR-/- NGF+/- NT3 +/-), neuron number decreases compared to
      p75NTR-/- NGF+/- NT3+/+. Thus, without p75NTR, NT3 substitutes for NGF,
      suggesting that p75 alters the neurotrophin specificity of TrkA in vivo.

PMID- 10412060
TI  - A sugar transporter as a candidate for the outer hair cell motor.
AB  - Forces developed by cochlear outer hair cells (OHCs) are responsible for the
      sharp tuning that underlies sensitivity and frequency selectivity in the ear.
      OHCs exhibit a voltage-dependent motility involving a 'motor' protein embedded in
      the basolateral membrane. The motor has so far resisted molecular identification.
      Here we provide evidence that it may be related to a fructose transporter. We
      show that OHCs are able to transport this sugar selectively and that the sugar
      alters electrical properties of the OHC motor. These data can be combined into an
      integrated model of a sugar carrier, that makes the novel prediction,
      demonstrated here, that such 'neutral' transporters can be voltage dependent.

PMID- 10412061
TI  - Reciprocal interactions between CA3 network activity and strength of recurrent
      collateral synapses.
AB  - In hippocampal slices, synchronous CA3 network activity induced persistent
      strengthening of active positive-feedback synapses. This altered network
      operation by increasing probability of future synchronous network activation.
      Long-term depression of synaptic strength induced by partial blockade of NMDA
      receptors during synchronous network activity reversed changes in probability of
      spontaneous network activation. These results suggest that specific network
      activity patterns selectively alter strength of active synapses. Stable,
      reversible alterations in network activity can also be effected by corresponding
      alterations in synaptic strength. These findings confirm the Hebb memory model at
      the neural-network level and suggest new therapies for pathological patterns of
      network activity in epilepsy.

PMID- 10412062
TI  - Influence of experience on orientation maps in cat visual cortex.
AB  - Experience is known to affect the development of ocular dominance maps in visual
      cortex, but it has remained controversial whether orientation preference maps are
      similarly affected by limiting visual experience to a single orientation early in
      life. Here we used optical imaging based on intrinsic signals to show that the
      visual cortex of kittens reared in a striped environment responded to all
      orientations, but devoted up to twice as much surface area to the experienced
      orientation as the orthogonal one. This effect is due to an instructive role of
      visual experience whereby some neurons shift their orientation preferences toward
      the experienced orientation. Thus, although cortical orientation maps are
      remarkably rigid in the sense that orientations that have never been seen by the
      animal occupy a large portion of the cortical territory, visual experience can
      nevertheless alter neuronal responses to oriented contours.

PMID- 10412063
TI  - Contrast's effect on spatial summation by macaque V1 neurons.
AB  - Stimulation outside the receptive field of a primary visual cortical (V1) neuron
      reveals intracortical neural interactions. However, previous investigators
      implicitly or explicitly considered the extent of cortical spatial summation and,
      therefore, the size of the classical receptive field to be fixed and independent
      of stimulus characteristics or of surrounding context. On the contrary, we found
      that the extent of spatial summation in macaque V1 neurons depended on contrast,
      and was on average 2.3-fold greater at low contrast. This adaptive increase in
      spatial summation at low contrast was seen in cells throughout V1 and was
      independent of surround inhibition.

PMID- 10412064
TI  - Reading population codes: a neural implementation of ideal observers.
AB  - Many sensory and motor variables are encoded in the nervous system by the
      activities of large populations of neurons with bell-shaped tuning curves.
      Extracting information from these population codes is difficult because of the
      noise inherent in neuronal responses. In most cases of interest, maximum
      likelihood (ML) is the best read-out method and would be used by an ideal
      observer. Using simulations and analysis, we show that a close approximation to
      ML can be implemented in a biologically plausible model of cortical circuitry.
      Our results apply to a wide range of nonlinear activation functions, suggesting
      that cortical areas may, in general, function as ideal observers of activity in
      preceding areas.

PMID- 10412065
TI  - Feedback interactions between neuronal pointers and maps for attentional
      processing.
AB  - Neural networks combining local excitatory feedback with recurrent inhibition are
      valuable models of neocortical processing. However, incorporating the attentional
      modulation observed in cortical neurons is problematic. We propose a simple
      architecture for attentional processing. Our network consists of two reciprocally
      connected populations of excitatory neurons; a large population (the map)
      processes a feedforward sensory input, and a small population (the pointer)
      modulates location and intensity of this processing in an attentional manner
      dependent on a control input to the pointer. This pointer-map network has rich
      dynamics despite its simple architecture and explains general computational
      features related to attention/intention observed in neocortex, making it
      interesting both theoretically and experimentally.

PMID- 10412066
TI  - Loss of attentional stimulus selection after extrastriate cortical lesions in
      macaques.
AB  - Many objects in natural visual scenes compete for attention. To identify the
      neural mechanisms necessary for visual attention, we made restricted lesions,
      affecting different quadrants of the visual field but leaving one quadrant
      intact, in extrastriate cortical areas V4 and TEO of two monkeys. Monkeys were
      trained to discriminate the orientation of a target grating surrounded by
      distracters. As distracter contrast increased, performance deteriorated in
      quadrants affected by V4 and TEO lesions, but not in the normal quadrant.
      Performance in affected quadrants was restored by increasing the contrast of the
      target relative to distracters. Thus, without V4 and TEO, visual attention is
      'captured' by strong stimuli, regardless of their behavioral relevance.

PMID- 10412067
TI  - Modality-specific frontal and parietal areas for auditory and visual spatial
      localization in humans.
AB  - Although the importance of the posterior parietal and prefrontal regions in
      spatial localization of visual stimuli is well established, their role in
      auditory space perception is less clear. Using positron emission tomography (PET)
      during auditory and visual spatial localization in the same subjects, modality
      specific areas were identified in the superior parietal lobule, middle temporal
      and lateral prefrontal cortices. These findings suggest that, similar to the
      visual system, the hierarchical organization of the auditory system extends
      beyond the temporal lobe to include areas in the posterior parietal and
      prefrontal regions specialized in auditory spatial processing. Our results may
      explain the dissociation of visual and auditory spatial localization deficits
      following lesions involving these regions.

PMID- 10412068
TI  - Manifestation of scotomas created by transcranial magnetic stimulation of human
      visual cortex.
AB  - Reduced visual performance under transcranial magnetic stimulation (TMS) of human
      visual cortex demonstrates suppression whose spatial extent is not directly
      visible. We created an artificial scotoma (region missing from a visual pattern)
      to directly visualize the location, size and shape of the TMS-induced suppression
      by following a large-field, patterned, visual stimulus with a magnetic pulse. The
      scotoma shifted with coil position according to known topography of visual
      cortex. Visual suppression resulted in pattern-dependent distortion, and the
      scotoma was filled in with temporally adjacent stimuli, suggesting spatial and
      temporal completion mechanisms. Thus, perceptual measurements of TMS-induced
      suppression may provide information about cortical processing via neuronal
      connections and temporal interactions of neural signals.

PMID- 10412069
TI  - ECRI responds to Newsweek article on dirty endoscopes.

PMID- 10412070
TI  - A matter of minutes. Using AEDs to improve cardiac arrest survival rates.

PMID- 10412071
TI  - Automated external defibrillators.
AB  - For this Update, we evaluated three automated external defibrillators (AEDs) from
      three suppliers: the Hewlett-Packard (HP) Heartstream ForeRunner, the Medtronic
      Physio-Control Lifepak 500, and the Survivalink FirstSave. We found the units to
      be good choices for each of three automated defibrillation applications: in
      hospital first response, traditional prehospital first response, and public
      access defibrillation, or PAD (we ranked the Medtronic Physio-Control unit
      slightly below the other two for this last application). None of these units are
      appropriate for the fourth application we considered, in-hospital use as a
      combination automated/manual unit (for use by both basic and advanced users).

PMID- 10412072
TI  - Automated external defibrillator selection considerations.
AB  - Before buying an automated external defibrillator (AED), you need answers to some
      fundamental questions about the technology. The AED Evaluations we've published
      provide most of the answers you need, but there are some questions that require
      additional comment. For example: Are low-energy biphasic AEDs as safe and
      effective as units that use the more traditional monophasic technology? Will
      rechargeable or nonrechargeable batteries prove the best choice for your
      organization? And should differences in units' ECG-rhythm-recognition algorithms
      affect your purchasing decision? We address these questions, describing the
      issues to consider and recommending courses of action, in the articles that
      follow.

PMID- 10412073
TI  - Excerpts from five minutes to midnight. Practical Y2K contingency plans for
      healthcare facilities.

PMID- 10412075
TI  - Fluorescent lights can activate Valley Forge Scientific Malis CMC III bipolar
      electrosurgical unit.

PMID- 10412074
TI  - Misusing forced-air hyperthermia units can burn patients.

PMID- 10412076
TI  - Managing hospital waste.

PMID- 10412077
TI  - Glycol incompatibility causes EXI Infant Security System umbilical transponders
      to break.

PMID- 10412078
TI  - Arthroscopic burs and blades are breaking in patients.

PMID- 10412079
TI  - FDA "approval" of medical devices.

PMID- 10412080
TI  - Conference overview: through the patient's eyes--improvement strategies that
      work.
AB  - BACKGROUND: To promote a continuing dialogue among innovators in patient-centered
      health care quality assessment and improvement, The Picker Institute (Boston)
      sponsored conferences in 1995 and 1996, and in July 1997 launched the first of
      its summer symposia designed primarily for its clients. This overview summarizes
      the work and ideas presented at The Picker Institute's second summer symposium,
      "Through the Patient's Eyes: Improvement Strategies That Work," held in
      Cambridge, Massachusetts, on July 9-10, 1998. ISSUES AND PARTICIPANTS: Plenary
      session speaker David H. Gustafson, PhD, emphasized four key themes in his
      discussion of breakthrough improvement and service-focus on customers, innovation
      through information technology, an empirical methodology for predicting success,
      and leadership. Donald M. Berwick, MD, argued that it is better to treat the
      consumer not as an inspector but as an integral element in the total system of
      health care. In the closing plenary session, John Stone, MD, stated that although
      physicians like to think of themselves as teachers, it is the patients who teach
      them with the stories they bring. "Listen to the patient," he concluded. "The
      patient is telling you the diagnosis." Health care researchers and professionals,
      representing a wide variety of settings and patient conditions, reported in
      breakout sessions on their practical experiences using patient-generated data on
      quality and strategies for improving care. Several presenters described their
      practical experience using patient-centered measures as part of a coordinated
      approach to systemwide improvement. In other sessions, presenters offered advice
      about how to present patient survey data to colleagues and encourage their
      participation in prioritizing and acting on improvement opportunities.

PMID- 10412081
TI  - Patient-centered measurement at an academic medical center.
AB  - BACKGROUND: Harborview Medical Center (Seattle, Wash) has collected patient data
      on operations since 1988 and has participated in the University HealthSystem
      Consortium's (UHC; Oak Brook, III) patient satisfaction measurement program since
      1996. The patient feedback program is intended to provide data suitable for the
      quality improvement process and benchmark Harborview's performance against that
      of other academic medical centers (AMCs). USE OF PATIENT FEEDBACK AT HARBORVIEW:
      The Picker Institute Adult Inpatient survey's seven dimensions of care are used
      to disseminate the patient data and focus the action plans. The areas with the
      largest problem scores and the highest correlation with overall satisfaction are
      identified, and then specific actions are devised to address those areas. For
      example, patient satisfaction data collected in May 1997 led the quality council
      to highlight information and education as an area for improvement for both
      inpatients and outpatients. Patients reported that they often got answers they
      could not understand. Also, they did not always get enough information at
      discharge to feel comfortable about going home. A Discharge/Transition Center CQI
      (continuous quality improvement) team was charged with developing a
      discharge/transition process that ensures continuity of care for patients as they
      move throughout the system. In addition, a hospitalwide Patient and Family
      Information team has been working on improving information delivery by developing
      both patient-friendly processes and useful educational materials. FUTURE
      DIRECTIONS: Harborview will continue to gather feedback through not only more
      targeted, specific surveys but also focus groups, which have been conducted
      around specific issues such as diabetes care, clinical pathways, pain management,
      and teen health.

PMID- 10412082
TI  - The built environment as a component of quality care: understanding and including
      the patient's perspective.
AB  - BACKGROUND: Although there has been little systematic assessment of how the built
      environment of health care facilities affects the quality of care, the built
      environment is a major element of structure of care--one of three facets of
      quality. Yet in contrast to the growing trend of using consumer perceptions of
      both processes and outcomes of care in QI activities, quality assessments of the
      structure of care do not currently rely on patient feedback. PURPOSE OF PROJECT:
      During the initial phase of a multiphase project, nine focus groups were
      conducted in 1997 to identify the salient dimensions of experience from the
      patient's perspective. The content of these focus groups guided the development
      of assessment tools in the second phase of the project, which began in February
      1998. FINDINGS: Participants in three focus groups that were held in each of
      three settings--ambulatory care, acute care, and long term care--described in
      detail a variety of reactions to the built environment. Analysis revealed eight
      consistent themes in what patients and family member consumers look for in the
      built environment of health care. In all three settings, they want an
      environment, for example, that facilitates a connection to staff and caregivers,
      is conducive to a sense of well-being, and facilitates a connection to the
      outside world. DISCUSSION: Data derived from the focus group research has guided
      the development of quantitative survey and assessment tools. For each setting,
      patient-centered checklists and questionnaires are designed to help institutions
      set priorities for the improvement of facility design from the patient's
      perspective.

PMID- 10412083
TI  - Moving out of the red zone: addressing staff allocation to improve patient
      satisfaction.
AB  - BACKGROUND: Each summer, Hermann Hospital (Houston), like virtually all health
      care organizations, faces staffing challenges because of employee vacations,
      increased patient load, and staff turnover. A "zone" system was developed to
      address staff allocation, which was identified as a factor in deterioration of
      the hospital's patient satisfaction performance. ZONE SYSTEM: Every day, each
      unit or department designated the zone most appropriate based on factors
      identified in root cause analysis--high patient census, high patient acuity,
      emergent activity, and the number of float, agency, or unfamiliar staff members.
      A green zone defines conditions where the staff is very comfortable; yellow
      reflects increased activity; and red indicates that staff members are stressed
      and overwhelmed with patient needs. ACTION STEPS: Management's action steps
      included decreasing the nursing vacancy rate to minimize reliance on agency and
      float staff members and securing longer-term commitments from temporary staff
      members. Individual units also generated contingency plans, such as identifying a
      "partner unit" to provide shared staff members, supplies, and other assistance.
      RESULTS: The percentage of patients rating their overall experience at Hermann
      Hospital as "good" or "excellent" increased from 83% in August 1997 to 89% in
      August 1998, despite increases in admissions, patient days, operating room cases,
      and emergency department visits. DISCUSSION: The zone system provides a rapid way
      to quantify contributing factors to patient dissatisfaction and respond to them.
      Hermann Hospital is currently developing a broader zone system to include staff
      vacancy rates by departments, areas of increased patient census for prolonged
      periods, and balancing episodic zones with prolonged zones.

PMID- 10412084
TI  - The Consumer Assessment of Health Plan Study (CAHPS) survey of children's health
      care.
AB  - BACKGROUND: Little is known about the experience of children and families with
      pediatric care. Asking parents about their experiences and the treatment of their
      children in health care plans can yield important information about selected
      aspects of medical care quality. Such data can be used to motivate, focus, and
      evaluate quality improvement efforts. METHODS: Development of the Child Core
      Survey followed the survey development principles of the Consumer Assessment of
      Health Plan Study (CAHPS) project, starting with assembly of existing
      instruments, consultation with experts, focus groups, and cognitive testing. A
      field test of the survey was conducted by mail among members enrolled in 1 of 25
      plans originally identified as providing health care services to the public
      employees of the state of Washington (response rate, 52%). RESULTS: The 3,083
      respondents rated personal doctors most highly, with overall care and specialty
      care rated nearly as well, and plan administration rated lowest. Parent-clinician
      and child-clinician communication, as well as spending sufficient time with the
      child were the strongest correlates of assessments of overall care and of
      personal doctors. Plans differed significantly in their performance along all the
      dimensions of child health care assessed in the survey except for aspects of
      access ("getting the care you need"). IMPLICATIONS: The Child Core Survey from
      the CAHPS provides a readily accessible method to assess the interpersonal care
      of children. Such data could be used to make plans accountable to the needs of
      children, to focus specific improvement initiatives, or both.

PMID- 10412085
TI  - Differential expression of SM22 isoforms in myofibroblasts and smooth muscle
      cells from rabbit bladder.
AB  - The E-11 and 1-B8 monoclonal antibodies raised to the smooth muscle (SM)-specific
      SM22 protein from pig stomach were used to study the in vivo and in vitro
      phenotypic characteristics of myofibroblasts (MF) and SM cells (SMC) from the
      bladder detrusor muscle and serosal thickening of male rabbit. The 22-kDa SM22
      band found in the SM extract appeared to be composed of distinct isoforms when
      examined in non-equilibrium two-dimensional gel electrophoresis (2D-EF): alpha
      (the most basic), beta, gamma, and delta (the most acidic) in the ratio of
      34(alpha):23(beta):36(gamma):8(delta). Western blots of 2D-electrophoresed
      bladder extracts treated with E-11 and 1-B8 showed that alpha, beta, and delta,
      but not gamma isoforms were labeled with E-11, whereas alpha, beta, and gamma
      isoforms were stained with 1-B8. This differential immunoreactivity was not
      influenced by phosphorylation. The tissue distribution of SM22 immunostaining was
      heterogeneous in the bladder SM and serosal thickening developed as a consequence
      of partial outflow obstruction of the urinary bladder. At the cellular level, the
      1-B8 and E-11 antibodies stained the SMC in a "diffuse" (the whole cytoplasm) and
      "honeycomb" (the peripheral cytoplasm) manner, whereas MF immunostaining was
      quite homogeneous. The two antibodies also reacted with cultured primary bladder
      SMC and MF grown in low serum conditions showing a heterogeneous SM22 cell
      distribution but an identical subcellular localization, i.e., the actin
      containing filamentous network, distinguishable in part from that found in vivo.
      The immunocytochemical, Western blotting and 2D-EF patterns of MF from thickened
      serosa indicated that the gamma isoform alone is expressed in this tissue. This
      SM22 variant appeared before the completion of the cellular transition from MF to
      fully differentiated SMC. This pattern is reminiscent of bladder ontogenesis
      where SM22 expression in the developing bladder wall precedes that of SM myosin.
      Taken together these data suggest that: (i) SM22 isoforms are differently
      assorted in MF vs. SMC; (ii) SM22 is a SMC-lineage marker inasmuch as its
      expression occurs in an experimental condition characterized by a time-related
      cell phenotypic transition from MF to SMC, and (iii) cell conversion ability of
      serosal cells in the adult might take place via the reactivation of a specific
      "foetal" gene programme.

PMID- 10412086
TI  - Transient expression of myosin heavy chain MHCI alpha in rabbit muscle during
      fast-to-slow transition.
AB  - The expression of an alpha-cardiac-like myosin heavy chain, MHCI alpha, was
      investigated at both the mRNA and protein levels in rabbit tibialis anterior
      muscle undergoing fast-to-slow transition by continuous chronic low-frequency
      stimulation (CLFS). According to sequence analyses of the PCR product, the MHCI
      alpha isoform was found to be identical to the alpha-cardiac MHC expressed in
      rabbit atrium. In muscles at different degrees of transformation, the
      upregulation of MHCI alpha mRNA preceded that of the MHCI beta mRNA. At more
      advanced stages of the transformation, MHCI alpha mRNA decayed while MHCI beta
      mRNA persisted at high levels. The expression of MHCI alpha, therefore, was
      transitory. Studies at the protein level were based on immunoblotting using a
      monoclonal antibody (F88 12F8,1), characterized to be specific to MHCI alpha in
      rabbit muscle. These studies revealed a similar relationship between initial
      increase and successive decline of the MHCI alpha protein as seen at the mRNA
      level. Immunohistochemistry of 30-day stimulated muscle revealed that up to 65%
      of the fibres expressed the MHCI alpha isoform in combination with other adult
      MHC isoforms. The most frequent patterns of coexistence were MHCIIa + MHCI alpha
      + MHCI beta (28%), MHCI alpha + MHCI beta (18%), and MHCIIa + MHCI alpha (11%).
      According to these combinations, the upregulation of MHCI alpha may be assigned
      as an intermediate step in the transformation of existing fibres during the
      MHCIIa-->MHCI beta transition. A small fraction of fibres contained, in addition
      to the MHCI alpha + MHCI beta and MHCIIa + MHCI alpha combinations, developmental
      myosin, suggesting that MHCI alpha was also expressed in regenerating fibres
      originating from satellite cell-derived myotubes.

PMID- 10412087
TI  - Alpha-cardiac-like myosin heavy chain MHCI alpha is not upregulated in
      transforming rat muscle.
AB  - The expression of MHCI alpha, an alpha-cardiac-like myosin heavy chain isoform,
      was studied in extensor digitorum longus (EDL) and tibialis anterior (TA) rat
      muscles undergoing fast-to-slow transition by chronic low-frequency stimulation
      (CLFS), a condition inducing a transient upregulation of MHCI alpha in rabbit
      muscle. In order to enhance the transformation process, CLFS was applied to
      hypothyroid rats. mRNA analyses were performed by RT-PCR, and studies at the
      protein level by immunoblotting and immunohistochemistry, using the F88 antibody
      (F88 12F8,1) demonstrated in the accompanying paper to be specific for MHCI
      alpha. In total RNA preparations from slow- and fast-twitch muscles, MHCI alpha
      mRNA was present at minute levels, at least three orders of magnitude lower than
      in cardiac atrium. As verified immunohistochemically, MHCI alpha is present only
      in intrafusal fibres of rat muscle. Moreover, MHCI alpha is not expressed in
      extrafusal fibres and, contrary to the rabbit, was not upregulated at both the
      mRNA and protein levels by CLFS. These results support our notion of species
      specific responses to CLFS. Another antibody reported to be specific to MHCI
      alpha, BA-G5, was also investigated by immunoblot and immunohistochemical
      analyses. Its specificity could not be validated for skeletal muscles of the rat.
      BG-A5 was shown to cross-react with MHCIIb and MHCI beta. These results question
      an upregulation of MHCI alpha in transforming rat muscles as reported in studies
      based on the use of this antibody.

PMID- 10412088
TI  - A weakly coupled version of the Huxley crossbridge model can simulate energetics
      of amphibian and mammalian skeletal muscle.
AB  - This study aimed to establish whether quantitatively accurate predictions of the
      rate of crossbridge-dependent energy output from shortening muscle could be made
      on the basis of a 2-state model of crossbridge kinetics incorporating weak
      coupling between mechanical cycles and ATP hydrolysis. The model was based on
      Huxley's (1957) model but included rapid detachment, without ATP hydrolysis, of
      crossbridges when their strain energy increased sufficiently that crossbridge
      free energy exceeded that of the unbound state (Cooke et al., 1994). An
      expression was derived relating force to steady-state velocity in terms of the
      model's rate constants. The values of the rate constants that both provided the
      best fit through force-velocity data and correctly predicted crossbridge
      dependent rate of energy output during an isometric contraction were found and
      used to predict the variation in rate of energy liberation with shortening
      velocity. The model predictions closely matched the estimated crossbridge
      energetics of frog sartorius muscle, including the decline in rate of enthalpy
      output at high shortening velocities. Data from fast- and slow-twitch muscles of
      the mouse were also simulated. The velocity-dependence of rate of energy
      liberation from fast-twitch EDL muscle was well described by the model. The model
      overestimated crossbridge-dependent energy output from slow-twitch soleus at low
      shortening velocities but provided accurate predictions of energy output at high
      velocities. In terms of this model, the distinctive energetics of fast and slow
      muscles cannot be explained exclusively by differences in cross-bridge detachment
      rate; differences in the relative rates of crossbridge attachment must also be
      considered to explain the different relations between energy output and
      shortening velocity.

PMID- 10412089
TI  - Expression of chicken gizzard RLC complements the cytokinesis and developmental
      defects of Dictyostelium RLC null cells.
AB  - Dictyostelium RLC null cells have defects in cytokinesis and development that can
      be rescued by expression of either the wild type Dictyostelium RLC or an RLC
      mutant that cannot be phosphorylated by MLCK (S13A) (Ostrow et al., 1994). The
      wild type and S13A mutant LCs rescued the cells equally well, despite the fact
      that RLC phosphorylation increases purified Dictyostelium myosin's activity 5
      fold. In this report, we assess the ability of foreign RLCs to rescue the RLC
      null phenotype. The RLC from smooth muscle myosin, whose activity is tightly
      controlled by phosphorylation, rescued the null cell phenotype. The purified
      hybrid myosin had an activity and motility comparable to phosphorylated
      Dictyostelium myosin. In contrast, cells expressing skeletal muscle RLC were
      deficient in cytokinesis and development, despite having an activity and motility
      similar to that of myosin with the unposphorylatable S13A mutant RLC. Neither
      foreign LC was phosphorylated when expressed in Dictyostelium. These results
      suggest that the level of actin-activated ATPase activity and motility is not the
      sole determinant of proper myosin function in vivo. Other heavy chain/light chain
      interactions, which occur only with the native RLC and smooth muscle RLC, appear
      to be necessary for optimal function.

PMID- 10412091
TI  - Parvalbumin concentration and diffusion coefficient in frog myoplasm.
AB  - The concentrations and diffusivity of two isoforms of parvalbumin, IVa and IVb,
      were measured using quantitative SDS PAGE in single fibers from semitendinosus
      muscles of the frog Rana temporaria. The concentrations of IVa and IVb were 2.9
      +/- 0.3 (SEM) and 4.5 +/- 0.5 g l-1 total fiber volume, respectively. The total
      concentration of parvalbumin (7.4 +/- 0.8 g l-1 total fiber) corresponds to a
      cytosolic concentration of 0.9 +/- 0.1 mmol l-1 myoplasmic water. Estimates for
      the transverse and longitudinal diffusion coefficients for parvalbumin at 4
      degrees C were obtained in two ways: (1) by diffusion of parvalbumin out of
      skinned fibers into droplets of relaxing solution, and (2) by diffusion of
      parvalbumin between two juxtaposed skinned fibers under oil. The transverse
      diffusion coefficient obtained using the droplet method was significantly lower
      than that obtained using juxtaposed fibers, but the longitudinal diffusion
      coefficients obtained from both methods were similar. The juxtaposed fiber method
      more accurately approximates parvalbumin diffusion in undisturbed myoplasm
      because no artificial solutions were used and, upon fiber-to-fiber contact, a
      potentially confounding oil barrier at the interface rapidly disperses. The
      juxtaposed fiber method yielded values for transverse (4.27 +/- 0.87 x 10(-7) cm2
      s-1) and longitudinal (3.20 +/- 0.74 x 10(-7) cm2 s-1) diffusion coefficients
      that were not significantly different, suggesting that diffusion of parvalbumin
      in myoplasm is essentially isotropic. The average diffusion coefficient of frog
      parvalbumin in myoplasm (3.74 +/- 0.81 x 10(-7) cm2 s-1; 4 degrees C) is
      approximately a third of that estimated for frog parvalbumin diffusing in bulk
      water into and out of 3% agarose cylinders (10.6 x 10(-7) cm2 s-1; 4 degrees C).
      The reduced translational mobility of parvalbumin in myoplasm reflects an
      elevated effective viscosity due to tortuosity and viscous drag imposed by the
      fixed proteins of the cytomatrix and the numerous diffusible particles of the
      cytosol.

PMID- 10412090
TI  - Alpha actinin-CapZ, an anchoring complex for thin filaments in Z-line.
AB  - CapZ is a widely distributed and highly conserved, heterodimeric protein, that
      nucleates actin polymerization and binds to the barbed ends of actin filaments,
      preventing the addition or loss of actin monomers. CapZ interaction with actin
      filaments was shown to be of high affinity and decreased in the presence of PIP2.
      CapZ was located in nascent Z-lines during skeletal muscle myofibrillogenesis
      before the striated appearance of thin filaments in sarcomers. In this study, the
      stabilization and the anchorage of thin filaments were explored through
      identification of CapZ partners in the Z-line. Fish (sea bass) striated white
      muscle and its related Z-line proteins were selected since they correspond to the
      simplest Z-line organization. We report here the interaction between purified
      CapZ and alpha-actinin, a major component of Z filaments and polar links in Z
      discs. Affinity of CapZ for alpha-actinin, estimated by fluorescence and
      immunochemical assays, is in the microM range. This association was found to be
      independent of actin and shown to be weakened in the presence of
      phosphoinositides. Binding contacts on the alpha-actinin molecule lie in the 55
      kDa repetitive domain. A model including CapZ/alpha-actinin/titin/actin
      interactions is proposed considering Luther's 3D Z-line reconstruction.

PMID- 10412092
TI  - Analysis of myosin heavy chains at the protein level in horse skeletal muscle.
AB  - Combined methodologies of enzyme-linked immunosorbent assay (ELISA), sodium
      dodecyl sulphate polyacrilamide gel electrophoresis (SDS-PAGE), immunoblotting,
      traditional myofibrillar ATPase (mATPase) histochemistry and immunocytochemistry
      of whole biopsied samples were used to study myosin heavy chain (MHC) isoforms in
      the equine gluteus medius muscle. The ELISA technique allowed the quantification
      of the three MHC isoforms known to be present in different horse muscles: slow
      (MHC-I) and two fast (termed MHC-IIA and MCH-IIX). The SDS-PAGE method resolved
      MHCs in three bands: MHC-I, MHC-IIX and MHC-IIA from the fastest to the slowest
      migrating band and a quantification by densitometry for each MHC isoform was also
      possible. The identity of these three MHCs was confirmed by immunoblots with
      specific monoclonal antibodies. Five fibre types were defined
      immunohistochemically according to their MHC content: I, I + IIA, IIA, the hybrid
      IIAX and IIX. When quantitative data obtained with the four different
      methodologies were combined and compared, they were consistent and, when
      considered together, showed significant correlation. Nevertheless, the percentage
      of MHC-IIA histochemically derived was underestimated, while that of MHC-IIX was
      overestimated in comparison with the immunocytochemical determination of these
      MHC isoforms. The percentage of MHC-I obtained by ELISA technique was
      underestimated. In short, these integrated methods for the analysis of MHCs at
      the protein level demonstrate that equine skeletal muscle does not express the
      MHC-IIB, so type II fibres have been misclassified in numerous previous studies
      based upon the vary traditional mATPase histochemistry. They also offer new
      prospects for muscle fibre typing in equine experimental studies and veterinary
      medicine.

PMID- 10412094
TI  - Can jet-injector devices transmit pathogens?

PMID- 10412093
TI  - Caffeine and excitation-contraction coupling in skeletal muscle: a stimulating
      story.

PMID- 10412095
TI  - A cost-benefit analysis of genetic screening for susceptibility to occupational
      toxicants.
AB  - Genetic screening can identify individuals with increased susceptibility to
      certain workplace toxicants. One conceivable benefit is a reduction in
      occupational disease costs. We examine this rationale by considering the
      associations among genetic traits, exposure, disease risk, and disease incidence.
      Given appropriate information, we describe methods for computing the expectation
      and variance of the future number of disease cases and of the differential
      screening cost per worker hired (a cost-benefit measure). We present two
      hypothetical scenarios: (1) benzene-induced cancer with few expected cases, and
      (2) chronic beryllium disease with many expected cases. We show that variability
      in disease incidence and cost outcomes must be considered because in specific
      instances, screening can be cost-beneficial on average but yield an unfavorable
      outcome with high probability. This circumstance pertains to scenarios involving
      small differences between the expected number of cases in screened versus
      unscreened cohorts.

PMID- 10412096
TI  - The Working Healthy Project: a worksite health-promotion trial targeting physical
      activity, diet, and smoking.
AB  - Worksites are a key channel for delivery of interventions designed to reduce
      chronic disease among adult populations. Although some evaluations of worksite
      physical-activity interventions have been conducted, to date very few randomized
      trials of worksite health promotion have included the goal of increasing physical
      activity levels as part of a comprehensive multiple risk factor approach to
      worksite health promotion. This article presents the results regarding behavior
      change found among the cohort of 2055 individuals who completed three health
      behavior assessments as part of their worksites' participation in The Working
      Healthy Project (WHP), a multiple risk factor intervention implemented in 26
      manufacturing worksites. In this study, a randomized matched-pair design was
      used. Fifty-one percent (n = 2,761) of the employees who completed the baseline
      assessment also completed the interim survey. Eighty-three percent of those who
      completed the interim assessment also completed the final survey. The WHP
      intervention targeted smoking, nutrition, and physical activity. At baseline, 38%
      of the sample reported engaging in regular exercise, and subjects reported
      consuming an average of 2.7 servings of fruits and vegetables per day, 7.9 grams
      of fiber per 1000 kilocalories, and 35.4% calories from fat per day; 28% of the
      sample were smokers. By the time of both the interim (intervention midpoint) and
      final (end of intervention) assessments, participants in the intervention
      condition had significantly increased their exercise behavior, compared with the
      control condition. There was also increased consumption of fruits and vegetables
      and fiber in the intervention condition by the time of the final assessment,
      compared with the control condition. No differences by condition were found with
      regard to percentage of calories from fat consumed or smoking cessation. These
      results suggest that among a cohort of participants in a worksite health
      promotion study, there were significant health behavior changes across two risk
      factors over time. These data suggest that further investigation of multiple risk
      factor worksite health promotion is warranted, particularly with a focus on ways
      to increase participation in these programs and to diffuse intervention effects
      throughout the entire workforce.

PMID- 10412097
TI  - Cancer mortality among workers exposed to chemicals during uranium processing.
AB  - Data provided by the Comprehensive Epidemiology Data Resource allowed us to study
      patterns of cancer mortality as experienced by 3814 uranium-processing workers
      employed at the Fernald Feed Materials Production Center in Fernald, Ohio. Using
      risk-set analyses for cohorts, we estimated the effects of exposure to
      trichloroethylene, cutting fluids, and kerosene on cancer mortality. Our results
      suggest that workers who were exposed to trichloroethylene experienced an
      increase in mortality from cancers of the liver. Cutting-fluid exposure was found
      to be strongly associated with laryngeal cancers and, furthermore, with brain,
      hemato- and lymphopoietic system, bladder, and kidney cancer mortality. Kerosene
      exposure increased the rate of death from several digestive-tract cancers
      (esophageal, stomach, pancreatic, colon, and rectal cancers) and from prostate
      cancer. Effect estimates for these cancers increased with duration and level of
      exposure and were stronger when exposure was lagged.

PMID- 10412098
TI  - The organizational context of non-lethal workplace violence: its interpersonal,
      temporal, and spatial correlates.
AB  - This article examines 993 violent incidents involving faculty, students, and
      staff that occurred at a highly ranked teaching and research university and its
      affiliated medical center. Violent incidents were included in the sample if they
      involved faculty, students, or staff, regardless of their specific location or
      context (i.e., whether they occurred on campus and/or off-campus and whether they
      occurred within the context of work or some other activity). The theoretical goal
      of the project was to compare work-related incidents with non-work-related
      incidents of interpersonal violence occurring in a single, multifunctioning, and
      professionally hierarchical organization. Data were collected over a 7-year
      period from three police departments (city, county, and university), university
      records, and criminal history records obtained from the state police. The coding
      protocol was developed to capture crime-scene information pertinent to each of
      the incidents. This included information about the victim, the perpetrator, the
      relationship between the victim and perpetrator, and the violent incident. The
      data were examined using nonparametric statistics and logistic regression to
      model predictive differences between the workplace and non-workplace incidents.
      The results suggest that the workplace incidents of violence differ from the non
      workplace incidents according to their time, victim age, degree of victim injury,
      and whether the workplace is a medical location. The authors conclude that these
      differences are better explained by the movement of people in and out of the
      workplace who bring societal violence with them, rather than by a category or
      type of workplace violence.

PMID- 10412099
TI  - Prevalence of self-reported respiratory symptoms in workers exposed to
      isocyanates.
AB  - Until now, no survey had been conducted to assess the prevalence of respiratory
      symptoms in a large population that had been occupationally exposed to
      isocyanates, compared with that in a control group. We performed such a survey,
      using questionnaires administered by occupational physicians. Overall, 1114
      workers' questionnaires (585 exposed and 529 control) were analyzed. Exposed
      workers, primarily painters from small factories, reported significantly (P <
      0.05) more wheezing (8.6% vs 3.6%), more breathlessness with wheezing (3.4% vs
      0.6%) in the last year, and more rhinitis (33.1% vs 19.1%) than did control
      workers. A trend for more asthma (2.1% vs 0.8%; P < or = 0.07) was also observed.
      Furthermore, 16.4%, 16.2%, and 10.6% of exposed workers reported (respectively)
      cough, rhinitis, and chest tightness when working in contact with isocyanates. We
      conclude that isocyanate-exposed workers demonstrate significantly higher
      prevalence rates of rhinitic and asthmatic symptoms than do control subjects.

PMID- 10412101
TI  - Weight change and lung function: implications for workplace surveillance studies.
AB  - This study evaluated the relationship between weight change and longitudinal
      measurement of lung function among 361 men providing at least five pulmonary
      function tests. The men in this study were participants in a workplace pulmonary
      surveillance program for subjects with exposure to refractory ceramic fibers
      (RCFs). Occupational and environmental studies are generally designed to evaluate
      factors suspected of causing excess decline in lung function. Failure to
      adequately account for all significant factors may lead to erroneous conclusions
      regarding change in lung function. This study utilized two different statistical
      models to evaluate longitudinal changes in a cohort of RCF workers. What was
      unique to this study was the modeling of longitudinally measured initial weight,
      weight change, and longitudinal exposure before and during the period of
      observation. Results showed a strong relationship between weight gain and
      longitudinal loss in lung function that approximated forced vital capacity
      declines of 16 mL for every kilogram of weight gain per year in both models. This
      value is comparable or greater in magnitude and significance to other factors
      known to be inversely related to lung function, such as age and pack-years
      smoking to time of initial testing. In conclusion, weight gain was found to have
      a significant impact on longitudinal change in lung function. Therefore, weight
      gain becomes a very important variable that requires consideration whenever
      longitudinal studies of pulmonary function are conducted.

PMID- 10412100
TI  - Correlates of body mass index in hazardous materials firefighters.
AB  - We analyzed results from the medical examinations of 340 hazardous materials
      (HAZMAT) firefighters and observed the relationships between selected parameters
      and body mass index (BMI). Heights and weights were available for 98% of the
      subjects (333 of 340). The mean BMI was 28.9 +/- 4.1 kg/m2. Eighty-seven percent
      (290 of 333) of subjects were overweight (BMI > or = 25) and 34% (113 of 333)
      were obese (BMI > or = 30). Two percent (7 of 333) were morbidly obese (BMI > or
      = 39). For comparison purposes, we divided subjects into low (BMI < 27), medium
      (BMI 27 to < 30), and high (BMI > or = 30) BMI groups. The results demonstrated
      adverse associations between increasing BMI and resting blood pressures, forced
      vital capacity, alanine aminotransferase, aspartate aminotransferase, serum
      cholesterol, and overall morbidity scores. The high prevalence of overweight and
      obesity and the associated adverse health effects support the development and
      implementation of fitness-promotion programs for firefighters.

PMID- 10412103
TI  - Analysis of race effects on drug-test results.
AB  - Substance abuse has become one of the most pressing public health problems of our
      times. Its impact on the US workforce is staggering, both in terms of lost
      productivity and the cost of providing medical care to its victims. Employers
      usually have programs in place to reduce the impact of substance abuse, which
      include testing prospective and/or current employees' body fluids or tissues for
      recreational drugs. Although urine testing remains the test of choice among most
      employers, the use of hair as a testing matrix has increased substantially in
      recent years. There has been a legal concern that there may be racial bias in
      hair testing. In studies of human populations, there has been limited
      investigation of this issue. This study investigates this question by evaluating
      the hair-test results of a large cohort of applicants for employment with a major
      metropolitan police department. The results of the study failed to show any
      racial bias and thereby suggest that hair-testing methodology would not create a
      disparity among applicants.

PMID- 10412102
TI  - Absenteeism among employees treated for depression.
AB  - Depression-related costs include a relatively large share of indirect costs. We
      describe the impact of antidepressant treatment on absenteeism among workers
      diagnosed and treated for depression. Monthly absenteeism counts from employers
      were summed in the 6 months before and after the initiation of antidepressant
      therapy in 630 workers treated for depression with a tricyclic antidepressant or
      a selective serotonin reuptake inhibitor (fluoxetine, sertraline, paroxetine).
      Monthly mean absenteeism was compared using pairwise t tests. Absenteeism
      increased before antidepressant initiation and decreased after the treatment
      began for all antidepressant cohorts. Absenteeism in the selective serotonin
      reuptake inhibitor cohorts decreased at similar rates for 4 months but was higher
      in the paroxetine cohort in months five and six after the treatment initiation.
      Our data suggest that alternative treatments for depression may have differential
      impact on indirect costs, but further research is warranted.

PMID- 10412104
TI  - Mosquito and aquatic predator communities in ground pools on lands deforested for
      rice field development in central Sulawesi, Indonesia.
AB  - Aquatic habitats, mosquitoes, and larvivorous predators were studied on
      deforested lands in Central Sulawesi, Indonesia. Open ground pools, mainly in
      depressions made by the treads of bulldozers and other heavy equipment, were
      numerous but because of their small size, comprised ca. 1% or less of the total
      area of the deforested lands studied. The dominant mosquitoes in these pools were
      Anopheles vagus, Culex vishnui, Culex tritaeniorhynchus, and Culex gelidus. The
      1st 2 species were dominant in clear pools, whereas the latter 2 species were
      dominant in turbid pools. The dominant metazoans other than mosquitoes were
      Crustacea, Ephemeroptera, and Chironomidae. Both aquatic and surface predators
      were abundant. Dominant among aquatic predators were Anisoptera and Zygoptera
      nymphs, Dytiscidae, and Notonectidae. These results are discussed in relation to
      mosquito control on deforested lands that transitionally but inevitably appear
      during the course of rice field development projects in Indonesia.

PMID- 10412105
TI  - Increased fecundity of Aedes aegypti fed human blood before release in a mark
      recapture study in Puerto Rico.
AB  - Laboratory experiments suggest that utilization of blood rather than natural
      sugar sources for energetic needs affords female Aedes aegypti a reproductive
      advantage over conspecifics that use sugar. To test this hypothesis under field
      conditions, we carried out a mark-release-recapture study in Florida, PR. Adult
      females (F1) reared from field-collected eggs were provided with a diet of human
      blood alone or human blood plus a 20% honey solution before their release.
      Backpack aspirators were used to collect mosquitoes from release houses for 5
      consecutive days beginning the 2nd day after release. Survival was estimated from
      the slope of the regression line of the log-transformed daily number of
      recaptures for each treatment group. To compare fecundity of the treatment
      groups, each recaptured female was dissected, ovaries were removed, oocytes
      counted, and Christophers' stages of oocyte development scored. Recapture rates
      were 30% for the blood-only group and 23% for blood plus honey group. The daily
      survival rate of the blood-only group (55%) was not statistically different from
      that of the blood plus honey group (69%) (t = 0.32, P > 0.05). By analysis of
      variance, fecundity (average number of stage III-V oocytes) was significantly
      higher in the females fed human blood alone (n = 103, 109 oocytes/female) than in
      the group fed on blood and honey (n = 50, 95 oocytes/female) (P = 0.0007). The
      observed gonotrophic cycle length of the recaptured females ranged from 3 to 7
      days. Results from our field study are consistent with laboratory life-table
      experiments that suggest feeding exclusively on human blood provides a
      reproductive advantage for female A. aegypti.

PMID- 10412106
TI  - Effects of sampling design on the estimation of adult mosquito abundance.
AB  - During 1994-5, Culex tarsalis comprised 75% of the 902,643 adult female
      mosquitoes collected by 63 dry-ice-baited Centers for Disease Control (CDC)-style
      traps operated biweekly in a uniform sampling grid that covered the southern
      Coachella Valley, Riverside County, California. The ln(y + 1) transformation
      successfully controlled the variance and normalized the distribution of catch
      size among trap nights. When tested by analysis of variance, abundance varied
      significantly among months, years, and trap sites. Although the trap by months
      interaction was not significant, female distribution changed seasonally as larval
      habitats shifted from wetlands along the Salton Sea to agriculture to managed
      duck marshes. Conditional simulations utilized subsets of trap sites to compare
      sampling designs that required no (uniform, random, and transect designs) or
      prior (best-estimate and stratified random designs) knowledge of mosquito spatial
      distribution. All designs provided similar information on population seasonal
      trends, but a stratified random design provided the most accurate and precise
      simulation. A uniform trap grid that employed every 2nd trap site subsequently
      was adopted by the Coachella Valley Mosquito and Vector Control District to
      provide information on focal changes in abundance indicative of missed or newly
      created larval habitats or control failures.

PMID- 10412107
TI  - An updated checklist of the mosquitoes of New Jersey.
AB  - The last checklist of New Jersey mosquitoes was published in 1983 and contained
      59 species from 10 genera. Since that time 4 additional species have been
      collected in New Jersey: Aedes thibaulti, Aedes infirmatus, Aedes aegypti, and
      Aedes albopictus. Aedes aegypti was not able to overwinter and is not part of New
      Jersey's mosquito fauna. As a result, the addition of 3 species brings the
      updated checklist of New Jersey mosquitoes to 62.

PMID- 10412108
TI  - A historical review of the F-1 strain of Anopheles freeborni as a host and vector
      for studies of malaria.
AB  - A review was made of the use of a specific strain of Anopheles freeborni from
      California (F-1) that has been used extensively in experimental investigations of
      malaria for more than 50 years. The F-1 strain of An. freeborni has been shown to
      be a suitable experimental host and vector for different species of Plasmodium
      that cause malaria in humans and nonhuman primates for biologic, immunologic, and
      chemotherapeutic studies. Eleven species of Plasmodium fully completed sporogonic
      development; development of sporozoites within mature oocysts occurred in an
      additional 7 species. Transmission through An. freeborni from human to human,
      monkey to human, or monkey to monkey has been demonstrated for 9 species of
      Plasmodium.

PMID- 10412109
TI  - Distribution of resting female Aedes vexans (Meigen) in wooded and nonwooded
      areas of metropolitan Minneapolis-St. Paul, Minnesota.
AB  - Daytime resting mosquito densities in 4 habitat types (wooded, residential yard,
      garden, and crop) were examined to determine if areas other than wooded ones may
      be serving as prime mosquito resting habitat. Adult Aedes vexans were collected
      in the Minneapolis-St. Paul metropolitan area with large battery-powered
      aspirators to determine mosquito densities at randomly chosen sites within the
      metropolitan area that supported all 4 habitats. Measurements were taken to
      estimate the total area of each habitat type within the sample areas. The highest
      densities of mosquitoes were found in wooded areas. Although agricultural crop
      areas had relatively low mosquito densities, they supported the 2nd largest
      number of mosquitoes because of the extremely large cropland area. Residential
      yards and gardens contained fewer mosquitoes compared with wooded areas. A
      greater percentage of bloodfed mosquitoes was collected within the wooded
      habitat.

PMID- 10412110
TI  - Activity and biological effects of neem products against arthropods of medical
      and veterinary importance.
AB  - Botanical insecticides are relatively safe and degradable, and are readily
      available sources of biopesticides. The most prominent phytochemical pesticides
      in recent years are those derived from neem trees, which have been studied
      extensively in the fields of entomology and phytochemistry, and have uses for
      medicinal and cosmetic purposes. The neem products have been obtained from
      several species of neem trees in the family Meliaceae. Six species in this family
      have been the subject of botanical pesticide research. They are Azadirachta
      indica A. Juss, Azadirachta excelsa Jack, Azadirachta siamens Valeton, Melia
      azedarach L., Melia toosendan Sieb. and Zucc., and Melia volkensii Gurke. The
      Meliaceae, especially A. indica (Indian neem tree), contains at least 35
      biologically active principles. Azadirachtin is the predominant insecticidal
      active ingredient in the seed, leaves, and other parts of the neem tree.
      Azadirachtin and other compounds in neem products exhibit various modes of action
      against insects such as antifeedancy, growth regulation, fecundity suppression
      and sterilization, oviposition repellency or attractancy, changes in biological
      fitness, and blocking development of vector-borne pathogens. Some of these
      bioactivity parameters of neem products have been investigated at least in some
      species of insects of medical and veterinary importance, such as mosquitoes,
      flies, triatomines, cockroaches, fleas, lice, and others. Here we review,
      synthesize, and analyze published information on the activity, modes of action,
      and other biological effects of neem products against arthropods of medical and
      veterinary importance. The amount of information on the activity, use, and
      application of neem products for the control of disease vectors and human and
      animal pests is limited. Additional research is needed to determine the potential
      usefulness of neem products in vector control programs.

PMID- 10412111
TI  - Effects of high temperature on the emergence and survival of adult Culex pipiens
      molestus and Culex quinquefasciatus in Japan.
AB  - The emergence rate and adult survival (longevity) of Japanese strains of Culex
      pipiens molestus and Culex quinquefasciatus were compared at temperatures of 21,
      25, and 30 degrees C. The pupation and emergence rates in both strains were
      higher at 21 and 25 degrees C than at 30 degrees C. The adult emergence rate,
      especially in females, was lower in Cx. p. molestus than in Cx. quinquefasciatus.
      Longevity of females and males was lower in Cx. p. molestus at 25 degrees C and
      above. The survival of Cx. p. molestus was adversely affected by temperatures of
      28 degrees C and higher. High temperature may restrict the distribution of this
      species. Therefore, if Cx. p. molestus infests the Okinawa region, the likelihood
      that it will become established is minimal.

PMID- 10412112
TI  - A description and morphometric comparison of eggs of species of the Anopheles
      gambiae complex.
AB  - Eggs of the 6 named species of the Anopheles gambiae complex are described from
      scanning electron micrographs of specimens obtained from laboratory colonies or
      wild-caught females. Morphometric measurements of eggs from 5 sources of
      Anopheles arabiensis, 2 of Anopheles gambiae, one of Anopheles quadriannulatus, 2
      of Anopheles bwambae, 2 of Anopheles merus, and one of Anopheles melas are
      compared, and relationships are analyzed by multivariate statistics. No
      morphologic characters were species-diagnostic, although tendencies of the
      saltwater species An. merus and An. melas to have wider decks and shorter floats
      were confirmed. Species and populations overlapped considerably in principal
      components and discriminant function analyses based on 10 attributes of eggs.
      Nevertheless, discriminant functions revealed similarities in eggs of species
      believed to be most closely related, namely, An. gambiae and An. arabiensis, An.
      merus and An. melas, and An. quadriannulatus and An. bwambae.

PMID- 10412113
TI  - Florida's salt-marsh management issues: 1991-98.
AB  - During the 1990s, Florida has continued to make important strides in managing
      salt marshes for both mosquito control and natural resource enhancement. The
      political mechanism for this progress continues to be interagency cooperation
      through the Florida Coordinating Council on Mosquito Control and its Subcommittee
      on Managed Marshes (SOMM). Continuing management experience and research has
      helped refine the most environmentally acceptable source reduction methods, which
      typically are Rotational Impoundment Management or Open Marsh Water Management.
      The development of regional marsh management plans for salt marshes within the
      Indian River Lagoon by the SOMM has helped direct the implementation of the best
      management practices for these marshes. Controversy occasionally occurs
      concerning what management technique is most appropriate for individual marshes.
      The most common disagreement is over the benefits of maintaining an impoundment
      in an "open" vs. "closed" condition, with the "closed" condition, allowing for
      summer mosquito control flooding or winter waterfowl management. New federal
      initiatives influencing salt-marsh management have included the Indian River
      Lagoon-National Estuary Program and the Pesticide Environmental Stewardship
      Program. A new Florida initiative is the Florida Department of Environmental
      Protection's Eco-system Management Program with continuing involvement by the
      Surface Water Improvement and Management program. A developing mitigation banking
      program has the potential to benefit marsh management but mosquito control
      interests may suffer if not handled properly. Larvicides remain as an important
      salt-marsh integrated pest management tool with the greatest acreage being
      treated with temephos, followed by Bacillus thuringiensis israelensis and
      methoprene. However, over the past 14 years, use of biorational larvicides has
      increased greatly.

PMID- 10412114
TI  - Buoyancy and diving behavior in mosquito pupae.
AB  - Mosquito pupal diving behavior has been studied mostly in Aedes aegypti and in
      this species pupal buoyancy varies relative to several factors. The research
      reported herein addresses the 2 following questions. Does diving behavior vary
      among different mosquito genera and species? How is diving behavior influenced by
      variation in buoyancy? Depth and duration of dive, and dive pattern, were
      compared among Ae. aegypti, Culex pipiens, Anopheles stephensi, Aedes albopictus,
      and Aedes triseriatus. In response to the stimulation associated with
      transferring pupae between containers, diving behavior varied dramatically among
      the different genera studied. Culex pipiens and An. stephensi make short
      duration, shallow dives and remain positively buoyant. The 3 aedine species
      studied make longer-duration dives, typically to a depth at which they become
      neutrally or negatively buoyant. Buoyancy reduction effects were studied in the 3
      aedine species. Normally buoyant pupae tend to dive to greater depths and for
      longer periods of time than reduced-buoyancy pupae. Aedine pupal diving behavior
      clearly is closely regulated relative to buoyancy variation. To the earlier
      hypotheses that pupal behavior may help avoid predation and be energy-conserving,
      we add the suggestion that the diving behavior displayed by the container
      breeding aedine pupae we studied represents an adaptation that helps keep them
      from being washed from their container habitat by overflowing water during
      rainfall. We also suggest that the diving behavior of all the species studied may
      help pupae survive heavy, pelting rainfall by enabling them to avoid the
      mechanical shock of a direct hit by a raindrop, which could cause disruption of
      the gas in the ventral air space, thereby causing the loss of hydrostatic balance
      and drowning.

PMID- 10412115
TI  - Wyeomyia (Prosopolepis) confusa (Lutz): subgeneric validation, species
      description, and recognition of Wyeomyia flui (Bonne-Wepster and Bonne) as the
      senior synonym of Wyeomyia kerri del Ponte and Cerqueira.
AB  - Prosopolepis Lutz is validated as a monotypic subgenus of Wyeomyia Theobald and
      the type species, Weomyia confusa (Lutz), is redescribed. The description
      includes illustrations of the male and female genitalia, the 4th-stage larva, and
      the pupa. Prosopolepis flui Bonne-Wepster and Bonne is resurrected from synonymy
      with Wy. confusa and recognized as the senior synonym of Wyeomyia kerri del Ponte
      and Cerqueira. Wyeomyia flui does not belong in the subgenus Prosopolepis and
      remains in the genus Wyeomyia without subgeneric placement. Trichoprosopon
      pusillum Lutz and Nunez-Tovar is not synonymous with Wy. confusa and is
      provisionally regarded as a nomen dubium within Wyeomyia. The identity of Wy.
      confusa is fixed by neotype selection.

PMID- 10412116
TI  - The check is in the male: male mosquitoes affect female physiology and behavior.
AB  - The accessory glands of male mosquitoes may produce substances that are
      transferred to females during mating and alter female physiology and behavior.
      The effects of male substances include the inhibition of subsequent female mating
      behavior, stimulation of oviposition and preoviposition behaviors, and the
      inhibition of host-seeking behavior. The circadian rhythmicity of females can
      also be altered and their metabolic priorities restructured, making them more
      likely to reproduce. The specific components that affect the female have yet to
      be completely identified, but the published reports are summarized.

PMID- 10412117
TI  - Aedes albopictus in the United States: current status and prospects for further
      spread.
AB  - Since its initial discovery in the continental USA in 1985, the Asian tiger
      mosquito, Aedes albopictus, has spread rapidly throughout the eastern part of the
      country. Infestations of Ae. albopictus now have been reported to the Centers for
      Disease Control and Prevention from 919 counties in 26 states in the continental
      USA. This species is believed to be established in 911 counties in 25 states.
      Single individuals or small numbers of Ae. albopictus have been intercepted and
      destroyed in 3 additional states (California, New Mexico, and Washington). Five
      states (Florida, Georgia, North Carolina, South Carolina, and Tennessee) have
      reported infestations in all of their counties. The current reported distribution
      of Ae. albopictus was compared to ecoregions of the U.S. Environmental Protection
      Agency's Level III ecoregion map. Several areas are identified as probable
      candidates for extension of this species based on ecological characteristics of
      the landscape. In other areas, populations seem likely to become locally abundant
      in urban or suburban oases that do not reflect the native ecology of the region.
      The ability of Ae. albopictus to transmit a variety of pathogens of human and
      veterinary public health importance, coupled with its ability to colonize diverse
      ecological settings makes continued surveillance an important issue.

PMID- 10412118
TI  - Use of the continuity principle to evaluate water processing rate of suspension
      feeding mosquito larvae.
AB  - Water processing rates of active suspension-feeding larvae of Culiseta morsitans
      and Culex quinquefasciatus 2nd and 4th instars were estimated through video image
      analysis of the conical jet flow driving the large recirculation patterns
      surrounding the organisms. In accordance with the principle of continuity,
      individual processing rates (PRs) were assessed by averaging a series of
      consecutive flow rates (Qx) defined as the product of the water velocity (Ux) and
      the associated cross-sectional area (Ax) along a transect passing through the
      center of the delineated jet flow. Results clearly show very tight adherence to
      the principle of continuity. They also demonstrate that, although extreme care
      must be taken when streamtube delineation is performed, the methodology used can
      generate reliable assessment of individual processing rates regardless of the
      instars or species studied. The small coefficient of variation observed in
      assessing PR at the larval level further underlines the consistency of the
      method. Significant differences in water processing rates were observed for
      different species and instars. These could partially be related to body size,
      head width, and the length of the lateral palatal brushes (LPBs), which are the
      structures involved in the production of the water jet. Assessment of the jet
      velocity at the feeding groove level suggests the key role of LPB beating
      frequency in the jet intensity, and consequently the magnitude of the processing
      rate. Analysis of data further indicates that obligate suspension feeders such as
      Cs. morsitans must sustain a larger flow pattern around the larvae to ensure
      sufficient particle entrapment than facultative suspension feeders (or even
      brushers) such as Cx. quinquefasciatus.

PMID- 10412119
TI  - Aedes (Finlaya) japonicus japonicus (Theobald), a new introduction into the
      United States.
AB  - Aedes (Finlaya) japonicus japonicus is recorded for the 1st time in the United
      States. Four adult females were collected in light traps at 2 sites in New York
      and one site in New Jersey during the months of August and September 1998. Notes
      on bionomics are provided. Illustrations of the adult female, male, and larva are
      included.

PMID- 10412120
TI  - Towards management of mosquitoes at Homebush Bay, Sydney, Australia. I. Seasonal
      activity and relative abundance of adults of Aedes vigilax, Culex sitiens, and
      other salt-marsh species, 1993-94 through 1997-98.
AB  - The mosquitoes associated with 2 saline wetlands at Homebush Bay, Sydney,
      Australia, were investigated over 5 consecutive seasons. Twenty-one species were
      collected in adult traps at the 2 sites but the saline wetlands supported larvae
      of only 4 species: Aedes alternans, Aedes camptorhynchus, Aedes vigilax, and
      Culex sitiens. Of these, Ae. vigilax and Cx. sitiens were the most common, and
      their peak abundances generally occurred during February and April, respectively.
      Both wetlands were influenced by tides and rainfall-runoff, and a lack of regular
      tidal exchange in the mangroves and inadequate drainage of the saltmarsh provided
      potential habitat. Populations of Ae. vigilax and Cx. sitiens at the Newington
      site were greater than those at the Bicentennial Park site, because of more
      extensive habitat at the former, but were diminished by irregular ground-based
      applications of temephos during the middle 3 years of the study. Populations at
      the Bicentennial Park site, not subjected to the larvicide, were typically
      smaller but more consistently related to influences of tide and rainfall through
      the 5 seasons. During the final season, populations of both species in both
      wetlands were enhanced by exceptional tide penetration and rainfall. Helicopter
      applications of Bacillus thuringiensis israelensis larvicide were employed at
      both sites and effectively suppressed populations of both pest species. For
      future management, provision of full tidal exchange and water recirculation to
      reduce the area of water impounded within the mangroves and retained in
      depressions on the marshes should significantly suppress the pest populations and
      relieve reliance on control agents.

PMID- 10412121
TI  - Culiseta impatiens (Walker) in Illinois, a new state record.
AB  - We report the 1st collection of Culiseta impatiens (Walker) from Illinois. Larvae
      of Culiseta subsequently identified as Cs. impatiens were collected from roadside
      ditches near Savoy, Champaign County, in east central Illinois in June 1997. This
      extends the known distribution of this species further south and east in the
      midwestern United States.

PMID- 10412122
TI  - [Babesiosis--a dangerous infection for splenectomized children and adults].
AB  - Babesiosis is a world-wide distributed protozoal zoonosis, and Babesia spp. are
      the most ubiquitous of the blood parasites of mammals, except the trypanosomes.
      The tick-transmitted protozoa infect various vertebrate reservoir hosts, like
      rodents, cattle and horses. Approximately 100 million cattle is exposed to the
      disease. In tropical and subtropical regions the infection causes considerable
      losses in livestock industry, but clinical cases of human babesiosis in these
      areas have not certainly been identified. In 1957, the first case of human
      babesiosis in an asplenic Yugoslav farmer was reported (35). Hitherto, hundreds
      of cases of human babesiosis in adults and children from Europe and the U.S.,
      with a broad range of clinical presentations, have been published (3, 4, 38).
      Most of the patients suffer from mild to moderate symptoms, whereas in asplenic
      individuals a fatal course of the infection prevails. Tick-bites in areas where
      human babesiosis occurs--mainly parts of Europe and the USA--can result in a
      deadly illness for persons without a spleen. The effect of treatment in
      splenectomized patients and when treatment is delayed, still is poor.

PMID- 10412123
TI  - [Ultrasound hip joint screening in newborn infants. Correlation of anamnestic
      risk factors and hip dysplasia].
AB  - BACKGROUND: Congenital dysplasia of the hip (CDH) is the most frequent inborn
      deformity of the locomotor apparatus. Hereditary, pelvic respectively breech
      presentation or abdominal delivery, premature as well as post-term birth and twin
      pregnancy are considered to be anamnestic risk factors for congenital dysplasia
      of the hip. The results of ultrasound hip screening from July 87 until December
      94 are presented with special regard to the correlation of these risk factors and
      the occurrence of pathologic hips. PATIENTS: 19 different orthopaedic surgeons
      examined the hips of 3739 newborns (female: 1837-49.1%; male: 1902-50.9%) by
      ultrasound (screening). 96% of the examinations were performed within a period of
      5 days after birth, in a few cases the babies were up to 19 days old. METHOD: The
      ultrasound examinations, the assessment of the echograms and classification into
      types of hip were performed according to Graf's technique. Two types of
      ultrasonographs were used: SL-1, Siemens--5 MHz scanner; LSC 7500, Picker--7.5
      MHz scanner). All investigations were assessed retrospectively over the period of
      time with the help of documentation forms (data of newborn baby, case history,
      clinical and sonographical findings, kind of therapy and procedure) and
      statistically checked (program SPSS 7.5, Chi-Quadrate-Test, logistic regression).
      RESULTS: In 239 children (6.4%) we found hips required therapy respectively
      control investigations (type IIa, alpha < 55 degrees or worse; Graf's
      classification). For the entire group we achieved the following types of hips
      (right/left side): Ia--214 (5.7%)/224 (6.0%); Ib--2069 (55.3%)/2008 (53.7%); IIa
      (> or = 55 degrees)--1318 (35.3%)/1322 (35.4%); IIa (< 55 degrees)--65 (1.7%)/74
      (2.0%); IIc--45 (1.2%)/71 (1.9%); D--18 (0.5%)/30 (0.8%); IIIa--8 (0.2%)/7
      (0.2%); IIIb--1 (< 0.1%)/2 (0.1%); IV--1 (< 0.1%)/1 (< 0.1%). With regard to the
      risk factors the distribution was as follows: hereditary--302 babies (8.1%),
      pelvic respectively breech presentation--149 (4%), abdominal delivery--359
      (6.5%), premature birth--188 (5.0%), post-term birth--164 (4.4%), twin pregnancy-
      73 (2%). CONCLUSIONS: In newborn babies with cases of hip dysplasia in their
      family (heredity) and pelvic respectively breech presentation at birth we found a
      significant higher rate (p < 0.05) of hips required therapy respectively control
      investigations (type IIa, alpha < 55 degrees or worse; Graf's classification).
      Also, for girls and the left hip a significant higher rate was achieved. A
      correlation of the other mentioned risk factors abdominal delivery, premature and
      post-term birth as well as twin pregnancy was not evident.

PMID- 10412125
TI  - [Why do newborn infants already suffer from "stroke". Studies of focal, arterial,
      ischemic infarct].
AB  - In most cases the etiology of the focal ischemic stroke in newborns is still
      obscure. We considered patients with congenital hemiparesis due to a lesion in
      the territory of the middle cerebral artery (shown by CT or MRI) as a model of
      this infarction. A detailed history including maternal and familiar data was
      obtained from 9 affected patients. Duplex-sonography was performed and
      biochemical parameters were analysed in all patients and their mothers. There
      were no convincing hints for a prenatal (for instance infectious, traumatic or
      toxic) origin. Also the reconstruction of the perinatal period could not explain
      the infarction. Duplex-sonography revealed no anatomic variants of the intra- or
      extracerebral arteries. Haemostasiological results were within normal limits-
      except the antiphospholipid antibodies, which were detected in 7 of the 9
      families (patient or mother). The significance of these results is still unknown.
      We propose, antiphospholipid antibodies and further haemostasiological parameters
      should be investigated as near as possible to the neonatal period.

PMID- 10412124
TI  - [Granulocyte function in premature infants before the 34th week of pregnancy and
      in mature newborn infants].
AB  - BACKGROUND: Preterm and term neonates have an increased risk to develop severe
      bacterial infections. Impairment of neutrophil function may be responsible for
      this increased risk. Other diseases related to prematurity like retinopathia of
      prematurity (ROP) or broncho-pulmonary dysplasia (BPD) on the other hand may be
      due to poorly controlled O2-radical production. PATIENTS AND METHODS: Blood
      samples of 112 premature (34 weeks of gestation and older) and term neonates were
      analysed. Blood samples of 23 healthy adults (18 to 50 years old) served as
      controls. O2-radical production and phagocytosis of neutrophils were determined
      by flow cytometry, using a commercial test system. RESULTS: Under the
      experimental conditions applied, the capacity to produce O2-radicals following
      vigorous stimulation (E. coli) is comparable between neutrophils of preterm/term
      neonates and healthy adults. However, unstimulated or weakly stimulated (fMLP)
      neutrophils of preterm and term neonates show a statistically higher O2-radical
      production as neutrophils of the control group. The production of oxygen radicals
      increases during the first 10 days of the life. The capability of neutrophils to
      phagocytose E. coli is significantly lower in newborns (preterm and term)
      compared to the adult controls. CONCLUSIONS: The values reported here for
      phagocytosis and O2-radical production utilizing a commercially available test
      system may serve as "preliminary normal values" for neonates. No differences were
      found between the groups of neonates with and without infection. Impaired
      neutrophil-phagocytosis possibly contributes to the increased risk of preterm and
      term neonates to acquire bacterial infections. The increased spontaneous O2
      radical production, on the other hand, may play a role for the development of so
      called "free radical diseases" such as ROP or BPD. However, our results cannot
      add further proof to this hypothesis.

PMID- 10412126
TI  - [Congenital hypothyroidism: causes for delayed initiation of treatment].
AB  - The aim of neonatal screening programs for congenital hypothyroidism is to ensure
      early treatment in order to prevent brain dysfunction. There are several reasons
      why infants are missed in the screening program. We report on three patients with
      congenital hypothyroidism, who had a pathological screening result and initiation
      of therapy was delayed. The first patient had an increased TSH level, but she was
      missed because of mistakes in the confirmatory serum test. During the follow-up
      the patient showed typical symptoms of hypothyroidism and got a thyroxine
      supplementation not before the age of three years. The second patient did not get
      a therapy before the age of six months because of the noncompliance of the
      parents and physicians. The third patient had a central hypothyroidism. The
      neonatal screening-program revealed no measurable TSH activity. Although the
      child had clinical signs of a severe hypothyroidism diagnosis was not made before
      the age of 5.5 months. Although different reasons are known for screening errors,
      all these 3 patients were missed because of failures in the follow-up of a
      pathological screening result, indicating a poor quality in the follow-up
      procedure.

PMID- 10412127
TI  - [Clinical, histopathologic and immunohistochemical studies of chronic sialectatic
      parotitis in childhood and adolescence].
AB  - Chronic sialectatic parotitis (CSP) causes problems in differential diagnosis and
      therapy. CSP shows the typical clinical features of chronic recurrent parotitis
      and will be investigated histopathologically only after ultimative parotidectomy.
      The etiology and pathogenesis of these unspecific inflammations is still unknown.
      Therefore no causal therapy is available and a lot of different trials
      (sialogoga, gland massage, infrared light, antibiotics, antiphlogistics,
      Trasylol, duct occlusion, duct ligation, gland denervation, radiotherapy) are not
      successful in the long run. MATERIAL AND METHOD: The salivary gland registry of
      the University of Hamburg (1965-1996) contains 22 infants and juvenile patients
      showing very severe courses of CSP. These cases have been investigated clinical
      (ultrasound, sialography), histopathological (paraffin embedded sections,
      histomorphometry of the ectatic duct lumina) and immunohistochemical (CK-MNF,
      AKTIN, KiM4) in a retrospective study to research the pathogenesis of CSP.
      RESULTS: Recurrent and always very dolent parotid swelling occurs between the age
      of 3 and 14 years for the first time. The courses vary from 3 months until 25
      years. Local findings as well as ultrasound and sialographic features allow no
      certain differentiation of chronic recurrent parotitis. Conservative therapy
      fails in each case and leads to the necessity of surgical treatment.
      Histopathological three different stages of development can be observed: Initial
      stages show regular lobular architectonic structure of the parotid gland
      parenchyme with duct ectasies surrounded by slight inflammation of lymphocytes
      and plasmacells. Advanced stages are characterized by an increase of periductal
      inflammation and the appearance of lymphfollicels. Nearly complete lymphatic
      transformation of the parenchyme with destruction of the lobular formation
      dominates the terminal "immunologic" stage. Some cases show multiple
      myoepithelial islands within this lymphatic stroma typically observed in benign
      lymphoepithelial lesions. Whether bacteria nor primary obstructive changes can be
      observed. The histomorphometric analyses of the average and maximal luminal duct
      diameters show marked increase of 39% respectively 46% from and- vanced to
      terminal stages of CSP. Therefore the pathognomonic duct ectasies seem to depend
      on the progredient inflammation and are not due to a hereditary malformation of
      the duct system. Immunohistochemical terminal stages show follicular lymphatic
      hyperplasia (KiM4) expressing overshooting humoral immune reaction of MALT.
      CONCLUSION: Concerning the pathogenesis CSP corresponds to a immunopathological
      disorder of MALT and seems to be a prestage of benign lymphoepithelial lesion.
      Consequently important changes in the diagnosis and therapy of CSP lead to early
      histopathological investigation to differentiate the stage of inflammation. In
      stage III conservative parotidectomy should be carried out because spontaneous
      healing can not be expected. In contrast initial cases should be treated at first
      by glucocorticoids and immunosuppressives.

PMID- 10412128
TI  - [Plexiform neurofibroma and basal ganglia anomaly in Watson syndrome].
AB  - A 4 year-old boy was referred for diagnostic reevaluation with known pulmonary
      valve stenosis. Physical examination revealed multiple cafe-au-lait spots,
      inguinal freckling and on the right side in supraclavicular region a softly, non
      painful tumour. The boy showed a mild mental and language retardation. Ultrasound
      and MRT demonstrated supraclavicular a plexiform neurofibroma and intracranial
      increased intensity lesions in basal ganglia and mesencephalon. In our patient,
      we have diagnosed a Watson-Syndrome, the overlap and differences to
      neurofibromatosis type I is discussed.

PMID- 10412129
TI  - [Isolated abnormality ("noncompaction") of the myocardium in 3 children].
AB  - In three asymptomatic children an isolated myocardial noncompaction was detected
      by echocardiography at age 11 months, 5 weeks and 5.5 years. In the first male
      infant both ventricles and septum were severely affected and myocardial function
      was depressed. Nevertheless, during a follow up of 16 months he remained
      asymptomatic on anticongestive therapy. In the other two children apex and
      lateral wall of the left ventricle were affected and myocardial function was
      still normal. The second boy had also an infantile epilepsy-encephalopathy
      syndrome and the third child (a girl) had a Wolff-Parkinson-White syndrome; an
      association of either syndromes with myocardial noncompaction has not been
      reported earlier. DISCUSSION: Myocardial noncompaction (spongy myocardium) is a
      rare maldevelopment, which occurs either associated with certain congenital heart
      defects or, even more rarely, isolated, as the two cases reported here.
      Myocardial failure, severe arrhythmias or thromboembolism may occur at any age
      and determine the outcome. Clinical course, therapy and prognosis are similar to
      dilatative cardiomyopathy, which represents an important differential diagnosis.

PMID- 10412131
TI  - [Muscular compliance of the auditory tube].
AB  - BACKGROUND: The simultaneous electromyographical assessment of innervation
      patterns of the mylohyoid and the tensor veli palatini muscle is introduced as a
      new technique for the examination of the auditory tube function. PATIENTS AND
      METHODS: Clinical studies were performed on 30 healthy volunteers and 50 patients
      suffering from chronic tubotympanic mucositis and cholesteatoma. Concentric
      needle electrodes were advanced into the tensor veli palatini muscle through the
      palate. The mylohyoid muscle was examined using surface electrodes. RESULTS:
      Innervation patterns of the tensor veli palatini muscle in volunteers were
      limited to the time interval of the mylohyoid innervation pattern only, i.e., the
      oral and pharyngeal phases of swallowing. In 14 of the chronic otitis patients
      these tensor muscle innervation patterns were found outside this interval.
      CONCLUSION: This observation provides a new pathophysiological explanation for
      the clinical concept of a relative closing failure of the auditory tube. These
      results emphasize the significance of coordination in muscular compliance of the
      tube.

PMID- 10412130
TI  - [Type I pachyonychia congenita (Jadarssohn-Lewandowsky)].
AB  - BACKGROUND: Pachyonychia congenita is considered to be a genodermatosis of
      autosomal inheritance. It is characterized by nail hypertrophy, shortly present
      after birth. Later on follicular keratosis of the extremities and hyperkeratosis
      of palms and soles can be found. HISTORY AND CLINICAL FINDINGS: We report a child
      with pachyonychia congenita type-I (Jadassohn-Lewandowsky). Shortly after birth
      nail hypertrophy of all finger- and toenails and leukoplakia of the palate and
      tongue were found. At the age of 3 years follicular keratosis of the extremities
      and plantar bullae could be found additionally. CONCLUSION: The underlying
      disturbance is a mutation within genes for keratin 6, 16 and 17 which leads to
      formation of abnormal tonofilaments. In adult patients retinoids can be used for
      symptomatic treatment especially of the palmoplantar keratosis.

PMID- 10412132
TI  - [Nd:YAG laser treatment of the lower turbinates with contact in hyperreflexic and
      allergic rhinopathy].
AB  - BACKGROUND: Nasal obstruction caused by mucosal swelling due to hyperreflectory
      or allergic rhinitis is a very frequent disorder. We would like to report about
      our first results (ENT department, University of Gottingen) in the reduction of
      hyperplastic inferior turbinates by Nd:YAG Laser treatment. PATIENTS AND METHOD:
      One hundred seventeen patients with nasal obstruction were treated by Nd:YAG
      laser between October 1993 and February 1997. We used the laser in "contact mode"
      and all outpatients were under local anaesthesia. Follow-up was possible in 83
      cases. A subjective scale was used to evaluate our results. One quarter of the
      patients suffered from an allergic rhinitis. RESULTS: For 80% the nasal airflow
      was increased. Sixty percent had excellent or good results without any nasal
      obstruction after therapy. The patients with allergic rhinitis performed as well
      as the patients with hyperreflectory rhinopathy. This improvement appeared as
      early as four weeks after treatment and was permanent in 37 of 40 cases with long
      term observation of at least one year. Side effects: 14% reported a dry nasal
      mucosa for two weeks; 31% had a bloody nasal secretion for two days after
      treatment, but did not bleed. Fifteen percent complained of pain during the
      procedure. CONCLUSION: The reduction of the inferior turbinates by Nd:YAG laser
      is an effective treatment of equal value in symptomatic therapy of the
      hyperplastic turbinates due to hyperreflectory and allergic rhinopathy. Seventy
      three percent of these patients would like to be treated in this way again if
      necessary.

PMID- 10412133
TI  - [Clinical and electrophysiologic studies of facial nerve function after
      hypoglossal-facial nerve anastomosis].
AB  - BACKGROUND: The functional and cosmetic results after hypoglossal-facial nerve
      anastomosis (HFA) have primarily been described using a subjective grading system
      of good, fair, or poor. To obtain more objective results, the postoperative mimic
      function was investigated using a combination of clinical and
      electrophysiological methods. METHODS: A total of 29 patients with hypoglossal
      facial anastomosis were evaluated using a standardized questionnaire and the
      Stennert's paralysis index as clinical scoring system and electroneurography
      (NMG/ENoG) and electromyography (EMG) as electrophysiological assessments.
      RESULTS: Twenty-six of 29 patients (89%) judged their own facial function as very
      good or good, and three as poor. Under resting tone conditions, no patient showed
      a difference between palpebral fissures (> 3 mm), an ectropium, a substantial
      loss of nasolabial fold, or a drop of angulus oris (> 3 mm). With attempted
      movement, the lid closure was complete in 76% of patients, and the cornea was lid
      covered in 100%. Sixty-seven percent of the patients were able to whistle. The
      second upper incisor was visible (full width) in 19%. No patient could frown
      sufficiently or expose the upper and lower canine teeth. The mean Stennert's
      score decreased from 9 to 4 after surgery. The relative amplitudes of the NMGs
      were increased in patients with low clinical indices. Patients with a complete
      eye closure showed a higher density of EMG patterns in their orbicularis oculi
      muscles. No significant differences for clinical or electrophysiological
      parameters could be observed based on age, sex, or time point of operation.
      CONCLUSION: Combining the Stennert's paralysis index with NMG and EMG allows a
      more objective assessment of functional and cosmetic results after HFA.

PMID- 10412134
TI  - [Stage 3 syphilis of the mouth cavity].
AB  - BACKGROUND: Untreated syphilis or lues is a chronic infectious disease. It is
      caused by treponema pallidum, which is most commonly transmitted by sexual
      contact and occasionally by blood transfusion or by intrauterine infection. If
      the disorder is not treated, its clinical course can be chronic, persisting for
      decades. During this time, a variety of morphological signs occur depending on
      the stage of the disease. CASE REPORT: We describe a case of tertiary syphilis in
      the oropharynx with a defect of the soft palate. In a 37-year-old woman, the
      first symptom was a dryness of the throat followed by a feeling of foreign body
      in the palate area. The patient had a history of sexual contact with a man who
      had had syphilis ten years ago, and our initial suspicion was confirmed by a
      final diagnosis of tertiary syphilis. Signs of primary or secondary syphilis were
      not observed. RESULTS: In the course of diagnostic procedures both further
      manifestatons of syphilis and other infectious or malignant causes were excluded.
      The serological results showed a typical constellation of Treponema and non
      Treponema serum reactions. The histopathological examination of an exploratory
      excision from the soft palate showed granulomatous changes with peripheral
      participation of plasma cells. We initiated appropriate antibiotic therapy, using
      clemizole penicillin G over a period of 21 days, which induced healing of the
      soft palate. CONCLUSIONS: A defect of the soft palate was diagnosed as a very
      rare sign of tertiary syphilis.

PMID- 10412135
TI  - [Outcome after resection of extensive oropharyngeal carcinomas and defect
      coverage by microvascular anastomosis of a radialis flap].
AB  - BACKGROUND: Extensive tumors of the oropharynx require an open approach and
      plastic reconstruction for good oncologic and functional results. PATIENTS AND
      METHODS: From January 1988 through December 1996 at the Department of
      Otolaryngology, Head and Neck Surgery, of the University of Wurzburg, 62 patients
      with extensive tumors of the oropharynx underwent surgical treatment (T2 = 6, T3
      = 24, T4 = 32). In 40 patients, the resection was performed via a median
      mandibulotomy approach, in 22 patients using a lateral pharyngotomy. All patients
      underwent postoperative radiotherapy up to 70 Gy. RESULTS: Using the Kaplan-Meier
      method, the five-year survival was 80% for T2, 52% for T3, and 22% for T4. Four
      patients (7%) presented with a second primary carcinoma, and one also had a third
      carcinoma. Seven patients who died of T3- and T4-tumors had distant metastases,
      among them 5 patients who were free of local disease. A regular oral diet was
      possible on average 14 days postoperatively. All patients underwent tracheostomy.
      Ninety percent of them were decanulated one year postoperatively. CONCLUSIONS:
      Resection of extensive carcinomas of the oropharynx and microvascular
      reconstruction produces good oncological and functional results. The best access
      to extensive tumors is provided by a mandibulotomy. The advantage of this
      excellent approach outweighs an increasing morbidity in occasional cases.

PMID- 10412136
TI  - [Focal aspects of prevention of infection and hygienic quality management in
      otorhinolaryngology with special reference to surgical interventions].
AB  - The main objective of hygiene in surgery is to avoid, detect, and control
      hospital infections. This primarily involves protecting the patient from
      infection, although the protection of health care personnel is also an important
      consideration. Available means of infection control should be applied in a
      balanced regime tailored to the specific setting. Every member of the health care
      team must make it his or her personal responsibility to ensure that infection
      control measures are intelligently and rigorously applied in every specific
      antiseptic regime in the vicinity of the patient. Adherence of health care
      personnel to principles of hygiene is facilitated by appropriate building design,
      instruments, and procedures codified in the form of hygiene plans. Coordinated
      working procedures and use of utilities verified at regular intervals reduce the
      risk of contaminating the patient and the plant and equipment. Aside from the
      ethical dimension of their origin in the hospital or physician's office,
      nosocomial infections that prolong the disorder and are accompanied by a reduced
      long-term survival rate and increased risk of mortality have legal consequences
      and significantly increase the cost of inpatient and outpatient treatment.

PMID- 10412137
TI  - [Concepts in hospital management and health care economics].

PMID- 10412138
TI  - [The nasopharynx and pharyngeal tonsil in the history of otology and rhinology.
      Pictures from the history of otorhinolaryngology, presented by instruments from
      the collection of the Ingolstadt Medical History Museum].
AB  - Anatomy, nomenclature, first clinical observations: In ancient Greece and Rome
      and in the Middle Ages the posterior opening of the nasal passage was known
      (Greek "choane" = funnel) as an atomical structure, and it was also known that
      chronic nasal catarrh is common in children, but it was not realized that this
      was associated with special pathological alterations. The anatomist H. von
      Luschka in Tubingen, Germany, was the first to describe the nasopharynx in
      detail, and he coined the term "pharyngeal tonsil." The otologists of the 19th
      century like Kramer and Toynbee had placed the Eustachian tube in the center of
      their investigations and carried out numerous dissections with demonstration of
      the tubal orifice. They also knew that middle ear infections usually originated
      in the nasopharynx, but they did not realize that the hypertrophic pharyngeal
      tonsil was the cause. Posterior rhinoscopy and the diagnosis of the hypertrophy
      of the pharyngeal tonsil: Czermak in Budapest in 1860 had invented posterior
      rhinoscopy, and he was the first to diagnose hypertrophic alterations around the
      tubal orifice and the first to realize that they were the cause of tubal
      malfunction. Wilhelm Meyer in Kopenhagen in 1868 and 1873-1874 described
      hypertrophy of the pharyngeal tonsil ("adenoid vegetations") in detail and
      associated this finding with a syndrome characterized by mouth-breathing,
      snoring, a typical facial expression, deafness, recurring middle-ear affections,
      and characteristic alterations of speech. He based his conclusions on 5 years'
      experience with 175 observations in his office and on examination of 2700
      children in Denmark and England. Surgical therapy of adenoid vegetations:
      Voltolini in Breslau in 1865 had observed a few cases of hypertrophy of the
      pharyngeal tonsil, and he was the first to treat them by galvanic cauterization.
      Meyer developed various instruments for reducing the pharyngeal tonsil. They were
      introduced through the nose while the application of the instrument was assisted
      digitally via the mouth and pharynx. The operation of the pharyngeal tonsil was
      adopted very eagerly by a great number of nasal surgeons. Among the numerous
      special instruments that subsequently were invented the most promising was the
      ring knife invented by Gottstein in 1886. Anesthesia and positioning: The
      pioneers of this intervention, Voltolini, Meyer, Semon and others, all operated
      without any anesthesia, but they usually would need up to 12 sessions (Semon)
      until the pharyngeal tonsil had been sufficiently reduced. Beckmann in Berlin,
      who had invented a modification of Gottstein's ring knife, reported in 1897 on
      more than 5000 cases in which he had removed the adenoids in just one session, in
      each case without anesthesia. Besides these surgeons, others used cocaine for
      local anesthesia or chlorethyl or bromethyl for general anesthesia. The German
      surgeon Edmund Rose (Berlin and Zurich) in 1874 introduced the position with the
      head suspended for larger interventions like resection ot the maxilla. Rudloff in
      Wiesbaden, Germany, in 1900 adopted this position for adenoidectomy, but this was
      generally accepted only after the mouth gags developed by Davis-Boyle and Negus
      had been introduced. The diagnostic and surgical interventions in the nasopharynx
      were a powerful link in the process of fusion between otology and
      rhinolaryngology around the turn of the century. This historical development is
      described in great detail with many figures and quotations from the literature.

PMID- 10412139
TI  - [Interesting case no. 24. Focal, poorly differentiated adenocarcinoma in a
      pleomorphic adenoma of the right parotid gland].

PMID- 10412140
TI  - [Postoperative hemorrhage after tonsillectomy. Clarification procedure of the
      federal court Hagen-71 Js 565/96-(implementing the clarification procedure
      according to section 170 Abs. 2 StPO)].

PMID- 10412141
TI  - [Surgery of malignant tumor of the larynx. Total excision of the larynx
      (laryngectomy)].

PMID- 10412142
TI  - [Surgical education in the 21st century: undergraduate education].
AB  - The purpose of medical education is to bring up good physicians with a high level
      of knowledge of science, art, and humanity. To achieve this goal, medical
      education should continue for life starting from the undergraduate period:
      surgical education should also be lifelong. Unlike the past when the education
      system was teacher driven, the new system should be student driven, and students
      must have the ability to question and solve problems. Themselves Bedside learning
      may offer undergraduates the best understanding of everyday surgical practice;
      therefore such learning programs should be devised. A nationwide standardized
      surgical education program is required, with specialized courses added by each
      medical school. Medical school staff including professors should recognize that
      their primary obligation is to impact education and spend more time on it.
      Surgical education for undergraduates is especially important since it influences
      their future careers as surgeons and should be revised as soon as possible.

PMID- 10412143
TI  - [Postgraduate education in surgery].
AB  - During the past 100 years, specialization and differentiation in medicine have
      developed rapidly. As a field of culture, medical science has progressively been
      deprived of the philosophical and ethical elements that are the most important
      part of the practice of medicine. New technology has improved surgical techniques
      for curing diseases but often the patient as a whole human being has been lost
      sight. Before imparting super-specialized knowledge and techniques to
      postgraduate medical students, a global standard of primary care, understanding,
      and sympathy for the patient must be provided. No super-specialty that does not
      also fulfill the minimum requirements for general, fundamental medical and
      surgical knowledge and techniques will be accepted and respected by the majority
      of people. So-called straight residency training in super-specialties starting
      immediately after medical school must cease. A residency program of several years
      including primary-care training for general surgery is mandatory to educate well
      balanced "surgical specialists." Such a curriculum must be developed and
      constantly revised in response to social needs.

PMID- 10412144
TI  - [Fusion of medicine and technology in endoscopic surgery].
AB  - Although endoscopic surgery has become widespread and is currently used in a wide
      range of general, thoracic, urologic, gynecologic, and orthopedic procedures,
      many major difficulties remain because sensorial information is restricted to a
      two-dimensional image, and effector instruments have limited maneuverability due
      to the rigid shaft axis fixed to the abdominal wall by the entry trocar. To
      overcome these problems, advanced engineering technology has been introduced in
      laparoscopic surgery which includes three-dimensional video imaging, robotic
      laparoscopic cameraholders, telemanipulated flexible effector instruments, and
      tactile feedback. A voice-controlled robotic laparoscopic holder (AESOP200,
      Computer Motion Inc. USA) provides stable support for the laparoscope during
      laparoscopic surgery performed by a single surgeon. A new computer-assisted
      telemanipulation robot (Intuitive Surgical Inc. USA) permits the performance of
      completely endoscopic coronary artery bypass and Nissen fundoplication.
      Furthermore, price reductions and technological advances in telecommunications
      have made telementoring in endoscopic surgery available for routine clinical use,
      and intercontinental surgical video teleconferences fruitful opportunities for
      discussing technical details. The fusion of medicine and technology in endoscopic
      surgery would overcome difficulties in the conventional endoscopic approach.

PMID- 10412145
TI  - [The present status and prospective view in organ transplantation].
AB  - Transplants are nothing new in terms of medical technology. Organ transplantation
      had been established in the cyclosporine era in 1980s. More than 70 percent of
      Transplant patients worldwide who received organs from brain-dead donors are
      still alive after transplantation. Organ shortage is the most serious concerning
      in the world. In Japan, liver transplants from living donors and kidney
      transplants from living donors or non heart-beating donors have been carried out
      regularly. The Organ Transplant Law of October 1997 paved the way for change in
      Japanese organ transplantation. Improving the quality of life of patient after
      transplant and tolerance induction are the obvious targets for organ
      transplantation in the next millennium.

PMID- 10412146
TI  - [The digital revolution in Japan].
AB  - The digital revolution will be achieved using three types of technology:
      platform; distribution; and content. Japan is advanced in these technologies,
      although its transformation to a new society has been slow. To keeping up with
      this global revolution, we need to change our mind set.

PMID- 10412147
TI  - [Informationization policies of local governments].
AB  - In line with the rapid progress in technical innovation, the wave of
      informationization is now reaching every aspect of Japanese society. With the
      explosive spread of the Internet, local governments are implementing
      administrative policies to facilitate the construction of information network
      systems which will help promote the spread of information at the local level. The
      Ministry of Posts and Telecommunications, the Ministry of International Trade and
      Industry, and other organizations of the Japanese government are also
      implemending a variety of measures to assist these moves on the part of local
      governments. A look at administrative services for local residents reveals a
      great need for the proliferation of information within the areas of welfare and
      medical care; in particular, counselling concerning nursing care and medical
      services in remote areas are needed. In order to realize new measures promoting
      informationization, however, the cooperation and understanding of local governors
      or mayors are essential. Because these people are very busy, short video and
      computer graphic presentations should be prepared in order to make the greatest
      impact in the least amount of time.

PMID- 10412148
TI  - [Prospect of computer aided surgery].
AB  - To develop the new surgical fields of minimally invasive surgery, noninvasive
      surgery, virtual reality microsurgery, telesurgery, fetal surgery and others in
      the next century, it is necessary to use various advanced technologies; surgical
      robots, three-dimensional medical images etc. based on computer technology.
      Therefore, this new surgical field is called Computer Aided Surgery (CAS). Three
      dimensional medical images provide the most recognizable information for medical
      doctors and the most advanced visualization for surgeons. Surgical robots
      function as advanced hands for surgeons, but do not perform the same actions as
      surgeons wielding scissors or scalpel. The advanced vision and hands available to
      surgeons are creating a new surgical environment. The philosophy behind the
      development of surgical robots is to assist surgeons in difficult procedures and
      extend the greatest possible help to patients with incurable disease.

PMID- 10412149
TI  - [Networked robotics: its present status and future prospect].
AB  - One of the most promising technologies today is the integration of virtual
      reality and robotics on a network. This is called network robotics in general and
      R-cubed (real-time remote robotics) in particular. R-cubed is a Japanese national
      R&D scheme to realize augmented telexistence (tele-existence) through various
      kinds of networks including the Internet. Telexistence is a concept named for the
      technology that enables people to have a real-time sensation of being present at
      a location other than the place where they actually exist, and to interact with a
      remote and/or virtual environment. They can thus "telexist" in a real environment
      that the robot is present or in a virtual environment that a computer has
      generated. It is also possible to telexist in a mixed environment of real and
      virtual which can be called augmented telexistence. The concept of telexistence,
      i.e., virtual existence in a remote or computer-generated environment, has
      developed into the national R-cubed R&D scheme to create an advanced and
      comfortable life for the network society of the 21st century. Based on the
      national R&D scheme of R-Cubed, the Humanoid Robotics Project (HRP) was launched
      in April 1998. This is an effort to integrate telerobotics, network technology,
      and virtual reality into networked telexistence, and significant results are
      expected.

PMID- 10412150
TI  - [Interaction between neutrophils and endothelial cells following
      ischemia/reperfusion].
AB  - The adherence of activated neutrophils to endothelial cells during
      ischemia/reperfusion injury is mediated by inside-out signal transduction.
      Subsequently, outside-in signal transduction occurs following ligation of
      adhesion molecules with their ligands triggering respiratory bursts of
      neutrophils. In addition, neutrophil elastase enhances CC- and CXC-chemokine
      production by monocytes and macrophages. MCP-1, a CC-chemokine, enhances tissue
      factor production by macrophages and increases ICAM-1 expression on endothelial
      cells. Chemotaxis and respiratory bursts of neutrophils are augmented by CXC
      chemokines. Furthermore, neutrophil elastase inactivates anticoagulants including
      antithrombin III, heparin cofactor II, and thrombomodulin, suggesting that
      neutrophil elastase aggravates microcirculatory disturbance after
      ischemia/reperfusion. Thus neutrophil elastase modulates the interation of
      neutrophils and endothelial cells during ischemia/reperfusion injury. Taken
      together with these observations, a therapeutic regimen with antibodies against
      adhesion molecules in combination with neutrophil elastase inhibitor and
      anticoagulants may attenuate ischemia/reperfusion injury.

PMID- 10412151
TI  - [Role of cytokines in hepatic ischemia and reperfusion injury].
AB  - The liver is an organ with abundant blood flow, consisting of hepatic arterial
      and portal blood flow. The viability of liver tissue depends on the condition of
      the hepatic microcirculation which is controlled by hepatic sinusoidal lining
      cells. Hepatic ischemia and reperfusion (HIR) injury is inevitable in surgical
      procedures for liver trauma and hepatectomy as well as liver transplantation.
      Reperfusion through an ischemically damaged organ enhances the tissue injury.
      Cytokines are pivotal factors in neutrophil-mediated liver injury following HIR,
      while various other mediators are involved in this insult. Advances in molecular
      biology have allowed the identification of various cytokines. Inflammatory
      cytokines such as TNF-alpha are associated with the induction of cellular
      adhesion molecules and hepatic microcirculatory impairment based on neutrophil
      vascular endothelial cell interaction. Members of the chemokine family such as IL
      8, CINC, MIP-2, and MCP-1 are involved in neutrophil infiltration in the liver
      and remote organs. Since each cytokine has a wide variety of actions and
      interacts' among others' via the cytokine network, their actions in HIR injury
      have not been determined completely. Kupffer cells have been focused on as a
      source of cytokine production in HIR injury. Further studies on the mechanisms of
      cytokine production after HIR and analysis of regulation in the cytokine network
      would clarify the pathophysiology of HIR injury and the most suitable therapeutic
      strategy for this insult.

PMID- 10412152
TI  - [Selective and unselective clamping in liver surgery].
AB  - Liver surgery requires a reduction in the operative blood loss to avoid
      postoperative liver failure. We carried out elective hepatic resection in 229
      patients with Pringle's maneuver, which involves complete, intermittent clamping
      of the hepatic flow, and in 56 patients with selective vascular occlusion. Twenty
      seven donors for living-related liver transplantation were also included in the
      latter series. The clinical outcomes were evaluated based on clamping method
      used. The cumulative clamping time and amount of blood loss were 64 +/- 46 min
      (mean +/- SD) and 828 +/- 665 ml in the Pringle's maneuver group and 88 +/- 44
      min and 907 +/- 555 ml in the selective vascular occlusion group. Laboratory data
      showed good tolerance of vascular clamping in both groups, and serum aspartate
      aminotransferase levels returned to the baseline within one week. Operative
      morbidity rates were 23% and 27%, respectively, and no operative deaths occurred
      in this series. In living-related liver transplantation, modified selective
      vascular occlusion can preserve graft viability, as verified by the fact that all
      the recipients in this series had a good postoperative course, except for one
      death and one graft loss. In conclusion, intermittent total or selective vascular
      clamping is indispensable procedure during hepatic resection.

PMID- 10412153
TI  - [Usefulness and problems of total hepatic vascular exclusion in liver surgery].
AB  - Total hepatic vascular exclusion (THVE) is an useful method enabling safe and
      sure hepatic resection in patients with liver tumors adjacent to the large
      hepatic veins or inferior vena cava (IVC), tumor thrombi, invasion of the IVC,
      etc. To avoid serious hypotension during THVE, test clamping of the IVC prior to
      the procedure is indispensable. Hemodynamics should be carefully maintained by
      blood transfusion and sufficient infusion of colloidal and electrolyte solutions
      during THVE. The veno-venous bypass method which shunts blood from the IVC and
      portal vein to the superior vena cava enables prolongation of the period of THVE
      and is useful to avoid postoperative renal dysfunction. In situ liver perfusion
      with cold solution during THVE is an additional modality by which the liver is
      protected from warm ischemic injury and the duration of THVE can be further
      prolonged. However, the maximum duration of THVE is still controversial,
      especially in patients with chronic liver damage. The most appropriate method for
      THVE should be carefully chosen in each case by considering the type of lesion,
      liver function, and the goal of the surgery.

PMID- 10412154
TI  - [Microcirculatory derangement and ischemia of the pancreas].
AB  - We present a review of the microvascular morphology of the pancreas and
      microstructure of the pancreatic lobule, and introduce our experimental results
      on pancreatic microcirculation following acute pancreatitis. Impairment of
      pancreatic microcirculation in the early phase of acute pancreatitis may play a
      key role in the progression of this disease. Possible contributory mechanisms
      include increased vascular permeability, reduced blood flow, leukocyte
      endothelial cell interaction, and intravascular thrombus formation. We achieved
      direct-visualization and quantification of changes in microvascular permeability
      and leukocyte behavior in the pancreas with acute pancreatitis using an in vivo
      microscope system and off-line computer analysis. Bradykinin and oxygen radicals
      have been demonstrated to be involved in the increased vascular permeability in
      the early stage of cerulein pancreatitis. Gabexate mesilate (FOY) prevents the
      increase in vascular permeability, resulting in a decreased number of rolling
      leukocytes. Leukocyte adherence to the pancreatic microcirculation is a secondary
      event following permeability changes in acute pancreatitis. Leukocyte
      infiltration during aggravation of acute pancreatitis is mediated by leukocyte
      endothelial cell interaction via leukocyte integrin CD11b/18. The diamino
      pyridine derivative IS-741 inhibits the progression of pancreatic inflammation by
      down-regulating the expression of CD11b/18.

PMID- 10412155
TI  - [Pathophysiology and diagnosis of ischemic colitis].
AB  - Ischemic colitis is the most common manifestation of gastrointestinal ischemia.
      The presumed etiologies are numerous; however, it typically develops
      spontaneously. It is classified into the transient type, stricture type, and
      gangrenous type. The majority of patients with ischemic colitis, excluding the
      gangrenous type, follow a benign clinical course in the absence of major
      vasculature occlusion. It usually presents as an acute abdominal illness with
      bloody diarrhea. Diagnosis is confirmed by colonoscopy and/or barium enema.
      Nongangrenous ischemic colitis usually requires only conservative therapy,
      including repeated careful assessment, pain control, and fluid replacement, and
      is associated with a good prognosis. It may lead to the sequela of persistent
      segmental colitis or colonic strictures, occasionally requiring surgery. Urgent
      surgery and high morbidity and mortality rates are hallmarks of the gangrenous
      type. Special consideration must be given to those patients in whom ischemic
      colitis develops in the context of colon cancer or obstructive colonic lesions.
      Successful management of a patient with ischemic colitis requires a high degree
      of clinical suspicion, early diagnosis, careful follow-up, and prompt recognition
      of persistent disease.

PMID- 10412156
TI  - [Vascular surgical approach to mesenteric ischemia].
AB  - With the increase in the number of the elderly, the incidence of mesenteric
      ischemia should also increase. However, clinical diagnosis of this critical
      condition is difficult. Angiography should be performed promptly in patients with
      suspected mesenteric ischemia. Restoration of mesenteric circulation is the first
      step in the treatment. Endovascular treatment using a catheter for direct
      thrombolysis is recommended immediately after the diagnostic angiography. In
      addition to endovascular treatment, surgical reconstruction can be performed in
      patients with imperfect circulatory restoration. Intraoperative evaluation of
      intestinal viability must be performed after blood flow reconstruction using an
      accurate technique such as Doppler flowmetry, and then a precise decision on
      bowel resection and safety anastomosis can be mode.

PMID- 10412157
TI  - [Splanchnic hypoperfusion and distant organ injury].
AB  - Acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF) are
      the most common causes of death in surgical intensive care units. A variety of
      stimuli, such as major surgery, trauma, shock, thermal injury, acute
      pancreatitis, and ischemia-reperfusion injury, initiate a systemic inflammatory
      response that contributes to the development of these complications. Splanchnic
      hypoperfusion is a common clinical event in critically ill patients. Recently,
      measurement of the adequacy of gut circulation has been demonstrated as an
      excellent tool for prediction of outcome in these patients. The emphasis of this
      review is on events associated with intestinal ischemia-reperfusion and
      subsequent distant organ injury.

PMID- 10412158
TI  - [Microcirculation in the brain: viewpoint of autoregulation].
AB  - The cerebral blood flow (CBF) is autoregulated to a steady flow within certain
      ranges. CBF increases and cerebrovascular resistance (CVR) decreases dramatically
      with breakthrough of autoregulation when systemic arterial blood pressure
      exceeded the upper limit of the range. Many kinds of components in the brain as
      well neurogenic factors affect the autoregulation. The breakthrough of
      autoregulation does not occur in the presence of nitric oxide (NO) synthesis
      inhibitors, angiotensin converting enzyme inhibitor, prostanoids (PG)
      administered in the brain, sympathetic denervation, and sinoaortic denervation.
      The abolishment of breakthrough of autoregulation may be due to an increased
      tolerance of cerebral vessels to hypertension and the inhibition of the release
      of a vasodilator substance such as NO or PG. It appears that the tone of brain
      microvessels is controlled towards dilation by cholinergic innervation
      originating from the nucleus basalis of Meynert, glutamatergic or GABAergic
      mediated GABAA receptor, and by a mediator such as NO, bradykinin, PGs. Also, it
      is likely that candidates for constricting factors in intraparenchymal
      microvessels are norepinephrinergic from the superior cervical ganglion,
      serotonergic involved in 5-HT1D beta- and 5-HT2B-specific receptor subtypes,
      GABAergic mediated GABAB receptor, thromboxane, PG F2 alpha and the angiotensin
      system. The autoregulation of CBF is maintained by these neurogenic factors to
      prevent brain ischemia and hyperemia.

PMID- 10412159
TI  - [Microcirculation in the nasal mucosa].
AB  - The nasal mucosa has important physiological roles, including the removal of
      foreign bodies and the warming and humidification of inspired air. The
      microcirculation in the nasal mucosa facilitates the above processes and plays a
      role in the periodic swelling and shrinking of the nasal mucosa. In the present
      article, we reviewed the unique vascular architecture of the nasal mucosa, the
      complicated feature of innervations by the sympathetic, parasympathetic and
      sensory nerves, the actions of some chemical mediators released under some
      pathologic conditions, and the state of microcirculation in the nasal mucosa in
      cases of nasal allergy and cold exposure. Although it is likely that the
      sympathetic neurotransmitter norepinephrine has a major role in controlling the
      microcirculation in the nasal mucosa, the physiological or pathophysiological
      roles of other transmitters such as neuropeptide Y, ATP, acetylcholine, and
      vasoactive intestinal polypeptide seem to be minor and vary between species.
      Nevertheless, nitric oxide, which is shown to be released from parasympathetic
      neurons, is believed to have some physiological and/or pathophysiological role.
      Unfortunately, we have yet to describe the mechanism of nasal congestion. Further
      study of the function of nasal congestion in various illnesses could result in
      the alleviation of unpleasant symptoms.

PMID- 10412160
TI  - [Microcirculatory hemodynamics in oral tissues with reference to neurogenic
      response and reactive oxygen species interaction].
AB  - The primary purpose of the microcirculation is to transport nutrients and oxygen
      and to remove metabolic waste products from tissues. It is also well known that
      the fundamental mechanism for vascular control is the local regulation of the
      basal vascular tone, which is reinforced by blood pressure and counteracted by
      tissue metabolites. Thus, the well-being of the tissue depends on the circulatory
      transport process, which is governed by many functional parameters of the
      microcirculation such as blood flow, blood volume, intravascular and
      extravascular pressures, and capillary permeability. Inflammatory reactions in
      oral tissues can be initiated by many different insults to the tissues, and the
      reaction itself can be expressed in various ways. In addition, the tissues seem
      to have many "backup" systems, so that any one response can be produced in
      several ways, which is important for a reaction that has a survival value. A
      recent concept is that repeated stimulation of sensitive teeth may induce pulpal
      changes; this could occur through induction of neurogenic inflammation and
      alteration of pulpal blood flow. One possibility is that production of reactive
      oxygen species, as well as release of the sensory neuropeptides, at sites of
      inflammation contributes to alterations in local blood flow. In addition to the
      part played by the neurogenic mediators, nitric oxide participation and its
      interaction with oxygen-derived free radicals in oral tissue hemodynamics are
      also discussed.

PMID- 10412161
TI  - [Microcirculation in the myocardium].
AB  - The coronary artery supplies the arterial blood that contains oxygen and
      nutrients for the myocardial tissue to produce high-energy phosphates
      aerobically. The left anterior descending and circumflex coronary arteries run on
      the epicardial surface of the left ventricle, turn toward the endocardium at a
      right angle, and nourish the tissues of the subendocardinal layers with the
      arterial blood. Cessation of coronary blood flow makes the myocardium ischemic.
      The endocardium is particularly susceptible to ischemia because the arteries that
      run to the endocardium are pressed due to extravascular compression during every
      systole. Coronary vasodilators are still used as anti-anginal drugs. However, a
      potent coronary vasodilator may cause coronary-steal and thereby worsen the
      ischemia-induced myocardial injury. We will demonstrate changes in the
      microcirculation of the ischemic myocardium caused by coronary vasodilators and
      demonstrate that a coronary vasodilator is not always effective on the ischemic
      myocardium.

PMID- 10412163
TI  - [Neuronal control of mesenteric circulation].
AB  - The mesenteric circulation plays an important role in maintenance of systemic
      blood pressure and regulation of tissue blood flow. The tone of the mesenteric
      artery and resistance blood vessels are mainly regulated by sympathetic
      adrenergic nerves through the release of neurotransmitter noradrenaline and also
      controlled by nonadrenergic noncholinergic (NANC) nerves and possibly by
      parasympathetic cholinergic nerves. Noradrenaline and adrenergic cotransmitters
      including neuropeptide Y and adenosine triphosphate act as a vasoconstrictor
      neurotransmitter for sympathetic nerves. While, dopamine, calcitonin gene-related
      peptide and acetylcholine act as a vasodilator neurotransmitter for adrenergic,
      NANC and cholinergic nerves, respectively. In the mesenteric circulation, these
      nerves containing various neurotransmitters and cotransmitters interact and
      modulate each other via feedback autoregulatory mechanisms and neuromodulation of
      various vasoactive substance to regulate vascular resistance.

PMID- 10412162
TI  - [Vasomotor control of the pulmonary circulation].
AB  - It was demonstrated that pulmonary vessels, in contrast to systemic vessels, 1)
      have a low basal vascular tone, 2) constrict in response to hypoxia and 3) do not
      display significantly prominent vasomotion during autonomic nerve stimulation.
      However, details about these characteristics have not been clarified sufficiently
      by conventional methods; namely, measuring pressure-flow relationships and
      vascular tension of isolated larger conduit pulmonary vessels. Recent
      technological advances in studying pulmonary circulation now permit us to reveal
      that vasomotor responses to respiratory gases and neurohumoral factors differ not
      only quantitatively but also qualitatively between the central conduit and
      peripheral resistance vessels (approximately 100- to 500-micron diam.). They also
      reveal that an increase in pulmonary sympathetic nerve activity can cause
      pulmonary vasodilation as well as vasoconstriction. The former has been partly
      explained by the most recent findings regarding the distribution differences of
      NO synthases and K+ channels between the resistance and conduit vessels.
      Concerning the latter, initial vascular tone appears to play an important role.
      The increased pulmonary sympathetic nerve activity has a beta-receptor-mediated
      pulmonary vasodilator effect under low pulmonary vascular tone conditions but an
      alpha-receptor-mediated constrictor effect under enhanced vascular tone
      conditions. This may serve to maintain homeostasis of the pulmonary circulation
      and a good balance between the right and left ventricle outputs. Here, I have
      reviewed new developments related to the mechanisms for controlling pulmonary
      vascular tone under different states: normal, acute and chronic hypoxia, and
      hemorrhagic hypotension. I have also described the effects of inhaled NO and PGI2
      as selective pulmonary vasodilators used for pulmonary hypertension.

PMID- 10412164
TI  - [Renal microcirculation].
AB  - The blood flow to the kidney averages about 20% of the cardiac output and the
      renal circulation affects urine formation. The renal microcirculation is unique.
      Glomerular circulation is mainly regulated by two resistance arterioles, the
      afferent arteriole and the efferent arteriole. Two capillary beds are arranged in
      series between the arterial and venous circulation. Many experimental findings
      show that each arteriole has a different sensitivity to various stimuli.
      Moreover, several anatomic characteristics of the renal circulation display
      heterogeneity. Several regional differences in the renal microcirculation may
      subserve the excretory function of the kidney. Technological advances now permit
      direct observation of renal arterioles and measurements of microvascular
      pressure, flows and resistances. In this mini review, we introduce 1)
      characteristics of renal circulation, 2) techniques for study of renal
      microcirculation, 3) effects of angiotensin II on the renal microvasculature, and
      4) future directions for the study of renal microcirculation.

PMID- 10412165
TI  - [Adhesive and sealing effects of TO-193 on tissues and organs in various
      experimental models].
AB  - We studied the adhesive and sealing effects of sheet style fibrin adhesive, TO
      193 (TachoComb), on some tissues and organs, comparing them with those of sheet
      style collagen agent, collagen sponge, Novacol, and Avitene and liquid fibrin
      adhesive agent, Beriplast P. TO-193 showed more a potent adhesive effect on liver
      than the sheet style collagen agents and was more potent on bone and skin than
      the liquid fibrin adhesive agent. Furthermore, TO-193 had a potent sealing effect
      at the site of incomplete suture immediately after application on a motile organ
      such as lung and stomach. These effects may be partly attributable to rapid
      expression of the effect due to the presence of a high concentration of
      fibrinogen on coverage. Enhancement of fibrin penetrability to the tissues by
      compression and inhibition of cleavage of coverage by the collagen sponge also
      may be participating in the effects of TO-193. These results suggest that TO-193
      will be a valuable adhesive and sealing agent.

PMID- 10412166
TI  - NP perspectives on an American tragedy.

PMID- 10412167
TI  - End of life.

PMID- 10412168
TI  - Assessing and managing the patient with headaches.
AB  - Headaches are considered the most common type of pain; more than 40 million
      Americans seek treatment each year. A clear understanding of the types and
      possible causes of headache pain is essential to adequately assess and manage the
      patient with headaches. Headaches can be categorized as either primary or
      secondary to an underlying and usually treatable cause. Most headaches are
      primary; this includes migraine and variants, and cluster and tension-type
      headaches. Before assuming a primary diagnosis, however, the clinician must rule
      out headaches secondary to an underlying cause so that further investigation,
      treatment, or referral may be initiated.

PMID- 10412169
TI  - Hyaluronic acid treatment for osteoarthritis of the knee.
AB  - Osteoarthritis of the knee is a leading cause of chronic disability in the United
      States. It is a heterogeneous condition that causes pathogenic changes that are
      presumably irreversible. In many cases, knee pain is often progressive and leads
      the patient to seek medical attention. Pharmacologic and nonmedicinal treatments
      are, in most cases, only modestly successful in relieving pain. Hyaluronic acid
      (HA) functions as the backbone of the proteoglycan aggregates necessary for the
      functional integrity of articular cartilage of the knee. Two drugs made up of HA
      derivatives have recently become available for patients in whom simple analgesics
      and conservative non-pharmacologic therapy have failed. This article reviews the
      epidemiology, pathogenesis, diagnosis, and medical management of osteoarthritis
      of the knee, with an emphasis on the physiologic and pharmacologic mechanisms of
      HA. Health care providers may administer HA via intra-articular injection in
      primary care, rheumatologic or orthopedic settings, or they may refer their
      patients to specialists for consultation.

PMID- 10412171
TI  - Using beta-blockers in the treatment of heart failure.

PMID- 10412170
TI  - Caring for the patient with Paget's disease of the bone.
AB  - Approximately 1 to 3 million Americans suffer from Paget's disease of the bone.
      This chronic disease often results in pain, deformity, and mobility impairments,
      and can dramatically impair a patient's quality of life. The primary care
      provider plays a pivotal role in diagnosing and managing the patient with Paget's
      disease. This article discusses Paget's disease diagnosis, management,
      pharmacologic therapy, referral, and follow-up.

PMID- 10412172
TI  - Aseptic herpetic meningitis: an uncommon genital herpes sequelae.
AB  - Aseptic herpetic meningitis is a clinical syndrome characterized by fever,
      headaches, confusion, and a combination of meningeal signs. The spinal fluid
      findings consist of an increase in mononuclear cells (mononuclear pleocytosis),
      increased protein concentration, and normal glucose concentrations. Aseptic
      herpetic meningitis is thought to be caused by a viral infection, although the
      specific virus is usually not demonstrated. The condition is self-limited and
      requires no treatment.

PMID- 10412173
TI  - [Christian beliefs and the performance of autopsies].

PMID- 10412174
TI  - [Confusing tissue samples: causes, consequences, prevention].
AB  - The rising numbers of tissue samples for securing a diagnosis has led to a
      multitude of tissue samples in pathology institutes. Criteria and measures for
      ensuring the quality of histological diagnosis have been developed. Corresponding
      rules for the organization of the tissue sampling up to their processing do not
      yet exist. Suspicion of interchanged samples occurs much more often than it
      actually happens; however, it is important to be aware of the possibility so as
      to inform the clinician and to eliminate any possible causes of the confusion.
      The civil and penal consequences of such an interchanging, the subsequent
      "incorrect" diagnosis and the therapeutic measures are secondary compared to the
      potentially dramatic consequences for the patient. Important causes for an
      interchanging and possible preventive measures are presented.

PMID- 10412175
TI  - [Argyrophilic grain disease: differentiation from Alzheimer disease].
AB  - Argyrophilic grain disease (AgD) constitutes one cause of late onset dementia and
      is histologically characterized by the presence of abundant argyrophilic grains
      and coiled bodies. Both abnormalities are found mainly in limbic structures,
      among them the sector CA1 of the hippocampus, the entorhinal cortex, and the
      amygdala. Using appropriate silver staining techniques, they are easily
      detectable and can easily be distinguished from neurofibrillary lesions of
      Alzheimer's disease (i.e., tangles and threads). Although the histopathology of
      AgD is well characterized, the nosological status is still unclear because most
      cases of AgD are associated with Alzheimer-type changes. For some authors,
      therefore, AgD is considered a variant of Alzheimer's disease rather than a
      distinct disease entity. The present review is aimed at presenting argyrophilic
      grain disease to a larger readership than just neuropathologists who are
      interested in neurodegenerative disorders. In this review we summarize
      morphological, immunohistochemical, clinico-pathological and genetic data
      obtained in more than 90 subjects with AgD. The main conclusions of this review
      are that AgD represents one of the most frequent, dementing disorders of old age
      and that it has to be clearly distinguished from Alzheimer's disease.

PMID- 10412176
TI  - [Peritoneal mesothelioma--incidence and etiology].
AB  - A total of 70 malignant and 4 benign peritoneal mesotheliomas were diagnosed by
      the German Mesothelioma Registry between 1992 and 1998. Malignant mesotheliomas
      developed mainly in men (55/70); only one man had a benign peritoneal alteration.
      Age at first diagnosis of malignant mesotheliomas is about 59 years; the women
      are on average 4 years younger than the men. Mean survival time ranges about 1
      year; in 6 of 38 patients longer survival times of up to 7 years are known. The
      epitheloid subtype predominates, but no effect on survival time is noticed. The
      percentage of patients with combined asbestos-associated lung fibrosis is higher
      than that for pleural mesotheliomas; these patients become ill about 6.5 years
      earlier. The latency period is 36 years on average. For most patients asbestos
      exposure is related to their occupation mainly in metal industries, asbestos
      industries, and in the building trade. There is no evidence for an induction of
      benign peritoneal alterations by asbestos dust.

PMID- 10412177
TI  - [Gorham-Stout idiopathic osteolysis--a local osteoclastic hyperactivity?].
AB  - One rare case of so-called massive idiopathic osteolysis Gorham-Stout is
      presented. In a 77-year-old female patient the whole right femoral head and neck
      of femur was resorbed within 2.5 month following trauma. As a histologic cause
      for the osteolysis, a marked stimulation of osteoclasts on the spongiosa,
      especially intracortically, was observed. The course and the clinical findings
      are described, and the pathogenesis and treatment are discussed in comparison
      with the present literature. The results suggest that an early antiresorptive
      therapy (calcitonin, bisphosphonates) could stop the progressive osteolytic
      changes.

PMID- 10412178
TI  - [Hyalinizing spindle cell tumor with giant rosettes. Case report with
      immunohistochemical characterization].
AB  - This is a case of a 46-years-old male patient with a long-standing history of
      lower abdominal complaints. A 6-cm measuring tumor was detected by CT and
      subsequently surgically removed. Classification of this tumor and prognosis was
      problematic in frozen section and paraffin-embedded material, including
      immunohistochemical studies. The immunohistochemical findings were compatible
      with myofibroblastic differentiation of tumor cells. The histologic pattern
      resembled a "hyalinizing spindle cell tumor with giant rosettes" as recently
      published. Even if there were certain discrepancies in the immunohistochemical
      findings in our case, we also recommended treating this tumor as a low-grade
      sarcoma. The malignancy was also supported by marked proliferative activity
      demonstrated by MIB 1/KI 67 expression in numerous tumor cells. Finally, it has
      not yet been determined whether the hyalinizing spindle cell tumor is a pattern
      associated with a certain cellular differentiation or a pattern common to several
      mesenchymal tumor types.

PMID- 10412179
TI  - [Renal oncocytomatosis].
AB  - Multiple and bilateral oncocytomas are rare. There are only ten cases that have
      been previously described. Three of these displayed multiple and bilateral
      oncocytomas and microoncocytomas, a so-called oncocytomatosis. This report
      describes a case of renal oncocytomatosis found at autopsy. In addition, we found
      an adrenal adenoma, a pheochromocytoma and thoracic cicatrices 4 years after
      curatively resected large cell carcinoma of the lung. In the distal renal tubules
      we found oncocytic epithelial cells, with partial transition into
      microoncocytomas. Immunohistochemically, these and the main oncocytomas were CD
      10 negative. These findings support the origin of oncocytoma from oncocytically
      transformed distal tubular epithelium. CGH analysis of the different tumors
      revealed no common cytogenetic changes. Coexistence of renal oncocytoma with
      other tumors is rare. Hitherto, coexistence of a renal oncocytomatosis with
      multiple tumors has not been described.

PMID- 10412180
TI  - [Recurrent, primary multifocal malignant melanoma of the mucous membrane of the
      upper respiratory tract. Peculiarities of the in-situ components].
AB  - We report on a patient who at 61 years of age presented with two nodular
      melanomas in the right nasal cavity. These tumors were limited to the mucosal
      membrane and were accompanied by a large amount of atypical hyperplasia of the
      melanocytes within the glandular and surface epithelium of various other samples
      of the mucous membrane, a finding also verified immunohistochemically. These
      tumors were treated surgically. In the clinical course, after a prolonged tumor
      free interval, a malignant melanoma of the contralateral nasal cavity occurred,
      in addition to recurrences in the area of the primary tumor. It seems likely that
      the large, diffuse proliferation of atypical melanocytes observed could have been
      the starting point of both the tumor recurrences and the second primary. Thus, in
      a histologically proven melanoma in the mucous membranes of the upper respiratory
      system, a more intense preoperative histological diagnostic procedure, in given
      cases with the assistance of immunohistochemical methods, could be useful to
      demonstrate intraepithelial atypical melanocytes. It is possible that by doing
      this the present poor prognosis for mucosal melanomas of the upper respiratory
      tract might be improved.

PMID- 10412181
TI  - [The Chemnitz Pathologic-Hygienic Institute and its leader from 1898 to 1998].
AB  - The 100-year-history of Pathological Anatomy in Chemnitz is described by
      edification and fall of its buildings as well as the main dates of its leaders.
      From these the founder of the institute Coelestin Nauwerck, his most important
      disciple Martin Staemmler and the newfounder after the 2nd world war Walther
      Panofsky are especially mentioned. The article also refers to the involvement of
      Staemmler in Nazism and the injury done to Panofsky by it. The importance of the
      microbiological-hygienical departure during a long period is accented.

PMID- 10412182
TI  - Psychiatric genetics in Israel.

PMID- 10412183
TI  - Park City, Utah Molecular Psychiatry Meeting, February 1998.

PMID- 10412184
TI  - Maternal inheritance of manic depression in hemizygotes for the G6PD
      Mediterranean mutation. Indirect evidence for Xq28 transmission in Sardinia.
AB  - Both X-linkage and a parent-of-origin effect have been hypothesized in manic
      depressive disorder. We have previously shown an allelic association between X
      linked G6PD deficiency and manic depression in Mediterranean populations. To test
      both X-linkage and a parent-of-origin effect in manic depression further, we have
      studied 274 Sardinian manic-depressive probands and their parents. Excess of
      maternal transmission (P = 0.005) of major affective disorder was found in male
      probands carrying the G6PD-Mediterranean mutation. Our results provide indirect
      molecular support for an association between manic depression and the Xq28
      chromosome region in Sardinia. Further studies on Xq28 using tests of allelic
      association and transmission disequilibrium with multiple DNA markers are
      required, to clarify the nature of the association we have found. Our study
      cannot implicate or exclude a direct role for G6PD deficiency in the aetiology of
      manic depression.

PMID- 10412185
TI  - Association analysis of exonic variants of the gene encoding the GABAB receptor
      and alcohol dependence.
AB  - The present association study tested whether genetic variation of the GABAB
      receptor (GABABR1) gene confers vulnerability to alcohol dependence. The
      genotypes of three DNA sequence variants in exons 1a1, 7 and 11 of the GABABR1
      gene were assessed in 234 German controls and 350 German alcohol-dependent
      subjects, including three more homogeneous subgroups of alcoholics, marked by (1)
      history of parental alcoholism (n = 121); (2) history of alcohol withdrawal
      seizure or delirium (n = 108); and (3) comorbidity of dissocial personality
      disorder (n = 60). The allele frequencies of none of the investigated GABABR1
      variants differed significantly between the controls and the groups of alcoholics
      when a correction for multiple testing was taken into account (P > 0.004).
      However, trends (P < 0.10) towards an excess of the Ser489 allele of the exon 7
      polymorphism were found in the subgroups of alcoholics, and of the common allele
      of the exon 11 polymorphism in the entire sample of alcoholics (P = 0.032),
      alcoholics with parental alcoholism (P = 0.084) and the dissocial alcoholics (P =
      0.037). Our findings suggest that the investigated GABABR1 variants do not
      contribute a substantial effect (RR > 3) to the genetic variance of alcohol
      dependence. Nevertheless, the hints towards potential allelic associations of the
      exon 7 and 11 polymorphisms with dissocial alcoholism emphasize further studies
      to test more defined phenotype-genotype relationships.

PMID- 10412186
TI  - Detecting QTLs for uni- and bipolar disorder using a variance component method.
AB  - The objective of this study was to use a robust variance component method to
      analyse unipolar and bipolar disorder in a large Scottish extended family (n =
      168) in which linkage between markers and disease has been previously reported on
      the short arm of chromosome 4. Data consisted of diagnosed clinical uni- or
      bipolar disorder on 143 individuals, with microsatellite marker information on
      109 of these individuals. The incidence of unipolar and bipolar disorder in the
      family was 17/143, and 11/143, respectively. Eleven linked markers on chromosome
      4, spanning a region of approximately 26 cM, were used in the analysis. The
      statistical analysis was performed in two steps. First, pairwise identify-by
      descent (IBD) coefficients for all individuals in the pedigree were calculated at
      1 cM intervals, using all marker data simultaneously, with a Monte Carlo Markov
      Chain algorithm. Second, the variance in the trait of interest was partitioned
      using residual maximum likelihood (REML). Three components of variance were
      estimated: (i) a genetic component associated with the average relationship
      between individuals using the numerator relationship matrix, (ii) a genetic
      component associated with a chromosome location using the estimated IBD
      coefficients, and (iii) a residual component. The test statistic (LOD score) was
      calculated from the maximum likelihood of the full model, fitting all three
      variance components, and the maximum likelihood value from the reduced model,
      fitting a polygenic and residual component. The largest LOD scores (maximum LOD =
      5.9), were found in a region spanning about 10 cM, when the trait was defined as
      the occurrence of either uni- or bipolar disorder. The putative QTL explained
      about 25% of the total variation in the trait.

PMID- 10412187
TI  - Psychiatric disorder and cognitive function in a family with an inherited novel
      mutation of the developmental control gene PAX6.
AB  - The PAX family of developmental control genes are known to play important roles
      in the early patterning of the central nervous system. One member of this family,
      PAX6, is involved in eye development in invertebrates as well as in mouse and
      man, but is also widely expressed in the developing forebrain. Humans with a
      mutation in this gene have abnormalities of eye development, and the results
      presented here suggest, for the first time, that this mutation may also be
      associated with subtle abnormalities of frontal lobe function in the family
      studied. We carried out genotyping of individuals within a single family, with
      and without the characteristic eye abnormalities of PAX6 mutation, and only those
      individuals with the mutation showed significant abnormalities on tests of
      frontal lobe function. These individuals also had higher rates of psychiatric
      disorder. PAX6 is highly conserved between mouse and man, and although the
      neuroanatomical phenotype associated with PAX6 heterozygosity has only been
      studied in mice, the resultant cellular disorganization seen in mice is likely to
      be present in the human forebrain. Although these mice have no obvious
      behavioural phenotype, the results presented here suggest that humans with the
      equivalent mutation display a neurobehavioural phenotype.

PMID- 10412189
TI  - Lack of association between suicide attempt and a polymorphism at the dopamine
      receptor D4 locus.
AB  - Dopaminergic neurotransmission has been implicated in suicidal behaviour. The 48
      bp-repeat polymorphism in the gene coding for dopamine receptor D4 was
      investigated in a sample of suicide attempters (n = 165) and healthy control
      subjects (n = 99). No association between suicide attempts and this polymorphism
      was observed. Neither did any significant differences emerge in comparison with
      control subjects when the suicide attempters were grouped into different
      diagnostic categories: unipolar (n = 45), anxiety (n = 23), adjustment (n = 37)
      and personality disorders, cluster B (n = 36). The results suggest that alleles
      defined by the investigated polymorphism do not have a major impact on suicidal
      behaviour.

PMID- 10412188
TI  - hSKCa3: a candidate gene for schizophrenia?
AB  - Recently, case-control studies have suggested an association between the
      polymorphic CAG repeat in the neuronal potassium channel gene hSKCa3 and an
      increased susceptibility to schizophrenia, with larger repeats being
      overrepresented in schizophrenic patients. Therefore, we have examined the CAG
      repeat polymorphism in hSKCa3 and four adjacent microsatellite markers in 12
      multiplex schizophrenia families. On performing the extended
      transmission/disequilibrium test (ETDT), neither allele-wise (P = 0.67) nor
      genotype-wise (P = 0.071) analysis yielded evidence to support linkage
      disequilibrium between schizophrenia and the hSKCa3 CAG repeat alleles. No
      significant results were produced performing parametric and non-parametric
      linkage analysis between schizophrenia and hSKCa3, as well as the four
      microsatellite markers. Thus, our study does not support the involvement of
      hSKCa3 in schizophrenia. Furthermore, we refined the physical localization on
      chromosome 1q21.3 using linkage analysis. No recombination was seen between
      markers D1S2624 and D1S1600 and the polymorphic CAG repeat in hSKCa3. LOD scores
      of 19.44 and 12.97, respectively, were obtained at a recombination fraction of
      0.00.

PMID- 10412191
TI  - A common C-1018G polymorphism in the human 5-HT1A receptor gene.

PMID- 10412190
TI  - Allelic variation of the 5-HT2C receptor (HTR2C) in bulimia nervosa and binge
      eating disorder.
AB  - The 5-HT2C (serotonin-2C, HTR2C) receptor is implicated in the pathophysiology of
      eating disorders. There is a common polymorphism of the human 5-HT2C receptor at
      codon 23 (cys23ser) which has been reported to be a risk factor for certain
      psychiatric disorders and a predictor of their pharmacotherapeutic response. We
      examined whether this variant was associated with the eating disorder bulimia
      nervosa or binge eating disorder in a well-characterized community sample of 163
      women, aged 16-35 years. Genotype and allele frequencies were entirely unaltered
      in both groups, compared to screened healthy controls from the same population.
      We conclude that allelic variation does not account for the involvement of the 5
      HT2C receptor in these eating disorders.

PMID- 10412192
TI  - A human period gene (HPER1) polymorphism is not associated with diurnal
      preference in normal adults.
AB  - Mammalian circadian rhythmicity has recently been shown to be regulated at the
      genetic level by transcription--translation feed-back loops. Key molecular
      components such as Clock, Bmal-1, Timeless and three Period proteins have been
      isolated in mammals. In this study, we hypothesized that polymorphisms at the
      level of one of these genes--HPER1--could be associated with differential
      morningness-eveningness tendencies. The sample comprised 463 middle-aged
      participants enrolled in the Wisconsin Sleep Cohort Study. Diurnal preferences
      were evaluated using the Horne-Ostberg questionnaire. An A to G synonymous
      substitution at position 2548 was identified in HPER1 c-DNA sequence by comparing
      available sequence data. This polymorphism was verified by sequencing and typed
      using established oligotyping techniques in all subjects, yielding allele
      frequencies of 0.85 and 0.15 for HPER1 2548G and HPER1 2548A, respectively.
      Morningness-eveningness scores were then compared between genotype groups. In
      contrast to data previously published using a Clock polymorphism, scores did not
      differ significantly across HPER1 groups. These results suggest that polymorphism
      at the level of HPER1 does not significantly modulate morningness-eveningness
      tendencies in the general population.

PMID- 10412193
TI  - Association study of the CACN1A4 (SCA6) triplet repeat and schizophrenia.
AB  - The P/Q type Ca2+ channel alpha 1-subunit (CACN1A4) gene on chromosome 19p13 is a
      promising candidate susceptibility locus for schizophrenia. Point mutations in
      CACN1A4 cause familial hemiplegic migraine and episodic ataxia. Expansion in a
      coding 3' CAG repeat causes spino-cerebellar ataxia type 6 (SCA6). The mouse
      mutant phenotype totterer has a form of petit-mal epilepsy. These are
      neurological conditions, all of which exhibit features in common with
      schizophrenia. The 19p13 area is also paralogous to other genomic regions of
      interest in schizophrenia genetics. For these reasons, we performed an
      association study with the CAG repeat and schizophrenia using 225 Scottish
      schizophrenia and 198 unrelated Scottish controls. The repeat was not associated
      with the disorder (P = 0.72) and neither did the schizophrenics have
      significantly longer alleles than the controls (P = 0.45). We conclude that the
      SCA6 CAG repeat is not associated with schizophrenia susceptibility. However, it
      remains possible that other variants in the region could be involved.

PMID- 10412194
TI  - [Pathophysiology of cerebral ischemia].
AB  - After cerebral ischemia, brain cells are injured by a number of different
      mechanisms. While the blood flow disturbance and consecutive energy depletion, is
      the initial event, excitotoxicity, peri-infarct-depolarisations, inflammation and
      apoptosis are most important subsequently. In this review, current knowledge on
      these events is summarized and it will be outlined how future treatment
      strategies can be derived from this knowledge.

PMID- 10412195
TI  - [Clinical diagnosis and stroke subtypes].
AB  - Sudden focal neurological symptoms are caused by stroke in 95%, either ischemic
      or hemorrhagic. Diagnosis and onset of treatment has to be rapid because the
      tolerance of the brain tissue to ischemia is lower than in any other tissue.
      First priority has stabilization of vital parameters such as maintenance of high
      blood pressure, rehydration, oxygen supply and correction of hyper-/hypoglycemia.
      Of equal importance is the prompt imaging of the brain to differentiate bleeding,
      complete brain infarction and early ischemic signs--only the latter permitting
      recanalization procedures by thrombolysis in a narrow time window of three hours.
      Distinct etiological diagnosis by Duplex scanning and echocardiography usually
      follows. This information determines the stroke subtype and the choice of
      secondary prevention measures.

PMID- 10412196
TI  - [Ultrasound diagnosis in acute stroke].
AB  - Doppler- and Duplex-sonography are noninvasive methods which provide helpful
      insight into brain blood supply by imaging extracranial neck (extracranial
      Doppler/Duplex) as well the intracranial basal arteries (transcranial Doppler,
      transcranial color-coded Duplex). Used in combination with ultrasound contrast
      agents, these methods are now able to supplement and often replace conventional
      angiography in clinical decision making processes. In acute stroke ultrasound
      techniques offer bedside options to localize the underlying pathogenic process
      and to record the actual cerebral blood flow. In addition, the Doppler method
      allows both detection of cerebral microemboli and their embolic source. Although
      technical limitation of the Doppler/Duplex method at present impairs imaging of
      the distal carotid arteries and of the vertebral arteries, extracranial and
      intracranial Doppler has been proven to be an important clinical tool providing
      highly useful clinical information with excellent reliability.

PMID- 10412197
TI  - [Which cardiologic diagnosis in patients with cerebral ischemia?].
AB  - There are few scenarios which need urgent clarification for the acute therapy of
      stroke. Normally, the patient's history, clinical findings, an electrocardiogram
      and a limited number of blood tests are suitable to govern precise management.
      Additional questions can be answered by transthoracic echocardiography (TTE)
      which gives information on left ventricular function, the development of thrombi
      after myocardial infarction, valvular lesions or vegetations. Transesophageal
      imaging (TEE) is required if TTE remains technically inadequate or if specific
      questions (e.g. the suspicion of a mitral valve prosthetic vegetation) shall be
      answered. The procedure is indicated only if therapeutic implications can be
      anticipated. Outside scientific protocols, the same criterion has to be applied
      when screening for potential sources of emboli (patent foramen ovale,
      atherosclerotic lesions of the ascending aorta) which can only be detected by TEE
      with adequate sensitivity and may be shown to require secondary prophylaxis in
      the near future.

PMID- 10412198
TI  - [Neuroradiologic diagnosis in acute stroke].
AB  - Noninvasive diagnostic procedures as spiral-CT (CT-angiography and perfusion-CT)
      as well as MRI-techniques (diffusion-imaging, perfusion-imaging and MR
      angiography) have enriched the diagnostic modalities in acute stroke. Angiography
      by MRI or CT has replaced digital subtraction angiography in most acute stroke
      cases. Despite of the advantages of MRI, CT still remains the procedure of choice
      in acute stroke. 1. Acute hematoma is easily detected by CT. 2. Occlusion of the
      main arterial stems are identified by CT-angiography. CT fulfills all the
      requirements for therapeutic decisions in acute stroke.

PMID- 10412199
TI  - [Acute therapy of stroke].
AB  - In recent years, organized basic care and the use of thrombolysis have been
      significantly effective in improving the acute stroke therapy especially for the
      ischemic stroke subtype. Combining the efforts for the basic care of stroke
      patients in the setting of the so-called stroke-units is the goal for a qualified
      therapy. Main parts in the basic care algorhythm are: optimization of the
      cerebral perfusion, maintenance of an initial high blood pressure, best oxygen
      supply, reduction of an increased body temperature and antiinfectious treatment,
      reduction in the rate of complications (like deep vein thrombosis, pneumonia,
      falls etc.) and the early physiotherapeutic therapy. Thrombolysis is restricted
      to selected patients with infarctions of the middle cerebral artery with symptoms
      starting not longer than three hours before treatment, without hemorrhage in CCT
      and fulfilling the strict in- and exclusion criteriae established by the recent
      multicenter trials. The use of rt-PA (0.9 mg/kg body weight) is recommended.
      Local fibrinolysis is used in patients suffering from basilar artery thrombosis.
      The use of other recanalizing techniques like PTA or stenting is yet still
      experimental in acute stroke patients. Neuroprotective agents which were proven
      in clinical trials are still not available. In recent years therapy with
      hemodilution was widely used, nowadays the intravenous application of fluids with
      hemodilutive properties is restricted to patients with reduced cardiac output and
      macroangiopathy to maintain or to improve cerebral perfusion. Early intravenous
      anticoagulation with heparin is defined as secondary prevention and not as
      therapeutical intervention.

PMID- 10412200
TI  - [Therapy of increased intracranial pressure in space-occupying media infarcts].
AB  - Following complete middle cerebral artery (MCA) infarction, up to 10% of all
      patients develop space-occupying brain edema. Despite intensive care therapy, 80%
      of these patients die due to transtentorial herniation. Over the past years, two
      alternative therapeutical options for the therapy of space-occupying MCA
      infarction have been developed. Decompressive surgery effectively decreases ICP
      and helps to improve outcome of these patients. Mortality can be reduced from 80%
      to less than 20%. Moderate hypothermia induced within the first hours after
      stroke has been shown to decrease ICP as well. However, the routine use of this
      therapy should not be recommended since further clinical studies are available.
      Knowledge on indications and limitations of different antiedema therapies will
      allow an effective therapy of increased ICP.

PMID- 10412201
TI  - [Secondary prevention of ischemic infarct].
AB  - Secondary prevention of transient or permanent cerebral ischemia is performed
      with antiplatelet drugs, e.g. aspirin, ticlopidine, clopidogrel or dipyridamole.
      The four substances have different indications and different side effect
      profiles. Patients with proven or suspected cardiac source of embolism are
      treated with anticoagulants. Patients with > 70% stenosis of the internal carotid
      artery and TIA or minor stroke receive carotid endarterectomy in combination with
      aspirin. Stroke risk is reduced between 20 and 65% by these measures.

PMID- 10412203
TI  - Microbial antagonism: a neglected avenue of natural products research.
AB  - Competition amongst microbes for space and nutrients in the marine environment is
      a powerful selective force which has led to the evolution of a variety of
      effective strategies for colonising and growing on surfaces. We are particularly
      interested in the chemical ecology of marine epibiotic bacteria which live on the
      surfaces of marine algae or invertebrates. Over 400 strains of surface-associated
      bacteria from various species of seaweed and invertebrate from Scottish coastal
      waters were isolated and 35% of them shown to produce antimicrobial compounds.
      This is a much higher proportion than free living marine isolates or soil
      bacteria. In addition, many strains which did not normally produce antibiotics
      could be induced to do so by exposing them to small amounts of live cells,
      supernatants from other bacterial cultures or other chemicals. Thus the number of
      strains able to produce antibiotics appears to be much higher than previously
      thought. Induction of antibiotic production was elicited by other marine
      epibionts and also by terrestrial human pathogens such as Bacillus subtilis,
      Escherichia coli and Pseudomonas aeruginosa. An understanding of this type of
      chemical induction and the factors regulating non-constitutive secretion of
      antimicrobial compounds will allow more effective strategies for searching for
      new chemotherapeutic antibiotics to be designed.

PMID- 10412202
TI  - The discovery and development of marine compounds with pharmaceutical potential.
AB  - An assessment of the current status of marine anticancer compounds is presented
      along with a case study on the aquaculture of Lissodendoryx n. sp. 1, a sponge
      that produces the antimitotic agents halichondrin B and isohomohalichondrin B.
      The use of polymer therapeutics to enhance the properties of marine natural
      products is considered.

PMID- 10412204
TI  - Screening of marine microalgae for bioremediation of cadmium-polluted seawater.
AB  - Twenty four strains out of 191 marine microalgal strains exhibited cadmium (Cd)
      resistance. They were tested for their Cd removal ability in growth media
      containing 50 microM Cd. Six strains out of 19 green algae and one out of five
      cyanobacteria removed more than 10% of total Cd from the medium. The marine green
      alga Chlorella sp. NKG16014 showed the highest removal of Cd 48.7% of total. Cd
      removal by NKG16014 was further quantitatively evaluated by measuring the amount
      of cell adsorption and intracellular accumulation. After 12 days incubation, 67%
      of the removed Cd was accumulated intracellularly and 25% of the Cd removed was
      adsorbed on the algal cell surface. The maximum Cd adsorption (qmax) was
      estimated to be 37.0 mg Cd (g dry cells)-1 using the Langmuir sorption model. The
      Cd removal by freeze-dried NKG16014 cells was also determined. Cd was more
      quickly adsorbed by dried cells than that by living cells, with a qmax of 91.0 mg
      Cd (g dry cells)-1.

PMID- 10412206
TI  - Cyanobacteria--a potential source of new biologically active substances.
AB  - Hydrophilic and lipophilic extracts of twelve cyanobacterial strains, isolated
      from fresh and brackish water, and two waterblooms, collected during the summer
      from the Baltic Sea, were investigated for their antibiotic activities against
      seven microorganisms. No inhibitory effects were found against the three Gram
      negative bacteria Escherichia coli, Proteus mirabilis and Serratia marcescens and
      the yeast Candida maltosa. Of all cyanobacterial samples, extracts from seven
      species inhibited the growth of at least one of the Gram-positive bacteria
      Micrococcus flavus, Staphylococcus aureus and Bacillus subtilis. M. flavus proved
      to be the most sensitive bacterium in the agar diffusion test system. In
      particular, the hexane and dichlormethane extracts showed antimicrobial effects.
      But only one water extract, prepared from material of a natural waterbloom, was
      found to be active.

PMID- 10412217
TI  - Gender and ethnic differences in the relationship between body esteem and self
      esteem.
AB  - Gender and ethnic differences in the relationship between body esteem and self
      esteem were examined to assess the degree to which these variables change in
      relation to each other over time. Difference scores (between Time 1 and Time 2, 1
      week apart) were obtained using the Self-Esteem Scale (M. Rosenberg, 1979) and
      the Body Esteem Scale (S. L. Franzoi & S. A. Shields, 1984) for 163 White women,
      140 White men, 55 Black women, and 37 Black men. The results indicated that the
      correlation of the difference scores was stronger for the group of White women
      than for the other 3 groups, suggesting that changes in self-esteem parallel
      changes in body esteem more for White women than for White men, Black men, and
      Black women. The findings are discussed in relation to the prevalence of bulimia
      nervosa among White women.

PMID- 10412218
TI  - The structure and correlates of kanashibari.
AB  - The present research is an examination of the parameters and correlates of
      kanashibari, operationally defined as being unable to move upon awakening or
      before falling asleep. Nonclinical Japanese individuals (N = 720), 34% of whom
      reported an experience of kanashibari at least once, were administered D. I.
      Templer's (1970) Death Anxiety Scale, R. Brown's (1990) Locus of Control Scale,
      and a questionnaire devised by the authors to collect information about
      kanashibari. The results showed that the kanashibari experience was positively
      correlated with death anxiety, with being a woman, and with external-other locus
      of control; this last measure assessed the extent to which these individuals felt
      that their lives were determined by fate, good luck, or chance.

PMID- 10412219
TI  - Family correlates of adolescent self-monitoring and social competence.
AB  - The purpose of this study was to investigate linkages between adolescent self
      monitoring, global social competence, and parenting and family environment
      dimensions of support and encouragement of autonomy. The sample consisted of 233
      young women and 199 young men at 2 southwestern universities. The primary
      measures used were the Family Environment Scale (R. H. Moos, 1981), the Parent
      Behavior Form (L. Worell & J. Worell, 1974), the revised Self-Monitoring Scale
      (M. Snyder, 1987), and the Texas Social Behavior Inventory (R. Helmreich, J.
      Stapp, & C. Ervin, 1974). Findings indicated that family variables are more
      strongly associated with social competence than with self-monitoring; family
      support was, overall, a more important ingredient of social competence than was
      autonomy. Women and men had different patterns of associations among specific
      variables.

PMID- 10412220
TI  - The effect on coping of monitoring, blunting, and the ability to achieve
      cognitive structure.
AB  - The effects of monitoring and blunting on individuals' choices of coping
      strategies and their effectiveness were examined. In addition, the authors
      explored the effect of the ability to achieve cognitive structure (AACS), defined
      as either or both of the following: (a) the ability to avoid information that
      either cannot be categorized or clashes with the individual's existing knowledge;
      (b) the ability to organize knowledge to fit an already existing cognitive
      structure. The results showed that in addition to the main effects of monitoring
      on problem-focused coping and social support seeking behaviors and of blunting on
      the use of wishful thinking, AACS was found to moderate blunting's influence on
      problem-focused coping as well as the effectiveness of distancing and avoidance
      coping. Finally, the results showed that the combination of high monitoring and
      high blunting sometimes contributes to coping effectiveness.

PMID- 10412221
TI  - The impact of emotional dissonance on organizational commitment and intention to
      turnover.
AB  - In the workplace, emotional dissonance is the conflict between experienced
      emotions and emotions expressed to conform to display rules. This study is an
      empirical examination of the impact of emotional dissonance on organizational
      criteria and its moderation by self-monitoring and social support. Emotional
      dissonance was theorized to stimulate turnover intentions, either solely through
      job dissatisfaction or through both job dissatisfaction and reduced
      organizational commitment. Job dissatisfaction was found to be the sole mediator.
      Emotional dissonance resulted in job dissatisfaction, which, in turn, stimulated
      withdrawal intentions. Self-monitoring and social support exerted moderator
      effects, albeit in opposing directions. Emotional dissonance aroused feelings of
      job dissatisfaction and reduced organizational commitment among high self
      monitors. In contrast, social support lessened the negative impact of emotional
      dissonance on organizational commitment.

PMID- 10412222
TI  - Continuity and change in the social competence of children with autism, Down
      syndrome, and developmental delays.
AB  - The aims of this longitudinal study were: (1) to assess the continuity and change
      in diagnosis, intelligence, and language skills in children with autism, Down
      syndrome, and other developmental delays, (2) to specify the deficits in social
      competence and language skills in these children, and (3) to identify precursors
      in the preschool period of gains in language skills and of peer engagement in the
      mid-school years. The initial sample consisted of 70 children with autism, 93
      children with Down syndrome, 59 children with developmental delays, and 108
      typically developing children, with the first three groups of children studied
      when they were between 2 and 6 years of age. At follow-up, 51 children with
      autism, 71 children with Down syndrome, and 33 children with developmental delays
      were assessed at mean ages around 10-13 years. The long-term follow-up showed
      little change in the diagnosis of autism but sizeable improvements in
      intellectual and language abilities within the autistic group, a pattern that was
      not seen in the children with Down syndrome. Unique deficits in joint attention,
      some forms of representational play, responsiveness to the emotions of others,
      and initiation of peer engagement were identified in the autistic children,
      whereas the children with Down syndrome seemed to have a specific deficit only in
      language. Joint attention skills were concurrently associated with language
      abilities in all groups and predicted long-term gains in expressive language for
      the children with autism. Children with autism, regardless of their level of
      functioning, were less socially engaged with classmates than the other
      developmentally disabled children because they infrequently initiated and
      accepted play bids, not because they were rebuffed by peers. Early nonverbal
      communication and play skills were predictors of the frequency of initiations of
      peer play for the children with Down syndrome as well as the extent of peer
      engagement of the children with autism. These results suggest that improvements
      in early communication and play skills may have long-term consequences for later
      language and social competence in these groups of children.

PMID- 10412223
TI  - Methodological issues in cross-syndrome comparisons: matching procedures,
      sensitivity (Se), and specificity (Sp).
AB  - We are impressed with the magnitude and potential importance of the studies
      presented by Sigman and Ruskin in this monograph. The within-syndrome findings
      for the children with autism concerning relations between early joint attention
      and a range of cognitive abilities a full 9 years later provide the strongest
      evidence so far that early nonverbal communication skills play an important role
      in the later development of language, intelligence, and social relations with
      peers. The purpose of the monograph was not limited to within-syndrome research
      questions, however. Sigman and Ruskin state that a major goal of the research
      reported in the monograph was to identify specific, unique, and universal
      deficits for autism and Down syndrome. They base their method of identifying such
      syndrome characteristics on the group-matching procedure. Given that this
      procedure is fraught with difficulties, we are concerned that many of Sigman and
      Ruskin's cross-syndrome comparisons may be incorrect. We do not mean to single
      out Sigman and Ruskin. The group-matching method is frequently used in special
      populations research, with the null hypothesis of no differences on the control
      variable being accepted at dangerously low p values. Our concerns with the group
      matching problem extend to much of the extant research that attempts to identify
      characteristics of individuals based on the performance of their syndrome group
      relative to a control group. The profiling procedure we outlined seems more
      fruitful and conceptually satisfying than the traditional matching method. When
      profiling is not possible, however, it is important to consider the impact of CA
      confounds and statistical decision procedures used to ensure matching on the
      control variable, when interpreting syndrome differences on variables of
      interest.

PMID- 10412224
TI  - Levels of selection, altruism, and primate behavior.
AB  - Altruistic behaviors seem anomalous from a traditional view of Darwinian natural
      selection, and evolutionary explanations for them have generated much discussion.
      The debate centers around four major explanations: classic individual-level
      selection, reciprocity and game theory, kin selection, and trait-group selection.
      The historical context and defining criteria of each model must be reviewed
      before its validity can be assessed. Of these proposed mechanisms, group
      selection historically has been the most controversial. Although the extent to
      which empirical data support group selection hypotheses is uncertain, there is
      evidence for group-level selection among avirulent virus strains and foraging ant
      queens. Researchers studying mammalian behavior, particularly primatologists,
      have largely dismissed models of group-level selection. Most discussion of
      altruism among primates has focused on differences in fitness among individuals
      within a single group, but students of altruistic behaviors exhibited by primates
      also need to investigate intergroup variation with respect to these behaviors.
      Various altruistic behaviors are likely to have evolved through different forms
      of selection, and each example of apparent altruism therefore needs to be
      evaluated separately.

PMID- 10412225
TI  - Interaction of the antitumour alkaloid coralyne with duplex deoxyribonucleic acid
      structures: spectroscopic and viscometric studies.
AB  - The interaction of coralyne, an antitumour alkaloid with natural and synthetic
      duplex DNAs was investigated under conditions where the drug existed fully as a
      true monomer for the first time using spectrophotometric, spectrofluorimetric,
      circular dichroic and viscometric techniques. The absorption spectrum of coralyne
      monomer showed hypochromic and bathochromic effects on binding to duplex DNAs.
      This effect was used to determine the binding parameters of coralyne. The binding
      constants for four natural DNAs and four synthetic polynucleotides obtained from
      spectrophotometric titration, according to an excluded site model, using McGhee
      von Hippel analysis, were all in the range of (0.38-9.8) x 10(5) M-1, and showed
      a relatively high specificity for the GC rich ML DNA and the alternating GC
      polynucleotide. The binding of coralyne decreased with increasing ionic strength,
      indicating that the binding affinity has a strong electrostatic component.
      Coralyne stabilized all the DNAs against thermal strand separation. The intense
      steady state fluorescence of coralyne was effectively quenched on binding to DNAs
      and the quantitative data on the Stern-Volmer quenching constant obtained was
      sequence dependent, being maximum with the GC rich DNA and alternating GC
      polymer. Circular dichriosm studies further evidenced for a strong perturbation
      of the B-conformation of DNAs consequent to coralyne binding with the concomitant
      development of extrinsic circular dichroic bands for the bound drug molecules
      suggesting their strong intercalated geometry in duplex DNAs. Further tests of
      intercalation using viscosity measurements on linear and covalently closed
      plasmid DNA conclusively proved the strong intercalation of coralyne in duplex
      DNA. Binding of the closely related natural alkaloid, berberine under these
      conditions showed considerably lower affinity to duplex DNAs in all experiments.
      Taken together, these results suggest that coralyne binds strongly to duplex DNAs
      by a mechanism of intercalation with specificity towards alternating GC duplex
      structure.

PMID- 10412226
TI  - Conformational features of a peptide model Ac-DTVKLMYKGQPMTFR-NH2, corresponding
      to an early folding beta hairpin region of staphylococcal nuclease.
AB  - Recent H-D exchange 1H NMR studies of the refolding of Staphylococcal nuclease
      (P117G) variant suggest that, a region of the protein corresponding to a beta
      hairpin in the native structure folded early in the refolding process. In order
      to investigate whether the formation of beta hairpin is an early folding event,
      we investigated the conformational features of the beta hairpin peptide model Ac
      DTVKLMYKGQPMTFR-NH2 from Staphylococcal nuclease with 1H NMR techniques. It
      appears that the peptide aggregates even at a low concentration. However, based
      on the observation of weak dnn(i, i + 1) NOEs between K8-G9, G9-Q10, an upfield
      shift of Gly9 NH and a low temperature coefficient (-d delta/dT) for Gly9 NH, we
      suggest that the sequence YKGQP as part of the beta hairpin peptide model samples
      conformational forms with reduced conformational entropy and turn potential. The
      presence of aggregation could be restricting the population of folded
      conformational forms and formation of beta hairpin at detectable concentrations.
      We suggest that, formation of beta hairpin could be an early event in the folding
      of Staphylococcal nuclease and this observation correlates with H-D exchange 1H
      NMR results and also with the prediction of a protein folding model proposed in
      literature.

PMID- 10412227
TI  - Chemical modification studies of Rhizomucor miehei protease: evidence for the
      role of basic amino acids in enzyme catalysis.
AB  - The effect of chemical modification on milk clotting and proteolytic activities
      of aspartyl protease obtained from Rhizomucor miehei NRRL 3500 was examined in
      the absence and the presence of its specific inhibitor pepstatin A. The effect on
      the ratio of milk clotting activity (MC) to proteolytic activity (PA), an index
      of the quality of milk clotting proteases was also determined. Modification of
      the enzyme with trinitrobenzenesulfonic acid, diethylpyrocarbonate and
      phenylglyoxal produced an increase in the ratio of MC/PA, while modification with
      2- hydroxy-5-nitrobenzyl bromide did not affect the ratio. Modification with N
      acetylimidazole resulted in a marginal increase in MC/PA ratio. Protection using
      pepstatin A during modification with phenylglyoxal, N-acetylimidazole and 2
      hydroxy-5-nitrobenzyl bromide, protected both MC and PA. In the case of
      modification by diethylpyrocarbonate, pepstatin A protected only MC. Pepstatin A
      did not protect both the activities on the modification of the enzyme by
      trinitrobenzene sulfonic acid. These observations indicate the presence of
      arginine, tyrosine and tryptophan at the catalytic site of the enzyme, for
      eliciting MC and PA of the enzyme. In general, modification of the positively
      charged residues increases the MC/PA ratio of the enzyme. In addition the
      modified lysine residues responsible for the inactivation of the enzyme were not
      involved in the active site of the enzyme. Thus the lysine residues might have a
      secondary role in enzyme catalysis. Further, histidine at the catalytic site was
      found to be exclusively involved in milk clotting activity. The enzyme with
      modified histidine residues were more susceptible to autocatalysis, indicating
      that histidine residues protect the enzyme against autolysis.

PMID- 10412228
TI  - Purification and characterizaton of plastidic pyruvate kinase from developing
      seeds of Brassica campestris L.
AB  - Plastidic pyruvate kinase (ATP: pyruvate phosphotransferase, EC 2.7.1.40) was
      purified to near homogeneity as judged by native PAGE with about 4% recovery from
      developing seeds of Brassica campestris using (NH4)2SO4 fractionation, DEAE
      cellulose chromatography, gel filtration through Sepharose-CL-6B and affinity
      chromatography through reactive blue Sepharose-CL-6B. The purified enzyme having
      molecular mass of about 266 kDa was quite stable and showed a broad pH optimum
      between pH 6.8-7.8. Typical Michaelis-Menten kinetics was obtained for both the
      substrates with K(m) values of 0.13 and 0.14 mM for PEP and ADP, respectively.
      The enzyme could also utilize CDP, GDP or UDP as alternative nucleotide to ADP,
      but with lower Vmax and higher K(m). The enzyme had an absolute requirement for a
      divalent and a monovalent cation for activity and was inhibited by oxalate,
      fumarate, citrate, isocitrate and ATP, and activated by AMP, aspartate, 3-PGA,
      tryptophan and inorganic phosphate. ATP inhibited the enzyme competitively with
      respect to PEP and non-competitively with respect to ADP. Similarly, oxalate
      inhibition was also of competitive type with respect to PEP and non-competitive
      with respect to ADP. This inhibition by either ATP or oxalate was not due to
      chelation of Mg2+, as the inhibition was not relieved on increasing Mg2+
      concentration even upto 30 mM. Initial velocity and product inhibition studies
      demonstrated the reaction mechanism to be compulsory ordered type. The enzyme
      seems to be regulated synergistically by ATP and citrate.

PMID- 10412229
TI  - Oxidation of phenols by horseradish peroxidase and lactoperoxidase compound II-
      kinetic considerations.
AB  - Oxidation of para substituted phenols by horseradish peroxidase compound II (HRP
      II) and lactoperoxidase compound II (LPO-II) were studied using stopped flow
      technique. Apparent second order rate constants (kapp) of the reactions were
      determined. The kinetics of oxidation of phenols by HRP-II and LPO-II have been
      compared with the oxidation potentials of the substrates. Reorganization energies
      of electron-transfer of phenols to the enzymes were estimated from the variation
      of second order rate constants with the thermodynamic driving force.

PMID- 10412231
TI  - Regional effects of ageing on Na+,K(+)-ATPase activity in rat brain and
      correlation with multiple unit action potentials and lipid peroxidation.
AB  - Effects of ageing on Na+,K(+)-ATPase activity in crude synaptosomal fractions
      from the rat brain parietal cortex, hippocampus, striatum and thalamus has been
      studied. From 12 months to 24 months, a progressive decline in enzyme activity in
      the parietal cortex, hippocampus and striatum was found which correlated with
      increase in lipid peroxidation in the three brain regions. In the thalamus,
      ageing did not affect the enzyme activity and lipid peroxidation. Age-related
      decline in multiple unit action potentials was also observed in two brain
      regions, viz. hippocampus and parietal cortex. Statistical correlations
      calculated by Pearson's correlation coefficient showed that decline in Na+,K(+)
      ATPase activity correlated to decline in multiple unit action potentials. There
      was rise in lipid peroxidation also and the data indicate that age-related
      changes in lipid peroxidation and Na+,K(+)-ATPase activity contribute to the
      deterioration of electrophysiological activity.

PMID- 10412230
TI  - A cysteine protease of Dieffenbachia maculata.
AB  - Plants of the genus Dieffenbachia, very popular as indoor ornamental plants, are
      known for their toxic as well as therapeutic properties. Their toxic
      manifestations have been partly attributed to their proteolytic activity. The
      work described in the present paper shows that stem leaves and petiole of
      Dieffenbachia maculata Schott, a commonly grown species, contain significant
      proteolytic activity, different parts showing different types of protease
      activities. Stem showed the highest enzyme activity and this protease was
      purified about 55 fold by solvent precipitation, gel filtration and ion exchange
      chromatography. The enzyme has a relative molecular mass of 61 kDa as determined
      by SDS-PAGE and has an optimum pH of 8.0 and optimum temperature of 50 degrees C.
      Effects of various substrates, inhibitors and activators indicate that the enzyme
      is a cysteine protease with leucylpeptidase activity.

PMID- 10412232
TI  - Decreased phospholipase A2 activity in butyrate differentiated HT29 cells.
AB  - Our earlier work has shown that in butyrate differentiated colonic HT29 cells,
      there is an alteration in phospholipid composition as compared to control. To
      know more about these changes, butyrate treated and control cell homogenates were
      incubated in presence of calcium and phospholipids were analyzed. It was observed
      that incubation with calcium was associated with increase in
      lysophosphatidylcholine (lysoPC) and free fatty acids and the increase was much
      higher in control as compared to butyrate treated cells. There was no alteration
      in lysoPC content. These products are formed by the action of phospholipase A2
      (PLA2) which is activated by calcium and suggests that butyrate-induced
      differentiation is associated with decrease in PLA2 activity.

PMID- 10412233
TI  - Characterisaton of human plasma thiol proteinase inhibitors.
AB  - Earlier, we had reported purification of three thiol proteinase inhibitors (TPI-1
      of 70 kDa, TPI-3 of 195 kDa and TPI-4 of 497 kDa) from human plasma. In the
      present study we report that TPI-1 binds to papain in the stoichiometry ratio
      (E/I) of 1:1 while TPI-3 and TPI-4 bind in the ratio of 1.5:1 and 3.2:1
      respectively. The K(m) for papain with BAPNA as substrate and Kcat/K(m) values
      for TPI-1, TPI-3 and TPI-4 were 2.7 x 10(-6) M, 0.84 nM/sec; 3.2 x 10(-6) M, 0.75
      nM/sec; and 3.6 x 10(-6) M, 0.72 nM/sec respectively. The Ki values were found to
      be 1.48 nM for TPI-1, 0.133 nM for TPI-3 and 0.117 nM for TPI-4. The UV
      absorption and fluorescence emission spectra study suggest involvement of
      aromatic residues in the binding process. This study suggests that TPI-4 is the
      most potent inhibitor of thiol proteinases.

PMID- 10412234
TI  - Erythrocyte sodium and Na+, K(+)-ATPase activity in untreated hypertensives and
      their first degree relatives.
AB  - In this paper we report the erythrocyte sodium concentration and Na+, K(+)-ATPase
      activity in 86 untreated hypertensives and their 77 first degree relatives and
      also in sex and age matched controls. There was significant increase in
      erythrocyte sodium both in the hypertensives and their first degree relatives (p
      < 0.01), whereas Na+, K(+)-ATPase activity was significantly reduced in the study
      group when compared with controls. The possibility of using these parameters as
      genetic markers is suggested.

PMID- 10412235
TI  - Heat mediated quick Coomassie blue protein staining and destaining of SDS-PAGE
      gels.
AB  - For the detection of proteins on sodium dodecyl sulphate-polyacrylamide gel
      electrophoresis, Coomassie blue is used commonly on account of its simplicity and
      reliability. In this report we show that enhanced heat, in addition to
      dramatically decreasing the time required for staining and destaining, also
      significantly increased the detection sensitivity. For a 1.5 mm gel, the staining
      time was 5 min at 55, 62.5 or 70 degrees C while the destaining time was 45, 45
      and 20 min respectively. For a 0.8 mm gel, the staining time could be reduced to
      1 min at 65 degrees C compared to 2 min at 60 degrees C and 5 min at 55 degrees
      C. The destaining time required was 8, 15 and 20 min at the respective
      temperatures.

PMID- 10412236
TI  - Quantitative structure-activity relationship study of iodinated analogues of
      trimetoquinol as highly potent beta 2-adrenoceptor ligands.
AB  - Trimetoquinol and its derivatives, reported to be highly potent beta 2
      adrenoceptor (beta 2-AR) and site-selective thromboxane A2/prostaglandin H2 (TP)
      receptor ligands are subjected to quantitative structure-activity relationship
      (QSAR) study. From the significant correlation equation, obtained between the
      binding affinity, pKi (beta 2-AR) and the substitutional physicochemical
      parameters such as molar refraction, (MR), hydrophobic constant, (pi) and
      resonance parameter, (R), the receptor binding interactions associated with the
      varying sites of these compounds are discussed. The QSAR study has also explored
      the possibilities of having the analogous of improved binding affinities in
      future synthetic efforts. Likewise, the ratio of binding affinities, expressed as
      log[Ki(beta 2-AR)/Ki alpha(TP)] related to two receptors are significantly
      correlated with MR and pi of the substituents and the relationship may,
      therefore, be helpful in developing the agents of greater selectivity on beta 2
      AR versus TP receptor and vice versa.

PMID- 10412237
TI  - QSAR study on 1-benzyl-4[w(substituted phthalimido)alkyl]piperidines:acetyl
      cholinesterase inhibitors.
AB  - QSAR studies on a series of 18 piperidine derivatives, which act as acetyl
      cholinesterase (AchE) inhibitors, have been performed using van der Waals volume
      (V omega) and topochemical index (tau). Significant correlations have been
      obtained, which make it clear that AchE inhibition activity is controlled
      dominantly by topo chemical index.

PMID- 10412238
TI  - I know where I stand!

PMID- 10412239
TI  - Dentists and HIV.

PMID- 10412240
TI  - Vital pulp capping: a worthwhile procedure.
AB  - Despite the progress made in the field of pulp biology, the technique and
      philosophy of direct vital pulp capping remains a controversial subject.
      Clinicians are well aware of the immediate and long-term success rates after root
      canal therapy, but are less certain of the success of vital pulp capping.
      Researchers have demonstrated that exposed pulps will heal and form reparative
      dentin. It is realized now that the variable prognosis of vital pulp capping is
      predominately a restorative issue. The factors that can produce a successful
      vital pulp cap are discussed in conjunction with two popular techniques.

PMID- 10412241
TI  - The truth about HIV/AIDS and infection control practices in dentistry.

PMID- 10412243
TI  - Antibiotics for the millennium bug in your practice.

PMID- 10412242
TI  - HIV/AIDS and infection control practices in dentistry: a rebuttal.

PMID- 10412244
TI  - Outcomes of irradiated polyglactin 910 Vicryl Rapide fast-absorbing suture in
      oral and scalp wounds.
AB  - BACKGROUND: This study evaluated the outcome of wounds closed with irradiated
      polyglactin 910 (IRPG) Vicryl Rapide (Ethicon, Somerville, N.J.). METHOD: Seventy
      one patients with 80 oral wounds and 42 patients with 42 scalp wounds closed with
      IRPG were evaluated on the day of surgery, then one, seven, 14, 28 and 90 days
      following surgery. The incidence of inflammation, suppuration and hypertrophic
      scarring was recorded, along with the timing of spontaneous suture disappearance.
      This suture material was compared with polytetrafluoroethylene (PTFE) sutures
      used in dental implant patients, traditional polyglycolic acid (PGLA) sutures
      used in osteotomy patients and skin staples used in patients with scalp wounds.
      RESULTS: In the group with intraoral wounds, there were two cases of suppuration
      with no inflammatory reactions or hypertrophic scarring when IRPG sutures were
      used, compared to three cases of suppuration with the traditional PGLA sutures.
      In the group with scalp wounds, there was no suppuration or hypertrophic scarring
      with IRPG sutures and one inflammatory reaction with skin staples. IRPG sutures
      never required removal, while all staples, PGLA and PTFE sutures eventually
      required separate removal. CONCLUSION: Irradiated polyglactin 910 Vicryl Rapide
      is a useful suture material with both intra- and extraoral applications in the
      pediatric and adult populations.

PMID- 10412245
TI  - Lung cancer incidence rates by histologic type in high- and low-risk areas; a
      population-based study in Osaka, Okinawa, and Saku Nagano, Japan.
AB  - We investigated lung cancer incidence by histologic type using the data from
      population-based cancer registries in high-risk (Osaka and Okinawa) and low-risk
      (Saku Nagano) areas. Since the proportion of cases with histologic types
      identified was not sufficiently high, sex- and age-specific incidence rates by
      histologic type were estimated assuming that the distribution of histologic types
      was the same across the same sex and age groups regardless of reporting status.
      Compared to Saku in Nagano Prefecture, the cumulative risk of lung cancer
      incidence rates in Osaka and Okinawa were 1.3 and 1.5 times higher for males and
      1.3 and 1.2 times higher for females, respectively. When divided by histologic
      type, male adenocarcinoma and small cell carcinoma were 1.6-2.1 times higher in
      Osaka and Okinawa, while squamous cell carcinoma was 1.6 times higher only in
      Okinawa compared to Saku Nagano. In females, squamous cell carcinoma and small
      cell carcinoma were 2.5-3.3 times higher in Osaka and Okinawa compared to Saku
      Nagano, while adenocarcinoma was almost equal in the 3 areas. These results
      indicate that the pattern of incidence of lung cancer by histologic type may
      differ between high- and low- risk areas.

PMID- 10412246
TI  - Behavioral factors predicting serum cotinine concentrations of male smokers in a
      Japanese community.
AB  - Cigarette-derived toxic substances are inhaled along with the nicotine that is
      absorbed to satisfy the smoker's physical demand. Therefore, serum cotinine, a
      metabolite of nicotine, may be considered to be an indirect marker of absorption
      of the other toxic substances from smoking. However, few studies have examined
      factors related to serum cotinine concentrations in natural settings. The
      authors, therefore, have studied relations among patterns of smoking behavior and
      serum cotinine concentrations of community residents. Subjects were 60 smoking
      men living in the town of Yamasaki, Hyogo Prefecture, Japan. Number of daily
      cigarettes, depth of inhalation, hours from the last cigarette smoked and the
      total nicotine tolerance score were significantly, while neither nicotine-yields
      nor butt length of a discarded cigarette was correlated with serum cotinine
      concentrations. Multiple regression analysis confirmed that depth of inhalation
      and hours from the last cigarette smoked were independently significant. This
      finding suggests that attention only to self-reported daily number of cigarettes
      smoked may not be sufficient to detect smokers who are actually at high risk.
      Healthcare workers should also pay attention to smokers' patterns of smoking,
      particularly depth of inhalation.

PMID- 10412247
TI  - Evaluation of the completeness of cancer case ascertainment in the Seoul male
      cohort study: application of the capture-recapture method.
AB  - Since the completeness of case ascertainment is directly related to the validity
      of a study, the evaluation of completeness is an essential feature of a cohort
      study. To estimate the completeness of cancer case ascertainment during a three
      year period (Jan. 1, 1993, to Dec. 31, 1995) in which the Seoul Male Cohort was
      followed up, we applied capture-recapture method. Data were obtained from the
      cancer registries, medical records and death certificates, with cases identified
      from each source numbering 103, 105, and 38, respectively. After eliminating
      duplicate cases, the total number was 141, and by using a log-linear model, the
      number of cases not detected by any of the three data sources was estimated to be
      16. For all cancers, the estimated completeness of follow-up was 89.9%.

PMID- 10412248
TI  - Current trend in prevalence of diabetes mellitus in Japan, 1964-1992.
AB  - Prevalence of diabetes mellitus in Japan was investigated through studying the
      published reports from 1964 to 1992 by searching the electronic data base and
      some leading Japanese journals following certain inclusion criteria. Out of total
      74 retrieved reports, 14 were found eligible for review, some containing data of
      multiple community and/or periods and were converted into total of 40 reports
      following a predetermined criteria. Review analysis of only the prevalence of
      diabetes was done paying much attention to age range, survey methodology and
      response rate. Oral glucose tolerance test (OGTT) was done in 19 (47.5%) with and
      in 21 (52.5%) reports without initial urine and/or blood sugar screening. OGTT
      was done using 75, 50, or 100 grams glucose following either Japan Diabetes
      Society or WHO criteria. The recent prevalence was estimated ranging from 9.6
      11.9% in both sexes of 40 years or over, 4.2-13.1% in men and 2.6-12.9% in women.
      The higher prevalences were found in and around 1990 and the lower values in and
      around 1970. Regression analysis shows the upward trend of the prevalence of
      diabetes 2.2% in men (p < 0.01), 1.6% in women (p < 0.01) by 10 years.

PMID- 10412249
TI  - Changes in body mass index and its relationships to other cardiovascular risk
      factors among Japanese population: results from the 1980 and 1990 national
      cardiovascular surveys in Japan.
AB  - Few studies have attempted to investigate the changes in body mass index (BMI)
      and its relationship to other cardiovascular factors in Asian populations,
      including Japanese. Data from two national cross-sectional surveys on circulatory
      disorders in 1980 and 1990 in Japan were used in this study. The sample consisted
      of 10,556 participants in the 1980 survey and 8,385 in the 1990 survey, aged > or
      = 30 years. The results show that after adjusting for age, smoking, alcohol
      consumption (ALC) and daily life physical activity (PA), mean BMI increased 0.49
      kg/m2 (95% confidence interval: 0.34-0.65) in men aged 30-59 and 0.61 kg/m2 (0.37
      0.86) in those aged > or = 60 from 1980 to 1990. In women, however, mean BMI
      decreased 0.24 kg/m2 (-0.39 0.09) in those aged 30-59 and increased 0.38 kg/m2
      (0.12-0.64) in those aged > or = 60. BMI was significantly associated with
      hypertension, diabetes and hypercholesterolaemia. In both genders, cu-smokers had
      lower mean BMI than never smokers, while among the cu-smokers, mean BMI was
      positively associated with the number of cigarettes smoked per day. In men, BMI
      was positively associated with ALC and negatively associated with PA, while in
      women, BMI was negatively associated with ALC and positively associated with PA.
      The results suggest that BMI has significantly increased in men and in elderly
      women. BMI, even in the Japanese population who are characterized by relative low
      BMI, is significantly associated with several cardiovascular risk factors.

PMID- 10412250
TI  - Sexual behaviour of commercial sex workers and their clients in Cambodia. Japan
      Cambodia Collaborating Research Group.
AB  - OBJECTIVE: This study surveyed the sexual behaviour of commercial sex workers and
      their clients in an attempt to identify factors of transmission of STDs
      (including HIV/AIDS) and to control their epidemics in Cambodia and South-East
      Asia. DESIGN: Cross-sectional study. SETTING: Trained questioners asked items of
      the questionnaires to each objective subject in December 1996. Data were analysed
      to show the descriptive status by risk group of each person. PARTICIPANTS: 200
      direct commercial sex workers, 220 indirect commercial sex workers, and 211
      clients in Phnom Penh. RESULTS: Prostitution was widely accepted by both young
      males and females, and this was an easy way for young girls to obtain money.
      Although commercial sex workers and clients were knowledgeable about prevention
      methods against STDs, they seldom used condoms. Some commercial sex workers had
      been infected with STDs many times, and many of them incompletely treated the
      diseases by themselves. Social support from governmental and non-governmental
      organisation was poor. CONCLUSIONS: It is very important to support both
      commercial sex workers in practicing preventive methods against STDs and also
      visiting physicians when they notice symptoms of STDs. It is strongly recommended
      that not only governmental but also non-governmental organisations should be more
      active in this area.

PMID- 10412251
TI  - Agreement between self- and partner reports obtained by a self-administered
      questionnaire: medical and lifestyle information.
AB  - We examined agreement between the subjects' self- and partner-reports of such
      epidemiological information as medical and family history, smoking and drinking
      habit and physical activity. Information was obtained by a self-administered
      questionnaire which was completed by 224 workers (subjects) and by their partners
      in 1997. Agreement was assessed by calculating kappa statistic, intraclass
      correlation coefficient (ICC), and per cent agreement. Per cent agreement ranged
      from a low of 76.2 for general life stress to a high of 98.0 for
      angina/myocardial infarction and diabetes mellitus as present illness. Kappa
      values ranged from a low of 0.34 for general life stress to a high of 0.86 for
      smoking habit. Compared to subjects, their partners tended to report lower level
      of both exposures (continuous variables) and presence (dichotomous variables).
      The average kappa was 0.64 for wife-surrogates, whereas 0.53 for husband
      surrogates. Overall, our finding suggested that partners could provide acceptable
      information for the concrete and directly-observable variables (e.g. such present
      illness as hypertension which required daily medication, or smoking/drinking
      habit itself), but not so for detailed/subjective variables (e.g. number of
      cigarettes smoked per day or general life stress).

PMID- 10412252
TI  - Development of substituted fatty acid food composition table for the use in
      nutritional epidemiologic studies for Japanese populations: its methodological
      backgrounds and the evaluation.
AB  - Results of dietary assessment are influenced by quality of food composition
      tables used for nutrient calculation. The Japanese food composition table has
      considerable missing values for fatty acid compositions. Substitution is often
      used for filling missing values. We examined reliability of the following 4 major
      substitution methods using available values of arbitrarily selected 83 sets of
      foods from the published fatty acid composition table of Japanese foods: by a
      different part of the same specie, by a similar specie, by a same specie in the
      United States' Department of Agriculture food composition table, and by recipe.
      The mean correlation coefficients of food pairs were 0.97, 0.96, 0.84, and 0.80
      respectively. Next, we substituted fatty acid compositions for the 794 missing
      foods using the 4 substitution methods, and developed the table with 1245 foods
      including those listed in the original (non-substituted) fatty acid composition
      table. Lastly, we calculated fatty acid intake levels with the original (non
      substituted) and the developed (substituted) tables using 28- or 14-day dietary
      records of 211 men and women as a sample data, and compared the results. The
      intakes of all five fatty acid groups increased. The increase was most marked in
      saturated fatty acids (26% in men and 31% in women in crude values). As a
      consequence, polyunsaturated to saturated fatty acid ratio decreased from 1.15 to
      1.01 in men and from 1.13 to 0.96 in women. The use of the developed fatty acid
      food composition table may increase the reliability on nutrition-disease
      association in future nutritional epidemiologic studies for Japanese populations.

PMID- 10412253
TI  - Abnormal head shapes in children: classifications and syndromes.

PMID- 10412254
TI  - Multiple spontaneously occurring coronary artery-left ventricular communications:
      a case report.
AB  - A search of the literature revealed that spontaneous coronary artery-left
      ventricular communications have only rarely been reported. These fistulae are
      frequently associated with angina pectoris which has been attributed to a
      ventricular steal phenomenon. The patient described herein presented with angina
      pectoris and was found to have multiple coronary arterioventricular
      communications without significant coronary atherosclerosis.

PMID- 10412255
TI  - Ardis D. Hoven, MD. AMA council on medical service. Interview by Sue Tharp.

PMID- 10412256
TI  - On nurturing.

PMID- 10412257
TI  - Computed tomography guidance in bone marrow aspiration for diagnosis of marrow
      necrosis and metastasis.
AB  - Bone marrow necrosis is most frequently diagnosed at postmortem examination.
      Antemortem diagnosis is still uncommon. We illustrate four cases where initial
      bedside attempts at needle aspiration and biopsy of primary and metastatic tumor
      tissue from the sternum were complicated by inadequate specimen retrieval
      secondary to marrow necrosis and/or tissue destruction by tumor. In these cases,
      CT guidance was useful in the precise localization of the bulk of the tissue mass
      and consequently the successful retrieval of adequate diagnostic specimens. We
      demonstrate CT guidance as an excellent and convenient alternative in
      circumstances where adequate marrow aspirations and biopsies are difficult and
      complicated.

PMID- 10412258
TI  - Bruce A. Scott, MD. Young physicians designated position, AMA board of trustees.

PMID- 10412259
TI  - Report on the doctor SmokeStopper project.

PMID- 10412260
TI  - An economics course in medical school?

PMID- 10412261
TI  - Alternative medicine.

PMID- 10412262
TI  - Births, marriages, divorces, and deaths: provisional data for 1998.

PMID- 10412263
TI  - [Cell death and tumor formation].
AB  - Proliferation and death (apoptosis) are the main cellular functions in the
      maintenance of the homeostasis of the organism. Disturbances in the regulation of
      these two basic phenomena may results in the continuous and irreversible
      accumulation of cells in time and space. This process which could become
      autonomous without any obvious biological "advantage". Both the overproduction of
      anti-apoptotic factors (e.g. bcl-2) or the failure of pro-apoptotic signals (e.g.
      p53) can contribute to tumorigenesis. Authors review the different phases of
      apoptosis with emphasis on the most important decision making elements in cell
      death, i.e. caspases and mitochondria, as well as on the interactions of the
      regulatory pathways. The better understanding of these coordinated and
      interdependent actions may help to achieve improvements in many fields of
      oncology.

PMID- 10412265
TI  - [Epidemiology of psychosomatic symptoms and subjective health evaluation among
      secondary school students].
AB  - The author investigated the prevalence of some common psychosomatic symptoms and
      self-perceived health in a sample of secondary school students in Szeged,
      Hungary. The sample (n = 1039, 14-19 years of age) was stratified by school type
      and sex. Self-completed questionnaire was used as a method of data collection.
      Two main purpose directed the study. First, to detect the most frequent
      psychosomatic symptoms and to experience how the secondary students evaluate
      their own health. Second, to investigate the role of psychological and social
      factors affecting the occurrence of psychosomatic symptoms and self-perceived
      health by using multivariate technique. In both sexes, chronic fatigue proved to
      be the most frequent psychosomatic symptoms which was followed by tension
      headache and lower back-pain in girls, while among boys lower back-pain and
      sleeping problems were reported as frequent symptoms. Comparing with the data of
      a previous research on university students, the secondary school students
      reported more symptoms, though they perceived their own health higher. In the
      background of the somatization both psychological (dysfunctional attitudes or
      inadequate coping) and social (father's unemployment or low level of social
      support from father) can be found beyond the developmental characteristics of the
      adolescence (e.g. a tendency for introspection). In case of the diagnose of
      psychosomatic symptoms in clinical practice there is a need for thinking about
      the social or psychological affecting factors and seeking professional help from
      a psychologist or social worker, if it is necessary.

PMID- 10412264
TI  - [Experience with ambulatory radioiodine therapy of hyperthyroidism].
AB  - Since 1993, outpatient radioiodine therapy has been available in Hungary. The
      reported study evaluated the efficacy of outpatient radioiodine treatment in
      subjects with hyperthyroidism. The data on 118 patients with Graves' disease and
      36 patients with thyroid autonomy were analysed retrospectively. All patients
      were treated within the period 1994-1997. The activities of radioiodine were
      individually calculated. The applied dose in Graves' disease was 150 Gy, and in
      thyroid autonomy 150 Gy or 300 Gy. The efficacy of the treatment were evaluated
      3, 6, and 12 months after radioiodine therapy. In patients with persistent
      hyperthyroidism repeated therapies were performed. Overall the radioiodine
      therapy was successful in 85% of the Graves' disease patients. The first 150 Gy
      treatment was effective in 70% of the patients with Graves' disease and in 43% of
      the patients with increased radioiodine turnover. In thyroid autonomy, the
      treatment with 150 Gy was successful in 71%, with 300 Gy in 89% of the patients.
      The efficacy of radioiodine treatment was similar to the results of one dose
      application. It was concluded, that radioiodine therapy with 150 Gy absorbed dose
      in Graves' disease and with 300 Gy absorbed dose in thyroid autonomy proved
      successful by the method of the authors.

PMID- 10412266
TI  - [Objective audiologic assessment of children treated with amikacin].
AB  - Hearing assessment of 14 children suffered from urinary tract infection and
      treated by amikacin is reported. The dosage of amikacin was 7.5 mg/kg/daily for
      10 days and the serum level of amikacin not exceeded the 35 mcg/ml. The aim of
      the study was on the one hand to determine the hearing damaging side effect of
      amikacin and on the other to assess the usefulness of objective methods for
      detection of hearing loss in this population. Authors used for screening a
      transient otoacoustic emission (TEOAE) during and after (2-4 weeks) therapy. If
      subjective and objective (TEOAE) methods gave a good result, no further checkup
      has considered as necessary, but if there were no evoked emission, acoustic
      brainstem response audiometry has been carried out for verification. It result no
      hearing loss could be detected in the measured specimen. In conclusion it has
      been stated that by proper dosage and serum level screening amikacin may no lead
      to hearing loss in children, and objective methods are valuable for hearing
      screening and monitoring of such population of children.

PMID- 10412267
TI  - [Adenomyomatosis of the gallbladder].
AB  - A 64-year-old male patient was reported, surveying radiology and pathology of the
      adenomyomatosis. The authors emphasize the role of high resolution ultrasound and
      computer tomography in the diagnosis of gallbladder adenomyomatosis. Intramural
      cystic formation (anechoic diverticula) with echogenic foci and/or reverberation
      artifacts together with a full or a partial thickening of the gallbladder's wall
      was considered as the diagnostic criteria of the ultrasound examinations. They
      assist in finding the proper way among the difficulties of the different
      diagnosis, in the same time call the attention for the frequently misdiagnosed
      cases.

PMID- 10412268
TI  - Address delivered on October 9, 1998 at the ceremony granting Prof. Stanislaw
      Woyke an honorary doctorate at the Pomeranian School of Medicine in Szczecin.

PMID- 10412269
TI  - Expression of P53, MDM2 and Ki-67 antigens in soft tissue sarcomas.
AB  - The expression of P53 and MDM2 proteins was examined by immunohistochemistry in
      115 soft-tissue sarcomas (STSs), including 32 malignant peripheral nerve sheath
      tumours, 27 liposarcomas, 18 leiomyosarcomas, 16 synovial sarcomas, 14
      fibrosarcomas and 8 dermatofibrosarcomas, to investigate their possible
      association with clinicopathologic features and proliferative rate. Positivity
      for P53 and MDM2 was found in 9.7% and 28.1% tumours, respectively. The fraction
      of P53 and MDM2 positive tumours was the highest in leiomyosarcomas (16.7% and
      17.2%, respectively) and the lowest in dermatofibrosarcomas (0% and 4.3%,
      respectively). Overall, P53(-)/MDM2(+) phenotype predominated (20.2%), while 7.9%
      of tumours were both P53 and MDM2 positive, and 1.8% of tumours were only P53
      positive. P53 accumulation was associated with a high histological malignancy
      grade and a higher proliferative rate. MDM2 immunoreactivity was revealed in
      tumours of all malignancy grades and there was no association between MDM2
      positivity and tumours proliferative activity. These results suggest that P53
      overexpression underlays rather late events in the oncogenesis of STSs, which
      might be a determinant of their proliferative rate. In contrast, MDM2
      deregulation seems to be an early rather than a late event in STSs, which may
      occur without involving stabilization and inactivation of P53 gene.

PMID- 10412270
TI  - Bcl2 and Bax expression in naevi and melanomas and their relation to ploidy
      status and proliferation.
AB  - Twenty-five naevi, 53 primary melanomas, 36 melanoma metastases were stained
      immunohistochemically for the presence of Bcl2, Bax and Ki-67 antigen in order to
      define the relation between apoptosis regulators and proliferative activity.
      Additionally, ploidy status and S-phase were measured. Bax demonstrated a
      tendency to increase and Bcl2 was decreasing along with melanoma progression. In
      the group of euploid cases Bcl2 showed a strong significant correlation with Bax
      expression (p = 0.0001) and both Bcl2 and Bax correlated with Ki-67 expression
      and S-phase. In the group of aneuploid cases only the correlation Bcl2-Ki-67 was
      preserved. Others did not reach the level of statistical significance.

PMID- 10412271
TI  - Prognostic and predictive evaluation of DNA content, S-phase fraction and
      immunophenotyping in non-Hodgkin's lymphomas in adults. A prospective study.
AB  - In non-Hodgkin's lymphoma (NHL) patients, prognostic significance of S-phase
      fraction (SPF) is well known, however the significance of DNA ploidy status and
      antigen expressions is still unclear. The purpose of the present study is to
      evaluate the prognostic and predictive impact of SPF, immunophenotype and DNA
      ploidy in prospectively analysed NHL patients. The study was performed on lymph
      node biopsies of 117 nodal NHL patients. The median follow-up of patients was 25
      months (range 1-64 months). All histologically verified lesions were considered
      according to the Working Formulation and Kiel classification. SPF,
      immunophenotype and ploidy were determined by flow cytometry. The rate of 2-year
      overall survival was 56%. SPF and DNA ploidy status were found to be independent
      prognostic factors in low and high grade lymphomas, respectively. Patients with
      near-tetraploid lymphomas were characterised by unfavourable clinical outcome,
      whereas hypertetraploidy was a favourable prognostic indicator. Among B-cell
      lymphomas CD5 expression seems to be of prognostic significance.

PMID- 10412272
TI  - Usefulness of cytologic examination of urinary sediment with the millipore method
      in routine diagnosis based on 125 cases.
AB  - The paper evaluates the usefulness of cytologic examination of urine sediment
      performed by millipore method, based on 125 cases. The method permits high
      quality cytologic smears obtained even from cellularly poor urines. The
      sensitivity of this analysis is directly proportional to the histological grade
      of the tumour. In the case of transitional cell carcinoma G1, the sensitivity was
      65%, in G2-79.3% and in G3-92.9%. High sensitivity of this examination was found
      in carcinoma in situ. Our study is of retrospective character, the results
      presented were obtained on the basis of one cytoanalysis of urine sediment.

PMID- 10412273
TI  - Remote microscopy through the internet.
AB  - A fully robotic microscope Axioplan2 (Zeiss) and CCD camera (RGB-Sony) mounted on
      this microscope have been connected to a computer dedicated as an Internet
      server. This server is available by means of an Internet browser with an
      interpreter of the Java programming language. We have used Java technology for
      remote control this full-motorized telemicroscope. The Java program for
      microscope control is automatically downloaded and started when the user selects
      the Web site of the corresponding microscope server with his Internet browser. At
      the client's side, there is no need for any additional software except for what
      is included in Netscape Navigator 3.0, Microsoft Explorer 3.0 or its later
      versions. Our remote microscope can be remotely controlled from any place in the
      world through the Internet. The user can move the microscope stage, change the
      magnification or can execute any other microscope operations by pressing the
      related buttons of the downloaded telemicroscopy client program. The microscope
      server receives the commands from the client program, executes the operation on
      the microscope and after every new command distributes the next microscope image
      to the connected telemicroscopy clients. There are also software modules which
      allow marking a field of interest in the image and discuss. Every Internet user
      can control the remote microscope and discuss the images with others who have
      direct access to the Internet on-line, or are connected by modem or ISDN. The
      quality of the transferred microscopic images and response time is sufficient for
      practical use. No complicated installation processes are necessary and the system
      is easy to use. The system design makes every pathologist, who is the Internet
      user, to be a possible consultant.

PMID- 10412275
TI  - Angiomyolipoma of the lung.

PMID- 10412274
TI  - Nesidioblastosis in an adult man--case report.
AB  - We report a case of nesidioblastosis in a 66-year-old man with chronic alcohol
      induced pancreatitis manifested by attacks of hypoglycemia for several years. The
      state of the patient improved after subtotal pancreatectomy.

PMID- 10412276
TI  - Fabry's disease. Report of the case diagnosed on the basis of routine
      ultrastructural examination of the renal biopsy.
AB  - A 45-year-old man who developed proteinuria was diagnosed as having Fabry's
      disease on the basis of renal histological findings and prominent decreases in
      alpha-galactosidase A activity in blood leukocytes.

PMID- 10412277
TI  - The ultrastructural changes in renal biopsy compatible with Fabry's disease. Case
      report.
AB  - The authors reported the accumulation of osmiophilic myelin-like bodies typical
      for Fabry's disease in the rebiopsied 19-year-old woman clinically presenting
      with intermittent mild microhematuria and trace proteinuria. The light microscopy
      examination of the first kidney biopsy specimen (10 years ago) showed the
      presence of vacuolated cells in glomeruli, but electron microscopy study was not
      performed. The family history was negative for renal diseases. A biochemical
      enzymatic assay for alpha-galactosidase A was not performed. It is concluded that
      electron microscopy examination of kidney biopsy specimen is important for the
      investigation of storage diseases.

PMID- 10412278
TI  - [Music and medicine].

PMID- 10412279
TI  - [Music--poison and cure].
AB  - There is no music in nature. Music is a purely human/psychologic phenomenon.
      Corresponding to the psyche it is bivalent, bipolar, dialectic, good and evil. A
      paradigm for this is the history of the organ.

PMID- 10412280
TI  - [How is the brain tuned?].
AB  - The brain is the organ which organizes the interaction between the organism and
      the environment. On the afferent side perceptive channels provide information
      from the outer and inner worlds. On the efferent side there is only the muscle
      system with its governing neural organisation. The brain as a tool or instrument
      can be put in tune like an instrument of music, in the best way by harmonizing
      inner intentions and desires with external demand.

PMID- 10412281
TI  - [Psychofonia--a neurophysiologic music therapy in migraine].
AB  - Migraine and other functional disorders are common and often difficult to treat.
      Alternative treatment modalities are clearly warranted and gain more widespread
      acceptance. Psychofonia is a new form of music therapy for treating migraine
      patients. For each patient an individualized sound pattern is created based on
      his individual EEG by using computer technology. In a cohort study we
      investigated prospectively 55 migraine patients treated with this EEG-based music
      therapy. 56% of the patients showed an improvement of at least 50% of their
      symptoms after a twelve months treatment period. Our results suggest that this
      form of music therapy is effective in treating migraine patients and should be
      studied in a prospective, randomized, controlled trial.

PMID- 10412282
TI  - [Music and heart rate variability. Study of the effect of music on heart rate
      variability in healthy adolescents].
AB  - The effect of trophotropic (relaxing) music on heart rate and heart rate
      variability has been investigated in 23 healthy young individuals by means of 24
      hour Holter-ECG. Relaxing music (Bach, Vivaldi, Mozart) resulted in significant
      reduction of heart rate and also significant reduction of heart rate variability.
      The significance of these results for the use of music in coronary heart disease
      is discussed.

PMID- 10412283
TI  - [The value of music in postoperative care].
AB  - During the immediate postoperative period good monitoring, adequate analgesia and
      competent, comprehensive care are of paramount importance. The effect of music in
      the recovery room raised my interest as an additional "instrumentarium". It is my
      intent to motivate to take advantage of the many-fold uses of music in the
      postoperative phase.

PMID- 10412284
TI  - [Healing of harmony: music therapy as a historical cultural phenomenon].
AB  - The interaction of music and psyche constitutes a phenomenon, which is known to
      man since antiquity, and, for this reason, was ever since used for healing
      purposes. The pythagoreans developed a system of musical theory that declared
      consonance to be a musical interval with the frequencies in a ratio of integer
      numbers. The cosmical music of the spheres, the played instrumental music and the
      inner music of man, these all they conceived as a unity. Varied in a manyfold
      way, this great theme was handed down over the centuries to the present day,
      being a source of inspiration to music and the sciences. Modern musical therapy
      is, in the last analysis, based on these intuitive findings.

PMID- 10412285
TI  - [The body--music--the "soul"].

PMID- 10412286
TI  - [Molecular mechanism of pain and genetic pharmacology].

PMID- 10412287
TI  - [Molecular mechanisms of opioidergic antinociception].

PMID- 10412288
TI  - [Structure-activity studies on nociceptive peptides].

PMID- 10412290
TI  - [Interaction of transcription factor PU. 1 with coactivator CBP].

PMID- 10412289
TI  - [Leptomycin: a specific inhibitor of protein nuclear export].

PMID- 10412291
TI  - [Recent progress of adenovirus vector].

PMID- 10412292
TI  - [Development of gene cloning system in E. coli: cloning for a lethal gene by new
      expression system].

PMID- 10412293
TI  - [Single molecule detection using fluorescence correlation spectroscopy].

PMID- 10412294
TI  - [Ten years with--and without--quality databases and evidence].

PMID- 10412295
TI  - [Pollution and fetal development].

PMID- 10412296
TI  - [Palliative chemotherapy in colorectal cancer--can we afford it?].

PMID- 10412297
TI  - [From an idea to a project].

PMID- 10412298
TI  - [Focusing on the molecular biology of aging].

PMID- 10412299
TI  - [Epigenetics: DNA methylation].

PMID- 10412300
TI  - [Systemic palliative chemotherapy with 5-fluorouracil and leucovorin in
      disseminated colorectal cancer].
AB  - Systemic palliative chemotherapy is usually regarded as ineffective in
      disseminated colorectal cancer, and the risk of toxic adverse effects is often
      considered a contraindication, as many patients are old and cannot be offered
      curative treatment. Randomized trials during the last decade have shown, however,
      that an effect on both survival and quality of life can be expected. Only
      casuistic reports of total remission have been published but a partial tumour
      response can be expected in 20-50% of patients. Toxicity is related to palliative
      chemotherapy and accelerated with old age (> 70 years). When disseminated
      colorectal cancer is diagnosed the possibility of palliative chemotherapy should
      be conferred with an oncologist.

PMID- 10412301
TI  - [Angiogenesis: prognostic marker in prostatic cancer].
AB  - Angiogenesis, the formation of new blood vessels, has been suggested to provide
      important prognostic information in prostate cancer. The aim of this study was to
      investigate, whether microvessel density (MVD) at diagnosis was correlated with
      disease-specific survival in a non-curative treated population of prostate cancer
      patients. MVD was immunohistochemically (factor VIII-related antigen) quantified
      in archival tumours obtained at diagnosis in 221 prostate cancer patients. The
      maximal MVD was quantified inside a 0.25 mm2 area of the tumour and the median
      MVD was 43 (range 16-151). MVD was statistically significantly correlated with
      clinicopathological characteristics and disease-specific survival. A multivariate
      analysis demonstrated that MVD was a significant predictor of disease-specific
      survival in the entire cancer population, as well as in the clinically localized
      cancer population. These findings suggest that quantitation of angiogenesis
      reflects the spontaneous clinical outcome of prostate cancer.

PMID- 10412302
TI  - [Systemic lupus erythematosus in the county of Fynen. An epidemiologic study].
AB  - The incidence and prevalence of systemic lupus erythematosus (SLE) has never been
      investigated in Denmark, whereas international studies have reached divergent
      results. In the study patients were ascertained from diagnosis-based registers of
      inpatients and outpatients, notifications from physicians, and an autoimmune
      register. Diagnoses were validated and patients classified according to the
      American College of Rheumatology criteria: definite SLE (D-SLE) > or = 4 and
      incomplete SLE (I-SLE) < 4 criteria. The point prevalence as of Jan. 1, 1995, was
      21.7/100,000 (CI 95% 17.3-26.8) for D-SLE and 5.2/ 100,000 (CI 95% 3.2-8.0) for I
      SLE. The mean annual incidence in 1990-94 was 2.5/100,000 (CI 95% 1.8-3.3).
      Figures for annual incidence and prevalence were in accordance with recent
      British reports but considerably lower than Swedish and Icelandic results.
      Although methodological issues should be considered, the results point to a
      different distribution of SLE in otherwise closely related nationalities.

PMID- 10412303
TI  - [Transcatheter occlusion of patent ductus arteriosus].
AB  - Percutaneous closure of a patent arterial duct was performed in 58 patients. A
      Rashkind double umbrella was inserted in 20 patients. A supplementary double
      umbrella or coils were implanted in four who had residual leaks after 12 months.
      Three complications: embolization, haemolysis and late bacteriaemia were managed
      successfully without surgery. A detachable PDA coil was inserted in 38 patients.
      Three coils embolized and one could not be retrieved. At complete follow-up of 28
      patients the duct was closed in all. Median procedure duration and fluoroscopy
      time was 60 min. and 12 min. respectively for double umbrella implantation, and
      20 min. and 5 min. for coil insertion. Transcatheter occlusion of the patent duct
      is effective and carries little morbidity.

PMID- 10412304
TI  - [Hypertension and hysterectomy in Danish women].
AB  - The aim was to assess whether hypertension is a risk factor for hysterectomy. In
      a prevalence study, 2301 Danish women were selected at random in 1982.
      Information about cardiovascular diseases, hypertension, use of medicine, weight
      history, life-styles, psychological factors, gynaecological history, and social
      background were obtained. Blood pressure was measured. In an incidence study, the
      cohort was followed from 1982-1990 to assess the incidence of hysterectomy. In
      the prevalence study, hypertension partly explained the relation between
      hysterectomy and cardiovascular diseases. There were interactions between
      hypertension and previously found risk factors for hysterectomy. In the incidence
      study, hypertension was a risk factor in educated women (adjusted relative risk
      2.88, 95% confidence interval 1.07-7.76) and in women with weight cycling
      (adjusted relative risk 3.31, 95% confidence interval 1.35-8.14). Hypertension
      might cause menorrhagia. These three risk factors contribute to women undergoing
      hysterectomy having an increased risk of cardiovascular diseases.

PMID- 10412305
TI  - [CT scanning in the diagnosis of internal carotid artery dissection].
AB  - Dissection of the internal carotid artery is becoming more frequently recognized
      as a cause of neurological deficits or stoke in younger adults. A dissection is
      diagnosed in relation to minor often primarily unrecognized trauma to the neck
      and the typical clinical features seen with dissection are headache, Horner's
      syndrome and symptoms of focal brain ischaemia. Treatment, i.e. anti-coagulant
      therapy, is initiated to avoid thrombosis or recurrent embolism from the damaged
      arterial wall. The prognosis is generally good. The diagnosis of carotid
      dissection can be confirmed with ultrasound-duplex-scanning, conventional
      angiography or magnetic resonance imaging/angiography. In this paper two cases
      are reported in which computed tomography (CT-scanning) with intravenous contrast
      enhancement has been a valuable diagnostic tool in the diagnosis of this entity.

PMID- 10412306
TI  - [Familial Mediterranean fever. No longer an elimination diagnosis].
AB  - Familial Mediterranean Fever (FMF) is a recessive trait mainly affecting Jews,
      Turks and Arabs. FMF is characterized by recurrent episodes of painful serositis
      and fever leaving no sequelae. Involvement of the peritoneum is the most common
      clinical form. In 1997 the gene that causes FMF (MEFV-gene) was cloned, thus
      given clinicians an opportunity to diagnose the disease. We have established the
      method in our laboratory. We describe the first patient diagnosed with FMF in our
      department by this method.

PMID- 10412307
TI  - [Implementation of evidence-based technique in Cesarean section].

PMID- 10412308
TI  - [Influence of health care services on the stage at diagnosis and treatment
      patterns in breast cancer].

PMID- 10412309
TI  - [Semen and zone therapy--about physicians and the media. Rapid communication or
      ejaculatio praecox?].

PMID- 10412310
TI  - [When is cancer caused by occupational exposure?].

PMID- 10412311
TI  - [On growth models and lung cancer].

PMID- 10412312
TI  - Evidence based medicine: how do we implement research results effectively?

PMID- 10412313
TI  - [Is our food dangerous?].

PMID- 10412314
TI  - [Treatment of disseminated sclerosis with beta-inferferon--why and why not?].

PMID- 10412315
TI  - [Diagnosis of bacterial gastroenteritis].

PMID- 10412316
TI  - [Zoonotic bacterial gastroenteritis in Denmark].

PMID- 10412317
TI  - [Acute bacterial gastroenteritis and hemolytic-uremic syndrome].

PMID- 10412318
TI  - [Treatment of bacterial gastroenteritis].

PMID- 10412319
TI  - [An outbreak of Salmonella enteritidis at the New Year celebration of the
      Copenhagen Medical Association].
AB  - In order to determine the extent and infectious vehicle of an outbreak of
      Salmonella enteritidis phage type 6 at the New Year celebration of the Copenhagen
      Medical Association on 15 January 1999, a cohort study including 77 guests (90%
      of the participants) and 11 staff was carried out. There was little variation in
      the degree of exposure among the guests, meaning that identification of the
      probable infectious vehicle was not possible here. However, among the staff,
      intake of minced raw salmon was associated with increased risk of disease.
      Uncooked eggs were used in the preparation of this dish and since S. enteritidis
      phage type 6 is in Denmark almost exclusively found among egg-laying hens, these
      findings led to the conclusion that the outbreak was most likely caused by the
      use of raw eggs. The importance of notification of suspected foodborne disease
      and microbiological examination of people thereby exposed is stressed.

PMID- 10412320
TI  - [The elderly in general psychiatry].
AB  - The Danish National Board of Health recommends that the counties offer
      psychogeriatric services. The target group for geriatric psychiatry in the County
      of North Jutland only concerns elderly people with severe dementia. It has been
      our aim to describe and discuss the geriatric psychiatric supply of services and
      admission pattern for elderly with psychiatric morbidity in the County of North
      Jutland. We have made a cross-sectional study of all patients referred to the
      general and psychogeriatric service in 1997. In psychogeriatric service 40 of 46
      referrals were dealt with as out-patient contact. In general psychiatry the 57
      referrals resulted in 33 admissions of which 31 were acute. There is a high
      number of acute admissions in general psychiatry. The County of North Jutland
      does not have a suitable service for diagnostic work-up and treatment of people
      with possible to moderate dementia.

PMID- 10412321
TI  - [Intraoral cancer in the county of Copenhagen].
AB  - A retrospective study of patients treated for intra-oral squamous cell carcinoma
      in Copenhagen county is reported. The material included 156 patients, 66 females
      and 90 males. Age at diagnosis varied between 35 and 95 years with a mean of 65
      years. Mean age of females/males was 70/62 years. Twelve therapeutic modalities
      were performed; surgery, radiotherapy, chemotherapy and different combinations of
      these. Five year disease specific survival related to tumours' T-classification
      was 84% for T1, 35% for T2, 20% for T3 and 27% for T4. A statistically
      significant relation between the tumours' T-classification and the disease
      specific survival was noted (p < 0.00001). Five year disease specific survival
      related to N-classification was 62% for N0, 30% for N1, 25% for N2 and 0% for N3.
      Crude five year survival was 37% overall, 61% for patients in stage I, 32% for
      patients in stage II, 16% for patients in stage III and 17% for patients in stage
      IV. The results are similar to those achieved in other centres. Since no
      significant improvement has been noted in patient survival during the last five
      to six decades and since the therapeutic morbidity has not always been acceptable
      to the patients, other therapeutic principles, such as the so called minimal
      invasive therapy should be considered in future treatment of intra-oral cancer.

PMID- 10412322
TI  - [Botulism caused by a commercially produced product].
AB  - Insufficient conserved home-made products are the main cause of botulism in
      Denmark. We present a case of botulism caused by a commercially produced
      vegetable pie conserved by traditional bottling without addition of
      preservatives. Clostridium botulinum was grown from faeces of the index case
      indicating an intestinal infection. An action plan set up by the medical and
      veterinarian authorities functioned well and further spread of the disease was
      avoided. More cases of botulism may be seen in the future, if procedures ensuring
      proper conservation in food production are not adhered to.

PMID- 10412323
TI  - [Acute transverse myelitis caused by enterovirus].
AB  - Enteroviruses comprise a group of commonly encountered small RNA viruses with
      genetic similarities. We report a case of transverse myelitis associated with an
      enterovirus infection. By use of PCR, enterovirus-specific RNA sequences were
      detected in the cerebrospinal fluid and in swabs from the throat and the rectum
      at the time of admission. Routine cultures and serology gave no other explanation
      for the clinical condition. The patient was treated with intravenous
      immunoglobulin and steroids and improved gradually. She was fully recovered 18
      months after onset of disease.

PMID- 10412324
TI  - [Is intravascular coagulation the cause of Legg-Calve-Perthes disease?].

PMID- 10412325
TI  - [Monitoring and tracing of the sources of infections caused by food intake. How
      can it be improved?].

PMID- 10412326
TI  - [Treatment of gallstones in Denmark].

PMID- 10412327
TI  - [Some experiences with questionnaire-based studies].

PMID- 10412328
TI  - Serum levels of folic acid and vitamin B12 in Korean patients with vitiligo.
AB  - The association of vitiligo and pernicious anemia has been previously documented.
      The low levels of folic acid and vitamin B12 were thought to be related to
      vitiligo. To date, there have been very few reports about the serum levels of
      folic acid and vitamin B12 in patients with vitiligo. Using radioimmunoassay, we
      measured the serum levels of folic acid and vitamin B12 in 100 Korean patients
      with vitiligo. The mean serum levels of folic acid and vitamin B12 were 6.31 +/-
      2.82 ng/ml and 630.25 +/- 230.94 pg/ml, respectively, in patients with vitiligo.
      These levels showed no significant difference compared to the normal control
      group, suggesting that folic acid and vitamin B12 do not appear to play a role in
      the pathogenesis of vitiligo.

PMID- 10412330
TI  - Correlation between EGFR and c-erbB-2 oncoprotein status and response to
      neoadjuvant chemotherapy in cervical carcinoma.
AB  - Neoadjuvant chemotherapy prior to definitive radical surgery or radiotherapy may
      be effective in reducing tumor volume or clinical stage and may even enhance
      pelvic control and survival. However, there are significant limitations to the
      use of neoadjuvant therapy in the non-responder group. They include delayed total
      treatment course, the presence of drug resistant clones which result in
      accelerated tumor growth, and limited bone marrow reserve for subsequent
      definitive therapy. Thus, there is a need to identify parameters providing a more
      precise indication of the response to neoadjuvant chemotherapy in patients with
      invasive cervical cancer. From Jan. 1995 to Jan. 1996, neoadjuvant chemotherapy
      with 3 courses of cisplatin and vincristine was used in 32 patients with invasive
      cervical cancer (FIGO stage Ib to IIIb; tumor size greater than 2 cm). Prior to
      chemotherapy, quantitative tissue levels of epidermal growth factor receptor
      (EGFR) and c-erbB-2 oncogene protein were measured by using an enzyme-linked
      immunosorbent assay (ELISA). Tumor size was estimated before and after
      chemotherapy. Relations between oncoproteins and reductions of tumor size were
      evaluated. Tumor size prior to neoadjuvant chemotherapy did not show any
      correlation with either the concentrations of EGFR or c-erbB-2 oncoprotein. As
      well, the tumor reduction index did not manifest any correlation with EGFR, it
      did had an inverse linear correlation with the c-erbB-2 oncoprotein levels (Rs = 
      0.71, P < 0.05). The results of this study suggest that c-erbB-2 oncoprotein is
      associated with a reduced response to neoadjuvant chemotherapy in primary
      treatment of invasive cervical cancer and may be useful in directing therapeutic
      approaches.

PMID- 10412329
TI  - Assessment of myocardial metaiodobenzylguanidine uptake and its relation to left
      ventricular systolic and diastolic functional parameters in dilated
      cardiomyopathy.
AB  - The purpose of this study was to assess the relation between myocardial
      metaiodobenzylguanidine (MIBG) uptake and left ventricular systolic and diastolic
      functional parameters, both of which are known as predictors of prognosis in
      patients with dilated cardiomyopathy. Echocardiography and iodine-123-MIBG
      myocardial scintigraphy were performed in 35 patients of dilated cardiomyopathy
      with normal sinus rhythm. Mean myocardial MIBG uptake in the patient group at
      early and delayed images were significantly lower than those in normal control
      subjects (10.6 +/- 1.1, 9.8 +/- 1.2 vs 12.4 +/- 1.0, 12.1 +/- 1.0, p < 0.01).
      There were, however, no significant differences of mean MIBG uptake in the lung
      and mediastinum between the two groups (p > 0.05). There were no significant
      correlations between myocardial MIBG uptake, expressed as the ratio of
      heart/mediastinum MIBG activity at delayed image, and left ventricular systolic
      and diastolic functional parameters [left ventricular ejection fraction, left
      ventricular end-diastolic dimension, peak velocity of early diastolic filling (E
      velocity), deceleration time of E wave, cardiac output, left ventricular end
      diastolic pressure]. In conclusion, the myocardial uptake of MIBG is decreased in
      patients with dilated cardiomyopathy assessed by iodine-123-MIBG myocardial
      scintigraphy. There were, however, no significant correlations between myocardial
      MIBG uptake and left ventricular systolic and diastolic functional parameters
      derived from echocardiography.

PMID- 10412331
TI  - Clinical and radiological differences between traumatic and idiopathic
      coccygodynia.
AB  - Several reports of coccygodynia have been confined to the causes, the methods of
      treatment, and the methods of radiological examination. As far as we know, there
      has been no previous study about the objective measurement of the coccyx. The
      purpose of this study was to find the possible cause of idiopathic coccygodynia
      by comparing the clinical and radiological differences between traumatic and
      idiopathic coccygodynia by innovative objective clinical and radiological
      measurements. Thirty-two patients with coccygodynia were evaluated
      retrospectively. We divided the patients into two groups. Group 1 consisted of 19
      patients with traumatic coccygodynia and group 2 consisted of 13 patients with
      idiopathic coccygodynia. We reviewed medical records and checked age, sex
      distribution, symptoms, and treatment outcome in each group. We also reviewed
      coccyx AP and lateral views of plain radiological film and measured the number of
      coccyx segments and the intercoccygeal angle in each group. The intercoccygeal
      angle devised by the authors was defined as the angle between the first and last
      segment of the coccyx. We also checked the intercoccygeal angle in a normal
      control group, which consisted of 18 women and 2 men, to observe the reference
      value of the intercoccygeal angle. The outcome of treatment was assessed by a
      visual analogue scale based on the pain score. Statistical analysis was done with
      Mann-Whitney U test and Chi-square test. Group 1 consisted of 1 male and 18
      female patients, while group 2 consisted of 2 male and 11 female patients. There
      were no statistically significant differences between the traumatic and
      idiopathic coccygodynia groups in terms of age (38.7 years versus 36.5 years),
      male/female sex ratio (1/18 versus 2/11), and the number of coccyx segments (2.9
      versus 2.7). There were significant differences between the traumatic and
      idiopathic coccygodynia groups in terms of the pain score (pain on sitting: 82
      versus 47, pain on defecation: 39 versus 87), the intercoccygeal angle (47.9
      degree versus 72.2 degrees), and the satisfactory outcome of conservative
      treatment (47.4% versus 92.3%). The reference value of the intercoccygeal angle
      in the normal control group was 52.3 degrees, which was significantly different
      from that of the idiopathic group. In conclusion, the intercoccygeal angle of the
      idiopathic coccygodynia group was greater than that of the traumatic group and
      normal control group. Based on the results of this study, the increased
      intercoccygeal angle can be considered a possible cause of idiopathic
      coccygodynia. The intercoccygeal angle was a useful radiological measurement to
      evaluate the forward angulation deformity of the coccyx.

PMID- 10412332
TI  - Analysis of the factors affecting decentration in photorefractive keratectomy and
      laser in situ keratomileusis for myopia.
AB  - To evaluate the relationship between ablation zone decentration measured by
      corneal topography and various factors such as sex, age, order of operation,
      preoperative sedative prescription, ablation diameter and depth, type of
      procedure (photorefractive keratectomy = PRK, laser in situ keratomileusis =
      LASIK), and the use of a passive eye tracker, we examined the data of 80 eyes in
      50 patients. The patients received PRK (43 eyes in 30 patients) or LASIK (37 eyes
      in 20 patients), and were followed for 3 months postoperatively. Statistical
      analysis of the data was performed using t-test, ANOVA and multiple regression
      analysis. The overall average ablation decentration from the pupil center was
      0.43 +/- 0.27 mm, 0.35 +/- 0.22 mm in PRK and 0.47 +/- 0.30 mm in LASIK. Overall
      91.3% of patients were decentered less than 0.75 mm and 95.0% were decentered
      less than 1.00 mm, while 93.9% of patients were decentered less than 0.75 mm in
      PRK and 88.7% were decentered less than 0.75 mm in LASIK. The most meridional
      displacement was toward the superonasal quadrant; 46% in PRK and 51% in LASIK.
      There was less decentration in males, in the 2nd-operated eye, in older age, PRK,
      in larger ablation diameter, and in shallower ablation depth, but these
      differences were not statistically significant.

PMID- 10412333
TI  - T2-weighted fast spin-echo MR findings of adenocarcinoma of the uterine cervix:
      comparison with squamous cell carcinoma.
AB  - The purpose of this study was to investigate the differences in MR findings of
      adenocarcinoma (AC) and squamous cell carcinoma (SCC) of the uterine cervix and
      to compare MR findings with pathologic findings. MR images of 17 patients with
      pathologically proven AC, using a fast spin-echo (FSE) T2-weighted image (T2WI)
      with pelvic phased-array coil on a 1.5-T unit, were retrospectively evaluated.
      After measurement of the signal intensity (SI) ratios of the region of interest
      between tumors and gluteus maximus muscle, we compared the ratios of AC with
      those of 16 patients with SCC. AC showed relatively high SI on FSE T2WI with
      multiseptated lesions in four cases and hydrometrocolpos in three cases. The mean
      SI ratio was 3.82 +/- 1.68 in AC and 2.35 +/- 0.42 in SCC (p < 0.0001, t-test).
      Multiple tumorous glands with cytoplasmic and intraglandular mucin or serous
      fluid were pathologically found in AC, but SCC revealed the compact cellularity
      of stratified squamous tumor cells. The cervical AC showed higher SI than SCC on
      FSE T2WI with occasional multiseptated lesions and hydrometrocolpos. If the SI
      ratio of the tumor was more than 3.0, AC could be diagnosed with a sensitivity of
      68.8% and a specificity of 100%.

PMID- 10412334
TI  - The effect of the haptic portion of intraocular lens on the development of
      posterior capsular opacification in rabbit.
AB  - Using a white rabbit model, the effect of the haptic portion of the intraocular
      lens (IOL) and intracapsular ring on the development of posterior capsular
      opacification (PCO) after extracapsular cataract extraction (ECCE) with
      phacoemulsification was studied. Implantation of both the intracapsular ring and
      IOL developed less PCO than implantation of the IOL alone. ECCE followed by
      implantation of the intracapsular ring alone also developed less PCO than ECCE
      alone. Through this experimental work in a rabbit model, it could be conceived
      that the haptic portion of IOL and the intracapsular ring can prevent the
      development of PCO.

PMID- 10412335
TI  - Environmental controls in reducing house dust mites and nasal symptoms in
      patients with allergic rhinitis.
AB  - A randomized comparison group pretest-posttest experimental design was used to
      quantitatively determine the effects of environmental control measures on
      patients with allergic rhinitis. Environmental controls included wrapping the
      mattress with a vinyl cover, washing the top bedding cover with 55 degrees C hot
      water every two weeks, removal of soft furniture, and wet cleaning of the bedroom
      floor every day. Thirty subjects were randomly assigned to experimental and
      control groups. The amount of house dust mites in dust samples collected from the
      bedroom floor, bedding and mattress, as well as the nasal symptoms of patients,
      were measured twice at one-month intervals. A significant decrease in house dust
      mites in dust samples and relief in patients' nasal symptoms were observed in the
      experimental group who had environmental controls.

PMID- 10412336
TI  - Prediction of oculocardiac reflex in strabismus surgery using neural networks.
AB  - Successfully predicting an oculocardiac reflex (OCR) is difficult to achieve
      despite various proposed maneuvers. The aim of this study was to test the models
      built up by neural networks to predict the occurrence of OCR during strabismus
      surgery in children. Premedication was not given. Atropine 0.01 mg/kg was
      medicated just before induction. Induction was performed with fentanyl or
      ketorolac, followed by propofol. Atracurium or vecuronium was given for
      intubation. Anesthesia was maintained with O2-N2O with continuous propofol
      infusion. Chi-square test was performed for induction agents, gender, weight,
      muscle blockade, repaired muscle, number of repaired muscles, duration of
      operation to detect any association between the occurrence of OCR and to develop
      the model of neural networks. The multi-layer perceptron, radial basis function
      and Bayesian backpropagation network were tested. The occurrence of OCR was
      significantly associated with gender and repaired muscle (p < 0.05). Gender,
      repaired muscle and age were considered as input for the multi-layer perceptron,
      radial basis function and Bayesian backpropagation network. Three neural networks
      had predicted the same correction rate in the occurrence of OCR as being 87.5%
      overall among 16 patients' records tested. These models are conceptually
      different in predicting compared to conventional maneuvers, and have the
      advantage of testing individually and foretelling the propensity. By comparison
      neural networks use grouped experiential data and predict OCR by the learning
      rule. Neural networks require a relatively abundant number of experienced and
      homogenous patients' records to establish an accurate model. The multi-layer
      perceptron, radial basis function and Bayesian backpropagation modeling network
      may be an alternative way, and preferable to vagal tone maneuvers if the
      associated relationships to the occurrence of OCR are more clearly defined.

PMID- 10412337
TI  - Early homogeneously enhancing hemangioma versus hepatocellular carcinoma:
      differentiation using quantitative analysis of multiphasic dynamic magnetic
      resonance imaging.
AB  - The aim of this study was to determine the usefulness of quantitative analysis of
      multiphasic dynamic contrast-enhanced magnetic resonance (MR) imaging in
      differentiating early homogeneously enhancing hemangiomas from hepatocellular
      carcinomas (HCCs). Four-phased dynamic MR imaging at 10 sec (first phase of
      dynamic contrast-enhanced imaging, P1), 35 sec (second phase, P2), 60 sec (third
      phase, P3) and 300 sec (delay phase, P4) immediately after intravenous
      administration of 0.1 mmol/kg Gadolinium-DTPA was obtained with 1.5-T unit with
      breath-hold multisection FLASH (fast low angle-shot) sequence (TR/TE, 113-130
      msec/4.1 msec; flip angle, 80 degrees). Thirty-three HCCs and 18 hemangiomas,
      homogeneously enhanced on P1, were included in the study. The images were
      evaluated quantitatively (SNR, signal-to-noise ratio; and CNR, contrast- to-
      noise ratio of lesions). Quantitatively, mean CNR was higher for hemangiomas than
      for HCCs on all phases, and the difference in CNRs between hemangioma and HCCs
      was statistically significant on P3 and P4 (p < 0.0001). When the cutoff for CNR
      was set at a value of 7.00 on P3 and 1.00 on P4, sensitivity, specificity and
      accuracy were 94.4%, 93.9%, and 94.1% on P3, and 94.4%, 81.8%, and 86.3% on P4,
      respectively. There was no statistically significant difference in SNRs between
      HCC and hemangioma. The differential diagnosis between early, homogeneously
      enhancing hemangiomas and HCCs was more confidently made with CNRs of lesions on
      P3 and P4 in dynamic contrast-enhanced MR imaging.

PMID- 10412338
TI  - Anterior interbody fusion in the treatment of the lumbar herniated nucleus
      pulposus.
AB  - One hundred and fourteen cases of lumbar herniated nucleus pulposus were studied
      retrospectively. I reviewed the clinical records and radiographs of patients
      treated with diskectomy and anterior interbody fusion. I followed the patients
      from 2 years up to 15 years, for an average of 2.9 years. The results were
      calculated statistically by Fisher exact test and Chi-square test. Among 114
      patients, 69 patients (60.5%) were male and 45 patients (39.5%) were female. The
      most common age group was in its twenties (28.1%), while the whole study group
      ranged from 19 to 65 years. The most commonly involved level was L4-5 (73 cases,
      60.4%). In clinical results, 83.3% of cases were excellent or good. The rate of
      solid fusion was 87.8%. The most common type of fusing pattern was type 1. The
      satisfying clinical result had statistical correlation with the solid union of
      grafted bone and the fusion state of maintained intervertebral disk height,
      respectively, by Fisher exact test (p < 0.001). The affecting factors in clinical
      results were the solid fusion and fusion with the state of maintenance of
      intervertebral disk height (fusing pattern type I and II). I concluded that
      anterior diskectomy and interbody fusion is a recommendable method of treatment
      for lumbar herniated nucleus pulposus.

PMID- 10412339
TI  - Simultaneous analysis of urinary 2-thiothiazolidine-4-carboxylic acid and
      thiocarbamide as a biological exposure index for carbon disulfide exposure.
AB  - The objectives of this study were to develop optimal analytic methods for
      detecting urinary 2-thiothiazolidine-4-carboxylic acid (TTCA) and thiocarbamide
      simultaneously and to evaluate the usefulness of these metabolites to a
      biological exposure index (BEI) for carbon disulfide (CS2) exposure. For this
      experiment, synthesized TTCA and thiocarbamide were used. The synthesized TTCA
      was identified by infrared spectrophotometer, nuclear magnetic resonance
      spectrometer and thin layer chromatography. The recovery rates of both
      metabolites were calculated to find the optimum analytical method. The amounts of
      urinary TTCA and thiocarbamide were measured by using an ultraviolet detector
      connected to high performance liquid chromatography (HPLC) after the
      administration of CS2 (350, 700 mg/kg) into Sprague-Dawley rats
      intraperitoneally. The maximum absorbance wave lengths for TTCA and thiocarbamide
      were 272 and 236 nm, respectively. Ethyl acetate extraction with NaCl as a
      salting-out reagent was used as a simultaneous extraction method for these
      metabolites. HPLC conditions for these metabolites included using a NH2 column,
      50 mM KH2PO4: acetonitrile (85:15) and pH 3. Excreted amounts of urinary TTCA and
      thiocarbamide were increased significantly following CS2 administration. TTCA,
      which was already adopted as a BEI for CS2 by the American Conference of
      Governmental Industrial Hygienists (ACGIH), seems to be a more useful BEI for CS2
      exposure than thiocarbamide. However further studies are needed to increase
      analytical efficiency before thiocarbamide can be adopted as a BEI and to apply
      this analytic method for simultaneous analysis of these metabolites in workers
      exposed to CS2.

PMID- 10412340
TI  - Ultrastructural changes of the external elastic lamina in experimental
      hypercholesterolemic porcine coronary arteries.
AB  - The external elastic lamina (EEL) serves as a barrier for cells and
      macromolecules between the media and adventitia in the vascular wall. We
      evaluated the morphological changes and quantitative assessments of the EEL
      architecture in the coronary circulation of pigs fed with a high cholesterol
      diet. Confocal microscopy analysis of the EEL from hypercholesterolemic coronary
      arteries revealed an altered pattern characterized by fragmentation and
      disorganization of the EEL associated with an increase in the thickness.
      Computerized digital analysis of the images obtained by confocal scanning
      microscopy demonstrated that compared to normal coronary arteries, the EEL of
      hypercholesterolemic coronary arteries decreased in the percentage of their
      elastin content (30.80 +/- 1.64% vs. 47.85 +/- 1.82%, p = 0.001). The percentage
      of elastin content was negatively correlated with the vessel wall area (r = 
      0.82, p = 0.001). The immunoreactivity for matrix metalloproteinase-3 (MMP-3)
      increased in cholesterol-fed coronary arteries, predominantly in the neointima
      and adventitia. This study demonstrates that experimental hypercholesterolemia
      induced ultrastructural changes of the EEL in coronary circulation. The EEL may
      also be an atherosclerosis-prone area compared with the intima. The EEL may play
      an important role in the development of structural changes which characterizes
      the early phase of coronary atherosclerosis and vascular remodeling.

PMID- 10412341
TI  - Identification and purification of IgE-reactive proteins in German cockroach
      extract.
AB  - Cockroaches have been implicated as a cause of respiratory allergy in urban areas
      worldwide. IgE-reactive German cockroach proteins were identified with molecular
      weights (MWs) of 90, 66, 50, 43 and 36 KD by immunoblot analysis in both immune
      BALB/c mice and sensitized humans. Prominent IgE-reactive proteins were purified
      using FPLC by ion-exchange chromatography, gel filtration and hydrophobic
      chromatography. The N-terminal amino acid sequence of a purified protein with a
      MW of 66 KD on SDS-PAGE was Val-Thr-Leu-Lys-Lys(Val)-Met-Ile-Lys-Thr-Phe-Tyr. No
      homologous protein was found through a search of GenBank that indicated a novel
      IgE-reactive protein in German cockroach extract. Another purified protein with a
      MW of 36 KD reacted strongly with a monoclonal antibody against Bla g 2.

PMID- 10412342
TI  - Carcinoma of the axillary breast.
AB  - Axillary breast is one of the varieties of polymastia which is characterized by
      the presence of more than 2 breasts. It may cause symptoms during pregnancy,
      lactation, or in the premenopausal period. Unless there are obvious symptoms of
      lactation or the assistance of further imaging studies such as mammography and
      breast ultrasound, the diagnosis is often confused with subcutaneous lipoma. The
      incidence of axillary breast cancer is low but it should be investigated and
      treated properly in view of another breast cancer in the embryonic milk-line. In
      this paper we reviewed 4 cases of axillary breast cancer and documented some
      articles regarding aberrant breast and carcinoma arising from it. It is suggested
      that subcutaneous nodules of uncertain origin around the periphery of the breast
      should be viewed with suspicion and treated properly.

PMID- 10412343
TI  - Neuro-Behcet's disease presenting with isolated unilateral lateral rectus muscle
      palsy.
AB  - The authors present the clinical findings of a 30-year-old female and a 29-year
      old male who both had isolated unilateral lateral rectus muscle palsy in neuro
      Behcet's disease. The clinical feature related to isolated abduscens nerve palsy
      was identified by CT, systemic assessment and extraocular examination. These
      patients' constellation of findings appear to be unique: it does not follow any
      previously reported pattern of ocular manifestations of neuro-Behcet's disease.

PMID- 10412344
TI  - A case of primary bilateral adrenal lymphoma with partial adrenal insufficiency.
AB  - Unilateral or bilateral non-Hodgkin's lymphomas arising primarily in the adrenal
      glands are extremely rare. These lymphomas are usually present with large,
      bilateral adrenal masses with or without lymphadenopathy, and may be accompanied
      by adrenal insufficiency in some cases. A review of the literature indicates that
      patients with primary lymphoma of the adrenal glands usually do not have disease
      elsewhere, and if present, it is frequently extranodal. We report here an unusual
      case of primary bilateral adrenal lymphoma with partial adrenal insufficiency.

PMID- 10412345
TI  - Antibiotics and heart disease.

PMID- 10412346
TI  - Online pharmacies.

PMID- 10412347
TI  - No rest for sciatica.

PMID- 10412348
TI  - Despite safety, transfusion dilemmas persist.

PMID- 10412349
TI  - Valley fever can cause serious illness.

PMID- 10412351
TI  - New clue to breast cancer risk.

PMID- 10412350
TI  - Meal replacements for weight loss?

PMID- 10412352
TI  - Parents asking for antibiotics.

PMID- 10412353
TI  - Does surgery ease varicose vein discomfort?

PMID- 10412354
TI  - Travel and blood clots.

PMID- 10412356
TI  - Mediterranean diet.

PMID- 10412355
TI  - Boost for short kids on growth hormones?

PMID- 10412357
TI  - [Prehospital emergencies (emergencies and acute cases) in childhood].
AB  - OBJECTIVE: To determine incidence and management of prehospital emergencies in
      children. METHODS: Between November 15, 1994 and March 14, 1995 in the City of
      Mainz (200,000 inhabitants) children with the diagnosis of a prehospital
      emergency were identified. RESULTS: 390 children were discovered, 62% in the age
      group 0-3 years. 85% of the emergency conditions occurred at home. In 71% the
      medical practitioner providing prehospital care was a paediatrician, in 14% an
      emergency physician. 48% of the children were transported to the Children's
      Hospital by the parents. 32 different types of emergency were diagnosed, 8 types
      more than 10 times. A retrospective analysis of 386 emergencies demonstrated an
      acute life-threatening situation in 12%. Lacking a final diagnosis in 19%, first
      and final diagnosis were identical in 64% of all children evaluated. CONCLUSIONS:
      In Germany acute life-threatening emergencies are rare. Paediatricians are mainly
      involved also in the care of children with emergency conditions. Most
      pediatricians and nonpaediatricians are familiar with the relevant prehospital
      emergency conditions in the young children mainly concerned.

PMID- 10412358
TI  - [Gangrene of the fingers caused by accidental intra-arterial injection of
      diazepam].
AB  - HISTORY: A 51-year-old woman was accidentally given an intra-arterial injection
      of 10 mg diazepam to control an acute claustrophobic anxiety attack. She
      complained of severe knocking pain in the entire left arm during the injection.
      On the second day the hand and lower arm were red an swollen and she complained
      of increasingly feeling cold and having paraesthesias. On the fifth day the
      radial half of the palm as well as the first to third digits showed livid
      discoloration. In the further course necrotic areas developed in the palmar
      aspect of the distal phalanx of the thumb and of the index finger proximal to the
      middle phalanx. INVESTIGATION: Angiography on the tenth day after the injection
      revealed very poor perfusion of the radial artery as far as the wrist, occlusion
      of the superficial palmar arterial arch and occlusions of the digital arteries of
      the five fingers. TREATMENT AND COURSE: Infusion of 25,000 IU heparin over 24 h
      brought no improvement. On the 24th day after the diazepam injection the palmar
      aspect of the distal phalanx of the thumb and the index finger became necrotic,
      requiring amputation of the latter and, after removal of necrotic tissue, flap
      plasty using subcutaneous soft tissue of the extensor surface of the index finger
      to cover the defect on the thumb. The patient was without symptoms on discharge
      and the wounds were healing well. CONCLUSION: Every doctor should be aware of the
      dangers of accidental intra-arterial injection. The slightest suspicion and
      symptoms require immediate and adequate treatment to save the limb.

PMID- 10412359
TI  - [Persistent arthralgias in Ross-River-Virus disease after travel to the South
      Pacific].
AB  - HISTORY AND CLINICAL FINDINGS: A 57-year-old patient presented with malaise and
      severe persistent arthralgia of the left shoulder. He reported an acute illness
      with fever, generalized myalgia and arthralgias of the large joints which had
      started one month earlier during his flight back to Germany after a two weeks
      trip to the South Pacific. Physical examination showed extensive pain on
      palpation of the glenohumeral and acromioclavicular joints with impairment of
      active and passive mobility. Investigation of the cervical spine was normal.
      INVESTIGATIONS: Apart from elevated C-reactive protein and erythrocyte
      sedimentation rate levels, routine laboratory investigations were normal
      including negative immunodiagnostic tests for autoantibodies and various global
      infections that may be associated with arthritis. Immunofluorescence tests showed
      significant levels of specific IgM- and IgG-antibodies against Ross River virus
      (RRV) but not against other arboviruses endemic in the South Pacific and
      Australia (Dengue, West Nile, Chikungunya, Sindbis, Barmah Forest). This was
      confirmed by a positive RRV neutralisation test. Attempts at virus isolation and
      detection of viral RNA by PCR were not successful. TREATMENT AND COURSE:
      Symptomatic treatment with high doses of diclofenac quickly led to pain relief,
      and arthralgias receded within 10 days after begin of treatment. However, several
      bouts of arthralgia of the left shoulder and left knee occurred during a period
      of 4 months. CONCLUSIONS: Because of the current epidemiological situation in the
      South Pacific and Australia, infections by arboviruses like RRV should be
      considered in travellers returning from these areas with severe and persistent
      arthralgia of unknown origin, even in the absence of fever and other symptoms of
      acute infection.

PMID- 10412360
TI  - [Diagnosis of parenchymal lung diseases. Possibilities and limits of
      transthoracic sonography].

PMID- 10412361
TI  - [Recognizing, correctly reading and understanding scientific accounts: the art of
      selecting and interpreting medical publications].

PMID- 10412362
TI  - [Arcus senilis].

PMID- 10412363
TI  - [Chronic pain after thoracotomy].

PMID- 10412364
TI  - [Cervical myelitis in herpes simplex virus (HSV) infections].

PMID- 10412365
TI  - The one-to-four rule and paralogues of sex-determining genes.
AB  - Because of two successive rounds of tetraploidization at their inception, the
      vertebrates contain four times more protein-coding genes in their genome than the
      invertebrates: 60,000 versus 15,000. Consequently, each invertebrate gene has
      been amplified to the maximum of four paralogous genes in vertebrates: the one-to
      four rule. When this rule is applied to genes pertinent to gonadal development
      and differentiation, the following emerged: (i) Two closely related zinc-finger
      transcription factor genes in invertebrates have been amplified to two paralogous
      groups in vertebrates. One consisted of EGR1, EGR2, EGR3 and EGR4, whereas the
      only known paralogue of the other is WT1, which controls the developmental fate
      of the entire nephric system, and therefore of gonads. Interestingly, EGR1 and
      WT1 act as antagonists of each other in nephroblastic cells. (ii) SF-1, which
      controls the fate of two steroid hormone-producing organs, adrenals and gonads,
      is descended from the invertebrate Ftz-F1 gene, and its only known paralogue is
      GCNF-1. (iii) The Y-linked SRY, the mammalian testis-determining gene, is a
      paralogue neither of SOX3 (SRX) nor of SOX9. Its ancient origin suggests that SRY
      once became extinct in earlier vertebrates, only to revive itself in the
      mammalian ancestor. (iv) Inasmuch as four paralogues of one invertebrate nuclear
      receptor gene have differentiated to receptors of androgen, mineralocoticoid,
      glucocorticoid and progesterone, there should at most be four paralogous estrogen
      receptor genes in the vertebrate genome. It is likely that one of them plays a
      pivotal role in the estrogen-dependent sex-determining mechanism so commonly
      found among reptiles, amphibians and fish.

PMID- 10412366
TI  - Genes essential for early events in gonadal development.
AB  - The acquisition of a sexually dimorphic phenotype is a critical event in
      mammalian development. The basic underlying principle of sexual development is
      that genetic sex-determined at fertilization by the presence or absence of the Y
      chromosome--directs the embryonic gonads to differentiate into either testes or
      ovaries. Thereafter, hormones produced by the testes direct the developmental
      program that leads to male sexual differentiation. In the absence of testicular
      hormones, the female pathway of sexual differentiation occurs. Recent studies
      have defined key roles in gonadal development for two transcription factors:
      Wilms' tumor suppressor 1 (WT1) and steroidogenic factor 1 (SF-1). After
      presenting a brief overview of gonadal development and sexual differentiation,
      this paper reviews the studies that led to the isolation and characterization of
      WT1 and SF-1, and then discusses how interactions between these two genes may
      mediate their key roles in a common developmental pathway.

PMID- 10412368
TI  - DAX-1, an 'antitestis' gene.
AB  - The DAX-1 gene has been involved in the dosage sensitive sex reversal (DSS)
      phenotype, a male-to-female sex-reversal syndrome due to the duplication of a
      small region of human chromosome Xp21. Dax-1 and Sry have been shown to act
      antagonistically in the mouse system, where increasing expression of the former
      leads to female development and increasing activity of the latter to male
      development. Although these data strongly implicate DAX-1 in sex determination,
      the mouse and human proteins appear to behave differently. Absence of DAX-1 is
      responsible for adrenal hypoplasia congenita, a human inherited disorder
      characterized by adrenal insufficiency and hypogonadotropic hypogonadism. Unlike
      human patients, Dax-1-deficient XY mice have normal levels of corticotropins and
      adrenal hormones but are sterile. Dax-1-deficient females are fertile. The DAX-1
      protein, an unusual member of the nuclear hormone receptor, may act as a
      transcriptional repressor. It has been shown to both repress transcriptional
      activators by direct protein-protein interactions and to bind DNA hairpin
      structures and repress target genes.

PMID- 10412367
TI  - Sry and Sox9: mammalian testis-determining genes.
AB  - Sry is the Y-chromosomal gene that acts as a trigger for male development in
      mammalian embryos. This gene encodes a high mobility group (HMG) box
      transcription factor that is known to bind to specific target sequences in DNA
      and to cause a bend in the chromatin. DNA bending appears to be part of the
      mechanism by which Sry influences transcription of genes downstream in a cascade
      of gene regulation leading to maleness, but the direct targets of Sry remain to
      be positively identified. One gene known to be downstream from Sry in this
      cascade is Sox9, which encodes a transcription factor related to Sry by the HMG
      box. Like Sry, mutations in Sox9 disrupt male development, but unlike Sry, the
      role of Sox9 is not limited to mammals. This review focuses on what is known
      about the two genes and their likely modes of action, and draws together recent
      data relating to how they might interconnect with the network of gene activity
      implicated in testis determination in mammals.

PMID- 10412369
TI  - Sex chromosomes and sex-determining genes: insights from marsupials and
      monotremes.
AB  - Comparative studies of the genes involved in sex determination in the three
      extant classes of mammals, and other vertebrates, has allowed us to identify
      genes that are highly conserved in vertebrate sex determination and those that
      have recently evolved roles in one lineage. Analysis of the conservation and
      function of candidate genes in different vertebrate groups has been crucial to
      our understanding of their function and positioning in a conserved vertebrate sex
      determining pathway. Here we review comparisons between genes in the sex
      determining pathway in different vertebrates, and ask how these comparisons
      affect our views on the role of each gene in vertebrate sex determination.

PMID- 10412370
TI  - Temperature-dependent sex determination and gonadal differentiation in reptiles.
AB  - In many reptile species, sexual differentiation of gonads is sensitive to
      temperature during a critical period of embryonic development (thermosensitive
      period, TSP). Experiments carried out with different models among which turtles,
      crocodilians and lizards have demonstrated the implication of estrogens and the
      key role played by aromatase (the enzyme complex that converts androgens to
      estrogens) in ovary differentiation during TSP and in maintenance of the ovarian
      structure after TSP. In some of these experiments, the occurrence of various
      degrees of gonadal intersexuality is related to weak differences in aromatase
      activity, suggesting subtle regulations of the aromatase gene at the
      transcription level. Temperature could intervene in these regulations. Present
      studies deal with cloning (complementary DNAs) and expression (messenger RNAs) of
      genes that have been shown, or are expected, to be involved in gonadal formation
      and/or differentiation in mammals. Preliminary results indicate that homologues
      of AMH, DAX1, SF1, SOX9 and WT1 genes with the same function(s) as in mammals
      exist in reptiles. How these genes could interact with aromatase is being
      examined.

PMID- 10412371
TI  - Amphibian sex determination and sex reversal.
AB  - Amphibians employ a genetic mechanism of sex determination, according to all
      available information on sex chromosomes or breeding tests. Sex reversal allows
      breeding tests to establish which sex is heterogametic and provides an indication
      of the mechanism of sex determination. Cases of spontaneous and experimental sex
      reversal (by temperature, hormones or surgery) are reviewed and illustrated by
      previously unpublished studies on crested newts. These newts respond
      conventionally to temperature and hormone treatment but provide anomalous results
      from breeding tests. It is suggested that both the evolution from temperature
      dependency to a genetic switch and from ZZ/ZW to XX/XY are superimposed on a
      generally uniform mechanism of sex determination in all vertebrates.

PMID- 10412372
TI  - An update on the mechanisms of action of the peroxisome proliferator-activated
      receptors (PPARs) and their roles in inflammation and cancer.
AB  - Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and
      have been initially described as molecular targets for compounds which induce
      peroxisome proliferation. The interest of researchers for PPARs increased
      dramatically when these receptors were shown to be directly activated by a number
      of medically relevant compounds. These compounds include: the fibrate class of
      hypolidemic drugs, the thiazolidinediones, which are insulin sensitizers used as
      orally active antidiabetic agents, certain non-steroidal anti-inflammatory drugs
      (NSAIDs), and naturally occurring fatty acid-derived molecules. Rapidly, it was
      demonstrated that PPARs are key regulators of lipid homeostasis and provide a
      molecular link between nutrition and gene regulation. Recently, detailed studies
      of PPAR expression profiles in different tissues pointed to the roles these
      receptors play in inflammation control and cell proliferation. In this review we
      will focus on the new insights gained into these two areas and we will also
      discuss our current knowledge of the regulation of PPAR transcriptional activity
      by cofactors.

PMID- 10412373
TI  - Semenogelin I: a coagulum forming, multifunctional seminal vesicle protein.
AB  - Human seminal plasma spontaneously coagulates after ejaculation. The major
      component of this coagulum is semenogelin 1, a 52-kDa protein expressed
      exclusively in the seminal vesicles. Recently, a sperm motility inhibitor has
      been found to be identical to semenogelin I, suggesting that it may also be a
      physiological sperm motility inhibitor. The protein is rapidly cleaved after
      ejaculation by the chymotrypsin-like prostatic protease prostate-specific
      antigen, resulting in liquefaction of the semen coagulum and the progressive
      release of motile spermatozoa. Some of the cleavage products of Sg I may also
      have various biological functions. While the semenogelin I protein is unique to
      human and higher primates, it has recently been shown to belong to a gene family
      having a similar gene structure but encoding widely differing proteins. The
      recently elucidated characteristics of the semenogelin I gene as well as the
      biochemical and functional properties of the encoded protein are reviewed, and an
      attempt is made to integrate the various findings into a model for semen
      coagulation, sperm immobilization and potential other functions.

PMID- 10412374
TI  - Enteropathogenic Escherichia coli: a pathogen that inserts its own receptor into
      host cells.
AB  - Enteropathogenic Escherichia coli (EPEC) is a major cause of infant diarrhea,
      killing hundreds of thousands of children per year worldwide. Intimate attachment
      to the host cell leading to the formation of actin-rich pedestals beneath the
      adhering bacteria is an essential feature of EPEC pathogenesis. EPEC attaches to
      host cells via the outer membrane adhesin, intimin. It was recently shown that
      EPEC inserts its own receptor for intimate adherence, Tir (translocated intimin
      receptor) into the host cell membrane. The focus of this review is on the
      discovery and characterization of this novel receptor, and our current
      understanding of its role in pedestal formation. Gram-negative bacterial
      secretion systems, including type III secretion systems, are reviewed and
      discussed in the context of Tir delivery into the host cell membrane. The
      relationship and relevance of in vitro models compared to the actual in vivo
      situation is essential to understanding disease. We have critically reviewed the
      use of animal models in studying EPEC infection. Elucidating the function of Tir
      will contribute to our understanding of how EPEC mediates disease.

PMID- 10412375
TI  - Biological activity and pathological implications of misfolded proteins.
AB  - The physiological metabolism of proteins guarantees that different cellular
      compartments contain the appropriate concentration of proteins to perform their
      biological functions and, after a variable period of wear and tear, mediates
      their natural catabolism. The equilibrium between protein synthesis and
      catabolism ensures an effective turnover, but hereditary or acquired
      abnormalities of protein structure can provoke a premature loss of biological
      function, an accelerated catabolism and diseases caused by the loss of an
      irreplaceable function. In certain proteins, abnormal structure and metabolism
      are associated with a strong tendency to self-aggregation into a polymeric
      fibrillar structure, and in these cases the disease is not principally caused by
      the loss of an irreplaceable function but by the action of this new biological
      entity. Amyloid fibrils are an apparently inert, insoluble, mainly extracellular
      protein polymer that kills the cell without tissue necrosis but by activation of
      the apoptotic mechanism. We analyzed the data reported so far on the structural
      and functional properties of four prototypic proteins with well-known biological
      functions (lysozyme, transthyretin, beta 2-microglobulin and apolipoprotein AI)
      that are able to create amyloid fibrils under certain conditions, with the
      perspective of evaluating whether the achievement of biological function favors
      or inhibits the process of fibril formation. Furthermore, studying the biological
      functions carried out by amyloid fibrils reveals new types of protein-protein
      interactions in the transmission of messages to cells and may provide new ideas
      for effective therapeutic strategies.

PMID- 10412376
TI  - Leptin, but not a beta 3-adrenergic agonist, upregulates muscle uncoupling
      protein-3 messenger RNA expression: short-term thermogenic interactions.
AB  - The short-term effects of leptin and a beta 3-adrenoceptor agonist on
      thermogenesis and expression of uncoupling proteins (UCPs) in brown adipose
      tissue (BAT) and muscle and their possible interactions were assessed. One hour
      after administration of the beta 3-adrenoceptor agonist Trecadrine, a
      statistically significant increase in UCP1 messenger RNA (mRNA) expression in BAT
      was observed, whereas UCP2 and UCP3 in both BAT and gastrocnemius muscle were
      unaffected. Leptin induced an upregulation of UCP3 mRNA in muscle, with no
      changes in BAT UCP1 mRNA. A statistical interaction was found between leptin and
      Trecadrine in rectal temperature. The present study provides evidence, for the
      first time, of the induction of UCP3 mRNA expression in skeletal muscle by leptin
      in nongenetically obese animals.

PMID- 10412377
TI  - A mixture theory for charged-hydrated soft tissues containing multi-electrolytes:
      passive transport and swelling behaviors.
AB  - A new mixture theory was developed to model the mechano-electrochemical behaviors
      of charged-hydrated soft tissues containing multi-electrolytes. The mixture is
      composed of n + 2 constituents (1 charged solid phase, 1 noncharged solvent
      phase, and n ion species). Results from this theory show that three types of
      force are involved in the transport of ions and solvent through such materials:
      (1) a mechanochemical force (including hydraulic and osmotic pressures); (2) an
      electrochemical force; and (3) an electrical force. Our results also show that
      three types of material coefficients are required to characterize the transport
      rates of these ions and solvent: (1) a hydraulic permeability; (2) mechano
      electrochemical coupling coefficients; and (3) an ionic conductance matrix.
      Specifically, we derived the fundamental governing relationships between these
      forces and material coefficients to describe such mechano-electrochemical
      transduction effects as streaming potential, streaming current, diffusion
      (membrane) potential, electro-osmosis, and anomalous (negative) osmosis. As an
      example, we showed that the well-known formula for the resting cell membrane
      potential (Hodgkin and Huxley, 1952a, b) could be derived using our new n + 2
      mixture model (a generalized triphasic theory). In general, the n + 2 mixture
      theory is consistent with and subsumes all previous theories pertaining to
      specific aspects of charged-hydrated tissues. In addition, our results provided
      the stress, strain, and fluid velocity fields within a tissue of finite thickness
      during a one-dimensional steady diffusion process. Numerical results were
      provided for the exchange of Na+ and Ca++ through the tissue. These numerical
      results support our hypothesis that tissue fixed charge density (CF) plays a
      significant role in modulating kinetics of ions and solvent transport through
      charged-hydrated soft tissues.

PMID- 10412378
TI  - Impact-induced fissuring of articular cartilage: an investigation of failure
      criteria.
AB  - Several candidate predictors for the occurrence of surface fissures in cartilage,
      including impact force, shear stress, and tensile strain have been previously
      proposed without an analytic basis. In this study a controlled impact experiment
      was performed where a dropped mass and three impact interfaces were used to
      identify loads associated with the initiation of fissuring. A Finite Element
      Model of each experiment was used to obtain stresses and strains associated with
      each impact event. The resulting experimental and analytical data were analyzed
      using logistic regression in order to determine the strongest predictor of a
      fissure, and thus to propose a failure criterion for articular cartilage during a
      blunt insult. The logistic regression indicated that shear stress, rather than
      impact force or drop height (an indicator of impact energy), was the strongest
      predictor for the occurrence of a fissure.

PMID- 10412379
TI  - Identification and determination of material properties for porohyperelastic
      analysis of large arteries.
AB  - A "porohyperelastic" (PHE) material model is described and the theoretical
      framework presented that allows identification of the necessary material
      properties functions for soft arterial tissues. A generalized Fung form is
      proposed for the PHE constitutive law in which the two fundamental Lagrangian
      material properties are the effective strain energy density function, W(e), and
      the hydraulic permeability, kij. The PHE model is based on isotropic forms using
      W(e) = Ue (phi) = 1/2C0(e phi - 1) and the radial component of permeability, kRR
      = kRR(phi), with phi = C1'(I1 - 3) + C2'(I2 - 3) + K'(J - 1)2. The methods for
      determination of these material properties are illustrated using experimental
      data from in situ rabbit aortas. Three experiments are described to determine
      parameters in Ue and kRR for the intima and media of the aortas, i.e., (1)
      undrained tests to determine C0, C1', and C2'; (2) drained tests to determine K';
      and (3) steady-state pressurization tests of intact and de-endothelialized
      vessels to determine intimal and medial permeability (adventitia removed in these
      models). Data-reduction procedures are presented that allow determination of kRR
      for the intima and media and Ue for the media using experimental data. The
      effectiveness and accuracy of these procedures are studied using input "data"
      from finite element models generated with the ABAQUS program. The isotropic
      theory and data-reduction methods give good approximations for the PHE properties
      of in situ aortas. These methods can be extended to include arterial tissue
      remodeling and anisotropic behavior when appropriate experimental data are
      available.

PMID- 10412380
TI  - Finite element formulation of biphasic poroviscoelastic model for articular
      cartilage.
AB  - The purpose of the present study was to develop a computationally efficient
      finite element model that could be useful for parametric analysis of the biphasic
      poroviscoelastic (BPVE) behavior of articular cartilage under various loading
      conditions. The articular cartilage was modeled as the BPVE mixture of a porous,
      linear viscoelastic, and incompressible solid and an inviscid and incompressible
      fluid. A finite element (FE) formulation of the BPVE model was developed using
      two different algorithms, the continuous and discrete spectrum relaxation
      functions for the viscoelasticity of the solid matrix. These algorithms were
      applied to the creep and stress relaxation responses to the confined compression
      of articular cartilage, and a comparison of their performances was made. It was
      found that the discrete spectrum algorithm significantly saved CPU time and
      memory, as compared to the continuous spectrum algorithm. The consistency
      analysis for the present FE formulation was performed in comparison with the
      IMSL, a commercially available numerical software package. It was found that the
      present FE formulation yielded consistent results in predicting model behavior,
      whereas the IMSL subroutine produced inconsistent results in the velocity field,
      and thereby in the strain calculation.

PMID- 10412381
TI  - A finite element based method to determine the properties of planar soft tissue.
AB  - A finite element based method to determine the incremental elastic material
      properties of planar membranes was developed and evaluated. The method is
      applicable to tissues that exhibit inhomogeneity, geometric and material
      nonlinearity, and anisotropy. Markers are placed on the tissue to form a four
      node quadrilateral element. The specimen is loaded to an initial reference state,
      then three incremental loading sets are applied and the nodal displacements
      recorded. One of these loadings must include shear. These data are used to solve
      an over-determined system of equations for the tangent stiffness matrix. The
      method was first verified using analytical data. Next, data obtained from a latex
      rubber sheet were used to evaluate experimental procedures. Finally, experiments
      conducted on preconditioned rat skin revealed nonlinear orthotropic behavior. The
      vector norm comparing the applied and calculated nodal force vectors was used to
      evaluate the accuracy of the solutions.

PMID- 10412382
TI  - Postsurgical changes of the opening angle of canine autogenous vein graft.
AB  - The opening angles of 30 canine autogenous vein grafts were measured to determine
      the postsurgical change of residual strain in the vein graft. Canine femoral
      veins were grafted to femoral arteries in the end-to-end anastomosis fashion.
      When harvested, the vein grafts were cut into short segments and the segments
      were cut open radially. The opened-up configurations were taken as the zero
      stress states of the vessels. Opening angle, defined as the angle between the two
      lines from the middle point to the tips of the inner wall, was used to describe
      the zero-stress states. Results show that the opening angles (mean +/- SD) are
      63.0 +/- 30.6 deg for normal femoral veins, and -0.4 +/- 4.6, 6.1 +/- 19.4, 25.4
      +/- 20.1, and 47.8 +/- 11.4 deg for vein grafts at 1 day, 1 week, 4 and 12 weeks
      postsurgery, respectively. The postsurgical changes in opening angle reveal
      nonuniform transmural tissue remodeling in the vascular wall. The relations
      between the changes in opening angle and the changes in the morphology of the
      vein grafts are discussed. Intimal hyperplasia is correlated to the opening angle
      and is suggested to be the main factor for the postsurgical increase in opening
      angle. The longitudinal strain in the vein graft is found to decrease
      postsurgically.

PMID- 10412383
TI  - Characteristics of glottis-induced turbulence in oscillatory flow: an empirical
      investigation.
AB  - Turbulence inducement from the glottis was scrutinized by employing an idealized
      model of the larynx and trachea for oscillatory flow conditions. The
      characterization of turbulence was achieved with the two-component velocity
      measurements of split-film probe anemometry and with the flow visualization of a
      smoke-wire technique. The apertures of two different (triangular and circular)
      shapes were utilized in the airway model to address the distinct effects of the
      triangular-shaped glottal aperture on the generation, development, and decay of
      turbulence. One of the salient turbulence characteristics for the triangular
      aperture case was found to be the relatively high turbulence levels around the
      center region (2r/D approximately 0) in conjunction with the asymmetric mean
      axial velocity across the frontal-rear (A-O-P) plane of the trachea at one
      tracheal diameter (x/D = 1) downstream from the glottis. The detailed turbulence
      properties such as the Reynolds shear stresses and turbulence intensities for the
      triangular aperture case differed significantly from those for the circular
      aperture case within a few tracheal diameters (x/D < 7) downstream from the
      apertures. The glottis-induced turbulence was incipient during the acceleration
      phase of inspiration and convected downstream with the traits of decaying
      turbulence.

PMID- 10412384
TI  - Alteration of mean wall shear stress near an oscillating stagnation point.
AB  - The site opposite an end-to-side anastomosis, resulting from femoral bypass
      surgery, and the carotid sinus are two regions well known to be prone to fibrous
      intimal hyperplasia or atherogenesis, respectively. The blood flow at these two
      sites features a stagnation point, which oscillates in strength and position.
      Mathematical models are used to determine some of the features of such a flow; in
      particular, the mean wall shear stress is calculated. The positional oscillations
      cause a significant change in the distribution and magnitude of the mean wall
      shear stress from that of the well-studied case of a stagnation point that
      oscillates only in strength. It is therefore proposed that the recorded effect of
      time dependence in the flow upon atherogenesis could still be a result of the
      distribution of the mean and not the time-varying components of the wall shear
      stress.

PMID- 10412385
TI  - Bolus contaminant dispersion in oscillating flow in curved tubes.
AB  - The investigation of longitudinal dispersion of tracer substances in unsteady
      flows has biomechanical application in the study of heat and mass transport
      within the bronchial airways during normal, abnormal, and artificial pulmonary
      ventilation. To model the effects of airway curvature on intrapulmonary gas
      transport, we have measured local gas dispersion in axially uniform helical tubes
      of slight pitch during volume-cycled oscillatory flow. Following a small argon
      bolus injection into the flow field, the time-averaged effective diffusion
      coefficient (Deff/Dmol) for axial transport of the contaminant was evaluated from
      the time-dependent local argon concentration measured with a mass spectrometer.
      The value of (Deff/Dmol) is extracted from the curve of concentration versus time
      by two techniques yielding identical results. Experiments were conducted in two
      helical coiled tubes (delta = 0.031, lambda = 0.022 or delta = 0.085, lambda =
      0.060) over a range of 2 < alpha < 15, 3 < A < 15, where delta is the ratio of
      tube radius to radius of curvature, lambda is the ratio of pitch height to radius
      of curvature, alpha is the Womersley parameter or dimensionless frequency, and A
      is the stroke amplitude or dimensionless tidal volume. Experimental results show
      that, when compared to transport in straight tubes, the effective diffusivity
      markedly increases in the presence of axial curvature. Results also compare
      favorably to mathematical predictions of bolus dispersion in a curved tube over
      the ranges of frequency and tidal volume studied.

PMID- 10412386
TI  - Pulsatile flow computational simulations of mitral regurgitation.
AB  - The noninvasive quantification of mitral regurgitation remains an important
      clinical goal. Recently, the flow convergence method was developed to estimate
      the regurgitant flow rate. This study used three-dimensional pulsatile flow
      computational simulations to evaluate the accuracy of the flow convergence method
      in the presence of complicating factors such as ventricular confinement,
      noncircular orifice shape, and the presence of aortic outflow. Results showed
      that in the absence of aortic outflow and ventricular confinement, there was a
      plateau zone where the calculated flow rate by the hemispheric formula
      approximated the true flow rate, independent of the orifice shape. In the
      presence of aortic outflow and in chambers of physiologic dimensions, there was
      no longer a clear zone where the hemispheric formula was valid. The hemi-elliptic
      modification of the flow convergence method worked in all cases, independent of
      the degree of ventricular confinement or the presence of aortic outflow.
      Therefore, application of the hemi-elliptic formula should be considered in
      future clinical studies.

PMID- 10412387
TI  - An evaluation of the wind chill factor: its development and applicability.
AB  - The wind chill factor has become a standard meteorologic term in cold climates.
      Meteorologic charts provide wind chill temperatures meant to represent the
      hypothetical air temperature that would, under conditions of no wind, effect the
      same heat loss from unclothed human skin as does the actual combination of air
      temperature and wind velocity. As this wind chill factor has social and economic
      significance, an investigation was conducted on the development of this factor
      and its applicability based on modern heat transfer principles. The currently
      used wind chill factor was found to be based on a primitive study conducted by
      the U.S. Antarctic Service over 50 years ago. The resultant equation for the wind
      chill temperature assumes an unrealistic constant skin temperature and utilizes
      heat transfer coefficients that differ markedly from those obtained from
      equations of modern convective heat transfer methods. The combined effect of
      these two factors is to overestimate the effect of a given wind velocity and to
      predict a wind chill temperature that is too low.

PMID- 10412388
TI  - Thermal expansion measurements of frozen biological tissues at cryogenic
      temperatures.
AB  - Thermal expansion data are essential for analyses of cryodestruction associated
      with thermal stresses during cryopreservation protocols as well as during
      cryosurgery. The present study tests a commonly used hypothesis that the thermal
      expansion of frozen tissues is similar to that of pure water ice crystals. This
      study further provides insight into the potential effect of the presence of
      cryoprotectants on thermal expansion. A new apparatus for thermal strain
      measurements of frozen biological tissues within a cryogenic temperature range is
      presented. Results are presented for fresh tissue samples taken from beef muscle,
      chicken muscle, rabbit muscle, rabbit bone, and pig liver. Pilot studies of the
      effect of cryoprotectants on thermal expansion are further presented for rabbit
      muscle immersed in dimethyl sulphoxide (2 mols/l) and glycerol (2 mols/l), and
      for pig liver perfused with dimethyl sulphoxide (2 mols/l). Thermal expansion of
      frozen soft biological tissues was found to be similar to that of water ice
      crystals in the absence of cryoprotectant. Thermal expansion of the rabbit bone
      was found to be about one half of that of frozen soft tissues. A significant
      reduction in the thermal expansion at higher temperatures was observed in the
      presence of cryoprotectants. A rapid change of thermal strain near -100 degrees C
      was also observed, which is likely to be associated with the glass transition
      process of the cryoprotectant solutions.

PMID- 10412389
TI  - Static and dynamic finite element analyses of an idealized structural model of
      vertebral trabecular bone.
AB  - An idealized three-dimensional finite element model of a rodlike trabecular bone
      structure was developed to study its static and dynamic responses under
      compressive loading, considering the effects of bone marrow and apparent density.
      Static analysis of the model predicted hydraulic stiffening of trabecular bone
      due to the presence of bone marrow. The predicted power equation relating
      trabecular bone apparent elastic modulus to its apparent density was in good
      agreement with those of the reported experimental investigations. The ratio of
      the maximum stress in the trabecular bone tissue to its apparent stress had a
      high value, decreasing with increasing bone apparent density. Frequency analyses
      of the model predicted higher natural frequencies for the bone without marrow
      than those for the bone with marrow. Adding a mass relatively large compared to
      that of bone rendered a single-degree-of-freedom response. In this case, the
      resonant frequency was higher for the bone with marrow than that for the bone
      without marrow. The predicted vibrational measurement of apparent modulus was in
      good agreement with that of the static measurement, suggesting vibrational
      testing as a method for nondestructive measurement of trabecular bone elastic
      moduli.

PMID- 10412390
TI  - Prediction of biomechanical parameters in the lumbar spine during static sagittal
      plane lifting.
AB  - A combined approach involving optimization and the finite element technique was
      used to predict biomechanical parameters in the lumbar spine during static
      lifting in the sagittal plane. Forces in muscle fascicles of the lumbar region
      were first predicted using an optimization-based force model including the entire
      lumbar spine. These muscle forces as well as the distributed upper body weight
      and the lifted load were then applied to a three-dimensional finite element model
      of the thoracolumbar spine and rib cage to predict deformation, the intradiskal
      pressure, strains, stresses, and load transfer paths in the spine. The predicted
      intradiskal pressures in the L3-4 disk at the most deviated from the in vivo
      measurements by 8.2 percent for the four lifting cases analyzed. The lumbosacral
      joint flexed, while the other lumbar joints extended for all of the four lifting
      cases studied (rotation of a joint is the relative rotation between its two
      vertebral bodies). High stresses were predicted in the posterolateral regions of
      the endplates and at the junctions of the pedicles and vertebral bodies. High
      interlaminar shear stresses were found in the posterolateral regions of the
      lumbar disks. While the facet joints of the upper two lumbar segments did not
      transmit any load, the facet joints of the lower two lumbar segments experienced
      significant loads. The ligaments of all lumbar motion segments except the
      lumbosacral junction provided only marginal moments. The limitations of the
      current model and possible improvements are discussed.

PMID- 10412391
TI  - The simplest walking model: stability, complexity, and scaling.
AB  - We demonstrate that an irreducibly simple, uncontrolled, two-dimensional, two
      link model, vaguely resembling human legs, can walk down a shallow slope, powered
      only by gravity. This model is the simplest special case of the passive-dynamic
      models pioneered by McGeer (1990a). It has two rigid massless legs hinged at the
      hip, a point-mass at the hip, and infinitesimal point-masses at the feet. The
      feet have plastic (no-slip, no-bounce) collisions with the slope surface, except
      during forward swinging, when geometric interference (foot scuffing) is ignored.
      After nondimensionalizing the governing equations, the model has only one free
      parameter, the ramp slope gamma. This model shows stable walking modes similar to
      more elaborate models, but allows some use of analytic methods to study its
      dynamics. The analytic calculations find initial conditions and stability
      estimates for period-one gait limit cycles. The model exhibits two period-one
      gait cycles, one of which is stable when 0 < gamma < 0.015 rad. With increasing
      gamma, stable cycles of higher periods appear, and the walking-like motions
      apparently become chaotic through a sequence of period doublings. Scaling laws
      for the model predict that walking speed is proportional to stance angle, stance
      angle is proportional to gamma 1/3, and that the gravitational power used is
      proportional to v4 where v is the velocity along the slope.

PMID- 10412392
TI  - The accuracy of digital image-based finite element models.
AB  - Digital image-based finite element meshing is an alternative approach to time
      consuming conventional meshing techniques for generating realistic three
      dimensional (3D) models of complex structures. Although not limited to biological
      applications, digital image-based modeling has been used to generate structure
      specific (i.e., non-generic) models of whole bones and trabecular bone
      microstructures. However, questions remain regarding the solution accuracy
      provided by the digital meshing approach, particularly at model or material
      boundaries. The purpose of this study was to compare the accuracy of digital and
      conventional smooth boundary models based on theoretical solutions for a two
      dimensional (2D) compression plate and a 3D circular cantilever beam. For both
      the plate and beam analyses, the predicted solution at digital model boundaries
      was characterized by local oscillations, which produced potentially high errors
      within individual boundary elements. Significantly, however, the digital model
      boundary solution oscillated approximately about the theoretical solution. A
      marked improvement in solution accuracy was therefore achieved by considering
      average results within a region composed of several elements. Absolute errors for
      Von Mises stress averaged over the beam cross section, for example, converged to
      less than 4 percent, and the predicted free-end displacement of the cantilever
      beam was within 1 percent of the theoretical solution. Analyses at several beam
      orientations and mesh resolutions suggested a minimum discretization of three to
      four digital finite elements through the beam cross section to avoid high
      numerical stiffening errors under bending.

PMID- 10412393
TI  - Porohyperelastic finite element analysis of large arteries using ABAQUS.

PMID- 10412394
TI  - A device for measuring relative angular displacement.
AB  - A simple, inexpensive, and accurate way to measure relative segmental rotations
      resulting from torsional loadings locally is described. To measure these
      rotations, we fabricated a planar spatial linkage (open-loop kinematic chain)
      requiring only one rotational displacement transducer. This paper describes this
      device, defines its kinematics, and examines its accuracy.

PMID- 10412395
TI  - A distributed pressure sensor for biomechanical measurements.

PMID- 10412396
TI  - Cervical spine vertebral and facet joint kinematics under whiplash.
AB  - Whiplash injuries sustained during a rear-end automobile collision have
      significant societal impact. The scientific literature on whiplash loading is
      both diverse and confusing. Definitive studies are lacking to describe the local
      mechanisms of injury that induce either acute or chronic pain symptoms. A
      methodology has been presented to quantify the kinematics of the cervical spine
      components by inducing controlled whiplash-type forces to intact human head-neck
      complexes. The localized facet joint kinematics and the overall segmental motions
      of the cervical spine are presented. It is anticipated that the use of this
      methodology will assist in a better delineation of the localized mechanisms of
      injury leading to whiplash pain.

PMID- 10412397
TI  - Influence of tensile strain on smooth muscle cell orientation in rat blood
      vessels.
AB  - Blood vessels are subject to tensile stress and associated strain which may
      influence the structure and organization of smooth muscle cells (SMCs) during
      physiological development and pathological remodeling. This study focused on the
      influence of the major tensile strain on the SMC orientation in the blood vessel
      wall. Several blood vessels, including the aorta, the mesenteric artery and vein,
      and the jugular vein of the rat were used to observe the normal distribution of
      tensile strains and SMC orientation; and a vein graft model was used to observe
      the influence of altered strain direction on the SMC orientation. The
      circumferential and longitudinal strains in these blood vessels were measured by
      using a biomechanical technique, and the SMC orientation was examined by
      fluorescent microscopy at times of 10, 20, and 30 days. Results showed that the
      SMCs were mainly oriented in the circumferential direction of straight blood
      vessels with an average angle of approximately 85 deg between the SMC axis and
      the vessel axis in all observed cases. The SMC orientation coincided with the
      principal direction of the circumferential strain, a major tensile strain, in the
      blood vessel wall. In vein grafts, the major tensile strain direction changed
      from the circumferential to the longitudinal direction at observation times of
      10, 20, and 30 days after graft surgery. This change was associated with a
      decrease in the angle between the axis of newly proliferated SMCs and that of the
      vessel at all observation times (43 +/- 11 deg, 42 +/- 10 deg, and 41 +/- 10 deg
      for days 10, 20, and 30, respectively), indicating a shift of the SMC orientation
      from the circumferential toward the longitudinal direction. These results
      suggested that the major tensile strain might play a role in the regulation of
      SMC orientation during the development of normal blood vessels as well as during
      remodeling of vein grafts.

PMID- 10412398
TI  - Stress wave velocities in bovine patellar tendon.
AB  - The velocity of longitudinal stress waves in an elastic body is given by the
      square root of the ratio of its elastic modulus to its density. In tendinous and
      ligamentous tissue, the elastic modulus increases with strain and with strain
      rate. Therefore, it was postulated that stress wave velocity would also increase
      with increasing strain and strain rate. The purpose of this study was to
      determine the velocity of stress waves in tendinous tissue as a function of
      strain and to compare these values to those predicted using the elastic modulus
      derived from quasi-static testing. Five bovine patellar tendons were harvested
      and potted as bone-tendon-bone specimens. Quasi-static mechanical properties were
      determined in tension at a deformation rate of 100 mm/s. Impact loading was
      employed to determine wave velocity at various strain levels, achieved by
      preloading the tendon. Following impact, there was a measurable delay in force
      transmission across the specimen and this delay decreased with increasing tendon
      strain. The wave velocities at tendon strains of 0.0075, 0.015, and 0.0225 were
      determined to be 260 +/- 52 m/s, 360 +/- 71 m/s, and 461 +/- 94 m/s,
      respectively. These velocities were significantly (p < 0.01) faster than those
      predicted using elastic moduli derived from the quasi-static tests by 52, 45, and
      41 percent, respectively. This study has documented that stress wave velocity in
      patellar tendon increases with increasing strain and is underestimated with a
      modulus estimated from quasi-static testing.

PMID- 10412399
TI  - An implantable transducer for measuring tension in an anterior cruciate ligament
      graft.
AB  - The goal of this study was to develop a new implantable transducer for measuring
      anterior cruciate ligament (ACL) graft tension postoperatively in patients who
      have undergone ACL reconstructive surgery. A unique approach was taken of
      integrating the transducer into a femoral fixation device. To devise a practical
      in vivo calibration protocol for the fixation device transducer (FDT), several
      hypotheses were investigated: (1) The use of a cable versus the actual graft as
      the means for applying load to the FDT during calibration has no significant
      effect on the accuracy of the FDT tension measurements; (2) the number of flexion
      angles at which the device is calibrated has no significant effect on the
      accuracy of the FDT measurements; (3) the friction between the graft and femoral
      tunnel has no significant effect on measurement accuracy. To provide data for
      testing these hypotheses, the FDT was first calibrated with both a cable and a
      graft over the full range of flexion. Then graft tension was measured
      simultaneously with both the FDT on the femoral side and load cells, which were
      connected to the graft on the tibial side, as five cadaver knees were loaded
      externally. Measurements were made with both standard and overdrilled tunnels.
      The error in the FDT tension measurements was the difference between the graft
      tension measured by the FDT and the load cells. Results of the statistical
      analyses showed that neither the means of applying the calibration load, the
      number of flexion angles used for calibration, nor the tunnel size had a
      significant effect on the accuracy of the FDT. Thus a cable may be used instead
      of the graft to transmit loads to the FDT during calibration, thus simplifying
      the procedure. Accurate calibration requires data from just three flexion angles
      of 0, 45, and 90 deg and a curve fit to obtain a calibration curve over a
      continuous range of flexion within the limits of this angle group. Since friction
      did not adversely affect the measurement accuracy of the FDT, the femoral tunnel
      can be drilled to match the diameter of the graft and does not need to be
      overdrilled. Following these procedures, the error in measuring graft tension
      with the FDT averages less than 10 percent relative to a full-scale load of 257
      N.

PMID- 10412400
TI  - Evaluation of performance criteria for simulation of submaximal steady-state
      cycling using a forward dynamic model.
AB  - The objectives of this study were twofold. The first was to develop a forward
      dynamic model of cycling and an optimization framework to simulate pedaling
      during submaximal steady-state cycling conditions. The second was to use the
      model and framework to identify the kinetic, kinematic, and muscle timing
      quantities that should be included in a performance criterion to reproduce
      natural pedaling mechanics best during these pedaling conditions. To make this
      identification, kinetic and kinematic data were collected from 6 subjects who
      pedaled at 90 rpm and 225 W. Intersegmental joint moments were computed using an
      inverse dynamics technique and the muscle excitation onset and offset were taken
      from electromyographic (EMG) data collected previously (Neptune et al., 1997).
      Average cycles and their standard deviations for the various quantities were used
      to describe normal pedaling mechanics. The model of the bicycle-rider system was
      driven by 15 muscle actuators per leg. The optimization framework determined both
      the timing and magnitude of the muscle excitations to simulate pedaling at 90 rpm
      and 225 W. Using the model and optimization framework, seven performance criteria
      were evaluated. The criterion that included all of the kinematic and kinetic
      quantities combined with the EMG timing was the most successful in replicating
      the experimental data. The close agreement between the simulation results and the
      experimentally collected kinetic, kinematic, and EMG data gives confidence in the
      model to investigate individual muscle coordination during submaximal steady
      state pedaling conditions from a theoretical perspective, which to date has only
      been performed experimentally.

PMID- 10412401
TI  - Uniform stress state in bone structure with residual stress.
AB  - Residual stress and strain in living tissues have been investigated from the
      viewpoint of mechanical optimality maintained by adaptive remodeling. In this
      study, the residual stresses in the cortical-cancellous bone complex of bovine
      coccygeal vertebrae were examined. Biaxial strain gages were bonded onto the
      cortical surface, so that the gage axes were aligned in the cephalocaudal and
      circumferential directions. Strains induced by removal of the end-plate and the
      cancellous bone were recorded sequentially. The results revealed the existence of
      compressive residual stress in the cortical bone and tensile residual stress in
      the cancellous bone in both the cephalocaudal and the circumferential direction.
      The observed strains were examined on the basis of the uniform stress hypothesis
      using a three-bar model for the cephalocaudal direction and a three-layered
      cylinder model for the circumferential direction. In this model study, the
      magnitude of effective stresses, which is defined as the macroscopic stress
      divided by the area fraction of bone material, was found not to differ
      significantly between cephalocaudal and circumferential directions, although they
      were evaluated using independent models. These results demonstrate that the
      uniform stress state of the cortical-cancellous bone structure is consistent with
      results obtained in the cutting experiment when the existence of residual stress
      is taken into account.

PMID- 10412402
TI  - A model for aortic growth based on fluid shear and fiber stresses.
AB  - Stress-modulated growth in the aorta is studied using a theoretical model. The
      model is a thick-walled tube composed of two pseudoelastic, orthotropic layers
      representing the intima/media and the adventitia. Both layers are assumed to
      follow a growth law in which the time rates of change of the growth stretch
      ratios depend linearly on the local smooth muscle fiber stress and on the shear
      stress due to blood flow on the endothelium. Using finite elasticity theory
      modified to include volumetric growth, we computed temporal changes in stress,
      geometry, and opening angle (residual strain) during development and following
      the onset of sudden hypertension. For appropriate values of the coefficients in
      the growth law, the model yields results in reasonable agreement with published
      data for global and local growth of the rat aorta.

PMID- 10412403
TI  - Swelling and curling behaviors of articular cartilage.
AB  - A new experimental method was developed to quantify parameters of swelling
      induced shape change in articular cartilage. Full-thickness strips of cartilage
      were studied in free-swelling tests and the swelling-induced stretch, curvature,
      and areal change were measured. In general, swelling-induced stretch and
      curvature were found to increase in cartilage with decreasing ion concentration,
      reflecting an increasing tendency to swell and "curl" at higher swelling
      pressures. An exception was observed at the articular surface, which was
      inextensible for all ionic conditions. The swelling-induced residual strain at
      physiological ionic conditions was estimated from the swelling-induced stretch
      and found to be tensile and from 3-15 percent. Parameters of swelling were found
      to vary with sample orientation, reflecting a role for matrix anisotropy in
      controlling the swelling-induced residual strains. In addition, the surface zone
      was found to be a structurally important element, which greatly limits swelling
      of the entire cartilage layer. The findings of this study provide the first
      quantitative measures of swelling-induced residual strain in cartilage ex situ,
      and may be readily adapted to studies of cartilage swelling in situ.

PMID- 10412404
TI  - Investigation into the biphasic properties of a hydrogel for use in a cushion
      form replacement joint.
AB  - A hydrogel with potential applications in the role of a cushion form replacement
      joint bearing surface material has been investigated. The material properties are
      required for further development and design studies and have not previously been
      quantified. Creep indentation experiments were therefore performed on samples of
      the hydrogel. The biphasic model developed by Mow and co-workers (Mak et al.,
      1987; Mow et al., 1989a) was used to curve-fit the experimental data to
      theoretical solutions in order to extract the three intrinsic biphasic material
      properties of the hydrogel (aggregate modulus, HA, Poisson's ratio, Vs, and
      permeability, k). Ranges of material properties were determined: aggregate
      modulus was calculated to be between 18.4 and 27.5 MPa, Poisson's ratio 0.0
      0.307, and permeability 0.012-7.27 x 10(-17) m4/Ns. The hydrogel thus had a
      higher aggregate modulus than values published for natural normal articular
      cartilage, the Poisson's ratios were similar to articular cartilage, and finally
      the hydrogel was found to be less permeable than articular cartilage. The
      determination of these values will facilitate further numerical analysis of the
      stress distribution in a cushion form replacement joint.

PMID- 10412405
TI  - A triphasic analysis of corneal swelling and hydration control.
AB  - Physiological studies strongly support the view that hydration control in the
      cornea is dependent on active ion transport at the corneal endothelium. However,
      the mechanism by which endothelial ion transport regulates corneal thickness has
      not been elaborated in detail. In this study, the corneal stroma is modeled as a
      triphasic material under steady-state conditions. An ion flux boundary condition
      is developed to represent active transport at the endothelium. The equations are
      solved in cylindrical coordinates for confined compression and in spherical
      coordinates to represent an intact cornea. The model provides a mechanism by
      which active ion transport at the endothelium regulates corneal hydration and
      provides a basis for explaining the origin of the "imbibition pressure" and
      stromal "swelling pressure." The model encapsulates the Donnan view of corneal
      swelling as well as the "pump-leak hypothesis."

PMID- 10412406
TI  - Heat-induced changes in the mechanics of a collagenous tissue: isothermal,
      isotonic shrinkage.
AB  - We present data from isothermal, isotonic-shrinkage tests wherein bovine chordae
      tendineae were subjected to well-defined constant temperatures (from 65 to 90
      degrees C), durations of heating (from 180 to 3600 s), and isotonic uniaxial
      stresses during heating (from 100 to 650 kPa). Tissue response during heating and
      "recovery" at 37 degrees C following heating was evaluated in terms of the axial
      shrinkage, a gross indicator of underlying heat-induced denaturation. There were
      three key findings. First, scaling the heating time via temperature and load
      dependent characteristic times for the denaturation process collapsed all
      shrinkage data to a single curve, and thereby revealed a time-temperature-load
      equivalency. Second, the characteristic times exhibited an Arrhenius-type
      behavior with temperature wherein the slopes were nearly independent of applied
      load--this suggested that applied loads during heating affect the activation
      entropy, not energy. Third, all specimens exhibited a time-dependent, partial
      recovery when returned to 37 degrees C following heating, but the degree of
      recovery decreased with increases in the load imposed during heating. These new
      findings on heat-induced changes in tissue behavior will aid in the design of
      improved clinical heating protocols and provide guidance for the requisite
      constitutive formulations.

PMID- 10412407
TI  - Simulation of a cold-stressed finger including the effects of wind, gloves, and
      cold-induced vasodilatation.
AB  - The thermal response of fingers exposed to cold weather conditions has been
      simulated. Energy balance equations were formulated, in a former study, for the
      tissue layers and the arterial, venous, and capillary blood vessels. The
      equations were solved by a finite difference scheme using the Thomas algorithm
      and the method of alternating directions. At this stage of development the model
      does not include any autonomic control functions. Model simulations assumed an
      electrical heating element to be embedded in the glove layers applied on the
      finger. A 1.3 W power input was calculated for maintaining finger temperatures at
      their pre-cold exposure level in a 0 degree C environment. Alternate assumptions
      of nutritional (low) and basal (high) blood flows in the finger demonstrated the
      dominance of this factor in maintaining finger temperatures at comfortable
      levels. Simulated exposures to still and windy air, at 4.17 m/s (15 km/h),
      indicated the profound chilling effects of wind on fingers in cold environments.
      Finally, the effects of variable blood flow in the finger, known as "cold-induced
      vasodilatation," were also investigated. Blood flow variations were assumed to be
      represented by periodic, symmetric triangular waves allowing for gradual opening
      closing cycles of blood supply to the tip of the finger. Results of this part of
      the simulation were compared with measured records of bare finger temperatures.
      Good conformity was obtained for a plausible pattern of change in blood flow,
      which was assumed to be provided in its entirety to the tip of the finger alone.

PMID- 10412408
TI  - A generic tissue convective energy balance equation: Part I--theory and
      derivation.
AB  - A new equation for calculating temperatures in living tissues, the tissue
      convective energy balance equation (TCEBE), is derived using only a few
      assumptions. The resulting equation is basic, general and applicable to any
      tissue. The (unsolved) TCEBE is used: (a) to relate both Pennes' BHTE perfusion
      related parameter (W) and the effective thermal conductivity equation's perfusion
      related parameter (keff) to the true capillary perfusion Pcap, and (b) to show
      that both W and keff are defined, nonphysiological variables, which are only
      related to Pcap in a problem-dependent manner. Finally, the derivation of the
      relationship between W and Pcap provides a complete derivation of Pennes' BHTE,
      something that has not been previously done.

PMID- 10412409
TI  - Augmentation of axial dispersion by intermittent oscillatory flow.
AB  - The efficiency of axial gas dispersion during ventilation with high-frequency
      oscillation (HFO) is improved by manipulating the oscillatory flow waveform such
      that intermittent oscillatory flow occurs. We therefore measured the velocity
      profiles and effective axial gas diffusivity during intermittent oscillatory flow
      in a straight tube to verify the intermittency augmentation effect on axial gas
      transfer. The effective diffusivity was dependent on the flow patterns and
      significantly increased with an increase in the duration of the stationary phase.
      It was also found that the ratio of effective diffusivity to molecular
      diffusivity is two times greater than that in sinusoidal oscillatory flow.
      Moreover, turbulence during deceleration or at the beginning of the stationary
      phase further augments axial dispersion, with the effective diffusivity being
      over three times as large, thereby proving that the use of intermittent
      oscillatory flow effectively augments axial dispersion for ventilation with HFO.

PMID- 10412411
TI  - Computational analysis of confined jet flow and mass transport in a blind tube.
AB  - A computational analysis of confined nonimpinging jet flow in a blind tube is
      performed as an initial investigation of the underlying fluid and mass transport
      mechanics of tracheal gas insufflation. A two-dimensional axisymmetric model of a
      laminar steady jet flow into a concentric blind-end tube is put forth and the
      governing continuity, momentum, and convection-diffusion equations are solved
      with a finite element code. The effects of the jet diameter based Reynolds number
      (Re(j)), the ratio of the jet-to-outer tube diameters (epsilon), and the Schmidt
      number (Sc) are evaluated with the determined velocity and contaminant
      concentration fields. The normalized penetration depth of the jet is found to
      increase linearly with increasing Re(j) for epsilon = O(0.1). For a given
      epsilon, a ring vortex that develops is observed to be displaced downstream and
      radially outward from the jet tip for increasing Re(j). The axial shear stress
      profile along the inside wall of the outer tube possesses regions of fixed shear
      stress in addition to a local minimum and maximum in the vicinity of the jet tip.
      Corresponding regions of axial shear stress gradients exist between the fixed
      shear stress regions and the local extrema. Contaminant concentration gradients
      develop across the ring vortex indicating the inward diffusion of contaminant
      into the jet flow. For fixed epsilon and Sc and Re(j) approximately 900,
      normalized contaminant flow rate is observed to be approximately twice that of
      simple diffusion. This model predicts modest net axial contaminant transport
      enhancement due to convection-diffusion interaction in the region of the ring
      vortex.

PMID- 10412410
TI  - Modeling of airflow in the pharynx with application to sleep apnea.
AB  - A three-dimensional numerical modeling of airflow in the human pharynx using an
      anatomically accurate model was conducted. The pharynx walls were assumed to be
      passive and rigid. The results showed that the pressure drop in the pharynx lies
      in the range 200-500 Pa. The onset of turbulence was found to increase the
      pressure drop by 40 percent. A wide range of pharynx geometries covering three
      sleep apnea treatment therapies (CPAP, mandibular repositioning devices, and
      surgery) were modeled and the resulting flow characteristics were investigated
      and compared. The results confirmed that the airflow in the pharynx lies in the
      laminar-to-turbulence transitional flow regime and thus, a subtle change in the
      morphology caused by these treatment therapies can significantly affect the
      airflow characteristics.

PMID- 10412412
TI  - Factors influencing accuracy of screw displacement axis detection with a D.C.
      based electromagnetic tracking system.
AB  - Recent technical improvements and cost reductions in electromagnetic motion
      tracking systems invite their application to motion axis determination in the
      surgical setting. After evaluation of the accuracy of a state-of-the-art D.C.
      electromagnetic tracking system, which generates complete three-dimensional
      kinematic outputs from just a single receiver, we calculated screw displacement
      axes (SDA's) from its source data. The accuracy of SDA determination from such
      source data was evaluated for various rotational increment sizes around a
      revolute joint. A novel smoothing procedure, customized for this type of source
      data, was developed, enabling SDA detection from incremental rotations of less
      than 1 deg, at an accuracy appropriate for intra-operative measurement of human
      joint motion. Examples of SDA determination are given for motion tracking of a
      ball joint and of the elbow articulation.

PMID- 10412413
TI  - Performance analysis of a cardiac assist device in counterpulsation.
AB  - Performance of a cardiac assist device pumping chamber in counterpulsation was
      evaluated using numerical simulations of the unsteady, three-dimensional flow
      inside the chamber and an analytical model of the force required to eject and
      fill the chamber. The wall shear stress within the device was similarly computed
      and modeled. The analytical model was scaled to match the numerical results and
      then used to predict performance at physiological operating conditions. According
      to these models for a stroke volume of 70 ml, between 0.4 and 1.0 W is required
      for counterpulsation at a frequency of 1.33 Hz against a restorative spring,
      depending on the spring constant chosen. The power and the maximum force
      calculated are within the ranges a trained skeletal muscle is capable of
      providing. Shear stress predictions show that platelet activation in the absence
      of surface effects and hemolysis due to high shear are unlikely to occur with
      this design. Furthermore, vortices that develop in the chamber during filling are
      predicted to increase blood mixing and provide favorable washing of the chamber
      walls. A computational-analytical approach such as this may have potential to aid
      rapid performance evaluation of new devices and streamline the design
      optimization process.

PMID- 10412414
TI  - Simulation of particle-hemodynamics in a partially occluded artery segment with
      implications to the initiation of microemboli and secondary stenoses.
AB  - Computational results of laminar incompressible blood-particle flow analyses in
      an axisymmetric artery segment with a smooth local area constriction of 75
      percent have been presented. The flow input waveform was sinusoidal with a
      nonzero average. The non-Newtonian behavior of blood was simulated with a
      modified Quemada model, platelet concentrations were calculated with a drift-flux
      model, and monocyte trajectories were described and compared for both Newtonian
      and Quemada rheologies. Indicators of "disturbed flow" included the time-averaged
      wall shear stress (WSS), the oscillatory shear index (OSI), and the wall shear
      stress gradient (WSSG). Implications of the vortical flow patterns behind the
      primary stenosis to the formation of microemboli and downstream stenoses are as
      follows. Elevated platelet concentrations due to accumulation in recirculation
      zones mixed with thrombin and ADP complexes assumed to be released upstream in
      high wall shear stress regions, could form microemboli, which are convected
      downstream. Distinct near-wall vortices causing a local increase in the WSSG and
      OSI as well as blood-particle entrainment with possible wall deposition, indicate
      sites susceptible to the onset of an additional stenosis proximal to the initial
      geometric disturbance.

PMID- 10412415
TI  - Simulation of pressure drop and energy dissipation for blood flow in a human
      fetal bifurcation.
AB  - The pressure drop from the umbilical vein to the heart plays a vital part in
      human fetal circulation. The bulk of the pressure drop is believed to take place
      at the inlet of the ductus venosus, a short narrow branch of the umbilical vein.
      In this study a generalized Bernoulli formulation was deduced to estimate this
      pressure drop. The model contains an energy dissipation term and flow-scaled
      velocities and pressures. The flow-scaled variables are related to their
      corresponding spatial mean velocities and pressures by certain shape factors.
      Further, based on physiological measurements, we established a simplified, rigid
      walled, three-dimensional computational model of the umbilical vein and ductus
      venosus bifurcation for stationary flow conditions. Simulations were carried out
      for Reynolds numbers and umbilical vein curvature ratios in their respective
      physiological ranges. The shape factors in the Bernoulli formulation were then
      estimated for our computational models. They showed no significant Reynolds
      number or curvature ratio dependency. Further, the energy dissipation in our
      models was estimated to constitute 24 to 31 percent of the pressure drop,
      depending on the Reynolds number and the curvature ratio. The energy dissipation
      should therefore be taken into account in pressure drop estimates.

PMID- 10412416
TI  - Pendelluft flow in symmetric airway bifurcations.
AB  - We propose a mathematical model for pendelluft flow in a single airway
      bifurcation. The model is motivated by an apparatus used in an experimental study
      of the pendelluft by Ultman et al. (1988). We derive differential equations
      governing the fluid flow, which directly connect physiological parameters to the
      variables determining the pendelluft; this approach allows us to include
      nonlinearity in the model. If nonlinearity is neglected, our model is identical
      to the R-I-C circuits used by previous investigators. If nonlinearity is
      retained, we show that pendelluft can occur even in perfectly symmetric airway
      bifurcations. For the specific apparatus used in the experiments of High et al.
      (1991), we demonstrate that two qualitatively different pendelluft flows can
      occur in the system.

PMID- 10412417
TI  - Numerical analysis for stability and self-excited oscillation in collapsible tube
      flow.
AB  - This paper describes numerical analysis of collapsible tube flow based on the one
      dimensional distributed parameter model of Hayashi. In the present model the
      effect of flow separation at the collapsed part is replaced with simple viscous
      friction along the tube, so no ad-hoc modeling for flow separation in former
      studies is required. A stable semi-implicit numerical procedure based on the
      SIMPLE method is developed for the problem of flow and tube interaction. The
      numerical result for a characteristic self-excited oscillation agrees
      qualitatively with the experimental result. Nonlinear stability of the steady
      state dependent on the amplitude of the disturbance is numerically investigated
      and the result is compared with the linear stability analysis based on the former
      lumped parameter model. Finally, initiation of the self-excited oscillation is
      examined by applying the initial disturbance at the upstream end of the tube. The
      disturbance propagates in the downstream direction and is amplified to the self
      excited oscillation.

PMID- 10412418
TI  - Structural changes in rat aortic intima due to transmural pressure.
AB  - Huang et al. (1997) propose a new hypothesis and develop a mathematical model to
      explain rationally the in vitro and in situ measured changes (Tedgui and Lever,
      1984; Baldwin and Wilson, 1993) in the hydraulic conductivity of the artery wall
      of rabbit aorta with transmural pressure. The model leads to the intriguing
      prediction that this hydraulic conductivity would decrease by one half if the
      thin intimal layer between the endothelium and the internal elastic lamina volume
      compresses approximately fivefold. This paper presents the first measurements of
      the effect of transmural pressure on intimal layer thickness and shows that the
      intimal matrix is, indeed, surprisingly compressible. We perfusion-fixed rat
      thoracic aortas in situ with 2 percent glutaraldehyde solution at 0, 50, 100, or
      150 mm Hg lumen pressure and sectioned for light and electron microscopic
      observations. Electron micrographs show a dramatic, nonlinear decrease in average
      intimal thickness, i.e., 0.62 +/- 0.26, 0.27 +/- 0.14, 0.15 +/- 0.10, and 0.12 +/
      0.07 (SD) micron for 0, 50, 100, and 150 mm Hg lumen pressure, respectively. The
      volume strain of the intima is more than 20 times greater than the radial strain
      of the artery wall due to hoop tension and two orders of magnitude greater than
      the consolidation of the artery wall as a whole assuming constant medial density
      (Chuong and Fung, 1984). Moreover, in both light and electron microscopic
      observations, it is easy to find numerous sites where the endothelium puckers
      into the fenestral pores at high lumen pressure, as predicted by the theory in
      Huang et al. (1997). In contrast, the average diameter of a fenestral pore
      increases only 10 percent as the lumen pressure is increased from 0 to 150 mm Hg.
      These results indicate that the thin intimal layer comprising less than 1 percent
      of the wall thickness can have a profound effect on the filtration properties of
      the wall due to the large change in Darcy permeability of the layer and the large
      reduction in the entrance area of the flow entering the fenestral pores, though
      the pores themselves experience only a minor enlargement due to hoop tension.

PMID- 10412419
TI  - Factor Xa generation at the surface of cultured rat vascular smooth muscle cells
      in an in vitro flow system.
AB  - The purpose of the present investigation was to explore the effects of well
      defined flow conditions on the activity of tissue factor (TF) expressed on the
      surface of cultured rat vascular smooth muscle cells. Cells were cultured to
      confluence on Permanox brand slides and stimulated to express TF by a 90 min
      incubation with fresh growth medium containing 10 percent calf serum. The
      stimulated cells were then placed in a parallel plate flow chamber and perfused
      with Hank's Balanced Salt Solution containing factor VIIa, factor X (FX), and
      calcium. The chamber effluent was collected and assayed for factor Xa (FXa) and
      the steady-state flux of FXa was calculated. The flux values were 68.73, 94.81,
      139.75, 138.19, 316.82, and 592.92 fmole/min/cm2 at wall shear rates of 10, 20,
      40, 80, 320, and 1280 s-1, respectively. The FXa flux depended on the wall shear
      rate to a greater degree than predicted by classical mass transport theory. The
      flux at each shear rate was three to five times less than that calculated
      according to the Leveque solution. These features of the experimental data imply
      nonclassical behavior, which may partially result from a direct effect of flow on
      the cell layer.

PMID- 10412420
TI  - A transversely isotropic biphasic model for unconfined compression of growth
      plate and chondroepiphysis.
AB  - Using the biphasic theory for hydrated soft tissues (Mow et al., 1980) and a
      transversely isotropic elastic model for the solid matrix, an analytical solution
      is presented for the unconfined compression of cylindrical disks of growth plate
      tissues compressed between two rigid platens with a frictionless interface. The
      axisymmetric case where the plane of transverse isotropy is perpendicular to the
      cylindrical axis is studied, and the stress-relaxation response to imposed step
      and ramp displacements is solved. This solution is then used to analyze
      experimental data from unconfined compression stress-relaxation tests performed
      on specimens from bovine distal ulnar growth plate and chondroepiphysis to
      determine the biphasic material parameters. The transversely isotropic biphasic
      model provides an excellent agreement between theory and experimental results,
      better than was previously achieved with an isotropic model, and can explain the
      observed experimental behavior in unconfined compression of these tissues.

PMID- 10412421
TI  - Strain inhomogeneity in the anterior cruciate ligament under application of
      external and muscular loads.
AB  - To determine whether mathematical relations between strains in different bundles
      and loads would be needed to predict injury of the anterior cruciate ligament
      (ACL), this work tested the hypothesis that strains developed in two bundles of
      the ACL were significantly different under the application of a number of loads
      important to injury etiology of the ACL. To provide the data for testing this
      hypothesis, liquid mercury strain gages were installed on both the anteromedial
      (AMB) and posterolateral (PLB) bundles of the ACL of ten specimens, which were
      then subjected to passive flexion/extension, hyperextension moment, anterior
      force, internal and external axial moments, quadriceps, and hamstrings forces.
      Various combinations of these loads were also applied. Flexion angles ranged from
      8 deg of hyperextension through 120 deg of flexion. The data were analyzed using
      a repeated measures analysis of variance. The analyses indicated that significant
      strain differences existed between the two bundles only for passive
      flexion/extension. However, the analyses did not support the hypothesis that AMB
      and PLB strains are significantly different from each other under the application
      of external and muscular loads. Because noticeable differences (> 3 percent)
      between bundle strains did exist in some load cases for limited ranges of flexion
      and the PLB strain was consistently higher than the AMB strain, it may be
      sufficient to consider strain in only the PLB when predicting ligament damage
      based on strain-load relations.

PMID- 10412422
TI  - A multiaxial constitutive law for mammalian left ventricular myocardium in steady
      state barium contracture or tetanus.
AB  - The constitutive law of the material comprising any structure is essential for
      mechanical analysis since this law enables calculation of the stresses from the
      deformations and vice versa. To date, there is no constitutive law for actively
      contracting myocardial tissue. Using 2,3-butanedione monoxime to protect the
      myocardium from mechanical trauma, we subjected thin midwall slices of rabbit
      myocardium to multiaxial stretching first in the passive state and then during
      steady-state barium contracture or during tetani in ryanodine-loaded tissue.
      Assuming transverse isotropy in both the passive and active conditions, we used
      our previously described methods (Humphrey et al., 1990a) to obtain both passive
      and active constitutive laws. The major results of this study are: (1) This is
      the first multiaxial constitutive law for actively contracting mammalian
      myocardium. (2) The functional forms of the constitutive law for barium
      contracture and ryanodine-induced tetani are the same but differ from those in
      the passive state. Hence, one cannot simply substitute differing values for the
      coefficients of the passive law to describe the active tissue properties. (3)
      There are significant stresses developed in the cross-fiber direction (more than
      40 percent of those in the fiber direction) that cannot be attributed to either
      deformation effects or nonparallel muscle fibers. These results provide the
      foundation for future mechanical analyses of the heart.

PMID- 10412423
TI  - The Penn State Safety Floor: Part I--Design parameters associated with walking
      deflections.
AB  - A new flooring system has been developed to reduce peak impact forces to the hips
      when humans fall. The new safety floor is designed to remain relatively rigid
      under normal walking conditions, but to deform elastically when impacted during a
      fall. Design objectives included minimizing peak force experienced by the femur
      during a fall-induced impact, while maintaining a maximum of 2 mm of floor
      deflection during walking. Finite Element Models (FEMs) were developed to capture
      the complex dynamics of impact response between two deformable bodies. Validation
      of the finite element models included analytical calculations of theoretical
      buckling column response, experimental quasi-static loading of full-scale
      flooring prototypes, and flooring response during walking trials. Finite Element
      Method results compared well with theoretical and experimental data. Both finite
      element and experimental data suggest that the proposed safety floor can
      effectively meet the design goal of 2 mm maximum deflection during walking, while
      effectively reducing impact forces during a fall.

PMID- 10412424
TI  - The Penn State Safety Floor: Part II--Reduction of fall-related peak impact
      forces on the femur.
AB  - The goal of this study was to develop and validate a finite element model (FEM)
      for use in the design of a flooring system that would provide a stable walking
      surface during normal locomotion but would also deform elastically under higher
      loads, such as those resulting from falls. The new flooring system is designed to
      reduce the peak force on the femoral neck during a lateral fall onto the hip. The
      new flooring system is passive in nature and exhibits two distinct stiffnesses.
      During normal activities, the floor remains essentially rigid. Upon impact, the
      floor collapses and becomes significantly softer. The flooring system consists of
      a multitude of columns supporting a continuous walking surface. The columns were
      designed to remain stiff up to a specific load and, after exceeding this load, to
      deform elastically. The flooring returns to its original shape after impact. Part
      I of this study presented finite element and experimental results demonstrating
      that the floor deflection during normal walking remained less than 2 mm. To
      facilitate the floor's development further, a nonlinear finite element model
      simulating the transient-impact response of a human hip against various floor
      configurations was developed. Nonlinearities included in the finite element
      models were: changing topology of deformable-body-to-deformable-body contact,
      snap-through buckling, soft tissue stiffness and damping, and large deformations.
      Experimental models developed for validating the finite element model included an
      anthropomorphic hip, an impact delivery mechanism, a data collection system, and
      four hand-fabricated floor tiles. The finite element model discussed in this
      study is shown to capture experimentally observed trends in peak femoral neck
      force reduction as a function of flooring design parameters. This study also
      indicates that a floor can be designed that deflects minimally during walking and
      reduces the peak force on the femoral neck during a fall-related impact by 15.2
      percent.

PMID- 10412425
TI  - An instrumented wheel for kinetic analysis of wheelchair propulsion.
AB  - An instrumented wheel system for three-dimensional kinetic analysis of upper
      extremity during wheelchair propulsion has been designed and validated. This
      system allows the direct measurements of three-dimensional dynamic forces and
      moments on the handrim during wheelchair propulsion in a laboratory setting as
      well as in the field. Static loading tests showed a high linearity and little
      drift (coefficient of determination, r2 > 0.999). Under dynamic loading, the
      instrumented wheel provided the well-matched measurement forces and moments with
      the predicted values from the inverse dynamic method using video-based kinematic
      data (correlation coefficient, p > 0.97). The three-dimensional handrim forces
      and moments during wheelchair propulsion by a non-disabled subject were
      demonstrated.

PMID- 10412426
TI  - An investigation of biphasic failure criteria for impact-induced fissuring of
      articular cartilage.
AB  - Articular cartilage consists of both solid and fluid phases with fissures
      observed on the surface occurring in the solid portion. In order to determine
      which of the solid phase stresses provides the best predictor for the initiation
      of a fissure, elastic stresses from a series of in vitro impact experiments were
      used to derive stresses in the solid phase of the cartilage. This stress
      information was then analyzed using a logistic regression to identify the best
      predictor of fissuring. The mechanical analysis indicated that low-magnitude
      tensile solid hoop stress develops in the solid phase within the contact zone in
      impacts involving the two smaller radius interfaces. The logistic regression,
      however, indicated that maximum shear stress in the solid (which is equal to the
      shear stress from the elastic analysis) was the best predictor of the occurrence
      of a fissure. This study helps support the suggestion that in stress fields
      dominated by compression, the maximum shear stress from an elastic analysis may
      be used to predict fissure initiation in cartilage.

PMID- 10412427
TI  - Measuring collagen fiber orientation: a two-dimensional quantitative macroscopic
      technique.
AB  - This paper describes the design, evaluation, and application of a new system for
      quantifying two-dimensional collagen fiber orientation in soft tissue. Series of
      transmitted polarized light images were collected using a custom-designed
      macroscope. Combined analysis of pixel brightness, and hue from images collected
      with a compensator plate, permitted the assignment of each pixel into the
      appropriate orientation band. Experiments were performed to quantify the
      linearity and noise of the system. Validation was performed on a specimen
      composed of strain-birefringent plastic strips at various orientations.
      Preliminary collagen fiber orientation data is presented from a tendon specimen.
      This study demonstrates the utility of this approach for studying collagen fiber
      orientation across large areas.

PMID- 10412428
TI  - Local mechanical anisotropy in human cranial dura mater allografts.
AB  - Human cranial dura mater (CDM) allograft's success as a repair biomaterial is
      partly due to its high mechanical strength, which facilitates its ability to form
      water-tight barriers and resist high in-vivo mechanical loads. Previous studies
      on CDM allograft mechanical behavior used large test specimens and concluded that
      the allograft was mechanically isotropic. However, we have quantified CDM
      microstructure using small angle light scattering (SALS) and found regions of
      well-aligned fibers displaying structural symmetry between the right and left
      halves (Jimenez et al., 1998). The high degree of fiber alignment in these
      regions suggests that they are mechanically anisotropic. However, identification
      of these regions using SALS requires irreversible tissue dehydration, which may
      affect mechanical properties. Instead, we utilized CDM structural symmetry to
      estimate the fiber architecture of one half of the CDM using computer graphics to
      flip the SALS fiber architecture map of the corresponding half about the plane of
      symmetry. Test specimens (20 mm x 4 mm) were selected parallel and perpendicular
      to the preferred fiber directions and subjected to uniaxial mechanical failure
      testing. CDM allografts were found to be locally anisotropic, having an ultimate
      tensile strength (UTS) parallel to the fibers of 12.76 +/- 1.65 MPa, and
      perpendicular to the fibers of 5.21 +/- 1.01 MPa (mean +/- sem). These results
      indicate that uniaxial mechanical tests on large samples used in previous studies
      tended to mask the local anisotropic nature of the smaller constituent sections.
      The testing methods established in this study can be used in the evaluation of
      new CDM processing methods and post-implant allograft mechanical integrity.

PMID- 10412429
TI  - An asymptotic model of viscous flow limitation in a highly collapsed channel.
AB  - A viscous flow through a long two-dimensional channel, one wall of which is
      formed by a finite-length membrane, experiences flow limitation when the channel
      is highly collapsed over a narrow region under high external pressure. Simple
      approximate relations between flow rate and pressure drop are obtained for this
      configuration by the use of matched asymptotic expansions. Weak inertial effects
      are also considered.

PMID- 10412430
TI  - A theoretical formulation for boundary friction in articular cartilage.

PMID- 10412431
TI  - The effect of dimethylsulfoxide on the water transport response of rat
      hepatocytes during freezing.
AB  - Successful improvement of cryopreservation protocols for cells in suspension
      requires knowledge of how such cells respond to the biophysical stresses of
      freezing (intracellular ice formation, water transport) while in the presence of
      a cryoprotective agent (CPA). This work investigates the biophysical water
      transport response in a clinically important cell type--isolated hepatocytes-
      during freezing in the presence of dimethylsulfoxide (DMSO). Sprague-Dawley rat
      liver hepatocytes were frozen in Williams E media supplemented with 0, 1, and 2 M
      DMSO, at rates of 5, 10, and 50 degrees C/min. The water transport was measured
      by cell volumetric changes as assessed by cryomicroscopy and image analysis.
      Assuming that water is the only species transported under these conditions, a
      water transport model of the form dV/dT = f(Lpg([CPA]), ELp([CPA]), T(t)) was
      curve-fit to the experimental data to obtain the biophysical parameters of water
      transport--the reference hydraulic permeability (Lpg) and activation energy of
      water transport (ELp)--for each DMSO concentration. These parameters were
      estimated two ways: (1) by curve-fitting the model to the average volume of the
      pooled cell data, and (2) by curve-fitting individual cell volume data and
      averaging the resulting parameters. The experimental data showed that less
      dehydration occurs during freezing at a given rate in the presence of DMSO at
      temperatures between 0 and -10 degrees C. However, dehydration was able to
      continue at lower temperatures (< -10 degrees C) in the presence of DMSO. The
      values of Lpg and ELp obtained using the individual cell volume data both
      decreased from their non-CPA values--4.33 x 10(-13) m3/N-s (2.69 microns/min-atm)
      and 317 kJ/mol (75.9 kcal/mol), respectively--to 0.873 x 10(-13) m3/N-s (0.542
      micron/min-atm) and 137 kJ/mol (32.8 kcal/mol), respectively, in 1 M DMSO and
      0.715 x 10(-13) m3/N-s (0.444 micron/min-atm) and 107 kJ/mol (25.7 kcal/mol),
      respectively, in 2 M DMSO. The trends in the pooled volume values for Lpg and ELp
      were very similar, but the overall fit was considered worse than for the
      individual volume parameters. A unique way of presenting the curve-fitting
      results supports a clear trend of reduction of both biophysical parameters in the
      presence of DMSO, and no clear trend in cooling rate dependence of the
      biophysical parameters. In addition, these results suggest that close proximity
      of the experimental cell volume data to the equilibrium volume curve may
      significantly reduce the efficiency of the curve-fitting process.

PMID- 10412432
TI  - Measurement of water transport during freezing in mammalian liver tissue: Part II
      -The use of differential scanning calorimetry.
AB  - There is currently a need for experimental techniques to assay the biophysical
      response (water transport or intracellular ice formation, IIF) during freezing in
      the cells of whole tissue slices. These data are important in understanding and
      optimizing biomedical applications of freezing, particularly in cryosurgery. This
      study presents a new technique using a Differential Scanning Calorimeter (DSC) to
      obtain dynamic and quantitative water transport data in whole tissue slices
      during freezing. Sprague-Dawley rat liver tissue was chosen as our model system.
      The DSC was used to monitor quantitatively the heat released by water transported
      from the unfrozen cell cytoplasm to the partially frozen vascular/extracellular
      space at 5 degrees C/min. This technique was previously described for use in a
      single cell suspension system (Devireddy, et al. 1998). A model of water
      transport was fit to the DSC data using a nonlinear regression curve-fitting
      technique, which assumes that the rat liver tissue behaves as a two-compartment
      Krogh cylinder model. The biophysical parameters of water transport for rat liver
      tissue at 5 degrees C/min were obtained as Lpg = 3.16 x 10(-13) m3/Ns (1.9
      microns/min-atm), ELp = 265 kJ/mole (63.4 kcal/mole), respectively. These results
      compare favorably to water transport parameters in whole liver tissue reported in
      the first part of this study obtained using a freeze substitution (FS) microscopy
      technique (Pazhayannur and Bischof, 1997). The DSC technique is shown to be a
      fast, quantitative, and reproducible technique to measure dynamic water transport
      in tissue systems. However, there are several limitations to the DSC technique:
      (a) a priori knowledge that the biophysical response is in fact water transport,
      (b) the technique cannot be used due to machine limitations at cooling rates
      greater than 40 degrees C/min, and (c) the tissue geometric dimensions (the Krogh
      model dimensions) and the osmotically inactive cell volumes Vb, must be
      determined by low-temperature microscopy techniques.

PMID- 10412434
TI  - Effect of intraluminal thrombus thickness and bulge diameter on the oxygen
      diffusion in abdominal aortic aneurysm.
AB  - The intraluminal thrombus (ILT) commonly found within abdominal aortic aneurysm
      (AAA) may serve as a barrier to oxygen diffusion from the lumen to the inner
      layers of the aortic wall. The purpose of this work was to address this
      hypothesis and to assess the effects of AAA bulge diameter (dAAA) and ILT
      thickness (delta) on the oxygen flow. A hypothetical, three-dimensional,
      axisymmetric model of AAA containing ILT was created for computational analysis.
      Commercial software was utilized to estimate the volume flow of O2 per cell,
      which resulted in zero oxygen tension at the AAA wall. Solutions were generated
      by holding one of the two parameters fixed while varying the other. The supply of
      O2 to the AAA wall increases slightly and linearly with dAAA for a fixed delta.
      This slight increase is due to the enlarged area through which diffusion of O2
      may take place. The supply of O2 was found to decrease quickly with increasing
      delta for a fixed dAAA due to the increased resistance to O2 transport by the ILT
      layer. The presence of even a thin, 3 mm ILT layer causes a diminished O2 supply
      (less than 4 x 10(-10) mumol/min/cell). Normally functioning smooth muscle cells
      require a supply of 21 x 10(-10) mumol/min/cell. Thus, our analysis serves to
      support our hypothesis that the presence of ILT alters the normal pattern of O2
      supply to the AAA wall. This may lead to hypoxic cell dysfunction in the AAA
      wall, which may further lead to wall weakening and increased potential for
      rupture.

PMID- 10412435
TI  - Experimental investigation of oscillatory flow through a symmetrically
      bifurcating tube.
AB  - To provide a quantitative description of the convection field of gas transport
      through the lung under both low and high-frequency ventilation conditions, volume
      cycled, purely oscillatory flow has been investigated in a symmetrically
      bifurcating model bronchial bifurcation. Significant differences in the flow
      properties that developed as the Reynolds number varied from 750 to 950 and the
      dimensionless frequency varied from 3 to 12 are described. At low frequency, the
      axial velocity field was found to approximate closely that of a steady flow
      through a bifurcation. However, even at alpha = 3, secondary velocity fields were
      confined to within a few diameters of the bifurcation, with less than 10 percent
      of the magnitude of the axial velocity. At high frequency they were still slower
      and more limited. These secondary velocity observations are discussed in terms of
      a physical mechanism balancing inviscid centripetal acceleration with viscous
      retardation. As the dimensionless frequency increased but the flow amplitude
      decreased, the magnitude of the axial drift velocity field was found to decrease.
      In addition, a burst of high-frequency velocity fluctuations was detected in both
      the axial and secondary velocity measurements in the parent tube, in low
      frequency flow, during the deceleration phase of expiration. The position and
      timing of this burst suggest that it derives from the free shear layer in the
      parent tube. Stability criteria for the flow were therefore evaluated.

PMID- 10412433
TI  - Intracellular calcium dynamics during photolysis.
AB  - The objective of this investigation was to gain a deeper understanding of the
      intracellular events that precede photolysis of cells. A model system, consisting
      of malignant melanoma cells pretreated with the calcium sensitive fluorescent
      dye, Fluo-3, was used to examine the intracellular calcium dynamics in single
      cell photolysis experiments. Exposure of the cells to 632 nm laser light in the
      presence of photosensitizer, tin chlorin e6, resulted in a rise in intracellular
      calcium. The increase in intracellular calcium was blocked using a variety of
      calcium channel blocking agents, including verapamil, nifedipine, and nickel.
      Treatment with the channel blockers was also effective in either decreasing or
      eliminating cell death despite the presence of lethal doses of photosensitizer
      and irradiation. These results show that intracellular calcium rises prior to
      plasma membrane lysis, and that this early rise in intracellular calcium is
      necessary for membrane rupture.

PMID- 10412436
TI  - Experiments on steady and oscillatory flows at moderate Reynolds numbers in a
      quasi-two-dimensional channel with a throat.
AB  - The study of steady and unsteady oscillatory static fluid pressures acting on the
      internal wall of a collapsible tube is essential for investigation of the
      complicated behavior observed when a flow is conveyed inside a tube. To examine
      the validity of two one-dimensional nonsteady theoretical flow models, this paper
      presents basic experimental observations of flow separation and reattachment and
      measured data on the static pressure distributions of the flow in a quasi-two
      dimensional channel with a throat, together with information on the corresponding
      shape of the wall deflection and motion. For combinations of moderate Reynolds
      numbers and angles of the divergent segment of the channel, a smooth flow is
      separated from the wall downstream of the minimum cross section and reattached to
      the wall farther downstream. The measured data are compared with numerical
      results calculated by the two flow models.

PMID- 10412437
TI  - Mechanical analysis of heterogeneous, atherosclerotic human aorta.
AB  - An experimental technique was developed to determine the finite strain field in
      heterogeneous, diseased human aortic cross sections at physiologic pressures in
      vitro. Also, the distributions within the cross sections of four histologic
      features (disease-free zones, lipid accumulations, fibrous intimal tissue, and
      regions of calcification) were quantified using light microscopic morphometry. A
      model incorporating heterogeneous, plane stress finite elements coupled the
      experimental and histologic data. Tissue constituent mechanical properties were
      determined through an optimization strategy, and the distributions of stress and
      strain energy in the diseased vascular wall were calculated. Results show that
      the constituents of atherosclerotic lesions exhibit large differences in their
      bilinear mechanical properties. The distributions of stress and strain energy in
      the diseased vascular wall are strongly influenced by both lesion structure and
      composition. These results suggest that accounting for heterogeneities in the
      mechanical analysis of atherosclerotic arterial tissue is critical to
      establishing links between lesion morphology and the susceptibility of plaque to
      mechanical disruption in vivo.

PMID- 10412438
TI  - An approach for the stress analysis of transversely isotropic biphasic cartilage
      under impact load.
AB  - Stress analysis of contact models for isotropic articular cartilage under
      impacting loads shows high shear stresses at the interface with the subchondral
      bone and normal compressive stresses near the surface of the cartilage. These
      stress distributions are not consistent, with lesions observed on the cartilage
      surface of rabbit patellae from blunt impact, for example, to the patello-femoral
      joint. The purpose of the present study was to analyze, using the elastic
      capabilities of a finite element code, the stress distribution in more
      morphologically realistic transversely isotropic biphasic contact models of
      cartilage. The elastic properties of an incompressible material, equivalent to
      those of the transversely isotropic biphasic material at time zero, were derived
      algebraically using stress-strain relations. Results of the stress analysis
      showed the highest shear stresses on the surface of the solid skeleton of the
      cartilage and tensile stresses in the zone of contact. These results can help
      explain the mechanisms responsible for surface injuries observed during blunt
      insult experiments.

PMID- 10412439
TI  - Load sharing between solid and fluid phases in articular cartilage: I-
      Experimental determination of in situ mechanical conditions in a porcine knee.
AB  - The in situ mechanical conditions of cartilage in the articulated knee were
      quantified during joint loading. Six porcine knees were subjected to a 445 N
      compressive load while cartilage deformations and contact pressures were
      measured. From roentgenograms, cartilage thickness before and during loading
      allowed the calculation of tissue deformation on the lateral femoral condyle at
      different times during the loading process. Contact pressures on the articular
      surface were measured with miniature fiber-optic pressure transducers. Results
      showed that the medial side of the lateral femoral condyle had higher contact
      pressures, as well as deformations. To begin to correlate the pressures and
      resulting deformations, the intrinsic material properties of the cartilage on the
      lateral condyle were obtained from indentation tests. Data from four normal
      control specimens indicated that the aggregate modulus of the medial side was
      significantly higher than in other areas of the condyle. These experimental
      measures of the in situ mechanical conditions of articular cartilage can be
      combined with theoretical modeling to obtain valuable information about the
      relative contributions of the solid and fluid phases to supporting the applied
      load on the cartilage surface (see Part II).

PMID- 10412440
TI  - Load sharing between solid and fluid phases in articular cartilage: II-
      Comparison of experimental results and u-p finite element predictions.
AB  - Experimental measurements in conjunction with theoretical predictions were used
      to determine the extent of load supported by the fluid phase of cartilage at the
      articular surface. The u-p finite element model was used to simulate the loading
      of six separate porcine knee joints and to predict surface deformations of the
      cartilage layer on the lateral femoral condyle. Representative geometry for the
      condyle, contact pressures, and intrinsic material properties of the cartilage
      layer were supplied from experimental measures (see Part I). The u-p finite
      element predictions for surface deformations of the cartilage layer were obtained
      for several load partitioning states between the solid and fluid phases of
      cartilage at the articular surface. These were then compared to actual surface
      deformations obtained experimentally. It appeared from the comparison that
      approximately 75 percent of the applied load was borne by the fluid phase at the
      articular surface under this loading regime. This was qualitatively in agreement
      with the hypothesis that an applied load to articular joints is partitioned at
      the surface to the two phases according to the surface area ratios of the solid
      and fluid phases. It appeared that the solid phase was shielded from the total
      applied stress on the articular surface by the fluid and could be a reason for
      the excellent durability of the tissue under the demanding conditions in a
      diarthrodial joint.

PMID- 10412441
TI  - In vivo determination of the direction of rotation and moment-angle relationship
      of individual elbow muscles.
AB  - The direction of rotation (DOR) of individual elbow muscles, defined as the
      direction in which a muscle rotates the forearm relative to the upper arm in
      three-dimensional space, was studied in vivo as a function of elbow flexion and
      forearm rotation. Electrical stimulation was used to activate an individual
      muscle selectively, and the resultant flexion-extension, supination-pronation,
      and varus-valgus moments were used to determine the DOR. Furthermore, multi-axis
      moment-angle relationships of individual muscles were determined by stimulating
      the muscle at a constant submaximal level across different joint positions, which
      was assumed to result in a constant level of muscle activation. The muscles
      generate significant moments about axes other than flexion-extension, which is
      potentially important for actively controlling joint movement and maintaining
      stability about all axes. Both the muscle DOR and the multi axis moments vary
      with the joint position systematically. Variations of the DOR and moment-angle
      relationship across muscle twitches of different amplitudes in a subject were
      small, while there were considerable variations between subjects.

PMID- 10412442
TI  - Muscular resistance to varus and valgus loads at the elbow.
AB  - Although the contributions of passive structures to stability of the elbow have
      been well documented, the role of active muscular resistance of varus and valgus
      loads at the elbow remains unclear. We hypothesized that muscles: (1) can produce
      substantial varus and valgus moments about the elbow, and (2) are activated in
      response to sustained varus and valgus loading of the elbow. To test the first
      hypothesis, we developed a detailed musculoskeletal model to estimate the varus
      and valgus moment-generating capacity of the muscles about the elbow. To test the
      second hypothesis, we measured EMGs from 11 muscles in four subjects during a
      series of isometric tasks that included flexion, extension, varus, and valgus
      moments about the elbow. The EMG recordings were used as inputs to the elbow
      model to estimate the contributions of individual muscles to flexion-extension
      and varus-valgus moments. Analysis of the model revealed that nearly all of the
      muscles that cross the elbow are capable of producing varus or valgus moments;
      the capacity of the muscles to produce varus moment (34 Nm) and valgus moment (35
      Nm) is roughly half of the maximum flexion moment (70 Nm). Analysis of the
      measured EMGs showed that the anconeus was the most significant contributor to
      valgus moments and the pronator teres was the largest contributor to varus
      moments. Although our results show that muscles were activated in response to
      static varus and valgus loads, their activations were modest and were not
      sufficient to balance the applied load.

PMID- 10412443
TI  - A global relationship between trabecular bone morphology and homogenized elastic
      properties.
AB  - An alternative concept of the relationship between morphological and elastic
      properties of trabecular bone is presented and applied to human tissue from
      several anatomical locations using a digital approach. The three-dimensional
      morphology of trabecular bone was assessed with a microcomputed tomography system
      and the method of directed secants as well as the star volume procedure were used
      to compute mean intercept length (MIL) and average bone length (ABL) of 4 mm
      cubic specimens. Assuming isotropic elastic properties for the trabecular tissue,
      the general elastic tensors of the bone specimens were determined using the
      homogenization method and the closest orthotropic tensors were calculated with an
      optimization algorithm. The assumption of orthotropy for trabecular bone was
      found to improve with specimen size and hold within 6.1 percent for a 4 mm cube
      size. A strong global relationship (r2 = 0.95) was obtained between fabric and
      the orthotropic elastic tensor with a minimal set of five constants. Mean
      intercept length and average bone length provided an equivalent power of
      prediction. These results support the hypothesis that the elastic properties of
      human trabecular bone from an arbitrary anatomical location can be estimated from
      an approximation of the anisotropic morphology and a prior knowledge of tissue
      properties.

PMID- 10412445
TI  - Effects of inserting a pressensor film into articular joints on the actual
      contact mechanics.
AB  - Fuji film has been widely used in studies aimed at obtaining the contact
      mechanics of articular joints. Once sealed for practical use in biological
      joints, Fuji Pressensor film has a total effective thickness of 0.30 mm, which is
      comparable to the cartilage thickness in the joints of many small animals. The
      average effective elastic modulus of Fuji film is approximately 100 MPa in
      compression, which is larger by a factor of 100-300 compared to that of normal
      articular cartilage. Therefore, inserting a Pressensor film into an articular
      joint will change the contact mechanics of the joint. The measurement precision
      of the Pressensor film has been determined systematically; however, the changes
      in contact mechanics associated with inserting the film into joints have not been
      investigated. This study was aimed at quantifying the changes in the contact
      mechanics associated with inserting sealed Fuji Pressensor film into joints.
      Spherical and cylindrical articular joint contact mechanics with and without
      Pressensor film and for varying degrees of surface congruency were analyzed and
      compared by using finite element models. The Pressensor film was taken as
      linearly elastic and the cartilage was assumed to be biphasic, composed of a
      linear elastic solid phase and an inviscid fluid phase. The present analyses
      showed that measurements of the joint contact pressures with Fuji Pressensor film
      will change the maximum true contact pressures by 10-26 percent depending on the
      loading, geometry of the joints, and the mechanical properties of cartilage.
      Considering this effect plus the measurement precision of the film (approximately
      10 percent), the measured joint contact pressures in a joint may contain errors
      as large as 14-28 percent.

PMID- 10412444
TI  - Creep contributes to the fatigue behavior of bovine trabecular bone.
AB  - Repetitive, low-intensity loading from normal daily activities can generate
      fatigue damage in trabecular bone, a potential cause of spontaneous fractures of
      the hip and spine. Finite element models of trabecular bone (Guo et al., 1994)
      suggest that both creep and slow crack growth contribute to fatigue failure. In
      an effort to characterize these damage mechanisms experimentally, we conducted
      fatigue and creep tests on 85 waisted specimens of trabecular bone obtained from
      76 bovine proximal tibiae. All applied stresses were normalized by the previously
      measured specimen modulus. Fatigue tests were conducted at room temperature;
      creep tests were conducted at 4, 15, 25, 37, 45, and 53 degrees C in a custom
      designed apparatus. The fatigue behavior was characterized by decreasing modulus
      and increasing hysteresis prior to failure. The hysteresis loops progressively
      displaced along the strain axis, indicating that creep was also involved in the
      fatigue process. The creep behavior was characterized by the three classical
      stages of decreasing, constant, and increasing creep rates. Strong and highly
      significant power-law relationships were found between cycles-to-failure, time-to
      failure, steady-state creep rate, and the applied loads. Creep analyses of the
      fatigue hysteresis loops also generated strong and highly significant power law
      relationships for time-to-failure and steady-state creep rate. Lastly, the
      products of creep rate and time-to-failure were constant for both the fatigue and
      creep tests and were equal to the measured failure strains, suggesting that creep
      plays a fundamental role in the fatigue behavior of trabecular bone. Additional
      analysis of the fatigue strain data suggests that creep and slow crack growth are
      not separate processes that dominate at high and low loads, respectively, but are
      present throughout all stages of fatigue.

PMID- 10412446
TI  - Engineered alignment in media equivalents: magnetic prealignment and mandrel
      compaction.
AB  - We predicted and measured the evolution of smooth muscle cell (SMC) orientation
      in media-equivalents (MEs) for four fabrication conditions (F-, M-, F+, M+) under
      Free or Mandrel compaction (F/M) with and without magnetic prealignment of the
      collagen fibrils in the circumferential direction (+/-). Mandrel compaction
      refers to SMC-induced compaction of the ME that is constrained by having a
      nonadhesive mandrel placed in the ME lumen. Predictions were made using our
      anisotropic biphasic theory (ABT) for tissue-equivalent mechanics. Successful
      prediction of trends of the SMC orientation data for all four fabrication cases
      was obtained: maintenance of the initial isotropic state for F-, loss of initial
      circumferential alignment for F+, development of circumferential alignment for M
      , and enhancement of initial circumferential alignment for M+. These results
      suggest two mechanisms by which the presence of the mandrel leads to much greater
      mechanical stiffness in the circumferential direction reported for mandrel
      compacted MEs relative to free compacted MEs: (1) by inducing an increasing
      circumferential alignment of the SMC and collagen, and (2) by inducing a large
      stress on the SMC, resulting in secretion and accumulation of stiffening
      components.

PMID- 10412447
TI  - A parametric study of acetabular cup design variables using finite element
      analysis and statistical design of experiments.
AB  - To isolate the primary variables influencing acetabular cup and interface
      stresses, we performed an evaluation of cup loading and cup support variables,
      using a Statistical Design of Experiments (SDOE) approach. We developed three
      dimensional finite element (FEM) models of the pelvis and adjacent bone. Cup
      support variables included fixation mechanism (cemented or noncemented), amount
      of bone support, and presence of metal backing. Cup loading variables included
      head size and cup thickness, cup/head friction, and conformity between the cup
      and head. Interaction between and among variables was determined using SDOE
      techniques. Of the variables tested, conformity, head size, and backing emerged
      as significant influences on stresses. Since initially nonconforming surfaces
      would be expected to wear into conforming surfaces, conformity is not expected to
      be a clinically significant variable. This indicates that head size should be
      tightly toleranced during manufacturing, and that small changes in head size can
      have a disproportionate influence on the stress environment. In addition,
      attention should be paid to the use of nonmetal backed cups, in limiting cup/bone
      interface stresses. No combination of secondary variables could compensate for,
      or override the effect of, the primary variables. Based on the results using the
      SDOE approach, adaptive FEM models simulating the wear process may be able to
      limit their parameters to head size and cup backing.

PMID- 10412448
TI  - Simulation of the superelastic response of SMA orthodontic wires.
AB  - Shape-memory alloys have properties that make them well suited to a variety of
      applications. One application for which their unique combination of properties
      (large elastic range, low modulus of elasticity, ability to deliver nearly
      constant forces over a wide range of deformations) seems ideally suited is for
      orthodontic retraction appliances where these properties are very desirable. The
      mechanical response of shape-memory alloys is modeled by a simple constitutive
      model that captures the essential superelastic behavior of the shape-memory
      wires. An initial value approach that iteratively converges to the appropriate
      boundary conditions is utilized to deliver numerical solutions. Qualitative
      agreement is shown with previous experimental works. The possible benefits of
      using such wires in an orthodontic retraction appliance are then investigated.

PMID- 10412449
TI  - An elastic-viscoplastic model for excised facial tissues.
AB  - Unified constitutive equations for elastic-viscoplastic materials were modified
      and used to model the highly nonlinear elastic and rate-dependent inelastic
      response exhibited in recent experiments on excised facial tissues. These
      included the skin and the underlying supportive tissue SMAS (the Superficial
      Musculoaponeurotic System). This study indicates a number of relevant results:
      The skin is more strain rate dependent than the SMAS; the nonlinearity of the
      elasticity of the skin is greater than that of the SMAS; both tissues exhibit a
      hardening effect indicated by increased resistance to inelastic deformation due
      to stress acting over a time period; the hardening effect leads to a decrease in
      time dependence and an increased elastic range, which is more pronounced for
      SMAS. Consequently, the SMAS can be viewed as the firmer elastic foundation of
      the more viscous skin. Moreover, the relaxation time for the skin is fairly short
      so the skin would be expected to conform to the deformation of the SMAS if it
      remained attached to the SMAS during stretching. This is relevant when it is
      undesirable to separate the skin from the SMAS for physiological reasons.

PMID- 10412450
TI  - Static and dynamic bending responses of the human cervical spine.
AB  - The quasi-static and dynamic bending responses of the human mid-lower cervical
      spine were determined using cadaver intervertebral joints fixed at the base to a
      six-axis load cell. Flexion bending moment was applied to the superior end of the
      specimen using an electrohydraulic piston. Each specimen was tested under three
      cycles of quasi-static load-unload and one high-speed dynamic load. A total of
      five specimens were included in this study. The maximum intervertebral rotation
      ranged from 11.0 to 15.4 deg for quasi-static tests and from 22.9 to 34.4 deg for
      dynamic tests. The resulting peak moments at the center of the intervertebral
      joint ranged from 3.8 to 6.9 Nm for quasi-static tests and from 14.0 to 31.8 Nm
      for dynamic tests. The quasi-static stiffness ranged from 0.80 to 1.35 Nm/deg
      with a mean of 1.03 Nm/deg (+/- 0.11 Nm/deg). The dynamic stiffness ranged from
      1.08 to 2.00 Nm/deg with a mean of 1.50 Nm/deg (+/- 0.17 Nm/deg). The differences
      between the two stiffnesses were statistically significant (p < 0.01).
      Exponential functions were derived to describe the quasi-static and dynamic
      moment-rotation responses. These results provide input data for lumped-parameter
      models and validation data for finite element models to better investigate the
      biomechanics of the human cervical spine.

PMID- 10412451
TI  - Estimates of the peak pressures in bone pore water.
AB  - The maximum pore fluid pressures due to uniaxial compression are determined for
      both the vascular porosity (Haversian and Volkmann's canals) and the lacunar
      canalicular porosity of live cortical bone. It is estimated that the peak pore
      water pressure will be 19 percent of the applied axial stress in the vascular
      porosity and 12 percent of the applied axial stress in the lacunar-canalicular
      porosity for an impulsive step loading. However, the estimated relaxation time
      for the vascular porosity (1.36 microseconds) is three orders of magnitude faster
      than that estimated for the lacunar-canalicular porosity (4.9 ms). Thus, under
      physiological loading, which has a stress rise time generally larger than 1 ms,
      pressures higher than the vascular pressure cannot be sustained in the vascular
      porosity due to the swift pressure relaxation in this porosity (unless the fluid
      drainage through the boundary is obstructed). The model also predicts a slight
      hydraulic stiffening of the bulk modulus due to longer draining time of the
      lacunar-canalicular porosity. The undrained bulk modulus is 6 percent higher than
      the drained bulk modulus in this case.

PMID- 10412452
TI  - Analysis of acute mechanical insult in an animal model of post-traumatic
      osteoarthrosis.
AB  - Chronic degeneration of articular cartilage and bone in a rabbit model of post
      traumatic osteoarthrosis has been hypothesized to occur due to acute stresses
      that exceed a threshold for injury. In this study, we impacted the rabbit
      patellofemoral joint at low and high intensities. High-intensity impacts produced
      degenerative changes in the joint, such as softening of retropatellar cartilage,
      as measured by indentation, an increase in histopathology of the cartilage, and
      an increase in thickness of subchondral bone underlying the cartilage. Low
      intensity impacts did not cause these progressive changes. These data suggest
      that low-intensity impacts produced acute tissue stresses below the injury
      threshold, while high-intensity impacts produced stresses that exceeded the
      threshold for disease pathogenesis. This study begins to identify "safe" and
      "unsafe" ranges of acute tissue stress, using the rabbit patella, which may have
      future utility in the design of injury prevention devices for the human.

PMID- 10412453
TI  - Residual strain in ischemic ventricular myocardium.
AB  - Structural remodeling during acute myocardial infarction affects ventricular wall
      stress and strain. To see whether acute myocardial infarction alters residual
      stress and strain in the left ventricle (LV), we measured opening angles in rat
      hearts after 30 minutes of left coronary artery occlusion. The mean opening angle
      in 18 ischemic hearts (51 +/- 20 deg) was significantly greater than in five sham
      operated controls (29 +/- 11 deg, P < 0.05). To determine whether these
      alterations in residual strain may be associated with strain softening caused by
      systolic overstretch of the noncontracting ischemic tissue, we also measured
      opening angles in isolated hearts that had been passively inflated to high LV
      pressures (120 mmHg). The mean opening angle of the strain-softened hearts was
      not significantly different from the sham-operated hearts (34 +/- 27 deg, P =
      0.74). Mean collagen area fractions in the myocardium were not significantly
      different between ischemic hearts (0.027 +/- 0.014) and the nonischemic group
      (0.022 +/- 0.011). Although there were significant differences in opening angles
      measured with ischemia, they do not appear to be a result of altered
      extracellular collagen content or softening associated with overstretch. Thus,
      there is a significant change in residual strain associated with acute ischemia
      that may be related to changes in collagen fiber structure, myocyte structure, or
      metabolic state.

PMID- 10412454
TI  - Left ventricular geometric remodeling and residual stress in the rat heart.
AB  - Theoretical considerations and observations of residual stress suggest that
      geometric remodeling in the heart may also alter residual stress and strain. We
      investigated whether changes in left ventricular geometry during physiologic
      growth were associated with corresponding changes in myocardial residual strain.
      In anesthetized rats from eight age groups ranging from 2-25+ weeks, the heart
      was arrested and isolated, and equatorial slices were obtained. The geometry of
      the intact, unloaded state was recorded, as well as the "opening angle" of the
      stress-free configuration after radial resection of the tissue slice. The tissue
      was fixed and embedded for histological examination of collagen area fraction.
      Heart weight increased 10-fold with age and unloaded internal radius increased
      almost 4-fold. However, wall thickness increased only 66 percent, so that the
      ratio of wall thickness to internal radius decreased significantly from 2.22 +/-
      0.29 (mean +/- SD) at 2 weeks to 0.81 +/- 0.47 at 25 weeks. Opening angle of the
      stress-free slice decreased significantly from 87 +/- 16 deg at 2 weeks to 51 +/-
      16 deg, and correlated linearly with wall thickness/radius ratio. Collagen area
      fraction increased with age. Hence physiologic ventricular remodeling in rats
      decreases myocardial residual strain in proportion to the relative reduction in
      wall thickness-radius ratio.

PMID- 10412455
TI  - Thermal stresses from large volumetric expansion during freezing of biomaterials.
AB  - Thermal stresses were studied in freezing of biomaterials containing significant
      amounts of water. An apparent specific heat formulation of the energy equation
      and a viscoelastic model for the mechanics problem were used to analyze the
      transient axi-symmetric freezing of a long cylinder. Viscoelastic properties were
      measured in an Instron machine. Results show that, before phase change occurs at
      any location, both radial and circumferential stresses are tensile and keep
      increasing until phase change begins. The maximum principal tensile stress during
      phase change increases with a decrease in boundary temperature (faster cooling).
      This is consistent with experimentally observed fractures at a lower boundary
      temperature. Large volumetric expansion during water to ice transformation was
      shown to be the primary contributor to large stress development. For very rapid
      freezing, relaxation may not be significant, and an elastic model may be
      sufficient.

PMID- 10412456
TI  - Safe touch temperatures for hot plates.
AB  - A finite difference heat transfer model has been developed to predict the Safe
      Touch Temperatures (STT) for plates made of different materials. SST can be
      defined as the highest temperature at which no pain is felt when the surface is
      touched for a long enough period to allow safe handling of the equipment. The
      criterion used to quantify damage is the "damage function" that was originally
      proposed by Henriques and Moritz. There are several uncertainties present in the
      physiological and thermal properties of the skin that give rise to a solution
      range rather than a single solution. Certain simplifying assumptions are made
      that tend to yield solutions for STT that are toward the lower or "safe" end of
      the solution range. The model developed is a two-dimensional axisymmetric model
      in cylindrical coordinates. A finite difference scheme that uses the Alternating
      Direction Implicit method is used to solve the problem. It is a second-order
      scheme in both space and time domains. A parametric analysis of the model is
      performed to isolate those factors that affect the STT to the greatest extent.
      Data are presented for a variety of cases, which cover commonly observed ranges
      in material and geometric properties. It is found that the material properties,
      namely thermal conductivity and volumetric heat capacity, and the plate thickness
      ratio are the three most important parameters. These three parameters account for
      a range of STT from 56 degrees C-100 degrees C with thick metals at the low end
      and thin metals and plastics in the high range. This method represents a
      significant improvement over existing standard practices.

PMID- 10412457
TI  - Theoretical and experimental study of intermittent blood flows in
      microcirculation: application to the in-vivo determination of compliance.
AB  - A new theoretical approach was used to study the nonlinear response of a
      microvascular segment subjected to a pressure step at one end. The method is
      suitable for both large and small deformations of the vessel wall in the case of
      an elastic response of the segment. It is shown that the use of this simulation
      permits an indirect determination of the compliance of the vessel. The procedure
      is applied in two cases of major interest: first the in-vivo study of the
      intermittent blood flow in the microcirculation, and second, the analysis of
      experiments using micropipettes. The resulting values of the compliance agree
      with other values found in the previous studies. The theoretical method is
      particularly adapted to nonlinear equations.

PMID- 10412458
TI  - A point cluster method for in vivo motion analysis: applied to a study of knee
      kinematics.
AB  - A new method for deriving limb segment motion from markers placed on the skin is
      described. The method provides a basis for determining the artifact associated
      with nonrigid body movement of points placed on the skin. The method is based on
      a cluster of points uniformly distributed on the limb segment. Each point is
      assigned an arbitrary mass. The center of mass and the inertia tensor of this
      cluster of points are calculated. The eigenvalues and eigenvectors of the inertia
      tensor are used to define a coordinate system in the cluster as well as to
      provide a basis for evaluating non-rigid body movement. The eigenvalues of the
      inertia tensor remain invariant if the segment is behaving as a rigid body,
      thereby providing a basis for determining variations for nonrigid body movement.
      The method was tested in a simulation model where systematic and random errors
      were introduced into a fixed cluster of points. The simulation demonstrated that
      the error due to nonrigid body movement could be substantially reduced. The
      method was also evaluated in a group of ten normal subjects during walking. The
      results for knee rotation and translation obtained from the point cluster method
      compared favorably to results previously obtained from normal subjects with intra
      cortical pins placed into the femur and tibia. The resulting methodology
      described in this paper provides a unique approach to the measurement of in vivo
      motion using skin-based marker systems.

PMID- 10412459
TI  - Increasing quadriceps loads affect the lengths of the ligaments and the
      kinematics of the knee.
AB  - The relationships between the lengths of the ligaments and kinematics of the knee
      and quadriceps load, for low to physiologic levels of quadriceps loads, have not
      previously been studied. We investigated the effects of increasing levels of
      quadriceps force, necessary to balance increasing levels of externally applied
      flexion moments, on the kinematics of the tibiofemoral joint and on the
      separation distances between insertions of selected fibers of the major ligaments
      of the knee in twelve cadavera. Static measurements were made using a six-degree
      of-freedom digitizer for flexion angles ranging from 0 to 120 deg in 15 deg
      increments. Quadriceps generated extension of the knee was performed by applying
      loads to the quadriceps tendon to equilibrate each of four magnitudes of external
      flexion moments equivalent to 8.33, 16.67, 25.00, and 33.33 percent of values
      previously reported for maximum isometric extension moments. The magnitude of
      quadriceps force increased linearly (p < 0.0001) as external flexion moment
      increased throughout the entire range of flexion. Anterior translation, internal
      rotation, and abduction of the tibia increased linearly (p < 0.0001, p < 0.001, p
      < 0.001) as external flexion moment and, hence, quadriceps load increased. For
      the fibers studied, the anterior cruciate ligament (p < 0.0076), posterior
      cruciate ligament (p < 0.0001), and medial collateral ligament (p < 0.0383)
      lengthened linearly while the lateral collateral ligament (p < 0.0124) shortened
      linearly as quadriceps load increased. Based on these results for low to
      physiologic levels of quadriceps loads, it is reasonable to assume that the
      ligament lengths or knee kinematics expected with higher quadriceps loads can be
      extrapolated.

PMID- 10412460
TI  - Material characterization of human medial collateral ligament.
AB  - The objectives of this study were to determine the longitudinal and transverse
      material properties of the human medial collateral ligament (MCL) and to evaluate
      the ability of three existing constitutive models to describe the material
      behavior of MCL. Uniaxial test specimens were punched from ten human cadaveric
      MCLs and tensile tested along and transverse to the collagen fiber direction.
      Using load and optical strain analysis information, the tangent modulus, tensile
      strength and ultimate strain were determined. The material coefficients for each
      constitutive model were determined using nonlinear regression. All specimens
      failed within the substance of the tissue. Specimens tested along the collagen
      fiber direction exhibited the typical nonlinear behavior reported for ligaments.
      This behavior was absent from the stress-strain curves of the transverse
      specimens. The average tensile strength, ultimate strain, and tangent modulus for
      the longitudinal specimens was 38.6 +/- 4.8 MPa, 17.1 +/- 1.5 percent, and 332.2
      +/- 58.3 MPa, respectively. The average tensile strength, ultimate strain, and
      tangent modulus for the transverse specimens was 1.7 +/- 0.5 MPa, 11.7 +/- 0.9
      percent, and 11.0 +/- 3.6 MPa, respectively. All three constitutive models
      described the longitudinal behavior of the ligament equally well. However, the
      ability of the models to describe the transverse behavior of the ligament varied.

PMID- 10412461
TI  - Influence of sensor size on the accuracy of in-vivo ligament and tendon force
      measurements.
AB  - In-vivo tendon forces are commonly measured using transducers, which detect
      tension in the tendon fibers. A poorly understood source of measurement errors is
      the difference in stress distribution within the tendon between experimental and
      transducer calibration conditions. The objective of this study was to investigate
      this source of error, and to determine whether these errors could be minimized by
      proper selection of transducer size. The study was conducted using the
      infrapatellar ligament (patellar tendon) of New Zealand White rabbits. Tendon
      force was measured with two different size implantable force transducers (IFTs),
      one Wide and one Narrow, and by a strain gaged load cell in series with the
      tendon. Tests were conducted at five different loading conditions selected to
      produce five different stress distributions within the tendon. One loading
      condition corresponded to a typical post-experiment calibration, and the data
      from that condition were used to develop a calibration equation for the
      transducer. The errors that resulted from using this calibration were determined
      by comparing the tendon force measured by the in-series load cell with the force
      predicted from the IFT output using the calibration equation. Changes in stress
      distribution produced measurement errors up to 64 N with the Narrow IFT but only
      24 N with the Wide IFT. We found the measurement error was dependent on sensor
      width. Our results support the hypothesis that measurement errors can be caused
      by differences in tendon stress distribution between calibration and experimental
      conditions. We further showed that these errors can be minimized by using an IFT,
      which samples the tension in a large percentage of the tendon fibers. Information
      from this study can be used for selection of an appropriately sized implantable
      force transducer for measuring tendon and ligament force.

PMID- 10412462
TI  - A tensegrity model of the cytoskeleton in spread and round cells.
AB  - Measurements on adherent cells have shown that spreading affects their mechanics.
      Highly spread cells are stiffer than less spread cells. The stiffness increases
      approximately linearly with increasing applied stress and more so in highly
      spread cells than in less spread cells. In this study, a six-strut tensegrity
      model of the cytoskeleton is used to analyze the effect of spreading on cellular
      mechanics. Two configurations are considered: a "round" configuration where a
      spherically shaped model is anchored to a flat rigid surface at three joints, and
      a "spread" configuration, where three additional joints of the model are attached
      to the surface. In both configurations a pulling force is applied at a free
      joint, distal from the anchoring surface, and the corresponding deformation is
      determined from equations of equilibrium. The model stiffness is obtained as the
      ratio of applied force to deformation. It is found that the stiffness changes
      with spreading consistently with the observations in cells. These findings
      suggest the possibility that the spreading-induced changes of the mechanical
      properties of the cell are the result of the concomitant changes in force
      distribution and microstructural geometry of the cytoskeleton.

PMID- 10412463
TI  - Stress intensity factors for a vertical surface crack in polyethylene subject to
      rolling and sliding contact.
AB  - Pitting wear is a dominant form of polyethylene surface damage in total knee
      replacements, and may originate from surface cracks that propagate under repeated
      tribological contact. In the present study, stress intensity factors, KI and KII,
      were calculated for a surface crack in a polyethylene-CoCr-bone system in the
      presence of rolling or sliding contact pressures. Variations in crack length and
      load location were studied to determine probable crack propagation mechanisms and
      modes. The crack tip experienced a wide range of mixed-mode conditions that
      varied as a function of crack length, load location, and sliding friction.
      Positive KI values were observed for shorter cracks in rolling contact and for
      all crack lengths when the sliding load moved away from the crack. KII was
      greatest when the load was directly adjacent to the crack (g/a = +/- 1), where
      coincidental Mode I stresses were predominantly compressive. Sliding friction
      substantially increased both KImax and KIImax. The effective Mode I stress
      intensity factors, Keff, were greatest at g/a = +/- 1, illustrating the
      significance of high shear stresses generated by loads adjacent to surface
      cracks. Keff trends suggest mechanisms for surface pitting by which surface
      cracks propagate along their original plane under repeated reciprocating rolling
      or sliding, and turn in the direction of sliding under unidirectional sliding
      contact.

PMID- 10412464
TI  - Development of wall surface tangent DPIV measurement techniques for arterial
      branch models.
AB  - Experimental techniques for measuring unsteady flow in a glass arterial
      bifurcation model have been developed to aid in quantifying three-dimensional
      wall shear fluctuations associated with arterial disease. The unique feature of
      the current technique is the use of a "curved" laser sheet, which was everywhere
      tangent to the inner wall of a daughter tube in an arterial bifurcation model.
      Surface tangent velocity vector field measurements were made to demonstrate the
      potential of this technique. Ensemble-averaged data showing weak secondary flows
      as well as statistical distributions of flow angles are presented. Measurements
      of this type may be used to estimate mean and instantaneous wall shear magnitude
      and direction, data that are necessary for understanding the importance of
      circumferential motions on arterial disease.

PMID- 10412465
TI  - Transducers for dynamic measurement of spine neural-space occlusions.

PMID- 10412466
TI  - Survival rate and failure characteristics of the all metal post and core
      restoration.
AB  - In this retrospective study 516 teeth restored with a cast post and core build-up
      were followed from 1970 till 1990. The data was derived from the dental records
      of 283 dental clinic patients treated by senior students. The survival rate was
      found to be 82% after 10 years for post and cores in the anterior region. The
      most frequent failure characteristic was recementation (46%), followed by
      rerestoration (32%). The solitary provisions in posterior teeth showed a relative
      high survival rate, compared with other tooth-types and locations.

PMID- 10412467
TI  - Comparison of the prevalence, severity and possible causes of occlusal tooth wear
      in two young adult populations.
AB  - Most reports of the prevalence and severity of tooth wear in contemporary Western
      populations claim that advanced wear in uncommon by comparison with certain non
      Western populations. Differing methods of wear evaluation in the various studies,
      however, preclude accurate comparisons from being made. This study records mean
      total and segmental wear indices obtained from the casts of a selected Swedish
      patient population sample, and age- and sex-matched Saudi high-wear and random
      samples. The wear experience of the Saudi random sample compared favourably with
      that of the Swedish selected one, while the wear of the Saudi high-wear sample
      was significantly higher than that of the Swedish sample (P < 0.01). The findings
      from a questionnaire revealed certain significant correlations between
      aetiological factors and wear, most notably, the relatively greater presence of
      bruxism (P < 0.01), absence of biting habits and minimal cola consumption (P <
      0.01) in the Swedish sample. Harsh environmental and climatic conditions probably
      account for the Saudi experience of high wear.

PMID- 10412468
TI  - Therapeutic effects of the plane occlusal splint on signs and symptoms of
      craniomandibular disorders in patients with nocturnal bruxism.
AB  - The long-term effects were studied of a full arch maxillary plane occlusal splint
      on chronic signs and symptoms of craniomandibular disorders (CMD) in 31 patients
      with nocturnal bruxism. The results revealed that the score and intensity of
      signs and symptoms in this type of patient fluctuate from day to day and even
      within a single day. In spite of continuation of nocturnal bruxism, the symptoms
      of CMD were cured or improved with the long-term use of the occlusal splint.
      However, in general, the symptoms recurred after discontinuation of splint
      therapy. The therapeutic mechanisms of the splint during sleep are discussed.

PMID- 10412469
TI  - Accuracy of models for indirect posterior restorations.
AB  - Effects of materials and techniques on the accuracy of models used to make
      indirect restorations was measured using a 4-unit posterior model containing a
      MOD and full crown preparation. Improved stone and fast setting epoxy dies backed
      with either improved stone or a thermoplastic hot melt stone were made from
      single-viscosity addition silicone impressions. Technique variations included
      heating or not heating the impression, cooling and pouring dies and placement of
      the hot melt stone on set or unset epoxy. The dimensions of the MOD (L, W, H) and
      of the crown (W, H) dies were measured at 1 and 24 h. No clinically significant
      changes occurred between 1 and 24 h. The stone control reproduced the dimensions
      of the master die best, and models made by pouring epoxy into the impression
      followed by immediate pouring of the hot melt stone gave the poorest
      reproduction. Other variations in technique using epoxy for the anatomical
      portion gave no practical differences in accuracy. Of the epoxy dies, those
      prepared from a previously heated impression with hot melt poured after the epoxy
      set had the best values; however, epoxy dies were smaller than stone dies. The
      fast set epoxy was noteworthy for rapid processing and sharp detail, however,
      negative changes for W and H of the crown and H and L of the MOD showed that a
      die spacer would be essential in the preparation of indirect restorations.

PMID- 10412470
TI  - Acupuncture treatment of xerostomia caused by irradiation of the head and neck
      region: case reports.
AB  - Salivary flow rates were monitored in two patients, treated with acupuncture for
      post-radiotherapy xerostomia. The flow rates improved after acupuncture and the
      effect persisted during the 2-year observation period.

PMID- 10412471
TI  - In vitro posterior composite polymerization recovery following hygroscopic
      expansion.
AB  - Post-operative pain has been associated with composite polymerization shrinkage.
      This study aimed to quantify the cuspal deflection resulting from the initial
      shrinkage and the subsequent hygroscopic expansion of a standard posterior
      composite resin. Thirty hydrated permanent molars were marked on the buccal and
      lingual cusp tips. Standardized conventional Class II preparations were made and
      restorations with composite resin were placed and: (A) polymerized as one
      complete unit; (B) polymerized in gingivo-occlusal increments; (C) polymerized in
      buccolingual increments. Ten untreated teeth were marked and acted as controls.
      All specimens were placed in water. Pre-operative, post-operative and 6-month
      photographs were projected on a digitizer pad and measured by two independent
      investigators. The mean cuspal deflection (micron) immediately post-operatively
      and 6 months respectively, was: (A) 22.4, 8.7; (B) 12.4, 5.3; (C) 9.8, 3.0. The
      percentage of natural tooth dimensional recovery, following hygroscopic expansion
      was: (A) 97.5%; (B) 98.6%; (C) 99.4%. Buccolingual incremental polymerization led
      to significantly less initial cuspal deflection and the most cuspal recovery
      after hygroscopic expansion. The technique of resin placement therefore may
      provide a decrease in post-operative sensitivity.

PMID- 10412472
TI  - Disc movements over the condylar head. Radiographical study on autopsy materials.
AB  - A radiographical study has been performed to evaluate the movement of the disc
      posterior band over the condylar head during mandibular opening. Six formal free
      embalmed subjects were selected as 'normal'. Micro stainless steel balls were
      used as landmarks both into the bone and into the disc for X-ray identification.
      The data was processed at each phase of movement in selected planes. The true
      coordinates of each disc landmark gave the potential to calculate the linear
      length of their path and any distance change between them. It can be concluded
      that there is a 5% width reduction during the opening movement and it also
      suggests strongly that a fair amount of translation movement between the disc and
      the condyle occurs in the lower compartment.

PMID- 10412473
TI  - The stability of temporary prosthetic base materials. II: Water sorption and its
      effects.
AB  - The bases of occlusal rims and trial dentures may sorb water during disinfection
      procedures, adjustment in the mouth and rinsing and cooling under running water.
      Such sorped water may adversely affect the properties of the baseplate materials.
      The room temperature water sorption of sheets of grey and pink shellac and cold
      cure acrylic resin was determined over 10 weeks by weighing. The Wallace surface
      hardness, linear dimension and transverse strength were also measured each week.
      Specimens were reweighed each week as they dried at room temperature. At the
      conclusion of the tests, the materials showed a change after soaking in weight,
      hardness, linear dimension and transverse strength, and change after drying
      relative to original mass for grey shellac of +1.5%, -48%, +0.7%, -58%, +0.33%;
      for pink shellac of +2.0%, -56%, +0.9%, -65%, +0.4%; and for acrylic resin of
      +1.2%, +10%, +0.4%, -30%, -2.1% respectively. The acrylic resin material was thus
      less affected by water sorption than the grey and pink shellac materials.

PMID- 10412474
TI  - A new method for measuring nocturnal tooth contacts.
AB  - A new portable system for measuring nocturnal tooth contacts has been devised.
      This system was suitable for patients to take home and record tooth contacts by
      themselves. A micro photo sensor using optical fibres was applied to detect tooth
      contacts. The sensor and the target were accurately fixed to opposed molars,
      respectively on the same side, with removable metal attachments. Patients were
      instructed to set the attachment to their tooth each experimental night. In the
      present study, data was assembled for four or five nights in three subjects who
      were free of masticatory pain and dysfunction. Each subject showed an individual
      tooth contact pattern. It is suggested that this new system is useful and
      convenient for measuring nocturnal tooth contacts.

PMID- 10412475
TI  - Comparison of two different silane compounds used for improving adhesion between
      fibres and acrylic denture base material.
AB  - This study was aimed at clarifying the effects of two different silane compounds
      on the adhesion between the different fibres and acrylic resin. The fibres used
      as reinforcement in the acrylic resin test specimens were glass, carbon and
      aramid fibres and the silane treated and untreated versions of each type of the
      fibres were tested. The fracture resistance of the test specimens were assessed
      and the fibres were studied by a scanning electron microscope (SEM) to establish
      the adhesion between the fibres and acrylic resin. The results showed that
      silanization of glass and aramid fibres enhances the adhesion between the fibres
      and acrylic resin. The findings were confirmed by the SEM photographs taken. The
      use of a scanning electron microscope proved to be useful for the investigation
      of the adhesive properties of the materials used.

PMID- 10412477
TI  - Photoelastic evaluation of the standard bionator appliance.
AB  - A study was undertaken to demonstrate the forces in the craniofacial complex
      generated by the activation of the standard bionator appliance. A three
      dimensional skull replica of an orthodontic patient with a Class II Division 1
      malocclusion in the mixed dentition was fabricated using a urethane based
      photoelastic material to simulate bone. Four muscles of mastication were
      simulated on the photoelastic model. Various anatomical areas of the skull were
      viewed in a circular polariscope and recorded photographically before and after
      inserting the bionator. The downward and forward repositioning of the lower jaw
      by the bionator appliance caused various stresses on the craniofacial complex.
      The photoelastic stresses visualized in this investigation would most likely
      cause: an increase in the gonial angle; downward repositioning of the midface;
      and a posterior displacement and expansion of the maxilla.

PMID- 10412476
TI  - Effects on local blood flux of acupuncture stimulation used to treat xerostomia
      in patients suffering from Sjogren's syndrome.
AB  - Twenty-one patients with Sjogren's syndrome were given four different kinds of
      acupuncture stimulation, at acupuncture points previously used to treat
      xerostomia. The local blood flux in the skin overlying the parotid gland was
      measured with laser Doppler flowmetry before, during and after the acupuncture
      stimulation. The results showed that the local blood flux increased significantly
      during and after both manual acupuncture and low-frequency (2 Hz) electro
      acupuncture as compared with superficial acupuncture. These results indicate that
      acupuncture induced an increase in the local blood flux which was more pronounced
      for those patients who had previously reacted with increased salivary flow to
      acupuncture.

PMID- 10412478
TI  - A 4-year clinical evaluation of extensive amalgam restorations--description of
      the failures.
AB  - The 4-year evaluation of a randomized controlled clinical trial to the
      functioning of Extensive Amalgam Restorations (EAR) is reported. In this trial
      300 EAR were made by three operators on molar teeth. Five different auxiliary
      retention methods were used to retain these restorations. In the evaluation a
      differentiation in 'absolute' and 'relative' failures was made. After 4 years
      seven absolute failures (EAR dislodged or removed) were encountered (2%). When
      relative failures (endodontic treatment or restoration at margin) are also taken
      into account the number of failures increased to 31 (10%). Due to the low number
      of failures, no significant influences from experimental variables (c.q.
      retention method or operator) could be detected. It may be concluded that the
      results of this interim analysis of the clinical functioning of EAR are
      promising. It is thought that careful evaluation of cusp strength and reducing
      weak cusps diminishes clinical failure and as a result, it is not necessary to
      protect an EAR with a cast restoration in the first 4 years of its clinical life.

PMID- 10412479
TI  - The carer's perspective: results of a survey of attitudes to dental care in 250
      residential homes in Manchester.
AB  - A postal survey of 250 residential homes in the Manchester area was undertaken in
      late spring 1991. The 152 questionnaires returned gave information about 3757
      residents. In spite of an apparently adequate understanding of the importance of
      dental care, carers did not appear to provide as effective a service as they
      thought necessary. Ninety-one percent of carers realised dentures do not last
      indefinitely and 77.4% thought dentures should be checked every 2 years. Yet, in
      over 50% of homes, there was no provision for regular dental checks and in only
      42.8% were residents seen every 2 years. It was pleasing to note that 70.7% of
      respondents welcomed the suggestion of a half-day educational workshop.
      Suggestions are made for assisting homes with areas of particular concern. The
      importance of good rapport with local dental surgeons is stressed.

PMID- 10412480
TI  - Clinical performance of different post and core systems--results of a pilot
      study.
AB  - During the period 1974-1986, 112 post and core build-ups were inserted in 74
      patients. The build-ups consisted of a metal prefabricated post (Dentatus,
      Unimetric or Radix) in combination with a composite core. After an average follow
      up period of 7.9 years, 14 failures (12.5%) were noticed. Eight teeth could be
      rerestored and six teeth had to be extracted. However, when correction was made
      for teeth with a bad initial prognosis and for extractions not related to the
      build-up restoration, eight failures remained caused by failure of the build-up
      (7.5%). The Dentatus posts seemed to increase the risk for failure.

PMID- 10412481
TI  - A model to describe how ligaments may control symmetrical jaw opening movements
      in man.
AB  - A mechanical model of the temporomandibular (TM) joint was converted into a
      computer program, with a graphic output, which tested the simultaneous effects on
      symmetrical jaw opening of the following three constraints: 1) the condyle could
      not move above the articular surface of the temporal bone; 2) the TM ligament and
      3) the sphenomandibular (SN) ligament could not be stretched. Cartesian
      coordinates describing the ligaments and bones of six different skulls were
      measured and entered into the model. Although the constraints in the model
      allowed five different types of jaw opening movement, only one of these was
      physically possible for any given position of the mandible during opening. Each
      movement changed the geometry of the constraints. The opening movements of the
      condyle followed those of the hinge and kinematic axes which have been observed
      in studies of symmetrical jaw opening. Together with the constraint of the
      articular eminence, the early phase of opening was controlled by the backwardly
      inclined TM ligament. The late phase of opening was controlled by the forwardly
      inclined SN ligament. This mechanical explanation for the observed movements of
      the condyle is consistent with the principle that accessory ligaments have
      evolved around joints to reduce the need for some neuromuscular controls by
      replacing them with mechanical controls.

PMID- 10412482
TI  - Effects of post-curing by heat on the mechanical properties of visible-light
      cured inlay composites.
AB  - The aim of this study was to evaluate the effects of post-curing by heat on the
      mechanical properties of visible-light (V-L) cured three inlay composites and
      three posterior filling composites. One group was only photo-cured according to
      the manufacturers' recommended methods, while the other group was heat-treated at
      100 degrees C for 15 min following initial cure by V-L. Knoop hardness, diametral
      tensile strength and compressive strength were measured to evaluate the
      mechanical properties. Cure performance was checked out by the solvent immersion
      test. Upon secondary-curing by heat, it was confirmed that the mechanical
      properties of the composites were increased moderately and the cure performance
      of the composites was also improved.

PMID- 10412483
TI  - Radiopacity of 12 visible-light-cured dental composite resins.
AB  - The radiopacity of 12 VL-cured composite resins was determined with reference to
      an aluminum step-wedge. Two anterior composites were radiolucent while two
      anterior and one anterior/posterior composites exhibited the radiopacity equal
      to, or slightly greater than, that of human enamel. Three posterior and one inlay
      composites possessed the radiopacity equivalent to, or in tiny excess of, that of
      human enamel. Three posterior composites had the radiopacity, fairly exceeding
      that of human enamel. Chemical analyses of the filler particles were carried out
      with SEM/EDX. It became evident that radiopaque fillers contained at least one
      radiopaque oxide component such as BaO, ZrO2 and Yb2O3 with varying
      concentrations. In general, the radiopacity of the composite resin was linearly
      proportional to the amount of the radiopaque oxide in the filler. It was
      suggested that ZrO2 was radiopacifier equivalent to, or even stronger than, BaO.

PMID- 10412484
TI  - Solubility of irradiated rat molar teeth.
AB  - The solubility of molar teeth of rats exposed to irradiation and fluoridated
      drinking water was studied. Irradiation resulted in an increased molar enamel
      resistance enhanced by fluoridated drinking water.

PMID- 10412485
TI  - Temporary prosthetic base materials: reproduction of surface detail.
AB  - The baseplate material that best reproduced the most grooves in a gypsum cast was
      filled cold cure acrylic resin, followed in turn by modelling wax, grey shellac
      and finally the pink shellac material. These latter three thermoplastic materials
      performed best when softened in a water bath and subsequently adapted to a
      prewarmed cast.

PMID- 10412486
TI  - Effect of loading and syringing on void formation in automixed addition silicone
      elastomers.
AB  - The effect of loading and syringing on void formation in five automixed addition
      silicones was evaluated by determining the voids created in the first and second
      halves of material loaded and dispensed from a metal syringe. Impressions were
      made of a model with six stainless-steel cylinders. The voids were counted at a
      predetermined site on 3 separate days using a binocular microscope at x 7
      magnification. Automixed addition silicones did not confirm the 'last out-fewer
      bubbles' phenomenon and specific loading and syringing technique did not appear
      to have a consistent effect on void formation in automixed elastomers.

PMID- 10412487
TI  - Periodontal cell migration into the apical pulp during the repair process after
      pulpectomy in immature teeth: an autoradiographic study.
AB  - The migration of dental papilla cells into the periodontium during the process of
      root development may occur as part of the process involved in the formation of
      the periodontal tissues. The question posed is whether such cells under
      pathological conditions could retromigrate from periodontium into dental pulp and
      together with other apical pulp cells of immature teeth, take part in the
      production of additional dental tissue, e.g. 1) the tertiary/dentine under deep
      carious lesion where odontoblasts had been destroyed 2) the dentine bridge on an
      amputation wound and 3) calcified tissue which closes an apex during the
      apexification process in immature teeth. The migration of periodontal cells
      locally marked by H3 thymidine immediately after partial pulpectomy in immature
      dog's teeth was analysed at observation periods of 2, 24 and 50 h and also
      without H3 thymidine labelling of periodontal cells 8 weeks after pulpectomy. The
      marked cells were found in the early observation periods after pulpectomy just in
      the places where the hard tissues were formed in the later observation period of
      8 weeks. They were found in large numbers just around the coagulated necrotic
      foci. The finding supports the assumption that firm necrotic masses are a very
      important stimulative factor in the reparation process in pulp and periodontium.
      The experiment also corroborated the existence of periodontal cell retromigration
      into apical dental papilla of immature teeth. Future research should assess the
      possible role of the pathological condition in the determination of
      undifferentiated odontogenic ectomesenchymal periodontal cells into odontoblasts.

PMID- 10412488
TI  - Dental high-speed cutting of four cast alloys.
AB  - The purpose of this study was to evaluate dental high-speed cutting behaviour of
      four cast alloys, namely Ag-Pd-Cu-Au alloy, Ag-Zn-In-Sn alloy, Ni-Cr alloy and
      Ti. Weight-load cutting tests were conducted on four cast alloys, using two
      rotary cutting instruments, namely a diamond point and a carbide bur, both driven
      by an air-turbine handpiece. While the constant transverse load of 80 g was
      applied on the workpiece for 5s, the handpiece speed was measured during cutting
      as well as the volume of workpiece removal which took place. The cutting tests
      were repeated 10 times. We found that the cutting volumes of soft Ag-Pd-Cu-Au
      alloy and Ag-Zn-In-Sn alloy were considerably larger than those of hard Ni-Cr
      alloy and Ti. It was also clarified that the cutting effectiveness of the carbide
      bur was generally superior to that of the diamond point. With continuing use,
      however, the cutting capability of the carbide bur tended to decline while that
      of the diamond point remained quasi-constant.

PMID- 10412489
TI  - Search for antifungal and anticancer compounds from native plant species of
      Cerrado and Atlantic Forest.
AB  - Bioactivity-guided fractionation of several bioactive extracts obtained from
      Cerrado and Atlantic Forest plant species led to the isolation of potent DNA
      damaging piperidine 1-5 and guanidine alkaloids 6-9 from Cassia leptophylla and
      Pterogyne nitens respectively, two common Leguminosae from Atlantic Forest. By
      means of biotechnological approach on Maytenus aquifolium, a species from
      Cerrado, moderate DNA-damaging sesquiterpene pyridine alkaloid 10-11 was
      isolated. Bioassay-guided fractionation on Casearia sylvestris, a medicinal plant
      species found in Cerrado and Atlantic Forest, led to the isolation of clerodane
      diterpenes 12-13 which showed effect on DNA. In addition, we have reported
      several interesting potent antifungal iridoids: 1 beta-hydroxy-dihydrocornin
      (14), 1 alpha-hydroxy-dihydrocornin (15), alpha-gardiol (16), beta-gardiol (17),
      plumericin (18), isoplumericin (19), 11-O-trans-caffeoylteucrein (20); ester
      derivative: 2-methyl-4-hydroxy-butyl-caffeoate (21), amide N-[7-(3',4'
      methylenedioxyphenyl)-2Z, 4Z-heptadienoyl] pyrrolidine (22) and triterpene
      viburgenin (23).

PMID- 10412490
TI  - Antipsychotic profile of alstonine: ethnopharmacology of a traditional Nigerian
      botanical remedy.
AB  - Although recently developed drugs have brought significant improvement, the
      treatment of psychotic disorders still presents serious drawbacks. Since inherent
      complexity and lack of satisfactory understanding of the underlying
      pathophysiology impose limits for rational drug design, resourceful approaches in
      the search for antipsychotics are pertinent. This paper reports pharmacological
      properties of alstonine, a heteroyohimbine type alkaloid, which exhibited an
      antipsychotic-like profile, inhibiting amphetamine-induced lethality, apomorphine
      induced stereotypy and potentiating barbiturate-induced sleeping time. Atypical
      features of alstonine were the prevention of haloperidol-induced catalepsy and
      lack of direct interaction with D1, D2 and 5-HT2A receptors, classically linked
      to antipsychotic mechanism of action.

PMID- 10412491
TI  - Pharmacological effects of essential oils of plants of the northeast of Brazil.
AB  - The authors have reviewed the pharmacological studies done with essential oils
      obtained in the state of Ceara, in Northeast of Brazil, from 15 species of
      aromatic plants, some of which are native to the phytogeographic semiarid region
      characteristic of the Northeast, the "caatingas". These studies have dealt with
      the effect of these oils on muscle contraction and with their antispasmodic,
      analgesic, antiinflammatory, anticonvulsant and antibacterial activity. The
      essential oils of the medicinal species have shown activity coherent with the use
      of these plants in folk medicine. The review is aimed primarily at summarizing
      the information relevant for a critical evaluation of the perspectives and
      potential of these oils as pharmacological and therapeutic agents.

PMID- 10412492
TI  - Prospects for Brazilian natural products.
AB  - Interest in natural products as a source of bioactive substances seems to be on
      the rise again. The pharmaceutical industry, the largest and most visible segment
      that develops and sells products based on active principles, is undergoing
      changes that will probably affect its way of doing business and conducting
      research. Recourse to what is often referred to as "alternative medicine" has
      stimulated a surge in the consumption of phytomedicines and dietary supplements,
      while a growing awareness that the Earth's biodiversity is a valuable resource
      has provided a strong impetus for conservation and/or sustainable development of
      important ecosystems. Prospects for countries like Brazil, that are rich in
      natural products, could be very favorable if an institutional framework capable
      of linking researchers in the area with world markets can be organized.

PMID- 10412493
TI  - Activities of the Pharmaceutical Technology Institute of the Oswaldo Cruz
      Foundation with medicinal, insecticidal and insect repellent plants.
AB  - In addition to original research, Far-Manguinhos, the Pharmaceutical Division of
      the Brazilian Ministry of Health's Oswaldo Cruz Foundation (FIOCRUZ), devotes
      major attention to the finalising of products for use in public health campaigns
      or, under contract, for private industrial development. Emphasis is on
      standardisation, adequate supply, safety in use and efficacy. Among the products
      discussed in this summary of some of its activities in the chemical and
      pharmaceutical fields are medicinal plants Bidens pilosa, Cymbopogon citratus,
      Copaifera species, Mentha crispa, Phyllanthus tenellus Roxb. and other
      Phyllanthus species, insecticidal plants, Lonchocarpus urucu and Quassia amara,
      and the insect antifeedant plants Carapa guianensis and Pterodon emarginatus.

PMID- 10412494
TI  - Action of chlorogenic acid on the complement system.
AB  - Previous research on plants used in folk medicine as antidotes against snake-bite
      revealed some constituents responsible for such protection. Chlorogenic acid (3-0
      caffeoyl quinic acid) was one of these substances, studied with more attention.
      It has been shown that this substance binds to proteins through hydrophobic
      interactions and hydrogen bonds. This paper shows the preliminary results about
      the anti-complementary action of chlorogenic acid. Human and guinea pig sera,
      treated with chlorogenic acid, were added to the hemolytic system (sheep
      erythrocyte sensitized with hemolysin) to study its effect on the activation of
      the classical complement pathway. The action on the alternative pathway was
      studied with human serum treated with chlorogenic acid and zymosan. Our results
      show that chlorogenic acid presents anti-complementary action at the classical
      pathway, since the sera are not able to lysis the indicator system. The presence
      of C3b fragments on the surface of the yeast cells demonstrates that the
      alternative pathway was not affected.

PMID- 10412495
TI  - [The Institutional Program for Health and Environment in the development process
      of the Oswaldo Cruz foundation].
AB  - The objective of this paper is to show the development program about health and
      environment in an institution of academic research and teaching, technological
      development and services. We analyse data from the register of projects in health
      and environment in the development process as the thematic axis for this program.
      We show the sectors which the projects are related, the key words of research and
      teaching, the construction of thematic axis that should guide and the different
      approach of interdisciplinary. At the end we show the challenges and perspectives
      for an interdisciplinar work about health and environment in an academic research
      and teaching institution.

PMID- 10412496
TI  - Brazil needs a national debate on bioprospecting.
AB  - An overview of current state-of-art methodologies and strategies applied in
      bioprospecting for drug discovery is presented. In view of the distance between
      these conditions and those being applied in Brazil a proposal is made concerning
      the urgent need for a national debate involving the society, scientific community
      and government agencies to build national policies, plans and goals for
      bioprospecting of Brazilian biodiversity. Some suggestions on how to implement
      such debate and questions that should be discussed are presented.

PMID- 10412497
TI  - Medicinal plants: pharmacopoeial prescriptions.
AB  - Medicinal plants still account for 25% of medical prescriptions in developed
      countries and for more than 80% in developing countries. Vegetable raw materials
      available in the commercial market frequently do not comply with the requirements
      of constant activity, efficacy and quality. There is a need for more strict
      specifications of vegetable drugs and the pharmacopoeial prescriptions usually
      provide these specifications. The characteristics of pharmacopoeial prescriptions
      are discussed in view of most common problems in drug quality.

PMID- 10412498
TI  - [Nutritional status of surgical patients without apparent nutritional
      compromise].
AB  - Nutritional status of 80 preoperative patients from programmed surgeries of
      hernias and lithiasis was studied by anthropometric and biochemical parameters.
      Nutritional deficiencies related to pathology were not expected in these
      patients. Results were as follows: 77% of the population showed overweight, being
      15% obese. Prevalent protein intake, evaluated by the urea nitrogen/creatinine
      ratio, was adequate in 87.5% of the patients; however, patients presented 72% of
      albumin, 52% of prealbumin and 50% of RBP below reference values. Transferrin,
      ceruloplasmin, alpha 2-macroglobulin and haptoglobin were not decreased.
      Assessment of vitamin A, carotenes and vitamin C showed plasmatic levels below
      reference values in 16% of the patients for vitamin A, 5% for carotenes and 27%
      for vitamin C. Respect to calcium status, data of calcium/creatinine ratio show
      deficiency in 45% of the population. Respect to iron, the nutritional status was
      in general adequate, patients at risk being 5% by Htc, 11% by Hb, 5% by TS% and
      12.5% by FEP, women showed over twice abnormal values than men. Although some
      isolated relations were observed, in this population sex, age and pathology were
      variable that did not affect in a relevant way the nutritional status. In spite
      of the individual analysis of each nutrient did not show important deficiencies,
      the analysis by patient showed that only a few of them (7%) presented an optimal
      biochemical profile with all the studied parameters within the reference values.

PMID- 10412499
TI  - [Iron nutritional status in pregnant adolescents, Sao Paulo, Brazil].
AB  - The frequency of anemia, iron deficiency and iron body stores was assessed in 155
      pregnant teenagers of low socioeconomic status in a prenatal care unit of a
      beneficent hospital in Sao Paulo, Brazil. By the criterion of the World Health
      Organization (Hb < 12 g/dL) 14.2% of the pregnant adolescents had anemia. The
      iron deficiency diagnostic by saturation of transferrin < 16% and zinc
      protoporphyrin concentration > 60 (mol/mol heme were 45.8 and 42.6%,
      respectively. The iron body store (serum ferritin < 12 micrograms/L) was depleted
      for 48.4% of adolescents. It is concluded that the iron nutritional status of
      these adolescents were characteristics of the pregravidic inadequate iron store.
      Despite low percentage of the anemia, the high frequency of iron deficiency and
      depleted iron stores suggest a practical procedure to detect iron deficiency and
      the use of iron supplementation in teenagers.

PMID- 10412500
TI  - [Early maturation: a risk factor of overweight and obesity during puberty?].
AB  - In the Caracas Longitudinal Study, 147 boys and 111 girls--8 to 16 years of age-
      who had been classified as early, average and late maturers, were analyzed in the
      context of risk of overweight and obesity. Differences in Body Mass Index (BMI),
      Arm Circumference (AC), Triceps and Subscapular Skinfolds (TRSK, SSSK) were
      assessed with an analysis of variance. A significant gradient early > average >
      late was found girls in all variables throughout follow-up and in AC in boys
      between 8 and 15 years of age and in BMI until age 11, although early maturers
      were significantly heavier at all ages. Skinfolds, in boys, presented this
      significant gradient up to age 11, while in girls it was found in TRSK between
      ages 8 and 15 and in SSSK between ages 11 and 15. Further analysis of sum of
      skinfolds, Arm Muscle Area (AMA) and Arm Fat Area (AFA) resulted in significant
      maturity gradients in girls for all the variables while, in boys, AMA presented
      this gradient up to age 15, whereas no gradients in and AFA were found from age
      12 onwards. Early maturers of both sexes are at risk of overweight; girls are at
      risk of obesity throughout puberty and boys at prepuberty and early puberty only.

PMID- 10412501
TI  - [Palm oil derivatives with different concentration of palmitic acid and
      antioxidants. Effects upon plasmatic lipids and platelet aggregation].
AB  - It was evaluated the effect of diet rich with cholesterol (0.1%) and different
      concentration of palmitic acid (16:0) and antioxidants (vitamin C, alpha
      tocopherol and retinol) upon plasmatic lipids and platelet aggregability in
      rabbits. The animals were distributed in three groups: I. Standard chow meal (Rp
      Conejarina) + cholesterol (chol) 0.1%; II. Standard chow meal + chol 0.1% +
      semipurified palm oil 10% (16:0 = 39.8%, oleic acid 48.7%, linoleic acid 11.4%,
      retinol 7.3 ug/dL, alpha tocopherol 157.6 ug/dL; III. Standard chow meal + chol
      0.1% + crude palm oil 10% (16:0 = 45.3%, oleic acid 46.3%, linoleic acid 7.9%,
      retinol 96.4 ug/dL, alpha tocopherol 322.8 ug/dL). Monthly determination of
      plasmatic lipids were done (Enzymatic methods) and at ten months platelet
      aggregability with ADP, plasmatic vitamin C, retinol and, alpha tocopherol
      determination were done. Total plasmatic cholesterol (TC) and LDLc increased
      significantly in the three groups of animals. Significant differences between
      groups were not found. Platelet aggregability was lower in the animals fed with
      palmitic acid rich diet (groups II and III) (P = 0.002 and 0.001). Retinol, alpha
      tocopherol plasmatic concentrations revealed no significant differences. Vitamin
      C in the groups I was lower than groups II and III (P < 0.05 < 0.02). In this
      study hypercholesterolemic rabbits fed with rich diets (crude and semipurified)
      had lower platelet aggregability without changes in plasmatic lipids
      concentrations.

PMID- 10412502
TI  - [Importance of n-3 polyunsaturated fatty acids (n-3 PUFA) in nutritional
      recovery].
AB  - Severe protein deprivation at weaning, may cause a stop in cellular proliferation
      and absolute number of T cells W3/13+ in the thymus of growing rats. The
      administration of a 20 g/100 casein recovery diet supplemented with 24 mg of n-3
      PUFA during 9 days, counteracted this effect suggesting for these essential
      nutrients a dose-dependent response. No changes were observed in hemostastic
      factors such as protrombine time (QUICK) and partial active tromboplastine time
      (KPTT). Even though total plasma lipids showed no changes, the LDL-cholesterol
      fraction presented a low increment in agreement with international data. Daily
      administration of this supplemented diet did not show an increase in hepatic
      lipid peroxidation in the experimental group, suggesting that natural
      antioxidants and vitamin E provided by the diet might be playing a protective
      role.

PMID- 10412503
TI  - [Food consumption and intake of several nutrients in a population of the
      University of Lujan, Argentina].
AB  - A dietary survey was carried out at the National University of Lujan (Argentina),
      with the objective of evaluating: a) food consumption and energy supply of
      cereals; b) the adequation of the intake of protein, calcium, iron, vitamins A,
      B1, B2, C and niacin, regarding the Recommended Dietary Allowances (RDA). A
      representative sample of 827 people (16% of the total population of 1991, equally
      distributed in the four seasons) was assessed with a 24 hour dietary recall.
      Sample was composed by: males: 189, aged 18-24 ys (GIM); 189, aged 25-50 ys
      (G2M); females: 209, aged 18-24 ys (GIF); 240, aged 25-50 ys (G2F). The results
      showed that cereals, 90% deriving from wheat products, supplied 32% of the total
      energy intake in G1F and between 40% and 48% in the other three groups. The mean
      daily intake of meat ranged between 90.5 g and 128.7 in females and over 140.0 g
      in males. Dairy products consumption was quite low, as well as fruits and
      vegetables in the whole of the population. Protein intake was over 1.25 g/d in
      50% of the population. Calcium intake was below the RDA in a great percentage of
      the population, the mean percentage of adequation being: G1F, 71%; G2F, 62%; G1M,
      64%; G2M, 65%. Iron mean daily intake was quite good, ranging between 16.4 and
      20.8 mg in females and between 17.5 and 19.2 mg in males. The percentage of iron
      supplied by meat was: G1F, 16%; G2F, 21%; G1M, 34% and G2M, 26%; therefore iron
      bioavailability can be considered high. Besides, "mate", which is drunk between
      meals, supplied between 25% and 29% of the total iron intake in females and
      between 12% and 56% in males. Vitamin A intake was below the RDA in 74% to 58% of
      the population. The mean intake of vitamin B1 was 89% of the RDA in G1M and over
      RDA in the other three groups. Intake and percentage of adequation of vitamin B2,
      vitamin C and niacin presented a great range, but the mean values were over the
      RDA. The overall results showed: a) a high protein intake, providing red meat
      between 26% and 39%; b) low consumption of dairy products, with the consequence
      of a low calcium and vitamin A intake; c) low consumption of fruits and
      vegetables, being in relation to the low intake of fibre and carotenes; d) high
      consumption of cereals, mainly wheat products, that must be controlled from the
      toxicological point of view, due to the variable presence of mycotoxins. These
      results are in agreement with other dietary surveys carried out in previous years
      and are a consequence of some characteristic feeding habits of the Argentine
      population. They show that nutritional education is necessary for promoting
      changes in the latter, with the aim of reaching a better nutritional status.

PMID- 10412504
TI  - [Chemical composition of 2 wild vegetable species compared with chard].
AB  - The nutritional quality of two wild vegetable species, Kochia scoparia (Ks) and
      Chenopodium album (Cha) was evaluated and compared with Beta vulgaris var.
      cicla(chard) (Bv), in order to propose their domestication as alternative protein
      sources. Chemical percentual analysis (AOAC), gaseous chromatography fatty acid
      determination, and antinutrient searching (by chemical, enzymatic and
      immunological method) were performed. Protein quality was determined by the
      following indexes: net protein utilization (NPU), true digestibility (tD) and
      biological value (BV). The three species exhibited similar protein concentration
      values, 25.8, 25.0 and 22.1 g/100 g for Ks, Cha and Bv, respectively. Kochia
      scoparia showed the highest value for fatty acid analysis (82%), with
      predominance of linolenic acid. Since the samples were subjected to boiling, the
      amounts of antinutrients found can be considered to be within levels not
      affecting health. As regards the biological quality, the obtained values for Ks,
      Cha and Bv, respectively, were: NPU: 68.0 +/- 0.4, 55.0 +/- 6.1 and 56.0 +/- 4.2;
      tD 70.0 +/- 0.7, 71.0 +/- 4.0 and 76.0 +/- 8.2; BV: 97, 77 and 74. The analysis
      of the biological quality indexes gave highest nitrogen profit for Ks. These
      results indicate that Kochia scoparia is suitable for the objective proposed.

PMID- 10412505
TI  - [Effect of concentration temperature of kiwi fruit pulp on color, chlorophyll and
      ascorbic acid].
AB  - A study was established to evaluate concentration temperatures (25, 30, 35, 40
      and 45 degrees C) on kiwi fruit pulp concentrated to 32 degrees Brix, with vacuum
      regulation. Munsell and sensorial colour, ascorbic acid and chlorophyll amount
      remanent were analyzed. Both, 25 and 30 degrees C concentration temperatures
      treatments, in the most of variables, experimented low deteriorate and differ
      with the other treatments. Ascorbic acid measurements had not significative
      differences (P < 0.95). Chlorophyll assays showed a decreased (70%) in the amount
      remanent over 35 degrees C in comparison to 25 degrees C treatments. 40 and 45
      degrees C treatments showed traces of chlorophyll. Sensorial colour did not
      showed variations on 25 and 30 degrees C treatments; they were classified as
      bright green. Other treatments present colour deteriorate: 35 degrees C treatment
      was green-yellowish classified, and 45 degrees C treatments brown-greenish
      categories. Munsell colour showed the same relations, were increasing the
      concentration temperatures, decrease the green colour and increase the yellow
      colour.

PMID- 10412506
TI  - [Heat treatment and dietary fiber effect on protein quality of artichoke and its
      sub-product].
AB  - Blanched (95 degrees C, 5 min), autoclaved (100 degrees C, 5 min) artichoke
      hearts and their by-product (external leaves and distal portion of stem) were
      analysed for amino acid composition, "in-vitro" protein digestibility (DIVP), and
      dietary fiber. Amino acid score of the three samples was in a good agreement with
      FAO/WHO recommendations including sulphur amino acids. Dietary fiber content was
      high in all samples, decreasing in autoclaved artichokes that might be relate
      with the improvement of DIVP. By-product was consider a potential food source
      because it showed a good amino acid profile and the highest levels of DIVP
      (76.4%), but fibrouness was also too high (51.6%).

PMID- 10412507
TI  - [Experience with knowledge development in food handlers with te implementation of
      Hazard Analysis Critical control points (HACCP) in a hospital food service].
AB  - The present article has as objective to describe the methodology of an experience
      of implantation of Hazard Analyses Critical Control Points (HACCP) with food
      handlers in a hospital food service establishment, inside of a conception of
      relationship and construction of knowledge. Meetings with the food handlers and
      nutritionists, with the objective of raising the difficulties poined for the
      sector and the work to be developed. The HACCP consisted of the evaluation of the
      operations, following the sequential steps recommended, looking itself to
      instruct the food handlers on the methods of the operations and its
      interpretations. The detected critical points, the measures of control, the
      criteria of correction and the monitoring have widely been argued, serving as
      didactic elements for the reconstruction of quality of the preparations. The
      discussions generated actions that were developed in short term, revealing the
      need of a more effective and continuous partnership for the new proposals.

PMID- 10412508
TI  - [A supplementary sportmen food formulation and characterization].
AB  - A supplementary sportman food, based on corn:soy extruded blend, freeze-dried egg
      albumen and protein soy isolate, was developed. The resulting powder was subject
      to physico-chemical, functional, nutritional and sensorial test and then compared
      with a commercial food that was used as reference. Chemical and biological
      analysis of both foods revealed lower protein content in the formulated food
      (65%) than the commercial product (90%) although NPR values are larger in product
      showed (4.86) that than the observed in the second (4.03). On the other hand RNPR
      values of teh developed product also presented higher values than the commercial
      (Prot 90) (83.76 and 69.48 respectively). Casein was used as standard.
      Digestibility results were similar (93.65 and 95.7 for formulated and commercial
      products respectively). The absence of ureasic, antitryptic or hemagglutinating
      activity of the formulated product are also reported. Physico-chemical analysis
      shown that available lysine values are larger for the formulated product (15 g/16
      g nitrogen) than those for the commercial food (7.80). Peroxide content was
      always very small (1.37 meq/kg) and in all cases micotoxine assay, for raw
      materials, was always negative. A comparison of other properties, such as colour,
      WAI, WSI and aw for both products, is also presented. Flow behavior of water,
      milk and orange juice suspensions showed pseudoplastic behavior on both products.
      Sedimentation experiments minutes revealed stability of suspensions without phase
      separation during the first 30 minutes. Sensorial analysis have shown that
      developed product received 78.5% acceptability and 100% preference.

PMID- 10412509
TI  - [Incidence of Plesiomonas shigelloides in tilapia tetrahibrids (Oreochromis
      sp.)].
AB  - Plesiomonas shigelloides, a member of the family Vibrionaceae, is a Gram negative
      rod associated with several gastroenteritis outbreaks, especially in tropical and
      subtropical countries. In same way, it has been related to some septicemia,
      meningitis and cholecystitis cases. The microorganism is normally found in water,
      fish and birds. The aim of this work was to study the incidence of Plesiomonas
      shigelloides in tetrahybrids of Oreochromis sp. (Pink Tilapia) located at the
      central region of Venezuela. Once the samples were homogenized, the techniques of
      enrichment and direct streaking were used simultaneously for the isolation of the
      microorganism. A high incidence of P. shigelloides was determined (73%), being
      higher in the intestinal tract (60%), followed by the skin (36.7%) and the gills
      (26.67%), without any correlation among them. In the fish pond, the microorganism
      isolation frequency was 41.67%. The direct streaking technique presented the
      highest isolation values in the different Tilapia tissues (60%) and in the water
      as well (41.60%). No significant differences were observed on the effectivity of
      the selective agars used for the isolation of P. shigelloides (Plesiomonas Agar
      and Inositol-Brilliant Green-Bile Salts Agar). A positive correlation was
      observed between the microorganism incidence and the pluviosity levels. A high
      incidence of E. coli was observed in the samples of Tilapia tissues and the water
      pond. No correlation was observed between incidence of P. shigelloides and E.
      coli. Due to the high prevalence of P. shigelloides found in the present study,
      it is important to assure a proper evisceration, washing and storage at
      temperatures lower than 8 degrees C, and a proper product cooking to diminish the
      customeris risk.

PMID- 10412510
TI  - [Thermoresistance of acid producing psychrotrophic bacteria isolated from milk].
AB  - An acidificant psychrotrophic bacteria was isolated from raw milk from
      Bromocresol Purple Agar medium, after incubation at 7 degrees C, for 10 days.
      Cells from the culture, at the beginning of the stationary phase, were inoculated
      sterilized in powder milk, reconstituted at 12% of total solids, resulting in
      approximately 10(8) cells per milliliter. Portions of 3 ml of inoculated milk
      were transferred to borosilicate tubes and were submitted to cells resistance
      determination at 62, 70, 75 and 80 degrees C, by the TDT tube method. The
      survival curves at the respective temperatures and the curve of thermal death
      were drawn. The bacteria presented a D75 degrees C value of 0.15 minutes and z =
      8.7 degrees C. Treatments LTLT and HTST of pasteurization promoted 5.27 and 0.53
      decimal reductions in the number of available bacteria cells, respectively. The
      conclusion of this study was that the isolated bacteria is destroyed only by the
      treatment LTLT of pasteurization.

PMID- 10412511
TI  - [Microbiological quality of pasteurized milk creams manufactured in Venezuela].
AB  - A total of 100 samples of pasteurized milk creams produced by eleven (11) dairy
      milk industries were analyzed for the presence of microoganisms. The dairy milk
      industries were distributed along different places of Venezuela. The samples were
      analyzed for the presence of mesophilic aerobic bacteria, psychotropic bacteria,
      Staphylococcus aureus, coliformes, molds and yeasts 75% of the analyzed samples
      did not reach the international standards for aerobic mesophilic bacteria,
      similarly, 95% for Staphylococcus aureus, 91% for coliformes and 58% for molds
      and yeasts, so pathogenic enterobacteria we have found: Salmonella Typhimurium,
      Shigella sonnei and Escherichia coli enteropathogenic.

PMID- 10412512
TI  - [Protein quality of three strains of Mexican mushrooms (Pleurotus ostreatus)].
AB  - The protein quality of fruits bodies of three Pleurotus ostreatus Mexican strains
      (INIREB-8, CDBB-H-896 and CDBB-H-897) was evaluated. The protein concentration
      (Nx4.38) ranged from 17.26 to 19.97 g/100 g dry weight; chemical scores were
      between 74 and 93% with available lysine as a first limiting amino acid in either
      INIREB-8 and CDBB-H-896 strains or leucine in CDBB-H-897 strain. The nutritional
      evaluation revealed 67.75 to 68.38% in vitro digestibility. Relative protein
      values were from 100.06-107.85%, which were lower than soybean meal and whole egg
      but larger than those of rice, maize, beans, fava beans and pasta, no differences
      were found between these values and those of skim milk powder, casein plus
      methionine and albumin. In accordance with the last results we concluded that due
      to their essential amino acids content, mushroom proteins are a good complement
      of cereals; furthermore, it is highly recommended to include Pleurotus in the
      daily diet.

PMID- 10412513
TI  - A pilot study of topiramate in children with Lennox-Gastaut syndrome.
AB  - We conducted an open, add-on study with topiramate (TPM) as adjunctive therapy in
      Lennox-Gastaut syndrome (LGS), to assess the long-term efficacy and safety and to
      evaluate quality of life (QL) measurements in the chronic use of TPM. We studied
      19 patients (11 male; age ranging from 4 to 14 years) with uncontrolled seizures
      receiving 2-3 anti-epileptic drugs. Patients were followed up to 36 months of
      treatment. A questionnaire was used to query parents about QL. Seven patients
      completed the study at 36 months and seizure frequency was reduced > or = 75% in
      4, and < 50% in 3 patients. Two children became seizure free for more than 24
      months. Most side effects were CNS related, with the most frequent being
      somnolence and anorexia. These were generally transient. One patient dropped-out
      due to powder in the urine. None of the patients required hospitalization. At 36
      months, patients' alertness (2/7), interaction with environment (5/7), ability to
      perform daily activities (5/7), and verbal performance (6/7) improved on TPM. We
      conclude that TPM may be useful as adjunctive therapy in the treatment of LGS.
      The efficacy of TPM was maintained in long-term treatment in more than 40% of
      patients, long term safety was confirmed and QL improved on TPM.

PMID- 10412514
TI  - Subacute sclerosing panencephalitis. Clinical aspects and prognosis. The
      Brazilian registry.
AB  - Subacute sclerosing panencephalitis (SSPE) is an inflammatory neurodegenerative
      disease related to the persistence of measles virus. Although its frequency is
      declining because of measles eradication, we still have some cases being
      diagnosed. With the aim to describe epidemiological aspects of SSPE in Brazil, we
      sent a protocol to Child Neurologists around the country, 48 patients were
      registered, 27 (56%) were from the southeast region, 34 (71%) were male and 35
      (73%) white, 27 (56%) had measles, 9 (19%) had measles and were also immunized, 7
      (14%) received only immunization, 1 patient had a probable neonatal form. Mean
      time between first symptoms and diagnosis was 12 months (22 started with
      myoclonus or tonic-clonic seizures, 7 (14%) with behavioral disturbances); 36
      patients (75%) had EEG with pseudoperiodic complexes. Follow up performed in 28
      (58%) patients showed: 12 died, 2 had complete remission and the others had
      variable neurological disability. Our data shows endemic regions in the country,
      a high incidence of post-immunization SSPE and a delay between first symptom and
      diagnosis.

PMID- 10412515
TI  - Impact of recombinant human growth hormone (RH-GH) treatment on psychiatric,
      neuropsychological and clinical profiles of GH deficient adults. A placebo
      controlled trial.
AB  - BACKGROUND: Untreated GH-deficient adults have a diversity of dysfunctions (e.g.
      reduced muscle strength, emotional instability during stress, depressive
      symptoms) that may cause deleterious effects on quality of life, and may be
      positively influenced by recombinant human growth hormone (rh-GH) therapy. AIM:
      To evaluate the impact of a clinical intervention with rh-GH therapy on GH-
      deficient adults. METHOD: The physical, psychiatric and neuropsychological status
      of 9 GH-deficient adults was determined before and after the administration of rh
      GH (0.250 IU/Kg/week) in a double blind placebo-controlled trial for six months.
      Patients then received rh-GH for a further period of 6 months and their status
      was re-evaluated. RESULTS: Rh-GH was significant better than placebo at 6th month
      (p < 0.05), producing increased serum Insulin like growth factor-I (IGF-I)
      levels, reduced body mass index (BMI) and body fat, increased lean body mass and
      water, reduced waist/hip ratio and increased energy expenditure. The rh-GH
      therapy was also significantly better than placebo on depressive features as
      measured by the Hamilton Depression Scale (17-items) (p = 0.0431) and the Beck
      Depression Inventory (p = 0.0431). Neuropsychological evaluations showed
      significant improvements in measures of Attention: Digit Backward (p = 0.035),
      Verbal Fluency (FAS) (p = 0.02) and Cognitive Efficiency (WAIS-R tests):
      Vocabulary (p = 0.027), Picture Arrangements (p = 0.017), and Comprehension (p =
      0.01) following rh-GH therapy. CONCLUSION: The clinical, psychiatric, and
      neuropsychological impairments of untreated GH-deficient adults can be decreased
      by rh-GH therapy.

PMID- 10412517
TI  - Comparison of nerve conduction techniques in 95 mild carpal tunnel syndrome
      hands.
AB  - Electrodiagnosis of carpal tunnel syndrome (CTS) were prospectively studied in 95
      hands. The following techniques were studied in all hands and when at least one
      abnormal value was found (onset-measured), it was included on results: 1. wrist
      index finger latency (WIF), abnormal > or = 2.8 ms, 140 mm; 2. palm-wrist latency
      (PW), abnormal > or = 1.8 ms, 80 mm; 3. comparison median/ulnar palm-wrist
      latency (CPW), abnormal > or = 0.4 ms; 4. comparison median/ulnar latency, wrist
      ring finger (CMU), abnormal > or = 0.5 ms, 140 mm; 5. comparison median/radial
      latency, wrist-thumb (CMR), abnormal > or = 0.4 ms, 100 mm. All 95 CTS hands
      selected have the WIF < or = 3.5 ms (mild CTS). We found the CMR (97.8%)
      technique the most sensitive for mild CTS electrodiagnosis and the only
      comparative method with all potentials recordable when compared to CPW (88.4%),
      PW (84.2%), CMU (72.6%) and WIF (68.4%).

PMID- 10412516
TI  - Hereditary motor and sensory neuropathy with congenital glaucoma. Report on a
      family.
AB  - We report three siblings of a family with hereditary motor and sensory
      polyneuropathy (HMSN) and buphthalmos. Electrophysiological studies showed a
      demyelinating neuropathy and pathological findings showed severe loss of
      myelinated fibers (MF), thin myelin sheaths and myelin infoldings in a few
      remaining MF. The presumed mode of inheritance is autosomal recessive. This
      family probably represents an unique form of CMT4 that may be related to one of
      the congenital glaucoma genic locus, particularly GLC3A and GLC3B, described in
      Turkish families.

PMID- 10412519
TI  - [Carpal tunnel syndrome: clinical and epidemiological study in 668 cases].
AB  - Between January/1989 and June/1996, 1,059 carpal tunnel syndrome hands (CTS) from
      668 patients were studied. None had been previously operated and all had
      bilateral conduction studies; peripheral neuropathy was excluded. The patients
      were selected with sensory median/radial difference (MRD) > or = 1.0 ms that
      strongly supports electrodiagnosis of CTS (standard deviation > 6) after
      stimulation on wrist and recording on thumb. Normal MRD were obtained in 125
      hands with upper limit of normality = 0.43 ms (mean + 2 SD). The age ranged from
      17 to 83 years (mean 47.5) and 91.3% were female; the complaints were bilateral
      in 72% and nocturnal/awakening in 85.3%. Pain, numbness and paraesthesia occurred
      in 64.4%; pain as the only symptom was rare but proximal extension was frequent
      (39.4%). All fingers were symptomatic in 42.5%, followed by middle, middle-ring,
      thumb-index-middle and then index-middle-ring ones. There was no correlation with
      traumatic past history on wrist. The duration CTS symptoms ranged from 1 to > 120
      months. Diabetes mellitus was present in 4.4% even after peripheral neuropathy
      exclusion.

PMID- 10412518
TI  - Duration of symptomatology and median segmental sensory latency in 993 carpal
      tunnel syndrome hands (668 cases).
AB  - According to median sensory nerve action potential onset-latency to index finger
      in a 140 mm fixed distance, 993 carpal tunnel syndrome (CTS) hands from 668
      patients were grouped into MIld (3.0 to 3.5 ms, 384 hands). MOderate (3.6 to 4.4
      ms, 332 hands), SEvere (> 4.4 ms, 135 hands) and UNrecordable (142 hands) and
      correlated with CTS symptomatology duration. All patients have sensory antidromic
      median-radial latency difference (MRD) e > or = 1.0 ms without any doubt about
      CTS diagnosis. Patients with systemic disease, trauma or previous surgery were
      excluded. There is a remarkable cumulative percentage increase from 1 to 12
      months in group UN (3.5% to 38.7%, 11 folds), much less than the group MI (13.8%
      to 54.6%, 3.9 folds). There is also a remarkable non-cumulative percentage
      increase in group UN, from 1 to 4-12 months; the group MI had a relatively
      uniform distribution in all symptomatic duration groups from 1 to > 60 months.
      The conclusion is that median nerve compression at carpal tunnel can lead to
      unrecordable potentials in a relatively short period from 1 to 12 months of
      evolution, suggesting acute/subacute deterioration. Electrophysiological
      evaluation must be done periodically in patients that underwent clinical
      treatment, since cumulative 38.7% of group UN was found in 12 months period.

PMID- 10412520
TI  - [Carpal tunnel syndrome: sensory median-radial latency difference versus
      conduction studies in 1059 hands (668 cases)].
AB  - Between January 1989 and June 1996, 1,059 carpal tunnel syndrome hands (CTS) from
      668 patients were studied. None had been previously operated and all had
      bilateral conduction studies; peripheral neuropathy was excluded. The patients
      were selected with sensory median/radial difference (MRD) > or = 1.0 ms that
      strongly supports electrodiagnosis of CTS (standard deviation > 6) after
      simultaneous stimulation on wrist and recording on thumb. Normal MRD were
      obtained in 125 hands with upper limit of normality = 0.43 ms (mean + 2SD). The
      age ranged from 17 to 83 years (mean 47.5) and 91.3% were female. MRD > or = 1.0
      ms correlates in 95% with median distal motor latency > 4.25 ms (80 mm distance)
      and with median distal sensory latency to index finger > or = 3.01 ms, middle
      finger > or = 3.14 ms and ring finger > or = 3.26 ms, all of them 140 mm
      distance, antidromic and onset-measured. The results have brought new values for
      the limit of normality in our EMG laboratory since MRD > or = 1.0 ms is very
      sensitive for CTS diagnosis.

PMID- 10412521
TI  - [New system of ambulatory EEG monitoring: analysis and classification of
      epileptic discharges in 100 patients].
AB  - We present the first results of a new medical instrument for ambulatory EEG
      monitoring (Cerebral Holter) used in Brazil since 1994. One hundred high quality
      recordings from epileptic and non-epileptic patients allowed the development of a
      systematic analysis of EEG and ECG signals, and classification of epileptic
      discharges during daily life activities.

PMID- 10412522
TI  - [Prevalence of "bayonet finger": a manifestation of attention-deficit
      hyperactivity disorder among male alcoholics and psychotics].
AB  - The prevalence of Bajonettfinger, a semiologic sign of attention-deficit disorder
      hyperactivity (ADHD), was determined in male alcoholics and psychotics from a
      psychiatric hospital. A control group was taken from the hospital staff. The
      morphologic alteration was observed in 35% of the 200 alcoholics, 45% of the 100
      psychotics and 16% of the 50 controls. The difference in prevalence of the sign
      between the alcoholics and psychotics groups was not significant but the
      differences between any of these groups and the controls was significant. The
      observations suggested that: (1) ADHD would be present, as judged through its
      high correlation with the prevalence of bajonettfinger, in approximately 1/3 of
      the alcoholics and 1/2 of the psychotics; (2) ADHD would be a vulnerability
      factor for alcoholism; (3) adolescents with bajonettfinger should deserve special
      preventive attention with respect to alcoholism.

PMID- 10412523
TI  - [Cognitive performance in patients with surgically treated cerebral aneurysms].
AB  - Twenty five patients with cerebral aneurysms submitted to surgery were evaluated
      with cognitive tests to quantify late disorders in language, praxis, orientation,
      logics, comprehension, memory, depression, dementia and visual gnosis. Results
      were correlated with age, Hunt-Hess scale, blood at CT (Fisher), angiographic
      vasospasm (George), side, site, and size of aneurysm. Delayed cognitive disorder
      was absent in 8 (32%), slight in 5 (20%), moderate in 6 (24%) and severe in 6
      (24%). Logics was more affected with 7 severe and moderate patients (28%), praxis
      was similarly affected in 6 (24%), orientation in 5 (20%), language and memory in
      4 (16%); visual gnosis abnormalities, dementia and depression were rarely seen.
      Patients aged 25-50 years had best cognitive results with sequels absent or
      slight in 9 patients (75%). Aneurysms of right posterior communicating artery had
      cognitive sequels absent or slight in 5 (71.42%), right medium cerebral artery in
      2 (66.66%). Aneurysms of left medium cerebral artery had the worse results with
      severe and moderate disabilities in 5 patients (71.42%). Delayed post operative
      cognitive results in patients operated with cerebral aneurysms are directly
      related to Hunt-Hess scale, amount of blood at CT, angiographic vasospasm and
      site of the aneurysm.

PMID- 10412524
TI  - [Chronic post-traumatic headache after mild head injuries].
AB  - Current evidence indicates that chronic post-traumatic headache (cPTH) has
      organic causes. Nevertheless, these patients are considered as neurotics or
      malingering by health professionals, mainly if the headache originates from mild
      head injuries (MHI). Our aim was to identify the features of cPTH after MHI. We
      studied 27 consecutive patients fulfilling the criteria established for cPTH and
      MHI. Headache began on the same day of the trauma in 51.8% of patients. The
      clinical features allowed the following diagnosis: migraine (70.3%); tension type
      headache (51.8%); cervicogenic headache (11.1%). Concomitance of migraine and
      tension type headache was found in 29.6%. Thirty three percent of employees, 40%
      of housewives and 50% of students in our series referred prejudice in their
      productive activities. However, only three patients (11.1%) were claiming for
      compensation. The lack of potential gain and the uniformity of the clinical
      presentation are suggestive that the cPTH has an organic cause.

PMID- 10412525
TI  - [Oligodendroglioma: a pathological and clinical study of 15 cases].
AB  - Oligodendrogliomas account for 4-5% of primary central nervous system tumours
      with a slow and infiltrative growth. We report the clinical and pathological
      findings of 15 cases of oligodendrogliomas. Eight patients were males and 7 were
      females. The ages ranged between 17 and 66 years, with a mean of 39.73 years. The
      symptoms reflected the growth and topography of the tumours; migraine (60%) and
      seizures (60%) were the most frequent symptoms. Frontal (n = 6), parietal (n =
      2), temporal (n = 1) and occipital (n = 1) lobes were affected. Five patients
      undergone total resection of the tumor and 10 were submitted to partial
      resection, from which 3 received adjuvant radiotherapy, 1 adjuvant chemotherapy
      and 1 chemotherapy and radiotherapy. The overall recurrence rate was 60% for a 32
      month follow up. Five recurrences were observed in patients submitted only to the
      surgical treatment and 4 in which adjuvant radio or chemotherapy were performed.
      These results are similar with the literature and may contribute to further
      understanding the biological behavior of these rare tumours.

PMID- 10412526
TI  - [Craniopharyngioma: clinical, epidemiological and pathological findings in 25
      cases].
AB  - We report the clinical and pathological findings of 25 cases of
      craniopharyngiomas. Fourteen patients were males and 11 were females. The ages
      ranged between 3 and 64 years, with a mean of 30.52 years. The symptoms reflected
      the growth and topography of the tumours; visual disorders (72%), headache (68%),
      vomits (40%) and papilledema (24%) were the most frequent symptoms. Twelve cases
      were suprasellar; 10 tumours arose from sellar region, from which 8 presented
      suprasellar extension; frontal lobe (n = 2) and ponto cererebellar angle (n = 1)
      were also affected. Eleven patients undergone total resection of the tumor and 14
      were submitted to partial resection, from which 1 received adjuvant chemotherapy.
      The overall recurrence rate was 48%. Eight recurrences were observed in the
      patients submitted to partial resection and 4 in which total resection were
      performed. These results are similar with the literature, corroborating to the
      extension of residual tumour after the surgical resection as the main prognostic
      factor for this neoplasm.

PMID- 10412527
TI  - [Ependymomas: Clinical, epidemiological and clinico-pathological findings of 22
      cases].
AB  - Ependymomas are composed of neoplastic ependymal cells, affecting mainly children
      and young adults. We report the clinical and pathological findings of 22 cases of
      ependymomas. Fourteen patients were males and 8 were females. The ages ranged
      between 1 and 58 years, with a mean of 24.63 years. The symptoms reflected the
      growth and topography of the tumours; muscle weakness (59.1%), gait disorders
      (36.3%), sensitive disorders (36.3%), hyperreflexia and intracranial hypertension
      syndrome were the most frequent symptoms. Ten tumours affected the medulla, 7 the
      cerebral hemispheres, 2 the cerebral ventricles and 1 brain stem. Seven patients
      were submitted total resection of the tumor, from which one received adjuvant
      radiotherapy. 15 other patients were submitted to partial resection; from which 4
      received adjuvant radiotherapy, 3 adjuvant chemotherapy and 1 chemotherapy and
      radiotherapy. The recurrence rate was 18.2%. These results are similar with the
      literature and may contribute to further understanding the biological behavior of
      these tumours.

PMID- 10412528
TI  - [Isaacs' syndrome. Report of three cases].
AB  - We report two females, and one male with Isaacs' syndrome. The patients presented
      with clinical myokymia activity, muscle cramps, delayed relaxation, and muscle
      hypertrophy and increased sweating. Needle electromyography in several muscles
      showed generalized continuous motor unit discharges, myokymic discharges, and
      normal nerve conduction studies. Muscle biopsy showed type two fiber atrophy.
      Treatment with carbamazepine was effective in two cases and prednisone in one.

PMID- 10412529
TI  - Pilonidal cyst on the vault. Case report.
AB  - Pilonidal cysts and sinuses are described as dermoid cysts which contain
      follicles of hairs and sebaceous glands. They clinically present as a classic
      case of inflammation which comes with pain, local infection and redness. The
      origin of pilonidal disease remains controverse. There are many hypothesis as
      lack of hygiene on the affected area and a penetration and growth of a hair in
      the subcutaneous tissue caused by constant friction or direct trauma on the
      damaged area. The option for clinical treatment is very frequent. However, taking
      into consideration the incidence and the possibility of recidive, surgical
      treatment is presently recommended. Complications include cellulitis and abscess
      formation. Pilonidal cysts are mostly found on the sacral region. In the
      literature is found description of pilonidal cysts on the penis, interdigital
      region on the hands as well as on the cervical region. We present a case of
      pilonidal cyst located on the vault biparietal region, without malignant
      degeneration.

PMID- 10412530
TI  - Amyotrophic lateral sclerosis with dementia. Case report.
AB  - A patient is described in whom a profound and rapidly progressive dementia
      occurred in association with clinical features of amyotrophic lateral sclerosis.
      A magnetic resonance imaging showed signs of frontal and especially left temporal
      atrophy. The pattern of dementia indicated impaired frontotemporal lobe
      functions, evidenced by reduced tracer uptake in the frontotemporal lobes on
      brain single photon emission computed tomography. Neuropathological examination
      in this patient revealed mild frontotemporal atrophy with spongiform changes and
      neuronal loss affecting mainly layers II and III of the frontotemporal cortices.
      There was atrophy of the hypoglossal nuclei. The spinal cord changes were
      consistent with motor neuron disease. The patient showed an irreversible and
      progressive course. A review of the relevant literature was made.

PMID- 10412531
TI  - Syringohydromyelia or HTLV-I-associated myelopathy/tropical spastic paraparesis.
      A diagnostic challenge. Case report.
AB  - Human T-cell lymphotropic virus type I (HTLV-I) associated myelopathy/tropical
      spastic paraparesis (HAM/TSP) is the most common chronic myelopathy in Brazil. We
      present the case of a 53 year old man that fulfilled the diagnostic criteria for
      HAM/TSP but had at the magnetic resonance imaging (MRI) of the spinal cord
      evidences of syringohydromyelia at the C6-C7 and D2-D7 levels along with Chiari
      type I malformation. The clinical picture was more typical of HAM/TSP than of
      syringohydromyelia, which was probably asymptomatic. The present case clearly
      demonstrates that serology and neuroimaging should be always used together. We
      conclude that, specially in places where HTLV-I is endemic, every patient with a
      spastic paraparesis, even with a radiological picture suggestive of a structural
      spinal cord lesion, should have a screening test for HTLV-I. The clinical picture
      must dictate the final direction of the diagnosis.

PMID- 10412532
TI  - Chronic Aspergillus sp. meningitis successfully treated with fluconazole. Case
      report.
AB  - We a case of chronic Aspergillus sp. meningitis in a healthy 43-year-old woman
      successfully treated with fluconazole given orally (300 ms/day). The diagnosis
      was made by detection of anti-aspergillus antibodies and positive culture to
      Aspergillus sp. in the cerebrospinal fluid.

PMID- 10412533
TI  - Median nerve SEP after a high medullary lesion. Preserved N18 and absent P14
      components. Case report.
AB  - Median nerve SEPs recorded from a patient with a high medullary lesion are
      described. The lesion involved the anteromedial and anterolateral right upper
      third of the medulla, as documented by MRI. Forty one days after the lesion, left
      median nerve SEP showed preserved N18 and absent P14 and N20 components;
      stimulation of the right median nerve evoked normal responses. These findings
      agree with the proposition that low medullary levels are involved in the
      generation of the N18 component of the median nerve SEP.

PMID- 10412534
TI  - [Giant cervical disc herniation: case report].
AB  - Disc herniation occurs commonly in neurosurgery. The Neurosurgery Department of
      Santa Casa de Belo Horizonte in 1997 had 17% of all surgeries for disc herniation
      and 7% of those were of cervical spine. We report a giant cervical disc
      herniation C4-C5 in a 72-year-old male patient, presenting with tetraparesis,
      sensory loss below C5 and urinary retention, who underwent microsurgical anterior
      decompression and internal fixation with iliac bone graft without plate fixation
      according Cloward. The patient had a satisfactory outcome. We propose a new
      classification for disc herniation according the dural compression: small (until
      12%), medium (12 to 25%), big (25 to 50%) and giant (more than 50%).

PMID- 10412535
TI  - [Intramedullary cysticercosis: case report].
AB  - Cysticercosis is the most ordinary parasitary disease involving the nervous
      system. The involvement of the spine is rare, ranging from 0.7% to 5.8%, and the
      intramedullary incidence is rather uncommon. We report the case of a 52-year-old
      female patient with intramedullary cysticercosis at the C4-C5 level, treated at
      the Neurology and Neurosurgery Service of Santa Casa de Belo Horizonte. The
      patient was operated with the complete exeresis of the lesion and had a good
      outcome. Forty-five cases of intramedullary cysticercosis were found in the
      literature review. We conclude that although it is a rare pathology,
      intramedullary cysticercosis should be included in the differential diagnosis of
      intramedullary lesions, mainly in cases of patients with previous diagnosis for
      neurocysticercosis and also of those who live in endemic areas.

PMID- 10412537
TI  - [Internal carotid bilateral occlusion, meningovascular syphilis and AIDS: case
      report].
AB  - We report a case of bilateral occlusion of internal carotid arteries, presenting
      with right hemiparesis and hypoesthesia, associated to meningovascular syphilis
      in a patient with AIDS. CT scan showed few small hypodense lesions, with a
      predominance on the left side, and the angiography showed bilateral occlusion of
      the carotid arteries. The association between syphilis and AIDS is not unusual,
      but the paucity of symptoms, probably due to a slow and gradual occlusion is not
      commonly reported.

PMID- 10412536
TI  - [High intensity signal in basal ganglia on T1 weighted images: case report in
      Manson's Schistosomiasis with portal systemic encephalopathy].
AB  - We report a case of mansonic schistosomiasis with portal systemic encephalopathy
      associated with a high intensity signal in basal ganglia on TI weighted images
      due to deposition of manganese in tissues related with portal-systemic collateral
      vessels. A bibliographic review was done focusing the magnetic resonance
      findings. To the best of our knowledge, these signal changes have not yet been
      associated with Manson's schistosomiasis.

PMID- 10412538
TI  - [Critical illness polyneuropathy: case report].
AB  - The critical illness polyneuropathy has an acute onset and an axonal
      predominantly motor nature. It occurs in sepsis or in multiple organ failure
      usually requiring mechanical ventilation in critical care units.
      Electroneuromyography corroborates the diagnosis. Usually it courses
      satisfactorily. We report on a 35-year-old female patient who, after a permanence
      in a critical care unit due to sepsis and removal of a dead phetus, developed
      tetraparesis. She had an important improvement in four months. Electromyography
      showed reduction of amplitude of motor and sensory action potentials, positive
      waves and fibrillations. The sural nerve biopsy showed axonmyelinic neuropathy.
      These findings are consistent with those in literature and we believe they
      support the diagnosis of critical illness neuropathy.

PMID- 10412539
TI  - [U-shaped chisel to cut the orbital roof: technical note].
AB  - We describe a new U-shaped chisel whose cutting edge allows for a precise and
      safer cutting of the orbital roof in the frontoorbital approach.

PMID- 10412540
TI  - [Ataxic instable Alajouanine-Akerman's hand: recovery of a semiologic sign].
AB  - It is aimed to recover, considering its historical value, a semiological sign
      described in 1931 by an eminent neurologist of Rio de Janeiro, together with a
      master of the French neurology. In the article by Alajouanine and Akerman, named
      "Attitude of the hand in an astereognostic monobrachial crisis of multiple
      esclerosis", a semiologic alteration was described which was characterized by "an
      instability in the attitude of the fingers, which is observed mainly with the
      hand extended in the attitude of swearing". This attitude of hand worsened a lot
      with the eyes closed and was accompanied by sensory ataxia, astereognosis, and
      impaired deep sensation in the affected member. From the original article, it is
      possible to consider at the present time the described semiologic alteration as a
      form of pseudoathetosis localized in the hand.

PMID- 10412541
TI  - [New dopaminergic agonists].
AB  - We present a brief review of the literature about dopaminergic agonists. We
      report the five known dopaminergic receptors, where they are located, the
      advantages and disadvantages of the employment in parkinsonian patients. The
      dopaminergic agonists were introduced to control the limitations of levodopa
      increasing the therapeutic window. We analyse the pharmacocynetic efficacy and
      the side effects of cabergoline, ropinirole and pramipexole.

PMID- 10412542
TI  - Centronuclear myopathy: subgroup characterized by tissue mosaicism.

PMID- 10412543
TI  - Trends on cerebrospinal fluid investigation: an overview.

PMID- 10412544
TI  - Two research paths for probing the roles of oxygen in metabolic regulation.
AB  - Tissues such as skeletal and cardiac muscles must sustain very large-scale
      changes in ATP turnover rate during equally large changes in work. In many
      skeletal muscles these changes can exceed 100-fold. Examination of a number of
      cell and whole-organism level systems identifies ATP concentration as a key
      parameter of the interior milieu that is nearly universally 'homeostatic'; it is
      common to observe no change in ATP concentration even while change in its
      turnover rate can increase or decrease by two orders of magnitude or more. A
      large number of other intermediates of cellular metabolism are also regulated
      within narrow concentration ranges, but none seemingly as precisely as is [ATP].
      In fact, the only other metabolite in aerobic energy metabolism that is seemingly
      as 'homeostatic' is oxygen--at least in working muscles where myoglobin serves to
      buffer oxygen concentrations at stable and constant values at work rates up to
      the aerobic maximum. In contrast to intracellular oxygen concentration, a 1:1
      relationship between oxygen delivery and metabolic rate is observed over
      biologically realistic and large-magnitude changes in work. The central
      regulatory question is how the oxygen delivery signal is transmitted to the
      intracellular metabolic machinery. Traditional explanations assume diffusion as
      the dominant mechanism, while proponents of an ultrastructurally dominated view
      of the cell assume an intracellular perfusion system to account for the data
      which have been most perplexing to metabolic biochemistry so far: the striking
      lack of correlation between changes in pathway reaction rates and changes in
      concentrations of pathway substrates, including oxygen and pathway intermediates.

PMID- 10412545
TI  - Partially folded intermediates during trypsinogen denaturation.
AB  - The equilibrium unfolding of bovine trypsinogen was studied by circular
      dichroism, differential spectra and size exclusion HPLC. The change in free
      energy of denaturation was delta GH2O = 6.99 +/- 1.40 kcal/mol for guanidine
      hydrochloride and delta GH2O = 6.37 +/- 0.57 kcal/mol for urea. Satisfactory fits
      of equilibrium unfolding transitions required a three-state model involving an
      intermediate in addition to the native and unfolded forms. Size exclusion HPLC
      allowed the detection of an intermediate population of trypsinogen whose Stokes
      radii varied from 24.1 +/- 0.4 A to 26.0 +/- 0.3 A for 1.5 M and 2.5 M guanidine
      hydrochloride, respectively. During urea denaturation, the range of Stokes radii
      varied from 23.9 +/- 0.3 A to 25.7 +/- 0.6 A for 4.0 M and 6.0 M urea,
      respectively. Maximal intrinsic fluorescence was observed at about 3.8 M urea
      with 8-aniline-1-naphthalene sulfonate (ANS) binding. These experimental data
      indicate that the unfolding of bovine trypsinogen is not a simple transition and
      suggest that the equilibrium intermediate population comprises one intermediate
      that may be characterized as a molten globule. To obtain further insight by
      studying intermediates representing different stages of unfolding, we hope to
      gain a better understanding of the complex interrelations between protein
      conformation and energetics.

PMID- 10412546
TI  - The erythrocyte cytoskeleton protein 4.2 is not demonstrable in several mammalian
      species.
AB  - Erythrocyte membrane proteins from 44 representative mammals were studied.
      Protein 4.2 was not detected in guinea pigs (Cavia porcellus) (N = 14), Southern
      Brazilian swamp large rats (Myocastor coypus) (N = 2), cutias (Dasyprocta sp) (N
      = 4), and horses (Equus caballus) (N = 13). These animals also presented high
      ankyrin concentrations except for the horse which did not exhibit a sharp band,
      although minor components located between proteins 2 and 3 could account for the
      ankyrin family. The rodents studied did present band 6, which was not detectable
      in other common rodents such as white rats (Rattus norvegicus) (N = 9) and mice
      (Mus musculus) (N = 12). Since the absence of protein 4.2 does not disrupt the
      cytoskeleton membrane, we suggest that it is not an essential protein. Its
      absence may be compensated physiologically by the higher ankyrin concentration
      observed.

PMID- 10412547
TI  - Lipid peroxidation, antioxidant enzymes and glutathione levels in human
      erythrocytes exposed to colloidal iron hydroxide in vitro.
AB  - The free form of the iron ion is one of the strongest oxidizing agents in the
      cellular environment. The effect of iron at different concentrations (0, 1, 5,
      10, 50, and 100 microM Fe3+) on the normal human red blood cell (RBC) antioxidant
      system was evaluated in vitro by measuring total (GSH) and oxidized (GSSG)
      glutathione levels, and superoxide dismutase (SOD), catalase, glutathione
      peroxidase (GSH-Px) and reductase (GSH-Rd) activities. Membrane lipid
      peroxidation was assessed by measuring thiobarbituric acid reactive substance
      (TBARS). The RBC were incubated with colloidal iron hydroxide and phosphate
      buffered saline, pH 7.45, at 37 degrees C, for 60 min. For each assay, the
      results for the control group were: a) GSH = 3.52 +/- 0.27 microM/g Hb; b) GSSG =
      0.17 +/- 0.03 microM/g Hb; c) GSH-Px = 19.60 +/- 1.96 IU/g Hb; d) GSH-Rd = 3.13
      +/- 0.17 IU/g Hb; e) catalase = 394.9 +/- 22.8 IU/g Hb; f) SOD = 5981 +/- 375
      IU/g Hb. The addition of 1 to 100 microM Fe3+ had no effect on the parameters
      analyzed. No change in TBARS levels was detected at any of the iron
      concentrations studied. Oxidative stress, measured by GSH kinetics over time,
      occurs when the RBC are incubated with colloidal iron hydroxide at concentrations
      higher than 10 microM of Fe3+. Overall, these results show that the intact human
      RBC is prone to oxidative stress when exposed to Fe3+ and that the RBC has a
      potent antioxidant system that can minimize the potential damage caused by acute
      exposure to a colloidal iron hydroxide in vitro.

PMID- 10412548
TI  - Fetal hemoglobin levels are related to metabolic control in diabetic subjects.
AB  - We have investigated the relationship between fetal hemoglobin (HbF) levels and
      metabolic control in subjects with insulin-dependent (N = 79) and non-insulin
      dependent diabetes mellitus (N = 242). HbF and hemoglobin A1c (HbA1c) levels were
      increased in subjects with type 1 and type 2 diabetes as compared to levels in
      nondiabetic individuals (P < 0.0001), and were significantly higher in type 1
      than in type 2 diabetes subjects. Lower levels of HbA1c and HbF were observed in
      type 2 diabetes subjects treated by diet, intermediate levels in those treated
      with oral hypoglycemic agents, and higher levels in those treated with insulin.
      HbF and HbA1c levels were correlated in type 1 diabetes (R2 = 0.57, P < 0.0001)
      and type 2 diabetes (R2 = 0.58, P < 0.0001) subjects. Following intense
      treatment, twelve diabetic patients showed significant improvement both in HbA1c
      and HbF values. We conclude that increased HbF levels reflect poor metabolic
      control in subjects with diabetes mellitus.

PMID- 10412549
TI  - Reference values for lung function tests. I. Static volumes.
AB  - Static lung volume (LV) measurements have a number of clinical and research
      applications; however, no previous studies have provided reference values for
      such tests using a healthy sample of the adult Brazilian population. With this as
      our main purpose, we prospectively evaluated 100 non-smoking subjects (50 males
      and 50 females), 20 to 80 years old, randomly selected from more than 8,000
      individuals. Gender-specific linear prediction equations were developed by
      multiple regression analysis with total lung capacity (TLC), functional residual
      capacity (FRC), residual volume (RV), RV/TLC ratio and inspiratory capacity (IC)
      as dependent variables, and with age, height, weight, lean body mass and indexes
      of physical fitness as independent ones. Simpler demographic and anthropometric
      variables were as useful as more complex measurements in predicting LV values,
      independent of gender and age (R2 values ranging from 0.49 to 0.78, P < 0.001).
      Interestingly, prediction equations from North American and European studies
      overestimated the LV at low volumes and underestimated them at high volumes (P <
      0.05). Our results, therefore, provide a more appropriate frame of reference to
      evaluate the normalcy of static lung volume values in Brazilian males and females
      aged 20 to 80 years.

PMID- 10412550
TI  - Reference values for lung function tests. II. Maximal respiratory pressures and
      voluntary ventilation.
AB  - The strength of the respiratory muscles can be evaluated from static measurements
      (maximal inspiratory and expiratory pressures, MIP and MEP) or inferred from
      dynamic maneuvers (maximal voluntary ventilation, MVV). Although these data could
      be suitable for a number of clinical and research applications, no previous
      studies have provided reference values for such tests using a healthy, randomly
      selected sample of the adult Brazilian population. With this main purpose, we
      prospectively evaluated 100 non-smoking subjects (50 males and 50 females), 20 to
      80 years old, selected from more than 8,000 individuals. Gender-specific linear
      prediction equations for MIP, MEP and MVV were developed by multiple regression
      analysis: age and, secondarily, anthropometric measurements explained up to 56%
      of the variability of the dependent variables. The most cited previous studies
      using either Caucasian or non-Caucasian samples systematically underestimated the
      observed values of MIP (P < 0.05). Interestingly, the self-reported level of
      regular physical activity and maximum aerobic power correlates strongly with both
      respiratory and peripheral muscular strength (knee extensor peak torque) (P <
      0.01). Our results, therefore, provide a new frame of reference to evaluate the
      normalcy of some useful indexes of respiratory muscle strength in Brazilian males
      and females aged 20 to 80.

PMID- 10412551
TI  - Reference values for lung function tests. III. Carbon monoxide diffusing capacity
      (transfer factor).
AB  - Carbon monoxide diffusing capacity (DLCO) or transfer factor (TLCO) is a
      particularly useful test of the appropriateness of gas exchange across the lung
      alveolocapillary membrane. With the purpose of establishing predictive equations
      for DLCO using a non-smoking sample of the adult Brazilian population, we
      prospectively evaluated 100 subjects (50 males and 50 females aged 20 to 80
      years), randomly selected from more than 8,000 individuals. Gender-specific
      linear prediction equations were developed by multiple regression analysis with
      single breath (SB) absolute and volume-corrected (VA) DLCO values as dependent
      variables. In the prediction equations, age (years) and height (cm) had opposite
      effects on DLCOSB (ml min-1 mmHg-1), independent of gender (-0.13 (age) + 0.32
      (height) - 13.07 in males and -0.075 (age) + 0.18 (height) + 0.20 in females). On
      the other hand, height had a positive effect on DLCOSB but a negative one on
      DLCOSB/ VA (P < 0.01). We found that the predictive values from the most cited
      studies using predominantly Caucasian samples were significantly different from
      the actually measured values (P < 0.05). Furthermore, oxygen uptake at maximal
      exercise (VO2max) correlated highly to DLCOSB (R = 0.71, P < 0.001); this
      variable, however, did not maintain an independent role to explain the VO2max
      variability in the multiple regression analysis (P > 0.05). Our results therefore
      provide an original frame of reference for either DLCOSB or DLCOSB/VA in
      Brazilian males and females aged 20 to 80 years, obtained from the standardized
      single-breath technique.

PMID- 10412552
TI  - The Lebanese mutation as an important cause of familial hypercholesterolemia in
      Brazil.
AB  - Familial hypercholesterolemia (FH) is a common autosomal disorder that affects
      about one in 500 individuals in most Western populations and is caused by a
      defect in the low-density-lipoprotein receptor (LDLr) gene. In this report we
      determined the molecular basis of FH in 59 patients from 31 unrelated Brazilian
      families. All patients were screened for the Lebanese mutation, gross
      abnormalities of the LDLr gene, and the point mutation in the codon 3500 of the
      apolipoprotein B-100 gene. None of the 59 patients presented the apoB-3500
      mutation, suggesting that familial defective ApoB-100 (FDB) is not a major cause
      of inherited hypercholesterolemia in Brazil. A novel 4-kb deletion in the LDLr
      gene, spanning from intron 12 to intron 14, was characterized in one family. Both
      5' and 3' breakpoint regions were located within Alu repetitive sequences, which
      are probably involved in the crossing over that generated this rearrangement. The
      Lebanese mutation was detected in 9 of the 31 families, always associated with
      Arab ancestry. Two different LDLr gene haplotypes were demonstrated in
      association with the Lebanese mutation. Our results suggest the importance of the
      Lebanese mutation as a cause of FH in Brazil and by analogy the same feature may
      be expected in other countries with a large Arab population, such as North
      American and Western European countries.

PMID- 10412553
TI  - A liquid phase blocking ELISA for the detection of antibodies against infectious
      bronchitis virus.
AB  - A liquid phase blocking ELISA (LPB-ELISA) was developed for the detection and
      measurement of antibodies against infectious bronchitis virus (IBV). The purified
      and nonpurified virus used as antigen, the capture and detector antibodies, and
      the chicken hyperimmune sera were prepared and standardized for this purpose. A
      total of 156 sera from vaccinated and 100 from specific pathogen-free chickens
      with no recorded contact with the virus were tested. The respective serum titers
      obtained in the serum neutralization test (SNT) were compared with those obtained
      in the LPB-ELISA. There was a high correlation (r2 = 0.8926) between the two
      tests. The LPB-ELISA represents a single test suitable for the rapid detection of
      antibodies against bronchitis virus in chicken sera, with good sensitivity (88%),
      specificity (100%) and agreement (95.31%).

PMID- 10412554
TI  - Administration of interferon-g to pregnant rats reverses the depressed adjuvant
      induced arthritis of their chronically Trypanosoma cruzi-infected offspring.
AB  - We demonstrated that administration of interferon gamma (IFN-gamma) to the inbred
      "I" strain of pregnant rats conferred partial resistance on their offspring to
      challenge with Trypanosoma cruzi. We now examine if this intervention also
      modifies the reportedly immunodepressed cellular responses which occur during
      chronic infection. Offspring were born to mothers undergoing one of the following
      procedures during gestation: subcutaneous injections of recombinant rat IFN
      gamma, 50,000 IU/rat, five times/week for 3 weeks, which was started on the day
      of mating (IFN-Mo); infection with 10(6) trypomastigotes of T. cruzi at 7, 14,
      and 21 days after mating plus IFN-gamma treatment as given to the former group
      (TcIFN-Mo); the same protocol except that physiological saline was injected
      instead of IFN-gamma (Te-Mo); injection of physiological saline only (control
      Mo). All offspring groups (N = 8-10/group) were infected at weaning and were
      assessed 90 days later for their adjuvant-induced arthritic response or levels of
      major T cell subsets in spleen and lymph nodes. TcIFN-Mo and IFN-Mo offspring
      showed a reestablished arthritic response, which remained within the range seen
      in controls. Immunolabeling studies on parallel groups of 90-day-infected
      offspring showed that the inverse CD4/CD8 cell ratio that is usually seen in
      lymphoid organs from these chronically infected rats (median 0.61) appeared to
      have recovered in the TcIFN-Mo and IFN-Mo groups (median 1.66 and 1.78,
      respectively) and was not different from uninfected controls (1.96). These
      studies indicate that early stimulation with IFN-gamma is able to reverse the
      immunosuppressive state that is usually present during the chronic period of the
      experimental infection.

PMID- 10412555
TI  - Effects of aluminum sulfate on delta-aminolevulinate dehydratase from kidney,
      brain, and liver of adult mice.
AB  - The purpose of the present study was to investigate the in vitro and in vivo
      effects of aluminum sulfate on delta-aminolevulinic acid dehydratase (ALA-D)
      activity from the brain, liver and kidney of adult mice (Swiss albine). In vitro
      experiments showed that the aluminum sulfate concentration needed to inhibit the
      enzyme activity was 1.0-5.0 mM (N = 3) in brain, 4.0-5.0 mM (N = 3) in liver and
      0.0-5.0 mM (N = 3) in kidney. The in vivo experiments were performed on three
      groups for one month: 1) control animals (N = 8); 2) animals treated with 1 g%
      (34 mM) sodium citrate (N = 8) and 3) animals treated with 1 g% (34 mM) sodium
      citrate plus 3.3 g% (49.5 mM) aluminum sulfate (N = 8). Exposure to aluminum
      sulfate in drinking water inhibited ALA-D activity in kidney (23.3 +/- 3.7%, mean
      +/- SEM, P < 0.05 compared to control), but enhanced it in liver (31.2 +/- 15.0%,
      mean +/- SEM, P < 0.05). The concentrations of aluminum in the brain, liver and
      kidney of adult mice were determined by graphite furnace atomic absorption
      spectrometry. The aluminum concentrations increased significantly in the liver
      (527 +/- 3.9%, mean +/- SEM, P < 0.05) and kidney (283 +/- 1.7%, mean +/- SEM, P
      < 0.05) but did not change in the brain of aluminum-exposed mice. One of the most
      important and striking observations was the increase in hepatic aluminum
      concentration in the mice treated only with 1 g% sodium citrate (34 mM) (217 +/-
      1.5%, mean +/- SEM, P < 0.05 compared to control). These results show that
      aluminum interferes with delta-aminolevulinate dehydratase activity in vitro and
      in vivo. The accumulation of this element was in the order: liver > kidney >
      brain. Furthermore, aluminum had only inhibitory properties in vitro, while in
      vivo it inhibited or stimulated the enzyme depending on the organ studied.

PMID- 10412556
TI  - An optically coupled power stimulus isolation unit with high voltage and fast
      rise time output.
AB  - Recent technological developments have created new devices that could improve and
      simplify the construction of stimulus isolators. HEXFET transistors can switch
      large currents and hundreds of volts in nanoseconds. The newer opto-isolators can
      give a pulse rise time of a few nanoseconds, with output compatible with MOSFET
      devices, in which delays are reduced to nanoseconds. Integrated DC/DC converters
      are now available. Using these new resources we developed a new electrical
      stimulus isolator circuit with selectable constant-current and constant-voltage
      modes, which are precise and easy to construct. The circuit works like a
      regulated power supply in both modes with output switched to zero or to free mode
      through an opto-isolator device. The isolator analyses showed good practical
      performance. The output to ground resistance was 10(11) ohms and capacitance 35
      picofarads. The rise time and fall time were identical (5 microseconds) and
      constant. The selectable voltage or current output mode made it very convenient
      to use. The current mode, with higher output resistance values in low current
      ranges, permits intracellular stimulation even with tip resistances close to 100
      megaohms. The high compliance of 200 V guarantees the value of the current
      stimulus. The very low output resistance in the voltage mode made the device
      highly suitable for extracellular stimulation with low impedance electrodes. Most
      importantly, these characteristics were achieved with a circuit that was easy to
      build and modify and assembled with components available in Brazil.

PMID- 10412557
TI  - Developed pressure data may provide misinformation when used alone to evaluate
      systolic function in isovolumetric left ventricle preparations.
AB  - We report data showing that developed pressure (DPmax) may lead to opposite
      conclusion with respect to maximal developed circumferential wall stress (sigma
      max) when used to assess contractile function in left ventricle isovolumic
      preparations. Isovolumetric left ventricle preparations of rats with cardiac
      hypertrophy (H; N = 10) induced by isoproterenol administration showed higher
      DPmax (174 +/- 14 mmHg) than control (C; N = 8) animals (155 +/- 12 mmHg) or rats
      with regression (R; N = 8) of hypertrophy (144 +/- 11 mmHg). In contrast, the
      estimated sigma max for C (145 +/- 26 kdynes/cm2) and R (133 +/- 17 kdynes/cm2)
      was higher than for H (110 +/- 13 kdynes/cm2). According to Laplace's law, the
      opposite results of DPmax and sigma max may depend on the increased mass/volume
      left ventricle ratio of the hypertrophied hearts, which favored pressure
      generation. These results clearly show that DPmax should be used with caution to
      analyze systolic function.

PMID- 10412558
TI  - Role of bradykinin in postprandial hypotension in humans.
AB  - A transient significant decrease in mean arterial blood pressure (MAP) from 107
      +/- 3 to 98 +/- 3 mmHg (P < 0.05) was observed in elderly (59-69 years of age),
      healthy volunteers 25-30 min following ingestion of a test meal. In young
      volunteers (22-34 years of age), a postprandial decrease of MAP from 88 +/- 3 to
      83 +/- 4 mmHg was also noted but it was not statistically significant. A 40%
      decrease in bradykinin (BK) content of circulatory high molecular weight
      kininogen had previously been observed in human subjects given the same test
      meal. We presently demonstrate by specific ELISA that the stable pentapeptide
      metabolite (1-5 BK) of BK increases from 2.5 +/- 1.0 to 11.0 +/- 2.5 pg/ml plasma
      (P < 0.05) in elderly volunteers and from 2.0 +/- 1.0 to 10.3 +/- 3.2 pg/ml
      plasma (P < 0.05) in young volunteers 3 h following food intake. This result
      suggests that ingestion of food stimulates BK release from kininogen in normal
      man. Postprandial splanchnic vasodilatation, demonstrated by a decrease of plasma
      half-life of intravenously administered indocyanine green (ICG), a marker of
      mesenteric blood flow to the liver, from 4.4 +/- 0.4 to 3.0 +/- 0.1 min (P <
      0.05) in young volunteers and from 5.2 +/- 1.0 to 4.0 +/- 0.5 min (P < 0.05) in
      elderly volunteers, accompanied BK release. The participation of BK in this
      response was investigated in subjects given the BK-potentiating drug captopril
      prior to food intake. Postprandial decreases of ICG half-lives were not changed
      by this treatment in either young or elderly subjects, a result which may
      indicate that BK released following food intake plays no role in postprandial
      splanchnic vasodilatation in normal man.

PMID- 10412559
TI  - Extracellular matrix: understanding the complexity.

PMID- 10412560
TI  - Integrins in vascular development.
AB  - Many growth factors and their protein kinase receptors play a role in regulating
      vascular development. In addition, cell adhesion molecules, such as integrins and
      their ligands in the extracellular matrix, play important roles in the adhesion,
      migration, proliferation, survival and differentiation of the cells that form the
      vasculature. Some integrins are known to be regulated by angiogenic growth
      factors and studies with inhibitors of integrin functions and using strains of
      mice lacking specific integrins clearly implicate some of these molecules in
      vasculogenesis and angiogenesis. However, the data are incomplete and sometimes
      discordant and it is unclear how angiogenic growth factors and integrin-mediated
      adhesive events cooperate in the diverse cell biological processes involved in
      forming the vasculature. Consideration of the results suggests working hypotheses
      and raises questions for future research directions.

PMID- 10412561
TI  - Leukocyte adhesion--a fundamental process in leukocyte physiology.
AB  - Leukocyte adhesion is of pivotal functional importance. The adhesion involves
      several different adhesion molecules, the most important of which are the
      leukocyte beta 2-integrins (CD11/CD18), the intercellular adhesion molecules, and
      the selectins. We and others have extensively studied the specificity and binding
      sites in the integrins and the intercellular adhesion molecules for their
      receptors and ligands. The integrins have to become activated to exert their
      functions but the possible mechanisms of activation remain poorly understood.
      Importantly, a few novel intercellular adhesion molecules have been recently
      described, which seem to function only in specific tissues. Furthermore, it is
      becoming increasingly apparent that changes in integrins and intercellular
      adhesion molecules are associated with a number of acute and chronic diseases.

PMID- 10412562
TI  - Structure and function of the selectin ligand PSGL-1.
AB  - P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric mucin-like 120-kDa
      glycoprotein on leukocyte surfaces that binds to P- and L-selectin and promotes
      cell adhesion in the inflammatory response. The extreme amino terminal
      extracellular domain of PSGL-1 is critical for these interactions, based on site
      directed mutagenesis, blocking monoclonal antibodies, and biochemical analyses.
      The current hypothesis is that for high affinity interactions with P-selectin,
      PSGL-1 must contain O-glycans with a core-2 branched motif containing the sialyl
      Lewis x antigen (NeuAc alpha 2-->3Gal beta 1-->4[Fuc alpha 1-->3]GlcNAc beta 1-
      >R). In addition, high affinity interactions require the co-expression of
      tyrosine sulfate on tyrosine residues near the critical O-glycan structure. This
      review addresses the biochemical evidence for this hypothesis and the evidence
      that PSGL-1 is an important in vivo ligand for cell adhesion.

PMID- 10412563
TI  - Heparan sulfates and heparins: similar compounds performing the same functions in
      vertebrates and invertebrates?
AB  - The distribution and structure of heparan sulfate and heparin are briefly
      reviewed. Heparan sulfate is a ubiquitous compound of animal cells whose
      structure has been maintained throughout evolution, showing an enormous
      variability regarding the relative amounts of its disaccharide units. Heparin, on
      the other hand, is present only in a few tissues and species of the animal
      kingdom and in the form of granules inside organelles in the cytoplasm of special
      cells. Thus, the distribution as well as the main structural features of the
      molecule, including its main disaccharide unit, have been maintained through
      evolution. These and other studies led to the proposal that heparan sulfate may
      be involved in the cell-cell recognition phenomena and control of cell growth,
      whereas heparin may be involved in defense mechanisms against bacteria and other
      foreign materials. All indications obtained thus far suggest that these molecules
      perform the same functions in vertebrates and invertebrates.

PMID- 10412564
TI  - Heparan sulfate and cell division.
AB  - Heparan sulfate is a component of vertebrate and invertebrate tissues which
      appears during the cytodifferentiation stage of embryonic development. Its
      structure varies according to the tissue and species of origin and is modified
      during neoplastic transformation. Several lines of experimental evidence suggest
      that heparan sulfate plays a role in cellular recognition, cellular adhesion and
      growth control. Heparan sulfate can participate in the process of cell division
      in two distinct ways, either as a positive or negative modulator of cellular
      proliferation, or as a response to a mitogenic stimulus.

PMID- 10412565
TI  - Preparation and purification of Flavobacterium heparinum chondroitinases AC and B
      by hydrophobic interaction chromatography.
AB  - Flavobacterium heparinum is a soil bacterium that produces several
      mucopolysaccharidases such as heparinase, heparitinases I and II, and
      chondroitinases AC, B, C and ABC. The purpose of the present study was to
      optimize the preparation of F. heparinum chondroitinases, which are very useful
      tools for the identification and structural characterization of chondroitin and
      dermatan sulfates. We observed that during the routine procedure for cell
      disruption (ultrasound, 100 kHz, 5 min) some of the chondroitinase B activity was
      lost. Using milder conditions (2 min), most of the chondroitinase B and AC
      protein was solubilized and the enzyme activities were preserved. Tryptic soy
      broth without glucose was the best culture medium both for bacterial growth and
      enzyme induction. Chondroitinases AC and B were separated from each other and
      also from glucuronidases and sulfatases by hydrophobic interaction chromatography
      on HP Phenyl-Sepharose. A rapid method for screening of the column fractions was
      also developed based on the metachromatic shift of the color of dimethylmethylene
      blue.

PMID- 10412566
TI  - Cellular and matrix interactions during the development of T lymphocytes.
AB  - The thymus contains an extensive extracellular matrix. Although thymocytes
      express integrins capable of binding to matrix molecules, the functional
      significance of the matrix for T cell development is uncertain. We have shown
      that the matrix is associated with thymic fibroblasts which are required for the
      CD44+ CD25+ stage of double negative (CD4-8-) thymocyte development. The survival
      of cells at this stage is dependent on IL-7 and we propose that the role of
      fibroblasts is to present, via the matrix, IL-7 to developing T cells.

PMID- 10412567
TI  - Galectin-1, an alternative signal for T cell death, is increased in activated
      macrophages.
AB  - Galectin-1 belongs to an evolutionarily conserved family of animal beta
      galactoside-binding proteins, which exert their functions by crosslinking the
      oligosaccharides of specific glycoconjugate ligands. During the past decade,
      attempts to identify the functional role of galectin-1 suggested participation in
      the regulation of the immune response. Only in the last few years has the
      molecular mechanism involved in these properties been clearly elucidated,
      revealing a critical role for galectin-1 as an alternative signal in the
      generation of T cell death. In the present study we will discuss the latest
      advances in galectin research in the context of the regulation of the immune
      response, not only at the central level but also at the periphery. Moreover, we
      will review the purification, biochemical properties and functional significance
      of a novel galectin-1-like protein from activated rat macrophages, whose
      expression is differentially regulated according to the activation state of the
      cells. The novel role of a carbohydrate-binding protein in the regulation of
      apoptosis is providing a breakthrough in galectin research and extending the
      interface between immunology, glycobiology and clinical medicine.

PMID- 10412568
TI  - The conveyor belt hypothesis for thymocyte migration: participation of adhesion
      and de-adhesion molecules.
AB  - Thymocyte differentiation is the process by which bone marrow-derived precursors
      enter the thymus, proliferate, rearrange the genes and express the corresponding
      T cell receptors, and undergo positive and/or negative selection, ultimately
      yielding mature T cells that will represent the so-called T cell repertoire. This
      process occurs in the context of cell migration, whose cellular and molecular
      basis is still poorly understood. Kinetic studies favor the idea that these cells
      leave the organ in an ordered pattern, as if they were moving on a conveyor belt.
      We have recently proposed that extracellular matrix glycoproteins, such as
      fibronectin, laminin and type IV collagen, among others, produced by non-lymphoid
      cells both in the cortex and in the medulla, would constitute a macromolecular
      arrangement allowing differentiating thymocytes to migrate. Here we discuss the
      participation of both molecules with adhesive and de-adhesive properties in the
      intrathymic T cell migration. Functional experiments demonstrated that galectin
      3, a soluble beta-galactoside-binding lectin secreted by thymic
      microenvironmental cells, is a likely candidate for de-adhesion proteins by
      decreasing thymocyte interaction with the thymic microenvironment.

PMID- 10412569
TI  - A role for angiogenesis in rheumatoid arthritis.
AB  - Rheumatoid arthritis (RA) is a chronic debilitating disease characterized by
      distinct autoimmune, inflammatory and fibrovascular components which lead to
      synovial proliferation and joint destruction. However, existing treatments
      specifically target only autoimmune and inflammatory components despite the fact
      that neovascularization of the inflamed synovium is a hallmark of rheumatoid
      arthritis. Angiogenesis may contribute to synovial growth, leukocyte recruitment
      and tissue remodeling, thus potentiating disease progression. Although no
      therapies currently target angiogenesis, several existing therapies have anti
      angiogenic activity. Recent advances in anti-angiogenic strategies in oncology,
      including the identification of integrin alpha v beta 3 as a crucial effector of
      angiogenesis, suggest a means to assess the role of angiogenesis in rheumatoid
      arthritis. Synovial endothelial cells have been shown to express integrin alpha v
      beta 3, suggesting that these cells may be targeted for angiogenesis inhibition.
      Prior studies in rat arthritis models have shown benefit after the addition of
      broad spectrum integrin antagonists. However, formal assessment of integrin
      targeted anti-angiogenic activity is now underway. These controlled studies will
      be important in assessing the efficacy of therapies which target angiogenesis in
      RA.

PMID- 10412570
TI  - Modulation of fibronectin expression in the central nervous system of Lewis rats
      with experimental autoimmune encephalomyelitis.
AB  - Fibronectin (FN), a large family of plasma and extracellular matrix (ECM)
      glycoproteins, plays an important role in leukocyte migration. In normal central
      nervous system (CNS), a fine and delicate mesh of FN is virtually restricted to
      the basal membrane of cerebral blood vessels and to the glial limitans externa.
      Experimental autoimmune encephalomyelitis (EAE), an inflammatory CNS
      demyelinating disease, was induced in Lewis rats with a spinal cord homogenate.
      During the preclinical phase and the onset of the disease, marked immunolabelling
      was observed on the endothelial luminal surface and basal lamina of spinal cord
      and brainstem microvasculature. In the paralytic phase, a discrete labelling was
      evident in blood vessels of spinal cord and brainstem associated or not with an
      inflammatory infiltrate. Conversely, intense immunolabelling was present in
      cerebral and cerebellar blood vessels, which were still free from inflammatory
      cuffs. Shortly after clinical recovery minimal labelling was observed in a few
      blood vessels. Brainstem and spinal cord returned to normal, but numerous
      inflammatory foci and demyelination were still evident near the ventricle walls,
      in the cerebral cortex and in the cerebellum. Intense expression of FN in brain
      vessels ascending from the spinal cord towards the encephalon preceded the
      appearance of inflammatory cells but faded away after the establishment of the
      inflammatory cuff. These results indicate an important role for FN in the
      pathogenesis of CNS inflammatory demyelinating events occurring during EAF.

PMID- 10412571
TI  - Expression of extracellular matrix components and their receptors in the central
      nervous system during experimental Toxoplasma gondii and Trypanosoma cruzi
      infection.
AB  - Alterations in extracellular matrix (ECM) expression in the central nervous
      system (CNS) usually associated with inflammatory lesions have been described in
      several pathological situations including neuroblastoma and demyelinating
      diseases. The participation of fibronectin (FN) and its receptor, the VLA-4
      molecule, in the migration of inflammatory cells into the CNS has been proposed.
      In Trypanosoma cruzi infection encephalitis occurs during the acute phase,
      whereas in Toxoplasma infection encephalitis is a chronic persisting process. In
      immunocompromised individuals such as AIDS patients. T. cruzi or T. gondii
      infection can lead to severe CNS damage. At the moment, there are no data
      available regarding the molecules involved in the entrance of inflammatory cells
      into the CNS during parasitic encephalitis. Herein, we characterized the
      expression of the ECM components FN and laminin (LN) and their receptors in the
      CNS of T. gondii- and T. cruzi-infected mice. An increased expression of FN and
      LN was detected in the meninges, leptomeninges, choroid plexus and basal lamina
      of blood vessels. A fine FN network was observed involving T. gondii-free and T.
      gondii-containing inflammatory infiltrates. Moreover, perivascular spaces
      presenting a FN-containing filamentous network filled with alpha 4+ and alpha 5+
      cells were observed. Although an increased expression of LN was detected in the
      basal lamina of blood vessels, the CNS inflammatory cells were alpha 6-negative.
      Taken together, our results suggest that FN and its receptors VLA-4 and VLA-5
      might be involved in the entrance, migration and retention of inflammatory cells
      into the CNS during parasitic infections.

PMID- 10412572
TI  - The hematopoietic stroma.
AB  - All blood cells are derived from a small common pool of totipotent cells, called
      hematopoietic stem cells. The process is strictly regulated by the hematopoietic
      microenvironment, which includes stromal cells, extracellular matrix molecules
      and soluble regulatory factors. Several experimental in vitro assays have been
      developed for the study of hematopoietic differentiation, and have provided
      valuable information on the stroma, which includes, among other cell types,
      macrophages, fibroblasts, adipocytes, and endothelial cells. The composition,
      ontogeny, and function in physiological as well as pathological conditions of
      stroma are discussed.

PMID- 10412573
TI  - Regulatory roles of microtubule-associated proteins in neuronal morphogenesis.
      Involvement of the extracellular matrix.
AB  - As a result of recent investigations, the cytoskeleton can be viewed as a
      cytoplasmic system of interconnected filaments with three major integrative
      levels: self-assembling macromolecules, filamentous polymers, e.g., microtubules,
      intermediate filaments and actin filaments, and supramolecular structures formed
      by bundles of these filaments or networks resulting from cross-bridges between
      these major cytoskeletal polymers. The organization of this biological structure
      appears to be sensitive to fine spatially and temporally dependent regulatory
      signals. In differentiating neurons, regulation of cytoskeleton organization is
      particularly relevant, and the microtubule-associated protein (MAP) tau appears
      to play roles in the extension of large neuritic processes and axons as well as
      in the stabilization of microtubular polymers along these processes. Within this
      context, tau is directly involved in defining neuronal polarity as well as in the
      generation of neuronal growth cones. There is increasing evidence that elements
      of the extracellular matrix contribute to the control of cytoskeleton
      organization in differentiating neurons, and that these regulations could be
      mediated by changes in MAP activity. In this brief review, we discuss the
      possible roles of tau in mediating the effects of extracellular matrix components
      on the internal cytoskeletal arrays and its organization in growing neurons.

PMID- 10412574
TI  - Glial fibrillary acidic protein (GFAP): modulation by growth factors and its
      implication in astrocyte differentiation.
AB  - Intermediate filament (IF) proteins constitute an extremely large multigene
      family of developmentally and tissue-regulated cytoskeleton proteins abundant in
      most vertebrate cell types. Astrocyte precursors of the CNS usually express
      vimentin as the major IF. Astrocyte maturation is followed by a switch between
      vimentin and glial fibrillary acidic protein (GFAP) expression, with the latter
      being recognized as an astrocyte maturation marker. Levels of GFAP are regulated
      under developmental and pathological conditions. Upregulation of GFAP expression
      is one of the main characteristics of the astrocytic reaction commonly observed
      after CNS lesion. In this way, studies on GFAP regulation have been shown to be
      useful to understand not only brain physiology but also neurological disease.
      Modulators of GFAP expression include several hormones such as thyroid hormone,
      glucocorticoids and several growth factors such as FGF, CNTF and TGF beta, among
      others. Studies of the GFAP gene have already identified several putative growth
      factor binding domains in its promoter region. Data obtained from transgenic and
      knockout mice have provided new insights into IF protein functions. This review
      highlights the most recent studies on the regulation of IF function by growth
      factors and hormones.

PMID- 10412575
TI  - Extracellular matrix molecules play diverse roles in the growth and guidance of
      central nervous system axons.
AB  - Axon growth and guidance represent complex biological processes in which probably
      intervene diverse sets of molecular cues that allow for the appropriate wiring of
      the central nervous system (CNS). The extracellular matrix (ECM) represents a
      major contributor of molecular signals either diffusible or membrane-bound that
      may regulate different stages of neural development. Some of the brain ECM
      molecules form tridimensional structures (tunnels and boundaries) that appear
      during time- and space-regulated events, possibly playing relevant roles in the
      control of axon elongation and pathfinding. This short review focuses mainly on
      the recognized roles played by proteoglycans, laminin, fibronectin and tenascin
      in axonal development during ontogenesis.

PMID- 10412577
TI  - Detection of the basement membrane-degrading proteolytic activity of
      Paracoccidioides brasiliensis after SDS-PAGE using agarose overlays containing
      Abz-MKALTLQ-EDDnp.
AB  - We have characterized, in the Paracoccidioides brasiliensis yeast phase, an
      exocellular SH-dependent serine proteinase activity against Abz-MKRLTL-EDDnp and
      analogous fluorescent-quenched peptides, and showed that it is also active
      against constituents of the basement membrane in vitro. In the present study, we
      separated the components of P. brasiliensis culture filtrates by electrophoresis
      and demonstrated that the serine-thiol exocellular proteinase has a diffuse and
      heterogeneous migration by SDS-PAGE, localizing in a region between 69 and 43
      kDa. The hydrolytic activity was demonstrable after SDS-PAGE using buffered
      agarose overlays of Abz-MKALTLQ-EDDnp, following incubation at 37 degrees C, and
      detection of fluorescent bands with a UV transilluminator. Hydrolysis was more
      intense when incubation was carried out at basic pH, and was completely inhibited
      with 2.5 mM PMSF and partially with sodium 7-hydroxymercuribenzoate (2.5 mM p
      HMB), suggesting its serine-thiol nature. A proteolytic band with similar
      characteristics was observed in conventional gelatin zymograms, but could not be
      correlated with a silver-stained component. Detection of the serine-thiol
      proteinase in substrate gels after SDS-PAGE provides a useful way of monitoring
      purification of the basement membrane degrading enzyme.

PMID- 10412576
TI  - Collagen arrangement in hepatic granuloma in mice infected with Schistosoma
      mansoni: dependence on fiber radiation centers.
AB  - The collagen structure of isolated and in situ liver granuloma from Swiss Webster
      mice infected with Schistosoma mansoni was sequentially and three-dimensionally
      analyzed during different times of infection (early acute, acute, transitional
      acute-chronic, and chronic phases) by laser scanning confocal microscopy and
      electron scanning variable vacuum microscopy. The initial granuloma structure is
      characterized by vascular collagen residues and by anchorage points (or fiber
      radiation centers), from where collagenous fibers are angularly shed and self
      assembled. During the exudative-productive stage, the self-assembly of these
      fibers minimizes energy and mass through continuous tension and focal
      compression. The curvature or angles between collagen fibers probably depends on
      the fibroblastic or myofibroblastic organization of stress fibers. Gradually, the
      loose unstable lattice of the exudative-productive stage transforms into a highly
      packed and stable architecture as a result of progressive compactness. The three
      dimensional architecture of granulomas provides increased tissue integrity,
      efficient distribution of soluble compounds and a haptotactic background to the
      cells.

PMID- 10412579
TI  - [One hundred years since setting up Bakhrushin hospital's prosectorium--Moscow
      City Center for Pathology Studies at A.A. Ostroumov Clinical Hospital No. 33].
AB  - A pathology department of the Bakhrushin Hospital was opened in 1898 and by 1998
      it had become the largest centralized pathology department and Moscow City Center
      of pathology studies. Well known pathologists were heads and staff members of the
      Center: G. V. Vlasov, N. I. Krich, V. A. Klirikov, B. A. Kronrod, V. A. Yavelov.

PMID- 10412578
TI  - Adhesion of the human pathogen Sporothrix schenckii to several extracellular
      matrix proteins.
AB  - The pathogenic fungus Sporothrix schenckii is the causative agent of
      sporotrichosis. This subcutaneous mycosis may disseminate in immunocompromised
      individuals and also affect several internal organs and tissues, most commonly
      the bone, joints and lung. Since adhesion is the first step involved with the
      dissemination of pathogens in the host, we have studied the interaction between
      S. schenckii and several extracellular matrix (ECM) proteins. The binding of two
      morphological phases of S. schenckii, yeast cells and conidia, to immobilized
      type II collagen, laminin, fibronectin, fibrinogen and thrombospondin was
      investigated. Poly (2-hydroxyethyl methacrylate) (poly-HEMA) was used as the
      negative control. Cell adhesion was assessed by ELISA with a rabbit anti-S.
      schenckii antiserum. The results indicate that both morphological phases of this
      fungus can bind significantly to type II collagen, fibronectin and laminin in
      comparison to the binding observed with BSA (used as blocking agent). The
      adhesion rate observed with the ECM proteins (type II collagen, fibronectin and
      laminin) was statistically significant (P < 0.05) when compared to the adhesion
      obtained with BSA. No significant binding of conidia was observed to either
      fibrinogen or thrombospondin, but yeast cells did bind to the fibrinogen. Our
      results indicate that S. schenckii can bind to fibronectin, laminin and type II
      collagen and also show differences in binding capacity according to the
      morphological form of the fungus.

PMID- 10412580
TI  - [Feasibility of pre-operative cytologic diagnosis of pathologic processes in the
      breast].
AB  - Results are available of clinical and cytological diagnosis for 200 patients with
      histologically established benign lesions of the mammary gland. The use of
      cytological method at the presurgery stage decreases the number of unjustified
      carcinoma suspects up to 5%. True cytological diagnosis is established in 90% of
      mastopathies, 84.6% of fibroadenomas and 80.8% of the inflammation cases.
      Pseudopositive conclusions about carcinoma were made in 2 cases (1% of all the
      examinees). Thus, the precision of the presurgical cytological diagnosis of
      benign breast lesions is 94%. This allows to consider it as a highly efficient
      method of presurgical morphological diagnosis.

PMID- 10412581
TI  - [Mesothelium and malignant mesothelioma of the pericardium].
AB  - Malignant mesothelioma of the pericardium is characterized by atypical solid
      growth of mesothelium with formation of atypical cavities, slits surrounded by a
      fibrous stroma. Unless early biopsy, diagnosis and surgery, the prognosis is
      unfavourable. It is desirable to create immunomorphological test for mesothelium.
      Recognition of epithelioid, fibrous and mixed forms of mesotheliomas is
      disputable.

PMID- 10412582
TI  - [Energy-dependent changes in the ultrastructure of human cardiomyocyte
      mitochondria in alcoholic heart disease].
AB  - It is shown for the first time that energy dependent alterations of mitochondrial
      ultrastructure, well studied in vitro, can be demonstrated in vivo in human
      cardiomyocytes on the material of endomyocardial biopsies of the left ventricles
      taken from patients with alcoholic heart disease. Mitochondria in cardiomyocytes
      of these patients were in four energy dependent ultrastructural states:
      orthodoxal, energized, energized-twisted, deenergized. These alterations are
      interpreted as resulting from mitochondrial energetic disturbance in alcoholic
      heart disease.

PMID- 10412583
TI  - [Cytophysiology of lung bronchiolar secretory cells--source of inflammation
      "antimediators"].
AB  - Literature and original authors' data on topography, structural organization and
      function of secretory bronchiolar Clara cells of the lungs in various
      representatives of mammals and humans are analyzed. Involvement of Clara cells in
      bronchiolar clearance, metabolization of xenobiotics and carcinogenic substances,
      synthesis of specific low molecular proteins (SLP), antimediators of
      inflammation. Special attention is drawn to the SLP properties; proteins with
      antiprotease properties are revealed among SLP. Other proteins are modulators of
      local inflammatory resection in the lungs or regulators of pulmonary surfactant
      function.

PMID- 10412584
TI  - [Morphofunctional disorders in the small intestine in acute occlusive ileus].
AB  - Activity of liminal and membrane enzymes and morphologic state of small
      intestinal mucosa were studied in experimental acute occlusive ileus in rats. It
      was established that degenerative alterations of intestinal mucosa epithelium
      above the site of obstruction are more pronounced than in the distal part. The
      activity of membrane enzymes (invertase) remained unaltered during 72 hours after
      the obturation, however, serious morphologic damage of the intestinal mucosa
      epithelium and sharp suppression of the liminal digestion were observed.

PMID- 10412585
TI  - [Desmoplastic malignant melanoma].
AB  - A rare case of desmoplastic malignant melanoma which produced many difficulties
      in diagnosis is reported. Analysis of histological structure of the primary tumor
      and its metastases as well as signs of melanocytic differentiation found at
      electron-microscopic level enabled differentiation of this tumor with neoplasms
      of another histogenesis which is important for treatment and prognosis.

PMID- 10412586
TI  - [A case of diagnosis of Landry ascending paralysis of herpetic etiology].
AB  - One clinical and pathomorphologic case of Landry paralysis with a proven
      etiological role of herpetic infection is reported. Acute clinical syndrome
      developed as a manifestation of exacerbation of chronic inflammation in the
      central nervous system. Advancement of the process and generalisation of herpetic
      infection was connected with immunodeficiency in this patient.

PMID- 10412588
TI  - [Smolensk Regional Institute of Pathology-- modern form of pathology service
      organization: organizational-tactical principles of creation and everyday
      activity].
AB  - Four main principles underlie organization and activity of the Smolensk Regional
      Institute of Pathology: 1) principle of a close link between pathology and
      clinical disciplines; 2) principle of optimal use of managerial effectiveness and
      initiative of the staff; 3) principle of association of practical and research
      activities; 4) principle of educational-methodological, practical and research
      activities as a basis of physician's clinical thinking. All these principles are
      used in everyday activity and may be used for creation of pathology institutes in
      other regions of the Russian Federation.

PMID- 10412587
TI  - [Chronic granulomatous disease, disguised as bladder tumor. Potential source of
      diagnostic error].
AB  - A case of chronic granulomatosis is reported. Its clinical manifestations were
      affection of the urinary tract with pseudotumors of the urinary bladder and
      ureteral obstruction. Recommendations for treatment of similar diseases are
      presented.

PMID- 10412589
TI  - [Experience at cooperation between the Moscow Municipal Center of Pathology
      Research and the Chair of Pathology of the Russian Medical Academy of
      Postgraduate Training].
AB  - Pathology service in Moscow, unlike in other cities of Russia, is not centralized
      and consists of 57 pathology departments of hospitals for adults and 5
      departments of children hospitals of municipal subordination; 30 federal
      pathology departments of hospitals, 20 departments and laboratories of research
      medical centers and 5 pathology chairs of medical institutes. In spite of high
      professional levels of the pathologists, the lack of a centralized city service
      is a negative aspect. Cooperation between Moscow City Pathology Center and Chair
      of Pathology of Russian Medical Academy for Postgraduate Education illustrates
      positive trends to consolidation of Moscow pathologists.

PMID- 10412590
TI  - [Use in immunohistochemical studies of a method of restoration of antigenic
      specificity as affected by microwaves in tissue fixed with formalin and embedded
      in paraffin].
AB  - Recovery of specific antigenic characteristics using microwave treatment of
      paraffin sections of tissues fixed by formalin allows to extend spectrum of
      antibodies for immunohistochemical diagnosis. Microwaves enable the reaction on
      the material prepared according to the standard technique, and macropreparations
      long stored in formalin and archive blocks.

PMID- 10412591
TI  - [Prion disease and brain amyloidosis].
AB  - Human prion disorders include Kuru, Creutzfeld-Jakob disease (CJD), Gerstman
      Straussler-Scheinkler syndrome (GSS), fatal familial insomnia (FFI) and prion
      protein cerebral amyloid angiopathy (PrPCAA). Prion diseases manifest as
      infections, genetic and sporadic disorders. In these diseases an abnormal form of
      the host's protein, prion protein protease-resistant (PrPres), is essential for
      pathogenic process. Host protein, prion protein protease-sensitive (PrPsen) in
      humans is encoded by a single copy gene (PRNP) located in the short arm of
      chromosome 20. To date, 19 different mutations in PRNP have been found that cause
      inherited prion disease. In these diseases PrPsen undergoes conformational
      changes involving a shift from alpha-helix to beta-sheet structures. This
      conversion is important for PrP-amyloidogenesis which occurs to the highest
      degree in GSS, while it is less frequently seen in other prion diseases.
      Pathomorphologically, amyloidogenesis in the brain is characterized by formation
      of PrPres conglomerates, diffuse homogeneous deposits and pleomorphic fibrillar
      amyloid plaques. The neurotoxic activity of PrPres and its fragments supports the
      causal relationship between PrPres deposits and neuropathological events in prion
      diseases. Congo-red and certain sulfated glycans potently inhibit PrPres
      formation. This raises the potential of therapeutic strategies for the treatment
      of these diseases.

PMID- 10412592
TI  - [Eccrine spiradenoma].
AB  - Benign epithelial tumor of the skin--eccrine spiradenoma--is characterized in
      detail clinically and morphologically.

PMID- 10412593
TI  - ["News" on the histogenesis of apud cells (discovery or mistake?].

PMID- 10412594
TI  - ["To pouch or not to pouch"].

PMID- 10412596
TI  - [Intestinal pouches: gastric reconstruction].
AB  - Reconstruction of the intestinal passage after a total gastrectomy is usually
      based on a direct esophagojejunostomy with end-to-side implantation of the
      afferent loop. The second principle of reconstruction is based on preservation of
      the duodenal passage. Long-term problems such as weight loss and malnutrition are
      further considerations that lead to the concept that gastric reconstruction
      should have the form of a reservoir. In addition to the construction of the
      reservoir itself, the clinical concern of avoiding gastroesophageal reflux is a
      further requirement for the choice of reconstruction type. Diversion of the
      duodenal content via a Roux-en-Y end-to-side anastomosis is considered to be the
      standard procedure. Interposition of a sufficiently long duodenal loop with
      maintenance of the duodenal passage also has the effect of preventing duodenal
      reflux. A theoretical advantage of this procedure is the linking of the motility
      of the duodenum with that of the interposed segment with improved synchronization
      of the aboral nutrient passage. When one considers complicated reconstructive
      procedures, the present literature suggests construction of a pouch is definitely
      functionally superior to the simple esophagojejunostomy. Whether the duodenal
      passage should be maintained or whether a Roux-Y technique should be used is a
      question that is still open for discussion.

PMID- 10412595
TI  - [The physiology of intestinal pouches].
AB  - To summarize, J-shaped and W-shaped ileal pouches serve as adequate neorectal
      reservoirs after proctocolectomy. These pouches anastomosed directly to the anal
      canal are as distensible and capacious and as readily evacuated as the rectum in
      health. However, the use of S- or H-shaped ileal pouches, which have efferent
      limbs positioned between the pouch and the anal canal, sometimes leads to outflow
      obstruction and incomplete evacuation. There is little doubt that neorectums made
      of ileum can allow patients to have entirely "normal" patterns of fecal
      continence. Nonetheless, with pouch distension, large-amplitude, propulsive pouch
      contractions occur. These large pressure waves bring on the urge to defecate.
      They stress the anal sphincters more acutely than either the infrequent, small
      amplitude, nonpropulsive contractions or clustered contractions of the healthy
      rectum. Nonetheless, patients learn to recognize the different signals heralding
      the impending need for evacuation from the ileal pouch and deal with them.
      Jejunal pouches, because of their greater distensibility and larger capacity, and
      the greater frequency of interdigestive migrating myoelectric complexes (MMCs)
      occurring in them, hold the promise of being a better rectal substitute than
      ileal pouches. They are more difficult to construct, however. Colonic pouches,
      when anastomosed to the anal canal after rectal resection, also act as adequate
      fecal reservoirs. Their main drawback is the inability of some patients to empty
      them. Small (5 cm) colonic pouches seem to empty better than larger (10-15 cm)
      ones. Jejunal pouches and colonic segments used as gastric substitutes after
      gastrectomy provide a better reservoir for ingested food than straight jejunal
      segments. The main drawback of the pouches is their inability to triturate the
      solid content of a meal and to regulate the rate of its emptying into the small
      intestine. Liquids and solids likely empty from these pouches at the same rate,
      in contrast to the slower emptying rate of solids from the healthy stomach. This
      likely leads to maldigestion of solids, perhaps contributing to the weight loss
      often found after gastrectomy.

PMID- 10412597
TI  - [Ileoanal pouch as rectal substitute].
AB  - The ileoanal pouch procedure (IAPP) was the most remarkable breakthrough in the
      surgical therapy of ulcerative colitis (UC) and familial adenomatous polyposis
      (FAP) in the last 20 years. The underlying disease is under control, the function
      preserved and the quality of life markedly improved. Alternative procedures
      (terminal ileostomy, ileorectal anastomosis) are only indicated in special cases.
      In the last 16 years we have operated on 662 patients (n = 493 UC; n = 169 FAP)
      with an ileoanal J-pouch, short rectal cuff, complete mucosectomy and hand-sewn
      anastomosis. Normally there is a good function for UC and FAP patients after
      IAPP. Surgical experience, technical modifications concerning the pouch design
      and the pouch-anal anastomosis, and a differentiated indication lead to a further
      improvement of these complex procedures with consecutive reduction of
      complications. Specific complications concerned mainly the pouch-anal anastomosis
      (fistulas, abscesses, consecutive stenosis) and inflammation of the pouch mucosa
      (pouchitis). A multivariate analysis showed, that increasing experience of the
      specialized center is a significant factor reducing inflammatory problems at the
      anastomosis. The cumulative incidence of pouchitis was 29%. In general there is
      no problem in successful treatment. But patients with chronic pouchitis are a
      problematic group (6.2%). Chronic pouchitis is difficult to treat. It is likely
      that there exists an inflammation dysplasia carcinoma sequence for the ileal
      pouch mucosa, analogous to the colorectum. Recently we diagnosed the first case
      of a real ileum pouch carcinoma with associated epithelial dysplasias following
      chronic pouchitis. Therefore patients with chronic pouchitis must be followed up
      by endoscopy and random biopsies in a surveillance program. Patients with UC and
      FAP can gain the life quality of healthy controls, if postoperative complications
      can be avoided or treated successfully. For the further development of the
      procedure and the individual long-term success a qualified follow-up and therapy
      of complications is essential. Both can be carried out only by a specialized
      center.

PMID- 10412598
TI  - [Colonic pouch].
AB  - The tendency towards sphincter-preserving resection for distal rectal cancers has
      led to a revival of the technique of coloanal anastomosis (CAA) in recent years.
      In order to improve functional results, creation of a colonic J-pouch in
      conjunction with a coloanal anastomosis (CPA) was proposed. Two different
      operation techniques exist: i) Double-stapling with the anastomosis close to the
      dentate line and ii) intersphincteric resection with the anastomosis located
      immediately at the dentate line. A long rectal remnant after double-stapling
      leads to urgency in 15% of the patients due to stool retention in the atonic
      remnant. No propulsive motility patterns were recorded from the pouch which is
      emptied passively by upper colonic peristalsis. Therefore colonic pouches should
      be fashioned of descending colon and should not exceed a length of 6 cm in order
      to prevent stool fragmentation. Under these conditions the average stool
      frequency is reduced from 2-6/d after CAA to 1-3/d after CPA. This effect is
      maximal during the first postoperative months, but is still significant after 3
      years. Colonic pouch construction also leads, due to better blood supply and
      prevention of pelvic hematomas, to a significant decrease of the anastomotic
      insufficiency rate from 10.0% after CAA to 5.4% after CPA. Therefore creation of
      a colonic J-pouch should be combined with coloanal reconstruction if the
      oncologic situation allows a sphincter-preserving procedure.

PMID- 10412599
TI  - [Cecum reservoir].
AB  - The choice of the best reconstruction technique following resection of either the
      stomach or the rectum remains a matter of discussion. While there is no problem
      in reconnecting intestinal segments, which do not serve as a reservoir, there are
      many different operation techniques to replace the stomach and rectum, producing
      significantly different functional results. The ileocecal segment offers an
      excellent intestinal reservoir combined with an antireflux mechanism, thus
      presenting an ideal replacement for the stomach. For replacement of the rectal
      reservoir as well, the ileocecal segment may be used in the first line of
      treatment. METHOD: The ileocecal segment was used in 20 patients following
      gastric resection and lymphadenectomy to reconstruct the intestinal passage
      between the esophagus and the duodenal stump (group A). In some further 44
      patients (group B) the ileocecal segment was used to replace the rectum between
      the descending colon and the dentate line following resection for very low-grade
      rectal cancer. Mortality and morbidity were investigated in both groups. In group
      A quality of life, weight loss, dumping and reflux symptoms were evaluated. In
      group B continence, discrimination, defecation quality, urge and the patient
      satisfaction were investigated. All data were recorded prospectively. RESULTS:
      Early and late mortality were not different compared to other reconstruction
      types. In each group one patient died within 60 days postoperatively due to
      myocardial infarction. The morbidity following stomach replacement was 20%,
      following rectal replacement 4.6% during hospitalization and 13.8% during follow
      up, respectively. One patient complained about heartburn, but endoscopically no
      pathology was detected in any patient. Three months postoperatively the patients'
      weight remained stable or started to increase. Three months following rectal
      replacement 87% of the patients were continent with further improvement over 2
      years. Soiling mainly during the night remained over 2 years in 44%. 88% of the
      patients were completely satisfied 2 years postoperatively. CONCLUSION: The
      replacement of either the stomach or the rectum using the ileocecal segment with
      an adequate surgical technique is safe and produces excellent functional outcome
      regarding the reconstruction of the intestinal passage as well as the reservoir
      function of the primary organ. Furthermore, preservation of the duodenal passage
      after gastrectomy may prevent dysregulation of the endocrine and exocrine
      pancreatic hormones.

PMID- 10412600
TI  - [Use of pedicled greater omentum-plasty as thoraco-abdominal defect repair
      following extensive tumor resection].
AB  - Patients suffering from long-untreated malignomas of the chest or abdominal wall
      may require plastic surgery due to extensive defects after tumor resection.
      Despite a variety of pedicled or free myocutaneous flaps, there are defects in
      which these reconstructional options may not be indicated. In these patients, the
      omental flaps are a valid alternative. Since a secondary split skin graft is
      mandatory with the omentum flap, antibacterial and granulation-enhancing
      xerodressings are required for wound bed conditioning. We report one patient in
      whom the omentum flap was used for coverage of an extensive defect after
      resection of a widespread basal cell carcinoma at the lateral thorax and
      abdominal wall. After wound conditioning with silver-impregnated activated
      charcoal xerodressing (Actisorb) in combination with a hydroactive polymer
      dressing (Allevyn), secondary skin grafting was performed. In this patient
      fibrosis and calcification of the omentum led to stable abdominal wall coverage
      even without the application of a synthetic mesh.

PMID- 10412601
TI  - [Results of surgical therapy of primary adenocarcinoma of the duodenum].
AB  - Between January 1983 and August 1998, a total of 18 patients (14 men, 4 women;
      median age 58 years, range 36-75 years) with primary adenocarcinoma of the
      duodenum underwent surgical therapy. Main clinical symptoms were upper abdominal
      pain (61%), weight loss (44%) and anaemia (38%). The tumors were resectable in 10
      patients (56%), and eight Whipple operations and two segmental duodenectomies
      were performed. Tumor classification according to the TNM system was pT2 (n = 2),
      pT3 (n = 6) and pT4 (n = 2). In eight patients, local lymph nodes were tumor
      positive (pN1), and in two patients synchronous liver metastases were excised.
      The UICC stage of the resected tumors was: stage I (n = 1), stage II (n = 1),
      stage III (n = 6) and stage IV (n = 2). In irresectable cases (n = 8), the
      patients underwent palliative (n = 6) or explorative (n = 2) operations. With no
      operative mortality, overall morbidity was 22% (4/18). Patients' survival was
      90%, 66.7% and 53.3%, respectively, at 1, 3 and 5 years after resection. None of
      the patients with irresectable tumors survived longer than 25 months. Survival
      was significantly better for the resection group (P = 0.0027). Due to the often
      unspecific symptoms, the diagnosis of duodenal adenocarcinoma is frequently
      established at advanced tumor stages, resulting in a low resectability rate.
      Radical surgical resection of the tumors, however, is able to provide a more
      favorable prognosis for duodenal carcinoma than for other periampullary tumors.

PMID- 10412602
TI  - [Management of primary non-classifiable anal fistulas].
AB  - In the surgery of anal fistulae, very demanding problems warranting special
      consideration are caused by the non-classifiable fistulae in ano. RESULTS: Of 823
      patients who underwent surgery for anal fistulae between 1993 and 1996, 38 (4.5%)
      were, according to Parks' classification, non-classifiable; the anal canal was
      intact. There was no internal opening. All patients had already undergone
      operations, some of them multiple. In 53%, complete healing of the fistula was
      achieved by using a single excision. In 47% a recurrence developed. During a
      second revision we explored the intersphincteric space and were able to
      reclassify the fistulae in 50% of the cases. A continent fistulectomy led to
      complete healing in these patients. CONCLUSION: Non-classifiable fistulae in ano,
      in which an internal opening of the fistula cannot be found, can primarily be
      treated by a single excision of the fistula. If recurrence does occur, the
      patient should undergo exploration of the intersphincteric space in the region,
      where the cryptoglandular infection is suspected.

PMID- 10412603
TI  - [Early operation of acute cholecystitis in advanced age].
AB  - In a 20-year period (1974-1993), 4230 patients underwent surgery of the
      gallbladder. Acute cholecystitis was the indication for emergency laparotomy in
      869 patients (20.5%). Retrospective analysis demonstrated that after adjustment
      for age, sex, and mode of surgery--elective versus emergency--advanced age is not
      a risk factor contributing to mortality in uncomplicated cases of emergency
      surgery. Cases of acute cholecystitis complicated by perforation, peritonitis,
      and/or the presence of concrements in the biliary duct are associated with an
      increased mortality, however. We were able to demonstrate that advanced age is a
      risk factor in complicated cases and contributes to increased postsurgical
      mortality.

PMID- 10412604
TI  - [Atypical heparin-induced thrombocytopenia (HIT)--"heparin allergy" with
      thrombocytosis].
AB  - We report a truck driver with severe soft tissue contusion of both legs who
      developed atypical heparin-induced thrombocytopenia (HIT) after a thrombosis
      prophylaxis with unfractionated heparin; despite a thrombosis the patient showed
      a systemic allergic reaction to heparin in combination with elevation of
      thrombocytes and positive heparin-dependent antibodies. Six days after the
      initial trauma deep vein thrombosis of the left lower leg was diagnosed and
      fasciotomy was performed, preventing an imminent compartment syndrome. Another 5
      days later the patient developed exanthema of the trunk and upper extremities and
      urticaria on his face, as well as severe headache. His platelet count increased
      from 134,000/microliter to 258,000/microliter. After exclusion of other causes
      for these symptoms, a reaction to heparin-dependent antibodies (heparin-platelet
      factor 4 complex) was demonstrated 2 days later. Thrombosis prophylaxis was
      changed to hirudin (Refludan) and elevation of thrombocytes to 445,000/microliter
      was noted. Shortly after rinsing of an intravenous line with less than 50 IE
      unfractionated heparin at day 36 after trauma the patient developed an
      anaphylactic shock, which could be managed with cortisone. We suggest that in HIT
      the thrombocytopenia may represent only one form of an allergic reaction to
      heparin. The cause of the thromboembolic event is an antigen-antibody reaction to
      heparin taking place on the surface of the thrombocyte. This is similar in all
      forms of systemic reaction to heparin application, even though the symptoms may
      vary. As thrombocytopenia may not be the main symptom of a heparin-induced
      antibody reaction--in our hospital only 5 of 10 patients with HIT--the disease
      should rather be named "heparin allergy". We suggest a new classification of
      different pattern of heparin allergy types I-IV. The new types I and II are
      similar to HIT types I and II. Type III is the reaction of antibodies without
      decrease of thrombocytes, and type IV the reaction of antibodies associated with
      systemic allergic symptoms.

PMID- 10412605
TI  - [Surgical aortic fenestration in acute thoracoabdominal aortic dissection with
      abdominal malperfusion and end organ ischemia].
AB  - Intestinal, renal, spinal or peripheral arterial ischemia or failure of branch
      artery recanalization following initial prosthetic repair of thoracoabdominal
      aortic dissection is still a problem, with high morbidity and mortality. Five
      consecutive patients with acute thoracoabdominal aortic dissection (two type A
      dissections, three type B dissections) suffering from concomitant intestinal,
      renal, spinal and acute peripheral arterial ischemia are reported. Considering
      the anatomical and pathophysiological basis of thoracoabdominal aortic dissection
      and concomitant organ ischemia, the aortic fenestration procedure as a primary or
      secondary operative approach succeeded in restoring blood flow in all cases
      without complications. Assessment of the long-term results after 3 years revealed
      that all patients are doing well without any residual complaints. We conclude
      that in the case of persistent or secondary onset of aortic branch artery
      ischemia following initial prosthetic repair of either type A or type B
      dissection, aortic fenestration can be recommended immediately as a staged
      operative approach. Primary abdominal aortic fenestration is justified in acute
      type B dissection when end-organ ischemia becomes the focus of clinical
      deterioration.

PMID- 10412606
TI  - [Foreign body-induced thoracic actinomycosis as differential mediastinal space
      occupying lesion diagnosis].
AB  - Thoracic actinomycosis is a rare disease often mistaken for malignancy. Untreated
      actinomycosis is associated with high mortality, the disease should, thus, be
      considered early. We report the case of a 58-year-old male patient who was
      referred to us for a suspected thoracic sarcoma. He had 6-month a history of
      hemoptysis, and there was severe deterioration in his general health. Only in a
      roundabout way was the diagnosis of thoracic actinomycosis established; it was
      caused by an aspirated chicken bone, as found by bronchoscopy. All symptoms
      rapidly regressed by antibiotic therapy and definitive healing was obtained. In
      the diagnostic work up of thoracic masses that may represent inflammatory
      diseases, lymphoma, thymus-associated, sarcomatous and germ-cell tumors,
      bronchoscopy is of primary diagnostic importance.

PMID- 10412607
TI  - [Lymphoepithelial carcinoma of the extrahepatic bile duct].
AB  - A 36-year-old female patient was transferred to our unit for surgical treatment
      of a biliary tract obstruction. ERC disclosed an obliteration of the common
      hepatic duct involving the hepatic bifurcation. Primary sclerotic cholangitis and
      carcinoma of the bile duct could not be confirmed histologically in the biopsy
      specimens. Tumor markers and autoimmune antibodies were normal. Histological
      examination of the ductus choledochus during the operation was not conclusive and
      a malignant lymphoma was considered. The macroscopic appearance comprised
      obliterative alterations extending to the right hepatic duct. Therefore,
      resection of the extrahepatic bile duct, right hemihepatectomy and
      hepaticojejunostomy were performed. The final histological statement revealed a
      lymphoepithelial carcinoma. The postoperative course of the patient was
      uneventful, and the patient is in good condition without any signs of recurrent
      disease 12 months after the operation. This tumor has been described as occurring
      as a neoplasm of the stomach and salivary glands exclusively and as being of low
      grade malignancy. Additional histological evaluations confirmed the diagnosis of
      lymphoepithelial carcinoma.

PMID- 10412608
TI  - [Iatrogenic necrosis of the large toe after tourniquet placement--clinical course
      and reconstruction].
AB  - We present a necrosis of the big toe in a 20-year-old woman with an ingrowing
      toenail after wedge-shaped excision in the big toe. The reason for the necrosis
      was a tourniquet that was left in place after the operation. The ischemia, which
      lasted for 2 days, resulted in subtotal necrosis of the big toe. Six weeks after
      the operation the patient underwent microsurgical reconstruction. This is a
      report on the treatment of this complication from the beginning. Early surgical
      intervention is advocated.

PMID- 10412609
TI  - [Breast saving mastectomy in benign and malignant diseases].

PMID- 10412610
TI  - [Current legal status of bone banks].

PMID- 10412611
TI  - [Complex catastrophies--the Rwanda crisis].

PMID- 10412612
TI  - Hormonal replacement therapy and gynecological cancer.
AB  - The problem of quality of life and lifestyle in elderly women is today a very
      important social problem all over the world but particularly in rich western
      countries. Life expectancy of the population will be longer and longer in the
      future and for both females and males the biological involution correlated with
      the aging process must be delayed. The gonadal hormones stimulate the healthy
      state of the entire body (heart, skin, brain, bones, urogenital apparatus and so
      on) and consequently hormonal replacement therapy (HRT) is mandatory. In women
      the biological clock of menopause allows us to intervene at the right time, with
      personalized estrogenic, estroprogestinic or estroandrogenic treatments. Health
      benefits and groundless risks allow today a careful hormonal management even in
      women treated for gynaecological cancers (breast and endometrium as well).

PMID- 10412613
TI  - Transitory pleural effusion in a trisomy 21 fetus at 14 weeks' gestation: case
      report.

PMID- 10412614
TI  - Congenital depression of the skull. Report of two cases.

PMID- 10412615
TI  - Evaluation of perioperative stress after laparoscopic and abdominal hysterectomy
      in premalignant and malignant disease of the uterine cervix and corpus.
AB  - OBJECTIVE: To compare the differences in laparoscopic and abdominal hysterectomy
      in surgery of premalignant and malignant uterine disease. DESIGN: Prospective
      study. SETTING: Baby Friendly Hospital, Kladno, Czech Republic. SUBJECT: A total
      32 patients underwent hysterectomies for premalignant and malignant uterine
      conditions. INTERVENTIONS: Patients were assigned to either laparoscopic-assisted
      vaginal hysterectomy or total abdominal hysterectomy (LAVH), with bilateral
      salpingo-oophorectomy and lymph node dissection. MEASURES: Clinical data and
      value of total creatine kinase and C-reactive protein were measured. RESULTS: All
      32 procedures were successfully completed. There were no major complications.
      Mean order of CRP concentrations was significantly lower (p = 0.001) in patients
      with LAHV. Mean order of total CK activities was also significantly lower in
      these patients (p = 0.003) and the median hospital stay was 4.1 days (p = 0.05).
      CONCLUSIONS: Laparoscopic procedures were followed by shorter hospital stays and
      the proposed evaluation of tissue damage using serum enzymes and proteins
      demonstrates that the laparoscopic approach to hysterectomy and accessory
      procedures has considerable importance in decreasing perioperative patient
      stress. The presented results are supported by clinical experience and should
      have a decisive impact on the chosen approach to the course and duration of
      convalescence in patients undergoing a hysterectomy in premalignant and malignant
      disease of the uterine cervix and corpus.

PMID- 10412616
TI  - New technique for artificial lung maturation. Direct intramuscular fetal
      corticosteroid therapy.
AB  - The aim of this study was to present a new technique of administration of
      antenatal corticosteroid therapy in order to cause fetal lung maturation. A
      single dexamethasone dose of 4 mg was applied directly to the fetal gluteal
      musculature by ultrasound-guided intramuscular injection 48 h before delivery.
      This technique of fetal corticosteroid therapy was applied in six cases. Our
      patients had high risk pregnancies (preeclampsia diabetes mellitus, intracranial
      hemorrhage, epilepsy, hyperthyreosis). The pregnancies were terminated in the
      mother's vital interest. The lecithin/sphyngomyelin (US) ratio was < 1.5:1. There
      were no procedure-related complications. The fetuses were delivered by cesarean,
      48 hours later except for the vaginal delivery in the patient in which fetal
      death occurred in utero. In five cases an uneventful outcome of fetuses indicated
      that direct fetal corticosteroid treatment improved postnatal lung function in
      preterm fetuses. A new technique of corticosteroid application successfully
      prevents respiratory distress in preterm infants decreasing the risk of maternal
      complications. To our knowledge, this is the first report of fetal intramuscular
      corticosteroid therapy in the human population.

PMID- 10412617
TI  - Genital tumors during childhood and adolescence. A clinical and pathological
      study of 71 cases.
AB  - Genital tumors during the first two decades of life are not common and they
      constitute 5-10% of all tumors. During the period 1993-1997, 71 cases of genital
      tumors were diagnosed and managed in the Divisions of Pediatric and Adolescent
      Gynecology of the 1st and 2nd Departments of Obstetrics and Gynecology,
      University of Athens. Ovarian tumors were found to be the most common uterine
      tumors -16.9% and cervical -28%. From the ovarian tumors -80.3% of all tumors; 
      77.2% of cases were found to be benign; 15.8% malignant and 7% borderline.
      Malignant tumors were found to be germ cell -44.5%, epithelial -22.2%, stromal 
      11.1%, lymphoma 11.1%, and mixed -11.1%.

PMID- 10412618
TI  - Epidemiology of cesarean sections: prolonged pregnancy.
AB  - The management of prolonged pregnancy is controversial when the cervix is not
      favourable to induction. From the results obtained by using topical PgE2 in
      postterm patients with unfavourable cervix, it is possible to conclude that in
      those subjects with preliminary cervical modifications (Bishop Score > 1) a
      regular onset of labour and spontaneous delivery were obtained. Conversely a high
      incidence of failure was shown in those subjects with no cervical maturation (BS
      = 0).

PMID- 10412619
TI  - The effect of combined iron therapy (Chemiron) and single iron therapy on the
      dexamethasone-estriol reaction test for placenta insufficiency during normal
      pregnancy.
AB  - Impaired uteroplacental perfusion has been shown to play a role in the
      pathogenesis of some complicated pregnancies with placenta insufficiency. Apart
      from this, lower oestrogen, magnesium and zinc are found in many of these
      conditions in the third trimester with placenta insufficiency. In this study, we
      examined the effect of a 4 mg intravenous dexamethasone injection on estriol,
      since maternal cortisol or synthetic corticosteroids cross the placental barrier
      and inhibit the release of dehydroepiandrostesone sulfate in the fetal adrenals.
      Dexamathasone was found to suppress estriol levels in all groups but a
      significant difference in suppression was found between the Chemiron--a new
      combination hematinic--and the control single iron therapy groups. Our
      preliminary results showed that Chemiron has a protective effect on the
      development of placenta insufficiency during the third trimester of pregnancy.

PMID- 10412620
TI  - Encouraging good deeds for those in need: the "Annual Moffic Award for ethical
      practice in public sector managed behavioral healthcare".

PMID- 10412621
TI  - The role of gender in engaging the dually diagnosed in treatment.
AB  - Individuals with both a serious mental illness and substance abuse are
      particularly difficult to engage in treatment. Given known gender differences in
      both substance abuse and schizophrenia, we examined the impact of gender on
      treatment engagement. Qualitative interviews with ten males and eleven females
      focused on how the client perceived the engagement process, and what obstacles
      they faced. While both males and females are difficult to engage, the interviews
      suggest that they experience the process differently and that they face different
      obstacles. We discuss the implication for service providers.

PMID- 10412622
TI  - Predictors of management problems in supported housing: a pilot study.
AB  - The study examined predictors of management problems among residents of a
      supported single room occupancy hotel (SRO) for persons with severe and
      persistent mental illness (SPMI). Case workers completed questionnaires on the
      prior six months. We found that medication-compliant residents without drug abuse
      were rarely disruptive, while those with co-morbid substance abuse were often
      disruptive. Residents non-compliant with medication also tended to cause
      management problems whether or not they abused drugs. Supported residences should
      be staffed and organized to minimize medication non-compliance and substance
      abuse which are associated with behavioral disruptiveness.

PMID- 10412623
TI  - The financial impact on community mental health centers of capitated contracts
      with Medicaid: the Utah Prepaid Mental Health Plan.
AB  - Under the Utah Prepaid Mental Health Plan, three of the eleven Community Mental
      Health Centers in Utah signed capitation contracts with the state Medicaid
      program. The capitated Centers initially accepted the risk for inpatient care,
      with the risk later being extended to also include outpatient services. This
      study contrasts the financial experiences of the capitated Centers and five
      noncontracting Centers. While various patterns of financial management are
      evident in the data, it appears that the decision to contract had, at worst, a
      neutral effect on overall financial performance. Managed care programs with
      different designs may have different results.

PMID- 10412626
TI  - What is a clubhouse? Report on the ICCD 1996 survey of USA clubhouses.
AB  - This article summarizes the findings from the ICCD 1996 Clubhouse Survey for the
      173 respondent clubhouses located in the United States. It is our intent in the
      present article to identify commonalties in clubhouse organizational structure
      and practice across diverse geographic areas of the USA and within diverse health
      care systems, and, thereby, to identify typical or 'average' clubhouse
      performance in a variety of organizational and practice domains.

PMID- 10412624
TI  - Service components of case management which reduce inpatient care use for persons
      with serious mental illness.
AB  - This is a study of two types of case management: case management (CM) which
      provided the service coordination functions, and Intensive Case Management (ICM)
      which consisted of both the coordination function and the provision of direct
      support to the client. Using secondary data on public clients, characteristics of
      mental health service use were analyzed for 80 ICM and 84 CM clients. The ICM
      clients had significantly fewer episodes per patient and less inpatient days per
      year than the CM clients. These findings suggest that direct support services
      make a significant difference in reducing annual hospital care.

PMID- 10412625
TI  - The effect of training in a strengths model of case management on client outcomes
      in a community mental health center.
AB  - The purpose of this study was to determine the effect on client outcomes produced
      by training case managers in a strengths model of case management. Outcomes of
      interest included client's quality of life, vocation/education, residential
      living, hospitalization rate, hospital days, and symptoms. It also compared the
      results obtained by the strengths model with results of a generalist model. Case
      managers at the experimental site were trained in the strengths model. Those at
      the control site received no training. Data were collected at both sites prior to
      training and three months later. Improvement in quality of life, symptoms, and
      vocational/educational outcomes were found in the experimental group. Quality of
      life and vocational/educational outcomes were better in the experimental group
      than in the control group.

PMID- 10412628
TI  - [Systemic therapy in the treatment concept of atopic eczema. Reliable treatment
      methods and experimental developments].
AB  - Our therapeutic approach to atopic eczema consists of a continuous topical
      dermatological basic therapy in combination with an antiinflammatory therapy in
      phases of exacerbations. In the treatment of exacerbated atopic eczema, systemic
      agents are added to achieve effective control more rapidly or to induce
      remissions in cases refractory to standard therapy. Antihistamines to control the
      pruritus, as well as antibiotics and acyclovir for antimicrobial superinfections
      are often used. In many patients exacerbations can be successfully controlled
      with phototherapy, especially with UVA1 light. The use of systemic
      immunosuppressants, like glucocorticosteroids, cyclosporine or azathioprine
      generally can be avoided and is a therapeutic alternative only in few selected
      cases. In the last years promising new experimental treatments have evolved,
      which could become therapeutic alternatives for the future.

PMID- 10412627
TI  - Work and social support: a comparison of consumers who have achieved stability in
      ACT and clubhouse programs.
AB  - A current debate in the field is whether consumers, who have achieved stability
      in Assertive Community Treatment programs, can be transferred to less intensive
      services. To bring some data to bear on this question, this study compared
      consumers and members, who have achieved stability, in either an Assertive
      Community Treatment (ACT) or a clubhouse program, on domains of vocational
      activity, social relationships/loneliness and community integration. The 51
      stable clients from the two programs who were interviewed, reported similar
      vocational activity, similar experiences with social relationships and social
      networks, and similar community integration. Clients in both groups were less
      lonely than previously reported in the literature. Study results indicate, that
      for those clients who have achieved stability, there are sufficient similarities
      between consumers in the two programs, to suggest a potential for movement from
      more to less intensive programs with less disruption than previously assumed
      possible.

PMID- 10412629
TI  - [Quality management in the German health care system].
AB  - With the increasing demands on hospitals for improved quality and lower costs,
      hospitals have been forced to reevaluate their manner of operation and quality
      assurance programs. Hospitals have also been faced with customer dissatisfaction
      and intense competition. This article reviews current quality-management systems
      and examines their position in dermatology.

PMID- 10412630
TI  - [Prevalence of psychological symptoms in dermatologic patients of an acute
      clinic].
AB  - There is a lot of information in the literature about psychological disturbances
      in somatic diseases. For dermatological patients such data are not available. In
      early spring 1998 we studied the psychological changes in 247 hospitalized
      patients in the dermatological department of the Ruhr University Bochum. We used
      the German version of the internationally accepted Hospital Anxiety and
      Depression Scale. We found the prevalence of psychological alterations ranged
      between 25.9% and 31%. The prevalence of psychological disturbances was a little
      higher than that seen in oncological, cardiological or neurological patient
      populations. Surprisingly skin cancer patients were less affected than patients
      with chronic inflammatory or angiological diseases. These results underline the
      necessity of improved psychological therapeutical strategies which must be
      standardized and evaluated.

PMID- 10412631
TI  - [Balneologic photochemotherapy of prurigo simplex subacuta].
AB  - Seventeen patients with extensive subacute prurigo, often resistant to different
      regimens of prior external and internal therapy, were treated with PUVA bath
      photochemotherapy (psoralen bath followed by UVA irradiation) using bath water
      containing 0.5 mg/l of 8-methoxypsoralen (8-MOP). In 15 of 17 patients treated,
      the skin lesions showed a significant improvement or even complete clearance
      within 8 weeks of therapy. In two patients, only limited clinical improvement was
      achieved. Follow-up after 6 weeks revealed sustained improvement in the
      successfully treated patients. The mean cumulative UVA dose given until clearance
      was 30.3 (SD +/- 12.6) J/cm2. Therefore, a mean of 24.1 (SD +/- 5.3) PUVA bath
      treatments was necessary. No side effects were seen except phototoxic reactions
      in two patients manifested as slight erythema. The results of this trial show
      that PUVA bath photochemotherapy with 8-MOP is an effective therapeutic
      alternative to other known therapies in subacute prurigo. Compared to oral PUVA
      therapy or other topical and systemic treatments, PUVA bath photochemotherapy
      with 8-MOP shows an excellent efficiency-side effect ratio. The clearance of
      chronic skin lesions refractive to other topical or systemic treatments by PUVA
      bath photochemotherapy with 8-MOP demonstrates that this therapy can be even
      superior to other common therapeutic modalities used for subacute prurigo.

PMID- 10412632
TI  - [Calciphylaxis of the skin as a sequela of terminal kidney failure. Report and
      discussion of 3 cases].
AB  - Calciphylaxis is a rare syndrome mostly affecting patients with secondary
      hyperparathyroidism and in some cases with functional protein C or protein S
      deficiency. Skin lesions begin as superficial painful patches that progress to
      deep necrotic lesions. The findings are often misdiagnosed as livedo vasculitis
      and the prognosis is poor. Histopathologically, calcification in the media of
      small arteries and arterioles with intimal hyperplasia is seen. It is unclear if
      this morphologic hallmark is pathogenetic. Therapeutically, the calcium-phosphate
      product should be lowered pharmacologically by an intensified and modified
      dialysis treatment and parathyroidectomy.

PMID- 10412633
TI  - [Pilomatrix carcinoma in an unusual location. Case report and review of the
      literature].
AB  - A 58-year-old man developed an extensive pilomatrical carcinoma in the left
      axilla. Clinically, a squamous cell carcinoma was suspected. Histological
      examination revealed the presence of proliferating basaloid cells with many
      atypical mitoses and mass necrosis infiltrating into the subcutaneous tissue. The
      tumor was removed by micrographic surgery with a 2 cm safety margin. Histological
      examination of 2 regional lymph nodes as well as further diagnostic procedures
      ruled out metastases. We review the clinical and histopathological differences
      between pilomatricoma and pilomatrical carcinoma, as well as the published cases
      of the malignant variant.

PMID- 10412634
TI  - [Ofuji papuloerythroderma: PUVA bath treatment].
AB  - Papuloerythroderma of Ofuji is a rare skin disorder described primarily in
      Japanese patients. It occurs primarily in elderly men. The initial lesions are
      diffuse red papules, sparing the face, palms and soles. Later the papules
      coalesce into an erythroderma, with typical sparing of the skin folds and creases
      (the deck chair sign). Pruritus is usually intense. Lymphadenopathy, peripheral
      blood eosinophilia and elevated IgE levels all are common. Both systemic
      corticosteroids and systemic PUVA therapy have been recommended. We describe a
      German male who fulfilled the diagnostic criteria for papuloerythroderma of Ofuji
      and responded well to PUVA bath therapy with both improvement in skin findings
      and reduction in pruritus.

PMID- 10412635
TI  - [Trichophyton tonsurans var. sulfureum subvar. perforans in Tinea gladiatorum].
AB  - This is the first report on an isolation of Trichophyton tonsurans var.sulfureum
      subvar.perforans in Germany. In our patient, the strain had caused typical tinea
      corporis, which was most likely acquired during a wrestling competition. Based on
      the macroscopic and microscopic morphology and on the physiologic properties
      occurring under various growth conditions, the identification of Trichophyton
      tonsurans and the particular characteristics of its var.sulfureum
      subvar.perforans are described. Partial 18S and 23S nuclear ribosomal RNA
      sequences and the internal transcribed spacer region I sequences of our strain
      were completely identical with those of a Trichophyton tonsurans reference
      strain. The epidemiology of Trichophyton tonsurans var.sulfureum subvar.perforans
      and a possible association of this variety with tinea in wrestlers (tinea
      gladiatorum) have not yet been investigated.

PMID- 10412636
TI  - [Koenen, Kothe and peri-ungual fibroma in tuberous sclerosis].
AB  - The periungual fibromas in tuberous sclerosis are also known as Koenen tumors.
      Joannes Henricus Maria Koenen was born on March 10, 1893, in Eindhoven and died
      in Bois-le-Duc May 29, 1956. From 1910 to 1918 he studied medicine at the
      University of Amsterdam. Then he worked as a physician at the "Coude-water"
      asylum in Rosmalen and from 1929 in the "Voorburg" asylum in Vught. In 1932 he
      published his publication concerning a family with tuberous sclerosis in which
      photographs of periungual fibromas are shown. His thesis in 1933 at the
      University in Leiden was titled "Imbecility in children. Its Importance in
      pedagogic and social regard, by reason of an investigation in some communities in
      Noord-Brabant". Later he was appointed director of a state mental institution.
      The periungual fibromas in tuberous sclerosis were first described by Richad
      Kothe in Munich in 1903.

PMID- 10412637
TI  - [Comment on the contribution by P. H. Hoger: "Topical antibiotics and
      antiseptics"].

PMID- 10412638
TI  - [Comment on the contribution by Alexander H. Enk and Jurgen Knop. "Adjuvant
      therapy of pemphigus vulgaris and pemphigus foliaceus with intravenous
      immunoglobulins"].

PMID- 10412640
TI  - [Joint involvement in inflammatory dermatoses].

PMID- 10412641
TI  - How cardiac cells die--necrosis, oncosis and apoptosis.

PMID- 10412642
TI  - Morphologic criteria and detection of apoptosis.
AB  - Apoptosis is an organized, energy dependent process, which leads to cell death.
      Its definition is based on distinct morphological features [10] and demonstration
      of internucleosomal DNA degradation [27], executed by selectively activated
      DNAses [4, 22]. The morphologic hallmarks of apoptosis include chromatic
      margination, nuclear condensation and fragmentation, and condensation of the cell
      with preservation of organelles. The process is followed by fragmentation of the
      cell into membrane-bound apoptotic bodies, which undergo phagocytosis by nearby
      cells without associated inflammation [10, 11]. Apoptosis characteristically
      occurs in insolated single cells. The duration of apoptosis is estimated to be
      from 12 to 24 hours, but in cell culture visible morphologic changes are
      accomplished in less than two hours [10, 16]. Non-apoptotic cell death, a
      prototype of which is cell death due to ischemia (oncosis), is characterized by
      depletion of intracellular ATP stores, swelling of the cell with disruption of
      organelles and rupture of the plasma membrane [15]. Groups of necrotic cells and
      inflammation are found in tissues [10, 15]. The significance of apoptosis has
      mostly been studied using the TUNEL assay that detects DNA strand breaks in
      tissue sections and allows quantification of apoptotic cells by light microscopy
      [6]. Common experience seems to be that the TUNEL assay is prone to false
      positive or negative findings. This has been explained by the dependence of the
      staining kinetics on the reagent concentration [17], fixation of the tissue [2]
      and the extent of proteolysis [17]. Active RNA synthesis [12] and DNA damage in
      necrotic cells [17, 19] may cause non-specific staining. To obtain reliable and
      reproducible results, TUNEL assay should be carefully standardized by using
      tissue sections treated with DNAse (positive control of apoptosis).
      Quantification of apoptosis should include enough microscopic fields and
      identification of the cell type undergoing apoptosis. The specificity of the
      results can be substantiated by combining other methods with TUNEL, such as
      assessment of the pattern of DNA fragmentation or evaluation of the morphological
      features. Even though there is high variation in the results obtained in
      consecutive studies under the same circumstances, increasing evidence shows that
      TUNEL-positive cardiomyocytes and internucleosomal DNA fragmentation are
      associated with various cardiac diseases, including acute myocardial infarction
      and heart failure [reviewed in 5, 9]. Some morphological features of apoptosis
      have been observed in TUNEL-positive cardiomyocytes using light microscopy
      (Figure 1) or confocal microscopy [20]. Electron microscopic evidence of
      apoptosis has been found in the degenerating conduction system [7], in
      experimental heart failure [23], and in human hibernating myocardium [3]. In
      acutely ischemic myocardium the interpretation of the findings remains
      controversial, since only non-apoptotic cell morphology has been found in
      electron microscopy [8, 19]. One explanation might be abortion of the apoptotic
      program due to the lack of ATP before the morphologic features are fully evident
      [14]. Another explanation is the possibility that non-apoptotic cell death and
      apoptosis share common mechanisms in the early phases of the processes [14, 19].
      The exact mechanisms of ischemic cell death remain to be clarified and the
      classification between apoptosis and non-apoptosis cell death to be specified.
      Recently, caspase activation has emerged as the central molecular event leading
      to apoptosis, preceding DNA degradation and the development of apoptotic
      morphology [22, 25]. New methods have been developed to demonstrate caspase
      activation [1, 13]. Inhibition of caspase may be an efficient way to prevent
      apoptotic cardiomyocyte death as well as to define and specifically probe the
      significance of apoptotic cell death in cardiac diseases.

PMID- 10412644
TI  - [Cell death in inflammatory heart muscle diseases--apoptosis or necrosis?].
AB  - Cell death can be induced by 2 different mechanisms: necrosis and apoptosis.
      Necrosis, on the one hand, is usually caused by unphysiological stress factors
      such as hyperthermia or hypoxia, apoptosis, on the other hand, is part of the
      normal organ development and controls for example immune responses.
      Morphologically, necrosis is characterized by swelling of cells and their
      organelles leading to the disruption of the cell membrane, which in turn causes
      an inflammatory reaction in the surrounding tissue. Morphological and biochemical
      criteria (Figure 1, Table 1) of apoptosis are the condensation of chromatin
      leading to the development of apoptotic bodies or membrane-enclosed vesicles
      containing oligonucleosomal DNA fragments. Important diagnostic tools of cell
      death (Table 2), such as the TUNEL test (Figure 2) or gel electrophoresis of
      extracted DNA (Figure 3) are based on the above mentioned biochemical
      characteristics, but a reliable differentiation of apoptotic versus necrotic
      processes is not always possible. Experimental studies in animals and studies in
      various diseases of the cardiovascular system were able to show that apoptosis in
      myocytes can be induced, an issue that has long been discussed controversially.
      Ischemia, reperfusion, and myocardial infarction were also shown to lead to
      apoptosis in cardiomyocytes, whereas cell destruction was caused mainly by
      necrosis. Several authors (Table 3) demonstrated apoptotic indices in
      cardiomyocytes of patients with dilatated cardiomyopathy, arrhythmogenic right
      ventricular cardiomyopathy and patients with acute infarction from 0.25 to 35% by
      the use of the TUNEL test. Others were able to demonstrate an elevated expression
      of Fas-receptor in cells of atheroslerotic plaques in patients with
      atherosclerosis and high indices of apoptotic cardiomyocytes in patients with
      chronic heart failure. We investigated endomyocardial biopsies of patients with
      inflammatory cardiomyopathy, DCM without inflammatory reaction but the presence
      of adenoviral or cytomegaloviral genome and idiopathic DCM using the TUNEL test.
      The percentage of apoptotic cardiomyocytes in biopsies of patients with DCMi was
      1.03 and in biopsies of patients with adenoviral genome 0.25, whereas in all
      other groups no apoptosis was found. If apoptosis plays a major role in
      myocardial diseases such as heart failure, arrhythmia and others, blocking this
      mechanism will have to be considered as a therapeutical strategy. Therefore,
      studies on the extent of apoptotic processes in diseased versus healthy cardiac
      tissue are of great importance.

PMID- 10412645
TI  - The role of apoptosis in dilated cardiomyopathy.
AB  - Dilated cardiomyopathy is a cardiac disease of unknown origin which is
      characterized by the gradual development of cardiac failure. Apoptosis, i.e.
      suicidal programmed cell death, may play a role in the development of heart
      failure. Only few studies have been carried out until now that describe the rate
      of apoptosis in human hearts with dilated cardiomyopathy. The numbers reported
      vary widely. This is also true for studies in different other cardiac diseases
      such as myocardial infarction or hibernating myocardium. The methods used to
      identify apoptosis include electron microscopy, labeling of the DNA fragments
      (TUNEL), staining with the Hoechst dye, annexin V labeling and documentation of
      DNA fragmentation using gel electrophoresis (laddering). None of these methods
      are totally reliable in tissue sections in which apoptosis is not a frequent
      event when they are not combined with another technique, e.g. TUNEL with electron
      microscopy or laddering. This has, however, only rarely been done. These
      technical difficulties may be the reason for the wide variation in the rate of
      apoptosis reported. From our own data we conclude that apoptosis plays a
      significant role in acute ischemia and in hibernating myocardium but its
      significance in the progression to heart failure in dilated cardiomyopathy has
      still to be established.

PMID- 10412643
TI  - [Apoptosis--what is it? Significance in coronary heart disease and myocardial
      infarct].
AB  - Apoptosis is a physiological, highly conserved program of cellular suicide,
      characterized by nuclear condensation with DNA-fragmentation, by alterations in
      the distribution of cell membrane phospholipids, and by cellular shrink-age.
      Apoptotic cellular remnants engulfed by cell membranes are phagocytized largely
      without activation of inflammatory reactions. The apoptotic program is executed
      by a cascade of highly specific caspases, activated by complexation of
      initiatorcaspases in cytosolic signalling complexes at receptors of the TNF
      family or at impaired mitochondria. In many forms of cellular stress with damage
      of nuclear DNA and mitochondria, mixed forms of cell death are triggered with
      regulated activation of the apoptotic program and concomitantly, with induction
      of catastrophic necrosis. Such a mixed form of myocyte death is observed in
      myocardial ischemia and reperfusion. Antiapoptotic interventions can delay
      ischemic myocardial damage in experiments. Therefore, those interventions appear
      conceivable as future strategy for acutely enhancing the available time interval
      for therapeutic reperfusion. However, chronic inhibition of apoptosis for ongoing
      prevention of myocardial ischemic damage may not become a plausible strategy
      because of disturbances of the immune system, because of putatively infavorable
      effects on arteriosclerotic lesions and because of likely disturbances in the
      physiologic elimination of damaged mitochondria.

PMID- 10412646
TI  - Control of apoptosis of cardiovascular fibroblasts: a novel drug target.
AB  - Adequate control of survival or programmed cell death (apoptosis) of
      cardiovascular cells appears as an important drug target. While prevention of
      apoptotic death of cardiomyocytes has been assessed in detail, selective
      induction of apoptosis of vascular smooth muscle cells or fibroblasts could also
      be of relevance. Thus, induction of apoptosis of vascular smooth muscle cells by
      p65 NF-kappa B and Bcl-xL antisense oligonucleotides or p53 overexpression could
      be useful for limiting vascular lesions associated with restenosis. Although
      fibroblasts represent the majority of cardiac cells, few attempts were made to
      induce fibroblast apoptosis in disorders associated with excessive collagen
      deposition and fibrosis. It is hypothesized that early interference with
      fibroblast proliferation after myocardial infarction or inflammatory heart
      disease limits fibrosis which further impairs cardiac performance. A candidate
      approach could involve growth factor analogues which are known to induce
      fibroblast apoptosis when an incomplete growth stimulus persists.

PMID- 10412647
TI  - Cell volume regulatory mechanisms in apoptotic cell death.
AB  - One of the hallmarks of apoptosis is cell shrinkage, which--at constant
      extracellular osmolarity--requires a decrease of cellular osmolarity. Moreover,
      apoptosis can be elicited by increase of extracellular osmolarity and the
      resistance of cells towards apoptosis correlates with their ability to regulate
      their volume in hypertonic environment. On the other hand, CD95-receptor-mediated
      apoptosis is blunted at moderate increases of extracellular osmolarity. Given the
      role of cell volume alterations it is not surprising that apoptosis is paralleled
      by marked alterations of cell volume regulatory mechanisms. Stimulation of the
      CD95-receptor, which confers apoptosis to a variety of cells, leads to activation
      of cell volume regulatory anion channel ORCC. However, activation of ORCC is
      paralleled by inhibition of cell volume regulatory K+ channel Kv1.3. It is only
      40 to 60 minutes after triggering of the CD95-receptor when the cells release the
      organic osmolyte taurine and shrink.

PMID- 10412648
TI  - Caspase inhibitors in prevention of apoptosis.
AB  - Apoptosis, a morphological distinct form of programmed cell death, is a crucial
      process during development, the maintenance of cell homeostasis and the
      regulation of the immune system. A variety of diseases have been found to
      correlate with physiological apoptosis including cancer, autoimmune disease,
      viral infection and degenerative disorders. Although very different signals
      initiate apoptosis, the phenotype of apoptosis is surprisingly similar even in
      different cell types suggesting that the final stages of apoptotic death are
      highly conserved. The execution of the death program is coordinated by a recently
      identified class of cysteine proteases termed caspases. The finding that caspases
      are mainly involved in regulation of this conserved part of the death program has
      boosted the search for caspase inhibitors which might offer a therapeutic
      approach to treat apoptotic disorders. Synthetic peptide inhibitors have been
      developed which exhibit some selectivity for the different caspases. In the last
      years several natural inhibitors have been discovered which either prevent
      caspase activation or caspase activity. This review will present the recent
      advances and discuss the potential of caspase inhibitors as future therapeutics.

PMID- 10412649
TI  - [Group therapy for heart patients--an assessment of current status].

PMID- 10412651
TI  - [Acquired laryngotracheal stenosis in childhood. Dilatation of resection?].

PMID- 10412650
TI  - [Plaque stabilization and endothelial protection by cholesterol synthesis
      inhibitors].

PMID- 10412652
TI  - [Chemosensory evoked potentials. Applications and significance in routine
      clinical practice].

PMID- 10412653
TI  - [Genetic screening for deafness].

PMID- 10412654
TI  - [Surgery of acquired laryngotracheal stenoses in childhood. Experiences and
      results from 1988 to 1998. I: Laryngotracheal reconstruction].
AB  - Subglottic laryngotracheal stenosis represents the most severe intubation injury
      and is increasingly encountered in children due to long-term ventilation during
      intensive care treatment. Since more than 90% of these children have
      tracheostomies their physical, psychosocial and speech development can be greatly
      impaired. A tracheostomy in infants can also be a potentially life-threatening
      condition, making necessary resolution of the laryngotracheal stenosis and
      removal of the tracheostoma as soon as possible. During the past 10 years, we
      have treated 46 children with laryngotracheal problems, including 18 children
      with severe laryngotracheal stenosis. Ten children (3 with grade II stenosis and
      7 with grade III stenosis) were treated by laryngotracheal reconstruction using
      an anterior rib cartilage graft as described by Cotton. One child with posterior
      glottic stenosis required a posterior laminotomy with a second rib cartilage
      graft. Differing from the original method, we stabilized the enlarged
      endotracheal lumen postoperatively with a Montgomery t-tube. This was kept in
      place for 10 months on average (shortest period, 6 months; longest period, 12
      months). All 10 children could be decannulated, and the tracheostoma closed.
      Three of the children were operated in other institutions and had a different
      technique prior to our intervention. Two of our operations failed initially.
      However, both patients were treated successfully by a second intervention (which
      was the fourth operation for one of the patients). The reasons for our
      modification, the operative technique and tips for postoperative management, as
      well as possible pitfalls and complications, are discussed.

PMID- 10412655
TI  - [Dendritic cells, T- and B-lymphocytes and macrophages in supraglottic and
      glottic squamous epithelial carcinoma. Location and correlation with prognosis of
      the illness].
AB  - Dendritic cells play an important role within the mucosal immune system of the
      upper aerodigestive tract. They process exogenous and endogenous antigens and are
      able to induce a cytotoxic Tc/s lymphocyte reaction against tumors. Recently
      published data indicate that the in vitro application of tumor lysate incubated
      dendritic cells can provide a defense against melanoma. Before these new
      therapeutic strategies are available for the therapy of laryngeal cancer, basic
      studies have to be performed concerning the distribution of dendritic cells and
      other subpopulations, such as T- and B-lymphocytes and macrophages. In the
      present study the distribution of these subpopulations were examined within the
      epithelial and connective tissue compartments ("tumor front") of 20T2 squamous
      cell carcinomas of the supraglottis and glottis. The number of dendritic cells
      was compared with clinical parameters to check whether a high number of dendritic
      cells could be correlated with a better prognosis. In contrast to T-lymphocytes,
      results showed that dendritic cells were mainly located within the epithelial
      compartment of the tumors, their number ranging from 20 cells/mm2 to > 700
      cells/mm2. By comparing each patient's clinical course with the number of
      dendritic cells, findings showed that those patients who died within the first
      postoperative year were characterized by a very small number of dendritic cells
      within their tumor tissue (< 100 cells/mm2). Although the number of patients was
      low, results indicate that a high number of dendritic cells within tumor tissue
      suggest a better prognosis.

PMID- 10412656
TI  - [Infrared and video oculography--alternatives to electrooculography?].
AB  - With the introduction of each new technique for registering eye movements, the
      question arises concerning whether these provide a reliable and accurate
      alternative for the diagnosis of labyrinthine dysfunction when compared to the
      most commonly used electro-oculographic technique. To answer this question we
      compared mean slow-phase velocity (SPV) using three different recording
      techniques:electro-oculography (EOG), video-oculography (VOG) and infrared
      oculography (IROG) during four different types of examinations. The examinations
      were the eye target tracking test (ETT), horizontal and vertical optokinetic
      nystagmus (OKN) tests and the rotating chair test of the horizontal vestibulo
      ocular reflex (HVOR). For the ETT tests the VOG provided consistently higher mean
      SPV values with low variance, presumably because of the accuracy and stability of
      the calibration. For the horizontal OKN and VOR rotating chair tests no
      significant differences were found between the mean SPV obtained with the
      different recording techniques, although the IROG recordings were associated with
      a larger variance. Vertical OKN mean SPV was consistently lower with IROG and VOG
      techniques presumably because of non-linearities and resolution limitations
      inherent in these techniques. These results indicate that the EOG technique
      despite its disadvantages of noise, time to apply and variability of calibration
      still provides an inexpensive, reliable and accurate means of measuring slow
      phase eye movements.

PMID- 10412658
TI  - [Effect of dental prosthesis on the voice].
AB  - It is well known that alterations to the oral cavity caused by dental prostheses
      may affect speech articulation, although influences on the voice are not assumed.
      In addition to the vocal fundamental frequency, vibrations of the vocal chords
      generate overtones. Through the shape of the larynx and the upper airway,
      resonances and antiresonances are formed, and in this way overtones are amplified
      to a variable extent. Nozzle changes caused by a dental prosthesis in the oral
      cavity may possibly influence overtones but influences on the vocal fundamental
      frequency seem unlikely. The influence of dental prostheses on the voice is
      demonstrated in a patient who owned two different dental prostheses. The
      fundamental frequency rose by up to five semitones during speech and his vocal
      range increased by up to four semitones when a thin denture was used instead of a
      normal denture. When the position of the mandible was checked by intraoral needle
      point placement, a more rostral position of the mandible was recorded with the
      thin denture than with the normal denture. Sagittal magnetic resonance tomography
      imaging also showed that the larynx was in a more cranial position. This change
      was presumed to be due to an upward movement of the larynx induced by the tongue,
      which itself was found to be in a more cranial position with the thin denture. In
      this situation, increased tension of the laryngeal muscles were believed to
      induce a rise in fundamental frequency, shifting the voice range toward higher
      frequencies. These findings show that dental prostheses can cause vocal changes
      in individual cases. The etiology of this occurrence is still not clear. Its
      consequences, however, should be known to the dentist, ENT surgeon and
      phoniatrist if patients notice changes in their voice after having altered or
      replaced their dentures.

PMID- 10412657
TI  - [Diagnosis of postoperative dysphagia and aspiration. Fiberoptic-endoscopic
      controlled methylene blue drinking].
AB  - Postoperative swallowing disorders are common after such function-preserving
      surgery as conventional resections or endoscopic laser procedures for carcinomas
      of the larynx and hypopharynx. In most cases a reduction in motility of the
      pharyngeal muscles and sensory impairment of the pharyngeal and laryngeal regions
      can occur because of postoperative tissue abnormalities, including scarring due
      to the healing process. We have used fiberoptic endoscopic examinations with
      methylene blue to analyze postoperative swallowing and observe whether staining
      or aspiration occurs. By so doing, we have improved postoperative swallowing in
      25 patients after extended surgery for cancer and were able to detect or exclude
      aspiration. The advantages of this minimally invasive, non-stressful diagnostic
      procedure are discussed and can be important for further successful care after
      surgery.

PMID- 10412659
TI  - [Nasal T-cell lymphoma of the lethal midline type. Case report and current
      aspects in the literature].
AB  - A case of nasal T-cell lymphoma as a cause of lethal midline granuloma in a 41
      year-old woman is described. Primary chemotherapy as management failed, and tumor
      control was achieved thereafter by local radiotherapy to a dose of 52 Gy.
      Fourteen months after diagnosis the patient died in multiorgan failure with
      involvement of her skin, lung and liver. Present studies give strong evidence
      that lethal midline granuloma is very often a type of T-cell lymphoma that might
      be caused by Epstein-Barr virus. According to the literature our findings support
      the hypothesis that tumors are best treated by local high-dose irradiation.

PMID- 10412660
TI  - [Megadolichobasilar artery as the etiology of sensorineural deafness in
      differential sudden deafness diagnosis].
AB  - The megadolichobasilar artery is a rare vascular anomaly that can cause a variety
      of clinical symptoms but is usually asymptomatic. Not much attention has been
      given as yet to a possible sensorineural hearing loss caused by a
      megadolichobasilar anomaly. Vascular compression of the vestibulocochlear nerve
      must be assumed to be the pathogenic factor. The megadolichobasilar anomaly
      represents a rare entity in the differential diagnosis of sudden idiopathic
      sensorineural hearing loss. More common causes are acoustic neuromas,
      monosymptomatic Meniere's disease and rupture of the round window membrane. We
      present the case of a 71-year-old white male in whom magnetic resonance
      angiography combined with contrast-enhanced computed tomography in three
      dimensional reconstruction eventually led to the diagnosis of megadolichobasilar
      anomaly. The combination of both imaging techniques may be required for the
      effective diagnosis of similar vascular anomalies.

PMID- 10412661
TI  - [Manifestation of epidermolysis bullosa acquisita (EBA) in the ENT area].
AB  - Epidermolysis bullosa acquisita (EBA) is a rare, chronic, acquired bullous
      autoimmune dermatosis. It is characterized by the formation of IgG autoantibodies
      against type VII procollagen of anchoring fibrils with subepidermal formation of
      bullous lesions and consequent scarring. The epidemiology of this disease and its
      characteristic clinical findings cannot be completely surveyed at present due to
      the limited number of available publications. In general, bullous lesions form on
      the entire integument and can also involve mucosa. The development of scar
      related adhesions on the mucosa of the upper airways and esophagus can lead to
      serious complications that are difficult to treat. We report our experience in
      managing a 44-year-old male patient in whom the diagnosis of EBA was established
      in 1993 on the basis of multiple persistent bullous lesions involving the eye,
      nose, skin and oral, pharyngeal and laryngeal mucosa. After failing previous
      medical and surgical therapies, interdisciplinary management resulted in the
      control of active lesions with extracorporal phototherapy and cyclosporin A.

PMID- 10412662
TI  - [The snap system. Advantages of a new attachment system for osseointegrated ear
      epitheses].

PMID- 10412664
TI  - [Rapidly progressing hearing loss. Lymphangioma of the cochlear nerve].

PMID- 10412663
TI  - [Pigmented tumor of the mouth mucosa. Amalgam tattooing].

PMID- 10412665
TI  - [Anatomy and physiology of the auditory tube. Therapeutic possibilities in
      chronic disorders of tubal function].

PMID- 10412667
TI  - Evaluation of solid phase microextraction for the analysis of hydrophilic
      compounds.
AB  - Two commercially available solid phase microextraction (SPME) fibers,
      polyacrylate and carboxen/polydimethylsiloxane (PDMS), were evaluated for their
      ability to extract hydrophilic compounds from drinking water. Conditions, such as
      desorption time, desorption temperature, sample temperature, sample stirring,
      methanol concentration in the sample, and ionic strength of the sample, were
      optimized for 12 hydrophilic compounds (e.g., amines and alcohols) with both
      fibers. Accuracy, precision, and method detection limits (MDLs) were determined
      for the target analytes with both fibers. In general, both fibers exhibited
      excellent accuracy and precision in the range of 91-110% and 1.0-13%,
      respectively. The carboxen/PDMS fiber extracted these hydrophilic compounds from
      water with 10 to 100 times lower MDLs (0.10 to 15 micrograms/l) than the
      polyacrylate fiber (1.5 to 80 micrograms/l). The MDLs of the carboxen/PDMS fiber
      demonstrate that SPME is a feasible approach for extracting hydrophilic compounds
      from drinking water.

PMID- 10412666
TI  - Mapping of volatile organic chemicals in New Jersey water systems.
AB  - To characterize volatile organic chemical (VOC) contamination in public water in
      New Jersey from 1978 through 1990, detailed GIS maps were developed, along with
      descriptive text and an associated contaminant database, broken into half-year
      periods. All water providers that served more than 500 service connections were
      mapped. Contamination status for nine VOCs, including total trihalomethanes
      (THMs), was estimated for about 90% of the state's population. Many water systems
      were partitioned into smaller subsystems in order to map service areas that were
      more homogeneous with regard to water quality in order to minimize exposure
      misclassification. Data used for this work included test results taken by the New
      Jersey Department of Environmental Protection or the water utilities (raw, plant,
      and distribution system samples), an analysis of probable water use and water
      flow (based on pumpage, population, system architecture, and advice from the
      water systems), and information on service area extensions during the period.
      Using GIS applications, these maps and databases were used to estimate the size
      of the population exposed to contaminants over time, demonstrating a dramatic
      decrease in exposed population after the New Jersey Safe Drinking Water Act was
      signed in 1984.

PMID- 10412668
TI  - Assessment of disinfection by-products in drinking water in Korea.
AB  - The main purpose of applying the chlorination process during water treatment is
      for disinfection. Research results, however, indicate that disinfection
      byproducts (DBPs) including trihalomethanes (THMs), haloacetic acids (HAAs),
      haloacetonitriles (HANs), haloketones (HKs), and chloropicrin (CP) can be
      produced by the chlorination process. Some of these DBPs are known to be
      potential human carcinogens. This 3-year project is designed to establish a
      standard analysis procedure for DBPs in drinking water of this country and
      investigate the distribution and sources of specific DBPs. The occurrence level
      of DBPs in drinking water was below 50 micrograms/l in most cases. THMs in plant
      effluent accounted for 60% of all DBPs measured, whereas HAAs accounted for 20%,
      HANs 12%, HKs 5% and CP 3%. Chloroform was found to be the major THMs compound
      (77%), followed by bromodichloromethane (BDCM, 18%) and bromoform (BF, 3%). The
      concentration of DBPs formed in distribution systems increased from those
      detected in plant effluent. Comparison of humic acid and sewage as precursors for
      THMs formation showed that humic acid was the major THMs precursor. Results would
      play an important role in exposure assessment as a part of the risk assessment
      process, and would give basic information for establishment of DBPs reduction and
      management procedures.

PMID- 10412669
TI  - Identification of drinking water contaminants in the course of a childhood cancer
      investigation in Toms River, New Jersey.
AB  - Using a combination of gas chromatography/mass spectrometry (GC/MS) and gas
      chromatography/infrared spectroscopy (GC/IR) spectroscopic techniques, chemical
      contaminants and their hydrolysis products were identified in well water sampled
      in connection with a suspected childhood cancer cluster located in Dover
      Township, Ocean County, New Jersey. The drinking water contamination resulted
      from the leaching of industrial waste chemicals from drums that were disposed of
      at the site known as Reich Farm. Contaminants identified include dinitrile
      tetralin compounds, known as 'trimers,' that are by-products of a polymerization
      process widely used by several polymer manufactures during the 1970s and 1980s
      (and still used today). Also identified were 'trimer' hydrolysis products, formed
      by the hydrolysis of their nitrile groups to amides. These industrial
      contaminants were not present in any of the mass or IR spectral library
      databases, and their identification required unconventional spectroscopic methods
      (including high resolution mass spectrometry, chemical ionization mass
      spectrometry, and IR spectroscopy), along with scientific reasoning and
      interpretation. It is currently not known whether these chemical contaminants are
      responsible for the childhood cancers observed in this area.

PMID- 10412670
TI  - Concentrations of volatile organic compounds in the passenger side and the back
      seat of automobiles.
AB  - The in-vehicle volatile organic compound (VOC) concentrations during commutes
      have previously been measured in only one single interior sampling location,
      considering a sample collected in the single interior location as representative
      of overall VOC concentrations within an automobile. The present study evaluated
      if the potential differences in VOC concentrations occur in the automobiles'
      interior during idling and commuting under different driving conditions
      associated with the use of air cleaning devices (ACDs) and interior fan. The
      experiments were conducted under the low ventilation condition with the windows
      and the vent closed and the fan off. The difference of VOC concentrations between
      passenger side and back seat during idling was small. The variability of VOC
      concentrations with location inside automobiles while commuting was not
      significant at p < 0.05, regardless of the use of ACDs and/or the interior fan,
      while inter-vehicle variability was significant at p < 0.05. In addition,
      currently available ACDs equipped with activated carbon filters in Korea were
      ineffective at removing VOCs from the interior of automobiles. The concentrations
      of the two lightest ones of the target compounds, benzene and toluene, were
      significantly higher inside two vehicles than in the roadway air at p < 0.05,
      while the in-vehicle and roadway concentrations of the other target compounds did
      not differ significantly at p < 0.05 for both vehicles. The concentrations of all
      target VOCs, except benzene, were significantly higher (p < 0.05) in the interior
      of older car than of newer car. Median in-vehicle concentrations of benzene,
      toluene, ethylbenzene, p-xylene, m-xylene, and o-xylene were 38.3, 107, 9.2, 7.8,
      16.9, and 10.7 micrograms/m3, respectively.

PMID- 10412671
TI  - Monitoring personal fine particle exposure with a particle counter.
AB  - Numerous epidemiological studies have demonstrated associations between ambient
      combustion-source particulates and adverse health outcomes. In order to better
      understand exposure to particles, we evaluated a portable particle counter for
      its ability to measure short-term peaks in personal particle exposure associated
      with various activities, such as proximity to vehicular traffic. In a series of
      laboratory and field measurements, a hand-held particle counter was evaluated by
      collecting simultaneous filter samples of particulate matter less than 2.5
      microns (PM2.5) using a personal monitor. Time activity information was collected
      using a Personal Digital Assistant (PDA) which allows for linking of exposure
      events and particle measurements with 1 min temporal resolution. Laboratory and
      field experiments comparing the particle counter with the personal PM2.5 samples
      indicated low correlations (R2 < or = 0.39) for all size ranges. Despite these
      rather poor correlations, field measurements collected during different commuting
      modes (walking/cycling, car, bus, subway) and in different microenvironments
      indicated the ability of the particle counter to measure short-term particle
      exposures, especially those associated with combustion sources. Stratifying the
      measured particle counts by proximity to different particle sources enabled us to
      identify activities/microenvironments which were associated with higher
      exposures. Outdoor particle counts were significantly higher than indoor counts
      for particles smaller than 5.0 microns. Significantly elevated particle exposures
      were associated with proximity to environmental tobacco smoke (ETS), cooking
      emissions, wood smoke and with travel in vehicles powered with internal
      combustion engines.

PMID- 10412672
TI  - Urban commuter exposure to particle matter and carbon monoxide inside an
      automobile.
AB  - In-vehicle exposures to different sizes of particles and carbon monoxide (CO)
      were determined while driving along a standardized route under a variety of
      traffic conditions in Kuopio, Finland during the 12-month period from January to
      December 1995. Arithmetic means of in-vehicle exposures during the morning rush
      hours were 5.7 parts per million (ppm) (geometric mean, GM = 3.1 ppm, geometric
      standard deviation, GSD = 1.7) for CO, 107 #/cm3 (GM = 75 #/cm3, GSD = 1.9) for
      fine particles (optical equivalent particle size range 0.3-1 micron) and 0.9
      #/cm3 (GM = 0.6 #/cm3, GSD = 2.1) for coarse particles (optical equivalent
      particle size range 1-10 microns). Fine particles and CO behaved similarly in
      different weather and traffic conditions, while the behavior of coarse particles
      was usually different, and often opposite. The driving conditions that affected
      the passengers' exposures to CO and fine particles were the time of day (morning
      vs. afternoon) and average speed (decreasing). The meteorological parameters that
      affected the passengers' exposures to CO and fine particles were wind speed
      (decreasing) and relative humidity (increasing). Wind speed, relative humidity
      and driving speed all had opposite effects on the exposure levels to fine vs.
      coarse particles. Added exposures (due to commuting on top of the background
      levels) to CO and fine particles were considerably higher in the morning vs. the
      afternoon runs and also higher in the slower vs. the faster runs.

PMID- 10412673
TI  - Models of exposure to carbon monoxide inside a vehicle on a Honolulu highway.
AB  - This paper presents statistical models of passenger exposure to carbon monoxide
      (CO) inside a motor vehicle as it traveled a coastal highway in Honolulu, Hawaii
      during morning periods between November, 1981 and May, 1982. The 3.85-mile study
      site was divided into three links. The models predict the average CO
      concentration inside the vehicle's passenger cabin on the third link as a
      function of several variables: the average CO concentrations inside the cabin on
      previous links; traffic, temporal, and meteorological variables; motor vehicle CO
      emission factors; and ambient CO concentrations. Based on data for 80 trips, the
      three most powerful models (adjusted R2 = 0.69) were nonlinear combinations of
      four variables: the average CO concentration inside the cabin for the second
      link; wind speed and direction; and either the travel time, vehicle speed or CO
      emission factor for the third link. Several nonlinear models were based on data
      for 62 trips for which nonzero, ambient CO concentrations were available. For
      this database, the most practical models (adjusted R2 = 0.67) combined three
      variables: the ambient CO concentration; the second-link travel time; and either
      the travel time, vehicle speed or CO emission factor for the third link. Two
      factors of third-link CO exposure varied seasonally. Relatively lighter traffic
      flows and stronger winds lowered cabin exposures during late fall, while heavier
      traffic flows and calmer winds elevated cabin exposures during winter and spring.
      This study confirms the importance of seasonal effects on cabin exposure, as
      observed by a California study, and adds new insights about their effects.

PMID- 10412674
TI  - The MTBE air concentrations in the cabin of automobiles while fueling.
AB  - Methyl tertiary-butyl ether (MTBE) is the most commonly used oxygenated compound
      added to gasoline to reduce ambient carbon monoxide levels. Complaints about
      perceived MTBE exposures and adverse health symptoms have been registered in
      several states, including New Jersey (NJ). Fueling automobiles is the activity
      thought to cause the highest environmental MTBE exposures. The current study was
      conducted to determine the MTBE concentrations inside automobile cabins during
      fueling, which represents the peak exposure that can occur at full service
      gasoline service stations, such as those that exist in NJ. Air samples were
      collected at service stations located on the NJ and PA turnpikes from March 1996
      to July 1997 during which the MTBE content in gasoline varied. A bimodal
      distribution of MTBE concentrations was found in the cabin of the cars while
      fueling. The median MTBE, benzene and toluene in cabin concentrations were 100,
      5.5 and 18 ppb, respectively, with the upper concentrations of the distribution
      exceeding 1 ppm for MTBE and 0.1 ppm for benzene and toluene. The highest in
      cabin concentrations occurred in a car that had a malfunctioning vapor recovery
      system and in a series of cars sampled on an unusually warm, calm winter day when
      the fuel volatility was high, the evaporation maximal and the dispersion by wind
      minimal. The in-cabin concentrations were typically higher when the car window
      was opened during the entire fueling process. Thus, exposure to MTBE during
      fueling can be reduced by properly maintaining the integrity of the fuel system
      and keeping the windows closed during fueling.

PMID- 10412675
TI  - Hidden presence of cow's milk proteins in foods.
AB  - Cow's milk is one of the first foreign proteins ingested by infants and is one of
      the most common and potent food allergens. The presence of cow's milk is
      widespread due also to its unlabelled inclusion as an ingredient, or to errors in
      cooking, processing and preparation, and in restaurant food. As several foods may
      contain cow's milk in a hidden form, foods for allergic babies should be prepared
      at home or with food items with all their ingredients listed on the label.
      Parents should be provided with appropriate material and instructed how to detect
      potential sources of hidden cow's milk by judiciously reading food labels to
      avoid possible untoward reactions. A study on products with potential hidden
      forms of cow's milk or its proteins is reported herein.

PMID- 10412677
TI  - Dermatophagoides pteronyssinus cluster immunotherapy. A controlled trial of
      safety and clinical efficacy.
AB  - We designed a cluster schedule of immunotherapy for patients allergic to
      Dermatophagoides pteronyssinus to reach the maximal recommended dose in 7 weeks.
      We compared its safety and clinical efficacy with those of a conventional
      schedule in a controlled trial. Sixty-three patients were randomized as follows:
      29 were treated with the cluster schedule, 15 with a conventional schedule and 19
      without immunotherapy. A standardized extract was used. Clinical efficacy was
      measured by visual analog scale, clinical severity score, symptom/medication
      diary cards and control of peak expiratory flow (PEF) in asthmatic patients,
      before immunotherapy (T0), on reaching the maintenance phase (T1), and after 6
      (T2), 12 (T3) and 18 months of maintenance (T4). The safety of immunotherapy was
      found to be good. Visual analog scale improved significantly at T4 in the cluster
      and conventional schedules, and clinical severity score also improved from T1 in
      these schedules. Diary cards improved from T1 in the cluster schedule and from T2
      in the conventional schedule in asthmatic patients. Significant improvements in
      diary cards in rhinitis patients and PEF were found only in the cluster schedule.
      There were no changes in the group without immunotherapy. In conclusion, our
      cluster schedule showed as good tolerance and clinical efficacy as the
      conventional schedule in patients allergic to D. pteronyssinus. These clinical
      improvements did not appear in the group without immunotherapy.

PMID- 10412676
TI  - Cluster versus conventional immunotherapy in patients allergic to
      Dermatophagoides pteronyssinus: a controlled study of in vivo and in vitro
      parameters.
AB  - We designed a cluster schedule of immunotherapy for patients allergic to
      Dermatophagoides pteronyssinus which showed good safety and clinical efficacy.
      Here we compare the in vivo and in vitro changes with those of a conventional
      schedule in a controlled trial. Sixty-three patients were randomized as follows:
      29 were treated with the cluster schedule, 15 with a conventional schedule and 19
      received no immunotherapy. A standardized extract was used. Changes in in vivo
      parameters (skin prick test and conjunctival provocation test) and in in vitro
      parameters (IgE, IgG, IgG1 and IgG4 for the complete extract, Der p 1 and Der p
      2) were measured before immunotherapy (T0), on reaching maintenance phase (T1),
      and after 6 (T2), 12 (T3) and 18 months of maintenance (T4). Cutaneous reactivity
      showed a significant decrease from T1 in both the cluster and conventional
      schedules, and conjunctival reactivity was also significantly lowered from T1 in
      these groups. Specific IgE decreased and specific IgG, IgG1 and IgG4 increased
      significantly from T1 in the cluster and conventional schedules. Neither of these
      parameters showed any changes in the group without immunotherapy. In conclusion,
      our cluster schedule induced changes in cutaneous and conjunctival reactivity and
      in immunological parameters that were similar to those achieved with the
      conventional schedule; these changes did not appear in patients who did not
      undergo immunotherapy.

PMID- 10412678
TI  - Detection of allergens in Aedes albifasciatus mosquito (Diptera: Culicidae)
      extracts by immunological methods.
AB  - Aedes albifasciatus (Diptera: Culicidae) is the most common mosquito species in
      Argentina and it has been demonstrated to be the vector for some pathogens. The
      objective of this study was to describe the allergen composition of this mosquito
      species endemic to Argentina using SDS-PAGE and immunoblotting methods. Sera from
      mosquito-bite allergic subjects were employed. The protein extracts, obtained
      from thoraxes containing salivary glands, showed a protein pattern with
      components of apparent molecular weights ranging from 14 to over 94 kDa. Some of
      the components could bind IgE in the 16, 20, 30, 36 and 50-67 kDa-zones, whereas
      the 14 kDa fraction detectable by SDS-PAGE did not behave as an allergen with any
      positive serum. This protein extract was used to develop in vitro assays to
      detect the presence of serum-specific IgE against proteins from A. albifasciatus
      (RAST and ELISA). Thirty-five sera from patients showing local reactions after
      mosquito bites were tested. The 21 positive sera were from subjects with clinical
      histories of atopic signs. Through immunoblotting, these sera revealed IgE
      reactivity against several fractions, mainly in the 16, 20, 30, 36 and 50-67 kDa
      zones. Comparing the serum IgE reactivity pattern against A. albifasciatus and
      Aedes aegypti, we observed that the main difference was found in the 14 kDa
      region where a strong reactivity was seen. The immunoblotting inhibition results
      indicate that there might be species-unique and species-shared antigens between
      A. albifasciatus and A. aegypti.

PMID- 10412679
TI  - Evaluation of drug-related hypersensitivity reactions in children.
AB  - Patients with drug reactions are often referred to allergists for "allergy". Skin
      testing and clinical history seem to have a good negative predictive value,
      however, although drug challenge could be dangerous, it is the only way to
      confirm the diagnosis. We aimed to demonstrate that most children with a history
      of non-life-threatening drug reactions do not have a true drug allergy and
      examined the use of drug challenge in childhood. Patients with reactions were
      referred to our clinic by pediatricians. In 1 year, 354 reactions were studied in
      239 children. Patients were classified according to their positive or negative
      history of drug allergy. Skin prick testing was done in all cases. Exclusion
      criteria for challenge included drug anaphylaxis, Stevens-Johnson syndrome,
      systemic reactions with severe concomitant illness, beta-inhibitor drug therapy
      or positive skin test to the implicated drug with a positive history. It was
      found that the beta-lactam antibiotics were involved in 50% of suspected
      reactions, aspirin in 10% and sulfonamides in 9%. Histories were considered
      positive only in 25%. Drug challenges confirmed only 4% of all reactions. It was
      concluded that drug challenge may be the gold standard for most childhood
      reactions that are considered to be allergic, non-life-threatening and drug
      related. Only 4% of these suspected reactions were exclusively caused by drug
      allergy.

PMID- 10412680
TI  - Effect of bacterial antigen lysate on IgG and IgA levels in children with
      recurrent infections and hypogammaglobulinemia.
AB  - To evaluate the effect of bacterial antigen lysate on serum immunoglobulin (Ig)
      levels, we studied 14 children with recurrent infections and
      hypogammaglobulinemia (IgG and IgA levels below 2 standard deviations for age).
      Patients were treated for a 60-90 day period with OM-85 BV and reevaluated both
      clinically and by measuring serum Ig levels at the end of follow-up. The control
      group consisted of 10 children with recurrent infections who received a placebo.
      Serum Ig levels were also compared with the reference values for age. The
      Wilcoxon and Mann-Whitney tests were used for statistical analysis. In the study
      group, IgG (pretreatment: 707 mg/dl; post-treatment: 1,022 mg/dl; p < 0.004) and
      IgA levels (pretreatment: 41 mg/dl; post-treatment: 83 mg/dl; p < 0.018)
      increased significantly. Furthermore, 13/14 children reached normal IgG levels,
      and 12/14 children reached normal age levels for serum IgA. Similarly, when
      comparing the pre- and post-treatment levels in the study group with the levels
      in the control group, they were significant for IgG (p < 0.002) as well as IgA
      levels (p < 0.04). The overall clinical response was favorable in all patients in
      the treated group. These results suggest an immunostimulant effect of OM-85 BV,
      both improving Ig levels and reducing recurrent infections.

PMID- 10412681
TI  - Allergen-specific IgE in circulating immune complexes in patients with inhalant
      allergy undergoing specific immunotherapy.
AB  - Specific immunotherapy (SIT) has been used worldwide since it was introduced near
      the beginning of this century. Although this mode of therapy has been known for
      over 80 years, its mechanism of action is still not definitely clear. The problem
      of the presence of allergen-specific IgE in IgE-containing circulating immune
      complexes of patients with inhalant allergy has been mentioned in the literature.
      However, there are no data concerning specific immunotherapy. The aim of our
      study was to evaluate the influence of SIT in patients with inhalant allergy on
      allergen-specific IgE in serum and in IgE circulating immune complexes. A total
      of 112 subjects with allergic rhinitis (57 with grass pollen allergy and 55
      sensitive to house dust mites Dermatophagoides pteronyssinus) were included in
      the study. SIT was administered to 29 patients suffering from pollinosis and 27
      patients sensitive to house dust mites. The remaining patients were treated with
      an H2-receptor antagonist only. The decrease of allergen-specific IgE
      concentration in IgE circulating immune complexes was parallel to the analogous
      changes in the serum only in the patients with pollinosis. Immunotherapy of house
      dust mite-sensitive patients caused a much slower decrease of allergen-specific
      IgE in circulating immune complexes than in serum. The binding index of allergen
      specific IgE in circulating immune complexes increased during the course of the
      treatment. No significant associations were found between the immunological
      indices studied and clinical score of the disease activity.

PMID- 10412682
TI  - Serum sickness-like syndrome due to mosquito bite.
AB  - Local inflammatory reactions at the site of a mosquito bite are frequent.
      Immediate systemic reactions have occasionally been reported. The first case of a
      patient with relapsing episodes of a serum sickness-like syndrome following
      mosquito bites is reported herein. A 62-year-old patient came to the emergency
      room complaining of sudden malaise, chills, fever, headache, cervical lymph node
      enlargement, arthromyalgia, generalized purpura and leukopenia 6 h after a
      mosquito bite. He had experienced multiple similar episodes in the last 20 years,
      also following mosquito bites. Infectious and autoimmune diseases were ruled out.
      Serum IgE was 9,102 kU/l. Prick test of whole-body Culex pipiens extract was
      positive. Specific IgE to Aedes communis was 2.25 kU/l. SDS-PAGE immunoblotting
      of the patient's serum with whole-body C. pipiens extract revealed 43 and 17 kDa
      IgG-binding proteins and 22 and 17 kDa IgE-binding proteins, neither of which
      were found with control sera. Skin biopsy was consistent with leukocytoclastic
      vasculitis. The presence of both mosquito-specific IgE and IgG in the patient's
      serum suggest a possible cooperative immune response leading to clinical
      manifestations of serum sickness.

PMID- 10412684
TI  - Immunoblotting technique for the detection of allergens of Aspergillus fumigatus:
      influence of Nonidet P-40 on the sensitivity.
AB  - Immunoblotting provides a useful technique for the study of antigens, antibodies
      and allergens. To overcome problems regarding the loss of antigenic properties
      during the blotting and developing procedures, several solutions have been
      described. The inclusion of Nonidet P-40, recommended to increase the sensitivity
      of developing procedures for immunoblots, in an existing procedure for the
      detection of allergens of Aspergillus fumigatus, however, led to decreased
      sensitivity of the method.

PMID- 10412683
TI  - Allergic dermatitis due to oral ebrotidine.
AB  - We report the case of a woman who developed generalized dermatitis after 1 week
      of treatment with ebrotidine, a new H2-receptor antagonist taken to prevent
      gastroduodenal lesions caused by nonsteroidal inflammatory drugs. Patch tests
      with ebrotidine and other H2-receptor antagonists ranitidine, cimetidine and
      famotidine were negative. Oral challenge test with ebrotidine showed the
      development of lesions similar to those appearing previously. Oral challenge test
      with ranitidine and cimetidine were negative, possibly due to the difference in
      the side chain chemical structure of ebrotidine and other H2-receptor
      antagonists. This is the first reported case of allergic dermatitis caused by
      ebrotidine.

PMID- 10412685
TI  - Stress accelerates the slide from HIV to AIDS.

PMID- 10412686
TI  - Parenting education as family support for low-income families of young children.
AB  - Parenting education programs can strengthen the family unit as a nurturing center
      of child development. The Establish Rapport-Offer Information-Promote Attachments
      Initiate Outreach guide provides a framework that addresses individual and family
      needs. Any parenting class should include opportunities for referral and out
      reach efforts to help parents who are facing multiple stressors.

PMID- 10412687
TI  - Wearing two hats. Consumer & provider.
AB  - To change public attitudes toward people with mental illness, consumers need
      positive visibility and a strong community voice. We are making progress,
      although slowly, to eliminate the stigma surrounding mental illness. Progress can
      be attributed to the fact that the mentally ill are now living in our communities
      among us, and people are beginning to understand them more.

PMID- 10412688
TI  - Women and anger.
AB  - Through gender role socialization, women have learned to suppress anger. This
      leads to somatization and a denial of a sense of self. To teach women how to
      express anger, methods of anger acknowledgment and expression have been provided.
      Through the teaching of these techniques, nurses can assist women to experience a
      paradigm shift: from the belief that "others are responsible for meeting women's
      needs" to the belief that "women are personally responsible for meeting their own
      needs." By teaching women assertive communication, nurses can provide women with
      effective tools to regain control of their life experiences. The "Exercise
      Application" presents an example of a paradigm shift for the experience of anger.

PMID- 10412689
TI  - Chronic sorrow: the experience of parents with children who are developmentally
      disabled.
AB  - 1. Adaptation mechanisms differ between mothers and fathers of developmentally
      disabled children. 2. Mothers' emotions radiate into chronic sorrow while
      fathers' reactions move toward resignation. 3. Patterns of grief and sadness
      reemerge and are most often precipitated by a health care crisis in women and
      comparison with social norms in fathers.

PMID- 10412690
TI  - Achieving spiritual wellness: using reflective questions.
AB  - Health care professionals are increasingly recognizing the importance of
      spiritual health as a precursor of physical health. As we emerge into the 21st
      century, we must place greater emphasis on promoting spiritual wellness so that
      clients do not develop spiritual distress. Assisting clients in developing their
      spiritual wellness is a rewarding experience for nurses. As health care
      providers, we have the opportunity to educate the public about spiritual wellness
      to prevent physical problems. Attentiveness to one's spirit is a key component to
      healing and becoming a whole person. With guidance, clients can initiate a plan
      to maintain their own spiritual needs.

PMID- 10412691
TI  - [Neurology--more than 100 years old and not yet grown up?].

PMID- 10412692
TI  - [New insights in the molecular genetics and pathophysiology of hereditary
      ataxias].
AB  - The hereditary ataxias are a heterogeneous group of inherited neurodegenerative
      disorders characterised by progressive ataxia that results from degeneration of
      the cerebellum and its afferent and efferent connections. With respect to the
      pathogenic mechanisms, the hereditary ataxias may be tentatively divided into
      three groups: (1) The recessive ataxias are induced by the functional impairment
      of a protein that is essential for the survival of specific neurons while the
      autosomal dominant ataxias are either caused by (2) mutations of genes coding for
      ion channels thus resulting in a channelopathy or by (3) a novel deleterious
      function of a extended polyglutamine sequence within the proteins encoded by the
      respective genes.

PMID- 10412693
TI  - [Neuropsychology of normal pressure hydrocephalus].
AB  - Although dementia is described as one of the constituent characteristics of
      normal pressure hydrocephalus (NPH), alongside gait disturbances and urinary
      incontinence, there is a rather limited number of controlled studies concerning
      neuropsychological deficits in the disease. A wide range of psychopathologically
      relevant symptoms have been described, but the common features of most cases
      include mental and motor slowing, apathy, emotional indifference, anosognosia,
      memory and attentional impairment. A number of other functional deficits such as
      dyslexia, dysgraphia, acalculia, apraxia can also frequently be found. Some
      emphasis is put on the work of J. de Mol (Brussels) which appears to be most
      important for the study of neuropsychological symptoms in NPH patients. The
      methodological standard of a number of studies has been found to be rather low,
      and yet a sound neuropsychological investigation may be of utmost importance for
      the diagnosis and neurosurgical outcome assessment. Concerning morphological
      correlates of the functional deficits in NPH, various hypotheses have been
      formulated, but it is argued that symptoms can neither be described as
      predominantly "diffuse" in nature, nor can they be reduced to unilocular
      dysfunctions. Recommendations for future research strategies are formulated.

PMID- 10412694
TI  - [Genetic counseling and prenatal diagnosis in mitochondrial diseases].
AB  - Since mitochondrial diseases lead frequently to severe phenotypes and are often
      hereditary, there is a need for genetic counselling of the affected families. The
      specific features of mitochondrial genetics, however, hamper straightforward
      definition of recurrence risks as in Mendelian diseases. Empirical risks were
      recently provided for MELAS and MERRF syndromes and for Leber hereditary optic
      neuropathy. In MELAS and MERFF, higher levels of mutant mtDNA in the mothers'
      blood were associated with an increased frequency of affected offspring. Chronic
      progressive external ophthalmoplegia and Kearns-Sayre syndrome are in general
      sporadic disorders without increased recurrence risks in the offspring. As Leigh
      syndrome is found with maternal, autosomal recessive or X chromosomal
      transmission, the definition of the molecular defect is crucial for genetic
      counselling. Prenatal diagnosis was reported only in one case of mitochondrial
      disease so far, and in our opinion it remains questionable because of the
      uncertain correlation of the proportion of mutant DNA in chorionic villi and in
      clinically relevant tissues such as brain.

PMID- 10412696
TI  - [Neuronavigation. Computer-assisted neurosurgery].
AB  - The use of stereotactic methods for the resection of subcortical lesions is
      heavily advocated in clinical neurosurgery introducing the term
      "neuronavigation". Though being an unequivocally elegant technique for the
      localisation and delineation of pathological lesions in the central nervous
      system neuronavigation has not been validated by any prospective randomized
      controlled trial. The method is prone to significant errors as to the
      intraoperative localisation based upon preoperative three-dimensional images. The
      maximum error can be up to 2.6 cm depending on the extent of the so-called brain
      shift. In comparison classical frame based stereotaxy has a mean error of +/- 1
      mm and remains the gold standard for the exact three-dimensional localisation of
      a given lesion. The value of neuronavigation is evident for small deep seated
      vascular lesions. For metastatic tumors or skull base tumors the usefulness is
      rather marginal because alternative therapies are available with proven and
      equivalent efficacy and reduced morbidity on one hand, and because of the anatomy
      of the tumor which makes neuronavigation unnecessary. For the currently most
      common application of neuronavigation, i.e. surgery of gliomas, no significant
      improvements of therapeutic results can be expected from neuronavigation. The
      biology of gliomas limits any mechanical approaches.

PMID- 10412695
TI  - [Matrix metalloproteinases. Potential targets for new treatments in inflammatory
      demyelinating diseases of the nervous system].
AB  - Inflammatory demyelinating diseases of the nervous system, such as multiple
      sclerosis or the Guillain-Barre syndrome represent severely disabling disorders,
      often seen by the neurologist, with still only limited means for therapeutical
      intervention. The underlying pathomechanisms remain in large part elusive,
      however mounting evidence suggests that enzymes of the family of matrix
      metalloproteinases are of relevance in the pathogenesis of these disorders.
      Experimental in vivo data as well as results from other medical fields emphasize
      that the selective inhibition of these proteases could be a promising
      therapeutical approach. The following review summarizes the role of matrix
      metalloproteinases in inflammatory demyelinating diseases of the central as well
      as peripheral nervous system and discusses the therapeutical application of
      synthetic inhibitors in these disorders.

PMID- 10412697
TI  - [Psychosocial handicap due to chronic headaches. Evaluation of the inventory of
      Disabilities caused by Headache].
AB  - Chronic primary headache has a considerable impact on the quality of life. To
      date, this impact has been evaluated by measurements of the general pain specific
      impairment of the quality of life. Headache specific measurements of quality of
      life or of disability caused by the headache are still missing for the German
      language. In America, a headache specific questionnaire, the "Headache Disability
      Inventory" (HDI), has been evaluated which is used in the presented study to
      create a German version, the "Inventar zur Beeintrachtigung durch Kopfschmerzen"
      (IBK). 94 consecutive patients with a primary headache disorder (59 female, 35
      male; mean age 40 +/- 12 years) were examined. Cronbach's alpha was a = 0.90, the
      test-retest-reliability after three months was r = 0.87. An analysis of subscales
      for emotional and functional disability showed similar values for the internal
      consistency and the test-retest-reliability of these subscales. The scores of the
      different headache types did not differ significantly. In post-hoc-analyses,
      however, cluster headache showed higher disability scores than migraine both in
      the total scale and in the subscales. The total score of the IBK was
      significantly correlated with the number of headache days per month (r = 0.41; p
      < 0.0003) but not with the duration of disease or other demographic parameters.
      The IBK is the first German headache specific measurement of certain aspects of
      the quality of life in chronic headache patients. It can be used in clinical
      settings to evaluate the current state of the patient or to monitor treatment and
      it can be used for scientific studies.

PMID- 10412698
TI  - ['Frontal lobe syndrome' caused by severe head trauma or cerebrovascular
      diseases].
AB  - The term "frontal lobe syndrome" comprises a variety of different clinical
      syndromes produced by focal lesions involving the prefrontal cortex. However,
      similar syndromes can be observed after lesions involving subcortical structures
      connected with the prefrontal cortex in neuronal networks. With respect to the
      different clinical pictures and underlying brain lesions, prefrontal lobe
      dysfunction may be divided into a disorganized type, caused by lesion of the
      dorsolateral prefrontal lobe and its connections, a disinhibited type that can be
      observed following lesions of the orbitofrontal cortex, and an apathetic type
      following lesions affecting the functional balance between the cingulum and the
      supplementary motor area. As intracerebral lesions are rarely limited to the
      brain regions described, in the majority of patients various degrees of
      behavioural dysfunction can be observed. The case reports of four patients
      illustrating the three major prefrontal syndromes following severe head injury (n
      = 2) or cerebrovascular disease (n = 2) are presented and diagnostic implications
      as well as possible treatment strategies are discussed.

PMID- 10412699
TI  - [Moderate hypothermia for the treatment of malignant middle cerebral artery
      infarct].
AB  - Moderate hypothermia was induced in 30 patients with malignant middle cerebral
      artery (MCA) territory infarction. Patients were kept at 33 degrees C body-core
      temperature for 48 to 72 h, and ICP, CPP, and brain temperature were monitored.
      Outcome at 4 weeks and at 3 months after the stroke as well as side effects of
      moderate hypothermia were analysed. Mortality of malignant MCA infarction could
      be reduced from 80% in historical controls, to 43% (13/30) under hypothermia.
      During hypothermia elevated ICP values could be significantly reduced. Herniation
      due to a secondary rise of ICP after rewarming was the cause of death in all 13
      patients. The most frequent complication of moderate hypothermia was pneumonia in
      12 of the 30 patients (40%). Other severe side effects of hypothermia could not
      be detected. Moderate hypothermia may improve clinical outcome in patients with
      malignant MCA infarction.

PMID- 10412700
TI  - [Juvenile dermatomyositis--acute recidivism or sepsis?].
AB  - A 22-year-old male with juvenile dermatomyositis presented with fever up to 40
      degrees C and acute pain in his right thigh accompanied by muscle weakness, a
      skin rash and a tender swelling. Serum aspartate aminotransferase (AST) and
      aldolase were mildly elevated. C-reactive protein (CRP) and fibrinogen were
      markedly increased. The differential white blood cell count revealed relative
      lymphopenia. Radiography showed diffuse calcifications particularly around the
      thighs and knees of both legs. Magnetic resonance imaging (MRI) demonstrated
      inflammatory infiltrates in the right thigh. The lesions were identified as
      phlegmone by immunoszintigraphy with 99mTc-labelled antigranulocyte antibodies.
      On the 10th day of treatment Staphylococcus aureus was cultured from blood.
      Patients with juvenile dermatomyositis and calcinosis may develop bacterial
      infections of soft tissue which sometimes mimic a disease flare. For differential
      diagnosis plain radiographs, CT scans and MRI are of limited value.
      Immunoszintigraphy is able to differentiate between infiltrates caused by
      granulocytes and lymphocytes.

PMID- 10412701
TI  - [Visual field defects due to antiepileptic drugs].
AB  - Within the last years several reports concerning visual field defects, associated
      with antiepileptic drugs, have been published. In addition to antiepileptic drugs
      several other causes (e.g. retinopathy or chloroquine, phenothiazine etc.) may
      induce visual field disturbances. Visual field defects have been observed during
      vigabatrine, tiagabine, gabapentine, diazepam, phenytoine, and carbamazepine
      treatment. In 13 to 46% visual field defects are reported to be linked with
      epilepsies. In addition to general population based studies concerning visual
      field defects and prospective etiological studies in epilepsies, preclinical
      studies for the examination of the pathomechanism of visual field defects are
      necessary.

PMID- 10412702
TI  - [Secondary normal pressure hydrocephalus. A complication of chronic
      neuroborreliosis].
AB  - We report about a 57-year-old patient suffering from the typical symptoms of
      normal-pressure hydrocephalus (NPH) including gait disturbance, urinary
      incontinence, and mental deterioration. CSF analysis established the diagnosis of
      chronic active Lyme neuroborreliosis with lymphocytic pleocytosis and intrathecal
      Borrelia burgdorferi antibody production. After several weeks of i.v. antibiotic
      treatment we observed normalization of CSF parameters as well as a clear
      improvement of clinical symptoms so that surgical shunting was no longer
      indicated. Interference with subarachnoid CSF flow may be a possible cause of the
      observed symptomatic NPH in a patient with chronic Lyme neuroborreliosis.

PMID- 10412703
TI  - [Amiodarone-induced bilateral optic atrophy--a case report].
AB  - We report a case of visual loss and bilateral papilloedema under therapy with the
      antiarrhythmic substance amiodarone, which is used in treatment of refractory and
      life-threatening supraventricular and ventricular cardial tachyarrhythmias. After
      excluding intracranial hypertension, local tumors and an inflammatory genesis we
      consider this case to be an amiodarone-induced toxic opticusneuropathy.
      Amiodarone, a diiodated benzofuran derivative, is a cationic amphiphilic drug,
      which is able to cause ceratopathy and neuropathy. The rarely described and less
      known opticusneuropathy caused problems in differential diagnosis. A brief review
      about current knowledge of pathophysiology, differential diagnosis and course of
      illness is presented.

PMID- 10412704
TI  - ['Fatigue' in multiple sclerosis].
AB  - Fatigue is a common symptom in patients with multiple sclerosis. Rapid exhaustion
      and reduced exercise tolerance leads to difficulties in maintaining a normal
      daily life for many patients. Regular resting and short breaks can help to
      compensate this to a certain degree. The pathophysiology of fatigue is currently
      unknown. Damage of specific neuroanatomic regions or a more generalized effect of
      inflammatory mediators in the central nervous system could be the causes of
      fatigue. Some drugs (e.g. amantadine) have proven effective in therapy of
      fatigue. Recent therapeutic approaches have begun using aminopyridines (4
      aminopyridine, 3,4-diaminopyridine). These two substances are thought to improve
      nerve conduction, but there might be a central stimulatory effect as well.
      Overdosage leads to an elevated risk of epileptic seizures and confusion.

PMID- 10412705
TI  - [The beginning of Emil Kraepelin's classification of psychoses. A historical
      methodological reflection on the occasion of the 100th anniversary of his
      "Heidelberg Address" 27 November 1898 on "nosologic dichotomy" of endogenous
      psychoses].
AB  - Emil Kraepelin's (1856-1926) famous lecture "Zur Diagnose und Prognose der
      Dementia praecox" was held in Heidelberg 100 years ago on 27. November 1889. In
      this lecture Kraepelin suggested for the first time his famous "nosological
      dichotomy" between the group of "manisch-depressives Irresein" and the so-called
      "Dementia-praecox-Gruppe". This dichotomy became world famous since the
      publication of his "Lehrbuch der Psychiatrie", 6th edition 1899. Kraepelin
      founded his psychiatric system on outcome observations and the nosological
      principles of Kahlbaum. His nosology is very influential to the present day. The
      revision of American psychiatry in the 1970's and 1980's is unthinkable without
      Kraepelin's concept. Therefore the name "Neo-Kraepelinianism" was created.

PMID- 10412706
TI  - [Does education prevent dementia?].
AB  - PURPOSE: The association of education and the risk of developing dementia are
      reviewed. Proposed underlying mechanisms are discussed with the particular
      reference to social aspects. METHODS: The discussion is based on recent work
      published on the association of education and dementia risk dealing with incident
      cases. RESULTS: Strength and consistency of the association as well as the partly
      established dose response relationship indicate that higher education is
      associated with a lower risk of developing dementia. This had been explained as a
      consequence of a greater "brain reserve capacity", which might be constituted by
      different mechanisms in early periods of CNS-development and during adulthood.
      CONCLUSIONS: Education rather compensates neuro-degenerative changes than
      protects from dementia. Clinical signs of dementia will be delayed but not
      prevented. The knowledge about social aspects of this process implies the search
      for interventions.

PMID- 10412707
TI  - [Similarities and differences in subjective quality of life of alcoholic women].
AB  - OBJECTIVE: The present study examined quality of life of alcoholic women in
      detoxification. The study aimed at providing data in line with a so-called
      subject oriented evaluation and at finding ways for improving clinical care.
      METHODS: 70 alcoholic women were asked about their quality of life and about
      their need for qualities help. A follow-up study, six months later, examined the
      extent of relapse. RESULTS: Alcoholic women differ in their subjective quality of
      life. Subgroups, which differ regarding the structure of quality of life, also
      vary in age, job situation and finances, age of admission and their view on their
      alcohol dependence. They differ in their needs, too. Subjective quality of life
      predicts relapse. CONCLUSIONS: The findings suggest that subjective quality of
      life may be useful evaluation criterion. The assessment of quality of life may
      yield useful hints for therapeutic interventions.

PMID- 10412708
TI  - [Cooperation and job satisfaction in a nursing-physician team. An analysis of
      nursing evaluation in psychiatry].
AB  - PURPOSE: Empirical studies of nursing in psychiatry rarely consider the
      collaboration between nurses and doctors. Which variables determine the quality
      of the cooperation between nurses and doctors? METHODS: In 1992 and 1997, all
      nurses of a psychiatric hospital were interrogated by means of questionnaire
      (FAPP) in order to measure the quality of collaboration. RESULTS: In spite of
      major changes in the hospital management and higher work-load assessment by the
      nurses concerning the collaboration with doctors and with other nurses, the
      quality of team-work and participating in treatment decisions, was more positive
      in 1997. Nurses with a "negative" collaboration with doctors, also have
      difficulties to collaborate with other nurses. This finding did not depend on
      gender, age or length of professional career. CONCLUSION: All institutional
      provisions that improve the cooperation, the competence, the responsibility, and
      the ward-atmosphere, also ameliorate the cooperation with other occupational
      groups in the hospital.

PMID- 10412709
TI  - [Effects of regional obligatory health care exemplified by a university clinic].
AB  - OBJECTIVE: Local care provision for the chronically mentally ill entails
      responsibility to be taken by all institutions involved in the care system of
      their respective area. In the clinical sphere regional responsibility is
      implement-ed to a large extent apart from a few university clinics. The
      University Psychiatry and Psychotherapy Clinic Tuebingen look after an area with
      obligatory provision of care consisting of 140,000 inhabitants in 1995. RESULTS:
      The comparative evaluation of the basic documentation showed minimal overall
      changes but an increase of older patients, of patients who are frequently
      hospitalised, and of addicts. The number of emergencies remained unchanged. The
      concomitant questioning of colleagues indicated delayed acceptance of the change.
      According to experiences made to date, the conditions for research and teaching
      have improved in certain areas thanks to the obligatory provision of care.

PMID- 10412710
TI  - [Occupational status of Saxony social psychiatry service clients as a result of
      the reunification of Germany].
AB  - PURPOSE: Evaluating the establishment of social psychiatry services (SPS) in
      Saxony was part of a public health research project. METHOD: One of the variables
      in a specifically designed assessment instrument--used in 8 SPS during the period
      08/95-01/97--was the retrospective statement concerning changes in the client's
      vocational situation caused by the social upheavals in 1989. RESULTS: 40.6% (n =
      335) answered in the affirmative. Men are significantly overrepresented in the
      group with vocational changes; compared to the population without vocational
      changes the proportion of currently unemployed persons (56%) is five times
      higher; only 16% are still employed. Neurotic/personality disorders as well as
      brief mental disturbances and dependency disorders are more frequent than in the
      whole SPS-clientele.--The most important constellation (19%) identified by a
      configuration-frequency analysis is that of patients with prolonged psychotic
      disorders (started < 1990, not associated with dependency disorder) who were
      employed at sheltered workplaces during the GDR-period despite of their mental
      disorder. CONCLUSION: Following the political German reunification possibilities
      of vocational rehabilitation have deteriorated and up to now the number of newly
      established alternatives in regional mental health services is insufficient.

PMID- 10412711
TI  - [Commitment and treatment of psychiatric patients in Great Britain and Germany.
      Comparison of legal principles and medical practice].
AB  - PURPOSE AND METHODS: The legal provisions concerning the admission to hospital,
      holding powers and compulsory treatment of mentally ill persons in Great Britain
      and Germany are compared and the underlying medicolegal conceptions analysed.
      RESULTS: Whereas British law gives key powers to multiprofessional decision
      making and relatives, German law requests formal court decisions even in routine
      issues. This reflects a different understanding of individual rights and their
      protection. The German mental health law is motivated by the experiences of the
      totalitarian National Socialist regime. It tries to protect the patient's rights
      by restricting physicians, hospitals and family members' influence. British law,
      on the other hand, assumes that experts as well as family members act
      benevolently in the patient's interest, prefers less formal mechanisms and
      expresses trust in professional ethics. CONCLUSION: Further research is necessary
      to analyse the situations in other countries and to investigate which of these
      approaches is the better one from the point of view of the mentally ill. This is
      even more important as in the long view European integration will touch these
      questions and will result in convergence of medicolegal issues.

PMID- 10412712
TI  - [Which patients participate in exercise therapy? An empirical study of a
      psychiatric clinic].
AB  - OBJECTIVE: The aim of our study is to find out in which clinical and
      sociodemographic parameters patients who take part in kinetic therapy and those,
      who don't, differ. METHODS: 38 patients of a psychiatric university clinic who
      regularly took part in movement therapy were compared with 32 patients who did
      not. RESULTS: The participants had a higher level of education, obtained fewer
      psychotropic drugs and were assessed as slightly less impaired by their disorder.
      CONCLUSIONS: Our findings cannot fully explain what determines participation in
      kinetic therapy. Other factors like the cut-off of five times for assignment, the
      therapist's influence and the theory of self-efficacy need to be discussed.

PMID- 10412713
TI  - [Presentation of obsessive-compulsive symptoms in a patient with schizophrenia
      treated with clozapine].
AB  - PURPOSE: Clozapine is an atypical antipsychotic agent for the treatment of
      schizophrenic patients whose symptoms do not respond to traditional antipsychotic
      drugs. The emergence of obsessive-compulsive symptoms during treatment of
      clozapine has been reported in some case studies. We report on the case of a 31
      year old man with chronic schizophrenia who had shown obsessive-compulsive
      symptoms during treatment with clozapine. RESULTS: A 31-year old patient with
      treatment refractory schizophrenia was treated with clozapine. During clozapine
      treatment, positive symptomatology decreased, but after 4 months after starting
      clozapine the patient showed obsessive and compulsive symptoms. This
      symptomatology had previously not been a feature of this patient's illness.
      CONCLUSIONS: Obsessive-compulsive symptoms were observed during treatment of
      clozapine in a schizophrenic patient. This may be explained either by the
      serotonin-receptor antagonism of clozapine or its atypical dopaminergic receptor
      effects.

PMID- 10412714
TI  - [Angel trumpets: case report of drug-induced psychosis caused by Brugmansia
      insigniis].
AB  - A case of a psychosis induced by ingestion of blossoms of the solanum Brugmansia
      insigniis is presented. This plant is used by young persons as a hallucinogenic
      drug. The psychopathology of this kind of intoxication has not been documented in
      the literature up to now. It is characterized by anticholinergic effects (e.g.
      mydriasis), disturbances of orientation, incoherent thoughts, flight of ideas,
      tangential thinking illusions, auditory hallucinations (e.g. verbal
      hallucinations), visual hallucinations and affective lability. In addition to
      hyoscine (scopolamine) and atropine, hallucinogenic effects may be related to
      previously identified alkaloids.

PMID- 10412715
TI  - [Paranoid schizophrenia as Munchausen syndrome in a forensic psychiatry setting].

PMID- 10412716
TI  - [Loss of consciousness during treatment with sertindole].

PMID- 10412717
TI  - Calnexin associates with Shaker K+ channel protein but is not involved in quality
      control of subunit folding or assembly.
AB  - Calnexin is part of an ER chaperone system that monitors and promotes the proper
      folding and assembly of glycosylated membrane proteins. To investigate the role
      of calnexin in the biogenesis of the voltage-dependent Shaker K+ channel, wild
      type and mutant Shaker proteins were expressed in mammalian cells. Association
      with calnexin was assayed by coimmunoprecipitation. Calnexin interacted
      transiently with wild-type Shaker protein in the ER. In contrast, calnexin failed
      to associate with an unglycosylated Shaker mutant that makes active, cell surface
      channels. Therefore, glycosylation of Shaker protein is required for association
      with calnexin, but calnexin is not required for the proper folding and assembly
      of Shaker channels. We also investigated whether calnexin is involved in the ER
      retention of mutant Shaker proteins defective in subunit folding, assembly, or
      pore formation. Each of the mutant proteins associated transiently with calnexin
      during biogenesis. Calnexin dissociated from wild-type and mutant proteins with
      similar time courses. Thus, non-native Shaker proteins escape the folding sensor
      of the calnexin chaperone system. Furthermore, stable association with calnexin
      is not the mechanism by which these mutant proteins are retained in the ER. Our
      results indicate that calnexin is not involved in the quality control of subunit
      folding, assembly, or pore formation in Shaker K+ channels.

PMID- 10412718
TI  - Characterization of Ca(2+)-inhibited potassium channels in the LNCaP human
      prostate cancer cell line.
AB  - Potassium plasma membrane channels have been studied in the LNCaP androgen
      sensitive human prostate cancer cell line, derived from a lymph node of a subject
      with metastatic carcinoma of the prostate. Membrane currents were recorded by the
      patchclamp technique, using the cell-attached, cell-free and whole-cell mode. A
      voltage-dependent, non-inactivating potassium channel (delayed rectifier) was the
      most commonly observed ion channel in LNCaP cells. The slope conductance of K+
      channels in a symmetrical 140 mM K+ gradient was 78 pS. In excised inside-out
      patches, the channel was inhibited by increasing the cytoplasmic Ca2+
      concentration (with half-block at 0.5 microM Ca2+) over a wide range of membrane
      potentials. The K+ channel had a high sensitivity to tetraethylammonium (TEA),
      that reduced the single channel conductance with Kd of 280 +/- 27 microM. The K+
      channel open probability was inhibited by alpha-dendrotoxin (DTX) (with a half
      blocking concentration of approximately 5 nM) and mast cell degranulating peptide
      (MCDP) (with half-blocking concentration of approximately 70 nM) at all membrane
      potentials and with very slow reversibility. In view of the biophysical and
      pharmacological properties of K+ channels in LNCaP cells, it is not possible to
      classify these channels as one of the previously characterized types of voltage-
      or ligand-gated K+ channels in other cell lines.

PMID- 10412719
TI  - Beta 2-adrenergic receptor endocytic pathway is controlled by a saturable
      mechanism distinct from that of transferrin receptor.
AB  - Agonist-dependent internalization is an important phase of beta 2-adrenergic
      receptor (beta 2AR) regulation. Recent reports have indicated that early steps of
      beta 2AR endocytosis may involve mechanisms different from those which regulate
      the internalization of constitutively recycling receptors, such as transferrin
      receptor (TfR). In the present study, we addressed this issue by comparing, in
      the same cells, the endocytic pathway of beta 2AR with that of the TfR. Upon
      incubation at 15 degrees C, activated beta 2ARs accumulated in peripheral
      endosomes of HEK-293 cells while they were targeted to perinuclear organelles at
      37 degrees C. The temperature block was not specific to beta 2ARs, since both
      peripheral and perinuclear beta 2AR-containing endosomes comigrated on sucrose
      gradients with those containing transferrin receptors and were loaded with
      horseradish peroxidase-coupled transferrin. Endocytosis of beta 2ARs was
      saturable in HEK-293 cells and did not increase upon overexpression of beta
      arrestin 1. TfR endocytosis was unaffected by the simultaneous internalization of
      overexpressed beta 2AR, indicating that the limiting components which regulate
      endocytosis of these two receptors are different. In conclusion, ligand activated
      beta 2AR and constitutively recycling receptors, such as TfR, enter the endocytic
      pathway via distinct saturable mechanisms but converge in the same endosomal
      compartments. Our results also indicate that a still unidentified component(s)
      controls beta 2AR endocytosis.

PMID- 10412720
TI  - Functional expression of rat VPAC1 receptor in Saccharomyces cerevisiae.
AB  - The yeast Saccharomyces cerevisiae was examined as host for heterologous
      expression of the G protein-coupled VPAC1 receptor. Rat VPAC1 receptor cDNA and
      two chimeric constructs encoding the yeast mating factor pre-pro alpha-leader
      peptide fused in-frame to rat VPAC1 receptor were expressed in yeast cells under
      control of a galactose inducible promoter. The rat VPAC1 receptor was fused to
      the HSV tag epitope to ensure proper immunological detection of the receptor.
      Crucial conditions for high-level expression of active rat VPAC1 receptor
      included growth in amino acid supplemented minimal medium, fusion to the yeast
      alpha-leader peptide and a temperature shift from 30 degrees C to 15 degrees C
      before promoter induction. Western blotting showed that the expressed receptor
      was highly glycosylated and a band of 47 kDa was obtained upon endoglycosidase H
      treatment. Binding with radioiodinated vasoactive intestinal polypeptide revealed
      a KD of 2.5 nM and an IC50 of 15 nM when displacing with unlabeled vasoactive
      intestinal polypeptide. VPAC1 receptor density quantified by Western blotting was
      510 pmol/mg membrane protein of which only 66 pmol/mg were able to bind
      vasoactive intestinal polypeptide.

PMID- 10412721
TI  - Variability of channel subconductance states of the cardiac sodium channel
      induced by protease.
AB  - Conductance and subconductance levels of voltage-activated sodium channels
      recorded using patch clamp techniques from isolated cardiac myocytes were
      accurately determined using signal processing techniques. From the tabulated
      amplitude distributions of the conductance levels, we inferred the most likely
      underlying distribution by applying the method of the kernel density estimate.
      When myocytes were prepared by dissociation of the heart with a solution
      containing collagenase as the only digestive enzyme, the fully open conductance
      level of the channel was 23 pS, with two prominent sublevels at 8 and 16 pS (280
      mM sodium). When cells were dissociated in an identical manner but with solution
      containing added protease, the most frequent open levels of the channel were 9
      and 15 pS. In these latter recordings, the channel also opened to 22 pS, but did
      so only rarely. The main conductance levels in cells dissociated with protease
      were essentially the same as the subconductance states in cells dissociated
      without protease. We infer that the conductance sublevels normally seen are,
      within experimental errors, 1/3 and 2/3 of the fully open level, and that the
      proteolytic enzyme modifies the channel such that it tends to open predominantly
      to the subconductance levels.

PMID- 10412722
TI  - Bacteriorhodopsin in a periodic boundary water-vacuum-water box as an example
      towards stable molecular dynamics simulations of G-protein coupled receptors.
AB  - This study presents an optimised set-up for molecular dynamics (MD) simulations
      of G-protein coupled receptors (GPCR). Such simulations are complicated because
      (1) the experimental template structure for GPCRs (bovine rhodopsin) is of low
      resolution, (2) the receptor surroundings are irregular (water exposed loops vs.
      lipid exposed transmembrane regions) and (3) the protonation and solvation states
      of the inner core receptor residues are unknown. We compared various simulations
      of the experimentally derived and refined electron density structure of the seven
      helical transmembrane protein bacteriorhodopsin (bR) under different MD
      conditions using AMBER 4.1. Our results demonstrate that the optimal MD set-up
      with minimal computational effort is a periodic boundary (PB) box containing two
      water shells solvating the extra- and intracellular loops separated by a vacuum
      layer surrounding the helical transmembrane (TM) regions. It was found that the
      vacuum layer and water layers are stable under periodic boundary conditions
      during at least 1 ns of MD simulation. In this set-up the bR structure is stable
      without any restraints. The average bR structure during the last 500 ps of the MD
      run has an excellent RMSD value relative to the original bR structure (RMSD =
      1.66 A for the C alpha atoms within the TM domains) and shows a very high helical
      stability within the TM regions (88.8% helix). The use of this MD set-up for
      simulations of GPCRs is discussed.

PMID- 10412723
TI  - Mutations of aromatic residues in the first transmembrane helix impair signalling
      by the secretin receptor.
AB  - The secretin amino terminal residues are essential for high affinity binding to
      the cognate receptor and for the subsequent activation of adenylate cyclase. It
      has been already established that two basic residues of the receptor TM 2 are
      involved in the interaction with aspartate 3 of the ligand. The present work
      investigated the hypothesis that two conserved tyrosine residues of the TM 1
      (Tyrosines 124 and 128) could also participate to the positioning of the amino
      terminus of the ligand. Tyrosines 124 and 128 were mutated into alanine and
      histidine residues, and the properties of the mutant receptors, expressed in CHO
      cells, were compared with those of the wild-type receptor. Mutation of tyrosine
      124 to Ala or His decreased the affinity of the receptor for secretin,
      [Glu3]secretin, [Asn3]secretin and the secretin fragment 2-27, and reduced the
      intrinsic activity of [Asn3]secretin. Mutation of tyrosine 128 to Ala, but not to
      His reduced 50-fold secretin and [Asn3]secretin affinity but only 3-fold that of
      [Glu3]secretin. Secretin and [Glu3]Sn were equipotent in that mutant receptor.
      These results suggested that tyrosine 128 of the secretin receptor interacted
      directly with the [Asp3] residue of secretin and thus that the amino terminal
      domain of secretin interacts with amino acids buried in both the TM 1 and TM 2
      helices.

PMID- 10412724
TI  - Molecular modelling of the 5-hydroxytryptamine receptors.
AB  - Molecular models of the 5-hydroxytryptamine receptors are reviewed with
      particular emphasis upon ligand receptor interactions. The use of such models in
      the areas of drug design and the design and rationalisation of experiments is
      discussed. It is clear that many groups have modelled the 5-HT receptors using
      either the bacteriorhodopsin structure, rhodopsin electron density map or
      rhodopsin alpha-carbon template. Although it is difficult to assess the accuracy
      of these models it is expected that the rhodopsin based models show improved
      accuracy over the bacteriorhodopsin based models. Nevertheless models that are
      thoroughly validated with experimental mutagenesis and ligand binding data are
      useful in a qualitative sense providing ideas upon target compounds to synthesise
      and the design and rationalisation of mutagenesis experiments.

PMID- 10412725
TI  - Recent advances in statins and the kidney.
AB  - BACKGROUND: Experimental and clinical studies have suggested a correlation
      between the progression of renal disease and dyslipidemia. Indeed, apolipoprotein
      B-containing lipoproteins have been demonstrated to be an independent risk factor
      for the progression of renal disease in humans. Interventional strategies in
      experimental models of renal disease have clearly demonstrated a beneficial
      effect on renal structure and function in a variety of models of renal disease.
      Investigations into the mechanisms whereby reduction of lipids by lipid-lowering
      agents benefits renal disease have suggested that the 3-hydroxy-3-methylglutaryl
      coenzyme reductase inhibitors, the so-called statin class of lipid-lowering
      agents, may have additional effects on the biology of inflammation that are
      germane to the progression of renal disease. METHODS: Both in vivo and in vitro
      studies that investigated secondary mechanisms of statin effects are reviewed. In
      addition, new studies that investigated the effects on novel cellular mechanisms
      are presented. RESULTS: Lipid-lowering agents appear to have biologically
      important effects in modulating a variety of intracellular signaling systems
      involved in cell proliferation, inflammatory responses that involve macrophage
      adhesion, recruitment, and maturation. In addition, the effects on fibrogenesis
      have been recently defined. These latter effects may influence not only the
      development of glomerulosclerosis, but also interstitial fibrosis. These
      potentially major effects of lipid-lowering agents appear to be related to the
      effects on intracellular synthesis of nonsterol isoprenoids, which are involved
      in prenylation of critical small molecular weight proteins involved in cell
      signal transduction. CONCLUSIONS: In addition to the beneficial effects of the
      reduction in serum lipids, statins and other lipid-lowering agents may influence
      important intracellular pathways that are involved in the inflammatory and
      fibrogenic responses, which are common components of many forms of progressive
      renal injury.

PMID- 10412726
TI  - Lipopheresis in the nephrotic syndrome.
AB  - BACKGROUND: Experimental models have established a role for lipoproteins in the
      pathogenesis of progressive renal failure. However, conventional treatment rarely
      normalizes the high serum cholesterol of the nephrotic syndrome. The removal of
      low-density lipoprotein by lipopheresis is discussed. METHODS: Lipopheresis may
      be beneficial in nephrotic patients with focal segmental glomerulosclerosis. The
      authors studied the long-term effects of low-density lipoprotein cholesterol (LDL
      C) removal using the Kaneka Liposorber system, which binds LDL-C to dextran
      sulfate in a controlled trial in 20 nephrotic patients with different renal
      diseases. RESULTS: A 21-month clamp of plasma total cholesterol at 6.0 mmol/liter
      or below was significantly lower than controls (chi 2 = 84.3, P < 0.001),
      followed 12 aphereses over 6 to 12 weeks in all but three apheresed patients.
      1/Cr slopes were unchanged when the 50-day average period of lipopheresis
      treatments was excluded from analysis. Proteinuria was not reduced, but serum
      albumin tended to rise (NS). Fibrinogen fell by 29.8%; high-density lipoprotein,
      apoA1, and Lp(a) were unchanged. Two apheresed patients had a prolonged remission
      with a reduction of proteinuria to less than 250 mg/24 hr. The reasons for
      prolonged reduction of total cholesterol include depletion of tissue cholesterol,
      an improved fractional catabolic rate of very low density lipoprotein (VLDL),
      increased hepatocyte LDL turnover, and the maintenance of statin therapy.
      CONCLUSION: Lipopheresis is a safe and effective method for the control of LDL in
      nephrotic syndrome. Early clamping of total cholesterol in the normal range
      resulted in a prolonged and significant reduction of LDL compared with controls.

PMID- 10412727
TI  - Association between hyperlipidemia and microalbuminuria in essential
      hypertension.
AB  - BACKGROUND: Some patients with essential hypertension manifest greater than
      normal urinary albumin excretion (UAE). A few retrospective studies have
      suggested that there is an association between microalbuminuria and
      cardiovascular risk. The reasons for this association are not well established,
      and they are the object of this review. RESULTS: We found that hypertensive
      patients with microalbuminuria manifest greater levels of blood pressure,
      particularly at night. Serum levels of cholesterol, triglycerides, and uric acid
      in patients with microalbuminuria were higher than levels in those with normal
      UAE, whereas levels of high-density lipoprotein cholesterol in patients with
      microalbuminuria were lower than levels in patients with normal UAE. Patients
      with microalbuminuria manifest a greater incidence of insulin resistance, and
      thicker carotid arteries. After a follow-up of seven 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
      logistical regression analysis showed that UAE, cholesterol level and diastolic
      blood pressure were independent predictors of the cardiovascular outcome. The
      rate of clearance of creatinine from patients with microalbuminuria decreased
      more than did that from those with normal urinary albumin excretion. CONCLUSIONS:
      These studies suggest that hypertensive individuals with microalbuminuria
      manifest a variety of biochemical and hormonal derangements with pathogenic
      potential, which result in greater incidence of cardiovascular events and a
      greater decline in renal function than do patients with normal UAE.

PMID- 10412728
TI  - Lipoprotein abnormalities as a risk factor for progressive nondiabetic renal
      disease.
AB  - Renal disease is accompanied by characteristic alterations of lipoprotein
      metabolism, which appear as a consequence of nephrotic syndrome or renal
      insufficiency and are primarily reflected in an altered apolipoprotein profile
      rather than elevated plasma lipid levels. Their full characterization requires
      identification of discrete lipoprotein particles. While nephrotic syndrome
      results in increased concentrations of both cholesterol- and triglyceride-rich
      apoB-containing lipoproteins, renal insufficiency is characterized by an
      accumulation of intact or partially metabolised triglyceride-rich apoB-containing
      lipoproteins. The dyslipidemia has been discussed as a contributory factor for
      the progression of renal insufficiency through development of glomerulosclerosis
      and tubulointerstitial lesions together with accelerated atherosclerosis. Several
      experimental studies have shown that hyperlipidemia accelerates renal damage.
      Lipid-lowering treatment can reduce renal lesions and preserve renal function.
      The documentation in human nondiabetic progressive renal insufficiency is more
      limited. We have found that increased concentrations of triglyceride-rich, but
      not cholesterol-rich, apoB-containing lipoproteins are, associated with a more
      rapid loss of renal function. The underlying pathophysiological mechanisms for
      the relation between triglyceride-rich apoB-containing lipoproteins and
      progression of renal insufficiency are not fully understood. Treatment with
      hypolipemic drugs may attenuate the renal dyslipidemia, but thus far there have
      been no reports about controlled clinical trials testing the possible effect of
      such treatment on the progression of renal insufficiency. In summary, there is
      evidence to suggest that some specific lipoprotein abnormalities are a risk
      factor for the progression of renal dysfunction, but the final test of such
      assumptions still rests on the results of urgently needed controlled intervention
      studies.

PMID- 10412729
TI  - New insights into lipid metabolism in the nephrotic syndrome.
AB  - Hyperlipidemia in the nephrotic syndrome results from increased synthesis and
      decreased catabolism of lipoproteins. The contribution of each to establishing
      blood lipid levels is unknown. Increased triglyceride rich lipoprotein
      concentration, very low density lipoprotein (VLDL) and intermediate density
      lipoprotein (IDL) primarily results from decreased clearance. This defect is due
      in part to reduced lipoprotein lipase (LPL) on the vascular endothelium resulting
      either from decreased synthesis or inadequate binding of this enzyme to
      endothelial surfaces. In contrast, both low density lipoprotein (LDL) and
      lipoprotein(a) [Lp(a)] concentrations are increased. Unlike the case of albumin
      or transferrin, or apoA-I in the rat, LDL apoB 100 synthesis is not related to
      that of albumin, suggesting a different mechanism of regulation or a response to
      a stimulus that is not the same as that augmenting the synthesis of
      nonlipoproteins. Evidence is presented for synthesis of LDL through a mechanism
      that bypasses the normal delipidation pathway that requires a VLDL precursor for
      LDL formation. HDL concentration is normal but maturation is impaired leading to
      a shift from the larger HDL2 to the smaller HDL3, a variant that is less
      effective as a transporter of the LPL cofactor apolipoprotein C II.

PMID- 10412730
TI  - Lipoprotein abnormalities in diabetic nephropathy.
AB  - BACKGROUND: The risk of death from coronary heart disease (CHD) is substantially
      increased in diabetic nephropathy compared with normal subjects or diabetes
      without nephropathy. I tried to define abnormal plasma lipoproteins profiles
      contributing to the increased CHD risk in diabetic nephropathy. This study
      included: middle-aged to older type 2 diabetic patients with normoalbuminuria,
      microalbuminuria, and overt albuminuria; nondiabetic patients with primary renal
      disease; and normal control subjects. RESULTS: Triglyceride (TG) levels were
      significantly increased in type 2 diabetic patients with microalbuminuria and
      overt proteinuria. Glycemic control or insulin resistance were not associated
      with TG levels. Intermediate-density lipoprotein (IDL) and remnant-like particle
      (RLP) cholesterol in type 2 diabetics were significantly elevated in patients
      with overt nephropathy. Hepatic TG lipase (HTGL) was significantly decreased in
      diabetic nephropathy, and their higher IDL levels were inversely related to
      decreased HTGL. Low-density lipoprotein (LDL) size was significantly smaller in
      diabetic nephropathy compared with nondiabetics with kidney disease. The TG
      response after the oral fat load was significantly greater in diabetic
      nephropathy, and the LDL size was inversely associated with the magnitude of
      postprandial lipemia. Microalbuminuric diabetic patients had a lower lipoprotein
      lipase (LPL) mass and a higher von Willebrand factor (vWF), an indicator of
      endothelial cell damage, than normoalbuminuric patients. The LPL mass was
      inversely associated with vWF, suggesting that widespread endothelial cell damage
      results in a reduction in LPL bound to endothelium in diabetic subjects with
      microalbuminuria. CONCLUSIONS: Plasma lipoprotein profiles become more
      atherogenic in patients with diabetic nephropathy, including the subclinical
      stage, compared with diabetics without nephropathy or those with nondiabetic
      kidney disease.

PMID- 10412731
TI  - Apolipoprotein E polymorphism and renal disease.
AB  - BACKGROUND: Lipid abnormalities are frequently found in end-stage renal disease
      (ESRD), and abnormal lipid metabolism may contribute to the progression of renal
      disease. Previous investigators have reported that apolipoprotein E (apoE) has an
      important role in lipoprotein metabolism and that the process of lipoprotein
      catabolism varies according to the apoE phenotype. In addition, the relative
      frequency of the apoE alleles is different among the races. In this study, we
      investigated the allele frequency of apoE phenotypes and evaluated the impact of
      apoE polymorphism on lipid profile in Japanese patients with renal disease.
      METHODS: ApoE phenotypes were determined using isoelectric focusing and Western
      blotting in 592 Japanese patients with renal disease [86 out of 107 patients with
      glomerulonephritis had proteinuria of not less than 0.25 g per 24 hr and 485 with
      ESRD; 448 were on hemodialysis (HD), and 37 were on continuous ambulatory
      peritoneal dialysis (CAPD)]. The allele frequency and apoE phenotype distribution
      were estimated by the gene-counting method. Serum lipid parameters related to
      lipid metabolism were measured after at least a 12-hour fast. RESULTS: The allele
      frequency of the three major apoE phenotypes (apoE2, apoE3, and apoE4) in 107
      glomerulonephritis patients (epsilon 2; 0.037, epsilon 3; 0.860, epsilon 4;
      0.103) was almost identical to that in the normal control population (epsilon 2;
      0.036, epsilon 3; 0.848, epsilon 4; 0.115). However, 86 glomerulonephritis
      patients with proteinuria had higher allele frequency of apoE2 (epsilon 2; 0.052,
      P < 0.01) and apoE4 (epsilon 4; 0.140, P < 0.001) and lower allele frequency of
      apoE3 (epsilon 3; 0.808, P < 0.001) than the controls. Furthermore, ESRD patients
      had higher allele frequency of apoE2 (epsilon 2; 0.058, P < 0.01) and lower
      allele frequency of apoE4 (epsilon 4; 0.091, P < 0.05) than the controls. Higher
      prevalence of nephrotic syndrome was found in proteinuric glomerulonephritis
      patients with apoE2. The impact of apoE polymorphism on serum lipid profile in
      patients with glomerulonephritis, HD, and CAPD was different from that generally
      expected. CONCLUSIONS: The higher frequency of apoE2 in ESRD patients suggests
      that apoE2 is a possible genetic predisposition to ESRD in a Japanese population.
      The impact of apoE2 and apoE4 on lipid profile in patients with renal disease was
      unique and different from that in the normal population.

PMID- 10412732
TI  - Role of circulating lipid abnormalities in chronic renal allograft rejection.
AB  - The evidence that circulating lipid abnormalities may play a role in the
      pathogenesis of chronic renal allograft rejection is tantalizing but
      circumstantial. In animal models of cardiac and aorta allograft rejection,
      lipogenic diets accelerate vascular injury, and treatment with 3-hydroxy-3
      methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce vascular injury.
      Histological studies have demonstrated foam cells and apolipoprotein deposits in
      the intima of arteries from chronically rejecting human kidneys. Observational
      studies have found correlations between plasma lipid levels and both acute and
      chronic rejection. The association between lipid levels and acute rejection in
      cyclosporine A (CsA)-treated renal transplant recipients suggests the possibility
      that plasma lipids may influence the immunosuppressive effects of CsA by
      modulating the lipoprotein-free levels of CsA. If true, such an effect could also
      explain the result of recent controlled trials showing that HMG-CoA reductase
      inhibitors reduced graft coronary artery disease and that they prolonged survival
      in heart transplant recipients. In any case, the hypothesis that circulating
      lipid abnormalities contribute to chronic renal allograft rejection deserves
      further testing in well-designed, clinical trials.

PMID- 10412733
TI  - Role of hyperlipidemia in progressive renal disease: focus on diabetic
      nephropathy.
AB  - BACKGROUND: It has been suggested that lipids promote renal injury and that 3
      hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors confer
      renoprotection in certain renal diseases, including diabetic nephropathy.
      METHODS: Sprague-Dawley rats were randomized to sham, subtotal nephrectomy (STNx)
      or STNx + atorvastatin groups. After 12 weeks, proteinuria, renal function,
      glomerular injury, renal transforming growth factor-beta (TGF-beta) gene
      expression and macrophage (ED1-positive cells) accumulation were assessed. In
      addition, the effects of HMG CoA reductase in human diabetic nephropathy were
      reviewed. RESULTS: Atorvastatin therapy was associated with a modest reduction in
      proteinuria and glomerulosclerosis without influencing lipid levels or renal
      function in STNx rats. These effects were associated with decreased renal TGF
      beta 1 gene expression and less glomerular and tubulointerstitial macrophage
      accumulation. The renoprotective effects of HMG CoA reductase inhibitors in both
      insulin- and non-insulin-dependent diabetic subjects with either incipient or
      overt nephropathy appear to be highly variable. CONCLUSIONS: HMG CoA reductase
      inhibition appears to confer renoprotection via effects on prosclerotic cytokines
      such as TGF-beta and macrophage accumulation, independent of their lipid-lowering
      properties. The role of lipid-lowering agents in early or overt diabetic
      nephropathy remains to be fully ascertained.

PMID- 10412734
TI  - Lipoprotein glomerulopathy: significance of lipoprotein and ultrastructural
      features.
AB  - BACKGROUND: Lipoprotein glomerulopathy (LPG) is a unique disease characterized by
      intraglomerular lipoprotein thrombi and type III hyperlipoproteinemia. Recently,
      we have demonstrated that LPG is associated with inherited apolipoprotein E
      (apoE) variants including apoE Sendai. On the other hand electron microscopy
      shows that intraglomerular lipoprotein thrombi consist of lipid granules of
      various sizes. To elucidate the relationship between the peculiar histology and
      abnormal lipid metabolism related to apoE Sendai, we studied lipoprotein profiles
      and ultrastructural features. METHODS: The subjects were 11 patients with LPG.
      Four patients were nephrotic, and two others became nephrotic within six months
      following the biopsy. Eight patients underwent apoE gene analysis and showed apoE
      Sendai. The other three were presumed to have apoE Sendai because this mutation
      was demonstrated in their kindreds. Under electron microscopy, diameters of more
      than 1000 lipid granules were measured in several glomeruli, and a mean value was
      calculated in each case. Lipoprotein profiles were analyzed by the
      ultracentrifugation methods. RESULTS: The mean diameter of intraglomerular lipid
      granules correlated inversely with the levels of plasma triglyceride (TG; rs = 
      0.73, P < 0.05), TG (rs = -0.77, P < 0.01) and cholesterol (Chol; rs = -0.75, P <
      0.05) in very low-density lipoprotein (VLDL) fraction and TG in high-density
      lipoprotein (HDL) fraction (rs = -0.75, P < 0.05). The inverse correlation was
      also seen between the mean lipid diameter and TG/Chol ratios in whole plasma (rs
      = -0.80, P < 0.01) and in HDL (rs = -0.80, P < 0.01). In addition, the cases
      showing smaller lipid granules and higher TG/Chol ratios in plasma and in HDL
      were nephrotic or became nephrotic within six months. CONCLUSION: These results
      suggest that the size of lipid granules in LPG may become smaller under the
      influence of hypertriglyceridemia and particularly elevated plasma VLDL and HDL
      TG, which may lead to heavy proteinuria.

PMID- 10412735
TI  - Effect of proteinuria reduction on prevention of focal glomerulosclerosis by
      angiotensin-converting enzyme inhibition is modifiable.
AB  - BACKGROUND: Proteinuria is associated with a progressive loss of renal function;
      we recently found that both intrarenal effects of proteinuria and the state of
      systemic nephrosis play an independent role in proteinuria-induced renal damage.
      Reduction of proteinuria is an important mechanism underlying the renoprotective
      effect of angiotensin-converting enzyme inhibition (ACEi). Both the reduction of
      proteinuria and the attenuation of the systemic state of nephrosis may be
      involved in the renoprotection by ACEi. METHODS: This article entails a post hoc
      analysis of a previous study on the renoprotective effect of ACEi lisinopril in
      adriamycin nephrosis. It was attempted to modify therapeutic efficacy of ACEi by
      increasing lisinopril dose and by dietary sodium restriction, respectively. In
      this analysis, we aimed to delineate the contribution of proteinuria reduction
      and the reduction of other intermediate parameters such as hyperlipidemia and
      blood pressure on the protection against focal glomerulosclerosis (FGS). RESULTS:
      We found that in adriamycin nephrosis, ACEi significantly reduced proteinuria,
      lipids, and blood pressure and provided protection against FGS. Treatment
      modification by increasing the lisinopril dose resulted in a further reduction of
      FGS without significant effects on intermediate parameters (proteinuria,
      hyperlipidemia, and blood pressure), whereas surprisingly, treatment modification
      by sodium restriction resulted in a further attenuation of intermediate
      parameters, without additional protection against FGS. CONCLUSIONS: The
      renoprotective benefit of an obtained attenuation of intermediate parameters is
      modified by other factors. Further optimization of renoprotective therapy
      requires identification of such factors and explicit consideration of therapeutic
      efficacy on intermediate parameters as well as hard end points.

PMID- 10412736
TI  - Mechanisms of glomerular macrophage infiltration in lipid-induced renal injury.
AB  - BACKGROUND: A number of studies have demonstrated an important role for
      macrophages (M phi) in lipid-induced glomerular injury; however, little is known
      of the mechanisms that facilitate M phi infiltration in this disease. This study
      examined the expression of M phi chemotactic molecules M phi migration inhibitory
      factor (MIF) and leukocyte adhesion molecules intercellular adhesion molecule-1
      (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) during the induction of
      glomerular M phi infiltration in ExHC rats, a strain that is susceptible to lipid
      induced glomerular injury. METHODS: Groups of five ExHC rats were fed a high
      cholesterol diet (HCD) containing 3% cholesterol, 0.6% sodium cholate, and 15%
      olive oil and were killed after three days or one, two, or six weeks. Control
      animals were killed on day 0 or after six weeks on a normal diet. RESULTS: ExHC
      rats fed an HCD showed marked hypercholesterolemia in the absence of any increase
      in plasma triglyceride levels from day 3 and developed mild proteinuria and
      segmental glomerular lesions at week 6. Immunoperoxidase staining identified a
      significant increase in glomerular ED1+ M phi at week 1, which was further
      increased at week 6, when M phi-derived foam cells were seen in almost all
      glomeruli. Many of the infiltrating glomerular M phi expressed lymphocyte
      function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4), which are
      ligands for ICAM-1 and VCAM-1, respectively. Coincident with the induction of
      hypercholesterolemia on day 3 and prior to significant M phi infiltration,
      combined in situ hybridization and immunohistochemistry staining demonstrated a
      marked up-regulation of M-CSF and MIF mRNA expression by glomerular mesangial
      cells and podocytes. There was also a significant increase in ICAM-1 and VCAM-1
      mRNA expression by intrinsic glomerular cells, including endothelial cells, on
      day 3 of the HCD. CONCLUSION: These results suggest that hypercholesterolemia can
      induce a classic proinflammatory response within the kidney glomerulus, involving
      production of well-described M phi chemotactic and adhesion molecules, which
      results in M phi recruitment and the development of glomerular injury.

PMID- 10412737
TI  - Effect of lipoproteins on mesangial cell proliferation.
AB  - BACKGROUND: Triglyceride (TG)-rich lipoproteins have been reported to promote
      atherosclerosis, but little is known about their role in kidney disease or about
      their effects on mesangial cells. Accordingly, the purpose of this study was to
      investigate which lipoproteins could influence mesangial cell proliferation in
      vitro. We assessed the effect of various lipoproteins [very low-density
      lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low density
      lipoprotein (LDL), oxidized LDL, and high-density lipoprotein (HDL)] on the
      proliferation of cultured human mesangial cells and also assessed the influence
      of these lipoproteins on cytokine production. METHODS: We investigated the effect
      of various lipoproteins on cultured human mesangial cells using 3H-thymidine
      incorporation and cell counting assays and investigated the levels of several
      cytokines [interleukin (IL)-6, platelet-derived growth factor (PDGF),
      transforming growth factor (TGF)-beta, and tumor necrosis factor-alpha] in
      mesangial cell culture supernatants after stimulation by the lipoproteins.
      RESULTS: Not only LDL but also TG-rich lipoproteins (VLDL and IDL) promoted the
      proliferation of mesangial cells up to certain concentrations, but cell growth
      was actually decreased at higher concentrations. Oxidized LDL caused a
      concentration-dependent decrease of 3H-thymidine incorporation, and HDL had no
      proliferative effect at any concentration. Exposure to VLDL, IDL, LDL, or a high
      concentration of HDL enhanced the secretion of IL-6, PDGF-AB, and TGF-beta by
      mesangial cells, whereas TNF-alpha secretion was stimulated by oxidized LDL.
      CONCLUSIONS: TG-rich lipoproteins, LDL, and oxidized LDL may be involved in
      mesangial cell proliferation and injury in patients with mesangial proliferative
      glomerulonephritis.

PMID- 10412738
TI  - Increased carbonyl modification by lipids and carbohydrates in diabetic
      nephropathy.
AB  - BACKGROUND: In diabetic nephropathy (DN), possible mediators of untoward effects
      of hyperglycemia include the advanced glycation end products (AGEs). Indeed, an
      AGE, carboxymethyllysine (CML), accumulates in expanded mesangial matrix and
      nodular lesions. An advanced lipoxidation end product (ALE), malondialdehyde
      lysine (MDA-lysine), generated on proteins during lipid peroxidation also
      accumulates in these lesions. As both ALEs and AGEs are formed by carbonyl amine
      chemistry between protein and carbonyl compounds derived from autoxidation of
      lipids and carbohydrates, their colocalization suggests an increased carbonyl
      modification of proteins. METHODS: To address this hypothesis, human diabetic
      renal tissues were examined to characterize carbonyl modification of proteins by
      lipids and carbohydrates: (a) ALEs, MDA-lysine and 4-hydroxynonenal (HNE) protein
      adduct, derived from lipids, and (b) AGEs, pentosidine and CML, derived from
      carbohydrates. Furthermore, to elucidate the biological effect of carbonyl
      modification on primary cultured human and rat mesangial cells, the intracellular
      protein phosphorylation was examined in the presence of various kinds of carbonyl
      compounds. RESULTS: The ALE and AGE adducts examined were identified in expanded
      mesangial matrix and nodular lesions. The exposure of cultured mesangial cells to
      carbonyl compounds resulted in phosphorylation of tyrosine residues of a number
      of intracellular proteins. CONCLUSIONS: These data suggest a broad derangement in
      nonenzymatic biochemistry involving both lipids and carbohydrates exists in
      diabetic glomerular lesions ("carbonyl stress").

PMID- 10412739
TI  - Endothelial function in proteinuric renal disease.
AB  - Nephrotic-range proteinuria is associated with a several-fold increase risk of
      cardiovascular infarction. This increased risk is accompanied by endothelial
      dysfunction, which is not related to increased blood pressure and is not
      correctable by acute administration of L-arginine. The latter is in direct
      contrast to what has been found in patients with primary hypercholesterolemia,
      suggesting that either hypoalbuminemia itself or other aspects of the
      dyslipidemia characteristic of the nephrotic syndrome impair endothelial
      function. Lysophosphatidylcholine (lyso-PC) is formed during oxidative
      modification of cholesterol, and lyso-PC in oxidized low-density lipoprotein
      (LDL) is responsible for reduced endothelial function in vitro. However, in the
      circulation, lyso-PC is tightly bound to albumin. Indeed, the addition of albumin
      can restore endothelial function, which was previously disturbed by lyso-PC.
      Hypoalbuminemia induces a shift in lyso-PC to lipoproteins, notably LDL, and to
      erythrocytes. The latter directly induces a reduction in deformability that can
      also be corrected by the addition of albumin. Hypoalbuminemia may disturb
      endothelial function, either by directly affecting Gi-protein-dependent signal
      transduction or indirectly by changing the configuration of the cell membrane.
      Such a change in cell membrane configuration will disturb binding of ligands to
      receptors and of endothelial nitric oxide (NO) synthase to caveolin. However,
      other pathways have been suggested, such as stimulation by lyso-PC of
      vasoconstriction mediated by protein kinase C. It remains to be shown whether
      lipid-lowering and antiproteinuric strategies have independent positive effects
      on endothelial function in nephrotic subjects.

PMID- 10412740
TI  - Atherogenic lipoproteins, oxidative stress, and cell death.
AB  - BACKGROUND: Glomerulosclerosis and atherosclerosis are chronic inflammatory
      processes that may be influenced by oxidized lipoproteins, oxidized low-density
      lipoproteins (oxLDL), and oxidized lipoprotein(a) [oxLp(a)]. We hypothesize that
      these lipoproteins contribute to the development of glomerulosclerosis and
      atherosclerosis through the induction of oxidative stress, which influences cell
      viability. We therefore determined the impact of oxLDL and oxLp(a) on O2-
      formation and on necrotic and apoptotic cell death in vascular and glomerular
      cells. METHODS: The impact of human LDL and Lp(a) (oxidized with CuSO4) on O2-
      formation (detected with a chemiluminescence method), apoptosis, and necrosis
      (determined with the annexin assay) was studied in cultured human umbilical vein
      endothelial cells (ECs) and in cultured human mesangial cells (MCs). RESULTS: O2-
      formation was increased by 10 micrograms/ml oxLDL (by factor 2.5 in ECs) and by 5
      micrograms/ml oxLp(a) (by factor 3.5 in ECs). OxLDL and oxLp(a) both
      significantly and dose-dependently increased the rate of apoptotic cell death in
      ECs and in MCs, with oxLp(a) being the more potent stimulus that also caused
      necrosis. The induction of apoptosis by oxLDL and oxLp(a) in ECs and MCs was
      enhanced by inhibition of the endogenous superoxide dismutase (SOD) with diethyl
      dithio-carbamate and was blunted by the antioxidants N-acetylcysteine, vitamin C
      + E, SOD, and catalase, suggesting that oxidative stress was the stimulus for
      apoptosis. CONCLUSIONS: These data suggest that oxLDL and oxLp(a) contribute to
      inflammation by stimulating O2- formation, leading to apoptotic cell death in the
      vascular wall and in the glomerulus. The oxidized lipoproteins may thereby
      influence the pathogenesis of atherosclerosis and glomerulosclerosis.

PMID- 10412741
TI  - Vitamin E treatment of experimental glomerular disease in rats.
AB  - BACKGROUND: Kidney mesangial cells (MCs) and vascular smooth muscle cells (VSMCs)
      are closely related in terms of origin, microscopic anatomy, histochemistry, and
      contractility. This relationship suggests a similarity between kidney glomerular
      sclerosis and atherosclerosis. Vitamin E appears beneficial in the prevention and
      treatment of coronary heart disease and it also inhibits the proliferation of
      VSMCs in vitro. Thus, we investigated the effect of vitamin E on glomerular
      sclerosis and MC-proliferative glomerulonephritis (GN) in two rat models of
      glomerular disease. METHODS: A remnant kidney rat model accelerated with
      hyperlipidemia was used to examine progressive glomerular sclerosis leading to
      chronic renal failure. A rat model of MC-proliferative GN was induced by the
      intravenous administration of absorbed rabbit anti-rat thymocyte serum (ATS).
      RESULTS: In the remnant kidney rat model, dietary supplementation with vitamin E
      (500 IU dl-alpha-tocopheryl acetate/kg) and cholesterol (2%) significantly
      inhibited glomerular sclerosis and macrophage infiltration in glomeruli relative
      to controls receiving basal and cholesterol-supplemented diets. In the ATS
      induced GN model, glomerular cell proliferation (principally MCs) was lower in
      rats fed diets supplemented with vitamin E (1000 IU dl-alpha-tocopheryl
      acetate/kg) compared with controls fed the basal diet only. Although the degree
      of glomerular macrophage infiltration was similar in both groups, fewer
      proliferative cell nuclear antigen (PCNA)-positive cells were observed in the
      vitamin E group, suggesting that MC proliferation was suppressed via the
      inhibition of intracellular transduction. CONCLUSIONS: Supplemental dietary
      vitamin E suppresses MC proliferation and glomerular sclerosis in models of
      glomerular disease in rats. This action of vitamin E in experimental nephritis
      suggests the value of clinical trials testing the potential benefit of vitamin E
      in chronic GN patients.

PMID- 10412742
TI  - Atherogenic lipoproteins and tyrosine kinase mitogenic signaling in mesangial
      cells.
AB  - BACKGROUND: Mesangial hypercellularity is a critical early histopathological
      finding seen in human and experimental glomerular diseases. Hyperlipidemia and
      the glomerular deposition of atherogenic lipoproteins [for example, low-density
      lipoprotein (LDL) and its oxidized variants, minimally oxidized/modified LDL (mm
      LDL)] are commonly associated with mesangial hypercellularity and the development
      of glomerular disease. This article reviews signal transduction pathways involved
      in cell proliferation and provides evidence for the participation of atherogenic
      lipoproteins in intracellular signaling pathways for mesangial cell
      proliferation. The mitogenic intracellular signaling pathways are regulated by
      the activation of a series of transmembrane and cytoplasmic protein tyrosine
      kinases that converge into the activation of Ras and downstream mitogen-activated
      protein (MAP) kinase. Activated MAP kinase, through translocating into the
      nucleus and the activation of various transcription factors and proto-oncogenes,
      regulates cellular proliferation. METHODS: Murine mesangial cells were stimulated
      with LDL and mm-LDL and were analyzed for the tyrosine kinase activity,
      phosphorylation of membrane proteins, activation of Ras and MAP kinase, and cell
      proliferation. RESULTS: The results indicated that the stimulation of mesangial
      cells with LDL and, with greater activity, mm-LDL induced the phosphorylation of
      membrane platelet-derived growth factor (PDGF) and epidermal growth factor (EGF)
      receptors, activated Ras, and resulted in sustained (up to 24 hr) activation of
      MAP kinase. LDL/mm-LDL-mediated mesangial cell proliferation and MAP kinase
      activation were dependent on the activation of tyrosine kinases. CONCLUSIONS: We
      suggest that the accumulation of LDL and more potently its oxidized forms within
      the glomerulus, through the activation of membrane receptor tyrosine kinases,
      activate the Ras and MAP kinase signaling cascade leading to DNA synthesis and
      subsequent cell proliferation.

PMID- 10412743
TI  - The central role of nuclear factor-kappa B in mesangial cell activation.
AB  - BACKGROUND: Nuclear factor-kappa B (NF-kappa B) is a family of transcription
      factors that is recognized by the kappa B enhancer element. Numerous
      proinflammatory genes have binding sites for NF-kappa B, and the products of
      these genes are an integral part of cellular activation and inflammatory response
      systems. Because there is a close relationship between NF-kappa B and mediators
      of cell activation, it is possible that a disruption of NF-kappa B-activating
      pathways may effectively influence mesangial cell activation. METHODS: We
      reviewed available studies related to both NF-kappa B and mesangial cells in
      order to provide evidence for the role of NF-kappa B in mesangial cell
      activation. RESULTS: Studies reported by this laboratory and others showed that
      various experimental maneuvers that modulate NF-kappa B activation result in a
      parallel modulation of proinflammatory molecule production in cultured mesangial
      cells. Likewise, the ability of the inhibitors of NF-kappa B activation to down
      regulate the inflammatory response in animal models of renal disease has been
      recently demonstrated. CONCLUSIONS: These data suggest a pivotal role of NF-kappa
      B in mesangial cell activation and designate it as an obvious target for the
      modulation of this activation. Studies are necessary to characterize the role of
      NF-kappa B in human renal injury.

PMID- 10412744
TI  - Importance of geranylgeranyl pyrophosphate for mesangial cell DNA synthesis.
AB  - BACKGROUND: Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP)
      are isoprenoid products of the intracellular mevalonate pathway used for
      prenylation of several low molecular weight G proteins, including Ras. It is
      likely that platelet-derived growth factor (PDGF) stimulation of mesangial cell
      proliferation requires prenylated, low molecular weight G proteins. The purpose
      of this study was to investigate the dependence of platelet-derived growth factor
      stimulated mesangial cell DNA synthesis and cell membrane Ras incorporation on
      FPP and GGPP. METHODS: Quiescent human mesangial cells were exposed to PDGF (25
      ng/ml) to stimulate DNA synthesis. Some cells were also treated with the HMG-CoA
      reductase inhibitor lovastatin (2.5 to 10.0 microM), which inhibits isoprenoid
      synthesis, in the presence or absence of exogenous FPP or GGPP. DNA synthesis was
      assessed by thymidine incorporation, and Western blot analysis was used to
      measure total cell membrane Ras. RESULTS: Stimulation of mesangial cells with
      PDGF did not increase total cell membrane Ras. Lovastatin reduced cell membrane
      Ras, and this was prevented by simultaneous exposure of mesangial cells to
      exogenous FPP (2.5 to 10.0 microM) or GGPP (1 to 5 microM). Lovastatin also
      reduced PDGF-stimulated mesangial cell DNA synthesis by 90%, and this was
      completely prevented by simultaneous exposure of cells to exogenous GGPP (1
      microM), but not to FPP. CONCLUSIONS: The results of this study suggest that both
      FPP and GGPP can provide for mesangial cell membrane Ras localization and that
      PDGF-stimulated mesangial cell DNA synthesis requires the isoprenoid GGPP.

PMID- 10412745
TI  - Effect of simvastatin on proliferative nephritis and cell-cycle protein
      expression.
AB  - BACKGROUND: Mesangial cell proliferation is important in subsequent mesangial
      matrix expansion in glomerular injury. Therefore, the regulation of mesangial
      cell proliferation may be critical in the treatment of glomerulonephritis.
      Inhibition of 3-hydro-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibits
      the production of mevalonate and has been shown to suppress proliferation in many
      cell types, including mesangial cells in vitro. It is expected that HMG-CoA
      reductase inhibitor may suppress mesangial cell proliferation and subsequent
      progression of glomerulonephritis. Recently, the tight relationship between cell
      cycle regulatory protein expression and mesangial cell proliferation in
      experimental glomerulonephritis was demonstrated. The aim of the present study is
      to examine the effect of simvastatin, one of the HMG-CoA reductase inhibitors, on
      the glomerular cell proliferation and on the expression of CDK2 or p27Kip1 in
      mesangial cells in experimental glomerulonephritis in vivo. METHODS: The effect
      of simvastatin on a rat mesangial proliferative glomerulonephritis induced by
      antithymocyte antibody (anti-Thy 1.1 GN) was studied. Administration of
      simvastatin or vehicle (for control GN) were started from two days before disease
      induction, and was continued to the day of nephrectomy. Nephrectomy was done at
      days 0, 2, 4, 7, 12 and 20 after disease induction. Immunohistochemistry for
      proliferating cells, macrophages, alpha-smooth muscle actin, type IV collagen and
      PDGF-B chain was performed, respectively, in addition to conventional periodic
      acid Schiff staining. Double immunostaining for CDK2/OX-7 or p27Kip1/OX-7 was
      also done, respectively. RESULTS: There was no difference in the degree of the
      initial injuries between simvastatin-treated and control GN rats. The most
      pronounced feature of simvastatin-treated GN was the suppression of the early
      glomerular cell proliferation (about 70% of proliferation was suppressed at day
      4). At day 4, alpha-smooth muscle actin expression was also decreased in
      simvastatin-treated GN rats. Inhibition of macrophage recruitment into glomeruli
      by simvastatin was also a prominent feature (about 30% decrease in the number of
      glomerular macrophages at day 2). Simvastatin significantly suppressed subsequent
      mesangial matrix expansion and type IV collagen accumulation in glomeruli.
      Although it might simply reflect the reduction in mesangial cells, glomerular
      PDGF-B chain expression was reduced. There was no significant difference in
      plasma lipids levels at day 2 and day 4. In vehicle-treated GN rats, the number
      of CDK2+/OX-7+ cells (CDK2-expressed mesangial cells) in glomeruli increased
      significantly from day 4 to day 7. Although simvastatin suppressed mesangial cell
      proliferation, the increase in the number of glomerular CDK2+/OX-7+ cells was
      also attenuated by simvastatin treatment. There was no difference in the number
      of p27Kip1+/OX-7+ cells (p27Kip1-expressed mesangial cells) in the glomerulus
      between vehicle-treated and simvastatin-treated GN rats. CONCLUSION: Simvastatin
      suppressed mesangial cell proliferation and subsequent matrix expansion, and
      macrophage infiltration into glomeruli in anti-Thy 1.1 GN rats. The
      antiproliferative effect of simvastatin in this model was also associated with
      the reduction of CDK2 expression in mesangial cells.

PMID- 10412746
TI  - Lipophilic statins induce apoptosis of human vascular smooth muscle cells.
AB  - BACKGROUND: The accumulation of vascular smooth muscle cells (VSMC) in the intima
      is an early feature of atherosclerosis that results from a balance of migration
      from the media, proliferation, and eventual death (including programmed cell
      death) of VSMC. Several reports have described that HMG-CoA reductase inhibitors
      (statins) attenuate both the migration and proliferation of VSMC. However, the
      potential effect of statins on VSMC programmed cell death has received little
      attention. METHODS: Human and rat VSMC were incubated with different
      concentration of statins in the presence of fetal bovine serum as a survival
      factor. The presence of apoptosis was evaluated by morphological criteria, flow
      cytometry and DNA electrophoresis. RESULTS: Lipophilic statins induced, in a dose
      dependent manner the appearance of VSMC apoptosis. The effect of statins was
      fully reversed by mevalonate, farnesylpyrophosphate, and
      geranylgeranypyrophosphate, but not by cholesterol or other mevalonate
      metabolites, suggesting a role for isoprenoids in VSMC apoptosis. In addition,
      the induction of apoptosis by statins was associated with the inhibition of
      prenylation of Rho B. CONCLUSIONS: The present results suggest that protein
      prenylation inhibition by statins may be involved in statin-induced VSMC
      apoptosis. These data provide a new potential mechanism by which statins may
      modulate the evolution of atherosclerotic lesions.

PMID- 10412747
TI  - Effect of lipid-lowering strategies on tubular cell biology.
AB  - BACKGROUND: Interstitial fibrosis and the development of renal cysts are crucial
      phenomena in renal disease progression. While 3-hydroxy-3-methylglutaryl coenzyme
      A (HMG-CoA) reductase inhibitors has been shown to reduce the progression of
      several experimental nephropathies, the mechanism of their potential protective
      effect remaines unclear. METHODS: The antiproliferative, apoptotic, and
      fibrinolytic effects of HMG-CoA reductase inhibitors were assessed in primary
      cultured rat (rPTCs) and mouse proximal tubule cells (mPTCs), in isolated rat
      proximal tubules, and in vivo in 5/6 nephrectomized rats (Nx). RESULTS: In vitro,
      lovastatin inhibited rPTC proliferation in a manner selectively prevented by
      mevalonate, farnesyl-, or geranylgeranyl-pyrophosphate (FPP or GGPP). Lovastatin
      reduced membrane-bound p21ras and fetal calf serum-induced c-fos and c-jun
      protein expression. Gel shift assay showed that lovastatin reduced activated
      protein-1 (AP-1) binding activity. In vivo, lovastatin inhibited tubular cell
      proliferation after Nx, as measured by proliferative cell nuclear antigen
      staining. Lovastatin-treated mPTCs displayed nucleus cleavage and DNA ladder
      formation, which were prevented by GGPP. Like C3 exoenzyme, lovastatin induced
      actin filament disruption, which preceded evidence of apoptosis. Lovastatin
      increased tissue-type plasminogen activator (PA) and decreased PA inhibitor
      activities and antigens; these effects were prevented by mevalonate and GGPP but
      not FPP, and were reproduced by C3 exoenzyme in a manner insensitive to GGPP.
      CONCLUSIONS: HMG-CoA reductase inhibitors decreased proliferation, increased
      apoptosis, and enhanced fibrinolytic activity of renal tubular cells via
      modulation of different isoprenylated proteins. These effects could participate
      to reduce the progression of renal diseases.

PMID- 10412748
TI  - Effect of pravastatin on type IV collagen secretion and mesangial cell
      proliferation.
AB  - BACKGROUND: The mevalonate pathway is important for the biosynthesis of
      isoprenoids such as geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate
      (FPP) as well as cholesterol. It has been reported that treatment with 3-hydroxy
      3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor ameliorates glomerular
      injury in several experimental models of progressive glomerular disease. The
      present investigation was performed to elucidate the role of mevalonate
      metabolites in mesangial cell proliferation and extracellular matrix
      accumulation. METHOD: Cycling or quiescent human mesangial cells were incubated
      in RPMI1640 containing 10% heat-inactivated fetal calf serum (FCS) in the absence
      or presence of pravastatin, an inhibitor of HMG-CoA reductase, and mevalonate
      metabolites. Type IV collagen secretion and mRNA expression, [3H]-thymidine
      incorporation was measured. Cell cycle phases were monitored by flow cytometry.
      RESULTS: Pravastatin inhibited FCS-stimulated type IV collagen secretion (IC50 =
      210 microM) and mRNA expression. Pravastatin also inhibited FCS-stimulated [3H]
      thymidine incorporation (IC50 = 430 microM). Analysis with flow cytometry
      revealed that pravastatin inhibited G1 to S phase transition of FCS-stimulated
      mesangial cells. Mevalonate reversed these inhibitory effects of pravastatin
      completely. Among two major metabolities of mevalonate, GGPP and FPP, only GGPP
      reversed pravastatin-induced inhibition of type IV collagen secretion, DNA
      synthesis and G1 to S phase progression. CONCLUSION: The present results suggest
      that GGPP plays a critical role in the type IV collagen secretion and G1 to S
      phase transition in FCS-stimulated human mesangial cells.

PMID- 10412750
TI  - Atherosclerotic nephropathy.
AB  - BACKGROUND: Lipid moieties may have direct or indirect effects on the kidney. The
      association of aortic atherosclerosis and renal artery stenosis has focused
      interest on this as an important cause of end-stage renal failure. This article
      seeks to examine the evidence for the entity of atherosclerotic nephropathy.
      METHODS: Published data on the incidence of atherosclerotic renal artery stenosis
      as the cause of end-stage renal failure are presented, as well as the associated
      features of atherosclerotic renal stenosis. RESULTS: Atherosclerotic renal artery
      stenosis (ARAS) has been estimated to be the cause of between 14 and 25% of
      patients reaching end-stage renal failure in older age groups. There is
      considerable evidence of proteinuria in patients with ARAS. Recent data have
      shown that renal length may decrease by 1 cm or more in 35% of kidneys with > 60%
      stenosis. However, other data suggest that renal function in kidneys without
      renal artery stenosis but with contralateral renal artery stenosis may be
      similarly decreased. CONCLUSION: Many processes contribute to renal dysfunction
      in atherosclerotic aortic disease. Although ischemia may play a role, there is
      considerable evidence that processes such as atheroembolic disease may be
      important, and it would be better to use the term "atherosclerotic nephropathy"
      for this important disease entity.

PMID- 10412749
TI  - Progression of diabetic nephropathy in normotensive type 1 diabetic patients.
AB  - BACKGROUND: The first aim of our long-term study was to describe the natural
      history of diabetic nephropathy in 59 normotensive type 1 diabetic patients.
      Secondly, we evaluated genetic and nongenetic progression promoters. METHODS: The
      following progression promoters were determined: the insertion/deletion
      polymorphism in the angiotensin converting enzyme (ACE) gene, blood pressure,
      albuminuria, hemoglobin A1c, cholesterol, smoking, height, and gender. We studied
      the natural history by measuring 51Cr-EDTA plasma clearance at yearly intervals
      at least three times during [median (range)] 5.5 (2.2 to 18.3) years. RESULTS: At
      baseline the three groups (II, N = 11; ID, N = 25, and DD, N = 23) had comparable
      GFR (103 +/- 16; 99 +/- 19; 113 +/- 22 ml/min/1.73 m2, respectively; mean +/-
      SD), arterial blood pressure, albuminuria, and hemoglobin A1c. During the follow
      up there was a median rate of decline in GFR in all 59 patients of 1.2 (range
      12.9 to -4.4) ml/min/year. During the study period no significant differences
      were observed in: the rate of decline in glomerular filtration rate [median
      (range) 0.9 (10.6 to -1.9); 2.5 (12.9 to -4.4); 1.4 (10.8 to -1.9 ml/min/year)],
      arterial blood pressure, albuminuria, hemoglobin A1c or cholesterol between the
      three groups (II, ID and DD), respectively. At baseline, multiple linear
      regression analysis including the above-mentioned putative risk factors revealed
      that albuminuria, short stature, and male gender independently predict an
      enhanced decline in GFR [R2 (adjusted) = 0.33; P < 0.002]. During the follow-up
      period, only albuminuria acted as an independent progression promoter [R2
      (adjusted) = 0.37; P < 0.0001]. CONCLUSIONS: Our study revealed a rather slow
      progression of kidney disease in normotensive type 1 diabetic patients with
      diabetic nephropathy. Albuminuria, short stature, and male gender act as
      progression promoters in such patients.

PMID- 10412751
TI  - Lipid-lowering therapy in membranous nephropathy.
AB  - Membranous nephropathy (MN) is a very common cause of nephrotic syndrome in
      adults, and lipid abnormalities are, therefore, frequently found in these
      subjects. Although efficient lipid-lowering therapy is available, almost nothing
      is known about the contribution of hyperlipidemia in the pathogenesis of
      progressive renal failure in MN. Studies in an experimental animal model of human
      MN, Heymann nephritis, have shown that lipids play an essential role in the
      pathogenesis of proteinuria. Local production of reactive oxygen species after
      subepithelial immune complex deposition leads to the formation of lipid
      peroxidation (LPO) adducts, which ultimately alter the composition of the
      glomerular basement membrane. As the magnitude of urinary protein excretion is
      associated with the long-term prognosis, a normalization of glomerular
      permselective properties has been used as a surrogate parameter for the
      beneficial effects of treatment. Probucol, a drug with LPO inhibitor potential,
      is able to reduce urinary protein excretion in rats with passive Heymann
      nephritis. In humans with MN, preliminary data also support this observation. It
      remains to be determined, however, if this intervention, which does not interfere
      with immune complex formation, will reduce the number of the patients reaching
      end-stage renal failure because of MN. In conclusion, lipids may contribute to
      glomerular injury in MN, as LPO might be an especially important factor, opening
      the possibility for new therapeutic interventions, thereby avoiding the side
      effects of the currently used treatment regimen.

PMID- 10412752
TI  - Simvastatin in nephrotic syndrome. Simvastatin in Nephrotic Syndrome Study Group.
AB  - BACKGROUND: Hyperlipidemia of the nephrotic syndrome is a risk factor for the
      development of systemic atherosclerosis, but it also may aggravate
      glomerulosclerosis and enhance the progression of glomerular disease. HMG-CoA
      reductase inhibitors are effective in reducing cardiovascular morbidity and
      mortality. Whether they may influence the progression of glomerular disease is
      not clear. The Simvastatin in Nephrotic Syndrome Study addressed the question of
      whether or not cholesterol lowering by the HMG-CoA reductase inhibitor
      simvastatin was superior to placebo treatment in limiting the decline of GFR and
      reducing proteinuria in nephrotic patients with primary glomerulonephritis.
      METHODS: This was a prospective, two-year, double-blind trial that included 56
      patients with primary glomerulonephritis, hypercholesterolemia due to the
      nephrotic syndrome (proteinuria > 3 g/24 hr), and a creatinine clearance > 40
      ml/min/1.73 m2. They were randomly assigned to treatment with simvastatin or
      placebo targeted to achieve low density lipoprotein (LDL) cholesterol levels
      below 120 mg/dl. The objectives were to determine the efficacy and safety of
      simvastatin, the rate of GFR decline as measured by inulin clearance, and the
      change in proteinuria over a two-year treatment period. RESULTS: Simvastatin
      produced a mean change in cholesterol, LDL cholesterol, high density lipoprotein
      (HDL) cholesterol and triglycerides of -39% -47%, +1%, and -30%, respectively.
      Serum lipoprotein(a) [Lp(a)] was not affected. No major simvastatin related
      events occurred. Minor events included elevations in serum creatine kinase
      without clinical symptoms. The course of renal function and of proteinuria during
      the study are still under evaluation and are not given here. CONCLUSIONS: Long
      term treatment with simvastatin in nephrotic patients with hypercholesterolemia
      is effective and safe.

PMID- 10412753
TI  - Effect of HMG-CoA reductase inhibitors on chronic allograft rejection.
AB  - BACKGROUND: Although chronic rejection is the most important cause of late
      allograft loss, none of the currently available immunosuppressive agents
      successfully target this problem. Clinical and laboratory studies suggest that 3
      hydroxy-3-methyl-glutaryl co-enzyme A (HMG-CoA) reductase inhibitors (HRIs) may
      decrease the incidence of and pathophysiologic factors leading to chronic
      rejection. METHODS: A number of clinical and laboratory investigations have been
      designed to evaluate the effect of HRIs on chronic rejection. RESULTS: Clinical
      trials in heart transplant patients suggest that HRIs decrease the incidence of
      chronic rejection in a manner that may be independent of lipid lowering.
      Subsequent studies in animal transplant models confirm that HRIs reduce chronic
      rejection. In further studies to elucidate the possible mechanisms of this
      effect, it has been observed that HRIs have an inhibitory effect on an number of
      lymphoid cell lines and vascular smooth muscle cells. HRIs may also prevent
      chronic rejection by protecting the endothelium from injury and dysfunction,
      perhaps by up-regulating nitric oxide synthesis. CONCLUSIONS: HRIs may be the
      first agents to be effective in preventing chronic rejection. Although the
      mechanism behind this protective effect is unclear, it seems likely that HRIs may
      affect multiple factors that could lead to chronic rejection.

PMID- 10412754
TI  - Low density lipoprotein apheresis therapy for steroid-resistant nephrotic
      syndrome. Kansai-FGS-Apheresis Treatment (K-FLAT) Study Group.
AB  - BACKGROUND: The pathogenic role of hyperlipidemia in long-standing nephrotic
      syndrome (NS) is known to be responsible for both the progression of
      glomerulosclerosis and tubulointerstitial injury, especially in focal segmental
      glomerulosclerosis (FGS). METHODS: Aggressive lipid lowering treatment by low
      density lipoprotein (LDL) apheresis (LDL-A) using a dextran sulfate cellulose
      column to treat patients with steroid-resistant or frequently recurrent severe NS
      was performed first without fixing the protocol in eight patients with FGS and
      one with minimal change nephrotic syndrome (MCNS). The period of NS before LDL-A,
      number and average intervals of LDL-A until the end of the therapy, and the
      prognosis were investigated. Next, a multicenter study with a fixed protocol of
      LDL-A treatment was designed in combination with steroid therapy for treatment
      twice a week for three weeks and weekly for six weeks, and was performed in 17
      patients with FGS. The effects on the state of NS in addition to the change of
      urinary eicosanoid metabolites and remission rates were evaluated. RESULTS: In
      the preliminary study, along with a rapid improvement of hyperlipidemia, a high
      incidence of remission was achieved by LDL-A performed at relatively short
      intervals. In the multicenter study with a fixed protocol, there was a
      significant decrease of urinary protein (P < 0.001) and increase of serum albumin
      (P < 0.02) as well as a decrease of thromboxane B2 (TXB2) excretion (P < 0.05)
      after the treatment. Urinary excretion of TXB2 was significantly reduced after
      LDL-A (P < 0.05). The rate of entering into complete or incomplete remission was
      71% with a relatively short duration of nephrotic-range proteinuria using the LDL
      A therapy in comparison with steroid therapy alone. CONCLUSION: The rapid
      improvement of hypercholesterolemia with LDL-A treatment may provide a new
      approach for a high rate of improvement in the degree of NS in steroid-resistant
      NS of FGS and MCNS.

PMID- 10412755
TI  - Effect of vitamin E on lipid metabolism and atherosclerosis in ESRD patients.
AB  - BACKGROUND: Oxidative stress is enhanced in patients with end-stage renal disease
      (ESRD) undergoing hemodialysis (HD). Bioincompatibility represents an important
      source of reactive oxygen species. HD patients exhibit altered anti-oxidative
      defences and anti-oxidative vitamins such as vitamin E and C are altered in
      uremia. Frequently, HD patients also suffer from atherosclerotic cardiac disease.
      We have previously reported that low density lipoprotein (LDL) of HD patients is
      rich in malondialdehyde (MDA), an end product of lipid peroxidation. MDA rich LDL
      is thought to be an atherogenic lipoprotein due to its enhancement of macrophage
      foam cell formation. METHODS: We conducted a controlled study for two years
      comparing the effects of a vitamin E coated cellulose membrane dialyzer and an
      ordinary cellulose membrane dialyzer on lipid metabolism and the progress of
      atherosclerosis. LDL-MDA and oxidized LDL (ox-LDL) were measured in HD patients
      using these two types of dialyzers. Plasma vitamin E and lipid concentrations
      were also evaluated. The aortic calcification index (ACI) was evaluated by CT
      scan to assess the progress of atherosclerosis before and for every year after
      treatment. RESULTS: Use of a vitamin E coated cellulose membrane dialyzer for six
      months, one year and two years resulted in a significant reduction in LDL-MDA and
      ox-LDL compared to the ordinary cellulose membrane dialyzer. Treatment with a
      vitamin E-coated dialyzer significantly reduced the percentage increase in ACI
      after 24 months compared to the control. There were no significant changes in
      plasma vitamin E and lipid concentrations between the two groups. CONCLUSIONS:
      These results suggest that the oxidative stress could be one of the stimulating
      factors of abnormal lipid metabolism and atherosclerosis in ESRD patients.

PMID- 10412756
TI  - Acute myocardial infarction in patients with end-stage renal disease.
AB  - BACKGROUND: Ischemic heart disease is the major cause of death in dialysis
      patients, with 22% of cardiac deaths attributed to acute myocardial infarction
      (AMI). Few data exist on survival of dialysis patients after AMI. METHODS: The
      United States Renal Data System (USRDS) database of 627,983 patients was used to
      examine outcomes of dialysis patients hospitalized from 1977 to 1995 for AMI.
      Long-term survival was estimated by life-table method and independent predictors
      of survival were examined in a comorbidity-adjusted Cox model. In preliminary
      analyses we examined the utilization of thrombolytic therapy for AMI in 1991 to
      1995 and separately analyzed outcomes of dialysis patients hospitalized 1977 to
      1994 at our own institution. RESULTS: There were 34,189 dialysis patients with
      AMI. The in-hospital death was 26%. The all-cause mortality was 59% at one year
      and 73% at two years. The one- and two-year cardiac mortality was 41% and 52%,
      respectively. Patients with AMI 1990 to 1995 (vs. 1977 to 1984) had decreased
      mortality with RR (relative risk) 0.87 (0.83, 0.90). There were 16,063 patients
      with AMI 1991 to 1995 receiving no reperfusion therapy, and only 95 patients
      received intravenous thrombolytics, of whom 16 received concurrent coronary
      revascularization. At our institution, the in-hospital death for 113 dialysis
      patients with AMI was 29% (52% mortality for transmural MI, 16% mortality for
      nontransmural MI). CONCLUSION: We conclude that dialysis patients with AMI suffer
      dismal long-term survival. Based on preliminary data, thrombolytic therapy
      appears to be under-utilized in dialysis patients with AMI in the United States.

PMID- 10412757
TI  - Effects of lipid-lowering drugs on intermediate-density lipoprotein in uremic
      patients.
AB  - BACKGROUND: Patients with chronic renal failure often have alterations in
      lipoprotein profile including elevated very-low density lipoprotein (VLDL) and
      intermediate density lipoprotein (IDL), and reduced high density lipoprotein
      (HDL) levels. Among these changes, raised IDL has been shown as an independent
      risk factor for atherosclerosis in hemodialysis patients. There are a limited
      number of studies reporting pharmacological approaches to IDL reduction in a
      uremic population. METHODS: We therefore summarize the effects of lipid-lowering
      drugs on IDL levels in patients with chronic renal failure treated by
      hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). RESULTS:
      First, a nicotinic acid analog niceritrol was given to hemodialysis patients. The
      drug increased HDL-cholesterol by 11%, but the reductions in VLDL-, IDL- and LDL
      cholesterol were not significant. Second, CAPD patients were treated with a
      fibric acid derivative clinofibrate, which was excreted mainly into bile unlike
      other drugs in this class. The fibrate resulted in a remarkable reduction in VLDL
      triglycerides, although it did not reduce IDL-cholesterol. Finally, an HMG-CoA
      reductase inhibitor (statin) pravastatin was used in HD and CAPD patients.
      Pravastatin reduced IDL- and LDL-cholesterol to the same extent (by 31%). None of
      these treatments caused serious adverse effects. CONCLUSIONS: We propose that IDL
      is an important target in the management of uremic dyslipidemia. To date, statins
      have been shown to be suitable for this purpose, although it remains to be
      clarified whether such an intervention reduces the risk for atherosclerotic
      vascular events in the uremic population.

PMID- 10412758
TI  - Calcineurin inhibitors enhance low-density lipoprotein oxidation in transplant
      patients.
AB  - BACKGROUND: Our objective was to assess the pro-oxidant status of neoral and
      tacrolimus in renal transplant patients and monitor the protection provided by
      vitamin C and vitamin E in normalizing low density lipoprotein (LDL) oxidation
      lag time of tacrolimus-treated patients. METHODS: Plasma LDL was isolated by
      density gradient ultracentrifugation from renal transplant patients receiving
      neoral, tacrolimus and tacrolimus with vitamin C and vitamin E. Oxidation was
      initiated by the addition of CuCl2 at 37 degrees C and monitored at 234 nm over
      480 minutes and oxidation lag time was computed. Total antioxidant capacity of
      serum was measured using the enhanced chemiluminescent method. RESULTS: LDL from
      tacrolimus-treated patients had significantly lower oxidation lag time and serum
      antioxidant activity in comparison with neoral-treated patients, and this was
      particularly significant during the first four months after transplantation.
      Vitamin C and E supplementation in tacrolimus treated patients provided
      protection against oxidation and normalized their oxidation lag time. CONCLUSION:
      Calcineurin-inhibiting drugs, CsA and tacrolimus, have pro-oxidant activity and
      they increase the susceptibility of LDL to oxidation. Neoral formulation is
      fortified with DL-alpha tocopherol and therefore provides protection against
      oxidation. The present study clearly demonstrates the benefit of giving vitamin C
      and E supplements to patients taking tacrolimus and this seems to be particularly
      important during the early period after transplantation.

PMID- 10412759
TI  - Ongoing clinical trials of lipid reduction therapy in patients with renal
      disease.
AB  - BACKGROUND: Lipid abnormalities in renal disease are associated with both a
      progressive decline in renal function and cardiovascular complications. Whether
      or not lipid anomalies are causal is not yet clear. Experimental studies have
      demonstrated that potentially atherogenic lipoproteins, such as low density
      lipoproteins (LDL), are associated with renal pathophysiological changes that
      result in progressive glomerular and interstitial damage and an ultimate
      reduction in renal function. These findings indicate that hyperlipidemia
      accelerates glomerular and interstitial damage in renal disease. Clinical studies
      also show that renal function declines more rapidly among patients with primary
      renal disease or diabetic nephropathy who have hyperlipidemia. However, few
      reports have demonstrated the effect of hypolipidemic agents on the progression
      of renal function among patients with renal disease, and those renal patients who
      were treated with lipid-lowering agents have not been clinically studied under
      large-scale controlled conditions. In addition, although cardiovascular
      complications are the most important factors associated with mortality in
      dialysis patients, randomized, large-scale trials studying the relationship
      between therapeutic intervention by lipid-lowering agents and prevention of
      cardiovascular complications have not been implemented. METHODS: We reviewed
      controlled and uncontrolled reported studies that examined the effects of lipid
      lowering therapy in patients with renal disease. RESULTS: Most studies showed
      that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce
      cholesterol-rich apolipoprotein (apo)B-containing lipoproteins with no effects on
      renal function or proteinuria among patients with progressive renal disease.
      Small uncontrolled studies show that simvastatin and probucol moderately reduce
      proteinuria among patients with membranous nephropathy. One small retrospective
      study showed that long-term vitamin E therapy reduces aortic calcification in
      dialysis patients. CONCLUSIONS: Prospective, randomized large-scale trials
      including ongoing clinical trials of lipid reduction therapy and therapeutic
      interventions such as the use of the combination therapy with hypolipidemic
      agents and angiotensin converting enzyme (ACE) inhibitors, vitamins, or LDL
      apheresis are urgently required. Such trials will clarify the effect of treating
      dyslipidemia on the progression of renal insufficiency and dialysis-related
      cardiovascular complications.

PMID- 10412760
TI  - Clinicopathological characteristics of interstitial foam cells in membranous
      nephropathy.
AB  - BACKGROUND: Interstitial foam cells are occasionally observed in various renal
      diseases, and they have been reported to belong to the monocyte/macrophage (M
      phi) lineage and to be associated with heavy proteinuria and hyperlipidemia. We
      investigated the characteristics of interstitial foam cells and their association
      with proteinuria and hyperlipidemia in idiopathic membranous nephropathy (MN).
      METHODS: Patients with MN (N = 320) were divided into two groups: group I
      consisted of 51 patients with interstitial foam cells, and group II consisted of
      the other 269 without foam cells. We compared clinical parameters and the
      findings of an immunohistochemical study using monoclonal antibodies to various
      types of leukocytes and adhesion molecules. RESULTS: The age at renal biopsy, the
      degree of proteinuria, serum levels of lipids, and other clinical parameters
      except for sex ratio were not different between the two groups. The ratio of
      nephrotic patients was compatible between groups I (56.9%) and II (52.8%). All
      interstitial foam cells were positive for CD68 and 25F9, which are markers for M
      phi and mature M phi, respectively, but were negative for CD3 or cytokeratin.
      Interstitial infiltrating cells were positive for CD68 and CD3 but were negative
      for 25F9. Furthermore, most of interstitial foam cells were positive for both
      leukocyte function associated antigen-1 (LFA-1) and intercellular adhesion
      molecule-1 (ICAM-1), but not for ICAM-3 (the third ligand for LFA-1). By
      contrast, most of infiltrating nonfoamy M phi s were positive for ICAM-3 and LFA
      1, however, ICAM-1 was observed on only some of them. CONCLUSION: These results
      suggest that interstitial foam cells in MN may not depend on proteinuria nor
      hyperlipidemia directly. The accumulation of foam cells, which have
      characteristics of mature M phi, may be related to ICAM-1 as a ligand of LFA-1,
      whereas infiltration of nonfoamy M phi s has a close relationship with ICAM-3.
      Thus, the formation of interstitial foam cells may be related to the phenotypical
      transformation of M phi s.

PMID- 10412761
TI  - Evaluation of serum lipid abnormalities in chronic nephritis.
AB  - BACKGROUND: In glomerular disease, disorders of lipid metabolism are suspected as
      factors exacerbating glomerular dysfunction. Although many reports have been
      published regarding metabolic disorders of lipids in renal disease, including
      nephrotic syndrome and chronic renal failure, there have been few published
      reports describing metabolic disorders of lipids in chronic nephritis. Therefore,
      in patients with IgA nephritis, we evaluated correlations between serum lipid
      levels and renal function and proteinuria. METHODS: In 191 patients with IgA
      nephritis, we evaluated the correlations between serum lipid levels and renal
      function [creatinine clearance (CCr)] and proteinuria (UP). Serum lipids examined
      included total cholesterol (TC), triglycerides (TG), high-density lipoprotein
      cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C),
      apolipoproteins, phospholipids (PL), lipoprotein(a) [Lp(a)], and malondialdehyde
      (MDA). RESULTS: Significant correlations were observed between serum lipid levels
      and CCr, UP, and age. There were no abnormalities in the mean values of
      respective serum lipids examined. Although TC levels increased with age, HDL-C
      levels were not correlated with age. Hyperlipidemia was observed in 39.8% of
      subjects. Significant correlations were observed between levels of TC, TG, PL,
      LDL-C, apoB, apoC-II, and apoC-III and Ccr, UP, and age. Significant correlations
      were also observed between levels of MDA, apoB/apoA-I, apoE/apoC-III, and Ccr and
      age, as well as between apoE levels and UP and age. The levels of apoA-I and apoA
      I/apoA-II ratio were significantly correlated with UP alone, whereas the apoC
      II/apoC-III ratio was significantly correlated with Ccr alone. There were no
      significant correlations between levels of HDL-C, apoA-II, and Lp(a) and Ccr, UP,
      and age. CONCLUSIONS: Age, proteinuria, and renal function were related with
      changes in serum lipid levels in IgA nephritis. There were correlations between
      proteinuria and levels of apoA, as well as between renal function and apoC
      levels.

PMID- 10412762
TI  - A high-fat diet aggravates tubulointerstitial but not glomerular lesions in obese
      Zucker rats.
AB  - BACKGROUND: Despite a large body of evidence that manipulation of dietary fat
      alters glomerular lesions, reports regarding the effects of dietary fat on
      tubulointerstitial lesions are limited. Obese Zucker rats (OZR) spontaneously
      develop glomerular and tubulointerstitial lesions in association with
      hyperlipidemia. We sought to elucidate the effects of dietary fat on glomerular
      and tubulointerstitial lesions in OZR versus lean Zucker rats (LZR) and to assess
      the involvement of macrophages in the development of these lesions. METHODS: We
      fed LZR and OZR either a low- (1%) or high-fat (20%) diet. After 30 weeks of the
      specified diet, the creatinine clearance (Ccr) and renal histology as well as
      plasma lipid concentrations were examined. For morphological evaluation,
      glomerular sclerosis (GSI) and tubulointerstitial indices (TII) were each
      determined by a point-counting method. Infiltrating macrophages were stained
      immunohistochemically using an avidin-biotin complex technique. RESULTS: The high
      fat diet increased the plasma low-density lipoprotein concentration in OZR. Both
      low- and high-fat OZR groups had higher GSI and TII than LZR receiving either
      diet. The high-fat diet aggravated TII but not GSI or Ccr in OZR; conversely,
      high fat intake worsened GSI and Ccr but not TII in LZR. Tubulointerstitial
      macrophages were most prominent in the high-fat OZR group, followed by the low
      fat OZR group. Glomerular macrophages were similar in number in all groups.
      CONCLUSIONS: The manipulation of dietary fat has diverse effects on the kidney. A
      high-fat diet aggravated macrophage-mediated tubulointerstitial lesions in OZR,
      whereas in LZR, the diet induced glomerulosclerosis.

PMID- 10412763
TI  - Imaging of hydroperoxides in a rat glomerulus stimulated by puromycin
      aminonucleoside.
AB  - BACKGROUND: To determine the locus of the increased oxidation induced by
      puromycin aminonucleoside (PAN), we imaged hydroperoxides in glomeruli stimulated
      by PAN in vivo and in vitro. METHODS: Dichlorofluorescein diacetate (DCFH-DA) in
      cells makes dichlorofluorescein, a substance that fluoresces when reacted with
      hydroperoxides. Fluorescence was detected using a photon detection video camera
      connected to a microscope. Two kinds of isolated glomeruli of Wistar rats were
      examined. One was the glomerulus obtained from rats on the seventh day following
      the injection of PAN. In this case, glomeruli were incubated in a buffer
      containing 5 mM DCFH-DA. Another was the glomerulus collected at 30 minutes after
      a large amount of DCFH-DA was intravenously injected. These glomeruli were
      incubated with either PAN or phorbol myristate acetate (PMA) in Krebs-Henseleite
      bicarbonate buffer. RESULTS: The images from the glomeruli treated by PAN in vivo
      resemble pictures of a galaxy by telescope. When the glomeruli were treated by
      PAN in vitro, two localized points appeared in each glomerulus after 15 minutes
      of incubation with PAN, and after 75 minutes of incubation, the fluorescence
      spread throughout the glomerulus. When glomeruli were incubated with PMA, two
      points that gave a very strong fluorescence were observed in each glomerulus, but
      they did not spread throughout the glomeruli. In both experiments, glomeruli
      without stimulants did not fluoresce. CONCLUSION: Increases in hydroperoxides
      were observed in the glomeruli from rats made nephrotic by exposure to PAN, and
      were also observed in glomeruli following 15 minutes of incubation with PAN in
      vitro.

PMID- 10412764
TI  - Lysophosphatidylcholine up-regulates IL-1 beta-induced iNOS expression in rat
      mesangial cells.
AB  - BACKGROUND: Nitric oxide (NO), a simple molecule synthesized from L-arginine by
      NO synthases (NOS), has been identified to play an important role in cell
      communication, cell defense and cell injury. Several studies have shown that
      glomeruli from rats with immune-mediated glomerular inflammation have increased
      production of NO. Recently, it was also reported that inducible NOS (iNOS) is
      localized in mesangial cells, glomerular epithelial cells and infiltrating cells
      in the diseased human glomeruli. On the other hand, while oxidized low density
      lipoprotein (ox-LDL) has been suggested to be related to progression of
      glomerular disease, the mechanism remains unknown. We investigated the effect of
      lysophosphatidylcholine (LPC), a modified phospholipid produced during LDL
      oxidation, on iNOS expression in rat mesangial cells. METHODS AND RESULTS:
      Treatment of mesangial cells with interleukin-1 beta (IL-1 beta) induced iNOS
      activity measured as nitrite levels in cell culture supernatants. Treatment with
      LPC had no effect. In contrast, coincubation with LPC and IL-1 beta resulted in a
      markedly higher nitrite content compared to that after incubation with IL-1 beta
      alone. Western blot analysis revealed that LPC caused a significant increase in
      the formation of iNOS protein in the presence of IL-1 beta. CONCLUSION: These
      findings suggest that LPC may contribute to progression of glomerular
      inflammation by augmenting IL-1 beta-induced iNOS expression.

PMID- 10412765
TI  - Lipid-binding proteins in rat and human kidney.
AB  - BACKGROUND: The kidney metabolizes actively lipophilic molecules. Several species
      of lipid-binding proteins (LBPs) have been well characterized, including fatty
      acid-binding proteins (FABPs), acyl-CoA binding protein (ACBP), sterol carrier
      protein 2 (SCP2), cellular retinol binding protein (CRBP), and
      phosphatidylinositol transfer protein (PITP). METHODS: To clarify which LBPs are
      expressed in isolated rat glomeruli (RG), cultured rat mesangial cells (RMC) and
      human kidney, RT-PCR, immunoblot analysis and immunohistochemistry were
      performed. RESULTS: Protein and mRNA expression of heart type (H-) FABP was found
      in RMC, but not in RG. Immunohistochemistry using antihuman H-FABP antibody
      revealed that an H-FABP like protein was present in the capillary wall and distal
      tubules of human glomeruli. Immunoblot analysis using the antibody showed that a
      110-kDa protein related to H-FABP was present in human isolated glomeruli but not
      in any other tissues tested including blood, liver, and heart, and that the 14
      kDa protein, H-FABP itself was localized in the distal tubules of human kidney.
      mRNA for SCP2, ACBP and PITP was detected in RG and RMC. CRBP and mRNA was
      detected in RG but not RMC. CONCLUSIONS: A variety of lipid-binding proteins are
      present in rat glomeruli. In human glomeruli, a novel 110-kDa H-FABP-related
      protein is localized specifically in the capillary wall.

PMID- 10412766
TI  - Human mesangial cells express inducible macrophage scavenger receptor: an Ap-1
      and ets mediated response.
AB  - BACKGROUND: Type A scavenger (SR) mediate the uptake of modified low-density
      lipoproteins by macrophages. The accumulation of lipid via this process is
      thought to lead to foam cell formation in atherosclerotic plaques. Human
      mesangial cells (HMC), which can be converted to foam cells in vivo, have not
      previously been shown to express SR in normal culture. We investigated whether or
      not there was an inducible form of SR in a human mesangial cell line (HMCL).
      METHODS: SR activity was analyzed by cellular uptake of fluorescently labeled
      acetylated low-density lipoprotein using a flow cytometer. SR mRNA expression was
      examined using RT-PCR followed by Southern blotting. To investigate the molecular
      mechanism of SR expression, several reporter gene constructs were designed. The
      first contained a full SR promoter, the second a part of the SR promoter that has
      both activated protein-1 (AP-1) and ets transcriptional factor binding sites.
      Other constructs were identical to the second except they contained either AP-1
      or ets motif mutations. RESULTS: Phorbol 12-myristate 13-acetate (PMA) increased
      both the percentage of SR positive cells and SR mean fluorescence intensity. PMA
      also increased SR mRNA and promoter activity in a time and dose responsive
      manner. Function analysis showed that both AP-1 and ets motifs were specific
      response elements to PMA stimulation in HMCL. CONCLUSIONS: The present study
      suggests that the combination of interaction between AP-1 and ets transcriptional
      factors may mediate the inducible expression of the SR gene in HMCL, which may
      contribute to foam cell formation.

PMID- 10412767
TI  - Probucol suppresses ICAM-1 expression in rat mesangial cells: possible role of IL
      1.
AB  - Interleukin-1 (IL-1) participates in the progression of glomerulonephritis by up
      regulating intercellular adhesion molecule-1 (ICAM-1) expression in experimental
      glomerulonephritis. Probucol, an anti-hyperlipidemic agent, ameliorates some
      types of glomerulonephritis regardless of serum cholesterol levels, and is also
      reported to inhibit IL-1 release from macrophages in atherosclerotic lesions.
      However, little is known about the mechanism of this favorable action on
      glomerular injury. We examined whether or not probucol inhibits ICAM-1 expression
      by suppression of IL-1 action in cultured rat mesangial cells. In this brief
      report, we review the actions of probucol on IL-1 secretion and discuss the
      possible mechanism by which probucol may suppress the glomerular injury.

PMID- 10412768
TI  - Phospholipase A2 activity in ox-LDL-stimulated mesangial cells and modulation by
      alpha-tocopherol.
AB  - BACKGROUND: Oxidized LDL increases the production of both prostaglandin E2 (PGE2)
      and thromboxane B2 (TXB2) in rat mesangial cells. These increases were suppressed
      by antioxidants such as alpha-tocopherol (alpha-Toc) or probucol. METHODS: We
      investigated the mechanism by which oxidized LDL leads to an increase in PGE2
      production using rat mesangial cells in culture. We also examined how alpha-Toc
      supresses this augmentation, by measuring intracellular Ca2- and phospholipase A2
      (PLA2) activity. RESULTS: In rat mesangial cells, oxidized LDL increased PLA2
      activity by increasing the intracellular calcium ion content, which resulted in
      the induction of PGE2 production. On the other hand, pretreatment of cells with
      alpha-Toc, which resulted in a large uptake of alpha-Toc in cell membranes,
      markedly suppressed the augmentation of PGE2 production and PLA2 activity by
      oxidized LDL in a dose dependent manner. However, cytosolic PLA2 partially
      purified from mesangial cells was not inhibited by alpha-Toc despite an increase
      of alpha-Toc. CONCLUSION: These results suggest that the augmentation of PLA2
      activity in mesangial cells by oxidized LDL in a result of oxidative stresses,
      and that the antioxidant action of alpha-Toc is responsible for the suppression
      of augmentation of PLA2 activity observed in mesangial cells exposed to oxidized
      LDL.

PMID- 10412769
TI  - Involvement of MCP-1 and M-CSF in glomerular foam cell formation in ExHC rats.
AB  - BACKGROUND: An increase in glomerular macrophages (MO) is considered a potential
      effector mechanism by which hypercholesterolemia exacerbates glomerular injury.
      To investigate the mechanism underlying recruitment of MO into glomeruli, the
      expression of glomerular monocyte chemoattractant protein-1 (MCP-1) and
      macrophage colony-stimulating factor (M-CSF) mRNA were examined using a lipid
      induced glomerular injury rat model. METHODS: Eight-week-old male ExHC rats, a
      strain susceptible to hyperlipidemia, were divided into the following 4 groups: a
      control group (C), a high cholesterol diet group (HH), a high cholesterol
      diet/standard diet group (HN), which were fed a high cholesterol diet for the
      first 4 weeks and a standard diet for the following 4 weeks, and a probucol
      treatment group (PT). Both MCP-1 and M-CSF mRNA expression in glomeruli were
      analyzed using the RT-PCR method. An additional experimental group (M) fed a high
      cholesterol diet was administered M-CSF daily for 4 weeks. RESULTS: The
      expression of MCP-1 mRNA in glomeruli increased accompanied by an increased total
      serum cholesterol level in HH and HN. However, M-CSF mRNA expression was
      significantly suppressed at 1 or 2 weeks and gradually increased to almost basal
      levels. In the PT group, MCP-1 mRNA expression was suppressed. The early
      suppression of M-CSF mRNA expression was inhibited in PT. Renal histology showed
      a significant increase in foam cells in glomeruli in HH and HN rats at 4 weeks.
      HH rats showed increased and expanded foam cells at 8 weeks. In HN rats, however,
      foam cells decreased significantly after the transfer to a standard diet from a
      high cholesterol diet. The MCP-1 mRNA expression was suppressed after the
      transfer. In the PT group, foam cell formation was also suppressed. Foam cells
      were identified as MO. M-CSF-treatment significantly suppressed foam cell
      formation in glomeruli when compared with the untreated group levels. CONCLUSION:
      These findings suggest that hypercholesterolemia stimulated the expression of MCP
      1 in glomeruli and attracted the MO into glomeruli. They also suggest that the
      reduction of hypercholesterolemia after the change in diet or treatment with
      probucol suppressed glomerular injury by suppressing the glomerular MCP-1
      expression. M-CSF may suppress the recruitment of MO into glomeruli and foam cell
      formation at an early stage of hypercholesterolemia-induced glomerular injury.

PMID- 10412770
TI  - Mechanism of preventive effect of HMG-CoA reductase inhibitor on diabetic
      nephropathy.
AB  - BACKGROUND: Previously, we have found that pravastatin prevents diabetic
      nephropathy in streptozotocin-induced diabetic rats independently of serum lipid
      levels. The aim of this study was to clarify the impact of pravastatin on the
      mesangial cells exposed to high glucose. METHODS: Rat mesangial cells were
      cultured in DMEM containing low glucose (5 mM glucose), high glucose (25 mM
      glucose) and 25 mM glucose with 500 microM pravastatin for 48 hours,
      respectively. After harvesting, we examined membrane-associated Ras with
      immunoblot analysis, activity of mitogen-activated protein kinase (MAPK) in the
      cytosol fraction with in-gel kinase assay and expressions of TGF-beta mRNA with
      Northern blot analysis. RESULTS: Membrane-associated Ras, activity of MAP kinase,
      and expression of transforming growth factor-beta (TGF-beta) mRNA were increased
      in the mesangial cells cultured exposed to high glucose compared to low glucose.
      Pravastatin suppressed all these changes in membrane-associated Ras, MAP kinase
      and TGF-beta mRNA in high glucose. CONCLUSIONS: This study suggests that
      pravastatin suppresses the activity of Ras-MAP kinase cascade and induction of
      TGF-beta in the mesangial cells that have been exposed to high glucose.

PMID- 10412771
TI  - Lysophosphatidylcholine induces platelet-derived growth factor gene expression in
      a human mesangial cell line.
AB  - BACKGROUND: Oxidized low-density lipoprotein (oxLDL) has been considered
      important in the pathogenesis of progressive renal injury.
      Lysophosphatidylcholine (lysoPC) is a major phospholipid component of oxLDL. On
      the other hand, platelet-derived growth factor (PDGF) has also been implicated in
      proliferative disease of the kidney. This study investigated the difference in
      the potential of PC and lysoPC to induce DNA synthesis and PDGF gene expression
      in a human glomerular mesangial cell line (HMCL). METHODS: DNA synthesis in HMCL
      was measured by [3H] thymidine incorporation. The mRNA expression levels of the
      PDGF A chain and B chain genes were measured using reverse transcription
      polymerase chain reaction. RESULTS: LysoPC treatment up-regulated the [3H]
      thymidine incorporation level in a dose-dependent fashion. The [3H] thymidine
      incorporation level in HMCL coincubated with lysoPC started to increase after 4
      hours of treatment, peaked at 24 hours, and decreased thereafter. The level in
      HMCL incubated with 100 microM of lysoPC (palmitoyl or stearoyl) increased to 7-
      or 10-fold of the control at peak time, respectively. However, PC treatment did
      not increase [3H] thymidine incorporation in HMCL. PC treatment did not induce
      mRNA expression of either PDGF A or B chain genes. LysoPC did not induce PDGF A
      chain mRNA expression either. The only B chain mRNA expression was induced by
      lysoPC. The mRNA expression level in HMCL treated with 50 microM lysoPC for two
      hours increased to 1.6-fold that of the control. CONCLUSION: LysoPC may induce
      DNA synthesis in a mesangial cell through the induction of PDGF BB as an
      autocrine and paracrine growth factor.

PMID- 10412772
TI  - A common mutation of cholesteryl ester transfer protein gene in dialysis
      patients.
AB  - BACKGROUND: In patients on maintenance hemodialysis, a decreased concentration of
      high-density lipoprotein cholesterol (HDL-C) is an apparent independent risk
      factor for vascular disease (VD). A common missense mutation of cholesteryl ester
      transfer protein (CETP) gene, D442G (Asp442 to Gly), increases HDL-C levels, but
      the mutation may also diminish the activity of reverse cholesterol transport.
      METHODS: We compared the genotype distribution of the D442G polymorphism and
      postprandial serum lipid levels between patients with and without VD in 414
      hemodialysis patients. RESULTS: Serum levels of total cholesterol and HDL-C did
      not differ in patients with the mutation [group M (+)] and without the mutation
      [group M (-)] and in patients with and without VD. However, patients with below
      median HDL-C levels (< 45 mg/dl) had a significantly higher prevalence of VD than
      those with above median HDL levels (26.0 vs. 15.2%, P < 0.01). Moreover, in this
      low-HDL-C subgroup, group M (+) patients had a significantly higher prevalence of
      VD than group M (-) patients (54.5 vs. 24.4%, P < 0.05). In the subgroup, group M
      (+) patients with VD had higher levels of total cholesterol and a higher
      atherogenic index than those without VD, whereas group M (-) patients with VD had
      lower levels of total cholesterol and a lower atherogenic index than those
      without VD. CONCLUSIONS: The D442G mutation may be a risk factor for
      atherosclerotic complications in dialysis patients with HDL-C levels below 45
      mg/dl. Atherogenic lipid profiles may promote atherosclerosis in the patients
      with the mutation, but not in those with no mutation.

PMID- 10412773
TI  - Mechanism of oral absorbent AST-120 in lipid abnormalities in experimental uremic
      rats.
AB  - BACKGROUND: We have reported that oral sorbent AST-120 (AST) is effective in
      delaying the induction of dialysis in patients with chronic renal failure (CRF)
      because of its effect on lipid metabolism. To clarify the precise mechanism of
      AST in lipid abnormalities in CRF, we examined the effect of AST on plasma lipid
      profile, total bile acids (TBA), and lipoprotein lipase (LPL) activity in
      experimental uremic rats. METHODS: Uremic rats were prepared using male Wistar
      rats by ligating 5/6 of the renal artery. Uremic rats were randomly divided into
      two groups as follows: a control group in which rats were maintained on the
      standard diet and an AST group in which rats were maintained on a diet containing
      5 g of AST per 100 g of standard diet for 10 weeks. Plasma LPL activity was
      measured as free fatty acid (FFA) generation after intravenous administration of
      heparin. RESULTS: Plasma creatinine at 1.5 +/- 0.1 mg/dl was lower in the AST
      group than the 1.9 +/- 0.5 mg/ml level in the control group. AST significantly
      decreased plasma total cholesterol from 192 +/- 29 to 142 +/- 25 mg/dl,
      triglycerides from 198 +/- 71 to 99 +/- 38 mg/dl, and TBA from 19.6 +/- 2.6
      mumol/liter to 8.8 +/- 3.5 mumol/ml. Plasma LPL activity at 0.22 +/- 0.01 mumol
      FFA/min/hr was significantly higher in the AST group than 0.15 +/- 0.03 mumol
      FFA/min/hr in the control group. CONCLUSIONS: These results suggest that AST may
      improve plasma lipid abnormalities by binding to bile acids in the intestinal
      lumen and preventing their reabsorption and inhibiting the reduction of LPL
      activity in experimental uremic rats.

PMID- 10412774
TI  - Oral adsorbent ameliorates renal TGF-beta 1 expression in hypercholesterolemic
      rats.
AB  - BACKGROUND: A spontaneously hypercholesterolemic Imai rat has recently been
      reported as a model of focal glomerulosclerosis that causes nephrotic syndrome
      followed by renal failure. This study was designed to determine if an oral
      adsorbent, AST-120, ameliorates renal lesions and TGF-beta 1 expression in the
      rats. METHODS: AST-120 was given orally to the Imai rats for 32 weeks, and renal
      function and pathology were compared between the AST-120-administered and control
      Imai rats. RESULTS: AST-120-administered rats showed significantly lower level of
      blood urea nitrogen, serum creatinine, urinary protein, serum total-cholesterol,
      serum triglyceride, and serum and urinary indoxyl sulfate, and significantly
      higher levels of serum albumin and creatinine clearance than control rats. AST
      120 reduced the glomerular sclerosis index, interstitial fibrosis area, and the
      extent of glomerular lipid deposition. Immunohistochemistry demonstrated that AST
      120 reduced the expression of transforming growth factor (TGF)-beta 1 and tissue
      inhibitor of metalloproteinase (TIMP)-1 as well as interstitial infiltration of
      macrophages in the renal cortex of the Imai rats. CONCLUSIONS: AST-120 prevented
      the progression of nephrotic syndrome and renal failure in the Imai rats by
      ameliorating glomerular sclerosis and interstitial fibrosis, accompanied with
      reduced expression of TGF-beta 1 and TIMP-1, and reduced infiltration of
      macrophages in the kidneys.

PMID- 10412775
TI  - Direct inhibitory effects of simvastatin on matrix accumulation in cultured
      murine mesangial cells.
AB  - BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors
      have been demonstrated to suppress glomerular injuries in various renal diseases.
      These agents inhibit in vitro proliferation of several cell types, including
      mesangial cells. This effect indicates the ability to ameliorate
      mesangioproliferative lesions, independent of the improvement of
      hypercholesterolemia. On the other hand, it is not clear whether HMG-CoA
      reductase inhibitors directly regulate extracellular matrix (ECM) accumulation
      from mesangial cells. METHODS: In this study, to examine the in vitro effects of
      simvastatin, an HMG-CoA reductase inhibitor, on mRNA expressions of matrix
      proteins, growth factors, and matrix turnover proteins, we incubated cultured
      murine mesangial cells stimulated by fetal calf serum (FCS) with or without
      simvastatin for 24 hours, and Northern analysis was performed. RESULTS:
      Simvastatin showed a slightly suppressive effect on mRNA expression of type IV
      collagen and fibronectin and a slightly up-regulative effect on that of type I
      collagen, whereas mRNA expression of type III collagen was markedly up-regulated.
      mRNA expression of platelet-derived growth factor (PDGF)-B chain and PDGF
      receptor beta-subunit was suppressed, whereas that of transforming growth factor
      beta (TGF-beta) was not affected by simvastatin. Concerning matrix turnover
      proteins, simvastatin markedly reduced mRNA expression of plsminogen activator
      inhibitor-1 (PAI-1) without affecting the expression of tissue-type plasminogen
      activator (tPA). CONCLUSION: These results suggest type-specific modulation of
      matrix protein production independent of TGF-beta and the suppressive effects of
      autocrine PDGF by administration of HMG-CoA reductase inhibitors in mesangial
      cells. Moreover, the beneficial effects of these agents on matrix protein
      accumulation may be through promoting ECM degradation derived from PAI-1
      suppression.

PMID- 10412776
TI  - Effects of lovastatin on expression of cell cycle regulatory proteins in vascular
      smooth muscle cells.
AB  - BACKGROUND: The sequential appearance of cyclins D and E is thought to initiate
      subsequent DNA synthesis in proliferating cells. Previous studies have reported
      that DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs) was
      suppressed by the HMG-CoA reductase inhibitor lovastatin. The effects of
      lovastatin on cell cycle regulatory proteins in proliferating VSMCs, however, are
      largely unknown. Thus, we investigated the sequential expression of cyclin D1,
      cyclin E, cyclin-dependent kinase (CDK) 4, CDK2, and p27Kip1 in cultured rat
      VSMCs stimulated by platelet-derived growth factor (PDGF)-BB in the presence or
      absence of lovastatin. METHODS: Quiescent VSMCs, with and without lovastatin (20
      microM) pretreatment for nine hours, were stimulated by PDGF-BB (25 ng/ml). The
      incorporation of tritiated thymidine was done to assess DNA synthesis. VSMC
      lysates were obtained every 6 hours for up to 36 hours after stimulation and were
      subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and
      Western blot analysis using relevant polyclonal antibodies. Autoradiograms were
      analyzed using a densitometer. RESULTS: The peak expression of cyclins D1 and E
      occurred at 18 and 30 hours of PDGF stimulation, respectively. Concomitant
      expression of CDK4 and CDK2 was also observed. The expression of p27Kip1, by
      contrast, was reduced in association with DNA synthesis. Lovastatin suppressed
      DNA synthesis and reduced the expression of cyclin D1 and cyclin E, whereas
      p27Kip1 expression was strongly induced by lovastatin pretreatment. CDK4 and CDK2
      expression was unaffected by lovastatin treatment. CONCLUSIONS: PDGF-BB induces
      cyclins D1 and E prior to the onset of DNA synthesis in VSMCs. Lovastatin may
      suppress DNA synthesis in VSMCs by inducing p27Kip1 and reducing expression of
      cyclins D1 and E.

PMID- 10412777
TI  - Low-density lipoprotein apheresis retards the progression of hyperlipidemic overt
      diabetic nephropathy.
AB  - BACKGROUND: Hyperlipidemia has recently received attention as being involved in
      the progression of diabetic nephropathy (DN). Low-density lipoprotein apheresis
      (LDL-A) can remove a large amount of plasma lipid directly from the patients in a
      short time. METHODS: Fifteen type 2 diabetic patients with overt nephropathy
      received LDL-A in two different manners: short-term intensive therapy (SIT) for
      nine patients and long-term intermittent therapy (LIT) for six patients. RESULTS:
      The changes in the monthly decline rates of reciprocal serum creatinine (1/Cr)
      were -0.035 +/- 0.020 in the three-month period before SIT, 0.047 +/- 0.041
      during and until two weeks after SIT, and -0.035 +/- 0.015 after a period of two
      weeks from the therapy. The mean duration of LIT in six patients was 8.2 +/- 7.4
      months, and the mean monthly decline rates of 1/Cr significantly decreased during
      the period of LIT as compared with the six-month period before the treatment.
      CONCLUSION: LDL-A can retard the progression of overt DN, especially when it is
      performed repeatedly for a long period at two-week intervals.

PMID- 10412778
TI  - Rapid normalization of interleukin-8 production after low-density lipoprotein
      apheresis in steroid-resistant nephrotic syndrome.
AB  - BACKGROUND: Low-density lipoprotein apheresis (LDL-A) treatment combined with
      steroids demonstrated significant improvement of nephrotic proteinuria in steroid
      or immunosuppressive-resistant patients from focal and segmental
      glomerulosclerosis (FGS). The mechanisms of the effect of LDL-A in nephrotic
      syndrome (NS) are unknown, but a reduction in inflammatory cytokines and
      chemokines secreted from macrophages has been supposed. METHODS: Serum levels of
      interleukin (IL)-8, tumor necrosis factor-alpha (TNF-alpha), and monocyte
      chemoattractant protein-1 (MCP-1) were measured by enzyme-linked immunosorbent
      assay in 27 patients with NS [13 with FGS and 14 with minimal change nephrotic
      syndrome (MCNS)] before and after LDL-A and in 13 age-matched, healthy controls.
      We also selected three FGS patients who were resistant to steroid therapy for at
      least one month and who had undergone six LDL-A procedures. The effects of
      steroids and LDL-A on the production of IL-8, TNF-alpha, and MCP-1 by peripheral
      blood mononuclear cells (PBMCs) were also determined in some patients. RESULTS:
      In NS, the serum levels of IL-8 and TNF-alpha, but not MCP-1, were significantly
      higher than in healthy controls. After LDL-A, IL-8 and TNF-alpha tended to
      decrease. IL-8 production by lipopolysaccharide (LPS)-stimulated PBMC, mainly
      adherent cells, was significantly reduced in both the steroid-resistant FGS group
      and nontreated NS group compared with controls, but TNF-alpha production was
      reduced in the only FGS group. After LDL-A, only IL-8 production recovered to the
      control group level. CONCLUSION: Significant amelioration of IL-8 production
      independent of any effect of steroids on LPS-stimulated PBMCs may reflect a
      beneficial effect of LDL-A in normalizing the function of circulating monocytes
      in steroid-resistant FGS.

PMID- 10412779
TI  - Erythropoietin supplement increases plasma lipoprotein lipase and hepatic
      triglyceride lipase levels in hemodialysis patients.
AB  - BACKGROUND: We reported in previous studies that plasma triglyceride levels, as
      well as remnant-like particles-cholesterol (RLP-C) and -triglyceride (RLP-TG)
      levels, were significantly lower in maintenance hemodialysis (HD) patients
      treated with erythropoietin (EPO) than in HD patients treated without EPO.
      However, little is known about the mechanisms underlying the improvements in
      abnormal RLP metabolism in HD patients. This study investigates whether EPO
      supplement therapy in cases of uremic anemia increases the plasma lipoprotein
      lipase (LPL) and hepatic triglyceride lipase (HTGL) levels in HD patients.
      METHODS: Twenty HD patients who had not previously received EPO were divided into
      two groups according to the stage of HD: 12 at the initial stage, defined as a
      mean HD duration of 0.35 +/- 0.68 months (range of 0 to 2.47 months), and 8 at
      the maintenance stage, defined as a mean HD duration of 114.1 +/- 91.9 months
      (range of 13.0 to 253.9 months). Fasting plasma was collected from the HD
      patients prior to the start of the EPO supplement therapy and at one month after
      the therapy. RLP-C levels were determined using a RLP-C JIMRO II kit. Fasting
      plasma was also collected from the HD patients 10 minutes after an intravenous
      injection of heparin (30 U/kg body wt). Plasma LPL levels were determined using
      an enzyme immunoassay, and HTGL levels were determined using a modified version
      of the Hernell et al method. RESULTS: Plasma RLP-C levels showed a tendency to
      decrease after the start of the EPO supplement therapy in HD patients at the
      maintenance stage. Plasma LPL levels were significantly higher in the two groups
      of HD patients one month after the start of the EPO supplement therapy than in
      the same patients prior to the start of the EPO supplement therapy. Plasma HTGL
      levels were significantly higher in HD patients at the maintenance stage one
      month after the start of the EPO supplement therapy than in HD patients at the
      maintenance stage prior to the start of the EPO supplement therapy. CONCLUSIONS:
      The results of this study suggest that the EPO supplement therapy may reduce
      plasma RLP-C levels by increasing the plasma LPL and HTGL levels in maintenance
      stage HD patients.

PMID- 10412780
TI  - Serum lipids status in patients with diabetic uremia on 10 years of maintenance
      hemodialysis.
AB  - BACKGROUND: Dyslipidemia in patients with diabetic uremic patients remains
      unclear. We previously reported that lipid abnormalities in diabetic uremia on
      short-term (3 to 28 months) hemodialysis therapy were more severe than those in
      nondiabetic uremic patients. The object of this study is to investigate the serum
      lipid profiles in diabetic uremic patients on 10 years of maintenance
      hemodialysis treatment. METHODS: Thirty diabetic uremic subjects and 40 age
      matched nondiabetic subjects on long-term hemodialysis therapy were selected, and
      their clinical characteristics and serum concentrations of lipids,
      apolipoproteins, lecithin cholesterol acyltransferase (LCAT) activity, and
      apolipoprotein (apo) E phenotype were evaluated. RESULTS: Patients with diabetic
      uremia had a higher prevalence of macrovascular complications, including ischemic
      heart diseases and cerebrovascular diseases. The mean levels of serum total
      cholesterol, triglyceride, and high-density lipoprotein cholesterol remained
      normal. Nondiabetic uremic patients exhibited a reduction in serum apo A-1 serum
      apo A-2, serum apo C-2, and LCAT activity and an increase in serum Apo C-3.
      Diabetic uremic patients showed a further reduction in serum apo A-1, serum apo A
      2, serum apo E, and LCAT activity. Frequencies of apo E isoforms were not
      significantly different between two groups of uremic patients. CONCLUSIONS: These
      results clearly indicate that lipid abnormalities in diabetic uremic patients on
      long-term hemodialysis therapy are more enhanced than those in nondiabetic uremic
      patients, suggesting that diabetic hemodialyzed patients are more prone to
      increase the individual risk for accelerated atherosclerosis to cause a higher
      incidence of cardiovascular diseases.

PMID- 10412782
TI  - Rationale and design of a trial improving outcome of type 2 diabetics on
      hemodialysis. Die Deutsche Diabetes Dialyse Studie Investigators.
AB  - BACKGROUND: Non-insulin-dependent diabetes mellitus dialysis patients have the
      highest cardiovascular mortality known in any group of patients. Mixed
      dyslipidemia with moderately elevated low-density lipoprotein (LDL) cholesterol
      and high levels of triglyceride-rich lipoproteins is common in this condition. It
      is not known, however, whether patients with type 2 diabetes on dialysis with
      this form of dyslipidemia derive benefit from lipid-lowering therapy. Recently,
      drugs have become available that potently lower triglyceride-rich, apoB
      containing lipoproteins and thus permit testing of this issue. This is the first
      trial to address specifically the issue of whether the excessive cardiovascular
      mortality of patients with type 2 diabetes on dialysis can be lowered by statins.
      METHODS: The Die Deutsche Diabetes Dialyse Studie is a prospective randomized
      placebo-controlled trial that tests the hypothesis that atorvastatin, a
      hydroxymethyl-glutaryl coenzyme A reductase inhibitor, decreases the rate of
      cardiovascular mortality and of nonfatal myocardial infarction in patients with
      type 2 diabetes who have been on hemodialysis treatment for no more than two
      years. The primary endpoint, cardiovascular mortality, includes fatal myocardial
      infarction, sudden death, death during coronary intervention, death from heart
      failure, and other coronary causes. Secondary endpoints comprise overall
      mortality, nonfatal cardiovascular events, fatal and nonfatal cerebrovascular
      disease, and the mean percentage change in lipid profile from baseline. The trial
      enrolls 1200 men and women on hemodialysis for less than two years and with type
      2 diabetes at 150 centers throughout Germany. Inclusion criteria are age of 18 to
      80 years, low-density cholesterol of 80 to 190 mg/dl (2.1 to 4.9 mmol/liter), and
      triglyceride levels of less than 1000 mg/dl (11.4 mmol/liter). Patients are
      randomized to cither inactive (placebo) or active (atorvastatin, 20 mg/day) drug
      therapy. The average duration of follow-up is more than 2.5 years. To protect
      against a lower than expected rate of events, the trial will be continued until a
      predetermined fixed number of endpoints occurs in the entire cohort so that the
      predefined power of the trial will be guaranteed. CONCLUSIONS: This trial was
      designed to demonstrate that lipid lowering with atorvastatin will improve life
      expectancy and quality of life in type 2 diabetics on hemodialysis. The
      resolution of this question is important because the genesis of vascular lesions
      in this condition is multifactorial and the precise role of dyslipidemia has not
      been defined.

PMID- 10412781
TI  - Effect of simvastatin on the lipid profile of hemodialysis patients.
AB  - BACKGROUND: Simvastatin, a 3-hydroxy 3-methylglutaryl co-enzyme A (HMG-CoA)
      reductase inhibitor, is used widely for treatment of hypercholesterolemia.
      Simvastatin may be a suitable treatment for dyslipidemia in hemodialysis (HD)
      patients. However, investigation of the side-effects and safety of long-term
      administration of simvastatin to HD patients has been limited. In this study, we
      investigated the effects and safety of simvastatin and its effects on lipoprotein
      metabolism in hypercholesterolemic patients on HD. METHODS: Simvastatin was
      administered at a dosage of 5 mg/day for 24 weeks to 38 HD patients with high
      serum total cholesterol (TC) levels (200 mg/dl) or low high-density lipoprotein
      cholesterol (HDL-C) levels (35 mg/dl). Every four weeks, serum lipids,
      apolipoprotein, lipoprotein (a) [Lp(a)] and malondialdehyde (MDA) levels were
      measured. In addition, lipid levels were determined in each lipoprotein fraction
      separated by ultracentrifugation. RESULTS: After 24 weeks of simvastatin
      administration, TC significantly decreased by 25.7%, and low-density lipoprotein
      cholesterol (LDL-C) was significantly decreased by 33.6%. Triglyceride (TG) and
      HDL-C showed no significant changes. Apolipoprotein (apo) B significantly
      decreased by 24.5% and apo E by 30.0%. No significant changes were observed in
      the other apolipoproteins. MDA was also significantly decreased, whereas Lp(a)
      was not significantly altered. In the lipoprotein fractions, very LDL cholesterol
      (VLDL-C), intermediate-density lipoprotein cholesterol (IDL-C), LDL1 cholesterol
      (LDL1-C), and LDL2 cholesterol (LDL2-C) showed significant decreases. No
      particular side-effects were observed during the 12 months of simvastatin
      administration. CONCLUSIONS: These results suggest that simvastatin appears to be
      safe and effective in HD patients with hypercholesterolemia.

PMID- 10412783
TI  - Role of hepatic lipase in intermediate-density lipoprotein and small, dense low
      density lipoprotein formation in hemodialysis patients.
AB  - BACKGROUND: It has been reported that remnant lipoproteins and small, dense low
      density lipoproteins (LDLs) are risk factors for cardiovascular disease. To
      determine whether these risk factors are present in hemodialysis (HD) patients
      who are suffering from a high incidence of atherosclerotic vascular disease, we
      measured concentrations of remnant lipoproteins and LDL particle diameter in HD
      patients and compared these with controls. We also measured lipoprotein lipase
      (LPL) and hepatic triglyceride lipase (HTGL) that play important roles in the
      generation of remnant lipoproteins and small, dense LDL, and we correlated these
      changes with plasma lipoprotein abnormalities in HD patients. METHODS:
      Lipoproteins were separated by ultracentrifugation. Apoprotein B in very low
      density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) fractions
      were measured by a sensitive enzyme-linked immunosorbent assay method. The
      average LDL particle diameter was measured by gradient gel electrophoresis.
      RESULTS: Plasma triglyceride, total cholesterol, and high-density lipoprotein
      (HDL) cholesterol concentrations were comparable between HD patients and
      controls, whereas LDL cholesterol was significantly lower in HD patients. The
      average LDL particle diameter was not significantly different between HD patients
      and controls. LDL particle diameter was inversely related to plasma triglyceride
      concentrations in all of the subjects. VLDL triglyceride, VLDL cholesterol, and
      VLDL apoprotein B were comparable between HD patients and controls. IDL
      triglyceride, IDL cholesterol, and IDL apoprotein B concentrations were all
      significantly increased in HD patients compared with those in controls. LPL mass
      was not altered, but HTGL activity was significantly decreased in HD patients.
      The HTGL activity was inversely related to IDL concentrations. CONCLUSIONS: These
      results suggest that a prominent characteristic of lipoprotein abnormalities in
      HD patients is a marked increase in IDL particle number. In addition, small,
      dense LDL is not associated with uremic dyslipidemia. Because HTGLs promote the
      conversion from IDL to LDL and the generation of lipid-poor LDL, a decrease in
      HTGL activity may contribute to the accumulation of IDL particle and may prevent
      small, dense LDL formation in HD patients.

PMID- 10412784
TI  - Effect of probucol on hypercholesterolemia in renal transplant patients.
AB  - BACKGROUND: Hypercholesterolemia is a well-known complication in kidney
      transplant recipients, although its pathogenesis may be multifactorial. The
      therapeutic effect of probucol on post-transplant hypercholesterolemia was
      prospectively evaluated. METHODS: Twelve hypercholesterolemic kidney transplant
      patients with serum total cholesterol > or = 250 mg/dl without diabetes mellitus
      or hypoproteinemia were prospectively treated with probucol (250 mg, bid, for
      three months). Before initiating and at the end of treatment, blood was drawn
      after at least a 12-hour fast to measure lipids in serum and lipoprotein
      fractions, apoproteins (apo), lipoprotein fractions, lethicin cholesterol acyl
      transferase (LCAT), free fatty acids (FFAs), and cholesterol ester. The lipid
      profiles of 17 healthy subjects were also examined. RESULTS: After treatment with
      probucol, serum total cholesterol, low-density lipoprotein (LDL) cholesterol,
      high-density lipoprotein (HDL) cholesterol, and apo AI were significantly
      decreased, whereas cholesterol ester increased significantly. CONCLUSIONS: Post
      transplant hypercholesterolemia is featured with abnormalities in very low
      density lipoprotein (VLDL) metabolism. Although HDL cholesterol decreased,
      probucol might have acted as an antiatherogenic by modulating HDL metabolism and
      stimulating reverse transfer of cholesterol from peripheral tissue.

PMID- 10412785
TI  - Fluvastatin and low-density lipoprotein oxidation in hypercholesterolemic renal
      transplant patients.
AB  - BACKGROUND: Hyperlipidemia contributes to the development and progression of
      vascular disease in organ transplant patients. Oxidative modification of low
      density lipoproteins (LDLs) has been suggested as a key event in early
      atherogenesis. METHODS: We conducted a pilot study in renal transplanted patients
      with persistent hypercholesterolemia above 6.5 mmol/liter. We studied the LDL
      oxidation before and after one year of fluvastatin treatment. Twenty patients (12
      males and 8 females, 46 +/- 10 years old) who received a kidney transplant 24 +/-
      18 months before the study were treated with fluvastatin (20 mg/day for 12
      weeks). Patients with a total cholesterol under 6.3 mmol/liter continued to
      receive 20 mg/day for another 40 weeks (group I, N = 10). Nine patients with a
      total cholesterol above 6.3 mmol/liter received 40 mg/day for a further 40 weeks
      (group II). RESULTS: Cyclosporine levels did not experience a significant
      variation. Total and LDL cholesterol decreased significantly in both groups (21.7
      and 27.9% in group I, 18.3 and 27.2% in group II, respectively). The lag-phase
      time, which was significantly enlarged before fluvastatin treatment in the
      patients with respect to the controls (N = 18, 82 +/- 45 vs. 50 +/- 8 min) was
      shortened after one year of fluvastatin treatment (64 +/- 24 vs. 50 +/- 8 min, P
      = 0.04). Fluvastatin was stopped in only one patient because of nausea and
      vomiting. Transaminases and creatin-phospho-kinase were not altered. All of the
      patients maintained a functioning graft during the study period. CONCLUSIONS:
      Fluvastatin significantly reduced total and LDL cholesterol, without
      interferences with cyclosporine A through levels. Fluvastatin has not
      demonstrated an antioxidant effect in our renal hypercholesterolemic transplant
      patients.

PMID- 10412787
TI  - Factors associated with calcification of the abdominal aorta in hemodialysis
      patients.
AB  - BACKGROUND: Cardiovascular and cerebrovascular injury caused by arteriosclerosis
      has been the major cause of the death in hemodialysis (HD) patients. We
      quantitatively analyzed and evaluated the severity of abdominal aortic
      calcification in HD patients in comparison to risk factors for arteriosclerosis.
      METHODS: One hundred thirty-seven HD patients were examined. Using image analysis
      software, areas of the calcified abdominal aorta were quantitatively analyzed on
      plain computerized tomography images. Other factors such as blood pressure (BP),
      lipid levels, and calcium (Ca) x phosphorus (Pi) value were also analyzed.
      RESULTS: Patients with a higher one-year average of systolic BP showed a higher
      severity of abdominal aortic calcification. That is, the severity of abdominal
      aortic calcification in patients with a one-year systolic BP average above 160 mm
      Hg was 31.5 +/- 13.6%, and this severity was significantly higher than that in
      patients with a one-year systolic BP average of less than 120 mm Hg (8.0 +/-
      7.7%, P < 0.01). The severity of abdominal aortic calcification in patients
      demonstrating risk values of ectopic calcification, that is serum Ca x Pi > or =
      60 (mg/dl), on more than 4 of 24 measurements within one year (25.8 +/- 13.6%)
      was significantly higher than the severity of aortic calcification in patients
      demonstrating this value less than four times in one year (P < 0.05). There was
      no correlation between levels of low-density lipoprotein cholesterol, high
      density lipoprotein cholesterol, triglyceride, lipoprotein(a), and severity of
      abdominal aortic calcification. CONCLUSIONS: Systolic BP levels and the product
      of serum Ca and Pi were related to the severity of abdominal aortic calcification
      in HD patients. These observations suggested that BP control, as well as control
      of serum Ca and Pi levels, was important in preventing the progression of
      abdominal aortic arteriosclerosis.

PMID- 10412788
TI  - Lipoprotein(a) as a risk factor for coronary artery disease in hemodialysis
      patients.
AB  - BACKGROUND: We studied whether lipoprotein(a) [Lp(a)] is an independent risk
      factor for coronary artery disease (CAD) in hemodialysis (HD) patients. METHODS:
      A serum concentration of Lp(a) was measured in 212 patients with chronic
      glomerulonephritis and 56 patients with diabetic nephropathy (a total of 268
      patients). The causes of death during five years of follow-up were studied and
      classified into either cardiovascular or noncardiovascular events. RESULTS: The
      mortality of these 268 HD patients during the observation period was 26.1%.
      Seventy-eight percent were due to cardiovascular events. Those who died of
      cardiovascular events had significantly higher serum Lp(a) levels than those died
      of noncardiovascular events. The relative risk of death from CAD was 0.71 in HD
      patients with a Lp(a) concentration above 30 mg/dl. CONCLUSIONS: This study
      indicates that the serum Lp(a) levels are independent indicators of the future
      risk of death from CAD in HD patients.

PMID- 10412786
TI  - Immunosuppression enhances atherogenicity of lipid profile after transplantation.
AB  - BACKGROUND: Patients after renal transplantation exhibit high cardiovascular
      morbidity and mortality because of the accumulation of cardiovascular risk
      factors such as hypertension or dyslipidemia. To elucidate the influence of
      immunosuppressive therapy on hyperlipidemia, we studied serum lipids and
      lipoproteins in renal transplant patients who received prednisone and either
      azathioprine or cyclosporine or triple immunosuppressive therapy. METHODS: Serum
      lipids and lipoprotein levels were measured in 216 renal transplant patients (81
      female and 135 male) with stable graft function of 4.8 +/- 2.3 years (range six
      months to eight years) after transplantation. Patients were divided into three
      groups according to one of the following immunosuppressive regimens: (a)
      prednisone and azathioprine, (b) prednisone and cyclosporine, or (c) prednisone,
      azathioprine, and cyclosporine. Healthy, age- and sex-matched subjects served as
      controls. In addition to measurement of total serum lipids, lipoproteins were
      isolated by preparative ultracentrifugation, and lipids were determined in very
      low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density
      lipoprotein (HDL) density classes. RESULTS: Total serum triglycerides, VLDL, and
      LDL triglycerides, as well as VLDL cholesterol were elevated in all renal
      transplant patients, but elevation was pronounced in female patients. In contrast
      to total serum cholesterol, which was significantly increased in only female
      patients, elevation of LDL-triglyceride/apo B ratio was more marked in male
      patients. Patients in group A exhibited only mild hypertriglyceridemia, whereas
      triglyceride enrichment in VLDL and LDL was more distinct in group B and was most
      pronounced in patients of group C. Furthermore, hypertriglyceridemia increased
      with the dose of administered prednisone. CONCLUSIONS: Immunosuppressive therapy
      in renal transplant patients leads to accumulation of triglyceride-enriched VLDL
      and LDL. Triglyceride enrichment in LDL indicates the accumulation of small,
      dense LDLs, which are known to bear enhanced atherosclerotic risk. This study
      provides data that underline the use of individually adjusted immunosuppressive
      therapy and steroid-sparing protocols in renal transplant patients to improve
      their atherogenic lipoprotein profile.

PMID- 10412789
TI  - Apolipoprotein E phenotypes in hemodialysis patients.
AB  - BACKGROUND: Apolipoprotein (apo) E polymorphism consists of three major
      isoproteins (E2, E3, and E4). Because of their difference in a lipid-modulating
      effect, the polymorphism has been reported to affect the morbidity of
      atherosclerosis in general population. Therefore, in hemodialysis (HD) patients,
      the apo E polymorphism may also modulate serum levels of cholesterol and
      susceptibility to atherosclerotic vascular disease. METHODS: We determined apo E
      phenotypes in 493 HD patients and 422 controls. We also investigated vascular
      risk profile and measured postprandial serum levels of lipids and apos in the
      dialysis patients. RESULTS: We found a similar phenotype distribution and allele
      frequency between HD patients and healthy controls. Serum levels of total
      cholesterol, triglyceride, and apo A I, A II, and C III did not differ
      significantly among patients with phenotypes apo E2/3, E3/3, and E3/4. Patients
      with apo E3/4 had significantly lower levels of high-density lipoprotein
      cholesterol, significantly higher levels of low-density lipoprotein cholesterol
      (LDL-C), and a higher atherogenic index than those with apo E2/3 (LDL-C, 100 +/-
      30 vs. 82 +/- 35 mg/dl, P < 0.01; the index, 3.3 +/- 1.7 vs. 2.3 +/- 1.3, P <
      0.01). Patients with apo E3/4 showed a tendency toward higher levels of apo B
      than patients with apo E2/3 or apo E3/3. Multiple logistic regression analysis
      revealed that age and diabetes mellitus, but not apo E phenotypes, were
      independent risk factors for vascular disease. CONCLUSIONS: Apo E polymorphism
      modulates cholesterol metabolism in dialysis patients but appears to have little
      association with the prevalence of atherosclerotic complications in the patients.

PMID- 10412790
TI  - Abnormalities in lipoprotein metabolism in hemodialysis patients.
AB  - BACKGROUND: Patients on chronic hemodialysis treatment are at elevated
      atherogenic risk, and dyslipidemia appears to be one of the major risk factors.
      However, most of these patients exhibit elevated serum triglycerides, whereas
      serum cholesterol and low-density lipoprotein (LDL) cholesterol levels are in the
      normal range. This study was therefore designed to examine the influence of
      hypertriglyceridemia under the condition of hemodialysis and diabetes mellitus on
      LDL metabolism. METHODS: LDL was isolated from healthy controls,
      hypertriglyceridemic diabetic patients, and nondiabetic hemodialysis patients (N
      = 30, 10 in each group), which were separated into six subfractions by density
      gradient ultracentrifugation and were characterized concerning lipid/protein
      composition, degree of glycation, and oxidation. Uptake of 125I-labeled LDL was
      examined via LDL receptors of HepG2 cells and scavenger receptors of mouse
      peritoneal macrophages. RESULTS: In hemodialysis patients, serum triglycerides
      were significantly elevated, whereas cholesterol levels were within the normal
      range. Triglyceride enrichment occurred in the very low-density lipoprotein
      (VLDL) class and LDL class, and an accumulation of a highly atherogenic small
      dense LDL subfraction could be detected predominantly in patients with non
      insulin-dependent diabetes mellitus. LDL of hemodialysis patients also contained
      elevated levels of lipid peroxidation products, which were even higher in
      diabetic patients. Alterations in composition, size, and configuration of LDL
      from diabetic and nondiabetic patients on hemodialysis impaired LDL receptor
      mediated degradation and enhanced the uptake of these modified LDL particles via
      nonsaturable scavenger receptors. CONCLUSION: Diminished LDL receptor-mediated
      uptake of modified, triglyceride-rich, small dense LDL most likely leads to
      accumulation of these lipoproteins in vivo, favoring the development of
      atherosclerotic lesions. Future clinical studies must demonstrate whether
      patients will benefit from reducing these atherogenic particles by lipid-lowering
      intervention.

PMID- 10412791
TI  - Lipoprotein(a) is a predictor for cardiovascular mortality of hemodialysis
      patients.
AB  - BACKGROUND: Although hemodialysis (HD) patients have been associated with
      elevations in serum lipoprotein(a) [Lp(a)] levels, relatively little has been
      published on the link between Lp(a) and the risk for atherosclerotic
      cardiovascular death in HD patients. METHODS: Lipoprotein(a) was measured in 390
      HD patients. The relationship between Lp(a) and mortality (overall and
      cardiovascular) was determined during 28 months of prospective follow-up.
      RESULTS: Hemodialysis patients demonstrated Lp(a) concentrations that were
      approximately two times as high as that of healthy controls (median, 16 vs. 8
      mg/dl, P < 0.001; mean, 22.9 vs. 12.1 mg/dl, P < 0.01). Lp(a) showed a
      significant correlation between albumin, total cholesterol, low-density
      lipoprotein cholesterol, and C-reactive protein. The high-Lp(a) group [Lp(a) > or
      = 30 mg/dl] showed significantly higher mortality than the low-Lp(a) group [Lp(a)
      < 30 mg/dl] in a Kaplan-Meier survival analysis (P < 0.05). Multiple logistic
      regression analysis demonstrated albumin, age, and diabetic state as significant
      risk factors for overall death. However, if confined to atherosclerotic
      cardiovascular death, Lp(a) (P < 0.01), age, and diabetic state were the only
      independent contributors. CONCLUSIONS: Lp(a) is an independent risk factor for
      atherosclerotic cardiovascular death in Japanese patients receiving chronic
      dialysis therapy.

PMID- 10412792
TI  - Phosphotyrosine of macrophage by low-density lipoproteins from hemodialysis
      patients.
AB  - BACKGROUND: Because of the possible importance of tyrosine phosphorylation in the
      signal transduction process, we investigated whether an interaction of low
      density lipoprotein (LDL) from hemodialysis patients (HD-LDL) and human
      macrophages induces tyrosine-phosphorylated proteins in the macrophages. METHODS:
      Human monocyte-derived macrophages were incubated with HD-LDL (100 micrograms/ml)
      or native LDL (100 micrograms/ml) for 15 minutes at 37 degrees C. Whole cells
      were lyzed with Tris-HCl buffer containing vanadate and Triton X-100. After
      centrifugation, lyzed proteins were divided into Triton-soluble and -insoluble
      fractions. Both fractions (soluble and insoluble) were separated by sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis and were electroblotted onto a
      polyvinylidene difluoride (PVDF) membrane. Immunoblotting was performed using an
      antibody against phosphotyrosine or c-Src. RESULTS: Several proteins in the range
      40 to 100 kDa were found to be phosphorylated constitutively in the macrophages
      and not affected by the addition of HD-LDL. HD-LDL did not induce any tyrosine
      phosphorylated proteins either in the soluble or insoluble fractions. Macrophages
      pretreated with tyrosine kinase inhibitor genestein drastically inhibited
      tyrosine phosphorylation of these proteins. The nonreceptor tyrosine kinase, c
      Src p60, was also strongly tyrosine phosphorylated in the macrophages, and this
      was not enhanced by the stimulation of HD-LDL. CONCLUSION: These data suggest
      that tyrosine autophosphorylated proteins may play a role in the early step of
      signal transduction in the macrophages.

PMID- 10412793
TI  - Role of glomerular epithelial cell-derived heat shock protein 47 in experimental
      lipid nephropathy.
AB  - BACKGROUND: Heat shock protein 47 (hsp47) is a collagen-specific stress protein
      and is shown to be involved in the synthesis/assembly of various collagens as a
      molecular chaperone. This study was undertaken to investigate the possible role
      of hsp47 in dietary-induced hypercholesterolemic rat kidneys, which showed
      glomerular hypercellularity with expansion of mesangial matrix. METHODS: Dietary
      induced hypercholesterolemia was induced in male Wistar rats by giving 2%
      cholesterol diet for four months. Immunohistochemistry was used for localization
      of protein products for collagens (types I, III, and IV). alpha-smooth muscle
      actin, vimentin, desmin, and ED-1, a macrophage/monocyte marker, and hsp47 in
      control and hypercholesterolemic rat kidneys. RESULTS: Compared with the control,
      increased accumulation of collagens was accompanied with increased expression of
      hsp47 in hypercholesterolemic rat kidneys, with predominant expression in the
      glomeruli. By double immunostaining, desmin-positive glomerular epithelial cells
      were found to be the main source of hsp47 in hypercholesterolemic rat kidneys.
      CONCLUSION: From these results, it is concluded that induced expression of hsp47
      by phenotypically altered glomerular epithelial cells might play a role in the
      excessive assembly/synthesis of collagens and could thereby contribute to the
      glomerulosclerosis found in dietary-induced hypercholesterolemic rat kidneys.

PMID- 10412794
TI  - Critical threshold cerebral hypoperfusion causes Alzheimer's disease?
AB  - After nearly a century of inquiry, the cause of Alzheimer's disease (AD) remains
      to be found. In this review, basic and clinical evidence is presented that
      assembles and hypothetically explains most of the key pathologic events
      associated with the development of AD. These pathologic events are triggered in
      AD by an impaired cerebral perfusion originating in the microvasculature which
      affects the optimal delivery of glucose and oxygen and results in a breakdown of
      metabolic energy pathways in brain cells such as in the biosynthetic and synaptic
      pathways. We propose that two factors need to be present before cognitive
      dysfunction and neurodegeneration is expressed in AD brain: advanced aging, and
      the presence of a condition that lowers cerebral perfusion. The first factor
      introduces a normal but potentially menacing process that lowers cerebral blood
      flow in correlation to increased aging, while the second factor adds a crucial
      element which further lowers brain perfusion and establishes the heterogeneic
      disease profile observed in AD patients. These two factors will lead to a
      critical threshold cerebral hypoperfusion. Critical threshold cerebral
      hypoperfusion is a self-perpetuating, contained and progressive circulatory
      insufficiency that will destabilize neurons, synapses, neurotransmission and
      cognitive function, creating in its wake a neurodegenerative process
      characterized by the formation of senile plaques, neurofibrillary tangles, and
      amyloid angiopathy. A discussion of target therapy based on the proposed
      pathogenesis of AD is also briefly reviewed.

PMID- 10412795
TI  - Cyclooxygenase-2 immunoreactivity in the human brain following cerebral ischemia.
AB  - The prostaglandin synthesizing enzyme cyclooxygenase-2 (COX-2) is up-regulated in
      the brain of rodents during cerebral ischemia and contributes to ischemic brain
      injury. This study sought to determine whether COX-2 is also up-regulated in the
      human brain in the acute stages of cerebral ischemic infarction. Paraffin
      embedded sections from patients who died 1-2 days following infarction in the
      middle cerebral artery territory were processed for COX-2 immunohistochemistry.
      COX-2 immunoreactivity was observed in infiltrating neutrophils, in vascular
      cells and in neurons located at the border of the infarct. The data suggest that
      COX-2 up-regulation is also relevant to cerebral ischemia in humans and raise the
      possibility that COX-2 reaction products participate in the mechanisms of
      ischemic injury also in the human brain.

PMID- 10412796
TI  - Systemic hypothermia following compression injury of rat spinal cord: reduction
      of plasma protein extravasation demonstrated by immunohistochemistry.
AB  - Systemic hypothermia has neuroprotective effects in experimental models of
      central nervous system ischemia caused by vascular occlusions. The present study
      addresses the question as to whether systemic hypothermia can influence the
      extravasation of plasma proteins following severe spinal cord compression trauma
      using immunohistochemistry to identify the plasma proteins albumin, fibrinogen
      and fibronectin. Fifteen rats were assigned to one of three groups and received
      either thoracic (T) laminectomy or severe spinal cord compression trauma of the
      T8-9 segment. One group comprised laminectomized animals without compression
      trauma submitted to a hypothermic procedure in which the core temperature was
      reduced from 38 degrees to 30 degrees C. The two trauma groups were either
      submitted to the same hypothermic procedure or kept normothermic during the
      corresponding time. All animals were killed 24 h following the surgical
      procedure. The normothermic and hypothermic trauma groups had indications of
      marked extravasation of albumin, fibrinogen and fibronectin at the site of the
      injury (T8-9). There was also pronounced extravasation in the cranial and caudal
      peri-injury zones (T7 and T10) of normothermic injured rats but, with few
      exceptions, not in the hypothermic ones with the same degree of compression. By
      measuring the cross-sectional area of the peri-injury zones we found in the
      hypothermic trauma group a significant reduction of the expansion compared with
      that present in normothermic injured rats. Our study thus indicates that
      hypothermia reduces the extravasation of the plasma proteins albumin, fibrinogen
      and fibronectin following spinal cord compression in the rat. Such a reduction
      may contribute to neuroprotective effects exerted by hypothermia.

PMID- 10412797
TI  - Clomethiazole (ZENDRA, CMZ) improves hind limb motor function and reduces
      neuronal damage after severe spinal cord injury in rat.
AB  - Clomethiazole (CMZ) has a neuroprotective effect in experimental focal and global
      forebrain ischemia. This neuroprotective effect may depend on its ability to
      enhance GABA receptor activity. We have studied the effect of pretreatment with
      CMZ on motor function recovery and nerve cell damage after spinal cord injury
      (SCI). Rats were randomized and 30 min before SCI they received a single
      intraperitoneal dose of CMZ (150 mg/kg) or saline. The spinal cord was injured
      with a 50 g (4.5 g/mm2) load, applied over the exposed dura, through a curved
      rectangular plate (2.2 x 5.0 mm) for 5 min at T8-9. The animals became paraplegic
      1 day after injury. The rats were evaluated for recovery of hind limb motor
      function. All animals recovered to some extent over the observation period of 12
      weeks. However, hind limb motor function was significantly better in the animals
      pretreated with CMZ. At 12 weeks the rats were killed and perfused/fixed for
      morphological investigations. Microtubule-associated protein 2 (MAP2)
      immunostaining was used to stain neurons and dendrites and Luxol-fast blue to
      stain myelinated tracts of the white matter. The injured segment of the spinal
      cord showed severe atrophy, distortion, cavitation and necrosis of grey and white
      matter. Compared to uninjured controls the transverse sectional area was reduced
      to 32.7 +/- 4% in untreated animals but only to 38.5% +/- 4.1 in CMZ-treated
      animals. MAP2 staining showed that, compared to uninjured controls, grey matter
      was reduced to 7.4 +/- 2.7% in saline-treated injured animals and to 22.7 +/-
      5.4% in CMZ-treated rats. Our results thus show that in this model CMZ improves
      hind limb motor function and attenuates the morphological damage to the spinal
      cord.

PMID- 10412798
TI  - Immunohistochemical, conventional and immunoelectron microscopical
      characteristics of periodic acid-Schiff-positive granules in the mouse brain.
AB  - Periodic acid-Schiff-positive granules (PGs) appear in the mouse brains in
      relation to advancing age. The exact location and pathophysiological significance
      of PGs, however, are not fully understood. The incidence, staining properties,
      and topographical distributions of PGs in the brains of 17 AKR mice ranging in
      age from 7 to 18 months were examined histochemically and immunohistochemically
      using antibody KM279 raised against a polyglucosan. In addition, to define the
      precise site of PG formation, we investigated the brains of 4 AKR mice of 24
      months of age using conventional and immunoelectron microscopy. PGs were seen in
      all mice examined and the levels were increased with age. The PGs were located
      predominantly in the hippocampus and, to a lesser extent, in the cerebellum and
      olfactory bulb. Immunohistochemically, PGs in the hippocampus and cerebellum were
      labeled uniformly with KM279. On immunoelectron microscopy with this monoclonal
      antibody, the fibrillar or membranous structures corresponding to PGs seen using
      light microscopy were labeled specifically with gold particles. With conventional
      electron microscopy, fibrillar or membranous structures were seen along with
      synaptic vesicles and dense-core granules. Moreover, around the cells containing
      PGs, a few synaptic junctions with neighboring cells were observed, indicating
      that the cells contributing to formation of PGs were neuronal cells. The positive
      immunoreactivity of AKR mouse PGs for the antibody KM279 suggests that the PGs
      and similar structures in other species may share a common antigenicity. Thus, it
      is assumed that PGs in AKR mice might result from some abnormalities in glucose
      metabolism.

PMID- 10412799
TI  - Survival and mitosis of myelinating oligodendrocytes in experimental autoimmune
      encephalomyelitis: an immunocytochemical study with Rip antibody.
AB  - The fate of myelin-forming oligodendrocytes in the spinal cord of Lewis rats with
      acute and chronic relapsing experimental autoimmune encephalomyelitis (EAE) was
      studied using the pre-embedding immunolabelling technique with the Rip monoclonal
      antibody which specifically labels the cytoplasm of the cell body and processes
      of the mature oligodendrocyte. Morphologically normal Rip-positive (Rip+) cells
      were found in close contact with demyelinated axons at the onset of demyelination
      and during the course of disease, indicating that oligodendrocytes survive the
      acute demyelinating insult. Occasional Rip+ oligodendrocytes were undergoing
      mitosis at the time of onset of neurological signs. These mitotic
      oligodendrocytes were present in both the grey and white matter. The majority of
      the mitotic oligodendrocytes had processes in direct contact with myelin sheaths
      for considerable lengths, indicating that they were myelinating cells. This study
      indicates that oligodendrocytes survive the acute demyelinating insult in EAE and
      that mature myelinating oligodendrocytes are able to undergo mitosis.

PMID- 10412800
TI  - Colonic enteric nervous system in patients with familial amyloidotic neuropathy.
AB  - The colonic enteric nervous system was investigated in autopsy specimens from 12
      patients with familial amyloidotic neuropathy (FAP) and 9 controls. The
      infiltration of amyloid deposits in the enteric nervous system was studied by
      double staining for amyloid and nerve elements. The myenteric plexus was
      immunostained for protein gene product (PGP) 9.5, vasoactive intestinal peptide
      (VIP), substance P and nitric oxide synthase (NOS). The immunostained nerve
      elements were quantified by computerised image analysis. Double staining revealed
      that there was no amyloid infiltration in the ganglia, or in the nerve fibres in
      the colonic enteric nervous system of FAP patients. The relative volume density
      of PGP 9.5-immunoreactive nerve fibres in both the circular and the longitudinal
      muscle layers in FAP patients did not differ significantly from that of controls.
      The relative volume density of VIP-immunoreactive nerve fibres in the circular
      muscle layer was significantly decreased in FAP patients compared with controls,
      but not in the longitudinal layer. The number of VIP-immunoreactive neurons/mm2
      myenteric ganglia was significantly decreased in FAP patients. There were no
      statistical differences in the relative volume density for substance P- and NOS
      immunoreactive nerve fibres between FAP patients and controls, nor was there any
      difference between FAP patients and controls regarding the number of NOS- and
      substance P-immunoreactive neurons/mm2 myenteric ganglia. It is concluded that
      the colonic enteric nervous system as a whole is intact and is not damaged by
      amyloid infiltration. The present observation of a reduction of VIP
      immunoreactive nerve fibres and neurons in myenteric plexus of FAP patients might
      be one of the factors that contribute to the motility disorders seen in FAP
      patients.

PMID- 10412801
TI  - Neuronal and glial DNA fragmentation in Pick's disease.
AB  - Pick's disease (PD) is characterized by severe neuronal loss and gliosis in a
      frontotemporal lobar distribution, often associated with Pick bodies and
      ballooned neurons. Abnormal tau metabolism has been implicated in the
      pathogenesis of PD; however, the underlying mechanism of neuronal degeneration
      remains poorly understood. Evidence from other neurodegenerative diseases has
      suggested that DNA damage and apoptosis may play a major role in cellular
      degeneration and death. In the present study, an in situ nucleotidyl transferase
      assay (ISNTA) was used to identify DNA fragmentation in three cases of classical
      PD with Pick bodies and ballooned neurons, and two PD "variants", one with
      ballooned neurons only and the other without Pick bodies or ballooned neurons. In
      all cases large numbers of ISNTA-positive neurons were present in anatomic
      regions having obvious degenerative changes (neuronal atrophy and loss, gliosis,
      cytoplasmic inclusions) by conventional histology. There was no clear association
      between neuronal DNA fragmentation and the presence of structural abnormalities
      such as Pick bodies or ballooned cytoplasm. ISNTA-positive glia were present in
      both cortex and subcortical white matter. Morphologic evidence of apoptosis was
      not detected in either neurons or glial cells. We suggest that DNA fragmentation
      in PD and probably other neurodegenerative disorders most likely specifies a
      population of potentially vulnerable cells in which both cell death and repair
      mechanisms have been activated. It is likely that only a very small number of
      these vulnerable cells at a given time will proceed to cell death; however, it is
      uncertain whether this occurs by apoptosis or some other mechanism.

PMID- 10412802
TI  - A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a tauopathy
      with dementia and supranuclear palsy.
AB  - Recently intronic and exonic mutations in the Tau gene have been found to be
      associated with familial neurodegenerative syndromes characterized not only by a
      predominantly frontotemporal dementia but also by the presence of neurological
      signs consistent with the dysfunction of multiple subcortical neuronal
      circuitries. Among families, the symptomatology appears to vary in quality and
      severity in relation to the specific Tau gene mutation and often may include
      parkinsonism, supranuclear palsies, and/or myoclonus, in addition to dementia. We
      carried out molecular genetic and neuropathological studies on two patients from
      a French family presenting, early in their fifth decade, a cognitive impairment
      and supranuclear palsy followed by an akinetic rigid syndrome and dementia. The
      proband died severely demented 7 years after the onset of the symptoms;
      currently, his brother is still alive although his disease is progressing. In
      both patients, we found a Tau gene mutation in exon 10 at codon 279, resulting in
      an asparagine to lysine substitution (N279K). Neuropathologically, widespread
      neuronal and glial tau accumulation in the cortex, basal ganglia, brain stem
      nuclei as well as in the white matter were the hallmark of the disease. These
      deposits were shown by immunohistochemistry and immunoelectron microscopy, using
      a battery of antibodies to phosphorylation-dependent and phosphorylation
      independent epitopes present in multiple tau regions. In the neocortex, tau
      immunopositive glial cells were more numerous than immunopositive neurons; the
      deeper cortical layers as well as the white matter adjacent to the cortex
      contained the largest amount of immunolabeled glial cells. In contrast, some
      brain stem nuclei contained more neurons with tau deposits than immunolabeled
      glial cells. The correlation of clinical, neuropathological and molecular genetic
      findings emphasize the phenotypic heterogeneity of diseases caused by Tau gene
      mutations. Furthermore, to test the effect of the N279K mutation and compare it
      with the effect of the P301L exon 10 mutation on alternative splicing of Tau exon
      10, we used an exon amplification assay. Our results suggest that the N279K
      mutation affects splicing similar to the intronic mutations, allowing exon 10 to
      be incorporated more frequently in the Tau transcript.

PMID- 10412803
TI  - Detection of beta-A4 amyloid and its precursor protein in the muscle of a patient
      with juvenile neuronal ceroid lipofuscinosis (Spielmeyer-Vogt-Sjogren).
AB  - Muscle biopsy tissue from a patient affected by the juvenile form of neuronal
      ceroid lipofuscinosis (NCL) was studied immunohistochemically using antibodies to
      beta-amyloid peptide and amyloid precursor protein. Positive reaction in muscle
      was specifically localized to autophagic vacuoles and blood vessel walls.
      Increased acid phosphatase reaction suggested enhanced lysosomal activity. We
      hypothesize that beta-amyloid is deposited in NCL muscle by a lysosomal mechanism
      similar to that proposed in other disorders involving beta-amyloid.

PMID- 10412804
TI  - The N-methyl-D-aspartate receptor channel blocker amantadine does not cause
      histopathological alterations in human brain tissue.
AB  - Low doses of N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonists
      induce morphological alterations in neurons of the cingulate gyrus and
      retrosplenial cortex of the rat. Neuronal cell death may result at higher doses.
      These effects are a major concern with regard to the introduction of new NMDA
      receptor antagonists into clinical trials. Amantadine is an uncompetitive NMDA
      receptor antagonist, which has been in clinical use for many years. In the
      present study we have looked for possible morphological alterations like necrosis
      in postmortem human brain tissue of patients previously treated with amantadine.
      Formalin-fixed tissue samples were taken from the hippocampus, cingulate gyrus,
      and retrosplenial cortex of 8 patients on previous amantadine medication and of
      11 controls. Histopathological examination of sections was performed blind. All
      brains except one revealed either nonspecific age-related or cerebrovascular
      changes or other neurodegenerative disorders including Alzheimer's, Parkinson's
      or Lewy body disease. In conclusion, histopathological examination of the
      hippocampus, retrosplenial cortex, and cingulate gyrus of human brain did not
      reveal changes suggested to be specific for previous amantadine treatment.

PMID- 10412805
TI  - Angulate lysosomes in skin biopsies of patients with degenerative neurological
      disorders: high frequency in neuronal ceroid lipofuscinosis.
AB  - Angulate lysosomes with intralysosomal trilamellar structures were first
      described in patients with metabolic peroxisomal disorders. In this
      ultrastructural study of skin biopsies of 139 patients with degenerative
      neurological disorders and 45 patients with static encephalopathies, we observed
      angulate lysosomes with similar ultrastructure exclusively in degenerative
      neurological disorders. They were found in only a few cases (8%), but especially
      in patients with degenerative metabolic disorders (72%). Because they were never
      observed in patients with static encephalopathies, angulate lysosomes in the skin
      would seem to be a sign of progressive encephalopathy. The great majority (75%)
      of angulate lysosomes were associated with neuronal ceroid-lipofuscinosis (NCL).
      Their presence in skin biopsy could suggest the diagnosis of NCL and eliminate a
      peroxisomal disorder. In the latter pathology, angulate lysosomes, numerous in
      the liver and in the brain, were never observed in the skin. As described in
      pigmentary retinopathy, a conspicuous feature of NCL, we suggest that in this
      lysosomal storage disorder, the angulate lysosomes in skin biopsies could result
      from the phagocytosis of melanin.

PMID- 10412807
TI  - Hippocampal sclerosis with hypertrophy of end folium pyramidal cells.
AB  - Mesial temporal lobectomy for the treatment of intractable temporal lobe seizures
      may show dual pathologies for example hippocampal sclerosis (HCS) combined with a
      malformation. In a lobectomy specimen from a 40-year-old female with typical
      radiological and pathological features of HCS, an additional histopathological
      finding was the presence of hypertrophic pyramidal cells in the dentate hilus, in
      which cytoplasmic accumulations of phosphorylated neurofilament were
      demonstrated. Although these cells closely resembled dysplastic nerve cells of
      cortical dysplasia, we argue that the cytoskeletal abnormalities observed are a
      result of ongoing alterations to hippocampal circuitry in an evolving HCS.

PMID- 10412806
TI  - Kinetics and differential expression of heat-stable antigen and GL7 in the normal
      and Toxoplasma gondii-infected murine brain.
AB  - The co-expression of various cell surface molecules by cells of the nervous
      system and the immune system is a remarkable feature. To identify novel molecules
      that are shared between cells of the neural and hematopoietic lineage, the
      expression and regulation of heat-stable antigen (HSA, CD24, nectadrin) and GL7,
      two hematolymphoid differentiation antigens that are involved in antigen
      presentation, cell adhesion, signal transduction and activation, was studied in
      the adult normal and Toxoplasma gondii-infected murine brain by
      immunohistochemistry and flow cytometry of isolated cerebral leukocytes. In the
      normal brain ependymal cells, plexus macrophages and a fraction of blood vessel
      endothelial cells were HSA positive (+), whereas the choroid plexus epithelium
      was GL7+. This basal expression of HSA and GL7 was not further modified on these
      cell populations in Toxoplasma encephalitis (TE). In acute and chronic TE, HSA
      and GL7 were strongly induced on resident brain cells, and activated astrocytes
      were the predominant HSA+ and GL7+ cell type. FACS analysis additionally
      identified a minor fraction of HSA+ microglia in the normal brain with a small,
      but significant increase in TE. The differential expression pattern of HSA and
      GL7 on distinct resident cell populations in various anatomic compartments of the
      normal adult brain and their up-regulation in TE may indicate that their
      intracerebral role is diverse and may include both immunological as well as non
      immunological functions.

PMID- 10412808
TI  - Molecular cytogenetic techniques for the diagnosis of chromosomal abnormalities
      in childhood disease.
AB  - Fluorescence in situ hybridisation and comparative genomic hybridisation are
      technologies firmly established in cytogenetics. These methods complement
      conventional banding techniques and offer additional clinical and research
      applications. The present paper has two purposes: (a) to introduce to these
      molecular cytogenetic techniques and (b) to give some examples of childhood
      diseases due to chromosomal aberrations.

PMID- 10412809
TI  - Ethical overview of paediatric research and practice in Europe from the Ethical
      Working Group of the Confederation of European Specialists in Paediatrics (CESP).

PMID- 10412810
TI  - Gastritis and peptic ulcer disease in childhood.
AB  - Inflammation of the gastric and duodenal mucosa is the end result of an imbalance
      between mucosal defensive and aggressive factors. The degree of inflammation and
      imbalance between defensive and aggressive factors can then result in varying
      degrees of gastritis and/or frank mucosal ulceration. Gastritis and ulcers of the
      duodenum or stomach can be classified either as primary or secondary. The
      majority of children with chronic active or chronic gastritis and ulcers in the
      stomach or duodenum have secondary inflammation or mucosal ulceration. These
      ulcers generally occur due to a systemic condition like head trauma or
      overwhelming sepsis, or, as sequelae to drug ingestion (i.e., non-steroidal anti
      inflammatory agents), but secondary gastroduodenal ulcers can also occur in
      specific disease conditions such as Zollinger-Ellison syndrome or Crohn's
      disease. The different causes of gastritis and peptic ulcer disease will be
      discussed in this paper. CONCLUSION: In almost all children presenting to their
      treating pediatric gastroenterologist with duodenal or gastric ulcers of these
      patients, mucosal inflammation and less frequently, ulceration is caused by a
      spiral shaped, gram-negative, microaerobic rod, properly named Helicobacter
      pylori. Recent epidemiological evidence has linked chronic H. pylori infection
      with the development of gastric carcinomas.

PMID- 10412811
TI  - A case of anorexia nervosa with hyperbilirubinaemia in a patient homozygous for a
      mutation in the bilirubin UDP-glucuronosyltransferase gene.
AB  - Gilbert syndrome was diagnosed in a girl with anorexia nervosa and unconjugated
      hyperbilirubinaemia. Since the patient was starved and hyperbilirubinaemic, the
      loading test was not used for the diagnosis but analysis of the bilirubin UDP
      glucuronosyltransferase gene (UGT1A1) instead. The patient was homozygous for a
      missense mutation that replaced guanine with adenine at nucleotide number 211
      (211G-->A: G71R). The unconjugated hyperbilirubinaemia was apparently induced by
      the fasting state. Homozygous missense mutations of the gene have been generally
      recognized as responsible for Crigler-Najjar syndrome type II; the results
      obtained here, however, confirm that Gilbert syndrome may also be caused by a
      homozygous missense mutation of UGT1A1. CONCLUSION: Since anorexia nervosa
      patients are in a fasting state, they may show moderate unconjugated
      hyperbilirubinaemia if they have Gilbert syndrome. Gene analysis of such cases
      will rule out hepatic damage. Homozygous missense mutations of the bilirubin-UDP
      glucuronosyltransferase gene cause not only Crigler-Najjar syndrome type II but
      also Gilbert syndrome.

PMID- 10412812
TI  - Lethal encephalopathy complicating childhood shigellosis.
AB  - A 6-year-old girl is described who died following rapid neurological
      deterioration, ending in lethal cerebral oedema. Despite the absence of severe
      intestinal and metabolic derangement, Shigella was cultured from the stool. Toxic
      encephalopathy is responsible for death following this rare complication of
      childhood shigellosis in developed countries. The pathophysiology is unknown.
      CONCLUSION: Lethal toxic encephalopathy can be caused by Shigella despite the
      absence of severe intestinal and metabolic derangement. If shigelllosis is
      suspected, headache may be a first significant sign for the development of toxic
      encephalopathy. Early recognition and rapid measures to prevent brain oedema may
      improve outcome.

PMID- 10412813
TI  - Haemophagocytosis in early congenital syphilis.
AB  - A previously healthy male infant developed hepatosplenomegaly, severe anaemia and
      thrombocytopenia 5 weeks after birth. Marked haemophagocytosis was present in the
      bone marrow. A typical maculopapular rash suggested early congenital syphilis.
      The diagnosis was confirmed by serology and by the presence of untreated syphilis
      in both parents. CONCLUSION: Syphilis needs to be excluded in infants suspected
      of haemophagocytic lymphohistiocytosis.

PMID- 10412814
TI  - Iron metabolism in burned children.
AB  - The administration of iron supplementation in children with burns has been a
      subject of controversy. Recent studies argue against its use in the acute phase
      of stress. To assess whether iron metabolism parameters show significant
      differences in the acute phase and the recovery phase of burn, 21 patients (age
      range: 17 months to 13 years) with burns of more than 10% of body surface who had
      not received blood transfusions or iron supplementation were studied. Sideraemia,
      ferritin, transferrin, transferrin saturation index (TSI) and C-reactive protein
      (CRP) were assessed both in the acute and the recovery phase after burn.
      Sideraemia, transferrin, and TSI were significantly lower in the acute than in
      the recovery phase (17.3 +/- 3 vs 53.8 +/- 6.6 microg/dL, 190.5 +/- 15 vs 287.9
      +/- 14.3 mg/dL and 7.7 +/- 1.3 vs 15.4 +/- 1.6%, P < 0.0001, P < 0.001 and P =
      0.0006, respectively) while plasma ferritin and CRP were significantly higher
      (84.7 +/- 8.8 vs 43.1 +/- 8.5 ng/mL and 9.5 +/- 1.5 vs 0.7 +/- 0.2 mg/dL, P =
      0.016 and P < 0.0001, respectively). When the above parameters were analysed
      based on age (< or = 2 years, > 2 years), the observed differences persisted.
      CONCLUSION: Hyposideraemia is a frequent finding in the acute phase of paediatric
      burns and is accompanied by increased ferritin levels and decreased transferrin
      concentrations. The low iron values tend to recover without the use of iron
      supplementation suggesting an endogenous block of iron release in the acute phase
      and indicates that iron therapy should be not recommended in the initial period
      of stress of the burned patient.

PMID- 10412816
TI  - Chromosome 22q11 microdeletion and congenital heart disease--a survey in a
      paediatric population.
AB  - Congenital heart disease is a common finding in patients with microdeletion of
      chromosome 22q11. To determine if the deletion is an epidemiologically important
      cause of congenital heart disease, we studied a consecutive series of children
      attending a paediatric cardiac clinic and of neonates diagnosed as having
      structural congenital heart disease. Venous blood samples were tested by
      fluorescent in-situ hybridisation analysis for microdeletion of chromosome 22q11
      using probe D22S75. Each patient was examined for the other clinical features
      associated with microdeletion of chromosome 22q11, and any family history of
      congenital heart disease recorded. Of 151 families approached, 111 participated
      and a fluorescent in-situ hybridisation result achieved in 87. One patient with
      microdeletion of chromosome 22q11 was identified; the clinical features were
      those of DiGeorge syndrome. Two patients with CHARGE association, two with nasal
      speech, ten with high arched palate, and 15 with minor facial dysmorphic features
      had no deletion. CONCLUSION: Microdeletion of chromosome 22q11 detected by probe
      D22S75 is rare in this consecutive series of patients with structural congenital
      heart disease.

PMID- 10412815
TI  - Circumstances of dying in hospitalized children.
AB  - Conditions of dying in a tertiary children's hospital were assessed in a
      retrospective cohort study. Non-survivors, excluding newborns and emergency room
      patients, were allocated to four groups: brain death (BD), failed cardiopulmonary
      resuscitation (failed CPR), death following a do-not-resuscitate (DNR) order and
      death following withholding or withdrawal of therapy (W/W). In a 4-year period
      190 (1.3%) of 14,903 admitted patients died. Of these 134 (71%) died on the
      paediatric intensive care unit, 42 (22%) on the ward and 14 (7%) in the operating
      room. W/W was found in 75 (39%), failed CPR in 57 (30%), BD in 32 (17%), and
      death following a DNR order in 26 (14%). Justifications for restrictions of
      treatment (W/W or DNR) were imminent death in 41 (41%), lack of future relational
      potential in 13 (13%) and excessive burden of disease in 47 (47%). In non
      survivors analgesics and sedatives were frequently used to relieve suffering in
      the terminal phase. General principles for the approach of terminally ill
      children in whom death may become an option instead of a fate are discussed.
      CONCLUSION: In the majority of children dying in hospital, death occurred
      following restrictions of life-sustaining treatment, comprising do-not
      resuscitate or other forms of withholding or withdrawal of therapy.

PMID- 10412817
TI  - Mosaic tetrasomy 9p in a girl with multiple congenital anomalies: cytogenetic and
      molecular-cytogenetic studies.
AB  - We report on a 16-year-old girl with tetrasomy 9p mosaicism. Clinical
      investigations disclosed a malformation syndrome with craniofacial abnormalities,
      dysplasia of the right clavicle, short neck with cervical ribs, patella
      dislocation, Dandy-Walker malformation, mental retardation and blindness.
      Karyotype analysis of blood lymphocytes indicated an additional marker in the
      size of a C-group chromosome with a large heterochromatic block in 88% of the
      investigated metaphases. The origin and structure of this additional marker could
      not be determined by chromosome banding. Application of fluorescence in situ
      hybridisation and comparative genomic hybridisation identified the origin of the
      marker chromosome, demonstrating the effectiveness of molecular-cytogenetic
      investigations in the diagnosis of structural and numerical chromosome
      abnormalities.

PMID- 10412818
TI  - Heart rate deceleration during the grasping reflex.
AB  - Heart rate changes were measured as a psychophysiological indicator during
      grasping reflex in 27 full-term healthy newborns at 2.5-50 h after birth. A
      significant heart rate deceleration accompanied the grasping response.
      CONCLUSION: Reflex grasping of a mother's hand, as a component of human
      attachment behaviour, may have a positive calming effect on the infant's state
      and could have therapeutic value for high risk mother-infant dyads.

PMID- 10412819
TI  - Long-term follow up of a new case of hawkinsinuria.
AB  - Hawkinsinuria is a rarely diagnosed autosomal dominantly transmitted inborn error
      of tyrosine metabolism with impaired conversion of 4-hydroxyphenylpyruvate to
      homogentisate. As a consequence of the defective 4-hydroxyphenylpyruvate
      dioxigenase activity, large amounts of the unusual, ninhydrin-positive amino acid
      hawkinsin and later on in life 4-hydroxycyclohexylacetic acid are formed and
      excreted. Clinically the disease is characterised mainly by chronic metabolic
      acidosis and severe growth retardation as a result of protein overload. As the
      ability to form 4-hydroxycyclohexylacetic acid and thereby to cope with the still
      not very well defined reactive and toxic intermediates increases, clinical
      symptoms vanish. We report here a new patient with hawkinsinuria having
      experienced a series of admissions because of unclear hepatopathy, growth
      retardation, and renal tubular acidosis. CONCLUSION: Prolonged tyrosyluria in the
      newborn and young baby should cause the clinical chemist not only to exclude
      tyrosinaemia, galactosaemia, and fructose intolerance but also to look carefully
      for hawkinsin in the aminoacid chromatogram.

PMID- 10412820
TI  - Cord blood alpha-fetoprotein concentrations in term newborns of smoking mothers.
AB  - To investigate the toxic effect of tobacco smoke on the fetus, we measured in
      cord blood the concentrations of alpha-fetoprotein (AFP), the principal serum
      protein in early ontogenic development, and erythropoietin (EPO), as an index of
      chronic fetal hypoxia. A total of 103 consecutively enrolled term newborns of
      smoking mothers and 103 term infants of nonsmoking parents were studied. The mean
      +/- SD AFP concentrations in the newborns of the mothers who smoked 1-50, 5-50,
      and 10-50 cigarettes/day were 86.4 +/- 88.9, 96.3 +/- 91.9 and 118.7 +/- 103.7
      ng/ml, respectively. The difference of all three groups from the control neonates
      (57.7 +/- 37.2) was significant. The EPO concentrations in the newborns of the
      mothers who smoked 1-50 (53.9 +/- 64.6 mU/ml) and 5-50 (56.3 +/- 68.5)
      cigarettes/day were significantly greater than in the control neonates (29.5 +/-
      16.1). In the newborns of the smoking mothers there was a significant positive
      correlation between AFP concentrations and number of cigarettes smoked per day,
      and a negative correlation between AFP and birth weight or length. There was no
      correlation between AFP and EPO concentrations, as well as between EPO and birth
      weight, length or number of cigarettes smoked per day. CONCLUSION: The absence of
      a correlation between erythropoietin and birth weight or length and the negative
      correlations between alpha-fetoprotein and these anthropometric parameters
      suggest that the intra-uterine growth retardation caused by maternal smoking is
      not due to tissue hypoxia, but that both growth retardation and elevated alpha
      fetoprotein result from the direct or indirect toxic effect of a factor(s)
      present in tobacco smoke.

PMID- 10412821
TI  - Outcome predictors in nitric oxide treated preterm infants.
AB  - Our aim was to identify factors predictive of death in preterm infants in whom
      inhaled nitric oxide was administered in response to poor oxygenation
      (oxygenation index > or =15). Of the 23 (median gestational age 28 weeks, range
      24-36) infants consecutively so treated, 15 died. Non-survival was commoner in
      infants with air leaks (12 of 12, P < 0.002) and/or a change in their oxygenation
      index of less than 30% in response to inhaled nitric oxide administration (P <
      0.05). CONCLUSION: In preterm infants given inhaled nitric oxide because of poor
      oxygenation, a diagnosis of airleak and a lack of initial response are predictive
      of death.

PMID- 10412822
TI  - Soluble vascular cell-adhesion molecule-1 and soluble intercellular adhesion
      molecule-1 correlate with lipid and apolipoprotein risk factors for coronary
      artery disease in children.
AB  - Atherosclerosis begins in childhood and progresses from fatty streaks to raised
      lesions in adolescence and young adulthood. This process is accelerated in
      children with risk factors for coronary artery disease (CAD). Cell adhesion
      molecules (CAMs) are supposed to play important roles in the initial development
      of atherosclerosis, which may suggest that the expression of CAMs is increased in
      children more than in older subjects or in CAD patients. To determine whether
      risk factors for CAD are associated with an increased expression of CAMs, we
      investigated the relationships of the serum levels of soluble vascular cell
      adhesion molecule-1 (VCAM-1), soluble intercellular adhesion molecule-1 (ICAM-1)
      and soluble P-selectin (P-selectin) with lipid and apolipoprotein parameters in
      children (40 boys and 45 girls). We also examined the relationships between
      soluble CAMs and the fractional esterification rate of cholesterol in HDL
      (FER(HDL)), particle size of LDL and lipoprotein containing apoA-I, but no apoA
      II (LpA-I). In children, soluble VCAM-1 levels were correlated with the levels of
      triglyceride (in boys) and apoB, the ratio of apoB to apoA-I and FER(HDL) (in
      girls). Similar associations were found for soluble ICAM-1. Furthermore, the
      soluble ICAM-1 level was inversely correlated with LpA-I level, LDL size (in
      boys) and HDL cholesterol level (in girls). Soluble P-selectin levels were not
      correlated with these parameters. CONCLUSION: Our data indicate that intervention
      to normalize risk factors for coronary artery disease should be started at a
      young age to prevent increased expression of cell adhesion molecules.

PMID- 10412823
TI  - Oral vitamin K1 prophylaxis for newborns with a new mixed-micellar preparation of
      phylloquinone: 3 years experience in Switzerland.
AB  - In 1995, a new water-soluble mixed-micellar analogue of vitamin K1 (Konakion MM
      paediatric) was introduced in Switzerland to replace the formerly used fat
      soluble Konakion drops for the prevention of vitamin K1-deficiency-bleeding
      (VKDB) in infants. According to the new guidelines, an oral dose of 2 mg is given
      after birth and again on the 4th day of life. We examined the compliance with
      these guidelines and the impact on the incidence of VKDB. To assess compliance,
      questionnaires were sent to all hospitals with delivery services 6 months after
      the introduction of the new guidelines. Using the database of the Swiss
      Paediatric Surveillance Unit (SPSU) which records rare paediatric diseases, we
      assessed the incidence of VKDB in Switzerland between July 1995 and June 1998. In
      addition, we determined the precise circumstances under which the episodes of
      VKDB occurred. More than 99% of infants received vitamin K1 prophylaxis. Since
      July 1995, 93% of newborns have received prophylaxis according to the new
      guidelines; the remaining infants were given fat-soluble Konakion drops or
      parenteral vitamin K1. Within 3 years, one case of classical and 12 cases of late
      onset VKDB (11 confirmed, 1 probable) were reported to the SPSU. Of the 11
      confirmed late-onset cases, 7 received the recommended prophylaxis, whereas 3 had
      not and 1 had been given fat-soluble Konakion drops. All confirmed cases of late
      onset VKDB occurred in fully breast-fed infants and 8 of 11 had hepatobiliary
      disease. CONCLUSION: With the introduction of two oral doses of a mixed-micellar
      vitamin K1 preparation administered in the 1st week of life, the incidence of
      late vitamin K1-deficiency-bleeding has decreased from 7.2:100,000 between 1986
      1987 to 2.8:100,000 between 1995 and 1998. This regimen may be suitable for
      prophylaxis of vitamin K1-deficiency-bleeding, however, it does not fully protect
      infants with cholestatic disease from late-onset bleeding. If oral prophylaxis is
      considered for these infants, vitamin K1 has to be administered repeatedly to all
      infants during the breast feeding period.

PMID- 10412824
TI  - Hormonally active organochlorines and breast cancer: don't believe every
      abstract.

PMID- 10412825
TI  - Sudden unexpected death in a 16-month-old child.

PMID- 10412826
TI  - Nebulized pentoxifylline in successful treatment of five premature neonates with
      bronchopulmonary dysplasia.

PMID- 10412827
TI  - Resistance to activated protein C in newborns with necrotizing enterocolitis.

PMID- 10412828
TI  - B-cell lymphoma associated with DiGeorge syndrome.

PMID- 10412829
TI  - Seizures after inadvertent umbilical venous infusion of synthetic surfactant
      (Exosurf): cause or coincidence?

PMID- 10412830
TI  - Enkephalin inhibits vagal control of heart rate, contractile force and coronary
      blood flow in the canine heart in vivo.
AB  - The following studies were conducted to determine if the ability of the intrinsic
      cardiac opioid, met-enkephalin-arg-phe to interrupt vagal bradycardia can be
      generalized to include the disruption of vagal effects on atrial contraction and
      coronary blood flow. Anesthetized dogs were instrumented to measure heart rate
      and left atrial contractile force or heart rate and coronary blood flow. The
      response of each variable was recorded at rest and during vagal stimulation.
      During the evaluation of vagal effects on contractile activity and coronary blood
      flow, heart rate was maintained constant by electrically pacing the hearts above
      their resting heart rate. In the first protocol, vagal stimulation reduced both
      heart rate and atrial contractile force in a frequency dependent fashion. When
      met-enkephalin-arg-phe (MEAP) was infused systemically for three min at 3 nmol
      min(-1) kg(-1), there were no observed changes in resting heart rate or atrial
      contraction. However, when the vagal stimuli were reapplied during the peptide
      infusion, the previously observed vagal effects on rate and contractile force
      were reduced in magnitude by one-half to two-thirds. The ability of MEAP to
      interrupt the vagal control of heart rate and contractile activity involves
      opiate receptors since the effect was eliminated in both cases by prior opiate
      receptor blockade with the high affinity antagonist, diprenorphine. In the second
      protocol, vagal stimulation produced a transient increase in coronary blood flow
      and an accompanying increase in myocardial oxygen consumption. These effects were
      reduced by approximately 80% during the systemic infusion of MEAP. A similar
      increase in coronary blood flow mediated by the direct acting muscarinic agonist,
      methacholine, was unaltered by the infusion of peptide. In summary, these data
      suggest that the intrinsic cardiac enkephalin, MEAP, is capable of inhibiting the
      vagal control of heart rate, contractile force and coronary blood flow and
      probably does so through a common opiate receptor located prejunctionally on
      vagal nerve terminals or within nearby parasympathetic ganglia.

PMID- 10412832
TI  - Plasticity in the mesenteric afferent response to cisplatin following vagotomy in
      the rat.
AB  - The aim of this study was to investigate the actions of the cytotoxic drug
      cisplatin on populations of mesenteric afferents supplying the rat jejunum.
      Extracellular whole mesenteric nerve discharge was monitored and the activity of
      individual single afferent units determined using waveform discriminator
      software. Baseline whole nerve discharge was 21.5 +/- 3.8 impulses s(-1). Nerve
      discharge began to increase approximately 10 min after cisplatin administration,
      reached a plateau around 30 min, and remained elevated at 60 min (35.3 +/- 5.7
      impulses s(-1), p < 0.01). Granisetron reversed the increase in nerve activity
      indicating that the response to cisplatin was mediated by the release of
      endogenous 5-HT acting on 5-HT3 receptors. Single afferent units, selected by
      waveform analysis on the basis of their response to exogenous 5-HT, showed a
      similar time course of activation following cisplatin. In contrast, the discharge
      frequency of afferent units that were insensitive to 5-HT was unaffected by
      cisplatin or granisetron. The sensitivity of mesenteric afferent bundles to
      exogenous 5-HT was absent in chronically vagotomized animals. However, cisplatin
      elicited an increase in nerve discharge in vagotomized animals that was not
      different from control (34.6 +/- 8.9 impulses s(-1)) but this increase was
      unaffected by treatment with granisetron. Thus, after vagotomy there is a switch
      from 5-HT3 mediated activation of vagal afferents to a 5-HT3-independent
      activation of non-vagal (possibly splanchnic) afferents. Since this later
      mechanism of activation is absent in control animals, it appears that there is
      plasticity in the gastrointestinal afferent sensitivity to cisplatin.

PMID- 10412831
TI  - Participation of arterial baroreceptors input and peripheral vasopressin in the
      suppression of renal sympathetic nerve activity induced by central salt loading
      in conscious rats.
AB  - We examined whether renal sympathetic nerve activity (RSNA) is suppressed in
      response to intracerebroventricular (i.c.v.) administration of hypertonic saline
      (HS) in conscious rats. RSNA was suppressed by i.c.v. administration of HS (0.3
      M, 0.67 M, and 1.0 M, 1 microl/min for 20 min) in a concentration-dependent
      manner, which was attenuated under pentobarbital anesthesia. To elucidate
      mechanisms responsible for central HS-induced decrease in RSNA, possible
      involvement of arterial baroreceptors and peripheral arginine vasopressin (AVP)
      secreted from the posterior pituitary gland was examined using sinoaortic
      denervated (SAD) rats and non-peptide vasopressin receptor antagonists. The
      maximum suppression of RSNA (-81.5 +/- 5.5%) in control rats was significantly
      attenuated to -32.5 +/- 6.7% in SAD rats and to -55.8 +/- 5.7% in rats pretreated
      with intravenous vasopressin V1 receptor antagonist, OPC-21268 (5 mg/kg, i.v.).
      However, in SAD rats, pretreatment with vasopressin V1 receptor antagonist did
      not further affect the RSNA inhibition induced by central salt loading. The
      results suggest that the suppression of RSNA during central salt loading is
      mainly dependent on the arterial baroreceptors input and the 'additive' role of
      peripheral vasopressin.

PMID- 10412833
TI  - Cardiovascular changes following acute and chronic chemical lesions of the dorsal
      periaqueductal gray in conscious rats.
AB  - This study was carried out to investigate the effects of chemical lesions of
      dorsal periaqueductal gray (DPAG) on resting arterial pressure (AP) and heart
      rate (HR) as well as on cardiac baroreflex of conscious normotensive rats.
      Lesions were performed by bilateral microinjections of 150 mM NMDA into the DPAG
      (DPAG-lesion group). Controls were similarly injected with 165 mM NaCl (DPAG-sham
      group). Animals with chronic lesions confined only to the superior colliculus (SC
      lesion group) were also used as controls of DPAG-lesion. Cardiovascular
      parameters were recorded 1 or 7 days after the microinjections of NMDA in acute
      and chronic groups, respectively. Cardiac baroreflex was assessed by measuring
      the HR responses to the intravenous injection of phenylephrine or sodium
      nitroprusside. Baroreflex was estimated by sigmoidal curve fitting of HR
      responses. An increased baroreflex gain was observed in chronic DPAG-lesion rats
      compared to both DPAG-sham (p < 0.01) and SC-lesion (p < 0.05) chronic groups.
      The chronic DPAG-lesion group showed also an elevation of both the tachycardia (p
      < 0.05) and bradycardia (p < 0.01) plateaus compared to chronic DPAG-sham rats,
      while the SC-lesion group showed an elevation of the bradycardia plateau only (p
      < 0.01). Similar results on baroreflex function were observed following acute
      lesion of the DPAG, i.e. an increase in baroreflex gain (p < 0.01) and the
      elevation of both tachycardia (p < 0.05) and bradycardia plateaus (p < 0.01)
      compared to the acute DPAG-sham group. Resting AP and HR did not differ among the
      chronic groups. In contrast, the acute lesion of the DPAG produced a reduction in
      AP (p < 0.01) accompanied by an increase in HR (p < 0.01). The present data
      suggest that the DPAG is involved in the tonic and reflex control of AP and HR in
      conscious rats. In addition, the SC seems to contribute to the baroreflex
      cardioinhibition.

PMID- 10412834
TI  - The origin of catecholaminergic nerve fibers in the subdiaphragmatic vagus nerve
      of rat.
AB  - It is known that the vagus nerve contains catecholaminergic fibers. However, the
      origin of these fibers has not been systematically examined. In this study, we
      addressed this issue using retrograde tracing from the subdiaphragmatic vagus
      nerve combined with immunocytochemistry. The cervical and thoracic sympathetic
      trunk ganglia, the nodose ganglia and the dorsal motor nucleus of the vagus nerve
      were examined following injection of Fluoro-Gold or cholera toxin horseradish
      peroxidase conjugate into the trunks of the subdiaphragmatic vagus nerve of rats.
      Numerous retrogradely labeled neurons were seen in the nodose ganglion and the
      dorsal motor nucleus of the vagus nerve. Very few labeled neurons were found in
      the sympathetic ganglia (less than 0.06% of the neurons in either superior
      cervical ganglion or cervicothoracic ganglion were retrogradely labeled). Double
      labeling with immunofluoresence for catecholamine synthesizing enzymes revealed
      that: (1) 92% of all Fluoro-Gold retrogradely labeled tyrosine hydroxylase
      immunoreactive neurons were found in parasympathetic sources (75% in the dorsal
      motor nucleus of the vagus nerve and 17% in the nodose ganglia), and only 8% in
      the cervicothoracic sympathetic ganglia; (2) 12% of the retrogradely labeled
      catecholaminergic neurons in the dorsal motor nucleus of the vagus nerve were
      also dopamine-beta-hydroxylase immunopositive neurons; (3) 70% of the
      retrogradely labeled neurons in the sympathetic ganglia were tyrosine hydroxylase
      immunopositive and 54% of these catecholaminergic neurons contained dopamine-beta
      hydroxylase, while 30% of the retrogradely labeled neurons were non
      catecholaminergic neurons. These results indicate that catecholaminergic fibers
      in the abdominal vagus nerve are primarily dopaminergic and of parasympathetic
      origin, and that only an extremely small number of these fibers, mostly
      noradrenergic in nature, arise from postganglionic sympathetic neurons.

PMID- 10412835
TI  - Effects of activation and blockade of P2x receptors in the ventrolateral medulla
      on arterial pressure and sympathetic activity.
AB  - Sympathoexcitatory and sympathoinhibitory neurons in the rostral and caudal
      ventrolateral medulla (VLM) play a crucial role in the tonic and reflex control
      of sympathetic vasomotor activity. Recent evidence also indicates that the VLM
      contains a high density of P2x purinoceptors. In this study, we investigated the
      cardiovascular effects of selective activation of P2x purinoceptors in the
      rostral and caudal VLM, and the effects of blockade of P2x purinoceptors in the
      rostral VLM on the tonic and reflex control of sympathetic vasomotor activity. In
      anesthetized barodenervated rabbits, microinjection into the rostral and caudal
      VLM of the P2x purinoceptor agonist, alpha,beta-methylene adenosine triphosphate
      (alpha,beta-meATP) (4-400 pmol) elicited dose-dependent increases and decreases,
      respectively, in arterial pressure (AP), heart rate (HR) and renal sympathetic
      nerve activity (RSNA). The response evoked by alpha,beta-meATP in the rostral VLM
      was blocked by prior injection into the same site of the P2 purinoceptor
      antagonist suramin but not by the ionotropic glutamate receptor antagonist
      kynurenic acid. Bilateral injections of suramin into the rostral VLM
      sympathoexcitatory region had no significant effect on resting cardiovascular
      variables, nor on the reflex increase in RSNA evoked by sciatic nerve stimulation
      (which is known to be mediated by the rostral VLM sympathoexcitatory neurons).
      The results demonstrate that: (1) activation of P2x purinoceptors in the VLM are
      capable of producing marked excitation of both sympathoexcitatory and
      sympathoinhibitory neurons; (2) these effects are not due to modulation of
      glutamatergic inputs to these neurons; and (3) P2x purinoceptors do not play a
      significant role in maintaining the tonic activity of rostral VLM
      sympathoexcitatory neurons or in modulating their responses to excitatory
      synaptic inputs evoked by stimulation of sciatic nerve afferents.

PMID- 10412836
TI  - Modulation of sympathetic nerve activity by microinjection of the 5-HT1A receptor
      agonist 8-OH-DPAT into the rostroventrolateral medulla.
AB  - In the present study, renal sympathetic nerve activity was recorded
      simultaneously with sympathetic nerve activity to skeletal muscle vasculature to
      determine if the sympatho-inhibition evoked by microinjection of the 5-HT1A
      receptor agonist 8-hydroxy-2-(di-n-propylamino)teralin (8-OH-DPAT) into the
      rostroventrolateral medulla (RVLM) was uniform or regional. Three patterns of
      sympatho-inhibition were observed in these sympathetic outflows and the type of
      response depended upon location of microinjection within the subretrofacial
      nucleus (SRF). Inhibition of renal nerve activity only was elicited by
      microinjections at rostral sites at the caudal pole of the facial nucleus. In
      contrast, inhibition of muscle sympathetic nerve activity was evoked from more
      caudal injections at the rostral pole of the inferior olives. Microinjection in
      the area between these two regions produced inhibition of both sympathetic
      outflows. This study demonstrates that differential inhibition of regional
      sympathetic outflows can be elicited by microinjection of the 5-HT1A receptor
      agonist 8-OH-DPAT into the RVLM. These data suggests that this modulation is due
      to differences in anatomical arrangement of the medullary neurons rather than
      differences in neuron sensitivity to the serotonergic agonist.

PMID- 10412837
TI  - CNS innervation of vagal preganglionic neurons controlling peripheral airways: a
      transneuronal labeling study using pseudorabies virus.
AB  - The CNS cell groups that project to vagal preganglionic neurons which innervate
      the most distal part of the airways were identified by the viral retrograde
      transneuronal labeling method. Pseudorabies virus (PRV) was injected into the
      lung parenchyma of C8 spinal rats and after 5 days survival, brain tissue
      sections from these animals were processed for immunohistochemical detection of
      PRV. Retrogradely labeled parasympathetic preganglionic cells (first-order
      neurons) were seen mainly in the ventral medulla oblongata: the compact portion
      of the nucleus ambiguus and the area ventral to it. Occasionally, a few labeled
      cells were seen within the rostral part of the dorsal vagal nucleus. This
      labeling pattern correlated well with the retrograde cell body labeling seen
      following cholera toxin beta-subunit (CT-b) injections in the lung parenchyma.
      PRV transneuronally labeled neurons (second-order and/or presumed third-order
      neurons) were found throughout the CNS with the characteristic labeling in the
      brainstem. Labeled neurons were identified along and just beneath the ventral
      medullary surface, and in nearby areas: the parapyramidal, retrotrapezoid,
      gigantocellular and lateral paragigantocellular reticular nuclei, as well as the
      caudal raphe nuclei (raphe pallidus, obscurus, and magnus). Several nucleus
      tractus solitarius (nTS) regions contained labeled cells including the
      commissural, medial, and ventrolateral nTS subnuclei. The A5 cell group and a
      small number of locus coeruleus neurons were also labeled. PRV-infected neurons
      were present in the Kolliker-Fuse and Barrington's nuclei. In the mesencephalon,
      neurons within the ventral periventricular gray matter were labeled. Labeling was
      present in the dorsal, lateral and paraventricular hypothalamic nuclei, and
      within the amygdaloid complex. In summary, the parasympathetic preganglionic
      neurons that innervate the peripheral airways are controlled by networks of lower
      brainstem and suprapontine neurons that lie in the same regions known to be
      involved in central regulation of autonomic functions.

PMID- 10412838
TI  - Stress induced changes in transmitter release from sympathetic varicosities of
      the mouse vas deferens.
AB  - Activation of the sympathetic nervous system is an important component of the
      response to stress, but the effects of prolonged stress on sympathetic
      neurotransmission have not been assessed. In the present study we have examined
      the effect of 3 to 10 days exposure to stress induced by frequent handling and
      sham injections on neurotransmitter release from sympathetic varicosities of the
      mouse vas deferens. DiOC2(5)-fluorescence was used to visualise the sympathetic
      varicosities so that extracellular electrodes could be placed over known numbers
      of varicosities to monitor transmitter release using electrophysiological
      techniques. The frequency of excitatory junction currents (EJCs) increased with
      increasing duration of exposure to stress. The mean and maximum EJC amplitude
      significantly increased by 107% and 43%, respectively after 10 days of exposure
      to stress. The density of sympathetic varicosities innervating smooth muscle of
      the mouse vas deferens was not changed throughout the duration of the exposure to
      stress. The findings from this study demonstrate that the efficacy of transmitter
      release from the sympathetic varicosities is altered by repeated exposure of mice
      to stressful stimuli, such as handling and sham injections. Since such procedures
      are routine in many pharmacological experiments, it is important that
      investigators are aware of these changes so that due consideration is given when
      interpreting the data obtained from animals treated in this way.

PMID- 10412839
TI  - Chaos and spectral analyses of heart rate variability during head-up tilting in
      essential hypertension.
AB  - To investigate nonlinear and linear components of heart rate variability (HRV) in
      essential hypertension (EHT), we analyzed HRV by chaos and spectral analyses in
      patients with EHT (n = 18) and normotensives (n = 10) during head-up tilting. We
      used the correlation dimension (CD) and Lyapunov exponents as the parameters of
      chaos. The CD, an index of complexity, was lower at rest in EHT group than in
      normotensives, and did not change in EHT group in response to head-up tilting,
      but decreased in normotensives. Head-up tilting did not change the Lyapunov
      exponents, an index of sensitive dependence on initial condition, a hallmark of
      chaos, in both groups. In the spectral analysis, the normalized high-frequency
      component (%HF) was decreased in EHT group at rest, and head-up tilting increased
      the low- to high-frequency ratio (L/H) and reduced the %HF in both groups. The CD
      and Lyapunov exponents at rest were correlated with the %HF and L/H. These
      results suggest that chaos analysis can assess the different aspect of HRV from
      spectral analysis and that nonlinear components of HRV may be associated with
      hypertension through an impaired dynamic regulation of HRV.

PMID- 10412840
TI  - Cerebrovascular mechanisms in neurocardiogenic syncope with and without postural
      tachycardia syndrome.
AB  - BACKGROUND AND PURPOSE: Recent transcranial Doppler studies in patients with
      neurocardiogenic syncopes (NCS) have demonstrated that the cerebrovascular
      response to sudden systemic hypotension is vasoconstriction instead of
      compensatory vasodilation (autoregulation). We tried to characterize the
      conditions leading to this unexpected response in NCS patients further by
      continuously monitoring autoregulation and autonomic parameters during a
      standardized tilt-table test (TTT). METHODS: Sixteen patients below the age of 50
      years with a history of at least three syncopes of undetermined cause and tilt
      table verified NCS and 20 normal controls were studied. Arterial blood pressure
      (ABP) and heart rate (HR) were monitored by Finapres and cerebral blood flow
      velocity (CBFV) of the left middle cerebral artery by transcranial Doppler.
      Baroreflex sensitivity and autoregulation parameters were measured continuously,
      using cross-spectral analysis of Mayer waves (3-9 cycles per minute oscillations)
      in ABP, HR and CBFV, respectively. Pulsatility indices (PI) of CBFV and ABP were
      determined continuously. Measurements were taken during 5 min in supine and
      during 5 min in tilted position. In patients, tilting was continued for a maximum
      of 45 min until the onset of syncope or presyncope. RESULTS: According to the
      maximum increase in heart rate (deltaHR) during the first 5 min of standing,
      heart rate responses were classified as postural tachycardia syndrome (POTS)
      (deltaHR > 35/min) or as normal. Only one out of 20 control subjects showed a
      POTS (5%) in contrast to seven patients (44%). Patients with a POTS had
      significantly lower PI values in ABP and higher ratios between the PI of CBFV and
      the PI of ABP both in supine and in tilted positions. Baroreflex sensitivity
      during standing decreased significantly in POTS patients when compared to
      controls. Although autoregulation remained intact during standing, mean CBFV
      decreased significantly and continuously. The nine patients without a POTS showed
      almost the same cardiovascular and cerebrovascular responses as the control
      subjects. All 16 patients showed similar circulatory responses during syncope
      (sudden hypotension, relative or absolute bradycardia, reduced CBFV and increased
      PI in CBFV). CONCLUSIONS: The development of a POTS during tilting indicates a
      high risk for fainting. The characteristic hemodynamic features in the initial
      phase of standing in these patients can be interpreted in terms of central
      hypovolemia (low PI of ABP) with sufficient ABP regulation and increased
      cerebrovascular resistance (defined as the ratio between PI of CBFV and ABP).
      Cerebral autoregulation seems not to be affected in patients suffering from NCS.

PMID- 10412841
TI  - The area postrema of newborn swine is activated by hypercapnia: relevance to
      sudden infant death syndrome?
AB  - This study was performed to investigate a role of the neonatal area postrema (AP)
      in the chemoreceptor response to hypercapnia which is defective in sudden infant
      death syndrome (SIDS). AP responses to CO2 inhalation were monitored in 1 to 5
      week old piglets by mapping neurons that were induced to express the c-fos gene
      product, Fos--a marker of functional activation. Interpretive confounds were
      minimized by controlling for hypoxia, the effects of surgical procedures and
      ambient environmental stressors on neuronal activity (c-fos expression). The AP
      demonstrated a powerful and reproducible response in neonatal swine breathing 10%
      CO2 for 1 h. Intensely immunolabeled nuclei were detected throughout the
      longitudinal extent of the circumventricular organ, and were especially heavily
      concentrated at rostral levels proximal to obex. Quantitative analysis verified
      statistically significant increases in numbers of cells that were induced to
      express Fos-like immunoreactivity (FLI) in the AP of CO2- stimulated piglets as
      compared to control groups. No detectable age-related differences were observed
      in AP response patterns. Conclusions. The AP responds to hypercapnic stress in
      the newborn piglet. A mature circumventricular organ response in the neonate may
      be crucial in defending against common environmental stressors, such as nicotine
      exposure--an emetic agent acting via the AP and a major risk factor in SIDS.
      Hence, a defect of the AP or its network may underlie a loss of state-dependent
      controls over cardiopulmonary reflex function in SIDS.

PMID- 10412842
TI  - Messenger molecules and receptor mRNA in the human trigeminal ganglion.
AB  - The presence and distribution of neuromessenger molecules and receptor mRNA in
      human trigeminal ganglion was studied with immunocytochemical, in situ
      hybridisation and RT-PCR techniques. Immunofluorescence staining revealed that
      calcitonin gene-related peptide (CGRP) immunoreactive (-ir) neurons occurred in
      high numbers, constituting 36-40% of all nerve cell bodies in the ganglion.
      Accordingly, in situ hybridisation demonstrated CGRP mRNA in a large portion of
      the trigeminal neurons. A small number of the nerve cell bodies showed substance
      P (SP)-ir, (18%), nitric oxide synthase (NOS)-ir (15%), and pituitary adenylate
      cyclase activating peptide (PACAP)-ir (20%). Double immunostaining revealed that
      only few CGRP-ir neurons also were NOS-ir (less than 5%). The C-terminal flanking
      peptide of neuropeptide Y, C-PON, was not visible in any of the nerve cell bodies
      studied. Agarose gel electrophoresis of the RT-PCR products from the ganglia
      demonstrated the presence of mRNA corresponding to CGRP1, NPY Y1 and Y2, and VIP1
      receptors. These results suggest both sympathetic and parasympathetic influence
      on the activity in the trigeminal ganglion.

PMID- 10412843
TI  - Cardiac sympathetic denervation in Ross syndrome demonstrated by MIBG-SPECT.
AB  - We investigated cardiac sympathetic innervation by metaiodobenzylguanidine (MIBG)
      imaging in a patient with tonic pupils, loss of tendon reflexes, and segmental
      anhidrosis (Ross syndrome). Despite normal cardiovascular reflex tests, we
      observed a reduced global myocardial MIBG uptake as well as a regional uptake
      defect over the posterolateral cardiac territory indicating left ventricular
      peripheral sympathetic denervation. MIBG imaging seems to be a useful noninvasive
      diagnostic method for detection of early--possibly subclinical--cardiac autonomic
      impairment in Ross syndrome and provides further evidence of injury to
      postganglionic autonomic neurons as the underlying pathological mechanism of the
      disease.

PMID- 10412844
TI  - Powered toothbrushes: a review of clinical trials.
AB  - There is now a vast range of powered toothbrushes (PTBs) available on the market
      and the efficacy of each product is usually determined in one, or a series of
      controlled clinical trials. This article reviews briefly the design of PTBs, some
      of the proposed indications for their use, and the principal observations from
      published studies of these products. The important issues regarding the
      regulation and design of trials involving PTBs are discussed and some
      recommendations are proposed with a view to developing a more structured approach
      to testing these products.

PMID- 10412845
TI  - Clinical evaluation of Bio-Oss: a bovine-derived xenograft for the treatment of
      periodontal osseous defects in humans.
AB  - The purpose of this study was to compare the bovine derived xenograft (BDX) Bio
      Oss to demineralized freeze dried bone allograft (DFDBA) in human intrabony
      defects. 17 healthy patients with no systemic disease with moderate-severe
      periodontitis (7 males, 10 females; aged 34-67), were treated. Surgically,
      defects were included only if the intraosseous defect depth was >3.0 mm. Final
      selection included 30 defects. The sites were randomly assigned treatment with
      DFDBA or BDX. Soft tissue and osseous defect measurements were taken the day of
      surgery and 6 months post-operatively at re-entry. Average baseline PD, CAL, and
      surgical defect depth for the DFDBA group were not statistically different from
      the BDX group. No adverse healing response occurred. The results showed a
      statistically significant improvement in PD and AL for both materials at 6 months
      in 26 defects (4 defects did not respond to therapy). Soft tissue measurements
      for the DFDBA group included PD reduction of 2.0+/-1.3 mm, and AL gain of 2.6+/
      1.6 mm, while the BDX group showed a PD reduction of 3.0+/-1.7 mm, and AL gain of
      3.6+/-1.8 mm. Osseous measurements showed bone fill of 2.4 mm (46.8%) for the
      DFDBA group and 3.0 mm (55.8%) for the BDX group. Defect resolution was 59.4% for
      the DFDBA group and 77.6% for the BDX group. Statistical analysis revealed there
      was no statistical difference between the 2 materials in all measurements.

PMID- 10412846
TI  - Conversion of plaque-area measurements to plaque index scores. An assessment of
      variation and discriminatory power.
AB  - Plaque areas recorded graphically or photographically provide a permanent record
      of plaque accumulations on teeth at a moment in time. As such, these records
      could be re-evaluated and converted into other index scores. The purpose of this
      study was to determine the reproducibility of scoring a plaque index from
      previously recorded plaque areas and to compare such scores with the original
      scores of the same index. A randomised blind, crossover study comparing 5
      treatments for plaque inhibition scored by plaque area and index was chosen. 2
      examiners, the original scorer PRH and another, NC, 2x scored the plaque area
      tooth charts according to the criteria of the plaque index system used in the
      original study. Standard deviations of the differences showed intra-examiner
      repeatability to be high particularly for the original examiner. Inter-examiner
      reproducibility for the original index scores was considered good but less than
      for intra-examiner repeatability. Correlation coefficients were complimentary to
      the differences analysis, being very high within examiners and less high for
      between examiners and original and rescored index. Separation between
      distributions of plaque area measurements for consecutive values of the index
      were particular good for scores 2 versus 3 and 3 versus 4 and less good for 1
      versus 2 and 4 versus 5. Reanalysis of the study for treatment differences using
      rescored data revealed a similar level of significance as using the original
      data. Rescored index had similar discriminatory power for the study as plaque
      area and original plaque index when both were derived from the same buccal tooth
      surfaces. However, discriminatory power was less by comparison with original
      plaque index derived from the buccal surfaces of all teeth. It is concluded that
      plaque area provides a permanent record of plaque distribution which can be
      converted into index data at a later date. Such data collection could make
      possible comparisons between studies using different indices.

PMID- 10412847
TI  - Measurement of clinical attachment levels using a constant-force periodontal
      probe modified to detect the cemento-enamel junction.
AB  - The handpiece of a Florida sleeve probe was modified to create a flange with the
      capability to detect the cemento-enamel junction (CEJ). This new instrument (the
      Pressure-controlled, Automated, Standardised Handpiece or Florida PASHA probe)
      was used to determine whether (a) the CEJ could be reproducibly detected in
      dried, human skulls and (b) clinical attachment levels could be reliably measured
      in human subjects. When using the Florida PASHA probe to detect the CEJ at 157
      different sites in four dried, human skulls, there were no statistically
      significant (p > or = 0.15) differences in mean CEJ detection measurements for
      any of the three participating examiners; either when the CEJ was visualised or
      obscured. The mean differences between first and second replicates ranged from
      0.00 to 0.08 mm. Intraclass correlation coefficients (ICCs) of repeated measures
      in both conditions ranged from 0.70 to 0.83 for tactile CEJ detection (CEJ
      obscured), and from 0.95 to 0.96 for visual detection (CEJ visible). In human
      studies, the Florida PASHA probe was used by two examiners to determine clinical
      attachment levels (CAL) at 660 sites in 5 human subjects undergoing supportive
      periodontal therapy. Intra-examiner agreement of replicate measurements recorded
      by the probe, as measured by calculating ICCs, ranged from 0.79 to 0.85 for the 2
      examiners, respectively. A statistically significant inter-examiner difference in
      mean CAL measurements when using the Florida PASHA probe was found (p<0.001).
      Notwithstanding this difference, inter-examiner agreement was good, with an ICC
      of 0.83. These data suggest that the Florida PASHA probe can reproducibly detect
      the CEJ and is proposed as a tool for measuring CAL in humans.

PMID- 10412848
TI  - Topical distribution of Fc gammaRI, Fc gammaRII and Fc gammaRIII in inflamed
      human gingiva.
AB  - The topical distribution of Fc gamma receptor types I, II and III (Fc gammaRI
      III) was analyzed by means of immunohistochemistry in human gingival tissue
      obtained from 12 patients with chronic periodontitis. CD68+ macrophages
      expressing all three classes of Fc gammaR were found throughout the whole
      gingival connective tissue (CT), whereas dense infiltrates of polymorphonuclear
      granulocytes (identified by staining for neutrophil elastase) with strong
      staining for Fc gammaRIII and Fc gammaRII were found subjacent to the apical part
      of the pocket epithelium (PE) and in the PE itself. CD19+ B lymphocytes with
      variable staining intensity for Fc gammaRII were observed in clusters subjacent
      to the PE and extending into the central part of the CT. Only a few scattered
      CD3+ T lymphocytes stained for Fc gammaRIII. Some spindle-shaped cells (CD68-,
      therefore non-macrophages) and apparently non-cellular fibrous tissue elements
      stained for Fc gammaRI and Fc gammaRII. In the epithelium, Fc gammaRII+ dendritic
      cells were frequently observed in the entire oral gingival epithelium and in the
      coronal part of the PE. Occasionally, some keratinocytes which stained for Fc
      gammaRII and Fc gammaRIII were found. The observations indicate that Fc gammaR of
      the various classes are amply expressed on numerous cell types in inflamed
      gingival tissue. The specific distribution pattern detected suggests that Fc
      gammaRs may play a role in the mediation of chronic inflammation in the
      periodontal lesion.

PMID- 10412849
TI  - The relationship between tooth cleaning behaviour and flexibility of working time
      schedule.
AB  - This study tested whether there is a relationship between levels of flexibility
      of working time schedule and the pattern (frequency of tooth cleaning), structure
      (range of items used in tooth cleaning), and performance (relative effectiveness
      of tooth cleaning measured by levels of dental plaque) of tooth cleaning. 471
      Brazilian workers from both sexes aged 24 to 44 years were selected from
      factories, offices, banks, shops and hospitals. Behavioural, socio-economic and
      clinical data were collected through structured interviews and clinical
      examination. Data analysis included frequency distribution and simple and
      multiple logistic regression. The response rate was 92.5%. Simple logistic
      regression showed there was a highly statistically significant relationship
      between flexibility of the working time schedule and tooth cleaning frequency,
      the range of oral hygiene aids used and the level of dental plaque. All 3
      associations remained highly statistically significant after adjusting for age,
      sex, socio-economic status and marital status. Socio-economic status was
      statistically significantly associated with tooth cleaning frequency, the use of
      oral hygiene aids and the level of dental plaque. It was concluded that high
      flexibility of working time schedule is related to pattern, structure and
      performance of tooth cleaning.

PMID- 10412850
TI  - Differences in the inflammatory response in young and old human subjects during
      the course of experimental gingivitis.
AB  - The aim of the present experiment was to study changes in (i) the composition of
      the inflammatory cell infiltrates and (ii) levels of alpha 2-macroglobulin,
      lactoferrin and IgG subclasses in gingival crevicular fluid in young and old
      individuals during 3 weeks of plaque formation. To establish healthy gingival
      conditions, all subjects received professional tooth cleaning during a 4 week pre
      experimental period. The experimental sites included the mesio-palatal, palatal,
      and disto-palatal surfaces of all teeth present in the 15...25 tooth region. At
      baseline (day 0) assessments of plaque and gingivitis, microbial sampling and
      gingival fluid assessment were performed and one gingival biopsy harvested from
      each subject. Following the baseline examination, the participants abolished
      mechanical tooth cleaning measures in the palatal and approximal surfaces of
      15...25. The clinical examination and the gingival fluid measurement were
      repeated on days 7, 14 and 21 of no oral hygiene. The microbiological sampling
      and the biopsy procedure were repeated on days 7 and 21. The gingival crevicular
      fluid samples harvested from the old individuals had higher levels of alpha 2
      macroglobulin and IgG3 compared to young subjects. The immunohistochemical
      analyses of the biopsies demonstrated that the gingival lesion representing the
      old individuals harbored a higher proportion of B-cells and a lower density of
      PMN cells compared to the infiltrate in the young group of subjects. It is
      suggested that differences exist in the inflammatory response to de novo plaque
      formation in young and old individuals.

PMID- 10412851
TI  - Clinical and microbiological effects of initial periodontal therapy in
      conjunction with amoxicillin and clavulanic acid in patients with adult
      periodontitis. A randomised double-blind, placebo-controlled study.
AB  - The aim of the present study was to investigate the clinical and microbiological
      effects of initial periodontal therapy in conjunction with systemic amoxicillin
      plus clavulanic acid in adult periodontitis patients using a double-blind,
      parallel-group, and placebo-controlled protocol. 21 patients with a clinical
      diagnosis of generalised adult periodontitis were recruited. Clinical
      measurements and microbiological assessments were carried out at baseline, 3, and
      12 months post-treatment. Approximately 6 weeks after initial periodontal
      treatment (3-6 h), patients were randomly assigned to receive coded study
      medication of 500 mg amoxicillin plus 125 mg clavulanic acid (Augmentin) or
      placebo, every 8 h for 10 days. Patients returned for follow-up visits 3, 6, 9,
      and 12 months after completion of the medication. The mean plaque index (PI) at
      baseline was 1.1 for placebo group and 0.9 for the test group. At 3 months, the
      PI had dropped to 0.3 in both groups, and was maintained during the rest of the
      study. The changes in bleeding on probing (BOP) and gingival index (GI) in the
      course of the study were similar in both groups. The mean whole mouth probing
      pocket depth (PPD) in the placebo group was 3.8 mm at baseline and 3.9 mm in the
      test group. A mean reduction of 1.0 mm in the placebo group and 0.9 mm in the
      test group was observed during the first 3 months. No further reduction in PPD
      was noticed during the study period in either group. There was no statistically
      significant difference in the PPD reduction between the 2 groups. The change in
      clinical attachment level (CAL) from baseline to 3 months amounted to 0.5 mm in
      both groups. Between 3 and 12 months, the CAL changed in neither group. In both
      groups, treatment resulted in a decrease in the number of spirochetes and motile
      rods in positive patients, but no significant differences between either group
      were noted in any of the dark field microscopy observations. At baseline, 1
      patient in the placebo group and 2 patients in the test group were culture
      positive for Actinobacillus actinomycetemcomitans (Aa). After therapy, Aa was not
      detectable in the placebo group and 1 patient remained positive in the test
      group. In the placebo group, the number of patients positive for Porphyromonas
      gingivalis (Pg) decreased from 7 to 2 after therapy. In the test group, the 4
      patients positive for Pg at baseline remained positive after therapy. In both
      groups, all subjects were positive for Prevotella intermedia (Pi) and
      Fusobacterium nucleatum (Fn) at baseline. At 12 months, all subjects had
      detectable subgingival Fn. 9 out of the 11 placebo and 8 of the 10 test patients
      remained positive for Pi. There were no differences in detection frequency of
      Peptostreptococcus micros (Pm) and Bacteroides forsythus (Bf) in both groups
      between baseline, 3, and 12 months post-treatment. The findings demonstrated
      that, in comparison to placebo, systemic amoxicillin plus clavulanic acid
      provided no additional clinical and microbiological effects in the treatment of
      adult periodontitis patients.

PMID- 10412852
TI  - Bacteremia after dental treatment in mentally handicapped people.
AB  - Bacteremia may occur after disruption of the oral mucous membrane, particularly
      after dental treatment. 18 mentally handicapped patients who underwent dental
      treatment with general anesthesia were included in our study. None of the
      patients had general illnesses or received antibiotic protection. From each
      patient several blood samples were drawn aseptically during dental treatment and
      cultured. The majority of aerobic bacteria recovered belonged to Streptococcus sp
      and Gemella sp., anaerobic bacteria mainly belonged to Porphyromonas gingivalis
      and Peptostreptococcus sp. Resistance of the isolated bacteria to penicillin as
      well as to oxacillin, erythromycin and Co-trimoxazole was substantial. The
      highest resistance rate could be shown against fucidic acid.

PMID- 10412853
TI  - Comparative antimicrobial activity of an essential oil and an amine
      fluoride/stannous fluoride mouthrinse in vitro.
AB  - Although laboratory studies are not necessarily predictive of clinical activity;
      they can help to elucidate mechanisms underlying clinical activity when the
      latter has been established. In a recent clinical study, an essential oil
      mouthrinse (Listerine Antiseptic) was shown to be significantly more effective
      than an amine fluoride/stannous fluoride mouthrinse (Meridol) in inhibiting
      supragingival plaque formation. This paper reports the results of laboratory
      studies comparing the antimicrobial effectiveness of these 2 mouthrinses using a
      kill kinetics assay and a plaque biofilm kill assay. In both assays, the
      essential oil mouthrinse was considerably more effective than the amine
      fluoride/stannous fluoride mouthrinse. These findings are consistent with the
      results of the clinical trial and may help to explain the observed differences in
      clinical activity.

PMID- 10412855
TI  - Evaluation of the incidence of gingival abrasion as a result of toothbrushing.

PMID- 10412854
TI  - Inability of intact cells of Treponema denticola to degrade human serum proteins
      IgA, IgG and albumin.
AB  - Treponema denticola has been shown to be associated with periodontitis in man and
      animals. The organism ferments amino acids and thrives on the proteins in the
      periodontal pocket. Accordingly, T. denticola possesses various proteolytic
      enzymes, including a chymotrypsin-like protease, capable of hydrolyzing a whole
      range of proteins, including immunoglobulins. Yet, it is not clear whether the
      intact cells of T. denticola can degrade immunoglobulins and albumin. The purpose
      of this study was to clarify this point. Three strains of T. denticola were
      cultured in liquid medium, and cells were harvested by centrifugation. Protein
      degradation in cell suspensions was assayed by capillary electrophoresis and
      immunonephelometry. None of the T. denticola strains appeared to be able to
      degrade IgA, IgG, or albumin, while a strain of P. gingivalis completely
      hydrolyzed these proteins. The findings suggest that, in the periodontal pocket,
      T. denticola depends on proteinases from other bacteria for utilization of the
      available serum proteins. This is in accordance with clinical data showing a
      close relationship between T. denticola and strongly proteolytic bacteria, such
      as Porphyromonas gingivalis and Bacteroides forsythus.

PMID- 10412856
TI  - Center volume effects in pediatric renal transplantation. A report of the North
      American Pediatric Renal Transplant Cooperative Study.
AB  - An inverse relationship between mortality and center volume has been established
      for several surgical procedures. Given the distinctiveness of pediatric renal
      transplantation and the large variation in center volume, investigation for
      relationships between center volume and graft outcome was pursued using the North
      American Pediatric Transplant Cooperative Study database. Center volume groups
      were based on the total number of pediatric transplants reported from 1987 to
      1995. Centers reporting > 100, 51-100, or < or = 50 transplants were grouped as
      high- (n=11), moderate- (n=28), or low-volume (n=65), respectively. Differences
      between groups included increasing rates of cadaver donor graft thrombosis (2.4%,
      4.3%, and 5.7%, P<0.01) and acute tubular necrosis (ATN) (10.2%, 11.5%, and
      14.0%, P<0.01) with decreasing center volume. Treatment differences included a
      higher rate of induction with an anti-T-cell antibody preparation in the larger
      volume groups, 60.2%, 51.8%, and 39.2% (P<0.001). Decreasing graft survival for
      decreasing center size groups was noted at 3 months post transplant, 90.4%,
      90.2%, and 88.4%. These differences were significant only with the exclusion of
      anti-T-cell induction from the proportional hazards model (relative risk=0.81 and
      =0.70 for the moderate- and high-volume groups, P<0.02). Superior graft survival
      in the high-volume centers noted at 3 months post transplant appears
      predominantly the result of lower rates of cadaver donor graft thrombosis and
      ATN. Analysis points to the need for low-volume centers to identify risk factors
      influencing these outcomes.

PMID- 10412857
TI  - Ovine aquaporin-2: cDNA cloning, ontogeny and control of renal gene expression.
AB  - The aim of this study was to test the hypothesis that the relative insensitivity
      of the ovine fetal kidney to arginine vasopressin (AVP) is due to low levels of
      expression of the gene for aquaporin-2 (AQP2) which encodes the AVP-regulated
      water channel. We report the cloning of the cDNA for the ovine AQP2 which has a
      major transcript at 4.2 kilobases (kb) and a minor transcript at 1.5 kb,
      resembling the human gene transcripts. At 40-60 days' (term = 145-150 days'),
      mRNA levels are very low, detectable only by reverse transcription-polymerase
      chain reaction (RT-PCR). By Northern blot analysis AQP2 mRNA is detectable at 75
      days'. The ratio of AQP2/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA
      increases approximately 2.4-fold between 100 and 140 days' when it is about 41%
      of adult values. Both glucocorticoids and the renin-angiotensin system are
      involved in maturation of renal function. When fetuses at 75 or 85 days of
      gestation were exposed to high levels of dexamethasone for 2-3 days, mRNAs for
      both GAPDH and AQP2 doubled, but the ratio was unchanged. Angiotensin I, infused
      for 3 days at 115-120 days' gestation, increased the AQP2/GAPDH mRNA ratios by
      twofold (major transcript) and sixfold (minor transcript), which were highly
      significant (P<0.001). The increasing sensitivity of the ovine fetal kidney to
      AVP, from 100-140 days of gestation, is largely due to increasing AQP2 gene
      expression over this period.

PMID- 10412858
TI  - Captopril reduces the proteinuric effect of human growth hormone in adriamycin
      nephrosis.
AB  - Developing male Sprague-Dawley rats (125 g) with adriamycin (doxorubicin
      hydrochloride) nephrosis (AN) were treated with growth hormone (GH) which may
      induce hyperfiltration potentiating glomerulosclerosis. Since captopril (CAP)
      reduces hyperfiltration, we studied its effects in GH-treated rats with AN. After
      41, 76, and 90 days of therapy, urine protein excretion was significantly
      (P<0.05) reduced in GH-treated AN plus CAP compared with AN rats receiving GH
      alone. After 90 days, urine protein, creatinine ratio was significantly (P<0.05)
      increased in GH-treated AN (95.2+/-13.9) compared with untreated AN (64.8+/-7.8)
      and GH-treated AN rats plus CAP (41.8+/-8.8). The mean serum cholesterol level
      was significantly (P<0.05) reduced in GH-treated AN rats receiving CAP compared
      with AN rats receiving GH alone and untreated AN controls. Histologically tubular
      dilation was significantly (P<0.05) reduced in GH-treated AN rats plus CAP
      compared with AN rats receiving GH alone. Tubular atrophy and scarring were
      significantly (P<0.05) increased in AN rats treated with GH compared with
      untreated AN rats, and normalized in GH-treated AN rats plus CAP. We conclude
      that CAP reduces the proteinuric response of GH in rats with AN and ameliorates
      tubular injury.

PMID- 10412859
TI  - Influence of three different types of hypercalciuria on bone. An experimental
      study.
AB  - The relationship between bone mineral status and hypercalciuria is controversial.
      The effect on bone composition of different forms of hypercalciuria was studied
      in female rats made hypercalciuric by 7-week administration of oral furosemide
      (F, n=12), intraperitoneal 1,25-dihydroxy vitamin D (VD, n=11), or oral ammonium
      chloride (AC, n=12). Seven untreated rats served as controls (C). Hypercalciuria
      (mg/100 g per 24 h, mean +/-SEM) of F (4.3+/-0.2), VD (4.1+/-0.4), and AC (3.9+/
      0.3) groups was of similar intensity (C rats 1.3+/-0.1, P<0.01). Weight and
      length gains and serum CO2, sodium, potassium, calcium, and phosphate were no
      different among the four groups. Bone was studied by dual-energy X-ray
      absorptiometry of left tibiae. AC rats had significantly less bone area (1.505+/
      0.018 cm2) than VD and C (1.602+/-0.020 and 1.587+/-0.019 cm2). Bone mineral
      content was decreased in F (0.357+/-0.007 g) and AC (0.362+/-0.006 g) compared
      with VD (0.407+/-0.008 g) and C (0.389+/-0.009 g) groups. Bone mineral density
      was different between F (0.231+/-0.002 g/cm2) and VD and C rats (0.254+/-0.004
      and 0.245+/-0.003 g/cm2), and also between AC (0.240+/-0.003 cm2) and VD rats. In
      these rat models, hypercalciuria of renal origin (F) and hypercalciuria caused by
      acid load (AC) adversely impaired bone mass.

PMID- 10412860
TI  - Hemodialysis for end-stage renal disease in children weighing less than 10 kg.
AB  - Hemodialysis (HD) of infants with end-stage renal disease (ESRD) is technically
      difficult and labor intensive, although there are few data in the literature to
      document the outcomes of this treatment. We retrospectively reviewed all patients
      with ESRD who received HD between 1983 and 1997 who weighed <10 kg at the
      beginning of HD. A total of ten patients aged 2-27 months, weighing 3.5-9.5 kg,
      were identified. All patients were dialyzed through a central venous line; three
      had a failed sapheno-femoral loop and one a failed brachial shunt. Line clot was
      observed in nine and line sepsis in six patients. Subclavian vein stenosis was
      documented in one patient following removal of a clotted subclavian line. The
      mean urea reduction ratios calculated during the 1st and 3rd month of HD were
      only 54% and 49%, respectively. Anemia was a frequent problem, despite the use of
      erythropoietin in seven of the infants. Outcomes included: successful renal
      transplant in four, switch back to peritoneal dialysis in two, improved renal
      function and dialysis discontinuation in one, and death after withdrawal of
      treatment in three patients. All three patients who died were <5 months of age,
      weighed <5 kg, and were anuric; two of the three had congenital nephrotic
      syndrome. In conclusion, successful HD is possible in small children with ESRD,
      but morbidity is substantial and mortality is high.

PMID- 10412861
TI  - Chronic dialysis in children and adolescents. The 1996 annual report of the North
      American Pediatric Renal Transplant Cooperative Study.
AB  - The 1996 annual report of the North American Pediatric Renal Transplant
      Cooperative Study (NAPRTCS) summarizes data submitted from 130 centers on 2,208
      patients in whom 2,787 independent courses of dialysis were performed between 1
      January 1992 and 16 January 1996. Approximately two-thirds of the dialysis
      population were maintained on peritoneal dialysis (PD), with automated PD
      remaining the preferred modality. There were 964 episodes of peritonitis in 1,018
      patient years, yielding an overall peritonitis rate of 1 episode every 13 patient
      months. More PD patients attended school full time than hemodialysis (HD)
      patients at baseline (77% vs. 45%), which continued at 6, 12, and 24 months of
      followup. There were fewer Hispanic patients who were full-time students, whether
      on HD or PD, compared with white or black patients; 18% of Hispanic patients did
      not attend school, even though they were medically capable. The majority of
      dialysis courses terminated due to transplantation (54%), with change in dialysis
      modality the next most-common reason (28%). Early dialysis termination for any
      reason was seen more often in HD than PD (40% vs. 23% at 6 months), but by 24
      months similar percentages of PD and HD courses had been terminated (75% HD, 72%
      PD). The most-common PD access was a Tenckhoff catheter with a single cuff, a
      straight tunnel and lateral exit site. The majority of HD accesses were external
      percutaneous catheters, with the sublcavian vein the most-common site.
      Erythropoietin was administered in 93% of HD and PD patients at 24 months.

PMID- 10412862
TI  - Comparison of two methods for predicting equilibrated Kt/V (eKt/V) using true
      eKt/V value.
AB  - Two methods have been suggested by Daugirdas and Schneditz (the rate equation),
      and Smye for predicting true equilibrated Kt/V (eKt/V) without the need for
      obtaining a blood sample 60 min after hemodialysis (HD). We compared the accuracy
      of these two methods when applied to pediatric HD. Thirty-eight standard
      pediatric HD sessions in 15 patients, (6 male, 9 female), aged 14.5+/-3.3 years,
      were analyzed. Kt/V was calculated by formal variable-volume single-pool urea
      kinetic model with post-HD urea taken at the end of HD (single-pool Kt/V), and
      with equilibrated urea (Ceq) taken 60 min after the end of HD (eKt/V). eKt/V was
      predicted by the rate equation from single-pool Kt/V and by the Smye method from
      predicted Ceq. Mean values obtained by both the rate equation (1.44+/-0.32,
      P>0.05) and by the Smye method (1.47+/-0.36, P>0.05) were similar to eKt/V
      (1.42+/-0.30), but correlation between results from the rate equation and eKt/V
      (r=0.863) was higher than between those from the Smye method and eKt/V (r=0.654).
      Average absolute error of the rate equation in predicting eKt/V was 0.118+/-0.114
      (median 0.095) Kt/V units and 8.53%+/-8.36% (median 6.29%), while for the Smye
      method it was significantly higher [0.221+/-0.180 (median 0.190) Kt/V units,
      P=0.001; 16.49%+/-15.98% (median 11.88%) P=0.004]. High correlation between eKt/V
      and results from the rate equation indicates that urea rebound (expressed as
      delta Kt/V) is a function of the rate of dialysis (K/V). To test this, we
      analyzed the relationship of K/V and other parameters (session duration, body
      mass index, ultrafiltration rate, blood flow, and urea distribution volume) with
      delta Kt/V. The only significant (P<0.01) and highest correlation (r=0.442) was
      found for K/V. We conclude that in children on chronic HD, the rate equation is a
      better predictor of eKt/V than the Smye method, and that HD efficiency is the
      strongest determinant of postdialysis urea rebound in children.

PMID- 10412863
TI  - Hemodiafiltration for vancomycin overdose in a neonate with end-stage renal
      failure.
AB  - We describe continuous venovenous hemodiafiltration (CVVHD) with a high-flux
      membrane as a novel treatment modality for vancomycin overdose associated with
      renal insufficiency. CVVHD was used in a 6-day-old male with a solitary
      hypodysplastic kidney, suspected sepsis, and anuric renal failure who
      subsequently received an accidental tenfold overdose of vancomycin. We
      furthermore present evidence for the importance of countercurrent dialysis in
      addition to continuous hemofiltration for optimal vancomycin removal.

PMID- 10412864
TI  - Tubulointerstitial nephritis and uveitis in children and adolescents. Four new
      cases and a review of the literature.
AB  - We identified 35 cases of tubulointerstitial nephritis and uveitis (TINU), 31
      from a MEDLINE search (1966-1996) of the English literature and 4 from our
      hospital records (1988-1996). To meet the case definition, the patient had to be
      less than 18 years old and have TINU of unknown cause. Common presenting symptoms
      included fatigue, weight loss, fever, and abdominal pain. The uveitis was usually
      anterior and could occur at any time with respect to the onset of the renal
      disease. Common laboratory features included anemia, increased erythrocyte
      sedimentation rate, and decreased creatinine clearance. Most patients (33 of 35)
      had renal biopsies that commonly revealed an intense inflammatory interstitial
      infiltrate, glomerular sparing, and negative immunofluorescence studies. Of the
      35 patients, 26 received systemic corticosteroid therapy (5 of 26 for eye
      disease); 22 had follow-up for at least 1 year; 13 of 35 patients had a
      recurrence of their uveitis. The outcome in all 35 cases was normal renal
      function with no documented visual loss. In conclusion, TINU is a unique syndrome
      with characteristic clinical features, laboratory changes, and renal biopsy
      results. Treatment is controversial, and the outcome in children, even if
      untreated, is excellent.

PMID- 10412865
TI  - Hypercalciuria and recurrent urinary tract infection in Venezuelan children.
AB  - Recurrent urinary tract infection (UTI) has not been widely recognized as a
      clinical manifestation of hypercalciuria in children. We studied 59 children with
      two or more episodes of UTI, a normal urinary tract, and with hypercalciuria.
      Clinical manifestations were fever, dysuria, straining with micturition,
      hematuria, polyuria, abdominal pain, and failure to thrive. Urinary
      calcium/creatinine ratio was 0.36+/-0.15 mg/mg. Renal function studies included
      serum bicarbonate (21+/-3 mmol/l), urinary/blood PCO2 difference (11+/-11 mmHg),
      urinary net acid excretion (63+/-3 micromol/min per 1.73 m2), uric acid
      fractional excretion (13%+/-12%), and maximal urinary osmolality (920+/-236
      mosmol/kg). Treatment included promotion of fluid intake, avoiding excessive salt
      and protein, and keeping dietary calcium between 900 and 1,200 mg/day. Potassium
      citrate or hydrochlorothiazide were indicated if hypercalciuria persisted. With
      this treatment, in 95% of the children, no further episodes of UTI occurred once
      normocalciuria was achieved. It is possible that hypercalciuria may play a
      predisposing role for recurrent UTI in children by promoting the formation of
      microcrystals which damage the uroepithelium. We advocate the investigation of
      urinary calcium excretion in children with recurrent UTI and a normal urinary
      tract.

PMID- 10412866
TI  - Blood pressure nomograms for children and adolescents in Turkey.
AB  - In order to obtain data on blood pressure (BP) distribution in Turkish children,
      a total of 5,599 Turkish children from birth to 18 years were studied. BP rises
      with age, and both systolic and diastolic BP showed a positive correlation with
      height and weight in both sexes. As the sampling was representative of Turkish
      children at different ages, the mean systolic and diastolic BP levels were
      compared for each age with the results reported in the study of the Second Task
      Force. The mean systolic and diastolic BP of Turkish children and the increase
      with growth and development were different from the Second Task Force study.
      Genetic, ethnic, and environmental factors were suggested to be responsible for
      this variation. In conclusion, normal BP curves should be applied with caution in
      childhood, and every population should use their own normal standards to define a
      measured BP level in children.

PMID- 10412867
TI  - Membranous nephropathy associated with childhood sarcoidosis.
AB  - Sarcoidosis is a chronic multisystemic granulomatous disease of unknown etiology.
      It is relatively rare in children. Renal involvement in sarcoidosis is described
      less commonly than other organ involvement such as pulmonary, eye,
      musculoskeletal, and skin. We report a 13-year-old girl with sarcoidosis and
      nephrotic syndrome. Renal biopsy showed findings of membranous nephropathy. She
      received intravenous pulse methylprednisolone and oral cyclophosphamide with
      resolution of the symptoms of fever and edema, and improvement of the
      proteinuria. Her condition is stable with no progression of her renal disease. To
      the best of our knowledge, this is the first report of membranous nephropathy
      associated with childhood sarcoidosis.

PMID- 10412868
TI  - The alternative pathway C3 convertase and glomerular deposits.
AB  - Five conditions in which the alternative pathway C3 convertase, C3b,Bb,
      circulates in excess as a result of factor H dysfunction are frequently
      accompanied by nephritis. These convertase-related nephritides are seen in
      association with heterozygous absence of a binding site for factor H on C3b
      (Marder disease), homozygous factor H deficiency, circulating factor H inhibitor,
      and with the nephritic factors, one of the amplification loop and the other of
      the terminal pathway, found in membranoproliferative glomerulonephritis (MPGN)
      types II and III, respectively. Observations which relate convertase to
      glomerular deposits are: (1) in MPGN type II, subepithelial deposits on the
      paramesangial segments of the glomerular basement membrane are with high
      frequency present in patients hypocomplementemic at biopsy, but not in those
      normocomplementemic; (2) in MPGN type III paramesangial deposits are similarly
      found with hypocomplementemia but are present for up to 1 year after
      normocomplementemia is achieved; (3) in MPGN type III, subendothelial deposits
      are present only with hypocomplementemia. The principal deposits found in factor
      H deficiency and in Marder disease are also paramesangial. Differences in the
      incidence, severity, and morphology of the nephritides accompanying convertase in
      excess may relate to the characteristics of the circulating convertase and/or to
      the C3 conversion products formed by it.

PMID- 10412870
TI  - Urinary proteins in infancy and childhood.

PMID- 10412869
TI  - The role of the polycystins in kidney development.
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease
      that affects both adults and children. Renal cysts are the cardinal sign of the
      disease that also causes cysts in liver, pancreas, testis, and ovary, as well as
      cardiac valvular insufficiency and arterial aneurysms. At least three genes cause
      ADPKD in humans. PKD1 and PKD2 have been cloned and sequenced, both code for
      novel proteins. Analyses of their primary structures suggest that polycystin-1,
      the PKD1 gene product, is a receptor, while similarities between the polycystins
      and calcium channel subunits suggest that these proteins are subunits of a novel
      channel. Individuals with mutations in PKD1 or PKD2 have identical phenotypes,
      which present at a later age in PKD2 patients. Recent evidence suggests that the
      two polycystins interact, providing a biochemical basis for the similarity of
      disease caused by mutations in PKD1 and PKD2. Consistent with its protean
      manifestations, polycystin-1 is widely expressed in both epithelial and
      nonepithelial tissues during embryological development. Mice with targeted
      mutations of either the PKD1 or the PKD2 genes die during embryogenesis. Thus,
      the PKD genes are required for normal fetal development. The observation that
      loss of polycystin-1 or -2 function causes death during embryogenesis suggests
      that PKD1 and PKD2 might be part of a morphoregulatory pathway.

PMID- 10412871
TI  - Is renal ultrasound informative in the screening of asymptomatic newborns for
      reflux?

PMID- 10412873
TI  - Recalling Barnard and Kibel's hypothesis on hemolytic uremic syndrome.

PMID- 10412872
TI  - Angiotensin converting enzyme inhibitors and reflux nephropathy: 2-year follow
      up.

PMID- 10412874
TI  - Isolated microscopic hematuria--is it a disease state?

PMID- 10412875
TI  - Alcohol and hypertension--how are they linked?

PMID- 10412876
TI  - Calcium antagonists and safety: the turning of the tide.

PMID- 10412877
TI  - Selective increase of the contractile response to endothelin-1 in subcutaneous
      arteries from patients with essential hypertension.
AB  - Endothelin-1 has been shown to contribute to basal vascular tone in man. Since
      endothelin-1 is a potent vasoconstrictor putatively involved in hypertension, we
      have compared the contractile responses of endothelin-1 and noradrenaline in
      relation to potassium chloride in subcutaneous resistance arteries from subjects
      with established essential hypertension with matched controls. Furthermore, with
      RT-PCR, the occurrence of mRNA for the ETA and ET(B) receptors was shown in the
      tunica media layer of subcutaneous arteries in controls and hypertensives. The
      maximum contractile response to endothelin-1 was significantly higher in the
      subcutaneous arteries of the hypertensives (by 88% with no change in potency) as
      compared to controls. The responses to noradrenaline, acetylcholine and potassium
      chloride did not differ between the groups. This selective increase in the
      contractile response to endothelin-1 might contribute to the development of
      essential hypertension.

PMID- 10412878
TI  - Skeletal muscle angiotensin-converting enzyme and its relationship to blood
      pressure in primary hypertension and healthy elderly men.
AB  - The aim of this study was to investigate the relationships between angiotensin
      converting enzyme (ACE) activity in serum and skeletal muscle to blood pressure
      and the long-term antihypertensive effects of fosinopril and atenolol. We
      examined 50 hypertensive patients randomized to receive 20 mg fosinopril or 50 mg
      atenolol daily for 16 weeks. ACE activity was measured in biopsy specimens from
      skeletal muscle. Measurements of office and ambulatory blood pressure, serum ACE,
      and left ventricular wall thickness were also performed. The same investigations
      were performed in a cross-sectional study of 50 healthy elderly men. Muscle ACE
      correlated inversely to blood pressure in cross-sectional analyses in both
      populations (p < 0.05). During atenolol treatment muscle ACE activity tended to
      increase (14%, p = 0.059), and this increase correlated inversely to the changes
      in standing systolic and diastolic blood pressure (r = -0.62, p = 0.0044, and r =
      0.54, p = 0.016, respectively). Muscle ACE was also inversely correlated to left
      ventricular wall thickness when the two populations were pooled (r =-0.29, p =
      0.0053). In the fosinopril group, muscle ACE activity was not different during
      treatment than at baseline (-2. 1%, p = 0.68). The inverse relationship between
      blood pressure and muscle ACE levels in this study indicate that muscle tissue
      ACE levels are influenced by haemodynamic factors in humans.

PMID- 10412879
TI  - Associations of the angiotensinogen gene (M235T, T174M) and the angiotensin I
      converting enzyme gene (I/D) with blood pressure in Japanese workers.
AB  - Blood pressure may be influenced by several polymorphisms associated with
      hypertension, such as the angiotensinogen gene (M235T, T174M) and the angiotensin
      I-converting enzyme gene (I/D). We investigated the associations of these
      polymorphisms with blood pressure and components of the renin-angiotensin system
      in Japanese workers. Additionally, we examined whether the polymorphisms were
      independently associated with blood pressure when other factors were taken into
      consideration in a general linear model. The study population, which was entirely
      Japanese, consisted of 196 male subjects. Subjects were selected from workers who
      received a company health examination. Systolic blood pressure of the M235T MM
      genotype was significantly higher than that of the MT genotype. Diastolic blood
      pressure of the M235T MM genotype was significantly higher than that of the MT or
      TT genotypes. Serum ACE activity of the ACE II genotype was significantly lower
      than that of the ID or DD genotypes. Multivariate analysis using a general linear
      model, including age and body mass index, demonstrated that the M235T MM genotype
      was one of the independent factors affecting blood pressure. The present study
      demonstrated that the M235T MM genotype was independently associated with
      systolic blood pressure and diastolic blood pressure in Japanese male workers.

PMID- 10412880
TI  - Clinical, anthropometric, metabolic and insulin profile of men with fast annual
      growth rates of benign prostatic hyperplasia.
AB  - The purpose of this study was to test the hypothesis of a causal relationship
      between high insulin levels and the development of benign prostatic hyperplasia
      (BPH) and to determine the clinical, anthropometric, metabolic and insulin
      profile in men with fast-growing BPH compared with men with slow-growing BPH. The
      present study was designed as a risk factor analysis of BPH in which the
      estimated annual BPH growth rate was related to components of the metabolic
      syndrome. Two hundred and fifty patients referred to the Urological Section,
      Department of Surgery, Central Hospital, Varberg, Sweden, with lower urinary
      tract symptoms with or without manifestations of the metabolic syndrome were
      consecutively included. The prevalences of atherosclerotic disease
      manifestations, non-insulin-dependent diabetes mellitus (NIDDM) and treated
      hypertension were obtained. Data on blood pressure, waist and hip measurement,
      body height and weight were collected and body mass index (BMI) and waist/hip
      ratio (WHR) were calculated. Blood samples were drawn from fasting patients to
      determine insulin, total cholesterol, triglycerides, HDL and LDL cholesterol,
      uric acid, alanine aminotransferase (ALAT) and prostate-specific antigen (PSA).
      The prostate gland volume was determined using ultrasound. The median annual BPH
      growth rate was 1.04 ml/year. Men with fast-growing BPH had a higher prevalence
      of NIDDM (p = 0.023) and treated hypertension (p = 0.049). These patients were
      also taller (p=0.004) and more obese as measured by body weight (p<0.001), BMI
      (p=0.026), waist measurement (p <0.001), hip measurement (p = 0.006) and WHR
      (p=0.029). Moreover, they had elevated fasting plasma insulin levels (p = 0.018)
      and lower HDL cholesterol levels (p = 0.021) than men with slow-growing BPH. The
      annual BPH growth rate correlated positively with diastolic blood pressure (rs =
      0.14; p = 0.009), BMI (rs = 0.24; p < 0.001) and four other expressions of
      obesity and fasting plasma insulin level (rs = 0.18; p = 0.008), and negatively
      with the HDL cholesterol level (rs = -0.22; p = 0.001). In conclusion, the data
      suggest that NIDDM, hypertension, tallness, obesity, high insulin and low HDL
      cholesterol levels constitute risk factors for the development of BPH. The
      results also suggest that BPH is a component of the metabolic syndrome and that
      BPH patients may share the same metabolic abnormality of a defective insulin
      mediated glucose uptake and secondary hyperinsulinaemia, as patients with the
      metabolic syndrome. The findings support the hypothesis of a causal relationship
      between high insulin levels and the development of BPH, and give rise to a
      hypothesis of increased sympathetic nerve activity in men with BPH.

PMID- 10412881
TI  - Effects of propranolol on cardiovascular and neurohumoral actions of alcohol in
      hypertensive patients.
AB  - Alcohol ingestion acutely lowers blood pressure (BP) with vasodilation and
      sympathetic activation in Oriental subjects. We examined the effects of beta
      blockade on cardiovascular and neurohumoral actions of alcohol in Japanese men
      with mild-to-moderate essential hypertension. Ten hypertensive patients (54+/-5
      years, mean+/-SE) were given 1 ml/kg of alcohol or isocaloric control drink with
      a light meal in the evening before and 5-7 days after treatment with propranolol
      (20 mg three times daily). BP and heart rate (HR) were measured every 30 min for
      24 h in each period. Blood sampling and echocardiographic examination were
      carried out before (17.00 h) and after (19.00 h) intake of alcohol or control
      drink, Before treatment, alcohol ingestion caused significant decreases in BP,
      total peripheral resistance and serum potassium concentration, while it increased
      heart rate (HR), cardiac output (CO), plasma norepinephrine and plasma renin
      activity (PRA). Treatment with propranolol significantly decreased BP and HR for
      24 h. Propranolol and alcohol showed an additive depressor effect on night-time
      BP, and the alcohol-induced hypotension was similar before and after propranolol
      treatment. The alcohol-induced changes in HR, CO, PRA and serum potassium were
      significantly attenuated by propranolol. These results suggest that activation of
      the sympathetic nervous system plays a role in alcohol-induced cardiac
      stimulation, renin release and hypokalemia through beta receptors. Moderate doses
      of beta-blockers may not modify alcohol-induced BP reduction in Oriental subjects
      with hypertension.

PMID- 10412882
TI  - Prolonged antihypertensive effect of amlodipine: a prospective double-blind
      randomized study.
AB  - Amlodipine is a calcium antagonist with a long elimination half-life (35 to 50 h)
      allowing a once daily dosing in the treatment of hypertension. This randomized,
      double-blind study was performed to assess the residual antihypertensive effect
      of amlodipine 5 mg O.D. 3 days after discontinuing therapy in previously well
      controlled mild to moderate hypertensive patients. Blood pressure (BP) was
      evaluated by conventional (OBP) and by ambulatory blood pressure monitoring
      (ABPM). Amlodipine 5 mg OD administered during a 6-week period, significantly
      reduced both OBP and ABPM mean values (p < 0.05), whereas no change in heart rate
      was observed. At the end of the active treatment period, adequately controlled
      patients were randomized either to amlodipine 5 mg OD (group A) or amlodipine for
      12 days followed by a 3-day period on placebo. After this double-blind treatment
      phase, group P exhibited no significant increase in BP (assessed by OBP or ABPM)
      when compared to group A. In conclusion, the duration of action of amlodipine
      extends largely beyond the 24-h span, and when patients omit their treatment for
      3 days BP does not significantly increase.

PMID- 10412883
TI  - Effects of ACE inhibition on cyclosporine A-induced hypertension and
      nephrotoxicity in spontaneously hypertensive rats on a high-sodium diet.
AB  - Cyclosporine A (CsA)-induced hypertension has been shown to be dependent on the
      level of dietary salt. The present study assessed the role of the renin
      angiotensin system in the development of CsA-induced hypertension and
      nephrotoxicity in spontaneously hypertensive rats (SHR) on a high-sodium diet. In
      addition, we examined whether ACE inhibition prevents the detrimental effects of
      CsA on blood pressure, kidney function and vascular morphology in SHR on high
      sodium intake. Eight-week-old SHR were divided into three different groups (n = 8
      in each group): (i) SHR control group receiving a high-sodium diet (Na 2.6% of
      the dry weight of the chow), (ii) CsA group (5 mg/kg s.c.) on a high-sodium diet
      and (iii) CsA + enalapril group (30 mg/kg p.o.) on a high-sodium diet. At the end
      of the six-week experimental period, systolic blood pressure in the CsA group was
      significantly higher compared to the control group (245+/-6 vs 208+/-9 mmHg,
      respectively, p < 0.05). Plasma renin activity was increased 20-fold by CsA
      treatment (p < 0.05 compared to controls). CsA increased serum creatinine by 22%,
      the 24-h urinary protein excretion by 190% and the 24-h urinary excretions of
      calcium, phosphorus and magnesium by 150%, 25% and 140%, respectively (p < 0.05
      compared to controls). Histologically, the kidneys of CsA-treated SHR showed
      severe thickening of the media of the afferent arteriole and fibrinoid necrosis
      of the arteriolar wall. Interestingly, CsA induced vascular injury also in the
      small myocardial arteries. Enalapril treatment prevented CsA-induced hypertension
      and deterioration of kidney function as well as CsA-induced vascular injuries in
      the kidneys and myocardium. Enalapril also decreased left ventricular weight-to
      body weight ratio and prevented CsA-induced increases in urinary calcium and
      phosphorus excretions. Our findings indicate that CsA has a detrimental effect on
      blood pressure, kidney function and vascular morphology in SHR on high sodium
      intake. ACE inhibition prevents the CsA-induced hypertension, nephrotoxicity and
      vascular injuries. Our findings thus suggest that increased activity of the renin
      angiotensin system is involved in the pathogenesis of CsA-induced hypertension
      and nephrotoxicity in SHR on a high-sodium diet.

PMID- 10412884
TI  - Extracellular matrix gene expression in the left ventricular tissue of
      spontaneously hypertensive rats.
AB  - The aim of this study was to investigate the extracellular matrix gene expression
      in the hypertrophied left ventricular tissue of spontaneously hypertensive rats
      (SHR) and Wistar-Kyoto (WKY) rats, at early and mature ages. Interestingly, with
      age, a marked increase (+85% and +187% at 25 and 30 weeks of age, respectively, p
      < 0.01, vs 5 weeks) in matrix metalloproteinase-1 (MMP-1) mRNA levels in SHR and
      a progressive decrease (-50%, -70%, -78%, -70% at 10, 15, 25 and 30 weeks,
      respectively, p < 0.01, vs 5 weeks) in WKY were seen. Moreover, mRNA levels were
      significantly lower in SHR at 5 weeks. The analysis of mRNA expression for the
      tissue inhibitor of metalloproteinase-1 (TIMP-1) showed a significant increase in
      WKY (+44% and +44%, vs 15 and 25 weeks, respectively, p < 0.05), whereas there
      were no significant changes in SHR with development. At 30 weeks TIMP-1 mRNA
      levels were significantly reduced in SHR. Temporal trends of procollagen
      alpha1(I) and procollagen alpha1(III) mRNA levels were similar in both strains,
      but lower levels for procollagen alpha1(III) were found in SHR at 5 and 30 weeks.
      Although no significant differences were measured between the strains, mRNA
      levels for fibronectin were found decreased in WKY and increased in SHR with age.
      The results of the present study suggest an altered balance between collagen
      deposition and collagen degradation with development in this model of left
      ventricular hypertrophy and hypertension.

PMID- 10412885
TI  - Pharmacokinetics of midazolam: comparison of sublingual and intravenous routes in
      rabbit.
AB  - In France, the legal routes used to administer midazolam to a patient are
      intravenously and intramuscularly. For anaesthetists, these routes are not well
      adapted to paediatric use; they lead to pain at injection site and stress on
      children. The sublingual route should be a good compromise between stress and
      quick efficiency. We have developed a sublingual tablet of midazolam. The aim of
      the present investigation is to compare the pharmacokinetic parameters of
      midazolam tablets administered by the sublingual and intravenous routes in 6
      rabbits to determine the bioequivalence between these routes. We have estimated
      the 1-hydroxy-midazolam serum level by difference between RRA and HPLC values. By
      the sublingual route, midazolam absorption is substantial and fast. The
      statistical analysis, on data obtained with HPLC dosage, shows no significant
      difference between pharmacokinetic parameter values calculated after intravenous
      and sublingual administration (0.5 mg). The absolute bioavailability was close to
      100%. With RRA dosage, however, AUCs were greater than those obtained by HPLC
      dosage (174%). 1-hydroxy-midazolam seems to have a great importance in BZD
      activity. To estimate the bioequivalence between intravenous and sublingual
      midazolam administration, it is necessary to take into account the active
      metabolites.

PMID- 10412886
TI  - Heterogeneity of paracetamol metabolism in Gilbert's syndrome.
AB  - Gilbert's syndrome (GS) is an inherited bilirubin UDP-glucuronosyl transferase
      deficiency. The object of this study was to investigate the possible effects of
      this disorder on the metabolism of a drug, such as paracetamol, which is
      basically eliminated by hepatic glucuronidation. We studied 32 healthy volunteers
      and 18 people with GS, all of whom were given 1.5 g of paracetamol orally. In the
      24 h urine collected, we determined the elimination of free paracetamol, the
      conjugates (glucuronide, sulphate) and the oxidation products (cysteine,
      mercapturic acid) by high pressure liquid chromatography (HPLC). The results are
      given as a percentage of the total quantity of paracetamol eliminated. The
      patients with GS were divided into 2 subgroups (GS-I and GS-II) according to
      whether glucuronidation was more or less than 50%. The overall results of the GS
      group showed no significant difference in the urinary elimination of metabolites
      as compared to the control group. However, in subgroup GS-I, a reduction in
      glucuronidation (P = 0.0012) and an increase in oxidation (P = 0.0051) was seen,
      as compared with the other 2 groups. There was inverse correlation between the
      glucuronide produced by conjugation and the oxidation products (r = -0.8718;
      P<0.005). People with GS are a heterogeneous group with respect to the metabolism
      of paracetamol. In one subgroup this was normal. In the other subgroup there was
      a marked reduction in glucuronidation and an increase in oxidation. These changes
      could mean that people in this subgroup are more liable to liver damage after an
      overdose of paracetamol.

PMID- 10412888
TI  - Pharmacokinetics of 2-methoxyphenylmetyrapone and 2-bromophenylmetyrapone in
      rats.
AB  - The pharmacokinetics of two 2-substituted phenylmetyrapone analogues, 2
      methoxyphenylmetyrapone (2-MPMP) and 2-bromophenylmetyrapone (2-BrPMP), developed
      as potential adrenal imaging agents, were investigated in conscious male rats
      following an intravenous dose of 25 mg/kg. Arterial blood samples (0.25 ml) were
      collected at various intervals for up to 7 h after dose and subjected to reversed
      phase HPLC analysis. Blood concentrations versus time profile for each compound
      was determined and the pharmacokinetic parameters calculated using the model
      independent approach. Blood concentrations of 2-MPMP declined biexponentially
      with mean initial (t1/2alpha) and terminal (t1/2beta) half-lives of 3.6 and 23.1
      min, respectively. The corresponding area under the curve (AUC(0-infinity)) was
      159.3 microg x min/ml, the total blood clearance (CI) was 158.3 ml/min and the
      volume of distribution (Vd) was 5.2 l. Two metabolites of 2-MPMP, namely 2
      hydroxyphenylmetyrapone (2-OHPMP) and 2-methoxyphenylmetyrapone N-oxide (2-MPMP
      NO), were detected in the blood and their elimination from blood was almost
      parallel to that of the parent compound. The maximum blood concentrations (Cmax)
      of 2-OHPMP and 2-MPMP-NO were approximately 0.9 and 1.7 microg/ml, respectively.
      Blood concentrations of 2-BrPMP declined monoexponentially with a mean t1/2beta
      of 12.0 min. The pharmacokinetic parameters for 2-BrPMP were: AUC(0-infinity),
      193.7 microg x min/ml; Cl, 131.7 ml/min and Vd, 2.3 l. 2-Bromophenylmetyrapone N
      oxide was the only one metabolite detected in the blood, its Cmax and AUC0
      infinity were 10.1 microg/ml and 1690.0 microg x min/ml, respectively.

PMID- 10412889
TI  - Influence of diet on the pattern of gastrointestinal biotransformation of
      netobimin and albendazole sulphoxide in sheep.
AB  - The in vitro biotransformation of the anthelmintic compounds, netobimin (NTB) pro
      drug and albendazole sulphoxide (ABZSO), by ruminal fluid obtained from sheep fed
      either hay or concentrate-based diets was investigated. No metabolic activity was
      observed in boiled samples of ruminal fluid, which confirms the importance of
      ruminal microflora in the metabolism of the xenobiotics under investigation. NTB
      pro-drug was efficiently biotransformed by ruminal fluid in vitro. Albendazole
      (ABZ) and its sulphoxide derivative were the metabolic products recovered. The
      thioether ABZ was formed by sulphoreduction of ABZSO by ruminal fluid in vitro. A
      more efficient nitroreduction of NTB and sulphoreduction of ABZSO were observed
      for ruminal fluid collected from sheep fed the concentrate diet. The type of diet
      determines the composition and distribution of the microbial population in the
      rumen; this affects the pattern of drug biotransformation in the gastrointestinal
      tract, which may impact on drug therapy.

PMID- 10412887
TI  - Microsomal metabolism of quinifuryl--a nitrofuryl-ethenyl-quinolone antiseptic
      possessing antitumor activity in vitro.
AB  - Quinifuryl, 2-(5'-nitro-2'-furanyl)ethenyl-4-[N-[4'-(N,N-diethylamino)-1'
      methylbuty l] carbamoyl] quinoline, is a representative of a family of nitrofuran
      ethenyl-quinoline antibiotics synthesized in the USSR by Dr N.M. Sukhova. The
      drug has been shown to be an effective cytostatic and radiosensitizer towards
      cancer cells in culture. While rapid metabolic consumption of these drugs by
      liver tissue has been shown, none of the drug metabolites have been isolated and
      characterized. Here, we present the results of experiments focusing on the
      isolation and characterization of quinifuryl metabolites. A pyridine derivative
      was the sole product detected and characterized by GC-MS analysis. An alteration
      of quinifuryl metabolism by peroxynitrite formed during the metabolism of the
      drug was assumed to be responsible for an unexpectedly high drug decomposition.

PMID- 10412890
TI  - A population approach to the forecasting of amikacin plasma and urinary levels
      using a prescribed dosage regimen.
AB  - We retrospectively analyzed amikacin pharmacokinetics in 19 critically ill
      patients who received amikacin intravenously. Fourteen subjects (577 serum
      amikacin concentrations, 167 urine measurements) were studied to obtain data for
      population modeling, while 5 patients (267 serum amikacin concentrations, 68
      urine measurements) were studied for the assessment of predictive performance.
      The population analysis was performed using serum and urine amikacin
      measurements; the renal clearance of amikacin was expressed as a function of
      creatinine clearance. A two-compartment model was fitted to the population data
      by using NONMEM. The population characteristics of the pharmacokinetic parameters
      (fixed and random effects) were estimated using the FOCE method. The population
      pharmacokinetic parameters with the interindividual variability (CV%) were as
      follows: slope (0.254, 126%) and intercept (3 l/h, 59.6%) of the linear model
      which relate the amikacin renal clearance to the creatinine clearance, initial
      volume of distribution (17.1 l, 22.2%), intercompartment clearance (5.22 l/h,
      104%), steady state volume of distribution (55.2 l, 64.1%) and urinary
      elimination (67.5%, 36.3%). The Bayesian approach developed in this study
      accurately predicts amikacin concentrations in serum and urine and allows for the
      estimation of amikacin pharmacokinetic parameters, minimizing the risk of bias in
      the prediction.

PMID- 10412891
TI  - Bioequivalence assessment of three different estradiol formulations in
      postmenopausal women in an open, randomized, single-dose, 3-way cross-over study.
AB  - OBJECTIVE: The aim of the study was to assess the bioavailability of estradiol
      (E2) following oral, single-dose administration of equimolar doses of three HRT
      preparations in a 3-way cross-over study in postmenopausal women. METHODS: 18
      healthy subjects were enrolled. Free E2 and estrone (E1) serum concentrations
      were determined using commercially available immunoassay kits. Bioequivalence
      testing was performed between the following oral formulations: (a) 1.5 mg E2
      tablets versus 2 mg E2V tablets; and (b) 1.5 mg E2 plus 0.15 mg DSG tablets
      versus 1.5 mg E2 tablets. RESULTS: For both E2 and E1 the E2 tablet was
      bioequivalent with both the E2V and the E2/DSG tablet with respect to the rate
      and extent of absorption (bioavailability). Although the mean tmax values of the
      three tablet formulations were similar, the variability was too large to prove
      formal bioequivalence. CONCLUSION: E2 tablets and E2/DSG tablets were
      bioequivalent and also bioequivalence of E2 tablets with commercially available
      E2V was found, which ensures a sequential HRT preparation without large
      variations in estrogen serum concentrations.

PMID- 10412892
TI  - Formulation of controlled release microspheres containing nicardipine: the role
      of pharmacokinetic modeling and computer simulation.
AB  - Nicardipine is an antihypertensive drug of the dihydropyridine series. It has
      high solubility in an acidic and low solubility in an alkaline medium. It is
      rapidly absorbed, extensively presystemically metabolized and excreted in the
      urine and faeces, mainly as inactive metabolites. Since the duration of its
      action can be extended by prolonging the absorption interval, the design of
      controlled release formulation is reasonable. The aim of the present study was to
      prepare microspheres which would release nicardipine at a decreased rate in
      gastric and increased rate in intestinal juice during a 12 h interval.
      Pharmacokinetic modeling based on compartment analysis and supported by analog
      computer and digital simulation technique showed that the target steady state
      peak plasma concentrations of 32 microg/l and trough plasma concentration of 7
      microg/l would be maintained if nicardipine were incorporated in a formulation
      releasing the drug as follows: 25% after 1 h, 40% after 2 h, 65% after 4 h, 80%
      after 6 h, 90% after 8 h and 100% by 12 h. Microspheres have been prepared from
      hydroxypropylmethylcellulose phthalate polymer using the solvent evaporation
      method. Drug content, scanning electron micrographs, particle size distribution
      and dissolution profile were determined. In vitro nicardipine release was
      described by a biphasic square root of time kinetics and was in accordance with
      the above values relating to the dissolution. Furthermore, a composed first-pass
      pharmacokinetic model with derived release function as an input was developed to
      predict nicardipine plasma concentrations after single- and 12 h multiple-dosage
      regimen scheme administration of controlled release microspheres.

PMID- 10412893
TI  - Interaction of chlormezanone enantiomers with rat liver microsomes.
AB  - Both chlormezanone enantiomers, for the first time obtained by enantiospecific
      HPLC with a 100% yield, bind to oxidized cytochrome P-450 in rat liver microsomes
      with a binding curve according to type I, similar to hexobarbital but less
      pronounced. There are no differences between the binding curves of the two
      enantiomers. Ethylmorphine N-demethylation, ethoxycoumarin and ethoxyresorufin O
      deethylation are inhibited by both chlormezanone enantiomers at 0.1-1 mM
      concentrations: no differences could be found. Luminol and lucigenin amplified
      chemiluminescence indicating the formation of reactive oxygen species was not
      influenced by either enantiomer in concentration ranges between millimolar and
      micromolar, whereas hydrogen peroxide formation was inhibited. NADPH/Fe
      stimulated lipid peroxidation was not influenced. Scavenger activity could not be
      demonstrated: the zymosan stimulated whole blood chemiluminescence was not
      influenced significantly.

PMID- 10412895
TI  - Pharmacokinetic interaction of Diabecon (D-400) with rifampicin and nifedipine.
AB  - In the present study, Diabecon (D-400), a herbomineral anti-diabetic preparation,
      was studied for its pharmacokinetic interaction with the commonly used drugs
      rifampicin and nifedipine. Interaction of Diabecon with rifampicin: The
      pharmacokinetic interaction of rifampicin and Diabecon (D-400) was studied in
      animal models as well as in healthy human volunteers. Twelve rabbits were divided
      into two groups of six each. Animals in group I were treated with rifampicin (100
      mg/kg body weight, p.o.) and group II with rifampicin (100 mg/kg body weight,
      p.o.) and Diabecon (D-400) (1 g/kg body weight, p.o.) for a period of 8 days.
      Rifampicin levels in plasma were estimated on day 1 and day 8 at 2, 4, 6 and 8 h
      after drug administration. On the basis of these findings, a clinical study in 9
      healthy human volunteers aged 25-35 years and weighing 50-75 kg was initiated.
      They were given 450 mg of rifampicin once only on day 1 and from the second day
      onwards were given 2 tablets of Diabecon (D-400) twice daily for 7 days. On day
      9, another dose of rifampicin (450 mg) was given along with 2 tablets of Diabecon
      (D-400). Blood samples were collected at 2, 4, 6 and 8 h after drug
      administration on day 1 and day 9 to estimate the rifampicin levels in plasma.
      Interaction of Diabecon with nifedipine: In another study, 12 rabbits were
      divided into two groups of 6 each. Group I animals were treated with nifedipine
      (2.5 mg/kg body weight, p.o.) and Group II animals were treated with nifedipine
      (2.5 mg/kg body weight, p.o.) and Diabecon (D-400) (1 g/kg body weight, p.o.) for
      a period of 8 days. On day 1 and day 8, blood samples were collected at 1, 2, 4
      and 6 h after drug administration and plasma nifedipine levels were estimated.
      The results of these three studies revealed that Diabecon (D-400) did not alter
      the pharmacokinetic profiles of rifampicin and nifedipine.

PMID- 10412894
TI  - Comparative open, randomized, cross-over bioequivalence study of two intravenous
      dexrazoxane formulations (Cardioxane and ICRF-187) in patients with advanced
      breast cancer, treated with 5-fluorouracil-doxorubicin-cyclophosphamide (FDC).
AB  - The purpose of this study was to compare the pharmacokinetic disposition of two
      intravenous dexrazoxane formulations, and their effects on doxorubicin's kinetics
      and metabolism. Plasma concentration versus time curves and pharmacokinetic
      parameters of dexrazoxane given as Cardioxane (dexrazoxane hydrochloride salt)
      and ICRF-187 reference formulation (dexrazoxane base) were determined and
      compared. Both formulations were administered as a single intravenous infusion
      prior to 5-fluorouracil-doxorubicin-cyclophosphamide administration. In addition,
      the pharmacokinetics of doxorubicin and its metabolites were studied after
      dexrazoxane administration. A total of 15 patients with advanced breast cancer
      participated in this open, randomized, cross-over study and 12 patients were
      evaluable. Plasma concentrations of dexrazoxane, doxorubicin and doxorubicin
      metabolites were determined by high-performance liquid chromatography in samples
      obtained in the 72 h after drug administration. No statistically significant
      differences were found in the tested kinetic parameters when the two products
      were compared by analysis of variance (ANOVA) on log-transformed data. Cardioxane
      fulfilled the bioequivalence criteria when compared with ICRF-187 reference
      formulation for all of the investigated parameters (AUC, t1/2beta, Vdss, Cl(tot),
      Cl(ren)). The parametric 90% confidence intervals were contained within the
      bioequivalence interval (0.8-1.25). Pharmacokinetic parameters and metabolism of
      doxorubicin were not different after the administration of either Cardioxane or
      ICRF-187 formulation. From the results of this study it can be concluded that the
      two formulations can be considered bioequivalent with regard to extent of
      absorption (AUC and Vdss) and elimination (t1/2beta, Cl(tot) and Cl(ren)).

PMID- 10412896
TI  - Isolation, identification and immunosuppressive activity of SDZ-IMM-125
      metabolites from human liver microsomes.
AB  - SDZ-IMM-125 N-methyl leucine 9 hydroxylated in the gamma position is a metabolite
      which was extracted from incubated human liver microsomes and subsequently
      separated by normal and reverse-phase HPLC. This metabolite was identified by
      fast atom bombardment mass spectrometry, electrospray-ms/ms mass spectrometry and
      nuclear magnetic resonance spectroscopy. The in vitro 50% inhibitory
      concentration, tested against bidirectional mixed lymphocyte reaction was 80
      microg/l indicating that this metabolite does not retain in vitro
      immunosuppressive activity most probably due to the structural modification of
      SDZ-IMM-125 in the recognized binding region to cyclophilin A reducing its
      binding affinity relative to the parent drug.

PMID- 10412897
TI  - Effect of tacrine hydrochloride on hepatic drug metabolism.
AB  - The aim was to assess tacrine hydrochloride (THA) as an inhibitor of rat hepatic
      oxidative enzymes. A model of hepatic microsome oxidative metabolism was
      established using antipyrine (AP) incubated with NADPH. AP and its metabolites, 3
      hydroxymethyl antipyrine (HMA). 4-hydroxy antipyrine (OHA) and norantipyrine
      (NORA) were measured by high performance liquid chromatography (HPLC). Aliquots
      of 200, 400 and 600 microg/ml antipyrine were incubated with the microsomal
      preparation alone, with 20 microg/ml cimetidine or with 40, 80 or 200 microg/ml
      THA. Cimetidine inhibited HMA production by 35-38% (P<0.001) and OHA production
      by 49-52% (P<0.001). Incubation with the 3 concentrations of THA inhibited HMA
      production by 17%, 24% and 41% (P<0.001) and OHA production by 52%, 55% and 79%,
      respectively (P<0.001). NORA was identifiable when antipyrine was incubated with
      NADPH alone, but could not be identified after incubation with either cimetidine
      or THA. This study has shown that THA causes the inhibition of AP metabolism to
      HMA, OHA and possibly NORA. We suggest THA is an inhibitor of three different
      hepatic microsomal cytochrome P-450 enzyme sub-families.

PMID- 10412898
TI  - Valproate metabolites in the rat brain--regional distribution in various brain
      areas.
AB  - To investigate the regional distribution of valproic acid (VPA) and 10 of its
      metabolites in the rat brain, the animals were treated with 300 mg/kg/day VPA
      i.p. on a 3 times daily dose regimen for 5 days, and the concentrations of the
      compounds in serum and 15 brain regions were measured. 2-(n-propyl)-(Z)-2
      pentenoic acid [(Z)-2-en], a VPA metabolite expected to possess neurotoxic
      potency in humans, was determined in brain tissue for the first time. The
      brain/serum concentration ratio of (Z)-2-en was found to be about 14-fold higher
      than the ratio for its (E)-isomer, thereby demonstrating the influence of the
      double-bond configuration in the unsaturated metabolites on their ability to
      penetrate into the central nervous system. The concentrations of VPA and its
      metabolites in the brain regions were compared to c(hom), the calculated
      concentration for an assumed homogeneous distribution. The parent drug and its
      metabolites exhibited individual distribution patterns with varying degrees of
      inhomogeneity. Elevated metabolite concentrations were found especially in the
      motorium and the medulla oblongata. Decreased concentrations of VPA and several
      metabolites were found in the visual cortex.

PMID- 10412899
TI  - Stereoselective de-ethylation of chloroquine in rat liver microsomes.
AB  - A qualitative kinetic study on the stereoselective hepatic metabolism of
      chloroquine was undertaken by separately incubating chloroquine enantiomers with
      rat liver microsomes. The dependency of desethylchloroquine formation on NADPH
      suggests a cytochrome P-450 isozyme catalysed metabolism. Over a wide
      concentration range (1-300 microM), chloroquine metabolism appeared not to follow
      simple Michaelis-Menten kinetics. The enantiomeric ratio (R/S) of
      desethylchloroquine was dependent on concentration, and ranged from 8 at 1 microM
      to 1 at 300 microM. Mutual enantiomer--enantiomer interaction studies at low
      concentration (1-5 microM) revealed that the formation of (R)-desethylchloroquine
      was strongly inhibited by (S)-chloroquine. The findings of the present study
      support the hypothesis that a high-affinity/low capacity enzyme is capable of
      stereoselective discrimination. At this point, it remains to be proven whether
      stereoselective metabolism and enantiomer-enantiomer interactions affect the in
      vivo disposition of chloroquine.

PMID- 10412900
TI  - Characterization, subcellular localization and nuclear targeting of casein kinase
      2 from Zea mays.
AB  - We have isolated and characterized the genomic clone of maize casein kinase 2
      (CK2) alpha subunit using the previously described alphaCK2-1 cDNA clone as a
      probe. The genomic clone is 7.5 kb long and contains 10 exons, separated by 9
      introns of different size, two larger than 1.5 kb and the others around 100-150
      bp. The sequence of the exons is 100% homologous to the sequence of the alphaCK2
      1 cDNA. Southern hybridization of total genomic DNA from maize embryos with aCK2
      cDNA indicated that the alphaCK2-1 gene is part of a multigenic family. We also
      isolated a new embryo cDNA clone coding for an alphaCK2-2 subunit. We studied the
      regulation of the enzyme in embryos at the mRNA level, at the protein level and
      by activity testing. By using immunocytochemistry the CK2 protein was localized
      in several types of cells of mature embryos. Particularly strong signals were
      visible in the cytoplasm of epidermis and meristematic cells. Decoration of
      nuclei of root cortex and scutellum cells was also observed suggesting that CK2
      can shift from the cytoplasm into nuclei in specific cell types. We examined
      whether CK2 contained specific protein domains which actively target the protein
      to the nucleus by using in-frame fusions of the maize CK2alpha subunit to the
      reporter gene encoding beta-glucuronidase (GUS) which were assayed in transiently
      transformed onion epidermal cells. Analysis of chimeric constructs identified one
      region containing a nuclear localization signal (NLS) that is highly conserved in
      other alphaCK2 proteins.

PMID- 10412901
TI  - Transgenic tomato plants with decreased sucrose synthase are unaltered in starch
      and sugar accumulation in the fruit.
AB  - Sucrose is the photoassimilate transported from the leaves to the fruit of tomato
      yet the fruit accumulates predominantly glucose and fructose. Hydrolysis of
      sucrose entering the fruit can be accomplished by invertase or sucrose synthase.
      Early in tomato fruit development there is a transient increase in sucrose
      synthase activity and starch which is correlated with fruit growth and sink
      strength suggesting a regulatory role for sucrose synthase in sugar import. Using
      an antisense sucrose synthase cDNA under the control of a fruit-specific promoter
      we show that sucrose synthase activity can be reduced by up to 99% in young fruit
      without affecting starch or sugar accumulation. This result calls into question
      the importance of sucrose synthase in regulating sink strength in tomato fruit.

PMID- 10412902
TI  - Selectable marker-free transgenic plants without sexual crossing: transient
      expression of cre recombinase and use of a conditional lethal dominant gene.
AB  - Transgenic tobacco plants were produced that contained single-copy pART54 T-DNA,
      with a 35S-uidA gene linked to loxP-flanked kanamycin resistance (nptII) and
      cytosine deaminase (codA) genes. Retransformation of these plants with pCre1
      (containing 35S transcribed cre recombinase and hygromycin (hpt) resistance
      genes) resulted in excision of the loxP-flanked genes from the genome. Phenotypes
      of progeny from selfed-retransformed plants confirmed nptII and codA excision and
      integration of the cre-linked hpt gene. To avoid integration of the hpt gene, and
      thereby generate plants totally free of marker genes, we attempted to transiently
      express the cre recombinase. Agrobacterium tumefaciens (pCre1) was cocultivated
      with leaf discs of two pART54-transformed lines and shoots were regenerated in
      the absence of hygromycin selection. Nineteen of 773 (0.25%) shoots showed
      tolerance to 5-fluorocytosine (5-fc) which is converted to the toxic 5
      fluorouracil by cytosine deaminase. 5-fc tolerance in six shoots was found to be
      due to excision of the loxP-flanked region of the pART54 T-DNA. In four of these
      shoots excision could be attributed to cre expression from integrated pCre1 T
      DNA, whereas in two shoots excision appeared to be a consequence of transient cre
      expression from pCre1 T-DNA molecules which had been transferred to the plant
      cells but not integrated into the genome. The absence of selectable marker genes
      was confirmed by the phenotype of the T1 progeny. Therefore, through transient
      cre expression, marker-free transgenic plants were produced without sexual
      crossing. This approach could be applicable to the elimination of marker genes
      from transgenic crops which must be vegetatively propagated to maintain their
      elite genotype.

PMID- 10412903
TI  - Identification of senescence-associated genes from daylily petals.
AB  - The petals of daylily (Hemerocallis hybrid) have a genetically based program that
      leads to senescence and cell death ca. 24 h after the flower opens. In order to
      determine the components of this program, six cDNAs, whose levels increase during
      petal senescence, were isolated and sequenced and designated DSA3, 4, 5, 6, 12
      and 15. All six DSAs are members of gene families and all but DSA5 and DSA6 have
      one to three other very similar genes. GenBank database homology searches
      indicate that DSA3 is most similar at the amino acid level to an in-chain fatty
      acid hydroxylase which is bound to cytochrome P450, DSA4 may be an aspartic
      proteinase, DSA5 is as yet unidentified, DSA6 is a putative S1-type nuclease,
      DSA12 is very similar to a cytochrome P450-containing allene oxide synthase, and
      DSA15 may be a fatty acid elongase. Except for DSA12, the genes are expressed at
      low levels in daylily roots. Levels of the DSA mRNAs in leaves are less than 4%
      of the maximum detected in petals, and there are no clear differences between
      younger and older leaves. With the exception of DSA4, accumulation of the DSA
      mRNAs is increased 3.2 to 43 times by a concentration of abscisic acid that
      causes premature senescence of the petals. The relationship of the putative DSA
      gene products to senescence and cell death of daylily petals is discussed.

PMID- 10412904
TI  - Upstream and downstream sequence elements determine the specificity of the rice
      tungro bacilliform virus promoter and influence RNA production after
      transcription initiation.
AB  - The contribution of sequences upstream and downstream of the transcription start
      site to the strength and specificity of the promoter of rice tungro bacilliform
      virus was analysed in transgenic rice plants. The promoter is strongly stimulated
      by downstream sequences which include an intron and is active in all vascular and
      epidermal cells. Expression in the vascular tissue requires a promoter element
      located between -100 and -164 to which protein(s) from rice nuclear extracts
      bind. Elimination of this region leads to specificity for the epidermis. Due to
      the presence of a polyadenylation signal in the intron, short-stop RNA is
      produced from the promoter in addition to full-length primary transcript and its
      spliced derivatives. The ratio between short-stop RNA and full-length or spliced
      RNA is determined by upstream promoter sequences, suggesting the assembly of RNA
      polymerase complexes with different processivity on this promoter.

PMID- 10412905
TI  - Diverse range of gene activity during Arabidopsis thaliana leaf senescence
      includes pathogen-independent induction of defense-related genes.
AB  - To determine the range of gene activities associated with leaf senescence, we
      have identified genes that show preferential transcript accumulation during this
      developmental stage. The mRNA levels of a diverse array of gene products
      increases during leaf senescence, including a protease, a ribosomal protein, two
      cinnamyl alcohol dehydrogenases, a nitrilase and glyoxalase II. Two of the genes
      identified are known to be pathogen-induced. The senescence specificity of each
      gene was determined by characterization of transcript accumulation during leaf
      development and in different tissues. The increased expression of nitrilase in
      senescent leaves is paralleled by an increase in free indole-3-acetic acid (IAA)
      levels. Additionally, we have demonstrated that the induction of defense-related
      genes during leaf senescence is pathogen-independent and that salicylic acid
      accumulation is not essential for this induction. Our data indicate that the
      induction of certain genes involved in plant defense responses is a component of
      the leaf senescence program.

PMID- 10412906
TI  - Enhanced tolerance to light stress of transgenic Arabidopsis plants that express
      the codA gene for a bacterial choline oxidase.
AB  - Arabidopsis thaliana was transformed with the codA gene from Arthrobacter
      globiformis. This gene encodes choline oxidase, an enzyme that converts choline
      to glycinebetaine. The photosynthetic activity, monitored in terms of chlorophyll
      fluorescence, of transformed plants was more tolerant to light stress than that
      of wild-type plants. This enhanced tolerance to light stress was caused by
      acceleration of the recovery of the photosystem II (PS II) complex from the photo
      inactivated state. The transformed plants synthesized glycinebetaine, but no
      changes were detected in the relative levels of membrane lipids or in the
      relative levels of fatty acids in the various membrane lipids. Transformation
      with the codA gene increased levels of H2O2, a by-product of the reaction
      catalyzed by choline oxidase, by only 50% to 100% under stress or non-stress
      conditions. The activity of ascorbate peroxidase and, to a lesser extent, that of
      catalase in transformed plants were significantly higher than in the wild-type
      plants. These observations suggest that H2O2 produced by choline oxidase in the
      transformed plants might have stimulated the expression of H2O2 scavenging
      enzymes, with resultant maintenance of the level of H2O2 within a certain limited
      range. It appears that glycinebetaine produced in vivo, but not changes in
      membrane lipids or in the level of H2O2, protected the PS II complex in
      transformed plants from damage due to light stress.

PMID- 10412907
TI  - Identification of disease response genes expressed in Gossypium hirsutum upon
      infection with the wilt pathogen Verticillium dahliae.
AB  - Verticillium wilt is a vascular disease of cotton (Gossypium spp.) caused by the
      fungal pathogen Verticillium dahliae. To begin to understand the molecular
      mechanisms of the disease response in cotton cultivars that display superior wilt
      tolerance, such as Gossypium hirsutum cv. Sicala V-1, a cDNA library was
      constructed with mRNA isolated from root tissue of Sicala V-1, 24 h after
      inoculation with V. dahliae. The library was screened by a differential screening
      technique which was successful in identifying differences in gene expression
      between uninfected and V. dahliae-infected G. hirsutum root tissue. Among the
      differentially expressed clones, 51% represented up-regulated genes which had the
      potential to be involved in the defence response of G. hirsutum. The temporal
      expression patterns of nine suspected defence response genes were examined by
      northern blot analysis at several time intervals after inoculation with V.
      dahliae. The rapid increase in mRNA transcripts corresponding to each of these
      clones upon infection suggests a role for these genes in the defence response of
      G. hirsutum. Genes not previously associated with the defence response of the
      cotton plant, such as those for a 14-3-3-like protein and pathogenesis-related
      (PR) proteins, have been identified together with presumably novel genes, for
      which a definite function could not be ascribed.

PMID- 10412908
TI  - Cloning and expression of a prokaryotic sucrose-phosphate synthase gene from the
      cyanobacterium Synechocystis sp. PCC 6803.
AB  - Sucrose is one of several low-molecular-weight compounds that cyanobacteria
      accumulate in response to osmotic stress and which are believed to act as
      osmoprotectants. The genome of the cyanobacterium Synechocystis sp. PCC 6803
      contains a 2163 bp open reading frame (ORF) that shows similarity to genes from
      higher plants encoding sucrose-phosphate synthase (SPS), the enzyme responsible
      for sucrose synthesis. The deduced amino acid sequence shows 35-39% identity with
      known higher-plant SPS sequences. The putative Synechocystis sps gene was cloned
      from genomic DNA by PCR amplification and expressed as a His6-tagged amino
      terminal fusion protein in Escherichia coli. The expressed protein was purified
      and shown to be a functional SPS enzyme, confirming the identity of the ORF,
      which is the first sps gene to be cloned from a prokaryotic organism. The
      Synechocystis SPS has a molecular mass of 81.5 kDa, which is smaller than the
      typical higher-plant SPS subunit (117-119 kDa), and lacks the phosphorylation
      site motifs associated with light- and osmotic stress-induced regulation of SPS
      in higher plants. The enzyme has Km values for UDPG1c and Fru6P of 2.9 mM and
      0.22 mM, respectively, with a Vmax of 17 micromol per minute per mg protein and a
      pH optimum of 8.5. Unlike the higher-plant enzyme, ADPG1c, CDPG1c and GDPG1c can
      substitute for UDPG1c as the glucosyl donor with Km values of 2.5, 7.2 and 1.8
      mM, respectively. The enzyme is activated by Mg2+ but not by G1c6P, and is only
      weakly inhibited by inorganic phosphate. The purified protein was used to raise a
      high-titre antiserum, which recognises a low-abundance 81 kDa protein in
      Synechocystis sp. PCC 6803 extracts. There was no apparent increase in expression
      of the 81 kDa protein when the cells were exposed to moderate salt stress, and
      SPS activity was very low in extracts from both unstressed and salt-stressed
      cells. These results and the lack of evidence for sucrose accumulation in
      Synechocystis sp. PCC6803 lead to the conclusion that expression of the sps gene
      plays no obvious role in adaptation to osmotic stress in this species.

PMID- 10412909
TI  - A thermophilic cyanobacterium Synechococcus elongatus has three different Class I
      prenyltransferase genes.
AB  - Prenyltransferases (prenyl diphosphate synthases), which are a broad group of
      enzymes that catalyze the consecutive condensation of homoallylic diphosphate of
      isopentenyl diphosphates (IPP, C5) with allylic diphosphates to synthesize prenyl
      diphosphates of various chain lengths, have highly conserved regions in their
      amino acid sequences. Based on the above information, three prenyltransferase
      homologue genes were cloned from a thermophilic cyanobacterium, Synechococcus
      elongatus. Through analyses of the reaction products of the enzymes encoded by
      these genes, it was revealed that one encodes a thermolabile geranylgeranyl (C20)
      diphosphate synthase, another encodes a farnesyl (C15) diphosphate synthase whose
      optimal reaction temperature is 60 degrees C, and the third one encodes a
      prenyltransferase whose optimal reaction temperature is 75 degrees C. The last
      enzyme could catalyze the synthesis of five prenyl diphosphates of farnesyl,
      geranylgeranyl, geranylfarnesyl (C25), hexaprenyl (C30), and heptaprenyl (C35)
      diphosphates from dimethylallyl (C5) diphosphate, geranyl (C10) diphosphate, or
      farnesyl diphosphate as the allylic substrates. The product specificity of this
      novel kind of enzyme varied according to the ratio of the allylic and homoallylic
      substrates. The situations of these three S. elongatus enzymes in a phylogenetic
      tree of prenyltransferases are discussed in comparison with a mesophilic
      cyanobacterium of Synechocystis PCC6803, whose complete genome has been reported
      by Kaneko et al. (1996).

PMID- 10412910
TI  - A novel E-type endo-beta-1,4-glucanase with a putative cellulose-binding domain
      is highly expressed in ripening strawberry fruits.
AB  - Two full-length cDNA clones (faEG1 and faEG3, respectively) have been isolated by
      screening a cDNA library representing transcripts from red strawberry fruits.
      Southern blot analysis of genomic DNA suggests that the strawberry endo-beta-1,4
      glucanases (EGases) are encoded by a multigene family. The cognate genes are
      predominantly expressed during the ripening process proper, although, in the case
      of faEG3, some expression has also been observed in large green fruits and, at
      low amounts, in young vegetative green tissues. In agreement with other ripening
      related genes in strawberry, also the expression of faEG1 and faEG3 is down
      regulated by treatment with an auxin analogue (1-naphthaleneacetic acid, NAA).
      Differences in temporal expression of the two EGase genes in fruits are not
      accompanied by differences in spatial expression. The pattern of expression and
      the sequence characteristics of the two polypeptides suggest that the two
      strawberry EGases operate in a synergistic and coordinate manner. The protein
      encoded by faEG1 looks like one of the usual higher-plant EGases (average
      molecular mass of 54 kDa), while the protein encoded by faEG3 has a greater
      deduced molecular mass (about 68 kDa) due to the presence of an extra peptide of
      about 130 amino acids at the C-terminus. Such unusual peptide shows some features
      also found in microbial cellulases and contains a putative cellulose-binding
      domain. We propose that the faEG3-encoded EGase might especially hydrolyse the
      xyloglucans coating the cellulose microfibrils, thus rendering the cell wall more
      susceptible to the subsequent hydrolytic activity of the faEG1-encoded EGase.

PMID- 10412911
TI  - Treatment with 24-epibrassinolide, a brassinosteroid, increases the basic
      thermotolerance of Brassica napus and tomato seedlings.
AB  - Brassinosteroids are plant growth-promoting compounds that exhibit structural
      similarities to animal steroid hormones. Recent studies have indicated that
      brassinosteroids are essential for proper plant development. In addition to a
      role in development, several lines of evidence suggest that brassinosteroids
      exert anti-stress effects on plants. However, the mechanism by which they
      modulate plant stress responses is not understood. We show here that Brassica
      napus and tomato seedlings grown in the presence of 24-epibrassinolide (EBR) are
      significantly more tolerant to a lethal heat treatment than are control seedlings
      grown in the absence of the compound. Since a preconditioning treatment of
      seedlings was not required to observe this effect, we conclude that EBR treatment
      increases the basic thermotolerance of seedlings. An analysis of heat shock
      proteins (HSPs) in B. napus seedlings by western blot analysis indicated that the
      HSPs did not preferentially accumulate in EBR-treated seedlings at the control
      temperature. However, after heat stress, HSP accumulation was higher in EBR
      treated than in untreated seedlings. The results of the present study provide the
      first direct evidence for EBR-induced expression of HSPs. The higher accumulation
      of HSPs in EBR-treated seedlings raises the possibility that HSPs contribute, at
      least in part, to thermotolerance in EBR-treated seedlings. A search for factors
      other than HSPs, which may directly or indirectly contribute to brassinosteroid
      mediated increase in thermotolerance, is underway.

PMID- 10412912
TI  - ZmOCL1, an HDGL2 family homeobox gene, is expressed in the outer cell layer
      throughout maize development.
AB  - The formation of a morphologically distinct outer cell layer or protoderm is one
      of the first and probably one of the most important steps in patterning of the
      plant embryo. Here we report the isolation of ZmOCL1 (OCL for outer cell layer),
      a member of the HDGL2 (also known as HD-ZIP IV) subclass of plant-specific HD-ZIP
      homeodomain proteins from maize. ZmOCL1 transcripts are detected very early in
      embryo development, before a morphologically distinct protoderm is visible, and
      expression then becomes localised to the protoderm of the embryo as it develops.
      Subsequently, expression is observed in the L1 cell layer of both the developing
      primary root and shoot meristems, and is maintained in developing leaves and
      floral organs. We propose that ZMOCL1 may play a role in the specification of
      protoderm identity within the embryo, the organisation of the primary root
      primordium or in the maintenance of the L1 cell layer in the shoot apical
      meristem. We also show that the expression of ZmOCL1 is different from that of
      another epidermal marker gene, LTP2 (lipid transfer protein) and, in meristems,
      is complementary to that of Kn1 (Knotted) which is transcribed only in underlying
      cell layers.

PMID- 10412914
TI  - cDNA cloning and heterologous expression of coniferin beta-glucosidase.
AB  - Coniferin beta-glucosidase (CBG) catalyzes the hydrolysis of monolignol
      glucosides to release the cinnamyl alcohols for oxidative polymerization to
      lignin. Utilizing the N-terminal amino acid sequence of the purified enzyme, the
      corresponding full-length cDNA sequence was isolated from a Pinus contorta xylem
      specific library. The isolated 1909 nucleotide cDNA was confirmed to be that of
      CBG on the basis of its high homology to family 1 glycosyl hydrolases, the
      sequence identity with the N-terminal amino acid residues of the purified enzyme,
      and the coniferin hydrolytic activity and substrate specificity profile displayed
      by the recombinant protein when expressed in Escherichia coli. The presence of a
      23 amino acid N-terminal signal peptide in the deduced 513 amino acid enzyme
      suggests that CBG is a secretory protein targeted to the ER. The isolation of CBG
      cDNA will facilitate the evaluation of the importance of this enzyme in the
      ultimate stages of lignin biosynthesis and could be a valuable tool in
      manipulating lignin levels in xylem cell walls.

PMID- 10412913
TI  - Expression and cellular localization of Atrab28 during arabidopsis embryogenesis.
AB  - The maize abscisic acid (ABA)-responsive gene rab28 has been shown to be ABA
      inducible in embryos and vegetative tissues, expression being mostly restricted
      to vascular elements during late embryogenesis. In the course of an expressed
      sequence tags (ESTs) programme, we have isolated an Arabidopsis thaliana gene,
      Atrab28, encoding the orthologue of maize rab28. The Atrab28 cDNA is 1090 bp
      long, including a poly(A)+ stretch, and encodes a polypeptide of 262 amino acids.
      Atrab28 antibody against the recombinant protein recognizes a polipeptide of
      about 30 kDa and pI 6, in close agreement with the predicted molecular mass and
      pI. As for maize rab28, expression studies with Atrab28 revealed high specificity
      for embryo tissues, transcription being stimulated by the transcriptional
      activator abi3. In contrast, Atrab28 was not induced in vegetative tissues by
      ABA, osmotic stress or dehydration. The expression of Atrab28 mRNA and the
      accumulation of Atrab28 protein was largely restricted to provascular tissues of
      mature embryos and in the seed coat outer tegument and embryo and silique
      epidermis, as revealed by in situ hybridization and immunocytochemistry with anti
      Atrab28 antibodies.

PMID- 10412915
TI  - Transmyocardial laser induces coronary hyperemia and reduces ischemia-related
      arrhythmias, but fails to delay development of myocardial necrosis after coronary
      artery occlusion in pigs.
AB  - BACKGROUND: Several investigators have reported that transmyocardial
      revascularization (TMR) prior to acute coronary artery occlusion improves
      regional myocardial function and reduces the infarct size in animals with
      significant coronary collateral circulation. Whether the protective effect of TMR
      is due to perfusion through the laser-made channels, increased collateral flow or
      other mechanisms remains unresolved. The aim of this study was to investigate
      whether TMR performed prior to acute coronary artery occlusion could offer
      protection from ischemic injury in the pig, an animal with limited native
      collateral coronary circulation. METHODS: In one group (n=4), TMR was performed
      in the anterior wall of the left ventricle 30 minutes prior to occlusion of the
      proximal LAD for 45 minutes. The other group (n=6) was subjected to transient
      ischemia of the same duration without previous TMR. Area at risk and infarct size
      were determined after sacrifice. RESULTS: No significant difference was found in
      the infarct size between the two groups (69+/-2% in the TMR group versus 62+/-4%
      in the control group). However, the arrhythmic index during the period of
      ischemia was significantly lower in the TMR group (1.0+/-0.3 vs 8.3+/-2.2,
      p<0.001). Blood flow in LAD increased to a maximum of 135+/-6% of baseline level
      three minutes after the end of the TMR procedure. CONCLUSIONS: TMR failed to
      reduce the infarct size following acute coronary artery occlusion in the pig, an
      animal with a small collateral coronary flow capacity, but reduced ischemia
      related arrhythmias and increased coronary flow transiently.

PMID- 10412916
TI  - The influence of age on the outcome of primary coronary artery bypass grafting.
AB  - BACKGROUND: With the steady increase in the number of elderly patients requiring
      coronary artery bypass grafting (CABG), scepticism still exists as to whether
      this operation is justified in older patients or not, and whether there is an
      upper age limit. The aim of this study was to examine the effects of increasing
      age on the outcome of CABG. METHODS: A retrospective review was performed on 2127
      consecutive patients undergoing primary CABG from January 1990 through June 1996.
      The patients were arbitrarily divided into age groups: 69 years or less (n=1607),
      70-75 years (n=371), 76-80 years (n=129) and older than 80 years (n=20).
      Mortality, morbidity and long-term survival for each group was compared. RESULTS:
      The groups containing the elderly patients showed an over-representation of
      women, as well as a higher frequency of arterial hypertension, hyperlipidemia,
      previous infarction and diabetes. More patients, amongst the elderly, had
      unstable angina and diffuse coronary disease requiring urgent surgery and
      coronary thrombendarterectomy compared to those <70 years. Hospital mortality did
      not differ between the groups, 1.8, 3.0, 2.3 and 5.0%. There was an increased
      incidence of low postoperative cardiac output and a higher incidence of gastro
      intestinal complications amongst the elderly. The 5-year survival was 92.2% (<70
      years), 87.0% (70-75 years) and 86.3% (76-80 years) and the cardiac event-free
      survival was 87.5% (<70 years), 78.4% (70-75 years) and 80.8% (76-80 years) at 5
      years. CONCLUSIONS: An acceptable early mortality and medium-term survival (5
      years) together with excellent functional medium-term results support the
      justification of primary CABG in older patients irrespective of age.

PMID- 10412917
TI  - Left ventricular rupture after mitral valve replacement.
AB  - BACKGROUND: What are the immediate and long term outcomes of patients who had
      rupture of the left ventricle after mitral valve replacement? METHODS: 
      EXPERIMENTAL DESIGN: A retrospective study with a 20-year follow-up. SETTING:
      Experience in a single tertiary referral cardiothoracic surgery hospital.
      PARTICIPANTS: 20 out of 3105 patients that received mitral valve replacement.
      INTERVENTION: All these 20 patients received re-exploration for a trial of repair
      of left ventricular rupture either by an internal or an external or a combined
      repair. MEASURES: Operative mortality and long term outcome of the survivals.
      RESULTS: Most patients (16.80%) were female and had rheumatic mitral valve
      disease. The mean age of the patients was 58.1 years. All patients underwent
      attempted repair, usually by removal of the prosthesis and reconstitution of the
      ventricle from within the left atrium (75%). Thirteen (65%) patients died. Two
      late deaths were of unrelated cause. One surviving patient developed a late
      ventricular false aneurysm but did not undergo repeat surgery. One patient
      developed severe mitral regurgitation due to tissue failure of the bioprosthesis
      12 years after surgery and she underwent a successful reoperation. CONCLUSIONS:
      We believe that all patients should be placed back on cardiopulmonary bypass for
      an internal repair. The long term outcome of the survivals is satisfactory.

PMID- 10412918
TI  - Bjork-Shiley convexo-concave valve: is a prophylactic re-replacement justified?
AB  - BACKGROUND: The Bjork-Shiley convexo-concave (BS-CC) heart valves represent the
      improved model of the standard valve first introduced with a different design of
      the disc valve to ameliorate hemodynamic performances and reduce thromboembolic
      complications. About 86,000 BS-CC were implanted during 1979-1986 and of them a
      small number developed an intrinsic dysfunction resulting in sudden death.
      METHODS: From 1979 to 1986 we implanted in 117 patients (48 males, 69 females,
      mean age 46.35+/-12.47, range 8-65 years) 125 BS-CC. In 38.5% (45/117) of the
      cases heart valve replacement represented the second cardiac procedure after a
      previous closed heart digital commissurotomy. The mean size of the implanted
      prosthesis was 25.6+/-2.8 for aortic valve and 29.5+/-1.2 for mitral valve.
      RESULTS: Hospital mortality was 4.27% (5/117) and survival rate at 10 years is
      71.4% and at 17 years 54.7% (Kaplan-Meier). At follow-up causes of death proved
      valve related in most of the patients but with no evidence of valve fracture. We
      had 1 case of sudden death in patients at high risk (largest size, aortic
      position) and 30 cases of death by unknown causes but they did not have an
      autopsy to confirm the cause of death. CONCLUSIONS: We conclude that in our
      population with BS-CC at the moment there is no indication for prophylactic
      replacement because of the higher risks of a reoperation (third or fourth in the
      35.4% of our patients) than a strut fracture. Nevertheless we believe an autopsy
      mandatory in all these patients at risk, when sudden death occurs.

PMID- 10412919
TI  - Multiple organ harvesting from a single donor for transplantation. A comparison
      of simple cooling technique and bypass technique.
AB  - BACKGROUND: We compared a simple, cooling technique to a cardiopulmonary bypass
      (CPB) technique for multiple organ harvesting (MOH) from a single donor. METHODS:
      Adult mongrel dogs were divided into three groups. In the in situ cooling group,
      the aorta and IVC were first clamped and the hepatic and renal vascular beds were
      washed out with a cold lactated Ringer's solution. In the peritoneal cooling
      group, hypothermia was induced using an ice slush in the abdominal cavity, and in
      the CPB group using CPB. As the esophageal temperature reached 25 degrees C, the
      liver and kidneys were harvested using the same procedure in all three groups.
      After the splanchnic perfusion, the heart was harvested while it continued to
      beat. The heart was preserved for 12 hours, and the liver and kidneys for 24
      hours in a cold UW solution. Myocardial high-energy phosphates were measured
      using 31P-MRS, and the hearts were transplanted. Hepatic vascular beds were
      flushed during preservation, and the effluent was analyzed. Following kidney
      transplantation, its function was measured. RESULTS: There's no significant
      difference in myocardial high-energy phosphate or in cardiac function after
      transplantation. During liver preservation, ALT and LDH levels of the effluent
      were significantly higher in the in situ group than those in other groups.
      There's no difference following kidney transplantation. CONCLUSION: The CPB
      method and peritoneal cooling technique demonstrated stronger early function of
      hepatic grafts compared with the in situ cooling method. The peritoneal cooling
      technique is a simpler, safer and more feasible alternative for MOH compared with
      CPB method, and it may have broad clinical application.

PMID- 10412920
TI  - Effects of coenzyme Q10 on myocardial protection during cardiac valve replacement
      and scavenging free radical activity in vitro.
AB  - BACKGROUND: To evaluate the effects of CoQ10 on myocardial protection in patients
      undergoing cardiac valve replacement and direct scavenging free radicals activity
      in vitro. METHODS: Twenty-four patients were randomly divided into two groups.
      Twelve patients in the CoQ10 group received intravenous and intracoronary CoQ10
      treated "round the operative period". Twelve patients in the control group
      received no CoQ10-treatment. MEASURES: Plasma malondialdehyde (MDA)
      concentration, erythrocyte superoxide dismutase (SOD) activity, and serum cardiac
      isoenzyme of creatine kinase (CK-MB) were measured in the perioperative and
      postoperative period. The effects of CoQ10 direct scavenging free radicals were
      determined with electron spin resonance (ESR) and spin-trapping techniques by an
      in vitro study. RESULTS: Plasma MDA concentration and serum CK-MB levels in the
      CoQ10 group were significantly lower than those in the control group. Erythrocyte
      SOD activity in the CoQ10 group was significantly higher than that in the control
      group. CoQ10 showed an obvious hydroxyl radical scavenging activity, but it could
      not scavenge superoxide anion radicals. CONCLUSIONS: These findings demonstrated
      that the use of intravenous and intracoronary CoQ10-treatment may play a more
      beneficial protective role during cardiac valve replacement through its
      antioxidant properties and membrane stabilization, as well as through its ability
      to scavenge hydroxyl radicals directly.

PMID- 10412921
TI  - Assessment of CABG-related risk in patients with CAD and LVD. Contribution of PET
      with [18F]FDG to the assessment of myocardial viability.
AB  - BACKGROUND: Previous studies have demonstrated that hibernating myocardium can be
      assessed by [18F]fluorodeoxyglucose ([18F]FDG) and positron emission tomography
      (PET). This study evaluated the use of [18F]FDG-PET for CABG related risk
      assessment in patients with coronary artery disease (CAD) and left ventricle
      dysfunction (LVD). METHODS: We retrospectively evaluated 241 to patients
      candidate CABG presenting with signs and symptoms of congestive heart failure
      (CHF) prevailing over ischemic signs. Of the 241 patients, 153 had undergone
      [18F]FDG-PET as well as conventional assessment: 110 out of 153 (group A) were
      operated because of PET evidence of hibernation. Of the 241 patients, 88 had not
      undergone [18F]FDG-PET: 86 out of 88 (group B) were operated on. The outcome of
      surgical patients was evaluated by considering all major perioperative
      complications including the use of mechanical and pharmacological support and in
      hospital mortality. After hospital discharge, each patient was examined at 1, 4
      and every 6 months thereafter. RESULTS: Perioperative use of mechanical supports
      and inotropic drugs, was significantly lower for the PET selected group (A) than
      for the non PET selected group (B). Mortality within 30 days of surgery was 0.9%
      in group A and 19.8% in group B. The only predictors of perioperative outcome
      were the presence of hibernating tissue and the ejection fraction. CONCLUSIONS:
      [18F]FDG-PET prior to CABG can be crucial for the assessment of perioperative
      risk in patients with CAD.

PMID- 10412922
TI  - Changes of antioxidant enzyme activities during cardiopulmonary bypass.
AB  - BACKGROUND: Reperfusion of ischemic heart causes the generation of free radicals,
      and these radicals play an important role in post-ischemic tissue damage. These
      free radicals are removed by scavenger enzymes and antioxidants in the cell. In
      this study, erythrocyte catalase, glutathione peroxidase and glutathione
      reductase enzyme activities were determined in patients undergoing
      cardiopulmonary bypass. METHODS:  EXPERIMENTAL DESIGN: Blood samples were
      obtained from the coronary sinus of patients at the following times: 1) Before
      cardiopulmonary bypass, 2) Immediately after cardiopulmonary bypass, 3) Fifteen
      minutes after the second specimen, 4) Thirty minutes after the second specimen.
      PATIENTS: this study was carried out on eleven patients undergoing open heart
      operation. MEASURES: catalase, glutathione peroxidase and glutathione reductase
      enzyme activities were determined in these patients. RESULTS. Catalase activity
      was significantly decreased in the third and fourth groups as compared with the
      first group, which was also the control group (p<0.05). Glutathione reductase
      activity in the third group was significantly higher as compared with control
      group (p<0.001). However, there were no differences in glutathione peroxidase
      activity among control group and other three groups (p>0.05). CONCLUSIONS: Our
      results indicate that the activities of antioxidant enzyme activities in
      erythrocytes are changed during the ischemia and reperfusion of the heart.

PMID- 10412923
TI  - Pericardial tamponade and massive pleural effusion complicating orthotopic heart
      transplantation.
AB  - Pericardial and pleural effusions occur commonly after open cardiac procedures.
      However, the combination of tamponade and massive pleural effusion is not often
      observed. We present a case of such a patient who received an orthotopic heart
      transplant in a setting of previously diagnosed systemic sarcoidosis. Treatment
      ultimately required the creation of a pericardial window and chemical
      pleurodesis.

PMID- 10412924
TI  - A surgical case of atypical aortic coarctation using cardiopulmonary bypass.
AB  - We report a 44-year-old woman with atypical aortic coarctation accompanied by
      cerebral artery disease. She was hospitalized for vertigo. An extra-anatomic
      bypass between the ascending aorta and abdominal aorta was performed using
      partial cardiopulmonary bypass under moderate hypothermia to reduce the after
      load of the left ventricle and maintain cerebral blood flow and cerebral
      perfusion pressure. The postoperative course was uneventful and there was no
      postoperative neurological deficiency.

PMID- 10412925
TI  - Myocardial revascularization with arterial conduits. The use of lateral costal
      artery.
AB  - We describe the long-term results of a case of complete myocardial
      revascularization with arterial conduit employing also lateral costal artery
      (LCA). A fifty-four-year-old man underwent revascularization with the implant of
      right internal artery mammary (RIMA) on the second portion of the right coronary
      artery (RCA), of the left internal mammary (LIMA) on the left artery descendent
      (LAD) and of LCA on the obtuse marginal arteries. The postoperative course was
      uneventful and a twelve-month postoperative coronary angiography showed arterial
      conduits to be functioning well. LCA is another source for complete myocardial
      revascularization with arterial conduits.

PMID- 10412926
TI  - Aneurysm of the vertebral artery near the atlas arch.
AB  - In this case report, we describe an nontraumatic extracranial aneurysm of the
      vertebral artery at the V3 segment. Its etiology and pathogenesis could not be
      clarified completely. The walnut-sized aneurysm was treated surgically by
      proximal ligation. There were no postoperative complications.

PMID- 10412927
TI  - Left atrial approach to big myxoma with angiographically visible neovascularity.
      Report of one case.
AB  - In this article, we report a 65-year-old man with a large atrial myxoma arising
      from the posterior wall and from the base of the right inferior pulmonary vein.
      The big neoplastic mass showed a large implant site. A rare atrial myxoma
      neovascularity arising from the atrial circumflex artery was very clearly
      visualized by selective coronary arteriography. The surgical approach used to
      resect this tumor was an isolated left atriotomy that provided excellent exposure
      and safe excision.

PMID- 10412928
TI  - Surgical decompression of the first part of vertebral artery for ischemic
      brainstem dysfunction.
AB  - BACKGROUND: Ischemic brainstem dysfunction can be caused by extrinsic compression
      or kinking of the proximal vertebral artery. This is a retrospective survey of
      operated patients comparing neurologic examinations done postoperatively with
      preoperative neurologic evaluation. No patient with arteriosclerotic obstruction
      of the proximal vertebral artery treated by endarterectomy is included in this
      series. METHODS: Over a 5 year period, 104 patients presented preoperatively with
      signs and symptoms of brainstem dysfunction, with negative computerized
      tomographic scans of the brain, and angiography which demonstrated radiographic
      findings compatible with impediment to and compromise of blood flow into the
      first part of the vertebral artery. All patients had surgical exploration of the
      proximal vertebral artery in the lower neck mainly under local infiltrative
      anesthesia. Extrinsic compression or kinking of the proximal vertebral artery was
      found in all patients and relieved by surgical decompression and arteriolysis.
      Thirty-eight (36%) of the 104 patients had staged bilateral vertebral artery
      decompression and arteriolysis. RESULTS: There was no operative mortality and
      only minimal morbidity in this series. Twenty four patients had postoperative
      aortic arch angiography which showed absence of any radiographic abnormalities
      seen preoperatively, and which further showed a more directly aligned flow path
      of the proximal vertebral artery with the subclavian artery. The one year
      postoperative results in the 104 patients were as follows: 71 (68%) had sustained
      partial restoration of lost neurologic function, 23 (22%) had no change in
      neurologic status, and 10 (10%) became worse in neurologic status. In the group
      of 71 patients who had sustained partial restoration of lost neurologic function
      for 1 year postoperatively, 19 patients were neurologically evaluated for from 16
      to 20 years postoperatively and continued to exhibit sustained partial
      restoration of lost neurologic function over that time. CONCLUSIONS: A safe,
      effective surgical procedure that can be performed under local anesthesia, namely
      decompression and arteriolysis of the proximal vertebral artery, is available for
      the treatment of ischemic brainstem dysfunction caused by extrinsic compression
      or kinking of the proximal vertebral artery.

PMID- 10412929
TI  - Ruptured abdominal aortic aneurysms: analysis of factors influencing surgical
      results in 184 patients.
AB  - BACKGROUND: Rupture is often the first manifestation in patients with abdominal
      aortic aneurysms. Although elective surgery for non-ruptured abdominal aortic
      aneurysms has provided satisfactory surgical results, operative mortality of
      ruptured abdominal aortic aneurysms (rAAA) has not improved. The purpose of this
      study was to identify predictors for early hospital death in patients with rAAA.
      METHODS:  DESIGN: A retrospective study. SETTING: A university hospital and 20
      affiliated hospitals. PATIENTS: PATIENTS undergoing surgical treatment for rAAA
      (n=183) between 1968 and 1997. INTERVENTIONS: All patients were surgically
      treated and divided into operative survivors (n=119) and non-survivors (n=64).
      MEASURES: The patient-related, procedure-related, and postoperative factors were
      compared between the two groups. A multivariate analysis was also conducted to
      determine predictors for hospital deaths. RESULTS: In univariate analysis, age at
      operation (p=0.004), preoperative hemodynamic conditions (p<0.0001), extent of
      hematoma (p<0.0001), preexistent renal dysfunction (p=0.001), and volumes of
      blood loss at operation (p=0.001) were significantly different between the two
      groups. The morbidity of postoperative renal failure (p<0.0001), gut ischemia
      (p=0.003), heart failure or ischemic heart disease (p<0.0001), and multiple organ
      dysfunction syndrome (p<0.0001) was higher in the non-survivors' group.
      Multivariate analysis also identified preoperative hemodynamic conditions, blood
      loss volume at operation, pre-existent renal dysfunction, postoperative renal
      failure, heart failure, and multiple organ dysfunction syndrome as incremental
      risk factors for hospital deaths. CONCLUSIONS: Every effort to maintain
      preoperative hemodynamic conditions, to reduce volumes of blood loss at
      operation, and to minimize deterioration of organ functions postoperatively is
      all essential to improve patient survival.

PMID- 10412930
TI  - Inflammatory aneurysm of the abdominal aorta. A prospective clinical study.
AB  - OBJECTIVE: This study was undertaken to investigate a consecutive series of
      abdominal aortic aneurysm studied with histology to highlight the etiology, the
      incidence, the value of preoperative studies and intraoperative findings.
      EXPERIMENTAL DESIGN: Prospective study. SETTING: University hospital. PATIENTS:
      Between 1992 and 1994, 102 patients underwent elective surgical repair of an
      abdominal aortic aneurysm. The patients were prospectively divided as having an
      inflammatory aneurysm (IA) or an atherosclerotic aneurysm (AA) on the basis of
      preoperative and intraoperative findings. Further histological evaluation
      assigned the patients to one of the two groups. RESULTS: The incidence of IA was
      15%. Overall, symptoms, CT scan studies, aneurysmal wall thickness, white
      glistening perianeurysmal fibrosis, bleeding from the aneurysmal wall and
      adhesion to the duodenum diagnosed 11 (73%) cases of IA. Histology showed that a
      granulomatous reaction against some components of the atherosclerotic plaques
      resulting in an auto-allergic response to this component could initiate the
      inflammatory process thus resulting in a progressive adventitial and peri
      adventitial fibrosis with inflammation, lymphadenitis and lymphatic dilatation.
      CONCLUSIONS: Preoperative and intraoperative findings underestimate the incidence
      of IA. Aortic resection can prevent the progression of the inflammatory process
      and the complications usually observed when the exposure to the allergen
      determines an involvement of the periaortic structures.

PMID- 10412932
TI  - Descending aorta substitution with expandable ends prosthesis. Case report.
AB  - A case of esophageal cancer infiltrating the left bronchus pars membranacea and
      the aneurysmal aortic wall was resected en bloc with the bronchial and aortic
      wall. Descending aorta was substituted by means of a Dacron prosthesis fitted
      with expandable devices at both ends, allowing a very significant reduction of
      the clamping time and simplification of this part of the procedure.

PMID- 10412931
TI  - Endovascular management of axillary artery trauma.
AB  - A 17-year-old man was seen with an expanding false aneurysm of the right axillary
      artery. This was treated by an intraluminal covered-stent introduced through the
      brachial artery via an 11F sheath. The covered-stent was constructed from a
      segment of great saphenous vein anchored in the axillary artery by a 29 mm Palmaz
      stent. Postoperative arteriography and duplex scanning confirmed normal flow
      through the axillary artery with complete exclusion of the aneurysm.
      Postoperative recovery was uneventful.

PMID- 10412933
TI  - Resection of abdominal aortic aneurysm in a patient with left-sided inferior vena
      cava and horseshoe kidney.
AB  - The presence of vascular and renal anatomical anomalies can create technical
      problems during abdominal aortic surgery and may give rise to serious
      intraoperative complications. We present a case of an abdominal aortic aneurysm
      resected in a patient with the extremely rare coexistence of a left-sided
      inferior vena cava and horseshoe kidney. The diagnosis of the anomalies was made
      prior to aortic surgery. CT-scan of the abdomen was the most accurate
      preoperative investigation. Aortic surgery was performed through a
      transperitoneal approach which allowed easy access to the aneurysm despite the
      presence of the left-sided inferior vena cava and horseshoe kidney. Recognition
      of vascular and renal anomalies on preoperative imaging studies is important in
      the surgical treatment of abdominal aortic aneurysms. If possible anomalies are
      recognized in time and treated correctly, the morbidity and mortality of aneurysm
      repair should not be influenced.

PMID- 10412934
TI  - Multivascular trauma on an adolescent. Perioperative management.
AB  - Penetrating vascular injury, in particular at the neck, is a life-threatening
      trauma not only of the nature and the anatomic proximity of cardiovascular,
      aerodigestive, glandular and neurologic system but also of the development of
      early and late complications. The following case report describes our experience
      with a penetrating wound patient, who was admitted to our emergencies twelve
      hours after the accident. The only demonstrable objective signs included a large
      hematoma at the right-side of the neck and distended mediastinum on the chest X
      ray. As the patient was cardiovascularly unstable he was immediately transported
      to the theater without any angiography. The mandatory operative exploration was
      initially unsuccessful and a median sternotomy with a standard cardiopulmonary
      bypass and deep hypothermia circulatory arrest was established to restore all the
      vascular lesions. Actually, the patient was in critical condition with a rupture
      of the right internal jugular vein, a large pseudoaneurysm of the innominate
      artery and an avulsion of the ascending aorta with the suspicion of a cardiac
      tamponade. The postoperative period lasted two full months, while complications
      appeared. The substantial message from this multivascular trauma is the early
      diagnosis of the life-threatening complications as exsanguinations, ventricular
      fibrillation and the ability to minimize postoperative complications, which will
      impair the normal functional life of the patient.

PMID- 10412935
TI  - Double layered autogenous vein graft patch reconstruction of the common carotid
      internal jugular fistula caused by gunshot wound.
AB  - Hereby we present a case with a common carotid-internal jugular fistula caused by
      gunshot wound. The patient was a 32-year old male who had an entrance hole of a
      bullet on his right anterior cervical area, at the C4 level with a hematoma
      surrounding it. The exit hole could be detected at the sublingual area. By
      palpation a thrill and on auscultation a souffle was noted. Neither crepitation,
      nor any neurologic deficit or any symptom of Horner's syndrome was present. The
      emergency digital subtraction angiography (DSA) showed a fistulisation to
      internal jugular vein (IJV) approximately 0.5 cm below the common carotid artery
      (CCA) bifurcation level. During the operation a hematoma and a false aneurysm was
      observed on the CCA. Also, proximally to the bifurcation, a communication of CCA
      with IJV was noted. The wall of the JJV was rather thinned and the size of the
      vessel had considerably enlarged. Following the evacuation of the hematoma and
      debridement, the integration of the artery was achieved by placing a double
      layered autogenous vein graft patch over the 0.5 x 1.5 cm defect. The 0.3 x 1.5
      cm defect laterally over the IJV was primarily sutured. The patient was
      discharged on the fifth day. The control DSA taken on the twelfth day showed a
      perfect integration of the vessels. We considered the case noticeable due to its
      rather rare incidence and the double layered autogen vein patch graft
      reconstruction.

PMID- 10412936
TI  - Surviving and proliferating faculty of fibroblasts cultured under no-serum and
      poor nutritional conditions. The basic study on hybridation of cultured cells
      with an artificial matrix.
AB  - BACKGROUND: In this study, we measured survival periods of fibroblasts cultured
      under conditions providing minimal nutrition. This investigation aims to develop
      the high affinity hybrid artificial organs on tissues or organs finally. METHODS:
      Dermal fibroblasts were inoculated on 96-well multiplate according to routine
      technique. The medium of these cells maintained for 24 hours replaced the new DME
      medium containing 10% FBS (group 1) or without FBS (group 2) and then cultured
      for 10 days without medium change. The surviving cell numbers were measured using
      MTS assay. RESULTS: Surviving cell numbers of both groups decreased progressively
      during the 10-day assay period. Overall 25-40% of the fibroblasts survived for at
      least 10 days. It decreased significantly, however, in group 2 from day 2 through
      day 4 as compared to group 1. In contrast, the cell number decreased in group 1
      to a greater extent than in group 2 after day 6. When the cells that survived
      until day 10 were then cultured with fresh DME medium containing 10% FBS for 3
      more days, the cell numbers returned to 50-100% of the initial level CONCLUSIONS:
      These results suggest that fibroblasts cell function is maintained under poor
      nutritional conditions, i.e., without serum, possibly via an autocrine or
      paracrine mechanism. These data could contribute much to the research of hybrid
      artificial organs, including an artificial trachea, in which hybridization of
      cultured cells with artificial matrices remains to be a basic process, and has to
      serve in bloodless postimplantation period.

PMID- 10412937
TI  - Protrusion and mixed deformities.
AB  - BACKGROUND: Considerable confusion is encountered in the literature relating
      classification respectively surgical repair of the anterior chest wall
      deformities in view of the asymmetric types which are arbitrarily ranged in one
      of the two main groups (impressions, protrusions). METHODS: Out of 420 operations
      89 (21%) were performed for pure protrusion, and 64 (15%) for mixed deformities,
      with asymmetric impression and protrusion present at the same time. Mixed
      deformities were limited to the parasternal area in 10 and extended to the entire
      anterior chest wall in 54 cases. Surgery was undertaken for both protrusion and
      mixed deformities beyond 10 years of age in 9.8%, while for a typical funnel
      chest deformity in 31% (p<0.001). Correction has been achieved performing double
      subperichondral excisions of the distorted cartilages and - if necessary -
      subperiosteal wedge incision of the bony segments, completed by a T shape wedge
      sternal incision. In order to preserve the repaired position a stainless steel
      stabiliser was introduced for one year behind the sternum and the entire
      mobilised wall area. RESULTS AND CONCLUSIONS: This method was used hitherto in 60
      patients with mixed, respectively severe funnel chest deformities without any
      complication. The "pectus index" calculated according to the equation A/Bx100, in
      which A is the internal sterno-vertebral distance and B is the transverse
      diameter of the chest at the level of the diaphragms in cm (normal values: 35%
      45%) was followed for 7.6+/-4.5 years in 63 patients. The preoperative 53+/-7.6%
      decreased to 44.2+/-6.3% (p<0.05).

PMID- 10412938
TI  - Post-thoracotomy spirometric lung function: the effect of analgesia. A review.
AB  - BACKGROUND: The effects of postthoracotomy pain management on pulmonary function
      has been assessed. METHODS: All English language publications involving
      prospective, randomised, controlled studies of patients undergoing postero
      lateral thoracotomy incisions where perioperative spirometry had been studied
      were included. The mean postoperative percentage preservation of preoperative
      lung function was recorded or determined for each analgesic regimen. RESULTS: 55
      studies were reviewed with a total of 1762 patients. The most effective analgesic
      method in terms of preservation of spirometric function was paravertebral
      analgesia, patients having approximately 75% of their preoperative values in the
      first 48 hours after surgery. Most other techniques e.g. intercostal nerve
      blocks, epidural local anaesthetics or local anaesthetic-opiate combinations
      produced approximately a 55% preservation by 48 hours. Interpleural analgesia was
      the least effective, with a mean of 35% preservation by 48 hours, less even than
      TENS or cryoanalgesia. CONCLUSIONS: A thoracotomy potentially produces a marked
      reduction in postoperative pulmonary function and the choice of pain management
      has major implications. Attenuation of postthoracotomy pulmonary dysfunction by
      effective analgesia should be provided for all patients undergoing chest surgery.
      Simply providing effective analgesia on its own without regard to pulmonary
      function is inadequate. Spirometric monitoring should be standard in all thoracic
      units and is essential for objective comparisons of the efficacy of different
      methods of pain management.

PMID- 10412939
TI  - Sarcoma of the main pulmonary artery: an unusual etiology for recurrent pulmonary
      emboli.
AB  - We describe a case of primary pulmonary artery (PA) trunk spindle cell sarcoma in
      an 86 year old female presenting clinically with debilitating signs of recurrent
      pulmonary embolism. Further extensive work aroused suspicion for pulmonary artery
      malignancy. Palliative wide surgical resection, pulmonary artery tumor
      embolectomy and reconstruction of the proximal pulmonary artery and right
      ventricle outflow tract (RVOT) with bovine pericardial tissue were performed. She
      survived the procedure with an improved quality of life, but expired due to
      recurrence at 6 months postoperatively. Albeit uncommon, pulmonary artery sarcoma
      is nowadays a more frequently preoperatively diagnosed and surgically treated
      malignancy. With a modern low perioperative mortality, aggressive surgical
      resection remains as the single most effective modality for its treatment and can
      result in short term palliation in selected patients.

PMID- 10412940
TI  - The Rumel technique. An aid for difficult diaphragmatic closures.
AB  - The inherent weakness of repairing the surgically divided respiratory diaphragm
      is that it is a muscle to muscle closure which can easily tear. During the
      thoracoabdominal exposure of the thoracolumbar vertebrae, the left hemidiaphragm
      is divided circumferentially. Possible due to unique conditions related to these
      operations the diaphragm could not initially be reapproximated primarily in about
      20% of the patients. A modified Rumel technique is described as an aid for
      closing these difficult divided diaphragms. This simple techniques succeeds by
      distributing the wound tension along the entire diaphragmatic suture line and not
      on one suture especially while being tied.

PMID- 10412941
TI  - Biomodulation of 5-fluorouracil by interferon-alpha in human renal carcinoma
      cells: relationship to the expression of thymidine phosphorylase.
AB  - PURPOSE: To provide the basis for improved therapeutic benefit in combination
      chemotherapy with interferon (IFN) and 5-fluorouracil (5-FU), we investigated the
      modulatory actions of human recombinant IFN alfa-2a on 5-FU in five renal cell
      carcinoma (RCC) cell lines in vitro, in particular focusing on thymidine
      phosphorylase (TP) expression. METHODS: The sensitivity of RCC cell lines to the
      drugs was evaluated using an AlamarBlue assay. An enzyme-linked immunosorbent
      assay (ELISA) was used to determine TP expression. RESULTS: IFN-alpha enhanced
      the sensitivity of three of five RCC cell lines to 5-FU in a dose- and schedule
      dependent manner. When IFN-alpha was given prior to 5-FU, sensitivity to 5-FU was
      significantly higher than when IFN-alpha was given simultaneously (P < 0.05). IFN
      alpha enhanced TP expression in a dose-dependent manner in three of five RCC cell
      lines (P < 0.05). The relative IFN-alpha-induced increase in sensitivity to 5-FU
      correlated with the relative IFN-alpha-induced increase in TP expression (P <
      0.05). In addition, two of three RCC cell lines with more than a twofold increase
      in sensitivity to 5-FU induced by IFN-alpha showed a higher TP expression without
      IFN-alpha stimulation. CONCLUSIONS: These results suggest that IFN-alpha
      upregulates TP expression and modulates 5-FU anabolism thus enhancing 5-FU
      cytotoxicity in a dose- and schedule-dependent manner in some RCC cells. The
      results imply that TP expression measurement in RCC could identify subgroups of
      metastatic RCC that may respond to IFN-alpha/5-FU combination therapy, and
      sequential administration of IFN-alpha followed by 5-FU may be beneficial in such
      cases.

PMID- 10412942
TI  - Antitumor mechanisms and metabolism of the novel antitumor nucleoside analogues,
      1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine and 1-(3-C-ethynyl-beta-D-ribo
      pentofuranosyl)uracil.
AB  - The antitumor ribonucleoside analogues 1-(3-C-ethynyl-beta-D-ribo
      pentofuranosyl)cytosine (ECyd) and 1-(3-C-ethynyl-beta-D-ribo
      pentofuranosyl)uracil (EUrd), first synthesized in 1995, have strong antitumor
      activity against human cancer xenografts without severe side effects. Here, we
      studied the antitumor mechanisms of ECyd and EUrd using mouse mammary tumor FM3A
      cells in vitro and the mechanism of selective cytotoxicity of ECyd using human
      tumor xenografts in nude rats in vivo. In FM3A cells, ECyd and EUrd were rapidly
      phosphorylated to ECyd 5'-triphosphate (ECTP) and EUrd 5'-triphosphate (EUTP),
      which strongly inhibiting RNA synthesis. Cells treated with EUrd were later found
      to contain both EUTP and ECTP, and ECTP accumulated as the final product.
      Probably the uracil moieties of EUrd derivatives were efficiently converted to
      cytosine moieties in the cells. EUrd and its derivatives were minor metabolites
      in the cells treated with ECyd, so cytidine forms probably were not converted to
      uridine forms at the nucleoside or nucleotide stage. The ultimate metabolite of
      ECyd and EUrd, ECTP, is stable in cultured cells with a half-life of at least 3
      days, so ECyd and EUrd are on a "closed" metabolic pathway to ECTP. These
      characteristics of ECyd and EUrd may be important for their antitumor activity.
      ECyd had strong and selective antitumor activity against the human tumor
      xenografts. ECyd-phosphorylating activity (uridine/cytidine kinase) in the
      xenografts was higher than that in the organs of the rats. This finding may
      account for the strong activity with mild side effects. ECyd and EUrd may be a
      new kind of antitumor nucleoside analogue for clinical use.

PMID- 10412944
TI  - Potentiation of the cytostatic effect of melphalan on colorectal cancer hepatic
      metastases by infusion of buthionine sulfoximine (BSO) in the rat: enhanced tumor
      glutathione depletion by infusion of BSO in the hepatic artery.
AB  - PURPOSE: Glutathione (GSH) plays an important role in the resistance of tumors to
      cytostatics. Therefore, depletion of GSH by the GSH synthesis inhibitor
      buthionine sulfoximine (BSO) has been proposed to enhance the efficacy of certain
      anticancer agents. We studied the effect of BSO in rats bearing intrahepatically
      implanted tumors of the CC531 colorectal cancer cell line on the antitumor
      activity of melphalan (L-PAM). Since these liver tumors tend to derive most of
      their blood supply from the hepatic artery, we evaluated whether delivery of BSO
      into the hepatic artery would more selectively decrease GSH levels in the
      implanted tumor tissue as compared with normal liver and extrahepatic tissues.
      METHODS: Tumor-bearing rats were treated with a 24-h continuous infusion of 0.375
      mmol/ kg BSO via the jugular vein, immediately followed by a bolus L-PAM (15
      micromol/kg; 4.5 mg/kg) infusion via the hepatic artery. Laparotomy was performed
      on day 14 and 28 after treatment for measurement of the liver tumors. For the
      evaluation of locoregional administration of BSO, a 24-h continuous infusion of
      0.375 mmol/kg BSO was delivered into either the hepatic artery, the portal vein,
      or the jugular vein in freely moving rats and GSH levels in the tumor, liver,
      kidney, lung, heart, bone marrow, and blood were measured. RESULTS: BSO infusion
      via the jugular vein increased the antitumor efficacy of L-PAM injected into the
      hepatic artery 2-fold as determined at 14 days after treatment. Although infusion
      of BSO via the hepatic artery depleted GSH more severely in the tumor as compared
      with jugular vein or portal vein administration, the additional effect was only
      slight (10%). No difference was observed in any other tissue. CONCLUSION: GSH
      depletion increased the cytostatic efficacy of L-PAM 2-fold in vivo as determined
      at 14 days after treatment. Hepatic artery infusion of BSO translated into a
      statistically significant, but probably not therapeutically relevant, increase in
      tumor GSH depletion as compared with the other routes of BSO administration.

PMID- 10412943
TI  - Activity of the multitargeted antifolate LY231514 in the human tumor cloning
      assay.
AB  - PURPOSE: This study was performed to evaluate the activity of the multitargeted
      antifolate (MTA or LY231514) against a broad range of human tumors taken directly
      from patients. MATERIALS AND METHODS: Human tumor colony-forming units were
      treated with MTA at concentrations of 0.1, 1.0, and 10 microg/ml in 1-h exposure
      studies. The responses of a limited number of specimens were also evaluated
      concurrently in 1-h exposures to cisplatin, fluorouracil, irinotecan, and/or
      paclitaxel. RESULTS: Of 358 specimens plated in the 1-h exposure studies, 148
      (41%) were evaluable. Overall, responses were observed in 3% of specimens (4/144)
      at 0.1 microg/ml, 11% (17/148) at 1.0 microg/ml, and 23% (33/141) at 10
      microg/ml. In this range of concentrations achievable clinically, there was a
      significant concentration-response relationship. At 10 microg/ml in the 1-h
      exposure studies, the response rate in colorectal cancer specimens was 32%
      (9/28), and the response rate in non-small-cell lung cancer was 25% (6/24).
      Responses were also observed in several chemoresistant tumors, including renal
      cell carcinoma, hepatocellular carcinoma, mesothelioma, and pancreatic carcinoma.
      The activity of MTA was not completely cross-resistant with that of cisplatin,
      fluorouracil, irinotecan, and paclitaxel. CONCLUSIONS: MTA demonstrated in vitro
      activity against a spectrum of tumors, including several tumors generally
      considered chemoresistant.

PMID- 10412945
TI  - Supraadditive effect of 2',2'-difluorodeoxycytidine (gemcitabine) in combination
      with oxaliplatin in human cancer cell lines.
AB  - PURPOSE: This study assessed the cytotoxic effects of the nucleoside analog
      gemcitabine in combination with the diaminocyclohexane platinum compound
      oxaliplatin. METHODS: Growth inhibition studies were performed using the human
      CEM leukemia cell line and the colon-cancer cell lines HCT 116 and Colo 320 DM.
      Gemcitabine-oxaliplatin combinations were compared with gemcitabine-cisplatin
      combinations in the same cell lines using similar experimental settings. Cells
      were exposed for 2 h to gemcitabine and then for 24 h to oxaliplatin or
      cisplatin, and vice versa. RESULTS: The 50% inhibitory concentrations (IC50
      values) in single-drug experiments using 2 h of exposure to gemcitabine and 24 h
      of exposure to oxaliplatin or cisplatin were, respectively, 89 pM, 11.1 microM,
      and 10.3 microM for CEM cells; 46 pM, 10.2 microM, and 2.7 microM for HCT 116
      cells; and 102 pM, 4.6 microM, and 8.6 microM for Colo 320 DM cells. Gemcitabine
      oxaliplatin combinations displayed supraadditive effects in human leukemia and
      colon-cancer cell lines. The sequence of gemcitabine followed by oxaliplatin was
      more effective than the opposite sequence in HCT 116 and Colo 320 DM colon-cancer
      cell lines, whereas the sequence of oxaliplatin followed by gemcitabine yielded
      to synergistic effects in CEM cells. The cytotoxic effects of gemcitabine
      oxaliplatin combinations were better than (HCT 116 cells) or equal to (CEM and
      Colo 320 DM cells) those of gemcitabine-cisplatin combinations. CONCLUSION: Our
      data show that the combination of gemcitabine with oxaliplatin exerts potent
      antiproliferative effects in human leukemia and colon cancer cells, warranting
      further investigations in the framework of phase I-II trials as an alternative
      for the treatment of solid malignancies.

PMID- 10412946
TI  - Phase II studies with DaunoXome in patients with nonresectable hepatocellular
      carcinoma: clinical and pharmacokinetic outcomes.
AB  - A total of 14 Chinese patients with inoperable hepatocellular carcinoma received
      a liposomal formulation of daunorubicin (DaunoXome) at a dose equivalent to 100
      mg/m2 of the free drug every 3 weeks. Altogether, 12 patients were assessable for
      response; 2 patients had stable disease for 8 weeks, but all eventually developed
      progressive disease and there was no responder. The drug was well tolerated, with
      no evidence of cardiac toxicity being observed. Deterioration of liver-function
      tests was attributed to progressive tumors in the terminal stage of the disease.
      Pharmacokinetics studies revealed a biexponential decay for daunorubicin in
      association with mean initial and terminal half-lives of 1.8 and 7.4 h,
      respectively, and a mean total clearance of 15.0+/-5.5 ml/min. The AUC ratio
      between the metabolite daunorubicinol and daunorubicin was 0.07. These data
      differ markedly from the pharmacokinetics of the free drug.

PMID- 10412947
TI  - Structure-activity profiles of eleutherobin analogs and their cross-resistance in
      Taxol-resistant cell lines.
AB  - PURPOSE: Eleutherobin, a natural product, is an antimitotic agent that promotes
      the polymerization of stable microtubules. Although its mechanism of action is
      similar to that of Taxol, its structure is distinct. A structure-activity profile
      of synthetic eleutherobin derivatives that have modifications at C3, C8 and C15
      was undertaken to define the structural requirements for microtubule
      stabilization and cross-resistance in Taxol-resistant cell lines. METHODS: The
      biological activity of five eleutherobin analogs was assessed using three
      techniques: (1) cytotoxicity and drug-resistance in three paired Taxol-sensitive
      and -resistant cell lines; (2) polymerization of microtubule protein in vitro in
      the absence of GTP and (3) induction of microtubule bundle formation in NIH3T3
      cells. RESULTS: Eleutherobin had an IC50 value comparable to that of Taxol,
      whereas neoeleutherobin, which has a carbohydrate domain that is enantiomeric
      with that of the parent compound, was less cytotoxic and had 69% of the maximum
      microtubule polymerization ability of eleutherobin. Both of these compounds
      exhibited cross-resistance in MDRI-expressing cell lines. Removal or replacement
      of the C15 sugar moiety resulted in reduced microtubule polymerization and
      cytotoxicity compared to eleutherobin and loss of cross-resistance in the cell
      lines SKVLB and J7-T3-1.6, both of which express high levels of P-glycoprotein.
      By contrast, removal of the urocanic acid group at C8 resulted in virtually
      complete abrogation of biological activity. The compound lost its ability to
      polymerize microtubules, and its cytotoxicity was reduced by a minimum of 2000
      fold in lung carcinoma A549 cells. CONCLUSIONS: Removal or modification of the
      sugar moiety alters the cytotoxic potency of eleutherobin and its pattern of
      cross-resistance in Taxol-resistant cells, although such compounds retain a small
      percentage of the microtubule-stabilizing activity of eleutherobin. The N(1)
      methylurocanic acid moiety of eleutherobin, or perhaps some other substituent at
      the C8 position, is essential for Taxol-like activity. These findings will be
      important for the future design and the synthesis of new and more potent
      eleutherobin derivatives.

PMID- 10412948
TI  - Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel.
AB  - PURPOSE: Results of several clinical studies suggest that the combination of
      doxorubicin (DOX) and paclitaxel (PTX) is highly active against solid tumors.
      Both drugs are known to cause adverse cardiac effects, cardiomyopathy in the case
      of DOX and acute changes in cardiac rhythm in the case of PTX. It has been
      suggested that the addition of dexrazoxane (DZR) to this regimen may reduce the
      risk of cardiotoxicity. A model of chronic cardiomyopathy in the rat was used to
      determine whether DZR was tolerated and cardioprotective in a DOX + PTX
      combination. METHODS: Male rats were treated once weekly for 7 weeks with one of
      the following vehicle and/or drug sequences: Group A, M/6 sodium
      lactate/saline/Cremophor EL (CEL); Group B, lactate/DOX/CEL; Group C,
      DZR/DOX/CEL; Group D, lactate/DOX/PTX; and Group E, DZR/DOX/PTX. DZR and DOX or
      their respective vehicles were given i.v. whilst PTX or CEL were given i.p. DZR,
      DOX and PTX were administered at 16 mg/kg, 0.8 mg/kg and 2.4 mg/kg, respectively,
      doses which caused minimal noncardiac toxicities. The hearts were examined
      histologically 5 weeks following the last treatment. RESULTS: There were no
      deaths and no signs of overt toxicity during the 12 weeks of study. There was a
      significant decrease (P < 0.01) in white blood cell count in rats treated with
      DZR + DOX, DOX + PTX or DZR + DOX + PTX but not in those given DOX alone. Liver
      and kidney weights were increased in rats given DOX (P < 0.05) but not in those
      given DZR + DOX. PTX had no effect on the DOX-induced liver and kidney changes
      and did not interfere with the protective effect of DZR on the kidney. The
      severity and extent of cardiomyopathy expressed as the mean total score (MTS) for
      each treatment group, was similar for DOX and DOX + PTX (4.6 and 4.2,
      respectively). DZR provided significant cardioprotection (P < 0.01) when added to
      either DOX (MTS 2.0) or to DOX + PTX (MTS 2.1). CONCLUSIONS: The results suggest
      that PTX does not exacerbate the chronic cardiomyopathy caused by DOX and when
      added to the DOX + PTX combination, DZR retains its protective activity against
      DOX-induced cardiotoxicity without increasing noncardiac toxicity.

PMID- 10412949
TI  - Adenovirus-mediated p53 gene therapy has greater efficacy when combined with
      chemotherapy against human head and neck, ovarian, prostate, and breast cancer.
AB  - PURPOSE: Adenovirus-mediated p53 gene therapy for cancer is currently undergoing
      phase I/II clinical trials. The drug used in our clinical trials (p53 Ad; ACN53;
      SCH58500) consists of a replication-deficient, type 5 adenovirus vector
      expressing human wildtype p53 tumor suppressor under the control of the
      cytomegalovirus promoter. In preclinical models, p53 Ad has therapeutic efficacy
      against a wide range of human tumor types containing nonfunctional p53, both in
      vitro and in vivo. Results from early clinical trials using p53 gene therapy by
      itself support optimism for the future of this therapeutic approach. However, it
      is likely that many phase II/III trials will incorporate an arm comparing
      traditional chemotherapy against chemotherapy combined with p53 gene therapy.
      Therefore, it is important to study possible interactions between p53 Ad and
      chemotherapeutic drugs in preclinical models before starting the clinical trials.
      METHODS: Proliferation of tumor cells was quantitated after incubation with
      various combinations of p53 Ad and chemotherapeutic drugs. Human tumor xenografts
      in scid mice were dosed with intraperitoneal or intratumoral p53 Ad with or
      without chemotherapeutic drugs and the tumor burden after therapy monitored.
      RESULTS: p53 Ad combined with cisplatin, doxorubicin, 5-fluorouracil,
      methotrexate, or etoposide inhibited cell proliferation more effectively than
      chemotherapy alone in SCC-9 head and neck, SCC-15 head and neck, SCC-25 head and
      neck, SK-OV-3 ovarian, DU-145 prostate, MDA-MB-468 breast, and MDA-MB-231 breast
      tumor cells. No obvious dependence on dosing schedule was observed. Greater
      anticancer efficacy was also demonstrated in four human tumor xenograft models in
      vivo. Of particular significance, there was enhanced efficacy using the three
      drug combination of p53 Ad, cisplatin, and paclitaxel in an ovarian cancer model.
      CONCLUSION: These results support the combination of p53 gene therapy with
      chemotherapy in clinical trials.

PMID- 10412950
TI  - Immunosuppressant inhibition of P-glycoprotein function is independent of drug
      induced suppression of peptide-prolyl isomerase and calcineurin activity.
AB  - PURPOSE: P-glycoprotein is a 170-kDa plasma membrane multidrug transporter that
      actively exports cytotoxic substances from cells. Overexpression of P
      glycoprotein by tumor cells is associated with a multidrug-resistant phenotype.
      Immunosuppressive agents such as cyclosporins and macrolides, have been shown to
      attenuate P-glycoprotein activity. However, the mechanism by which some
      immunosuppressants inhibit P-glycoprotein function has not been determined. Since
      cyclosporin and macrolide immunosuppressants inhibit calcineurin (CaN)
      phosphatase and FKBP12 peptideprolyl isomerase (FKBP12 PPI) activity, studies
      were conducted to determine if these effects are directly related to the
      inhibitory effects these immunosuppressants have on P-glycoprotein function.
      METHODS: Western blot analysis was performed to assess CaN and FKBP12 protein
      levels in P-glycoprotein-negative (MCF-7) and -positive (MCF-7/Adr) breast cancer
      cell lines. P-glycoprotein function was determined by intracellular doxorubicin
      accumulation and/or cytotoxicity assays before and after CaN and FKBP12 were
      independently inhibited by pharmacological antagonists. RESULTS: CaN and FKBP12
      levels were similar in MCF-7 and MCF-7/Adr cells. P-glycoprotein function was not
      affected by treatment of P-glycoprotein-expressing MCF-7/Adr cells with CaN and
      FKBP12 antagonists. CONCLUSIONS: These results demonstrate that the inhibitory
      effects of immunosuppressive agents on P-glycoprotein function are independent of
      CaN or FKBP12 PPI activity.

PMID- 10412951
TI  - Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in
      patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus
      based chemotherapy: a phase II study.
AB  - Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus
      5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the
      duration of exposure to the latter is prolonged. The main objective of this study
      was therefore to determine the activity of a prolonged infusion schedule of 5-FU
      + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus
      based chemotherapy. Only patients with metastatic measurable disease in
      progression during or within 2 months of the end of a 5-FU bolus +/- LV-based
      chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day
      c.i. every 28 days, the 5-FU dose being 200 mg/m2 per day and the l-LV dose being
      5 mg/m2 per day. A total of 59 patients entered the study, of which 48 were
      resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well
      tolerated, and WHO grade 3-4 toxicities were uncommon (11% of patients developed
      stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59
      patients obtained an objective response (1 complete response, 9 partial
      responses), for an objective response rate of 16% (95% confidence interval 8
      25%). The median progression-free survival and overall survival were 4 and 9
      months, respectively. The protracted 5-FU + LV c.i. schedule used in the present
      study is a well-tolerated and moderately active regimen in metastatic colorectal
      cancer patients resistant to 5-FU bolus +/- LV. Only randomized studies can
      determine whether this palliative treatment has advantages in comparison with
      other second-line therapies such as 5-FU c.i. without LV, irinotecan, or
      oxaliplatin.

PMID- 10412953
TI  - Increased urinary losses of carnitine during ifosfamide chemotherapy.
AB  - Chloroacetaldehyde and thiodiglycolic acid, two metabolites of ifosfamide,
      interfere with mitochondrial function and may sequester carnitine. Urinary
      excretion of carnitine was measured in five patients before and during a
      continuous infusion of ifosfamide over 5 days at a dose of 2.8-3.2 g/m2 per day.
      The excretion of free and total carnitine increased from 85+/-53 to 2697+/-1393
      micromol/day on the 1st day of chemotherapy and then gradually decreased. The
      average loss of carnitine during a chemotherapy cycle amounted to 8.5 mmol. The
      formation and excretion of esters of carnitine and metabolites of ifosfamide
      and/or a decreased renal tubular reabsorption could account for this marked loss,
      which might lead to symptomatic carnitine deficiency after several chemotherapy
      cycles.

PMID- 10412952
TI  - Reversible nephrotoxicity of onconase and effect of lysine pH on renal onconase
      uptake.
AB  - PURPOSE: To examine the histopathology of the kidney in mice following repeated
      injections of the antitumor drug onconase, and to determine whether lysine, which
      reportedly blocks kidney uptake of other basic proteins, blocks the high renal
      uptake of onconase. METHODS: Mice received repeated intraperitoneal onconase
      injections over 3 weeks. Kidneys were examined by light microscopy after 1 week,
      3 weeks, and 5 weeks (2 weeks after cessation of injections) and compared to
      kidneys from animals receiving a similar schedule of PBS injections. Renal uptake
      of radioiodinated onconase was measured in animals receiving intraperitoneal
      injections of lysine solutions of acidic and neutral pH given at -30, 0 and + 5
      min relative to intravenous onconase injection. Renal onconase uptake was also
      measured in animals made metabolically acidotic by ingestion of ammonium
      chloride, arginine chloride or lysine dihydrochloride from the drinking water.
      RESULTS: Onconase caused acute moderate multifocal proximal renal tubular
      necrosis, and this toxicity was reversed by 2 weeks after drug withdrawal.
      Intraperitoneal injections of lysine dihydrochloride in PBS (pH 1.5) reduced
      renal onconase uptake at 15 min from 67.9+/-13.4% to 17.0+/-3.8% of the injected
      dose without affecting the plasma concentration and also reduced the fraction of
      degraded onconase in the urine. However, neutral solutions of lysine
      dihydrochloride at pH 7.4 or lysine acetate at pH 7.1 were ineffective at
      blocking renal onconase uptake. Furthermore, renal onconase uptake was minimally
      or not affected by a state of metabolic acidosis. CONCLUSIONS: Proximal tubular
      toxicity of onconase was reversible. Renal onconase uptake was blocked by lysine
      at pH 1.5 but not at neutral pH.

PMID- 10412954
TI  - Distribution of daunorubicin and daunorubicinol in human glioma tumors after
      administration of liposomal daunorubicin.
AB  - DaunoXome is a liposome formulation containing daunorubicin (DM). Encapsulation
      of the drug in liposomes presents the advantage of low-level systemic exposure
      and better drug penetration into the tumor. We studied the distribution of DM and
      its 13-dihydro metabolite, daunorubicinol (DMol), in surgical biopsies from
      different parts of glioblastomas. The study was performed in eight patients with
      recurrent glioblastoma, all of whom had previously undergone surgery and been
      treated with radiotherapy and chemotherapy, who received 50 mg of DaunoXome as a
      1-h infusion. Surgery was performed at 24 and 48 h after the infusion in seven
      cases and one case, respectively. Biopsies were divided into three parts: the
      central area of the tumor, peripheral tumor tissue, and brain-adjacent tumor
      (BAT) tissue. A complete plasma pharmacokinetics study was conducted in seven
      cases, with samples being taken for up to 48 h after the end of the infusion. DM
      and DMol were determined in plasma and tissue by high-performance liquid
      chromatography with fluorescence detection after solvent extraction. At 24 h,
      concentrations of DM and DMol in the central part of the tumor ranged between <
      0.005 and 0.80 microg/g and between 0.005 and 1.58 microg/g, respectively.
      Concentrations were similar in the peripheral tumor and in BAT tissue. From the
      data obtained on the patient who underwent surgery at 48 h it appears that DM and
      DMol remain in tumor tissue for a long time, the concentrations being 0.4 and 2.8
      microg/g, respectively. DaunoXome was rapidly cleared from the body, with the
      plasma levels of DM and DMol determined at 48 h lying in the range of < 5-50 and
      < 5-20 ng/ml, respectively. The mean (+/-SD) half-life and plasmatic clearance of
      DM were 4.8+/-1.0 h and 0.2+/-0.06 l h(-1) m(-2). In conclusion, DaunoXome
      achieved and maintained potentially cytotoxic levels of both DM and DMol in
      glioblastoma for a long time in association with low-level systemic exposure.
      Further studies are therefore warranted. Although only preliminary and obtained
      in previously treated patients, these data suggest that DaunoXome merits
      investigation in CNS tumors.

PMID- 10412955
TI  - Seeking causal explanations in social epidemiology.
AB  - Social factors are associated with a wide variety of health outcomes. Social
      epidemiology has successfully used the traditional methods of surveillance and
      description to establish consistent relations between social factors and health
      status. Epidemiology as an etiologic science, however, has been largely
      ineffective in moving toward causal explanations for these observed patterns.
      Using the counterfactual approach to causal inference, the authors describe
      several fundamental problems that often arise when researchers seek to infer
      explanatory mechanisms from data on social factors. Contrasts that form standard
      causal effect estimates require implicit unobserved (counterfactual) quantities,
      because observational data provide only one exposure state for each individual.
      Although application of counterfactual arguments has successfully advanced
      etiologic understanding in other observational settings, the particular nature of
      social factors often leads to logical contradictions or misleading inferences
      when investigators fail to clearly articulate the counterfactual contrasts that
      are implied. For example, because social factors are often attributes of
      individuals and are components of structured social relations, random assignment
      is not plausible even as a hypothetical experiment, making typical epidemiologic
      contrasts inappropriate and the inference equivocal at best. Accordingly, more
      deliberate and creative approaches to causal inference in social epidemiology are
      required. Infectious disease epidemiology and systems analysis provide examples
      of approaches to causal inference that can be used when statistical mimicry of
      simple experimental designs is not tenable. In an era of increasing social
      inequality, valid approaches for the study of social factors and health are
      needed more urgently than ever.

PMID- 10412956
TI  - Invited commentary: social mechanisms, race, and social epidemiology.

PMID- 10412958
TI  - Socioeconomic status and aortic atherosclerosis in Dutch elderly people: the
      Rotterdam Study.
AB  - An inverse association has been reported between socioeconomic status (SES) and
      cardiovascular morbidity and mortality. Studies on subclinical manifestations of
      atherosclerotic disease are limited and have not been carried out among elderly
      persons. The authors investigated the relation between SES and aortic
      atherosclerosis among elderly people. As part of the Rotterdam Study, data on SES
      and atherosclerosis were collected for 4,451 persons aged 55-94 years.
      Atherosclerosis was estimated by radiographic assessment of calcified deposits in
      the abdominal aorta. Aortic atherosclerosis was more common among women in the
      lower educational and occupational strata. The lowest educational group and the
      lowest occupational group had increased risks of aortic atherosclerosis compared
      with the highest groups (odds ratios were 1.3 (95% confidence interval (CI) 1.0
      1.6) and 1.3 (95% CI 1.0-1.8), respectively). The odds ratios for severe
      atherosclerosis among women in the lowest socioeconomic stratum compared with
      those in the highest stratum were 1.6 (95% CI 1.0-2.7) for education, 2.8 (95% CI
      1.1-7.5) for occupation, and 1.7 (95% CI 0.9-3.3) for income. After exclusion of
      persons with a history of cardiovascular disease, the same trends still emerged.
      No relations were observed among men. These findings show that SES is related to
      aortic atherosclerosis in women. This suggests that SES affects the incidence of
      cardiovascular disease before its clinical manifestation.

PMID- 10412957
TI  - Relations between individual and neighborhood-based measures of socioeconomic
      position and bone lead concentrations among community-exposed men: the Normative
      Aging Study.
AB  - To examine the association between lead exposure and both individual and
      geographic area indicators of socioeconomic position, the authors measured tibia
      lead concentration, a biomarker of cumulative lead exposure, using K x-ray
      fluorescence in a cross-sectional survey of 538 white males aged 50-92 years who
      were healthy when enrolled in the Normative Aging Study (Boston, Massachusetts)
      in the 1960s. Data on individual risk factors, education, occupation, and income
      were collected by questionnaire. Using subjects' residential addresses at the
      time of the tibia lead measurements, the authors obtained geographic area
      specific measures of education, social class, and poverty by linking records to
      1990 US Census block group data. In multivariate linear regression analysis
      controlling for age and cumulative smoking, tibia lead concentrations were 10.39
      microg/g (95% confidence interval (CI) 7.80-12.97) higher in men who did not
      graduate from high school than in men with > or =4 years of college. Among the
      former men (non-high school graduates), living in an undereducated area was
      associated with a 9.28 microg/g (95% CI 1.59-16.97) increase in tibia lead level
      compared with living in a non-undereducated area; among the latter men (college
      graduates), no difference existed by residential area education (beta = 0.72, 95%
      CI -5.35 to 6.78). The authors conclude that the influence of individual
      socioeconomic position on cumulative lead exposure is modified by geographic area
      conditions.

PMID- 10412959
TI  - Chlamydia pneumoniae infection and incident coronary heart disease: the
      Atherosclerosis Risk in Communities Study.
AB  - Pathologic findings and cross-sectional epidemiologic studies suggest that past
      infection with Chlamydia pneumoniae is associated with clinical and subclinical
      atherosclerotic disease, although evidence from prospective studies is still
      scarce. The association between chronic infection by C. pneumoniae and incident
      coronary heart disease (CHD) was investigated in a case-cohort study conducted
      among participants in the Atherosclerosis Risk in Communities Study who were free
      of CHD at the baseline examination (1986-1989). Levels of C. pneumoniae
      immunoglobulin G (IgG) antibodies in serum collected at baseline from 246
      incident cases of CHD identified during follow-up (median, 3.3 years; maximum, 5
      years) were compared with those from a stratified sample of the baseline cohort
      (n = 550). Among incident CHD cases, 65% had IgG antibody titers > or =1:64,
      compared with 55% of noncases (compared with negative IgG titers, the relative
      hazard of CHD was 1.6 (p < 0.01)). In multivariate analyses controlling for other
      risk factors (age, gender, smoking, serum cholesterol, hypertension, diabetes
      mellitus, and educational level), the above estimates were substantially reduced
      and became statistically nonsignificant (relative hazard = 1.2). A significantly
      increased CHD hazard associated with IgG antibody titers > or =1:64 was observed
      among nonsmokers, even after adjustment for other risk factors. Overall, these
      results do not provide strong support for the hypothesis that C. pneumoniae
      infection is a risk factor for clinical CHD. Studies with longer follow-up
      periods will be necessary to determine whether C. pneumoniae infection is
      involved as an etiologic factor in earlier phases of atherogenesis.

PMID- 10412960
TI  - Effects of pesticide exposure on time to pregnancy: results of a multicenter
      study in France and Denmark. ASCLEPIOS Study Group.
AB  - The aim of this study was to determine whether there was a relation between male
      exposure to pesticides and the amount of time needed to conceive (time to
      pregnancy) for farmers and agricultural workers in France and Denmark. The
      authors used retrospective studies to compare the time to pregnancy of couples in
      which the man was exposed to pesticides during the year before the birth of their
      youngest child with that of couples in which the man was not exposed. In 1995 and
      1996, the authors studied 362 French rural workers (142 exposed to pesticides and
      220 not exposed), 449 Danish farmers (326 conventional farmers exposed to
      pesticides and 123 nonexposed organic farmers), and 121 Danish greenhouse workers
      exposed to pesticides. The fecundability ratio for exposure to pesticides (Cox
      model, before and after adjustment for confounding factors) did not differ from 1
      in any of the three populations. In France, the adjusted fecundability ratio was
      1.17 (95% confidence interval (CI) 0.89-1.55) for exposed and nonexposed
      agricultural workers. In Denmark, it was 1.09 (95% CI 0.82-1.43) for exposed and
      nonexposed farmers and 0.83 (95% CI 0.69-1.18) for greenhouse workers and
      nonexposed farmers. Thus, this study found no relation between fertility (time to
      pregnancy) and male exposure to pesticides.

PMID- 10412961
TI  - Evaluation of an intervention to reduce sun exposure in children: design and
      baseline results.
AB  - The Kidskin Study is a 5-year intervention study (1995-1999) involving 1,776 5-
      and 6-year-old children attending 33 primary schools in Perth, Western Australia.
      The aim of the study is to design, implement, and evaluate an intervention to
      reduce sun exposure in young children. There are three study groups: a control
      group, a "moderate intervention" group, and a "high intervention" group. The
      control schools receive the standard Western Australian health education
      curriculum, while the moderate and high intervention schools receive a specially
      designed curricular intervention. In addition, children in the high intervention
      group receive program materials over the summer holidays, when exposure is likely
      to be highest, and are offered sun-protective swimwear at low cost. The main
      outcome measure is the number of nevi on the back. Other outcomes include nevi on
      the chest (boys only), face, and arms, levels of suntanning, degree of freckling,
      and sun-related behaviors. At baseline, the three groups were similar with
      respect to nevi and freckling after adjustment for observer and month of
      observation. Sun exposure was slightly higher in the high intervention group. The
      groups were also similar with respect to most potential confounders, although
      they differed with respect to Southern European ethnicity and parental education.

PMID- 10412962
TI  - Lactation in relation to postmenopausal breast cancer.
AB  - A modest inverse association between lactation and breast cancer risk has most
      consistently been observed in premenopausal women, and certain breastfeeding
      patterns, such as prolonged duration and early age at first lactation, may be
      important determinants of risk. However, these associations have not generally
      been observed in relation to postmenopausal breast cancer. As part of a
      multicenter population-based case-control study, the authors examined
      postmenopausal breast cancer risk according to breastfeeding characteristics.
      Breast cancer patients aged 50-79 years were identified from statewide tumor
      registries in Massachusetts, New Hampshire, and Wisconsin from July 1992 through
      July 1995. Similarly aged control women were randomly selected from population
      lists. Information regarding lactation history and breast cancer risk factors was
      obtained through telephone interviews. This analysis included only data on parous
      postmenopausal women (3,633 cases and 3,790 controls). After adjustment for age,
      parity, age at first birth, and other breast cancer risk factors, breastfeeding
      for at least 2 weeks was associated with a slightly reduced risk of breast cancer
      in comparison with women who had never lactated (relative risk = 0.87, 95%
      confidence interval 0.78-0.96). There was only a modest suggestion that
      increasing cumulative duration of lactation was inversely associated with breast
      cancer risk; the relative risk for women who had breastfed for > or =24 months
      was 0.73 (95% confidence interval 0.56-0.94) (p-trend for duration = 0.10). Age
      at first lactation was not consistently associated with risk. Modest inverse
      associations appeared to persist even up to 50 years since first lactation. Use
      of hormones to suppress lactation was not associated with postmenopausal breast
      cancer, nor was inability to breastfeed related to risk. These results suggest
      that lactation may have a slight and perhaps long-lasting protective effect on
      postmenopausal breast cancer risk.

PMID- 10412963
TI  - Lactose absorption in patients with ovarian cancer.
AB  - To determine whether lactase persistence might be related to ovarian cancer risk,
      in 1994-1995 the authors assessed the capacity to digest lactose by measuring
      breath hydrogen production after oral administration of lactose in 50 women with
      ovarian cancer and 100 healthy controls. All of the women came from Sassari
      (Sardinia), Italy, an area where the population has a high frequency of lactose
      malabsorption. Thirty percent of cases were lactose absorbers, as compared with
      15% of controls. The odds ratio for ovarian cancer among lactose absorbers was
      2.51 (95% confidence interval 1.10-5.68). These results provide some support for
      a role of lactose ingestion and galactose cytotoxicity in the pathogenesis of
      ovarian cancer.

PMID- 10412964
TI  - Nutrient intake and use of beverages and the risk of kidney stones among male
      smokers.
AB  - High intakes of calcium, potassium, and fluids have been shown to be associated
      with lowered risk of kidney stones. The authors studied the associations between
      diet and risk of kidney stones in a cohort of 27,001 Finnish male smokers aged 50
      69 years who were initially free of kidney stones. All men participated in the
      Alpha-Tocopherol, Beta-Carotene Lung Cancer Prevention Study and completed a
      validated dietary questionnaire at baseline. After 5 years of follow-up (1985
      1988), 329 men had been diagnosed with kidney stones. After data were controlled
      for possible confounders, the relative risk of kidney stones for men in the
      highest quartile of magnesium intake was 0.52 (95% confidence interval (CI) 0.32
      0.85) as compared with men in the lowest quartile. Intake of fiber was directly
      associated with risk (relative risk (RR) = 2.06, 95% CI 1.39-3.03). Calcium
      intake was not associated with the risk of kidney stones. Beer consumption was
      inversely associated with risk of kidney stones; each bottle of beer consumed per
      day was estimated to reduce risk by 40% (RR = 0.60, 95% CI 0.47-0.76). In
      conclusion, the authors observed that magnesium intake and beer consumption were
      inversely associated and fiber intake was directly associated with risk of kidney
      stones.

PMID- 10412965
TI  - Reliability of recall of physical activity in the distant past.
AB  - Substantial data exist supporting the role of physical activity in the etiology
      of several chronic diseases. Many chronic diseases begin developing 20-30 years
      before they become clinically evident. Since researchers often must rely on
      recall to characterize the long term habits of study participants, the accuracy
      of recall of physical activity is an important methodological issue in etiologic
      studies. The purpose of this study was to examine the quality of recall of
      physical activity in the distant past in a cohort of western New York residents
      followed since 1960. Paired t tests and intraclass correlation coefficients
      (ICCs) were used to compare "original" (1960) and "recalled" (1992-1996) reports
      of weekday (occupational) and free-day (leisure time) physical activity. Results
      showed that the recalled reports underestimated past weekday activities when
      overall activity was examined; estimates closer to the originals were found when
      levels of activity were examined. Recall was best for weekday light (ICC = 0.43)
      and weekday moderate (ICC = 0.45) activity in both sexes and free-day hard
      activity in females (ICC = 0.45). Most participants underestimated past free-day
      activity, but males overestimated free-day hard activity. Correlations for free
      day activity were highest for summer sports in females (ICC = 0.29) and winter
      sports in both sexes (ICC = 0.39) and were low for walking and "other activity."
      Considering the length of time between the original interviews and the recall
      interviews, the correlations found here are remarkable and close to those found
      in other studies where recall intervals were 10 years or less.

PMID- 10412966
TI  - Evaluation of old and new tests of heterogeneity in epidemiologic meta-analysis.
AB  - The identification of heterogeneity in effects between studies is a key issue in
      meta-analyses of observational studies, since it is critical for determining
      whether it is appropriate to pool the individual results into one summary
      measure. The result of a hypothesis test is often used as the decision criterion.
      In this paper, the authors use a large simulation study patterned from the key
      features of five published epidemiologic meta-analyses to investigate the type I
      error and statistical power of five previously proposed asymptotic homogeneity
      tests, a parametric bootstrap version of each of the tests, and tau2-bootstrap, a
      test proposed by the authors. The results show that the asymptotic DerSimonian
      and Laird Q statistic and the bootstrap versions of the other tests give the
      correct type I error under the null hypothesis but that all of the tests
      considered have low statistical power, especially when the number of studies
      included in the meta-analysis is small (<20). From the point of view of validity,
      power, and computational ease, the Q statistic is clearly the best choice. The
      authors found that the performance of all of the tests considered did not depend
      appreciably upon the value of the pooled odds ratio, both for size and for power.
      Because tests for heterogeneity will often be underpowered, random effects models
      can be used routinely, and heterogeneity can be quantified by means of R(I), the
      proportion of the total variance of the pooled effect measure due to between
      study variance, and CV(B), the between-study coefficient of variation.

PMID- 10412967
TI  - Re: The Gulf War syndrome controversy.

PMID- 10412968
TI  - Re: "Biologic plausibility in causal inference: current method and practice".

PMID- 10412970
TI  - Re: "Combined analysis of matched and unmatched case-control studies: comparison
      of risk estimates from different studies".

PMID- 10412969
TI  - Re: "Self-perceived health and 5-year mortality risks among the elderly in
      Shanghai, China".

PMID- 10412971
TI  - A didactic device for teaching epidemiology students how to anticipate the effect
      of a third factor on an exposure-outcome relation.

PMID- 10412972
TI  - Re: "Population attributable risk of renal cell cancer in Minnesota".

PMID- 10412973
TI  - Re: "Power-frequency electric and magnetic fields and risk of childhood leukemia
      in Canada".

PMID- 10412974
TI  - Fundamentally different logic of gene regulation in eukaryotes and prokaryotes.

PMID- 10412975
TI  - Intercellular connections are developmentally controlled to help move molecules
      through the plant.

PMID- 10412976
TI  - New insights into the interaction of Ras with the plasma membrane.

PMID- 10412977
TI  - Insights into the function of Rim protein in photoreceptors and etiology of
      Stargardt's disease from the phenotype in abcr knockout mice.
AB  - Rim protein (RmP) is an ABC transporter of unknown function in rod outer segment
      discs. The human gene for RmP (ABCR) is affected in several recessive retinal
      degenerations. Here, we characterize the ocular phenotype in abcr knockout mice.
      Mice lacking RmP show delayed dark adaptation, increased all-trans-retinaldehyde
      (all-trans-RAL) following light exposure, elevated phosphatidylethanolamine (PE)
      in outer segments, accumulation of the protonated Schiff base complex of all
      trans-RAL and PE (N-retinylidene-PE), and striking deposition of a major
      lipofuscin fluorophore (A2-E) in retinal pigment epithelium (RPE). These data
      suggest that RmP functions as an outwardly directed flippase for N-retinylidene
      PE. Delayed dark adaptation is likely due to accumulation in discs of the
      noncovalent complex between opsin and all-trans-RAL. Finally, ABCR-mediated
      retinal degeneration may result from "poisoning" of the RPE due to A2-E
      accumulation, with secondary photoreceptor degeneration due to loss of the RPE
      support role.

PMID- 10412978
TI  - MIG-13 positions migrating cells along the anteroposterior body axis of C.
      elegans.
AB  - The C. elegans Q neuroblasts and their descendants migrate along the
      anteroposterior (A/P) body axis to positions that are not associated with any
      obvious landmarks. We find that a novel protein, MIG-13, is required to position
      these cells correctly. MIG-13 is a transmembrane protein whose expression is
      restricted to the anterior and central body regions by Hox gene activity. MIG-13
      functions non-cell autonomously within these regions to promote migration toward
      the anterior: loss of mig-13 activity shifts the Q descendants toward the
      posterior, whereas increasing the level of MIG-13 shifts them anteriorly in a
      dose-dependent manner. Our findings suggest that MIG-13 is a component of a
      global A/P migration system, and that the level of MIG-13 determines where along
      the body axis these migrating cells stop.

PMID- 10412979
TI  - Stabilization of chromatin structure by PRC1, a Polycomb complex.
AB  - The Polycomb group (PcG) genes are required for maintenance of homeotic gene
      repression during development. Mutations in these genes can be suppressed by
      mutations in genes of the SWI/SNF family. We have purified a complex, termed PRC1
      (Polycomb repressive complex 1), that contains the products of the PcG genes
      Polycomb, Posterior sex combs, polyhomeotic, Sex combs on midleg, and several
      other proteins. Preincubation of PRC1 with nucleosomal arrays blocked the ability
      of these arrays to be remodeled by SWI/SNF. Addition of PRC1 to arrays at the
      same time as SWI/SNF did not block remodeling. Thus, PRC1 and SWI/SNF might
      compete with each other for the nucleosomal template. Several different types of
      repressive complexes, including deacetylases, interact with histone tails. In
      contrast, PRC1 was active on nucleosomal arrays formed with tailless histones.

PMID- 10412980
TI  - Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic
      cell apoptosis in autoimmune lymphoproliferative syndrome type II.
AB  - Caspases are cysteine proteases that mediate programmed cell death in
      phylogenetically diverse multicellular organisms. We report here two kindreds
      with autoimmune lymphoproliferative syndrome (ALPS) type II, characterized by
      abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects,
      that harbor independent missense mutations in Caspase 10. These encode amino acid
      substitutions that decrease caspase activity and interfere with death receptor
      induced apoptosis, particularly that stimulated by Fas ligand and TRAIL. These
      results provide evidence that inherited nonlethal caspase abnormalities cause
      pleiotropic apoptosis defects underlying autoimmunity in ALPS type II.

PMID- 10412981
TI  - Gbetagamma-mediated regulation of Golgi organization is through the direct
      activation of protein kinase D.
AB  - We have shown previously that the betagamma subunits of the heterotrimeric G
      proteins regulate the organization of the pericentriolarly localized Golgi
      stacks. In this report, evidence is presented that the downstream target of
      Gbetagamma is protein kinase D (PKD), an isoform of protein kinase C. PKD, unlike
      other members of this class of serine/threonine kinases, contains a pleckstrin
      homology (PH) domain. Our results demonstrate that Gbetagamma directly activates
      PKD by interacting with its PH domain. Inhibition of PKD activity through the use
      of pharmacological agents, synthetic peptide substrates, and, more specifically,
      the PH domain of PKD prevents Gbetagamma-mediated Golgi breakdown. Our findings
      suggest a possible mechanism by which the direct interaction of Gbetagamma with
      PKD regulates the dynamics of Golgi membranes and protein secretion.

PMID- 10412982
TI  - Endomembrane trafficking of ras: the CAAX motif targets proteins to the ER and
      Golgi.
AB  - We show that Nras is transiently localized in the Golgi prior to the plasma
      membrane (PM). Moreover, green fluorescent protein (GFP)-tagged Nras illuminated
      motile, peri-Golgi vesicles, and prolonged BFA treatment blocked PM expression.
      GFP-Hras colocalized with GFP-Nras, but GFP-Kras4B revealed less Golgi and no
      vesicular fluorescence. Whereas a secondary membrane targeting signal was
      required for PM expression, the CAAX motif alone was necessary and sufficient to
      target proteins to the endomembrane where they were methylated, a modification
      required for efficient membrane association. Thus, prenylated CAAX proteins do
      not associate directly with the PM but instead associate with the endomembrane
      and are subsequently transported to the PM, a process that requires a secondary
      targeting motif.

PMID- 10412983
TI  - Vesicular tubular clusters between the ER and Golgi mediate concentration of
      soluble secretory proteins by exclusion from COPI-coated vesicles.
AB  - We have determined the concentrations of the secretory proteins amylase and
      chymotrypsinogen and the membrane proteins KDELr and rBet1 in COPII- and COPI
      coated pre-Golgi compartments of pancreatic cells by quantitative immunoelectron
      microscopy. COPII was confined to ER membrane buds and adjacent vesicles. COPI
      occurred on vesicular tubular clusters (VTCs), Golgi cisternae, the trans-Golgi
      network, and immature secretory granules. Both secretory proteins exhibited a
      first, significant concentration step in noncoated segments of VTC tubules and
      were excluded from COPI-coated tips. By contrast, KDELr and rBet1 showed a first,
      significant concentration in COPII-coated ER buds and vesicles and were
      prominently present in COPI-coated tips of VTC tubules. These data suggest an
      important role of VTCs in soluble cargo concentration by exclusion from COPI
      coated domains.

PMID- 10412984
TI  - A central role for cohesins in sister chromatid cohesion, formation of axial
      elements, and recombination during yeast meiosis.
AB  - A multisubunit complex, called cohesin, containing Smc1p, Smc3p, Scc1p, and
      Scc3p, is required for sister chromatid cohesion in mitotic cells. We show here
      that Smc3p and a meiotic version of Scc1p called Rec8p are required for cohesion
      between sister chromatids, for formation of axial elements, for reciprocal
      recombination, and for preventing hyperresection of double-strand breaks during
      meiosis. Both Rec8p and Smc3p colocalize with chromosome cores independently of
      synapsis during prophase I and largely disappear from chromosome arms after
      pachytene but persist in the neighborhood of centromeres until the onset of
      anaphase II. The eukaryotic cell's cohesion apparatus is required both for the
      repair of recombinogenic lesions and for chromosome segregation and therefore
      appears to lie at the heart of the meiotic process.

PMID- 10412985
TI  - Nitric oxide contributes to behavioral, cellular, and developmental responses to
      low oxygen in Drosophila.
AB  - A nitric oxide (NO)/cyclic GMP (cGMP) signaling pathway is thought to play an
      important role in mammalian vasodilation during hypoxia. We show that Drosophila
      utilizes components of this pathway to respond to hypoxia. Hypoxic exposure
      rapidly induced exploratory behavior in larvae and arrested the cell cycle. These
      behavioral and cellular responses were diminished by an inhibitor of NO synthase
      and by a polymorphism affecting a form of cGMP-dependent protein kinase.
      Conversely, these responses were induced by ectopic expression of NO synthase.
      Perturbing components of the NO/cGMP pathway altered both tracheal development
      and survival during prolonged hypoxia. These results indicate that NO and protein
      kinase G contribute to Drosophila's ability to respond to oxygen deprivation.

PMID- 10412987
TI  - The geometry of slipped capital femoral epiphysis: implications for movement,
      impingement, and corrective osteotomy.
AB  - Metaphyseal impingement limits motion in high-grade slipped capital femoral
      epiphysis (SCFE). A three-dimensional volume/surface computer model was used to
      study the geometry of impingement, which may take the form of impaction, which
      causes levering or requires compensatory alteration in motion, or inclusion that
      occurs after remodeling and may lead to acetabular cartilage damage. The majority
      of deformities seen clinically can be reproduced with posterior epiphyseal
      displacement in the plane of the physis. By using the 3-D movements of normal
      walking, this model predicts little anterior metaphyseal impingement in the
      normal hip. As posterior slip angle increases to 25 degrees , minor impingement
      can be eliminated with as little as 20 degrees of external rotation. High-grade
      posterior slips (75 degrees ) require external rotation of 50-60 degrees during
      walking to minimize impaction. Sitting increases impingement for all slip
      geometries, requiring proportionately greater external rotation. As remodeling
      restores a more normal arc of motion, an increasing proportion of the femoral
      head is composed of the remodeled, included metaphyseal prominence. This study
      explores the potential role of contact between the acetabulum and the metaphysis
      in the production of abnormal range of motion after SCFE, and simulation
      estimates the correction needed by osteotomy to allow normal walking and sitting.
      The inclusion of significant metaphyseal surfaces in the remodeled hip may be one
      factor in subsequent degenerative changes associated with SCFE.

PMID- 10412986
TI  - Mechanisms controlling mitochondrial biogenesis and respiration through the
      thermogenic coactivator PGC-1.
AB  - Mitochondrial number and function are altered in response to external stimuli in
      eukaryotes. While several transcription/replication factors directly regulate
      mitochondrial genes, the coordination of these factors into a program responsive
      to the environment is not understood. We show here that PGC-1, a cold-inducible
      coactivator of nuclear receptors, stimulates mitochondrial biogenesis and
      respiration in muscle cells through an induction of uncoupling protein 2 (UCP-2)
      and through regulation of the nuclear respiratory factors (NRFs). PGC-1
      stimulates a powerful induction of NRF-1 and NRF-2 gene expression; in addition,
      PGC-1 binds to and coactivates the transcriptional function of NRF-1 on the
      promoter for mitochondrial transcription factor A (mtTFA), a direct regulator of
      mitochondrial DNA replication/transcription. These data elucidate a pathway that
      directly links external physiological stimuli to the regulation of mitochondrial
      biogenesis and function.

PMID- 10412988
TI  - Fate of the psoas muscle after open reduction for developmental dislocation of
      the hip (DDH).
AB  - We evaluated the anatomic and functional consequences of psoas lengthening during
      operative intervention for developmental dislocation of the hip (DDH). Possible
      anatomic changes were assessed by magnetic resonance imaging (MRI), and
      functional assessment included strength determination by an isokinetic
      dynamometer and gait analysis. Six girls and one boy, ranging in age from 15 to
      20 months, had operative reduction of a unilateral DDH. One closed and six open
      reductions (three anteromedial and three anterolateral approaches) were
      performed. Follow-up ranged from 4 years 0 months to 9 years 2 months. The cross
      sectional area determined by MRI of the lengthened psoas muscles was markedly
      reduced for all of the six open-reduction patients (three moderate and three
      severe). Atrophy of the iliacus muscle also was apparent by MRI in five of the
      six open-reduction patients. Maximum flexion torque, as determined by the
      isokinetic dynamometer, was diminished on the DDH side for the three patients
      whose hips were reduced open through the anteromedial approach. Average hip
      flexion torque over the entire range of motion was decreased for both
      anteromedial and anterolateral groups on the operated-on side. Lengthening of the
      psoas tendon during open reduction of a DDH is associated with considerable
      atrophy of the psoas muscle.

PMID- 10412989
TI  - The contribution of the ossific nucleus to the structural stiffness of the
      capital femoral epiphysis: a porcine model for DDH.
AB  - The preosseous femoral head is thought to be vulnerable to compressive ischemic
      injury during the treatment of developmental dysplasia of the hip. The ossific
      nucleus has been proposed to increase the mechanical strength of the capital
      femoral epiphysis (CFE) and to decrease the risk of avascular necrosis. Sixty
      mixed-breed fetal and postgestational femoral head specimens were evaluated for
      structural stiffness in relation to the size of the ossific nucleus within the
      CFE. The structural stiffness of the CFE in the porcine model was found to
      increase exponentially with the size of the ossific nucleus. A finite-element
      model revealed that the presence of an ossific nucleus occupying 40% of the
      epiphyseal volume reduced the compressive strain in the region of the posterior
      superior branch of the medial circumflex artery by an average of 54%. The results
      of this study support the hypothesis that the presence of the ossific nucleus may
      protect the CFE from compressive ischemic injury in the treatment of DDH.

PMID- 10412990
TI  - Anteversion of the acetabulum in developmental dysplasia of the hip: analysis
      with computed tomography.
AB  - Acetabular anteversion was measured by using two-dimensional (2-D) computed
      tomography (CT) scans in 39 dysplastic and 27 normal hips (patient age range, 3
      33 years), and averaged 19.7 degrees in the dysplastic hips and 18.1 degrees in
      the normal hips. There was no statistically significant difference between the
      two groups, with a wide range of acetabular anteversion values noted in both
      groups (8-32 degrees ). Although acetabular anteversion may be increased in some
      patients with developmental dysplasia of the hip (DDH), it is not a universal
      finding. We believe that assessment and understanding of acetabular anteversion
      is needed before performing corrective osteotomies for hip dysplasia to optimize
      results and avoid the complications of acetabular retroversion.

PMID- 10412991
TI  - Normal radiographic values for cartilage thickness and physeal angle in the
      pediatric hip.
AB  - Ninety-three standing anteroposterior (AP) pelvis roentgenograms in 87 patients
      were measured for a total of 186 normal hips in children aged 1-17 years. For
      each hip, the physeal angle relative to the floor, the physeal angle relative to
      the pelvis, the cartilage thickness perpendicular to the floor, and the cartilage
      thickness perpendicular to the physis were measured and recorded. The physeal
      angle varied from ages 1-7 years, stabilizing at age 8 at a mean of 23 degrees .
      Physeal angle is best measured relative to the floor because pelvic obliquity
      introduces significant variability to the measurements. Cartilage thickness
      ("joint space") declined after age 7 years, with measurements in three
      statistically distinct groups. There was a statistically significant difference
      between cartilage-thickness measurements of boys versus girls, with girls showing
      a slightly smaller cartilage thickness than boys. Cartilage thickness measured
      perpendicular to the floor was not statistically significantly different from
      that measured perpendicular to the physis. We describe and recommend standard
      measurement techniques for physeal angle and cartilage thickness. These
      established normal values may be helpful in the diagnosis and evaluation of coxa
      vara and chondrolysis, and in identifying the head at risk for slipped capital
      femoral epiphysis or Legg-Calve-Perthes disease.

PMID- 10412992
TI  - Idiopathic chondrolysis of the hip: long-term evolution.
AB  - Idiopathic chondrolysis of the hip is characterized by the destruction of the
      articular cartilage due to an unknown cause, principally affecting women during
      adolescence and producing premature degeneration of the hip. Twelve cases (11
      patients) were reviewed at our hospital, with an average follow-up period of 13.2
      years, during which a clinical and radiologic study was performed. Despite the
      treatment implemented, idiopathic chondrolysis of the hip causes progressive
      degeneration of the joint with the appearance of almost constant pain, stiffness,
      and anomalous positions. Radiologic studies show concentric narrowing of the
      articular space, decrease in the width of the femoral head and neck, and
      shortening of the affected member due to alteration in the growth physis of the
      upper extremity of the femur.

PMID- 10412993
TI  - Knee pain as the initial symptom of slipped capital femoral epiphysis: an
      analysis of initial presentation and treatment.
AB  - A retrospective review was performed of 106 patients to determine the effect of
      knee pain as the initial complaint of slipped capital femoral epiphysis (SCFE).
      Sixteen (15%) patients had a primary complaint of distal thigh or knee pain or
      both at initial presentation to our institution or to a referring physician.
      Ninety (85%) patients described primarily hip, groin, or proximal thigh
      discomfort. Of the 106 patients with SCFE, 65 patients received no operative
      treatment before being evaluated at our institution and were the subject of the
      remainder of the study. Of these, 15 (23%) patients had distal thigh or knee pain
      or both as their chief complaint (group I), and 50 (77%) patients had hip, groin,
      or proximal thigh pain (group II). There was no difference between the groups
      with respect to age, gender, or slip stability. Group I patients were more likely
      to receive a misdiagnosis (p < 0.05) and undergo unnecessary or uninformative
      radiographs (p < 0.05). Additionally, patients in group I were found to have
      slips of greater radiographic severity (p < 0.05). Although not statistically
      significant, there was a trend for group I patients to experience a longer delay
      to diagnosis and to require a proximal femoral osteotomy as treatment for their
      slips. We conclude that isolated distal thigh or knee pain or both is a common
      presentation of SCFE. Furthermore, this symptom complex, when compared with the
      more classic presentation of SCFE, leads to higher rates of unnecessary
      radiographs, misdiagnoses, and severe slips, potentially increasing long-term
      morbidity.

PMID- 10412994
TI  - Voluntary (normal) versus obligatory (cerebral palsy) toe-walking in children: a
      kinematic, kinetic, and electromyographic analysis.
AB  - Surgical management of toe-walking gait in children with cerebral palsy currently
      favors simultaneous, multilevel soft-tissue and bony interventions. Formulation
      of such a surgical plan is based on our ability to determine which of the gait
      deviations present are primary and which are secondary or compensatory. To
      evaluate this issue further, 32 normal children, walking normally and voluntarily
      toe-walking, were compared to 15 children with cerebral palsy walking in an
      obligatory toe-walking gait pattern. Computer-based analysis of gait was
      performed for each child, including time-distance, kinematic, kinetic, and
      electromyographic analyses. Significant deviations common to both normal and
      cerebral palsy toe-walking groups were determined to be due, at least in part, to
      the biomechanical constraints associated with a toe-walking gait pattern.
      Deviations unique to the cerebral palsy group were thought to represent primary
      gait deviations related to the underlying injury to the central nervous system.
      This study identifies the need to develop more sophisticated techniques of data
      collection and analysis and supports the inclusion of more varied and demanding
      functional activities for distinguishing between primary and secondary gait
      deviations in children with cerebral palsy.

PMID- 10412995
TI  - The effects of fixed and articulated ankle-foot orthoses on gait patterns in
      subjects with cerebral palsy.
AB  - Twenty-one subjects with spastic diplegic cerebral palsy were studied to quantify
      the effects of fixed and articulated ankle-foot orthoses (AFOs) on gait and
      delineate criteria for their use. Children underwent gait analysis under three
      conditions, fixed AFOs (FAFOs), articulated AFOs (AAFOs), and shoes alone.
      Greater dorsiflexion occurred at initial contact with both FAFOs and AAFOs than
      shoes alone. Dorsiflexion at terminal stance was greatest in AAFOs. Plantarflexor
      power generation at preswing was preserved in AAFOs. No differences were found in
      knee position during stance. Knee-extensor strength was positively related to
      knee extension during stance. No relationships were found between dorsiflexion
      range of motion, calf spasticity and strength, and peak dorsiflexion during
      stance. AAFOs are appropriate for subjects with varying degrees of calf
      spasticity, as long as adequate passive range of motion is available. These
      findings can be applied primarily to children who do not have a preexisting
      tendency to crouch.

PMID- 10412996
TI  - Age-related kinetic changes in normal pediatrics.
AB  - Kinetic data have become an important adjunct to kinematic and electromyography
      data in the interpretation of gait data and in the clinical decision making for
      children with pathologic gait patterns. A normative database is essential for
      comparison with the patterns of walking in children with gait abnormalities. Gait
      analyses of 23 able-bodied children (ages 4-10 years) were compared with those of
      five able-bodied adults. The patterns and amplitudes of the normal able-bodied
      children's kinetics showed five significant differences from those of the adults:
      (a) diminished hip-abduction moment, (b) diminished plantar-flexion moment, (c)
      diminished A2 power generation, (d) diminished knee-extensor moment, and (e)
      pattern of knee-power data. The data indicated a progression toward the adult
      normals because differences were more significant in the youngest group (4- to 5
      year-olds) than in the older groups (6- to 7- and 8- to 10-year-olds).

PMID- 10412997
TI  - Asymmetric hip deformity and subluxation in cerebral palsy: an analysis of
      surgical treatment.
AB  - Thirty-seven cerebral palsy patients were followed with measurements of the
      migration index (MI), infrapelvic obliquity, and suprapelvic obliquity over a
      mean period of 73 months to evaluate the development of the windblown deformity.
      The infrapelvic asymmetry was apparent before the suprapelvic obliquity; however,
      65% eventually had both. The final pattern of infrapelvic obliquity and the most
      subluxed hip could not be predicted from initial radiographs or from the pattern
      of scoliosis. Hip subluxation strongly correlated with the degree of femoral
      adduction and weakly with the magnitude of suprapelvic obliquity. The suprapelvic
      obliquity and scoliosis increased over time and influenced the final windblown
      appearance. Soft-tissue surgeries did not have a significant effect on the final
      MI. Severe abduction deformities generally followed ipsilateral adductor
      releases. Finally, despite improvement in the MI of the initially more subluxed
      hip, 33% of patients still had one hip with a MI >50%.

PMID- 10412998
TI  - Computer modeling of the pathomechanics of spastic hip dislocation in children.
AB  - Spastic muscles about the hip cause subluxation, dislocation, and lead to
      acetabular dysplasia. Spastic hip disease occurs when the muscles about the hip
      exert forces that are too high or in the wrong direction or both. To determine
      the role of the hip forces in the progression of spastic hip disease and the
      effect of both muscle-lengthening and bony reconstructive surgeries, a
      computerized mathematical model of a spastic hip joint was created. The magnitude
      and direction of the forces of spastic hips undergoing surgery were analyzed
      preoperatively and postoperatively to determine which procedure is best suited
      for the treatment of spastic hip disease. The muscle-lengthening procedures
      included (a) the adductor longus, (b) the psoas, iliacus, gracilis, adductor
      brevis, and adductor longus, and (3) the psoas, iliacus, gracilis, adductor
      brevis, adductor longus, semimembranosus, and semitendinosus. The bony
      reconstructive and muscle-lengthening procedures included (a) lengthening the
      psoas, iliacus, gracilis, adductor brevis, adductor longus, semimembranosus, and
      semitendinosus combined with changing femoral neck anteversion from 45 to 10
      degrees , (b) lengthening of the psoas, iliacus, gracilis, adductor brevis,
      adductor longus, semimembranosus, and semitendinosus combined with changing neck
      shaft angle from 165 to 135 degrees , and (c) lengthening of the psoas, iliacus,
      gracilis, adductor brevis, adductor longus, semimembranosus, and semitendinosus
      combined with changing femoral neck anteversion from 45 to 10 degrees and neck
      shaft angle from 165 to 135 degrees . Results show that a child with spastic hip
      disease has a hip-force magnitude 3 times that of the a child with a normal hip
      in the normal physiologic position. Based on this mathematical model the best to
      normalize the magnitude of the hip-joint reaction force, the muscles to be
      lengthened should include the psoas, iliacus, gracilis, adductor brevis, and the
      adductor longus. To normalize the direction of the hip force, the extremity
      should be positioned in the normal physiologic position. The impact of decreasing
      the femoral anteversion or femoral neck-shaft angle or both had little additional
      effect on the direction or magnitude of hip forces.

PMID- 10412999
TI  - Cognitive strategies and self-esteem as predictors of brace-wear noncompliance in
      patients with idiopathic scoliosis and kyphosis.
AB  - Psychological determinants of brace-wear compliance were analyzed among 113
      patients who used a brace because of an adolescent idiopathic scoliosis (92%),
      kyphosis (5%), or both (3%). The results showed that noncompliant girls did not
      expect to succeed in dealing with scoliosis and that they were anxious about the
      possibility of failure. They also had low self-esteem and did not seek social
      support from other people. Noncompliant boys, in contrast, had high self-esteem
      and high achievement success expectation. Among patients with a short time of
      brace use, low compliance was best predicted by low amount of reflective thinking
      and a good body-image. In turn, among patients who had used the brace for >6
      months, low compliance was best predicted by high amount of reflective thinking,
      poor body-image, low social success expectation, and low master orientation in
      social behavior. Only sleeping problems predicted compliance across gender and
      the time of brace use: the more the patients experienced sleeping problems, the
      less they used the brace.

PMID- 10413000
TI  - Modification of Cotrel-Dubousset's original hook constructs for idiopathic
      scoliosis.
AB  - We performed a retrospective review of 41 patients (ages 9-18 years) who
      underwent posterior spinal fusion with either Isola or Cotrel-Dubousset (CD)
      instrumentation to determine whether the presence of an apical hook on the
      thoracic convexity affected initial and long-term sagittal and coronal correction
      in adolescent idiopathic scoliosis surgery. A study group of 38 female and three
      male patients was evaluated (2-5 years of follow-up). Twenty-three patients
      (Group A) were treated with an up-going hook at the convex apex of the thoracic
      curve, and 18 patients (Group B) with similar curves were instrumented without an
      apical hook. Results showed that Group A's average preoperative coronal curve of
      48 degrees decreased to 17 degrees , whereas Group B's preoperative average of 52
      degrees decreased to 25 degrees . At follow-up, no statistical significance was
      noted in either coronal curve correction (p = 0.203) or sagittal kyphosis (p =
      0.38) between Groups A and B. We conclude that omission of the up-going hook at
      the apex of the thoracic convexity can reduce postoperative discomfort in
      patients undergoing posterior spinal fusion, without sacrificing curve correction
      or balance.

PMID- 10413001
TI  - The feet in Apert's syndrome.
AB  - Apert's syndrome (acrocephalosyndactyly type 1) is characterised by anomalies of
      the cranium, hands, and feet. The cranial and hand anomalies have been
      investigated, and the management of these is well established. In contrast, the
      anomalies affecting the feet and their management has previously received little
      attention. Forty-three children with Apert's syndrome underwent investigation of
      the anomalies affecting their feet. This consisted of history, clinical
      examination, and where possible, radiographic examination to establish the
      anomalies present, how these altered during development, and their clinical
      significance. The conclusion of the study is that there are widespread anomalies
      of the feet, with defects including both predictable dysmorphic changes and
      progressive fusions of the skeletal components during skeletal maturity. These
      fusions and their effect on growth combine to produce increasing deformity during
      childhood. The clinical significance of the anomalies is that walking is often
      delayed, and the increasing deformity results in difficulty obtaining footwear.
      This is the most common reason for surgery to the feet being undertaken during
      childhood to improve the shape of the feet to facilitate the provision of
      footwear. The unexpectedly high incidence of surgery in this study suggests that
      the management of foot deformities may require surgery more frequently than
      current literature would suggest.

PMID- 10413002
TI  - Symptomatic talonavicular coalition.
AB  - Talonavicular coalition is reported as an asymptomatic congenital anomaly of the
      foot that is noticed incidentally on radiographs of the foot, and is often
      associated with symphalangism, clinodactyly, ball-and-socket ankle joint, a great
      toe that is shorter than the second toe, and an autosomal dominant inheritance
      pattern. We describe here three patients with five involved feet. All three
      patients had chronic foot pain not secondary to trauma, and all five feet
      required treatment to alleviate the pain.

PMID- 10413003
TI  - Popliteal fossa block for postoperative analgesia after foot surgery in infants
      and children.
AB  - The efficacy of a popliteal fossa block (PFB) was evaluated after foot and ankle
      surgery in children. With the child still anesthetized, a PFB was performed with
      0.75 ml/kg of 0.2% ropivacaine. Postoperative analgesia was assessed by using an
      objective pain score, assigned at 2-h intervals. Patients with scores of > or =3
      received intravenous nalbuphine. PFBs were performed in 20 children ranging in
      age from 0.5 to 12 years and in weight from 6 to 41 kg. In five patients, the PFB
      block was supplemented with a saphenous nerve block at the ankle. The PFB was
      unsuccessful in one patient. The remaining 19 patients required no analgesic
      agents during the first 8 postoperative hours. Eight patients required no
      analgesic agents during the first 12 postoperative hours. The duration of the
      analgesia varied from 8 to 12 hours. PFB provides effective analgesia after foot
      and ankle surgery in children.

PMID- 10413004
TI  - Ankle valgus and clubfeet.
AB  - Congenital equinovarus is a complex deformity that involves the ankle as well as
      the foot. Although equinus is the obvious and presenting ankle deformity that is
      typically addressed with serial manipulation, casts, and surgery, ankle valgus is
      a more insidious and often overlooked problem that evolves with growth. With a
      high prevalence (67% in this series), it may, in some cases, ameliorate the
      effects of residual hindfoot varus. More commonly, it may result in prominence of
      the medial malleolus, lateral shift of the ground reactive forces, compression of
      the lateral portion of the distal tibial epiphysis, fibular impingement, and
      excessive shoe wear. If mistaken for hindfoot valgus ("overcorrected clubfoot"),
      inappropriate hindfoot surgery may result. Although one may temporize with
      orthoses, definitive treatment options include medial malleolar epiphysiodesis
      or, in mature patients, supramalleolar osteotomy. We recommend a weight-bearing
      anteroposterior radiograph of the ankles in any patient presenting with valgus
      and suspected of having overcorrected congenital equinovarus, particularly if
      surgical intervention is being contemplated. If valgus deformity is noted in the
      ankle, hindfoot surgery may be contraindicated.

PMID- 10413005
TI  - Supracondylar fractures: posterolateral type with brachialis muscle penetration
      and neurovascular injury.
AB  - Twenty-seven children with vascular deficit associated with the displaced
      posterolateral type of supracondylar fracture were explored surgically. Twenty
      two children had median nerve signs. Associated clinical findings were bruising,
      tethering or puckering of the skin in the antecubital region, and a palpable
      subcutaneous medial spike of the proximal humeral fragment, indicating that the
      brachialis muscle was penetrated. Manipulation was avoided in such cases. At
      exploration, the neurovascular bundle was found trapped anterior to the fracture
      edge in 18 cases, dislocated behind the fracture edge in five cases, and
      separated by the spike in four cases. Fasciotomy of the antecubital region was
      performed, and the neurovascular bundle was released from entrapment. The vessel
      pulsated after release in 21 cases, vascular procedures were done in four, and
      the vessel ends were ligated in two completely lacerated vessels. Manipulation
      should be avoided in displaced posterolateral supracondylar fractures with
      neurovascular deficit when there is clinical evidence that the brachialis muscle
      belly has been buttonholed.

PMID- 10413006
TI  - Tardy displacement of traumatic radial head dislocation in childhood.
AB  - The diagnosis of traumatic dislocation of the radial head, either isolated or as
      part of a Monteggia fracture-dislocation, was delayed in 10 of the 110 children
      treated with these injuries during the study period. In eight children, the
      dislocation was overlooked on the initial radiographs. In two children, the
      radial head was reduced on the initial elbow radiographs, but it was dislocated
      10 days later in one child and 21 days later in the other. The most likely
      explanation is that the radial head dislocated at the time of impact,
      spontaneously reduced by the time the first radiographs were obtained, and
      redislocated while the arm was in a cast. We conclude that radiographic
      assessments of the radiocapitellar joint, by using the radiocapitellar line, are
      required in children with elbow and forearm injuries at presentation and when the
      cast is removed.

PMID- 10413007
TI  - Fibrous lesion of the distal femur associated with angular deformity.
AB  - Unilateral femoral angulation is uncommon. We describe two children with
      unilateral progressive distal femoral varus and limb-length discrepancy. These
      deformities were associated with a fibrous lesion involving the medial aspect of
      the distal femoral metaphysis. Both patients were 15 to 16 months old. In both,
      the deformity was progressive, resulting in excisional biopsy and osteotomy. The
      gross and microscopic appearance of both lesions was similar, and the histology
      was dense fibrous connective tissue. The patients' femoral alignment was
      maintained at follow-up of a minimum of 16-36 months. The etiology of these
      lesions is unknown; they are associated with progressive deformity and appear to
      respond well to surgical intervention.

PMID- 10413008
TI  - Rotational profile of lower extremities in bladder exstrophy patients with
      unapproximated pelvis: a clinical and radiologic study in children older than 7
      years.
AB  - Fourteen patients (nine boys, five girls) with bladder exstrophy were analyzed
      radiologically and clinically. All were older than 7 years and had a pubic
      diastasis >2 cm. Anteroposterior and lateral center-edge angles were measured by
      direct radiography. Acetabular version, femoral anteversion, tibial torsion
      angles, and patellofemoral congruency angle were measured by computed tomography
      imaging. All were active with regard to their daily life and sports activities.
      The average foot-progression angle was +8 degrees . Spherical congruency was
      present in all hips, and none showed dysplasia. The average angle of acetabular
      version was apparently less than normal, but femoral anteversion angles were
      found to be increased. Increased external tibial torsion was observed in all
      patients. Twelve (71%) of 14 patients had positive congruence angles, the average
      being +6.1 degrees . Two patients had subjective complaints of patellofemoral
      instability. Increased femoral anteversion and external tibial torsion may lead
      to patellofemoral instability, and the bladder exstrophy patients should be
      followed up regarding this problem as well.

PMID- 10413009
TI  - Osteotomy and distraction of the anterior segment of the pelvic ring in
      epispadias repair: case report.
AB  - We report a new therapeutic approach for bladder exstrophy and epispadias in one
      case of failed epispadias repair. The width of the pelvis was measured by what we
      defined as the anteroposterior diameter (APD) on combined transverse computed
      tomography (CT) scan cuts of the pelvis. The APD was half the normal value in an
      incontinent patient with failed epispadias repair. He underwent a supraacetabular
      osteotomy of the pelvis with progressive anterior distraction of the anterior
      segment of the pelvic ring. Four months later, hardware was removed, and the APD
      was near normal value. Within 9 months of follow-up, the patient was dry day and
      night. We believe that in patients with failed exstrophy and epispadias repair,
      APD seems to be a predictive criterion for continence, and results of the
      reconstructive surgery with osteotomy should be improved by distraction of the
      anterior segment of the pelvic ring.

PMID- 10413010
TI  - Treatment of aneurysmal bone cysts with saucerization and bone marrow injection
      in children.
AB  - In four consecutive children, healing of large, active aneurysmal cysts of the
      long bones was achieved with saucerization, closure of the periosteum, and
      instillation of autologous bone marrow into the cavity. The saucerization
      procedure consisted of excision of the subperiosteal new bone with its attached
      cyst contents and curettage of the remaining cortical bone. A centripetal pattern
      of bone healing was observed in which an ossification front advanced from the
      periphery to the center of the cavity. We conclude that autologous bone marrow
      injections are a simple means of augmenting the healing of aneurysmal cysts of
      long bones treated with saucerization. The procedure avoids the morbidity and
      costs associated with alternative methods of bone grafting.

PMID- 10413011
TI  - Indications for epiphyseal preservation in metaphyseal malignant bone tumors of
      children: relationship between image methods and histological findings.
AB  - We compared several image methods in the evaluation of the possible physeal
      effect in 47 osteosarcomas and 18 Ewing's sarcomas in children. The minimal
      follow-up was 3 years (range, 3-17). In the histological study, the physis was
      affected in 53% of the cases. We correlated the histological findings and the
      findings from the different image methods. There were more false-positive than
      false-negative results, and in the computed tomography and magnetic resonance
      imaging (MRI) studies, there were no false negatives. The accuracy of MRI
      (predictive positive value plus predictive negative value) was the best (90.3%),
      and it is the technique that we prefer. According to these findings, we can
      safely preserve the epiphysis in cases of metaphyseal tumors showing no contact
      between the tumor and the growth plate in the MRI images. If the tumor shows
      contact with part of the physis, it is also possible to preserve the epiphysis.

PMID- 10413012
TI  - Soft-tissue realignment for adolescent patellar instability.
AB  - Patellar malalignment or instability is a frequent problem in adolescents.
      Patients with persistent symptoms require operative correction with procedures
      often requiring osteotomies of the tibial tubercle. Insall described a soft
      tissue procedure to correct instability in adults, and others have used this in
      adolescents. Short-term results have seemingly been satisfactory in the
      skeletally immature population. A long-term outcome study was performed to
      evaluate the effectiveness of soft-tissue realignment for patellar instability in
      adolescents. From 1980 to 1996, 54 patients (65 knees) underwent Insall proximal
      distal soft-tissue realignment. No concomitant bony or other soft-tissue
      procedures were performed. Follow-up averaged 6 years (range, 2-15 years),
      assessing stability, strength, range of motion, and congruence angle on the
      Merchant's view. Eighty-seven percent had a good to excellent result; 8%, a fair
      result; and 5%, poor results.

PMID- 10413013
TI  - Does pediatric orthopedic subspecialization affect hospital utilization and
      charges?
AB  - In the current climate of health care reform, there is a perception that
      overspecialization is responsible for increased medical costs. Few studies
      support the premise that high-quality surgical subspecialization improves the
      cost effectiveness of care. The purpose of this study was to compare hospital
      utilization and charges between a pediatric hospital staffed by pediatric
      orthopedic subspecialists and a community hospital system for the care of closed
      femur fractures and slipped capital femoral epiphysis (SCFE) in a pediatric
      population. We reviewed hospital charges and length-of-stay (LOS) data for all
      children treated for closed femoral shaft fractures and SCFE between 1992 and
      1994 within the Intermountain Health Care System (IHC). Within the IHC, there are
      23 community hospitals and one children's hospital (PCMC). Patients were matched
      for age and injury severity. Four of six orthopedic surgeons at PCMC are
      pediatric orthopedists, but none of the community orthopedists has subspecialty
      training in pediatric orthopedics. For closed femoral shaft fractures (n = 334),
      the average hospital charges were less (PCMC, $4,943/Other IHC, $9,031), and
      length of stay was shorter (PCMC, 2.81 days/Other IHC, 8.91 days) when the child
      was treated at the children's hospital by pediatric orthopedic subspecialists.
      For SCFE (n = 63), the average hospital charges were less (PCMC, $2,824/Other
      IHC, $3,544) and the length of stay was shorter (PCMC, 1.13 days/Other IHC, 1.64
      days) at the children's hospital. These data suggest that hospital utilization
      and charges were significantly decreased if the care was provided by pediatric
      orthopedic subspecialists in a children's hospital.

PMID- 10413014
TI  - MRI-based brain volumetrics: emergence of a developmental brain science.
AB  - MRI-based brain volumetrics is an established methodology of great versatility
      and reliability with a broad range of potential applications in medicine and
      basic human brain science. We consider here, more theoretical implications of
      brain tissue volumes. Specifically, we suggest that volume is an evolutionarily
      and developmentally regulated fundamental property of tissue, in this instance
      the brain and its component structures. Within this framework (1), regularities
      in relative variation of volumes with respect to mean volume of a structure are
      viewed as systematic manifestations of the rules of histogenetic process (2),
      regularities in the relative strength of correlation of volumes of structures are
      suggested to reflect constraints which serve systematically the requirements of
      neural systems operation. These hypotheses, if supported by extensive
      observation, may guide the design of applications of MRI based volumetric
      analysis of the human brain.

PMID- 10413015
TI  - Diagnosis of Angelman syndrome: clinical and EEG criteria.
AB  - In order to evaluate which diagnostic criteria can be indicative for an early
      diagnosis of Angelman syndrome (AS), 144 children with severe epilepsy and mental
      retardation were evaluated. In 10 of them the diagnostic criteria indicated by
      Williams were present. Of the remaining 134 patients we were able to diagnose one
      15-year-old patient with AS, on the basis of the EEG findings, even though the
      typical clinical features of the syndrome were absent. In all patients the
      diagnosis of AS was confirmed by fluorescent in situ hybridization (FISH) in 10
      patients and by methylation analysis in one patient. AS is very likely when both
      typical clinical and EEG findings are present. Nevertheless, it must be
      considered in all patients affected by severe epilepsy and mental retardation,
      when the EEG pattern is sufficiently indicative, and FISH and/or molecular
      analysis should be performed even in absence of typical clinical signs.

PMID- 10413016
TI  - Lamotrigine in typical absence epilepsy.
AB  - Lamotrigine (LTG) is an anti-epileptic drug effective in partial seizures and
      generalized epilepsy. There is growing evidence of the usefulness of LTG in
      childhood (CAE) orjuvenile (JAE) absences resistant to previous treatment. In
      this study all patients were identified using strict diagnostic criteria and
      subdivided into two groups. (1) Eight patients affected by absence seizures
      resistant to valproic acid or ethosuximide, received LTG as an-add-on therapy,
      (2) seven patients affected by typical absence seizures not previously treated,
      received LTG monotherapy after the diagnosis. In the patients with resistant
      absence seizures, a full control of seizures was obtained. In five of them, after
      a mean period of 12.5 months, the previous anti-epileptic drugs were withdrawn
      leaving the patients on LTG monotherapy. In one patient, absences relapsed and
      valproic acid was therefore added again to LTG to regain control of the seizures.
      In six of the seven patients on LTG monotherapy after the diagnosis, a full
      control of seizures was obtained. In the seventh patient the drug was stopped due
      to a skin rash. In conclusion LTG appears to be effective in resistant absence
      seizures in combination with valproic acid. Moreover, our preliminary data
      suggest that lamotrigine might be used as monotherapy in typical absence
      seizures. The advantages and disadvantages of LTG monotherapy in this type of
      epilepsy are discussed.

PMID- 10413017
TI  - Gastrointestinal manifestations in children with cerebral palsy.
AB  - We describe the prevalence and nature of gastrointestinal (GI) symptoms in 58
      children affected by cerebral palsy (range: from 6 months to 12 years of age)
      referred to a pediatric neurology outpatient clinic. In each patient we assessed
      (GI) symptoms and defined the associated GI functional or structural
      abnormalities. Furthermore, we tried to correlate the type of GI dysfunction with
      findings on computed tomography (CT) or magnetic resonance imaging (MRI) of the
      brain. Our results showed that 92% of children with cerebral palsy had clinically
      significant gastrointestinal symptoms. Swallowing disorders were present in 60%
      of patients, regurgitation and/or vomiting in 32%, abdominal pain in 32%,
      episodes of chronic pulmonary aspiration in 41% and chronic constipation in 74%.
      Dysfunction of the oral and/or pharyngeal phase of swallowing was found in 28 of
      30 (93%) patients with swallowing disorders. Of the 45 patients with symptoms
      suggesting gastroesophageal reflux, 41 (91%) had an abnormal pH-monitoring and/or
      esophagitis. Furthermore, a significant delay in the scintigraphic gastric
      emptying of liquids was found in 12 of 18 patients (67%) and an abnormal
      esophageal motility in 11 of the 18 (61%) investigated patients. In 25 patients
      with chronic constipation evaluation of colonic transit showed a delay at level
      of the proximal segments of the colon in 13 (52%), at level of the left colon and
      rectum in 9 (36%) and in 3 (12%) at level of the rectum only. Computed tomography
      and/or magnetic resonance imaging were normal in 5 (9%) and abnormal in 53 (91%)
      of the 58 children with cerebral palsy. No GI symptom was significantly
      associated with any kind of abnormal neuroimaging. In conclusion, children with
      cerebral palsy exhibited diffuse GI clinical manifestations, mostly due to
      disorders of GI motility. The GI symptoms seemed not to be related to any
      specific finding on CT or MRI of the brain.

PMID- 10413018
TI  - 18Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in propionic acidemia:
      clinical and MRI correlations.
AB  - The clinical data and the imaging findings of the positron emission tomography
      (PET) and the magnetic resonance imaging (MRI) studies in five patients,
      previously diagnosed to have propionic acidemia, were retrospectively reviewed.
      The patients were all normal at birth. The first clinical signs, typically
      hypotonia and failure to thrive, appeared during the first 2 years of life. With
      progression of the disease, the neurological findings consisted of variable
      degrees of dementia and extrapyramidal symptoms, notably dystonia,
      choreoathetosis and rigidity of variable degrees. Initial cerebral PET and MRI
      studies were normal. Follow-up MRI examinations showed progressive basal ganglia
      degeneration, with evidence of atrophy and signal abnormalities within the
      caudate nuclei and the putamina. The thalamic structures were normal. The PET
      studies demonstrated increased uptake in the basal ganglia and thalami, followed
      by decreased uptake in the basal ganglia at a later stage of the disease. The
      structural (MRI) and the functional (PET) studies of the brain were found to be
      complementary in the evaluation of propionic acidemia, and were in good
      correlation with the clinical findings.

PMID- 10413019
TI  - Effects of hyperthermia and continuous hippocampal stimulation on the immature
      and adult brain.
AB  - Whether febrile seizures lead to hippocampal necrosis is a question of paramount
      clinical importance. This study attempted to simulate a complex febrile seizure,
      compared with hyperthermia (HYP) alone and prolonged seizure alone (produced by
      continuous hippocampal stimulation (CHS)). Four groups of rats were studied at
      each of two ages, immature (postnatal day, P20) and adult (P60). Group 1 was
      subjected to 45 min of HYP (body temperature 40 degrees C) plus CHS, Group 2
      received 45 min of HYP alone, Group 3 got 45 min of CHS alone, and Group 4 was
      sham-handled control rats. Baseline and post-session EEGs were recorded in all
      groups. Subsequently, brains were examined histologically for evidence of
      hippocampal damage. Both CHS-treated groups (with and without HYP) exhibited
      behavioral and EEG seizures while the group undergoing HYP alone did not have
      seizures. There were no gross histological lesions in any group. Cell counts in
      regions CA1, CA3, dentate gyrus and dentate hilus did not differ in rats under
      any condition of hyperthermia and CHS, in either P20 or P60 rats compared to age
      matched controls. These results indicate that both immature and mature rodents
      are resistant to hyperthermic brain damage and raises the question of whether
      febrile seizures play a role in the genesis of mesial temporal sclerosis.

PMID- 10413021
TI  - A patient with cerebral palsy whose mother had a traffic accident during
      pregnancy: a diffuse axonal injury?
AB  - A 16-year-old girl had spastic cerebral palsy (CP) with triplegia and focal
      epilepsy. The patient's past history included her mother's lower abdominal trauma
      caused by a traffic accident at the 7th month of gestation. Brain examination
      with magnetic resonance imaging (MRI) revealed encephalomalacia at the bilateral
      parieto-temporal lobes and the left caudate nucleus, segmental narrowing of the
      splenium of the corpus callosum, dilatation of the left lateral ventricle and an
      abnormally high intensity at the right posterior portion of the internal capsule.
      These findings might indicate a diffuse axonal injury (DAI), but not an asphyxic
      brain damage. In this patient, CP might be caused by an intrauterine DAI when her
      mother was involved in the accident.

PMID- 10413022
TI  - Diffuse central nervous system lupus involving white matter, basal ganglia,
      thalami and brainstem.
AB  - We described an 11-year-old girl with acute central nervous system lupus showing
      diffuse lesions. She developed generalized convulsions followed by prolonged
      coma, and her psychomotor ability recovered fully after 3 months of steroid
      therapy. Cranial magnetic resonance imaging (MRI) showed high signal intensity in
      the cerebral deep white matter, bilateral basal ganglia, thalami, and brainstem
      on T2-weighted image. These lesions resolved over 1 month with residual atrophic
      change in the heads of the caudate nucleus on MRI. Acute SLE leukoencephalopathy
      may be recognized as a subtype of CNS lupus.

PMID- 10413020
TI  - Neurodegeneration in hereditary nucleotide repair disorders.
AB  - Both xeroderma pigmentosum group A (XPA) and Cockayne syndrome (CS) are rare
      autosomal disorders, have a genetic defect in the step of nucleotide repair, and
      involve various neurological abnormalities caused by progressive
      neurodegeneration. We performed comprehensive neuropathological analysis of five
      cases of XPA and four cases of CS. The XPA cases showed widespread neuronal loss
      throughout the central nervous system, in sharp contrast to the comparative
      preservation of neurons in the CS cases, who rather exhibited patchy
      demyelination in the cerebral and cerebellar white matter, and multifocal calcium
      deposition in the basal ganglia and cerebral white matter, respectively.
      Exceptionally in the cerebellar cortex, neuronal loss was more severe in CS than
      in XPA. Grumose or foamy spheroid bodies occurred in the globus pallidus and
      substantia nigra, and axonal torpedoes were increased in the cerebellar cortex in
      both disorders. Neither silver impregnation nor immunohistochemistry for
      ubiquitin or tau succeeded in visualizing neurofibrillary tangles, senile plaques
      or augmented ubiquitination in either disorder, and these findings did not
      support the involvement of facilitated aging in the neurodegeneration in XPA or
      CS.

PMID- 10413023
TI  - Acquired aphasia in acute disseminated encephalomyelitis.
AB  - A 12-year-old boy developed a convulsion, hemiparesis, and acquired aphasia with
      paroxysmal electroencephalogram (EEG) abnormalities consisting of repetitive
      spikes and waves in the left centro-parietal region. T2-weighted magnetic
      resonance imaging disclosed high intensity lesions in the left pre-Sylvian and
      right frontal areas. He was diagnosed as having acute disseminated
      encephalomyelitis, and thus the oral administration of phenytoin and steroid
      pulse therapy were begun. With these treatments, his hemiparesis disappeared and
      the aphasia also improved gradually. Magnetic resonance imaging examination
      revealed the disappearance of the previously noted abnormalities, and the EEG
      abnormalities disappeared as well. This patient is a rare case of acute
      disseminated encephalomyelitis presenting an acquired aphasia. A focal lesion of
      acute disseminated encephalomyelitis may be responsible for the acquired aphasia.
      The distinction from Landau-Kleffner syndrome is also discussed.

PMID- 10413024
TI  - Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission
      tomography of the brain, MR spectroscopy, and therapeutic attempts in
      methylenetetrahydrofolate reductase deficiency.
AB  - The cases of three infants, two Saudi and one Bahraini, with
      methylenetetrahydrofolate reductase (MTHFR) deficiency are reported. They
      presented in the neonatal period with lethargy, poor feeding, hypotonia, and
      frequent apneas. Tandem mass spectrometry (MS/MS) of a blood spot indicated very
      low methionine level and of urine revealed high homocysteine. The diagnosis was
      confirmed by demonstrating severe deficiency of MTHFR in the cultured skin
      fibroblast. All patients were treated with folinic acid, vitamin B12, betaine,
      and methionine, with good initial response to the therapy. In two patients, the
      diagnosis was late and their disease was severe, resulting in neurological
      crippling. However, in the third patient, who was diagnosed and treated early,
      the current neurological status is normal. In her case, at 1 month of age, the
      brain FDG PET scan documented very faint cerebral and cerebellar cortical
      activities. After 5 months of intensive therapy, that included 200-600 mg/kg per
      day methionine, she had a dramatic clinical and biochemical recovery as well as a
      parallel improvement in FDG PET. Brain MR spectroscopy indicated normal neuronal
      glial and myelin markers for her age. We conclude that the functional changes
      confirmed by the FDG PET study were better correlated with the clinical course of
      the patient and adequately monitored the response to therapy. This disease
      warrants early detection through neonatal screening program, since the beneficial
      effect of early administration of adequate therapy with combined use of betaine
      and a high dose of methionine is rewarding and may be the treatment of choice for
      MTHFR deficiency.

PMID- 10413025
TI  - Annual bibliography series of congenital muscular dystrophies--cobblestone
      lissencephalies: Series I (1997).

PMID- 10413026
TI  - Measuring cerebral blood flow using magnetic resonance imaging techniques.
AB  - Magnetic resonance imaging techniques measuring CBF have developed rapidly in the
      last decade, resulting in a wide range of available methods. The most successful
      approaches are based either on dynamic tracking of a bolus of a paramagnetic
      contrast agent (dynamic susceptibility contrast) or on arterial spin labeling.
      This review discusses their principles, possible pitfalls, and potential for
      absolute quantification and outlines clinical and neuroscientific applications.

PMID- 10413027
TI  - Blockade of the mitochondrial permeability transition pore diminishes infarct
      size in the rat after transient middle cerebral artery occlusion.
AB  - The mitochondrial permeability transition pore is an inducer of cell death.
      During the reperfusion phase after cerebral ischemia, calcium accumulates in
      mitochondria, and a burst of free radical formation occurs, conditions that favor
      the activation of the mitochondrial permeability transition pore. Here the
      authors demonstrate that a blocker of the mitochondrial permeability transition
      pore, the nonimmunosuppressive cyclosporin A analogue N-methyl-Val-4-cyclosporin
      A (10 mg/kg intraperitoneally), administered during reperfusion and at 24 hours
      of reperfusion, diminishes infarct size in a rat model of transient focal
      ischemia of 2 hours' duration. The mitochondrial permeability transition pore may
      be an important target for drugs against stroke.

PMID- 10413028
TI  - Indefatigable CA1 sector neuroprotection with mild hypothermia induced 6 hours
      after severe forebrain ischemia in rats.
AB  - Considerable controversy exists about whether postischemic hypothermia can
      permanently salvage hippocampal CA1 neurons or just postpone injury. Studies of
      very brief cooling in rat have found transient benefit, whereas experiments in
      gerbil using protracted hypothermia report lasting protection. This discrepancy
      might be because of the greater efficacy of longer cooling or it might, for
      example, represent an important species difference. In the present study, a 48
      hour period of mild hypothermia was induced starting 6 hours after 10 minutes of
      severe four-vessel occlusion ischemia in rats. Untreated normothermic ischemia
      resulted in total CA1 cell loss (99%), whereas delayed hypothermia treatment
      reduced neuronal loss to 14% at a 28-day survival. In unregulated rats, brain
      temperature spontaneously fell during ischemia, and stayed subnormal for an
      extended period after ischemia. This mild cooling resulted in more variable and
      less severe CA1 injury (75%). Finally, vertebral artery cauterization under
      halothane anesthesia caused an approximately 2 degrees C drop in brain
      temperature for 1 hour, but prevention of this hypothermia did not significantly
      affect CA1 damage. In summary, protracted postischemic hypothermia provided
      robust and long-term CA1 protection in rat. These results encourage the clinical
      assessment of prolonged hypothermia and its use as a model to understand ischemic
      CA1 injury.

PMID- 10413029
TI  - Ubiquitin stress response in postischemic hippocampal neurons under nontolerant
      and tolerant conditions.
AB  - Ubiquitin, an essential protein in nonlysosomal proteolytic system, is expressed
      after metabolic stress to the cell. The authors investigated stress response of
      ubiquitin in the hippocampus of the Mongolian gerbil after forebrain ischemia.
      The level of hippocampal ubiquitin was compared with that under ischemic
      tolerance induced by ischemic preconditioning. The authors also studied ubiquitin
      gene expression using in situ hybridization method. Transient ischemia resulted
      in consumption of free ubiquitin and an increase of multiubiquitin chains. These
      changes were transient in the hippocampus outside of the CA1 region where neurons
      survived, whereas it was persistent in the CA1 region where neurons were destined
      to die after ischemia. Under tolerant condition, subsequent ischemia provoked
      rapid recovery and further increase of free ubiquitin. The signal of ubiquitin
      messenger ribonucleic acid was continuously detected after ischemia, not only
      under tolerant conditions, but without tolerance induced by preconditioning.
      Thus, ubiquitin stress response takes place, at least at a transcriptional level,
      in dying CA1 neurons. Under tolerant conditions, however, subsequent ischemia in
      the CA1 region induces the stress response of ubiquitin up to the translational
      level, leading to the rapid restoration of protein synthesis and to eventual
      neuronal survival.

PMID- 10413030
TI  - Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery
      occlusion in mice.
AB  - In a process called ischemic preconditioning, a brief, sublethal ischemic insult
      protects tissue from subsequent, more severe injury. There have been no reports
      of rapidly induced ischemic preconditioning. The authors sought to develop a
      model of cerebral ischemic preconditioning in the mouse that can be applied to
      transgenic and knockout animals. They found that brief middle cerebral artery
      (MCA) occlusion only minutes before a severe ischemic insult can induce
      protection from that insult. Here the investigators describe a mouse model of
      preconditioning using intraluminal MCA occlusion as both the conditioning and the
      test stimulus. One or three 5-minute episodes of ischemia given 30 minutes before
      MCA occlusion for 1 or 24 hours (permanent occlusion) confer significant
      protection as assessed by infarct volume measurements 24 hours later.

PMID- 10413031
TI  - Increased vulnerability of NFH-LacZ transgenic mouse to traumatic brain injury
      induced behavioral deficits and cortical damage.
AB  - The authors evaluated the neurobehavioral and neuropathologic sequelae after
      traumatic brain injury (TBI) in transgenic (TG) mice expressing truncated high
      molecular weight neurofilament (NF) protein fused to beta-galactosidase (NFH
      LacZ), which develop Lewy body-like NF-rich inclusions throughout the CNS. TG
      mice and their wild-type (WT) littermates were subjected to controlled cortical
      impact brain injury (TG, n = 19; WT, n = 17) or served as uninjured controls (TG,
      n = 11; WT, n = 11). During a 3-week period, mice were evaluated with an array of
      neuromotor function tests including neuroscore, beam balance, and both fast and
      slow acceleration rotarod. Brain-injured WT and TG mice showed significant motor
      dysfunction until 15 days and 21 days post-injury, respectively (P<.025).
      Compared with brain-injured WT mice, brain-injured TG mice had significantly
      greater motor dysfunction as assessed by neuroscore (P<.01) up to and including
      15 days post-injury. Similarly, brain-injured TG mice performed significantly
      worse than brain-injured WT mice on slow acceleration rotarod at 2, 8, and 15
      days post-injury (P<.05), and beam balance over 2 weeks post-injury (P<.01).
      Histopathologic analysis showed significantly greater tissue loss in the injured
      hemisphere in TG mice at 4 weeks post-injury (P<.01). Together these data show
      that NFH-LacZ TG mice are more behaviorally and histologically vulnerable to TBI
      than WT mice, suggesting that the presence of NF-rich inclusions may exacerbate
      neuromotor dysfunction and cell death after TBI.

PMID- 10413032
TI  - Kynurenine hydroxylase inhibitors reduce ischemic brain damage: studies with (m
      nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]
      benzenesulfonamide (Ro 61-8048) in models of focal or global brain ischemia.
AB  - Two kynurenine hydroxylase inhibitors, (m-nitrobenzoyl)-alanine (mNBA) and 3,4
      dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfona mide (Ro 61-8048), have
      been tested as neuroprotective agents on brain lesions induced by bilateral
      carotid occlusion in gerbils or by middle cerebral artery occlusion in rats. The
      percentage of lesioned pyramidal neurones found in the hippocampal CA1 region of
      gerbils subjected to bilateral carotid occlusion for 5 minutes decreased from
      92+/-10% in vehicle-treated animals to 7+/-6% after mNBA (400 mg/kg
      intraperitoneally, three times at 1, 30, and 180 minutes after occlusion) or to
      10+/-11% after Ro 61-8048 (40 mg/kg intraperitoneally, three times). A
      significant reduction in infarct volumes also was found when the kynurenine
      hydroxylase inhibitors were given to rats after permanent middle cerebral artery
      occlusion (from 207+/-111 mm3 in vehicle-treated rats to 82+/-18 and to 62+/-57
      mm3 in rats treated with mNBA, 400 mg/kg intraperitoneally, or with Ro 61-8048,
      40 mg/kg intraperitoneally, respectively). The administration of mNBA (400 mg/kg
      intraperitoneally) or Ro 61-8048 (40 mg/kg intraperitoneally) to gerbils with a
      dialysis probe in their dorsal hippocampus or to rats with a dialysis probe in
      their parietal cortex significantly increased kynurenic acid concentration in the
      dialysates. The data suggest that inhibition of kynurenine hydroxylase could be a
      new avenue to reduce neuronal loss in brain ischemia.

PMID- 10413033
TI  - Neuroprotective effects of a novel nitrone, NXY-059, after transient focal
      cerebral ischemia in the rat.
AB  - Recent results have demonstrated that the spin trapping agent alpha-phenyl-N-tert
      butyl nitrone (PBN) reduces infarct volume in rats subjected to 2 hours of middle
      cerebral artery occlusion, even when given 1 to 3 hours after the start of
      recirculation. In the current study, the authors assessed the effect of NXY-059,
      a novel nitrone that is more soluble than PBN. Loading doses were given of 0.30,
      3.0, or 30 mg x kg(-1) followed by 0.30, 3.0, or 30 mg x kg(-1) x h(-1) for 24 or
      48 hours. Dose-response studies showed that when treatment was begun 1 hour after
      recirculation, 0.30 mg x kg(-1) had a small and 30 mg x kg(-1) a marked effect on
      infarct volume. At equimolar doses (3.0 mg x kg(-1) for NXY-059 and 1.4 mg x kg(
      1) for PBN), NXY-059 was more efficacious than PBN. Similar results were obtained
      when a recovery period of 7 days was allowed. The window of therapeutic
      opportunity for NXY-059 was 3 to 6 hours after the start of recirculation.
      Studies of the transfer constant of [14C]NXY-059 showed that, in contrast to PBN,
      this more soluble nitrone penetrates the blood-brain barrier less extensively.
      This fact, and the pronounced antiischemic effect of NXY-059, suggest that the
      delayed events leading to infarction may be influenced by reactions occurring at
      the blood-endothelial interface.

PMID- 10413034
TI  - Breakdown of calcium homeostasis in relation to tissue depolarization: comparison
      between gray and white matter ischemia.
AB  - In vitro studies suggest that ischemic injury of cerebral white matter is
      mediated by nonsynaptic cellular mechanisms, such as Ca2+ entry into axons
      through reversal of the Na+ -Ca2+ exchanger. The authors investigated
      extracellular Ca2+ concentration in relation to tissue depolarization (direct
      current potential) in vivo using ion-selective electrodes in cortical gray and
      subcortical white matter of alpha-chloralose-anesthetized cats during 120 minutes
      of global cerebral ischemia. On induction of ischemia, regional CBF, as measured
      by hydrogen clearance, ceased. The direct current potential decreased rapidly
      within minutes in gray matter and with little time delay in white matter.
      Extracellular Ca2+ concentration decreased just as quickly in gray matter. In
      white matter, in contrast, extracellular Ca2+ increased in the first 20 to 30
      minutes, and a delayed and much slower decline, compared with gray matter, was
      observed thereafter, reaching a minimal level only about 60 minutes after
      occlusion. Our results suggest that smaller and delayed transmembrane shifts of
      Ca2+ are correlates of delayed ischemic membrane dysfunction in central white
      matter tracts, which may be explained by a lack of synaptic mechanisms.

PMID- 10413035
TI  - Functional acetylcholine muscarinic receptor subtypes in human brain
      microcirculation: identification and cellular localization.
AB  - Acetylcholine is an important regulator of local cerebral blood flow. There is,
      however, limited information available on the possible sites of action of this
      neurotransmitter on brain intraparenchymal microvessels. In this study, a
      combination of molecular and functional approaches was used to identify which of
      the five muscarinic acetylcholine receptors (mAChR) are present in human brain
      microvessels and their intimately associated astroglial cells. Microvessel and
      capillary fractions isolated from human cerebral cortex were found by reverse
      transcriptase-polymerase chain reaction to express m2, m3, and, occasionally, m1
      and m5 receptor subtypes. To localize these receptors to a specific cellular
      compartment of the vessel wall, cultures of human brain microvascular endothelial
      and smooth muscle cells were used, together with cultured human brain astrocytes.
      Endothelial cells invariably expressed m2 and m5 receptors, and occasionally the
      m1 receptor; smooth muscle cells exhibited messages for all except the m4 mAChR
      subtypes, whereas messages for all five muscarinic receptors were identified in
      astrocytes. In all three cell types studied, acetylcholine induced a pirenzepine
      sensitive increase (62% to 176%, P<0.05 to 0.01) in inositol trisphosphate,
      suggesting functional coupling of m1, m3, or m5 mAChR to a phospholipase C
      signaling cascade. Similarly, coupling of m2 or m4 mAChR to adenylate cyclase
      inhibition in endothelial cells and astrocytes, but not in smooth muscle cells,
      was demonstrated by the ability of carbachol to significantly reduce (44% to 50%,
      P<0.05 to 0.01) the forskolin-stimulated increase in cAMP levels. This effect was
      reversed by the mAChR antagonist AFDX 384. The results indicate that microvessels
      are able to respond to neurally released acetylcholine and that mAChR,
      distributed in different vascular and astroglial compartments, could regulate
      cortical perfusion and, possibly, blood-brain barrier permeability, functions
      that could become jeopardized in neurodegenerative disorders such as Alzheimer's
      disease.

PMID- 10413036
TI  - Measurement of changes in opioid receptor binding in vivo during trigeminal
      neuralgic pain using [11C] diprenorphine and positron emission tomography.
AB  - The binding of [11C]diprenorphine to mu, kappa, and delta subsites in cortical
      and subcortical structures was measured by positron emission tomography in vivo
      in six patients before and after surgical relief of trigeminal neuralgia pain.
      The volume of distribution of [11C]diprenorphine binding was significantly
      increased after thermocoagulation of the relevant trigeminal division in the
      following areas: prefrontal, insular, perigenual, mid-cingulate and inferior
      parietal cortices, basal ganglia, and thalamus bilaterally. In addition to the
      pain relief associated with the surgical procedure, there also was an improvement
      in anxiety and depression scores. In the context of other studies, these changes
      in binding most likely resulted from the change in the pain state. The results
      suggest an increased occupancy by endogenous opioid peptides during trigeminal
      pain but cannot exclude coexistent down-regulation of binding sites.

PMID- 10413037
TI  - In vivo determination of absolute cerebral blood volume using hemoglobin as a
      natural contrast agent: an MRI study using altered arterial carbon dioxide
      tension.
AB  - The ability of the magnetic resonance imaging transverse relaxation time, R2 =
      1/T2, to quantify cerebral blood volume (CBV) without the need for an exogenous
      contrast agent was studied in cats (n = 7) under pentobarbital anesthesia. This
      approach is possible because R2 is directly affected by changes in CBF, CBV,
      CMRO2, and hematocrit (Hct), a phenomena better known as the blood-oxygenation
      level-dependent (BOLD) effect. Changes in CBF and CBV were accomplished by
      altering the carbon dioxide pressure, PaCO2, over a range from 20 to 140 mm Hg.
      For each PaCO2 value, R2 in gray and white matter were determined using MRI, and
      the whole-brain oxygen extraction ratio was obtained from arteriovenous
      differences (sagittal sinus catheter). Assuming a constant CMRO2, the
      microvascular CBV was obtained from an exact fit to the BOLD theory for the spin
      echo effect. The resulting CBV values at normal PaCO2 and normalized to a common
      total hemoglobin concentration of 6.88 mmol/L were 42+/-18 microL/g (n = 7) and
      29+/-19 microL/g (n = 5) for gray and white matter, respectively, in good
      agreement with the range of literature values published using independent
      methodologies. The present study confirms the validity of the spin-echo BOLD
      theory and, in addition, shows that blood volume can be quantified from the
      magnetic resonance imaging spin relaxation rate R2 using a regulated carbon
      dioxide experiment.

PMID- 10413038
TI  - Cloning and kinetic characterization of the Trypanosoma cruzi S
      adenosylmethionine decarboxylase.
AB  - The gene for S-adenosylmethionine decarboxylase (AdoMetDC), a rate-limiting
      enzyme in the biosynthesis of polyamines, has been cloned from a Trypanosoma cruz
      cDNA library. The cDNA clone contains a 1.1 kb open reading frame predicted to
      encode a 42 kDa protein that shares 31% sequence identity to the human proenzyme.
      T. cruzi AdoMetDC expressed and purified from E. coli is auto-catalytically
      processed into two subunits of 32 kDa (alpha) and 10 kDa (beta). The catalytic
      activity of the purified recombinant enzyme is activated by the addition of
      putrescine to the reaction. To determine the effect of putrescine on the kinetics
      of the reaction, the velocity data collected at various substrate and putrescine
      concentrations were fit to the rate equation describing a non-essential
      activator. In the presence of fully saturating putrescine, k(cat) increases by 9
      fold over the unactivated rate to 0.06 s(-1). The model derived Km for AdoMet is
      0.05 mM in the absence of putrescine and the model-derived Kd for putrescine
      binding to free enzyme is 2.5 mM. The Km for AdoMet increases by alpha 2-fold
      when the enzyme is fully saturated with putrescine. Unlike human AdoMetDC,
      cadaverine activates the T. cruzi enzyme to a similar extent as putrescine.

PMID- 10413039
TI  - Cloning and expression in Escherichia coli of a Fasciola hepatica gene encoding a
      calcium-binding protein.
AB  - A Fasciola hepatica cDNA clone of 994 bp was isolated from an adult worm cDNA
      expression library using a rabbit serum against the excretory-secretory antigens.
      The nucleotide sequence of the cDNA clone revealed the presence of an open
      reading frame of 572 bp which encoded a 22 kDa polypeptide (Fh22) showing
      putative EF-hand domains. This gene was expressed in Escherichia coli and the
      recombinant protein used for the production of specific antibodies.
      Immunoblotting studies using the anti-Fh22 serum showed the presence of a
      polypeptide of similar molecular mass in the excretory-secretory extract of the
      adult parasite. The recombinant Fh22 polypeptide showed calcium-dependent
      electrophoretic mobility (decreased with Ca2(+)-ions and increased with EGTA).
      The observed behaviour of recombinant Fh22 in gel filtration experiments also
      suggested calcium-induced conformational changes.

PMID- 10413040
TI  - Karyotype and synteny among the chromosomes of all four species of human malaria
      parasite.
AB  - The karyotype and chromosomes of the human malaria parasite Plasmodium falciparum
      have been well characterized in recent years. Here we present karyotype maps of
      the three other human malaria species, P. vivax, P. malariae and P. ovale.
      Chromosomes of these species were found to be of significantly higher molecular
      weight than those of P. falciparum. Some 14 P. vivax chromosomes were
      distinguishable, and 12-14 P. malariae and P. ovale chromosomes. The chromosome
      location of 15 genes, known to be present within five synteny groups between P.
      falciparum and the rodent malarias, were analyzed, and four of these synteny
      groups were found to be conserved between all of the human malaria species. In
      addition, a more detailed genome map of P. vivax was made using ten housekeeping
      and antigen genes. These data represent the first karyotype maps of all species
      of malaria which infect man.

PMID- 10413041
TI  - Identification of NF-AT-like transcription factor in Schistosoma mansoni: its
      possible involvement in the antiparasitic action of cyclosporin A.
AB  - Cyclosporin A (CsA) has been found to exert potent anti-parasite activity against
      a wide range of protozoan and helminth parasites. In schistosomes, evidence has
      been accumulated to propose that the drug damages parasites by mechanisms
      independent of its immunosuppressive properties. Moreover, the absence of
      correlation between anti-schistosomal properties and inhibition of peptidyl
      prolyl cis-trans isomerase activity of cyclophilins (CsA receptors) for various
      drug analogs, argued against a direct implication of cyclophilins in the lethal
      effect of CsA. We describe, in S. mansoni, the existence of NF-AT-like
      transcription factors, a protein family already characterized by its sensitivity
      to CsA. The observation that CsA treatment of S. mansoni larvae inhibited the
      expression of the Sm28GST protein and the characterization of a functional NF-AT
      like site in the gene encoding this protein, provide new insights in the
      understanding of the antischistosomal effect of CsA. Our results also support the
      hypothesis that the regulatory function of NF-AT-like proteins might be
      responsible for parasite development and survival in the host and open new
      perspectives in studies of helminth biology.

PMID- 10413042
TI  - Chelation of iron within the erythrocytic Plasmodium falciparum parasite by iron
      chelators.
AB  - To examine the site of action of antimalarial iron chelators, iron ligands were
      added to control erythrocytes and to erythrocytes parasitized with Plasmodium
      falciparum, and the concentration of intracellular labile iron was monitored with
      the fluorescent probe, calcein. The fluorescence of calcein quenches upon binding
      iron and increases upon releasing iron. The chelators included desferrioxamine B,
      2',2'-bipyridyl, and aminophenol II, a compound that is being newly reported as
      having anti-plasmodial properties. Calcein-loaded parasitized cells displayed
      fluorescence predominantly within the cytosol of both rings and trophozoites. The
      addition of chelators to both control and parasitized erythrocytes led to
      significant increases of fluorescence (P < 0.001). Fluorescence was observed to
      increase within the parasite itself after addition of iron chelators, indicating
      that these agents bound labile iron within the plasmodium. The relative increases
      of fluorescence after addition of chelators were greater in control than
      parasitized erythrocytes (P < 0.05) as were the estimated labile iron
      concentrations (P < or = 0.001). These results suggest that (i) the anti-malarial
      action of iron chelators might result from the ability to reach the infected
      cell's parasite compartment and bind iron within the parasite cytosol, and (ii)
      the labile iron pool of the host red cell may be either utilized or stored during
      plasmodial growth.

PMID- 10413043
TI  - Identification of calcium binding sites in the trypanosome flagellar calcium-acyl
      switch protein.
AB  - The 24 kDa flagellar calcium binding protein (FCaBP) of the protozoan Trypanosoma
      cruzi is a calcium-acyl switch protein. FCaBP is modified by the addition of
      myristate and palmitate at its amino terminal segment and both modifications are
      required for calcium-modulated flagellar membrane association. FCaBP has four
      sequence motifs for potential calcium binding, and comparison to other calcium
      acyl switch proteins, such as recoverin, suggested that only two of these sites
      are functional. Because it is not possible to predict with certainty the calcium
      binding affinity or selectivity based on motif analysis alone, we determined the
      quantitative calcium binding activity of FCaBP by direct ligand binding using the
      flow dialysis method. The results demonstrated the presence of two calcium
      binding sites in the full length FCaBP and in a mutant (FCaBPdelta12) lacking the
      amino terminal pair of sites. FCaBPdelta12 retains its ability to localize to the
      flagellum. A mutant FCaBP lacking the two carboxyl-terminal sites (FCaBPdelta34),
      did not bind calcium with high affinity and selectivity under the conditions
      used. The calcium binding properties of FCaBP are therefore distinct from other
      myristoyl switch proteins such as recoverin. The results add to a growing body of
      knowledge about the correlation of sequence motifs with calcium binding activity.
      Moreover, they demonstrate the need to determine the apparently novel mechanism
      by which FCaBP undergoes calcium modulated flagellar membrane association and its
      relation to calcium signal transduction.

PMID- 10413044
TI  - Artemisinin and its derivatives are transported by a vacuolar-network of
      Plasmodium falciparum and their anti-malarial activities are additive with toxic
      sphingolipid analogues that block the network.
AB  - There is great need to identify and characterize drug targets and
      chemotherapeutic strategies against malaria. Here we show that a vacuolar-network
      induced by the human malaria parasite Plasmodium falciparum, is a major import
      pathway for artemisinin, a leading, new anti-malarial that is known to be
      effective against drug resistant strains. We also show that artemisinin-treatment
      induces aberrant, budding of a vacuolar-network membrane protein and its
      antimalarial activity is additive with toxic sphingolipid analogues that block
      the network. The data suggest that artemisinin alters membrane protein export
      from the vacuolar-network and combinations with anti-network reagents have the
      potential to provide powerful new chemotherapy for drug resistant malaria.

PMID- 10413045
TI  - Transcription of 'inactive' expression sites in African trypanosomes leads to
      expression of multiple transferrin receptor RNAs in bloodstream forms.
AB  - African trypanosomes express a heterodimeric transferrin receptor that mediates
      iron uptake from the host bloodstream. The genes encoding the receptor, ESAG6 and
      ESAG7, are found at the beginning of VSG expression sites: these are telomeric,
      polycistronic transcription units that each terminate with a gene encoding a
      trypanosome variant surface glycoprotein, VSG. Approximately 20 of these VSG
      expression sites are found in the trypanosome genome, but only one VSG is
      expressed at a time. The conventional view is that one expression site promoter
      is extremely active whereas the others are either inactive or show very low,
      poorly processive activity, and that all transferrin receptor molecules are
      encoded by the active expression site. The 3'-end of the ESAG6 gene is more than
      5 kb from the promoter. We show here that 20% of ESAG6 mRNA originates from the
      'inactive' expression sites. We suggest that many expression site promoters in
      trypanosomes show low-level activity throughout the life cycle, and that
      transcription proceeds for at least 5 kb. This suggests a simplified model of VSG
      expression site control, whereby the only regulated event is the strong
      activation of a single expression site promoter in bloodstream forms.

PMID- 10413047
TI  - Intra-cluster recombination and var transcription switches in the antigenic
      variation of Plasmodium falciparum.
AB  - Antigenic variation and immune evasion by Plasmodium falciparum parasitized
      erythrocytes are mediated by expression switches among members of the multicopy
      var gene family. Here we describe a cluster of var genes on chromosome 12 that
      showed spontaneous recombination and switches in the transcription of individual
      genes. The transcription switches were not associated with sequence changes in
      promoter regions. Transfected episomes containing a luciferase reporter under
      control of a var promoter were expressed regardless of the transcriptional status
      of the endogenous promoter. The results suggest epigenetic regulation of P.
      falciparum var gene transcription that depends upon the local structure of
      chromatin and its associated proteins.

PMID- 10413046
TI  - Alternative-splicing of serotonin receptor isoforms in the pharynx and muscle of
      the parasitic nematode, Ascaris suum.
AB  - Pharyngeal pumping is essential for nematode feeding and survival and is
      dramatically stimulated by serotonin (5-HT). In the present study, a cDNA pool
      was prepared from poly A + RNA isolated from pharynxes dissected from the
      parasitic nematode, Ascaris suum, and was used as a template for RT-PCR with
      degenerate primers designed from sequences conserved in 5-HT receptors from a
      variety of sources. A putative 5-HT receptor cDNA (AS1) was identified which
      exhibited most identity to the 5-HT2 family of receptors. AS1 was 1925
      nucleotides, did not appear to be trans-spliced and contained a 3' untranslated
      region of 127 nucleotides with a polyadenylation signal (ATTAAA) and a short poly
      A+ tail. The coding region predicted a protein of 532 amino acids with a
      molecular weight of 60 176. When AS1 was transiently expressed in COS-7 cells,
      isolated membranes exhibited the high affinity, saturable binding of [125I]LSD.
      More importantly, [125I]LSD binding was inhibited by 5-HT, but not other biogenic
      amines, supporting the identification of AS1 as a 5-HT receptor. Additional cDNAs
      identical, in part, to AS1 were also identified. AS1deltaIV lacked a predicted 42
      amino acids at the carboxy terminus of the third intracellular loop, while AS2
      and AS3 contained different COOH-termini, regions implicated in G-protein
      coupling in other heptahelical receptors. A portion of the gene (5htn) encoding
      AS1 also was cloned and sequenced. This genomic fragment was about 10 kb,
      contained the entire AS1 open reading frame and included eight exons and seven
      introns. From this analysis, it appears that these different AS cDNAs were
      generated by alternative-splicing, AS1deltaIV from the deletion of exon IV, and
      AS2 and AS3 from the use of alternative sites within exon VII as 5' splice
      acceptor sites for exon VIII. Using RT-PCR and primers specific for each of the
      isoforms, AS1 -3 appeared to be expressed in pharynx, while only AS1 and AS2 were
      present in body wall muscle. More importantly, the deletion of exon IV appeared
      to be associated exclusively with AS1 in pharynx and AS2 in muscle.

PMID- 10413048
TI  - Evidence for localisation of a Theileria parasite AT hook DNA-binding protein to
      the nucleus of immortalised bovine host cells.
AB  - Immortalisation of bovine leukocytes by the macroschizont stage of the tick
      transmitted protozoan parasite, Theileria annulata, results in the clonal
      expansion of infected cells and dissemination throughout the bovine host. The
      parasite-encoded factors which induce this unique transformation event have not
      been defined to date. In this study, a gene family (TashAT) has been
      characterised that encodes polypeptides with homology to known DNA-binding
      proteins. Expression of TashAT genes occurs at the intracellular macroschizont
      stage of the parasite life cycle and during differentiation to the merozoite,
      negative regulation of TashAT genes is detected early relative to other
      macroschizont genes. Interestingly, the early reduction in TashAT expression
      coincides with the initial decrease in host cell proliferation. One member of the
      family, TashAT2, was characterised in detail and the predicted polypeptide
      sequence was found to harbor three AT hook DNA-binding domains. Antisera
      generated against two distinct regions of TashAT2 both located the antigen to the
      host cell nucleus and, combined with protein translation inhibition and
      immunoprecipitation studies, provide evidence that this polypeptide could be
      transported from the parasite to this location. Further evidence for this
      postulation was provided by transfection studies which demonstrated that TashAT2
      does encode the structural information required for localisation to the nucleus
      of a mammalian cell. Thus, TashAT2 is a potential candidate for a parasite
      encoded factor that modulates host cell gene expression and may be involved in
      the control of host cell proliferation.

PMID- 10413050
TI  - Molecular cloning and characterization of the polypeptide backbone of Schistosoma
      mansoni circulating cathodic antigen.
AB  - One of the candidate schistosome antigens for the development of a circulating
      antigen detection diagnostic assay is the circulating cathodic antigen (CCA).
      Detection of CCA in urine provides a non-invasive assay with high sensitivity.
      Previously we reported that CCA is secreted in patients' urine as a small
      molecular weight material which is probably of a proteinaceous nature. In an
      attempt to further characterize the secreted component of CCA, we used a
      monoclonal antibody (MAb) reactive with urine-CCA to isolate an adult worm cDNA
      clone (SmN3-1) that encodes the polypeptide backbone of CCA. The sequence, gene
      organization and expression of SmN3-1 were analyzed. The 1.6 kb nucleotide and
      347 amino acid sequences of SmN3-1 showed no significant homology to any
      published sequence. The size and antigenic properties of the expression product
      of SmN3-1 in Escherichia coli greatly resembled the CCA molecule excreted in
      urine, suggesting that the latter is primarily composed of the protein element of
      CCA.

PMID- 10413049
TI  - Plasmodium vivax merozoite surface protein-3 contains coiled-coil motifs in an
      alanine-rich central domain.
AB  - Plasmodium merozoites are covered with a palisade layer of proteins that are
      arranged as organized bundles or appear as protruding spikes by electron
      microscopy. Here we present a third Plasmodium vivax merozoite surface protein,
      PvMSP-3, which is associated with but not anchored in the merozoite membrane.
      Serum from a P. vivax immune squirrel monkey was used to screen a lambdagt11 P.
      vivax genomic DNA (gDNA) library. Plaque-selected antibodies from clone no. 6.1,
      and rabbit antisera against its encoded protein, produced a pattern in
      immunofluorescence assays (IFAs) that is consistent with a localization at the
      surface of mature schizonts and free merozoites. Specific antisera also
      agglutinated merozoites and recognized a protein of 150 000 Da by SDS-PAGE. The
      complete msp-3 gene and flanking sequences were cloned from a P. vivax lambda
      Dash II gDNA library and also partly characterized by RACE (rapid amplification
      of cDNA ends). The immediate upstream sequence contains non-coding repeats and a
      putative protein encoding open reading frame (ORF), which are also present on the
      msp-3 5'RACE gene product. Pvmsp-3 encodes a protein with a calculated mass of 89
      573 Da, which has a potential signal peptide and a major central alanine-rich
      domain (31%) that exhibits largely alpha-helical secondary structure and is
      flanked by charged regions. The protein does not have a putative transmembrane
      domain or a consensus sequence for a glycosylphosphatidylinositol (GPI) anchor
      modification. However, the alanine-rich domain has heptad repeats that are
      predicted to form coiled-coil tertiary structures, which mediate protein-protein
      interactions. PvMSP-3 is structurally related to P. falciparum MSP-3 and the
      140000 Da MSP of P. knowlesi. Characterization of PvMSP-3, thus, also begins to
      define a new interspecies family of evolutionarily related Plasmodium merozoite
      proteins.

PMID- 10413051
TI  - A protein linked to mitochondrion development in Trypanosoma brucei.
AB  - The use of the two-hybrid system in yeast allowed us to isolate a new
      mitochondrial protein of Trypanosoma brucei, termed PIE8, for putative protein
      interacting with ESAG8. This protein was found to localize progressively in the
      single mitochondrion of the parasite during the mitochondrial reactivation needed
      to adapt the parasite from the glycolysis-based metabolism in the mammalian host,
      to the cytochrome-mediated respiration in the fly vector. Once this reactivation
      is established, PIE8 is lost from the mitochondrion. Thus, the temporary presence
      of PIE8 in the mitochondrion is linked to mitochondrial reactivation.

PMID- 10413052
TI  - cut-1-like genes are present in the filarial nematodes, Brugia pahangi and Brugia
      malayi, and, as in other nematodes, code for components of the cuticle.
AB  - A fragment of a cut-1 like gene from the filarial nematode Brugia pahangi
      (designated Bp-cut-1) was isolated by PCR from genomic DNA. The sequence was used
      to design primers for use in RT-PCR and resulted in the isolation of a cDNA
      fragment from larvae in the process of the L3-L4 moult. Screening of a B. malayi
      genomic library identified a single clone, Bm-cut-1. Using primers designed from
      the Brugia sequences, semi-quantitative RT-PCR was carried out on 11 different
      life cycle stages chosen to cover periods around the moult and inter-moult
      periods. This analysis demonstrated that the cut-1 mRNA was most abundant
      preceding the moult, consistent with its function as a cuticular protein. Immuno
      gold electron microscopy using an affinity purified antiserum raised to the
      highly conserved region of Ascaris CUT-1 confirmed that the protein was
      restricted to a tight band in the median layer of the cuticle. Despite the fact
      that no transcripts could be detected in mature adult worms by RT-PCR, immuno
      gold microscopy revealed staining of the microfilarial cuticle within the uterus
      of the adult female worm, suggesting that other cut-1-like genes are present in
      Brugia.

PMID- 10413054
TI  - The organization of a galectin gene from Teladorsagia circumcincta.
AB  - Galectins are a family of soluble beta-galactoside-binding lectins that are
      conserved amongst a broad range of organisms. We have previously isolated cDNA
      clones coding for galectins from the sheep gastrointestinal nematode parasites
      Teladorsagia circumcincta, Haemonchus contortus and Trichostrongylus
      colubriformis, revealing a high level of identity between these molecules. This
      subsequent study reports the organization of the T. circumcincta Tci-gal-1
      galectin gene. The coding region is broken into eight exons covering 6.6 kbp,
      with introns ranging in size from 55 base pairs (bp) to 2.8 kbp. Comparisons with
      recently reported galectin structures from Caenorhabditis elegans reveal strong
      architectural similarity between galectins from the parasitic and free-living
      nematodes, but this structure is not conserved in mammalian galectins.

PMID- 10413053
TI  - Analysis of kappa and omega repeats of the cg2 gene and chloroquine
      susceptibility in isolates of Plasmodium falciparum from sub-Saharan Africa.
AB  - The correlation between the structure of two short sequences from the Plasmodium
      falciparum cg2 gene and parasite chloroquine susceptibility was evaluated in
      unselected clinical isolates obtained from travellers returning mainly from
      Africa to France in 1995 and 1996. As determined by an isotopic semi-microtest,
      74 isolates were susceptible to chloroquine (50% inhibitory concentration < 80
      nM), 13 were intermediate (80 nM < 50% inhibitory concentration < 110 nM) and 53
      were resistant (50% inhibitory concentration > 110 nM). Two polymerase chain
      reaction assays were developed, one for the kappa and one for the omega repeat
      domains of cg2 gene. The kappa and the omega repeat domains of 99 isolates were
      sequenced. A variation in the unit number of kappa and omega repeats was
      observed. Variations in repetitive sequences, which were not previously
      described, were found: three for the kappa repeat region: kappa9; kappa10 and
      kappa11 and three for the omega repeat region: omega8; omega9 and omega22. A
      polymorphism was observed inside the repeat units of kappa and omega regions.
      There were six possible kappa repeat units and seven possible omega repeat units.
      The presence of a particular pattern, containing kappa14 and omega16 repeat
      units, was associated with a lack of chloroquine susceptibility in 44 out of 46
      cases. However, not all resistant isolates had this 'resistant' genotype. Among
      43 resistant isolates, 36 (84%) had the kappa14 repeats sequence and 36 had the
      omega16 repeats sequence. These results lend further support to linkage between
      cg2 polymorphisms and chloroquine resistance without excluding the existence of
      other resistance component(s).

PMID- 10413055
TI  - Genomic instability in Schistosoma mansoni.
AB  - In schistosomes, the W chromosome characterizes the heterogametic female-sex (ZW)
      whereas males are homogametic (ZZ). In the heterochromatic region of the W
      chromosome, the repetitive elements W1 and W2 are located which had originally
      been found as female-specific sequences in Puerto Rican isolates of Schistosoma
      mansoni. An analysis of the strain- and sex-specific occurrence of these elements
      revealed that both elements can occur gender-independently in other Puerto Rican
      isolates and in a variety of other strains of S. mansoni. This result
      contradicted earlier findings and indicated the existence of polymorphic Z
      chromosomes. A genetic analysis of the occurrence of W1 and W2 in a series of
      clonal populations of Schistsoma mansoni is presented. Although clones of this
      parasite are regarded as genetically identical, striking inter- and even intra
      clonal variations have been found by PCR and Southern-blot experiments with the
      DNA of individual clones and of the progeny of crossing experiments. The results
      do not support the hypothesis of polymorphic Z chromosomes. Instead, they
      strongly suggest genomic instability probably originating from unusual DNA
      recombination events at the meiotic and mitotic level. These findings suggest a
      further method of generating variability within schistosomes. rights reserved.

PMID- 10413056
TI  - Representational difference analysis of cDNA between two Dd2 clones of Plasmodium
      falciparum.

PMID- 10413057
TI  - Identification of additional members define a Plasmodium falciparum gene
      superfamily which includes Pfs48/45 and Pfs230.

PMID- 10413058
TI  - Sequence homology within a minicircle class of the Leishmania donovani complex.

PMID- 10413059
TI  - Prolonged sinus node recovery time in humans after the intracoronary
      administration of a nitric oxide synthase inhibitor.
AB  - In vitro studies indicate that nitric oxide synthase (NOS) inhibitors alter sinus
      node automaticity. Moreover, whereas the systemic delivery of N(G)-monomethyl-L
      arginine (L-NMMA), a NOS inhibitor, results in sinus bradycardia and arterial
      hypertension, its intracoronary administration has little effect on sinus heart
      rate. Therefore whether L-NMMA directly alters sinus node function in humans is
      not known. By using a crossover design, we evaluated the effect of intracoronary
      L-NMMA (20 micromol/min x 10 min) on corrected sinus node recovery time (CSNRT),
      heart rate, mean arterial blood pressure, electrocardiographic intervals, and
      coronary artery blood flow in nine men and 13 women aged 48+/-12 years. All were
      in sinus rhythm and had normal baseline CSNRTs. Baseline measurements were made
      during a dextrose infusion, and then L-NMMA was administered, and these
      parameters remeasured. In 11 patients, the infusions were near the origin of the
      sinus node artery (Concordant), whereas in the remaining 11, they were into the
      opposite coronary circulation (Discordant). After L-NMMA, significant
      prolongations in CSNRT were seen in Concordant (p < 0.001) and Discordant
      patients (p < 0.05), but were most pronounced in the Concordant group (p < 0.05).
      Although a significant reduction in coronary artery blood flow and nonsignificant
      changes in blood pressure and heart rate were observed after L-NMMA, these
      changes were not related to changes in CSNRT (r2 < or = 0.2; p > or = 0.2). These
      data support the notion that NO is a modifier of human sinus node automaticity.

PMID- 10413060
TI  - Adenosine stimulates ANP expression in cultured ventricular cardiomyocytes.
AB  - Adenosine protects the ischemic myocardium by coronary vasodilation and the
      depression of heart rate and contractility, improving myocardial energy balance.
      Adenosine effects on the myocardium are mediated predominantly by the type A1
      receptors. Atrial natriuretic peptide (ANP), a vasodilator and regulator of blood
      volume, is secreted from either atrial or ventricular myocytes in response to
      cellular distention. In vivo, adenosine infusion has been shown to induce a rapid
      increase in plasma ANP, independent of blood pressure. We examined the
      possibility that adenosine enhances ANP-gene expression in cardiac myocytes.
      Administration of adenosine (10 microM) to cultured neonatal rat cardiomyocytes
      led to a 1.7-fold increase (p = 0.014, n = 9) in the abundance of ANP messenger
      RNA (mRNA) within 30 min, as measured by Northern blot hybridization. No such
      increase was obtained when adenosine was coadministered with 8-cyclopentyl
      1,3dipropylxanthine (CPX, 10 microM), an adenosine A1-receptor antagonist. Our
      results point at adenosine as regulator of ANP mRNA level in cardiac myocytes.

PMID- 10413061
TI  - Eugenodilol: a third-generation beta-adrenoceptor blocker, derived from eugenol,
      with alpha-adrenoceptor blocking and beta2-adrenoceptor agonist-associated
      vasorelaxant activities.
AB  - Eugenodilol, derived from natural eugenol, was first investigated with in vivo
      and in vitro models. In our in vivo study, eugenodilol (0.5, 1.0, and 1.5 mg/kg,
      i.v.) produced dose-dependent hypotensive and bradycardic responses in
      pentobarbital-anesthetized Wistar rats. Eugenodilol also inhibited the
      tachycardia and arterial pressor effects induced by (-)isoproterenol and
      phenylephrine, respectively. In our in vitro study, eugenodilol competitively
      antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects
      and tracheal-relaxation responses on isolated guinea pig tissues in a
      concentration-dependent manner. The apparent pA2 values were 7.88+/-0.12 for
      right atria, 7.52+/-0.05 for left atria, and 7.33+/-0.15 for trachea, indicating
      that eugenodilol was a nonselective beta-adrenoceptor blocker. In thoracic aorta
      experiments, the apparent pA2 values of alpha-adrenoceptor blockade were 7.05+/
      0.25 and 6.87+/-0.08 for eugenodilol and labetalol, respectively. In addition,
      eugenodilol produced cumulative relaxation responses on isolated guinea pig
      tracheal strips. The effects were competitively antagonized by ICI 118,551 (10(
      8)-10(-6) M), a relatively selective beta2-adrenoceptor antagonist. In the
      radioligand-binding assay, the Ki values of [3H]CGP-12177 binding to rat
      ventricle and lung membranes were 9.72 and 48.29 nM, respectively, and the value
      of [3H]prazosin binding to rat brain membrane was 38.72 nM. These results further
      confirmed the alpha/beta-adrenoceptors-blocking activities of eugenodilol
      reported in the functional studies. We conclude that eugenodilol is a novel third
      generation beta-adrenoceptor blocker with ancillary blocking activity at alpha
      adrenoceptors and weak sympathomimetic activity at beta2-adrenoceptors.

PMID- 10413062
TI  - Renal vascular interaction of angiotensin II and prostaglandins in renovascular
      hypertension.
AB  - The vascular responses to angiotensin II (Ang II) in the renal circulation are
      increased in kidneys from rats with aortic coarctation compared with sham
      operated rats. We have suggested that these differences are related to changes in
      mediators of the Ang II effect. The aim of this study was to investigate the role
      of arachidonic acid (AA) metabolites on the Ang II effect in the renal
      circulation of normotensive and hypertensive rats. We evaluated vascular renal
      reactivity in the rat isolated perfused kidney. Bolus injection of Ang II (9, 18,
      36, 72 ng) increased perfusion pressure in a dose-dependent manner by 16.5+/-4,
      23.5+/-4, 35.5+/-7, and 42.5+/-7 mm Hg in sham-operated rats and 50+/-6, 72+/-10,
      92+/-6, and 120+/-6 mm Hg in rats with aortic coarctation. Ang II-induced
      vasoconstriction was prevented in hypertensive rats and potentiated in
      normotensive rats by the presence of indomethacin (1 microg/ml) in the perfusion
      solution. Furthermore, the use of the endoperoxide/thromboxane blocker (SQ29548,
      1 microM) did not alter the effect of Ang II on the normotensive rats but
      prevented its effect in hypertensive rats. Moreover, the prostaglandin/
      thromboxane (PGH2/TxA2) receptor agonist U46619 increased perfusion pressure to
      similar values in both kidneys from sham-operated or aortic coarctation rats. Ang
      II stimulated AA and prostaglandin release from isolated perfused kidneys.
      However, autacoid release was higher in kidneys from rats with aortic
      coarctation. In conclusion, we suggest that during the development of
      hypertension, the AA metabolism of vasoconstrictor prostaglandins is increased,
      and it mediates the vasoconstrictive effects of Ang II.

PMID- 10413063
TI  - Effects of quinapril and losartan on insulin sensitivity in genetic hypertensive
      rats with different metabolic abnormalities.
AB  - This study was designed to investigate the effects of the angiotensin-converting
      enzyme (ACE) inhibitor quinapril and the angiotensin II-receptor antagonist
      losartan on insulin sensitivity in two types of genetic hypertensive rats with
      insulin resistance. Quinapril (3 mg/kg) and losartan (10 mg/kg) decreased the
      systolic blood pressure to almost the same extent in both spontaneously
      hypertensive rats (SHRs) and Dahl salt-sensitive (Dahl S) rats. Quinapril
      increased the glucose requirement for the euglycemic clamp test in both SHRs and
      Dahl S rats, whereas losartan increased it in SHRs but not in Dahl S rats. The
      severity of the metabolic abnormalities may be responsible for the failure of
      losartan to improve the insulin sensitivity in Dahl S rats because serum insulin,
      total cholesterol, triglyceride, and free fatty acids (FFAs) were higher in the
      Dahl S rats than in SHRs. A kinin antagonist, Hoe 140, inhibited the increase in
      the glucose requirement by quinapril without affecting the depressor effect of
      quinapril in SHRs. In conclusion, quinapril improved the insulin sensitivity more
      effectively than did losartan in the genetic hypertensive rats with insulin
      resistance and relatively severe metabolic abnormalities. Based on our findings,
      one of the mechanisms underlying the difference between quinapril and losartan
      may thus be endogenous kinins.

PMID- 10413064
TI  - Effect of short- and long-term heart failure on small artery morphology and
      endothelial function in the rat.
AB  - Chronic heart failure (HF) is associated with hemodynamic changes and activation
      of several neurohormonal systems, which are able both to inhibit and to
      facilitate arterial growth or remodeling and also to influence endothelial
      function. As these vascular changes may depend on the duration of HF, we
      evaluated morphologic and endothelial functional alterations in a rat model of HF
      after a short and long duration of HF. Rats with coronary ligation and sham
      operated controls were investigated either 8 or 26 weeks after the operation with
      measurements of hemodynamics and isolated mesenteric small artery morphology and
      endothelial function. The effect of HF and duration of HF were examined by using
      two-way analysis of variance (ANOVA). HF rats had altered hemodynamics with
      reductions in cardiac output, left ventricular systolic pressure, and mean blood
      pressure, whereas left ventricular diastolic pressure was increased. HF caused
      remodeling of anatomically well-defined mesenteric small arteries with a
      reduction in media thickness and media-to-lumen ratio, but without change in the
      media cross-sectional area. Neither HF nor time had any influence on sensitivity
      or maximal relaxation to acetylcholine in the presence of indomethacin, but HF
      reduced vasoconstriction due to nitric oxide synthase blockade with N(G)-nitro-L
      arginine independent of time. Our results indicate that HF, induced by coronary
      ligation in the rat, has a remodeling effect on mesenteric small arteries.
      However, the remodeling is moderate compared with that observed in hypertension.
      Furthermore, our results suggest that HF reduces basal release of NO.

PMID- 10413065
TI  - Effects of rilmenidine on stress-induced peak blood pressure and renal function.
AB  - Rilmenidine is an imidazoline I1-receptor agonist that centrally acts by reducing
      the sympathetic tone. There is strong experimental evidence that natriuresis
      could be evoked by proximal tubular I1-receptors that have also been isolated in
      human kidneys. However, in humans, the natriuretic effects of proximal tubular I1
      receptors have never been demonstrated. Because stress tests elicited a
      sympathetically mediated increase in blood pressure and in sodium reabsorption,
      this study examined whether a short-term infusion of rilmenidine (1 mg) may
      interfere with stress-induced cardiovascular response and renal sodium handling
      in normotensive men, in a double-blind, crossover, placebo-controlled study. The
      stress test used is an efficient and reproducible computerized version of the
      Stroop's stress test. During the experimental sessions, both basal and stress
      renal functional parameters were determined: glomerular filtration rate, renal
      plasma flow, filtration fraction, sodium excretion, and segmental sodium tubular
      reabsorption (lithium clearance). During the placebo phase, stress induced a
      significant increase in systolic blood pressure (SBP; 22.2+/-10.1 mm Hg) and
      diastolic blood pressure (DBP; 11.0+/-5.0 mm Hg). During stress, glomerular
      filtration rate and renal plasma flow tended to decrease, resulting in a
      nonsignificant increase in filtration fraction. Despite the increase in BP,
      stress induced a significant decrease in sodium excretion that was due mainly to
      a nonsignificant increase in sodium reabsorption in the proximal parts of the
      tubules. Rilmenidine significantly reduced rest and stress BP, but the
      cardiovascular reactivity to stress was not altered. The treatment slightly
      decreased basal glomerular filtration rate and increased renal plasma flow, so
      that the filtration fraction significantly decreased. The treatment-related
      decrease in BP was associated with a significant increase in basal sodium
      reabsorption. Stress-induced modifications in renal function and sodium handling
      were not altered by the treatment. In conclusion, rilmenidine reduced rest BP and
      preserved stress-induced reactivity in BP and heart rate. Renal effects of
      rilmenidine are characterized by a decrease in glomerular filtration rate and in
      filtration fraction and an increase in sodium reabsorption. The study failed to
      demonstrate any effect of rilmenidine on stress-induced increase in sodium
      reabsorption.

PMID- 10413066
TI  - Can the MAP technique be applied to detect delayed afterdepolarization?
      Electrophysiologic and pharmacologic evidence.
AB  - The purpose of this study was to assess whether the monophasic action potentials
      (MAPs) technique can be applied to detect delayed afterdepolarizations (DADs).
      The canine isolated, blood-perfused ventricular septum preparation was used to
      obtain stable MAP signals (n = 8). The preparation was electrically driven by
      trains of 15 stimuli at each cycle length of 600-300 ms under the monitoring of
      MAP and papillary muscle contraction. In a basal condition, neither DADs nor
      premature ventricular contractions (PVCs) were induced by the train stimulation,
      whereas the coupling interval between electrograms of the last driven contraction
      and the first spontaneously developed contraction was prolonged by shortening the
      pacing cycle length. Then 40-45 microg of ouabain was intravenously administered
      into the blood-donor dog. Both DADs and PVCs were induced in all preparations by
      the pacing protocol 10-15 min after the ouabain injection; however, PVCs did not
      occur spontaneously. Small aftercontractions also were detected during the
      electrical pacing in four preparations. By shortening the pacing cycle length,
      the DADs were enhanced, the coupling interval was shortened, and the number of
      PVCs increased. After the administration of ryanodine, verapamil, tetrodotoxin,
      or lidocaine (n = 4--6), the small aftercontractions disappeared, the DADs
      attenuated, the coupling interval was prolonged, and the number of PVCs
      decreased. These observations suggest that PVCs observed in this model may be
      derived from the DAD-related triggered activity, and moreover, show the
      feasibility of recording DADs and triggered activity by the MAP technique.

PMID- 10413067
TI  - A comparison of the binding characteristics of class I antiarrhythmic agents for
      human muscarinic m1-m3 receptors.
AB  - The binding characteristics of the class 1 antiarrhythmic agents, cibenzoline,
      disopyramide, disopyramide metabolite (the main active metabolite of disopyramide
      in humans), and pirmenol, for human muscarinic receptors (m1-m3) stably expressed
      in Chinese hamster ovary cells (CHO) were investigated by binding assay with
      [3H]N-methylscopolamine ([3H]NMS) as a ligand. All of these agents inhibited the
      specific [3H]NMS binding to membrane preparations in a concentration-dependent
      manner. The potencies of affinity of these agents for m1, m2, and m3 receptors
      (compared by IC50) were disopyramide > pirmenol > disopyramide metabolite >
      cibenzoline, pirmenol > cibenzoline > disopyramide > disopyramide metabolite, and
      disopyramide > disopyramide metabolite > pirmenol > cibenzoline, respectively.
      Some competition curves of cibenzoline, disopyramide, and pirmenol were shallow,
      and Hill coefficients of these curves differed from unity, suggesting that these
      agents have allosteric binding characteristics for human muscarinic receptors.
      The m2-selective ratios to m1 (IC50 m1/IC50 m2) and m3 (IC50 m3/IC50 m2) of
      cibenzoline were 4.0 and 16, and those of pirmenol were 6.5 and 43, respectively,
      whereas those of disopyramide and its metabolite ranged from 0.46 to 1.6,
      suggesting that cibenzoline and pirmenol exerted high selectivity to the m2
      receptor. We conclude that (a) all class 1 antiarrhythmic agents in this study
      have inhibitory effects on human m1, m2, and m3 receptors, and some of those
      binding may show allosteric characterization; (b) disopyramide and its metabolite
      have similar affinity to m1 to m3 receptors; and (c) cibenzoline and pirmenol
      have high m2-selective ratios to m1 and m3.

PMID- 10413068
TI  - Effect of micronized fenofibrate and losartan combination on uric acid metabolism
      in hypertensive patients with hyperuricemia.
AB  - It has been reported that micronized fenofibrate and losartan can significantly
      decrease serum uric acid levels by augmenting uric acid excretion. We undertook
      this study to evaluate the effects of the combination treatment with micronized
      fenofibrate and losartan in nondiabetic hypertensive dyslipidemic patients with
      hyperuricemia (serum uric acid, >7 mg/ dl). A total of 25 patients (15 men, 10
      women) aged 21-66 years was studied. In all patients, serum lipid parameters,
      including Lp(a), fibrinogen, and uric acid levels, as well as fractional
      excretion of uric acid (FEUA) were obtained before treatment, 8 weeks after
      micronized fenofibrate treatment (200 mg daily), and 8 weeks after combination
      therapy with micronized fenofibrate (200 mg daily) and losartan (50 mg daily).
      Fenofibrate alone significantly decreased total cholesterol, low-density
      lipoprotein (LDL) cholesterol, triglycerides, Apo B, Lp(a), fibrinogen, and uric
      acid levels (from 7.6+/-0.55 to 5.6 +/-0.5 mg/dl; p < 0.0001) and increased high
      density lipoprotein (HDL) cholesterol, Apo A1, and FEUA (from 6.5+/-1.8% to
      12.2+/-4%; p < 0.0001). The addition of losartan beyond the decrease in blood
      pressure values did not significantly alter serum metabolic parameters. However,
      a small additional decrease in serum uric acid levels (from 5.6+/-0.5 to 4.9+/-1
      mg/dl; p < 0.05) was found because of a further increase in FEUA (from 12.2+/-4%
      to 14+/-5.5%; p < 0.05). It is concluded that the combination of micronized
      fenofibrate and losartan is useful for the management of patients with multiple
      metabolic abnormalities, including hyperuricemia.

PMID- 10413069
TI  - Influence of FR 167653, an inhibitor of TNF-alpha and IL-1, on the cardiovascular
      responses to chronic infusion of lipopolysaccharide in conscious rats.
AB  - Conscious, male Long Evans rats (350-450 g) chronically instrumented for the
      measurement of regional haemodynamics, were infused with FR 167653, a dual
      inhibitor of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1)
      synthesis (0.32 mg/kg/h) for 24 h, beginning 1 h before coinfusion of saline, or
      with saline for 24 h beginning 1 h before coinfusion of lipopolysaccharide (150
      microg/kg/h), or with FR 167653 beginning 1 h before coinfusion of
      lipopolysaccharide. Animals infused with FR 167653 and saline showed progressive
      hindquarters vasoconstriction over the 24-h period, but this was not different
      from the change seen in animals (n = 3) infused with saline alone. However,
      plasma analysis at the end of the coinfusion of FR 167653 and saline showed
      substantial elevation in levels of creatine kinase, lactate dehydrogenase, and
      potassium, consistent with some tissue damage (heart, liver, or skeletal muscle,
      or a combination of these). Animals coinfused with saline and lipopolysaccharide
      showed biphasic decreases in mean arterial blood pressure accompanied by renal
      hyperaemic vasodilatation, and decreases followed by increases in mesenteric and
      hindquarters flows and vascular conductances. At the end of the infusion period,
      plasma analysis showed signs of renal dysfunction (elevated creatinine) and
      hepatic dysfunction (elevated alkaline phosphatase, gamma-glutamyl transferase,
      and alanine aminotransferase). In the presence of FR 167653, the hypotensive
      effects of lipopolysaccharide were abolished, but regional haemodynamics were
      unchanged, as were signs of organ dysfunction. One explanation of these
      observations is that FR 167653 causes a relative improvement in cardiac function
      during infusion of lipopolysaccharide, and this opposes the hypotensive effects
      of the latter, in spite of its persistent vasodilator effects.

PMID- 10413070
TI  - Electrophysiologic, cardiohemodynamic and beta-blocking actions of a new ultra
      short-acting beta-blocker, ONO-1101, assessed by the in vivo canine model in
      comparison with esmolol.
AB  - The purpose of this study was to assess the cardiovascular effects of an ultra
      short-acting beta-blocker, ONO-1101, by using halothane-anesthetized beagle dogs
      in comparison with esmolol. ONO-1101 (n = 6) or esmolol (n = 6) was administered
      at four infusion rates of 0.3, 3, 30, and 300 microg/ kg/min. Each infusion was
      performed over a 30-min period, and the parameters were measured at 20-30 min
      after the start of each infusion. ONO-1101 significantly decreased the heart
      rate, rate-pressure product, left ventricular contraction, cardiac output, and
      relative refractory period of the right ventricle, suppressed the AV nodal
      conduction, and increased the effective refractory period of the right ventricle,
      whereas no significant change was observed in the preload and afterload of the
      left ventricle, intrinsic sinus nodal automaticity, His-Purkinje-ventricular
      conduction, and the monophasic action-potential duration of the right ventricle.
      The cardiovascular effects of esmolol were comparable to those of ONO-1101,
      except that the preload of the left ventricle was significantly increased, and
      the ventricular repolarization phase was shortened by 300 microg/kg/min of
      esmolol infusion. Meanwhile, ONO-1101 as well as esmolol significantly reduced
      the isoproterenol-induced increase in heart rate and ventricular contraction, but
      the inhibitory action of ONO-1101 was 6-8 times greater than that of esmolol.
      These results suggest that the suppressive effects of ONO-1101 on cardiovascular
      performance are significantly less potent than those of esmolol at equipotent
      beta-blocking doses.

PMID- 10413071
TI  - The angiotensin II AT1-receptor antagonist candesartan improves functional
      recovery and reduces the no-reflow area in reperfused ischemic rat hearts.
AB  - It is not yet clear if cardiac angiotensin II is involved in the pathophysiology
      of myocardial ischemia/ reperfusion injury. The aim of this study was to
      investigate the effect of the angiotensin II AT1-receptor antagonist candesartan
      on myocardial functional recovery in isolated rat hearts subjected to ischemia
      and reperfusion. Three groups of hearts perfused in the Langendorff mode with
      Krebs-Henseleit buffer under constant pressure received either vehicle (n = 7),
      candesartan, 1 nM (n = 6), or 100 nM (n = 7) at the start of 30 min of global
      ischemia. The recovery of the double product was significantly higher in the
      candesartan, 100 nM, group (75+/-9.2%) than in the vehicle group (40+/-5.1%; p <
      0.05). At the end of 30 min of reperfusion, left ventricular end diastolic
      pressure was lower in rats given candesartan, 100 nM, than in rats given vehicle
      (10+/-4.3 vs. 38+/-4.8 mm Hg; p < 0.05). After ischemia and reperfusion, there
      was a large no-reflow area in the vehicle group (28+/-3.1% of the left
      ventricle), which was reduced by candesartan, 100 nM (12+/-1.3%; p < 0.05). In
      rats given candesartan, 1 nM, there was a trend toward a higher recovery of the
      double product (73+/-13.4%), a lower left ventricular end-diastolic pressure
      (29+/-6.6 mm Hg), and a smaller no-reflow area (19+/-3.5% of the left ventricle)
      compared with the rats receiving vehicle. These trends did, however, not reach
      statistical significance. Our results demonstrate that candesartan reduces
      myocardial ischemia/reperfusion injury, thus indicating that endogenous cardiac
      angiotensin II is involved in the tissue injury after myocardial ischemia and
      reperfusion.

PMID- 10413072
TI  - Comparison of tegaserod (HTF 919) and its main human metabolite with cisapride
      and erythromycin on cardiac repolarization in the isolated rabbit heart.
AB  - Tegaserod (HTF 919) is a new drug being developed for gastrointestinal motility
      disorders. Because other gastrointestinal prokinetic agents, such as cisapride
      and erythromycin, cause slowing of cardiac repolarization and have been
      implicated in the development of the potentially fatal ventricular arrhythmia,
      torsades de pointes, a study was initiated to determine whether tegaserod and its
      main human metabolite adversely influence cardiac repolarization. By using
      isolated Langendorff-perfused rabbit hearts, we show that QT intervals remain
      unchanged at concentrations of tegaserod from 0.5 to 10 microM. It was not until
      the tegaserod concentration was increased to 50 microM (roughly 500-5,000 times
      more concentrated than those typically found in human plasma after administration
      of recommended clinical dosages), that a small, but significant increase in the
      QT interval (12+/-4%; p < 0.05; n = 4) was observed. No significant changes in QT
      occurred in the presence of the tegaserod metabolite at any of the concentrations
      tested (0.5-50 microM). In contrast, cisapride caused QT lengthening at
      concentrations as low as 0.1 microM, with significant QT increases occurring when
      5-50 microM cisapride was used (22+/-4% to >70%, respectively; p < 0.01; n = 4).
      Erythromycin also caused significant lengthening of QT intervals (11+/-2%; p <
      0.001; n = 4), although 100 microM concentrations of this drug were required to
      achieve this effect. These results demonstrate that both cisapride and
      erythromycin can slow cardiac repolarization at therapeutic doses and that
      tegaserod's lack of QT prolongation at therapeutic doses suggests that it has the
      potential to be a safer alternative to cisapride as a gastrointestinal prokinetic
      agent.

PMID- 10413073
TI  - Effects of subcutaneous naratriptan on systemic and pulmonary haemodynamics and
      coronary artery diameter in humans.
AB  - Naratriptan, an effective antimigraine agent, is a selective 5-hydroxytryptamine
      (5-HT1 )-receptor agonist with a pharmacologic profile similar to that of
      sumatriptan. The object of this study was to assess the haemodynamic effects of
      naratriptan in a clinical model previously applied to sumatriptan. Cardiac
      haemodynamics and coronary artery diameter were measured at baseline and after
      subcutaneous injections of placebo and naratriptan (1.5 mg, s.c.) in 10 patients
      undergoing diagnostic cardiac catheterisation. No statistically significant
      change in mean coronary artery diameter was observed after naratriptan [95%
      confidence interval (CI), -0.27-0.11 mm: p = 0.37]. Naratriptan injection was
      associated with statistically significant increases in systolic arterial pressure
      (95% CI, 7.6-22.0 mm Hg; p = 0.0015), total systemic vascular resistance (95% CI,
      74-253 dyn/s/cc; p = 0.003), pulmonary artery systolic pressure (95% CI, 2.0-6.9
      mm Hg; p = 0.003), pulmonary vascular resistance (95% CI, 3-34 dyn/s/cc; p =
      0.025), and pulmonary artery wedge pressure (95% CI, 1.9-2.4 mm Hg; p = 0.009).
      Naratriptan, a selective 5-HT1-receptor agonist, caused a vasopressor response in
      the systemic and pulmonary arterial circulations but was not associated with
      coronary artery vasoconstriction.

PMID- 10413074
TI  - Differential effects of pravastatin, simvastatin, and atorvastatin on Ca2+
      release and vascular reactivity.
AB  - The direct effects of the cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl
      coenzyme A (HMG CoA) reductase inhibitors, on vascular smooth muscle
      responsiveness were examined by incubation of isolated aorta from
      normocholesterolemic rats with simvastatin, atorvastatin, or pravastatin. The
      smooth muscle contractions caused by phenylephrine were progressively inhibited
      with increasing concentrations of simvastatin. Similarly, atorvastatin at the
      higher concentration caused decreased responses to phenylephrine. In contrast,
      incubation with pravastatin had no significant effect at all concentrations
      studied. In Ca2+-free buffer, the transient contraction caused by phenylephrine,
      which results from intracellular release of Ca2+, also was inhibited by
      simvastatin and atorvastatin but not by pravastatin. In cultured rat aortic
      smooth muscle cells loaded with fura-2, increases in intracellular free-Ca2+
      concentration ([Ca2+]i) induced by angiotensin II were markedly inhibited in
      cells incubated with simvastatin and atorvastatin but not pravastatin. The
      inhibitory effects of simvastatin and atorvastatin were reversed by mevalonate.
      These findings demonstrate that inhibition of HMG CoA reductase by using
      simvastatin and atorvastatin, but not pravastatin, has effects on vascular smooth
      muscle cell responsiveness that involve alteration of Ca2+ homeostasis through a
      mevalonate-dependent pathway.

PMID- 10413075
TI  - Enalapril improves arterial elastic properties in rats with myocardial
      infarction.
AB  - Systemic arterial elastic properties, important determinants of left ventricular
      function and coronary blood flow, are compromised in myocardial infarction (MI).
      The cardiac effect of angiotensin-converting enzyme inhibitors (ACEIs) has been
      extensively studied, whereas their arterial effect has been poorly reported in
      MI. The aim of this work was to study the effect of prolonged ACEI enalapril
      treatment on systemic arterial structure and elastic properties in rats with MI.
      One week after the induction of an MI, 40 male Wistar rats received either no
      treatment (n = 20) or ACEI enalapril (2 mg/kg; n = 20) for 17 weeks. At the end
      of the treatment period, blood pressure, cardiac output, total peripheral
      resistance, systemic arterial compliance, characteristic impedance, and left
      ventricular power were measured in anesthetized rats. Then the rats were killed
      for infarct-size determination and aortic histomorphometric study. Infarct size,
      heart, and left and right ventricular weights were similar in the ACEI-treated
      and untreated infarcted rats. Prolonged ACEI enalapril treatment reduced blood
      pressure by 17% (p < 0.001), total peripheral resistance by 22% (p < 0.01), and
      characteristic impedance by 26% (p < 0.03), and increased systemic arterial
      compliance by 35% (p < 0.01), in comparison with untreated infarcted rats.
      Enalapril reduced aortic media wall thickness by 9% (p < 0.02) and increased
      elastin content by 22% (p < 0.03) and elastin-to-collagen content ratio by 42% (p
      < 0.01). Enalapril did not affect cardiac output and left ventricular power.
      Smooth muscle cell nuclei number and size and collagen content of aortic wall
      were similar in the ACEI-treated and untreated infarcted rats. These results
      indicate that long-term treatment with ACEI enalapril improves arterial elastic
      properties through structural modifications of arterial wall in rats with MI.
      This vascular effect may contribute to improve the left ventricular function and
      the coronary perfusion of infarcted myocardium, and added to the cardiac effect,
      may explain the prevention of left ventricular remodeling observed with ACEI in
      this model.

PMID- 10413076
TI  - Perflubron emulsion improves tolerance to low-flow ischemia in isolated rabbit
      hearts.
AB  - The efficacy of the temporary oxygen carrier perflubron emulsion (PFC) in
      maintaining oxygen delivery, tissue oxygenation, high-energy phosphates (HEPs),
      and myocardial function was investigated during low-flow ischemia. Perfusion
      rate, oxygen tensions, and cardiac function were measured during stabilization (5
      min), controlled-flow (22 ml/min x 20 min), and low-flow (0.22 ml/min x 120 min)
      periods in isolated rabbit hearts. Hearts were perfused with Krebs-Henseleit (KH)
      solution (Control), or 10 or 20% PFC (vol/vol; n = 8 per group) 5 min before and
      throughout the low-flow period. Myocardial tissue was then frozen for biochemical
      and metabolic measurements. Myocardial oxygenation was measured at incremental
      flow rates by using 20% PFC (n = 4) or KH (n = 6). In PFC hearts, oxygen delivery
      and intramyocardial tissue Po2 were improved at all evaluated time points and
      flow rates, respectively (p < 0.05). In Control hearts, left ventricular end
      diastolic pressure was elevated at 60, 90, and 120 min of low-flow ischemia (p <
      0.05). Tissue lactate was higher (p < 0.05) and HEPs lower (p < 0.05) in Control
      hearts during low-flow ischemia. These results indicate that PFC treatment
      improves myocardial oxygenation, maintains HEPs, prevents ischemic contracture,
      and may increase the margin of safety during low-flow ischemia in isolated rabbit
      hearts.

PMID- 10413077
TI  - Regional blood flow responses to acute ANG II infusion: effects of nitric oxide
      synthase inhibition.
AB  - We hypothesized that nitric oxide (NO) opposes regional vasoconstriction caused
      by acute angiotensin II (ANG II) infusion in conscious rats. Mean arterial
      pressure (MAP), blood flow, and vascular conductance (regional blood flow/ MAP;
      ml/min/100 g/mm Hg) were measured and/or calculated before and at 2 min of ANG II
      infusion (0.05 or 1 microg/kg/min, i.a.) in the absence and presence of NO
      synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME), 0.25 or 1
      mg/kg, i.a.]. ANG II reduced stomach and hindlimb conductance only after NOS
      inhibition. For example, whereas 0.05 microg/kg/min ANG II did not attenuate
      conductance in the stomach (i.e., 1.04+/-0.08 to 0.93+/-0.12 ml/min/100 g/mm Hg),
      this variable was reduced (i.e., 0.57+/-0.14 to 0.34-/+0.05 ml/min/100 g/mm Hg; p
      < 0.05) when ANG II was infused after 0.25 mg/kg L-NAME. In addition, whereas
      hindlimb conductance was similar before and after administering 1 microg/kg/min
      ANG II (i.e., 0.13+/-0.01 and 0.09+/-0.02, respectively), this variable was
      reduced (i.e., 0.07+/-0.01 and 0.02+/-0.00, respectively; p < 0.05) when ANG II
      was infused after 1 mg/kg L-NAME. These findings indicate that NO opposes ANG II
      induced vasoconstriction in the stomach and hindlimb. In contrast, whereas both
      doses of ANG II decreased (p < 0.05) vascular conductance in the kidneys and
      small and large intestine regardless of whether NOS inhibition was present,
      absolute vascular conductance was lower (p < 0.05) after L-NAME. For example, 1
      microg/kg ANG II reduced renal conductance from 3.34+/-0.31 to 1.22+/-0.14 (p <
      0.05). After 1 mg/kg L-NAME, renal conductance decreased from 1.39+/-0.18 to
      0.72+/-0.16 (p < 0.05) during ANG II administration. Therefore the constrictor
      effects of NOS inhibition and ANG II are additive in these circulations. Taken
      together, our results indicate that the ability of NO to oppose ANG II-induced
      constriction is not homogeneous among regional circulations.

PMID- 10413078
TI  - Effect of prolonged treatment with amlodipine on enhanced vascular contractility
      in cardiomyopathic hamsters.
AB  - This study examined the effects of prolonged treatment with amlodipine on the
      enhanced vascular contractions in dilated cardiomyopathic (CM) hamsters. From the
      ages of 5 to 20 weeks, CM hamsters (BIO 53.58) orally received amlodipine. Then
      we compared the contractile responses to vasoconstrictors in aortas and
      mesenteric arteries from CM hamsters with or without treatment with those in the
      arteries from controls (F1b). We also investigated the effect of amlodipine
      treatment on the Ca2+ sensitivity of tension in beta-escin-skinned smooth muscle
      of mesenteric artery. The contractile responses to phenylephrine, angiotensin II,
      and high K+ in both aorta and mesenteric artery were greatly enhanced in CM
      hamsters compared with controls. Amlodipine treatment slightly but significantly
      inhibited the enhanced responses in aorta but did not alter the responses in
      mesenteric arteries. The Ca2+ sensitivity of tension was significantly increased
      in CM hamster preparations, which was unaffected by amlodipine treatment. These
      data indicate that amlodipine treatment differentially affects the enhanced
      responses to vasoconstrictors between large and small blood vessels from CM
      hamsters. The lack of effect of amlodipine treatment on the responsiveness of CM
      mesenteric artery leads to the suggestion that the preventive effect of
      amlodipine on focal myocytolytic necrosis of cardiomyocytes, which was previously
      reported to be the main cause of cardiomyopathy, results from an action on
      cardiomyocytes.

PMID- 10413079
TI  - Functional and binding studies of insurmountable antagonism of 606A, a novel AT1
      receptor antagonist in rabbit tissues.
AB  - Angiotensin AT1-receptor antagonists can be classified into two types,
      surmountable and insurmountable ones, based on the way they inhibit angiotensin
      II (AII)-induced vasoconstriction. To elucidate the causes of the difference, we
      studied how several antagonists associate with and dissociate from AT1-receptor
      sites by using rabbit adrenal cortical membrane. Four antagonists, 606A, EXP3174,
      CV11974, and E4177, showed equipotent competitive antagonism when they were added
      simultaneous with [125I]-AII in binding experiments. However, in AII-induced
      contraction studies with rabbit aorta, 606A, EXP3174, and CV11974 inhibited the
      contraction noncompetitively, whereas E4177 inhibited competitively. The longer
      the pretreatment period with EXP3174 or CV11974, the more effectively the
      antagonists suppressed AII-induced contraction. However, the suppression of
      contraction by 606A and E4177 changed little with the length of the pretreatment
      period. AII-induced contraction of 606A- or E4177-treated aorta recovered easily
      by washout, but that of CV11974-treated aorta was hard to recover by washout.
      These results obtained in the aorta were consistent with their characteristics
      observed in the AII binding study in the rabbit adrenal cortical membrane in
      cases of EXP3174 and CV11974. The differences between association rate with and
      dissociation rate from the AT1 receptor of E4177 and 606A were slight, in spite
      of the clear difference between their action in the contraction study. Because of
      the variations observed with the four compounds, mechanisms of insurmountable
      antagonism may not be uniform among AT1-receptor antagonists.

PMID- 10413080
TI  - Pharmacological characterization of PABSA, an orally active and highly potent
      endothelin-receptor antagonist.
AB  - The pharmacological characterization of a nonpeptide endothelin (ET)-receptor
      antagonist, PABSA [(R)-(--)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropyl-phenylsulfon
      yl)-2-(6-methyl-2-propylpyridin-3-yloxy)-acetamide hydrochloride] was studied.
      PABSA competitively inhibited the binding of [125I]-ET-1 to A7r5 cells expressing
      ET(A) receptors and of [125I]-ET-3 to COS cells expressing porcine ET(B)
      receptors with Ki values of 0.11 and 25 nM, respectively. PABSA inhibited ET(A)
      receptor-mediated and ET(B) receptor-mediated vasocontraction and ET(B) receptor
      mediated vasorelaxation in isolated rabbit vessels with K(b) values of 0.46, 94,
      and 26 nM, respectively. The antagonist potency of PABSA for ET(A) receptor
      mediated vasocontraction was 63- and 87-fold more potent than those of BQ-123 and
      bosentan, respectively, and was similar to those of TAK-044 and SB209670. Oral
      administration of PABSA (1-10 mg/kg) caused dose-dependent inhibition of the
      pressor response to exogenous ET- 1 (0.1 nmol/kg) in conscious normotensive rats.
      PABSA (10-100 mg/kg, p.o.) reduced blood pressure in deoxycorticosterone acetate
      (DOCA)-salt hypertensive rats, spontaneously hypertensive rats (SHRs), and stroke
      prone spontaneously hypertensive rats (SHRSPs). The hypotensive effect of PABSA
      was sustained for > or =24 h in these rats. These results suggest that PABSA is a
      highly potent ET(A)-receptor antagonist with weak ET(B)-receptor antagonist
      activity. Because PABSA has a long duration of action in vivo, this antagonist
      should be useful in the therapy of ET-related disease.

PMID- 10413081
TI  - Alpha2-adrenoceptor antagonists evoke endothelium-dependent and -independent
      relaxations in the isolated rat aorta.
AB  - This study was designed to determine whether the alpha2-adrenoceptor antagonists
      idazoxan, yohimbine, and rauwolscine cause endothelium-dependent and -independent
      responses in the rat aorta. Rings of rat aorta, with and without endothelium,
      were suspended for the measurement of isometric force in modified Krebs-Ringer
      bicarbonate solution (37 degrees C; aerated with 95% O2 and 5% CO2). The alpha2
      adrenoceptor antagonists, in the concentration range of 10(-8)-10(-6) M, relaxed
      phenylephrine-contracted rings with, but not those without endothelium. alpha2
      Adrenoceptor antagonists (3 x 10(-6) M for 1 min) increased the accumulation of
      cyclic guanosine monophosphate (cGMP) about twofold in the aortas with
      endothelium. The relaxation and the increased cGMP induced by alpha2-antagonists
      were attenuated by methylene blue (10(-6) M) and N(G)-nitro-L-arginine (L-NA, 3 x
      10(-5) M), whereas propranolol (10(-6) M) did not affect the relaxation. In
      concentrations >10(-6) M, alpha2-adrenoceptor antagonists relaxed the rat aorta
      without endothelium. The endothelium-independent relaxation by alpha2
      adrenoceptor antagonists was abolished by increased external K+ and reduced
      significantly by tetraethylammonium (TEA, 10(-2) M, a Ca2+-dependent K+ channel
      blocker), but not inhibited by glibenclamide (10(-5) M, an ATP-sensitive K+
      channel blocker). In the rabbit aorta, only endothelium-independent relaxations
      were observed with alpha2-adrenoceptor antagonists in the concentration range of
      10(-8)-10(-5) M, and these relaxations were not antagonized by TEA. These results
      suggest that alpha2-adrenoceptor antagonists relax the rat aorta through
      endothelium-dependent mechanism at lower concentrations and endothelium
      independent mechanisms at higher concentrations. The endothelium-dependent
      relaxations are likely to be mediated by the endothelium-derived relaxing factor
      (EDRF)/NO pathway because they are associated with the accumulation of cGMP,
      whereas the endothelium-independent relaxations may be caused by the opening of
      potassium channels in the vascular smooth muscle.

PMID- 10413083
TI  - Protection of human myocardium in vitro by K(ATP) activation with low
      concentrations of bimakalim.
AB  - We investigated whether the adenosine triphosphate (ATP)-sensitive K+ (K(ATP))
      channel activation by bimakalim, at concentrations devoid of both negative
      inotropic and action-potential duration (APD) shortening effects, might exhibit
      myocardial protection after hypoxia and reoxygenation in human atrial myocardium
      by using 112 preparations. The recovery of contractility of human atrial
      trabeculae, subjected either to short-duration (5 min) or to long-duration (60
      min) and severe (high pacing rate) hypoxia followed by reoxygenation, was
      assessed by challenging with dobutamine. Treated preparations were exposed to 10
      or 100 nM bimakalim, 1 microM glibenclamide, or both before hypoxia. Variations
      of isometric developed tension (%DT) or APD90 were studied. At concentrations
      <100 nM, bimakalim showed no negative inotropic effects and did not modify
      significantly APD90 either in normoxia or in hypoxic conditions. In the short
      duration hypoxia protocol, preparations treated with bimakalim showed a
      dobutamine-induced %DT increase significantly higher (p < 0.001) than in controls
      and similar to that observed in the absence of hypoxia. This bimakalim effect was
      blocked by glibenclamide. In the long-duration hypoxia protocol, %DT after
      dobutamine was 50% of that observed in normoxic preparations. Preparations
      treated with bimakalim showed after dobutamine %DT more than twofold above
      controls (p < 0.001), whereas in the glibenclamide group, recovery of DT with
      dobutamine remained 50% of what observed in normoxia (p < 0.001). In conclusion,
      exposure to hypoxia (either short- or long-lasting) and reoxygenation affects
      contractility of human atrial myocardium with pronounced reduction of the
      positive inotropic action of dobutamine. Pretreatment with bimakalim restores the
      response expected in the absence of hypoxia, and glibenclamide blocks the effect
      of bimakalim or further impairs the response to dobutamine when used alone before
      long-duration hypoxia. Evidence is provided for protective effects of the K(ATP)
      opener bimakalim on the human myocardial contractile function in conditions of
      hypoxia/reoxygenation, at concentrations at which negative inotropism and APD90
      shortening are not contributory.

PMID- 10413084
TI  - Efficient expression, purification and crystallisation of two hyperthermostable
      enzymes of histidine biosynthesis.
AB  - Enzymes from hyperthermophiles can be efficiently purified after expression in
      mesophilic hosts and are well-suited for crystallisation attempts. Two enzymes of
      histidine biosynthesis from Thermotoga maritima, N'-((5'-phosphoribosyl)
      formimino)-5-aminoimidazol-4-carb oxamid ribonucleotide isomerase and the cyclase
      moiety of imidazoleglycerol phosphate synthase, were overexpressed in Escherichia
      coli, both in their native and seleno-methionine-labelled forms, purified by heat
      precipitation of host proteins and crystallised. N'-((5'-phosphoribosyl)
      formimino)-5-aminoimidazol-4-carb oxamid ribonucleotide isomerase crystallised in
      four different forms, all suitable for X-ray structure solution, and the cyclase
      moiety of imidazoleglycerol phosphate synthase yielded one crystal form that
      diffracted to atomic resolution. The obtained crystals will enable the
      determination of the first three-dimensional structures of enzymes from the
      histidine biosynthetic pathway.

PMID- 10413082
TI  - Reduction of myocardial infarct size after ischemia and reperfusion by the
      glycosaminoglycan pentosan polysulfate.
AB  - Activation of the complement system contributes to the tissue destruction
      associated with myocardial ischemia/reperfusion. Pentosan polysulfate (PPS), a
      negatively charged sulfated glycosaminoglycan (GAG) and an effective inhibitor of
      complement activation, was studied for its potential to decrease infarct size in
      an experimental model of myocardial ischemia/reperfusion injury. Open-chest
      rabbits were subjected to 30-min occlusion of the left coronary artery followed
      by 5 h of reperfusion. Vehicle (saline) or PPS (30 mg/kg/h) was administered
      intravenously immediately before the onset of reperfusion and every hour during
      the reperfusion period. Treatment with PPS significantly (p < 0.05) reduced
      infarct size as compared with vehicle-treated animals (27.5+/-2.9% vs. 13.34+/
      2.6%). Analysis of tissue demonstrated decreased deposition of membrane-attack
      complex and neutrophil accumulation in the area at risk. The results indicate
      that, like heparin and related GAGs, PPS possesses the ability to decrease
      infarct size after an acute period of myocardial ischemia and reperfusion. The
      observations are consistent with the suggestion that PPS may mediate its
      cytoprotective effect through modulation of the complement cascade.

PMID- 10413085
TI  - The effect of 17beta-estradiol-DNA adducts on the replication of exon # 5 of the
      human suppressor gene p53.
AB  - Using a PCR technique, exon # 5 of the human tumor suppressor gene p53 was
      amplified and ligated into the pCRII vector and transformed into Escherichia coli
      INV alphaF' competent cells. The cloned exon # 5 was 184 bp long. Evidence is
      presented to show that after dimethyldioxirane epoxidation, 17beta-estradiol was
      able to form 17beta-estradiol-DNA adducts and to strongly inhibit the replication
      of the cloned exon # 5 producing smaller sizes of DNA fragments and introducing
      errors of incorporation at the 3'-end of the terminating DNAs. The errors
      occurred mainly at the clusters of the complementary 'G' and 'A' bases on the
      template strand DNA, presumably, the major sites where the 17beta-estradiol-DNA
      adducts were formed.

PMID- 10413086
TI  - Mutational analysis of subunit i beta2 (MECL-1) demonstrates conservation of
      cleavage specificity between yeast and mammalian proteasomes.
AB  - Proteasomes are the major protein-degrading complexes in the cytosol and regulate
      many cellular processes. To examine the functional importance of the MC14/MECL-1
      proteasome active site subunits, cell lines expressing a catalytically inactive
      form of MECL-1 were established. Whereas mutant MECL-1 was readily incorporated
      into cytosolic proteasomes, replacing the constitutive MC14 subunit, removal of
      the prosequence was incomplete indicating that its processing required
      autocatalytic cleavage. Functional analyses showed that the absence of the
      MC14/MECL-1 active sites abrogated proteasomal trypsin-like activity, but did not
      affect other catalytic activities. Our data demonstrate a conservation of
      cleavage specificity between mammalian and yeast proteasomes.

PMID- 10413087
TI  - The zebrafish genome contains two distinct selenocysteine tRNA[Ser]sec genes.
AB  - The zebrafish is widely used as a model system for studying mammalian
      developmental genetics and more recently, as a model system for carcinogenesis.
      Since there is mounting evidence that selenium can prevent cancer in mammals,
      including humans, we characterized the selenocysteine tRNA[Ser]sec gene and its
      product in zebrafish. Two genes for this tRNA were isolated and sequenced and
      were found to map at different loci within the zebrafish genome. The encoding
      sequences of both are identical and their flanking sequences are highly
      homologous for several hundred bases in both directions. The two genes likely
      arose from gene duplication which is a common phenomenon among many genes in this
      species. In addition, zebrafish tRNA[Ser]sec was isolated from the total tRNA
      population and shown to decode UGA in a ribosomal binding assay.

PMID- 10413088
TI  - A pure S = 3/2 [Fe4S4]+ cluster in the A33Y variant of Pyrococcus furiosus
      ferredoxin.
AB  - The properties of the [4Fe-4S]2+/+ cluster in wild-type and the A33Y variant of
      Pyrococcus furiosus ferredoxin have been investigated by the combination of EPR,
      variable-temperature magnetic circular dichroism (VTMCD) and resonance Raman (RR)
      spectroscopies. The A33Y variant involves the replacement of an alanine whose
      alpha-C is less than 4 A from one of the cluster iron atoms by a tyrosine
      residue. Although the spectroscopic results give no indication of tyrosyl cluster
      ligation, the presence of a tyrosine residue in close proximity to the cluster
      results in a 38-mV decrease in the midpoint potential of the [4Fe-4S]2+/+ couple
      and has a marked effect on the ground state properties of the reduced cluster.
      The mixed spin [4Fe-4S]+ cluster in the wild-type protein, 80% S = 3/2 (E/D =
      0.22, D = +3.3 cm(-1)) and 20% S = 1/2 (g = 2.10, 1.87, 1.80), is converted into
      a homogeneous S = 3/2 (E/D = 0.30, D = -0.7 cm(-1)) form in the A33Y variant. As
      the first example of a pure S = 3/2 [4Fe-4S]+ cluster in a ferredoxin, this
      variant affords the opportunity for detailed characterization of the excited
      electronic properties via VTMCD studies and demonstrates that the protein
      environment can play a crucial role in determining the ground state properties of
      [4Fe-4S]+ clusters.

PMID- 10413089
TI  - Thiazolidinedione inhibits the production of monocyte chemoattractant protein-1
      in cytokine-treated human vascular endothelial cells.
AB  - The chemokine monocyte chemoattractant protein-1 is a potent chemoattractant for
      monocytes. Monocyte chemoattractant protein-1 is produced by vascular endothelial
      cells during inflammatory diseases such as atherosclerosis. In this study, we
      examined the effects of a thiazolidinedione on monocyte chemoattractant protein-1
      expression in human vascular endothelial cells. In human vascular endothelial
      cells, interleukin-1beta and tumor necrosis factor-alpha induced endogenous
      monocyte chemoattractant protein-1 protein secretion, mRNA expression and
      promoter activity. The thiazolidinedione inhibited these effects. In summary, our
      results indicated that the suppression of the expression of monocyte
      chemoattractant protein-1 can be accomplished by thiazolidinedione treatment,
      raising the possibility that thiazolidinedione may be of therapeutic value in the
      treatment of diseases such as atherosclerosis.

PMID- 10413090
TI  - Prediction of the maximal stability temperature of monomeric globular proteins
      solely from amino acid sequence.
AB  - Globular protein thermostability is characterized the cold denaturation, maximal
      stability (Tms) and heat denaturation temperatures. For mesophilic globular
      proteins, Tms typically ranges from -25 degrees C to +35 degrees C. We show that
      the indirect estimate of Tms from calorimetry and the direct estimate from
      chemical denaturation performed in a range of temperatures are in close
      agreement. The heat capacity change of unfolding per mol residue (delta Cp) alone
      is shown to accurately predict Tms. Delta Cp and hence Tms can be predicted
      solely from the protein sequence. The average difference in free energy of
      unfolding at the observed and predicted values of Tms is 1.0 kcal mol(-1), which
      is small compared to typical values of the total free energy of unfolding.

PMID- 10413091
TI  - The nuclear origin of the non-phosphorylating NADH dehydrogenases of plant
      mitochondria.
AB  - The oxidation of matrix and cytosolic NADH by isolated beetroot and wheat leaf
      mitochondria was investigated to determine whether the rotenone-insensitive NADH
      dehydrogenases of plant mitochondria were the products of nuclear or
      mitochondrial genes. After aging beetroot tissue (slicing and incubating in a
      CaSO4 solution), the induction of the level of matrix NADH oxidation in the
      presence of rotenone was greatly reduced in mitochondria isolated from tissue
      treated with cycloheximide, a nuclear protein synthesis inhibitor. This was also
      true for the oxidation of cytosolic NADH. Mitochondria isolated from
      chloramphenicol-treated tissue exhibited greatly increased levels of both matrix
      and external rotenone-insensitive NADH oxidation when compared to the increase
      due to the aging process alone. This increase was not accompanied by an increase
      in matrix NAD-linked substrate dehydrogenases such as malic enzyme nor intra
      mitochondrial NAD levels. Possible explanations for this increase in rotenone
      insensitive NADH oxidation are discussed. Based on these results we have
      concluded that the matrix facing rotenone-insensitive NADH dehydrogenase of plant
      mitochondria is encoded by a nuclear gene and synthesis of the protein occurs in
      the cytosol.

PMID- 10413092
TI  - Selective activation of phospholipase D2 by unsaturated fatty acid.
AB  - Although oleate has been implicated in the regulation of phospholipase D (PLD)
      activity, the molecular identity of the oleate-stimulated PLD is still poorly
      understood. We now report that oleate selectively stimulates the enzymatic
      activity of PLD2 but not of PLD1, with an optimal concentration of 20 microM in
      vitro. Intriguingly, phosphatidylinositol 4,5-bisphosphate (PIP2) synergistically
      stimulates the oleate-dependent PLD2 activity with an optimal concentration of
      2.5 microM. These results provide the first evidence that oleate is a PLD2
      specific activating factor and PLD2 activity is synergistically stimulated by
      oleate and PIP2.

PMID- 10413093
TI  - The N-linked glycan of the V3 region of HIV-1 gp120 and CXCR4-dependent
      multiplication of a human immunodeficiency virus type 1 lymphocyte-tropic
      variant.
AB  - We have previously shown that an N-glycosylation site of N306 of HIV-1 gp120 is
      not necessary for the HIV-1 infectivity but protects HIV-1 from neutralising
      antibodies. In contrast Nakayama et al. [FEBS Lett. (1998) 426, 367-372], using a
      virus with an identical V3 region, suggested that elimination of this particular
      glycan reduced the ability of T-tropic HIV to bind to CXCR4 and hence its ability
      to infect T cell lines. We therefore re-examined the ability of a mutant virus,
      lacking the N306 glycan, to replicate in various types of cells and found no
      change in co-receptor usage for mutant virus. The ability of mutant virus to
      replicate or to induce syncytia in infected cells was similar to that of wild
      type virus. These results corroborate our original observation, confirming that
      the induced mutation in the N306 glycosylation site neither impairs nor improves
      the ability of mutant virus to replicate in permissive cells.

PMID- 10413094
TI  - Protein kinase D activation by deletion of its cysteine-rich motifs.
AB  - Protein kinase D is a serine/threonine kinase that binds phorbol esters in a
      phospholipid-dependent manner via a tandemly repeated cysteine-rich, zinc finger
      like motif (the cysteine-rich domain). Here, we examined whether the cysteine
      rich domain plays an additional role in the control of the catalytic kinase
      activity independently of the binding of allosteric effectors. We found that
      deletion of cys1, cys2 or the entire cysteine-rich domain increases the basal
      activity of protein kinase D leading to a constitutively active form of this
      enzyme. Our results demonstrate, for the first time, that the cysteine-rich
      domain of Protein kinase D plays a negative role in the regulation of protein
      kinase D kinase activity.

PMID- 10413095
TI  - Deletion of a proline-rich region and a transmembrane domain in fatty acid amide
      hydrolase.
AB  - Fatty acid amide hydrolase contains a proline-rich sequence matching a consensus
      sequence for SH3-binding domains as well as a transmembrane domain. In this
      study, deletion mutants lacking the proline-rich region and the transmembrane
      domain were generated. Transfection experiments demonstrated that the proline
      rich deleted amidase was enzymatically inactive. While immunostaining of the wild
      type was always punctate with strong perinuclear staining characteristic for
      endoplasmic reticulum, the staining of the mutant was diffuse and distributed
      throughout the cytoplasm and perinuclear region. These observations along with
      the loss of activity suggest that the proline-rich region may play a role in the
      subcellular localization and enzymatic function. The transmembrane domain-deleted
      mutant was indistinguishable from the wild-type enzyme.

PMID- 10413096
TI  - PKC-dependent phosphorylation of the p97 repressor regulates the transcription of
      aldolase A L-type promoter.
AB  - Expression of mouse aldolase A L-type mRNA is negatively modulated by a cis
      element (AldA-NRE), located within the aldolase A distal promoter (pL). AldA-NRE
      interacts with a 97-kDa repressor protein (p97), which binds DNA in a cell cycle
      dependent manner. We demonstrate that the binding between AldA-NRE and p97
      decreases during differentiation of human Caco-2 cells and is inversely
      correlated with L-type mRNA expression. Phosphorylation of the p97 repressor
      weakened its DNA binding activity in differentiated Caco-2 cells, while
      dephosphorylation enhanced the binding in proliferating cells. Stimulation of
      protein kinase C (PKC) in vivo decreased the binding of p97 to AldA-NRE and
      stimulated transcription, while inhibition of PKC stimulated p97 binding and
      downregulated transcription. These findings suggest that PKC is a mediator of the
      binding and silencing function of the p97/AldA-NRE repressor complex.

PMID- 10413097
TI  - Enterococcus hirae vacuolar ATPase is expressed in response to pH as well as
      sodium.
AB  - The Enterococcus hirae ntp operon encodes both a vacuolar ATPase, which
      transports Na+ as well as Li+, and the KtrII K+ transporter. A plasmid, in which
      the chloramphenicol acetyltransferase gene (CAT) was placed downstream of the ntp
      promoter, was introduced into a mutant totally defective in Na+ extrusion. The
      CAT activity of this transformant was increased preferentially by addition of
      NaCl, but not by LiCl, in the media or by elevating the medium pH, correlating
      well with the increase in amounts of the ATPase subunits observed by Western
      blotting. The physiological significance of these responses of the ntp promoter
      is discussed.

PMID- 10413098
TI  - Interaction with free beta' subunit unmasks DNA-binding domain of RNA polymerase
      sigma subunit.
AB  - The promoter recognition site on the sigma70 initiation factor is shielded from
      interaction with DNA unless sigma70 is bound to the core component of RNA
      polymerase (RNAP). It is shown that interaction of sigma70 with the isolated
      beta' subunit of Escherichia coli RNAP is sufficient to induce unshielding of the
      DNA binding site. Using UV-induced DNA-protein cross-linking we demonstrate that
      free beta' stimulates specific cross-links between region 2 of the sigma70
      polypeptide and a fragment of the non-template promoter strand containing the
      TATAAT sequence. Thus the sigmabeta' subassembly of RNAP can assume a
      functionally competent conformation independently of the bulk of the RNAP core.

PMID- 10413099
TI  - Evolutionary aspects of inorganic pyrophosphatase.
AB  - Based on the primary structure, soluble inorganic pyrophosphatases can be divided
      into two families which exhibit no sequence similarity to each other. Family I,
      comprising most of the known pyrophosphatase sequences, can be further divided
      into prokaryotic, plant and animal/fungal pyrophosphatases. Interestingly, plant
      pyrophosphatases bear a closer similarity to prokaryotic than to animal/fungal
      pyrophosphatases. Only 17 residues are conserved in all 37 pyrophosphatases of
      family I and remarkably, 15 of these residues are located at the active site.
      Subunit interface residues are conserved in animal/fungal but not in prokaryotic
      pyrophosphatases.

PMID- 10413100
TI  - The expression of the H19 gene and its function in human bladder carcinoma cell
      lines.
AB  - The human H19 gene is a paternally imprinted oncofetal gene, highly expressed in
      several fetal tissues, down-regulated in nearly all adult tissues but re
      expressed in carcinomas of tissues which express the gene in fetal life. It has
      no known protein product and till today, no function could be designated to H19
      RNA. Cells derived from bladder carcinomas and hepatocellular carcinomas were
      transfected with plasmids carrying a luciferase reporter gene under the control
      of a 800 nucleotides long promoter region of the H19 gene either alone or
      together with different parts of a 5 kb downstream region, previously shown to
      possess enhancer activity. Our results provide evidence that three regions of the
      3' downstream sequence can independently stimulate the H19 promoter activity in a
      tissue and cell specific manner. The growth rate of two cell populations, both
      derived from the same bladder carcinoma cell line and which differ in their H19
      RNA content, were compared. The cells with a high H19 RNA level stopped their
      proliferation after 48 h when cultivated in a low serum containing media while
      the cells lacking H19 RNA continued their proliferation for at least an
      additional 48 h period.

PMID- 10413101
TI  - Arfaptin 1 forms a complex with ADP-ribosylation factor and inhibits
      phospholipase D.
AB  - ADP-ribosylation factors (ARFs) regulate coatomer assembly on the Golgi as well
      as recruitment of clathrin adapter proteins and are therefore involved in vesicle
      budding from the Golgi and vesicular transport. They are also regulators of
      phospholipase D (PLD) activity. Arfaptin 1 is an ARF binding protein that
      inhibits PLD activation, vesicular trafficking and secretion. In the present
      report, we show that arfaptin 1 interacts with 'high speed' membranes
      independently of ARF. However, addition of myristoylated ARF3 (myrARF3) increases
      the association of arfaptin 1 with the membranes, suggesting that arfaptin 1 and
      ARF form a complex on the Golgi. Utilizing several deletion mutants of arfaptin 1
      it is shown that the association of arfaptin 1 with myrARF3 is mediated via two
      binding sites on arfaptin 1. These two domains are needed for arfaptin 1
      inhibition of PLD activation by myrARF3 in vitro.

PMID- 10413102
TI  - Novel tetravalent and bispecific IgG-like antibody molecules combining single
      chain diabodies with the immunoglobulin gamma1 Fc or CH3 region.
AB  - Although bispecific IgG molecules have been successfully applied for antibody
      mediated immunotherapy of tumours, applicability is hampered by the difficulties
      associated with their generation. In the present study, we have used a bispecific
      single-chain diabody (scDb) directed against carcinoembryonic antigen and
      Escherichia coli beta-galactosidase as a model to generate bispecific IgG-like
      antibody molecules. We show that the fusion of this single-chain diabody to the
      Fc (scDb-Fc) or CH3 (scDb-CH3) region of the human immunoglobulin gamma1 chain
      results in the expression of dimeric fusion proteins exhibiting four functional
      antigen binding sites with increased functional affinity. This strategy
      represents a new and convenient way to generate IgG-like multivalent and
      bispecific molecules that are efficiently secreted from mammalian cells.

PMID- 10413103
TI  - Reduction of G-box binding factor DNA binding activity, but not G-box binding
      factor abundance, causes the downregulation of RBCS2 expression during early
      tomato fruit development.
AB  - The downregulation of RBCS2 promoter activity during tomato fruit development has
      been investigated by transient gene expression. A major drop in promoter activity
      occurs between 5 and 25 mm fruit diameter, corresponding to the late cell
      division to early cell enlargement phase. This drop is abolished by a mutation of
      the single G-box element necessary for high RBCS2 promoter activity in young
      tomato fruit. The G-box binding activity of fruit nuclear and total protein
      extracts drops concomitantly with the reduction of RBCS2 promoter activity while
      G-box binding factor expression is not affected. The data indicate that the
      developmental signal that downregulates the RBCS2 promoter acts on the regulation
      of DNA binding activity of constitutively expressed G-box binding factors.

PMID- 10413104
TI  - Identification of cytosolic aldehyde dehydrogenase 1 from non-small cell lung
      carcinomas as a flavopiridol-binding protein.
AB  - The synthetic flavone flavopiridol can be cytostatic or cytotoxic to mammalian
      cells, depending on the concentration of the drug and the duration of exposure.
      It has been shown to inhibit the cyclin-dependent kinase (CDK) family of cell
      cycle regulatory enzymes. However, the existence of additional potential targets
      for drug action remains a matter of interest to define. To identify cellular
      targets, flavopiridol was immobilized. CDKs, particularly CDK 4, bound weakly to
      immobilized flavopiridol when ATP was absent but not in its presence. Two
      proteins with molecular weights of 40 kDa and 120 kDa had high affinities to the
      immobilized flavopiridol independent of the presence of ATP. They were present in
      all cell lines analyzed: cervical (HeLa), prostate and non-small cell lung
      carcinoma (NSCLC) cell lines. A 60-kDa protein, which was present only in NSCLC
      cells and bound similarly well to immobilized flavopiridol, was identified as
      cytosolic aldehyde dehydrogenase class 1 (ALDH-1). The level of this protein
      correlated with the resistance of NSCLC cell lines to cytotoxicity caused by 500
      nM flavopiridol but not higher flavopiridol concentrations. Despite binding to
      ALDH-1, there was no inhibition of dehydrogenase activity by flavopiridol
      concentrations as high as 20 microM and flavopiridol was not metabolized by ALDH
      1. The results suggest that high cellular levels of ALDH-1 may reduce
      cytotoxicity of flavopiridol and contribute to relative resistance to the drug.
      This is the first report that flavopiridol binds to proteins other than CDKs.

PMID- 10413105
TI  - Interaction of soluble and surface-bound heparin binding growth-associated
      molecule with heparin.
AB  - The interaction of heparin with heparin binding growth-associated molecule (HB
      GAM) was studied using isothermal titration calorimetry (ITC) and surface plasmon
      resonance (SPR). ITC studies showed that, in solution, heparin bound HB-GAM with
      a deltaH of -30 kcal/mole corresponding to a dissociation constant (Kd) of 460
      nM. The stoichiometry of interaction was 3 moles of HB-GAM per mole of heparin,
      corresponding to a minimum heparin binding site for HB-GAM of 12-16 saccharide
      residues. Kinetic measurements of heparin interaction with HB-GAM made by SPR
      afforded a Kd of 4 nM, suggesting considerably tighter binding when HB-GAM was
      immobilized on a surface. Affinity chromatography of a sized mixture of heparin
      oligosaccharides, having a degree of polymerization (dp) of > 14 saccharide
      units, on HB-GAM-Sepharose demonstrated that oligosaccharides having more than 18
      saccharide residues showed the tightest interaction.

PMID- 10413106
TI  - Characterization of the shrimp eyestalk cDNA encoding a novel fushi tarazu-factor
      1 (FTZ-F1).
AB  - To study the role of ecdysone and the ecdysone inducible gene in the regulation
      of molting and development in crustaceans, we have cloned a cDNA encoding an
      orphan nuclear receptor family member from the eyestalk of the shrimp Metapenaeus
      ensis. The size of the cDNA is 4.3 kb with the longest open reading frame (ORF)
      encoding a protein of 545 amino acid residues. The deduced amino acid sequence of
      the shrimp cDNA consists of regions that are characteristic of those of the
      nuclear hormone receptors. It shows a high degree of amino acid sequence identity
      in the DNA binding domain, ligand binding domain and the FTZ box as compared to
      those of invertebrates and vertebrates. Unlike the insects Drosophila
      melanogaster and Bombyx mori, an AF2 transactivation domain was present in the
      shrimp FTZ-F1. Northern blot analysis using total RNA indicated that the FTZ-F1
      mRNA could also be detected in the mature ovary. Northern blot analysis and RT
      PCR analysis showed that the shrimp FTZ-F1 transcripts could be detected in the
      ovary, newly hatched nauplius, testis, eyestalk and epidermis of the adult
      shrimp. Although the cDNA clone was isolated from the eyestalk library, the
      shrimp FTZ-F1 appeared to express most abundantly in the mature oocytes. The
      presence of abundant FTZ-F1 specific maternal message in the late vitellogenic
      ovary and early nauplius indicates that it may be important for the early
      embryonic and larval development of the shrimp. Interestingly, shrimp FTZ-F1 can
      also be found in testis of the male shrimp. The presence of FTZ-F1 in other
      tissues such as epidermis suggests that it may also be involved in other
      physiological processes such as molting.

PMID- 10413107
TI  - A novel form of rhodopsin kinase from chicken retina and pineal gland.
AB  - The G protein-coupled receptor kinases (GRKs) are important enzymes in the
      desensitization of activated G protein-coupled receptors (GPCR). Seven members of
      the GRK family have been identified to date. Among these enzymes, GRK1 is
      involved in phototransduction and is the most specialized kinase of the family.
      GRK1 phosphorylates photoactivated rhodopsin (Rho*), initiating steps in its
      deactivation. In this study, we found that chicken retina and pineal gland
      express a novel form of GRK that has sequence features characteristic of GRK1.
      However, unlike bovine GRK1 which is farnesylated, chicken GRK1 contains a
      consensus sequence for geranylgeranylation. Peptides corresponding to the C
      terminal sequence of chicken GRK1 are geranylgeranylated by a cytosolic extract
      of chicken liver. Based on results of molecular cloning and immunolocalization,
      it appears that both rod and cone photoreceptors express this novel GRK1. These
      data indicate a larger sequence diversity of photoreceptor GRKs than anticipated
      previously.

PMID- 10413108
TI  - Amyloid-like aggregates of a plant protein: a case of a sweet-tasting protein,
      monellin.
AB  - We report here a novel case of amyloid-like aggregation of a plant protein. A
      sweet-tasting protein, monellin, experiences an irreversible heat denaturation at
      pH 2.5 and 85 degrees C. Addition of 100 mM NaCl couples this process with
      protein aggregation. The aggregates were structured as regular fibers with
      approximately 10 nm width and capable of binding to Congo red, similarly to well
      known amyloid fibrils. The amyloid-like aggregation process was also successfully
      monitored with a calorimetric method. This work supports the universality of the
      amyloid-like aggregation, not restricted to some special categories of protein.

PMID- 10413109
TI  - Nitrite reductase activity is a novel function of mammalian mitochondria.
AB  - Nitrite, which is the major stable degradation product of nitric oxide, exists in
      all tissues capable of nitric oxide synthesis from L-arginine. The present study
      provides experimental evidence that nitrite in contact with respiring
      mitochondria accepts reducing equivalents from the ubiquinone cycle of the
      respiratory chain. Univalent reduction of nitrite was totally inhibited by
      myxothiazol. We therefore conclude on the involvement of redox cycling that
      ubisemiquinone is associated with the bc1 complex. Recycling of nitric oxide
      degradation products via these electron carriers may become a threat to energy
      linked respiration since nitric oxide in direct contact with mitochondria was
      shown to slow the energy-linked respiration down and to trigger a mitochondrial
      source for superoxide radicals. Until now, the existence of nitrite reductase
      activity was only demonstrated in plants and bacteria. In addition, the present
      observation elucidates the existence of a nitric oxide synthase-independent
      nitric oxide source.

PMID- 10413110
TI  - Human release factor eRF1: structural organisation of the unique functional gene
      on chromosome 5 and of the three processed pseudogenes.
AB  - In lower and higher eukaryotes, a family of tightly related proteins designated
      eRF1 (for eukaryotic release factor 1) catalyses termination of protein synthesis
      at all three stop codons. The human genome contains four eRF1 homologous
      sequences localised on chromosomes 5, 6, 7 and X. We report here the cloning and
      the structural analysis of the human eRF1 gene family. It appears that the gene
      located on chromosome 5 alone is potentially functional, whereas the other three
      sequences resemble processed pseudogenes. This is the first description of the
      structural organisation of the human eRF1 gene, which has been remarkably
      conserved during evolution and which is essential in the translation termination
      process.

PMID- 10413111
TI  - Differential effects of free and liposome-associated 1-O-octadecyl-2-O
      methylglycerophosphocholine on protein kinase C.
AB  - Incorporation of ET-18-OCH3 into well-characterized liposomes known as ELL-12 has
      eliminated its gastrointestinal and hemolytic toxicity without loss of growth
      inhibiting activity. ET-18-OCH3, but not ELL-12, blunted the increase in membrane
      protein kinase C (PKC) activity induced by 12-O-tetradecanoylphorbol 13-myristate
      (TPA) and markedly reduced levels of PKC alpha in NIH 3T3 fibroblasts.
      Furthermore, prolonged treatment with ELL-12 neither inhibited TPA-induced
      translocations of PKC alpha and PKC delta to the particulate fraction nor caused
      down-regulation, and did not affect the cellular distribution of TPA-insensitive
      PKC zeta. In Jurkat T cells, where ELL-12 markedly induced apoptosis that was
      blocked by an inhibitor of caspase-3-like activities, it had no effect on PKC
      activity or translocation induced by TPA. Thus, it seems unlikely that PKC is
      involved in the therapeutic effects of ELL-12.

PMID- 10413112
TI  - Mutagenesis and crystallographic studies of Zymomonas mobilis tRNA-guanine
      transglycosylase to elucidate the role of serine 103 for enzymatic activity.
AB  - The tRNA modifying enzyme tRNA-guanine transglycosylase (TGT) is involved in the
      exchange of guanine in the first position of the anticodon with preQ1 as part of
      the biosynthesis of the hypermodified base queuine (Q). Mutation of Ser90 to an
      alanine in Escherichia coli TGT leads to a dramatic reduction of enzymatic
      activity (Reuter, K. et al. (1994) Biochemistry 33, 7041-7046). To further
      clarify the role of this residue in the catalytic center, we have mutated the
      corresponding Ser103 of the crystallizable Zymomonas mobilis TGT into alanine.
      The crystal structure of a TGT(S103A)/preQ1 complex combined with biochemical
      data presented in this paper suggest that Ser103 is essential for substrate
      orientation in the TGT reaction.

PMID- 10413113
TI  - Cloning and expression of three cecropin cDNAs from a mosquito cell line.
AB  - We have characterized full-length cDNAs encoding three isoforms of the antibiotic
      cecropin secreted by the C7-10 cell line from the mosquito, Aedes albopictus. The
      existence of two cecropin isoforms that differed from the previously described
      AalCecA was predicted by mass spectrometry and amino acid sequence analysis of
      peptides that eluted from reversed phase high performance liquid chromatography
      as a single peak just behind the previously described cecropin, AalCecA. Based on
      the amino acid sequence of the mature AalCecA peptide, we designed primers that
      amplified partial cDNAs encoding three different A. albopictus cecropins in
      reverse transcriptase polymerase chain reactions. Rapid amplification of cDNA
      ends was then used to complete the cDNA sequences of AalCecA, AalCecB and
      AalCecC, respectively. Each cDNA encoded a translation product containing a
      signal peptide, a pro region, and a mature cecropin peptide consistent with amino
      acid sequence data from chymotryptic digests. Although the mosquito cecropins
      shared 70-86% identity among each other, they shared only approximately 40%
      identity to cecropins from Drosophila melanogaster. Each of the cecropins was
      expressed within 2 to 4 h after induction, and transcripts measuring 0.3 to 0.5
      kb continued to accumulate over 24 h. The three cecropins were secreted in
      roughly equimolar proportions, and 30 to 90% of AalCecB was amidated at the
      terminal glycine residue. In contrast, amidated forms of AalCecA and AalCecC
      constituted a smaller proportion of these isoforms.

PMID- 10413114
TI  - Specific binding of glucosaminylmuramyl peptides to histones.
AB  - Intracellular N-acetylglucosaminylmuramyl peptide-binding proteins of murine
      macrophages and myelomonocytic WEHI-3 cells were characterized. SDS-PAGE and
      Western blotting revealed proteins with molecular masses of 18, 32 and 34 kDa
      retaining the ability to specifically bind glucosaminylmuramyl dipeptide. The
      inhibition analysis demonstrated that only biologically active muramyl peptides
      but not inactive analogs or fragments of glucosaminylmuramyl dipeptide could
      inhibit glucosaminylmuramyl dipeptide-binding to these proteins. Purification of
      these proteins and sequencing of peptides obtained after in-gel trypsin digestion
      enabled us to identify the above mentioned proteins as histones H1 and H3. These
      findings suggest that nuclear histones might be target molecules for muramyl
      peptides.

PMID- 10413115
TI  - Phosphorylation of tau protein by recombinant GSK-3beta: pronounced
      phosphorylation at select Ser/Thr-Pro motifs but no phosphorylation at Ser262 in
      the repeat domain.
AB  - Glycogen synthase kinase-3beta (GSK-3beta) has been described as a proline
      directed kinase which phosphorylates tau protein at several sites that are
      elevated in Alzheimer paired helical filaments. However, it has been claimed that
      GSK-3beta can also phosphorylate the non-proline-directed KXGS motifs in the
      presence of heparin, including Ser262 in the repeat domain of tau, which could
      induce the detachment of tau from microtubules. We have analyzed the activity of
      recombinant GSK-3beta and of GSK-3beta preparations purified from tissue, using
      two-dimensional phosphopeptide mapping, immunoblotting with phosphorylation
      sensitive antibodies, and phosphopeptide sequencing. The most prominent
      phosphorylation sites on tau are Ser396 and Ser404 (PHF-1 epitope), Ser46 and
      Thr50 in the first insert, followed by a less efficient phosphorylation of other
      Alzheimer phosphoepitopes (antibodies AT-8, AT-270, etc). We also show that the
      non-proline-directed activity at KXGS motifs is not due to GSK-3beta itself, but
      to kinase contaminations in common GSK-3beta preparations from tissues which are
      activated upon addition of heparin.

PMID- 10413116
TI  - Examination of the signal transduction pathways leading to activation of
      extracellular signal-regulated kinase by formyl-methionyl-leucyl-phenylalanine in
      rat neutrophils.
AB  - The signaling pathways leading to extracellular signal-regulated kinase (ERK)
      activation in formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated rat
      neutrophils were examined. fMLP-stimulated ERK activation based on immunoblot
      analysis with antibodies against the phosphorylation form of ERK was attenuated
      by the pretreatment of cells with pertussis toxin but not with a dual cyclo
      oxygenase/lipoxygenase inhibitor BW755C. Exposure of cells to the tyrosine kinase
      inhibitor genistein, phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin
      and LY294002, or protein kinase C (PKC) inhibitors Go6976, Go6983, and GF109203X
      inhibited fMLP-stimulated ERK phosphorylation in a concentration-dependent
      manner. In addition, both the phospholipase C (PLC) inhibitor U73122 and the Ca2+
      chelator BAPTA attenuated ERK activation. These results indicate that G(i/o)
      protein, tyrosine kinase, P13K, PKC, and PLC/Ca2+, but not arachidonate
      metabolites, act upstream of fMLP-stimulated ERK activation.

PMID- 10413117
TI  - Detection of putative Zn(II) binding sites within Escherichia coli RNA
      polymerase: inconsistency between sequence-based prediction and 65Zn blotting.
AB  - The availability of repeating 'Cys' and/or 'His' units in a particular order
      prompts the prediction of Zn(II) finger motifs in a protein. Escherichia coli RNA
      polymerase has two tightly bound Zn(II) per molecule of the enzyme as detected by
      atomic absorption spectroscopy. One Zn(II) was identified to be at the beta
      subunit, whereas the other putative Zn(II) binding site has recently been
      predicted to be at the N-terminal half of the beta' subunit, from primary
      sequence analysis. We show here that the beta' subunit has no ability to bind
      65Zn(II). On the other hand, the N-terminal domain of the alpha subunit has
      strong Zn(II) binding ability with no obvious functional implications.

PMID- 10413118
TI  - Inside-outside technique for posterior occipitocervical spine instrumentation and
      stabilization: preliminary results.
AB  - OBJECT: The authors present a series of 16 patients who underwent inside-outside
      occipital and posterior cervical spine stabilization. METHODS: In this technique,
      the screw was placed from the inside of the occiput to the outside. An articular
      (lateral) mass plate was contoured to the shape of the occipital bone and the
      cervical spine and affixed to the occiput with a flat-headed screw or stud placed
      through a burr hole in the calvaria with the flat head of the screw in the
      epidural space and the threads facing outward. The bone plate was then secured
      with a nut to the occipital screw and the cervical plate was attached to the
      spine with a bone screw that coursed through the plate and into the articular
      pillar. Our series included six children and 10 adults. In five patients,
      previous fusion had failed; in two patients spinal instability was secondary to
      Down's syndrome; two patients' instability was related to developmental
      anomalies; and in five patients spinal instability was due to the presence of
      tumor. One patient with rheumatoid arthritis had undergone a transoral procedure.
      Two patients had suffered traumatic fracture. Three patients died of causes
      unrelated to the procedure, one patient died of metastatic cancer, and one
      patient died in a long term care facility of cardiopulmonary complications. One
      patient with renal failure suffered a hemorrhage from an arteriovenous fistula
      after being treated with dialysis. In one child, a nut backed off after 3 months.
      The nut was reseated, and a maturing arthrodesis was present. CONCLUSIONS: The
      authors conclude that the inside-outside occipitocervical fixation is an
      effective technique for stabilizing the cervical spine.

PMID- 10413119
TI  - Anterior cervical discectomy: is fusion necessary?
AB  - OBJECT: A prospective, randomized trial was performed to compare the efficacy of
      anterior cervical discectomy (ACD) with ACD and fusion (ACDF) for the treatment
      of cervical spondylosis in patients with neurological compromise. METHODS: Forty
      four patients underwent ACD and 40 underwent ACDF. Operative time and length of
      hospital stay were shorter and there was less need for analgesia in the ACD
      group. It was found that whereas the incidence of fusion was greater in the ACDF
      group compared to the ACD group (97 compared with 70%, respectively; p<0.01),
      patient satisfaction and a return to preoperative activity level was similar
      between groups. CONCLUSIONS: Analysis of the results suggests that the addition
      of a fusion procedure may be unnecessary.

PMID- 10413120
TI  - Risk of early closed reduction in cervical spine subluxation injuries.
AB  - OBJECT: The authors retrospectively reviewed 121 patients with traumatic cervical
      spine injuries to determine the risk of neurological deterioration following
      early closed reduction. METHODS: After excluding minor fractures and injuries
      without subluxation, the medical records and imaging studies (computerized
      tomography and magnetic resonance [MR] images) of 82 patients with bilateral and
      unilateral locked facet dislocations, burst fractures, extension injuries, or
      miscellaneous cervical fractures with subluxation were reviewed. Disc injury was
      defined on MR imaging as the presence of herniation or disruption: a herniation
      was described as deforming the thecal sac or nerve roots, and a disruption was
      defined as a disc with high T2-weighted signal characteristics in a widened disc
      space. Fifty-eight percent of patients presented with complete or incomplete
      spinal cord injuries. Thirteen percent of patients presented with a cervical
      radiculopathy, 22% were intact, and 9% had only transient neurological deficits
      in the field. Early, rapid closed reduction, using serial plain radiographs or
      fluoroscopy and Gardner-Wells craniocervical traction, was achieved in 97.6% of
      patients. In two patients (2.4%) closed reduction failed and they underwent
      emergency open surgical reduction. The average time to achieve closed reduction
      was 2.1+/-0.24 hours (standard error of the mean). The incidence of disc
      herniation and disruption in the 80 patients who underwent postreduction MR
      imaging was 22% and 24%, respectively. However, the presence of disc herniation
      or disruption did not affect the degree of neurological recovery, as measured by
      American Spinal Injury Association motor score and the Frankel scale following
      early closed reduction. Only one (1.3%) of 80 patients deteriorated, but that
      occurred more than 6 hours following closed reduction. CONCLUSIONS: Although disc
      herniation and disruption can occur following all types of traumatic cervical
      fracture subluxations, the incidence of neurological deterioration following
      closed reduction in these patients is rare. The authors recommend early closed
      reduction in patients presenting with significant motor deficits without prior MR
      imaging.

PMID- 10413121
TI  - One-stage posterior decompression and reconstruction of the cervical spine by
      using pedicle screw fixation systems.
AB  - OBJECT: This retrospective study was conducted to analyze the results of one
      stage posterior decompression and reconstruction of the cervical spine by using
      pedicle screw fixation systems in 46 patients. METHODS: Causes of cervical
      myelopathy in these 46 patients included spondylosis or ossification of the
      posterior longitudinal ligament, rheumatoid arthritis, metastatic or primary
      vertebral tumors, cervical spinal injuries, and spinal cord tumor. Thirty-three
      patients underwent this one-stage procedure as primary surgery. In the remaining
      13 patients who had previously undergone laminectomies, the one-stage procedure
      was performed as salvage surgery. Cervical pedicle screws were inserted into the
      pedicles after probing and tapping. Graft bone was placed on the bilateral
      lateral masses, and pedicle screws were interconnected longitudinally by either
      plates or rods. Postoperatively, 26 patients showed improved neurological status
      (at least one grade improvement on Frankel's functional classification). There
      were no cases of neurological deterioration postoperatively. Solid bony fusion
      was obtained in all patients, except in seven patients with metastatic tumor who
      did not receive bone grafts. Correction of kyphosis was satisfactory.
      Postoperative radiological evaluation revealed that 10 (5.3%) of 190 screws
      inserted into the cervical vertebrae had perforated the cortex of the pedicles;
      however, no neurovascular complications were caused by the perforations.
      CONCLUSIONS: The pedicle screw fixation procedure, which does not require the
      lamina to be used as a stabilizing anchor, has proven to be valuable when
      performing one-stage posterior decompressive and reconstructive surgery in the
      cervical spine. The risk to neurovascular structures in this procedure, however,
      cannot be completely eliminated. Thorough knowledge of local anatomy and
      application of established surgical techniques are essential for this procedure.

PMID- 10413122
TI  - Anterior cervical plating for the treatment of neoplasms in the cervical
      vertebrae.
AB  - OBJECT: To assess clinical outcome and survival in patients with cervical
      vertebral spinal neoplasms after they have undergone anterior decompression and
      cervical plate stabilization (ACPS) by using either autologous bone graft or
      polymethylmethacrylate (PMMA) as the anterior load-bearing support structure.
      METHODS: This was a retrospective case study composed of 30 patients harboring
      cervical spinal vertebral neoplasms who underwent anterior cervical decompression
      and (ACPS) within a 7-year period. Postoperative immobilization included
      treatment in a halo brace in two cases and in a hard cervical collar for the
      remaining patients. Postoperatively most patients underwent radio- and/or
      chemotherapy. All patients except one benefited from a significantly improved
      quality of life with decreased pain and/or improved neurological status. The mean
      Kaplan-Meier survivoral estimate was 35.8 months (range 8 days-11.3 years, with
      10 patients alive at most recent follow-up contact). Patients achieved long-term
      or lifelong mechanical stability in the cervical spine, and only one patient
      required a repeated posterior stabilization procedure. No hardware-related
      complications occurred. One patient died 8 days postoperatively of pneumonia. A
      nonsignificant difference in survival (p = 0.2164) was observed between patients
      harboring metastatic neoplasms (26.8 months) and those harboring lymphomatous and
      multiple myeloma neoplasms (54 months). CONCLUSIONS: Favorable clinical outcome
      of both neurological symptoms and pain can be achieved using ACPS after surgery
      for neoplasms in the cervical vertebrae. Furthermore, long-term or lifelong
      cervical spine mechanical stability with bone fusion is achieved using this
      technique even when radiation therapy is delivered to the site of the bone graft.

PMID- 10413123
TI  - Cervical corpectomy: report of 185 cases and review of the literature.
AB  - OBJECT: This study was conducted to determine the indications, safety, efficacy,
      and complication rate associated with performing corpectomy to achieve anterior
      decompression of neural elements or for removing anterior lesions. METHODS:
      Between 1987 and 1998, 185 patients underwent cervical corpectomy for the
      treatment of degenerative spondylitic disease (81 cases), ossification of
      posterior longitudinal ligament (16 cases), correction of postoperative kyphosis
      (31 cases), trauma (39 cases), tumor (10 cases), and infection (eight cases).
      Ninety-nine patients presented with myelopathy, 48 with radiculomyelopathy, 24
      with radicular pain, and 14 with neck muscle pain. Eighty-seven patients
      underwent a one-level corpectomy; 45 of these patients underwent a discectomy at
      a different level. Seventy patients underwent a two-level corpectomy; 27 of these
      patients underwent a discectomy at a different level. Twenty-eight patients
      underwent a three-level corpectomy. Autograft (iliac crest) was used in 141 cases
      and allograft (fibula) in 44 cases. All but six patients underwent fixation with
      an anterior plate-screw system. There were no operative deaths. During the
      procedure the vertebral artery was injured in four patients and preserved in two
      of them. No neurological sequelae were encountered. Postoperative hoarseness,
      transient dysphagia, and pain at the graft site were transitory and successfully
      managed. The fusion rate was 98.8%. Six patients experienced transient
      deterioration after surgery but they improved. No patient experienced permanent
      neurological deterioration and 160 (86.5%) improved. CONCLUSIONS: Corpectomy has
      an important role in the management of various degenerative, traumatic,
      neoplastic, or infectious disorders of cervical spine. Following treatment in
      this series, radiculopathy always improved and myelopathy was reversed in most
      patients.

PMID- 10413124
TI  - Palliative subtotal vertebrectomy with anterior and posterior reconstruction via
      a single posterior approach.
AB  - OBJECT: Laminectomy for the treatment of spinal metastatic disease is
      ineffective. Total spondylectomy requiring both anterior and posterior operations
      may cause undue morbidity in patients with a limited life expectancy. The authors
      demonstrate the technique, feasibility, and success of subtotal vertebrectomy
      that is followed by anterior and posterior reconstruction via a simple posterior
      approach. Although this remains a palliative procedure, it provides
      circumferential decompression and spinal stabilization by using rigid hardware.
      METHODS: The authors present a review of nine of 43 consecutive patients with
      spinal metastatic disease who underwent operation in a 42-month period. Via a
      single midline posterior approach, the authors performed single-stage
      circumferential decompression of the theca followed by anterior and posterior
      reconstruction. Anterior support is provided by a methylmethacrylate
      reconstruction retained with Steinmann pins. Posterior reconstruction is achieved
      by placement of rigid hook or pedicle screw and rod instrumentation. Eight of the
      nine patients died of progression of underlying disease. All patients remained
      pain free until days before they died. Except for a patient with paraplegia who
      did not recover, all other patients remained ambulatory. Despite radio-, chemo-,
      and steroid therapy, there were no wound infections or breakdowns. One patient
      underwent reoperation because of a technical error. CONCLUSIONS: Use of the near
      total vertebrectomy followed by anterior and posterior reconstruction from T2 to
      L3 by using a single midline posterior approach spares the patient, who has a
      limited life expectancy, the operative risks associated with thoracotomy or
      thoracoabdominal approaches. The authors restrict the procedure for use in
      patients with extensive bony disease, noncontiguous spinal involvement, visceral
      metastases, other contraindications to a transcavitary procedure, and those with
      advanced age.

PMID- 10413125
TI  - Intraoperative spinal angiography.
AB  - OBJECT: The use of intraoperative angiography of the spine has become available
      to neurosurgeons as an adjunct in the management of complex spinal vascular
      malformations. These vascular malformations are rare, and the use of
      intraoperative angiography of the spine has not been well described. The authors
      report their recent experience with the use of this diagnostic modality. METHODS:
      Between 1995 and 1997, nine consecutive patients with type II or Type IV spinal
      arteriovenous malformations (AVMs) underwent intraoperative spinal angiography.
      The cervical spine was involved in three patients, the thoracic spine in five,
      and the thoracolumbar junction in one. In three patients, intraoperative spinal
      angiography revealed an unexpected finding (residual filling of the AVM). The
      results obtained using postoperative spinal angiography in all patients showed
      complete agreement with the intraoperative studies. No complications arose from
      obtaining the intraoperative spinal angiograms. CONCLUSIONS: Intraoperative
      spinal angiography is technically feasible, can be performed safely, and has
      adequate resolution. It detects unexpected residual AVM in one-third of cases.

PMID- 10413126
TI  - Lateral exit-zone stenosis and lumbar radiculopathy.
AB  - OBJECT: Hypertrophy of the superior facet of the inferior vertebra, resulting in
      a compression of the nerve root at the lateral foraminal exit, is a recognized
      cause of radicular symptoms, particularly in patients in whom previous lumbar
      spine surgery has failed. The lesion-specific presenting symptoms, imaging
      findings, and surgical treatment of this lesion, however, have received little
      attention. The authors prospectively studied a series of eight consecutive
      patients, in whom a diagnosis of lumbar stenosis at the lateral foraminal exit
      had been made, to elucidate the common presenting signs and symptoms of this
      disorder, as well as to evaluate the success of the operative treatment. METHODS:
      The eight patients were selected from a group of 250 consecutive patients who
      presented to a tertiary-care hospital and in whom a diagnosis of long-standing
      lumbar radiculopathy had been made. In all cases the diagnosis was confirmed by
      imaging studies and by intraoperative findings. The authors performed
      decompressive procedures on the nerve root via a medial facet-sparing approach.
      CONCLUSIONS: The authors conclude that this lesion presents with characteristic
      physical findings and on imaging studies that distinguish it from other causes of
      radiculopathy, and they propose a lesion-specific, facet-sparing surgical
      technique that has yielded excellent results.

PMID- 10413127
TI  - Long-term follow up of patients surgically treated by the far-lateral approach
      for foraminal and extraforaminal lumbar disc herniations.
AB  - OBJECT: This study was undertaken to evaluate the long-term benefit in 202
      patients who were surgically treated via a microsurgical far-lateral approach for
      foraminal or extraforaminal lumbar disc herniations. METHODS: All patients
      underwent surgery at the authors' institute since 1987 and represented 6.5% of
      all lumbar spinal disc surgeries. There were 67 women and 135 men who ranged in
      age from 19 to 78 years (mean age 58 years). All patients had unilateral leg pain
      due to lumbar disc herniations into or lateral to the lateral interpedicular
      compartment. One patient underwent surgery at the L1-2 level, nine at L2-3, 48 at
      L3-4, 86 at L4-5, and 58 at the L5-S1 level. The mean follow-up period was 50
      months (range 12-120 months). Outcome was defined as excellent (no pain), good
      (some back pain), fair (moderate radiculopathy), and poor (unchanged or worse)
      based on Macnab classification. Overall, excellent and good results were achieved
      in 62 (31%) and 85 (42%) patients, respectively, and fair and poor results in 40
      (20%) and 15 (7%) patients, respectively. Of 11 recurrent disc herniations, four
      presented in an extreme-lateral position, five in a paramedian location, and two
      on the contralateral side. There were three minor complications related to
      surgery, seven general complications, and no case of spinal instability.
      CONCLUSIONS: The far-lateral approach is a safe, effective procedure that avoids
      the risk of secondary spinal instability.

PMID- 10413128
TI  - The role of bupivacaine in early postoperative pain control after lumbar
      decompression.
AB  - OBJECT: The authors studied the effect of immediate postoperative administration
      of bupivacaine in patients who underwent a lumbar decompressive procedure.
      METHODS: In this randomized double-blind trial, 50 patients who underwent
      elective lumbar decompression after induction of general anesthetic received a
      postoperative bilateral paravertebral 40-ml intramuscular application of either
      saline (0.9%) or bupivacaine (0.25%). For delivering morphine, both groups used a
      patient-controlled analgesia system for 24 hours postsurgery. Pain scores, 10-cm
      visual analog scale scores, and morphine consumption were similar between groups
      with no significant differences (p>0.05). CONCLUSIONS: Results of subgroup
      analysis suggested strongly that perioperative administration of
      methylprednisolone in a sustained-release preparation was associated with a
      reduction in postoperative pain (p<0.05).

PMID- 10413129
TI  - Chondrosarcoma of the spine: 1954 to 1997.
AB  - OBJECT: Primary chondrosarcoma of the spine is extremely rare. During the last 43
      years only 21 patients with this disease were registered at The University of
      Texas M. D. Anderson Cancer Center. The purpose of this study was to examine the
      demographic characteristics, treatments, and outcomes of this set of patients.
      METHODS: Medical records for 21 patients were reviewed. Age, sex, race, clinical
      presentation, tumor histology, tumor location in the spinal column, treatments,
      surgical details, and response to treatment were recorded. Surgical procedures
      were categorized as either gross-total resection or subtotal excision of tumor.
      Neurological function was assessed using Frankel's functional classification.
      Time to recurrence and survival analyses were performed using the Kaplan-Meier
      method. The median age of patients was 51 years, with fairly equal gender
      representation. Eighteen patients underwent at least one surgical procedure for a
      total of 28 surgical procedures: seven radical resections and 21 subtotal
      excisions. Radiation therapy was used in conjunction with 10 of the 28 surgical
      procedures. The median Kaplan-Meier estimate of overall survival for the entire
      group was 6 years (range 6 months-17 years). Tumors recurred after 18 of the 28
      procedures. Kaplan-Meier analysis revealed a statistically significant difference
      in the per-procedure disease-free interval after gross-total resection relative
      to subtotal excision (exact log rank 3.39; p = 0.04). The addition of radiation
      therapy prolonged the median disease-free interval from 16 to 44 months, although
      this was not statistically significant (exact log rank 2.63; p = 0.16).
      CONCLUSIONS: Our results suggest that gross-total resection of the chondrosarcoma
      provides the best chance for prolonging the disease-free interval in patients.
      Subtotal excision should be avoided whenever possible. Addition of radiation
      therapy does not appear to lengthen significantly the disease-free interval in
      this patient population.

PMID- 10413130
TI  - Electrical spinal cord stimulation in reflex sympathetic dystrophy: retrospective
      analysis of 23 patients.
AB  - OBJECT: The aim of the study was to assess retrospectively the clinical efficacy
      and possible adverse effects of electrical spinal cord stimulation (SCS) for the
      treatment of patients with reflex sympathetic dystrophy (RSD). METHODS: Twenty
      three patients who suffered severe pain due to RSD were included in the study.
      The SCS system was implanted only after a positive 1-week test period. The visual
      analog scale (VAS) score for pain (1-10) was obtained in all patients prior to
      treatment, 1 month postimplantation, and at last follow up. At final follow-up
      examination, patients were asked to rate the effect of their treatment on the 7
      point global perceived effect scale. Eighteen (78%) of 23 patients treated
      between 1991 and 1997 reported improvement during the test period. Permanent
      implantation of SCS system was not performed in the other five patients.
      Complications occurred in nine (50%) of 18 patients. The system was removed in
      three patients after implantation (17%). At the end of follow up (mean 32 months)
      15 patients still had an implanted system. The mean pain score had decreased from
      7.9 to 5.4 (p<0.001). In the other eight patients the pain score had not changed
      significantly. In 13 patients (57%) in whom the SCS system was implanted,
      clinical status had much improved or improved; these cases were regarded as
      successful. CONCLUSIONS: In this retrospective series, the majority of patients
      with RSD reported a subjective improvement after implantation of an SCS system.

PMID- 10413131
TI  - A biomechanical evaluation of occipitocervical instrumentation: screw compared
      with wire fixation.
AB  - OBJECT: The purpose of this study was to compare cable techniques used in
      occipitocervical fixation with two types of screw fixation. The authors
      hypothesized that screw fixation would provide superior immobilization compared
      with cable methods. METHODS: Ten cadaveric specimens were prepared for
      biomechanical analyses by using standard techniques. Angular and linear
      displacement data were recorded from the occiput to C-6 with infrared optical
      sensors after conditioning runs. Specimens underwent retesting after fatiguing.
      Six methods of fixation were analyzed: Steinmann pin with and without C-1
      incorporation; Cotrel-Dubousett horseshoe with and without C-1 incorporation;
      Mayfield loop with C1-2 transarticular screw fixation; and a custom-designed
      occipitocervical transarticular screw-plate system. Sublaminar techniques were
      extended to include C-3 in the fusion construct, whereas transarticular
      techniques incorporated the occiput, C-1, and C-2 only. All methods of fixation
      provided significant immobilization in all specimens compared with the
      nonconstrained destabilized state. Despite incorporation of an additional
      vertebral segment, sublaminar techniques performed worse as a function of applied
      load than screw fixation techniques. Following fatiguing, these differences were
      more pronounced. The sublaminar techniques failed most prominently in flexion
      extension and in axial rotation. On gross inspection, increased angular
      displacement associated with loosening of the sublaminar cables was observed.
      CONCLUSION: Occipitocervical fixation can be performed using a variety of
      techniques; all bestow significant immobilization compared with the destabilized
      spine. All methods tested in this study were susceptible to fatigue and loss of
      reduction and were weakest in resisting vertical settling. Screw fixation of the
      occiput-C2 reduces the number of vertebral segments that are necessary to
      incorporate into the fusion construct while providing superior immobilization and
      resistance to fatigue and vertical settling compared with sublaminar methods.

PMID- 10413132
TI  - Stability of the craniovertebral junction after unilateral occipital condyle
      resection: a biomechanical study.
AB  - OBJECT: The authors sought to determine the biomechanics of the occipitoatlantal
      (occiput [Oc]-C1) and atlantoaxial (C1-2) motion segments after unilateral
      gradient condylectomy. METHODS: Six human cadaveric specimens (skull with
      attached upper cervical spine) underwent nondestructive biomechanical testing
      (physiological loads) during flexion-extension, lateral bending, and axial
      rotation. Axial translation from tension to compression was also studied across
      Oc-C2. Each specimen served as its own control and underwent baseline testing in
      the intact state. The specimens were then tested after progressive unilateral
      condylectomy (25% resection until completion), which was performed using
      frameless stereotactic guidance. At Oc-C1 for all motions that were tested,
      mobility increased significantly compared to baseline after a 50% condylectomy.
      Flexion-extension, lateral bending, and axial rotation increased 15.3%, 40.8%,
      and 28.1%, respectively. At C1-2, hypermobility during flexion-extension occurred
      after a 25% condylectomy, during axial rotation after 75% condylectomy, and
      during lateral bending after a 100% condylectomy. CONCLUSIONS: Resection of 50%
      or more of the occipital condyle produces statistically significant hypermobility
      at Oc-C1. After a 75% resection, the biomechanics of the Oc-C1 and C1-2 motion
      segments change considerably. Performing fusion of the craniovertebral junction
      should therefore be considered if half or more of one occipital condyle is
      resected.

PMID- 10413133
TI  - Adenoviral nerve growth factor and beta-galactosidase transfer to spinal cord: a
      behavioral and histological analysis.
AB  - OBJECT: The present study characterizes the time course and loci of gene
      expression induced by the administration of adenoviral vectors into spinal cord.
      Although a marked inflammatory response to these vectors occurred, no effect on
      spinal cord function was seen in the 1st postoperative week. The expression of
      transgenic genes delivered by viral vectors is being exploited throughout the
      nervous system. The present study utilized adenoviral vectors containing the Rous
      sarcoma virus (RSV) promoter and a nuclear localization signal to achieve
      transgenic expression in mammalian spinal cord. METHODS: Initial experiments
      utilizing the vector Ad.RSVlacZ (10(12) particles/ml) injected into the region of
      the central canal resulted in viral gene expression stretching over approximately
      1.2 cm of spinal cord. Gene expression was first detected 3 days following viral
      administration and lasted until postinjection Day 14 with peak expression at Day
      7. A variety of cell types in both white and gray matter expressed lacZ.
      Transgenic expression of the neurotrophin nerve growth factor (NGF) was achieved
      using injections of Ad.RSVNGF. On histological examination mononuclear
      inflammatory infiltrate and gliosis were revealed surrounding the injection sites
      of spinal cords receiving adenovirus but not vehicle. To assess spinal cord
      function during viral gene expression, animals previously trained in an operant
      runway task were tested at 7 days postinjection (the peak of viral gene
      expression) and demonstrated no changes in spinal cord function. CONCLUSIONS:
      Results of this study using adenoviral neurotrophic gene transfer indicate that
      it provided an effective tool for the delivery of potentially therapeutic
      proteins to the injured or diseased spinal cord.

PMID- 10413135
TI  - Convective delivery of macromolecules into the naive and traumatized spinal cords
      of rats.
AB  - OBJECT: Many macromolecules have the potential to enhance recovery after injury
      and other lesions of the spinal cord, but because of the limited penetration of
      these compounds across the blood-spinal cord barrier, they cannot be used
      effectively. To determine if convective delivery could be used in a common animal
      model to investigate potential therapeutic macromolecules and to examine the
      effects of trauma on convective delivery in that model, the authors examined the
      distribution of a macromolecule in naive and traumatized rat spinal cords.
      METHODS: Using convection, various infusion volumes ([Vi]; 1, 2, and 4 microl) of
      14C-albumin were infused into the dorsal columns of 13 naive and five traumatized
      rat spinal cords. Volume of distribution (Vd), homogeneity, percentage of
      recovery, and anatomical location were determined using quantitative
      autoradiography, scintillation analysis, calculation of kurtosis (K) value, and
      histological analysis. In the nontraumatized group, Vd was linearly proportional
      (R2 = 0.98) to Vi (Vd/Vi, 4.3+/-0.6; mean +/- standard deviation), with increases
      in Vd resulting from linear expansion (R2 = 0.94) primarily in the craniocaudal
      dimension. In the traumatized spinal cords, the Vd/Vi ratio (3.7+/-0.5) was
      smaller (p<0.02) and distributions were less confined to the craniocaudal
      dimension, with significantly larger cross-sectional distributions in the region
      of injury (p<0.02) compared to the noninjured spinal cords. Histological analysis
      revealed that after infusion into the dorsal columns, albumin distribution in
      naive cords was limited to the dorsal white matter, but in the traumatized cords
      there was penetration into the central gray matter. The distribution of the
      infusate was homogeneous in the nontraumatized (K = -1.1) and traumatized (K = 
      1.1) spinal cords. Recovery of radioactivity was not significantly different
      (p>0.05) between the nontraumatized (84.8+/-6.8%) and traumatized (79.7+/-12.1%)
      groups. CONCLUSIONS: Direct convective delivery of infusate can be used to
      distribute macromolecules in a predictable, homogeneous manner over significant
      volumes of naive and traumatized rat spinal cord. These characteristics make it a
      valuable tool to investigate the therapeutic potential of various compounds for
      the treatment of injury and spinal cord disease.

PMID- 10413134
TI  - Percutaneous spinal fusion using bone morphogenetic protein-2 gene therapy.
AB  - OBJECT: Gene therapy has many potential applications in neurosurgery. One
      application involves bone morphogenetic protein-2 (BMP-2), a low-molecular-weight
      glycoprotein that induces bone formation in vivo. Numerous studies have
      demonstrated that the BMP-2 protein can enhance spinal fusion. This study was
      undertaken to determine whether direct injection of an adenoviral construct
      containing the BMP-2 gene can be used for spinal fusion. METHODS: Twelve athymic
      nude rats were used in this study. Recombinant, replication-defective type 5
      adenovirus with the cytomegalovirus (CMV) promoter and BMP-2 gene (Ad-BMP-2) was
      used. A second adenovirus constructed with the CMV promoter and beta
      galactosidase (beta-gal) gene (Ad-beta-gal) was used as a control. In three
      groups (four rats each) 7.5 microl of virus (5x10(8) particles/microl) was
      injected percutaneously and paraspinally at the lumbosacral junction: Group 1
      received Ad-BMP-2 bilaterally; Group 2 received Ad-BMP-2 on the right, Ad-beta
      gal on the left; and Group 3 received Ad-beta-gal bilaterally. Computerized
      tomography (CT) scans of the lumbosacral spine were obtained at 3, 5, 8, and 12
      weeks. At 12 weeks, the animals were killed and underwent histological
      inspection. Ectopic bone formation was observed both on three-dimensionally
      reconstructed CT scans and histological examination in all rats at sites treated
      with Ad-BMP-2. Histological analysis demonstrated bone at different stages of
      maturity adjacent to the spinous processes, laminae, and transverse processes.
      CONCLUSIONS: Results of this study clearly demonstrated that it is possible to
      produce in vivo endochondral bone formation by using direct adenoviral construct
      injection into the paraspinal musculature, which suggests that gene therapy may
      be useful for spinal fusion in the future.

PMID- 10413137
TI  - Intramedullary tuberculoma of the spinal cord. Case report and review of the
      literature.
AB  - Intramedullary spinal tuberculosis infection remains an extremely rare disease
      entity. In the most recent reviews only 148 cases have been reported in the world
      literature, although numerous recent reports from developing countries and on
      human immunodeficiency virus (HIV)-positive patients have increased this number.
      The authors present an unusual case of intramedullary tuberculoma in an HIV
      negative patient from the southern United States who demonstrated no other signs
      or symptoms of tuberculosis infection. The authors believe that this is the first
      case of its kind to be presented in recent literature. The presentation of
      miliary disease via an isolated intramedullary spinal mass in a patient with no
      evident risk factors for tuberculosis infection emphasizes the importance of
      including tuberculosis in the differential diagnosis of spinal cord masses.

PMID- 10413136
TI  - Development of postoperative fibromatosis after resection of an intraspinal
      meningioma. Case report.
AB  - The authors report the case of an adult female patient who developed a
      paraspinous thoracic fibromatosis (desmoid tumor) after undergoing resection of
      an intraspinal thoracic meningioma that was complicated by postoperative wound
      infection. To the best of the authors' knowledge, this is the first report of
      such a tumor occurring after resection of a spinal meningioma. Awareness of the
      development of postoperative fibromatosis and recognition of its association with
      wound sepsis is important. Although rare, this distinctive lesion should be
      considered in the differential diagnosis of the apparent rapid regrowth of
      otherwise indolent lesions including meningioma.

PMID- 10413138
TI  - Renal cell carcinoma: a rare source of cauda equina metastasis. Case report.
AB  - The authors present the case of a patient in whom intradural metastasis from
      renal cell carcinoma spread to the cauda equina. To the authors' knowledge, this
      is only the second report of its kind. This male patient had undergone
      nephrectomy for the treatment of renal cell carcinoma for 5 years and was
      diagnosed as having metastatic lung disease 1 year prior to admission. The
      patient presented with lower back pain that radiated to both legs, but he
      exhibited no sensorimotor deficits. The majority of cauda equina tumors are
      primary tumors, and metastases are very rare. The literature is reviewed with
      reference to current molecular genetic paradigms of metastatic renal cell
      carcinoma.

PMID- 10413140
TI  - Spontaneous regression of a herniated cervical disc in a patient with myelopathy.
      Case report.
AB  - The authors present a case of spontaneous regression of a herniated cervical
      nucleus pulposus in a patient with myelopathy. This 37-year-old woman developed
      sudden quadriparesis; she had reported no history of trauma. Magnetic resonance
      (MR) imaging revealed a large disc herniation and increased signal intensity of
      the cord at the C5-6 level. The extruded disc fragment was found to have resolved
      on follow-up MR imaging after 28 months, despite the fact that the patient had
      undergone no specific treatment. The patient's symptoms had subsided almost
      totally. This is the first case of MR-documented regression of a cervical disc
      herniation in a patient with myelopathy.

PMID- 10413139
TI  - Complex cervical spine neoplastic disease: reconstruction after surgery by using
      a vascularized fibular strut graft. Case report.
AB  - The authors report a case of an aggressive chordoma in the cervical spine of a 15
      year-old girl who underwent radical resection followed by reconstruction using an
      anterior vascularized fibular strut graft and posterior arthrodesis prior to
      receiving immediate postoperative radiation therapy. The patient had successful
      graft incorporation 4 months postoperatively. The authors review the advantages
      of using vascularized fibular strut grafts for the treatment of multilevel
      cervical spine neoplastic disease and discuss the theoretical advantages of using
      vascularized grafts that tolerate therapeutic levels of radiation.

PMID- 10413141
TI  - Subaxial cervical synovial cyst presenting with myelopathy. Report of three
      cases.
AB  - Synovial cysts occur infrequently in the spinal canal and are most often
      associated with degenerative facet joints. Despite the prevalence of degenerative
      spinal disease, symptomatic synovial cysts are extremely uncommon. There have
      been only two previously reported cases of subaxial degenerative synovial cysts
      of the cervical spine in patients who presented with a clinical picture of spinal
      cord compression. The authors report three additional patients treated for
      degenerative cervical synovial cysts who presented with myelopathy. In all three
      patients the cyst was successfully excised and a good clinical outcome achieved.

PMID- 10413142
TI  - Cervical cord compression caused by a pillow in a postlaminectomy patient
      undergoing magnetic resonance imaging. Case report.
AB  - A 66-year-old man, who had undergone osteoplastic laminectomy for posttraumatic
      cervical myelopathy, underwent a second operation in which the replaced laminae
      were removed because of postoperative deep wound infection. Follow-up dynamic
      magnetic resonance imaging with flexion and extension views of the neck 1 year
      postsurgery demonstrated that the cervical cord was markedly compressed from
      behind in the extended position, although a wide subarachnoid space was observed
      in this region when the neck was in the flexed position. The cause of cord
      compression was the pillow that was placed underneath the patient's neck for
      maintaining the extended position, not the neck extension itself. This finding
      indicates that care must be taken during neuroradiological examination not to
      place a pillow under the neck of a patient who has undergone laminectomy. Nuchal
      compression could lead to cervical cord injury after laminectomy. Laminoplasty
      benefits the patient by protecting the cervical cord from secondary injury.

PMID- 10413143
TI  - Transarterial embolization of aneurysms associated with spinal cord arteriovenous
      malformations. Report of four cases.
AB  - The authors sought to show the feasibility and discuss the rationale of
      embolization of aneurysms associated with spinal cord arteriovenous malformations
      (SCAVMs). The authors reviewed the clinical presentation, magnetic resonance (MR)
      images, spinal angiograms, and clinical evolution of four patients treated for
      aneurysms associated with an SCAVM. Aneurysms were located on branches of the
      anterior spinal artery in three patients and on radiculopial arteries in two
      patients; one patient harbored two lesions. Treatment consisted of superselective
      bucrylate embolization of the branches harboring the aneurysms, with preservation
      of the arterial axis. Follow-up angiograms were obtained at 3 to 6 months
      postembolization in all patients. All patients presented with hemorrhagic events.
      Hematomyelia was clearly related to a sulcocommissural or a vasa corona aneutrysm
      in two patients. Another sulcocommissural aneurysm and multiple radiculopial
      aneurysms were presumed to be the cause of subarachnoid hemorrhage in two other
      patients. One patient harbored aneurysms on a sulcocommissural artery and on a
      radiculopial artery. All aneurysms were permanently obliterated. In one patient
      with a single fistula, the SCAVM was cured. The SCAVM was only partially
      obliterated (95, 50, and 20% in apparent volume) in three other patients. There
      were no complications or rebleeding episodes during a follow-up period of 17 to
      37 months. Aneurysms associated with SCAVMs can be eradicated by supraselective
      embolization, even on the anterior spinal artery territory. For patients
      presenting with hemorrhage and prohibitive risk of complete resection,
      embolization of aneurysms may decrease the risk of further rebleeding.

PMID- 10413145
TI  - Screw fixation of fibular graft in the axis. Case illustration.

PMID- 10413144
TI  - Vascular pedicle rib graft in anterior transthoracic fusion procedures. Technical
      note.
AB  - A method is described in which anterior fusion of the thoracic vertebral column
      is performed using a rib strut graft maintained on its vascular pedicle. This
      straightforward technique is useful in selected patients undergoing anterior
      thoracic fusion procedures and can be used in conjunction with other anterior
      spinal implants. By maintaining bone graft blood supply, this technique promotes
      an optimum fusion environment, which may enhance the speed of graft incorporation
      and the ultimate strength of the construct.

PMID- 10413146
TI  - Hemangioblastoma of the L-5 nerve root. Case illustration.

PMID- 10413147
TI  - Intramedullary epidermoid cyst in cervicodorsal spinal cord.

PMID- 10413148
TI  - Osteomyelitis and pathological fracture of the axis. Case illustration.

PMID- 10413149
TI  - Microvascular decompression of cranial nerves: lessons learned after 4400
      operations.
AB  - OBJECT: Microvascular decompression has become an accepted surgical technique for
      the treatment of trigeminal neuralgia, hemifacial spasm, glossopharyngeal
      neuralgia, and other cranial nerve rhizopathies. The senior author (P.J.J.) began
      performing this procedure in 1969 and has performed more than 4400 operations.
      The purpose of this article is to review some of the nuances of the technical
      aspects of this procedure. METHODS: A review of 4415 operations shows that
      numerous modifications to the technique of microvascular decompression have
      occurred during the last 29 years. Of the 2420 operations performed for
      trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia before
      1990, cerebellar injury occurred in 21 cases (0.87%), hearing loss in 48 (1.98%),
      and cerebrospinal fluid (CSF) leakage in 59 cases (2.44%). Of the 1995 operations
      performed since 1990, cerebellar injuries declined to nine cases (0.45%), hearing
      loss to 16 (0.8%), and CSF leakage to 37 (1.85% p < 0.01, test for equality of
      distributions). The authors describe slight variations made to maximize surgical
      exposure and minimize potential complications in each of the six principal steps
      of this operation. These modifications have led to decreasing complication rates
      in recent years. CONCLUSIONS: Using the techniques described in this report,
      microvascular decompression is an extremely safe and effective treatment for many
      cranial nerve rhizopathies.

PMID- 10413150
TI  - Elevated jugular venous oxygen saturation after severe head injury.
AB  - OBJECT: The aim of this study was to investigate the incidence of elevated (> or
      = 75%) jugular venous oxygen saturation (SjvO2) and its relationship to cerebral
      hemodynamic and metabolic parameters and to outcome after severe head injury.
      METHODS: Data from 450 severely head injured patients admitted to the
      Neurosurgical Intensive Care Unit of Ben Taub General Hospital were analyzed
      retrospectively. The SjvO2 was measured in blood obtained from indwelling jugular
      bulb catheters. Patients were classified into the following categories: high
      (Group I), normal (Group II), or low SjvO2 (Group III) if their mean SjvO2 over
      the duration of monitoring was 75% or higher, 74 to 56%, or 55% or lower,
      respectively. A high SjvO2 occurred in 19.1% of patients. There was no consistent
      relationship between SjvO2 and simultaneous cerebral blood flow (CBF) or cerebral
      perfusion pressure measurements. Compared with Groups II and III, the patients in
      Group I had a significantly higher CBF and lower cerebral metabolic rate of
      oxygen (CMRO2). In Group I, the outcomes were death or persistent vegetative
      state in 48.8% of patients and severe disability in 25.6%. These outcomes were
      significantly worse than for patients in Group II. Within Group I, the patients
      with a poor neurological outcome were older and more likely to have suffered a
      focal head injury; they demonstrated a lower CMRO2 and a greater rate of cerebral
      lactate production than the patients who attained a favorable outcome.
      CONCLUSIONS: Posttraumatic elevation of SjvO2 is common but cannot be
      automatically equated with hyperemia. Instead, elevated SjvO2 is a heterogeneous
      condition that is associated with poor outcome after head injury and may carry
      important implications for the management of comatose patients.

PMID- 10413151
TI  - Interhemispheric supratentorial intracranial pressure gradients in head-injured
      patients: are they clinically important?
AB  - OBJECT: It is generally accepted that the intracranial compartment behaves as a
      unicameral space in which intracranial pressure (ICP) is uniformly distributed.
      However, this concept has been challenged many times. Although there is general
      agreement on the existence of craniospinal and suprainfratentorial gradients, the
      existence of interhemispheric gradients is still a matter of debate. The object
      of this study was to reexamine the issue of interhemispheric supratentorial ICP
      gradients in patients with head injuries and the clinical significance of these
      gradients in their management. METHODS: The authors present the results of a
      prospective study conducted in 50 head-injured patients to determine the clinical
      significance of supratentorial ICP gradients. In each case a concurrent bilateral
      frontal intraparenchymatous device was implanted within the 6-hour window after
      computerized tomography (CT) scanning. According to CT criteria, each patient was
      categorized into one of three different groups: 1) diffuse lesions, in which no
      unilaterally measured volumes greater than 25 ml were present and the midline
      shift was 3 mm or less; 2) Focal A, in which added hemispheric volumes were
      greater than 25 ml and midline shift was 3 mm or less; and 3) Focal B, in which
      all patients with a midline shift greater than 3 mm were included. From the
      results of the entire group the authors were able to distinguish four different
      patterns of supratentorial ICP. In Pattern I, the intracranial compartment
      behaved as a true unicameral space with similar mean ICPs and pulse amplitudes in
      both hemispheres; in Pattern II, different mean ICPs and amplitudes were observed
      although ICP increases or decreases were congruent; and in Pattern III, patients
      with different mean ICPs, different ICP amplitudes, and no congruent increases or
      decreases of ICP were included. All (15 cases) but one patient with a diffuse
      lesion presented with ICP Pattern I. Fifteen patients with focal lesions showed a
      Type II pattern, whereas only one patient presented with a Type III pattern. In
      10 patients, of whom all but one presented with a focal lesion, transient
      gradients that disappeared in less than 4 hours were also observed. CONCLUSIONS:
      In many patients with focal lesions, clinically important interhemispheric ICP
      gradients exist. In this subset, transient gradients that disappear with time are
      frequently observed and may indicate an increase in the size of the lesion. The
      clinical relevance of such gradients is discussed and guidelines for adequately
      monitoring ICP are suggested to optimize head injury management and to avoid
      suboptimal or even harmful care in patients with mass lesions.

PMID- 10413152
TI  - New technique of side-to-end hypoglossal-facial nerve attachment with
      translocation of the infratemporal facial nerve.
AB  - OBJECT: The goal of this study was to assess the clinical results of hypoglossal
      facial nerve attachment (HFA), which was primarily performed in patients
      following excision of tumors of the cerebellopontine angle. In six of the
      patients a new side-to-end procedure was used. METHODS: The authors have
      performed a retrospective study of 33 patients who underwent HFA, including 24
      classic end-to-end, three May, and six side-to-end procedures. For the latter
      procedure, a hemihypoglossal-facial nerve attachment was performed by rerouting
      the intratemporal facial nerve; this avoided the jump-cable graft used in May's
      technique. The goal of the new procedure is to reduce the incidence of morbidity
      due to hemilingual paralysis (difficulty in chewing, speaking, and swallowing).
      The incidence of hemilingual paralysis was evaluated based on the findings of a
      questionnaire that was completed by the patients. The patient's facial mobility
      was assessed using the House and Brackmann grading system and the author's
      analytic scoring system. CONCLUSIONS: The HFA offers good functional results. Of
      the 28 cases evaluated, nine had House and Brackmann Grade III, 17 Grade IV, and
      only two Grade V at 18 months. When the new technique of side-to-end
      hemihypoglossal-facial nerve attachment was used, there was considerable
      reduction, if not complete disappearance, of lingual morbidity and the facial
      functional results were constant and satisfactory: there were five patients with
      House and Brackmann Grade III and one with Grade IV, and their mean percentage of
      facial mobility was 43.3%.

PMID- 10413153
TI  - Awake craniotomy with brain mapping as the routine surgical approach to treating
      patients with supratentorial intraaxial tumors: a prospective trial of 200 cases.
AB  - OBJECT: Awake craniotomy was performed as the standard surgical approach to
      supratentorial intraaxial tumors, regardless of the involvement of eloquent
      cortex, in a prospective trial of 200 patients surgically treated by the same
      surgeon at a single institution. METHODS: Patient presentations, comorbid
      conditions, tumor locations, and the histological characteristics of lesions were
      recorded. Brain mapping was possible in 195 (97.5%) of 200 patients. The total
      number of patients sustaining complications was 33 for an overall complication
      rate of 16.5%. There were two deaths in this series, for a mortality rate of 1%.
      New postoperative neurological deficits were seen in 13% of the patients, but
      these were permanent in only 4.5% of them. Complication rates were higher in
      patients who had gliomas or preoperative neurological deficits and in those who
      had undergone prior radiation therapy or surgery. No patient who entered the
      operating room neurologically intact sustained a permanent neurological deficit
      postoperatively. Of the most recent 50 patients treated, three (6%) required a
      stay in the intensive care unit, and the median total hospital stay was 1 day.
      CONCLUSIONS: Use of awake craniotomy can result in a considerable reduction in
      resource utilization without compromising patient care by minimizing intensive
      care time and total hospital stay. Awake craniotomy is a practical and effective
      standard surgical approach to supratentorial tumors with a low complication rate,
      and provides an excellent alternative to craniotomy performed with the patient in
      the state of general anesthesia because it allows the opportunity for brain
      mapping and avoids general anesthesia.

PMID- 10413154
TI  - Risk of injury to cranial nerves after gamma knife radiosurgery for skull base
      meningiomas: experience in 88 patients.
AB  - OBJECT: In this study the authors sought to determine the neurological risks and
      potential clinical benefits of gamma knife radiosurgery for skull base
      meningiomas. METHODS: A consecutive series of 88 patients harboring skull base
      meningiomas were treated between 1990 and 1996 by using the Leksell gamma knife
      in a prospective clinical study that included a strict dose-volume protocol.
      Forty-nine patients had previously undergone surgery, and six had received
      external-beam radiotherapy. The median treatment volume was 10 cm3, and the
      median dose to the tumor margin was 16 Gy. The radiosurgical dosage to the optic
      nerve, the cavernous sinus, and Meckel's cave was calculated and correlated with
      clinical outcome. The median patient follow-up time was 35 months (range 12-83
      months). Two tumors (2.3%) progressed after radiosurgery; the progression-free 5
      year survival rate was 95%. At last follow-up review, 60 (68%) tumors were
      smaller and 26 (29.5%) remained unchanged. Clinical improvement (in vision,
      trigeminal pain, or other cranial nerve symptoms) occurred in 15 patients.
      Functioning optic nerves received a median dose of 10 Gy (range 1-16 Gy), and no
      treatment-induced visual loss occurred. Among nine patients with new trigeminal
      neuropathy, six received doses of more than 19 Gy to Meckel's cave. CONCLUSIONS:
      Gamma knife radiosurgery appeared to be an effective method to control the growth
      of most skull base meningiomas in this intermediate-term study. The risk of
      trigeminal neuropathy seemed to be associated with doses of more than 19 Gy, and
      the optic apparatus appeared to tolerate doses greater than 10 Gy. Considering
      the risks to cranial nerves associated with open surgery for comparable tumors,
      the authors believe that gamma knife radiosurgery is a useful method for the
      management of properly selected recurrent, residual, or newly diagnosed skull
      base meningiomas.

PMID- 10413155
TI  - Cavernous malformations of the brainstem: experience with 100 patients.
AB  - OBJECT: In this study the authors review surgical experience with cavernous
      malformations of the brainstem (CMBs) in an attempt to define more clearly the
      natural history, indications, and risks of surgical management of these lesions.
      METHODS: The authors retrospectively reviewed the cases of 100 patients (38 males
      and 62 females; mean age 37 years) harboring 103 lesions at treated a single
      institution between 1984 and 1997. Clinical histories, radiographs, pathology
      records, and operative reports were evaluated. The brainstem lesions were
      distributed as follows: pons in 39 patients, medulla in 16, midbrain in 16,
      pontomesencephalic junction in 15, pontomedullary junction in 10, midbrain
      hypothalamus/thalamus region in two patients, and more than two brainstem levels
      in five. The retrospective annual hemorrhage rate was most conservatively
      estimated at 5% per lesion per year. Standard skull base approaches were used to
      resect lesions in 86 of the 100 patients. Intraoperatively, all 86 patients were
      found to have a venous anomaly in association with the CMB. Follow up was
      available in 98% (84 of 86) of the surgical patients. Of these, 73 (87%) were the
      same or better after surgical intervention, eight (10%) were worse, and three
      (4%) died. Two surgical patients were lost to follow-up review. Incidences of
      permanent or severe morbidity occurred in 10 (12%) of the surgically treated
      patients. The average postoperative Glasgow Outcome Scale score for surgically
      treated patients was 4.5, with a mean follow-up period of 35 months. CONCLUSIONS:
      The natural history of CMBs is worse than that of cavernous malformations in
      other locations. These CMBs can be resected using skull base approaches, which
      should be considered in patients with symptomatic hemorrhage who harbor lesions
      that approach the pial surface. Venous anomalies are always associated with CMBs
      and must be preserved.

PMID- 10413156
TI  - Resumption of work after aneurysmal subarachnoid hemorrhage in middle-aged
      Japanese patients.
AB  - OBJECT: Previous reports on the results of treatment for aneurysmal subarachnoid
      hemorrhage (SAH) have been based only on activities of daily living after
      discharge, whereas resumption of work has received insufficient attention. Most
      Japanese work under a lifetime employment system, and it is best for those who
      have recovered from SAH to return to work for their previous employer. The
      present study was conducted to determine the extent to which discharged patients
      who have suffered an SAH resume their former occupations in Japan, focusing on
      those between 40 and 49 years of age, who usually have a strong desire to return
      to work. METHODS: The participants consisted of 193 patients with SAH. Based on
      the results of telephone interviews or written questionnaires, their work status
      at 1 year after onset was analyzed. The work resumption rates for patients with
      Hunt and Kosnik neurological Grades 1 or 2 on admission were higher than for
      those with Grades 3 or 4 (p = 0.015) and lower for patients with basilar artery
      aneurysms than for those with aneurysms at other sites (p = 0.028). With regard
      to premorbid occupation, the work resumption rates were high (80%) for
      professionals and engineers, many of whom were public servants, or teachers at
      junior or senior high schools. The resumption rates were also high for primary
      industry workers (80%), but lowest (20%) for professional drivers (p = 0.04
      0.001). The work resumption rate was lower for women than for men (p = 0.01).
      CONCLUSIONS: These findings indicate that resumption of work is determined not
      only by medical factors, but also by social factors including gender, type of
      occupation, employment system, and socioeconomic background.

PMID- 10413157
TI  - Endovascular thrombolysis for symptomatic cerebral venous thrombosis.
AB  - OBJECT: The authors sought to treat potentially catastrophic intracranial dural
      and deep cerebral venous thrombosis by using a multimodality endovascular
      approach. METHODS: Six patients aged 14 to 75 years presented with progressive
      symptoms of thrombotic intracranial venous occlusion. Five presented with
      neurological deficits, and one patient had a progressive and intractable
      headache. All six had known risk factors for venous thrombosis: inflammatory
      bowel disease (two patients), nephrotic syndrome (one), cancer (one), use of oral
      contraceptive pills (one), and puerperium (one). Four had combined dural and deep
      venous thrombosis, whereas clot formation was limited to the dural venous sinuses
      in two patients. All patients underwent diagnostic cerebral arteriograms followed
      by transvenous catheterization and selective sinus and deep venous
      microcatheterization. Urokinase was delivered at the proximal aspect of the
      thrombus in dosages of 200,000 to 1,000,000 IU. In two patients with thrombus
      refractory to pharmacological thrombolytic treatment, mechanical wire microsnare
      maceration of the thrombus resulted in sinus patency. Radiological studies
      obtained 24 hours after thrombolysis reconfirmed sinus/vein patency in all
      patients. All patients' symptoms and neurological deficits improved, and no
      procedural complications ensued. Follow-up periods ranged from 12 to 35 months,
      and all six patients remain free of any symptomatic venous reocclusion. Factors
      including patients' age, preexisting medical conditions, and duration of symptoms
      had no statistical bearing on the outcome. CONCLUSIONS: Patients with both dural
      and deep cerebral venous thrombosis often have a variable clinical course and an
      unpredictable neurological outcome. With recent improvements in interventional
      techniques, endovascular therapy is warranted in symptomatic patients early in
      the disease course, prior to morbid and potentially fatal neurological
      deterioration.

PMID- 10413158
TI  - Treatment of patients with primary glioblastoma multiforme with standard
      postoperative radiotherapy and radiosurgical boost: prognostic factors and long
      term outcome.
AB  - OBJECT: To assess the value of stereotactic radiosurgery (SRS) as adjunct therapy
      in patients suffering from glioblastoma multiforme (GBM), the authors analyzed
      their experience with 78 patients. METHODS: Between June 1988 and January 1995,
      78 patients underwent SRS as part of their initial treatment for GBM. All
      patients had undergone initial surgery or biopsy confirming the diagnosis of GBM
      and received conventional external beam radiotherapy. Stereotactic radiosurgery
      was performed using a dedicated 6-MV stereotactic linear accelerator. Thirteen
      patients were alive at the time of analysis with a median follow-up period of
      40.8 months. The median length of actuarial survival for all patients was 19.9
      months. Twelve- and 24-month survival rates were 88.5% and 35.9%, respectively.
      Patient age and Radiation Therapy Oncology Group (RTOG) class were significant
      prognostic indicators according to univariate analysis (p < 0.05). Twenty-three
      patients aged younger than 40 years had a median survival time of 48.6 months
      compared with 55 older patients who had 18.2 months (p < 0.001). Patients in this
      series fell into RTOG Classes III (27 patients), IV (29 patients), or V (22
      patients). Class III patients had a median survival time of 29.5 months following
      diagnosis; this was significantly longer than median survival times for Classes
      IV and V, which were 19.2 and 18.2 months, respectively (p = 0.001). Only patient
      age (< 40 years) was a significant prognostic factor according to multivariate
      analysis. Acute complications were unusual and limited to exacerbation of
      existing symptoms. There were no new neuropathies secondary to SRS. Thirty-nine
      patients (50%) underwent reoperation for symptomatic necrosis or recurrent tumor.
      The rate of reoperation at 24 months following SRS was 54.8%. CONCLUSIONS: The
      addition of a radiosurgery boost appears to confer a survival advantage to
      selected patients.

PMID- 10413159
TI  - Early rebleeding from intracranial dural arteriovenous fistulas: report of 20
      cases and review of the literature.
AB  - OBJECT: In this study the authors sought to estimate the frequency, seriousness,
      and delay of rebleeding in a homogeneous series of 20 patients whom they treated
      between May 1987 and May 1997 for arteriovenous fistulas (AVFs) that were
      revealed by intracranial hemorrhage (ICH). The natural history of intracranial
      dural AVFs remains obscure. In many studies attempts have been made to evaluate
      the risk of spontaneous hemorrhage, especially as a function of the pattern of
      venous drainage: a higher occurrence of bleeding was reported in AVFs with
      retrograde cortical venous drainage, with an overall estimated rate of 1.8% per
      year in the largest series in the literature. However, very few studies have been
      designed to establish the risk of rebleeding, an omission that the authors seek
      to remedy. METHODS: Presenting symptoms in the 20 patients (17 men and three
      women, mean age 54 years) were acute headache in 12 patients (60%), acute
      neurological deficit in eight (40%), loss of consciousness in five (25%), and
      generalized seizures in one (5%). Results of the clinical examination were normal
      in five patients and demonstrated a neurological deficit in 12 and coma in three.
      Computerized tomography scanning revealed intracranial bleeding in all cases (15
      intraparenchymal hematomas, three subarachnoid hemorrhages, and two subdural
      hematomas). A diagnosis of AVF was made with the aid of angiographic studies in
      19 patients, whereas it was a perioperative discovery in the remaining patient.
      There were 12 Type III and eight Type IV AVFs according to the revised
      classification of Djindjian and Merland, which meant that all AVFs in this study
      had retrograde cortical venous drainage. The mean duration between the first
      hemorrhage and treatment was 20 days. Seven patients (35%) presented with acute
      worsening during this delay due to radiologically proven early rebleeding.
      Treatment consisted of surgery alone in 10 patients, combined embolization and
      surgery in eight, embolization only in one, and stereotactic radiosurgery in one.
      Three patients died, one worsened, and in 16 (80%) neurological status improved,
      with 15 of 16 AVFs totally occluded on repeated angiographic studies (median
      follow up 10 months). CONCLUSIONS: The authors found that AVFs with retrograde
      cortical venous drainage present a high risk of early rebleeding (35% within 2
      weeks after the first hemorrhage), with graver consequences than the first
      hemorrhage. They therefore advocate complete and early treatment in all cases of
      AVF with cortical venous drainage revealed by an ICH.

PMID- 10413160
TI  - Magnetoencephalographic mapping of the language-specific cortex.
AB  - OBJECT: In this paper the authors introduce a novel use of magnetoencephalography
      (MEG) for noninvasive mapping of language-specific cortex in individual patients
      and in healthy volunteers. METHODS: The authors describe a series of six
      experiments in which normative MEG data were collected and the reliability,
      validity, and topographical accuracy of the data were assessed in patients who
      had also undergone the Wada procedure or language mapping through intraoperative
      cortical stimulation. CONCLUSIONS: Findings include: 1) receptive language
      specific areas can be reliably activated by simple language tasks and this
      activation can be readily recorded in short MEG sessions; 2) MEG-derived maps of
      each individual are reliable because they remain stable over time and are
      independent of whether auditory or visual stimuli are used to activate the brain;
      and 3) these maps are also valid because they concur with results of the Wada
      procedure in assessing hemispheric dominance for language and with the results of
      cortical stimulation in identifying the precise topography of receptive language
      regions within the dominant hemisphere. Although the MEG mapping technique should
      be further refined, it has been shown to be efficacious by correctly identifying
      the language-dominant hemisphere and specific language-related regions within
      this hemisphere. Further development of the technique may render it a valuable
      adjunct for routine presurgical planning in many patients who harbor tumors or
      have epilepsy.

PMID- 10413161
TI  - Optimizing accuracy in magnetic resonance imaging-guided stereotaxis: a technique
      with validation based on the anterior commissure-posterior commissure line.
AB  - OBJECT: Some of the earliest successful frame-based stereotactic interventions
      directed toward the thalamus and basal ganglia depended on identifying the
      anterior commissure (AC) and posterior commissure (PC) in a sagittal
      ventriculogram and defining the intercommissural line that connects them in the
      midsagittal plane. The AC-PC line became the essential landmark for the
      localization of neuroanatomical targets in the basal ganglia and diencephalon and
      for relating them to stereotactic atlases. Stereotactic/functional neurosurgery
      has come to rely increasingly on magnetic resonance (MR) imaging guidance, and
      methods for accurately determining the AC-PC line on MR imaging are being
      developed. The goal of the present article is to present the authors' technique.
      METHODS: The technique described uses MR sequences that minimize geometric
      distortion and registration error, thereby maximizing accuracy in AC-PC line
      determinations from axially displayed MR data. The technique is based on the
      authors' experience with the Leksell G-frame but can be generalized to other MR
      imaging-based stereotactic systems. This methodology has been used in a series of
      62 stereotactic procedures in 47 adults (55 pallidotomies and seven
      thalamotomies) with preliminary results that compare favorably with results
      reported when using microelectrode recordings. The measurements of the AC-PC line
      reported here also compare favorably with those based on ventriculography and
      computerized tomography scanning. CONCLUSIONS: The methodology reported here is
      critical in maintaining the accuracy and utility of MR imaging as its role in
      modern stereotaxy expands. Accurate parameters such as these aid in ensuring the
      safety, efficacy, and reproducibility of MR-guided stereotactic procedures.

PMID- 10413162
TI  - Presence of vitronectin and activated complement factor C9 on
      ventriculoperitoneal shunts and temporary ventricular drainage catheters.
AB  - OBJECT: The pathogenesis of cerebrospinal fluid (CSF) shunt infection is
      characterized by staphylococcal adhesion to the polymeric surface of the shunt
      catheter. Proteins from the CSF--fibronectin, vitronectin, and fibrinogen--are
      adsorbed to the surface of the catheter immediately after insertion. These
      proteins can interfere with the biological systems of the host and mediate
      staphylococcal adhesion to the surface of the catheter. In the present study, the
      presence of fibronectin, vitronectin, and fibrinogen on CSF shunts and temporary
      ventricular drainage catheters is shown. The presence of fragments of fibrinogen
      is also examined. METHODS: The authors used the following methods: binding
      radiolabeled antibodies to the catheter surface, immunoblotting of catheter
      eluates, and scanning force microscopy of immunogold bound to the catheter
      surface. The immunoblot showed that vitronectin was adsorbed in its native form
      and that fibronectin was degraded into small fragments. Furthermore, the study
      demonstrated that the level of vitronectin in CSF increased in patients with an
      impaired CSF-blood barrier. To study complement activation, an antibody that
      recognizes the neoepitope of activated complement factor C9 was used. The
      presence of activated complement factor C9 was shown on both temporary catheters
      and shunts. CONCLUSIONS: Activation of complement close to the surface of an
      inserted catheter could contribute to the pathogenesis of CSF shunt infection.

PMID- 10413163
TI  - Use of magnetic resonance imaging for in vivo measurements of water content in
      human brain: method and normal values.
AB  - OBJECT: The authors present a quantitative in vivo magnetic resonance (MR)
      imaging method and propose its use for the accurate assessment of brain water in
      humans. METHODS: With this technique, a pure T1-weighted image of a selected
      brain slice in a patient is generated, and the image is subsequently converted to
      a pure water image by means of an equation derived from a tissue relaxation
      model. The image intensity in the resulting water map directly yields absolute
      measures of water expressed in grams of water per gram of tissue at a given
      anatomical location. The method has been validated previously in a series of
      phantom experiments and in an infusion model of brain edema in cats. In this
      report, the authors evaluate the method by using samples of tissue harvested from
      patients who underwent surgery for brain tumor removal and apply the technique to
      a series of normal volunteers, providing average regional brain water content
      (f(w)) values for a range of tissues. Application of the method in pathological
      conditions such as head trauma, tumor, and hydrocephalus allows quantification of
      regional or global increases in f(w) that result from edema. CONCLUSIONS: It is
      now possible to obtain accurate brain water measurements with the anatomical
      resolution of MR imaging. This permits monitoring of the development and
      resolution of edema in a variety of clinical circumstances, thus enhancing
      understanding of the underlying pathophysiological processes.

PMID- 10413164
TI  - Survival and integration of transplanted postmitotic human neurons following
      experimental brain injury in immunocompetent rats.
AB  - OBJECT: Limitations regarding cell homogeneity and survivability do not affect
      neuronlike hNT cells, which are derived from a human teratocarcinoma cell line
      (Ntera2) that differentiates into postmitotic neurons with exposure to retinoic
      acid. Because NT2N neurons survive longer than 1 year after transplantation into
      nude mice brains, the authors grafted these cells into the brains of
      immunocompetent rats following lateral fluid-percussion brain injury to determine
      the long-term survivability of NT2N cell grafts in cortices damaged by traumatic
      brain injury (TBI) and the therapeutic effect of NT2N neurons on cognitive and
      motor deficits. METHODS: Seventy-two adult male Sprague-Dawley rats, each
      weighing between 340 and 370 g, were given an anesthetic agent and subjected to
      lateral fluid percussion brain injury of moderate severity (2.2-2.5 atm in 46
      rats) or to surgery without TBI (shamoperation, 26 rats). Twenty-four hours
      postinjury, 10(5) NT2N cells (24 injured animals) or 3 microl of vehicle (22
      injured and 14 control animals) was stereotactically implanted into the
      periinjured or control cerebral cortex. Motor function was assessed at weekly
      intervals and all animals were killed at 2 or 4 weeks after their posttraumatic
      learning ability was assessed using a Morris water maze paradigm. Viable NT2N
      grafts were routinely observed to extend human neural cell adhesion molecule-(MOC
      1)immunoreactive processes into the periinjured cortex at 2 and 4 weeks
      posttransplantation, although no significant improvement in motor or cognitive
      function was noted. Inflammation identified around the transplant at both time
      points was assessed by immunohistochemical identification of macrophages (ED-1)
      and microglia (isolectin B4). CONCLUSIONS: Long-term survival and integration of
      NT2N cells in the periinjured cortex of immunocompetent rats provides the
      researcher with an important cellular system that can be used to study
      maturation, regulation, and neurite outgrowth of transplanted neurons following
      TBI.

PMID- 10413165
TI  - Growth of precultured human glioma specimens in nude rat brain.
AB  - OBJECT: The aim of this study was to develop an improved animal model for brain
      tumor study. The need for better and more relevant brain tumor models is
      generally acknowledged. Glioma tissue can be cultured directly from the biopsy
      specimen as tumor spheroids. Using such precultured tissue, a new in vivo model
      for studying human gliomas was established. METHODS: Precultured small tumor
      spheroids (< 300 microm) prepared from cell lines or tumor biopsy fragments were
      injected into the brains of immunodeficient rats by using a 5-microl Hamilton
      syringe that had a piston in the needle. Tumors could be established by injecting
      a single spheroid derived from the U-87MG cell line, whereas inoculation of 10
      spheroids resulted in a tumor take comparable to that attained with injection of
      10(6) single cells. Biopsy specimens obtained from six patients who underwent
      surgery for glioblastoma multiforme were cultured as organotypic spheroids for 11
      to 18 days before inoculation into the rats. The animals were killed 3 months
      after spheroid implantation. Microscopic examination revealed tumor growth in
      87.5 to 100% of the animals inoculated with tumor spheroids from all but one of
      the tumor biopsy specimens. Extensive invasion and cell migration along the nerve
      tracts of the corpus callosum was found in tumors that originated from four of
      the six biopsy specimens. CONCLUSIONS: This approach, in which spheroids from
      precultured biopsy specimens are injected into the brains of immunodeficient
      animals, provides new means for experimental studies of human malignant brain
      tumors in a clinically relevant animal model.

PMID- 10413166
TI  - Preliminary observations for a new treatment in children with primary
      intracranial yolk sac tumor or embryonal carcinoma. Report of five cases.
AB  - The authors evaluated the effect of adjuvant therapy (preoperative chemotherapy
      combined with radiotherapy) followed by radical tumor removal in the treatment of
      children with primary intracranial yolk sac tumor, embryonal carcinoma, or mixed
      germ cell tumors containing yolk sac tumor components. Between 1988 and 1995,
      five consecutive patients were treated with adjuvant therapy followed by total
      tumor removal. The diagnosis was based on markedly elevated concentrations of
      serum alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (beta-HCG)
      in four children and the results of biopsy sampling in one child. The
      chemotherapy regimen consisted of cisplatin (20 mg/m2) and etoposide (60 mg/m2)
      daily for 5 days (one course) given three times at 4-weeks intervals.
      Radiotherapy consisted of 30 to 40 Gy to the whole brain or an area including all
      ventricles and a 15- to 20-Gy boost to the tumor site. Spinal radiation of 25 Gy
      was added in one patient. In all patients the serum level of AFP and beta-HCG
      gradually decreased during the adjuvant therapy and disappeared completely on its
      completion. In two of the five patients the tumor disappeared as well. In the
      other three patients the tumor size was moderately or markedly reduced and the
      remaining tumor was totally removed; there were no neurological deficits.
      Chemotherapy was maintained after the initial treatment and was repeated every 2
      to 4 months for less than 2 years. All children are alive and well without
      recurrence at 33 to 118 months (average 88 months) after the start of adjuvant
      therapy. Our preliminary results indicate that adjuvant therapy consisting of
      combination chemotherapy with cisplatin and etoposide and concomitant
      radiotherapy, followed by removal of the tumor, is highly effective in the
      treatment of pediatric patients with primary intracranial yolk sac tumor,
      embryonal carcinoma, or mixed germ cell tumors containing yolk sac tumor
      components.

PMID- 10413168
TI  - Peripheral-type primitive neuroectodermal tumor arising in the tentorium. Case
      report.
AB  - The authors report the case of a peripheral primitive neuroectodermal tumor
      (PNET) arising in the tentorium in a 5-year-old boy who presented with frequent
      vomiting and mild palsy of the left abducent nerve. Following complete surgical
      excision of the tumor via a transpetrosal approach, the patient has thus far been
      disease free for 7 years. The tumor tissue was composed of small cells with
      uniform round nuclei and minimal identifiable cytoplasm. Homer-Wright rosettes
      were frequently observed. Immunohistochemical studies demonstrated a positive
      reaction to HBA-71, which recognizes the cell surface glycoprotein p30/32, a
      product of the MIC2 gene. Both the clinical and immunohistochemical
      characteristics of this tumor are consistent with a diagnosis of peripheral PNET,
      which is genetically distinct from the more common intracranial PNET.

PMID- 10413167
TI  - Intracranial extension of an eccrine porocarcinoma. Case report and review of the
      literature.
AB  - Eccrine porocarcinoma is a rare malignant tumor of the true sweat gland. It
      commonly presents in the lower extremities with lymphatic metastasis. The authors
      describe the clinical presentation, radiographic evidence, operative discoveries,
      and pathological findings in a patient with an eccrine porocarcinoma involving
      the soft tissue of the occiput, which had eroded through the cranium. A review of
      the literature failed to reveal any other such case. The discussion includes the
      epidemiology, pathogenesis, treatment, and outcome of eccrine porocarcinomas. The
      six reported cases of scalp eccrine tumors are reviewed.

PMID- 10413169
TI  - Aseptic meningitis caused by Teflon implantation for microvascular decompression.
      Case report.
AB  - The authors present the case of a 47-year-old man who, after undergoing
      microvascular decompression for trigeminal neuralgia, experienced symptomatic
      pain relief but developed prolonged aseptic meningitis. This case is unusual in
      that the patient remained dependent on steroid medications for nearly 5 months
      following the initial surgery and the aseptic meningitis did not resolve until
      after surgical removal of the Teflon used to pad the trigeminal nerve. The
      pathophysiological characteristics of the body's reaction to implanted Teflon are
      discussed along with the rationale for removing this substance in cases of
      prolonged intractable aseptic meningitis.

PMID- 10413170
TI  - Destructive tophaceous calcium hydroxyapatite tumor of the infratemporal fossa.
      Case report and review of the literature.
AB  - Tophaceous pseudogout is one of the rarest forms of crystal deposition disease,
      typically presenting as a destructive and invasive mass involving the
      temporomandibular joint or the infratemporal fossa region in the absence of any
      other articular manifestations. Previous cases have been assumed to be caused by
      calcium pyrophosphate dihydrate (CPPD) crystal deposition, based on finding
      weakly birefringent crystals in the involved tissues. The authors present the
      unique case of a 65-year-old woman with a destructive and invasive facial mass
      extending to the middle cranial fossa with microscopic and clinical features
      consistent with tophaceous pseudogout. High-resolution x-ray crystallographic
      powder diffraction and Fourier transformed infrared spectroscopy subsequently
      revealed that the crystals were composed of calcium hydroxyapatite without CPPD.
      The patient was later found to have primary hyperparathyroidism and mild
      hypercalcemia. This case demonstrates that tissue deposits of calcium
      hydroxyapatite can cause a destructive and invasive mass containing weakly
      birefringent crystals and raises the question of whether previous cases
      attributed to tophaceous pseudogout resulting from CPPD actually were composed of
      birefringent calcium hydroxyapatite.

PMID- 10413171
TI  - Fatal subarachnoid hemorrhage after endoscopic third ventriculostomy. Case
      report.
AB  - In recent years, endoscopic third ventriculostomy has become a well-established
      procedure for the treatment of various forms of noncommunicating hydrocephalus.
      Endoscopic third ventriculostomy is considered to be an easy and safe procedure.
      Complications have rarely been reported in the literature. The authors present a
      case in which the patient suffered a fatal subarachnoid hemorrhage (SAH) after
      endoscopic third ventriculostomy. This 63-year-old man presented with confusion
      and drowsiness and was admitted in to the hospital in poor general condition.
      Computerized tomography scanning revealed an obstructive hydrocephalus caused by
      a tumor located in the cerebellopontine angle. An endoscopic third
      ventriculostomy was performed with the aid of a Fogarty balloon catheter. Some
      hours postoperatively, the patient became comatose. Computerized tomography
      scanning revealed a severe perimesencephalic-peripontine SAH and progressive
      hydrocephalus. Despite emergency external ventricular drainage, the patient died
      a few hours later. Although endoscopic third ventriculostomy is considered to be
      a simple and safe procedure, one should be aware that severe and sometimes fatal
      complications may occur. To avoid vascular injury, perforation of the floor of
      the third ventricle should be performed in the midline, halfway between the
      infundibular recess and the mammillary bodies, just behind the dorsum sellae.

PMID- 10413172
TI  - Use of a microvascular Doppler probe to avoid basilar artery injury during
      endoscopic third ventriculostomy. Technical note.
AB  - Basilar artery (BA) injury has been reported in a number of cases as a major
      complication of third ventriculostomy for hydrocephalus. This report describes
      the deployment of a pulsed-wave microvascular Doppler probe through the endoscope
      to locate the BA complex and subsequently to select a safe zone for perforation
      of the third ventricular floor. This procedure is quick and easily learned, and
      it is hoped that it can decrease the risk of vascular injury during third
      ventriculostomy.

PMID- 10413173
TI  - Accuracy of true frameless stereotaxy: in vivo measurement and laboratory phantom
      studies. Technical note.
AB  - The authors present the results of accuracy measurements, obtained in both
      laboratory phantom studies and an in vivo assessment, for a technique of
      frameless stereotaxy. An instrument holder was developed to facilitate
      stereotactic guidance and enable introduction of frameless methods to traditional
      frame-based procedures. The accuracy of frameless stereotaxy was assessed for
      images acquired using 0.5-tesla or 1.5-tesla magnetic resonance (MR) imaging or 2
      mm axial, 3-mm axial, or 3-mm helical computerized tomography (CT) scanning. A
      clinical series is reported in which biopsy samples were obtained using a
      frameless stereotactic procedure, and the accuracy of these procedures was
      assessed using postoperative MR images and image fusion. The overall mean error
      of phantom frameless stereotaxy was found to be 1.3 mm (standard deviation [SD]
      0.6 mm). The mean error for CT-directed frameless stereotaxy was 1.1 mm (SD 0.5
      mm) and that for MR image-directed procedures was 1.4 mm (SD 0.7 mm). The CT
      guided frameless stereotaxy was significantly more accurate than MR image
      directed stereotaxy (p = 0.0001). In addition, 2-mm axial CT-guided stereotaxy
      was significantly more accurate than 3-mm axial CT-guided stereotaxy (p = 0.025).
      In the clinical series of 21 frameless stereotactically obtained biopsies, all
      specimens yielded the appropriate diagnosis and no complications ensued. Early
      postoperative MR images were obtained in 16 of these cases and displacement of
      the biopsy site from the intraoperative target was determined by fusion of pre-
      and postoperative image data sets. The mean in vivo linear error of frameless
      stereotactic biopsy sampling was 2.3 mm (SD 1.9 mm). The mean in vivo Euclidean
      error was 4.8 mm (SD 2 mm). The implications of these accuracy measurements and
      of error in stereotaxy are discussed.

PMID- 10413174
TI  - Syringomyelia, hemangioblastomas, and Chiari I malformation. Case illustration.

PMID- 10413175
TI  - Neurohypophyseal germinoma with prolactinoma. Case illustration.

PMID- 10413176
TI  - Primary intracranial leiomyoma. Case illustration.

PMID- 10413177
TI  - Direct brainstem surgery.

PMID- 10413178
TI  - Tethered cord.

PMID- 10413179
TI  - Crusade for microelectrode guidance in pallidotomy.

PMID- 10413180
TI  - Magnetic resonance imaging of cotton.

PMID- 10413181
TI  - Stereotactic biopsy and hemorrhage.

PMID- 10413182
TI  - Stereotactic biopsy and hemorrhage.

PMID- 10413183
TI  - Methods for biological monitoring of propylene oxide exposure in Fischer 344
      rats.
AB  - Propylene oxide (PO) is used as an intermediate in the chemical industry. Human
      exposure to PO may occur in the work place. Propylene, an important industrial
      chemical and a component of, for example, car exhausts and cigarette smoke, is
      another source of PO exposure. Once taken up in the organism, this epoxide
      alkylates macromolecules, such as haemoglobin and DNA. The aim of the present
      investigation was to compare two methods for determination of in vivo dose, the
      steady state concentration of PO in blood of exposed rats and the level of
      haemoglobin adducts. Male Fischer 344 rats were exposed for 4 weeks (6 h/day, 5
      days/week) to PO at a mean atmospheric concentration of 500 ppm (19.9
      micromol/l). Immediately after the last exposure blood was collected in order to
      determine the steady state concentration of PO. Free PO was measured in blood
      samples of three animals by means of a head space method to be 37 +/- 2
      micromol/l blood (mean +/- S.D.). Blood samples were also harvested for the
      measurement of haemoglobin adducts. N-2-Hydroxypropyl adducts with N-terminal
      valine in haemoglobin were quantified using the N-alkyl Edman method with globin
      containing adducts of deuterium-substituted PO as an internal standard and N-D,L
      2-hydroxypropyl-Val-Leu-anilide as a reference compound. Tandem mass spectrometry
      was used for adduct quantification. The adduct levels were < 0.02 and 77.7 +/-
      4.7 nmol/g globin (mean +/- S.D.) in control animals (n = 7) and in exposed
      animals (n = 34), respectively. The adduct levels expected at the end of exposure
      were calculated to be 71.7 +/- 4.1 nmol/g globin (mean +/- S.D.) using the
      measured steady state concentration of PO in blood and taking into account the
      growth of animals, the life span of erythrocytes, the exposure conditions and the
      second order rate constant for adduct formation. The good agreement between the
      estimated and measured adduct levels indicates that both end-points investigated
      are suitable for biological monitoring.

PMID- 10413184
TI  - Are circulating cytokines interleukin-6 and tumor necrosis factor alpha involved
      in chlorpyrifos-induced fever?
AB  - Oral exposure to chlorpyrifos (CHP) in the rat results in an initial hypothermic
      response followed by a delayed fever. Fever from infection is mediated by the
      release of cytokines, including interleukin-6 (IL-6) and tumor necrosis factor
      (TNF alpha). This study determined if the CHP-induced fever involves cytokine
      mediated mechanisms similar to that of infectious fevers. Long-Evans rats were
      gavaged with the corn oil vehicle or CHP (10-50 mg/kg). The rats were euthanized
      and blood collected at various times that corresponded with the hypothermic and
      febrile effects of CHP. Plasma IL-6, TNF alpha, cholinesterase activity (ChE),
      total iron, unsaturated iron binding capacity (UIBC), and zinc were measured. ChE
      activity was reduced by approximately 50% 4 h after CHP. There was no effect of
      CHP on IL-6 when measured during the period of CHP-induced hypothermia or fever.
      TNF alpha levels nearly doubled in female rats 48 h after 25 mg/kg CHP. The
      changes in plasma cytokine levels following CHP were relatively small when
      compared to > 1000-fold increase in IL-6 and > 10-fold rise in TNF alpha
      following lipopolysaccharide (E. coli; 50 microg/kg; i.p.)-induced fever. This
      does not preclude a role of cytokines in CHP-induced fever. Nonetheless, the data
      suggest that the delayed fever from CHP is unique, involving mechanisms other
      than TNF alpha and IL-6 release into the circulation characteristic of infectious
      fevers.

PMID- 10413185
TI  - Lead inhibits meso-2,3-dimercaptosuccinic acid induced calcium transients in
      cultured rhesus monkey kidney cells.
AB  - Previously we have shown that meso-2,3-dimercaptosuccinic acid (DMSA, 15-500
      microM) elicits concentration-dependent increases in intracellular calcium levels
      ([Ca2+]i) in untreated rhesus monkey kidney cells (LLC-MK2) (Pokorski et al.,
      1997, unpublished results). Little is known about the restorative effects of the
      chelating agent 2,3-dimercaptosuccinic acid on intracellular calcium homeostasis
      in the presence of lead. Lead interacts at numerous sites in Ca2+ homeostasis and
      may mimic Ca2+ to interfere with Ca2+-mediated intracellular signaling. To
      examine the effects of lead on [Ca2+]i and DMSA-induced calcium transients, LLC
      MK2 were plated on 35 mm coverslip dishes (10(4) cells/dish) and pre-treated with
      non-cytotoxic concentrations of lead (0-100 microM) for 24 h. Cells were washed,
      loaded with the calcium-sensitive probe Fura-2/AM, rinsed again, and examined in
      loading buffer in the absence of any additional lead. Intracellular calcium was
      measured using a dual-wavelength calcium imaging system. Basal [Ca2+]i levels did
      not change between Pb-exposed (0-50 microM, 24 h) and non-lead exposed cells. In
      cells treated with > or = 10 microM lead for 24 h, the ability of DMSA to elicit
      a calcium response was blocked. These results provide evidence that pre-exposure
      to lead blocks the entry of extracellular calcium into LLC-MK2 cells when
      stimulated by specific calcium mobilizing agents.

PMID- 10413186
TI  - Effect of lowered temperature on the toxicity of sulphur mustard in vitro and in
      vivo.
AB  - Primary cultures of chick embryo neurons were exposed to sulphur mustard (HD) and
      L-nitroarginine methyl ester (L-NAME) and then incubated at either 25 or 37
      degrees C. Lowering the temperature of the cultures decreased the 24-h toxicity
      of HD, but did not increase the efficacy of L-NAME protection. However, the
      length of time post-HD treatment in which L-NAME was maximally effective in
      protecting against HD toxicity was dramatically enhanced, out to 12 h after HD
      exposure. In addition, the persistence of L-NAME protection of the cells against
      HD was significantly lengthened. Tests conducted in human skin keratinocytes also
      showed that lowering the incubation temperature of actively proliferating, just
      confluent or post-confluent cultures significantly and persistently decreased the
      cytotoxicity of HD. The persistence of L-NAME protection was increased in non
      proliferating cells. Finally, cooling of HD-vapour exposed sites on hairless
      guinea pigs for 4.5 h decreased the severity of the resultant lesions out to 72 h
      post-exposure.

PMID- 10413187
TI  - Increased radiation-induced apoptosis in mouse thymus in the absence of
      metallothionein.
AB  - Metallothionein (MT) has been shown to protect cells from free radical induced
      DNA damage after exposure to copper, hydrogen peroxide and also radiation. In
      order to study the role of MT in radiation induced apoptosis, age-matched male
      control mice (C57BL/6J), MT-I overexpressing (MT-I*) and MT-null transgenic mice
      were exposed to whole body cobalt 60 gamma-irradiation at 0, 5, or 10 Gy, and
      their thymus were removed 24 h later. The basal levels of MT and zinc
      concentrations in the thymus were measured by 109Cadmium-heme assay and atomic
      absorption spectrophotometry, respectively. The MT expression after radiation was
      determined by immunohistochemical staining using a polyclonal antibody to MT. The
      extent of apoptosis in thymocytes was determined by histology (H&E stain). DNA
      was isolated from the thymus, and DNA fragmentation was determined by agarose gel
      electrophoresis. The results showed that the basal level of MT protein in MT-I*
      thymus was 2.4-fold higher than control mice, and that MT was inducible in both
      MT-I* and control C57BL6 thymus after radiation exposure. Minimal MT protein was
      detected in MT-null mice thymus before or after radiation, while, a significantly
      higher number of apoptotic cells and DNA fragmentation were found in MT-null
      thymus after whole body irradiation. These data demonstrated a protective role
      for MT in radiation-induced apoptosis in mouse thymus.

PMID- 10413188
TI  - Adriamycin-induced changes of creatine kinase activity in vivo and in
      cardiomyocyte culture.
AB  - Adriamycin (ADM) is an anthracycline anti-neoplastic agent, whose clinical
      effectiveness is limited by severe side effects, including cardiotoxicity. The
      toxic effects of ADM are likely to be the consequence of the generation of free
      radicals. This study demonstrates that ADM induces significant changes in the
      activity of the oxidative sensitive enzyme creatine kinase (CK) in the heart in
      vivo and in a cardiomyocyte culture model. The changes observed are likely to
      reflect the ability of ADM to damage the plasma membrane of cardiac cells and to
      induce the direct inactivation of CK. The role for ADM-derived free radicals is
      one of the possible mechanisms for the CK inactivation observed during the ADM
      treatment.

PMID- 10413189
TI  - Elevated immunoglobulin E (IgE) levels in children with exposure to environmental
      lead.
AB  - Lead has been reported to be an immunosuppressive agent in animal systems at
      levels far below those recognized as overtly toxic. Little data exist on lead's
      effects on the human immune system, especially in young children who are at
      greatest risk for exposure to this environmental hazard. The effects of
      environmental lead exposure on the human immune system were examined in a
      population of young children, age 9 months-6 years, from the urban population of
      Springfield-Greene County, Missouri. Reported here are data from 279 children
      with blood lead levels ranging from 1 to 45 microg/dl. White blood cell
      populations have been enumerated and examined for cell surface expression of
      activation markers. Serum has been analyzed for IgE, specific titers to Rubella
      vaccine, sCD25 (the soluble form of the IL2 receptor), sCD27 (the soluble form of
      the lymphocyte specific member of the tumor necrosis factor receptor family), and
      IL4 (the cytokine interleukin 4). Variation of these assays with age of the child
      was considered in statistical analysis of data. A statistically significant
      relationship of IgE and blood lead level was found in this population; as blood
      lead (PbB) level increases, IgE level increases. No other statistically
      significant differences between risk categories or other associations with blood
      lead level were found. The exact mechanism for this apparent stimulus of IgE
      producing B cells remains to be elucidated. The development of allergic symptoms
      is often preceded by an increase in IgE. These data indicate that ingested lead
      could play a role in this process by stimulating IgE production.

PMID- 10413190
TI  - Persistent suppression of delayed-type hypersensitivity in adult F344 rats after
      perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
AB  - Recently we observed a suppressed delayed-type hypersensitivity (DTH) response to
      bovine serum albumin (BSA) in the 4-5-month-old offspring of F344 rat dams
      receiving as little as 1.0 microg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg
      on gestational day (GD) 14. This study was designed to characterize better this
      suppression of the DTH response. First, the persistence of the DTH suppression
      was determined by measuring the DTH response to BSA in the offspring of dams
      dosed orally with 3.0 microg TCDD/kg on GD14 as well as in age-matched controls
      at 4, 8, 12 and 19 months of age. TCDD significantly suppressed the males' DTH
      response through 19 months of age. While the females' DTH response was reduced at
      8, 12 and 19 months, significant suppression was observed only at 4 months of
      age. Secondly, the lowest maternal dose of TCDD that produced DTH suppression was
      determined by measuring the DTH response to BSA in the 4- and 14-month-old
      offspring of dams dosed orally with 0, 0.1, 0.3 or 1.0 microg TCDD/kg on GD14. In
      the males, suppression was observed at a maternal dose as low as 0.1 microg
      TCDD/kg at 14 months of age, while a maternal dose of 0.3 microg TCDD/kg was
      necessary to cause suppression in the 14-month-old females. Both males and
      females were more sensitive to the suppression at 14 months of age than at 4
      months of age. Lastly, the DTH response to a second antigen was examined by
      measuring the DTH response to either BSA or keyhole limpet hemocyanin (KLH) in
      the 5- or 4-month-old male offspring, respectively, of dams dosed orally with
      either 0 or 3.0 microg TCDD/kg on GD14. The DTH response to both antigens was
      suppressed significantly. Phenotypic analysis was performed on thymus and lymph
      node suspensions. Significant effects in the thymus included an increased
      percentage of gammadelta TCR+ cells and a decreased percentage of gammadelta
      TCR+/CD4- CD8- and MHCI- MHCII- cells. In the popliteal lymph node draining the
      BSA-injected footpad, there was a decreased percentage of gammadelta TCR+ and
      MHCI- MHCII- cells and an increased percentage of MHCI+ cells. In conclusion, the
      suppression of the DTH response associated with perinatal TCDD exposure is
      persistent through late adulthood, occurs at a low dose (i.e. 0.1 microg TCDD/kg)
      to the dam, and is more pronounced in males than females. While phenotypic
      analysis identified differences in subsets of thymocytes and lymph node cells
      between control and TCDD exposed offspring, no clear correlations were
      established between altered subpopulations and suppressed DTH responses.

PMID- 10413191
TI  - Molecular modelling of the human cytochrome P450 isoform CYP2A6 and
      investigations of CYP2A substrate selectivity.
AB  - (1) The generation of a homology model of CYP2A6, the major catalyst of human
      hepatic coumarin 7-hydroxylase activity, involves the use of the recently
      published substrate-bound CYP102 crystal structure as a template. (2) A
      substantial number of structurally diverse CYP2A6 substrates are found to dock
      satisfactorily within the putative active site of the enzyme, leading to the
      formulation of a structural template (or pharmacophore) for CYP2A6
      specificity/selectivity. (3) The CYP2A6 model is consistent with available
      evidence from site-directed mutagenesis studies carried out on CYP2A subfamily
      isoforms, and enables some explanation of species differences in CYP2A-mediated
      metabolism of certain substrates. (4) Quantitative structure-activity
      relationship (QSAR) analysis of CYP2A5 (the mouse orthologue) mutants yields
      statistically significant correlations between various properties of amino acid
      residues and coumarin 7-hydroxylase activity.

PMID- 10413192
TI  - Evaluation of the effect of smokeless tobacco purified products and extracts on
      latent Epstein-Barr virus.
AB  - Numerous chemical tumor promoters induce latent Epstein Barr virus (EBV) to
      active replication. The effect of smokeless tobacco purified products N
      nitrosonornicotine (NNN), 4-(N-methyl-N-nitrosamine)-1-3-pyridinyl)-1-butanone
      (NNK), benzo(a)pyrene (BaP), and smokeless tobacco extracts (dry snuff, moist
      snuff, and loose leaf tobacco) was tested for induction of latent EBV in Raji
      cells using fluorescence-activated cell sorter flow cytometry detection of the
      restricted component of EBV early antigen (EA-R). Concentrations of smokeless
      tobacco purified products or preparations were used that have carcinogenic
      effects in animal cell lines. There was no discernible effect for the 6-7-day
      duration of treatment on viability of Raji cells, or on induction of latent EBV
      in Raji cells. Results were comparable using paraformaldehyde- or acetone-fixed
      cells. There does not appear to be an in vitro effect of smokeless tobacco
      constituents on EBV-infected lymphocytes that may contribute to development of
      oral cancers.

PMID- 10413194
TI  - Use of immunotoxicity data in health risk assessments: uncertainties and research
      to improve the process.
AB  - A number of environmental contaminants can suppress immune responses and enhance
      susceptibility to infectious and/or neoplastic disease. Most of the evidence for
      immunotoxicity of such contaminants has been obtained from laboratory animal
      studies and risk assessors must make decisions about risk to the human population
      based on these studies. Uncertainties associated with this process include
      determining what level of immune suppression is adverse, extrapolating across
      species from rodent to human, and across levels of biologic organization from
      effects on immune function at the cellular level to effects on incidence of
      disease at the population level, accounting for intra-species variability, and
      assessing the relationship between effects following acute, subchronic, and
      chronic exposure. This paper reviews immunotoxicity data that may be applied to
      the development of risk assessment methods and models designed to reduce some of
      these uncertainties.

PMID- 10413193
TI  - Characterization of cadmium-induced apoptosis in rat lung epithelial cells:
      evidence for the participation of oxidant stress.
AB  - The mode of cadmium-induced cell death was investigated in a rat lung epithelial
      cell line. Cells, grown to near confluence, were exposed to 0-30 microM CdCl2 for
      0-72 h. Phase contrast microscopy and fluorescent nuclear staining showed that Cd
      caused morphological alterations in lung epithelial cells that are characteristic
      of apoptosis. These changes included cell shrinkage, detachment of the cell from
      its neighbors, cytoplasmic and chromatin condensation, and fragmentation of the
      nucleus into multiple chromatin bodies surrounded by remnants of the nuclear
      envelope. Apoptotic DNA degradation was validated and quantitated using a
      sensitive enzyme-linked immunosorbent assay (ELISA) which measures the amount of
      histone-bound DNA fragments in the cytosol. Using this technique, a maximum level
      of apoptosis (5-fold higher than control) was observed in cultures exposed for 48
      h to 20 microM CdCl2. The terminal deoxyribonucleotidyl transferase mediated dUTP
      nick end labeling method (TUNEL) was subsequently used to determine the
      percentage of cells that contained Cd-induced DNA strand breaks. After 48 h,
      approximately 54% of the cells exposed to 20 microM Cd were TUNEL positive
      compared to less than 2% for control cells. Although the mechanisms by which Cd
      initiates apoptosis in these cells are presently not known, reactive oxygen
      species are likely to play a role. This possibility is supported by the finding
      that the first morphological features indicative of apoptosis were preceded by
      the up-regulation of oxidant stress genes (glutathione S-transferase-alpha, gamma
      glutamylcysteine synthetase, and metallothionein-1), activation of redox
      sensitive transcription factors (AP-1 and NF-kappaB), and changes in various
      forms of glutathione (reduced, oxidized, and protein-bound).

PMID- 10413195
TI  - Passive smoking and lung cancer in Chandigarh, India.
AB  - The aim of this study is to assess the relationship between exposure to
      environmental tobacco smoke (ETS) and lung cancer in non-smokers, a case-control
      study among lifetime non-smokers was conducted in Chandigarh, India. Cases
      consisted of 58 non-smoking histologically confirmed lung cancer patients; two
      controls for each case were selected, one among other patients admitted to the
      wards and one among the visitors to hospital patients. Subjects were asked about
      ETS exposure from different tobacco products in childhood and in adulthood at
      home, at the work place and in vehicles. Multivariate logistic regression
      analysis was used to assess the effects of the ETS exposure variables on lung
      cancer. Exposure to ETS during childhood was strongly associated with lung cancer
      (odds ratio (OR) = 3.9; 95% confidence interval (CI) = 1.9-8.2), the effect
      mostly arising from exposure to cigarettes smoke. The excess risk was observed
      with either a smoking father or mother. An increasing risk was found with
      increasing number of smokers and duration of exposure. Restricting the analysis
      to women produced higher estimates of the risk. No increased risk was found with
      exposure to a smoking spouse, except for those exposed only to cigarette smoke
      (OR = 5.1; 95% CI = 1.5-17). A weak association was seen between lung cancer and
      ETS exposure at the workplace, which increased with the number of years of
      exposure. Exposure in vehicles also was detected as a risk factor for lung cancer
      in non-smokers. This study suggests that ETS exposure may be a strong risk factor
      for lung cancer also in India, a country with low prevalence of smoking and,
      therefore, low rates of lung cancer. Other studies need to be conducted in
      similar settings to confirm the role played by ETS exposure early in life in the
      causation of lung cancer.

PMID- 10413196
TI  - Gene therapy for lung cancer.
AB  - In the pre-clinical research into the development of gene therapy for cancer,
      different strategies have evolved and shown promising results in the laboratory.
      However, most of these strategies will need further refinement to obtain clinical
      success. This is partly due to the lack of suitable vector systems which
      specifically can deliver the therapeutic gene to the target cells, and ensure
      expression of the therapeutic gene. In this review we will give an introduction
      to different strategies used in cancer gene therapy for neoplasms of the lung,
      and focus on how to target gene delivery to disseminated lung cancer cells. Tumor
      specific gene expression can be accomplished at different levels. One way to
      accomplish targeted gene delivery is by coupling of receptor specific ligands to
      the vector. Specific gene delivery to cells expressing the target receptor will
      occur by receptor mediated endocytosis of the vector. Further restriction of gene
      expression to cancer cells can be accomplished by utilizing promoters
      predominantly active in tumors. When gene therapy is targeted at different
      levels, efficient gene delivery to disseminated cancer cells by systemic vector
      administration will be an attractive future prospect.

PMID- 10413197
TI  - Autocrine growth loops dependent on peptidyl alpha-amidating enzyme as targets
      for novel tumor cell growth inhibitors.
AB  - Many small cell lung tumors are dependent in vitro and in vivo on autocrine
      growth loops. The prototypical small cell lung cancer autocrine growth factor,
      gastrin-releasing peptide (GRP), is one of many peptide hormones which require
      post-translational carboxy-terminal alpha-amidation for bioactivity. We have
      reported that neuroendocrine human lung tumor cell lines express the bifunctional
      enzyme PAM which catalyzes the biosynthesis of alpha-amidated peptides in a two
      step process, and have recently shown that non-small cell lung cancer cell lines
      and tumors, generally considered to be non-endocrine in nature, also express PAM.
      We have also shown that two chemical classes of PAM inhibitors, substrate
      analogues and specific copper chelators, inhibit amidating enzyme activity in
      cell-free extracts. Here we demonstrate in vitro growth inhibition of lung cancer
      tumor cell lines by both these classes of PAM inhibitors using the MTT assay and
      the clonogenic assay. Growth inhibition in a small cell lung cancer cell line can
      be overcome by exogenous addition of synthetic alpha-amidated GRP. Similar growth
      suppressive effects are seen in cell lines stably transfected with a vector
      expressing antisense PAM RNA. These data support the mechanism of inhibition for
      a new type of chemotherapeutic/intervention agent, directed at synthesis and
      activation of peptide growth factors, and support our postulate that alpha
      amidated peptide hormones are a common component in lung tumor autocrine growth
      biology which can be inhibited by targeting the biochemical mechanisms necessary
      for growth factor synthesis.

PMID- 10413198
TI  - Gap junctional communication in cultured human lung carcinoma cells.
AB  - Animal tumor models have demonstrated a close correlation between gap junctional,
      intercellular communication (GJIC) and tumor metastasis. To examine GJIC levels
      in human lung carcinoma cells, a novel technique was developed: cells were grown
      on a glass slide, half of which was coated with electrically conductive,
      optically transparent, indium-tin oxide. An electric pulse which opens transient
      pores on the plasma membrane was applied in the presence of the fluorescent dye,
      Lucifer yellow, causing the dye's penetration into the cells growing on the
      conductive part of the slide. The migration of the dye through gap junctions to
      the non-electroporated cells growing on the non-conductive area was then observed
      microscopically under fluorescence illumination. The results show that this is a
      rapid, precise and highly reproducible assay for GJIC assessment in lines
      established from lung carcinomas or freshly explanted lung tumor cells. Out of 17
      established lines only two had extensive junctional communication, while out of
      16 fresh tumor specimens none displayed GJIC. On the other hand, fibroblasts
      isolated from the same tumors had extensive junctional permeability. The
      examination of GJIC in a large number of samples could establish a correlation
      between GJIC and metastasis which might have prognostic value.

PMID- 10413199
TI  - Chemoradiation for inoperable non small cell lung cancer: a phase II study using
      a regimen with acceptable toxicity.
AB  - Over the past few years there have been numerous schedules of combined modality
      therapy proposed as being useful in the management of inoperable non-small cell
      lung cancer (NSCLC). These have generally involved the use of high dose radiation
      therapy to doses of the order of 60 Gy combined with chemotherapy given prior to
      or concurrently with the radiation. Concurrent chemotherapy has been given with
      the intention of being both active in NSCLC and with the role of being a possible
      radiosensitiser. The most commonly employed drugs have been cisplatin, etoposide,
      5-fluorouracil, vindesine and mitomycin. Although response rates of the primary
      tumour to the combined therapy have been optimistic, there has not been a great
      survival benefit with the median survival in most series remaining at just over
      12 months. In this study we have prospectively treated a group of patients with
      non-metastatic inoperable NSCLC with a regimen of known acceptable toxicity.
      These patients were inoperable because they were unfit for surgery or had locally
      advanced disease. The local radiological response rate was 86% and the median
      survival for the whole group was 13 months. Adenocarcinomas appeared to do
      significantly worse than squamous cell carcinomas. Toxicity was acceptable and
      lower than reported in other similar series. There was one treatment related
      death. We feel that this combination of radiation therapy and chemotherapy is a
      reasonable compromise for a disease which still has a very poor outlook.

PMID- 10413200
TI  - Evolving spectrum of mortality and morbidity in SLE.

PMID- 10413201
TI  - Intense immunosuppression and stem cell transplantation or rescue for severe
      systemic lupus erythematosus.

PMID- 10413202
TI  - The pulmonary-renal syndrome: a poorly understood clinicopathologic condition.
AB  - The co-existence of pulmonary hemorrhage and glomerulonephritis delineates a
      severe syndrome, often underestimated, resulting from several diseases and
      frequently associated with serum positivity for antineutrophil cytoplasmic
      antibodies (ANCA) or antiglomerular basement membrane (GBM) antibodies. The most
      common illness presenting as pulmonary-renal syndrome is systemic vasculitis.
      Moreover, the idiopathic pulmonary-renal syndrome is a distinctive
      clinicopathologic entity with different pathogenetic mechanisms. Tissue
      immunofluorescence studies are fundamental in distinguishing anti-GBM antibody
      mediated forms from immune-complex-mediated and ANCA-associated forms. The type
      of glomerular or alveolar immunologic injury is the main factor determining the
      outcome and thus the prognosis of the pulmonary-renal syndrome. Development and
      improvement of appropriate serologic detection techniques have given reliable and
      early guidance for diagnosing these cases.

PMID- 10413203
TI  - Antiphospholipid (Hughes') syndrome in African-Americans: IgA aCL and abeta2
      glycoprotein-I is the most frequent isotype.
AB  - Antiphospholipid (Hughes') syndrome (APS) has not been reported in African
      Americans (A-A) as frequently as in other ethnic groups. We describe eight A-A
      female patients with APS, including two cases of primary APS (PAPS), four with
      APS secondary to systemic lupus erythematosus (SLE), one with Sjogren's syndrome,
      and one with overlap connective tissue disease (CTD). Their mean age was 34 y
      (range 24-47 y). Patients were followed for a mean of 6 y (range 0.3-11 y).
      During follow up, both anticardiolipin (aCL) and anti-beta2glycoprotein-I
      (abeta2GPI) antibodies were measured in stored sera by enzyme-linked
      immunosorbent assay (ELISA). IgA was the most frequent isotype of aCL and
      abeta2GPI, and co-occurred with the IgM isotype in three of four patients with
      neurologic manifestations.

PMID- 10413205
TI  - Immunological abnormalities in primary APS evolving into SLE: 6 years follow-up
      in women with repeated pregnancy loss.
AB  - We have performed a prospective study to determine the prevalence of
      immunological abnormalities and the evolution from primary antiphospholipid
      syndrome (APS) into systemic lupus erythematosus (SLE) in women who had had
      unexplained repeated pregnancy loss (PL) and APS. Of 105 women with abortions or
      fetal deaths, 33(31%) fulfilled criteria for APS. Among these patients with
      primary APS, 24% had antinuclear antibodies (ANA), 91% had elevated circulating
      immune complexes (CIC), 70% had low total haemolytic complement (CH100), 52% had
      low levels of complement 4 (C4) and 30% had low levels of complement 3 (C3), in a
      significantly higher prevalence than women whose pregnancies were successful
      (control group). Through out a 6 y follow-up, 3 (9%) of the patients with APS who
      had autoimmune related abnormalities when entered into the study developed
      features of lupus like disease (LLD) or fullblown SLE. Our findings suggest that
      women with unexplained repeated PL with APS who presented with positive ANA, high
      levels of CIC, low levels of CH100, C3 and C4, may define a subset of patients
      exhibiting immunological alterations similar to those of SLE. These parameters
      may help in the assessment of prognosis in APS patients with PL. Those patients
      should be carefully surveyed with regard to the development of connective tissue
      diseases.

PMID- 10413204
TI  - Seasonal variations in activity of systemic lupus erythematosus in a subarctic
      region.
AB  - Photosensitivity is one of the major clinical features of Systemic Lupus
      Erythematosus (SLE), and is considered to be implicated in the disease
      pathogenesis. We studied seasonal variations of SLE disease activity at latitude
      70 degrees North where there is no sunlight in the winter time, in contrast to 24
      h daily sunlight in the summer (midnight sun). The associations between the level
      of plasma melatonin in June and December with disease manifestations were also
      studied. Twenty-one SLE patients were examined each month for 1 y, and disease
      activity was assessed by laboratory parameters as well as clinical disease
      activity parameters SLEDAI and doctor's global assessment. Melatonin levels were
      quantified by a RIA-assay. There was no significant change of clinical measures
      or laboratory parameters of disease activity from one month to the next during
      the one year, except photosensitive rashes. January was the only month without
      SLE-flares or arthritis, in contrast to rest of the year. The levels of plasma
      melatonin were highest in December for seven patients and highest in June for one
      patient (P < 0.005). Plasma melatonin levels did not correlate with measures of
      clinical disease activity. At a latitude of 70 degrees North there were no major
      seasonal variations in SLE disease activity during the one year. There was an
      accumulation of photosensitivity in the summer months, but no indications of
      worsening of the disease in the winter months. In contrast to the rest of the
      year, there was no flare in January which had only 5.6 h of sunshine. The level
      of p-melatonin did not correlate with measures of disease activity.

PMID- 10413206
TI  - Clinical and immunological manifestations in 134 Puerto Rican patients with
      systemic lupus erythematosus.
AB  - To gain a better understanding of systemic lupus erythematosus (SLE) in Puerto
      Ricans we studied the clinical and serologic manifestations in a cohort of 134
      patients. The female to male ratio was 18:1. Mean age at diagnosis was 32 +/- 12
      y. The mean duration of disease and follow-up were 7.4 +/- 6.0 and 5.8 +/- 6.0
      years respectively. Mortality was 3%. Photosensitivity (76.9%) and malar rash
      (71.9%) were the most common clinical manifestations. Arthritis was observed in
      67.5% of patients. Anemia was seen in 67.2% of patients, but only 12.7% had
      autoimmune hemolytic anemia. Leukopenia (41.8%) and lymphopenia (64.9%) were also
      common. Serositis was observed in only 28%. Severe kidney damage such as
      nephrotic syndrome (14.2%) or renal failure (4%) was infrequent. Cardiovascular
      (12.7%) and neurologic (9.0%) manifestations were also uncommon. Antinuclear
      antibodies (ANA) were detected in 93.3%, anti-dsDNA antibodies in 54.5%, anti-Ro
      antibodies in 30.1% and anti-La antibodies in 14.2%. Low C3 and low C4 were
      observed in 38.3% and 35.7% respectively. This study suggests that Puerto Ricans
      with SLE present a mild form of disease predominantly manifested by cutaneous,
      musculoskeletal and hematologic involvement, but low prevalence of major organ
      damage and low mortality.

PMID- 10413207
TI  - Immunological and clinical differences between juvenile and adult onset of
      systemic lupus erythematosus.
AB  - INTRODUCTION: Systemic lupus erythematosus (SLE) in children usually follows a
      more severe course than in adults, but sometimes in the previous studies reported
      there are many confounding factors. OBJECTIVE: To analyse the immunological and
      clinical characteristics of SLE juvenile onset and SLE adult onset. METHODS: We
      studied 179 patients with SLE, 49 patients were aged 6-18 yrs at onset of
      disease. Anti-dsDNA antibodies were detected by radioimmunoassay and antibodies
      to extractable nuclear antigens (ENA): anti-nRNP, anti-Sm, anti-Ro/SS-A and anti
      La/SS-B antibodies by ELISA, counterimmuno-electrophoresis and immunoblotting.
      RESULTS: Juvenile-onset SLE shows a higher frequency of cutaneous vasculitis
      (44.8% vs 27.6%; P < 0.05), seizures (18.3% vs 7.6%; P < 0.05) nephropathy (67.3%
      vs 48.4%; P < 0.025), and discoid lupus erythematosus (26.5% vs 13.8%; P < 0.05).
      The incidence of articular manifestations is lower than in adults (85.7% vs
      96.1%; P < 0.025). No significant differences were found between the two groups
      in relation with the prevalence of antinuclear antibodies. CONCLUSIONS: Juvenile
      onset SLE has more frequent neurological and renal manifestations than adult
      onset SLE, but immunological markers are similar in both groups. These features
      suggest the most severe clinical manifestations in the juvenile-onset SLE group
      are not related with the presence of studied antibodies by different methods.

PMID- 10413208
TI  - Impaired cytotoxic T lymphocyte activity in systemic lupus erythematosus
      following in vitro polyclonal T cell stimulation: a contributory role for non-T
      cells.
AB  - To determine whether non-T cells contribute to impaired generation of
      nonrestricted cytotoxic T lymphocyte (CTL) activity in human SLE, peripheral
      blood mononuclear cells (PBMC) and sort-purified T cells from normal subjects and
      SLE patients were stimulated with anti-CD3 mAb, maintained in IL2, and assayed
      for cytolytic activity against 51Cr-labeled Daudi target cells. In addition, T
      cell and non-T cell fractions were isolated from nine pairs of monozygotic (MZ)
      twins discordant for SLE, reconstituted in a criss-cross pattern, and stimulated
      and assayed for cytolytic activity. Cytolytic responses were significantly lower
      in SLE PBMC cultures than in normal PBMC cultures. Addition of SLE serum to
      normal PBMC cultures did not inhibit generation of normal cytolytic responses,
      and neither 'resting' SLE PBMC prior to stimulation nor addition of neutralizing
      anti-IL10 mAb or costimulating anti-CD28 mAb restored generation of SLE cytolytic
      responses to normal. Nevertheless, despite the significantly greater cytolytic
      responses in normal PBMC cultures than in SLE PBMC cultures, cytolytic responses
      in normal purified T cell cultures were only modestly and insignificantly greater
      than those in SLE purified T cell cultures. Moreover, substitution of 'healthy'
      non-T cells for SLE non-T cells in four of the nine MZ twin-pairs appreciably
      enhanced cytolytic responses, and substitution of SLE non-T cells for 'healthy'
      non-T cells in five of the seven twin-pairs tested appreciably diminished
      cytolytic responses. Taken together, these results indicate that, in addition to
      any inherent SLE T cell abnormalities, impaired function of SLE non-T cells
      contributes to impaired generation of nonrestricted CTL activity.

PMID- 10413209
TI  - C1q inhibits autoantibody binding to calreticulin.
AB  - Calreticulin (CR) is a new rheumatic disease-associated autoantigen that is
      intimately associated with the Ro/SS-A ribonucleoprotein. CR autoantibodies are
      frequently observed in patients with photosensitive forms of lupus erythematosus
      (LE). CR has been shown to be highly homologous to cC1q-R, the cell surface
      receptor that binds the collagenous domain of the first component of complement,
      C1q. C1q has also been shown to directly bind to CR. We therefore asked whether
      the binding of C1q to CR might interfere with the binding of CR autoantibody to
      CR. Full-length recombinant human CR, an E. coli fusion proteins was used as
      antigen in a direct enzyme-linked immunosorbent assay (ELISA). CR autoantibody
      containing sera were assayed before and after C1q removal by two different
      methods: by heating sera at 56 degrees C for 30 min or adding monoclonal anti-C1q
      antibodies. ELISA optical density (OD) values were found to be consistently
      higher in sera depleted of C1q by both methods compared to unmodified sera. The
      addition of purified C1q to C1q-depleted sera resulted in ELISA OD values similar
      to those of unmodified sera. These results suggest that C1q levels present in
      human serum can inhibit the binding of CR autoantibody to CR. One can speculate
      that the failure of C1q to mask CR autoepitopes in individuals with genetic
      deficiency of C1q could contribute to the high rate of photosensitive LE that
      occurs in such individuals.

PMID- 10413210
TI  - Human Fc gamma receptor IIA (FcgammaRIIA) genotyping and association with
      systemic lupus erythematosus (SLE) in Chinese and Malays in Malaysia.
AB  - SLE is an autoimmune and polygenic disorder characterized by an accumulation and
      deposition of immune complexes. Several studies have indicated differential
      impact of FcgammaR polymorphism genotypes in different ethnic groups studied. The
      Fc receptor for IgG class IIA gene (FcgammaRIIA) occurs in two allelic forms. The
      allele FcgammaRIIA-H131 encodes a receptor with a histidine at the 131 amino acid
      position; the other allele FcgammaRIIA-R131 encodes an arginine. This
      polymorphism is believed to determine the affinity of the receptor for hIgG2 in
      immune complexes. FcgammaRIIA-H131 has a higher capacity for hIgG2 compared to
      FcgammaRIIA-R131 as measured by in vitro studies of insoluble immune complex
      clearance. We have investigated the polymorphism for FcgammaRIIA using a novel
      polymerase chain reaction-allele specific primer (PCR-ASP) method designed
      specifically to distinguish the two allelic forms. Our studies were based on 175
      Chinese and 50 Malays SLE patients as well as 108 and 50 ethnically matched
      healthy controls for the respective groups. Analysis of the data (chi2 test with
      Yates correction factors and odds ratios) revealed that there were no significant
      differences between SLE patients and controls. We have not found evidence of a
      protective effect conferred by FcgammaRIIA-H131 in the ethnic groups studied.

PMID- 10413211
TI  - CD4 TCRBV CDR3 analysis in prevalent SLE cases from two ethnic groups.
AB  - We examined CD4+ T cell TCRBV-CDR3 transcripts from 19 lupus patients and 16
      controls to test the hypothesis that CD4+ TCRBV-CDR3 expression in SLE differs
      from normals. Within the disease group we also performed exploratory analyses to
      determine the association between risk of oligoclonality and HLA-DRB
      specificities and the duration of the CDR3 patterns. Oligoclonal patterns
      consistent with CDR3 restriction were three times more likely in SLE than in
      controls (OR = 3.7). TCRBV1, BV4, BV5.1, BV7, BV9, BV18 and BV22 gene segment
      CDR3 patterns of oligoclonality were seen exclusively among lupus patients. HLA
      DRB3 increased the risk of oligoclonal expression in SLE. In four patients
      studied over time, the pattern of TCRBV-CDR3 expression was stable in a second
      sample obtained 6-14 months later. The increased frequency of CD4+ T cell TCRBV
      CDR3 oligoclonal expression in SLE when compared to controls and the persistence
      of these patterns are consistent with an expanded pool of autoreactive CD4 T
      cells in SLE which recognize peptides derived from autoantigens. The association
      of HLA-DRB3 genes with increased risk of CDR3 oligoclonality among the SLE
      subjects is compatible with the hypothesis that molecules encoded by HLA-DRB3 may
      facilitate autoantigen recognition by CD4 T cells.

PMID- 10413212
TI  - Control of severe systemic lupus erythematosus after high-dose immunusuppressive
      therapy and transplantation of CD34+ purified autologous stem cells from
      peripheral blood.
AB  - A 35 y old woman with severe and progressive systemic lupus erythematosus (SLE)
      received high-dose chemotherapy followed by a T cell depleted autologous stem
      cell transplantation. Peripheral blood stem cell were mobilised with
      Cyclophosphamide 4.5 g/m2 followed by Granulocyte-Colony Stimulating Factor (G
      CSF). A CD34 positive selection provided a 3 log T cell depletion. High-dose
      immunosuppression consisted of the BEAM regimen. The purified autograft was
      reinfused on day 0. In the post transplant period, hemopoietic growth factors, G
      CSF, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and
      Erythropoietin, were administered, engraftment was rapid. Both the mobilisation
      and the transplant procedures were easily performed and well tolerated. One year
      later, the patient is in clinical remission. The ANA and anti-SSA-antibodies were
      undetectable at 1 and 6 months after intensification, but reappeared at low
      levels at 9 months. Corticosteroid requirement has gradually decreased. In
      conclusion, we report here the favourable evolution of a patient with a severe
      SLE, who clinically improved with high-dose immunosuppressive therapy and
      autologous stem cell transplantation, and showed a 9 month serological remission.

PMID- 10413214
TI  - Pulmonary hypertension secondary to systemic lupus erythematosus: prolonged
      survival following treatment with intermittent low dose iloprost.
AB  - Pulmonary hypertension (PHT) associated with systemic lupus erythematosus (SLE)
      has a dismal prognosis. Vasodilators and immunosuppressive therapy have been
      tried over the years with discouraging results. Prostacyclin (PGI2) which has
      potent vasodilatatory and anti-platelet effects has been demonstrated to
      significantly decrease pulmonary arterial pressure and pulmonary vascular
      resistance during acute infusion. Satisfactory response has been reported in SLE
      patients with PHT treated with short-term intravenous continuous PGI2 infusion.
      We report here a 48-month experience of the use of monthly low dose infusion of a
      PGI2 analogue, iloprost, in a SLE patient with pulmonary hypertension in New York
      Heart Association functional Class III. There was an initial haemodynamic
      response to an acute infusion of iloprost. Repeated infusions were followed by
      marked improvement in her functional status and her mean pulmonary arterial
      pressure dropped from 80 mmHg in the first few months and remained static at
      around 55 mmHg for the subsequent years.

PMID- 10413213
TI  - Treatment of chronic bilateral pleural effusions with intravenous immunoglobulin
      and cyclosporin.
AB  - A 48 y old woman with unremarkable medical history was admitted with bilateral
      pleural effusions; even though the fluid was drained, it re-accumulated and
      necessitated many repeated drainages in the following 2.5 y (56
      hospitalisations). The patient underwent an extensive diagnostic work-up that
      disclosed elevated serum antinuclear antibodies, serum anti-dsDNA antibodies,
      pleural fluid anti-dsDNA and decreased pleural fluid C3 and C4. During that
      period she has been treated with a variety of immunomodulating agents, several
      pleural talcage and pleurectomy, without any apparent response. Thereafter, she
      received six courses of IVIg (2 g/kg body weight) in monthly intervals, followed
      by four months treatment with cyclosporin. This treatment resulted in gradual and
      eventually complete disappearance of the pleural effusion, and now after more
      than 2 y the patient is free of symptoms and receives no further medications.

PMID- 10413215
TI  - How long does it take to describe 25 SLE antigen/antibody systems?

PMID- 10413216
TI  - Fibromyalgia in Spanish patients with systemic lupus erythematosus.

PMID- 10413217
TI  - Biochemical assessment of pregnancy performance in the second trimester.

PMID- 10413218
TI  - Large lipoma of the vulva.
AB  - Vulvar lipoma is a rare entity. A 52-year-old woman presented with a large mass
      arising in the right major labium. CT scan revealed that the mass contained
      adipose tissue. During operation a lipomatous tumor was found which at histologic
      examination proved to be a lipoma.

PMID- 10413219
TI  - Comparison of the modified Pereyra procedure using permanent suture material and
      Burch urethropexy.
AB  - OBJECTIVE: To evaluate the results of the modified Pereyra procedure, using
      permanent suture, and Burch urethropexy. STUDY DESIGN: In 49 women undergoing
      modified Pereyra procedure and 48 women undergoing Burch urethropexy between
      January 1990 and January 1996 results were evaluated using questionnaire based
      outcomes analysis. RESULTS: Follow up of all women undergoing needle suspension
      and Burch urethropexy showed that patient satisfaction was achieved in 86% and
      81% respectively. Complete cure was achieved in 65% and 63% respectively.
      CONCLUSIONS: Patient satisfaction in both procedures appeared not totally
      dependent on the presence or absence of complete cure. The study supports the
      hypothesis that the modified Pereyra needle suspension using permanent suture is
      well suited for the treatment of uncomplicated stress urinary incontinence, when
      compared to Burch urethropexy after a follow up of 1 to 6 years. The results
      support the impression that permanent suture should be used in the modified
      Pereyra procedure.

PMID- 10413220
TI  - How useful is the Chlamydia micro-immunofluorescence (MIF) test for the
      gynaecologist?
AB  - Three patients with a chlamydial respiratory tract infection showed significant
      titre rises for the three chlamydial micro-immunofluorescence tests, performed
      with Chlamydia pneumoniae, C. psittaci and C. trachomatis. Such cross-reactions
      procure an inaccurate discrimination between the various Chlamydia species which
      remains speculative anyhow when only a positive serological profile against one
      chlamydial subspecies is performed. We consider that using the serologic assay as
      proof for past sexually transmitted C. trachomatis infection falls outside the
      limits of prudent interpretation of laboratory tests.

PMID- 10413221
TI  - Immediate breast reconstruction with deepidermalized transverse rectus abdominis
      musculocutaneous flap after skin-sparing mastectomy.
AB  - Use of the transverse rectus abdominis musculocutaneous (TRAM) flap for breast
      reconstruction is widely accepted and indications have been well-defined over the
      past years. More recently, the moratorium prohibiting pre-filled silicone gel
      implants both in esthetic surgery and in reconstruction breast surgery, has
      incited more and more patients to refuse prostheses, even saline filled implants.
      Total mastectomy with skin-sparing technique, beyond the limitations dictated by
      oncology factors which must be taken into account because of the risk of local
      recurrence, raises the question of immediate breast reconstruction since
      implants, when possible, may give unsatisfactory results either more or less
      short-term. The deepidermalized TRAM flap is an interesting alternative for
      selected patients, especially those with an adapted abdominal morphology,
      allowing stable and natural autologous breast reconstruction.

PMID- 10413222
TI  - What predisposes young women to genital prolapse?
AB  - OBJECTIVE: To determine the predictive factors for genital prolapse. STUDY
      DESIGN: We studied 85 young (< or = 45 year old) women who had been operated on
      for genital prolapse. The control group consisted of women of the same age
      operated on for benign ovarian tumor. RESULTS: In the study group the number of
      deliveries was higher and the babies were heavier than in the control group.
      However, the study group had not had more instrumental deliveries. In addition,
      the women with prolapses more often had operations of abdominal hernias and also
      had more chronic pulmonary disease, e.g. asthma. The incidence of preterm
      delivery was the same in the women with genital prolapse as in the controls.
      Familial incidence of genital prolapse was about 30%. CONCLUSION: Our study
      confirms that there are both acquired and congenital factors that predispose
      women to genital prolapse.

PMID- 10413223
TI  - Prognostic factors in ductal carcinoma in situ of the breast: results of a
      retrospective study of 575 cases. The Association for Research in Oncologic
      Gynecology.
AB  - OBJECTIVE: Conservative treatment for ductal carcinoma in situ of the breast
      exposes patients to the risk of infiltrating recurrence which can lead to
      metastasis. The primary purposes of this retrospective study were to evaluate
      diagnostic and therapeutic methods over a 10-year period and to validate
      prognostic factors. This information should greatly improve patient selection for
      conservative treatment or mastectomy. STUDY DESIGN: A multi-institutional data
      base including 575 patients treated between 1983 and 1993 was established by
      combining data from 16 French institutions. Survival at 5 and 7 years was studied
      as a function of various prognostic factors. RESULTS: Recurrence-free survival at
      7 years was 0.96 after modified radical mastectomy and 0.83 after breast
      conserving treatment and radiotherapy (P=0.003). Metastasis-free survival at 7
      years was 0.99 after modified radical mastectomy and 0.94 after breast-conserving
      treatment and radiotherapy (not significant). No factor was predictive of local
      recurrence after mastectomy. Clinical stage was the only factor significantly
      correlated with metastasis after mastectomy. Recurrence-free survival after
      breast-conserving treatment with radiotherapy was significantly lower for
      patients with comedo carcinoma, multifocal lesions, or unclear resection margins,
      regardless of whether the histological type was comedo or non-comedo carcinoma.
      Metastasis-free survival was significantly lower for patients with multifocal
      lesions and for patients with unclear margins after excision of comedo carcinoma.
      CONCLUSIONS: Breast-conserving treatment with radiotherapy is a valid alternative
      to mastectomy. Patients must be selected carefully on the basis of morphological
      criteria. Swift gains in therapeutic outcome can be obtained by stressing quality
      control at each stage of diagnosis and treatment.

PMID- 10413224
TI  - Revisiting the epidemiological standard of preeclampsia: primigravidity or
      primipaternity?
AB  - Pregnancy-induced hypertensive disorders, and especially preeclampsia, are
      documented to occur primarily in first pregnancies and rarely in subsequent
      pregnancies. Therefore, the concept of primigravidity is the epidemiological
      cornerstone of this disease. The authors propose a concept in which preeclampsia
      is a disease of new couples, especially after a short period of sexual
      cohabitation, and explore if this alternative primipaternity model, as compared
      with the primigravidity concept, provides a better fit with well-known
      epidemiologic descriptions. First, the primipaternity model provides a
      mathematical modelling which may explain the prevalence of approximately 10% in
      long-term monogamic populations. Further, it proposes explanations for many
      epidemiological descriptions which were previously difficult to understand and
      assemble in a single concept.

PMID- 10413225
TI  - Ten years of experience in periconceptional care.
AB  - OBJECTIVES: To describe the methods of the periconceptional care, consisting of
      counselling, examinations and medical intervention in Hungary. The term
      periconceptional is used instead of preconceptional because early
      postconceptional period is also involved to this service. METHODS: A model was
      developed based on three steps: check-up of reproductive health (i.e.
      preconceptional screening), the 3-month preparation for conception, and better
      protection in early pregnancy for the most sensitive early development of embryo
      for voluntary and eligible couples. Data of 8837 female and 7600 male
      participants from the coordinating centre of the Hungarian periconceptional care
      between 1 February 1984 and 31 January 1994 are summarized. Mean maternal age was
      25.8+/-3.4 years, 84 and 60% of female participants were primiparae, and had high
      education (> or = 13 classes), respectively. RESULTS: It was possible to
      establish periconceptional care performed and/or supervised by qualified nurses.
      Participants with positive family history, case history and where genitourinary
      infections were detected, had a more effective flow towards secondary care.
      Infertile couples were diagnosed and treated sooner. The periconceptional care is
      effective for the introduction of periconceptional folic acid/multivitamin
      supplementation and for the reduction of smoking and alcohol consumption in
      females in the preconceptional period. The rate of major congenital abnormalities
      (20.6/1000) was significantly lower than expected (35/1000). CONCLUSIONS:
      Periconceptional care is feasible and has many benefits. Thus, proper preparation
      for conception is the earliest and probably the most important method of health
      promotion in general, particularly for the prevention of congenital
      abnormalities.

PMID- 10413226
TI  - Pre-term delivery by Caesarean section 'en caul': a case series.
AB  - Twenty-four pre-term infants (24-32 weeks) were delivered by Caesarean section
      'en caul', i.e. with the membranes left intact until the whole pregnancy sac had
      been delivered. Seventeen survived to discharge from hospital (29% mortality, 26%
      after exclusion of lethal congenital abnormality). Three babies had a cord
      haemoglobin below 15 g/dl at delivery and 11 required blood transfusion. None had
      any other recognisable cause for the anaemia. Although en caul delivery has
      obvious theoretical advantages, the danger of causing fetal blood loss is real
      and should be evaluated in a randomised controlled trial before widespread
      application.

PMID- 10413227
TI  - Patent foramen ovale as a potential cause of paradoxical embolism in the
      postpartum period.
AB  - We report a case of previously healthy woman who suffered cerebral embolism after
      delivery. Echocardiography with contrast medium confirmed the patent foramen
      ovale (PFO). PFO may be a mechanism of paradoxical embolism causing a transient
      ischemic attack or stroke.

PMID- 10413228
TI  - Neurofibromatosis in pregnancy. Maternal and perinatal outcome.
AB  - OBJECTIVE: The aim of this study was to assess the maternal and perinatal outcome
      in pregnant patients with neurofibromatosis (NF). STUDY DESIGN: During the period
      between January 1994 and December 1996 eight women with NF were delivered at the
      Soroka University Medical Center. Maternal age, parity, gravidy and ethnic origin
      were matched with a control group that included 65 healthy parturients out of a
      total of 31,642 deliveries that occurred in our institution during this period.
      Maternal outcome and perinatal complications were compared between the two
      groups. RESULTS: The prevalence of NF during the study period was 1:2434
      deliveries. The mean gestational age at delivery was significantly lower in the
      study group as compared to the control group, 36.8+/-3.3 vs. 39.2+/-1.5 weeks,
      respectively (P=0.029). The rate of intrauterine growth restriction was
      significantly higher in the study group, (46.2% vs. 8.95%, respectively,
      P=0.0005), as well as stillbirth rate (23% vs. 1.5%, respectively, P=0.011) and
      cesarean section rate (38.5% vs. 7.7%, respectively, P=0.01). CONCLUSION:
      Patients with NF have an increased risk of perinatal complications. Thus, close
      antenatal observation at high risk tertiary centers is required.

PMID- 10413229
TI  - Defective antioxidant mechanisms via changes in serum ceruloplasmin and total
      iron binding capacity of serum in women with pre-eclampsia.
AB  - OBJECTIVES: The aim of this study was to investigate the role of serum
      ceruloplasmin, its ferroxidase activity and total iron binding capacity in women
      with pre-eclampsia. METHODS: Thirty primigravidas between 32 and 36 weeks of
      gestation were studied. The subjects were divided into two groups: group A
      consisted of 15 normal pregnancies with a mean gestational age of 33.9 weeks, and
      group B consisted of 15 pre-eclamptics with a mean gestational age of 32.8 weeks.
      RESULTS: The pre-eclamptics presented significantly higher serum ceruloplasmin
      levels compared to those with normal pregnancies (P<0.01), while the mean
      ferroxidase activity levels of ceruloplasmin did not differ significantly between
      the two groups (450.13+/-110.88 and 467.26+/-135.35 micromol/l/min in groups A
      and B, respectively). The mean+/-S.D. serum iron level (104.48+/-39.81 microg/dl)
      was greater whereas the total iron binding capacity (55.59+/-8.47 micromol/l) was
      lower in women with preeclampsia when compared to normal pregnancies (P<0.01 and
      P<0.0001 respectively). CONCLUSIONS: Our results indicate that the plasma of pre
      eclamptic women shows a loss of ferroxidase activity of ceruloplasmin as well as
      a reduction of total iron binding capacity. Thus, it seems that the plasma of pre
      eclamptic women lacks the protective anti-oxidative action of these substances.

PMID- 10413231
TI  - Vesicouterine fistula after manual removal of placenta in a woman with previous
      cesarean section.
AB  - Vesicouterine fistula is one of the less common acquired urogenital fistula and a
      rare event in obstetrics. We report a case which occurred after a vaginal
      delivery followed by manual removal of placenta in a woman who had a previous
      cesarean section. The fistula was successfully repaired 5 weeks after delivery.

PMID- 10413230
TI  - Failure to demonstrate postpartum functional iron deficiency using quantitative
      red blood cell analysis.
AB  - OBJECTIVE: The aim of this prospective study was to assess erythropoiesis and
      test for functional iron deficiency in the postpartum period using quantitative
      red blood cell analysis. STUDY DESIGN: Parameters were determined on admission
      for delivery and postpartum from 82 obstetric patients at Zurich University
      Hospital: full blood count, hypochromic and microcytic red cells, reticulocyte
      count (including subsets), reticulocyte mean corpuscular volume, reticulocyte
      mean hemoglobin content and reticulocyte mean corpuscular hemoglobin
      concentration. RESULTS: Microcytic cells increased from 0.9% prepartum to 1.4% on
      day 42 postpartum; hypochromic cells decreased from 4.3 to 1.9%; reticulocyte
      mean corpuscular volume decreased from 134 to 125 fl; reticulocyte mean
      hemoglobin content was unchanged. CONCLUSION: To our knowledge, this is the first
      medium scale application of quantitative red blood cell analysis to normal pre-
      and postpartum women. Our data show no evidence of functional iron deficiency or
      increased erythropoiesis in the postpartum period.

PMID- 10413232
TI  - Hypermobility and peripartum pelvic pain syndrome in pregnant South African
      women.
AB  - OBJECTIVE: To determine the incidence and correlation of joint hypermobility (HM)
      and peripartum pelvic pain (PPPP) in an homogeneous pregnant South African
      population. STUDY DESIGN: A cross-sectional study among Cape Coloured pregnant
      women. Joint mobility was measured by Beighton score; PPPP with a specially
      developed PPPP score. RESULTS: Using the Beighton scores with a cut-off point of
      HM > or = 5/9, only 4.9% of the 509 pregnant women were hypermobile.
      Hyperextension of the elbow was the largest contributor to HM (35.4%). No
      correlation of HM with the incidence of PPPP was established. Only 20 very mild
      cases of PPPP were recorded. Back pain increased significantly during pregnancy
      to a mean of 38%. Right handedness occurred in 95.9%. No significant relation was
      found between HM and the non-dominant side. CONCLUSION: Hypermobility in pregnant
      Cape Coloured women was surprisingly low (4.9%) with a decrease with age, but no
      increase during pregnancy. Peripartum pelvic pain is virtually absent and has no
      correlation with joint laxity. Back pain increased during pregnancy to a mean of
      38%. Right handedness was high (96%) in comparison with the world-wide figure of
      85%. No correlation was found between the dominant body side and hypermobility.

PMID- 10413233
TI  - Cervical ripening after treatment with prostaglandin E2 or antiprogestin (RU486).
      Possible mechanisms in relation to gonadal steroids.
AB  - OBJECTIVE: To compare the mechanisms for cervical ripening after treatment with
      prostaglandin E2 or antiprogestin (RU486) to spontaneous cervical ripening, with
      focus on gonadal steroid receptors. STUDY DESIGN: Cervical biopsies were obtained
      from postpartal women after treatment with prostaglandin E2 (n=10), or
      antiprogestin (n=5). Postpartal women after spontaneous cervical ripening (n=10)
      served as controls. Levels of estrogen and progesterone receptors, their mRNAs,
      insulin-like growth factor I mRNA and serum estradiol and progesterone were
      quantitated. The collagen concentration and solubility by pepsin were determined.
      Statistical tests used were Kruskal-Wallis and Mann-Whitney U test. RESULTS:
      After prostaglandin E2 treatment the collagen concentration was higher (P<0.05)
      as compared to spontaneous ripening. After antiprogestin treatment the estrogen
      receptor concentration was higher (P<0.05) in comparison to spontaneous ripening.
      CONCLUSION: The elevated estrogen receptor concentration after antiprogestin
      treatment, in contrast to spontaneous ripening, and prostaglandin E2 treatment,
      indicates a that a receptor-mediated progesterone withdrawal does not explain the
      events behind spontaneous cervical ripening at parturition.

PMID- 10413234
TI  - Chest wall resection for local recurrence of breast cancer. Presented at the 99th
      Meeting of the Royal Belgium Society of Obstetrics and Gynecology, Brussels May
      9th 1998, Belgium.
AB  - We present three cases of chest wall resection for locally recurrent breast
      cancer and a Medline review of the current literature. In selected cases full
      thickness resection of the chest wall may be used as a salvage procedure to
      improve the quality of life and prolong the survival at low morbidity and
      mortality.

PMID- 10413235
TI  - Leptin administration to lactating rats is unable to induce changes in lipid
      metabolism in white adipose tissue or mammary gland.
AB  - During lactation in the rat, despite hyperphagia, there are no changes in either
      the plasma levels or the gene expression of leptin. Removal of the litter,
      however, results in an important increase in the circulating concentration of
      leptin. Administration of leptin to lactating rats resulted in no changes in the
      in vivo lipogenic rate and lipoprotein lipase (LPL) activity in either adipose
      tissue or mammary gland, although there was an increase in insulin levels as a
      consequence of leptin administration. Conversely, litter removal resulted in an
      important decrease of LPL activity and lipogenic rate in the mammary gland while
      an increase in these parameters took place in adipose tissue. It is concluded
      that leptin is not the signal responsible for the changes in lipid metabolism
      that take place both in adipose tissue and mammary gland following litter
      removal.

PMID- 10413236
TI  - Successful intrauterine term pregnancy after resection of corneal pregnancy.
AB  - A woman with previous bilateral salpingectomia, including wedge-formed corneal
      resection, became heterotopic pregnant after in-vitro-fertilization. Ultrasound
      revealed a twin corneal pregnancy and an intrauterine pregnancy. Undergoing
      laparotomy, the uterine corner with the ectopic pregnancy was resected. The
      intrauterine pregnancy proceeded uncomplicated. She delivered a healthy girl, at
      38 weeks of gestation.

PMID- 10413237
TI  - Intrauterine resuscitation by rapid urinary bladder instillation in a case of
      occult prolapse of an excessively long umbilical cord.
AB  - Occult umbilical cord prolapse is a dramatic obstetrical emergency jeopardizing
      health and life of the fetus. Distending the maternal urinary bladder provides
      alleviation of pressure on the cord by reducing uterine contractions and by
      maintaining fetal structures elevated in order to protect the fetus from asphyxia
      until Cesarean delivery.

PMID- 10413238
TI  - Survival of cornual (interstitial) pregnancy.
AB  - We report a case of a singleton cornual (interstitial) pregnancy following
      spontaneous conception in a primigravida with no risk factors for ectopic
      pregnancy. She presented at 30 weeks gestation with haemoperitoneum, due to a
      small rupture on the posterior surface of the cornual pregnancy. At laparotomy,
      an incision was made in the cornu, the baby was delivered and survived after
      spending 39 days in a special care baby unit.

PMID- 10413239
TI  - Multiple pregnancies in women after renal transplantation. Case report that rises
      a management dilemma.
AB  - OBJECTIVES: To report the pregnancy outcome in women with multiple pregnancies
      after renal transplantation. MATERIALS AND METHODS: We report two cases of
      multiple pregnancies (triplets and twins) in renal allograft recipients and
      evaluate the pregnancy courses and maternal and fetal outcome of these patients.
      RESULTS: After fetal reduction from triplet to twin pregnancy the first patient
      delivered healthy twin babies at 36 weeks gestation. Six months after delivery
      the woman is well with no signs of renal function impairment. Although the second
      patient did not meet the optimal criteria for consideration of pregnancy in renal
      transplant recipients, she delivered normal twin babies at 33 weeks' gestation.
      Maternal complications during pregnancy included preeclampsia, mild deterioration
      of renal function tests, and secondary complications due to drug therapy that was
      resolved after delivery. No graft rejection episodes were noted in either case
      during pregnancy. CONCLUSIONS: Multifetal gestation in renal allograft recipients
      represents a high-risk pregnancy that should be managed at a tertiary care
      institution. The overall outcome in properly consulted patients can be considered
      favorable. Based on our limited experience with two cases, we suggest reduction
      of triplets to a twin pregnancy which is consistent with the current literature
      data.

PMID- 10413240
TI  - Acute onset of blindness during labor: report of a case of transient cortical
      blindness in association with HELLP syndrome.
AB  - The coincidence of HELLP syndrome and cortical blindness is an uncommon but very
      dramatic event, for the patient as well as the obstetrician. This report
      describes the first case of HELLP-syndrome-associated cortical blindness occuring
      suddenly in the third stage of labour. There were only modest correlates of
      cortical blindness in cerebral CT, MRI and angiography findings, but no signs of
      a posterior leucoencephalopathy syndrome. Mother and baby were discharged from
      hospital to outpatient care in good health on the 12th day.

PMID- 10413241
TI  - Hemodynamic abnormalities in sodium monofluoroacetate intoxication.
AB  - Hypotension is one of the most important predictors of mortality in sodium
      monofluoroacetate (SMFA) intoxication. This paper reports the hemodynamic
      response in one fatal and another survival case of SMFA intoxication. Despite
      correction of hypovolemia and with inotropic support, the patients remained in
      shock. Hemodynamic observations have provided evidence that shock after SMFA
      intoxication is due to diminished systemic vascular resistance and increased
      cardiac output. This is the first report in which such an invasive hemodynamic
      investigation has been recorded in a clinical case of SMFA intoxication.

PMID- 10413242
TI  - Production of reactive oxygen species by man-made vitreous fibres in human
      polymorphonuclear leukocytes.
AB  - Human polymorphonuclear leukocytes (PMNL) or erythrocytes, isolated from human
      blood, were exposed to graded doses of asbestos (chrysotile), quartz, or man-made
      vitreous fibres (MMVF), i.e. refractory ceramic fibres (RCF), glasswool, or
      rockwool fibres. None of the MMVF affected either the viability of PMNL, as
      measured by trypan blue exclusion test, or induced haemolysis, whereas the
      positive controls, quartz and chrysotile, dose-dependently induced haemolysis in
      PMNL. MMVF did not increase the release of lactate dehydrogenase (LDH) from the
      PMNL, whereas the positive controls, chrysotile and quartz, induced a marked and
      dose-dependent release of LDH. When PMNL were exposed to MMVF, some of the fibre
      types slightly increased the levels of free intracellular calcium ([Ca2+]i)
      within the cells in a manner similar to that induced by chrysotile or quartz. All
      MMVF induced a dose-dependent production of reactive oxygen species (ROS) in
      PMNL, with RCF-induced production of ROS being the most marked. Production of ROS
      by MMVF seemed to depend on the availability of extracellular calcium because it
      could be attenuated with a Ca2+ channel blocker, verapamil, or a Ca2+ chelating
      agent, EGTA. Production of ROS may be a common pathway through which PMNL respond
      to MMVF-induced cell activation, but alterations of levels of free intracellular
      Ca2+ do not seem to be an absolute prerequisite for this effect. Fibre length
      seemed not to be an important factor in affecting the ability of MMVF to induce
      ROS production in PMNL. However, the balance between different elements in the
      fibre seemed importantly to affect the biological activity of a fibre.

PMID- 10413243
TI  - An evaluation of the carcinogenic potential of the herbicide alachlor to man.
AB  - Chronic bioassays have revealed that alachlor caused nasal, thyroid, and stomach
      tumours in rats but was not carcinogenic in mice. Significant increases in
      thyroid and stomach tumours were observed only at doses that exceeded the maximum
      tolerated dose (MTD). While nasal tumours were found at doses below the MTD, they
      were small and benign in nature. This publication describes the work undertaken
      by Monsanto to understand the carcinogenic mode of action of alachlor in the rat
      and to investigate the relevance to humans. The genetic toxicity of alachlor has
      been investigated in an extensive battery of in vitro and in vivo test systems.
      In addition, target-specific mutagenicity tests, such as the COMET assay and DNA
      binding in nasal tissue, were carried out to investigate any possible in-situ
      genotoxic action. The weight-of-evidence analysis of all available data clearly
      demonstrates that alachlor exerts its carcinogenicity in the rat by non-genotoxic
      mechanisms. In the rat, alachlor is initially metabolised primarily in the liver
      through the P-450 pathway and by glutathione conjugation. The glutathione
      conjugates and their metabolites undergo enterohepatic circulation with further
      metabolism in the gastrointestinal tract, liver, and then nasal tissue where they
      can be converted to a diethyliminoquinone metabolite (DEIQ). This electrophilic
      species binds to the cysteine moiety of proteins leading to cell damage and
      increased cell turnover. When comparisons of in vitro nasal metabolic capability
      were made, the rat's capacity to form DEIQ from precursor metabolites was 38
      times greater than for the mouse, 30-fold higher than monkey, and 751 times
      greater than that of humans. This data is consistent with the results of studies
      showing in vivo formation of DEIQ-protein adducts in the nasal tissue of rats but
      not mice or monkeys. The lack of DEIQ nasal adducts in mice is consistent with
      the lack of nasal tumours in that species. When the differences between rat and
      humans in the capacity for initial glutathione conjugation by the liver and nasal
      tissue are also taken into account, the rat is found to be even more susceptible
      to DEIQ formation than man. Based on this, it is clear that the potential for
      DEIQ formation and nasal tumour development in humans is negligible. The
      mechanism of stomach tumour formation has been studied in the rat. The results
      demonstrated that the mechanism is threshold-sensitive and involves a combination
      of regenerative cell proliferation and a gastrin-induced tropic effect on
      enterochromaffin-like (ECL) cells and stem cells of the mucosal epithelium. The
      absence of a carcinogenic effect in mice and of any preneoplastic effect in
      monkeys treated with very high doses is indicative ofthe species-specific aspect
      of this mechanism of action. The results of studies on thyroid tumour production
      indicate that alachlor is acting indirectly through the pituitary-thyroid axis by
      increasing the excretion of T4 by enhanced glucuronidation and subsequent biliary
      excretion. The increased excretion reduces plasma T4 levels and a feedback
      mechanism leads to increased synthesis of TSH by the pituitary. Chronic
      stimulation of the follicular epithelium of the thyroid by TSH produces
      hyperplasia and ultimately tumour formation. This non-genotoxic, threshold-based
      mechanism is well established and widely considered to be not relevant to humans.
      In this work, the modes of action for the three types of tumours elicited in the
      rat by alachlor were investigated. All are based on non-genotoxic, threshold
      sensitive processes. From all the data presented it can be concluded that the
      tumours detected in the rat are not relevant to man and that alachlor presents no
      significant cancer risk to humans. This conclusion is supported by the lack of
      mortality and tumours in an epidemiology study of alachlor manufacturing workers.

PMID- 10413244
TI  - The comparative arthropathy of fluoroquinolones in dogs.
AB  - 1. Fluoroquinolone antibiotics are generally only prescribed to paediatric
      patients on compassionate grounds. This is because they are known to cause
      lesions in the cartilage of the major diarthroidal joints in immature
      experimental animals. As dogs are considered to be the most sensitive species, a
      series of studies was performed to compare the potential for grepafloxacin (a new
      fluoroquinolone) to cause arthropathy to that of ofloxacin and ciprofloxacin in
      juvenile (3 month old) beagles. 2. Grepafloxacin was administered once daily to
      male juvenile dogs at dosages of up to 100 mg/kg/day (intravenously), 60
      mg/kg/day (orally) or 30 mg/kg/day (subcutaneously) for 1 week. Blister formation
      was observed on the surface of the joints in one of the three animals treated
      with grepafloxacin intravenously at 100 mg/kg/day. No abnormalities were observed
      at lower dosages or when grepafloxacin was administered orally or subcutaneously,
      regardless of dose. In animals treated with ofloxacin or ciprofloxacin at dosages
      of 10-30 mg/kg/day, blister formation or erosion was observed on the surface of
      joints regardless of dose or route of administration. 3. Histopathological
      examination of the joint surfaces of affected animals revealed the loss of
      cartilaginous matrix and chondrocytes, cavitation within the intermediate zone of
      cartilage accompanied by cartilage fibrillation or chondrocyte clustering, or
      loss of the surface layer which covers the cavitation (or loss of outer wall of
      the cavity). These findings were not present in the absence of grossly observed
      lesions. 4. Absorption following oral administration of grepafloxacin was low.
      Examination of plasma concentrations of drug following intravenous administration
      showed that joint toxicity was seen with ofloxacin and ciprofloxacin at maximum
      concentrations as low as 3.80 and 4.24 mg/l, respectively, while plasma levels of
      grepafloxacin of up to 11.95 mg/l failed to cause such lesions. When the
      concentration of grepafloxacin was 18.69 mg/l a single joint lesion was seen.
      Following subcutaneous administration of grepafloxacin, systemic exposure (area
      under the curve) of approximately 1.5 times that seen in man was not associated
      with joint lesions. However, lesions were noted for ofloxacin and ciprofloxacin
      treated animals at exposures equal to or below those seen in man. Therefore
      grepafloxacin appeared to have a relatively low potential for joint toxicity;
      this was not due to lack of penetration into the synovial fluid.

PMID- 10413245
TI  - Acute airway effects of formaldehyde and ozone in BALB/c mice.
AB  - 1. Concentration and time-effect relationships of formaldehyde and ozone on the
      airways were investigated in BALB/c mice. The effects were obtained by continuous
      monitoring of the respiratory rate, tidal volume, expiratory flow rate, time of
      inspiration, time of expiration, and respiratory patterns. 2. With concentrations
      up to 4 p.p.m., formaldehyde showed mainly sensory irritation effects of the
      upper airways that decrease the respiratory rate from a trigeminal reflex. The no
      effect level (NOEL) was about 0.3 p.p.m. This value is close to the human NOEL,
      which is about 0.08 p.p.m. 3. Ozone caused rapid, shallow breathing in BALB/c
      mice. Later on, the respiratory rate decreased due to another vagal response that
      indicated an incipient lung oedema. The NOEL in mice was about 1 p.p.m. during 30
      min of ozone exposure. No major effect occurs in resting humans at about 0.4
      p.p.m. 4. Thus, the upper airway irritant, formaldehyde, and the deep lung
      irritant, ozone, showed the same types of respiratory effects in humans and in
      BALB/c mice. Also, the sensitivity was nearly identical. Continuous monitoring of
      respiratory effects in BALB/c mice, therefore, may be a valuable method for the
      study of effects of other environmental pollutants, which, however, should be
      confirmed in further studies.

PMID- 10413246
TI  - Karyomegaly of tubular cells as early stage marker of the nephrotoxicity induced
      by ochratoxin A in rats.
AB  - Cases of karyomegaly were described by Sclare and by Mihatch in patients affected
      with tubular-interstitial nephropathy. The Karyomegalic cells showed enlarged
      nuclei with accumulation of genetic material. No aetiology was suggested. Our
      study of rats experimentally intoxicated by ochratoxin A, a well-known
      nephrotoxic compound, indicates the presence of karyomegaly with alteration of
      the tubular tissue. In control animals no karyomegalic cells were detected. These
      observations suggest that karyomegaly with megacytosis may be caused by the
      nephrotoxic ochratoxin A in the kidney. In addition abnormal mitosis together
      with karyomegalic cells were observed at an earlier stage of the intoxication (30
      days) suggesting possible regeneration if the OTA insults are stopped. After 90
      days of treatment, the degeneration increased and only karyomegalic and apoptotic
      like cells were observed indicating that the regeneration no longer occurs and
      that the degeneration becomes irreversible.

PMID- 10413247
TI  - Clinicopathologic and immunogenetic analysis of mucosa-associated lymphoid tissue
      lymphomas arising in conjunctiva.
AB  - PURPOSE: To identify mucosa-associated lymphoid tissue (MALT) type lymphoma in
      conjunctival infiltrates. METHODS: Clinical, histopathologic, immunophenotypic,
      and immunogenotypic studies were performed on 14 patients with conjunctival
      lymphoid infiltrates. Surgical biopsy specimens were subjected to
      histopathologic, immunohistochemical, and gene rearrangement analysis. RESULTS:
      Thirteen of the 14 patients (92.9%) met the diagnostic criteria for MALT
      lymphoma, and the remaining patient showed morphologic features of diffuse, small
      lymphocytic lymphoma. Genotypic analysis confirmed immunoglobulin heavy chain
      gene rearrangement in all of the 12 patients on whom the analysis was performed.
      Two patients with bilateral lesions exhibited identical immunoglobulin
      rearrangement patterns in each pair of lesions. All patients were alive at the
      last follow-up (mean: 39.9 months). Nine of the 14 patients were alive without
      disease, 4 had localized recurrences, and 1 had a residual tumor. CONCLUSIONS:
      These findings indicate that conjunctival lymphoid infiltrates usually have the
      features of MALT lymphoma with genotypic B lymphocytic monoclonality and a
      favorable prognosis.

PMID- 10413248
TI  - Microbiologic analysis of aqueous humor in phacoemulsification.
AB  - PURPOSE: This study was designed as a microbiologic survey of the fluids
      aspirated from the anterior chamber at the end of cataract extraction performed
      by phacoemulsification, and to correlate the contamination rate of the anterior
      chamber to the surgical technique used. METHODS: One hundred and one consecutive
      patients (126 eyes) who underwent cataract extraction by phacoemulsification and
      posterior chamber intraocular lens implantation were included in the study.
      Microscopical examination, culture, and determination of the number of colonies
      were carried out on the bacteria and fungi in the anterior chamber fluids
      aspirated at the end of surgery, before final suture placement. RESULTS: Anterior
      chamber fluids yielded positive cultures in nine specimens (8.14%), six of which
      were identified as coagulase-negative staphylococci. Quantification disclosed
      colony counts ranging between 2-10 and 10-40 per mL. CONCLUSIONS: Preliminary
      results in a small population show that the contamination of the aqueous humor is
      significantly less frequent if the cataract extraction is performed by
      phacoemulsification.

PMID- 10413249
TI  - Effects of aging on fluorescein leakage in the iris and angle in normal subjects.
AB  - PURPOSE: To determine the presence of fluorescein leakage from the iris and angle
      in normal subjects, and how it is affected by aging. METHODS: The subjects were
      92 normal volunteers and patients with senile cataract who ranged in age from 20
      to 93 years and were free from any systemic or ocular diseases. Fluorescein iris
      and angle photography and color iris and angle photography were performed using a
      goniolens and a photo slit lamp. RESULTS: Radial ciliary body vessels were found
      in 22 eyes (24%), radial iris vessels or trabecular vessels in 7 eyes (8%), and
      circular ciliary band vessels were seen in 4 eyes (4%). Goniovessels were found
      in 8 of 30 eyes (27%) of those under 50 years of age. No significant difference
      in the incidence of goniovessels was found between those over and under age 50 (P
      < .01). In the pupillary margin, fluorescein leakage was seen in 1 of 30 eyes
      (3%) in the age group under 50 years, whereas leakage was found in 30 of 62 eyes
      (48%) in the age group over 50 years. In the anterior chamber angle, leakage was
      seen in 4 of 30 eyes (13%) under age 50 years, and in 38 of 62 eyes (61%) over
      age 50 years (P < .05). CONCLUSIONS: These findings suggested that the incidence
      of leakage of fluorescein from the pupillary margin and anterior chamber angle
      tends to increase with age. Thus, when leakage of fluorescein in angle and iris
      is observed, it is important to consider the physiological changes resulting from
      aging.

PMID- 10413250
TI  - Retinal cell death by light damage.
AB  - PURPOSE: To determine the relationship between apoptotic photoreceptor cell death
      and the duration of light exposure. METHODS: Ten-week-old male albino rats
      (Wistar strain) were dark-adapted for 2 days and then exposed to intense light
      for 12 hours, and 1, 2, 3, 7, 14, 21, and 28 days. The presence of apoptosis was
      confirmed by electron microscopy and the terminal deoxynucleotidyl transferase
      (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) method. Differences in the
      apoptotic processes of the photoreceptor cells in the superior, posterior pole,
      and inferior portions of the retina were determined. RESULTS: Photoreceptor cells
      showed TUNEL-positive staining, whereas the cells in the inner nuclear layer,
      ganglion cell layer and retinal pigment epithelia exhibited weak positive or
      negative TUNEL staining. By electron microscopy, photoreceptor cells showed
      typical apoptotic nuclear changes and formation of apoptotic bodies. CONCLUSIONS:
      The sensitivity to light damage and style of death differed among retinal cells
      by location and cell type.

PMID- 10413251
TI  - Relationship between age and the thickness of the retinal nerve fiber layer in
      normal subjects.
AB  - PURPOSE: To determine it there are any age-dependent changes in the thickness of
      the retinal nerve fiber layer (RNFL) in the peripapillary area. METHODS: Sixty
      normal volunteers (31 men, 29 women) (120 eyes) whose ages ranged from 23-75
      years (mean 48.4 years) participated in this study. The thickness of the RNFL was
      determined using a scanning laser polarimeter along the peripapillary area with a
      1.75 disc diameter and along another ring 0.8 mm away from the disc margin.
      RESULTS: The thickness of the RNFL was not significantly correlated with age in
      either of the two ring areas. However, the RNFL thickness ratio of total/nasal
      area decreased significantly with increase in age in both rings. There was an
      increase in the difference of RNFL thickness between the right and left eyes of
      the same individual with aging, in both rings. CONCLUSIONS: It was suggested that
      the RNFL thickness determined along both rings demonstrated almost identically
      the relationship between age and RNFL thickness in normal subjects.

PMID- 10413252
TI  - Real-time blood velocity measurements in human retinal vein using the laser
      speckle phenomenon.
AB  - PURPOSE: To measure the in vivo blood velocity in human retinal veins using a
      laser speckle system. METHODS: The system consists of a fundus camera, a diode
      laser, an image sensor, and a personal computer system. The fundus area,
      including a target retinal vein, is illuminated with a diode laser through a
      fundus camera and the laser speckle pattern is imaged onto the area sensor. From
      the time change of the contrast of the speckle pattern, the normalized blur (NB)
      value, a quantitative index of blood velocity, was calculated using a logic
      board. RESULTS: In an in vitro experiment, the NB obtained from blood flow in 50
      300 microm internal diameter glass capillary tubes, used as an analogue of a
      retinal vein, correlated with the diameter of the tube, the actual blood flow
      rate, and the background NB value, which was used as an analogue of choroidal
      circulation. In the in vivo experiment, the blood velocity in human retinal veins
      of approximately 50 microm in diameter was estimated in 16 normal human eyes
      using nomograms based on the result of the in vitro experiment. Velocity averaged
      11.1+/-0.6 mm/s (mean +/- SD, n = 16) in retinal veins 53+/-6 microm in diameter.
      The coefficient of reproducibility of 5-minute interval measurements was 2.5+/
      0.9%, and it took 63+/-15 seconds for one measurement. CONCLUSIONS: The present
      methodology is clinically valid for measuring blood velocity in retinal veins.

PMID- 10413253
TI  - Exclusive homoplasmic 11778 mutation in mitochondrial DNA of Chinese patients
      with Leber's hereditary optic neuropathy.
AB  - PURPOSE: To investigate the degree of heteroplasmy of the 11778 mtDNA mutation in
      Chinese patients with Leber's hereditary optic neuropathy (LHON). METHODS:
      Seventeen Chinese Leber's pedigrees, including 24 patients, 17 unaffected
      maternal lineages, 4 internal controls, and 6 unrelated controls, were screened
      for the 11778 mtDNA mutation. This was carried out by analysis of the restriction
      fragment length polymorphism, single-strand conformation polymorphism, and DNA
      sequencing. RESULTS: All patients and unaffected maternal lineages, regardless of
      their symptoms, had homoplastic 11778 mtDNA mutation, which was revealed by
      restriction fragment length polymorphism analysis and single-strand conformation
      polymorphism analysis. CONCLUSION: Exclusive homoplasmy of the 11778 mtDNA
      mutation in Chinese LHON patients was found in this study. Homoplasmy of the
      11778 mtDNA mutation cannot account for the variation in the clinical phenotype
      of Chinese Leber's patients.

PMID- 10413255
TI  - Histopathological findings in proliferative membrane from a patient with sarcoid
      uveitis.
AB  - BACKGROUND: Sarcoid uveitis is occasionally accompanied by proliferative changes,
      such as retinal neovascularization and vitreous hemorrhage. Steroid
      administration, retinal photocoagulation, and vitrectomy may be indicated in such
      proliferative cases. CASE: A 19-year-old woman presented with proliferative
      sarcoid uveitis accompanied by recurrent vitreous hemorrhage. OBSERVATIONS: At
      the initial examination, bilateral vitreous opacity, retinal exudates, mild
      vitreous hemorrhage, retinal vasculitis, and neovascularization of the retina and
      optic disc were observed. Although prednisolone was administered and panretinal
      photocoagulation was performed several times, recurrent vitreous hemorrhage
      continued. Since the vitreous hemorrhage was not absorbed, pars plana vitrectomy
      and lensectomy were performed. After surgery, neovascularization and intraocular
      inflammation decreased, and the corrected visual acuity in the right eye improved
      to 20/50. Histopathologic analysis of the proliferative membrane removed during
      surgery revealed substantial neovascularization and numerous neutrophils in the
      vessels. CONCLUSIONS: Based on these findings, an inflammatory reaction as well
      as retinal ischemia were thought to be involved in the proliferative changes in
      this patient.

PMID- 10413256
TI  - Central retinal vein occlusion during remission of ulcerative colitis.
AB  - BACKGROUND: Retinal vascular disease is a rare complication of ulcerative
      colitis. CASE: We report a patient who developed unilateral nonischemic central
      retinal vein occlusion (CRVO) (papillophlebitis) without any other retinal
      vascular disease during remission of ulcerative colitis. OBSERVATIONS: The best
      corrected visual acuities were 1.5 OD and 0.7 OS. Dilated and tortuous retinal
      veins and retinal bleeding were seen in the left eye. Macular edema and leakage
      from the papilla and the retinal veins of the left eye were evident on
      fluorescein angiography. After increased dosage of systemic prednisolone was
      prescribed, the retinal vascular changes resulting from CRVO (papillophlebitis)
      in the left eye gradually abated. CONCLUSIONS: Retinal vascular diseases should
      be monitored during both remission and activation of intestinal symptoms of
      ulcerative colitis.

PMID- 10413254
TI  - Enlargement of the globe with ocular malformations in c-Myc transgenic mice.
AB  - PURPOSE: To study the ocular development in transgenic mice carrying the mouse c
      myc gene under the control of the Mx gene promoter (Mx-c-myc). METHODS:
      Transgenic mice were generated by standard techniques. For histological studies,
      the tissues were fixed with 10% buffered formalin, embedded in paraffin according
      to the standard procedure and sliced in 4-microm sections. c-Myc expression was
      investigated by reverse transcriptase-polymerase chain reaction and Southern blot
      analysis. RESULTS: A line of the Mx-c-myc mice displayed progressive enlargement
      of the globe with other ocular malformations. Histologically, the enlarged eyes
      exhibited closed cornea-iris angle, microphakia, corneal epithelial disorders,
      and attenuation of the inner retinal layers. Developmental analysis of eyes from
      these Mx-c-myc mice revealed irregular development of the iris and ciliary body
      at embryonic day 15.5 and the closed angle at 1 week of age. Leaky exogenous c
      myc expression was detected in cornea, iris, lens, and retina from the Mx-c-myc
      mice by reverse transcriptase-polymerase chain reaction and Southern blot
      analysis. No other developmental abnormalities were observed in the Mx-c-myc
      mice. The anterior segment of the enlarged eyes showed the closed angle with
      elongation of the iris and ciliary body. There was no attenuation in the outer
      retinal layers from the outer plexiform layer to the retinal pigment epithelium.
      CONCLUSIONS: We conclude that the buphthalmos and accompanying changes were not
      due to expression of the exogenous c-myc in cornea and retina but may be the
      secondary changes of elevated intraocular pressure. We suggest that Mx-c-myc mice
      can serve as a useful model for investigating the development of the anterior
      segment and the genesis of buphthalmos.

PMID- 10413257
TI  - Long-term visual outcome in proliferative diabetic retinopathy patients after
      panretinal photocoagulation.
AB  - BACKGROUND: There is the need for a long-term study on the visual outcome of
      panretinal photocoagulation (PRP) for proliferative diabetic retinopathy (PDR)
      patients. CASES: We retrospectively reviewed the clinical course and visual
      results in 66 eyes of 59 patients with PDR who were followed-up for at least 10
      years after argon or krypton laser PRP. OBSERVATIONS: Thirty-nine eyes had stage
      B-II, whereas 8 eyes had stage B-III retinopathy. Stage B-IV and B-V retinopathy
      were seen in 15 and 4 eyes, respectively. Although active stages of diabetic
      retinopathy were encountered after 5 years, complete regression could be
      successfully attained after 10 years. Long-term visual prospects were promising
      for eyes with stage B-II DR; 28.2% still enjoyed 20/40 or better visual acuity by
      5 years. Most cases had maintained the same visual acuity at 10 years. Eyes with
      stage B-III DR did not attain 20/40 vision by 10 years. Panretinal
      photocoagulation in cases with neovascularization of the optic nerve head was
      seen to be beneficial but limited, suggesting that such cases might benefit from
      maximal initial and supplemental PRP followed by vitrectomy and intraoperative
      endophotocoagulation when necessary. Although 20% of the eyes with stage B-IV and
      25% of the eyes with stage B-V DR had 20/40 or better visual acuity, analyses of
      the visual change revealed that about half the eyes with stage B-IV and all eyes
      with stage B-V DR experienced a visual loss of two lines or more. CONCLUSIONS:
      Progression of lens opacities, chronic macular edema, vitreous hemorrhage,
      macular traction, and neovascular glaucoma were the main causes of visual loss in
      this series. Panretinal photocoagulation for PDR provides good anatomical and
      visual outcome for 10 years or longer.

PMID- 10413258
TI  - Changes in optic disc parameters after intraocular pressure reduction in adult
      glaucoma patients.
AB  - PURPOSE: To quantitatively evaluate the change in the optic disc topographic
      parameters associated with reduction in the intraocular pressure (IOP) after
      trabeculectomy in adult patients with glaucoma. METHODS: A series of 22 patients
      (mean age: 45.7+/-15.1 years) with several types of glaucoma were examined for
      various parameters of optic disc before and after trabeculectomy. Cup area, cup
      to-disc area ratio, cup volume, rim volume, mean cup depth, and maximum cup depth
      were determined by means of laser scanning tomography (LST), and the parameters
      were correlated with the degree of postsurgical IOP decrease. RESULTS: The IOP in
      adult glaucoma patients showed significant reductions after trabeculectomy. The
      values for all topographic parameters examined. except cup volume, showed
      statistically significant postsurgical changes as compared to the presurgical
      values. Of all postsurgical changes in parameters. the increase in the rim volume
      was the most noticeable; it was remarkably evident in those eyes with
      postsurgical IOP levels less than 15 mm Hg. It was also demonstrated that the
      anterior displacement of the glaucomatous cupping may occur after surgery.
      CONCLUSIONS: It is obvious that optic disc parameters can change after IOP
      reduction after successful surgery in adult glaucoma patients as well as in
      infantile glaucoma patients. The site of changeable glaucomatous optic cupping is
      topographically variable among patients and it may be related to the presurgical
      shape of the optic cup.

PMID- 10413259
TI  - Complications associated with vortex vein damage in scleral buckling surgery for
      rhegmatogenous retinal detachment.
AB  - PURPOSE: To further understand postoperative complications after vortex vein
      damage during scleral buckling surgery. METHODS: The records of 34 patients (34
      eyes) with vortex vein damage during scleral buckling surgery for rhegmatogenous
      retinal detachment were reviewed and compared with the records of 410 eyes
      undergoing similar surgery without vortex vein damage. RESULTS: Postoperative
      complications were noted in 16 eyes (47%) of the damaged vortex vein group. The
      incidence of choroidal detachment, vitreous opacities, intraocular pressure
      elevation, and vitreous hemorrhage were 27%, 18%, 9%, and 6%, respectively, with
      a higher incidence than in the group without vortex vein damage. Other
      complications included development of epiretinal membrane (9%), subretinal
      hemorrhage (3%), and anterior segment ischemia (3%). Serous choroidal detachment
      occurred in the early postoperative days and subsided within 3 weeks. Vitreous
      opacification became marked in the later periods and continued for 2 months or
      longer. The incidence of postoperative choroidal detachment in the vortex vein
      damage group was related to the patient's age (P = .002) and the cutting of the
      vortex veins (P = .048), but was not related to preoperative conditions of
      retinal detachment or the number of vortex veins damaged. All the eyes except one
      achieved retinal reattachment after initial surgery. CONCLUSIONS: Choroidal
      detachment and vitreous opacity are common after scleral buckling surgery with
      vortex vein damage. Although intervention of the vortex veins during scleral
      buckling surgery is acceptable when performing otherwise difficult to achieve
      ample scleral indentation, it should be minimized to avoid increased incidence of
      postoperative complications.

PMID- 10413260
TI  - Ocular injury caused by an air bag for a driver wearing eyeglasses.
AB  - BACKGROUND: Although air bags have been shown to reduce the number of fatalities
      and serious injuries caused by motor vehicle accidents, there have been many
      reports of air bag-related ocular injuries. We recently treated air bag-related
      corneal laceration in a patient wearing eyeglasses at the time of a motor
      accident. CASE: A 38-year-old Japanese man was driving a car at approximately 40
      km per hour when he struck a stopped 2-ton truck. He was wearing a three-point
      lap-shoulder seat belt. At impact, the driver's-side air bag deployed and struck
      the man on the left side of his face. He was wearing eyeglasses with glass
      lenses, and the air bag broke the left lens of his eyeglasses, and glass
      fragments lacerated his cornea. OBSERVATIONS: External examination showed
      multiple superficial abrasions of the skin and ecchymosis of the left side of his
      face. Slit-lamp examination of his left eye showed corneal laceration and
      hyphema. The lens had opacities and was covered with fibrin membrane. Repair of
      the corneal laceration and phacoemulsification of the lens were performed. Six
      months later, his best corrected visual acuity was 20/20 in the left eye.
      CONCLUSIONS: As cars are increasingly equipped with air bags, reports of air bag
      related eye injuries have increased. To our knowledge, this is the first reported
      case of corneal laceration caused by a shattered lens in an air bag-related
      injury. Ophthalmologists should caution patients about the danger of eye injuries
      in air bag-equipped cars, and thought should be given to improving the materials
      for eyeglasses.

PMID- 10413261
TI  - Seasonal allergic conjunctivitis induced by Japanese pear pollen.
AB  - PURPOSE: To evaluate the ocular findings in patients with Japanese pear (Pyrus
      pyrifolia Nakai) pollinosis. METHODS: Twenty-two farmers working on artificial
      pollination in Japanese pear orchards were examined for ocular itching,
      conjunctival conditions, presence of eosinophils in the conjunctival specimen,
      and nasal symptoms. Serum IgE antibody to Japanese pear pollen was determined in
      16 farmers. RESULTS: Of the 22 subjects, 3 (Nos. 3, 4, and 13) exhibited ocular
      itching, conjunctival hyperemia, eosinophils in the conjunctival specimen, and
      positive serum IgE antibodies to Japanese pear pollen. In these patients, the
      conjunctivitis disappeared after treatment with topical cromoglycate. CONCLUSION:
      The present study demonstrated that seasonal allergic conjunctivitis may be
      induced by Japanese pear pollen (entomophilous flower pollen).

PMID- 10413262
TI  - The effects of cognitive and somatic anxiety and self-confidence on components of
      performance during competition.
AB  - This study considered the influence of competitive anxiety and self-confidence
      state responses upon components of performance. Basketball players (n = 12) were
      trained to self-report their cognitive anxiety, somatic anxiety and self
      confidence as a single response on several occasions immediately before going on
      court to play. Performance was video-recorded and aspects of performance that
      could be characterized as requiring either largely anaerobic power (height
      jumped) or working memory (successful passes and assists) were measured. Intra
      individual performance scores were computed from these measures and the data from
      seven matches were subjected to regression analyses and then hierarchical
      regression analyses. The results indicated that, as anticipated, somatic anxiety
      positively predicted performance that involved anaerobic demands. Self
      confidence, and not cognitive anxiety, was the main predictor of performance
      scores with working memory demands. It would appear that different competitive
      state responses exert differential effects upon aspects of actual performance.
      Identifying these differences will be valuable in recommending intervention
      strategies designed to facilitate performance.

PMID- 10413263
TI  - Decision training: the effects of complex instruction, variable practice and
      reduced delayed feedback on the acquisition and transfer of a motor skill.
AB  - Novice, intermediate and advanced baseball hitters followed a 7-week training
      programme, in which they received either behavioural training or decision
      training. Participants in the behavioural training group received simple-to
      complex instruction, variable practice and an abundance of feedback throughout
      the acquisition period; the decision training group received complex instruction,
      variable practice and reduced delayed feedback. As predicted, the intermediate
      and advanced hitters who received decision training hit at a lower level (%)
      during acquisition but at a higher level during a transfer test in week 7.
      Novices in the behavioural training group were better than novices in the
      decision training group over both acquisition and transfer trials.

PMID- 10413264
TI  - The effect of exercise and diet on mental health and quality of life in middle
      aged individuals with elevated risk factors for cardiovascular disease.
AB  - Mental health and quality of life were assessed before and after a one-year
      exercise and diet intervention among 219 healthy individuals, aged 41-50 years,
      with elevated risk factors for cardiovascular disease. The participants were
      randomized to four groups: diet (n = 55), diet and exercise (n = 67), exercise (n
      = 54) and no active intervention (n = 43). Quality of life was measured with one
      eight-item scale and two one-item scales. Mental health was measured by the
      General Health Questionnaire (30-item version). Depression, anxiety, feelings of
      competence and self-esteem, coping and social dysfunction were measured using
      subscales of the General Health Questionnaire. Somatic anxiety was measured by
      the anxiety subscale of the Symptom Check List-90. Exercise improved the total
      GHQ scores, perceived competence/self-esteem, and coping as measured by the GHQ
      subscales. There were no significant effects of diet or exercise on quality of
      life, depression or anxiety. A high rate of participation in the exercise
      programme (>70%) was associated with greater improvements in total GHQ scores,
      anxiety, perceived competence/self-esteem and coping.

PMID- 10413265
TI  - The effect of tennis racket string vibration dampers on racket handle vibrations
      and discomfort following impacts.
AB  - In this study, we evaluated the effect of the use of tennis racket string
      vibration dampers on racket handle vibrations, and perceptions of hand and arm
      discomfort experienced by tennis players owing to stationary racket impacts.
      Twenty tennis players (10 males, 10 females) aged 18-29 years volunteered for the
      study. Two different racket models were impacted at the geometric centre of the
      racket face and 100 mm distal to the centre both with and without string
      vibration dampers in place. The participants could neither see nor hear the
      impacts, and they indicated their discomfort immediately after each impact using
      a visual analogue scale. An analysis of variance (2 x 2 x 2 factorial) was
      performed on the scaled discomfort ratings with the factors damping condition,
      racket type and impact location. No significant differences in discomfort ratings
      between damped and undamped impacts or between the two racket types were found.
      Also, central impacts were found to be more comfortable than impacts 100 mm
      distal to the centre (P< 0.05). There were no significant interaction effects.
      Vibration traces from an accelerometer mounted on the racket handle revealed that
      string vibration dampers quickly absorbed high-frequency string vibration without
      attenuating the lower-frequency frame vibration. In conclusion, we found no
      evidence to support the contention that string vibration dampers reduce hand and
      arm impact discomfort.

PMID- 10413266
TI  - Muscular soreness following prolonged intermittent high-intensity shuttle
      running.
AB  - The aim of this study was to examine the impact of prolonged intermittent high
      intensity shuttle running on soreness and markers of muscle damage. Sixteen males
      took part in the study, half of whom were assigned to a running group and half to
      a resting control group. The exercise protocol involved 90 min of intermittent
      shuttle running and walking (Loughborough Intermittent Shuttle Test: LIST),
      reflecting the activity pattern found in multiple-sprint sports such as soccer.
      Immediately after exercise, there was a significant increase (P < 0.05) in serum
      activities of creatine kinase and aspartate aminotransferase, and values remained
      above baseline for 48 h (P < 0.05). Median peak activities of creatine kinase and
      aspartate aminotransferase occurred 24 h post-exercise and were 774 and 43 U x l(
      1), respectively. The intensity of general muscle soreness, and in the specific
      muscles investigated, was greater than baseline for 72 h after the shuttle test
      (P < 0.05), peaking 24-48 h post-exercise (P < 0.05). Muscle soreness was not
      correlated with either creatine kinase or aspartate aminotransferase activity.
      Soreness was most frequently reported in the hamstrings. Neither soreness nor
      serum enzyme activity changed in the controls over the 4 day observation period.
      It appears that unaccustomed performance of prolonged intermittent shuttle
      running produces a significant increase in both soreness and markers of muscle
      damage.

PMID- 10413267
TI  - Indirect evidence of human skeletal muscle damage and collagen breakdown after
      eccentric muscle actions.
AB  - Indirect markers of muscle damage and collagen breakdown were recorded for up to
      9 days after a bout of concentric, followed by a bout of eccentric, muscle
      actions. Nine untrained participants performed two bouts of 50 maximum effort
      repetitions on an isokinetic dynamometer (angular velocity 1.05 rad x s(-1),
      range of motion 1.75 rad). An initial concentric bout of muscle actions was
      followed by an eccentric bout 21 days later, using the same knee extensors.
      Concentric actions induced no changes in maximum voluntary isometric contraction
      force (MVC), nor induced any changes in the serum enzyme activities of creatine
      kinase, a lactate dehydrogenase isoenzyme (LDH-1), or alkaline phosphatase.
      Similarly, concentric actions induced no change in markers of collagen breakdown,
      namely plasma hydroxyproline and serum type 1 collagen concentration. In
      contrast, eccentric actions induced a 23.5+/-19.0% (mean+/-s) decrease in MVC
      immediately post-exercise (P < 0.05), and increased the serum enzyme activities
      of creatine kinase and LDH-1 to 486+/-792 and 90+/-11 IU.l(-1) respectively on
      day 3 post-exercise, and to 189+/-159 and 96+/-13 IU x l(-1) respectively on day
      7 post-exercise (all P< 0.05). Eccentric actions induced no significant changes
      in plasma hydroxyproline, but increased collagen concentration on days 1 and 9
      post-exercise (48.6% and 44.3% increases above pre-exercise on days 1 and 9
      respectively; both P < 0.05). We conclude that eccentric but not concentric
      actions may result in temporary muscle damage, and that collagen breakdown may
      also be affected by eccentric actions. With caution, indices of collagen
      breakdown may be used to identify exercise-induced damage to connective tissue.

PMID- 10413268
TI  - Learned helplessness: a survey of cognitive, motivational and perceptual-motor
      consequences in motor tasks.
AB  - The aim of this study was to observe the effects of demonstration and
      controllability on causal attributions, self-efficacy expectations, number of
      attempts and performances on a pistol shooting task. Video demonstrations were
      used to induce different social comparisons bound to personal or universal
      helplessness. Students were randomly assigned in a 3 x 3 (demonstration x
      controllability) factorial design. The demonstration conditions were: watching a
      video designed to have participants believe the task was very easy (1), or very
      difficult (2), or not being exposed to a demonstration (3). The controllability
      conditions were: a controllable shooting task at a moving target on the computer
      screen (1), an uncontrollable task at a moving target on the computer screen (2),
      and a control condition in which participants were given a reading task (3).
      Finally, a different shooting task was used as a test measure. Analyses of
      variance showed that different demonstration conditions did not distinguish
      between personal and universal helplessness. Participants in the controllable
      condition demonstrated the best performances. Participants confronted with the
      uncontrollable condition were the least persistent. These findings in part
      support the general literature on learned helplessness and warrant further
      research into motor skills.

PMID- 10413269
TI  - A modified incremental shuttle run test for the determination of peak shuttle
      running speed and the prediction of maximal oxygen uptake.
AB  - The aim of this study was to determine the incidence of subject drop-out on a
      multi-stage shuttle run test and a modified incremental shuttle run test in which
      speed was increased by 0.014 m x s(-1) every 20-m shuttle to avoid the need for
      verbal speed cues. Analysis of the multi-stage shuttle run test with 208 elite
      female netball players and 381 elite male lacrosse players found that 13 (+/-3)
      players stopped after the first shuttle of each new level, in comparison with 5
      (+/-2) players on any other shuttle. No obvious drop-out pattern was observed on
      the incremental shuttle run test with 273 male and 79 female undergraduate
      students. The mean difference between a test-retest condition (n = 20) for peak
      shuttle running speed (-0.03+/-0.01 m x s(-1)) and maximal heart rate (0.4+/-0.1
      beats x min(-1)) on the incremental test showed no bias (P > 0.05). The 95%
      absolute confidence limits of agreement were+/-0.11 m x s(-1) for peak shuttle
      running speed and+/-5 beats min(-1) for maximal heart rate. The relationship (n =
      27) between peak shuttle running speed on the incremental shuttle run test
      (4.22+/-0.14 m x s(-1)) and VO2max (59.0+/-1.7 ml kg(-1) x min(-1)) was r= 0.91
      (P< 0.01), with a standard error of prediction of +/-2.6 ml x kg(-1) x min(-1).
      These results suggest verbal cues during the multi-stage shuttle run test may
      influence subject drop-out. The incremental shuttle run test shows no obvious
      drop-out patten and provides a valid estimate of VO2max.

PMID- 10413270
TI  - Social support dimensions and components of performance in tennis.
AB  - The aim of this study was to explore the relationships between dimensions of
      social support and components of performance in tennis. A post-match performance
      measure was completed by 144 British tournament tennis players. Principal
      components analysis yielded eight components, labelled Execution of (Flexible)
      Plan, Loss of Composure, Feeling Flat, Positive Tension, Worry, Flow, Effective
      Tactics and Double Faults. Before the match, 46 players had also completed the
      Interpersonal Support Evaluation List. Stepwise regression analyses revealed
      significant effects of the Belonging and Appraisal dimensions of the
      Interpersonal Support Evaluation List on five of the performance components. The
      correlations between total support and four of these performance components were
      also significant. Logistic regression analyses revealed no significant effects of
      the dimensions of the Interpersonal Support Evaluation List or Total Support upon
      winning versus losing. Effects of social support upon performance were therefore
      only apparent when attention was focused on the components of performance.

PMID- 10413271
TI  - Transfusion-associated immunomodulation and universal white cell reduction: are
      we putting the cart before the horse?

PMID- 10413272
TI  - Selective therapeutic extraction of plasma constituents, revisited.

PMID- 10413273
TI  - Clinical consequences of alterations in platelet transfusion dose: a prospective,
      randomized, double-blind trial.
AB  - BACKGROUND: The dose-response relationship for platelet transfusion has become
      increasingly important as the use of platelet transfusion has grown. STUDY DESIGN
      AND METHODS: One hundred fifty-eight prophylactic apheresis platelet transfusions
      were administered to 46 patients undergoing high-dose therapy followed by
      hematopoietic progenitor cell transplantation in a prospective, randomized,
      double-blind, multiple-crossover study. Transfusions were administered in pairs,
      differing only in platelet content. Each pair consisted of a lower-dose platelet
      component (LDP) and a higher-dose platelet component (HDP) administered in random
      order to the same patient. LDPs contained a mean of 3.1 x 10(11) platelets
      (range, 2.3-3.5 x 10(11)), and HDPs contained a mean of 5.0 x 10(11) platelets
      (range, 4.5-6.1 x 10(11)). Patients with active bleeding and those who were
      refractory to platelet transfusions were excluded. RESULTS: The mean
      posttransfusion platelet count increment with LDP was 17,010 per microL, and that
      with HDP was 31,057 per microL (p<0.0001). Only 37 percent of LDPs resulted in
      platelet count increments of at least 20,000 per microL, whereas 81 percent of
      HDPs resulted in increments above this level (p<0.0001). The mean transfusion
      free interval with LDP was 2.16 days, whereas that with HDP was 3.03 days
      (p<0.01). Administration of LDPs was associated with a 39 to 82 percent increase
      in the relative risk (per day) of requiring subsequent platelet transfusions
      (p<0.0001). CONCLUSION: As compared to the administration of HDPs, the
      administration of LDPs for prophylactic transfusion in hematopoietic progenitor
      cell transplant patients results in a lower platelet count increment, a lower
      likelihood of obtaining a posttransfusion platelet increment >20,000 per microL,
      a shorter transfusion-free interval, and a greater relative risk per day of
      requiring additional transfusions.

PMID- 10413274
TI  - Clinical evaluation of a staphylococcal protein A immunoadsorption system in the
      treatment of myasthenia gravis patients.
AB  - BACKGROUND: The role of plasma exchange is well established in the management of
      myasthenia gravis, an autoimmune disorder characterized by muscle weakness and
      caused by circulating IgG antibodies with specificity against the acetylcholine
      receptor. Plasma antibody removal by conventional means, however, is nonselective
      and uses replacement fluids (chiefly, albumin solution) derived from human
      plasma. STUDY DESIGN AND METHODS: The Canadian Apheresis Group undertook a study
      at two Canadian apheresis centers to clinically evaluate a staphylococcal protein
      A immunoadsorption system (EXCORIM) in myasthenia gravis patients. RESULTS: The
      immunoadsorption system was safe and well tolerated. Ten of 12 patients had
      improvement in their neurologic status, as measured by a 20-point scoring system.
      The mean improvement in the weakness score was significant for the group (p =
      0.0013). CONCLUSION: Patients with myasthenia gravis respond to treatment with
      plasma immunoadsorption. Further studies are required for a cost-benefit
      analysis.

PMID- 10413275
TI  - Redefining the HIV-infectious window period in the chimpanzee model: evidence to
      suggest that viral nucleic acid testing can prevent blood-borne transmission.
AB  - BACKGROUND: Although it is rare, blood-transmitted HIV infection can occur when a
      donor presents in the window period between HIV-1 exposure and the first
      appearance of detectable p24 antigen. STUDY DESIGN AND METHODS: To study this
      seronegative window period, a chimpanzee (X034) was inoculated with 38 median
      tissue culture infective doses of HIV-1 IIIB; serum and peripheral blood
      mononuclear cells were obtained one to two times per week for 12 weeks and then
      biweekly for 12 weeks. Infectivity was monitored by the detection of serum HIV
      RNA, cell-associated HIV DNA, p24 antigen, and anti-HIV and by co-culture
      methods. RESULTS: No HIV markers were noted until 5 weeks after inoculation, at
      which time virus was isolated and HIV RNA and DNA were detected in plasma and
      cells, respectively. Anti-HIV and HIV p24 antigen were not present until 8 weeks
      after inoculation. Plasma and cells obtained from Chimpanzee X034 3 or 4 weeks
      after exposure were then sequentially inoculated into a second chimpanzee (X176);
      no HIV infection was observed in this animal during serial follow-up for 24 weeks
      after each inoculation. In contrast, when the fifth-week HIV-1 RNA- and DNA
      positive sample was inoculated, Chimpanzee X176 was unequivocally infected with
      HIV-1. CONCLUSIONS: Nucleic acid testing narrowed the seronegative window by 3
      weeks (37%). More important, there was no demonstrable infectivity in either
      plasma or peripheral blood mononuclear cells obtained before molecular markers
      were detectable. This suggests that the infectious window may be considerably
      shorter than the total window as measured from exposure and that nucleic acid
      testing might not only shorten the seronegative window, but totally prevent
      transfusion-transmitted HIV infection.

PMID- 10413277
TI  - Transfusion and postoperative pneumonia in coronary artery bypass graft surgery:
      effect of the length of storage of transfused red cells.
AB  - BACKGROUND: Various bioactive substances are released from white cell (WBC)
      granules into red cell (RBC) components in a time-dependent manner during blood
      storage. Some of these substances may have immunosuppressive effects and may
      contribute to transfusion-induced immunomodulation. RBCs transfused after
      prolonged storage may be associated with a higher incidence of postoperative
      infections than fresh RBCs. This hypothesis does not seem to have been
      investigated in a clinical study. STUDY DESIGN AND METHODS: The records of 416
      consecutive patients undergoing coronary artery bypass graft operations at the
      Massachusetts General Hospital were reviewed. The association between the length
      of storage of the transfused RBCs, as well as the number of units of non-WBC
      reduced allogeneic RBCs and/or platelets transfused, and the occurrence of
      postoperative pneumonia was calculated by logistic regression analyses adjusting
      for the effects of confounding factors. Among these were the numbers of days of
      intubation, days of impaired consciousness, and units of RBCs transfused.
      RESULTS: By Centers for Disease Control and Prevention criteria, pneumonia
      developed in 54 patients (13.0%). Among 269 patients given RBCs, the risk of
      pneumonia increased by 1 percent per day of increase in the mean storage time of
      the transfused RBCs (p<0.005). In an analysis of all patients, the risk of
      pneumonia increased by 5 percent per unit of non-WBC-reduced allogeneic RBCs
      and/or platelets received (p = 0.0584). CONCLUSION: After adjustment for the
      effects of the risk factors for pneumonia and the number of transfused RBCs, an
      association was observed between the length of storage of transfused RBCs and the
      development of postoperative pneumonia. This association should be investigated
      further in future studies of the outcomes of blood transfusion.

PMID- 10413276
TI  - Risk of bacterial infection associated with allogeneic blood transfusion among
      patients undergoing hip fracture repair.
AB  - BACKGROUND: The relationship between allogeneic blood transfusion and bacterial
      infection remains uncertain. An increased risk of bacterial infection would
      represent the most important risk of allogeneic transfusion, because viral
      disease transmission has become so rare. STUDY DESIGN AND METHODS: A
      retrospective cohort study of 9598 consecutive hip fracture patients at least 60
      years old who underwent surgical repair was performed. The primary outcome was
      serious bacterial infection, defined as bacteremia, pneumonia, deep wound
      infection, or septic arthritis or osteomyelitis. Secondary outcomes included two
      individual infections, pneumonia and urinary tract infection (UTI), and the cost
      of infection. Hospital cost of infection was assessed by linking the study
      population to Medicare data. RESULTS: Fifty-eight percent of patients received at
      least one transfusion. Serious bacterial infection occurred in 437 patients
      (4.6%); 28.8 percent of this group died during the hospital stay. Pneumonia
      occurred in 361 patients (3.8%) and UTI occurred in 1157 patients (12.1%). The
      adjusted risk of serious bacterial infection associated with transfusion was 1.35
      (95% CI, 1.10-1.66). The adjusted risk for pneumonia was 1.52 (95% CI, 1.21
      1.91), and that for UTI was 1.03 (95% CI, 0.91-1.17). A dose-response
      relationship was present for serious bacterial infection (p = 0.001) and
      pneumonia (p = 0.001). The cost of hospitalization was $14,000 greater for
      patients with serious infection than for patients without infection. CONCLUSION:
      Blood transfusion is associated with a 35-percent greater risk of serious
      bacterial infection and a 52-percent greater risk of pneumonia. Postoperative
      infections are costly. The risk of bacterial infection may be the most common
      life-threatening adverse effect of allogeneic blood transfusion.

PMID- 10413278
TI  - A recombinant peptide antigen line immunoassay optimized for the confirmation of
      Chagas' disease.
AB  - BACKGROUND: The transfusion of contaminated blood has become the major route of
      transmission for Chagas' disease in Brazil. Current screening tests are
      insensitive and yield conflicting results, while confirmatory assays do not
      exist. A line immunoassay (INNO-LIA Chagas Ab [INNO-LIA]) combining relevant,
      immunodominant recombinant and synthetic antigens on a single nylon membrane
      strip was evaluated for the serologic confirmation of Chagas' disease. STUDY
      DESIGN AND METHODS: Sera from 1062 patients and healthy residents of four
      Brazilian regions endemic for Chagas' disease were used for test optimization.
      The established confirmation algorithm was evaluated with an independent set of
      positive (n = 75) and negative (n = 148) samples. RESULTS: In the optimization
      phase, without an established comparative gold standard, the results with the
      INNO-LIA were compared with those obtained in four other screening assays. In the
      validation phase, the INNO-LIA showed a sensitivity of 100 percent (95% CI, 95.21
      100) and a specificity of 99.32 percent (95% CI, 96.29-99.98) for well
      characterized sera. Moreover, its specificity reached 100 percent with a set of
      40 sera obtained from patients with documented leishmaniasis. The interpretation
      criteria defined in this study indicated that the INNO-LIA accurately detected
      the presence of antibodies to various specific antigens of Trypanosoma cruzi.
      CONCLUSION: The INNO-LIA Chagas Ab assay may become the first commercial assay to
      reliably confirm the presence of antibodies to T. cruzi.

PMID- 10413279
TI  - The effect of unmodified or prestorage white cell-reduced allogeneic red cell
      transfusions on the immune responsiveness in orthopedic surgery patients.
AB  - BACKGROUND: The immunomodulatory effects of allogeneic blood transfusions have
      been attributed to the white cells (WBCs) present in the cellular blood
      components transfused to patients. STUDY DESIGN AND METHODS: The effect of the
      transfusion of allogeneic red cells (RBCs) or allogeneic prestorage WBC-reduced
      RBCs (WBC-reduced RBCs) on host immune responsiveness was evaluated by measuring
      the lymphocyte subsets and the in-vitro cytokine production in response to
      phytohemagglutinin stimulation of WBCs of orthopedic surgery patients. Forty
      seven patients undergoing hip replacement surgery were randomly assigned to
      receive allogeneic RBCs (n = 17) or WBC-reduced RBCs (n = 14; 99.95% WBC
      removal). Sixteen patients were not transfused. Patient blood samples taken
      before surgery and on Days 1 and 4 after surgery were tested for complete blood
      count, lymphocyte subset analysis, and measurement of cytokine levels. RESULTS:
      After surgery, the lymphocyte count was significantly decreased in patients
      transfused with > or = 3 units of allogeneic RBCs (2.0 +/- 0.5 vs. 1.3 +/- 0.3 x
      10(9)/L; p = 0.017), but not in patients transfused with > or = 3 units of WBC
      reduced RBCs (2.0 +/- 0.9 vs. 1.7 +/- 0.8 x 10(9)/L). Compared with preoperative
      levels, on Day 4 after surgery, patients transfused with > or = 3 units of
      allogeneic RBCs also had a decrease in the number of natural killer cells (0.07
      +/- 0.05 vs. 0.04 +/- 0.03 x 10(9)/L; p = 0.018). Postoperatively, interleukin-2
      was decreased in one patient who received WBC-reduced RBCs compared with that in
      four patients transfused with allogeneic RBCs (p = 0.32), and eight untransfused
      patients (p = 0.01). On Day 4, about 70 percent of patients transfused with
      allogeneic RBCs showed a 20-percent decrease in the interferon gamma level.
      CONCLUSION: Taken together, these data support the hypothesis that transfusion of
      > or = 3 units of allogeneic RBCs is associated with early postoperative
      lymphopenia in otherwise healthy individuals undergoing surgery. These findings
      were not observed in those individuals transfused with RBCs that had undergone
      prestorage WBC reduction.

PMID- 10413280
TI  - Effects of prestorage white cell reduction on platelet aggregate formation and
      the activation state of platelets and plasma enzyme systems.
AB  - BACKGROUND: The introduction of prestorage white cell (WBC) reduction in random
      donor platelet concentrates in Canada has increased the occurrence of particulate
      material in PCs. The effects of filtration on platelet activation state and the
      activation of plasma enzyme systems were assessed. STUDY DESIGN AND METHODS:
      Particulate material was examined by light microscopy, electron microscopy,
      protein electrophoresis, and biochemical analysis. Thirty PCs (10 unfiltered, 20
      filtered) were examined during processing and 5-day storage for pH, platelet
      count and mean volume, morphology, activation marker expression, and hypotonic
      shock response. Complement activation, thrombin generation, and fibrinolysis were
      assessed by using specific enzyme immunoassays or chromogenic assays. RESULTS: By
      all analyses, the particulate material appeared to be platelet aggregates.
      Platelets exposed to WBC-reduction filters expressed a significantly higher level
      of activation markers CD62 and CD63, altered morphology, and increased platelet
      microparticles throughout the storage period than did unfiltered platelets.
      Complement activation at the C3 level was significantly increased in filtered
      units with little evidence of coagulation or fibrinolytic system activation.
      CONCLUSION: Exposure of platelets to filters during prestorage WBC reduction
      increased platelet activation and mildly increased complement activation over the
      levels during the storage period. These alterations can contribute to the
      formation of irreversible platelet aggregates during processing.

PMID- 10413281
TI  - Platelet surface p-selectin, platelet-granulocyte heterotypic aggregates, and
      plasma-soluble p-selectin during plateletpheresis.
AB  - BACKGROUND: Plateletpheresis components have been shown to contain p-selectin
      positive platelets after collection and storage. P-selectin mediates binding of
      activated platelets to granulocytes and monocytes. This study was undertaken to
      assess platelet activation, granulocyte activation, platelet-granulocyte
      heterotypic aggregate formation, and the plasma-soluble p-selectin level during
      plateletpheresis performed on a particular instrument (MCS+, Haemonetics). STUDY
      DESIGN AND METHODS: Flow cytometry was used to assay platelet surface p-selectin,
      granulocyte iC3b receptor, and platelet-granulocyte aggregates in the platelet
      component, residual blood in the disposable polycarbonate bowl of the MCS+, and
      in the donor blood with and without the addition of in vitro agonists before,
      during, and after plateletpheresis. The plasma-soluble p-selectin levels in the
      platelet component, disposable bowl, and donor venous blood were measured by an
      enzyme-linked immunosorbent assay. RESULTS: Levels of p-selectin-positive
      platelets, activated granulocytes, and platelet-granulocyte aggregates were
      greater in the disposable bowl than in the preapheresis donor blood. Levels of p
      selectin-positive platelets, activated granulocytes, and platelet-granulocyte
      aggregates in the postapheresis donor blood were similar to those in the
      preapheresis donor blood. The platelet components contained no activated
      granulocytes or detectable platelet-granulocyte heterotypic aggregates, and only
      about 10-percent activated platelets. The plasma-soluble p-selectin level in the
      platelet component was significantly greater than that in the preapheresis donor
      blood, the residual blood in the disposable bowl, or the postapheresis donor
      blood. CONCLUSIONS: Measurements of platelet surface p-selectin, platelet
      granulocyte heterotypic aggregates, and plasma-soluble p-selectin can be used to
      detect platelet activation during plateletpheresis.

PMID- 10413283
TI  - Factor VIII/von Willebrand factor complex in methylene blue-treated fresh plasma.
AB  - BACKGROUND: The effect of virus inactivation of fresh plasma with methylene blue
      has been studied on the factor VIII/von Willebrand factor molecular complex
      (FVIII/vWF), factor XIII, and fibrinogen. STUDY DESIGN AND METHODS: FVIII
      function or activity, vWF activity, vWF antigen, vWF:Ag, vWF multimeric
      structure, fibrinogen, and factor XIII were analyzed in paired samples of control
      fresh plasma (untreated) and the same fresh plasma treated with methylene blue.
      Treated plasma was filtered (0.8-1.2 microm), mixed with a methylene blue
      solution (300 microg/L), and illuminated at 50,000 lux for 30 minutes on both
      sides. RESULTS: Average loss of biologic activity of coagulation factors studied
      was 25 percent (FVIII function, 29%; fibrinogen, 39%; factor XIII, 16%; and vWF
      activity, 18%). Reduction in vWF activity was significantly lower than that in
      FVIII function (p<0.05), and the vWF multimeric structure did not show
      alterations. CONCLUSION: Methylene blue-treated plasma and the cryoprecipitates
      obtained from it may be effective for replacement therapy in cases of von
      Willebrand disease and deficiencies of factor XIII and fibrinogen, but the
      clinical studies are needed to verify that possibility.

PMID- 10413282
TI  - Biocompatibility of a new cell separator studied by flow cytometry: analyses of
      platelet antigens during apheresis and storage.
AB  - BACKGROUND: Alterations of platelet antigens are known to occur during
      cytapheresis and storage. These changes have been shown to be dependent on the
      biomaterials, techniques, and devices used. In this study, the influence of a new
      cell separator (AMICUS) and storage container (PL-2410) on platelet glycoproteins
      was analyzed. STUDY DESIGN AND METHODS: During plateletpheresis and storage, the
      levels of platelet glycoproteins and binding of fibrinogen were determined by
      flow cytometry. RESULTS: During apheresis, mean channel fluorescence intensity of
      CD41 a did not change significantly (p = 0.06). A small increase was evident in
      CD42b mean channel fluorescence intensity, which rose from a baseline level of
      178.6 +/- 68.3 to 231.5 +/- 97.9 at the end of the procedure (p<0.05); in CD62p
      positive platelets, which increased from 2.0 +/- 0.9 percent to 9.9 +/- 3.9
      percent (p<0.05); in CD63-positive platelets, which increased from 1.7 +/- 0.7
      percent to 7.9 +/- 2.6 percent (p<0.05); and in the binding of fibrinogen, which
      increased from 1.9 +/- 0.8 percent positive platelets to 10.5 +/- 2.6 percent
      (p<0.05). During storage, the mean channel fluorescence intensity of CD41a and
      CD42b, the percentage of CD62p- and CD63-positive platelets, and the binding of
      fibrinogen to platelets showed no significant change. CONCLUSION: These studies
      show that alterations in platelet antigens and platelet activation occur to a
      small degree during apheresis and storage. These findings demonstrate generally
      good biocompatibility of this new cell separator.

PMID- 10413284
TI  - Complement receptor 1 red cell expression is not controlled by the In(Lu) gene.
AB  - BACKGROUND: The In(Lu) gene reportedly suppresses several blood group antigens
      that are not part of the Lutheran system, including the high-incidence antigens
      of the Knops blood group system. Because complement receptor 1 (CR1), which is
      known to carry the Knops system antigens, has a red cell (RBC) expression
      polymorphism, the role of In(Lu) in the expression of the Knops system antigens
      was reinvestigated. STUDY DESIGN AND METHODS: Blood samples from nine donors
      having the Lu(a-b-) phenotype were obtained and immediately phenotyped for Lu(b),
      Kn(a), McC(a), Sl(a), and Yk(a). The samples were also tested for Lu(a), P1, and
      AnWj. Immunoblots were performed to study both the CR1 and Lutheran glycoproteins
      from these donors. RBC expression of CR1 was quantified with an enzyme-linked
      immunosorbent assay, and the genetic inheritance of the high-expression (H) or
      low-expression (L) allele for CR1 was determined by Southern blot. RESULTS: Lu(b)
      was demonstrable only by absorption and elution techniques on all nine samples;
      however, the high-incidence Knops system antigens were readily detectable by
      hemagglutination. Two Lu(a-b-) donors (sibs) demonstrated weak Lutheran
      glycoprotein bands of 78 and 85 kDa on immunoblots, while the other seven Lu(a-b
      ) samples had no detectable glycoprotein. All donors had CR1*1, and one donor
      also had CR1*2 on immunoblot. Only one donor was homozygous for the L allele, and
      all had RBC copy numbers of CR1 within the normal range. CONCLUSIONS: Nine donors
      with the Lu(a-b-) phenotype showed suppression of the Lutheran system antigens
      but normal expression of CR1 glycoprotein and the Knops system blood group
      antigens. This suggests that the genes that suppress Lutheran system antigens do
      not suppress CR1 or its related blood group antigens.

PMID- 10413285
TI  - Immunoglobulin isotype identification in red cell antibodies using flow
      cytometry.
AB  - BACKGROUND: Identifying the isotype of an immunoglobulin (IgM vs. IgG) detected
      in a patient sample is especially important in anticipating the risk of hemolytic
      disease of the newborn. Currently, 2-mercaptoethanol (2-ME) treatment of a sample
      is used in the authors' laboratory to degrade IgM, and this is followed by
      retesting. This method has multiple drawbacks. The purpose of this study was to
      develop a flow cytometry (FC) assay that would replace the 2-ME treatment
      protocol (2-ME treatment). STUDY DESIGN AND METHODS: A preliminary FC assay was
      developed, modified, and refined through the use of stock antibodies. Then, 10
      samples containing antibodies were tested in parallel by the FC assay and 2-ME
      treatment. RESULTS: When a 10-unit mean channel fluorescence change was used as
      an index of a positive result, the FC assay detected all isotypes identified by 2
      ME treatment. The FC assay was also able to identify mixtures of isotypes. One
      antibody that had not reacted in conventional agglutination testing was detected
      by the FC assay. The amount of fluorescence and the agglutinating strength of the
      antibody did not parallel each other. In one case, this discrepancy may have
      reflected an antibody that was primarily IgA. CONCLUSIONS: The FC assay appears
      to be as accurate as 2-ME treatment in differentiating IgG from IgM. The FC assay
      produces a positive endpoint for both isotypes, will identify IgA, requires less
      sample, and has no odor.

PMID- 10413286
TI  - Alloimmunization after blood transfusion in patients with hematologic and
      oncologic diseases.
AB  - BACKGROUND: Because of intensive marrow depression and improved survival,
      patients with hematologic and oncologic malignancies are dependent on transfusion
      for a longer period. It has been advocated that these patients should receive
      blood that is matched for blood group antigens other than ABO and D. A
      retrospective study was performed on the rate of alloimmunization against red
      cell antigens in 564 patients with malignant hematologic diseases over a period
      of 10 years. STUDY DESIGN AND METHODS: Records of transfusion and
      immunohematologic studies of all patients (n = 1066) with malignant
      myeloproliferative and lymphoproliferative diseases diagnosed between 1987 and
      1996 at one hospital were collected from the hospital computer blood bank files.
      Transfusions were correlated with antibody formation. Factors affecting this
      correlation were analyzed. RESULTS: Seventy-one antibodies were found in 51
      patients. The overall immunization rate was 9.0 percent. Fifty percent of
      antibodies were formed after 13 units had been transfused. Once a patient had
      formed an antibody, the probability of additional antibodies increased 3.3-fold.
      Anti-c, anti-E, and anti-K composed the majority of antibodies found. Four
      patients formed Rh system antibodies after incompatible platelet transfusions.
      Patients who underwent intensive chemotherapy formed antibodies at a much lower
      rate than other patients. More than 40 percent of antibodies became undetectable
      after the first detection. No difficulty was encountered in finding compatible
      blood for these patients. CONCLUSIONS: Antibody formation in hematologic
      malignancies is comparable to that in other diseases requiring multiple blood
      transfusions. Extensive antigen matching before transfusion of patients with
      hematologic and oncologic malignancies is not necessary and leads to increased
      costs.

PMID- 10413287
TI  - Antibodies to private and public HLA class I epitopes in platelet recipients.
AB  - BACKGROUND: Transfusions or pregnancies can cause immunization against private
      HLA determinants and public epitopes shared by more than one private HLA antigen.
      HLA antibodies are correlated with febrile transfusion reactions, lower platelet
      response following platelet transfusion, and an increased rate of renal
      transplant rejection. Until now, antibody specificities in alloantisera from
      platelet recipients have been poorly characterized. STUDY DESIGN AND METHODS:
      Consecutive serum screens from platelet recipients were analyzed for antibodies
      against private HLA class I antigens and public HLA epitopes using a serum
      analysis program based on the 2 x 2 table analysis of correlations. Serum screens
      of highly immunized patients and of patients with new alloimmunization events
      were reviewed separately. RESULTS: Of the serum screens from 566 platelet
      recipients, 1577 indicated alloimmunization (panel-reactive antibodies >5%). The
      program assigned a specificity in 1024 of these screens (64.9%) and at least once
      in 522 of 566 patients (92.2%). In 267 patients, antibodies detecting public
      epitopes in the combined A- or B-locus cross-reacting groups were found; other
      public markers were detected in 39 patients. Patterns of reactivity were
      remarkably less stable than in patient groups previously studied. In many
      patients, antibodies with apparent private epitope specificity preceded the
      identification of antibodies against a shared marker of the same cross-reactive
      group. However, the disappearance of antibodies (whether or not this was followed
      by a new antibody against a private or public marker belonging to another cross
      reacting group) was also observed. CONCLUSION: The computerized analysis of
      microlymphocytotoxicity tests enhances the rate of antibody specification in sera
      from platelet recipients with lymphocytotoxic antibodies. The identified
      antibodies should be taken into account in the selection of platelet donors. The
      data confirm and extend previous observations on HLA class I antibodies and
      elucidate new alloimmunization events.

PMID- 10413288
TI  - Rapid phenotyping of HPA-1a using either diabody-based hemagglutination or
      recombinant IgG1-based assays.
AB  - BACKGROUND: The HPA-1 system is carried on the beta3 integrin. HPA-1a (Zw(a),
      Pl(A1)) is immunogenic in an HPA-1b homozygote (HPA-1b1b). In pregnancy, 1 of 365
      women forms anti-HPA-1a, which causes severe thrombocytopenia in 1 in 1100
      neonates. Identification of women at risk of forming anti-HPA-1a and the
      screening of donors to obtain HPA-1a-negative platelets for therapy need
      reliable, low-cost, automated assays. STUDY DESIGN AND METHODS: A diabody with
      dual specificity for HPA-1a x D and an IgG1 anti-HPA-1a have been constructed by
      the use of the genes encoding the first anti-HPA-1a fragment. With these
      reagents, two complementary HPA-1a phenotyping assays have been developed.
      RESULTS: This diabody was used in a simple hemagglutination technique to perform
      HPA-1a phenotyping on soluble glycoprotein IIb/IIIa from EDTA plasma samples.
      Over 1000 unselected donors have been correctly HPA-1a-phenotyped by use of the
      diabody. The human recombinant IgG1 anti-HPA-1a was produced in a rat myeloma
      cell line and was fluorescein labeled for use in a whole-blood flow cytometric
      HPA-1a phenotyping assay. This IgG1 anti-HPA-1a shows a clear differential
      between HPA-1a-positive and HPA-1a-negative platelets at nM antibody
      concentrations. CONCLUSIONS: The two recombinant reagents described are highly
      suitable for screening and confirmatory HPA-1a phenotyping. They permit rapid
      determination of the HPA-1a phenotype and are amenable to automation.

PMID- 10413289
TI  - Hemoglobin losses due to plateletpheresis.

PMID- 10413290
TI  - GB virus type C/hepatitis G virus infection in French blood donors with anti-NS5
      isolated reactivities by recombinant immunoblot assay for hepatitis C virus.

PMID- 10413291
TI  - Role of antimetabolites of purine and pyrimidine nucleotide metabolism in tumor
      cell differentiation.
AB  - Transformed cells are characterized by imbalances in metabolic routes. In
      particular, different key enzymes of nucleotide metabolism and DNA biosynthesis,
      such as CTP synthetase, thymidylate synthase, dihydrofolate reductase, IMP
      dehydrogenase, ribonucleotide reductase, DNA polymerase, and DNA
      methyltransferase, are markedly up-regulated in certain tumor cells. Together
      with the concomitant down-modulation of the purine and pyrimidine degradation
      enzymes, the increased anabolic propensity supports the excessive proliferation
      of transformed cells. However, many types of cancer cells have maintained the
      ability to differentiate terminally into mature, non-proliferating cells not only
      in response to physiological receptor ligands, such as retinoic acid, vitamin D
      metabolites, and cytokines, but also following exposure to a wide variety of non
      physiological agents such as antimetabolites. Interestingly, induction of tumor
      cell differentiation is often associated with reversal of the transformation
      related enzyme deregulations. An important class of differentiating compounds
      comprises the antimetabolites of purine and pyrimidine nucleotide metabolism and
      nucleic acid synthesis, the majority being structural analogs of natural
      nucleosides. The CTP synthetase inhibitors cyclopentenylcytosine and 3
      deazauridine, the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine, the
      dihydrofolate reductase inhibitor methotrexate, the IMP dehydrogenase inhibitors
      tiazofurin, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide
      (EICAR) and mycophenolic acid, the ribonucleotide reductase inhibitors
      hydroxyurea and deferoxamine, and the DNA polymerase inhibitors ara-C, 9-(2
      phosphonylmethoxyethyl)adenine (PMEA), and aphidicolin, as well as several
      nucleoside analogs perturbing the DNA methylation pattern, have been found to
      induce tumor cell differentiation through impairment of DNA synthesis and/or
      function. Thus, by selectively targeting those anabolic enzymes that contribute
      to the neoplastic behavior of cancer cells, the normal cellular differentiation
      program may be reactivated and the malignant phenotype suppressed.

PMID- 10413292
TI  - New insights into the biology and pharmacology of the multidrug resistance
      protein (MRP) from gene knockout models.
AB  - Growing interest in the MRP (multidrug resistance protein) gene stems from its
      importance in multidrug resistance to chemotherapy, its possible use in gene
      therapy, and its relationship with the glutathione system. The recent generation
      of mrp gene knockout models in vitro and in vivo is providing information on the
      mechanism of action and the physiological function(s) of mrp. The importance of
      mrp in protection of normal tissues from the toxicity of the anticancer agent
      etoposide has been established. A total block of mrp has been found to be
      compatible with life, suggesting that MRP inhibitors can be safely used for
      treating cancer patients. In some sub-classes of leukocytes, mrp contributes to
      the transport of leukotriene C4, an endogenous glutathione-S-conjugate. However,
      the baseline expression of mrp does not appear to contribute to the export of
      glutathione-S-conjugates of alkylating agents, and thus does not exert a
      protective role against their toxicity. Besides being capable of exporting
      certain glutathione-S-conjugates, mrp also catalyzes the co-transport of GSH and
      drug and, presumably, a presently unknown endogenous metabolite(s).

PMID- 10413293
TI  - Effects of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and Nomega(6)-nitro
      L-arginine methyl ester (NAME) on cyclic GMP levels during muscarinic activation
      of tracheal smooth muscle.
AB  - The effects of carbachol on the cyclic GMP (cGMP) content of bovine tracheal
      smooth muscle in the absence of phosphodiesterase inhibitors were evaluated.
      Carbachol (1 x 10(-5) M) induced two cGMP peaks, at 20 and 60 sec. Both cGMP
      signals were carbachol concentration-dependent (1 x 10(-11) to 1 x 10(-5) M), the
      first being higher than the second. The cGMP signal induction was studied using
      an inhibitor of the soluble guanylyl cyclase (GC), 1H-[1,2,4]oxadiazolo[4,3
      a]quinoxalin-1-one (ODQ), and a nitric oxide (NO) synthase inhibitor, Nomega(6)
      nitro-L-arginine methyl ester (NAME). ODQ (1 x 10(-7) M) did not affect the
      second cGMP peak but abolished the first peak, suggesting that a soluble GC may
      be involved. NAME (1 x 10(-4) M) did not affect the cGMP signals, but changed
      their 2:1 ratio and also induced a time-shift of the first peak to 10 sec and the
      second to 50 sec. These results indicate that the NO-soluble GC cascade is not
      responsible for these muscarinic effects on cGMP levels.

PMID- 10413294
TI  - Interaction of the P-glycoprotein multidrug transporter (MDR1) with high affinity
      peptide chemosensitizers in isolated membranes, reconstituted systems, and intact
      cells.
AB  - P-glycoprotein-mediated multidrug resistance can be reversed by the action of a
      group of compounds known as chemosensitizers. The interactions with P
      glycoprotein of two novel hydrophobic peptide chemosensitizers (reversins 121 and
      205) have been studied in model systems in vitro, and in a variety of MDR1
      expressing intact tumor cells. The reversins bound to purified P-glycoprotein
      with high affinity (77-154 nM), as assessed by a quenching assay using
      fluorescently labeled purified protein. The peptides modulated P-glycoprotein
      ATPase activity in Sf9 insect cell membranes expressing human MDR1, plasma
      membrane vesicles from multidrug-resistant cells, and reconstituted
      proteoliposomes. Both peptides induced a large stimulation of ATPase activity;
      however, higher concentrations, especially of reversin 205, led to inhibition.
      This pattern was different from that of simple linear peptides, and resembled
      that of chemosensitizers such as verapamil. In both membrane vesicles and
      reconstituted proteoliposomes, 1-2 microM reversins were more effective than
      cyclosporin A at blocking colchicine transport. Reversin 121 and reversin 205
      restored the uptake of [3H]daunorubicin and rhodamine 123 in MDR1-expressing
      cells to the level observed in the drug-sensitive parent cell lines, and also
      effectively inhibited the extrusion of calcein acetoxymethyl ester from intact
      cells. In cytotoxicity assays, reversin 121 and reversin 205 eliminated the
      resistance of MDR1-expressing tumor cells against MDR1-substrate anticancer
      drugs, and they had no toxic effects in MDR1-negative control cells. We suggest
      that peptides of the reversin type interact with the MDR1 protein with high
      affinity and specificity, and thus they may be good candidates for the
      development of MDR1-modulating agents to sensitize drug resistance in cancer.

PMID- 10413295
TI  - Differential effects of ganodermic acid S on the thromboxane A2-signaling
      pathways in human platelets.
AB  - Ganodermic acid S (GAS) [lanosta-7,9(11),24-triene-3beta,15alpha-diacetoxy-26-oic
      acid], isolated from the Chinese medicinal fungus Ganoderma lucidum (Fr.) Karst
      (Polyporaceae), exerted a concentration-dependent inhibition on the response of
      human gel-filtered platelets (GFP) to U46619 (9,11-dideoxy-9alpha,11alpha
      methanoepoxyprostaglandin F2alpha), a thromboxane (TX) A2 mimetic. GAS at 2
      microM inhibited 50% of cell aggregation. GAS at 7.5 microM inhibited 80% of Ca2+
      mobilization, 40% of phosphorylation of myosin light chain and pleckstrin, 80% of
      alpha-granule secretion, and over 95% of aggregation. GAS also strongly inhibited
      U46619-induced diacylglycerol formation, arachidonic acid release, and TXB2
      formation. An immunoblotting study of protein-tyrosine phosphorylation showed
      that GAS inhibited the formation of phosphotyrosine proteins at the steps
      involving the engagement of integrin alphaIIbbeta3 and aggregation. However, GAS
      did not inhibit U46619-induced platelet shape change or the inhibitory effect of
      U46619 on the prostaglandin E1-evoked cyclic AMP level in GFP. It is concluded
      that GAS inhibits platelet response to TXA2 on the receptor-Gq-phospholipase
      Cbeta1 pathway, but not on the receptor-G1 pathway.

PMID- 10413296
TI  - Coordinated induction of the c-jun gene with genes encoding quinone
      oxidoreductases in response to xenobiotics and antioxidants.
AB  - Xenobiotics and antioxidants induce expression of detoxifying enzymes including
      NAD(P)H: quinone oxidoreductase (NQO1), NRH:quinone oxidoreductase (NQO2), and
      glutathione S-transferase Ya (GST Ya), presumably to provide protection to cells
      against electrophilic and oxidative stress. Antioxidant response elements (AREs)
      have been found in the promoter regions of the various detoxifying enzyme genes.
      An ARE is required for basal expression and induction of the various detoxifying
      enzyme genes in response to xenobiotics and antioxidants. In this study, we
      demonstrated that exposure of cells to xenobiotics [e.g. beta-naphthoflavone
      (beta-NF)] and antioxidants [e.g. tert-butyl hydroquinone (t-BHQ)] also induced
      the expression of the proto-oncogene c-jun. The induction of c-jun gene
      expression followed kinetics similar to the induction of NQO1 and NQO2 genes with
      respect to the level and time of exposure. Sequence analysis of the c-jun gene
      promoter revealed the presence of an ARE between nucleotides -538 and -514. The c
      jun ARE was highly homologous to the AREs from genes encoding NQO1, NQO2, and GST
      Ya. Constructs containing the c-jun ARE and 1.7 and 4.5 kb of the c-jun promoter
      ligated to the chloramphenicol acetyltransferase (CAT) gene, upon transfection in
      human hepatoblastoma (Hep-G2) cells, expressed the CAT gene, which was inducible
      with beta-NF and t-BHQ. Band shift assays indicated binding of two specific
      nuclear protein complexes with the c-jun gene ARE. The faster running c-jun gene
      ARE-nuclear protein complex was specifically competed out by unlabeled NQO1 and
      GST Ya gene AREs. These results suggest that c-jun gene expression is
      coordinately induced and regulated with detoxifying enzyme genes in response to
      xenobiotics and antioxidants. The results also suggest involvement of an ARE
      mediated mechanism of induction of c-jun gene expression. However, a comparison
      of fold induction of endogenous c-jun gene and transfected c-jun promoter/ARE-CAT
      constructs indicated involvement of another ARE upstream of the 4.5-kb promoter
      and/or additional mechanisms such as stabilization of c-Jun RNA in response to
      exposure to xenobiotics and antioxidants.

PMID- 10413297
TI  - Human phenol sulfotransferases SULT1A2 and SULT1A1: genetic polymorphisms,
      allozyme properties, and human liver genotype-phenotype correlations.
AB  - Phenol sulfotransferases (PSTs or phenol SULTs) catalyze the sulfate conjugation
      of phenolic drugs, xenobiotics, and monoamines. Two human PST isoforms have been
      defined biochemically, a thermostable (TS), or phenol-preferring, and a
      thermolabile (TL), or monoamine-preferring form. Pharmacogenetic studies showed
      that levels of both TS PST activity and TS PST thermal stability (an indirect
      measure of variation in amino acid sequence) in the platelet were regulated by
      genetic polymorphisms. Subsequent molecular genetic experiments revealed the
      existence of three human PST genes, two of which, SULT1A1 and SULT1A2, encode
      proteins with "TS PST-like" activity. We recently reported common nucleotide
      polymorphisms for SULT1A1 that are associated with variations in platelet TS PST
      activity and thermal stability. In the present experiments, we set out to
      determine whether functionally significant DNA polymorphisms also might exist for
      SULT1A2, to compare the biochemical properties of all common allozymes encoded by
      SULT1A2 and SULT1A1, and to study phenol SULT genotype-phenotype correlations in
      the human liver. We phenotyped 61 human liver biopsy samples for TS PST thermal
      stability and activity. The open reading frames of SULT1A2 and SULT1A1 then were
      amplified with the polymerase chain reaction and sequenced for each of these
      hepatic tissue samples. We observed 13 SULT1A2 alleles that encoded 6 allozymes.
      These alleles were in linkage disequilibrium with alleles for SULT1A1.
      Biochemical characterization of common allozymes encoded by both genes suggested
      that SULT1A1 was primarily responsible for "TS PST phenotype" in the human liver.
      In summary, both SULT1A2 and SULT1A1 have a series of common alleles encoding
      enzymes that differ functionally and are associated with individual differences
      in phenol SULT properties in the liver.

PMID- 10413298
TI  - Interaction of anisatin with rat brain gamma-aminobutyric acidA receptors:
      allosteric modulation by competitive antagonists.
AB  - Anisatin, a toxic sesquiterpene isolated from the Japanese star anise (Illicium
      anisatum L.), competitively inhibited the specific binding of [3H]4'-ethynyl-4-n
      propylbicycloorthobenzoate ([3H]EBOB), a non-competitive antagonist of gamma
      aminobutyric acid (GABA)A receptors, to rat brain membranes with an IC50 value of
      0.43 microM. R 5135, a competitive GABA antagonist, decreased the potency of
      anisatin in inhibiting [3H]EBOB binding in a negatively cooperative manner. Two
      other competitive antagonists, SR 95531 (gabazine) and (-)-bicuculline
      methiodide, had similar effects. On the other hand, R 5135 exerted little
      influence on the potencies of the other non-competitive antagonists tested: EBOB,
      picrotoxinin, isopropylbicyclophosphate, and dieldrin. Thus, anisatin was clearly
      different from the other non-competitive antagonists in responding to the action
      of competitive antagonists on (GABA)A receptors. These findings suggest that the
      binding region of anisatin might overlap with that of the other non-competitive
      antagonists, but that anisatin must interact with other specific region(s).

PMID- 10413300
TI  - Differential signaling of human Mel1a and Mel1b melatonin receptors through the
      cyclic guanosine 3'-5'-monophosphate pathway.
AB  - Cyclic guanosine 3'-5'-monophosphate (cGMP) has recently been shown to constitute
      a second messenger for Xenopus laevis melatonin Mel1c receptors. To verify
      whether cGMP levels are also modulated by mammalian melatonin receptors, we
      cloned the genes encoding the human Mel1a and Mel1b receptor subtypes and
      expressed them in human embryonic kidney cells. Pharmacological profiles and
      inhibition of forskolin-stimulated adenosine 3'-5'-cyclic monophosphate levels by
      melatonin confirmed functional expression of high-affinity melatonin receptors.
      Mel1b receptor-transfected cells modulated cGMP levels in a dose-dependent manner
      via the soluble guanylyl cyclase pathway. In contrast, Mel1a receptors had no
      effect on cGMP levels. These results demonstrate that mammalian melatonin
      receptors modulate cGMP levels and reveal for the first time differences in
      signaling between melatonin receptor subtypes, which may explain the necessity to
      express different receptor subtypes.

PMID- 10413299
TI  - Mechanisms of inhibitory effects of zinc and cadmium ions on agonist binding to
      adenosine A1 receptors in rat brain.
AB  - The dose-dependent inhibition of zinc and cadmium ions of agonist binding to A1
      adenosine receptors in rat brain is prevented by histidine and cysteine,
      respectively. In the present study, the possible different mechanisms of Zn2+ and
      Cd2+ inhibitions were examined. The effects of Zn2+ and Cd2+ on equilibrium
      binding parameters of the agonists N6-cyclohexyl-[2,8-3H]-adenosine ([3H]CHA) or
      chloro-N6-cyclopentyl-adenosine ([3H]CCPA) and the antagonist cyclopentyl-1,3
      dipropylxanthine ([3H]DPCPX) were compared with those effects of reagents or
      binding conditions which altered histidyl or cysteinyl residues of the A1
      receptor. Zn2+ pretreatment did not change A1 agonist or antagonist affinity, but
      did reduce the Bmax. The inhibitory effects of Zn2+ pretreatments were also
      maintained after several membrane washings. Diethylpyrocarbonate, a histidine
      specific alkylating reagent, behaved like zinc ions: pretreatment with A1 agonist
      protected the histidyl residues of the [3H]CHA binding site against modification
      by Zn2+, while the modification of the protonation state of the nitrogen of the
      imidazole group of histidines by changing pH indicated that the interactions of
      Zn2+ with the histidyl residues were feasible with their unprotonated form. These
      findings suggest the formation of coordination bonds between Zn2+ and histidines
      critical for [3H]CHA or [3H]DPCPX binding, which may prevent the ligand
      interaction with the specific sites without modifying the binding kinetics of
      radioligand to the non-chelated recognition sites. Cd2+ pretreatment reduced the
      [3H]CCPA affinity, but did not modify the affinity of the antagonist [3H]DPCPX,
      the Bmax remaining unaffected. As with cadmium effects, the oxidation of the
      thiol group of cysteine by dithionitrobenzoic acid (DTNB) reduced [3H]CCPA
      affinity without changing the number of binding sites. The reducing reagent
      dithiothreitol, which alone was unable to modify [3H]CCPA binding, overcame the
      inhibiting effects of both Cd2+ and DTNB. These findings suggest that cadmium
      ions may oxidize SH groups of cysteines localized on the A1 receptor molecule or
      a cysteine localized in the region of G(i)alpha subunit involved in the coupling
      with receptors. This mechanism can justify potential conformational modifications
      of the receptor molecule producing the decrease in affinity.

PMID- 10413301
TI  - Accumulation of alpha-oxoaldehydes during oxidative stress: a role in
      cytotoxicity.
AB  - Glyoxal, methylglyoxal (MG), and 3-deoxyglucosone (3-DG) are physiological alpha
      oxoaldehydes formed by lipid peroxidation, glycation, and degradation of
      glycolytic intermediates. They are enzymatically detoxified in cells by the
      cytosolic glutathione-dependent glyoxalase system (glyoxal and MG only) and by
      NADPH-dependent reductase and NAD(P)+-dependent dehydrogenase. In this study, the
      changes in the cellular and extracellular concentrations of these alpha
      oxoaldehydes were investigated in murine P388D1 macrophages during necrotic cell
      death induced by median toxic concentrations of hydrogen peroxide and 1-chloro
      2,4-dinitrobenzene (CDNB). Alpha-oxoaldehyde concentrations were determined by
      derivatization with 1,2-diamino-4,5-dimethoxybenzene. There were relatively small
      increases in cellular and extracellular glyoxal concentration, except that
      extracellular glyoxal was decreased with hydrogen peroxide. The cytosolic
      concentration of 3-DG and the cytosolic and extracellular concentrations of MG,
      however, increased markedly. Aminoguanidine inhibited alpha-oxoaldehyde
      accumulation and prevented cytotoxicity induced by hydrogen peroxide and CDNB.
      The accumulation of glyoxal and MG in toxicant-treated cells was a likely
      consequence of decreased in situ activity of glyoxalase 1. The effect was marked
      for MG but not for glyoxal, suggestive of a greater metabolic flux of MG
      formation than of glyoxal. The accumulation of 3-DG in toxicant-treated cells was
      probably due to the decreased availability of pyridine nucleotide cofactors for
      the detoxification of 3-DG. Impairment of alpha-oxoaldehyde detoxification is
      cytotoxic, and this may contribute to toxicity associated with GSH oxidation and
      S conjugation in oxidative stress and chemical toxicity, and to chronic
      pathogenesis associated with diabetes mellitus where there is oxidative stress
      and the formation of glyoxal, MG, and 3-DG is increased.

PMID- 10413302
TI  - Involvement of nitric oxide and biopterin in proinflammatory cytokine-induced
      apoptotic cell death in mouse osteoblastic cell line MC3T3-E1.
AB  - We previously demonstrated that the addition of proinflammatory cytokines (tumor
      necrosis factor-alpha, interleukin-1beta, and interferon-gamma) caused induction
      of mRNAs for inducible nitric oxide (NO) synthase and GTP cyclohydrolase I, a
      rate-limiting enzyme for 5,6,7,8-tetrahydrobiopterin (BH4) biosynthesis, and
      produced their end-products, NO and BH4, in osteoblastic cells. In the present
      study, we examined whether NO and BH4, biologically active substances produced in
      response to proinflammatory cytokines, are involved in the effect of these
      cytokines on cell viability and apoptotic cell death involving DNA fragmentation.
      Cytokines as well as S-nitroso-N-acetyl-d,l-penicillamine, an NO generator,
      decreased cell viability, whereas sepiapterin, which was converted
      intracellularly to BH4, increased it. The examination of cytotoxicity measured in
      terms of lactate dehydrogenase release and apoptotic cell death assessed by flow
      cytometric analysis showed that cytokine-induced reduction of cell viability may
      be based upon cell death by apoptosis, but not lytic death as in necrosis. In the
      presence of sepiapterin, cytokine treatment resulted in a statistically
      pronounced reduction in the amount of DNA fragmentation. Furthermore, this
      fragmentation could be blocked by 2-(4-carboxy-phenyl)-4,4,5,5
      tetramethylimidazole-1-oxyl 3-oxide, an NO scavenger. These results suggest that
      cytokine-induced apoptotic cell death is attributed to NO and is protected by
      BH4, and that osteoblastic cells in response to proinflammatory cytokines operate
      both a stimulatory process resulting in NO production and an inhibitory one
      resulting in BH4 production for apoptotic cell death. Cytokine-induced apoptotic
      cell death may be a consequence of the predominance of the stimulatory process
      over the inhibitory process.

PMID- 10413303
TI  - Effect of glutathione depletion on inhibition of cell cycle progression and
      induction of apoptosis by melphalan (L-phenylalanine mustard) in human colorectal
      cancer cells.
AB  - Intracellular levels of glutathione have been shown to affect the sensitivity of
      cells to cell death-inducing stimuli, as well as the mode of cell death. We found
      in five human colorectal cancer cell lines (HT-29, LS-180, LOVO, SW837, and
      SW1116) that GSH depletion by L-buthionine-[S,R]-sulfoximine (BSO) below 20% of
      control values increased L-phenylalanine mustard (L-PAM; Melphalan) cytotoxicity
      2- to 3-fold. Effects on kinetics of both cell cycle progression and cell death
      were further investigated in the HT-29 cell line. BSO treatment alone had no
      effect on cell cycle kinetics, but did enhance the inhibition of S phase
      progression as induced by L-PAM; at high concentration of of L-PAM, BSO
      pretreatment resulted in blockage in all phases of the cell cycle. Yet, BSO
      pretreatment did not affect the intracellular L-PAM content. L-PAM induced
      apoptosis in both normal and GSH-depleted cells. A combination of annexin V
      labeling and propidium iodide staining revealed that even the higher
      concentration of L-PAM (420 microM) did not induce apoptosis until 48 hr after
      treatment, but that induction of cell death was markedly accelerated as a result
      of GSH depletion: 48 hours after L-PAM (420 microM) treatment, GSH-depleted cells
      showed a 4-fold increase in DNA fragmentation and a 7-fold increase in the
      fraction of apoptotic (annexin V-positive) cells as compared to cells with normal
      GSH levels. Various antioxidant treatment modalities could not prevent this
      potentiating effect of GSH depletion on L-PAM cytotoxicity, suggesting that
      reactive oxygen species do not play a role. These data show that after BSO
      treatment the mode of L-PAM-induced cell death does not necessarily switch from
      apoptosis to necrosis.

PMID- 10413304
TI  - Mitochondrial permeability transition and release of cytochrome c induced by
      retinoic acids.
AB  - Retinoic acids, structurally related to vitamin A, inhibit the in vitro
      proliferation of different types of normal and neoplastic cells. The effects of
      all-trans, 9-cis, and 13-cis retinoic acids were tested on mitochondria isolated
      from rat liver. All the compounds were able to induce the membrane permeability
      transition observed as swelling and decrease in membrane potential, but 13-cis
      retinoic acid appeared to be the most effective. The latter was also shown to
      stimulate the release of cytochrome c from mitochondria, suggesting a potential
      target of retinoids in the induction of cell apoptosis. Interestingly, EGTA and
      cyclosporin A, which strongly inhibit the permeability transition induced by 13
      cis retinoic acid, were without effect on the release of cytochrome c from the
      mitochondrial intermembrane space.

PMID- 10413305
TI  - Differential interactions of nitric oxide donors with rat oxyhemoglobin.
AB  - To estimate the reaction of two primary redox-related species of nitric oxide
      (i.e. NO+ vs NO*) from a variety of NO donors, we employed the differential
      interactions of these NO forms with oxyhemoglobin (oxyHb) as a chemical assay.
      NO+ formation was estimated by the S-nitrosation reaction with oxyHb, and NO*
      formation via its reaction with the oxygen-heme complex of oxyHb. Under the
      conditions employed, all NO donors caused concentration-dependent formation of
      methemoglobin, indicative of NO* liberation. However, the extent of S-nitrosation
      was substantially different among the NO donors studied. A representative S
      nitrosothiol, S-nitroso-N-acetyl-penicillamine, caused significantly more S
      nitrosation than nitroglycerin, isobutyl nitrite, sodium nitroprusside, and 3
      morpholino-sydnonimine (ANOVA, P < 0.05). These results indicated that NO donors
      can differ in their interactions with oxyHb, and possibly with other target
      proteins, in part because they liberate or transfer different ratios of NO redox
      forms. This difference may contribute, in part, to the diversity of
      pharmacological effects elicited by NO donors.

PMID- 10413306
TI  - Permanent cell cycle arrest in asynchronously proliferating normal human
      fibroblasts treated with doxorubicin or etoposide but not camptothecin.
AB  - Damage to DNA has been implicated in the induction of permanent cell cycle arrest
      or premature senescence in normal human fibroblasts. We tested the ability of a
      group of cancer chemotherapeutic agents or related compounds, which can cause DNA
      double-strand breaks (DSBs) directly or indirectly, to induce a permanent cell
      cycle arrest in normal proliferating fibroblasts. A brief treatment with
      etoposide, doxorubicin, cisplatin, or phleomycin D1 induced a block to S phase
      entry sustained through 15 days. Lower levels of these drugs did not induce
      appreciable levels of transient cell cycle arrest. Higher concentrations caused
      cell death that lacked the DNA degradation characteristic of apoptosis.
      Camptothecin, an agent that causes DNA single-strand breaks, which are converted
      to DSBs during S phase, was able to induce an efficient, but only transient, cell
      cycle arrest in these normal cells. The cells did not enter S phase until after
      removal of the camptothecin. These findings support the idea that permanent cell
      cycle arrest and cell death are typical reactions of these normal cells to drugs
      that can cause DSBs. In addition, we report data consistent with the concept that
      both actinomycin D and doxorubicin are sequestered by cells and slowly released
      in active form. This is consistent with the observation that both these drugs
      bind reversibly to intracellular components.

PMID- 10413307
TI  - Effect of nitric oxide donors and nitric oxide synthase inhibitors in neonatal
      rat endotoxic shock.
AB  - Previous studies have shown an increased mortality in response to endotoxin in 24
      hr-old neonatal rats compared with older neonates and adults. This increased
      susceptibility may be related to increased nitric oxide (NO) and thromboxane
      (TxB2) production. Twenty-four-hour-old neonatal rat pups were given either N(G)
      nitro-L-arginine methyl ester (L-NAME; a nonspecific NO synthase inhibitor), S
      methylthioisourea (SMT; a specific NO synthase inhibitor), or molsidomine (a NO
      donor) subcutaneously prior to or after an LD50 of intracardiac endotoxin.
      Mortality was followed for 72 hr. There was no statistically significant
      difference in mortality between control animals and those pretreated with L-NAME,
      SMT, or molsidomine. A trend toward increased mortality with nonspecific NO
      synthase inhibition and decreased mortality with the NO donor was noted. Splenic
      cells were obtained for in vitro cytokine stimulation studies. In vitro adherent
      splenic cell stimulation studies confirmed an increase in NO production with NO
      donor pretreatment and decreased production of NO with NO synthase inhibition
      pretreatment. There was no difference in TxB2 production with either the NO
      synthase inhibitor or the NO donor. In conclusion, at the several doses employed,
      neither nonselective or selective NO synthase inhibitors nor NO donors prevented
      endotoxin-induced mortality in rat neonatal shock. Although these findings do not
      preclude possible involvement of NO in neonatal pathophysiology, increased NO
      production thus does not appear to be the primary determinant of the increased
      susceptibility of the neonatal rat to endotoxic shock.

PMID- 10413308
TI  - Characterization of a chlorambucil-resistant human ovarian carcinoma cell line
      overexpressing glutathione S-transferase mu.
AB  - Ovarian carcinoma cells 10-fold resistant to the alkylating agent chlorambucil
      (CBL) were isolated after repeated exposure of the parent cells to gradually
      escalating concentrations of the drug. The resistant variant, A2780(100), was
      highly cross-resistant (9-fold) to melphalan and showed lower-level resistance to
      other cross-linking agents. The resistant A2780(100) cells had almost 5-fold
      higher glutathione S-transferase (GST) activity than the parental A2780 cells
      with 1-chloro-2,4-dinitrobenzene (CDNB) as substrate. The pi-class GST(s) was the
      major isoform(s) in both cell lines. However, the resistant A2780(100) cells had
      at least 11-fold higher GST mu as compared with the parental cells, in which this
      isoform was barely detectable. A significant induction of GST mu was observed in
      A2780 cells, but not in the resistant cells, 18 hr after a single exposure to 100
      microM CBL. The induction of GST mu by CBL was both time- and concentration
      dependent. Assays of the conjugation of CBL with GSH showed that the human mu
      class GST had 3.6- and 5.2-fold higher catalytic efficiency relative to the pi-
      and alpha-class GSTs, respectively. This difference was reflected in the
      relatively higher (about 6-fold) efficiency of CBL conjugation in A2780(100)
      cells as compared with the parental cells. These results have demonstrated for
      the first time a near-linear correlation between CBL resistance and
      overexpression of mu-class GSTs and suggest that this overexpression maybe
      responsible, at least in part, for the acquired resistance of ovarian carcinoma
      cells to CBL, and possibly the other bifunctional alkylating agents. Consistent
      with this hypothesis, we found evidence for decreased formation of DNA lesions in
      A2780(100) compared with the drug-sensitive A2780 cells after exposure to CBL.

PMID- 10413309
TI  - Inhibition of DNA topoisomerase II catalytic activity by the antiviral agents 7
      chloro-1,3-dihydroxyacridone and 1,3,7-trihydroxyacridone.
AB  - Previously we reported that the antiproliferative and antiviral actions of 7
      chloro-1,3 dihydroxyacridone (compound 1) and its derivatives may be mediated
      through the inhibition of mammalian DNA topoisomerase II. In the present work, we
      have extended our investigation into the mechanism of topoisomerase II inhibition
      by these agents. Both compound 1 and its 7-OH derivative, compound 2, inhibited
      topoisomerase II catalytic activity in vitro, yet neither agent affected the
      activity of topoisomerase I. DNA unwinding assays indicated that compound 1 and
      compound 2 bound to DNA, although no correlation was found between DNA unwinding
      and topoisomerase II catalytic inhibition. Neither agent enhanced topoisomerase
      II-mediated DNA cleavage in vitro; however, both compound 1 and compound 2
      antagonized breaks induced by etoposide and amsacrine. Experiments indicate that
      interference with etoposide-stimulated breaks results from inhibition of
      topoisomerase II * DNA binding by compound 1. These findings suggest that
      compound 1 and its derivatives may represent a novel structural class of
      topoisomerase II catalytic inhibitors.

PMID- 10413310
TI  - 9-(2-Phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cpr-PMEDAP) as a
      prodrug of 9-(2-phosphonylmethoxyethyl)guanine (PMEG).
AB  - 9-(2-Phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cpr-PMEDAP) is an
      acyclic nucleotide analog of the [9-(2-phosphonylmethoxyethyl)-] (PME) series
      containing a cyclopropyl substituent on the N6 position of the 2,6-diaminopurine
      (DAP) base. Growth inhibition assays in a broad range of tumor cell lines
      demonstrated that this analog had potent antiproliferative activity with IC50
      values similar to those of the structurally related guanine analog 9-(2
      phosphonylmethoxyethyl)guanine (PMEG). A substantially lower growth inhibitory
      effect was observed for the 2,6-diaminopurine analog, PMEDAP. To dissect the
      basis for these varying potencies, the metabolism of the three analogs was
      examined in a human pancreatic carcinoma cell line, BxPC-3. HPLC analysis of the
      intracellular metabolites demonstrated that the cpr-PMEDAP was deaminated to PMEG
      and subsequently phosphorylated to PMEG mono- and diphosphates (PMEGp and
      PMEGpp). The level of PMEGpp generated from cpr-PMEDAP-treated cells was 50%
      greater than the level generated from cells incubated with PMEG. The presence of
      PMEG in the DNA of cells incubated with cpr-PMEDAP confirmed that the cpr-PMEDAP
      was converted to PMEG. In contrast, PMEDAP was not deaminated to PMEG, but
      directly phosphorylated to PMEDAPp and PMEDAPpp. The adenylate deaminase
      inhibitor 2'-deoxycoformycin (dCF) inhibited the conversion of cpr-PMEDAP in a
      rat liver cytosolic extract and increased the IC50 value for growth inhibition by
      40-fold. The antiproliferative activities of PMEG and PMEDAP were unaffected by
      dCF. Thus, it appears that cpr-PMEDAP, but not PMEDAP, is converted by an
      adenylate deaminase-like enzyme and functions as a prodrug of PMEG.

PMID- 10413311
TI  - Effect of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline
      carboxamide (PK11195), a specific ligand of the peripheral benzodiazepine
      receptor, on the lipid fluidity of mitochondria in human glioma cells.
AB  - When human glioma cells were incubated for 24 hr in serum-free medium with
      nanomolar concentrations of 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3
      isoquinoline carboxamide (PK11195), a specific ligand of the peripheral
      benzodiazepine receptor (PBR), a significant increase in the membrane fluidity of
      mitochondria isolated from these cells was registered. These effects were not
      observed with a shorter incubation time (2 hr) of the cells with PK11195 nor in
      the presence of serum. Other significant associated changes were observed: a
      significant increase of 16+/-4% of [3H]thymidine incorporation into DNA was
      detected in cells in the presence of PK11195 in serum-free medium, and an
      increase of 33+/-5% as compared to controls in nonyl acridine orange uptake, as
      indicator of mitochondrial mass, was also registered in cells treated with 10 nM
      PK11195. [3H]PK11195 binding was decreased in cells incubated with PK11195; a 45%
      decrease compared to controls was obtained. In view of the effect of PBR ligands
      on DNA synthesis, changes in mitochondrial lipid metabolism through interaction
      with PBRs might lead to biogenesis of mitochondria to support the increased
      metabolic requirements for cell division, which is even higher in malignant
      cells.

PMID- 10413312
TI  - Coordinate up-regulation of CYP1A1 and heme oxygenase-1 (HO-1) expression and
      modulation of delta-aminolevulinic acid synthase and tryptophan pyrrolase
      activities in pyridine-treated rats.
AB  - To determine the changes in heme metabolism associated with induction of
      cytochrome P450 expression by pyridine, we compared the time course of CYP1A
      expression with the time course of (i) expression of heme oxygenase-1 (HO-1) (EC
      1.14.99.3), (ii) activity of delta-aminolevulinic acid synthetase (ALAS) (EC
      2.3.1.37), and (iii) heme saturation of tryptophan pyrrolase (TPO) (EC
      1.13.11.11) in tissues of rats administered a single 100 or 150 mg/kg i.p. dose
      of pyridine. Both mRNA and protein of HO-1 and CYP1A1 were induced in the liver,
      kidney, and lung, with the induction of HO-1 mRNA preceding and paralleling that
      of CYP1A1 mRNA in the liver and lung but not kidney. Induction of CYP1A1 mRNA
      expression peaked within 9-12 hr and returned to control levels by 24 hr in all
      tissues examined, whereas induction of HO-1 mRNA expression was sustained for 48
      hr in the lung and liver. In contrast to the transient up-regulation of CYP1A1
      mRNA, increased microsomal CYP1A1 protein was sustained in all three tissues.
      Similar to the induction of HO-1 expression, lipid peroxidation was stimulated by
      pyridine treatment in the kidney, lung, and liver, but with the stimulation being
      more persistent in the liver and lung than in the kidney. Increased hepatic
      CYP1A1 or CYP1A2 activity was preceded by increased activities of HO-1 and ALAS.
      Pyridine treatment negatively modulated heme saturation of hepatic TPO. The
      findings indicate that pyridine stimulates the synthesis, utilization, and
      degradation of heme in a coordinate manner, and suggest that these alterations in
      heme metabolism may contribute to CYP1A1 induction by pyridine.

PMID- 10413314
TI  - Development of kindling-prone and kindling-resistant rats: selective breeding and
      electrophysiological studies.
AB  - Because of the growing need for an animal model of complex partial seizures based
      on a genetic predisposition, we combined the kindling model of epilepsy with
      selective-breeding procedures to develop two new lines (or strains) of rats that
      are kindling-prone or kindling-resistant. The selection of these strains was
      based on their rates of amygdala kindling. From a parent population of Long Evans
      hooded and Wistar rats, the males and females that showed the fastest and slowest
      amygdala kindling rates were selected and bred. Similar selection procedures
      continued through F11, although there was little or no overlap in the
      distribution of kindling rates for the two new strains (FAST and SLOW) by F6.
      Examination of both local and propagating seizure profiles of the new strains
      from F6 to F10 revealed that the FAST and SLOW rats had similar amygdala
      afterdischarge (AD) thresholds and associated AD durations. Also, the convulsion
      profiles of the stage-5 responses were similar, although the severity was greater
      in the FAST rats. Clearly the selection was not based on local mechanisms
      controlling the threshold for amygdala AD evocation, but rather for the spread of
      AD from the focus and the recruitment of other structures, ultimately triggering
      convulsive seizures. Although evoked potentials and potentiation effects were
      similar between the strains, the SLOW rats showed a greater paired-pulse
      depression, raising the possibility that they differ in inhibitory mechanisms.
      The specificity of strain differences for the amygdala and its associated
      networks is described in our accompanying paper (McIntyre et al., 1999. FAST and
      SLOW amygdala kindling rat strains: Comparison of amygdala, hippocampal, piriform
      and perirhinal cortex kindling. Epilepsy Res. 35, 197-209). These strains should
      provide many clues to the dispositional differences between individuals for the
      development of epilepsy originating in temporal lobe structures.

PMID- 10413313
TI  - Effects of zonisamide on K+ and Ca2+ evoked release of monoamine as well as K+
      evoked intracellular Ca2+ mobilization in rat hippocampus.
AB  - To clarify the effects of zonisamide (ZNS) on neurotransmission and intracellular
      Ca2+ mobilization, both Ca2+ and K+ evoked hippocampal releases of dopamine (DA)
      and serotonin (5-HT) were determined by in vivo microdialysis, and K+ (25 and 50
      mM) evoked elevation of intracellular Ca2+ level was determined by fluorescence
      microscopy in vitro. Therapeutic concentrations of ZNS had different effects on
      Ca2+ and K+ evoked release of monoamine. ZNS stimulated Ca2+ evoked monoamine
      release, while ZNS inhibited K+ evoked monoamine release. ZNS inhibited K+ evoked
      elevation of hippocampal intracellular Ca2+ levels in a concentration dependent
      manner. These results suggest that ZNS inhibits the depolarization induced by
      neuronal excitation, whereas ZNS might enhance the N-type Ca2+ channel activity
      or N-type Ca2+ channel related exocytosis mechanisms.

PMID- 10413316
TI  - Proton magnetic resonance spectroscopy of brain biopsies from patients with
      intractable epilepsy.
AB  - In the present study metabolite concentrations were determined by proton magnetic
      resonance spectroscopy (MRS) in biopsies obtained from patients suffering
      intractable epilepsy from several different causes. Seven patients had gliosis,
      four had mild cortical dysplasia, three had tuberous sclerosis, two had
      astrocytomas, and one had a cavernous angioma. No significant differences were
      found in gliotic tissue in comparison with controls except for an increase in
      lactate. However, in the subgroup with tuberous sclerosis an increase was found
      in GABA and a dramatic decrease in N-acetyl aspartate (NAA). The most marked
      changes were found in the group with mild cortical dysplasia. There was a
      considerable decrease in NAA as well as large increases in GABA, alanine,
      tyrosine, acetate, inositol, glucose and lactate. The GABA content did not appear
      to correlate with antiepileptic therapy. Moreover, since all these patients
      required surgery, an elevated GABA level does not necessarily provide protection
      from seizures. The results indicate that use of proton MRS could become a useful
      presurgical predictor of underlying pathology.

PMID- 10413317
TI  - Medium- and long-term alterations of brain A1 and A2A adenosine receptor
      characteristics following repeated seizures in developing rats.
AB  - In order to assess long-lasting consequences of recurrent seizures during
      development, the effects of repeated seizures in developing rats were
      investigated on brain adenosine A1 and A2A receptors. The characteristics of A1
      and A2A receptors were analyzed by measuring the binding of the selective
      agonists [3H]CHA (N6-cyclohexyladenosine) and [3H]CGS 21680 (2-[p-(2
      carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido adenosine), respectively, on
      cerebral membrane preparations, whereas receptor coupling to G-proteins was
      examined by using a GTP analogue (Gpp(NH)p; guanylyl-5'-imidodiphosphate).
      Seizures were induced by bicuculline once a day at two different developmental
      stages: either from postnatal day 5 to postnatal day 7 (P5-P7) or from P15 to
      P17. Adenosine receptors were then studied at P15, P25 and P60. P5-P7 seizures
      led to an increase in A1 receptor density at P60 and to a decrease in their
      coupling to G-proteins at P15, but they did not affect A2A receptors. P15-P17
      seizures decreased the coupling of A1 receptors to G-proteins at P25 and P60,
      reduced the density of A2A receptors at P25 and increased their affinity at P60.
      These results depict a persistent sensitivity of both A1 and A2A brain adenosine
      receptors to repeated seizures, with selective receptor alterations according to
      the cerebral maturational stage when seizures occur. In respect to the
      neuromodulatory and anticonvulsant properties of adenosine, such changes might be
      implicated in long-term functional brain reorganization after early seizures and
      future susceptibility to convulsive disorders.

PMID- 10413318
TI  - Auditory naming and temporal lobe epilepsy.
AB  - Patients with left (i.e. language-dominant) temporal lobe epilepsy (TLE)
      typically report word finding difficulties. However, these deficits are not
      reliably detected with traditional visual object naming tests. We administered
      both visual and auditory naming tests to left and right TLE patients and normal
      controls. We hypothesized that an auditory naming test might be more sensitive
      since it better simulates the conditions under which word finding problems occur
      in daily living. The left TLE group obtained significantly lower scores than
      other groups on auditory naming, whereas their performance on visual naming was
      indistinguishable from that of right TLE patients and normals. Furthermore,
      whereas cut-off scores on the auditory naming task predicted seizure focus
      laterality in 85% of patients, performance on the visual naming task predicted
      laterality in only 60% of patients. These findings suggest that compared with
      visual naming, as assessed in the present study, auditory naming may more
      accurately characterize and lateralize TLE-associated language dysfunction. These
      results also propose a more complex understanding of word retrieval that
      incorporates modality and contextual information.

PMID- 10413319
TI  - Applications of neural network analyses to in vivo 1H magnetic resonance
      spectroscopy of epilepsy patients.
AB  - A total of 67 in vivo water-suppressed proton magnetic resonance spectra of the
      temporal lobes were recorded from 15 patients with long standing temporal lobe
      epilepsy and 13 healthy volunteers. Conventional data analysis indicated slightly
      lower N-acetyl aspartate levels in epileptic patients compared with controls. For
      further analysis of data, a spectral region (4.0-1.5 ppm) was used as input for
      artificial neural network analysis. Correct classification of spectra was
      obtained in 66 out of 67 cases, disregarding from which side of the brain the
      spectra were recorded. The ability of the trained network to recognize spectra
      recorded both contalaterally and ipsilaterally to the epileptic focus strongly
      indicates bilateral metabolic changes. Artificial neural networks could also be
      trained to recognize whether the spectra were recorded from the ipsilateral or
      contralateral side of the epileptic focus, indicating that neural network
      analysis of in vivo proton MR spectra can be used as an additional tool for pre
      surgical lateralization of seizure foci.

PMID- 10413322
TI  - Expression of a non-inactivating K+ channel driven by a rat heat shock promoter
      increased the resting potential in Aplysia silent neurons.
AB  - We assessed the role of a non-inactivating K+ channel (aKv5.1) in the resting
      potential by overexpressing this channel by heat shock in the neurons. A reporter
      gene lacZ linked to a promoter region spanning from the -285 to the +88 base of
      the rat HSP70ib gene was induced 62.5-fold when this DNA construct was
      microinjected into the neurons of the marine mollusk Aplysia and treated with
      heat shock at 30 degrees C for 3 h. Using this efficient induction system, we
      induced the expression of aKv5.1 by heat shock in cultured, electrically silent
      neurons of Aplysia and examined its effect on the resting potential. The channel
      expression increased the resting potential by approximately 10 mV. This increase
      was specific to heat shock induction and abolished by treatment with TEA, a
      specific K+ channel blocker. These results provide the direct evidence that a low
      voltage-activated, non-inactivating K+ channel can contribute to the resting
      potential.

PMID- 10413320
TI  - A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin.
AB  - CYP2C9 is mainly responsible for the metabolic clearance of phenytoin and (S)
      warfarin. We have shown previously that mutations in the CYP2C9 gene are
      associated with diminished metabolism of (S)-warfarin, and so we have now studied
      the metabolism of phenytoin to its primary inactive metabolite, (S)-pHPPH, by
      these mutant enzymes. Kinetic parameters were determined for (S)-pHPPH formation
      using recombinant CYP2C9 variants purified from insect cells. The data
      demonstrate that the CYP2C9*3 gene product retains only 4-6% of the metabolic
      efficiency of the wild-type protein, CYP2C9*1, towards phenytoin and (S)
      warfarin. Consequently, we suggest that homozygous expression of CYP2C9*3 may
      represent a common genetic basis for (apparently) idiosyncratic toxicities that
      have been reported for these two low therapeutic index drugs.

PMID- 10413315
TI  - FAST and SLOW amygdala kindling rat strains: comparison of amygdala, hippocampal,
      piriform and perirhinal cortex kindling.
AB  - In our companion paper, we selectively bred offspring of a Long Evans Hooded and
      Wistar rat cross for either fast or slow rates of amygdala kindling (Racine et
      al., 1999. Development of kindling-prone and kindling resistant rats: Selective
      breeding and electrophysiological studies, Epilepsy Res. 35, 183-195). Within 10
      generations, there was no overlap in the distribution of kindling rates between
      these newly developed FAST and SLOW kindling strains. In the present report, we
      compared the local excitability, kindling rates, and convulsion profiles of
      kindling sites in either the amygdala, dorsal hippocampus, piriform cortex or
      perirhinal cortex in the two strains. Local excitability, measured as the local
      afterdischarge (AD) threshold and its duration, showed varied effects between
      structures and strains. Before kindling, the AD threshold was lower in the FAST
      than the SLOW rats in the hippocampus, piriform and perirhinal cortices, but not
      the amygdala (the selection structure). Also, the duration of the AD threshold
      duration was significantly longer in the FAST than in the SLOW rats in all
      structures, except the CA1 hippocampus. Most of these differences were maintained
      after kindling. Kindling itself was significantly faster in the FAST compared
      with the SLOW rats in all structures; however, the different structural kindling
      rates showed proportional differences between strains that were about five times
      different in the amygdala compared with only about two times different in the
      hippocampus. This suggested a selection bias for the amygdala and its networks.
      As in other rat strains, the fastest kindling rates were seen in the perirhinal
      cortex followed by the piriform cortex, amygdala and hippocampus in both FAST and
      SLOW rats. Other important differences between strains and structures occurred in
      the stage-5 convulsion profiles, including latency to forelimb clonus, clonus
      duration and duration of associated local afterdischarges. The differences in
      kindling profiles between strains and structures were discussed with respect to
      possible underlying mechanisms, significance for epileptogenesis, and impact on
      other normal behaviours.

PMID- 10413323
TI  - Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain.
AB  - Neurofibrillary tangles (NFT) in Alzheimer's disease (AD) consist largely of
      hyperphosphorylated tau protein. Many of the phosphorylation sites on tau are
      serine/threonine-proline sequences, several of which are phosphorylated in vitro
      by neuronal Cdc2-like kinase (Nclk), a kinase composed of Cdk5 and its
      activator(s). Thus, tau hyperphosphorylation in AD may result in part from
      deregulation of Nclk. To test this hypothesis, we examined Nclk activity in
      prefrontal and cerebellar cortex from 15 postmortem AD and 16 age-matched control
      subjects, and corrected either for Cdk5 level or for neuronal loss. The ratio of
      Nclk activity in prefrontal versus cerebellar cortex was then compared. When
      corrections were made for neuronal loss, the ratios of kinase activity in
      prefrontal versus cerebellar cortex were significantly higher in AD (6.45+/-0.86)
      than the controls (3.13+/-0.46; P = 0.003). This finding is consistent with a
      role for Nclk in the pathogenesis of NFT in AD.

PMID- 10413321
TI  - Dipeptidyl aminopeptidase IV and aminopeptidase P, two proline specific enzymes
      from the cytoplasm of guinea-pig brain: their role in metabolism of peptides
      containing consecutive prolines.
AB  - In this study the majority of dipeptidyl aminopeptidase IV and aminopeptidase P
      activities of guinea-pig brain are reported to reside in the cytoplasm. Both
      activities were purified and soluble dipeptidyl aminopeptidase IV was found to
      have a relative molecular mass of 194000 and to be comprised of two equal
      subunits of relative molecular mass 93000 while native soluble aminopeptidase P
      had a relative molecular mass of 140000. Both activities require proline or
      alanine in the penultimate position from the N-terminus. Dipeptidyl
      aminopeptidase IV removed the N-terminal dipeptide whereas aminopeptidase P
      removed only the N-terminal amino acid. Dipeptidyl aminopeptidase IV was inactive
      if proline was also present in the third position from the N-terminus whereas
      aminopeptidase P was unable to remove the N-terminal glycyl, pyroglutamyl or
      prolyl residues even though proline was present in the second position. Soluble
      dipeptidyl aminopeptidase IV was differentiated from the previously reported
      particulate form by its sensitivity to p-chloromercuribenzoate, N-ethyl maleimide
      and puromycin. The metabolism of Leu-Pro-Pro-Ser by guinea-pig cytoplasm was
      investigated in the presence of inhibitors to evaluate the contribution by
      dipeptidyl aminopeptidase IV and aminopeptidase P to the hydrolysis of a peptide
      containing two consecutive proline residues. The results indicated that either
      dipeptidyl aminopeptidase IV or prolyl oligopeptidase were required along with
      aminopeptidase P and prolidase to achieve complete hydrolysis of this
      tetrapeptide.

PMID- 10413324
TI  - Influence of gamma-aminobutyric acid on retinal cells excitotoxicity upon glucose
      deprivation.
AB  - The role of extracellular endogenous gamma-aminobutyric acid (GABA) in rescuing
      retinal cells in culture from the decrease in viability induced by Glu under
      metabolic inhibition is analyzed. Glutamate (10 microM-10 mM) dose-dependently
      decreased the intracellular GABA content, but increased the extracellular
      accumulation of GABA. In the absence of glucose, Glu (10-100 microM) decreased
      the intracellular GABA (2-fold), whereas the extracellular accumulation of GABA
      was increased by about 4-fold. Glu-mediated decrement in cell survival was not
      affected by inhibiting the GABA(A) receptors with bicuculline (1 or 10 microM) or
      by blocking the Na+ -dependent release of GABA with 1-(4,4-diphenyl-3-butenyl)-3
      piperidinecarboxylic acid (SKF89976-A). Data suggest a non-protective role of
      endogenous GABA release after metabolic deprivation of retinal cells submitted to
      Glu.

PMID- 10413325
TI  - Changes in reflex responses of the masseter and digastric muscles during sleep in
      freely behaving rabbits.
AB  - The aim of this study was to clarify the modulation of motoneuron excitability in
      masticatory muscles during sleep. For this purpose, changes in the reflex
      responses of the masseter and digastric muscles between sleep and wakefulness
      were studied in freely behaving rabbits. Stimulation of the jaw closing muscle
      spindle afferents induced the masseteric monosynaptic reflex (MMR). During quiet
      sleep (QS), which gradually replaced quiet wakefulness, the mean MMR amplitude
      showed no change. During active sleep (AS). MMR amplitudes were markedly reduced,
      but they were confounded by the occasional occurrence of facilitation in the
      amplitude. The facilitatory reflexes were often related to rapid eye movements
      (REMs). However, the excitatory input probably did not originate from the same
      region as the REM generator, since the REM and the large MMR did not always occur
      simultaneously. On the other hand, jaw opening reflexes remained inhibited. The
      results indicated that there is mainly a difference in the excitability between
      the two groups of motoneurons during AS; masseter motoneuron activity was
      inhibited but occasionally facilitated by excitatory inputs occurring in
      association with REMs, however, the digastric motoneuron activity was remained
      inhibited. The excitatory inputs may induce dysfunctional muscle contraction of
      the jaw closing muscles as seen in bruxism.

PMID- 10413326
TI  - The temporal and spatial development of CRF binding sites in the postnatal mouse
      cerebellum.
AB  - This study describes the distribution and relative level of labeling of binding
      sites for corticotrophin releasing factor (CRF) in the postnatal mouse
      cerebellum. At birth low levels of labeling are present throughout the
      cerebellum. However, this labeling is most densely distributed in the caudal and
      lateral aspects of the cerebellum. By P3 CRF binding sites are present throughout
      the cerebellum, although the greatest level of labeling is in the posterior lobe
      of the vermis, especially lobules IX and X; this correlates with the early
      differential pattern of CRF distribution in cerebellar afferents within these
      same lobules. At P10, the adult pattern of distribution and level of labeling
      begins to emerge. The presence of CRF and CRF binding sites at birth, and during
      postnatal growth, suggests that this peptide could play a role in the regulation
      of developmental events within the cerebellum.

PMID- 10413328
TI  - Reduction in terminal excitability of nigrostriatal dopaminergic neurons in rats
      following chronic L-dopa administration.
AB  - The effects of chronic L-dopa administration on antidromic excitability and the
      firing rate of nigrostriatal dopaminergic neurons were investigated in urethane
      anesthetized rats. Rats that received daily L-dopa (100 mg/kg) and carbidopa (25
      mg/kg) for 60 days showed a marked decrease in terminal excitability compared
      with the controls. There were no significant differences in the firing rates
      between the two groups. This finding may be related to impaired striatal dopamine
      release from exogenous L-dopa subsequent to chronic L-dopa treatment.

PMID- 10413327
TI  - Extrastriatal dopaminergic innervation of human basal ganglia.
AB  - A tyrosine-hydroxylase immunohistochemical analysis of the brains of normal human
      individuals has revealed nigrostriatal axons providing collaterals that arborize
      in the pallidum and subthalamic nucleus. These thin and varicose collaterals
      emerge from thick and smooth axons that course backward along the main output
      pathways of the basal ganglia, including the ansa lenticularis, the lenticular
      fasciculus and Wilson's pencils. Many of these fibers run within pallidal
      medullary laminae before reaching the putamen, whereas others climb along the
      reticular thalamic nucleus to reach the caudate nucleus. This extrastriatal
      innervation, which allows nigral dopaminergic neurons to directly affect the
      pallidum and subthalamic nucleus, may play a crucial role in the functional
      organization of human basal ganglia, in both health and disease.

PMID- 10413329
TI  - Case-control studies using only malformed infants: are we interpreting the
      results correctly?

PMID- 10413331
TI  - First-trimester exposure to topical tretinoin: its safety is not warranted.

PMID- 10413330
TI  - Acute toxicity of folic acid in pregnant women.

PMID- 10413332
TI  - Effects of methionine supplement on methionine incorporation in rat embryos
      cultured in vitro.
AB  - The effect of supplementary L-methionine (Met) on the incorporation of methionine
      was evaluated in 9.5-day rat conceptuses cultured in vitro. Parallel experiments
      with L-leucine (Leu) were performed for comparison. Conceptuses were cultured for
      24 hr in the presence of 3H-labeled Met or Leu, and the incorporation of
      radiolabel into the embryo and visceral yolk sac was measured. Supplementary Met
      proportionately increased the incorporation of Met, but supplementary Leu did not
      have as great an effect on the incorporation of Leu. A hypothesis is presented to
      explain these findings. It is proposed that Met, but not Leu, is a rate-limiting
      nutrient for organogenesis-stage rat embryos cultured in rat serum. The results
      are also discussed with reference to the established efficacy of supplementary
      folic acid in decreasing the incidence of neural tube defects in human
      populations and to claims that Met reverses certain teratogenic phenomena, both
      in vitro and in vivo.

PMID- 10413333
TI  - Developmental delay in fetal aminopterin/methotrexate syndrome.
AB  - Maternal exposures to aminopterin and methotrexate have been associated with a
      pattern of malformation which includes prenatal-onset growth deficiency, severe
      lack of ossification of the calvarium, hypoplastic supraorbital ridges, small,
      low-set ears, micrognathia, and limb abnormalities. We report on a patient whose
      mother received methotrexate during the first trimester of pregnancy and who, in
      addition to the structural anomalies typical of maternal methotrexate exposure,
      has significant developmental delay. This is the third patient exposed to folic
      acid antagonists with mental retardation, providing further evidence that
      developmental delay is one feature of fetal aminopterin-methotrexate syndrome.
      Therefore, it is recommended that formal developmental testing be performed in
      all patients prenatally exposed to methotrexate.

PMID- 10413334
TI  - Differential sensitivity of the SWV and C57BL/6 mouse strains to the teratogenic
      action of single administrations of cadmium given throughout the period of
      anterior neuropore closure.
AB  - When administered to mice during gestation, the heavy metal, cadmium, is known to
      induce malformations of the neural tube, craniofacial region, limbs, trunk,
      viscera, and axial skeleton that vary in scope and severity among inbred strains
      of mice. Two strains, C57BL/6 and SWV, were previously shown to differ in their
      susceptibility to exencephaly induced by many teratogenic treatments, including
      sodium 2-ethylhexanoate, hyperthermia, valproic acid, and carbon dioxide, with
      the SWV strain being consistently more sensitive than the C57BL/6 strain. These
      findings support the observation of Finnell et al. ([1988] Teratology 38:313-320)
      of shared hierarchies of relative susceptibility to exencephaly induced by
      biochemically distinct teratogens, and suggest that the SWV strain would also be
      more sensitive to exencephaly induced by cadmium. In the present study, pregnant
      mice from the two strains were exposed to single i.p. injections of cadmium
      chloride at 4 mg/kg-BW on day 6.5, 7.0, 7.5, 8.0, 8.5, or 9.0 of gestation.
      Fetuses were removed by cesarean section on day 18 of gestation and scored for
      malformations. The C57BL/6 strain was observed to be more sensitive than the SWV
      strain to the induction of exencephaly by cadmium on days 6.5, 7.0, and 8.0, with
      mean litter percentages of 3.6%, 88.3%, and 62.2%, respectively, compared to
      0.0%, 4.1%, and 27.7% for the SWV strain. This finding provides evidence in
      contrast to the hypothesis of shared hierarchies of sensitivity to teratogen
      induced exencephaly. Data on a number of other cadmium-induced malformations are
      also presented.

PMID- 10413335
TI  - Cystic malformation of the posterior cerebellar vermis in transgenic mice that
      ectopically express Engrailed-1, a homeodomain transcription factor.
AB  - In WEXPZ-En-1 transgenic mice, Engrailed-1, a homeodomain-containing
      transcription factor, is ectopically expressed in the developing brain under
      control of the Wnt-1 enhancer. En-1 is a developmental regulatory control gene
      which has an essential role in the formation of the midbrain and cerebellum.
      Approximately 28% of WEXPZ-En-1 + mice develop cystic malformations of the
      posterior lobe of the cerebellar vermis, fourth ventricular dilatation, and
      postnatal hydrocephalus. These anatomic features are also found among the
      spectrum of posterior fossa malformations in humans. Expression characteristics
      of the WEXP transgene suggest that the neuropathology observed in WEXPZ-En-1+
      mice stems from overexpression of En-1 during fetal and neonatal phases of
      cerebellar development. These observations raise the possibility that abnormal
      regulation of Engrailed genes, or targets of Engrailed, may be involved in the
      pathogenesis of cystic central nervous system malformations of the posterior
      fossa in humans.

PMID- 10413336
TI  - Awareness of folic acid for neural tube defect prevention among Israeli women.
AB  - The failure of neural tube closure during early embryogenesis results in a range
      of neural tube defects (NTD), the most common of which is spina bifida. The role
      of folic acid in reducing the rate of NTD has been well-established. Three recent
      cases of infants with NTD inspired this investigative study into the level of
      awareness and knowledge of folic acid and its function in the prevention of NTD
      among Israeli women. Of 920 women interviewed, only 51 (5.5%) had heard of folic
      acid, and 27 (2.8%) were reported to have taken it. The source of information and
      the motivation for self-medication were also explored with regard to
      socioeconomic and health profile. Awareness of folic acid was significant among
      women aged 17-29 years (P = 0.005) and those aged 30-39 years (P = 0.009), and
      among semireligious and nonreligious women (P = 0.008 and 0.01, respectively).
      Among women who were aware of folic acid, only nonreligious women tended to take
      it. No correlation was found between folic acid intake and age, religiosity,
      nationality, number of pregnancies, and health status among women who were aware
      of folic acid intake. The poor level of awareness, evident in our study, demands
      that the medical community broadcast the benefit of folic acid. Furthermore,
      government health initiatives, such as the addition of folic acid to flour
      preparations, may effectively ensure its appropriate daily intake. These improved
      education and prevention programs may forcibly reduce the rate of NTD-affected
      pregnancies.

PMID- 10413338
TI  - RAPADILINO syndrome: a multiple malformation syndrome with radial and patellar
      aplasia.

PMID- 10413337
TI  - Improvement of drug exposure data in a registration of congenital anomalies.
      Pilot-study: pharmacist and mother as sources for drug exposure data during
      pregnancy. EuroMAP Group. Europen Medicine and Pregnancy Group.
AB  - We examined the possibilities of improving the retrospective collection of data
      on drug use during pregnancy. The European Registration of Congenital Anomalies
      (EUROCAT) has registered information on maternal drug exposure in the northern
      Netherlands through a question on the notification form for the registration of
      birth defects, filled out by physicians or midwives since 1981. Furthermore,
      hospital records are used and general practitioners are asked to add information
      on drug use. The present pilot study used pharmacy records and maternal
      questionnaires as well as maternal interview data to complete the data on drug
      exposure in the EUROCAT registration. Combined information from pharmacies,
      questionnaires, and interviews with the mother were used as the reference
      standard. Pharmacy records provided detailed data on 57% of drugs used
      (prescription drugs, mainly). Mothers were able to report 76% of drug groups
      used, but when only data on the exact name of the drug were studied, this figure
      was 52%. Of the drugs dispensed by the pharmacy, 6% were not used (false
      positives). We conclude that pharmacy records and maternal interviews are both
      indispensable sources of information on maternal drug exposure that provide much
      added value.

PMID- 10413339
TI  - Minireview: summary of the initial development of the human nervous system.
AB  - Ten points concerning the early development of the human nervous system and that
      are rarely appreciated in the literature are summarized. Opportune and
      discriminative comments on prenatal age are included, and a scheme illustrating
      the 10 points is provided.

PMID- 10413340
TI  - Teratogen update: methylene blue.

PMID- 10413341
TI  - Is there a rational basis for post-surgical lifting restrictions? 1. Current
      understanding.
AB  - Lifting restrictions postoperatively are quite common, but there appears to be
      little scientific basis for them. Lifting restrictions are inhibitory in terms of
      return to work and may be a factor in chronicity. The mean functional spinal
      motion unit stiffness changes with in vitro or computer-simulated discectomies,
      facetectomies and laminectomies were reviewed from the literature. We modified
      the NIOSH lifting equation to include another multiplier related to stiffness
      change post surgery. The new recommended lifts were computed for different
      lifting conditions seen in industry. The reduction of rotational stiffness ranged
      from 21% to 41% for a discectomy, 1% to 59% for a facetectomy and 4% to 16% for a
      partial laminectomy. The recommended lifts based on our modified equation were
      adjusted accordingly. There is no rational basis for current lifting
      restrictions. The risk to the spine is a function of many other variables as well
      as weight (i.e., distance of weight from body). The adjusted NIOSH guidelines
      provide a reasonable way to estimate weight restrictions and accommodations such
      as lifting aids. Such restrictions should be as liberal as possible so as to
      facilitate, not prevent, return to work. Patients need more advice regarding
      lifting activities and clinicians should be more knowledgeable about the working
      conditions and constraints of a given workplace to effectively match the solution
      to the patient's condition.

PMID- 10413342
TI  - Is there a rational basis for post-surgical lifting restrictions? 2. Possible
      scientific approach.
AB  - Lifting restrictions postoperatively are quite common but there appears to be
      little scientific basis for them. Lifting restricitions are inhibitory in terms
      of return to work and may be a factor in chronicity. The mean changes in
      functional spinal motion unit (FSU) stiffness with in vitro or computer-simulated
      discectomies, facetectomies and laminectomies were reviewed from the literature.
      We modified the NIOSH lifting equation to include another multiplier related to
      stiffness change post surgery. The new recommended lifts were computed for
      different lifting conditions seen in industry. The reduction of rotational
      stiffness ranged from 21% to 41% for a discectomy, 1% to 59% for a facetectomy
      and 4% to 16% for a partial laminectomy. The recommended lifts based on our
      modified equation were adjusted accordingly. There is no rational basis for
      current lifting resctrictions. The risk to the spine is a function of many other
      variables as well as weight (i.e., distance of weight from body). The adjusted
      NIOSH guidelines provide a reasonable way to estimate weight restrictions and
      accomodations such as lifting aids. Such resitrictions should be as liberal as
      possible so as to facilitate, not prevent, return to work. Patients need more
      advice regarding lifting activities and clinicians should be more knowledgeable
      about the working conditions and constraints of a given workplace to effectively
      match the solution to the patient's condition.

PMID- 10413343
TI  - Sitting and low back pain: the positive effect of rotary dynamic stimuli during
      prolonged sitting.
AB  - In this study the effect of dynamic stimuli on low back pain during prolonged
      sitting was investigated. The pain experience of two groups of 60 subjects with a
      specific low back pain was recorded. All subjects were investigated on pain
      behaviour by the Multidimensional Pain Inventory (MPI) and pain was measured on
      an open visual analogue scale (VAS). During sitting, one group received dynamic
      stimuli that were generated by alternating rotations in the horizontal plane of
      the seat of the chair, with back and arm rests in fixed position. Two different
      frequencies of rotation were applied in subgroups. The authors concluded that
      such stimuli, especially of the lower frequency, reduced pain in prolonged
      sitting.

PMID- 10413344
TI  - Correlation of MR images of disc injuries with anatomic sections in experimental
      thoracolumbar spine fractures.
AB  - This cadaver study evaluated the value of MR images for detection of acute
      intervertebral disc damage associated with fractures of the thoracolumbar spine.
      Damage to the intervertebral disc may be a major contributor to chronic
      instability in non-operative treatment or failure of fixation and recurrence of
      deformity in posterior fixation methods. MR imaging can help us to understand the
      injury patterns and their prognostic significance. However, before we can justify
      the use of MRI in clinical cases, determination of MRI's ability to detect acute
      injury to the disc is necessary. Ten fresh cadaver specimens were used for this
      study. After obtaining radiograms and MR images, injuries were created with a
      weight-dropping apparatus using a variety of weights and compression angles. Post
      injury radiograms and MR images were taken and the specimens were frozen at -20
      degrees C. Slides of these specimens obtained with cryosection techniques were
      compared with MR images for evaluation of the damage to different parts of the
      discs. A total of 20 fractures were observed on cryosections. In 12 of the discs
      adjacent to fractured vertebral bodies, macroscopic damage was seen on the
      sections. These were all detected on the corresponding MR images. The study
      showed that MRI is able to detect acute, macroscopic injury to the intervertebral
      disc. It is therefore justified to use MR for the study of acute disc damage
      associated with thoracolumbar fractures.

PMID- 10413345
TI  - The value of MR imaging in differentiating between hard and soft cervical disc
      disease: a comparison with intraoperative findings.
AB  - The aim of this study is to assess the accuracy of MRI alone in the
      differentiation of soft cervical disc protrusion from osteophytic compression in
      cervical disc disease. In a retrospective study, the MRI scans of 41 patients
      with cervical disc disease, who had previously undergone surgery, were presented
      to three independent observers, randomly on two different occasions, to identify
      the accuracy of the diagnosis of the presence of hard or soft disc or both as a
      cause of compression. The observers (two neurosurgeons and one neuroradiologist)
      were not involved with the treatment of the cases at any stage and were unaware
      of the surgical findings. Their observations were compared with those of the
      surgeon recorded at operation. The intra-observer agreement was poor for
      diagnosis into three categories as hard or soft disc or both. In distinguishing
      between the presence or absence of hard disc, there was moderate to good (Kappa =
      0.6) intra observer and fair to moderate (Kappa = 0.4) interobserver agreement.
      The sensitivity of diagnosis of a hard disc was high (87%) but specificity was
      low (44%), due to the overestimation of the presence of hard disc. There was a
      significantly higher incidence of hard disc in the elderly age group (76% over
      the fifth decade, P = 0.0073). It is concluded that MRI alone is not a very
      efficient diagnostic tool in distinguishing between hard and soft disc in the
      cervical disc disease.

PMID- 10413346
TI  - Bone scintigraphy in tuberculous spondylodiscitis.
AB  - Tuberculous affection of the spine can present in different ways. Plain
      radiographs may fail to show any abnormality. Bone scintigraphy can be a very
      useful tool in the diagnosis and management of patients with tuberculous
      spondylodiscitis. This is a retrospective study of 40 patients in whom bone scan
      was performed using 99mTc-MDP (technetium methylene diphosphonate) before
      starting anti-tuberculous therapy or any surgical intervention. Four different
      types of uptake were noted. The uptake was abnormal in 38 out of 40 patients,
      giving a sensitivity of 95%. Multicentricity was picked up in 25% of cases. No
      skull lesion was noticed in any of these patients. Rib lesions were found in six
      patients (ten ribs affected). The rib lesion was always a typical band pattern.
      This paper outlines the advantages as well as limitations of bone scan in
      tuberculous affection of the spine.

PMID- 10413347
TI  - Artificial disc replacement with the modular type SB Charite III: 2-year results
      in 50 prospectively studied patients.
AB  - The Modular Type SB Charite disc prosthesis has been developed as a device for
      artificial disc replacement (ADR) in patients with symptomatic discopathies.
      Here, we report on our first series of 50 (out of 350) patients, who had a
      satisfactory clinical result in 70% of cases (2 years' follow-up). Subgroup
      analysis revealed that patients with an isolated discopathy without previous
      spinal operations or other pathology at the same or other spinal level benefitted
      more from the surgery. However, this technique was associated with some problems:
      a 13% rate of permanent side-effects and/or complications was observed caused by
      the anterior approach. Four percent were related to poor implantation technique.
      There were no problems related to the material of the prosthesis. Twelve patients
      needed re-operation, but this was beneficial in only three of them. In one
      patient we had to convert to an interbody fusion. We conclude that in patients
      with severe isolated symptomatic discopathies that are resistant to conservative
      treatment, a mobile disc prosthesis is worth considering as a real alternative to
      a spondylodesis. However, accurate patient selection is imperative. With these
      criteria we were encouraged by our results to continue the implantation of this
      artificial disc.

PMID- 10413348
TI  - Lumbosacral extradural arachnoid cysts: diagnostic and indication for surgery.
AB  - No critical discussion of the indication for the surgical treatment of
      lumbosacral extradural arachnoid cysts is found in the literature. Therefore, we
      want to compare the results in patients with operative and conservative treatment
      to define standards for a good surgical result. Over a period of 9 years, we
      operated on eight patients with a lumbosacral extradural arachnoid cyst and
      treated eight others conservatively. Only three of the operated patients
      experienced a postoperative relief of pain, but none was symptom free. The only
      one with continuing success had a preoperative history of 1 year only. MRI scans
      without contrast agent were misinterpreted in one included and one excluded case.
      The results of conservative treatment were nearly the same as those of operative
      treatment. MRI is the best diagnostic tool, but a variety of sequences must be
      used. Patients with a short pain history and a clear neurological deficit
      profited most from surgery. Patients with slight and not clearly related
      uncharacteristic symptoms should be excluded from surgery.

PMID- 10413349
TI  - Preliminary CT study of C1-C2 rotational mobility in normal subjects.
AB  - A CT study of normal atlanto-axial (C1-C2) rotary mobility was carried out on ten
      normal immature subjects. In order to determine the limits of normality, the ten
      children underwent clinical and radiological examination. The clinical study
      included checking for objective signs of joint laxity and measurement of
      rotational neck mobility. The radiological study included standard lateral
      radiographs in neutral and maximal flexion positions and a CT scan taken in
      maximal left and right side rotation at the C1-C2 articular processes joint. The
      superpositioning of the images taken in every rotational direction showed, in all
      ten children, a wide contact loss between the C1-C2 corresponding facets, ranging
      from 74 to 85% of the total articular surface. The report on these images,
      carried out by three independent radiologists, concluded that there was a rotary
      subluxation in all cases. In the ten children studied, there were no significant
      differences with regard to neck mobility or laxity signs in clinical or standard
      X-ray examination. Our results lead us to conclude that, except for complete C1
      C2 rotational dislocation with facet interlocking, a CT scan showing a wide - but
      incomplete - rotational facet displacement is not sufficient to define a status
      of subluxation. This leads us to perceive that there is a risk of overdiagnosis
      when evaluating upper cervical spine rotational problems in children. The concept
      of both rotary C1-C2 fixation and subluxation should be revised.

PMID- 10413350
TI  - The 'MW' sacropelvic construct: an enhanced fixation of the lumbosacral junction
      in neuromuscular pelvic obliquity.
AB  - Fixation to the lumbosacral spine to correct pelvic obliquity in neuromuscular
      scoliosis has always remained a surgical challenge. The strongest fixation of the
      lumbosacral junction has been achieved with either a Galveston technique with
      rods or screws or with iliosacral screws. We have devised a new fixation system,
      in which iliosacral screws are combined with iliac screws. This is made possible
      by using the AO Universal Spine System with side opening hooks above and below
      the iliosacral screws and iliac screws below it. The whole sacropelvis is thus
      encompassed by a maximum width (MW) fixation, which gives an 'M' appearance on
      the pelvic radiographs and a 'W' appearance in the axial plane. We report on our
      surgical technique and the early results where such a technique was used. We feel
      that this new means of fixation (by combining the strongest fixation systems) is
      extremely solid and should be included in the wide armamentarium of sacropelvic
      fixation.

PMID- 10413351
TI  - Cervical synovial cysts: case report and review of the literature.
AB  - The authors describe the case of a 58-year-old man with a 6-month history of
      severe myelopathy. CT scan and MRI of the spine revealed a cystic formation,
      measuring about 1 cm in diameter, at C7-T1 at a right posterolateral site at the
      level of the articular facet. At operation the mass appeared to originate from
      the ligamentum flavum at the level of the articular facet and was in contact with
      the dura mater. Once the mass had been removed, there was a significant
      amelioration of the patient's symptoms. As previously suspected, histological
      aspect was synovial cyst. Cervical synovial cysts are extremely rare and, as far
      as we know, only 22 cases have so far been described in the literature.
      Diagnostic radiological investigations used were CT scan and MRI. At CT scan the
      most important diagnostic findings are a posterolateral juxtafacet location of
      the mass, egg-shell calcifications on the wall of the cyst, and air inside the
      cyst. At MRI the contents of the cyst are iso/hypointense on T1- and hyperintense
      on T2-weighted images. There may also be a hypointense rim on T2-weighted images,
      which enhances after i.v. administration of gadolinium. Surgical treatment
      consists of removal of the mass. Fixation of the vertebral segments involved is
      not always necessary.

PMID- 10413352
TI  - Myelopathy due to calcification of the cervical ligamenta flava: a report of two
      cases in West Indian patients.
AB  - Two cases of cervical myelopathy due to calcification of the ligamenta flava
      (CLF) are described for the first time in black patients from the French West
      Indies. A pre-operative CT scan differentiated the diagnosis from one of
      ossification of the ligamenta flava. Microanalysis on the operatively excised
      specimen in one patient revealed a mixture of calcium pyrophosphate dihydrate
      crystals and hydroxypatite crystals. Poor outcome in one patient contrasting with
      excellent recovery in the other one, who had undergone posterior decompressive
      laminectomy, emphasizes the importance of surgery in the management of CLF.

PMID- 10413353
TI  - Vertical atlantoaxial dislocation.
AB  - An unusual case of vertical atlantoaxial dislocation without medulla oblongata or
      spinal cord injury is reported. The pathogenic process suggested occipito-axial
      dislocation. The case was treated surgically with excellent results on mobility
      and pain.

PMID- 10413354
TI  - Acute spinal cord compression due to intraspinal bleeding from a vertebral
      hemangioma: two case-reports.
AB  - Vertebral hemangiomas can cause acute spinal cord compression either after a
      minor trauma or during the last 3 months of pregnancy. Failure to recognize the
      lesion can lead to potentially serious treatment delays. An emergency MRI scan
      usually establishes the diagnosis of vertebral hemangioma responsible for spinal
      cord compression requiring laminectomy. We report two cases showing that
      posterior fixation should be considered: in our experience it prevents vertebral
      collapse during the interval preceding secondary vertebroplasty, which, if
      performed, provides highly significant pain relief.

PMID- 10413355
TI  - Induction of antibody response by DNA immunization of newborn baboons against
      influenza virus.
AB  - Previous studies showed that DNA immunization of newborn mice with plasmids
      expressing influenza virus antigens induced protective immunity. We have now
      extended the study of neonatal responsiveness to DNA vaccines to nonhuman
      primates. Baboons immunized as neonates with plasmids expressing type A influenza
      virus hemagglutinin (HA) and nucleoprotein (NP) in doses ranging from 40 microg
      to 1 mg per plasmid per dose developed virus-specific humoral responses. The
      titer and kinetics of appearance of virus-specific IgG antibodies were dose
      dependent. Specific antibodies were detected by enzyme-linked immunosorbent assay
      (ELISA) as early as 1 month after birth in baboons immunized with the highest and
      intermediate doses of vaccine. Virus-neutralizing antibodies were detected in the
      group of baboons immunized with the highest dose. The specificity of virus
      neutralizing antibodies was found to be directed against homologous determinants
      of HA; however, the IgG antibodies also cross-reacted with HA of a drift variant.
      Thus, DNA vaccination of newborn baboons with a prototype vaccine against
      influenza virus resulted in induction of specific humoral immunity.

PMID- 10413356
TI  - Recombinant vaccinia viruses protect against Clostridium perfringens alpha-toxin.
AB  - Recombinant vaccinia viruses that expressed the nontoxic C-domain of Clostridium
      perfringens alpha-toxin were constructed. The J2R (thymidine kinase [TK] gene)
      and B13R (serpin 2 [SPI-2] gene) loci were used as insertion sites for the
      clostridial DNA, and expression of the foreign protein was measured in each case.
      A double recombinant that encoded the alpha-toxin truncate at the B13R locus and
      the protective antigen of Bacillus anthracis at the J2R locus was also
      constructed. Although differences in expression of the alpha-toxin C-domain were
      recorded, all of the vaccinia recombinants protected mice against a lethal
      challenge with alpha-toxin demonstrating that a recombinant vaccinia virus can be
      used to provide protection against a toxin challenge that is known to be solely
      antibody mediated.

PMID- 10413357
TI  - Antigen-specific cytokine and antibody isotype profiles induced by mucosal and
      systemic immunization with recombinant adenoviruses.
AB  - We investigated antigen-specific antibody and T-cell responses in mice immunized
      with human adenovirus type 5 (HAd5) vectors expressing either the authentic or
      truncated form of glycoprotein D (gD and tgD, respectively) of bovine herpesvirus
      type 1 (BHV-1). We also tested whether different routes of immunization
      influenced the level and type of immunity. Immunization intranasally (i.n.)
      stimulated higher levels of gD-specific IgA in the lung and nasal washes and
      induced a higher frequency of gD-specific antibody secreting cells (CSs) in the
      lung than did immunization subcutaneously (s.c.). In addition, immunization i.n.
      stimulated gD-specific systemic antibody responses of a higher IgG1/IgG2a ratio
      and lower numbers of gD-specific interferon (IFN)-gamma SCs in the spleen than
      did immunization s.c. HAd5-specific responses also depended on the route of
      immunization and were characterized by lower IFN-gamma interleukin (IL)-4 ratios
      than gD-specific responses. Immunization with the tgD-expressing vector induced
      generally lower antibody and cytokine responses than the gD-expressing vector.
      Higher numbers of antigen-specific IgA SCs in the lung as measured by enzyme
      linked immunospot (ELISPOT) assay correlated with higher levels of IgA in the
      respiratory tract as measured by enzyme-linked immunosorbent (ELISA) assay,
      although there was no such correlation for IgG responses of any isotype. In
      conclusion, the route of immunization and form of antigen had an impact on the
      level and type of immune responses induced by adenovirus vectors.

PMID- 10413358
TI  - Induction of cytotoxic and helper T cell responses by modified simian
      immunodeficiency virus hypervariable epitope constructs.
AB  - We previously reported the broad humoral immunogenicity of peptides synthesized
      according to the cumulative variability of an epitope (1,16). These peptides,
      hypervariable epitope constructs (HECs), are designed to represent the envelope
      glycoproteins of several isolates of the simian immunodeficiency virus (SIV).
      When HEC peptides were conjugated to palmitic acid and palmitic acid ester
      (lipoHECs), they promoted the induction of cellular immune responses. SIV
      envelope lipoHEC immunization of BALB/c and ICR mice resulted in up to 80%
      cytotoxic T lymphocyte (CTL) lysis of SIV envelope-expressing target cells and
      SIV envelope-specific delayed type hypersensitivity (DTH). This DTH response was
      significantly higher than that of single peptide controls, and the response
      peaked at 24 hours. Strong SIV envelope-specific T-cell proliferative responses
      were also induced in mice with stimulation indexes higher than 20 for spleen
      cells and higher than 10 for lymph node cells. Overall, our results demonstrate
      that conjugation of these variable synthetic peptides to a lipid moiety results
      in an immunogen capable of inducing strong and cross-reactive cellular immune
      responses.

PMID- 10413359
TI  - Relationship between immunoclinical status and prevalence of viral sexually
      transmitted diseases among human immunodeficiency virus-1 seropositive patients
      in Ghana.
AB  - In view of the strong association between the acquired immunodeficiency syndrome
      (AIDS) and sexually transmitted diseases (STDs), we screened 182 human
      immunodeficiency virus (HIV)-1 infected patients over a 15-month period for
      serological markers to previously encountered or current STDs, most of viral
      etiology. The relationship between their immunological and clinical status and
      the prevalence of STDs was assessed and compared with that of 88 HIV-seronegative
      patients. Hepatitis B virus and Treponema pallidum were the most frequently
      occurring pathogens in both HIV-1-infected and HIV-seronegative patients.
      Hepatitis C virus (HCV) infection was also observed in both groups, but no HIV
      seronegative patient was infected with human T-lymphotropic virus type 1 (HTLV
      1). The Centers for Disease Control clinical staging of A1 through C3,
      representing asymptomatic to severe AIDS conditions, was observed in HIV-1
      patients with or without STDs. A mean CD4 count of 288 cells per microliter (95%
      CI of 237-340 cells per microliter) in HIV-1 patients was significantly lower (P
      < 0.05) than that in HIV-seronegative individuals with 1019 cells per microliter
      (95% CI of 924-1115 cells per microliter), irrespective of whether subjects in
      either group had previous or current STDs. The mean CD4 count of patients with a
      single infection from HIV-1 was not significantly different (P = 0.36) from that
      of HIV-1 patients with multiple infections. HIV-1 infection alone appears to be
      responsible for the marked immunodeficiency status of seropositive patients
      observed in this study.

PMID- 10413361
TI  - Bovine lymphocyte antigen-A11--specific peptide motif as a means to identify
      cytotoxic T-lymphocyte epitopes of bovine herpesvirus 1.
AB  - Major histocompatibility complex (MHC) class I molecules present 8- to 10-mer
      viral peptides to antiviral cytotoxic T lymphocytes (CTLs). Identification of the
      allele-specific peptide motifs (ASPMs) of class I molecules enables the
      prediction of potential CTL epitopes of a virus from its protein sequences. Based
      on the bovine herpesvirus 1 (BHV-1) protein sequences that conform to the BoLA
      A11 ASPM that we identified previously, potential CTL epitopes of BHV-1 were
      synthesized for use in cytotoxicity assays with CTLs from BHV-1-immunized calves.
      A peptide binding assay used to select the peptides that are most likely to be
      CTL epitopes categorized the peptides into groups of high, intermediate, and low
      binding capacity. Synthetic peptides stimulated lymphocytes from BHV-1-immunized
      calves to secrete interferon-gamma. Groups of peptides from the major
      glycoproteins of BHV-1 restimulated CTLs in vitro and sensitized targets for
      lysis by means of restimulated bulk CTLs.

PMID- 10413360
TI  - Correlation of clinical parameters and immunological function with human
      immunodeficiency virus plasma viremia in children.
AB  - Studies of immune function in human immunodeficiency virus (HIV)-infected
      children are important, because functional abnormalities can precede CD4+ T-cell
      loss and are associated with the development of opportunistic and bacterial
      infections. We sought to correlate clinical parameters and immunological function
      with HIV RNA plasma levels in 20 children. HIV RNA levels were measured by a
      polymerase chain reaction assay. We analyzed T-cell responses to mitogens
      (phytohemagglutinin, concanavalin A, and pokeweed [PWM]) and antigens (tetanus
      toxoid and Candida albicans); T-cell suppressor activity; and humoral immunity to
      Haemophilus influenzae, hepatitis B, tetanus, and diphtheria vaccines. The median
      age of the children was 6 years. Eight children had HIV RNA levels less than 200
      to 9621 copies per milliliter (group I). Four children had 37,970 to 82,630
      copies per milliliter (group II). Eight children had 102,100 to 191,200 copies
      per milliliter (group III). There were no differences in the HIV-related
      complications between group I and II children. Group I/II children had
      significantly higher CD4+ T-cell counts (P = 0.02), less symptomatic HIV disease
      (P = 0.005), and more detectable protective vaccine immunity (P = 0.014) compared
      with group III children. Responses to mitogens were conserved in most children.
      Group I children tended to have higher responses to tetanus toxoid than group II
      children and significantly higher responses than group III children (P = 0.01).
      Group I had significantly higher responses to C. albicans than groups II (P =
      0.016) and III (P = 0.001). Group I/II children tended to have lower suppressor
      activity compared with group III children (median, 0 vs 64%). We demonstrated
      that humoral and cellular immune dysfunction exists at all stages of disease in
      HIV-infected children but was most severe in children with greater than or equal
      to 100,000 HIV RNA copies per milliliter. Function was the most intact in
      children with less than 10,000 copies per milliliter.

PMID- 10413362
TI  - Regulation of immune complexes during infection of mice with lactate
      dehydrogenase-elevating virus: studies with interferon-gamma gene knockout and
      tolerant mice.
AB  - Mice persistently infected with lactate dehydrogenase-elevating virus (LDV)
      develop circulating IgG-containing hydrophobic immune complexes, with a molecular
      mass of 150 to 300 kd, which bind to the surfaces of high-capacity enzyme-linked
      immunosorbent assay (ELISA) plates. LDV infection also stimulates polyclonal B
      cell activation and autoimmunity. For this study, interferon-gamma gene knockout
      (GKO) mice were utilized to study circulating immune complexes and other
      parameters of LDV infection. The kinetics of LDV viremia, formation of plasma IgG
      anti-LDV antibodies, and LDV replication in the spleen and liver were essentially
      normal in GKO mice. Polyclonal activation of B cells, as reflected by increased
      total plasma IgG concentration during LDV infection, was found to be intact in
      GKO mice, although at a lower magnitude than in control mice. The plasma
      concentration of IgG-containing hydrophobic immune complexes was reduced about
      75% in LDV-infected GKO mice relative to normal LDV-infected controls. Allogeneic
      tissue responses were also found to be reduced in LDV-infected GKO mice relative
      to those in normal LDV-infected controls. These results dissociate specific anti
      LDV immunity from formation of hydrophobic immune complexes, show that the IgG
      anti-LDV response as well as LDV replication in the spleen and liver are
      insensitive to physiological levels of interferon (IFN)-gamma, and suggest that
      IgG-containing immune complexes stimulated by LDV infection are a marker for
      autoimmunity.

PMID- 10413363
TI  - Effect of beta-chemokines on human immunodeficiency virus type 1 replication,
      binding, uncoating, and CCR5 receptor expression in human monocyte-derived
      macrophages.
AB  - OBJECTIVES: We examined the effect and time of addition of beta-chemokines on
      human immunodeficiency virus type 1 (HIV-1) replication, binding, and uncoating
      in human macrophages and measured CCR5 receptor expression during virus binding
      and uncoating. METHODS: Macrophages were treated with beta-chemokines before
      infection, at infection, or postinfection, and virus replication was determined
      by p24 antigen level. Binding and uncoating of 35[S]-methionine-labeled HIV-1 was
      measured. CCR5 expression was determined by flow cytometry. RESULTS: The beta
      chemokines potently inhibited virus replication. The strongest inhibition
      occurred when cultures were pretreated and maintained with beta-chemokines. Beta
      chemokines also caused strong inhibition of viral uncoating and a considerable
      decrease in CCR5 expression during uncoating. CONCLUSIONS: CCR5 receptors appear
      to be internalized and recycled to the cell surfaces during HIV entry. The down
      regulation of CCR5 expression by beta-chemokines during virus uncoating probably
      accounts for the reduction in virus uncoating (entry) and hence in virus
      replication.

PMID- 10413364
TI  - In vitro phenotype of SDF1 gene mutant that delays the onset of human
      immunodeficiency virus disease in vivo.
AB  - OBJECTIVE: Inheritance of a mutant allele of the SDF1 gene delays the onset of
      human immunodeficiency virus type 1 (HIV-1) disease. Because the mutation lies in
      the 3' untranslated region of the gene, it was suggested that this mutation may
      upregulate transcription of the gene, resulting in more abundant SDF1, which in
      turn inhibits T-tropic HIV-1 and delays disease onset. This implies that this
      segment of SDF1 gene contains a negative regulatory element. We directly tested
      this hypothesis in vitro. STUDY DESIGN/METHODS: We cloned the wild-type and the
      mutant SDF1 gene in an HIV-2 gene transfer vector as well as in a baculovirus
      expression vector. We expressed the cloned genes in human and insect cells in
      culture and analyzed the abundance of SDF1 RNA by hybridization and protein using
      antiviral assays. RESULTS: The abundance of SDF1 RNA synthesized by the mutant
      clone with the mutation in the 3' untranslated region was no different from that
      synthesized by the wild-type clone in cultured cells. This was the case for both
      the HIV-2 long terminal repeat (LTR)-directed expression in human cells and
      baculovirus promoter-directed expression in insect cells. Both clones apparently
      synthesized SDF1 with equivalent biologic activity. Similar results were obtained
      for a mutant with the deletion of a GC-rich segment in the 5' untranslated
      region. CONCLUSIONS: Mutation of the 3' untranslated exon did not affect SDF1 RNA
      synthesis in vitro. It also did not appear to affect translation of SDF1 RNA. A
      similar mutational analysis of the 5' noncoding exon suggested that this region
      also did not regulate SDF1 expression.

PMID- 10413365
TI  - Increased expression of nitric oxide synthase and dendritic injury in simian
      immunodeficiency virus encephalitis.
AB  - OBJECTIVES: Widespread dendritic injury may be one mechanism involved in the
      neurologic impairment that occurs in HIV-1 infection. The objectives of this
      study were to quantitate the extent of dendritic injury in a primate model of
      central nervous system (CNS) infection, investigate the role of nitric oxide (NO)
      as a mediator of neuropathologic changes, and evaluate the relation of these
      changes to cognitive and motor function. STUDY DESIGN/METHODS: Cognitive and
      motor function was assessed in rhesus macaque monkeys infected with simian
      immunodeficiency virus (SIV). In situ hybridization, immunohistochemistry, and
      quantitative image analysis were employed to assess the relations among
      productive infection, NO synthase (iNOS), and dendritic injury. RESULTS:
      Productive infection of cells of the macrophage lineage in CNS is associated with
      inflammation, increased expression of iNOS, and dendritic injury. The tests of
      cognitive and motor function employed were abnormal in both animals that had
      evidence of productive infection and those that did not. CONCLUSIONS: Increased
      NO accompanying productive infection and encephalitis may be one cause of
      neuronal injury in lentivirus infections of the CNS. Extension of tests of
      cognitive and motor function to late-stage AIDS in rhesus monkeys is needed to
      assess the potential role of NO-induced dendritic damage in lentiviral
      encephalopathy/AIDS dementia complex.

PMID- 10413366
TI  - Identification of insertion mutations in HIV-1 reverse transcriptase causing
      multiple drug resistance to nucleoside analogue reverse transcriptase inhibitors.
AB  - OBJECTIVE: A novel 2-amino acid insertion between codons 69 and 70 of human
      immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) which confers
      multiple drug resistance has recently been reported. Independently, we have
      identified similar insertion mutations in Japanese hemophiliacs and attempted to
      analyze their emergence in conjunction with therapy regimens and their
      contribution to drug resistance using recombinant technology. METHODS: The plasma
      and peripheral blood mononuclear cells (PBMCs) of 348 HIV-1-infected hemophiliacs
      were screened for HIV-1 RT mutations relevant to nucleoside analogue inhibitors
      and isolating viruses. Contribution of each insertion to drug resistance was
      studied by introducing the mutations into a T-cell line-tropic NL4-3 infectious
      clone and testing the drug susceptibilities of the recovered virus. RESULTS:
      Insertion of the 2-amino acid residue was found in 4 of the 348 cases and was
      strongly associated with prolonged chemotherapy with zidovudine (AZT) and
      didanosine (ddI). The virus isolated from 1 of the 4 cases possessed the same
      insertion. Characterization of these virus and the recombinant NL4-3 with the
      insertion strongly suggested that the insertion caused resistance not only to AZT
      and ddI but also to lamivudine (3TC) and zalcitabine (ddC). CONCLUSION: A 2-amino
      acid insertion between codons 69 and 70 of RT was detected in 4 of 348 (1.1%)
      Japanese hemophiliacs and was found to be associated with multiple drug
      resistance to nucleoside analogue RT inhibitors.

PMID- 10413367
TI  - Analysis of HIV-1 in the cervicovaginal secretions and blood of pregnant and
      nonpregnant women.
AB  - OBJECTIVES: To detect HIV-1 in cellular and acellular fractions of cervicovaginal
      secretions obtained by cervicovaginal lavage (CVL) and evaluate viral genotypes
      in the HIV-1-positive CVL samples. STUDY DESIGN/METHODS: This study consists of
      37 HIV-1-seropositive pregnant and nonpregnant women from the United States. A
      total of 63 paired CVL and blood samples were collected. HIV-1 DNA from cervical
      cells (CC) and virion RNA from cervical supernatant (CS) was detected by gag
      polymerase chain reaction (PCR) assays. The HIV-1 genotypes were determined by
      analyzing the nested PCR-amplified V3 region sequences of the HIV-1 gp120
      envelope gene. RESULTS: Within this cohort, 95% of the women were on single or
      combination antiretroviral therapy. Of the pregnant women, 63% of samples had HIV
      1 viral DNA in the CC, and 29% of samples were positive for viral RNA in the CS.
      Among nonpregnant women, 71% of samples were positive for HIV-1 DNA in CC, and
      46% of samples tested positive for virion RNA in CS. Plasma viral load ranged
      between 10,000 and 100,000 copies/mL and showed significant correlation with the
      detection of HIV-1 RNA in the CVL; this relation was less apparent with viral DNA
      in CC. The viral blood and CVL specimens were further analyzed by evaluating the
      genotypes of HIV-1 variants. In most patients, a high degree of similarity was
      observed between the viral sequences derived from blood and CVL samples. Two
      patients demonstrated closely related but somewhat distinct genotypic variants in
      CVL and blood. One subject showed clear compartmentalization in which distinct
      viral genotypes were observed in CVL and blood. Based on V3 loop analyses of
      gp120, with one exception, the cervicovaginal secretions harbored viral
      populations with a macrophage (CCR5)-tropic phenotype. CONCLUSIONS: This study
      demonstrates the unique characteris tics of HIV-1 strains in the genital
      secretions of a relatively large cohort of HIV-1-infected women in the United
      States. These results are important for further analysis of HIV-1 transmission
      and pathogenesis in vivo and for rational vaccine design.

PMID- 10413368
TI  - Transactivation is a conserved function among primate lentivirus Vpr proteins but
      is not shared by Vpx.
AB  - OBJECTIVE: To investigate the transactivating activity of Vpr proteins from human
      immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2) and simian
      immunodeficiency viruses (SIVs) on various primate lentivirus long terminal
      repeats (LTRs), and to determine whether the Vpx proteins shared by HIV-2 and SIV
      are able to transactivate any HIV or SIV promoter. STUDY DESIGN/METHODS: The vpr
      and vpx genes of the HIVs and SIVs encode virion-associated proteins, which are
      implicated in viral replication and pathogenesis. HIV-1 Vpr is involved in the
      transport of the preintegration complex (PIC) to the nucleus, transactivates the
      viral LTR, and induces cell cycle arrest. HIV-2 and SIV Vpx proteins share amino
      acid sequence similarities with Vpr and are involved in PIC translocation into
      the nucleus but are unable to induce cell cycle arrest. We cloned and expressed
      the vpr and vpx genes from several primate lentiviruses and tested their
      transactivating ability on HIV-1, HIV-2, SIVmac and SIVagm LTRs cloned upstream
      of the CAT reporter gene. RESULTS: All Vpr tested had a transactivating effect on
      several viral LTRs; however, none of the Vpx proteins showed a detectable
      transactivating effect. CONCLUSIONS: These results indicate that the
      transactivating properties of Vpr proteins were conserved throughout evolution in
      primate lentiviruses, which suggests that they have an important role in virus
      replication.

PMID- 10413370
TI  - Clinical experience with the new detection algorithms for atrial fibrillation of
      a defibrillator with dual chamber sensing and pacing.
AB  - INTRODUCTION: A major drawback of therapy with an implantable defibrillator is
      the nonspecificity of detection. Theoretically, adding atrial sensing information
      to a decision algorithm could improve specificity of detection. METHODS AND
      RESULTS: This open-label nonrandomized study compares the detection algorithm of
      the Ventak AV and the Ventak Mini implantable defibrillators. The Ventak AV (n =
      39) uses dual chamber detection as opposed to single chamber detection (with rate
      stability) in the Ventak Mini (n = 55). Programmed zone configurations, rate
      thresholds, and stability criteria were identical in all patients. In the Ventak
      AV group, 235 ventricular tachyarrhythmias were adequately detected and treated
      by the device. In the Mini group, 699 episodes of ventricular
      fibrillation/tachycardia occurred. All but six of the latter episodes were
      correctly identified and treated: one patient with incessant ventricular
      tachycardia had five episodes not terminated by the device, another episode
      occurred in a patient with a device/lead defect. In the Ventak AV group, 33
      episodes of sinus tachycardia and 166 episodes of atrial fibrillation/flutter
      activated the device; inappropriate therapy was applied to 41% of atrial
      fibrillation/flutter episodes. In the Ventak Mini group, 226 supraventricular
      tachyarrhythmias activated the device, eight of which were sinus tachycardia and
      218 were atrial fibrillation or flutter; of the atrial fibrillation/ flutter
      episodes 24% were treated inappropriately (fewer vs Ventak AV, P < 0.001).
      CONCLUSION: The new detection algorithm incorporated in the Ventak AV did not
      inadvertently withhold therapy for ventricular tachyarrhythmias, but at the same
      time the number of inappropriate therapies for atrial fibrillation was not
      decreased in comparison to a single chamber device.

PMID- 10413369
TI  - Distinctive RR dynamics preceding two modes of onset of spontaneous sustained
      ventricular tachycardia. (ESVEM) Investigators. Electrophysiologic Study Versus
      Electrocardiographic Monitoring.
AB  - INTRODUCTION: We hypothesized that autonomic activity preceding spontaneous
      sustained monomorphic ventricular tachycardia (VTsm) as assessed by heart rate
      (HR) and RR interval variability (RRV) differs between type 1 VTsm which is
      initiated by morphologically distinct, early cycle, possibly triggering premature
      ventricular complexes (PVCs) and type 2 VTsm in which the initial complex has a
      QRS waveform identical to subsequent complexes. METHODS AND RESULTS: Baseline
      Holter tapes (1,646) from a clinical trial were scanned for VTsm. QRS complexes
      of VTsm were compared by two-lead cross-correlation to distinguish type 1 and
      type 2 VTsm. Frequency domain RRV index were estimated over 5 minutes, 15
      minutes, and 24 hours. Type 1 and type 2 VTsm were present in 15 (group 1) and 33
      (group 2) of 48 patients, respectively. HR did not change in group 1 (88.4+/-15.2
      to 89.7+/-13.0 beats/min, P = 0.89), but increased before the onset of VTsm in
      group 2 (74.3+/-16.3 to 81.2+/-18.0 beats/min, P < 0.001). RRV index were
      severely depressed in both groups. No RRV index changed significantly before the
      onset of type 1 VTsm, whereas significant changes occurred before type 2 VTsm
      from 24-hour average to 30 minutes before VTsm in very low (very low-frequency
      power [VLFP]: 6.62+/-1.53 to 6.20+/-2.07 ln msec2, P = 0.036), low (low-frequency
      power [LFP]: 5.61+/-1.43 to 5.28+/-1.59 ln msec2, P = 0.004), normalized low
      (normalized low-frequency power [LFPn]: -0.48+/-0.58 to -0.55+/-0.64 normalized
      units [nu], P = 0.05) and the ratio of LFP to high-frequency power (HFP)
      (LFP/HFP: 4.20+/-3.47 to 3.45+/-2.53, P = 0.017). Declines in RRV index between 2
      hours to the 30-minute period before VTsm occurred in group 2 but not group 1 in
      LFP (5.85 +/- 1.42 to 5.28 +/- 1.59 In msec, P = 0.043) and HFP (4.94 +/- 5.14 to
      3.46 +/- 2.52 In msec2, P = 0.008), with a downward trend in LFP/HFP (4.94+/-5.14
      to 3.45+/-2.53, P = 0.127) and LFPn (-0.38+/-0.36 to -0.55+/-0.64, P = 0.15),
      while HFPn tended to rise (-1.47+/-0.65 to -1.27+/-0.64, P = 0.15). CONCLUSIONS:
      HR and RRV did not change before type 1 VTsm, suggesting that short-term changes
      in autonomic activity were not essential to initiation of apparent PVC-triggered
      VTsm. In contrast, RR interval dynamics before type 2 VTsm suggested that short
      term changes in neurohormonal activity contributed to arrhythmia initiation.
      Heterogeneities in arrhythmia onset may reflect distinct triggers and substrate
      properties that could provide a basis for effective therapeutic targets.

PMID- 10413371
TI  - Noninvasive diagnosis in patients with undocumented tachycardias: value of the
      adenosine test to predict AV nodal reentrant tachycardia.
AB  - INTRODUCTION: Patients with symptoms suggestive of paroxysmal supraventricular
      tachycardia (PSVT) but no tachycardia documentation often undergo diagnostic
      electrophysiologic study. In dual AV node physiology with AV node reentrant
      tachycardia (AVNRT), the anterograde fast pathway is more sensitive than the slow
      pathway to the effects of adenosine. The purpose of the study was to test the
      hypothesis that adenosine can be used as a bedside test for the diagnosis of dual
      AV node physiology and hence for AVNRT. METHODS AND RESULTS: During
      electrophysiologic study, 37 patients without prior documentation but symptoms
      indicative for PSVT received incremental dosages of adenosine during sinus rhythm
      until second-degree or greater AV block was observed. Suggestive signs of dual AV
      node physiology on the surface ECG (sudden jump of PQ interval > or = 50 msec)
      were found in 13 (76%) of 17 patients with inducible AVNRT but in only 1 (5%) of
      the remaining patients (P < 0.01). In the AVNRT group, the maximal increase of
      the PQ interval between two beats was greater (88+/-45 msec) than in the
      remaining 20 patients (17+/-11 msec) (P < 0.01). CONCLUSION: Careful evaluation
      of surface ECG during administration of adenosine helps to identify patients
      prone to AVNRT. The adenosine test is a valuable noninvasive adjunct in patients
      with undocumented palpitations suggestive of PSVT.

PMID- 10413373
TI  - Effects of multisite ventricular pacing on cardiac function in normal dogs and
      dogs with heart failure.
AB  - INTRODUCTION: We studied the effects on cardiac function of pacing two right and
      two left ventricular sites in normal and failing hearts with a normal QRS
      duration. METHODS AND RESULTS: Hemodynamic parameters were studied in isoflurane
      anesthetized dogs with normal hearts and dogs with heart failure induced by rapid
      ventricular pacing. Unipolar intramyocardial electrodes were placed at the high
      right atrium and the apex (A) and base (B) of the left (L) and right (R)
      ventricles (V). Data were collected after pacing for 5 to 20 minutes. In normal
      dogs, without bundle branch block (BBB), pacing at either the apex or the base of
      the left ventricle increased cardiac output by approximately 10% compared with
      right ventricular apex (RVA) pacing with an AV delay of 0 msec. Positive dP/dt
      increased approximately 10% during four-site left and right ventricular apex and
      base (LRVAB) pacing compared with RVA pacing. In dogs with heart failure but
      without BBB, cardiac output increased by 8.5% (P < 0.01) during four-site
      ventricular pacing with AV delays of 0 and 60 msec compared with RVA pacing.
      Positive dp/dt increased by 23.5% (P < 0.001) with an AV delay of 0 msec and 9.6%
      (P < 0.001) with an AV delay of 60 msec during LRVAB pacing compared with RVA
      pacing. His-bundle pacing was associated with increased cardiac output compared
      with RVA pacing. CONCLUSIONS: We conclude that pacing simultaneously at two right
      and two left ventricular sites significantly improves cardiac function compared
      with single RVA pacing, with or without sequential AV synchrony, in dogs with
      rapid ventricular pacing-induced heart failure and no BBB.

PMID- 10413372
TI  - Radiofrequency catheter ablation of frequent monomorphic ventricular ectopic
      activity.
AB  - INTRODUCTION: Frequent ventricular ectopic beats can result in severe symptoms
      and may even be incapacitating in some patients. Although radiofrequency catheter
      ablation is an effective and safe therapy for drug refractory idiopathic
      ventricular tachycardia, it has not been widely used in ventricular ectopy. The
      purpose of this study was: (1) to assess the potential role of catheter ablation
      in eliminating monomorphic ventricular ectopy in symptomatic patients regarding
      feasibility and safety and (2) to determine the usefulness of various mapping
      strategies. METHODS AND RESULTS: Forty-one patients with symptomatic ventricular
      ectopic activity (right ventricular origin in 23 patients, left ventricular
      origin in 18 patients) were enrolled. The mean frequency of ventricular ectopic
      beats was 1512+/-583/hour documented by Holter ECG monitoring. These patients had
      previously been unable to tolerate or had been unsuccessfully treated with a mean
      of 3+/-1 antiarrhythmic agents. The site of origin was mapped using earliest
      endocardial activation times, unipolar electrograms and pace mapping.
      Radiofrequency ablation was successful in 34 (83 %) of 41 patients. Multivariate
      logistic regression analysis revealed pace mapping as the only independent
      predictor for a successful ablation site (P < 0.01). After a follow-up of 3
      months, the overall success rate was 71%. The mean frequency of ventricular
      ectopic beats after successful ablation was 12+/-10 ventricular premature
      beat/hour. CONCLUSION: Radiofrequency catheter ablation is an effective and safe
      treatment for frequent symptomatic drug refractory monomorphic ventricular
      ectopic activity. Pace mapping predicts best successful ablation of ventricular
      ectopic beats.

PMID- 10413374
TI  - Measurement of funny current (I(f)) channel mRNA in human atrial tissue:
      correlation with left atrial filling pressure and atrial fibrillation.
AB  - INTRODUCTION: The funny current (I(f)) contributes to phase IV spontaneous
      depolarization in cardiac pacemaker tissue. Enhanced I(f) activity in myocardial
      tissue may lead to increased automaticity and therefore tachyarrhythmia. We
      measured the amount of I(f) activity in the messenger ribonucleic acid (mRNA) in
      human atrial tissue and correlated the mRNA amount to left atrial filling
      pressure and atrial fibrillation (AF). METHODS AND RESULTS: A total of 34
      patients undergoing open heart surgery were included (15 men and 19 women, aged
      55+/-10 years). Atrial tissue was obtained from the right atrial free wall, the
      right atrial appendage, the left atrial free wall, and the left atrial appendage,
      respectively. The mRNA amount of the I(f) channel was measured by reverse
      transcription polymerase chain reaction and was normalized to the mRNA levels of
      glyceraldehyde 3-phosphate dehydrogenase. We found that the I(f) channel mRNA was
      present at all the atrial sampling sites. A higher left atrial filling pressure,
      an indicator of congestive heart failure, was associated with a higher I(f) mRNA
      level (r2 = 0.446, P < 0.01 by linear regression). We also found that the mRNA
      amount was significantly higher in patients with AF than in patients without AF
      (1.68+/-0.49 vs 1.27+/-0.43; P < 0.05). Age, sex, right atrial filling pressure,
      left atrial dimension, and left ventricular ejection fraction had no significant
      effect on the mRNA level. CONCLUSION: The mRNA of the I(f) channel is present in
      the free-wall area and appendage area from both atria. Increased left atrial
      filling pressure and clinical AF are associated with increased I(f) mRNA level.

PMID- 10413375
TI  - Characteristics, circuit, mechanism, and ablation of reentry in the rabbit
      atrioventricular node.
AB  - INTRODUCTION: The circuitry underlying AV nodal reentry remains debated. We
      developed a model of AV nodal reentry and assessed the role of nodal inputs,
      compact node, and its posterior nodal extension (PNE) in this phenomenon. METHODS
      AND RESULTS: A fine scanning of short coupling interval range with an atrial
      premature beat consistently initiated slow-fast AV nodal reentrant beats that
      occurred 37+/-31 msec (mean+/-SD) after His-bundle activation in 11 of 16
      consecutive rabbit heart preparations. The repeated testing (>40 times) of a
      chosen coupling interval within reentry window (6+/-9 msec, n = 11) yielded
      reentrant intervals that varied by 2+/-1 msec (mean SD for 40 beats+/-SD, n =
      11). The breakthrough point of reentrant activation, as assessed from four
      perinodal sites, varied in different preparations from diffuse (4) to anterior
      (1), medial (3), or posterior (3); mean reentrant interval did not differ between
      perinodal sites. Antegrade perinodal activation pattern did not differ at
      reentrant versus nonreentrant coupling intervals and thus was not a primary
      determinant of reentry. A PNE ablation (n = 4) interrupted the slow pathway
      conduction and prevented reentry without affecting antegrade perinodal activation
      or fast pathway conduction. CONCLUSION: A reproducible model of AV nodal
      reentrant beats was developed and used to study underlying circuitry. The AV
      nodal reentry involves unaltered antegrade perinodal activation, slow PNE
      conduction and retrograde broad invasion of perinodal tissues starting at a
      preparation-dependent breakthrough point. A PNE ablation abolishes the reentry.

PMID- 10413376
TI  - Effects of spatial segmentation in the continuous model of excitation propagation
      in cardiac muscle.
AB  - INTRODUCTION: Spatial segmentation is essential for the numerical simulation of
      excitation propagation in cardiac muscle. METHODS AND RESULTS: This study
      evaluated the effects of spatial segmentation on action potential and on the
      velocity of propagation in a continuous one-dimensional model of cardiac muscle
      [intracellular and extracellular resistivities along (L) and transverse (T) to
      the muscle fibers: 402 omega(cm) (R(e), L), 3,620 omega(cm) (R(e), T), 48
      omega(cm) (R(e), L), and 126 omega(cm) (R(e), T), J of Physiol 255:335-346, 1976)
      and either Luo-Rudy (L-R, Circ Res 68:1501-1526, 1991) or Beeler-Reuter (B-R, J
      Physiol 268:177-210, 1977) ionic currents. Related cable equations for active
      membrane are derived. Spatial segmentations of < 31.2 microm (L, L-R), < 11.5
      microm (T, L-R), < 44.7 microm (L, B-R), and < 16.5 microm (T, B-R) were required
      for < 1% errors in the characteristic parameters of action potential. Similarly,
      spatial segmentations of < 54.5 microm (L, L-R), < 20.1 microm (T, L-R), < 84.3
      microm (L, B-R), and < 31.2 microm (T, B-R) were required for < 1 % errors in the
      velocity of conduction. CONCLUSION: In general, spatial segmentations of < 26.9%
      and < 50.8% of the space constant of a fully activated membrane gave < 1.0%
      errors in the characteristic parameters of action potential and in the velocity
      of propagation, respectively, for both membranes. The action potential duration
      was relatively insensitive to the spatial segmentation. Our analysis suggests
      that lambda(full is a better criterion for the selection of spatial segmentation
      in numerical simulation than the space constant of the resting membrane.

PMID- 10413377
TI  - A four-shock Bayesian up-down estimator of the 80% effective defibrillation dose.
AB  - INTRODUCTION: New defibrillation techniques are often compared to standard
      approaches using the defibrillation threshold. However, inference from
      thresholding data necessitates extrapolation from reactions to relatively
      ineffective shocks, an error prone procedure requiring large sample sizes for
      hypothesis testing and large safety margins for defibrillator implantation. In
      contrast, this article presents a clinically validated statistical model of a
      minimum error, four-shock defibrillation testing protocol for estimating the 80%
      effective defibrillation strength for a given patient (ED80). METHODS AND
      RESULTS: A Bayesian statistical model was constructed assuming that the
      defibrillation dose-response curve is sigmoidal, and the ED80 is between 150 and
      750 V. The model was used to design a minimum predicted error testing protocol
      and estimates. To prospectively validate the testing protocol and estimates, 170
      patients received voltage-programmed biphasic testing. Four fibrillation episodes
      were induced and terminated in each patient according to the Bayesian up-down
      protocol. In addition, a validation attempt was made at the estimated ED80
      rounded up to the nearest 50 V. In order to estimate the safety margin, in 136
      patients, a defibrillation attempt was made at the rounded ED80 + 100 V. Of the
      170 attempts at the rounded ED80, 143 (84%) attempts terminated fibrillation. Of
      the 136 attempts at the rounded ED80 + 100 V, 133 (98%) were effective.
      CONCLUSIONS: The four-shock Bayesian up-down protocol is the first clinical
      protocol to accurately predict an ED80 voltage. A 100 V increment above the ED80
      provides an adequate safety margin. This simple and accurate method for
      estimating a highly effective defibrillation dose may be a valuable tool for
      population-based clinical hypothesis testing, as well as defibrillator
      implantation.

PMID- 10413378
TI  - The autonomic control of the transmural dispersion of ventricular repolarization
      in anesthetized dogs.
AB  - INTRODUCTION: The initiation of ventricular arrhythmias is in part associated
      with autonomic nervous tone. We investigated the effects of sympathetic and
      parasympathetic stimulation on the monophasic action potentials (MAPs) of the
      epicardium (EPi), mid-myocardial (M) region, and endocardium (Endo) in vivo.
      METHODS AND RESULTS: In 12 mongrel open chest anesthetized dogs, both sides of
      the cervical vagus nerves and stellate ganglia were crushed with a tight
      ligature. Right atrial pacing at 600 msec cycle length was begun after the sinus
      nodal area had been crushed. MAPs from the M region were measured by two needle
      electrodes that were supported by a W-shaped plastic frame. The epicardial, M
      region, and endocardial MAP durations at 90% repolarization (MAPD90) were 287+/
      7, 315+/-7, and 290+/-8 msec, respectively. The MAPD90 from M cells was longer
      than that from Epi or Endo. Sympathetic stimulation shortened MAPD90 more in the
      M region (53+/-4 msec) than that in the Epi (27+/-3 msec) or Endo (26+/-4 msec).
      The transmural dispersion of repolarization during sympathetic stimulation was
      shorter than that of the control. Parasympathetic stimulation did not
      significantly affect any of the MAPD90 values. Simultaneous sympathetic and
      parasympathetic stimulation produced changes not significantly to those produced
      by sympathetic stimulation alone. CONCLUSION: Our results suggest that
      sympathetic activity can reduce transmural dispersion of repolarization under
      autonomic control in the canine heart under baseline conditions.

PMID- 10413379
TI  - Junctional communication between isolated pairs of canine atrial cells is
      mediated by homogeneous and heterogeneous gap junction channels.
AB  - INTRODUCTION: The expression of multiple connexins (Cxs) in the canine right
      atria raises the possibility that heterogeneous gap junction channels might be
      formed. METHODS AND RESULTS: We compared the unitary conductance (gamma(j)) of
      gap junction channels between isolated canine atrial cell pairs with those of
      homogeneous cardiac gap junction channels expressed in other systems. After
      partial uncoupling with halothane (2 mmol/L), the (gamma)j calculations for
      atrial isolated cardiocytes ranged from 30 to 220 pS and their distribution in
      event histograms was spread over the entire range, with a small peak at
      approximately 100 pS. This distribution deviates from the discrete peaks
      calculated from (gamma)j of homogeneous channels. All-points histograms of
      junctional current traces revealed distinct open-state levels. Some of these are
      related to the main open state of connexin43 (Cx43) (approximately 100 pS),
      observed between canine ventricular cells, or connexin40 (Cx40) (approximately
      215 pS) observed between transfected N2A cells under similar recording
      conditions. Intermediate values for (gamma)j were not observed in recordings from
      ventricular cells, which express mostly Cx43, nor in those from N2A cells
      expressing Cx40, but were observed consistently between atrial cells. Because
      they were measured as first openings from the nonconductance state, these
      intermediate values most likely represent main conductance states of
      heterogeneous channels rather than subconductance states of homogeneous channels.
      CONCLUSION: This suggests that regulation of cell-to-cell coupling in the heart
      depends not only on posttranslational modulation of preexisting Cxs, but also on
      the intracellular assembly mechanisms, and the way individual Cxs interact with
      others within a connexon and/or with other connexons from adjacent cells.

PMID- 10413380
TI  - Radiofrequency catheter ablation of left ventricular outflow tract tachycardia
      from the coronary cusp: a new approach to the tachycardia focus.
AB  - INTRODUCTION: Idiopathic ventricular tachycardia (VT) originating from the left
      ventricular outflow tract (LVOT) is rare. Previously reported were two cases of
      LVOT tachycardia which were treated with radiofrequency (RF) catheter ablation
      through endocardial aortomitral continuity. We report here a case of a repetitive
      LVOT tachycardia in which the QRS morphology during VT exhibited an atypical left
      bundle branch block and inferior axis. Pace mapping revealed that the origin of
      this VT was very close to the left sinus of Valsalva. Transcoronary cusp RF
      catheter ablation abolished the VT in this patient and is a new approach for the
      treatment of this kind of VT. The application of this approach to the other types
      of VT has yet to be determined.

PMID- 10413381
TI  - Transient local changes in right ventricular monophasic action potentials due to
      ajmaline in a patient with Brugada Syndrome.
AB  - A 48-year-old patient with recurrent episodes of palpitations and syncope
      presented with transient ST segment elevation in the right precordial ECG leads.
      Structural heart disease was excluded. No arrhythmias were inducible by
      programmed ventricular stimulation. Parallel to ST elevation after intravenous
      ajmaline, a gradual and reversible delay in the upstroke of right ventricular
      (RV) monophasic action potentials (MAPs) occurred that was most marked in the RV
      outflow tract and nearly absent at right free-wall recordings. Ajmaline led to a
      cycle length-dependent increase in RV dispersion of repolarization. Thus, right
      endocardial MAPs may demonstrate regionally different action potential changes
      that may contribute to the ECG changes in Brugada syndrome.

PMID- 10413383
TI  - Discontinuous propagation of the cardiac impulse and arrhythmogenesis.

PMID- 10413382
TI  - Review: Clinical aspects of vascular remodeling.
AB  - Vascular remodeling represents a spectrum of structural changes whereby the
      vascular wall responds to changes in its hemodynamic environment. Such changes
      may be classified as vessel enlargement (outward remodeling), diminution (inward
      remodeling), alternatively as adaptive (compensatory, appropriate to the
      hemodynamic stimulus), or maladaptive (dysfunctional, inappropriate). The
      direction and scale of remodeling are coordinated by endothelial production of
      growth factors, proteases, and cellular adhesion molecules in response to sensed
      changes in blood flow. In early atherosclerosis, outward remodeling preserves
      lumen size. Although protective in the long-term, the matrix degradation involved
      in this process may predispose atherosclerotic plaques to rupture, hence
      increasing the risks of acute coronary syndromes. Inward remodeling also occurs
      in advanced atherosclerotic lesions, whereby the vessel shrinks rather than
      enlarging, exacerbating rather than ameliorating stenosis. In transplant coronary
      artery disease, early inward remodeling may be a more important component of
      vessel stenosis than intimal thickening, while inappropriate inward remodeling
      appears to be as least as important as excessive intimal growth in the
      development of restenosis after angioplasty. Increased awareness of vascular
      remodeling, and in particular its malaptive forms, may provide new therapeutic
      insights for the future.

PMID- 10413384
TI  - Dual wide QRS complex tachycardias: what is the mechanism?

PMID- 10413385
TI  - Interaction between atrial pacing lead and epicardial ventricular wire resulting
      in unintended ventricular capture by pacemaker atrial output.

PMID- 10413386
TI  - Patients' socio-demographics characteristics and utilization of health care:
      looking beyond appearances...at last.

PMID- 10413387
TI  - Evidence suggesting that a chronic disease self-management program can improve
      health status while reducing hospitalization: a randomized trial.
AB  - OBJECTIVES: This study evaluated the effectiveness (changes in health behaviors,
      health status, and health service utilization) of a self-management program for
      chronic disease designed for use with a heterogeneous group of chronic disease
      patients. It also explored the differential effectiveness of the intervention for
      subjects with specific diseases and comorbidities. METHODS: The study was a six
      month randomized, controlled trial at community-based sites comparing treatment
      subjects with wait-list control subjects. Participants were 952 patients 40 years
      of age or older with a physician-confirmed diagnosis of heart disease, lung
      disease, stroke, or arthritis. Health behaviors, health status, and health
      service utilization, as determined by mailed, self-administered questionnaires,
      were measured. RESULTS: Treatment subjects, when compared with control subjects,
      demonstrated improvements at 6 months in weekly minutes of exercise, frequency of
      cognitive symptom management, communication with physicians, self-reported
      health, health distress, fatigue, disability, and social/role activities
      limitations. They also had fewer hospitalizations and days in the hospital. No
      differences were found in pain/physical discomfort, shortness of breath, or
      psychological well-being. CONCLUSIONS: An intervention designed specifically to
      meet the needs of a heterogeneous group of chronic disease patients, including
      those with comorbid conditions, was feasible and beneficial beyond usual care in
      terms of improved health behaviors and health status. It also resulted in fewer
      hospitalizations and days of hospitalization.

PMID- 10413388
TI  - Measurement of health-related quality of life in patients with amyotrophic
      lateral sclerosis in clinical trials of new therapies.
AB  - OBJECTIVES: Recent trials of amyotrophic lateral sclerosis (ALS) therapies have
      included the Sickness Impact Profile (SIP) to evaluate health-related quality of
      life (HQL). The purpose of this study was to assess the feasibility, psychometric
      properties, and interpretation of the Sickness Impact Profile in this setting.
      METHODS: The Sickness Impact Profile was administered at baseline, 3, 6, and 9
      months during a double-blind, placebo-controlled study of recombinant human
      insulin-like growth factor I. The frequency of missing Sickness Impact Profile
      data and administration time were recorded. Patients' scores on the Appel ALS
      (AALS) Rating Scale were used to identify a stable subgroup for reliability
      testing and clinically distinct groups for validity testing. Internal consistency
      reliability and reproducibility were evaluated using Cronbach's alpha and
      intraclass correlation coefficients, respectively. Analysis of variance (ANOVA)
      models and t tests were used to assess validity. Effect sizes and the
      responsiveness index were used to assess responsiveness. RESULTS: At baseline,
      259 (97%) patients completed a 30-minute Sickness Impact Profile interview. At
      subsequent assessments, response rates ranged from 92% to 97% and mean
      administration times ranged from 25 to 27 minutes. The overall Sickness Impact
      Profile score demonstrated alpha reliability and 3-month stability coefficients
      of 0.94 and 0.80, respectively. Baseline overall Sickness Impact Profile scores
      discriminated between patients in the two AALS-defined groups with a mean of
      13.0+/-7.8 and 24.0+/-11.7 in the better and worse AALS groups, respectively.
      Similarly, mean overall SIP change scores discriminated patients progressing at
      different rates (slow to moderate = 4.00+/-7.97; rapid = 10.74+/-8.76). With few
      exceptions, dimension and category scores met similar criteria. Responsiveness
      statistics for the physical and overall Sickness Impact Profile scores were lower
      at 3 months and higher at 6 and 9 months. CONCLUSIONS: The feasibility,
      psychometric, and interpretive findings support the validity of the Sickness
      Impact Profile for assessing outcomes of amyotrophic lateral sclerosis and its
      treatment. Based on these findings, we recommend including the Sickness Impact
      Profile in future amyotrophic lateral sclerosis clinical trials.

PMID- 10413390
TI  - Carepartner experiences with hospital care.
AB  - OBJECTIVES: Family members and other "carepartners" often play an important role
      in the care and support of patients during and after hospitalization, yet little
      is known about how they assess their hospital experience or the factors that may
      influence their perceptions. METHODS: A nationwide telephone survey of 1,800
      recently discharged patients and their carepartners about their hospital
      experience was conducted. Carepartner responses in six domains of care were
      summarized, and multivariable regression analysis was used to detect independent
      predictors of more frequent problem reports by carepartners. RESULTS:
      Carepartners reported problems most frequently in the domains of emotional
      support (23.9%), discharge planning (20.3%), and family participation (17.6%).
      Independent predictors of more frequent carepartner problem reports included poor
      subjective patient health status, emergency hospitalization, nonsurgical
      admission, carepartner income less than $7,500/year, younger carepartner age,
      noninvolvement of the patient's regular doctor, less frequent carepartner visits
      during the hospitalization, and less time spent with the patient after discharge.
      CONCLUSIONS: Better awareness of the problems carepartners experience and
      attention to improving quality in these areas may facilitate family involvement
      in patient care and enhance carepartner and patient satisfaction.

PMID- 10413389
TI  - Health utilities in Alzheimer's disease: a cross-sectional study of patients and
      caregivers.
AB  - OBJECTIVES: Although the broad impacts of Alzheimer's disease (AD) are
      increasingly recognized, little work has focused on the overall health-related
      quality of life experienced by Alzheimer's disease patients and their caregivers.
      The study had two main objectives: (1) to test the feasibility of measuring
      health utilities in Alzheimer's disease with a generic preference-weighted
      instrument using proxy respondents and (2) to assess the utility scores of
      Alzheimer's disease patients (and their caregivers) in different disease stages
      and care setting. METHODS: A cross-sectional study of 679 Alzheimer's disease
      patient/caregiver pairs was conducted at 13 sites in the United States: four
      academic medical centers, four managed care plans, two assisted living
      facilities, and three nursing homes. The Health Utilities Index Mark II (HUI:2)
      questionnaire was administered to caregivers of patients who responded both as
      proxies for patients and for themselves. Responses to the questionnaire were
      converted into a global utility score, between 0 and 1, using the HUI:2 multi
      attribute utility function. RESULTS: Global utility scores varied considerably
      across patients' Alzheimer's disease stage: for the six stages assessed
      (questionable, mild, moderate, severe, profound, and terminal), mean utility
      scores were 0.73, 0.69, 0.53, 0.38, 0.27, and 0.14, respectively. In multiple
      regression analyses, Alzheimer's disease stage was a negative and significant
      predictor of utility scores for patients; setting did not exert an independent
      effect. Utility scores for the caregivers were insensitive to patients'
      Alzheimer's disease stage and setting. CONCLUSIONS: Patients' Alzheimer's disease
      stage had a substantial influence on health utilities, as measured by the HUI:2.
      More research is needed to assess the validity of using proxy respondents.

PMID- 10413391
TI  - Evaluating dispensing error detection rates in a hospital pharmacy.
AB  - OBJECTIVES: The filling of unit dose orders and checking for filling errors are
      two essential distributive responsibilities of a hospital pharmacy. Previous
      studies have shown that nonpharmacists, usually technicians, are capable of
      assuming these distributive tasks traditionally performed by hospital
      pharmacists. The study tested whether nonpharmacists, in this case licensed
      practical nurses/medication nurses, were as competent as pharmacists in checking
      for errors in unit dose cassettes prepared for hospital patients. METHODS: A
      university teaching hospital was used for the study. Artificial errors (n = 812)
      were introduced into the drug distribution system during a 4-month period in
      1995. Included in the study were seven staff pharmacists and nine medication
      nurses (licensed practical nurses) involved in the decentralized drug
      distribution system. The primary measure was the ratio of errors detected to the
      number of artificial errors introduced into the system. This primary measure is
      different from those used in prior studies that do not separate dispensing errors
      and checking errors. RESULTS: Overall, pharmacists were significantly more
      accurate in detecting errors (87.7% vs. 82.1%). In one category of serious
      errors, that of wrong strength, the difference between pharmacists and licensed
      practical nurses was even greater (93.3% vs. 83.3%). CONCLUSIONS: This study's
      results do not support conclusions of prior studies that nonpharmacists can match
      the error detection accuracy of pharmacists. It demonstrates the importance of
      considering the types of errors under examination and of using appropriate
      measures of error checkers when drawing conclusions on relative competence.

PMID- 10413392
TI  - The relation of parent and provider characteristics to vaccination status of
      children in private practices and managed care organizations in Maryland.
AB  - OBJECTIVES: This study sought to identify provider practices and policies in
      private pediatric settings that relate to vaccination status, controlling for the
      characteristics of the children served. METHODS: Vaccination data came from the
      medical records of 709 randomly selected 2-year-old children at 18 private
      practices and managed care organizations in Maryland, family data from 466
      telephone interviews with the children's parents, and provider characteristics
      from 18 site questionnaires and 42 individual physician and nurse practitioner
      questionnaires. Logistic regression and generalized estimating equations were
      used to estimate the relation of provider characteristics to vaccination status.
      Three age-appropriate (AA) and two up-to-date (UTD) vaccination status variables
      characterized successful vaccination. RESULTS: Approximately 70% of the study
      children were up-to-date by age 2 years for the full vaccination series,
      excluding hepatitis B vaccine. Family demographic characteristics were the
      strongest correlates of undervaccination. Neither parents' knowledge and
      attitudes about immunization nor the children's insurance coverage was
      statistically related to vaccination status. Site reminder or follow-up systems
      and provider perceptions about appointment scheduling and receipt of vaccine
      information from health departments were positively related to vaccination.
      Concern for liability was associated with a reduced odds of age-appropriate and
      up-to-date vaccination. CONCLUSIONS: Family demographics strongly correlate with
      vaccination status; however, they are generally not modifiable. This study's
      findings encourage providers to operate a tracking system, to remain current on
      immunization recommendations, to use all clinical encounters to screen and
      vaccinate children, and to ensure the availability and convenience of vaccination
      services.

PMID- 10413393
TI  - An international comparison of the reliability and responsiveness of the Duke
      Health Profile for measuring health-related quality of life of patients treated
      with alprostadil for erectile dysfunction.
AB  - OBJECTIVES: It is important that health measures are both reliable and responsive
      to clinical change. The aim of this study was to assess the reliability and
      responsiveness of the physical, mental, and social health scales of the Duke
      Health Profile (DUKE). METHODS: Impotent males self-administered the Duke Health
      Profile before and during treatment with alprostadil for erectile dysfunction
      during a 19-month period. Subjects were 490 patients in the United States and 583
      patients in 12 other countries. Each of the three basic Duke Health Profile
      scales has only five items, and each is heterogeneous because each measures more
      than one health concept. RESULTS: Cronbach's alpha reliability estimates were:
      physical health, 0.68 for United States and 0.64 for other countries; mental
      health, 0.62 and 0.52, respectively; and social health, 0.53 and 0.47,
      respectively. Alprostadil was expected to improve mental health primarily, and
      results of the study were consistent with this hypothesis. For example, at
      approximately 14 months from therapy onset, mental health improved for patients
      both in the United States (standardized response mean, SRM, = 0.17) and other
      countries (mean SRM = 0.30), whereas physical health worsened in the United
      States and was unchanged in other countries, and social health was unchanged in
      the United States and improved in other countries. Maximum responsiveness was
      shown for mental health in the other countries, where the mean standardized
      response means at four follow-ups during a 19-month period were 0.11, 0.21, 0.30,
      and 0.36. CONCLUSIONS: This study provides support for the responsiveness of the
      Duke Health Profile mental health scale.

PMID- 10413394
TI  - Access to coronary artery bypass surgery by race/ethnicity and gender among
      patients who are appropriate for surgery.
AB  - OBJECTIVE: The study sought to determine if there were race/ethnicity or gender
      differences in access to coronary artery bypass graft (CABG) surgery among
      patients who have been designated as appropriate and as necessary for that
      surgery according to the RAND methodology. METHODS: RAND appropriateness and
      necessity criteria were used to identify a race/gender stratified sample of
      postangiography patients who would benefit from coronary artery bypass graft
      surgery. These patients were tracked for 3 months to determine if they had
      undergone coronary artery bypass graft surgery in New York State. Subjects were a
      total of 1,261 postangiography patients in eight New York hospitals in 1994 to
      1996. Measures included percentages of patients for whom coronary artery bypass
      graft surgery was appropriate and necessary undergoing surgery by race/ethnicity
      and gender, as well as multivariate odds ratios for race/ethnicity and gender.
      RESULTS: After controlling for age, payer, number of vessels diseased, and
      presence of left main disease, African-American and Hispanic patients were found
      to be significantly less likely to undergo coronary artery bypass graft surgery
      than white non-Hispanic patients (respective odds ratios 0.64 and 0.60). When
      "necessity" was used as a criterion instead of "appropriateness," significant
      differences in access for African-American patients remained. The gatekeeper
      physician recommended surgery only 10% of the time that patients did not undergo
      "appropriate" coronary artery bypass graft surgery, and this percentage did not
      vary significantly by race/ethnicity or gender of the patient. CONCLUSIONS: Even
      after controlling for appropriateness and necessity for coronary artery bypass
      graft surgery in a prospective study, African-American patients had significant
      access problems in obtaining coronary artery bypass graft surgery. These problems
      appeared not to be related to patient refusals.

PMID- 10413395
TI  - Differences between family physicians' and general internists' medical charges.
AB  - OBJECTIVES: Data from 509 primary care patients were analyzed to determine
      whether practice style differences between family physicians and general
      internists generate differential utilization of health care resources leading to
      differential medical charges. METHODS: New adult patients were prospectively
      randomized to care by family physicians and general internists. Utilization of
      medical care services and associated charges then were monitored for 1 year of
      care. RESULTS: Family practice patients had a significantly higher mean number of
      visits to their primary care clinic and significantly fewer emergency room visits
      than patients assigned to Internal Medicine. Mean charges for primary care and
      emergency department treatment were significantly lower for patients assigned to
      Family Practice than for those assigned to General Internal Medicine. There were
      no significant differences in charges for specialty clinic visits,
      hospitalizations, or diagnostic services. CONCLUSIONS: Practice style differences
      between family physicians and general internists were associated with
      differential medical charges, with family physicians generating lower charges for
      some aspects of care.

PMID- 10413396
TI  - Accuracy of risk-adjusted mortality rate as a measure of hospital quality of
      care.
AB  - OBJECTIVES: Reports on hospital quality performance are being produced with
      increasing frequency by state agencies, commercial data vendors, and health care
      purchasers. Risk-adjusted mortality rate is the most commonly used measure of
      quality in these reports. The purpose of this study was to determine whether risk
      adjusted mortality rates are valid indicators of hospital quality performance.
      METHODS: Based on an analytical model of random measurement error, sensitivity
      and predictive error of mortality rate indicators of hospital performance were
      estimated. RESULTS: The following six parameters were shown to determine
      accuracy: (1) mortality risks of patients who receive good quality care and (2)
      of those who receive poor quality care, (3) proportion of patients (across all
      hospitals) who receive poor quality care, (4) proportion of hospitals considered
      to be "poor quality," (5) patients' relative risk of receiving poor quality care
      in "good quality" and in "poor quality" hospitals, and (6) number of patients
      treated per hospital. Using best available values for model parameters, analyses
      demonstrated that in nearly all situations, even with perfect risk adjustment,
      identifying poor quality hospitals on the basis of mortality rate performance is
      highly inaccurate. Of hospitals that delivered poor quality care, fewer than 12%
      were identified as high mortality rate outliers, and more than 60% of outliers
      were actually good quality hospitals. CONCLUSIONS: Under virtually all realistic
      assumptions for model parameter values, sensitivity was less than 20% and
      predictive error was greater than 50%. Reports that measure quality using risk
      adjusted mortality rates misinform the public about hospital performance.

PMID- 10413397
TI  - Prestige of training programs and experience of bypass surgeons as factors in
      adjusted patient mortality rates.
AB  - OBJECTIVES: The relation of physician performance to physician training and
      experience is not well understood. The aim of this study was to examine whether
      indicators of physician background and experience were associated with an
      objective measure of physician performance. METHODS: Physician background
      information obtained from the Directory of Board-Certified Medical Specialists
      was linked to physician risk-adjusted mortality rates obtained from three
      statewide data bases of coronary artery bypass surgeons. Subjects were 275
      surgeons who performed CABG surgery on 83,547 patients during the years 1989 to
      1992. Surgical performance was measured by the mortality ratio (MR), the ratio of
      the observed to the predicted patient mortality rate as determined by detailed
      clinical information. Training institutions and physicians were characterized as
      prestigious if they were listed as outstanding in published articles. RESULTS:
      Surgical performance was not associated with graduation from an American medical
      school; attendance at a prestigious medical school, residency, or fellowship
      program; or an academic appointment. Mortality ratios decreased with increased
      volume and increased with years of experience, age, and academic rank. Surgeons
      were more likely to be considered a "best doctor" if they had more years
      experience and trained at a prestigious residency or fellowship program.
      CONCLUSIONS: Training at a prestigious institution was associated with
      identification as a "best" doctor but not with lower mortality ratios.

PMID- 10413398
TI  - When asked, patients tell: disclosure of sensitive health-risk behaviors.
AB  - OBJECTIVES: National health care organizations recommend routinely screening
      patients for behavioral health risks, the effectiveness of which depends on
      patients' willingness to disclose risky behaviors. This study aimed to determine
      if primary care patients' disclosures of potentially stigmatizing behaviors would
      be affected by (1) their expectation about whether or not their physician would
      see their disclosures and (2) the assessment method. METHODS: One thousand nine
      hundred fifty-two primary care patients completed a questionnaire assessing human
      immunodeficiency virus (HIV), alcohol, drug, domestic violence, tobacco, oral
      health, and seat belt risks; half were told their responses would be seen by the
      researcher and their physician and half were told that their responses would be
      seen by the researcher only. Patients were randomly assigned to one of five
      assessment methods: written, face-to-face, audio-based, computer-based, or video
      based. RESULTS: Across all risk areas, patients did not disclose differently
      whether or not they believed their physician would see their disclosures.
      Technologically advanced assessment methods (audio, computer, and video) produced
      greater risk disclosure (4%-8% greater) than traditional methods in three of
      seven risk areas. CONCLUSIONS: These findings suggest patients are not less
      willing to disclose health risks to a research assistant knowing that this
      information would be shared with their physician and that a number of assessment
      methods can effectively elicit patient disclosure. Potentially small increases in
      risk disclosure must be weighed against other factors, such as cost and
      convenience, in determining which method(s) to use in different health care
      settings.

PMID- 10413399
TI  - The involvement of genome researchers in high school science education.
AB  - The rapid accumulation of genetic information generated by the Human Genome
      Project and related research has heightened public awareness of genetics issues.
      Education in genome science is needed at all levels in our society by specific
      audiences and the general public so that individuals can make well-informed
      decisions related to public policy and issues such as genetic testing. Many
      scientists have found that an effective vehicle for reaching a broad sector of
      society is through high school biology courses. From an educational perspective,
      genome science offers many ways to meet emerging science learning goals, which
      are influencing science teaching nationally. To effectively meet the goals of the
      science and education communities, genome education needs to include several
      major components-accurate and current information about genomics, hands-on
      experience with DNA techniques, education in ethical decision-making, and career
      counseling and preparation. To be most successful, we have found that genome
      education programs require the collaborative efforts of science teachers, genome
      researchers, ethicists, genetic counselors, and business partners. This report is
      intended as a guide for genome researchers with an interest in participating in
      pre-college education, providing rationale for their involvement and
      recommendations for ways they can contribute, and highlighting a few exemplary
      programs. World Wide Web addresses for all of the programs discussed in this
      report are given in Table 1. We are developing a database of outreach programs
      offering genetics education () and request that readers submit an entry
      describing their programs. We invite researchers to contact us for more
      information about activities in their local area.

PMID- 10413400
TI  - Comparative genomics of the Archaea (Euryarchaeota): evolution of conserved
      protein families, the stable core, and the variable shell.
AB  - Comparative analysis of the protein sequences encoded in the four euryarchaeal
      species whose genomes have been sequenced completely (Methanococcus jannaschii,
      Methanobacterium thermoautotrophicum, Archaeoglobus fulgidus, and Pyrococcus
      horikoshii) revealed 1326 orthologous sets, of which 543 are represented in all
      four species. The proteins that belong to these conserved euryarchaeal families
      comprise 31%-35% of the gene complement and may be considered the evolutionarily
      stable core of the archaeal genomes. The core gene set includes the great
      majority of genes coding for proteins involved in genome replication and
      expression, but only a relatively small subset of metabolic functions. For many
      gene families that are conserved in all euryarchaea, previously undetected
      orthologs in bacteria and eukaryotes were identified. A number of euryarchaeal
      synapomorphies (unique shared characters) were identified; these are protein
      families that possess sequence signatures or domain architectures that are
      conserved in all euryarchaea but are not found in bacteria or eukaryotes. In
      addition, euryarchaea-specific expansions of several protein and domain families
      were detected. In terms of their apparent phylogenetic affinities, the archaeal
      protein families split into bacterial and eukaryotic families. The majority of
      the proteins that have only eukaryotic orthologs or show the greatest similarity
      to their eukaryotic counterparts belong to the core set. The families of
      euryarchaeal genes that are conserved in only two or three species constitute a
      relatively mobile component of the genomes whose evolution should have involved
      multiple events of lineage-specific gene loss and horizontal gene transfer.
      Frequently these proteins have detectable orthologs only in bacteria or show the
      greatest similarity to the bacterial homologs, which might suggest a significant
      role of horizontal gene transfer from bacteria in the evolution of the
      euryarchaeota.

PMID- 10413401
TI  - The evolution of trichromatic color vision by opsin gene duplication in New World
      and Old World primates.
AB  - Trichromacy in all Old World primates is dependent on separate X-linked MW and LW
      opsin genes that are organized into a head-to-tail tandem array flanked on the
      upstream side by a locus control region (LCR). The 5' regions of these two genes
      show homology for only the first 236 bp, although within this region, the
      differences are conserved in humans, chimpanzees, and two species of
      cercopithecoid monkeys. In contrast, most New World primates have only a single
      polymorphic X-linked opsin gene; all males are dichromats and trichromacy is
      achieved only in those females that possess a different form of this gene on each
      X chromosome. By sequencing the upstream region of this gene in a New World
      monkey, the marmoset, we have been able to demonstrate the presence of an LCR in
      an equivalent position to that in Old World primates. Moreover, the marmoset
      sequence shows extensive homology from the coding region to the LCR with the
      upstream sequence of the human LW gene, a distance of >3 kb, whereas homology
      with the human MW gene is again limited to the first 236 bp, indicating that the
      divergent MW sequence identifies the site of insertion of the duplicated gene.
      This is further supported by the presence of an incomplete Alu element on the
      upstream side of this insertion point in the MW gene of both humans and a
      cercopithecoid monkey, with additional Alu elements present further upstream.
      Therefore, these Alu elements may have been involved in the initial gene
      duplication and may also be responsible for the high frequency of gene loss and
      gene duplication within the opsin gene array. Full trichromacy is present in one
      species of New World monkey, the howler monkey, in which separate MW and LW genes
      are again present. In contrast to the separate genes in humans, however, the
      upstream sequences of the two howler genes show homology with the marmoset for at
      least 600 bp, which is well beyond the point of divergence of the human MW and LW
      genes, and each sequence is associated with a different LCR, indicating that the
      duplication in the howler monkey involved the entire upstream region. [The
      sequence data described in this paper have been submitted to GenBank under
      accession nos. AF155218, AF156715, and AF156716.]

PMID- 10413402
TI  - Linkage disequilibrium and physical mapping of Pas1 in mice.
AB  - By using linkage disequilibrium (LD) analysis in 21 strains of known
      susceptibility to lung cancer and by assembling a YAC contig, we mapped to a
      approximately 1.5-Mb region on distal mouse chromosome 6 the Pas1 locus, the
      major determinant of lung cancer predisposition in mice. Our results, on the
      basis of haplotype and phenetic analysis, suggest that the Pas1(s) susceptibility
      allele is shared by several mouse-inbred strains of independent origin, which
      show either high or intermediate predisposition to lung tumorigenesis. Therefore,
      the Pas1(s) allele is probably derived from an ancestral mouse rather than from
      independent mutations of the same gene. We showed the feasibility of LD in common
      inbred strains for the fine mapping of disease loci, and provided the biological
      basis and the reagents for the cloning of the Pas1 gene.

PMID- 10413404
TI  - Separation of micronuclear DNA of Stylonychia lemnae by pulsed-field
      electrophoresis and identification of a DNA molecule with a high copy number.
AB  - DNA from the hypotrichous ciliatae Stylonychia lemnae was separated by PFGE. In
      addition to the separation of the macronuclear DNA molecules with a size up to
      approximately 40 kb, we were able to separate the micronuclear DNA with a size
      between approximately 90 kb and 2 Mb. One very prominent 90-kb DNA band appeared
      on the pulsed-field gels. We propose that this 90-kb DNA fragment represents a
      linear plasmid residing in the micronucleus in a very high copy number. About 10%
      of the micronuclear DNA consists of the 90-kb DNA molecule. It appears in the
      micronucleus as well as in the macronuclear anlagen during macronuclear
      development but not in the mature macronucleus. Thus, the multicopy DNA is
      eliminated during fragmentation of the macronuclear anlagen DNA in the course of
      macronuclear development. Therefore, this 90-kb DNA molecule might serve as an
      excellent tool to study the recognition and elimination of DNA during nuclear
      differentiation of hypotrichous ciliates.

PMID- 10413403
TI  - Finding new human minisatellite sequences in the vicinity of long CA-rich
      sequences.
AB  - Microsatellites and minisatellites are two classes of tandem repeat sequences
      differing in their size, mutation processes, and chromosomal distribution. The
      boundary between the two classes is not defined. We have developed a convenient,
      hybridization-based human library screening procedure able to detect long CA-rich
      sequences. Analysis of cosmid clones derived from a chromosome 1 library show
      that cross-hybridizing sequences tested are imperfect CA-rich sequences, some of
      them showing a minisatellite organization. All but one of the 13 positive
      chromosome 1 clones studied are localized in chromosomal bands to which
      minisatellites have previously been assigned, such as the 1pter cluster. To test
      the applicability of the procedure to minisatellite detection on a larger scale,
      we then used a large-insert whole-genome PAC library. Altogether, 22 new
      minisatellites have been identified in positive PAC and cosmid clones and 20 of
      them are telomeric. Among the 42 positive PAC clones localized within the human
      genome by FISH and/or linkage analysis, 25 (60%) are assigned to a terminal band
      of the karyotype, 4 (9%) are juxtacentromeric, and 13 (31%) are interstitial. The
      localization of at least two of the interstitial PAC clones corresponds to
      previously characterized minisatellite-containing regions and/or ancestrally
      telomeric bands, in agreement with this minisatellite-like distribution. The data
      obtained are in close agreement with the parallel investigation of human genome
      sequence data and suggest that long human (CA)s are imperfect CA repeats
      belonging to the minisatellite class of sequences. This approach provides a new
      tool to efficiently target genomic clones originating from subtelomeric domains,
      from which minisatellite sequences can readily be obtained. [The sequence data
      described in this paper have been submitted to the EMBL data library under
      accession nos. AJ000377-AJ000383.]

PMID- 10413406
TI  - MEMORANDUM FOR: science writers and editors on the journal press list 

PMID- 10413408
TI  - Zn(2+) fingers and cervical cancer.

PMID- 10413405
TI  - A 3-Mb high-resolution BAC/PAC contig of 12q22 encompassing the 830-kb consensus
      minimal deletion in male germ cell tumors.
AB  - Cytogenetic and molecular genetic analyses have shown that the 12q22 region is
      recurrently deleted in male germ cell tumors (GCTs), suggesting that this site
      may harbor a tumor suppressor gene (TSG). Previous loss of heterozygosity (LOH)
      analyses identified a consensus minimal deleted region between the markers
      D12S377 and D12S296, and a YAC clone contig covering the region was generated.
      Here, we describe a high-resolution sequence-ready physical map of this contig
      covering a 3-Mb region. The map comprised of 52 cosmids, 49 PACs, and 168 BACs
      that were anchored to the previous YAC contig; 99 polymorphic, nonpolymorphic,
      EST, and gene-based markers are now placed on this map in a unique order. Of
      these, 61 markers were isolated in the present study, including one that was
      polymorphic. In addition, we have narrowed the minimal deletion to approximately
      830 kb between D12S1716 (proximal) and P382A8-AG (distal) by LOH analysis of 108
      normal-tumor DNAs from GCT patients using 21 polymorphic STSs. These physical and
      deletion maps should prove useful for identification of the candidate TSG in
      GCTs, provide framework to generate complete DNA sequence, and ultimately
      generate a gene map of this segment of the chromosome 12. [The sequence data
      described in this paper have been submitted to the Genome Survey Sequence under
      accession nos. AQ254896-AQ254955 and AQ269251-AQ269266. Online supplementary
      material is available at http://www.genome.org]

PMID- 10413407
TI  - Enhancing cytotoxic sensitivity of tumor cells to antifolates: another
      opportunity for gene therapy?

PMID- 10413409
TI  - Why randomized surgical oncology trials are so scarce.

PMID- 10413411
TI  - UK cancer experts meet tony blair 

PMID- 10413410
TI  - UK's Tony Blair announces crusade to fight cancer.

PMID- 10413414
TI  - Sources of cancer research funding 

PMID- 10413412
TI  - Early trials probe COX-2 inhibitors' cancer-fighting potential.

PMID- 10413413
TI  - Cancer research funding now has many financial players.

PMID- 10413415
TI  - Sources of funding of cancer research, 1997 

PMID- 10413417
TI  - Stat bite: U.S. pancreatic cancer survival rates by age.

PMID- 10413416
TI  - Congressional Committee explores alternative medicine and women's cancers.

PMID- 10413419
TI  - National cancer institute leases new supercomputer 

PMID- 10413418
TI  - Institute of Medicine finds no link between breast implants and disease.

PMID- 10413420
TI  - Vaccine research center at NIH gets a cornerstone 

PMID- 10413421
TI  - Tobacco smoke carcinogens and lung cancer.
AB  - The complexity of tobacco smoke leads to some confusion about the mechanisms by
      which it causes lung cancer. Among the multiple components of tobacco smoke, 20
      carcinogens convincingly cause lung tumors in laboratory animals or humans and
      are, therefore, likely to be involved in lung cancer induction. Of these,
      polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine 4
      (methylnitrosamino)-1-(3-pyridyl)-1-butanone are likely to play major roles. This
      review focuses on carcinogens in tobacco smoke as a means of simplifying and
      clarifying the relevant information that provides a mechanistic framework linking
      nicotine addiction with lung cancer through exposure to such compounds. Included
      is a discussion of the mechanisms by which tobacco smoke carcinogens interact
      with DNA and cause genetic changes--mechanisms that are reasonably well
      understood--and the less well defined relationship between exposure to specific
      tobacco smoke carcinogens and mutations in oncogenes and tumor suppressor genes.
      Molecular epidemiologic studies of gene-carcinogen interactions and lung cancer-
      an approach that has not yet reached its full potential--are also discussed, as
      are inhalation studies of tobacco smoke in laboratory animals and the potential
      role of free radicals and oxidative damage in tobacco-associated carcinogenesis.
      By focusing in this review on several important carcinogens in tobacco smoke, the
      complexities in understanding tobacco-induced cancer can be reduced, and new
      approaches for lung cancer prevention can be envisioned.

PMID- 10413422
TI  - Potential drugs against cervical cancer: zinc-ejecting inhibitors of the human
      papillomavirus type 16 E6 oncoprotein.
AB  - BACKGROUND: The principal agent in the etiology of cervical cancer, i.e., human
      papillomavirus (HPV) type 16, encodes three oncoproteins, E5, E6, and E7.
      Structural and mutational studies have identified two potential zinc-finger
      domains as critical for E6 protein function. We investigated several assays to
      identify and characterize compounds that interfere with the binding of zinc to
      E6. METHODS: Thirty-six compounds were selected on the basis of their structure,
      which would facilitate their participation in sulfhydryl residue-specific redox
      reactions, and were tested for their ability to release zinc from E6 protein. The
      zinc-ejecting compounds were then tested for their ability to inhibit E6 binding
      to E6-associated protein (E6AP) and E6-binding protein (E6BP), two coactivators
      of E6-mediated cellular transformation. The binding of E6 to E6BP and E6AP was
      measured by use of surface plasmon resonance (a technique that monitors molecular
      interactions by measuring changes in refractive index) and by use of in vitro
      translation assays. The compounds were also tested for their effects on the
      viability of HPV-containing cell lines. RESULTS: Nine of the 36 tested compounds
      ejected zinc from E6. Two of the nine compounds inhibited the interaction of E6
      with E6AP and E6BP, and one of these two, 4, 4'-dithiodimorpholine, selectively
      inhibited cell viability and induced higher levels of p53 protein (associated
      with the induction of apoptosis [programmed cell death]) in tumorigenic HPV
      containing cells. CONCLUSION: We have described assay systems to identify
      compounds, such as 4,4'-dithiodimorpholine, that can potentially interfere with
      the biology and pathology of HPV. These assay systems may be useful in the
      development of drugs against cervical cancer, genital warts, and asymptomatic
      infections by genital HPVs.

PMID- 10413423
TI  - Frequent microsatellite instability and mismatch repair gene mutations in young
      Chinese patients with colorectal cancer.
AB  - BACKGROUND: The incidence of colorectal cancer in persons under 46 years of age
      is substantially higher in Hong Kong than in Scotland and many other countries.
      Consequently, we examined whether there is a hereditary predisposition for
      colorectal cancer in this Southern Chinese population. METHODS: We investigated
      the incidence of microsatellite instability (MSI) at 10 DNA sites in 117
      colorectal cancer specimens from Chinese patients of various ages. Those tumors
      with new alleles at 40% or more of the sites investigated were identified as
      highly unstable MSI (MSI-H). In young patients, we also searched for germline
      mutations in three mismatch repair genes (hMSH2, hMLH1, and hMSH6). RESULTS: The
      incidence of MSI-H varied statistically significantly with age, being observed in
      more than 60% of those younger than age 31 years at diagnosis and in fewer than
      15% of those age 46 years or older. In 15 patients (<46 years old) whose
      colorectal cancers showed MSI-H, eight possessed germline mutations in either
      hMSH2 or hMLH1. When mutations in hMSH6 were included, more than 80% of Chinese
      colorectal cancer patients younger than 31 years had germline mutations in
      mismatch repair genes. We found a novel germline missense mutation in hMSH6 in a
      29-year-old man whose tumor showed no MSI. Two patients had a 4-base-pair
      insertion in exon 10 causing a truncated protein; this insertion is a common
      polymorphism with a population allele frequency in Chinese of 5.6%. CONCLUSIONS:
      Our results indicate that germline mutations in mismatch repair genes contribute
      substantially to the pathogenesis and high incidence of colorectal cancer in
      young Hong Kong Chinese. However, because young Chinese and Caucasians show
      similar proportions of colorectal cancers with MSI-H, despite the higher
      incidence in the former, additional factors may underlie the high susceptibility
      of young Chinese to colorectal cancer.

PMID- 10413424
TI  - Effect of antioxidants on androgen-induced AP-1 and NF-kappaB DNA-binding
      activity in prostate carcinoma cells.
AB  - BACKGROUND: Previous studies have suggested that male hormones (androgens) and
      certain forms of oxygen (reactive oxygen species) are linked to the development
      of prostate cancer. We hypothesized that androgens contribute to prostate
      carcinogenesis by increasing oxidative stress. We further hypothesized that
      antioxidants reduce prostate cancer risk by modulating androgen effects on
      cellular processes. METHODS: To test these hypotheses, we looked for 1) a change
      in the level of reactive oxygen species in the presence of androgens, 2) androgen
      induced binding activity of transcriptional activators AP-1 and NF-kappaB, whose
      activities are known to be altered during cell proliferation, and 3) the effect
      of antioxidants on androgen-induced transcription factor binding. RESULTS:
      Physiologic concentrations (1 nM) of 5alpha-dihydrotestosterone or 1-10 nM R1881,
      a synthetic androgen, produced sustained elevation of AP-1 and NF-kappaB DNA
      binding activity in LNCaP cells, an androgen-responsive human prostate carcinoma
      cell line. Androgen-independent DU145 cells (another human prostate carcinoma
      cell line) were unaffected by R1881 treatment. AP-1-binding activity increased 5
      hours after 1 nM R1881 treatment; NF-kappaB DNA-binding activity increased after
      36 hours. Both activities remained elevated for at least 120 hours. Nuclear AP-1
      and NF-kappaB protein levels were not elevated. Antioxidant vitamins C plus E
      blocked both androgen-induced DNA-binding activity and production of reactive
      oxygen species. CONCLUSION: Physiologic concentrations of androgens induce
      production of reactive oxygen species and cause prolonged AP-1 and NF-kappaB DNA
      binding activities, which are diminished by vitamins C and E.

PMID- 10413425
TI  - Folylpolyglutamyl synthetase gene transfer and glioma antifolate sensitivity in
      culture and in vivo.
AB  - BACKGROUND: Although antifolates are popular agents for use in chemotherapy, they
      display minimal toxicity against slow-growing tumors and are toxic to actively
      replicating cells in normal tissues. These drugs are converted intracellularly
      into polyglutamate derivatives by the enzyme folylpolyglutamyl synthetase (FPGS).
      Because tumors with high expression of FPGS often respond to nontoxic antifolate
      doses, we investigated whether augmenting tumoral FPGS activity by gene delivery
      would enhance tumoral antifolate sensitivity. METHODS: 9L rat gliosarcoma cells
      were stably transfected with a human FPGS complementary DNA (cDNA), producing
      9L/FPGS cells. The sensitivity of these cells to the antifolates methotrexate and
      edatrexate was measured in culture and in subcutaneous tumors, as was their
      ability to increase the chemosensitivity of nearby nontransfected cells, i.e., a
      bystander effect. The antifolate sensitivity of nonselected cells transduced with
      a hybrid amplicon vector that expressed FPGS was also ascertained. RESULTS: In
      comparison with 9L cells, 9L/FPGS cells displayed enhanced sensitivity to 4-hour
      pulses of antifolate. Subcutaneous 9L/FPGS tumors responded as well to
      methotrexate given every third day as 9L tumors did to daily treatment. A modest
      bystander effect was observed with edatrexate treatment in culture and in vivo.
      The observed bystander effect appeared to result from the release of antifolates
      by transfected cells after the removal of extracellular drug. In culture,
      enhanced antifolate sensitivity was also seen in other stably transfected rodent
      and human glioma cell lines, including one with high pre-existing FPGS activity,
      and in canine and human glioblastoma cell lines transduced with a vector bearing
      FPGS cDNA. CONCLUSIONS: FPGS gene delivery enhances the antifolate sensitivity of
      several glioma cell lines and merits further evaluation as a therapeutic
      strategy.

PMID- 10413426
TI  - Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected
      Ashkenazi Jewish women with breast cancer.
AB  - BACKGROUND: Approximately 2.0%-2.5% of Ashkenazi Jewish women carry one of three
      founding mutations in the BRCA1 and BRCA2 genes, and each mutation is associated
      with a high lifetime risk of invasive breast cancer. We investigated the extent
      to which these three mutations contribute to breast cancer incidence in the
      Ashkenazi Jewish population. METHODS: We ascertained 457 Jewish women with
      prevalent cases of breast cancer who were unselected for age or family history of
      the disease; 412 of these women were tested for the three founder mutations (case
      patients). Control subjects consisted of 360 non-Jewish women with breast cancer
      (control patients) and 380 healthy Jewish women with no history of cancer
      (control subjects). RESULTS: Mutations were found in 48 (11.7%) of 412 Jewish
      case patients. Forty-six of 48 mutations occurred in women with early-onset
      breast cancer (<50 years) or a history of ovarian or early-onset breast cancer in
      a first-, second-, or third-degree relative. The estimated penetrance to age 70
      years for breast cancer was 59.9% for the BRCA1 gene mutations and 28.3% for the
      BRCA2 gene mutation. Compared with Jewish control subjects, the relative risk
      (RR) of breast cancer for first-degree relatives of mutation carriers was 5.16
      (95% confidence interval [CI] = 3.14-8. 48), but risk was also increased for
      relatives of noncarriers (RR = 1.66; 95% CI = 1.18-2.33). The RR of prostate
      cancer for first-degree relatives of Jewish case patients was 3.36 (95% CI = 1.
      49-7.56). CONCLUSIONS: Approximately 12% of breast cancers in the Ashkenazi
      Jewish population are attributable to mutations in the BRCA1 or BRCA2 gene.
      Genetic testing may be useful when Jewish women with breast cancer are diagnosed
      before age 50 years or have a close relative with ovarian or early-onset breast
      cancer. An association between breast and prostate cancers was observed in our
      study population.

PMID- 10413427
TI  - Re: Effect of BRCA1 and BRCA2 on the association between breast cancer risk and
      family history.

PMID- 10413428
TI  - Re: Benefits and risks of screening mammography for women in their forties: a
      statistical appraisal.

PMID- 10413430
TI  - EDITOR'S NOTE: re: benefits and risks of screening mammography for women in their
      forties: a statistical appraisal 

PMID- 10413429
TI  - RESPONSE: re: benefits and risks of screening mammography for women in their
      forties: a statistical appraisal 

PMID- 10413431
TI  - EDITOR'S NOTE: re: benefits and risks of screening mammography for women in their
      forties: a statistical appraisal 

PMID- 10413432
TI  - Teaching psychodynamic psychotherapy to medical students: papers from the
      american psychoanalytic association: introduction

PMID- 10413433
TI  - Opportunities for psychoanalysis in American medical education: An overview.

PMID- 10413434
TI  - Teaching psychodynamic psychiatry during medical school and residency: specific
      skills and beyond.

PMID- 10413435
TI  - Psychodynamic social science and medical education.

PMID- 10413436
TI  - Psychoanalysts teaching medical students: how to succeed.

PMID- 10413437
TI  - How to think like an analyst 101: A model for teaching psychotherapy to medical
      students.

PMID- 10413438
TI  - A psychoanalyst in a medical school's student health psychiatric service.

PMID- 10413440
TI  - The psychoanalyst in the academic community.

PMID- 10413439
TI  - Teaching psychodynamic psychiatry to students on general medical rotations.

PMID- 10413441
TI  - Emotional control theory and the concept of defense: A teaching document.
AB  - Defensiveness in intrapsychic and interpersonal activities is a generally
      accepted concept among psychodynamic theorists, but a theoretically grounded
      classification of emotional control processes is needed. As a result of intensive
      case-by-case clinical and empirical studies, such a system was assembled. The
      system is organized by three major categories of processes that can regulate
      emotions. These are sets of mental operations that control 1) content of thought
      and communications, 2) form of thought and communications, and 3) person schemas
      that organize beliefs and interpersonal expressions. Each category of defensive
      control processes is linked to observable outcomes at intrapsychic and
      interpersonal levels. This classification system can be used to formulate how
      patterns of avoidance and distortion are formed.(The Journal of Psychotherapy
      Practice and Research 1999; 8:213-224)

PMID- 10413442
TI  - Projective identification, self-disclosure, and the patient's view of the object:
      the need for flexibility.
AB  - Certain patients, through projective identification and splitting mechanisms,
      test the boundaries of the analytic situation. These patients are usually
      experiencing overwhelming paranoid-schizoid anxieties and view the object as
      ruthless and persecutory. Using a Kleinian perspective, the author advocates
      greater analytic flexibility with these difficult patients who seem unable to use
      the standard analytic environment. The concept of self-disclosure is examined,
      and the author discusses certain technical situations where self-disclosure may
      be helpful. (The Journal of Psychotherapy Practice and Research 1999; 8:225-233)

PMID- 10413444
TI  - Is there a cost offset to psychotherapy?

PMID- 10413443
TI  - Theory and technique in psychodynamic treatment of panic disorder.
AB  - The authors elaborate psychodynamic factors that are relevant to the treatment of
      panic disorder. They outline psychoanalytic concepts that were employed to
      develop a psychodynamic approach to panic disorder, including the idea of
      unconscious mental life and the existence of defense mechanisms, compromise
      formations, the pleasure principle, and the transference. The authors then
      describe a panic-focused psychodynamic treatment based on a psychodynamic
      formulation of panic. Clinical techniques used in this approach, such as working
      with transference and working through, are described. Finally, a case vignette is
      employed to illustrate the relevance of these factors to panic disorder and the
      use of this treatment.(The Journal of Psychotherapy Practice and Research 1999;
      8:234-242)

PMID- 10413445
TI  - Role of N- and L-type calcium channels in depolarization-induced activation of
      tyrosine hydroxylase and release of norepinephrine by sympathetic cell bodies and
      nerve terminals.
AB  - Multiple types of voltage-activated calcium (Ca(2+)) channels are present in all
      nerve cells examined so far; however, the underlying functional consequences of
      their presence is often unclear. We have examined the contribution of Ca(2+)
      influx through N- and L- type voltage-activated Ca(2+) channels in sympathetic
      neurons to the depolarization-induced activation of tyrosine hydroxylase (TH),
      the rate-limiting enzyme in norepinephrine (NE) synthesis, and the depolarization
      induced release of NE. Superior cervical ganglia (SCG) were decentralized 4 days
      prior to their use to eliminate the possibility of indirect effects of
      depolarization via preganglionic nerve terminals. The presence of both omega
      conotoxin GVIA (1 microM), a specific blocker of N-type channels, and nimodipine
      (1 microM), a specific blocker of L-type Ca(2+) channels, was necessary to
      inhibit completely the stimulation of TH activity by 55 mM K(+), indicating that
      Ca(2+) influx through both types of channels contributes to enzyme activation. In
      contrast, K(+) stimulation of TH activity in nerve fibers and terminals in the
      iris could be inhibited completely by omega-conotoxin GVIA alone and was
      unaffected by nimodipine as previously shown. K(+) stimulation of NE release from
      both ganglia and irises was also blocked completely when omega-conotoxin GVIA was
      included in the medium, while nimodipine had no significant effect in either
      tissue. These results indicate that particular cellular processes in specific
      areas of a neuron are differentially dependent on Ca(2+) influx through N- and L
      type Ca(2+) channels.

PMID- 10413446
TI  - Interactions between nerve growth factor binding and estradiol in early
      development of the zebra finch telencephalon.
AB  - The zebra finch telencephalon exhibits rapid and substantial development in the
      first few weeks after hatching. In parallel, the rate of estradiol synthesis is
      very high in the zebra finch forebrain, and estradiol can have potent
      neurotrophic effects in specific telencephalic regions, including those that
      control the learning and production of song. In an attempt to elucidate
      mechanisms regulating telencephalic development, potentially including a role for
      the large capacity for estrogen production, (125)I-nerve growth factor (NGF)
      binding was measured in homogenates of telencephalon from zebra finches age 3,
      15, 30, 60, and 120 days. The highest density of low- and high-affinity (125)I
      NGF binding sites was observed in 3-day-old finches. Using an aromatase
      inhibitor, Fadrozole, to reduce estradiol levels in 1 to 4-day-old zebra finches
      significantly decreased both high- and low-affinity (125)I-NGF binding sites.
      Conversely, treating adult or 8 to 14-day-old hatchlings with estradiol increased
      high-affinity (125)I-NGF binding sites. These results are consistent with the
      hypothesis that estradiol influences the level of NGF receptors, and suggest one
      mechanism through which the steroid could affect brain development. The data also
      indicate that estradiol and NGF activity may be important for very early
      development of the telencephalon.

PMID- 10413447
TI  - Altered outward K(+) currents in Drosophila larval neurons of memory mutants
      rutabaga and amnesiac.
AB  - K(+) currents in cultured Drosophila larval neurons have been classified into
      four categories according to their inactivation time constants, relative
      amplitude, and response to K(+) channel blockers 4-AP and tetraethylammonium. The
      percentage (65%) of neurons displaying K(+) currents which were reduced to 30% in
      amplitude by 5 mM cyclic adenosine monophosphate (cAMP) analog 8-bromo-cAMP in
      both Drosophila memory mutants rutabaga (rut) and amnesiac (amn) was
      significantly larger than that (50%) in wild type. This initial characterization
      provides evidence for altered K(+) currents in both rut and amn mutants.
      Arachidonic acid, a specifical inhibitor of Kv4 family (shal) K(+) channels, was
      found to inhibit K(+) currents in cultured Drosophila neurons, suggesting the
      presence of shal channels in these neurons.

PMID- 10413448
TI  - Neuronal intracellular pH directly mediates nitric oxide-induced programmed cell
      death.
AB  - Neuronal injury is intricately linked to the activation of three distinct
      neuronal endonucleases. Since these endonucleases are exquisitely pH dependent,
      we investigated in primary rat hippocampal neurons the role of intracellular pH
      (pH(i)) regulation during nitric oxide (NO)-induced toxicity. Neuronal injury was
      assessed by both a 0.4% Trypan blue dye exclusion survival assay and programmed
      cell death (PCD) with terminal deoxynucleotidyl transferase nick-end labeling
      (TUNEL) 24 h following treatment with the NO generators sodium nitroprusside (300
      microM), 3-morpholinosydnonimine (300 microM), or 6-(2-hyrdroxy-1-methyl-2
      nitrosohydrazino)-N-methyl-1-hex anamine (300 microM). The pH(i) was measured
      using the fluorescent probe BCECF. NO exposure yielded a rapid intracellular
      acidification during the initial 30 min from pH(i) 7.36 +/- 0.01 to approximately
      7.00 (p <.0001). Within 45 min, a biphasic alkaline response was evident, with
      pH(i) reaching 7.40 +/- 0.02, that was persistent for a 6-h period. To mimic the
      effect of NO-induced acidification, neurons were acid-loaded with ammonium ions
      to yield a pH(i) of 7.09 +/- 0.02 for 30 min. Similar to NO toxicity, neuronal
      survival decreased to 45 +/- 2% (24 h) and DNA fragmentation increased to 58 +/-
      8% (24 h) (p <.0001). Although neuronal caspases did not play a dominant role,
      neuronal injury and the induction of PCD during intracellular acidification were
      dependent upon enhanced endonuclease activity. Furthermore, maintenance of an
      alkaline pH(i) of 7.60 +/- 0.02 during the initial 30 min of NO exposure
      prevented neuronal injury, suggesting the necessity for the rapid but transient
      induction of intracellular acidification during NO toxicity. Through the
      identification of the critical role of both NO-induced intracellular
      acidification and the induction of the neuronal endonuclease activity, our work
      suggests a potential regulatory trigger for the prevention of neuronal
      degeneration.

PMID- 10413450
TI  - Sexual dimorphisms in a neuromuscular system regulating courtship in the green
      anole lizard: effects of season and androgen treatment.
AB  - During the breeding season, male green anoles (Anolis carolinensis) court females
      by extending a red throat fan called a dewlap. Motoneurons controlling this
      sexually dimorphic behavior are located in two portions of the brain stem: (a)
      the vagal portion of nucleus ambiguus (AmbX), and (b) the region containing the
      glossopharyngeal portion of nucleus ambiguus and the ventral motor nucleus of the
      facial nerve (AmbIX/VIImv). These motoneurons project to the ceratohyoideus
      muscle via the ramus pharyngo-laryngeus IX+X. To investigate the effects of
      season on and androgen regulation of neural and peripheral structures controlling
      dewlap extension, two experiments were conducted: (a) During the breeding and
      nonbreeding seasons, motoneuron number, soma size, and nucleus size were
      investigated in intact males and females and in castrated males treated with a
      testosterone propionate (TP) or a blank Silastic capsule. (b) Cross-sectional
      area of the nerve and muscle fiber size, number, and density were investigated in
      the four treatment groups during the breeding season only. No significant
      differences were found in motoneuron number. In the breeding season, subtle male
      biased sex differences existed in both AmbX and AmbIX/VIImv soma size. Nerve
      cross-sectional area and muscle fiber size and number were substantially larger
      in males than females. Muscle fiber density was higher in females. No consistent
      effects due to season or androgen treatment were detected, although
      characteristics of motoneurons were in some cases slightly larger in the
      nonbreeding season. These results suggest that, while parallels to behavior exist
      between the sexes, morphological changes in adulthood in the dewlap motoneurons
      and muscle do not normally regulate courtship behavior in the male green anole.

PMID- 10413449
TI  - Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with
      oxidative stress and is apoptosis.
AB  - The mechanisms for motor neuron degeneration and regeneration in adult spinal
      cord following axotomy and target deprivation are not fully understood. We used a
      unilateral sciatic nerve avulsion model in adult rats to test the hypothesis that
      retrograde degeneration of motor neurons resembles apoptosis. By 21 days
      postlesion, the number of large motor neurons in lumbar spinal cord was reduced
      by approximately 30%. The death of motor neurons was confirmed using the terminal
      transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling method
      for detecting fragmentation of nuclear DNA. Motor neuron degeneration was
      characterized by aberrant accumulation of perikaryal phosphorylated
      neurofilaments. Structurally, motor neuron death was apoptosis. Apoptotic motor
      neurons undergo chromatolysis followed by progressive cytoplasmic and nuclear
      condensation with chromatin compaction into uniformly large round clumps. Prior
      to apoptosis, functionally active mitochondria accumulate within chromatolytic
      motor neurons, as determined by cytochrome c oxidase activity. These dying motor
      neurons sustain oxidative damage to proteins and nucleic acids within the first 7
      days after injury during the progression of apoptosis, as identified by
      immunodetection of nitrotyrosine and hydroxyl-modified deoxyguanosine and
      guanosine. We conclude that the retrograde death of motor neurons in the adult
      spinal cord after sciatic nerve avulsion is apoptosis. Accumulation of active
      mitochondria within the perikaryon and oxidative damage to nucleic acids and
      proteins may contribute to the mechanisms for apoptosis of motor neurons in the
      adult spinal cord.

PMID- 10413451
TI  - Modulation of HERG current and herg gene expression during retinoic acid
      treatment of human neuroblastoma cells: potentiating effects of BDNF.
AB  - The modulation of herg gene and HERG currents (I(HERG)) was studied in SH-SY5Y
      neuroblastoma (NB) cells treated with all-trans-retinoic acid (RA) in the absence
      or presence of the neurotrophin brain-derived neurotrophic factor (BDNF). Both
      treatments produced a strong increase in the percentage of cells differentiated
      along the neuronal pathway, with an orientation to a cholinergic phenotype, while
      a minority of cells displayed a glial phenotype particularly evident after long
      term exposure to the inducers. Differentiation of NB cells was accompanied by an
      increase in herg gene transcription, which attained its maximum after 6 days of
      treatment with RA and was not further increased by BDNF. This effect evidently
      reflected on HERG currents: In fact, RA produced an increase in HERG current
      density which was strongly potentiated by BDNF. Moreover, RA treatment affected
      the biophysical properties of I(HERG), inducing an increase in the deactivation
      time constant and a left shift of the activation curve. These effects were not
      substantially affected by BDNF. This modulation of I(HERG) influenced the value
      of the resting potential (V(REST)), which resulted significantly hyperpolarized
      in (RA with or without BDNF)-treated cells. Interestingly, these effects were
      absent in the glial population, which prevailed in cultures after long-term
      exposure to the inducers. On the whole, we demonstrate that besides expressing
      IRK currents, NB cells display another strategy to hyperpolarize their V(REST),
      based on the appropriate modulation of HERG currents. Different from what happens
      in normal neuroblast development, the latter are never lost by cancer cells
      despite the progression of these cells along the neuronal differentiative
      pathway, raising intriguing questions about the role of HERG currents in tumour
      behavior.

PMID- 10413452
TI  - Continual neurogenesis of vomeronasal neurons in vitro.
AB  - We developed a culture system of vomeronasal neurons in which continuous
      degeneration and regeneration of axon bundles were observed. Partially
      dissociated vomeronasal cells from rat embryonic day 15 were grown in culture and
      formed a miniature vomeronasal-like epithelium. We called these structures
      vomeronasal pockets. They contained both vomeronasal neurons and supporting
      cells. They formed a spherical structure with a central cavity where microvilli
      protruded from supporting cells. Mature vomeronasal neurons with well-developed
      microvilli were not observed in the vomeronasal pocket. The time period between
      degeneration of axon bundles and the next was about 2 weeks. When vomeronasal
      pockets were incubated with 5 microgram/mL aphidicolin, an inhibitor of cell
      division, regeneration of axon bundles was not observed after degeneration. These
      results suggest that vomeronasal neurons in culture undergo continuous
      regeneration but do not fully mature. In this culture system, vomeronasal pockets
      survived for over 1 year.

PMID- 10413453
TI  - Down-regulation of striatin, a neuronal calmodulin-binding protein, impairs rat
      locomotor activity.
AB  - Striatin, an intraneuronal, calmodulin-binding protein addressed to dendrites and
      spines, is expressed in the motor system, particularly the striatum and
      motoneurons. Striatin contains a high number of domains mediating protein-protein
      interactions, suggesting a role within a dendritic Ca(2+)-signaling pathway.
      Here, we explored the hypothesis of a direct role of striatin in the motor
      control of behaving rats, by using an antisense strategy based on
      oligodeoxynucleotides (ODN). Rats were treated by intracerebroventricular
      infusion of a striatin antisense ODN (A-ODN) or mismatch ODN (M-ODN) delivered by
      osmotic pumps over 6 days. A significant decrease in the nocturnal locomotor
      activity of A-ODN-treated rats was observed after 5 days of treatment.
      Hypomotricity was correlated with a 60% decrease in striatin content of the
      striata of A-ODN-treated rats sacrificed on day 6. Striatin thus plays a role in
      the control of motor function. To approach the cellular mechanisms in which
      striatin is involved, striatin down-regulation was studied in a comparatively
      simpler model: purified rat spinal motoneurons which retain their polarity in
      culture. Treatment of cells by the striatin A-ODN resulted in the impairement of
      the growth of dendrites but not axon. The decrease in dendritic growth paralleled
      the loss of striatin. This model allows analysis of the molecular basis of
      striatin function in the dynamic changes occurring in growing dendrites, and
      offers clues to unravel its function within spines.

PMID- 10413454
TI  - Gliarin and macrolin, two novel intermediate filament proteins specifically
      expressed in sets and subsets of glial cells in leech central nervous system.
AB  - Using monoclonal antibodies, we have identified two novel intermediate filament
      (IF) proteins, Gliarin and Macrolin, which are specifically expressed in the
      central nervous system of an invertebrate. The two proteins both contain the
      coiled-coil rod domain typical of the superfamily of IF proteins flanked by
      unique N- and C-terminal domains. Gliarin was found in all glial cells including
      macro- and microglial cells, whereas Macrolin was expressed in only a single pair
      of giant connective glial cells. The identification of Macrolin and Gliarin
      together with the characterization of the strictly neuronal IF protein Filarin in
      leech central nervous system demonstrate that multiple neuron- and glial-specific
      IFs are not unique to the vertebrate nervous system but are also found in
      invertebrates. Interestingly, phylogenetic analysis based on maximum parsimony
      indicated that the presence of neuron- and glial cell-specific IFs in coelomate
      protostomes as well as in vertebrates is not of monophyletic origin, but rather
      represents convergent evolution and appears to have arisen independently.

PMID- 10413456
TI  - REPLY: re: benefits and risks of screening mammography for women in their
      forties: a statistical appraisal 

PMID- 10413455
TI  - BDNF and NT4/5 promote survival and neurite outgrowth of pontocerebellar mossy
      fiber neurons.
AB  - The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor
      (BDNF), neurotrophin-3 (NT3), and NT4/5 are all found in the developing
      cerebellum. Granule cells, the major target neurons of mossy fibers, express BDNF
      during mossy fiber synaptogenesis. To determine whether neurotrophins contribute
      to the development of cerebellar afferent axons, we characterized the effects of
      neurotrophins on the growth of mossy fiber neurons from mice and rats in vitro.
      For a mossy fiber source, we used the basilar pontine nuclei (BPN), the major
      source of cerebellar mossy fibers in mammals. BDNF and NT4/5 increased BPN neuron
      survival, neurite outgrowth, growth cone size, and elongation rate, while neither
      NT3 nor NGF increased survival or outgrowth. In addition, BDNF and NT4/5 reduced
      the size of neurite bundles. Consistent with these effects, in situ hybridization
      on cultured basilar pontine neurons revealed the presence of mRNA encoding the
      TrkB receptor which binds both BDNF and NT4/5 with high affinity. We detected
      little or no message encoding the TrkC receptor which preferentially binds NT3.
      BDNF and NT4/5 also increased TrkB mRNA levels in BPN neurons. In addition to
      previously established functions as an autocrine/paracrine trophic factor for
      granule cells, the present results indicate that cerebellar BDNF may also act as
      a target-derived trophic factor for basilar pontine mossy fibers.

PMID- 10413457
TI  - Ser/Thr protein phosphatase type 5 (PP5) is a negative regulator of
      glucocorticoid receptor-mediated growth arrest.
AB  - Ligand-induced glucocorticoid receptor (GR) activation has recently been linked
      to the inhibition of cell proliferation via the transcriptional induction of
      p21(WAF1/Cip1), which functions as a universal inhibitor of cyclin-dependent
      protein kinases. Herein, we identify a Ser/Thr protein phosphatase (PP5) that
      promotes cellular proliferation by inhibiting both glucocorticoid and p53
      mediated signaling pathways leading to p21(WAF1/Cip1)-mediated growth arrest. The
      suppression of PP5 expression (1) markedly increases the association of GR with
      its cognate DNA-binding sequence, (2) induces GR transcriptional activity without
      the addition of hormone, and (3) increases dexamethasone-mediated induction of GR
      reporter activity to a level that is approximately 10 times greater than the
      maximal response obtainable in the presence of PP5. PP5 has no apparent effect on
      the binding of hormone to the GR, and dexamethasone-mediated growth arrest
      correlates with an increase in p53 phosphorylation. Comparative studies in p53
      wild-type, p53-defective, and p53-deficient cell lines indicate that either (1)
      p53 participates in GR-mediated induction of p21(WAF1/Cip1), with the
      hyperphosphorylation of basal p53 induced by glucocorticoids sufficient for the
      propagation of an antiproliferative response when PP5 expression is inhibited, or
      (2) PP5 acts where p53-mediated and GR-induced signaling networks converge to
      regulate the transcriptional induction of p21(WAF1/Cip1). Thus, aberrant PP5
      expression may have an additive effect on the development of human cancers by
      promoting cell proliferation via the inhibition of a GR-induced antiproliferative
      signaling cascade, and facilitating neoplastic transformation via the inhibition
      of a growth-arresting p53-mediated response that guards against genomic
      instability.

PMID- 10413458
TI  - A novel endogenous antimalarial: Fe(II)-protoporphyrin IX alpha (heme) inhibits
      hematin polymerization to beta-hematin (malaria pigment) and kills malaria
      parasites.
AB  - The polymerization of hemoglobin-derived ferric-protoporphyrin IX [Fe(III)PPIX]
      to inert hemozoin (malaria pigment) is a crucial and unique process for
      intraerythrocytic plasmodia to prevent heme toxicity and thus a good target for
      new antimalarials. Quinoline drugs, i.e., chloroquine, and non-iron porphyrins
      have been shown to block polymerization by forming electronic pi-pi interactions
      with heme monomers. Here, we report the identification of ferrous-protoporphyrin
      IX [Fe(II)PPIX] as a novel endogenous anti-malarial. Fe(II)PPIX molecules,
      released from the proteolysis of hemoglobin, are first oxidized and then
      polymerized to hemozoin. We obtained Fe(II)PPIX on preparative scale by
      electrochemical reduction of Fe(III)PPIX, and the reaction was monitored by
      cyclic voltammetry. Polymerization assays at acidic pH were conducted with the
      resulting Fe(II)PPIX using a spectrophotometric microassay of heme polymerization
      adapted to anaerobic conditions and the products characterized by infrared
      spectroscopy. Fe(II)PPIX (a) did not polymerize and (b) produced a dose-dependent
      inhibition of Fe(III)PPIX polymerization (IC(50) = 0.4 molar equiv). Moreover,
      Fe(II)PPIX produced by chemical reduction with thiol-containing compounds gave
      similar results: a dose-dependent inhibition of heme polymerization was observed
      using either L-cysteine, N-acetylcysteine, or DL-homocysteine, but not with L
      cystine. Cyclic voltammetry confirmed that the inhibition of heme polymerization
      was due to the Fe(II)PPIX molecules generated by the thiol-mediated reduction of
      Fe(III)PPIX. These results point to Fe(II)PPIX as a potential endogenous
      antimalarial and to Fe(III)PPIX reduction as a potential new pharmacological
      target.

PMID- 10413459
TI  - Substrate and inhibitor-induced conformational changes in the structurally
      related enzymes UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) and 5
      enolpyruvylshikimate 3-phosphate synthase (EPSPS).
AB  - UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) and 5-enolpyruvylshikimate
      3-phosphate synthase (EPSPS) have both a unique three-dimensional topology and
      overall reaction mechanism in common. In the case of MurA, the substrate-free,
      unliganded protein exhibits an "open" conformation. Upon binding of substrates,
      the protein forms a much more tightly packed so-called "closed" form following an
      induced fit mechanism. In this closed form, the substrates are properly
      positioned for catalysis. On the basis of the structural and mechanistic
      similarities of MurA and EPSPS, a similar conformational change is likely to
      occur in EPSPS to generate a catalytically competent active site. However, there
      is currently little experimental evidence available to support the occurrence of
      such a conformational change in EPSPS. Using limited tryptic digestion of
      MurA,(1) it could be shown that formation of the "closed" conformation of MurA is
      accompanied by a marked increase of stability toward proteolytic degradation.
      Formation of the closed conformation was achieved by addition of either an excess
      of both substrates or the sugar nucleotide substrate in conjunction with the
      antibiotic fosfomycin. Analysis of the MurA tryptic fragments by MALDI-TOF mass
      spectrometry demonstrates that the protection of the protein in either case is
      caused by (1) a specific shielding of regions thereby becoming less accessible as
      a result of the conformational change, and (2) an unspecific overall protection
      of the whole protein due to an apparently reduced flexibility of the peptide
      backbone in the binary and ternary complexes. The establishment of methods to
      describe the effects of tryptic digestion on MurA under various conditions was
      then extended to EPSPS. Although EPSPS was found to be much more stable toward
      proteolysis than MurA, the presence of shikimate 3-phosphate (S3P) and the
      inhibitor glyphosate led to a pronounced suppression of proteolytic degradation.
      When unliganded EPSPS was treated with trypsin, three of the peptide fragments
      obtained could be identified by mass spectrometry. Two of these are located in a
      region corresponding to the "catalytic" loop in MurA which participates in the
      conformational change. This indicates a conformational change in EPSPS, similar
      to the one observed in MurA, leading to the protection mentioned above.
      Corroborating evidence was obtained using a conformational sensitive monoclonal
      antibody against EPSPS which showed a 20-fold reduced affinity toward the protein
      complexed with S3P and glyphosate as compared to the unliganded enzyme.

PMID- 10413460
TI  - Aminoethylcysteine can replace the function of the essential active site lysine
      of Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl coenzyme A reductase.
AB  - The biodegradative 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase of
      Pseudomonas mevalonii catalyzes the NAD(+)-dependent conversion of (S)-HMG-CoA to
      (R)-mevalonate. Crystallographic analysis of abortive ternary complexes of this
      enzyme revealed lysine 267 located at a position in the active site, suggesting
      that it might serve as the general acid/base for catalysis. Site-directed
      mutagenesis and subsequent chemical derivatization were therefore employed to
      investigate this active site lysine. Replacement of lysine 267 by alanine,
      histidine, or arginine resulted in mutant enzymes that lacked detectable
      activity. Lysine 267 was next replaced by the lysine analogues aminoethylcysteine
      and carboxyamidomethylcysteine. Using instead of the wild-type enzyme the fully
      active, cysteine-free mutant enzyme C156A/C296A, lysine 267 was first replaced by
      cysteine. Cysteine 267 of mutant enzyme C156A/C296A/K267C was then treated with
      bromoethylamine or iodoacetamide to insert aminoethylcysteine (AEC) or
      carboxyamidomethylcysteine at position 267. The carboxyamidomethylcysteine
      derivative was inactive, whereas mutant enzyme C156A/C296A/K267AEC exhibited high
      catalytic activity. That aminoethylcysteine, but not other basic amino acids, can
      replace the function of lysine 267 documents both the importance of this residue
      and the requirement for a precisely positioned positive charge at the active site
      of the enzyme.

PMID- 10413461
TI  - Structural changes of the active site tunnel of Humicola insolens
      cellobiohydrolase, Cel6A, upon oligosaccharide binding.
AB  - The mechanisms of crystalline cellulose degradation by cellulases are of
      paramount importance for the exploitation of these enzymes in applied processes,
      such as biomass conversion. Cellulases have traditionally been classified into
      cellobiohydrolases, which are effective in the degradation of crystalline
      materials, and endoglucanases, which appear to act on "soluble" regions of the
      substrate. Humicola insolensCel6A (CBH II) is a cellobiohydrolase from glycoside
      hydrolase family 6 whose native structure has been determined at 1.9 A resolution
      [Varrot, A., Hastrup, S., Schulein, M., and Davies, G. J. (1999) Biochem. J. 337,
      297-304]. Here we present the structure of the catalytic core domain of Humicola
      insolens cellobiohydrolase II Cel6A in complex with glucose/cellotetraose at 1.7
      A resolution. Crystals of Cel6A, grown in the presence of cellobiose, reveal six
      binding subsites, with a single glucose moiety bound in the -2 subsite and
      cellotetraose in the +1 to +4 subsites. The complex structure is strongly
      supportive of the assignment of Asp 226 as the catalytic acid and consistent with
      proposals that Asp 405 acts as the catalytic base. The structure undergoes
      several conformational changes upon substrate binding, the most significant of
      which is a closing of the two active site loops (residues 174-196 and 397-435)
      with main-chain movements of up to 4.5 A observed. This complex not only defines
      the polysaccharide-enzyme interactions but also provides the first three
      dimensional demonstration of conformational change in this class of enzymes.

PMID- 10413462
TI  - The mobility of an HIV-1 integrase active site loop is correlated with catalytic
      activity.
AB  - Replication of HIV-1 requires the covalent integration of the viral cDNA into the
      host chromosomal DNA directed by the virus-encoded integrase protein. Here we
      explore the importance of a protein surface loop near the integrase active site
      using protein engineering and X-ray crystallography. We have redetermined the
      structure of the integrase catalytic domain (residues 50-212) using an
      independent phase set at 1.7 A resolution. The structure extends helix alpha4 on
      its N-terminal side (residues 149-154), thus defining the position of the three
      conserved active site residues. Evident in this and in previous structures is a
      conformationally flexible loop composed of residues 141-148. To probe the role of
      flexibility in this loop, we replaced Gly 140 and Gly 149, residues that appear
      to act as conformational hinges, with Ala residues. X-ray structures of the
      catalytic domain mutants G149A and G140A/G149A show further rigidity of alpha4
      and the adjoining loop. Activity assays in vitro revealed that these mutants are
      impaired in catalysis. The DNA binding affinity, however, is minimally affected
      by these mutants as assayed by UV cross-linking. We propose that the
      conformational flexibility of this active site loop is important for a
      postbinding catalytic step.

PMID- 10413463
TI  - The native state conformational ensemble of the SH3 domain from alpha-spectrin.
AB  - The folding/unfolding equilibrium of the alpha-spectrin SH3 domain has been
      measured by NMR-detected hydrogen/deuterium exchange and by differential scanning
      calorimetry. Protection factors against exchange have been obtained under native
      conditions for more than half of the residues in the domain. Most protected
      residues are located at the beta-strands, the short 3(10) helix, and part of the
      long RT loop, whereas the loops connecting secondary structure elements show no
      measurable protection. Apparent stability constants per residue and their
      corresponding Gibbs energies have been calculated from the exchange experiments.
      The most stable region of the SH3 domain is defined by the central portions of
      the beta-strands. The peptide binding region, on the other hand, is composed of a
      highly stable region (residues 53-57) and a highly unstable region, the loop
      between residues 34-41 (n-Src loop). All residues in the domain have apparent
      Gibbs energies lower than the global unfolding Gibbs energy measured by
      differential scanning calorimetry, indicating that under our experimental
      conditions the amide exchange of all residues in the SH3 domain occurs primarily
      via local unfolding reactions. A structure-based thermodynamic analysis has
      allowed us to predict correctly the thermodynamics of the global unfolding of the
      domain and to define the ensemble of conformational states that quantitatively
      accounts for the observed pattern of hydrogen exchange protection. These results
      demonstrate that under native conditions the SH3 domain needs to be considered as
      an ensemble of conformations and that the hydrogen exchange data obtained under
      those conditions cannot be interpreted by a two-state equilibrium. The
      observation that specific regions of a protein are able to undergo independent
      local folding/unfolding reactions indicates that under native conditions the
      scale of cooperative interactions is regional rather than global.

PMID- 10413464
TI  - Characterization of the AhR-hsp90-XAP2 core complex and the role of the
      immunophilin-related protein XAP2 in AhR stabilization.
AB  - The unliganded aryl hydrocarbon receptor (AhR) exists in the cytoplasm in a
      tetrameric 9S core complex, consisting of the AhR ligand-binding subunit, a dimer
      of hsp90, and the hepatitis B virus X-associated protein 2 (XAP2), an
      immunophilin-related protein sharing homologous regions with FKBP12 and FKBP52.
      Interactions between the recently identified XAP2 subunit and other members of
      the unliganded AhR complex and its precise role in the AhR signal transduction
      pathway are presently unknown. Mapping studies indicate that XAP2 requires the
      PAS, hsp90, and ligand binding domain(s) of the AhR for binding, and that both
      proteins directly interact in the absence of hsp90. XAP2 is also able to interact
      with hsp90 complexes in the absence of the AhR, and C-terminal sequences of XAP2
      are required for this interaction. XAP2 binds to the C-terminal end of hsp90,
      which contains a tetratricopeptide repeat domain acceptor site, whereas the AhR
      binds to a domain in the middle of hsp90. XAP2 was not found to be associated
      with the AhR-Arnt heterocomplex either in vitro or in nuclear extracts isolated
      from Hepa 1 cells treated with TCDD. Transient expression of XAP2 in COS-1 cells
      resulted in enhanced cytosolic AhR levels, suggesting a role for XAP2 in
      regulating the rate of AhR turnover.

PMID- 10413465
TI  - Contribution of cysteine 158, the glycosylation site threonine 194, the amino-
      and carboxy-terminal domains of apolipoprotein E in the binding to amyloid
      peptide beta (1-40).
AB  - Recent studies have shown that at physiological conditions (pH 7.6, 37 degrees
      C), the reactivity of recombinant apoE isoforms secreted by mammalian cells
      toward amyloid peptide beta (Abeta40) follows the order apoE2 > apoE3 > apoE4 for
      the apoE monomer and apoE2 > apoE3 for apoE dimer that is formed via that
      intramolecular disulfide bridges. Different Abeta binding properties have been
      reported for the plasma-derived apoE and commercially available apoE preparations
      that differ from the native apoE forms in the degree of their O-glycosylation. To
      define structural elements of apoE involved in the interaction with Abeta, we
      have introduced point mutations as well as amino- and carboxy-terminal deletions
      in the apoE structure. The mutant apoE forms were expressed transiently using the
      Semliki Forest Virus system, and the culture medium was utilized to study the
      reactivity of the mutated proteins with Abeta 40. This analysis showed that a
      mutation in the O-glycosylation site of apoE2 (Thr194-Ala) did not affect the SDS
      stable binding of apoE to Abeta. In contrast, introduction of cysteine at
      position 158 of apoE4 (Arg112, Cys158) increased the SDS-stable binding of apoE
      to Abeta to the levels similar to those observed in apoE2. Similar analysis
      showed that apoE truncated at residues 259, 249, 239, and 229 retains the SDS
      stable binding to Abeta40, whereas apoE truncated at residues 185 and 165 does
      not bind to Abeta. The deletion of aminoterminal residues 2-19 reduced the SDS
      stable binding of apoE2 to Abeta and deletion of residues 2-81 abolished binding
      to Abeta. It is also noteworthy that the (Delta2-81) apoE mutant exists
      predominantly as a dimer, suggesting that removal of residues 2-81 promoted
      dimerization of apoE. These findings suggest that the amino- and carboxy-terminal
      residues of apoE are required for SDS-stable binding of apoE to Abeta and that
      the presence of at least one cysteine contributes to the efficient Abeta binding.

PMID- 10413466
TI  - Hydrogen exchange shows peptide binding stabilizes motions in Hck SH2.
AB  - Src-homology-2 domains are small, 100 amino acid protein modules that are present
      in a number of signal transduction proteins. Previous NMR studies of SH2 domain
      dynamics indicate that peptide binding decreases protein motions in the pico- to
      nanosecond, and perhaps slower, time range. We suggest that amide hydrogen
      exchange and mass spectrometry may be useful for detecting changes in protein
      dynamics because hydrogen exchange rates are relatively insensitive to the time
      domains of the dynamics. In the present study, hydrogen exchange and mass
      spectrometry were used to probe hematopoietic cell kinase SH2 that was either
      free or bound to a 12-residue high-affinity peptide. Hydrogen exchange rates were
      determined by exposing free and bound SH2 to D(2)O, fragmenting the SH2 with
      pepsin, and determining the deuterium level in the peptic fragments. Binding
      generally decreased hydrogen exchange along much of the SH2 backbone, indicating
      a widespread reduction in dynamics. Alterations in the exchange of the most
      rapidly exchanging amide hydrogens, which was detected following acid quench and
      analysis by mass spectrometry, were used to locate differences in low-amplitude
      motion when SH2 was bound to the peptide. In addition, the results indicate that
      hydrogen exchange from the folded form of SH2 is an important process along the
      entire SH2 backbone.

PMID- 10413467
TI  - Platelet responses to compound interactions with thrombin.
AB  - Catalytic and noncatalytic interactions of thrombin with platelets are
      investigated with use of thrombin variants with altered specificities and with
      ligands of thrombin receptors on platelets. Both alpha-thrombin and weakly
      coagulant meizothrombin-des-fragment-1 (mu-thrombin) hydrolyze proteolytically
      activated receptor 1 for thrombin (rPAR1(T), recombinant) with catalytic
      efficiencies of >10(7) M(-)(1) s(-)(1), whereas rPAR1(T) is not a substrate for
      weakly coagulant beta-thrombin. In contrast, both mu-thrombin and beta-thrombin
      are weak agonists of platelet dense body (ATP) secretion. Antibodies that block
      rPAR1(T) cleavage strongly inhibit the secretory reaction to alpha- and mu
      thrombins but not to beta-thrombin or to thrombin receptor activating peptide
      (TRAP). However, catalytically inactive FPR-thrombin, which binds glycoprotein Ib
      but does not inhibit rPAR1(T) cleavage, inhibits responses to TRAP as well as
      those to alpha- and mu-thrombins, which indicates that binding of the inactive
      enzyme to platelets influences the function of PAR1(T). An antibody that inhibits
      binding of thrombin to platelet glycoprotein Ib inhibits secretory responses to
      thrombin but not to TRAP, so occupancy of glycoprotein Ib per se accounts for
      only part of the attenuation. All three thrombins stimulate a rise in cytosolic
      Ca(II), and the dose response to beta-thrombin is congruent with that for ATP
      secretion. However, the response of cytosolic Ca(II) is 10-100 times more
      sensitive to mu-thrombin and alpha-thrombin than ATP secretion is, and is
      inhibited by neither anti-PAR1(T) Ig nor FPR-thrombin. Thus, alpha-thrombin
      appears to have an activity not shared by either mu- or beta-thrombins. This
      activity is owed to more than coupling of independent signals from cleavage of
      two proteolytically activated receptors, as there is no synergism when mu
      thrombin and beta-thrombin costimulate secretion. It is concluded either that
      alpha-thrombin has a third interaction site on platelets with which neither mu
      thrombin nor beta-thrombin interacts or that dual receptors are coordinately
      cleaved. In either case, the strong secretory response to thrombin appears to be
      moderated, independently of cytosolic Ca(II), by occupancy of a noncatalytic
      interaction site such as glycoprotein Ib.

PMID- 10413468
TI  - The second epidermal growth factor-like domain of human factor IXa mediates
      factor IXa binding to platelets and assembly of the factor X activating complex.
AB  - Factor IXa binding to the activated platelet surface is required for efficient
      catalysis of factor X activation. Platelets possess a specific binding site for
      factor IXa, occupancy of which has been correlated with rates of factor X
      activation. However, the specific regions of the factor IXa molecule that are
      critical to this interaction have not yet been fully elucidated. To assess the
      importance of the second epidermal growth factor (EGF2) domain of factor IXa for
      platelet binding and catalysis, a chimeric protein (factor IXa(Xegf2)) was
      created by replacement of the EGF2 domain of factor IX with that of factor X.
      Competition binding experiments showed 2 different binding sites on activated
      platelets (approximately 250 each/platelet): (1) a specific factor IXa binding
      site requiring the intact EGF2 domain; and (2) a shared factor IX/IXa binding
      site mediated by residues G(4)-Q(11) within the Gla domain. In kinetic studies,
      the decreased V(max) of factor IXa(Xegf2) activation of factor X on the platelet
      surface (V(max) 2. 90 +/- 0.37 pM/min) versus normal factor IXa (37.6 +/- 0.15
      pM/min) was due to its decreased affinity for the platelet surface (K(d) 64.7 +/-
      3.9 nM) versus normal factor IXa (K(d) 1.21 +/- 0.07 nM), resulting in less bound
      enzyme (functional complex) under experimental conditions. The hypothesis that
      the binding defects of factor IXa(Xegf2) are the cause of the kinetic
      perturbations is further supported by the normal k(cat) of bound factor
      IXa(Xegf2) (1701 min(-)(1)) indicating (1) an intact catalytic site and (2) the
      normal behavior of bound factor IXa(Xegf2). The EGF2 domain is not a cofactor
      binding site since the mutant shows a normal rate enhancement upon the addition
      of cofactor. Thus, the intact EGF2 domain of factor IXa is critical for the
      formation of the factor X activating complex on the surface of activated
      platelets.

PMID- 10413469
TI  - Spt16 and Pob3 of Saccharomyces cerevisiae form an essential, abundant
      heterodimer that is nuclear, chromatin-associated, and copurifies with DNA
      polymerase alpha.
AB  - Previously we showed that the yeast proteins Spt16 (Cdc68) and Pob3 are
      physically associated, and interact physically and genetically with the catalytic
      subunit of DNA polymerase alpha, Pol1 [Wittmeyer and Formosa (1997) Mol. Cell.
      Biol. 17, 4178-4190]. Here we show that purified Spt16 and Pob3 form a stable,
      abundant, elongated heterodimer and provide evidence that this is the functional
      form of these proteins. Genetic interactions between mutations in SPT16 and POB3
      support the importance of the Spt16-Pob3 interaction in vivo. Spt16, Pob3, and
      Pol1 proteins were all found to localize to the nucleus in S. cerevisiae. A
      portion of the total cellular Spt16-Pob3 was found to be chromatin-associated,
      consistent with the proposed roles in modulating chromatin function. Some of the
      Spt16-Pob3 complex was found to copurify with the yeast DNA polymerase
      alpha/primase complex, further supporting a connection between Spt16-Pob3 and DNA
      replication.

PMID- 10413470
TI  - Assembly of A beta amyloid protofibrils: an in vitro model for a possible early
      event in Alzheimer's disease.
AB  - Amyloid fibrils comprising primarily the peptides A beta 40 and A beta 42 are a
      defining feature of the Alzheimer's disease (AD) brain, and convergent evidence
      suggests that the process of their formation plays a central role in the AD
      pathogenic pathway. Elucidation of fibril assembly is critical for the discovery
      of potential AD diagnostics and therapeutics, since the pathogenic entity is not
      necessarily the product fibril, but could be a precursor species whose formation
      is linked to fibrillogenesis in vivo. Atomic force microscopy allowed the
      identification of an unanticipated intermediate in in vitro fibril formation, the
      A beta amyloid protofibril. This manuscript describes studies of the structure of
      the A beta 40 protofibril and its in vitro assembly and disassembly using atomic
      force microscopy (AFM). The A beta 40 protofibril has a height of ca. 4.3 +/- 0.5
      nm and a periodicity of ca. 20 +/- 4.7 nm. The rate of its elongation depends on
      the total concentration of A beta 40, the temperature, and ionic strength of the
      medium. A beta 42 and A beta 40 protofibrils elongate at a comparable rate.
      Statistical analysis of AFM data reveals a decrease in the number of protofibrils
      with time, indicating that coalescence of smaller protofibrils contributes to
      protofibril elongation. Similar analysis reveals that protofibrils shorten while
      the number of protofibrils also decrease following dilution, indicating that
      protofibril disassembly does not proceed by a reverse of the assembly process.
      These investigations provide systematic data defining factors affecting A beta
      fibrillization and, thus, should be valuable in the design of high-throughput
      assays to identify agents which alter A beta protofibril assembly.

PMID- 10413471
TI  - Mossbauer and electron paramagnetic resonance studies of the cytochrome bf
      complex.
AB  - The (57)Fe-enriched cytochrome bf complex has been isolated from hydrocultures of
      spinach. It has been studied at different redox states by optical, EPR, and
      Mossbauer spectroscopy. The Mossbauer spectrum of the native complex at 190 K
      with all iron centers in the oxidized state reveals the presence of four
      different iron sites: low-spin ferric iron in cytochrome b [with an isomer shift
      (delta) of 0.20 mm/s, a quadrupole splitting (DeltaE(Q)) of 1.77 mm/s, and a
      relative area of 40%], low-spin ferric iron of cytochrome f (delta = 0.26 mm/s,
      DeltaE(Q) = 1.90 mm/s, and a relative area of 20%), and two high-spin ferric iron
      sites of the Rieske iron-sulfur protein (ISP) with a bis-cysteine and a bis
      histidine ligated iron (delta(1) = 0.15 mm/s, DeltaE(Q1) = 0.70 mm/s, and a
      relative area of 20%, and delta(2) = 0.25 mm/s, DeltaE(Q2) = 0.90 mm/s, and a
      relative area of 20%, respectively). EPR and magnetic Mossbauer measurements at
      low temperatures corroborate these results. A crystal-field analysis of the EPR
      data and of the magnetic Mossbauer data yields estimates for the g-tensors
      (g(z)(), g(y)(), and g(x)()) of cytochrome b (3.60, 1.35, and 1.1) and of
      cytochrome f (3.51, 1.69, and 0.9). Addition of ascorbate reduces not only the
      iron of cytochrome f to the ferrous low-spin state (delta = 0.43 mm/s, DeltaE(Q)
      = 1.12 mm/s at 4.2 K) but also the bis-histidine coordinated iron of the Rieske
      2Fe-2S center to the ferrous high-spin state (delta(2) = 0.73 mm/s, DeltaE(Q2) = 
      2.95 mm/s at 4.2 K). At this redox step, the Mossbauer parameters of cytochrome b
      have not changed, indicating that the redox changes of cytochrome f and the
      Rieske protein did not change the first ligand sphere of the low-spin ferric iron
      in cytochrome b. Reduction with dithionite further reduces the two hemes of
      cytochrome b to the ferrous low-spin state (delta = 0.49 mm/s, DeltaE(Q) = 1.08
      mm/s at 4.2 K). The spin Hamiltonian analysis of the magnetic Mossbauer spectra
      at 4.2 K yields hyperfine parameters of the reduced Rieske 2Fe-2S center in the
      cytochrome bf complex which are very similar to those reported for the Rieske
      center from Thermus thermophilus [Fee, J. A., Findling, K. L., Yoshida, T., et
      al. (1984) J. Biol. Chem. 259, 124-133].

PMID- 10413472
TI  - Catalytic electron transport in Chromatium vinosum [NiFe]-hydrogenase:
      application of voltammetry in detecting redox-active centers and establishing
      that hydrogen oxidation is very fast even at potentials close to the reversible
      H+/H2 value.
AB  - The nickel-iron hydrogenase from Chromatium vinosum adsorbs at a pyrolytic
      graphite edge-plane (PGE) electrode and catalyzes rapid interconversion of
      H(+)((aq)) and H(2) at potentials expected for the half-cell reaction 2H(+) right
      arrow over left arrow H(2), i.e., without the need for overpotentials. The
      voltammetry mirrors characteristics determined by conventional methods, while
      affording the capabilities for exquisite control and measurement of potential
      dependent activities and substrate-product mass transport. Oxidation of H(2) is
      extremely rapid; at 10% partial pressure H(2), mass transport control persists
      even at the highest electrode rotation rates. The turnover number for H(2)
      oxidation lies in the range of 1500-9000 s(-)(1) at 30 degrees C (pH 5-8), which
      is significantly higher than that observed using methylene blue as the electron
      acceptor. By contrast, proton reduction is slower and controlled by processes
      occurring in the enzyme. Carbon monoxide, which binds reversibly to the NiFe site
      in the active form, inhibits electrocatalysis and allows improved definition of
      signals that can be attributed to the reversible (non-turnover) oxidation and
      reduction of redox centers. One signal, at -30 mV vs SHE (pH 7.0, 30 degrees C),
      is assigned to the [3Fe-4S](+/0) cluster on the basis of potentiometric
      measurements. The second, at -301 mV and having a 1. 5-2.5-fold greater
      amplitude, is tentatively assigned to the two [4Fe-4S](2+/+) clusters with
      similar reduction potentials. No other redox couples are observed, suggesting
      that these two sets of centers are the only ones in CO-inhibited hydrogenase
      capable of undergoing simple rapid cycling of their redox states. With the buried
      NiFe active site very unlikely to undergo direct electron exchange with the
      electrode, at least one and more likely each of the three iron-sulfur clusters
      must serve as relay sites. The fact that H(2) oxidation is rapid even at
      potentials nearly 300 mV more negative than the reduction potential of the [3Fe
      4S](+/0) cluster shows that its singularly high equilibrium reduction potential
      does not compromise catalytic efficiency.

PMID- 10413473
TI  - Models for molybdenum coordination during the catalytic cycle of periplasmic
      nitrate reductase from Paracoccus denitrificans derived from EPR and EXAFS
      spectroscopy.
AB  - The periplasmic nitrate reductase from Paracoccus denitrificans is a soluble two
      subunit enzyme which binds two hemes (c-type), a [4Fe-4S] center, and a bis
      molybdopterin guanine dinucleotide cofactor (bis-MGD). A catalytic cycle for this
      enzyme is presented based on a study of these redox centers using electron
      paramagnetic resonance (EPR) and extended X-ray absorption fine structure (EXAFS)
      spectroscopies. The Mo(V) EPR signal of resting NAP (High g [resting]) has g(av)
      = 1.9898 is rhombic, exhibits low anisotropy, and is split by two weakly
      interacting protons which are not solvent-exchangeable. Addition of exogenous
      ligands to this resting state (e.g., nitrate, nitrite, azide) did not change the
      form of the signal. A distinct form of the High g Mo(V) signal, which has
      slightly lower anisotropy and higher rhombicity, was trapped during turnover of
      nitrate and may represent a catalytically relevant Mo(V) intermediate (High g
      [nitrate]). Mo K-edge EXAFS analysis was undertaken on the ferricyanide oxidized
      enzyme, a reduced sample frozen within 10 min of dithionite addition, and a
      nitrate-reoxidized form of the enzyme. The oxidized enzyme was fitted best as a
      di-oxo Mo(VI) species with 5 sulfur ligands (4 at 2. 43 A and 1 at 2.82 A), and
      the reduced form was fitted best as a mono-oxo Mo(IV) species with 3 sulfur
      ligands at 2.35 A. The addition of nitrate to the reduced enzyme resulted in
      reoxidation to a di-oxo Mo(VI) species similar to the resting enzyme. Prolonged
      incubation of NAP with dithionite in the absence of nitrate (i.e., nonturnover
      conditions) resulted in the formation of a species with a Mo(V) EPR signal that
      is quite distinct from the High g family and which has a g(av) = 1.973 (Low g
      [unsplit]). This signal resembles those of the mono-MGD xanthine oxidase family
      and is proposed to arise from an inactive form of the nitrate reductase in which
      the Mo(V) form is only coordinated by the dithiolene of one MGD. In samples of
      NAP that had been reduced with dithionite, treated with azide or cyanide, and
      then reoxidized with ferricyanide, two Mo(V) signals were detected with g(av)
      elevated compared to the High g signals. Kinetic analysis demonstrated that azide
      and cyanide displayed competitive and noncompetitive inhibition, respectively.
      EXAFS analysis of azide-treated samples show improvement to the fit when two
      nitrogens are included in the molybdenum coordination sphere at 2.52 A,
      suggesting that azide binds directly to Mo(IV). Based on these spectroscopic and
      kinetic data, models for Mo coordination during turnover have been proposed.

PMID- 10413474
TI  - Domain orientation and dynamics in multidomain proteins from residual dipolar
      couplings.
AB  - The data most commonly available for the determination of macromolecular
      structures in solution are NOE based distance estimates and spin-spin coupling
      constant based dihedral angle estimates. This information is, unfortunately,
      inherently short-range in nature. Thus, for many multidomain proteins, little
      information is available to accurately position weakly interacting domains with
      respect to each other. Recent studies of proteins aligned in dilute liquid
      crystalline solvents have shown the utility of measuring anisotropic spin
      interactions, such as residual dipolar couplings, to obtain unique long-range
      structural information. In this work, the latter approach is taken to explore the
      relative domain orientation in a two-domain fragment from the protein barley
      lectin. An approach based on singular value decomposition as opposed to simulated
      annealing is used to directly determine order tensors for each domain from
      residual (15)N-(1)H dipolar couplings, and the limitations of the two approaches
      are discussed. Comparison of the order tensor principal axis frames as separately
      determined for each domain indicates that the two domains are not oriented as in
      the crystal structure of wheat germ agglutinin, a highly homologous protein (
      approximately 95% sequence identical). Furthermore, differences in the order
      tensor values suggest that the two domains are not statically positioned but are
      experiencing different reorientational dynamics and, to a large degree, may be
      considered to reorient independently. Data are also presented that suggest that a
      specific association occurs between one domain and the lipid bicelles comprising
      the liquid crystal solvent.

PMID- 10413475
TI  - Role of helix-helix interactions in assembly of the bacteriorhodopsin lattice.
AB  - The purple membrane of Halobacterium salinarium is a two-dimensional lattice of
      lipids and the integral membrane protein bacteriorhodopsin (BR). To determine
      whether helix-helix interactions within the membrane core stabilize this complex,
      we substituted amino acid residues at the helix-helix interface between BR
      monomers and examined the assembly of the protein into the lattice. Lattice
      assembly was demonstrated to fit a cooperative self-assembly model that exhibits
      a critical concentration in vivo. Using this model as the basis for a
      quantitative assay of lattice stability, bulky substitutions at the helix-helix
      interface between BR monomers within the membrane core were shown to be
      destabilizing, probably due to steric clash. Ala substitutions of two residues at
      the helix-helix interface also reduced stability, suggesting that the side chains
      of these residues participate in favorable van der Waals packing interactions.
      However, the stabilizing interactions were restricted to a small region of the
      interface, and most of the substitutions had little effect. Thus, the
      contribution of helix-helix interactions to lattice stability appears limited,
      and favorable interactions between other regions of neighboring BR monomers or
      between BR and lipid molecules must also contribute.

PMID- 10413476
TI  - Phospholipase digestion of bound cardiolipin reversibly inactivates bovine
      cytochrome bc1.
AB  - Phospholipids and tightly bound cardiolipin (CL) can be removed from Tween 20
      solubilized bovine cytochrome bc(1) (EC 1.10.2.2) by digestion with Crotalus
      atrox phospholipase A(2). The resulting CL-free enzyme exhibits all the spectral
      properties of native cytochrome bc(1), but is completely inactive. Full electron
      transfer activity is restored by exogenous cardiolipin added in the presence of
      dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylethanolamine (DOPE),
      but not by cardiolipin alone or by mixtures of phospholipids lacking cardiolipin.
      Acidic, nonmitochondrial phospholipids, e.g., monolysocardiolipin or
      phosphatidylglycerol, partially reactivate CL-free cytochrome bc(1) if they are
      added together with DOPC and DOPE. Phospholipid removal from the Tween 20
      solubilized enzyme, including the tightly bound cardiolipin, does not perturb the
      environment of either cytochrome b(562) or b(566), nor does it cause the
      autoreduction of cytochrome c(1). Cardiolipin-free cytochrome bc(1) also binds
      antimycin and myxothiazol normally with the expected red shifts in b(562) and
      b(566), respectively. However, the CL-free enzyme is much less stable than the
      lipid-rich preparation, i.e., (1) many chromatographic methods perturb both
      cytochrome b(566)() (manifested by a hypsochromic effect, i.e., blue shift of 1.5
      1.7 nm) and cytochrome c(1) (evidenced by autoreduction in the absence of
      reducing agents); (2) affinity chromatographic purification of the enzyme causes
      pronounced loss of subunits VII and XI (65-80% decrease) and less significant
      loss of subunits I, IV, V, and X (20-30% decrease); and (3) high detergent-to
      protein ratios result in disassembly of the complex. We conclude that the major
      role of the phospholipids surrounding cytochrome bc(1), especially cardiolipin,
      is to stabilize the quaternary structure. In addition, bound cardiolipin has an
      additional functional role in that it is essential for enzyme activity.

PMID- 10413477
TI  - Relative role of anions and cations in the stabilization of halophilic malate
      dehydrogenase.
AB  - Halophilic malate dehydrogenase unfolds at low salt, and increasing the salt
      concentration stabilizes, first, the folded form and then, in some cases,
      destabilizes it. From inactivation and fluorescence measurements performed on the
      protein after its incubation in the presence of various salts in a large range of
      concentrations, the apparent effects of anions and cations were found to
      superimpose. A large range of ions was examined, including conditions that are in
      general not of physiological relevance, to explore the physical chemistry driving
      adaptation to extreme environments. The order of efficiency of cations and anions
      to maintain the folded form is, for the low-salt transition, Ca(2+) approximately
      Mg(2+) > Li(+) approximately NH(4)(+) approximately Na(+) > K(+) > Rb(+) > Cs(+),
      and SO(4)(2)(-) approximately OAc(-) approximately F(-) > Cl(-), and for the high
      salt transition, NH(4)(+) approximately Na(+) approximately K(+) approximately
      Cs(+) > Li(+) > Mg(2+) > Ca(2+), and SO(4)(2)(-) approximately OAc(-)
      approximately F(-) > Cl(-) > Br(-) > I(-). If a cation or anion is very
      stabilizing, the effect of the salt ion of opposite charge is limited. Anions of
      high charge density are always the most efficient to stabilize the folded form,
      in accordance with the order found in the Hofmeister series, while cations of
      high charge density are the most efficient only at the lower salt concentrations
      and tend to denature the protein at higher salt concentrations. The stabilizing
      efficiency of cations and anions can be related in a minor way to their effect on
      the surface tension of the solution, but the interaction of ions with sites only
      present in the folded protein has also to be taken into account. Unfolding at
      high salt concentrations corresponds to interactions of anions of low charge
      density and cations of high charge density with the peptide bond, as found for
      nonhalophilic proteins.

PMID- 10413478
TI  - 1-Butaneboronic acid binding to Aeromonas proteolytica aminopeptidase: a case of
      arrested development.
AB  - Hydrolases containing two metal ions connected by a bridging ligand catalyze
      reactions important in carcinogensis, tissue repair, post-translational
      modification, control and regulation of biochemical pathways, and protein
      degradation. The aminopeptidase from Aeromonas proteolytica serves as a paradigm
      for the study of such bridged bimetallic proteases since its three-dimensional
      structure is known to very high resolution and its catalytic reaction is amenable
      to spectroscopic examination. Herein, we report the X-ray crystal structure at
      1.9 A resolution of AAP complexed with 1-butaneboronic acid (BuBA). This
      structure suggests that this complex represents a snapshot of the proteolytic
      reaction in an arrested form between the Michaelis complex and the transition
      state. Comparison of the structure with spectroscopic and other data allows us to
      conclude that the apparently structurally symmetrical dizinc site is actually
      asymmetric electrostatically.

PMID- 10413479
TI  - Metal binding specificity in carbonic anhydrase is influenced by conserved
      hydrophobic core residues.
AB  - The role of highly conserved aromatic residues surrounding the zinc binding site
      of human carbonic anhydrase II (CAII) in determining the metal ion binding
      specificity of this enzyme has been examined by mutagenesis. Residues F93, F95,
      and W97 are located along a beta-strand containing two residues that coordinate
      zinc, H94 and H96, and these aromatic amino acids contribute to the high zinc
      affinity and slow zinc dissociation rate constant of CAII [Hunt, J. A., and
      Fierke, C. A. (1997) J. Biol. Chem. 272, 20364-20372]. Substitutions of these
      aromatic amino acids with smaller side chains enhance the copper affinity (up to
      100-fold) while decreasing the affinity of both cobalt and zinc, thereby altering
      the metal binding specificity up to 10(4)-fold. Furthermore, the free energy of
      the stability of native CAII, determined by solvent-induced denaturation,
      correlates positively with increased hydrophobicity of the amino acids at
      positions 93, 95, and 97 as well as with cobalt and zinc affinity. Conversely,
      increased copper affinity correlates with decreased protein stability. Zinc
      specificity is therefore enhanced by formation of the native enzyme structure.
      These data suggest that the hydrophobic cluster in CAII is important for
      orienting the histidine residues to stabilize metals bound with a distorted
      tetrahedral geometry and to destabilize the trigonal bipyramidal geometry of
      bound copper. Knowledge of the structural factors that lead to high metal ion
      specificity will aid in the design of metal ion biosensors and de novo catalytic
      sites.

PMID- 10413480
TI  - Slow binding inhibition of S-adenosylmethionine synthetase by imidophosphate
      analogues of an intermediate and product.
AB  - S-Adenosylmethionine (AdoMet) synthetase catalyzes the only known route of
      biosynthesis of the primary in vivo alkylating agent. Inhibitors of this enzyme
      could provide useful modifiers of biological methylation and polyamine
      biosynthetic processes. The AdoMet synthetase catalyzed reaction converts ATP and
      L-methionine to AdoMet, PP(i), and P(i), with formation of tripolyphosphate as a
      tightly bound intermediate. This work describes a nonhydrolyzable analogue of the
      tripolyphosphate (PPP(i)) reaction intermediate, diimidotriphosphate (O(3)P-NH
      PO(2)-NH-PO(3)(5)(-)), as a potent inhibitor. In the presence of AdoMet, PNPNP is
      a slow-binding inhibitor with an overall inhibition constant (K(i)) of 2 nM and a
      dissociation rate of 0.6 h(-)(1). In contrast, in the absence of AdoMet PNPNP is
      a classical competitive inhibitor with a K(i) of 0.5 microM, a slightly higher
      affinity than PPP(i) itself (K(i) = 3 microM). The imido analogue of the product
      pyrophosphate, imidodiphosphate (O(3)P-NH-PO(3)(4)(-)) also displays slow onset
      inhibition only in the presence of AdoMet, with a K(i) of 0.8 microM, compared to
      K(i) of 250 microM for PP(i). Circular dichroism spectra of the unliganded enzyme
      and various complexes are indistinguishable indicating that the protein secondary
      structure is not greatly altered upon complex formation, suggesting local
      rearrangements at the active site during the slow binding process. A model based
      on ionization of the bridging -NH- moiety is presented which could account for
      the potent inhibition by PNP and PNPNP.

PMID- 10413481
TI  - RNA and protein catalysis in group II intron splicing and mobility reactions
      using purified components.
AB  - Group II introns encode proteins with reverse transcriptase activity. These
      proteins also promote RNA splicing (maturase activity) and then, with the excised
      intron, form a site-specific DNA endonuclease that promotes intron mobility by
      reverse splicing into DNA followed by target DNA-primed reverse transcription.
      Here, we used an Escherichia coli expression system for the Lactococcus lactis
      group II intron Ll.LtrB to show that the intron-encoded protein (LtrA) alone is
      sufficient for maturase activity, and that RNP particles containing only the LtrA
      protein and excised intron RNA have site-specific DNA endonuclease and target DNA
      primed reverse transcriptase activity. Detailed analysis of the splicing reaction
      indicates that LtrA is an intron-specific splicing factor that binds to unspliced
      precursor RNA with a K(d) of </=0.12 pM at 30 degrees C. This binding occurs in a
      rapid bimolecular reaction, which is followed by a slower step, presumably an RNA
      conformational change, required for splicing to occur. Our results constitute the
      first biochemical analysis of protein-dependent splicing of a group II intron and
      demonstrate that a single intron-encoded protein can interact with the intron RNA
      to carry out a coordinated series of reactions leading to splicing and mobility.

PMID- 10413482
TI  - Discrimination of tRNALeu isoacceptors by the insertion mutant of Escherichia
      coli leucyl-tRNA synthetase.
AB  - A variant (LeuRS-A) of Escherichia coli leucyl-tRNA synthetase (LeuRS) carrying a
      40-residue duplication in its connective peptide 1 (CP1) has a 3-fold lower
      specificity for than for, whereas wild-type LeuRS has the same specificity for
      these two isoacceptors. The replacement of the acceptor stem of with yields a
      chimeric tRNA(Leu) for which wild-type LeuRS has the same specificity as it does
      for the two normal isoacceptors mentioned, but for which LeuRS-A has a reduced
      specificity similar to that for, indicating a difference between these two
      acceptor stems. LeuRS-A is slightly less stable than the native enzyme. Wild-type
      LeuRS and LeuRS-A have almost same K(d) value for their interaction with as
      determined by fluorescence quenching. No difference was detected between these
      two proteins by CD and fluorescence spectroscopy. These results show that LeuRS-A
      can discriminate between the two isoacceptors of tRNA(Leu).

PMID- 10413483
TI  - Effects of structure on alpha C-H bond enthalpies of amino acid residues:
      relevance to H transfers in enzyme mechanisms and in protein oxidation.
AB  - The bond dissociation enthalpies (BDE) of all of the amino acid residues, modeled
      by HC(O)NHCH(R)C(O)NH(2) (PH(res)), were determined at the B3LYP/6-31G//B3LYP/6
      31G level, coupled with isodesmic reactions. The results for neutral side chains
      with phi, psi angles approximately 180 degrees, approximately 180 degrees in
      ascending order, to an expected accuracy of +/-10 kJ mol(-)(1), are Asn 326;
      cystine 330; Asp 332; Gln 334; Trp 337; Arg 340; Lys 340; Met 343; His 344; Phe
      344; Tyr 344; Leu 344; Ala 345; Cys 346; Ser 349; Gly 350; Ile 351; Val 352; Glu
      354; Thr 357; Pro-cis 358; Pro-trans 369. BDEs calculated at the ROMP2/6
      31G//B3LYP/6-31G level exhibit the same trends but are approximately 7 kJ mol(
      )(1) higher. All BDEs are smaller than those of typical secondary or tertiary C-H
      bonds due to the phenomenon of captodative stabilization. The stabilization is
      reduced by changes in the phi,psi angles. As a result the BDEs increase by about
      10 kJ mol(-)(1) in beta-sheet and 40 kJ mol(-)(1) in alpha-helical environments,
      respectively. In effect the alpha C-H BDEs can be "tuned" from about 345 to 400
      kJ mol(-)(1) by adjusting the local environment. Some very significant effects of
      this are seen in the current literature on H-transfer processes in enzyme
      mechanisms and in oxidative damage to proteins. These observations are discussed
      in terms of the findings of the present study.

PMID- 10413484
TI  - Rotational dynamics of the regulatory light chain in scallop muscle detected by
      time-resolved phosphorescence anisotropy.
AB  - We have used time-resolved phosphorescence anisotropy (TPA) to study the
      rotational dynamics of chicken gizzard regulatory light chain (RLC) bound to
      scallop adductor muscle myofibrils in key physiological states. Native RLC from
      scallop myofibrils was extracted and replaced completely with gizzard RLC labeled
      specifically at Cys 108 with erythrosin iodoacetamide (ErIA). The calcium
      sensitivity of the ATPase activity of the labeled myofibril preparation was quite
      similar to that of the native sample, indicating that the ErIA-labeled RLC is
      functionally bound to the myosin head. In rigor (in the absence of ATP, when all
      the myosin heads are rigidly bound to the thin filament), a slight decay was
      observed in the first few microseconds, followed by no change in the anisotropy.
      This indicates small-amplitude restricted motions of the RLC or the entire LC
      domain of myosin. Addition of calcium to rigor restricts these motions further.
      Relaxation with ATP (no Ca) causes a large decay in the anisotropy, indicating
      large-amplitude rotational motion with correlation times of 5-50 micros. Further
      addition of calcium, to induce contraction, resulted in a decrease in the rate
      and amplitude of anisotropy decay. In particular, there is clear evidence for a
      slow rotational motion with a correlation time of approximately 300 micros, which
      is not present either in rigor or relaxation. This indicates rotational motion
      that specifically correlates with force generation. The changes in the rotational
      dynamics of the light-chain domain in rigor, relaxation, and contraction support
      earlier work based on probes of the catalytic domain that muscle contraction is
      accompanied by a disorder-to-order transition of the myosin head. However, the
      motions of the LC domain are different from those of the catalytic domain, which
      indicates rotation of the two domains relative to each other.

PMID- 10413485
TI  - Probing Aplysia californica adenosine 5'-diphosphate ribosyl cyclase for
      substrate binding requirements: design of potent inhibitors.
AB  - Readily synthesized nicotinamide adenine dinucleotide (NAD(+)) analogues have
      been used to investigate aspects of the cyclization of NAD(+) to cyclic adenosine
      5'-O-diphosphate ribose (cADPR) catalyzed by the enzyme adenosine 5'-O
      diphosphate (ADP) ribosyl cyclase and to produce the first potent inhibitors of
      this enzyme. In all cases, inhibition of Aplysia californica cyclase by various
      substrate analogues was found to be competitive while inhibition by nicotinamide
      exhibited mixed-behavior characteristics. Nicotinamide hypoxanthine dinucleotide
      (NHD(+)), nicotinamide guanine dinucleotide (NGD(+)), C1'-m-benzamide adenine
      dinucleotide (Bp(2)A), and C1'-m-benzamide nicotinamide dinucleotide (Bp(2)N)
      were found to be nanomolar potency inhibitors with inhibition constants of 70,
      143, 189, and 201 nM, respectively. However, NHD(+) and NGD(+) are also known
      substrates and are slowly converted to cyclic products, thus preventing their
      further use as inhibitors. The symmetrical bis-nucleotides, bis-adenine
      dinucleotide (Ap(2)A), bis-hypoxanthine dinucleotide (Hp(2)H), and bis
      nicotinamide dinucleotide (Np(2)N), exhibited micromolar competitive inhibition,
      with Ap(2)A displaying the greatest affinity for the enzyme. 2',3'-Di-O-acetyl
      nicotinamide adenine dinucleotide (AcONAD(+)) was not a substrate for the A.
      californica cyclase but also displayed some inhibition at a micromolar level.
      Finally, inhibition of the cyclase by adenosine 5'-O-diphosphate ribose (ADPR)
      and inosine 5'-O-diphosphate ribose (IDPR) was observed at millimolar
      concentration. The nicotinamide aromatic ring appears to be the optimal motif
      required for enzymatic recognition, while modifications of the 2'- and 3'
      hydroxyls of the nicotinamide ribose seem to hamper binding to the enzyme.
      Stabilizing enzyme/inhibitor interactions and the inability of the enzyme to
      release unprocessed material are both considered to explain nanomolar inhibition.
      Recognition of inhibitors by other ADP ribosyl cyclases has also been
      investigated, and this study now provides the first potent nonhydrolyzable sea
      urchin ADP ribosyl cyclase and cADPR hydrolase inhibitor Bp(2)A, with inhibition
      observed at the micromolar and nanomolar level, respectively. The benzamide
      derivatives did not inhibit CD38 cyclase or hydrolase activity when NGD(+) was
      used as substrate. These results emphasize the difference between CD38 and other
      enzymes in which the cADPR cyclase activity predominates.

PMID- 10413486
TI  - Cysteine-directed cross-linking demonstrates that helix 3 of SecE is close to
      helix 2 of SecY and helix 3 of a neighboring SecE.
AB  - Preprotein translocation in Escherichia coli is mediated by translocase, a
      multimeric membrane protein complex with SecA as the peripheral ATPase and SecYEG
      as the translocation pore. Unique cysteines were introduced into transmembrane
      segment (TMS) 2 of SecY and TMS 3 of SecE to probe possible sites of interaction
      between the integral membrane subunits. The SecY and SecE single-Cys mutants were
      cloned individually and in pairs into a secYEG expression vector and functionally
      overexpressed. Oxidation of the single-Cys pairs revealed periodic contacts
      between SecY and SecE that are confined to a specific alpha-helical face of TMS 2
      and 3, respectively. A Cys at the opposite alpha-helical face of TMS 3 of SecE
      was found to interact with a neighboring SecE molecule. Formation of this SecE
      dimer did not affect the high-affinity binding of SecA to SecYEG and ATP
      hydrolysis, but blocked preprotein translocation and thus uncouples the SecA
      ATPase activity from translocation. Conditions that prevent membrane deinsertion
      of SecA markedly stimulated the interhelical contact between the SecE molecules.
      The latter demonstrates a SecA-mediated modulation of the protein translocation
      channel that is sensed by SecE.

PMID- 10413487
TI  - The oxidized (3,3) state of manganese catalase. Comparison of enzymes from
      Thermus thermophilus and Lactobacillus plantarum.
AB  - Manganese catalases contain a binuclear manganese cluster that catalyzes the
      redox dismutation of hydrogen peroxide, interconverting between dimanganese(II)
      [(2,2)] and dimanganese(III) [(3,3)] oxidation states during turnover. We have
      investigated the oxidized (3,3) states of the homologous enzymes from Thermus
      thermophilus and Lactobacillus plantarum using a combination of optical
      absorption, CD, MCD, and EPR spectroscopies as sensitive probes of the electronic
      structure and protein environment for the active site metal clusters. Comparison
      of results for these two enzymes allows the essential features of the active
      sites to be recognized and the differences identified. For both enzymes,
      preparations having the highest catalytic activity have diamagnetic ground
      states, consistent with the bis-mu-bridging dimanganese core structure that has
      been defined crystallographically. Oxidative damage and exogenous ligand binding
      perturb the core structure of LPC, converting the enzyme to a distinct form in
      which the cluster becomes paramagnetic as a result of altered exchange coupling
      mediated by the bridging ligands. The TTC cluster does not exhibit this
      sensitivity to ligand binding, implying a different reactivity for the bridges in
      that enzyme. A mechanism is proposed involving distinct coordination modes for
      peroxide substrate in each of the two half-reactions for enzyme turnover.

PMID- 10413488
TI  - Role of lysine 240 in the mechanism of yeast pyruvate kinase catalysis.
AB  - Site-directed mutagenesis was used to change Lys 240 of yeast pyruvate kinase
      (Lys 269 in muscle PK) to Met. K240M has an absolute requirement for FBP for
      catalysis. K240M is 100- and 1000-fold less active than wild-type YPK in the
      presence of Mn(2+) and Mg(2+), respectively. Steady-state fluorescence titration
      data suggest that the substrate PEP binds to K240M with the same affinity as it
      does to wild-type YPK. The rate of phosphoryl transfer in K240M has been
      decreased >1000-fold compared to wild-type YPK. The detritiation of 3
      [(3)H]pyruvate catalyzed by YPK occurs at a rate significantly greater than the
      spontaneous rate. Detritiation of pyruvate by wild-type YPK occurs as a divalent
      metal- and FBP-dependent process requiring ATP. There is no detectable
      detritiation of pyruvate catalyzed by K240M. The solvent deuterium isotope effect
      on k(cat) is 2.7 +/- 0.2 and 1.6 +/- 0.1 for the wild type and for K240M YPK,
      respectively. This suggests that the isotope sensitive step in the PK reaction
      does not involve Lys 240 and that the enolpyruvate intermediate is still
      protonated by K240M. Isotope trapping was used to characterize enolpyruvate
      protonation by K240M. While there was enrichment of the methyl protons of
      pyruvate from labeled solvent formed by catalysis with muscle PK and wild-type
      YPK, only background levels of tritium were trapped with K240M. In K240M, the
      proton donor exchanges protons with the solvent at a higher rate relative to
      turnover than does the proton donor in wild-type YPK. The pH-rate profile of
      K240M exhibits the loss of a pK(a) value of 8. 8 observed with wild-type YPK. The
      above data and recent crystal structure data suggest that Lys 240 interacts with
      the phosphoryl group of phosphoenolpyruvate and helps to stabilize the
      pentavalent phosphate transition state during phosphoryl transfer. Phosphoryl
      transfer is highly coupled to proton transfer, or Lys 240 also affects enolate
      protonation.

PMID- 10413490
TI  - Observation of multistate kinetics during the slow folding and unfolding of
      barstar.
AB  - The kinetics of the slow folding and unfolding reactions of barstar, a bacterial
      ribonuclease inhibitor protein, have been studied at 23(+/-1) degrees C, pH 8, by
      the use of tryptophan fluorescence, far-UV circular dichroism (CD), near-UV CD,
      and transient mixing (1)H nuclear magnetic resonance (NMR) spectroscopic
      measurements in the 0-4 M range of guanidine hydrochloride (GdnHCl)
      concentration. The denaturant dependences of the rates of folding and unfolding
      processes, and of the initial and final values of optical signals associated with
      these kinetic processes, have been determined for each of the four probes of
      measurement. Values determined for rates as well as amplitudes are shown to be
      very much probe dependent. Significant differences in the intensities and rates
      of appearance and disappearance of several resolved resonances in the real-time
      one-dimensional NMR spectra have been noted. The NMR spectra also show increasing
      dispersion of chemical shifts during the slow phase of refolding. The denaturant
      dependences of rates display characteristic folding chevrons with distinct
      rollovers under strongly native as well as strongly unfolding conditions.
      Analyses of the data and comparison of the results obtained with different probes
      of measurement appear to indicate the accumulation of a myriad of intermediates
      on parallel folding and unfolding pathways, and suggest the existence of an
      ensemble of transition states. The energetic stabilities of the intermediates
      estimated from kinetic data suggest that they are approximately half as stable as
      the fully folded protein. The slowness of the folding and unfolding processes
      (tau = 10-333 s) and values of 20.5 (+/-1.4) and 18 (+/-0.5) kcal mol(-)(1) for
      the activation energies of the slow refolding and unfolding reactions suggest
      that proline isomerization is involved in these reactions, and that the
      intermediates accumulate and are therefore detectable because the slow proline
      isomerization reaction serves as a kinetic trap during folding.

PMID- 10413489
TI  - Proton NMR investigation of the heme active site structure of an engineered
      cytochrome c peroxidase that mimics manganese peroxidase.
AB  - The heme active site structure of an engineered cytochrome c peroxidase [MnCcP;
      see Yeung, B. K., et al. (1997) Chem. Biol. 4, 215-221] that closely mimics
      manganese peroxidase (MnP) has been characterized by both one- and two
      dimensional NMR spectroscopy. All hyperfine-shifted resonances from the heme
      pocket as well as resonances from catalytically relevant amino acid residues in
      the congested diamagnetic envelope have been assigned. From the NMR spectral
      assignment and the line broadening pattern of specific protons in NOESY spectra
      of MnCcP, the location of the engineered Mn(II) center is firmly identified.
      Furthermore, we found that the creation of the Mn(II)-binding site in CcP
      resulted in no detectable structural changes on the distal heme pocket of the
      protein. However, notable structural changes are observed at the proximal side of
      the heme cavity. Both CepsilonH shift of the proximal histidine and (15)N shift
      of the bound C(15)N(-) suggest a weaker heme Fe(III)-N(His) bond in MnCcP
      compared to WtCcP. Our results indicate that the engineered Mn(II)-binding site
      in CcP resulted in not only a similar Mn(II)-binding affinity and improved MnP
      activity, but also weakened the Fe(III)-N(His) bond strength of the template
      protein CcP so that its bond strength is similar to that of the target protein
      MnP. The results presented here help elucidate the impact of designing a metal
      binding site on both the local and global structure of the enzyme, and provide a
      structural basis for engineering the next generation of MnCcP that mimics MnP
      more closely.

PMID- 10413491
TI  - Stability and folding of dihydrofolate reductase from the hyperthermophilic
      bacterium Thermotoga maritima.
AB  - Dihydrofolate reductase (DHFR) has been a well-established model system for
      protein folding. The enzyme DHFR from the hyperthermophilic bacterium Thermotoga
      maritima (TmDHFR) displays distinct adaptations toward high temperatures at the
      level of both structure and stability. The enzyme represents an extremely stable
      dimer; no isolated structured monomers could be detected in equilibrium or during
      unfolding. The equilibrium unfolding strictly follows the two-state model for a
      dimer (N(2) right harpoon over left harpoon 2U), with a free energy of
      stabilization of DeltaG = -142 +/- 10 kJ/mol at 15 degrees C. The two-state model
      is applicable over the whole temperature range (5-70 degrees C), yielding a
      DeltaG vs T profile with maximum stability at around 35 degrees C. There is no
      flattening of the stability profile. Instead, the enhanced thermostability is
      characterized by shifts toward higher overall stability and higher temperature of
      maximum stability. TmDHFR unfolds in a highly cooperative manner via a nativelike
      transition state without intermediates. The unfolding reaction is much slower
      (ca. 10(8) times) compared to DHFR from Escherichia coli (EcDHFR). In contrast to
      EcDHFR, no evidence for heterogeneity of the native state is detectable.
      Refolding proceeds via at least two intermediates and a burst-phase of rather low
      amplitude. Reassociation of monomeric intermediates is not rate-limiting on the
      folding pathway due to the high association constant of the dimer.

PMID- 10413492
TI  - Direct evidence for a tyrosine radical in the reaction of cytochrome c oxidase
      with hydrogen peroxide.
AB  - Cytochrome c oxidase (COX) catalyzes the reduction of oxygen to water, a process
      which is accompanied by the pumping of four protons across the membrane.
      Elucidation of the structures of intermediates in these processes is crucial for
      understanding the mechanism of oxygen reduction. In the work presented here, the
      reaction of H(2)O(2) with the fully oxidized protein at pH 6.0 has been
      investigated with electron paramagnetic resonance (EPR) spectroscopy. The results
      reveal an EPR signal with partially resolved hyperfine structure typical of an
      organic radical. The yield of this radical based on comparison with other
      paramagnetic centers in COX was approximately 20%. Recent crystallographic data
      have shown that one of the Cu(B) ligands, His 276 (in the bacterial case), is
      cross-linked to Tyr 280 and that this cross-linked tyrosine is ideally positioned
      to participate in dioxygen activation. Here selectively deuterated tyrosine has
      been incorporated into the protein, and a drastic change in the line shape of the
      EPR signal observed above has been detected. This would suggest that the observed
      EPR signal does indeed arise from a tyrosine radical species. It would seem also
      quite possible that this radical is an intermediate in the mechanism of oxygen
      reduction.

PMID- 10413493
TI  - Modulating dipoles for structure-function correlations in the gramicidin A
      channel.
AB  - Dipoles of the tryptophan indole side chains have a direct impact on ion
      conductance in the gramicidin channel. Here, fluorination of the indoles (both 5-
      and 6-fluoro) is used to manipulate both the orientations and the magnitudes of
      the dipoles. The orientations and positions with respect to the channel axis were
      determined using (2)H solid state NMR of uniformly aligned lipid bilayer
      preparations. By exchange of the remaining four protons in the indole ring for
      deuterium, comparison could be made to d(5)-indole spectra that have previously
      been recorded for each of the four indoles of gramicidin A. After making the
      assignments which were aided by the observation of (19)F-(2)H dipolar
      interactions, we found that fluorination caused only minor changes in side chain
      conformation. With the high-resolution structural characterization of the
      fluorinated indoles in position 11, 13, and 15, the electrostatic interactions
      with a cation at the channel and bilayer center can be predicted and the
      influence of the modified dipoles on ion conductance estimated. The importance of
      the long-range electrostatic interaction was recently documented with the
      observation of alpha-helical dipoles oriented toward the bilayer center on the
      ion conductance pathway for the Streptomyces K(+) channel. We present direct
      measurements of the orientation of gramicidin channel F-Trp positions for use in
      analysis of dipole effects on channel permeation.

PMID- 10413494
TI  - Glutamic acid 472 and lysine 480 of the sodium pump alpha 1 subunit are essential
      for activity. Their conservation in pyrophosphatases suggests their involvement
      in recognition of ATP phosphates.
AB  - P-type ATPases such as the Na+,K+-ATPase (sodium pump) hydrolyze ATP to pump ions
      through biological membranes against their electrochemical gradients. The
      mechanisms that couple ATP hydrolysis to the vectorial ion transport are not yet
      understood, but unveiling structures that participate in ATP binding and in the
      formation of the ionophore might help to gain insight into this process. Looking
      at the alpha- and beta-phosphates of ATP as a pyrophosphate molecule, we found
      that peptides highly conserved among all soluble inorganic pyrophosphatases are
      also present in ion-transporting ATPases. Included therein are Glu48 and Lys56 of
      the Saccharomyces cerevisiae pyrophosphatase (SCE1-PPase) that are essential for
      the activity of this enzyme and have been shown in crystallographic analysis to
      interact with phosphate molecules. To test the hypothesis that equivalent amino
      acids are also essential for the activity of ion-transporting ATPases, Glu472 and
      Lys480 of the sodium pump alpha 1 subunit corresponding to Glu48 and Lys56 of
      SCE1-PPase were mutated to various amino acids. Mutants of the sodium pump alpha1
      subunit were expressed in yeast and analyzed for their ATPase activity and their
      ability to bind ouabain in the presence of either ATP, Mg2+, and Na+ or phosphate
      and Mg2+. All four mutants investigated, Glu472Ala, Glu472Asp, Lys480Ala, and
      Lys480Arg, display only a fraction of the ATPase activity obtained with the wild
      type enzyme. The same applies with respect to their ability to bind ouabain,
      where maximum ouabain binding to the mutants accounts for only about 10% of the
      binding obtained with the wild-type enzyme. On the basis of our results, we
      conclude that Glu472 and Lys480 are essential for the activity of the sodium
      pump. Their function is probably to arrest the alpha- and beta-phosphate groups
      of ATP in a proper position prior to hydrolysis of the gamma-phosphate group. The
      identification of these amino acids as essential components of the ATP
      recognizing mechanism of the pump has resulted in a testable hypothesis for the
      initial interactions of the sodium pump, and possibly of other P-type ATPases,
      with ATP.

PMID- 10413495
TI  - Specificity and catalysis of uracil DNA glycosylase. A molecular dynamics study
      of reactant and product complexes with DNA.
AB  - The structure of uracil DNA glycosylase (UDG) in complex with a nonamer duplex
      DNA containing a uracil has been determined only in the product state. The
      reactant state was constructed by reattaching uracil to the deoxyribose, and both
      complexes were studied by molecular dynamics simulations. Significant changes in
      the positions of secondary structural elements in the enzyme are induced by the
      hydrolysis of the glycosidic bond. The simulations show that the specificity of
      the uracil pocket in the enzyme is largely retained in both complexes with the
      exception of Asn-204, which has been identified as a residue that contributes to
      discrimination between uracil and cytosine. The hydrogen bond between the amide
      group of Asn-204 and O(4) of uracil is disrupted by fluctuations of the side
      chain in the reactant state and is replaced by a hydrogen bond to water molecules
      trapped in the interior of the protein behind the uracil binding pocket. The role
      of two residues implicated by mutation experiments to be important in catalysis,
      His-268 and Asp-145, is clarified by the simulations. In the reactant state, His
      268 is found 3.45 +/- 0.34 A from the uracil, allowing a water molecule to form a
      bridge to O(2). The environment in the enzyme raises the pK(a) value of His-268
      to 7.1, establishing a protonated residue for assisting in the hydrolysis of the
      glycosidic bond. In agreement with the crystallographic structure, the DNA
      backbone retracts after the hydrolysis to allow His-268 to approach the O(2) of
      uracil with a concomitant release of the bridging water molecule and a reduction
      in the pK(a) to 5.5, which releases the proton to the product. The side chain of
      Asp-145 is fully solvated in the reactant state and H-bonded through a water
      molecule to the 3'-phosphate of uridine. Both the proximity of Asp-145 to the
      negatively charged phosphate and its pK(a) of 4.4 indicate that it cannot act as
      a general base catalyst. We propose a mechanism in which the bridging water
      between Asp-145 and the 3'-phosphate accepts a proton from another water to
      stabilize the bridge through a hydronium ion as well as to produce the hydroxide
      anion required for the hydrolytic step. The mechanism is consistent with known
      experimental data.

PMID- 10413497
TI  - Molecular recognition of adenophostin, a very potent Ca2+ inducer, at the D-myo
      inositol 1,4,5-trisphosphate receptor.
AB  - The recognition mode of adenophostin A at the D-myo-inositol 1,4, 5-trisphosphate
      [Ins(1,4,5)P(3)] receptor was investigated. Comparison of conformations of
      Ins(1,4,5)P(3) and adenophostin A by using the combination of NMR and molecular
      mechanics (MM) calculations demonstrated that adenophostin A adopted a moderately
      extended conformation regarding the distance between the 2'-phosphoryl group and
      the 3' ',4' '-bisphosphate motif, as suggested previously [Wilcox, R. A. et al.
      (1995) Mol. Pharmacol. 47, 1204-1211]. Based on the nuclear Overhauser effect
      (NOE) observed between 3'-H and 1' '-H and on MM calculations, the molecular
      shape of adenophostin A proved to be an extended form at least in solution, in
      contrast to Wilcox's compactly folded, preliminary hairpin model.
      GlcdR(2,3',4')P(3), an adenophostin analogue without adenine moiety, was found to
      be less potent than adenophostin A and almost equipotent to Ins(1,4,5)P(3). We
      propose the possibility that (i) the optimal spatial arrangement of the three
      phosphoryl groups and/or (ii) the interaction of the adenine moiety of
      adenophostin A with the putative binding site, if it exists in the vicinity of
      the Ins(1,4,5)P(3)-binding site, might account for the exceptional potency of
      adenophostin A.

PMID- 10413496
TI  - Crystal structure of the topoisomerase II poison 9-amino-[N-(2
      dimethylamino)ethyl]acridine-4-carboxamide bound to the DNA hexanucleotide
      d(CGTACG)2.
AB  - The structure of the complex formed between d(CGTACG)(2) and the antitumor agent
      9-amino-[N-(2-dimethylamino)ethyl]acridine-4-carboxamide has been solved to a
      resolution of 1.6 A using X-ray crystallography. The complex crystallized in
      space group P6(4) with unit cell dimensions a = b = 30.2 A and c = 39.7 A, alpha
      = beta = 90 degrees, gamma = 120 degrees. The asymmetric unit contains a single
      strand of DNA, 1. 5 drug molecules, and 29 water molecules. The final structure
      has an overall R factor of 19.3%. A drug molecule intercalates between each of
      the CpG dinucleotide steps with its side chain lying in the major groove, and the
      protonated dimethylamino group partially occupies positions close to (
      approximately 3.0 A) the N7 and O6 atoms of guanine G2. A water molecule forms
      bridging hydrogen bonds between the 4-carboxamide NH and the phosphate group of
      the same guanine. Sugar rings adopt the C2'-endo conformation except for cytosine
      C1 which moves to C3'-endo, thereby preventing steric collision between its C2'
      methylene group and the intercalated acridine ring. The intercalation cavity is
      opened by rotations of the main chain torsion angles alpha and gamma at guanines
      G2 and G6. Intercalation perturbs helix winding throughout the hexanucleotide
      compared to B-DNA, steps 1 and 2 being unwound by 8 degrees and 12 degrees,
      respectively, whereas the central TpA step is overwound by 17 degrees. An
      additional drug molecule, lying with the 2-fold axis in the plane of the acridine
      ring, is located at the end of each DNA helix, linking it to the next duplex to
      form a continuously stacked structure. The protonated N,N-dimethylamino group of
      this "end-stacked" drug hydrogen bonds to the N7 atom of guanine G6. In both drug
      molecules, the 4-carboxamide group is internally hydrogen bonded to the
      protonated N-10 atom of the acridine ring. The structure of the intercalated
      complex enables a rationalization of the known structure-activity relationships
      for inhibition of topoisomerase II activity, cytotoxicity, and DNA-binding
      kinetics for 9-aminoacridine-4-carboxamides.

PMID- 10413498
TI  - Ubiquitin binding interface mapping on yeast ubiquitin hydrolase by NMR chemical
      shift perturbation.
AB  - The interaction between the 26 kDa yeast ubiquitin hydrolase (YUH1), involved in
      maintaining the monomeric ubiquitin pool in cells, and the 8.5 kDa yeast
      ubiquitin protein has been studied by heteronuclear multidimensional NMR
      spectroscopy. Chemical shift perturbation of backbone (1)H(N), (15)N, and
      (13)C(alpha) resonances of YUH1, in a YUH1-ubiquitin mixture and in a 35 kDa
      covalent complex with ubiquitin (a stable analogue of the tetrahedral reaction
      intermediate), was employed to identify the ubiquitin binding interface of YUH1.
      This interface mapped on the secondary structure of YUH1 suggests a wide area of
      contact for ubiquitin, encompassing the N-terminus, alpha1, alpha4, beta2, beta3,
      and beta6, coincident with the high specificity of YUH1 for ubiquitin. The
      presence of several hydrophobic clusters in the ubiquitin binding interface of
      YUH1 suggests that hydrophobic interactions are equally important as ionic
      interactions in contacting ubiquitin. The residues in the binding interface
      exhibit a high percentage of homology among the members of the ubiquitin C
      terminal hydrolase family, indicating the well-conserved nature of the ubiquitin
      binding interface reported in this study. The secondary structure of YUH1, from
      our NMR studies, was similar to the recently determined structure of its human
      homologue ubiquitin C-terminal hydrolase L3 (UCH-L3), except for the absence of
      the helix H3 of UCH-L3. This region in YUH1 (helix H3 of UCH-L3) was least
      perturbed upon ubiquitin binding. Therefore, the binding interface was mapped
      onto the corresponding residues in the UCH-L3 crystal structure. A model for
      ubiquitin binding to YUH1 is proposed, in which a good correlation was observed
      for the lateral binding of ubiquitin to UCH-L3 (YUH1), stabilized by the
      electrostatic and hydrophobic interactions.

PMID- 10413499
TI  - Probing the kinetic mechanism and coenzyme specificity of glutathione reductase
      from the cyanobacterium Anabaena PCC 7120 by redesign of the pyridine-nucleotide
      binding site.
AB  - Glutathione reductase from the cyanobacterium Anabaena PCC 7120 contains a
      pyridine-nucleotide-binding motif differing from that of the enzyme from other
      sources and an insertion of 10 amino acid residues. Homology modeling was used to
      obtain a model of the enzyme structure. It revealed that in the Anabaena enzyme
      Lys(203) replaces Arg, found to interact with the 2'-phosphate of NADP(H) in the
      enzyme from other sources, and that it has an extra loop near the entrance of the
      pyridine-nucleotide-binding site. The steady-state and preequilibrium kinetic
      properties were characterized for the wild-type enzyme, a K203R, and a loop
      deletion mutant. All enzyme forms had higher catalytic efficiency with NADPH than
      with NADH, although the difference was less than for glutathione reductase from
      other sources. The specificity was most pronounced in the formation of the charge
      transfer complex between the pyridine nucleotide and oxidized enzyme-bound FAD,
      as compared to later steps in the reaction. Unexpectedly, by replacing Lys(203)
      with Arg, the specificity for NADPH was diminished in the complete redox
      reaction. Ser(174) appears to interact with the 2'-phosphate of NADPH and
      introduction of arginine instead of lysine, therefore, has little effect on the
      interaction with this coenzyme. However, the efficiency in forming the charge
      transfer complex between the pyridine nucleotide and oxidized enzyme-bound FAD
      was increased in the K203R mutant using NADPH but not with NADH. The lack of
      affinity toward 2',5'-ADP-Sepharose by the wild-type enzyme was not changed by
      replacing Lys(203) with Arg but deletion of the loop resulted in an enzyme that
      bound to the immobilized ligand. Removal of the loop increased the efficiency of
      the enzyme in the reductive half-reaction with both pyridine-nucleotides as well
      as in the overall catalytic mechanism.

PMID- 10413500
TI  - Site-directed mutagenesis and molecular modeling identify a crucial amino acid in
      specifying the heparin affinity of FGF-1.
AB  - Heparin potentiates the mitogenic activity of FGF-1 by increasing the affinity
      for its receptor and by extending its biological half-life. During the course of
      labeling human FGF-1 with Na(125)I and chloramine T, it was observed that the
      protein lost its ability to bind to heparin. In contrast, bovine FGF-1 retained
      its heparin affinity even after iodination. To localize the region responsible
      for the lost heparin affinity, chimeric FGF-1 proteins were constructed from
      human and bovine FGF-1 expression constructs and tested for their heparin
      affinity after iodination. The results showed that the C-terminal region of human
      FGF-1 was responsible for the loss of heparin affinity. This region harbors a
      single tyrosine residue in human FGF-1 in contrast to a phenylalanine at this
      position in bovine FGF-1. Mutating this tyrosine residue in the human FGF-1
      sequence to phenylalanine did not restore the heparin affinity of the iodinated
      protein. Likewise, changing the phenylalanine to tyrosine in the bovine FGF-1 did
      not reduce the ability of the iodinated protein to bind to heparin. In contrast,
      a mutant human FGF-1 that has cysteine-131 replaced with serine (C131S) was able
      to bind to heparin even after iodination while bovine FGF-1 (S131C) lost its
      binding affinity to heparin upon iodination. In addition, the human FGF-1 C131S
      mutant showed a decrease in homodimer formation when exposed to CuCl(2).
      Molecular modeling showed that the heparin-binding domain of FGF-1 includes
      cysteine-131 and that cysteine-131, upon oxidation to cysteic acid during the
      iodination procedures, would interact with lysine-126 and lysine-132. This
      interaction alters the conformation of the basic residues such that they no
      longer bind to heparin.

PMID- 10413501
TI  - Superadditive and subadditive effects of "hot spot" mutations within the
      interfaces of placental ribonuclease inhibitor with angiogenin and ribonuclease
      A.
AB  - Previous single-site mutagenesis studies on the complexes of ribonuclease
      inhibitor (RI) with angiogenin (Ang) and RNase A suggested that in both cases a
      substantial fraction of the binding energy is concentrated within one small part
      of the crystallographically observed interface, involving RI residues 434-438.
      Such energetic "hot spots" are common in protein-protein complexes, but their
      physical meaning is generally unclear. Here we have investigated this question by
      examining the detailed interactions within the RI.ligand hot spots and the extent
      to which they function independently. The effects of Phe versus Ala substitutions
      show that the key residue Tyr434 interacts with both ligands primarily through
      its phenyl ring; for Tyr437, the OH group forms the important contacts with RNase
      A, whereas the phenyl group interacts with Ang. Kinetic characterization of
      complexes containing multiple substitutions reveals striking, but distinctive,
      cooperativity in the interactions of RI with the two ligands. The losses in
      binding energy for the RNase complex associated with replacements of Tyr434 and
      Asp435, and Tyr434 and Tyr437, are markedly less than additive (i.e., by 2.4 and
      1.3 kcal/mol, respectively). In contrast, the energetic effects of the 434 and
      435, and 434 and 437, substitution pairs on binding of Ang are fully additive and
      2.5 kcal/mol beyond additive, respectively. Superadditivities (0.9-2.4 kcal/mol)
      are also observed for several multisite replacements involving these inhibitor
      residues and two Ang residues, Arg5 and Lys40, from this part of the interface.
      Consequently, the decreases in binding energy for some triple-variant complexes
      are as large as 8.5-10.1 kcal/mol (compared to a total DeltaG of -21.0 kcal/mol
      for the wild-type complex). Potential explanations for these functional
      couplings, many of which occur over distances of >13 A and are not mediated by
      direct or triangulated contacts, are proposed. These findings show that the basis
      for the generation of hot spots can be complex, and that these sites can assume
      significantly more (as with Ang) or less (as with RNase) importance than
      indicated from the effects of single-site mutations.

PMID- 10413502
TI  - Differential mobility of skeletal and cardiac tropomyosin on the surface of F
      actin.
AB  - Polarized phosphorescence from the triplet probe erythrosin-5-iodoacetamide
      attached to sulfhydryls in rabbit skeletal and cardiac muscle tropomyosin (Tm)
      was used to measure the microsecond rotational dynamics of these tropomyosins in
      a complex with F-actin. The steady-state phosphorescence anisotropy of skeletal
      tropomyosin on F-actin was 0.025 +/- 0.005 at 20 degrees C; the comparable
      anisotropy for cardiac tropomyosin was 0.010 +/- 0. 003. Measurements of the
      anisotropy as a function of temperature and solution viscosity (modulated by
      addition of glycerol) indicated that both skeletal and cardiac tropomyosin
      undergo complex rotational motions on the surface of F-actin. Models assuming
      either long axis rotation of a rigid rod or torsional twisting of a flexible rod
      adequately fit these data; both analyses indicated that cardiac Tm is more mobile
      than skeletal Tm and that the increased mobility on the surface of F-actin
      reflected either the rotational motion of a smaller physical unit or the
      torsional twisting of a less rigid molecule. The binding of myosin heads (S1) to
      the Tm-F-actin complexes increased the anisotropy to 0.049 +/- 0.004 for skeletal
      and 0.054 +/- 0.007 for cardiac tropomyosin. The titration of the skeletal
      tropomyosin-F-actin complex by S1 showed a break at an S1/actin ratio of 0.14;
      this complex had an anisotropy of 0.040 +/- 0.007, suggesting that one bound head
      effectively restricted the motion of each skeletal tropomyosin. A similar
      titration with cardiac tropomyosin reached a plateau at an S1/actin ratio of 0.4,
      suggesting that 2-3 myosin heads are required to immobilize cardiac Tm. Surface
      mobility is predicted by structural models of the interaction of tropomyosin with
      the actin filament while the decrease in tropomyosin mobility upon S1 binding is
      consistent with current theories for the proposed role of myosin binding in the
      mechanism of tropomyosin-based regulation of muscle contraction.

PMID- 10413503
TI  - Changes of the fluidity of mitochondrial membranes induced by the permeability
      transition.
AB  - The dynamic properties of protein and lipid regions of mitochondrial membranes
      during the permeability transition (PT) process were studied by following the
      anisotropy changes of hematoporphyrin (HP) and 1,6-diphenyl-1,3,5-hexatriene
      (DPH), respectively. We show that opening of the PT pore is accompanied by a
      remarkable increase of mitochondrial membrane fluidity which is specifically
      localized to protein sites, while lipid domains are unaffected. The increased
      membrane fluidity is not related to the collapse of transmembrane potential that
      follows the PT, as demonstrated by a comparison between the anisotropy properties
      of permeabilized mitochondria and impermeable, depolarized organelles. Parameters
      such as osmotic swelling and temperature, which are shown to affect the
      mitochondrial membrane dynamics in the absence of permeability transition, cannot
      alone account for the pore dynamical properties. We suggest that the observed
      increase in fluidity is mainly due to a conformational change of pore-forming
      protein(s) during the "assembly" of the PT pore.

PMID- 10413504
TI  - Different anesthetic sensitivities of skeletal and cardiac isoforms of the Ca
      ATPase.
AB  - We have previously shown that low levels of the volatile anesthetic halothane
      activate the Ca-ATPase in skeletal sarcoplasmic reticulum (SR), but inhibit the
      Ca-ATPase in cardiac SR. In this study, we ask whether the differential
      inhibition is due to (a) the presence of the regulatory protein phospholamban in
      cardiac SR, (b) different lipid environments in skeletal and cardiac SR, or (c)
      the different Ca-ATPase isoforms present in the two tissues. By expressing
      skeletal (SERCA 1) and cardiac (SERCA 2a) isoforms of the Ca-ATPase in Sf21
      insect cell organelles, we found that differential anesthetic effects in skeletal
      and cardiac SR are due to differential sensitivities of the SERCA 1 and SERCA 2a
      isoforms to anesthetics. Low levels of halothane inhibit the SERCA 2a isoform of
      the Ca-ATPase, and have little effect on the SERCA 1 isoform. The biochemical
      mechanism of halothane inhibition involves stabilization of E2 conformations of
      the Ca-ATPase, suggesting direct anesthetic interaction with the ATPase. This
      study establishes a biochemical model for the mechanism of action of an
      anesthetic on a membrane protein, and should lead to the identification of
      anesthetic binding sites on the SERCA 1 and SERCA 2a isoforms of the Ca-ATPase.

PMID- 10413505
TI  - Shutoff and agonist-triggered internalization of protease-activated receptor 1
      can be separated by mutation of putative phosphorylation sites in the cytoplasmic
      tail.
AB  - The thrombin receptor PAR1 becomes rapidly phosphorylated upon activation by
      either thrombin or exogenous SFLLRN agonist peptide. Substitution of alanine for
      all serine and threonine residues in the receptor's cytoplasmic carboxyl-terminal
      tail ablated phosphorylation and yielded a receptor defective in both shutoff and
      agonist-triggered internalization. These observations suggested that activation
      dependent phosphorylation of PAR1's cytoplasmic tail is required for both shutoff
      and agonist-triggered internalization. To identify the phosphorylation site(s)
      that are necessary for these functions, we generated three mutant receptors in
      which alanine was substituted for serine and threonine residues in the amino
      terminal, middle, and carboxyl-terminal thirds of PAR1's cytoplasmic tail. When
      stably expressed in fibroblasts, all three mutated receptors were rapidly
      phosphorylated in response to agonist, while a mutant in which all serines and
      threonines in the cytoplasmic tail were converted to alanines was not. This
      result suggests that phosphorylation can occur at multiple sites in PAR1's
      cytoplasmic tail. Alanine substitutions in the N-terminal and C-terminal portions
      of the tail had no effect on either receptor shutoff or agonist-triggered
      internalization. By contrast, alanine substitutions in the "middle" serine
      cluster between Ser(391) and Ser(406) yielded a receptor with considerably slower
      shutoff of signaling after thrombin activation than the wild type. Surprisingly,
      this same mutant was indistinguishable from the wild type in agonist-triggered
      internalization and degradation. Overexpression of G protein-coupled receptor
      kinase 2 (GRK2) and GRK3 "suppressed" the shutoff defect of the S --> A (391-406)
      mutant, consistent with this defect being due to altered receptor
      phosphorylation. These results suggest that specific phosphorylation sites are
      required for rapid receptor shutoff, but phosphorylation at multiple alternative
      sites is sufficient for agonist-triggered internalization. The observation that
      internalization and acute shutoff were dissociated by mutation of PAR1 suggests
      that there are quantitative or qualitative differences in the requirements or
      mechanisms for these two processes.

PMID- 10413506
TI  - Signaling domain of the aspartate receptor is a helical hairpin with a localized
      kinase docking surface: cysteine and disulfide scanning studies.
AB  - Cysteine and disulfide scanning has been employed to probe the signaling domain,
      a highly conserved motif found in the cytoplasmic region of the aspartate
      receptor of bacterial chemotaxis and related members of the taxis receptor
      family. Previous work has characterized the N-terminal section of the signaling
      domain [Bass, R. B., and Falke, J. J. (1998) J. Biol. Chem. 273, 25006-25014],
      while the present study focuses on the C-terminal section and the interactions
      between these two regions. Engineered cysteine residues are incorporated at
      positions Gly388 through Ile419 in the signaling domain, thereby generating a
      library of receptors each containing a single cysteine per receptor subunit. The
      solvent exposure of each cysteine is ascertained by chemical reactivity
      measurements, revealing a periodic pattern of buried hydrophobic and exposed
      polar residues characteristic of an amphipathic alpha-helix, denoted helix
      alpha8. The helix begins between positions R392 and Val401, then continues
      through the last residue scanned, Ile419. Activity assays carried out both in
      vivo and in vitro indicate that both the buried and exposed faces of this
      amphipathic helix are critical for proper receptor function and the buried
      surface is especially important for kinase downregulation. Patterns of disulfide
      bond formation suggest that helix alpha8, together with the immediately N
      terminal helix alpha7, forms a helical hairpin that associates with a symmetric
      hairpin from the other subunit of the homodimer, generating an antiparallel four
      helix bundle containing helices alpha7, alpha7', alpha8, and alpha8'. Finally,
      the protein-interactions-by-cysteine-modification (PICM) method suggests that the
      loop between helices alpha7 and alpha8 interacts with the kinase CheA and/or the
      coupling protein CheW, expanding the receptor surface implicated in kinase
      docking.

PMID- 10413507
TI  - Modulation of folding and assembly of the membrane protein bacteriorhodopsin by
      intermolecular forces within the lipid bilayer.
AB  - Three different lipid systems have been developed to investigate the effect of
      physicochemical forces within the lipid bilayer on the folding of the integral
      membrane protein bacteriorhodopsin. Each system consists of lipid vesicles
      containing two lipid species, one with phosphatidylcholine and the other with
      phosphatidylethanolamine headgroups, but the same hydrocarbon chains: either L
      alpha-1, 2-dioleoyl, L-alpha-1,2-dipalmitoleoyl, or L-alpha-1,2-dimyristoyl.
      Increasing the mole fraction of the phosphatidylethanolamine lipid increases the
      desire of each monolayer leaflet in the bilayer to curve toward water. This
      increases the torque tension of such monolayers, when they are constrained to
      remain flat in the vesicle bilayer. Consequently, the lateral pressure in the
      hydrocarbon chain region increases, and we have used excimer fluorescence from
      pyrene-labeled phosphatidylcholine lipids to probe these pressure changes. We
      show that bacteriorhodopsin regenerates to about 95% yield in vesicles of 100%
      phosphatidylcholine. The regeneration yield decreases as the mole fraction of the
      corresponding phosphatidylethanolamine component is increased. The decrease in
      yield correlates with the increase in lateral pressure which the lipid chains
      exert on the refolding protein. We suggest that the increase in lipid chain
      pressure either hinders insertion of the denatured state of bacterioopsin into
      the bilayer or slows a folding step within the bilayer, to the extent that an
      intermediate involved in bacteriorhodopsin regeneration is effectively trapped.

PMID- 10413508
TI  - Membrane fusion induced by a short fusogenic peptide is assessed by its insertion
      and orientation into target bilayers.
AB  - To clarify the molecular mechanism by which an amphipathic negatively charged
      peptide consisting of 11 residues (WAE) induces fusion, and the relevance of
      these features for fusion, its mode of insertion and orientation into target
      bilayers were investigated. Using attenuated total reflection Fourier transform
      infrared spectroscopy (ATR-FTIR) in combination with techniques based on
      tryptophan fluorescence, the peptide was found to form an alpha-helix, shallowly
      inserted into the membrane to which it is anchored. Interestingly, in the
      presence of target membranes, WAE inserts into the target bilayer as an alpha
      helix oriented almost parallel to the lipid acyl chains. The accessibility of the
      peptide to either acrylamide (as an aqueous quencher of Trp fluorescence) or
      deuterium oxide (on the course of an FTIR deuteration kinetics) was lower in the
      presence than in the absence of target membranes, confirming that under those
      conditions, the peptide was shielded from the aqueous environment. Since fusion
      experiments have shown a temperature dependence, the effect of this later
      parameter on the structure and mode of insertion of the peptide was also
      analyzed. In the presence of target membrane, but not in their absence, the
      amount of alpha-helical structure increased with temperature, reflecting a
      similar temperature-dependent increase in the rate and extent of WAE-induced
      fusion. Also, the extent of penetration of the helix into the target membrane was
      greater at 37 degrees C than at lower temperatures. This temperature-dependent
      distinction was revealed by a decreased accessibility of the peptide to deuterium
      oxide and acrylamide at 37 degrees C as compared to that at lower temperatures.
      These data underscore the role of peptide structure, peptide penetration, and
      orientation in the mechanism of protein-induced membrane fusion.

PMID- 10413509
TI  - Epidermal growth factor receptor internalization rate is regulated by negative
      charges near the SH2 binding site Tyr992.
AB  - This study examines the effects of mutations at and in the vicinity of tyrosine
      992 of the epidermal growth factor receptor (EGFr) on epidermal growth factor-
      (EGF-) stimulated internalization of the receptor. Two regions of the EGFr
      adjacent to this domain have been defined previously as internalization domains.
      The present work shows that the mutation of negatively charged amino acid
      residues near Tyr992 to their uncharged analogues increases the rate of EGF
      receptor internalization. In addition, the conversion of Tyr992, which is an EGFr
      ligand-induced autophosphorylation site, to phenylalanine also increases the rate
      of receptor internalization. However, the mutation of Tyr992 to a glutamate
      residue does not alter the receptor internalization rate. In addition, the
      truncation of the EGFr at glutamate 996 reduces the internalization rate by half.
      This result confirms previous reports that residues immediately C-terminal to
      Glu996 are necessary to allow the normal rate of ligand-induced receptor
      endocytosis. The data suggest that negative charge in the vicinity of Tyr992, and
      potentially the phosphorylation of the EGFr at Tyr992, reduces the rate of ligand
      induced receptor endocytosis. This reduction in internalization rate increases
      the lifetime of the activated EGFr in the plasma membrane by about 70%, thus
      suggesting that phosphorylation of Tyr992 acts to increase the signaling capacity
      of the EGF receptor even as it directly acts as an SH2 binding site.

PMID- 10413510
TI  - Copurification of the FpvA ferric pyoverdin receptor of Pseudomonas aeruginosa
      with its iron-free ligand: implications for siderophore-mediated iron transport.
AB  - The Pseudomonas aeruginosa FpvA receptor is a TonB-dependent outer membrane
      transport protein that catalyzes uptake of ferric pyoverdin across the outer
      membrane. Surprisingly, FpvA expressed in P. aeruginosa grown in an iron
      deficient medium copurifies with a ligand X that we have characterized by UV,
      fluorescence, and mass spectrometry as being iron-free pyoverdin (apo-PaA). PaA
      was absent from FpvA purified from a PaA-deficient P. aeruginosa strain. The
      properties of ligand binding in vitro revealed very similar affinities of apo-PaA
      and ferric-PaA to FpvA. Fluorescence resonance energy transfer was used to study
      in vitro the formation of the FpvA-PaA-Fe complex in the presence of PaA-Fe or
      citrate-Fe. The circular dichroism spectrum of FpvA indicated a 57% beta
      structure content typical of porins and in agreement with the 3D structures of
      the siderophore receptors FhuA and FepA. In the absence of the protease's
      inhibitors, a truncated form of FpvA lacking 87 amino acids at its N-terminus was
      purified. This truncated form still bound PaA, and its beta-sheet content was
      conserved. This N-terminal region displays significant homology to the N-terminal
      periplasmic extensions of FecA from Escherichia coli and PupB from Pseudomonas
      putida, which were previously shown to be involved in signal transduction. This
      suggests a similar function for FpvA. The mechanism of iron transport in P.
      aeruginosa via the pyoverdin pathway is discussed in the light of all these new
      findings.

PMID- 10413511
TI  - An aspartate residue at the extracellular boundary of TMII and an arginine
      residue in TMVII of the gastrin-releasing peptide receptor interact to facilitate
      heterotrimeric G protein coupling.
AB  - The mammalian bombesin receptor subfamily of G protein-coupled receptors
      currently consists of the gastrin-releasing peptide receptor (GRP-R), neuromedin
      B receptor, and bombesin receptor subtype 3. All three receptors contain a
      conserved aspartate residue (D98) at the extracellular boundary of transmembrane
      domain II and a conserved arginine residue (R309) near the extracellular boundary
      of transmembrane domain VII. To evaluate the functional role of these residues,
      site-directed GRP-R mutants were expressed in fibroblasts and assayed for their
      ability to both bind agonist and catalyze exchange of guanine nucleotides.
      Alanine substitution at GRP-R position 98 or 309 reduced agonist binding affinity
      by 24- and 56-fold, respectively, compared to wild-type GRP-R. Single swap GRP-R
      mutations either resulted in no receptor expression in the membrane (D98R) or the
      protein was not able to bind agonist (R309D). In contrast, the double swap
      mutation (D98R/R309D) had high-affinity agonist binding, reduced from wild-type
      GRP-R by only 6-fold. In situ reconstitution of urea-extracted membranes
      expressing either wild-type or mutant (D98A or R309A) GRP-R with G(q) indicated
      that alanine substitution greatly reduced G protein catalytic exchange compared
      to wild-type GRP-R. The D98R/R309D GRP-R had both a higher intrinsic basal
      activity and a higher overall catalytic exchange activity compared to wild-type;
      however, the wild-type GRP-R produced a larger agonist-stimulated response
      relative to the double swap mutant. Taken together, these data show that GRP-R
      residues D98 and R309 are critical for efficient coupling of GRP-R to G(q).
      Furthermore, our findings are consistent with a salt bridge interaction between
      these two polar and oppositely charged amino acids that maintains the proper
      receptor conformation necessary to interact with G proteins.

PMID- 10413512
TI  - Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A
      beta peptide of Alzheimer's disease.
AB  - Metal ions such as Zn(2+) and Cu(2+) have been implicated in both the aggregation
      and neurotoxicity of the beta-amyloid (Abeta) peptide that is present in the
      brains of Alzheimer's sufferers. Zinc ions in particular have been shown to
      induce rapid aggregation of Abeta. Rat Abeta binds zinc ions much less avidly
      than human Abeta, and rats do not form cerebral Abeta amyloid. Rat Abeta differs
      from human Abeta by the substitution of Gly for Arg, Phe for Tyr, and Arg for His
      at positions 5, 10, and 13, respectively. Through the use of synthetic peptides
      corresponding to the first 28 residues of human Abeta, rat Abeta, and single
      residue variations, we use circular dichroism spectroscopy, sedimentation assays,
      and immobilized metal ion affinity chromatography to show that the substitution
      of Arg for His-13 is responsible for the different Zn(2+)-induced aggregation
      behavior of rat and human Abeta. The coordination of Zn(2+) to histidine-13 is
      critical to the zinc ion induced aggregation of Abeta.

PMID- 10413513
TI  - Direct observation of the self-association of dilute proteins in the presence of
      inert macromolecules at high concentration via tracer sedimentation equilibrium:
      theory, experiment, and biological significance.
AB  - The technique of tracer sedimentation equilibrium [Rivas, G., et al. (1994)
      Biochemistry, 2341-2348 (1); Rivas, G., et al. (1996) J. Mol. Recognit. 9, 31-38
      (2)] is utilized, together with an extension of the theory of sedimentation
      equilibrium of highly nonideal solutions [Chatelier and Minton, (1987)
      Biopolymers 26, 1097-1113 (3)], to characterize the thermodynamic activity and/or
      the state of association of a dilute, labeled macromolecular solute in the
      presence of an arbitary concentration of a second, unlabeled macromolecular
      solute. Experiments are performed on solutions of labeled fibrinogen (0.25-1 g/L)
      in bovine serum albumin (0-100 g/L) in the presence and absence of divalent
      cations (Ca(2+), Mg(2+)), and on solutions of labeled tubulin (0.2-0.6 g/L) in
      dextran (0-100 g/L). It is found that in the absence of the divalent cations, the
      large dependence of the thermodynamic activity of fibrinogen on BSA concentration
      is well accounted for by a simple model for steric repulsion. In the presence of
      the cations and sufficiently large concentrations of BSA (>30 g/L), fibrinogen
      appears to self-associate to a weight-average molar mass approximately twice that
      of monomeric fibrinogen. Tubulin appears to self-associate to an extent that
      increases monotonically with increasing dextran concentration, reaching a weight
      average molar mass almost 3 times that of the alphabeta dimer in the presence of
      100 g/L dextran. Possible biological ramifications are discussed.

PMID- 10413514
TI  - Characterization of the lysyl adducts formed from prostaglandin H2 via the
      levuglandin pathway.
AB  - Prostaglandin H(2) has been demonstrated to rearrange to gamma-ketoaldehyde
      prostanoids termed levuglandins E(2) and D(2). As gamma-dicarbonyl molecules, the
      levuglandins react readily with amines. We sought to characterize the adducts
      formed by synthetic levuglandin E(2) and prostaglandin H(2)-derived levuglandins
      with lysine. Using liquid chromatography/electrospray mass spectrometry, we found
      that the reaction predominantly produces lysyl-levuglandin Schiff base adducts
      that readily dehydrate to form lysyl-anhydrolevuglandin Schiff base adducts.
      These adducts were characterized by examination of their mass spectra, by
      analysis of the products of their reaction with sodium cyanide, sodium
      borohydride, and methoxylamine and by the mass spectra derived from collision
      induced dissociation in tandem mass spectrometry. The Schiff base adducts also
      are formed on peptide-bound lysyl residues. In addition, synthetic levuglandin
      E(2) and prostaglandin H(2)-derived levuglandins produced pyrrole-derived lactam
      and hydroxylactam adducts upon reaction with lysine as determined by tandem mass
      spectrometry. A marked time dependence in the formation of these adducts was
      observed: Schiff base adducts formed very rapidly and robustly, whereas the
      lactam and hydroxylactam adducts formed more slowly but accumulated throughout
      the time of the experiment. These findings provide a basis for investigating
      protein modification induced by oxygenation of arachidonic acid by the
      cyclooxygenases.

PMID- 10413515
TI  - A cyanobacterial gene family coding for single-helix proteins resembling part of
      the light-harvesting proteins from higher plants.
AB  - In the cyanobacterium Synechocystis sp. PCC 6803 five genes were identified with
      significant sequence similarity to regions of members of the eukaryotic
      chlorophyll a/b binding gene family (Cab family) and to hliA, a gene coding for a
      small high-light-induced protein in Synechococcus sp. PCC 7942. Four of these
      five genes are 174-213 bp in length and code for small proteins predicted to have
      a single transmembrane helix. The fifth Cab-like gene in Synechocystis sp. PCC
      6803 is much longer and codes for a protein of which the N-terminal 80% resemble
      ferrochelatase but the C-terminal domain has similarity to Cab regions. The small
      genes were expressed preferentially in the absence of photosystem I, but gene
      expression was not significantly enhanced at moderately high light intensity.
      Therefore they were not designated as hli (high-light-induced) as was done for
      the Synechococcus sp. PCC 7942 homolog. Instead, the genes have been named scp,
      as the corresponding polypeptides of Synechocystis sp. PCC 6803 are small Cab
      like proteins (SCP). The scpA gene, which codes for ferrochelatase with a C
      terminal Cab-like extension, was interrupted by the insertion of a kanamycin
      resistance cassette between the ferrochelatase and Cab-like gene domains. In the
      PS I-less background, interruption of scpA was found to lead to increased
      tolerance to high light intensity and to the requirement of a slightly higher
      light intensity to drive photosystem II electron transfer, suggestive of
      decreased light-harvesting efficiency in the absence of the C-terminal extension
      of ScpA. Immunodetection of ScpC and ScpD indicated that either or both
      accumulated in PS I-less strains. These proteins were also detected in bands of
      more than 45 kDa on denaturing gels, raising the possibility that they may occur
      as stable oligomers. The SCPs represent a new group of cyanobacterial proteins
      that, in view of their primary structure and response to deletion of photosystem
      I, are likely to be involved in transient pigment binding.

PMID- 10413516
TI  - Conformational changes of gp120 in epitopes near the CCR5 binding site are
      induced by CD4 and a CD4 miniprotein mimetic.
AB  - Binding of the T-cell antigen CD4 to human immunodeficiency virus type 1 (HIV-1)
      envelope glycoprotein gp120 has been reported to induce conformational
      rearrangements in the envelope complex that facilitate recognition of the CCR5
      coreceptor and consequent viral entry into cells. To better understand the
      mechanism of virus docking and cell fusion, we developed a three-component gp120
      CD4-17b optical biosensor assay to visualize the CD4-induced conformational
      change of gp120 as seen through envelope binding to a neutralizing human
      antibody, 17b, which binds to epitopes overlapping the CCR5 binding site. The 17b
      Fab fragment was immobilized on a dextran sensor surface, and kinetics of gp120
      binding were evaluated by both global and linear transformation analyses. Adding
      soluble CD4 (sCD4) increased the association rate of full-length JR-FL gp120 by
      25-fold. This change is consistent with greater exposure of the 17b binding
      epitope on gp120 when CD4 is bound and correlates with CD4-induced conformational
      changes in gp120 leading to higher affinity binding to coreceptor. A smaller
      enhancement of 17b binding by sCD4 was observed with a mutant of gp120, DeltaJR
      FL protein, which lacks V1 and V2 variable loops and N- and C-termini. Biosensor
      results for JR-FL and DeltaJR-FL argue that CD4-induced conformational changes in
      the equilibrium state of gp120 lead both to movement of V1/V2 loops and to
      conformational rearrangement in the gp120 core structure and that both of these
      lead to greater exposure of the coreceptor-binding epitope in gp120. A 17b
      binding enhancement effect on JR-FL also was observed with a 32-amino acid
      charybdotoxin miniprotein construct that contains an epitope predicted to mimic
      the Phe 43/Arg 59 region of CD4 and that competes with CD4 for gp120 binding.
      Results with this construct argue that CD4-mimicking molecules with surrogate
      structural elements for the Phe 43/Arg 59 components of CD4 are sufficient to
      elicit a similar gp120 conformational isomerization as expressed by CD4 itself.

PMID- 10413517
TI  - Domain mapping of the DNA binding, endonuclease, and ERCC1 binding properties of
      the human DNA repair protein XPF.
AB  - During nucleotide excision repair, one of the two incisions necessary for removal
      of a broad spectrum of DNA adducts is made by the human XPF/ERCC1 protein
      complex. To characterize the biochemical function of XPF, we have expressed and
      purified the independent 104 kDa recombinant XPF protein from E. coli and
      determined that it is an endonuclease and can bind DNA in the absence of the
      ERCC1 subunit. Endonuclease activity was also identified in a stable 70 kDa
      proteolysis fragment of XPF obtained during protein expression, indicating an N
      terminal catalytic domain. Sequence homology and secondary structure predictions
      indicated a second functional domain at the C-terminus of XPF. To investigate the
      significance of the two predicted domains, a series of XPF deletion fragments
      spanning the entire protein were designed and examined for DNA binding,
      endonuclease activity, and ERCC1 subunit binding. Our results indicate that the N
      terminal 378 amino acids of XPF are capable of binding and hydrolyzing DNA, while
      the C-terminal 214 residues are capable of binding specifically to ERCC1. We
      propose that the N-terminal domain of XPF contributes to the junction-specific
      endonuclease activity observed during DNA repair and recombination events. In
      addition, evidence presented here suggests that the C-terminal domain of XPF is
      responsible for XPF/ERCC1 complex formation. A working model for the XPF protein
      is presented illustrating the function of XPF in the nucleotide excision pathway
      and depicting the two functional domains interacting with DNA and ERCC1.

PMID- 10413518
TI  - Identification of phosphorylation sites in native lamina-associated polypeptide 2
      beta.
AB  - Lamina-associated polypeptide 2 beta (LAP 2 beta), an integral protein of the
      inner nuclear membrane, appears to be involved in the spatial organization of the
      interface between nucleoplasma, lamina, and nuclear envelope. Its ability to
      interact with other proteins and the structural integrity of the nuclear envelope
      is probably regulated by phosphorylation. Here, we report nonmitotic LAP 2 beta
      phosphorylation sites that are phosphorylated in the native protein when purified
      from nuclear envelopes of mouse neuroblastoma Neuro2a cells. Five phosphorylation
      sites were detected by nano-electrospray mass spectrometric analysis of tryptic
      LAP 2 beta peptides using parent ion scans specific for phosphopeptides. By mass
      spectrometric sequencing of these peptides, we identified as phosphorylated
      residues Thr 74, Thr 159, Ser 176, and Ser 179. Two of the phosphorylation sites,
      Thr 74 (within a region known to bind chromatin) and Thr 159, are part of
      consensus sequences of proline-directed kinases. Ser 179 is part of a consensus
      site for protein kinase C which is able to highly phosphorylate LAP 2 beta in
      vitro. Three phosphorylation sites, Thr 159, Ser 176, and Ser 179, are located
      within a stretch of 20 amino acids, thereby forming a highly phosphorylated
      protein domain which may integrate signaling by multiple protein kinases.
      Additionally, we identified for the first time at the protein level the LAP 2
      splice variant LAP 2 epsilon in nuclear envelopes.

PMID- 10413519
TI  - Substrate specificity of Deinococcus radiodurans Fpg protein.
AB  - A DNA repair enzyme has recently been isolated from the ionizing radiation
      resistant bacterium Deinococcus radiodurans [Bauche, C., and Laval, J. (1999) J.
      Bacteriol. 181, 262-269]. This enzyme is a homologue of the Fpg protein of
      Escherichia coli. We investigated the substrate specificity of this enzyme for
      products of oxidative DNA base damage using gas chromatography/isotope-dilution
      mass spectrometry and DNA substrates, which were either gamma-irradiated or
      treated with H(2)O(2)/Fe(III)-EDTA/ascorbic acid. Excision of purine lesions 2,6
      diamino-4-hydroxy-5-formamidopyrimidine (FapyGua), 4,6-diamino-5
      formamidopyrimidine (FapyAde), and 8-hydroxyguanine (8-OH-Gua) was observed among
      17 lesions detected in damaged DNA substrates. The extent of excision was
      determined as a function of enzyme concentration, time, and substrate
      concentration. FapyGua and FapyAde were excised with similar specificities from
      three DNA substrates, whereas 8-OH-Gua was the least preferred lesion. The
      results show that D. radiodurans Fpg protein and its homologue E. coli Fpg
      protein excise the same modified DNA bases, but the excision rates of these
      enzymes are significantly different. Formamidopyrimidines are preferred
      substrates of D. radiodurans Fpg protein over 8-OH-Gua, whereas E. coli Fpg
      protein excises these three lesions with similar efficiencies from various DNA
      substrates. Substrate specificities of these enzymes were also compared with that
      of Saccharomyces cerevisiae Ogg1 protein, which excises FapyGua and 8-OH-Gua, but
      not FapyAde.

PMID- 10413520
TI  - Mechanistic studies examining the efficiency and fidelity of DNA synthesis by the
      3TC-resistant mutant (184V) of HIV-1 reverse transcriptase.
AB  - A single amino acid substitution from methionine-184 to valine (M184V) of HIV-1
      reverse transcriptase (RT) evokes the 1000-fold 3TC (Lamivudine) resistance by
      the HIV-1 virus observed in the clinic. The M184V mutant HIV-1 RT was studied to
      assess its catalytic efficiency during single nucleotide incorporation using a
      transient kinetic approach. The maximum rate of polymerization (k(pol)), binding
      affinity (K(d)), and incorporation efficiency (k(pol)/K(d)) were determined for
      incorporating dCTP and 3TC-TP by wild-type and 3TC-resistant HIV-1 RT. The 3TC
      resistant HIV-1 RT showed a similar efficiency of incorporation compared with the
      wild-type enzyme during DNA-dependent DNA polymerization; however, the
      incorporation efficiency is reduced 3.5-fold during RNA-dependent polymerization.
      A dramatic 146- and 117-fold decrease in incorporation efficiency was observed
      for 3TC-MP incorporation by M184V RT for DNA- and RNA-dependent DNA
      polymerization, respectively, as compared with wild-type HIV-1 RT. While the
      k(pol) was slower and the K(d) was weaker for 3TC-TP incorporation by the M184V
      RT, the decrease in the efficiency of incorporation is primarily due to a
      substantially reduced binding affinity for the 3TC-TP to the enzyme.DNA (or RNA)
      complex poised for DNA elongation. The fidelity of M184V RT was also examined to
      evaluate mispair formation since this mutant has been suggested to exhibit a
      higher level of fidelity. The results of our studies indicate that there is a
      maximum 2.4-fold increase in fidelity for M184V RT as compared with wild-type HIV
      1 RT. Both the wild-type and 3TC-resistant mutant RT showed higher fidelity using
      an RNA template as contrasted with the corresponding DNA template. This
      mechanistic information provides insight into our understanding of the molecular
      mechanism of 3TC-drug resistance and supports suggestions that increased RT
      fidelity and decreased fitness of the M184V HIV-1 virus may be factors
      contributing to the strong antiviral effect of AZT-3TC combination therapy.

PMID- 10413521
TI  - Existence of two L photointermediates of halorhodopsin from Halobacterium
      salinarium, differing in their protein and water FTIR bands.
AB  - FTIR difference spectra were recorded for the photoreactions of halorhodopsin
      from Halobacterium salinarium at 170 and 250 K. Obvious differences at the two
      temperatures were noted in neither the visible spectra nor the FTIR bands of the
      chromophore. However, perturbation of Asp141 is observed in the L intermediate at
      250 K but not at 170 K. We named these photoproducts La (at 170 K) and Lb (at 250
      K). The spectrum of Lb is distinct from that of La also in the different shifts
      of water O-H stretching bands, and larger changes in the bands from the protein
      backbone with different sensitivities to varying the halide. These results
      suggest that the photocycle of halorhodopsin contains two L states, La and Lb, in
      which the structure of protein and internal water molecules is different but
      chloride stays at the same site close to the Schiff base.

PMID- 10413522
TI  - Complex formation in vesicle-reconstituted mitochondrial cytochrome P450 systems
      (CYP11A1 and CYP11B1) as evidenced by rotational diffusion experiments using EPR
      and ST-EPR.
AB  - Rotational diffusion measurements using EPR and saturation transfer EPR were
      applied to analyze complex formation between the electron-transfer components of
      the mitochondrial steroid-hydroxylating cytochrome P450 systems (CYP11A1 and
      CYP11B1) in phosphatidylcholine/phosphatidylethanolamine/cardiolipin vesicles
      prepared by octyl glucoside dialysis/adsorption. Octyl glucoside reconstitution
      of P450SCC results in large vesicles, which have an advantage over small vesicles
      in that vesicle tumbling does not contribute to measured rotational diffusion
      rates. Immobilization of spin-labeled adrenodoxin by both P450SCC and adrenodoxin
      reductase indicates equimolar complexation between P450SCC and adrenodoxin as
      well as between adrenodoxin reductase and adrenodoxin. Combination of rotational
      diffusion and antibody cross-linking confirmed the complexation of adrenodoxin
      with P450SCC and for the first time provided direct evidence of a complex between
      P450SCC and P45011beta in the membrane. In contrast, no evidence was found for
      the existence of adrenodoxin reductase-P450SCC complexes or a ternary complex of
      all three proteins. Thus, these experiments confirm the shuttle mechanism of
      electron transfer to vesicle-reconstituted P450SCC and P45011beta.

PMID- 10413523
TI  - Dynamic mobility of genetically expressed fusion protein between cytochrome
      P4501A1 and NADPH-cytochrome P450 reductase in yeast microsomes.
AB  - A fusion protein of rat liver CYP1A1 with NADPH-cytochrome P450 reductase was
      expressed genetically in yeast microsomal membranes. This flavo-cytochrome is
      active in 6-hydroxylation of zoxazolamine. Rotational diffusion of the fusion
      protein was examined by observing the flash-induced absorption anisotropy r(t) of
      the P450.CO complex. Theoretical analysis of r(t) was performed based on a
      "rotation-about-membrane normal" model. The absorption anisotropy decayed within
      2 ms to a time-independent value r(3). Forty percent of the fusion protein
      rotated with a rotational relaxation time phi of 1.35 ms. Treatment with high
      salt increased the mobile population of the fusion protein to 62% with phi = 0.96
      ms. The mobile population of the fusion protein is close to that of CYP1A1
      coexpressed with the P450 reductase and greater than that of CYP1A1 alone [Iwase
      et al. (1991) Biochemistry 30, 8347-8351]. The large mobile population of the
      fusion protein provides evidence that CYP1A1 is mobilized by forming associations
      with P450 reductase in microsomal membranes.

PMID- 10413524
TI  - Stoichiometry of the interaction between the major histocompatibility complex
      related Fc receptor and its Fc ligand.
AB  - The neonatal Fc receptor (FcRn) transports immunoglobulin G (IgG) across
      epithelia, providing passive immunity and protecting serum IgG from degradation.
      For both functions, FcRn binds to IgG at the acidic pH of intracellular vesicles
      (pH </= 6.5) and releases IgG at the basic pH of the bloodstream (pH
      approximately 7.4). Crystallographic studies show that rat FcRn can interact with
      the Fc portion of IgG in a repeating array in which FcRn dimers are bridged by Fc
      fragments to create an "oligomeric ribbon" with a 2n:n stoichiometry. The
      stoichiometry of the interaction between soluble FcRn and Fc has been reported as
      either 2:1 for rat FcRn [Huber et al. (1993) J. Mol. Biol. 230, 1077-1083] or 1:1
      for mouse FcRn [Popov et al. (1996) Mol. Immunol. 33, 521-530]. To ascertain the
      reasons for this difference, we analyzed complexes formed in solution between
      soluble rat or mouse FcRn and Fc. Using a gel-filtration assay under
      nonequilibrium conditions, we find that both forms of FcRn produce 2:1 receptor
      ligand complexes, but that alterations of the carbohydrate moieties on mouse FcRn
      can result in an apparent stoichiometry of 1:1. However, under equilibrium
      conditions, all forms of FcRn make complexes with a 2:1 stoichiometry. We
      conclude that rat and mouse FcRn share the same general ligand binding properties
      but that small differences in affinities can produce apparent differences under
      nonequilibrium conditions.

PMID- 10413525
TI  - Intrinsic fluorescence study of the interaction of human apolipoprotein H with
      phospholipid vesicles.
AB  - Apolipoprotein H (ApoH) is a plasma glycoprotein with its in vivo physiological
      and pathogenic roles being closely related to its interaction with negatively
      charged membranes. In this paper, the interaction of ApoH with phospholipid
      vesicles was characterized by (i) detecting the wavelength shift of the
      fluorescence spectrum of ApoH and (ii) measuring the fluorescence quenching
      extent of ApoH by the membrane resident quencher 1-palmitoyl-2-stearoyl-(5-doxyl)
      sn-glycero-3-phosphocholine (DPC). The observed blue shift upon addition of DMPG
      vesicles indicated that the tryptophan residues of ApoH moved from a polar to a
      nonpolar environment. The insertion ability of ApoH into PG-containing vesicles
      did not depend on the PG content in a stoichiometric way as did the blue shift,
      indicating that the negatively charged DMPG does not serve as a specific binding
      site but rather provides a suitable microenvironment for ApoH interaction. The
      finding that the detachment effect of cations on the blue shift is remarkably
      different from that on the quenching extent suggests that ApoH is capable of
      existing in two different conformations when membrane-bound.

PMID- 10413526
TI  - Synthesis and nucleosome structure of DNA containing a UV photoproduct at a
      specific site.
AB  - A strategy was developed to assemble nucleosomes specifically damaged at only one
      site and one structural orientation. The most prevalent UV photoproduct, a cis
      syn cyclobutane thymine dimer (cs CTD), was chemically synthesized and
      incorporated into a 30 base oligonucleotide harboring the glucocorticoid hormone
      response element. This oligonucleotide was assembled into a 165 base pair double
      stranded DNA molecule with nucleosome positioning elements on each side of the cs
      CTD-containing insert. Proton NMR verified that the synthetic photoproduct is the
      cis-syn stereoisomer of the CTD. Moreover, two different pyrimidine dimer
      specific endonucleases cut approximately 90% of the dsDNA molecules. This
      cleavage is completely reversed by photoreactivation with E. coli UV photolyase,
      further demonstrating the correct stereochemistry of the photoproduct.
      Nucleosomes were reconstituted by histone octamer exchange from chicken
      erythocyte core particles, and contained a unique translational and rotational
      setting of the insert on the histone surface. Hydroxyl radical footprinting
      demonstrates that the minor groove at the cs CTD is positioned away from the
      histone surface about 5 bases from the nucleosome dyad. Competitive gel-shift
      analysis indicates there is a small increase in histone binding energy required
      for the damaged fragment (DeltaDeltaG approximately 0.15 kcal/mol), which does
      not prevent complete nucleosome loading under our conditions. Finally, folding of
      the synthetic DNA into nucleosomes dramatically inhibits cleavage at the cs CTD
      by T4 endonuclease V and photoreversal by UV photolyase. Thus, specifically
      damaged nucleosomes can be experimentally designed for in vitro DNA repair
      studies.

PMID- 10413527
TI  - De novo proteins as models of radical enzymes.
AB  - Catalytically essential side-chain radicals have been recognized in a growing
      number of redox enzymes. Here we present a novel approach to study this class of
      redox cofactors. Our aim is to construct a de novo protein, a radical maquette,
      that will provide a protein framework in which to investigate how side-chain
      radicals are generated, controlled, and directed toward catalysis. A tryptophan
      and a tyrosine radical maquette, denoted alpha(3)W(1) and alpha(3)Y(1),
      respectively, have been synthesized. alpha(3)W(1) and alpha(3)Y(1) contain 65
      residues each and have molecular masses of 7.4 kDa. The proteins differ only in
      residue 32, which is the position of their single aromatic side chain. Structural
      characterization reveals that the proteins fold in water solution into
      thermodynamically stable, alpha-helical conformations with well-defined tertiary
      structures. The proteins are resistant to pH changes and remain stable through
      the physiological pH range. The aromatic residues are shown to be located within
      the protein interior and shielded from the bulk phase, as designed. Differential
      pulse voltammetry was used to examine the reduction potentials of the aromatic
      side chains in alpha(3)W(1) and alpha(3)Y(1) and compare them to the potentials
      of tryptophan and tyrosine when dissolved in water. The tryptophan and tyrosine
      potentials were raised considerably when moved from a solution environment to a
      well-ordered protein milieu. We propose that the increase in reduction potential
      of the aromatic residues buried within the protein, relative to the solution
      potentials, is due to a lack of an effective protonic contact between the
      aromatic residues and the bulk solution.

PMID- 10413528
TI  - Role of glutamate 144 and glutamate 164 in the catalytic mechanism of enoyl-CoA
      hydratase.
AB  - The role of two glutamate residues (E164 and E144) in the active site of enoyl
      CoA hydratase has been probed by site-directed mutagenesis. The catalytic
      activity of the E164Q and E144Q mutants has been determined using 3'
      dephosphocrotonyl-CoA. Removal of the 3'-phosphate group reduces the affinity of
      the substrate for the enzyme, thereby facilitating the determination of K(m) and
      simplifying the analysis of the enzymes' pH dependence. k(cat) for the hydration
      of 3'-dephosphocrotonyl-CoA is reduced 7700-fold for the E144Q mutant and 630000
      fold for the E164Q mutant, while K(m) is unaffected. These results indicate that
      both glutamate residues play crucial roles in the hydration chemistry catalyzed
      by the enzyme. Previously, we reported that, in contrast to the wild-type enzyme,
      the E164Q mutant was unable to exchange the alpha-proton of butyryl-CoA with
      D(2)O [D'Ordine, R. L., Bahnson, B. J., Tonge, P. J. , and Anderson, V. E. (1994)
      Biochemistry 33, 14733-14742]. Here we demonstrate that E144Q is also unable to
      catalyze alpha-proton exchange even though E164, the glutamate that is positioned
      to abstract the alpha-proton, is intact in the active site. The catalytic
      function of each residue has been further investigated by exploring the ability
      of the wild-type and mutant enzymes to eliminate 2-mercaptobenzothiazole from 4
      (2-benzothiazole)-4-thiabutanoyl-CoA (BTTB-CoA). As expected, reactivity toward
      BTTB-CoA is substantially reduced (690-fold) for the E164Q enzyme compared to
      wild-type. However, E144Q is also less active than wild-type (180-fold) even
      though elimination of 2-mercaptobenzothiazole (pK(a) 6.8) should require no
      assistance from an acid catalyst. Clearly, the ability of E164 to function as an
      acid-base in the active site is affected by mutation of E144 and it is concluded
      that the two glutamates act in concert to effect catalysis.

PMID- 10413529
TI  - Glutamyl substrate-induced exposure of a free cysteine residue in the vitamin K
      dependent gamma-glutamyl carboxylase is critical for vitamin K epoxidation.
AB  - The vitamin K-dependent carboxylase catalyzes the posttranslational modification
      of glutamic acid to gamma-carboxyglutamic acid in the vitamin K-dependent
      proteins of blood and bone. The vitamin K-dependent carboxylase also catalyzes
      the epoxidation of vitamin K hydroquinone, an obligatory step in gamma
      carboxylation. Using recombinant vitamin K-dependent carboxylase, purified in the
      absence of propeptide and glutamic acid-containing substrate using a FLAG epitope
      tag, the role of free cysteine residues in these reactions was examined.
      Incubation of the vitamin K-dependent carboxylase with the sulfhydryl-reactive
      reagent N-ethylmaleimide inhibited both the carboxylase and epoxidase activities
      of the enzyme. This inhibition was proportional to the incorporation of
      radiolabeled N-ethylmaleimide. Stoichiometric analyses using [(3)H]-N
      ethylmaleimide indicated that the vitamin K-dependent carboxylase contains two or
      three free cysteine residues. Incubation with propeptide, glutamic acid
      containing substrate, and vitamin K hydroquinone, alone or in combination,
      indicated that the binding of a glutamic acid-containing substrate to the
      carboxylase makes accessible a free cysteine residue that is important for
      interaction with vitamin K hydroquinone. This is consistent with our previous
      observation that binding of a glutamic acid-containing substrate activates
      vitamin K epoxidation and supports the hypothesis that binding of the
      carboxylatable substrate to the enzyme results in a conformational change which
      renders the enzyme catalytically competent.

PMID- 10413530
TI  - Modifying the substrate specificity of staphylococcal lipases.
AB  - The lipase from Staphylococcus hyicus (SHL) displays a high phospholipase
      activity whereas the homologous S. aureus lipase (SAL) is not active or hardly
      active on phospholipid substrates. Previously, it has been shown that elements
      within the region comprising residues 254-358 are essential for the recognition
      of phospholipids by SHL. To specifically identify the important residues, nine
      small clusters of SHL were individually replaced by the corresponding SAL
      sequence within region 254-358. For cloning convenience, a synthetic gene
      fragment of SHL was assembled, thereby introducing restriction sites into the SHL
      gene and optimizing the codon usage. All nine chimeras were well-expressed as
      active enzymes. Eight chimeras showed lipase and phospholipase activities within
      a factor of 2 comparable to WT-SHL in standard activity assays. Exchange of the
      polar SHL region 293-300 by the more hydrophobic SAL region resulted in a 32-fold
      increased k(cat)/K(m) value for lipase activity and a concomitant 68-fold
      decrease in k(cat)/K(m) for phospholipase activity. Both changes are due to
      effects on catalytic turnover as well as on substrate affinity. Subsequently, six
      point mutants were generated; G293N, E295F, T297P, K298F, I299V, and L300I.
      Residue E295 appeared to play a minor role whereas K298 was the major determinant
      for phospholipase activity. The mutation K298F caused a 60-fold decrease in
      k(cat)/K(m) on the phospholipid substrate due to changes in both k(cat) and K(m).
      Substitution of F298 by a lysine in SAL resulted in a 4-fold increase in
      phospholipase activity. Two additional hydrophobic to polar substitutions further
      increased the phospholipase activity 23-fold compared to WT-SAL.

PMID- 10413531
TI  - Defining folding and unfolding reactions of apocytochrome b5 using equilibrium
      and kinetic fluorescence measurements.
AB  - The refolding and unfolding kinetics of a soluble domain of apocytochrome b5
      extending from residue 1 to 104 have been characterized using stopped flow and
      equilibrium-based fluorescence methods. The isolated apoprotein unfolds
      reversibly in the presence of GuHCl. From cooperative unfolding curves, the
      conformational stability (Delta G(uw)), in the absence of denaturant, is
      estimated to be 11.6 +/- 1.5 kJ mol-1 at 10 degrees C. The stability of
      apocytochrome b5 is lower than that of the corresponding form of the holoprotein
      (Delta G approximately 25 kJ mol-1) and exhibits a transition midpoint at 1.6 M
      GuHCl. Kinetic studies support the concept of a two-state model with both
      unfolding and refolding rates showing an exponential dependence on denaturant
      concentration with no evidence of the formation of transient intermediates in
      either limb of the chevron plot. Apocytochrome b5 is therefore an example of a
      protein in which both kinetics and equilibria associated with folding are
      described by a two-state model. The values of mku and mkf obtained from kinetic
      analysis are an indication of a transition state (mku/meq of 0.29) that resembles
      the native form by retaining similar solvent accessibility and many of the
      noncovalent interactions found in the apoprotein. The changes in heat capacity
      support a transition state that resembles the apoprotein with a value for Delta
      Cpf of -3.6 kJ mol-1 K-1 estimated for the refolding reaction. From these
      measurements, a model of refolding that involves the rapid nucleation of
      hydrophobic residues around Trp26 is suggested as a major event in the formation
      of the native apoprotein.

PMID- 10413532
TI  - HlyC, the internal protein acyltransferase that activates hemolysin toxin: roles
      of various conserved residues in enzymatic activity as probed by site-directed
      mutagenesis.
AB  - Hemolysin, a toxic protein produced by pathogenic Escherichia coli, is one of a
      family of homologous toxins and toxin-processing proteins produced by Gram
      negative bacteria. HlyC, an internal protein acyltransferase, converts it from
      nontoxic prohemolysin to toxic hemolysin. Acyl-acyl carrier protein is the
      essential acyl donor. The acyltransferase reaction progresses through formation
      of a binary complex between acyl-ACP and HlyC to a reactive acyl-HlyC
      intermediate [Trent, M. S., Worsham, L. M., and Ernst-Fonberg, M. L. (1998)
      Biochemistry 37, 4644-4655]. The homologous acyltransferases of the family have a
      number of conserved amino acid residues that may be catalytically important.
      Experiments to illuminate the reaction mechanism were done. The formation of an
      acyl-enzyme intermediate suggested that the reaction likely proceeded through two
      partial reactions. The reversibility of the first partial reaction was shown by
      using separately subcloned, purified, and expressed substrates and enzyme. The
      effects of single site-directed mutations of conserved residues of HlyC on
      different portions of reaction progress (binary complex formation, acyl-enzyme
      formation, and enzyme activity, including kinetic parameters) were determined.
      Mutations of His23, the only residue essential for activity, formed normal binary
      complexes but were unable to form acyl-HlyC. The same was seen with S20A, a
      mutant with greatly impaired activity. Mutation of two conserved tyrosines
      separately to glycines results in greatly impaired binary complex and acyl-HlyC
      formation, but mutation of those residues to phenylalanines restored behavior to
      wild-type.

PMID- 10413534
TI  - Primary Charge Separation Routes in the BChl:BPhe Heterodimer Reaction Centers of
      Rhodobacter sphaeroides.

PMID- 10413535
TI  - Mother species-father species: unidirectional hybridization in animals with
      female choice.
AB  - As mitochondria are inherited in a matrilinear way, an animal hybrid contains the
      mitochondrial DNA of its 'mother species'. Of 80 studies that analysed the
      mitochondrial DNA of at least five hybrid individuals, 50 showed that all hybrids
      contained the mitochondrial DNA of only one of the two parental species,
      indicating either mating of females of species A with males of species B but not
      vice versa (unidirectional hybridization) or the disappearance of one of the two
      parental mtDNA types after reciprocal hybridization. I review and discuss factors
      promoting unidirectional or reciprocal hybridization and present a sexual
      selection hypothesis for unidirectional hybridization. The inequality of the
      sexes in parental investment leads to the sex that invests more being the more
      discriminating one. In the presence of conspecific males, females reject
      allospecific males and, consequently, a male in an environment of both
      allospecific sexes is unlikely to mate, while in the absence of conspecific
      males, females sometimes accept fertilizations by males of other species. Thus,
      hybrid matings are usually between the females of a rare species and the males of
      a common species, but not vice versa. Copyright 1999 The Association for the
      Study of Animal Behaviour.

PMID- 10413533
TI  - A biochemical and biophysical characterization of recombinant mutants of fetal
      hemoglobin and their interaction with sickle cell hemoglobin.
AB  - Three recombinant mutants of human fetal hemoglobin (Hb F) have been constructed
      to determine what effects specific amino acid residues in the gamma chain have on
      the biophysical and biochemical properties of the native protein molecule. Target
      residues in these recombinant fetal hemoglobins were replaced with the
      corresponding amino acids in the beta chain of human normal adult hemoglobin (Hb
      A). The recombinant mutants of Hb F included rHb F (gamma 112Thr --> Cys), rHb F
      (gamma 130Trp --> Tyr), and rHb F (gamma 112Thr --> Cys/gamma 130Trp --> Tyr).
      Specifically, the importance of gamma 112Thr and gamma 130Trp to the stability of
      Hb F against alkaline denaturation and in the interaction with sickle cell
      hemoglobin (Hb S) was investigated. Contrary to expectations, these rHbs were
      found to be as stable against alkaline denaturation as Hb F, suggesting that the
      amino acid residues mentioned above are not responsible for the stability of Hb F
      against the alkaline denaturation as compared to that of Hb A. Sub-zero
      isoelectric focusing (IEF) was employed to investigate the extent of hybrid
      formation in equilibrium mixtures of Hb S with these hemoglobins and with several
      other hemoglobins in the carbon monoxy form. Equimolar mixtures of Hb A and Hb S
      and of Hb A(2) and Hb S indicate that 48-49% of the Hb exists as the hybrid
      tetramer, which is in agreement with the expected binomial distribution. Similar
      mixtures of Hb F and Hb S contain only 44% hybrid tetramer. The results for two
      of our recombinant mutants of Hb F were identical to the results for mixtures of
      Hb F and Hb S, while the other mutant, rHb F (gamma 130Trp --> Tyr), produced 42%
      hybrid tetramer. The sub-zero IEF technique discussed here is more convenient
      than room-temperature IEF techniques, which require Hb mixtures in the deoxy
      state. These recombinant mutants of Hb F were further characterized by
      equilibrium oxygen binding studies, which indicated no significant differences
      from Hb F. While these mutants of Hb F did not have tetramer-dimer dissociation
      properties significantly altered from those of Hb F, future mutants of Hb F may
      yet prove useful to the development of a gene therapy for the treatment of
      patients with sickle cell anemia.

PMID- 10413536
TI  - Mate, neighbour and stranger songs: a female song sparrow perspective.
AB  - We investigated discrimination by female song sparrows Melospiza melodia, between
      different categories of male song using the copulation solicitation display as a
      preference assay. Females responded most strongly to songs recorded from their
      mates, less strongly to songs of neighbouring males and least strongly to songs
      of stranger males. Among the stranger songs, however, females preferred songs
      that were most similar structurally to song types in their mates' repertoires
      (matching songs). These results are interpreted as evidence that females can
      recognize individual males based on the songs in their repertoires. Moreover, the
      observed female preferences for nonmatching neighbour and matching stranger song
      over nonmatching stranger song, suggest that any male with songs structurally
      similar to mate songs or even to nonmate but local neighbourhood songs, will be
      at an advantage in sexual interactions with local females. Copyright 1999 The
      Association for the Study of Animal Behaviour.

PMID- 10413537
TI  - Ecological influences on vocal development in the white-crowned sparrow.
AB  - Gambel's white-crowned sparrow, Zonotrichia leucophrys gambelii, is a long
      distance migrant that, in contrast to other subspecies of white-crowned sparrow,
      does not form vocal dialects. I studied the process of vocal development in the
      field and laboratory to determine how it differed from the process in three other
      subspecies previously studied. Four common song types existed in a random spatial
      pattern in my 2.6-km(2)study area. Of 106 males studied in 2 years, all arrived
      at the beginning of the breeding season singing their adult repertoire and no
      male changed his song during the season. In the laboratory, hand-reared males
      overproduced as much as other migratory subspecies of white-crowned sparrow. They
      learned their songs during the shortest sensitive phase of any white-crowned
      sparrow yet studied. In contrast to other subspecies that form vocal dialects,
      male gambelii chose their final adult song at random from their overproduced
      repertoire. I suggest the absence of vocal dialects in Gambel's sparrow results
      from the short, delayed breeding season on their sub-Arctic breeding grounds. The
      short breeding season has favoured a narrow sensitive phase in hatching-year
      birds, and prevents the extended vocal interactions among adults that lead to
      vocal dialects in populations breeding at temperate latitudes. Copyright 1999 The
      Association for the Study of Animal Behaviour.

PMID- 10413538
TI  - Song types as fundamental units in vocal repertoires.
AB  - We investigated whether song types function as fundamental units of song
      variation in song sparrows, Melospiza melodia. As the size of a male song
      sparrow's repertoire increases, so does the mean similarity of his song types, as
      measured by the sharing of minimal units of production (MUPs). It follows that if
      MUP similarity is important perceptually, then small repertoires (of dissimilar
      song types) may be functionally equivalent to large repertoires (of similar song
      types). We performed two experiments to test whether MUP similarity is important
      perceptually to male song sparrows. Both experiments used a habituation/recovery
      design, in which recovery in response at a switch in stimuli is used to gauge the
      subject's perception of the similarity of the stimuli. The results of both
      experiments indicate that the level of perceived similarity between pairs of
      songs does not depend on their level of MUP similarity, within the range of MUP
      similarities found between song types. Songs with high enough MUP similarity to
      be judged as variants of the same song type are, however, perceived to be much
      more similar than are any two song types. The results are compatible with a
      categorical model of song type perception. Copyright 1999 The Association for the
      Study of Animal Behaviour.

PMID- 10413539
TI  - Male bonnet macaques use information about third-party rank relationships to
      recruit allies.
AB  - Social challenges may have driven the evolution of intelligence in primates and
      other taxa. In primates, the social intelligence hypothesis is supported by
      evidence that primates know a lot about their own relationships to others and
      also know something about the nature of relationships among other individuals
      (third-party relationships). Knowledge of third-party relationships is likely to
      play an especially important role in coalitions, which occur when one individual
      intervenes in an ongoing dispute involving other group members, by helping
      individuals to predict who will support or intervene against them when they are
      fighting with particular opponents, and to assess which potential allies are
      likely to be effective in coalitions against their opponents. To date, however,
      there is no evidence that primates make use of knowledge of third-party
      relationships when they form coalitions. Here, I show that male bonnet macaques,
      Macaca radiata, use information about third-party rank relationships when they
      recruit support from other males. Males consistently chose allies that outranked
      themselves and their opponents, and made such choices considerably more often
      than would be expected by chance alone. The analysis shows that the data do not
      fit simpler explanations based upon males' knowledge of their own relationships
      to other males or males' ability to recognize powerful allies. Copyright 1999 The
      Association for the Study of Animal Behaviour.

PMID- 10413540
TI  - The role of the vomeronasal organ of crotalines (Reptilia: Serpentes: Viperidae)
      in predator detection.
AB  - Most reptiles and mammals, with the exceptions of crocodilians, aquatic mammals
      and some primates, have a functional vomeronasal organ that detects and perceives
      semi-volatile chemicals in the environment. This organ is used in detection of
      prey and is also important for recognition of conspecifics and potential
      predators. We tested eight species of North American pit vipers for behavioural
      responses to an ophiophagous (snake-eating) predator, the common kingsnake,
      Lampropeltis getula. Kingsnakes have a substance in their skin that is recognized
      by crotalines, which react with a series of defensive responses including, but
      not limited to, avoidance, fleeing, body bridging and head hiding. The
      vomeronasal duct of the pit vipers was sutured closed to determine the role of
      this organ in detection of kingsnakes. Pit vipers with intact and sutured
      vomeronasal ducts were tested in a neutral cage with a kingsnake and monitored
      for behavioural responses. Results demonstrated that the vomeronasal organ is
      important in the recognition of kingsnakes by pit vipers and raises doubts that
      any other sense plays a major role in this behaviour. Copyright 1999 The
      Association for the Study of Animal Behaviour.

PMID- 10413541
TI  - Context-dependent, risk-sensitive foraging preferences in wild rufous
      hummingbirds.
AB  - We tested the risk-sensitive foraging preferences of wild rufous hummingbirds,
      Selasphorus rufus, with three types of artificial flowers. All three flower types
      provided the same mean volume of 30 ul of sucrose, but differed in terms of
      variability of the reward: constant, low variance and high variance. In trinary
      comparisons, subjects preferred the low-variance reward over the constant reward,
      and the constant reward over the high-variance reward; a result not predicted by
      risk-sensitive foraging theory. However, when tested with traditional binary
      comparisons, hummingbirds showed conventional risk-averse behaviour and selected
      the constant reward over the low- or high-variance rewards. This reversal of
      preference represents a context-dependent foraging preference. The utility of
      selecting intermediate levels of risk and the source of the preference reversal
      are discussed relative to risk-sensitive foraging theory and the effects of local
      context on foraging choices. Copyright 1999 The Association for the Study of
      Animal Behaviour.

PMID- 10413542
TI  - Recognition of other individuals' social relationships by female baboons.
AB  - We describe a series of playback experiments designed to test whether free
      ranging baboons, Papio cynocephalus ursinus, recognize the calls of other group
      members and also associate signallers with their close genetic relatives. Pairs
      of unrelated females were played sequences of calls that mimicked a fight between
      their relatives. As controls, the same females heard sequences that involved
      either (1) only the more dominant female's relative or (2) neither of the
      females' relatives. When call sequences involved their relatives, subjects looked
      towards the speaker for a longer duration than when the sequences involved
      nonkin. When the sequences involved the other female's relative, they also looked
      towards that female. Subjects did not look towards one another when call
      sequences involved nonkin. Dominant subjects were more likely to supplant their
      subordinate partners following playbacks of sequences that mimicked a dispute
      between their relatives than following the two control trials. In contrast, both
      subjects were more likely to approach one another and to interact in a friendly
      manner following the two control trials than following the test trial. Results
      indicate that female baboons recognize the screams and threat grunts not only of
      their own close relatives but also of unrelated individuals. They also replicate
      previous studies in suggesting that female monkeys recognize the close associates
      of other individuals and adjust their interactions with others according to
      recent events involving individuals other than themselves. Copyright 1999 The
      Association for the Study of Animal Behaviour.

PMID- 10413543
TI  - Laboratory endurance capacity predicts variation in field locomotor behaviour
      among lizard species.
AB  - I measured locomotor endurance capacities of lizards on a motorized treadmill in
      the laboratory and compared average values for different species with
      quantitative measures of their movement in the field (percentage of time moving,
      N=15 species; moves/min, N=13; daily movement distance, N=11). I hypothesized
      that endurance would be positively related to all three movement indices.
      Relationships between log endurance and log movement were computed as
      conventional Pearson product-moment correlations and as the equivalent with
      phylogenetically independent contrasts. Endurance was significantly positively
      related to both the percentage of time moving and the daily movement distance.
      This is the first study to demonstrate such relationships with phylogenetically
      based statistical methods. These results suggest that endurance capacities of
      lizards are coadapted with their typical locomotor behaviour. Copyright 1999 The
      Association for the Study of Animal Behaviour.

PMID- 10413544
TI  - The use of landmarks to define territorial boundaries.
AB  - Numerous anecdotal reports suggest that members of many territorial species use
      naturally occurring landmarks to define the boundaries of their territories. In
      the work reported here, we first tested whether artificial landmarks would be
      adopted as boundaries by territorial male cicada killer wasps, Sphecius
      speciosus. To perform this test, we set out wooden dowels on a flat, grassy lawn
      on which male wasps were defending mating territories. The dowels were situated
      so that they did not coincide with any existing territorial boundary. After we
      provided the dowels, the wasps established new territorial boundaries coinciding
      with the dowels. We hypothesized that using visual landmarks as territorial
      borders might lower defensive costs, and indeed, focal samples on territorial
      wasps revealed that borders that were defined by dowels cost less to defend than
      did borders that were not defined by any landmark. This result suggests that the
      use of natural landmarks as territorial boundaries may have evolved as a result
      of the reduced defensive costs that accrue to these boundaries. Furthermore,
      defensive costs may not depend directly on territory size: territory owners may
      be able to reduce defensive costs by selecting sites with high tactical
      defensibility. Copyright 1999 The Association for the Study of Animal Behaviour.

PMID- 10413545
TI  - Permissiveness in the learning and development of song syntax in swamp sparrows.
AB  - Vocal learning in swamp sparrows, Melospiza georgiana, is subject to a host of
      sensory and motor limitations. One such limitation is that young swamp sparrows
      almost invariably crystallize their songs with a simple trilled syntax,
      irrespective of the syntax of vocal models from which they learn. A striking
      exception to this pattern was recently identified by Podos (1996, Animal
      Behaviour, 51, 1061-1070), who found that large-scale organizational changes in
      vocal syntax, including the production of an intermittent or 'broken' syntax,
      were produced when birds faced limits on vocal performance capacities during
      motor ontogeny. Our goal in the present study was to determine whether song
      models with broken syntax could serve as suitable training models for young swamp
      sparrows, and, if so, if broken syntax could be faithfully reproduced. We hand
      reared 10 male swamp sparrows and exposed them to control, rapid and broken song
      models. Control song models were copied with a high degree of accuracy, as in
      previous studies. Rapid song models were copied with deficiencies that suggested
      performance limits on vocal production; such deficiencies included the production
      of songs with broken syntax and the production of songs in which notes were
      dropped out as songs progressed. Broken songs proved suitable as training models.
      Furthermore, copies of broken song models were crystallized either with normal or
      with broken syntax. These data identify an unexpected direction of permissiveness
      in the types of songs swamp sparrows will memorize and accurately reproduce, and
      also point to a possible proximate basis for syntactical changes in the evolution
      of sparrow songs. Copyright 1999 The Association for the Study of Animal
      Behaviour.

PMID- 10413546
TI  - Auditory preference for conspecific song in isolation-reared zebra finches.
AB  - Seven female and six male zebra finches, Taeniopygia guttata, were reared in
      acoustic isolation from song and tested for their preference for conspecific song
      when 28-53 days old by allowing them to select exposure to zebra finch or
      European starling, Sturnus vulgaris, song. The birds hopped more frequently on a
      perch that generated zebra finch song than one that produced starling song, and
      they spent more time listening to zebra finch song. There were no sex
      differences. The results indicate that during their sensitive period for song
      learning, and prior to experience with song, zebra finches prefer conspecific
      song to heterospecific song. Copyright 1999 The Association for the Study of
      Animal Behaviour.

PMID- 10413547
TI  - Modelling territorial behaviour of animals in variable environments.
AB  - We present an individual-based model describing the distribution and resource
      gain of territorial individuals in situations where the rank order of territory
      quality changes over time. The model integrates both competitive (territory
      holding ability) asymmetries and a memory function. A balance of effects resulted
      in a peak in movement rates, but not resource gain, for individuals of
      intermediate ability. Furthermore, when the system was reduced to a linear array
      of territories (as commonly used in empirical studies) the model generated quite
      different predictions because of the severe limitation in movement that the
      linear array imposes. We suggest that the model can be used to generate testable
      predictions for territorial species such as salmonids, and that future empirical
      work should take into account the consequences of reductions in movement imposed
      by a linear array of territories. Copyright 1999 The Association for the Study of
      Animal Behaviour.

PMID- 10413548
TI  - Effects of body size and home range on access to mates and paternity in male
      bridled nailtail wallabies.
AB  - The bridled nailtail wallaby, Onychogalea fraenata, is a relatively small,
      solitary and sexually size dimorphic macropod. We studied the mating system of
      free-ranging wallabies over 3 years, using microsatellite analysis of paternity,
      radiotelemetry and behavioural observations. Both sexes were promiscuous, and
      general reproductive behaviour was similar to that of larger, better-known
      macropods. Home range size influenced the number of associations with oestrous
      females, and was a significant component of male reproductive success. Female
      population density varied within the site, but males with home ranges that
      overlapped more females did not sire more offspring. Aggression between males
      occurred only around oestrous females and males did not establish a predetermined
      dominance hierarchy. Male body weight strongly influenced priority of access to
      oestrous females, and was related to age. The number of times that males were
      seen closest to an oestrous female when other males were present (priority of
      access) was the most important predictor of variation in the number of offspring
      sired. Females mated with several males within and between oestrous cycles, and
      may have influenced male-male competition by prolonging advertisement of
      approaching oestrus, expanding their home ranges at oestrus and engaging in mate
      chases that attracted groups of up to six males. Despite overall similarities in
      the mating system of this species and that of other macropods, male mating
      success may be less skewed in bridled nailtail wallabies than in other species,
      although paternity analysis of free-ranging populations of other species is
      required to confirm this conclusion. Copyright 1999 The Association for the Study
      of Animal Behaviour.

PMID- 10413549
TI  - Gregarious development in alysiine parasitoids evolved through a reduction in
      larval aggression.
AB  - Population genetic models have suggested that siblicide between the larvae of
      parasitoid wasps, once gained, can be lost only under stringent conditions,
      making transitions from solitary to gregarious development rare. However,
      phylogenetic studies suggest that gregarious development has evolved on numerous
      occasions, although the mechanisms are largely unknown. We report experiments, on
      two morphologically similar species of alysiine braconids, directed at an
      understanding of how gregarious development evolved in one subfamily. We compared
      the oviposition behaviour and development of Aphaereta genevensis and A. pallipes
      in the laboratory, on the host Drosophila virilis. Aphaereta genevensis usually
      lays a single egg in each host, and only a single wasp usually develops
      successfully even when several eggs are laid. However, A. pallipes often lays
      more than one egg in each host, and several offspring often complete development.
      Dissections of superparasitized hosts showed that this difference is accompanied
      by differences in larval behaviour: first-instar A. genevensis use their sharp
      mandibles to kill other parasitoid eggs or larvae in the same host. First-instar
      A. pallipes also have sharp mandibles, but do not attack conspecific larvae,
      suggesting that siblicide might have been lost by a simple change in larval
      behaviour. Aphaereta genevensis shows some features that may have helped select
      for reduction in larval aggression in the subfamily: a longer development time,
      multiple egg clutches and incomplete brood reduction. Aphaereta spp. show great
      promise as model systems for studying the evolution of siblicide. Copyright 1999
      The Association for the Study of Animal Behaviour.

PMID- 10413550
TI  - Auditory-visual stimulus pairing enhances perceptual learning in a songbird.
AB  - In many oscine birds, song learning is affected by social variables, for example
      the behaviour of a tutor. This implies that both auditory and visual perceptual
      systems should be involved in the acquisition process. To examine whether and how
      particular visual stimuli can affect song acquisition, we tested the impact of a
      tutoring design in which the presentation of auditory stimuli (i.e. species
      specific master songs) was paired with a well-defined nonauditory stimulus (i.e.
      stroboscope light flashes: Strobe regime). The subjects were male hand-reared
      nightingales, Luscinia megarhynchos. For controls, males were exposed to tutoring
      without a light stimulus (Control regime). The males' singing recorded 9 months
      later showed that the Strobe regime had enhanced the acquisition of song
      patterns. During this treatment birds had acquired more songs than during the
      Control regime; the observed increase in repertoire size was from 20 to 30% in
      most cases. Furthermore, the copy quality of imitations acquired during the
      Strobe regime was better than that of imitations developed from the Control
      regime, and this was due to a significant increase in the number of 'perfect'
      song copies. We conclude that these effects were mediated by an intrinsic
      component (e.g. attention or arousal) which specifically responded to the Strobe
      regime. Our findings also show that mechanisms of song learning are well prepared
      to process information from cross-modal perception. Thus, more detailed enquiries
      into stimulus complexes that are usually referred to as social variables are
      promising. Copyright 1999 The Association for the Study of Animal Behaviour.

PMID- 10413551
TI  - Stimulus learning and response learning by observation in the European starling,
      in a two-object/two-action test.
AB  - Juvenile European starlings, Sturnus vulgaris, were allowed to observe a
      conspecific demonstrator using its beak to remove one of two distinctively
      coloured objects (i.e. a red or a black plug) from a hole in the lid of a plastic
      box. Both plugs could be removed by either pulling up on a loop of string
      inserted through the centre of the plug, or pushing down on the plug. When
      subsequently allowed access to the plugs, and rewarded with food for all removal
      responses, regardless of the object to which they were made and their direction,
      observer birds removed the same plug in the same direction as their demonstrator.
      These results suggest that the two-object/two-action paradigm is a valuable
      procedure for testing for the simultaneous effects of learning about a stimulus
      and a response, an object and an action, through conspecific observation.
      Copyright 1999 The Association for the Study of Animal Behaviour.

PMID- 10413552
TI  - Nest attendance during egg laying in pheasants.
AB  - As precocial bird species hatch synchronously, incubation during the egg-laying
      stage should be disadvantageous because it makes the embryos develop
      asynchronously. We established the patterns of nest attendance during egg laying
      and the start of incubation in ring-necked pheasants, Phasianus colchicus, and
      tested three hypotheses regarding the advantage of early incubation. To determine
      nest attendance, we measured egg temperatures in real pheasant nests. Females
      spent more time on the nest as laying progressed, with an average of 6.4 h at a
      clutch size of 10. At the start of incubation, nest attendance increased to over
      20 h/day. On the day before full incubation, time spent on the nest was
      positively correlated with the female's condition and negatively with the number
      of breeding attempts she had already made that season. The hypothesis that an
      early start of incubation improves egg viability was rejected, as the predicted
      relationship between the number of eggs laid after the start of incubation and
      the number laid before the start of incubation was not significant. We also
      rejected the possibility that early incubation reduces the risk of nest
      parasitism, as it was negatively related to the number of females radiotracked
      around the nest. Our data supported the hypothesis that early incubation reduces
      the risk of nest predation by shortening the period of exposure, as the number of
      eggs laid after incubation started was positively related to the number of
      breeding attempts made by the female, and thus to the perceived predation risk,
      but was negatively related to the time of season. Copyright 1999 The Association
      for the Study of Animal Behaviour.

PMID- 10413553
TI  - Reconciliation patterns among stumptailed macaques: a multivariate approach.
AB  - This study focused on two aspects of the dynamics of reconciliation in
      stumptailed macaques, Macaca arctoides. First, we investigated the combined
      effects of multiple variables (i.e. sex, age, rank, conflict intensity, outcome,
      or number of participants, interopponent distance, kinship and friendship) on the
      occurrence of reconciliation. Second, we investigated whether opponents used
      different behaviour patterns in their postconflict reunions depending on the
      characteristics of their conflicts or their relationship with their opponents. We
      studied a multimale, multifemale group of 38 stumptailed macaques housed in a
      large outdoor compound. Three types of data were collected: (1) instantaneous
      scan sampling of contact sitting to infer 'friendship'; (2) ad libitum data on
      bared-teeth and teeth-chattering displays to infer dominance rank; (3) 10-min
      focal observations during postconflict (PC) and matched control (MC) periods in
      which we recorded interopponent distance at the beginning of the observation and
      all aggressive and affiliative behaviours between former opponents. Our study
      confirmed the high conciliatory tendency of stumptailed macaques previously
      reported for other groups. A stepwise logistic regression revealed that initial
      interopponent distance in PC, friendship and kinship were the only factors that
      independently contributed to explain the occurrence of reconciliation. Two main
      clusters of postconflict behavioural patterns emerged: allogrooming+contact
      sitting and sociosexual behaviours (e.g. hold-bottom). It is hypothesized that
      postconflict allogrooming and contact sitting may be used for the maintenance of
      valuable relationships, whereas sociosexual behaviours may be used more
      indiscriminately by any pair of opponents as a buffering mechanism to prevent
      immediate recurrence of aggression. Copyright 1999 The Association for the Study
      of Animal Behaviour.

PMID- 10413554
TI  - Hard work impinges on fitness: an experimental study with zebra finches.
AB  - In experiments in which brood size is manipulated, it is impossible to
      disentangle the effects of changes in intensity and duration of parental care on
      parental fitness from those of changes in the parental energy budget. To
      determine whether a change in parental energy budget affects the costs of
      reproduction, we assessed the effects of increased levels of hopping activity,
      independent of parental care, on later reproductive decisions in zebra finches,
      Taeniopygia guttata. We imposed two levels of workload on individual, nonbreeding
      birds. After the workload periods, the birds were allowed to breed in ad libitum
      conditions. Each bird went through three alternating periods of working followed
      by breeding. The birds were more active, but weighed less and ate less, during
      the high workload than during the low workload periods. Clutch sizes and brood
      sizes did not vary with the previous work level. However, after a period on the
      high workload, reproduction, on average, was started 6 days later than after a
      low workload period. Females gained weight just before egg laying, but this might
      have been a result of egg production. If so, the delay in reproduction did not
      simply reflect extra time needed to restore body mass after a period of increased
      activity. We conclude that the level of daily activity itself, or the resulting
      energy budget during the workload periods, delayed reproduction. We suggest that
      these observations on the effects of increased activity demonstrate a causal
      mechanism for reduced residual fitness of parents. Copyright 1999 The Association
      for the Study of Animal Behaviour.

PMID- 10413555
TI  - Mate choice in divergent morphs of the gastropod mollusc Littorina saxatilis
      (Olivi): speciation in action?
AB  - We investigated mate choice in the gastropod Littorina saxatilis (Olivi) in the
      laboratory, using snails taken from two shores, 20 km apart. The snails occur in
      two distinct shell morphs in the high (H) and mid (M) shore zones, known to show
      signs of a postzygotic reproductive barrier between them. We found that mating
      was assortative not only between the forms H and M on a single shore, but also
      between snails from the two different shores. Mating preference appeared to be
      based on morph type over this distance. The snails may be detecting and
      responding to an extrinsic attribute reflecting a common microhabitat (but across
      a distance of 20 km), and/or an intrinsic attribute to do with the organisms
      themselves. These findings are further evidence of behaviour associated with the
      evolution of reproductive isolation in this gastropod species. Copyright 1999 The
      Association for the Study of Animal Behaviour.

PMID- 10413556
TI  - Signals and assessment in African elephants: evidence from playback experiments.
AB  - A series of playback experiments using two elephant vocalizations, the 'musth
      rumble' and the 'oestrous call', was carried out in Amboseli National Park to
      examine signalling and assessment in African elephants, Loxodonta africana. In
      response to the musth rumble of a high-ranking male other musth males approached
      the speaker aggressively, whereas nonmusth males walked away from the stimulus.
      The call of an oestrous female, too, attracted musth males who approached the
      speaker rapidly, while nonmusth males listened and then walked away. Females
      listened and often showed considerable interest in the musth rumbles of males,
      approaching the speaker and sometimes responding by vocalizing and or secreting
      from the temporal glands. The experiments bear out earlier observational data and
      game theory predictions which suggest that by being in or out of musth a male may
      be conveying information about the relative value he places on contesting his
      dominance rank and his access to oestrous females. When not visibly in musth, a
      male may be indicating his intention not to contest access to oestrous females.
      Copyright 1999 The Association for the Study of Animal Behaviour.

PMID- 10413557
TI  - Individual differences in parental care and behaviour profile in the convict
      cichlid: a correlation study.
AB  - We examined whether individual differences in patterns of parental care relate to
      individual differences in situations involving novelty, risk and aggression in
      the convict cichlid, Cichlasoma (Archocentrus) nigrofasciatum. Individual
      differences in situations of novelty and risk could be summarized along two axes:
      Freezing versus Activity and Activity-Inspection versus Freezing. However, these
      factors were not independent and formed a single higher-order dimension of
      general activity. Parental locomotor activity was negatively correlated with the
      Freezing versus Activity factor in females. Males that did little brood
      provisioning tended to be less active in the presence of a novel fish.
      Individuals that spent more time near their offspring at late brood stages were
      less inhibited in behavioural tests. Furthermore, extreme assortative mating by
      body size was found (r(S)=0.91). The cichlids also spawned assortatively by the
      factor Freezing versus Activity and by the general activity factor (r(S)>/=0.49),
      but not by the factor Activity- Inspection versus Freezing or by aggressiveness.
      Copyright 1999 The Association for the Study of Animal Behaviour.

PMID- 10413558
TI  - Early development of climbing skills in harvest mice.
AB  - The tiny harvest mouse, Micromys minutus, is skilled at climbing among grasses.
      Owing to the short lactation period of 15-16 days, young harvest mice need to
      achieve this climbing skill very rapidly. We examined the early development of
      five components of climbing behaviour and the final climbing pattern of harvest
      mice from birth to weaning. During the lactation period, the pups' climbing
      ability developed rapidly and they were able to climb a vertical bar by the time
      they first emerged from their nest. Climbing skills were acquired in the
      following order: hand grasping at 3-7 days; foot grasping at 6-9 days; quadruped
      stance at 6-11 days; tail prehension at 10-11 days; and righting at 10-12 days.
      The ratio of foot digit length to foot length was greater in harvest mice than in
      laboratory mice, Mus musculus, indicating a better grasping ability in the
      former. Copyright 1999 The Association for the Study of Animal Behaviour.

PMID- 10413559
TI  - T-maze behaviour in domestic chicks: a search for underlying variables.
AB  - We investigated whether contrasting T-maze behaviour shown by domestic chicks,
      Gallus gallus domesticus, of a broiler strain reflected underlying differences in
      their general activity levels, fearfulness or sociality. The time taken by 2-day
      old chicks to traverse a T maze and thereby regain visual contact with their
      companions was measured. Chicks were categorized according to whether they
      completed this task quickly (HP, high performance, <25 s) or slowly (LP, low
      performance, >75 s) and then housed in same-category groups, each of eight
      chicks. In experiment 1, we compared the numbers of HP and LP chicks showing
      certain home cage behaviours (ambulation, standing, resting, maintenance,
      pecking, preening). No significant differences were found. In experiment 2, we
      compared the behaviour of HP and LP chicks in two tests of sociality (home cage
      proximity, runway) and in two tests of fear (emergence, tonic immobility). The HP
      chicks stayed closer together in the home cage than did their LP counterparts and
      they spent significantly longer near a goal box containing conspecifics in the
      runway than did LP ones. Conversely, there were no significant differences
      between HP and LP chicks in their latency to emerge from a sheltered area into an
      exposed and, hence, potentially frightening one or in their tonic immobility fear
      reactions. These findings suggest that contrasting T-maze performance was
      unlikely to have reflected differences in underlying activity levels or in
      fearfulness. Conversely, individual variation in underlying sociality was
      probably an influential variable. Copyright 1999 The Association for the Study of
      Animal Behaviour.

PMID- 10413560
TI  - Phytohaemagglutinin injection assay and physiological stress in nestling house
      martins.

PMID- 10413561
TI  - Reflections on self-recognition in nonhuman primates.

PMID- 10413562
TI  - The contribution of subcortical structures in cognition and language.

PMID- 10413563
TI  - Acute and long-term administration of anticholinergics in Parkinson's disease:
      specific effects on the subcortico-frontal syndrome.
AB  - Parkinson's Disease (PD) is often associated with a subcortico-frontal syndrome
      (SCFS) that is mainly characterized by executive dysfunctions. The complete
      biochemistry of these dysfunctions remain misunderstood. Most studies have
      focused on the well-known nigro-striatal dopaminergic degenerations of PD, but a
      more satisfying understanding of the SCFS has come from the study of the
      cholinergic systems. We present here two new experiments carried out with long
      term and acute anticholinergic treatments in PD. In the first experiment, the
      effects of a 2-week treatment with trihexyphenidyl were compared to those
      observed under placebo on a neuropsychological battery. Results showed that
      anticholinergic-induced deficits in PD were exclusively concerned with executive
      functions. In the second experiment, the effects of an acute subclinical dose of
      scopolamine were compared between normal controls and PD patients who were devoid
      of cognitive deficit on a subset of executive tasks. Results indicates that PD
      patients but not normal controls developed a transient SCFS for the duration of
      the drug action. In contrast to other populations with cholinergic depletions
      such as Alzheimer's disease-cholinergic blockade in PD exacerbates specifically
      the SCFS. Such a discrepancy between these two neuropsychological profiles are
      discussed in terms of the specificity of the underlying cholinergic lesions.

PMID- 10413564
TI  - Apraxia differs in corticobasal degeneration and left-parietal stroke: A case
      study.
AB  - Corticobasal degeneration (CBD) is a progressive disorder characterized by both
      cortical and basal ganglia dysfunction such as asymmetrical apraxia, and akinetic
      rigidity, involuntary movements, and cortical sensory loss. Although apraxia is a
      key finding for the differential diagnosis of CBD, it has not been determined
      whether the features of apraxia seen in subjects with CBD are similar to those
      features exhibited by subjects with left-hemisphere damage from stroke.
      Therefore, for both clinical purposes and in order to better understand the brain
      mechanisms that lead to apraxia in CBD, we studied praxis in a patient with CBD
      and compared him to patients who are apraxic from left-parietal strokes. We used
      three-dimensional movement analyses to compare the features of apraxic movement.
      This subject with CBD was a dentist whose initial complaint had been that he
      "forgot" how to use his tools in the mouths of his patients. Analyses were
      performed on the trajectories made when using a knife to actually slice bread,
      and when repetitively gesturing slicing made to verbal command. Movements of the
      left hand, wrist, elbow, and shoulder were digitized in 3-D space. Although the
      CBD subject was clearly apraxic, the features of his apraxia differed markedly
      from those of the subjects with lesions in the left parietal lobe. For movements
      to command, the CBD subject showed joint coordination deficits, but his wrist
      trajectories were produced in the appropriate spatial plane, were correctly
      restricted to a single plane, and, like control subjects, were linear in path
      shape. However, when he was actually manipulating the tool and object, all of
      these aspects of his trajectories became impaired. In contrast, the deficits of
      the apraxic subjects with left-parietal damage were most pronounced to verbal
      command with their movements improving slightly although remaining impaired
      during actual tool and object manipulation. Unlike patients with parietal
      strokes, patients with CBD have degeneration in several systems and perhaps
      deficits in these other areas may account for the differences in praxic behavior.

PMID- 10413565
TI  - Apraxia in corticobasal degeneration.
AB  - Corticobasal degeneration (CBD) is a degenerative disease that often presents
      with an asymmetric progressive ideomotor limb apraxia. Some apraxic subjects may
      fail to perform skilled purposive movements on command because they have lost the
      memories or representations that specify how these movements should be performed
      (representational deficit). In contrast, other apraxic subjects may have the
      movement representations but are unable to utilize the information contained in
      them to execute skilled purposive movements (production-execution deficit). To
      learn if the apraxic deficit in CBD is induced by a representational or a
      production-execution deficit, we tested three nondemented subjects with CBD on
      tasks requiring production of meaningful or meaningless gestures to command,
      gesture imitation, gesture discrimination, and novel gesture learning. A fourth
      subject with incomplete data also is presented. The results suggest that the
      apraxia associated with CBD is initially induced by a production-execution defect
      with relative sparing of the movement representations.

PMID- 10413566
TI  - Articulatory consequences of Parkinson's disease: perspectives from two
      modalities.
AB  - Language production involves complex yet productively varying motor behavior.
      Rule-governed combinations yield a finite set of formational units combined in an
      infinite number of ways. The creativity of language ensures that no particular
      articulation will be highly automatized. Linguistic articulation is highly
      complex and varied. As such, it differs from the other more automatized motor
      behaviors typically studied such as learned movements in apraxia studies or
      repetitive behavior as occurs in walking or other everyday activities. Language
      also strives to maintain a balance between ease of articulation and ease of
      perception, while maintaining linguistically relevant distinctions. We report
      here a number of studies on the articulatory consequences of Parkinson's disease
      (PD) in the spoken and signed modalities. Our goal is to highlight the
      commonalities and distinctions between the two modalities of speech and sign that
      will allow us to better understand the impingements of PD on language production
      in general.

PMID- 10413567
TI  - Sentence processing in Parkinson's disease.
AB  - Parkinson's disease (PD) is a neurodegenerative condition that is associated with
      the depletion of dopamine (DA)-containing neurons in specific brain regions. This
      article reviews one consequence of this defect-sentence comprehension difficulty
      in nondemented patients with PD. The first section describes the pattern of
      cognitive deficits seen in patients with PD, focusing specifically on their
      difficulties with language processing. Subsequent sections relate the profile of
      cognitive impairments in PD to studies investigating compromised DA metabolism in
      fronto-striatal brain regions. The findings suggest that the sentence
      comprehension deficit in PD is due in large part to limitations in the strategic
      distribution of cognitive resources such as selective attention that contribute
      to the processing of complex material. The physiological basis for this deficit
      appears to be associated with the disruption of a fronto-striatal cerebral
      network that is compromised following degradation of the DA projection system.

PMID- 10413569
TI  - Investigation of possible participation of nucleoside transport systems in the
      postischemic release of purines and pyrimidines from cold stored liver.
AB  - The aim of the study was to elucidate the role of nucleoside transport systems in
      the postischemic release of nucleosides and nucleobases accumulated by the rat
      liver during cold storage. Livers were preserved for 24 h in Euro-Collins (EC) or
      in a lactobionate-based solution (LBS) without exogenous adenosine. The rates of
      release of uric acid, xanthine, hypoxanthine, inosine, adenosine, uridine, and
      cytidine were monitored during early reperfusion. The greater part of the purines
      and pyrimidines (up to 80%) was lost in the first 2 min of reperfusion. After
      storage in EC, uric acid and xanthine formed more than 90% of the total purines
      released; nucleosides did not exceed 5% of the total. After storage in LBS,
      hypoxanthine formed more than 80% of purine efflux and the release of inosine and
      uridine was increased 5-10 times. These changes were shown to be due to the
      presence of allopurinol in LBS. Dipyridamole (an inhibitor of equilibrative
      nucleoside transporters) decreased the efflux of uric acid after storage in EC
      but residual release remained high. Dipyridamole exerted the most pronounced
      effect on the release of nucleosides (inosine and uridine) from livers stored in
      LBS. The use of sodium-free media for liver preservation and reperfusion did not
      alter the rates of purine and pyrimidine release. We conclude that equilibrative
      nucleoside transporters mediate the postischemic release of nucleosides and also,
      but to a less degree, of uric acid. Simple diffusion is an important factor in
      the release of nucleobases. Active Na(+)/nucleoside cotransport does not play an
      important role in early reperfusion.

PMID- 10413568
TI  - Subcortical mechanisms in language: lexical-semantic mechanisms and the thalamus.
AB  - Four previously published cases of dominant thalamic lesion in which the author
      has participated are reviewed to gain a better understanding of thalamic
      participation in lexical-semantic functions. Naming deficits in two cases support
      Nadeau and Crosson's (1997) hypothesis of a selective engagement mechanism
      involving the frontal lobes, inferior thalamic peduncle, nucleus reticularis, and
      other thalamic nuclei, possibly the centromedian nucleus. This mechanism
      selectively engages those cortical areas required to perform a cognitive task,
      while maintaining other areas in a state of relative disengagement. Deficits in
      selective engagement disproportionately affect lexical retrieval based on
      semantic input, as opposed to lexical and sublexical processes, because the
      former is more dependent upon this attentional system. The concept of selective
      engagement is also useful in understanding thalamic participation in working
      memory, as supported by data from one recent functional neuroimaging study. Other
      processes also may be compromised in more posterior thalamic lesions which damage
      the pulvinar but not other components of this selective engagement system. A
      third case with aphasia after a more superior and posterior thalamic lesion also
      had oral reading errors similar to those in neglect dyslexia. The pattern of
      deficits suggested a visual processing problem in the early stages of reading.
      The fourth case had a category-specific naming deficit after posterior thalamic
      lesion. Taken together, the latter two cases indicate that the nature of language
      functions in more posterior regions of the dominant thalamus depends upon the
      cortical connectivity of the thalamic region. Together, findings from the four
      cases suggest that thalamic nuclei and systems are involved in multiple processes
      which directly or indirectly support cortical language functions.

PMID- 10413570
TI  - Restoration of resistance to osmotic swelling of vitrified mouse embryos by short
      term culture.
AB  - In cryopreservation of mammalian embryos, embryos can be injured by osmotic
      swelling during removal of the cryoprotectant after warming. We have shown that
      vitrified embryos are more sensitive to osmotic swelling than fresh cells but
      that sensitivity is reduced or abolished if vitrified cells are cultured for a
      short period before subjecting them to hypotonic stress. In the present study, we
      examined the mechanism by which vitrified two-cell mouse embryos regain their
      resistance to osmotic swelling by culturing the embryos in the presence of
      various inhibitors before hypotonic treatment. New synthesis of RNA and proteins
      during culture was not required for regaining resistance to osmotic swelling
      because actinomycin D and cycloheximide failed to inhibit restoration. Inhibitors
      of polymerization of microfilaments and microtubules (cytochalasin B and
      demecolcine, respectively) also did not affect restoration of resistance to
      osmotic swelling, suggesting that rearrangement or repolymerization of
      cytoskeletal components is not involved in this process. On the other hand,
      brefeldin A and concanamycin A, which inhibit intracellular vesicular transport,
      strongly suppressed restoration of resistance. These results suggest that the
      intracellular vesicular transport system plays a crucial role in restoration of
      resistance of vitrified embryos to osmotic swelling during short-term culture.

PMID- 10413571
TI  - Gut colonization by an ice nucleation active bacterium, Erwinia (Pantoea) ananas
      reduces the cold hardiness of mulberry pyralid larvae.
AB  - To evaluate the suitability of using ice nucleation active (INA) bacteria for the
      biological control of insect pests, the supercooling point (SCP) of larvae of
      mulberry pyralid, Glyphodes duplicalis, and silkworm, Bombyx mori, ingesting INA
      strains of Erwinia (Pantoea) ananas and Pseudomonas syringae was determined. Mean
      SCP of the guts of silkworm larvae ingesting INA strains of E. ananas ranged from
      -2.5 to -2.8 degrees C, being 5 degrees C higher than that in control treatments.
      Similarly, mean SCP of mulberry pyralid larvae ingesting INA strain of E. ananas,
      which can grow well in the gut, was -4.7 degrees C at 3 days after treatment,
      being 6.5 degrees C higher than that in control treatments. On the other hand,
      mean SCP of the larvae-ingesting INA strain of P. syringae, which cannot grow in
      the gut, was -9.0 degrees C at 3 days after treatment, rising by only 2.5 degrees
      C higher than that in the control treatments. In addition, more than 80% of the
      larvae of mulberry pyralid ingesting the INA strain of E. ananas froze and
      eventually died when exposed to -6 degrees C for 18 h, while only 36% of the
      larvae ingesting the INA strain of P. syringae, or approximately 20% of the
      control larvae, froze and died. Thus, the gut colonization by INA strains of E.
      ananas reduced remarkably the cold hardiness of the insects. These findings
      suggest that INA strains of E. ananas could be effective as a potential
      biological control agent of insect pests.

PMID- 10413572
TI  - Cryopreservation of cattle oocytes: effects of meiotic stage, cycloheximide
      treatment, and vitrification procedure.
AB  - Different parameters likely to influence the survival of bovine oocytes after a
      vitrification procedure were evaluated: oocyte meiotic stage, cycloheximide
      treatment at the beginning or the end of maturation, and three vitrification
      procedures using conventional straws, open pulled straws (OPS), or microdrops.
      For each procedure a mixture of cryoprotectants (25% ethylene glycol and 25%
      glycerol) was used. After the oocytes were warmed and subjected to in vitro
      maturation and fertilization, the number that developed into blastocysts was
      determined. Results show that cryoprotectant exposure reduced embryo development
      and that cycloheximide treatment had no beneficial effect on oocytes vitrified in
      conventional straws. Among the three vitrification procedures, only the OPS
      method yielded blastocysts (approximately 3% of vitrified oocytes) irrespective
      of their initial meiotic stage. This result highlights the major influence of the
      cooling rate in an oocyte vitrification protocol.

PMID- 10413573
TI  - Cryopreservation of bovine ovarian tissue: structural normality of follicles
      after thawing and culture in vitro.
AB  - The recovery of viable follicles from cryopreserved ovarian tissue would be of
      benefit in many areas of assisted reproduction. Structural integrity needs to be
      maintained following cryopreservation of ovarian tissue in order to retrieve
      healthy follicles which can then be cultured in vitro to produce viable oocytes.
      We have assessed the effect of in vitro culture of bovine tissue for 0, 1, 4, 24,
      or 48 h after exposure to, or cryopreservation in, dimethylsulphoxide.
      Immediately after freezing, normality of primary and preantral follicles within
      the tissue was significantly lower than for tissue exposed to the cryoprotectant
      without freezing or for control tissue. After 4 h in culture, cryopreserved
      tissue appeared to have recovered from damage caused by freezing, although the
      percentage of tissue with normal morphology declined after 24 and 48 h of
      culture. There was no significant difference between percentage normality in
      control tissue and tissue exposed to the cryoprotectant without freezing for any
      of the culture times studied. These data indicate that it is possible to
      freeze/thaw bovine ovarian tissue while retaining a reasonable yield of
      morphologically intact follicles and that a short period of post-thaw culture may
      enhance follicle recovery.

PMID- 10413574
TI  - Liver freezing response of the freeze-tolerant wood frog, Rana sylvatica, in the
      presence and absence of glucose. I. Experimental measures.
AB  - In this study, two methods are used to assess the equilibrium and dynamic cell
      volumes in Rana sylvatica liver tissue during freezing in the presence and
      absence of a cryoprotectant (glucose). The first is a "two-step" low-temperature
      microscopy (equilibrium and dynamic) freezing method and the second is a
      differential scanning calorimeter (DSC) technique. These two techniques were used
      to study (i) the in vitro architecture of R. sylvatica frog liver tissue and to
      measure its characteristic Krogh cylinder dimensions; (ii) the "equilibrium"
      (infinitely slow) cooling behavior and the osmotically inactive cell volume
      (V(b)) of R. sylvatica liver cells; and (iii) the dynamic water transport
      response of R. sylvatica liver cells in the presence and absence of the CPA
      (glucose) at a cooling rate of 5 degrees C/min. Stereological analysis of the
      slam frozen (>1000 degrees C/min) micrographs led to the determination that 74%
      of the liver tissue in control frogs was cellular versus 26% that was
      extracellular (vascular or interstitial). Mapping the stereological measurements
      onto a standard Krogh cylinder geometry (Model 1) yielded distance between
      adjacent sinusoid centers, DeltaX = 64 microm; original sinusoid (vascular)
      radius, r(vo) = 18.4 microm; and length of the Krogh cylinder, L = 0.71 microm
      (based on an isolated frog hepatocyte cell diameter of 16 microm). A significant
      observation was that approximately 24% of the frog hepatocyte cells are not in
      direct contact with the vasculature. To account for the cell-cell contact in the
      frog liver architecture a modified Krogh cylinder geometry (Model 2) was
      constructed. In this model (Model 2) a second radius, r(2) = 28.7 microm, was
      defined (in addition to the original sinusoid radius, r(vo) = 18.4 microm,
      defined above) as the radius of the membrane between the adjacent cells (directly
      adjacent to vascular spaces) and embedded cells (removed from vascular spaces).
      By plotting the two-step equilibrium cooling results on a Boyle-van't Hoff plot,
      the osmotically inactive cell volume, V(b) was obtained as 0.4. V(o) (where V(o)
      is the isotonic cell volume). The two-step dynamic micrographs and the heat
      release measurements from the DSC were used to obtain water transport data during
      freezing. The DSC technique confirmed that R. sylvatica cells in control liver
      tissue do not dehydrate completely when cooled at 5 degrees C/min but do so when
      cooled at 2 degrees C/min.

PMID- 10413575
TI  - Liver freezing response of the freeze-tolerant wood frog, Rana sylvatica, in the
      presence and absence of glucose. II. Mathematical modeling.
AB  - The "two-step" low-temperature microscopy (equilibrium and dynamic) freezing
      methods and a differential scanning calorimetry (DSC) technique were used to
      assess the equilibrium and dynamic cell volumes in Rana sylvatica liver tissue
      during freezing, in Part I of this study. In this study, the experimentally
      determined dynamic water transport data are curve fit to a model of water
      transport using a standard Krogh cylinder geometry (Model 1) to predict the
      biophysical parameters of water transport: L(pg) = 1.76 microm/min-atm and
      E(L(p)) = 75.5 kcal/mol for control liver cells and L(pg)[cpa] = 1.18 microm/min
      atm and E(L(p))[cpa] = 69.0 kcal/mol for liver cells equilibrated with 0.4 M
      glucose. The DSC technique confirmed that R. sylvatica cells in control liver
      tissue do not dehydrate completely when cooled at 5 degrees C/min but do so when
      cooled at 2 degrees C/min. Cells also retained twice as much intracellular fluid
      in the presence of 0.4 M glucose than in control tissue when cooled at 5 degrees
      C/min. The ability of R. sylvatica liver cells to retain water during fast
      cooling (>/=5 degrees C/min) appears to be primarily due to its liver tissue
      architecture and not to a dramatically lower permeability to water, in comparison
      to mammalian (rat) liver cells which do dehydrate completely when cooled at 5
      degrees C/min. A modified Krogh model (Model 2) was constructed to account for
      the cell-cell contact in frog liver architecture. Using the same biophysical
      permeability parameters obtained with Model 1, the modified Krogh model (Model 2)
      is used in this study to qualitatively explain the experimentally measured water
      retention in some cells during freezing on the basis of different volumetric
      responses by cells directly adjacent to vascular space versus cells at least one
      cell removed from the vascular space. However, at much slower cooling rates (1-2
      degrees C/h) experienced by the frog in nature, the deciding factor in water
      retention is the presence of glucose and the maintenance of a sufficiently high
      subzero temperature (>/=-8 degrees C).

PMID- 10413576
TI  - Subzero osmotic characteristics of intact and disaggregated hepatocyte spheroids.
AB  - This study has been conducted to examine basic transport characteristics of pig
      hepatocytes cultured as spheroids for use in a bioartificial liver. Static
      osmotic experiments were conducted by subjecting hepatocyte spheroids in
      solutions of increasing sucrose concentrations. A Boyle-van't Hoff plot was used
      to extrapolate an osmotically inactive volume, V(b), of 0.60, which is unusually
      high and might not represent the inactive volume of the individual cells. The
      spheroids were disaggregated and low-temperature cryomicroscopy experiments
      performed to examine the transport and intracellular ice formation (IIF)
      characteristics. A hydraulic permeability, L(pg), of 7.6 x 10(15) m(3)/Ns and an
      activation energy, E(lp), of 82 kJ/mol was determined for the individual cells.
      The kinetic (Omega(o)) and thermodynamic (kappa(o)) coefficients for IIF were
      determined to be 5.9 x 10(8) m(-2) s(-1) and 3.0 x 10(9) K(5), respectively.
      These results infer a decrease in the temperature range over which IIF is
      observed compared to freshly isolated pig hepatocytes. The technique of freeze
      substitution was used to examine the structure inside the spheroid during
      freezing. At a low cooling rate of 1 degrees C/min, increasing amounts of
      intercellular ice formed between the cells. At a higher cooling rate of 100
      degrees C/min small intracellular ice crystals formed. This study shows the
      location of ice in a freezing hepatocyte spheroid and confirms that the cells
      cultured as spheroids do not transport water in the same manner as isolated
      cells.

PMID- 10413577
TI  - Freeze-induced alterations of translatable mRNA populations in wood frog organs.
AB  - To investigate the roles that gene expression and new protein synthesis play in
      freezing survival by the wood frog, Rana sylvatica, we compared the in vitro
      translation products made from mRNA isolated from six tissues (liver, brain,
      heart, muscle, kidney, gut) of control (5 degrees C), frozen (24 h at -2.5
      degrees C), and thawed (24 h at 5 degrees C after 24 h frozen) frogs.
      [(35)S]Methionine-labeled proteins were separated by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis and located by fluorography. Results indicated
      specific changes in the translatable populations of mRNA in tissues of freezing
      exposed frogs that were largely reversed upon thawing. Differential protein
      expression was greatest in the comparison of liver from control versus frozen
      frogs with proteins ranging from 45 to 14.8 kDa identified as enhanced or unique
      to the frozen state. One unique protein appeared in skeletal muscle (116 kDa) of
      freeze-exposed frogs while another (52.5 kDa) was enhanced. Analysis of brain and
      heart each revealed the presence of one protein unique to the frozen state in
      each (58.9 and 5.9 kDa, respectively) whereas no change in the pattern of in
      vitro translation products was seen in gut (stomach + intestine combined) or
      kidney between the three experimental states. These freeze-induced alterations in
      the populations of translatable mRNA suggest that changes in the complement of
      specific proteins underlie various adaptive responses that contribute to the
      freezing survival of this amphibian.

PMID- 10413579
TI  - State and phase transition behaviors of quercus rubra seed axes and cotyledonary
      tissues: relevance to the desiccation sensitivity and cryopreservation of
      recalcitrant seeds 
AB  - Freezing and melting transitions of cellular water in embryonic axes and
      cotyledonary tissues of recalcitrant Quercus rubra (red oak) seeds were compared
      under slow and rapid cooling conditions. The relevance of desiccation sensitivity
      (critical water content) and state/phase transition behaviors to cryopreservation
      was examined. Under a slow to intermediate cooling condition (</=10 degrees C
      min(-1)), unfrozen water content in the tissues decreased to less than the
      critical water content, resulting in a dehydration damage. Under a rapid cooling
      condition (>100 degrees C min(-1)) using liquid nitrogen (LN(2)), freeze-induced
      dehydration damage could be avoided if the initial water content was >0.50 g g(
      1) dry wt. However, at water content >0.50 g g(-1) dry wt, the vitrified cellular
      matrix was highly unstable upon warming at 10 degrees C min(-1). These results
      offered a theoretical explanation on the difficulty for successful
      cryopreservation of recalcitrant red oak embryonic axes. A complete state/phase
      transition diagram for red oak axes was constructed, and a vitrification-based
      cryopreservation protocol that employed predehydration and rapid cooling was
      examined. State/phase transition behaviors of cellular water are important
      parameters for cryopreservation; however, vitrification alone was not sufficient
      for seed tissues to survive the cryopreservation condition. Copyright 1999
      Academic Press.

PMID- 10413578
TI  - Intracellular ice formation is affected by cell interactions.
AB  - Cell-to-cell and cell-to-surface interactions are important to the structure and
      function of tissues. These interactions are also important determinants of low
      temperature responses in tissues. Four in vitro models using hamster fibroblast
      cells in tissue culture were used to investigate the influence of cell-cell and
      cell-surface interactions on intracellular ice formation in these systems. The
      four models were: (a) single cells in suspension; (b) cells individually attached
      to glass with only cell-to-surface adhesion; (c) colonies of cells attached to
      glass with both cell-cell and cell-surface interactions; and (d) multicellular
      spheroids with extensive cell-cell contacts. Cryomicroscopy was used to monitor
      the prevalence and kinetics of intracellular ice formation after ice nucleation
      in the extracellular solution. The temperature for intracellular freezing in 50%
      of the cells was significantly affected by both cell-cell and cell-surface
      interactions. There was also evidence of intercellular nucleation through cell
      cell interactions. The results indicate that cell-cell and cell-surface
      interactions play a significant role in the low-temperature response of tissue
      systems.

PMID- 10413580
TI  - Cryopreservation of specific pathogen-free (SPF) pig islet cells: effect of
      culture time before cryopreservation and after thawing.
AB  - The aim of this study was to determine the optimal conditions (effect of culture
      time before and after cryopreservation) for cryopreservation of specific pathogen
      free pig islet cells. METHODS: (1) Glucose-induced insulin secretion by fresh
      islet cells cultured for 10 days was compared to that by islet cells
      cryopreserved 7 days after isolation and cultured 3 days after thawing. (2) Islet
      cells were cryopreserved 1, 7, or 14 days after isolation and cultured 3, 7, 14,
      or 21 days after thawing. Islet cell number, insulin content, and insulin
      response under perifusion tests were investigated. RESULTS: (1) Insulin response
      by cryopreserved islet cells was identical to that by fresh islet cells
      (basal/stimulation index: 2. 13 +/- 0.19 vs 2.17 +/- 0.16, n = 4, NS), although
      the amount of secreted insulin was reduced by 40% (area under the curve: 2136 +/-
      198 pM/10(4) cells/180 min vs 3564 +/- 636 pM/10(4) cells/180 min, P = 0.104).
      (2) Cell number 6 days after thawing was reduced by 54, 40, and 63% when
      cryopreservations were carried out at D1, D7, and D14. (3) Insulin content in
      cultured or cryopreserved islet cells increased between 7 and 14 days of culture.
      (4) Whatever the culture time before and after cryopreservation, insulin
      secretion in response to glucose was maintained. The insulin release was the
      highest for islet cells cryopreserved 14 days after isolation and cultured 14
      days after thawing (stimulation index: 6.19 +/- 2.68). CONCLUSIONS: SPF pig islet
      cells remained functional after cryopreservation in polyethylene glycol and it
      may be important to culture islet cells over 14 days before and after
      cryopreservation.

PMID- 10413581
TI  - Separation of racemic from meso-2,3-butanediol 
AB  - 2,3-Butanediol containing less than 3% of the meso form has been obtained from
      samples containing up to 50% of the meso form. The diacetate was obtained by
      esterification with acetic anhydride in the presence of traces of sulfuric acid
      as a catalyst and was then purified. When the diacetate was held at 4 degrees C,
      crystals of racemic 2,3-butanediol diacetate formed, and these were separated by
      filtration. The diacetate was then transformed back to 2, 3-butanediol by
      transesterification with methanol in the presence of sodium methylate as a
      catalyst. The resulting 2,3-butanediol contained less than 3% of the meso form.
      For an original batch of 2, 3-butanediol containing 50% dl and 50% meso, this
      method can isolate up to 70% of the racemate content. If the original 2,3
      butanediol contains too much meso form, racemic 2,3-butanediol diacetate does not
      crystallize, but 2,3-butanediol containing up to 60% of the meso form can be
      enriched up to 70% racemate by distillation. Copyright 1999 Academic Press.

PMID- 10413582
TI  - Equations for obtaining melting points for the ternary system ethylene
      glycol/sodium chloride/water and their application to cryopreservation.
AB  - The present study describes the H(2)O-NaCl-ethylene glycol ternary system by
      using a differential scanning calorimeter to measure melting points (T(m)) of
      four different ratios (R) of ethylene glycol to NaCl and then devising equations
      to fit the experimental measurements. Ultimately an equation is derived which
      characterizes the liquidus surface above the eutectic for any R value in the
      system. This study focuses on ethylene glycol in part because of recent evidence
      indicating it may be less toxic to pancreatic islets than Me(2)SO, which is
      currently used routinely for islet cryopreservation. The resulting physical data
      and previously determined information regarding the osmotic characteristics of
      canine pancreatic islets are combined in a mathematical model to describe the
      volumetric response to equilibrium-rate freezing in varying initial
      concentrations of ethylene glycol.

PMID- 10413583
TI  - Mechanisms of myofibroblast activity and phenotypic modulation.

PMID- 10413584
TI  - Embryonal carcinoma cell lines stably transfected with mRARbeta2-lacZ: sensitive
      system for measuring levels of active retinoids.
AB  - Embryonal carcinoma cell lines (F9 EC and P19 EC) were stably transfected with
      1.8 kb promoter sequence of RARbeta2 coupled to the lacZ gene as a system for
      measuring active retinoids. These stable transfectants, designated F9-1.8 and P19
      1.8, were used as reporter cell lines to investigate different retinoids for
      their ability to activate the reporter gene. F9-1.8 cells showed similar EC(50)
      values for the acidic retinoids all-trans retinoic acid (RA), 4-oxo RA, 9-cis RA,
      and 13-cis RA, in the range of 1-7 nM, while P19-1.8 cells were less sensitive.
      Retinal showed decreased activity compared to the RA isomers in both lines.
      However, P19-1.8 cells hardly showed beta-gal activity after treatment with
      retinol, while the lacZ reporter in F9-1.8 cells was still inducible by this
      retinoid. In addition, the reporter system was used to investigate RA metabolism
      and its inhibition by P450 inhibitors. A combination of RA and liarozole showed a
      10 times greater induction of the RARbeta2-lacZ reporter in P19-1.8 cells, but
      not in F9-1.8 cells. The EC(50) value for 4-oxo RA, however, was not altered,
      indicating that metabolic conversion of RA to 4-oxo RA is the target for
      inhibition by liarozole in P19-1.8 cells. HPLC analysis revealed nearly complete
      inhibition of RA metabolism after liarozole treatment in P19-1.8 cells, resulting
      in higher levels of RA. Finally, the F9-1.8 cells were used to detect active
      retinoids during different stages of chick limb bud development, demonstrating
      that it is the limb bud mesenchyme which generates RA and not the epidermis, with
      a twofold higher level of RA in the posterior half than in the anterior half.

PMID- 10413585
TI  - Regulation of the type II hemidesmosomal plaque assembly in intestinal epithelial
      cells.
AB  - Hemidesmosomes (HDs) are cellular junctions that anchor epithelial cells to the
      extracellular matrix (ECM) and are associated morphologically with the
      cytoskeleton. Hemidesmosomal molecular components include two proteins involved
      in linking intermediate filaments, HD1/plectin and BP230, and two transmembrane
      proteins, BP180 and the alpha6beta4 integrin, a laminin receptor. In cells
      lacking BP230 and BP180, HD1/plectin still associates with alpha6beta4 integrin,
      forming HD-like structures, called type II HDs. In the present study, we used an
      intestinal epithelial cell line that expresses HD1/plectin and the alpha6beta4
      integrin to investigate the regulation of assembly of these proteins in type II
      HDs. These compounds were found to be clustered at sites of cell-ECM contact and
      their polarized localization was influenced by either cell confluency or
      extracellular matrix deposition. Conventional and immunoelectron microscopy
      showed that HD1/plectin and the beta4 integrin subunit are colocalized in an
      adhesion structure. Using cytoskeleton-disrupting drugs and confocal microscopy,
      we demonstrated that type II HDs are made up of numerous individual plaques whose
      assembly into a cluster requires actin filaments, but not microtubules.

PMID- 10413586
TI  - The HMG protein T160 colocalizes with DNA replication foci and is down-regulated
      during cell differentiation.
AB  - The high mobility group protein T160, the murine homolog of the human structure
      specific recognition protein 1, was first supposed to be involved in the process
      of V-(D)-J recombination, since it could bind to recombination signal sequence
      probes. We have recently cloned T160 by using an unrelated DNA probe and shown
      that it binds to either cruciform or linear DNA with no sequence specificity. In
      this work, we performed a detailed analysis of T160 expression and
      immunolocalization. We show that T160 is a phosphoprotein broadly conserved from
      yeast to mammals, with a high level of expression in all the cell lines tested
      and in tissues containing a high degree of proliferating cells. Indirect
      immunofluorescence analysis by confocal laser microscopy revealed that T160
      distribution in the cell nucleus is not uniform, and focus-like staining was
      observed. Cell cycle studies by BrdU incorporation suggest that the appearance of
      T160 nuclear foci is specific of mid to late S phase. Furthermore, while T160
      expression does not change during the cell cycle, it is dramatically down
      regulated when cells begin to differentiate, as highlighted in C2C12 myoblasts
      and myotubes. The disappearance of T160 nuclear staining in multinucleated
      myotubes is shown. Taken together, these data suggest that its function may be
      less specific than V-(D)-J recombination and more related to some cellular basic
      process, such as DNA replication or repair.

PMID- 10413587
TI  - Increased tyrosine kinase activity but not calcium mobilization is required for
      ceramide-induced apoptosis.
AB  - The insulin-like growth factors (IGFs) are capable of blocking apoptosis in many
      cell lines in vitro, potentially via activation of the IGF-I receptor (IGF-IR).
      We have previously shown that lower doses of the sphingolipid analogue C2
      ceramide are required to induce apoptosis in IGF-IR-minus vs -positive murine
      fibroblasts, indicating a protective feedback loop in the latter and
      corroborating evidence that the IGF-IR functions as a survival receptor [1, 2].
      Since, unexpectedly, C2-ceramide was capable of activating MAP kinase,
      phosphorylating the IGF-I receptor, and promoting entry into the G2 phase of the
      cell cycle, we wished to further determine the mechanisms involved. Using IGF-IR
      positive fibroblasts we demonstrate here for the first time that ceramide is
      capable of activating a tyrosine kinase which acts at the level of the IGF-IR to
      increase cell death. We also demonstrate that in the presence of sodium
      orthovanadate, ceramide-induced death is increased, and the phosphorylation of a
      75-kDa protein which associates with the IGF-I receptor is enhanced. Although the
      identity of this protein is not known, we speculate that it may link into the Raf
      kinase signaling pathway; indeed, inhibitors of MEKK reduce ceramide-induced
      apoptosis, thus substantiating this theory [1, 2]. Although calcium mobilization
      did cause apoptosis in these cells, it was not required as a mediator of ceramide
      induced apoptosis. Finally, the potential hydrolysis of ceramide to sphingosine-1
      phosphate was not the cause of increased MAP kinase activation, substantiating
      the role of an IGF-IR interacting tyrosine kinase, which may be involved in
      apoptosis.

PMID- 10413588
TI  - p53-independent apoptosis and p53-dependent block of DNA rereplication following
      mitotic spindle inhibition in human cells.
AB  - We have studied the response of human transformed cells to mitotic spindle
      inhibition. Two paired cell lines, K562 and its parvovirus-resistant KS
      derivative clone, respectively nonexpressing and expressing p53, were
      continuously exposed to nocodazole. Apoptotic cells were observed in both lines,
      indicating that mitotic spindle impairment induced p53-independent apoptosis.
      After a transient mitotic delay, both cell lines exited mitosis, as revealed by
      flow-cytometric determination of MPM2 antigen and cyclin B1 expression, coupled
      to cytogenetic analysis of sister centromere separation. Both cell lines exited
      mitosis without chromatid segregation. K562 p53-deficient cells further resumed
      DNA synthesis, giving rise to cells with a DNA content above 4C, and reentered a
      polyploid cycle. In contrast, KS cells underwent a subsequent G1 arrest in the
      tetraploid state. Thus, G1 arrest in tetraploid cells requires p53 function in
      the rereplication checkpoint which prevents the G1/S transition following
      aberrant mitosis; in contrast, p53 expression is dispensable for triggering the
      apoptotic response in the absence of mitotic spindle.

PMID- 10413589
TI  - p38 mitogen-activated protein kinase functionally contributes to chondrogenesis
      induced by growth/differentiation factor-5 in ATDC5 cells.
AB  - Recent studies of intracellular signal transduction mechanisms for the
      transforming growth factor-beta (TGF-beta) superfamily have focused on Smad
      proteins, but have paid little attention to mitogen-activated protein (MAP)
      kinase cascades. Here we demonstrate that growth/differentiation factor-5 (GDF
      5), but neither bone morphogenetic protein-2 (BMP-2) nor TGF-beta1, fully
      promotes the early phase of the chondrogenic response by inducing cellular
      condensation followed by cartilage nodule formation in a mouse chondrogenic cell
      line, ATDC5. We investigated which, if any, of the three major types of MAP
      kinase plays a functional role in the promotion of chondrogenesis induced by GDF
      5. GDF-5 induced phosphorylation of p38 MAP kinase and extracellular signal
      regulated kinase (ERK) but not that of c-Jun N-terminal kinase (JNK). The
      phosphorylation of p38 MAP kinase was also induced by BMP-2 and TGF-beta1. An
      inhibitor of p38 and p38 beta MAP kinase, SB202190, showed complete inhibition of
      cartilage nodule formation but failed to affect alkaline phosphatase (ALP)
      activity induced by GDF-5. Expression of the type II collagen gene, a hallmark of
      chondrogenesis in vertebrates, was also induced by GDF-5 treatment and strongly
      suppressed by SB202190. On the other hand, although an inhibitor of MAP/ERK
      kinase, PD98059, inhibited the rapid phosphorylation of ERK by GDF-5, it
      inhibited neither ALP activity nor cartilage nodule formation induced by GDF-5.
      These results strongly suggest that the p38 MAP kinase cascade is involved in GDF
      5 signaling pathways and that a role of the p38 MAP kinase pathway is necessary
      over a longer period to promote chondrogenesis in ATDC5 cells.

PMID- 10413590
TI  - Identification of avian sarcoplasmic reticulum Ca(2+)-ATPase (SERCA3) as a novel
      1,25(OH)(2)D(3) target gene in the monocytic lineage.
AB  - Osteoclasts are postmitotic, multinucleated giant cells generated by the fusion
      of hematopoietic mononuclear precursors from the monocyte-macrophage lineage. In
      culture, adherent macrophages from blood-derived monocytes grow, gather, and fuse
      together to form multinucleated osteoclast-like cells. These events are
      controlled by 1,25(OH)(2)D(3). To sort out new 1,25(OH)(2)D(3) target genes
      involved in osteoclast differentiation, we have performed an RT-PCR differential
      display using mRNA from macrophages induced for 10 h by 1,25(OH)(2)D(3) compared
      to nontreated cells. We have identified a new target gene, a chick ATP-dependent
      Ca(2+) pump, ChkSERCA3. Although the level of the corresponding transcript
      increases during the differentiation process from macrophages to osteoclast-like
      cells, its steady-state level is downregulated by hormone treatment. The action
      of 1,25(OH)(2)D(3) on the Ca(2+)-ATPase gene expression is independent of de novo
      protein synthesis and is hormone dose dependent. This expression in adult chick
      was restricted to the hematopoietic cell lineage, spleen, lung, intestine, and
      brain, whereas no expression was detected in embryos. The function of the protein
      can be predicted from its high homology with the other members of the SR ATP
      dependent Ca(2+) pump family, i.e., storage and control of cytosolic Ca(2+)
      directly regulated by 1, 25(OH)(2)D(3), further supporting the critical role for
      intracellular calcium in highly specialized cells such as osteoclasts.

PMID- 10413592
TI  - Isolation of a species-specific satellite DNA with a novel CENP-B-like box from
      the North African rodent Lemniscomys barbarus.
AB  - A species-specific satellite DNA (Lb-MspISAT) was isolated from the North African
      rodent Lemniscomys barbarus. This DNA is highly homogeneous in the sequence of
      different repeats and shows no internal repetitions. Filter and in situ
      hybridizations demonstrated that it is tandemly repeated at the centromeres of
      all chromosomes of the complement. A 19-bp CENP-B-like motif was found in Lb
      MspISAT which conserves 12 of the 17-bp of the human CENP-B box, but only 5 of
      the 9-bp of the canonical sequence that is necessary to bind the CENP-B protein.
      Compared with the human CENP-B box, nucleotide substitutions and insertions
      increase the palindromic structure of this motif. The possibilities that it may
      be involved in centromeric function or in homogenization of the Lb-MspISAT
      sequence are discussed.

PMID- 10413591
TI  - Sphingosine 1-phosphate regulates heat shock protein 27 induction by a p38 MAP
      kinase-dependent mechanism in aortic smooth muscle cells.
AB  - In an aortic smooth muscle cell line, A10 cells, we investigated the effect of
      sphingosine 1-phosphate on the induction of heat shock protein 27 (HSP27), a low
      molecular-weight heat shock protein. Sphingosine 1-phosphate significantly
      induced the accumulation of HSP27 in a pertussis toxin-sensitive manner. The
      effect was dose-dependent in the range between 0.1 and 30 microM. Sphingosine 1
      phosphate stimulated an increase in the levels of mRNA for HSP27. Sphingosine 1
      phosphate stimulated both p42/p44 mitogen-activated protein (MAP) kinase and p38
      MAP kinase activation. PD98059, an inhibitor of the upstream kinase that
      activates p42/p44 MAP kinase, did not affect sphingosine 1-phosphate-stimulated
      HSP27 induction. In contrast, SB203580, an inhibitor of p38 MAP kinase, reduced
      sphingosine 1-phosphate-induced HSP27 induction. SB203580 reduced the levels of
      mRNA for HSP27 induced by sphingosine 1-phosphate. These results indicate that
      sphingosine 1-phosphate stimulates the induction of HSP27 via p38 MAP kinase
      activation in aortic smooth muscle cells.

PMID- 10413593
TI  - Recombinant rhodostomin substrates induce transformation and active calcium
      oscillation in human platelets.
AB  - Platelet activation has been a focus of numerous studies in normal and abnormal
      states. Morphological changes and calcium signals found with activated platelets
      in vitro have been well characterized. However, the rate of cell spreading on
      substrates and the frequency of calcium oscillation within individual platelets
      upon activation have not yet been reported. In this study, we first examined the
      ability of a recombinant fusion protein of rhodostomin (GST-rhodostomin), a snake
      disintegrin containing an Arg-Gly-Asp (RGD) motif, to activate platelets when GST
      rhodostomin served as a substrate. Four aspects of platelet activities induced by
      immobilized GST-rhodostomin and fibrinogen were analyzed in parallel.
      Examinations of (1) translocation of P-selectin from intracellular compartments
      to the plasma membrane, (2) platelet adhesion to and spreading on substrates, (3)
      platelet contact pattern on substrates, and (4) the degree of phosphorylation of
      focal adhesion kinase in platelets indicated that GST-rhodostomin was a better
      substrate for platelet activation than fibrinogen. Analysis of the rate of
      platelet spreading on GST-rhodostomin was examined by time-lapsed video
      microscopy. The spreading rate averaged 0.43 micrometer/minute, while cell
      spreading averaged 0.22 micrometer/minute when platelets were plated on
      fibrinogen and treated with thrombin. A newly developed method, using time-lapsed
      microscopy and the Metamorph program, was used to analyze calcium signals within
      platelets. We found that platelets on GST-rhodostomin evoked calcium oscillation
      at a frequency of 4.77 spike/cell/minute vs 2.76 spike/cell/minute on fibrinogen.
      The results of cell spreading and calcium oscillation were consistent with the
      results of microscopic and biochemical assays. We therefore conclude that the
      determination of the rate of platelet spreading and the frequency of calcium
      oscillation within platelets performed in this study provides more quantitative
      parameters for measuring platelet activities. Our results also suggest that GST
      rhodostomin might potentially be used as a probe to dissect the molecular
      mechanisms underlying the kinetic processes of platelet activation.

PMID- 10413594
TI  - The nuclear localization signal of the human Ku70 is a variant bipartite type
      recognized by the two components of nuclear pore-targeting complex.
AB  - Ku protein is a complex of two subunits, Ku70 and Ku80. Ku is suspected to
      participate in both DNA double-strand break repair and transcription. Since both
      of these processes take place in the cell nucleus, we have been investigating the
      subcellular localization and nuclear transport of Ku proteins. In the present
      study, we analyzed the subcellular localization and nuclear localization signal
      (NLS) of Ku70. Fusion proteins of Ku70 and green fluorescent protein (GFP)
      transiently expressed in cells were clearly localized in the nuclei of interphase
      cells. Ku70 staining was distributed throughout both the nucleus and the
      cytoplasm in late telophase to early G1 phase cells. The NLS of Ku70 was located
      at the region composed of 18 amino acid residues (positions 539 to 556). This
      region overlapped with the Ku80-independent DNA-binding domain reported
      previously. The Ku70 NLS consisted of two basic subregions and a nonbasic
      intervening region. All the subregions were necessary for complete NLS activity.
      The amino acids in the nonbasic intervening region of Ku70 might be important for
      full NLS activity not only to provide sufficient length between the two separated
      clusters of basic amino acids but also to have an adequate amino acid sequence.
      All of the basic amino acid residues in the basic subregions were conserved among
      mammalian and avian homologues, confirming their importance in the nuclear
      translocation of Ku70. The structure of the Ku70 NLS resembled the consensus of a
      bipartite-type NLS. The Ku70 NLS was mediated to target to the nuclear rim by two
      components of the nuclear pore-targeting complex, PTAC58 and PTAC97.

PMID- 10413595
TI  - Comparison of chromatin remodeling and transcriptional activation of the mouse
      mammary tumor virus promoter by the androgen and glucocorticoid receptor.
AB  - We examined the interaction between the androgen (AR) and glucocorticoid receptor
      (GR) at the transcriptional level using mouse fibroblast cell lines harboring an
      integrated mouse mammary tumor virus (MMTV) promoter. We found that the AR, after
      induction with dihydrotestosterone (DHT), caused a progressive increase in MMTV
      CAT reporter activity over 72 h which was correlated to an increase in chromatin
      remodeling of the MMTV promoter in the vicinity of the hormone response element
      (HRE). In contrast, stimulation of the GR by the synthetic glucocorticoid
      dexamethasone (Dex) caused a transient increase in MMTV transcriptional activity
      which returned to basal levels after 72 h. These changes were correlated to a
      transient increase in chromatin remodeling in the region of the HRE. Neither
      cotreatment nor pretreatment with Dex affected the DHT response. In fact, there
      was a more than additive effect of the two hormones on transcription at early
      time points. This suggests that the inability of GR to remodel chromatin, after
      24 h of hormone treatment, is most likely related to changes in the GR itself and
      not the chromatin remodeling process. Consistent with this, nuclear GR levels
      dropped by greater than 50% after Dex treatment whereas the AR was induced
      fourfold after 24 h of DHT treatment. We conclude that a promoter with an ordered
      chromatin structure can still respond to androgens even after its glucocorticoid
      responsiveness is lost. This may be one mechanism cells utilize to establish
      target gene specificity for nuclear receptors that recognize identical DNA
      sequences.

PMID- 10413596
TI  - Studies on the cellular uptake of retinol binding protein and retinol.
AB  - The uptake and release of (125)I-RBP and of holoRBP labeled with [(3)H]retinol
      ((3)H-ROH) were studied in two cell lines which synthesize and secrete RBP, the
      HepG2 hepatocarcinoma cell line and the Caki-1 kidney adenocarcinoma cell line,
      and in HeLa cells that do not express the endogenous RBP gene. In all three cell
      lines a part of endocytosed (125)I-RBP is recycled to the extracellular medium
      and part is degraded. Nonspecific endocytosis of (125)I-RBP was estimated to be
      approximately 10% of total endocytosed (125)I-RBP. In HepG2 cells the (3)H-ROH
      from the [(3)H]retinol-RBP complex ((3)H-ROH-RBP) is recycled bound to RBP into
      serum-free chase medium. This (3)H-ROH recycling is blocked in HepG2 cells by
      cyclohexymide and by brefeldin A, an inhibitor of protein export from the main
      secretory route, and is absent in HeLa cells, which do not synthesize RBP. These
      data suggest that at least part of retinol taken up from exogenous holoRBP is
      delivered to newly synthesized RBP. (3)H-ROH recycled by HeLa cells is bound to
      serum albumin, as is a portion of that recycled by HepG2 cells. Transfer of (3)H
      ROH from RBP to serum albumin does not occur in the absence of cells. We conclude
      that RBP is endocytosed through a specific pathway and that the RBP-associated
      retinol is transferred to newly synthesized RBP or to serum albumin.

PMID- 10413597
TI  - Astrocytes and neurons express the tight junction-specific protein occludin in
      vitro.
AB  - The expression of occludin, an integral plasma membrane protein specifically
      located at tight junctions, was studied in various epithelial and nonepithelial
      tissues by means of RT-PCR, Western blotting, and immunofluorescent staining.
      Besides detection in epithelial and endothelial tissue, expression of occludin
      was found in primary and secondary cultures of neurons and astrocytes.
      Differentiation of astrocytes in vitro led to a marked decrease in occludin
      expression. Extractability of occludin from plasma membranes differed
      considerably between epithelial and nonepithelial cells. Following treatment with
      Triton X-100, occludin was completely extracted from astrocytic membranes but not
      from membranes derived from MDCK cells, suggesting a difference in the
      cytoplasmic and/or plasma membrane anchoring of occludin between these cell
      types.

PMID- 10413598
TI  - Characterization of the 2A7 antigen as a 85-kDa human nucleocytoplasmic shuttling
      protein.
AB  - The murine monoclonal antibody 2A7 was found to react specifically with a 85-kDa
      human protein which is distributed throughout the nuclear interior in interphase
      and becomes associated with condensed chromosomes during mitosis. The 2A7 epitope
      was not detected in cells from other species. Two-dimensional immunoblotting
      analysis of HeLa cell homogenates further indicated that the 85-kDa polypeptide
      species recognized by the 2A7 antibody corresponds to an acidic protein which may
      be complexed in vivo within high-molecular-weight protein structures.
      Immunofluorescence monitoring of the 2A7 staining pattern during in situ
      preparation of nuclear matrices from HeLa cells demonstrated that the
      nucleoplasmic fraction of the antigen is readily solubilized by detergent and
      salts, whereas the nucleolar fraction resists detergent/salt extraction and DNase
      digestion, to be released only upon RNase activity. Mobility assays in human
      mouse heterokaryons provided evidence that the 2A7 antigen is a nucleocytoplasmic
      shuttling protein. The nuclear distribution of this antigen remained unchanged
      upon drug-induced inhibition of RNA synthesis but was markedly altered by heat
      shock stress. All together, the data presented here suggest that the 2A7 antigen
      may have a function in RNA metabolism.

PMID- 10413600
TI  - Isoform-specific attachment of osteoprogenitors to laminins: mapping to the short
      arms of laminin-1.
AB  - The recruitment of osteoblast progenitors involves their migration and attachment
      to the sites of bone formation through interactions with matrix proteins. In a
      time-limited cell attachment assay, coated laminin-1 inhibits the adhesion of
      most rat calvaria cells but attaches specifically to osteoprogenitors, as
      quantified by the number of bone colonies (nodules) formed in the cultures. In
      order to determine the molecular mechanisms involved in osteoprogenitor
      attachment to laminin-1, we investigated the effects of laminin-5, a N-truncated
      laminin variant. In contrast to laminin-1, laminin-5 increased (1.5-fold) rat
      calvaria cell attachment and did not display any specific affinity for
      osteoprogenitors. In competition experiments on laminin-5, blocking antibodies
      directed against either the integrin chain beta1 or the C-terminal portion of
      laminin-5, as well as thermic denaturation of the protein at 80 degrees C,
      inhibited rat calvaria cell attachment, suggesting the implication of integrin
      alpha3beta1 binding to the conformation-dependent C-terminal end of laminin-5.
      Stepwise thermic denaturation did not suppress the anti-adhesive activity of
      laminin-1, while osteoprogenitor recruitment was abolished after denaturation
      above 60 degrees C, suggesting that different domains are involved in these two
      effects. The anti-beta1 antibody further decreased RC cell attachment to laminin
      1, providing evidence for concomitant anti-adhesive and beta1-dependent cell
      attachment activities. Blocking of beta1 integrin subunit did not, however,
      reduce osteoprogenitor recruitment. Finally, purified elastase digestion fragment
      E1+, encompassing the N-terminal short arms of laminin-1, reproduced the effects
      of the complete molecule in the assay, while C-terminal fragment E8 did not
      display any cell attachment or osteoprogenitor recruitment properties. In
      conclusion, the anti-adhesive and osteoprogenitor-selective effects of laminin-1
      on rat calvaria cell populations are distinct, beta1-integrin-independent
      properties mapping to the short arms of the molecule and thus not displayed by
      the truncated laminin-5.

PMID- 10413599
TI  - The arm-repeat protein NPRAP (neurojungin) is a constituent of the plaques of the
      outer limiting zone in the retina, defining a novel type of adhering junction.
AB  - In the retina, special plaque-bearing adhering junctions are aligned to form a
      planar system (the "outer limiting zone," OLZ) of heterotypic connections between
      the photoreceptor cells and the surrounding glial cells ("Muller cells"),
      together with homotypic junctions. In the plaques of these junctions, which
      contain N-cadherin-and possibly also related cadherins-we have identified, by
      immunolocalization techniques, a recently discovered neural tissue-specific
      protein, neurojungin, a member of the plakoglobin/armadillo protein family. In
      these plaques we have also detected other adherens plaque proteins, such as alpha
      and beta-catenin, protein p120, and vinculin, as well as proteins known as
      constituents of tight junction plaques, such as symplekin and protein ZO-1, and
      the desmosomal plaque protein plakophilin 2. This unusual combination of proteins
      and the demonstrated absence of plakoglobin define the OLZ junctions as a new and
      distinct category of adhering junction, which probably has special architectural
      functions.

PMID- 10413601
TI  - Opposite effects of Ras or PKC activation on the expression of the SPRR2A
      keratinocyte terminal differentiation marker.
AB  - Epidermal growth factor (EGF) enhances the expression of the keratinocyte
      terminal differentiation marker SPRR2A, when added to monolayers of basal
      keratinocytes, induced to stratify by increasing the extracellular calcium
      concentration. A similar stimulation is found during suspension-induced
      differentiation in methylcellulose. This effect, which is observed after several
      hours of EGF addition, is restricted to terminally differentiating keratinocytes
      and is dependent on PKC signaling. EGF also transiently activates the Ras
      signaling pathway, with a maximum induction after 10 min (Medema et al., 1994,
      Mol. Cell. Biol. 14, 7078-7085). The cellular effects of activated Ras were
      determined by transient transfection of Ha-ras(Leu-61) into normal human
      keratinocytes. Activated Ras completely inhibited PKC-mediated expression of
      SPRR2A. This inhibition is mediated via c-Jun as it is reversed by a dominant
      negative c-Jun mutant (cJunDelta6/194) and c-Jun can substitute for activated
      Ras. The inhibitory effect is targeted to a 150-bp minimal promoter region, which
      is essential and sufficient for SPRR2A expression during keratinocyte terminal
      differentiation. This indicates that the Ras and PKC pathways, which both can be
      triggered by EGF, although at different time points, have opposite effects on
      SPRR2A gene expression.

PMID- 10413602
TI  - A recombinant human TGF-beta1 fusion protein with collagen-binding domain
      promotes migration, growth, and differentiation of bone marrow mesenchymal cells.
AB  - A continuous source of osteoblasts for normal bone maintenance, as well as
      remodeling and regeneration during fracture repair, is ensured by the mesenchymal
      osteoprogenitor stem cells of the bone marrow (BM). The differentiation and
      maturation of osteoprogenitor cells into osteoblasts are thought to be modulated
      by transforming growth factors-beta (TGF-beta1 and TGF-beta2) and TGF-beta
      related bone morphogenetic proteins (BMPs). To define the responses of
      mesenchymal osteoprogenitor stem cells to several growth factors (GFs), we
      cultured Fischer 344 rat BM cells in a collagen gel medium containing 0.5% fetal
      bovine serum for prolonged periods of time. Under these conditions, survival of
      BM mesenchymal stem cells was dependent on the addition of GFs. Recombinant hTGF
      beta1-F2, a fusion protein engineered to contain an auxiliary collagen binding
      domain, demonstrated the ability to support survival colony formation and growth
      of the surviving cells, whereas commercial hTGF-beta1 did not. Initially, cells
      were selected from a whole BM cell population and captured inside a collagen
      network, on the basis of their survival response to added exogenous GFs. After
      the 10-day selection period, the surviving cells in the rhTGF-beta1-F2 test
      groups proliferated rapidly in response to serum factors (10% FBS), and maximal
      DNA synthesis levels were observed. Upon the addition of osteoinductive factors,
      osteogenic differentiation in vitro was evaluated by the induction of alkaline
      phosphatase (ALP) expression, the production of osteocalcin (OC), and the
      formation of mineralized matrix. Concomitant with a down-regulation of cell
      proliferation, osteoinduction is marked by increased ALP expression and the
      formation of colonies that are competent for mineralization. During the induction
      period, when cells organize into nodules and mineralize, the expression of OC was
      significantly elevated along with the onset of extracellular matrix
      mineralization. Differentiation of BM mesenchymal stem cells into putative bone
      cells as shown by increased ALP, OC synthesis, and in vitro mineralization
      required the presence of specific GFs, as well as dexamethasone (dex) and beta
      glycerophosphate (beta-GP). Although rhTGF-beta1-F2-selected cells exhibited the
      capacity to mineralize, maximal ALP activity and OC synthesis were observed in
      the presence of rhBMPs. We further report that a novel rhTGF-beta1-F2 fusion
      protein, containing a von Willebrand's factor-derived collagen binding domain
      combined with a type I collage matrix, is able to capture, amplify, and stimulate
      the differentiation of a population of cells present in rat BM. When these cells
      are subsequently implanted in inactivated demineralized bone matrix (iDBM) and/or
      diffusion chambers into older rats they are able to produce bone and cartilage.
      The population of progenitor cells captured by rhTGF-beta1-F2 is distinct from
      the committed progenitor cells captured by rhBMPs, which exhibit a considerably
      more differentiated phenotype.

PMID- 10413603
TI  - Ectopic expression of (Mm)Kin17 protein inhibits cell proliferation of human
      tumor-derived cells.
AB  - To characterize the biological role of Kin17 protein, a mammalian nuclear protein
      which participates in the response to UV and ionizing radiation and binds to
      curved DNA, EBV-derived vectors carrying (Mm)Kin17 cDNA were constructed and
      transfected in tumorigenic cells harboring different p53 profiles (HeLa, H1299,
      and HCT116) and in immortalized HEK 293 cells. (Mm)Kin17 protein expression
      induced a tremendous decrease in cell proliferation of the three tumorigenic cell
      lines 2 weeks after transfection. Transfection of HEK 293 cells with an
      pEBVCMV(Mm)Kin17 plasmid gave rise to numerous (Mm)Kin17-expressing cells which
      constantly disappeared with time, preventing the establishment of (Mm)Kin17
      expressing cells. Several independent clones were isolated from HEK 293 cells
      carrying a pEBVMT(Mm)Kin17 vector. The two clones described here (B223.1 and
      B223.2) exhibited different (Mm)Kin17 protein levels and displayed a gradual
      decrease in their proliferative capacities. In B223.1 cells, the basal expression
      of (Mm)Kin17 greatly reduced plating efficiency and cell growth. B223.1 cell
      morphology was altered, with numerous round-shaped cells whose spreading on the
      culture support was hampered. We observed giant multinucleated cells or cells
      containing micronuclei-like structures and/or multilobed nuclei. To conclude,
      (Mm)Kin17 overexpression reduced the proliferation of tumorigenic cells
      independently of their p53 status and modified cell growth and cell morphology of
      established HEK 293 cells producing (Mm)Kin17 protein. It is likely that
      (Mm)Kin17 may interfere with DNA replication.

PMID- 10413604
TI  - Chromosome separation and exit from mitosis in budding yeast: dependence on
      growth revealed by cAMP-mediated inhibition.
AB  - Cell cycle progression of somatic cells depends on net mass accumulation. In
      Saccharomyces cerevisiae the cAMP-dependent kinases (PKAs) promote cytoplasmic
      growth and modulate the growth-regulated mechanism triggering the begin of DNA
      synthesis. By altering the cAMP signal in budding yeast cells we show here that
      mitotic events can also depend on growth. In fact, the hyperactivation of PKAs
      permanently inhibited both anaphase and exit from mitosis when cell growth was
      repressed. In S. cerevisiae the anaphase promoting complex (APC) triggers entry
      into anaphase by mediating the degradation of Pds1p. The cAMP pathway activation
      was lethal together with a partial impairment of the Cdc16p APC subunit, causing
      a preanaphase arrest, and conversely low PKA activity suppressed the lethality of
      cdc16-1 cells. Deregulated PKAs partially prevented the decrease of Pds1p
      intracellular levels concomitantly with the anaphase inhibition, and the PKA
      dependent preanaphase arrest could be suppressed in pds1(-) cells. Thus, the cAMP
      pathway and APC functionally interact in S. cerevisiae and Pds1p is required for
      the cAMP-mediated inhibition of chromosome separation. Exit from mitosis requires
      APC, Cdc15p, and the polo-like Cdc5p kinase. PKA hyperactivation and a cdc15
      mutation were synthetically lethal and brought to a telophase arrest. Finally, a
      low cAMP signal allowed cell division at a small cell size and suppressed the
      lethality of cdc15-2 or cdc5-1 cells. We propose that mitosis progression and the
      M/G1 phase transition specifically depend on cell growth through a mechanism
      modulated by PKAs and interacting with the APC/CDC15/CDC5 mitotic system. A
      possible functional antagonism between PKAs and the mitosis promoting factor is
      also discussed.

PMID- 10413605
TI  - Effects of mutations in the cytoplasmic domain of integrin beta(1) to talin
      binding and cell spreading.
AB  - Integrins are transmembrane proteins linking the extracellular matrix or certain
      cell-cell contacts to the cytoskeleton. To study integrin-cytoskeleton
      interactions we wanted to relate talin-integrin interaction to integrin function
      in cell spreading and formation of focal adhesions. For talin-binding studies we
      used fusion proteins of glutathione S-transferase and the cytoplasmic domain of
      integrin beta(1) (GST-cytobeta(1)) expressed in bacteria. For functional studies
      chimeric integrins containing the extracellular and transmembrane parts of
      beta(3) linked to the cytoplasmic domain of beta(1) were expressed in CHO cells
      as a dimer with the alpha(IIb) subunit. Point mutations in the amino acid
      sequence N(785)PIY(788) of beta(1) disrupted both the integrin-talin interaction
      and the ability of the integrin to mediate cell spreading. COOH-terminal
      truncation of beta(1) at the amino acid position 797 disrupted its ability to
      mediate cell spreading, whereas the disruption of talin binding required deletion
      of five more amino acids (truncation at position 792). A synthetic peptide from
      this region of beta(1) (W(780)DTGENPIYKSAV(792)) bound to purified talin and
      inhibited talin binding to GST-cytobeta(1). The ability of the mutants to mediate
      focal adhesion formation or to codistribute to focal adhesions formed by other
      integrins correlated with their ability to mediate cell spreading. These results
      confirm the previous finding that a talin-binding site in the integrin beta(1)
      tail resides at or close to the central NPXY motif and suggest that the integrin
      talin interaction is necessary but not sufficient for integrin-mediated cell
      spreading.

PMID- 10413606
TI  - Upstream stimulatory factor 1 regulates osteopontin expression in smooth muscle
      cells.
AB  - Vascular smooth muscle cells (SMCs) undergo a dramatic phenotypic transition in
      response to injury and ex vivo culture that includes enhanced proliferation,
      migration, matrix deposition, and alterations in gene expression. Osteopontin is
      a good marker for the injury-induced SMC phenotypic state in vivo and in vitro.
      To identify transcription factors that might control the regulation of
      osteopontin expression, we investigated cultured vascular SMCs that express high
      and low levels of osteopontin. Using nuclear run-on assays, mRNA stability
      studies, and deletion analysis, we demonstrate that regulation of osteopontin
      steady-state mRNA levels in SMCs occurs at the transcriptional level. Transient
      transfection and gel-shift analyses of osteopontin promoter indicated that a
      region between -123 and +66 was involved in the expression of osteopontin.
      Supershift EMSAs identified the bHLH-leucine zipper transcription factor upstream
      stimulatory factor-1 (USF1) as the protein binding to this sequence. Finally, we
      show that USF1 protein is induced in vivo within 24 h of balloon angioplasty of
      rat carotids coordinately with osteopontin induction. These data suggest that
      USF1 governs expression of osteopontin in cultured vascular SMCs and might
      contribute to initial osteopontin expression observed post carotid injury and in
      vascular pathologies in vivo.

PMID- 10413607
TI  - Soluble collagen VI induces tyrosine phosphorylation of paxillin and focal
      adhesion kinase and activates the MAP kinase erk2 in fibroblasts.
AB  - Signals from the extracellular matrix can modulate cellular differentiation and
      gene expression. We have shown previously that in contrast to other extracellular
      matrix molecules pepsin-solubilized collagen VI (CVI) can stimulate DNA synthesis
      of various mesenchymal cell types, apparently independent of integrin-mediated
      signal transduction. In order to further elucidate collagen VI-induced signaling
      events, we exposed mouse 3T3 fibroblasts and human HT1080 fibrosarcoma cells to
      soluble CVI. CVI induced tyrosine phosphorylation of proteins that associate with
      focal adhesions, such as paxillin, focal adhesion kinase (FAK), and p130CAS.
      Furthermore, it activated the mitogen-activated protein kinase, erk2. Kinetic
      analysis showed that these phosphorylations were transient, reaching a maximum
      after 5 min for transformed HT1080 cells and 30 min for 3T3 fibroblasts. These
      effects were partly inhibited by a beta1-integrin function blocking antibody and
      by single chains of CVI. Our results indicate that soluble fragments of native
      collagen VI, a ubiquitous component of the interstitial extracellular matrix, can
      mediate stimulation of DNA synthesis via tyrosine phosphorylation of paxillin,
      FAK, p130CAS, and erk2 in the absence of classical growth factors. Thus, CVI may
      serve as a matrix-derived sensor that allows for rapid reconstitution of a tissue
      defect by activating nearby mesenchymal cells.

PMID- 10413609
TI  - In the nucleus and cytoplasm of chicken erythroleukemic cells, prosomes
      containing the p23K subunit are found in centers of globin (pre-)mRNA processing
      and accumulation.
AB  - Prosomes were originally identified as 20S particles associated with untranslated
      mRNA; they also constitute the core of the 26S proteasomes. The cellular
      distribution of three types of prosomes characterized by the presence of subunits
      with molecular masses of 23, 27, and 30 kDa was analyzed using an
      immunocytochemical approach on cultured chicken erythroblasts. The prosomes
      containing the p27K and p30K subunits were found in diffuse distribution in both
      nuclei and cytoplasm. In contrast, the prosomes containing the p23K subunit,
      although relatively rare in the nuclear space, were found concentrated in one or
      two large spots. Using in situ hybridization with an alpha(A)-globin gene
      specific riboprobe we found that the p23K-type prosomes colocalize in the nucleus
      with centers of globin (pre-)mRNA processing, and of mRNA accumulation in the
      cytoplasm. This result suggests there is local coincidence of specific-type
      prosome function with processing and, possibly, transport of a particular kind of
      (pre-)mRNA.

PMID- 10413608
TI  - Stimulus-induced selective association of actin-associated proteins (alpha
      actinin) and protein kinase C isoforms with the cytoskeleton of human
      neutrophils.
AB  - We report a selective, differential stimulus-dependent enrichment of the actin
      associated protein alpha-actinin and of isoforms of the signaling enzyme protein
      kinase C (PKC) in the neutrophil cytoskeleton. Chemotactic peptide, activators of
      PKC, and cell adhesion all induce a significant increase in the amount of
      cytoskeletal alpha-actinin and actin. Increased association of PKCbetaI and
      betaII with the cytoskeletal fraction of stimulated cells was also observed, with
      phorbol ester being more effective than chemotactic peptide. A fraction of
      phosphatase 2A was constitutively associated with the cytoskeleton independent of
      cell activation. None of the stimuli promoted association of vinculin or myosin
      II with the cytoskeleton. Phosphatase inhibitors okadaic acid and calyculin A
      prevented increases in cytoskeletal actin, alpha-actinin, and PKCbetaII induced
      by phorbol ester, suggesting the requirement for phosphatase activity in these
      events. Increases in cytoskeletal alpha-actinin and PKCbetaII showed differing
      sensitivity to agents that prevent actin polymerization (cytochalasin D,
      latrunculin A). Latrunculin A (1 microM) completely blocked PMA-induced increases
      in cytoskeletal alpha-actinin but reduced cytoskeletal recruitment of PKCbetaII
      only by 16%. Higher concentrations of latrunculin A (4 microM), which almost
      abolished the cytoskeletal actin pool, reduced cytoskeletal PKCbetaII by 43%. In
      conclusion, a selective enrichment of cytoskeletal and signaling proteins in the
      cytoskeleton of human neutrophils is induced by specific stimuli.

PMID- 10413610
TI  - Cell-substrate contact: another factor may influence transepithelial electrical
      resistance of cell layers cultured on permeable filters.
AB  - Transepithelial resistance (TER) measurement has often been used to study the
      paracellular transport properties of epithelia grown on permeable filters,
      especially the barrier function of tight junctions. However, the TER value
      includes another source, the resistance caused by cell-substrate contact, that
      may give rise to a high TER value if cell-substrate separation is small. In this
      study we use electric cell-substrate impedance sensing (ECIS) to measure both
      paracellular resistance and the average cell-substrate distance of MDCK (II), HEp
      2, and WI-38 VA13 cells. Comparing ECIS data with those from TER measurements of
      cell layers cultured on polycarbonate filters, we can obtain the approximate
      extra resistance resulting from cell-substrate contact for each cell type. The
      value of cell-substrate resistance was also estimated by two theoretical
      calculations that bracket the true values. Our results demonstrate that cell
      substrate contact substantially influences the TER data measured using
      polycarbonate filters and that the extra resistance due to cell-substrate spaces
      depends on both cell type and filter property.

PMID- 10413611
TI  - Mitosis in filamentous fungi: how we got where we are.
AB  - This review traces the principal advances in the study of mitosis in filamentous
      fungi from its beginnings near the end of the 19(th) century to the present day.
      Meiosis and mitosis had been accurately described and illustrated by the second
      decade of the present century and were known to closely resemble nuclear
      divisions in higher eukaryotes. This information was effectively lost in the mid
      1950s, and the essential features of mitosis were then rediscovered from about
      the mid-1960s to the mid-1970s. Interest in the forces that separate chromatids
      and spindle poles during fungal mitosis followed closely on the heels of detailed
      descriptions of the mitotic apparatus in vivo and ultrastructurally during this
      and the following decade. About the same time, fundamental studies of the
      structure of fungal chromatin and biochemical characterization of fungal tubulin
      were being carried out. These cytological and biochemical studies set the stage
      for a surge of renewed interest in fungal mitosis that was issued in by the age
      of molecular biology. Filamentous fungi have provided model studies of the
      cytology and genetics of mitosis, including important advances in the study of
      mitotic forces, microtubule-associated motor proteins, and mitotic regulatory
      mechanisms.

PMID- 10413612
TI  - What triggers senescence in Podospora anserina?
AB  - Senescence of Podospora anserina is triggered by a cytoplasmic and infectious
      factor (the determinant of senescence) and is always correlated with
      mitochondrial DNA modifications, especially with the accumulation of small
      circular subgenomic DNA molecules, the senDNAs. Several observations have
      suggested that the senDNAs could be the cytoplasmic and infectious determinant.
      However, we show here (1) that senDNA molecules can be transferred to a young
      culture without the cotransmission of the determinant of senescence and (2) that
      the determinant of senescence does not segregate as a mitochondrial DNA mutation.
      Overall, our data strongly argue that amplification of senDNA molecules in the
      mitochondria is not an intrinsic property of these small DNA molecules. They
      question the nature of the actual determinant of senescence.

PMID- 10413614
TI  - Ploidy study in sporothrix schenkii 
AB  - Sporothrix schenckii is a dimorphic fungus that is pathogenic for humans. No
      sexual cycle has been reported for this fungus and little is known of its genetic
      constitution. To inquire into the ploidy state of Sporothrix schenckii, different
      approaches were followed: DNA content during transition from conidia to yeast,
      survival to ultraviolet irradiation, chemical mutagenesis, and induction of
      mitotic recombination. No change in ploidy was detected between the conidia and
      yeast phases of the fungi. Resistance to cell inactivation by UV irradiation was
      higher in S. schenckii and in Sacharomyces cerevisiae in its diploid state than
      in isogenic haploids a and alpha from S. cerevisiae that were inactivated at
      lower doses. Two mutant phenotypes, auxotrophy and albinism, were screened after
      chemical mutagenesis. One-step mutagenesis with either nitrous acid or
      ultraviolet light was unsuccessful in inducing auxotrophy but was sufficient to
      induce albino colonies. Two-step mutagenesis with nitrous acid in combination
      with UV light was necessary to attain two auxotrophic requirements: adenine and
      methionine. Prototrophic and pigmented revertants behaved as heterozygotes; after
      exposure to UV light they gave rise to derivatives which resemble the original
      mutation. The experiments presented in this work suggest that S. schenckii is a
      diploid, although aneuploidy cannot be excluded. Copyright 1999 Academic Press.

PMID- 10413613
TI  - Molecular analysis of the Cryptococcus neoformans ADE2 gene, a selectable marker
      for transformation and gene disruption.
AB  - Cryptococcus neoformans is an important fungal pathogen of man. The incidence of
      cryptococcal disease has increased dramatically in patients immunocompromised
      because of HIV infection, organ transplantation, or treatment with cytotoxic
      chemotherapy or corticosteroids. This organism is an excellent model for
      molecular dissection of fungal pathogenesis and virulence factors. Here we report
      the nucleotide sequence of the C. neoformans serotype D genomic ADE2 gene, which
      encodes a phosphoribosylaminoimidazole carboxylase required for purine
      biosynthesis. Importantly, this version of the ADE2 gene has been used as the
      selectable marker for virtually all gene disruptions by transformation and
      homologous recombination in C. neoformans. We compare the nucleotide and amino
      acid sequences of the ADE2 gene and product to other highly related adenine
      biosynthetic genes and enzymes from other yeasts and fungi. We also describe a
      series of convenient ADE2 cassettes for gene disruption construct preparation.
      Finally, we have identified the ade2 mutations in strains M001 and M049, adenine
      auxotrophic mutants derived from the serotype A strain H99. These mutant strains
      have served as recipients for targeted gene disruptions using the ADE2 gene.
      These studies should facilitate transformation and gene disruption approaches
      using the ADE2 selectable marker in this important human fungal pathogen.

PMID- 10413615
TI  - Molecular cloning and characterization of Aspergillus nidulans cyclophilin B.
AB  - Cyclophilins are an evolutionarily conserved family of proteins which serve as
      the intracellular receptors for the immunosuppressive drug cyclosporin A. Here we
      report the characterization of the first cyclophilin cloned from the filamentous
      fungus Aspergillus nidulans (CYPB). Sequence analysis of the cypB gene predicts
      an encoded protein with highest homology to the murine cyclophilin B protein. The
      sequence similarity includes an N-terminal sequence predicted to target the
      protein to the endoplasmic reticulum (ER) as well as a C-terminal sequence
      predicted to retain the mature protein in the ER. The bacterially expressed hexa
      histidine tagged protein displays peptidyl-prolyl isomerase activity which is
      inhibited by cyclosporin A. In the presence of cyclosporin A, the expressed
      protein also inhibits purified calcineurin. When the endogenous cypB gene was
      disrupted and placed under the control of the regulatable alcohol dehydrogenase
      promoter, the strain demonstrated no detectable growth phenotype under conditions
      which induce or repress cypB transcription. Induction or repression of the cypB
      gene also did not effect sensitivity of A. nidulans to cyclosporin A. cypB mRNA
      levels were significantly elevated under severe heat shock conditions, indicating
      a possible role for the A. nidulans cyclophilin B protein during growth in high
      stress environments.

PMID- 10413616
TI  - Folyt1, a new member of the hAT family, is active in the genome of the plant
      pathogen Fusarium oxysporum.
AB  - An active transposable element, Folyt1, has been isolated from the tomato
      pathogen Fusarium oxysporum f. sp. lycopersici as an insertion sequence within
      the coding region of the nitrate reductase gene (nit 1) in two independent
      mutants (CO66 and CO108). Folyt1 was 2615 bp in length and contained 9-bp
      imperfect inverted terminal repeats (ITRs) and 8 bp duplicated at the target site
      upon insertion. The element contained a long open reading frame interrupted by a
      single putative intron. The predicted amino acid sequence showed similarity to
      conserved domains of transposases from hobo, Ac, and Tam3 elements, which belong
      to the hAT family. The excision frequency of Folyt1 was determined to be less
      than 10(-5) in both mutants. These events restored the nit 1 wild-type allele
      without leaving footprints in all the revertants of strain CO66. Nevertheless,
      some revertants of strain CO108 showed a point mutation footprint at the target
      sequence. Expression of the Folyt1 transposase was detected by Northern analysis
      as a 2.1-kb transcript. The element exists in about 10 copies per genome in F.
      oxysporum f. sp. lycopersici and appears to be widely distributed among different
      formae speciales of F. oxysporum.

PMID- 10413617
TI  - Imaging of total calcium in urediospore germlings of Uromyces by ion microscopy.
AB  - Calcium has been implicated in growth and appressorium formation of urediospore
      germlings of the bean rust fungus, Uromyces appendiculatus. Using ion microscopy,
      a mass spectrometry-based imaging technique, intracellular stores of calcium were
      analyzed by direct imaging of total calcium in frozen freeze-dried germlings.
      Calcium concentration was calculated by ratioing and spatially registering (40)Ca
      to (12)C signals. Intracellular distributions of total potassium, sodium,
      magnesium, and carbon were similarly imaged in the same germlings for a direct
      comparison of their localizations to total calcium. Calcium was remarkably
      heterogeneous with highest concentrations (2 to 10 mM) in the mid-region of the
      germling between the nuclei and the apex. A similar distribution of Ca(2+)
      (assessed using Fluo-3) was also noted sequestered in organelles in live
      germlings. Distributions of remaining elements (K, Na, Mg, and C) were mostly
      homogeneous throughout the cytoplasm and nuclei of the fungal cell. The K/Na
      ratio ranged from 17 to 31.

PMID- 10413619
TI  - A polyketide synthase gene required for biosynthesis of fumonisin mycotoxins in
      Gibberella fujikuroi mating population A.
AB  - Fumonisins are toxins associated with several mycotoxicoses and are produced by
      the maize pathogen Gibberella fujikuroi mating population A (MP-A). Biochemical
      analyses indicate that fumonisins are a product of either polyketide or fatty
      acid biosynthesis. To isolate a putative polyketide synthase (PKS) gene involved
      in fumonisin biosynthesis, we employed PCR with degenerate PKS primers and a cDNA
      template prepared from a fumonisin-producing culture of G. fujikuroi. Sequence
      analysis of the single PCR product and its flanking DNA revealed a gene (FUM5)
      with a 7.8-kb coding region. The predicted FUM5 translation product was highly
      similar to bacterial and fungal Type I PKSs. Transformation of a cosmid clone
      carrying FUM5 into G. fujikuroi enhanced production in three strains and restored
      wild-type production in a fumonisin nonproducing mutant. Disruption of FUM5
      reduced fumonisin production by over 99% in G. fujikuroi MP-A. Together, these
      results indicate that FUM5 is a PKS gene required for fumonisin biosynthesis.

PMID- 10413618
TI  - Developmental regulation of cmp1, a gene encoding a multidomain conidiospore
      surface protein of Trichoderma.
AB  - A gene encoding a developmentally regulated polypeptide of Trichoderma (strain
      ATCC 32173) was isolated, with the help of an antibody against a 62-kDa protein
      whose abundance strongly increases during photoinduced sporulation. The amino
      acid sequence deduced from this gene, cmp1 (conidial multidomain protein), is a
      135-kDa polypeptide consisting of several domains. Although reminiscent of known
      structural modules, two of the domains may define novel families. The protein is
      apparently processed to give the 62-kDa species. Immunogold labeling electron
      microscopy localized the antigen to the membrane or inner wall layers. The mRNA
      is strongly up-regulated during sporulation. At least part of this regulation is
      likely to be conferred by several elements identified in the upstream region,
      with homology to elements recognized by fungal transcription factors for
      regulation by conidiation, light, and nitrogen stress. The developmental
      regulation, cell surface location, and modular structure suggest a function in
      cell-cell interactions, detection of the wall by the cell, or anchoring of the
      plasma membrane to the wall.

PMID- 10413620
TI  - Phylogenetic study of complete cytochrome b genes in musk deer (genus Moschus)
      using museum samples.
AB  - As an endangered animal group, musk deer (genus Moschus) are not only a great
      concern of wildlife conservation, but also of special interest to evolutionary
      studies due to long-standing arguments on the taxonomic and phylogenetic
      associations in this group. Using museum samples, we sequenced complete
      mitochondrial cytochrome b genes (1140 bp) of all suggested species of musk deer
      in order to reconstruct their phylogenetic history through molecular information.
      Our results showed that the cytochrome b gene tree is rather robust and concurred
      for all the algorithms employed (parsimony, maximum likelihood, and distance
      methods). Further, the relative rate test indicated a constant sequence
      substitution rate among all the species, permitting the dating of divergence
      events by molecular clock. According to the molecular topology, M. moschiferus
      branched off the earliest from a common ancestor of musk deer (about 700,000
      years ago); then followed the bifurcation forming the M. berezovskii lineage and
      the lineage clustering M. fuscus, M. chrysogaster, and M. leucogaster (around
      370,000 years before present). Interestingly, the most recent speciation event in
      musk deer happened rather recently (140,000 years ago), which might have resulted
      from the diversified habitats and geographic barriers in southwest China caused
      by gigantic movements of the Qinghai-Tibetan Plateau in history. Combining the
      data of current distributions, fossil records, and molecular data of this study,
      we suggest that the historical dispersion of musk deer might be from north to
      south in China. Additionally, in our further analyses involving other pecora
      species, musk deer was strongly supported as a monophyletic group and a valid
      family in Artiodactyla, closely related to Cervidae.

PMID- 10413622
TI  - A case of rapid diversification in the neotropics: phylogenetic relationships
      among Cranioleuca spinetails (Aves, Furnariidae).
AB  - Relationships among the 18-19 species of spinetails of the genus Cranioleuca are
      difficult to establish. Attempts based on traditional taxonomic characters have
      failed because of a high degree of homoplasy. Most morphological characters vary
      independently, producing leap-frog patterns of variation along the Eastern
      Brazilian Andean track, and behavior and vocalizations vary little. We use mtDNA
      sequence data from the cyt b and ND2 genes in an attempt to clarify relationships
      within the genus. We show (i) that Cranioleuca represents a recent burst of
      speciation and (ii) that a set of species thought by Maijer and Fjeldsa (1997) to
      form a natural group is in fact a paraphyletic assemblage which also includes
      humid forest species with different pigmentations and vocalizations. However,
      synapomorphic variation in the sequences is not sufficient to unambiguously
      resolve the relationships within the genus. Several species (C. baroni, C.
      antisiensis, C. pyrrhophia, C. albiceps) show more than one haplotype, without
      any obvious correlation between genetic and geographic or morphological
      variation, and the different species do not always show reciprocal monophyly in
      haplotype diversity. Nevertheless, low genetic differentiation characterizes not
      only allopatric taxa but also some forms which are essentially sympatric,
      supporting species rank for the former. Our data suggest a recent diversification
      and proliferation possibly linked to Pleistocene climatic variation and its
      consequent vegetational shifts, at least in the Andean species.

PMID- 10413621
TI  - Molecular phylogenetics, tRNA evolution, and historical biogeography in anguid
      lizards and related taxonomic families.
AB  - Phylogenetic relationships among lizards of the families Anguidae, Anniellidae,
      Xenosauridae, and Shinisauridae are investigated using 2001 aligned bases of
      mitochondrial DNA sequence from the genes encoding ND1 (subunit one of NADH
      dehydrogenase), tRNA(Ile), tRNA(Gln), tRNA(Met), ND2, tRNA(Trp), tRNA(Ala),
      tRNA(Asn), tRNA(Cys), tRNA(Tyr), and COI (subunit I of cytochrome c oxidase),
      plus the origin for light-strand replication (O(L)) between the tRNA(Asn) and the
      tRNA(Cys) genes. The aligned sequences contain 1013 phylogenetically informative
      characters. A well-resolved phylogenetic hypothesis is obtained. Because
      monophyly of the family Xenosauridae (Shinisaurus and Xenosaurus) is
      statistically rejected, we recommend placing Shinisaurus in a separate family,
      the Shinisauridae. The family Anniellidae and the anguid subfamilies
      Gerrhonotinae and Anguinae each form monophyletic groups receiving statistical
      support. The Diploglossinae*, which appears monophyletic, is retained as a
      metataxon (denoted with an asterisk) because its monophyly is statistically
      neither supported nor rejected. The family Anguidae appears monophyletic in
      analyses of the DNA sequence data, and statistical support for its monophyly is
      provided by reanalysis of previously published allozymic data. Anguid lizards
      appear to have had a northern origin in Laurasia. Taxa currently located on
      Gondwanan plates arrived there by dispersal from the north in two separate
      events, one from the West Indies to South America and another from a Laurasian
      plate to Morocco. Because basal anguine lineages are located in western Eurasia
      and Morocco, formation of the Atlantic Ocean (late Eocene) is implicated in the
      separation of the Anguinae from its North American sister taxon, the
      Gerrhonotinae. Subsequent dispersal of anguine lizards to East Asia and North
      America appears to have followed the Oligocene drying of the Turgai Sea. The
      alternative hypothesis, that anguine lizards originated in North America and
      dispersed to Asia via the Bering land bridge with subsequent colonization of
      Europe and Morocco, requires a phylogenetic tree seven steps longer than the most
      parsimonious hypothesis. North African, European, and West Asian anguines were
      isolated from others by the rapid uplift of Tibet in the late Oligocene to
      Miocene. Phylogenetic analysis of evolutionary changes in the gene encoding
      tRNA(Cys) suggests gradual reduction of dihydrouridine (D) stems by successive
      deletion of bases in some lineages. This evolutionary pattern contrasts with the
      one observed for parallel elimination of the D-stem in mitochondrial tRNAs of
      eight other reptile groups, in which replication slippage produces direct
      repeats. An unusual, enlarged TpsiC (T) stem is inferred for tRNA(Cys) in most
      species.

PMID- 10413623
TI  - Phylogenetic signal in the COI, 16S, and 28S genes for inferring relationships
      among genera of Microgastrinae (Hymenoptera; Braconidae): evidence of a high
      diversification rate in this group of parasitoids.
AB  - The subfamily Microgastrinae is a highly diversified group of parasitoid wasps
      that attacks all of the different groups of Lepidoptera. We explore here the
      phylogenetic signal in three gene (mitochondrial COI and 16S, and nuclear 28S)
      fragments as an assessment of their utility in resolving generic relationships
      within this species-rich insect group. These genes were chosen because their
      level of sequence divergence is thought to be appropriate for this study and
      because they have resolved relationships among other braconid wasps at similar
      taxonomic levels. True phylogenetic signal, as opposed to random signal or noise,
      was detected in the 16S and 28S data sets. Phylogenetic analyses conducted on
      each microgastrine data set, however, have all resulted in poorly resolved trees,
      with most clades being supported by low bootstrap values. The phylogenetic
      signal, if present, is therefore concentrated on a few well-supported clades.
      Some rapidly evolving sites may be too saturated to be phylogenetically useful.
      Nonetheless, the sequence data (nearly 2300 nucleotides) used here appear to
      exhibit the appropriate level of variation, theoretically, to resolve the
      relationships studied. Moreover, the clades that are well supported by the data
      are usually supported by more than one data set and represent different levels of
      sequence divergence. We suggest that the lack of phylogenetic signal observed is
      an indication of the presence of many short internal branches on the phylogeny
      being estimated, which in turn might be the result of a rapid diversification of
      the taxa examined. Relative specialization of diet, which is typically associated
      with parasitic behavior, is believed to result in high radiation rates, which may
      have been especially high in microgastrine wasps because of the great diversity
      of their lepidopteran hosts. This hypothesis of a rapid diversification caused by
      an abundance of host species remains speculative and more data will be needed to
      test it further.

PMID- 10413624
TI  - Sequence insertions and ITS data provide congruent information on Roccella
      canariensis and R. tuberculata (Arthoniales, Euascomycetes) phylogeny.
AB  - Four Roccella species, R. canariensis, R. fimbriata, R. montagnei, and R.
      tuberculata, were found to possess sequence insertions in up to four locations in
      the first half of the SSU rDNA. Insertions from one of these positions have been
      classified as group I introns, while the others may represent degenerative forms
      of group I introns or messenger RNA introns. Two of the insertion-containing
      taxa, R. canariensis and R. tuberculata, differ only in their dispersal strategy:
      R. canariensis is sexual, producing only fruiting bodies and R. tuberculata is
      sterile, producing only vegetative propagules, i.e., soredia. Because insertions
      occurred in specimens of both taxa, they were used to examine the phylogenetic
      relationships between and within the two species. The sequence insertions from
      each of the four positions were aligned and cladistically analyzed separately.
      Internal transcribed spacers (ITS) were additionally sequenced to study the
      phylogeny of all R. canariensis and R. tuberculata specimens. Three other
      Roccella species (R. babingtonii, R. fimbriata, and R. montagnei) and Dirina
      catalinariae were used as outgroups in this parsimony analysis. Sequence
      insertions were found to be potentially useful in phylogenetic studies, although
      due to the sequence dissimilarity, homology relations were difficult to establish
      above the species level and in some cases even within the species. The
      phylogenies obtained from the insertion matrices were totally consistent with the
      ITS data and the insertions were concluded to have been inherited. When the
      insertion and ITS data were combined for total evidence, R. canariensis and R.
      tuberculata did not form distinct lineages in the phylogenetic tree, but appeared
      mixed in well-supported groups containing both sorediate and fertile specimens.

PMID- 10413625
TI  - Chloroplast-expressed glutamine synthetase (ncpGS): potential utility for
      phylogenetic studies with an example from Oxalis (Oxalidaceae).
AB  - Chloroplast-expressed glutamine synthetase (ncpGS), a nuclear-encoded gene
      containing several introns, is introduced as a tool for phylogenetic studies at
      lower taxonomic levels. This gene is a member of a multigene family, but it
      diverged long ago from the cytosolic-expressed members of the family and appears
      to be single copy in the majority of taxa examined to date. The conservation of
      both coding sequence and position of introns has allowed the design of primers
      for use in a broad range of dicot taxa to amplify and sequence a region of ncpGS
      that contains four introns. The utility of this region in phylogenetic studies of
      congeneric species is illustrated by an example using eight Oxalis species. The
      four introns in these taxa are typical in size (76 to 136 bp), base composition
      (high T content), and structure (e.g., sequence of splice sites and putative
      branch points) for plant internal introns. Levels of variation among these ncpGS
      sequences compare favorably with those of the internal transcribed spacer of
      nuclear ribosomal DNA (ITS) from the same taxa, and results of phylogenetic
      analysis of ncpGS data are generally congruent with previous results using ITS.

PMID- 10413627
TI  - Phylogeny, biogeography, and processes of molecular differentiation in Quercus
      subgenus Quercus (Fagaceae).
AB  - Quercus is one of the most abundant and economically important genera of woody
      plants in the Northern Hemisphere. To infer phylogenetic relationships within
      Quercus subgenus Quercus, chloroplast DNA (cpDNA) restriction sites and
      nucleotide sequences of the internal transcribed spacers (ITS) and the 5.8S
      coding region of the nuclear ribosomal DNA repeat were obtained for 44
      individuals, including 25 species, intraspecific samples, and three outgroups.
      Separate parsimony analyses of each data set showed that individual gene trees
      were congruent and often complementary in supporting clades that generally
      corresponded to previously recognized taxonomic groups. Only one instance of
      strongly supported gene tree incongruence was detected and this anomalous pattern
      was explained best by ancient introgression of cpDNA across sectional boundaries.
      Simultaneous parsimony analysis of the pruned data sets supported the recognition
      of the strictly Eurasian section Cerris and resolved a novel hypothesis for the
      major infrageneric groups (Cerris- (Lobatae- (Protobalanus + Quercus sensu
      stricto))). The biogeographic hypothesis that all major oak lineages evolved
      locally at middle latitudes within the general distribution of their fossil
      ancestors was fully supported. This set of relationships also suggested a New
      World origin for the widespread white oaks of the Northern Hemisphere (section
      Quercus s. s.). For both data sets, inter- and intraspecific sampling within
      section Protobalanus showed little correspondence to morphological species.
      Greater cladistic structure among the samples was obtained by cpDNA restriction
      sites and two well-delimited plastomes types comprising a total of 15 distinct
      haplotypes were resolved. Haplotypes of 2 of the peripheral species in this
      species complex occupy terminal portions of one of the plastome clades,
      suggesting a more recent origin relative to those of more widespread species. The
      phylogeography of the two divergent plastome types suggested a north-south
      pattern, consistent with a Late Tertiary disjunction in the ancestral
      distribution of section Protobalanus.

PMID- 10413626
TI  - Vicariant patterns of fragmentation among gekkonid lizards of the genus
      Teratoscincus produced by the Indian collision: A molecular phylogenetic
      perspective and an area cladogram for Central Asia.
AB  - A well-supported phylogenetic hypothesis is presented for gekkonid lizards of the
      genus Teratoscincus. Phylogenetic relationships of four of the five species are
      investigated using 1733 aligned bases of mitochondrial DNA sequence from the
      genes encoding ND1 (subunit one of NADH dehydrogenase), tRNA(Ile), tRNA(Gln),
      tRNA(Met), ND2, tRNA(Trp), tRNA(Ala), tRNA(Asn), tRNA(Cys), tRNA(Tyr), and COI
      (subunit I of cytochrome c oxidase). A single most parsimonious tree depicts T.
      przewalskii and T. roborowskii as a monophyletic group, with T. scincus as their
      sister taxon and T. microlepis as the sister taxon to the clade containing the
      first three species. The aligned sequences contain 341 phylogenetically
      informative characters. Each node is supported by a bootstrap value of 100% and
      the shortest suboptimal tree requires 29 additional steps. Allozymic variation is
      presented for proteins encoded by 19 loci but these data are largely
      uninformative phylogenetically. Teratoscincus species occur on tectonic plates of
      Gondwanan origin that were compressed by the impinging Indian Subcontinent,
      resulting in massive montane uplifting along plate boundaries. Taxa occurring in
      China (Tarim Block) form a monophyletic group showing vicariant separation from
      taxa in former Soviet Central Asia and northern Afghanistan (Farah Block);
      alternative biogeographic hypotheses are statistically rejected. This vicariant
      event involved the rise of the Tien Shan-Pamir and is well dated to 10 million
      years before present. Using this date for separation of taxa occurring on
      opposite sides of the Tien Shan-Pamir, an evolutionary rate of 0.57% divergence
      per lineage per million years is calculated. This rate is similar to estimates
      derived from fish, bufonid frogs, and agamid lizards for the same region of the
      mitochondrial genome ( approximately 0.65% divergence per lineage per million
      years). Evolutionary divergence of the mitochondrial genome has a surprisingly
      stable rate across vertebrates.

PMID- 10413628
TI  - Higher level relationships of leeches (Annelida: Clitellata: Euhirudinea) based
      on morphology and gene sequences.
AB  - The evolutionary patterns of divergence of seven euhirudinean families were
      investigated by cladistic analysis of 33 euhirudinean species. Oligochaetes,
      Acanthobdella peledina, and branchiobdellidans were included as outgroup taxa.
      Cladistic analysis employed 1.8 kb of nuclear 18S ribosomal DNA and 651 bp of
      mitochondrial cytochrome c oxidase subunit I in addition to morphological data.
      The use of two molecular data sets, one nuclear gene and one mitochondrial gene,
      as well as morphological data combined historical information evolving under a
      variety of different constraints and therefore was less susceptible to the biases
      that could confound the use of only one type of data. Results suggest that the
      nuclear 18S rDNA gene yields a meaningful historical signal for determining
      higher level relationships. The more rapidly evolving CO-I gene was informative
      for recent or local areas of the evolutionary hypothesis, such as within-family
      relationships. Analyses combining all data from the three character sets yielded
      one most-parsimonious tree. Most of the higher taxa in recent leech systematics
      were well corroborated in the resulting topology. However, these results
      suggested paraphyly of the order Rhynchobdellida, which contradicts the presence
      of a proboscis as a synapomorphy. The medicinal leech family Hirudinidae was
      polyphyletic because Haemadipsidae and Haemopidae each have a hirudinid ancestor.
      In addition, all but one of the genera within the family Erpobdellidae must be
      either abandoned or renamed. Unusual findings included compelling evidence of
      historical plasticity in bloodfeeding behavior, having been lost at least four
      times in the course of euhirudinean evolution. Biogeographic patterns supported a
      New World origin for Arhynchobdellida.

PMID- 10413629
TI  - Polyphyly and convergent morphological evolution in Commelinales and
      Commelinidae: evidence from rbcL sequence data.
AB  - Phylogenetic relationships of the five families of the order Commelinales remain
      an area of deep uncertainty in higher-level monocot systematics, despite
      intensive morphological and anatomical study. To test the monophyly of the
      Commelinales and the subclass Commelinidae, evaluate their relationships, and
      analyze evolutionary trends in their morphology, ecology, and biogeography, we
      conducted parsimony analyses on 95 rbcL sequences representing 17 taxa of
      Commelinales, 16 taxa of other Commelinidae, and 63 taxa from Arecidae, Liliidae,
      and Zingiberidae. Commelinales is polyphyletic and Commelinidae paraphyletic,
      with Eriocaulaceae and Xyridaceae sister to Poaceae and its relatives,
      Rapateaceae sister to Bromeliaceae and Mayacaceae, and Commelinaceae sister to
      Philydrales and allies. Thurnia is sister to Prionium at the base of Cyperaceae
      Juncaceae; only 1 of Cronquist's multifamily commelinoid orders is diagnosed as
      monophyletic. We propose a revised Commelinidae, incorporating 4 revised
      superorders (Bromelianae, Commelinanae, Dasypogonanae, Arecanae) and 10 orders
      ((Poales, Eriocaulales, Cyperales, Typhales, Bromeliales), (Commelinales,
      Philydrales, Zingiberales), (Dasypogonales), (Arecales)). Morphological and
      anatomical characters used to define the original Commelinales and Commelinidae
      appear to be plesiomorphic or to reflect convergence or recurrent mutation;
      several characters supporting our revised classification are anatomical traits
      that seem relatively insulated from environmental selection pressures. The
      Commelinidae distal to the Arecales arose in South America, with amphiatlantic
      Bromeliaceae-Mayacaceae-Rapateaceae originating in the Guayana Shield. Ecological
      diversification involved the repeated invasion of shady, infertile, or arid
      microsites. The numbers of species in families of the revised Commelinidae are
      related partly to the extent of adaptive radiation in those families, but seem
      more strongly related to nonadaptive features promoting speciation, such as
      restricted seed dispersal (especially in forest interior groups with fleshy
      fruits), polyploidy, aneuploidy, and apomixis. Species diversity is unrelated to
      the rate/amount of rbcL sequence evolution.

PMID- 10413630
TI  - Carotid endarterectomy for recently symptomatic carotid stenosis: consistent
      results from two large randomized controlled trials.

PMID- 10413631
TI  - Synthetic direct thrombin inhibitors in unstable angina - more questions than
      answers.

PMID- 10413632
TI  - The use of free and fixed drug combinations to improve hypertension control in
      our populations.

PMID- 10413633
TI  - Distribution of spectral energy on the body surface: a physiological road map to
      improve identification of patients vulnerable to sustained ventricular
      arrhythmias.

PMID- 10413634
TI  - The incidence and epidemiology of myocarditis.

PMID- 10413635
TI  - Coronary surgery, ethnic origin, and value in health care.

PMID- 10413636
TI  - Living anatomy of the atrioventricular junctions. A guide to electrophysiological
      mapping. A Consensus Statement from the Cardiac Nomenclature Study Group, Working
      Group of Arrythmias, European Society of Cardiology, and the Task Force on
      Cardiac Nomenclature from NASPE. North American Society of Pacing and
      Electrophysiology.
AB  - Current nomenclature for atrioventricular junctions derives from a surgically
      distorted view, placing the valvar rings and the triangle of Koch in a single
      plane with antero-posterior and right-left lateral coordinates. Within this
      convention, the aorta is considered to occupy an anterior position, while the
      mouth of the coronary sinus is shown as being posterior. While this nomenclature
      has served its purpose for the description and treatment of arrhythmias dependent
      on accessory pathways and atrioventricular nodal re-entry, it is less than
      satisfactory for the description of atrial and ventricular mapping. To correct
      these deficiencies, a consensus document has been prepared by experts from the
      Working Group of Arrhythmias of the European Society of Cardiology, and the North
      American Society of Pacing and Electrophysiology. It proposes a new, anatomically
      sound, nomenclature that will be applicable to all chambers of the heart. In this
      report, we discuss its value as regards the description of the atrioventricular
      junctions, establishing the principles of this new nomenclature.

PMID- 10413637
TI  - The Denolin Lecture 1998. Towards measurement of coronary blood flow in patients
      and its alteration by interventions.
AB  - AIM: Several methods of measuring coronary blood flow in intact conscious man are
      reviewed, on the basis of personal contributions or the experiences of our teams.
      METHODS AND RESULTS: It is important to distinguish between global, regional and
      transmural blood flow measurements. The advantages and limitations of the
      following methods are discussed: diffusible inert and radioactive tracers, dye
      dilution, roentgendensitometry, magnetic resonance imaging and contrast
      echocardiography. In interventional cardiology it is most important to be able to
      measure flow through single coronary vessels. Information on coronary artery
      Doppler velocity during vasodilation and at rest is less useful than the concept
      of fractional flow reserve. This is based on pressure measurements under maximal
      vasodilation to ascertain the presence of borderline flow-limiting lesions. This
      information is necessary in order to decide whether to proceed with angioplasty
      or not. CONCLUSIONS: The historical design of percutaneous coronary angioplasty
      and beta-irradiation of coronary restenosis, established under the author's
      guidance, are put into perspective. The author pays tribute to many excellent
      colleagues who worked with him at the Zurich and Geneva University Hospitals.

PMID- 10413638
TI  - Factors associated with failure of medical therapy in patients with unstable
      angina and non-Q wave myocardial infarction. A TIMI-IIIB database study.
AB  - CONTEXT: Current management of patients with unstable angina and non-Q wave
      myocardial infarction generally consists of intensive medical therapy, with
      angiography and revascularization sometimes limited to those who fail such
      therapy. AIM: To determine if certain baseline characteristics are predictive of
      patients who fail medical therapy, since such patients could then be
      expeditiously directed to a more invasive strategy in a cost-effective manner.
      METHODS: The study cohort consisted of the 733 patients in the Thrombolysis in
      Myocardial Ischemia (TIMI) IIIB study who were randomized to conservative
      strategy. Patients were to be treated with bedrest, anti-ischaemic medications,
      aspirin, and heparin, and were to undergo risk-stratifying tests, consisting of
      an exercise test with ECG and thallium scintigraphy, scheduled to be performed
      within 3 days prior to, or 5 days after, hospital discharge and 24 h Holter
      monitoring scheduled to begin 2-5 days after randomization. Baseline clinical and
      ECG characteristics were compared between patients who 'failed' medical therapy
      and those who did not 'fail'. Failure was defined using clinical end-points
      (death, myocardial infarction, or spontaneous ischaemia by 6 weeks after
      randomization) or a strongly positive risk-stratifying test. For each test an
      ordered failure profile of results was calculated and consisted of death,
      myocardial infarction, or rest ischaemia occurring prior to performance of the
      test, a markedly abnormal test result, and no abnormality. RESULTS: Clinical end
      points occurred in 241 (33%) patients and were more likely to occur in patients
      who at presentation were older, had ST-segment depression on the qualifying ECG,
      or were being treated with heparin or aspirin. Characteristics independently
      predictive of developing a clinical event or an abnormal exercise treadmill test
      included: ST-segment depression on the qualifying ECG, history of prior angina,
      family history of premature coronary disease (i.e. onset <55 years of age), prior
      use of heparin or aspirin, and increasing age. By combining these baseline risk
      characteristics for each outcome the incidence of developing a clinical event
      ranged from 8% if none was present to 63% if all six were present, and of
      developing a markedly abnormal risk stratifying test from 8-21% if none were
      present to approximately 90% if all six were present. CONCLUSIONS: Baseline
      characteristics associated with developing a clinical event or a markedly
      abnormal risk stratifying test were similar: rest anginal episode accompanied by
      ST-segment depression and occurring despite treatment with aspirin and heparin, a
      history of angina, older age, and family history of coronary disease. Patients
      with these characteristics are appropriate candidates for expeditious cardiac
      catheterization and consideration for revascularization, while patients without
      them may be suitable for medical management alone.

PMID- 10413639
TI  - Comparison of primary coronary artery bypass surgery in a British Indo-Asian and
      white Caucasian population.
AB  - AIM: To compare the clinical characteristics, at the time of admission and after
      coronary revascularization by bypass surgery, among British patients of Indo
      Asian and white Caucasian descent. METHOD: One hundred and ninety-four pairs of
      patients admitted between November 1994 and January 1997 were matched for age
      (within 3 years), sex and date of admission (within 3 months). Their clinical
      characteristics at the time of admission for coronary artery bypass grafting
      surgery, and the incidence of hospital morbidity, hospital mortality and length
      of stay in the intensive therapy unit or hospital following coronary artery
      bypass grafting were determined. RESULTS: A higher proportion of Indo-Asian
      patients underwent coronary revascularization on a non-elective basis (43% vs 32%
      white Caucasian patients, P =0.018), had a higher prevalence of diabetes (39% vs
      12%, P =0.0001), a lower prevalence of smoking (36% vs 80%, P =0.0001) and a
      lower rate of previous myocardial infarction (47% vs 62%, P =0.012). As regards
      revascularization, although there was no significant difference in the number of
      vessels revascularized, there was a lower use of the arterial conduit (internal
      mammary artery) in the Indo-Asian patients (72% vs 81%, P =0.028) particularly
      for those undergoing emergency/urgent surgery (59% vs 72%, P =0.001) and with a
      previous myocardial infarction (65% vs 81%;P =0.01) when compared with their
      white Caucasian counterparts. Following surgery there were no differences in the
      types of support required for vital functions. There was no significant
      difference in the proportion of major post-operative complications, that is,
      haemorrhage, cerebrovascular accident, renal failure requiring dialysis or
      respiratory failure. Similarly, there were no differences in the length of
      intensive therapy unit stay (median stay 1 day vs 1 day, P =0.4) and hospital
      stay following surgery (median stay 6 days vs 6 days, P =0.5) between the two
      groups. Although there was a trend towards a higher in-hospital (30 day)
      mortality (6.7% [95% confidence intervals CI 3.18-10.21] vs 2.6% [CI 0.35-4.9;P
      =0.0618]), in Indo-Asians compared to white Caucasians this trend disappeared
      when patients in the two groups undergoing non-elective surgery only were
      compared (9% vs 7%;P =0.7). CONCLUSIONS: A higher proportion of Indo-Asians
      underwent non-elective coronary revascularization, with a significantly lower use
      of the arterial conduit and a relatively higher in-hospital mortality. Following
      coronary revascularization the medical management, length of stay and hospital
      morbidity in Indo-Asian patients was no different from that of their white
      Caucasian counterparts. This is despite a perceived poorer outcome in Indo-Asians
      compared to white Caucasians.

PMID- 10413640
TI  - Anticoagulant properties, clinical efficacy and safety of efegatran, a direct
      thrombin inhibitor, in patients with unstable angina.
AB  - AIMS: Thrombin plays a key role in the clinical syndrome of unstable angina. We
      investigated the safety and efficacy of five dose levels of efegatran sulphate, a
      direct thrombin inhibitor, compared to heparin in patients with unstable angina.
      METHODS: Four hundred and thirty-two patients with unstable angina were enrolled.
      Five dose levels of efegatran were studied sequentially, ranging from 0.105 mg.
      kg(-1). h(-1)to 1.2 mg. kg(-1). h(-1)over 48 h. Safety was assessed clinically,
      with reference to bleeding and by measuring clinical laboratory parameters.
      Efficacy was assessed by the number of patients experiencing any episode of
      recurrent ischaemia as measured by computer-assisted continuous ECG ischaemia
      monitoring. Clinical end-points were: episodes of recurrent angina, myocardial
      infarction, coronary intervention (PTCA or CABG), and death. RESULTS: Efegatran
      demonstrated dose dependent ex-vivo anticoagulant activity with the highest dose
      level of 1.2 mg. kg(-1). h(-1)resulting in steady state mean activated partial
      thromboplastin time values of approximately three times baseline. Thrombin time
      was also increased. Neither of the efegatran doses studied were able to suppress
      myocardial ischaemia during continuous ECG ischaemia monitoring to a greater
      extent than that seen with heparin. There were no statistically significant
      differences in clinical outcome or major bleeding between the efegatran and
      heparin groups. Minor bleeding and thrombophlebitis occurred more frequently in
      the efegatran treated patients. CONCLUSION: Administration of efegatran sulphate
      at levels of at least 0.63 mg. kg(-1). h(-1)provided an anti-thrombotic effect
      which is at least comparable to an activated partial thromboplastin time adjusted
      heparin infusion. There was no excess of major bleeding. The level of thrombin
      inhibition by efegatran, as measured by activated partial thromboplastin time,
      appeared to be more stable than with heparin. Thus, like other thrombin
      inhibitors, efegatran sulphate is easier to administer than heparin. However, no
      clinical benefits of efegatran over heparin were apparent.

PMID- 10413641
TI  - Minimal myocardial damage during coronary intervention is associated with
      impaired outcome.
AB  - AIMS: Studies on the glycoprotein IIb-IIIa receptor blocker abciximab in patients
      undergoing percutaneous coronary intervention consistently show a reduction in
      procedure-related myocardial infarction. Some such infarcts are characterized by
      elevated creatine kinase or creatine kinase-MB, without apparent clinical
      symptoms. The clinical relevance of such 'creatine kinase leaks' has been
      questioned. Therefore we investigated the relationship between post-procedural
      creatine kinase-MB elevation and outcome at the 6 month follow-up. METHODS AND
      RESULTS: Creatine kinase-MB, or total creatine kinase values were analysed in
      5025 out of 6156 patients enrolled in the CAPTURE, EPIC and EPILOG studies. A
      consistent gradual increase in 6 month mortality was observed as creatine kinase
      MB or creatine kinase levels increased: 1.1%, 2.1%, 1.8%, 3. 6% and 6.7% for
      creatine-MB or creatine ratios (relative to upper limit of normal) <1, 1-3, 3-5,
      5-10 and >/=10, respectively. Also the incidence of death or (recurrent)
      myocardial infarction was related to creatine kinase-MB or creatine kinase
      ratios. Subsequent revascularization was not related to periprocedural myocardial
      infarction. By multivariable analysis, correcting for clinical and angiographic
      characteristics, mortality at 6 months was related to the enzyme (creatine
      kinase, creatine kinase-MB) ratio, a history of heart failure and age. The
      combined end-point of death and myocardial infarction was also related to these
      factors, as well as to a history of bypass surgery and unstable angina.
      CONCLUSION: Modest elevation of cardiac enzymes (creatine kinase-MB, creatine
      kinase) after percutaneous coronary intervention is associated with an increased
      risk of mortality and reinfarction during the 6 month follow-up. Measures to
      reduce such periprocedural infarcts are warranted.

PMID- 10413642
TI  - Incidence of three presentations of acute myocarditis in young men in military
      service. A 20-year experience.
AB  - AIMS: The incidence of myocarditis is uncertain as diagnostic criteria have been
      vague. We evaluated the incidence of myocarditis presenting in three well defined
      forms (mimicking myocardial infarction, presenting as dilated cardiomyopathy, and
      as a cause of sudden death) in young men in military service over a 20-year
      period. METHODS AND RESULTS: The study population consisted of 672 672 Finnish
      men at a mean age of 20 years conscripted from 1977-1996. All those suspected of
      having myocardial disease were studied prospectively in the same institution. A
      clinical diagnosis of myocarditis mimicking myocardial infarction required ECG
      signs (ST-segment elevation followed by T-wave inversion) and a simultaneous
      detection of serum markers of acute myocardial injury (CK-MB and/or troponin T)
      in an infectious patient with chest pain. This form of myocarditis was diagnosed
      in 98 men, the incidence being 0.17 (95% CI 0.14-0.21). 1000 man-years(-1).
      Causative microbes were those commonly infecting the conscripts, but
      Coxsackievirus aetiology could be confirmed in only 4% of the cases. Nine
      patients presented with dilated cardiomyopathy of recent origin (incidence 0.02.
      1000 man-years(-1)). None had histopathological evidence of myocarditis.
      Myocarditis caused one of the 10 sudden unexpected deaths (incidence 0.002. 1000
      man-years(-1)). CONCLUSIONS: The usual presentation of acute myocarditis in young
      men mimicks alterations evoked by myocardial infarction but not those of dilated
      cardiomyopathy.

PMID- 10413643
TI  - Low-frequency component of body surface potential maps identifies patients at
      risk for ventricular tachycardia.
AB  - AIMS: To investigate the ability of spectral features of signal-averaged body
      surface potential maps in identifying post-infarction patients who are at risk of
      developing ventricular tachycardia. METHODS AND RESULTS: We recorded 120 lead
      body surface potential maps during sinus rhythm in 135 subjects (45 patients with
      healed myocardial infarction but no history of ventricular tachycardia, 45
      patients with both healed myocardial infarction and at least one episode of
      sustained ventricular tachycardia, and 45 normal subjects) and analysed spectral
      features of body surface potential maps selected on the basis of isoharmonic maps
      for given bands of the frequency spectrum. We found that in the low-frequency
      band (1-11 Hertz), the group-mean power spectra of leads located at isoharmonic
      map maxima were significantly different (P<0.0001) between the two groups of
      myocardial infarction patients. We estimated that this single feature alone can
      prospectively identify myocardial infarction patients at risk for ventricular
      tachycardia with a predictive accuracy of 74+/-6%. CONCLUSION: Our results
      suggest that the bulk of diagnostic information associated with arrhythmogenicity
      resides in the low-frequency band of the power spectrum. This finding is at
      variance with the established notion that only the high-frequency component of
      signal-averaged electrocardiograms carries such information.

PMID- 10413644
TI  - Heart rate variability and prognosis in coronary artery disease.

PMID- 10413645
TI  - A reply to: heart rate variability and prognosis in coronary artery disease 

PMID- 10413646
TI  - Telomeres, telomerase, and lymphocyte replicative life span.

PMID- 10413647
TI  - HIV infection and the dynamic interplay between the thymus and the peripheral T
      cell pool.

PMID- 10413648
TI  - Anti-sclerotic effect of transforming growth factor-beta antibody in a mouse
      model of bleomycin-induced scleroderma.
AB  - Recent studies have demonstrated the evidence of the crucial role of transforming
      growth factor-beta (TGF-beta) in the pathogenesis of tissue fibrosis; however,
      its precise role has not been fully elucidated. Administration of anti-TGF-beta
      antibody is shown to be effective for inhibiting lung fibrosis induced by
      bleomycin in an experimental animal model. We have recently established a mouse
      model for scleroderma by repeated injections of bleomycin. In this study, we
      examined whether the suppression of TGF-beta leads to the improvement of dermal
      sclerotic lesion by using this model. We induced dermal sclerosis in C3H mice by
      subcutaneous injections of bleomycin (100 microg/ml) for 3 weeks, and separate
      groups of mice were also injected with bleomycin with either anti-TGF-beta
      antibody (10 microg/ml) or control normal rabbit serum for 3 weeks. Thus treated
      skins were harvested and analyzed for histological sclerosis, serum cytokine, and
      influx of mast cells and eosinophils, both of which are known to release
      fibrogenic cytokines or several mediators responsible for tissue fibrosis. The
      result showed that anti-TGF-beta antibody caused a significant reduction in
      cutaneous sclerosis characterized by histological features and hydroxyproline
      contents. Examination of tissue sections also revealed a significant suppression
      of influx of mast cells and eosinophils. Serum interleukin-4 (IL-4) and IL-6
      levels determined by enzyme-linked immunosorbent assay exhibited a significant
      reduction after anti-TGF-beta antibody treatment. Our results suggest that
      administration of an antibody against TGF-beta is useful in preventing
      experimental dermal sclerosis induced by bleomycin and raises a possibility of
      the therapeutic approach of anti-TGF-beta antibody in scleroderma.

PMID- 10413649
TI  - Increases in T cell telomere length in HIV infection after antiretroviral
      combination therapy for HIV-1 infection implicate distinct population dynamics in
      CD4+ and CD8+ T cells.
AB  - Changes in mean telomeric terminal restriction fragment (TRF) length were
      examined as a marker for cellular replicative history in HIV-1-infected
      individuals after institution of anti-retroviral therapy (ART). Increases in mean
      T cell TRF lengths were observed in most patients following therapy; however, the
      contribution of individual T cell subsets was complex. An elongation of CD8+ T
      cell TRF was nearly uniformly observed while changes in mean TRF length in CD4+ T
      cells were heterogeneous as, despite potent suppression of viral replication, CD4
      cell telomeres recovered in some patients, yet continued to decline in others.
      Increases in CD8 cell TRF correlated with decreased memory cells, suggesting a
      negative selection in the periphery for CD8 cells with extensive replicative
      history. In contrast, increases in CD4+ T cell TRF length correlated with
      increases in naive cell subsets, suggesting that the CD4+ T cell TRF increase may
      reflect a thymic contribution in some patients. These are the first increases in
      somatic cell telomere length in a population of cells observed in vivo, and the
      findings are compatible with therapy-induced reconstitution of the lymphoid
      compartment with cells having a more extensive replicative potential. These
      findings further distinguish lymphocytes from other somatic cell populations
      where only decreases in TRF over time have been noted. Thus, institution of ART
      in persons with moderately advanced HIV-1 disease reveals distinct population
      dynamics of CD4 and CD8 T cell subsets and also shows that the lymphocyte
      replicative history is dynamic.

PMID- 10413650
TI  - Primary HIV infection of infants: the effects of somatic growth on lymphocyte and
      virus dynamics.
AB  - Acute HIV infection is characterized by the appearance of high concentrations of
      virus in the peripheral blood. In adults, this high-level viremia spontaneously
      abates after several weeks. In contrast, after perinatal infection of infants,
      blood virus levels remain high for many months, during which the concentration of
      circulating CD4+ lymphocytes remains well above normal values for adults. Here we
      suggest an explanation for these differences, based on developmental factors
      including somatic growth and immunological ontogeny. Flow cytometric analysis
      revealed that at birth the thymus contains elevated levels of mature T
      lymphocytes, compared to the thymus after 3 months of age. A mathematical model
      is proposed incorporating immunological and virological data from longitudinally
      evaluated infants who acquired infection at the time of birth. This model
      explains the pattern of high-level viremia in infants as resulting from the
      replication of HIV within the progressively expanding lymphoid cell mass.

PMID- 10413651
TI  - Common variable immunodeficiency: clinical and immunological features of 248
      patients.
AB  - Common variable immunodeficiency (CVI) is a primary immunodeficiency disease
      characterized by reduced serum immunoglobulins and heterogeneous clinical
      features. In these studies we describe the clinical and immunological status of
      248 consecutively referred CVI patients of age range 3-79 years who have been
      followed for a period of 1-25 years. The median age at the time of onset of
      symptoms was 23 years for males and 28 years for females; the mean age at which
      the diagnosis of CVI was made was 29 years for males and 33 years for females.
      Forty percent of patients had impaired T cell proliferation to one or more
      mitogens; lymphocyte transformation to mitogens was directly related to the level
      of the serum IgG. Females at all ages had higher levels of serum IgM than males.
      Survival 20 years after diagnosis of CVI was 64% for males and 67% for females,
      compared to the expected 92% population survival for males and 94% for females.
      Parameters associated with mortality in this period were lower levels of serum
      IgG, poorer T cell responses to phytohemagglutinin, and, particularly, a lower
      percentage of peripheral B cells (P < 0.006).

PMID- 10413652
TI  - Interferon-gamma therapy reduces blood leukocyte levels in patients with atopic
      dermatitis: correlation with clinical improvement.
AB  - Atopic dermatitis (AD) is a chronic inflammatory skin disease with abnormalities
      of both cellular and humoral immunity. Subcutaneous recombinant human interferon
      gamma (IFN-gamma) provides therapeutic benefit to AD patients. In contrast to
      expectations, IFN-gamma does not cause a decrease in the elevated levels of
      circulating IgE levels in AD patients. We sought to determine cellular targets of
      IFN-gamma treatment that might explain its clinical benefit. Therefore, we
      evaluated blood leukocyte subsets by multiparameter flow cytometry in AD patients
      receiving IFN-gamma (n = 10) or placebo (n = 11) therapy compared to untreated
      normal volunteers (n = 14). Treated patients demonstrated reductions in WBC,
      eosinophil, and lymphocyte counts. Compared to normals, there was a reduced
      CD4/CD8 ratio in AD patients among activated, large mononuclear cells that was
      partially corrected with IFN-gamma treatment. Clinical improvement correlated
      with reductions in WBC (r = 0.9, P = 0.0003), eosinophil (r = 0.7, P = 0.035) and
      lymphocyte (r = 0.8, P = 0.013) counts, and with normalization of the CD4/CD8
      ratio among large lymphocytes (r = 0.9, P = 0.04). The data indicate two
      potential modes of action for INF-gamma in AD. One mechanism represents
      normalization of selected immunologic abnormalities in AD; a second mechanism may
      be the modest reduction of circulating inflammatory cells. Adequacy of IFN-gamma
      therapy of AD may depend on bringing about these changes.

PMID- 10413653
TI  - Chagas' disease encephalitis: intense CD8+ lymphocytic infiltrate is restricted
      to the acute phase, but is not related to the presence of Trypanosoma cruzi
      antigens.
AB  - Central nervous system (CNS) damage can occur during Chagas' disease, especially
      in children and immunosuppressed patients. During the acute phase, amastigotes
      are rarely found, but inflammatory infiltrates are scattered throughout the CNS.
      Moreover, peripheral lymphocytes and antibodies recognizing neural components
      were described, suggesting the participation of the immune system in the genesis
      of neural lesions. Herein, we performed a histopathological study of Colombian
      infected C3H/He mice, comparing the distribution of CNS-inflammatory infiltrates
      versus Trypanosoma cruzi antigens. Inflammatory infiltrates were observed during
      the acute phase, but did not correlate with the presence of detectable T. cruzi
      antigens. Infiltrates consisted mainly of CD8+ lymphocytes, although macrophages
      and a few CD4+ cells were observed. In the chronic stage of infection, although
      neuropathies were a common finding, only mild inflammatory infiltrates could be
      detected. Our results suggest that the presence of CNS inflammatory infiltrates
      is not directly related to the presence of parasite antigens and indicate that,
      different from chronic myocarditis, encephalitis resolves during the acute phase
      of Chagas' disease.

PMID- 10413654
TI  - Induction of immunity to antigens expressed by recombinant adeno-associated virus
      depends on the route of administration.
AB  - Recombinant adeno-associated virus (rAAV) is a replication-defective parvovirus
      which is being explored as a vector for gene therapy because of its broad host
      range, excellent safety profile, and durable transgene expression in infected
      hosts. rAAV has also been reported by several groups to induce little or no
      immune response to its encoded transgene products. In this study we examined the
      immunogenicity of rAAV by studying the immune response of C57BL/6 mice to a
      single dose of rAAV-encoding ovalbumin (AAV-Ova) administered by a variety of
      routes. Mice injected with AAV-Ova intraperitoneally (ip), intravenously, or
      subcutaneously developed potent ovalbumin-specific cytotoxic T lymphocytes (CTL)
      as well as anti-ovalbumin antibodies and antibodies to AAV. In contrast, mice
      injected with AAV-Ova intramuscularly developed a humoral response to the virus
      and the transgene but minimal ovalbumin-specific CTLs. The induced CTL response
      after ip administration of AAV-Ova protected mice against a subsequent tumor
      challenge with an ovalbumin-transfected B16 melanoma cell line. Studies of the
      mechanism by which AAV-Ova induces CTL confirmed that the virus delivers the
      transgene product into the classical MHC class I pathway of antigen processing.
      Mice that previously had been exposed to rAAV vectors failed to develop ovalbumin
      specific CTL following administration of AAV-Ova. Analysis of these mice revealed
      the presence of circulating anti-AAV antibodies that blocked rAAV transduction in
      vitro and inhibited CTL induction in vivo. These results suggest a possible role
      for rAAV in the immunotherapy of malignancies and viral infections, although
      induced antibody responses to AAV may limit its ability to be administered for
      repeated vaccinations.

PMID- 10413655
TI  - Attenuated deltaguaBA Salmonella typhi vaccine strain CVD 915 as a live vector
      utilizing prokaryotic or eukaryotic expression systems to deliver foreign
      antigens and elicit immune responses.
AB  - Attenuated Salmonella typhi strain CVD 915, harboring a deletion in guaBA that
      interrupts the biosynthesis of guanine nucleotides, was evaluated as a live
      vector vaccine for delivering foreign antigens utilizing prokaryotic or
      eukaryotic expression systems. Plasmids pTETnir15 and pcDNA3tetC encoding
      fragment C (Frag C) of tetanus toxin under the control of prokaryotic or
      eukaryotic promoters, respectively, were introduced into CVD 915 and administered
      intranasally to mice. Purified pcDNA3tetC and Frag C were given intramuscularly.
      High titers of serum IgG1, IgG2a, and IgG2b antibodies against Frag C were
      elicited by CVD 915(pTETnir15) and CVD 915(pcDNA3tetC). These responses were
      significantly higher than those induced by pcDNA3tetC. Proliferative responses
      and IL-2 and IFN-gamma production were observed in splenocytes exposed to S.
      typhi antigens and Frag C. We conclude that CVD 915 is a highly efficient live
      vector to carry foreign genes under eukaryotic or prokaryotic control and elicit
      potent immune responses.

PMID- 10413656
TI  - Immunization of RANTES expression plasmid with a DNA vaccine enhances HIV-1
      specific immunity.
AB  - Cytokines play important roles in regulating immune response. This study
      evaluated the adjuvant effect of an expression plasmid encoding RANTES (regulated
      on activation normal T-cell expressed and secreted) chemokine on the immunity
      induced by a DNA vaccine. This vaccine consists of expression plasmids encoding
      the env and rev genes of human immunodeficiency virus type 1 (HIV-1). DNA
      vaccination with RANTES plasmid induced significantly higher titers of serum HIV
      1-specific IgG and IgG2a antibodies than DNA vaccination alone on both
      intramuscular and intranasal immunization. This combination also increased HIV-1
      specific cytotoxic T lymphocyte activity and delayed-type hypersensitivity.
      Intranasal immunization induced a higher titer of fecal secretory IgA antibody
      than intramuscular immunization. These results demonstrate that coadministration
      of RANTES plasmid dominantly induced HIV-1-specific cell-mediated immunity.

PMID- 10413657
TI  - The role of sialidase in the development of hypocomplementemia in postinfectious
      acute glomerulonephritis.
AB  - The role of sialidase in complement activation and in development of
      hypocomplementemia in patients with postinfectious acute glomerulonephritis (AGN)
      was investigated. In sera from 17 patients with AGN and 14 healthy controls,
      sialidase activity and serum levels of free and total sialic acid were measured
      by previously established methods. Circulating sialidase activity and serum
      levels of free and total sialic acid and haptoglobin were increased, and the C3
      level was decreased in the acute phase of AGN. There was no correlation between
      free sialic acid and total sialic acid, which increased in parallel with serum
      levels of haptoglobin, one of the acute-phase reactants. A follow-up study of
      these parameters in a typical case reflected this tendency and suggested that
      increased sialidase after infection, in addition to complement activation by the
      infectious substance, could play a role in development of hypocomplementemia. To
      clarify this mechanism, purified neuraminidase was incubated with normal human
      serum under various conditions. Complement breakdown products were measured in
      the incubation mixture by enzyme-linked immunosorbent assay using monoclonal
      antibodies against iC3b, Bb, and C4d neoantigens. iC3b was generated dose
      dependently in the presence of neuraminidase. Further examination revealed that
      iC3b and Bb were generated in the incubation mixture with neuraminidase and NHS
      and that C4d was not detected in the same mixture. These findings indicate that
      neuraminidase activates the alternative complement pathway. These in vitro data,
      together with the former in vivo data led us to conclude that increased sialidase
      after infection could accelerate the complement amplification system, resulting
      in hypocomplementemia in the acute phase of postinfectious AGN.

PMID- 10413658
TI  - Acetyl-L-carnitine administration increases insulin-like growth factor 1 levels
      in asymptomatic HIV-1-infected subjects: correlation with its suppressive effect
      on lymphocyte apoptosis and ceramide generation.
AB  - The aim of this study was to investigate the impact of long-term acetyl-L
      carnitine administration on CD4 and CD8 absolute counts, apoptosis, and insulin
      like growth factor-1 (IGF-1) serum levels in HIV-1-infected subjects. The
      generation of cell-associated ceramide and HIV-1 viremia were also investigated.
      Eleven asymptomatic, HIV-1-infected subjects were treated daily with acetyl-L
      carnitine (3 g) for 5 months. Immunologic and virologic measures and safety were
      monitored at the start of the treatment and then on days 90 and 150. Altogether
      our findings suggest that acetyl-L-carnitine administration has a substantial
      impact on the main immunologic abnormality associated with HIV infection, the
      loss of CD4 cells, by reducing the rate of apoptotic lymphocyte death. The
      reduction of ceramide generation and the increase of the serum levels of IGF-1, a
      major survival factor able to protect cells from apoptosis by different stimuli
      and conditions, could represent two important mechanisms underlying the observed
      anti-apoptotic effects of acetyl-L-carnitine.

PMID- 10413659
TI  - Enhanced IFN-gamma production in vitro by CD8+ T cells in hemophiliacs with AIDS
      as demonstrated on the single-cell level.
AB  - We examined T cells from HIV-infected hemophiliacs under antiviral therapy, on
      the single-cell level, for cytokine production in vitro in response to
      stimulation. The percentage of IL-2-producing cells was markedly decreased among
      both CD3+CD8- and CD3+CD8+ cells, while the proportion of IFN-gamma-producing
      cells was preserved among CD3+CD8- cells and increased among CD3+CD8+ cells in
      HIV+ subjects, compared with HIV-uninfected controls. The increase in IFN-gamma
      producing CD8+ cells was accounted for by the expansion of CD8+CD28- cells among
      total CD8+ T cells and by the higher percentage of IFN-gamma-expressing cells
      among both CD8+CD28+ and CD8+CD28- cells in HIV+ individuals, compared with
      controls. The enhanced IFN-gamma production in CD8+ cells from individuals in the
      advanced phase of HIV infection might implicate the host's response to chronic
      viral infection or senescence of host CD8+ cells.

PMID- 10413661
TI  - The first detection of the insertion sequence ISW1 in the intracellular
      reproductive parasite Wolbachia.
AB  - Wolbachia are maternally inherited intracellular rickettsia-like bacteria known
      to infect a wide range of arthropods. They are associated with a number of
      different reproductive phenotypes in their hosts, such as cytoplasmic
      incompatibility, parthenogenesis, and feminization. We report on a novel
      insertion sequence (IS), ISW1, which was identified in the region downstream of
      groEL of a Wolbachia strain, wTai. The 573-bp-long ISW1 sequence is the first IS
      element observed in this organism, displays significant similarity to IS200, and
      lacks terminal inverted repeats. There were more than 20 copies of ISW1 on the
      chromosome of wTai. Sequence analysis of nine distinct ISW1 copies and their
      flanking regions showed that the copies were identical and suggested that ISW1
      has no preference for its insertion sites. Possible roles of ISW1 in the
      adaptation of Wolbachia to intracellular environments and in various reproductive
      alterations caused by this bacterium are discussed.

PMID- 10413660
TI  - Genetic structure and transcriptional analysis of a mobilizable, antibiotic
      resistance transposon from Bacteroides.
AB  - Tn4555 is a 12.1-kb Bacteroides antibiotic resistance transposon representative
      of a novel class of transmissible genetic elements that can be transferred by
      resident conjugative tetracycline resistance transposons (Tc(r)-elements) but are
      not capable of self-transfer. Previously it was shown that Tn4555 transposes by a
      site-specific recombination mechanism that utilizes a circular intermediate. This
      circular form is induced by tetracycline and it also is the substrate for
      conjugation. To better understand the mechanism of transposition, the entire
      nucleotide sequence of Tn4555 was determined and a set of genes potentially
      involved in transposition was identified. The transposon was 12,105 bp including
      a variable 6-bp coupling sequence associated with one of the transposon termini.
      The element had a 44.3% G + C composition and nine potential protein coding
      regions were observed, eight of which were encoded on the forward strand. Two
      putative transposition genes were found. The int gene product had significant C
      terminal homology to the lambda family of integrases and the xis gene product was
      similar to several excisionase proteins encoded by both plasmids and conjugative
      transposons. The mobA mobilization gene and cfxA beta-lactamase gene of Tn4555
      had been previously identified, and the remaining five open reading frames had no
      significant matches with sequences in the available databases. Northern
      hybridization analysis revealed that all Tn4555 genes except for orf-9 were
      expressed and two sets of genes, tnpA, int and xis, orf-5, orf-6 were organized
      in operons. None of the genes seemed to be induced significantly by the addition
      of tetracycline to cultures. Although a small 0.4-kb xis-specific transcript
      appeared in tetracycline-treated cultures it was not clear if this was due to an
      induction or if it was a specific degradation product.

PMID- 10413662
TI  - Analysis of the replication elements of the pMJ101 plasmid from the fish pathogen
      Vibrio ordalii.
AB  - Vibrio ordalii is a major cause of vibriosis in wild and cultured marine
      salmonids and carries pMJ101, a 30-kb cryptic plasmid that replicates in the
      absence of DNA polymerase I without producing single-stranded intermediates. A
      recombinant derivative harboring the pMJ101 replication region proved to be
      compatible with pJM1, a plasmid containing the iron acquisition system required
      for the virulence of V. anguillarum 775, another important pathogen that causes
      vibriosis. Sequence analysis of a 1.56-kb fragment harboring the pMJ101
      replication region revealed the presence of typical features found in DNA origins
      including an AT-rich region, 11 dam-methylation sites of which 5 are within the
      putative ori region, and five copies of the 9-bp consensus sequence for DnaA
      binding. Gel retardation assays demonstrated that the latter replication element
      indeed binds DnaA purified from Escherichia coli. A potential open reading frame
      encoding a hydrophilic protein with a predicted pI of 10.3 and an M(r) of 33,826
      was found adjacent to the ori region. Although these properties are typical of
      DNA-binding proteins, no significant homology was found between this predicted
      protein, named RepM, and other previously characterized proteins. Reverse
      transcriptase-polymerase chain reaction analysis of total RNA demonstrated the
      presence of repM mRNA in V. ordalii. The major initiation site of this mRNA was
      located 187 nucleotides upstream of the GTG initiation codon as determined by
      nuclease S1 protection assays. This transcription initiation site is preceded by
      putative -10 and -35 promoter sequences that control the expression of the repM
      replication gene. These results demonstrate that the replication region of pMJ101
      shares some structural and sequence similarities with other DNA replication
      regions, which include DnaA binding and methylation sites and an open reading
      frame encoding a distinct protein required for its replication.

PMID- 10413663
TI  - Cloning of erythromycin-resistance determinants and replication origins from
      indigenous plasmids of Lactobacillus reuteri for potential use in construction of
      cloning vectors.
AB  - Lactobacillus reuteri L1 and N16 strains contain a 7.0-kb plasmid (pTE80) and a
      15-kb plasmid (pTE15), respectively, encoding resistance to erythromycin (Em(r)).
      Physical maps of both plasmids were established. Nucleotide sequences of the
      genetic determinants encoding Em(r) on pTE80 and pTE15 revealed the existence of
      a very similar (ca. 99% nucleotide sequence and ca. 98% amino acid sequence
      identity) open reading frame for an Em(r) transmethylase gene (erm) in both
      plasmids. These structural erm genes, 753 and 750 bp in length, respectively,
      were highly related (ca. 98% nucleotide sequence and ca. 97% amino acid sequence
      identity) to the erm gene of L. fermentum plasmid pLEM3. Sequence analysis showed
      that these two erm genes from pTE80 and pTE15 could be categorized under the ermB
      (ermAM) class. These are the first members of the ermB (ermAM) class of Em(r)
      determinant from L. reuteri to be characterized at the nucleotide sequence level.
      The Em(r) gene from pTE80 (erm80) was then ligated into pUC18/19 to construct
      replication origin (RO)-screening vectors pUE80(+) and pUE80(-) (pUE80(+/-)).
      These plasmids contain the pUC18/19-derived multiple cloning site, ampicillin
      resistance trait, and the LacZ' gene, which enable direct screening for
      recombinants in Escherichia coli. Once the recombinant contains a RO from L.
      reuteri, the Em(r) trait of erm80 is used as a selection marker for the
      replication of the chimeric plasmid as it is transformed into L. reuteri using
      the cloned RO as a replicon. Replication regions from pTE80 and pTE15 were
      successfully cloned into the constructed vector pUE80(-). The RO cloned from
      pTE80 was further identified as being highly stable in L. reuteri and also
      bearing a relatively narrow host range compared with that of pTE15. The Em(r)
      determinant (erm80) and RO cloned from pTE80 could be used in the future
      construction of derivatives of cloning vectors for this microbe. Moreover, the
      pUE80(+/-) and pTE80-RO constructed in this study have the potential to be
      developed as a suicide vector and an E. coli-L. reuteri shuttle vector,
      respectively.

PMID- 10413664
TI  - Cloning of insertion sequence IS1485 from Enterococcus species.
AB  - We have cloned and identified an insertion sequence, IS1485, that was present in
      several members of the genus Enterococcus. IS1485 exists in varying copy numbers
      with at least 12 copies in E. durans (ATCC 11576), 3 copies in E. faecium (ATCC
      19434), and one copy each in E. faecalis (ATCC 19433) and E. avium (ATCC 14024).
      It was also detected in clinical strains of E. gallinarum, E. casseliflavus, and
      E. saccharolyticus. IS1485 is 1366 bp in length, it has imperfect terminal
      inverted repeats with 25 of the terminal 39 residues matched, and it contains
      three open reading frames exceeding 50 codons, designated orfA, orfB, and orfC.
      The largest, orfB, was located 36 bp downstream and in the -1 reading frame
      relative to orfA; orfC is oriented in the opposite direction and overlaps orfA.
      The genetic organization of IS1485 resembles that of members of the IS3 family of
      transposable elements. Sequence homology exists with several members of the IS3
      family especially with IS199 from Streptococcus mutans.

PMID- 10413666
TI  - Conditionally lethal genes in the N pilus region of plasmid pCU1.
AB  - Plasmid genes or regions that are conditionally lethal to Escherichia coli have
      been called kil and those lethal to Klebsiella but not to E. coli have been
      called kik. Both classes of genes are found in or close to the N pilus region of
      the plasmid pCU1 and the closely related plasmid pKM101. Here we describe two new
      and overlapping lethal genes that are located between kikA and traA of the
      plasmid pCU1 and display host specificity. KilC is lethal in E. coli and
      Klebsiella while kikC is lethal only in Klebsiella. The previously identified
      korA gene is sufficient to override the lethality of kilC in trans or in cis but
      is insufficient to override kikC. kilC expression in E. coli leads to cell death
      accompanied by an increase in average cell length without affecting septum
      formation.

PMID- 10413665
TI  - Complete nucleotide sequence of a cryptic plasmid from the ruminal bacterium
      Selenomonas ruminantium HD4 and identification of two predicted open reading
      frames.
AB  - A cryptic plasmid (pSR1) isolated from Selenomonas ruminantium HD4 was previously
      cloned into the HindIII site of pBR322 and a restriction map was constructed
      using HindIII, ClaI, BamHI, and PvuII (S. A. Martin and R. G. Dean, Appl.
      Environ. Microbiol. 55(12), 3035-3038, 1989). Analysis of the nucleotide sequence
      of pSR1 revealed two major open reading frames (ORFs) located in the minus strand
      at different frames. Analysis of ORF-1 revealed that it has 325 amino acids with
      a predicted MW of 36,588, and ORF-2 has 379 amino acids with a predicted MW of
      42,651. The ORF-1 amino acids showed 30 to 32% sequence homology to the
      hypothetical protein YtqA in Bacillus subtilis and another hypothetical protein
      in the thermophilic bacterium Aquifex aeolicus. ORF-2 showed limited homology
      (23%) to the hypothetical protein ICFG in the photosynthetic cyanobacteria
      Synechocystis PCC6803.

PMID- 10413667
TI  - Characterization of the Acinetobacter plasmid, pRAY, and the identification of
      regulatory sequences upstream of an aadB gene cassette on this plasmid.
AB  - Primer extension analyses carried out to identify the transcription start site of
      an aadB gene, which is part of a gene cassette recombined at a secondary site on
      an Acinetobacter plasmid, pRAY, suggest that transcription control signals in
      Acinetobacter are similar but not identical to their counterparts in Escherichia
      coli. pRAY was sequenced. An AT-rich region, containing eight copies of the
      consensus sequence, AAAAAATAT, previously shown to be present in the origins of
      replication of other Acinetobacter plasmids, was predicted to be the origin of
      pRAY. The translation product of one of the 10 open reading frames identified on
      pRAY shows homology to the mobilization protein, MbeA.

PMID- 10413668
TI  - Streptococcal reporter gene-fusion vector for identification of in vivo expressed
      genes.
AB  - To study streptococcal genes that are specifically induced in the host during
      endocarditis, we have developed a novel plasmid for use in in vivo expression
      technology (IVET). This IVET uses an integration plasmid, pAK36, that carries
      dual (amy-cat) reporter genes. A gene-fusion strain library was constructed with
      the plasmid randomly inserted into the chromosome of Streptococcus gordonii V288
      by insertion-duplication. The library was inoculated intravenously into a rabbit
      that had been prepared for experimental endocarditis. Beginning 6 h after the
      inoculation, the rabbit was given chloramphenicol (Cm) intravenously twice a day
      to a final serum level of 5 microg/ml and was euthanized 3 days later. The aortic
      valve vegetations containing Cm(R) S. gordonii clones were cultured. Colonies
      were screened in vitro for negative amylase activity and sensitivity to Cm. Forty
      eight such colonies showed 13 different insertion patterns when Southern
      hybridization blots were probed with labeled pAK36. For each of the 13 isolates,
      the gene fragment proximal to the insertion of the reporter amy-cat was cloned,
      and its nucleotide sequence was determined. Functions of these genes were
      inferred by their homology to known genes. Therefore, this novel IVET vector can
      be useful for identification of in vivo induced genes in S. gordonii and other
      streptococcal species.

PMID- 10413669
TI  - Chromatid cohesion during mitosis: lessons from meiosis.
AB  - The equal distribution of chromosomes during mitosis and meiosis is dependent on
      the maintenance of sister chromatid cohesion. In this commentary we review the
      evidence that, during meiosis, the mechanism underlying the cohesion of
      chromatids along their arms is different from that responsible for cohesion in
      the centromere region. We then argue that the chromatids on a mitotic chromosome
      are also tethered along their arms and in the centromere by different mechanisms,
      and that the functional action of these two mechanisms can be temporally
      separated under various conditions. Finally, we demonstrate that in the absence
      of a centromeric tether, arm cohesion is sufficient to maintain chromatid
      cohesion during prometaphase of mitosis. This finding provides a straightforward
      explanation for why mutants in proteins responsible for centromeric cohesion in
      Drosophila (e.g. ord, mei-s332) disrupt meiosis but not mitosis.

PMID- 10413670
TI  - The alpha3 laminin subunit, alpha6beta4 and alpha3beta1 integrin coordinately
      regulate wound healing in cultured epithelial cells and in the skin.
AB  - Previously, we demonstrated that proteolytic processing within the globular
      domain of the alpha3 subunit of laminin-5 (LN5) converts LN5 from a cell motility
      inducing factor to a protein complex that can trigger the formation of
      hemidesmosomes, certain cell-matrix attachment sites found in epithelial cells.
      We have prepared a monoclonal antibody (12C4) whose epitope is located toward the
      carboxy terminus of the globular domain of the alpha3 laminin subunit. This
      epitope is lost from the alpha3 subunit as a consequence of proteolytic
      processing. Antibody 12C4 stains throughout the matrix of cells that fail to
      process the alpha3 laminin subunit, but does not recognize the matrix of
      confluent cultures of MCF-10A cells, which efficiently process their alpha3
      laminin chain. In subconfluent populations of MCF-10A cells, 12C4 only stains
      matrix deposited at the outer edges of cell colonies. In these cells, integrin
      alpha3beta1 occasionally colocalizes with the staining generated by the 12C4
      antibody but alpha6beta4 integrin does not. In wounded MCF-10A cell cultures, the
      12C4 antibody stains the extracellular matrix beneath those cells at the very
      edge of the cellular sheet that moves to cover the wound site. A similar
      phenomenon is observed in human skin wounds, since we also detect expression of
      the unprocessed alpha3 laminin subunit at the leading tip of the sheet of
      epidermal cells that epithelializes skin wounds in vivo. In addition, using
      alpha3 laminin subunit and integrin function-inhibiting antibodies, we provide
      evidence that LN5 and its two integrin receptors (alpha6beta4 and alpha3beta1)
      appear necessary for wound healing to occur in MCF-10A cell culture wounds. We
      propose a model for healing of wounded epithelial tissues based on these results.

PMID- 10413671
TI  - The nuclear envelope serves as an intermediary between the ER and Golgi complex
      in the intracellular parasite Toxoplasma gondii.
AB  - Morphological examination of the highly polarized protozoan parasite Toxoplasma
      gondii suggests that secretory traffic in this organism progresses from the
      endoplasmic reticulum to the Golgi apparatus using the nuclear envelope as an
      intermediate compartment. While the endoplasmic reticulum is predominantly
      located near the basal end of the parasite, the Golgi is invariably adjacent to
      the apical end of the nucleus, and the space between the Golgi and nuclear
      envelope is filled with numerous coatomer-coated vesicles. Staining with
      antiserum raised against recombinant T. gondii beta-COP confirms its association
      with the apical juxtanuclear region. Perturbation of protein secretion using
      brefeldin A, microtubule inhibitors or dithiothreitol disrupts the Golgi, causing
      swelling of the nuclear envelope, particularly at its basal end. Prolonged drug
      treatment leads to gross distention of the endoplasmic reticulum, filling the
      basal end of the parasite. Cloning and sequencing of the T. gondii homolog of the
      chaperonin protein BiP identifies the carboxy-terminal amino acid sequence HDEL
      as this organism's endoplasmic reticulum-retention signal. Appending the HDEL
      motif to a recombinant secretory protein (a chimera between the parasite's major
      surface protein fusion, P30, and the Green Fluorescent Protein) causes this
      secretory reporter to be retained intracellularly. P30-GFP-HDEL fluorescence was
      most intense within the nuclear envelope, particularly at the apical end. These
      data support a model of secretion in which protein traffic from the endoplasmic
      reticulum to Golgi occurs via the apical end of the nuclear envelope.

PMID- 10413672
TI  - Cytological transformations associated with parietal cell stimulation: critical
      steps in the activation cascade.
AB  - Cultured rabbit parietal cells were used to evaluate morphological responses to
      activators and inhibitors of HCl secretion. Immunofluorescence was used to
      localize the proton pump protein, H, K-ATPase, and the apical membrane
      cytoskeletal linker protein, ezrin; fluorescent-labeled phalloidin was used as a
      marker of F-actin. Treatment of healthy control parietal cells with secretagogues
      resulted in exaggerated swelling of apical membrane vacuoles, presumably with the
      accumulation of HCl and water. Thus stimulation-associated swelling of apical
      vacuoles was blocked by inhibitors that work at various steps in the secretion
      activation cascade. When secretion was blocked by agents that prevent the
      translocation of H,K-ATPase-rich tubulovesicles to apical membrane vacuoles (such
      as H2-receptor antagonists and protein kinase A inhibitors), the general resting
      morphology was maintained. ME-3407 (a functional analogue of wortmannin) was
      unique in preventing H, K-ATPase redistribution and effecting the delocalization
      of ezrin from apical membrane vacuoles. When secretion was blocked by agents that
      inhibit the H+ pump or induce H+ backflux, the translocation of H,K-ATPase to
      apical membrane vacuoles occurred but the large vacuolar swelling associated with
      HCl and H2O accumulation was greatly diminished. These data support the membrane
      recycling/recruitment hypothesis of HCl secretion in which H, K-ATPase-rich
      tubulovesicles are recruited from a cytoplasmic domain to the apical surface, and
      they are inconsistent with models proposing that the tubulovesicles, regardless
      of shape, are contiguous with the apical plasma membrane. These studies also
      demonstrate the utility of the parietal cell culture model in distinguishing a
      general site of action for various inhibitors and antisecretory agents.

PMID- 10413673
TI  - The casein kinase Ialpha isoform is both physically positioned and functionally
      competent to regulate multiple events of mRNA metabolism.
AB  - Casein kinase I is a highly conserved family of serine/threonine protein kinases
      present in every organism tested from yeast to humans. To date, little is known
      about the function of the higher eukaryotic isoforms in this family. The CKI
      isoforms in Saccharomyces cerevisiae, however, have been genetically linked to
      the regulation of DNA repair, cell cycle progression and cytokinesis. It has also
      been established that the nuclear localization of two of these isoforms is
      essential for their function. The work presented here demonstrates that the
      higher eukaryotic CKIalpha isoform is also present within nuclei of certain
      established cell lines and associated with discrete nuclear structures. The
      nature of its nuclear localization was characterized. In this regard, CKIalpha
      was shown to colocalize with factors involved in pre-mRNA splicing at nuclear
      speckles and that its association with these structures exhibited several
      biochemical properties in common with known splicing factors. The kinase was also
      shown to be associated with a complex that contained certain splicing factors.
      Finally, in vitro, CKIalpha was shown to be capable of phosphorylating particular
      splicing factors within a region rich in serine/arginine dipeptide repeat motifs
      suggesting that it has both the opportunity and the capacity to regulate one or
      more steps of mRNA metabolism.

PMID- 10413674
TI  - Induced differentiation in HT29, a human colon adenocarcinoma cell line.
AB  - The human colon adenocarcinoma cell line HT29 displays an undifferentiated
      phenotype under standard growth conditions. When these cells were cultured for 21
      days and then treated with forskolin, most of the cells formed brush borders on
      their apical surfaces. Brush border formation was inhibited by cytochalasin D but
      not by colchicine. Colchicine, nocodazole and taxol were found to induce
      differentiation and apoptosis in HT29 cells. Differentiation was characterized by
      flattening of the cells, formation of brush borders on apical surfaces and tight
      junctions between adjacent cells. Apoptosis was characterized by detachment of
      round cells from the cell layer, condensation of nuclear DNA and annexin V
      binding to cell surfaces. Treatment with colchicine or forskolin induced the
      association of E-cadherin to the cytoskeleton fraction of subconfluent HT29
      cells. This effect was less prominent in post confluent cells. Our data indicate
      that microtubule-interfering agents may serve as an important tool in the study
      of differentiation and apoptosis in intestinal carcinoma.

PMID- 10413675
TI  - Metalloproteinase-mediated release of the ectodomain of L1 adhesion molecule.
AB  - The L1 adhesion molecule is an approx. 200-220 kDa type I membrane glycoprotein
      belonging to the immunoglobulin (Ig) superfamily. L1 can bind in a homotypic
      fashion and was shown to support integrin-mediated binding via RGDs in the 6th Ig
      like domain. In addition to its cell-surface expression, L1 can occur in the
      extracellular matrix (ECM). Here we demonstrate that L1 is constitutively
      released from the cell surface by membrane-proximal cleavage. L1 shed from B16F10
      melanoma cells remains intact and can serve as substrate for integrin-mediated
      cell adhesion and migration. The release of L1 occurs in mouse and human cells
      and is blocked by the metalloproteinase inhibitor TAPI (Immunex compound 3). This
      compound has been shown previously to block release of L-selectin and TNF-alpha
      which is mediated by the membrane-bound metalloproteinase TNF-alpha converting
      enzyme (TACE). Using CHO cells that are low in TACE expression and do not release
      L-selectin we demonstrate that L1 release is distinct from L-selectin shedding.
      We propose that cell-surface release may be necessary for the conversion of L1
      from a membrane into an ECM protein.

PMID- 10413676
TI  - Required role of focal adhesion kinase (FAK) for integrin-stimulated cell
      migration.
AB  - FAK localizes to sites of transmembrane integrin receptor clustering and
      facilitates intracellular signaling events. FAK-null (FAK-) fibroblasts exhibit a
      rounded morphology, defects in cell migration, and an elevated number of cell
      substratum contact sites. Here we show that stable re-expression of epitope
      tagged FAK reversed the morphological defects of the FAK- cells through the
      dynamic regulation of actin structures and focal contact sites in fibronectin
      (FN) stimulated cells. FAK re-expressing fibroblasts (clones DA2 and DP3) exhibit
      a characteristic fibrillar shape and display indistinguishable FN receptor
      stimulated migration properties compared to normal fibroblasts. Expression of
      various FAK mutants in the FAK- cells showed that FAK kinase activity, the Tyr
      397/SH2 domain binding site, and the first proline-rich SH3 binding region in the
      FAK C-terminal domain were individually needed to promote full FAK-mediated FAK-
      cell migration to FN whereas direct paxillin binding to FAK was not required.
      Expression of the FAK Phe-397 mutant did not promote FAK- cell migration and
      overexpression of p50(csk) in DA2 cells inhibited migration to FN suggesting that
      Src-family PTKs play important roles in FAK-mediated motility events. Expression
      of the FAK C-terminal domain, FRNK, promoted FAK dephosphorylation at Tyr-397 and
      potently blocked FAK-mediated cell migration. This dominant-negative effect of
      FRNK was reversed by a point mutation (Leu-1034 to Ser) which prevented FRNK
      localization to focal contact sites. Our results show that FAK functions as a key
      regulator of fibronectin receptor stimulated cell migration events through the
      recruitment of both SH2 and SH3 domain-containing signaling proteins to sites of
      integrin receptor clustering.

PMID- 10413677
TI  - Nucleolar localization of murine nuclear DNA helicase II (RNA helicase A).
AB  - Nuclear DNA helicase II (NDH II) is a highly conserved member of the DEXH
      superfamily of eukaryotic helicases, whose physiological role is still unclear.
      To explore the function of NDH II, we studied the intracellular distribution of
      NDH II of different mammalian species by immunofluorescence and compared these
      findings with the known role of the Drosophila homologue MLE that is involved in
      sex-specific gene dosage compensation. NDH II displayed an apparent nucleolar
      localization in murine cells, whereas in cells from all other mammalian species
      examined so far the protein was confined to the nucleoplasm and apparently
      excluded from the nucleoli. The nucleolar localization of mouse NDH II strongly
      suggests a role in ribosomal RNA biosynthesis. Immunoelectron microscopic studies
      revealed that the mouse NDH II was found at the dense fibrillar components of the
      nucleoli, and a significant percentage of NDH II molecules colocalized with the
      RNA polymerase I (Pol I) transcription factor UBF (upstream binding factor).
      Additionally, the nucleolar localization of NDH II coincided with a preferential
      immunolabeling pattern of nascent transcripts with bromouridine (BrUMP).
      Furthermore, mouse NDH II redistributed in mitosis in a manner highly correlated
      with Pol I activity. Conditions leading to the inhibition of Pol I activity in
      the interphase decreased the amount of NDH II in the nucleoli that diffused into
      the nucleoplasm and the cytosol. Contrary to the effect of inhibiting rRNA
      synthesis, treatment of mouse cells with the translation inhibitor cycloheximide
      did not compromise the nucleolar localization of murine NDH II.

PMID- 10413678
TI  - Quantitative measurement of mammalian chromosome mitotic loss rates using the
      green fluorescent protein.
AB  - We have measured the mitotic loss rates of mammalian chromosomes in cultured
      cells. The green fluorescent protein (GFP) gene was incorporated into a non
      essential chromosome so that cells containing the chromosome fluoresced green,
      while those lacking it did not. The proportions of fluorescent and non
      fluorescent cells were measured by fluorescence activated cell sorter (FACS)
      analysis. Loss rates ranged from 0.005% to 0.20% per cell division in mouse LA-9
      cells, and from 0.02% to 0.40% in human HeLa cells. The rate of loss was elevated
      by treatment with aneugens, demonstrating that the system rapidly identifies
      agents which induce chromosome loss in mammalian cells.

PMID- 10413679
TI  - Functional characterisation of tetanus and botulinum neurotoxins binding domains.
AB  - Tetanus and botulinum neurotoxins constitute a family of bacterial protein toxins
      responsible for two deadly syndromes in humans (tetanus and botulism,
      respectively). They bind with high affinity to neurons wherein they cause a
      complete inhibition of evoked neurotransmitter release. Here we report on the
      cloning, expression and use of the recombinant fragments of the heavy chains of
      tetanus neurotoxin and botulinum neurotoxin serotypes A, B and E as tools to
      study the neurospecific binding of the holotoxins. We found that the recombinant
      50 kDa carboxy-terminal domains of tetanus and botulinum neurotoxins alone are
      responsible for the specific binding and internalisation into spinal cord cells
      in culture. Moreover, we provide evidence that the recombinant fragments block
      the internalization of the parental holotoxins in a dose-dependent manner, as
      determined by following the neurotoxin-dependent cleavage of their targets
      VAMP/synaptobrevin and SNAP-25. In addition, the recombinant binding fragments
      cause a significant delay in the paralysis induced by the corresponding holotoxin
      on the mouse phrenic nerve-hemidiaphragm preparation. Taken together, these
      results show that the carboxy-terminal domain of tetanus and botulinum
      neurotoxins is necessary and sufficient for the binding and internalisation of
      these proteins in neurons and open the possibility to use them as tools for the
      functional characterisation of the intracellular transport of clostridial
      neurotoxins.

PMID- 10413680
TI  - mAKAP: an A-kinase anchoring protein targeted to the nuclear membrane of
      differentiated myocytes.
AB  - The compartmentalization of second messenger-activated protein kinases
      contributes to the fidelity of hormone-mediated signal transduction events. For
      example, the cAMP-dependent protein kinase is tethered at specific intracellular
      locations through association with A-kinase anchoring proteins (AKAPs). We now
      report the cloning of mAKAP, an anchoring protein found predominantly in heart,
      skeletal muscle and brain, and whose expression is induced in neonatal
      ventriculocytes by treatment with hypertrophic stimuli. mAKAP is targeted to the
      nuclear membrane of differentiated myocytes. Analysis of mAKAP-green fluorescent
      protein (GFP) fusion constructs revealed that nuclear membrane targeting is
      conferred by two regions of the protein, between residues 772-915 and 915-1065,
      which contain spectrin-like repeat sequences. Heterologous expression of the
      mAKAP targeting sequences displaced the endogenous anchoring protein from the
      nuclear membrane, demonstrating that mAKAP targeting is saturable. Collectively,
      these data suggest that a domain containing spectrin-like repeats mediates
      targeting of the anchoring protein mAKAP and the cAMP-dependent protein kinase
      holoenzyme to the nuclear membrane in response to differentiation signals.

PMID- 10413681
TI  - Three actin cross-linking proteins, the 34 kDa actin-bundling protein, alpha
      actinin and gelation factor (ABP-120), have both unique and redundant roles in
      the growth and development of Dictyostelium.
AB  - The contribution of three actin cross-linking proteins, alpha-actinin (alphaA),
      gelation factor (ABP-120), and the 34 kDa actin-bundling protein to cellular
      functions has been studied in three single mutant (alphaA-, 120-, and 34-) and
      three double mutant (alphaA-/120-, 34-/alphaA-, 34-/120-) strains of
      Dictyostelium generated by homologous recombination. Strains alphaA-/120- and 34
      /alphaA- exhibited a reduced rate of pinocytosis, grew to lower saturation
      densities, and produced small cells in shaking cultures. All strains grew
      normally in bacterial suspensions and on agar plates with a bacterial lawn. Slow
      growth under conditions of reduced temperature and increased osmolarity was
      observed in single mutants 34- and alphaA-, respectively, as well as in some of
      the double mutant strains. Motility, chemotaxis, and development were largely
      unaltered in 34-/alphaA- and 34-/120- cells. However, 34-/alphaA- cells showed
      enhanced aggregation when starved in suspension. Moreover, morphogenesis was
      impaired in both double mutant strains and fruiting bodies of aberrant morphology
      were observed. These defects were reverted by re-expression of one of the lacking
      cross-linking proteins. The additive and synthetic phenotypes of these mutations
      indicate that actin cross-linking proteins serve both unique and overlapping
      functions in the actin cytoskeleton.

PMID- 10413682
TI  - Genetic dissection of the Leishmania paraflagellar rod, a unique flagellar
      cytoskeleton structure.
AB  - The paraflagellar rod (PFR) is a unique network of cytoskeletal filaments that
      lies alongside the axoneme in the flagella of most trypanosomatids. While little
      is known about how two major Leishmania mexicana PFR protein components, PFR1 and
      PFR2, assemble into this complex structure, previous analysis of PFR2 null
      mutants demonstrated that the PFR is essential for proper cell motility. The
      structural roles of PFR1 and PFR2 are now examined through comparison of PFR2
      null mutants with new PFR1 null mutant and PFR1/PFR2 double null mutant
      parasites. Both PFR1 and PFR2 were essential for PFR formation and cell motility.
      When elimination of one PFR gene prevented assembly of a native PFR structure,
      the other PFR protein accumulated at the distal flagellar tip. Comparison of PFR
      substructures remaining in each mutant revealed that: (1) fibers that attach the
      PFR to the axoneme did not contain PFR1 or PFR2, and assemble in the absence of a
      PFR. (2) PFR1 was synthesized and transported to the flagella in the absence of
      PFR2, where it formed a stable association with the axoneme attachment fibers.
      (3) PFR2 was synthesized and transported to the flagella in the absence of PFR1,
      though it was not found associated with the axoneme attachment fibers. (4) PFR1
      and PFR2 were located throughout the subdomains of the PFR. These data suggest
      that while PFR filaments contain both PFR1 and PFR2, the PFR is attached to the
      axoneme by interaction of PFR1 with the axoneme attachment fibers.

PMID- 10413683
TI  - Human heat shock factor 1 is predominantly a nuclear protein before and after
      heat stress.
AB  - The induction of the heat shock genes in eukaryotes by heat and other forms of
      stress is mediated by a transcription factor known as heat shock factor 1 (HSF1).
      HSF1 is present in unstressed metazoan cells as a monomer with low affinity for
      DNA, and upon exposure to stress it is converted to an 'active' homotrimer that
      binds the promoters of heat shock genes with high affinity and induces their
      transcription. The conversion of HSF1 to its active form is hypothesized to be a
      multistep process involving physical changes in the HSF1 molecule and the
      possible translocation of HSF1 from the cytoplasm to the nucleus. While all
      studies to date have found active HSF1 to be a nuclear protein, there have been
      conflicting reports on whether the inactive form of HSF is predominantly a
      cytoplasmic or nuclear protein. In this study, we have made antibodies against
      human HSF1 and have reexamined its localization in unstressed and heat-shocked
      human HeLa and A549 cells, and in green monkey Vero cells. Biochemical
      fractionation of heat-shocked HeLa cells followed by western blot analysis showed
      that HSF1 was mostly found in the nuclear fraction. In extracts made from
      unshocked cells, HSF1 was predominantly found in the cytoplasmic fraction using
      one fractionation procedure, but was distributed approximately equally between
      the cytoplasmic and nuclear fractions when a different procedure was used.
      Immunofluorescence microscopy revealed that HSF1 was predominantly a nuclear
      protein in both heat shocked and unstressed cells. Quantification of HSF1
      staining showed that approximately 80% of HSF1 was present in the nucleus both
      before and after heat stress. These results suggest that HSF1 is predominantly a
      nuclear protein prior to being exposed to stress, but has low affinity for the
      nucleus and is easily extracted using most biochemical fractionation procedures.
      These results also imply that HSF1 translocation is probably not part of the
      multistep process in HSF1 activation for many cell types.

PMID- 10413684
TI  - In vitro reconstitution of calreticulin-substrate interactions.
AB  - Calreticulin is a soluble, endoplasmic reticulum-resident protein and a molecular
      chaperone for glycoproteins. We have reconstituted the binding of recombinant
      calreticulin to two glycoprotein substrates, vesicular stomatitis virus G protein
      and influenza hemagglutinin, in vitro. The binding was found to be direct and to
      require monoglucosylated, asparagine-linked oligosaccharides on the substrate
      glycoprotein but no other cellular factors. The binding could be modulated in
      vitro by incubation of substrate with purified preparations of the glycan
      modifying enzymes glucosidase II and the UDP-glucose:glycoprotein
      glucosyltransferase, thus recapitulating the regulation of calreticulin-binding
      by glycan modification that occurs in vivo. Using the purified ER enzymes and the
      recombinant calreticulin, an assay was established for reconstituting a complex,
      multicomponent chaperone binding cycle in vitro. We demonstrated, moreover, that
      the acidic C-terminal 62 residues of calreticulin are dispensable for substrate
      binding whereas further deletions inhibit substrate binding.

PMID- 10413685
TI  - The level of cell surface beta1,4-galactosyltransferase I influences the invasive
      potential of murine melanoma cells.
AB  - Beta1,4-Galactosyltransferase I (GalT I) is localized on the leading lamellipodia
      of migrating cells, where it associates with the cytoskeleton and facilitates
      cell spreading and migration on basal lamina matrices. It has previously been
      reported that a variety of highly metastatic murine and human cell lines are
      characterized by elevated levels of cell surface GalT I, although the
      intracellular biosynthetic pool is similar between cells of high and low
      metastatic potential. In this study, we examined whether the elevated expression
      of surface GalT I characteristic of metastatic cells is instructive or incidental
      to their metastatic behavior by altering the expression of surface GalT I and by
      the use of GalT I-specific perturbants. Surface GalT I levels were positively and
      negatively altered on murine melanoma cells by either overexpressing full-length
      GalT I or by homologous recombination, respectively. The consequences of altered
      surface GalT I expression on cell invasion in vitro and lung colonization in vivo
      were determined. Increasing surface GalT I expression on cells of low metastatic
      potential to levels characteristic of highly metastatic cells recapitulated the
      highly invasive phenotype in vitro. Alternatively, decreasing surface GalT I
      expression on highly metastatic cells to levels characteristic of low metastatic
      cells reduced their invasive behavior in vitro and metastatic activity in vivo.
      Within the physiological range of surface GalT I expression, the invasive
      potential of each clonal cell line correlated strongly with the level of surface
      GalT I expressed. As an independent means to assess the involvement of surface
      GalT I in metastatic behavior, cells were pretreated with two different classes
      of surface GalT I perturbants, a competitive oligosaccharide substrate and a
      substrate modifier protein. Both perturbants inhibited metastatic colonization of
      the lung, whereas control reagents did not. Finally, as reported by others,
      surface GalT I on metastatic cells selectively interacted with one glycoprotein
      substrate, or ligand, of approximately 100 kDa, the identity of which remains
      obscure. These results show that the elevated expression of surface GalT I
      characteristic of highly metastatic cells contributes to their invasive phenotype
      in vitro and to their metastatic phenotype in vivo.

PMID- 10413686
TI  - Cataract surgery--quantity and quality.

PMID- 10413687
TI  - Wellcome Trust support for vision research.

PMID- 10413688
TI  - Profile of patients presenting for cataract surgery in the UK: national data
      collection.
AB  - AIMS/METHODS: A national data collection exercise was carried out in more than
      100 hospital eye service units within the UK to provide clinical and
      administrative information on patients undergoing cataract surgery. This included
      patient clinical data such as visual acuity at the time of wait listing and at
      the time of admission for surgery, presence of other eye disorders, other serious
      medical disorders, and data on waiting time and type of admission. RESULTS: The
      profiles of the 18 454 patients aged 50 years or older are reported. Findings of
      particular note were as follows. At the time of wait listing for cataract surgery
      31% had visual acuity of 6/12 or better, 54% had visual acuity between 6/18 and
      6/60, and 15% had less than 6/60 vision. Considering those who had visual acuity
      of 6/12 or better at the time of wait listing, by the time of admission for
      surgery, the vision deteriorated to 6/18-6/60 in 33% and in a further 3% the
      vision deteriorated to below 6/60. In patients with moderately poor visual acuity
      (<6/12-6/60) at the time of wait listing, 13% had less than 6/60 vision by the
      time of admission for surgery. CONCLUSION: This type of data collection and
      reporting exercise provides new material that can be used in the planning and
      provision of cataract surgery services in the UK.

PMID- 10413689
TI  - Audit of extracapsular cataract extraction and posterior chamber lens
      implantation as a routine treatment for age related cataract in east Africa.
AB  - AIMS: To evaluate the outcome of extracapsular cataract extraction (ECCE) and
      posterior chamber intraocular lens implantation (PC-IOL) in an African eye clinic
      during the transition from intracapsular cataract extraction to ECCE and PC-IOL.
      METHODS: A retrospective survey of 461 consecutive operations for age related
      cataract with a mean follow up of 52.9 weeks (range 0-275) and a minimum follow
      up of 4 weeks in 87.9% of eyes. RESULTS: A best corrected vision of 6/18 or
      better was obtained in 94.3% of eyes, and an uncorrected vision of 6/18 or better
      in 78.2% of eyes. Six eyes (1.5%) had a best corrected vision of less than 6/60.
      The visual acuity at 2 months was strongly predictive of the vision at 1 year or
      more after surgery. Preoperative biometry and IOL power calculation increased the
      proportion of eyes obtaining an uncorrected vision of 6/18 or better from 73.8%
      to 81.3%. Four eyes developed visually significant posterior capsule opacity.
      CONCLUSION: ECCE and PC-IOL can give very good results in an African setting. A
      better visual outcome should lead to increased demand for cataract surgery, which
      will eventually reduce the number of cataract blind people in Africa.

PMID- 10413691
TI  - Effect of software manipulation (Photoshop) of digitised retinal images on the
      grading of diabetic retinopathy.
AB  - AIMS: To determine whether software processing of digitised retinal images using
      a "sharpen" filter improves the ability to grade diabetic retinopathy. METHODS:
      150 macula centred retinal images were taken as 35 mm colour transparencies
      representing a spectrum of diabetic retinopathy, digitised, and graded in random
      order before and after the application of a sharpen filter (Adobe Photoshop).
      Digital enhancement of contrast and brightness was performed and a X2 digital
      zoom was utilised. The grades from the unenhanced and enhanced digitised images
      were compared with the same retinal fields viewed as slides. RESULTS: Overall
      agreement in retinopathy grade from the digitised images improved from 83.3%
      (125/150) to 94.0% (141/150) with sight threatening diabetic retinopathy (STDR)
      correctly identified in 95.5% (84/88) and 98.9% (87/88) of cases when using
      unenhanced and enhanced images respectively. In total, five images were
      overgraded and four undergraded from the enhanced images compared with 17 and
      eight images respectively when using unenhanced images. CONCLUSION: This study
      demonstrates that the already good agreement in grading performance can be
      further improved by software manipulation or processing of digitised retinal
      images.

PMID- 10413690
TI  - Automated localisation of the optic disc, fovea, and retinal blood vessels from
      digital colour fundus images.
AB  - AIM: To recognise automatically the main components of the fundus on digital
      colour images. METHODS: The main features of a fundus retinal image were defined
      as the optic disc, fovea, and blood vessels. Methods are described for their
      automatic recognition and location. 112 retinal images were preprocessed via
      adaptive, local, contrast enhancement. The optic discs were located by
      identifying the area with the highest variation in intensity of adjacent pixels.
      Blood vessels were identified by means of a multilayer perceptron neural net, for
      which the inputs were derived from a principal component analysis (PCA) of the
      image and edge detection of the first component of PCA. The foveas were
      identified using matching correlation together with characteristics typical of a
      fovea-for example, darkest area in the neighbourhood of the optic disc. The main
      components of the image were identified by an experienced ophthalmologist for
      comparison with computerised methods. RESULTS: The sensitivity and specificity of
      the recognition of each retinal main component was as follows: 99.1% and 99.1%
      for the optic disc; 83.3% and 91.0% for blood vessels; 80.4% and 99.1% for the
      fovea. CONCLUSIONS: In this study the optic disc, blood vessels, and fovea were
      accurately detected. The identification of the normal components of the retinal
      image will aid the future detection of diseases in these regions. In diabetic
      retinopathy, for example, an image could be analysed for retinopathy with
      reference to sight threatening complications such as disc neovascularisation,
      vascular changes, or foveal exudation.

PMID- 10413692
TI  - Phenotypic variations in a family with retinal dystrophy as result of different
      mutations in the ABCR gene.
AB  - AIMS: To describe two phenotypic variations of autosomal recessive retinal
      dystrophy occurring in a consanguineous family in a pseudodominant pattern,
      resulting from mutations in the ATP binding cassette transporter (ABCR) gene.
      METHODS: Patients of this family underwent an extensive ophthalmic evaluation,
      including fundus photography, fluorescein angiography, and electroretinography
      (ERG). Genetic analysis comprised sequence analysis of the retina specific ABCR
      gene. RESULTS: Five patients presented with decreased visual acuity in the second
      decade, central chorioretinal atrophy associated with a central scotoma, and
      severely decreased photopic and scotopic ERG responses. This clinical picture,
      which in our opinion resembles a cone-rod dystrophy (CRD), was associated with
      compound heterozygosity for IVS30+ 1g -->t and IVS40+5g-->a mutations in the ABCR
      gene. The four remaining patients presented with night blindness in the first
      decade because of a retinitis pigmentosa-like (RP-like) dystrophy. In addition to
      a pale "waxy" optic disc, attenuated retinal vessels and bone spicule deposits, a
      widespread chorioretinal atrophy was observed. The scotopic ERG was extinguished
      and the photopic ERG was severely diminished. Genetic analysis revealed a
      homozygous 5' splice mutation IVS30+1g -->t in the ABCR gene. CONCLUSION:
      Mutations in the ABCR gene can cause clinical pictures resembling autosomal
      recessive RP and autosomal recessive CRD.

PMID- 10413693
TI  - Phenotype of autosomal recessive congenital microphthalmia mapping to chromosome
      14q32.
AB  - BACKGROUND: Congenital microphthalmia (OMIM: 309700) may occur in isolation or in
      association with a variety of systemic malformations. Isolated microphthalmia may
      be inherited as an autosomal dominant, an autosomal recessive, or an X linked
      trait. METHODS: Based on a whole genome linkage analysis, in a six generation
      consanguineous family with autosomal recessive inheritance, the first locus for
      isolated microphthalmia was mapped to chromosome 14q32. Eight members of this
      family underwent clinical examination to determine the nature of the
      microphthalmia phenotype associated with this locus. RESULTS: All affected
      individuals in this family suffered from bilateral microphthalmia in association
      with anterior segment abnormalities, and the best visual acuity achieved was
      "perception of light". Corneal changes included partial or complete congenital
      sclerocornea, and the later development of corneal vascularisation and anterior
      staphyloma. Intraocular pressure, as measured by Schiotz tonometry, was greatly
      elevated in many cases. CONCLUSIONS: This combination of ocular defects suggests
      an embryological disorder involving tissues derived from both the neuroectoderm
      and neural crest. Other families with defects in the microphthalmia gene located
      on 14q32 may have a similar ocular phenotype aiding their identification.

PMID- 10413695
TI  - Causes of childhood blindness in the People's Republic of China: results from
      1131 blind school students in 18 provinces.
AB  - AIMS: To determine the anatomical site and underlying causes of blindness and
      severe visual impairment in children under 16 years of age in special education
      in the People's Republic of China with a view to determining potentially
      preventable and treatable causes. METHODS: A national study of children attending
      schools for the blind in China was conducted between April and June 1998 using
      the WHO Prevention of Blindness Programme (WHO/PBL) eye examination record for
      children with blindness and low vision. Eight Chinese ophthalmologists attended a
      training workshop before conducting the study. 36 blind schools in 18 provinces
      of China were included. RESULTS: 1245 children aged between 5 and 15 years were
      examined, of whom 1131 (91%) were blind or severely visually impaired (visual
      acuity less than 6/60 in the better eye). The commonest anatomical sites of
      visual loss were whole globe (mainly microphthalmos) 25.5% and retina (mainly
      dystrophies) 24.9%. Lens was the major site in 18. 8%, optic nerve in 13.6%, and
      glaucoma in 9%. Corneal scarring was not a major cause of visual loss. The
      aetiology was unknown in 52.9%, hereditary factors were responsible in 30.7%, and
      childhood causes in 14%. 15% of cases were considered potentially preventable and
      22. 5% potentially treatable. CONCLUSION: The pattern of childhood blindness seen
      in this study is likely to reflect the improved health and socioeconomic status
      of China but may partly reflect bias in admission to, and location of, blind
      schools, with higher socioeconomic groups overrepresented. Nutritional and
      infective causes of blindness are uncommon, and hereditary and unknown factors
      are now the predominant causes.

PMID- 10413694
TI  - Long term results of radiotherapy for subfoveal choroidal neovascularisation in
      age related macular degeneration.
AB  - BACKGROUND/AIMS: Radiotherapy has been proposed as an alternative treatment for
      patients with subfoveal choroidal neovascularisation (CNV) that is untreatable
      according to macular photocoagulation study guidelines. This prospective study
      was designed to evaluate whether radiotherapy may affect the functional and
      anatomical outcome in a large cohort of patients affected by subfoveal CNV, with
      a follow up period up to 24 months. METHODS: 212 patients (231 eyes) with newly
      diagnosed subfoveal CNV not amenable to laser therapy were included in this
      study. Two radiotherapy methods, the lateral beam technique (6 MV, 20 Gy in five
      fractions) and lateral arc therapy (25 MV, 16 to 20 Gy, in four or five
      fractions), were used. Comparisons of best corrected visual acuity (VA),
      fluorescein (FA) and indocyanine green (ICG) angiography, at inclusion and 6, 12,
      18, and 24 months after radiotherapy were performed using univariate analysis.
      RESULTS: A VA improvement of two or more lines was observed in 34% at 12 months,
      31% at 18 months, and 32% of the eyes at 24 months. Paired comparisons of CNV
      areas in FA and ICG showed no significant change between baseline and each visit.
      However, 12 and 18 months after treatment, 47% of the eyes showed a decrease of
      10% or more in CNV size both in ICG and FA. Radiation side effects included
      radiation retinopathy (eight eyes), optic neuropathy (four eyes), choroidal
      vasculopathy (five eyes), and branch retinal vein occlusion (three eyes).
      CONCLUSION: Compared with the natural course of subfoveal CNV, the results of
      this prospective study suggest that radiotherapy could stabilise visual and
      anatomical outcome in selected cases.

PMID- 10413696
TI  - Eye injuries in children: the current picture.
AB  - AIMS: To investigate the current causes and outcomes of paediatric ocular trauma.
      METHODS: A prospective observational study of all children admitted to hospital
      with ocular trauma in Scotland over a 1 year period. RESULTS: The commonest
      mechanism of injury was blunt trauma, accounting for 65% of the total. 60% of the
      patients were admitted with a hyphaema. Injuries necessitating admission occurred
      most frequently at home (51%). Sporting activities were the commonest cause of
      injury in the 5-14 age group. There were no injuries caused by road traffic
      accidents or fireworks. Patients were admitted to hospital for a mean of 4.2 days
      (range 1-25 days). One (1%) child had an acuity in the "visually impaired" range
      (6/18-6/60) and one (1%) was "blind" (6/60) in the affected eye. No child was
      bilaterally blinded by injury and none required blind or partial sight
      registration. CONCLUSION: This study has shown that the incidence of eye injuries
      affecting children has fallen. The outcome of ocular trauma has improved
      significantly, and for the first time paediatric injuries appear to have a better
      prognosis than injuries affecting adults.

PMID- 10413697
TI  - Population based assessment of diabetic retinopathy in an urban population in
      southern India.
AB  - AIM: To assess the prevalence of diabetic retinopathy and the visual impairment
      caused by it in an urban population in southern India in order to determine its
      public health significance. METHODS: 2522 subjects (85.4% of those eligible), a
      representative sample of the population of Hyderabad city in southern India,
      underwent interview and detailed dilated eye examination during 1996-7 as part of
      the Andhra Pradesh Eye Disease Study. RESULTS: 124 subjects, all >/=30 years old,
      reported that they had diabetes, an age-sex adjusted prevalence of 7.82% (95%
      confidence interval (CI) 5.76-9.88%) in this age group. Diabetes was diagnosed at
      age >/=30 years in all but two subjects. The duration since diagnosis of diabetes
      was <10 years in 75.6% and >/=15 years in 6.7%. Diabetic retinopathy was present
      in 28 subjects, 1.78% (95% CI 1.09-2.48%) of those >/=30 years old. Most of the
      diabetic retinopathy was of the mild (50%) or moderate (39.3%) non-proliferative
      type; one subject (3.6%) had proliferative retinopathy. Multiple logistic
      regression revealed that the odds of having diabetic retinopathy were
      significantly higher in those >/=50 years than in those 30-49 years old (odds
      ratio 7.78, 95% CI 2.92-20. 73). Three subjects had visual impairment between
      6/12 and 6/38 in either eye due to diabetic retinopathy, 0.19% (95% CI 0-0.41%)
      of those >/=30 years old. CONCLUSION: Visual impairment due to diabetic
      retinopathy was relatively uncommon in this urban Indian population in 1996-7.
      However, this could change in the near future with an increase in duration of
      diabetes because of the anticipated aging of India's population and the recent
      suggestion of increase in diabetes prevalence in urban India, and therefore
      should be monitored.

PMID- 10413698
TI  - Incidence of corneal melting in association with systemic disease in the
      Yorkshire Region, 1995-7.
AB  - AIMS: To estimate the incidence of corneal melting or necrotising keratitis in
      association with systemic disease in the Yorkshire Region and to determine the
      type and duration of the systemic association. METHODS: In a prospective study,
      vigorous attempts were made to identify all patients presenting with newly
      diagnosed corneal melting over a 3 year period. RESULTS: 27 patients were
      identified during the study period. Rheumatoid arthritis and Wegener's
      granulomatosis were the most common disease associations. Corneal melting was a
      late complication of rheumatoid arthritis, but usually occurred during early and
      overt systemic disease in patients with Wegener's granulomatosis. CONCLUSION: The
      annual incidence of corneal melting in the Yorkshire Region is 3.01/million/year
      (95% CI = 0.7-9.6).

PMID- 10413699
TI  - Prophylactic scleral buckle for prevention of retinal detachment following
      vitrectomy for macular hole.
AB  - AIM: To review the rate of retinal detachment after macular hole surgery in
      patients who received vitrectomy and scleral buckle versus those who had
      vitrectomy alone. METHODS: All patient charts and hospital records were examined
      for patients who underwent vitrectomy surgery for macular hole between September
      1993 and June 1997. A total of 326 patients were identified and all were followed
      for a minimum of 6 months. Clinical records were examined for details of the
      surgical procedure, visual acuity, hole closure status, adjuvant therapies used,
      and postoperative retinal attachment status. Relative risks (the ratio of the
      incidence rate in the exposed to that in the unexposed) with 95% confidence
      intervals and chi(2) tests were calculated to determine which variables were
      associated with retinal detachment. The primary outcome measure in this review
      was retinal attachment status. RESULTS: Of 326 eyes which underwent surgery for
      macular hole during the study period, scleral buckles were utilised in 152
      (46.6%) patients. Analysis revealed a detachment rate of 13.2% in patients who
      did not receive a scleral buckle compared with 5.9% detachment rate in those who
      did. Analysis of these results indicated a 2.42 times greater risk of developing
      a retinal detachment in patients without a scleral buckle. Complications related
      to the use of scleral buckles occurred in two of 152 cases (1.3%) CONCLUSIONS: A
      reduction in the rate of retinal detachment was noted in patients receiving
      prophylactic scleral buckles. Those finding suggest a possible beneficial effect
      of this adjunctive procedure in preventing postoperative retinal detachments. The
      authors are currently preparing a multicentred, prospective, clinical trial to
      further study this hypothesis

PMID- 10413700
TI  - Endoscopy of the lacrimal system.
AB  - BACKGROUND/AIM: Until recently, diagnosis of disorders of the lacrimal system has
      depended on digital dacryocystography and on clinical examinations such as the
      fluorescein dye test, lacrimal probing, and irrigation. The lacrimal system and
      its mucous membranes can now be viewed directly with a lacrimal endoscope. While
      the first endoscopes were rigid and limited by poor picture quality in axial
      illuminations, the new generation of endoscopes are a great leap forward for new
      diagnostic and therapeutic approaches. METHODS: 132 patients ranging in age from
      8 months to 73 years with nasolacrimal obstruction were referred to the lacrimal
      department. Diagnostic lacrimal imaging utilising various small calibre
      endoscopes less than 0.5 mm in external diameter was performed. The endoscopes
      are coupled to specially designed lacrimal probes as well as a CCD camera and a
      video recorder. The imaging was performed during standard lacrimal probing and
      irrigation in an outpatient clinic setting in 120 of 132 patients RESULTS: All
      patients reported the pain of endoscopy as being similar to that of standard
      lacrimal probing and irrigation. No adverse effects such as bleeding or lacrimal
      perforation were noted. Endoscopic manipulation was not too difficult and the
      picture quality, depth of focus, and illumination were satisfactory in all cases.
      The most common site of stenosis was the nasolacrimal duct (59 patients),
      followed by the lacrimal sac (39 patients) and the canaliculi (34 patients). In
      25 patients, partial obstruction, rather than complete stenosis, was visualised
      as a narrow lumen, which widened during irrigation. In 14 of 28 patients,
      obstruction was due to canalicular submucosal folds and was removed with laser.
      In addition, the colour and consistency of the lining mucosa correlated with type
      of obstruction. Normal mucosa is smooth and light pink in colour. Inflammatory
      changes manifest as thickened and reddish grey mucosa. More complete stenosis is
      shown as fibrotic plaques with grey white inelastic membranes. CONCLUSION:
      Lacrimal endoscopy is a new, non-invasive method used to view directly and
      localise obstructions precisely. It allows differentiation between inflammatory,
      partial, and complete stenosis. Endoscopy enables one to choose the appropriate
      surgical therapy for patients. Patients tolerated the procedure well without any
      adverse reactions or effects. While it may not replace standard probing and
      irrigation, this technique is an extremely useful adjunct in determining the
      proper surgical modality, ease, and tolerance of the endoscopic manipulation by
      patients, and obtaining sharp and clear images of the nasolacrimal outflow system
      anatomy and pathology. Differentiation of various types of obstruction by precise
      location and severity can be achieved.

PMID- 10413701
TI  - Vitreous levels of intercellular adhesion molecule 1 (ICAM-1) as a risk indicator
      of proliferative vitreoretinopathy.
AB  - AIM: To investigate whether high vitreous levels of the soluble intercellular
      adhesion molecule 1 (sICAM-1) may be related to clinical risk factors of
      proliferative vitreoretinopathy (PVR) and whether their measurement may serve as
      an additional risk indicator of this complication in eyes with rhegmatogenous
      retinal detachment (RRD). METHODS: Levels of sICAM-1 were measured by enzyme
      linked immunosorbent assays (ELISA) in vitreous from 36 eyes with RRD clinically
      considered to be at high risk of developing PVR (large retinal breaks, vitreous
      haemorrhage, long standing RRD, and previous vitreoretinal surgery). Levels of
      sICAM-1 in this group were compared with those in vitreous from 31 eyes with RRD
      without clinical risk factors for PVR, 32 eyes with established PVR and 10 eyes
      with macular holes. RESULTS: Vitreous from eyes with RRD at high risk of
      developing PVR contained significantly higher levels of sICAM-1 (range 6.1-97.7
      ng/ml; Mann-Whitney test, p=0.0002) than those from eyes with RRD at low risk of
      developing this complication (range 4.8-17.7 ng/ml). Vitreous sICAM-1 levels in
      eyes with RRD at high risk of developing PVR were significantly lower than in
      eyes with established PVR (p=0.037), but higher than in eyes with macular holes
      (p <0.0001). Levels of sICAM-1 >/=15 ng/ml (3 x median of the levels present in
      control eyes) provide a useful cut off point for a highly specific test (96.7%)
      with high positive (91.6%) and negative (96.7%) predictive values, despite a
      relatively low sensitivity (30. 5%). CONCLUSIONS: The present findings suggest
      that laboratory measurement of sICAM-1 levels in vitreous from eyes with RRD may
      constitute an additional factor for identifying patients at high risk of PVR.
      Hence, determination of sICAM-1 levels may aid in the monitoring of patients
      likely to develop this complication and in the identification of patients who may
      benefit from adjuvant anti-inflammatory therapy.

PMID- 10413702
TI  - Detection of herpes simplex virus DNA in atypical epithelial keratitis using
      polymerase chain reaction.
AB  - AIM: To study herpes simplex virus (HSV) DNA in tears from patients with atypical
      epithelial keratitis of unknown aetiology. METHODS: Tear samples were collected
      from 17 affected eyes of 17 consecutive patients suffering from epithelial
      keratitis in whom HSV keratitis was suspected but whose diagnosis was difficult
      on the basis of clinical manifestations alone. Using reduced sensitivity
      polymerase chain reaction (PCR), tear samples were tested for HSV DNA. Tears from
      the unaffected eyes of the 17 patients were also examined, along with 38 tear
      samples from 19 normal volunteers. Southern blot analysis was performed to
      confirm that amplified DNA bands were specific for HSV. Clinical correlation with
      photographs of corneal lesions was also investigated. RESULTS: HSV DNA was
      detected in tears from the affected eyes of eight of the 17 patients with
      suspected HSV keratitis. Tears from the affected eyes of the other patients were
      PCR negative, as were tears from the unaffected eyes of all 17 patients, and from
      the 38 normal eyes. There was no correlation between PCR results and clinical
      manifestation of keratitis. CONCLUSIONS: Based on the sensitivity of the PCR
      system, eight of 17 suspected HSV keratitis patients were confirmed as suffering
      from HSV keratitis. HSV keratitis should therefore be considered as a possible
      diagnosis in atypical epithelial keratitis.

PMID- 10413703
TI  - Effect of the cytostatic agent idarubicin on fibroblasts of the human Tenon's
      capsule compared with mitomycin C.
AB  - BACKGROUND/AIMS: To investigate the in vitro effect of a short time exposure to
      the anthracycline idarubicin on proliferation, protein synthesis, and motility of
      human Tenon's capsule fibroblasts in comparison with the antitumour antibiotic
      mitomycin C. METHODS: After determination of effective concentrations of
      idarubicin, fibroblasts of the human Tenon's capsule were exposed to idarubicin
      or mitomycin C at concentrations ranging from 0.1 microg/ml to 1 microg/ml or
      from 2.5 microg/ml to 250 microg/ml, respectively, for 0.5, 2, or 5 minutes and
      cultured for 60 days. Cell death by apoptosis caused by idarubicin treatment was
      confirmed by Hoechst 33258 staining. Further proliferation was explored by cell
      counting and by (3)H-thymidine uptake. Protein synthesis was measured by (3)H
      proline uptake and motility was assessed by agarose droplet motility assay.
      RESULTS: Idarubicin is able to exert toxicity and to induce apoptosis during a
      short time exposure of 0.5 minutes at concentrations of 0.3-1 microg/ml resulting
      in a significant reduction in cell number compared with the control after 60
      days. For mitomycin C, higher concentrations and longer expositions were
      necessary. Even after treatment with 1 microg/ml idarubicin or 250 microg/ml
      mitomycin C a few cells were able to incorporate (3)H-thymidine. (3)H-proline
      uptake up to 10 days after exposure to 0.3 microg/ml idarubicin was found not to
      be decreased. Cell motility was reduced after treatment with 1 microg/ml
      idarubicin for 5 minutes or with 250 microg/ml mitomycin C for 2 or 5 minutes.
      For low mitomycin C concentrations, an increase in motility was found during the
      first 10 days. CONCLUSION: Idarubicin reduces proliferation of human Tenons's
      capsule fibroblasts after incubation for 0.5 minutes at concentrations as low as
      0.3-1 microg/ml. In comparison, mitomycin C requires longer exposure times and
      higher doses for equal results. Therefore, idarubicin may be useful in the
      prevention of glaucoma filtering surgery failure.

PMID- 10413704
TI  - New animal model for human ocular toxocariasis: ophthalmoscopic observation.
AB  - BACKGROUND/AIMS: Although human ocular toxocariasis causes severe vision defect,
      little is known about its aetiology, diagnosis, and treatment. To develop a new
      animal model for human ocular toxocariasis, ophthalmological findings of fundi in
      Mongolian gerbils, Meriones unguiculatus, and BALB/c mice were investigated
      following infection with Toxocara canis. METHODS: Using an ophthalmoscope, which
      was specifically developed to observe the fundi of small animals, ocular changes
      of fundi of 20 gerbils and 11 mice were monitored after oral infection with
      embryonated eggs of T canis. RESULTS: Vitreous, choroidal, and retinal
      haemorrhages were consistently observed in Mongolian gerbils, but rarely in mice.
      Severe exudative lesions and vasculitis were often present in gerbils but not in
      mice. Migrating larvae were also frequently observed in gerbils. CONCLUSION:
      Mongolian gerbils are more appropriate animal model for human ocular toxocariasis
      than previously used experimental animal such as mice, guinea pigs, rabbits, and
      monkeys because of its high susceptibility of ocular infection.

PMID- 10413705
TI  - Suppression of induction of experimental immune mediated blepharoconjunctivitis
      by tolerogenic conjugates of the antigen and monomethoxypolyethylene glycol.
AB  - AIM: Covalent conjugates consisting of diverse antigens coupled to optimal
      numbers of monomethoxypolyethylene glycol (mPEG) molecules have been shown to
      suppress antigen specific antibody formation. In this study, the possibility was
      examined that the same conjugates might prevent experimental immune mediated
      blepharoconjunctivitis (EC, formerly EAC) which had been shown to be caused by
      CD4(+) T cells-that is, to cell mediated immunity. METHODS: 6-8 week old male
      Lewis rats were used. The test groups of rats received two intravenous
      injections, each of 300 microg, of a conjugate of ovalbumin mPEG (OVA(mPEG)(11))
      in phosphate buffered saline (PBS), 14 and 28 days before the single immunisation
      with OVA in complete Freund's adjuvant. The rats were challenged 3 weeks later by
      eye drops containing OVA; 24 hours later they were sacrificed, and their eyes,
      blood, and lymph nodes were harvested for histological examination and
      determination of anti-OVA antibody titres and levels of cellular immunity. Two
      control groups received PBS or OVA in PBS before immunisation. Furthermore, the
      possibility that OVA(mPEG)(11) may have induced OVA specific suppressor cells was
      tested by establishing the effects of the co-transfer of splenocytes from
      OVA(mPEG)(11) treated rats with OVA primed lymph node cells on the manifestations
      of EC. RESULTS: Either PBS or OVA pretreated rats, which had not received
      OVA(mPEG)(11), developed high levels of antibodies and cell mediated immune
      responses to OVA, and application of eye drops led to blepharoconjunctivitis with
      massive cellular infiltration. In contrast, pretreatment with OVA(mPEG)(11)
      prevented cellular infiltration into the lids and conjunctivas, as well as the
      formation of detectable humoral and cellular immunity against OVA. Co-transfer of
      splenocytes from OVA(mPEG)(11) treated rats with OVA primed lymph node cells
      suppressed the cellular infiltration on application of OVA on the conjunctiva.
      CONCLUSIONS: These data indicate that intravenous injection of OVA(mPEG)(11)
      conjugates suppressed both humoral and cellular immunity by the effects of
      antigen specific suppressor cells, thus leading to the inhibition of development
      of EC.

PMID- 10413707
TI  - Use of polymerase chain reaction in detection of Mycobacterium tuberculosis
      complex DNA from vitreous sample of Eales' disease.

PMID- 10413706
TI  - Ganglion cell death in glaucoma: what do we really know?

PMID- 10413708
TI  - Vertical cup/disc ratio in relation to optic disc size.

PMID- 10413710
TI  - Assessing Children's Vision.

PMID- 10413709
TI  - Suggestion for IL-2 treatment of conjunctival squamous carcinoma.

PMID- 10413712
TI  - Vitreoretinal Disease: The Essentials.

PMID- 10413711
TI  - Atlas of Glaucoma.

PMID- 10413713
TI  - Diabetic retinopathy. A guide for diabetes care teams.

PMID- 10413714
TI  - Parasite infections and the risk of asthma and atopy.

PMID- 10413715
TI  - Nebulised corticosteroids in the treatment of patients with asthma.

PMID- 10413716
TI  - Relationship between early life respiratory illness, family size over time, and
      the development of asthma and hay fever: a seven year follow up study.
AB  - BACKGROUND: The timing and mechanism of the inverse association between
      increasing sibling number and atopic disease are not yet understood. A study was
      undertaken to examine how family size at birth predicts early respiratory
      illness, to report the association between infant respiratory illness and
      childhood atopic disease, and to determine whether the protective effect of large
      family size operates during infancy or later childhood. METHODS: A prospective
      follow up study was carried out on 863 children (78%) of 1111 participants in the
      Tasmanian Infant Health Survey performed in 1988. In 1988 household size and
      history of respiratory illness were obtained by parental interview at home
      (median age 35 days) and later by telephone (median age 85 days). In 1995 asthma,
      hay fever, and household size were assessed by parental questionnaire in a large
      cross sectional survey. RESULTS: In 1988 increasing resident number (per
      resident) (adjusted odds ratio (AOR) 1.17 (95% CI 1.05 to 1.31)) and resident
      density (AOR 1.77 (95% CI 1.07 to 2.94)) were related to parental report of an
      upper respiratory tract infection (URTI) by one month of age. Children with a
      reported URTI by home interview were more likely to have subsequent asthma
      (adjusted relative risk (ARR) 1.27 (95% CI 1.05 to 1.53)). The association
      between lower respiratory tract infection (LRTI) at telephone interview (relative
      risk (RR) 1.34 (95% CI 1.02 to 1.75) and asthma was reduced after adjustment for
      family history of asthma (ARR 1.27 (95% CI 0.98 to 1.66)). Antibiotic use by home
      interview was not associated with subsequent asthma or hay fever. Indicators of
      family size in 1988 were associated with hay fever but not asthma but, in
      contrast, resident number in 1995 was inversely associated with asthma (AOR 0.82
      (95% CI 0.72 to 0.92) per resident) and hay fever (AOR 0.82 (95% CI 0.71 to 0.96)
      per resident). Children with no siblings were at risk for current asthma,
      particularly if symptoms began after the age of four (RR 2.81 (95% CI 1.36 to
      5.84)). CONCLUSIONS: The apparent protective effect of large household size and
      asthma could not be explained by an increase in reported early respiratory
      illness. The first year of life may not be the most critical time for the
      protective effect of large household size to be mediated in relation to asthma,
      but this effect occurred by the seventh year of life.

PMID- 10413717
TI  - Long term outcome of soybean epidemic asthma after an allergen reduction
      intervention.
AB  - BACKGROUND: Asthma outbreaks due to the inhalation of soybean dust released from
      handling of soybean in the city harbour occurred in Barcelona, Spain from 1981 to
      1987. The installation of bag filters in the responsible silo was followed by a
      substantial reduction of airborne soybean dust released into the atmosphere and
      the disappearance of asthma outbreaks. A study was undertaken to assess the
      relevant outcomes in asthma patients affected by soybean epidemic asthma eight
      years after this environmental intervention. METHODS: A repeat case-control study
      was performed in 1995 on a population of subjects with epidemic and non-epidemic
      asthma previously assessed in 1989. The same protocol was used in both surveys to
      collect data from patients via a questionnaire and respiratory function, skin and
      laboratory tests were performed under blinded conditions with regard to epidemic
      and non-epidemic status. Environmental soybean allergen in pollution filters was
      measured by means of a RAST inhibition technique. RESULTS: During 1995 and 1996
      the 24 hour mean airborne levels of soybean allergen on a sample of 39 unloading
      days (range 31-269 U/m(3)) were systematically below the lowest level ever
      detected during an epidemic day (1500 U/m(3)). Measurable levels of serum IgE
      antibodies against soybean were still present in 55% of patients with epidemic
      asthma compared with 6.0% of those with non-epidemic asthma (p<0.05). These
      proportions were almost identical to those observed in 1989. The proportion of
      patients with soybean asthma with symptoms in 1989 who reported the absence of
      symptoms in 1995 was similar to the control subjects, so most of the relative
      risks (RRs) of improvement were near to 1. The only statistically significant
      differences between the two groups were a smaller proportion of patients with
      epidemic asthma showing improvement in terms of being woken up by attacks of
      coughing (RR improvement 0.47; 95% CI 0.22 to 0.99) and the need for treatment at
      the emergency room (RR improvement 0.63; 95% CI 0.41 to 0.96). CONCLUSIONS: Eight
      years after a large reduction in the levels of airborne soybean allergen half of
      the former soybean epidemic asthma patients were still sensitised to soybean.
      These results indicate an initial improvement in soybean epidemic asthma in the
      two years following the intervention with no further improvement in subsequent
      years.

PMID- 10413718
TI  - Mite, cat, and cockroach exposure, allergen sensitisation, and asthma in
      children: a case-control study of three schools.
AB  - BACKGROUND: The amount of allergen necessary to sensitise genetically "at risk"
      children is unclear. The relation between allergen exposure and asthma is also
      uncertain. METHODS: To ensure a wide range of allergen exposures the data from
      case-control studies of asthma in children aged 12-14 years attending three
      schools in Los Alamos, New Mexico and Central Virginia were combined. Skin prick
      tests to indoor and outdoor allergens and bronchial hyperreactivity to histamine
      were assessed in children with and without symptoms of asthma. The concentration
      of mite, cat, and cockroach allergens in dust from the children's homes was used
      as a marker of exposure. RESULTS: Three hundred and thirty two children (157 with
      asthmatic symptoms and 175 controls) were investigated. One hundred and eighty
      three were classified as atopic on the basis of allergen skin prick tests and 68
      as asthmatic (symptoms plus bronchial responsiveness). The prevalence and degree
      of sensitisation to mite and cockroach, but not cat, was strongly associated in
      atopic children with increasing domestic concentrations of these allergens.
      Asthma was strongly associated with sensitisation to indoor allergens (p<10(-6))
      and weakly to outdoor allergens (p = 0.026). There was an association between
      current asthma and the concentration of mite allergen amongst atopic children (p
      = 0.008) but not amongst those who were specifically mite sensitised (p = 0.16).
      CONCLUSIONS: The domestic reservoir concentration of mite and cockroach, but not
      cat, allergen was closely related to the prevalence of sensitisation in atopic
      children. However, the prevalence of current asthma had a limited relationship to
      these allergen measurements, suggesting that other factors play a major part in
      determining which allergic individuals develop asthma.

PMID- 10413720
TI  - Prevalence of depression in patients with chronic obstructive pulmonary disease:
      a systematic review.
AB  - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have
      repeatedly been characterised as a population of chronically ill patients with a
      higher than normal prevalence of depression. Susceptibility for depression has
      been noted in patients with certain other chronic conditions. This systematic
      review was conducted to achieve a more definite answer to the question: do
      patients with COPD show a higher than normal prevalence of depression? METHODS:
      Studies in English language journals were retrieved by an electronic search over
      the period from 1966 to December 1997 and by an extended search of reference
      lists, and were included or excluded according to a system of diagnostic and
      methodological criteria. RESULTS: Ten studies were included, of which only four
      had a case-control design. Three of the case-control studies reported an
      increased prevalence of depression among patients with COPD which was
      statistically significant in only one. The fourth controlled study found a
      significantly increased depression score among COPD patients. Of the remaining
      six uncontrolled studies three found a high baseline prevalence of depression
      among their study group. CONCLUSIONS: An association between COPD and depression
      was found in the four controlled studies. The two methodologically best conducted
      studies that did not detect a statistically significant higher prevalence lacked
      power. The two studies that did find a significant association used a
      questionable depression measure. The prevalence of depression was high compared
      with general population figures in three of six non-controlled studies. The
      empirical evidence for a significant risk of depression in patients with COPD
      remains inconclusive, due to the poor methodological quality of most of the
      published studies, the lack of studies with an adequate sample size, and
      variability in instruments and cut off scores used to measure depression.

PMID- 10413719
TI  - Objectives, methods and content of patient education programmes for adults with
      asthma: systematic review of studies published between 1979 and 1998.
AB  - BACKGROUND: Education programmes for adults with asthma vary widely. Such
      variability suggests a lack of consensus on what works and what does not. The
      objectives of this paper are to describe asthma education programmes and assess
      their variability. METHODS: A systematic review of reports published between 1979
      and 1998 was conducted. Medline, the CINAHL database, the PsycINFO database, the
      Cochrane collaboration database, the Dissertation Index database, and cross
      referencing were used to identify educational interventions; 77 projects
      including 94 interventions that involved 7953 patients were analysed. A standard
      form was used to record characteristics of studies (design, setting, size, year,
      and country of publication), projects (theoretical framework, objectives), and
      education (methods, duration, intensity, educator, and content). RESULTS: Most
      reports did not specify the general (56%) and educational objectives (60%) of the
      intervention. Important training characteristics were often not available:
      duration of education (45%) and number of sessions (22%), who delivered education
      (15%), whether training was conducted in groups or was individualised (28%). When
      this information was available there were wide variations in training methods and
      content: training duration ranged from 0 (self-education) to 58 hours and the
      number of sessions from 0 to 36; training tools such as peak flow meters, diary
      cards or books were used in various proportions of interventions (19%, 27%, and
      23%, respectively). The content of education also differed widely between
      programmes. CONCLUSIONS: Insufficient documentation of asthma education
      programmes for adults precludes their replication. This, together with excessive
      variability, reduces the possibility of identifying their most effective
      components. A more systematic description of asthma training programmes should be
      promoted.

PMID- 10413721
TI  - Glutathione S-transferase P1 (GSTP1) polymorphism in patients with chronic
      obstructive pulmonary disease.
AB  - BACKGROUND: Enzymes that contribute to the local detoxification in alveoli and
      bronchioles have an important role in the defence mechanism against tobacco
      smoke. It has been suggested that genetic susceptibility to smoking injury may
      confer a risk for the development of chronic obstructive pulmonary disease
      (COPD). The polymorphisms in glutathione S-transferase P1 (GSTP1), a xenobiotic
      metabolising enzyme, were investigated in patients with COPD. METHODS: Polymerase
      chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were
      performed to genotype GSTP1 polymorphisms in exon 5 (Ile105Val) and exon 6
      (Ala114Val). Blood samples were taken from 53 patients with COPD and 50 control
      subjects at the Tokyo University Hospital, the Juntendo University Hospital, and
      the Tokyo Kenbikyoin Clinic for use in the study. RESULTS: The proportion of
      GSTP1/Ile105 homozygotes was significantly higher in the patients with COPD than
      in the control subjects (79% vs 52%). The odds ratio for GSTP1/Ile105 homozygotes
      versus all other genotypes was 3.5 (95% CI 2.7 to 4.6) for COPD. Polymorphism at
      residue 114 of GSTP1 was not found in either group. CONCLUSIONS: Genetic
      polymorphism of exon 5 of GSTP1 may be associated with COPD because the
      GSTP1/Ile105 genotype is predominantly found in COPD. It is suggested that the
      GSTP1/Ile105 genotype may be less protective against xenobiotics in tobacco
      smoke.

PMID- 10413722
TI  - Variation of bronchoalveolar lymphocyte phenotypes with age in the
      physiologically normal human lung.
AB  - BACKGROUND: Changes in T lymphocyte subsets have been observed in various forms
      of pulmonary disease. However, bronchoalveolar lymphocyte subsets have not been
      well characterised for healthy individuals differing in age. A study was
      undertaken to investigate the bronchoalveolar lavage (BAL) and peripheral blood
      lymphocyte subsets in clinically normal volunteers of two different age groups
      (19-36 and 64-83 years). METHODS: Bronchoalveolar lavage was performed on all
      individuals in both age groups and peripheral venous blood was drawn just prior
      to BAL. Bronchoalveolar cell profiles were characterised by morphological
      criteria, and cell surface antigen expression of lymphocytes was determined by
      flow cytometry. RESULTS: A significant increase in total BAL lymphocytes was
      observed for the oldest group compared with the youngest age group. Mean
      lymphocyte subset (CD4+/CD8+) ratios were significantly increased in BAL fluid
      from the older group compared with the younger group (mean (SE) 7.6 (1.5) vs 1.9
      (0.2); p<0.0001). The increase in the BAL CD4+/CD8+ T cell ratio was mostly due
      to an increase in relative numbers of CD4+ lymphocytes, and the BAL CD4/CD8 ratio
      was disproportionately increased compared with peripheral blood in the older
      group. Increased expression of HLA-DR and CD69 on CD4+ T lymphocytes was observed
      in the oldest age group. Relative numbers of natural killer (NK) cells did not
      vary with age, and gammadelta T cells and CD5+ B cells were present in very low
      numbers in both age groups. CONCLUSIONS: CD4+ T cells accumulate in air spaces of
      the lower respiratory tract with age in healthy adults and express increased
      amounts of HLA-DR and CD69 on their surfaces, suggesting a relative degree of
      CD4+ T lymphocyte activation for healthy older individuals who have normal lung
      function.

PMID- 10413723
TI  - Management of antenatally diagnosed pulmonary sequestration associated with
      congenital cystic adenomatoid malformation.
AB  - BACKGROUND: Sequestration with associated cystic adenomatoid malformation is
      rare. A study was undertaken to determine whether pulmonary sequestration
      associated with congenital cystic adenomatoid malformation has a more favourable
      natural history than that of sequestration without associated cystic adenomatoid
      malformation. METHODS: An outline of the postnatal work up leading to the
      management of extralobar or intralobar pulmonary sequestration with congenital
      cystic adenomatoid malformation diagnosed antenatally as pulmonary malformation
      is presented and the indications for surgical intervention are discussed.
      RESULTS: In five infants in whom an antenatal ultrasound scan had detected a
      congenital lung malformation at 18-19 weeks gestation a final diagnosis of
      extralobar or intralobar pulmonary sequestration with congenital cystic
      adenomatoid malformation was made postnatally. Postnatal ultrasound and
      computerised axial tomographic scans confirmed the diagnosis of sequestration by
      delineating anomalous vascular supply. Cystic changes were also observed in the
      basal area of the sequestration in all patients. Four children remained
      asymptomatic and one infant presented at 10 months of age with pneumonia. The
      mean age at surgical resection was 6.8 months (range 2-10). Histopathological
      examination confirmed intralobar pulmonary sequestration with associated Stocker
      type 2 congenital cystic adenomatoid malformation in two patients and extralobar
      pulmonary sequestration with associated Stocker type 2 congenital cystic
      adenomatoid malformation in three patients. The mean period of follow up was four
      years (range 1-8). The children remain well and are developing normally.
      CONCLUSIONS: The importance of seeking an anomalous blood supply in children with
      congenital lung lesions is emphasised. Pulmonary sequestration and congenital
      cystic adenomatoid malformation probably share a common embryogenesis despite
      diverse morphology. The natural history of antenatally diagnosed lung masses is
      variable. Early postnatal surgical resection of pulmonary sequestration with
      cystic adenomatoid malformation is recommended. Surgical excision should be
      conservative, sparing the normal lung parenchyma.

PMID- 10413724
TI  - Vascular endothelial growth factor (VEGF) in inflammatory and malignant pleural
      effusions.
AB  - BACKGROUND: Investigation and management of pleural effusions is an important
      clinical problem yet the pathogenesis of pleural fluid accumulation is poorly
      understood. Vascular endothelial growth factor (VEGF) is a potent inducer of
      capillary permeability that is produced by both malignant and inflammatory cells.
      A study was undertaken to determine whether VEGF has a potential pathogenic role
      in the development of pleural effusions and whether VEGF receptors are present on
      human pleural mesothelial cells. METHODS: Normal and inflamed pleura were
      examined immunohistochemically for the presence of FLT-1 (the fms-like tyrosine
      kinase receptor of VEGF). VEGF levels were measured by ELISA in 78 consecutive
      patients presenting with undiagnosed unilateral pleural effusions and the levels
      were correlated with the aetiology of the effusions. RESULTS: Immunohistochemical
      staining of normal and diseased pleura demonstrated the presence of the FLT-1
      VEGF receptor on human mesothelial cells. Median VEGF levels were 2500 pg/ml in
      the malignant group and 305 pg/ml in the non-malignant group (median difference
      1397.5 pg/ml (95% CI 851 to 2693), p<0.005). Median VEGF levels varied according
      to tumour histology. VEGF levels were also significantly raised compared with
      transudates (median 36.5 pg/ml) in empyema (4651 pg/ml (95% CI 833 to 10 000),
      p<0.001) and parainfectious effusions (360 pg/ml (95% CI 46 to 597), p<0.005).
      CONCLUSIONS: This first report of VEGF receptors on pleural mesothelial cells has
      indicated a potential mechanism for the biological activity of VEGF on pleural
      tissue. VEGF levels are raised in the majority of exudative effusions, implying a
      pathogenic role for this molecule in the development of pleural effusions.

PMID- 10413725
TI  - Effect of high versus low ambient humidity on the severity of obstructive sleep
      apnoea.
AB  - BACKGROUND: Surface tension forces appear to make a significant contribution to
      upper airway closure in patients with obstructive sleep apnoea (OSA). It is
      possible that drying of the upper airway mucosa at night might contribute to
      these surface tension forces and the severity of OSA might therefore change with
      alteration of the ambient humidity. METHODS: A randomised single blind crossover
      study of high ambient relative humidity (HRH) versus low ambient relative
      humidity (LRH) was performed in 12 men of mean (SD) age 49 (9) years with mild
      OSA (apnoea/hypopnoea index (AHI) 14 (5.2)). On one night patients slept in
      continuous HRH (85 (4)%, range 80-93%) and on the other in LRH (16 (4)%, range 11
      22%). RESULTS: The AHI was similar on the HRH and LRH nights (mean difference 3;
      95% CI -2 to 9, p = 0.20 and no statistically significant differences in AHI were
      observed on the two nights after standardising for body position and sleep stage.
      Sleep stage distribution and the proportion of time spent in the supine position
      were similar on the HRH and LRH nights. The number of non-respiratory arousals
      was also similar on the two nights. CONCLUSION: Altering ambient humidity alone
      has no significant impact on the severity of OSA.

PMID- 10413727
TI  - Long acting beta(2) agonists and theophylline in stable chronic obstructive
      pulmonary disease.

PMID- 10413726
TI  - Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations:
      issues in clinical management and review of pathogenic mechanisms.

PMID- 10413730
TI  - Acute anaphylaxis following midline catheterisation in a patient with cystic
      fibrosis.
AB  - A 16 year old male with cystic fibrosis experienced an acute life threatening
      anaphylactic reaction following the insertion of an Ohmeda Hydrocath(TM) midline
      peripheral venous catheter. The catheter was immediately withdrawn and treatment
      with intravenous adrenaline, hydrocortisone, chlorpheniramine, and colloid over a
      24 hour period resulted in a gradual resolution of symptoms.

PMID- 10413729
TI  - A clinical approach to the use of methotrexate for sarcoidosis.

PMID- 10413728
TI  - Socioeconomic status and chronic obstructive pulmonary disease.

PMID- 10413731
TI  - Pulmonary artery sarcoma diagnosed using intravascular ultrasound images.
AB  - Primary and secondary malignant intravascular tumours of the pulmonary artery
      occur infrequently and the diagnosis is usually delayed as symptoms and findings
      from conventional examinations are non-specific. The case is presented of a
      patient with a pulmonary artery sarcoma, probably arising from ribs resected some
      years previously, in which intravascular ultrasound (IVUS) provided important
      diagnostic findings.

PMID- 10413732
TI  - Reform of the Public Health Act.

PMID- 10413733
TI  - Sex-based differences in early mortality after myocardial infarction. National
      Registry of Myocardial Infarction 2 Participants.
AB  - BACKGROUND: There is conflicting information about whether short-term mortality
      after myocardial infarction is higher among women than among men after adjustment
      for age and other prognostic factors. We hypothesized that younger, but not
      older, women have higher mortality rates during hospitalization than their male
      peers. METHODS: We analyzed data on 384,878 patients (155,565 women and 229,313
      men) who were 30 to 89 years of age and who had been enrolled in the National
      Registry of Myocardial Infarction 2 between June 1994 and January 1998. Patients
      who had been transferred from or to other hospitals were excluded. RESULTS: The
      overall mortality rate during hospitalization was 16.7 percent among the women
      and 11.5 percent among the men. Sex-based differences in the rates varied
      according to age. Among patients less than 50 years of age, the mortality rate
      for the women was more than twice that for the men. The difference in the rates
      decreased with increasing age and was no longer significant after the age of 74
      (P< 0.001 for the interaction between sex and age). Logistic-regression analysis
      showed that the odds of death were 11.1 percent greater for women than for men
      with every five-year decrease in age (95 percent confidence interval, 10.1 to
      12.1 percent). Differences in medical history, the clinical severity of the
      infarction, and early management accounted for only about one third of the
      difference in the risk. After adjustment for these factors, women still had a
      higher risk of death for every five years of decreasing age (increase in the odds
      of death, 7.0 percent; 95 percent confidence interval, 5.9 to 8.1 percent).
      CONCLUSIONS: After myocardial infarction, younger women, but not older women,
      have higher rates of death during hospitalization than men of the same age. The
      younger the age of the patients, the higher the risk of death among women
      relative to men. Younger women with myocardial infarction represent a high-risk
      group deserving of special study.

PMID- 10413734
TI  - Sex, clinical presentation, and outcome in patients with acute coronary
      syndromes. Global Use of Strategies to Open Occluded Coronary Arteries in Acute
      Coronary Syndromes IIb Investigators.
AB  - BACKGROUND: Studies have reported that women with acute myocardial infarction
      have in-hospital and long-term outcomes that are worse than those of men.
      METHODS: To assess sex-based differences in presentation and outcome, we examined
      data from the Global Use of Strategies to Open Occluded Coronary Arteries in
      Acute Coronary Syndromes IIb study, which enrolled 12,142 patients (3662 women
      and 8480 men) with acute coronary syndromes, including infarction with ST-segment
      elevation, infarction with no ST-segment elevation, and unstable angina. RESULTS:
      Overall, the women were older than the men, and had significantly higher rates of
      diabetes, hypertension, and prior congestive heart failure. They had
      significantly lower rates of prior myocardial infarction and were less likely
      ever to have smoked. A smaller percentage of women than men had infarction with
      ST elevation (27.2 percent vs. 37.0 percent, P<0.001), and of the patients who
      presented with no ST elevation (those with myocardial infarction or unstable
      angina), fewer women than men had myocardial infarction (36.6 percent vs. 47.6
      percent, P<0.001). Women had more complications than men during hospitalization
      and a higher mortality rate at 30 days (6.0 percent vs. 4.0 percent, P<0.001) but
      had similar rates of reinfarction at 30 days after presentation. However, there
      was a significant interaction between sex and the type of coronary syndrome at
      presentation (P=0.001). After stratification according to coronary syndrome and
      adjustment for base-line variables, there was a nonsignificant trend toward an
      increased risk of death or reinfarction among women as compared with men only in
      the group with infarction and ST elevation (odds ratio, 1.27; 95 percent
      confidence interval, 0.98 to 1.63; P=0.07). Among patients with unstable angina,
      female sex was associated with an independent protective effect (odds ratio for
      infarction or death, 0.65; 95 percent confidence interval, 0.49 to 0.87;
      P=0.003). CONCLUSIONS: Women and men with acute coronary syndromes had different
      clinical profiles, presentation, and outcomes. These differences could not be
      entirely accounted for by differences in base-line characteristics and may
      reflect pathophysiologic and anatomical differences between men and women.

PMID- 10413735
TI  - Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in
      Canada. Canadian Bacterial Surveillance Network.
AB  - BACKGROUND: Fluoroquinolones are now recommended for the treatment of respiratory
      tract infections due to Streptococcus pneumoniae, particularly when the isolates
      are resistant to beta-lactam antibiotics. Although pneumococci with reduced
      susceptibility to fluoroquinolones have been identified, their prevalence has not
      been determined in a defined population. METHODS: We performed susceptibility
      testing on 7551 isolates of S. pneumoniae obtained from surveillance in Canada in
      1988 and from 1993 to 1998. Pneumococci with reduced susceptibility to
      fluoroquinolones (defined as a minimal inhibitory concentration of ciprofloxacin
      of at least 4 microg per milliliter) were further characterized. We also examined
      antibiotic prescriptions dispensed in Canadian retail pharmacies. RESULTS:
      Between 1988 and 1997, fluoroquinolone prescriptions increased from 0.8 to 5.5
      per 100 persons per year. The prevalence of pneumococci with reduced
      susceptibility to fluoroquinolones increased from 0 percent in 1993 to 1.7
      percent in 1997 and 1998 (P=0.01). Among adults, the prevalence increased from
      1.5 percent in 1993 and 1994 combined to 2.9 percent in 1997 and 1998 combined.
      The prevalence was higher in isolates from older patients (2.6 percent among
      those 65 years of age or older vs. 1.0 percent among those 15 to 64 years of age,
      P<0.001) and among those from Ontario (1.5 percent, vs. 0.4 percent among those
      from the rest of Canada; P< 0.001). Fluoroquinolone use was greatest among the
      elderly and in Ontario. The 75 isolates (17 serotypes) of pneumococci with
      reduced susceptibility to fluoroquinolones were submitted by 40 laboratories in
      eight provinces. Reduced susceptibility to fluoroquinolones was associated with
      resistance to penicillin. CONCLUSIONS: The prevalence of pneumococci with reduced
      susceptibility to fluoroquinolones is increasing in Canada, probably as a result
      of selective pressure from the increased use of fluoroquinolones.

PMID- 10413736
TI  - Impaired glucose transport as a cause of decreased insulin-stimulated muscle
      glycogen synthesis in type 2 diabetes.
AB  - BACKGROUND: Insulin resistance, a major factor in the pathogenesis of type 2
      diabetes mellitus, is due mostly to decreased stimulation of glycogen synthesis
      in muscle by insulin. The primary rate-controlling step responsible for the
      decrease in muscle glycogen synthesis is not known, although hexokinase activity
      and glucose transport have been implicated. METHODS: We used a novel nuclear
      magnetic resonance approach with carbon-13 and phosphorus-31 to measure
      intramuscular glucose, glucose-6-phosphate, and glycogen concentrations under
      hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per
      deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients
      with type 2 diabetes and seven normal subjects. In vivo microdialysis of muscle
      tissue was used to determine the gradient between plasma and interstitial-fluid
      glucose concentrations, and open-flow microperfusion was used to determine the
      concentrations of insulin in interstitial fluid. RESULTS: The time course and
      concentration of insulin in interstitial fluid were similar in the patients with
      diabetes and the normal subjects. The rates of whole-body glucose metabolism and
      muscle glycogen synthesis and the glucose-6-phosphate concentrations in muscle
      were approximately 80 percent lower in the patients with diabetes than in the
      normal subjects under conditions of matched plasma insulin concentrations. The
      mean (+/-SD) intracellular glucose concentration was 2.0+/-8.2 mg per deciliter
      (0.11+/-0.46 mmol per liter) in the normal subjects. In the patients with
      diabetes, the intracellular glucose concentration was 4.3+/-4.9 mg per deciliter
      (0.24+/-0.27 mmol per liter), a value that was 1/25 of what it would be if
      hexokinase were the rate-controlling enzyme in glucose metabolism. CONCLUSIONS:
      Impaired insulin-stimulated glucose transport is responsible for the reduced rate
      of insulin-stimulated muscle glycogen synthesis in patients with type 2 diabetes
      mellitus.

PMID- 10413737
TI  - Images in clinical medicine. Rupture of papillary muscle during acute myocardial
      infarction.

PMID- 10413739
TI  - Magnetic resonance cholangiopancreatography.

PMID- 10413738
TI  - Glucose transporters and insulin action--implications for insulin resistance and
      diabetes mellitus.

PMID- 10413740
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 22-1999. A 68-year-old woman with multiple myeloma, diabetes
      mellitus, and an inflamed eye.

PMID- 10413741
TI  - Studies of acute coronary syndromes in women--lessons for everyone.

PMID- 10413742
TI  - DNA vaccines--designer vaccines for the 21st century.

PMID- 10413743
TI  - Misunderstandings about the effects of race and sex on physicians' referrals for
      cardiac catheterization.

PMID- 10413745
TI  - Support for academic medical centers--revisiting the 1997 Balanced Budget Act.

PMID- 10413746
TI  - Doppler sonographic study of the effect of indomethacin on cardiac and pulmonary
      hemodynamics of the preterm infant.
AB  - OBJECTIVE: Indomethacin (INDO) causes an increase in systemic vascular resistance
      and decrease in perfusion of important organ systems in preterm infants treated
      for patent ductus arteriosus (PDA). Information on the effect of INDO on cardiac
      and pulmonary hemodynamics of these babies is scarce. METHODS: The left
      ventricular output (LVO), resistance in the ascending aorta (R(Ao)), determined
      mean cerebral blood velocity (cerebral-mv), ductal-peak and mean blood velocity
      (ductal-pv and -mv) and pulmonary artery peak and mean blood velocity (pulmonary
      pv and -mv) were measured, before, and up to 12 h after 0.1 mg/kg of INDO in 20
      preterm infants with PDA using Doppler echocardiography. RESULTS: LVO was
      abnormally high (mean+/-S.E.M.: 354+/-50 ml/min/kg) before INDO treatment, and an
      important left-to-right shunt through the ductus was detectable in all infants.
      At 1 h after INDO treatment, R(Ao) had significantly increased with a significant
      decrease in LVO and cerebral-mv. Ductal patency and pulmonary vascular resistance
      seemed not to be affected at this early stage, as indicated by unchanged ductal
      and pulmonary arterial blood velocities. At 4 h post-INDO, ductal-pv and -mv, and
      to a lesser extent pulmonary-pv and -mv, were transiently lower as compared to
      pre-INDO, 1 and 12 h post-INDO values. This coincided with a transient absence of
      clinical signs of PDA at 4 h post-INDO in a substantial number of infants. R(Ao)
      steadily decreased and LVO steadily increased, whereas cerebral-mv normalized
      from 4 h post-INDO onward. CONCLUSIONS: no important action of INDO was detected
      on pulmonary arterial blood velocity or pulmonary function.

PMID- 10413747
TI  - Four-gated transcranial Doppler ultrasound in the detection of circulating
      microemboli.
AB  - OBJECTIVE: Embolus detection by transcranial Doppler ultrasound is very time
      consuming and semi-automated detection is mandatory. The device studied, a
      TC4040, Nicolet-EME, uses the four-gate technique and allows for audiovisual off
      line verification of the recorded events. METHODS: Twenty controls, 10 patients
      with mechanical prosthetic heart valves and 12 patients with occlusive carotid
      artery disease were investigated by transcranial colour-coded duplex sonography
      and, subsequently, underwent a 1-h unilateral embolus detection from the middle
      cerebral artery using four-gate TCD. We investigated the Doppler spectrum
      background, microembolic signals (MES) and artefacts produced. A detection
      threshold of 5 dB or more was defined taking into account natural fluctuations of
      the Doppler spectrum. RESULTS: Sensitivity of the software was 91.9% and observer
      software agreement on MES was 7.8% in the valve patients, and 77.7% and 7.5% in
      the carotid artery disease patients, respectively. Weaker MES were more likely
      not to be detected in all four channels. The artefact signal rejection rate was
      62%. MES produced either positive or zero time delays in adjacent channels.
      Artefact signals produced either no delay, or a positive or a negative time
      delay. Duration of MES ranged from 1-88 ms. CONCLUSIONS: Besides refined
      recognition of MES using the time delay, four gates give faint MES no less than
      four opportunities to overcome the detection threshold. With this device's
      satisfying sensitivity, regions of interest in a 1-h recording can audiovisually
      be evaluated off-line in a few minutes by an investigator.

PMID- 10413748
TI  - Assessment of the biliary tract by ultrasonography and cholangiography during
      laparoscopic cholecystectomy: a prospective study.
AB  - OBJECTIVE: The introduction of laparoscopic cholecystectomy (Lap-chol) has
      induced routine cholangiography to map the biliary tree and identify common bile
      duct (CBD) stones. However, the use of more selective criteria for performing
      intraoperative cholangiography (IOC), drawbacks of IOC and experience with
      laparoscopic ultrasonography (LU) re-introduced intraoperative ultrasonography
      for the CBD. The purpose of this study was to compare the accuracy of LU and IOC
      to identify the anatomy of the CBD and the presence of stones. METHODS: A total
      of 50 unselected patients undergoing elective laparoscopic cholecystectomy were
      evaluated by LU and IOC. Stones were found in three patients by IOC and could be
      confirmed by ultrasonography and CBD exploration in two. RESULTS: Anatomic
      definition of the biliary tract and success of the procedure was better for LU
      (90 and 98%) than IOC (86 and 72%). CONCLUSION: For Surgical groups with
      experience in LU this technique appears to become the standard technique to
      identify the anatomy of the CBD and assessment of CBD stones.

PMID- 10413749
TI  - Myocardial tissue characterization in heart failure by real-time integrated
      backscatter.
AB  - OBJECTIVE: Differentiation between normal and abnormal physical state of the
      myocardium, not possible with conventional echocardiography, so far could be done
      with integrated backscatter (IBS) as a research tool only. METHODS: This study
      investigates myocardial texture analysis with new commercially available real
      time IBS in 12 normal individuals and in 18 patients with severe left ventricular
      dysfunction due to coronary artery disease (CAD) in 8 and dilated cardiomyopathy
      (DCM) in 10 patients. Analysis of IBS amplitude and cyclic variation (dB) in the
      parasternal long and short axis view of the septum and the posterior wall were
      measured and corrected with IBS curve of the blood to get absolute values.
      RESULTS: Compared to normal individuals patients with left ventricular
      dysfunction had a reduced myocardial cyclic variation (P<0.0001), which
      correlated to regional systolic wall thickening (r=0.64, P=0.001) and global
      shortening fraction (r=0.62, P<0.01). Although systolic wall thickening in the
      posterior wall was lower in CAD patients (% thickening, 11.9+/-10 vs. 21.9+/-8,
      P=0.004), absolute cyclic variation was reduced in both, CAD and DCM patients in
      the same order of magnitude. However, the higher maximal IBS amplitude in the
      posterior wall observed in CAD when compared to DCM patients (13.2+/-4.4 vs.
      9.2+/-2.4 dB; P=0.002) indicate fibrosis or scar. The dissociation between cyclic
      variation and systolic wall thickening could implicate hybernating myocardium.
      CONCLUSION: Real-time IBS has progressed from research to routine as a tool to
      obtain additional and valuable information to conventional echocardiography in
      daily practice.

PMID- 10413750
TI  - Ultrasound-guided percutaneous treatment of hepatocellular carcinoma by
      radiofrequency hyperthermia with a 'cooled-tip needle'. A preliminary clinical
      experience.
AB  - OBJECTIVE: Radiofrequency hyperthermia using the newly-developed 'cooled-tip'
      needle has recently been proposed as a therapeutic modality for hepatocellular
      carcinoma (HCC). Herein we report our preliminary results on feasibility and
      effectiveness of the thermal ablation of mono- or pauci-focal hepatocellular
      carcinoma with the cooled-tip needle. MATERIALS AND METHODS: We treated 15
      cirrhotic patients (mean age 68.8 years; 12 males; 14 HCV-positive; 13 in Child's
      Class A and 2 in Class B) with 20 hepatocellular carcinoma nodules (mean diameter
      28.1 mm; range 10-43 mm; nine lesions with diameter greater than 3 cm). None of
      the patients had portal thrombosis and/or extrahepatic spread. We used a
      radiofrequency generator (100 W of power) connected to a 18 g perfusion electrode
      needle with an exposed tip of 2-3 cm. The circuit was closed through a dispersive
      electrode positioned under the patient's thighs. A peristaltic pump infused a
      chilled (2-5 degrees C) saline solution to guarantee the continuous cooling of
      the needle tip. The needle was placed into target lesions under US guidance. The
      interventional procedure was carried out in general anesthesia without
      intubation. Dynamic helical CT was carried out 15-20 days after thermal ablation
      to assess therapeutic efficacy. RESULTS: In all, 38 areas of coagulation necrosis
      (at 1000-1200 mA for 10-15 min) were generated in 24 sessions in the 20
      hepatocellular carcinoma nodules (mean 1.9 lesions per nodule and 1.2 sessions
      per nodule). Complete necrosis as assessed at dynamic CT (lack of enhancement
      during the arteriographic phase) was achieved in 75% of cases in a single
      session; after a second RF session success rate was 90% (18 out of 20 nodules). A
      self-limited pleurisy along with a 5-fold increase in transaminases occurred in
      one patient; a 3-fold elevation of transaminases was encountered in three other
      patients. During the follow-up (median 15 months) five patients had recurrent
      hepatocellular carcinoma with a 1-year disease free interval of 64%. Of the three
      recorded deaths, two were due to intrahepatic tumor diffusion. CONCLUSIONS: In
      our experience radiofrequency hyperthermia with the cooled-tip needle afforded an
      effective and safe percutaneous ablative method for HCC in cirrhosis and
      shortened treatment time.

PMID- 10413751
TI  - Living-related liver transplantation: is Doppler sonography sufficient to define
      the hepatic artery anatomy before surgery?
AB  - OBJECTIVE: to evaluate the accuracy of colour Doppler sonography (CDS) in the
      assessment of the left hepatic arterial supply in living donors before hepatic
      transplantation. MATERIAL AND METHODS: Pre-operative sonographic Doppler data of
      the left hepatic artery (LHA) were compared retrospectively with the selective
      hepatic angiographic data and the intra-operative observations in 60 living
      donors. RESULTS: Pre-operative Doppler data of the LHA were available in 53 cases
      and incomplete or absent in seven cases. In 51 cases (96%) the origin of the LHA
      or an accessory LHA were correctly described at Doppler sonography (44 classical
      LHA in anatomic position, seven accessory LHA). In 11 cases (21%), Doppler data
      were insufficient or incorrect to define the arterial supply of the hepatic
      segments II, III and IV. Doppler studies were unable to determine the length or
      the diameter of the LHA. CONCLUSION: Doppler sonography seems to be able to
      define the main left hepatic artery anatomy. Selective hepatic angiography is
      still indicated to determine the length, diameter and intra-hepatic segmental
      supply.

PMID- 10413752
TI  - Imaging of neonatal hemangiomas, two cases.
AB  - Hemangiomas are the most common tumor of infancy. Most hemangiomas are harmless
      and follow a benign clinical course and undergo regression with time. Sometimes
      they can destroy vital organs and become life-threatening. We report two cases of
      neonatal hemangiomas which presented very different clinical aspects and course.

PMID- 10413753
TI  - The influence of Doppler system settings on the clearance kinetics of different
      ultrasound contrast agents.
AB  - OBJECTIVE: To evaluate the influence of different Doppler system settings on time
      intensity curves after ultrasound contrast agent (UCA) bolus injection. This is
      important for the comparison of different UCAs. METHODS: Six sedated dogs were
      investigated with a transcranial Doppler system and Doppler power, sample volume
      size and high pass filter settings were modified during the procedure. Mean time
      intensity curves were determined and peak values of mean intensity as well as the
      decrease in Doppler intensity were compared for the different system settings.
      Three different UCAs were used (SonoVue(TM), BY963 and Levovist(TM)). RESULTS:
      The Doppler time intensity curves showed a typical two phase decrease with a
      distribution phase alpha and an elimination phase beta with all three UCAs.
      Altering the system settings had a significant effect on the mean peak Doppler
      intensity for SonoVue(TM) (P=0.02) but not for BY963 or Levovist(TM) (P=0.07 and
      P=0.39, respectively), due to high variation of the Levovist(TM) and BY963
      intensity values. There were no significant differences between the alpha slopes
      of BY963 and Levovist(TM) (P=0.96), or the beta slope of Levovist(TM) and
      SonoVue(TM) (P=0.62), when the results of all system settings were combined.
      CONCLUSION: Different Doppler system settings show no significant influence on
      the decrease of mean Doppler intensity, but have a significant effect on peak
      intensity.

PMID- 10413754
TI  - Laparoscopic ultrasonography--a method for staging of upper gastrointestinal
      cancer.
AB  - Laparoscopic ultrasonography (LUS) is a method that can be useful in the staging
      of upper gastrointestinal cancer. Dedicated transducers are available, and
      preliminary studies have proposed indications for the use of LUS staging of
      hepatic, esophageal, gastric, and pancreatic cancer disease. In the staging and
      resectability assessment of upper gastrointestinal cancer LUS seems to provide
      important additional information thus avoiding futile laparotomies in non
      resectable patients. This short review summarizes some of the most relevant
      references concerning the use of LUS in upper gastrointestinal tract cancer.

PMID- 10413755
TI  - In vitro measurement of muscle volume with 3-dimensional ultrasound.
AB  - The aim was to test the accuracy of muscle volume measurements with a new 3
      dimensional (3-D) ultrasound system, which allows a freehand scanning of the
      transducer with an improved quality of the ultrasound images and therefore the
      outlines of the muscles. Five resected cadaveric hand muscles were insonated and
      the muscle volumes calculated by 3-D reconstructions of the acquired 2-D
      ultrasound sections. Intra-reader, inter-reader and follow-up variability were
      calculated, as well as the volume of the muscle tissue measured by water
      displacement. In the results, 3-D ultrasound and water displacement measurements
      showed an average deviation of 10.1%; Data of 3-D ultrasound measurements were:
      intra-reader variability 2.8%; inter-reader variability 2.4% and follow-up
      variability 2.3%. 3-D measurements of muscle volume are valid and reliable.
      Serial sonographic measurements of muscle may be able to quantitate changes in
      muscle volume that occur in disease and recovery.

PMID- 10413756
TI  - European Committee for Medical Ultrasound Safety (ECMUS).

PMID- 10413757
TI  - Safety of ultrasonic contrast agents. European Committee for Medical Ultrasound
      Safety.

PMID- 10413758
TI  - Arterial grafts in coronary bypass surgery.
AB  - During the last three decades, coronary artery bypass grafting (CABG) emerged,
      was developed and has progressed. The search for suitable conduits has been
      investigated aggressively and several venous, arterial and artificial grafts have
      been utilized clinically. It is clear now that the saphenous vein graft
      deteriorates with time and the occlusion rate reaches up to 50% at 10 years after
      CABG mainly due to atherosclerosis in the graft called "vein graft disease." The
      internal thoracic artery (ITA) graft, on the contrary, has very good long-term
      patency and this evidence directly relates to the superior outcome in terms of
      longevity and postoperative cardiac events in the long run. Based on this
      evidence, the use of arterial conduits for myocardial revascularization has been
      extended. Several autologous arteries have been investigated and utilized
      clinically such as the right gastroepiploic artery, the inferior epigastric
      artery, and the radial artery. With proper use of these new arterial conduits in
      addition to ITA, higher quality CABG can be performed safely, and a better long
      term result can be expected.

PMID- 10413759
TI  - Surgical treatment of 22 cardiac myxomas: A review.
AB  - Twenty-two cases of cardiac myxomas were reviewed. The patients were 8 men and 14
      women ranging in age from 12 to 73 (mean: 50.8 +/- 16. 6) at operation. They
      suffered from dyspnea, palpitation, and cough, similar to mitral disease
      symptoms, and cerebral emboli in 6 patients (30%) with left atrial myxomas.
      Echocardiography, especially transesophageal, was useful in diagnosing cardiac
      tumors and location. In 20 cases, tumors were at the left atrium and at the right
      in 2. Left atrial myxomas were approached through a septal incision in 17 cases;
      a large circular incision of the biatrium was used in 3 patients with large
      tumors or mitral regurgitation. Left atrial myxomas were attached to the atrial
      septum in 17 cases, the posterior wall of the left atrium in 2, and near the
      posterior commissure of the mitral valve in 1. Right atrial myxomas were attached
      to the atrial septum in 1 and posterior wall beside the inferior vena cava in 1.
      Resected myxomas weighed from 10 to 90 (mean: 39.1 +/- 19.1) g. No correlation
      was seen between features such as neurologic symptoms, feeding artery on coronary
      angiography, or functional status and tumor weight. No recurrence was seen.

PMID- 10413760
TI  - Direct expiratory gas analysis after hypothermic cardiopulmonary bypass.
AB  - We hypothesized that patients who have undergone hypothermic cardiopulmonary
      bypass may have abnormal oxygen metabolism after cardiac surgery because of
      oxygen debts that occurred during cardiopulmonary bypass. A prospective study was
      designed to determine oxygen consumption and carbon dioxide production using an
      indirect calorimeter in 45 adult patients who underwent hypothermic
      cardiopulmonary bypass. Inspiratory and expiratory gases were analyzed and the
      respiratory exchange ratio (carbon dioxide production/ oxygen consumption) was
      obtained every 6 hours up to 24 hours after surgery. The respiratory exchange
      ratio immediately following cardiopulmonary bypass was abnormally high then
      gradually decreased. The respiratory exchange ratio at 18 or 24 hours after
      surgery was significantly lower than the one on admission to the intensive care
      unit. Duration of cardiopulmonary bypass was the most significant parameter which
      correlated to the respiratory exchange ratio on admission to the intensive care
      unit (r = 0.82, p < 0.001). We conclude that the respiratory exchange ratio can
      be used to monitor systemic metabolism, especially during the recovery phase from
      metabolic abnormality following hypothermic cardiopulmonary bypass.

PMID- 10413761
TI  - Evaluation of heparin-coated circuits with full heparin dose strategy.
AB  - Heparin-coated cardiopulmonary circuits (HCC) in combination with a reduced
      systemic heparin dose has been demonstrated to reduce postoperative hemorrhage
      after cardiac surgery. But, it has still been equivocal whether this effect was
      related to the improved bio-compatibility or to the reduced exposure of the
      circulating heparin. Sixty patients undergoing elective coronary artery bypass
      grafting were randomly allocated into two groups either to be operated by HCC (30
      patients) or uncoated but otherwise identical circuits (NHCC). Full systemic
      heparinization was induced in both groups. Hemodynamic parameters, hematological
      and biocompatibility tests were monitored within 24 hours. Postoperative blood
      loss, requirements for transfusions, clinical performance were recorded. Arterial
      filters were examined electron microscopically. Platelet levels remained
      significantly higher in the HCC group starting at the tenth minute following the
      institution of cardiopulmonary bypass until postoperative 24 hours. Electron
      microscopy showed significantly more platelet adhesion and pseudopod formation in
      the NHCC group. The mean amount of shed pleural and mediastinal blood measured
      from the time of the sternal closure was significantly lower in the HCC group
      (316 +/- 30 cc for HCC and 550 +/- 35 cc for NHCC). Mean postoperative
      transfusion requirements were also lower in the HCC group (230 +/- 23 cc for HCC
      and 320 +/- 25 cc for NHCC). The use of HCC and full systemic heparinization did
      not change the inflammatory response or biocompatibility but demonstrated
      benefits in platelet preservation and postoperative bleeding.

PMID- 10413762
TI  - Contrast media radiography in patients with retrosternal irrigation drainage for
      severe sternal wound infection.
AB  - Severe wound infection after open-heart surgery is a potentially life-threatening
      complication, which is mostly treated by re-operation with debridement, and
      insertion of closed irrigation drainage. Until now there is no consensus about
      the appropriate duration of irrigation therapy. Since the retrosternal irrigation
      cavity is likely to become continually smaller as the infection heals, this study
      was intended to answer the question, as to whether this process can be made
      visible by the use of contrast media radiography, and whether this information
      could be used to determine when an irrigation therapy can safely be discontinued.
      In 1997, 34 patients suffered from sternal wound healing disturbances which
      required re-operation at our institution (incidence = 0.97%). During the re
      operation, a closed retrosternal irrigation drainage was inserted. Of the 34
      patients contrast media radiography examinations were carried out on the first,
      4th and 12th postoperative day (POD), which consisted of an antero-posterior x
      ray of the chest after contrast media injection through each inlet tube. At POD 4
      and 12 in the majority of cases, the retrosternal irrigation cavity became
      smaller when compared with the previous x-ray examination. Only in three of the
      non-survivors there was a huge irrigation cavity visible at the 12th POD, which
      sometimes even included the pleural cavity. We conclude that in patients with
      mediastinitis treated by insertion of a closed irrigation drainage, the
      retrosternally irrigated cavity seems to become smaller over the therapeutic
      course of treatment. This process can be visualized by contrast media
      radiography. Results from this examination should be included in decision making
      about the best time for discontinuation of the irrigation therapy.

PMID- 10413763
TI  - Aortic valve area: measurement by transesophageal echocardiography and prediction
      by left ventricular outflow tract area.
AB  - We compared three techniques of aortic valve area (AVA) measurement using
      transesophageal echocardiography (TEE) and determined if AVA can be predicted
      from simple patient or echocardiographic measurements. AVA was simultaneously
      measured with direct planimetry, the continuity equation and with a novel
      technique combining stroke volume using thermodilution and continuous wave
      Doppler. Using planimetry as the reference in patients with normal valves, left
      ventricular outflow tract area (LVOTA), lean body mass (LBM), body surface area
      (BSA) and height were assessed as predictors of AVA. All three methods of AVA
      measurement showed close agreement and can be used interchangeably. Both LVOTA
      and LBM were predictors of AVA, but LVOTA was better. BSA and height were not
      acceptable as predictors of AVA. TEE can be used to measure AVA either with
      planimetry, the continuity equation, or in combination with thermodilution. LVOTA
      was the best predictor of AVA.

PMID- 10413764
TI  - Experimental studies on application of small-caliber vascular prosthesis produced
      by polyurethane.
AB  - It has been suggested that a microporous structure enhances fast and complete
      endothelialization. For long-term patency, antithrombogenicity and microporous
      structure are very important factors. In this paper, we have developed a new
      technique to give a micro-porous structure to small-caliber vascular prosthesis
      produced by polyurethane which has favorable antithrombogenecity. A mixed
      solution (tetrahydrofuran: dimethylformamide = 1:1) containing 13 wt% of
      segmented polyurethane and a variable amount of calcium carbonate (mean particle
      size of 8 mm in diameter) was dip-coated on a glass mandril of 3 mm and 6 mm in
      diameter and placed into distilled water for 24 hours. After the glass mandrill
      was removed, this polyurethane tube was placed into 1 mmol hydrochloric acid for
      1 hour, and a microporous polyurethane vascular prosthesis of 20 mm in length was
      completed. These prostheses of 3 mm and 6 mm in diameter were implanted into the
      femoral and the carotid arteries, and the abdominal aorta of the dogs,
      respectively. Patency was recognized by arteriography and Duplex scanning and the
      removed grafts were inspected macro- and microscopically. Greater hydraulic
      permeability of this graft was obtained with an increase in the quantity of
      calcium carbonate mixed with polyurethane. In elasticity, this graft was more
      similar to the canine jugular vein than the polytetrafluoroethylene graft.
      Patency was observed 8 weeks after implantation on the arteriogram, and neointima
      was observed microscopically on the smooth and lustrous lumen. The new
      polyurethane vascular prosthesis we developed might provide a potential
      prosthesis for small-caliber vascular reconstruction.

PMID- 10413765
TI  - Surgical treatment for carcinoma of the esophagus in the elderly patient.
AB  - Sixty-three elderly patients with carcinoma of the esophagus were operated upon
      in the department of chest cancer in Tianjin Cancer Hospital from January 1978 to
      January 1992. Eleven patients had a tumor located in the upper part of the
      thoracic esophagus; 30 patients in the middle part and 22 patients in the lower
      part. Squamous cell carcinoma was 55 cases, adenocarcinoma was 7 cases and small
      cell carcinoma was 1 case. The classification by stages according to criteria
      established by UICC, based on operative evaluation, showed 3 patients in stage I;
      24 patients in stage II and 25 patients in stage III. Forty-seven patients were
      operated as "curative" resection, 5 patients as "palliative" resection and 11
      patients underwent exploratory laparotomy or thoracotomy alone. The total
      resection rate was 82.5%. For tumors in the upper thoracic part of the esophagus,
      a total esophagectomy was performed using the triple approach. In the remaining
      patients, a subtotal esophagectomy was performed using the Sweet technique. There
      were no operative deaths in all patients. One or more postoperative complications
      were seen in 16 patients (25.4%). The most frequently recorded complications were
      pulmonary ones. The survival rate at two, three and five years were respectively
      65, 35 and 20% in patients who underwent "curative" resection. The survival rates
      for patients in whom resection was considered "palliative" was zero after 3 years
      and for patients who received exploration alone was zero after one year. The
      survival rates at 3 years for patients who underwent "curative" resection were
      respectively 100, 35 and 25% in stage I, stage II and staged III. We hold the
      view that the esophagectomy is still a predominant measure for esophageal
      carcinoma in the elderly and limited surgery (palliative resection) was
      recommended in consideration of the postoperative quality of life. If the elderly
      can tolerate the operative procedure, long-term survival with excellent
      functional status is attainable in this age group.

PMID- 10413766
TI  - Five cases of asymptomatic spontaneous pneumothorax.
AB  - Asymptomatic spontaneous pneumothorax (ASPT) is an uncommon condition. Between
      January 1, 1989 and December 31, 1997, 269 patients were admitted to our
      department with spontaneous pneumothorax. Of the 269 patients, 5 had no symptoms
      at the time of discovery. Their ages ranged from 15 to 61 years (mean, 37.8
      years), and all of them were male. Of the 5 patients with no complaints, 2 had
      bilateral metachronous pneumothoraces and 3 had hemilateral pneumothorax. All of
      these ASPTs were revealed by chest roentgenographs taken during medical
      examinations or follow-up studies relating to other diseases. The mean value of
      body mass index (BMI) was 19.96 +/- 1.4 (range 18.7 - 22.1). Two of the 5
      patients underwent bilateral partial lung resection. Histopathological
      examination of the resected specimens showed elastofibrosis, scar formation, and
      an interruption of the elastic fiber of the pleura. In these 5 cases, clinical
      courses were uneventful, and relapse of the pneumothorax did not occur. Clinical
      physicians should be aware of the possibility of asymptomatic pneumothorax, as
      well as the optimal radiographic techniques for revealing small pneumothoraces.

PMID- 10413767
TI  - Minimally invasive port-access coronary artery bypass grafting.
AB  - The Port-Access endovascular cardiopulmonary bypass system (Heartport, Inc.,
      Redwood City, CA, USA), a recent technological innovation in minimally invasive
      cardiac surgery, was conducted successfully in coronary artery bypass grafting on
      a 69-year-old woman. The left internal thoracic artery was harvested through a
      limited left anterior thoracotomy and anastomosed to the left anterior descending
      coronary artery on a protected and arrested heart. Intraoperative coronary
      angiography confirmed good graft patency. The patient was discharged from the
      hospital in good condition 7 days after the operation. This was the first
      successful minimally invasive Port-Access coronary artery bypass grafting in
      Japan.

PMID- 10413768
TI  - Successful surgical treatment of primary aorto-duodenal fistula associated with
      inflammatory abdominal aortic aneurysm: A case report.
AB  - We report a rare case of a 50-year-old woman with intermittent gastrointestinal
      (GI) bleeding and diagnosed as having primary aortoenteric fistula (PAEF) with
      inflammatory abdominal aortic aneurysm (IAAA). She was transferred to our
      institution with suspected PAEF as assessed by duodenoscopy and CT scan. As the
      patient was in shock due to massive GI-bleeding two days after admission, we
      performed an emergency laparotomy. The fistula was closed and the aneurysm
      replaced by a Woven Dacron Graft with an inter-positioning omental flap. A high
      index of suspicion is the most important diagnostic aid to prevent overlooking
      this often fatal disease.

PMID- 10413769
TI  - Acute traumatic dissection and blunt rupture of the thoracic descending aorta: A
      case report.
AB  - Rupture of the thoracic aorta following blunt trauma is increasing in incidence
      and remains a highly lethal injury. Blunt traumatic rupture and acute dissection
      of the thoracic aorta is very rare. A 50-year-old man involved in a motor vehicle
      accident on March 3, 1998 was admitted to our hospital one and a half hours
      following the accident. On admission, he was alert and his hemodynamics were
      stable. Chest roentgenogram demonstrated a widened mediastinum and multiple left
      sided rib fractures. Enhanced chest CT revealed a periaortic hematoma just distal
      to the isthmus, dissection of the descending thoracic aorta and mediastinal
      hematoma. With the diagnosis of thoracic aortic rupture and acute DeBakey type
      IIIB dissection, an emergency operation was performed. Intraoperative
      transesophageal echocardiogram showed a mobile intimal flap and diminished
      caliber of the proximal descending aorta. Disruption and dissection of the
      descending thoracic aorta were found. Prosthetic graft interposition was
      accomplished with the aid of left atrium-left femoral artery bypass using a
      centrifugal pump and heparin-coated circuits and a blood collection device for
      blood conservation. The weak dissected aortic wall was glued and reapproximated
      with Gelatine-Resorcine-Formol glue. The postoperative course was uneventful.

PMID- 10413770
TI  - A single-stage operation for bicuspid aortic valve, annulo-aortic ectasia,
      hypoplastic aortic arch, and coarctation of the aorta: A case report.
AB  - The patient was an 18-year-old man who had been diagnosed as having a bicuspid
      aortic valve and dilatation of the ascending aorta six years previously. As he
      grew up, aneurysmal change of the ascending aorta and hypertension in the upper
      body gradually progressed. Preoperative evaluation showed annulo-aortic ectasia
      and the following congenital abnormalities: bicuspid aortic valve, hypoplastic
      aortic arch, and coarctation of the aorta. Composite graft replacement and
      extended total aortic arch replacement were carried out.

PMID- 10413771
TI  - Endovascular stent-grafting via the aortic arch for distal arch aneurysm: An
      alternative of endovascular stent-grafting in a complicated case.
AB  - A 67-year-old man with severe discomfort was diagnosed with a rupture of the
      thoraco-abdominal aneurysm, a distal arch aneurysm and triple coronary artery
      disease. After emergency surgery for a thoracoabdominal aneurysm, a scheduled
      surgery for coronary artery bypass grafting and endoluminal stent-grafting for
      the distal arch aneurysm was performed simultaneously. A stent-graft was
      introduced into the descending aorta via a small incision on the arch aorta. Open
      endovascular stent-grafting via the arch aorta is an alternative for repairing a
      distal arch aneurysm with coronary artery bypass grafting.

PMID- 10413772
TI  - Neural development in metatherian and eutherian mammals: variation and
      constraint.
AB  - A model for predicting the timing of neurogenesis in mammals (Finlay and
      Darlington [1995] Science 268:1578-1584) is here extended to an additional five
      metatherian species and to a variety of other events in neural development. The
      timing of both the outgrowth of axonal processes and the establishment and
      segregation of connections proves to be as highly predictable as neurogenesis.
      Expressed on a logarithmic scale, late developmental events are as predictable as
      early ones. The fundamental order of events is the same in eutherian and
      metatherian animals, but there is a curvilinear relation between the event scales
      of the two; for metatherians, later events are slowed relative to earlier events.
      Furthermore, in metatherians, the timing of developmental events is more variable
      than in eutherians. The slowing of late developmental events in metatherians is
      associated with their considerably longer time to weaning compared with
      eutherians.

PMID- 10413773
TI  - Functional organization of tactile inputs from the hand in the cuneate nucleus
      and its relationship to organization in the somatosensory cortex.
AB  - Central processing of tactile inputs from the hand begins in the main cuneate
      nucleus and continues in the thalamus and area 3b cortex. Little is known about
      cuneate functional organization in primates or about how cuneate and area 3b
      organization are related. In this study, neurophysiologic approaches were used to
      evaluate how tactile inputs from the hand and adjacent body are organized in the
      cuneate nucleus of squirrel monkeys. Cuneate data on the organization of hand
      inputs were then compared with analogous area 3b data from our earlier cortical
      studies that used the same approaches. Evaluations of several cuneate properties,
      including (1) responsiveness to tactile stimulation, (2) incidences and sizes of
      receptive fields, (3) somatotopic progressions, (4) properties of
      representations, and (5) relationships between functional inputs and cytochrome
      oxidase staining, suggest that tactile afferents from the hand form consistently
      organized cuneate representations that, in turn, relate to the parcellated
      organization of cuneate structural substrates. Comparisons of cuneate and area 3b
      organization indicate that tactile processing from the brainstem to cortex
      involves a preservation of tactile responsiveness and somatotopic organization
      but, in addition, involves transformations that produce receptive field
      sharpening, suppression of hairy hand inputs, amplification and refinement of
      glabrous inputs, and relocations of representations. Ascending lemniscal
      substrates are characterized by cascading excitatory convergence/divergence that
      increments at successively higher levels between sensory afferents and area 3b.
      It is suggested that the observed preservations and transformations reflect this
      organization but, in addition, reflect mechanisms that cause counterbalancing
      sharpening and suppressions of hand inputs.

PMID- 10413775
TI  - Substantia gelatinosa neurons in the medullary dorsal horn: An intracellular
      labeling study in the rat.
AB  - Morphologic features and electrical membrane properties of neurons in the
      substantia gelatinosa (SG) of the caudal spinal trigeminal nucleus (the medullary
      dorsal horn; MDH) were examined in the rat. Intracellular recording and biocytin
      injection combined with histochemical staining were performed in horizontal
      slices. Twenty-four SG (lamina II) neurons were recorded stably and stained
      successfully. Both projection neurons (PNs; n = 9) that sent axons to regions
      outside the MDH and intrinsic neurons (INs; n = 15) that sent axons only to the
      MDH were observed. The INs were divided into those with dense axonal arborization
      (INDAs; n = 7) and those with sparse axonal arborization (INSAs; n = 8). In the
      PNs, the dendrites with spines spread to all MDH layers (laminae I-III). The main
      axons sent collaterals within the SG and rostrally, caudally, or medially to
      laminae I and III of the MDH, interpolar spinal trigeminal nucleus, spinal tract
      of the trigeminal nerve, or upper cervical cord segments. In the INDAs, the
      dendrites arising from the rostral and caudal pole of the cell bodies mainly
      extended rostrally and caudally parallel to the rostrocaudal axis of the SG: the
      dendritic trees were elongated and oval in shape and were confined within the SG.
      The axonal field of each INDA, a dense mesh of axonal processes, was elongated
      and oval in shape and almost was confined within the SG. In the INSAs, a small,
      round cell body was located in the center of each dendritic field, which usually
      was limited within the SG. Axonal processes ran radially to spread to all layers
      of the MDH, constituting round or oval axonal fields. The three groups of SG
      neurons showed more or less different intracellular responses to current
      injections. In particular, adaptation of spike frequency, hyperpolarizing sag,
      and rebound excitation were observed in the PNs and INSAs but not in the INDAs.
      Slow ramp depolarization and slow afterdepolarization were recorded only in
      INDAs.

PMID- 10413774
TI  - Traumatic brain injury in young, amyloid-beta peptide overexpressing transgenic
      mice induces marked ipsilateral hippocampal atrophy and diminished Abeta
      deposition during aging.
AB  - Traumatic brain injury (TBI) is an epigenetic risk factor for Alzheimer's disease
      (AD). To test the hypothesis that TBI contributes to the onset and/or progression
      of AD-like beta-amyloid peptide (Abeta) deposits, we studied the long-term
      effects of TBI in transgenic mice that overexpress human Abeta from a mutant
      Abeta precursor protein (APP) minigene driven by a platelet derived (PD) growth
      factor promoter (PDAPP mice). TBI was induced in 4-month-old PDAPP and wild type
      (WT) mice by controlled cortical impact (CCI). Because Abeta begins to deposit
      progressively in the PDAPP brain by 6 months, we examined WT and PDAPP mice at 2,
      5, and 8 months after TBI or sham treatment (i.e., at 6, 9, and 12 months of
      age). Hippocampal atrophy in the PDAPP mice was more severe ipsilateral versus
      contralateral to TBI, and immunohistochemical studies with antibodies to
      different Abeta peptides demonstrated a statistically significant reduction in
      hippocampus and cingulate cortex Abeta deposits ipsilateral versus contralateral
      to CCI in 9-12 month-old PDAPP mice. Hippocampal atrophy and reduced Abeta
      deposits were not seen in hippocampus or cingulate cortex of sham-injured PDAPP
      mice or in any WT mice. These data suggest that the vulnerability of brain cells
      to Abeta toxicity increases and that the accumulation of Abeta deposits decrease
      in the penumbra of CCI months after TBI. Thus, in addition to providing unique
      opportunities for elucidating genetic mechanisms of AD, transgenic mice that
      recapitulate AD pathology also may be relevant animal models for investigating
      the poorly understood role that TBI and other epigenetic risk factors play in the
      onset and/or progression of AD.

PMID- 10413776
TI  - Diversity of the calretinin immunoreactivity in the dentate gyrus of gerbils,
      hamsters, guinea pigs, and laboratory shrews.
AB  - We have recently reported that calretinin (CR) immunoreactivity in the mouse
      dentate gyrus (DG) is prominently different from that in the rat and monkey
      dentate gyrus. The CR-immunoreactive (IR) neuronal components characteristic of
      mouse DG were (1) mossy cells in the ventral hilus, (2) punctate elements in the
      inner molecular layer, (3) Cajal-Retzius cells in the molecular layer, and (4)
      immature granule cells at the basal part of the granule cell layer, which were
      also IR for highly polysialylated neural cell adhesion molecule. In this study,
      we examine the CR-IR elements in the DG of the gerbil, hamster, guinea pig, and
      laboratory shrew, and compare them with those of the rat, monkey, and mouse,
      reported previously. We show that mossy cells are distributed throughout the
      dorsoventral axis in all these animals, but mossy cells in the ventral hilus of
      the hamster, gerbil, and laboratory shrew are CR-IR, resembling those of the
      mouse, whereas mossy cells of the guinea pig are CR negative, like those of the
      rat. The inner molecular layer, the target zone of mossy cells, was observed to
      contain CR-IR punctae in the hamster, gerbil, and laboratory shrew, which
      corresponds to the CR immunoreactivity of the mossy cells. In addition, we
      observed CR-IR presumed Cajal-Retzius cells in all animals examined. On the other
      hand, CR-IR immature granule cells were encountered in the laboratory shrew, but
      not in other animals. The present study reveals prominent species differences in
      the CR-IR elements of the DG.

PMID- 10413777
TI  - Developmental expression of the group III metabotropic glutamate receptor mGluR4a
      in the medial nucleus of the trapezoid body of the rat.
AB  - A preembedding immunocytochemical method for light microscopy was used to study
      the postnatal development of expression of the group III metabotropic glutamate
      receptor mGluR4a in the medial nucleus of the trapezoid body (MNTB) of the rat.
      Immunoreactivity for mGluR4a was localized in axonal endings wrapping the
      principal globular neurons in MNTB, known as calyces of Held. The percentage of
      calyces of Held immunoreactive for mGluR4a increased progressively from postnatal
      day 3 (PND3), showing the highest density of labeled calyces by PND9. From this
      postnatal age on, a gradual reduction in the number of mGluR4a-immunopositive
      calyces of Held was observed, reaching the lowest level of labeled profiles in
      adult tissue. The developmental expression of mGluR4a in calyces of Held
      correlates well with previous studies in young animals showing a modulation of
      synaptic neurotransmission by group III mGluRs in these giant excitatory synapses
      made on MNTB principal neurons. All these observations together suggest that the
      expression of mGluR4a mainly between PND7 and PND12 might be relevant to the
      maturation and modulation of synaptic transmission at the calyces of Held.

PMID- 10413778
TI  - Nitric oxide synthase activity reveals an asymmetrical organization of the frog
      habenulae during development: A histochemical and cytoarchitectonic study from
      tadpoles to the mature Rana esculenta, with notes on the pineal complex.
AB  - In the adult frog, structural asymmetry of the left dorsal habenula in respect to
      the right counterpart has been repeatedly documented in previous studies. In the
      present investigation, histochemical expression of beta-nicotinamide adenine
      dinucleotide phosphate (NADPH)-diaphorase activity was examined in the habenulae
      of the developing and adult Rana esculenta. In tadpoles and during metamorphosis,
      selective neuropil staining was consistently found within a lateral compartment
      of the medial subnucleus of the left dorsal habenula. The staining was still
      present in the same location, but much less intense, in the mature frog,
      indicating that the neurochemical pattern observed during development was at
      least in part transient. Thus, the present data point out a peculiar
      neurochemical pattern of the habenular asymmetry in the frog, suggesting that
      nitric oxide may be involved in the developmental shaping which leads to an
      asymmetrical configuration of the habenulae. In addition, NADPH-diaphorase
      positive cells were detected in the frontal organ (the extracranial component of
      the pineal complex in strict relationship with the habenulae in the frog), and
      labeled fibers were found in the frontal nerve, which arises from the frontal
      organ. This latter finding supports the postulated relationship of the habenular
      asymmetry with the occurrence of the frontal organ. The finding of NADPH
      diaphorase histochemical reactivity confined to a distinct portion of the medial
      subnucleus of the left dorsal habenula prompted a reexamination of the
      cytoarchitecture of the developing and mature habenular complex in the frog. The
      bicompartmentalization detected with histochemistry in the medial subnucleus of
      the left dorsal habenula of the developing and adult frog was fully supported by
      the study of Nissl-stained epithalamic sections. These data point out that the
      left-right structural differences of the frog habenular complex are more complex
      than previously believed, and may be subserved by chemically regulated
      developmental processes.

PMID- 10413779
TI  - Tectotectal connectivity in goldfish.
AB  - The vertebrate optic tectum is a functionally coupled bilateral structure which
      plays a major role in the generation of motor commands for orienting responses.
      However, the characteristics of the tectotectal connectivity are unknown in fish,
      and have been reported only to a limited extent in other vertebrates. The purpose
      of the present study was to determine the anatomical basis underlying the
      functional coupling between tecta in goldfish, and to identify both similarities
      and differences to those features reported in other vertebrate species. The
      present experiments used the bidirectional tracer biotinylated dextran amine to
      map the distribution of labeled cells and synaptic boutons in the contralateral
      tectum following injections into identified tectal sites. Fibers that
      interconnect both tecta coursed through the tectal commissure. The cells of
      origin of these fibers, the tectotectal cells, and their synaptic endings were
      located in the deep layers, mainly in the strata periventricular and griseum
      central, respectively. Corresponding sites throughout the two tecta were
      interconnected in a symmetrical point-to-point fashion. The tectal commissure was
      composed of at least two distinct bundles of axons, which differed in their
      dorsoventral location, fiber diameter, and projection targets. The dorsal axons
      were tectotectal axons, they were thinner in diameter and profusely branched, and
      gave off en passant and terminal boutons in the deep layers of the contralateral
      tectum. The ventral axons were thicker in diameter, and formed the contralateral
      tectofugal-descending tract. Such fibers had few axon collaterals and boutons in
      the contralateral tectum. Boutons adjacent to retrogradely labeled tectotectal
      cells were very scarce. The data are discussed in terms of the coupling between
      tecta generating the motor commands required for orienting movements.

PMID- 10413780
TI  - Motoneurons of the axial swimming muscles in hatchling Xenopus tadpoles:
      features, distribution, and central synapses.
AB  - Xenopus tadpole motoneurons make cholinergic synapses within the spinal cord.
      This excitation changes with longitudinal position and contributes to the
      excitation that controls motor activity and its longitudinal spread during
      swimming. To explore the anatomic constraints on this excitation, backfilling has
      been used to examine the anatomy and distribution of the whole population of
      spinal motoneurons, to define the extent of their central axons and to find where
      they make synapses. Motoneuron features show considerable variation but do not
      allow their separation into primary and secondary. Most motoneurons have
      descending central axons and it is likely that central synapses are made from
      these axons as longitudinal dendritic extent is very limited. Motoneuron density
      reaches a broad plateau over the mid-trunk region at 12-13 per 100 microm. Soma
      size does not change with longitudinal position, but the dorsoventral extent of
      the dendrites decreases caudally, whereas the central axon length increases.
      Motoneuron distribution data were used to estimate the longitudinal distribution
      of central motoneuron axons. This has a broad plateau at 12-14 per 100 microm
      over much of the trunk and only decreases significantly caudal to the anus. This
      distribution correlates with cholinergic excitation during swimming. Transmission
      electron microscopy of motoneurons backfilled with horseradish peroxidase was
      used to show that central motoneuron axons make en passant synapses with
      motoneuron dendrites and the dendrites of other unstained neurons. By using
      measures of synapse frequency and total dendrite length, trunk motoneurons are
      estimated to each receive 100-200 synapses.

PMID- 10413781
TI  - Fate of new neurons in adult canary high vocal center during the first 30 days
      after their formation.
AB  - Projection neurons are added to the high vocal center (HVC) of adult songbirds.
      Here we report on events associated with their initial arrival in HVC. Neurons
      formed in adult canaries were labeled with [(3)H]-thymidine and examined 8, 15,
      22, and 31 days later. By 8 days, some [(3)H]-labeled cells with the nuclear
      profile of postmigratory neurons were already present in HVC but could not be
      retrogradely labeled by Fluoro-Gold injections in the robust nucleus of the
      archistriatum (RA); 7 days later, a few such cells could be backfilled from RA.
      Thus, new neurons may arrive in HVC as much as 1 week prior to establishing
      connections with RA. By 31 days, 43% of the [(3)H]-labeled neurons could be
      backfilled from RA. In no case were new neurons backfilled by tracer injections
      into Area X, suggesting that newly formed HVC cells do not establish a transient
      connection with this region. At all survival times, the somata of new neurons
      were often clustered tightly together with other HVC neurons that differed in age
      and projection. Between days 15 and 25 after their birth, half of the new HVC
      neurons disappeared. We conclude: (1) that neurons arrive in HVC earlier than
      previously thought, (2) that soon after their arrival they become part of cell
      clusters in HVC, and (3) that in addition to the previously described death of
      new neurons that occurs over a period of months, there is an early wave of death
      that occurs soon after new neurons adopt a postmigratory phenotype.

PMID- 10413782
TI  - Neurogenesis in the adult rat dentate gyrus is enhanced by vitamin E deficiency.
AB  - Neurogenesis occurs throughout adult life in rat dentate gyrus. Factors and
      mechanisms of adult neurogenesis regulation are not well known. Vitamin E
      deficiency has been found to deliver a neurogenetic potential in rat dorsal root
      ganglia. To determine whether the role of tocopherols in adult neurogenesis may
      be generalized to the central nervous system, changes in adult rat dentate gyrus
      neurogenesis were investigated in vitamin E deficiency. Neurogenesis was
      quantitatively studied by determination of the density of 5-bromo-2'-deoxyuridine
      (BrdU)-labeled cells and by determination of the total number of cells in the
      granule cell layer. The BrdU-labeled cells were immunocytochemically
      characterized by demonstration of neuronal marker calbindin D28K. The following
      results were found: (1) the volume of the granule layer increased in controls
      from 1 to 5 months of age, mainly due to cell density decrease; (2) the volume
      increased by a similar amount in vitamin E-deficient rats, mainly because of an
      increase in cell number; (3) BrdU-positive cells were more numerous in vitamin E
      deficient rats in comparison to age-matched controls; (4) the increase in
      proliferated cells was located in the hilus and in the plexiform layer. This
      study confirms that neurogenesis occurs within adult dentate gyrus and
      demonstrates that this process is enhanced in vitamin E deficiency. This finding
      indicates that vitamin E may be an exogenous factor regulating adult
      neurogenesis.

PMID- 10413783
TI  - Topographic organisation of extrastriate areas in the flying fox: implications
      for the evolution of mammalian visual cortex.
AB  - The organisation of extrastriate cortex was studied in anaesthetised flying foxes
      (Pteropus poliocephalus) by using multiunit recording techniques. Based on the
      visuotopic organisation and response characteristics, the cortex immediately
      rostral to the second visual area (V2) was subdivided into two fields: visual
      area 3 (V3) laterally and the occipitoparietal area (OP) medially. Area V3 is a
      1.0-1.5 mm wide strip of cortex that represents the entire contralateral
      hemifield as a mirror image of the representation found in V2. The representation
      of the vertical meridian and the area centralis form the rostral border of V3. In
      area OP, receptive fields are much larger than those of V3 and form a separate
      visuotopic map, with the upper quadrant represented rostral to the lower
      quadrant. Multiunit clusters in the cortex rostral to area OP (posterior parietal
      area) respond to both visual and somatosensory stimuli. Farther laterally, in the
      cortex rostral to V3, the occipitotemporal area (OT) was found to form yet
      another map of the visual field. Similar to the middle temporal area in primates,
      area OT in the flying fox forms a first-order representation of the visual field,
      with the lower quadrant represented medially, the upper quadrant represented
      laterally, the area centralis represented caudally, and the visual field
      periphery represented rostrally. The cortex surrounding area OT rostrally and
      ventrally is also visually responsive but could not be subdivided due to the
      large receptive fields. Finally, visual responses were elicited from an area
      adjacent to the peripheral representation in the first visual area (V1) in the
      splenial sulcus. These results demonstrate that nearly half of the flying fox
      cortex is related to vision, which contrasts with that of microchiropteran bats,
      in which auditory areas predominate. A comparison of the flying fox with other
      mammals suggests that several areas, including homologues of V1, V2, V3, OT, and
      the splenial area, may have originated early in mammalian evolution and have been
      inherited by most present-day eutherians. However, studies in other species will
      be needed to distinguish patterns of common ancestry from parallel evolution.

PMID- 10413785
TI  - Development of a mouse limb transplantation model.
AB  - A tremendous amount of research has been dedicated to laying the groundwork that
      will eventually lead to successful limb transplantation in humans. Limb
      transplantation in animal models has also been widely used for evaluating
      composite tissue allografts and various immunosuppressive regimens. Currently,
      there is no mouse model of limb transplantation. Such a model is attractive
      because it would allow investigators to apply the well-defined genetic
      characteristics of the mouse to the challenging field of limb transplantation. In
      this study, 12 mice underwent orthotopic hind limb transplantations using end-to
      end anastomoses of the femoral vessels. The success rate of this surgical
      procedure was 83%, with 10 of the 12 limbs surviving. Experimental devices,
      operative procedures, and the major elements of success are discussed.

PMID- 10413784
TI  - Origin, distribution, and morphology of galaninergic fibers in the rodent
      trigeminal system.
AB  - The neuropeptide galanin (Gal) is found throughout the central nervous system. Of
      particular interest is the fact that Gal is present within the majority of
      noradrenergic locus coeruleus (LC) neurons. However, very few, if any, Gal
      immunoreactive fibers have been identified in many of the major efferent targets
      of LC, including sensory neocortex and dorsal thalamus. The goal of the present
      study was to examine the Gal fiber innervation of the rodent trigeminal
      somatosensory system and its connection to the LC. Our results show that at least
      two different morphological profiles of Gal-immunoreactive fibers are present
      within relay nuclei along the ascending trigeminal pathway. Numerous small
      caliber Gal-immunoreactive fibers with bouton-like swellings were noted within
      the barrel cortex, the ventroposterior medial (VPM) nucleus, the posterior medial
      (POm) nucleus, the zona incerta (ZI), the reticular nucleus (nRT) of the
      thalamus, and the principal (PrV) and spinal (SpV) nuclei of the trigeminal
      complex. Immunoreactive fibers were prevalent in, but not restricted to, layer I
      of the barrel cortex. Within the somatosensory thalamus, the density of Gal
      immunoreactive fibers was higher in POm than in VPM. Laminae I and II of SpV and
      the nRT and ZI also contained dense, large-diameter Gal-immunoreactive fibers.
      These large-diameter Gal-immunoreactive fibers did not co-contain dopamine beta
      hydroxylase (DBH). In contrast, virtually every small-caliber Gal-immunoreactive
      fiber colocalized with DBH. To determine whether Gal-immunoreactive fibers
      originated from LC, we combined immunohistochemical procedures with fluorescent
      tracing techniques. After retrograde tracer injections into several trigeminal
      relay nuclei, we observed that approximately 50% of the labeled LC neuronal
      population was immunoreactive for Gal. Our results suggest an extensive Gal
      immunoreactive fiber innervation of the rodent trigeminal system, much of which
      may originate from LC neurons in the brainstem.

PMID- 10413787
TI  - Restoration of walking in paraplegia by transferring the ulnar nerve to the hip:
      A report on the first patient.
AB  - There is no known way to make paraplegics walk when their spinal cord is
      completely transected. Many researchers worldwide have been developing different
      methods to solve this problem. We believe that transferring a sound nerve from
      the upper limb to the main muscles of the hip could help paraplegics to walk,
      although light orthotic devices would still be needed. We chose to transfer the
      ulnar nerve because it is the longest in the upper limb and can reach the glutei
      without grafts. In addition, palsy of the ulnar nerve can be repaired by
      classical reconstructive surgery. After many years of research in animals and
      after obtaining permission from the Ethical Committee of the National Health
      Surgery, we operated on three human beings bilaterally. The first patient is
      walking. Two are still recovering.

PMID- 10413786
TI  - Microcirculatory changes following different temperature washouts in a free flap
      model.
AB  - In spite of the extensive experimental work on vascular washout in free flap
      surgery, an optimal temperature for the washout solution has not been
      established. This study was designed to determine the effect of the washout
      solution temperature on the degree to which the microcirculation is cleared of
      blood. The cremaster muscle flap in the rat was used, in which the
      microcirculation can be directly viewed and the presence of blood and perfusion
      parameters within various vessels can be measured during and after washout.
      Washout was started with a single, high-pressure infusion and continued at 130
      mmHg for 15 minutes. The temperature of the washout solution was either 2-3, 20
      22, or 35 degrees C. In all three groups, washout cleared the microcirculation
      almost completely within the first minute. However, we observed that a cold or
      room temperature washout cleared the microcirculation more completely than a warm
      washout did. The temperature of the washout solution did not effect post washout
      capillary perfusion and/or arterial diameters.

PMID- 10413788
TI  - Calf augmentation using free TRAM flap.
AB  - Augmentation of the calf for correction of contour deformities has been most
      frequently performed utilizing silicone implants. Results of such implants have
      often been unsatisfactory. We report the case of a 27-year-old woman who chose
      the use of a transverse rectus abdominis myocutaneous (TRAM) free flap for
      correction of a left calf contour deformity from childhood polio. This is the
      first report of calf augmentation with the use of a TRAM free flap and excellent
      results were obtained.

PMID- 10413790
TI  - Experimental study on vascularized island pedicle bone graft: bony fusion between
      the graft and the recipient floor.
AB  - To evaluate the process of bony fusion between the recipient floor and the bone
      graft, where a muscle sleeve has been interposed, an experimental model for a
      vascularized island pedicle bone graft was prepared using rats. The proximal two
      thirds of the tibia pedicled with the popliteal artery and vein was collected to
      be used as a vascularized bone. This was onlay grafted to the femur of the same
      limb in such a manner that the muscle sleeve was interposed between the bone
      graft and the recipient floor. The animals subjected to this procedure were
      designated as the vascularized island pedicle bone graft group (hereafter called
      group V, n = 32). In another group, vascular pedicles were interrupted by
      ligation and the animals were subjected to nonvascularized bone graft (hereafter
      called group N, n = 32). In the third group, an appropriate amount of bone chips
      was transplanted throughout the length of the grafted floor; then the animals
      were subjected to additional vascularized island pedicle bone graft (hereafter
      called group B, n = 13). In groups V and B, the vascularized bone graft formed
      new bone at the site where the bone graft faced the recipient floor 6 weeks after
      surgery. Hypertrophy of the bone graft was noted. Bony fusion at the section
      where a muscle sleeve had been interposed was recognized only in group B.
      Chondrocytes were found around the free bone graft, suggesting chondrocyte
      participation in osteogenesis. In group N, the bone graft had been absorbed and
      no bony fusion was recognized between the bone graft and recipient floor in any
      of the samples. These findings imply that it is important to minimize the size of
      the muscle sleeve attached to the vascularized island pedicle bone graft and add
      free bone chips around the grafted bone to assure bony fusion between a
      vascularized bone graft and the recipient floor in clinical practice.

PMID- 10413789
TI  - Anterolateral thigh flap: A review of 168 cases.
AB  - The anterolateral thigh flap based on the descending branch of the lateral
      circumflex femoral vessel is one of the musculocutaneous or septocutaneous flaps
      in the thigh. The descending branch of the lateral circumflex femoral vessel has
      either perforating branches or direct cutaneous branches from the intermuscular
      space to the anterolateral femoral skin. Since 1983, we have transferred 168
      anterolateral thigh flaps for reconstruction of old burn scars, infected wounds,
      carcinoma excisions, for coverage of open bone fracture of the lower leg, and for
      congenital diseases. One hundred fifty-two cases were free flaps. The other 16
      cases were pedicled flaps. The skin branches were divided into four types in our
      clinical series: musculocutaneous perforators (135/168 [80.4%]); intermuscular
      cutaneous perforators (16/168 [9.5%]); direct cutaneous branches (14/168 [8.3%]);
      and tiny cutaneous perforators (3/168 [1.8%]). The results were satisfactory.
      Only one case resulted in a failure due to tiny cutaneous branches.

PMID- 10413791
TI  - Long-term evaluation of functional nerve recovery after reconstruction with a
      thin-walled biodegradable poly (DL-lactide-epsilon-caprolactone) nerve guide,
      using walking track analysis and electrostimulation tests.
AB  - This study was performed to evaluate the long-term functional nerve recovery
      after reconstruction of a 10-mm gap in the sciatic nerve of the rat, with a thin
      walled nerve guide, composed of a biodegradable copolymer of DL-lactide and
      epsilon-caprolactone [p(DLLA-epsilon-CL)]. To evaluate both motor and sensory
      nerve recovery, walking track analysis and electrostimulation tests were carried
      out after implantation periods ranging from 3 to 52 weeks postoperatively. The
      first signs of both motor and sensory nerve recovery could be observed after 5
      weeks. After 15 weeks, 70% of the sciatic function and 90% of the sensory nerve
      function had been recovered. After this period, the sciatic function index (SFI)
      did not improve further, whereas the sensory nerve function appeared to return to
      normal. When the results of the SFI measurements, minus those obtained from rats
      with severe automutilation, are extrapolated, further improvement of the SFI
      might be expected after 52 weeks. The fact that 100% sensory nerve recovery was
      obtained, as measured by the electrostimulation test, could be explained by
      sensory reinnervation from surrounding areas. The SFI was not fully reestablished
      because automutilation had a great impact on the use of walking track assessment.

PMID- 10413792
TI  - Measurement of blood flow and oxygen tension in adjacent tissues in pedicled and
      free flap head and neck reconstruction.
AB  - The purpose of this study was to evaluate blood flow and transcutaneous partial
      oxygen pressure (TcPO(2)) in adjacent tissues to free and pedicled flaps
      following reconstructive procedures used in conjunction with radical surgery for
      head and neck cancers. Fifty patients were included. Fourteen patients had
      reconstruction with pedicled flaps and 36 with free flaps. For each patient,
      TcPO(2) and laser Doppler flow measurements were taken at the center of the flap,
      in adjacent tissue, and in a corresponding contralateral site. Three laser
      Doppler measurements were performed at each site and a mean value recorded. All
      patients had undergone reconstruction up to 6 months prior to the time of the
      measurements. The collected data were analyzed using a Wilcoxon signed rank test.
      There were no statistically significant differences in partial oxygen tension or
      laser Doppler values between tissues adjacent to free compared to pedicled flaps.
      Although there is strong evidence to support that free flaps have improved blood
      flow and partial oxygen tension over pedicled flaps, further study is required to
      evaluate adjacent tissues. Flap choice may assist with alteration in blood flow
      in less favorable defects such as those in previously irradiated fields and those
      resulting from burn scars or chronic infections.

PMID- 10413793
TI  - Stoichiometry of the Topa Quinone Biogenesis Reaction in Copper Amine Oxidases.

PMID- 10413794
TI  - Backbone Dynamics of Apocytochrome b(5) in Its Native, Partially Folded State.

PMID- 10413796
TI  - Correction: A Comparison of Three Months of Anticoagulation with Extended
      Anticoagulation for a First Episode of Idiopathic Venous Thromboembolism.

PMID- 10413795
TI  - Marked differences in lipid-lowering drug use in bologna, italy and funen,
      denmark 

PMID- 10413797
TI  - [Early rehabilitation in the hospital--time for structural changes].
AB  - Although it has long been undisputed that successful rehabilitation outcomes
      require early-onset, comprehensive rehabilitative intervention, research findings
      show that major shortcomings exist concerning the provision of rehabilitative
      care in hospitals. Contrary to the statutory premises at hand, a majority of
      hospitals continue to consider rehabilitation a treatment phase scheduled to set
      in only after completion of acute care. "Rehabilitation of the first day", a long
      standing demand among the professional community, is hardly taking place at all.
      The rank of hospital-integrated early rehabilitation has now been confirmed in
      the framework of a model facility supported by the Federal ministry of labour and
      social order, with the recently completed scientific follow-along of the
      Ingolstadt Klinikum department for transdisciplinary early rehabilitation having
      made available research evidence of the effectiveness and efficiency of early
      onset, comprehensive rehabilitation interventions in the hospital, and presented
      in this article for the first time.

PMID- 10413798
TI  - [Treatment satisfaction in cardiologic rehabilitation and attitude to various
      forms of rehabilitation].
AB  - A great majority (85% to 92%, N = 196) of the cardiological patients in inpatient
      rehabilitation, who were investigated in this study, expressed clear satisfaction
      with inpatient care and in particular with medical treatment as well as with the
      commitment and skills of doctors and other caregivers. The usefulness of
      treatments and measures was mainly confirmed, especially with respect to remedial
      gymnastics, physiotherapy and rehabilitation sports. But unspecific offers of
      inpatient rehabilitation are obviously also evaluated positively, e.g.
      "distancing from everyday stress" and "cultural events" outside the clinics.
      Relaxation training and psychosocial counseling were used only by one third
      approximately, but most of the users gave "useful" or "very useful" evaluation
      ratings. 77% would again choose inpatient rehabilitation if they were confronted
      with this decision. 15% would prefer partial-hospitalization, only 4% ambulatory
      rehabilitation. 36% say that "near-home rehabilitation" basically is more
      favourable, but 33% prefer the opposite and say that rehabilitation far away from
      home has greater advantages. Only 8% consider ambulatory rehabilitation a
      possible replacement of inpatient rehabilitation, 66% say it is complementary to
      the inpatient mode.

PMID- 10413799
TI  - [Ambulatory heart groups after inpatient cardiologic rehabilitation].
AB  - In n = 1504 consecutive patients after inpatient cardiac rehabilitation, we
      investigate how many patients can be motivated to join a so-called outpatient
      heart group, which sociographical and medical variables influence participation,
      and whether participation in a heart group prompts a more health-orientated
      nutrition. Applying a special team-based motivation programme, almost 30% of
      patients undergoing cardiac rehabilitation under the pension insurance scheme for
      workers can be motivated to join a heart group, who otherwise can hardly be
      prompted to do so. About 75% of them still participate in the heart group 7
      months later. Initial and continuing participation are more probable in patients
      of middle age, male gender, with previous PTCA, moderately or severely restricted
      left ventricular function, and--for patients up to the age of 55 years--in case
      of reintegration or expected reintegration into work life. Patients after heart
      valve surgery are significantly less liable to join a heart group than CHD
      patients. Seven months after cardiac rehabilitation, medium cholesterol values
      have less increased among participants of heart groups than among non
      participants. This may indicate a more stabilized health-orientated lifestyle
      among members of heart groups.

PMID- 10413800
TI  - [Prognostic criteria for rehabilitation of stroke patients].
AB  - The present study had been aimed at identifying factors influencing the
      rehabilitation outcome of stroke patients and at verifying the rank of these
      factors from a prognostic angle. It was found on a population of 361 patients
      that age, gender and the risk factors arterial hypertension and diabetes
      mellitus, when viewed in isolation, do not have a significant influence on
      rehabilitation outcome. In light of this finding, great prognostic significance
      is attached to the course of therapy as such. We have been able to show that, in
      a majority of the patients, a reliable estimate of the final outcome attained can
      already be made within the initial four weeks of treatment based on an
      empirically determined targeted weekly gain of 5 Barthel points. It is shown on a
      group of 118 patients that application of this prognostic index has benefitted
      some 87% of the patients in terms of duration of therapy.

PMID- 10413801
TI  - [Conceptual development of partial inpatient psychosomatic rehabilitation].
AB  - The conceptual development of partial hospitalization treatment is a present-day
      task for psychosomatic rehabilitation. For this task the general regulations of
      the pension insurance agencies as well as the conceptions existing in the field
      of psychosomatics and psychotherapy can serve as a sufficient basis for the
      conceptual development of partial hospitalization psychosomatic rehabilitation
      inspite of several differences between them. The elaboration of concrete outlines
      of this kind of psychosomatic rehabilitation takes place within a framework of
      structural models which encompasses different variants of institutional,
      organizational, functional and content forms of partial hospitalization
      rehabilitation. Moreover, the conceptual development of day treatment in
      rehabilitation raises several questions of the overall system of psychosomatic
      rehabilitation and offers possible solutions of general problems in psychosomatic
      rehabilitation. On this conceptual basis, in the further construction of partial
      hospitalization in psychosomatic rehabilitation concrete models should be
      designed and tested in clinical practice along with scientific evaluation.

PMID- 10413802
TI  - [Community integrated living with reliable care in the service home: the status
      of young handicapped patients in a model project "House at Weinberg" in
      Stuttgart].
AB  - A novel form of residence for persons with physical disablement is presented on
      the example of the Stuttgart "House on the Vineyard". In fully self-contained
      apartments integrated in a service residence, physically disabled individuals
      under age 60 live door-to-door with elderly people, with custom services being
      available as and when needed, ranging from nursing, Social Service, meals and
      home-making, janitor, to nursing and care services on a long-term basis as well
      as in case of extensive care needs. Findings presented from the model project's
      scientific evaluation inter alia refer to the long-term development seen in how
      Old and Young or those with lesser and more extensive care needs are getting
      along, and implications are set out that should be heeded in planning similar
      projects. A major source for compiling this information had been structured
      qualitative interviews with the tenants concerned.

PMID- 10413803
TI  - [Expert assessment of rehabilitation for social medicine legal experts--a
      discussion contribution to quality assurance. From the Quality Management Study
      Group of the German Society of Social Medicine and Prevention].

PMID- 10413804
TI  - [Public health structural reform and health insurance--corner stones of the
      German Society of Rehabilitation of Handicapped Persons].

PMID- 10413805
TI  - ["Supporting the rights of the handicapped"--memorandum by the German Society of
      Rehabilitation of Handicapped Persons].

PMID- 10413806
TI  - [Recommendations of the German Society of Rehabilitation of Handicapped for
      establishing a qualified ambulatory community rehabilitation].

PMID- 10413807
TI  - [Promotion and therapy of children with hearing loss (hearing aids)--statement of
      the DVfR Study Committee of Hearing, Voice and Speech Disorders].

PMID- 10413808
TI  - [7th European Regional Conference of International Rehabilitation with Assembly
      and Panel Meetings 1998 from 29 November to 4 December 1998 in Jerusalem].

PMID- 10413809
TI  - ["General practice" educational goals: the role of anatomy, exemplified by the
      lymphatic system].
AB  - One of the most frequent criticisms of present-day medical studies is that they
      are unrelated to practical clinical needs. This criticism is levelled in
      particular at the preclinical stage. The present article is a contribution to
      finding a pragmatic solution to this problem. The design of the study is a survey
      of a representative sample of general practitioners who were asked to identify,
      from a complete list of structures included in the international anatomic
      nomenclature, those items that they regarded as indispensable in practice. Two
      main conclusions emerged from the survey: (1) there was a very high degree of
      concordance among the choices made by the physicians involved (including 92.3% of
      structures listed for the lymphatic system); (2) the quota of structures
      considered to be of practical clinical relevance was small (15.4%). These results
      suggest that it would be possible to teach a clinically relevant common trunk of
      knowledge to medical students. For this purpose, however, similar studies need to
      be undertaken for the other basic medical sciences. Furthermore, to ensure that
      medical education is really related to practical needs, clinicians will need to
      exert influence on the policy and content of teaching programmes in departments
      of basic medical science.

PMID- 10413810
TI  - [Development of mortality in Switzerland since 1950. I. International comparison
      and differences in sex, age and nationality].
AB  - BACKGROUND: All-cause mortality is an important criterion for assessing the
      health status and the living conditions of a population, thus indicating possible
      preventive measures. DATA AND METHODS: Descriptive analyses of Swiss mortality
      records and a comparison with the WHO mortality data bank for the period since
      1950. RESULTS: Age-specific mortality trends in Switzerland are traced back to
      1950 and compared with the situation in other European countries. At the
      beginning of the 1950s Swiss all-cause mortality rates were about the European
      average; now they are among the lowest worldwide. In most age classes, rates
      declined by more than one third between 1951/54 and 1990/94, in females even by
      more than 50%. This rather optimistic overall picture conceals less favourable
      partial trends. The decline in mortality rates in men aged 20-49 and women aged
      20-34 years did not continue after 1970, and for males aged 20-44 and females
      aged 25-34 mortality risks have even increased in recent years. In both males and
      females, mortality rates from injury and poisoning (mainly accidents and suicide)
      exceed those of European low-incidence countries by 100%. On an international
      scale Swiss subjects aged between 15 and 44 years are at much higher risk, even
      when deaths from injury and poisoning, the most important cause of death in these
      ages, are excluded. When compared with their Swedish contemporaries, Swiss males
      aged 25-34 years have almost twice the risk of dying from a "natural" as well as
      from an "external" cause. As a rule, male/female sex ratios of mortality
      continued to increase, except in subjects aged 45-64 years. CONCLUSION: In spite
      of low overall mortality risks, international age-specific rates suggest
      considerable potential for preventive measures in Switzerland. There is some
      evidence of substantial under-registration of the mortality risks of foreigners
      living in Switzerland. As foreigners represent a substantial part of the total
      population--with a maximum of 30% of men aged 25-34 years--figures for
      Switzerland as a whole may be biased seriously. Therefore, for mortality analyses
      and comparisons with international data, we suggest the study be restricted to
      Swiss citizens. When assessing mortality risks for foreigners in Switzerland
      alternative data sources and methods should be taken into account.

PMID- 10413811
TI  - [Medically indicated termination of pregnancy in giant uterine myoma and mono
      amniotic twin pregnancy: a case report].
AB  - We report the rare combination of a monoamniotic twin pregnancy with giant
      uterine leiomyomas in a 33-year-old para 0, gravida 1. Considering the restricted
      capacity of uterine expansion during pregnancy and the known complications
      associated with myomas, as well as the elevated morbidity and mortality of
      monoamniotic twin pregnancies, we opted for a medically indicated abortion at 12
      weeks' gestation. After abortion the patient developed fever and abdominal pain.
      In differential diagnosis we considered endomyometritis and necrosis of the
      myomas. Despite adequate conservative treatment the symptoms persisted and
      myomectomy was performed in view of the patient's desire to maintain fertility.

PMID- 10413812
TI  - [Distal radius fractures].
AB  - Fractures of the distal end of the radius are the most common fractures in
      humans. The variants of type of fracture and associated injuries are numerous,
      depending on the mechanism of injury, the amount of energy absorbed and the
      quality of the bone. Treatment concepts evolve as our understanding of the
      physiopathology of this heterogeneous group of injuries increases. It is now
      commonly accepted that extraarticular anatomy and joint congruency, as well as
      ligamentous integrity, should be restored to obtain a good functional result.
      This paper provides an overview of current knowledge and discusses possible
      future trends.

PMID- 10413813
TI  - [Pelvic plasmacytoma].

PMID- 10413814
TI  - [Indications criteria for total cavopulmonary anastomosis (Fontan operation)].
AB  - OBJECTIVES: In a retrospective study we evaluated the predictive value of the
      traditional risk factors (Fontan criteria) for mortality and morbidity after
      total cavopulmonary anastomosis (Fontan operation). DESIGN: We studied 51
      consecutive patients who underwent Fontan operations from 1982 through 1994.
      Morbidity was assessed by a score taking equally into account rhythm
      disturbances, cardiovascular hospital admissions and heart failure. RESULTS: The
      mean age at operation was 4.1 +/- 3.4 years. Diagnoses were tricuspid atresia in
      20, complex single ventricle in 13 and various complex congenital heart defects
      in 18 patients. All Fontan criteria were fulfilled in 11 patients while in the
      remaining 40 up to 6 criteria were not met. The criteria least fulfilled were age
      in 31 patients and pulmonary artery anatomy in 11. The mean follow-up was 4.6 +/-
      3.0 years. The overall 30-day survival was 84% and 1- and 10-year survival 76.5%
      respectively. All patients who fulfilled all the Fontan criteria survived. The
      overall mortality and early mortality were associated with a significantly higher
      number of unfulfilled Fontan criteria (p < 0.01). Age below 2 years at operation
      and pulmonary resistance > 4 Woods units were risk factors for overall mortality
      (p < 0.01). The number of unmet Fontan criteria was not significantly different
      in patients with and without postoperative late morbidity. CONCLUSIONS: The
      Fontan criteria are reliable predictors for mortality but have little predictive
      value for morbidity. Surviving patients who do not fulfil all criteria suggest
      that some criteria may need to be modified. Our limited data support a lower age
      limit of 2 instead of 4 years.

PMID- 10413816
TI  - Revival of tetracyclines--in the treatment of visceral leishmaniasis?
AB  - A 37-year-old immigrant from Kosovo who had been in Switzerland for 2 years
      developed fever, cough, weight loss and malaise. Serology (complement binding
      reaction) was positive for leptospirosis. The symptoms resolved very rapidly
      under vibramycin 2 x 100 mg/day for 3 weeks. However, a flare-up occurred after
      cessation of medication. Reexposure to tetracyclines improved the symptoms though
      they did not subside completely. Bone marrow analysis demonstrated intracellular
      leishmania (amastigotes). Analysis of frozen serum preserved since the first
      hospitalisation and samples from the second admission were positive for
      leishmania (indirect fluorescence antibody test) and confirmed the diagnosis of
      visceral leishmaniasis. Reevaluation of the serology for leptospirosis was
      negative using the specific microagglutination method. Treatment with antimony
      for 28 days resolved all symptoms. The parasites of visceral leishmaniasis grow
      intracellularly and eradication may be impossible in patients with an impaired
      cellular immune response. Flare-ups thus recur in 60-100% of patients with organ
      transplants or AIDS, despite regular treatment. Our finding raises the question
      whether relapses are suppressed in immunocompromised patients by tetracyclines,
      drugs known to be well tolerated even under long-term exposure. Randomised
      studies are required in this setting.

PMID- 10413815
TI  - [Changes in mortality in Switzerland since 1950. II. Regional differences within
      Switzerland].
AB  - OBJECTIVES: To examine regional variations in all-cause mortality in Switzerland
      around 1990 and trends since 1950. Special emphasis is placed on unfavourable
      aspects that have been identified by comparisons with international trends. DATA
      AND METHODS: Descriptive analysis of Swiss mortality statistics taken from
      individual records (1969-94) and data published by the Swiss Federal Statistical
      Office (1949-68). RESULTS: Swiss citizens aged between 15 and 79 years often show
      mortality ratios of 1.5 and more between the best and the worst of the 106
      regions of Switzerland. In subjects aged under 50 years, relative risk ranges are
      even larger. However, the regional mortality patterns before and after 50 rarely
      correspond. Generally, the relative risk difference between the best and the
      worst regions has not diminished since 1950, whereas the geographical patterns
      have completely changed. Instead of an obvious rural-urban gradient in 1950,
      mortality rates are now highest in the largest cities and, at least in men, are
      at their lowest in the wealthy suburbs. On a larger scale (division into 9
      geographical units), central Switzerland has changed significantly from clearly
      elevated mortality rates in 1950 into a decidedly favourable position in 1990. A
      contrast between German and French Switzerland has existed for many decades: in
      the younger and middle age groups the francophone part of Switzerland has a
      higher mortality rate than the German-speaking part, whereas at ages over 70
      French Switzerland has lower rates than German Switzerland. In some urban areas
      of Switzerland, the turning-point from a decreasing to an increasing trend in the
      mortality risks of subjects aged 15-49 years was reached around 1960,
      occasionally resulting in age-specific rates being higher in 1990 than in 1950.
      This unfavourable partial trend has spread over most, but not all, of Switzerland
      since 1970. Even in subjects aged 25-34 years, the age group for which
      Switzerland has the worst relative position on an international scale, some parts
      of the country do not have elevated all-cause mortality rates, whereas for men in
      the largest cities mortality risks are more than three times as high as in Japan.
      The deaths from "external" causes (mainly accidents and suicide) show marked
      geographical patterns within Switzerland; however, in all parts of the country,
      deaths from this group are much more frequent than, for example, in Italy or the
      Netherlands. CONCLUSION: Geographical differences in mortality risks within
      Switzerland, as well as international disparities, suggest that there is a need
      for preventive measures in Switzerland, first and foremost concerning males aged
      15-49 years and deaths from "external" causes.

PMID- 10413818
TI  - Posterior mediastinal neurofibrosarcoma in a patient with von Recklinghausen's
      disease.

PMID- 10413817
TI  - [Persistent erythema after total CO2 skin resurfacing].
AB  - Erythema after carbon dioxide laser resurfacing is one among other known side
      effects of the treatment. Postoperative erythema is considered to be an
      obligatory complication after resurfacing of facial rhytides or senile
      lentigines. Duration and intensity of the erythema is dependent on various
      factors, as shown in the following case report on a 77-year-old female patient.
      Detailed preoperative information is important in ensuring realistic expectations
      in regard to the postoperative results and averting liability claims.

PMID- 10413819
TI  - [Maculopapular exanthema: should suspected drugs continue to be used?].

PMID- 10413820
TI  - [The atypical nevus: a risk situation?].
AB  - Many studies using different approaches and sets of data have concluded that
      there is a significantly increased risk of malignant melanoma in patients with
      atypical moles. For clinical identification, the features of ABCD's (Asymmetry,
      Border, Colour, Dimension) are used, the "ugly duckling" sign (the naevus that
      does not resemble its "brother naevi"), dermatoscopy and digital approaches.
      After excision, histologic criteria are used to identify naevi with architectural
      changes. It has recently been possible to identify allelic losses within known
      tumour suppressor genes in microdissected atypical moles, using microdissection
      and loss of heterozygosity analysis, thus providing additional evidence for the
      concept of the atypical mole as a precursor lesion of melanoma.

PMID- 10413821
TI  - [Prevalence of coronary risk factors in 233 men with coronary heart disease. Role
      of HDL cholesterol].
AB  - In 233 male patients (age 35 to 90 years) with coronary heart disease, chiefly
      myocardial infarction, the prevalence of the established coronary risk factors
      was investigated: total cholesterol, HDL- and LDL-cholesterol, triglycerides,
      hypertension, smoking, overweight, diabetes, heredity, physical inactivity and
      psychosocial stress. Cigarette smoking shows the highest prevalence (54%),
      followed by hypertension (39%), overweight (38.6%) and hypercholesterolaemia
      (34.7%). In patients over 65 the prevalence of these coronary risk factors is
      lower, whereas physical inactivity and diabetes are more frequent than in the
      younger group. Combinations of the main coronary risk factors are much more
      frequent in the younger group. HDL-cholesterol was found to be lower than normal
      (below 0.91 mmol/l) in 27% irrespective of age. The lower the concentration of
      HDL-cholesterol the more frequent are the following coronary risk factors:
      smoking, overweight, diabetes, physical inactivity and hypertriglyceridaemia. We
      suspect that a low HDL-cholesterol concentration in many individuals may be the
      result of a clustering of the aforementioned risk factors. For practical purposes
      it seems important to evaluate all relevant risk factors in an individual and to
      concentrate intervention on those with a fair chance of success, especially
      smoking and hypertension in the younger subjects. Normal or elevated HDL
      cholesterol in itself is not a reliable cardioprotective factor since it is
      normal or elevated in two thirds of our coronary heart disease patients.

PMID- 10413822
TI  - [Possible future of the project for quality assurance of indications and outcome
      in interventional cardiology and gynecology].
AB  - In the last few years the basis for national guidelines for the indications of
      coronary angiography, coronary revascularisation and hysterectomy has been
      established. The guidelines have been published and are accessible to medical
      doctors and patients on the Internet using a database system called "Second
      Opinion System": http:/(/)sos.inf.ethz.ch Dissemination, implementation and
      validation of the guidelines will be of major importance in the near future. With
      reference to validation, the question remains whether the established guidelines
      are correct for the everyday treatment of patients. A suitable method of
      answering this important question is comparison between the appropriateness and
      necessity rates of the various indication groups, combined with outcome
      measurements. The Internet-based second opinion system (SOS) may be used for data
      collection in order to verify hypotheses. Because of the database architecture,
      only relevant information about the patients is collected via Internet,
      independent of time and place. In addition, the system allows users to evaluate
      their individual data, and special attention is given to data protection. The
      discussion about priorities in health care (rationing) will be increasingly
      important in the near future. The present project may offer a way of maintaining
      adequate access to health care services for patients. Therefore, the
      participation of as many institutions as possible in the project "quality
      assurance of indication and outcome in interventional cardiology and in
      gynaecology" is of great importance.

PMID- 10413823
TI  - [Leptospirosis (Weil's syndrome) with renal failure, severe jaundice,
      disseminated hemorrhages and xanthopsia].
AB  - We report a case of a 48-year-old man from western Austria with severe
      leptospirosis. This disease occurs worldwide but predominates in the tropics. The
      infectious urine of a wide variety of domestic and wild animals mediates
      transmission of the infection, which characteristically has a biphasic pattern.
      It begins with the "leptospiraemic phase" with high fever, conjunctival
      suffusion, muscle pain and headache. Hepatitis, nephritis and haemorrhages may
      follow. The second "immune phase" has a greater variety of clinical
      manifestations. Fever and the initial symptoms may recur and the central and
      peripheral nervous system may be involved. The patient reported showed all major
      characteristics except conjunctival suffusion. The outcome was favourable despite
      some conditions with a poor prognosis (jaundice, renal failure, haemorrhages).
      The extreme severity of jaundice and the xanthopsia (yellow vision) make the case
      unique.

PMID- 10413824
TI  - [Liver metastasis?].

PMID- 10413825
TI  - [Allergology: quo vadis?].
AB  - The discovery of the immunoglobulin E 30 years ago, and the subsequent
      availability of serological techniques for in vitro allergy tests, have given
      fresh impetus to allergy diagnosis in clinical practice. Independently of the
      more refined allergy diagnosis, there has been a continuous increase in allergic
      diseases in recent decades. Various factors, summed by the term "Western
      lifestyle", have produced this increase. As well as individual measures (primary,
      secondary and tertiary allergy prevention), intensive interdisciplinary
      cooperation is necessary to arrive at a broad and successful prevention concept.
      Governments and the political community should accord higher priority than
      hitherto to fighting allergies, which are now the primary environmental diseases.
      Parallel to progress in fundamental immunology and the introduction of effective
      drugs for symptomatic treatment of the various atopic manifestations, a problem
      facing us today is the growing popularity among the public of "alternative
      medicine" for the treatment of allergies, even though many of these
      unconventional diagnostic and therapeutic methods are judged pseudoscientific and
      their efficacy is unproven. The allergy patient is increasingly caught in the tug
      of-war between allopathic and "alternative" medicine, pharmacists, so-called
      "natural healers", patient and consumer organisations and the mass media.
      Expectations of successful results from "natural", "soft", "Chinese" or "Tibetan"
      medicine are high, along with the corresponding marked placebo effect and
      scepticism about allopathic medicine. This "nocebo" effect thrives on
      psychosocial territory and is fostered by public opinion. Evidence of this is the
      rise of new environment-related forms of disease for which there is no proof of a
      toxic or immunologic origin ("idiopathic environment-related intolerances",
      according to the new WHO terminology). Allopathic and complementary medicine are
      often consumed together, thus increasing treatment costs. At the same time, fewer
      and fewer allergy patients are treated by allergen immunotherapy, the only
      treatment which can affect the natural course of allergic disease and which may
      also prevent the development of asthma in patients which allergic rhinitis.

PMID- 10413826
TI  - [Adverse internal medicine drug effects at hospital admission].
AB  - Hospital admissions due to adverse drug reactions are an important concern, but
      there are few data concerning the specific situation in Switzerland. During one
      year we therefore prospectively studied all admissions to our medical department
      to determine the profile. 138 of 2168 patients presented a total of 150 adverse
      drug reactions at hospitalisation (6.4%) and among them 65% of the admissions
      were directly related to adverse drug reaction. Age stratification revealed that
      with each decade of age there was an increasing risk of adverse drug reactions
      and that the patients were sicker (more diagnoses), were consuming more drugs and
      had longer stays. The majority of adverse drug reactions were type A reactions
      and therefore potentially preventable. Cardio- and cerebrovascular drugs
      (diuretics, ACE-inhibitors, platelet aggregation inhibiting therapy) accounted
      for 65% of the side effects. Analysed by affected organ system, the most frequent
      adverse drug reactions were gastrointestinal complications followed by
      dehydration (contracted extracellular fluid volume) and hypo-/hyperkalaemia. Non
      compliance by the patients was less frequently at the origin of the admission
      than iatrogenic causes related to physician errors. The patients generally did
      not know the reasons, details and side effects of their medical treatment. Based
      on our data, we estimate that the national number of drug-related hospital
      admissions caused by inappropriate or unnecessary treatment is 12,000-16,000,
      with direct annual extra costs of 70-100 million Swiss francs. Adverse drug
      reactions therefore represent a serious medical and financial problem.
      Specialised computing systems designed to reduce these events should be
      introduced in hospitals and ambulatory care.

PMID- 10413827
TI  - Sustained improvement of performance and haemodynamics with long-term aerosolised
      prostacyclin therapy in severe pulmonary hypertension.
AB  - Primary pulmonary hypertension and pulmonary hypertension associated with
      collagen vascular disease or HIV infection are rapidly progressive fatal diseases
      in spite of conventional medical therapy. Continuous intravenous infusion of
      prostacyclin has been shown to prolong life in severe primary pulmonary
      hypertension, and aerosolised prostacyclin has been used successfully on a short
      term basis in patients with pulmonary hypertension. We investigated the effects
      of acute administration of aerosolised prostacyclin or its analogue iloprost in 5
      patients with severe pulmonary hypertension; 4 of these patients were followed
      over a period of 7 months. On acute testing, mean pulmonary artery pressure
      decreased from 59 to 46 mm Hg (p = 0.01); echocardiographically estimated
      systolic pulmonary pressure further declined from 66 mm Hg after 2 days'
      treatment to 54 mm Hg after 7 months (p = 0.03). Symptom-limited walking distance
      significantly improved from 42 to 87 m after 2 days' treatment (p = 0.003); a
      further 2- to 8-fold increase was observed in single patients during follow-up.
      In severe pulmonary hypertension, aerosolised prostacyclin or iloprost improves
      exercise capacity and lowers pulmonary artery pressure beyond the level achieved
      on acute exposure.

PMID- 10413828
TI  - [Food intolerance and food allergy].
AB  - Confirmed adverse reactions to foods may be caused by toxic, enzymatic,
      pharmacological, "pseudoallergic" or allergic mechanisms. True food allergies are
      mostly IgE-mediated and directed against one or only a few food proteins. They
      appear typically as eczema and gastrointestinal symptoms (vomiting, diarrhoea,
      abdominal cramps) among infants and as oral allergy syndrome,
      urticaria/angioedema, rhinoconjunctivitis or anaphylaxis among adults. The
      majority of food allergies among adults is caused by cross-reactivity of IgE
      against inhalative allergens also reacting with food proteins. This must be
      considered in investigations by skin-prick testing and/or specific IgE
      measurement, since the sensitivity of these tests for inhalative allergens is
      higher than for food proteins. The most frequent differential diagnoses of true
      allergies are pseudoallergic reactions to food additives or pharmacological
      reactions to biogenic amines. The diagnosis of these reactions can usually be
      based on the history and course under a corresponding diet. In clinical practice
      additional investigations by double-blind placebo-controlled food challenges are
      rarely required. A positive challenge test demonstrates only the cause-and-effect
      relationship of the foods and the patient's symptoms but does not demonstrate the
      underlying mechanism. The therapy of food intolerance is a corresponding diet.
      This requires a careful diagnosis and identification of the causative foods.

PMID- 10413830
TI  - [Autonomic symptoms of epilepsy].

PMID- 10413829
TI  - [Thoracic pain and bloody diarrhea].

PMID- 10413831
TI  - The complement system: pathophysiology and clinical relevance.
AB  - In the present article we review selected aspects of the complement system as a
      major determinant of innate immunity. Besides a detailed description of the
      components of the complement system, its mode of action, cellular receptors and
      regulatory control mechanisms, we have focused on the role of the complement
      system in mutual defence strategies of invading viral pathogens and the host.
      Since a detrimental activation of the complement cascade is a critical element of
      several pathological conditions in diverse organs, we summarise the role of a
      deteriorated complement system in dermatology, nephrology, neurology and
      xenotransplantation.

PMID- 10413832
TI  - Autonomic epilepsy--the influence of epileptic discharges on heart rate and
      rhythm.
AB  - PURPOSE: To study cardiac alterations (changes in heart rate and cardiac
      arrhythmias) at the transition from the pre-ictal to the ictal state during focal
      epileptic seizures. METHODS: We assessed ECG changes during 92 seizures recorded
      with scalp EEG in 30 patients and 35 seizures in 11 patients evaluated with
      subdural strip and/or grid electrodes. Consecutive RR intervals were analyzed
      with a newly developed mathematical model for a total of 90 seconds (60 seconds
      pre-ictal, 30 seconds ictal). RESULTS: We found an ictal tachycardia (heart rate
      increase > 10 bpm) in 82.5% of seizures, and an ictal bradycardia (heart rate
      decrease > 10 bpm) in 3.3% of seizures. Bradycardia was only observed in seizures
      of frontal lobe origin. Heart rate changes occurred several seconds prior to EEG
      seizure onset on scalp-EEG in 76.1% of seizures, but also prior to EEG seizure
      onset on invasive EEG in 45.7% of seizures. Early tachycardia occurred
      significantly more often in temporal than in frontal lobe origin seizures. We
      found no significant effect of the side of seizure onset on both the quality and
      quantity of ictal heart rate changes. The occurrence of an aura or of awakening
      prior to the seizure had no influence on peri-ictal heart rate changes. Low risk
      cardiac arrhythmias were more frequently observed in frontal lobe origin
      seizures. CONCLUSIONS: Epileptic discharges directly influence portions of the
      central autonomic network, within a brain area too small or too deep to be
      detected on EEG, most likely deep mesial structures such as the amygdala or
      portions of the hippocampus. The potential clinical applications of our results
      include (1) automatic seizure detection, (2) differentiation between seizures of
      temporal and frontal lobe origin, (3) detection of peri-ictal cardiac
      arrhythmias, and (4) clarification of SUDS (sudden unexplained death syndrome) in
      epilepsy.

PMID- 10413833
TI  - Trends in the prescription of psychotropic drugs and hormone substitutes in
      Austria.
AB  - INTRODUCTION: Psychological instability as a result of changing hormone levels
      are commonly observed during menopause. We examined the question whether the
      prescription of psychotropic drugs is related to age or gender and whether the
      increase in the prescription rate of hormone substitutes has an impact on this
      phenomenon. METHODS: Age and gender-specific prescription rates of psychotropic
      drugs and hormone substitutes were examined in a retrospective study using data
      of the European Pharmaceutical Market Research Association of Austria. The
      relevant Austrian figures were established on the basis of representative
      samples. RESULTS: There are no gender-specific differences in terms of
      prescription frequency up to the age of 45 years. After the age of 45, there is a
      significant increase in the prescription of psychotropic drugs for women. When
      comparing the years 1991 and 1996, we find a reduction in the number of
      prescriptions of psychotropic drugs and an increase in the prescription rate of
      hormone replacement drugs. DISCUSSION: An increase in the prescription rate of
      hormone substitutes may contribute to the psychological stabilisation of
      menopausal women and thereby reduce the need for psychotropic drugs.

PMID- 10413835
TI  - [Congenital syphilis: late diagnosis in spite of screening].
AB  - We report the case of an infant in whom congenital syphilis was diagnosed at the
      age of 5 weeks. The case is remarkable because of (a) the negative venereal
      disease laboratory test from the cord blood, (b) the incidental diagnosis of the
      disease in the fifth week of life, (c) pneumonia alba being one of the symptoms,
      (d) the occurrence of a mild Jarisch-Herxheimer reaction after initiation of
      penicillin therapy and (e) the successful treatment of infection related anaemia
      with recombinant human erythropoietin.

PMID- 10413834
TI  - Local anaesthesia versus general anaesthesia for cardioverter-defibrillator
      implantation.
AB  - AIMS: Cardioverter-defibrillators are conventionally implanted under general
      anaesthesia. However, implantation under conscious sedation is being increasingly
      used. It has been shown that cardioverter-defibrillators can be implanted in a
      more pacemaker-like approach: under local anaesthesia for the surgical procedure,
      and with mild sedation for defibrillation threshold testing only. The aim of the
      present study was to compare local and general anaesthesia in defibrillation
      threshold testing and implantation of cardioverter-defibrillators. METHODS AND
      RESULTS: Forty patients were assigned to two groups: in the first 20 consecutive
      patients the cardioverter-defibrillator was implanted under general anaesthesia
      (GA), and in the subsequent 20 patients under local anaesthesia (LA). There was
      no significant difference between the two groups in regard of age, body weight,
      underlying disease, left ventricular ejection fraction, and NYHA classification.
      The defibrillation threshold was 13.7 +/- 5.5 J under local anaesthesia versus
      10.7 +/- 4.7 J under general anaesthesia (n.s.). For defibrillation threshold
      testing 7.9 +/- 3.6 shocks had to be applied in patients under general
      anaesthesia versus 6.2 +/- 1.3 shocks under local anaesthesia (n.s.). Mean heart
      rate, arterial oxygen saturation and mean arterial blood pressure remained stable
      throughout defibrillation threshold testing, irrespective of the type of
      anaesthesia used. The duration of the surgical procedure was 62 +/- 16 min under
      GA and 60 +/- 14 min under LA (n.s.), however, the entire implantation procedure
      was significantly longer in patients under general anaesthesia than in those
      under local anaesthesia (124 +/- 24 min and 97 +/- 22 min, respectively, p <
      0.005). There were no complications in either group and the procedure was well
      tolerated. With the use of local anaesthesia the cost of anaesthesia were reduced
      by 72%. CONCLUSION: Local anaesthesia in combination with mild sedation is as
      safe and well tolerated as general anaesthesia in cardioverter-defibrillator
      implantation. Lidocaine used for local anaesthesia does not adversely affect the
      defibrillation threshold. Device implantation in a pacemaker-like approach
      results in a significant reduction in total procedure time and costs, and
      facilitates scheduling of the procedure.

PMID- 10413836
TI  - [Extended life expectancy with physical activity].
AB  - New connections between physical activity and aging, arteriosclerosis and
      carcinoma point towards life extension by physical activity. For the slow down of
      the aging process, the reduction of highly reactive radicals generated from
      reactive radicals seems to be important by upregulating endogenous antioxidative
      mechanisms by physical activity. Preventive effects for arteriosclerosis by
      physical activity were found by positive influences on lipid and carbohydrate
      metabolism, blood pressure regulation, rheology and the vegetative nervous
      system. New data confirm this idea also as to older people. Associations between
      physical activity and carcinoma were lately found more often. These associations
      mainly concern hormone depending carcinoma in men and women, and also colon
      carcinoma; physical activity extents favourable effects on the hormonal system.
      Increasing evidence for protective effects of physical activity on aging,
      onkogenesis and arteriosclerosis must not lead to the assumption of causal
      connections.

PMID- 10413837
TI  - Association between serum pepsinogen A and C levels, serum gastrin concentrations
      and Helicobacter pylori antibodies.
AB  - Pepsinogen A and C as well as gastrin were measured in the serum of 117 patients
      with rheumatic diseases. Moreover, the patients were divided up in groups by aids
      of a semiquantitative, rapid enzyme immunoassay for detection of Helicobacter
      pylori: 20 patients without H. pylori antibodies (AB) negative, 18 positive + (=
      weak AB-titre), 21 positive +2 (medium AB-titre), and 58 positive +3 (high AB
      titre). The semiquantitative determinations of H. pylori-AB correlated with
      pepsinogen A, C and gastrin. Patients with H. pylori-AB positive +3 showed
      significantly higher values of pepsinogen C (p < or = 0.01) as well as pepsinogen
      A and gastrin (p < or = 0.05) than H. pylori-AB negative patients. Significantly
      increased levels of pepsinogen A (> 150 ng/ml) and C (> 25 ng/ml) were found to
      occur in 39% and 100% of patients with high H. pylori-AB titres. The measurement
      of serum pepsinogen C concentrations may provide additional diagnostic
      information of the extent of mucosal lesions in patients with positive H. pylori
      AB titres treated with antirheumatic drugs. Our findings suggest that the semi
      quantitative classification of positive AB-results can be useful in cases
      determining H. pylori infection and mucosal irritation if other investigations
      are not available.

PMID- 10413838
TI  - [Fourier analysis of pupil oscillations for measuring central activation in
      psychosomatic patients].
AB  - The aim of the study was to answer the question if there are any differences in
      the central activation of different groups of psychosomatic patients and patients
      with eating disorders, which was measured by means of Fourier analysis of
      pupillary oscillations. A total of 132 patients (110 f, 22 m) with a mean age of
      29.69 years (standard deviation: 9.9) participated in the study. In anorectic and
      bulimic patients high central activation was observed. Different groups of
      psychosomatic patients showed significant differences in their central nervous
      activation. In the group of subjects with the ICD-10 diagnosis F 41.3 (mixed
      anxiety disorders) the highest amplitudes was observed not only in the particular
      frequency bands but also in the total spectrum (power), which reflects high
      central activation. Reduced activation was found in subjects with somatoform
      autonomic function disorder of the upper and lower gastrointestinal tract (F
      45.3). The measurement of central activation in psychosomatic disorders could
      have consequences for therapeutic interventions.

PMID- 10413840
TI  - [Suicide with drugs in psychiatry with special reference to antidepressive
      drugs].
AB  - The fact, that recently some new compounds and also subgroups of antidepressants
      appeared, justifies a reevaluation of that theme. Especially the class of
      selective serotonin reuptake inhibitors is able to show a very favourable lethal
      dosis, contrasting very much to the classical tricyclics.

PMID- 10413839
TI  - [Is depression a women's disease?].
AB  - The female preponderance in depression is one of the most robust findings in
      psychiatric epidemiology. The pertintent hypothesis of a possible role of
      biological and psychosocial factors and their relevance for the explanation of
      this gender gap are presented and discussed. Available data suggest that
      biological factors seem to exert an influence on the emergence of depression, but
      are unlikely to account for the gender differences in morbidity rates.
      Considering psychosocial factors like age, marital and employment status
      indicates that the claim that depression is more frequent in women is an
      oversimplification. There are groups were due to these variables no gender gap or
      even higher rates for males are observed.

PMID- 10413841
TI  - Immunohistochemical study of HBV antigens in 338 liver cell carcinomas.
AB  - Tumor tissue (n = 338) and liver parenchyma (n = 276) from patients of Asian (n =
      31) and European descent (n = 307) with hepatocellular carcinoma (HCC, n = 299),
      cholangiocellular carcinoma (CCC, n = 16) and combined HCC/CCC (n = 23) were
      screened with immunohistochemical methods for HBV antigens (HBs, preS1, preS2,
      HBc, HBe and HBx). Of the HCC cases nine were of the fibrolamellar type (FLC).
      All cases of HCC/CCC and CCC were from Western European patients. HBV antigens
      could be demonstrated more frequently in HCC cases of Asian descent (59.09% in
      liver parenchyma and 66.67% in tumor tissue) compared to Western European HCC
      cases (23.11% and 30.77%; chi-square test, p = 0.0003 and p = 0.0001,
      respectively), HCC/CCC (26.32% and 30.43%), CCC (7.14% and 20%) and FLC (0% and
      25%). Results for HBx were not considered here due to questionnable HBV
      specificity of the antibodies employed. Immunohistochemical detection mainly HBs,
      whereas HBc, HBe and preS antigens played only a minor part. Comparing the
      results obtained with a rabbit and a goat polyclonal HBs antibody and a cocktail
      of seven monoclonal HBs antibodies showed statistically significant superior
      sensitivity for the goat antibody. Reactivity of tumor tissue for HBc and/or HBe
      as observed in twelve cases is suggestive of virus replication within tumor
      tissue. These data plus the demonstration of HBV antigens within so-called
      proliferated bile ducts, which represent metaplastic hepatocytes, underscore the
      nature of CCC as malignant counterpart of proliferated bile ducts. Consequently,
      it is proposed to divide the entity liver cell carcinoma (LCC) into the
      subcategories HCC and CCC in contrast to adenocarcinomas arising from bile ducts
      or peribiliary glands. In conclusion, HBV seems to play a part in the
      pathogenesis of LCC in Asian and in Western European patients. Further factors
      like HCV and other chronic inflammatory processes may be employed here.

PMID- 10413842
TI  - [Endosonographically controlled fine needle aspiration cytology--indications and
      results in routine diagnosis].
AB  - The usefulness and clinical utility of routine EUS-guided fine needle aspiration
      cytology (FNA) in the diagnosis of lesions adjacent to the upper gastrointestinal
      tract was prospectively studied. METHODS: EUS/FNA was performed in 122 patients
      for 125 lesions: Mediastinal lymph nodes (n = 56), pancreatic lesions (n = 45),
      paragastric masses (n = 12), submucosal tumors (n = 4) and small hepatic lesions
      (n = 2) were successfully punctured for cytological diagnosis. RESULTS: Adequate
      material was gained in 119 out of 125 punctures (95%). Overall sensitivity,
      specifity, positive and negative predictive value were 90%, 98%, 98% and 89%.
      Results of EUS/FNA in mediastinal lymph nodes were superior (95%, 100%, 100%,
      90%) to those in pancreatic lesions (80%, 100%, 100%, 80%). In paragastric masses
      sensitivity was 100% whereas specifity was only 67%--due to one false-positive
      result. Out of four submucosal tumors diagnosis was revealed in three. Two liver
      metastasis were successfully punctured. 35 out of 56 mediastinal nodes showed
      malignancy. 27 metastases of lung-, three of gastric-, two of renal cancer and
      three Non-Hodgkins's lymphoma were diagnosed. The cytological results of 45
      pancreatic lesions showed cancer in 19 and chronic inflammation in 21, two
      abscesses and three benign cysts. There were no complications. 37 patients were
      treated on outpatient's basis. CONCLUSIONS: EUS-guided FNA is an accurate and
      safe technique to sample cytology from lesions adjacent to the wall of the upper
      gastrointestinal tract. New indications may be established for the diagnosis of
      lung cancer or metastases of other spreading out into the mediastinum or the
      celiac axis.

PMID- 10413843
TI  - [Guidelines of the German Society of Digestive and Metabolic Diseases for
      diagnosis and therapy of hepatocellular carcinoma. German Society of Digestive
      and Metabolic Diseases].

PMID- 10413844
TI  - [Liver damage caused by drugs].
AB  - The liver has a central role in the metabolism of many drugs, since this organ is
      the main site of biotransformation of endo- and xenobiotics. Water-soluble drugs
      have a small volume of distribution and can be eliminated unchanged in the urine.
      By contrast, lipid-soluble drugs have a larger volume of distribution and require
      conversion to water-soluble metabolites for their elimination in urine or bile.
      The liver with its specific receptors, transporters and enzymes is responsible
      for the uptake, transformation and excretion of the lipophilic drugs. While most
      of the drugs are transformed into stable metabolites, other drugs form reactive,
      potentially toxic, metabolites producing liver cell damage. Liver injury caused
      by drugs may mimic almost any kind of liver disease. Clinical findings are
      gastrointestinal symptoms with nausea, vomiting and abdominal pain, cholestatic
      liver injury with jaundice and pruritus of severe inflammatory and cirrhotic
      liver damage with signs of liver failure, encephalopathy and cerebral edema. The
      morphological changes vary from hepatitis, cholestasis, fatty liver,
      granulomatous hepatitis, peri-/portal inflammation, to fibrosis with cirrhotic
      alterations and vascular lesions and tumors. The most commonly used drugs causing
      severe liver injury are discussed in detail. These are anabolics, oral
      contraceptives, antituberculous and antifungal agents, nonsteroidal anti
      inflammatory drugs, ring substituted amphetamins ("designer drugs"),
      antiarrhythmics and antibiotics.

PMID- 10413845
TI  - [Cystic liver tumor resembling echinococcosis].
AB  - The hepatobiliary cytadenoma or -carcinoma is a cystic, multilocular,
      intrahepatic tumor in the liver affecting mainly middle-aged people. In most
      cases hepatobiliary cystadenomas or -carcinomas cannot be definitely
      differentiated by sonography and CT from other cystic lesions in the liver.
      Resection of the tumorous parts of the liver as early as possible is essential
      for the prognosis for the patients because malignant transformation of the
      lesions might occur.

PMID- 10413846
TI  - Hereditary hemorrhagic telangiectasia with juvenile polyposis--coincidence or
      linked autosomal dominant inheritance?
AB  - Hereditary hemorrhagic telangiectasia (HHT) and familial juvenile polyposis (EJP)
      are two rare autosomal dominant disorders, Genetic heterogeneity has been shown
      for HHT and is likely for FJP as well. This paper describes the coexistence of
      both diseases in a girl and her father in addition to twelve members of five
      families and two sporadic cases reported in the literature. This implies a new
      phenotype which may be important in elucidating the underlying genetics in HHT
      and FJP. Clinical diagnosis of one disease should induce screening for symptoms
      of the other.

PMID- 10413847
TI  - [Receptors for cholecystokinin and gastrin].
AB  - Cholecystokinin (CCK) and gastrin belong to one family of gastrointestinal
      peptides that regulate a variety of functions in the gastrointestinal tract and
      in the central nervous system. On the basis of pharmacological, physiological and
      molecular studies, receptors for these peptides can be divided into at least two
      different types: CCKA- and CCKB-receptors. CCKA- and CCKB-receptors are both G
      protein coupled receptors and are highly conserved between species. Molecular
      techniques have revealed a distinct species- and tissue-specific variation in
      receptor expression and pharmacology. In addition, previously unknown targets for
      CCK and gastrin such as the kidney were identified. This review discusses the
      physiological functions of the hormones CCK and gastrin and their receptors. The
      molecular structure of these receptors and the results of recent structure
      function analysis are reviewed.

PMID- 10413849
TI  - [Good and poor "metabolizers"--what is the role of physical activity?].

PMID- 10413848
TI  - [Different functions of transcription factors GATA-4, -5 and -6 in regulation of
      intestinal epithelial differentiation].

PMID- 10413850
TI  - [Escherichia coli in Crohn dis: pathogenesis or commensal organism?].

PMID- 10413851
TI  - [Prevention of stomach carcinoma by Helicobacter pylori eradication. Invitation
      to participate in the PRISMA Study].

PMID- 10413852
TI  - [The significance of physical activity on the physiological stress reaction].
AB  - The extent of physical activity and the dynamic performance capacity show an
      inverse relationship to cardiovascular mortality, independent of the influence of
      other risk factors, but the underlying mechanism remains uncertain. Most concepts
      assume that the aerobic capacity of the peripheral musculature is increased by
      training, and thus improved cardiocirculatory regulation and especially a more
      favorable stress reaction pattern are attained. This adaptation is essentially an
      inverse adaptation mechanism as in established cardiocirculatory insufficiency.
      Based on an extended stress concept, it can be seen that training effects,
      especially in autonomic circulatory regulation, occur under physiological
      conditions to a lower degree in the renin-angiotensin-aldosterone system and in
      inflammatory reaction. The training effects depend on the form of exercise, the
      baseline condition, the extent of training, and genetic predisposition. It can be
      particularly demonstrated when the aerobic capacity has been sufficiently
      enlarged in an adequate proportion of the peripheral musculature. To what extent
      and under what conditions these training effects can be used under the
      pathophysiological conditions of established cardiocirculatory insufficiency is
      presently under investigation.

PMID- 10413853
TI  - [Blood coagulation and fibrinolysis in arteriosclerosis].
AB  - Thrombus formation at the site of atherosclerotic lesions, especially on a
      ruptured plaque, plays a central role in the "atherothrombosis" hypothesis. An
      activation of the hemostasis and a disturbed fibrinolysis are known. These
      alterations are especially marked in patients with acute coronary syndromes. In
      stable coronary artery disease, fibrinogen is elevated. Furthermore, minor
      alterations of the contact phase factor VII and consecutively of the thrombin
      system are detectable depending on the study population. Thrombin generation and
      activation become marked in patients with unstable angina pectoris or acute
      myocardial infarction. Possible reasons for this activation are an activation of
      the contact phase factor XII system and the release of tissue factor both from
      the ruptured plaque and from stimulated monocytes. The fibrinolytic system is
      markedly altered already in patients with stable coronary heart disease.
      Increased levels of tissue-type plasminogen activator and of urokinase-type
      plasminogen activator/receptor are measurable in atheromas. Tissue-type
      plasminogen activator mass concentration is systemically elevated already at
      early stages of atherosclerosis. Especially in patients with increased risk for
      acute coronary syndromes, the plasminogen activator inhibitor activity is
      significantly increased. Furthermore, a hypercoagulative state with increased d
      dimer levels and plasmin-antiplasmin complexes can be measured. The alterations
      of hemostasis and especially of fibrinolysis are detectable for prolonged time
      period and persist much longer than the clinical symptoms of the patients. The
      increased plasminogen activator inhibitor activity is associated with the
      metabolic syndrome and constitutes an (in part genetically determined)
      disturbance in patients with stable or unstable coronary heart disease. However,
      the large intra- und interobserver as well as diurnal variability of this marker
      limits its use as a routine measure for risk stratification in patients.
      Alterations of the hemostasis and disturbances of fibrinolysis are detectable
      during the chronic as well as the acute phase of atherosclerosis. These changes
      are best documented for coronary heart disease, whereas less data are available
      for other manifestations of atherosclerosis. The use of newly developed molecular
      markers for single reaction steps of pathways instead of global functional tests
      and of new molecular biological methods did considerably improve the detailed
      knowledge on the pathomechanisms of the development of atherosclerosis, making
      the development of targeted therapies, e.g., against receptors possible. Future
      studies will investigate the quantitative impact of the various activated
      pathways (cause or reaction) and the effects of interventions on these
      pathomechanisms in patients with acute coronary syndromes. Studies will have to
      focus especially on the meaning of polymorphisms, early changes in the
      development of atherosclerosis and interactions with inflammatory processes.

PMID- 10413854
TI  - [Cell polarity in the cardiovascular system].
AB  - The importance of cell polarity as a fundamental biological principle is
      increasingly recognized in the cardiovascular system. Polar cell mechanisms
      underlie not only the development of the heart and blood vessels, but also play a
      major role in the adult organism for polarized endothelial functions such as the
      separation of the intra- and extravascular compartment and the vectorial exchange
      of substances between these compartments. Endothelial cells are connected through
      intercellular junctions which separate the functionally and structurally distinct
      luminal and abluminal cell surfaces. The luminal plasma membrane is in contact
      with the blood and takes part in the regulation of hemostasis. The abluminal cell
      membrane connects the endothelial cell with the basement membrane and modulates
      blood flow through the release of vasoactive substances. Results from epithelial
      model systems have shown that the polarized cell phenotype is generated by
      specific protein sorting and regulated protein trafficking between the trans
      Golgi network and the cell surface. The polarized distribution of cell membrane
      proteins is maintained by anchorage with the cytoskeleton and limitation of
      lateral diffusion by tight junctions. Disturbances of cell polarity may
      contribute to the pathogenesis of disease states, including ischemic and
      radiocontrast-induced acute renal failure and carcinomas. Recent results have
      demonstrated the importance of cholesterol for protein traffic from the trans
      Golgi network to the apical cell membrane. This novel intracellular function of
      cholesterol could point to a connection between cell polarity and the
      pathogenesis of arteriosclerosis. The polarity of the endothelium also has to be
      taken into account when developing gene-therapeutic strategies, since therapeutic
      success will not only depend on the efficient expression of the desired gene
      product, but also on its correct cellular location or secretion into the correct
      extracellular compartment. These examples demonstrate the biological and
      potentially clinical relevance of cell polarity in the cardiovascular system.

PMID- 10413855
TI  - [Dual sequence method for analysis of spontaneous baroreceptor reflex sensitivity
      in patients with dilated cardiomyopathy].
AB  - The analysis of heart rate variability (HRV) and blood pressure variability (BPV)
      improves the characterization of patients with dilated cardiomyopathy (DCM). In
      this study we tested the hypothesis that patients with DCM and controls show a
      different behavior in the baroreflex (BR) regulation. In contrast to other
      methods, the new dual sequence method (DSM) analyzes the baroreflex sensitivity
      (BRS) as a response of the heart rate (interbeat interval, IBI) on dual
      spontaneous fluctuations of blood pressure (BP). The DSM includes the analysis of
      bradycardiac fluctuations (an increase of BP causes an increase of IBI) and
      tachycardiac fluctuations (decrease of BP causes a decrease of IBI) to obtain
      enhanced information about the sympathetic-vagal regulation. DCM patients show a
      40-50% lower number of correlated blood pressure-heart rate fluctuations (DCM
      patients: male 154 +/- 93, female 93 +/- 40 vs. control group: m 245 +/- 112, f
      150 +/- 55, p < 0.05). The BRS in DCM patients is significantly lower than in
      controls (5.2 +/- 1.9 vs. 8.0 +/- 5.4 (ms/mm Hg), p < 0.05). Using the DSM the
      discriminant function analysis (6 parameters) classifies correctly 84% of DCM
      patients and the control group. Using the classical sequence method, only 76%
      were correctly classified. The DSM is a useful method for analyzing the BRS based
      on the spontaneous BR to obtain an increased classification of patients with DCM.
      BRS in patients with DCM is significantly reduced and apparently more
      ineffective.

PMID- 10413856
TI  - [Early decrease in diastolic function in young type I diabetic patients as an
      initial manifestation of diabetic cardiomyopathy].
AB  - INTRODUCTION: The early determination of the myocardial manifestation is of
      considerable importance, since the prognosis of patients (P) with insulin
      dependent diabetes mellitus (IDDM) is generally masked by secondary cardiac
      complications. The aim of this study was to investigate whether young,
      asymptomatic P with IDDM and persisting normal systolic left ventricular (LV)
      function already show a diastolic LV dysfunction. METHODS: An echocardiographical
      examination of 92 IDDM patients (age: 25 +/- 4 years) without known cardiac
      disease and of 50 control persons (C) of similar ages was carried out. P with a
      cardiac disease or long-term diabetic syndrome were excluded. Using M-mode
      echocardiography, morphological parameters and systolic time-intervals
      (fractional shortening; ejection fraction) were determined. Doppler indices were
      then measured: maximal early and late diastolic flow velocity (VE; VA), E/A
      ratio, acceleration and deceleration time (DT), isovolumetric relaxation time
      (IVRT). RESULTS: Although the left atrial and left ventricular dimensions, as
      well as the systolic functional parameters of all P with IDDM were normal, they
      showed a diastolic dysfunction with a reduction of the early diastolic filling
      (VE; 0.54 +/- 0.07 m/s vs 0.72 +/- 0.04 m/s; p < 0.01) and the E/A ratio (0.9 +/-
      0.15 vs 1.99 +/- 0.22; p < 0.01), an increase in the atrial filling (VA; 0.76 +/-
      0.05 m/s vs 0.39 +/- 0.04 m/s, p < 0.01), an extension of the IVRT (129 +/- 23 ms
      vs 78 +/- 6 ms, p < 0.01), and an increased DT (248 +/- 27 ms vs 188 +/- 8 ms, p
      < 0.01). CONCLUSION: Even young P with IDDM, with a normal systolic ventricular
      function, suffer a diastolic dysfunction which serves as a marker of a diabetic
      cardiomyopathy. Therefore, echocardiography with measurements of systolic and
      diastolic functional parameters appears to be a sensible method for evaluating
      the course of diabetic cardiomyopathy.

PMID- 10413857
TI  - [Incidence and treatment of reactive infundibular obstruction after balloon
      dilatation of critical pulmonary valve stenoses].
AB  - Seventeen consecutive newborn and premature babies with critical pulmonary
      stenosis underwent a technically successful balloon valvuloplasty at our
      institution from March 1991 to February 1998. The only major complication was a
      thrombosis of the femoral vein in one patient, causing no clinical problems. Four
      patients (24%) showed a reactive infundibular obstruction after balloon
      valvuloplasty. The outflow tract obstruction became evident immediately after
      successful dilatation of the pulmonary valve with persistently high pressures in
      the right ventricle. Pathognomonic was a typical notch in the ascending part of
      the right ventricular pressure curve. We were unable to predict this reaction
      based on echocardiography or angiography. To relieve the muscular subvalvar
      obstruction, we treated the first two patients with i.v. Propranolol (0.05 mg/kg
      over 2 min). The last 2 patients received Esmolol (0.5 mg/kg over 2 min followed
      by a continuous infusion with 100 micrograms/kg/min), a very short acting beta
      blocker. In the medium-term follow-up, all 17 patients had a very good result
      with only mild pulmonary valve regurgitation. All 4 patients with a reactive
      infundibular obstruction required no repeat intervention. In the medium-term
      follow-up there were no differences between these 4 patients and the whole group.

PMID- 10413858
TI  - [Analysis of mitral annulus excursion with tissue Doppler echocardiography
      (tissue Doppler echocardiography = TDE). Noninvasive assessment of left
      ventricular, diastolic dysfunction].
AB  - BACKGROUND: Mitral inflow velocity, deceleration time, and isovolumic relaxation
      time recorded by Doppler echocardiography have been widely used to evaluate left
      ventricular diastolic function but are affected by age, heart rate, loading
      conditions, and other factors. The diastolic mitral anulus velocity assessed by
      tissue Doppler echocardiography (TDE) was suggested to provide additional
      information about LV relaxation less affected by filling pressures. AIM OF THE
      STUDY: This study was designed to assess the clinical utility of mitral anulus
      velocity in the evaluation of left ventricular diastolic function. PATIENTS AND
      METHODS: Three groups of patients with a systolic ejection fraction > 45% were
      separated: 10 normal volunteers (60 +/- 10 y, CON group), 15 asymptomatic
      patients with known coronary artery disease (60 +/- 11 y, CAD group) and 15
      patients with long-term arterial hypertension and heart failure symptoms (58 +/-
      9 y, HYP group). The mitral inflow profile (E, A, E/A) was measured by pulsed
      Doppler, and the deceleration time (DT) and the isovolumic relaxation period
      (IVRT) were calculated. Systolic, early, and late diastolic velocities of the
      septal mitral anulus (ST, ET, AT, ET/AT) were assessed by pulsed TDE. All study
      subjects had invasive measurements of left ventricular end diastolic filling
      pressures during left heart catheterization. RESULTS: In the AH group, ET (6.9 +/
      4.8 cm/s) and ET/AT (0.71 +/- 0.28) were reduced compared to the CON group (11.7
      +/- 4.7 cm/s and 1.11 +/- 0.36, p < 0.05, respectively) and the CAD group (8.9 +/
      5.4 cm/s and 0.85 +/- 0.26, respectively, p = ns). The groups did not differ
      with respect to the mitral E/A ratio, the deceleration time and the isovolumic
      relaxation time. LVED in the HYP group (16 +/- 8 mm Hg) was elevated compared to
      the CON group (8 +/- 3, p < 0.05) and the CAD group (12 +/- 6 mm Hg, p = ns). No
      correlation was found between ET and LVED (r = 0.26). When the combination of
      mitral E/A ratio > 1 with LVED > or = 15 mm Hg was classified as
      pseudonormalization, the pseudonormalization could be identified by a peak early
      diastolic mitral anulus velocity (ET) < 7 cm/s and an ET/AT ratio < 1 with a
      sensitivity of 77% and a specificity of 88%. CONCLUSIONS: The early diastolic
      mitral anulus velocity assessed by TDE (ET) is a preload-independent index of LV
      relaxation. TDE permits the detection of diastolic dysfunction in patients with a
      pseudonormal mitral inflow and elevated filling pressures.

PMID- 10413859
TI  - [Homografts for mitral valve replacement in florid endocarditis--an alternative
      to prosthetic replacement].
AB  - INTRODUCTION: Homografts for valve replacement are indicated in acute valve
      endocarditis. It is assumed that they possess anti-infective properties.
      Homografts are an established indication in aortic valve replacement. We present
      our early results with homografts for mitral valve replacement in acute
      endocarditis. PATIENTS AND METHODS: Between July 1996 and March 1998 we used
      cryopreserved homografts for mitral valve replacement in seven patients. In three
      cases (age 24, 42, and 34 years) the indication was an acute endocarditis with
      subsequent severe mitral valve insufficiency. The size of the required homograft
      was measured preoperatively using transesophageal echocardiography. For
      implantation the technique described by A. Carpentier was used; for stabilization
      of the mitral anulus a valvular ring (Physio) was implanted. Follow-up was done
      every six months including clinical and echocardiographical examinations. After
      the first postoperative year an Ultrafast-CT was done in addition. RESULTS: One
      patient had complete mitral valve replacement, in the other two cases the
      diseased parts of the valve were completely excised and the valve was repaired
      using a partial homograft. There were no perioperative deaths. In the follow-ups,
      up to 24 months of uneventful homograft function was documented by
      echocardiography; no insufficiency > degree I was seen on color Doppler
      echocardiography. At the last follow-up (mean follow-up 16 months, range 12 to 24
      months) the average mitral valve orifice was 2.5 +/- 0.5 cm2, the mean pressure
      gradient 2.8 +/- 0.8 mm Hg. In Ultrafast-CT no morphological abnormalities of the
      mitral valves and no dilatation of the left ventricle were seen. There were no
      signs of a recurrence of the endocarditis in any patient during the follow-up
      period. CONCLUSION: Homografts for mitral valve replacement are an interesting
      alternative to prosthetic valve replacement, especially in younger patients. In
      cases with acute endocarditis, in which mechanical prosthesis should not be used,
      a reconstruction or repair of the mitral valve with preservation of the
      ventricular geometry is possible even if large parts of the mitral valve are
      infected.

PMID- 10413861
TI  - [Myocardial ischemia caused by ICD electrodes?].
AB  - We report on a 65 year old man, in whom an ICD was implanted. Seven months later
      we found a remarkable close relation between the tip of the ICD electrode and the
      distal part of the left anterior descending artery (LAD). LAD seems to be
      compressed from electrode during systole. This is possibly the cause of an
      ischemia in myocardial scintigraphy.

PMID- 10413860
TI  - [Verapamil sensitive ventricular tachycardia with myocardial failure in a 2-year
      old child].
AB  - Ventricular arrhythmias can both result from and cause myocardial dysfunction. We
      report a case of a two-year-old girl with ventricular tachycardia showing signs
      of heart failure consisting with a tachycardiomyopathy. The therapy with class I
      and class III antiarrhythmic drugs did not improve the cardiac situation
      significantly. The cardiologic investigations were consistent with the verapamil
      sensitive ventricular tachycardia in young adults. The treatment with verapamil
      led to a normal rhythm and function of the heart. CONCLUSION: Verapamil-type
      calcium channel blockers can also be used in children for the treatment of
      ventricular tachycardias if the corresponding investigations show characteristic
      findings.

PMID- 10413862
TI  - Determination of corneal gel dynamics.
AB  - From observations of the dynamics of light scattered by the cornea, intensity
      autocorrelation functions that revealed two independent diffusion coefficients, D
      (fast) = 2.4 +/- 0.2 x 10(-7) cm2/s and D (slow) = 9.4 +/- 1.3 x 10(-9) cm2/s,
      were obtained. The diffusion coefficients were found to be statistically
      independent of the position and depth on the lateral surface of the cornea from
      which the scattered light was sampled. The slow diffusion coefficients obtained
      from light sampled from within cross-sections of the cornea were, however,
      measurably different. Diffusion coefficients obtained independently from
      observations of the kinetics of corneal swelling for comparison were found to be
      several orders of magnitude greater than those obtained from light scattering.
      The large disparity in the diffusion coefficients obtained from the two
      independent methods invoked the possibility that the lamellar layers within the
      cornea behave as individual gel sheets. Irrespective of this additional
      hypothesis, divergent behavior in the measured total scattered light intensities
      and diffusion coefficients upon varying external conditions, such as temperature
      or pressure (stretching), was observed. Namely, a slowing down of the dynamic
      modes accompanied by increased "static" scattered light intensities was observed.
      Although the slowing down of the dynamic modes is possibly indicative of the
      reduced affinity of protein binding to the gel matrix that "softens" the gel, the
      divergent behavior in the scattered light intensities and diffusion coefficients
      is, however, more characteristic of a phase transition. In addition, the
      divergent behavior in the scattered light intensities and diffusion coefficients
      was reversible up to a critical temperature (approximately 50 degrees C) or
      stretching (approximately 16%).

PMID- 10413863
TI  - Structure, force, and energy of a double-stranded DNA oligonucleotide under
      tensile loads.
AB  - The end-to-end stretching of a duplex DNA oligonucleotide has been studied using
      potential of mean force (PMF) calculations based on molecular dynamics (MD)
      simulations and atomic force microscopy (AFM) experiments. Near quantitative
      agreement between the calculations and experiments was obtained for both the
      extension length and forces associated with strand separation. The PMF
      calculations show that the oligonucleotide extends without a significant
      energetic barrier from a length shorter than A-DNA to a length 2.4 times the
      contour length of B-DNA at which the barrier to strand separation is encountered.
      Calculated forces associated with the barrier are 0.09 +/- 0.03 nN, based on
      assumptions concerning tip and thermal-activated barrier crossing contributions
      to the forces. Direct AFM measurements show the oligonucleotide strands
      separating at 2.6 +/- 0.8 contour lengths with a force of 0.13 +/- 0.05 nN.
      Analysis of the energies from the MD simulations during extension reveals
      compensation between increases in the DNA-self energy and decreases in the DNA
      solvent interaction energy, allowing for the barrierless extension of DNA beyond
      the canonical B form. The barrier to strand separation occurs when unfavorable
      DNA interstrand repulsion cannot be compensated for by favorable DNA-solvent
      interactions. The present combination of single molecule theoretical and
      experimental approaches produces a comprehensive picture of the free energy
      surface of biological macromolecular structural transitions.

PMID- 10413864
TI  - The interactions of the N-terminal fusogenic peptide of HIV-1 gp41 with neutral
      phospholipids.
AB  - We have studied the interactions with neutral phospholipid bilayers of FPI, the
      23-residue fusogenic N-terminal peptide of the HIV-1LAI transmembrane
      glycoprotein gp41, by CD, EPR, NMR, and solid state NMR (SSNMR) with the
      objective of understanding how it lyses and fuses cells. Using small unilamellar
      vesicles made from egg yolk phoshatidylcholine which were not fused or
      permeabilised by the peptide we obtained results suggesting that it was capable
      of inserting as an alpha-helix into neutral phospholipid bilayers but was only
      completely monomeric at peptide/lipid (P/L) ratios of 1/2000 or lower. Above this
      value, mixed populations of monomeric and multimeric forms were found with the
      proportion of multimer increasing proportionally to P/L, as calculated from
      studies on the interaction between the peptide and spin-labelled phospholipid.
      The CD data indicated that, at P/L between 1/200 and 1/100, approximately 68% of
      the peptide appeared to be in alpha-helical form. When P/L = 1/25 the alpha
      helical content had decreased to 41%. Measurement at a P/L of 1/100 of the spin
      lattice relaxation effect on the 13C nuclei of the phospholipid acyl chains of an
      N-terminal spin label attached to the peptide showed that most of the peptide N
      termini were located in the interior hydrocarbon region of the membrane. SSNMR on
      multilayers of ditetradecylphosphatidyl choline at P/Ls of 1/10, 1/20 and 1/30
      showed that the peptide formed multimers that affected the motion of the lipid
      chains and disrupted the lipid alignment. We suggest that these aggregates may be
      relevant to the membrane-fusing and lytic activities of FPI and that they are
      worthy of further study.

PMID- 10413865
TI  - Isolation of Vibrio vulnificus from sea water and sand along the Dan region coast
      of the Mediterranean.
AB  - The occurrence of Vibrio vulnificus incoastal sea water and sand was
      investigated. Samples (286 in toto) were taken during the period between November
      1993 and July 1994. Ten V. vulnificus isolates (6.9%) were recovered from sea
      water and two isolates were recovered from sand (1.4%). The total isolation rate
      for this period was 4.2%. In a longer period of investigation, from June 1996
      until June 1998 (24 months), 1,248 samples were taken and 205 V. vulnificus
      isolates were recorded (32.8%) in sea water while only 18 isolates in sand
      (2.9%). The total isolation rate was 17.9%. The monthly occurrence of this
      bacterial species in the various beaches surveyed demonstrated that V. vulnificus
      is more frequent during the months of July, August and September. The increase in
      the number of isolates during the past 2 years started as early as March and
      finished as late as October. Antibiotic sensitivity testing revealed that this
      species is sensitive to most antibiotics, except polymyxin B and colistin. The
      relatively high isolation rate of this bacterium from sea water may be dangerous
      to bathers, fishermen and divers with predisposed wounds.

PMID- 10413866
TI  - Liver tissue expression of CD80 and CD95 antigens in chronic hepatitis C:
      relationship with biological and histological disease activities.
AB  - The well known discrepancy between cytotoxic T lymphocyte (CTL) infiltration in
      the liver and disease biological activity, as assessed by alanine
      aminotransferase (ALT) levels, during the course of chronic hepatitis C virus
      (HCV) infection, suggests the possible failure of cytotoxic mechanisms devoted to
      virus clearance. To further investigate the biological events involved in CTL
      mediated lysis, i.e. B7/CD28 costimulatory and Fas/Fas-ligand pathways, the CD80
      and CD95 antigen expression in liver tissue specimens from chronically HCV
      infected patients was evaluated. The results were analysed in relation to serum
      ALT values and the histological activity (HAI) of liver disease. The data provide
      evidence for a strong and comparable hepatocyte CD80 and C95 structure expression
      in chronically HCV-infected livers. CD80- and CD95-carrying liver cells were more
      frequently distributed at the periportal region of the hepatic lobule, above all
      near piecemeal necrosis areas, among infiltrating CTL. On the other hand, a
      negative correlation was found between liver tissue expression of both antigens
      and serum ALT activity. The relationship with HAI was not statistically
      significant. The results imply that HCV infection triggers CD80 and CD95 molecule
      expression on hepatocytes. Further studies are required to clarify the relevance
      of such a finding in the context of virus-host interactions.

PMID- 10413867
TI  - Effects of a recombinant gene product and growth conditions on plasmid stability
      in pectinolytic Escherichia coli cells.
AB  - The genes encoding pectin methylesterase (pme) and pectate lyase (pel) from
      Bacteroides thetaiotaomicron were previously cloned in Escherichia coli. In the
      absence of selective pressure the recombinant vectors harbouring a functional pel
      gene were rapidly lost. This instability was due to a toxic effect of the pel
      gene product when overproduced and was closely related (1) to a decrease of the
      growth rate, and (2) to the impossibility of transforming different strains of E.
      coli with the recombinant plasmids harbouring a functional pel gene. When the
      expression level of the pel gene was reduced and the tet gene partially deleted,
      the stability was greatly improved. The export of pectate lyase in the
      extracellular medium was significantly enhanced in the presence of glycine with a
      positive effect on plasmid stability for low concentrations. Furthermore, using a
      factorial design at two levels, the effects of tetracycline, ampicillin, glucose
      and magnesium on pBT4 stability were quantified.

PMID- 10413868
TI  - Physiological consequences of mutations in Escherichia coli heat shock dnaK and
      dnaJ genes.
AB  - Mutations in the heat shock genes, dnaK and dnaJ, cause severe defects of several
      cellular functions. Null dnaJ and dnaKdnaJ mutations can be transduced in a
      restricted range of temperature. The efficiency of transformation with three
      unrelated plasmids, viz pACYC184, pBR322 and pSC101, is two times lower in dnaK
      mutants while the dnaJ mutant is characterized by slightly impaired
      transformation with pSC101 only. The lack of DnaJ function negatively influences
      the stability of pSC101 at 42 degrees C, and this plasmid cannot be stably
      maintained at 30 degrees C in the delta dnaKdnaJ mutant. The double deletion
      mutant, delta dbaKdnaJ, is characterized by impaired osmoadaptation. The
      galactokinase content is lower in both mutants tested compared with wild-type
      strains even at 30 degrees C. The efficient complementation of some of these
      defects by the wild-type alleles present on low-copy number plasmid was achieved.

PMID- 10413869
TI  - Appearance in Japan of highly macrolide-resistant Escherichia coli producing
      macrolide 2'-phosphotransferase II.
AB  - Escherichia coli CU1, a clinical isolate recovered in Japan in 1997, was found to
      be highly-resistant to both 14-membered and 16-membered ring macrolide
      antibiotics. A crude extract prepared from strain CU1 inactivated 14-, 15- and 16
      membered ring macrolides in the presence of ATP and the Rf value of inactivated
      oleandomycin was identical to that of oleandomycin 2'-phosphate. This suggested
      that strain CU1 produced the enzyme macrolide 2'-phosphotransferase [MPH(2')].
      Substrate specificity of the crude enzyme from strain CU1 against 14-, 15- and 16
      membered ring macrolides was basically similar to that of MPH(2')II from strain
      BM2506, differing in that the former more effectively inactivated roxithromycin
      and tylosin. Subsequent attempts were made to clone the novel mph gene encoding
      for MPH(2') in strain CU1. The mph gene carried by strain CU1 was located on
      nontransmissible plasmid DNA, designated pCU001. Its molecular weight, estimated
      by agarose electrophoresis, was approximately 57 kD. The DNA sequence of the
      cloned mph gene from the Japanese isolate CU1 was identical to that of mphB,
      which until now had only been recovered in France. The variance in the substrate
      specificity of MPH(2')II from each strain led us to speculate that other factors
      in the reaction affect the enzymatic inactivation activity.

PMID- 10413870
TI  - Pharmacodynamic parameters and hydrophobicity changes induced by meropenem in
      Acinetobacter baumannii.
AB  - The suppression of bacterial growth of four Acinetobacter baumannii strains after
      60 min exposure to meropenem at supra-inhibitory concentrations (postantibiotic
      effect; PAE) or at supra-subinhibitory concentrations (postantibiotic-sub-MIC
      effect; PA SME) was studied. The duration of the PAE was dependent on antibiotic
      concentration and on the strain. Meropenem at 2x or 4x the minimum inhibitory
      concentration (MIC), with the exception of one strain treated with 4x MIC, did
      not provoke suppression of bacterial growth compared with untreated controls. The
      highest concentration of meropenem (8x MIC) induced PAE for the strains tested in
      the range of 0.6-6.9 h. The effect of supra-subinhibitory concentrations of
      meropenem (2x, 4x or 8x MIC + 0.2x MIC) on bacterial growth was more efficient
      compared with supra-inhibitory concentrations alone. Two out of the four strains
      treated did not renew their growth. Bacterial suspensions exposed to meropenem
      showed reduced surface hydrophobicity. Decreases in hydrophobicity were
      associated with longer PAE and PA SME depending on the strain.

PMID- 10413871
TI  - Coccoid forms of Helicobacter pylori can be viable.
AB  - Controversy exists as to whether the coccoid form of Helicobacter pylori can
      exist in a viable form. Conversion of helical to coccoid morphology occurs in
      culture over several days. In this study, the morphology was correlated with
      parameters of genetic integrity in the reference NCTC 11637 strain over 21 days
      of culture. The capacity to regrow colonies of helical form was demonstrated from
      a culture where the coccoid form constituted up to 95% and negligible urease
      activity could be detected. Urease enzyme activity and its mRNA decreased between
      day 0 and 10 while 26 kD mRNA and 16S rRNA were expressed unchanged for up to 14
      and 21 days of culture, respectively. Expression of mRNA for the Cag A gene
      behaved in a similar fashion to that of urease. No evidence of DNA fragmentation
      was detected. These data suggest that a viable form of non-urease producing H.
      pylori exists after short to intermediate culture and that some if not all of
      these viable bacteria have coccoid morphology.

PMID- 10413872
TI  - Variations in the gene for vacuolating toxin, vacA, in Japanese isolates of
      Helicobacter pylori.
AB  - Each of 284 strains of Helicobacter pylori which had been isolated in Japan was
      shown, by use of the polymerase chain reaction (PCR), to be positive for the vacA
      genes. The amplified vacA genes generated by PCR were classified into six classes
      (five for the clinical isolates, and one which corresponded to the standard
      strains). Endoscopic analysis revealed that cases of gastritis were most likely
      to be associated with class D, while none were associated with class A. The
      patterns of products of PCR obtained from the Japanese isolates were compared
      with theoretical patterns derived from sequences of vacA which had been reported
      previously. The nucleotide sequences of amplified fragments of vacA from
      representative strains in each class were determined and compared with those of
      previously reported vacA genes.

PMID- 10413873
TI  - Effect of oleanolic acid-cyclodextrin inclusion compounds on dental caries by in
      vitro experiment and rat-caries model.
AB  - Earlier work in vitro showed that oleanolic acid (OA) was a potential inhibitor
      of insoluble glucan (ISG) synthesis from mutans streptococci (MS). In this study,
      two oleanolic acid-cyclodextrin inclusion compounds (OA-CDs), oleanolic acid-G1
      beta-cyclodextrin (OA-G1-beta CD) and oleanolic acid-beta-cyclodextrin (OA-beta
      CD), were assayed for their effects on ISG synthesis from Streptococcus mutans
      MT8148R, and on the growth of oral bacteria. OA-beta CD inhibited ISG synthesis
      by 55.3 and 37.4% at 62.5 and 15.6 micrograms/ml of OA, respectively. Both OA-CDs
      inhibited the growth of MS, S. sanguis, and S. salivarius at 4 to 8 micrograms/ml
      of OA. The anticariogenic effect of the OA-beta CD was examined in a rat-caries
      model. Rats in the infected control groups showed the highest caries score. The
      infected treatment group B (0.5% OA in diet) showed lower scores than the control
      group. These results suggest that OA-beta CD is a potential anti-caries agent.

PMID- 10413874
TI  - Efficacy of disinfectants and heat against Escherichia coli O157:H7.
AB  - The bactericidal activity of disinfectants and hot water against ten Escherichia
      coli O157:H7 strains, which were isolated from faeces of patients with
      enterohaemorrhagic E. coli infection, were evaluated and showed different DNA
      patterns. After exposure to 0.1% benzalkonium chloride, 0.1% chlorhexidine
      gluconate containing a nonionic surfactant, and 80% (v/v) ethanol, 99.99% of
      viable bacterial cells were killed at 20 degrees C within 15 s irrespective of
      the presence or absence of 0.1% albumin. On the other hand, after exposure to hot
      water, 99.99% of the bacterial cells were killed within 15 s at 70 degrees C.
      These results suggest that benzalkonium chloride, chlorhexidine gluconate
      containing a nonionic surfactant, ethanol, and hot water at 70 degrees C or more
      are effective for disinfection of E. coli O157:H7 in hospitals.

PMID- 10413875
TI  - Purification and characterization of an arylamine N-acetyltransferase in the
      nematode Enterobius vermicularis.
AB  - N-acetyltransferase (NAT) activities were determined by incubation of Enterobius
      vermicularis cytosols with 2-aminofluorene (2-AF) as the substrate followed by
      high pressure liquid chromatography assays. The NAT activity from E. vermicularis
      was found to be 0.41 +/- 0.08 nmol/min/mg protein for 2-AF. The apparent K(m) and
      Vmax values obtained were 0.81 +/- 0.11 mM and 2.25 +/- 0.22 nmol/min/mg protein
      respectively, for 2-AF. The optimal pH value for the enzyme activity was 7.5 for
      2-AF. The optimal temperature for enzyme activity was 37 degrees C for the 2-AF
      substrate. The molecular weight of NAT from E. vermicularis was 44.9 kD. Among a
      series of divalent cations and salts, Zn2+, Ca2+, and Fe2+ were the most potent
      inhibitors. Of the protease inhibitors, only ethylenediaminetetraacetic acid
      significantly protected the NAT. Iodoacetate, in contrast to other agents,
      markedly inhibited NAT activity. This report is the first demonstration of acetyl
      coenzyme A-dependent arylamine NAT activity in E. vermicularis and extends the
      number of phyla in which this activity has been found.

PMID- 10413876
TI  - An evaluation of chromogenic substrates for characterization of serine protease
      produced by pathogenic Vibrio alginolyticus.
AB  - Four chromogenic substrates for characterizing serine protease of Vibrio
      alginolyticus were evaluated. The protease activity of bacterial extracellular
      products, or the fractions of 33 kD protease purified by the AKTA purifier system
      with various columns, was completely inhibited by ethylenediamine tetra-acetic
      acid, ethylene glycol-bis(beta-amino-ethyl ether) N,N,N',N'-tetraacetic acid
      (EGTA), antipain and phenylmethylsulphonyl fluoride (PMSF) using water-soluble
      substrates (azoalbumin and azocasein). It was only completely inhibited by
      antipain and PMSF using water-insoluble substrates (azocoll and hide powder
      azure). The protease activity was not, or only partially, inhibited by 1,10
      phenanthroline and sodium dodecyl sulphate (SDS) using all four substrates. Since
      chelating agents and 1,10-phenanthroline are commonly employed as inhibitors to
      identify metalloprotease, the two water-soluble substrates may not be appropriate
      for this purpose, except for using 1,10-phenanthroline as an inhibitor. Chelating
      agents may be still applicable as inhibitors using water-insoluble substrates and
      1,10-phenanthroline is highly recommended in the characterization for
      metalloprotease to avoid confusion. In the present study, the 33 kD protease was
      further confirmed as an SDS-resistant serine protease and not a metalloprotease.

PMID- 10413877
TI  - Unchanged characteristics of Helicobacter pylori during its morphological
      conversion.
AB  - Helicobacter pylori strains RH 54 and NCTC 11637 were grown in brain-heart
      infusion broth up to 56 days, and the coccoid form was obtained during prolonged
      incubation. Two morphological types of coccoids were observed, one of which was
      electron-dense and had an intact cellular membrane and flagella, indicating that
      it was likely to be viable. The other coccoid form was sphaeroblast-like and
      weakly stained, showing features of degeneration. Catalase activity was positive
      for aged cultures even up to 160 days. Sodium dodecyl sulphate polyacrylamide gel
      electrophoresis showed that most of the protein bands appeared to be similar in
      both the spiral and coccoid forms. In addition, Lewis blood group antigens were
      detected in cultures of up to 8 weeks. Furthermore, two sets of primers for the
      vacA and cagA genes were used in polymerase chain reaction, and these two
      important genes remained conserved in both the spiral and coccoid forms. The
      present study shows that the coccoid form of H. pylori retained many important
      characteristics present in the spiral form despite the morphological conversion,
      and thus supports the notion that some of the coccoid forms of H. pylori are
      likely to be viable.

PMID- 10413878
TI  - [Experimental Chagas' disease: I. Study of different immunization conditions in
      the infection course].
AB  - In previous works it has been demonstrated that Balb/c albino mice immunized with
      Trypanosoma rangeli developed cellular and humoral immune response to Tripanosoma
      cruzi. Moreover, the immunized animals were protected against lethal infection by
      virulent T. cruzi trypomastigotes. In fact, immunized mice had significantly
      lower parasitemias and longer survival than controls. To go further in this
      experimental model, the aim of the present work was to analyze the effect of the
      number of antigenic stimuli and the conservation of the antigen on the
      effectiveness of protective effect. For that purpose, three different
      immunization schedules injecting T. rangeli epimastigotes fixed with
      glutaraldehide and emulsified with Saponin (SAP) as adjuvant were assayed.
      Different lots of mice which received only phosphate buffer saline or SAP were
      used as controls. In another set of experiments the conservation of the antigen
      during 90 days at 4 degrees C was studied. In all the experiments mice were
      infected with 100 trypomastigotes of T. cruzi, Tulahuen strain. The parasitemias
      were analyzed on 13th, 16th and 21st post infection days, and the survival until
      the 60th day. The results revealed that one dose of antigen was inadequate to
      give an effective protection. On the other hand, mice immunized with 2 and 3 dose
      showed a significant decrease of parasitemia with regard to controls (p < 0.001 -
      p < 0.0001) and the survival were markedly increased. Likewise, the antigen kept
      during 90th days at 4 degrees C showed similar protective efficacy than fresh
      antigen. Both of these experimental groups showed significant differences with
      respect to control animals in parasitemia (p < 0.05 - p > 0.01) and survival (p <
      0.01). In conclusion, the results of this work showed that in the experimental
      conditions assayed, the immunization with T. rangeli trigger and adequate immune
      response when mice received at least two antigenic stimuli. Likewise, it is
      interesting to point out the stability of the antigenic preparation during at
      least 90th days.

PMID- 10413879
TI  - Ultrastructural alterations in glomerulopathy associated with hydatidosis in
      sheep.
AB  - In the present study we investigated the ultrastructural alterations occurring in
      the renal glomeruli of sheep with hydatidosis. Renal samples from 39 sheep, 34
      with hydatidosis and 5 without parasitosis, were examined by transmission
      electron microscopy. Additionally, biochemical analysis was performed by
      determining serum concentrations of creatinine, urea, total protein and albumin.
      The ultrastructural alterations identified were the presence of dense mesangial,
      subendothelial and intra-membranous deposits, mesangial cell proliferation with
      areas showing segmental sclerosis and interposition of mesangial cells with the
      formation of a neomembrane. Biochemical analysis revealed a significant increase
      in total serum protein in the experimental group compared with the control. Our
      results demonstrated that glomerulonephritis associated with hydatidosis in sheep
      can be classified into four categories: minimal lesions, mesangial
      glomerulonephritis, segmental and focal glomerulonephritis and
      membranoproliferative glomerulonephritis, being membranoproliferative and
      mesangial glomerulonephritis the most predominant categories.

PMID- 10413880
TI  - Identification of immunodominant antigens by immunoelectrotransfer in hydatid
      fluid.
AB  - Identification and characterization of immunodominant antigens in hydatid fluid
      was performed by electrophoresis in polyacrylamide gels (SDS PAGE) followed by
      immunoelectrotransfer (Western Blot). The studies were performed in sera of 23
      patients with surgically confirmed hydatid disease, 12 patients with clinical
      suspicion of the infection and positive serology according to conventional
      serology (double diffusion with detection of are 5 and ELISA test), 28 healthy
      subject and 23 patients with parasitic infections different from hydatidosis. The
      results showed 7 antigenic bands located between 8 and 120 kDa, two
      immunodominant bands (MW 8 and 12 kDa) were recognized by the sera of patients
      suffering from hydatid disease and those with positive serology. Two additional
      bands were detected by the sera of healthy subjects and by the samples of
      patients presenting cysticercosis. It is concluded that the antigens with
      molecular weights of 8 and 12 kDa. would be those of major diagnostic value,
      while those of 32 and 60 kDa are nonspecific.

PMID- 10413881
TI  - [Blastocystis hominis in patients at the Ruiz y Paez University Hospital from
      Bolivar City, Venezuela].
AB  - Blastocystis hominis is a polymorphic protozoan of discussed taxonomic position,
      which is currently associated with human intestinal disease. In order to
      determine the prevalence of the microorganism in a sample of hospitalized
      patients, a study was carried out from november 1996 to april 1997 on 100 adult
      patients of both sexes aged 20 to 79 years at the "Ruiz y Paez" University
      Hospital of Bolivar city, Venezuela. A coproparasitological study was carried out
      using direct examination and Faust method. Infection by parasites and/or
      commensals was demonstrated in 48 patients. The most frequent agent was B.
      hominis with a prevalence of 42.0%. We did not find a statistically association
      between sex (P > 0.05) or age (X2 = 3.52; d.f; = 3) and B. hominis infection. B.
      hominis was most frequently identified as the single parasite (88.1%), and with a
      number of less than 5 cells per 400X microscopic field (73.8%). The infection was
      more common in patients with base chronic-immunosuppressive diseases, the major
      one being cancer. Diarrhea was observed in 27.0% of cases. Due to its high
      prevalence, especially as a single agent, together with the particular
      immunological characteristics of the patients studied, a potential pathogenic
      role of the opportunistic type is suggested for B. hominis.

PMID- 10413882
TI  - [Heterakis infection in Numida meleagris (Numididae)].
AB  - A case of caecum nematodiasis is described in a guinea fowl (Numida melagris)
      from the Municipal Zoo, Presidencia Roque Saenz Pena (Chaco) Argentina. Nematodes
      obtained from the caecum were observed in optic microscopy. According to their
      morphometric characteristics and location in the definitive host, were identified
      as belonging to the family Heterakidae, species Heterakis gallinarum, (Schrank,
      1788) Maden, 1949.

PMID- 10413883
TI  - Redescription of Anonchocephalus chilensis (Riggenbach, 1896) (Pseudophyllidea:
      Triaenophoridae) and description of A. patagonicus n. sp.

PMID- 10413884
TI  - [Cutaneous loxoscelism with edematous predominance].
AB  - Loxoscelism is the clinical condition produced by the venom of spiders belonging
      to the genus Loxosceles. Human cases of loxoscelism have been observed in diverse
      countries of different continents in temperate and tropical regions. In Chile
      loxoscelism is caused by Loxosceles laeta, spider with domestic habits.
      Loxoscelism can be observed into two well definited clinical variants: cutaneous
      loxoscelism (CL) and systemic or viscerocutaneous loxoscelism (VCL) which occur
      in around 83.3 and 16.7% cases respectively. Within the universe of CL patients a
      clinical modality in which necrotic lesion is not present or is insignificant,
      but presenting a remarkable edema, particularly when the bite is on the face,
      which has received the name of CL with an edematous predominance (CLEP). In this
      paper the individual description and the assambled analysis of 10 cases, four
      males and six females, age ranging from 6 to 68 years, of CLEP are presented.
      Nine cases occurred in warm periods spring through fall and one in winter. In six
      cases the accident causing spider was seen and two of these were identified as L.
      laeta adult females. In all cases the patients went or were transported to
      emergency medical services 4-24 h after the bite. The predominant initial symptom
      was a burning stinging sensation at the site of the bite, followed by intensive
      pain which expanded the neighbour areas concomitantly with the emerging and
      progressive edema. In four of the nine patients in who the bite was on the face,
      the edema involved all of it, closed both eyelids and expanded to the neck and
      upper part of the thorax. In three cases the enormous edema was the only
      significant clinical manifestation, whereas in the remaining seven conjunctly
      with the edema, a small violaceous plaque or a blister of serous content gave
      place to a little livedoid plaque (diameter 0.3-0.8 cm) which evolved to
      desquamation without leaving any scarring. The edema was characterized by its
      brilliant rose color, painful and hard which is not accompanied by regional
      adenopathy. Treatment of the 10 patients depended on the moment in they were seen
      by us. It consisted on parenteral administration, according to age and weight, of
      5-10 mg of chloroprofenpyridamine maleate every 8 hours for be continued every 12
      24 hours until the patient was discharged. Parenteral route was preferred in
      order that it was going to be adequately absorbed. With the beginning of the
      antihistaminic treatment a clear diminution of pain and edema was obtained, being
      possible its total disappearance within 4-10 days. CLEP occurs in about 4% of
      loxoscelism cases, has a benign prognosis and an early response to adequate
      medical treatment. Without discarding the sensibility factor of the affected
      individual, there exist the impression that the edema may abort the necrotic
      process when it dilutes the enzymatic process produced by L.laeta venom. In
      Chile, the differential diagnosis must be planted with the following clinical
      entities: bites of hematophagous insects on the face, bee stings, Chagas' disease
      with facial port of entry and angioneurotic edema.

PMID- 10413885
TI  - [Relationships in the prevalence of geohelminth infections in humans from
      Venezuela].
AB  - By means of Kato-Katz technique 113,254 coprological samples of the human
      population belonging to 100 counties from Venezuela were analyzed. It was
      determined the following prevalences: Ascaris lumbricoides 26.8%, Trichuris
      trichiura 32.7% and hookworm 5.6%. It was found a strong correlation between A.
      lumbricoides and T. trichiura infection (p < 0.001), a significant correlation
      between T. trichiura and hookworm (p < 0.5) and no correlation between A.
      lumbricoides and hookworm.

PMID- 10413886
TI  - [Prevalence of Giardia lamblia, its detection in water and its relationship with
      environmental factors in Gualeguaychu, Argentina].
AB  - The increasing environmental contamination affects the water quality, and is
      going to raise the waterborne intestinal infections such as giardiosis. This
      study determined the prevalence of G.lamblia infection in 1201 persons of
      Gualeguaychu, Argentina. It was observed the relationship between giardiosis and
      the detection of G.lamblia in the recreational and drinking water and with homes
      environmental factors. General rate of infection was 19.7%. The group 2-11 years
      old was the highest (28.0%). No cysts of G.lamblia were found in drinking water,
      but recreational water was contaminated. Higher rate of infected persons lived in
      suburban dwellings with dirt floor, latrine, ground-water and close contact with
      dogs. It is concluded that to drink water is no risk-infection at present, but it
      will be if this community continues discharging excretsa into the river because
      this is the source of water for the habitants.

PMID- 10413887
TI  - [Validation of data collection for an American trypanosomiasis epidemiologic
      study in the State of Morelos, Mexico].
AB  - The purpose of this paper is to show up the importance of the standardization
      concepts in American Trypanosomiasis epidemiological studies. The consistence in
      the measurement of some dwelling characteristics was evaluated. A validation of
      the Queretaro antigen for indirect hemagglutination reaction as a diagnostic test
      and the interobserver concordance for the serologic readings were also made. The
      observers were instructed in some sessions. The pretests were made in the
      laboratory with positive and negative sera, with sera from the studied
      population. Results show that the interobserver concordance after the
      instruction, for the dwelling variables ranged from 70% to 100%. Sensitivity of
      the Queretaro antigen was 100%, specificity 55%, the predictive value of a
      positive test 55%, and the predictive value of a negative test 93%. The
      interobserver concordance was 47%. The pretest and the pilot study are very
      important in getting the objectives of the principal study.

PMID- 10413888
TI  - [Prevalence of Trypanosoma cruzi antibodies in blood donors].
AB  - Blood transfusion is the second most common transmission route of Chagas' disease
      in endemic areas. Discrepancies between the available diagnostic kits are common,
      which indicates that a single test is not satisfactory. The aim of this work was
      to study the seroprevalence of anti-Trypanosoma cruzi markers, to compare
      sensitivity and specificity of the two screening assays currently in use and to
      confirm the results with a third test. A total of 20,860 volunteer blood donors
      were studied. Donations were screened with indirect hemagglutination assay (IHA)
      and enzyme immunoassay (EIA). Repeatedly reactive samples were assayed with an
      EIA carried out on strips, to which a mixture of T. cruzi antigens was applied as
      an horizontal line (DB). Sera that reacted in at least two tests were considered
      positive. A total of 576 samples were reactive for one or both screening tests
      (2.76%) and 391 of them (1.87%) were confirmed positive. EIA proved to be more
      sensitive, with no false negative results (100% sensibility), whereas 98 samples
      (0.47%) were IHA false negative (74.93% sensibility). Specificity for EIA was
      99.3% and for IHA 99.8%. In our case, almost 0.9% of donated blood is discarded
      because of false reactive anti-T. cruzi results; two thirds correspond to false
      positive EIA and one third to false positive IHA. It is important to note that in
      our population we have not registered false negative results for EIA but there
      were false negative IHA. This fact implies that although the first method is less
      specific, it is much more sensitive. It is important to confirm the screening
      results in order to avoid unnecessary donor counselling and permit future
      donations. The DB test employed in our study results a useful alternative for
      this purpose.

PMID- 10413889
TI  - [Autosomal dominant polycystic kidney disease: detection of a new mutation in the
      PKD1 gene].
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder
      characterized by genetic heterogeneity. Up to three loci are involved in this
      disease, PKD1 on chromosome 16p13.3, PKD2 on 4q21, and a third locus of unknown
      location. Since the identification of the PKD1 gene, the interest was centered in
      the characterization of the mutations responsible for the disease. Most mutations
      found were diverse and situated throughout the gene with no phenotypic
      correlation. Here we describe a new mutation in exon 44 from PKD1 gene in a
      family previously characterized as PKD1 by linkage analysis. The mutation is a
      single base substitution from a C to a T at position 12220 originating a stop
      codon at the mutation site. This would lead to premature termination and the
      formation of a truncated protein lacking part of the carboxi-terminus.

PMID- 10413890
TI  - [Epidemiologic consistency of polymerase chain reaction (PCR) based methods for
      the study of Acinotobacter baumannii infections].
AB  - Acinetobacter baumannii is one of the most frequent causative agents of
      nosocomial infections outbreaks. Consequently, a rapid and specific typing method
      that can identify epidemic strains is important in preventing their
      dissemination. To evaluate PCR (polymerase chain reaction)-based methods as
      epidemiological markers, epidemiologic concordance (EC) and the discriminatory
      power (D) of two of those methods: 1) arbitrary primed-PCR (AP-PCR), and 2)
      repetitive extragenic palindrome sequence-based PCR (REP-PCR), were analyzed. The
      results were compared with that of ribotyping using EcoRI, BglII and ClaI as
      restriction enzymes. These methods were applied to 69 A. baumannii isolates that
      included: 15 epidemiological unrelated isolates, 31 recovered from two outbreaks,
      and 23 obtained from endemic infections. Considering the unrelated isolates, D of
      ribotyping, AP-PCR and REP-PCR were 0.915, 0.904 and 0.847, respectively. The
      three methods showed the same EC with respect to the two analyzed outbreaks (100%
      and 83%, respectively), and the epidemic strains were uniformi differentiated
      from the co-transferred ones. Ribotyping classified the 23 isolates recovered
      from endemic infections in 4 different strains, while AP-PCR and REP-PCR
      identified 3 of them. Although, the 3 methods identified the most frequent
      disseminated strain. The mayor advantages of REP-PCR versus AP-PCR were
      reproducibility, and easier optimization. These advantages, in addition to the
      similar EC of the 3 methods, confirm REP-PCR as an appropriate marker to be used
      when rapid information about epidemiological A. baumannii infection analysis is
      required.

PMID- 10413892
TI  - Metabolism of the complex monofluorophosphate-alpha 2-macroglobulin in the rat.
AB  - Sodium monofluorophosphate (MFP) is a drug used in the treatment of primary
      osteoporosis. Following the intake of MFP, a small fraction of the drug is
      absorbed intact and forms a complex with alpha 2-macroglobulin (MFP-alpha 2M)
      inactivating the antiproteasic activity of the globulin. The complex has been
      shown to occur in the serum of rats and human being. This paper reports data on
      the metabolism of this complex in the rat. In vitro experiments showed that liver
      and bone tissue remove MFP-alpha 2M from the incubation medium. When the
      experiments were pursued beyond the time needed to reduce the complex
      concentration to very low levels, fluorine (F) reappears in the medium in two
      forms: bound to low molecular weight macromolecule/s (2,200 +/- 600 Da) and as
      ionic F. Concentrations of these F fractions increase while that of the complex
      decreases as a function of time. In vitro, uptake of the complex by liver or bone
      tissue was not affected by the presence of colchicine or methylamine. These
      drugs, however, inhibited intracellular metabolism of the complex, as indicated
      by the impairment of the return of F species to the extracellular space and the
      increase in F content of the tissue. The cellular receptors responsible for the
      uptake of the complex in liver and bone are insensitive to low concentration of
      calcium and inhibited by polyinosinic acid[5']. These features characterize the
      "scavenger" receptor, one of the two receptor types known to remove inactive
      alpha 2M from the circulation. Injection of polyinosinic acid [5'] to living rats
      also hindered the disappearance of the complex from serum. It is concluded that
      the metabolism of the MFP-alpha 2M complex involves binding to receptors, uptake
      by cells, lysosomal degradation and return of F bound to low molecular weight
      macromolecule/s to the extracellular space. It is assumed, however, that
      inorganic F is the final product of lysosomal hydrolysis of the protein moiety.

PMID- 10413891
TI  - [Spontaneous infectious spondylodiscitis in adults. Analysis of 30 cases].
AB  - We revised retrospectively 30 cases of Spontaneous Infectious Spondylodiskitis
      (SIS) in adults, diagnosed between 1986 and 1997. The mean age of the patients
      was 68.8 years; 56.7% were males. The identifiable causes were infectious
      endocarditis 13 (43.3%); tuberculosis 7 (23.3%); urinary tract infection 4
      (13.3%); bacteremia with focus 2 (6.7%) and without focus 2 (6.7%). The cause was
      not identified in other 2 cases (6.7%). Infections were due to pyogenic bacteriae
      in 19 (63.3%); tuberculosis 6 (20%) and unknown 5 (16.7%). All patients had
      localized pain, 70% fever, 36.7% irradiated pain and 23.3% paraparesis. Fever was
      more frequent in patients with pyogenic etiology than in those with tuberculous
      SIS (p = 0.004). Blood cultures were positive in 70.4%. Percutaneous aspiration
      of the disc was performed in 13 patients; cultures were positive in 7. Causal
      germs were Streptococcus spp. 33.3%; Mycobacterium tuberculosis 20%;
      Staphylococcus spp. 16.6%; Escherichia coli 6.6%; Pseudomonas aeruginosa 6.6%.
      There was no bacteriological recovery in 5 (16.7%). Localization was lumbar in 18
      (60%), dorsal in 8 (26.6%) and cervical in 4 (13.3%). X-ray of the spine was
      positive in 63.3% of the cases. Technetium scan in 90.5%, CT in 85.7% and MRI in
      100% of cases in which it was carried out. All patients received antibiotic
      treatment with a median duration of 6 weeks for pyogenic SIS and one year for
      tuberculous SIS. Eighty three percent required immobilizing brace and 10% surgery
      for stabilization. Thirty six percent of patients presented complications, most
      of them related to the causal disease. There was a statistically significant
      association between mortality and diabetes.

PMID- 10413893
TI  - In postmenopausal osteoporosis the bone increasing effect of monofluorophosphate
      is not dependent on serum fluoride.
AB  - According to previous pharmacokinetic studies the bioavailability of fluorine (F)
      from sodium monofluorophosphate (MFP) doubles that of sodium fluoride (NaF). This
      paper reports a study designed to verify whether the vertebral bone mass
      increasing effect of NaF (30 mg F/day) was comparable to that of MFP (15 mg
      F/day), given for 18 months to osteoporotic postmenopausal women. The BMD of
      lumbar vertebrae of both groups showed significant increases (MFP: 60 +/- 15
      mg/cm2, NaF: and 71 +/- 12 mg/cm2) over basal levels (P < 0.001). The difference
      between treatments was not significant (P = 0.532). The serum levels of ionic F
      (the mitogenic species on osteoblasts) were not related to the above mentioned
      effects. In NaF-treated patients, the fasting levels of total serum F increased
      significantly (6.7 +/- 0.9 microM vs. Basal: 2.0 +/- 0.8 microM; P < 0.001). This
      phenomenon was accounted for by ionic fluoride that increased over 20-fold (6.5
      +/- 1.9 microM vs. Basal: 0.3 +/- 0.04 microM). In MFP-treated patients the
      fasting serum levels of total (7.0 +/- 0.7 microM vs. Basal: 2.2 +/- 0.9 M) and
      diffusible F (0.5 +/- 0.02 microM vs. Basal 0.2 +/- 0.02 microM) increased
      significantly (P < 0.001). The increase in the non diffusible F fraction is
      accounted for by protein-bound F, probably by the complexes formed between MFP
      and alpha 2-macroglobulin and C3. Serum diffusible F was formed by two fractions:
      ionic F and F bound to low molecular weight macromolecule/s (2,200 +/- 600 Da),
      in approximately equal amounts. The general information afforded by the present
      observations support the hypothesis that ionic F is released progressively during
      the metabolism of MFP bound to alpha 2-macroglobulin and C3. These phenomena
      explain why comparable effects to those obtained with 30 mg F/d of NaF could by
      obtained with one half the dose of MFP.

PMID- 10413894
TI  - Interleukin-2 restores natural killer activity inhibited by sera from HIV+
      hemophilic patients.
AB  - Natural killer (NK) activity is impaired in patients with positive serology for
      the human immunodeficiency virus (HIV). We previously found an inhibitory effect
      of sera from hemophilic (He) HIV+ patients on normal NK activity. In the present
      study, we have further characterized this effect by studying its reversibility,
      temperature and time incubation dependence. Since interleukin 2 (IL-2) is able to
      enhance NK levels, we analyzed the capacity of this lymphokine to reverse the
      effect of He HIV+ sera. We found that when IL-2 activation of NK activity
      occurred simultaneously or after HIV+ serum-treatment, a significant restoration
      of NK function was observed. In contrast, preincubation with IL-2 did not affect
      the inhibitory effect exerted by HIV+ sera.

PMID- 10413896
TI  - Cell differentiation increases astrocyte phagocytic activity. A quantitative
      analysis of both GFAP labeling and PAS-stained yeast cells.
AB  - Since efficiency of phagocytic potential in activated astrocytes is still a
      subject of controversy, an attempt was made to quantify simultaneously phagocytic
      activity and astrocyte differentiation. Resorting to Junin virus, known to induce
      astrocyte activation, infected vs control samples of cultured rat astroglial
      cells were serially harvested up to day 12 post-inoculation (pi), and subjected
      to a triple staining procedure consisting in immunoperoxidase labeling of GFAP,
      periodic acid-Schiff (PAS) reaction in added baker's yeast cells and hematoxylin
      for nuclear staining of the whole cell monolayer. Adopting GFAP labeling as a
      specific marker of astrocyte differentiation, the immunoprecipitate development
      over time was measured. Direct calculation of the initial reaction rate was
      feasible given its linear behavior during the first 10 min, so that GFAP amount
      was regarded proportional to peroxidase activity. As determined by digital image
      analysis, mean optical density (MOD) values of GFAP in infected samples increased
      from 0.618 +/- 0.082 at day 1 pi to 0.825 +/- 0.125 at day 3, leveling off at
      1.010 +/- 0.101 as from day 9, while control uninfected samples remained
      unchanged at roughly 0.6 during the entire observation period. In turn,
      phagocytosis was quantified by PAS staining densitometry, whose intensity varied
      according to wall degradation of yeast cells. MOD levels of PAS-stained
      phagocytized yeast cells were significantly lower (p < 0.05) in infected vs
      control cultures at 48 and 72 h following their addition to the astroglial
      monolayer. According to simultaneous quantification of two components of
      astrocyte response to viral infection, it is concluded that phagocytic activity
      increases with astrocyte differentiation.

PMID- 10413895
TI  - [Blood lead levels in children of Cordoba City].
AB  - Exposure to environmental lead is a major hazard to public health. International
      Environmental Agencies have assessed that blood lead concentrations of 10.0-15.0
      micrograms/dl or even lower may be a risk factor for children. This survey
      focussed on environmental lead contamination and tried to provide information
      about blood lead levels in the children population of Cordoba City. A total of
      172 children between 6 months and 9 years of age assisted in health centers and
      hospitals from December 1995 to December 1996 were surveyed. Lead assessment was
      performed by atomic absorption spectrophotometry with graphite furnace. Results
      revealed that 73.3% of the children population studied exhibited blood lead
      levels lower than 10.0 micrograms/dl; 19.2% evidenced risk concentration levels
      (10.0-14.9 micrograms/dl) and 7.6% showed concentrations higher than 15.0
      micrograms/dl. It was confirmed that children with elevated concentrations lived
      in areas where numerous car repair shops are located. Three of the subjects lived
      in slums. From the group with low blood lead levels (< 10.0 micrograms/dl), 25
      children lived downtown or near main avenues of heavy traffic and belonged to
      middle class families. Our survey showed a high occurrence of children with lead
      levels higher than 15.0 micrograms/dl (7.6%) whose etiology risk factors have
      been identified. Prevention should be able to cut down this occurrence through a
      safe control of environmental lead sources.

PMID- 10413898
TI  - [Lung dirofilariasis].

PMID- 10413897
TI  - [Central pontine myelinolysis induced by hyperemesis gravidarum].
AB  - An 18-year-old woman in her first pregnancy with hyperemesis gravidarum,
      presented dehydration, without hyponatremia. She was confused with profound
      disorientation, apathy, and drowsiness. She presented upbeating nistagmus on
      upward gaze and gate ataxia recognised as Wernicke's encephalopathy. Laboratory
      tests demonstrated hypokalemia, hypernatremia and aminotransferase elevation. The
      serum osmolality was 319 mOsm/kg and the water deficiency 2.73 l. The patient
      developed weakness in the four limbs, with hypotonicity, absence of tendon
      reflexes and showed bilateral Babinski signs. A T2 weighted sagittal cranial
      magnetic resonance imaging revealed a high signal within mid-pons suggesting
      central pontine myelinolysis. In this case we highlight the absence of
      hyponatremia. Furthermore, the central pontine myelinolysis was probably
      secondary to hypokalemia, hypernatremia and hyperosmolality.

PMID- 10413899
TI  - [Pulmonary thromboembolism: complete obstruction of the right pulmonary artery.
      Helicoidal computerised tomography].

PMID- 10413900
TI  - [Membranous glomerulonephritis, necrotizing arteritis and pulmonary interstitial
      disease].

PMID- 10413901
TI  - [Pneumocystis carinii pneumonia in AIDS. New concepts for an old problem].
AB  - Pneumocystis carinii (PC) is an ubiquitous pathogen phylogenetically considered a
      fungus. In individuals with T-cell deficiency, PC produces typically an
      interstitial pneumonia. The primary infection is, perhaps, transmitted airborne,
      and is acquired during early infancy. PC was a rare cause of disease until the
      advent of AIDS. In susceptible patients infected with HIV it remains a major
      cause of morbidity and mortality despite appropriate prophylaxis and treatment.
      Mutations in the gene that encodes the enzyme dihydropteroate synthase are
      seemingly accountable for the failure of prophylaxis in some individuals. The
      incidence of new cases of PC pneumonia (PCP) in patients with infection with HIV
      has dropped substantially since the advent of highly active antiretroviral
      therapy (HAART). Ongoing trials are designed to study the effect of withdrawing
      prophylaxis for PCP in patients whose T-cell count has risen over 200/mm3 in
      response to HAART.

PMID- 10413902
TI  - [Euthanasia and physician-assisted suicide in Argentina and in other countries].
AB  - Medical decisions concerning the end of a patient's life have been widely
      practiced for centuries and there are strong arguments for and against. Advocates
      typically adduced that terminally ill patients have the right to impose, with
      physicians' help, their self-determination to avoid extreme suffering and a
      painful death. Opponents argued that legalizing those practices would not be
      ethical because it is against the principles of society and the medical
      profession. During the last years, debates about medical decisions concerning the
      end of a patient's life have increased in many regions of the planet after these
      became legal in several countries. In Argentina, those practices are illegal;
      however, there is evidence that they are frequently practiced. Nevertheless,
      public discussion on the subject is limited in Argentina. A profound debate on
      the position of society and physicians concerning terminally ill patients must be
      initiated.

PMID- 10413903
TI  - [Nobel Prize in medicine 1998: resurrection of an inorganic gas into a molecule
      of high biological significance].

PMID- 10413904
TI  - [Clinical importance of fluorine pharmacokinetics].

PMID- 10413905
TI  - [Socrates and hemlock].

PMID- 10413906
TI  - [Explained quotations: Azara and Indians' medicine].

PMID- 10413907
TI  - [Pulmonary dirofilariasis].

PMID- 10413908
TI  - [Vesicular microlithiasis and ursodeoxycholic acid].

PMID- 10413909
TI  - [The physician-scientist: from academy to partnership].

PMID- 10413910
TI  - [Mast cell hyperplasia in bone oxalosis].
AB  - BACKGROUND: To assess by means of histomorphometry the incidence of bone marrow
      mast cell hyperplasia in patients with chronic renal failure and oxalosis.
      MATERIAL AND METHODS: Eighteen individuals were assigned to three groups: 6 (4
      males and 2 females, aged 26.31 +/- 2.5 yrs) had chronic renal failure (CRF) and
      oxalosis of bone; 6 (1 male and 5 females aged 22.1 +/- 3.56 yrs) had CRF and 6
      normal (5 males and 1 female aged 23 +/- 2.78 yrs) individuals entered the
      control group. Quantitative histologic assessments were completed in
      undecalcified sections of plastic embedded iliac crest bone biopsies stained by
      the Toluidine Blue method for identification of mast cells. The number of mast
      cells (cell/mm2 tissue area, x +/- sd) was determined by a semiautomatic image
      analyzing system. RESULTS: The number of mast cells was greater in patients with
      oxalosis of bone, 32.67 +/- 9.59, than in patients with CRF (20.84 +/- 5.04, p <
      0.05) and than in the control group (3.26 +/- 1.03, p < 0.001). CONCLUSIONS:
      Oxalosis of bone is associated with substantial increases in the number of mast
      cells in the bone marrow. Such a change is not related to chronic renal failure
      per se and does not appear to represent a non-specific response to bone marrow
      fibrosis. Mast cell accumulation may contribute to the development of bone marrow
      fibrosis seen in this disorder.

PMID- 10413911
TI  - [Intra-operative identification of the ostium of Wirsung's pancreatic duct after
      papillosphincterotomy].
AB  - PURPOSE: The aim of this study is to suggest a feasible method to find the ostium
      of the Wirsung's duct during sphincteroplasty of the Vater's papilla, in order to
      avoid post-operative complications such as acute pancreatitis. PATIENTS AND
      METHODS: A total of 27 patients were submitted to sphincteroplasty for
      choledocolithiasis with or without Odditis. After therapeutic papillotomy and
      sphincterotomy through the duodenun, the location of the ostium of the Wirsung's
      duct was determined and studied. After papillotomy, the Vater's papilla becomes
      an isosceles triangle and its measurements were made with a compass. Thereby the
      ostium of Wirsung's duct was easily detected and a catheter was inserted before
      the suture of the mucosa of the papilla. RESULTS: The ostium was generally found
      medially, on the left side of the triangle, 0.19 cm to 0.25 cm on average above
      its base whether there was inflammation or not, respectively. CONCLUSION: The
      transoperative determination of the dimensions as proposed in this study, allows
      a safety detection and cannulation of the Wirsung's duct with or without
      inflammation of the Oddi's sphincter.

PMID- 10413912
TI  - [Treatment of inguinal hernias. Is the Bassani's technique current yet? A
      prospective, randomized trial comparing three operative techniques: Bassini,
      Shouldice and McVay].
AB  - OBJECTIVE: To compare late results (recurrence) of three different techniques for
      treatment of inguinal hernias in the adult: Bassini, Shouldice and McVay.
      PATIENTS AND METHODS: The operative late results of three surgical techniques:
      Bassini, Shouldice and McVay in 119 adult patients with inguinal hernias (some
      with bilateral pathology, totalizing 136 hernias) were analyzed. The majority of
      patients were males (93.3%). The analysis was prospective, randomized, with
      uniform distribution of all three types of inguinal hernia (direct, indirect and
      combined) among the three groups of operative techniques. The number of
      recurrences was submitted to an actuarial analysis for a period of 4 years. The
      results underwent statistical analysis by the Kaplan-Mayer test with actuarial
      survival curves. RESULTS: Eight hernia operations by the Bassini technique
      recurred in this time span, 3 in the Shouldice group and 2 in McVay. Among the
      Bassini recurrences, the worst results were observed with direct hernias (29%
      recurrence) when compared with indirect ones (16% recurrence). Overall recurrence
      rates plotted in an actuarial survival curve for 4 years, revealed statistically
      significant differences between Bassini and Shouldice: 35.7% versus 23.7%; the
      same happened when comparing Bassini to McVay: 35.7% versus 8.5%. The differences
      between Shouldice and McVay were not significant. CONCLUSION: A recurrence rate
      of 35.7% for inguinal herniorraphy with the Bassini technique in a General
      Surgery University Clinic was surprising and obliged us to interrupt the trial.
      Our observations point to a prohibitive high failure rate when dealing with the
      Bassini technique, which was, over a century, the most popular treatment of
      inguinal hernia all over the world. Shouldice and McVay techniques, even though
      more complex, should be preferred whenever one makes the choice for
      "conventional" hernia treatment.

PMID- 10413913
TI  - [Racial differences between patients with focal segmental glomerulosclerosis and
      membranoproliferative glomerulonephritis from the State of Bahia].
AB  - OBJECTIVE: To assess the association between race and type of glomerulonephritis,
      taking into account age, gender and the presence of hepatosplenic schistosomiasis
      mansoni. METHODS: Patients from the Renal Service of the Federal University of
      Bahia, Brazil, 80 with focal segmental glomerulosclerosis (FSG) and 50 with
      membranoproliferative glomerulonephritis (MPGN) were compared regarding the
      distribution of the racial types (black, mulatto, white). Patients with systemic
      lupus erythematosus or any kind of autoimmune disease were not included in the
      present analysis. Adjusted comparisons were performed using the Mantel-Haenszel
      method and a multivariate logistic regression model. RESULTS: Race was
      significantly associated with histologic type; the odds of being classified as
      black or mulatto were approximately 2.4 times higher (odds ratio = 2.43; IC 95% =
      1.09-5.45) in patients with FSG than in those with MPGN. The association between
      race and histologic type was not influenced by the potential effects of age,
      gender and hepatosplenic schistosomiasis. In the multivariate logistic regression
      model, race was significantly associated (p = 0.037) with type of
      glomerulonephritis (odds ratio = 2.54; IC 95% = 1.06-6.06). CONCLUSION: A higher
      frequency of negroes and mulattoes in the FSG group (compared with MPGN) in this
      sample from the State of Bahia is consistent with findings of previous studies
      from the United States. The data support the possibility of a greater
      susceptibility to FSG among negroes and mulattoes, independently of age, gender
      and schistosomiasis. The identification of the mechanisms that determine this
      racial difference represents an important question for future investigations.

PMID- 10413914
TI  - [Lethality in hospitalized infants with acute diarrhea: risk factors associated
      with death].
AB  - OBJECTIVES: Acute diarrhea is a very frequent disease in developing countries and
      is the first cause of death in infants under 2 years of age. This study was
      designed to evaluate the clinical and epidemiological factors associated to the
      death of 17 out of 511 infants hospitalized owing to severe acute diarrhea,
      between January 1989 and December 1995. PATIENTS AND METHODS: The patients were
      divided into two groups according to their clinical evolution: Group I--Death and
      Group II--Survival. The following parameters were evaluated: birth weight, sex,
      age, duration of diarrhea (days) prior to admission, nutritional status,
      hydration, presence of an enteropathogenic agent in the stools, food intolerance
      and duration of hospitalization. RESULTS: The analyzed factors have shown a
      significant association with death for the following variables: age, relative
      risk (RR) = 4.0 for infants less than 6 months of age, identification of an
      enteropathogenic Escherichia coli (EPEC) strain in the stools (RR = 3.3), severe
      malnutrition at admission to the hospital (RR = 4.5), Occurrence of food
      intolerance during hospitalization (RR = 2.7). Some enteropathogenic agent was
      identified in the stools of 253 (54.9%) infants, among the 461 (90.2%) studied.
      Group I revealed the presence of an enteropathogenic agent in 75% of the cases.
      The most frequent agents identified in Group I was: EPEC (56.3%) and Shigella
      (12.5%), while in Group II EPEC was identified in 26.5% of the patients.
      CONCLUSIONS: The association of some factors such as age less than 6 months,
      severe malnutrition, food intolerance and the identification of EPEC strains in
      the stool culture are indicators of high risk of death in infants hospitalized
      due to severe acute diarrhea.

PMID- 10413915
TI  - [Spontaneous bacterial peritonitis in hepatic cirrhosis: prevalence, predictive
      factors and prognosis].
AB  - BACKGROUND: Spontaneous Bacterial Peritonitis (SBP) is a common and potentially
      fatal complication of cirrhosis. Multiple variants of this infection have been
      described during the past decade. Few studies have investigated SBP in Brazil.
      MATERIAL AND METHOD: In order to investigate prospectively prevalence, predictive
      factors and prognosis of the episode of SBP, we studied 143 in and outpatients
      with cirrhosis admitted to HUCFF and HUPE between January, 1995 and January,
      1996. All patients were submitted to a questionnaire, physical examination, blood
      analysis and abdominal paracentesis with ascitic fluid analysis. They were
      followed for a mean follow-up period of 4 months and survival was determined.
      RESULTS: The prevalence of SBP was 20%. Culture-positive SBP, Culture-negative
      Neutrocytic Ascites and Bacterascites were identified in 24%, 66% and 10%,
      respectively. After uni- and multivariate analysis, only anterior
      gastrointestinal hemorrhage, serum albumin and ascitic fluid C4 reached
      statistical significance (p = 0.05) as predictive factors for the development of
      the SBP. The in-hospital and follow-up mortality rates were 33.3% and 53.8% for
      the SBP patients and 8.5% and 31.9% for the non-SBP patients, respectively (p =
      0.01 and p = 0.04). The cumulative probability of survival in the SBP group was
      significantly lower than the probability of the non-SBP group (p = 0.05).
      CONCLUSIONS: We conclude that SBP is a frequent complication, depends of the
      severity of liver failure and is a marker for poor prognosis in patients with
      liver cirrhosis.

PMID- 10413916
TI  - [Exercise test: abnormal ST segments restricted to recovery phase].
AB  - PURPOSE: To determine the incidence of atherosclerotic coronary artery disease
      (CAD) and or myocardial ischemia in patients (pt) with abnormal ST segments
      restrict to recovery phase (RRAST) of exercise testing (ET). MATERIAL AND METHOD:
      Retrospective study in 19 non consecutive pt with RRAST, related to coronary
      arteriography or exercise planar scyntillography (18 men, 58 +/- 9 years, 18
      asymptomatic). RESULTS: RRAST corresponded to ST segment depression from 1 to 4
      mm, with T inversion during early recovery (2 pt); late (14 pt) or both (4 pt).
      It was documented CAD (14 pt and 9) with artery-by-pass surgery); hypertensive
      myocardiopathy with normal coronary (3 pt), and mitral prolapse valve (1 pt). In
      13 pt with coronary arteriography or exercise scyntillography, within the first 6
      months from exercise testing, myocardial ischemia was confirmed in 8 pt in 3 pt,
      successive exercise testing showed RRAST reproductive in 2 cases. CONCLUSION: The
      authors report the high incidence of CAD and or transitory hypoperfusion during
      myocardial scyntillography in symptomatic men with middle age with RRAST during
      exercise testing.

PMID- 10413917
TI  - [Acute phase response and serum magnesium levels among hospitalized patients].
AB  - The acute phase response (APR) is characterized by proteolysis with decreased
      body cell mass, hyperglycemia, body water retention and renal dysfunction, which
      we hypothesised could affect magnesium serum levels. The aim of this study was to
      compare serum magnesium levels among hospitalized patients with or without APR.
      METHOD: All serum magnesium results (n = 527) corresponding to a six-months
      period were searched at University Hospital mainframe. Relevant laboratorial and
      clinical details were also registered. All cases of diabetes mellitus, chronic
      renal insufficiency, or serum creatinine > 1.5 mg/dl were excluded. APR was
      defined by the presence of fever plus severe trauma or infection plus leukopenia
      or leukocytosis. RESULTS: From a total of 214 patients, sixty-nine (32.2%) met
      the criteria for APR positivity (APR [symbol: see text]). Groups were paired for
      age, color, gender, diuretic use and edema presence. Hypomagnesemia was
      registered among 72% of cases, without statistical difference (p = 0.06) among
      APR [symbol: see text] and APR theta patients (63.8 vs 75.9%). Serum magnesium
      levels (median; range) were higher among APR [symbol: see text] cases, when
      compared to APR theta ones: 1.75; 1-3 vs 1.6; 0.9-2.9 m/dl, the same occurring
      with glycemia (115; 49-236 vs 99; 61-191 mg/dl) and serum creatinine (mean +/-
      SD): 0.8840 +/- 306 vs 0.803 +/- 0.257 mg/dl. Hypermagnesemia was more common
      among APR [symbol: see text] cases: 8.7 vs 2.1%. CONCLUSIONS: Our results suggest
      that higher magnesium serum levels seen in APR [symbol: see text] patients may be
      attributed to subclinical renal ischemia and possibly to increased glucose serum
      levels.

PMID- 10413918
TI  - [Evaluation of polymorphonuclear neutrophils in moderate malnutrition].
AB  - PURPOSE: To evaluate the phagocytic function of polymorphonuclear neutrophils in
      moderate malnutrition. METHODS: The phagocytic function of neutrophils obtained
      through peripheral blood sampling of twenty two children with moderate
      malnutrition without infections was analyzed. The results were compared to a
      group of twenty well nourished children matched for age (two to five years old).
      The phagocytic function was assessed by the ingestion of zymosan particles and
      nitro blue tetrazolium reduction among 200 cells. RESULTS: The mean number of
      zymosan particles ingested by neutrophils incubated with homologous human serum
      and autologous human serum were 18, 41 and 46 in the malnutrition group compared
      to 20, 57 and 63 in the well nourished group. The spontaneous and stimulated
      reduction of nitro blue tetrazolium was 6 and 11 in the malnourished patients,
      respectively, and 12 and 17 in the well nourished group. CONCLUSION: A decrease
      in the process of ingestion and digestion during phagocytosis occurs in
      malnourished patients.

PMID- 10413919
TI  - [The physician-scientist: from academy to partnership].
AB  - OBJECTIVES: To illustrate the changes in academy and in industry that are
      reshaping the profile of the physician-scientist. METHODS AND RESULTS: Data were
      extracted from the literature and from primary sources as well as from the
      authors' own experiences. CONCLUSIONS: Within an academy-industry relationship,
      the market demands a physician-scientist best suited to orient research
      activities towards patient-oriented and disease-oriented goals.

PMID- 10413920
TI  - [Primary cutaneous malignant melanoma: retrospective studyfrom 1963 to 1997 at
      Hospital do Servidor Publico Estadual de Sao Paulo].
AB  - OBJECTIVES: A retrospective study on the Primary Cutaneous Malignant Melanoma in
      the Hospital do Servidor Publico Estadual de Sao Paulo (HSPE-SP) analyzing its
      distribution according to age, sex, race and cutaneous site. METHODOLOGY: We
      studied 222 patients with Primary Cutaneous Malignant Melanoma as diagnosed at
      Hospital do Servidor Publico Estadual de Sao Paulo, Brazil between the period
      from 1963 to 1997. A retrospective study was performed. Data were expressed as
      inance of caucasians (98.19%) over afro-americans (1.81) and of the female sex
      (69.36%) over the male sex (30.63%) was found. The predominant age on the
      occasion of the diagnosis was between 50 and 60 years for the women (25.32%) and
      between 60 and 69 years for the men (22.52%). The most frequent site of the
      cancer in men was the back region (29.41%) and in the lower members in the women
      (38.31%). The most frequent level of the tumor invasion (Clark) was IV (39.77%),
      and the average of tumor thickeness (Breslow) was < 0.75 mm (28.4%). A 5 years
      survival was observed in 73.3% of the patients. CONCLUSIONS: At our Hospital the
      incidence of Primary Cutaneous Malignant Melanoma has shown an increase in recent
      years; these results are compatible with the most recent international surveys.

PMID- 10413921
TI  - [The HIV-positive health care worker: lessons for biosafety and ethics].
AB  - After the contamination with HIV of 6 patients by an american dentist, great
      concern about the work of HIV-positive health care workers emerged. In spite of
      the good effects of preventive programs (also including other viruses more
      contagious than HIV, like the hepatitis virus), that concern is still confuse and
      misunderstood, blurred by social prejudice and intolerance with regard to HIV
      patients. This article shows that a policy of segregation of HIV-positive health
      workers is neither fair nor effective to improve biosafety. On the other hand, a
      responsible behavior by the positive worker is appropriate, avoiding to
      participate on exposure-prone proceedings. If an accident happens, anti-HIV
      prophylaxis with drugs, active and passive immunization against HBV should be
      offered to the patient. Acting on a better informed basis will brings other
      benefits and turn possible a new way, more human and less positivist, on facing
      the challenges of this new epidemic.

PMID- 10413922
TI  - [Percutaneous renal allograft biopsy: where are we going?].

PMID- 10413923
TI  - [Immunologic aspects of type 1 diabetes mellitus].

PMID- 10413924
TI  - [Cell response to stress].

PMID- 10413925
TI  - [Epistaxis treatment].

PMID- 10413926
TI  - [Lethal midline granuloma: clinical management of three cases].

PMID- 10413927
TI  - [Social and ethical responsibility of scientists].

PMID- 10413928
TI  - [Popular education and child nutrition: experience with women in a rural area of
      Mexico].
AB  - OBJECTIVE: Community intervention was undertaken using the health promotion
      strategy, the objective being to develop a health education program for women.
      METHODS: The popular education methodology was used with the purpose of
      generating organizational and social participation processes to improve hates of
      child nutrition and survival. RESULTS: The main results are linked with the
      generation of community self-care processes and the creation of a health
      promoters' group which has been working with women, focusing their work on
      improving child nutrition and family health. The health promoters have taken
      charge of the epidemiological surveillance program for child nutrition and,
      together with the mothers, have undertaken a series of actions which have helped
      to decrease the rate of malnutrition among the children participating in this
      programs. CONCLUSIONS: There would be greater possibility of success if the
      general population were involved in the solution of this problem. This would be
      possible by the use of an adequate methodology which brought about greater
      community participation in such a way as to leave room for its own improvement.
      Popular education provides such a tool. It is necessary to continue to increase
      experience in health education with this type of methodology.

PMID- 10413929
TI  - [Prevalence of serologic markers of hepatitis B virus in hospital personnel].
AB  - OBJECTIVE: To verify the prevalence of the anti-HBc, anti-HBs and HBsAg markers
      of hepatitis B virus, and to identify the risk factors determining occupational
      infection with this virus among hospital personnel. METHODS: Samples of serum
      from 210 persons both male and female who work in different occupations at a
      hospital university, were analysed. The technique employed was the
      immunoenzymatic assay using commercial kits. RESULTS: As a control group, samples
      of serum from 45 volunteer blood donors were utilized. It was verified that 20.5%
      of the hospital personnel presented a positive reaction to at least one of the
      markers songht, as against 6.6% of the control group. The prevalence of each
      marker separately was: anti-HBc 8.1%, anti-HBs 5.2%, and HBsAg 2.9% in the
      hospital personnel; and 4.4%, 2.2% and 0.0% in the control group. The
      simultaneous presence of the anti-HBc and anti-HBs markers was detected in 4.3%
      of the workers. In the control group, the presence of the anti-HBc and anti-HBs
      markers was detected, isolately, with respective prevalences of 4.4% and 2.2%.
      Those who presented the highest rates of positivite reaction were: laboratory
      technicians 24.0%, nurses 23.6%, physicians 20.8%, and cleaning personnel 18.2%.
      CONCLUSIONS: The findings suggest that direct contact with patients and handling
      of blood and other body fluids are risk factors related to occupational infection
      with HBV. Therefore, it is recommended that hospital personnel be vaccinated
      against hepatitis B.

PMID- 10413930
TI  - [Trends of mortality from avoidable causes and expansion of municipal health
      resources in a southern Brazilian city].
AB  - OBJECTIVE: An assessment of the evolution of the profile of mortality from
      avoidable diseases, in the municipality of Maringa, PR (Brazil), 1980 through
      1993, as related to the quality of health attendance. METHODS: Based on the
      proposal to study caregiving results, eleven causes of avoidable deaths were
      selected. The evolution of resources available, level of schooling and sanitation
      were associated with the evolution of mortality. RESULTS AND DISCUSSION: The data
      revealed that the mortality rates for most of the avoidable causes tended to
      decline faster than those for other causes (a reduction of 39% as against 16%). A
      significant improvement in schooling and sanitary conditions was also observed
      over the same period. The positive evolution of the general health status of the
      population makes it difficult to credit the decline of avoidable deaths directly
      to the health services, but the difference between the mortality rates from
      avoidable causes and others allows one to infer that if despite the satisfactory
      living conditions there were an outbreak of avoidable deaths it would indicate a
      lack of efficiency on the part of the health services. Under the circumstances
      verified, the decrease in the rate of mortality from avoidable causes can be
      partly attributed to the expansion of the health services.

PMID- 10413931
TI  - [Workers' perception of exposure to workload and risks of accidents in a southern
      Brazilian city].
AB  - OBJECTIVE: The study of the association between workers' perceptions of
      occupational hazards and the risk of occupational accidents. DESIGN: Case control
      study. POPULATION: The cases were 264 workers who presented a "typical"
      occupational accident, registered at the National Institute of Social Security in
      the city of Pelotas, between January and July, 1996. Fatal accidents (two) were
      excluded, as were those leading to an absence of less than seven days from work.
      The cases were interviewed in their homes with a standard questionnaire. For each
      case, three controls were chosen: a fellow-work, a neighbor and a population
      control. Controls were matched to the cases by age (+/- 5 years) and sex; workers
      who had suffered an occupational accident in the preceding month were excluded
      from the control group. All cases and controls were formally employed and lived
      in the urban area. The data were analyzed using conditional logistic regression.
      RESULTS AND CONCLUSIONS: The risk of occupational accidents was found to double
      among workers who reported having faced emergency situations at work, working in
      high places, facing constant danger or noisy environments. Working in
      uncomfortable positions or intense physical activities were associated with a 50%
      increase in risk. The remaining occupational hazards under study were not
      significantly associated with the risk of accidents. All of the above results
      were adjusted for confounding factors.

PMID- 10413932
TI  - [Vaccination coverage and risk factors associated to non-vaccination in a urban
      area of northeastern Brazil, 1994].
AB  - INTRODUCTION: The assessment of vaccination coverage and risk factors for non
      vaccination is important to evaluate vaccination programs and to identify
      children not properly vaccinated. METHODS: A cross-sectional household survey was
      carried out in the municipality of S. Luis, Maranhao, Brazil by means of a
      standardized questionnaire. Multistage cluster sampling was used to identify
      children of 12-59 months of age residing in the city in 1994. The mother or other
      person responsible for the children was interviewed. Fifty census clusters were
      visited and 40 households were sampled in each. On average, 15 children were
      found in each cluster. Design effect was calculated for each estimate. Health
      service utilization was analyzed according to socioeconomic and demographic
      indicators, and perceived morbidity using proportional hazard modeling (Cox's
      regression). RESULTS: Vaccination coverage levels were 72.4% for BCG, 59.9% for
      three doses of polio vaccine, 57% for three doses of DTP vaccine and 54.7% for
      measles vaccine. Vaccination levels have remained statistically unchanged over
      the last three years. Lower maternal schooling continues to be associated with
      increased risk of non-vaccination in the multivariable analysis. CONCLUSION:
      Vaccination levels were low. Health education activities are one of the suggested
      strategies to increase vaccination coverage.

PMID- 10413934
TI  - [Analysis of productivity, quality and cost of first grade laboratories: blood
      biometry].
AB  - OBJECTIVE: Assessment of productivity, quality and production costs and
      determination of the efficiency of top grade clinical laboratories in Mexico.
      METHODS: Ten laboratories were selected from among the total number (52) existing
      in Mexico City, and the Donabedian model of structure, process and results were
      applied. Blood count was selected as a tracer. RESULTS: The principal problems
      found were: inadequate distribution of trained human resources, poor glass
      material, inadequate analytic process and low productivity. These factors are
      reflected in the unit costs, which exceed reference laboratory costs by 200%.
      Only 50% of the laboratories analyzed generate reliable results. Only 20% of the
      laboratories studied operate efficiently. CONCLUSIONS: To solve the problems
      identified requires integral strategies at different levels. A specific
      recomendation for the improvement of quality and productivity is an assessment of
      the cost/benefit of creating a central laboratory and using the remaining sites
      exclusively for the collection of samples.

PMID- 10413933
TI  - [Simplified periodontal record for pregnant women].
AB  - PURPOSE: The assessment using the PSR (Periodontal Screening and Recording) of
      the prevalence and severity of and the basic treatment needs for periodontal
      disease in a group of pregnant women who attended the Preventive Dentistry Clinic
      at the School of Dentistry of Araraquara--UNESP. METHODS: Forty-one pregnant
      women of 16 to 37 years of age, were examined. The PSR index was evaluated with a
      suitable periodontal probe (Trinity-model 621-WHO) with index codes scores of
      from 0 to 4, capable of indicating the presence of the following conditions:
      periodontal health, bleeding on probing, calculus, shallow and deep pockets.
      These codes were attributed to each sextant and could be marked with an asterisk
      (*) to indicate the presence of gingival recession, furcation lesions, mobility
      or any other mucogingival alterations. RESULT: It is shown that 100% of the
      pregnant women had some kind of gingival alteration, represented mainly by PSR
      code 2 (56.1%) and "*" (19.5%). The women in the youngest age groups, 15-19 and
      20-24 years, had code 2 as their highest score with no sextant excluded. In the
      25-29 age group, the PSR code 2 still prevailed (54.5%) although codes 3 and 4
      were already appearing. The code "*" and the occurrence of excluded sextants
      tended to increase in the oldest age group (30-37). In general, the affected
      sextants showed codes 1 and 2 more frequently, corresponding to 41.6% and 39.8%
      respectively, which represented a mean of 2.49 and 2.39 sextants affected in each
      pregnant woman. Regarding the treatment needs, 90.2% of the women needed some
      treatment beyond the preventive measures begun, including scaling and root
      planning and/or corrections of defective restorative margins (61%), and more
      complex treatment (29.2%). CONCLUSION: The meeting of the treatment needs during
      pregnancy must include special efforts to increase motivation and promote oral
      health, minimizing the possibility of vertical transmission of pathogenic
      microrganisms to the child, and thus contributing to the primary prevention of
      the main oral diseases.

PMID- 10413935
TI  - [Child prostitution from the point of view of society and health].
AB  - OBJECTIVE: The social representations and the structural relationships related to
      child prostitution, as presented in the depositions made before of the
      Parliamentary Commission Inquiry dealing with the problem are analyzed. METHODS:
      On the basis of qualitative methodology, the analysis attempts to identify the
      units of meaning present in the depositions. RESULTS: Data on the subject are
      presented by region. A vision of the social scene is built up on the basis of the
      data such as to being out the related historical and cultural determining
      factors. CONCLUSION: The child juvenile prostitution is based on the
      commercialization of the body as coercion or slavery is seen as a means of
      meeting the basis needs of survival. The need for social action is brought out,
      including that of collective health, so that the theme does not serve only the
      amposes of rhetoric on statistics, because in calls for decisive action.

PMID- 10413936
TI  - [Physical aggression and social class].
AB  - OBJECTIVE: Considering the increase of violence and the scarcity of informations
      about the relation between social class and victimization by physical aggression,
      a study was conducted to investigate this association. METHODS: A hospital-based
      case-control study. Cases and controls were recruited at a hospital, first-aid
      clinic, from 1/10/93 to 19/1/95. The study included 191 cases and 222 controls
      selected from among patients with non-violent clinical-surgical complaints,
      frequency-matched to cases by sex and age. Using a standardized questionnaire
      applied by trained interviewers, information obtained included social class, skin
      color, marital status, smoking habits, alcohol consumption and illicit drug use.
      RESULTS: Adjusting for sex and age, the risk of victimization by physical
      aggression was significantly higher for the subproletariat, Odds Ratio (OR) 4.20,
      95% Confidence Interval (95% CI) 1.99-8.84; single (OR = 2.10) or informal union
      (OR = 2.62) as marital status (reference group = married); smokers of more than
      10 cigarettes/day (OR = 2.75); alcohol consumption (OR = 2.08 for < or = 240
      grams/week and OR = 24.05 for > 240 grams/week); and illicit drug users (OR =
      3.07). After adjusting for all factors studied a significant risk remained for
      the subproletariat (OR = 3.28, 95% CI 1.42-7.59); single as marital status (OR =
      2.05, 95% CI 1.09-3.88); and alcohol consumption (OR = 2.01, 95% IC 1.07-3.77 for
      < or = 240 and OR = 15.93, 95% CI 5.09-49.8 for > 240 grams/week) CONCLUSION:
      Social class is an important factor in the phenomenon of victimization by
      physical aggression, with the subproletariat deserving special attention in the
      strategies of intervention regarding this problem.

PMID- 10413937
TI  - [Inequalities in mortality, space and social strata].
AB  - OBJECTIVE: A description of the mortality differentials in Salvador, Bahia,
      Brazil, is presented. METHODS: An ecological study was carried out. The city was
      divided into 75 information areas and its population into six social strata.
      Standardized Mortality Rates, Age Specific Mortality Rates, Proportional Infant
      Mortality and the Proportional Mortality Ratio were calculated for each region
      and social strata. Data were obtained from Death Certificates and the
      Populational Census. RESULTS: The mortality ratio difference between the strata
      with best living conditions and the poorer strata ranged from 43.1% to 142.0%
      which corresponds to an inequality ratio ranging from 1.4 to 2.4. When that
      analysis was carried out in smaller areas, these differences reached 656.3%.
      CONCLUSIONS: These findings show the persistence of health inequalities in
      Salvador in more serious disproportion than that found in other studies. Despite
      the methodological problems related to the nature of the data and the study,
      project the authors it was highlight, the meaning of this kind of research
      concerned with new approaches to health planning and health promotion.

PMID- 10413938
TI  - [Application of the Portuguese version of the instrument for the assessment of
      quality of life of the World Health Organization (WHOQOL-100)].
AB  - OBJECTIVE: The WHOQOL group have developed an instrument to evaluate Quality of
      Life, the WHOQOL-100, available in 20 different languages (WHOQOL Group, 1998).
      The field trial of the portuguese version of the instrument is presented.
      METHODS: Two hundred and fifty patients from four main medical areas (Psychiatry,
      Clinical, Surgery and Ginecology) of the Hospital de Clinicas de Porto Alegre and
      50 controls were evaluated with the Portuguese version of the WHO Quality of Life
      Instrument (WHOQOL-100), Beck Depression Inventory (BDI) and Beck Hopelessness
      Scale (BHS) in Porto Alegre, south Brazil. RESULTS AND CONCLUSION: The instrument
      showed a good psychometric performance with good internal consistency,
      discriminant validity, criterion validity, concurrent validity and reliability.
      The authors conclude that the intrument is ready for use in Brazil, it being
      important to evaluate its performance in other regions and with different
      samples.

PMID- 10413939
TI  - Epidemiological methods for research with drug misusers: review of methods for
      studying prevalence and morbidity.
AB  - Epidemiological studies of drug misusers have until recently relied on two main
      forms of sampling: probability and convenience. The former has been used when the
      aim was simply to estimate the prevalence of the condition and the latter when in
      depth studies of the characteristics, profiles and behaviour of drug users were
      required, but each method has its limitations. Probability samples become
      impracticable when the prevalence of the condition is very low, less than 0.5%
      for example, or when the condition being studied is a clandestine activity such
      as illicit drug use. When stratified random samples are used, it may be difficult
      to obtain a truly representative sample, depending on the quality of the
      information used to develop the stratification strategy. The main limitation of
      studies using convenience samples is that the results cannot be generalised to
      the whole population of drug users due to selection bias and a lack of
      information concerning the sampling frame. New methods have been developed which
      aim to overcome some of these difficulties, for example, social network analysis,
      snowball sampling, capture-recapture techniques, privileged access interviewer
      method and contact tracing. All these methods have been applied to the study of
      drug misuse. The various methods are described and examples of their use given,
      drawn from both the Brazilian and international drug misuse literature.

PMID- 10413940
TI  - Young forms of Trypanosoma cruzi in the circulation of experimentally infected
      mice.

PMID- 10413941
TI  - [Ambulatory anorectal surgery under local anesthesia: analysis of 351
      procedures].
AB  - Three hundred and twenty-eight patients with anorectal diseases were submitted
      ambulatory surgery, under local anesthesia, in a three-year period. Three hundred
      and fifty one operations were performed in outpatient service. Local anesthesia
      by Hook-Needle Puncture technique was used in 37 operations and the rest of them
      by classical technique through infiltration of both lateral anal quadrants.
      Hemorrhoids, fistulas, fissures and pilonidal cysts were the most frequent
      diseases treated (71.6%). The incidence of early and late complications was 19.6%
      and 4.8%, respectively. The most common complication was severe pain (16.1%).
      Five patients (1.5%) required hospitalization due postoperative complications.
      The surgery on an outpatient basis was a well-accepted procedure for two hundred
      eighty-eight patients (88%). The main benefit reported by patients was the
      possibility of recovery at home, which is more comfortable. The ambulatory
      anorectal surgery under local anesthesia is a safe and effective method, with the
      additional advantage of the costs saved and increase of available beds for more
      complex surgery.

PMID- 10413942
TI  - [Mechanical study of stiffness in LIM-41 external fixator assemblages submitted
      to torsion strain].
AB  - The mechanical stiffness of LIM-41 external fixator assemlages submitted to
      torsional strain was studied. A condition of unstable fracture was reproduced.
      The authors evaluated the effect of of Schanz pin configurations, defined as
      "distal", "standard" and "proximal", and of the distance, 20 mm, 40 mm or 60 mm
      between the external fixator and the element employed to simulate bone. The
      authors conclude that stiffer LIM-41 assemblages are obtained if the "standard"
      or "proximal" configurations are employed, on which some pins are placed near the
      fracture simulation site, and if the external fixator body is fitted closer to
      the bone simulating element, having the former variable greater influence over
      the stiffness coefficient.

PMID- 10413943
TI  - [Respiratory distress in low birth weight: influence of intrauterine growth
      retardation].
AB  - The aim of this study is to evaluate the influence of intra-uterine growth
      retardation (IUGR), as well as it's types and severity on the development of
      respiratory distress among low-birth-weight infants. A total of 673 neonates were
      studied, the small-for-dates infants (SFD), 40% of total, were divided according
      to the type of IUGR, in proportionate and disproportionate, and according to the
      severity, in birth weight below 3rd and between 3rd and 10th percentile.
      Respiratory distress was more frequent among the appropriate for gestational age
      (57.3%) compared to the SFD infants (33.7%), (p < 0.0001), and among males
      (52.6%) compared to females (47.4%) (p = 0.01). There was an inverse relationship
      between gestational age, as well as birth weight and respiratory distress. It
      occurred in 90.6% of very-low-birth-weight infants and in 39% of the others, with
      a predominance among the appropriate for gestational age newborns. Respiratory
      distress occurred in 80% of neonates below 34 weeks of gestational age and in 26%
      of the neonates above it (p < 0.0001). Regarding to the small-for-dates infants,
      respiratory distress occurred more frequently among the disproportionate (42.5%),
      when compared to proportionate infants (28.1%) (p = 0.03). The severity of IUGR
      had no influence on these results. The authors concluded that among low birth
      weight infants, the groups with increased risk for respiratory distress are the
      appropriate for gestational age and, among small-for-dates and disproportionate
      infants, those weighing less than 1500 g.

PMID- 10413944
TI  - Experimental injury to the spleen study of interaction:
      contamination/preservation.
AB  - Ablation of the spleen leads to a significant risk of postsplenectomy invasive
      sepsis. This concept has become very important in the last three decades because
      of awareness of the spleen's important role in immunological functions. Hence,
      this has led many research centers to study hemostasis of the injured spleen in
      order to preserve its function. The objective of this study is to analyze the use
      of nylon mesh for preservation of the wounded spleen in the presence or absence
      of local contamination. Twenty dogs were operated, randomly divided into two
      groups and followed postoperatively for eight weeks. A standard splenic injury
      was produced in all animals and hemostasis accomplished by attaching nylon mesh
      to the organ. Postoperatively, in one of the groups the "wounded organ + mesh"
      was contaminated with a bacterial count proportional to the animal's weight. The
      other group was not contaminated, maintaining it as control. Both groups were
      studied as to interaction of contamination/preservation, i.e., body weight,
      surgical findings, splenic size and histology, blood and tissue culture and
      hematological data. The dogs adequately withstood the standardized trauma
      regardless of local contamination. And the nylon mesh effectively arrested
      bleeding in all animals. At sacrifice inoculated germs were confirmed in the
      contaminated group by histological methods or tissue cultures. A cellular
      infiltrate of lymphocytes and plasmocytes was present close to the mesh only in
      the latter. The mesh attached to the injured spleen did not lead to abscesses,
      intrasplenic or intraperitoneal fluid collections. Based on analysis of the data,
      we can infer that local contamination of the injured spleen and the presence of
      non-absorbable material (nylon mesh) did not markedly alter the overall behavior
      of the dogs compared to the uncontaminated group.

PMID- 10413945
TI  - [Retrospective study of traffic accident victims: incidence after the new
      National Traffic Code implantation].
AB  - The authors present a study about the frequency of the injuries caused by traffic
      accidents on the orthopedic patients admitted to the emergency of Institute of
      Orthopedics and Traumatology at the Hospital das Clinicas of the School of
      Medicine Sao Paulo University, before and after the new National Traffic Code.
      They found a decreased number of polytraumatized patients and severe injuries
      after the beginning of this new legislation.

PMID- 10413946
TI  - [Immunological behavior (IgG, IgM, IgA) and total complement (CH50) of newborns
      infants with risk factors for early onset sepsis. Comparative analysis of
      newborns with and without infection].
AB  - Immunological behavior (IgG, IgM, IgA) and total Complement (CH50) of newborns
      infants with risk factors for early onset sepsis. Comparative analysis between
      newborns with and without infection. Rev. Hosp. Clin. Fac. Med. S. Paulo, 53(6):
      303-310, 1998. The objective of this study was to verify the immunological
      behavior of the newborn infant in front of an infection. We studied 60 newborn
      infants that had risk factors for early onset sepsis (premature rupture
      membranes, clinic amnionitis or tract urinary infection) from de immunological
      and infection point of view. They were classified into three gestational age
      groups: < 34 weeks, between 34 and 36 6/7 weeks and > or = 37 weeks. Sepsis
      diagnosis was done through clinical and laboratorial data and we also included
      the followings exams: Immunological types (IgG, IgM, IgA) and total complement
      (CH50) obtained from the newborn at birth and on the fifth day of life. We could
      verify that 15 newborns (25%) presented early sepsis. There was a statistical
      association between perinatal asfixia and infection in the group with gestational
      age < 34 weeks and this same group presented statistical association between
      infection and death. The serical levels of IgG and CH50 were directly related to
      the gestational age and there were significant statistical differences between
      levels of IgG, IgM and total Complement between infected and not infected
      newborns within the same group os gestional age. We observed that the infection
      was associated to low levels of IgG and CH50, at birth and on the fifth day,
      mainly in the group of infected newborns with gestional age < 34 weeks, being
      this group, therefore, the one that would mostly benefit from an immunological
      support in front of and infection.

PMID- 10413947
TI  - [Clinical, laboratory and liver histology of HBsAg-positive volunteer blood
      donors in Belo Horizonte, State of Minas Gerais, Brazil].
AB  - Two hundred and fifty two blood donors HBsAg positive (mean age = 32.6, 91, 7%
      male) were searched into a transversal study to determine their clinical,
      laboratorial and histological characteristics. It was also compared the
      positiviness and negativiness of the serologic markers HBeAg, anti-Hbe and IgM
      anti-HBc with the values of serum aminotransferases. Hepatomegaly and
      splenomegaly were detected in 9.9% (25/252) and in 2.4% (6/252) respectively. In
      17.5% (44/251) and 28.3% (71/251) the AST and ALT were respectively, over 50
      UI/I. The positive frequencies of the various serologic markers of hepatitis B
      virus in 120 patients were: anti-HBc total in 89.5% (102/114), HBeAg in 25.7%
      (28/109) anti-Hbe in 67.3% (66/98), IgM anti-HBc in 40.8% (49/120); anti-Delta in
      0.0% (0.66). Thirty one patients were submitted to liver biopsy, due do clinical
      alteration and/or of the aminotransferases. The hystological findings were:
      normal liver in 16.1% (5/31), non specific hystological alterations in 22.6%
      (7/31), persistent chronic hepatitis in 22.6% (7/31), active chronic hepatitis in
      6.5% (2/31), cirrhosis in 12.9% (4/31), alcoholic hepatitis in 3.2% (1/31),
      lobular chronic hepatitis in 3.2% (1/31) and alterations exclusively due to
      schistosomiasis in 12.9% (4/31). Schistosomiasis elements (granuloma and/or
      Symmers fibrosis) were also notived in 7 patients. The comparative analysis of
      positiveness and negativeness of the serologic markers with the aminotransferases
      ("t" test of Student) showed significative difference of the averages (p < 0.05)
      only in relation to the simultaneous positeveness and negativeness of the HBeAg
      and IgM anti-HBc (average of AST = 56.11 and ALT = 78.00 when HBeAg and IgM anti
      HBc were positive; average of AST = 24.25 and ALT = 27.00 when HBeAg and IgM anti
      HBc were negative). According to this study the conclusion are: 1) The presence
      of two markers (HBeAg and IgM anti-HBc) and not only one determinant of viral
      replication in asymptomatic HBsAg carriers can strongly indicate a significant
      biochemical activity suggestive of hepatocellular lesion. 2) The presence of
      HBeAg in 25.7% (28/109) clearly shows the high rate of carriers with a potential
      of infectivity. 3) The results of hepatic histology shows that the majority of
      our patients had either normal liver or mild histological alterations. It is
      important to notice that only the cases with elevated aminotransferases were
      submitted to liver biopsies. The alterations caused by schistosomiasis shows, as
      is well known, the high prevalence of the parasitism in our surroundings. 4) The
      clinical aspects of the patients studied did not show significant alterations.
      Risk factors to get the infection were low. The hematologic and biochemical
      parameters (except aminotransferases) were either normal or just slightly
      abnormal. It was not detected a statistically significant difference. 5) The co
      infections by delta virus was null.

PMID- 10413948
TI  - [Transsacral rectopexy for treatment of bleeding rectal prolapse in a patient
      with severe liver disease: case report].
AB  - Rectal procidentia is an uncommon but debilitating condition that often affects
      elderly patients with significant medical problems. Fecal incontinence is usually
      frequent. Abdominal rectopexy with or without sigmoid resection repeatedly
      demonstrate lower recurrence rates (2-4%) but in high-risk patients, morbidity
      and mortality may be significant. Perineal or transacral approaches may be used
      in these patients to avoid the complications of abdominal procedures and general
      anesthesia. The lack of experience with transacral approach has limited your
      utilization by colon and rectal surgeons. We describe a case of rectal
      procidentia in patient with severe liver disease (Child C) sucssefull treated
      with transacral rectopexy, detailing the technique used.

PMID- 10413949
TI  - [Post-graduation aspects in Medical School of the Universidade de Minas Gerais].
AB  - The post-graduation at Medical School of Federal University of Minas Gerais
      (UFMG) is composed by 9 courses and has been for 30 years. Among these, 6 courses
      have Masterate and Doctorate levels, and 3 have only Masterate. It has already
      been produced 584 thesis and dissertati Doctorate courses with A (20%), B (20%),
      C (60%). The average amount of produced thesis and dissertations has been through
      2 and 8 by year. The integration proposal of Medical internship and Masterate
      will be an opportunity of reducing the length of Masterate. The Post-Graduation
      Center (CPG) coordenates the post-graduation politics and activities at Medical
      School of UFMG.

PMID- 10413950
TI  - [Career in medicine and elective internship: a cohort study].
AB  - A study of career choice was undertaken with students of the new curriculum of
      the University of Brasilia Medical program that graduated from 1994 to 1997. The
      purpose was to assess the impact of selective training during the internship on
      the choice of medical residency and the relationships with some selected personal
      and academic factors. Data from 196 participants were obtained at the beginning
      of the medical program, after registration for the elective, and after the
      medical residency examination. Chi-square tests and logistic regression analysis
      were applied to the data. Results showed that about 74% of the choices for
      medical residency favor four specialties: internal medicine, general surgery,
      pediatrics and obstetrics-gynecology and define a demand profile compatible with
      the offer profile. Regression analysis with three predictor variables revealed
      that selective training was the strongest influence in each case. The other
      variables showed independent but weaker association: sex (general surgery and
      internal medicine) and initial preference (general surgery and pediatrics).
      Another analysis verified that initial preference was the main influence in the
      choice of selective training. Three other factors (learning style, self
      confidence as a learner, and grade point average) showed weak association with
      some areas of selective training or specialty choice. In conclusion, the study
      confirmed the hypothesis of the prediction power of the selective training on
      career choice and revealed other distinct influences.

PMID- 10413951
TI  - The teaching of basic clinical skills at School of Medicine, University of Sao
      Paulo.
AB  - This article describes how is the teaching of basic clinical skills given to the
      3rd in the undergraduate program, at the School of Medicine, University of Sao
      Paulo. This course has been implementing some techniques of teaching-learning for
      last years in order to become it more dynamic and interesting. Small group
      teaching is the main feature of the course "Basic Clinical Skills" given at the
      University of Sao Paulo, School of Medicine. This technique is improved by
      keeping each group with a teacher for a long time to allow better integration
      between them and to facilitate a better acquisition of attitudes towards the
      patient and all the team involved in the care of patient. All the classes are
      practical with early contact with real cases. Medical students learn how to take
      down the medical history, how to perform an adequate physical examination and
      make diagnoses under supervision of their teachers. Discussion cases, recognition
      of medical patterns and hypothetic-deductive strategy are used to develop an
      efficient medical reasoning. The authors show the results obtained through
      questionnaires filled in by the students at the end of the course and the
      analysis of which demonstrates that the students are highly satisfied with these
      kind of strategies and profit better from them. In 1996 and 1997, respectively,
      the course's satisfaction was 93.13% and 88.08% (excellent + good). The students'
      capacity to perform their objectives is situated in their majority between 6 and
      8, these values represent a good and sufficient to very good performance.

PMID- 10413952
TI  - Prevalence of hepatitis B and hepatitis C markers in alcoholics with and without
      clinically evident hepatic cirrhosis.
AB  - We assessed the frequency of serological markers of hepatitis B virus (HBV) and
      hepatitis C virus (HCV) infections in 365 alcoholics by determining, by ELISA,
      the presence of HBsAg, anti-HBc, anti-HBs and anti-HCV. Fifty patients were
      cirrhotics and 315 had no evidence of hepatic cirrhosis; of the latter HBsAg was
      assessed in all, anti-HBc and anti-HBs in 130, and anti-HCV in 210. Among the
      alcoholics the frequencies of HBsAg (1.9%), anti-HBc (28.3%) and anti-HCV (3.8%)
      were higher (p < 0.001) than among the controls (N = 17,059), 0.4%, 4.0% and 0.4%
      respectively. The frequency of positive HBsAg was higher (p < 0.001) in the
      cirrhotic patients (8.0%) than in alcoholics without cirrhosis (0.95%) and in
      controls (0.4%), and similar between the latter; of anti-HBc in alcoholics
      without cirrhosis (28.5%) was similar in cirrhotics patients (28.0%) and higher
      (p < 0.001) than in the controls (4.0%); of anti-HBs in alcoholics without
      cirrhosis (20.8%) was similar to that of the cirrhotic patients (10.0%), and the
      anti-HCV was similar between alcoholics with (6.0%) and without cirrhosis (3.3%)
      and higher (p < 0.001) than in controls (0.4%). We concluded that: a) alcoholics
      with or without cirrhosis have similar frequencies of infection with HBV and HCV
      between them, and higher than in nonalcoholics; b) alcoholics without cirrhosis
      had a frequency of HBV active infection (HBsAg+) which was similar to the
      controls, whereas among those who progressed to cirrhosis this frequency was
      significantly higher, what suggests that HBV may be implicated in the
      pathogenesis of cirrhosis in a few alcoholic individuals.

PMID- 10413953
TI  - A ten-year survey of Tinea pedis in the central region of the Rio Grande do Sul,
      Brazil.
AB  - Tinea pedis in the most common type of dermatophytosis, but can mimic many
      cutaneous diseases and tend to be chronic. We present a study of the frequency,
      epidemiology and clinical aspects of tinea pedis in the central region of Rio
      Grande do Sul during the period 1988-1997.

PMID- 10413954
TI  - Paracoccidioides brasiliensis. A mycologic and immunochemical study of two
      strains.
AB  - The authors conducted a mycologic, immunochemical and molecular biology study on
      two strains of Paracoccidioides brasiliensis, one of them, called IBIA, isolated
      from soil in the municipality of IBIA (Minas Gerais) by Silva-Vergara et al.
      (1996, 1998), and the other, BAT, cultivated from a human case of
      paracoccidioidomycosis in Ribeirao Preto (Sao Paulo/Brazil) by Freitas Da Silva
      (1996). Both strains showed cotton-like (M) and yeast-like (Y) forms and were
      pathogenic for testicularly inoculated guinea pigs, producing granulomatous
      and/or suppurative orchitis. Immunochemically was demonstrated the presence of
      gp43 by double immunodiffusion, immunoelectrophoresis and immunoblotting.

PMID- 10413955
TI  - Influence of microbiota in experimental cutaneous leishmaniasis in Swiss mice.
AB  - Infection of Swiss/NIH mice with Leishmania major was compared with infection in
      isogenic resistant C57BL/6 and susceptible BALB/c mice. Swiss/NIH mice showed
      self-controlled lesions in the injected foot pad. The production of high levels
      of interferon-gamma (IFN-gamma) and low levels of interleukin-4 (IL-4) by cells
      from these animals suggests that they mount a Th1-type immune response. The
      importance of the indigenous microbiota on the development of murine
      leishmaniasis was investigated by infecting germfree Swiss/NIH in the hind
      footpad with L. major and conventionalizing after 3 weeks of infection. Lesions
      from conventionalized Swiss/NIH mice were significantly larger than conventional
      mice. Histopathological analysis of lesions from conventionalized animals showed
      abscesses of variable shapes and sizes and high numbers of parasitized
      macrophages. In the lesions from conventional mice, besides the absence of
      abscess formation, parasites were rarely observed. On the other hand, cells from
      conventional and conventionalized mice produced similar Th1-type response
      characterized by high levels of IFN-gamma and low levels of IL-4. In this study,
      we demonstrated that Swiss/NIH mice are resistant to L. major infection and that
      the absence of the normal microbiota at the beginning of infection significantly
      influenced the lesion size and the inflammatory response at the site of
      infection.

PMID- 10413956
TI  - Toxocariasis: serological diagnosis by indirect antibody competition ELISA.
AB  - Toxocariasis is caused by infection of man by Toxocara canis and Toxocara cati
      larvae, the common roundworm of dogs and cats. Because larvae are difficult to
      detect in tissues, diagnosis is mostly based on serology. Non specific reactions
      are observed mainly due to cross-reactivity with Ascaris sp antigens. This
      investigation aimed at developing and evaluating an indirect antibody competition
      ELISA (IACE) employing a specific rabbit IgG anti-Toxocara canis excretory
      secretory antigens as the competition antibody, in order to improve indirect
      ELISA specificity performed for toxocariasis diagnosis. For that, the rabbit IgG
      was previously absorbed by Ascaris suum adult antigens. Sensitivity and
      specificity of IACE were first evaluated in 28 serum samples of mice
      experimentally infected with T. canis embryonated eggs. Adopting cut-off value
      established in this population before infection, sensitivity and specificity were
      100% after 20 days post-inoculation. For human population IACE was evaluated
      using sera from 440 patients with clinical signs of toxocariasis and the cut-off
      value was established with 60 serum samples from apparently healthy individuals.
      Using as reference test the indirect ELISA performed by Adolfo Lutz Institute,
      sensitivity was 60.2%, specificity was 98% and concordance was 77.3%.
      Repeatability of IACE was evaluated by the inter-reactions variation coefficient
      (2.4%).

PMID- 10413957
TI  - Larvicidal activity of Bacillus sphaericus 2362 against Anopheles nuneztovari,
      Anopheles darlingi and Anopheles braziliensis (Diptera, Culicidae).
AB  - In this present study, preliminary data was obtained regarding the mortality rate
      of the Amazonian anophelines, Anopheles nuneztovari, Anopheles darlingi and
      Anopheles braziliensis when subjected to treatment with Bacillus sphaericus
      strain 2362, the WHO standard strain. Initially, experiments were conducted to
      test the mortality rate of the three species of anopheline larvae. The third
      larval instar of An. nuneztovari and the second and third larval instars of An.
      darlingi proved to be the least susceptible. In other experiments, the same three
      mosquito species were tested with the standard strain 2362, An. nuneztovari was
      the least susceptible to this insect pathogen, while An. braziliensis was the
      most susceptible. This latter species showed a difference in the level of LC50
      concentration, when compared to the former, of 2.4, 2.5 and 1.8 in readings taken
      24, 48 and 72 hours after exposure to the bacillus.

PMID- 10413958
TI  - Effect of bacillus of Calmette-Guerin, avridine and Propionibacterium acnes as
      immunomodulators on rabies in mice.
AB  - The cellular and humoral immune responses of mice inoculated with rabies virus
      and treated with the Bacillus of Calmette-Guerin, Avridine and Propionibacterium
      acnes were evaluated in this paper. There was a higher percentage of surviving
      mice in groups submitted to P. acnes treatment. Lower levels of interferon-gamma
      (IFN-gamma) were found in infected mice. The intra-pad inoculation test (IPI) was
      not effective to detect cellular immune response, contrary to the results found
      in MIF reaction. The survival of mice did not present correlation with the levels
      of antirabies serum neutralizing (SN) antibodies titers, IFN-gamma concentration
      and MIF response.

PMID- 10413959
TI  - Analysis of Treponema pallidum recombinant antigens for diagnosis of syphilis by
      western blotting technique.
AB  - Three GST fusion recombinant antigen of Treponema pallidum, described as GST
      rTp47, GST-rTp17 and GST-rTp15 were analyzed by Western blotting techniques. We
      have tested 53 serum samples: 25 from patients at different clinical stages of
      syphilis, all of them presenting anti-treponemal antibody, 25 from healthy blood
      donors and three from patients with sexually transmitted disease (STD) other than
      syphilis. Almost all samples from patients with syphilis presented a strong
      reactivity with GST-rTp17 antigen. Some samples were non-reactive or showed a
      weak reaction with GST-rTp47 and/or GST-rTp15, and apparently there was no
      correlation with the stage of disease. There was no seropositivity among blood
      donors. No sample reacted with purified GST. We concluded that due to their
      specificity these recombinant antigens can be used as GST fusion protein for
      development of syphilis diagnostic assays.

PMID- 10413960
TI  - Headache in chagasic women.
AB  - The aim of this study was to compare the frequency of headache between Chagasic
      and Non-chagasic women. The cross-sectional study comprised 647 female > or = 40
      years old, Chagasic (n = 362) and Controls (n = 285) at a Brazilian University
      Hospital. Chagasic were classified as Cardiac (n = 179), Megas (n = 58) or
      Indeterminate (n = 125) clinical forms. Headache was ascertained according to
      Headache International Society diagnostic criteria. The age (57.0 +/- 11.3 versus
      57.3 +/- 10.4 years), and the percentage of white women (75.8% versus 77.1%) were
      similar between Chagasic and Controls, respectively. Headache was more prevalent
      among Chagasic (32.9%) than Controls (16.1%), mainly in Cardiac form (odds ratio,
      2.41; 95% confidence interval, 1.38-4.23), phenomenon possibly related to
      parasympathetic denervation and cerebral vessels changes.

PMID- 10413961
TI  - Microcirculation and Chagas' disease: hypothesis and recent results.
AB  - This review focuses on studies that support the microvascular hypothesis, as well
      as on immunological and neurogenic mechanisms, and the role of the parasite
      itself, to explain further the pathology and clinical course of myocardial
      involvement in chagasic cardiomyopathy. The salient features of coronary
      microcirculation and Chagas' disease are discussed.

PMID- 10413962
TI  - Hantavirus pulmonary syndrome (HPS) in Guariba, SP, Brazil. Report of 2 cases.
AB  - Human infections caused by a hantavirus were reported in different regions of the
      State of Sao Paulo (SP), Brazil during the first six months of 1998. Two cases of
      fatal pulmonary syndrome occurred in May of 1998 in the City of Guariba, located
      in the Northeastern Region of SP. Both patients worked in a corn storage barn
      infested by rodents. These patients, after 2 or 3 days of non-specific febrile
      illness, developed a severe interstitial pneumonia spreading widely in both
      lungs, causing respiratory failure and death. At autopsy both patients showed
      lung interstitial edema with immunoblast-like mononuclear cell infiltrates,
      consistent with a viral etiology. Hantavirus infection was diagnosed by ELISA in
      both cases and by RT-PCR in one of the patients. Aspects of the clinical
      presentation, physiopathology and differential diagnosis of Hantavirus Pulmonary
      Syndrome are discussed.

PMID- 10413963
TI  - Eumycetoma by Madurella grisea. Report of the first case observed in the southern
      Brazilian region.
AB  - The first case of eumycetoma by Madurella grisea occurred in Southern Brazilian
      Region is herein related. In addition, Brazilian literature on this subject was
      reviewed and, the geographic distribution of this eumycetoma is presented.

PMID- 10413964
TI  - Uniform requirements for manuscripts, CONSORT statement and more informative
      abstracts: three fundamental papers for improving the quality of medical
      publications.

PMID- 10413966
TI  - Nutritional assessment and serum zinc and copper concentration in leukemic
      children.
AB  - CONTEXT: Malnutrition in childhood cancer is commonly a serious problem. Changes
      in blood zinc and copper have also been found in malignant diseases. OBJECTIVE:
      To describe the protein-energy nutritional status and serum zinc and copper of
      children with newly diagnosed leukemia. DESIGN: Cross-sectional study. SETTING:
      University referral center. PARTICIPANTS: 23 children with newly diagnosed acute
      lymphocytic leukemia (ALL) or acute non-lymphocytic leukemia (ANLL) between the
      ages of 1 and 10 years. The control subjects were 31 healthy school children of
      similar age from local schools. MAIN MEASURES: Anthropometric measurements of
      height/age and weight/height, food intake and serum levels of zinc and copper.
      RESULTS: Almost the entire group of children were eutrophic. Zinc and copper
      intake were below the recommended values. Serum zinc levels were significantly
      lower and serum copper levels were significantly higher in the leukemic group
      when compared to normal children. CONCLUSION: At the time of diagnosis the
      children suffering from leukemia were not overtly malnourished but blood analysis
      showed alterations in concentrations of the trace elements zinc and copper.

PMID- 10413965
TI  - Maternal mortality in Campinas: evolution, under-registration and avoidance.
AB  - CONTEXT: Up until a few years ago, maternal mortality did not merit much
      attention as a worldwide public health issue. The health and social development
      indicator almost exclusively used was infant death. OBJECTIVE: To study the
      number, characteristics, basic causes and avoidance of maternal mortality (MM)
      among women living in the city of Campinas, which occurred between 1985 and 1991,
      identified from all death certificates of women aged 10 through 49 years. DESIGN:
      Retrospective and descriptive population-based study. SETTING: University Referal
      Center. SAMPLES: All eligible death certificates classified as declared and
      presumed maternal deaths according to the Laurenti criteria for the cause of
      death were selected and complementary studies of the clinical records were
      performed. MAIN MEASURES: Day of the week and place of occurrence of death;
      period of occurrence; transfer from another hospital; number of days from
      delivery/abortion to death; blood transfusion; opportunity for transfusion;
      complications; autopsy; basic cause of death. RESULTS: Initially 39 declared
      maternal deaths were identified and a total of 62 were confirmed by the end of
      the study. This corresponds to an under-registration rate of 37.1% and to an MM
      ratio of 45.5 per 100,000 live births. Around three-fourths of these maternal
      deaths were due to a direct obstetrical cause and were considered avoidable.
      CONCLUSION: Maternal mortality still is high in the municipality of Campinas,
      although lower than the mean estimated for Brazil. The predominance of direct
      obstetric causes and avoidable deaths reinforces the need for public health
      interventions directed towards avoiding them.

PMID- 10413967
TI  - Is glycosuria a reliable indicator of adequacy of glucose infusion rate in
      preterm infants?
AB  - CONTEXT: Adequacy of glucose infusion may be monitored via the glycosuria levels,
      as there is a relationship between glycemia and glycosuria regulated by the renal
      glucose threshold. In the neonatal period, however, this relationship is not so
      clear. OBJECTIVE: To evaluate the occurrence of glycosuria in preferm infants
      submitted to glucose infusion and to verify the relationship between glycosuria
      and blood glucose level. DESIGN: Accuracy study. SETTING: Neonatal intensive care
      unit of General Maternity Hospital. PATIENTS: 40 Preterm newborns receiving
      glucose infusion. PROCEDURES: 511 concomitant determinations of glycemia and
      glycosuria were performed. These 511 pairs were divided into stable and unstable,
      according to the clinical status of the newborn at the time of data collection,
      and they were studied in relation to the gestational age, birth weight and
      glucose infusion rate. RESULTS: The results revealed a greater frequency of
      glycosuria in gestational age < or = 30 weeks, birth weight < 1500 g and glucose
      infusion rate > 6 mg/kg/min. Eight (25.8%) episodes of positive glycosuria
      occurred in the absence of hyperglycemia, indicating only a moderate concordance
      between them. CONCLUSION: Glycosuria alone is an unreliable marker of blood
      glucose concentration and adequacy of glucose infusion rate. It is therefore
      necessary to monitor blood glucose levels in infants submitted to continuous
      glucose infusion.

PMID- 10413968
TI  - Delimitation of homogeneous regions in the UNIFESP/EPM healthcare center coverage
      area based on sociodemographic indicators.
AB  - CONTEXT: The drawing up of adequate Public Health action planning to address the
      true needs of the population would increase the chances of effectiveness and
      decrease unnecessary expenses. OBJECTIVE: To identify homogeneous regions in the
      UNIFESP/EPM healthcare center (HCC) coverage area based on sociodemographic
      indicators and to relate them to causes of deaths in 1995. DESIGN: Secondary data
      analysis. SETTING: HCC coverage area; primary care. SAMPLE: Sociodemographic
      indicators were obtained from special tabulations of the Demographic Census of
      1991. MAIN MEASURES: Proportion of children and elderly in the population; family
      providers' education level (maximum: > 15 years, minimum: < 1 year) and income
      level (maximum: > 20 minimum wages, minimum: < 1 minimum wage); proportional
      mortality distribution RESULTS: The maximum income permitted the construction of
      four homogeneous regions, according to income ranking. Although the proportion of
      children and of elderly did not vary significantly among the regions, minimum
      income and education showed a statistically significant (p < 0.05) difference
      between the first region (least affluent) and the others. A clear trend of
      increasing maximum education was observed across the regions. Mortality also
      differed in the first region, with deaths generated by possibly preventable
      infections. CONCLUSION: The inequalities observed may contribute to primary
      health prevention.

PMID- 10413969
TI  - Parapharyngeal space tumors: considerations in 26 cases.
AB  - CONTEXT: Parapharyngeal space tumors comprise less than 0.5% of all head and neck
      neoplasms. The majority of these tumors are benign, but surgery is usually
      required to establish the diagnosis and treat the patients. We present 26
      patients treated surgically for tumors arising in the parapharyngeal space (PPS)
      at the State University of Campinas Hospital--UNICAMP. CASES SERIES: Of these, 17
      (65.5%) had benign and 9 (34.6%) malignant neoplasms. The surgical and
      pathological data relevant to these cases are highlighted, observing any local
      recurrence, surgical complications and the five-year survival. Neurogenic tumors
      and soft tissue sarcomas were, respectively, the most frequent benign (35.3%) and
      malignant neoplasms (44.5%). Benign tumors accounted for the majority of the
      cases and involved minimal surgical morbidity with no recurrence during a median
      follow-up of five years. Malignant tumors had a high rate of recurrence and
      mortality. Surgery is the treatment of choice for PPS tumors. A knowledge of the
      anatomy of this site is essential for the safe performance of surgical
      procedures. Malignant neoplasms have a poor prognosis. Fine needle aspiration was
      helpful in diagnosis of all tumors.

PMID- 10413970
TI  - Delayed hemolytic transfusion reaction presenting as a painful crisis in a
      patient with sickle cell anemia.
AB  - CONTEXT: Patients with sickle cell anemia (SCA) are frequently transfused with
      red blood cells (RBC). Recently we reported that the calculated risk of RBC
      alloimmunization per transfussed unit in Brazilian patients with SCA is 1.15%. We
      describe a delayed hemolytic transfusion reaction (DHTR) presenting as a painful
      crisis in a patient with SCA. CASE REPORT: A 35-year-old Brazilian female with
      homozygous SCA was admitted for a program of partial exchange transfusion prior
      to cholecystectomy. Her blood group was O RhD positive and no atypical RBC
      alloantibody was detected using the indirect antiglobulin technique. Pre
      transfusional hemoglobin (Hb) was 8.7 g/dL and isovolumic partial exchange
      transfusion was performed using 4 units of ABO compatible packed RBC. Five days
      after the last transfusion she developed generalized joint pain and fever of 39
      degrees C. Her Hb level dropped from 12.0 g/dL to 9.3 g/dL and the unconjugated
      bilirrubin level rose to 27 mmol/L. She was jaundiced and had hemoglobinuria.
      Hemoglobin electrophoresis showed 48.7% HbS, 46.6% HbA1, 2.7% HbA2, and 2.0% HbF.
      The patient's extended RBC phenotype was CDe, K-k+, Kp(a-b+), Fy(a-b-), M+N+s+,
      Le(a+b-), Di(a-). An RBC alloantibody with specificity to the Rh system (anti-c,
      titer 1:16.384) was identified by the indirect antiglobulin test. The Rh
      phenotype of the RBC used in the last packed RBC transfusion was CcDEe. The
      patient was discharged, asymptomatic, 7 days after admission.

PMID- 10413971
TI  - Should there be a recommended limit to the number of references in a scientific
      article?

PMID- 10413972
TI  - [A combined vaccine against hepatitis A and B].

PMID- 10413973
TI  - [The pediatric prescription according to its origin and the motive for the
      consultation in a basic rural health area].
AB  - OBJECTIVE: To describe the paediatric prescription in a rural health district in
      terms of the origin and reason for consultation. DESIGN: Cross-sectional
      descriptive study. SETTING: Garraf Rural Health District, Barcelona.
      PARTICIPANTS: The 3 basic care paediatrics units in the district. MEASUREMENTS
      AND MAIN RESULTS: 1068 attendances of children of both sexes under 15 were
      collected. Recorded on each visit to the paediatrics clinic were: age, sex,
      reason for consultation (RC), and, if medicine was given, the product prescribed
      and the origin of the prescription. The number of children receiving treatment
      increased progressively with age. 87% +/- 2.8% of prescriptions originated with
      the paediatrician. Therapeutic groups of respiratory apparatus and systemic anti
      infection drugs accounted for 69% +/- 2.9% of all prescriptions. Only 2.3% +/-
      0.5% had fixed-dose associations. The most common RC was upper-tract respiratory
      infection, mainly treated with a single therapy (76.6% +/- 6.1%). In the case of
      the second most common RC, acute bronchitis, 94.6% +/- 4.2% of all cases received
      drugs treatment with single therapy or two simultaneous treatments. Acute
      tonsillitis was mainly treated with antibiotics (86.4% +/- 6.6%). CONCLUSIONS:
      The frequencies of the pathology groups detected in the Health District correlate
      with other studies' findings. Analysis of the origin of prescriptions shows the
      high decision-making capacity of the Health District's paediatricians. The
      pharmacological profile employed is good, though it could be improved.

PMID- 10413974
TI  - [The evaluation of the structural quality of clinical physiotherapy protocols
      produced in primary care. Members of the Protocol Evaluation Team].
AB  - OBJECTIVE: To evaluate the quality of the design (structural) of the clinical
      protocols elaborated in all the health centers, ambulatory or consulting of Spain
      with protocolized physical therapy activities. DESIGN: Observational
      retrospective study lasting 7 years. SETTING: Primary care of health.
      PARTICIPATING: All the clinical physical therapy protocols elaborated from 1990
      to 1997. MEASUREMENTS: They are elaborated 8 criteria of quality of the design of
      the protocols. Assessment of the reliability inter-rather of those criteria,
      adding explanations to two of they. It is proceeded to the evaluation of the
      quality of the design of 158 gathered protocols, being obtained the number from
      nonfulfillments. RESULTS: Compliance of the criteria: 49.36% (78) have record
      system. 32.91% (52) have anticipated their/its/your/his evaluation. 20.88% (33)
      have some algorithm. 38.6% (61) have page of history and/or specific exploration.
      96.83% (153) have a minor extension of 20 pages. Only 22.15% (35) have index.
      36.7% (58) do not have formal writing defects and legibility and 22.7% (36)
      provide bibliography. Only one of the eight criteria is complianced in more than
      50% of the protocols; it being fulfilled in less than 30% other three. By and
      large the clinical protocols present a total of 758 defects, with a defects
      average by protocol of 5.24 (0 defects in a case). CONCLUSIONS: The structural
      quality of the clinical physical therapy protocols elaborated in primary
      attention until 1997 is decreases (globally fulfil 40.03% of the proposed
      criteria). The decrease quality of the protocols is significantly heterogeneous
      between the autonomous community and the elaboration years. They are necessary
      corrective measures to improve this situation.

PMID- 10413975
TI  - [Drug substitutions in the pharmacy offices of the Community of Madrid].
AB  - OBJECTIVES: To evaluate the stock failure and substitutions of drugs in community
      pharmacies. DESIGN: A descriptive cross-sectional study. SETTING: Community
      pharmacies in Madrid. PARTICIPANTS: Nine pharmacies which voluntarily accepted to
      work in this study. The data were collected during four months in a year.
      MEASUREMENTS AND MAIN RESULTS: The total stock failure was 1.72%. New
      pharmaceuticals correspond with 10.73% of all stock failure. The pharmacists
      substituted the 31.04% of the total stock failure. Antibiotics and
      chemotherapeutics were the drugs most substituted with 46.98% of all
      substitutions. Patients accepted to substitute 78.39% of the proposals of the
      pharmacists. CONCLUSIONS: High percentage of the stock failure belongs to new
      brand pharmaceuticals. In this study there were few substitutions (0.53%) of the
      total dispensings. The drugs most substituted were antibiotics and
      chemotherapeutics. Substitutions depend on pharmacists' wishes and on patients'
      approval.

PMID- 10413976
TI  - [The stability of the microalbuminuria numbers in relation to their reading time
      and mode of preservation].
AB  - OBJECTIVE: To evaluate the stability of microalbuminuria figures in urine samples
      of diabetic patients, in terms of how the samples are kept, and the time between
      taking and reading. DESIGN: Descriptive, prospective and observational study.
      SETTING: Primary care. Teaching health centre, Burgos. PATIENTS: 40 type-2
      diabetics had their urinary excretion of albumin measured in 91 first-in-the
      morning urine samples with Micral Test II reactive strips. INTERVENTIONS: Samples
      were analysed the day of their collection, then protected from light and kept at
      +4 degrees C, with further readings at 24, 48 and 72 hours and at 7, 14, 21 and
      28 days after collection. MEASUREMENTS AND MAIN RESULTS: 49 (53.84%) of the 91
      samples taken did not vary over the 28 days of the study. In the first three
      days, there were 64 with unvaried measurements (70.2%). Friedman's test showed p
      = 0.905. > 93% of samples positive at the beginning remained positive all the
      time; > 83% of samples negative at the beginning remained negative. Concordance
      observed was > 90%; kappa index > 80%. CONCLUSIONS: Collection of first urine
      samples in the morning, stored at +4 degrees C in a fridge and protected from
      light, did not significantly alter the result of the reading for 4 weeks. Such
      samples are useful in order to aid study of the albumin excretion rate using
      Micral Test II reactive strips.

PMID- 10413977
TI  - [The influence of tobacco consumption on the prevalence of symptoms related to
      asthma].
AB  - OBJECTIVE: To determine whether tobacco consumption affects the prevalence of
      asthmatic symptoms. The European Asthma Study Questionnaire was used. DESIGN:
      Cross-sectional descriptive study. SETTING: Guadalajara Health Area. PATIENTS:
      Sample of 3000 people between 20 and 44 living in Guadalajara. INTERVENTIONS:
      None. MEASUREMENTS AND MAIN RESULTS: Measuring instrument was the European Asthma
      Study Questionnaire, to which two items on tobacco dependency were added. All the
      symptoms except asthma attack changed in function of the amount of tobacco
      consumed. Sibilant noises varied from 8.3% in non-smokers (NS), to 17.5% in light
      smokers (LS), 28.7% in moderate smokers (MS) and 42.6% in heavy smokers (HS).
      Night cough also increased in parallel with consumption: 14.1% in NS, 23.2% in
      LS, 41.2% in HS. Nocturnal thoracic pressure (14.7%), attacks of breathlessness
      (12.3%) and being considered to have asthma symptoms (14.2%) were more common in
      heavy smokers. Non-smokers had greater prevalence of sibilant noise with
      breathlessness (NS 57.7%, LS 39.2%, MS 30.4%, HS 34.5%) and without an associated
      cold (NS 45.2%, LS 20.3%, MS 23.4%, HS 29.9%), and used asthma treatments more
      often (NS 3.5%, LS 1.7%, MS 1.5%, HS 1%). CONCLUSIONS: The studies using this
      questionnaire should include additional questions on the tobacco history of the
      participants, since it seems that tobacco smoking and its amount may affect
      findings.

PMID- 10413978
TI  - [A comparative study of the evolution of caries in mentally retarded subjects of
      5 years' duration].
AB  - OBJECTIVE: To study the evolution of caries in two groups of mentally retarded
      individuals. DESIGN: Longitudinal, prospective, non randomized study, with a five
      years follow-up period, with intervention and control groups. SETTING: Community
      trial. Primary health care centre in Martorell. SUBJECTS: Mentally retarded
      individuals attending a workshop school (intervention group, N = 29) and living
      in a boarding school (control group, N = 25). INTERVENTION: One group was on a
      program of prevention and treatment of caries, the other one received the usual
      care and acted as a control group. MEASUREMENT AND MAIN RESULTS: The number of
      absent, filled and caries teeth were studied from 1992-1997. An analysis of the
      variance with repeated measures was carried out. The groups were comparable for
      most demographic characteristics and basal odontological parameters. While in the
      control group the number of caries increased (mean92 = 2.2; standard error [SE] =
      0.5); mean97 = 3.3; SE = 0.5; p = 0.03) in the intervention group it did not
      change (mean92 = 1.8: SE = 0.4; mean97 = 1.7; SE = 0.2; p = 0.73). The variation
      over time was significantly different between the groups (p = 0.03). The mean of
      filled teeth increased in the intervention group (mean92 = 0.7; SE = 0.4; mean97
      = 2.2; SE = 0.4; p < 0.0001) and it did not change in the control group (mean92 =
      1.2; SE = 0.5; mean97 = 1.4; SE = 0.6; p = 0.48). There were statistical
      significant differences between the two groups in the variation over time (p =
      0.017). CONCLUSIONS: Preventive and curative odontological intervention in
      mentally retarded individuals can be useful to improve the evolution of caries.

PMID- 10413979
TI  - [The use of medical terminology. A thesaurus. Medical Subject Headings (I)].

PMID- 10413980
TI  - [The repercussions of a displaced population on a rural health center].

PMID- 10413981
TI  - [The usefulness of audiometry in primary care].

PMID- 10413982
TI  - [Overutilization and psychosocial factors: myth or reality?].

PMID- 10413983
TI  - [The introduction of quality control: the auditing of an arterial hypertension
      protocol].

PMID- 10413984
TI  - Battery-powered miniature implant for electrical nerve stimulation.
AB  - The range of application of implantable stimulators in functional electrical
      stimulation (FES) for therapeutic purposes and for the restoration of lost or
      damaged functions has steadily grown within the last 20 years. Each time a
      clinically used method is improved, a new field of FES application explored or
      basic research conducted, animal experiments are needed to check and evaluate the
      findings and results. It is precisely for this use that the stimulation system
      described in this paper was developed. The battery-powered single-channel
      stimulator can be used for the excitation of motor and sensory nerves with
      monophasic or biphasic impulses. All parameters and functions are programmable
      via the bidirectional telemetry circuit. Implant programming is achieved by a
      laptop computer, supported by a graphical user interface, instead of by a
      specially designed programmer. The maximum settings of the stimulation parameters
      are: frequency 100 Hz, monophasic pulse duration 0.8 ms, biphasic pulse duration
      1.6 ms, stimulation current 3 mA. The implant volume was reduced to 2 cm3 (length
      23 mm, width 13 mm, height 7.5 mm), lowering the weight to 3.6 g. Due to this
      small volume the implant can be used in small animals. The power supply via
      battery obviates the need for transcutaneous tunneling or permanent external high
      frequency senders and facilitates the keeping of the animals.

PMID- 10413985
TI  - [Signal analysis of the hemodynamics of extracorporeal circulation for the
      evaluation of patient status].
AB  - The present paper describes the intra-operative evaluation of circulation
      dynamics during open-heart surgery, with the aim of providing the anaesthetist
      with objective data for assessing patient status during the procedure. For this
      purpose, the parameters pulse wave velocity and biological impedance were used.
      With the aid of these parameters it is possible, in the extracorporeal model, to
      detect different kinds of stenosis, volume losses, vessel dilatation and vessel
      constriction. In addition, the influence of arteriosclerosis on circulation
      dynamics was investigated. The assignment of the parameters to various events is
      effected using a "decision tree" and a neural network. Finally, the technique is
      verified using data obtained from animal experiments.

PMID- 10413986
TI  - [Thermographic visualization of changes in peripheral perfusion during
      acupuncture].
AB  - Using infrared thermography, the present study evaluated the effects of changes
      in peripheral perfusion occurring during the initial phase of manual acupuncture
      (Nei Guan, Qu Chi) under standardised conditions. Thermographic recordings (AGEMA
      570 PRO, Flir Systems Inc., Portland, USA) were used to assess superficial
      changes in temperature in the hands of 6 normal subjects (mean age 33.3 +/- 7.5
      years, 3 females, 3 males). Baseline status, acupuncture needling and stimulation
      were analysed in a single session under controlled conditions (24 degrees C
      ambient temperature). In all subjects a significant (p = 0.015) short-term
      cooling effect on superficial hand temperature occurred following needle
      placement. Thereafter, acupuncture stimulation produced different generalised
      long-lasting effects. In three subjects a warming effect was seen (increase > 2
      degrees C) while in the other three subjects the temperature decreased in all
      fingers and in the wrist.

PMID- 10413987
TI  - [TNF-alpha secretion by human macrophage-like cells in response to wear particles
      and its modification by drugs].
AB  - Tumour necrosis factor (TNF) is considered to be the initiator protein of
      particle disease leading to aseptic loosening of endoprostheses. The aim of the
      present study was to investigate the TNF response of the macrophage-like cells
      (MLC) to the periprosthetic particles typically found during revision surgery.
      For this purpose, particles of polyethylene (PE), pure titanium (Ti), chromium
      (Cr), cobalt (Co), alumina ceramic (Al2O3) and zirconium dioxide (ZrO2) were
      used. Additionally, the therapeutic effect of non-steroidal and steroidal drugs,
      biphosphonates and pentoxyfylline on PE particles was investigated with the aim
      of differentiating drugs with, from those without, a positive effect on aseptic
      loosening. METHOD: In an established macrophage model (Rader et al. 1999), THP1
      cells (human monocytic cell line) were differentiated over a period of five days
      in the presence of vitamin D3 and GM-CSF in macrophage-like cells (MLC). To
      obtain a TNF profile of the different materials, 10(6) MLC were incubated with
      each of a range of different particle concentrations. For drug testing purposes
      80 x 10(8) PE particles, which evoked a maximum TNF response, were applied
      together with increasing drug concentrations in the same manner. The supernatant
      was then investigated for TNF secretion using ELISA. RESULTS: It was found that
      the greatest TNF response was provoked by Co and PE particles, and was 25 and 23
      times as high, respectively, in comparison with control. The smallest TNF
      secretion was seen with Al2O3 (4 x control) and ZrO2 (5 x control). At the
      recommended dose, non-steroidal anti-inflammatory drugs (NSAIDs) produced no
      decrease in TNF secretion. The biphosphonates, etidronate and ibendronate
      significantly reduced the TNF response of the PE-stimulated macrophages (by 1/7
      and 1/5, respectively). Therapeutic doses of pentoxyfylline also led to a
      decrease of 1/5 in maximum TNF release. CONCLUSION: Ceramic articulating surfaces
      are superior to metal/metal or PE/PE matings in terms of the biological effects
      of their wear particles. At therapeutic doses, NSAIDs have no beneficial effect
      on the process of aseptic loosening. Certain biphosphonates and pentoxyfylline
      have a positive effect on aseptic loosening.

PMID- 10413988
TI  - [Possibilities of avoiding an intra-femoral increase in pressure during hip
      revision surgery].
AB  - An earlier experimental study carried out by us revealed an increase in
      intrafemoral pressure during removal of cement in hip revision arthroplasty. This
      increase is greater while removing cement from the distal femoral shaft. Maximum
      pressure increases occurred while removing the medullary plug (cement stopper),
      and the measured pressure of more than 150 mmHg is associated with an increased
      risk of fat embolism. The present study shows that this phenomenon can be avoided
      through the use of cannulated instruments.

PMID- 10414008
TI  - Home visiting: recent program evaluations--analysis and recommendations.

PMID- 10414009
TI  - Understanding evaluations of home visitation programs.
AB  - This journal issue comprises reports concerning program evaluations of key
      national home visitation models. No single evaluation can answer all the
      questions of interest about a program, nor is any evaluation perfect, which means
      that readers must carefully weigh the intended purpose of the evaluation and the
      evaluation's strengths and weaknesses before deciding what conclusions can
      credibly be drawn from its results. This article begins with a discussion of the
      role of evaluation both in improving programs and in determining program effects.
      The choices required to craft a strong and methodologically rigorous evaluation
      are described: what outcomes to measure and how; what methods to use in designing
      the evaluation and building a comparison group; how many participants to enroll;
      and how to devise a strong plan for data analysis involving subgroups of the
      enrolled families. The article then discusses additional factors policymakers and
      practitioners should consider when interpreting the results of home visiting
      evaluations: attrition, the policy and functional importance of the outcomes, and
      the likely generalizability of the results to other communities or other
      populations. The evaluations that appear in this journal issue are used as
      examples throughout the article, and the measures that were used in those
      evaluations are summarized. The evaluations included in this journal issue have
      both strengths and weaknesses but are probably among the better evaluations in
      the home visiting field.

PMID- 10414010
TI  - Prenatal and infancy home visitation by nurses: recent findings.
AB  - This article describes a 20-year program of research on the Nurse Home Visitation
      Program, a model in which nurses visit mothers beginning during pregnancy and
      continuing through their children's second birthdays to improve pregnancy
      outcomes, to promote children's health and development, and to strengthen
      families' economic self-sufficiency. The results of two randomized trials (one in
      Elmira, New York, and the second in Memphis, Tennessee) are summarized, and an
      ongoing trial in Denver, Colorado, is briefly described. Results of the Elmira
      and Memphis trials suggest the following: The program benefits the neediest
      families (low-income unmarried women) but provides little benefit for the broader
      population. Among low-income unmarried women, the program helps reduce rates of
      childhood injuries and ingestions that may be associated with child abuse and
      neglect, and helps mothers defer subsequent pregnancies and move into the
      workforce. Long-term follow-up of families in Elmira indicates that nurse-visited
      mothers were less likely to abuse or neglect their children or to have rapid
      successive pregnancies. Having fewer children enabled women to find work, become
      economically self-sufficient, and eventually avoid substance abuse and criminal
      behavior. Their children benefitted too. By the time the children were 15 years
      of age, they had had fewer arrests and convictions, smoked and drank less, and
      had had fewer sexual partners. The program produced few effects on children's
      development or on birth outcomes, except for children born to women who smoked
      cigarettes when they registered during pregnancy. The positive effects of the
      program on child abuse and injuries to children were most pronounced among
      mothers who, at registration, had the lowest psychological resources (defined as
      high levels of mental health symptoms, limited intellectual functioning, and
      little belief in their control of their lives). Generally, effects in Elmira were
      of greater magnitude and covered a broader range of outcomes than in Memphis,
      perhaps because of differences between the populations studied, community
      contexts, or a higher rate of turnover among home visitors in Memphis than in
      Elmira. The article concludes that the use of nurses as home visitors is key;
      that services should be targeted to the neediest populations, rather than being
      offered on a universal basis; that clinically tested methods of changing health
      and behavioral risks should be incorporated into program protocols; and that
      services must be implemented with fidelity to the model tested if program
      benefits found in scientifically controlled studies are to be reproduced as the
      program is replicated in new communities.

PMID- 10414011
TI  - Evaluation of Hawaii's Healthy Start Program.
AB  - Hawaii's Healthy Start Program (HSP) is designed to prevent child abuse and
      neglect and to promote child health and development in newborns of families at
      risk for poor child outcomes. The program operates statewide in Hawaii and has
      inspired national and international adaptations, including Healthy Families
      America. This article describes HSP, its ongoing evaluation study, and evaluation
      findings at the end of two of a planned three years of family program
      participation and follow-up. After two years of service provision to families,
      HSP was successful in linking families with pediatric medical care, improving
      maternal parenting efficacy, decreasing maternal parenting stress, promoting the
      use of nonviolent discipline, and decreasing injuries resulting from partner
      violence in the home. No overall positive program impact emerged after two years
      of service in terms of the adequacy of well-child health care; maternal life
      skills, mental health, social support, or substance use; child development; the
      child's home learning environment or parent-child interaction; pediatric health
      care use for illness or injury; or child maltreatment (according to maternal
      reports and child protective services reports). However, there were agency
      specific positive program effects on several outcomes, including parent-child
      interaction, child development, maternal confidence in adult relationships, and
      partner violence. Significant differences were found in program implementation
      between the three administering agencies included in the evaluation. These
      differences had implications for family participation and involvement levels and,
      possibly, for outcomes achieved. The authors conclude that home visiting programs
      and evaluations should monitor program implementation for faithfulness to the
      program model, and should employ comparison groups to determine program impact.

PMID- 10414012
TI  - The Parents as Teachers program: results from two demonstrations.
AB  - The Parents as Teachers (PAT) program is a parent-education program that includes
      home visiting and is designed to begin prenatally or at birth. Through home
      visits, visitors called parent educators help parents to strengthen their
      parenting skills and knowledge of child development and to prepare young children
      for school. This article describes the PAT program and reports the results of
      evaluations of two randomized trials of PAT: (1) the Northern California (Salinas
      Valley) Parents as Teachers Demonstration, which served primarily Latino parents
      in the Salinas Valley of California's Monterey County; and (2) the Teen Parents
      as Teachers Demonstration, which served adolescent parents in four counties in
      Southern California. The two evaluations revealed small and inconsistent positive
      effects on parent knowledge, attitudes, and behavior, and no gains in child
      development or health, when analyses compared the experimental and control groups
      overall. However, subgroup analyses in the Salinas Valley program indicated that
      children in primarily Spanish-speaking Latino families benefitted more than
      either non-Latino or English-speaking Latino families, with significant gains in
      cognitive, communication, social, and self-help development. Subgroup analyses in
      the Teen PAT Demonstration indicated that families that received both PAT
      services and comprehensive case management services designed to help mothers
      improve their life course benefitted most. Subgroup analyses in the Salinas
      Valley study suggested that children in families that received more intensive
      services benefitted more than children whose families received less intensive
      services. Results from that study suggested that home visits produced about a one
      month developmental advantage per 10 visits for participating children.

PMID- 10414013
TI  - The Home Instruction Program for Preschool Youngsters (HIPPY).
AB  - The Home Instruction Program for Preschool Youngsters (HIPPY) is a two-year home
      based early education intervention program designed to help parents with limited
      formal education prepare their four- and five-year-old children for school. This
      article begins with a brief overview of the HIPPY program and then presents the
      findings from a series of interconnected research studies, including a two-site,
      two-cohort evaluation in New York and Arkansas, a one-site case study, and a
      three-site qualitative study. With respect to program effectiveness, results
      varied across the New York and Arkansas sites and across participating cohorts at
      each site. For Cohort I, children who had been enrolled in HIPPY scored higher
      than children in the control/comparison groups on measures of cognitive skills
      (New York), classroom adaptation (New York and Arkansas), and standardized
      reading (New York); and more children were promoted to first grade (Arkansas).
      For Cohort II, comparison group children outperformed HIPPY children on school
      readiness and standardized achievement at posttest (Arkansas). Analyses to
      account for the differing results between cohorts were inconclusive. Qualitative
      analyses revealed considerable variation in parent involvement in HIPPY. Program
      staff identified four patterns of attrition from HIPPY: (1) early attrition
      within the first month after enrollment, (2) attrition between the program's
      first and second years, (3) attrition due to changes in the life circumstances of
      participating families, and (4) attrition due to turnover among the home
      visitors. Families were more likely to participate in in-home than out-of-home
      aspects of the program (for example, group meetings), but different family
      characteristics were associated with participation in the in- and out-of-home
      aspects of the program. The authors conclude with recommendations for future
      practice and research.

PMID- 10414014
TI  - Using home visits for multiple purposes: the Comprehensive Child Development
      Program.
AB  - The Comprehensive Child Development Program (CCDP) was a two-generation program
      that employed case management and home visiting to assure low-income children and
      their parents of a range of educational, health, and social services. Designed to
      meet the complex needs of disadvantaged families, CCDP was predicted by its
      planners to generate positive short- and long-term effects across a variety of
      child and parent well-being indicators. This article describes the CCDP program
      and reviews the results of the program evaluation. The evaluation of 21 project
      sites and 4,410 families followed for five years found no statistically
      significant impact of CCDP on program families when they were compared with
      control families in any of the assessed domains: early childhood education, child
      and family health, parenting education, family economic self-sufficiency, or
      maternal life course. The authors conclude that the results of this evaluation do
      not support home visiting as an effective means of social service delivery and
      parenting education for low-income families.

PMID- 10414015
TI  - Healthy Families America: using research to enhance practice.
AB  - The Healthy Families America (HFA) initiative seeks to expand the availability of
      high-quality, intensive home visitation services and to create communitywide
      commitments to these services and others that promote a supportive atmosphere for
      all new parents. This article briefly describes HFA's theoretical framework, its
      history, and its current status. The HFA Research Network, a partnership among
      researchers who are engaged in evaluating HFA programs around the country, is
      also highlighted. Preliminary findings of the research partners suggest that HFA
      programs may have the most success at improving parent-child interactions, with
      more limited or mixed success in the areas of health care status and utilization,
      the prevention of child abuse and neglect, and improved maternal life course
      outcomes. HFA programs so far have not demonstrated significant improvements in
      children's development or maternal social support. The authors report variability
      in both outcomes and attrition rates across subgroups of families in these
      studies, but there are no consistent patterns to identify who is most likely to
      stay enrolled in an HFA program or who is most likely to benefit from that
      enrollment. The authors conclude that these and several other areas require
      additional research. They further recommend that researchers and practitioners
      move beyond a singular focus on individualized interventions and work to create a
      communitywide and national context in which support for all new parents is the
      norm.

PMID- 10414016
TI  - [How significant is the comparison for length of stay in psychiatric hospitals
      based on diagnosis and age?].
AB  - AIM OF THE STUDY: According to German Hospital Financing Regulations hospital
      comparisons are undertaken to serve as information basis to providers and
      purchasers concerning budget findings. The current purchasers' hospital
      comparison includes diagnosis and patients' age to compare costs between
      hospitals. This study aims at evaluating diagnosis, age and additional variables
      as predictors of length of stay for psychiatric inpatient treatment. METHODS:
      Data of one year's admissions of a German state psychiatric hospital (N = 2450)
      were evaluated by a linear regression analysis. RESULTS: The purchasers' model of
      diagnosis and age accounts for 10.5% of the variation of length of stay. A second
      model with additional sociodemographic and clinical variables accounts only for
      11.3% of the variation. CONCLUSIONS: Results of this study are confirmed by
      several international studies on length of stay in psychiatric hospitals. It is
      concluded that diagnosis and age do not account sufficiently for the variation of
      length of stay in psychiatry. Meaningful hospital comparisons should include
      disease specific clinical, biographical and sociodemographic measures.

PMID- 10414017
TI  - [Quality of life and well-being in a housing project in Berlin--experiences
      gained in cooperation between a community health promotion office and a
      university-based public health project].
AB  - The realization of a community-based health promotion within the framework of a
      cooperation between a public health office and a university-based PH project is
      described and discussed. First of all, the project, the cooperating partners and
      the common aims are described. We will then deal with telephone survey as the
      method used, and present the results. In a third step the methods and results of
      the "future workshops" are discussed. Finally there is a critical reflection on
      the course of the project, the limiting factors of the actions and consideration
      of further developments. The project dealt with was a cooperation of a community
      public health agency (Plan- und Leitstelle) in the district of Berlin-Wilmersdorf
      and the research project A8 "Cooperative project development for communal health
      promotion" of the Berlin Centre for Public Health at the Technical University
      Berlin. Starting point was the agreement for those politically responsible of the
      district that the living quarter "Schlangenbader Strasse" was a focus of social
      problems. The quarter had been built in 1980 above a highway with 1800 apartments
      for 4000 people. Health promotion was defined as a concern of a wide range of
      sectors within the community. Mutual rights and responsibilities of the
      cooperating partners were laid down in a contract. The Plan- und Leitstelle tried
      to gain experience with the definition of health promotion the university
      partners stood for. This introduces a notion of health beyond bio-medical
      understanding and deals with the connection of quality of life, well-being and
      the environment in the residential area. Thus health- or sickness-related
      variables were not specifically asked for. One result is that actors within the
      given framework are reluctant to permit operationalisation of this concept. The
      telephone survey reached 324 household within 10 working days. 68p.c. of the
      interviewed were pleased with the comfort of the apartments, 37p.c. enjoyed the
      peace and quiet and 35p.c. the green around the housing project. Unpleasant were
      for 51p.c. the dirt, 33p.c. complained about vandalism, 30p.c. about the high
      rent, especially the extras. Safety improvements were asked for by 17p.c. Some
      12p.c. were willing to become involved in bringing about those improvements. This
      willingness was confirmed by the good response to two future workshops with those
      living in the quarter.

PMID- 10414018
TI  - [Investigation of foodborne outbreak due to Salmonella infantis using
      epidemiological and microbiological methods].
AB  - In foodborne outbreaks, direct microbiological diagnosis is often not possible
      due to lack of remaining food samples. Therefore, in this investigation of an
      outbreak of Salmonella infantis at a fair, we chose an epidemiological approach
      in addition to microbiological testing. In a case control study, fair
      participants with symptoms of acute gastroenteritis as well as participants
      showing no signs of disease were interviewed by telephone. Questions concerning
      what food had been eaten at the fair and the course of disease had priority. Data
      analysis showed a significantly elevated odds ratio of 144 (p < 0.00001) for the
      consumption of potato salad. Salmonella infantis was cultured in faeces of
      symptomatic individuals as well as from left-over potato salad in high
      concentration. In conclusion, our data show that the cause of a foodborne
      outbreak can be detected through the application of epidemiologic methods with a
      high degree of certainty. In order to eliminate memory bias, a structured
      interview should be carried out as soon as possible after the initial outbreak.

PMID- 10414019
TI  - [TEIS--a system for public health offices for assessing, presenting, evaluating
      and communicating data on the quality of drinking water].
AB  - Monitoring the quality of drinking water is a cardinal task of German Public
      Health Offices and of the relevant Ministries of Health of the German Federal
      states ("Lander"). Today this can be tackled on a large scale and economically
      only with computer assistance. A system has been developed in North Rhine
      Westphalia on behalf of the Ministry of Health, for data assessment and
      communication which is suitable for practical work and user friendly. It aims at
      supporting the Public Health Offices in their daily work and at improving and
      simplifying the monitoring of drinking water supply systems and of drinking water
      quality control.

PMID- 10414020
TI  - [Problem orientation in social medicine--participation in social medicine].
AB  - Problem-oriented learning is gaining increasing importance in medical education.
      The current discussion on reforming medical education in the medical schools in
      Austria reflects this importance. At the medical school in Graz for many years
      teaching the core module "social medicine" has been problem-oriented. Small
      groups of students work on selected topics of public health. The topics are
      related to every day practice and their particular psychosocial ramifications and
      consequences are illucidated. This subject is required in the last year of
      medical school. The students are not familiar with problem-based learning and
      have difficulties in adapting. To be better prepared for the coming changes in
      the discipline of medicine, the social dimension should be integrated earlier
      into medical education. The most efficient way of doing so should be clarified in
      the discussion of the reform in medical education.

PMID- 10414021
TI  - ["Doctor" without being an M.D.--how do non-graduate MDs view medical
      dissertations?].
AB  - Both the ranking and the quality of medical dissertations have for some time been
      a controversial moot point. Previous studies showed that successful doctorate
      candidates still regard medical dissertations as a meaningful addition to medical
      studies. Studies on the views of the value have been placed on a medical
      dissertation by practising physicians who did not write a dissertation lacking to
      date. Using an anonymous questionnaire containing 16 questions we carried out a
      study of all the practising doctors in Mid-Franconia, Germany, who did not write
      a dissertation (n = 243). We asked about their intentions to write a
      dissertation, reasons for prematurely breaking off the dissertation and their
      views on the value of medical dissertations. Evaluation was carried out using
      descriptive statistics in the sense of an exploratory data analysis. The
      questionnaire was answered in a usable form by 140 physicians (return quote 58%).
      The average age of the participants was 44 years (33-89 years). The vast majority
      (89%) had attempted one or several dissertations, 32% still intended to write a
      dissertation. 59% regarded writing a dissertation alongside daily practice as
      very difficult of impossible. Private/family reasons were stated less often than
      deficits in planning, implementation and supervision for prematurely breaking off
      the dissertation. 65% of the practising physicians in Mid-Franconia who did not
      write a dissertation regard medical dissertation today as no longer relevant. 58%
      are of the opinion that the title "doctor" should be awarded automatically with
      the final exams. The majority of practising physicians asked had in the meantime
      given up their intention of writing a dissertation and today tend to disfavour
      medical dissertations. Nevertheless, one third of those who participated in the
      study still intend to write a dissertation. In view of this it should be
      discussed to what extent practising physicians interested in scientific questions
      can be helped to write a dissertation alongside their daily practice. In
      particular professors and lecturers of general medicine are called upon to make
      this possible.

PMID- 10414022
TI  - [The new law concerning public health services in North Rhine- Westphalia-
      essentials and perspectives in dentistry].
AB  - A new regulation affecting the public health services (OGDG) in North Rhine
      Westphalia has been in effect since 1st January 1998. The present authors-
      members of a ministerial workgroup responsible for guidelines and recommendations
      for the implementation of the new regulation--have made an attempt to formulate
      the substantial and formal essentials of section 13 ODGD (dental health in
      children and the young) and its future perspectives in light of the reorientation
      of the national health service and, in particular, of dental services.

PMID- 10414023
TI  - [Performance assessment by average case fee and special pay--is it worth it?].

PMID- 10414024
TI  - Single-step reverse transcriptase-polymerase chain reaction for detection of
      Borna disease virus RNA in vitro and in vivo.
AB  - There are few copies of Borna disease virus (BDV) genome in peripheral blood
      mononuclear cells and no reliable standard reverse transcriptase-polymerase chain
      reaction (RT-PCR) method for the detection of BDV RNA, which is both highly
      sensitive and free of contamination. Single-step RT-PCR, in which both reverse
      transcription and amplification by Taq DNA polymerase work efficiently in a
      single buffer, was applied to detect the p24 region of BDV RNA in vitro and in
      vivo. Using in vitro synthesized RNA, it was demonstrated that at least 100
      copies of BDV RNA could be detected and the sensitivity and specificity were
      nearly equal to those obtained by RT-nested PCR. We could detect BDV RNA from
      more than 1 pg of cellular RNA obtained from BDV-persistently infected MDCK
      cells. Furthermore, this method was successfully performed on brain specimens
      obtained from a BDV-infected rat at 11 weeks post-inoculation. This single-step
      RT-PCR method will be convenient for detecting limited amounts of BDV RNA in
      various cells and tissue samples.

PMID- 10414025
TI  - Antigenic and genetic analyses of H5 influenza viruses isolated from ducks in
      Asia.
AB  - The hemagglutinin (HA) of six H5 influenza virus strains isolated from ducks in
      Japan and China in 1976 to 1996 were analyzed antigenically and genetically.
      Antigenic analysis using a panel of monoclonal antibodies revealed that the HA of
      H5 influenza viruses isolated from ducks are antigenically closely related to
      each other. Phylogenetic analysis indicates that the isolates from ducks in
      Hokkaido were derived from an ancestor common with the highly pathogenic isolates
      from chickens and humans in Hong Kong in 1997.

PMID- 10414026
TI  - Characterization of proteolytic enzymes expressed in the midgut of Haemaphysalis
      longicornis.
AB  - The proteolytic activities present in midguts of both fed and unfed Haemaphysalis
      longicornis were assessed by using the gelatin-substrate gel electrophoresis and
      inhibitor sensitivity analyses. Three predominant (116, 48 and 48 kDa) and two
      weak (55 and 60 kDa) proteinase bands were commonly expressed in both unfed and
      fed ticks, while a weak 80 kDa band was only present in fed ticks. Consistent
      with observations on other tick species, proteolytic activity against the gelatin
      substrate was observed only under acidic conditions. Inhibition studies against
      the gelatin substrate using a panel of inhibitors showed that the predominant
      proteolytic enzymes of 40 and 48 kDa molecular mass are cysteine proteinases.
      These results are discussed in the context of host vaccination as an alternative
      tick control method to the current use of chemical acaricides.

PMID- 10414027
TI  - Evaluation of coproantigen diagnosis for natural Echinococcus multilocularis
      infection in red foxes.
AB  - The validity of a coproantigen ELISA for Echinococcus multilocularis was
      evaluated by comparison of three diagnostic methods; autopsy, egg examination and
      the ELISA. Of 71 foxes, 39 were found to be infected with the cestode at autopsy.
      The overall mean of worm burdens was 3,451, but the number varied (1-34,522). The
      ELISA could detect 94.9% (37/39) of the worm positives and there were no false
      positives. Two false-negatives were infected with 1 and 4 cestodes, whereas 3
      cases with similar worm burdens (2, 4 and 6 worms) were diagnosed as positives.
      This indicates the detection limit of the assay may be equivalent to less than 10
      (in the worm burden). On the other hand, egg examination showed low sensitivity
      (43.6%, 17/39). These results suggest the ELISA has a potential to replace for
      the conventional methods.

PMID- 10414028
TI  - On the theory of partially inbreeding finite populations. VI. The survival
      probability of a two-locus allele combination when there is partial selfing.
AB  - Consider a large population with two loci that may be linked, with one having
      alleles A and a and the second alleles B and b. Let there be initially one
      individual with genotype AB/ab in a population otherwise consisting of ab/ab
      individuals. We assume that AB/ab, Ab/aB, AB/aB, AB/Ab and AB/AB individuals have
      higher probabilities of survival to adulthood than individuals with genotype
      ab/ab. The probability that AB ultimately survives, if there is a positive
      probability of selfing, is calculated. To simplify calculations, it is assumed
      that the number of offspring produced by any individual follows a Poisson
      distribution and that genotypes of separate offspring are independent. If
      recombination is possible, we conclude that a population with a high probability
      of selfing is more likely to accumulate epistatically favorable genes than one
      reproducing largely by random mating. This advantage of selfing becomes more
      pronounced as the strength of selection in favor of AB increases.

PMID- 10414030
TI  - Effective rate models for the analysis of transport-dependent biosensor data.
AB  - Optical biosensors, including the BIACORE, provide an increasingly popular method
      for determining reaction rates of biomolecules. In a flow chamber, with one
      reactant immobilized on a chip on the sensor surface, a solution containing the
      other reactant (the analyte) flows through the chamber. The time course of
      binding of the reactants is monitored. Scientists using the BIACORE to understand
      biomolecular reactions need to be able to separate intrinsic reaction rates from
      the effects of transport in the biosensor. For a model to provide a useful basis
      for such an analysis, it must reflect transport accurately, while remaining
      simple enough to couple with a routine for estimating reaction rates from BIACORE
      data. Models have been proposed previously for this purpose, consisting of an
      ordinary differential equation with 'effective rate coefficients' incorporating
      reaction and transport parameters. In this paper we investigate both the
      theoretical basis and numerical accuracy of these and related models.

PMID- 10414029
TI  - Strategies to control the genital herpes epidemic.
AB  - Genital herpes is a widely prevalent sexually transmitted disease. We introduce a
      spatial stochastic model to discuss strategies to control the epidemic. Our
      caricatural description suggests three different directions in order to control
      the epidemic. First, if the transmission rate is low enough there can be no
      epidemic. Second, even for a high transmission rate the epidemic will be avoided
      if the mean time a viral outbreak lasts in a patient is short enough. Finally,
      the mean time between two viral outbreaks in a patient is useful to control only
      for an intermediate transmission rate: if the transmission rate is high enough
      then there will be an epidemic even if the time between two viral outbreaks in a
      patient is arbitrarily long.

PMID- 10414031
TI  - Use of in vitro gas production models in ruminal kinetics.
AB  - Physiological systems models for ruminant animals are used to predict the extent
      of ruminal carbohydrate digestion, based on rates of intake, digestion, and
      passage to the lower tract. Digestion of feed carbohydrates is described in these
      models by a first-order rate constant. Recently, an in vitro gas production
      technique has been developed to determine the digestion kinetics in batch
      fermentation, and nonlinear mathematical models have been fitted to the
      cumulative gas production data from these experiments. In this paper, we present
      an analysis that converts these gas production models to an effective first-order
      rate constant that can be used directly in rumen systems models. The analysis
      considers the digestion of an incremental mass of substrate entering the rumen.
      The occurrence of passage is represented probabilistically, and integration
      through time gives the total mass of substrate and total rate of digestion in the
      rumen. To demonstrate the analysis, several gas production models are fitted to a
      sample data set for corn silage, and the effective first-order rate constants are
      calculated. The rate constants for digestion depend on ruminal passage rate, an
      interaction that arises from the nonlinearity of the gas production models.

PMID- 10414032
TI  - Locations of radiation-produced DNA double strand breaks along chromosomes: a
      stochastic cluster process formalism.
AB  - Ionizing radiation produces DNA double strand breaks (DSBs) in chromosomes. For
      densely ionizing radiation, the DSBs are not spaced randomly along a chromosome:
      recent data for size distributions of DNA fragments indicate break clustering on
      kbp-Mbp scales. Different DSB clusters on a chromosome are typically made by
      different, statistically independent, stochastically structured radiation tracks,
      and the average number of tracks involved can be small. We therefore model DSB
      positions along a chromosome as a stationary Poisson cluster process, i.e. a
      stochastic process consisting of secondary point processes whose locations are
      determined by a primary point process that is Poisson. Each secondary process
      represents a break cluster, typically consisting of 1-10 DSBs in a comparatively
      localized stochastic pattern determined by chromatin geometry and radiation track
      structure. Using this Poisson cluster process model, which we call the randomly
      located clusters (RLC) formalism, theorems are derived for how the DNA fragment
      size distribution depends on radiation dose. The RLC dose-response relations
      become non-linear when the dose becomes so high that DSB clusters from different
      tracks overlap or adjoin closely. The RLC formalism generalizes previous models,
      fits current data adequately and facilitates mechanistically based extrapolations
      from high-dose experiments to the much lower doses of interest for most
      applications.

PMID- 10414033
TI  - A random walk model of oligodendrocyte generation in vitro and associated
      estimation problems.
AB  - A branching stochastic process proposed earlier to model oligodendrocyte
      generation by O-2A progenitor cells under in vitro conditions does not allow
      invoking the maximum likelihood techniques for estimation purposes. To overcome
      this difficulty, we propose a partial likelihood function based on an embedded
      random walk model of clonal growth and differentiation of O-2A progenitor cells.
      Under certain conditions, the partial likelihood function yields consistent
      estimates of model parameters. The usefulness of this approach is illustrated
      with computer simulations and data analyses.

PMID- 10414034
TI  - [The use of informational modelling for detecting the parasitological markers of
      the unhealthiness of human ecology].

PMID- 10414035
TI  - [The effect of the technogenic pollution of the natural environment on the
      prevalence of parasitic diseases in the Republic of Byelarus].
AB  - The paper shows that in 1986-1995 a radiation area polluted with radionuclides at
      15 qi/km2 was marked by 4.9-fold (from 3.9 to 19.1%) and 4.3-fold (from 2.2 to
      9.4%) increases in infections with seat worms and lamblia, respectively. The
      infection rates for other helminthic species in 1995 do not greatly differ from
      those in 1986. In the area polluted with chemicals there was a steady-state
      decrease in the rates for intestinal parasites.

PMID- 10414036
TI  - [The trichinelliasis situation in Zakarpats'ka 1984-1997].

PMID- 10414038
TI  - [The clinical picture and course of Lyme disease in children in the city of
      Krasnoyarsk].
AB  - The paper describes the clinical picture and course of Lyme's disease (LD) in
      children from the city of Krasnoyarsk. The disease was ascertained to have a wide
      range of clinical manifestations: cutaneous changes, visceral abnormalities,
      involvement of the locomotor and nervous systems into the pathological process.
      The paper characterizes possible late consequences of the prior disease, which
      justifies the necessity of timely diagnosis and treatment of LD in children.

PMID- 10414037
TI  - [An analysis of the space-time changes in tick-borne encephalitis morbidity in
      Novosibirsk Province].
AB  - The authors analyzed data on space and time changes in tick-borne encephalitis
      (TBE) morbidity in Novosibirsk Province from 1955 to 1995 by using the method of
      principal components (PCs). The first PC (26.0% of total variance) was linearly
      represented. Judging the the loading scores, this component can be interpreted as
      redistribution of TBE morbidity rates between southeastern taiga foci in Salair
      foothills and northern forest-steppe foci in vicinity of the Ob' River valley.
      The second PC (22.6% of total variance) can be read as regional differences with
      long-term cyclic changes. The first PC correlated with the annual average
      temperature (r = 0.45; P < 0.05) and this correlation can be determined by global
      climate warming-up.

PMID- 10414040
TI  - [The landscape-malariological characteristics of the territory and the
      epidemiological features of malaria in the Kabardino-Balkarian Republic].
AB  - Malaria was widely spread in the Republic of Kabardino-Balkaria in the past, but
      its incidence rates varied in different areas, which depended on natural and
      climatic and socio-economic factors. Malaria was transmitted in the whole
      republic, except for its high-altitude areas. Malaria was most common in the
      lowlands. In the season of malaria transmission, P. vivax, the causative agent of
      the disease, can made 4 cycles in the plain, only 3 and, occasionally, 4 cycles
      in the piedmont. The climatic features of the republic give rise to the emergence
      of as many as 5 vector generations in the lowland in the epidemiological period.
      The peculiarities of malaria in the republic were seasonal fluctuations of
      malaria manifestation among the population with a winter interval of its
      transmission. The monthly distribution of malaria patients was typical of the
      "southern" type of a morbidity curve. The curve was two-peaked: the first peak
      was characterised by a small elevation of morbidity in March and April with the
      maximum in May and June, the second peak was characterised by a more drastically
      significant elevation in August and September owing to the varying proportions of
      two types of vivax malaria: that with long- and short-term incubation (30%
      against 70%). The bulk (as high as 70%) patients with malaria was recorded in its
      transmission season (June to September), in the period of the highest activity
      and the maximum size of vectors. In the republic, tertian malaria was mainly
      detected, cases of quartan and tropical malaria being registered.

PMID- 10414039
TI  - [The entomological and acarological situation in Nizhegorod Province].
AB  - Ixodes, persulcatus, I. ricinus, D. reticulatus, D. marginatus, H. concinna were
      recorded in different regional environmental regions. The northern districts of
      the region are endemic for tick-borne encephalitis (TBE) and Ixodes tick-borne
      borreliosis (ITBB). The infection of ticks with TBE virus is 0.25%, that with
      Borrelia is 10.3% of the total number of the examinees. In 1997 TBE and TTBB
      morbidity rates were 1.91 and 2.0 per 100,000, respectively. Data on the
      phenology of prevailing Anopheles messeae are given. Human malaria contamination
      may take 99-102 days (the first ten days of June to the second ten days of
      September). The large size of malaria mosquitoes and the presence of imported
      cases of malaria make it possible to deteriorate the malaria epidemiological
      situation. The larvicidal activity of a preparation derived from shepherd's-purse
      (Capsella bursa pastoris) [correction of caseweed (Bursae pastoris)] was tested.
      80-85% deaths of larvae of second-third ages occurred 48 hours after treatment
      with the preparation, 1 kg/ha.

PMID- 10414042
TI  - [A comparative analysis of the potential epidemiological importance of mosquitoes
      in the genus Anopheles under the conditions of the anthropogenic landscapes in
      the Chu Valley, Kyrgyz Republic. II. The spread of malarial mosquitoes by the
      types of day resting places].
AB  - The distribution of malaria mosquitoes was analyzed by the types of day's rest
      within the farmsteads to determine what feed different Anopheles species
      preferred in the Chu River valley, which is the most densely populated in the
      Republic of Kirghizia. Field trials were made in the April to October of 1991 and
      1992. Above 12,000 mosquito imagoes were collected. The predominant An. claviger
      was found mainly in the living spaces of the farmsteads which were located in
      vicinity of breeding sites. This exophilic species readily attacks both cattle
      and man who have found themselves in the places of its day's rest. An. messeae
      was chiefly detected indoors. The species readily attacks human beings. In the
      valley of the Chu River, A. hyrcanus actively attacks man indoors. In the Chu
      River valley, An. martinius is a completely exophilic type which prefers the
      accumulation of large prey.

PMID- 10414041
TI  - [Malignant tropical malaria in native Africans living in a large city].
AB  - The clinical and laboratory features of severe Plasmodium falciparum-induced
      malaria were analyzed in 91 adult patients living a large African city. Within a
      week, 52 patients developed the disease from the manifestations of overall
      intoxication to the complete picture of severe malaria accompanied by coma. Fifty
      eight patients were found to be residents of Conakry and 54 of them left the city
      2 months before the malaria attack. Eighty one patients had experienced malaria,
      including 38 patients had 1-2 attacks in the past year. The patients were
      parenterally treated with quinine in a dose of 750-850 mg of the active
      ingredient for 24 hours during 4.1 +/- 1.7 days at hospital. In 17 of 34
      patients, parasitemia disappeared from single to 5-10 parasites and more in the
      field of thick drop field, in the other 17 patients it decreased from 5-10 to
      single parasites at recovery. Twenty four comatose patients died at days 3-8 of
      hospital stay, most of them had symptoms of oligoanuria. The high cost of
      hospitalization and specific drugs were the reasons for late referral to hospital
      and for the use of low daily and course doses of quinine. The necessity of
      reviewing the principal trends of a national malaria control programme.

PMID- 10414043
TI  - [The blood-sucking midges (Diptera, Ceratopogonidae, Leptoconopidae) of the
      eastern Caspian Sea region (Mangyshlak)].
AB  - Fifteen types of biting midges belonging to two families Ceratopogonidae and
      Leptoconopidae were recorded in the eastern Caspian Sea region. The insect
      breeding foci and the seasonal and daily activity of flights were determined.

PMID- 10414044
TI  - [Observations on the development of Phlebotomus papatasi Scop. under laboratory
      conditions].
AB  - The development of Phlebotomus papatasi Scop., 1786 was observed at a laboratory
      of the Martsinovskii Institute of Medical Parasitology and Tropical Medicine in
      1988-1994. There was a flight of 9,809 imagoes. Among the mosquitoes developed
      from spring (May-June) clutches, most imagoes (as high as 98.9% of the total
      number of the flying imagoes) flew out in summer. As high as 6.7% flew out in
      autumn and up to 16.8 & of the total number did after diapause, i.e. the
      following spring. The paper shows it possible to interrupt the diapause on
      exposure larvae to elevated temperatures and light. However, mosquitoes of
      different strains are responsive to light in varying degrees. P. papatasi from
      Turkmenistan developed in the dark best al all, which is natural for them since
      in nature their breeding mainly occurs in the Arenaria burrows. The mosquitoes of
      mixed strains (females from Arabia, males from Turkmenistan) most frequently flew
      out in day and night light.

PMID- 10414045
TI  - [Optimization of the placement density and feed composition for the maintenance
      of the larvae of Anopheles superpictus Grassi and Anopheles pulcherrimus Theob].
AB  - The optimal density of placement of An. superpictus and An. pulcherrimus larvae
      in the culture is 50 individuals/dm2 of the water surface. This provided about
      90% survival, 2.5- and 2.3-mg weights of chrysalids, respectively, 5.8 and 5.3
      chrysalid multiplication per dm2 a day. A mixture containing ground combined
      fodder, Daphnia and wheat bran in a ratio of 2:1:4 is recommended for feeding
      both species of larvae.

PMID- 10414046
TI  - [The results of a study of the acaricidal activity of the preparation Fewry-med].
AB  - The acaricidal activity of Fewry-med (10% zeta-zipermethrin) against Ixodes
      persulcatus was studied in laboratory and field conditions. The drug's doses of
      0.01-0.005 g/m2 (as calculated for active ingredient) provided 100% death of
      ticks when forest areas (Tyumen' Province) were treated. The efficiency of
      treatment preserved within 31 days (the follow-up period). When Fewry-med was
      used in a dose of 0.005 and 0.01 g/m2, the soil levels of zeta-zipermethrin was
      lower than the maximum allowable concentration at days 7 and 14 after treatment.
      In the treated areas, the size of crawling representatives of the entomofauna
      restored at day 25. The drug may be recommended for industrial trials.

PMID- 10414047
TI  - [The potential for using the preparations Icon and Karate in medical insect
      control].
AB  - The insecticidal activity of Aikon, 10% wettable powder, and Carate, 5%
      emulsified concentrate, and 5% water soluble granules, (Zeneka Plant Protection,
      UK) was studied in laboratory and field tests. Their effective doses were 0.001
      0.5 g/m2 (as calculated for active ingredients) for synanthropic insects
      (cockroaches, flies, fleas). The agents belong to moderate hazard class 3
      substances. Their use has been approved by the Ministry of Health of the Russian
      Federation for treatment for non-living accommodations and subsidiary premises by
      specialists. Individual protective means should be used while contacting the
      agents.

PMID- 10414049
TI  - [The technology for manufacturing antiparasitic preparations. 9. The new
      preparation tizanox and an evaluation of its anti-Hymenolepis activity].
AB  - The paper describes a procedure for manufacturing the new anthelminthic Tizanox.
      It shows it necessary to administer a larger dose of the drug than that of azinox
      (praziquantel) to treat experimental hymenolepiasis. However, the lower toxicity
      of Tizanox enhances its chemotherapeutical index.

PMID- 10414048
TI  - [The detection of antibodies to the trophozoite antigens of Lamblia by an
      immunoenzyme method].
AB  - Whether purified antigens of Lamblia intestinalis trophozoites can be used to
      detect these antibodies by immunoassay. The drugs of immunodominant Lamblia
      antigens were prepared by anion-exchange chromatography of solubilized
      trophozoite components and they are mainly presented by proteins having molecular
      weights of 70, 56, and 49 kD. Immunoassay using these antigens revealed
      antibodies to Lamblia trophozoite antigens in sera of 87.6% of patients with
      lambliasis (its diagnosis was established on the basis of microscopic data on the
      duodenal content) and only in 16.2% of clinically healthy blood donors. Twenty
      six sera from patients with trichomoniasis having high levels of antibodies to
      trichomonad antigens were studied to evaluate the specificity of this method for
      detection of antibodies. It has been found that the proportion of subjects in
      this group who have also antibodies to Lamblia antigens does not greatly differ
      from that of healthy blood donors (19.2 and 16.2, respectively).

PMID- 10414050
TI  - [The experimental chemotherapy of larval alveolar echinococcosis. The search for
      an optimal regimen of albendazole use].
AB  - The antiechinococcal activity of albendazole resynthesized at the E. I.
      Martsinovskii Institute of Medical Parasitology and Tropical Medicine was studied
      on infection models in rats and mouse in different experimental modifications.
      The efficiency of the therapy was determined in relation to the dose of the drug
      and its routes administrations, to the single or intermittent daily dose, to the
      presence or absence of intervals in the treatment regimen, to dosage forms. The
      trials indicated that albendazole was most active against larval alveolar
      echinococcosis of mice or cotton rats when it was used with their feed, i.e.
      through the gastrointestinal tract.

PMID- 10414051
TI  - [The survival of the causative agent of plaque in the long-tailed suslik from a
      Tuva natural focus in wintertime].
AB  - The survival of the causative agent of plague in the long-tailed souslik in the
      Tuva natural focus in winter was experimentally studied. They were made in a
      special bunker laboratory just in the focus. The experimental conditions were
      close to the hygrothermal parameters of a long-tailed souslik's burrow.
      Inoculation and placement of the animals and fleas into the bunker were
      accomplished in the September to early October. The rodents and ectoparasites
      were examined after their hibernation in the late April to early May of the
      following year. The duration of the experiment was 7.5 months. It has been found
      that the long-tailed souslik can be infected with the causative agent of plague
      before hibernation through transmission. There were no cases of plague microbial
      infection through the bite of fleas in sousliks following hibernation. Low
      infection rates of the fleas hibernating with their host were notified. The
      causative agent was found to survive in the mummified carcasses of sousliks for
      7.5 months (the follow-up period).

PMID- 10414052
TI  - [Experience in controlling and preventing zoonotic cutaneous leishmaniasis in
      Uzbekistan].

PMID- 10414053
TI  - [The clinical picture of hemorrhagic fever with renal syndrome in the children of
      Udmurtia].

PMID- 10414054
TI  - [Enterobiasis in preschool institutions].

PMID- 10414055
TI  - The HCA "Battle-Lab".

PMID- 10414056
TI  - Levels of medical support for United Nations peacekeeping operations.
AB  - It is important to standardize the classification of medical units in United
      Nations (U.N.) peacekeeping operations to ensure that they meet operational
      requirements and to facilitate planning and administration. It further ensures
      interoperability between medical facilities from different countries. The U.N.
      Department of Peacekeeping Operations has adopted a four-level medical support
      organization, with the classification level of a unit largely determined by its
      treatment capability and capacity. Planning and allocation of medical resources
      depend largely on the peacekeeping mandate, the type of peacekeeping operation,
      existing medical infrastructure, geographical factors, and assessed medical
      threats. A summary of medical units currently deployed in U.N. peacekeeping
      missions is presented. This should promote understanding of the U.N. medical
      support concept and assist national military organizations in the planning for
      such operations.

PMID- 10414057
TI  - Use of host nation facilities as medical force multipliers at the Operation Joint
      Guard intermediate staging base, March to October 1997.
AB  - In March 1997, a transition occurred in the health service support of the
      intermediate staging base of Operation Joint Guard in Taszar, Hungary, by which a
      level III, 32-bed Deployable Medical Systems facility staffed by 178 personnel
      was replaced by a level II+ clinic staffed by 48 personnel with no organic
      surgical or blood transfusion capabilities. This was achieved by the use of local
      host nation facilities for surgery, sophisticated diagnostics, and medical
      specialty hospitalization. In the ensuing 7 months, 34 American patients were
      admitted to Hungarian hospitals for a total of 100 inpatient days, and 8 of them
      underwent surgery. This successful use of host nation facilities as medical force
      multipliers allowed great savings in cost and personnel and should be considered
      in future operations other than war that involve low-intensity conflict.

PMID- 10414058
TI  - Hospitalization of British troops during Operation Joint Endeavor (Bosnia).
AB  - Of 414 recorded hospitalizations among British troops during Operation Joint
      Endeavor (Bosnia) in 1996, 2% were attributable to battle injuries, 46% to
      routine injuries, and 52% to disease; most injuries were to the lower limbs, and
      most diseases were of the skin and musculoskeletal system. The median length of
      inpatient stay was 4 days for injury (range, 1-146 days) and 3 days for disease
      (range, 1-60 days). Correcting for uncaptured data, the number of
      hospitalizations attributable to both injury and disease was significantly lower
      than the number predicted from the NATO planning figures (p < 0.0001). The NATO
      planning estimates for expected hospitalizations need to be revised. The
      electronic recording at source of all patient information should be introduced
      during military deployments to optimize data capture, facilitate the audit of
      clinical activity, and inform future medical planning. All hospitalizations
      occurring during military missions should be recorded, and surgical interventions
      during deployments should be coded at source. Ineffective paper-based morbidity
      surveillance procedures such as Jefferson 97 (or J97) must be discontinued and
      replaced by an electronic, fully integrated, NATO-wide clinical information
      system. This clinical information system should encompass primary care, secondary
      care, medical training, and medical supply. It should be built on a Microsoft
      Office platform and should be capable of interfacing electronically with existing
      civilian databases. Important clinical outcomes should be structured
      hierarchically within the data set. The database should be configured so that it
      can be accessed locally by clinicians and remotely by epidemiologists and
      planners.

PMID- 10414060
TI  - Self-collection of group B Streptococcus cultures in pregnant women.
AB  - OBJECTIVE: This study assesses the sensitivity of self-collected rectovaginal
      culture specimens for group B Streptococcus by pregnant patients. METHODS: A
      volunteer sample of 240 pregnant women at 28 weeks gestation self-collected
      rectovaginal culture swabs to screen for the presence of group B Streptococcus.
      The patients' physicians collected second specimens for comparison. RESULTS:
      Twenty-four of 240 women grew group B Streptococcus on at least one culture
      (incidence, 10%). Twenty physician-collected specimens and 19 patient-collected
      specimens were positive (83 and 79% sensitivity, respectively). Fifteen patients
      (62.5%) had both physician-collected and patient-collected cultures grow group B
      Streptococcus. Cohen's kappa (kappa = 0.75) indicates a high degree of agreement
      between patient-collected and physician-collected cultures. CONCLUSIONS: Pregnant
      women are as likely as their attending physicians to obtain positive cultures for
      group B Streptococcus by self-collection of rectovaginal swabs.

PMID- 10414061
TI  - A theoretical model for the study of active and passive smoking in military
      women: an at-risk population.
AB  - This paper presents a model designed for the study of active and passive smoking
      in military women with children. Some constructs have been adapted from a
      transtheoretical model of behavior change. Transtheoretical model constructs of
      relevance to this model include (1) stages of behavior change, (2) decisional
      balance, and (3) self-efficacy. Other model constructs include (1) personal and
      situational factors, (2) a mother's self-efficacy to reduce the child's smoke
      exposure, (3) a mother's expectation for the child's smoke exposure, (4) smoke
      avoidance, (5) nicotine dependence, and (6) social support for quitting smoking.
      The occurrence of health problems associated with smoking is the outcome
      variable. The results of a study under way at present may support the use of this
      model and may make data available to substantiate the need for behavior-specific
      interventions designed to prevent and reduce active and passive smoking among
      military personnel.

PMID- 10414059
TI  - Improving maternal and newborn nursing services in a military medical center.
AB  - As military treatment facility leaders become more knowledgeable regarding
      apportionment of resources, decision making involving primary family member
      support services must be clear and concise. Continuing in its effort to meet the
      maternal and child health care expectations of its patients, a large military
      treatment facility command instituted several changes to consolidate its maternal
      and newborn services. This article presents findings and outcomes of actions
      taken in support of quality improvement and efficient use of budgetary resources
      to maximize patient satisfaction and bring about cost savings.

PMID- 10414062
TI  - Advances in Navy pharmacy information technology: accessing Micromedex via the
      Composite Healthcare Computer System and local area networks.
AB  - The pharmacy profession has long used technology to more effectively bring health
      care to the patient. Navy pharmacy has embraced technology advances in its daily
      operations, from computers to dispensing robots. Evolving from the traditional
      role of compounding and dispensing specialists, pharmacists are establishing
      themselves as vital team members in direct patient care: on the ward, in
      ambulatory clinics, in specialty clinics, and in other specialty patient care
      programs (e.g., smoking cessation). An important part of the evolution is the
      timely access to the most up-to-date information available. Micromedex, Inc.
      (Denver, Colorado), has developed a number of computer CD-ROM-based full-text
      pharmacy, toxicology, emergency medicine, and patient education products.
      Micromedex is a recognized leader with regard to total pharmaceutical information
      availability. This article discusses the implementation of Micromedex products
      within the established Composite Healthcare Computer System and the subsequent
      use by and effect on the international Navy pharmacy community.

PMID- 10414063
TI  - Reducing medical attrition: the role of the Accession Medical Standards Analysis
      and Research Activity.
AB  - This paper illustrates how adding an epidemiologic perspective to medical
      accession policy development allows the Department of Defense to address
      unacceptably high rates of premature attrition, lost duty time, avoidable medical
      care costs, sick leave, disability, and various wasteful, inefficient practices.
      The Accession Medical Standards Analysis and Research Activity is a major new
      epidemiologic entity. Historically, military medical accession policy and waiver
      deliberations were based heavily on expert opinion. A common limitation of expert
      opinion is that although experience teaches much about individuals with certain
      conditions who develop problems, it does not teach about individuals with the
      same conditions who remain well. The Accession Medical Standards Analysis and
      Research Activity produces the analyses of epidemiologic data necessary for the
      joint personnel and medical flag-level Department of Defense Accessions Medical
      Standards Steering Committee to make evidence-based accession policy decisions.

PMID- 10414064
TI  - U.S. Army dietitians deploy in support of Cobra Gold: a humanitarian mission.
AB  - Dietitians are multifunctional and play an important role in humanitarian
      missions as educators, planners, and consultants. Three dietitians deployed to
      Thailand in support of the 16th Annual Joint and Combined Exercise, Cobra Gold
      1997. The goal of the Medical Civic Assistance Program (MEDCAP) was to promote
      long-term public health improvements in rural Thai villages. The dietitians
      counseled 140 patients and taught an additional 5,300 individuals during
      nutrition classes. The primary nutrition-related clinical diagnoses included
      malnutrition, anemia, diabetes, hypertension, goiter, and poor appetite. The
      dietitian who deployed as the medical planner and MEDCAP executive officer
      facilitated coordination and planning for all phases of the MEDCAP operation. The
      teams were made up of U.S. and Thai military forces and Thai civilian medical
      personnel. The mission requirements were established with the Royal Thai Supreme
      Command, Thai governors, Ministry of Public Health officers, military and medical
      officers, and veterinarians of the three provinces.

PMID- 10414065
TI  - Dietary supplement use in U.S. Army Special Operations candidates.
AB  - We administered a dietary supplement survey to 2,215 males (mean age, 25 years;
      range, 18-47 years) entering U.S. Army Special Forces and Ranger training
      schools. The survey contained questions on demographics and health as well as the
      use of vitamin, mineral, protein, pro-performance, and other cofactor
      supplements; answers were made on a five-point frequency scale. Eighty-five
      percent of the men reported past or present use of a supplement, 64% reported
      current use, and 35% reported daily use. Individuals using a supplement at least
      occasionally were significantly less likely to smoke (p < 0.05) and more likely
      to exercise on a daily basis. Recent U.S. Department of Agriculture survey data
      (1994) reported that 39% of males 20 to 39 years old used a dietary supplement at
      least occasionally. Our data indicate that the rate of supplement use in this
      study group was much higher than in the general population of young men. This
      observation supports the need to study more extensively the use and benefits or
      potential harm of dietary supplementation by otherwise healthy individuals.

PMID- 10414066
TI  - Fluid replacement recommendations for training in hot weather.
AB  - The U.S. Army's fluid replacement guidelines emphasize fluid replacement during
      hot weather training to prevent degradation of performance and minimize the risk
      of heat injury. Little consideration has been given, however, to possible
      overhydration and development of water intoxication. Sufficient epidemiological
      evidence is available to demonstrate an increasing incidence of water
      intoxication during military training. This article summarizes the development
      and validation of revised fluid replacement guidelines for hot weather training.
      The end product is an easy-to-read table that provides the user with the
      appropriate hourly work time and fluid intake to support work during hot weather
      training. The guidelines include the range of hot weather conditions likely to be
      encountered during military training and cover a broad range of military
      activities. It is expected that the revised guidelines will sustain hydration and
      minimize the number of heat injuries during military training while protecting
      the soldier from becoming sick from overdrinking.

PMID- 10414067
TI  - Evaluation of psychological risk factors: prospective prediction of
      psychopathology during basic training.
AB  - OBJECTIVE: Three theoretically derived cognitive risk factors were evaluated to
      determine whether they predicted the development of stress responding in the
      context of Basic Cadet Training (BCT). METHOD: A large sample of cadets (N =
      1,401) was prospectively followed for the 5-week BCT period. RESULTS: All risk
      factors were found to significantly and independently predict the development of
      psychopathology and impairment as well as changes in symptoms during basic
      training. Risk factors conveyed approximately two to five times greater
      likelihood of experiencing clinically significant levels of symptoms at the end
      of BCT. CONCLUSIONS: These data provide strong evidence for three psychological
      risk factors in the development of anxiety and mood symptoms. Implications for
      screening and primary prevention are discussed.

PMID- 10414068
TI  - Clinical procedures for the neuropsychological evaluation of U.S. Air Force
      pilots.
AB  - The neuropsychological assessment of U.S. Air Force pilots presents several
      unique problems given their relatively high cognitive functioning. The U.S. Air
      Force currently has a baselining procedure whereby student pilots undergo
      computerized cognitive assessment. The intent of this assessment is to archive
      premorbid data against which to compare potential future postinsult performance.
      The current work provides the background, clinical methods, and data needed to
      assess pilots who have suffered cortical insult such as trauma, disease, or
      exposure to toxins. Methods are delineated for pilots with premorbid testing and
      for pilots without such testing.

PMID- 10414069
TI  - Humanity and radiation: the good, the bad, and the unusual.
AB  - Radiation has permeated the universe since time began. People disagree widely
      about the merits and dangers of nuclear technology. Radiation is often associated
      in the minds of people with bombs, fallout, destruction, and death rather than
      with the many benefits of nuclear technology that are present in our daily lives.
      Rarely do individuals focus on the medical applications of radiation and the fact
      that nuclear technology saves lives. Over the years, accidents have happened in
      the nuclear industry; some have produced fatalities, but most proved to be a
      major source of concern only to the local populace. Since the discovery of
      naturally occurring radium and uranium and the advent of synthetic radionuclides,
      a number of consumer products have used radiation, some of which were beneficial
      and some which were of no benefit at all.

PMID- 10414070
TI  - Military free fall training injuries.
AB  - Military free fall or HALO (high altitude-low opening) is a distinct form of
      tactical parachuting used by the elite forces of the U.S. military. This study
      was undertaken to examine the type, location, and mechanism of injuries sustained
      by the military HALO parachutist during training. A retrospective study
      identified 134 parachutists with 141 injuries attributed to HALO training. The
      most common injuries were fractures (35.5%) and sprains/strains (34.7%). The
      sites most commonly injured were the lower extremities (52.5%), upper extremities
      (19.8%), and spine (14.9%). Landing was the most frequently encountered mechanism
      of injury (61.2%), followed by ground free fall simulation (wind tunnel training)
      and canopy deployment. Night jumping, wearing of combat equipment, and use of
      oxygen during high-altitude jumps were all variables that contributed to injury.
      The military free fall parachutist is predisposed to a wide array of
      musculoskeletal injuries at different training phases.

PMID- 10414071
TI  - Use of a critical pathway to move laparoscopic cholecystectomy to the ambulatory
      surgery arena.
AB  - Critical pathways are being implemented in health care facilities across the
      nation as a cost-containment tool. When developed using best practice based on a
      literature review and the collaboration of a multidisciplinary team, critical
      pathways can be very successful in maintaining or increasing the quality of care
      while controlling the cost of the care provided. The Department of Defense
      Utilization Management Plan strongly encourages the use of pathways. Here we
      discuss the development and implementation of a critical pathway for laparoscopic
      cholecystectomy patients, with the goal being to transfer the medical care from
      the inpatient setting to the ambulatory surgery arena. The use of this pathway
      resulted in almost a 50% increase in patients treated in the ambulatory surgery
      arena.

PMID- 10414072
TI  - Modified closed circuit underwater breathing apparatus LAR VII and laryngeal mask
      airway as adjuncts for dive buddy artificial ventilation.
AB  - This study evaluated the feasibility of using the modified semi-closed circuit
      underwater rebreathing system (URS) LAR VII in connection with a laryngeal mask
      airway (LMA) as an expedient ventilatory adjunct in an operational setting.
      Fourteen combat swimmers, unfamiliar with this equipment, underwent
      cardiopulmonary resuscitation (CPR) mannequin training using these devices.
      Eighteen subjects, using a standard AMBU bag for ventilation, served as controls.
      Thirteen test persons were able to ventilate with the modified URS. Tidal volumes
      were significantly lower with the LAR VII/LMA than with the AMBU bag (medians,
      350 vs. 800 mL). No significant difference was found in total time required for
      10 CPR cycles (medians, 78 vs. 68.5 seconds). The median delay between
      recognition of cardiac arrest and first chest compression, however, was markedly
      increased with the LAR VII/LMA than with the AMBU bag (medians, 76.5 vs. 14.5
      seconds). After proper training, divers might use a modified URS such as the LAR
      VII for CPR in connection with a LMA. Lower tidal volumes might prevent gastric
      inflation. Chest compression should be continued during LMA insertion.

PMID- 10414073
TI  - [Address of the president of the Society. Society of Oromaxillofacial Surgery].

PMID- 10414074
TI  - [Address of the congress president. German Society of Oromaxillofacial Surgery].

PMID- 10414075
TI  - [Skull and mandible. On Joseph Beuys' "ancient sled." Medical art history
      observation].
AB  - Few people are aware that Joseph Beuys (1921-1986), one of the most important
      artists at the end of the twentieth century, studied various aspects of the human
      skull. Beuys used teeth (especially molars), antlers, and horns as organically
      differentiated formations of solid substances of the viscerocranium, associating
      them in a very visual way with the "streaming circulation" principle. In
      addition, in his early drawings, in particular, Beuys replaced the lower jaw with
      a sledge. The artist has thus created interesting and strange constructions
      concerned with the structure of the jaw and the craniovertebral transition.
      Certain characteristic structural elements of sledges show a remarkable formal
      analogy to the ramus of mandible. The base of the body of mandible becomes a
      sliding surface, the iron runners of the sledge. Replacing the lower jaw with a
      sledge raises questions concerning movement and the effect of energy on the skull
      and on the earth. The artist's understanding of anatomy goes for beyond than that
      of normal medicine. It is formed by his thinking, his energy plan, and by his own
      theory of metamorphosis. With his skull and Urschlitten motif, Beuys makes us
      aware of the transitory layers of consciousness between life and death. "Head"
      and "sledge" are early forms of sculptural thinking in the work of Joseph Beuys.

PMID- 10414076
TI  - [Significance of the height and width of the alveolar ridge in implantology in
      the edentulous maxilla. Analysis of 95 cadaver jaws and 24 consecutive patients].
AB  - Consideration of alveolar profiles and clinical experience demonstrate that the
      transversal dimension has been neglected in dental implantology so far. For a
      comprehensive evaluation of the impact of alveolar bone height and width, 95
      edentulous bony maxillae with standardized, measured, and classified cross
      sections were analyzed. With four types of implants (minimum length, 10 mm), 1076
      insertions were simulated at 269 cross-sections and evaluated with regard to type
      of implant, position of cross-section, and class of atrophy. Similar evaluation
      was carried out in the clinical part of the study on 24 consecutive patients with
      edentulous maxillae. Implant insertion could only be simulated in 35% of the
      cadaver cross-sections, but had been expected in an additional 4.5% based on
      their sufficient bone height; length reductions were necessary in another 6%.
      These results depended largely on the class of atrophy. Anterior cross-sections
      offered better conditions than posterior ones. In contrast, implant insertion was
      impossible in all 24 patients. Height was primarily inadequate in 22 patients,
      and in two patients with sufficient bone height inadequate transversal dimensions
      were only recognised intraoperatively. These results allow a quantification of
      the impact of vertical and transversal maxillary alveolar bone dimensions. This
      impact primarily depends on bone height, but even with sufficient height,
      reductions of implant length often become necessary. Both for the cadaver
      maxillae (12% of the cross-sections with expected implant insertion) and for the
      patients (8%), alveolar profiles remain in which height measurement alone leads
      to incorrect assessment and may even result in the interruption of precisely
      planned surgical procedures. The complexity and expense of implant-borne
      rehabilitation and the consequences resulting from incorrect preoperative
      planning therefore generally justify extended cross-sectional diagnostic
      measuring.

PMID- 10414077
TI  - [Endosseous implants for functional masticatory rehabilitation in the extremely
      atrophied edentulous maxilla].
AB  - PURPOSE: The aim of this retrospective study was to evaluate the long-term
      survival rate of dental implants in edentulous patients suffering from severe
      atrophy of the alveolar ridges in the upper jaw. PATIENTS AND METHODS: In total,
      964 implants were inserted in 140 patients. A total of 481 implants were combined
      with an osteoplastic augmentation of the maxilla, and 483 implants were inserted
      directly in the atrophic bone. The success rate was determined using survival
      analysis, log rank tests and a Cox regression analysis. RESULTS: The overall
      survival rate for all implants was 42.2% during an observation period of 11
      years. Between implants combined with an osteoplasty and implants inserted in
      local bone tissue there were no significant differences in the survival rate. The
      survival rate of implants combined with an osteoplasty was significantly reduced
      in women and in the case of repeated insertion or augmentation. Interestingly, a
      few of the patients treated with an osteoplasty demonstrated high numbers of
      individual implant failures. Those patients were postmenopausal women
      exclusively. Among them there is probably a certain group with a very high risk
      of implant failures. CONCLUSION: This study shows that oral rehabilitation with
      osteointegrated implants in patients with severely atrophic alveolar ridges in
      the upper jaw is still problematic.

PMID- 10414078
TI  - [Horse shoe Le Fort I osteotomy. Surgical technique for reconstruction of the
      extremely atrophied maxilla].
AB  - Twenty-three patients with class VI atrophy of the maxilla were treated with
      horseshoe Le Fort I osteotomy. In ten patients, simultaneous placement of the
      implants was carried out, and in 12 the implantation was done in a second
      procedure 6-9 months later. A total of 178 implants were placed, and 15 were
      lost. In one patient, five implants were lost due to an oronasal fistula, leading
      to loss of part of the bone graft. The implant survival rate for all the implants
      was 89.0-88.2% in the one-step procedure and 90.0% in the two-step procedure.
      There was no difference between the one-step and the two-step procedure with
      respect to the peri-implant soft tissues in follow-up of least 2 years after
      implantation. We favor the two-step procedure because it allows more precise
      positioning of implants.

PMID- 10414079
TI  - [Follow-up studies of 3-dimensional osteoplastic reconstruction of the extremely
      atrophied maxilla combined with implants].
AB  - In the severely resorbed maxilla, a 10-year success rate of only 49-74% of
      implants in combination with autogenous bone grafts has been reported. We
      developed a modified technique of antral inlay grafting and lateral and vertical
      onlay grafting of the severely resorbed maxilla for inserting implants to retain
      dentures. The clinical and radiologic results are presented. In 21 patients with
      severely resorbed edentulous maxillae, a total of 20 bilateral and one unilateral
      antral inlay graftings and lateral and vertical onlay graftings were performed
      after a prosthodontic setup. We opened the maxillary sinus by removing a bony
      window from the anterolateral wall and, after elevation of the sinus lining,
      grafted the sinus floor with corticocancellous iliac crest bone grafts. The
      maxilla was also augmented in the lateral and vertical direction. The bone grafts
      were fixed by osteosynthesis. After a median of 5 months, a total of 134 implants
      (Branemark) were placed and later loaded by prosthodontic rehabilitation.
      Computed tomography (CT) scans were taken before the grafting procedure,
      immediately after grafting, after 4 months, and every year thereafter. A total of
      94.8% of the implants were successful at the time of the abutment operation.
      After loading, two additional failures were seen in an average follow-up period
      of 2.5 years. Most patients were provided with implant-borne dentures. CT scans
      showed an average initial gain of vertical bone height of 3.7-17.7 mm. One year
      after grafting, a loss of 1.3 mm or 7% occurred. In the following 2 years, no
      major atrophy was observed. Statistical analysis showed no correlation between
      sex, bone height before augmentation, augmented bone height, and resorption of
      the grafted bone. We observed undisturbed healing and obtained large vertical
      bone heights, a high success rate, minimal resorption, and fully satisfactory
      prosthodontic rehabilitation; we can thus recommend our modified technique of
      reconstruction of the severely resorbed maxilla for routine use.

PMID- 10414080
TI  - [Prosthetic scintigraphic study of healing of implants combined with bone
      transplantation in extreme atrophy and after tumor resection].
AB  - The aim of the present study was to evaluate the healing of onlay grafts to
      edentulous jaws and after tumor ablation in conjunction with osseointegrated
      implants using sequential bone scintigraphy and single photon emission computed
      tomography (SPECT). A total of 24 patients were examined after onlay grafting of
      extremely atrophic edentulous jaws and after tumor ablation with secondary
      implant placement 21.4 weeks after grafting. Technetium-99m (MDP) scintigrams
      were performed immediately after grafting, before and after implant placement,
      and before abutment connection. Tracer accumulation was assessed
      semiquantitatively by calculating ratios of count densities between the uptake
      over the calvaria and over the grafted jaws. There was a significant decrease in
      tracer uptake during graft healing, which was followed by a significant increase
      after implant placement and a subsequent decrease during implant healing. In
      patients with complicated healing, tracer uptake in areas of subsequent graft
      infection immediately after grafting was significantly lower compared with
      patients with uneventful healing. These areas also showed a lower increase in
      tracer accumulation after implant placement due to inferior graft quality,
      followed by a significant increase of tracer uptake at the time of abutment
      connection, representing inflammatory peri-implant bone reaction. Sequential bone
      scintigrams and bone SPECT have the prognostic potential to detect areas of
      inferior graft revascularization leading to graft infection or failure in the
      osseointegration of implants. Only bone SPECT allows an exact localization of
      areas with complicated healing.

PMID- 10414081
TI  - [Augmentation of the extremely atrophied maxilla and mandible by autologous
      calvarial bone transplantation].
AB  - Rehabilitation in patients with severe alveolar ridge atrophy of the maxilla or
      mandible is problematic and can often only be achieved by long-term treatment. In
      most cases, autologous bone grafting with iliac crest bone has been used to
      augment severely atrophied upper jaws. In our experience, iliac bone grafts are
      less useful, since iliac bone appears to be of inferior quality; in elderly
      osteoporotic women, the bone is soft, indentable, and of poor osteogenic potency.
      In our department, we have been using only autologous calvarial bone grafts for
      augmentation of alveolar ridge atrophy since 1993. The bone is removed from the
      outer table of the skull only, trimmed to the alveolar ridge, und fixed with
      titanium lag scews. The skull defect created is covered with crushed bone or a
      titanium mesh to avoid aesthetic problems. Insertion of dental implants follows
      after a healing period of the bone grafts of 5-6 months. A total of 63 patients
      underwent calvarial split-graft augmentation; augmentation of the maxilla and
      mandible was carried out in 15 of these patients, of the maxilla only in eight,
      and of the mandible only in 40. The investigations 1 year later showed a
      resorption rate of approximately 10%. This is lower than when using iliac bone
      grafting. The resorption results were stable between 6 and 12 months after
      augmentation. Using dental implants (12 patients with 32 implants), the
      resorption rate was low and constant. We have never seen total loss of bone
      grafts or intracranial complications. All patients were pleased with the
      treatment. In our opinion, severe alveolar atrophy of the maxilla or mandible
      should be compensated for by augmentation with autologous calvarial bone grafts
      to obtain good long-term results.

PMID- 10414082
TI  - [The maxilla--a poor implant site?].
AB  - In the maxilla, it is sometimes necessary to use implants to achieve a good
      prosthetic result. However, an increased failure rate of maxillary implants seems
      to be a common clinical experience. This experience was investigated in a
      retrospective statistical analysis. In a retrospective study of 665 patients
      between 1987 and 1997, 2484 implants were examined. The implants in the upper jaw
      were compared to those in the lower jaw. Implants with and without autogenous
      bone grafts and fixtures in patients with alveolar ridge atrophy, tumor, or
      trauma were explored. In particular, the data obtained from the orthopantomograms
      after completion of the prosthetic superstructures were controlled for peri
      implantary bone loss evaluation. A total of 40% of the fixtures were placed in
      the maxilla, and 30% of these implants were combined with a local or an iliac
      bone graft. Out of 2484 implants, 207 were lost, largely during the healing
      period. The failure rates in the groups of patients with alveolar ridge atrophy,
      tumor, and trauma were between 6 and 27.5%, and the differences between these
      groups were higher than the difference between the upper and the lower jaw.
      Especially in the maxilla and after osteoplasty, horizontal peri-implantary bone
      loss was increased, with some cases of dramatic bone loss and decrease of the
      osseous integration of the fixtures. There was no statistic evidence of a
      significantly higher failure rate in the upper jaw than in the lower jaw.
      However, besides the rate of implant loss, additional markers should also be
      considered for adequate evaluation of implant prognosis in the maxilla.

PMID- 10414083
TI  - [Significance of profile prognosis in implant management of the atrophic
      maxilla].
AB  - Postoperative cosmetic results in soft tissue after combined surgical and
      prosthetic treatment of the extremely atrophic edentulous maxilla by maxillary
      advancement, sinus lift, and insertion of enosseous implants are rarely
      considered during preoperative planning. In a prospective study that began in
      1993 in 23 patients, the treatment concept was determined by a medical rapid
      prototyping model and video imaging to predict the soft tissue profile, taking
      into consideration the appearance of the front teeth. In eight patients, the
      surgical and/or the prosthetic concept was modified according to the treatment
      plan decided on with the patient. All patients were highly satisfied with the
      aesthetic and functional result achieved. Profile prediction using video imaging
      is a useful tool in planning rehabilitation of the atrophic maxilla and takes
      into account the interplay of various factors--the amount of maxillary
      advancement, the direction of insertion of enosseous implants, and the type of
      supraconstruction. This procedure shows a very high level of acceptance by
      patients.

PMID- 10414085
TI  - [Roentgenologic, endoscopic and ultrasound evaluation of the maxillary sinus
      after sinus lift with simultaneous endosseous implantation].
AB  - X-ray, ultrasound, and endoscopy were used in follow-up after sinus floor
      augmentation. In 23 out of 63 patients, healing was uneventful. Water's view
      revealed opacification of the maxillary sinus 1 week postoperatively in 40
      patients, and opacification persisted in four patients. In these patients,
      endoscopy showed inflammatory reactions of the mucosa. Ultrasound proved to be a
      valuable tool in follow-up. Sinusitis occurred in three patients and was due to
      migration of bone chips in two of these. Out of 132 inserted implants, eight were
      lost during the healing period and three more during the loading period.

PMID- 10414084
TI  - [Comparative studies of sinus floor elevation with autologous or allogeneic bone
      tissue].
AB  - In 63 patients, 82 elevations of the maxillary sinus were performed. As
      augmentation, materials autografts from the iliac crest (combined with alveolar
      ridge augmentations in 16 sinus lifts) were transplanted in 39 cases and
      osteoinductive, allogeneic bone powder (AAA bone (autolyzed, antigen-extracted,
      allogeneic bone): n = 8, DFDBA (demineralized freeze-dried bone allograft) and/or
      Grafton (demineralized bone matrix gel): n = 35) were used in 43 cases. Some 4-6
      months after implantation, osteoinductive, allogeneic (demineralized) bone
      implants showed radio-opaque areas as an equivalent of bone formation.
      Histological examinations revealed that osteoinductive implants were completely
      transformed into patients' own bone tissue. The average augmentation height after
      autograft transplantations was 14 (+/- 3) mm in comparison with 9 (+/- 3) mm
      after allograft implantations. Histologically as well as radiologically no
      differences of the bone quality could be determined between the two augmentation
      materials. Endoscopic controls showed, in both groups, nonirritated mucous
      membranes. On an average 2 endosseous implants (Bone Lock or ITI-screw implants)
      were inserted into the augmentated maxillary sinus floors in both groups. No
      osseointegration was achieved in 4 out of 67 dental implants when bone autografts
      were used and in 2 out of 74 dental implants of the allogeneic bone group.
      Patients with bone autografts suffered from postoperative complaints on an
      average of 19 (+/- 9) days (without consideration of 2 patients with
      postoperative complaints persisting for more than 90 days). The average
      postoperative complaints of recipients of allogeneic bone implants continued for
      3 (+/- 5) days. The 13 patients who underwent an ambulant sinus lift procedure
      with allogeneic bone powder were already symptom-free several hours after the
      operation. Under critical consideration of all investigated parameters,
      osteoinductive bone implants are preferable to iliac bone autografts for
      maxillary sinus augmentations in those cases in which no additional alveolar
      ridge augmentation is required.

PMID- 10414086
TI  - Morbidity and complications of bone grafting of the floor of the maxillary sinus
      for the placement of endosseous implants.
AB  - Placement of endosseous implants in the atrophic maxilla is often limited because
      of a lack of supporting bone. A technique to augment the floor of the maxillary
      sinus with autogenous bone graft seems to be a new reliable treatment modality.
      The morbidity and complication rate of augmentation of the maxillary sinus floor
      was studied in 75 patients. The sinus floor was augmented with iliac crest (n =
      65, 128 sinuses, 276 implants), mandibular symphysis (n = 8, ten sinuses, 21
      implants), or maxillary tuberosity grafts (n = 2, two sinuses, two implants). The
      width of the alveolar crest had to be reconstructed in 52 patients, while in the
      other 23 patients augmentation and implantation were performed simultaneously.
      Perforation of the sinus membrane occurred in 45 patients, but this did not
      predispose them to the development of sinusitis. Loss of bone particles and
      sequesters were observed in one (diabetic) patient only, in whom a mucosal
      dehiscence occurred. A second augmentation procedure was successful. Symptoms of
      transient sinusitis were observed in two of the seven patients with a
      predisposition for sinusitis. These symptoms were successfully treated with
      decongestants and antibiotics. One patient developed a purulent sinusitis which
      resolved after a nasal amrostomy. The bone volume was sufficient for insertion
      implants in all patients. Twenty of 299 patients (6.7%) in whom Branemark
      implants had been inserted were lost to follow-up (mean, 32 months); no sinus
      pathology was observed. The patients received implant-supported overdentures (58
      patients) or fixed bridges (17 patients) and experienced no complaints with
      regard to the grafts or implants. We conclude that the morbidity and complication
      rate of bone grafting of the floor of the maxillary sinus floor with autogenous
      bone is low.

PMID- 10414087
TI  - [Minimally invasive sinus lift. Limits and possibilities in the atrophic
      maxilla].
AB  - The minimal invasive sinus lift is a procedure done by osteotome technique via a
      crestal approach in contrast to the sinus elevation via lateral osteotomy to
      achieve adequate bone-height for setting of implants. The purpose of this
      anatomical and clinical study was to evaluate by endoscopic control if the
      minimal sinus lift is practicable by a residual bone height of less than 8 mm
      without mucosal damage. An endoscopic controlled sinus lift was done on 10 fresh
      cadavers. The original bone height was 3-6 mm in the lateral maxilla. The sinus
      mucosa was elevated by an osteotome at least up to 10 mm. A sinus augmentation
      was performed with a bone substitute material (Algipore) over the implant bed.
      There was no tear visible on endoscopic control. Finally, the maxilla was removed
      and the mucosa inspected. No laceration of the mucosa was found in any case. The
      clinical study included 7 patients. 5 Patients had bone condensation,
      augmentation of bone and implantation of 13 mm implants in a one stage procedure.
      The originally bone height was between 6-8 mm in all patients. One of the five
      patients did show a small perforation of the mucosa during mucosal elevation at
      one implant-bed. The implant was inserted and an endoscopic control after 6 weeks
      showed regular mucosa. 2 patients received augmentation only at a primary bone
      height of only 3-5 mm. A post-operative CT-scan showed that the bone height was
      augmented to a total height of 13-16 mm. As a result of our study a sufficient
      bone height can be achieved by the minimal invasive sinus lift procedure. The
      advantage of this crestal approach is the protection of the intraosseous vessels
      in the maxilla and less postoperative morbidity. As a disadvantage, the insertion
      of bone material limited only to the area surrounding the implant bed, might be
      discussed.

PMID- 10414088
TI  - [Initial experiences with a new distraction implant system for alveolar ridge
      augmentation].
AB  - The masticatory rehabilitation of patients is dependent on the quality and volume
      of residual jaw bone. Loss of volume caused by tumor-related mandibular ridge
      resection or age-related atrophies may cause considerable problems.
      Reconstructive methods using free iliac bone, external tabula, or sandwich
      plasties are only a few examples of the common surgical treatment modalities.
      Doing without bone grafts, alveolar ridge augmentation by means of distraction
      osteogenesis might become a value method to improve the denture-bearing area. A
      new distraction implant system is shown and its first clinical use reported. Two
      distraction implants were inserted after an anterior segmental osteotomy. The
      alveolar ridge was then elevated 1 mm each day until the required augmentation of
      about 8 mm was achieved. After a latency period for pre-ossification of the
      callus, the distraction implants were replaced by the endosseous implants. The
      implant system and the surgical technique are shown, and the results are
      discussed. We believe that the implant distraction procedure will make useful
      contribution to the management of masticatory rehabilitation.

PMID- 10414089
TI  - [Initial outcome of vertical distraction osteogenesis of the atrophic alveolar
      ridge].
AB  - Besides several conventional therapeutic regimens to treat severe forms of
      alveolar ridge atrophy the distraction osteogenesis is an alternative method. We
      introduced a new technique for the treatment of alveolar ridge atrophy encouraged
      by the advantages of distraction osteogenesis in the last decade. A new technique
      called "vertical distraction osteogenesis (VDO)" has been developed by our study
      group to move dentolous and edentolous segments of the alveolar process
      vertically with a device in microplate-design. Vertical distraction osteogenesis
      was completed successfully in nine patients with segments length ranging from 6.5
      mm to 43 mm with an average of 23.7 mm. The vertical distraction rate was 9.9 mm
      on average in seven mandibular and two maxillar segments. In all cases we found
      good stability and the predicted movement of the segments. In contrast to bone
      transplantation an earlier mineralization in the vertically distracted area could
      be seen by radiological examination and biopsy. Five patients were treated with
      dental implants 12 weeks after distraction procedure. Main advantages of vertical
      distraction osteogenesis are: 1. No bone harvesting, 2. decreased resorption
      tendency, 3. lower morbidity compared with conventional techniques, 4. lower
      infection rate and 5. feasibility to insert dental implants 12 weeks after
      distraction procedure, 6. gain of soft tissue.

PMID- 10414090
TI  - [Microsurgical anastomosis of the bone transplant as implant site in the
      maxilla].
AB  - A total of 27 vascularized iliac crest segments and four vascularized scapula
      transplants were transferred to achieve masticatory rehabilitation in 31 patients
      suffering from extensive maxillary defects; 83 Branemark implants and 16 IMZ
      implants were inserted 4-8 months after the bone transplantation. The implants
      were uncovered 6-8 months after insertion. All patients were provided with a bar
      fixed, removable prosthesis. At an average insertion period of 4.5 years, the
      implant loss rate was 18.8%. The effectiveness of a combination of microsurgical
      bone transplantation and implantation in treating serious maxillary defects is
      thus demonstrated.

PMID- 10414091
TI  - [Complex reconstruction of the area of the maxilla and mid-face after radical
      tumor surgery].
AB  - The esthetic and functional restoration of facial defects is always a daunting
      challenge. The advent of free vascularized tissue transfers in combination with
      oral implants enables the surgeon to attain a high level of flexibility in the
      treatment of such defects. Due to its anatomical properties, the osteocutaneous
      scapula flap qualifies to a high degree for reconstruction purposes in the
      midfacial area. From July 1990 to February 1997, reconstruction of complex facial
      defects after oncologic surgery was performed in 17 patients using free
      vascularized tissue transfer. In four cases, a free scapula flap was used.
      Advantages and disadvantages of this technique are illustrated in these patients.
      Complete oral rehabilitation requires bony continuity of the jaws and stable
      dentition. To attain this goal, additional grafting procedures are required in
      most cases when insertion of oral implants is planned. As for the soft tissues,
      the problem of measuring the amount of tissue needed often leads to an
      overcorrection, requiring several debulking procedures.

PMID- 10414092
TI  - [Titanium magnets on implants as an aid in rehabilitation after tumor treatment].
AB  - After the resection of a tumor, many patients need a reconstruction with hard and
      soft tissue and also with sufficient dentures. Often, only little space is
      available for the implantation. Implant length and diameter have to be reduced,
      and the result is a change in the biomechanics with a possible mechanical
      overloading of the implant. We examined 52 tumor patients undergoing
      reconstruction with 189 implants. A new concept involving attachment with the
      help of magnets is presented, offering a satisfactory solution in these difficult
      cases after tumor resection and reconstruction.

PMID- 10414093
TI  - [Implants in avascular iliac crest bone transplants. Prospective study of 176
      implants].
AB  - Total and subtotal defects of the upper and lower alveolar ridge require bone
      grafts to make masticatory rehabilitation possible using alloplastic dental
      implants. The aim of this study was to establish the survival rate of dental
      implants inserted in avascular iliac bone grafts. Furthermore, we aimed to
      discover whether the prognosis of implants can be influenced by choosing one
      stage or a two-stage procedure. In a prospective study, jaw defects in 40
      patients were treated with avascular mono- or bicortical bone transplants taken
      from the right iliac wing. A total of 134 of 176 dental implants were inserted
      into an onlay osteoplasty. In 19 cases, 95 implants could have been inserted in a
      one-stage procedure, while in the other 13 cases 39 implants have been inserted
      in a two-stage procedure. One-stage insertion of implants was done in cases of
      definite primary stability only; otherwise, the two-stage method was preferred.
      After treatment, all patients were examined at least once every year. Both the
      rate of loss of implants and the time-dependent crestal bone loss were recorded.
      Of the 134 implants, 88% (i.e., 118 implants) were still in situ 6.8 years after
      abutment connection, and after 8.5 years 78% (i.e., 104 implants) were in situ.
      The interval of confidence was 95%. Projected over 8 years, 83 implants inserted
      in a one-stage procedure (i.e., 87%) were still functioning, while differently
      only 26 of the implants inserted in a two-stage procedure (i.e., 66%) were still
      functioning. The probability that implants stay in situ for a particular time
      corresponds to the results of former studies. The results of other studies with
      regard to one-stage or two-stage procedures could not be confirmed. The
      probability of total retention time for implants inserted in a two-stage
      procedure is lower than for those inserted in a one-stage procedure. The
      unfavorable starting point with the lack of primary stability of the implants in
      local bone within the two-stage procedure might be a reason for this.

PMID- 10414094
TI  - [Oral rehabilitation of tumor patients with endosseous implants. Implant success
      with special reference to peri-implant tissue].
AB  - In a prospective study, the influence of the status of the peri-implant hard and
      soft tissues on the success of enosseous dental implants in tumor patients was
      assessed. Out of 59 tumor patients with 261 implants, treated between July 1988
      and August 1996, a pool of 23 patients with 99 implants provided with dentures
      for at least 1 year was obtained. Eighteen of these patients suffered from a
      squamous cell carcinoma of the oral cavity. Seventeen patients underwent
      preoperative radiation (40 Gy). A total of 68 out of 99 implants were inserted
      into autologous bone transplanted to reconstruct the mandible. In order to assess
      the peri-implant hard and soft tissues, the Hygiene Index, the Sulcus Bleeding
      Index, the Gingiva Index, the pocket-probing depth. the peri-implant bone
      resorption, and the periotest were used. The results in the tumor patients were
      compared with the results in a pool of nontumor patients. Tumor patients had
      significantly worse periimplant parameters than nontumor patients. The peri
      implant pocket-probing depth proved to have significant influence on the success
      rate. The overall success rate was 77.8%.

PMID- 10414095
TI  - [Masticatory rehabilitation of tumor patients by endosseous implants. 10 year
      analysis].
AB  - A total of 409 implants was inserted into 83 consecutive patients, who had tumor
      related intraoral resections of soft tissue and bone. A life table analysis was
      used to determine the survival rate of the implants placed over a period of 13
      years. Log rank tests and a Cox regression analysis were employed to identify
      relevant effects of surgical parameters on implant survival. A total of 38
      implant failures were encountered. Most of the losses (n = 16) occurred during
      the first year of functional loading. The cumulative, overall survival rate of
      implants was 56.5%. Previous radiation therapy, insertion into grafted bone or
      original jaw bone, and insertion into microsurgically revascularized grafts did
      not significantly affect the survival rates. In the Cox regression, only the
      timing of implant placement was significantly related to the survival rate in the
      group of patients with bone grafts (P = 0.0197), with a lower survival rate of
      36.2% of primary inserted implants and 67.1% survival in the group with secondary
      implant placement.

PMID- 10414096
TI  - [Prosthetic-implantology defect treatment concept for oral rehabilitation of the
      mandibular area after tumor treatment].
AB  - Between 1988 and 1997, tumor resection was carried out in 18 irradiated patients
      group 1: 36-72 Gy. 83 implants) and 22 nonirradiated patients (group 2: 92
      implants) in the mandible and floor of the mouth, and these patients subsequently
      underwent mandibular endosseous implant rehabilitation. A total of 23 patients
      were treated with exclusively implant-supported prostheses, and 16 with implant
      tissue-supported constructions. Between 1988 and 1991, group 1 and 2 patients
      received implant tissue-supported prostheses (using two to four implants). Due to
      prosthesis-related pressure lesions, the strategy has now been changed. Since
      1992, group 1 patients have received exclusively implant-supported prostheses
      (using five to six implants), while group 2 patients have received implant tissue
      supported constructions (using four implants). Special criteria for the success
      of implant-supported maxillofacial prosthetics were drawn up. With an average
      follow-up period of 37 months 160 fixtures (91%) were clinically osseointegrated.
      Both types of restoration provided sufficient oral rehabilitation. However, only
      completely implant-supported prostheses avoided soft tissue ulcers. The overall
      success rate was about 77% after 7 years in group 1 and about 87% after 9 years
      in group 2. With regard to implants placed after strategy change, the 5-year
      success rate was approximately 86% (group 1) and 94% (group 2). In irradiated
      patients, an exclusively implant-supported prosthesis without any mucosal contact
      (thus avoiding soft tissue ulcers with a potential to develop osteoradionecrosis)
      should therefore be fabricated. Implant tissue-supported restoration is also
      possible in nonirradiated oral cancer patients.

PMID- 10414097
TI  - [Prognosis and prognostic factors of endosseous implants in the irradiated jaw].
AB  - In comparison to tumor patients not receiving radiotherapy, the rehabilitation of
      masticatory function after head and neck irradiation is limited due to radiation
      induced caries, radioxerostomia, and the risk of osteoradionecrosis. This study
      focused on implants in the irradiated jaw and on the evaluation of the prognosis
      and the effect of potential factors on the prognosis. The retrospective study
      covered 197 implants (47 patients) from 1988 to 1997. The implant prognosis was
      determined by implant survival statistics (Kaplan-Meier). Losses not related to
      the implants were censored. In addition, groups were formed according to factors
      potentially affecting the prognosis. The significance of differences in the
      groups relative to survival were tested using the log-rank test. Twelve (6.1%)
      implants from a total of 197 were lost due to peri-implantitis, and eight (4.1%)
      due to possible biomechanical stress. A total of 52 losses (26.4%) due to death
      of patients and two (1.0%) due to resection of the jaw were censored; 111 (56.3%)
      implants remained at recall and the average interval was 33 months. The rates of
      implant survival (Kaplan-Meier) after 1 and 2 years were 95%, after 3 and 4 years
      92%, and after 5 and 6 years 72%. The univariate analysis of group comparisons
      showed a significantly lower rate of loss after perimplant flap reconstruction (p
      = 0.036). There was no effect due to the doses of irradiation (p = 0.16),
      chemotherapy (p = 0.90), or peri-implant osteoplasty (p = 0.84). Although none of
      the implants inserted before radiotherapy had to be explanted, the implant
      survival difference in the very heterogeneous groups was not significant
      (preirradiation, n = 29; postirradiation: n = 156; p = 0.13). According to the
      literature, the rate of survival of teeth which were sound before radiotherapy (1
      year, 75%; 5 years, 45%) was distinctly lower than the survival of enossal
      implants (1 year, 95%; 5 years, 72%). The high-quality rehabilitation of
      masticatory function with implant-based protheses is the preferred method of
      treatment for irradiated tumor patients. In addition, contraindications for
      enossal implants were ruled out for all studied factors affecting prognosis.

PMID- 10414098
TI  - [Comparative studies of Branemark implants in the irradiated and not irradiated
      mandible].
AB  - A comparative study was carried out of 276 Branemark fixtures in the irradiated
      and nonirradiated anterior mandible with a mean follow-up period of 58.2 months.
      Postoperative radiotherapy with 60 Gy and 100% isodose for the anterior mandible
      using a 6-MV linear accelerator, conventional fractioning, and a split-course
      technique was administered in the irradiated patient group. HBO therapy was not
      applied. A statistical difference in the 5-year success rate between the
      irradiated and nonirradiated group was not found. Nevertheless, a significantly
      higher rate of perioperative soft tissue complications at implant insertion was
      seen in the irradiated group. The statistical analysis showed no significance for
      sex, interval between radiation and implant insertion (with a minimum of 10
      months), or type of periimplant soft tissue (regional vs. flap). The prognosis
      for implants in the irradiated mandible was, however, statistically improved (n =
      0.0035) when the healing period was longer than 4 months. Mobile periimplant soft
      tissue proved to be the main problem regardless of radiation load. Late
      complications have not been observed so far. The available results and clinical
      studies support a positive assessment of the regenerative potential of the
      irradiated mandible with regard to osteointegration of endosseous implants. A
      preceding radiotherapy up to 60 Gy should therefore not be considered as a
      contraindication for an implant/prosthetic rehabilitation.

PMID- 10414099
TI  - [Endosseous implants after tumor resection of the face].
AB  - Endosteal implants after tumor surgery of the face are helpful in reconstructing
      facial defects. A retrospective study of our patients treated using craniofacial
      implants was conducted to evaluate long-term results. A total of 128 implants
      were inserted, 110 implants in the periorbital, 12 implants in the mastoid, and
      six implants in the paranasal region; 113 implants were short craniofacial
      Branemark implants, and 15 implants were dental implants. The success rate for
      implant survival was 94.5%. Long-term results were promising and more than
      satisfactory, leading to a large indication for these endosteal implants.

PMID- 10414100
TI  - [EHBMP-2. Initial BMP analog with osteoinductive properties].
AB  - For the first time a non natural BMP-variant (EHBMP-2) with osteoinductive
      properties was produced by expression in E. coli through specific mutation of the
      amino acid sequence. The substitution of 12 N-terminal amino acids by a nonsense
      sequence results in a neglectible affinity of EHBMP-2 to the extracellular
      matrix. In vitro EHBMP-2 induces dose-dependent cartilage formation in neonatal
      muscle tissue. Single intramuscular implantation in mice results in the formation
      of an ossicle with functional active bone marrow. The size of the ossicle depends
      on the amount of implanted EHBMP-2 and can significantly be increased by the
      combination with a collagen carrier. The largest bone formation is observed after
      injection of EHBMP-2 containing collagen suspensions. In rats a stronger
      osteoinductive activity can be achieved by coupling of EHBMP-2 to collagen discs
      than by coupling natural BMP-2 to the same collagen carrier. Critical size
      defects in rats' mandibular angels can be restored by the combination of granular
      collagenous bone matrix (ICBM) with EHBMP-2. Further investigations have to show
      whether the altered pharmacokinetics of EHBMP-2 has advantages regarding its
      therapeutical use and tissue-engineering.

PMID- 10414101
TI  - [Distraction osteogenesis with a fully implantable system. Experimental study].
AB  - Distraction osteogenesis using external or intraoral devices is an established
      method for lengthening the human mandible. In this preliminary study on sheep, a
      completely implanted device for mandibular lengthening is presented. After
      osteotomy of the mandible, the electromechanical device was fixed to the mandible
      and the power and control unit were inserted subcutaneously in the neck region.
      After a healing period of 5 days, the device was activated magnetically and
      allowed calibrated distraction steps of 0.04 mm/h, achieving a total of 1.0 mm
      per day. With this method, it was possible to lengthen the mandible automatically
      over a period of 14 days without transmucosal activation. In our study, this
      newly designed internal device was successfully used for distraction
      osteogenesis, and a maximum mandibular lengthening of 13.6 mm was achieved.
      Further research is necessary to achieve progression to human clinical
      application in the near future.

PMID- 10414102
TI  - [Effect of combined carboplatin and ifosfamide with local hyperthermia on human
      mouth carcinoma in the animal model].
AB  - The therapeutic efficiency of Carboplatin (CP) and Ifosfamide (IF) with and
      without local hyperthermia (41 degrees C and 43 degrees C for 60 min
      respectively) was measured in human-derived oral squamous cell carcinomas (n =
      97) growing on the shank of nude mice. Untreated tumors showed exponential tumor
      growth. The animals were randomly assigned to 10 different treatment groups (n =
      9-10). The average tumor volume of the treated animals was compared to the
      untreated controls and statistically evaluated. CP alone demonstrated only
      significant growth delay (duration 60 days). IF (62.5 and 125 mg/kg b.w.) alone
      caused partial tumor regression. Combination of CP or IF with hyperthermia led to
      significant tumor regression. Tumor-free survival 60 days after treatment was
      observed as well after application of CP (6 mg/kg b.w.) and hyperthermia (43
      degrees C) as well as after IF (125 mg/kg b.w.) and hyperthermia (41 degrees C).

PMID- 10414103
TI  - [A new experimental model for repetitive osseous blood supply measurement].
AB  - The aim of this study was to establish a novel model permitting repetitive
      analysis of osseous perfusion over a period of 33 days using the fluorescent
      microsphere technique. After implantation of two port systems into the right and
      left carotid artery in New Zealand rabbits (n = 3), fluorescent microspheres were
      injected into the left ventricle, while blood samples for reference probes were
      taken from the descending aorta. Using seven different fluorescently labeled
      microspheres, injections were repeatedly performed starting 3 days after
      implantation (t = 0) at days 1, 3, 5, 12, 19, 26, and 33. Osseous blood flow was
      semiquantitatively analyzed by counting the number of trapped microspheres within
      the bone sections performed through the distal femur condyle (n = 8) using a
      fluorescence microscope. Over the entire observation period of 33 days,
      intraindividual variance in the number of trapped microspheres was low while
      there were marked interindividual differences between animals. The mean osseous
      perfusion in the three animals evaluated so far remained constant over the
      observation period of 33 days. The present model is the first to allow repetitive
      analysis of osseous perfusion over an observation period of 33 days. Using this
      model, the role of regional osseous perfusion can be studied under conditions
      such as impaired bone healing following radiotherapy- and/or chemotherapy,
      implantation of biomaterials, and transplantation of bone.

PMID- 10414104
TI  - One-step resection and reconstruction of the mandible using computer-aided
      techniques--experimental and clinical results.
AB  - In patients with advanced oral cancer, a resection of the mandible continuity is
      often indicated. This new method presented here uses computer-aided design and
      manufacturing (CAD/CAM) for preoperative fabrication of individual mandibular
      prostheses and their corresponding resection templates in a direct fashion
      without the need for additional physical models. In this experimental
      application, a segment of a dried mandible was resected and replaced by a
      titanium prosthesis prefabricated by CAD/CAM. It was the aim of this
      investigation to verify the processing chain and its precision, i.e., the fit of
      an individual implant, such as this. Although this new technique offers
      fascinating opportunities, possible clinical drawbacks have to be taken into
      account.

PMID- 10414105
TI  - [Quantitative diagnosis of hypernasality in cleft lip and palate patients by
      computerized nasal quality assessment].
AB  - In patients with cleft lip and palate (CLP), the assessment of velopharyngeal
      morphology and function and the quantitative analysis of perceptual consequences
      of velopharyngeal insufficiency are of major importance regarding the effective
      planning of velopharyngoplasties for speech improvement. The NasalView, a new
      instrument for the objective assessment of rhinophonia, is presented. The
      NasalView measures nasalance, the relative sound pressure level of the nasal
      signal in speech, expressed as a percentage. In order to evaluate the
      effectiveness of the computerised measurement of nasalance, 156 patients with
      surgically treated CLP were examined. The NasalView differentiated with high
      sensitivity and specificity between patients with normal nasal resonance and
      patients with varying degrees of hypernasality. To illustrate the importance of
      the NasalView for making the decision for a velopharyngoplasty, a single case is
      presented.

PMID- 10414106
TI  - [Dental MRI. Phantom study and clinical results].
AB  - Magnetic resonance imaging (MRI) is used as a diagnostic tool for special
      indications in oral and maxillofacial surgery. We describe a new MRI technique
      that presents images in a panoramic view analogous to orthopantomography. This
      technique is based on three-dimensional T1- and T2-weighted sequences. The
      familiar panoramic view in MRI provides better orientation and makes diagnosis
      faster and easier. However, the acquisition time is long (6-12 min per sequence),
      with a correspondingly high risk of motion artifacts. Moreover, the final workup
      is also time-consuming. These restrictions could be overcome by progress in
      hardware and software. There are promising indications for dental MRI.

PMID- 10414107
TI  - [Laser surgery in esthetic surgery. Review].
AB  - Since the introduction of laser therapy was developed continuously. New
      indications are possible in the aesthetic surgery. The laser is used for the
      treatment of naevi, hemangiomas, wide port-wine-stains, teleangiectasias,
      tattoos, epilations and skin resurfacing. To fulfill the expectations of the
      patients and the remands of a plastic aesthetic surgeon it is important to find
      the correct indication and choose the right laser. Vascular and pigmental
      disorders can be successfully treated with the flash lamp pumped pulsed dye
      laser. Laser containing different wave lengths are available. For the treatment
      of the aged skin the Ultrapuls-CO2-Laser offers advantages in comparison with the
      Erbium-YAG-Laser. However these lasers can not replace a facelift or
      blepharoplasty.

PMID- 10414108
TI  - Correlation of the combination of alcoholism and smoking with the occurrence of
      cancer in the oral cavity. A screening study in an endangered population.
AB  - A number of studies have previously been carried out on patients with tumors of
      the oral cavity, a majority of whom proved to be heavy smokers and heavy
      drinkers. However, we are not aware of literature reports relating to the
      converse situation: a study of alcoholics and strong smokers to establish the
      incidence of malignant processes of the oral cavity among them. Accordingly, the
      present aim was to investigate the occurrence of oral cavity lesions among 300
      subjects who were alcoholic and heavy smokers and of the opinion that they had no
      tumor. Malignant processes were detected in the oral cavity or its environment in
      2.66% of the 300 subjects, and more than 19% of them were found to harbour benign
      tumors and precancerous lesions. These investigations highlight the importance of
      screening examinations of the endangered population.

PMID- 10414109
TI  - [Results of the application of the Goettingen concept for three-dimensional
      repositioning of the maxilla in orthognathic surgery].
AB  - During orthodontic-surgical treatment, a three-dimensional repositioning of the
      maxilla is needed after Le Fort I osteotomy. The preoperatively planned and
      desired position of the maxilla could often not be implemented satisfactorily in
      the surgical procedure. Several authors described deviations of up to 15 mm in
      the vertical dimension and 5 mm in the sagittal dimension between the planned and
      the achieved position. In order to avoid this error, the "model-repositioning
      instrument" for three-dimensionally controlled cast surgery and the "three
      dimensional doublesplint method" in combination with a surgical facebow for
      actual surgery were developed. A group of 20 adult patients with severe
      dentofacial deformities were treated according to the Goettingen concept for
      combined orthodontic-surgical treatment with condylar position control with a
      surgical facebow. For each patient the position of three marked reference points
      on the maxillary dental arch under pre- and postoperative conditions was
      evaluated using superimposed tracings of lateral radiographs. These values were
      compared with the performed movements of the dental maxillary arch during cast
      surgery. It can be shown that with the new developments the planned position of
      the maxillary dental arch could be transferred from cast surgery to actual
      surgery with an accuracy of +/- 1 mm vertically and sagittally.

PMID- 10414110
TI  - [Partial loss of the auricle: multiphase reconstruction and complete preservation
      of the helix].
AB  - The loss of the auricle is a dramatic event in terms of aesthetics of the face.
      Secondary reconstruction of the ear is difficult and complicated. Therefore, a
      replantation of the amputated part should be tried. Proper securing and transport
      of the amputate is essential, in addition to the patient being sent to a
      specialized clinic. An anatomically correct form of the auricle is necessary for
      successful reconstruction of the ear. The amputated auricular cartilage is
      denuded of the skin except for the helical portion and is inserted into a
      retroauricular pocket. The helix is treated as a composite graft. After 1 to 2
      months, the replanted auricular cartilage is elevated, adapted to the remaining
      ear stump and covered with a skin graft retroauricularly. By means of a
      representative case, a replantation method is demonstrated which allows complete
      reconstruction of the helix. In consequence, the replanted ear does not show any
      deficits compared with the original state.

PMID- 10414111
TI  - [Quality of life research in patients with cleft lip and palate: preliminary
      results].
AB  - While esthetic and functional outcomes of treatment have improved for patients
      with cleft lip and palate (CLP), a CLP remains a severe problem for patients and
      relatives. To date, psychological research has dealt with issues such as
      intelligence, self-consciousness or treatment satisfaction but the long-term
      impact of a CLP on a psychological construct such as quality of life has yet to
      be explored. From a pool of 156 patients with CLP, subgroups of varying sizes
      were examined with a set of standardized questionnaires (KINDL, SF-36, Social
      Support Survey). In all patients, primary operative treatment had been
      accomplished. Long-term impact of the CLP on family life was assessed by 112 of
      the patients' parents by filling in the Impact on Family Scale. A set of
      questionnaires, especially developed for patients with CLP, was administered as
      well. For all patients who have been being treated in an interdisciplinary cleft
      center for their entire life, the results presented indicate that quality of life
      is good and within a normal range. Social support appears to be within a normal
      range. Parents report only minor long-term impact of the CLP on family life and
      family planning. Treatment satisfaction is high in the CLP patients. The
      questionnaires especially aimed at CLP patients indicate more specific problems
      mainly concerning social acceptance, where patients think the CLP had a negative
      impact. The standardized questionnaires employed so far failed to capture these
      problems. The combination of the two types of questionnaires is a sufficiently
      sensitive assessment procedure.

PMID- 10414112
TI  - [Micromorphological findings in jaw bone after radiotherapy. Confocal laser
      scanning microscopy and fluorescence darkfield microscopy studies].
AB  - Early radiation effects on human bone may lead to osteoradionecrosis (ORN).
      Direct bone cellular lesions [28] as well as fibrous degeneration of blood
      vessels [21] are considered to be pathologically relevant. Only few data on
      initial subclinical radiation effects are available. Patients were grouped
      according to the dose of radiation and clinical findings. Group 1: sound human
      bone of lower jaw, mostly collected during orthodontic surgery (n = 10 patients);
      group 2: specimens of lower jaw from patients with ORN (n = 12 patients); group
      3: specimens of lower jaw from patients with head and neck cancer who were
      preoperatively treated with 36 Gy radiation; group 4: specimens of lower jaw from
      patients with head and neck cancer (n = 9) who were treated with 60-70 Gy
      radiation. Specimens were studied by confocal laser scanning microscopy (CLSM),
      by conventional light microscopy (DL) and by fluorescence darkfield microscopy
      (DFM) after bisbenzimide staining (H 33258) of the viable cellular nuclei. For
      the correlating study of identical areas in CLSM and DL the specimens were
      prepared according to the sawing and grinding technique [8]. All the radiated
      bony specimens, regardless of the dose of radiation, showed areas of extensive or
      total loss of vitality of the osteocytes. This finding was also evident after 36
      Gy and a short interval between radiation and sample collection (group 3).
      Additionally, in CLSM micromorphologic lesions of the lamellate structure were
      seen. With these results we can confirm the loss of vitality of the osteocytes as
      an initial radiation effect as described earlier [10, 23, 28]. In addition to
      these findings, alteration of the lamellate microstructure was found in the early
      phase after radiation. The functional and mechanical significance of these
      findings should be the subject of further studies.

PMID- 10414113
TI  - [Evaluation of minimally invasive therapy of zygomatic bone fractures with a
      classification proposal].
AB  - The pre- and postoperative symptoms of zygomatic bone fractures were examined in
      a follow-up study to prepare a classification proposal. A differential indication
      for minimally invasive therapy modes was looked for with respect to this
      proposal. Therapy of isolated zygomatic bone fractures consisted in repositioning
      with a hook and miniplate fixation across the frontozygomatic suture. The aims of
      this study were clinical and radiological assessment of the repositioning result
      in terms of aesthetics and stability and quantification of the postoperative
      remission of disturbances of sensitivity of the infraorbital nerve. A total of 52
      patients were examined. After the operation (on average after 3.5 days following
      the trauma) they were followed-up postoperatively for 12 months according to a
      strict schedule. Preoperatively, 49 patients reported disturbances of sensitivity
      of the infraorbital nerve. Other symptoms, such as periorbital haematoma and
      flattening of the zygomatic prominence, were observed in 49 patients and 45
      patients, respectively. All fractures were repositioned well as assessed
      clinically and radiologically. The aesthetic result was evaluated as symmetric
      and durable in all cases. Six months postoperatively 41 patients reported normal
      sensitivity in the area of the infraorbital nerve. In only five patients (10.2%)
      was the sensitivity loss persistent throughout the entire follow-up period.
      Patients with primarily lacking diplopia developed neither eye motility
      disturbances nor postoperative enophthalmus in the following period. It can be
      concluded that the treatment of an isolated zygomatic bone fracture which
      satisfies aesthetic and functional requirements is possible by reposition and
      fixation with one miniplate at the lateral orbital rim. An additional
      osteosynthesis at the infraorbital rim or at the zygomaticomaxillary crista is
      not necessary. A routine revision of the orbital floor is only indicated in cases
      of preoperative diplopia. A zygomatic bone fracture connected with diplopia
      should be classified as combined zygomatic-/orbital floor fracture.

PMID- 10414115
TI  - [Oral manifestations of Lpngerhans' cell histiocytosis. Therapeutic strategies
      involving oral and maxillofacial surgery].
AB  - The definition of Langerhans' cell histiocytosis (formerly known as histiocytosis
      X) includes the clinical syndromes Hand-Schuller-Christian syndrome, Abt-Letterer
      Siwe syndrome and eosinophilic granuloma, which in the past were considered
      separate entities. The prognosis of this disease varies between "favorable" and
      "infaust", depending on the age of the patient at first manifestation and the
      number of the organs involved. With the aid of various prospective clinical
      studies, suitable therapeutic schemes are currently being sought for. In the
      course of this search chemotherapy is gaining in significance and radiation
      therapy is merely playing a minor role. The surgical status has not changed
      inasmuch as it concerns solitary "operable" lesions. Based on three case reports
      from our clinic, different courses of illness are described. Oral manifestations
      of a Langerhans' cell histiocytosis have to be considered, especially with regard
      to therapy-resistant parodontopathies or with radiologically conspicuous,
      unexplained osteolysis. The immunohistological and electronic microscopic
      examinations confirm the diagnosis. The etiology of the disease has still not
      been clarified.

PMID- 10414114
TI  - [Examining patients with facial skull fractures from an etiological and legal
      perspective].
AB  - Maxillofacial traumas are common and often associated with other injuries. From a
      forensic point of view, it is often necessary to relate the traumatic event to
      the subsequent injuries. The aim of this study was to explore the etiology of
      maxillofacial injuries due to objective signs and the anamnestic history of
      patients. In a prospective study over a 1-year period, all patients presenting
      with mandibular and midface fractures seeking treatment at the University Medical
      Center in Munster. Germany, were investigated. Demographic data, patient history,
      and pattern and etiology of injury were recorded, along with evaluations of the
      patients' descriptions. Thorough clinical and radiological investigation was
      performed and photographic records were taken. In our study, 122 patients, with a
      male to female ratio of 2:1 were included. The mean age was 30.7 +/- 13.4 years.
      Assault was the most common etiology (40%), followed by traffic accidents (29%)
      and falls (17%). Alcohol was reported to play a role in 40% of all injuries.
      There was no difference in the number of patients with mandibular or midface
      fractures. In 75%, maxillofacial fractures were associated with other injuries.
      The patients' descriptions of the orofacial traumas seemed to be highly. For age,
      anatomical location, concomitant injuries, and other signs of trauma, we found no
      statistical association with the underlying etiology.

PMID- 10414116
TI  - [Preliminary results of the use of resorbable plates and screws in craniofacial
      surgery].
AB  - In ten patients with craniosynostoses resorbable plates and screws (Lactosorb)
      consisting of poly-L-lactic acid (82%) and poly-glycolic acid (18%) were used to
      stabilize the segments after frontoorbital advancement. As our experience
      increased, an exact adaptation of the plates and simple handling proved to be
      possible. The plates were stable enough to retain a favorable functional and
      aesthetic result after redraping the soft tissue envelope. In one patient with
      Chotzen's syndrome the intended use of the resorbable material was abandoned: the
      thin osseous structures did not offer enough primary stability to the high pitch
      of the screws. During an observation period of up to 21 months no infection,
      exposure, instability or dislocation was observed. The clinical use of the
      resorbable material in frontoorbital advancement proved to be a stable method of
      segment fixation if the bone was of sufficient thickness. These promising
      preliminary results will have to observed in a larger group and over a longer
      period of time.

PMID- 10414117
TI  - [Photodynamic therapy: ICG angiography findings].
AB  - PURPOSE: Photodynamic therapy (PDT) has been shown to provide immediate occlusion
      of choroidal neovascularization (CNV), followed by recurrent leakage after single
      PDT in the majority of the cases after 3 months. Indocyanine green angiography
      (ICG-A) was used to evaluate completeness of CNV occlusion, effects on
      physiological choroid and patterns of CNV recurrence. METHODS: ICG-A was
      performed using a confocal laser scanning ophthalmoscope (HRA) before PDT at 1
      week, 4 and 12 weeks following PDT. Twenty patients with single and 10 patients
      with repeated PDT treatments with administration of benzoporphyrin derivative and
      radiant exposures between 50 and 150 J/cm2 were evaluated. RESULTS: Before PDT
      well-defined CNV was detectable during early ICG-A in all lesions. Depending on
      the number of treatments, CNV was absent in early phase ICG-A in 46-83%. CNV
      reappeared at week 4 in many and at 12 weeks in 77 (66%) of the cases. The
      treated area regularly showed hypofluorescence, which persisted until week 12.
      The intensity of choroidal hypofluorescence showed wide interindividual
      variability. Recurrence may originate from persistent feeder vessels. CONCLUSION:
      With ICG-A we demonstrated that PDT induces hypofluorescence of CNV and choroid
      possibly due to perfusion changes or blockade phenomena. Recurrence may be due to
      reperfusion of the preexisting CNV or regrowth from feeder vessels.

PMID- 10414118
TI  - [Decreased serum level of free bioavailable IGF-I in patients with diabetic
      retinopathy].
AB  - BACKGROUND: Growth factors like IGF-I have been implicated in the pathogenesis of
      diabetic retinopathy. To investigate the role and bioavailability of IGF-I we
      measured not only total but also free serum levels of IGF-I in diabetic patients.
      METHODS: A total of 159 patients with and without diabetic retinopathy were
      investigated (60 diabetic patients without and 99 with clinically and
      angiographically diagnosed diabetic retinopathy). One hundred ten healthy
      volunteers served as controls. The data were analyzed by Student's t-test,
      analysis of variance and correlation; P < 0.05 was considered statistically
      significant. RESULTS: Diabetic patients with retinopathy showed significantly
      lower serum levels of free IGF-I than diabetics without retinopathy. Free IGF-I
      was negatively correlated with glycosylated hemoglobin 1c. IGFBP-3 levels were
      diminished in type 2 patients with diabetic retinopathy, while type 1 patients
      with diabetic retinopathy showed higher IGFBP-1 levels. CONCLUSION: Diabetic
      patients with retinopathy showed significantly reduced serum levels of free IGF
      I. Low IGF-I was associated with poor metabolic control.

PMID- 10414119
TI  - [Diode laser thermokeratoplasty. Initial clinical experiences].
AB  - PURPOSE: Pulsed holmium lasers are currently used to correct hyperopia by means
      of laser thermokeratoplasty (LTK). Series of microsecond laser pulses are applied
      with a high repetition rate to induce shrinkage of corneal collagen fibers. The
      pulsed energy application results in intrastromal temperature peaks of up to 200
      degrees C. A continuously emitting laser diode can--as we demonstrated recently
      in an invivo study on minipigs--be used for LTK and may be of advantage because
      the temperature rise is more steady. The aim of this study was to examine the
      safety, amount, and stability of hyperopic correction of diode LTK on blind human
      eyes. METHODS: We used a laserdiode that was set to continuously emit light at
      lambda = 1.854 microns/mu a = 1.04 mm-1 (group I, n = 4) or 1.87 microns/mu a =
      1.92 mm-1 (group II, n = 4). Radiation energy was 100 to 150 mW for 10 s per
      coagulation. Eight coagulations on a single ring (group I) and 16 coagulations on
      a double ring (group II) diameter were applied in the cornea concentric to the
      entrance pupil by means of a vacuum-fixed application mask (group I =
      conjunctival fixation; group II = corneal fixation) and a handpiece with a
      focusing optic. Preoperatively as well as 1 week, 1, 2, 3, 6 12 and 18 months
      postoperative ophthalmologic controls were performed and the corneal refractive
      power was measured. RESULTS: In group I initial refractive changes of up to +4.9
      D were achieved (1 week postoperative). However, due to the great penetration
      depth of the laser irradiation, large endothelial defects resulted beneath the
      stromal coagulations. In group II an initial refractive change of up to +6.8 D
      was achieved and as a result of the reduced penetration depth, the endothelial
      cell damage was much reduced. Partial regression of the refractive effect
      occurred in all subjects, which continued in higher refractive changes during the
      2nd postoperative year. The refractive effect at 12 months was +0.6 to +1.5 D in
      group I and +0.9 to +5.7 D in group II. At 12 months the induced astigmatism was
      0.5 to 2.2 D in group I and 0.3 to 1.6 D in group II. No serious adverse effects
      were noticed. CONCLUSION: A continously emitting laser diode working at a
      wavelength of 1.87 microns can be used to correct hyperopia by means of LTK
      safely and effectively. Regression occurs predominantly in the first 6
      postoperative months. Further studies must be conducted to determine the
      importance of patient inherent parameters such as age in establishing a nomogram.

PMID- 10414120
TI  - [Combined phacoemulsification and goniotrepanation in primary chronic open angle
      glaucoma and classical pseudoexfoliation glaucoma].
AB  - BACKGROUND: Combined glaucoma and cataract operation has been demonstrated to be
      effective in controlling IOP and increasing visual acuity. Because of the
      differences between patients with primary open-angle glaucoma (POAG) and
      pseudoexfoliation glaucoma (PXEG), for cataract and glaucoma surgery alone we
      evaluated the effects and complications for simultanous surgical management.
      PATIENTS AND METHODS: In a retrospective study 103 patients were examined who
      underwent a combined phacoemulsification and goniotrephination between January
      1993 and January 1997 and had no surgery before (110 eyes with POWG, 22 eyes with
      PXEG). RESULTS: The average age in the POAG group (75.1 +/- 8.7 years) was
      significantly less than in the PXEG group (79.3 +/- 5.9 years) (P < 0.05). The
      mean preoperative IOP in PXEG (31.8 +/- 10.3 mmHG) was significantly higher than
      in POAG (25.0 +/- 6.4 mmHg) (P < 0.0005). Due to the combined surgery the mean
      intraocular pressure decreased in both groups < 10 mmHg (days 1 and 7). PXEG had
      a significantly higher IOP at day 3 than POAG (12.3 +/- 8.4 mmHg versus 8.5 +/-
      5.7 mmHg) (P < 0.05) and developed after combined operation IOP peaks > 25 mmHg
      into a significantly higher level (P < 0.05). Moreover, zonulolysis, rupture of
      the posterior capsule, vitreous loss and persistence of inflammatory response
      occurred more often in PXEG, but there was no significant difference compared to
      POAG. CONCLUSION: PXEG has an higher incidence of typical problems of
      phacoemulsification, a temporary increase of IOP and prolonged inflammation after
      combined cataract and glaucoma surgery than POAG, but there is a similar risk
      compared to a single procedure.

PMID- 10414122
TI  - [Microperimetry and reading saccades in retinopathia solaris. Follow-up with the
      scanning laser ophthalmoscope].
AB  - Patients with solar retinopathy often complain of minute central scotomas and are
      handicapped when reading. The purpose of this study was to verify scotomas that
      are too small to be detected by standard perimeters and to analyze patients'
      reading patterns. METHODS: Nineteen patients (12 female, 7 male, aged 5-46 years)
      with acute solar retinopathy after watching a solar eclipse on 12 October 1996
      underwent scanning laser ophthalmoscope (SLO) microperimetry within 10 days after
      exposure using stimulus size Goldmann I (0.11 degree) with the 20 degrees field.
      Size and depth of scotomas were measured. Eye movements during reading were
      recorded on videotape. Follow-up was at 1 and 6 months. RESULTS: Thirty-one eyes
      (7 patients unilateral, 12 bilateral) showed scotomas. Four eyes showed anatomic
      changes in the retinal pigment epithelium but no functional loss. VA was 0.16 to
      0.5 in 5 eyes, 26 had VA of 0.8-1.2. Scotomas could be detected in all eyes with
      subjective impairment. Scotoma size varied from 0.3 to 1.7 degrees (1 patient 6
      degrees). Forty-four percent were deep scotomas (0 dB). All defects improved at 1
      and at 6 months; 25% were no longer detectable. Reading speed was reduced in 75%
      of eyes (42% at 6 months): 200-560 signs/min, median: 510, normal > or = 660 (at
      6 months: 350-920 signs/min, median 670). This was especially due to increased
      number of regressions (in 81% of eyes, 21% at 6 months). The frequency and width
      of saccades were no different from normal subjects. CONCLUSION: Minute scotomas
      (diameter = 0.3 degree) can be detected with the SLO. All patients showed
      objective improvement of their field defect up to 6 months, even when this was
      not noted by the patient or thought to be due to habituation. Small scotomas can
      dramatically reduce reading performance.

PMID- 10414121
TI  - [Therapy refractory unilateral chronic blepharokeratoconjunctivitis as the chief
      manifestation of auto-aggression syndrome. Clinico-histopathologic findings].
AB  - Autoaggressive syndromes as causes of diseases underlying chronic blepharitis and
      keratoconjunctivitis that are refractory to treatment are often difficult to
      recognize. PATIENTS: Three female patients (age 21, 25, 41 years) and one male
      patient (age 42 years) had suffered from a right-(4x) or left-(1x) handed
      treatment-refractory blepharokeratoconjunctivitis for 1, 2, 11 and 30 months
      prior to admission. In each case more than 5 ophthalmologists and 2-6 eye
      hospitals had been consulted, and extraocular surgery had been performed 1-4
      times. RESULTS: Patients presented with a visual acuity of 0.3 p (1x), 0.1 (1x),
      FC (1x), HM (1x). In three patients contact eczema of the facial skin and lids
      and a corneal pannus were observed; in two patients we saw purulent
      pseudomembranous and in two patients chronic cicatrizing keratoconjunctivitis.
      Conjunctival smears grew P. aeruginosa, and S. aureus; impression cytology showed
      infiltration with neutrophils and epithelial keratinization; histopathology
      indicated chronic inflammatory, partly purulent subepithelial and stromal
      conjunctival infiltrate with hyper- and parakeratosis fibrous strands and
      epithelial cell loss; the lower lids showed parakeratosis, focal necrosis,
      intercellular edema and a lymphohistiocytic round-cell infiltrate. Furthermore,
      multiple allergies to antibiotics and preservatives (4x), lacerations of the arms
      and legs (2x) and an irritative-toxic dermatitis (1x) were substantiated. In the
      patients who agreed to a psychiatric consultation, somatized-agitated longing for
      care combined with a dependent and infantile personality (1x) and reactive
      depression (2x) were verified. CONCLUSIONS: In patients suffering from treatment
      refractory unilateral chronic blepharokeratoconjunctivitis correlated with the
      hand, one must take into consideration the fact that other factors may be
      involved: possible exacerbation prior to examinations; multiple inpatient
      diagnostic and surgical procedures in different locations; histopathological
      mixed inflammatory patterns; and psychiatric syndromes.

PMID- 10414123
TI  - [Endoscopic laser dacryoplasty. Methodology and outcome after 3 months].
AB  - BACKGROUND: After performing endoscopy of the lacrimal passage, the endoscopic
      system can be connected to an erbium-YAG laser if the indications are
      appropriate. MATERIALS AND METHODS: In a bi-center study we performed laser
      dacryoplasty in 53 cases out of 261 endoscopy procedures (18 stenoses of the
      canaliculi, 19 stenoses of the sac, 9 stenoses of the nasolacrimal duct, 9
      restenoses following DCR). In 35 cases an examination was done and in all 53
      cases the results were obtained by means of a questionnaire. RESULTS: Epiphora
      and irrigation were improved in more than 75%. CONCLUSION: Suitable indications
      are small stenoses in the sac or duct membranes following DCR. Laser dacryoplasty
      is a promising method, but more studies still need to be conducted to obtain long
      term results. The technical system must also still be improved to make it easier
      to handle.

PMID- 10414124
TI  - [r-tPA in keratoplasty a chaud. Report of 50 patients].
AB  - BACKGROUND: Fibrinolytic treatment using recombinant plasminogen activator (r
      tPA) has been reported in cataract surgery; however, reports are lacking with
      respect to complex surgical interventions including keratoplasty because of
      anterior segment infections. PATIENTS AND METHODS: This report deals with a
      prospective study comprising 50 patients (50 eyes) suffering from a serpent ulcer
      treated by keratoplasty a chaud. r-tPA (25 micrograms) was instilled
      intracamerally at the end of surgery in 25 eyes. RESULTS: The 25 eyes treated
      with r-tPA were subsequently less inflamed than the control population (decrease
      in inflammatory cells 1.5 days vs 7 days, fibrin reaction 1x vs 12x), had highly
      significantly better visual acuity and there was significantly reduced inpatient
      hospitalization (median 9.9 vs 19.3 days). No hemorrhages were observed in either
      population; medically treated infection recurrences (S. aureus, C. tropicalis,
      acanthameba) were observed in 3 and primary graft failure or rejection in both
      populations 3x. CONCLUSIONS: This study showed that perioperative application of
      r-tPA had a beneficial effect. This therapeutic avenue should be further
      evaluated in a randomized, double-masked multicenter study.

PMID- 10414125
TI  - [Secondary glaucoma caused by iris tumor. Iris metastasis of adenocarcinoma of
      the breast].

PMID- 10414126
TI  - [Legal aspects of postoperative complications].

PMID- 10414127
TI  - [Intraocular gases in vitreous and retinal surgery. I: Basic principles].

PMID- 10414129
TI  - Death by spontaneous combustion: Charles Dickens and the strange case of Mr.
      Krook.

PMID- 10414128
TI  - Holy Grail, sliding scale, and refusal as symptom: competency determinations for
      medical and psychiatric patients.

PMID- 10414130
TI  - A little pregnant, or not at all?

PMID- 10414131
TI  - Have we come a long way, baby? American abortion at the open and close of the
      twentieth century.

PMID- 10414132
TI  - Waiting for Melissa.

PMID- 10414133
TI  - Osler's "L'envoi" revisited: the ideal of idealism.

PMID- 10414134
TI  - Questions and reflections.

PMID- 10414135
TI  - Transmission of genetic defects.

PMID- 10414136
TI  - Managed care and psychiatric services.

PMID- 10414137
TI  - The patient and public policy.

PMID- 10414138
TI  - The patient and public policy.

PMID- 10414139
TI  - The patient and public policy.

PMID- 10414140
TI  - The patient and public policy.

PMID- 10414141
TI  - [Influence of pulmonary hemodynamics on right ventricular ejection fraction in
      chronic obstructive pulmonary disease].
AB  - Right ventricular dysfunction is common in patients with chronic obstructive
      pulmonary disease. Right ventricular function might be influenced by the
      afterload, which depends on pulmonary artery pressure (PAP) and pulmonary
      vascular resistance (PVR). To evaluate the influence of the right ventricular
      afterload on right ventricular performance, we investigated 30 patients with
      chronic obstructive pulmonary disease without clinical signs or history of left
      heart failure or coronary heart disease. The study includes lung function tests,
      analysis of blood gases and right heart catheterisation. RV function was assessed
      by a thermodilution technique using a pulmonary artery catheter equipped with a
      rapid response thermistor (produced by Baxter, USA). There are 9 patients with
      normal, 12 with latent and 9 with fixed pulmonary hypertension. Median RVEF was
      measured to be 33.3% (19-44%). There was a significant correlation between RVEF
      and PAP (r = -0.66; p < 0.0001) and RVEF and PVR (r = -0.54; p < 0.0018). RVEF
      was not directly influenced by lungfunction or pulmonary capillary wedge pressure
      (PCWP). Under treadmill exercise RVEF and cardiac index increased without a
      change of PCWP. A low RVEF at rest seems to be a predictive value for a reduced
      exercise capacity. A reduced RVEF has a predictive value of pulmonary
      hypertension with a sensitivity of 66% in patients with unstable and 89% in
      patients with lasting pulmonary hypertension. In a subgroup of 6 cases treadmill
      exercise led to a RVEF decrease. These patients showed no difference in
      afterload, blood gases or lung function-tests compared with the total group. In
      conclusion, right ventricular ejection fraction seems to be influenced by PVR and
      PAP which determinate the right ventricular afterload. The validity of the method
      depends on the severity of pulmonary hypertension, and hence measurement of RVEF
      might not provide a reliable estimation of pulmonary arterial pressure in
      patients suffering from mild to moderate pulmonary hypertension.

PMID- 10414142
TI  - [Sleep and the treatment of bronchial obstruction].

PMID- 10414143
TI  - [Reference values of hemosiderin-laden alveolar macrophages in bronchoalveolar
      lavage in children].
AB  - Pulmonary haemosiderosis is a rare disease of unknown etiology, mainly affecting
      children and adolescents. Pulmonary haemosiderosis may occur in association with
      several respiratory or other disease (Lupus erythematosus, Goodpastures
      syndrome). Delay in diagnosing can lead to fatal complications. BAL appears to be
      the method of choice to detect haemosiderin-laden macrophages. No reference
      values are available for children to date. 64 bronchoalveolar lavages were
      performed to establish reference values of haemosiderin-laden macrophages in
      children. Less haemosiderin was found in children compared to adults, and hence a
      new haemosiderin score was established for paediatric patients. Compared to
      healthy children, no elevated haemosiderine levels were found in children with
      chronic pulmonary disease such as bronchiectasis or chronic aspiration caused by
      gastro-oesophageal reflux. Therefore even a mildly increased amount of
      haemosiderin-laden macrophages in children requires medical attention.

PMID- 10414144
TI  - [Therapy of malignant pleural mesothelioma--a permanent dilemma].
AB  - Although still a rare tumour, incidence of malignant pleural mesothelioma (MPM)
      is increasing. The cause, with the exception of some not clearly identified
      environmental factors, is asbestos. The prognosis is influenced by the stage of
      the disease. A new staging system has not modified the fact that staging is still
      a clinical problem. Tumour volume, histological subtype, sex and performance
      score are some of the important prognostic factors. Most patients (pts) are
      diagnosed in advanced stages only. Surgery will only cure or significantly
      prolong survival in the rare event of an early stage with no survival advantage
      for pleuropneumonectomy over pleurectomy. In early stages adjuvant immunological
      treatments (e.g. interferon or interleukin) may be of some value. Adjuvant first
      generation photodynamic therapy is not superior to operation only. The majority
      of patients, however, are diagnosed in advanced stages, where neither radiation
      nor chemotherapy, nor multimodality treatments can significantly alter the poor
      prognosis. There is no standard therapy, and no advantage to poly- versus
      monochemotherapy. Chemotherapy, however, seems to have some palliative effect in
      symptomatic patients, as well as radiotherapy, the latter also as prophylaxis
      against tumour invasion after puncture and thoracoscopy.

PMID- 10414145
TI  - [The relative importance of humoral tumor markers in the diagnosis and therapy of
      primary bronchial carcinoma and pulmonary metastasis].

PMID- 10414146
TI  - [Invasive diagnosis of coronary heart disease in patients over 75 years old].
AB  - Between January 1, 1993, and August 31, 1995, 268 patients over 75 years
      underwent coronary angiography at the University Hospital of Bern. Their clinical
      reports were analyzed in order to determine whether invasive diagnosis of
      coronary artery disease (CAD) is justifiable also in the elderly considering
      risks and complications. The main indication for coronary angiography were
      symptoms of ischemic heart disease. Twenty-nine underwent the procedure for
      planned cardiac surgery, mostly valve replacement. In 79% of patients, coronary
      angiography revealed CAD. In the remaining 21% there were no significant coronary
      stenoses, but 82% of them had valvular heart disease. Only 4% had neither
      coronary nor valvular heart disease. Following coronary angiography 63% of
      patients had a therapeutical intervention: 24% coronary angioplasty (PTCA), 13%
      bypass-grafting, 17% valve replacement, 8% combined surgery (revascularization
      and valve-replacement), and 1% another intervention. Four percent had no cardiac
      disease, 1% died before a planned surgery. The remaining 32% were continued on
      medical therapy. As indicators of appropriateness and success of the invasive
      procedure the rates of complications and the duration of hospitalization were
      analyzed. The incidence of deaths, myocardial infarctions, cerebral
      complications, and arrhythmias was five to ten times higher for cardiac surgery
      than for PTCA or conservative treatment. Invasive diagnosis and therapy of CAD in
      patients over 75 years can nevertheless be reasonable and successful if the
      decision is taken carefully considering risk factors and concomitant disease.

PMID- 10414147
TI  - [Diagnostic and therapeutic difficulties with tertian malaria].
AB  - Diagnosis of malaria tertiana is not uncommonly missed or delayed because of a
      long incubation period, relapses after an unnoticed primary attack or due to
      suppressed parasitemia under antibiotics or antimalarials. The presently
      available rapid tests are not suitable for diagnosis of malaria tertiana. Malaria
      tertiana acquired in Southeast Asia carries a considerable risk of resistance to
      chloroquine. In this situation mefloquine is used in first place at total dose of
      1000-1500 mg. Relapse of malaria tertiana even after primaquine have been
      described in travellers returning from the tropics. The efficacy of primaquine
      can be improved by raising the dose. Hereby an increased risk of hemolysis in
      concomitant glucose-6-phosphate-dehydrogenase deficiency and, more commonly,
      gastrointestinal side effects have to be considered.

PMID- 10414148
TI  - [Otorhinolaryngologic causes of headache].
AB  - Headache is very common and it has many different causes. It can be a
      challenging, difficult, and interesting diagnostic problem. The knowledge of the
      complex sensory innervation of the ear, nose and paranasal sinuses is important.
      Heterotopic or referred pain must be differentiated from homotopic pain that is
      experienced at the point of injury. The nervous pathways of heterotopic otalgia
      are shown. From the otolaryngologist's point of view, there are multiple causes
      for the frequent symptom of facial pain and headaches: headaches due to ear
      diseases: pain extending to the ear region, with special regard to "referred
      otalgia" involving the cranial nerves V, IX, X; facial pain due to
      temporomandibular dysfunction; rhinological causes of facial pain and headaches,
      including posttraumatic trigeminal neuralgia and "facial sympathalgies"; the
      syndrome of the elongated styloid process. The quality of pain of the most common
      rhinological and otological diseases is reported. A detailed history and a
      carefully performed and focussed physical and laboratory evaluation will aid in
      the complex differential diagnosis.

PMID- 10414149
TI  - [Confusional states in old age].

PMID- 10414150
TI  - [Headaches in a 26 year old woman. Sinus venous thrombosis in the sinus sagittal
      superior, at the confluens sinuum and sinus transversus].

PMID- 10414151
TI  - [UV exposure in Switzerland: time- and topography-associated factors important
      for the skin].
AB  - The intensity of UV-A and UV-B-radiation in Switzerland shows big differences
      that result from the various altitudes, the season and the time of the day.
      Additionally the intensity of UV-radiation is influenced by other factors like
      aerosols, cloudiness and ozone. In higher altitudes there is an additional
      enhancement by reflection of snow. The most important consequences of the UV
      radiation for the population are, however, relevant in spring and summer time
      during the bathing season and during the late winter season for ski tourists. On
      a day with a clear sky in summer the UV-radiation can reach maximum values for UV
      A of 45 W/m2 and for UV-B of 0.175 W/m2. The ratio of UV-A/UV-B shows an annual
      course with a maximum in winter of about 500 and a minimum of about 220 in
      summer. The possible effects on health by extensive UV-exposition are
      photoageing, skin cancer, inflammation processes and cataract. In Switzerland
      about 5000 new melanoma cases in men and about 4000 in women occur per year. In
      contrast to other environmental factors like pollen UV-radiation has the big
      advantage that the personal exposition can be controlled. Therefore, it is very
      essential that the general rules of a judicious behaviour such as avoiding the
      sun at noon, always wearing a hat, shirt and trousers as well as sunglasses with
      UV-filter are often reiterated.

PMID- 10414152
TI  - [Drug allergy].
AB  - Drug reactions can be differentiated into immediate and delayed types. Immediate
      type reactions are life threatening or manifest themselves as urticaria
      /angioedema, asthma or anaphylaxis. They may be mediated by specific IgE
      antibodies or more frequently by non-immunological mechanisms (so-called
      "pseudoallergies"). Delayed type reactions are the most frequent immunological
      reactions. They appear mostly as maculo-papulous exanthema. Rarely they may
      become life threatening and lead to fever and involvement of visceral organs. In
      life threatening reactions further exposure to the causative drug should be
      strictly avoided. If the diagnosis of a drug allergy and of the causative drug is
      insecure, further allergological investigations are justified.

PMID- 10414153
TI  - [Why are infants prone to respiratory failure?].

PMID- 10414154
TI  - [I have a backache].

PMID- 10414155
TI  - [Extensive eosinophilic pulmonary infiltrates in a depressive patient treated
      with maprotiline].
AB  - A 74 year old man developed progressive dyspnea under treatment with the
      tetracyclic antidepressant maprotiline for three months. A chest x-ray revealed
      extended pulmonary infiltrates. Marked eosinophilia of the periperal blood was
      found (up to 2300/microliter). Rapid clinical and radiological improvement was
      observed solely by withholding the drug. The eosinophil count retourned to normal
      within a few weeks. The possible pathogenesis is discussed and the literature
      reviewed.

PMID- 10414156
TI  - [Membranous glomerulonephritis].

PMID- 10414157
TI  - [How well do laboratory values correlate with histological activity of chronic
      hepatitis B infection?].

PMID- 10414158
TI  - The physically disabled in Singapore.

PMID- 10414159
TI  - Cause, treatment and outcome of patients with life-threatening haemoptysis.
AB  - BACKGROUND: Massive haemoptysis is a life-threatening situation which requires
      immediate medical attention and intervention. We reviewed 23 patients with life
      threatening haemoptysis to document the cause, describe the treatment of these
      patients and to determine which form of treatment had a better outcome. DESIGN:
      Retrospective case study. METHODS: Consecutive patients were reviewed and data
      collected for the underlying cause, treatment and outcome of patients with life
      threatening haemoptysis. RESULTS: Out of 23 patients, nine patients had active
      pulmonary tuberculosis and nine patients had post-tuberculous lung disease.
      Fifteen patients underwent bronchial embolisation, one patient had surgical
      resection and seven patients had received medical treatment. Five patients
      required intubation. Bronchial embolisation was significantly better than medical
      treatment at immediate cessation of haemoptysis (p < 0.05). Three (13%) patients
      died from haemoptysis. Follow-up duration averaged 16 months. CONCLUSIONS: The
      most common causes of haemoptysis were pulmonary tuberculosis and post
      tuberculous bronchiectasis. Urgent bronchial artery embolisation was better at
      immediate cessation of haemoptysis than medical treatment.

PMID- 10414160
TI  - Graves' Disease during pregnancy--results of antithyroid drug therapy.
AB  - AIM OF STUDY: To assess the maternal and fetal outcome of pregnancies in
      thyrotoxic women. METHOD: Thyrotoxic women who conceived while on treatment or
      who conceived within two years after stopping treatment, were recruited into the
      study. The antithyroid drugs (PTU and methimazole) dosage were adjusted to keep
      T3 and T4 within the upper normal range for these women. Cord blood and baby's
      blood (between days 4 and 10) were assayed for T3, T4 and TSH. RESULTS: Thirteen
      women (16 pregnancies) required antithyroid drugs during pregnancy. The drug
      dosage remained the same during pregnancy in 8 women while it was increased in 5
      women and reduced in 3 women. One woman who was in remission at the time of
      conception remained euthyroid throughout her pregnancy. There were 14 spontaneous
      vaginal deliveries and 3 Caesarean sections. One baby had a small VSD while no
      other congenital malformations or perinatal death occurred. CONCLUSIONS: Drug
      therapy can adequately control thyrotoxicosis during pregnancy and improve
      maternal and fetal outcome.

PMID- 10414161
TI  - Minimally invasive direct coronary artery bypass.
AB  - BACKGROUND: Minimally invasive cardiac surgery is a new and promising approach to
      the treatment of coronary artery disease allowing surgery to be performed through
      smaller incisions with lesser morbidity. METHODOLOGY: From November 1995 to
      February 1997, ten minimally invasive direct coronary artery bypass (MIDCAB)
      grafts were performed. The left internal mammary artery was used to bypass the
      left anterior descending coronary artery (LAD) through a limited left anterior
      thoracotomy. PATIENTS: There were seven males and three females and their ages
      ranged from 42 to 72 years (mean = 60 years). Two patients had prior
      interventional procedures. Cardiopulmonary bypass was used in the first two
      patients. Two patients were converted to conventional surgery early in the
      series. RESULTS: There was no mortality nor major morbidity. Mean post-operative
      hospital stay was seven days. To date, three patients have had post-operative
      angiography confirming the patency of the left internal mammary artery to LAD
      anastomosis. CONCLUSION: Early results of the MIDCAB procedure are encouraging.
      However, the definitive place of such procedures awaits longer term follow-up.

PMID- 10414162
TI  - Is there a role for the obstetric flying squad in Peninsula Malaysia?
AB  - BACKGROUND: The Obstetric Flying Squad (OFS) has been operating in Peninsular
      Malaysia for over three decades. In the light of current controversies regarding
      its role in modern day obstetric practice, its status in Malaysia over the last
      12 years is reviewed. METHOD: Statistics from three Malaysian states (Kelantan,
      Trengganu and Malacca) were reviewed with regard to the numbers and places of
      delivery as well as OFS and ambulance call out rate (per 1000 deliveries). These
      statistics were obtained from the annual reports of the three state hospitals.
      Improvement in socioeconomic development was reviewed in order to study its
      impact on the requirement of OFS service. RESULTS: The last decade has witnessed
      a marked decrease in home deliveries, a higher proportion of high risk
      pregnancies delivering under medical supervision and a dramatic increase in the
      availability of telecommunication, transport and rural medical facilities. The
      OFS callout rate has fallen significantly, though the principal indication for
      calls were due to post-partum haemorrhage and retained placenta. The average time
      taken to reach a patient is 47 minutes for an OFS call compared to 26 minutes for
      an ambulance call in Kelantan. CONCLUSIONS: Given the disadvantages of longer
      response time and the requirement for a skilled specialist to man the service,
      the OFS service can be completely replaced by the ambulance service (with
      training of drivers in first aid) in the general Malaysian setting. However,
      there may still be a limited role for the OFS in the isolated rural communities
      where access by land transport is extremely difficult.

PMID- 10414163
TI  - Skin stapled bowel anastomosis in a canine model.
AB  - AIM OF STUDY: The aim of this study is to compare the safety and cost
      effectiveness of the use of staples designed for skin closure in the construction
      of colonic anastomoses. METHOD: Twenty healthy dogs were prospectively randomised
      to either skin stapled or sutured anastomosis. The ascending colon was transected
      and reanastomosed. This segment was excised and used to test early bursting
      strength. There was no significant difference between the two groups. The ends of
      the colon were reanastomosed. RESULTS: The time taken to perform the anastomosis
      and the cost of the suture or staples were noted. The time taken for the stapled
      anastomosis was significantly faster (p < 0.001) with a mean of 7.95 minutes
      versus a mean of 23.5 minutes for the handsewn anastomosis. The cost was also
      significantly less (p = 0.18) with a mean of SGD17.85 compared to a mean of
      SGD21.15 for the handsewn anastomosis. Two weeks later, the dogs were sacrificed
      and the late bursting pressures were tested and no significant difference was
      found between the two groups. The anastomotic site was then sent for histological
      examination. The four animals, one in the handsewn group and 3 in the skin
      stapled group, dying prior to sacrifice, were subjected to post-mortem.
      CONCLUSION: The results show that skin stapled anastomoses are easy to learn and
      perform and may constitute a viable alternative to hand suture techniques.

PMID- 10414164
TI  - Haematological and plasma electrolyte changes after long distance running in high
      heat and humidity.
AB  - AIM OF STUDY: To investigate the acute effects of an 18 km run on the
      haematological and plasma electrolyte parameters, in recreational runners under
      conditions of high temperatures and humidity. METHOD: Haematological and
      electrolyte parameters changes were measured in 21 acclimatised recreational
      runners before and after an 18 km run in environmental temperatures and relative
      humidity of 27.1 +/- 0.3 degrees C and 85.0 +/- 1.7% respectively, which was
      measured using the wet bulb globe monitor. RESULTS: There was a loss of weight
      which averaged 2.5 +/- 0.2% (p < 0.001) of initial body weight. Rectal
      temperature increased by an average of 2.7 +/- 0.2 degrees C (an increase of 7.2
      +/- 0.7%; p < 0.001). Immediately after the race, there was a significant (p <
      0.01) increase in haemoglobin, haemotocrit and plasma osmolality. Mean plasma
      volume decreased by 4.1 +/- 1.1%. Plasma sodium and potassium significantly (p <
      0.01) increased by 4.5 +/- 0.5% and 20.3 +/- 3.5% respectively, while magnesium
      significantly (p < 0.01) decreased by 9.0 +/- 1.8%. Peripheral blood profile
      showed significant increases in the post-race white blood cell counts (p < 0.001)
      and platelets (p < 0.01). CONCLUSION: The acute changes in haematological
      variables and plasma electrolytes reported in this study at relatively high
      ambient temperature and humidity were found to be similar to that seen after long
      distance running under cooler climatic conditions. However, it is recommended
      that long-distance runners should be hyperhydrated just before the race and also
      be encouraged to consume 150 mL to 300 mL every 15 minutes while running to
      prevent the effects of dehydration.

PMID- 10414165
TI  - A comparison of laparoscopic surgery and laparotomy in the treatment of ectopic
      pregnancy.
AB  - OBJECTIVES: To compare the laparoscopic approach with laparotomy in the treatment
      of ectopic pregnancy. The aim of this study was to evaluate the efficiency of
      laparoscopic surgery for ectopic pregnancies in China. METHOD: A retrospective
      analysis involving 142 patients with ectopic pregnancies was done. Seventy-two of
      the 142 patients were treated laparoscopically. RESULTS: In the laparoscopic
      group, the operating time and post-hospital stay were significantly shorter but
      the total cost was higher compared with the laparotomy group. CONCLUSION:
      Although the laparoscopic surgery for ectopic pregnancies is a new approach and
      it is not widely practiced in China; it has more advantages than open surgery and
      it has been well accepted by the surgeons and patients. It is a safe and feasible
      approach, but the rate of laparoscopic approach for ectopic pregnancy is still
      low in China when compared with the developed countries.

PMID- 10414166
TI  - A clinical study of 100 new admissions to an adolescent psychiatric inpatient
      unit in Singapore.
AB  - BACKGROUND: Psychiatric inpatient services for children and adolescents in
      Singapore began in 1982 when Woodbridge Hospital started the Child and Adolescent
      Inpatient Unit. To date, this is the only unit with specialised facilities and
      staff in the management of young patients. Admissions were mainly based on a need
      for custodial management of acute major behavioural disturbances. Patients were
      discharged for outpatient treatment once these behaviours subsided. METHODS: This
      is a retrospective clinical study of 100 consecutive new patients admitted from
      April 1993 to August 1994. RESULTS: Majority of admissions (92%) were adolescents
      above age 12, who were either attending secondary or vocational school. Most came
      from nuclear families. Forty-eight percent of referrals were intradepartmental.
      Ten percent were from general hospitals with 16% as self referrals. Psychoses
      accounted for the diagnosis in 43%, schizophrenia being the main type. Neurosis
      and adjustment disorders formed the other main diagnoses. All patients received
      individual and family treatment. Liaison with schools was required in a third of
      the cases. Sixty-one percent received pharmacological treatment. Ninety-one
      percent were discharged home after a stay of less than 3 months. Majority
      returned to school upon discharge from the hospital. CONCLUSION: The main
      criteria for admission in this unit, located in an adult psychiatric hospital, is
      that of custody of young patients with disturbed and unmanageable behaviour. This
      provides additional stigma for the admissions of young patients with minor
      psychiatric problems and interferes with comprehensive care including admission
      required for some adolescents with psychiatric problems.

PMID- 10414167
TI  - Epidemiology of Haemophilus influenzae invasive disease in hospitalised
      Kelantanese children, 1985-1994.
AB  - AIM: Data is lacking with regard to the epidemiology of invasive haemophilus
      influenzae (HI) disease in Malaysia. This study was carried out to document the
      epidemiology of invasive HI disease in hospitalised Kelantanese children.
      METHODS: We conducted a retrospective study of 65 children who had invasive HI
      disease from June 1985 to December 1994. Data regarding age, sex, duration of
      illness, weight, diagnosis, complications, duration of hospitalisation, outcome,
      full blood count and sensitivity pattern of HI to various antibiotics were
      reviewed. RESULTS: The age distribution varied from one day to 72 months with a
      mean of 13 months. Peak incidence occurred in the 7-12 months age group. Majority
      (89.1%) was below two years of age. The relative frequencies of the 75 clinical
      entities documented were as follows: meningitis 64%, pneumonia 29.3%, septicaemia
      5.4%, and abscess 1.3%. In addition, 13.5% of cases had meningitis associated
      with pneumonia. Serotype b accounted for all strains in cases where serotyping
      was done. Anaemia (Hb < 10 g%) was seen in 71.4% of cases. Long term
      complications were noted in 41.5% of cases of meningitis. Case fatality rate was
      12.3%. The percentage of HI strains sensitive to penicillin, ampicillin,
      chloramphenicol and co-trimoxazole were 83.7%, 87.7%, 98.2% and 89.7%,
      respectively. CONCLUSION: The data suggest that invasive HI disease causes
      considerable morbidity and mortality in Kelantanese children.

PMID- 10414168
TI  - Orbital cellulitis as a sole symptom of odontogenic infection.
AB  - A case of periapical infection resulting in unilateral maxillary sinusitis and
      cellulitis of the ipsilateral lower eyelid is presented. The sole symptom was
      right orbital swelling. The possible pathway for the spread of this type of
      infection predisposing factors and possible complications are reviewed. The value
      of radiographic examination and antibiotic therapy are also discussed.

PMID- 10414169
TI  - Weils' syndrome and concomitant hepatitis B infection.
AB  - Leptospirosis is a ubiquitous, spirochetal zoonosis which presents with a broad
      clinical spectrum. Weil's syndrome, characterised by jaundice, renal failure and
      bleeding manifestations is the most severe form. A high index of suspicion for
      the diagnosis is required to institute therapy promptly. We describe a case of
      serologically confirmed Weil's syndrome with concomitant hepatitis B infection.

PMID- 10414170
TI  - Splenic angiosarcoma--an unusual cause of bleeding gastrointestinal tract.
AB  - Splenic angiosarcoma is a rare malignant vascular tumour with about 100 reported
      cases to date. The presentation of splenic angiosarcoma is highly variable,
      frequently causing diagnostic difficulty. It usually presents with splenomegaly,
      abdominal pain and occasionally with a microangiopathic type of anaemia. Here we
      report an additional case of primary angiosarcoma of the spleen presenting as a
      problem of bleeding from the gastrointestinal tract.

PMID- 10414171
TI  - Large lower segment myoma--myomectomy at lower segment caesarean section--a
      report of two cases.
AB  - Uterine leiomyoma is found in approximately 2% of pregnant women. One in ten
      women will have complications related to myoma in pregnancy. Myomectomy during
      pregnancy especially at Caesarean section is much discouraged in the literature.
      We present here 2 cases of large uterine myoma, situated in the anterior aspect
      of the lower segment, complicating pregnancy at term. Myomectomy in both
      instances allowed delivery of the fetus through the lower segment, making vaginal
      delivery in subsequent pregnancies possible.

PMID- 10414172
TI  - A case report on aggressive fibromatosis with bone involvement.
AB  - Aggressive fibromatosis is a locally infiltrative fibroblastic tumour that arises
      from fascial planes of soft tissue but does not metastasize. It is known to
      invade muscle, subcutaneous tissue and neurovascular structures. However, bone
      involvement is very rare and there has been few reports of bone involvement. We
      present a case of a young man with aggressive fibromatosis of the right lower leg
      with fibula involvement.

PMID- 10414173
TI  - Surfactant replacement therapy in RSV-induced acute respiratory distress syndrome
      (ARDS).
AB  - Acute respiratory distress syndrome (ARDS) associated with severe respiratory
      syncytial virus infection is rare. We report a 5-month-old Indian girl who was
      admitted to our intensive care ward with severe respiratory failure who fulfilled
      the criteria for ARDS using both Murray's Lung Injury Score of > 2.5 and the
      American-European Consensus Conference definition for ARDS. She developed diffuse
      bilateral alveolar infiltrates, severe hypoxaemia (PaO2/FiO2 < 100) and required
      high PEEP (> 15 cm H2O) 24 hours after admission. RSV was isolated from her
      nasopharyngeal secretion. She also had clinical features suggestive of a primary
      immunodeficiency and had laboratory evidence of combined T and B cell defect.
      There was unsustained clinical improvement with a dose of surfactant administered
      at 36 hours of PICU stay, and she continued to deteriorate and succumbed after 19
      days in the PICU.

PMID- 10414174
TI  - Clinics in diagnostic imaging (34). Invasive pituitary macroadenoma.
AB  - A 44-year-old woman presenting with headache and decreased visual acuity was
      found to have bilateral papilloedema. Radiograph showed an enlarged pituitary
      fossa. MR scans demonstrated a large solid tumor with central necrosis, and both
      suprasellar and infrasellar extension. The invasive pituitary macroadenoma was
      surgically debulked, followed by radiotherapy. The clinical and imaging features
      of pituitary macroadenomas are discussed.

PMID- 10414175
TI  - What you need to know--medications for rhinitis--uses and abuses.

PMID- 10414176
TI  - Modern liver surgery for HCC.

PMID- 10414177
TI  - Assessment of liver function prior to hepatic resection.
AB  - Improved surgical technique, improved anesthesia, better postoperative care and
      better selection of patients have all contributed to the marked decrease in
      mortality of partial hepatectomy over the past few years. Preoperative assessment
      of portal pressure and of hepatic function with indocyanine green and an oral
      glucose load can help identify patients who will not tolerate a major hepatic
      resection. The predictive value of the indocyanine green retention can be
      improved if the volume fraction of the liver remaining after resection is
      determined preoperatively by computer tomography. Factors other than hepatic
      function, such as age, concomitant diseases and characteristics of the operation
      itself, will of course also play an important role in determining the outcome of
      partial hepatectomy.

PMID- 10414178
TI  - [Indication, technique and results of surgical intervention in hepatocellular
      carcinoma].

PMID- 10414179
TI  - Molecular aspects of hepatocellular carcinoma.
AB  - Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis.
      The success of its established treatment modalities is frequently limited by the
      advanced stage of the tumor at the time of diagnosis. Therefore, it is important
      to understand the mechanisms that control its growth behavior. In the present
      study, we review some aspects of molecular and cellular processes involved in
      growth control and metastatic potential of HCC. These include some growth factors
      and their receptors, oncogenes and tumor suppressor genes, and factors that
      control angiogenesis and extracellular matrix formation. These factors may be
      important targets for novel therapeutic approaches in the future.

PMID- 10414180
TI  - Surgical therapy of hepatocellular carcinoma in the cirrhotic liver.
AB  - Hepatectomy for hepatocellular carcinoma (HCC) associated with cirrhosis was
      considered by some surgeons contraindicated because the hospital mortality rate,
      especially for major hepatectomy, was very high. The author reported his surgical
      approach to hepatectomy associated with cirrhosis. Between 1989 and 1995, 66
      major hepatectomies and 32 minor hepatectomies were performed in 98 cirrhotic
      patients. The selection of patients for hepatectomy was based on results of
      indocyanine green clearance test. The surgical technique was designed to reduce
      blood loss, ischaemic injury to the liver remnant and preservation of liver
      parenchyma. The postoperative care was designed to maintain or improve liver
      function. By such an approach, the hospital mortality rate of the cirrhotic
      patients having hepatectomy decreased from 40% in 1989 to 5% in 1995. The 5-year
      survival rate also improved to 41.2%, which is not statistically different from
      that of those with a normal liver or chronic hepatitis. With refinement in
      surgical technique and perioperative care, patients with cirrhosis can also
      benefit from hepatectomy for HCC.

PMID- 10414181
TI  - Surgical treatment of cholangiocellular carcinoma.
AB  - Cholangiocarcinoma is a primary liver tumor arising from the small bile ducts
      within the liver. According to its different location, clinical features,
      frequency of metastases, treatment modalities and prognosis, intrahepatic
      cholangiocarcinoma should well be differentiated from proximal bile duct
      carcinoma. To date, there is no therapeutic measure with curative potential apart
      from surgical treatment. Partial hepatectomy is the treatment of choice. It is of
      overriding importance to achieve microscopically tumor-free margins. However,
      only few patients treated in an early stage have a prolonged recurrence-free
      survival or a chance for cure. Liver transplantation is not an alternative
      therapeutic option for unresectable cholangiocarcinoma, due to early tumor
      recurrence in almost all recipients. Liver transplantation has a place in
      preventing cholangiocarcinoma in primary sclerosing cholangitis, although the
      timing of replacement is still a matter of debate. Results of surgery need
      further improvement by adjuvant or neoadjuvant treatment protocols.

PMID- 10414182
TI  - Nonsurgical therapies for hepatocellular and cholangiocellular carcinoma.
AB  - Surgical resection is the first choice of treatment for patients with
      hepatocellular (HCC) and cholangiocellular carcinomas. Prolongation of survival
      is, however, the only realistic goal for most patients, which can be often
      achieved by nonsurgical therapies. Inoperable patients with large or multiple
      HCCs are usually treated with transarterial chemoembolization (TACE) with
      lipiodol in combination with a chemotherapeutic drug and gelfoam. Three-year
      survival depends on the stage of the disease and is about 20%. Patients with
      earlier tumor stages (one or two tumor nodules less than 3 cm in size) are
      suitable for treatment with percutaneous ethanol injection (PEI) alone or in
      combination with TACE. Several studies have shown that in these early stages, the
      3-year survival rate is approximately 55%-70% in the actively treated patients
      which is significantly higher than in untreated patients. In advanced stages of
      the disease, TACE and PEI have no effect on survival and should not be performed.
      Some of these patients have been successfully treated with octreotide. Patients
      with inoperable cholangiocellular carcinoma are treated by endoscopic or
      percutaneous stent placement. If stenting does not achieve adequate biliary
      drainage, multidisciplinary therapy including internal/external radiotherapy or
      photodynamic therapy should be considered in patients with potential long-term
      survival. In conclusion, nonresectional therapies play an essential role in the
      therapy of inoperable hepato- and cholangiocellular carcinomas as they lead to
      satisfactory survival. Multidisciplinary therapy appears to be the current trend
      of management.

PMID- 10414183
TI  - Management of focal nodular hyperplasia and hepatocellular adenoma.
AB  - Hepatocellular adenoma and focal nodular hyperplasia are two benign hepatic
      tumors which are mainly detected in healthy young women. Hepatocellular adenoma
      is an indication for surgery due to the risk of haemorrhage and malignant
      transformation. By contrast, focal nodular hyperplasia should be managed
      conservatively. However, precise diagnosis of these benign liver tumors remains
      difficult and sometimes impossible, despite new imaging techniques. Because of
      the risk of diagnostic error, resection or large biopsies of presumed liver
      tumors should be performed in young women (and a fortiori in men and older
      patients in whom focal nodular hyperplasia is less prevalent) when the diagnosis
      of focal nodular hyperplasia is not firmly established. The risk of liver surgery
      in young patients with normal liver parenchyma is, in the opinion of the authors,
      lower than the risk of a mistaken diagnosis.

PMID- 10414184
TI  - [Surgical treatment of echinococcosis of the liver].
AB  - Echinococcosis is a parasitic disease which is most frequently located in the
      liver. The treatment of choice is surgery. METHODS: A total of 23 patients were
      hospitalised for liver echinococcosis during the period from January 1993 to
      September 1998. RESULTS: The diagnosis was in 20 cases (87%) cystic
      echinococcosis and in 3 patients (13%) alveolar echinococcosis. The regular
      intervention of cyst desinfection with cystectomy was carried out in 85% of the
      cases with cystic echinococcosis, whereas atypical or segmental liver resections
      were performed in 15%. Two patients with alveolar echinococcosis were operated
      upon by radical/extended liver resections, one was found intraoperatively
      inoperable. The mean hospital stay was 15.4 days with a mortality of 0% and a
      postoperative morbidity of 57%, including bile leaks in 30%. A perioperative
      antiparasitic chemotherapy with albendazole was prescribed in 91%. The apparent
      rate of recurrence was 7% for uncomplicated cystic echinococcosis. CONCLUSIONS:
      Cyst desinfection with cystectomy has been proved to be effective as the standard
      operative intervention for cystic echinococcosis. For alveolar echinococcosis,
      radical resections are required. Due to the risk of recurrence (especially in
      alveolar echinococcosis), the effectiveness of surgery should be improved by a
      perioperative chemotherapy with albendazole.

PMID- 10414185
TI  - [Surgical treatment of giant hemangiomas of the liver].
AB  - Giant liver hemangiomas are defined as hemangiomas with a diameter of more than 4
      cm. They often require surgery due to bleeding tendencies or local compression.
      Between 1994 and 1998 we operated 11 patients with giant hemangiomas (median
      diameter 5.8 cm, range 4-12.5 cm). Average age was 50 years (range 23-85 years).
      6 patients complained of pain, 1 patient sustained a bleeding. 7 hemangiomas were
      enucleated, 2 segmentally resected, 1 patient underwent a hemihepatectomy. 1
      patient suffered from a bile leakage. Mortality was 0%. We conclude that
      clinically symptomatic liver hemangiomas can be safely resected. In a right sided
      localisation a enucleation has the best parenchyma sparing effect, in left sided
      locations a segmentectomy or bisegmentectomy can be performed with little blood
      loss.

PMID- 10414186
TI  - [Solitary liver cysts and polycystic liver disease: aspects of surgical
      management of congenital cystic liver disease].
AB  - Congenital cystic liver disease represents a rare entity and only in 5%-20% the
      cysts cause symptoms or complications that demand therapy. In the past decades
      several therapeutic approaches have been developed with variable long-term
      outcome. We report herein our results and the postoperative outcome of 26
      patients treated from 1987 to 1998 in our department because of symptomatic or
      complicated congenital cystic liver disease. In cases of symptom-producing
      solitary liver cysts our therapy of choice was laparoscopic fenestration. In
      cases of adult polycystic liver disease we mostly performed partial hepatic
      resection and fenestration. Both therapeutic approaches have proven a favorable
      long-term outcome. However, some types of adult polycystic liver disease possess
      a high risk of reappearance. Preoperative pathomorphological assessment of
      polycystic liver disease should be performed to choose the operative procedure in
      relation to the expected recurrence rate. Because of the progresses made in
      dialysis therapy and transplantation surgery in patients with adult polycystic
      kidney disease, an increase of patients with symptomatic polycystic liver disease
      has to be expected in the near future.

PMID- 10414187
TI  - The Glissonian approach of the hilum.
AB  - The detailed knowledge of the segmental anatomy of the liver has led to a rapid
      evolution in resectional surgery based on the intrahepatic distribution of the
      portal trinity (the hepatic artery, hepatic duct and portal vein). The classical
      intrafascial or extrahepatic approach is to isolate the appropriate branch of the
      portal vein, hepatic artery and the hepatic duct, outside the liver substance.
      Another method, the extrafascial approach, is to dissect the whole sheath of the
      pedicle directly after division of a substantial amount of the hepatic tissue to
      reach the pedicle, which is surrounded by a sheath, derived from Glisson's
      capsule. This Glissonian sheath encloses the portal trinity. In the transfissural
      or intrahepatic approach, these sheaths can be approached either anteriorly
      (after division of the main, right or umbilical fissure) or posteriorly from
      behind the porta hepatis. We describe the technique for approaching the
      Glissonian sheath and hence the hepatic pedicle structures and their branches by
      the intrahepatic posterior approach that allows early delineation of the liver
      segment without the need for ancillary techniques. In addition, the indications
      for the use of this technique in the technical and oncologic settings are also
      discussed.

PMID- 10414188
TI  - [The message of genomes in surgery].

PMID- 10414189
TI  - [Mechanical hemorrhoidectomy using circular staples: warning to colleagues].

PMID- 10414190
TI  - [E-biomed--future dissemination of research?].

PMID- 10414191
TI  - [Increasing use of antilipemic agents].

PMID- 10414192
TI  - [Chlamydia diagnosis].

PMID- 10414193
TI  - [Adolescents and health].

PMID- 10414194
TI  - [Young victims in Oslo--a problem of immigration?].
AB  - There has been considerable concern over victimization from violence in Norway
      over the last couple of years. This study investigated risk groups for
      victimization with special emphasis on the importance of immigrant background.
      All students enrolled in the secondary school system in Oslo (ages 13-18, N =
      10,812) filled in a questionnaire at school. 79% had a background from Norway,
      the rest had a background from other countries. 32% had experienced mild
      victimization, 12% had experienced moderately serious victimization, while 6% had
      experienced serious victimization--defined as being hurt so hard as to need
      medical treatment. Serious victimization was related to working-class background,
      having parents who were economically inactive, living in the eastern part of
      Oslo, and to immigrant background. However, immigrant adolescents also had low
      rates of mild and moderate victimization, and thus high rates of non
      victimization. These associations to immigrant background persisted, also when we
      controlled for other variables. Overall, immigrant background is associated with
      reduced risk for victimization. However, a sub-segment of immigrants are at
      increased risk of serious violent victimization, also when we control for other
      risk factors.

PMID- 10414195
TI  - [Antibodies against Herpes simplex virus type 2 among pregnant women in Norway].
AB  - The prevalence of antibodies against herpes simplex virus type 2 (anti-HSV-2)
      among pregnant women in Norway is not known. To study the prevalence of anti-HSV
      2, a random sample of 961 women was drawn from a study population of 35,940
      pregnant women in Norway during 1992-94. 27% (256/961) had anti-HSV-2. The
      prevalence increased with age. 17% of the 20-24-year-olds and 34% of the 35 year
      old or older had anti-HSV-2. The presence of antibodies also varied
      geographically, from 18% in the south to 39% in the north of Norway. Among women
      with repeated anti-HSV-2 tests during pregnancy, 2.6% of the seronegative women
      seroconverted (16/623). HSV-2 infection is common among pregnant women in Norway.
      The public health implications of this infection need to be clarified.

PMID- 10414196
TI  - [Consumption of fruit and vegetables in a teenage cohort--observed changes].
AB  - The purpose of the study was to investigate the consumption of fruit and
      vegetables among boys and girls in a teenage cohort with respect to changes,
      gender differences and stability of consumption over time. In 1990, a
      representative sample of 13-year-olds from Hordaland county was recruited (n =
      924) and surveyed regularly until the age of 19. The frequency of consumption
      decreased dramatically from the age of 13 to the age of 19. At the age of 13, 57%
      reported eating fruit daily, whereas only 21% of the boys and 37% of the girls
      reported eating fruit daily at the age of 19. Corresponding results for the
      consumption of vegetables showed that 42% reported eating vegetables daily at the
      age of 13, compared to 29% at the age of 19. No clear gender differences were
      found. The consumption frequency at group level at the age of 13 was a good
      indicator of the consumption frequency at a later age during adolescence. While
      younger adolescents until now have been at the focus of campaigns aimed at
      increasing fruit and vegetable consumption, our results point to the importance
      of focusing also on the older adolescents.

PMID- 10414197
TI  - [Experience of family break-up during childhood--health and health behavior in
      adolescence].
AB  - During recent years the prevalence of family break-up has increased. Every third
      child growing up in Norway today may experience divorce among their parents. In
      this paper we try to illustrate to what extent experiencing divorce during
      childhood is related to subjective health and health behaviour in adolescence.
      The study is based on a self-administered questionnaire among 828 students in
      secondary schools in Forde (91% of all). Every fifth student reported experience
      of family break-up, and we compared this group with the rest concerning
      subjective health and health behaviour. We found significant differences in the
      disfavour of adolescents whose parents were divorced, with regard to both
      physical and emotional health complaints. We also demonstrated marked differences
      concerning health risk behaviour, especially smoking. The subjective assessment
      of wellbeing and performance in school were lower among adolescents with divorce
      experience. It is concluded that family break-up represents a major stressful
      event for children with marked health consequences in adolescence. Such
      consequences should be considered in plans for preventive health measures and
      health care for children and adolescents.

PMID- 10414198
TI  - [Tension free vaginal tape--a new surgical method for stress incontinence in
      women].
AB  - A new, minimally invasive procedure for female stress incontinence has recently
      been developed. A prolene tape is placed without tension under mid-urethra,
      usually using local anaesthesia and mild sedation. Postoperative catheterisation
      is not employed. Our experience with the first 42 patients is presented. 42 women
      with urodynamically verified severe urinary stress incontinence were operated in
      1996 and 1997. They underwent subjective and objective follow-up in 1998 with
      mean follow-up time 16 months, range 6-27 months. The procedure was well
      tolerated. All patients except four (90%) were discharged within 24 hours. There
      were two bladder perforations which healed spontaneously, and in one case the
      vaginal wound required resuturing. Subjectively, 85% were cured of their stress
      incontinence and a further 10% had slight incontinence only and used no
      protection. Objectively, 81% were cured and 12% were > 90% improved. There were
      no cases of long term voiding problems, recurrent urinary tract infections, de
      novo urge incontinence, or sling rejections. With medium term follow-up this
      procedure appears to have results equivalent to those of colposuspension, and few
      complications.

PMID- 10414199
TI  - [A new minimally invasive surgical method for stress incontinence in women].
AB  - Present surgical methods in the treatment of female urinary incontinence require
      relatively extensive surgery and several days in hospital. 84 consecutive
      patients (age 34-78 years) with proven stress incontinence were operated with the
      new tension-free vaginal tape procedure (TVT) and studied prospectively from
      November 1996 to August 1998. The operation was carried out under local
      anaesthesia, a procedure which allows the surgeon to check during the operation
      that continence is achieved. 52 patients (62%) were discharged from the hospital
      the same day. After four months, 79 out of 82 patients (96%) were cured or had
      improved considerably. No serious complications occurred. Four patients
      experienced various degrees of retention. The tension-free vaginal tape method
      seems to be an effective minimal invasive surgical procedure for the treatment of
      female stress incontinence. However, randomized controlled studies and long term
      follow-up are needed for a more complete evaluation of its merits versus the
      Burch colposuspension which is considered the "gold standard".

PMID- 10414200
TI  - [Opsoclonus and ocular flutter--eye motility disorders of great diagnostic
      value].
AB  - Opsoclonus and ocular flutter are rare but well-defined disorders of the saccadic
      system. Ocular flutter is a burst of back-to-back horizontal saccades without an
      intersaccadic interval. If these saccades occur in all directions, the
      involuntary eye movements are called opsoclonus. The most common aetiologies are
      paraneoplastic, postinfectious, toxic-metabolic and idiopathic. The underlying
      malignancy is usually neuronal crest tumors in children or lung, breast or
      gynaecologic cancer in adults. The appearance of these syndromes should prompt
      the search for an occult malignancy.

PMID- 10414201
TI  - [DNA amplification in the diagnosis of urogenital Chlamydia trachomatis
      infection].
AB  - Sexually transmitted Chlamydia trachomatis infections are common and a major
      cause of pelvic inflammatory disease and its complications (infertility, ectopic
      pregnancy and chronic abdominal pain). No pathognomonic sign exists and the
      majority of infected individuals are asymptomatic. During the last eight years
      numerous evaluations of methods of detecting C trachomatis infections by use of
      DNA amplification have been published. The clinical sensitivity of the methods
      seem to be superior to antigen detection methods and cell culture. However,
      inhibitoric components may reduce the sensitivity of certain DNA tests and sample
      types. The increased sensitivity of DNA amplification tests allows the use of
      sample material which contain fewer organisms than the conventional swab sample,
      e.g. urine and vaginal samples. A strategy using home-obtained and mailed samples
      increases the efficacy of contact tracing and universal screening. Wider use of
      this strategy may reduce the risk of complications for the individual and reduce
      the prevalence of the infection in the society.

PMID- 10414202
TI  - [Are children and adolescents less physically active today than in the past?].
AB  - In recent years it has been claimed that Norwegian children and youth have
      reduced their level of physical activity and fitness. The aim of this systematic
      review was to investigate whether the amount of physical activity or level of
      physical fitness have changed among Norwegian children and youth during the past
      decades. We searched for relevant information in databases and reference lists
      and established contacts with scientists working in this field. The quality of
      the studies was evaluated on the basis of selection bias, information bias and
      adequate reporting of results. Five repeated cross-sectional studies of healthy
      boys and girls in the period from 1950 to 1997 were included. Three are based on
      tests of physical fitness and two of self-reported physical activity. The studies
      indicate that the physical fitness of the older boys has been reduced, the level
      of activity has been lowered, the percentage of inactive youth has increased and
      there are now larger variations in physical fitness. We conclude that there seems
      to be a negative trend in the level of physical fitness and physical activity of
      children and youth. This shows the need for interventions. The need for
      standardised parameters for physical activity is apparent.

PMID- 10414203
TI  - [A case of migraine attack followed by abdominal pain].

PMID- 10414204
TI  - [Sick-listing--the easiest way?].

PMID- 10414205
TI  - [Agricultural workers' health].

PMID- 10414206
TI  - [Reforms of the British health care--paradigmatic shift, political rhetorics or
      challenge for health professionals?].

PMID- 10414207
TI  - [Directions on spinal medicine and doubtful statistics].

PMID- 10414208
TI  - [Length of stay in maternity wards].

PMID- 10414209
TI  - [Accidental hypothermia].

PMID- 10414210
TI  - [Requirements in connection with continuing education in anesthesiology].

PMID- 10414211
TI  - [Play and creativeness as training method in performance anxiety].

PMID- 10414213
TI  - Clinical pharmacology & therapeutics.

PMID- 10414212
TI  - Air bag safety: what physicians should know.
AB  - The presence of air bags in motor vehicles has been credited with saving
      thousands of lives in frontal, high-speed collisions. However, air bags have also
      contributed to the deaths of some children and adults in the driver and front
      passenger positions in low-speed crashes. It is important for physicians to
      understand the relative benefits and risks of air bags and to inform the public
      repeatedly that all motor vehicle occupants should be buckled at all times and
      that all children ages 12 and under should ride properly restrained in the back
      seat. With very few exceptions, air bags should NOT be deactivated. Through in
      office counseling and community speaking and writing, physicians have the
      opportunity to give advice that could save many lives in motor vehicle crashes.

PMID- 10414214
TI  - MORP: we have come a long way.

PMID- 10414215
TI  - The state of asthma in the state of Wisconsin.

PMID- 10414216
TI  - The State Medical Society of Wisconsin Asthma Outcome Study--initial findings.

PMID- 10414217
TI  - The Medical Outcomes Research Project Pediatric Asthma Study.

PMID- 10414218
TI  - Prevalence of penicillin resistant and multi-drug resistant Streptococcus
      pneumoniae at a children's hospital.
AB  - Streptococcus pneumoniae isolated at Children's Hospital of Wisconsin during the
      winter of 1994 to 1995 and the winter of 1996 to 1997 were tested for
      susceptibility to penicillin, cephalosporins and other potentially
      therapeutically useful antimicrobial agents to determine the prevalence of
      penicillin and multi-drug resistant isolates. During those years, the prevalence
      of S. pneumomiae not susceptible to penicillin was 27% and 28%, respectively,
      with 14% and 18%, respectively, of the respiratory isolates being high-level
      penicillin resistant. Despite the stable numbers of penicillin resistant
      isolates, there was evidence of significant increase in the resistance of these
      isolates to other antimicrobial agents. Respiratory isolates not susceptible to
      cefotaxime increased (p = .01; Fisher exact test) from 3% in 1995 to 20% in 1997.
      There was also a significant increase in the isolates not susceptible to
      erythromycin (p = .09; Fisher exact test) and trimethoprim/sulfamethoxazole (p <
      .01; Fisher exact test). This increase in resistance to multiple antimicrobial
      agents has significant implications for antibiotic therapy of children with
      infections likely to be due to Streptococcus pneumoniae.

PMID- 10414219
TI  - MAC prophylaxis in the era of polypharmacy.
AB  - In the advanced stages of AIDS, patients are increasingly susceptible to
      disseminated Mycobacterium avium-intracellulare (MAC) infection, causing
      significant morbidity and mortality. It has been shown that prophylaxis against
      this infection is effective in reducing the incidence as well as the symptoms of
      MAC. Although chemoprophylaxis against MAC is a standard recommendation, it is
      not always carried out due to a variety of reasons. Several agents are now
      approved for this purpose, adding to the complexity of the decision to start the
      prophylaxis. This article reviews the need for prophylaxis against MAC, and
      considers the different agents available, with the aim of helping readers come to
      an informed decision about starting MAC prophylaxis in their patients. This issue
      will be of rising importance with the effective prevention of other opportunistic
      infections in patients with advancing immune deficiency.

PMID- 10414220
TI  - Barriers to the physician decision to offer hospice as an option for terminal
      care.
AB  - Hospice is one care alternative available to the terminally ill, but if
      physicians do not offer this option, it is not likely to be considered by a
      patient who is making end-of-life decisions. A 15-item questionnaire to determine
      which barriers hinder or delay a physician's decision to discuss hospice with
      patients was sent to 147 physicians in one area of western Wisconsin. The study
      population included primary care physicians (family practitioners, internists and
      pediatricians) and specialists (cardiologists, gastroenterologists,
      nephrologists, neurologists, oncologists, pulmonologists, radiation oncologists,
      and urologists). The barriers receiving the most citations were: "patient or
      family hasn't accepted the terminal diagnosis," "patient or family desires to
      continue life-prolonging treatment," "patient has no family or friends to help
      hospice provide care," and "difficult to prognosticate amount of time patient has
      to live." Personal interviews with 13 of the participating physicians revealed
      additional barriers: "concern over loss of involvement with patient," "admitting
      patient to hospice causes some inconvenience," "deficit in physician knowledge of
      local hospice program," "introduction of hospice late in course of illness," and
      "use of home health services instead of hospice." Knowledge of these barriers may
      lead to an interdisciplinary approach to ensure that patients receive information
      of all alternatives available for terminal care.

PMID- 10414221
TI  - Pica and iron deficiency. A case report.

PMID- 10414222
TI  - Partnering among HCFA, PROs and Medicare + choice organizations.

PMID- 10414223
TI  - Does Psi exist? Lack of replication of an anomalous process of information
      transfer.
AB  - D. J. Bem and C. Honorton (1994) recently presented in this journal a set of
      ganzfeld extrasensory perception (ESP) experiments conducted by C. Honorton that
      appeared to support the existence of a communication anomaly. In this article,
      the authors present a meta-analysis of 30 ganzfeld ESP studies from 7 independent
      laboratories adhering to the same stringent methodological guidelines that C.
      Honorton followed. The studies failed to confirm his main effect of participants
      scoring above chance on the ESP task, Stouffer z = 0.70, p = .24, one-tailed; M
      effect size (z/N1/2) = 0.013, SD = 0.23. The new studies included replication
      attempts of 3 out of 5 internal effects reported as statistically significant by
      D. J. Bem and C. Honorton. Only 1 was confirmed, and the authors found that D. J.
      Bem and C. Honorton were mistaken in describing the original effect as being
      statistically significant. The authors conclude that the ganzfeld technique does
      not at present offer a replicable method for producing ESP in the laboratory.

PMID- 10414224
TI  - Implications of the restricted range of family environments for estimates of
      heritability and nonshared environment in behavior-genetic adoption studies.
AB  - Group and individual-difference adoption designs lead to opposite conclusions
      concerning the importance of shared environment (SE) for the child outcomes of IQ
      and antisocial behavior. This paradox could be due to the range restriction (RR)
      of family environments (FE) that goes with adoption studies. Measures of FE from
      2 of the most recent adoption studies indicate that RR is substantial, about 67%,
      which corresponds to the top half of a normal FE distribution. RR of 67% cuts
      effect sizes and R2 statistics by factors of 3 and 2-2.5, respectively. Because
      selection into an adoption study in inherently a between-family process and
      assuming that comparable restriction of genetic (G) influences are absent,
      estimates of SE, G, and nonshared influences will be substantially biased,
      respectively, down, up, and up by RR. Corrections for RR applied to adoption
      studies indicate that SE could account for as much as 50% of the variance in IQ.

PMID- 10414225
TI  - Connectionist modeling of speech perception.
AB  - Connectionist models of perception and cognition, including the process of
      deducing meaningful messages from patterns of acoustic waves emitted by vocal
      tracts, are developed and refined as human understanding of brain function,
      psychological processes, and the properties of massively parallel architectures
      advances. The present article presents several important contributions from
      diverse points of view in the area of connectionist modeling of speech perception
      and discusses their relative merits with respect to specific theoretical issues
      and empirical findings. TRACE, the Elman/Norris net, and Adaptive Resonance
      Theory constitute pivotal points exemplifying overall modeling success, progress
      in temporal representation, and plausible modeling of learning, respectively.
      Other modeling efforts are presented for the specific insights they offer, and
      the article concludes with a discussion of computational versus dynamic modeling
      of phonological processes.

PMID- 10414226
TI  - Gender differences in self-esteem: a meta-analysis.
AB  - Two analyses were conducted to examine gender differences in global self-esteem.
      In analysis I, a computerized literature search yielded 216 effect sizes,
      representing the testing of 97,121 respondents. The overall effect size was 0.21,
      a small difference favoring males. A significant quadratic effect of age
      indicated that the largest effect emerged in late adolescence (d = 0.33). In
      Analysis II, gender differences were examined using 3 large, nationally
      representative data sets from the National Center for Education Statistics
      (NCES). All of the NCES effect sizes, which collectively summarize the responses
      of approximately 48,000 young Americans, indicated higher male self-esteem (ds
      ranged from 0.04 to 0.24). Taken together, the 2 analyses provide evidence that
      males score higher on standard measures of global self-esteem than females, but
      the difference is small. Potential reasons for the small yet consistent effect
      size are discussed.

PMID- 10414227
TI  - [Activated protein C resistance and venous thrombophilia: molecular genetic
      prevalence study in the German population].
AB  - BACKGROUND AND OBJECTIVE: Resistance against activated protein C (APC), caused by
      factor V R506Q mutation (factor V Leiden mutation), is among the most important
      hereditary clotting defects that are associated with an increased risk of venous
      thrombosis. As there are hardly any data for Germany regarding APC resistance
      that have been validated by genetic analysis, this study was undertaken to
      determine the prevalence of factor V Leiden (fVL) mutations in a sizeable group
      of patients in Germany with venous thromboembolism (VTE) and a control group of
      healthy persons. PATIENTS AND METHODS: 1200 consecutive patients (689 females,
      511 males) from various regions of Germany were examined who, at an age between
      0.1 and 45 years, had developed primary deep vein thrombosis (DVT) and/or
      pulmonary embolism (PE), as confirmed by imaging tests. The control group
      consisted of 740 healthy persons (332 females and 408 males; median age 33 years)
      for whom there was no evidence in their personal or family history of TE.
      Analysis of the fV-1691 genotype was by Mnll-restriction analysis of genomic fV
      DNA fragments, amplified by polymerase chain reaction. RESULTS: The prevalence in
      the control group was 7.5% the for heterozygotic fV:Q506 mutant (25 females, 30
      males). For the patients the prevalence of the fV R506Q mutation was 27.2% (32.1%
      heterozygotes [165 females, 112 males]; 4.1% homozygotes [33 females, 16 males],
      i.e. significantly higher than in the healthy controls (P < 0.0001). In 81.3% of
      the patients with fV:Q506 DVT in the leg-pelvic vein region was found as the
      first manifestation, thrombosis in an atypical site in 14.4% and isolated PE in
      4.3%. The first manifestation had occurred spontaneously in 36% of patients with
      the fV:Q506 mutant (44 females, 75 males), in 53.1% of homozygotes and in 33.5%
      of heterozygotic carriers of the mutation. CONCLUSION: The fV Leiden mutation due
      to APC resistance is the most common cause of venous thrombosis and apparently
      one of the most common inherited diseases.

PMID- 10414228
TI  - [Severe nephrotic syndrome with reversible acute kidney failure in lupus
      associated membranous nephropathy].
AB  - HISTORY AND CLINICAL FINDINGS: A 20 year old, previously healthy woman presented
      with a four week history of progressive oedema of the legs and the eyelids and a
      weight gain of 10 kg. INVESTIGATIONS: Biochemical tests revealed a nephrotic
      syndrome with a protein-loss in urine of 13.6 g/24 hours and a serum-albumin of
      1.2 g/dl. Serological tests showed positive response for antinuclear antibodies,
      anti-double-stranded-DNA antibodies and cardiolipin antibodies. Renal histology
      revealed a lupus-associated diffuse membranous nephropathy (WHO-type Vd).
      DIAGNOSIS, TREATMENT AND COURSE: We first started a treatment regimen with oral
      steroids and intravenous loop-diuretics without improvement of the nephrotic
      syndrome. Two weeks after initial presentation the patient developed dialysis
      dependent, acute renal failure. Having excluded a renal vein-thrombosis and the
      transition to diffuse proliferative form of the glomerulonephritis we suggested a
      nephrotic etiology of the acute renal failure. We initiated cyclophosphamide
      pulse-therapy which led to dramatic improvement of the nephrotic syndrome after
      the first cycle with reduction of protein-loss to 6 g/24 hours. Concurrently
      renal function recovered and treatment with hemodialysis could be stopped after 3
      weeks. CONCLUSION: Acute renal failure in nephrotic syndrome has also to be
      considered in an acute form of a membranous lupus nephritis. Renal recovery is
      much better when acute renal failure is caused by nephrotic syndrome.

PMID- 10414229
TI  - [Isolated thrombosis of the vena profunda femoris as the source of embolisms. A
      diagnosis easy to supply using duplex sonography].
AB  - HISTORY AND ADMISSION FINDINGS: A 79-year old man was admitted because of
      increasing dyspnoea. At physical examination he had dyspnoea at rest,
      auscultation of the lung was unremarkable and there was no peripheral oedema or
      unilateral swelling of a leg to suggest venous thrombosis. INVESTIGATIONS AND
      DIAGNOSIS: Chest radiogram was unremarkable. Perfusion scintigraphy of the lung,
      performed to exclude pulmonary embolism, revealed several defects typical of
      emboli. Duplex sonography revealed an isolated thrombosis of the left profunda
      femoris vein, while the deep veins were patent. TREATMENT AND COURSE:
      Anticoagulation with heparin followed by phenprocoumon rapidly improved the
      symptoms and the patient was discharged after 10 days. CONCLUSION: Thrombosis of
      the profunda femoris vein can cause clinically relevant pulmonary embolism. While
      this vessel cannot be visualized by phlebography, duplex sonography easily
      establishes the diagnosis and should be used routinely in the investigation of
      suspected thrombosis of the leg veins.

PMID- 10414230
TI  - [Diagnosis of orthostatic hypotension].

PMID- 10414231
TI  - [Low molecular weight heparin in atherothrombotic cardiovascular diseases. Value
      in coronary disease, ischemic stroke and peripheral arterial occlusive disease].

PMID- 10414232
TI  - [Ambulatory therapy for deep leg vein thrombosis?].

PMID- 10414233
TI  - Expression of exon v6-containing CD44 isoforms is related to poor prognosis of
      acute myelocytic leukemia.
AB  - CD44 is a cell surface glycoprotein with a number of isoforms generated by
      alternative splicing of ten 'variant' exons in humans. Variant exon 6-containing
      isoforms of CD44 (CD44v6) have been implicated in the metastatic potential of rat
      carcinoma cell lines. Human homologues of CD44v6 are expressed in several tumour
      types and are involved in their progression. In the present study, we examined
      the expression of CD44 mRNA in 20 acute myelocytic leukemias by semiquantitative
      RT-PCR analysis and assessed its prognostic value. In all leukemic cells the
      predominant isoform was the 'standard' form of CD44 (CD44H), and intense bands
      were found in eight cases. CD44v6 was expressed in 11 cases, although its levels
      and those of other variants containing exon v7 through to v10 were much lower
      than those of CD44H. Isoforms containing exon v4 or v5 could not be detected. The
      expression of CD44v6 correlated with the death rate from leukemia (p > 0.05), but
      was not related to other risk factors. On the other hand, the intense expression
      of CD44H did not correlate with the prognosis of leukemia. CD44v6 thus appears to
      be a marker for the poor prognosis of acute myelocytic leukemia.

PMID- 10414234
TI  - Abnormal levels of proinflammatory cytokines in serum and monocyte cultures from
      patients with chronic myeloid leukemia in different stages, and their role in
      prognosis.
AB  - Interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF
      alpha), primarily monocyte-derived cytokines, form a group of proinflammatory
      cytokines with related and overlapping spectra of activities. The role of these
      cytokines in chronic myeloid leukemia (CML) has been investigated. A distinctive
      pattern of cytokine secretion has been found in chronic myeloid leukemia in
      chronic phase (CML-CP), in blastic crisis (CML-BC) and in normal subjects. Serum
      IL-6 levels in CML-CP and CML-BC were significantly raised compared with normal
      controls (p = 0.0026 for CML-CP and p = 0.0011 for CML-BC). IL-6 was
      significantly elevated in blastic crisis of CML (103.5 +/- 20.77 pg ml-1)
      compared with CML-CP (37.35 +/- 10.88 pg ml-1; p = 0.014). IL-6 serum levels were
      found to correlate significantly with peripheral blood monocyte counts and bone
      marrow blast and basophil counts. We have analysed monocyte/macrophage function
      with respect to their ability to produce IL-1, IL-6 and TNF-alpha, spontaneously
      as well as in response to LPS, in comparison with normal controls. A direct
      correlation of IL-6 levels in unstimulated and stimulated cultures with bone
      marrow blast and basophil counts has been observed. From these results it is
      inferred that the monocyte function is impaired in CML patients, and the cytokine
      secretion is deficient. Our limited data suggest that serum IL-6 levels may play
      an important role as a prognostic marker for CML.

PMID- 10414235
TI  - Allogeneic peripheral blood stem cell transplantation in acute non-lymphoblastic
      leukemia.
AB  - Unmodified allogeneic peripheral blood stem cell transplantation (alloPBSCT) was
      performed in 20 consecutive acute non-lymphoblastic leukemia (ANLL) patients from
      their HLA-identical siblings. There were 11 males and 9 females. Median age was
      34 years (range 17-43). Donors were primed with 2.5-15 micrograms/kg/day s.c.
      granulocyte-colony stimulating factor (G-CSF, Neupogen, Roche). Conditioning
      regimen was Bu (16 mg/kg) + Cy (120 mg/kg) in 19 patients and high dose Ara-C (3
      gr/m2 twice daily for 3 days) for one patient who relapsed after bone marrow
      transplantation. Eighteen patients were in CR1. CsA + short-term MTX (n = 19) or
      CsA alone (n = 1) were used for graft versus host disease (GVHD) prophylaxis. The
      median number of apheresis procedures for each patient was 2 (2-4). A median of
      6.5 (3.2-38.2) x 10(8)/kg MNC or 9.4 (2.2-12.4) x 10(6)/kg CD34+ cells were
      given. Median days to reach granulocyte of > 0.5 x 10(9)/l and platelet of > 50 x
      10(9)/l were 12 (10-14) and 15 (11-35) respectively. Day 100 transplant-related
      mortality was 20 per cent (4/20). Grade 2 to 4 AGVHD was seen in 8 out of 17
      (47%) evaluable patients. Severe AGVHD occurred in 3 out of 17 (18%). Clinical
      CGVHD of all grades developed in 12 out of 17 (70%) evaluable patients. The mean
      disease-free survival and overall survival were 17 (range: 8-33 months) and 18
      months (range: 10-34 months), respectively. In conclusion, alloPBSCT in ANLL is
      associated with a faster engraftment, no greater incidence of AGVHD, but
      increased risk of CGVHD.

PMID- 10414237
TI  - Recent publications in hematological oncology.

PMID- 10414236
TI  - Allogeneic bone marrow transplantation for adult acute lymphoblastic leukemia: a
      single-centre experience.
AB  - Between 1990 and 1997, we performed 29 allogeneic BMTs for acute lymphoblastic
      leukemia (ALL) patients with HLA-identical sibs. Their median age was 31 years
      (range 15 to 43); there were 15 males and 14 females. The conditioning protocol
      was Cy-TBI (n = 15), VP16-Cy-TBI(n = 12), CBV (n = 1) and Bu-Cy (n = 1).
      Cyclosporin and methotrexate were used for GVHD prophylaxis. The median disease
      free survival (DFS) was 12 months (range 1 to 92) with an actuarial 4-years DFS
      of 42.3 per cent. Three patients died of transplant-related complications before
      100 days. Relapse occurred in 11 cases at a median time of 5 months (range 3 to
      14). All nine patients relapsing within one year died form resistant leukemia.
      Three patients died of late treatment-related complications. There were 13
      survivors (median follow-up 38 months, range 12-98), with 12 in remission. Only
      four had limited cGVHD, and all had 100 per cent performance scores. One patient
      also cleared her chronic hepatitis B carrier status due to acquired immunity. The
      DFS rates amongst CR1 cases and R1/CR2 cases were comparable (p = 0.39). No long
      term DFS is obtained from patients with resistant disease (n = 4). The survival
      results for BMT at CR1 were superior to those using intensive chemotherapy
      consolidation (p = 0.29), mainly due to poor late results in the chemotherapy
      arm. For young ALL patients with HLA-matched siblings, the option of BMT should
      be considered in light of local consolidation survival results.

PMID- 10414238
TI  - [Sacro-iliac involvement in he course of Paget disease. Report of 6 cases].
AB  - OBJECTIVES: Determine the characteristic features of sacroiliac lesions observed
      in patients with Paget's disease. PATIENTS AND METHODS: A retrospective analysis
      of the hospital files of 87 patients cared for over a period of 12 years was
      performed. Six patients, 4 women and 2 men, mean age 79 years, were retained for
      study. In 4 patients one or both sacroiliac joints were involved with complete
      fusion of the sacral and iliac bones, confirmed by CT-scan in 3. In the 2 other
      patients, only one border was involved. Scintigraphy showed polyostotic Paget's
      disease in 3 cases with pelvic localization in the 3 others. Ankylosing
      spondylarthritis (B27+) was associated in 1 case and in 2 joint chondrocalcinosis
      without a calcium rim was visualized at the sacroiliac joint. Sacroiliac fusion
      was related either to new bone forming a bridge in front of the articular space
      or destruction of the joint cartilage with pagetic fusion. CONCLUSION: Sacroiliac
      involvement in Paget's disease leads to joint fusion by cartilaginous destruction
      and should suggest possible ankylosing spondylarthritis, ankylosing vertebral
      hyperostosis, or joint chondrocalcinosis.

PMID- 10414239
TI  - [A new type of iliac fracture caused by bone insufficiency].
AB  - BACKGROUND: The iliac bone is an uncommon localization for bone insufficiency
      fractures. We report a new type. CASE REPORT: A 51-year-old woman with post
      menopause osteoporosis was seen for a fracture of the ischio-pubic branch of the
      iliac bone. X-ray also revealed an unknown fracture situated above the anterior
      superior iliac spine continuing cranially and medially towards the iliac crest.
      DISCUSSION: Three types of iliac fractures due to bone deficiency have been
      described. Type 1, (oblique iliac), the fracture is oblique beginning in the
      greater sciatic notch and extending a more or less into the iliac wing. Type 2
      (superior medial iliac) involves the most medial part of the iliac wing,
      approximately parallel to the sacroiliac joint. In type 3 (supra-acetabular), the
      fracture is in a supra-acetabular localization. Our case suggests a fourth type
      should be individualized.

PMID- 10414240
TI  - [Femoral neck fracture complicating algodystrophy in pregnancy].
AB  - BACKGROUND: Sympathetic reflex dystrophy is an uncommon cause of pelvic pain not
      to be overlooked in pregnant women. CASE REPORT: At 8 months pregnancy, a 27-year
      old woman complained of invalidating pain of the left hip. Magnetic resonance
      imaging of the pelvis performed the day after delivery evidenced a non-displaced
      fracture of the femoral neck and a typical aspect of sympathetic reflex
      dystrophy. DISCUSSION: The true frequency of sympathetic reflex dystrophy during
      pregnancy is probably underestimated. Approximately one hundred cases have been
      reported. The hip joint is involved in 9 out of 10 cases. Such localizations are
      uncommon outside pregnancy, accounting for 14 to 17% of all cases.

PMID- 10414241
TI  - [Pseudotumoral calcinosis of the wrist in a patient with scleroderma].

PMID- 10414242
TI  - [Bed rest not necessary for the treatment of sciatica].

PMID- 10414243
TI  - [Evaluation and follow up of chronic pain in adults under ambulatory care].

PMID- 10414244
TI  - [Imaging of low back pain common in adults].

PMID- 10414245
TI  - [Role of diagnostic imaging of common cervicalgia, cervico-brachial neuralgia and
      chronic cervical myelopathy].

PMID- 10414246
TI  - [COX-2 selective NSAID inhibitors: hopes and doubts].

PMID- 10414248
TI  - [Hormone replacement therapy in the prevention of osteoporosis. Evolution of
      therapeutic methods].
AB  - ESTABLISHED FACTS: Many studies have evidenced that hormone replacement therapy
      can help prevent post-menopausal osteoporosis and osteoporotic fractures in
      menopaused women. Thanks to recent advances in pharmacology, hormone replacement
      therapy can now closely mimic ovarian physiology and thus eliminate most of the
      contraindications related to metabolic disorders. UNRESOLVED QUESTIONS: The need
      for prolonged treatment to reach optimal efficacy raises the problems of safety
      and compliance. This is particularly true for the prevention of fractures of the
      femoral neck which usually occur in older women, suggesting it could be useful to
      revisit the estrogen strategy. NEW COMPOUNDS: The action of selective estrogen
      receptor modulators (SERM) depends on the target organ. They have an estrogen
      agonist effect on bone and lipid metabolism but no such effect on the uterus.
      SERMs could offer new therapeutic opportunities for the prevention of post
      menopausal osteoporosis.

PMID- 10414247
TI  - [Specific inhibitors of cyclo-oxygenase-2: a revolution?].
AB  - A NEW CLASS OF NSAID: All non-steroidal antiinflammatory drugs (NSAID) inhibit
      cyclooxygenase (COX) and prostaglandin synthesis implicated in inflammatory
      processes and also participate in protecting the gastric mucosa. The discovery of
      two isoforms of COX, called COX-1 and COX-2 has led to further research into
      dissociating NSAID efficacy and intolerance. COX-1 AND COX-2: It appears that the
      antiinflammatory and antalgesic effects of NSAID is related to COX-2 inhibition
      while the undesirable effects on the gastric mucosa would be related to COX-1
      inhibition. A COX-2 specific inhibitor would thus provide the same efficacy as
      classic NSAID but without the digestive disadvantages. CLINICAL RESULTS:
      Celecoxib and rofecoxib are two COX-2 specific inhibitors. They have been found
      to have an effect comparable to classical NSAID. FURTHER INFORMATION NEEDED: The
      fact that healthy gastric mucosa tolerates COX-2 specific inhibitors better does
      not necessarily mean that the same would be true for ulcerated mucosa, poorly
      repaired mucosa or simple areas of erosion.

PMID- 10414249
TI  - [Efficacy and role of topical treatment of gonarthrosis].
AB  - INDICATIONS: To relieve pain in patients with knee osteoarthritis, local
      treatments can be effective both for episodes of acute congestion, characterized
      by inflammatory pain, intraarticular effusion and risk of acute chondrolysis, and
      for slowly progressive disease (with a characteristic lack of effusion). ACUTE
      CONGESTION: Local care is essential. Relief can be achieved by draining the
      effusion, associated with corticosteroid injections which may be repeated and
      followed by a 24 h rest. In case of failure or rapid development of chondrolysis,
      joint lavage (1 liter saline solution--two 2-mm needles) followed by cortico
      steroid infiltration is indicated. Weight bearing should be avoided for 6 weeks
      (cane) until the effusion has been absorbed. In case of radiological evidence of
      chondrocalcinosis and chronic serous or bloody effusion, yttrium 90
      synoviorthesis may be proposed as an alternative. SLOWLY PROGRESSIVE DISEASE: In
      patients with no effusion who continue to suffer despite physical and medical
      treatment, intraarticular injections of hyaluronic acid can be helpful. They are
      particularly effective in case of moderate disease. Hyaluronic acid is an
      interesting alternative to non-steroidal antiinflammatory drugs and is especially
      indicated after a rapidly progressive period of chondrolysis.

PMID- 10414250
TI  - [Gougerot-Sjogren syndrome. Diagnostic criteria and therapeutic methods].
AB  - CLASSIFICATION CRITERIA: Several systems of classification criteria have been
      developed for Sjogren's syndrome. These systems allow patient classification but
      do not constitute diagnostic criteria. The most widely used is based on the Fox
      criteria which are totally specific but have low sensitivity. The European
      criteria have satisfactory sensitivity and specificity. IN CLINICAL PRACTICE: In
      all cases, the elements comprising the sicca syndrome must be identified. A
      labial biopsy for histology of the accessory salivary glands may be helpful. A
      less extensive search is sometimes sufficient if the aim is uniquely diagnostic.
      TREATMENT OF SJOGREN'S SYNDROME: Symptomatic treatment of the sicca syndrome with
      local procedures is aimed at reducing the functional disorder. The systemic route
      is used to treat the dysimmune component. As in most connective tissue diseases,
      most patients can be stabilized, limiting the functional consequences of the
      disease, but cure remains illusive.

PMID- 10414252
TI  - [Gougerot-Sjogren syndrome. Risk of lymphoma].
AB  - LYMPHOMA RISK: Lymphoma is a very severe complication of primary Sjogren's
      syndrome: 5 to 10% of patients followed for more than 10 years will develop a
      lymphoma. Predictive factors include serum monoclonal immunoglobulins or
      cryoglobulins and a B clone population in accessory salivary glands. TYPICAL
      CLINICAL AND HISTOLOGICAL PRESENTATION: Mucosal involvement (parotid as well as
      gastric or pulmonary localizations) is frequent. According to the recent
      classification of lymphomas, most lymphomas developing in patients with Sjogren's
      syndrome are B lymphomas of the marginal zone: MALT lymphomas or low-grade nodal
      monocytoid lymphomas which are sometimes not identified until transformation to
      the giant cell stage. SIMILARITIES WITH HEPATITIS C LYMPHOMAS: The
      pathophysiology of lymphoma in Sjogren's syndrome remains unknown. To date, there
      is no argument favoring a viral infection or a deregulation of a unique oncogene
      or anti-oncogene. Certain similarities between lymphomas in Sjogren's syndrome
      and lymphomas associated with hepatitic C virus would suggest a common
      pathogenisis: possibly a permanent stimulation of auto-reactive B cells carrying
      a surface immunoglobulin with rheumatoid factor activity in the target organs of
      the autoimmune disease. These B lymphocytes would then proliferate secondarily.

PMID- 10414251
TI  - [Gougerot-Sjogren syndrome. Neurologic complications].
AB  - PERIPHERAL NERVE INVOLVEMENT: Peripheral nerve involvement is better known than
      central nervous system involvement. The dominant features are sensoromotor
      polyneuropathies or pure sensorial polyneuropathies. CENTRAL NERVOUS SYSTEM: The
      manifestations are polymorphous, generally presenting as encephalitis and/or
      focal or multifocal involvement of the spinal cord. OTHER LOCALIZATIONS: Diffuse
      encephalic involvement is less common: acute aseptic meningitis, intellectual
      deterioration. Psychiatric manifestations are also frequently observed.
      THERAPEUTIC OPTIONS: Response to corticosteroid therapy or immunosuppressor
      therapy can be spectacular but is unpredictable.

PMID- 10414253
TI  - European radiology: the nowhere building. An initial success of the Italian
      Society of Medical Radiology.

PMID- 10414254
TI  - [Assessment of geometric, biomechanical, and osteodensitometric properties of the
      ultradistal radius with peripheral quantitative computerized tomography in uremic
      patients with severe hyperparathyroidism].
AB  - INTRODUCTION: Bone integrity and mineral status were studied with a noninvasive
      method in uremic patients with severe secondary hyperparathyroidism undergoing
      maintenance hemodialysis. MATERIAL AND METHODS: Volumetric cortical and
      trabecular mineral density (cBMD, tBMD) and bone geometrical properties were
      evaluated in 16 patients (11 women and 5 men) candidate to parathyroidectomy.
      Peripheral quantitative Computed Tomography (pQCT) was used to make measurements
      at the distal radius of the nondominant forearm. Thirty-two age-matched healthy
      subjects were chosen as a control group. Cortical area (CA), cross-sectional area
      (Total A), cortical thickness (CThk) and stress strain index (SSI) were assessed
      as biomechanical parameters. Serum intact PTH levels were assessed with a
      radioimmunoassay method (IRMA). RESULTS: Both cBMD and tBMD were decreased in all
      patients and the difference was more significant in women (p < .0004 and p <
      .009) than in the smaller group of men (p < .01 and p < .01). Serum PTH levels
      correlated negatively with cBMD (r = .52; p < .01), CThk (r = .51; p < .04), CA
      (r = .52; p < .03) and SSI (r = .54; p < .02), as well as tBMD (r = .34), though
      not significantly. Dialysis duration did not significantly correlate with cBMD (r
      = .33), tBMD (r = .20), CA (r = .31), CThk (r = .40) and SSI (r = .35). As for
      geometrical and biomechanical parameters, CA, CThk and SSI were significantly
      different in both male and female uremic patients in comparison with the relative
      controls. Bone quantitative analysis and three-dimensional (3D) representation
      with the paraboloid revolution model also demonstrated osteopenia. CONCLUSIONS:
      pQCT shows significant cortical and trabecular osteopenia in uremic patients with
      severe secondary hyperparathyroidism. Osteopenia is associated with geometrical
      and mechanical impairment with consequently increased bone fragility and thus a
      higher risk of fracture. Prolonged PTH hyperexpression seems to be mainly
      associated with intracortical porosity and cortical-endosteal resorption. Bone
      quantitative analysis and 3D representation provide rapid automated information
      on the cortex mineral status.

PMID- 10414255
TI  - [Usefulness of selective partial inversion recover (SPIR) sequences in optic
      nerve diseases].
AB  - PURPOSE: To evaluate the yield of SPIR sequences with fat suppression in the
      diagnosis of optic nerve lesions. MATERIAL AND METHODS: Ten patients with
      suspected optic nerve involvement on the basis of clinical data and abnormalities
      of visual evoked potentials were examined. MRI was performed with a 1.5 T unit
      (Philips NT 15) using T1 weighted conventional spin-echo and T1- and T2 weighted
      SPIR sequences with fat suppression. Axial images were obtained along the optic
      nerve course, while coronal images throughout the optic nerve axis; slices were 3
      mm thick. Axial T2 weighted SPIR sequences were also performed with the
      volumetric technique (1.5 mm thickness); coronal and parasagittal reconstructions
      along the nerve axis were obtained too. After paramagnetic contrast medium
      injection, conventional T1 weighted and SPIR sequences were performed on axial
      and coronal planes. RESULTS: Optic nerve lesions consistent with the diagnosis of
      neuritis were demonstrated with T2 weighted images in 4 of 10 patients. No
      abnormalities and/or nerve enlargement were found on T1 weighted images. An
      enhancement area was seen after contrast medium injection in only one case. MRI
      showed a pilocytic astrocytoma in one patient and selective atrophy of the right
      optic nerve in another. MRI showed normal findings in 4 patients. CONCLUSIONS: T1
      and T2 weighted fat-suppressed SPIR imaging of the optic nerve improves
      anatomical definition, lesion detection and characterization in optic nerve
      conditions.

PMID- 10414256
TI  - [Cerebral vascular autoregulatory dysfunction. Neuroradiologic aspects].
AB  - PURPOSE: We report the neuroimaging findings in a group of systemic disorders
      with a common pathophysiological pattern of derangements in cerebral vascular
      autoregulatory mechanism producting potentially reversible brain lesions.
      MATERIAL AND METHODS: We reviewed the brain CT and MR examinations of 14 patients
      with clinical diagnosis of vasculopathy not related to atherosclerosis or
      cardiogenic embolism. The patients were admitted at the onset of neurologic
      deficit and were affected with one of the following systemic disorders:
      thrombotic thrombocytopenic purpura (TTP, 6 cases), uremic encephalopathy (4
      cases), eclampsia (2 cases), 1 chronic renal failure from systemic lupus
      erythematosus and 1 cyclosporin neurotoxicity. All patients underwent
      neuroimaging follow-up within 7-20 days of the onset of neurologic deficit and
      the start of anti-edema therapy. RESULTS: CT and MR findings were characterized
      by cortical-subcortical or deep brain lesions related to edema. Ten patients
      presented bilateral lesions, which were symmetric in 4 cases. Edema resolution
      was demonstrated on follow-up examinations after therapy in 4 patients (2 with
      eclampsia, 1 with TTP and 1 with uremic encephalopathy). The lesions showed no
      signs of regression in 10 patients. CONCLUSIONS: Brain lesions with a common
      pathogenesis from derangements in vascular autoregulatory mechanism--i.e., not
      due to atherosclerosis or cardiogenic embolism--should be properly and promptly
      recognized because they can be reversible and readily treatable.

PMID- 10414257
TI  - [Computerized tomography features of intestinal infarction: 56 surgically treated
      patients of which 5 with reversible mesenteric ischemia].
AB  - PURPOSE: Bowel infarction is a rare and typical condition of the elderly; despite
      improvements in diagnostic imaging and vascular surgery, bowel infarction remains
      a major cause of acute abdomen, with mortality rates ranging 70-80%. Diagnosis is
      often late because clinical signs, laboratory data and radiologic findings are
      aspecific. We investigated radiographic and particularly CT patterns of
      intestinal infarction in 56 patients submitted to surgery within 12 hours of
      admission. We also report the CT findings of 5 of these patients who had
      reversible mesenteric ischemia. MATERIAL AND METHODS: We retrospectively reviewed
      56 cases of bowel infarction. The patients were 29 men and 27 women ranging in
      age 46-84 years (mean: 63). All the patients were submitted to plain radiography
      of the abdomen in different projections; emergency CT was carried out with i.v.
      contrast agent injection. We considered the following CT patterns: dilatation of
      intestinal loops > 2.5-3 mm, wall thickening > 3-4 mm, intraperitoneal effusion,
      stuffing of mesenteric vessels with diameter > 3 mm, air-fluid levels. RESULTS:
      Patients in the 7th decade of life were most frequently affected (38 cases), with
      an overall mortality rate of 59% (33 deaths). Plain radiography showed distention
      of bowel loops with air-fluid levels in 91% of cases. CT proved to be an accurate
      technique with higher sensitivity than radiography in detecting mesenteric edema
      and hemorrhage (68%), abdominal and pelvic effusion (88%), parietal pneumatosis
      (9%), wall thickening (29%), intraportal gas (7%), and thrombosis of superior
      mesenteric artery (3.5%). CT patterns in the 5 patients with reversible
      intestinal ischemia were wall thickening (80%), peritoneal effusion (80%),
      meteoric dilatatation (40%), a blurred appearance of mesenteric fat (40%).
      CONCLUSIONS: Angiography is a valuable imaging and treatment technique permitting
      the diagnosis of vascular occlusion and the intraarterial infusion of
      vasodilators, but it can be carried out in emergency in few centers only. This
      makes conventional radiology, and particularly CT, the only tool providing useful
      information for early diagnosis and treatment of bowel infarction. CT is more
      sensitive than radiography and does not exhibit the limitations of angiography-
      i.e., invasiveness, radiation exposure and complex organization. Therefore CT can
      presently be considered the method of choice in patients with suspected bowel
      infarction.

PMID- 10414258
TI  - [Abdominal mass in childhood: characterization with fine needle percutaneous
      biopsy guided with computerized tomography].
AB  - INTRODUCTION: CT-guided fine needle aspiration biopsy (FNAB) is known to improve
      diagnosis of expansile abdominal lesions, especially relative to more invasive
      procedures like explorative laparotomy. FNAB is not commonly used in pediatric
      patients because of their poor collaboration and of associated risks. We
      investigated the feasibility of FNAB in the pediatric age. MATERIAL AND METHODS:
      Over a 2-year period, we performed CT-guided FNAB of 21 abdominal lesions in a
      series of pediatric patients ranging in age 10 days to 14 years. Thirteen lesions
      were in intraperitoneal and 8 in retroperitoneal sites. CT had been performed in
      all patients but had failed to make a diagnosis. Cytologic samples were obtained
      with 22-23 G needles; the cytologist was always present to ensure adequate
      sampling. Follow-up CT was performed to assess the possible onset of
      complications. RESULTS: First-pass diagnosis was made in 14 of 21 biopsies and
      second-pass diagnosis in 5; histology was needed in three cases. Cytologic
      findings were compared with postoperative histologic results in 13 cases;
      clinical follow-up and further instrumental studies confirmed the diagnosis in
      nonsurgical patients. CONCLUSIONS: CT-guided FNAB can be performed in pediatric
      patients with accuracy and confidence. These patients' age calls for great skills
      of the operator and possible contraindications must be accurately evaluated;
      complications must not be neglected. FNAB should be performed during CT
      examination because young patients often require anesthesia. The pathologist's
      presence during biopsy permits to repeat sampling, if necessary, without
      repeating the anesthesia. CT-guided FNAB is a valid alternative to explorative
      laparotomy in the workup of expansile abdominal masses also in pediatric
      patients.

PMID- 10414259
TI  - [Tridimensional ultrasonography. First clinical experience with dedicated devices
      and review of the literature].
AB  - PURPOSE: We report our preliminary clinical experience with three-dimensional
      ultrasound (3D US) in abdominal and small parts imaging, comparing the yield of
      3D versus 2D US and through a literature review. MATERIAL AND METHODS: We used a
      Tomtec Echo-Scan 3.1 connected to a Philips P 700 unit with a 3.5 MHz convex
      probe and to a Toshiba SSA-340 A (equipped with power Doppler) with a 3.5 MHz
      convex and a 7.5 MHz linear probes. The system consists of: a) a workstation (166
      MHz Intel Pentium, 128 Mbytes RAM, 520 Mbytes hard disk, 1.3 Gbyte Magneto
      Optical drive); b) a spatial location system (3D Freehand Scanning) whose sensor,
      attached to the probe, provides spatial coordinates for each US scan in an
      electromagnetic field created by a transmitter; the software can thus correctly
      stack 2D US images to make 3D reconstructions of anatomical structures. The
      technical steps are: 1) setting; 2) image acquisition; 3) image processing and 3D
      rendering using surface or volume modes; 4) image archiving. 2D US was performed
      on 50 subjects, namely 20 volunteers and 30 patients with different pathologic
      conditions and 3D reconstructions were obtained from the best US images. We
      evaluated which anatomical structures and pathologic conditions are best suited
      for 3D rendering. RESULTS: The best 3D images were obtained from anatomical
      structures and pathologic conditions with a liquid content (i.e., bladder and
      gallbladder; cysts), or those adjacent to them (i.e., uterus and prostate). Major
      limitations were encountered in the assessment of the parenchyma of liver,
      kidneys, pancreas, thyroid, testis and breast, due to intrinsic texture low
      contrast, while intraparenchymal liquid structures (i.e., vessels, urinary
      cavities) and structures surrounded by liquid (i.e., hydrocele, ascites) were
      better demonstrated. DISCUSSION: The system permits accurate spatial location,
      and therefore stacking, of each US scan; this provides good-quality 3D images
      with fewer artifacts. The system can be connected to any existing US unit and to
      many kinds of probes. Incorrect processing or rendering may worsen 3D image
      quality and thus anatomical reconstructions; other drawbacks may come from
      difficult stacking of reconstructed images or limited field of view. Our personal
      experience and the review of 3D US literature indicate that the system may be
      used for the following clinical applications: anatomical assessment of lesions
      for minimally invasive treatment; targeting areas of interest and adjacent
      structures during radiotherapy; lesion volume studies during therapy; 3D vascular
      mapping with power Doppler; 3D reconstructions by intraluminal approach; real
      time 3D scanning for US guidance during minimally invasive procedures.
      CONCLUSIONS: Our preliminary experience suggests that technological progress will
      soon lead to a widespread use of 3D US and its applications.

PMID- 10414260
TI  - [Heart tomography with 99mTc sestamibi and echocardiography with dobutamine in
      the identification of reversible left ventricular dysfunction in patients with
      acute myocardial infarction].
AB  - INTRODUCTION: We investigated the role of technetium-99m (99mTc) sestamibi
      cardiac imaging and dobutamine echocardiography in detecting myocardial viability
      early after acute myocardial infarction. MATERIAL AND METHODS: Nineteen patients
      (mean age 52 +/- 10 years) underwent coronary angiography, low-dose dobutamine
      echocardiography and rest 99mTc sestamibi imaging within 10 days of myocardial
      infarction. All patients were revascularized. Resting echocardiogram was repeated
      8 months later to evaluate segmental functional recovery. RESULTS: Sixty-one of
      108 akinetic or dyskinetic segments at baseline showed functional recovery after
      revascularization. Sensitivity in predicting segmental functional recovery was
      87% for sestamibi imaging and 66% for dobutamine echocardiography (p < 0.001),
      while specificity and accuracy were comparable. Sestamibi activity was the
      strongest predictor of segmental functional recovery (p < 0.001). CONCLUSIONS:
      Dobutamine echocardiography predicts functional recovery after myocardial
      infarction. However, sestamibi imaging is useful to identify patients with
      dysfunctional segments without contractile reserve which may benefit by
      revascularization.

PMID- 10414261
TI  - [Integration of computerized tomography imaging with single photon emission in a
      commercial system for developing radiotherapy fields: application to
      conformational irradiation for lung carcinoma].
AB  - PURPOSE: Single photon emission computed tomography (SPECT) of lung perfusion
      permits to map functioning lung parenchyma with higher sensitivity than CT.
      Delivering higher radiation doses is used to increase local control in lung
      carcinoma; this strategy is based on radiobiological and clinical studies. Lung
      parenchyma is a dose-limiting tissue in patients irradiated for lung cancer.
      Functional mapping based on SPECT and CT findings permits to design radiation
      beams such as to minimize irradiation of functioning lung. MATERIAL AND METHODS:
      CT and SPECT were used to examine a patient with non small cell lung carcinoma
      (stage IIIB, T4N0, left lung) candidate to conformal irradiation. Images were
      spatially correlated based on lung contours and using CT findings as reference.
      SPECT images were normalized to mean right lung value and expressed as perfusion
      (functional) contours. CT images and perfusion contours were transferred to the
      treatment planning system (Cadplan V 2.79, Varian-Dosetek Oy): in this way both
      functional (SPECT) and anatomical (CT) data were available for planning. A
      comparison was made between two irradiation techniques defined at TPS with
      (technique B) or without (technique A) SPECT contour information. The prescribed
      dose was 70.2 Gy. Rival plans were compared using dose volume histograms of
      target and risk organs. Both functional and anatomical regions were considered in
      the lung, together with single lung(s) and lung parenchyma. A second perfusion
      SPECT was obtained 5 months after irradiation and correlated with pretreatment CT
      images. RESULTS: SPECT lung scans showed marked heterogeneity in the left lung,
      which was found neither at CT nor at classic lung function tests. The lung volume
      with perfusion exceeding 80% of average corresponds to about 70% of the
      anatomical volume. Mean doses to anatomical and to functional lung parenchyma
      were 24 Gy and 19 Gy, respectively, with technique A and 23 Gy and 18 Gy,
      respectively, with technique B. Thirty-five percent and 20%, respectively of
      anatomical and functional lung parenchyma received > or = 25 Gy (V25) with
      technique B. The figure for functional lung parenchyma was reduced by 5% with
      technique B. Optimal design of irradiation field geometry decreased the area of
      functional parenchyma given high doses, which sparing was greater with smaller
      irradiation volumes. CONCLUSIONS: We have integrated the functional data provided
      by SPECT lung perfusion into a commercial irradiation planning system. Lung
      function mapping permits to design irradiation portals sparing larger areas of
      functional lung parenchyma.

PMID- 10414262
TI  - [Study and implementation of a computerized program for personalized
      prescriptions for patients treated with radioiodine to be discharged].
AB  - INTRODUCTION: Iodine-131 (131I) therapy is widely used to treat some thyroid
      diseases such as hyperthyroidism and thyroid carcinoma. The discharge of a
      radioiodine treated patient is a potential problem for the radiation protection
      of the general population. To keep the absorbed dose to the general population as
      low as possible, patients are given some recommendations, on discharge usually a
      quite standard list of behaviors to avoid for an amount of time depending only on
      the administered activity. Thus, recommendations usually consider neither the
      individual kinetics of 131I nor disease type, while both factors account for
      major differences in iodine uptake and retention. We investigated the feasibility
      of customizing recommendations according to recent Euratom guidelines. MATERIAL
      AND METHODS: Individual 131I kinetics can be evaluated from previous work
      characterizing dose rate decay as a function of time for different thyroid
      diseases, together with measurements of iodine uptake or dose rate to the
      patient. Based on individual kinetics, the committed effective dose to the
      general population is calculated according to the kind of relationship with the
      patient, resulting in different amounts of time spent near him/her. RESULTS: The
      calculation procedure was implemented in a user-friendly software which requires
      input of few data and measurements to give each patient a customized list of
      precautions. Using the program on patient's discharge takes no longer than 10
      minutes. The precautions are in good agreement with those reported in the
      literature. CONCLUSIONS: We have been using our program for nine months. Data
      show that most patients treated for thyroid cancer must follow the
      recommendations for a shorter time than hyperthyroid patients. The program is
      suitable for routine use in a nuclear medicine department.

PMID- 10414263
TI  - [Assessment of potential exposure risk for radiotherapy staff working with lineal
      accelerators].
AB  - INTRODUCTION: Radiation exposure to the radiotherapy staff operating with linear
      accelerators comes from both normal exposure, which can be easily quantified by
      direct measurement, and potential exposure, whose evaluation is made difficult by
      its stochastic character. International guidelines recommend that risk be of the
      same order of magnitude for both types of exposure. We evaluated the health risk
      associated with potential exposure following the fault-tree approach suggested by
      the International Commission on Radiological Protection (IRCP) in its Publication
      76. MATERIAL AND METHODS: Considering a typical radiotherapy installation we
      identified four possible staff irradiation scenarios, namely: 1) entry into the
      treatment room after a high-energy photon beam treatment, when induced
      radioactivity from photonuclear reactions has not decayed; 2) unintentional entry
      into the treatment room when the radiation beam is on; 3) beam failing to turn
      off at the end of treatment, and subsequent entry into the treatment room; 4)
      treatment room door inadvertently left ajar, and subsequent entry when the
      radiation beam is on. Each scenario depends on a particular set of parameters
      which are related to failure probabilities and workload. Average absorbed dose,
      exposure probability and related risk have been evaluated for each scenario.
      RESULTS: Under standard parameter set-up, the overall risk did not exceed the
      IRCP threshold (i.e., .0002) by more than four orders of magnitude. Two main
      sources of potential exposure have been identified, that is early entry into the
      treatment room before safe decay of activation products and unintentional entry
      during treatment. By varying the parameters within reasonable ranges, risk has
      been shown to correlate with personnel training, workload, installation
      characteristics and operational procedures. To optimize protection, quantitative
      limitations have been set for human error probability, daily workload, number and
      quality of safety devices and waiting time before entry after a treatment with
      high-energy radiations. CONCLUSIONS: Although the potential exposure risk for a
      typical radiotherapy department with standard safety devices is well below
      international recommended values, our results indicate that risk can be further
      decreased by improving personnel training, in particular relative to minimum time
      to entry after a high-energy treatment, to respecting warning signs and being
      skilled in emergency procedures. In addition, failing to install some safety
      devices or removing them after a failure may result in rapidly exceeding IRCP
      thresholds.

PMID- 10414264
TI  - [Survey of public health services].

PMID- 10414265
TI  - [Benign distal irregularities of the femur. Radiographic and magnetic resonance
      study of a case].

PMID- 10414266
TI  - [Cystic cerebral metastasis. Report of a case].

PMID- 10414267
TI  - Bronchiolitis obliterans with organizing pneumonia (BOOP), presenting as a ring
      shaped opacity at HRCT (the atoll sign). A case report.

PMID- 10414268
TI  - [Vertebral erosion caused by aortic pseudoaneurysm. Findings with computerized
      tomography and magnetic resonance].

PMID- 10414269
TI  - [Neonatal necrotizing enterocolitis. Ultrasonographic findings of gas in the
      portal vein in two cases].

PMID- 10414270
TI  - [Intestinal Langerhans cell histiocytosis: computerized tomography findings in a
      case].

PMID- 10414271
TI  - [Cecal volvulus. Diagnosis with computerized tomography in a case].

PMID- 10414272
TI  - [Hepatoblastoma in an HCV-positive adult. Report of a case].

PMID- 10414273
TI  - [Xanthogranulomatous cholecystitis. Findings with computerized tomography in two
      cases].

PMID- 10414274
TI  - [Gas-containing calculi of the gallbladder. Report of a case studied with spiral
      computerized tomography].

PMID- 10414275
TI  - [Renal leukemia. Magnetic resonance features of a case].

PMID- 10414276
TI  - [Bronchoscopy in pregnancy...].

PMID- 10414277
TI  - Molecular diversity of ion channels and cell function.

PMID- 10414278
TI  - The "psychic" neuron of the cerebral cortex.
AB  - Remarkable advances in the identification, cloning, and localization of ion
      channels and receptors in the central nervous system have opened up unprecedented
      possibilities for relating structure to physiological function at the subcellular
      level of analysis. A singularly advanced property of select central nervous
      system neurons is their ability to exhibit increases in firing rate in relation
      to the mnemonic trace of a preceding event, a property that has been referred to
      as "working memory." Single-cell recordings from the prefrontal cortex of
      nonhuman primates have revealed neurons in the prefrontal cortex that possess
      "memory fields" analogous to the receptive field properties of sensory neurons.
      The integrity of these neurons has been shown to be essential for accurate
      performance in memory tasks performed by trained monkeys (and humans). We can now
      show that the excitability and/or tuning of these prefrontal neurons are subject
      to modulatory influences by dopamine, serotonin, GABA, and glutamate among other
      peptides and conventional neurotransmitters. I will describe the dopaminergic,
      serotonergic, and GABAergic innervation of pyramidal neurons engaged in working
      memory and the localization of neurotransmitter receptors through which they
      exert their actions. The findings reveal a remarkable degree of diversity in the
      subcellular localization and functionality of the five cloned dopamine receptors
      (D1, D2, D3, D4, and D5) and two serotonin (5HT2A and 5HT3) receptors that have
      been examined to date. The potential now exists for linking systems neurobiology
      with molecular biophysics to comprehend the highest functions of information
      processing that distinguish our species.

PMID- 10414279
TI  - Studies on conditional gene expression in the brain.
AB  - This manuscript summarizes our recent attempts to regulate in vitro and in vivo
      the expression of genes encoding components and regulators of the postsynaptic
      machinery along with marker genes such as lacZ and GFP. In particular, we studied
      tTA-dependent regulation and utilized Cre in combination with reversible
      silencing by intron engineering of dominant negative alleles. We further present
      a "knockin" approach for on-site artificial regulation of chromosomal genes.

PMID- 10414280
TI  - Diversity of mammalian voltage-gated sodium channels.
AB  - A variety of different isoforms of mammalian voltage-gated sodium channels have
      been identified. These channels can be classified into three different types.
      Eight type 1 isoforms have been identified in the CNS, PNS, skeletal muscle, and
      heart. All of these channels have been expressed in exogenous systems, and all of
      the genes have been mapped. Three type 2 isoforms have been identified in heart,
      uterus, and muscle. These channels diverge from the type 1 channels in critical
      regions, and have not been functionally expressed, so their significance is
      unknown. A single isoform identified in the PNS may represent a third class of
      channels, in that it diverges from both type 1 and 2 channels. The type 3 channel
      has not been functionally expressed.

PMID- 10414281
TI  - RNA editing of a Drosophila sodium channel gene.
AB  - Extensive analysis of cDNAs from the para locus in D. melanogaster reveals
      posttranscriptional modifications indicative of adenosine-to-inosine RNA editing.
      Most of these edits occur in highly conserved regions of the Na+ channel, and
      they occur in distant relatives of D. melanogaster as well. Sequence comparison
      between species has identified putative cis-acting elements important for each
      RNA editing site. Double-stranded RNA secondary structures with striking
      similarity to known RNA editing sites were generated based on these data. In
      addition, the RNA editing sites appear to be developmentally regulated. We have
      cloned a potential RNA editase, DRED, with a high degree of homology to the
      mammalian RED1,2 genes. The DRED locus itself is highly regulated by
      transcription from alternative promoters and alternative splicings.

PMID- 10414282
TI  - H(+)-gated cation channels.
AB  - H(+)-gated cation channels are members of a new family of ionic channels, which
      includes the epithelial Na+ channel and the FMRFamide-activated Na+ channel.
      ASIC, the first member of the H(+)-gated Na+ channel subfamily, is expressed in
      brain and dorsal root ganglion cells (DRGs). It is activated by pHe variations
      below pH 7. The presence of this channel throughout the brain suggests that the
      H+ might play an essential role as a neurotransmitter or neuromodulator. The ASIC
      channel is also present in dorsal root ganglion cells, as is its homolog DRASIC,
      which is specifically present in DRGs and absent in the brain. Since external
      acidification is a major factor in pain associated with inflammation, hematomas,
      cardiac or muscle ischemia, or cancer, these two channel proteins are potentially
      central players in pain perception. ASIC activates and inactivates rapidly, while
      DRASIC has both a fast and sustained component. Other members of this family such
      as MDEG1 and MDEG2 are either H(+)-gated Na+ channels by themselves (MDEG1) or
      modulators of H(+)-gated channels formed by ASIC and DRASIC. MDEG1 is of
      particular interest because the same mutations that produce selective
      neurodegeneration in C. elegans mechanosensitive neurons, when introduced in
      MDEG1, also produce neurodegeneration. MDEG2 is selectively expressed in DRGs,
      where it assembles with DRASIC to radically change its biophysical properties,
      making it similar to the native H(+)-gated channel, which is presently the best
      candidate for pain perception.

PMID- 10414283
TI  - Identification of voltage-activated Na+ and K+ channels in human steroid
      secreting ovarian cells.

PMID- 10414284
TI  - Cloning and functional analysis of the type III Na+ channel from human brain.

PMID- 10414285
TI  - Slow voltage-dependent inactivation of a sustained sodium current in stellate
      cells of rat entorhinal cortex layer II.

PMID- 10414286
TI  - Differential distribution of voltage-gated sodium channel alpha- and beta
      subunits in human brain.

PMID- 10414287
TI  - Properties of sodium currents and action potential firing in isolated cerebellar
      Purkinje neurons.

PMID- 10414288
TI  - Slow sodium channel inactivation in CA1 pyramidal cells.

PMID- 10414289
TI  - Molecular and functional diversity of voltage-gated calcium channels.
AB  - The contributing roles of voltage-gated calcium channels (VGCC) to the generation
      of electrical signaling are well documented. VGCCs open in response to
      depolarization of the plasma membrane and mediate the flux of calcium into
      excitable cells, which further depolarizes the membrane. But a more relevant role
      of VGCCs is to serve as highly regulated mechanisms to deliver calcium ions into
      specific intracellular locales for a variety of calcium-dependent processes
      including neurotransmitter release, hormone secretion, neuronal survival, and
      muscle contraction. Recent biochemical and molecular biological studies have
      demonstrated that the calcium channel pore-forming subunit (alpha 1) is not an
      isolated entity, but in fact interacts physically with a variety of strategically
      localized proteins. The functional consequences of such interactions as well as
      other molecular aspects of VGCC will be discussed. Finally, although far from a
      final conclusion, what is currently known about the molecular composition of
      native calcium channels will be summarized.

PMID- 10414290
TI  - alpha 1B N-type calcium channel isoforms with distinct biophysical properties.
AB  - N-type calcium channels both generate the initial calcium signal to trigger
      neurotransmitter release and also interact with synaptic release proteins at many
      mammalian central nervous system synapses. Two isoforms of the alpha 1B N-type
      channel from rat brain (alpha 1B-I and alpha 1B-II) were found to differ in four
      regions: (1) a glutamate (Glu) to glycine (Gly) substitution in domain I S3; (2)
      a Gly to Glu substitution in the domain I-II linker; (3) the insertion or
      deletion of an alanine (Ala) in the domain I-II linker; and (4) the presence or
      absence of serine/phenylalanine/methionine/glycine (SFMG) in the linker between
      domain III S3-S4. Comparison of the electrophysiological properties of the alpha
      1B-I and alpha 1B-II N-type channels shows that they exhibit distinct kinetics as
      well as altered current-voltage relations. Utilizing chimeric alpha 1B-I and
      alpha 1B-II cDNAs, we show that: (1) the Glu 177 to Gly substitution in domain I
      S3 increases the rate of activation by approximately 15-fold; (2) the presence or
      absence of Ala 415 in the domain I-II linker alters current-voltage relations by
      approximately 10 mV but does not affect channel kinetics; (3) the substitution of
      Gly 387 to Glu in the domain I-II linker also has no effect on kinetics; and (4)
      the presence or absence of SFMG (1236-1239) in domain III S3-S4 did not
      significantly affect channel current-voltage relations, kinetics, or steady state
      inactivation. We conclude that molecularly distinct alpha 1B isoforms are
      expressed in rat brain and may account for some of the functional diversity of N
      type currents in native cells.

PMID- 10414291
TI  - Molecular characterization of two members of the T-type calcium channel family.
AB  - In this chapter we review our recent studies on the cloning of two novel cDNAs
      (alpha 1G and alpha 1H), and present electrophysiological evidence that they
      encode low voltage-activated, T-type calcium channels (CavT.1 and CavT.2,
      respectively). The nucleotide sequences of these T channels are very different
      from high voltage-activated Ca2+ channels, which explains why they were not
      cloned earlier using homology-based strategies. We used a bioinformatic approach,
      cloning the first fragment in silico. We then used this fragment to screen human
      heart and rat brain lambda gt10 libraries, leading to the cloning of two full
      length cDNAs derived from distinct genes (CACNA1G and CACNA1H). The deduced amino
      acid sequences of the T channels (alpha 1G and alpha 1H) are also very different
      from previously cloned Ca2+ and Na+ channels; however, there are regions of
      structural similarity. For example, the T channels also contain four repeats, and
      within each repeat there are six putative membrane-spanning regions and a pore
      loop. Expression of these cloned channels in either Xenopus oocytes or HEK-293
      cells leads to the formation of typical T-type currents. As observed for native T
      currents, these channels activate at potentials near the resting membrane
      potential, inactivate rapidly, deactivate slowly, and have a tiny single-channel
      conductance. The currents generated by alpha 1G and alpha 1H are nearly identical
      in terms of their voltage dependence and kinetics. We present preliminary
      evidence that nickel may serve as a valuable tool in discriminating between these
      subtypes.

PMID- 10414292
TI  - Interactions of presynaptic Ca2+ channels and snare proteins in neurotransmitter
      release.
AB  - N- and P/Q-type Ca2+ channels are localized in high density in presynaptic nerve
      terminals and are crucial elements in neuronal excitation-secretion coupling. In
      addition to mediating Ca2+ entry to initiate transmitter release, they are
      thought to interact directly with proteins of the synaptic vesicle docking/fusion
      machinery. These Ca2+ channels can be purified from brain as a complex with SNARE
      proteins, which are involved in exocytosis. In addition, N-type and P/Q-type Ca2+
      channels are colocalized with syntaxin in high-density clusters in nerve
      terminals. The synaptic protein interaction (synprint) sites in the intracellular
      loop II-III (LII-III) of both alpha 1B and alpha 1A subunits of N-type and P/Q
      type Ca2+ channels bind to syntaxin, SNAP-25, and synaptotagmin. Ca2+ has a
      biphasic effect on the interactions of N-type Ca2+ channels with SNARE complexes,
      stimulating optimal binding in the range of 10-30 microM. PKC or CaM KII
      phosphorylation of the N-type synprint peptide inhibits interactions with SNARE
      complexes containing syntaxin and SNAP-25. Introduction of the synprint peptides
      into presynaptic superior cervical ganglion neurons reversibly inhibits EPSPs
      from synchronous transmitter release by 42%. At physiological Ca2+
      concentrations, synprint peptides significantly reduce transmitter release in
      injected frog neuromuscular junctions in cell culture, consistent with detachment
      of 70% of the docked vesicles from Ca2+ channels as analyzed by a theoretical
      model. Together, these studies suggest that presynaptic Ca2+ channels not only
      provide the Ca2+ signal required by the exocytotic machinery, but also contain
      structural elements that are integral to vesicle docking, priming, and fusion
      processes.

PMID- 10414293
TI  - Dissection of the calcium channel domains responsible for modulation of neuronal
      voltage-dependent calcium channels by G proteins.
AB  - The molecular determinants for G-protein regulation of neuronal calcium channels
      remain controversial. We have generated a series of alpha 1B/alpha 1E chimeric
      channels, since rat brain alpha 1E (rbEII), unlike human alpha 1E, showed no G
      protein modulation. The study, carried out in parallel using D2 receptor
      modulation of calcium currents in Xenopus oocytes of G beta gamma modulation of
      calcium currents in COS-7 cells, consistently showed an essential role for domain
      I (from the N terminus to the end of the I-II loop) of the alpha 1B Ca2+ channel
      in G-protein regulation, with no additional effect of the C terminal of alpha 1B.
      The I-II loop alone of alpha 1B, or the I-II loop together with the C-terminal
      tail, was insufficient to confer G-protein modulation of alpha 1E (rbEII). We
      have further observed that the alpha 1E clone rbEII is truncated at the N
      terminus compared to other alpha 1 subunits, and we isolated a PCR product from
      rat brain equivalent to a longer N-terminal isoform. The long N-terminal alpha
      1E, unlike the short form, showed G-protein modulation. Furthermore, the
      equivalent truncation of alpha 1B (delta N1-55) abolished G-protein modulation of
      alpha 1B. Thus, we propose that the N terminus of alpha 1B and alpha 1E calcium
      channels contains essential molecular determinants for membrane-delimited G
      protein inhibition, and that other regions, including the I-II loop and the C
      terminus, do not play a conclusive role alone.

PMID- 10414294
TI  - Neuronal voltage-activated calcium channels: on the roles of the alpha 1E and
      beta 3 subunits.
AB  - Many neurons of the central and peripheral nervous systems display multiple high
      voltage-activated (HVA) Ca2+ currents, often classified as L-, N-, P-, Q, and R
      type. The heterogeneous properties of these channels have been attributed to
      diversity in their pore-forming alpha 1, subunits, in association with various
      beta subunits. However, there are large gaps in understanding how individual
      subunits contribute to Ca2+ channel diversity. Here we describe experiments to
      investigate the roles of alpha 1E and beta 3 subunits in mammalian neurons. The
      alpha 1E subunit is the leading candidate to account for the R-type channel, the
      least understood of the various types of high voltage-activated Ca2+ channels.
      Incubation with alpha 1E antisense oligonucleotide caused a 53% decrease in the
      peak R-type current density, while no significant changes in the current
      expression were seen in sense oligonucleotide-treated cells. The specificity of
      the alpha 1E antisense oligonucleotides was supported by the lack of change in
      the amplitude of P/Q current. These results upheld the hypothesis that members of
      the E class of alpha 1 subunits support the high voltage-activated R-type current
      in cerebellar granule cells. We studied the role of the Ca2+ channel beta 3
      subunit using a gene targeting strategy. In sympathetic beta 3-/- neurons, the L
      type current was significantly reduced relative to wild type (wt). In addition, N
      type Ca2+ channels made up a smaller proportion of the total Ca2+ current than in
      wt due to a lower N-type current density in a group of neurons with small total
      currents. Voltage-dependent activation of P/Q-type Ca2+ channels was described by
      two Boltzmann components with different voltage dependence. The absence of the
      beta 3 subunit was associated with a shift in the more depolarized component of
      the activation along the voltage axis toward more negative potentials. The
      overall conclusion is that deletion of the beta 3 subunit affects at least three
      distinct types of HVA Ca2+ channel, but no single type of channel is solely
      dependent on beta 3.

PMID- 10414296
TI  - Lambert-Eaton antibodies promote activity-dependent enhancement of exocytosis in
      bovine adrenal chromaffin cells.

PMID- 10414295
TI  - Voltage-dependent calcium channel mutations in neurological disease.
AB  - Calcium ion channel mutations disrupt channel function and create recognizable
      disease phenotypes in the nervous system. The broad array of underlying cellular
      alterations is commensurate with the expanding genetic diversity of the voltage
      gated calcium ion channel complex and its critical role in regulating cell
      function. Currently, 16 calcium channel genes are known, and mutations in 7 of
      these are associated with distinct inherited neurological disorders. These
      mutations provide new insight into the structure and function of the channels,
      and link specific subunits to cellular disease processes, including altered
      excitability, synaptic signaling, and cell death. Studies of mutant channel
      behavior, subunit interactions, and the differentiation of neural networks
      demonstrate unique patterns of downstream rearrangement. Developmental analysis
      of molecular plasticity in these mutants is a critical step to define the
      intervening mechanisms that translate aberrant ion channel behavior into the
      diverse clinical phenotypes observed.

PMID- 10414297
TI  - L-type calcium channel regulation of abnormal tyrosine hydroxylase expression in
      cerebella of tottering mice.

PMID- 10414298
TI  - Okadaic acid antagonizes the inhibitory action of internal GTP-gamma-S on the
      calcium current of dorsal raphe neurons but not that of 5-HT1A receptor
      activation.

PMID- 10414299
TI  - Sensitivity to conotoxin block of splice variants of rat alpha 1B (rbBII) subunit
      of the N-type calcium channel coexpressed with different beta subunits in Xenopus
      oocytes.

PMID- 10414300
TI  - Quantitative fluorescent RT-PCR measurements of postnatal calcium channel gene
      expression in rat hippocampal subfields.

PMID- 10414301
TI  - Molecular diversity of K+ channels.
AB  - K+ channel principal subunits are by far the largest and most diverse of the ion
      channels. This diversity originates partly from the large number of genes coding
      for K+ channel principal subunits, but also from other processes such as
      alternative splicing, generating multiple mRNA transcripts from a single gene,
      heteromeric assembly of different principal subunits, as well as possible RNA
      editing and posttranslational modifications. In this chapter, we attempt to give
      an overview (mostly in tabular format) of the different genes coding for K+
      channel principal and accessory subunits and their genealogical relationships. We
      discuss the possible correlation of different principal subunits with native K+
      channels, the biophysical and pharmacological properties of channels formed when
      principal subunits are expressed in heterologous expression systems, and their
      patterns of tissue expression. In addition, we devote a section to describing how
      diversity of K+ channels can be conferred by heteromultimer formation, accessory
      subunits, alternative splicing, RNA editing and posttranslational modifications.
      We trust that this collection of facts will be of use to those attempting to
      compare the properties of new subunits to the properties of others already known
      or to those interested in a comparison between native channels and cloned
      candidates.

PMID- 10414302
TI  - Genomic organization of nematode 4TM K+ channels.
AB  - As many as 50 genes in the C. elegans genome may encode K+ channels belonging to
      the novel structural class of two-pore (4TM) channels. Many 4TM channels can be
      grouped into channel subfamilies. We analyzed 4TM channels in C. elegans using
      methods made possible by having complete genomic sequence. Two genes were chosen
      for comprehensive analysis, n2P16 and n2P17. By comparing the pattern of
      conservation in genomic DNA sequences between C. elegans and a closely related
      species, C. briggsae, we were able to identify all coding regions and predict the
      gene structure for these two genes. Given the extent of the 4TM channel family,
      we were surprised to discover that n2P17 produced at least six alternative
      transcripts encoding a constant central region and variable amino- and carboxyl
      termini. Blocks of highly conserved DNA sequences in noncoding regions were also
      apparent and most likely confer important regulatory functions. The interspecies
      comparison of the deduced channel proteins revealed that the extracellular loop
      between M1 and P1 is an apparent hot spot for evolutionary change in both
      channels. This contrasts with the membrane-spanning domains that are highly
      conserved. Analysis of intron positions for 36 channels revealed that introns are
      frequently present at an identical position within the pore region, but very few
      are located in membrane-spanning domains.

PMID- 10414304
TI  - Functional and molecular aspects of voltage-gated K+ channel beta subunits.
AB  - Voltage-gated potassium channels (Kv) of the Shaker-related superfamily are
      assembled from membrane-integrated alpha subunits and auxiliary beta subunits.
      The beta subunits may increase Kv channel surface expression and/or confer A-type
      behavior to noninactivating Kv channels in heterologous expression systems. The
      interaction of Kv alpha and Kv beta subunits depends on the presence or absence
      of several domains including the amino-terminal N-type inactivating and NIP
      domains and the Kv alpha and Kv beta binding domains. Loss of function of Kv beta
      1.1 subunits leads to a reduction of A-type Kv channel activity in hippocampal
      and striatal neurons of knock-out mice. This reduction may be correlated with
      altered cognition and motor control in the knock-out mice.

PMID- 10414303
TI  - Contributions of Kv3 channels to neuronal excitability.
AB  - Four mammalian Kv3 genes have been identified, each of which generates, by
      alternative splicing, multiple protein products differing in their C-terminal
      sequence. Products of the Kv3.1 and Kv3.2 genes express similar delayed-rectifier
      type currents in heterologous expression systems, while Kv3.3 and Kv3.4 proteins
      express A-type currents. All Kv3 currents activate relatively fast at voltages
      more positive than -10 mV, and deactivate very fast. The distribution of Kv3
      mRNAs in the rodent CNS was studied by in situ hybridization, and the
      localization of Kv3.1 and Kv3.2 proteins has been studied by
      immunohistochemistry. Most Kv3.2 mRNAs (approximately 90%) are present in
      thalamic-relay neurons throughout the dorsal thalamus. The protein is expressed
      mainly in the axons and terminals of these neurons. Kv3.2 channels are thought to
      be important for thalamocortical signal transmission. Kv3.1 and Kv3.2 proteins
      are coexpressed in some neuronal populations such as in fast-spiking interneurons
      of the cortex and hippocampus, and neurons in the globus pallidus.
      Coprecipitation studies suggest that in these cells the two types of protein form
      heteromeric channels. Kv3 proteins appear to mediate, in native neurons, similar
      currents to those seen in heterologous expression systems. The activation voltage
      and fast deactivation rates are believed to allow these channels to help
      repolarize action potentials fast without affecting the threshold for action
      potential generation. The fast deactivating current generates a quickly
      recovering after hyperpolarization, thus maximizing the rate of recovery of Na+
      channel inactivation without contributing to an increase in the duration of the
      refractory period. These properties are believed to contribute to the ability of
      neurons to fire at high frequencies and to help regulate the fidelity of synaptic
      transmission. Experimental evidence has now become available showing that Kv3.1
      Kv3.2 channels play critical roles in the generation of fast-spiking properties
      in cortical GABAergic interneurons.

PMID- 10414306
TI  - Small-conductance calcium-activated potassium channels.
AB  - SK channels play a fundamental role in all excitable cells. SK channels are
      potassium selective and are activated by an increase in the level of
      intracellular calcium, such as occurs during an action potential. Their
      activation causes membrane hyperpolarization, which inhibits cell firing and
      limits the firing frequency of repetitive action potentials. The intracellular
      calcium increase evoked by action potential firing decays slowly, allowing SK
      channel activation to generate a long-lasting hyperpolarization termed the slow
      afterhyperpolarization (sAHP). This spike-frequency adaptation protects the cell
      from the deleterious effects of continuous tetanic activity and is essential for
      normal neurotransmission. Slow AHPs can be classified into two groups, based on
      sensitivity to the bee venom toxin apamin. In general, apamin-sensitive sAHPs
      activate rapidly following a single action potential and decay with a time
      constant of approximately 150 ms. In contrast, apamin-insensitive sAHPs rise
      slowly and decay with a time constant of approximately 1.5 s. The basis for this
      kinetic difference is not yet understood. Apamin-sensitive and apamin-insensitive
      SK channels have recently been cloned. This chapter will compare with different
      classes of sAHPs, discuss the cloned SK channels and how they are gated by
      calcium ions, describe the molecular basis for their different pharmacologies,
      and review the possible role of SK channels in several pathological conditions.

PMID- 10414305
TI  - The eag family of K+ channels in Drosophila and mammals.
AB  - Mutations of eag, first identified in Drosophila on the basis of their leg
      shaking phenotype, cause repetitive firing and enhanced transmitter release in
      motor neurons. The encoded EAG polypeptide is related both to voltage-gated K+
      channels and to cyclic nucleotide-gated cation channels. Homology screens
      identified a family of eag-related channel polypeptides, highly conserved from
      nematodes to humans, comprising three subfamilies: EAG, ELK, and ERG. When
      expressed in frog oocytes, EAG channels behave as voltage-dependent, outwardly
      rectifying K(+)-selective channels. Mutations of the human eag-related gene
      (HERG) result in a form of cardiac arrhythmia that can lead to ventricular
      fibrillation and sudden death. Electrophysiological and pharmacological studies
      have provided evidence that HERG channels specify one component of the delayed
      rectifier, IKr, that contributes to the repolarization phase of cardiac action
      potentials. An important role for HERG channels in neuronal excitability is also
      suggested by the expression of these channels in brain tissue. Moreover,
      mutations of ERG-type channels in the Drosophila sei mutant cause temperature
      induced convulsive seizures associated with aberrant bursting activity in the
      flight motor pathway. The in vivo function of ELK channels has not yet been
      established, but when these channels are expressed in frog oocytes, they display
      properties intermediate between those of EAG- and ERG-type channels. Coexpression
      of the K(+)-channel beta subunit encoded by Hk with EAG in oocytes dramatically
      increases current amplitude and also affects the gating and modulation of these
      currents. Biochemical evidence indicates a direct physical interaction between
      EAG and HK proteins. Overall, these studies highlight the diverse properties of
      the eag family of K+ channels, which are likely to subserve diverse functions in
      vivo.

PMID- 10414307
TI  - The functional role of alternative splicing of Ca(2+)-activated K+ channels in
      auditory hair cells.
AB  - Turtle auditory hair cells are frequency tuned by the activity of large
      conductance calcium-activated potassium (KCa) channels, the frequency range being
      dictated primarily by the channel kinetics. Seven alternatively spliced isoforms
      of the KCa channel alpha-subunit, resulting from exon insertion at two splice
      sites, were isolated from turtle hair cells. These, when expressed in Xenopus
      oocytes, produced KCa channels with a range of apparent calcium sensitivities and
      channel kinetics. However, most expressed channels were less calcium sensitive
      than the hair cells' native KCa channels. Coexpression of alpha-subunit with a
      bovine beta-subunit substantially increased the channel's calcium sensitivity
      while markedly slowing its kinetics, but kinetic differences between isoforms
      were preserved. These data suggest a molecular mechanism for hair cell frequency
      tuning involving differential expression of different KCa channel alpha-subunits
      in conjunction with an expression gradient of a regulatory beta-subunit.

PMID- 10414308
TI  - Structure, G protein activation, and functional relevance of the cardiac G
      protein-gated K+ channel, IKACh.
AB  - The muscarinic-gated atrial potassium channel IKACh has been well characterized
      functionally, and has been an excellent model system for studying G
      protein/effector interactions. Complementary DNAs encoding the composite subunits
      of IKACh have been identified, allowing direct probing of structural and
      functional features of the channel. Here, we highlight recent approaches taken in
      our laboratory to determine the oligomeric structure of native cardiac IKACh, the
      mechanism of activation of IKACh by G proteins, and the relevance of IKACh to
      cardiac physiology.

PMID- 10414309
TI  - Potassium currents in developing neurons.
AB  - In Xenopus spinal neurons, delayed rectifier type voltage-dependent potassium
      currents (IKv) are developmentally regulated. These currents play a pivotal role
      in maturation of the action potential from a long-duration calcium-dependent
      impulse to a brief sodium-dependent one. Although spinal neurons are
      heterogeneous, IKv undergoes a synchronized and homogeneous developmental
      functional up-regulation across this diverse population of motor, sensory, and
      interneurons. This finding suggested that the diverse population of neurons
      expressed a common potassium channel. Thus, recent efforts have been directed
      towards cloning the relevant potassium channel gene. However, these molecular
      studies reveal an unsuspected heterogeneity in the molecular components of
      voltage-dependent potassium channels. Further, synchronous differentiation of IKv
      is achieved via heterogeneous Kv channel gene expression.

PMID- 10414310
TI  - Dysfunction of delayed rectifier potassium channels in an inherited cardiac
      arrhythmia.
AB  - The rapid (IKr) and slow (IKs) delayed rectifier K+ currents are key regulators
      of cardiac repolarization. HERG encodes the Kr channel, and KVLQT1 and hminK
      encode subunits that coassemble to form Ks channels. Mutations in any one of
      these genes cause Romano-Ward syndrome, an autosomal dominant form of long QT
      syndrome (LQT). Mutations in KVLQT1 and HERG are the most common cause of LQT.
      Not all missense mutations of HERG or KVLQT1 have the same effect on K+ channel
      function. Most mutations result in a dominant-negative effect, but the severity
      of the resulting phenotype varies widely, as judged by reduction of current
      induced by coexpression of wild-type and mutant subunits in heterologous
      expression systems. Mutations in hminK (S74L, D76N) reduce IKs by shifting the
      voltage dependence of activation and accelerating channel deactivation. A
      recessive form of LQT is caused by mutations in either KVLQT1 or hminK. The
      functional consequences of mutations in delayed rectifier K+ channel subunits are
      delayed cardiac repolarization, lengthened QT interval, and an increased risk of
      torsade de pointes and sudden death.

PMID- 10414311
TI  - Topology of the pore region of an inward rectifier K+ channel, Kir2.1.

PMID- 10414312
TI  - Virus-mediated modification of cellular excitability.

PMID- 10414313
TI  - Functional characterization of a cloned human intermediate-conductance Ca(2+)
      activated K+ channel.

PMID- 10414314
TI  - Probing the potassium channel Kv beta 1/Kv1.1 interaction using a random peptide
      display library.

PMID- 10414316
TI  - The role of Kir2.1 in the genesis of native cardiac inward-rectifier K+ currents
      during pre- and postnatal development.
AB  - Our results demonstrate that (a) the Kir2.1 gene encodes a native K+ channel
      protein with a 21-pS conductance; (b) this channel has an important role in the
      genesis of adult ventricular 1K1; and (c) the contribution of Kir2.1 channel
      proteins to 1K1 changes during development. The lack of contribution of Kir2.1 to
      fetal 1K1 channels is interesting from the point of view of possible future
      generation of knockout mice lacking Kir2.1, since cardiac abnormalities would not
      be expected to result in fetal lethality. These observations provide further
      support for a generalized hypothesis that different genes may code for 1K1
      channel proteins at various developmental stages. However, the effects of these
      AS-oligos must first be examined on native 1K1 channels in cardiac myocytes
      before definite conclusions can be reached.

PMID- 10414315
TI  - PKC modulation of minK current involves multiple phosphorylation sites.

PMID- 10414318
TI  - Functional characterization of a novel mutation in KCNA1 in episodic ataxia type
      1 associated with epilepsy.

PMID- 10414317
TI  - Kv2.1/Kv9.3, an ATP-dependent delayed-rectifier K+ channel in pulmonary artery
      myocytes.

PMID- 10414319
TI  - Regulation of a human neuronal voltage-gated potassium channel (hKv1.1) by
      protein tyrosine phosphorylation and dephosphorylation.

PMID- 10414320
TI  - Regulation of firing pattern through modulation of non-Sh K+ currents by
      calcium/calmodulin-dependent protein kinase II in Drosophila embryonic neurons.

PMID- 10414321
TI  - Expression of Kv1.2 potassium channels in rat sensory ganglia. An
      immunohistochemical study.

PMID- 10414322
TI  - Effects on ion permeation with hydrophobic substitutions at a residue in Shaker
      S6 that interacts with a signature sequence amino acid.

PMID- 10414323
TI  - Recent excitement in the ionotropic glutamate receptor field.
AB  - The synapse is a specialized cellular junction with an elaborate and highly
      evolved capacity for signal transduction. At excitatory synapses, the
      neurotransmitter glutamate is released from the presynaptic nerve terminal and
      stimulates several types of glutamate receptors in the postsynaptic membrane.
      These include the ionotropic receptors, which are glutamate-gated cation
      channels, and the metabotropic receptors, which are G protein-coupled seven
      transmembrane receptors. The ionotropic glutamate receptors have received special
      attention because of growing evidence that changes in their synaptic abundance,
      posttranslational modification, or molecular interactions can provide long-term
      changes in synaptic strength. This review summarizes new information about the
      ionotropic glutamate receptors and relates receptor function to the organization
      of the postsynaptic membrane and the regulation of electrophysiologic and
      biochemical signaling at the synapse.

PMID- 10414324
TI  - The arrangement of glutamate receptors in excitatory synapses.
AB  - Electron microscopic immunogold analyses have revealed a highly differentiated
      arrangement of glutamate receptors at excitatory synapses in the central nervous
      system. Studies focused on the hippocampus and cerebellum have shown that the
      postsynaptic specialization is the preferential site of NMDA and AMPA receptor
      expression, and that the delta 2 receptor is similarly concentrated at this site.
      In cases of colocalization (AMPA and NMDA, or AMPA and delta 2) the two receptor
      types appear to be intermingled rather than segregated to separate parts of the
      membrane. The different groups of metabotropic receptor exhibit distinct
      distributions at the synapse: group I receptors occur in membrane domains lateral
      to the postsynaptic specialization; group II receptors are expressed in
      preterminal membranes or extra-synaptically; whereas group III receptors are
      found in, or close to, the presynaptic active zone consistent with their roles as
      autoreceptors. The differentiated distribution of glutamate receptors reflects
      their functional heterogeneity and explains why some receptors are activated only
      at high firing frequencies.

PMID- 10414325
TI  - Glutamate receptor anchoring proteins and the molecular organization of
      excitatory synapses.
AB  - Ionotropic glutamate receptors are concentrated at postsynaptic sites in
      excitatory synapses. The cytoplasmic C-terminal tail of certain glutamate
      receptor subunits interact with specific PDZ domain-containing proteins. NMDA
      receptor NR2 subunits bind to the PSD-95 family of proteins, whereas AMPA
      receptor subunits GluR2/3 bind to GRIP. These interactions may underlie the
      clustering, targeting, and immobilization of the glutamate receptors at
      postsynaptic sites. By virtue of their multiple protein-binding domains (e.g.,
      three PDZs in PSD-95 and seven PDZs in GRIP), PSD-95 and GRIP can function as
      multivalent proteins that organize a specific cytoskeletal and signaling complex
      associated with each class of glutamate receptor. The network of protein-protein
      interactions mediated by these abundant PDZ proteins is likely to contribute
      significantly to the molecular scaffold of the postsynaptic density.

PMID- 10414326
TI  - Mice with genetically modified NMDA and AMPA receptors.
AB  - This manuscript summarizes mouse mutants for ionotropic glutamate receptors that
      were generated by different laboratories to analyze the function of the NMDA and
      AMPA receptors in the mouse. Thus, NMDA receptor mutant mice that were generated
      by the "knock-in" technology demonstrate that the NR1 and the NR2B subunits
      participate in the formation of NMDA receptors that are involved in vital
      functions like breathing and suckling of a newborn mouse. Mice that lack NR2A, 
      2C, and -2D subunits were described to be viable and have been used to study the
      role of NMDA receptors in adult mice. The depletion of the GluR-B subunit
      revealed an NMDA receptor-independent form of long-term potentiation (LTP). This
      AMPA receptor-mediated LTP at CA3/CA1 synapses was also observed in mice that
      carry an editing-deficient GluR-B allele even though these mice die prematurely
      after heavy epileptic seizures. In other mutants, the intracellular COOH-terminal
      domain of the NMDA receptor was truncated; and when compared to NMDA receptor
      "knock-out" mice, a functional knock-out of the NMDA receptor was observed.
      However, in the synapses of NR2AC/AC mutants, gatable NMDA receptors were
      synaptically activated, indicating that the knock-out phenotypes mediated by the
      COOH-terminally truncated NMDA receptors appear to reflect defective
      intracellular signaling.

PMID- 10414328
TI  - Expression mechanisms underlying NMDA receptor-dependent long-term potentiation.
AB  - Long-term potentiation (LTP) is currently the best available cellular model for
      learning and memory in the mammalian brain. In the CA1 region of the hippocampus,
      as well as in many other areas of the CNS, its induction requires a rise in
      postsynaptic Ca2+ via activation of NMDA receptors. What happens after the rise
      in postsynaptic Ca2+ is less clear. This paper summarizes experiments performed
      over the last decade in slice preparations that address the site of expression of
      LTP. While a large number of laboratories have contributed importantly to this
      issue, this review will rely primarily on experiments performed in the authors'
      laboratory. The experiments to be discussed can be broadly divided into two
      groups: those designed to determine if an increase in glutamate release occurs
      during LTP and those designed to determine if a change in postsynaptic
      sensitivity to glutamate occurs during LTP. Experiments in the first category
      include the analysis of dual-component excitatory postsynaptic currents (EPSCs),
      paired-pulse facilitation, saturating release probability, the use of MK-801 to
      measure release probability, and glial glutamate transporter currents to measure
      directly the synaptic release of glutamate. Experiments in the second category
      include analysis of miniature EPSC amplitudes, measurements of synaptic potency,
      the consequences of loading cells with the constitutively activated form of CaM
      kinase II, and the evidence that during LTP postsynaptically silent synapses
      become functional. We will argue that, while numerous experiments fail to support
      a presynaptic expression mechanism, many experiments do point to a postsynaptic
      expression mechanism. The decrease in synaptic failures during LTP, the only
      generally accepted experimental result that supports a presynaptic expression
      mechanism, can be explained by postsynaptically silent synapses. Future
      directions for research in this field include activity-dependent targeting of
      glutamate receptors and the functional consequences of phosphorylation of AMPA
      receptors.

PMID- 10414327
TI  - GluR delta 2 and the development and death of cerebellar Purkinje neurons in
      lurcher mice.
AB  - Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation.
      Heterozygous lurcher mice (Lc/+) display ataxia due to a selective, cell
      autonomous, apoptotic death of 90% of cerebellar Purkinje cells during postnatal
      development. Homozygous lurcher mice (Lc/Lc) die shortly after birth due to
      massive loss of mid- and hindbrain neurons during late embryogenesis. We
      identified the mutations responsible for neurodegeneration in two independent Lc
      alleles as identical G-to-A transitions that change a highly conserved alanine to
      a threonine residue in transmembrane domain III of the mouse delta 2 glutamate
      receptor gene (GluRE2). Lc/+ Purkinje cells displayed a very high membrane
      conductance and a depolarized resting potential, indicating the presence of a
      large, constitutive inward current. Expression of the mutant GluR delta 2Lc
      protein in Xenopus oocytes confirmed these results, demonstrating that lurcher is
      an inherited neurodegenerative disorder resulting from a gain-of-function
      mutation in a glutamate receptor gene. Further characterization of GluR delta 2
      signaling and the activation of apoptotic death in Lc Purkinje cells have begun
      to yield mechanistic insights into this neurodegenerative disease, and to
      highlight its relationship to neuronal loss following ischemia.

PMID- 10414329
TI  - Activation of N-methyl-D-aspartate receptors reverses desensitization of
      metabotropic glutamate receptor, mGluR5, in native and recombinant systems.

PMID- 10414330
TI  - Distribution of group III mGluRs in rat basal ganglia with subtype-specific
      antibodies.

PMID- 10414331
TI  - Characterization, expression, and distribution of GRIP protein.

PMID- 10414332
TI  - GluR2 antisense knockdown produces seizure behavior and hippocampal
      neurodegeneration during a critical window.

PMID- 10414333
TI  - Activation of kainate receptors on rat sensory neurons evokes action potential
      firing and may modulate transmitter release.

PMID- 10414334
TI  - An immunocytochemical assay for activity-dependent redistribution of glutamate
      receptors from the postsynaptic plasma membrane.

PMID- 10414335
TI  - Activation of PKC disrupts presynaptic inhibition by group II and group III
      metabotropic glutamate receptors and uncouples the receptor from GTP-binding
      proteins.

PMID- 10414336
TI  - AMPA receptor forms a biochemically functional complex with NSF and alpha- and
      beta-SNAPs.

PMID- 10414337
TI  - ABP: a novel AMPA receptor binding protein.
AB  - We review the cloning of a novel AMPA receptor binding protein (ABP) that
      interacts with GluR2/3 and is homologous to GRIP. ABP is enriched in the PSD with
      GluR2 and is localized to the PSD by EM. ABP binds GluR2 via the C-terminal VXI
      motif through a Class I PDZ interaction. ABP and GRIP can also homo- and
      heteromultimerize. Thus, ABP and GRIP may be involved in AMPA receptor regulation
      and localization, by linking it to other cytoskeletal or signaling molecules. We
      suggest that the ABP/GRIP and PSD-95 families form distinct scaffolds that
      anchor, respectively, AMPA and NMDA receptors. We are currently investigating
      proteins that bind ABP and that may regulate the AMPA receptor.

PMID- 10414338
TI  - Molecular diversity of neuronal nicotinic acetylcholine receptors.
AB  - The potent behavioral and cognitive effects of nicotine highlight the
      physiological importance of nicotinic acetylcholine receptors (nAChRs). These
      receptors are part of the superfamily of neurotransmitter-gated ion channels that
      are responsible for rapid intercellular communication. Molecular cloning of the
      protein subunits that make up these receptors has led to greater understanding of
      the pharmacology and physiology of nAChRs. This review outlines our current
      understanding of the molecular constituents of these receptors and some of the
      recent studies of the structural determinants of receptors function.

PMID- 10414339
TI  - Heteromeric complexes of alpha 5 and/or alpha 7 subunits. Effects of calcium and
      potential role in nicotine-induced presynaptic facilitation.
AB  - Nicotine alters a broad spectrum of behaviors, including attention, arousal,
      anxiety, and memory. The cellular physiology of nicotine is comparably diverse:
      nicotine interacts with an array of ionotropic receptors whose gating can lead to
      direct depolarization of neurons or to an indirect modulation of neuronal
      excitability by presynaptic facilitation. Furthermore, as many laboratories have
      shown, the alpha- and beta-type subunits that comprise neuronal nicotinic
      acetylcholine receptors (nAChRs) are encoded by multiple, homologous genes,
      yielding at least seven alpha and three beta subunits, distinct in primary
      sequence. nAChRs that differ in subunit composition differ in pharmacology,
      conductance, and kinetics as well as in their permeability to and modulation by
      calcium. We will first discuss recent studies on the biophysics of a special
      (peculiar?) subset of nAChRs, focusing on heteromeric nAChRs comprised of alpha 4
      beta 2 +/- alpha 5 or alpha 7 +/- beta 2 and alpha 5. These nAChR channel
      subtypes are potently and differentially modulated by changes in intracellular
      calcium ([Ca]). Thus, the Po, tau o, and desensitization kinetics of alpha 4 beta
      2 channels are altered by changes in [Ca]int from 0 to 50 microM; nAChRs that
      include the alpha 5 subunit are oppositely regulated. Mutagenesis of specific
      residues within the M1 and M2 domain of alpha 4, beta 2, and alpha 5 suggest a
      possible Ca binding "pocket." The assembly of functional nAChRs that include
      alpha 5 and/or alpha 7 and the potential role of these novel heteromeric
      complexes in presynaptic facilitation will also be presented.

PMID- 10414340
TI  - Nicotinic modulation of glutamate and GABA synaptic transmission of hippocampal
      neurons.
AB  - Although the hippocampus expresses nicotinic acetylcholine receptors (nAChRs) and
      receives cholinergic innervation, the functional roles of these receptors are not
      completely understood. Our results indicated that presynaptic nAChRs mediated a
      calcium influx that enhanced the release of both glutamate and GABA. Fura-2
      detection of calcium in single mossy fiber presynaptic terminals indicated that
      nAChRs directly mediated a calcium influx. In hippocampal neurons in primary
      culture, both spontaneous vesicular release and evoked release of glutamate and
      GABA were enhanced by nicotine. The nicotinic current displayed rapid
      desensitization kinetics, and the response to nicotine was inhibited by alpha
      bungarotoxin and methyllcaconitine, suggesting that nAChRs containing the alpha 7
      subunit mediated the effect. Modulation of synaptic activity by presynaptic
      calcium influx may represent a physiological role of acetylcholine in the brain,
      as well as a mechanism of action of nicotine.

PMID- 10414341
TI  - The role of beta 2-subunit-containing nicotinic acetylcholine receptors in the
      brain explored with a mutant mouse.
AB  - Neuronal nicotinic receptors comprise a family of pentameric oligomers made up of
      a combination of 10 different subunits. The beta 2 subunit has the widest pattern
      of expression in the brain and is thus likely to form a significant fraction of
      neuronal nicotinic receptors. Using mice lacking the beta 2 subunit, we have
      shown that nAChRs containing this subunit are responsible for most of the high
      affinity binding sites for nicotine, cytisine, and epibatidine in the brain.
      Functional receptors containing the beta 2-subunit are found in the
      somatodendritic compartment as well as the axonal compartment of neurons. We have
      examined the contribution of these receptors to the effects of nicotine on the
      mesolimbic DA system, which mediates the reinforcing properties of many addictive
      drugs (including nicotine). Submicromolar doses of nicotine, corresponding to the
      concentrations of nicotine in vivo in self-administration paradigms, increased
      the firing rate of dopaminergic neurons in vitro in normal mice but not in mice
      lacking the beta 2 subunit. Consistently, systemic injection of nicotine induced
      an increase in extracellular dopamine in normal mice but not in mutant mice, and
      nicotine self-administration was reduced or suppressed in mutant mice. These data
      support the view that the beta 2-containing receptors are involved in mediating
      the reinforcing properties of nicotine.

PMID- 10414342
TI  - Development of a novel class of subtype-selective nicotinic receptor antagonist:
      pyridine-N-substituted nicotine analogs.

PMID- 10414343
TI  - Desensitization of nicotinic receptors in the central nervous system.

PMID- 10414344
TI  - Methyllycaconitine-, alpha-bungarotoxin-sensitive neuronal nicotinic receptor
      operates slow calcium signal in skeletal muscle end plate.

PMID- 10414345
TI  - Ultrastructural immunolocalization of the alpha 7 nAChR subunit in guinea pig
      medial prefrontal cortex.

PMID- 10414346
TI  - Nicotinic receptor subunit mRNA expression in dopaminergic neurons of the rat
      brain.

PMID- 10414347
TI  - Physostigmine and atropine potentiate and inhibit neuronal alpha 4 beta 4
      nicotinic receptors.

PMID- 10414348
TI  - The long cytoplasmic loop of the alpha 3 subunit targets specific nAChR subtypes
      to synapses on neurons in vivo.

PMID- 10414349
TI  - Molecular and functional diversity of the expanding GABA-A receptor gene family.
AB  - Fast inhibitory neurotransmission in the mammalian CNS is mediated primarily by
      the neurotransmitter gamma-aminobutyric acid (GABA), which, upon binding to its
      receptor, leads to opening of the intrinsic ion channel, allowing chloride to
      enter the cell. Over the past 10 years it has become clear that a family of GABA
      A receptor subtypes exists, generated through the coassembly of polypeptides
      selected from alpha 1-alpha 6, beta 1-beta 3, gamma 1-gamma 3, delta, epsilon,
      and pie to form what is most likely a pentomeric macromolecule. The gene
      transcripts, and indeed the polypeptides, show distinct patterns of temporal and
      spatial expression, such that the GABA-A receptor subtypes have a defined
      localization that presumably reflects their physiological role. A picture is
      beginning to emerge of the properties conferred to receptor subtypes by the
      different subunits; these include different functional properties, differential
      modulation by protein kinases, and the targeting to different membrane
      compartments. These properties presumably underlie the different physiological
      roles of the various receptor subtypes. Recently we have identified a further
      member of the GABA-A receptor gene family, which we have termed theta, which
      appears to be most closely related to the beta subunits. The structure, function,
      and distribution of theta-containing receptors, and receptors containing the
      recently reported epsilon subunit, are described.

PMID- 10414350
TI  - Activity-dependent regulation of GABAA receptors.
AB  - GABAA receptor heterogeneity is based on the combinatorial assembly of a large
      family of subunits into distinct receptor subtypes. A neuron-specific expression
      pattern of receptor subtypes has been demonstrated in adult rat brain, which can
      be reproduced in vitro in primary neuron cultures. This suggests that genetic
      programs established during ontogeny govern the expression of gamma-aminobutyric
      acid (GABAA) receptor subtypes. Activity-dependent mechanisms nevertheless
      modulate on a short-term basis the cell surface expression of GABAA receptors, as
      demonstrated in cultured hippocampal neurons upon blockade of synaptic
      transmission or application of brain-derived neurotrophic factor. Preliminary
      evidence points to changes in protein phosphorylation as a mechanism underlying
      short-term activity-dependent regulation of GABAA receptors. In vivo, chronic
      pharmacological modulation of neuronal activity during development, while having
      marked effects on the rate of cortical growth, failed to influence the expression
      of GABAA receptor subtypes, suggesting that additional factors are involved.

PMID- 10414351
TI  - Structure and functions of inhibitory and excitatory glycine receptors.
AB  - The strychnine-sensitive glycine receptor (GlyR) is a pentameric chloride channel
      protein that exists in several developmentally and regionally regulated isoforms
      in the CNS. These result from the differential expression of four genes encoding
      different variants (alpha 1-alpha 4) of the ligand-binding subunit of the GlyR.
      Their assembly with the structural beta subunit is governed by "assembly
      cassettes" within the extracellular domains of these proteins and creates
      chloride channels of distinct conductance properties. GlyR gating is potentiated
      by Zn2+, a metal ion co-released with different neurotransmitters. Site-directed
      mutagenesis has unraveled major determinants of agonist binding and Zn2+
      potentiation. During development, glycine receptors mediate excitation that
      results in Ca2+ influx and neurotransmitter release. Ca2+ influx triggered by the
      activation of embryonic GlyRs is required for the synaptic localization of the
      GlyR and its anchoring protein gepyhrin. In the adult, mutations in GlyR-subunit
      genes result in motor disorders. The spastic and spasmodic phenotypes in mouse as
      well as human hereditary startle disease will be discussed.

PMID- 10414352
TI  - Changes in GABAA receptor-mediated synaptic transmission in oxytocin neurons
      during female reproduction: plasticity in a neuroendocrine context.

PMID- 10414353
TI  - Structure-function relationships of the human glycine receptor: insights from
      hyperekplexia mutations.

PMID- 10414354
TI  - Regulation of glycine transport in cultured Muller cells by Ca2+/calmodulin
      dependent enzymes.

PMID- 10414355
TI  - Processing of GABABR1 in heterologous expression systems.

PMID- 10414356
TI  - Postsynaptic colocalization of gephyrin and GABAA receptors.

PMID- 10414357
TI  - Structural requirements for the interaction of unsaturated free fatty acids with
      recombinant human GABAA receptor complexes.

PMID- 10414358
TI  - 5-HT receptor knockout mice: pharmacological tools or models of psychiatric
      disorders.
AB  - The molecular diversity of cloned serotonin receptor subtypes in the brain makes
      it difficult to understand the specific modulatory roles played by different
      receptors. In order to understand the role of the 5-HT1B receptor subtype in
      behavior and neuropsychiatric disorders, we have been studying genetic knockout
      mice lacking the 5-HT1B receptor. The 5-HT1B knockout mice show evidence of
      increased aggression and impulsivity, behavioral patterns that are also
      associated with reduced 5-HT function. They also show reduced or absent locomotor
      stimulation to some serotoninergic drugs, indicating that the locomotor effects
      of these drugs require the 5-HT1B receptor. However, in some cases, data obtained
      with knockout mice conflicts with the pharmacological data. The 5-HT1B receptor
      knockout mice show a phenotype of increased vulnerability to drugs of abuse such
      as cocaine. However, pharmacological studies suggest that 5-HT1B stimulation
      enhances the effects of cocaine, while 5-HT1B blockade can attenuate some of the
      effects of cocaine. Compensations that enhance dopamine function appear to be
      responsible for the drug-vulnerable phenotype of 5-HT1B receptor knockout mice.
      By studying these compensations and changes in neural function, we can learn more
      about the fundamental mechanisms underlying addiction. The 5-HT1B knockout mice
      should be considered a model for the disease state of vulnerability to drugs of
      abuse, rather than a direct pharmacological model of 5-HT1B receptor function.

PMID- 10414359
TI  - Functional and molecular diversity of purinergic ion channel receptors.
AB  - P2X receptors are membrane ion channels gated by extracellular adenosine 5'
      triphosphate (ATP); nucleotides also activate a family of seven transmembrane G
      protein-coupled receptors (P2Y). P2X receptors are widely expressed on mammalian
      cells, where they can be broadly differentiated into three groups. The first
      group is almost equally well activated by ATP and its analog alpha beta
      methyleneATP (alpha beta meATP), whereas a second group is not activated by alpha
      beta meATP. A third-group type of receptor (termed P2Z) is distinguished by the
      fact that the channel opening is followed by cell permeabilization and lysis if
      the agonist application is continued for more than a few seconds. Seven cDNAs
      have been cloned that encode P2X receptor subunits. When expressed individually
      in heterologous systems, P2X1 and P2X3 subunits form channels activated by ATP or
      alpha beta meATP; whereas P2X2, P2X4, and P2X5 form channels activated by ATP but
      not alpha beta meATP. P2X6 receptors do not express readily, and P2X7 receptors
      correspond closely in their properties to P2Z. Further phenotypes can be produced
      when two subunits are coexpressed, indicating hetero-multimerization. This
      chapter compares the properties of the native P2X receptors with those of the
      cloned and expressed subunits.

PMID- 10414360
TI  - Cyclic nucleotide-gated channels. Molecular mechanisms of activation.
AB  - Activation of cyclic nucleotide-gated (CNG) channels represents the final step in
      the transduction pathways in both vision and olfaction. Over the past several
      years, CNG channels have been found in a variety of other cell types where they
      might fulfill various physiological functions. The olfactory and photoreceptor
      CNG channels rely on the binding of at least two molecules of cAMP or cGMP at
      intracellular sites on the channel protein to open a nonspecific cation
      conductance with a significant permeability to Ca ions. A series of elegant
      experiments with cloned channels and chimeric constructs has revealed significant
      information regarding the binding and gating reactions that lead to CNG channel
      activation. These recent studies have identified several regions as well as
      specific amino acid residues distributed on the retinal or the olfactory CNG
      channel subunits that play a key role in channel regulation. In this review, we
      will focus on these specific molecular sites of activation and modulation of CNG
      channels.

PMID- 10414361
TI  - The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker
      channels.
AB  - The molecular basis of the hyperpolarization-activated cation channels that
      underlie the anomalous rectifying current variously termed Ih, Iq, or I(f) is
      discussed. On the basis of the expression patterns and biophysical properties of
      the newly cloned HCN ion channels, an initial attempt at defining the identity
      and subunit composition of channels underlying native Ih is undertaken. By
      comparing the sequences of HCN channels to other members of the K channel
      superfamily, we discuss how channel opening may be coupled to membrane
      hyperpolarization and to direct binding of cyclic nucleotide. Finally, we
      consider some of the questions in cardiovascular physiology and neurobiology that
      can be addressed as a result of the demonstration that Ih is encoded by the HCN
      gene family.

PMID- 10414362
TI  - Ca(2+)-mediated up-regulation of Ih in the thalamus. How cell-intrinsic ionic
      currents may shape network activity.

PMID- 10414363
TI  - Cell tropism of Staphylococcus aureus in bovine mammary gland cell cultures.
AB  - Staphylococcus aureus is one of the most important pathogens of the bovine
      mammary gland. The interaction of S. aureus with cells of the bovine mammary
      gland is considered to play an essential role in the pathogenesis. In this study,
      we identified a new target cell for S. aureus adhesion and invasion. For that
      purpose, cells which compose the alveoli of the mammary gland were cultured. In
      these cultures, two morphologically different cell types, elongated and cubic
      cells, were observed. Adhesion and invasion of S. aureus was studied using
      microscopical and microbiological methods. S. aureus adhered specifically and in
      large numbers (about 300 bacteria/cell) to the elongated cell type. No adhesion
      to the cubic cell type was observed. In addition, bacteria were also found
      intracellularly in the elongated cells, and enclosed in membrane vesicles.
      Adhesion and invasion were time dependent and reached maximum levels after 4 h.
      Invasion was strongly reduced by staurosporine and genistein. The newly
      identified target cell was further characterized.

PMID- 10414364
TI  - Bovine CD18 identified as a species specific receptor for Pasteurella haemolytica
      leukotoxin.
AB  - Ligand blotting of Pasteurella haemolytica leukotoxin (LKT) susceptible BL3
      bovine lymphoma cell membranes with LKT detected two putative receptors with Mr
      of 95 and 100 kDa, whereas no LKT binding to membrane proteins was detected for
      LKT non-susceptible human leukemic cells. Anti-bovine CD18 and CD11a/CD18 mAb
      recognized 95 and 100kDa bands from BL3 cell membranes. CD18 isolated from BL3
      cell membranes bound LKT. Pre-incubation of BL3 cells with anti-bovine CD18 or
      CD11a/CD18 mAb caused partial inhibition of LKT-induced leukolysis. Therefore, we
      propose that bovine CD18 acts as a species-specific leukocyte receptor for P.
      haemolytica LKT.

PMID- 10414365
TI  - Binding of extracellular matrix proteins by animal strains of staphylococcal
      species.
AB  - All 81 strains of Staphylococcus species isolated mainly from animals express
      high surface hydrophobicity as a stable property upon cultivation on blood agar.
      Bovine lactoferrin, human vitronectin, human fibronectin, heparin, human and
      bovine serum albumin were immobilized on latex beads to detect protein-binding
      cell surface components of 67 non-autoaggregating staphylococcal strains by a
      particle agglutination assay. Bovine lactoferrin was bound well by 22 strains (3
      or 2) while 15 strains reacted weakly (1) and 30 did not react (0) with the
      lactoferrin-coated latex beads. The particle agglutination assay showed similar
      differences among staphylococcal strains in binding other proteins with the
      exception of human and bovine serum albumins for which 66 of 67 strains were
      negative (0). The specificity of the agglutination reaction was confirmed by a
      particle agglutination inhibition assay by preincubating bacterial cells with the
      protein (lactoferrin, vitronectin, etc.) used subsequently in particle
      agglutination assay. Autoaggregating strains together with some non
      autoaggregating strains were selected for microtitre plate assay. According to
      absorbance at 570 nm, 14 strains were classified as non-adherent, 16 strains as
      weakly adherent and 18 strains as strongly adherent to bovine lactoferrin in
      microtitre plate assays. A direct correlation was found between the absorbance
      values at 570 nm of microtitre plate binding assay and test values obtained in
      particle agglutination assay. Binding of bovine lactoferrin to 81 staphylococcal
      strains as well as of human vitronectin and human fibronectin to a selected
      number of these strains was studied with radiolabeled (125I-labeled) proteins.
      Radiolabeled bovine lactoferrin was bound common by all except four strains (7 to
      39%). Staphylococcal strains isolated from diseased pigs commonly bound 125I
      labeled vitronectin (21 to 42% of the vitronectin added). Binding of vitronectin
      and lactoferrin was efficiently inhibited by preincubating of staphylococcal
      cells with sulphated carbohydrate compounds as heparin, dextran sulphate and
      fucoidan, but not by other non-sulphated highly charged glycoconjugates such as
      hyaluronic acid.

PMID- 10414366
TI  - Development and evaluation of an immunomagnetic separation-ELISA for the
      detection of Staphylococcus aureus thermostable nuclease in composite milk.
AB  - An ELISA method based on monodisperse magnetic beads was developed for the
      detection of Staphylococcus aureus thermostable nuclease (TNase) in composite
      milk, wherein S. aureus TNase is captured by magnetic beads coated with
      monoclonal antibodies directed against TNase and subsequently detected by an
      enzyme-labelled MAb against the same antigen. Sensitivity of the test was
      approximately 1 ng TNase, which corresponds to the amount of TNase produced and
      secreted by approximately 10(5) S. aureus per ml. The Immuno Magnetic Separation
      (IMS)-ELISA detected TNase in samples from which no S. aureus could be
      demonstrated on culture. The total test time is 3 h and can be performed either
      on preserved or fresh milk. The method may be automated.

PMID- 10414367
TI  - Molecular subtyping of Staphylococcus aureus isolates from cases of bovine
      mastitis in Brazil.
AB  - Sixty-six isolates of Staphylococcus aureus obtained from milk samples of dairy
      cows suffering from subclinical mastitis in southern Brazil were analysed by five
      different molecular typing methods. These included the analysis of plasmid
      profiles, the analysis of coagulase (coa) gene polymorphisms by PCR amplification
      of the 3' terminal region of the coa gene, the PCR-based detection of
      polymorphisms in the X region of the protein A gene (spa), the PCR-directed
      analysis of variations in the spacer region between 16S and 23S rRNA, and the
      comparison of pulsed-field gel electrophoretically separated genomic SmaI
      fragment patterns. The molecular typing methods were supplemented with the
      biochemical characterization of the isolates and the determination of their in
      vitro susceptibility to 14 different antibiotics. All genotypic and phenotypic
      typing methods were analyzed for their ability to discriminate between the
      isolates. Macrorestriction analysis proved to be the most discriminatory single
      method (D = 0.96) followed by rRNA spacer typing (D = 0.85), coa PCR (D = 0.82),
      and spa PCR (D = 0.80).

PMID- 10414368
TI  - Detection of virulent strains of Streptococcus suis type 2 and highly virulent
      strains of Streptococcus suis type 1 in tonsillar specimens of pigs by PCR.
AB  - We developed a PCR assay for the rapid and sensitive detection of virulent
      Streptococcus suis type 2 and highly virulent S. suis type 1 in tonsillar
      specimens from pigs. The PCR primers were based on the sequence of the gene
      encoding the EF-protein of virulent S. suis type 2 strains (MRP+EF+) and highly
      virulent S. suis type 1 strains (MRP(s)EF+) and of the EF protein of weakly
      virulent S. suis type 2 strains (MRP+EF). The latter strains give rise to larger
      PCR products than the virulent strains of S. suis type 1 and 2. A positive
      control template was included in the assay to identify false negative results.
      The PCR was evaluated using tonsillar specimens from herds known (or suspected)
      to be infected and herds without an S. suis history. The results obtained with
      the PCR assay were compared with the results obtained with a newly developed
      bacteriological examination. In this bacteriological examination we were able to
      identify the EF-positive strains directly in the tonsillar specimens. From the 99
      tonsils examined, 48 were positive in the PCR and 51 negative. All specimens from
      which EF-positive S. suis strains were isolated were also positive in the PCR
      assay. Three samples were positive in the PCR, but negative by bacteriological
      examination. The results demonstrated that the PCR is a highly specific and
      sensitive diagnostic tool for the detection of pigs carrying virulent strains of
      S. suis type 2 and highly virulent strains of type 1. Application of the assay
      may contribute to the control of S. suis infections.

PMID- 10414369
TI  - Breast and cervical cancer screening: knowledge, attitudes and behavior among
      schoolteachers in Italy.
AB  - The study explores knowledge, attitudes and behavior regarding screening for
      breast and cervical cancers. All female teachers in primary and secondary schools
      in Crotone and in Cassino (Italy) received a questionnaire on demographic and
      socioeconomic characteristics, clinical history, knowledge, behavior and
      attitudes about breast and cervical cancer and related screening procedures. A
      response rate of 65% was achieved. Knowledge on effectiveness of mammography and
      pap test in finding related cancers was widely spread in the sample. Only about
      30% and 50% had respectively undergone their last mammogram and pap test
      according to the recommended time interval. Having been examined by a physician
      in the previous year and having had a screening CBE or a screening pap smear in
      the past three years were significantly more likely in women who underwent
      mammography for screening purposes in the past two years. Pap smear in the
      previous three years was significantly more likely in women in their forties,
      with a higher family income and in those who had been examined by a physician in
      the previous year. The results strongly recommend continued emphasis of
      physicians on education of women regarding mammography and pap smear.

PMID- 10414370
TI  - Is there a reduced risk of breast cancer among women with hip fractures?
AB  - To test the hypothesis that osteoporosis, which results partly from long-term
      estrogen deficiency, is associated with a lowered risk of breast cancer, a
      population-based cohort study was performed in Amiens. To ascertain the incidence
      of breast cancer, 1300 women were followed through after a first hip fracture.
      Overall, 18 cases of cancer were observed cf. 21.8 expected (standardized
      incidence ratio (SIR): 0.82; 95% confidence interval (CI): 0.5-1.3). The results
      are consistent with previous studies which concluded that long-term estrogen
      deficiency is associated with a reduced risk of developing breast cancer.

PMID- 10414371
TI  - Serum IgG antibodies to human herpesvirus-6 (HHV-6) do not predict the
      progression of HIV disease to AIDS. Italian Seroconversion Study group.
AB  - OBJECTIVES: To evaluate if different levels of human herpesvirus 6 (HHV-6)
      antibodies can predict HIV disease progression. DESIGN: Longitudinal study of
      individuals with a documented date of HIV seroconversion. SETTING: Clinical
      centers located throughout Italy. PATIENTS: Individuals who serconverted for HIV
      between 1983 and 1995 in Italy. METHODS: Sera were tested for IgG antibodies to
      HHV-6 using a commercial enzyme immunoassay. A serum sample with an optical
      density (OD) > or =242 (i.e. the mean value of 10 negative controls +4x standard
      deviation) was considered as HHV-6 positive; the progression of HIV disease was
      evaluated estimating the relative hazards (RH) of AIDS (by Cox models) for
      individuals with higher levels vs. lower levels of HHV-6 antibodies or
      considering levels of antibodies based on 10% increase of the distribution
      (deciles). Rates of CD4 decline fitting linear regression were also estimated.
      RESULTS: A total of 381 persons were followed for a median time of 4 years
      (range: 0.15-9 years) following the date of collection of the serum sample. The
      median OD value of HHV-6 antibodies was 306, with an interquartile range of 241
      440 and a range of 48-2330. A slight inverse correlation was found between HHV-6
      antibody levels and age of the individual at the time of serum collection
      (Spearman rank correlation coefficient, -0.16; p = 0.0013). No association was
      found between HHV-6 and CD4 level or between HHV-6 and CD8 level at the date of
      serum collection. The unadjusted RH of progression to AIDS was 0.63 (95% CI: 0.42
      0.96) for HHV-6 positive individuals vs. HHV-6 negative; when adjusting for
      possible confounders (CD4, age, pre-AIDS HIV-related pathologies at the date of
      sera collection, and previous anti-herpes treatment), the RH of AIDS increased to
      0.80 (95% CI: 0.51-1.23). No particular association with HIV disease progression
      was found when using the deciles of the distribution of HHV-6 antibodies. The
      median CD4 cell loss was 5.0x10(6) cells/l per month among HHV-6 positive
      individuals and 5.7x10(6) cells/l per month among the others. CONCLUSIONS: The
      presence of high levels of HHV-6 antibodies does not seem to predict the clinical
      or immunologic progression of HIV disease.

PMID- 10414372
TI  - Prevalence of angina pectoris in Spain. PANES Study group.
AB  - The frequency of coronary heart disease in a community is usually measured by
      myocardial infarction incidence and mortality rates. The measurement of the
      prevalence of angina pectoris may, however, become a convenient way of assessing
      coronary heart disease morbidity in the future. The aim of this study was to
      determine the prevalence of angina and validity of the Rose questionnaire in the
      Spanish population aged from 45 to 74 years. A cross-sectional study was
      conducted in 10,248 subjects (45-74 years), representative of the Spanish
      population. The WHO Rose questionnaire was used and a construct validation
      against regional mortality rates and cardiovascular risk factor prevalence was
      devised. The overall angina prevalence increased with age both in men and women,
      but was higher in the latter (7.3% and 7.7%, respectively). Angina prevalence
      also increased with the number of cardiovascular risk factors present and
      correlated with regional CHD mortality rates (r = 0.66). Sensitivity and
      specificity results of the Rose questionnaire were low when tested against
      exercise test (52.9% and 52.1%, respectively). As conclusions, Rose questionnaire
      is a reliable tool for assessing angina prevalence in the Spanish population
      which is similar to that of other industrialized countries with higher myocardial
      infarction morbidity and mortality.

PMID- 10414373
TI  - Time trends, cohort effect and spatial distribution of cerebrovascular disease
      mortality in Spain.
AB  - STUDY OBJECTIVE: This study describes mortality due to cerebrovascular disease
      (CVD) in Spain, based on time-series analysis in the period 1951-1995 by age,
      sex, and cohort of birth; spatial distribution observed for the five-year period
      1991 1995, and time-spatial analysis in the period 1992-1995 vs. 1988-1991.
      Special attention is paid to risk of medium aged population. DESIGN: Longitudinal
      and cross-sectional observational study. SETTING AND PARTICIPANTS: Spanish
      population. All mortality data used were taken from official statistics. Time
      trends and spatial distribution were analyzed using log-linear Poisson regression
      models. MAIN RESULTS: CVD mortality declined over the last two decades of the
      study period (1974-1995) by an annual average of 4.16% (95% CI: 3.95-4.36) and
      4.00% (95% CI: 3.77-4.24) in men and women, respectively. The downward trends
      were accelerated in last decade. An excess of male mortality was in evidence. For
      all age groups mortality declined with more recent cohorts, but the decline was
      less marked among ages 35 64. Spatial distribution of CVD mortality revealed a
      north-south pattern, but this is being difuminated by increasing rates in the
      lower risk provinces. Internationally, Spain ranks midway to low in terms of its
      overall CVD mortality. CONCLUSIONS: Efforts to reduce CVD incidence and case
      fatality are the essential prerequisite for any long-term improvement in
      mortality. Accordingly, further research is called for into current disease
      morbidity and the risk factors to be targeted at a general population level,
      nationwide.

PMID- 10414374
TI  - Relationship between lifestyle and serum lipid and lipoprotein levels in middle
      aged Japanese men.
AB  - Cross-sectional associations between lifestyle factors [cigarette smoking,
      alcohol intake, overall obesity indicated by body mass index (BMI), eating
      breakfast, snacking between meals, considering nutritional balance, coffee
      drinking, physical exercise, and hours of work and sleep] and serum lipid and
      lipoprotein levels were examined in 1580 middle-aged Japanese men in Osaka,
      Japan. From stepwise regression analyses, significant correlates with low-density
      lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and
      Log triglyceride levels were, in the order of relative importance: BMI, alcohol
      intake (negative), and age for LDL cholesterol level; BMI (negative), cigarette
      smoking (negative), alcohol intake, considering nutritional balance, and physical
      exercise for HDL cholesterol level; and BMI, cigarette smoking, working hours
      (negative), considering nutritional balance (negative), alcohol intake, and
      coffee drinking (negative) for Log triglyceride level. The cumulative percentages
      of variation for LDL cholesterol, HDL cholesterol and Log triglyceride levels
      were 4.2%, 15.4% and 14.7%, respectively. From stepwise regression analyses,
      excluding BMI as a factor in the model, snacking between meals emerged as a
      significant factor for LDL cholesterol level and HDL cholesterol level
      (negative). The cumulative percentage of variation for each serum lipid and
      lipoprotein level was decreased (1.5% for LDL cholesterol, 6.8% for HDL
      cholesterol, and 3.1% for Log triglyceride). These results suggest that BMI has
      the strongest association with serum lipid and lipoprotein levels and that good
      daily lifestyles may have an anti-atherogenic effect by altering serum lipid and
      lipoprotein levels in middle-aged Japanese men.

PMID- 10414375
TI  - Prevalence of smoking among currently married Kuwaiti males and females.
AB  - A structured questionnaire was administered to a random sample of 608 Kuwaiti
      couples through a household face-to-face interview. Both spouses were non-smokers
      in more than half (50.8%) of all the couples, and there was a single couple
      (0.2%) with both spouses currently smoking. Only 0.5% of the wives reported
      current smoking. The prevalence of smoking was 3.2% among divorced/widowed women
      from the same households. The difference between the two groups of women remained
      significant upon controlling for the confounding effect of age. Among the
      husbands, frequencies of current and ex-smokers were 37% and 11%, respectively.
      Younger respondents consumed more tobacco and were initiated to smoking at an
      earlier age. Logistic regression showed that people with one to 11 years of
      formal education were more likely to be current smokers as compared to the rest
      of the respondents (adjusted relative risk: 2.07, 95% confidence interval (CI):
      1.46-2.93). Reasons for the observed findings have been discussed.

PMID- 10414376
TI  - The German Food Code and Nutrient Data Base (BLS II.2).
AB  - This article describes the conception and structure of the German Food Code and
      Nutrient Data Base (BLS). The data bank contains approx. 12,000 coded foods,
      menus and menu components in different stages of processing with up to 158
      nutritional data for each product. Since comparatively few analytical data on the
      composition of foods are available, the majority of the data in the BLS are based
      on nutritional data calculated from recipes. Thus, a standard instrument for an
      uninterrupted (no missing values) evaluation of consumption surveys is made
      available.

PMID- 10414377
TI  - Clinical and epidemiological aspects of respiratory syncytial virus lower
      respiratory tract infections.
AB  - This paper has analyzed respiratory syncytial virus lower respiratory tract
      infections in 201 hospitalized children. In children with wheezing, erythrocyte
      sedimentation rate (ESR) was significantly higher in those with pneumonia than
      with syndroma pertussis, while the white blood cell (WBC) count was significantly
      lower in patients with bronchitis than in those with bronchiolitis and syndroma
      pertussis. Bronchodilatators were applied in 75.6% and corticosteroids in 20% of
      patients. Ten patients were ventilated. Fatal disease outcome was observed in one
      infant. Twelve consecutive-year study of respiratory syncytial virus (RSV)
      infections showed that 27.3% of these diseases were bronchiolitis and pneumonia.

PMID- 10414378
TI  - Outbreak of cholera in Ibadan, Nigeria.
AB  - The changing epidemiology of cholera in Ibadan, Nigeria, has become a public
      health challenge, and outbreaks of the disease have been occurring with
      increasing frequency since the first outbreak in modern times in 1970. In this
      outbreak, 1384 persons were seen, diagnosed and treated for the disease at the
      cholera unit, Ibadan from January to December 1996. The outbreak lasted for a
      whole year. No child under one year was seen. The age adjusted case fatality rate
      was 5.3%. Diarrhoea and vomiting were the most common combination of symptoms
      present in 97.3% of all cases, followed by diarrhoea, vomiting and dehydration
      (84.3%). The median number of days spent on admission was only 2 days. Cholera
      cases were clustered within the densely populated and poorly planned areas of the
      city. Though significantly more cases were seen during the rainy season than
      during the dry season (p<0.01), the deaths were not seasonally related (p =
      0.67). Contamination of otherwise potable sources of water, late presentation to
      the cholera treatment unit and low levels of knowledge about diseases need to be
      addressed in order to effectively control this disease in the community. Progress
      should also be made towards developing a suitable vaccine for the control of this
      internationally important public health disease so that the responsibility of its
      control is not left entirely to individuals and communities, particularly in
      developing countries.

PMID- 10414379
TI  - Low risk of Lyme borreliosis in a protected area on the Tyrrhenian coast, in
      central Italy.
AB  - A comprehensive Lyme borreliosis risk assessment process was applied in S.
      Rossore Estate, on the Tyrrhenian coast, near Pisa, Italy. Host-seeking Ixodes
      ricinus nymphs peaked in May in oak-dominated deciduous wood (median, Q1-Q3,
      number of nymphs/50 m dragging = 4.5, 2.5-8), whereas host-seeking larvae peaked
      in August in the same habitat type (6.0, 4-17/50 m dragging). Prevalence of I.
      ricinus infestation was 88.9% in wild rodents (n = 11), 64.3% in fallow deer (n =
      28) and 0.0% in wild boars (n = 5). Borrelia burgdorferi sensu lato was not
      isolated from rodents' organs, and from 80 I. ricinus nymphs and 50 adults.
      Moreover, PCR for B. burgdorferi sl carried out on 110 nymphs and 12 adult ticks
      also gave negative results. Forest workers were at higher risk of tick bite than
      other Estate employees (relative risk (RR): 1.7, p = 0.02). In spite of high
      levels of tick exposure, B. burgdorferi sl specific antibodies were not detected
      in sera from Estate personnel (n = 30) and sentinel animals (dogs, n = 23, fallow
      deer, n = 61).

PMID- 10414380
TI  - Faecal excretion of Vibrio cholerae during convalescence of cholera patients in
      Calabar, Nigeria.
AB  - The pattern of faecal excretion of Vibrio cholerae was studied over a duration of
      eight months among 13 cholera convalescents by two-weekly surveillance cultures.
      Stools and rectal swabs were cultured on Thiosulphate citrate bile salts sucrose
      (TCBS) agar for the recovery of vibrio pathogens. Clinical phase and convalescent
      phase V. cholerae strains were compared for antibiogram profiles. The population
      of vibrios recovered from faecal inocula was usually scanty (<10(3) vibrios/g).
      All clinical isolates except three were concordant with convalescent phase
      strains. Sensitivity to tetracycline was uniform for concordant V. cholerae
      strains, with minimum inhibitory concentration (MIC) ranging from 0.54-4.0
      microg/ml. Nine (69.2%) of the convalescents had positive faecal cultures for
      periods ranging from two weeks to more than seven months. Two adults whose
      excretions lasted several months also tested positive for human immuno-deficiency
      virus (HIV) infections. The significance of stool surveillance cultures for
      identifying asymptomatic infections among convalescents who may need chemotherapy
      to abolish excretion is emphasised. However, it could not be established with
      certainty if vibrios excreted during convalescence were from enteric colonization
      by the causative strains, or re-infections with the common strains in
      circulation.

PMID- 10414381
TI  - Histoplasmosis and Paracoccidioidomycosis in northwestern Argentina III.
      Epidemiological survey in Vipos, La Toma, and Choromoro - Trancas, Tucuman,
      Argentina.
AB  - The present work was undertaken to obtain epidemiological data on the extent and
      distribution of Histoplasma capsulatum var. capsulatum and Paracoccidiodes
      brasiliensis diseases in the Vipos, La Toma and Choromoro areas. Skin test
      surveys with histoplasmin and paracoccidioidin were carried out in the permanent
      human population of those localities. Mycological sputum studies and serological
      tests were performed to skin test reactors to determine if there were signs or
      symptoms of active mycotic disease. La Toma and Choromoro are highly prevalent
      areas of histoplasmosis (>30% the histoplasmin positive individuals) whereas
      Vipos can be relatively considered a highly prevalent area (between 20-30% the
      histoplasmin reactors) according to the normally accepted range used to define an
      endemic disease [2]. Early Histoplasma capsulatum infection (<10 years old) is
      reported for Vipos and Choromoro. La Toma has the highest rate of previous
      exposure to P. brasiliensis detected in the studied area (10.2%). Vipos residents
      are not infected with P. brasiliensis.

PMID- 10414382
TI  - Prevalence and clinical relevance of Blastocystis hominis in diverse patient
      cohorts.
AB  - The pathogenicity of Blastocystis hominis is extensively debated in the medical
      literature. Therefore, we did a prevalence study to investigate the association
      between the presence of several intestinal parasites and gastrointestinal
      symptoms in diverse patient cohorts. The study population consisted of 1216
      adults, including immunocompromised patients, institutionalized psychiatric or
      elder subjects, immigrants from developing countries, travellers to developing
      tropical countries and controls. Several variables for each risk group were
      considered. Stools specimens, collected in triplicate, were processed by the same
      technicians. Clinical data about each subject were provided by standardized
      questionnaires. The presence of gastrointestinal symptoms were related to the
      presence of any parasite. In addition, on the basis of microbiological results,
      five subgroups of subjects were evaluated. The results showed a high prevalence
      of parasites in all the risk groups. Immunocompromised status, recent arrival
      from developing countries and the presence of behavioural aberrations were
      significantly related to presence of parasites. B. hominis was the parasite most
      frequently detected in each studied group. B. hominis showed a significant
      correlation with gastrointestinal symptoms only when detected in the group
      including subjects with a severe immunodepression. Immunodepression seems to be a
      factor of primary importance of the pathogenic role of B. hominis.

PMID- 10414383
TI  - Comparison of two Salmonella enteritidis phage typing schemes.
AB  - The comparison of two phage typing schemes for Salmonella enteritidis was
      performed. A total of 517 strains were phage-typed according to the schemes of
      Lalko [27] and Ward et al. [21]. Strains were isolated from food-poisoning
      outbreaks and other common sources in Poland, between 1986-1995. Above 99% of all
      strains tested were differentiated to the definitive phage type using the Lalko
      collection of typing phages. Phage types 1 and 7 (PTs 1, 7) were the most
      isolated. The typing phages of Ward enabled to assign 56.5% of all strains (a
      total of 14 phage types were presented), 37.1% - reacted with phages without
      showing any of the designated phage types and 6.4% were untypable. Phage type 8
      (PT8) predominated. The majority of Salmonella enteritidis strains from one phage
      type outbreaks of Lalko presented different types of lytic reactions with the
      Ward phages. Only the correspondence of Salmonella enteritidis PT7 of Lalko with
      PT8 of Ward et al. [21] was observed.

PMID- 10414384
TI  - Epidemiology, and diagnostic and surgical trends in atrioventricular septal
      defect in Malta.
AB  - Atrioventricular septal defect (AVSD) is a common congenital cardiac
      malformation, associated with Down's syndrome. AVSD causes heart failure, and if
      not treated early, irreversible pulmonary hypertension. In Malta, a decline in
      age at diagnosis and at surgery was present from 1944 to 1994. The birth
      prevalence was 0.31/1000 live births, within the range obtained from a literature
      review. Down's syndrome children are now treated as are non-syndromic children.

PMID- 10414385
TI  - Measurements of dyspnoea during bronchoconstriction.

PMID- 10414387
TI  - Mucus transport and physiotherapy--a new series.

PMID- 10414386
TI  - Elastase and its physiological inhibitors in ARDS: what decides between
      inflammatory storm or dead calm?

PMID- 10414388
TI  - Human bronchial smooth muscle cells in culture produce stem cell factor.
AB  - A mast cell infiltration of the bronchial smooth muscle layer has been reported
      in patients sensitized to common allergens. Stem cell factor (SCF) is a
      chemotactic and survival factor for mast cells. SCF is expressed as a soluble
      (sSCF) and a membrane-bound (mSCF) form, after alternative splicing of the exon
      encoding the proteolytic cleavage site. SCF expression by human bronchial smooth
      muscle cells in culture was evaluated, comparing it to that of human lung
      fibroblasts in culture. sSCF released in the culture supernatant was assessed by
      an enzyme-linked immunosorbent assay. Total SCF messenger ribonucleic acid (mRNA)
      was measured by competitive polymerase chain reaction (PCR) after reverse
      transcription. Expression of the two forms of SCF mRNA was assessed by PCR, with
      primers spanning the alternatively spliced exon. Smooth muscle cells produced
      sSCF (21.9+/-2.6 pg x mL(-1)), although at lower levels than fibroblasts (35.9+/
      3.5 pg x mL(-1)); the expression of total SCF mRNA was also at lower levels than
      in fibroblasts (8.6+/-0.2 and 19.0+/-2.0 amol x fmol glyceraldehyde 3-phosphate
      dehydrogenase complementary deoxyribonucleic acid(-1), respectively). However,
      smooth muscle cells expressed proportionally more (1.7-fold) mSCF mRNA than did
      fibroblasts. In conclusion, this study shows that bronchial smooth muscle cells
      express stem cell factor, with a relatively high expression of membrane-bound
      stem cell factor. This might be related to the presence of mast cells within the
      bronchial smooth muscle layer, i.e. at the site of bronchoconstriction, with
      possible implications in the pathophysiology of asthma.

PMID- 10414389
TI  - Measuring breathlessness during histamine challenge: a simple standardized
      procedure in asthmatic patients.
AB  - One of the problems in research on symptom perception during histamine challenge
      has been the difficulty in finding both a valid and practical parameter of the
      "perceptiveness" for bronchoconstriction in a subject. The purpose of this study
      was to validate whether the slope in the linear regression model between stimulus
      and sensation during histamine challenge is an appropriate index for the
      "perceptiveness" for bronchoconstriction by comparing it with the classical
      Stevens' law. One hundred and thirty-four asthmatic patients were included in the
      study and underwent a bronchial challenge with histamine. The relationship
      between the change in visual analogue scale (VAS) values and the change in forced
      expiratory volume in one second (FEV1) as percentage of baseline value was
      analysed by determining both the exponent n in deltaVAS=k x (%deltaFEV1)n and the
      slope alpha in deltaVAS=k + alpha(%deltaFEV1). The best-fitting line of both the
      exponential and the linear regression model were determined by the least-squares
      method in which the percentage explained variation (R2) was compared. The median
      value of R2 of the exponential regression line and the linear regression line was
      0.76 and 0.83, respectively, and significantly different. The Spearman rank
      correlation coefficient between exponent n in the exponential model deltaVAS=k x
      (%deltaFEV1)n and the slope alpha in the linear regression model deltaVAS=k +
      alpha(%deltaFEV1) was 0.87 (95% confidence interval 0.83-0.91). On the basis of
      the results, it was concluded that the linear regression coefficient can be used
      as a valid expression to describe the "perceptiveness" of an asthmatic subject
      instead of Stevens' power function during histamine challenge.

PMID- 10414390
TI  - Suppression of immediate and late responses to antigen by a non-anaphylactogenic
      anti-IgE antibody in a murine model of asthma.
AB  - Eosinophils are recruited to the airways during allergic reactions, but animal
      models have shown that their mere presence is not sufficient for the development
      of bronchopulmonary hyperreactivity. Other factors, such as immunoglobulin (Ig)E,
      seem to be required. Using mice selected for the production of large amounts of
      IgE, the effects of antibody neutralization of IgE on antigen-induced lung
      recruitment of eosinophils and induction of bronchopulmonary hyperreactivity and
      of other indicators of inflammation were studied. A monoclonal non
      anaphylactogenic rat anti-mouse IgE (mAb1-5), given within 24 h of the challenge
      with antigen, reduced tissue eosinophilia, the recruitment of IgE-bearing cells
      identified as basophils, mucous cell metaplasia, anaphylactic bronchoconstriction
      and bronchopulmonary hyperreactivity. mAb1-5 inhibited interleukin (IL)4 titres
      in the bronchoalveolar lavage fluid, but not those of I1-5. Inhibition by mAb1-5
      may result from competitive displacement of immunoglobulin E from its different
      receptors, thus preventing cell stimulation. Moreover, the inhibition of the
      massive recruitment of immunoglobulin E-bearing basophils into the lungs within
      hours after challenge and of interleukin4 production by mAb1-5 may be important
      factors leading to the reduction of pulmonary eosinophilia and bronchopulmonary
      hyperreactivity. Thus, immunoglobulin (Ig)E and allergic IgE-bearing cells seem
      to play an essential role in the initial development of the late allergic airway
      responses.

PMID- 10414391
TI  - IL-3 does not affect the allergic airway responses and leukotriene production
      after allergen challenge in rats.
AB  - T cell cytokines are important in asthma. Interleukin (IL)-3, an important growth
      factor for mast cells and eosinophils has been shown to be increased in the
      airways of asthmatic subjects, but its precise functions are uncertain. The aim
      of this study was to determine whether recombinant human (rh) IL-3 affected
      airway responses, inflammation and leukotriene production after antigen challenge
      in Brown Norway (BN) rats. Having established that rhIL-3 (>12.5 microg
      subcutaneously b.i.d. for 4 days) caused a doubling of mast cell numbers in the
      airways of BN rats, sensitized rats were pretreated with rhIL-3 (50 microg) or
      vehicle subcutaneously b.i.d. for 4 days. Ovalbumin (OA) challenge was performed
      and the early (EAR), and late (LAR) airway response and the associated biliary
      leukotriene (LT) excretion measured. The pulmonary cellularity was evaluated by
      means of lung digestion 8 h after challenge. IL-3 increased the number of
      eosinophils isolated from the lungs after antigen challenge (0.77+/-0.23 versus
      0.38+/-0.12 x 10(6) cells, p=0.03). However, there were no effects on the numbers
      of neutrophils, lymphocytes and macrophages. Neither the EAR nor the LAR after OA
      challenge were altered by IL-3. Likewise biliary cysteinyl-LT excretion was
      similar in IL-3-treated animals and controls after challenge. In conclusion,
      interleukin-3 caused an increase in the numbers of mast cells and eosinophils
      around the airways without affecting the magnitude of either early or late airway
      responses or mediator release after antigen challenge. The present results
      suggest that airway inflammation can occur in rats without increasing the
      allergic asthmatic response.

PMID- 10414392
TI  - Effect of respiratory syncytial virus on subsequent allergic sensitization to
      ovalbumin in guinea-pigs.
AB  - Children with acute respiratory syncytial virus (RSV) bronchiolitis often develop
      recurrent wheezing, asthma and allergic sensitization, but the role of RSV in the
      pathogenesis of these sequelae is unclear. This study examined whether RSV
      infection potentiates subsequent allergic sensitization, airway
      hyperresponsiveness (AHR) and airway inflammation induced by repeated exposures
      to aerosolized ovalbumin (OA) in guinea-pigs. Guinea-pigs received either RSV or
      sham inoculum, followed by exposures to OA- or saline-containing aerosols to form
      the following groups: 1) noninfected, nonsensitized controls (sham/saline group);
      2) RSV-infected, nonsensitized animals (RSV/ saline group); 3) noninfected, OA
      sensitized animals (sham/OA group); 4) RSV infection and first OA exposure on the
      same day (RSV/OA group), and 5) RSV infection six days prior to first OA exposure
      (RSV6/OA group). Three days after the final aerosol exposure, circulating OA
      specific immunoglobulin (Ig)G1 antibody titres and AHR to inhalation
      acetylcholine challenge were measured and morphometry performed to evaluate
      allergic inflammation of the airways. OA-exposed animals developed OA-specific
      IgG1 antibodies, AHR and airway eosinophilia (sham/OA, RSV/OA and RSV6/OA groups.
      RSV infection alone induced significant AHR and airway eosinophilia (RSV/saline
      group). RSV infection, and concomitant exposure to OA (RSV/OA group) enhanced OA
      specific IgG1 antibodies, but not airway eosinophilia or AHR. Such increases were
      not observed in the RSV6/OA group. In conclusion, respiratory syncytial virus
      potentiates the production of ovalbumin-specific immunoglobulin G1 antibodies in
      guinea-pigs, but circulating titres of these antibodies do not reflect the extent
      of airway hyperresponsiveness or airway inflammation. In addition, respiratory
      syncytial virus infection alone can produce slight increases in airway
      hyperresponsiveness that are associated with increased numbers of eosinophils in
      the airways.

PMID- 10414393
TI  - The prevalence of reported asthma is independent of exposure in house dust mite
      sensitized children.
AB  - In areas with low house dust mite (HDM) allergen exposure, both mite
      sensitization and asthma prevalence are low. In most other areas, HDM allergen
      exposure is higher than the threshold for sensitization. In this setting, is HDM
      allergen exposure a factor which is causally related to the development of asthma
      in HDM-sensitive individuals? To answer this question, the cumulative prevalence
      of asthma was evaluated in a group of 157 schoolchildren, aged 10 and 11 yrs, who
      were allergic to HDM allergen, and compared it with HDM allergen exposure and
      atopic status, using univariate and multivariate analysis. HDM allergen levels
      were measured in mattress dust using an enzyme-linked immunosorbent assay (ELISA)
      method. Of mattress dust samples, 94% had an HDM allergen level >2 microg x g
      dust(-1). Atopy was evaluated by means of skin prick tests using five common
      allergens. Among the predictive variables studied by means of univariate
      analysis, only the number of positive skin tests and male sex correlated with
      asthma prevalence, but not HDM allergen exposure. Logistic regression analysis
      also demonstrated that the number of positive skin tests correlated with asthma
      prevalence (odds ratio (OR)=1.38, p=0.05), whereas the OR for HDM allergen
      exposure was 1.0. This survey suggests that, in a geographical area with high HDM
      allergen exposure, asthma prevalence is not linked with HDM allergen levels.

PMID- 10414394
TI  - Comparison of formoterol, salbutamol and salmeterol in methacholine-induced
      severe bronchoconstriction.
AB  - The onset of the bronchodilating effect of formoterol (12 microg by Turbuhaler)
      was compared with that of salbutamol (50 microg by Turbuhaler), salmeterol (50
      microg by Diskhaler) and placebo in methacholine-induced severe
      bronchoconstriction. Seventeen subjects with mild-to-moderate asthma completed
      this randomized, double blind, cross-over, double-dummy study. On four study
      days, baseline forced expiratory volume in one second (FEV1) was recorded and the
      subjects were challenged with methacholine until FEV1 fell by at least 30%.
      Immediately thereafter, the study drugs were inhaled and lung function was
      assessed for 60 min. The geometric mean time for FEV1 to return to 85% of
      baseline was 7.2 min with formoterol, 6.5 min with salbutamol, 14.1 min with
      salmeterol and 34.7 min with placebo (p=0.0001, overall ANOVA). The difference
      between formoterol and salmeterol was statistically significant (p=0.01); there
      was no difference between formoterol and salbutamol (p=0.69). In conclusion,
      formoterol reversed methacholine-induced severe bronchoconstriction as rapidly as
      salbutamol and more rapidly than salmeterol. Classifying beta2-agonists as "fast"
      and "slow"- acting may be supplemental to "short"- and "long"-acting.

PMID- 10414396
TI  - Expression and localization of COX-2 in human airways and cultured airway
      epithelial cells.
AB  - Cyclo-oxygenase is the rate-limiting enzyme in the prostanoid pathway. Although
      expression of the inducible isoform of cyclo-oxygenase (COX-2) is associated with
      cytokine-mediated inflammation, recent evidence suggests a homeostatic role for
      epithelial COX-2 in the gastrointestinal tract. The aim of this study was to
      examine the expression and localization of COX-2 in human airway epithelium both
      in vivo and in vitro. Human airway specimens from patients undergoing lung
      resection surgery for primary lung tumours (n=10) or nasal mucosal resection for
      non-inflammatory nasal obstruction (n=5) were examined for COX-2 expression by in
      situ hybridization and immunohistochemistry. COX-2 expression was also studied in
      two human airway epithelial cell lines (BEAS-2B and A549) using reverse
      transcription polymerase chain reaction and Northern and Western blot analysis.
      COX-2 messenger ribonucleic acid (mRNA) and protein were localized to individual
      columnar epithelial cells and to airway resident inflammatory cells in 9/10 lower
      and 5/5 upper airway specimens. Expression of COX-2 did not correlate with
      evidence of airway inflammation. Focal expression of COX-2 mRNA and protein was
      observed in bronchus-associated lymphoid tissue. Both COX-2 mRNA and protein were
      detected in BEAS-2B and A549 cells cultured under standard conditions. In
      conclusion, expression of COX-2 in human airway epithelium occurs in the upper
      and lower airways, is widespread in airway epithelial and airway resident
      inflammatory cells in the absence of overt airway inflammation, and is detectable
      in cultured human airway epithelial cells in the absence of inflammatory cytokine
      stimulation. These data suggest a potentially important homeostatic role for COX
      2 in the regulation of human airway contractility, inflammation and immune
      responses.

PMID- 10414395
TI  - Skin bruising, adrenal function and markers of bone metabolism in asthmatics
      using inhaled beclomethasone and fluticasone.
AB  - Fluticasone propionate (FP) is generally considered to have twice the efficacy of
      beclomethasone dipropionate (BDP) on a weight-to-weight basis for the control of
      asthma, and may have lesser effects on adrenal function. However, the effects of
      FP and BDP on skin integrity and bone metabolism markers require further
      examination. Sixty-nine asthmatic subjects were enrolled in a double-blind
      crossover study in which, after a baseline period, they received BDP or FP (at
      half the dose of BDP) for two 4-month periods each. A questionnaire on skin
      bruising, a skin examination, tests of adrenal function and of markers of bone
      metabolism were performed after 2 months of each period. The number of asthma
      exacerbations was not significantly different for the two treatment periods
      (eight for BDP and nine for FP), nor were various indices of asthma control.
      Whereas the frequency of bruising reported by the questionnaire was not
      different, there were more bruises on examination for BDP (1.6+/-2.5) than for FP
      (1.2+/-2.3) (p=0.04). Although baseline serum cortisol was not significantly
      different for the two drugs, the increase in cortisol after cortrosyn was lower
      for BDP (357+/-158 micromol x dL(-1)) than for FP (422+/-144 micromol x dL(-1))
      (p<0.01). Serum osteocalcin levels were significantly lower in subject on BDP
      (2.8+/-1.7 microg x mL(-1)) than on FP (3.5+/-1.9 ng x mL(-1)) (p=0.003). Other
      markers of bone metabolism were not significantly altered. The three major side
      effects were loosely, but significantly correlated with the periods on BDP and
      FP. However, skin bruises, increase in cortisol after Cortrosyn and osteocalcin
      were not significantly correlated for the period on either BDP or FP. In
      conclusion, whereas fluticasone propionate used at half the dose of
      beclomethasone dipropionate has a comparable effect on the control of asthma,
      fluticasone propionate demonstrated fewer side-effects in terms of skin bruising,
      adrenal suppression and bone metabolism.

PMID- 10414397
TI  - IL-12 receptor beta2 and CD30 expression in paranasal sinus mucosa of patients
      with chronic sinusitis.
AB  - The aetiology of chronic sinusitis is still poorly understood. The expression of
      T-helper 1 (Th1) and T-helper 2 (Th2) cell markers, interleukin (IL)-12 receptor
      beta2 subunit (IL-12Rbeta2) messenger ribonucleic acid (mRNA) and CD30,
      respectively, were investigated in the paranasal sinus mucosa of patients with
      chronic sinusitis in an attempt to elucidate the involvement of Th1 and Th2 cells
      in this disease. Anterior ethmoidal mucosae were surgically obtained from two
      groups of patients with chronic sinusitis: those who had allergic rhinitis
      (allergic group, n=11) and those without allergy (nonallergic group, n=11). IL
      12Rbeta2 mRNA was quantified by means of the reverse transcription polymerase
      chain reaction, and CD30-positive cells were examined immunohistochemically. Both
      IL-12Rbeta2 mRNA and CD30 were expressed in the sinus mucosa of the allergic and
      nonallergic groups. The proportion of mononuclear cells which were CD30-positive
      in the sinus mucosa was significantly greater in the allergic than in the
      nonallergic group. The expression levels of IL-12Rbeta2 mRNA were virtually
      equivalent in both groups. These results suggest a T-helper 2-dominated mucosal
      reaction in the allergic compared to the nonallergic group, and indicate T-helper
      1 activity in the sinus mucosa of both groups. The ubiquity of T-helper 1 cells
      suggests that they play a role in maintaining local mucosal defences against
      foreign antigens, which continually enter the upper respiratory tract.

PMID- 10414398
TI  - Clara cell protein as a marker of Clara cell damage and bronchoalveolar blood
      barrier permeability.
AB  - The 16 kDa Clara cell protein (CC16), an abundant component of airway secretions,
      has recently been proposed in humans as a pulmonary marker measurable not only in
      bronchoalveolar lavage fluid (BALF) but also in serum. The aim of the present
      study was to investigate the changes and determinants of CC16 concentrations in
      these fluids in normal rats and rats with lung injury. Female Sprague-Dawley rats
      were given a single i.p. injection of arachis oil (n=20) or chemicals in arachis
      oil (n=10) that mainly damage Clara cells (4-ipomeanol (IPO) 8 mg x kg(-1) and
      methylcyclopentadienyl manganese tricarbonyl (MMT) 5 mg x kg(-1)) or endothelial
      cells (alpha-naphthylthiourea (ANTU) 5 mg x kg(-1)). CC16 concentration (mean+/
      sD in microg x L(-1)), measured by a sensitive latex immunoassay, was
      significantly reduced in BALF of all treated groups (IPO 380+/-100; MMT 730+/
      200; ANTU 1,070+/-200; controls 1,700+/-470). The same pattern of decrease was
      observed in the labelling of Clara cells with an anti-CC16 antiserum as well as
      in the CC16 messenger ribonucleic acid levels assessed by Northern enzyme-linked
      immunosorbent assay. In serum, by contrast, CC16 was significantly increased in
      all treated groups (IPO 31+/-7; MMT 22+/-12; ANTU 52+/-24; controls 15+/-6). This
      rise of CC16 in serum was associated with an elevation of albumin in BALF which
      is an index of increased bronchoalveolar/blood barrier permeability. In
      conclusion, lung injury induces a decrease of the 16 kDa Clara cell protein in
      bronchoalveolar lavage fluid owing to a reduced production by damaged Clara
      cells, and an increase in serum protein levels resulting from its enhanced
      leakage across the bronchoalveolar/blood barrier. This study provides new
      insights into the understanding of the changes of lung secretory proteins in
      bronchoalveolar lavage fluid and serum.

PMID- 10414399
TI  - The effects of ketolides on bioactive phospholipid-induced injury to human
      respiratory epithelium in vitro.
AB  - The potential of the novel ketolide antimicrobial agents, HMR 3004 and HMR 3647,
      to antagonize the injurious effects of the bioactive phospholipids (PL), platelet
      activating factor (PAF), lyso-PAF, and lysophosphatidylcholine (LPC) on the
      ciliary beat frequency and structural integrity of human ciliated respiratory
      epithelium in vitro was investigated, in the presence or absence of
      polymorphonuclear leukocytes (PMNL). The ciliary beat frequency of human nasal
      respiratory epithelium, obtained by nasal brushing of healthy volunteers, was
      measured using a photo-transistor technique, while superoxide generation by
      activated human PMNL and membrane-stabilizing activity were measured by lucigenin
      enhanced chemiluminescence and haemolytic procedures, respectively. All three PL,
      at concentrations of 2.5 microg x mL(-1), caused significant (p<0.005) ciliary
      slowing and epithelial damage, while treatment of the epithelial strips with the
      ketolides, in particular HMR 3004, caused dose-related attenuation of these
      direct adverse effects of the PL on ciliated epithelium, apparently by a membrane
      stabilizing mechanism. When epithelial strips were exposed to the combination of
      PMNL (1 x 10(6) cells x mL(-1)) and PAF (1 microg x mL(-1)), significant ciliary
      dysfunction and epithelial damage were also observed, which were mediated
      predominantly by neutrophil-derived oxidants. These injurious effects of PAF were
      antagonized by preincubation of the epithelial strips or the PMNL with HMR 3004
      (10 microg x mL(-1)). The ketolide antimicrobial agents, in particular HMR 3004,
      antagonize the direct and polymorphonuclear leukocyte-mediated injurious effects
      of phospholipids on human ciliated epithelium and may have beneficial effects in
      inflammatory disorders of the airways, such as asthma, chronic bronchitis,
      diffuse panbronchiolitis and bronchiectasis.

PMID- 10414400
TI  - Secretory leukocyte proteinase inhibitor is preferentially increased in patients
      with acute respiratory distress syndrome.
AB  - Inappropriate release of proteases from inflammatory and stromal cells can lead
      to destruction of the lung parenchyma. Antiproteinases such as alpha-1-proteinase
      inhibitor (alpha1-Pi), secretory leukocyte proteinase inhibitor (SLPI) and
      elastase-specific inhibitor (elafin) control excess production of human
      neutrophil elastase. In the present study, the concentrations of alpha1-Pi, SLPI
      and elafin found in bronchoalveolar lavage (BAL) fluid from control subjects,
      patients at risk of developing acute respiratory distress syndrome (ARDS) and
      patients with established ARDS were determined. Levels of all three inhibitors
      were raised in patients compared with normal subjects. SLPI was increased in the
      group of patients who were at risk of ARDS and went on to develop the condition,
      compared with the "at-risk" group who did not progress to ARDS (p=0.0083). Alpha1
      Pi and elafin levels were similar in these two populations. In patients with
      established ARDS, both alpha1-Pi and SLPI levels were significantly increased,
      compared to patients at risk of ARDS who did (p=0.0089) or did not (p=0.0003)
      progress to ARDS. The finding of increased antiproteinases shortly before the
      development of acute respiratory distress syndrome provide further evidence for
      enhanced inflammation prior to clinical disease.

PMID- 10414401
TI  - Exogenous surfactant improves survival and surfactant function in ischaemia
      reperfusion injury in minipigs.
AB  - Reperfusion injury is the major cause of early morbidity and mortality after lung
      transplantation. This complication has been experimentally linked to dysfunction
      of pulmonary surfactant. Therefore, the hypothesis that reperfusion injury might
      be preventable by exogenous surfactant treatment was tested. Left lungs of
      minipigs were exposed to 120 min of ischaemia, and the lungs were then reperfused
      for up to 7 h. Animals were divided into a control group and a surfactant group
      (n=5 each). The surfactant group received 50 mg x kg(-1) Alveofact
      intrabronchially via a bronchoscope at the beginning of the ischaemic period.
      Bronchoalveolar lavage was performed at baseline before ischaemia and 90 min
      after reperfusion. Surfactant treatment significantly improved short-term
      survival. Pulmonary vascular resistance increased markedly in control animals
      leading to right heart failure and death within 3 h after reperfusion whereas the
      surfactant-treated animals survived the 7 h observation period. After
      reperfusion, alveolar accumulation of neutrophils and exuded proteins was present
      in both groups to the same extent. Surfactant activity after reperfusion
      deteriorated markedly in the control group but was preserved in the surfactant
      group. In conclusion, early surfactant treatment alleviates the deterioration of
      surfactant function and improves survival in this minipig model of ischaemia
      reperfusion injury.

PMID- 10414402
TI  - Validity of transcutaneous oxygen/carbon dioxide pressure measurement in the
      monitoring of mechanical ventilation in stable chronic respiratory failure.
AB  - The accuracy and precision of transcutaneous pressure measurements of oxygen
      (Ptc,O2) and carbon dioxide (Ptc,CO2) in the monitoring of nocturnal assisted
      ventilation in adult patients were evaluated. Transcutaneous measurements
      obtained with two analysers, Radiometer TINATCM3 (R) and Kontron MicroGas-7650
      (K), were compared with arterial blood gases analysed in blood samples withdrawn
      simultaneously in 10 patients. Sensors were heated to 43 degrees C. Measurements
      of transcutaneous blood gases and arterial blood gases were collected six times
      at 1-h intervals. The data obtained with both instruments were similar and did
      not significantly change over the 5 h test period. Measurement of Ptc,O2
      underestimated arterial oxygen tension (Pa,O2) and this underestimation increased
      with the level of Pa,O2 (p<0.01). Measurements of Ptc,CO2 overestimated arterial
      carbon dioxide tension (Pa,CO2) and this overestimation increased with the level
      of Pa,CO2 (p<0.05). These errors suggested an instrumental bias. Mathematical
      correction of this bias neutralized the error in accuracy and improved the
      precision (SD of the differences transcutaneous blood gases - arterial blood
      gases). An additional correction, suppressing the between-subject scattering,
      improved the actual precision: precision was reduced from 1.9 to 0.8 kPa (14.4 to
      5.7 mmHg) (R) and from 1.7 to 0.5 kPa (13.1 to 3.7 mmHg) (K) for oxygen, and from
      1.0 kPa (7.8 mmHg) (R) and 0.7 kPa (5.6 mmHg) (K) to 0.4 kPa (3.2 mmHg) for
      carbon dioxide (R and K). In conclusion, with these two successive corrections,
      transcutaneous oxygen and carbon dioxide provide a reliable estimation of blood
      gases to monitor nocturnal ventilation in adults with chronic respiratory
      failure.

PMID- 10414404
TI  - Cross-bridge kinetics in fatigued mouse diaphragm.
AB  - The aim of this study was to determine cross-bridge number and kinetics in the
      diaphragm during fatigue and early recovery. Experiments were conducted in
      isolated mouse diaphragm (n=10). The force of a single cross-bridge (pi), the
      number of cross-bridges (m x 10(9) x mm2), the time cycle (tc) and the rate
      constants for cross-bridge attachment (f1) and detachment (g2) were calculated
      from the equations of A.F. Huxley. Following the fatigue protocol, peak isometric
      tension (Po) and maximum unloaded shortening velocity fell by 40+/-1% and 17+/
      2%, respectively. In fatigued diaphragm, m fell by approximately 40% and returned
      to baseline after 10 min. When compared to baseline, g2 fell in fatigued
      diaphragm and remained significantly lower during the 15-min recovery period. In
      contrast, fatigue did not significantly modify pi, f1, or tc. There was a strong
      linear relationship between Po and m (p<0.001, r=0.988). No relationship was
      observed between tc and g2. These results indicate that changes in tension during
      fatigue and recovery run parallel to changes in the number of active cross
      bridges, with no change in the force generated per cross-bridge. It is
      conceivable that fatigue durably impairs adenosine diphosphate release from the
      actomyosin complex without modifying the total duration of the cross-bridge
      cycle.

PMID- 10414403
TI  - Volumetric capnography in patients with acute lung injury: effects of positive
      end-expiratory pressure.
AB  - The aim of the study was to analyse the effects of positive end-expiratory
      pressure (PEEP) on volumetric capnography and respiratory system mechanics in
      mechanically ventilated patients. Eight normal subjects (control group), nine
      patients with moderate acute lung injury (ALI group) and eight patients with
      acute respiratory distress syndrome (ARDS group) were studied. Respiratory system
      mechanics, alveolar ejection volume as a fraction of tidal volume (VAE/VT), phase
      III slopes of expired CO2 beyond VAE and Bohr's dead space (VD/VT(Bohr)) at
      different levels of PEEP were measured. No differences in respiratory system
      resistances were found between the ALI and ARDS groups. VD/VT(Bohr) and expired
      CO2 slope beyond VAE were higher in ALI patients (0.52+/-0.01 and 13.9+/-0.7 mmHg
      x L(-1), respectively) compared with control patients (0.46+/-0.01 and 7.7+/-0.4
      mmHg x L(-1), p<0.01, respectively) and in ARDS patients (0.61+/-0.02 and 24.9+/
      1.6 mmHg x L(-1), p<0.01, respectively) compared with ALI patients. VAE/VT
      differed similarly (0.6+/-0.01 in control group, 0.43+/-0.01 in ALI group and
      0.31+/-0.01 in ARDS group, p<0.01). PEEP had no effect on VAE/VT, expired CO2
      slope beyond VAE and VD/VT(Bohr) in any group. A significant correlation (p<0.01)
      was found between VAE/VT and expired CO2 slope beyond VAE and lung injury score
      at zero PEEP. Indices of volumetric capnography are affected by the severity of
      the lung injury, but are unmodified by the application of positive end-expiratory
      pressure.

PMID- 10414405
TI  - Effects of anabolic steroids on diaphragm impairment induced by
      methylprednisolone in emphysematous hamsters.
AB  - This study was designed to investigate whether the administration of the anabolic
      steroid nandrolone decanoate is able to antagonize the loss in diaphragm function
      induced by long-term administration of a low-dose of methylprednisolone in
      emphysematous hamsters. Normal and emphysematous male hamsters were randomized to
      receive either saline or methylprednisolone 0.2 mg x kg(-1) x day(-1) for 9
      months, with or without nandrolone decanoate 1 mg x kg(-1) x week(-1) i.m. during
      the final 3 months. Diaphragm contractile properties and myosin heavy chain
      composition were determined. Compared to control hamsters, the force generating
      capacity of isolated diaphragm strips decreased by approximately 12% in the
      emphysema group and by approximately 22% in the emphysema plus methylprednisolone
      group. Addition of nandrolone decanoate to the emphysema plus methylprednisolone
      hamsters significantly improved force generation. The atrophy of type IIa and IIx
      diaphragm fibres in the emphysema plus methylprednisolone group was completely
      reversed to the level of control hamsters by the addition of nandrolone
      decanoate. In conclusion, nandrolone decanoate in part reversed the loss in
      diaphragm force-generating capacity in emphysematous hamsters treated with
      methylprednisolone, and reversed type IIa and IIx fibre atrophy completely.

PMID- 10414406
TI  - Diaphragm strength and cross-bridge properties during chronic growth hormone
      hypersecretion.
AB  - The aim of the study was to determine diaphragm performance and cross-bridge
      properties in rats bearing a growth hormone (GH)-secreting tumour. The tumour was
      induced by subcutaneous injection of GH-hypersecreting cells (GC cells) into the
      flank. Eighteen weeks after GC cell injection, rats developed a GH-secreting
      tumour (45.4+/-5.1 g) and the GH plasma level reached 5,408+/-648 microg x L(-1)
      in GH rats versus 7.2+/-2.2 microg x L(-1) in control rats (p<0.001). Diaphragm
      mechanics and cross-bridge properties were studied by applying the equations of
      A. Huxley in isolated diaphragm strips (control rats: n=12; GH rats n=20). In
      comparison to control rats, the total tension and total number of cross-bridges x
      mm(-2) in GH rats were lower in both twitch and tetanus (p<0.001). A linear
      relationship was observed between total tension and total cross-bridge number
      (r=0.94; p<0.001). Conversely, the cross-bridge single force and peak mechanical
      efficiency did not differ between control and GH rats, in either twitch or
      tetanus modes. In conclusion, the diaphragm strength was significantly lower in
      rats bearing growth hormone secreting tumours, and this was essentially
      determined by the lower cross-bridge number x mm(-2) without change in cross
      bridge single force.

PMID- 10414407
TI  - In normal subjects bracing impairs the function of the inspiratory muscles.
AB  - Normal subjects can increase their capacity to sustain hyperpnoea by bracing
      their arms on fixed objects, a procedure which is also known to reduce dyspnoea
      in patients with chronic obstructive pulmonary disease (COPD). In the present
      study, it was tested whether bracing per se could improve the function of the
      diaphragm. The effect of bracing on diaphragm function was studied in six normal
      subjects by recording changes in oesophageal (delta Poes) and transdiaphragmatic
      (delta Pdi) pressure during inspiratory capacity (IC) manoeuvres in the seated
      and upright postures, and in the seated posture, also during bilateral phrenic
      nerve stimulation (BPNS) at functional residual capacity (FRC). The pattern of
      ribcage motion and deformation associated with bracing and with diaphragm
      contraction was also evaluated using inductance plethysmography and
      magnetometers. Bracing increased FRC by >300 mL and reduced IC by approximately
      200 mL, in both postures. Delta Pdi during BPNS decreased on average by 15%
      indicating an impaired diaphragmatic function. The ribcage was deformed with
      bracing and was more distortable during BPNS. In conclusion, in normal subjects,
      bracing impairs the function of the inspiratory muscles and reduces ribcage
      stability. These negative effects cannot explain the improved capacity to sustain
      hyperpnoea when the arms are braced.

PMID- 10414408
TI  - Subjective efficacy of nasal CPAP therapy in obstructive sleep apnoea syndrome: a
      prospective controlled study.
AB  - The response to nasal continuous positive airways pressure (nCPAP) of a wide
      variety of symptoms recognized to be associated with obstructive sleep apnoea
      syndrome (OSAS) was examined. Fifty-six consecutive patients with OSAS, confirmed
      by polysomnography (mean (SD) apnoea-hypopnoea index (AHI) 49.6 (22.6) events x
      h(-1), Epworth score 15.4 (5.0)), were asked to complete paired symptom
      evaluation questionnaires, before treatment and again after 4 months of nCPAP.
      The response rate was 80%. A control group of 21 consecutive OSAS patients of
      similar age, body mass index (BMI), AHI and Epworth score to the treated group
      but managed with conservative measures, completed the same questionnaires on two
      occasions, 4 months apart. The nCPAP-treated group showed significant reductions
      (Wilcoxon matched pairs test) in the symptoms of daytime sleepiness, restless
      sleep, heartburn, nocturia, enuresis, headache and nocturnal sweating, whereas
      controls showed no significant changes in these symptoms. There were no changes
      in BMI, smoking, alcohol consumption or exercise habits in either group. It was
      concluded that, in addition to improvements in symptoms of daytime sleepiness and
      restless sleep, a wide range of other symptoms may improve significantly with
      nasal continuous positive airways pressure therapy.

PMID- 10414409
TI  - Prognostic value of lung function and pulmonary haemodynamics in OSA patients
      treated with CPAP.
AB  - The aim of the present study was to determine survival rates of obstructive sleep
      apnoea patients treated with continuous positive airway pressure (CPAP) and to
      investigate the prognostic value of pretreatment lung function and pulmonary
      haemodynamics. Two hundred and ninety-six patients, exhibiting > or = 20 apnoeas
      plus hypopnoeas per hour of sleep, were included. Patients were treated with
      nasal CPAP and regularly followed up. The cumulative survival rates were 0.96
      (95% confidence interval (CI): 0.94-0.99) at 3 yrs and 0.93 (95% CI: 0.91-0.97)
      at 5 yrs. Most patients died from cardiovascular disease. Apart from age,
      covariates associated with a lower survival were the presence of a heavy smoking
      history, a low vital capacity, a low forced expiratory volume in one second
      (FEV1) and a high mean pulmonary artery pressure. Only three covariates were
      included by forward stepwise selection in the multivariate analysis, smoking
      habit (>30 pack-yrs), age and FEV1. The observed survival rates of the group as a
      whole were similar to those of the general population matched in terms of age,
      sex and smoking habit, except for patients between 50 and 60 yrs old who had
      reduced survival. This difference disappeared when patients of the present study
      with an associated chronic obstructive pulmonary disease were excluded from the
      comparison. In conclusion, survival of obstructive sleep apnoea patients treated
      with nasal continuous positive airway pressure is near to that of the general
      population. The prognosis is worse in subgroups of patients with a history of
      heavy smoking and with an associated chronic obstructive pulmonary disease.

PMID- 10414410
TI  - Autonomic dysfunction in patients with nocturnal hypoventilation in
      extrapulmonary restrictive disease.
AB  - In chronic obstructive pulmonary disease, persistent hypoxia may be associated
      with autonomic dysfunction. The effect of nocturnal oxygen desaturation on
      autonomic function in patients with chest wall deformities and neuromuscular
      disease is unknown. This study examined the effect of nocturnal oxygen
      desaturation upon heart rate variability, a sensitive measure of autonomic
      function. Twenty-seven patients with chest wall deformity or neuromuscular
      disease underwent analysis of overnight oximetry, blood gases, and 24 h heart
      rate variability (HRV), specifically the standard deviation of normal-to-normal
      (SDNN) RR intervals, and the number of increases in successive NN intervals >50
      ms (SNN50). Subjects were grouped according to nocturnal arterial oxygen
      saturation (Sa,O2): group 1 had episodes of Sa,O2 <90%, group 2 had Sa,O2 >90%
      throughout the night, and group 3 were 27 healthy age-matched controls who also
      underwent HRV analysis. The mean+/-SD SDNN for group 1 was 79.3+/-23.7 ms, less
      than group 2 (149.8+/-58.9 ms, p<0.02) and group 3 (155.1+/-37.1 ms, p<0.001).
      The geometric mean sNN50 was less in group 1 than group 2 (1,530 versus 5,843,
      p<0.01), but not significantly different from group 3 (2,712, p=0.053). There was
      no significant difference between groups 2 and 3. Within group 1, both SDNN and
      sNN50 were significantly lower in those patients with more severe nocturnal
      hypoxia. The minimum overnight Sa,O2 was the best predictor of abnormal HRV. In
      conclusion, patients with nocturnal hypoxia have evidence of autonomic
      dysfunction, even in cases with only transient episodes of nocturnal oxygen
      desaturation. The severity of autonomic dysfunction is related to the degree of
      nocturnal oxygen desaturation.

PMID- 10414411
TI  - Effects of formoterol in apparently poorly reversible chronic obstructive
      pulmonary disease.
AB  - This randomized, double-blind, placebo-controlled, crossover study was designed
      to investigate the effects of the long-acting beta2-adrenoreceptor agonist
      formoterol fumarate in 12 current or exsmokers having chronic obstructive
      pulmonary disease, with a mean forced expiratory volume in one second (FEV1) 47%
      of predicted, poorly reversible (5.1% pred) after terbutaline sulphate
      inhalation. After inhaling a single dose of formoterol (6 or 24 microg), or
      placebo via Turbuhaler, FEV1 and pulmonary function parameters measured during
      quiet breathing (work of breathing (WoB) and airway resistance (Raw)) were
      recorded over 12 h on three test days. Immediate changes in FEV1 were modest,
      although each dose of formoterol caused a response >12% pred within 10 min in one
      subject. Compared to placebo, both doses of formoterol induced a clinically and
      statistically relevant improvement in WoB (>25%) and Raw (>20%), which occurred
      within 10 min and lasted over a period of 12 h (p < or = 0.02, analysis of
      variance). Thus, inhaled formoterol causes long-lasting lung functional
      improvements in apparently poorly reversible chronic obstructive pulmonary
      disease. Additional lung function measurements during quiet breathing after
      forced expiration tests may be useful in such patients to assess beneficial
      effects of bronchodilators.

PMID- 10414412
TI  - Socioeconomic status, lung function and admission to hospital for COPD: results
      from the Copenhagen City Heart Study.
AB  - This study analysed the effect of education and income on development of chronic
      obstructive pulmonary disease (COPD) assessing lung function and hospital
      admission. The study population consisted of 14,223 subjects, aged 20-90 yrs,
      randomly sampled from the population of Copenhagen in 1976. Association between
      socioeconomic factors and forced expiratory volume in one second (FEV1) and
      forced vital capacity (FVC) at study entry was analysed by linear regression. The
      relation between socioeconomic factors and risk of admission to hospital for COPD
      from study entry until 1993 was assessed by register linkage. Education and
      income were independently associated with FEV1 and FVC. The age- and height
      adjusted difference in FEV1 (mean+/-SEM) between the highest and lowest level of
      education and income was 259+/-31 mL in females and 400+/-39 mL in males. After
      additional adjustment for quantity and duration of smoking and inhalation, the
      difference was 220+/-31 mL and 363+/-39 mL in females and males, respectively.
      Results for FVC were of the same magnitude. Using a socioeconomic index which
      combined information on education and household income the association with lung
      function did not differ by age. A total of 219 females and 265 males were
      admitted to hospital for COPD during follow-up. Education and income were
      significantly associated with admission to hospital. After detailed adjustment
      for smoking the relative risks (95% confidence intervals) for medium and high
      versus low socioeconomic index in females were 0.74 (0.55-1.02) and 0.27 (0.10
      0.73), respectively. Corresponding relative risks in males were 0.47 (0.36-0.63)
      and 0.35 (0.17-0.70). The results indicate that socioeconomic factors operating
      from early in life affect the adult risk of developing chronic obstructive
      pulmonary disease independently of smoking in both females and males.

PMID- 10414413
TI  - Associations between white blood cell count, lung function, respiratory illness
      and mortality: the Busselton Health Study.
AB  - An independent association between reduced levels of lung function and increased
      mortality from nonrespiratory causes has been observed in a number of studies.
      Since the total white blood cell count (WBC) has been related to both death from
      coronary heart disease and to levels of lung function, the relationship between
      these parameters was examined in subjects from the Busselton Health Surveys.
      Questionnaires regarding respiratory and cardiac illness and smoking habits were
      administered and total WBC, forced expiratory volume in one second (FEV1) and
      forced vital capacity measured in 2,105 males and 2,186 females at their initial
      attendance at a Busselton Health Survey in 1969, 1972 or 1975. Mortality follow
      up to 1995 was completed. Multiple linear regression showed that smoking,
      increasing age, reduced FEV1 (% predicted) and a history of bronchitis were
      associated with increased WBC. Reduction of FEV1 (% pred) by 20%, a history of
      dyspnoea and an increase in WBC of 1,300 cells x mL(-1) were predictive of
      increased mortality from all causes or coronary heart disease by approximately
      20, 100 and 10% respectively, independent of smoking. Removing WBC from the
      regression model did not significantly change the relationship between FEV1 and
      mortality. The study shows that the white blood cell count, forced expiratory
      volume in one second and dyspnoea are independently related to mortality in both
      males and females and that the effect of forced expiratory volume in one second
      on mortality is not explained by the white blood cell count.

PMID- 10414414
TI  - Additional value of K-ras point mutations in bronchial wash fluids for diagnosis
      of peripheral lung tumours.
AB  - The purpose of this study was to examine the additional diagnostic value of K-ras
      point mutations in the clinical diagnosis of peripheral lung tumours. To this
      end, bronchial wash fluids obtained during bronchoscopy from patients suspected
      of having lung cancer were studied. Only those patients were investigated for
      whom the cytological diagnosis was not conclusive for malignancy. As a control
      group, patients without lung cancer were investigated. The method of "point
      mutation detection using the exonuclease amplification coupled capture technique"
      (Point-EXACCT) for analysis of K-ras codon 12 was performed in bronchial wash
      fluids and the corresponding tumour tissue, if available. K-ras point mutations
      were identified in 4 out of 19 (21%) bronchial wash fluids from patients without
      a decisive diagnosis of malignancy. The diagnosis of malignancy was further based
      on cytological examination of bronchial brush specimens, perthoracic needle
      aspiration, histological investigation of biopsy and resection specimens, needle
      aspiration of a lymph node in the neck and pleural fluid examination. Four of the
      patients who were K-ras-positive yielded positive malignant tissue via
      bronchoscopy even though the bronchial wash was negative for malignancy. The
      bronchial wash was positive for K-ras in two of the four patients whose tumour
      tissue demonstrated the K-ras mutations. Analysis of bronchial wash fluids from
      11 patients without lung cancer revealed no K-ras codon 12 mutations. In
      conclusion, K-ras point mutations can be identified in bronchial wash fluids
      obtained during bronchoscopic procedures. K-ras can be used as a biomarker in the
      clinical diagnosis of lung cancer and may serve as an adjunct to cytology in lung
      cancer diagnosis.

PMID- 10414415
TI  - Recombinant E1-deleted adenovirus vector induces apoptosis in two lung cancer
      cell lines.
AB  - Although replication-defective adenoviruses (Ads) are used as vectors for
      delivering therapeutic genes to cancer cells, various effects of the viruses on
      the proliferation of lung cancer cells have been reported. Experiments were
      carried out to determine whether or not E1-deleted Ad vectors (Ad5-CMV-lacZ)
      affected cell kinetics in two different types of lung cancer cell line in vitro.
      A dose-dependent relationship was measured between the vector multiplicity of
      infection (MOI) and the efficiency of lacZ gene transfer to lung cancer cells.
      The growth curves of vector-infected cells were shifted to the right compared
      with those of vehicle-exposed cells in a vector MOI-dependent fashion. The slowed
      cell proliferation resulted from both increased cell death and slower cell cycle
      progression of the vector-infected cells. The morphology of vector-exposed cells
      revealed apoptotic features including nuclear condensation and fragmented nuclei.
      These results indicate that using a higher vector MOI causes a higher gene
      transfer rate, but may induce apoptosis of infected cells. Although vector
      induced apoptosis may be advantageous in inhibiting tumour growth, apoptosis of
      vector-infected cells may also reduce transgene expression in cancer cells.
      Minimization of the induction of apoptosis of vector-infected cells is important
      for the prolongation of the transduction efficiency of Ad vectors.

PMID- 10414416
TI  - Aggressive primary mediastinal non-Hodgkin's lymphomas: a study of 29 cases.
AB  - Aggressive primary mediastinal non-Hodgkin's lymphomas (NHL) represent a
      particular entity among intrathoracic neoplasms. Twenty-nine patients with
      primary mediastinal aggressive NHL diagnosed and treated in the author's
      institution were studied. According to the Revised European-American Lymphoma
      (REAL) classification, there were 15 diffuse large B-cell, eight T-lymphoblastic,
      four anaplastic, one large T-cell and one Burkitt's lymphomas. The study group
      consisted of 14 females and 15 males, with a mean age of 38 yrs. Symptoms arose
      from an aggressive anterior mediastinal mass, with a high prevalence of superior
      vena caval syndrome, pleural, and pericardial effusions. At the time of
      diagnosis, disease was confined to supradiaphragmatic areas in 24 patients, while
      subdiaphragmatic nodal or extranodal involvement was also present in five. All
      patients received a combination of aggressive chemotherapy regimens, mainly
      according to the French protocols for the treatment of NHL. A chest radiograph
      response of <50% after the first course of chemotherapy and failure to achieve a
      complete remission after the first line of chemotherapy were significantly
      associated with unfavourable prognosis. Overall 5-yr and 9-yr survival rates were
      55 and 48%, respectively. Patients properly diagnosed and treated with a combined
      modality of chemotherapy can experience prolonged survival.

PMID- 10414418
TI  - Pulmonary effects of short-term exposure to low levels of toluene diisocyanate in
      asymptomatic subjects.
AB  - Isocyanates may be involved in the development of chronic obstructive airway
      disease among exposed workers. A short-term exposure to toluene diisocyanate
      (TDI) at concentrations near the permissible levels was investigated to examine
      whether there was an association with changes in pulmonary function tests and in
      potential markers of airway injury and inflammation in bronchial lavage (BL) and
      bronchoalveolar lavage (BAL). Seventeen subjects without respiratory symptoms
      (eight smokers and nine nonsmokers) were exposed once to ambient air and once to
      TDI (5 parts per billion (ppb) for 6 h followed by 20 ppb for 20 min) in a
      randomized, single-blind sequence. Pulmonary function tests were repeatedly
      assessed during exposure and BAL was performed 1 h after each exposure.
      Biochemical studies on lavage fluids included albumin, immunoglobulins,
      antiproteases (alpha2-macroglobulin and alpha1-proteinase inhibitor), potential
      indicators of epithelial cell function (secretory component and Clara cell
      protein), and cytokines (tumour necrosis factor-alpha, interleukin (IL)-4, IL-5,
      IL-6, and IL-8). Exposure to TDI caused a modest decrease in specific airway
      conductance (sGaw) (p=0.053) and in maximal expiratory flow at 25% of forced
      vital capacity (MEF25%) (p=0.015) when compared with ambient air. Exposure to TDI
      resulted in a slight increase in BAL albumin level (TDI: 26.4+/-12.5 versus air:
      21.8+/-8.6 microg x mL(-1), p=0.044) and in BL alpha2-macroglobulin concentration
      (TDI: 0.07+/-0.061 versus air: 0.05+/-0.04 microg x mL(-1), p=0.021). This study
      suggests that exposure to low toluene disocyanate concentrations is associated
      with minimal but detectable changes in airway calibre and in epithelial barrier
      permeability. The pulmonary effects of long-term exposure to low levels of
      isocyanates require further investigation.

PMID- 10414417
TI  - Allergen exposure, atopy and smoking as determinants of allergy to rats in a
      cohort of laboratory employees.
AB  - This study aimed to examine the relationship between exposure to rat urinary
      allergens, atopic status, smoking and the development of allergic symptoms and
      specific sensitization. It is a case-referent analysis of a cohort of 342 newly
      employed laboratory animal workers. Cases comprised persons developing symptoms
      of laboratory animal allergy or a positive skin prick test to rat urinary
      allergens; each was matched with up to two asymptomatic referents. Subjects were
      assigned to categories of exposure based on measurements of airborne rat urinary
      allergens. Of the cases, 80% reported that their symptoms started within 2 yrs of
      employment. The odds ratio (OR) for development of each symptom type
      (respiratory, eye or nose and skin) and of an immediate skin test reaction was
      increased in those with direct contact with rats. A gradient of increasing OR for
      the development of any such symptom across exposure categories was found; for
      respiratory symptoms and skin test reactions the OR for subjects in the highest
      exposure category were lower than those in intermediate categories, a pattern
      attenuated when the analysis was confined to outcomes developing within 2 yrs of
      first exposure. Atopy increased the OR of most outcomes as did cigarette smoking,
      although there was no evidence of a relationship between smoking and the
      development of a specific skin test reaction. In conclusion, allergen exposure
      was confirmed as the most important determinant of laboratory animal allergy; by
      implication, measures to reduce exposure may be the most effective means to
      reduce its incidence.

PMID- 10414420
TI  - An in vivo comparison of a catheter mounted pressure transducer system with
      conventional balloon catheters.
AB  - In the assessment of respiratory muscle function balloon catheters have been
      widely used for pressure measurements. However, this type of investigation is
      poorly tolerated by acutely ill patients. This study assessed the performance of
      a possible alternative, a catheter-mounted miniature pressure transducer (CMT).
      The assessment consisted of a laboratory study of the linearity, frequency
      response, and stability of gain and baseline of the CMT system, and an in vivo
      study directly comparing the CMT and balloon catheter systems in seven normal
      subjects for a range of respiratory manoeuvres. These were: 1) maximal
      inspiratory and expiratory pressures against a closed airway, 2) twitch
      transdiaphragmatic pressure elicited by cervical magnetic phrenic nerve
      stimulation, and 3) tidal breathing, sniffs and coughs in five body positions.
      The agreement of the two systems was analysed for measurements of 1) absolute
      pressures, 2) magnitude of changes in pressure, and 3) rate of change of pressure
      (maximum relaxation rate after sniff manoeuvres). The CMT system was linear, with
      a high frequency response and stable gain, but showed baseline drift. The two
      systems agreed well for measurements of change and rate of change of pressure,
      but less well for measurements of absolute pressure. The CMT system tested is
      potentially useful for studies of acute changes in respiratory pressures, or
      studies of respiratory muscle strength, but would be less useful where accurate
      measurements of absolute pressures are required.

PMID- 10414419
TI  - Airways inflammation among workers in a paper industry.
AB  - Exposure to organic dusts may cause airways inflammation in a large proportion of
      exposed persons. Most studies have relied on questionnaires and spirometry for
      diagnosis. To assess the possibility of determining the presence of inflammation
      using clinical diagnostic procedures, a study was undertaken among workers in a
      paper industry. Participants were 83 workers and 44 controls. Airborne endotoxin
      and (1-->3)-beta-D-glucan levels at the worksites were determined. The effects of
      this exposure were evaluated using a questionnaire, spirometry and measurements
      of airway responsiveness (methacholine) and levels of eosinophil cationic protein
      (ECP), myeloperoxidase (MPO), and C-reactive protein (CRP) in serum. The workers
      had a decreased baseline forced expiratory volume in one second (FEV1) and an
      increased airway responsiveness compared with controls. The concentrations of ECP
      and MPO were elevated compared with controls. There was a relation between
      exposure to endotoxin and (1-->3)-beta-D-glucan and airway responsiveness as well
      as ECP levels, when controlling for age, sex, smoking habits, atopy and asthma.
      The results suggest an increased prevalence of subjective respiratory symptoms,
      and an increased airway responsiveness among exposed workers. There was also a
      relationship between the serum concentration of eosinophil cationic protein and
      airway responsiveness. Taken together, the results suggest the presence of
      airways inflammation in the workers.

PMID- 10414421
TI  - An in vitro analysis of the output of salbutamol from different nebulizers.
AB  - The objective of this study was to determine the particle size and mass output of
      salbutamol from different nebulizers used under simulated breathing conditions.
      Seven nebulizer/compressor combinations were assessed. Each nebulizer was charged
      with 5 mg salbutamol solution and connected to a breathing simulator operating at
      tidal volumes of 150 mL and 600 mL. Nebulizers were operated for 15 min.
      Salbutamol collected on the filters was measured by liquid chromatography.
      Aerosol particle size was determined separately by laser diffraction. The Pari LC
      Star nebulizer delivered the most salbutamol at both tidal volumes. The maximal
      output of the Medicaid Ventstream and Sidestream nebulizers was two-thirds that
      of the LC Star, and they delivered less salbutamol than the LC Star or LC Plus
      nebulizers. The Intersurgical Cirrus nebulizer delivered the least salbutamol at
      both tidal volumes, although there was only a small difference between the Cirrus
      and Ventstream or Sidestream nebulizers at 150 mL tidal volume. The LC Plus
      nebulizer produced larger particles, mass median diameter 5.3 microm, compared
      with 3.6-4.0 microm for the other nebulizers. In conclusion, there were large
      differences in the delivery of salbutamol between the nebulizers studied, even
      between nebulizers of apparently the same class, and this should be borne in mind
      by regulatory authorities, clinicians and researchers.

PMID- 10414422
TI  - Short- and long-term functional results after lung volume reduction surgery for
      severe emphysema.
AB  - Lung volume reduction surgery (LVRS) has emerged as a surgical therapeutic
      intervention for advanced emphysema. Designed for the relief of dyspnoea, LVRS
      has been demonstrated to be efficacious in a subset of carefully selected
      patients. Short-term improvements in dyspnoea are accompanied by improvements in
      forced expiratory volume in one second ranging 13-96%. Lung volumes likewise
      improve, with lessening of trapped gas, residual volume, and total lung capacity.
      Improvements in functional status and quality-of-life measures parallel the
      improvements in dyspnoea and lung function. One preliminary study suggests that
      life expectancy after 3 yrs may be improved following LVRS. Many questions
      regarding lung volume reduction surgery in terms of operative technique,
      selection of patients, and outcome remain to be answered. Data are available
      which begin to address some of these issues. Bilateral procedures have greater
      short-term improvements than unilateral procedures, but the rate of loss of
      function following the surgery may also be greater. Stapled resection of lung
      tissue has been demonstrated to be superior to laser ablation. In a majority of
      reports, outcome is superior in patients with heterogeneous distribution of their
      emphysema, and patients with alpha1-proteinase inhibitor deficiency emphysema do
      less well than patients with smoker's emphysema.

PMID- 10414423
TI  - Regulation of mucociliary clearance in health and disease.
AB  - Airway secretions are cleared by mucociliary clearance (MCC), in addition to
      other mechanisms such as cough, peristalsis, two-phase gas-liquid flow and
      alveolar clearance. MCC comprises the cephalad movement of mucus caused by the
      cilia lining the conducting airways until it can be swallowed or expectorated.
      MCC is a very complex process in which many variables are involved, all of which
      may modify the final outcome. The structure, number, movement and co-ordination
      of the cilia present in the airways as well as the amount, composition and
      rheological properties of the periciliary and mucus layers are determinants of
      MCC. Physiological factors such as age, sex, posture, sleep and exercise are
      reported to influence MCC due to a change in the cilia, the mucus or the
      periciliary layer, or a combination of these. Environmental pollution is
      suspected to have a depressant effect on MCC dependent on different factors such
      as pollutant concentration and the duration of exposure. Most studies focus on
      sulphur dioxide, sulphuric acid, nitrogen dioxide and ozone. Tobacco smoke and
      hairspray have been noted to have a negative influence on MCC. Some diseases are
      known to affect MCC, mostly negatively. The underlying mechanism differs from one
      illness to another. Immotile cilia syndrome, asthma, bronchiectasis, chronic
      bronchitis, cystic fibrosis and some acute respiratory tract infections are among
      the most frequently reported. The present paper reviews normal mucociliary
      clearance and the effects of diseases on this process.

PMID- 10414424
TI  - Occupational asthma induced by cephalosporins.
AB  - A 20-yr-old pharmaceutical worker who developed attacks of shortness of breath
      and wheezing 9 months after beginning work on a process in which cefadroxil
      powder was bottled or encapsulated will be described. Skin test with cefaxodril
      was negative. Baseline spirometry and methacholine inhalation test were normal. A
      controlled bronchial challenge test was carried out in a closed-circuit system
      with assessment of respirable dust concentration. Exposure to cefadroxil powder
      at a mean concentration of 10 mg x m(-3) for 10 min elicited an isolated
      immediate asthmatic response, but no response was observed to control challenge
      with lactose. Single-blind oral challenge test with amoxicillin up to 500 mg was
      well tolerated, whereas the oral challenge with cephalexin (25 mg) elicited an
      immediate asthmatic response. This patient had developed occupational asthma
      caused by inhalation of cefadroxil as confirmed by specific inhalation test.
      Since she tolerated oral amoxicillin, a synthetic penicillin with the side-chain
      identical to that of cefadroxil, it seems that she may be sensitized to the
      dihydrothiazine ring of cephalosporins.

PMID- 10414425
TI  - Reactive airways dysfunction syndrome following exposure to a fluorocarbon.
AB  - This report describes the case of a 43-yr-old male who developed reactive airways
      dysfunction syndrome after exposure to a high level of bromotrifluoromethane
      (CF3Br, Halon 1301), a fluorocarbon widely used in automatic fire extinguishing
      systems. The patient was a previously healthy, nonatopic male, who developed
      wheezing and intermittent and reversible obstructive ventilatory impairment
      starting immediately after a large accidental nonfire-related release of CF3Br in
      a confined space.

PMID- 10414426
TI  - Hunter's syndrome and associated sleep apnoea cured by CPAP and surgery.
AB  - A 42-yr-old male with Hunter's syndrome presented with severe obstructive sleep
      apnoea syndrome (OSAS) and daytime respiratory failure. Continuous positive
      airway pressure (CPAP) therapy was initially ineffective and produced acute
      respiratory distress. Extensive Hunter's disease infiltration of the upper airway
      with a myxoma was confirmed. Following surgery to remove the myxoma at the level
      of the vocal cords, CPAP therapy was highly effective and well tolerated. This
      report demonstrates the necessity of evaluating fully the upper airway in
      patients with unusual variants of OSAS, particularly where the disease is not
      adequately controlled by CPAP.

PMID- 10414427
TI  - Difficult/therapy-resistant asthma: the need for an integrated approach to define
      clinical phenotypes, evaluate risk factors, understand pathophysiology and find
      novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European
      Respiratory Society.

PMID- 10414428
TI  - Long-term oxygen therapy: do current guidelines need revision?

PMID- 10414429
TI  - CO2-response in chronic obstructive pulmonary disease.

PMID- 10414430
TI  - Anorectic efficacy of the fenfluramine/phentermine combination in rats:
      additivity or synergy?
AB  - Fenfluramine + phentermine was a widely used combination for weight loss.
      Fenfluramine and phentermine are believed to act via serotonin and
      catecholamines, respectively. To what extent these drugs interact has not been
      well-established. We compared the anorectic efficacy of a range of doses of the
      combination (using dexfenfluramine instead of fenfluramine) relative to a range
      of doses of the individual drugs in 90 min sweetened milk intake tests in
      deprived and nondeprived rats. Results were plotted on isobolograms to determine
      whether the anorectic effects of the combination were either additive or
      synergistic. Collectively, the isobolographic analysis revealed that: (1) under
      acute conditions, dexfenfluramine and phentermine interact for the most part in a
      synergistic manner, and (2) with the exception of phentermine alone, deprivation
      state at time of testing did not alter the efficacy of the anorectics. These
      findings suggest that combined drug treatment for obesity is a theoretical
      approach that merits further investigation.

PMID- 10414431
TI  - The effect of caffeine in animal models of learning and memory.
AB  - In the present investigation we studied the effect of caffeine on memory task
      inhibitory avoidance and habituation to a new environment. Caffeine impaired
      retention scores in mice submitted to inhibitory avoidance and habituation when
      administered 30 min before training at the doses of 10-30 mg/kg. These effects
      cannot be explained by state-dependency since the administration of caffeine 30
      min before the test session did not reverse the effect of pre-training caffeine
      administration, but can more probably be explained by an impairment in the
      acquisition or by interference with attentional processes. On the other hand,
      caffeine improved the inhibitory avoidance (but not habituation) retention scores
      when administered immediately after the training or 30 min before the test
      session at the doses of 1-30 mg/kg or 3-10 mg/kg, respectively. These results
      suggest that caffeine differentially affects the different stages of memory
      processing and that this effect depends on particularities of the memory task
      under study.

PMID- 10414432
TI  - Influence of peptide CRF receptor antagonists upon the behavioural effects of
      human/rat CRF.
AB  - The effects of the corticotropin-releasing factor (CRF) receptor antagonists,
      alpha-helical CRF-(9-41), [D-Phe12,Nle21,38, CalphaMe-Leu37]humanCRF-(12-41) (D
      PheCRF-(12-41)) and astressin ([cyclo(30-33)[D-Phe12,Nle21,38,Glu30,Lys33]h
      umanCRF-(12-41) upon hypophagic and motor activation response to human/ratCRF
      (h/rCRF) were investigated. All three antagonists (100 microg
      intracerebroventricular (i.c.v.)) blocked the effects of h/rCRF (1 microg i.c.v.)
      upon food intake and body weight change in food-deprived rats. In contrast, alpha
      helical CRF-(9-41) and astressin (both at 100 microg i.c.v., but not lower
      doses), but not D-PheCRF-(12-41) (up to 100 microg i.c.v.), blocked h/rCRF (0.3
      microg i.c.v.)-induced motor activation in rats in a familiar environment. The
      ability of D-PheCRF-(12-41) to block CRF-induced hypophagia, but not motor
      activation, suggests a selective action of this antagonist upon the behavioural
      effects of centrally administered h/rCRF.

PMID- 10414433
TI  - Metyrapone alleviates ischemic neuronal damage in the gerbil hippocampus.
AB  - Transient forebrain ischemia was induced in gerbils, and the effect of a pre
      ischemic treatment with metyrapone (100 mg/kg) on delayed neuronal death in
      hippocampal CA1 neurons was evaluated. The effect of metyrapone on the ischemic
      release of amino acids in the CA1 region was also examined by microdialysis.
      Hippocampal slices were used for the evaluation of the hypoxia-induced
      intracellular Ca2+ increase by microfluorometry. The metyrapone treatment
      morphologically improved the damage provoked by 3 min of ischemia, although it
      did not alleviate the damage by 5 min. Ischemia for 3 min produced a 306%
      increase in the glutamate concentration in perfusates, and metyrapone suppressed
      the peak value to 42% of that in the control group. The extent of the increase in
      fluorescence intensity by intracellular Ca2+ was lower by 16% in slices from
      metyrapone-treated animals than in controls 600 s after induction of hypoxia. The
      removal of Ca2+ from the perfusion medium suppressed the hypoxic Ca2+ increase,
      and the increase was further reduced in slices pretreated with metyrapone. The
      increase in the level of endogenous glucocorticoids, which occurs in cerebral
      ischemia, may aggravate ischemic neuronal damage.

PMID- 10414434
TI  - Effects of diazepam on extracellular brain neurotransmitters in pilocarpine
      induced seizures in rats.
AB  - The present study was undertaken to gain insights into the mechanism of action of
      diazepam in focally-evoked pilocarpine-induced seizures by concomitantly
      assessing the changes produced in the extracellular levels of glutamate, GABA
      (gamma-aminobutyric acid) and dopamine. In vivo microdialysis, coupled to
      continuous monitoring of electrocorticographic (ECoG) recordings, was performed
      in freely moving rats. Intrahippocampal perfusion with 10 mM pilocarpine (40 min,
      2 microl/min) produced limbic seizures. A single dose of intraperitoneal diazepam
      (5 mg/kg) was administered 2 h after pilocarpine perfusion was started.
      Dialysates were sampled both from hippocampus and cerebellum and analysed by
      microbore liquid chromatography. Diazepam produced instant inhibition of
      behavioural and ECoG seizure activity. Pilocarpine-induced increases in the
      extracellular levels of glutamate and dopamine in hippocampus were promptly
      reduced by diazepam. No concurrent alterations in pilocarpine-induced increases
      in the extracellular levels of GABA in either hippocampus or cerebellum were
      seen. Pilocarpine enhanced cerebellar glutamate levels only transiently and
      levels returned to baseline before diazepam administration. No further changes in
      cerebellar glutamate levels were observed with diazepam. Our findings suggest
      that the anti-convulsant action of diazepam against pilocarpine-induced seizures
      is associated with a prompt attenuation of extracellular hippocampal glutamate
      overflow without concurrent alteration of pilocarpine-induced increases in
      endogenous GABA levels. Diazepam also significantly decreased pilocarpine-induced
      increases in extracellular dopamine levels within the hippocampus. No immediate
      alterations of the basal levels of the neurotransmitters monitored were observed
      with diazepam.

PMID- 10414436
TI  - Differential effects of (R)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin on
      the monosynaptic spinal reflex in rats.
AB  - We examined the effects of (R)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin
      hydrobromide (8-OH-DPAT) on the monosynaptic spinal reflex in rats. In intact
      rats, (R)-8-OH-DPAT (10 microg/kg, i.v.) enhanced the amplitude of the
      monosynaptic reflex, whereas at 100 microg/kg, it reduced the amplitude. (S)-8-OH
      DPAT enhanced the monosynaptic reflex dose-dependently. In spinalized rats, (R)-8
      OH-DPAT produced dose-dependent inhibition, but the (S)-enantiomer did not affect
      the monosynaptic reflex. Pretreatment with spiroxatrine or 1-(2-methoxyphenyl)-4
      [4-(2-phthalimido)butyl]-piperazine (NAN-190) inhibited (R)-8-OH-DPAT-induced
      monosynaptic reflex enhancement in intact rats, as did 5-hydroxytryptamine (5-HT)
      depletion. Ketanserin reduced the effect of (R)-8-OH-DPAT. These pretreatment
      regimens had no effect on the monosynaptic reflex depression produced by the (R)
      enantiomer in intact and spinalized rats. Pretreatment with prazosin inhibited
      (S)-8-OH-DPAT-induced monosynaptic reflex enhancement in intact rats, as did
      noradrenaline and 5-HT depletion. These results suggest that supraspinal 5-HT1A
      receptors and the descending serotonergic system are involved in the stimulatory
      effect of (R)-8-OH-DPAT on the monosynaptic reflex, while both the descending
      serotonergic and noradrenergic systems, the latter acting via alpha1
      adrenoceptors, are involved in the effect of the (S)-enantiomer on this reflex.

PMID- 10414435
TI  - Cu2+ induces Ca2+-dependent neurotransmitter release from brain catecholaminergic
      nerve terminals.
AB  - CuCl2, ZnCl2 and NiCl2, but not CdCl2 or CoCl2, induced transmitter release from
      superfused rat hippocampal and striatal synaptosomes preloaded with,
      respectively, [3H]noradrenaline and [3H]dopamine. Cu2+ was the most potent and
      effective, acting in a concentration- (0.1-300 microM) and time-dependent (peak
      effect occurring at 2-3 min) manner. The amount of Cu2+-induced release over a 5
      min period is similar to that induced by depolarization with high KCl or the K+
      channel blocker 4-aminopyridine. However, the time course of the Cu2+-induced
      release is slower and the effect of Cu2+ is not reversed by washout. Cu2+-induced
      catecholamine release requires extracellular calcium (Ca2+) and is inhibited by
      the Ca2+ channel blocker Cd2+, and in the case of noradrenaline, by the voltage
      gated Na+ channel blocker tetrodotoxin. The ability of Cu2+ to induce massive
      Ca2+-dependent transmitter release from brain catecholaminergic nerve terminals
      may contribute to the neuropathological processes associated with Cu2+ toxicity
      in Wilson's disease.

PMID- 10414437
TI  - Possible mechanisms for insulin-induced attenuation of the antinociceptive effect
      of [D-Ala2, N-MePhe4, Gly-ol5]enkephalin.
AB  - The effects of pretreatment with protein kinase C and protein kinase A inhibitors
      on the intraventricular insulin-induced attenuation of the antinociceptive effect
      of [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAMGO) were studied in mice.
      Intracerebroventricular (i.c.v.) pretreatment with insulin dose- and time
      dependently attenuated the antinociceptive effect of i.c.v. DAMGO (5.6 ng) in
      mice. Intracerebroventricular pretreatment with a highly selective tyrosine
      kinase inhibitor, herbimycin A, at doses of 200 and 600 ng for 70 min, dose
      dependently reversed the attenuation of the antinociceptive effect of DAMGO (5.6
      ng, i.c.v.) caused by insulin. Furthermore, i.c.v. pretreatment with
      serine/threonin kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine
      hydrochloride (H7), at doses of 3-30 nmol for 60 min, dose-dependently reversed
      the attenuation of the antinociceptive effect of DAMGO (5.6 ng, i.c.v.) caused by
      insulin. Intracerebroventricular pretreatment with selective protein kinase C
      inhibitor, calphostin C, at doses of 1 and 3 pmol for 60 min, but not with a
      highly protein kinase A inhibitor, (8R, 9S, 11S)-(-)-9-hydroxy-9-n-hexyloxy
      carbonyl-8-methyl-2, 3, 9, 20-tetrahydro-8, 11-epoxy-1H, 8H, 11H-2, 7b, 11a
      triaqzadibenzo[a, g]cycloocta[c, d, e]-trinden-1-one (KT5720), at dose of 10 pmol
      for 60 min, reversed the attenuation of the antinociceptive effect of DAMGO (5.6
      ng, i.c.v.) caused by insulin. These results suggest that the reduction of DAMGO
      induced antinociception by insulin in mice may be, in part, due to the activation
      of protein kinase C followed by the activation of tyrosine kinase.

PMID- 10414438
TI  - Chronic methylphenidate alters locomotor activity and dopamine transporters
      differently from cocaine.
AB  - Continuous infusion of cocaine produces partial behavioral tolerance to its
      locomotor activating effects, while daily injections produce sensitization.
      Methylphenidate binds with a similar affinity to cocaine at the dopamine
      transporter, but has a much lower affinity for the serotonin transporter than
      does cocaine. This study was done to compare the effects of chronic
      methylphenidate with chronic cocaine. The pattern of locomotor activity over a 7
      day treatment period was significantly different from cocaine. Methylphenidate
      elevated activity on each day, compared to saline, yet neither tolerance to a
      continuous infusion of the drug, nor sensitization to repeated daily injections
      was produced. We have previously shown that neither of these treatments with
      cocaine produces significant alterations in dopamine transporter density 1 day
      after the end of treatment. In contrast, methylphenidate injections significantly
      decreased dopamine transporters in rostral caudate putamen, with no change in
      nucleus accumbens. Continuous infusion of methylphenidate had no effect on
      dopamine transporters in either brain region. These findings provide further
      evidence that different classes of dopamine uptake inhibitors may interact with
      the dopamine transporter in qualitatively different manners. Furthermore, it is
      possible that the inhibition of serotonin uptake by cocaine may contribute to the
      adaptations in behavioral activity that are seen during chronic treatment.

PMID- 10414440
TI  - Inhibitory mechanism of N(G)-nitro-L-arginine on acetylcholine-induced depressor
      responses in dogs.
AB  - The significance of the blood pressure elevation caused by N(G)-nitro-L-arginine
      (L-NNA) to inhibitory mechanism of the drug on depressor responses to
      acetylcholine in anesthetized dogs was investigated. L-NNA (50 mg kg(-1), i.v.)
      elevated blood pressure to a plateau of 30-50 mm Hg above baseline level and
      shifted the dose-response curve for acetylcholine-induced responses to the right
      by about 70-fold. Prevention by hydralazine (1 mg kg(-1), i.v.) of the blood
      pressure elevation over baseline level caused by L-NNA attenuated the inhibitory
      effect of L-NNA on the responses to acetylcholine. Intravenous neostigmine (30
      microg kg(-1) bolus followed by 15 microg kg(-1) min(-1)) attenuated the
      inhibitory effect of L-NNA. The magnitude of the rightward shift in the dose
      response curve for carbachol-induced depressor responses was only 3-fold. These
      results suggest that the accelerated acetylcholine metabolism by blood pressure
      elevation contributes to a considerable degree to the inhibitory mechanism of L
      NNA.

PMID- 10414439
TI  - Effect of Ca2+ channel blockers on arterial hypertension and heart ischaemic
      lesions induced by chronic blockade of nitric oxide in the rat.
AB  - The effects of the Ca2+ channel blockers diltiazem, nifedipine and amlodipine
      were investigated on both arterial hypertension and myocardial changes induced by
      chronic blockade of nitric oxide synthesis. Control male Wistar rats received
      Nomega-nitro-L-arginine methyl ester (L-NAME; 20 mg rat(-1) day(-1)) in the
      drinking water for 8 weeks; blood pressure and body weight were monitored weekly.
      The Ca2+ channel blockers were given concomitantly to L-NAME, as follows:
      diltiazem (13.5 mg rat(-1) day(-1)) and amlodipine (6.25 mg rat(-1) day(-1)) were
      administered in the drinking water whereas nifedipine (6.25 mg rat(-1) day(-1))
      was given in the chow. Nomega-nitro-L-arginine methyl ester induced a time
      dependent increase in blood pressure which was significantly attenuated by
      diltiazem (154+/-1.6 vs. 139+/-1.6 mm Hg, p < 0.05), nifedipine (166+/-2.7 vs.
      150+/-2.1 mm Hg, p < 0.05) and amlodipine (208+/-5.8 vs. 158+/-1.8 mm Hg, p <
      0.05) at the last week of the treatment. Rats treated with the L-NAME also
      developed myocardial ischaemia, as indicated by the increased percentage of
      fibrous tissue found in the left ventricles of these animals (10.9+/-0.1%, p <
      0.01) when compared to control ones (6.3+/-0.1%). Neither diltiazem (14.9+/-1.2%)
      nor nifedipine (11.1+/-1.5%) prevented this effect whereas amlodipine (6.9+/
      1.1%, p < 0.01) virtually abolished the increase in fibrous tissue induced by L
      NAME. The plasma concentration of the Ca2+ channel blockers was measured by
      liquid chromatography coupled to mass spectrometry at two different time points
      (morning and afternoon). Only amlodipine treatment was able to maintain constant
      levels (186+/-46 ng ml(-1) in the morning and 110+/-19 ng ml(-1) in the evening)
      compared to nifedipine (3003+/-578 ng ml(-1) in the morning and 436+/-100 ng ml(
      1) in the evening) and diltiazem (77+/-51 ng ml(-1) in the morning and not
      detectable in the evening). In conclusion, our results indicate that amlodipine
      (but not diltiazem and nifedipine) can efficiently control myocardial ischaemia
      in nitric oxide deficient rats, probably due to its intrinsically long half-life.

PMID- 10414441
TI  - Granulocyte-macrophage colony-stimulating factor enhances interleukin-1beta
      stimulated histamine release in the preovulatory rat ovary.
AB  - The existence of immune cells including macrophages and mast cells in rat ovary
      implies that various cytokines from these cells may play a role in ovarian
      functions. The aim of the present study was to investigate whether granulocyte
      macrophage colony stimulating factor (GM-CSF) and interleukin-1beta are capable
      of stimulating histamine release and steroidogenesis in rat ovary, and to
      determine the sites of histamine production in the ovary. Histamine release from
      preovulatory ovarian tissues was stimulated in a dose-dependent manner at 3-30
      ng/ml of GM-CSF in the presence of interleukin-1beta (10 ng/ml). However,
      treatment with GM-CSF and interleukin-1beta did not cause any significant change
      in the levels of ovarian steroids. Intense staining of histidine decarboxylase in
      the ovary was immunohistochemically detected in large granular cells on the
      morning of the pro-oestrus day. These results indicate that GM-CSF may be
      involved in the regulation of ovarian histamine secretion in mast cells partially
      by enhancing interleukin-1beta-induced histamine release in the process of
      ovulation.

PMID- 10414442
TI  - Partial agonism at serotonin 5-HT1B and dopamine D2L receptors using a luciferase
      reporter gene assay.
AB  - We have used a luciferase reporter gene assay to study the functional responses
      of two G-protein-coupled receptors in Chinese hamster ovary (CHO) cells. The rank
      order of potency of drugs for the endogenous 5-HT1B receptor was 5
      Hydroxytryptamine (5-HT) > zolmitriptan > dihydroergocristine > (-)lisuride (with
      no response to bromocriptine). However, only 5-HT and (-)lisuride produced a full
      functional response, with zolmitriptan and dihydroergocristine achieving 69+/-2%
      and 50+/-1% of the maximal response. In the same cells stably transfected with
      the rat dopamine D2L receptor, dopamine and bromocriptine produced a full agonist
      functional response, whilst (-)lisuride produced a biphasic response curve,
      indicating activity at both the endogenous 5-HT1B and exogenous dopamine D2L
      receptors. Using the receptor specific antagonists, pindolol and (+)butaclamol, (
      )lisuride was shown to produce 52% of the maximal response at the dopamine D2
      receptor relative to dopamine. In comparison to a cAMP accumulation assay, the
      rank orders of potency and intrinsic activity were the same for all compounds
      used. These results demonstrate that this reporter gene assay is capable of
      discriminating both potency and efficacy of drugs and can be used to characterise
      partial agonists at endogenously and heterologously expressed receptors in CHO
      cells.

PMID- 10414443
TI  - Propafenone blocks ATP-sensitive K+ channels in rabbit atrial and ventricular
      cardiomyocytes.
AB  - Propafenone, a class I antiarrhythmic agent, inhibits several membrane currents
      (I(Na), I(Ca), I(K), Ito), however, its effects on ATP-sensitive potassium
      current (I(K)ATP) of cardiac cells have not been tested. We evaluated the
      blocking effects of 0.1 to 100 microM propafenone applications at 35 degrees C on
      the whole-cell I(K)ATP as triggered by dinitrophenol (75 microM) in adult rabbit
      dissociated atrial and ventricular cardiomyocytes in comparison. The block of
      I(K)ATP by propafenone was dose-dependent, fully reversible and voltage
      independent. The dose-response relation, as evaluated at 0 mV for atrial myocytes
      (ED50 = 1.26+/-0.17 microM, Hill number = 1.25+/-0.22) was significantly shifted
      to the left vs. that in ventricular myocytes (ED50 = 4.94+/-0.59 microM, Hill
      number = 1.22+/-0.14). It is concluded that propafenone blocks cardiac I(K)ATP at
      a single site with 4 times higher affinity for the drug in atrial myocytes. This
      block of cardiac I(K)ATP might play a role in the beneficial and adverse effects
      of the drug.

PMID- 10414444
TI  - The difference between methadone and morphine in regulation of delta-opioid
      receptors underlies the antagonistic effect of methadone on morphine-mediated
      cellular actions.
AB  - To investigate the cellular and molecular basis for using methadone in
      substitution therapy for morphine addiction, the difference between methadone and
      morphine in causing desensitization of delta-opioid receptors was examined, and
      the effects of methadone pretreatment on opiate-induced inhibition of forskolin
      stimulated cAMP accumulation was studied. Methadone substantially attenuated the
      ability of [D-Ala2,D-Leu5]enkephalin (DADLE), morphine and methadone to inhibit
      forskolin-stimulated cAMP accumulation. Methadone was able to block the morphine
      induced compensatory increase in intracellular cAMP levels and naloxone
      precipitated cAMP overshoot after chronic exposure to morphine. The protein
      kinase inhibitor (1-5-isoquinolinesulfony)-2-methylpiperazine) (H7) could
      significantly block the chronic methadone treatment-induced loss of the ability
      of DADLE to inhibit adenylate cyclase. The protein kinase inhibitor chelerythrine
      was able to block the acute methadone treatment-induced loss of the ability of
      DADLE to inhibit adenylate cyclase. In contrast, morphine did not cause a
      substantial desensitization of the delta-opioid receptor. These results indicate
      that methadone is different from morphine in its regulation of the delta-opioid
      receptor. In addition, these results also indicate that the mechanisms of delta
      opioid receptor desensitization induced by acute and chronic methadone treatment
      are different.

PMID- 10414445
TI  - Irreversible labelling of the opioid receptors by a melphalan-substituted
      [Met5]enkephalin-Arg-Phe derivative.
AB  - [Met5]enkephalin-Arg-Phe (Tyr-Gly-Gly-Phe-Met-Arg-Phe) was modified with the
      methyl esther of melphalan (Mel; 4-bis(2-chloroethyl)amino-L-phenylalanine) and
      the resulting compounds were studied for their opioid binding properties in
      guinea pig and rat brain membranes. Three new peptides, with a substitution of a
      single amino acid, were synthesized (Mel-Gly-Gly-Phe-Met-Arg-Phe, Tyr-Gly-Gly-Mel
      Met-Arg-Phe and Tyr-Gly-Gly-Phe-Met-Arg-Mel). In the rat brain, none of these
      ligands displayed any type specificity, whereas in guinea pig brain membranes the
      C-terminally modified peptide, Tyr-Gly-Gly-Phe-Met-Arg-Mel ([Mel7]peptide),
      displayed a kappa-binding profile and was a weak kappa-opioid-receptor agonist in
      isolated guinea pig ileum. The effect of sodium ions on [Mel7]peptide competition
      against [3H]naloxone binding indicated a weak agonist nature of the compound.
      When guinea pig brain membranes were preincubated with 1-10 microM of
      [Mel7]peptide, an apparently irreversible inhibition of [3H]naloxone ligand
      binding was observed. These results suggest that the heptapeptide containing
      melphalan at the C-terminus can be used as a relatively high-affinity
      irreversible label for the kappa-opioid receptor.

PMID- 10414446
TI  - Characterization of a new AMPA receptor radioligand, [3H]2-amino-3-(3-carboxy-5
      methyl-4-isoxazolyl)propionic acid.
AB  - (RS)-2-Amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), which is a
      potent and selective agonist at (RS)-2-amino-3-(3-hydroxy-5-methyl-4
      isoxazolyl)propionic acid (AMPA) receptors, has previously been shown to
      desensitize AMPA receptors to a much lower degree than AMPA itself. We now report
      the synthesis of [3H]ACPA (32.5 Ci/mmol), the neurochemical and pharmacological
      characterization of [3H]ACPA binding, and a comparison of the distribution of
      [3H]ACPA, [3H]AMPA, and [3H](S)-5-fluorowillardiine binding sites in rat brain.
      Under equilibrium conditions, [3H]ACPA was shown to bind to a single population
      of receptor sites on rat brain membranes. [3H]ACPA was shown to bind with single
      and similar affinities (15-45 nM) to cloned AMPA receptor subunits (GluR1-4),
      expressed in insect cells, whereas a K(D) value of 330 nM was determined for the
      binding of [3H]ACPA to cloned kainic acid preferring GluR5 subunits. Whereas Bmax
      and K(D) values for [3H]ACPA binding, determined using filtration techniques,
      were different from such obtained in centrifugation assays, Bmax and K(D) values
      as well as association and dissociation constants were not significantly affected
      by the addition of the chaotropic agent KSCN. K(D) values, determined under
      equilibrium conditions, were, however, markedly different from K(D) values
      derived from kinetic data. Furthermore, the results of analyses of these kinetic
      data were consistent with the existence of two different populations of [3H]ACPA
      binding sites. The pharmacology of [3H]ACPA binding sites was characterized using
      a series of AMPA receptor agonists and antagonists. Whereas addition of KSCN had
      little effect on the affinities of AMPA receptor agonists for [3H]ACPA binding,
      this chaotropic agent reduced the affinities of AMPA receptor antagonists
      structurally related to AMPA. Based on these and previously reported data, the
      AMPA receptor agonists, ACPA, AMPA and (S)-5-fluorowillardiine, seem to bind to
      and activate AMPA receptors in a nonidentical fashion, and these three agonists
      together may be useful tools for studies of AMPA receptor mechanisms.

PMID- 10414447
TI  - Sympathectomy prevents fructose-induced hyperinsulinemia and hypertension.
AB  - The fructose-induced hypertensive rat is a widely used model to study the inter
      relationship between hyperinsulinemia, insulin resistance and high blood
      pressure. Evidence suggests that hyperinsulinemia and insulin resistance may be
      pathogenic in the development of high blood pressure in this model. To determine
      the contribution of the sympathetic nervous system towards fructose-induced
      hypertension, the present study examined the effects of chemical sympathectomy
      (adrenal medullectomy, followed by weekly 6-hydroxydopamine injections) on plasma
      insulin levels and systolic blood pressure in control and fructose-induced
      hypertensive rats. Sympathectomy abrogated the development of both
      hyperinsulinemia and hypertension in fructose hypertensive rats without affecting
      these parameters in control rats. These data uncover, for the first time, the
      primacy of the sympathetic nervous system as a mediator of both elevated plasma
      insulin levels and high blood pressure in rats fed a high fructose diet.

PMID- 10414448
TI  - Occurrence of cytokine receptors on different lymphoid leukaemic cells.
AB  - We have studied the expression of cytokine receptors CD25 (IL-2R alpha, 55 kD),
      CD116 (hGM-CSFR, 145 kD), CD117 (CSFR, 145 kD), CD120a (TNFR, 55 kD), CD120b
      (TNFR, 75 kD), CD121a (IL-1R, type I, 80 kD), CDw123 (IL-3R), CD124 (IL-4R, 140
      kD), CD126 (IL-6R, 80 kD), CD127 (IL-7R, 75 kD), CDw128 (IL-8R), CD130 (gp130
      subunit), CDw131 (common beta), CD132 (IL-2Rgamma), CD134 (OX40) and also CD95
      (Fas antigen) on the lymphoid leukaemic cells. Cells from peripheral blood or
      bone marrow of 24 patients with disorders in lymphoid lineage mostly included
      acute lymphoid leukaemias (with a high leukocyte count and percentage of blasts)
      were analysed for the expression of surface membrane molecules by the
      immunofluorescence method evaluated by flow cytometry. The findings indicate that
      some monoclonal antibodies have a reactivity against cytokine receptors of
      pathological cells in individual cases, but with very variable qualitative and
      quantitative expression (number copies/cell). The lymphoid leukaemic cells
      demonstrate unique cytokine receptor profiles, which reveal the great diversity
      of immunophenotypes within the main functional characterisation of T and B
      lymphoproliferative malignancies.

PMID- 10414449
TI  - In vitro effect of granulocyte-colony stimulating factor and all-trans retinoic
      acid on the expression of inflammatory cytokines and adhesion molecules in acute
      promyelocytic leukemic cells.
AB  - Differentiation therapy with all-trans retinoic acid (ATRA) represents a landmark
      approach in the treatment of acute promyelocytic leukemia (APL). However, a
      potentially fatal complication of retinoic acid (RA) syndrome occurs in about a
      quarter of patients and its pathophysiology is still unclear. In order to
      investigate whether or not the treatment with ATRA leads to increased elaboration
      of inflammatory cytokines and adhesion molecules by the APL cells, the expression
      of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-8, L-selectin
      and intercellular adhesion molecule-1 (ICAM-1) was examined in the APL cells
      after induction of differentiation with ATRA in the presence or absence of
      granulocyte-colony stimulating factor (G-CSF) or IL-3 in the present study.
      Cytokine elaboration by the treated cells was detected using both Northern
      blotting and enzyme-linked immunosorbent assay. Our results have shown that ATRA
      induces an increased expression of IL-8, IL-1beta, TNF-alpha and ICAM-1 in APL
      cells, which can be amplified by the addition of G-CSF. These data imply that the
      induction of inflammatory cytokines in APL cells may play an important role in
      the pathogenesis of RA syndrome. Furthermore, G-CSF, through its potent
      differentiating activity, may increase the risk of such complications during ATRA
      treatment.

PMID- 10414450
TI  - Serum beta-2-microglobulin, TNF-alpha and interleukins in myeloproliferative
      disorders.
AB  - Whereas beta-2-microglobulin (beta2M) has mainly been used as a prognostic factor
      in patients with lymphoproliferative disorders, some studies have reported the
      value of beta2M in myeloproliferative disorders (MPD). In order to investigate a
      potential role in the pathogenesis of MPD and to find a possible value as
      indicators in monitoring the course of the disease, we measured beta2M, TNF
      alpha, IL-1alpha, IL-1beta, IL-2, sIL-2R, IL-6 and IL-10 in 55 patients with MPD,
      at diagnosis and during the course of the disease. In progressive disease and
      particularly when transformation to acute leukemia occurred, high levels of
      beta2M, IL-2 and sIL-2R were found in all patients; the elevation was
      progressive, which suggests a potential prognostic usefulness in the individual
      patient.

PMID- 10414451
TI  - Pathogenetic factors underlying juvenile deep vein thrombosis (DVT) in Indians.
AB  - The role of hereditary antithrombotic protein defects in juvenile deep vein
      thrombosis (DVT) was evaluated. Fifty six young patients (age <45 yr) with
      doppler-proven DVT were investigated for the presence of resistance to activated
      protein C (APC-R), lupus anticoagulant (LA), anticardiolipin antibodies and
      deficiencies of protein C, protein S, ATIII activities. Fifty nine normal healthy
      individuals served as controls. APC-R was observed to be the commonest defect
      underlying the Indian DVT as seen in 39.2% of patients followed by elevated ACA
      (5.3%), PAI (2.8%), presence of LA (2.8%) and reduced ATIII levels (2.8%). None
      of the subjects had protein C or S deficiency. APC-R was associated with ATIII
      deficiency in one case, and elevated ACA in two cases. In two subjects, APC-R was
      associated with elevated PAI levels. Patients with more than one prothrombotic
      factor had a higher prevalence of pulmonary thromboembolism, suggesting that the
      thrombogenic potential of APC-R is enhanced by the presence of coexisting
      hereditary or acquired prothrombotic defect.

PMID- 10414452
TI  - Reduction of bioactive substances in stored donor blood: prestorage versus
      bedside leucofiltration.
AB  - Leucocyte filtration has been suggested to improve transfusion products. We
      studied the effect of prestorage versus bedside leucofiltration on reduction of
      bioactive substances and leucocyte content in donor blood. Forty-five units of
      whole blood from healthy blood donors were studied. Of these units, 9 were stored
      under standard conditions for 35 d, 9 were leucofiltered after donation and then
      stored for 35 d, and 3x9 units were stored for 7, 21 and 35 d, respectively,
      before leucofiltration. Samples were collected from blood units immediately after
      donation, and before and after leucofiltration, and analysed by ELISA and RIA
      methods for extracellular content of myeloperoxidase (MPO), eosinophil cationic
      protein (ECP), histamine (HIS) and plasminogen activator inhibitor-1 (PAI-1).
      Leucocyte content was counted in all samples. In non-filtered blood extracellular
      MPO, ECP, HIS and PAI-1 were accumulated in a storage time-dependent manner,
      while prestorage leucofiltration prevented this accumulation. Leucofiltration
      after storage for 7, 21 or 35 d did not significantly reduce the accumulated
      bioactive substances, which were similar to levels in non-filtered blood stored
      for the same period of time. Prestorage and bedside leucofiltration on day 7
      reduced the leucocyte content to less than 0.5x10(6)/L, whereas the median
      content in blood stored for 21 or 35 d was only reduced to 32.0 and 52.2x10(6)/L,
      respectively. Prestorage leucofiltration may thus be advantageous to bedside
      leucofiltration.

PMID- 10414453
TI  - Effect of a 2-hour infusion of 2-chlorodeoxyadenosine in the treatment of
      refractory or previously untreated Waldenstrom's macroglobulinemia.
AB  - 2-Chlorodeoxyadenosine (2-CdA) is a new purine analogue active in indolent
      lymphoid malignancies. In this retrospective study 22 patients with Waldenstrom's
      macroglobulinemia (MW) were treated with 2-CdA given in 2-h intravenous
      infusions. Nine of them were untreated and 13 relapsed or were refractory to
      previous therapeutic modalities with chlorambucil/prednisone (11 patients) or COP
      (2 patients). The patients were given 1-11 (median 4) courses of 2-CdA at the
      dose of 0.14 mg/kg daily in 2-h intravenous infusion for 5 consecutive days. The
      courses were repeated every 28-35 d. If severe myelosuppression or infection
      developed, 2-CdA therapy was stopped until the haematological parameters
      increased. The effectiveness of the treatment was evaluated after the 3 cycles
      and after completion of therapy. None of the patients has achieved complete
      response (CR) after 3 courses of treatment and only one (4.5%) has obtained CR
      after 5 courses. Partial response (PR) was achieved in 8 (36.4%) patients, giving
      an overall response rate of 40.9%. Ten further patients (45.4%) responded to the
      treatment with less than 50% decrease in monoclonal protein (defined as
      stabilisation). There was no significant difference between the response rate in
      previously pretreated (38.5%) and untreated (44.4%) patients (p>0.05). Mean
      observed decrease in monoclonal protein was 41%. In the group of 9 patients
      responding to 2-CdA treatment mean duration of response was 12 months (range 3
      34). Myelosuppression was the most prominent side-effect. Neutropenia was present
      in 17 (77.3%) and thrombocytopenia in 7 (31.8%) patients. In 6 patients
      myelosuppression was the reason for treatment discontinuation after 1 or 2
      courses without significant therapeutic effect. Seven patients died, including 4
      from the responding group and all three non-responding patients. Treatment
      related thrombocytopenia and fatal haemorrhage was the course of death in 1
      patient. In conclusion, the results of our study show that 2-CdA given in 2-h
      infusions is an effective agent in WM and may be given on an outpatient basis.
      However, myelosuppression is frequent and the drug must be administered with
      caution.

PMID- 10414454
TI  - A cloned CD15s-negative variant of HL60 cells is deficient in expression of FUT7
      and does not adhere to cytokine-stimulated endothelial cells.
AB  - The initial steps of leukocyte adhesion depend on selectin/ligand interactions.
      Surface ligands on leukocytes are often modified by addition of the sialyl Lewis
      x (CD15s) determinant. Biosynthesis of CD15s is dependent upon
      alpha(2,3)sialyltransferases and alpha(1,3)fucosyltransferases. We report the
      isolation of an HL60 cell line variant, HL60A2, that no longer expresses CD15s.
      HL60A2 cells do not adhere to cytokine-stimulated endothelial cells. Enzymatic
      assays reveal that this cell line has normal alpha(2,3)sialyltransferase activity
      but is deficient in the alpha(1,3)fucosyltransferase responsible for biosynthesis
      of CD15s (FUT7). The fucosyltransferase that constructs the non-sialylated
      antigen, Lewis x (CD15), is expressed at high levels (FUT4). Transcript analyses
      show that FUT7 and FUT4 are inversely expressed in HL60 and variant cell lines.
      HL60A2 cells provide a tool to study the regulation of selectin ligands and
      corresponding human fucosyltransferase genes.

PMID- 10414455
TI  - Effects of hTNFalpha expression in T cells on haematopoiesis in transgenic mice.
AB  - A transgenic line of mice carrying one copy of the hTNFalpha gene under the
      control of its own promoter and the CD2 locus control region has been analysed
      for the effects of TNFalpha on haematopoiesis. A low level constitutive
      expression of hTNFalpha in lymphoid tissue was observed. Human TNFalpha binds to
      and activates the murine p55 receptor, but not the p75 receptor. This implies
      that the observed effects of hTNFalpha in mice were mediated only through the p55
      receptor. Various lymphoid tissues were depleted of lymphocytes, especially
      thymus, spleen and peripheral blood. Effects on thymus development were detected
      already at 3 wk of age, more general effects on haematopoiesis were evident by 5
      wk: a drop in total blood leukocytes, mainly due to a 67% decline in lymphocytes.
      At 16 wk the mice had developed anaemia, whereas platelets, neutrophils and
      monocytes had increased. The fall in lymphocytes was due to lowered levels of T
      cells as well as B cells. The cause of the shortened lifespan of the transgenic
      mice was probably not the haematological effects of hTNFalpha directly. Absence
      of trophic factors supplied by the normal T cell population remains possible.

PMID- 10414456
TI  - In situ hybridization evidence of the donor origin of a post-transplant
      lymphoproliferative disorder.

PMID- 10414457
TI  - Inversions of the factor VIII gene in Slovenian patients with severe haemophilia
      A.

PMID- 10414458
TI  - Kaposi's sarcoma associated with Castleman's disease.

PMID- 10414459
TI  - Interferon gamma and antisense transforming growth factor beta transgenes
      synergize to enhance the immunogenicity of a murine mammary carcinoma.
AB  - Transforming growth factor beta (TGFbeta) is an immunosuppressive cytokine that
      contributes to the immunological escape of tumor cells. In a previous study we
      demonstrated that inhibition of TGFbeta production by EMT6 murine mammary tumor
      cells expressing an antisense TGF-beta transgene reduces their tumorigenicity. On
      the basis of this observation we hypothesized that down-regulation of TGFbeta
      production coupled with interferon gamma (IFNgamma) stimulation would induce an
      immune response superior to that generated by either strategy alone. In this
      study, EMT6 tumor cells expressing antisense TGFbeta were transduced with the
      murine IFNgamma gene. Tumor cells expressing either or both transgenes grew more
      slowly than mock-transduced tumors. Dual-transgene-expressing tumor cells were
      more immunogenic than tumor cells expressing either transgene alone. Studies in
      mice depleted of T cell subsets indicated that CD8+ T cells are the primary
      effectors of the antitumor activity observed. These results suggest that down
      regulation of immunosuppression combined with cytokine-mediated immune
      augmentation is a useful strategy to improve antitumor immunity.

PMID- 10414460
TI  - Increased generation of autologous tumor-reactive lymphocytes by anti-CD3
      monoclonal antibody and prothymosin alpha.
AB  - Anti-CD3 monoclonal antibody (mAb) activates in vitro peripheral blood
      mononuclear cells (PBMC) to lyse a variety of tumor cell lines in a non-major
      histocompatibility-complex(MHC)-restricted manner [subsequently referred to as
      anti-CD3-activated killer (AAK) cytotoxicity]. Prothymosin alpha (ProTalpha) is a
      biological response modifier that exerts its effects primarily on mononuclear
      cells, especially when these cells' effector functions are impaired. In this
      study, we report that ProTalpha enhances the AAK cytotoxicity in PBMC from
      healthy donors. This effect was more profound with cancer patients' PBMC, which
      were deficient in their ability to respond with enhanced AAK cytotoxicity upon in
      vitro stimulation with anti-CD3. Thus, cancer patients' PBMC, activated with a
      combination of anti-CD3 and ProTalpha, exhibited increased AAK activity and
      efficiently lysed both autologous tumor and Daudi targets. The ProTalpha effect
      on PBMC was demonstrated to involve stimulation of adhesion molecules (CD2, CD18,
      CD54, CD49f) and CD25 expression, up-regulation of perforin mRNA transcription,
      increased numbers of perforin-positive (+) cells and elevated production of
      interleukin-2 (IL-2), interleukin-1beta (IL-1beta) and tumor necrosis factor
      alpha (TNFalpha). Moreover, effector CD8+ and CD56+ cells pretreated with anti
      CD3 and ProTalpha contained high cytoplasmic perforin levels and increased
      expression of IL-1beta- and TNFalpha-specific receptors. The induction of
      autologous-tumor-reactive CD8+ and CD56+ lymphocytes in anti-CD3-activated PBMC
      by ProTalpha provides an alternative protocol aimed at the improvement of
      clinical results in cellular adoptive immunotherapy of cancer.

PMID- 10414461
TI  - Neuronal autoantibody titers in the course of small-cell lung carcinoma and
      platinum-associated neuropathy.
AB  - The aims of this study were to investigate, in patients with newly diagnosed
      small-cell lung carcinoma (SCLC), whether or not there may be a relationship
      between the presence, type or titer of circulating neuronal autoantibodies and
      (i) the extent of SCLC dissemination at presentation, (ii) the development of
      peripheral neuropathy during platinum chemotherapy, (iii) survival time. We
      studied stored serum from 58 patients with uncomplicated SCLC who had
      participated in two trials conducted by the North Central Cancer Treatment Group
      (NCCTG); 29 had extensive disease and 29 had limited disease. No patient had
      neuropathy or other neurological or paraneoplastic problems at the time of
      enrollment but each group included 14 or 15 patients respectively who developed
      peripheral neuropathy in the course of chemotherapy. We tested five consecutive
      serum specimens from each patient in blinded fashion by (i) an indirect
      immunofluorescence assay optimized to detect neuron-restricted nuclear and
      cytoplasmic antibodies (triple substrate of mouse cerebellum, gut and kidney),
      and (ii) immunoprecipitation assays to detect neuronal Ca2+-channel-binding
      antibodies (N-type and P/Q-type). Sera that were positive by immunofluorescence
      were analyzed further by Western blotting. Neuronal autoantibodies were
      significantly more frequent in patients who had limited SCLC at presentation
      (12/29 or 41% positive) than in those with extensive SCLC (5/29 or 17% positive,
      P = 0.02). Neuronal autoantibodies of nuclear or cytoplasmic specificity were
      found in 50% of the seropositive patients with limited SCLC (21% of the total
      group), but in no patient with extensive SCLC (P = 0.01). The frequency of
      neuronal autoantibodies did not differ significantly among patients who did and
      did not develop peripheral neuropathy. Titers fell progressively during
      chemotherapy and did not rise again when peripheral neuropathy became clinically
      evident. This argues against a synergism between drug toxicity and neuronal
      autoimmunity as the mechanism of platinum-associated peripheral neuropathy.
      Seropositivity for neuronal autoantibodies did not affect the survival of
      patients with either limited or extensive SCLC. It is conceivable that the
      immunosuppression attendant on combined cisplatin/etoposide therapy cancels a pre
      existing protective antitumor immune response (presumably cytotoxic-T-cell
      mediated) for which the nuclear and cytoplasmic paraneoplastic IgG autoantibodies
      serve as a surrogate marker. Testing of this hypothesis would require the
      survival of seropositive and seronegative patients to be compared in a larger
      trial, using a therapeutic modality that does not compromise immunocompetence.

PMID- 10414462
TI  - Treatment of medullary thyroid carcinoma by combined expression of suicide and
      interleukin-2 genes.
AB  - Inherited medullary thyroid carcinomas (MTC) are aggressive and resistant to
      conventional chemo- and radiotherapies. We evaluated a novel strategy for
      treatment of MTC, combining "suicide" and interleukin-2 (IL-2) gene therapies.
      Tumors were produced in Wag/Rij rats by orthotopic injection of the rMTC 6-23
      cell line, and/or derivatives expressing the herpes simplex virus 1 thymidine
      kinase (HSV1-TK) gene (rMTC-TK). Ganciclovir, a nucleoside analog selectively
      transformed to a toxic metabolite by HSV1-TK, totally eradicated rMTC-TK tumors
      in 60% of the animals. 1:1 rMTC and rMTC-TK mixed tumors were also strongly
      inhibited by ganciclovir (P < 0.05), indicating the occurrence of an efficient
      "bystander" effect in vivo. Double labelling of rMTC cell membranes and apoptotic
      nuclei revealed that, as with the TK+ cells, some TK- cells died by apoptosis. A
      1:1 mixture of rMTC and rMTC-TK cells was administered to produce established
      tumors and then rMTC cells, transfected to express the IL-2 gene (rMTC-IL2), were
      inoculated. Combined ganciclovir and IL-2 treatment improved the inhibition of
      tumor growth compared to that following ganciclovir alone (86% compared to 54%, P
      < 0.05). This treatment also significantly enhanced macrophage activation and
      tumor infiltration by CD8+ and CD4+ T lymphocytes. These results open an avenue
      for combining suicide and immunoregulatory gene therapies for MTC management in
      man.

PMID- 10414463
TI  - Differential lytic and agglutinating activity of the anti-Lewis(x) monoclonal
      antibody FC-2.15 on human polymorphonuclear neutrophils and MCF-7 breast tumor
      cells. In vitro and ex vivo studies.
AB  - The Lewis(x) (Le(x)) trisaccharide (CD15) linked to proteins and glycolipids is
      highly expressed on the surface of normal human polymorphonuclear neutrophils
      (PMN) and several human neoplasias, such as breast and gastrointestinal
      carcinomas and chronic myeloid leukemias. FC-2.15 is an IgM murine mAb that
      specifically recognizes Le(x) and has been previously shown to mediate the in
      vitro lysis of Le(x)(+) cells by human complement. In a phase I clinical trial of
      FC-2.15, a temporary neutropenia was the main toxicity, and antitumor responses
      were observed. In order to characterize FC-2.15 further and determine the
      physiological relevance of Le(x) binding, the reactivity of FC-2.15 on PMN was
      investigated under several conditions. Flow cytometry revealed a strong
      reactivity of FC-2.15 with almost 100% of PMN, and Scatchard analysis
      demonstrated an affinity constant of 5.14 x 10(9) M(-1) and 1.11 x 10(6) antigen
      sites/cell. In vitro, the binding of Le(x) epitopes by FC-2.15 induced PMN
      homotypic aggregation, only 28.4 +/- 4.1% remaining as single cells. When PMN and
      the Le(x)(+) MCF-7 breast cancer cells were co-incubated, FC-2.15 induced
      heterotypic aggregation. In 51Cr-release assays employing human complement, FC
      2.15 lysed 93.4 +/- 7.9% of PMN and 87.8 +/- 10.7% of MCF-7 cells. However, when
      the effect of FC-2.15 was tested in ex vivo circulating blood, no lytic activity
      against PMN was detected, whereas MCF-7 cells were still lysed. Blood smears
      demonstrated that FC-2.15 induced PMN agglutination and heterotypic aggregates
      when MCF-7 cells were present. A pretreatment of PMN with colchicine impaired PMN
      agglutination both in vitro (single PMN = 81.15 +/- 4.35%) and in ex vivo
      circulating blood. In the latter condition, FC-2.15-lytic activity was restored,
      suggesting that PMN homotypic aggregation by FC-2.15, but not lysis, is dependent
      on microtubule integrity and that PMN agglutination hinders their lysis.
      Moreover, when 51Cr-release assays were performed following agglutination, FC
      2.15 cytotoxicity was restricted to isolated PMN. It is suggested that
      crosslinking of Le(x) epitopes by FC-2.15 induces PMN to form homotypic
      aggregates. It is suggested that the neutropenia observed in FC-2.15-treated
      patients would be due to PMN agglutination and margination, rather than lysis. In
      addition, FC-2.15 appears to be able to lyse Le(x)(+) tumor cells in circulation.

PMID- 10414464
TI  - Simultaneous exposure to interleukin-18 and interleukin-10 in vitro
      synergistically augments murine spleen natural killer cell activity.
AB  - Interleukin-18 (IL-18) enhances interferon gamma (IFNgamma) production and
      natural killer (NK) cell activity, and elicits protective antitumor effects in
      vivo. IL-18 and IL-12 synergistically augment IFNgamma production reportedly
      because IL-12 enhances IL-18 receptor (IL-18R) expression. We now show that IL-18
      also synergizes with IL-10 to augment murine splenic NK activity against Yac-1
      cells in a standard 4-h chromium-release assay, but IFNgamma production is only
      slightly enhanced. This pattern of NK activity was also observed with severe
      combined immunodeficient (SCID) mouse spleen cells indicating that the cytokines
      were not acting on T or B cells. The cytokines had no priming activity on the
      spleen cells and, when cells were left unstimulated for 24 h in culture, little
      NK activity was induced when IL-18 was added for the next 24 h. The reverse
      transcriptase/polymerase chain reaction revealed that IL-18 receptor (IL-18R)
      mRNA was expressed early during in vitro spleen cell culture but none was
      expressed after culture for 24 h regardless of the stimulus. Binding of 125I
      labeled IL-18 revealed that exposure to IL-10 only slightly increased IL-18R
      expression. Expression of perforin mRNA was constitutive and was unaffected by
      the cytokines; however, Fas ligand (FasL) mRNA expression was strong in cultures
      with IL-18 alone or combined with IL-10. When Fas-expressing cells and their
      parental cells were used as targets, weak Fas-mediated cytolytic activity was
      observed after exposure to IL-18, and this was further enhanced by combination
      with IL-10. Finally, the augmentation of NK activity was abrogated by the
      inhibitor concanamycin A, indicating that the enhanced NK activity is perforin
      dependent.

PMID- 10414465
TI  - Homing of intravenously and intralymphatically injected human dendritic cells
      generated in vitro from CD34+ hematopoietic progenitor cells.
AB  - Dendritic cells (DC) are professional antigen-presenting cells that can be
      generated in vitro from CD34+ peripheral blood progenitor cells by recombinant
      cytokines. These cells have potential implications for immunotherapeutic
      approaches in the treatment of cancer and other diseases. Physiologically,
      immature DC in the periphery capture and process antigens, then mature to
      interdigitating DC and migrate to lymphoid organs, where they activate
      lymphocytes. However, it is not known if DC generated in vitro have the capacity
      to traffic in vivo to the lymphoid tissues, such as spleen and lymph nodes. We
      have investigated whether human radiolabeled DC differentiated in vitro migrate
      and localize to lymphoid tissues after intravenous and intralymphatic injection.
      The distribution and localization of the DC were evaluated in five patients with
      malignant melanoma using serial whole-body gamma camera imaging. Intravenously
      infused DC demonstrated transient lung uptake followed by localization in the
      spleen and liver for at least 7 days. DC injected into a lymphatic vessel at the
      dorsal foot were rapidly detected in the draining lymph nodes where they remained
      for more than 24 h. These data suggest that DC differentiated in vitro localize
      preferentially to lymphoid tissue, where they could induce specific immune
      responses.

PMID- 10414466
TI  - Granulocyte/macrophage-colony-stimulating factor released by adenovirally
      transduced CT26 cells leads to the local expression of macrophage inflammatory
      protein 1alpha and accumulation of dendritic cells at vaccination sites in vivo.
AB  - Antigen presenting cells (APC) play an essential role in the generation of tumor
      specific immune responses. Dendritic cells are the most potent of APC, capable of
      activating both antigen-specific CD4+ and CD8+ T cells. Previously, we have
      described how vaccination of mice with irradiated tumor cells producing
      granulocyte/macrophage-colony-stimulating factor (GM-CSF) induces tumor-specific
      immunity capable of protecting mice from a subsequent tumor challenge. The
      present study extends these findings to examine the types of APC infiltrating
      vaccination sites and the chemokines responsible for their recruitment. GM-CSF
      released from genetically engineered tumor cells led to the local accumulation of
      dendritic cells in and around the vaccination site. Quantification revealed a
      significant ten-fold increase in the number of dendritic cells infiltrating GM
      CSF-producing as opposed to beta-galactosidase-producing (control) vaccination
      sites. Reverse transcription/polymerase chain reaction, enzyme-linked
      immunosorbent assay, and immunohistochemical analysis of vaccination sites
      revealed that MIP-1alpha may be responsible for dendritic cell infiltration into
      GM-CSF-producing tissues. These findings suggest that GM-CSF may indirectly
      recruit dendritic cells into vaccination sites through the local production of
      MIP-1alpha.

PMID- 10414467
TI  - In vitro analysis of the melanoma/endothelium interaction increasing the release
      of soluble intercellular adhesion molecule 1 by endothelial cells.
AB  - Melanoma cells constitutively release intercellular adhesion molecule 1 (ICAM-1)
      as soluble ICAM-1 (sICAM-1), and its levels are elevated in melanoma patients and
      correlate with disease progression. However, this correlation is not absolute,
      suggesting that specific characteristics of neoplastic cells and/or ICAM-1
      positive non-neoplastic cells may influence the amounts of circulating sICAM-1.
      In this study, we found a weak correlation (r = 0.55; r2 = 0.3) between sICAM-1
      release by 40 metastatic melanomas (36 primary cultures and 4 cell lines), and
      ICAM-1 expression on neoplastic cells. In addition, melanoma-secreted interleukin
      1alpha (IL-1alpha) (1/40) but not vascular endothelial growth factor (VEGF)
      (29/40), significantly (P < 0.05) up-regulated the shedding of sICAM-1 by human
      umbilical vein endothelial cells (HUVEC). This was completely abolished by IL
      1alpha/beta neutralizing antibodies both at the protein and mRNA level.
      Altogether, our results suggest that (i) the extent of sICAM-1 release is
      distinctive for individual melanomas and can be independent of ICAM-1 expression;
      (ii) tumor endothelia may sustain levels of sICAM-1 in selected melanomas; (iii)
      melanoma-released VEGF does not affect ICAM-1 expression and sICAM-1 release by
      HUVEC. Melanoma-derived sICAM-1 inhibits cell-mediated cytotoxicity of melanoma
      cells; therefore, constitutive levels of sICAM-1 release and IL-1alpha secretion
      by individual melanomas can differentially influence tumor progression and the
      clinical effectiveness of cytotoxic-cell-based vaccines.

PMID- 10414468
TI  - The role of interleukin-2 in regulating the sensitivity of natural killer cells
      for Fas-mediated apoptosis.
AB  - The Fas/Fas-ligand (FasL) system seems to play a key role in regulating
      immunoresponses. Highly purified CD56+CD3- natural killer (NK) cells were found
      to be resistant to the apoptosis-inducing Fas mAb CH11 in the absence or in the
      presence of interleukin-2 (IL-2) for up to 3 days. However, NK cells activated
      with IL-2 for 3 days became apoptotic following combined treatment with CH11 and
      actinomycin D, suggesting the presence of an intact apoptotic machinery. In
      contrast, NK cells cultivated in IL-2 for 6 days became sensitive to CH11-induced
      apoptosis without addition of actinomycin D. At this time, a pronounced up
      regulation of the Fas protein on the NK cell membrane was detected. By using
      reverse transcription/polymerase chain reaction it was found that the anti
      apoptotic gene FLIP was strongly expressed in NK cells for up to 6 days of IL-2
      stimulation. After day 6, a time-dependent decrease in the expression of FLIP was
      observed concomitantly with increased sensitivity for Fas-mediated apoptosis. The
      amount of apoptotic and necrotic NK cells in the presence of IL-2 increased in a
      time-dependent manner, reaching 40% at day 6 of culture. The amount of apoptotic
      and necrotic NK cells was reduced in the presence of Fas-Fc protein. In addition,
      IL-2 stimulated the NK cells to release soluble FasL in a time-dependent manner,
      whereas membrane FasL did not seem to increase in a similar manner. These results
      indicate that Fas/FasL interactions are involved in the down-regulation of IL-2
      activated human NK cells.

PMID- 10414469
TI  - Study of HLA class I restriction and the directed antigens of cytotoxic T
      lymphocytes at the tumor sites of ovarian cancer.
AB  - The molecular basis of T-cell-mediated recognition of ovarian cancer cells
      remains to be fully addressed. In this study we investigated HLA class I
      restriction and directed antigens of cytotoxic T lymphocytes (CTL) at the sites
      of ovarian cancer. Three HLA-class-I-restricted CTL lines were established from
      the tumor sites of ovarian cancer by culturing tumor-infiltrating lymphocytes or
      tumor-associated ascitic lymphocytes with interleukin-2: (1) HLA-A2402-restricted
      and ovarian-adenocarcinoma-specific CTL, (2) HLA-A2-restricted CTL recognizing
      histologically different cancers, and (3) HLA-B52-restricted and ovarian-cancer
      specific CTL. HLA-A0201, HLA-A0206 and HLA-A0207 tumor cells were lysed by the
      HLA-A2-restricted CTL. HLA-B52 restriction of the third CTL line was confirmed by
      the transfection of HLA-B5201 cDNA into the tumor cells. The HLA-A2-restricted
      CTL recognized the SART-1, but not the MAGE-1 or MAGE-3 antigen. These results
      may facilitate a better understanding of the molecular basis of tumor-specific
      immunity at the tumor site of ovarian cancer.

PMID- 10414470
TI  - Signaling through CD40 enhances cytotoxic T lymphocyte generation by CD8+ T cells
      from mice bearing large tumors.
AB  - Recent studies have demonstrated the importance of CD40/CD154 (CD40L)
      interactions for the generation of cell-mediated antitumor immune responses. Here
      we show that signaling via CD40 (through the use of the activating anti-CD40 mAb,
      IC10) can actually promote the in vitro generation of CTL activity by CD8+
      splenic T cells from mice bearing a large MOPC-315 tumor. Anti-CD40 mAb had to be
      added at the initiation of the stimulation cultures of tumor-bearing splenic
      cells in order to realize fully its potentiating activity for cytotoxic T
      lymphocyte (CTL) generation, suggesting that signaling through CD40 is important
      at the inductive stage of antitumor cytotoxicity. Moreover, anti-CD40 mAb was
      found to enhance the expression of the B7-2 (CD86) and, to a lesser extent, the
      B7-1 (CD80) costimulatory molecules on B220+ cells (i.e., B cells), and B7-2 and,
      to a lesser extent, B7-1 molecules played an important role in the potentiating
      effect of anti-CD40 mAb for CTL generation by tumor-bearer splenic cells.
      Furthermore, B220+ cells were found to be essential for the potentiating effect
      of anti-CD40 mAb, as depletion of B220+ cells at the inductive stage completely
      abrogated the ability of anti-CD40 mAb to enhance CTL generation. Thus, signaling
      through CD40 enhances CTL generation by CD8+ T cells from tumor-bearing mice by a
      mechanism that involves the up-regulation of B7-2 and, to a lesser extent, B7-1
      expression on B220+ cells.

PMID- 10414471
TI  - Treatment of chronic pain with antiepileptic drugs: a new era.
AB  - BACKGROUND: Shortcomings of traditional pain relief agents have led physicians to
      investigate other alternatives, such as antiepileptic drugs. Safe, effective,
      nonhabituating agents are currently available to enhance pain treatment
      strategies. METHODS: In this article, various pharmacologic options and their
      mechanisms of action are reviewed briefly, with a focus on treatment of chronic
      pain with antiepileptic drugs (AEDs). RESULTS: Antiepileptic drugs have been
      widely studied and prescribed for the relief of acute and chronic pain.
      Similarities in the neurophysiology of pain and epilepsy suggest that AEDs may be
      a suitable adjunct in the management of chronic pain. Of the newer AEDs,
      gabapentin shows the greatest potential and appears to be well tolerated by
      patients. CONCLUSIONS: Treatment of chronic pain remains a challenge for
      physicians and patients. Further research is required to identify the role of
      various agents and their effect on patient return to function and quality of
      life.

PMID- 10414472
TI  - Companion animal issues and the physician.
AB  - BACKGROUND: The companion animal population in the United States is both large in
      numbers and diverse in composition. Nearly 60% of households have one or more
      animals. Associated with this large and diverse group of animals are considerable
      risks for injuries and transmission of infections to humans. METHODS: Through a
      review of the relevant literature and our collective professional experience in
      public health and veterinary medicine, we framed issues regarding companion
      animals and human health and safety. RESULTS: We placed the identified issues in
      general contexts that could be applied to varying circumstances. CONCLUSIONS:
      Physicians, veterinarians, public health officials, and others need to work
      together to ensure that animal ownership is as risk free for people as possible.

PMID- 10414473
TI  - To end itself by death: suicide in Shakespeare's tragedies.
AB  - The tragedies of William Shakespeare make frequent use of suicide, some
      accomplished, some merely contemplated. Although his intent was their dramatic
      context, the Bard nonetheless clearly anticipated many features being discussed
      today, including assisted suicide, imitative ("copycat") suicide, and suicidal
      ideation by individuals with depression or disabilities. Recent debate over how
      often these factors influence the incidence of suicide rarely invokes their
      historical longevity. They are not new, so changes over the years in societal,
      religious, legal, and medical attitudes toward suicide must be considered when
      trying to understand their role. This review attempts to show that many such
      features of and attitudes toward suicide circa 1600 were perceived by Shakespeare
      and incorporated into his plays. In the 15 plays classified as tragedies, there
      are 13 definite and 8 possible suicides, ie, a total of 21 incidents for
      evaluation. Among the 13 overt suicides, at least 7 are depicted as being
      admirable under the circumstances at the time. Also, in various ways, 4 of these
      13 were assisted, and at least 3 others contain an imitative element. Overall,
      the action of taking one's life is presented in a neutral or even favorable
      light, and the audience is left with a mingling of pity and admiration for the
      victim, not reproach.

PMID- 10414475
TI  - South Florida survey on the relationship between academic medical centers and
      community physicians.
AB  - BACKGROUND: Little is known about the relationship between academic medical
      centers (AMCs) and community physicians (CPs). We examined this relationship for
      an individual specialty-dermatology. METHODS: South Florida dermatologists were
      queried regarding their practice and referral patterns, as well as the effect of
      managed care on these patterns. RESULTS: On average, the respondents see 7,342
      patients annually. Ninety-eight percent refer one or more patients for aid in
      therapy (39%) and diagnosis (27%). Most were satisfied with the amount (63%) and
      quality (77%) of the service provided. Overall, only 0.2% of patients are
      referred. Sixty percent reported that managed care caused alterations in referral
      patterns. CONCLUSIONS: We found that, although community dermatologists diagnose
      and treat the vast majority of patients with skin disease seen by dermatologists,
      they also use and are satisfied with the AMC's services. Changes in referral
      patterns have occurred but have not negatively affected the relationship between
      the AMC and the CP.

PMID- 10414474
TI  - Improved control of type 2 diabetes mellitus: a practical education/behavior
      modification program in a primary care clinic.
AB  - BACKGROUND: This study was done to determine the efficacy and ease of
      administration of education/behavior modification classes, provided by a nurse
      and a dietitian in a primary care clinic for improving control of type 2 diabetes
      mellitus. METHODS: Patients were divided randomly into two groups. Eighteen
      patients completed 6 months of structured, office-based classes, and 20 similar
      patients served as control subjects. All were patients of the same group practice
      and had their usual office visits. Glycemic control, lipid levels, body weight,
      knowledge about diabetes, medication requirements, and symptoms were monitored
      during the 6 months, with follow-up at 12 months. RESULTS: At the end of 6
      months, the intervention group had significant reductions in mean fasting blood
      glucose, glycosylated hemoglobin, total cholesterol, and low-density lipoprotein
      cholesterol (LDL-C) values. Their mean body weight was significantly reduced at
      12 months, and their knowledge of diabetes was improved. Control patients had
      significant improvement only in glycosylated hemoglobin and body weight at 6
      months. Minimal physician time was required. CONCLUSION: The education/behavior
      modification program was clinically worthwhile, and it was easy to administer.

PMID- 10414476
TI  - HIV/AIDS in nonurban Alabama: risk activities and access to services among HIV
      infected persons.
AB  - BACKGROUND: Because AIDS is increasing in rural areas and small cities of the
      United States, we sought to further describe the epidemiology of HIV/AIDS in
      nonurban Alabama. METHODS: Extensive interviews of HIV-infected residents of
      Alabama living outside of urban Birmingham were conducted at clinics throughout
      the state. RESULTS: Of the 417 HIV-infected persons interviewed from January 1995
      through January 1997, 310 (74%) were male, 229 (55%) were white, and 179 (43%)
      were black. Over time, increasing proportions of HIV infections have likely been
      acquired in nonurban areas. Of the 417 subjects, 43 (10%) had visited an STD
      clinic in the past year, and 31 (7%) had smoked crack-cocaine during the past
      month. Of the 166 persons who had been sexually active in the past month, 59
      (36%) had used alcohol before sex and 56 (34%) used condoms inconsistently. Of
      the 417 subjects, 161 (39%) currently had no health insurance, and 68 (16%) had
      lost medical insurance since becoming HIV-infected. CONCLUSION: HIV-infected
      persons in nonurban Alabama are likely to have practiced high-risk behavior, to
      have acquired HIV in nonurban settings, and to have inadequate health insurance.

PMID- 10414477
TI  - Manifestations of AIDS in the head and neck.
AB  - BACKGROUND: A significant number of patients with the acquired immunodeficiency
      syndrome (AIDS) are initially seen with symptoms related to the head and neck. It
      is becoming increasingly challenging for clinicians to accurately diagnose new
      lesions, considering the vast array of manifestations of AIDS in this region and
      their many atypical presentations. A comprehensive review is a valuable clinical
      tool. METHODS: A MEDLINE search of the English language literature from 1984 to
      the present was done for this study. RESULTS: Dermatologic, otologic,
      nose/paranasal sinuses/nasopharynx, oral cavity/oropharynx, laryngeal, and neck
      manifestations are reviewed. The gross and microscopic appearances of lesions are
      described, with particular emphasis on various presentations of the same lesion
      and lesions that may mimic the appearance of others. Practical treatment
      strategies are also discussed. CONCLUSIONS: Accurate and early recognition of the
      many common and uncommon manifestations of AIDS in the head and neck is of
      critical importance to the timely and effective management of these patients.

PMID- 10414478
TI  - Melanoma vaccines as a therapeutic option.
AB  - BACKGROUND: In 1998, 41,600 new cases of melanoma with 7,300 deaths were
      expected. Worldwide, the incidence has risen 5% a year against a backdrop of
      generally decreasing cancer trends. Later stages of melanoma carry a severe
      prognosis. The need for newer, more effective therapeutic strategies for cancer
      is obvious. For melanoma, early diagnosis and surgical treatment are the only
      options that are currently curative. Chemotherapy and radiation therapy are of
      limited efficacy. METHODS: We reviewed the various forms of immunotherapy,
      concentrating on vaccine therapy. We then reviewed the history of our own vaccine
      in the context of the field of immunotherapy, and compared efficacy, immune
      response, production methods, and survival. RESULTS: Survival is improved among
      recipients of melanoma vaccine when compared with patients receiving conventional
      therapy. CONCLUSIONS: Imnmunotherapy in the form of melanoma vaccines is better
      than conventional therapy and is trending toward purer antigenic preparations.

PMID- 10414479
TI  - Mycobacterium fortuitum infection of ventriculoperitoneal shunt.
AB  - Mycobacterium fortuitum is one of the rapidly growing mycobacteria found in soil,
      dust, and water. It can be isolated as a normal colonizing organism, but as a
      pathogen this organism causes mainly skin and soft tissue infection preceded by
      trauma. A wide variety of infections can occur in individuals with predisposing
      conditions. Central nervous system infection with M fortuitum is rare, and
      meningitis occurs after surgery or trauma. We believe that ventriculoperitoneal
      (VP) shunt infection with this organism has not been reported in the literature.
      Practitioners should be aware of this rare entity and should suspect it in the
      presence of cerebrospinal fluid pleocytosis with sterile culture, and after
      trauma, surgery, or manipulation of the VP shunt hardware. Mycobacterium
      fortuitum is resistant to most first-line and second-line antituberculous drugs,
      and treatment should include surgical debridement in addition to prolonged
      antimicrobial therapy.

PMID- 10414480
TI  - Lightning strikes at a mass gathering.
AB  - Among natural disasters, lightning is a leading cause of morbidity and mortality
      throughout the world. A well-informed bystander and an astute physician can make
      the difference between an outcome of death or lifelong disability versus complete
      or near-complete recovery. What is done in the first few minutes after such an
      event is the predominant predictor of success. This case report describes a young
      woman who was struck by lightning while talking on a cellular telephone at a mass
      gathering in an outdoor stadium. The discussion that follows the case centers on
      the pathophysiology of being struck by lightning and on issues unique to being
      struck in a stadium full of people.

PMID- 10414481
TI  - Diclofenac-associated hepatitis.
AB  - This patient, who had a history of osteoarthritis, had severe hepatitis 5 weeks
      after being started on diclofenac for increasing pain in the joints. A week
      before the onset of hepatitis, the patient complained of upper gastrointestinal
      symptoms and was treated for gastritis. Seven days later, she had full-blown,
      severe hepatitis. Diclofenac was immediately stopped, leading to a complete
      restoration of liver functions over the course of the next few months. We
      highlight the importance of having a high index of suspicion for hepatic side
      effects of diclofenac and emphasize the need for increased awareness of this rare
      but potentially serious problem. We also review relevant literature regarding
      incidence and management.

PMID- 10414482
TI  - Intramural anomalous left coronary artery from the right sinus of Valsalva
      supported with venoarterial extracorporeal membrane oxygenation.
AB  - We report the case of a 14-month-old girl with a wide complex dysrhythmia and
      cardiogenic shock due to abnormal coronary anatomy. She was kept alive for 20
      days by full cardiocirculatory support, using venoarterial extracorporeal
      membrane oxygenation (VA ECMO). While she was on VA ECMO, a diagnosis was made of
      extensive myocardial infarction and an anomalous left main coronary artery. The
      patient was listed for heart transplantation and received a donor heart 20 days
      after beginning VA ECMO. We discuss the unusual presentation and course of the
      coronary arteries and the use of VA ECMO to support this patient before heart
      transplantation.

PMID- 10414483
TI  - Insulin receptor antibodies and insulin resistance.
AB  - The presence of insulin receptor antibodies is a rare cause of insulin
      resistance. Patients usually have a combination of hyperglycemia, insulin
      resistance, acanthosis nigricans, and autoimmune features. We report a patient
      with systemic lupus erythematosus and severe insulin resistance due to insulin
      receptor antibodies. The most striking aspect of the clinical presentation is the
      resistance to insulin therapy, with our patient unresponsive to doses of up to
      154,075 units in a day. While on a low-dose glucocorticoid therapy, the patient
      had clinical improvement, and glucose levels subsequently became normal even
      without insulin and glucocorticoid.

PMID- 10414485
TI  - Hydrosalpinx due to asymptomatic bilateral tubal pregnancies associated with
      metaplastic papillary tumor of the fallopian tube.
AB  - The patient described in this report had bilateral hydrosalpinx due to
      pregnancies in both fallopian tubes, treated by laparoscopic resection.
      Histologically, both fallopian tubes revealed intratubal occlusion by
      degenerated, partially calcified chorionic tissue. An incidental finding was an
      intraluminal papillary epithelial tumor in one of the fallopian tubes. The
      clinical significance and complications of asymptomatic tubal ectopic pregnancy
      and the pathogenesis and biologic behavior of papillary epithelial tumors of the
      fallopian tube are briefly discussed.

PMID- 10414484
TI  - Radiation-induced bronchial stenosis: a new cause of platypnea-orthodeoxia.
AB  - Platypnea-orthodeoxia is encountered in a variety of cardiac, pulmonary, and
      hepatic disorders. We report its occurrence in a 59-year-old man who had had
      combined external-beam and high dose-rate iridium brachytherapy for a stage I non
      small-cell carcinoma of the right upper lobe 2 years earlier. The post-radiation
      course was complicated by a severe radiation bronchitis; the onset of platypnea
      orthodeoxia signalled the development of severe bronchial stenosis that was
      transiently relieved, initially by dilatation, and later by stent placement,
      though the patient ultimately died of a pulmonary hemorrhage. The dosage of
      brachytherapy given, the combined external-beam therapy, and the long survival
      after completion of radiation therapy were likely factors in the development of
      bronchial stenosis. We discuss the tomographic and bronchoscopic features of
      radiation-induced bronchial stenosis.

PMID- 10414486
TI  - Bacterial complications of strongyloidiasis: Streptococcus bovis meningitis.
AB  - We report the case of a 64-year-old veteran who had Streptococcus bovis
      meningitis as a result of a long latent Strongyloides infection that became acute
      when he was treated with prednisone. We reviewed 38 reported cases of serious
      bacterial infections associated with strongyloidiasis. Patients most frequently
      had nonspecific gastrointestinal symptoms. Of these 38 patients, 21 (55%) had
      meningitis, and 28 (73%) had bacteremia that was polymicrobial in 3 cases (8%).
      Other sites of infection included lung, bone marrow, ascites, mitral valve, and
      lymph node. Most infections were due to enteric gram-negative bacteria. There is
      one previously reported case of S bovis meningitis. Thirty-four of the patients
      (89%) were immunosuppressed; 21 of these (55%) were taking pharmacologic doses of
      adrenal corticosteroids. Thirty-three of the 38 (87%) patients died. Patients
      with enteric bacterial infection without an obvious cause should be tested for
      the presence of strongyloidiasis.

PMID- 10414487
TI  - Hope for the infrared tympanic thermometer: one model outperforms the others.

PMID- 10414488
TI  - Acute anxiety and depression induced by loss of sensation and muscle control
      after botulinum toxin A injection.

PMID- 10414489
TI  - Gastric cancer and intestinal metaplasia.

PMID- 10414490
TI  - Vasculopathy of small muscular arteries in pediatric patients after bone marrow
      transplantation.
AB  - Bone Marrow Transplant (BMT) is a critical therapeutic intervention for a variety
      of diseases occurring in the pediatric patient. Complications of allogeneic BMT
      include graft-versus-host disease (GVHD), infection, drug toxicity, thrombotic
      microangiopathy, and veno-occlusive disease. With solid organ transplantation,
      chronic vascular rejection has emerged as a major factor limiting long-term
      survival of the graft. We present a vasculopathy of small muscular arteries in 6
      patients after allogeneic BMT. Cases include 4 boys and 2 girls ranging in age
      from 4 months to 13 years with full or partial human leukocyte antigen matching.
      Five of the 6 transplants were from related donors. The vasculopathy occurred 13
      to 418 days after transplant and was noted in surgical specimens (2) and at
      autopsy (4). It was seen in the gastrointestinal tract and lung in 3 cases each.
      Vascular changes in small muscular arteries include concentric intimal or medial
      hyperplasia with luminal narrowing, prominent myxoid change, extravasated red
      blood cells, and presence of some foamy histiocytes with no evidence of
      thrombotic microangiopathy. Vasculopathy contributed to intestinal compromise
      requiring surgical intervention 3 times in 1 patient, and diffuse alveolar damage
      with hemorrhage in another. All 6 patients are dead. The cause of this unusual
      vasculopathy present in patients after BMT is likely to be multifactorial,
      involving effects of irradiation, chemotherapy, cyclosporine, and GVHD. Together
      these may create a negative synergy which produces an obliterative arteriopathy
      that should be recognized as a pathological entity and may be a harbinger of a
      poor prognosis.

PMID- 10414491
TI  - The dark side of the gastric biopsy.
AB  - Based on the assumption that both sides of a gastric biopsy sample have a similar
      appearance, the choice of which side of a specimen is to be sectioned is usually
      random. We tested the hypothesis that the diagnosis reached by examining the two
      sides of a gastric biopsy may differ. Eighty-one antral biopsy specimens from
      patients with neither focal lesions nor previous gastric surgery were evaluated.
      After preparing 8-10 sections from each of the two opposite faces of each biopsy,
      sections were scored for Helicobacter pylori, activity, atrophy, intestinal
      metaplasia, lymphoid follicles. The presence of other lesions was also noted.
      Intrabiopsy agreement (the consistency in the identification of histological
      lesions on the opposite sides of the same sample) was calculated by using kappa
      statistics. A kappa value lower than 0.5 was considered "poor"; between 0.51 and
      1.00 "moderate to excellent." The intrabiopsy agreement kappa values were:
      activity = 0.83, atrophy = 0.54, intestinal metaplasia = 0.51 and lymphoid
      follicles = 0.19. A mean of 42 serial sections (ranging from a mean of 22 for
      lymphoid follicles to a mean of 81 for xanthogranulomata) was needed to achieve
      an excellent (ie, kappa > or = 0.75) intrabiopsy agreement between the features
      showed at the opposite sides of a biopsy specimen. Intrabiopsy variability may
      represent a hitherto unrecognized source of error, and it should be minimized or
      avoided. In a research context information about the number of sections examined
      from a biopsy would provide a crucial element necessary to evaluate the accuracy
      of the histological data.

PMID- 10414492
TI  - Polypoid dysplasia in Barrett's esophagus: a clinicopathologic,
      immunohistochemical, and molecular study of five cases.
AB  - Dysplasia in Barrett's esophagus (BE) is a precursor to adenocarcinoma and most
      commonly occurs as a flat, grossly undetectable lesion. Rarely, dysplasia in BE
      may grow as a polypoid lesion. Most BE-associated polypoid dysplastic lesions
      have been referred to as "adenomas" because of their histological similarity to a
      colonic adenoma. BE-associated polypoid dysplastic lesions have been less well
      characterized than the flat type. Therefore, our aim was to characterize the
      clinicopathologic and molecular features of five cases of BE-associated polypoid
      dysplasia and to review the literature on this entity. The cases were evaluated
      clinically, histologically, immunostained for MIB-1 and p53, and genotyped for
      loss of heterozygosity (LOH) at the adenomatous polyposis coli (APC) locus.
      Mucosal biopsy specimens of five BE patients without dysplasia, and five BE cases
      with high-grade flat dysplasia, were used as controls. The study patients were
      all male (average age, 71 years) who presented with symptoms of gastroesophageal
      reflux disease. Endoscopically, all five cases had a well-defined sessile or
      pedunculated polypoid lesion ranging from 0.4 to 1.5 cm in size in the mid (n =
      1) or distal (n = 4) esophagus and were associated with specialized-type BE (four
      long segment, one short segment). Histologically, the polyps consisted of
      intestinalized epithelium with low- and high-grade dysplasia. All five cases
      contained adenocarcinoma (four within the polyp, one in adjacent BE). All polyps
      showed increased cell proliferation in the form of surface MiB-1 staining and
      showed positive p53 staining. Three of three (100%) informative cases showed LOH
      at the APC locus in the dysplastic epithelium and in areas of adenocarcinoma. All
      five flat dysplasia controls also showed surface MIB-1 staining and p53
      positivity, and three of three informative controls showed LOH for APC. None of
      the nondysplastic BE controls showed any of these findings. Three patients were
      treated with esophagectomy and two with polypectomy. All were alive, without
      metastasis, from 2 months to 6 years later. A literature review of esophageal
      "adenomas" uncovered 12 cases. Four of these had no clinical or pathological
      information, two were, in fact, gastric heterotopic lesions, one was composed
      entirely of intestinal-type epithelium, and five were polypoid dysplastic lesions
      similar to the cases described here (three male, two female; mean age, 59 years).
      Four of these five cases were associated with adenocarcinoma in the polyp (two
      intramucosal, two submucosal). In summary, BE-associated polypoid dysplasia share
      similar clinical, pathological, and molecular features as flat dysplasia and are
      often associated with adenocarcinoma. Thus, we agree with other authors who
      recommend that the term adenoma, which usually carries a benign connotation, be
      abandoned in favor of a descriptive diagnostic term, such as "BE-associated
      polypoid dysplasia." BE patients with this lesion should be considered strong
      candidates for esophageal resection similar to lesions of this kind that occur in
      inflammatory bowel disease.

PMID- 10414493
TI  - Prognostic significance and effect of chemoradiotherapy on microvessel density
      (angiogenesis) in esophageal Barrett's esophagus-associated adenocarcinoma and
      squamous cell carcinoma.
AB  - Previous studies have shown that intratumoral microvessel density (IMD)
      correlates with clinical outcome in a variety of human neoplasms, such as those
      that arise in the breast, colon, and stomach, suggesting that angiogenesis is
      important in cancer progression. The aims of this study were to evaluate the
      prognostic utility of IMD in esophageal Barrett's-associated adenocarcinoma
      (AdCa) and squamous cell carcinoma (SCC), and to determine the effect of
      preoperative chemoradiotherapy (chemrad) on this process. Tissue sections of
      tumor from 67 patients with esophageal carcinoma (45 with Barrett's-associated
      AdCa, 22 with SCC) were stained with the vascular marker CD31. The IMD was
      calculated by evaluating at least 5 different 200 x fields of tumor hot spot
      areas to obtain the mean microvessel count (MVC). The data then were correlated
      with the clinical and pathological features, chemrad status, and patient
      survival. The MVC was significantly higher in AdCa (143 +/- 63.2) compared with
      SCC (77.2 +/- 38.6, P = 0.0001). In AdCa, no correlation was noted between the
      MVC and any of the clinical or pathological features, including chemrad status.
      In contrast, in SCC, a statistically significant higher MVC was detected in
      patients who did not receive chemrad (97.2 +/- 37.3) compared with those who did
      (48.3 +/- 15.9, P = .002) and in tumors that were larger in size (P = .02).
      However, the MVC did not correlate with survival in either AdCa or SCC (P > .05).
      The degree of angiogenesis is not a significant prognostic indicator in either
      esophageal AdCa or SCC. Preoperative chemrad has a positive effect on reducing
      the degree of angiogenesis in esophageal carcinoma, particularly SCC.

PMID- 10414494
TI  - Fetal thrombotic vasculopathy in the placenta: cerebral thrombi and infarcts,
      coagulopathies, and cerebral palsy.
AB  - Thrombi in the fetal circulation of the placenta cause a pattern of clustered
      fibrotic villi called fetal thrombotic vasculopathy (FTV), which has been
      associated with serious injuries to neonates, especially brain injuries.
      Correlation of FTV with visceral thrombi in autopsy specimens might lead to a
      more accurate estimate of the prevalence of somatic thrombi as a significant and
      underrecognized cause of prenatal injury or perinatal death, and show the
      potential validity of placental FTV as an indicator of thrombotic lesions in the
      fetus and newborns who survive. Clinicopathologic correlation was used to perform
      a 3-year retrospective autopsy review. We identified 16 cases (19%) among 84
      perinatal autopsy specimens in which placental FTV was associated with
      stillbirth, intrapartum, or neonatal death. Two liveborn neonates survived 2.5
      hours, and one for 24 hours; there was one intrapartum death, and the rest were
      stillborn. Clinical evidence of severe central nervous system (CNS) injury to two
      of the liveborn infants was evident at birth. Twelve stillborns died from 12 to
      48 hours before delivery. Placental FTV had features of organization that clearly
      antedated the fetal death. Autopsy findings confirmed somatic thrombi in six
      cases (37.5%) of the 16 with FTV, including cerebral thrombi or infarcts (three
      cases), renal thromboemboli (three cases), and pulmonary thromboemboli (two
      cases). One mother had history of deep vein thrombosis, and four of eight tested
      had abnormal coagulation test results. Placental FTV indicates a significant
      probability of thrombi in the fetus and represents an important, possibly
      underrecognized cause of perinatal mortality and neonatal injury. Parental
      coagulopathy as a significant factor in prenatal injury and death deserves more
      comprehensive study. The placenta remains an undervalued and underutilized
      surgical specimen in the evaluation of perinatal injury, especially cerebral
      palsy.

PMID- 10414495
TI  - Posttraumatic fibro-osseous lesion of rib.
AB  - Eleven cases are described of an unusual, benign, fibro-osseous lesion of rib
      previously reported under a variety of designations, including painless fibro
      osseous lesion resembling osteoid osteoma, symmetrical fibro-osseous dysplasia,
      focal Erdheim-Chester disease, and fibro-osseous pseudotumor. All patients were
      adults, most of whom were asymptomatic, the lesion discovered by bone scans done
      to rule out metastatic disease. A single rib was involved in eight patients and
      multiple ribs in three. A roentgenographic abnormality was apparent in only five
      patients. Histologically, all lesions showed a bland fibrous stroma in which
      resided an anastomosing network of bone trabeculae, having a zonal pattern of
      maturation from metaplastic woven to mature lamellar bone, with or without an
      associated xanthomatous component. Seven patients had a history of previous
      trauma, three with fractured ribs. Considering the relative infrequency of
      solitary rib lesions attributable to metastatic disease, it is proposed that in
      most cases there is no need for a diagnostic rib resection for these incidentally
      discovered, posttraumatic reparative lesions.

PMID- 10414496
TI  - High prevalence of a 30-base pair deletion in the Epstein-Barr virus (EBV) latent
      membrane protein 1 gene and of strain type B EBV in Mexican classical Hodgkin's
      disease and reactive lymphoid tissue.
AB  - Depending on geographic location and patient age Hodgkin's disease (HD) is
      associated with Epstein-Barr virus (EBV), mostly type A EBV, in 20% to 100%. The
      highest prevalence occurs in children of developing countries. Molecular analysis
      of the oncogene coding for the latent membrane protein 1 (LMP-1) revealed a 30
      base pair (bp) deletion in up to 46% of EBV-positive HD. We investigated the
      presence of EBV in a series of Mexican classical HD (n = 57) and reactive
      lymphoid tissues (n = 20) from a private and a public hospital with special
      emphasis on the prevalence of the 30-bp deletion and the type of EBV. EBV
      infection was analyzed at the cellular level by Epstein-Barr encoded early RNA
      transcripts (EBER) in situ hybridization (ISH) and by LMP-1 protein
      immunohistochemistry (IHC). Molecular analysis of the LMP-1 gene configuration
      was performed by polymerase chain reaction (PCR) with primers spanning the site
      of the deletion and subsequent Southern and/or dot blot hybridization using wild
      type and deletion-specific probes. The prevalence of type A and type B EBV was
      investigated by PCR-analysis for divergence in the coding region of Epstein-Barr
      nuclear antigen (EBNA)-2. EBV was detected in Hodgkin- and Reed-Sternberg cells
      (H-RS) by LMP-1 IHC and/or EBER ISH in 35/57 (61%) Mexican HD including 18/32
      (56%) with nodular sclerosis, 15/20 (75%) with mixed cellularity and 2/4 (50%)
      with lymphocyte depletion. In addition, LMP-1 gene sequences were detected by PCR
      in 9 cases of HD without LMP/EBER expression by H-RS cells and in 17/20 (85%)
      reactive lymph nodes, supposedly originating from rare latently infected B cells.
      Surprisingly, the 30-bp LMP-1 deletion was found in 28/35 (80%) EBV-positive HD.
      This deletion, however, was also found in all 9 (100%) HD with H-RS cells
      negative for EBV and in 10/17 (59%) reactive lymph nodes. Thus, the overall LMP-1
      del prevalence in reactive tissue is 73% (19/26). Typing of EBV was successful in
      26 cases of EBV-positive HD, 10 of these were infected by type B EBV (38%). Of
      the reactive lymphoid tissue, 9 (47%) were infected by type A, and 10 (53%) by
      type B; All 20 cases (100%) associated with type B, whether neoplastic or
      reactive, displayed the LMP-1 del variant compared with 18/25 (72%) infected by
      type A EBV. To our knowledge, this is the highest incidence for both the LMP-1
      deletion variant and the infection by type B EBV in HD reported so far worldwide.
      Our data suggest that EBV infection contributes to the pathogenesis of the
      majority of Hodgkin's disease cases in Mexico. The specific tumorigenic role of
      the LMP-1 deletion variant, however, is doubtful with regard to its high
      frequency in nonneoplastic lesions. Moreover, type B infection frequently occurs
      in Mexican HD and reactive lymphoid tissue and is consistently associated with
      the deletion variant pointing to a pathogenetic role of this combined genotype.

PMID- 10414497
TI  - The expression of basic fibroblast growth factor (bFGF) in tumor-associated
      stromal cells and vessels is inversely correlated with non-small cell lung cancer
      progression.
AB  - Tumor progression results from complex interactions between tumor and tumor
      associated host tissue. Basic fibroblast growth factor (bFGF), via activation of
      its receptor, FGFR-1, has been postulated to be an important inducer of host
      stromal response and angiogenesis. To assess the putative role of tumor
      associated stromal cells and vessels in tumor progression, we studied non-small
      cell lung cancer (NSCLC) from 84 patients, including 51 squamous cell carcinomas
      and 33 nonsquamous cell carcinomas, by immunohistochemical detection. bFGF and
      FGFR-1 immunoreactivity was observed in tumor and in tumor-associated stromal
      cells and vessels. The expression of bFGF and FGFR-1 in stromal cells was higher
      in squamous than in non-squamous cell carcinomas (respectively, P = .007 and P =
      .0004). We found that bFGF and FGFR-1 expression in tumor and tumor-associated
      stromal cells and vessels was directly correlated with host stromal response, as
      assessed by intratumoral extension of stroma, but not with angiogenic response,
      as assessed by microvessel count. Although FGFR-1 expression of tumor cells was
      directly correlated with T-stage (P = .03), bFGF expressions of tumor-associated
      stromal cells and vessels were inversely correlated with lymph node metastasis
      (respectively, P = .0001 and P = .0002) and advanced pathological stage
      (respectively, P = .03 and P = .01). These findings suggest that bFGF might
      mediate host stromal response in NSCLC and that the expression of bFGF in tumor
      associated stromal cells and vessels might have an inhibitory role in NSCLC
      progression.

PMID- 10414498
TI  - Differential expression of tissue inhibitors of metalloproteinases (TIMP-1, -2, 
      3, and -4) in normal and aberrant wound healing.
AB  - Wound healing is characterized by hemostasis, re-epithelialization, granulation
      tissue formation, and remodeling of the extracellular matrix. Matrix
      metalloproteinases and their specific inhibitors, TIMPs, contribute to these
      events. We investigated a total of 47 samples of normally healing wounds, chronic
      venous ulcers, ulcerative vasculitis, and suction blisters using
      immunohistochemistry and in situ hybridization, to clarify the role of TIMPs in
      normal and aberrant wound repair. Expression of TIMP-1 and -3 mRNAs was found in
      proliferating keratinocytes in 3- to 5-day-old normally healing wounds, whereas
      no epidermal expression was detected in chronic ulcers. However, TIMP-3 protein
      was found in the proliferating epidermis in 20 of 24 samples representing both
      full-thickness acute and chronic wounds. TIMP-1 and TIMP-3 also were abundantly
      expressed by spindle-shaped, fibroblast-like, and plump, macrophage-like stromal
      cells, as well as by endothelial cells. In normally healing wounds, TIMP-2
      protein localized under the migrating epithelial tip and to the stromal tissue
      under the eschar more frequently than in chronic ulcers. Occasional staining for
      TIMP-4 protein was detected in stromal cells of chronic ulcers near blood
      vessels. Our results indicate that TIMP-1 and TIMP-3 may be involved both in the
      regeneration of the epidermis by stabilizing the basement membrane zone and in
      the regulation of stromal remodeling and angiogenesis of the wound bed. Lack of
      TIMP-2 near the migrating epithelial wound edges might contribute to uncontrolled
      activity of MMP-2 in chronic ulcers. We conclude also that TIMPs are temporally
      and spatially tightly regulated and that the imbalance between metalloproteinases
      and TIMPs-1, -2, and -3 may lead to delayed wound healing.

PMID- 10414499
TI  - Bcl-6 and Bcl-2 protein expression in diffuse large B-cell lymphoma and
      follicular lymphoma: correlation with 3q27 and 18q21 chromosomal abnormalities.
AB  - The bcl-2 gene on chromosome 18 at q21 and the bcl-6 gene on chromosome 3 at q27
      are both highly regulated during B-cell differentiation and show an inverse
      relationship of expression in the normal secondary lymphoid follicle. The
      objective of this study was to investigate the relationship between bcl-2 and bcl
      6 protein expression and the relationship between protein expression and the
      corresponding chromosomal alterations in malignant lymphomas, including those
      associated with the germinal center. Expression of bcl-2 and bcl-6 proteins was
      studied in 55 cases of diffuse large B-cell lymphoma (DLBCL) and 21 cases of
      follicular lymphoma (FL), and the results correlated with the presence of
      t(14;18) and 3q27 abnormalities in a subset of 52 cases with cytogenetic
      analysis. These cases were selected to represent a spectrum of nodal and
      extranodal lymphomas, including those with and without a t(14;18). It was shown
      that the neoplastic cells in 71% of DLBCLs and 100% of FLs expressed bcl-6
      protein. Expression of bcl-6 was seen more frequently in diffuse large B-cell
      lymphomas with large noncleaved morphology compared with immunoblastic morphology
      (82% v 27%, P = .0015), but failed to correlate with 3q27 abnormalities. Thirty
      eight percent of cases with 3q27 abnormalities were bcl-6 protein negative,
      whereas 85% of cases without a 3q27 abnormalities were bcl-6 protein positive.
      Expression of bcl-2 protein was shown in 51% DLBCLs (nodal v extranodal, 71% v
      30%, P = .012). bcl-2 protein was expressed in 89% of FLs with t(14;18), in
      contrast to 25% of FLs without t(14;18) (P = .016). In DLBCL and FL with
      t(14;18), the most common pattern of expression was bcl-2+/bcl-6+. In lymphomas
      without t(14;18), there was not an inverse relationship between bcl-2 and bcl-6
      protein expression. In conclusion, these data suggest that mechanisms other than
      gene rearrangements can deregulate bcl-2 and bcl-6 expression in lymphomas, and
      there does not appear to be an inverse relationship between these two proteins as
      seen in the normal germinal center.

PMID- 10414500
TI  - Loss of heterozygosity at chromosome arm 13q and RB1 status in human prostate
      cancer.
AB  - Aberrations of the long arm of chromosome 13 are common in prostate cancer and
      were initially attributed to alterations of the RB1 gene in band q14 of the
      chromosome. However, prostate tumors generally yield normal p110RB1 nuclear
      staining despite loss of heterozygosity (LOH) at the RB1 locus. Our previous
      analysis of chromosome arm 13q showed allelic loss in 41% of primary prostate
      tumors. To refine our knowledge of 13q, we extended our previous LOH study by
      using more polymorphic markers to analyze more prostate tumors. Sixty human
      prostate carcinomas were screened for allelic loss on 13q by using 13 13q
      specific markers. LOH on the long arm of chromosome 13 was found in 39 (65%) of
      the 60 tumors. Furthermore, 33 of these 39 tumors had evidence of allelic loss
      involving a region of 13q14 containing RB1. Because immunohistochemical
      assessment of pRb expression is controversial in prostate tumors, we used a
      quantitative reverse transcription polymerase chain reaction (RT-PCR) method to
      determine whether RB1 is the target tumor suppressor gene in this region. RB1
      mRNA steady-state levels were determined in 12 prostate tumors preselected on the
      basis of presumed deletion at the RB1 locus and four prostate tumors without LOH
      at the RB1 locus; five normal prostate specimens were used as controls. One of
      the 12 assessable prostate tumors with presumed LOH at RB1 showed a corresponding
      decreased in RB1 mRNA expression, whereas none of the four tumors without LOH at
      RB1 locus showed such a decrease. This study, based on another technical
      approach, confirms that RB1 is not the main target of the observed LOH at
      13q14.3, and raises the possibility that another tumor suppressor gene in this
      region plays a key role in prostate cancer.

PMID- 10414501
TI  - Atypical glandular cells of undetermined significance (AGUS): cytopathologic
      features, histopathologic results, and human papillomavirus DNA detection.
AB  - We intensively reviewed 137 smears initially classified as atypical glandular
      cells of undetermined significance (AGUS) to refine cytological criteria for
      evaluating these cases, evaluate histological outcomes, and assess the value of
      human papillomavirus (HPV) DNA testing in management. Consenting, nonpregnant
      study participants were identified from a cohort of 46,009 women receiving
      routine Pap smear screening in a managed care setting. Colposcopy was performed
      on all women, and at least one histological sample was obtained from each. Review
      diagnoses were assigned to smears and biopsy specimens by two separate panels of
      pathologists. DNA testing for cancer-associated HPV types was performed on rinses
      of cytological samplers after a smear and thin-layer slide had been made. On
      review, 47 (34%) smears were reclassified as negative, 44 (32%) as AGUS, 30 (22%)
      as atypical squamous cells of undetermined significance (ASCUS), and 16 (12%) as
      squamous intraepithelial lesions (SIL). The 19 smears interpreted as high-grade
      intraepithelial lesions on review included 13 high-grade SIL (HSIL), two HSIL
      with AGUS, favor neoplastic (endocervical adenocarcinoma in situ [AIS]), and four
      AGUS, favor neoplastic (AIS). Review histological diagnoses were negative in 105
      (77%), squamous or glandular atypia in four (3%), low-grade SIL (LSIL) in nine
      (7%), HSIL in 12 (9%), AIS in five (4%, including two with concurrent HSIL), and
      endometrial carcinoma in one (1%). HPV testing identified 11 (92%) of 12 women
      with histologically confirmed HSIL and all five with AIS (100%). A high-grade
      intraepithelial lesion or carcinoma is detected in approximately 14% of women
      with community-based diagnoses of AGUS who are referred for immediate evaluation.
      Use of refined cytological criteria and HPV DNA testing may permit improved
      management of women with AGUS.

PMID- 10414502
TI  - Well-differentiated adenocarcinoma mimicking complete-type intestinal metaplasia
      in the stomach.
AB  - We describe extremely well-differentiated intestinal-type adenocarcinomas of the
      stomach which mimic complete-type intestinal metaplasia. It is often difficult to
      discriminate such neoplastic lesions from inflamed or regenerative changes of
      intestinal metaplasia histologically. The aim of this study was to elucidate the
      clinicopathologic features of this unique carcinoma. Eight cases of gastric
      carcinoma of this type that were invasive beyond the muscularis mucosae were
      selected for mucin histochemical and immunohistochemical analyses. The carcinomas
      showed the following features: (1) predominant cells that had differentiated to
      mature neoplastic cells, with features of small intestinal absorptive cells
      (complete-type intestinal metaplastic cells), which have sialomucin, MUC2
      positive cells, and brush border features detected by CD10 (56C6) staining; (2)
      neoplastic tubules in the mucosa showing branching, tortuous, anastomosing, and
      plexiform structures, which were more pathognomonic than the cytological
      features; (3) lesions distributed predominantly in the middle third of the
      stomach and surrounded by the fundic mucosa; and (4) zonal distribution of Ki-67
      positive proliferative cells like those of intestinal metaplasia in the lower
      third to half of the cancerous tubules in the mucosa. The lesions consisted
      mainly of illusory carcinoma; however, there were foci of pathognomonic elements
      in some areas of the tumors. Several biopsy samplings of the lesion would ensure
      the histopathologic diagnosis. This unique lesion forms a subgroup of intestinal
      type carcinomas of the stomach and is suggested to have a close link with
      complete-type intestinal metaplasia, previously ignored as a precancerous lesion.

PMID- 10414503
TI  - Lymphoid proliferations and lymphomas associated with gastric metaplasia,
      dysplasia, and carcinoma.
AB  - Gastric carcinomas are invariably accompanied by lymphoid proliferations. We
      studied their features in 22 resected gastric carcinomas in which the lymphoid
      proliferations ranged from reactive lymphoid follicles to mucosa-associated
      lymphoid tissue (MALT) lymphomas. In most cases, the collections of lymphocytes
      were abundant, which is remarkable considering the lack of lymphoid tissue in the
      normal stomach. They were not haphazardly located but in direct contact with the
      metaplastic, dysplastic, and neoplastic epithelial cells, in positions suggestive
      of defense barriers. They consisted of newly formed lymphoid follicles with
      reactive germinal centers sometimes high up in the superficial mucosa,
      collections of plasma cells beneath the surface epithelium, and large aggregates
      of B cells above and below the muscularis mucosae as well as abundant T cells.
      The latter, both CD4+ and CD8+, were seen within metaplastic epithelial cells as
      well as within carcinomatous glands that were partially destroyed, resembling
      apparent neoplastic lympho-epithelial lesions (LEL). In three cases, the B cells
      infiltrating the gastric muscular layers represented MALT-lymphomas adjacent to
      gastric carcinomas, as confirmed by polymerase chain reaction (PCR) analysis in
      two cases. In a case of lymphoepithelioma-like carcinoma, the excessive lymphoid
      cells were predominantly of T-CD8+ type. In this case, EBV identified by EBV
      encoded RNA and latent membrane protein was present in large amounts.
      Helicobacter pylori was seen in only six cases in areas of chronic gastritis that
      were distant from carcinoma. H. pylori was not present in the areas of
      metaplasia, dysplasia, or carcinoma. It appears that the lymphoid proliferations
      accompanying these gastric changes do not arise in response to the pathogenic
      agent H. pylori, which caused the persistent infection leading to them yet is no
      longer present, but rather in response to the existence of the abnormal
      epithelial cells. Thus the lymphoid proliferations consistently associated with
      gastric metaplasia, dysplasia, and neoplasia may be regarded as immune reactions
      to the long-term cellular changes triggered by the initial chronic gastritis. On
      rare occasions, the exaggerated lymphoid proliferations may reach the end of the
      spectrum, resulting in MALT lymphomas coexistent with gastric carcinomas.

PMID- 10414504
TI  - Medullary adenocarcinoma of the colon: clinicopathologic study of 11 cases.
AB  - Colonic carcinomas with minimal or no glandular differentiation are a
      heterogeneous group of neoplasms which differ in their histologic appearance,
      clinical features, prognosis and molecular characteristics. Since 1990, we
      prospectively identified 11 patients with a predominantly solid (nonglandular)
      adenocarcinoma of the colon for which the term medullary adenocarcinoma of the
      colon (MAC) is proposed. The clinical, histological, histochemical, and
      immunohistochemical features of these neoplasms were studied. All patients with
      MAC were women with tumors in the cecum or proximal colon. Histological analysis
      showed nests or trabeculae of regular small to medium-sized cells with moderate
      amounts of eosinophilic cytoplasm; some cells contained mucin vacuoles. The
      nuclei had an open chromatin pattern and exhibited prominent nucleoli. Lymphatic
      permeation was present in most cases. Immunohistochemical reactions were positive
      for cytokeratin, carcinoembryonic antigen, and epithelial membrane antigen.
      Despite its histological resemblance with endocrine tumors, MAC is negative for
      endocrine markers. Of the eight patients for whom follow-up is available, four
      patients (two Dukes B and two Dukes C) are alive and well 1 to 4 years after
      surgery, one patient (Dukes C) died of tumor, one patient is alive with liver
      metastasis 4 years after surgery, and two patients died in the postoperative
      period. MAC appears to be a distinctive clinicopathologic entity. This tumor
      should be distinguished from other more aggressive, nonglandular tumors of the
      colon.

PMID- 10414505
TI  - Histological and immunophenotypic profile of nasal NK/T cell lymphomas from Peru:
      high prevalence of p53 overexpression.
AB  - Nasal NK/T-cell lymphoma is a unique form of lymphoma highly associated with
      Epstein-Barr virus (EBV). These lymphomas are rare in Western populations and
      much more prevalent in some Asian and Latin American countries. Although there
      are several sizable studies from Asian countries, the same is not true from South
      America. The aim of this study was to analyze a series of 32 cases of nasal T
      cell lymphoma from Peru and to further extend the characterization of this
      disease. Immunohistochemistry was performed on paraffin sections using the
      following antibodies: CD20 (L26), CD45RO, CD3, Ki67, CD57, CD56, TIA-1, bcl-2,
      and p53. The presence of EBV was investigated with immunohistochemical analysis
      for latent membrane protein (LMP)-1 and in situ hybridization using an antisense
      riboprobe to EBER 1. The 32 patients included 18 men and 14 women (M:F ratio,
      1.2:1), with a median age of 43 years (11 to 72). Three categories were
      identified: (1) Nasal NK/T cell lymphomas (28 cases): The morphology ranged from
      small or medium-sized cells to large transformed cells. Necrosis was present in
      86% of the cases, and angioinvasion was seen in 36% of the cases. All cases were
      positive for CD45RO, CD3, and for TIA-1. CD56 was positive in 21 of 27 cases
      (78%), and CD57 was negative in all cases. EBER 1 positivity was identified in
      most of the tumor cells in 27 of 28 cases (96%), including the six cases in which
      CD56 was negative. Overexpression of p53 was detected in 24 cases (86%). (2)
      Blastic NK cell lymphoma (1 case): The neoplastic cells resembled those of
      lymphoblastic lymphoma. CD56 and CD45RO were positive; TIA-1, TdT, and EBER-1
      were negative. (3) Peripheral T-cell lymphoma (PTCL) unspecified (3 cases): CD56,
      TIA-1, and EBER-1 were negative. Nasal lymphomas from Peru with a T cell
      phenotype are predominantly EBV-associated NK/T cell lymphomas, similar to those
      described in Asian countries. The expression of CD56, TIA-1, and EBER-1, in
      combination, are very useful markers for the diagnosis of nasal NK/T cell
      lymphoma in paraffin-embedded tissue. The differential diagnosis of T-cell
      lymphomas in the nasal region should include rare cases of PTCL unspecified and
      the blastic variant of NK cell lymphoma. P53 is overexpressed in 86% of the
      cases. The significance of this finding with regard to clinical behavior and
      prognosis remains to be determined.

PMID- 10414506
TI  - Wolffian adnexal tumor, so-called female adnexal tumor of probable Wolffian
      origin (FATWO): immunohistochemical evidence in support of a Wolffian origin.
AB  - Wolffian adnexal tumor (WAT) is a rare neoplasm believed to originate from
      wolffian remnants on the basis of its location in areas where these remnants are
      abundant. To study its histogenesis, the immunoprofile of 25 WATs was compared
      with that of 10 cervical and vaginal mesonephric remnants and 12 rete ovarii.
      WATs were unilaterally located in the broad ligament (n = 10), mesosalpinx (n =
      9), ovarian hilus (n = 5), and pelvis, not otherwise specified (n = 1). They
      showed varying morphologies with solid (spindle cells), tubular (lined by
      columnar cells), retiform and multicystic (spaces lined by cuboidal and
      attenuated cells) patterns. WATs were immunoreactive for pan-cytokeratin (AE1/3,
      CK1) (100%), CAM 5.2 (100%), cytokeratin 7 (CK7) (88%, focal staining), keratin
      903 (17%), epithelial membrane antigen (EMA) (12%), estrogen receptor (28%),
      progesterone receptor (24%), androgen receptor (78%), inhibin (68%), calretinin
      (91%), and vimentin (100%). No immunostaining was detected with monoclonal
      carcinoembryonic antigen and cytokeratin 20. The pattern of staining was nearly
      identical to that of the rete ovarii and differed somewhat from mesonephric
      remnants, which were diffusely immunoreactive for CK7, immunopositive for EMA
      (apical staining), and nonreactive for inhibin. Our findings provide
      immunohistochemical support for the derivation of WATs from wolffian remnants, in
      particular from the rete ovarii. Because of immunoreactivity for inhibin and
      calretinin in a significant number of WATs, our results further show that these
      immunostains alone do not allow absolute distinction of WATs from sex cord
      stromal tumors and adenomatoid tumors, respectively, with which they may be
      confused.

PMID- 10414507
TI  - The role of trisomy 8 in the pathogenesis of chronic eosinophilic leukemia.
AB  - A case of chronic eosinophilic leukemia (CEL) manifesting as spinal cord
      compression by an extradural eosinophilic chloroma in a 32-year-old Chinese man
      was presented, who subsequently developed extramedullary transformation at the
      skin and then peritoneal cavity. Cytogenetic study of bone marrow cells at
      diagnosis showed a clonal karyotypic abnormality of trisomy 8 (+8), which on
      fluorescence in situ hybridization (FISH) was shown to be present in a clone of
      abnormal eosinophils, hence showing the neoplastic nature of the eosinophilic
      proliferation. There was another population of abnormal eosinophils that did not
      show +8. At blastic transformation, all blast cells in ascitic fluid were shown
      by FISH to harbor +8. These findings suggest that +8 in this case may have arisen
      from clonal evolution and is not the primary genetic event in leukemogenesis, but
      +8 most probably imparts a further survival advantage to the clone responsible
      for subsequent blastic transformation.

PMID- 10414508
TI  - Secondary myeloid/natural killer cell precursor acute leukemia following
      essential thrombocythemia.
AB  - The de novo leukemic transformation of essential thrombocythemia is a rare event,
      and usually associated with previous treatments. We describe a patient who
      received treatments with nitrosourea for long-standing essential thrombocythemia
      and subsequently developed extramedullary tumors, tentatively diagnosed as
      lymphoblastic lymphoma. Combination chemotherapy was initially successful, but
      relapsed with marked bone marrow involvement. Surface marker analysis revealed
      that the tumor cells had CD5, CD7, CD33, CD34, and CD56 antigens but lacked other
      T-cell, and B-cell markers. Immunogenotypical studies revealed germline
      configurations for both T-cell receptors and immunoglobulin genes. These clinical
      and phenotypical features are consistent with a myeloid/natural killer cell
      precursor leukemia, a recently proposed distinct clinical entity. To our
      knowledge, this is the first report of secondary leukemia of myeloid/ natural
      killer cell precursor origin, and suggest that myeloid/natural killer cell
      precursor might be a potent target of therapy-related leukemia.

PMID- 10414509
TI  - Primary non-Hodgkin's lymphoma and malakoplakia of the vagina: a case report.
AB  - The vagina is a rare site for both primary non-Hodgkin's lymphoma and
      malakoplakia. We report a case of concurrent diffuse large B-cell lymphoma and
      malakoplakia of the vagina in a 67-year-old woman presenting with a vaginal
      discharge and a vaginal mass. The patient had two biopsy specimens reported as
      showing malakoplakia only, followed by a third biopsy specimen 10 months later
      which was diagnosed as diffuse large B-cell lymphoma. Review of the first two
      biopsy specimens showed areas of histiocytes with Michaelis-Gutman bodies merging
      with areas of cells with slightly larger nuclei and more amphophilic cytoplasm.
      Immunohistochemistry for the B-cell marker L-26 (CD20) and polymerase chain
      reaction analysis of the immunoglobulin heavy chain gene were helpful in
      retrospectively distinguishing the population of diffuse large B-cell lymphoma
      from the areas of malakoplakia. The third biopsy specimen showed sheets of large
      atypical lymphoid cells characteristic of a large cell lymphoma. Malakoplakia has
      been described in association with a variety of cancers, and this is only the
      second report of malakoplakia associated with non-Hodgkin's lymphoma. Considering
      the rarity of these two entities in the vagina, it is unlikely that the
      association in this case is coincidental, raising the possibilities of an unusual
      reaction to the presence of lymphoma or a common pathogenesis such as underlying
      chronic inflammation. Epstein-Barr virus DNA was detected in the second biopsy
      specimen, suggesting a possible role in the pathogenesis of this lymphoma.

PMID- 10414510
TI  - Fatal Chaetomium cerebritis in a bone marrow transplant patient.
AB  - The number of opportunistic infections in the central nervous system (CNS) has
      been steadily increasing because of a rising number of immunocompromised
      patients. A rare form of CNS infection can be caused by Chaetomium species, one
      of the largest genera of saprophytic ascomycetes. The CNS lesions in the present
      case were caused by Chaetomium atrobrunneum. The main characteristic of almost
      all Chaetomium species is presence of hairs or setae covering the ascomata.
      Microbiological studies are the only definitive way to correctly identify this
      fungal organism. The rapid evolvement of the cerebral infection suggests that the
      brain tissue provides a favorable environment for growth and proliferation of
      these fungi. This is the second documented case of a fatal brain abscess caused
      by Chaetomium atrobrunneum, and the first case report in a bone marrow transplant
      patient.

PMID- 10414511
TI  - The "WHO/ISUP Consensus Classification of Urothelial (Transitional Cell)
      Neoplasms": continued discussion.

PMID- 10414512
TI  - Motor evoked potentials in a rhesus macaque model of neuro-AIDS.
AB  - Previous work using bone marrow passaged SIVmac239 (simian immunodeficiency
      virus) has shown that macrophage tropic strains of this virus enter the rhesus
      macaque brain early following inoculation (Sharma et al, 1992; Desrosiers et al,
      1991; Zhu et al, 1995; and Narayan et al, 1997). As part of an effort to more
      fully characterize the extent of neurologic impairment associated with SIV
      infection of the brain, we used transcranial electrical stimulation of motor
      cortex and the spinal cord to evoke EMG potentials in two forelimb (EDC and APB)
      and two hindlimb (LG and AH) muscles. The latencies, magnitudes and thresholds of
      motor evoked potentials (MEPs) recorded from nine monkeys infected with
      neurovirulent SIVmac R71/17E were compared to pre-inoculation records from the
      same monkeys. Seven of nine monkeys developed simian AIDS within 4 months of
      inoculation and were euthanized. Two monkeys remained free of AIDS-related
      clinical illness for over 18 months following inoculation. Six of the seven
      monkeys with rapidly progressing disease showed post-inoculation latency
      increases ( > or = 2 s.d. of control) in at least one cortical MEP. Increases in
      cortical MEP latency ranged from 21-97% in different monkeys. All seven rapidly
      progressing animals showed post-inoculation increases in at least one spinal cord
      MEP latency. Maximum spinal cord MEP latency increases ranged from 22-147%.
      Increases in central conduction time (CCT) ranged up to 204% and exceeded two
      standard deviations of control in four monkeys. Neither of the two monkeys with
      slowly progressing disease showed significant increases in either cortical or
      spinal cord MEP latency or CCT. Only the monkeys with rapidly progressing disease
      exhibited classic AIDS-related neuropathology, although there was no consistent
      relationship between the severity of neuropathology and the extent of MEP
      abnormalities. In conclusion, our results demonstrate clear deficits in the
      functional integrity of both central and peripheral motor system structures
      associated with SIV infection and further support the use of SIV-infected rhesus
      macaques as a model of neuro-AIDS.

PMID- 10414513
TI  - Viral load and neuropathology in the SIV model.
AB  - To investigate neuropathological processes involved in HIV infection, a
      longitudinal analysis of central nervous system (CNS) changes was performed using
      the SIV-infected macaque model. Five animals were studied during the early phase
      and 13 during the asymptomatic and symptomatic phases. Histopathological analyses
      were performed on one cerebral fixed hemisphere whereas on the other frozen
      hemisphere in situ hybridisation, immunohistochemistry and RT-PCR were performed.
      Viral load was quantified by in situ hybridisation, CD4 and CD8 T cell
      infiltration by immunohistochemistry and mRNA cytokine expression (IL1beta, IL2,
      IL6, TNFalpha, IFNgamma and TGF-beta1) by semiquantitative RT-PCR. As reported
      for HIV-infected humans, the neuropathological analysis of SIV infected animals
      revealed four distinct lesion profiles: minimal changes, early encephalitis,
      leukoencephalopathy and encephalitis. No relationship was found between
      neuropathological findings, numbers of SIV replicating cells and T cell
      infiltration. CNS infection was found to be an early event characterised by glial
      activation, an increase in the level of IL1beta, TNFalpha and IL6 mRNA
      expression. During the asymptomatic and symptomatic phases, IL6 and IL1beta mRNAs
      increase coincided with gliosis and the development of myelin lesions. The
      absence of relationship between neuropathological findings and viral load
      suggests that cerebral lesions are caused by an indirect mechanism. Inflammatory
      cytokine pattern associated with severe lesions show the key role of glial
      activation in the SIV neuropathological process.

PMID- 10414515
TI  - Modulation of acute coronavirus-induced encephalomyelitis in gamma-irradiated
      rats by transfer of naive lymphocyte subsets before infection.
AB  - Clinical course, recovery of infectious virus from brain tissue and
      histopathology of the central nervous system were examined in gamma-irradiated
      Lewis rats reconstituted by naive lymphocytes before infection with coronavirus
      MHV-4 (strain JHM). Up to 9 days past infection, no differences were seen between
      immunologically competent and immuno-deficient animals in terms of onset and
      progression of neurological disease. However, in the latter animals neurological
      symptoms were dominated by signs of encephalitis instead of paralytic disease as
      usually seen in immunocompetent animals. Nevertheless, despite high titers of
      infectious virus in the CNS of immunodeficient animals only mild
      histopathological changes were noticeable. In contrast, infectious virus in the
      CNS of immunologically competent animals was below the detection limit of the
      assay. Paralytic disease and tissue destruction were T lymphocyte mediated
      because gamma-irradiated rats that were reconstituted by CD4+ or CD8+ T
      lymphocyte enriched cells in the absence of B lymphocytes revealed an earlier
      onset of clinical symptoms and a more rapid deterioration of their clinical state
      compared to fully competent animals. Whereas in CD4+ T cell reconstituted animals
      infectious virus was moderately reduced and tissue destruction as well as
      inflammatory changes in the CNS were focal, in CD8+ T cell reconstituted animals
      vacuolizing white matter inflammation was diffuse without reduction of infectious
      virus in brain tissue. From the presented data we conclude that in the acute
      stage of JHMV-induced encephalomyelitis of Lewis rats: (i) tissue destruction and
      paralytic clinical symptomatology are mainly T cell-mediated; (ii) CD4+ T
      lymphocytes can directly contribute to reduction of viral load in the brain and
      (iii) only coordinated action of both, the T and the B cell compartment enables
      animals to survive the infection and recover from disease.

PMID- 10414514
TI  - Detection of human T-lymphotropic virus type I p40tax protein in cerebrospinal
      fluid cells from patients with human T-lymphotropic virus type I-associated
      myelopathy/tropical spastic paraparesis.
AB  - We investigated the role of viral transcripts of human T-lymphotropic virus type
      I (HTLV-I) in the cerebrospinal fluid (CSF) cells and peripheral blood
      mononuclear cells (PBMCs) of patients with human T-lymphotropic virus type I
      associated myelopathy (HAM)/tropical spastic paraparesis (TSP). To detect the
      HTLV-I p40tax protein, we developed a new sensitive method of
      immunohistochemistry combined with tyramide signal amplification and quantitative
      analysis. Seven patients with HAM/TSP were examined. As controls, four patients
      with other neurological diseases were examined; two of these patients were
      infected with HTLV-I and the other two were not. Both the CSF cells and PBMCs
      were reacted with a monoclonal antibody, Lt-4, for p40tax protein, followed by
      secondary antibody labeled with horseradish peroxidase. This was visualized by
      fluorescein directly labeled with tyramide and the number of positive cells was
      quantified with a Laser Scanning Cytometer. In the samples from patients with
      HAM/TSP, the HTLV-I p40tax protein was successfully detected by tyramide signal
      amplification, but not without it. In HAM/TSP patients, 0.04-1.16% of the CSF
      cells and 0.02-0.54% of PBMCs were positive for the HTLV-I p40tax protein,
      respectively. The expression of the HTLV-I p40tax protein in the CSF cells was
      more frequent than that in PBMCs in both HAM/TSP patients and HTLV-I carriers,
      and was also more frequent in the patients with HAM/TSP of shorter duration of
      illness. This technique could be a powerful tool to investigate the pathogenic
      mechanism of diseases associated with HTLV-I.

PMID- 10414516
TI  - Establishment of a quiescent herpes simplex virus type 1 infection in neurally
      differentiated PC12 cells.
AB  - Rat pheochromocytoma (PC12) cells differentiated with nerve growth factor (Nd
      PC12) were used to investigate the establishment of a non-productive herpes
      simplex virus type 1 (HSV-1) infection that is reversible. The results of this
      work are as follows: (i) Nd-PC12 cultures could be maintained as long term (>7
      weeks) non-dividing cultures only when plated on collagen-coated dishes in the
      absence of serum; (ii) Infection of Nd-PC12 with HSV-1 strains KOS and 17 in the
      transient presence of acycloguanosine (ACV) resulted in all cultures free of
      detectable levels of infectious virus at the time of ACV removal and ACV was not
      needed to maintain the non-productive quiescent state in the subsequent 8 weeks;
      (iii) These persistently infected and quiescent (QIF)-PC12 cultures demonstrated
      both spontaneous and forskolin-inducible virus production, at low (5%) and high
      frequencies (92-100%), respectively during the first 2 weeks post-ACV withdrawal.
      (iv) In contrast to other in vitro models, HSV-1 failed to reactivate following
      removal of nerve growth factor. (v) A high percentage of QIF-PC12 cultures (50
      100%) produced virus in response to forskolin treatment as long as 7 weeks post
      ACV withdrawal. (vi) Expression of HSV-1 productive genes (i.e. alpha0, alpha4,
      alpha27, UL30 and UL18) dropped precipitously in the presence of ACV and remained
      undetectable or continued to decline following its removal, whereas the levels of
      LAT and the host gene G3PDH remained relatively constant throughout the 31 day
      study period as measured by RT-PCR. These results indicate that QIF-PC12 cells
      offer a novel, neuronal cell culture system that may enhance our ability to study
      HSV-1 reactivation from a cryptic, latent-like, non-productive state in the
      absence of replication inhibitors.

PMID- 10414517
TI  - Cyclosporin A reduces the inflammatory response to a multi-mutant herpes simplex
      virus type-1 leading to improved transgene expression in sympathetic
      preganglionic neurons in hamsters.
AB  - Herpes simplex virus type 1 (HSV-1) based vectors hold great promise for gene
      transfer to CNS neurons. Problems such as loss of transgene expression, vector
      associated cytotoxicity and the immune response to the vector or encoded
      transgene still remain obstacles to success. We used a replication-defective, HSV
      1 vector (14Hdelta3vhsZ) that was engineered to have reduced cytotoxicity and
      express recombinant beta-galactosidase. A previous study in our laboratory showed
      no evidence for cytotoxicity in infected neurons although an inflammatory
      infiltrate occurred around infected cells and transgene expression was lost
      between 5 and 8 days. The immune response consisted of a primary response at the
      site of inoculation (adrenal gland), and a secondary immune response in the
      spinal cord around infected adrenal sympathetic preganglionic neurons due to
      retrograde transport of the vector. We tested whether conventional
      immunosuppressants could reduce the secondary immune response, leading to
      improved transgene expression at the secondary CNS site. 14Hdelta3vhsZ was
      injected into the adrenal gland in hamsters 1 day after immunosuppressant
      treatment began. Non-drug treated, 14Hdelta3vhzZ-infected hamsters were used as
      controls. Cyclosporin A administration led to the most persistent beta
      galactosidase activity in neurons at 5 and 8 days. Methylprednisolone treatment
      resulted in the greatest reduction in the inflammatory cell infiltrate but the
      numbers of infected neurons did not increase concomitantly. This suggested no
      direct relationship between extent of the inflammatory cell infiltrate and level
      of transgene expression. These data demonstrate the potential of cyclosporin A as
      an immunosuppressant adjunct treatment for HSV-1 vector-mediated gene transfer
      from a peripheral site to neurons in the spinal cord.

PMID- 10414518
TI  - Differential effects on the survival of neuronal and non-neuronal cells after
      infection by herpes simplex virus type 1 mutants.
AB  - Replication-defective mutants of herpes simplex virus type 1 (HSV-1) are powerful
      tools to transfer genes into postmitotic neurons and show promise for gene
      therapy protocols in vivo. To evaluate the efficacy and safety of these vectors
      for the treatment of deafness we infected dissociated cochlear ganglia with HSV
      mutants defective in the immediate early genes IE 2 (5dl1.2) or IE 3 (d120). Our
      results reveal striking differences in the survival of neuronal and non-neuronal
      cells caused by these mutants. Surprisingly, cochlear neurons infected with
      5dl1.2 at various concentrations show a significant increase in survival after 2
      days in culture. In contrast, many non-neuronal cells undergo apoptosis reducing
      cell number to less than 50%. In both neuronal and non-neuronal cell types we
      also observe a population of cells with important changes in morphology. Analysis
      of dissociated cochlear ganglia infected with d120 reveals a decrease of neuronal
      survival, whereas non-neuronal cells were almost unaffected. To further
      characterize and compare the effects of 5dl1.2 and d120 we transduced central
      nervous system-derived cell types including cortical neurons and astrocytes.
      Similarly, as observed for cochlear neurons, infection with 5dl1.2 results in
      increased survival of cortical neurons, whereas d120 shows cytotoxic effects.
      Survival of astrocytes is equally reduced by both HSV deletion mutants. We
      conclude that HSV-1 mutants defective in immediate early genes cause very
      distinct cytopathic phenotypes depending on the cellular context. Possible
      reasons for these differences, like various patterns of cellular and viral gene
      expression, and the implications for the use of HSV-1 vectors for gene transfer
      are discussed.

PMID- 10414519
TI  - Suppression of PrP(Sc)- and HIV-1 gp120 induced neuronal cell death by sulfated
      colominic acid.
AB  - The scrapie prion protein (PrP(Sc)) has been shown to induce apoptosis of rat
      cortical neurons in vitro. Here we demonstrate that the toxic effect displayed by
      PrP(Sc) can be blocked by sulfated colominic acid (polymer of N-acetylneuraminic
      acid). This compound acts neuroprotectively at a concentration of > or = 0.3
      microg/ml when preincubated with the neurons or PrP(Sc). Rat cortical cells also
      undergo apoptosis after incubation with the HIV-1 coat protein gpl20 in vitro.
      This effect was abolished also by sulfated colominic acid when preincubated with
      the cells or gpl20. Addition of 0.3 microg/ml of compound resulted in an increase
      in cell viability by about 1.6-1.9-fold compared to cultures incubated for 18 h
      with 30 ng/ml of PrP(Sc) or 20 ng/ml of gpl20 alone (containing about 40% viable
      cells). Sulfated colominic acid does not act as antagonist of NMDA receptor
      channels at concentrations of up to 3 microg/ml when co-administered with 100
      microg/ml of NMDA. It displayed a strong cytoprotective effect on human T
      lymphoblastoid CEM cells exposed to HIV-1; a 50% protection occurred after
      preincubation of the cells with 0.43 microg/ml of compound. At the same
      concentration, the compound caused an inhibition of HIV-1-induced syncytium
      formation. Sulfated colominic acid may be a promising compound for treatment of
      dementia caused by PrP(Sc) and HIV-1 infections.

PMID- 10414520
TI  - Characterization of antibodies raised against bovine-PrP-peptides.
AB  - To analyze the antigenicity of peptides derived from bovine prion protein (PrP)
      cDNA, we immunized rabbits with four synthetic peptides and compared the
      immunoreactivity of antibodies to PrPs from various species by immunoblotting and
      immunohistochemistry. Two of the antibodies reacted strongly with all PrPs. The
      other antibodies, raised against overlapping peptides close to two glycosylation
      sites, did not recognize PrPSc-mouse but did recognize PrPSc-sheep which contains
      two sugar residues and PrPCJD with or without a sugar residue. Our results
      suggest that these antibodies may have species-specificity for both glycosylation
      status and amino acid sequences of the protein. In conclusion, we identified two
      regions in bovine-PrP which appear suitable for raising antibodies that detect
      various kinds of PrPs, and one region (Ab103-121) which appears suitable for
      raising antibodies that detect several species of PrPs. These antibodies may be
      useful for diagnosing prion diseases and for researching their pathogenesis.

PMID- 10414521
TI  - Differences in kinetics of human cytomegalovirus cell-free viral release after in
      vitro infection of human microglial cells, astrocytes and monocyte-derived
      macrophages.
AB  - Microglial cells and astrocytes isolated from human embryonic proencephalon were
      compared to monocyte-derived macrophages (MDM) for their ability to replicate
      human cytomegalovirus (HCMV) in vitro. A specific cytopathic effect was observed
      in microglial cells and astrocytes, but not in MDM. A high percentage of glial
      cells but a low percentage of MDM expressed immediate-early and late viral
      antigens. The ability of HCMV-infected microglial cells and astrocytes to release
      viral particles in their supernatants was significantly higher than that of
      infected MDM. Human microglial cells and astrocytes at an early stage of
      development are highly susceptible to HCMV infection.

PMID- 10414522
TI  - Chronic systemic administration of tumor necrosis factor alpha and HIV gp120:
      effects on adult rodent brain and blood-brain barrier.
AB  - Since tumor necrosis factor alpha (TNF-alpha) and HIV gpl20 glycoprotein are both
      neurotoxic, the possibility that systemic sources of these two agents mediate
      AIDS-associated blood-brain barrier (BBB) breakdown and brain damage was tested
      in two murine models: (1) intramuscular implantation of a TNF-alpha-transfected
      tumor in nu/nu mice and (2) daily subcutaneous injections of HIV gpl20 in BALB/c
      mice. The BBB remained intact; brain damage was not found, and apoptotic cell
      numbers did not increase. These results show that normal adult brain and BBB is
      unaffected by exposure to TNF-alpha or HIV gpl20 and suggest that severity of
      brain disease is not directly affected by systemic levels of these compounds.

PMID- 10414523
TI  - Detection and quasispecies analysis of hepatitis C virus in the cerebrospinal
      fluid of infected patients.
AB  - Hepatitis C virus (HCV) is a leading cause of liver damage and has also been
      implicated in extrahepatic pathologies. We examined for HCV RNA paired CSF and
      plasma samples from 12 viremia positive patients using PCR. The CSF from 5/5 HIV
      infected patients and 5/7 HIV-negative patients were HCV RNA positive. Branched
      DNA analysis showed that HCV loads in CSF were much lower than in plasma. Several
      HCV-positive CSF showed no evidence of blood contamination, impaired blood-brain
      barrier, or intrathecal IgG production. Comparison of HCV quasispecies in three
      sets of samples suggested that the virus in CSF was of plasma origin.

PMID- 10414524
TI  - Origin of nine base pair duplication in the 3' terminus of the SV40 T-Ag gene.

PMID- 10414525
TI  - Transient effects of nerve injury on estimates of sensory neuron number in
      juvenile bullfrog.
AB  - The effect of lumbar spinal nerve (SN) transection on estimates of neuron number
      was investigated in the dorsal root ganglia (DRGs) of juvenile bullfrogs (Rana
      catesbeiana). SN8 and SN10 were transected on one side, and SN9 was left intact.
      Two weeks after nerve injury, estimates of neuron number in DRG8 and DRG10 on
      both the operated and unoperated sides were more than twice the estimates
      obtained from control animals. Neuron number in the uninjured DRG9 was also
      elevated relative to that of control animals. Eight weeks after axotomy,
      differences in neuron number were less apparent. The mean cross-sectional area of
      DRG neurons was reduced 2 weeks after nerve injury in all DRGs. The decrease in
      mean area was the result of the addition of neurons to the smallest size classes.
      These data are discussed in the context of previous results showing that neurons
      are added as juvenile frogs grow to adult size (St. Wecker and Farel [1994] J.
      Comp. Neurol. 342:430-438). This addition results from the maturation of a
      population of incompletely differentiated neurons (Meeker and Farel [1997] J.
      Comp. Neurol. 389:569-576). The present results suggest that axotomy precipitates
      differentiation of these incompletely differentiated neurons, perhaps as a
      compensatory response to nerve injury.

PMID- 10414526
TI  - Organization of cortical projections to the medullary subnucleus reticularis
      dorsalis: a retrograde and anterograde tracing study in the rat.
AB  - The distribution and organization of cortical projections to the subnucleus
      reticularis dorsalis (SRD), the neighboring cuneate nucleus (Cu), and trigeminal
      nucleus caudalis (Sp5C) were studied in the rat using microinjections of wheat
      germ agglutinin-apo horseradish peroxidase-gold and Biotin-Dextran. Cortical
      cells projecting to the caudal medulla were confined to the contralateral layer V
      with their descending axons crossing the midline at the level of pyramidal
      decussation. Cortical afferents to Sp5C originated from cells located mainly in
      the primary somatosensory cortex (S1) and the insular cortex, whereas cortical
      projections to the Cu originated mainly from the primary motor cortex (M1), the
      primary and secondary somatosensory cortex (S1 and S2). The SRD received dense
      cortical afferents from larger, widespread cortical areas: M1, M2, S1, S2, and
      the insular cortex. The existence of dense cortico-SRD connections supports the
      possibility of a pyramidal influence over SRD neurons, which might modify
      nociceptive information ascending to the cortex itself. This proposal is
      consistent with the fact that SRD efferents terminate densely in thalamic areas
      that influence sensorimotor cortical regions which in turn project to the SRD.
      Moreover, these corticofugal mechanisms could allow the cortex to select its own
      input by suppressing or augmenting transmission of signals through SRD
      hindbrain/forebrain pathways or by coordinating activities in spino-SRD-spinal
      circuits and thus selecting the relevant information produced by the noxious
      stimulus.

PMID- 10414527
TI  - Cholinergic axon terminals in the ventral tegmental area target a subpopulation
      of neurons expressing low levels of the dopamine transporter.
AB  - Cholinergic activation of dopaminergic neurons in the ventral tegmental area
      (VTA) is thought to play a major role in cognitive functions and reward. These
      dopaminergic neurons differentially project to cortical and limbic forebrain
      regions, where their terminals differ in levels of expression of the plasmalemmal
      dopamine transporter (DAT). This transporter selectively identifies dopaminergic
      neurons, whereas the vesicular acetylcholine transporter (VAchT) is present only
      in the neurons that store and release acetylcholine. We examined immunogold
      labeling for DAT and immunoperoxidase localization of VAchT antipeptide antisera
      in single sections of the rat VTA to determine whether dopaminergic somata and
      dendrites in this region differ in their levels of expression of DAT and/or input
      from cholinergic terminals. VAchT immunoreactivity was prominently localized to
      membranes of small synaptic vesicles in unmyelinated axons and axon terminals.
      VAchT-immunoreactive terminals formed almost exclusively asymmetric synapses with
      dendrites. Of 159 dendrites that were identified as cholinergic targets, 35%
      contained plasmalemmal DAT, and 65% were without detectable DAT immunoreactivity.
      The DAT-immunoreactive dendrites postsynaptic to VAchT-labeled terminals
      contained less than half the density of gold particles as seen in other dendrites
      receiving input only from unlabeled terminals. These results suggest selective
      targeting of cholinergic afferents in the VTA to non-dopaminergic neurons and a
      subpopulation of dopaminergic neurons that have a limited capacity for
      plasmalemmal reuptake of dopamine, a characteristic of those that project to the
      frontal cortex.

PMID- 10414528
TI  - Comparing thalamocortical and corticothalamic microstructure and spatial
      reciprocity in the macaque ventral posterolateral nucleus (VPLc) and medial
      pulvinar.
AB  - The detailed morphology of thalamocortical (TC) and corticothalamic (CT) pathways
      connecting the ventral posterolateral nucleus (VPLc) with the primary
      somatosensory cortex (areas 3b and 1) and the thalamic pulvinar with the
      posterior parietal cortex (primarily area 7a), was compared. Each pathway
      processes information relevant to directed reaching tasks, but whereas VPLc
      receives its major input from the spinal cord and external environment, the
      primary afferent to the pulvinar is cortical. Using combined tracer and thick
      fixed slice procedures, the soma/dendritic morphology of TC neuron populations
      (with known destination) was shown to be quantitatively similar within VPLc and
      the pulvinar. This implies that differences in information processing in VPLc (a
      primary relay) and the pulvinar (an integrative thalamic nucleus) are not defined
      by a distinctive TC morphology, but rather by the connections of these neuron
      populations. Two morphologically distinct types of CT axon were observed within
      the medial pulvinar and VPLc. The more common "Type E" were fine, had boutons en
      passant and diffuse terminal bifurcations ending in masses of tiny boutons. "Type
      R" axons were thicker, smooth, and terminated in localised clusters of large
      terminal boutons. Each type had a unique pattern of termination reflecting a
      distinct action on target neuron populations. The spatial relationship between TC
      distribution territories and CT terminal fields was examined within the medial
      pulvinar and VPLc by using anterograde and retrograde tracers injected together
      within cortical areas 7a, and 3b/1, respectively. Spatial overlap was incomplete
      within both thalamic nuclei. Our findings show a more complex relationship
      between TC and CT neuron populations than previously demonstrated.

PMID- 10414529
TI  - Hemispheric differences in variability of fissural patterns in parasylvian and
      cingulate regions of human brains.
AB  - We have determined different patterns of fissurization in Broca's area, the gyrus
      of Heschl, the planum temporale, the inferior parietal lobe, and the cingulate
      sulcus. Such patterns were asymmetrically distributed, indicating increased
      folding on the left side in most cases. More folding can sometimes be related to
      a larger cortical area, resulting in increased processing capacities in the
      respective brain region. Furthermore, the brain regions associated with the
      asymmetrical sulci are involved in lateralized functions. Of special interest are
      the asymmetries observed in regions corresponding to the inferior parietal lobe
      (the accessory postcentral sulcus and the intraparietal sulcus), which, according
      to recent studies, is involved in linguistic working memory. We did not detect a
      tendency of distinct fissurization patterns in a given brain region to be
      associated with specific patterns in other fissures, indicating that the
      different fissure types develop independently in each brain region and can
      therefore be determined by local processes. These descriptions are of relevance
      to imaging studies that intend to establish correspondences between gross
      morphology and functional parameters such as behavior and brain activation.

PMID- 10414530
TI  - Metabotropic glutamate receptor 2/3 immunoreactivity in the developing rat
      cerebellar cortex.
AB  - In adult rat cerebellar cortex, the metabotropic glutamate receptors (mGluRs) 2
      and 3 (mGluR2/3) are present in somata, dendrites, and terminals of Golgi cells
      as well as in presumed glial processes (Ohishi et al. [1994], Neuron 13:55-66).
      In the present study, spatiotemporal changes in immunostaining for mGluR2/3 were
      examined in postnatal rat cerebellar cortex. mGluR2/3-immunoreactive Golgi cell
      somata appeared first in the internal granular layer at postnatal day 3 (P3) and
      were restricted to lobules IX and X; however, by P5, they were present in all
      lobules. Immunoreactive Golgi cell axons were adult-like, appearing as tortuous
      fibers with clusters of varicosities. They were observed first in the internal
      granular layer at P7 and increased in number and complexity with time. It was
      confirmed that mGluR2/3-immunoreactive Golgi cell axon terminals belong to the
      synaptic glomerulus by P10. Immunoreactive Golgi cell dendrites extending into
      the molecular layer became prominent after P15. By that time, the immunostaining
      pattern was characteristic of Golgi cells, as seen typically in adults. Many
      intensely immunoreactive radial processes existed at birth (P0). These traversed
      the molecular and external granular layers, reaching the pial surface in every
      cerebellar lobule. Because they showed coimmunoreactivity for glial fibrillary
      acidic protein, they were confirmed to be Bergmann glial fibers. After P9, they
      began to lose immunoreactivity at the portion corresponding to the molecular
      layer, while an immunostained granular pattern appeared in that layer.
      Immunoreactive radial processes, however, remained in the external granular
      layer, and finally, at P21, they disappeared together along with the external
      granular layer. Granular staining in the molecular layer reached background
      levels at this time. These spatiotemporal changes in mGluR2/3 distribution
      suggested that there may be distinct roles for mGluR2/3 in Golgi cells and
      Bergmann glial cells during the early postnatal period. mGluR2/3 in Golgi cells
      might be associated closely with systemic maturation, whereas mGluR2/3 in
      Bergmann glia might be needed for neuron-glia interactions related to granule
      cell development.

PMID- 10414531
TI  - Immunohistochemical evidence for the brevican-tenascin-R interaction:
      colocalization in perineuronal nets suggests a physiological role for the
      interaction in the adult rat brain.
AB  - Brevican is one of the most abundant chondroitin sulfate proteoglycans in the
      adult rat brain. We have recently shown that the C-type lectin domain of brevican
      binds fibronectin type III domains 3-5 of tenascin-R. Here we report strong
      evidence for a physiological basis for this interaction. Substantial brevican
      immunoreactivity was detected in a number of nuclei and in the reticular
      formations throughout the midbrain and hindbrain, including, but not limited to,
      the deep cerebellar nuclei, the trapezoid body, the red nucleus, the oculomotor
      nucleus, the vestibular nucleus, the cochlear nucleus, the gigantocellular
      reticular nucleus, the motor trigeminal nucleus, and the lateral superior olive.
      Most of the brevican immunoreactivity exhibited pericellular and reticular
      staining patterns. In almost all of these sites, brevican immunoreactivity
      colocalized with that of tenascin-R, which was also substantially codistributed
      with versican, another member of the lectican family. Detailed analysis revealed
      that the pericellular staining of brevican resembled that in perineuronal nets in
      which tenascin-R has been localized. Immunoelectron microscopy identified
      brevican immunoreactivity in the intercellular spaces surrounding presynaptic
      boutons and on their surfaces, but not in the synaptic clefts or in their
      immediate vicinity, a distribution pattern consistent with perineuronal nets.
      Taken together, our results provide strong evidence that the previously reported
      interactions between brevican and tenascin-R may play a functional role within
      the perineuronal nets.

PMID- 10414532
TI  - Input-output relationships of the dorsal nucleus of the lateral lemniscus:
      possible substrate for the processing of dynamic spatial cues.
AB  - One organizing principle of the auditory system is the progressive representation
      of best tuning frequency. Superimposed on this tonotopy are nucleotopic
      organizations, some of which are related to the processing of different spatial
      cues. In the present study, we correlated asymmetries in the outputs of the
      dorsal nucleus of the lateral lemniscus (DNLL) to the two inferior colliculi
      (ICs), with asymmetries in the inputs to DNLL from the two lateral superior
      olives (LSOs). The positions of DNLL neurons with crossed and uncrossed
      projections were plotted from cases with unilateral injections of retrograde
      tracers in the IC. We found an orderly dorsal-to-ventral progression to the
      output that recapitulated the tonotopy of DNLL. In addition, we found a
      nucleotopic organization in the ventral (high-frequency) part of DNLL. Neurons
      with projections to the ventromedial (high-frequency) part of the contralateral
      IC were preferentially located ventrolaterally in DNLL; those with projections to
      the ventromedial part of the ipsilateral IC were preferentially located
      ventromedially in DNLL. This partial segregation of outputs corresponded with a
      partial segregation of inputs from the two LSOs in cases which received closely
      matched bilateral injections of anterograde tracers in LSO. The ventral part of
      DNLL received a heavy projection medially from the opposite LSO and a heavy
      projection laterally from the ipsilateral LSO. The findings suggest a direct
      relationship in the ventral part of the DNLL between inputs from the two LSOs and
      outputs to the two ICs. Possible roles for this segregation of pathways in DNLL
      are discussed in relation to the processing of static and dynamic spatial cues.

PMID- 10414533
TI  - Distribution of glutamic acid decarboxylase mRNA in the forebrain of the rainbow
      trout as studied by in situ hybridization.
AB  - By using degenerate primers designed from glutamate decarboxylase (GAD) sequences
      of mammals, Xenopus and Drosophila, a 270-bp cDNA fragment was cloned by reverse
      transcriptase-polymerase chain reaction (RT-PCR) from cerebellum total RNA of
      rainbow trout. This partial cDNA shows 90% identity with mammalian GAD 65 and
      presents the Asn-Pro-His-Lys (NPHK) sequence corresponding to the pyridoxal
      binding region of porcine DOPA decarboxylase or mammalian GAD. The distribution
      of GAD 65 mRNA-expressing neurons in the forebrain of the trout was studied by in
      situ hybridization using either digoxigenin- or 35S-labeled probes. The results
      demonstrate that gamma-amino butyric acid (GABA) neurons are widely distributed
      throughout the forebrain, with a high density in the periventricular regions. In
      this study, we report their precise distribution in the telencephalon and
      diencephalon. GAD mRNA-expressing cells were particularly abundant in the
      preoptic region and the mediobasal hypothalamus, two major neuroendocrine and
      estrogen-sensitive regions in fish. The presence of GAD mRNA-expressing neurons
      was observed in visually related structures such as the suprachiasmatic nucleus,
      the pretectal region, and the thalamus. Immunohistochemistry with antibodies
      directed against mouse GAD failed to demonstrate the presence of immunoreactive
      cell bodies, but showed a very high concentration of GAD-immunoreactive fibers in
      many brain regions, notably in the preoptic area, hypothalamus, and
      neurohypophyseal digitations of the pituitary, in particular in the proximal pars
      distalis. These results indicate that GABA neurons are ideally placed to modulate
      neuroendocrine activities at the hypothalamic and pituitary levels and to
      participate in the processing of sensorial information.

PMID- 10414534
TI  - Spatial correspondence between R-cadherin expression domains and retinal ganglion
      cell axons in developing zebrafish.
AB  - Mechanisms underlying axonal pathfinding have been investigated for decades, and
      numerous molecules have been shown to play roles in this process, including
      members of the cadherin family of cell adhesion molecules. We showed in the
      companion paper that a member of the cadherin family (zebrafish R-cadherin) is
      expressed in retinal ganglion cells, and in presumptive visual structures in
      zebrafish brain, during periods when the axons were actively extending toward
      their targets. The present study extends the earlier work by using 1,1'
      dioctadecyl-3,3,3',3', tetramethylindocarbocyanine perchlorate (DiI) anterograde
      tracing techniques to label retinal ganglion cell axons combined with R-cadherin
      in situ hybridization to explicitly examine the association ofretinal axons and
      brain regions expressing R-cadherin message. We found that in zebrafish embryos
      at 46-54 hours postfertilization, DiI-labeled retinal axons were closely
      associated with cells expressing R-cadherin message in the hypothalamus, the
      pretectum, and the anterolateral optic tectum. These results demonstrate that R
      cadherin is appropriately distributed to play a role in regulating development of
      the zebrafish visual system, and in particular, pathfinding and synaptogenesis of
      retinal ganglion cell axons.

PMID- 10414535
TI  - R-cadherin expression in the developing and adult zebrafish visual system.
AB  - Cell adhesion molecules in the cadherin family have been implicated in
      histogenesis and maintenance of cellular structure and function in several
      organs. Zebrafish have emerged as an important new developmental model, but only
      three zebrafish cadherin molecules have been identified to date (N-cadherin,
      paraxial protocadherin, and VN-cadherin). We began a systematic study to identify
      other zebrafish cadherins by screening zebrafish cDNA libraries using an antibody
      raised to the cytoplasmic domain of mouse E-cadherin. Here, we report a partial
      cDNA with extensive sequence homology to R-cadherin. Spatial and temporal
      expression of this putative zebrafish R-cadherin was examined in embryos and
      adults by Northern analysis, RNase protection, and in situ hybridization. R
      cadherin message increased during embryogenesis up to 80 hours postfertilization
      (hpf) and persisted in adults. In the embryonic brain, R-cadherin was first
      expressed in groups of cells in the diencephalon and pretectum. In adult
      zebrafish brain, R-cadherin continued to be expressed in several specific regions
      including primary visual targets. In the retina, R-cadherin was first detected at
      about 33 hours postfertilization in the retinal ganglion cell layer and the inner
      part of the inner nuclear layer. Expression levels were highest during periods of
      axon outgrowth and synaptogenesis. Retrograde labeling of the optic nerve with
      1,1'-dioctadecyl-3,3,3',3', tetramethylindocarbocyanine perchlorate (DiI)
      followed by in situ hybridization confirmed that a subset of retinal ganglion
      cells in the embryo expressed R-cadherin message. In the adult, R-cadherin
      expression continued in a subpopulation of retinal ganglion cells. These results
      suggest that R-cadherin-mediated adhesion plays a role in development and
      maintenance of neuronal connections in zebrafish visual system.

PMID- 10414536
TI  - Projections of the dorsal motor nucleus of the vagus to cardiac ganglia of rat
      atria: an anterograde tracing study.
AB  - We injected the anterograde fluorescent tracer 1,1'-dioleyl-3,3,3',3'
      tetramethylindocarbocyanine methanesulfonate (DiI) into the dorsal motor nucleus
      of the vagus (DmnX), counterstained the cardiac ganglia with Fluorogold (FG), and
      used confocal microscopy to examine the distributions and different types of DmnX
      fibers in wholemounts of the atria. We also quantified the number of DmnX cardiac
      axons and the number of innervated cardiac principal neurons (PNs). Rats with
      unilateral DiI injections were used in three different experiments, including
      unilateral FG soaking of cervical vagal trunks, intracranially rhizotomizing the
      vagal afferent roots, or contralaterally sectioning the cervical vagus. These
      manipulations indicated that DiI-labeled cardiac fibers were exclusively from the
      DmnX. Our observations established that: (1) three major ganglionic plexuses were
      localized in the epicardium; (2) both sides of the DmnX supplied significant
      fibers to each of the plexuses; (3) these cardiac efferents formed dense basket
      terminals around individual PNs; (4) collaterals of individual DmnX fibers
      diverged, producing calyx endings on multiple PNs; (5) small intensely
      fluorescent (SIF) cells in the cardiac plexuses were innervated pericellularly;
      (6) individual axons could innervate both PNs and SIF cells; (7) the total number
      of DmnX fibers were in the range of [68, 96; left] and [67, 115; right]; (8)
      these fibers innervated 709 (left) and 494 (right), or at least 18% and 12%, of
      the PNs, respectively; and (9) vagal preganglionics exhibited a degree of
      lateralization: Significantly more PNs were contacted by fiber varicosities in
      the sinoatrial plexus than in the atrioventricular plexus after right DmnX
      injections. In summary, the present observations suggest that the DmnX plays a
      significant role(s) in controlling the heart.

PMID- 10414537
TI  - Mini-laparoscopic cholecystectomy: validating a new approach.
AB  - Advances in instrumentation have led to the development of 2-mm laparoscopic
      equipment. The purpose of our investigation was to validate the safety and
      efficacy of laparoscopic cholecystectomy (LC) using one 10-mm and three 2-mm
      ports (mini-LC). Mini-LC was performed using a 2-mm fiberoptic videolaparoscope
      inserted via a midepigastric port, 2-mm graspers inserted via right upper
      quadrant ports, and standard dissection, clipping, and cautery instruments
      inserted via the umbilical port. Data from 100 sequential patients were acquired
      between July 1996 and August 1997 and compared with those of 100 sequential
      patients who had undergone conventional LC (C-LC). The operative time ranged from
      30 to 256 minutes for the mini-LC group and 25 to 255 minutes for the C-LC group,
      with means of 89 and 82 minutes, respectively (P > 0.05). Postoperative length of
      stay ranged from 0 to 18 days for the mini-LC group and 0 to 21 days for the C-LC
      group, with means of 1.5 and 1.9 days, respectively (P > 0.05). There were no
      conversions to open cholecystectomy. These data suggest that a more minimalist
      approach to laparoscopic cholecystectomy can be accomplished safely and
      effectively.

PMID- 10414538
TI  - Surgical treatment of complete rectal prolapse: results of abdominal and perineal
      approaches.
AB  - This retrospective study reports the results of our 5-year experience in the
      diagnosis and treatment of rectal prolapse with fecal incontinence by the
      abdominal (laparotomy or laparoscopy) and perineal approaches. Twenty-five
      patients (group A; 22 women and 3 men; mean age 57.3 years; range 22-76 years)
      were operated on by the abdominal approach and ten (group B; 8 women and 2 men;
      mean age 68.9 years; range 58-84 years) by the perineal approach. All patients
      were evaluated by clinical examination, proctosigmoidoscopy, pancolonic transit
      time, dynamic defecography, anorectal manometry, and anal electromyography
      preparatory to surgery. In patients of group A, we performed an abdominal
      rectopexy in 19 cases (7 by laparoscopy) and in the remaining 6 cases, a sigmoid
      resection-rectopexy (3 of which were by laparoscopy). All patients of group B
      were treated by a perineal operation using Delorme's mucosectomy in 4 cases and
      Altemeier's rectosigmoidectomy with total perineoplasty in 6 cases. The mean
      follow-up was 38.8 months in group A and 25.7 months in group B. The
      postoperative complication rate was 8% (two cases) in group A, whereas no
      significant complications occurred in group B. Dyschezia and fecal incontinence
      improved significantly in both groups (P < 0.05 in group A and P < 0.005 in group
      B), whereas anoperineal pain was not significantly reduced. At 1-year follow-up,
      the recurrences rates were 8% in group A and 30% in group B. Rectopexy or
      resection-rectopexy proved to be a safe and effective procedure for external
      prolapse, without a discernible difference between the laparotomic and
      laparoscopic techniques. In selected cases, the perineal approach gives good
      results regarding fecal incontinence without complications, even if in these
      patients, the likelihood of recurrence is high.

PMID- 10414539
TI  - Routine laparoscopy for nonpalpable testes?
AB  - There are still no accepted criteria for the selection of patients with
      nonpalpable testes for laparoscopy versus a primary surgical exploration. We here
      report our experience using routine laparoscopy in such patients. The aim was to
      determine whether laparoscopy should be the first operative intervention or
      follow an inguinal exploration. Included in the study were 61 boys with 69
      nonpalpable testes. Thirty-three testes were found in the abdomen, and 36 testes
      were extra-abdominal or nonexistent. If an exploration of the inguinal region had
      been the initial surgical intervention, six testes would have been found, making
      laparoscopy unnecessary. On the other hand, in the search for 63 missing testes,
      laparoscopy saved the patients from laparotomy or an extensive inguinal
      exploration. We conclude that an accurate knowledge of testis, vas, and vessel
      location gained by laparoscopy facilitates the selection of an appropriate
      surgical strategy, saving at least 51% of patients from laparotomy or an
      extensive inguinal exploration.

PMID- 10414540
TI  - Factors contributing to laparoscopic failure during the learning curve for
      laparoscopic Nissen fundoplication in a community hospital.
AB  - This study was done to determine the factors contributing to laparoscopic failure
      (conversion to open surgery or early reoperation) during the learning curve for
      laparoscopic Nissen fundoplication in a 228-bed nonteaching community hospital.
      Data were gathered prospectively for the first 100 consecutive patients booked
      for elective laparoscopic Nissen fundoplication by the four general surgeons at
      the hospital. All complications were recorded contemporaneously, and particular
      note was taken of the factors surrounding conversion to open surgery and
      reoperation within 100 days of surgery. There were no deaths. The conversion rate
      was 20% and the early reoperation rate 6%. There were two late recurrences. The
      average operative time was 117 minutes and the average length of stay 1.8 days;
      37 operations were performed on outpatients. The laparoscopic failure rate was
      26% (18/68) during a surgeon's first 20 operations and 11% (3/28) thereafter (P <
      0.09); the corresponding conversion rates were 22% and 4% (P < 0.05). During a
      surgeon's first 20 operations, the laparoscopic failure rate rose from 21%
      (12/57) to 55% (6/11) (P < 0.04) if a second surgeon did not assist. After 20
      operations, this difference lost its significance. Intrathoracic herniation of
      the stomach was found preoperatively in 11 (44%) of 25 operations followed by
      laparoscopic failure and (8%) 6 of 75 without (P < 0.0002). Laparoscopic failure
      had no correlation with patient age, sex, ASA classification, duration of
      symptoms, or referring physician's specialty. The individual learning curve for
      laparoscopic Nissen fundoplication requires about 20 operations to surmount.
      Factors leading to laparoscopic failure during the learning curve are the
      surgeon's inexperience, absence of experienced help, and the presence of
      intrathoracic herniation.

PMID- 10414541
TI  - Five-year follow-up of laparoscopic bladder neck suspension using synthetic mesh
      and surgical staples.
AB  - We report long-term follow-up of 40 patients who underwent a laparoscopic
      adaptation of the Burch procedure between May 1990 and December 1992. This
      procedure, in which synthetic mesh and surgical staples are used in place of
      sutures to effect the suspension, was previously described by the principal
      author and colleagues for use in the treatment of genuine stress urinary
      incontinence (J Laparoendosc Surg 1993;3:563-566). Minimum 5-year follow-up has
      been obtained for 34 of these patients either by office visit with the principal
      author (27 patients) or by telephone interview with the patient or the patient's
      primary-care physician (7 patients). Six patients were lost to follow-up, four
      after 1 year and two more after 3 years. None of these patients was leaking at
      last follow-up. This operation initially succeeded in resolving incontinence in
      37 of 40 patients (93%). Of the three patients in whom the surgery failed
      initially, none chose further surgery, and all three were still leaking after 5
      years of follow-up. One additional patient developed urgency incontinence 3 years
      postoperatively. The five-year success rate, defined as no recurrent leaking, was
      88% (30 of 34 confirmed outcomes). This modification of the Burch procedure
      offers the advantages of the laparoscopic approach and affords an inherently
      shorter learning curve than that associated with laparoscopic suturing in the
      confined pelvic space.

PMID- 10414542
TI  - The EndoHand: comparison with standard laparoscopic instrumentation.
AB  - Laparoscopic instrumentation is constantly being refined in an attempt to achieve
      the proficiency, flexibility, and tactile feedback that would be available if the
      human hand were small enough to be used in laparoscopic surgery. The EndoHand
      (DAUM GmbH, Schwerin, Germany) is a novel laparoscopic three-fingered hand
      developed as an advancement over standard laparoscopic tools. Grasping and
      manipulation ability, dexterity, and tactile feedback were compared with those of
      current laparoscopic instrumentation. Experiments included measurement of
      achievable angles of approach to a fixed point behind a 2-cm-tall obstruction,
      completion time and error rates during a pelvic trainer dexterity task, and
      tactile feedback using a device invented to simulate tissue resistance.
      Subjectively, the EndoHand was able to pick up a range of objects similar to
      those graspable by a Babcock clamp. More complex types of manipulation were
      possible with the EndoHand because of its wrist joint. The range of approach
      angles to the fixed point was 35 degrees to 90 degrees with the EndoHand and 70
      degrees to 90 degrees with the straight instruments. The dexterity of the
      EndoHand was significantly less than that of the other two instruments, as
      measured by time (P = 0.0002) and errors (P = 0.02). Standard instruments were
      also more accurate in the tactile feedback trials (P = 0.02). The EndoHand is a
      prototype of a unique new generation of laparoscopic instruments. Although it
      falls short in both dexterity and tactile feedback, significant promise is shown
      in its ability to perform sophisticated manipulation of objects and its
      flexibility to work at a larger range of angles to the target tissue. The
      EndoHand may be most useful on the nondominant hand of the surgeon to assist with
      positioning and holding tissue in a specific orientation. Clinical trials will
      determine its eventual role in laparoscopic surgery.

PMID- 10414543
TI  - Accurate guidance for percutaneous access to a specific target in soft tissues:
      preclinical study of computer-assisted pericardiocentesis.
AB  - In the field of percutaneous access to soft tissues, our project was to improve
      classical pericardiocentesis by performing accurate guidance to a selected
      target, according to a model of the pericardial effusion acquired through three
      dimensional (3D) data recording. Required hardware is an echocardiographic device
      and a needle, both linked to a 3D localizer, and a computer. After acquiring
      echographic data, a modeling procedure allows definition of the optimal puncture
      strategy, taking into consideration the mobility of the heart, by determining a
      stable region, whatever the period of the cardiac cycle. A passive guidance
      system is then used to reach the planned target accurately, generally a site in
      the middle of the stable region. After validation on a dynamic phantom and a
      feasibility study in dogs, an accuracy and reliability analysis protocol was
      realized on pigs with experimental pericardial effusion. Ten consecutive
      successful punctures using various trajectories were performed on eight pigs.
      Nonbloody liquid was collected from pericardial effusions in the stable region (5
      to 9 mm wide) within 10 to 15 minutes from echographic acquisition to drainage.
      Accuracy of at least 2.5 mm was demonstrated. This study demonstrates the
      feasibility of computer-assisted pericardiocentesis. Beyond the simple
      improvement of the current technique, this method could be a new way to reach the
      heart or a new tool for percutaneous access and image-guided puncture of soft
      tissues. Further investigation will be necessary before routine human
      application.

PMID- 10414544
TI  - Transversalis fascia: historical aspects and its place in contemporary inguinal
      herniorrhaphy.
AB  - Since the introduction of the term "fascia transversalis" by Sir Ashley Cooper in
      1840, this thin layer of tissue has been discovered, denied, and redefined. The
      transversalis fascia was originally described as a bilaminar membrane. Although
      most subsequent descriptions do not reflect this analysis, some authors,
      especially in the surgical literature, believe that a posterior lamina of the
      transversalis fascia exists. Others believe that the posterior lamina of the
      transversalis fascia is, in fact, part of the preperitoneal fascia. The
      usefulness of the transversalis fascia and its derivatives or analogues; e.g.,
      the crura of the deep inguinal ring, have also been extensively discussed. The
      aim of this paper is to provide a brief survey of the historical literature
      concerning the transversalis fascia and a discussion of some of the contemporary
      views on its morphology and significance in current laparoscopic hernia repair.

PMID- 10414545
TI  - Management of chylothorax after thoracoscopic splanchnicectomy.
AB  - Thoracoscopic splanchnicectomy is a minimally invasive procedure used in the
      treatment of recalcitrant abdominal pain in patients with chronic pancreatitis or
      pancreatic carcinoma. Chylothorax, an uncommon complication of thoracoscopic
      splanchnicectomy, may lead to a protracted, costly hospital course of treatment
      usually consisting of central venous hyperalimentation, restricted oral intake,
      and tube thoracostomy. In our series of 25 patients who underwent thoracoscopic
      splanchnicectomy, 2 developed postoperative chylothorax. Both patients failed
      conservative management and ultimately underwent operative reintervention, at
      which time, leaking lymphatics were easily identified and closed using minimally
      invasive techniques. On the basis of this experience, we advocate early
      thoracoscopic reintervention in patients with chylothorax after thoracoscopic
      splanchnicectomy.

PMID- 10414546
TI  - Paroxysmal tachycardia and hypertension with or without ventricular fibrillation
      during laparoscopic adrenalectomy: two case reports in patients with
      noncatecholamine-secreting adrenocortical adenomas.
AB  - We present two cases of sudden unanticipated cardiovascular complications in
      patients with noncatecholamine-secreting adrenocortical adenomas during
      laparoscopic adrenalectomy. In the first case, the patient developed paroxysmal
      tachycardia and hypertension followed by ventricular fibrillation shortly after
      clipping of the adrenal vein. In the second case, the patient suffered
      hypertension and bigeminy during manipulation of the adrenal gland just around
      the adrenal vein. Awareness of such complications during either conventional or
      laparoscopic adrenalectomy is important even if the operation is performed in a
      patient with an apparently noncatecholamine-secreting adrenocortical adenoma.

PMID- 10414547
TI  - Port-site metastasis after laparoscopic cholecystectomy for benign disease.
AB  - We describe the case history of a patient presenting with a port-site metastasis
      from an occult pancreatic malignancy after laparoscopy for benign gallbladder
      disease. While port-site recurrence is well recognized after laparoscopy for
      malignant disease, its presentation after laparoscopy for benign disease is rare,
      this being only the third such case to be reported in the literature. It
      emphasizes that all pathology localizing to port sites after surgery should be
      investigated, as it may represent the earliest sign of a hitherto occult intra
      abdominal malignancy.

PMID- 10414548
TI  - Tack entrapment of the ilioinguinal nerve during laparoscopic hernia repair.
AB  - Nerve injury has a reported incidence of 2% during laparoscopic hernia repair.
      These injuries usually involve the femoral branch of the genitofemoral nerve and
      the lateral cutaneous nerve of the thigh. Recently, in an effort to decrease the
      size of the port sites, surgeons have been using 5-mm tacking devices. These
      devices penetrate tissue more deeply and in so doing may injure nerves not
      classically at risk, such as the ilioinguinal and the iliohypogastric. We report
      the first documented injury to the ilioinguinal nerve during laparoscopic hernia
      repair. In addition, we review the anatomy and technique in an effort to help
      avoid this complication in the future.

PMID- 10414549
TI  - Laparoscopic cholecystectomy in penetrating trauma.
AB  - Laparoscopy in trauma is useful in diagnosing but limited in treatment. We report
      the case of a patient with a stab wound in the right upper quadrant and
      gallbladder perforation who underwent diagnostic and laparoscopic treatment. The
      therapeutic opportunities in abdominal trauma are scant for laparoscopic surgery;
      the isolated gallbladder injury is one of them, it being possible to apply the
      usefulness of this less invasive technique in this case.

PMID- 10414550
TI  - Insulinoma diagnosed by endoscopic ultrasonography-guided biopsy.
AB  - Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) is a new
      technique that seems to expand the utility of EUS, making definitive diagnosis of
      pancreatic lesions possible. However, the exact indications for the method, as
      well as its limitations, are not fully defined. We report on a patient with an
      insulinoma in the tail of the pancreas undetected by other imaging modalities
      that was conclusively diagnosed by EUS-FNA. Endoscopic ultrasonography is a
      unique imaging modality for localization of small pancreatic lesions. In
      combination with FNA, it represents a significant improvement for the exact
      diagnosis of these tumors.

PMID- 10414551
TI  - Laparoscopic management of pseudomyxoma peritonei secondary to adenocarcinoma of
      the appendix.
AB  - Pseudomyxoma peritonei is a rare disease in which the abdominal cavity fills with
      thick mucoid material secondary to either benign or malignant conditions. We
      discuss a case where pseudomyxoma peritonei secondary to adenocarcinoma of the
      appendix was diagnosed and managed laparoscopically. The laparoscopic approach
      allows thorough exploration of the abdomen, as well as irrigation and aspiration
      of the thick mucinous material using a 10-mm suction cannula and the instillation
      of mucolytic agents such as 5% dextrose solution. Appendectomy or right
      hemicolectomy can be performed with minimal disturbance of the anterior abdominal
      wall, thus minimizing future adhesions as well as possible tumor-cell
      implantation. Intraperitoneal catheters for chemotherapy can be placed easily
      through the port sites. These measures offer an alternative to radical peritoneal
      dissection and can be accomplished during the initial laparoscopic exploration.

PMID- 10414552
TI  - Impact of laparoscopy with carbon dioxide versus helium on local and systemic
      inflammation in an animal model of peritonitis.
AB  - Increased intraperitoneal pressure and insufflation of carbon dioxide during
      laparoscopy may cause sepsis by promoting systemic inflammation in patients with
      intra-abdominal inflammatory diseases. The influence of carbon dioxide and helium
      during laparoscopy on bacteremia, endotoxemia, the plasma concentration of tumor
      necrosis factor-alpha (TNF-alpha), TNF-alpha secretion ex vivo by peripheral
      blood mononuclear cells (PBMCs), and intraperitoneal abscess formation was
      investigated in an animal model. A standardized fecal inoculum was injected
      intraperitoneally, and rats underwent laparoscopy with either carbon dioxide (N =
      20) or helium (N = 20) or no further manipulation (control group; N = 20).
      Bacteremia was significantly more common 1 hour after laparoscopy with CO2 than
      in animals receiving helium or the control group. Furthermore, helium use led to
      a significant decrease of bacteremia 1 week after intervention. Fecal inoculation
      caused significant leukocytopenia in all groups within 1 hour after intervention,
      with complete recovery only in the helium-treated group (p < 0.05). The TNF-alpha
      plasma concentration was significantly lower in the helium-treated group, and
      suppression of ex vivo production recovered only in the animals undergoing
      laparoscopy with helium (p < 0.05). The number of intraperitoneal abscesses was
      significantly lower after laparoscopy with helium (2+/-1.5) than after CO2
      laparoscopy (6.3+/-5.1) or in the control group (5.2+/-4.8). Laparoscopy with CO2
      increased systemic inflammation only slightly, while helium use was associated
      with a significant lower incidence of bacteremia and local and systemic
      inflammation compared with the control group.

PMID- 10414553
TI  - Why mini-laparoscopic cholecystectomy?

PMID- 10414555
TI  - Maximum-Likelihood-Binomial method for genetic model-free linkage analysis of
      quantitative traits in sibships.
AB  - Sib-pair linkage studies are widely used to investigate the genetic factors
      implicated in complex quantitative traits. To analyze these data, we propose a
      Maximum-Likelihood-Binomial (MLB) approach, which considers the sibship as a
      whole and relies on the idea of binomial distributions of parental alleles among
      offsprings. The method is based on the introduction of a latent binary variable
      capturing the linkage information between the observed quantitative trait and the
      marker, and the final likelihood can be expressed assuming a parametric
      distribution for the studied trait but also without any assumption on this
      distribution. The test for linkage is a simple likelihood ratio test involving a
      single parameter. The performances of the MLB method are assessed by a simulation
      study in different kinds of family samples. In the case of families with various
      sibship sizes, both MLB approaches (assuming or not a parametric distribution for
      the quantitative trait) provide very consistent results in terms of type I errors
      and yield power levels generally higher than those of the classical Haseman
      Elston method. In the case of extremely discordant sib pairs, we analytically
      show that, for a common asymptotic type I error, the distribution-free MLB
      statistic is expected to be more powerful than the test proposed by Risch and
      Zhang [(1995) Science 268:1584-1589]. In samples including both extremely
      concordant and discordant sib-pairs, simulation studies show that the MLB
      approach is at least as powerful as the EDAC method [Gu et al. (1996) Genet
      Epidemiol 13:513-533]. This MLB method, which can be easily extended to perform
      multipoint analysis and to account for genetic heterogeneity, appears to be quite
      an interesting alternative for mapping quantitative trait loci in humans.

PMID- 10414554
TI  - Multipoint linkage disequilibrium mapping with particular reference to the
      African-American population.
AB  - A new approach to scanning the genome is presented to detect linkage
      disequilibrium caused specifically by population admixture. In contrast to
      current linkage genome scanning methods to find causal genes for complex
      diseases, this new method should be powerful to find genes for multilocus traits,
      particularly those genes that lead to the highest population attributable risk.
      Such a scan using the African-American population is generally feasible for
      mapping common diseases. A conservative threshold is also provided for such
      association mapping.

PMID- 10414556
TI  - Genetic variance components analysis for binary phenotypes using generalized
      linear mixed models (GLMMs) and Gibbs sampling.
AB  - The common complex diseases such as asthma are an important focus of genetic
      research, and studies based on large numbers of simple pedigrees ascertained from
      population-based sampling frames are becoming commonplace. Many of the genetic
      and environmental factors causing these diseases are unknown and there is often a
      strong residual covariance between relatives even after all known determinants
      are taken into account. This must be modelled correctly whether scientific
      interest is focused on fixed effects, as in an association analysis, or on the
      covariances themselves. Analysis is straightforward for multivariate Normal
      phenotypes, but difficulties arise with other types of trait. Generalized linear
      mixed models (GLMMs) offer a potentially unifying approach to analysis for many
      classes of phenotype including multivariate Normal traits, binary traits, and
      censored survival times. Markov Chain Monte Carlo methods, including Gibbs
      sampling, provide a convenient framework within which such models may be fitted.
      In this paper, Bayesian inference Using Gibbs Sampling (a generic Gibbs sampler;
      BUGS) is used to fit GLMMs for multivariate Normal and binary phenotypes in
      nuclear families. BUGS is easy to use and readily available. We motivate a
      suitable model structure for Normal phenotypes and show how the model extends to
      binary traits. We discuss parameter interpretation and statistical inference and
      show how to circumvent a number of important theoretical and practical problems
      that we encountered. Using simulated data we show that model parameters seem
      consistent and appear unbiased in smaller data sets. We illustrate our methods
      using data from an ongoing cohort study.

PMID- 10414558
TI  - Validity of family history diagnosis for dementia.

PMID- 10414557
TI  - Accuracy of proband reported family history: the NHLBI Family Heart Study (FHS).
AB  - Proband-reported family histories are widely used in research and counseling, yet
      little is known about the validity of family history reporting. The Family Heart
      Study (FHS), a population-based study of familial cardiovascular disease,
      gathered family history information from 3,020 middle-aged probands in four U.S.
      communities. Probands reported on the history of coronary heart disease (CHD),
      diabetes, hypertension, and asthma among a total of 10,316 living relatives
      (9,186 siblings, 1,130 parents) and 2,685 spouses. Questionnaires were returned
      by 6,672 siblings, 901 parents, and 2,347 spouses, yielding response rates of 73,
      79, and 87%, respectively. Utilizing the relatives' self-report as the standard,
      sensitivity of the proband report on their spouse, parent, and sibling was 87,
      85, and 81% for CHD, 83, 87, and 72% for diabetes, 77, 76, and 56% for
      hypertension, and 66, 53, and 39% for asthma, respectively. Most specificity
      values were above 90%. Analyses using generalized estimating equations (GEE) were
      performed to evaluate differences in proband accuracy based on the proband's age,
      gender, disease state, center, and ethnicity. In multivariate models, age,
      gender, and disease status were significantly associated with the accuracy of
      proband's report of sibling disease history, but had little effect on the
      accuracy of their report on spouses or parents. In general, older probands were
      significantly less accurate reporters of disease than younger probands. These
      results demonstrate that CHD family history can be captured effectively based on
      proband reports, but suggest that additional family contacts may be helpful when
      working with older probands or with chronic diseases that have few recognized
      medical events or procedures.

PMID- 10414559
TI  - Growth hormone-secreting pituitary adenomas in childhood and adolescence:
      features and results of transnasal surgery.
AB  - OBJECTIVE: Pituitary tumors causing gigantism are rare in childhood and
      adolescence. In a review of 2367 patients with pituitary adenomas who were
      treated between 1970 and 1997, we found 15 cases (0.63%, 9 male and 6 female
      patients) of growth hormone-secreting pituitary adenomas in patients who were
      less than 20 years of age at the time of surgery, and we compared their
      characteristics with those of adenomas in an adult group. METHODS: Patients were
      grouped according to their ages at the first operation, with five patients
      (33.3%) in the prepubescent group (0-11 yr), eight (53.3%) in the pubescent group
      (12-17 yr), and two (13.3%) in the postpubescent group (18-19 yr). All 15
      patients exhibited the typical symptoms of growth hormone oversecretion. The
      incidence of hyperprolactinemia among patients with prepubescent onset was 66.7%.
      Radiological examinations demonstrated microadenomas in 4 patients (26.7%) and
      macroadenomas in 11 patients (73.3%). The mean follow-up period was 73.5 months.
      RESULTS: Direct transnasal explorations were performed for all patients. Tumor
      invasion into the cavernous sinus was observed in six patients (40%). Radical
      tumor resection was performed for four patients (80%) in the prepubescent group,
      for five patients (62.5%) in the pubescent group, and for neither patient in the
      postpubescent group. Surgical morbidity was caused by permanent diabetes
      insipidus in three patients (20%). Rapid growth was postoperatively improved in
      80% of the prepubescent age group. The recurrence rate was 13.3% (2 of 15
      patients). CONCLUSION: Transnasal pituitary surgery was found to be as safe in
      pediatric patients with gigantism as in adults. Growth hormone-secreting
      pituitary adenomas in childhood and adolescence were more likely to be invasive
      or aggressive than were those in adulthood. The clinical biological
      characteristics for children were different from those for adults.

PMID- 10414560
TI  - Stereotactic radiosurgery for trigeminal schwannomas.
AB  - OBJECTIVE: Schwannomas that arise from the trigeminal nerve are rare and are
      usually managed by surgical resection. The role of radiosurgery in the care of
      patients with these basal tumors remains to be defined. METHODS: We reviewed the
      clinical presentation, management, and outcomes for 16 trigeminal schwannoma
      patients who underwent gamma knife stereotactic radiosurgery. Fifteen of the 16
      patients presented with trigeminal sensory dysfunction. Nine patients had tumors
      in the region of the ganglion, six in the region of the trigeminal nerve root,
      and one in the region of the mandibular branch. Six patients had undergone one or
      more previous resections before radiosurgery. Ten underwent radiosurgery as the
      first procedure. The mean tumor volume was 5.3 cc (range, 1-17.8 cc). The mean
      tumor margin dose was 15.3 Gy (range, 12-20 Gy). RESULTS: During the average
      imaging follow-up of 44 months (range, 8-116 mo), the tumor control rate was 100%
      (regression in nine patients and no further tumor growth in seven patients). Five
      patients had improvement of clinical symptoms, and 11 remained unchanged. No new
      cranial nerve deficit developed in any patient. CONCLUSION: As a minimally
      invasive alternative to microsurgery, gamma knife radiosurgery proved to be an
      alternative primary or adjuvant strategy that controlled tumor growth, did not
      cause new deficits, and often improved presenting symptoms.

PMID- 10414561
TI  - Morbidity and survival after 1,3-bis(2-chloroethyl)-1-nitrosourea wafer
      implantation for recurrent glioblastoma: a retrospective case-matched cohort
      series.
AB  - OBJECTIVE: To determine the risks and survival benefit associated with
      implantation of an absorbable, 1,3-bis(2chloroethyl)-1-nitrosourea-impregnated
      polymer wafer, we prospectively studied patients with recurrent glioblastoma
      multiforme and compared them with a demographically matched cohort group.
      METHODS: Over a 29-month period, 62 patients underwent operations. All had tumor
      growth despite standard treatment, a Karnofsky performance score of > or =70, and
      histopathological confirmation of glioblastoma. Seventeen patients underwent
      gross total resection with placement of 1,3-bis(2-chloroethyl)-1-nitrosourea
      wafers (wafer group) at a median 44 weeks from diagnosis (6 women, 11 men; median
      age, 56 years). A cohort group of 45 patients undergoing surgery for recurrent
      glioblastoma during the same time period, but not receiving wafers, was
      identified. Surgery was performed at a median 47 weeks from diagnosis (14 women,
      31 men; median age, 54 years). RESULTS: Within 6 weeks of surgery, 13
      complications were identified in 8 patients in the wafer group. In the cohort
      group, 6 patients sustained 8 complications. We were unable to identify any
      survival advantage using Kaplan-Meier analysis. In the wafer group, median
      survival was 58 weeks from diagnosis and 14 weeks from wafer implantation. In the
      cohort group, median survival was 97 weeks from diagnosis and 50 weeks from
      operation. CONCLUSION: 1,3-bis(2-chloroethyl)-1-Nitrosourea wafer implantation
      for recurrent glioblastoma was associated with a higher risk of postoperative
      complications, particularly those related to infection and wound healing. No
      clear survival benefit associated with wafer implantation was identified.

PMID- 10414562
TI  - Endothelial nitric oxide synthase expression in tumor vasculature is correlated
      with malignancy in human supratentorial astrocytic tumors.
AB  - OBJECTIVE: Endothelial nitric oxide synthase (eNOS) may play an important role in
      the regulation of tumor blood flow and vascular permeability. However, there have
      been no reports describing alterations of eNOS expression in relation to
      malignant progression in human astrocytic tumors. We immunohistochemically
      studied the relationship between eNOS expression in tumor vasculature and
      malignancy in supratentorial astrocytic tumors. METHODS: Tissue samples were
      obtained from 12 patients with low-grade astrocytomas, 10 with anaplastic
      astrocytomas, and 17 with glioblastomas. Normal brain tissue samples were
      obtained from four patients with other brain diseases. Immunohistochemical
      staining was performed using the avidin-biotin complex method, with polyclonal
      anti-eNOS antibody, and the levels of eNOS expression in endothelial cells were
      evaluated as slight, moderate, or intense on the basis of eNOS immunoreactivity.
      The proliferative potential was assessed as the MIB-1 staining index for tumor
      cells. RESULTS: The expression of eNOS was slight in all specimens of normal
      brain tissue, slight in 7 and moderate in 5 specimens of low-grade astrocytoma,
      slight in 2, moderate in 6, and intense in 2 specimens of anaplastic astrocytoma,
      and moderate in 5 and intense in 12 specimens of glioblastoma. The MIB-1 staining
      index (mean+/-standard deviation) was 0.2+/-0.2% for normal specimens, 1.8+/-0.6%
      for low-grade astrocytomas, 9.6+/-6.9% for anaplastic astrocytomas, and 18.5+/
      7.7% for glioblastomas. The MIB-1 staining indices for slight, moderate, and
      intense eNOS expression were 2.0+/-2.3%, 10.8+/-9.8%, and 16.9+/-7.7%,
      respectively. CONCLUSION: Expression of eNOS in tumor vessels was significantly
      correlated with histological grade and proliferative potential. These findings
      suggest that astrocytic tumor vessels possess higher activity for nitric oxide
      production than do normal vessels.

PMID- 10414563
TI  - Patients with spinal cord cavernous malformations are at an increased risk for
      multiple neuraxis cavernous malformations.
AB  - OBJECTIVE: To determine the prevalence of multiple neuraxis cavernous
      malformations in patients who initially presented with intramedullary spinal cord
      (IMSC) cavernous malformations without knowledge of cavernous malformations
      elsewhere in the neuraxis. METHODS: Hospital records and radiographic files were
      analyzed for 17 patients who subsequently underwent surgical resection of an IMSC
      cavernous malformation (histologically proven) and also underwent brain magnetic
      resonance imaging studies. These 17 patients represented a subset of 32 patients
      who underwent surgical resection of an IMSC cavernous malformation during the
      same period. RESULTS: Of 17 patients, 8 (47%) harbored multiple cavernous
      malformations. This group was composed of five women and three men (mean age,
      35.9 yr). There were four Caucasian and four Hispanic patients. CONCLUSION: The
      prevalence of multiple cavernous malformations in the neuraxis seems to be
      increased in patients who harbor IMSC cavernous malformations. This finding has
      important implications for the evaluation and management of these patients and,
      in some cases, their family members.

PMID- 10414564
TI  - Absence of plasma protease-antiprotease imbalance in the formation of saccular
      cerebral aneurysms.
AB  - OBJECTIVE: We examined the hypothesis that a plasma protease-antiprotease
      imbalance contributes to the formation of saccular cerebral aneurysms and the
      suggestion that the assay of these enzymes might be a screening tool for people
      at higher risk for aneurysm formation. METHODS: From June 1997 through May 1998,
      the plasma leukocyte elastase, which is an important proteolytic enzyme, and
      alpha-antitrypsin and alpha2-macroglobulin, which are important antiproteolytic
      enzyme plasma proteins, were examined in 18 patients with ruptured aneurysms, 9
      patients with unruptured aneurysms, and 22 controls. RESULTS: The elastase:alpha1
      antitrypsin ratio and the elastase:alpha2-macroglobulin ratios were significantly
      higher in patients with ruptured aneurysms within 24 hours after subarachnoid
      hemorrhage (SAH) than in the controls. The protease-antiprotease imbalance
      depended on the elevation of the elastase level, which might be correlated with
      leukocytosis after SAH. The elastase level decreased to the control level 3
      months after the onset of SAH. No significant difference in the elastase:alpha1
      antitrypsin and elastase:alpha2-macroglobulin ratios was observed between the
      patients with unruptured aneurysms and the controls. CONCLUSION: These results do
      not support the hypothesis that a plasma protease-antiprotease imbalance is a
      potential marker to predict the formation of saccular cerebral aneurysms. The
      increase in plasma elastase levels in patients with ruptured aneurysms might be
      attributable to leukocytosis after SAH.

PMID- 10414565
TI  - Subthalamic nucleus stimulation for gait disturbance in Parkinson's disease.
AB  - OBJECTIVE: A preliminary study of subthalamic nucleus (STN) stimulation was
      performed to determine its applicability for the treatment of gait and postural
      disturbances in Parkinson's disease. METHODS: Five Parkinson's disease patients
      with freezing gait and postural instability were selected for this study. Their
      ages ranged from 60 to 73 years (mean+/-standard deviation, 65.6+/-4.8 years).
      Semi-microelectrode recording was used to identify the STN and to place a chronic
      electrical stimulation electrode within the right STN in all patients. The
      Unified Parkinson's Disease Rating Scale and the modified Hoehn and Yahr Staging
      Scale were used to assess patients in on- and off-drug conditions before surgery
      and 3 months after surgery. RESULTS: The scores on the Hoehn and Yahr Staging
      Scale and the total Unified Parkinson's Disease Rating Scale for akinesia (P <
      0.05), gait (P < 0.05), and gait and posture (P < 0.01) in off-drug on
      stimulation conditions significantly improved over the preoperative and
      postoperative off-drug off-stimulation conditions (analysis of variance [ANOVA],
      P < 0.01). Improvement over the preoperative scores was 24% on the Hoehn and Yahr
      Staging Scale, 43.6% on the total Unified Parkinson's Disease Rating Scale, 33.4%
      for akinesia, 36.6% for gait, and 38.7% for gait and posture. However,
      stimulation in the on-drug phase did not show a significant difference compared
      with pre- and postoperative conditions (ANOVA, P > 0.05). Comparisons between
      preoperative on-drug and postoperative off-drug on-stimulation conditions
      revealed that there were no significant differences in the scores, except for
      gait (ANOVA, P < 0.05). The scores on subscales for falling, freezing, walking,
      and gait in off-drug on-stimulation conditions were significantly improved over
      the scores for preoperative and postoperative off-stimulation (ANOVA, P < 0.05),
      but the score for postural stability remained unchanged. CONCLUSION: Our findings
      showed that STN stimulation effectively alleviates freezing gait and improves
      walking to its status during the preoperative on-drug phase and can be applied
      for treatment of Parkinson's disease patients with these symptoms.

PMID- 10414566
TI  - Direct and combined revascularization in pediatric moyamoya disease.
AB  - OBJECTIVE: Surgical revascularization of moyamoya disease can improve
      neurological outcomes, compared with the natural history of the disease or the
      results of medical treatment. Controversy exists regarding whether direct or
      indirect revascularization yields better outcomes. This study involves a single
      center experience with direct anastomosis and is the first North American series
      using direct revascularization for pediatric patients with moyamoya disease.
      METHODS: Twelve patients (age range, 5-17 yr; mean age, 10.2 yr) underwent direct
      revascularization of 21 hemispheres. Two patients had experienced failure of
      previous indirect revascularization procedures, with continued clinical
      deterioration. Superficial temporal artery-middle cerebral artery anastomosis was
      performed in 19 hemispheres (with concurrent encephaloduroarteriosynangiosis in
      6). Middle meningeal artery-middle cerebral artery anastomosis and omental
      transposition were each performed in one hemisphere. Follow-up periods ranged
      from 12 to 65 months (mean, 35 mo), and monitoring included neurological
      examinations, angiography, magnetic resonance imaging, and cerebral blood flow
      studies. RESULTS: The neurological conditions of all patients were stable or
      improved after surgery. None of the patients developed new strokes, and no new
      ischemic lesions were seen in magnetic resonance imaging scans. All grafts
      evaluated by follow-up angiography were patent. Postoperative cerebral blood flow
      studies showed significantly improved blood flow (54.4 versus 42.5 ml/100 g/min;
      P = 0.017, n = 4) and hemodynamic reserve (70.3 versus 43.9 ml/100 g/min; P =
      0.009, n = 4), compared with preoperative studies. CONCLUSION: Surgical
      revascularization by direct anastomosis in pediatric patients is technically
      feasible, is well tolerated, and can improve the progressive natural history, the
      angiographic appearance, and the cerebral blood flow abnormalities associated
      with the disease. Direct revascularization has the advantage of providing
      immediate and high-flow revascularization and is particularly useful for patients
      who have experienced failure of previous indirect revascularization procedures.

PMID- 10414567
TI  - Long-term follow-up of patients treated with cervical radiofrequency neurotomy
      for chronic neck pain.
AB  - OBJECTIVE: To determine the long-term efficacy of percutaneous radiofrequency
      medial branch neurotomy in the treatment of chronic neck pain. METHODS: Between
      1991 and 1996, radiofrequency neurotomy was performed in 28 patients diagnosed as
      having cervical zygapophysial joint pain on the basis of controlled diagnostic
      blocks. The procedure was repeated in patients whose pain recurred. Outcome
      measures were the proportion of patients who responded to the initial procedure
      and the duration of relief subsequently obtained. Outcome was correlated with the
      operator performing the procedure, the type of electrode used, litigation status,
      and the type of diagnostic blocks used to establish the diagnosis. RESULTS:
      Complete relief of pain was obtained in 71% of patients after an initial
      procedure. No patient who failed to respond to a first procedure responded to a
      repeat procedure, but if pain returned after a successful initial procedure,
      relief could be reinstated by a repeat procedure. The median duration of relief
      after a first procedure was 219 days when failures are included but 422 days when
      only successful cases are considered. The median duration of relief after repeat
      procedures was at least 219 days; several patients had ongoing relief at the time
      of follow-up. Outcome did not differ according to the operator, the type of
      electrode used, litigation status, or the type of diagnostic block used.
      CONCLUSION: Radiofrequency neurotomy provides clinically significant and
      satisfying periods of freedom from pain, and its effects can be reinstated if
      pain recurs.

PMID- 10414568
TI  - Comparative study of propofol and midazolam effects on somatosensory evoked
      potentials during surgical treatment of scoliosis.
AB  - OBJECTIVE: Studies of the effects on lower-limb cortical somatosensory evoked
      potentials (CSEP) during total intravenous anesthesia are sparse for propofol and
      are lacking for midazolam. This study was designed to compare the effects of
      propofol and midazolam on CSEP under total intravenous anesthesia during
      intraoperative monitoring for surgical treatment of scoliosis. METHODS: CSEPs
      were recorded in two groups of 15 patients during posterior instrumentation for
      treatment of idiopathic scoliosis. The anesthesia used the combination of
      atracurium, alfentanil, and an hypnotic agent (propofol for Group I or midazolam
      for Group II). The main characteristics of the CSEPs (P40 latency and N34-P40 and
      P40-N50 amplitudes) were recorded using ankle posterior tibial nerve stimulation.
      The CSEPs were recorded before induction, 10, 70, 100, 130, and 160 minutes after
      induction, and before the wake-up test. The statistical analysis involved
      analysis of variance for repeated measures. Both groups were homogeneous before
      induction. RESULTS: Neither CSEP deterioration during risk-associated surgical
      procedures nor postoperative clinical abnormalities were observed. Both propofol
      and midazolam induced increases in P40 latencies, with the increases being
      greater and more regular for the propofol-treated group. The amplitude values
      changed with time for both groups, decreasing mainly after induction; in the
      midazolam-treated group, the amplitudes were smaller but more stable. Propofol
      modified the morphological characteristics of the response by decreasing the late
      P60 component amplitude; the W-shaped CSEP morphological pattern was maintained
      with midazolam. CONCLUSION: This study demonstrates the appropriate use of either
      propofol or midazolam in scoliosis monitoring. Preoperative small-amplitude CSEPs
      might favor the use of propofol anesthesia.

PMID- 10414569
TI  - Transcranial Doppler ultrasonography-guided management of internal carotid artery
      closure.
AB  - OBJECTIVE: To emphasize the integrated use of transcranial Doppler
      ultrasonography (TCD) in the management of internal carotid artery (ICA) closure.
      METHODS: Thirty-three patients being considered for ICA closure underwent TCD
      assessment, vasomotor reserve testing/estimation, and carotid artery test
      occlusion with concomitant middle cerebral artery (MCA) blood velocity (V(MCA))
      monitoring, including calculation of the MCA pulsatility index. Twelve of these
      patients proceeded to undergo ICA sacrifice. Sequential TCD sonograms guided
      their postoperative treatment. RESULTS: ICA aneurysms and neck neoplasms affected
      the TCD results and vasomotor reserve insignificantly, whereas carotid-cavernous
      fistulae induced characteristic circulatory alterations. The 10 subjects who
      tolerated ICA sacrifice hemodynamically all showed an initial decrease in the
      ipsilateral V(MCA) to > or =60% of the preocclusion value and a progressively
      decreasing MCA pulsatility index during carotid artery test occlusion. The two
      patients who developed hemodynamic cerebral infarctions exhibited a decrease in
      V(MCA) to <60% and a MCA pulsatility index that remained stable after a vast
      initial reduction. Postoperative hypervolemic and hypertensive support was safely
      titrated in all patients who received postoperative TCD surveillance, providing
      an ipsilateral V(MCA) of > or =80% of the preocclusion value. ICA closure
      permanently altered the cerebral circulatory pattern. CONCLUSION: The hemodynamic
      outcome of ICA sacrifice can be correctly predicted by using the TCD occlusion
      test. TCD provides the means to titrate the extent of postoperative
      hypervolemic/hypertensive support.

PMID- 10414570
TI  - Angles between A1 and A2 segments of the anterior cerebral artery visualized by
      three-dimensional computed tomographic angiography and association of anterior
      communicating artery aneurysms.
AB  - OBJECTIVE: The angle of arteries at bifurcations, as well as the blood flow, are
      factors of hemodynamic stress on the apical region, where aneurysms often
      develop. Using images obtained with three-dimensional computed tomographic
      angiography, we sought to determine the angles between the A1 and A2 segments of
      the anterior cerebral artery of the anterior communicating artery (ACoA) complex
      associated with aneurysms. These angles cannot be detected by conventional
      cerebral angiography. METHODS: The course of the anterior cerebral artery was
      studied using three-dimensional computed tomographic angiography in 42
      consecutive patients with ACoA aneurysms. Twenty-one other subjects, randomly
      chosen from patients without aneurysms, served as controls. Bilateral A1-A2
      angles of the contrast-opacified anterior cerebral artery were measured by three
      dimensional computed tomographic angiography in patients with normoplastic A1
      segments, and the relationship between the angle and the association of aneurysms
      was analyzed using cerebral angiography. RESULTS: Of the 42 patients with ACoA
      aneurysms, 19 patients showed hypo- or aplastic A1 segments, as did only 2 of the
      21 patients without ACoA aneurysms. The average A1-A2 angle was determined to be
      116+/-24 degrees (mean+/-standard deviation) in 18 patients having ACoA complexes
      with normoplastic A1 segments with aneurysms; 17 patients without aneurysms had
      A1-A2 angles measuring 143+/-14 degrees (P < 0.0001). The A1-A2 angle associated
      with ACoA aneurysms was 103+/-20 degrees, which was much smaller than that of the
      non-aneurysm side in the former group (128+/-20 degrees) (P = 0.0036).
      CONCLUSION: ACoA aneurysms are associated with the smaller A1-A2 angle junction
      of the ACoA complex, where higher hemodynamic stress may occur in patients with
      normoplastic A1 segments.

PMID- 10414571
TI  - Far lateral transcondylar approach: dimensional anatomy.
AB  - OBJECTIVE: The far lateral extension of the classic suboccipital craniectomy has
      been found to reduce the depth of the field and improve the angle of surgical
      perspective to the ventrolateral clivus. The goal of the present study is to
      determine and compare the dimensions of the far lateral transcondylar approach
      with the suboccipital craniectomy. METHODS: Ten cadaveric specimens were used to
      study the anatomy at the foramen magnum (FM), occipital condyle (OC), and
      vertebral artery. The distances from the posterior midline of the FM to the
      medial and lateral borders of the OC were measured. The distance of the vertebral
      artery from the transverse foramen of C1 to its dural entry and the distance from
      the dural entry to the posteroinferior cerebellar artery were measured. The
      amount of OC removal that was necessary to expose the contralateral jugular
      tubercle was determined. A reference line was constructed from the posterior
      margin of the FM to the border of the OC. From this line, the angle of surgical
      approach provided by each exposure was measured. RESULTS: The mean distance of
      the vertebral artery from the transverse foramen of C1 to its dural entry was
      22+/-3 mm (standard deviation), and the distance from the dural entry to the
      posteroinferior cerebellar artery was 17+/-8 mm. The distance from the posterior
      midline of the FM to the medial border of the OC was 27+/-0.5 mm; the distance
      from the posterior midline of the FM to the lateral border of the OC was 40+/-0.4
      mm; and the long axis of the OC was 30+/-0.4 mm. The amount of OC removal to
      expose the contralateral jugular tubercle without brainstem retraction was 17+/-1
      mm. The angle of surgical approach versus the reference line decreased from 88+/
      2 degrees with the suboccipital craniectomy alone to 47+/-2 degrees for the far
      lateral transcondylar exposure (P < 0.001). This angle decreased an average of
      2.4 degrees per millimeter of OC removal. CONCLUSION: Understanding the
      dimensions of the craniovertebral junction has clear implications for surgery in
      this area. If a lesion may be approached through a perpendicular exposure, the
      suboccipital craniectomy alone may be sufficient. Additional exposure of the
      ventrolateral clivus without brainstem retraction requires condylar removal. A
      more limited condylar removal than the 17 mm described in this report may be
      adequate if the entire 47-degree angle is not needed.

PMID- 10414573
TI  - Effects of brain ventricular shape on periventricular biomechanics: a finite
      element analysis.
AB  - OBJECTIVE: A computer simulation based on the finite-element method was used to
      study the biomechanics of acute obstructive hydrocephalus and, in particular, to
      define why periventricular edema is most prominent in the anterior and posterior
      horns. METHODS: Brain parenchyma was modeled as a two-phase material composed of
      a porous elastic matrix saturated by interstitial fluid. The effects of the
      cerebrovascular system were not included in this model. The change in the shape
      of the ventricles as they enlarged was described by two variables, i.e., the
      stretch of the ependyma and the concavity of the ventricular wall. The
      distribution of stresses and strains in the tissue was defined by two standard
      mechanical measures, i.e., the mean effective stress and the void ratio. RESULTS:
      With obstruction to cerebrospinal fluid flow, the simulation revealed that the
      degree of ventricular expansion at equilibrium depended on the pressure gradient
      between the ventricles and the subarachnoid space. Periventricular edema was
      associated with the appearance of expansive (tensile) stresses in the tissues
      surrounding the frontal and occipital horns. In contrast, the concave shape in
      the region of the body of the ventricle created compressive stresses in the
      parenchyma. Both of these stresses seem to be direct consequences of the
      concave/convex geometry of the ventricular wall, which serves to selectively
      focus the forces (perpendicular to the ependyma) produced by the increased
      intraventricular fluid pressure in the periventricular tissues. CONCLUSION: The
      distribution of periventricular edema in acute hydrocephalus is a result not only
      of increased intraventricular pressure but also of ventricular geometry.

PMID- 10414574
TI  - Effects of size and shape (aspect ratio) on the hemodynamics of saccular
      aneurysms: a possible index for surgical treatment of intracranial aneurysms.
AB  - OBJECTIVE: The present study was undertaken to explore the relationship between
      the characteristic geometry of aneurysms prone to rupture and the blood flow
      patterns therein, using microsurgically produced aneurysms that simulated human
      middle cerebral artery aneurysms in scale and shape. METHODS: We measured in vivo
      velocity profiles using our 20-MHz, 80-channel, Doppler ultrasound velocimeter.
      We produced small (< or =5 mm, 5 cases) and large (6-13 mm, 12 cases) aneurysms
      with round, dumbbell, or multilobular shapes. RESULTS: The fundamental patterns
      of intra-aneurysmal flow were composed of inflow, circulating flow, and outflow.
      The inflow, which entered the aneurysm only during the systolic phase, was
      strongly influenced by the position and size of the neck and the flow ratio into
      the distal branches. The outflow was usually nonpulsatile and of low velocity.
      The circulating flow depended on the aspect ratio (depth/neck width). A single
      recirculation zone was observed in aneurysms with aspect ratios of less than 1.6.
      This circulation did not seem to extend to areas with aspect ratios greater than
      this value; in aneurysms with aspect ratios of more than 1.6, a much slower
      circulation was observed near the dome. Furthermore, in the dome of dumbbell
      shaped aneurysms and daughter aneurysms, no flow was detected. Intra-aneurysmal
      flow was determined by the aspect ratio, rather than the aneurysm size.
      CONCLUSION: The localized, extremely low-flow condition that was observed in the
      dome of aneurysms with aspect ratios of more than 1.6 is a common flow
      characteristic in the geometry of ruptured aneurysms, so great care should be
      taken for patients with unruptured intracranial aneurysms with aspect ratios of
      more than 1.6.

PMID- 10414572
TI  - Outcome data and analysis in pediatric neurosurgery.
AB  - OBJECTIVE: The purpose of this study was to analyze the outcomes of five commonly
      performed pediatric neurosurgical operations: 1) initial shunt insertion; 2)
      first shunt revision; 3) craniotomy for brain tumor; 4) correction of sagittal
      synostosis; and 5) release of tethered cords. A second purpose was to analyze the
      neurological outcome data after tethered cord releases. METHODS: Morbidity and
      mortality records, patient charts, and operative records were reviewed to
      determine length of hospitalization and, for each disorder, the pertinent
      outcomes such as duration of shunt function and incidence of infection or
      neurological morbidity. RESULTS: Many outcome data were expected, such as a high
      long-term shunt function rate after primary shunt insertion (65% at 5 yr), a low
      mortality rate (1%) and permanent morbidity rate (10%) after craniotomy for brain
      tumor, and a low frequency of transfusion (20%) for sagittal synostosis
      operations. The outcomes among the three neurosurgeons varied more than expected,
      e.g., the duration of hospitalization after sagittal reconstructions ranged from
      3.1 to 5.8 days; the frequency of infections of primary shunt revisions ranged
      from 0 to 15%; and the neurological morbidity after tethered cord releases ranged
      from 0 to 12%, with all neurological morbidity occurring in patients undergoing
      their second or third tether release. CONCLUSION: The data may serve as a basis
      for outcome comparisons for these procedures. Outcome data allow us to analyze
      factors to improve patient care, but outcome analysis is complex.

PMID- 10414575
TI  - Characterization of adenoviral gene expression in spinal cord after remote vector
      delivery.
AB  - OBJECTIVES: Recent work has established that the remote injection of attenuated
      adenoviral vectors may result in central nervous system (CNS) gene expression.
      These studies suggest that virus passes through peripheral nerves into the CNS.
      The present experiment attempts to characterize this phenomenon systematically.
      METHODS: Spinal cord cells staining for the reporter gene beta-galactosidase were
      histologically quantified after microinjection of the viral vector Ad5RSVntLacZ
      into rat footpad, muscle, or sciatic nerve. The effects of injection location,
      titer, and time, as well as nerve crush and dexamethasone, were examined.
      RESULTS: Sciatic nerve viral vector injection results in significantly higher CNS
      uptake than intramuscular and subcutaneous injections (P < 0.05). Nerve crush
      injury caused a time-dependent reduction in spinal cord gene uptake after sciatic
      nerve adenoviral injection (P < 0.05). Neuronal staining reaches its peak at 6
      days after injection (P < 0.002). Peripheral nerve delivery to the CNS increases
      with augmented titers (P < 0.03). Finally, gene expression is augmented by
      administration of dexamethasone (P < 0.0001). CONCLUSION: Remote adenoviral
      vector injection represents a potential method for spinal cord gene therapy that
      avoids any manipulation of CNS tissue.

PMID- 10414577
TI  - Stone age skull surgery in Mecklenburg-Vorpommern: a systematic study.
AB  - OBJECTIVE: Trephination of the cranial vault is the oldest known surgical
      procedure and has often been reported in the literature. The present study was
      performed to study the incidence, the techniques used, and possible indications
      for trephinations in the region of Mecklenburg-Vorpommern, the most northeastern
      German state. METHODS: One hundred thirteen of a total of 115 Neolithic (c. 2000
      3500 BC) skulls and eight smaller skull fragments found in the region of
      Mecklenburg-Vorpommern were examined. Defects and abrasions were detected in 31
      of these skulls and underwent further examination (careful microscopic and/or
      endoscopic examination, three-dimensional computed tomography, and x-rays).
      RESULTS: Six skulls showed defects resulting from trephination, mainly located
      along the midline or in the left parieto-occipital region. There was good
      osteological evidence that at least five of these operations had been survived.
      Two different techniques for trephination (circular cuts and scraping) had been
      used. CONCLUSION: From the present study, we conclude that the incidence of
      trephination in Neolithic skulls in our region is at least 5% and that these
      operations had been survived in singular cases. There is increasing evidence that
      these procedures were intended to be curative.

PMID- 10414576
TI  - Expression and changes of Fos protein in the rat forebrain after gamma knife
      irradiation targeted to the caudate putamen.
AB  - OBJECTIVE: Forebrain expression and changes of Fos protein immunoreactivity were
      investigated in rats subjected to gamma knife irradiation (dose, 100 Gy),
      focusing on the right caudate nucleus. METHODS: Serial cryostat forebrain
      sections were processed with Fos protein antiserum and then by avidin-biotin
      peroxidase complex immunohistochemistry after gamma knife irradiation. RESULTS:
      Some neurons, glial cells, and endothelial cells were positive for Fos-like
      immunoreactivity (LI). Fos-LI was mainly distributed in the target area of
      irradiation, as well as in white matter surrounding lateral ventricles, cortex,
      hippocampus, and certain nuclei reportedly implicated in the regulation of stress
      responses. From 0.5 hour to 30 days after irradiation, expression of Fos-LI
      displayed two peaks. The first peak arose from 3 hours to 24 hours, with cell
      nuclei being positive for Fos-LI. The second peak was noticeable at the 14th day
      postirradiation. Subsequently, three types of Fos-LI-positive cells were
      identified during the period between 14 and 30 days: in the first type, only the
      nucleus was positive; in the second type, the cytoplasm was stained; and in the
      third type, the cells were positive in both the nucleus and the cytoplasm.
      CONCLUSION: During the early stages after gamma knife irradiation, a specific
      stress response (significant Fos expression with two peaks) is observed not only
      in the target region but also in the surrounding forebrain regions. The
      characteristics and significance of two types of Fos-LI-positive cells are
      discussed in the context of this investigation.

PMID- 10414578
TI  - The arachnoid and the myth of Arachne.
AB  - The discovery of the arachnoid membrane is a relatively recent advance. Ancient
      anatomists noted the presence of the dura mater and pia mater, but the
      intervening arachnoid membrane was left undescribed. It was not until the 17th
      century that anatomists discovered a layer separating the pia mater from the dura
      mater and named this cobweb-like layer the "arachnoid." Arachnoid means "spider
      like" and has an interesting etymology that can be traced to the ancient Greek
      myth of Arachne.

PMID- 10414579
TI  - Cerebellar hemorrhage after supratentorial surgery for treatment of epilepsy:
      report of three cases.
AB  - OBJECTIVE AND IMPORTANCE: We report three cases of cerebellar hemorrhage
      complicating supratentorial craniotomies for the treatment of epilepsy. In a
      literature review, we identified only four similar cases of cerebellar hemorrhage
      after temporal lobectomy for the treatment of epilepsy. CLINICAL PRESENTATION AND
      RESULTS: Three young and otherwise healthy patients underwent frontal, occipital,
      and temporal resections for the treatment of refractory epilepsy. The hemorrhage
      manifested as peduncular tremor, ataxia, and decerebrate posturing presenting
      early in the postoperative period. The diagnosis was established by computed
      tomography and/or magnetic resonance imaging. Benign outcomes were observed for
      all patients. CONCLUSION: Based on the available data, it is our opinion that
      brain dislocation resulting from excessive intraoperative cerebrospinal fluid
      drainage is a possible mechanism for this rare complication of supratentorial
      craniotomy. The overdrainage seems to be less hazardous when the procedure is
      performed for the removal of space-occupying mass lesions. In contrast, the
      resection of nonexpanding tissues, such as in lobectomies for the treatment of
      epilepsy, may be an additional risk factor, because the incidence of this
      complication seems to be higher in these situations.

PMID- 10414580
TI  - Symptomatic spinal epidural lipomatosis after local epidural corticosteroid
      injections: case report.
AB  - OBJECTIVE AND IMPORTANCE: Spinal epidural lipomatosis, which causes symptomatic
      compression of neural elements, is a well known but uncommon complication of
      Cushing's syndrome. Spinal epidural lipomatosis has been reported frequently in
      association with chronic systemic corticosteroid therapy, but thus far only one
      case has been attributed to local epidural corticosteroid injections. CLINICAL
      PRESENTATION: We report another case of symptomatic spinal epidural lipomatosis
      after epidural corticosteroid injections. This is the first such case documented
      by magnetic resonance imaging and confirmed with surgical exploration.
      INTERVENTION: The patient's symptoms of neurogenic claudication resolved after
      lumbar laminectomy in the region of previous corticosteroid injections and the
      removal of epidural fat, which was compressing the thecal sac. CONCLUSION: This
      case should alert clinicians that epidural lipomatosis, which causes symptomatic
      thecal sac compression, is a possible complication, not only of systemic
      glucocorticoid therapy, but also of local epidural corticosteroid injections.

PMID- 10414581
TI  - Primary brain myxoma, an unusual tumor of meningeal origin: case report.
AB  - OBJECTIVE AND IMPORTANCE: Primary myxoma of the central nervous system is an
      extremely rare tumor arising from cells of primitive mesenchymal origin. Only two
      cases of primary intracranial myxoma have been described previously. We report a
      patient with a primary myxoma originating from the right frontoparietal convexity
      dura, which we studied in detail with diagnostic imaging and pathological
      analysis. CLINICAL PRESENTATION: A female adolescent presented to the emergency
      department with a 3-day history of mild headache, abdominal pain, and
      intermittent left-sided focal motor seizures. Neurological examination was
      remarkable for left leg hyperreflexia and difficulty with tandem gait. Cranial
      computed tomography and magnetic resonance imaging demonstrated an
      inhomogeneously enhancing mass in the right frontoparietal region. INTERVENTION:
      A right frontoparietal craniotomy was performed. During surgery, a tumor
      appearing similar to a typical convexity meningioma was completely removed along
      with the dural attachment. CONCLUSION: The patient had an uneventful recovery and
      returned to normal activity. Primary intracranial myxoma should be distinguished
      from other meningeal tumors and metastatic cardiac myxoma by appropriate
      pathological analysis and cardiac evaluation. A circumscribed myxoma completely
      excised with adequate dural margin carries a good prognosis for surgical cure.

PMID- 10414582
TI  - A cerebrospinal fluid protein associated with moyamoya disease: report of three
      cases.
AB  - OBJECTIVE: The pathogenesis of moyamoya disease is unknown. The purpose of this
      study was to detect proteins associated with the pathogenesis of moyamoya
      disease. CLINICAL PRESENTATION: Cerebrospinal fluid (CSF) samples from three
      patients with moyamoya disease and four control patients who had cervical lesions
      but no intracranial lesion were studied. INTERVENTION: CSF proteins separated by
      two-dimensional polyacrylamide gel electrophoresis were analyzed with the SWISS
      2DPAGE and SWISS-PROT databases. In the CSF samples from all three patients with
      moyamoya disease, a polypeptide spot (Mr = 12,000, pI = 5.35) was observed. This
      spot was not evident in samples from the four control patients and has not been
      reported in the SWISS-2DPAGE and SWISS-PROT databases. CONCLUSION: A CSF protein,
      which is possibly novel and associated with moyamoya disease, has been detected.
      The analysis of CSF by two-dimensional polyacrylamide gel electrophoresis may
      reveal a clue by which the molecular mechanism of moyamoya disease may be
      elucidated.

PMID- 10414583
TI  - Role of radical surgery for intracranial melanotic neuroectodermal tumor of
      infancy: case report.
AB  - OBJECTIVE AND IMPORTANCE: Melanotic neuroectodermal tumor of infancy (MNTI) is a
      rare, locally aggressive tumor that arises most commonly from the maxilla or
      mandible. Infrequently, it originates from the cranial vault, and recent reports
      have described a favorable outcome after radical surgery. Some lesions are
      particularly problematic, such as those located along the cranial midline or
      cranial base and those with significant intracranial extension. Currently, there
      is no effective adjuvant therapy for MNTI; radiation is precluded by the
      patients' young age, and chemotherapy trials have not demonstrated long-term
      efficacy. CLINICAL PRESENTATION: A 2-month-old infant boy presented with a firm,
      immobile subcutaneous mass behind the right ear. The mass had been present at
      birth and enlarged with time. INTERVENTION: Initial resective surgery down to the
      dura resulted in massive tumor recurrence within weeks. Successful management
      required repeat surgery including excision of the dura and dural venous sinuses.
      CONCLUSION: This patient's large MNTI of the cranial base was successfully
      managed by radical surgery. Although MNTI is a rapidly growing tumor that is
      locally highly invasive, radical surgery may be associated with a favorable
      outcome and offers the potential for long-term cure.

PMID- 10414584
TI  - Treatment of carotid tandem stenosis by combined carotid endarterectomy and
      balloon angioplasty: technical case report.
AB  - OBJECTIVE AND IMPORTANCE: Cervical internal carotid artery disease associated
      with high-grade carotid siphon stenosis poses a therapeutic challenge. This
      report describes the combination therapy of carotid end-arterectomy and
      intraoperative transluminal balloon angioplasty of the carotid siphon. CLINICAL
      PRESENTATION: A 67-year-old man sustained repeated left hemispheric and retinal
      transient ischemic attacks. Results of a diagnostic examination, including
      angiography, disclosed a 70% ulcerative stenosis of the left extracranial
      internal carotid artery as well as a 90% stenosis of the left intracavernous
      carotid artery. The decision was made for combined open and endovascular therapy.
      INTERVENTION: After standard endarterectomy, an introducer for the dilation
      catheter was placed into the common carotid artery before final closure of the
      arteriotomy and recirculation. Under intraoperative fluoroscopy, a 3-mm dilation
      balloon was navigated into the carotid siphon stenosis and inflated several
      times. A 30% residual stenosis in the carotid siphon was obtained as a final
      result. The intervention was completed without complications. No further
      neurological symptoms were observed during the follow-up period of 30 months.
      CONCLUSION: Carotid endarterectomy, combined with intraoperative transluminal
      angioplasty of carotid siphon stenosis, is a feasible procedure for selected
      patients with carotid tandem stenosis.

PMID- 10414585
TI  - Thallium-201 single-photon emission computed tomographic and proton magnetic
      resonance spectroscopic characteristics of intracranial ganglioglioma: three
      technical case reports.
AB  - OBJECTIVE: The correlation between thallium-201 (201TI) uptake, semiquantitative
      choline-containing compound values measured by proton magnetic resonance
      spectroscopy (1H-MRS), and Ki-67 labeling indexes (LIs) was investigated in three
      gangliogliomas. METHODS: The early and delayed 201TI indexes were calculated as
      the ratio of tumor to normal brain tissue uptake by 201TI single-photon emission
      computed tomography. Single-voxel 1H-MRS was performed to measure the levels of
      metabolites in the tumors. Ki-67 LI was measured in the surgical specimens.
      RESULTS: All three gangliogliomas showed very high 201TI uptake on both early and
      delayed images. 1H-MRS demonstrated malignancy based on the high choline peak
      relative to the creatine and N-acetylaspartate peaks. Ki-67 LI was less than 1%
      in two gangliogliomas and 3.5% in an anaplastic ganglioglioma. CONCLUSION: Both
      201TI single-photon emission computed tomography and 1H-MRS indicated malignancy,
      whereas Ki-67 LI indicated low growth activity. 201TI single-photon emission
      computed tomography and 1H-MRS of ganglioglioma might be affected by metabolic
      characteristics other than growth activity.

PMID- 10414586
TI  - Accuracy of a miniature intracranial pressure monitor, its function during
      magnetic resonance scanning, and assessment of image artifact generation.
AB  - OBJECTIVE: We examined the accuracy and repeatability of an intracranial pressure
      (ICP) monitor (Codman MicroSensor; Johnson & Johnson Professional, Inc., Raynham,
      MA) in a nonmagnetic environment and during magnetic resonance imaging (MRI). The
      resulting image artifact generation was calculated. ICP monitoring is essential
      in management of severe head injury, but few ICP monitoring devices are
      compatible with use in an MRI scanner. The use of MRI to assess head injury is
      increasing, and developing safe methods of continuously monitoring ICP may
      improve patient care. METHODS: A water manometer was used as the standard for
      comparison. We assessed pressure readings from the ICP monitor in a nonmagnetic
      environment using a standard and a long connector cable between the pressure
      transducer and display unit. This long cable permitted testing during MRI
      sequences because the display unit could be distanced from the magnet. Accuracy
      was determined during T2-weighted imaging, proton spectroscopy, and diffusion
      weighted imaging, and artifact generation was assessed. RESULTS: We found a high
      degree of accuracy for repeated measurements over a clinical pressure range using
      both standard and long connector cables outside the MRI room. During MRI
      scanning, the ICP monitor was accurate during T2 and proton spectroscopy
      sequences. Accuracy during diffusion-weighted imaging, however, was clinically
      unacceptable. This ICP monitor creates a reduction in signal-to-noise ratio in
      the received signal during T2-weighted imaging and proton spectroscopic imaging,
      with the obtained images still radiologically interpretable. CONCLUSION: The
      Codman ICP monitor is sufficiently accurate and free of artifact generation to be
      used during most clinical MRI applications. This could enhance patient monitoring
      and safety.

PMID- 10414587
TI  - Library: historical perspective. Leo M. Davidoff (1898-1975).

PMID- 10414588
TI  - Ablative surgery and deep brain stimulation for Parkinson's disease.

PMID- 10414589
TI  - Cerebral fungal infections in the immunocompromised host: a literature review and
      a new pathogen--Chaetomium atrobrunneum: case report.

PMID- 10414590
TI  - Cell-mediated allergy to a cerebral aneurysm clip: case report.

PMID- 10414591
TI  - Trigeminal neuralgia resulting from infarction of the root entry zone of the
      trigeminal nerve: case report.

PMID- 10414592
TI  - An otherwise typical case of non-Japanese hairy cell leukemia with CD10 and CDw75
      expression: response to cladaribine phosphate therapy.
AB  - Hairy cell leukemia (HCL) in Western patients typically expresses CD19, CD20,
      CD11c, CD25, HLA-DR, and IgG/lambda and lacks expression of CD5 and CD10. The
      immunophenotype is in contrast to Japanese HCL which typically expresses CD5 and
      CD10. Western and Japanese HCL also differ in their clinical presentation and
      response to treatment with alpha-interferon. We report a case of non-Japanese HCL
      which presented typically with pancytopenia; however, the immunophenotype was
      atypical with expression of CD10 and CDw75. CDw75 expression has not previously
      been described in either Japanese or non-Japanese HCL. The patient achieved a
      marked partial pathologic response and complete clinical response to treatment
      with cladaribine phosphate.

PMID- 10414593
TI  - Simultaneous analysis of serum immunoglobulins in patients with M protein using
      cellulose acetate membrane isoelectric focusing.
AB  - We developed a method for the simultaneous analysis of microheterogeneity of
      human serum IgG, IgA, IgM, IgD, and IgE, and serum protein pattern using
      cellulose acetate membrane isoelectric focusing, and analyzed in 11 healthy
      subjects and 67 patients with M protein (17 cases of multiple myeloma [MM] and 50
      cases of monoclonal gammopathy of undetermined significance [MGUS]). Using this
      method, bands indicating the microheterogeneity of each immunoglobulin could
      clearly be detected.Among healthy subjects, the detected IgG, IgA, and IgM bands
      did not vary, but the detected IgE and IgD bands did vary. Therefore, IgA, IgM,
      and IgG were selected for comparison of serum immunoglobulins in MM and in MGUS.
      In the IgA-type M protein group, normal IgM and IgG bands were decreased in MM
      patients compared to MGUS patients, while the M band and other bands were
      increased in MM patients compared to MGUS patients, but the differences between
      the two groups were not significant. In the IgG-type M protein group, normal IgM,
      IgA, and IgG were significantly decreased in MM patients compared to MGUS
      patients. We examined the changes in electrophoretic pattern in six MM patients
      and eight MGUS patients with IgA-type M protein after neuraminidase treatment.
      The width of the M band in MM patients with IgA-type M protein decreased with
      neuraminidase treatment. On the other hand, the width of the M band in MGUS
      patients with IgA-type M protein increased with neuraminidase treatment. We
      concluded that the decrease of the normal immunoglobulins in MM patients with IgG
      type M protein could be detected by this method, and IgA type of M protein
      binding sugar chain were different between MM and MGUS patients.

PMID- 10414594
TI  - Measurement of total and diffusible serum fluoride.
AB  - This article describes a technique for the measurement of total and diffusible F
      content of serum, at clinical significant concentrations of F (1-10 microM). The
      proposed procedure avoids the interference of unknown serum components with the
      ion-specific electrode. Sample F is concentrated fivefold through distillation of
      hydrofluoric acid (Taves' method). Ionic fluoride is presented to the electrode
      in a simple solution at concentrations within the linear response of the
      electrode. Average recoveries of F from serum or its ultrafiltrate were 96+/-7%
      (21%) and 97+/-12% (53%) (mean+/-SEM [CV]), respectively. With four replicates of
      each sample, the technique produce within-run standard deviations of 0.6 microM
      and 2.2 microM at 1 and 10 microM F, respectively. Total precision assessment
      gave standard deviations of 0.6 microM and 2.6 microM at 1 and 10 microM F,
      respectively. The fasting serum F levels of normal climacteric women, 45 to 65
      years, showed an asymmetric distribution. The data obtained started at the
      detection limit of the technique (0.1 mM). The 75 percentile was 1.85 microM for
      total and 0.5 microM for diffusible F. In patients (n = 25) treated with NaF (30
      mg F/day) the fasting levels of total serum F (4.5 +/-1.7 microM) did not differ
      from those of diffusible F (4.2+/-1.5 microM). In patients (n = 50) treated with
      sodium monofluorophosphate (15 mg F/day) the fasting levels of total and
      diffusible serum F were 6.5+/-1.7 microM and 0.5+/-0.03 microM, respectively. In
      conclusion, this paper establishes the presence of two fractions of serum
      fluorine: diffusible and nondiffusible (or protein bound) and describes a
      technique for their clinical estimation. In untreated subjects and in patients
      receiving NaF, the former fraction contains ionic fluoride. In patients treated
      with MFP, diffusible serum fluorine is composed by ionic fluoride and low
      molecular weight, peptide-bound, acid-labile fluorine.

PMID- 10414595
TI  - Changes in concanavalin A-reactive proteins in neurological disorders.
AB  - Changes of glycosylation of cerebrospinal fluid proteins such as alpha2
      macroglobulin, and prostaglandin D synthase were studied by lectin blotting,
      using concanavalinA, in multiple sclerosis (n = 42) and neuropathies (n = 20) in
      comparison to neurological controls (n = 22). The concanavalinA-reactivity of
      alpha2-macroglobulin, which was increased in the neuropathies but not in multiple
      sclerosis compared to controls, correlated with the total concanavalinA
      reactivity in controls and neuropathies but not in multiple sclerosis, indicating
      that the protein could be abnormally glycosylated in the latter disease. Although
      the concentration and the concanavalinA-reactivity of prostaglandin D synthase
      were not significantly different in the three groups, the two parameters
      correlated only in neuropathies but not in controls or multiple sclerosis,
      probably due to the high heterogeneity of the protein. These changes deserve to
      be studied in further detail in view of their potential clinical applications.

PMID- 10414596
TI  - Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like
      growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood
      circulation.
AB  - Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) play an
      important role in cell growth and differentiation. Clinical and epidemiological
      studies have indicated that measuring IGFs and IGFBPs in blood has potential
      implications in assessing growth-related abnormalities and risks of certain types
      of cancer. To facilitate the application, we reported a large collection of
      reference ranges of IGFs and IGFBPs in normal population and evaluations of these
      molecules in serum and plasma as well as the impact of freeze-thaw cycles on the
      measurement. IGF-I, IGFBP-3 andALS showed a similar pattern of change associated
      with age. Levels of these molecules were low at birth and increased with age
      through puberty. After puberty the levels declined slowly with age. Overall, IGF
      I, IGFBP-3 and ALS were slightly higher in females than in males. Free IGF-I
      accounted for about 1% of the total IGF-I and its variation with age was similar
      to total IGF-I. IGF-II levels were also increased with age from birth to puberty,
      but became stable after puberty. There was little difference in IGF-II levels
      between genders. IGFBP-2 levels declined with age from birth to puberty. Levels
      of IGFBP-6 in contrast were increased with age. These IGF binding proteins were
      higher in males than in females. IGFs, IGFBP-3 and ALS were 5-10% higher in serum
      than in plasma. IGFBP-2 and IGFBP-6 differed substantially between serum and
      plasma. Freeze-thaw treatment up to five cycles had little impact on plasma
      levels of IGFs and IGFBP-3. Our observations suggest that levels of IGFs and
      their binding proteins are varied with age, gender, and types of specimen and
      that these variations need to be taken into consideration when IGFs and their
      binding proteins are utilized in clinic and research.

PMID- 10414597
TI  - Inhibitory effect of free sialic acid on complement activation and its
      significance in hypocomplementemic glomerulonephritis.
AB  - The role of free sialic acid on complement activation was investigated. The serum
      levels of free sialic acid and total sialic acid were measured by previously
      described methods in 16 patients with acute post-infectious glomerulonephritis
      (AGN), 27 patients with systemic lupus erythematosus (SLE), 15 patients with
      persistent hypocomplementemic membranoproliferative glomerulonephritis (MPGN),
      and 13 healthy controls. A statistical study demonstrated an increased level of
      free sialic acid in patients with AGN and SLE in which the hypocomplementemia
      improved throughout the course and a decreased level of free sialic acid in
      patients with MPGN and SLE in which hypocomplementemia continued throughout the
      course. The levels of total sialic acid were significantly increased in patients
      with AGN and SLE and were significantly decreased in patients with MPGN. There
      was no correlation between the levels of free sialic acid and total sialic acid
      in patients with AGN, in whom the levels of both total and free sialic acids were
      increased. To examine the effect of free sialic acid on the complement cascade,
      lipopolysaccharide (LPS) was incubated with normal human serum (NHS) in the
      various concentrations of N-acetyl neuraminic acid (NANA), a member of the sialic
      acid group. The incubation mixtures were examined by enzyme immunoassay using
      monoclonal anti-iC3b antibody or anti-Bb antibody. Native C3 or Factor B in NHS
      broke down less following the addition of NANA. To elucidate the role of NANA on
      the hemolytic function of C3, a rabbit erythrocyte (Ra E) hemolytic assay was
      carried out. Ra E lysed completely in the presence of R3 with native C3. However,
      hemolysis occurred to a lesser degree in C3-depleted serum (R3) or R3 with NANA
      treated C3. To investigate the influence of NANA on complement components, the
      levels of complement components were measured in the incubation mixture with
      various doses of NANA and NHS. The levels of C3 and C5 were significantly
      decreased after the addition of NANA, even though the levels of Factor H and
      Factor I were not markedly changed. These data indicate that NANA exerts an
      influence on the complement components even though it has no effect on the
      regulatory proteins of complement. Our in vitro findings, together with the in
      vivo data, suggest that free sialic acid might have an inhibitory effect on the
      activation of C3 and the following complement cascade, and might also have been
      responsible for the improvement of hypocomplementemia.

PMID- 10414598
TI  - High-sensitivity dye binding assay for albumin in urine.
AB  - We developed a dye-binding method for albumin in urine based on bis (3',3"
      diiodo4'4"-dihydroxy-5'5"-dinitrophenyl)-3,4,5,6-tetrabr omosulfonphthalein
      (DIDNTB), a dye that has a higher chemical sensitivity and specificity for
      albumin when compared to two other commonly used dyes. We prepared urine
      dipsticks with DIDNTB and certain other compounds to prevent "nonspecific"
      binding to the dipstick matrix. The detection limit for albumin with DIDNTB as
      the dye is about 10 mg/L. The extent of dye binding to proteins and other
      compounds was studied using ultracentrifugation and a selectively permeable
      membrane that permitted the passage of free but not bound dye; we believe this
      method is superior to photometric titration. The affinity of the dyes for albumin
      was found to be pH dependent with stronger binding at pH 1.8 than at pH 7.0. At
      pH 1.8, DIDNTB had a ca.10-fold greater binding coefficient to albumin when
      compared to the widely used dyes, tetrabromophenol blue (CI 4430-25-5) or
      bromophenol blue (CI 115-39-9). We developed a system that minimized nonspecific
      binding by the dye through the use of polymethyl vinyl ethers and bis
      (heptapropylene glycol) carbonate. DIDNTB showed a greater chemical specificity
      for albumin when compared to most other proteins. The new albumin dipsticks are
      resistant to many potential interferences at substantial concentrations, making
      the dipsticks suitable to screen for albuminuria.

PMID- 10414599
TI  - Application of FTA sample collection and DNA purification system on the
      determination of CTG trinucleotide repeat size by PCR-based Southern blotting.
AB  - Myotonic dystrophy (DM) is caused by a CTG trinucleotide expansion mutation at
      exon 15 of the myotonic dystrophy protein kinase gene. The clinical severity of
      this disease correlates with the length of the CTG trinucleotide repeats.
      Determination of the CTG repeat length has been primarily relied on by Southern
      blot analysis of restriction enzyme-digested genomic DNA. The development of PCR
      based Southern blotting methodology provides a much more sensitive and simpler
      protocol for DM diagnosis. However, the quality of the template and the high
      (G+C) ratio of the amplified region hamper the use of PCR on the diagnosis of DM.
      A modified PCR protocol to amplify different lengths of CTG repeat region using
      various concentrations of 7deaza-dGTP has been reported (1). Here we describe a
      procedure including sample collection, DNA purification, and PCR analysis of CTG
      repeat length without using 7-deaza-dGTP. This protocol is very sensitive and
      convenient because only a small number of nucleate cells are needed for detection
      of CTG expansion. Therefore, it could be very useful in clinical and prenatal
      diagnosis as well as in prevalence study of DM.

PMID- 10414600
TI  - Serum antibodies anti-H. pylori and anti-CagA: a comparison between four
      different assays.
AB  - The authors compare efficacy of two ELISA assays (one supplied by DIAMEDIX [Delta
      Biological s.r.l.], and the other by RADIM [RADIM I]) in detecting total anti-H.
      pylori antibodies, and of two further ELISA methods (one supplied by EUROSPITAL
      [Helori CTX IgG] and the other by RADIM [RADIM 2]) in identifying anti-CagA
      antibodies, using sera from 69 controls (20 adults and 49 children) and from 96
      patients, obtained before endoscopy. Seventy-three of the patients had H. pylori
      infection, while the remaining 23 were H. pylori negative (histology and
      polymerase chain reaction [PCR]). Fifty-two of the H. pylori positive patients,
      had cagA-positive strain infection, identified by PCR. The DIAMEDIX assay was
      found to be more sensitive (92%) than RADIM 1 (79%) in identifying H. pylori
      positive patients, irrespective of the infecting strain. On the other hand, the
      DIAMEDIX assay was less specific than RADIM 1 for H. pylori-negative patients
      (43% vs. 83%). However, when patients already treated for H. pylori infection
      were excluded from the group of H. pylori-negative patients, the DIAMEDIX assay
      had a specificity of 89%. In identifying anti-CagA antibodies, the kit supplied
      by RADIM (RADIM 2) had a sensitivity of 90% and a specificity of 94%, whereas
      that supplied by EUROSPITAL had a sensitivity of 100% and a specificity of 76%.
      The performances of the two methods in the identification of anti-CagA antibodies
      were found to be similar. The authors conclude that, in view of its high
      sensitivity, the DIAMEDIX assay may be useful in screening for H. pylori
      infection.

PMID- 10414601
TI  - ESBRA-Nordmann 1998 Award Lecture: Visual P3 as a potential vulnerability marker
      of alcoholism: evidence from the Amsterdam study of children of alcoholics.
      European Society for Biomedical Research on Alcoholism.
AB  - Recent data from the Amsterdam Study of Children of Alcoholics add to the
      evidence for considering the P300 or P3 component of the event-related potential
      (ERP) as a potential vulnerability marker of alcoholism. In this study, multi
      channel ERPs were recorded from 7- to 18-year-old children of alcoholics (COAs)
      and age- and sex-matched low-risk controls using several experimental paradigms,
      including a visual novelty oddball task and a visual selective attention task.
      The results indicated that differences between COAs and controls in the visual P3
      amplitude: (1) can be elicited both actively by task-relevant target stimuli and
      passively by irrelevant novel stimuli; (2) are a function of both the attentional
      relevance and the target properties of the eliciting stimulus; (3) are mediated
      by multiple brain generators, rather than by a single generator; (4) originate
      from a difference in the strength, rather than in the spatial configuration, of
      the underlying brain generators; (5) cannot be accounted for by differences in
      visual attention-related earlier occurring ERP components; and (6) can be
      moderated by current behavioural and emotional problems, general intellectual
      ability, and socio-economic background. These findings support the notion that a
      relatively small visual P3 amplitude in COAs reflects heritable biases in
      attention and information processing that are related to their increased
      vulnerability to alcoholism.

PMID- 10414602
TI  - Dizocilpine (MK-801) prevents the development of sensitization to ethanol in
      DBA/2J mice.
AB  - DBA/2J mice repeatedly exposed to ethanol (2 g/kg, i.p. every 48 h for 8 days)
      exhibit sensitization to the locomotor stimulant effects of ethanol. Pretreatment
      with the NMDA receptor antagonist dizocilpine (0.2-0.3 mg/kg, i.p.) completely
      prevents the development of sensitization. Thus, NMDA receptors appear to play an
      important role in behavioural sensitization to ethanol.

PMID- 10414603
TI  - Effects of chronic ethanol exposure on neurophysiological responses to
      corticotropin-releasing factor and neuropeptide Y.
AB  - Stress has been reported to influence ethanol consumption and relapse in
      abstinent alcoholics. The present study examined if prolonged alterations in
      neurophysiological responses to corticotropin-releasing factor (CRF) and
      neuropeptide Y (NPY), peptides known to influence stress responses, would persist
      during protracted ethanol abstinence. Male Wistar rats were chronically exposed
      to ethanol vapour (EtOH group) or air (control group) for 6 weeks. Upon removal
      from the vapour chambers, recording electrodes were implanted in the cortex and
      amygdala. The effects of intracerebroventricular infusions of CRF and NPY on
      electroencephalogram (EEG) and event-related potentials (ERPs) were then assessed
      10-15 weeks after withdrawal from ethanol. Following abstinence from ethanol, the
      EtOH group displayed increased power in the 6-8 Hz frequency range and increased
      stability in the cortical EEG. In addition, in the EtOH group the amplitude of
      the P2 ERP component in the frontal cortex was decreased and the latency of the
      P3 ERP component in the parietal cortex was delayed, compared to the control
      group during baseline recording conditions. The EtOH group was also more
      responsive to CRF and NPY. CRF significantly increased cortical power (6-8 Hz)
      and increased cortical EEG stability in the EtOH group, compared to controls.
      Additionally, NPY significantly decreased the amplitude of the N1 ERP component
      in the amygdala of the EtOH group, but not in the control group. This enhanced
      sensitivity to CRF and NPY following chronic ethanol exposure and abstinence
      suggests that these peptidergic systems may play a role in the symptomatology of
      the prolonged abstinence syndrome.

PMID- 10414604
TI  - Flow cytometric and fluorescence microscopic analysis of ethanol-induced G2+M
      block: ethanol dose-dependently delays the progression of the M phase.
AB  - We found previously that short-term (3 and 6 h) exposure to ethanol (100 and 200
      mM) induced the transient arrest of L929 cells at the G2+M phase. To identify the
      exact site blocked during the G2+M phase, we carried out flow cytometry and
      microscopic analysis with asynchronous L929 cells exposed to ethanol (12.5-330
      mM) for 3, 6 or 24 h. Flow cytometry (the simultaneous analysis of cellular DNA
      and cyclin B1 content) revealed that the percentage of 4c (tetraploid) cells with
      a high level of cyclin B1 increased after continuous 6 h exposure to ethanol (>
      or =82.5 mM) and decreased after 24 h exposure, which supports the idea of a
      transient M-phase block. To determine the sub-M phase of 4c cells with high
      levels of cyclin B1 based on spindle microtubules and their karyotype, we viewed
      immunofluorescent images by double staining with Hoechst 33258 (bis-benzimide
      trihydrochloride) for DNA and with fluorescein isothiocyanate-labelled antibody
      for cyclin B1 or beta-tubulin. A 6 h exposure to intermediate concentrations (50
      100 mM) of ethanol increased the number of early-anaphase cells, compared with
      the control, suggesting an inhibition of the elongation of polar microtubules.
      Both 6 and 24 h exposure to higher concentrations (100-200 mM) of ethanol
      increased metaphase cells, indicating an arrest at the spindle assembly
      checkpoint and suggesting an inhibition of the shortening of kinetochore
      microtubules and/or the degradation of cyclin B . Moreover, 6 h exposure to 330
      mM ethanol increased round, probably early-prophase, cells, suggesting inhibition
      of the formation of spindle microtubules. Thus, it is likely that higher
      concentrations of ethanol affect the elongation, contraction, and formation of
      the spindle microtubules of L929 cells dose-dependently and also disrupt the
      correlation between microtubule organization and the synthesis and degradation of
      cyclin B1, thereby delaying the progress of karyokinesis, which may lead to an
      ethanol-induced G2+M block.

PMID- 10414605
TI  - Short-term ethanol exposure increases the expression of Kupffer cell CD14
      receptor and lipopolysaccharide binding protein in rat liver.
AB  - Gut-derived endotoxins (lipopolysaccharide, LPS) complexed to LPS-binding protein
      (LBP) activate liver Kupffer cells via their CD14 receptor. Pro-inflammatory
      cytokines are released and this is postulated to promote liver injury. We
      previously demonstrated enhanced expression of CD14 endotoxin receptor after 2
      weeks of alcohol administration. A similar result, based on 6 weeks of ethanol
      treatment, was recently reported and suggested to correlate with alcohol-induced
      liver injury. To establish whether this occurs prior to or after the initiation
      of damage, we investigated the temporal effect of continuous ethanol exposure on
      the expression of CD14 and the associated LBP. In addition, we studied the effect
      of treatment with gadolinium chloride (GdCl3) that inactivates Kupffer cells and
      alleviates alcohol-induced liver damage. The amount of CD14 and LBP mRNA, as
      determined by reverse transcriptase-polymerase chain reaction (RT-PCR), was
      unchanged 4-8 h after intragastric ethanol administration. However, after 24-48 h
      of repeated ethanol administration, CD14 and LBP mRNA both increased
      significantly and reached a level similar to that observed after 6 weeks of
      ethanol exposure by liquid diet. Immunostaining experiments with ED2 antibody
      demonstrated that GdCl3 efficiently inactivated Kupffer cells. However, there was
      no concomitant reduction in the expression of CD14 mRNA, suggesting that
      compensatory infiltration by ED2-negative, but CD14-positive, macrophages had
      occurred. Our results demonstrate that soon after the initiation of ethanol
      exposure, i.e. within 24-48 h, the hepatic expression of both the CD14 receptor
      and LBP is increased. This suggests that these increases could contribute to the
      initiation of alcoholic damage rather than being a consequence of the injury.

PMID- 10414607
TI  - Drinking pattern and alcohol-related medical disorders.
AB  - Although heavy alcohol intake is known to be one of the most common causative
      factors of liver disease, pancreatitis, upper gastrointestinal and neurological
      disorders, the influence of the drinking pattern is largely unknown. The study
      investigated the relationship of alcohol-related medical disorders in alcoholics
      and their drinking pattern. Two hundred and forty-one chronic alcoholics were
      referred consecutively for detoxification and their drinking pattern was
      sufficient for them to be included in this study. History of alcohol abuse as
      well as drinking behaviour in the last 6 months were assessed by a semi
      structured interview. Findings included intensive clinical examination with
      abdominal ultrasound in most subjects. Heavy drinking with frequent inebriation
      was most often found in our sample (44.4%), whereas continuous heavy alcohol
      consumption without intoxication (33.6%), and an episodic drinking style (22.0%)
      were less frequent. The heavy drinkers suffered more often from pancreatitis,
      oesophageal varices, polyneuropathy or erectile dysfunction than episodic
      drinkers. They also showed more upper gastrointestinal disorders, although the
      estimated life-time alcohol intake was comparable to continuous drinkers. No
      difference relating to withdrawal delirium or seizures could be found between the
      groups of alcoholics. Frequent heavy drinkers showed a trend to more alcohol
      related medical disorders than alcoholics with a different drinking pattern,
      although they were younger and their estimated life-time alcohol intake was
      comparable to that of continuous drinkers. Thus, the drinking pattern,
      particularly frequent inebriation, has an influence on the occurrence of alcohol
      related disorders.

PMID- 10414606
TI  - Alcohol-related problems among adolescent suicides in Finland.
AB  - We studied 106 adolescent suicides out of a total nationwide population of 1397
      suicides. Forty-four (42%) of these 13-22-year-old victims were classified as
      having suffered either a DSM-III-R alcohol use disorder or diagnostically
      subthreshold alcohol misuse according to retrospective evaluation using the
      Michigan Alcoholism Screening Test (MAST). These victims were found to differ
      from the other adolescent suicides in several characteristics: they were more
      likely to have comorbid categorical DSM-III-R disorders, antisocial behaviour,
      disturbed family backgrounds, precipitating life-events as stressors and severe
      psychosocial impairment. In addition, they also had a greater tendency to be
      alcohol-intoxicated at the time of the suicidal act, which tended to occur during
      weekends, suggesting that drinking in itself, and its weekly pattern, each
      contributed to the completion of their suicides.

PMID- 10414608
TI  - Patients with chronic alcohol abuse in Dutch family practices.
AB  - Routine data from the Dutch Transition project on 236 027 episodes of care
      collected by 54 family physicians (FPs) for 93 297 patient years in their listed
      practices and classified with the International Classification of Primary Care,
      were used to analyse chronic alcohol abuse episodes of care in Dutch family
      practices. Data on 332 episodes are presented. In a subsample with a 4-year
      registration period, 70 patients were identified. Important reasons for an
      encounter are the patient's explicit presentation of the problem and the FPs'
      initiatives. FPs show considerable sensitivity to psychosocial problems,
      including alcohol abuse. It is concluded that over the years registered FPs
      actively deal with chronic alcohol abuse in approximately 2% of all visiting men
      aged 25-64 years. In an average Dutch family practice with 2200 listed patients,
      approximately 20 patients are known by the FP to have chronic alcohol abuse. Real
      life studies in registered family practice populations are necessary to better
      establish how patients with abundant alcohol consumption as a risk factor develop
      the chronic alcohol abuse episode of care, and what FPs can do to prevent this
      effectively.

PMID- 10414609
TI  - Persistence of substance use-related hospital utilization among psychiatric
      consultation patients.
AB  - Among 86 consecutive consultation-liaison (C-L) patients with current substance
      use-related hospital attendance, the case records revealed an average history of
      5.9 years in male patients and 5.3 years in female patients of repeated substance
      use-related hospital visits. A history of at least 1 year was found in 60%
      (52/86) of patients. The history had started at the age of early 30s with
      attempted suicide as the most common principal diagnosis. By the age of 40, there
      had been several hospital visits for various health problems. However, 48%
      (41/86) of the patients had never received substance use treatment. It appeared
      that opportunities to intervene with substance use were frequently missed on
      hospital encounters, a finding also observed in earlier studies.

PMID- 10414610
TI  - Platelet and erythrocyte membrane fluidity changes in alcohol-dependent patients
      undergoing acute withdrawal.
AB  - This study tested the hypothesis that membrane fluidity may alter during the
      alcohol-withdrawal syndrome. Platelet membranes of alcohol-dependent patients (n
      = 7) were significantly more rigid than controls (n = 7) at the start of alcohol
      withdrawal (mean fluorescence anisotropy 203.1 x 10(-3) vs 195.5 x 10(-3)
      respectively, P = 0.03), but were significantly more fluid when withdrawal was
      complete (191.4 x 10(-3) vs 199.2 x 10(-3), P = 0.03). Consequently platelet
      membranes of patients adapted to the known acute fluidizing effect of alcohol by
      becoming more rigid, but underwent a marked fluidization during withdrawal. There
      were no significant changes in erythrocyte membrane fluidity during withdrawal.

PMID- 10414611
TI  - Introduction to personality-biological interactions in alcoholism: 'The Markku
      Linnoila Memorial Symposium'.

PMID- 10414612
TI  - Personality and alcohol/substance-use disorder patient relapse and attendance at
      self-help group meetings.
AB  - This study evaluated the role of personality in the short-term outcome of
      alcohol/substance-use disorder patients. Detoxifying alcohol/substance-use
      disorder patients were administered the Myers-Briggs Type Indicator (MBTI), the
      Tridimensional Personality Questionnaire (TPQ), the Michigan Alcohol Screening
      Test (MAST), the CAGE Questionnaire, and the Beck Depression Inventory (BDI).
      These patients were subsequently evaluated over a 1-month period for relapse and
      attendance at self-help group meetings. High TPQ Persistence scale scores
      predicted abstinence. When the Thinking and Feeling groups were considered
      separately, and when these two groups were combined into a single group, high
      scores for the individual groups and the combined group (i.e. Thinking and
      Feeling types together) predicted abstinence. High TPQ Persistence scale scores
      and low Shyness with Strangers and Fear of Uncertainty subscale scores predicted
      attendance at self-help group meetings. High MBTI Extroversion and high MBTI
      Thinking scores also predicted attendance at self-help group meetings. When the
      Extroverted and Introverted types and the Thinking and Feeling types respectively
      were combined, as with abstinence, high scores predicted attendance at self-help
      group meetings. Age, gender, CAGE, MAST, and BDI scores did not predict outcome.
      The above information suggests that specific personality variables may predict
      abstinence and attendance at self-help group meetings in recently detoxified
      alcoholics, and this may have prognostic and therapeutic significance.

PMID- 10414613
TI  - Underlying personality differences between alcohol/substance-use disorder
      patients with and without an affective disorder.
AB  - The Myers-Briggs Type Indicator (MBTI), a popular personality test, was used to
      profile the personalities of in-patient alcoholics/substance-use disorder
      patients who had, and those who did not have, a concurrent affective disorder
      diagnosis. The MBTI divides individuals into eight categories: Extroverts and
      Introverts, Sensors and Intuitives, Thinkers and Feelers, and Judgers and
      Perceivers. Alcohol/substance-use disorder patients with no affective disorder
      differed from a normative population only in being significantly more often
      Sensing and significantly less often Intuitive single-factor types. The
      Extroverted/Sensing/ Feeling/Judging four-factor type was also significantly over
      represented in this group, compared to a normative population. In contrast, mood
      disordered alcohol/substance-use disorder patients were significantly more often
      Introverted, Sensing, Feeling, and Perceiving and significantly less often
      Extroverted, Intuitive, Thinking, and Judging single-factor types. They were also
      significantly more often Introverted/Sensing/ Feeling/Perceiving and
      Introverted/Intuitive/Feeling/Perceiving four-factor types. 'Pure' alcohol/
      substance-use disorder patients differed from alcohol/substance-use disorder
      patients with a mood disorder in that they were significantly more often
      Extroverted and Thinking and significantly less often Introverted and Feeling
      single-factor types; and significantly less often were an Introverted/Sensing/
      Feeling/Perceiving four-factor type. The above results may have psychogenetic,
      diagnostic, and psychotherapeutic implications.

PMID- 10414615
TI  - Association between preference for sweets and excessive alcohol intake: a review
      of animal and human studies.
AB  - This report reviews a series of studies demonstrating a relationship between the
      consumption of sweets and alcohol consumption. There is consistent evidence
      linking the consumption of sweets to alcohol intake in both animals and humans,
      and there are indications that this relationship may be at least partially
      genetic in nature. Alcohol-preferring rats have a tendency to consume sucrose and
      saccharin solutions far beyond the limits of their normal fluid intake and this
      has been proposed to be a model of the clinical phenomenon known as loss of
      control. Furthermore, rats and mice, genetically bred to prefer alcohol, tend to
      choose more concentrated sweet solutions, compared to animals which do not prefer
      alcohol. Similar tendencies to prefer ultra-sweet solutions have been noted in
      studies of alcoholic subjects, with most alcoholics preferring sweeter sucrose
      solutions than do controls. Evidence also exists that those alcoholics who prefer
      sweeter solutions may represent a familial form of alcoholism. Finally,
      consumption of sweets and/or sweet solutions may significantly suppress alcohol
      intake in both animals and in alcoholics. Carbohydrate structure and sweet taste
      may contribute to this effect through different physiological mechanisms
      involving serotonergic, opioid, and dopaminergic functions. The possibility that
      there is concordance between sweet liking and alcohol consumption and/or
      alcoholism has theoretical, biological, and diagnostic/practical implications.

PMID- 10414614
TI  - Behavioural features of alcohol-preferring rats: focus on inbred strains.
AB  - A recent study conducted a factor analysis on 18 behavioural measures obtained
      from four alcohol-preferring and five alcohol-non-preferring rat lines/strains.
      It was concluded that variables such as saccharin intake, ultrasonic
      vocalizations following an air puff, and defaecation in an open field were
      associated with voluntary and forced alcohol consumption. In contrast, measures
      such as time immobile in the forced swim test and time spent in the open arms of
      the elevated plus maze were not consistently associated with voluntary alcohol
      intake. The present study focuses on alcohol intake and related measures in four
      inbred strains of Fawn-Hooded (FH) rats that differ in voluntary alcohol intake
      and the ACI/N inbred rat strain, which voluntarily consumes very little alcohol.
      FH rats inbred by Jean Dodds (FH/Wjd) drank significantly more alcohol than FH
      rats inbred by Gordon Harrington (FH/Har) or selectively inbred by Abraham
      Provoost (FHH/Eur and FHL/EUR). In contrast, only the FH/Har strain was active in
      the forced swim test, suggesting that immobility and voluntary alcohol intake may
      be influenced by different genetic factors. The FH/Wjd rats were also much more
      immobile than the ACI/N rats in the forced swim test and drank almost 10 times as
      much alcohol voluntarily. Comparing the two parental lines with reciprocal F1
      crosses revealed that alcohol consumption was influenced largely by additive
      genetic factors (F1 progeny had intermediate scores), whereas immobility was also
      influenced by dominance genetic factors (F progeny resembled the FH/Wjd parent).
      Preliminary analysis of 43 F2 progeny indicated that alcohol intake and
      immobility were not correlated. Thus, immobility in the forced swim test and high
      voluntary consumption of alcohol, two prominent features of the FH/Wjd rat strain
      which may be related to its serotonergic dysfunction, appear to be mediated by
      different genetic factors.

PMID- 10414616
TI  - Dependence, locus of control, parental bonding, and personality disorders: a
      study in alcoholics and controls.
AB  - Personality traits, socio-cultural factors, and dysfunctional family systems are
      considered to be important in the aetiology and clinical development of
      alcoholism. Particularly, conflict and issues involving psychological (emotional)
      dependence have long been associated with alcohol addiction. The present work,
      part of a more extensive study to validate a new rating scale to measure
      emotional dependence, the Dependence Self-rating Scale (DSRS), assesses
      dependence, orientation of locus of control, parental bonding perceptions, and
      personality disorders (PDs) in alcoholic and non-alcoholic samples. The
      alcoholics showed a prevalence of PDs of 31.3%. The most frequent is the Schizoid
      PD (40%) followed by the Dependent PD (20%). Subjects with antisocial PD were not
      included in our selection criteria. The alcoholics scored higher on the DSRS than
      the controls, but this difference was not statistically significant. By making a
      comparison between subjects with and without PDs, the DSRS scores were
      significantly higher in alcoholics with PDs. No significant differences between
      alcoholics and non-alcoholics in the parental perceptions and locus of control
      were seen. These findings are sufficiently coherent to encourage further studies
      on psychological emotional dependence in alcoholics using the DSRS.

PMID- 10414617
TI  - Central nervous system serotonin and personality as variables contributing to
      excessive alcohol consumption in non-human primates.
AB  - Non-human primates will readily consume an alcohol solution for its reinforcing
      effects when such a solution is palatable, with some subjects consuming alcohol
      to excess. In this review, we discuss variables that contribute to high alcohol
      consumption and the behaviours that are correlated with it in a non-human primate
      model. Developmental and behavioural correlates of central nervous system (CNS)
      serotonergic activity, as measured by concentrations of the serotonin metabolite
      5-hydroxyindol-3-ylacetic acid (5-HIAA) in the cerebrospinal fluid (CSF), were
      used to investigate neurogenetic influences on alcohol consumption, as well as
      personality traits that characterize excessive alcohol intake. Inter-individual
      differences in CSF 5-HIAA concentrations were shown to have trait-like qualities,
      and with stable inter-individual differences across time and settings. Research
      has shown numerous similarities between human and non-human primates with respect
      to Type I- and II-like alcohol abuse and their associated behaviours. In the
      present series of studies, features characteristic of Type I alcohol misuse, such
      as high levels of anxiety, hypothalamic-pituitary-adrenal output, and situational
      stress predicted high alcohol intake. Primates with low CSF 5-HIAA concentrations
      also exhibited behaviours characteristic of Type II alcohol abuse. Principal
      among the traits that these subjects exhibited were deficits in impulse control.
      For example, subjects with low CSF 5-HIAA concentrations engaged in spontaneous
      behaviours that bring reinforcement but placed them at risk, such as entering
      food baited traps, jumping from dangerous heights to get from one tree to
      another, and consuming large amounts of alcohol. They can be characterized by
      other Type II-like deficits, such as impaired social competence, social
      alienation, and unrestrained, violent aggression. Non-human primates with low CSF
      5-HIAA concentrations also exhibited high intrinsic tolerance following modest
      intakes of alcohol, and high rates of aggression during intoxication. High
      preferences for sweet solutions were shown to predict excessive alcohol
      consumption. Maternal and paternal genetic influences played major roles in
      producing low CNS serotonin function and excessive alcohol consumption. These
      genetic influences on serotonin function were exacerbated by early rearing
      experiences, particularly parental deprivation.

PMID- 10414618
TI  - Ethics committees and qualitative health research in New Zealand.

PMID- 10414619
TI  - The prevalence of asthma symptoms, bronchial hyperresponsiveness and atopy in New
      Zealand adults.
AB  - AIMS: To examine the prevalence of asthma symptoms, bronchial hyperresponsiveness
      (BHR) and atopy in a random population sample of New Zealand adults. METHODS: A
      random sample of 2004 adults, aged 20-44 years, in Hawkes Bay, Wellington and
      Christchurch, were selected from respondents to a one-page respiratory screening
      questionnaire and invited to take part in further testing. Subjects attending the
      testing centres' laboratories underwent a detailed respiratory symptom
      questionnaire, Phazet testing to eleven common allergens, blood samples for total
      and specific IgE, and measurement of bronchial hyperresponsiveness. Subjects who
      did not wish to participate were encouraged to complete the questionnaire by
      telephone. RESULTS: A participation rate of 67% (1257 of 1877 eligibles) was
      achieved. We found a high prevalence for all measures of asthma in the previous
      12 months: wheezing was reported by 28.5%, waking with shortness of breath by
      7.7%, a physician diagnosis of asthma by 15.9% and asthma medications were used
      by 8.5%. Bronchial hyperresponsiveness was found in 24.9%, atopy in 34.8% and
      elevated serum IgE levels in 30.5%. Asthma symptoms (in the past 12 months) and
      atopy decreased with increasing age, whereas bronchial hyperresponsiveness
      increased with age. Females reported higher prevalences of waking with coughing
      (45.9%), nasal allergies (43.5%) and skin allergies (48.8%) compared to males
      (30.5%, 31.9% and 37.0%, respectively). There were no significant regional
      differences. CONCLUSIONS: Asthma symptoms, bronchial hyperresponsiveness and
      atopy are all common in adult New Zealanders. Their prevalence is associated with
      age, gender and current smoking but there are no significant regional differences
      between Hawkes Bay, Wellington and Christchurch.

PMID- 10414620
TI  - Iron deficiency anaemia and adverse dietary habits in hospitalised children.
AB  - AIMS: To determine the prevalence of iron deficiency anaemia in children
      hospitalised with acute illness and the frequency of adverse dietary habits in
      the children with iron deficiency anaemia. METHODS: This was a prospective study
      of all children, aged 9 to 23 months resident in metropolitan Auckland who were
      hospitalised at Starship Children's Hospital, from July to October 1997, with an
      acute medical illness and had a full blood count performed. Iron deficiency
      anaemia was defined as haemoglobin <110 g/L, red cell distribution width >14.5%
      and either serum ferritin <10 microg/L or transferrin saturation <10%. Ethnicity
      and dietary habits of the children were determined by interviewing parents.
      RESULTS: During the study period 284 children, aged 9 to 23 months were admitted,
      of whom 206 (73%) had a full blood count performed. Sixty (29%) of these 206
      children had iron deficiency anaemia. A larger proportion of Pacific Islands (P)
      compared to Maori (M) or European children (E) had iron deficiency anaemia. (P vs
      M:43% vs 21%, p=0.01; P vs E:43% vs 14%, p<0.001; M vs E 21% vs 14%, P=0.27).
      Sixty-nine percent of the children with iron deficiency anaemia had a dietary
      factor (early introduction of cows milk, late introduction of meat or regular
      consumption of tea) likely to have contributed to their iron deficiency.
      CONCLUSIONS: Iron deficiency is prevalent in Auckland children aged 9 to 23
      months, hospitalised with an acute illness. The prevalence varies with ethnicity.
      Adverse dietary habits are present in 69% of the children with iron deficiency
      anaemia.

PMID- 10414621
TI  - Diabetes in New Zealand--better information needed.
AB  - AIMS: To review the availability and quality of data on the epidemiology of
      diabetes in New Zealand. METHODS: A search was undertaken for all Medline-indexed
      publications on diabetes in New Zealand. Hospitalisation and mortality data (ICD9
      code 250) from the New Zealand Health Information Service (NZHIS) were examined.
      RESULTS: Information on diabetes in New Zealand has come from community surveys,
      national surveys, diabetes registers, hospitalisation data and mortality data.
      Much of this information has been valuable, but there is still inadequate
      national information on diabetes prevalence, incidence and time trends.
      CONCLUSION: Information technology provides an opportunity to couple the
      surveillance of diabetes with improved diabetes care. Medical practitioners need
      to support the development of their own practice-based registers/recall systems
      and to contribute to the development of district-based diabetes registers where
      these have a central focus on improving diabetes care.

PMID- 10414622
TI  - Laparoscopic appendicectomy--a trainee's experience.
AB  - AIM: A retrospective audit was carried out of a single advance surgical trainee's
      experience with laparoscopic appendicectomy, in an attempt to justify its ongoing
      utilization in the management of patients with this acute surgical presentation.
      RESULTS: Two hundred laparoscopic appendicectomies have been performed over the
      last four years on an intention-to-treat basis. Sixty-five per cent have been
      female, with an average population age of 24 years. There was a true appendicitis
      rate of 79%, with a conversion rate of 6%, and a mean operating time of 32
      minutes. Complications have included intra-abdominal sepsis in three (1.5%) and
      postoperative ileus (1%). There have been no reported wound infections. The mean
      times to discharge were two days in the laparoscopic group and 3.7 days in the
      converted group. CONCLUSION: This study supports the utilization of laparoscopic
      appendicectomy as a safe and effective operation for surgical trainees to gain
      laparoscopic experience.

PMID- 10414623
TI  - A qualitative study of general practitioner access to diagnostic imaging services
      in the Central Region.
AB  - AIMS: To determine general practitioners' views about access to diagnostic
      imaging services in the Central Region, particularly for low-income patients, and
      the perceived impact of limited access on patient outcomes. METHOD: A key general
      practitioner in each of 21 main geographical localities facilitated a discussion
      with a group of general practitioners using a pretested questionnaire. Each group
      tried to reach a consensus view and these responses were analysed to determine
      the common themes and ideas. RESULTS: General practitioners identified
      difficulties and barriers to access for all common diagnostic imaging procedures
      throughout the Central Region. Cost was the main barrier to access. Limited
      access resulted in increased risk for patients, unnecessary use of outpatient
      facilities and wasted time for general practitioners. Up to 40% of patients with
      restricted access to diagnostic imaging services were referred to outpatient
      departments and up to 20% went without the service. CONCLUSION: Many general
      practitioners in the Central Region do not have direct access to diagnostic
      imaging services except for patients who can afford private services. This is
      thought to generate significant additional costs and risks for patients. Improved
      access to these services would reduce hospital outpatient waiting times and
      provide a better service for patients.

PMID- 10414624
TI  - Medical students and debt.

PMID- 10414626
TI  - Family practice as a career choice.

PMID- 10414625
TI  - The frequency in New Zealand of a mitochondrial DNA mutation (1555 A to G)
      associated with aminoglycoside-induced hearing loss.

PMID- 10414627
TI  - Pain, depression and survival.

PMID- 10414628
TI  - Physician reimbursement issues in home health care.

PMID- 10414629
TI  - Male dyspareunia in the uncircumcised patient.

PMID- 10414630
TI  - Hypnosis in the treatment of hyperemesis gravidarum.

PMID- 10414631
TI  - Common causes of vision loss in elderly patients.
AB  - Vision loss among the elderly is a major health care problem. Approximately one
      person in three has some form of vision-reducing eye disease by the age of 65.
      The most common causes of vision loss among the elderly are age-related macular
      degeneration, glaucoma, cataract and diabetic retinopathy. Age-related macular
      degeneration is characterized by the loss of central vision. Primary open-angle
      glaucoma results in optic nerve damage and visual field loss. Because this
      condition may initially be asymptomatic, regular screening examinations are
      recommended for elderly patients. Cataract is a common cause of vision impairment
      among the elderly, but surgery is often effective in restoring vision. Diabetic
      retinopathy may be observed in the elderly at the time of diagnosis or during the
      first few years of diabetes. Patients should undergo eye examinations with
      dilation when diabetes is diagnosed and annually thereafter.

PMID- 10414632
TI  - Ludwig's angina in children.
AB  - Ludwig's angina is a potentially life-threatening, rapidly expanding, diffuse
      inflammation of the submandibular and sublingual spaces that occurs most often in
      young adults with dental infections. However, this disorder can develop in
      children, in whom it can cause serious airway compromise. Symptoms include severe
      neck pain and swelling, fever, malaise and dysphagia. Stridor suggests an
      impending airway crisis. Causative bacteria include many gram-negative and
      anaerobic organisms, streptococci and staphylococci. Initial treatment consists
      of high doses of penicillin G given intravenously, sometimes in combination with
      other drugs. Patients usually recover without complications.

PMID- 10414633
TI  - Prevention and treatment of traveler's diarrhea.
AB  - Common pathogens in traveler's diarrhea include enterotoxigenic Escherichia coli,
      Campylobacter, Shigella, Salmonella, Yersinia and many other species. Viruses and
      protozoa are the cause in many cases. Fortunately, traveler's diarrhea can
      usually be avoided by carefully selecting foods and beverages. Although drug
      prophylaxis is now discouraged, treatment with loperamide (in the absence of
      dysentery) and a fluoroquinolone, such as ciprofloxacin (500 mg twice daily for
      one to three days), is usually safe and effective in adults with traveler's
      diarrhea. Trimethoprim-sulfamethoxazole and doxycycline are alternatives, but
      resistance increasingly limits their usefulness. Antibiotic treatment is best
      reserved for cases that fail to quickly respond to loperamide. Antibiotic
      resistance is now widespread. Nonabsorbable antibiotics, immunoprophylaxis with
      vaccines and biotherapeutic microbes that inhibit pathogen infection may
      eventually supplant antibiotic treatment. In the meantime, azithromycin and new
      fluoroquinolones show promise as possible replacements for the older agents.
      Ultimately, the best solution is improvements in sanitary engineering and the
      development of safe water supplies.

PMID- 10414634
TI  - Vasectomy techniques.
AB  - Vasectomy can be performed by means of various techniques, although each
      vasectomy technique requires isolation and division of the vas and operative
      management of the vasal ends. Removal of at least 15 mm of vas is recommended,
      although division of the vas without removal of a segment is effective when this
      technique is combined with other techniques for handling the vasal ends, such as
      thermal luminal fulguration and proximal fascial interposition. Ligation of the
      ends without the aid of surgical clips may result in necrosis and sloughing of
      the ends, which may cause early failure. Leaving the testicular end of the vas
      open has been shown to be effective and to result in a lower incidence of
      epididymal congestion and sperm granuloma. The no-scalpel technique offers
      shorter operating time, less pain and swelling, and faster recovery.

PMID- 10414635
TI  - A rational approach to the treatment of hypertension in special populations.
AB  - Hypertension in blacks is usually characterized by low renin, expanded volume and
      sensitivity to salt. Diuretics are the preferred initial therapy, but response to
      calcium channel antagonists is also good. The blood pressure response to
      monotherapy with beta blockers or angiotensin-converting enzyme (ACE) inhibitors
      is blunted, but this effect is abolished with concomitant use of diuretics. The
      two major types of hypertension in older persons are isolated systolic
      hypertension and combined systolic and diastolic hypertension. Strong data
      support the treatment of combined hypertension in patients 60 to 79 years of age
      and isolated systolic hypertension in patients 60 to 96 years of age. Diuretics
      and long-acting dihydropyridine calcium channel antagonists are the recommended
      initial therapies for isolated systolic hypertension. More studies are necessary
      before recommendations can be made about the treatment of combined hypertension
      in patients 80 years of age and older.

PMID- 10414636
TI  - Responses to questions about the specialty of family practice as a career.
AB  - This article provides answers to many of the questions medical students ask about
      the specialty of family practice. It is the fourth update of a previous article
      and was developed in response to feedback from medical students at the 1997
      National Congress of Student Members held by the American Academy of Family
      Physicians. Students at the 1998 Congress also identified areas of interest and
      concern. This article discusses the hours and income of the family physician, the
      scope of medical practice in the specialty, required continuing medical education
      and board certification, family practice residency training and combined
      specialty training.

PMID- 10414637
TI  - Screening for developmental dysplasia of the hip.
AB  - Screening programs relying primarily on physical examination techniques for the
      early detection and treatment of congenital hip abnormalities have not been as
      consistently successful as expected. Since the 1980s, increased attention has
      been given to ultrasound imaging of the hip in young infants (less than five
      months of age) as a possible tool for improving patient outcomes. Although
      ultrasound examination may not provide advantages over careful repeated physician
      examination for universal screening, a growing body of evidence indicates that
      ultrasound surveillance of mild abnormalities can reduce the need for bracing
      without worsening outcomes. Radiographic documentation of hip normality after the
      femoral nucleus of ossification has appeared (at three to five month of age) is
      still appropriate to rule out hip dysplasia.

PMID- 10414638
TI  - Prevention of osteoporosis and fractures.
AB  - Osteoporosis and low bone density are associated with a risk of fracture as a
      result of even minimally traumatic events. The estimated lifetime risk of
      osteoporotic fracture is as high as 50 percent, especially in white and Asian
      women. The use of caffeine, tobacco and steroids is associated with a decrease in
      bone density. Cognitive impairment, vision problems and postural instability
      increase the risk of falling and sustaining a fracture. Medications such as long
      acting sedative hypnotics, anticonvulsants and tricyclic antidepressants also
      increase this risk. Combinations of clinical and radiographic findings can
      predict fracture risk more effectively than bone densitometry, but often only
      after the first fracture has occurred. The addition of dietary calcium and/or
      vitamin D is clearly both cost-effective and significant in reducing the
      likelihood of fractures. Bisphosphonates reduce fracture risk but at a cost that
      may be prohibitive for some patients. Estrogen and estrogen-receptor modulators
      have not been well studied in randomized trials evaluating the reduction of
      fractures, but they are known to increase bone density. Pharmacologic therapy and
      the reduction of sensory and environmental hazards can prevent osteoporotic
      fractures in some patients.

PMID- 10414639
TI  - Disorders of puberty.
AB  - Normal puberty begins between eight and 14 years of age in girls and between nine
      and 14 years of age in boys. Pubic hair distribution is used to stage puberty,
      along with breast size and contour in girls and testicular volume in boys. Some
      children experience constitutional sexual precocity, but precocity is likely to
      be pathologic if it occurs in very young children, if there is contrasexual
      development or if the sequence of normal pubertal milestones is disrupted.
      Delayed puberty may be constitutional, but pathologic causes should be
      considered. The etiology of a pubertal disorder can often be determined with the
      use of a focused medical history, a directed physical examination and appropriate
      diagnostic tests. Treatment for disorders of puberty is determined by the
      underlying cause.

PMID- 10414640
TI  - Depression in women: diagnostic and treatment considerations.
AB  - Women experience depression twice as often as men. The diagnostic criteria for
      depression are the same for both sexes, but women with depression more frequently
      experience guilt, anxiety, increased appetite and sleep, weight gain and comorbid
      eating disorders. Women may achieve higher plasma concentrations of
      antidepressants and thus may require lower dosages of these medications.
      Depending on the patient's age, the potential effects of antidepressants on a
      fetus or neonate may need to be considered. Research indicates no increased
      teratogenic risk from in utero exposure to selective serotonin reuptake
      inhibitors (SSRIs) and tricyclic antidepressants. SSRIs are effective in treating
      premenstrual dysphoric disorder and many comorbid conditions associated with
      depression in women. Psychotherapy may be used alone in women with mild to
      moderate depression, or it may be used adjunctively with antidepressant drug
      therapy. Women who have severe depression accompanied by active suicidal thoughts
      or plans should usually be managed in conjunction with a psychiatrist.

PMID- 10414641
TI  - A finger infection in a pet store employee.

PMID- 10414642
TI  - A troubled teen: matters of confidentiality.

PMID- 10414643
TI  - Medical genetics. American Academy of Family Physicians.

PMID- 10414644
TI  - Advisory Committee on Immunization Practices issues recommendations for the 1999
      2000 influenza season.

PMID- 10414645
TI  - National Stroke Association develops a consensus statement on prevention of
      stroke.

PMID- 10414646
TI  - My needlestick.

PMID- 10414647
TI  - Multifactorial analysis of firearm wounds to the head with attention to anatomic
      location.
AB  - Firearm wounds to the head are often fatal and are routinely encountered in the
      practice of forensic pathology in the United States. Often, the anatomic site of
      the entrance wound is used to support or refute the manner of death indicated by
      the scene investigation and/or circumstances of the case. The present
      retrospective study of 120 fatalities resulting from 140 firearm wounds to the
      head correlates the anatomic region of the entrance wound and range of fire with
      the manner of death. Other demographic data analyzed include age, race, and
      gender of the decedents, as well as evidence of drug and/or ethanol use. It is
      hoped that this study will provide concrete data to support the largely anecdotal
      associations between the specific site of entry of firearm injuries to the head
      and the manner of death.

PMID- 10414648
TI  - An experimental study of death in a reverse suspension.
AB  - To investigate the course of respiration and circulation in a head-down position,
      14 rabbits were set in reverse suspension. The respiratory rate increased a
      little, but the amplitude of the respiratory movements did not change in the
      beginning of the experiment. The amplitude of respiratory movements then began to
      reduce gradually, and toward the end of the experiment, it reduced suddenly. PaO2
      increased in the beginning of the experiment and then began to decrease in
      accordance with the reduction of the amplitude of the respiratory movements. The
      blood pressure decreased with relation to the decrease of PaO2 resulting from the
      reduction of the amplitude of the respiratory movements. All rabbits died in 17
      to 44 hours (average, 26 hours). The results suggested that the cause of death in
      a head-down position is due to postural asphyxia resulting from hindered
      respiratory movements, and that it is possible to survive for at least half a day
      in a head-down position.

PMID- 10414649
TI  - Cocaine-associated rhabdomyolysis and excited delirium: different stages of the
      same syndrome.
AB  - Previous case reports indicate that cocaine-associated rhabdomyolysis and excited
      delirium share many similar features, suggesting that they may be different
      stages of the same syndrome. We tested this hypothesis by comparing data from 150
      cases of cocaine-associated rhabdomyolysis reported in the medical literature
      with data from an autopsy registry for 58 victims of fatal excited delirium and
      125 victims of fatal acute cocaine toxicity. Patients with rhabdomyolysis are
      similar to victims of fatal excited delirium with regard to age; gender; race;
      route of cocaine administration; the experiencing of excitement, delirium, and
      hyperthermia; and the absence of seizures. Compared with victims of fatal acute
      cocaine toxicity, patients with rhabdomyolysis are different with regard to each
      of these variables. Compared with victims of fatal acute cocaine toxicity, both
      victims of rhabdomyolysis and fatal excited delirium are more likely to be black,
      male, and younger; to have administered cocaine by smoking or injection; and to
      have experienced excitement, delirium, and hyperthermia; they are also less
      likely to have had seizures. Because cocaine-associated rhabdomyolysis and
      excited delirium have similar clinical features and risk factors, occur in
      similar populations of drug users, and can be explained by the same
      pathophysiologic processes, we conclude that they are different stages of the
      same syndrome. It appears that this syndrome is caused by changes in dopamine
      processing induced by chronic and intense use of cocaine rather than by the acute
      toxic effects of the drug.

PMID- 10414650
TI  - Frequency of neck organ fractures in hanging.
AB  - This study is a retrospective analysis of 307 accidental and suicidal hangings
      for the presence or absence of neck organ fractures. Approximately 9% of cases
      showed such fractures. This is in agreement with one prior study and in
      disagreement with others. The factor most likely to be predictive of fractures is
      advanced age. Gender, height of suspension, and ligature type do not seem to be
      of predictive value.

PMID- 10414651
TI  - Schizophrenia and sudden death: a medical examiner case study.
AB  - This study reviews the causes of sudden death of 66 schizophrenic patients who
      presented to the Office of the Chief Medical Examiner (OCME) for the State of
      Maryland over a 3-year period from 1994 through 1996. We identified an increased
      incidence of suicide compared with the general population of OCME cases. This
      observation is consistent with reports by other investigators. The majority of
      the deaths were the result of natural diseases, mostly atherosclerotic
      cardiovascular disease. Accidents, suicides, and 1 homicide were also present in
      this group.

PMID- 10414652
TI  - Suicide by pipe bomb: a case report.
AB  - While lying down, a 23-year-old man detonated an improvised explosive device
      placed behind his head. The posterior neck and shoulders were singed, and much of
      the brain was avulsed. Death was due to laceration and partial avulsion of the
      cerebrum, midbrain, and brain stem. The injuries had a directional nature. Facts
      derived from the scene investigation and gross dissection, including nature,
      distribution, and extent of the wounds, in conjunction with preceding medical and
      social history, allowed for a reasonable reconstruction of the circumstances.

PMID- 10414653
TI  - Concealed homicidal strangulation by burning.
AB  - Compression of the neck, either with the hands or by a ligature, is not an
      uncommon method of homicide. Burning of the body to try to conceal the homicide
      may complicate the situation by making it difficult to interpret the findings. We
      hereby report two cases of homicidal ligature strangulation with extensive
      burning of the bodies. In both cases, external findings included the presence of
      a soft piece of fabric around the neck that, when removed, disclosed a portion of
      pale, unburned skin that vividly contrasted with surrounding areas.
      Osteocartilaginous lesions were present in only one case. Carboxyhemoglobin
      levels in both cases were very low, and the histopathologic examination of distal
      airways for soot particles was negative.

PMID- 10414654
TI  - Retrospective analysis of medicolegal cases and evaluation for erectile function.
AB  - Erectile function (EF) is an important question in lawsuits for divorce, rape,
      and damages. In this study, a method to evaluate medicolegal cases is defined,
      and the characteristics of the 265 cases screened for EF between 1989 and 1997
      were analyzed. Interview, physical examination, psychometric evaluation,
      nocturnal penile tumescence, serum hormone levels and blood chemistry,
      intracavernosal drug injection, penile Doppler ultrasonography, and
      pharmacocavernosometry and pharmacocavernosography tests were used for diagnosis.
      The tests performed were selected according to the age of the subject. Of the 265
      cases 128 (48.3%) were for divorce, 116 (43.7%) were for rape, and 21 (8%) were
      for indemnity relating to lawsuits for damages. In only 7 cases (2.7%) was the
      defendant <15 years of age. Organic pathology for erectile dysfunction (ED) was
      present in 22% of lawsuits for divorce, 40.5% of lawsuits for rape, and 33.4% of
      lawsuits for damages. Three men in cases of divorce and 2 men after genital
      trauma due to traffic accident suffered psychological ED. This study indicates
      that lawyers may abuse the assertion of ED in lawsuits for divorce and rape. In
      128 divorce cases the defendant was accused of being impotent, but evaluation
      proved that 75.8% had normal EF. In lawsuits for rape, 59.5% of defendants had
      normal EF although the lawyers of the rapist claimed their clients were impotent.
      The investigation, interpretation, and characteristics of medicolegal cases may
      differ in countries with different cultures.

PMID- 10414655
TI  - Thymus alterations related to intravenous drug abuse.
AB  - It has been noticed on forensic material that Hassall's corpuscles of the thymus
      are more often calcified in intravenous drug abusers than in healthy persons.
      Thymuses of 15 intravenous heroin addicts were histologically examined and
      compared with thymuses of 15 healthy persons. Acute bleeding and dystrophic
      calcification in the thymocyte's parenchyma were more common among intravenous
      drug abusers (p = .005 and p = .001, respectively). The degree of physiologic
      involution measured by fatty replacement and the clarity of border between cortex
      and medulla was equal. No significant diversity was found in the features of
      Hassall's bodies. Our study emphasizes the necessity for a defined criteria of
      morphologic changes in the thymus that could be expected in intravenous drug
      abusers. In that way it would be possible to complete the forensic findings as
      well as to examine immunologic system alterations of that risk population.

PMID- 10414656
TI  - Use of liquid nitrogen to remove duct tape from a homicide victim.
AB  - Removal of duct tape or similar adhesive products from a homicide victim may be
      facilitated by rapidly chilling the tape surface with liquid nitrogen. Physical
      separation of tape layers can be performed using the same technique.
      Cyanoacrylate glue (i.e., "super-glue") may be used to preserve fingerprints on
      the outer surface of the tape for recovery, or other techniques may be used to
      recover fingerprints from the outer surface prior to tape removal.

PMID- 10414658
TI  - Cultural influence on the incidence and choice of method of suicide in Saudi
      Arabia.
AB  - The present study was undertaken to explore how racial and cultural factors could
      possibly influence suicidal rates and patterns in Saudi Arabia. During the 10
      year period from 1986 to 1995, 221 cases of suicide were examined at the Medico
      legal Center, Dammam, Saudi Arabia. The suicide rate for the entire population
      averaged 1.1/100,000 population per annum. The male-to-female ratio was 4.5:1.
      The highest suicide rate was among the age group from 30 to 39 years (44.3%),
      followed by the age group from 20 to 29 years (32.6%), and the lowest suicide
      rate was among the age group <20 years (1.8%). The rate in the group >60 years
      was also low (3.2%). Immigrants formed 77% of the cases, and of these, Asians
      accounted for 70% of the overall cases and Indians showed the highest suicidal
      rates (43%). The most common means of suicide chosen was hanging (63%), followed
      by jumping from heights (12%) and gunshot injuries (9%); death from poisoning
      accounted for only 6% of cases. This study showed an increasing rate of suicide
      during the second 5-year period compared with the first 5-year period.

PMID- 10414657
TI  - Nontraumatic clostridial myonecrosis.
AB  - We describe three cases of nontraumatic clostridial myonecrosis seen at the
      Victorian Institute of Forensic Medicine. Nontraumatic clostridial myonecrosis is
      an uncommon and often fatal condition that requires immediate institution of
      appropriate medical and surgical therapy. It is most commonly caused by
      Clostridium perfringens and Clostridium septicum and is associated with
      gastrointestinal and hematologic malignancies, diabetes mellitus, and peripheral
      vascular disease. The clinical features include a rapidly evolving acute illness
      with severe pain, marked tachycardia, and brawny discoloration of the skin with
      bullae formation and crepitus, followed by hypotension and acute renal failure.
      Features at autopsy include reddish brown skin discoloration with bullae
      formation and necrotic skeletal muscle. Radiographs may be of use prior to the
      postmortem in detecting gas within the soft tissues. Gram stain and microbiologic
      culture are important in establishing a definitive diagnosis; although the major
      factors in suggesting the diagnosis are the recognition of the typical clinical
      history and macroscopic autopsy findings.

PMID- 10414659
TI  - A decade of pediatric homicide: a retrospective study at the Medical University
      of South Carolina.
AB  - More than 3 million children are abused and/or neglected each year in the United
      States. Unfortunately, a significant percentage of these cases result in homicide
      by child abuse or child neglect. Causes of death range from blunt force trauma
      and shaking to asphyxia to immolation. We retrospectively reviewed all pediatric
      forensic cases referred to the Medical University of South Carolina Forensic
      Pathology Section over the past 10 years, from January 1986 to December 1995. Of
      these, we looked only at children < or =5 years of age. The majority (342 cases,
      69%) of these deaths were classified as natural, 96 (19%) as accident, and 60
      (12%) as homicide. Of the homicides, we examined the cause of death; age, gender,
      and race of the victim; relationship to the perpetrator; time interval between
      injury and death; and the initial history given as to the cause of the injury.
      The cause of death fell into nine categories, the number one category being head
      trauma. Forty-five percent of the homicides were by head trauma, 12% by abdominal
      or body trauma, 25% by asphyxia (with half of these due to drowning), 10% by
      carbon monoxide poisoning or thermal injury, and the remaining 8% involving cases
      of neglect, stabbing, and poisoning. The majority of the homicide victims were
      male (67%) and black (67%). Forty-six percent were < or =1 year of age.
      Approximately 25% of the homicide cases were designated as shaken baby syndrome
      (SBS). In 97% of the cases, the assailant was known to the victim and was a
      family relative in 77%. Sixty-three percent of the assailants were female and 45%
      of the assailants were male; in 12%, the assailants were both parents, and in 1
      case, the assailant remains unknown. Of the asphyxia deaths, 87% of the
      assailants were female. The time interval between injury and death ranged from
      minutes to hours in most cases to months in cases of repeated abuse and chronic
      injury and sequelae. The time interval between injury and the onset of symptoms
      remains unknown in most cases due to inconsistencies in the history and lack of
      credibility of the caretaker. The most common initial history given was "a fall"
      (20%). We report our findings of a decade of pediatric homicides to increase
      awareness of the common scenarios and case histories, demographics of the
      victims, causes of death, and perpetrators of pediatric homicide.

PMID- 10414660
TI  - Mountaineering fatalities on Mount Rainier, Washington, 1977-1997: autopsy and
      investigative findings.
AB  - Mountain climbing is a popular recreational activity with a growing number of
      participants and associated fatalities. To define the characteristics of these
      fatal incidents and the typical autopsy findings in the victims, we reviewed the
      autopsy and investigative findings of all fatalities that occurred on Mount
      Rainier from 1977 through 1997. A total of 50 deaths occurred in 29 separate
      incidents. Fifty-eight percent of accident victims died as the result of a fall;
      another 34% died as a result of an avalanche. The incidents leading to death
      occurred at an average altitude of 3652 m (11,977 feet); range, 2073 to 4389 m
      (6800-14,400 feet). The average age of the victims was 31.2 years (range, 17-55
      years), and 47 of the 50 were men (94%). Bodies were not recovered in 13 cases
      (26%). Autopsies were performed in 30 of the remaining 37 cases. At autopsy, the
      cause of death was ascribed to multiple injuries in 12 cases (40%), isolated head
      and neck injuries in 7 cases (23%), and chest injuries in 1 case (3%). Asphyxia
      and hypothermia were the cause of death in 8 cases (27%) and 2 cases (7%),
      respectively. The frequency of specific injuries is presented by anatomic region.
      The unique autopsy and investigative features of mountaineering deaths are
      discussed.

PMID- 10414661
TI  - Sudden death due to a central neurocytoma.
AB  - The central neurocytoma is a common, usually intraventricular tumor with bland
      histologic features. We report a case of a 51-year-old man who died suddenly. At
      autopsy, a neurocytoma with acute hemorrhage filled the anterior left lateral
      ventricle. The tumor matrix and surrounding brain tissue contained accumulations
      of hemosiderin. Previously, 2 cases of central neurocytoma with associated
      hemorrhage have been reported. Hemorrhage appears to be a serious complication
      associated with these neoplasms.

PMID- 10414662
TI  - Esophagoaortic perforation by foreign body (coin) causing sudden death in a 3
      year-old child.
AB  - We report an extremely unusual consequence to foreign body ingestion in a case of
      a 3-year-old boy who died suddenly and at autopsy was found to have an
      esophagoaortic fistula. This fistula was caused by a coin which lodged
      posteriorly and eroded through the esophagus into the aorta. Serious
      complications following foreign body ingestion are rare and include stricture
      formation, intramural abscess, and the formation of fistula tracts. This case
      illustrates the potentially unpredictable behavior of impacted foreign bodies.
      The child's parents were initially suspected of child abuse based on the terminal
      hemoptysis.

PMID- 10414663
TI  - Death due to thrombotic thrombocytopenic purpura in pregnancy: case report with
      review of thrombotic microangiopathies of pregnancy.
AB  - Maternal death during pregnancy, although uncommon, may result from a broad range
      of conditions. In this paper, a case of thrombotic thrombocytopenic purpura
      diagnosed by postmortem examination is presented. Thrombotic thrombocytopenic
      purpura is one of a subset of diseases that result in the formation of
      microthrombi within the vasculature, either as a primary or secondary
      manifestation. Other conditions included in the differential diagnosis during
      pregnancy are hemolytic uremic syndrome, systemic lupus erythematosus,
      preeclampsia-eclampsia and the HELLP syndrome, acute fatty liver of pregnancy,
      antiphospholipid antibody syndrome, and disseminated intravascular coagulation.
      The histologic manifestations of these diseases can be similar and in most cases
      do not provide adequate information to accurately differentiate these diseases in
      the postmortem period. This paper addresses the need for clinical history (i.e.,
      symptomatology, trimester of onset) and antemortem laboratory testing in addition
      to a thorough autopsy to accurately differentiate among the conditions named
      previously. In the absence of an adequate clinical history and antemortem
      laboratory testing, the more general diagnosis of "thrombotic microangiopathy of
      pregnancy" is acceptable.

PMID- 10414665
TI  - Changing trends in acute poisoning in Chandigarh zone: a 25-year autopsy
      experience from a tertiary care hospital in northern India.
AB  - A 25-year autopsy study (1972-1997) of acute poisoning deaths from a tertiary
      care hospital in northern India (Postgraduate Institute of Medical Education and
      Research, Chandigarh) revealed a steep increase in the incidence of acute
      poisoning since 1987. The majority (68%) of subjects were between the ages of 14
      and 30 years, and there was a male preponderance (69%). The main victims were
      students and unemployed youths, followed by agricultural workers and domestic
      workers. The proportion of urban victims increased from 45% in the period from
      1972 to 1977 to 72% in the period from 1992 to 1997. The proportion of suicidal
      deaths increased from 34% in the period from 1972 to 1977 to 77% in the period
      from 1992 to 1997, whereas accidental deaths decreased from 63% to 17% in the
      same period. Barbiturates (37%) and copper sulfate (22%) were the most common
      poisons causing mortality between 1972 and 1977; organophosphates (46%) became
      the most common between 1977 and 1982. Since 1982, aluminum phosphide (65%) has
      been the most common poison.

PMID- 10414664
TI  - Acute intoxication with guaifenesin, diphenhydramine, and chlorpheniramine.
AB  - Mixed drug reactions are frequently encountered in emergency department overdose
      cases and also in fatal intoxications. Assessment of the relative contribution of
      each drug in producing adverse effects is often compounded by lack of case
      history and the paucity of cases reported in the literature. This report
      describes a fatal intoxication with three common over-the-counter medications:
      guaifenesin, diphenhydramine, and chlorpheniramine. A 48-year-old woman was found
      dead in the attic bedroom of her residence. Specimens obtained at autopsy for
      toxicologic analysis included heart blood, urine, bile, gastric contents,
      vitreous humor, and cerebrospinal fluid. The over-the-counter drugs were
      identified and quantitated by acid/neutral or basic liquid-liquid extraction
      followed by gas chromatographic analysis with nitrogen phosphorus detection.
      Concentrations of guaifenesin, diphenhydramine, and chlorpheniramine detected in
      the heart blood were 27.4, 8.8, and 0.2 mg/L, respectively. The cause of death
      was determined to be acute intoxication by the combined effects of guaifenesin,
      diphenhydramine, and chlorpheniramine, and the manner of death was determined to
      be suicide. To our knowledge, the blood guaifenesin concentration in this case is
      the highest reported concentration to date associated with an acute intoxication.

PMID- 10414666
TI  - Sudden death in an infant caused by rupture of a basilar artery aneurysm.
AB  - Ruptured aneurysms of the cerebrovasculature in infancy and early childhood,
      except for "giant" aneurysms and arteriovenous malformations, are rare. Seizures,
      loss of consciousness, and apnea are the usual presenting signs in infancy;
      symptoms such as headache or visual disturbances and signs such as cranial nerve
      compression or meningeal irritation commonly found in older children or adults
      are absent in infants. However, the morphologic findings (i.e., subarachnoid and
      retinal hemorrhage, and occasionally subdural hemorrhage) may be mistaken for
      inflicted trauma, especially if the aneurysm is not identified. Sudden death
      caused by rupture of a cerebral aneurysm has not been previously described in an
      infant. This report outlines the investigation and autopsy findings in a 7-month
      old infant who died unexpectedly as a result of rupture of a complex basilar
      artery aneurysm.

PMID- 10414667
TI  - Social and forensic aspects of sudden infant death.

PMID- 10414668
TI  - "Improvement" of age estimation using amino acid racemization in a case of pink
      teeth.

PMID- 10414669
TI  - QT dispersion after subarachnoid hemorrhage.
AB  - Subarachnoid hemorrhage (SAH) causes a stress response with increased
      concentrations of plasma catecholamines and serious cardiac arrhythmias.
      Increased QT dispersion has been shown to predispose to cardiac arrhythmias. In
      SAH patients, QT dispersion has not been studied previously. QT dispersion was
      analyzed in 26 patients with SAH and in 16 patients (control group) scheduled for
      ligation of a nonruptured cerebral aneurysm. In 15 patients with SAH, the plasma
      concentrations of catecholamines were analyzed, and an 18-hour continuous
      electrocardiogram (ECG) recording was obtained. In the other 11 patients,
      electrocardiography was repeated daily for up to 9 days for analysis of QT
      dispersion. The median (25th and 75th percentiles) QT dispersion in all SAH
      patients was 78 milliseconds (50 and 109 milliseconds, respectively), and in
      control patients, it was 25 milliseconds (15 and 33 milliseconds, respectively)
      (P < .001). There was a positive correlation with QT dispersion and the plasma
      concentration of DHPG, a metabolite of norepinephrine (P < .05). All patients had
      episodes of cardiac arrhythmia during the 18-hour recording period. In
      conclusion, increased QT dispersion is a common finding after SAH and may be a
      result of high plasma concentrations of catecholamines in these patients.

PMID- 10414670
TI  - Blood loss and transfusion practice in the perioperative management of
      craniosynostosis repair.
AB  - During the past 5 years, the surgical repair for sagittal synostosis has been
      modified to a more complex and involved procedure. This led to a retrospective
      evaluation of the current transfusion practice in a large series of
      craniosynostosis repairs. The charts of 76 patients (81 surgical procedures)
      undergoing craniosynostosis repair from January 1990 to November 1996 were
      examined. The calculated volume of blood loss (BL) was determined for each
      surgical procedure and related to the estimated blood volume (EBV) and acceptable
      blood loss (ABL). The anesthesiologist's ability to estimate BL was compared with
      the calculated blood loss (CBL). In most surgical procedures for
      craniosynostosis, especially in the complex sagittal repairs, CBL was
      underestimated and exceeded ABL. Packed red blood cell transfusion occurred in
      96.3% of the patients and was appropriate for most procedures based on ABL. Thus,
      transfusion for craniosynostosis repair is almost inevitable, and the preventive
      preparation of blood on the order of the mean estimated blood loss (EBL) plus 2
      SD is appropriate. With the increased complexity of sagittal repair and its
      performance in a younger population, the cosmetic benefit of surgical repair has
      major implications for management of blood and fluids.

PMID- 10414671
TI  - Effects of clonidine on human middle cerebral artery flow velocity and
      cerebrovascular CO2 response during sevoflurane anesthesia.
AB  - The present study was designed to evaluate the effects of clonidine on human
      middle cerebral artery flow velocity and the cerebrovascular CO2 response during
      sevoflurane anesthesia using transcranial Doppler ultrasonography. The subjects
      were nine awake volunteers (group A) and 18 patients receiving oral preanesthetic
      medication of clonidine, 3-4 mcg/kg, (group C), or placebo (group S). In groups C
      and S, anesthesia was induced with inhalation of sevoflurane-nitrous oxide. After
      tracheal intubation, anesthesia was maintained with 2% end-tidal sevoflurane
      alone. In group A, each volunteer wore a nose clip and breathed through a
      mouthpiece using a Mapleson D breathing system. The time-mean middle cerebral
      artery flow velocity (Vmca) was measured during hypocapnia, normocapnia, and
      hypercapnia. In groups S and C, the Vmca values were significantly lower than
      those of group A at each PaCO2 level. The Vmca value of group C was significantly
      lower than that of group S in hypercapnia, but not in hypocapnia or normocapnia.
      The CO2 response slope of group C was significantly lower than those of groups A
      and S. The results indicate that clonidine, administered as an oral preanesthetic
      medication, reduces Vmca in hypercapnia but not in hypocapnia or normocapnia, and
      reduces the cerebrovascular CO2 response during sevoflurane anesthesia.

PMID- 10414672
TI  - Administration of hypertonic (3%) sodium chloride/acetate in hyponatremic
      patients with symptomatic vasospasm following subarachnoid hemorrhage.
AB  - A retrospective study was carried out to evaluate the effect of hypertonic (3%)
      saline chloride/acetate on various hemodynamic parameters in mildly hyponatremic
      patients with symptomatic vasospasm following aneurysmal subarachnoid hemorrhage
      (SAH). We identified 29 hyponatremic (serum sodium < 135 mEq/L) patients who
      received hypertonic (3%) sodium chloride/acetate as a continuous infusion.
      Administration of hypertonic (3%) sodium chloride/acetate resulted in higher
      central venous pressures and positive fluid balance, with a concomitant increase
      in serum sodium and chloride concentrations without metabolic acidosis. There
      were no changes in mean cerebral blood flow velocities after infusion of
      hypertonic (3%) sodium chloride/acetate. We found no reports of congestive heart
      failure, pulmonary edema, metabolic acidosis, coagulopathy, intracranial
      hemorrhages, or central pontine myelinolysis in any of these patients. We
      conclude that hypertonic (3%) sodium chloride/acetate can be administered to
      patients with mild hyponatremia in the setting of symptomatic vasospasm following
      SAH without untoward effects. Sample size and limitations of a retrospective
      analysis preclude conclusions about safety and efficacy of hypertonic (3%) sodium
      chloride/acetate administration in this patient population. However, our results
      support justification for a prospective, randomized, double-blind trial of
      hypertonic (3%) sodium chloride/acetate versus normal saline in patients with
      symptomatic vasospasm following SAH.

PMID- 10414673
TI  - Internal jugular vein cannulation in neurosurgical patients: a new approach.
AB  - A new approach to internal jugular vein (IJV) cannulation with the head and neck
      placed in the neutral position is described. The junction of the medial two
      thirds and lateral one third between the angle of the mandible and symphysis
      menti is identified. A vertical line is drawn from this point to join another
      line drawn between the mastoid process and the medial end of the clavicle. The
      junction is the puncture point. In 120 patients studied, the failure rate was
      1.66%, and there were no complications. We propose this technique as a safe and
      reliable alternative in neurosurgical patients.

PMID- 10414674
TI  - Effects of nonsteroidal anti-inflammatory drugs on hemostasis in patients with
      aneurysmal subarachnoid hemorrhage.
AB  - Platelet function is impaired by nonsteroidal anti-inflammatory drugs (NSAIDs)
      with prominent anti-inflammatory properties. Their safety in patients undergoing
      intracranial surgery is under debate. Patients with aneurysmal subarachnoid
      hemorrhage (SAH) were randomized to receive either ketoprofen, 100 mg, three
      times a day (ketoprofen group, n = 9) or a weak NSAID, acetaminophen, 1 g, three
      times a day (acetaminophen group, n = 9) starting immediately after the diagnosis
      of aneurysmal SAH. Treatment was continued for 3 days postoperatively. Test blood
      samples were taken before treatment and surgery as well as on the first, third,
      and fifth postoperative mornings. Maximal platelet aggregation induced by 6
      microM of adenosine diphosphate decreased after administration of ketoprofen.
      Aggregation was lower (P < .05) in the ketoprofen group than in the acetaminophen
      group just before surgery and on the third postoperative day. In contrast,
      maximal platelet aggregation increased in the acetaminophen group on the third
      postoperative day as compared with the pretreatment platelet aggregation results
      (P < .05). One patient in the ketoprofen group developed a postoperative
      intracranial hematoma. Coagulation (prothrombin time [PT], activated partial
      thromboplastin time [APPT], fibrinogen concentration, and antithrombin III [AT
      III]) was comparable between the two groups. Ketoprofen but not acetaminophen
      impaired platelet function in patients with SAH. If ketoprofen is used before
      surgery on cerebral artery aneurysms, it may pose an additional risk factor for
      hemorrhage.

PMID- 10414675
TI  - Heart rate variability and plasma catecholamines in patients during opioid
      detoxification.
AB  - It has been shown that rapid opioid detoxification is associated with increased
      sympathetic activity (SYMP) and plasma catecholamines. Heart rate (HR)
      variability may provide a noninvasive method of evaluating withdrawal and
      sympathetic activation caused by the reversal of opioid binding in patients who
      are opioid dependent. The purpose of this study was to evaluate the relationship
      between HR variability and plasma catecholamines during opioid detoxification.
      Patients were anesthetized with propofol, intubated, paralyzed with rocuronium
      infusion, and ventilated. The bispectral index (BIS) of the electroencephalogram
      was recorded with the patient awake as well as during propofol anesthesia. SYMP
      was determined by power spectral analysis of HR variability. Plasma epinephrine
      and norepinephrine were measured at baseline propofol anesthesia and during
      naltrexone treatment in eight opioid-dependent patients. Nonopioid-dependent
      controls (n = 7) were monitored during surgery without naltrexone treatment or
      measurement of plasma catecholamines. Compared with an awake status, propofol
      anesthesia significantly decreased the BIS and SYMP in both groups of patients.
      Controls showed no change from baseline anesthetized levels during surgery.
      Plasma norepinephrine and epinephrine as well as SYMP increased 300 to 400% (P <
      .05) during naltrexone treatment in opioid-dependent patients, and the time to
      peak increase in plasma norepinephrine correlated with the increase in SYMP (r =
      0.89, P < .01). These results confirm that opioid detoxification increases plasma
      catecholamines and SYMP in a similar manner. HR rate variability may provide a
      low-cost real-time noninvasive method of evaluating the reversal of opioid
      binding in opioid-dependent patients.

PMID- 10414676
TI  - Pneumoencephalus and convulsions after ventriculoscopy: a potentially
      catastrophic complication.
AB  - A nine-year-old boy with hydrocephalus underwent ventriculoscopy under general
      anesthesia. After introduction of ventriculoscope the patient had sudden
      bradycardia, hypotension, and shrinkage of ipsilateral cerebral hemisphere. The
      ventriculostomy was abandoned. At the end of anesthesia and endotracheal
      extubation, the patient developed generalized convulsions. Reexploration of wound
      did not reveal anything significant; however, postoperative CT scan of head
      showed massive pneumoencephalus. The patients received elective ventilation of
      lungs for 24 hours and made complete recovery. The authors describe the reasons
      for these complications and further management.

PMID- 10414677
TI  - Coronary artery spasm induced by trigeminal nerve stimulation and vagal reflex
      during intracranial operation.
AB  - This report describes a case of ventricular fibrillation resulting from coronary
      vasospasm during intracranial operation under general anesthesia. An autonomic
      response associated with the intracranial procedure caused a coronary spasm,
      which was worsened by alpha-agonists. Nitroglycerin effectively resolved the
      coronary spasm and co-complications persisted.

PMID- 10414678
TI  - Anesthesia for ruptured cerebral aneurysm surgery associated with chronic renal
      failure.
AB  - The management of patients with chronic renal failure (CRF) undergoing cerebral
      aneurysm surgery has been documented on only a few occasions. We report a 58-year
      old man with CRF and subarachnoid hemorrhage (SAH) due to aneurysm rupture. We
      describe the patient's perioperative anesthetic management, discussing the
      current methods for maintaining an appropriate cerebral perfusion pressure and
      for preventing rehemorrhage from the aneurysm. We suggest that heparin-aided
      hemodialysis be avoided in these cases.

PMID- 10414679
TI  - Acute left ventricular dysfunction and subarachnoid hemorrhage.
AB  - OBJECTIVE: Severe left ventricular (LV) dysfunction associated with acute
      subarachnoid hemorrhage (SAH) due to cerebral aneurysm rupture. SETTING: An adult
      12-bed surgical intensive care unit of a university hospital. PATIENT: A female
      patient presenting with SAH (Hunt & Hess grade III) and severe left ventricular
      dysfunction. INTERVENTIONS: Central venous pressure, arterial blood pressure,
      extravascular lung water catheter, transesophageal echocardiography, blood gas
      analysis, electrocardiograms, and chest x-ray for clinical management.
      MEASUREMENTS AND MAIN RESULTS: On admission to the district hospital, an
      electrocardiogram (ECG) revealed a sinus rhythm with transient ST elevations. A
      transesophageal echocardiography showed a left ventricular ejection fraction (LV
      EF) of approximately 10%. Severe LV dysfunction required inotropic and
      vasopressor support to maintain mean arterial pressure above 60 mmHg, while the
      first measurement of an extravascular lung water catheter revealed a cardiac
      index of 2.0 L/min/m2 and moderate hypovolemia. Despite stepwise volume loading
      that increased intrathoracic blood volume--an indicator of cardiac preload--from
      719 mL/m2 to 927 mL/m2, cardiac index remained poor. Enoximone lead to a marked
      increase of cardiac index up to 3.9 L/min/m2 and LV-EF to about 30%, but had to
      be stopped due to thrombopenia. Surgical clipping of an intracranial aneurysm was
      postponed because of the impaired cardiac function and was performed on day 18
      after admission. Interestingly, neurologic outcome was not as poor as might be
      expected from the literature. CONCLUSION: Severe left ventricular dysfunction may
      occur in acute SAH and may necessitate delay of aneurysm surgery.

PMID- 10414680
TI  - Dealing with a hemophilia-A patient undergoing cerebral aneurysm surgery.
AB  - In this article anesthesiologic and hematologic aspects of a patient with
      Hemophilia-A, who underwent craniotomy for a right middle cerebral artery
      aneurysm, are discussed.

PMID- 10414681
TI  - pH and concentration of bilirubin in feeding tube aspirates as predictors of tube
      placement.
AB  - BACKGROUND: Currently available bedside methods for determining feeding tube
      placement often provide inconclusive results. Therefore, additional data are
      needed to assist nurses in making decisions regarding tube location. OBJECTIVES:
      To describe the usual concentration of bilirubin in aspirates from newly inserted
      feeding tubes and to determine the extent to which these measures can contribute
      to pH alone in correctly predicting feeding tube location. METHODS:
      Gastrointestinal samples for concurrent pH and bilirubin testing were obtained
      from adult, acutely ill patients with newly inserted small-bore feeding tubes
      (nasogastric, n = 209; nasointestinal, n = 228) within 5 minutes of radiographs
      taken to determine tube location. Respiratory samples were tested
      (tracheobronchial, n = 126; pleural, n = 24). pH was measured with a pH meter,
      and bilirubin content was assayed spectrophotometrically. Results from the pH and
      bilirubin tests were compared with tube location as determined by radiography.
      RESULTS: Mean pH levels in the lung (7.73) and intestine (7.35) were
      significantly higher than the mean pH level in the stomach (3.90; p < .001 for
      each comparison). Mean bilirubin levels in the lung (.08 mg/dl) and stomach (1.28
      mg/dl) were significantly lower than the mean bilirubin level in the intestine
      (12.73 mg/dl; p < .001 for each). By visually inspecting distribution overlap and
      mean differences by tube site, results were dichotomized so that a combination of
      pH and bilirubin values could be used to develop a predictive algorithm. A pH of
      >5 and a bilirubin value of <5 mg/dl correctly identified all respiratory cases,
      whereas a pH >5 coupled with a bilirubin level of > or =5 mg/dl correctly
      identified three fourths of the intestinal cases. A pH of < or =5 coupled with a
      bilirubin value of <5 correctly identified more than two thirds of the gastric
      cases. CONCLUSIONS: Preliminary laboratory-based data indicate that appropriate
      use of the proposed algorithm could significantly reduce the number of x-rays
      needed to exclude respiratory placement and to distinguish between gastric and
      intestinal placement.

PMID- 10414682
TI  - Predicting intentions to obtain a Pap smear among African American and Latina
      women: testing the theory of planned behavior.
AB  - OBJECTIVE: To determine the empirical adequacy of the theory of planned behavior
      (TPB) to explain Pap smear use intentions in African American and Latina women.
      METHOD: A correlational design was used, and a convenience sample of 108 African
      American and 96 Latina adult women were recruited from urban community-based
      agencies located in a large mid-Atlantic metropolitan area. The Pap Smear
      Questionnaire (PSQ) was designed and used. The Demographic Assessment Survey
      collected demographic information (age and socioeconomic status for both groups;
      and level of acculturation for the Latinas). RESULTS: Direct relationships
      between attitude and perceived behavioral control and intention to obtain an
      annual Pap smear were found for African American and Latina women. The subjective
      norm did not significantly predict intention. Attitude (beta = .58; p < .001)
      provided the best explanation of intention among African American women to obtain
      an annual Pap smear, followed by perceived behavioral control (beta = .30; p <
      .001). Among Latinas, the findings reflected those of the African American
      sample. However, attitude (beta = .40; p < .001) and perceived behavioral control
      (beta = .35; p < .001) were weighted similarly. The external variables of age and
      income had indirect effects on intention for African American and Latina women,
      respectively. CONCLUSION: The study findings did not support the empirical
      adequacy of the TPB for either of the ethnic groups. Future studies should test a
      modified version of the TPB that includes measures of both social support and
      subjective norms. Direct measure items of subjective norm, group-specific
      measures of perceptions of control, and other measures of acculturation should be
      added to the PSQ and further tested.

PMID- 10414683
TI  - Burden experienced by caregivers of relatives with dementia in Taiwan.
AB  - BACKGROUND: The burden produced by caring for relatives with dementia is an
      increasing problem in the United States and Taiwan, necessitating a better
      understanding of the interrelationships of the factors that influence burden.
      OBJECTIVES: To test a theoretical model specifying how the demands of care,
      filial obligation, caregiving self-efficacy, coping strategies, and caregiving
      involvement affect caregiver burden. METHOD: A descriptive cross-sectional design
      with a convenience sample (n = 150) from outpatient clinics of three hospitals in
      Taiwan was used. The Caregiver Burden Inventory and the Cost of Care Index
      assessed caregiver burden. The antecedents of burden were assessed by the
      Physical Self-Maintenance Scale, Instrumental Activities of Daily Living, the
      Mini-Mental State Examination, the Revised Memory and Behavior Problem Checklist,
      the Montgomery obligation subscale, Cicirelli's obligation scale, the Caregiving
      Self-efficacy Scale, the Caregiving Involvement Scale, and the Ways of Coping
      Questionnaire. RESULTS: The original model did not fit the data well but minor
      respecifications produced a good model as evidenced by a chi2/df ratio of 2.1, a
      goodness-of-fit index of .89, and a comparative fit index of .93. Demands of care
      on the caregiver and filial obligation had direct positive effects on caregiving
      involvement. Caregiving involvement and emotion-focused coping had direct
      positive effects on caregiving burden. Filial obligation, caregiving self
      efficacy, and problem-focused coping had direct negative effects on caregiving
      burden. Six of the seven original hypothesized structural relationships were
      confirmed in the final model. CONCLUSIONS: The Burden Model tested in this study
      corroborates findings from other burden studies and extends our knowledge of
      caregiver burden. Filial obligation, self-efficacy, demands of care, involvement
      in care, and coping were shown to predict burden in this sample of Taiwanese
      caregivers. Future study is needed to evaluate interventions designed for family
      caregivers of persons with dementia. Especially needed is research in the area of
      counseling and mental health services to assist caregivers in dealing with
      manifestations of burden.

PMID- 10414684
TI  - The effects of sense of belonging, social support, conflict, and loneliness on
      depression.
AB  - BACKGROUND: A number of interpersonal phenomena have been linked to depression,
      including sense of belonging, social support, conflict, and loneliness.
      OBJECTIVES: To examine the effects of the interpersonal phenomena of sense of
      belonging, social support, loneliness, and conflict on depression, and to
      describe the predictive value of sense of belonging for depression in the context
      of other interpersonal phenomenon. METHOD: A sample of clients with major
      depressive disorder and students in a midwestern community college participated
      in the study by completing questionnaires. RESULTS: Path analysis showed
      significant direct paths as postulated, with 64% of the variance of depression
      explained by the variables in the model. Social support had only an indirect
      effect on depression, and this finding supported the buffer theory of social
      support. Sense of belonging was a better predictor of depression. CONCLUSIONS:
      The study findings emphasize the importance of relationship-oriented experiences
      as part of assessment and intervention strategies for individuals with
      depression.

PMID- 10414685
TI  - Outcomes of a nonaversive behavior intervention in intellectually impaired
      individuals using goal attainment scaling.
AB  - BACKGROUND: Intellectually impaired individuals with severe behavior problems
      pose a challenge to caregivers in treatment and management. The use of behavioral
      intervention techniques, for example, differential reinforcement of other
      behavior (DRO), has been shown the most effective with this client group type.
      Studies suggest that DRO is effective and may result in generalization of
      treatment effects. OBJECTIVES: To test which of three behavior interventions
      (DRO, mutual goal setting [MGS], and routine care) improve self-care behaviors in
      moderately intellectually impaired individuals with behavioral problems, and to
      examine whether the use of goal attainment scaling (GAS) in evaluating
      interventions reflects improvement in self-care behavior. METHOD: A quasi
      experimental design with small-group and single-subject repeated measures were
      used. The participants (15 congenitally moderately intellectually impaired
      residents with inadequate self-care behaviors) were randomly assigned to one of
      the three interventions for fostering self-care behaviors. To evaluate the
      outcome of treatment, GAS was used. Staff in the DRO and MGS groups developed and
      evaluated rehabilitation plans with each participant. Participants in the DRO
      group, but not the MGS group, were positively reinforced immediately. Staff in
      the routine care group assisted residents. The intervention continued for 22
      weeks; follow-up was 16 weeks. RESULTS: A change score was calculated from the
      GAS for each participant and group. The expected range of mean GAS scores for
      individuals and groups was between 23 and 77, with 23 (-2) representing less than
      and 77 (+2) much more than expected improvement. CONCLUSIONS: Findings showed DRO
      to be more effective than the other interventions in improving self-care
      behaviors. Comparisons of the GAS mean baseline and mean intervention scores in
      all three interventions demonstrated the actual improvement in the self-care
      behaviors.

PMID- 10414686
TI  - Bridging the gap between the pros and cons in treating ordinal scales as interval
      scales from an analysis point of view.

PMID- 10414687
TI  - Overlapping samples in organizational research.

PMID- 10414688
TI  - Item-response theory approach in scale development.

PMID- 10414689
TI  - Alternatives to mandated organ donation.

PMID- 10414691
TI  - External compression dressing versus standard dressing after axillary
      lymphadenectomy.
AB  - BACKGROUND: Closed-catheter drainage after axillary lymph node dissection (ALND)
      for breast cancer may constitute a significant inconvenience to the recovering
      patient, and may also serve as portals of entry for bacteria. Any intervention
      that could reduce the volume and duration of postoperative drainage would be
      beneficial. The purpose of this study was to determine whether an external
      compression dressing after ALND would decrease postoperative drainage, afford
      earlier drain removal, and reduce subsequent seroma formation. PATIENTS AND
      METHODS: One hundred thirty-five women undergoing definitive surgical treatment
      for breast cancer were randomized to receive a compression dressing (n = 66) or
      standard dressing (n = 69). They were also stratified for modified radical
      mastectomy (MRM; n = 74) or breast conservation therapy (BCT; n = 61). All
      patients had ALND. The compression dressing consisted of a circumferential chest
      wrap of two 6-inch Ace bandages, held in place by circumferential Elastoplast
      bandage, and it was applied by the same nurse. This dressing remained intact
      until postoperative day 4. Patients in the standard dressing group (control) were
      fitted with a front-fastening Surgibra only. Drains were removed when the total
      daily amount was <50 cc. Postoperative drainage volume, total days with drain,
      and frequency of seroma formation were recorded for each patient. RESULTS: After
      4 days, wound drainage in both groups was nearly identical (compression = 490 cc,
      standard = 517 cc; P = 0.48). Total days with drain were also similar
      (compression = 6.4 days, standard = 6.1 days; P = 0.69). The compression dressing
      did not reduce seroma formation. In fact, there was a statistically significant
      increase in the number of seroma aspirations per patient in the compression group
      (compression = 2.9, standard = 1.8; P <0.01). The increase in seroma aspirations
      was more significant in MRM patients (compression = 3.1, standard = 1.7; P <0.01)
      than in BCT patients (compression = 2.6, standard = 1.8; P = 0.20). CONCLUSIONS:
      External compression dressing fails to decrease postoperative drainage and may
      increase the incidence of seroma formation after drain removal. Thus, routine use
      of a compression dressing to reduce postoperative drainage after ALND for breast
      cancer is not warranted.

PMID- 10414690
TI  - Routine preoperative lymphoscintigraphy is not necessary prior to sentinel node
      biopsy for breast cancer.
AB  - BACKGROUND: This prospective study was performed to ascertain the added benefit
      of lymphoscintigraphy to a standard method of intraoperative lymphatic mapping
      and sentinel node biopsy for breast cancer. METHODS: Patients with invasive
      breast cancer were injected with 99mTc sulfur colloid prior to sentinel node
      biopsy; preoperative lymphoscintigraphy was then performed in half of the patient
      population. RESULTS: Sentinel node identification was possible in 45 of 50
      patients (90%). All 14 patients (31%) with axillary nodal metastases had at least
      one histologically positive sentinel node (0% false negative rate).
      Lymphoscintigraphy revealed sentinel nodes in 17 of the 24 patients (70.8%)
      imaged. All 17 of these patients had one or more axillary sentinel nodes
      identified using intraoperative lymphatic mapping. In addition, 5 of 7 patients
      with a negative preoperative lymphoscintogram had an axillary sentinel lymph
      node(s) identified intraoperatively. None of the tumors showed drainage to the
      internal mammary lymph node chain by lymphoscintigraphy despite the fact that
      there were 5 patients with inner quadrant tumors. There was no significant
      advantage with respect to sentinel lymph node localization (91.7% versus 88.5%, P
      = not significant) or false negative rate (0%, both groups, P = not significant)
      in the group undergoing preoperative lymphoscintigraphy when compared with the
      patients in whom lymphoscintigraphy was not performed. CONCLUSIONS: Preoperative
      lymphoscintigraphy adds little additional information to intraoperative lymphatic
      mapping, and its routine use is not justified.

PMID- 10414692
TI  - Monocyte human leukocyte antigen-DR expression correlates with intrapulmonary
      shunting after major trauma.
AB  - BACKGROUND: Severe injury is often complicated by the development of sepsis and
      the adult respiratory distress syndrome. Since the outcome from severe injury
      also correlates with changes in monocyte human leukocyte antigen (HLA)-DR
      expression in such patients, the present study aimed to determine whether or not
      there was a relationship between monocyte HLA-DR expression and indicators of
      early pulmonary dysfunction. METHODS: Monocyte HLA-DR expression and serum
      interleukin (IL)-6 were measured on admission and then again on days 1, 3, 5, and
      7 after major injury in 29 patients admitted for the management of trauma with an
      injury severity score of 9 or more. Noninvasive intrapulmonary shunt measurement
      was also performed in all these patients within 6 hours of emergency surgery in
      all patients. RESULTS: Monocyte HLA-DR followed the characteristic suppression
      followed by recovery in those who followed an uncomplicated course but
      progressively declined in those who suffered septic complications. The degree of
      intrapulmonary shunting observed 6 hours after injury in the patients who
      developed sepsis was significantly higher than that in the uncomplicated group.
      Peak monocyte HLA-DR expression during the recovery phase correlated inversely
      with the degree of intrapulmonary shunting. CONCLUSIONS: The degree of
      intrapulmonary shunting observed following severe trauma correlates with the
      failure of circulating monocytes to re-express HLA-DR antigen, and this may
      provide some insights into the early events that result in the adult respiratory
      distress syndrome after major injury.

PMID- 10414693
TI  - Appendicitis is a place for clinical judgement.
AB  - BACKGROUND: Acute appendicitis remains a clinical entity. Reports of negative
      appendectomies range from 9% to 40%. The goal of this study is to evaluate
      clinical performance and factors associated with complicated appendicitis.
      METHODS: Records of patients with a preoperative or postoperative diagnosis of
      appendicitis between January 1994 and December 1997 were reviewed. Demographic,
      clinical, and paraclinical data were collected. Multivariate analysis was carried
      out by logistical regression. RESULTS: Two hundred and thirty-seven consecutive
      cases were reviewed (male 132, female 105). The mean age was 31.4 +/- 16.8.
      Twenty-three cases had other surgical conditions. In the remaining cases (n =
      214), 127 (59.4%) had noncomplicated appendicitis, 69 (32.2%) had complicated
      appendicitis, and 18 (8.4%) had negative exploration. Delays occurring before
      first medical consultation were significantly longer in patients with complicated
      appendicitis (3.30 days) and negative exploration (3.00 days) compared to
      patients with noncomplicated appendicitis (1.24 days) (P < 0.001). CONCLUSIONS:
      Acceptable rates of negative appendix and complicated appendicitis can be
      obtained from clinical data. The presence of complicated appendicitis is
      primarily associated with a longer delay before first medical consultation.

PMID- 10414694
TI  - Techniques and complications of ileostomy takedown.
AB  - OBJECTIVE: We use a loop ileostomy for temporary fecal diversion because of ease
      of technical construction and assumed low complication rate. Here, we review our
      complications of loop ileostomy and takedown using three techniques of closure.
      METHODS: We reviewed charts of all patients who had temporary ileostomies
      constructed during 1987 to 1995 (n = 366). Ileostomy takedown was performed in
      339 patients using one of three closure techniques: enterotomy suture (65%),
      resection with handsewn anastomosis (20%), and stapled anastomosis (15%).
      Complications were recorded for pre-takedown and 30-day post-takedown intervals.
      RESULTS: Overall complication rate was 28%. Pre-takedown complications occurred
      in 21 patients (5.7%), including small bowel obstruction (2.5%) and
      dehydration/electrolyte derangement (2.2%). Post-takedown complications occurred
      in 83 patients (24.5%), including wound infection (14.2%), small bowel
      obstruction (5%), anastomotic leak (2.9%), and 1 death from a cardiac event. Post
      takedown obstruction was higher for closure using resection with sutured
      anastomosis (12%) compared with enterotomy suture (2.3%), P < or = 0.003. Stapled
      anastomosis had an intermediate rate of obstruction (7.7%). Anastomotic leak was
      similar between closure techniques. CONCLUSIONS: Loop ileostomy and takedown are
      associated with low rates of serious complications (5% or less). As such, we
      continue to advocate use of loop ileostomy as a diversion procedure. Closure by
      enterotomy suture is preferred over resection. However, if resection is required,
      closure by stapled anastomosis is preferred over suture anastomosis.

PMID- 10414695
TI  - Outcome analysis of external coloanal anastomosis.
AB  - BACKGROUND: To evaluate the safety and efficacy of treating low-lying rectal
      lesions with resection and primary repair using a pull-through technique with
      rectal stump eversion and external coloanal anastomosis with immediate
      reintroduction into the pelvis. METHODS: All coloanal anastomoses with the above
      technique on the Gastrointestinal Surgery Service at the University of Pittsburgh
      from March 1990 to September 1995 were evaluated. RESULTS: Fifty-two patients
      underwent coloanal anastomoses with the above technique, and follow-up was
      available for 96% (50 of 52) of patients. Rectal lesions in the 50 patients
      included cancer (n = 34), rectal adenomas (n = 13), and other lesions (n = 3).
      Mean follow-up period was 29.6 +/- 21.8 months (28.5 months for patients with
      carcinoma). Fecal continence was normal or good in 88% (44 of 50) of patients.
      Moderate or complete incontinence was present in 12% (6 of 50) of patients. The
      local recurrence rate of rectal cancer was 0%. Morbidity occurred in 22% (11 of
      50) of patients. Survival was 90% (45 of 50 patients). CONCLUSIONS: Coloanal
      anastomosis with this technique provides effective treatment for low-lying
      malignant or benign rectal lesions and has an acceptable complication rate.

PMID- 10414696
TI  - Late bile duct cancer complicating biliary-enteric anastomosis for benign
      disease.
AB  - BACKGROUND: Anastomosis between the biliary tree and the intestinal tract has
      been, and is, a relatively common procedure. Aside from cholangitis secondary to
      anastomotic stricture, it is generally regarded as innocuous. METHODS: The recent
      experience with 3 patients who developed bile duct cancer many years after
      biliary-enteric anastomosis for benign disease prompted a review of whether the
      procedure was potentially carcinogenic. RESULTS: There have been very few reports
      of late cholangiocarcinoma complicating this surgery for benign disease. However,
      there is some experimental evidence to support the hypothesis, and the time
      interval between surgery and the development of malignancy may be important.
      CONCLUSIONS: Reflux of duodenal or small intestinal contents into the biliary
      tree causes changes in the biliary epithelium that may be adaptive to the new
      environment but also have the potential to progress to malignant transformation.

PMID- 10414697
TI  - Molecular detection of circulating cancer cells during surgery in patients with
      biliary-pancreatic cancer.
AB  - BACKGROUND: It remains unclear whether surgical treatment for biliary-pancreatic
      cancers provokes the hematogenous dissemination of cancer cells. The aim of this
      study was to detect circulating cancer cells in the blood stream before and
      during tumor resection for biliary-pancreatic cancer. METHODS: We analyzed blood
      samples obtained perioperatively from the portal vein, peripheral artery, and
      superior vena cava, using a carcinoembryonic antigen (CEA)-specific nested
      reverse transcriptase-polymerase chain reaction. RESULTS: CEA-mRNA expression was
      detected in the blood of 21 (52.5%) of 40 patients with biliary-pancreatic
      cancer. The patients with detectable CEA-mRNA expression included 8 (42.1%) of 19
      with bile duct cancers and 13 (61.9%) of 21 with pancreatic cancers. CEA-mRNA
      expression was not detected in blood obtained from 15 healthy volunteers and 15
      patients with benign disease. The positive rate of CEA-mRNA of advanced clinical
      stage (TNM pStage III and IV) showed higher than that of early stage (pStage I
      and II; P <0.05). Tumor resection increased significantly the positive rates of
      CEA-mRNA in the blood stream of three kinds of vessel. CONCLUSIONS: Surgical
      procedures provoke the hematogenous dissemination of cancer cells
      perioperatively. Therefore, new strategies during operations to prevent liver
      metastases are needed to improve the survival of patients with biliary-pancreatic
      cancer.

PMID- 10414698
TI  - A prospective evaluation of video-assisted thoracic surgery for persistent air
      leak due to trauma.
AB  - BACKGROUND: The time required for air leak resolution after chest trauma is not
      well described. Based on an institutional review of posttraumatic air leaks our
      hypothesis was that video-assisted thoracic surgery (VATS) for persistent
      posttraumatic air leak would decrease chest tube days and length of stay compared
      with nonoperative management. METHODS: Patients were offered VATS versus
      nonoperative management when air leaks persisted longer than 3 days and the
      patients were otherwise ready for discharge. Chest tube days and length of stay
      were recorded. RESULTS: Of 223 trauma patients requiring chest tubes, 50 had
      persistent air leaks, 39 of whom were otherwise ready for discharge. Twenty-five
      chose VATS and 14 nonoperative (NOP) treatment. The mean chest tube days was 8.1
      for VATS versus 11.8 for NOP (P = 0.001). Mean length of stay was 9.7 days for
      VATS and 16.5 days for NOP (P = 0.002). CONCLUSIONS: In patients otherwise ready
      for discharge VATS reduces chest tube days and length of stay when used to treat
      persistent posttraumatic air leak.

PMID- 10414699
TI  - The recurrent laryngeal nerve related to thyroid surgery.
AB  - BACKGROUND: Iatrogenic injury of inferior laryngeal nerve is one of the most
      serious concerns in thyroid surgery. Paralysis of vocal cords is a common sequela
      of thyroidectomy. It represents a serious complication inducing, when bilateral,
      serious functional sequelae such as phonatory, respiratory and psychological
      problems that limit working capacities and social relationships of patients. We
      carried out an intraoperative study aimed to define anatomical relationships
      between the recurrent laryngeal nerve and the adjacent structures (the inferior
      thyroid artery in particular), intraoperative identification of which may allow
      prevention of iatrogenic injuries of the laryngeal nerve. METHODS: One hundred
      ninety-two patients (165 females, 27 males whose age was between 18 and 90 years,
      median age 55) who had undergone thyroidectomy in our department in the last 3
      years. Among them, 179 patients underwent total extracapsular thyroidectomy, and
      of the 13 remaining, 12 were completions of thyroidectomy in patients who had
      previously undergone a first thyroid surgical intervention and underwent istmo
      lobectomy. RESULTS: Despite a systematic intraoperative search, we identified the
      recurrent laryngeal nerve in 158 of 192 patients (82.3%), while in the remaining
      34 (17.7%), the recurrent laryngeal nerve was not identified. In 122 out of the
      158 patients (77.2%) in whom the recurrent laryngeal nerve had been detected, the
      nerve was identified bilaterally: in 19 of 158 (12%) only on the right side; in
      17 of 158 (10.7%) only on the left. Concerning the postoperative results we
      noticed only one case (0.5%) of recurrent laryngeal nerve injury for neoplastic
      infiltration of its own branch, one case (0.5%) of monolateral cordal
      hypomotility, and two cases (1.04%) of bilateral cordal hypomotility with
      temporary disphonia, which regressed in 6 months of time. CONCLUSION: The results
      of our study may confirm that iatrogenic injury to the recurrent laryngeal nerve,
      or to its branches, might be better avoided by searching, identifying, and
      exposing the nerve itself and by following its course with care. In our view,
      total extracapsular thyroidectomy, with systematic search for the nerve, is the
      best approach. We believe that deep knowledge of the thyroid region's surgical
      anatomy and the awareness of the extremely varying course of the recurrent
      laryngeal nerve and the inferior thyroid artery and their relations should be
      taken into account by surgeons.

PMID- 10414700
TI  - Elevated basilic vein arteriovenous fistula.
AB  - BACKGROUND: Many surgeons continue to use prosthetic arteriovenous grafts for
      dialysis access despite the clear superiority of native arteriovenous fistulas.
      This study was undertaken to review our experience with elevated brachial-basilic
      fistulas as an alternative to prosthetic grafts in patients lacking veins
      suitable for more conventional arteriovenous fistulas. METHODS: We
      retrospectively reviewed the outcomes of 67 patients receiving elevated brachial
      basilic arteriovenous fistulas over a 10-year period. Operative complications and
      causes of failure were identified and actuarial fistula patency determined.
      RESULTS: No patients suffered wound infections, and only 1 developed a steal
      syndrome in the late postoperative period. Actuarial fistula patency was 84% at 1
      year, 73% at 3 and 5 years, and 52% at 10 years. CONCLUSIONS: The elevated
      brachial-basilic arteriovenous fistula is a superb alternative to prosthetic
      arteriovenous grafts in patients lacking suitable cephalic veins for native
      arteriovenous fistulas. Operative complications are uncommon, vascular steal is
      rare, and long-term patency is excellent.

PMID- 10414701
TI  - Acute colonic pseudo-obstruction (Ogilvie's syndrome) after renal
      transplantation.
AB  - BACKGROUND: Acute colonic pseudo-obstruction (Ogilvie's syndrome) in the
      immunosuppressed patient is associated with increased morbidity and mortality.
      Renal transplant recipients possess several comorbidities that increase the risk
      of acute pseudo-obstruction of the colon. The aims of this study were to present
      our experience with this syndrome and to evaluate the potentiating factors in
      these patients. A review of the literature for pseudo-obstruction following renal
      transplantation is presented. METHODS: Seven patients who developed Ogilvie's
      syndrome were identified in a retrospective review of 550 kidney-only
      transplants. Pretransplant data, potential risk factors, presentation,
      management, and outcome details were retrieved. The medical literature was
      reviewed using Medline. RESULTS: Seventy-eight patients with Ogilvie's syndrome
      in the early posttransplant period have been reported. The associated morbidity
      and mortality was heightened in this immunocompromised population. Obese
      transplant recipients (body mass index >30 kg/m2) were at significantly increased
      risk for developing this syndrome. CONCLUSION: A broad armamentarium of treatment
      options is available, but the key to successful resolution lies in early
      recognition.

PMID- 10414702
TI  - The p53 gene mutation is of prognostic value in esophageal squamous cell
      carcinoma patients in unified stages of curability.
AB  - BACKGROUND: The p53 gene alteration is identified in approximately half of all
      human tumors, and is now thought to be a key gene for regulating the cell cycle
      through the induction of p21(WAF1/CIP1) and inducing apoptosis through some genes
      such as BAX. In this study, we investigated the prognostic value of p53 mutation
      for postoperative esophageal squamous cell carcinoma patients. METHODS: The
      subjects studied were 42 esophageal squamous cell carcinoma patients who
      underwent esophagectomy with complete curability in our department. The cases
      were limited to stage II and III. DNA was extracted from paraffin-embedded
      tissues. A p53 gene mutation was detected by polymerase chain reaction-single
      strand conformation polymorphism and subsequent direct sequencing method for
      exons 5 to 9. The 5-year survival rate was calculated and statistically compared
      between the p53 mutation(+) and (-) groups by the log rank test. RESULTS: The p53
      gene mutation was identified in 14 cases (33.3%). The 5-year survival rate of the
      p53 mutation(-) group (n = 28) was significantly higher than the (+) group (n =
      14; 51.0% versus 35.7%, P <0.05 by the log rank test). Recurrence could be
      identified in 10 of 14 p53 mutation(+) cases (71.4%), whereas it was found in 12
      of 28 (-) cases (42.8%). CONCLUSION: The current study indicated that p53
      mutation of tumor tissues might be a prognostic factor for esophageal squamous
      cell carcinoma cases and one of the risk factors for its recurrence.

PMID- 10414704
TI  - Prokinetic agents in the surgical patient.

PMID- 10414703
TI  - Role of preoperative chemoradiation in the management of upper third thoracic
      esophageal squamous cell carcinoma.
AB  - BACKGROUND: The treatment of upper thoracic esophageal cancer remains
      challenging, and combined treatment is necessary to improve the outcome. We
      conducted preoperative chemoradiation therapy (CRT) for potential T4 tumors
      located in the upper third esophagus and carried out a retrospective study to
      elucidate the role of preoperative CRT. METHODS: Surgical resection was performed
      on 64 patients with upper thoracic esophageal cancer. Thirty-seven of these
      patients underwent primary resection, while 27 underwent preoperative CRT and
      surgery. The regimen of chemotherapy consisted of daily tegaful or 5-fluorouracil
      plus cisplatin. Concurrent radiation therapy of 4,000 cGy was conducted over 4
      weeks. RESULTS: There were no differences in either tumor depth and nodal
      involvement or the surgical morbidity and mortality between the two groups. Seven
      of 27 patients downstaged to a complete pathologic response, and 13 patients
      showed a partial response. The 5-year survival rates were 42% in the preoperative
      CRT group and 27% in the surgery group, and these were not significantly
      different. In all patients, the depth of tumor influenced the prognosis
      significantly, while operative curability, nodal involvement, or the number of
      metastatic nodes showed a tendency to influence the prognosis. CONCLUSIONS:
      Preoperative CRT contributed to downstaging of the tumors and did not increase
      the operative mortality. Preoperative CRT was useful in the management of upper
      thoracic esophageal cancer, especially in advanced cases.

PMID- 10414705
TI  - Gasless laparoscopically assisted colonic surgery.
AB  - BACKGROUND: Laparoscopic technique has been applied to a variety of colonic and
      rectal operations, generally using carbon dioxide insufflation (CDI). However,
      CDI is inevitably associated with cardiopulmonary loading and can cause
      complications. The objective of this study was to determine the feasibility of
      gasless laparoscopic colonic surgery. METHODS: The abdominal wall was lifted up
      using an originally designed retractor. A small incision, 3 to 5 cm in length,
      was made at the start of the operation. The surgeon operated through this
      incision using both conventional and laparoscopic instruments. RESULTS:
      Operations were undertaken in 67 patients. In 6 patients (9%), conversion to open
      surgery was necessitated. In the remaining 61 patients, operations were completed
      with gasless laparoscopically assisted technique. Four reoperations (7%) were
      performed because of postoperative bleeding, anastomotic rotation, anastomotic
      stricture, and transmesenteric hernia. Fifty-three patients with colonic cancer
      were operated on with potentially curative intent. Of these, 1 (2%) developed
      hepatic recurrence during the mean follow-up period of 23.8 months. There was no
      port site recurrence. CONCLUSIONS: Gasless laparoscopic colonic surgery is
      technically feasible. CDI is not necessary to perform minimal access surgery.

PMID- 10414706
TI  - Breast cancer screening.
AB  - PURPOSE AND DESIGN: Three breast cancer screening methods are commonly employed:
      mammography, breast self examination (BSE), and physical examination by trained
      personnel (PE). Case-control, retrospective, and prospective studies have
      examined the efficacy of these screening modalities in reducing breast cancer
      mortality. However, there are three biases pertinent to many of these studies:
      lead-time, length, and selection biases. The best way to exclude these biases is
      to compare screened and unscreened women in a randomized controlled trial with
      breast cancer mortality as the end point. Eight trials have examined the effect
      of mammographic screening on breast cancer mortality and two have examined the
      impact of screening with BSE. In addition, a large trial will soon be initiated
      in India to assess the impact of screening by PE on breast cancer mortality. This
      article reviews these trials and discusses the implications of the studies.
      RESULTS: The overall results of the randomized controlled trials indicate that
      mammographic screening in women over age 50 can reduce breast cancer mortality by
      about 25%. However, its efficacy in women between the ages of 40 and 49 is
      disputed, and another large trial has been initiated in the United Kingdom to
      resolve this controversy. Preliminary results of two trials indicate that BSE has
      no impact on breast cancer mortality. However, longer follow-up of these trials
      is necessary before drawing any conclusions regarding BSE. CONCLUSIONS:
      Mammographic screening in postmenopausal women is an effective means of reducing
      breast cancer mortality. However, the impact of mammographic screening on breast
      cancer mortality in premenopausal women is disputed. At least four potentially
      harmful consequences of mammographic screening merit consideration: lead time
      effect, radiation exposure, false-positives, and overdiagnosis. Thus, women
      between the ages of 40 and 49, in particular, should be informed of the potential
      for benefit and harm prior to mammographic screening.

PMID- 10414707
TI  - Resolution of problem needed.

PMID- 10414708
TI  - Resolution of problem needed.

PMID- 10414709
TI  - Preoperative diagnosis of strangulated obturator hernia using ultrasonography.

PMID- 10414710
TI  - Pancreatitis associated with pancreatic islet cell tumors.

PMID- 10414711
TI  - Activated state of blood coagulation and fibrinolysis in patients with abdominal
      aortic aneurysm.

PMID- 10414712
TI  - Intraoperative ultrasound does not improve detection of liver metastases.

PMID- 10414713
TI  - Early versus late necrosectomy for necrotizing pancreatitis.

PMID- 10414714
TI  - Re: VSD problem. Verb-subject disagreement.

PMID- 10414715
TI  - Apico-aortic shunt: an alternate to the aorto-aortic shunt.

PMID- 10414716
TI  - Complexed PSA: the newest advance in PSA testing.

PMID- 10414717
TI  - Can complexed PSA be used as a single test for detecting prostate cancer?

PMID- 10414718
TI  - Tubularized incised plate hypospadias repair: indications, technique, and
      complications.

PMID- 10414719
TI  - Viagra--after one year.

PMID- 10414720
TI  - High-energy transurethral microwave thermotherapy in patients with acute urinary
      retention due to benign prostatic hyperplasia.
AB  - OBJECTIVES: To evaluate the efficacy and safety of targeted high-energy
      transurethral microwave thermotherapy (HE-TUMT) in the treatment of acute urinary
      retention (AUR) due to benign prostatic hyperplasia (BPH). METHODS: In this
      prospective cohort study, 31 patients with painful AUR due to BPH underwent HE
      TUMT. Patient evaluation before treatment and during a 12-week follow-up interval
      included determination of International Prostate Symptom Score (IPSS), quality of
      life (QOL) score, peak flow rate (Qmax) by uroflowmetry, and postvoid residual
      urine. Patients also underwent urodynamic evaluation before treatment and at 16
      weeks. RESULTS: By 4 weeks after HE-TUMT, 29 (94%) of 31 patients had regained
      the ability to void spontaneously. The actuarial median time for restoration of
      spontaneous voiding was 3.0 weeks (95% confidence interval [CI] 2.2 to 3.8). At
      12 weeks, the mean IPSS (9.4; 95% CI 8.3 to 10.5) was 50% below (P <0.0005) that
      before retention (18.9; 95% CI 18.2 to 19.6). Improvements in the mean QOL score
      were similar in pattern and relative magnitude to those in the mean IPSS. A 69%
      increase in mean Qmax (P <0.0005) determined by uroflowmetry was observed by 12
      weeks versus 1 week after HE-TUMT. Complications were infrequent. CONCLUSIONS:
      This study provides preliminary evidence that HE-TUMT may potentially afford a
      novel and useful option for the patient with AUR who is not a suitable candidate
      for surgery.

PMID- 10414721
TI  - Abuse of guaifenesin-containing medications generates an excess of a carboxylate
      salt of beta-(2-methoxyphenoxy)-lactic acid, a guaifenesin metabolite, and
      results in urolithiasis.
AB  - OBJECTIVES: Several urinary calculi were submitted to our institution for
      compositional analysis. The typical techniques of analysis, polarized light
      microscopy, electron microprobe analysis, and infrared spectroscopy proved
      inadequate for a definitive identification. As a result, a more detailed organic
      analysis was conducted to determine the exact chemical structure of the material.
      METHODS: Infrared spectroscopy and mass spectrometric analysis were carried out
      on the solid material, providing information concerning the functional groups and
      the molecular mass of the organic constituent and its components. The stone was
      solubilized in deuterated solvents and analyzed by nuclear magnetic resonance
      spectroscopy, which resulted in a definitive chemical structure. RESULTS: The
      spectroscopic analysis indicated that the stones were composed of a calcium salt
      of beta-(2-methoxyphenoxy)-lactic acid, a metabolite of the pharmaceutical
      guaifenesin, which is used as an expectorant. CONCLUSIONS: Guaifenesin, an
      expectorant common in over-the-counter cold and allergy remedies, can cause
      urolithiasis if taken in excess. Discussions with physicians and their patients
      confirmed that most patients admitted to taking large doses of guaifenesin
      containing medications.

PMID- 10414722
TI  - Lack of association between renal cell carcinoma and non-Hodgkin's lymphoma.
AB  - OBJECTIVES: To determine the incidence of non-Hodgkin's lymphoma (NHL) and renal
      cell carcinoma (RCC) after a diagnosis of the other malignancy. METHODS: The 1973
      to 1994 Surveillance, Epidemiology, and End Results (SEER) data base was used to
      determine the age-, sex-, race-, and calendar year-specific incidence rates for
      each year for RCC and NHL. The expected number of second cancers for each sex,
      race, and follow-up period (less than 1, 1 to 5, 5 to 10, and 10 or more years)
      was obtained by multiplying these incidence rates by the age-, sex-, race-, and
      calendar year-specific number of person-years at risk, with these products summed
      over the different age groups and calendar years. The standardized incidence
      ratio (SIR) was calculated (observed/expected number of second cancers), with
      statistical significance determined using the Poisson test. RESULTS: From 1973 to
      1994, 32,293 individuals in the SEER data base were diagnosed with RCC and 63,997
      with NHL. NHL was diagnosed after RCC in 67 cases versus 59.8 expected (SIR 1.12,
      P = 0.19) and RCC after NHL in 96 cases versus 56.1 expected (SIR 1.71, P
      <0.0001). Only white males and females had a significantly increased risk of RCC
      after NHL, which was limited to the first year of follow-up. Excluding the first
      year of follow-up, NHL was diagnosed after RCC in 54 cases versus 49.3 expected
      (SIR 1.10, P = 0.27) and RCC after NHL in 54 cases versus 45.1 expected (SIR
      1.20, P = 0.11). CONCLUSIONS: When the first year of follow-up is excluded, there
      is no increased risk of NHL after RCC or vice versa.

PMID- 10414723
TI  - Penetrating ureteral trauma at an urban trauma center: 10-year experience.
AB  - OBJECTIVES: To review the evaluation and management of patients with penetrating
      ureteral injuries not associated with iatrogenic etiology. METHODS: A
      retrospective analysis of 20 patients with penetrating ureteral injuries during a
      10-year period at a Level 1 trauma center was performed. Data were collected
      regarding the mechanism of injury, initial urinalysis and radiographic studies,
      operative procedure, associated injuries, postoperative complications, and
      outcome. RESULTS: In general, patients were young (mean age 27.8 years) men
      (95%). All injuries were unilateral (14 left and 6 right), were primarily caused
      by gunshot wounds (95%), and were associated with other injuries (100%). Three
      injuries were to the proximal ureter, 7 to the middle, and 10 to the distal
      ureter. Admission urinalysis failed to show gross or microscopic hematuria in 25%
      of cases. Preoperative intravenous urography (IVU) was diagnostic in 25% of
      cases. Fifteen injuries were diagnosed intraoperatively, including 2 with
      diagnostic IVU. Delayed diagnoses were made in 4 cases at 3 to 11 days; two by
      IVU postoperatively and the other two by computed tomography. All patients were
      treated surgically by ureteroneocystostomy, ureteroureterostomy, or pyeloplasty.
      Every repair was stented for a mean of 38 days (range 10 to 72). All three major
      complications (ureteral stricture, persistent urinary leak, and ureterocutaneous
      fistula) were managed successfully. Thirteen patients with long-term follow-up
      demonstrated no evidence of obstruction. CONCLUSIONS: Ureteral injuries must be
      considered early during the evaluation of penetrating abdominal injuries. The
      admission urinalysis may be falsely normal and initial IVU may be nondiagnostic.
      The diagnosis may be made intraoperatively or be delayed. The surgical repair
      should be stented, and long-term success can be anticipated.

PMID- 10414724
TI  - Urethral dilation in women: a questionnaire-based analysis of practice patterns.
AB  - OBJECTIVES: To assess current practice patterns among urologists and to determine
      the perceived efficacy of urethral dilation. Urethral dilation has been advocated
      as a treatment for a variety of urologic disorders in women for several decades.
      Recent changes in Medicare reimbursement have again focused attention on this
      issue. METHODS: A 15-item questionnaire was mailed to all urologists actively
      practicing in the state of Texas (n = 642). The questionnaire consisted of 12
      items about indications for, technique of, and outcome of urethral dilation, and
      three demographic questions regarding location and type of practice and number of
      years since completing residency. RESULTS: A total of 194 physicians completed
      and returned the questionnaire (30%). Overall, 48.2% of practitioners used
      dilation six or fewer times during the past year; 23.7% reported having used it
      more than 30 times. Most urologists used dilation for urethral syndrome only
      (61.1%), although urethral stricture was also a frequently reported condition
      requiring dilation (29%). Most urologists trained within the past decade (60.9%)
      reported never offering dilation for urethral syndrome; only 34.2% of the
      remainder never offered it (P = 0.002). Urologists normally performed this
      procedure with local or no anesthesia (85%) and most commonly dilated to 32F
      (45%). Overall, 21% of urologists trained more than 10 years ago considered
      dilation very or extremely successful in treating urethral syndrome; 0 of 42
      trained more recently considered it to be this successful (P = 0.014).
      CONCLUSIONS: The use of urethral dilation in women remains controversial.
      Recently trained urologists use it less frequently and find it less efficacious
      than those who have been practicing for longer periods. Since such obvious biases
      exist, it is imperative that the clinical merit of urethral dilation be carefully
      scrutinized.

PMID- 10414725
TI  - Voiding function of orthotopic ileal neobladder in women.
AB  - OBJECTIVES: Although the advent of orthotopic lower urinary reconstruction in
      women is a major achievement in the evolution of urinary diversion, the mechanism
      of voiding dysfunction remains incompletely understood. We report on the voiding
      function of ileal neobladder in 12 female patients. METHODS: A neobladder was
      constructed using an ileal segment. Voiding function was evaluated in terms of
      voiding pattern and continence. Chain cystography was performed postoperatively
      to detect the existence of urethral angulation. Median follow-up was 33.2 months
      (range 8.4 to 77.4). RESULTS: Of the 1 2 patients, 10 (83.3%) achieved excellent
      daytime continence, and 6 (50%) had nighttime incontinence despite regular
      voiding during the night. Three patients (25%) sometimes or often performed self
      catheterization because of difficulty in urinating. One patient (8.3%) was unable
      to void and required regular intermittent catheterization. Chain cystogram
      revealed urethral angulation in the 3 patients with difficulty in urinating or
      hypercontinence. CONCLUSIONS: An orthotopic neobladder can be constructed in
      women with excellent functional results. Urethral angulation appears to be one of
      the main mechanisms for voiding dysfunction, and further studies on the
      functional anatomy of the female urethra are needed to improve the voiding
      function of the orthotopic neobladder in women.

PMID- 10414727
TI  - Quinolone antibiotics: a potential adjunct to intravesical chemotherapy for
      bladder cancer.
AB  - OBJECTIVES: Despite complete transurethral resection of superficial bladder
      tumors, the recurrence rate averages 88% at 15 years. Intravesical chemotherapy
      decreases the recurrence rate, particularly if given immediately after tumor
      resection. Anticancer drugs such as doxorubicin target topoisomerase II as do the
      quinolone antibiotics. We evaluated two fluoroquinolones independently and in
      combination with doxorubicin for cytotoxic effects against bladder cancer cells
      in vitro. METHODS: Three human transitional carcinoma cell lines, T24 (grade I),
      HTB9 (grade II), and TccSup (grade IV), were exposed to either ciprofloxacin or
      ofloxacin in concentrations ranging from 0 (control) to 1000 microg/mL for 24,
      48, and 96 hours. In a separate experiment, a 30% cytotoxic dose (IC30) of
      doxorubicin was applied to the cell cultures for 1 hour and washed off, followed
      by exposure to ciprofloxacin or ofloxacin for 48 and 96 hours. Cytotoxicity was
      evaluated using the MTT colorimetric assay. RESULTS: At 96 hours, significant
      cytotoxicity (P <0.05) for ciprofloxacin was seen starting at 12.5 microg/mL
      (HTB9, TccSup) and 50 microg/mL (T24) and for ofloxacin at 12.5 microg/mL (HTB9)
      and 50 microg/mL (TccSup, T24). Maximum cytotoxicity with ciprofloxacin was
      95.4+/-0.4% (HTB9, 400 microg/mL) and with ofloxacin was 95.2+/-0.3% (HTB9, 800
      microg/mL). Exposure to doxorubicin (IC30, 1 hour) resulted in cell kill rates of
      30.9+/-5.2% (T24), 50.7+/-2.7% (HTB9), and 25.4+/-10.6% (TccSup). The addition of
      as little as 25 microg/mL of ciprofloxacin increased kill rates to 78.5+/-1.2%
      (T24), 61.2+/-1.6% (HTB9), and 74.2+/-2.4% (TccSup); P < 0.05 relative to
      doxorubicin alone. Similarly, 50 microg/mL of ofloxacin significantly increased
      kill rates to 81.8+/-1.6% (T24), 63.3+/-2.5% (HTB9), and 67.8+/-2.0% (TccSup).
      Both drugs showed even greater synergism at higher concentrations. CONCLUSIONS:
      Ciprofloxacin and ofloxacin exhibit significant time- and dose-dependent
      cytotoxicity against transitional carcinoma cells and significantly enhance the
      cytotoxicity of doxorubicin. These effects occur at concentrations achievable in
      the urine of patients after oral administration. This suggests that quinolone
      antibiotics might be useful as an adjunct to intravesical chemotherapy and might
      reduce seeding of cancer cells after transurethral resection of bladder tumors.

PMID- 10414726
TI  - Prognostic significance of angiogenesis and immunoreactivity of cathepsin D and
      type IV collagen in high-grade stage T1 primary bladder cancer.
AB  - OBJECTIVES: To assess the prognostic significance of biologic parameters such as
      angiogenesis, expression of cathepsin D (a lysosomal protease), and degradation
      of type IV collagen (a basement membrane protein), we studied 20 patients with
      primary grade III Stage T1 transitional cell carcinoma of the bladder. METHODS:
      Endothelial cells were labeled immunohistochemically using factor VIII-related
      antigen. The vascular surface density (VSD) and the microvessel number (NVES)
      were assessed by means of stereology. The tumor tissues were also analyzed by
      immunohistochemical methods for the expression of cathepsin D and the staining
      pattern of type IV collagen. RESULTS: Eight patients (40%) having either
      recurrence or progressive disease showed greater NVES and VSD values (P = 0.002
      and P = 0.01, respectively) than patients without. The significance of vascular
      parameters was found to be statistically independent from coexisting carcinoma in
      situ, bacille Calmette-Guerin (BCG) treatment, tumor size, and number.
      Additionally, these parameters did not show statistical significance between
      progressive and recurrent tumors. However, tumors with solid morphologic features
      had higher VSD values and a significantly greater rate of recurrence or
      progression (P = 0.01 and P = 0.07, respectively). Tissue from 17 (85%) of 20
      tumors showed absent or patchy basement membrane staining for type IV collagen,
      and 12 (60%) showed strong immunoreactivity for cathepsin D antibody. There were
      no differences for either molecule with either BCG treatment or other parameters
      related to prognosis. CONCLUSIONS: Angiogenesis may have an independent role in
      predicting prognosis in grade III Stage T1 bladder carcinoma. Grade III Stage pT1
      tumors with solid morphologic features have higher angiogenetic activity and a
      worse prognosis. Cathepsin D and type IV collagen do not seem to play a role in
      predicting biologic behavior.

PMID- 10414728
TI  - Monitoring patients for bladder neoplasms: what can be expected of urinary
      cytology consultations in clinical practice.
AB  - OBJECTIVES: To determine what practitioners could reasonably expect from urinary
      cytology (UC) consultations by analyzing their role in our clinical practice.
      METHODS: Reports of 227 consecutive interpretations on 130 patients collected
      during a 13-month period were correlated with all available follow-up
      information. RESULTS: In our practice, UC consultations can predict the presence
      of bladder carcinoma in nearly 90% of patients, the major mitigating factor being
      the absence of tumor cells in specimens from patients harboring bladder
      neoplasms. High-grade neoplasms are most reliably detected with UC. Very low
      grade neoplasms are difficult to detect, primarily because the cells of these
      lesions lack features of carcinoma. Significant interobserver variation did not
      occur. CONCLUSIONS: Pathology consultations based on UC can be associated with
      high diagnostic yields provided that certain factors are understood. These
      include that (a) the clinical import of diagnostic terms may vary among observers
      and should be mutually understood in individual practice settings; (b) UC
      specimens may not contain tumor cells even when patients have bladder cancer; (c)
      correlative information may be difficult to obtain and thus seem to inflate
      calculations for false-positive results; (d) interobserver variation can be
      reduced if cytopathologists use limited and uniform diagnostic terms; and (e) a
      high level of diagnostic expertise from cytopathologists should be expected.

PMID- 10414729
TI  - Does transurethral microwave thermotherapy have a different effect on prostate
      cancer than on benign or hyperplastic tissue?
AB  - OBJECTIVES: Transurethral microwave thermotherapy is useful for the treatment of
      benign prostatic hyperplasia, but its effect on cancer is not documented. We
      analyzed the pathologic changes occurring after microwave thermotherapy in whole
      mount radical prostatectomy specimens from patients with cancer. METHODS: Nine
      patients scheduled for radical prostatectomy for clinically localized prostate
      cancer were treated with transurethral microwave thermotherapy (Urologix Targis
      System). Patients ranged in age from 64 to 72 years (mean 68). Seven patients
      underwent prostatectomy 4 to 90 hours after thermotherapy, and 2 other patients
      underwent prostatectomy 12 months after thermotherapy. Whole mount totally
      embedded prostates were mapped for necrosis and cancer, and the volume of each
      was measured by the grid method. RESULTS: Pathologic stages were T2a (n = 4), T2b
      (n = 4), and T3b (n = 1). The prostates from patients who underwent radical
      prostatectomy within 4 to 90 hours of thermotherapy had a mean prostate weight of
      47.4 g (range 19.5 to 70.3). Each consistently showed hemorrhagic necrosis and
      tissue devitalization without significant inflammation. Necrosis involved
      contiguous areas of benign epithelium, stroma, and cancer without skip areas. The
      mean volume of necrosis was 8.8 cc (range 1.4 to 17.8), and the mean percentage
      of the prostate involved by necrosis was 22% (range 3% to 39%). The necrosis was
      symmetric around the urethra in 6 of 7 cases. Urethral dilation was observed in 3
      patients, and the mean maximum radial distance of necrotic tissue was 1.4 cm
      (range 0.6 to 1.8). Necrotic change was noted in 80% to 100% of the volume of
      cancer in 4 cases, 40% to 60% in 2 cases, and 5% in 1 case. The prostates from
      the 2 patients who underwent radical prostatectomy 12 months after thermotherapy
      had a mean weight of 88 g (55 and 121 g, respectively). Each showed periurethral
      fibrosis, nonspecific chronic inflammation, and squamous metaplasia of the
      urothelium. The mean volume of necrosis remaining was 0.2 cc. The mean percentage
      of the prostate involved by necrosis 1 year after thermotherapy was less than 1%.
      There was some reabsorption of dead tissue. The mean maximum radial distance of
      the necrotic tissue was 0.4 cm (0.2 and 0.7 cm, respectively). The prostatic
      urethra had viable and partially denuded urothelium in all cases. CONCLUSIONS:
      Microwave thermotherapy is clinically useful for ablation of benign prostate and
      cancer contiguous to the urethra, resulting in hemorrhagic necrosis with minimal
      damage to the urethra. There was no apparent differential morphologic sensitivity
      of benign prostatic tissue, hyperplastic tissue, or cancer to thermotherapy.

PMID- 10414730
TI  - Temporary intraurethral prostatic bridge-catheter compared with neoadjuvant and
      adjuvant alpha-blockade to improve early results of high-energy transurethral
      microwave thermotherapy.
AB  - OBJECTIVES: The maximal effect of transurethral microwave thermotherapy (TUMT)
      for lower urinary tract symptoms (LUTS) of benign prostatic hyperplasia (BPH)
      occurs 3 to 6 months after treatment. In the acute period after TUMT, little
      change in symptoms, quality of life (QOL), and peak urinary flow rate (Qmax) is
      observed versus baseline. Some men may also develop acute urinary retention
      secondary to thermally induced edema. Recent reports suggest that early results
      of TUMT may be improved with concomitant use of either a temporary intraurethral
      prostatic bridge-catheter (PBC) or neoadjuvant and adjuvant alpha-blocker
      therapy. This report compares the results of these two adjunctive modalities
      directly. METHODS: This nonrandomized retrospective comparison of results in 186
      patients with LUTS of BPH is based on findings of three recently reported
      prospective clinical trials. All patients underwent targeted high-energy TUMT.
      Ninety-one patients received no further treatment (TUMT alone group), 54 an
      indwelling PBC for up to 1 month (TUMT + PBC group), and 41 neoadjuvant and
      adjuvant tamsulosin (0.4 mg daily) treatment (TUMT + tamsulosin group). The
      International Prostate Symptom Score (IPSS), QOL score, and Qmax were determined
      at baseline and 2 weeks after TUMT. RESULTS: All three study groups experienced
      statistically significant improvements in mean IPSS and QOL score at 2 weeks
      versus baseline (P <0.0005). Nevertheless, the magnitude of improvement was
      greater in the TUMT + PBC group than the other two groups and greater in the TUMT
      + tamsulosin group than the TUMT alone group. A high proportion of the TUMT + PBC
      group (87.8%) attained a 50% or more IPSS improvement, compared with 4.5% of the
      TUMT alone group and none of the TUMT + tamsulosin group, and a similar pattern
      of between-group differences was noted with respect to the proportion of patients
      having 50% or more improvement in QOL score. The TUMT + PBC group was the only
      group to achieve significant Qmax improvement at 2 weeks compared with baseline.
      In the TUMT alone group, urinary retention 1 week or longer in duration occurred
      in 10 (11%) of 91 patients compared with 1 (2.4%) of 41 in the TUMT + tamsulosin
      group and none in the TUMT + PBC group. Early PBC removal was required in 11% of
      the TUMT + PBC group as a consequence of urinary retention secondary to clot
      formation or PBC migration. CONCLUSIONS: Both PBC placement and neoadjuvant and
      adjuvant alpha-blocker treatment are effective in alleviating symptoms and
      improving QOL during the acute period after TUMT. PBC usage also resulted in
      substantial early Qmax improvement. Either of these adjunctive modalities may be
      appropriate to consider in the treatment of TUMT patients during the early
      postprocedure recovery period.

PMID- 10414731
TI  - Effects of terazosin therapy on blood pressure in men with benign prostatic
      hyperplasia concurrently treated with other antihypertensive medications.
AB  - OBJECTIVES: To review and assess the cardiovascular safety of the alpha1-blocker
      terazosin when used to treat symptomatic benign prostatic hyperplasia (BPH) in
      patients taking concurrent antihypertensive medications. METHODS: This
      retrospective analysis focused on blood pressure changes and blood pressure
      related side effects in 555 of 2084 patients randomized to either terazosin or
      placebo in the Hytrin Community Assessment Trial (HYCAT) study who were following
      either single or combination antihypertensive regimens (treated patients). We
      also compared results in normotensive and hypertensive patients, whether treated
      or not. RESULTS: The addition of terazosin lowered mean systolic blood pressure
      by 5.3 mm Hg for untreated patients and 6.7 mm Hg for treated patients. For
      patients hypertensive on entry, mean reductions in systolic blood pressure in
      those untreated and treated were 12.1 and 11.1 mm Hg, respectively. The addition
      of terazosin to an existing antihypertensive regimen had its greatest impact (a
      mean reduction of 12.3 mm Hg) in those receiving diuretic therapy alone.
      Diastolic pressure changes followed a similar pattern. The incidences of blood
      pressure-related side effects in patients on terazosin were comparable between
      untreated (13.5%) and treated patients (14.3%), as were premature withdrawal
      rates, with 4.2% of untreated patients and 4.5% of treated patients withdrawing
      due to blood pressure-related side effects. CONCLUSIONS: Terazosin can be safely
      used to treat patients with symptomatic BPH regardless of their blood pressure
      status and antihypertensive regimen. Terazosin may be safely added to ongoing
      antihypertensive therapy.

PMID- 10414732
TI  - Phytotherapeutic agents in the treatment of lower urinary tract symptoms: a
      demographic analysis of awareness and use at the University of Chicago.
AB  - OBJECTIVES: To assess awareness and use of phytotherapeutic agents in treating
      lower urinary tract symptoms (LUTS). METHODS: A survey was conducted of 1280
      patients presenting to the University of Chicago Hospitals urology clinic. The
      questions pertained to age, race, educational level, and use of prescription and
      nonprescription medications for urinary symptoms. RESULTS: Of 1264 patients
      filling out the surveys correctly, the 51 to 60-year-old age range demonstrated
      the greatest percentage of use of these agents. Whites were nearly twice as
      likely as their African American counterparts to use medicinal botanicals. Men
      with college or graduate school degrees were 1.5 times as likely to use medicinal
      botanicals in treating LUTS. More than 50% of men using phytotherapeutic drugs
      were also taking prescription medications for the urinary symptoms. CONCLUSIONS:
      There is significant use of phytotherapeutic agents in men with LUTS, although
      there is variability in their use between patient groups. American physicians
      need some understanding of these agents to best advise and treat their patients.

PMID- 10414733
TI  - Clinical prostate score for diagnosis of bladder outlet obstruction by prostate
      measurements and uroflowmetry.
AB  - OBJECTIVES: To establish a clinical prostate score based on the parameters of
      uroflowmetry and prostate measurements to provide a better prediction of benign
      prostatic obstruction (BPO) in men with lower urinary tract symptoms (LUTS) and
      small prostate volume. METHODS: From October 1997 to September 1998, a
      prospective study of 324 consecutive men with LUTS was conducted in a community
      hospital in Taiwan. All patients were first evaluated by uroflowmetry and
      transrectal sonography of the prostate, and a videourodynamic study (VUDS) was
      performed before any medication was given. Patients were grouped as obstructed or
      unobstructed according to the results of the VUDS. Parameters from uroflowmetry
      and prostate measurements were evaluated for their sensitivity in predicting BPO.
      A clinical prostate score was established by summing scores on seven prostatic
      and uroflowmetric items: maximal flow rate (Qmax), flow pattern, voided volume,
      residual urine amount, total prostate volume (TPV), transition zone index (TZI),
      and prostatic configuration. Each of these items had a score representing the
      grade of sensitivity of BPO. RESULTS: Among the 324 men examined, only 65.4% were
      found to have obstruction by VUDS. A value of Qmax 10 mL/s or less had a
      sensitivity of only 75.4% and specificity of only 63.7% for BPO. A constrictive
      flow pattern had 87.2% sensitivity, residual urine 100 mL or greater had 86.1%,
      TPV 40 mL or greater had 94.6%, TZI 0.5 or greater had 87.8%, and the presence of
      a median lobe had 87.1% sensitivity; the presence of any of these factors added 2
      points to the score. The other parameters were scored as 1, 0, and -1,
      representing their sensitivity as slightly superior or inferior to that of LUTS.
      A prostate score of 3 or greater had a sensitivity of 87.2% and a specificity of
      60.8% for BPO. On the basis of this prostate score, 148 patients (46%) would have
      been treated for BPO without the need for further investigation, of whom 19
      (5.9%) would have been misdiagnosed. The remaining 176 patients (54%) would have
      undergone a VUDS and 93 of these patients (28.7%) were unobstructed. CONCLUSIONS:
      By combining uroflowmetry and transrectal sonography of the prostate, patients
      with LUTS can be diagnosed with a good sensitivity and specificity. Using the
      parameters in the uroflow and prostate measurements, a prostate score could be
      established and used as an indicator of BPO for selecting patients with LUTS who
      require further treatment or invasive VUDS.

PMID- 10414734
TI  - Contrast-enhanced three-dimensional power Doppler angiography of the human
      prostate: correlation with biopsy outcome.
AB  - OBJECTIVES: To determine the feasibility of contrast-enhanced three-dimensional
      (3D) imaging of the prostatic vasculature using power Doppler imaging and to
      analyze whether semiquantitative judgments of 3D images with respect to symmetry
      and distribution of vascular structures correlated with biopsy outcome. METHODS:
      3D power Doppler images were obtained before and after intravenous administration
      of 2.5 g Levovist. Subsequently, random and/or directed transrectal ultrasound
      (TRUS)-guided biopsies were performed. Vascular images were analyzed by two
      experts. Prostate vasculature was judged with respect to symmetry and vessel
      distribution using a (scale) grading system. RESULTS: Eighteen patients with a
      suspicion of prostate cancer either because of an elevated prostate-specific
      antigen (greater than 4.0 ng/mL; Tandem-R-assay) or an abnormal digital rectal
      examination were included in the study. Prostate cancer was detected in 13
      patients. Vascular anatomy was judged abnormal in unenhanced images in 6 cases,
      of which 5 proved malignant. Enhanced images were considered suspicious for
      malignancy in 12 cases, including 1 benign and 11 malignant biopsy results.
      Sensitivity of enhanced images was 85% (specificity 80%) compared with 38% for
      unenhanced images (specificity 80%) and 77% for conventional gray-scale TRUS
      (specificity 60%). Of 6 patients who showed no B-mode abnormalities, vascular
      patterns were judged abnormal in 4 cases, of which 3 were malignant. CONCLUSIONS:
      Contrast-enhanced 3D power Doppler angiography is feasible in patients with
      suspicion of prostate cancer who are scheduled for prostate biopsies. The
      sensitivity of power Doppler 3D imaging for the detection of prostate malignancy
      increased from 38% (5 of 13) to 85% (11 of 13) after administration of
      intravascular microbubble contrast (Levovist), and specificity was found to be
      80% (4 of 5) for both imaging modalities. Thus, the use of Levovist when combined
      with the power Doppler display mode and 3D image reconstruction offers a
      promising new research area that might prove useful in prostate cancer detection
      in the future.

PMID- 10414735
TI  - Comparison of clinically nonpalpable prostate-specific antigen-detected (cT1c)
      versus palpable (cT2) prostate cancers in patients undergoing radical retropubic
      prostatectomy.
AB  - OBJECTIVES: Serum prostate-specific antigen (PSA) testing has led to increased
      detection of clinically localized prostate cancer. We analyzed the clinical
      characteristics and outcome of digitally palpable (cT2) and PSA detected (cT1c)
      prostate cancers. METHODS: We evaluated 4453 patients with clinically localized
      prostate cancer who underwent radical retropubic prostatectomy (RRP) between 1987
      and 1995 at the Mayo Clinic. Overall, 1041 (23.4%), 1076 (24.2%), and 2336
      (52.5%) patients had cT1c, cT2a, and cT2b/c disease, respectively. Patients were
      analyzed with regard to Gleason score, preoperative PSA, pathologic stage,
      deoxyribonucleic acid (DNA) ploidy, margin status, tumor volume, and adjuvant
      treatment. Survival outcomes at 5 and 7 years were estimated using the Kaplan
      Meier method with respect to the end points of systemic/local clinical
      progression and clinical and/or PSA progression (greater than 0.2 microg/mL).
      Multivariate analysis was employed to estimate the relative risk of progression
      associated with each clinical stage when adjusted for the above factors. RESULTS:
      Clinical T1c tumors were more likely to be organ confined (76% versus 54%), have
      a Gleason score less than 7 (75% versus 61%), and be diploid (80% versus 70%)
      than cT2b/c tumors (P <0.001). Clinical T1c disease closely resembled cT2b/c
      disease with respect to preoperative PSA. Considering pathologic stage, DNA
      ploidy, and tumor volume, cT1c tumors were comparable to cT2a lesions. Of the
      patients with T1c cancers, 96.2% had clinically significant cancer on the basis
      of pathologic grade and tumor volume. The 5 (and 7 year) systemic/local clinical
      progression-free and PSA progression-free survivals for cT1c tumors were 97.7+/
      0.7% (96.4+/-1.1%) and 82.2+/-1.7% (72.9+/-3.8%), respectively. There was a
      significant survival advantage at 5 and 7 years regarding both end points for
      cT1c and cT2a compared with cT2b/c tumors (P <0.001). Multivariate analysis
      revealed a continued benefit in PSA and systemic/local clinical progression for
      cT1c tumors compared with cT2b/c tumors adjusting for the above factors.
      CONCLUSIONS: Clinical T1c tumors are clinically significant cancers. When
      compared with digitally palpable tumors, progression-free survival rates for cT1c
      tumors are similar to cT2a lesions, but are significantly better than cT2b/c
      lesions. This supports continued use of serum PSA to detect potentially curable
      prostate cancer.

PMID- 10414736
TI  - Treatment outcome with adjuvant and salvage irradiation after radical
      prostatectomy for prostate cancer.
AB  - OBJECTIVES: To determine the factors associated with outcome by reviewing our
      institution's experience treating patients with external beam radiation therapy
      (RT) after radical prostatectomy. METHODS: Sixty-one patients received RT to the
      prostatic fossa after radical prostatectomy for prostate cancer (median dose 59.4
      Gy). Thirty-eight patients received adjuvant RT within 6 months of surgery for
      adverse pathologic findings only. Therapeutic RT was administered to 23 patients
      either for a persistently elevated postoperative prostate-specific antigen (PSA)
      level (n = 2), a rising PSA level more than 6 months after surgery (n = 9), or a
      biopsy-proven local recurrence (n = 12). Preoperative and preradiation PSA
      values, Gleason score, pathologic findings, patient age, total RT dose, and
      indication for RT were analyzed for their impact on biochemical control. The
      median follow-up was 48 months. RESULTS: Patients treated with adjuvant RT
      achieved 3 and 5-year biochemical control rates of 84% and 67%, respectively.
      Multiple clinical, pathologic, and treatment-related factors were analyzed for an
      association with biochemical control. No variable was associated with 5-year
      outcome. The 5-year actuarial rate of biochemical control for patients treated
      with therapeutic RT was 16%. Multiple clinical, pathologic, and treatment-related
      factors were analyzed for an association with biochemical control. Only a pre-RT
      PSA level of 2 ng/mL or less was associated with an improved rate of biochemical
      control at 3 years (80% versus 27%, P = 0.001). However, at 5 years, this
      difference was not statistically significant. A separate analysis was performed
      to determine the prognostic factors associated with outcome for the entire group
      of patients. Only the indication for RT (adjuvant versus therapeutic) was
      associated with 5-year outcome. Patients treated with adjuvant RT had a
      statistically significant improvement in 5-year actuarial rates of biochemical
      control (67% versus 16%, P <0.001) and disease-free survival (66% versus 46%, P =
      0.037) but not in overall survival. There were no statistically significant
      differences between patient groups with respect to age, preoperative PSA, Gleason
      score, pathologic T stage, median follow-up, and total RT dose. CONCLUSIONS: At
      our institution, patients treated with adjuvant RT after prostatectomy for
      adverse pathologic findings achieved excellent rates of biochemical control that
      were significantly better than that of similar patients treated therapeutically
      for persistent or rising PSA or clinical local recurrence.

PMID- 10414737
TI  - Preliminary results of a bone marrow magnetic resonance imaging protocol for
      patients with high-risk prostate cancer.
AB  - OBJECTIVES: To compare the accuracy of a bone marrow magnetic resonance imaging
      (MRI) protocol in patients at high risk of metastatic disease with radioisotopic
      bone scans, the standard method for detection of bony metastases in patients with
      prostate cancer. METHODS: The study group consisted of 19 men with prostate
      cancer who underwent a bone marrow MRI between November 1993 and February 1996.
      This protocol images the marrow of the thoracolumbar spine, sacrum, pelvis, and
      femurs. Indications for MRI included an equivocal bone scan and/or staging of
      locally advanced or recurrent disease. The findings on MRI and bone scan were
      compared and the results correlated with the subsequent clinical patient outcome.
      RESULTS: The bone marrow MRI protocol detected metastatic disease in 1 (7%) of 13
      patients with negative bone scans. Four patients had an indeterminate bone scan:
      2 had true-positive MRIs, 1 a true-negative MRI, and 1 a false-positive MRI on
      the basis of subsequent clinical follow-up. Two patients with positive bone scans
      had true-positive MRIs. CONCLUSIONS: Although not recommended for routine
      staging, MRI was useful in this study for clarifying an equivocal bone scan. The
      bone marrow MRI protocol images a high yield volume of the bony skeleton and is
      fast and economical compared with obtaining many focused MRI scans of these areas
      separately. These preliminary data suggest that further investigation of its
      clinical utility for staging locally advanced or recurrent disease is justified.

PMID- 10414738
TI  - Sexual dysfunction after radical radiation therapy for prostate cancer: a
      prospective evaluation.
AB  - OBJECTIVES: To determine the rate of loss of potency after radiation therapy
      (RT). METHODS: Two hundred ninety men with localized prostate cancer were
      evaluated prospectively before and after RT to the prostate alone for change in
      erectile function. Data were collected before treatment by way of a questionnaire
      using a simple three-tier potency scale and after RT by the clinician at each
      follow-up visit. RESULTS: At 12 months, 62% of men (90 of 146) who were potent
      before RT preserved their potency; at 24 months, this figure was 41%. Men who had
      "normal" potency before RT were statistically significantly more likely to remain
      potent after RT. CONCLUSIONS: We believe that detailed knowledge of potency rates
      before and after RT is important for current decision-making and for evaluating
      new treatment techniques.

PMID- 10414739
TI  - Use of preoperative autologous blood donation in patients undergoing radical
      retropubic prostatectomy.
AB  - OBJECTIVES: To evaluate the appropriateness of autologous blood (AB) transfusion
      during radical retropubic prostatectomy in relation to the cardiopulmonary risk
      of the patient. METHODS: We reviewed the medical records of 100 patients with
      American Society of Anesthesiologists status I, II, or III who underwent radical
      retropubic prostatectomy under general or combined general and epidural
      anesthesia. All patients had donated 2 units (U) of autologous blood, received 0,
      1, or 2 U of autologous blood perioperatively, and received no allogeneic blood.
      Patients were placed in three cardiopulmonary risk groups on the basis of risk
      factors or documented cardiopulmonary disease. The low-risk group was assigned a
      target discharge hematocrit of 24% or less; moderate-risk, 25% to 28%; and high
      risk, 29% or greater. The appropriateness of transfusion was determined by
      whether patients' hematocrit was in their group's preassigned range at discharge.
      RESULTS: On the basis of discharge hematocrit, significantly more low-risk
      patients underwent inappropriate transfusion than moderate-risk (64% versus 26%,
      P = 0.006) or high-risk (64% versus 13%, P = 0.001) patients. Seventy-five AB
      units were discarded and at least 53 U were inappropriately transfused. We found
      an increase in the number of units of autologous blood transfused when a larger
      estimated blood loss was reported (P < 0.001). The estimated charge for the units
      discarded and inappropriately transfused exceeded $12,000. CONCLUSIONS: Sixty
      four percent of autologous blood units were discarded or inappropriately
      transfused during radical retropubic prostatectomy. Transfusion of autologous
      blood was not governed by cardiopulmonary risk stratification. If the decision to
      transfuse had been based on cardiopulmonary risk factors instead of estimated
      blood loss, fewer patients would have received autologous blood.

PMID- 10414740
TI  - Cryosurgery for prostate cancer: improved glandular ablation by use of 6 to 8
      cryoprobes.
AB  - OBJECTIVES: To describe and assess the efficacy for increased glandular
      destruction by using 6 to 8 cryoprobes in place of the traditional 5 probes.
      METHODS: In April 1996, a revised method for cryosurgery was begun that uses 6 to
      8 cryoprobes, and by July 1997, 81 men had been treated. This group was compared
      retrospectively to our last 82 cases done before April 1996 using 5 cryoprobes.
      All cases were consecutive. To ensure that the groups were similar, comparison
      was performed of entrance prostate-specific antigen (PSA), clinical stage, and
      Gleason score. Six months after cryosurgery, PSA and residual epithelial acini
      were compared between the two groups. RESULTS: The two groups were comparable for
      all the above parameters (P >0.05). The degree of overall glandular kill was
      greater for the 6 to 8-probe method (P = 0.023). Complete glandular ablation for
      the 5-probe and 6 to 8-probe methods was 39% and 53%, respectively, and the
      difference was not significant (P = 0.072). However, when one combined the
      complete glandular ablation group with the none to few residual acini group,
      67.5% for the 5-probe method and 88.9% for the 6 to 8-probe method, a significant
      difference was found (P = 0.001). The odds of having many remaining acini versus
      having none to few were 3.5 times greater in the 5-probe group than in the 6 to 8
      probe group. The mean and median PSA for the 5- and 6 to 8-probe groups were 0.19
      and 0.1 versus 0.11 and 0.07 ng/mL, respectively, a significant difference (P =
      0.02). No difference was found in rates of tumor persistence or complications.
      CONCLUSIONS: A revised method for cryosurgery using 6 to 8 cryoprobes has proved
      to be more effective for near-glandular ablation than the traditional 5-probe
      method. It was easily applied, had a wide margin of safety, and even shortened
      learning time. These innovations have permitted a closer approach to the goal of
      complete glandular destruction.

PMID- 10414741
TI  - Mucin-producing carcinoma of the prostate: review of 88 cases.
AB  - OBJECTIVES: To report on a case of mucinous carcinoma of the prostate and discuss
      the clinical and histopathologic features of the mucin-producing carcinoma of the
      prostate from a review of published reports. METHODS: Our case and 87 other
      previously reported cases were evaluated clinically and histologically. RESULTS:
      We encountered a case of mucinous carcinoma of the prostate, Stage C, which was
      treated by radical prostatectomy. After reviewing it and the 87 other cases, we
      believe that these cases of mucin-producing carcinomas can be divided into three
      groups: 60 cases of mucinous carcinoma, 17 cases of primary signet-ring cell
      carcinoma, and 11 cases of mucinous carcinoma with signet-ring cells. Mucinous
      carcinoma is a variant of high-grade adenocarcinoma of the prostate, wherein
      there is a 77.8% rate of prostate-specific antigen elevation and a similar rate
      (77.8%) of response to endocrine therapy. Fifty percent of patients survived 3
      years and 25%, 5 years. In contrast, primary signet-ring cell carcinoma conveys
      one of the worst prognoses among patients with prostate cancer. There are no
      reliable tumor markers, and there was no response to endocrine therapy. Patients
      with primary signet-ring cell carcinoma had a 27.3% 3-year survival rate; none
      survived to 5 years. The clinical features of mucinous carcinoma with signet-ring
      cells are very similar to primary signet-ring cell carcinoma; again, there was no
      response to endocrine therapy and the 3-year survival rate was 16.7%.
      CONCLUSIONS: Although it has been suggested that mucinous carcinoma is a variant
      of high-grade adenocarcinoma of the prostate, signet-ring cell carcinoma and
      mucinous carcinoma with signet-ring cells are other variants of carcinoma that
      develop in the prostate, and their prognoses are very poor.

PMID- 10414742
TI  - Penile implant success in patients with corporal fibrosis using multiple
      incisions and minimal scar tissue excision.
AB  - OBJECTIVES: To establish the efficacy of "minimal scar tissue excision" in the
      treatment of penile fibrosis. METHODS: Thirty-four patients with extensive penile
      fibrosis who underwent placement of penile implant from October 1989 to April
      1998 were evaluated by a chart review of the patient's follow-up data. Function
      of the implant was evaluated at follow-up visits. The follow-up ranged from 4 to
      84 months (mean 23.7, median 22). All patients had undergone minimal scar tissue
      excision of the fibrous tissue in the penis. RESULTS: All patients underwent
      successful introduction of the penile implant, and in no patient was the
      procedure abandoned because of technical difficulty. Intraoperatively, 1 patient
      developed a tear in the crus. It was not recognized during the initial operation
      but was repaired at a subsequent date by Gore-Tex grafting. The Uniflate
      prosthesis of another patient failed 2 years after the initial surgery and was
      replaced with the Mentor alpha-1 implant. None of the patients developed
      infection. All the patients had a functioning implant at the time of last review.
      CONCLUSIONS: Minimal scar tissue excision is a safe and effective method in the
      management of extensive penile fibrosis.

PMID- 10414743
TI  - Fracture at the input tube-cylinder junction of AMS 700 inflatable penile
      prostheses as a complication of a modified implantation technique in a series of
      99 patients.
AB  - OBJECTIVES: To compare the incidence of a specific failure mode of the penile
      implant, fracture at the input tube-cylinder junction, with respect to two
      methods of managing the input tube. METHODS: AMS 700 series three-piece
      inflatable penile prostheses were implanted in the first 26 patients using an
      ordinary technique in which the input tubing runs alongside the cylinder within
      the corpus and exits through the corporotomy (method A). In the subsequent 73
      men, the input tube exited through a separate stab wound in the proximal corpus
      using a modification of the basic surgical technique (method C). The mean follow
      up period was 136.4 months for method A and 69.0 months for method C. The
      incidence of fracture at the junction of the input tube and cylinder was compared
      according to the variables of input tube management, prosthesis type, and width
      of the proximal corpora. RESULTS: The overall incidence of mechanical failure was
      12.1%. Fractures at the input tube-cylinder junction with leaking occurred in 7
      patients. The cylinders in these patients were all implanted using method C. The
      incidence of fracture at the junction was significantly higher (P <0.05) in men
      with narrow corpora (17.1%) than in the others (0%), regardless of the type of
      prosthesis implanted. The average functional duration of the failed prostheses
      was 66.1 months. CONCLUSIONS: The modified surgical procedure (method C) should
      be avoided in patients with a narrow-width penis because of an increased
      likelihood of damage to the input tube-cylinder junction.

PMID- 10414744
TI  - Clinical applications of the Monti procedure as a continent catheterizable stoma.
AB  - OBJECTIVES: Monti et al. recently described a technique for the construction of a
      continent catheterizable conduit using short segments of small bowel in a canine
      model. We review our experience with 25 adult and pediatric patients in whom the
      Monti procedure was used in their reconstructive efforts. METHODS: Since October
      1995, 25 patients (13 males and 12 females), aged 4 to 67 years (median 29),
      underwent the construction of 29 catheterizable stomas with a short (2.5 cm)
      segment of bowel following the Monti technique. Twenty-seven tubes were created
      as urinary stomas and two as part of the Malone antegrade continent enema
      procedure (MACE). Continence is based on the Mitrofanoff flap valve mechanism.
      Tubes were created when the appendix was unavailable as part of urinary
      reconstructive efforts or after exenterative oncologic surgery of the lower
      urinary tract. Tubes were created using ileum (24) and sigmoid colon (5). Ten
      tubes (34.5%) were done in combination with a simultaneous bowel patch in the
      same pedicle for bladder augmentation. Tubes were implanted in the ileum (13),
      bladder (9), sigmoid colon (3), stomach (1), and descending colon (1). The two
      tubes created to do a MACE procedure were anastomosed into the cecum. Double
      tubes were necessary in 7 adult patients for adequate length. The length of the
      tubes varied from 6 to 14 cm. RESULTS: Follow-up ranged between 3 and 26 months
      (mean 13). One adult patient (4%) with bladder cancer died of myocardial
      infarction 14 days postoperatively. Three patients (12%) received a new Monti
      tube because of ischemic stenosis of the tube. All of them were continent at a
      follow-up of 1, 6, and 20 months, respectively. Two patients (8%) experienced
      leakage through the stoma, requiring additional procedures and pharmacologic
      manipulation to become continent. All patients used intermittent catheterization
      through the stoma without problems. CONCLUSIONS: Although the appendix remains
      the tissue of choice, the Monti procedure has substantial advantages over other
      efferent catheterizable tubes, including the need for a very short segment of
      bowel (2.5 cm), adequate lumen size (16F to 18F), length, reliable blood supply,
      and the versatility to combine with a simultaneous bowel patch in the same
      pedicle for bladder augmentation.

PMID- 10414745
TI  - Role of magnetic resonance imaging in children with voiding dysfunction:
      retrospective analysis of 81 patients.
AB  - OBJECTIVES: To investigate the role of magnetic resonance imaging (MRI) in
      children with voiding dysfunction and a normal neuro-orthopedic assessment. The
      differential diagnosis of neurogenic and non-neurogenic voiding dysfunction,
      particularly in children with occult neurogenic pathologic findings without a
      clinically demonstrable neurologic defect, is a commonly encountered problem.
      METHODS: Eighty-one children with voiding dysfunction, including a history of
      diurnal incontinence, frequency, urgency, urge incontinence, incomplete bladder
      emptying, recurrent urinary tract infection, and persistent vesicoureteral
      reflux, constituted our study group. A detailed neuro-orthopedic evaluation was
      performed in all patients. The urologic evaluation consisted of a detailed
      history (including bowel function disturbances), renal sonography or excretory
      urography, spinal x-ray, urinalysis and culture, voiding cystourethrography, and
      multichannel water cystometry. In all cases, lumbosacral spinal axial and
      sagittal T1- and T2-weighted MRI performed with a 1.5-Tesla surface coil was
      reviewed by one neuroradiologist. RESULTS: MRI revealed pathologic findings in 17
      (38.6%) of 44 patients who had voiding dysfunction and a normal neuro-orthopedic
      assessment. All these patients underwent early surgical intervention in our
      pediatric neurosurgery department. In the postoperative period, objective and/or
      subjective improvement in voiding symptoms within short (6 months) and long (14
      months) periods was observed in 8 (47.0%) and 5 (29.4%) patients, respectively.
      Ten (58.8%) of those 17 patients had a history of voiding dysfunction refractory
      to conservative management. CONCLUSIONS: Our results revealed that MRI of the
      lower spinal cord is a valuable tool in the diagnosis of occult spinal cord
      disorders, especially in patients with voiding dysfunction refractory to
      conservative management strategies and normal neurologic and orthopedic
      assessments.

PMID- 10414746
TI  - Transforming growth factor-beta type II receptor confers tumor suppressor
      activity in murine renal carcinoma (Renca) cells.
AB  - OBJECTIVES: To demonstrate that the introduction of the transforming growth
      factor-beta (TGF-beta) type II receptor (TbetaR-II) decreases tumorigenicity in
      an aggressive murine renal carcinoma line, Renca. These cells do not express
      TbetaR-II. Because the presence of TbetaR-II in benign epithelial cells is
      ubiquitous, the ability to restore tumor suppressor activity in the Renca cell
      line with its introduction would elucidate the role of TbetaR-II as a tumor
      suppressor gene. METHODS: Renca cells were stably transfected with a retrovirus
      mediated TbetaR-II expression vector. In vitro sensitivity to growth inhibitory
      effect of TGF-beta was assessed by the 3H-thymidine incorporation assay. For in
      vivo testing, xenograft tumors were produced by subcutaneous injection of tumor
      cells into immunodeficient nude mice. The tumorigenicity of these TbetaR-II
      transfected cells was tested. Wild-type Renca cells and cells transfected with
      the control vector were also tested for comparison. RESULTS: Expression of TbetaR
      II mRNA was evident in Renca cells after transfection with the TbetaR-II
      construct. In vitro sensitivity to the growth inhibitory effect of TGF-beta was
      restored. This effect of TGF-beta was reversible with a neutralizing antibody
      specific for the extracellular domain of TbetaR-II. Xenografts grown from TbetaR
      II transfected cells were significantly smaller, weighed less, and developed
      tumors later than those developed from wild-type Renca cells and those
      transfected with the control vector. CONCLUSIONS: We conclude that TbetaR-II is a
      central mediator of tumorigenicity in Renca cells. As with other tumor suppressor
      genes, the loss of TbetaR-II expression allows for the development of an
      aggressive phenotype.

PMID- 10414747
TI  - Differential effects of vitamin D on normal human prostate epithelial and stromal
      cells in primary culture.
AB  - OBJECTIVES: Because epidemiologic evidence has demonstrated that vitamin D may
      play a role in the etiology of prostate cancer, we tested the inhibitory effect
      of the biologically active form of vitamin D (1,25-D) on the cell proliferation
      of human prostate epithelial and stromal cells in a chemically defined situation
      in the presence and absence of dihydrotestosterone (DHT). We also tested the
      effect of 1,25-D in castrated rats in the presence and absence of flutamide, an
      androgen receptor blocker. METHODS: Prostate stromal and epithelial cells were
      isolated from freshly collected human prostatectomy specimens, and cell
      proliferation was measured with the MTT assay. Immunohistochemistry was performed
      to detect the presence of 1,25-D receptors, androgen receptors, smooth muscle
      actin, and E-cadherin. For in vivo analysis of 1,25-D, male Sprague-Dawley rats
      were castrated, then treated with either 1,25-D, 1,25-D with flutamide, or
      vehicle control. RESULTS: Incubation of primary cultures of prostate epithelial
      cells with 1,25-D at a concentration of 10(-8) M reduced cell proliferation by
      40% of controls. The inhibition of growth by 1,25-D was maintained in the
      presence of DHT. Conversely, the effect of a similar dose of 1,25-D on stromal
      cell exposure was increased proliferation. In vivo, 1,25-D increased the
      prostatic weight of castrated rats that had serum testosterone levels below the
      detectable limit. The addition of flutamide did not alter this effect.
      CONCLUSIONS: These results confirm that vitamin D may be an effective
      antiproliferative agent of epithelial cells in prostate cancer therapy and
      support in vivo studies performed in the normal rat prostate.

PMID- 10414748
TI  - Racial differences in insulin-like growth factor binding protein-3 in men at
      increased risk of prostate cancer.
AB  - OBJECTIVES: To determine the overall plasma levels of insulin-like growth factor
      1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) in a group
      of men at higher risk of prostate cancer development and to investigate the
      relationships between demographics and these levels, particularly with regard to
      race. METHODS: An enzyme-linked immunosorbant assay was used to quantitate plasma
      levels of IGF-1 and IGFBP-3. The study group consisted of 105 men (63 African
      American [AA], 42 white), aged 35 to 69 years, with no personal history of
      prostate cancer, but having at least one first-degree relative diagnosed with the
      disease, unless they were AA. Differences in plasma levels and categorical
      covariates were assessed using the nonparametric Wilcoxon test. Associations
      between plasma levels and the continuous variables were quantified using the
      nonparametric Spearman correlation coefficient. RESULTS: The mean plasma level of
      IGF-1 was not significantly different between AA (162.3 ng/mL) and white (172.1
      ng/mL) men (P = 0.415). However, the mean plasma level of IGFBP-3 was lower in AA
      (2789 ng/mL) than in white (3216 ng/mL) men, and this decrease was highly
      significant (P = 0.0045). No correlation between IGFBP-3 plasma level and age was
      detected in the group as a whole, but an inverse relationship between IGF-1
      plasma level and age was evident (P = 0.0079). CONCLUSIONS: Our results
      demonstrate that IGFBP-3 plasma levels are lower in AA men than in white men.
      Since IGFBP-3 can control IGF-1 bioavailability, the lowered IGFBP-3 could
      explain in part the increased risk of prostate cancer in AA men.

PMID- 10414750
TI  - Dr. James Brown and catheterization of the male ureter: June 9, 1893.

PMID- 10414749
TI  - Sucrose diuresis protects rat bladder from outlet partial obstruction-induced
      contractile dysfunction.
AB  - OBJECTIVES: Evidence is accumulating that bladder dysfunction caused by
      experimental partial obstruction of the bladder outlet can be reduced or reversed
      by treatment that results in upregulation of bladder function, even in the
      presence of obstruction. Inducing diuresis in rats or rabbits results in a
      significant increase in bladder mass and increased contractility in response to
      stimulation. The objective of the present study was to determine whether diuresis
      induced amplification of bladder function in the rat could protect the bladder
      from contractile dysfunctions caused by partial outlet obstruction. METHODS:
      Thirty-two rats were separated into four groups of 8 rats each. Groups 2 and 4
      were fed 5% sucrose instead of water; groups 1 and 3 were fed only water. Three
      weeks later, partial outlet obstructions were created in groups 3 and 4. After 4
      weeks of obstruction, all bladders were rapidly excised and cut into longitudinal
      strips; each strip was mounted in an isolated muscle bath for contractile
      studies. RESULTS: Sucrose-induced diuresis caused a moderate but significant
      increase in bladder mass. Partial outlet obstruction stimulated significant
      increases in bladder mass in both water-drinking and sucrose-drinking groups; the
      bladder mass of sucrose-drinking rats, however, increased less than that of water
      drinking rats. In water-drinking rats, partial outlet obstruction resulted in
      significantly decreased bladder strip contractility in vitro in response to field
      stimulation (1 to 32 Hz), carbachol (0.1 to 22 microM), and KCl (120 mM). After 3
      weeks of sucrose-induced diuresis, partial obstruction of the rat bladder outlet
      did not result in decreased in vitro contractile responses to any form of
      stimulation applied. CONCLUSIONS: Sucrose-induced diuresis caused an increase in
      bladder mass and an increase in contractile strength, consequently protecting the
      rat bladder from the contractile dysfunctions that usually follow partial outlet
      obstruction.

PMID- 10414751
TI  - Ipsilateral adrenalectomy during radical nephrectomy for renal cell carcinoma.

PMID- 10414752
TI  - Testicular androgen ablation for prostate cancer.

PMID- 10414753
TI  - Relative potency of bicalutamide (Casodex) and flutamide (Eulexin)

PMID- 10414754
TI  - A multicenter investigation of age-related differences in lengths of stay,
      hospitalization charges, and outcomes for a matched tetraplegia sample.
AB  - OBJECTIVE: To examine the effects of age at injury on lengths of stay, treatment
      costs, and outcomes using a matched sample of tetraplegic spinal cord injury
      (SCI) patients. DESIGN: Differences were examined by separating the sample into
      three age categories (18 to 34, 35 to 64, and 65+ years old) matched for American
      Spinal Injury Association (ASIA) Motor Impairment Classification and level of
      neurologic preservation bilaterally. Analysis of variance was used to examine age
      group differences for lengths of stay, medical expenses, and functional outcome.
      SETTING: Sixteen medical centers in the federally sponsored Spinal Cord Injury
      Model Systems Project. PARTICIPANTS: Three hundred seventy-five adult patients
      with tetraplegic SCI admitted between 1988 and 1996 were assessed at acute care
      admission, inpatient rehabilitation admission, and inpatient rehabilitation
      discharge. MAIN OUTCOME MEASURES: ASIA Motor Index and Functional Independence
      Measure (FIM) admission, discharge, and efficiency scores; acute care and
      rehabilitation lengths of stay and medical care charges; and discharge
      disposition. RESULTS: Analyses revealed equivalent lengths of stay and charges
      for all age groups. There were no age-related differences in ASIA and FIM Motor
      scores at acute care and inpatient rehabilitation admission. Younger patients'
      scores on the FIM Motor subscale improved significantly more than did middle and
      older patients'. The two younger groups of patients had a more significant
      improvement than did older patients, as indicated by ASIA Motor Index scores.
      When taking lengths of stay into account, the FIM motor scores of the youngest
      group of patients improved more quickly than those of the two older groups.
      Furthermore, the younger and middle age groups demonstrated greater treatment
      efficiency than the older patient group based on ASIA Motor Index score ratios.
      Younger patients were least likely to be discharged to institutional settings.
      CONCLUSIONS: Along with neurologic and functional status, age should be
      considered when formulating treatment plans and prognostic statements. For older
      patients, alternative rehabilitation settings with lower-intensity treatment and
      lower charges may prove to be a more efficacious use of resources.

PMID- 10414755
TI  - Abdominal weight and inspiratory resistance: their immediate effects on
      inspiratory muscle functions during maximal voluntary breathing in chronic
      tetraplegic patients.
AB  - OBJECTIVE: To study the immediate effects of maximal voluntary (MV) breathing,
      with and without abdominal weight (AW) or inspiratory resistance (IR), on
      inspiratory muscle functions in chronic tetraplegic patients. DESIGN: A crossover
      trial design. SETTING: Rehabilitation department of a university hospital.
      PARTICIPANTS: Nine tetraplegic men injured at the C4 to T1 levels, with a mean
      duration of injury of 72.8 months. INTERVENTIONS: Each subject performed MV
      breathing without and with AW load (AWMV breathing) and IR load (IRMV breathing)
      separately. MAIN OUTCOME MEASURES: Electromyographic (EMG) activity of the
      inspiratory muscles, mouth pressure, inspiratory flow, and inspiratory volume.
      RESULTS: AWMV breathing evoked greater diaphragmatic EMG activity, inspiratory
      flow, and inspiratory volume than did IRMV breathing, although the increase of
      diaphragmatic EMG activity was not statistically significant. Conversely, IRMV
      breathing produced greater sternocleidomastoid EMG activity and negative mouth
      pressure than did AWMV breathing. Both AWMV and IRMV breathing evoked greater
      inspiratory muscle EMG activity than did MV breathing. CONCLUSION: AW and IR
      loads have differential immediate effects on the inspiratory muscle functions
      during MV breathing in patients with chronic tetraplegia, suggesting that these
      two breathing maneuvers may have dissimilar mechanisms of training in such
      patients. The muscle EMG activity evoked during MV breathing with AW or IR is
      greater than that without a mechanical load, implying that mechanically loaded
      training in tetraplegic patients results in load compensatory adjustments via
      their respiratory motor output to improve respiratory function.

PMID- 10414757
TI  - Electromyographic activity of the lumbar extensor muscles: effect of angle and
      hand position during Roman chair exercise.
AB  - OBJECTIVE: To evaluate the effects of angle and hand position during variable
      angle Roman chair (VARC) back extension exercise on lumbar paraspinal
      electromyographic (EMG) activity. DESIGN: Descriptive, repeated measures.
      SETTING: University-based musculoskeletal research laboratory. PARTICIPANTS: Two
      female and eight male volunteers recruited from a university setting.
      INTERVENTION AND OUTCOME MEASURES: Surface integrated EMG activity was recorded
      from the L3-L4 paraspinal region during 24 10-second repetitions of dynamic back
      extension exercise, each consisting of a unique VARC angle (six total) and
      subject hand position (four total). Lumbar paraspinal surface integrated EMG
      activity measured in millivolts per repetition was used for analysis. RESULTS:
      Significant lumbar paraspinal EMG activity was evident during each of the 24
      repetitions (p < or = .05), with a 104% increase in activity noted between the
      lowest and highest. EMG activity increased progressively among hand positions and
      as the VARC angle became more horizontal. VARC angle affected EMG activity more
      than hand position, but the greatest impact on EMG activity was produced by
      modifying both angle and hand position. CONCLUSION: Lumbar paraspinal EMG
      activity can be altered during VARC back extension exercise by changing angle and
      hand position. Clinicians can use these data to develop progressive resistance
      exercise programs using the VARC apparatus.

PMID- 10414756
TI  - Moderate-intensity exercise training with elements of step aerobics in patients
      with severe chronic heart failure.
AB  - OBJECTIVE: To evaluate whether a specific program of moderate-intensity step
      aerobics training may be sufficient to improve the exercise tolerance of patients
      with severe chronic heart failure. PATIENTS: Twenty-six patients (22 men, 4
      women; mean +/- SD age, 54 +/- 9yrs) with a history of severe chronic heart
      failure (left ventricular ejection fraction of 18% +/- 8%). STUDY DESIGN:
      Prospective, randomized, controlled trial. Patients were randomized into exercise
      and control groups. All patients underwent a clinical examination and a ramp
      pattern cycle exercise test before and after the observation period. The exercise
      group underwent a moderate-intensity (50% of peak oxygen uptake) 12-week training
      program, progressing to 100 minutes per week of step aerobics and 50 minutes per
      week of cycling. The control group did not perform a training program. MAIN
      OUTCOME MEASURES: Peak oxygen uptake, peak workload, percent of predicted power
      ability. RESULTS: Significant increases in peak oxygen uptake (15 +/- 3.4 to 18.5
      +/- 2.9mL/kg/min; p = .001), peak workload (77 +/- 26 to 99 +/- 31 watts; p =
      .000), and percent of predicted power ability (43% +/- 10% to 56% +/- 13%; p =
      .000) were observed in the exercise group. No significant changes in baseline
      parameters occurred in the control group. There were no critical changes in heart
      rate or blood pressure in either group. CONCLUSION: Moderate-intensity step
      aerobics training significantly increases peak oxygen uptake and peak workloads
      in patients with severe chronic heart failure.

PMID- 10414758
TI  - Median-to-ulnar sensory nerve action potential amplitude ratio as an
      electrodiagnostic adjunct for carpal tunnel syndrome.
AB  - OBJECTIVES: (1) To obtain normative data for the median-to-ulnar sensory nerve
      action potential (SNAP) amplitude ratio (MUSAR) and (2) to discuss the adjunctive
      use of MUSAR in electrodiagnosis of carpal tunnel syndrome. DESIGN: Analysis of
      previously collected normative data. SETTING: Veterans Administration
      electromyography laboratory. SUBJECTS: Forty-six apparently healthy male
      volunteers without neurologic complaints. MAIN OUTCOME MEASURES: Antidromic
      median and ulnar SNAPs were recorded and the respective MUSAR ratios were
      calculated. Descriptive statistical analysis was completed, with the assumption
      that SNAP values are not Gaussian in distribution. RESULTS: The normal MUSAR
      ranged from .74 (5th percentile) to 2.5 (95th percentile). CONCLUSION: The MUSAR,
      being an intrapersonal ratio, may decrease the false positives and false
      negatives that would otherwise arise when using absolute values of SNAP
      amplitudes. Hence, it may increase the diagnostic specificity for carpal tunnel
      syndrome. Further studies are needed to confirm the clinical and presurgical
      application of the MUSAR value.

PMID- 10414759
TI  - Validity of the PULSES profile compared with the Functional Independence Measure
      for measuring disability in a stroke rehabilitation setting.
AB  - OBJECTIVES: To test the validity of the PULSES profile for measuring the
      disability of stroke rehabilitation patients and to compare it with the
      Functional Independence Measure (FIM); and to determine the ability of the PULSES
      score to predict discharge home from a stroke rehabilitation setting. STUDY
      DESIGN: Retrospective cohort. SETTING: A tertiary stroke rehabilitation unit.
      PATIENTS: One hundred ninety-seven patients admitted consecutively to a stroke
      rehabilitation unit from September 1992 to April 1995. METHODS: The PULSES
      profile was tested for internal consistency. Criterion validity was evaluated by
      comparing with the FIM. Construct validity was tested using the multimethod
      multitrait matrix method and by performing logistic regression to determine if
      admission PULSES score was predictive of discharge home. RESULTS: Internal
      consistency of the PULSES profile was supported with a Cronbach's alpha of .74.
      There was a high correlation between the PULSES and FIM admission and discharge
      scores of -.82 and -.88, respectively. The multimethod-multitrait matrix
      correlations demonstrated good convergent and divergent validity for the
      correlation of the PULSES profile items and the FIM subcategories. Multivariate
      logistic regression determined the admission PULSES total score to be an
      independent variable in the model to predict discharge home. CONCLUSIONS: The
      PULSES profile is a valid measure for assessing disability in the stroke
      rehabilitation setting. The PULSES profile correlates highly with the FIM. The
      admission PULSES total score is predictive of discharge home from a stroke
      rehabilitation program.

PMID- 10414760
TI  - Task-dependent weakness at the elbow in patients with hemiparesis.
AB  - OBJECTIVE: To investigate the task dependence of elbow weakness in patients with
      hemiparesis. DESIGN: Descriptive study based on interlimb comparisons of maximum
      voluntary torques (MVTs) generated isometrically in elbow flexion and extension
      under four task conditions: without explicit control of the torques at adjacent
      joints and in combination with each of three submaximal shoulder
      abduction/adduction torque levels. SETTING: Rehabilitation center research
      laboratory. PATIENTS: Volunteer samples of six patients with chronic hemiparesis
      and four controls. MAIN OUTCOME MEASURE: Residual strength (RS), defined as the
      ratio of MVTs for the paretic and nonparetic limbs of patients and nondominant
      and dominant limbs of controls. RESULTS: For the patient group a significant
      effect of task condition on RS was found (analysis of variance, p = .0003 and p =
      .002 for elbow flexion and extension, respectively). With increasing shoulder
      abduction torque level, elbow flexion RS increased and elbow extension RS
      decreased. In contrast, for the control group, the effect of task condition on RS
      was not significant. CONCLUSION: In hemiparetic patients, weakness of the paretic
      elbow musculature shows a strong task dependence. This task dependence likely
      reflects the existence of abnormal synergies between elbow and shoulder muscles
      of the paretic limb and has important implications for the rehabilitation of
      motor function following hemiparesis.

PMID- 10414761
TI  - Brief cognitive screening of right hemisphere stroke: relation to functional
      outcome.
AB  - OBJECTIVES: Traditional mental status screens have limited sensitivity in
      detection of focal brain damage and are particularly insensitive to right
      hemisphere stroke (RHS). Addition of a simple measure of constructional ability,
      clock drawing, should enhance the sensitivity of the Modified Mini-Mental State
      Exam (3MS) in RHS. The relation between the 3MS-clock drawing screen and
      functional outcome in RHS was also examined. DESIGN: Logistic regression analysis
      (Study 1) with cross validation on an independent sample (Study 2). SETTING:
      Inpatient medical rehabilitation. PATIENTS: Study 1: 32 acute RHS patients (mean
      age 75.2yrs) and 35 age- and education-matched healthy controls. Study 2 (cross
      validation): 32 acute RHS patients (mean age 72.8yrs) and 36 matched healthy
      controls. OUTCOME MEASURES: 3MS, clock drawing, and Functional Independence
      Measure scores. RESULTS: The 3MS-clock screen accurately distinguished RHS
      patients from controls. The clock drawing was a valuable and unique addition to
      the 3MS. RHS patients who were impaired on the 3MS-clock drawing screen had
      significantly worse FIM scores at discharge than RHS patients who were not
      impaired on the cognitive screen. CONCLUSION: Clinicians can enhance the
      sensitivity of their brief mental status examination of RHS patients, in addition
      to obtaining useful prognostic information, by including a clock drawing task in
      their screen.

PMID- 10414762
TI  - Hemiplegic gait of stroke patients: the effect of using a cane.
AB  - OBJECTIVE: To assess the effects of cane use on the hemiplegic gait of stroke
      patients, focusing on the temporal, spatial, and kinematic variables. DESIGN:
      Case-control study comparing the effect of walking with and without a cane using
      a six-camera computerized motion analysis system. SETTING: Stroke clinic of a
      tertiary care hospital. PARTICIPANTS: Fifteen ambulatory stroke patients were
      analyzed, including 10 men and 5 women (mean age, 56.9 years; mean time since
      stroke, 9.8 weeks). Nine age-matched healthy elderly subjects were recruited as a
      control group. RESULTS: Stroke patients walking with a cane showed significantly
      increased stride period, stride length, and affected side step length, as well as
      decreased cadence and step width (p < .05) in comparison with those who walked
      without a cane. There were no significant differences in the gait phases and the
      five gait events of hemiplegic gait walking with or without a cane. Cane use thus
      may have more effect on spatial variables than on temporal variables. The
      affected-side kinematics of hemiplegic gait with a cane showed increased pelvic
      obliquity, hip abduction, and ankle eversion during terminal stance phase;
      increased hip extension, knee extension, and ankle plantar-flexion during
      preswing phase; and increased hip adduction, knee flexion, and ankle dorsiflexion
      during swing phase as compared with hemiplegic gait without a cane. A cane thus
      improved the hemiplegic gait by assisting the affected limb to smoothly shift the
      center of body mass toward the sound limb and to enhance push off during preswing
      phase. It also improved circumduction gait during swing phase. CONCLUSION: Stroke
      patients walking with a cane demonstrated more normal spatial variables and joint
      motion than did those without a cane.

PMID- 10414763
TI  - Discharge disposition from model spinal cord injury care system rehabilitation
      programs.
AB  - OBJECTIVE: To identify and quantify factors associated with discharge to a
      nursing home for people with spinal cord injuries. DESIGN: Case control within a
      cohort of spinal cord injured persons. SETTING: Model spinal cord injury care
      systems throughout the United States. PATIENTS: A total 16,633 patients
      consecutively discharged alive between 1973 and 1996 who were admitted to the
      model system within 1 year of injury, who were both injured in and resided in the
      catchment area of the model system, and who were discharged to either a nursing
      home or a community residence. MAIN OUTCOME MEASURE: Discharge disposition.
      RESULTS: Overall, 4.3% of patients were discharged to a nursing home. Factors
      that were significantly associated (p < .0001) with place of discharge were age,
      race, employment status at injury, bladder management method at discharge,
      education level, marital status, Frankel grade, functional independence in
      performing activities of daily living, independent ambulation, geographic region,
      neurologic level of injury, ventilator dependency, and third-party sponsor of
      rehabilitation. A multivariate predictive model was developed from these factors
      and was both 78% sensitive and specific in identifying patients who were
      discharged to a nursing home. CONCLUSIONS: Knowing the probability of nursing
      home placement can assist in evaluating the success of a rehabilitation program
      by allowing adjustment for case-mix differences across facilities.

PMID- 10414764
TI  - Muscle strength changes as measured by dynamometry following functional
      rehabilitation in individuals with spinal cord injury.
AB  - OBJECTIVE: To objectively quantify muscle strength changes over the course of
      functional rehabilitation and up to 15 months postdischarge in individuals with
      spinal cord injury (SCI). METHOD: Hand-held dynamometry was used to evaluate the
      strength of six muscle groups in 31 individuals after acute SCI (tetraplegia, n =
      13, paraplegia, n = 18). Assessment was performed by a single research therapist
      at admittance and discharge from functional rehabilitation and 3 months and 15
      months after discharge. RESULTS: There were significant increases of mean
      strength values for all muscle groups between admittance and discharge in
      individuals with parapalegia (median value between 13% and 22%) and tetraplegia
      (median value between 33% and 83%). Three months after discharge, only
      individuals with tetraplegia continued to significantly improve their mean
      strength for four muscle groups (elbow flexors-extensors and shoulder flexors
      extensors). One year later, elbow flexors were significantly improved in both
      paraplegic and tetraplegic persons, while shoulder extensors showed significant
      gains only in individuals with paraplegia. Study results showed a large
      variability in the individual profiles of upper limb strength recovery,
      particularly in tetraplegic individuals. Although some individuals showed
      strength gains exceeding 200%, some strength decreases were noted. CONCLUSION:
      Recovery of muscle strength in individuals with tetraplegia over individuals with
      parapalegia continues for a longer period since it depends initially on recovery
      of muscle innervation. This study quantified strength improvements during
      rehabilitation and clearly showed that these gains can be maintained or even
      increased when the person returns to community living.

PMID- 10414765
TI  - Use of computerized insole sensor system to evaluate the efficacy of a modified
      ankle-foot orthosis for redistributing heel pressures.
AB  - OBJECTIVE: Evaluation of orthosis purported to decrease pressure on the heel
      while walking. DESIGN: The Multipodus System is an orthotic device, designed for
      this purpose, that can be worn with flat or rocker bottom boot. Ten subjects
      underwent four trials: first, an initial walk wearing their usual shoes, then
      using the orthosis on the left, with a flat bottom boot, then with a rocker
      bottom boot, and a final walk. Pressures exerted on the plantar surface of the
      hindfoot, midfoot, and forefoot were measured electronically and analyzed.
      SETTING AND PARTICIPANTS: Ten consecutive normal subjects were tested on a
      conventional tile floor in a gait laboratory. RESULTS: Peak pressures in the
      initial walk averaged: heel, 9.6 +/- 2.3psi; midfoot, 2.6 +/- 1.7psi; and
      forefoot, 10.3 +/- 2.6psi. Pressures on the foot were redistributed significantly
      when the orthosis was used. Heel pressure was reduced significantly compared to
      the ordinary shoes using both the flat bottom boot (5.0 +/- 1.2psi, a decrease of
      48% [p = .0001]) and the rocker bottom boot (4.5 +/- 1.5psi, a decrease of 53% [p
      = .0001]). Pressure was increased at the midfoot with both the flat bottom boot
      (6.6 +/- 3.2psi, an increase of 61% [p = .0001]) and the rocker bottom boot (6.8
      +/- 2.9psi, an increase of 62% [p = .0001]). Pressures at the forefoot decreased
      19% (8.3psi) with the flat bottom boot and 32% (7.0psi; p = .0003) with the
      rocker bottom boot. CONCLUSIONS: Redistribution of pressure on the foot with
      orthosis is characterized by reduction at the hindfoot and forefoot and increase
      at the midfoot with both the flat and rocker bottom boots, thereby promoting
      healing of calcaneal and forefoot ulcers. The integrity of the midfoot, however,
      must not be compromised.

PMID- 10414767
TI  - Psychosocial adjustment in patients after a first acute myocardial infarction:
      the contribution of salutogenic and pathogenic variables. Israel Study Group on
      First Acute Myocardial Infarction.
AB  - OBJECTIVE: To ascertain the differential and independent impact of
      sociodemographic, medical, and psychologic variables assessed at patients'
      hospital discharge on these patients' psychosocial adjustment in several domains
      of life 3 to 6 months later. DESIGN: Two-hundred ninety Israeli male patients,
      aged 30 to 65 years, with a documented first acute myocardial infarction (AMI)
      were interviewed once before discharge and again 3 to 6 months postinfarct.
      Sociodemographic, medical, and psychologic data were elicited at the first
      interview and completed from medical information in the hospital files.
      Psychosocial adjustment in seven significant life domains was evaluated by the
      Psychosocial Adjustment to Illness Scale-Self-Report Version (PAIS-SR) at the
      second interview. Hierarchical regression analysis was used to examine the
      relation between the sociodemographic, medical, and psychologic variables at
      discharge to psychosocial adjustment in the different life domains 3 to 6 months
      later. RESULTS: Psychologic variables, such as depression, sense of coherence,
      and social support, and the sociodemographic variable of educational level at
      discharge predicted a relatively substantial amount of variance in psychosocial
      adjustment in most PAIS-SR-measured life domains. Low to moderate relations were
      found between such medical variables as Killip class, heart disease before AMI,
      other medical conditions, and perceived health before first AMI and psychosocial
      adjustment in specific life domains. The results also raised the possibility that
      part of the impact of the medical variables at discharge on psychosocial
      adjustment 3 to 6 months later may have been mediated by the psychologic
      variables. The centrality of the psychologic and domestic life domains to
      psychosocial adjustment in post-AMI patients was also suggested by the results.
      CONCLUSIONS: Both external and internal pathogenic (depression) and health
      proneness variables (sense of coherence and social support) at discharge predict
      psychosocial adjustment in most life domains 3 to 6 months after AMI.

PMID- 10414766
TI  - In-shoe pressure measurements with a viscoelastic heel orthosis.
AB  - OBJECTIVE: To detect the mechanical effect of a viscoelastic heel orthosis.
      DESIGN: Two-factor analysis of variance with interactions between the orthosis
      and the subjects. The number of subjects was determined by presuming the effect
      of the orthosis to be twice as large as the error-free standard deviation (SD) of
      the interactions, the step-to-step SD four times as large as the error-free SD of
      the interactions, type 1 error probability equal to .05, and type 2 error
      probability equal to .20. SETTING: A gait laboratory in a university hospital.
      SUBJECTS: Twenty-two consecutive patients with treated heel pain. MAIN OUTCOME
      MEASURES: Peak pressure (PP), pressure-time integral (PTI), and foot-to-sensor
      contact time (CoT) measured for five steps at 24 discrete sensors of
      predetermined positions in the foot with treated heel pain. RESULTS: The orthosis
      reduced PPs, PTIs, and CoT (p < .05) in the median midfoot and lateral midfoot;
      reduced PPs and PTIs (p < .05) in the posterior heel and medial midfoot;
      increased PP and PTI (p < .05) in the anterior part of the first metatarsal head;
      and increased PTI (p < .05) in the lateral part of the hallux. The ratios of the
      estimated step-to-step SDs to the estimated error-free SDs of the interactions of
      PPs, PTIs, and CoT were less than four at all the sensors. CONCLUSION: Proper
      design and estimation of the variations ensured that there was sufficient power
      to detect the effect of an a priori specified size as statistically significant:
      the orthosis reduced the mechanical loads in the posterior heel and the midfoot
      and increased the mechanical loads in the anterior part of the first metatarsal
      head and the lateral part of the hallux during walking.

PMID- 10414768
TI  - Toddlers with limb deficiency: conceptual basis and initial application of a
      functional status outcome measure.
AB  - OBJECTIVE: To describe the conceptual foundation, development, and initial
      psychometric analyses of a new outcome measure of functional status in toddlers
      with limb deficiency. DESIGN: Parents of children with limb deficiency completed
      self-report measures during a routine medical clinic visit. SETTING: Outpatient
      orthopedic pediatric clinic. PARTICIPANTS: Twenty parents (mothers) of children
      (ages 1 to 4 years) with acquired or congenital limb deficiency. MAIN OUTCOME
      MEASURE: The newly developed Child Amputee Prosthetics Project-Functional Status
      Inventory for Toddlers (CAPP-FSIT). RESULTS: Estimates of internal consistency
      reliability of the measure are high, suggesting conceptual congruence among the
      items. Initial validity studies confirm the CAPP-FSIT differentiates between
      toddlers with upper limb deficiency and lower limb deficiency in terms of
      functional activity and prosthesis use. The new measure does not appear to be
      contaminated by gender or socioeconomic status. CONCLUSION: The CAPP-FSIT is a
      promising measure for assessing functional abilities in toddlers with limb
      deficiency.

PMID- 10414769
TI  - The Timed "up and go" test: reliability and validity in persons with unilateral
      lower limb amputation.
AB  - OBJECTIVE: To determine the interrater and intrarater reliability and the
      validity of the Timed "up and go" test as a measure for physical mobility in
      elderly patients with an amputation of the lower extremity. DESIGN: To test
      interrater reliability, the test was performed for two observers at different
      times of the same day in an alternating order. To test intrarater reliability,
      the patients performed the test for one observer on two consecutive visits with
      an interval of 2 weeks. To test validity, the results of the Timed "up and go"
      test were compared with the results on the Sickness Impact Profile, 68-item
      version (SIP68), and the Groningen Activity Restriction Scale (GARS). PATIENTS:
      Thirty-two patients, age 60 yrs or older, with unilateral transtibial or
      transfemoral amputation because of peripheral vascular disease. RESULTS: The
      Timed "up and go" test showed good intrarater and interrater reliability (r = .93
      and .96, respectively). A moderate relationship exists between the Timed "up and
      go" test and the GARS, a good relationship exists with the "physical subscales"
      of the SIP68, and there is no relationship with the "mental subscales" of the
      SIP68. CONCLUSIONS: The Timed "up and go" test is a reliable instrument with
      adequate concurrent validity to measure the physical mobility of patients with an
      amputation of the lower extremity.

PMID- 10414770
TI  - Warm-up effect on active and passive arthrometric assessment of knee laxity.
AB  - OBJECTIVE: To determine the influence of a warm-up protocol suitable for use in
      clinical settings on tibial displacement and muscle activity during arthrometric
      knee laxity assessment. DESIGN: Intervention study in which the subjects served
      as their own controls. SETTING: The Biomechanics Research Laboratory, University
      of Wollongong, Wollongong, New South Wales, Australia. SUBJECTS: Ten volunteers
      who reported no history of knee trauma or disease. INTERVENTION: A warm-up
      consisting of 10 minutes of ergometer cycling (60rpm) followed by two sets of
      three hamstring muscle stretches. MAIN OUTCOME MEASURES: Outcome measures were:
      (1) anterior tibial translation and knee extension force assessed using a Dynamic
      Cruciate Tester for each subject's right knee during active and passive testing,
      and (2) intensity of quadriceps and hamstring muscle activity during knee laxity
      testing. RESULTS: There was significantly less quadriceps activity after warm-up
      (t = 2.419, p = .039). However, there was no significant difference between
      anterior tibial translation, knee extension force, or hamstring muscle activity
      results before and after warm-up in either active or passive tests. CONCLUSION: A
      warm-up suitable for use in a clinical setting is not required before
      arthrometric assessment of knee laxity.

PMID- 10414771
TI  - Mobility-related function in older adults: assessment with a 6-minute walk test.
AB  - OBJECTIVE: To determine the usefulness of the 6-minute walk test as an integrated
      measure of mobility in older adults. DESIGN: Observational study. SETTING:
      Community centers and retirement homes in the Los Angeles area. PATIENTS: Eighty
      six older adults without significant disease. INTERVENTIONS: None. MAIN OUTCOME
      MEASURES: Assessments included the 6-minute walk, chair stands, standing balance,
      gait speed, body mass index, and self-reported physical functioning and general
      health perceptions. RESULTS: One-week test-retest reliability of the 6-minute
      walk was .95. As hypothesized, the 6-minute walk distance was significantly
      greater for active than for inactive older adults (p < .0001), moderately
      correlated with chair stands (r = .67), standing balance (r = .52), and gait
      speed (r = -.73). It had a low correlation with body mass index (r = -.07). The
      correlation of the 6-minute walk with self-reported physical functioning was .55,
      and its correlation with general health perceptions was .39. Self-report and
      performance measures explained 69% of the variance in 6-minute walk scores.
      CONCLUSIONS: The 6-minute walk test is reliable and is valid in relation to the
      performance and self-reported indicators of physical functioning tested in this
      study. It could serve as a useful integrated measure of mobility.

PMID- 10414772
TI  - Back and hip extensor muscle function during therapeutic exercises.
AB  - BACKGROUND: Therapeutic exercises are widely used in the treatment of low back
      problems. Clinical knowledge about targeting the load in these exercises,
      however, is insufficient. This study assessed the L2 and L5 level paraspinal and
      gluteus maximus muscle activities in different therapeutic exercises.
      Intramuscular and surface electromyography (EMG) measurements were obtained to
      study whether surface EMG measurements can be used in the assessment of
      multifidus muscle function. METHODS: Eleven healthy subjects (5 men, 6 women) 21
      to 38 years of age volunteered for the study. The subjects performed 18 different
      therapeutic exercises. During the exercises paraspinal EMG was recorded using
      fine wire and surface electrodes. The normalized peak and average muscle EMG
      activities (percentage of amplitude in maximal voluntary contraction [MVC])
      during each task were determined. RESULTS: The correlations between the average
      intramuscular and surface activities of the normalized EMG (% of MVC) at the L2
      and L5 levels were .928 and .950, respectively. The peak and average EMG
      amplitudes of the exercises were below 50% and 25% of MVC, respectively. At the
      L5 level, the multifidus peak and average EMG amplitudes (% MVC) were higher in
      women than in men, whereas no significant difference was found at the L2 level.
      In women, the normalized multifidus EMG amplitude was higher at the L5 level than
      at the L2 level, whereas no significant difference was found in men. In both
      sexes, the normalized EMG amplitude was higher in the multifidus than in the
      longissimus muscle. CONCLUSION: Surface EMG measurements may be used in the
      assessment of multifidus muscle function. Simple therapeutic exercises are
      effective in activating the lumbar paraspinal muscles.

PMID- 10414773
TI  - Horizontal transfers between adjacent surfaces: forces required using different
      methods.
AB  - OBJECTIVE: To describe and compare pull forces required to move supine subjects
      between adjacent surfaces using different devices and methods. DESIGN:
      Descriptive, correlational, explicatory experiment. SUBJECTS: Convenience sample
      of volunteers. INTERVENTION: Alternative transfer devices and methods. MAIN
      OUTCOME MEASURES: Pull forces measured with dynamometers. RESULTS: Pull forces
      associated with transfers with no device, a draw sheet, a Patient Shifter, and an
      Easy Slide differed significantly (F = 245.1, p < .001), but were correlated
      significantly (p < .001) with one another (r > .89) and subjects' body weights (r
      > .82). Pull forces required for transfers with the Easy Slide were lowest.
      CONCLUSIONS: Use of friction-reducing transfer devices significantly decreased
      the forces required for transferring individuals between adjacent surfaces. The
      magnitude of this decrease in this study was greatest with the Easy Slide.

PMID- 10414774
TI  - Prostheses for persons with lower-limb amputations: an extra joint increases
      range of motion.
AB  - This report describes two cases in which the addition of an extra joint enhanced
      range of motion and improved function in persons with unilateral lower-limb
      amputation. Both individuals had significant disability in the workplace and at
      home before this modification. In the first case, an individual with a
      hemipelvectomy had inadequate hip-joint flexion for maneuvering during photo
      shoots. In the second case, the individual's transfemoral prosthesis provided
      insufficient knee flexion for kneeling and working in tight spaces. In each case,
      a manual-locking, single-axis knee joint was added adjacent to the joint with the
      limited range of motion. In both cases, the addition of the second joint provided
      the increased flexibility needed. The first person's hip-flexion range improved
      from 125 degrees to 190 degrees, and the second person's knee-flexion range
      improved from 140 degrees to 170 degrees. In repeated follow-up, both patients
      remained highly satisfied with the intervention. The addition of an extra joint
      is an option that should be considered when inadequate range interferes with
      function.

PMID- 10414775
TI  - Not all facial paralysis is Bell's palsy: a case report.
AB  - Bell's palsy or idiopathic facial paralysis is the most common cause of
      unilateral facial paralysis. This case report describes a patient referred for
      physical therapy evaluation and treatment with a diagnosis of Bell's palsy. On
      initial presentation in physical therapy the patient had unilateral facial
      paralysis, ipsilateral regional facial pain and numbness, and a history of a
      gradual, progressive onset of symptoms. The process of evaluating this patient in
      physical therapy, as well as the recognition of signs and symptoms typical and
      atypical of Bell's palsy, are described. This report emphasizes the importance of
      early recognition of the signs and symptoms inconsistent with a diagnosis of
      Bell's palsy, and indications for prompt, appropriate referral for additional
      diagnostic services.

PMID- 10414776
TI  - Pesticide monitoring and its health problems in Egypt, a Third World country.
AB  - Health profiles for 300 pesticide formulators and 300 pesticide applicators
      revealed peripheral neuritis (> 40%), psychiatric manifestations (> 40%),
      electroencephalographic (EEG) changes (> 25%), and hepatorenal dysfunction (>
      80%); all these manifestations were confirmed by different diagnostic tools. The
      frequency of carrier state of hepatitis (HbsAg) was 7.4% and of transitory state
      was 21.5%. The cytogenetic changes were confirmed by measuring chromosomal
      aberrations (CAs) among formulators and applicators, and proved to be more than
      twice those of controls. Pesticides residues among 130 milk, cheese, butter,
      yoghurt and milk powder samples (DDT, HCH and Dieldrin) were confirmed.
      Registration schemes, and post-registration programs (monitoring requirements,
      training needs and control of pesticide and fertilizer imports) should be
      mandatory.

PMID- 10414777
TI  - Excretion study of endosulfan in urine of a pest control operator.
AB  - A study of endosulfan excretion in human urine was carried out by using an
      agricultural worker involved with spraying, wearing protective overall, gloves
      and breathing mask. The urine samples were extracted with Solid Phase Extraction
      (SPE) cartridges and the compounds were separated and detected using Gas
      Chromatography-Tandem Mass Spectrometry (GC-MS/MS) due to their high sensitivity
      and selectivity in preventing most matrix interferences. The alpha- and beta
      isomers of endosulfan were detected (total concentrations ranged between 5368 and
      2239 pg/ml) but endosulfan-ether, -lactone or -sulphate were not found above the
      detection limits. The results obtained were compared with the concentrations
      found for a non-occupational exposed man. Statistical interpretation of the
      excretion-rate of the insecticide was performed by assuming that it can be
      described as a first-order kinetic. The constant rate and the half-lives were
      determined.

PMID- 10414778
TI  - The influence of various factors on immune toxicity assessment of pesticide
      chemicals.
AB  - Various physiological and environmental factors are known to modulate pesticide
      induced immune toxicity. Some of these factors studied in our laboratory are: (a)
      level of exposure (amount, duration and frequency), (b) human cases/animal
      models, (c) antigen, its route and adjuvant used, (d) immunological method used,
      (e) nutritional status and pathological conditions, (f) biotransformation and
      activity of metabolites, (g) physical/emotional stress, and (h) oxidative stress.
      These factors complicate the assessment of immune toxicity of pesticide,
      generally affecting the dose at which toxic effects are observed. Working with
      organochlorine, organophosphate and carbamate compound, we have found that: (1)
      dietary protein deficiency makes the immune system more susceptible to the toxic
      effects of pesticides; (2) suppression of immune responses by the immediate
      metabolites is an important determinant of the toxicity of parent compound; (3)
      the type and duration of physical or emotional stress and possible involvement of
      free radicals (oxidative stress) are important in the potentiation of pesticide
      induced immune toxicity. An understanding of these risk factors depends largely
      upon the cellular and molecular events underlying pesticide-induced immune
      alterations in experimental animals. These factors, therefore, must be considered
      in the safety/toxicity evaluation of any pesticide. This paper reviews the
      influence of these factors on the immune-toxicity of some common pesticides.

PMID- 10414779
TI  - Biochemical effects of some pesticides on lipid peroxidation and free-radical
      scavengers.
AB  - Oxidative stress was studied in blood samples obtained from lindane, malathion
      and propoxur poisoning cases admitted to the Guru Teg Bahadur Hospital, Delhi and
      evaluated for lipid peroxidation, oxygen free radical (OFR) scavenging enzymes,
      and glutathione (GSH) and related enzymes. Acetylcholine esterase (AChE), gamma
      glutamyl transpeptidase (GGT) and GSH level were also assayed in lymphocytes. The
      level of thiobarbituric acid reacting substances and activities of superoxide
      dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and GGT
      were increased and GSH level was decreased in pesticide poisoning. Apparently
      lindane (at the concentration examined) was more potent than malathion and
      propoxur in producing alteration in lipid peroxidation, GSH related parameters
      and OFR scavenging enzymes. However, AChE activity and GSH level in lymphocytes
      of malathion poisoning cases were reduced and GGT activity was enhanced in
      comparison to control subjects. The present results suggest that OFR scavenging
      enzymes were induced while combating oxidative stress in a differential manner in
      organochlorine, organophosphate and carbamate poisoning. Increased lipid
      peroxidation, coupled with altered levels of GSH and OFR scavenging enzymes in
      the blood are discussed in the light of oxidative stress.

PMID- 10414780
TI  - A spectrophotometric assay for pyrethroid-cleaving enzymes in human serum.
AB  - A direct continuous spectrophotometric assay to measure pyrethroid-cleaving
      enzymes in human serum was developed using cis- and trans-alpha-naphthyl-(2,2
      dichlorovinyl)-2,2-dimethylcyclopropane carboxylate (cis- and trans-naphthyl
      Cl2CA). These substrates show a structure very similar to the pyrethroids most
      often used (e.g. permethrin, cyfluthrin). The method is based on an increase in
      absorbance at 321 nm which occurs with the hydrolysis of the alpha-naphthyl
      esters to alpha-naphthol. The assay was optimised regarding type of buffer, pH
      and substrate concentrations, it was linear for at least 10 min at 37 degrees C.
      These esterases were completely inhibited by bis-(4-nitrophenylphosphate), a
      specific carboxyesterase inhibitor. They displayed a great individual variability
      in human serum, activities were between less than 40 and 1000 U/l for cis
      naphthyl-Cl2CA, between less than 40 and 2000 U/l for trans-naphthyl-Cl2CA,
      respectively. However, a correlation of enzyme activity to sex or age could not
      be observed. Furthermore, the activity of pyrethroid-cleaving esterases did not
      correspond to the activities of acylesterase, arylesterase, acetylcholinesterase
      or butyrylcholinesterase.

PMID- 10414781
TI  - Electrophysiological biomarkers of an organophosphorous pesticide, dichlorvos.
AB  - The correlations between the relatively low level, chronic dichlorvos (DDVP)
      treatment and the early electrophysiological changes were investigated in three
      series of experiments. In the first series, male Wistar rats were orally given
      daily by gavage 0.98, 1.96 and 3.92 mg/kg of DDVP for 4, 8, or 12 weeks, and
      recordings were made at the end of each period. In the second one, the male and
      female rats of three consecutive generations were treated with the same doses,
      the investigated parameters were recorded at the age of 12 weeks of the male
      animals. In the third experiment, the doses were administered in different stages
      of development: during pregnancy, pregnancy + lactation, pregnancy + lactation +
      postweaning, and the electrophysiological markers were recorded also at the age
      of 12 weeks of male offspring. The analyzed elecrophysiological parameters were:
      electrocorticogram, sensoric cortical evoked potentials, conduction velocity and
      refractory periods of peripheral nerve. The data showed that the relatively low
      level dichlorvos exposure caused dose-, duration-, generation-, developmental
      stage-dependent and partly significant alterations in all the investigated
      electrophysiological parameters. The analyzed functional parameters proved to be
      sensitive biomarkers of the exposure as they were changed by the lower doses,
      while the brain cholinesterase activity was considerably inhibited only in the
      groups given the highest dose.

PMID- 10414782
TI  - Pyrethroids and piperonyl-butoxide affect human T-lymphocytes in vitro.
AB  - Synthetic pyrethroids are increasingly used as insecticides and are claimed to
      have a relatively low human toxicity. The aim of this study was to examine the in
      vitro effects of the synthetic pyrethroid S-bioallethrin alone and in combination
      with the common synergist piperonyl-butoxide (PBO) on human blood lymphocytes and
      basophils in atopic individuals and non-atopic control subjects. S-bioallethrin
      and PBO also caused inhibition of lymphocyte proliferation (MTT-test) after a 72
      h culture period in a concentration dependent manner. In contrast to the MTT
      measurements the combined agents are more effective in inhibiting interleukin-4
      (IL-4)- and interferon-gamma (IFN-gamma)-production. The regulatory IL-4/IFN
      gamma balance showed a significant difference between atopic and non-atopic
      subjects after a culture period of 24-48 h in the presence of micromolar S
      bioallethrin (P < 0.001). Furthermore S-bioallethrin, PBO and the combined agents
      induced histamine release from human basophils. Although this effect was little
      compared to histamine liberators like FMLP and anti-IgE, the response to S
      bioallethrin and PBO was significantly different in atopic donors compared with
      non-atopics (P < 0.01). In scratch test experiments 4 of 18 tested atopic
      volunteers showed positive reaction (wheals and flares) to S-bioallethrin and
      permethrin, whereas no reaction could be measured in the control group (age
      matched). These findings demonstrate the immuno- and allergo-toxicological
      properties of the synthetic pyrethroid S-bioallethrin combined with the
      synergistic PBO using this in vitro approach with human lymphocytes and
      basophils.

PMID- 10414783
TI  - Pest control in public institutions.
AB  - After the spraying of insecticides against cockroaches in a kindergarten
      insecticide residues were detected over several months in spite of extensive
      decontamination. This prompted measurements in a home for asylum seekers, where
      insect pests had been controlled regularly by a commercial firm; here the
      presence of various biocides was demonstrated. As the insecticides could not be
      sufficiently decontaminated, the further administration was discontinued and
      instead cockroach traps and baits were set up. This alternative method which was
      well accepted by the inhabitants of the home as well as the administrative staff
      was subsequently successfully employed in other public institutions, e.g. a
      school and another kindergarten.

PMID- 10414784
TI  - Induction of mitotic cell division distrubances and mitotic arrest by pyrethroids
      in V79 cell cultures.
AB  - Five pyrethroids (fenvalerate, deltamethrin, cypermethrin, permethrin,
      cyfluthrin) differing in their chemical purity were investigated on their
      cytotoxic effects, especially on their ability to induce mitotic cell division
      disturbances using Chinese hamster lung cells of line V79. The colony forming
      ability (CFA) resulted in distinct differences of the cytotoxic effect of the
      tested pyrethroids, whereby permethrin was found to be most toxic. With the
      exception of fenvalerate all tested pyrethroids gave rise to inhibition of cell
      cycle progression as shown by G2/M-arrest of synchronized V79 cells by flow
      cytometry as well as by the increase of the mitotic index as evaluated by light
      microscopy. The mitotic arresting activity could be attributed to the occurrence
      of abnormal mitotic figures such as initial and full C-metaphases. The results
      however indicate, that pyrethroids per se do not contribute to the cytotoxic
      effects but that other factors such as chemical impurities, source as well as
      manufacturing process and isomer composition may be responsible for the observed
      cytotoxic effects.

PMID- 10414785
TI  - Biological monitoring of exposure to pirimicarb: hydroxypyrimidines in human
      urine.
AB  - Pirimicarb (2-dimethylamino-5,6-dimethylpyrimidin-4-yldimethylcarbamate ) is used
      as insecticide in agriculture and fruit growing. During its metabolism in mammals
      the carbamate moiety is hydrolysed and subsequent demethylation at the
      dimethylaminogroup which is attached to the heterocyclic moiety results in the
      following major metabolites which are excreted in urine: 2-dimethylamino-5,6
      dimethyl-4-hydroxypyrimidine (DDHP), 2-methylamino-5,6-dimethyl-4
      hydroxypyrimidine (MDHP), and 2-amino-5,6-dimethyl-4-hydroxypyrimidine (ADHP).
      These metabolites were detected in every urine sample of seven workers who had
      applied pirimicarb. Concentrations of the MDHP and ADHP were much higher than
      that of DDHP indicating a considerable demethylation capacity in humans. No
      metabolites were found in urine specimens of controls. The investigated
      pyrimidines represent sensitive and specific parameters for biological monitoring
      of exposure to pirimicarb.

PMID- 10414786
TI  - Biocides Steering Group on human exposure assessment: a preliminary report.
AB  - In a project granted by DG XI of the European Commission, it is attempted to
      collate experimental and theoretical data on human (workers and consumers)
      exposure assessment to biocidal products, and to outline the methodology for
      sampling and measurement. On the basis of the available evidence, approaches are
      presented for the exposure assessment to be used for estimation of risks in
      authorization procedures under the recently accepted Directive 98/8/EC. Gaps in
      knowledge are indicated, making it possible to study the issues involved in a
      comprehensive and cost-effective way. Some recommendations are given on how to
      best do this. The current project has been detailed in a final report.

PMID- 10414787
TI  - Risk assessment of pollution with pesticides in food in the Eastern Romania area
      (1996-1997).
AB  - The extensive use of pesticides in agriculture can entail risks for environment
      and non-target organisms. Hence the need to assess the nature and degree of the
      risk and at the same time to take preventive measures aimed at minimizing
      possible damages. The aim of the present study was to investigate the pesticide
      residues in food and the human body (maternal, young) in the Eastern Romania
      area, between 1996 and 1997. The organochlorine pesticide residues were analyzed
      using gas-chromatographic method. DDT-total and HCH-total were determined in
      'food' (milk, bread, diets, coffee) sampled in the Eastern Romania area;
      'maternal body' (placenta, milk, urine) and 'young body' (serum, urine) from the
      Iassy district. These pollutants present in all analyzed products involve the
      necessity of the pollution reduction by a rational use of the pesticides and the
      continuation of the chemical pollutants determination in the environment elements
      for cancer prevention and the control of the exposure to environmental
      carcinogens and their effects.

PMID- 10414788
TI  - Metabolism of (S)-bioallethrin and related compounds in humans.
AB  - Chrysanthemate insecticides like (S)-bioallethrin, natural pyrethins, and related
      pyrethroids are subjected to extensive hydrolytic and oxidative degeneration by
      the mammalian metabolism, leading to a complex series of metabolites partially
      conjugated and finally eliminated in the urine. The major oxidation products of
      chrysanthemic acid, cis-(E)- and trans-(E)-chrysanthemumdicarboxcylic acid (cis
      (E) and trans-(E)-CDCA), were synthesized and their structures were established
      by nuclear magnetic resonance spectrometry (H1-NMR) and mass spectrometry (MS).
      Diastereoselective separation was by high performance liquid chromatography
      (HPLC) and capillary gas chromatography (GC). An analytical method for extraction
      and identification of CDCA from human urine was developed. Quantitation was by
      gas chromatography and electron-impact mass spectrometry (GC/MS). The limit of
      detection was 20 microg/l for cis-(E)-CDCA and 10 microg/l for trans-(E)-CDCA. To
      test the applicability of the presented method, urine samples of humans exposed
      to (S)-bioallethrin were investigated. Urinary peak excretion of trans-(E)-CDCA
      occurred within 24 h after exposure.

PMID- 10414789
TI  - The influence of individual susceptibility in pyrethroid exposure.
AB  - The aim of this study was to find a suitable biomarker for pyrethroid adverse
      effects. It was shown that there is a correlation between the half-life time
      (t(1/2)) of pyrethroids in plasma and the clinical findings. We hypothized that
      this finding indicates an interindividual different amount of total esterase
      activity or even a polymorphism. By in vitro experiments it was demonstrated that
      pyrethroids are cleaved by carboxylesterases. After it turned out that
      carboxylesterase activity in human plasma is too low for detection, a method for
      specific determination of carboxylesterase activity in human isolated lymphocytes
      was developed. As a substrate for carboxylesterase activity, cyfluthrin was added
      to the lymphocyte suspension. As a proof for cyfluthrin degradation by
      carboxylesterases the produced hydrocyanic acid was determined by GC/MS. First
      hints for interindividual differences in carboxylesterase activity in lymphocytes
      were found.

PMID- 10414790
TI  - Consideration of individual susceptibility in adverse pesticide effects.
AB  - The modern environmental awareness leads to the realisation that the human
      metabolism is stressed by a huge number of chemical substances. Generally, these
      background exposures, consisting predominantly from natural and partly from
      industrial as well as life style sources, are tolerated without any adverse
      effects. Pesticides are chemicals intentionally introduced to the environment and
      have become necessities in modern agriculture as well as in indoor pest control.
      Their residues, therefore, is attracting more and more concern. For the majority
      of pesticides neither occupational nor environmental medical risk evaluations are
      so far available. Therefore, at the moment the occupational as well as the
      environmental supported preventive concept may only be achieved, if binding
      instructions upon experience and guide values are developed for the assessment of
      the individual risk of handling pesticides. In the occupational and environmental
      pesticide prophylaxis the ubiquitous background exposure levels in consideration
      with individual susceptibility factors should be recommended as provisional
      biological tolerance guide values. The suitability of this guide values concept
      for pesticides is demonstrated by determining the background exposure and the
      biomarkers of susceptibility of 250 unexposed persons as well as of more than
      1200 occupationally exposed persons. As a result, a significant dependence of
      their health fidelity from the background exposure profile impressed on the
      individual polymorphism of the key enzymes was observed. Especially, the
      cumulative adducts of electrophilic substances and their metabolites with
      macromolecules like HSA and Hb turned out to be sensitive markers for the
      capacity of the individual metabolic rate. For alkylating and arylating
      pesticides the observed interindividual susceptibility to their adverse effects
      depends on the variability of the individual 'toxifying' and 'detoxifying'
      metabolic rates. Until scientific evaluation of official biological tolerance
      values for pesticides is carried out, it is advisable for risk prophylaxis to
      orientate the assessment of any individual tolerable stress and strain from
      pesticides to the synergism between background exposure, life style factors and
      biomarkers of specific susceptibility. They may be examined by a monitoring of
      conjugates and polymorphism marked by the individual metabolic rate. The
      monitoring and surveillance of pesticide exposures is mainly introduced by the
      recommendation of tolerable biological values from the reference value concept.
      This concept is an essential contribution to an objective risk discussion with
      regard to individual stress and strain profiles in environmental exposure
      scenarios.

PMID- 10414791
TI  - Risk assessment and management of occupational exposure to pesticides.
AB  - Occupational exposure to pesticides in agriculture and public health applications
      may cause acute and long-term health effects. Prevention of adverse effects in
      the users requires actions to be undertaken in the pre-marketing and post
      marketing phase of these products. The pre-marketing preventive actions are
      primary responsibility of industry and the public administration. Admission of
      pesticide use (registration) is carried out by considering the toxicological
      properties of each pesticide (hazard identification), determining the dose
      response relationship (NOEL identification), assessing or predicting the exposure
      level in the various scenarios of their use, and characterising the risk. The
      decision about admission takes into consideration the balance between risks and
      benefits. The post-marketing preventive activities consist of the promotion of a
      proper risk management at the workplace. Such a management includes the risk
      assessment of the specific conditions of use, the adoption of proper work
      practices, and the health surveillance of the workers. Each country should
      develop an adequate National Plan for Prevention of Pesticide Risk which
      allocates different roles and tasks at the central, regional and local level.

PMID- 10414792
TI  - Photometric determination of human serum bromide levels--a convenient
      biomonitoring parameter for methyl bromide exposure.
AB  - Methyl bromide is one of the most important pesticides for the control of
      insects, fungi and nematodes. Serum bromide has been proposed as a biomonitor for
      occupational exposure to methyl bromide. Therefore, a novel, sensitive
      photometric method was developed for the determination of serum bromide at
      concentrations relevant for such exposure. Further possible applications are
      monitoring of intoxication victims and halothane narcosis. Using the method we
      have established a mean serum bromide level of 4.13 +/- S.D. 1.05 mg/l (n/64) in
      a group of healthy female and male volunteers not knowingly exposed to bromide or
      bromine containing organics. Serum of a subject accidently exposed to methyl
      bromide revealed a bromide level of 11.5 mg/l serum, while two individuals
      exposed to methyl iodide had no elevated levels. A group of 30 agricultural
      workers showed a mean serum bromide level of 15.33 +/- S.D. 1.90 mg/l at the end
      of the methyl bromide application season.

PMID- 10414793
TI  - Chronic sequelae and irreversible injuries following acute pyrethroid
      intoxication.
AB  - For patients the author has observed, the majority of complaints following an
      acute pyrethroid intoxication disappeared after the end of exposure. Residuals
      frequently observed after more than 2 years were: (1) cerebro-organic disorders
      (reduced intellectual performance with 20-30% reduction of endurance during
      mental work, personality disorder), visual disturbances, dysacousia, tinnitus;
      (2) sensomotor-polyneuropathy most frequently in the lower legs; (3) vegetative
      nervous disorders (paroxysmal tachycardia, pollakisuria, increased heat
      sensitivity, orthostatic hypotonia and reduced exercise tolerance due to
      circulatory disorder). Non-neurological symptoms include deficiency of cellular
      and humoral immune system established by laboratory findings: opportunistic
      infections, especially Candida-infections of the gastro-intestinal tract,
      relapsing infections of the urinary and respiratory tract, the latter often
      aggravating to respiratory obstruction. Most of the patients exhibit positive epi
      or intracutantest against pyrethroids or pyrethrines, and acquainted sensitivity
      also to other antigens. Many of these patients exhibit pathological autoimmune
      diagnostical findings and developed autoimmune diseases as for instance
      scleroderma-like syndrome, myasthenia-like syndrome with progredient muscle
      atrophy, autoimmun-hemolysis and autoimmun-thrombocytopenic purpura.

PMID- 10414794
TI  - The role of metabolism in determining susceptibility to parathion toxicity in
      man.
AB  - Human liver microsomes (n = 16) activated parathion (O, O, diethyl O-p
      nitrophenyl phosphorothioate, 20 and 200 microM) to paraoxon at a rate of 23.3
      199.3 and 18.7-310.3 pmol/min per mg protein, respectively. p-Nitrophenol, was
      also formed, at 321.1-769.2 and 406.2-778.3 pmol/min per mg protein. This
      represented a 16-fold and 2-fold range in capacity to activate and detoxify
      parathion, respectively. Parathion was activated with an apparent Km of 9-16
      microM (n = 3). The activation of parathion (200 microM) was positively
      correlated with nifedipine oxidation, indicating the involvement of CYP3A.
      Correlations were not significant with ethoxyresorufin-O-dealkylation (CYP1A1/2),
      pentoxyresorufin-O-dealkylation (CYP2B6), p-nitrophenol hydroxylation (CYP2E1),
      paraoxon hydrolysis (A-esterase) or phenylvalerate hydrolysis (B-esterase).
      Paraoxon formation from parathion was markedly reduced by CYP3A inhibitors.
      Experiments with EDTA indicated that A-esterase was not functionally important at
      low levels of paraoxon. Human P450s 3A4 and 3A5 expressed microsomes were the
      most efficient at biotransforming parathion to paraoxon, although P450s 1A1, 2B6
      and 2C8 also catalysed the reaction. This study has determined wide
      interindividual variations in capacity to metabolise parathion, mainly by CYP3A,
      which may influence its manifest toxicity.

PMID- 10414795
TI  - Indoor air pollution by lindane and DDT indicated by head hair samples of
      children.
AB  - The use of the pesticides DDT and lindane as wood preservatives causes indoor air
      contamination and subsequently exposure of the occupants of these rooms. As hair
      acts as a passive sampler for air contaminants, we tested pesticide
      concentrations in hair measured by the GC/MS technique. A comparison of the DDT
      and lindane concentrations in hair samples of 193 pre-school children from a
      rural area around Rostock with information concerning their home environments
      showed that this is a suitable method for screening purposes.

PMID- 10414796
TI  - Hazard identification and risk assessment of pyrethroids in the indoor
      environment.
AB  - Household insecticide products raise several important considerations concerning
      safety. These are related to the use of insecticides by untrained individuals,
      the difficulty of controlling the use of these products once purchased by the
      consumer and the potential exposure of the very young and very old, possibly with
      or without pre-existing pulmonary disease. Exposure to pyrethroids contained in
      mats or vaporizers, being slow release systems, have particular potential for
      long-term low-level exposure whilst for foggers, spray-cans or sprayed
      formulations the short-term high-level exposures may be of more concern.
      According to the volatility of the active ingredient contained in the household
      insecticide, its persistence in a non-inhalable matrix, i.e. sedimented house
      dust, may be short or long for highly volatile or low volatile active
      ingredients, respectively. On the other hand, the potential of exposure is
      apparently just reciprocal. This demonstrates that the extent and duration of
      exposure may be highly product-specific. Accordingly, the extent of exposure has
      to be accounted for and for risk assessment both concentration-dependent (e.g.
      sensory irritation) as well as concentration x time (= dose) related effects have
      to be considered and addressed in adequate bioassays. The issue as to whether
      pyrethroids adhering to house dust is of concern has been addressed in a model
      study using carpets treated with pyrethroids. This study has demonstrated that
      the total mass of pyrethroid applied to the carpet and that brushed off within an
      18-h period is too small to be of any relevance for risk assessment. Therefore,
      assessment of health hazards in the indoor environment based simply on
      methodologies of emptying the household vacuum cleaner and analysing its content,
      which addresses contamination only, rather than examination of the actual
      airborne concentration, including other relevant airborne materials, is prone to
      tremendous errors and misjudgments. Due to the many substances potentially
      present in house dust and indoor air, e.g. bioaerosols originating from animals,
      pests and microorganisms, volatile organic substances (VOCs) or metals, prudent
      expert judgment is needed to assess the relevance of analytical findings. The
      complex indoor exposure scenario makes it especially difficult to causally relate
      clinical and epidemiological findings to arbitrarily selected indicator
      substances contained in a matrix not readily available to inhalation exposure.

PMID- 10414797
TI  - Herbicide use on railway tracks for safety reasons in Germany?
AB  - A short overview on the occurrence of herbicides in groundwater and drinking
      water located in the vicinity of railway tracks in Germany is presented. The
      study has been conducted using the experience of various water supply companies
      and includes a literature research on the subject. It has been documented that in
      Germany only 1% of the total area treated with pesticides was under management of
      the former Deutsche Bundesbahn before 1990. The specific amount applied on the
      railway tracks was, however, a factor of 6 higher than that used in agriculture,
      although it must be borne in mind that the retaining capacity of railway tracks
      for pesticides is much lower. The herbicides applied ranged from 2,4-D and 2,4,5
      T, triazine derivatives, e.g. atrazine and urea derivatives such as diuron.
      Traces of almost all of the herbicides applied could be detected in samples of
      groundwater and drinking water in the vicinity of railway tracks. Since 1997 only
      glyphosate has been used.

PMID- 10414798
TI  - Absorption and mass balance of piperonyl butoxide following an 8-h dermal
      exposure in human volunteers.
AB  - Dermal absorption, metabolism and excretion of piperonyl butoxide (PBO) was
      studied using 14C-PBO either by itself as a 3% (w/w) solution in isopropyl
      alcohol or as a 4% (w/w) solution in an aqueous end-use formulation. Each of
      these two formulations were tested on four young, healthy male volunteers, using
      a single topical application on the ventral forearm under non-occlusive
      conditions for an 8-h period. The application sites were thoroughly cleaned with
      cotton swabs moistened with isopropyl alcohol, then rinsed with isopropyl
      alcohol. Blood from the ipsilateral and contralateral arms, urine and feces were
      collected at selected intervals during the 8-h application and through a 120-h
      post-application period. The application area was also tape-stripped to determine
      if any of the test material accumulated in the stratum corneum. These samples
      provided data which permitted insight into the kinetics of penetration and
      elimination processes of PBO. The absorption of PBO either by itself or
      formulated was very poor, as demonstrated by the radioactivity excreted in the
      urine, and radioactivity in the ipsilateral plasma. When dosed by itself,
      approximately 1.78% of the dose was excreted in the urine. In contrast, only
      0.47% of the formulated PBO was excreted in the urine. Trace radioactivity was
      detected in the feces from both formulations. The absorbed radioactivity was
      rapidly eliminated in the urine. There was no evidence of accumulation of PBO in
      the skin as evidenced by low amounts of radioactivity in the tape-strippings. The
      majority of the applied radioactivity was recovered from the skin surface. Total
      recovery of the applied radioactivity was 100.86 and 104.22% for PBO and the
      formulated product respectively. Absorbed PBO was completely metabolized to at
      least three major metabolites prior to its excretion in the urine. The three
      metabolites represented over 70% of the excreted radioactivity for PBO. The HPLC
      retention times for these metabolites are different than that seen in rats. The
      structures of these metabolites have not been elucidated.

PMID- 10414799
TI  - Immunological parameters in humans exposed to pesticides in the agricultural
      environment.
AB  - Immune parameters were examined in 224 sera of non-exposed controls and in 304
      sera of pesticide applicators in the agricultural environment. In comparison to
      the control group pesticide applicators showed significant increased odds ratios
      for neopterin and soluble tumor necrosis factor receptor (sTNF RII) and a
      decreased odds ratio for immunoglobulin M. Obtained results indicate an enhanced
      macrophage activation and an impaired humoral defense. These alterations have
      been found to correlate with exposure duration in the group of pesticide
      applicators in agriculture. For subjects who worked in indoor pest control an
      inverse correlation for sTNF RII with exposure duration was obtained indicating
      impairment of cell mediated immune function. It can be concluded that exposure to
      pesticides in the agricultural environment may contribute to modulation of the
      immune system. Since immune modulating agents can potentially lead to adverse
      health consequences the involvement of immune biomarkers in pesticide-related
      health studies seems to be of considerable value for risk assessment studies.

PMID- 10414800
TI  - Disruption of male sex hormones with regard to pesticides: pathophysiological and
      regulatory aspects.
AB  - Several pesticides used as herbicides, insecticides and fungicides are known to
      be endocrine disrupting chemicals (EDCs). In three pair-matched studies we found
      changes in sex hormone concentrations and T-lymphocytes in relation to acute and
      chronic pesticide exposure. After acute exposure, 1 day later the concentrations
      of testosterone and especially estradiol decreased. T4- and T8-lymphocytes
      slightly increased. Effects of chronic occupational pesticide exposure were
      expressed by a higher level of testosterone and a larger ratio of T4-/T8
      lymphocytes in comparison to control persons. Concentrations of LH in exposed men
      were higher after exposure than before. We assume an inhibition of the aromatase
      system by testosterone metabolites. The studies show two effects with regard to
      the duration of exposure: a hormonal and immune suppression after acute exposure
      and an activation of both systems following chronic exposure.

PMID- 10414802
TI  - Regulating pesticides in the UK: a case study of risk management problems
      relating to the organophosphate diazinon.
AB  - OBJECTIVES: (1) To assess aspects of occupational and related environmental
      health risk assessment and risk management decisions of UK regulatory bodies on
      diazinon used in sheep dip; and (2) to benchmark those decisions against 'the
      public health precautionary approach'. METHODS: Analysis of diazinon health and
      safety data available within Government Departments, industry and from users in
      animal husbandry practice. RESULTS: (1) Data on diazinon produced by the
      manufacturing companies for the UK pesticide regulatory agencies are not fully
      transparent; (2) UK regulatory health and safety processes assume accuracy of
      manufacturer's data and information provided on personal protective equipment
      (PPE) and application effectiveness; (3) data available reveal gaps and problems
      with diazinon toxicity, PPE and application methods; and (4) little published
      evidence shows that industry followed up the health of dippers after product
      registration or that government departments adopted a public health approach to
      regulation. CONCLUSIONS: Diazinon sheep dip illustrates the need for the
      application of a rigorous precautionary principle in both initial registration
      and later monitoring of chemicals.

PMID- 10414801
TI  - Modern strategies in therapy of organophosphate poisoning.
AB  - Considering the various microscopic reactions as well as toxicokinetic and
      pharmacokinetic principles in therapy of organophosphate poisoning, the
      administration of obidoxime by an initial bolus dose followed by continuous
      infusion appears rational. Using this protocol, six patients each with parathion
      or oxydemeton methyl poisoning were treated. In parathion poisoning, reactivation
      was possible up to 7 days. At paraoxon concentrations > 0.1 microM obidoxime only
      partially reactivated acetylcholinesterase (AChE) of erythrocytes in vivo
      although reactivation could be assessed in vitro, which roughly fitted
      theoretical calculations. AChE-inhibitory material was detected up to 5 days.
      Cholinergic signs soon subsided when AChE was above 20% of normal, and atropine
      plasma levels could be kept below 7 ng/ml. In one patient brain damage persisted.
      Oxydemeton methyl poisoning responded to obidoxime therapy only when the oxime
      was instituted shortly after poisoning. Out of six patients one died. No
      intermediate syndrome and no signs of permanent hepatic dysfunction were found in
      the 12 patients.

PMID- 10414803
TI  - Electroneurophysiological studies in rats of acute dimethoate poisoning.
AB  - In order to investigate the mechanism of muscular weakness in the intermediate
      myasthenia syndrome (IMS) following acute organophosphate poisoning, the effect
      of dimethoate on the neuromuscular transmission was studied in rats by using the
      electrical stimulation single fiber electromyography (SSFEMG) and repetitive
      nerve stimulation (RNS). The results showed that there was a prolongation of mean
      consecutive difference (MCD) of the latencies of single fiber potential shown by
      SSFEMG in dimethoate intoxicated rats during the presence of muscle weakness when
      the stimuli were given at 10 or 20 Hz, and there was a remarkable decrement of
      compound muscle action potential (CMAP) of gastrocnemius muscle evoked by RNS on
      the sciatic nerve at 20 Hz in some rats with myasthenia. The frequency of
      neuromuscular transmission abnormalities detected by SSFEMG was significantly
      higher than those detected by RNS. This study demonstrates that the SSFEMG is a
      more sensitive electrophysiological method in the detection of neuromuscular
      transmission block occurred in rats of acute organophosphate poisoning with
      muscle weakness.

PMID- 10414804
TI  - When is a shared decision not (quite) a shared decision? Negotiating preferences
      in a general practice encounter.
AB  - We consider whether there are situations in which 'shared decision making' in
      primary care is inherently problematic, such as in the demand for antibiotics to
      treat viral disorders. In such an instance there might be a lack of the equipoise
      necessary for a decision-making context in which apparent choices are genuine
      options. Using the techniques of discourse analysis on the transcript of a
      consultation with the parents of an infant with tonsillitis, we illustrate how a
      general practitioner's (GP's) efforts to reach a 'shared decision' come unstuck
      through a combination of the embedded power imbalance and the conflict between
      the GP's own prescription preferences and those of the parent.

PMID- 10414805
TI  - Patient assertiveness and physician decision-making among older breast cancer
      patients.
AB  - The objective of this study was to determine whether assertive patient behavior
      influences physician decision-making in the treatment of older breast cancer
      patients. One hundred and twenty-eight physicians saw videotapes depicting women
      seeking care for breast cancer and then recommended evaluation and treatment
      plans. Identical scripts were used, but the age, race, socioeconomic status,
      mobility, general health, and assertive behavior of the patients were
      experimentally varied along with the physician's specialty and length of
      practice. No direct effects of assertive patient behavior were seen. However,
      black, comorbid, and lower SES women were more likely to have full staging of
      their tumors ordered when they made an assertive request. Treatment
      recommendations also showed an interaction of assertiveness with patient's age
      and social class as well as physicians' specialty. The results indicate that a
      moderately assertive patient request may change provider behavior, although the
      effects of assertiveness vary most by what type of patient demonstrates this
      behavior. In particular, assertiveness led to more careful diagnostic testing for
      patients who came from groups that are "disadvantaged."

PMID- 10414806
TI  - Prescribing benzodiazepines--a critical incident study of a physician dilemma.
AB  - Use of benzodiazepines has been discussed extensively both among the public and
      within the medical society. The aim of this study was to explore the quality of
      dilemmas experienced by physicians when prescribing benzodiazepines. A
      questionnaire was sent to 213 Swedish General Practitioners. The critical
      incident technique was chosen as an appropriate method for surveying professional
      experiences. Concern for the patient and threats to the integrity of the
      physician were common dilemmas. The physicians did not believe that the patients
      were telling the truth or did not trust the patients' ability to handle the
      medicine. The most frequent consequences of the dilemmas were worry about a
      disturbed relationship with patients indicating an uncertainty as to how to
      create a good relationship with them. The participants in the study were aware of
      the national guidelines for prescribing benzodiazepines, but due to insufficient
      time a prescription was often chosen as a way to handle the dilemmas. Improvement
      in the rational use of benzodiazepines is not achieved by the medical board
      making new rules but rather by offering physicians education in communication and
      negotiating skills as well as more time with the individual patient who is
      requesting benzodiazepines.

PMID- 10414807
TI  - Women's control and choice regarding HRT.
AB  - The promotion and use of hormone replacement therapy (HRT) is the focus of much
      medical activity and a social phenomenon studied by sociology. The decision to
      prescribe HRT by a doctor may be a response to a woman's distress and is a
      decision involving uncertainty about risks and benefits. Sociological analysis
      has seen the promotion and use of HRT as medicalisation of the menopause. Through
      individual interviews and focus groups, this study hears from women how they
      approach the decision to take HRT or not, and what influences them. The
      interviews reveal how women who dislike medication in general may consider HRT,
      influenced by fear of ill health which may be enhanced by the experience of
      illness in the family and by medical advice. For the women the media and their
      social contacts were the major sources of information about HRT. In the focus
      groups the women explored the control they had over the choice to take HRT and
      what limited this control and they explored the uncertainties and complexities of
      the decision to take HRT or not. This study brings lay women's voices to the
      debate about the use and promotion of HRT. The results are also used to test the
      limits of the theory of medicalisation and to inform doctors of the issues women
      may bring to a consultation about HRT.

PMID- 10414808
TI  - Disputed diagnoses: the cases of RSI and childhood cancer.
AB  - Recently, greater emphasis has been accorded lay views and involvement in debates
      on health care provision. At the macro level, policy makers are urged to take
      heed of the opinions of the general public when formulating new policies for
      health care or making changes to existing ones. Furthermore, it is suggested that
      this accommodation should be repeated at the level of the individual, namely in
      encounters between doctors and patients. However, imbalances in the doctor
      patient power relationship, compounded by structural barriers, can create
      problems which prevent this sort of collaborative interaction from taking place.
      Against this background, the paper draws on evidence from studies of two quite
      different conditions, repetitive strain injury (RSI) and childhood cancer, to
      explore lay perspectives and empowerment in relation to obtaining a diagnosis.
      The findings of the studies are scrutinised in respect of four related areas of
      concern: how much lay views count, exercising choice, referral pathways and the
      withdrawal of trust from medical practitioners. The evidence suggests that a
      substantial number of patients with RSI and parents of children with cancer felt
      their experiences and knowledge were disregarded by doctors in the diagnostic
      process. Denying the validity of an individual's perceptions had implications for
      obtaining an accurate diagnosis, which could in turn make access to appropriate
      health care and treatment problematic. Their experiences led some people with RSI
      to show a general distrust of medicine; this was less the case for parents of
      children with cancer. A key issue to emerge from the analysis is the need for
      additional training in two areas of the medical curriculum: communication skills
      and occupational health problems. The underlying problems of attitudes,
      especially giving weight to the informed views of lay people, is another matter
      which needs to be addressed.

PMID- 10414809
TI  - Determinants of socioeconomic differences in change in physical and mental
      functioning.
AB  - Continuous decline in functioning is not an inevitable consequence of ageing, as
      some individuals maintain high levels of functioning to old age. The origins of
      functional problems in old age are not only related to current circumstances, but
      may be traced back to earlier life-experiences. Previous analyses show that
      change in functioning is related to socioeconomic status, but it is uncertain to
      what extent these differences can be accounted for by the same health behaviours
      and material and psychosocial factors that are related to socioeconomic
      differences in morbidity and mortality. This paper investigates socioeconomic
      differences in change in mental and physical functioning in a relatively young
      and healthy population over a three year follow-up period. The data come from the
      Whitehall II Study of London based civil servants aged 39-63 in 1991-93. We
      measured functioning with the Short Form 36 (SF-36) General Health Survey and
      socioeconomic status by civil service employment grade. Among lower employment
      grade men the odds ratio of being in the quartile of rapid decline in mental and
      physical functioning was 1.79 and 1.56 respectively. For women the odds ratio for
      physical functioning was 1.34, but employment grade differences in mental
      functioning were inconsistent. Among men health behaviours were the most
      important determinants of employment grade differences in physical functioning
      change. In addition, material problems and job decision latitude accounted for
      employment grade differences in physical as well as mental functioning change.
      However, among women employment grade differences in change in physical
      functioning can not be accounted for with these risk factors. Analyses of change
      in determinants may provide further insight into the underlying pathways. Early
      detection of functional decline and intervention may be a key to better
      functioning in ageing populations.

PMID- 10414810
TI  - The influence of adult ill health on occupational class mobility and mobility out
      of and into employment in the The Netherlands.
AB  - In the debate about the explanation of socio-economic health inequalities one of
      the important issues is the relative importance of health selection. The aim of
      this study was to investigate to what extent occupational class mobility and
      mobility out of and into employment are health-related, and in addition, to
      estimate the contribution of health-related social mobility to socio-economic
      health differences in the working population. Data were taken from the
      Longitudinal Study on Socio-Economic Health Differences in the Netherlands, which
      started in 1991; follow-up data were collected in 1995. The analysis is based on
      2533 persons aged 15-59 at baseline. The influence of health problems in 1991
      (perceived general health, health complaints and chronic conditions) on changes
      in occupational class between 1991 and 1995 was negligible. Neither upward nor
      downward mobility was affected by health problems. However, health problems in
      1991 were significantly associated with a higher risk of mobility out of
      employment and a lower risk of mobility into employment in 1995. For example, for
      mobility out of employment among persons that reported at least one chronic
      condition in 1991, the odds ratio was 1.46. Health-related mobility out of
      employment substantially influences the estimate of socio-economic health
      inequalities in the working population (measured by current occupation). For
      manual workers, as compared to non-manual workers, the odds ratio for a less-than
      good perceived general health was underestimated by 34% in 1995. Selective
      mobility into employment overestimates socio-economic inequalities in health in
      the working population by 9%. Respondents that moved into and out of employment
      were healthier than those that remained economically inactive, but their health
      was worse than of those that remained employed (both manual and non-manual).
      Implications for health policy are that the prospects for people with health
      problems to stay in paid employment should be improved.

PMID- 10414811
TI  - Diarrheal disease risk in Matlab, Bangladesh.
AB  - The objective of this research project is to assess risk for diarrheal disease in
      rural Bangladesh by analyzing the complex and dynamic interaction of biological,
      socioeconomic, cultural/behavioral and environmental factors over time and space.
      Risk factors of cholera and non-cholera water diarrheal disease are calculated to
      compare the relative importance of risk for several independent variables.
      Diarrheal disease data were collected for people who were hospitalized at the
      International Centre for Diarrhoeal Disease Research (ICDDR) hospital from
      January 1, 1992 to December 31, 1994. Using laboratory and hospital records,
      cases were assigned to one of two diarrhea disease categories (cholera or non
      cholera watery diarrhea) that were used as dependent variables in the analysis
      stage of the research. Age-matched individuals were randomly chosen from the
      community to be controls. Information was collected for independent variables
      that were hypothesized to be related to watery diarrhea. This information was
      collected by administering questionnaires, obtaining secondary data from the
      ICDDR's demographic surveillance system records and community health worker
      record books and calculating variables using a geographic information system
      database. Sanitation and water availability and use are extremely important in
      the effort to reduce secondary cholera and non-cholera, watery diarrhea
      transmission. Water use and availability variables were more important for non
      cholera watery diarrheal risk than for cholera but nevertheless they were
      important for both. Socioeconomic status is an important indirect cause of both
      of these diseases because poverty is the root cause of many of the other
      variables, such as lack of sanitation and clean water. Flood-control was related
      to both types of diarrhea but it is not understood why. Since the Bangladesh
      Flood Action Plan will continue to build and maintains flood-control embankments,
      it is important to investigate whether there is a pattern to this relationship
      throughout the country and to investigate why the relationship exists.

PMID- 10414812
TI  - Defecation practices of young children in a Peruvian shanty town.
AB  - Little is known about feces disposal practices, their determinants and
      feasibility for change, despite their importance in the control of diarrheal
      diseases. We report here the results of formative research for the development of
      an intervention to promote sanitary disposal of feces of young children. The
      study was conducted in a densely populated shanty town area of Lima, where water
      and sanitation systems are scarce. In-depth interviews were undertaken with
      mothers, husbands and community leaders. Group discussions were held with mothers
      in order to validate findings from the interviews, investigate particular topics
      further and explore reactions to possible intervention strategies. The principal
      defecation sites for young children were diapers, potties, the ground in or near
      the home, the hill, latrines and flush toilets. The main determinants found were
      the age of the child, the effort required by the method, perceptions of dirtiness
      and the availability of resources. Almost all children under one year of age use
      diapers but the high resource cost of diaper washing is a strong motivation for
      mothers to move their children on as early as possible. Potties were considered
      the most socially acceptable and 'hygienic' defecation method for children
      between one and three years of age. Nevertheless, defecation directly onto the
      ground is common at this age. Potty training is deemed to be quite difficult and
      the long term achievements are determined by the initial training success. In
      most cases, the training process is authoritative and inconsistent. The use of
      latrines and flush toilets is not considered appropriate for children until they
      are three to four years old. Based on these initial findings, a micro-trial was
      conducted to assess the feasibility and acceptability of promoting greater use of
      potties and associated practices. The results of the trial were very encouraging
      and provided valuable information for the design of a community-wide
      intervention. Our findings help explain why the emphasis given in most sanitation
      projects, where efforts have been concentrated on the promotion of latrines, has
      failed to induce their utilization by small children. Sanitation projects should
      incorporate interventions that will promote hygienic defecation and stool
      clearance practices for infants and small children.

PMID- 10414813
TI  - Modernization of medical care in Korea (1876-1990).
AB  - This article explores the modernization of traditional Korean medicine in an
      attempt to answer why Korea has a dual system of professionalized care, and
      argues that the dual system has been shaped by conflicts between herbal doctors
      and Western-trained doctors throughout the various stages of historical
      development. I do not attempt comparisons with other countries, but social
      scientists have created a large body of work on the interaction between Western
      and Asian medical traditions in India, China, Japan, and other countries. Korea
      has been absent from this research. The present essay should draw attention to
      its sociological relevance.

PMID- 10414814
TI  - Valuing the benefits of publicly-provided health care: does 'ability to pay'
      preclude the use of 'willingness to pay'?
AB  - The case against the use of willingness to pay (WTP) methods to value the
      benefits of publicly-provided health care is often made on the basis that WTP is
      associated with ability to pay. In this paper, it is demonstrated that this
      argument is not so straightforward, depending on two criteria: (a) the
      association of people's preferences with ability to pay and (b) the disparities
      of WTP for given options within categories of ability to pay. A method of dealing
      with ability to pay, based on these criteria, is proposed and illustrated through
      the use of data from a case study.

PMID- 10414815
TI  - Survival vs. quality of life: a study of the Israeli public priorities in medical
      care.
AB  - Public opinion has become one of the primary inputs in setting priorities,
      rationing and allocating health resources. The present study focuses on the
      priorities of the Israeli public aged 45-75 in allocating scarce medical
      resources between prolonging survival (the 'Rule of Rescue') and preventing a
      severe and permanent disability (quality of life). The findings indicate that the
      'Rule of Rescue' is dominant for more than a quarter of the population even when
      death is postponed by only one month. More than a tenth of the population are
      ready to adopt prioritization by lottery. Economic condition, gender and health
      status have no effect on priority choices. The main determinants of the choices
      are age and religiosity, with older individuals more likely to choose random
      prioritization and religious people tending to prefer saving life even when the
      opportunity costs are high.

PMID- 10414816
TI  - Stability of elderly persons' expressed preferences regarding the use of life
      sustaining treatments.
AB  - The purpose of the study was to assess the stability of expressed preferences for
      the use of life-sustaining treatments (LST) in severe illness conditions over two
      years. The two year longitudinal study included three structured interviews with
      a one-year interval (1994, 1995, and 1996). At baseline, 1138 Israeli elderly
      persons (70+) were interviewed, 802 and 638 were interviewed in the following
      stages. Stability over time was assessed on the basis of score differences on two
      different indices that measured the wish to prolong life. Overall 70% of the
      respondents had stable preferences for the use of LST over time. This result was
      similar on both indices. The large majority of those with stable preferences
      (86%) did not want to prolong life already in the baseline interview. This was
      the most stable group. Among those who changed their wishes, the group that
      wanted LST less at stage 3 (20%) was twice as large as the group that wanted LST
      more (10%). These findings, which are similar to those reported in a study of an
      American sample, indicate a high level of stability in elderly persons' expressed
      preferences for LST at the end of life, and, therefore, strengthen the ethical
      basis for using advance directives. They also indicate that elderly persons of
      different cultural backgrounds may face similar problems regarding the
      prolongation of life and respond to them similarly.

PMID- 10414817
TI  - Attitudes towards informed consent, confidentiality, and substitute treatment
      decisions in southern African medical students: a case study from Zimbabwe.
AB  - This study explored the attitudes of biomedical science students (medical
      students) in a non-Western setting towards three medical ethics concepts that are
      based on fundamental Western culture ethical principles. A dichotomous
      (agree/disagree) response questionnaire was constructed using Western
      ethnocentric culture (WEC) based perspectives of informed consent,
      confidentiality, and substitute decision-making. Hypothesized WEC-Biased
      responses were assigned to the questionnaire's questions or propositions. A
      number of useful responses (169) were obtained from a large, cross-sectional,
      convenience sample of the MBChB students at the University of Zimbabwe Medical
      School. Statistical analysis described the differences in response patterns
      between the student's responses compared to the hypothesized WEC-Biased response.
      The effect of the nine independent variables on selected dependent variables
      (responses to certain questionnaire questions) was analyzed by stepwise logistic
      regression. Students concurred with the hypothesized WEC-Biased responses for two
      thirds of the questionnaire items. This agreement included support for the role
      of legal advocacy in the substitute decision-making process. The students
      disagreed with the hypothesized WEC-Biased responses in several important medical
      ethics aspects. Most notably, the students indicated that persons with mental
      dysfunctions, as a class, were properly considered incompetent to make treatment
      decisions. None of the studied independent variables was often associated with
      students' responses, but training year was more frequently implicated than either
      ethnicity or gender. In order to develop internationally and culturally relevant
      medical ethics standards, non-Western perspectives ought to be acknowledged and
      incorporated. Two main areas for further efforts include: curriculum development
      in ethics reasoning and related clinical (medico-legal) decision-making processes
      that would be relevant to medical students from various cultures, and; the
      testing of models that could increase legal system input in the clinical process
      in societies with limited jurisprudence resources.

PMID- 10414818
TI  - Ethics education and physician morality.
AB  - Medical ethics education remains an important venue of moral education. In spite
      of the intensity of these efforts, the desired outcomes of medical ethics
      education remain obscure, undefined and largely untested. In the first part of
      this study, the goals of medical ethics are operationalized along cognitive,
      behavioral and attitudinal dimensions. This includes a written moral judgment
      test, a survey of ethical confidence, competence and interest, attitudinal
      surveys of physician assisted suicide, and aggressive treatment of newborns and,
      finally, self-reported behavior about the frequency of pro-bono work and
      treatment of self-abusive patients. Medical ethics education is operationalized
      by the type, scope and intensity of ethics education throughout a physician's
      education and subsequent career. Data were collected by a questionnaire
      distributed to the staff of a large urban hospital in 1996 (n = 200, response
      rate = 41%). Causal models measure the effects of medical education. The results
      suggest that ethics education plays an important but limited role in the
      attainment of these cognitive, attitudinal and behavioral outcomes. While some
      outcomes such as moral development, and ethical confidence are unaffected by
      ethics education, other attitudinal and behavioral objectives, such as ethics
      interest and pro-bono work are positively associated with formal ethics training
      as well as with demographic variables such as religious observance and age.
      Ethics education does not function as an isolated factor but as part of a web of
      interrelated factors that influence educational outcomes. In addition, it is
      clear that ethics education resists quantitative analysis to some extent. Rather,
      it is sometimes viewed as a discipline that is studied for its own sake with the
      hope that it may contribute to one's all around character in a way that cannot be
      directly assessed. These implications are explored in the conclusion of the
      paper.

PMID- 10414819
TI  - Balancing effectiveness, side-effects and work: women's perceptions and
      experiences with modern contraceptive technology in Cambodia.
AB  - This community-based study presents the results of 17 focus-group discussions
      primarily among poor married women of reproductive age in urban and rural
      Cambodia regarding their experiences with modern contraceptive methods and their
      preferences for different technical attributes, including effectiveness, mode of
      administration, secrecy and rapid return of fertility. Key findings indicate that
      women who use modern contraceptive technologies desire highly effective methods
      of birth control. Cambodian women are primarily interested in longer-acting
      methods, view weight gain positively and are less concerned about a rapid return
      to fertility upon discontinuation of a method or secrecy from their partners.
      Women report a high level of side-effects as well as a high level of individual
      variation between side-effects and each modern contraceptive method used. Women
      with more knowledge and experience of modern contraceptive technologies alter
      their preference for highly effective methods based on a method's perceived
      suitability. Specifically, women may switch from a modern method associated with
      negative side-effects to a lesser effective traditional method, either to take a
      break from unwanted side-effects or discontinue modern methods altogether, if
      another suitable method is unavailable. These and other findings point to the
      need for greater development and choice of contraceptive methods with different
      technical attributes; improved information that clearly and simply describes how
      each method works within a women's body and its expected side-effects; improved
      access to reproductive health services; and improved assessment of women's
      underlying burden of reproductive illness not directly associated with modern
      contraceptives.

PMID- 10414821
TI  - Obligatory medical insurance in Russia: the participants' perspective.
AB  - The Russian Federation adopted a nation-wide system of obligatory medical
      insurance in 1993 in an effort to earmark a targeted source of funding for health
      care and to reverse a steep decline in health outcomes. The author conducted a
      survey in 1995-1996 of managers of two of the new institutional participants in
      Russia's health insurance scheme: Territorial Health Insurance Funds and private
      medical insurance companies. The survey results reveal deep dissatisfaction with
      the level of financing provided by the new system; continuing confusion and
      substantial regional variation in the implementation of the insurance
      legislation; fierce bureaucratic and institutional infighting between the major
      players, stemming primarily from controversy over delineation of responsibilities
      and ongoing battles for control over resources; promising hints of competition
      and other market-based incentives emerging from the current chaos; and broad
      agreement that further structural reform must accompany increased infusions of
      resources in order for significant systemic improvements to be realized.

PMID- 10414820
TI  - 'Because of the risks': how US pregnant women account for refusing prenatal
      screening.
AB  - Most research on prenatal fetal testing in general, and maternal alpha
      fetoprotein (AFP) screening in particular, has focused on women who accept and
      even actively seek prenatal diagnosis. Much of this work suggests that agreeing
      to prenatal diagnosis is inextricably linked to the processes associated with the
      'medicalization' of reproduction and that most women do not see refusal as an
      option. In contrast, little attention has been paid to women who decline fetal
      diagnosis. Instead, it is generally assumed that women who do so are resisting
      this thrust toward medicalization and/or are opposed to abortion. Our research is
      designed to address this imbalance. We analyze how a group of US women who
      refused the offer of AFP screening account for their decisions and compare their
      explanations with those of women who took the test. Contrary to our expectations,
      we found that refusal did not signify rejection of and/or resistance to the
      offerings of science and technology. Rather, women who refused often employed
      biomedical categories, particularly the concept of 'risk', to reject its very
      offerings. Furthermore, refusers and acceptors were more alike than different in
      their views on abortion, medicalization and pregnancy. We conclude that the key
      difference between the two groups lies in their interpretation and application of
      biomedical concepts and modern risk-assessment.

PMID- 10414822
TI  - A case-control study of employment status and mortality in a cohort of Australian
      youth.
AB  - Recent studies have demonstrated a link in young populations between unemployment
      and ill health. The purpose of this study is to correlate mortality with
      employment status in two cohorts of young Australian males, aged 17-25 years,
      from 1984 to 1988. Two youth cohorts consisting of an initially unemployed sample
      (n = 1424 males) and a population sample (n = 4573 males), were surveyed annually
      throughout the study period. Those lost to follow-up during the survey period
      were matched with death registries across Australia. Employment status was
      determined from weekly diaries and death certificates and was designated as:
      employed or student; unemployed; not in the work force (excluding students).
      Conditional logistic regression, using age- and cohort- matched cases (deaths)
      and controls (alive), was used to estimate the odds ratio (OR) of dying with
      regard to employment status, taking into account potential confounders such as
      ethnicity, aboriginality, educational attainment, pre-existing health problems,
      socio-economic status of parents, and other factors. Twenty three male survey
      respondents were positively matched to death registry records. Compared to those
      employed or students (referent group), significantly elevated ORs were found to
      be associated with neither being in the workforce nor a student for all cause,
      external cause, and external cause mortality other than suicide. Odds ratios were
      adjusted for age, survey cohort, ethnicity, pre-existing physical and mental
      health status, education level, and socio-economic status of parent(s). A
      statistically significant increasing linear trend in odds ratios of male
      mortality for most cause groups was found across the employment categories, from
      those employed or student (lowest ORs), through those unemployed, to those not in
      the workforce (highest ORs). Suicide was higher, but not statistically
      significantly, in those unemployed or not in the workforce. Suicide also was
      associated, though not significantly, with the respondent not living with their
      parents when they were 14 years of age. No association was found between
      mortality and past unemployment experience, as measured by length of time spent
      unemployed, or the number of spells of unemployment experienced during the
      survey. The results of this study underscore the elevated risk to survival in
      young males as a consequence of being neither employed nor a student.

PMID- 10414823
TI  - Encompassing treatment with prevention: the path for a lasting control of
      tuberculosis.
AB  - Tuberculosis is an important cause of death, mainly in the less developed
      countries. Thus far the strategy for its control had relied on the diagnosis of
      sick individuals and provision of chemotherapy. However, this strategy is
      problematic for several reasons: poor education about the disease and the low
      income of people with tuberculosis are important barriers for them to have access
      to early diagnosis and to keep adherence to treatment; provision of 'preventive
      therapy' to the enormous pool of people infected with tuberculosis is not
      feasible in less developed countries; and finally, long-term political commitment
      with the strategy is unlikely. Several facts indicate that tuberculosis patterns
      in different populations are shaped by biological, behavioral and socio-economic
      factors. This paper argues that a lasting control of tuberculosis requires a
      strategy based on a broader model of causality, which takes account of all these
      three causal factors.

PMID- 10414824
TI  - Resource dependency, doctors and the state: quality control in Sweden.
AB  - This paper focuses on the interaction between the state and the medical
      profession on the national level in Sweden with respect to issues concerning
      quality in health care. Using the concepts of policy network and resource
      dependency as points of departure, two examples of interorganisational
      relationships are analysed which relate to medical/professional quality and
      organisational quality, respectively. These are (1) the control of the national
      quality registers and (2) the development of third-party accreditation in health
      care organisations. During the 1990s the state has become increasingly dependent
      on participation by the profession in order to obtain outcome data and other
      resources controlled by the profession. In Sweden, a fragmented state has
      established various types of linkages with the organised medical profession, all
      of which are characterised by mutual resource dependency.

PMID- 10414826
TI  - Planning reproductive health in conflict: a conceptual framework.
AB  - A conceptual framework for planning reproductive health services for refugees is
      presented for use by those involved in planning field activities. Secondary
      sources of data are recommended to describe pre-existing patterns and trends in
      reproductive health status and likely determinants of any change in status, for
      populations which have been subsequently affected by conflict. The interaction
      between these patterns and the conflict itself is then analyzed, taking into
      account the shift in health status and service availability as the conflict
      progresses through various recognized phases. The potential impact of conflict is
      thus hypothesized in order to make initial plans for incorporating reproductive
      health services into standard relief packages. Two case studies are presented:
      Rwanda demonstrates the use of the framework in a relatively short but dramatic
      conflict, for which there was also substantial prior evidence on reproductive
      health status; Cambodia is used, in contrast, to demonstrate the use of the
      framework in a much more complex conflict which has been occurring over the last
      20 years.

PMID- 10414825
TI  - Effects of distances to hospital and GP surgery on hospital inpatient episodes,
      controlling for needs and provision.
AB  - Age and sex adjusted inpatient episode ratios were calculated from hospital
      records over a two year period for 555 census wards in Cambridgeshire, Norfolk
      and Suffolk, UK. Hospital episodes were divided into acute, psychiatric and
      geriatric specialties, and elective and emergency acute admissions were
      distinguished. Variations in inpatient episode ratios between wards were compared
      with census indicators of the 'needs' of local populations for inpatient
      services, measures of the local provision of hospital and other related services,
      and measures of the distance to the nearest general practitioner surgery and the
      distance to the nearest hospital. Hospital episodes were found to be strongly
      related to both distance measures, but the associations were partially explained
      by a tendency for the health status of local populations (measured by the needs
      indicators) to be worst in urban areas close to health services. Including needs
      and provision variables together with the distance variables explained most of
      the variations in age and sex adjusted inpatient ratios for small areas. Needs
      were the most important determinants of emergency acute and psychiatric inpatient
      rates, but service provision was more important for elective acute and geriatric
      inpatients. Controlling for needs and provision, distance to hospital produced
      17% reduction in acute episodes, 37% reduction in psychiatric episodes and 23%
      reduction in geriatric episodes over the range of distances observed. Distance to
      nearest GP surgery reduced elective acute episodes by up to 15% after controlling
      for confounders. These results demonstrate that the NHS is falling short of its
      aim to provide fair access to services irrespective of geography, and new
      policies will be required if geographical inequities are to be reduced.

PMID- 10414827
TI  - Lifeboat versus corporate ethic: social and demographic implications of stem and
      joint families.
AB  - We contrast stem and joint family systems, to show how differences in norms of
      inheritance and residence profoundly influence our values and social constructs.
      They shape how people evaluate each other and patterns of conflict and
      cooperation within and between generations. Through this, they influence many
      fundamental aspects of social organization and behaviour. These influence health
      outcomes through categorizing people into those whose health is encouraged to
      prosper or to fail. It also influences a wide range of other outcomes, including
      strategies of household resource management; migration; ways of exploiting
      commercial opportunities and the operation of civil society. A number of
      hypotheses are developed about the nature of these interrelationships, some of
      which are substantiated empirically and others which can be tested.

PMID- 10414828
TI  - Planned orphanhood.
AB  - Medical technology, which today makes it possible to bear a child after death,
      enables planned orphanhood. The first part of this paper will discuss the medical
      innovations in human conception, the psycho-social aspects of the wish for
      children from the genes of someone who is no longer alive, and the ensuing
      orphanhood and its implications. The second part will discuss the ethical issues
      relating to planned orphanhood: Who are involved in the matter of planned
      orphanhood? Is the decision to produce a planned orphan a private or public
      matter? Whose responsibility is the birth and bringing up of the planned orphan?
      To whom does society have more responsibility - the children who already exist or
      future children? And can planned orphanhood be regarded as a justification for
      wrongful conception? The last part of the paper will examine the judicial aspects
      of planned orphanhood in Israel and elsewhere and discuss the application of the
      principles of human dignity, human welfare, and justice. The paper argues for
      discouraging planned orphanhood so as to avoid violating the principles of human
      dignity and liberty, human welfare, and human justice, from the perspectives of
      both those who are involved in the process in general and the orphan who is the
      target of the medical intervention in particular. Its aim is to encourage deep
      and comprehensive public discussion of this issue in all its aspects.

PMID- 10414829
TI  - Maternal mortality, women's status, and economic dependency in less developed
      countries: a cross-national analysis.
AB  - While much has been written about the medical, economic, and social causes of
      cross-national differences in some mortality related phenomena such as in life
      expectancy and infant mortality, much less attention has been given to maternal
      mortality, the focus of the present study. In the studies of maternal mortality
      that have been done, there has been very little effort to assess the potential
      relevance of the gender stratification and dependency theory perspectives. Using
      lagged cross-sectional and path analysis with a sample of 79 less developed
      countries, this article focuses on the impact of predictors linked to three
      theoretical perspectives - modernization, economic dependency, and gender
      stratification. We find that women's status, as measured by indicators such as
      level of education relative to men, age at first marriage, and reproductive
      autonomy, is a strong predictor of maternal mortality. We find that economic
      dependency, especially multinational corporate investment, has a detrimental
      effect on maternal mortality that is mediated by its harmful impacts on economic
      growth and the status of women. We also find support for developmental theory, a
      variant of modernization theory.

PMID- 10414830
TI  - Rationality in medical treatment decisions: is there a sunk-cost effect?
AB  - OBJECTIVE: To assess residents' propensity to display the sunk-cost effect, an
      irrational decision-making bias, in medical treatment decisions; and to compare
      residents' and undergraduates' susceptibility to the bias in non-medical,
      everyday behaviors. DESIGN: Cross-sectional, in-person survey. SETTING: Louisiana
      State University, two locations: Medical Center-Baton Rouge and Main Campus
      Psychology Department. PARTICIPANTS: Internal medicine and family practice
      residents (N = 36, Mdn age = 27) and college undergraduates (N = 40, Mdn age =
      20). MEASUREMENTS AND MAIN RESULTS: Residents evaluated medical and non-medical
      situations that varied the amount of previous investment and whether the present
      decision maker was the same or different from the person who had made the initial
      investment. They rated reasons both for continuing the initial decision (e.g.,
      stay with the medication already in use) and for switching to a new alternative
      (e.g., a different medication). There were two main findings: First, the
      residents' ratings of whether to continue or switch medical treatments were not
      influenced by the amount of the initial investment (p's>0.05). Second, residents'
      reasoning was more normative in medical than in non-medical situations, in which
      it paralleled that of undergraduates (p's<0.05). CONCLUSIONS: Medical residents'
      evaluation of treatment decisions reflected good reasoning, in that they were not
      influenced by the amount of time and/or money that had already been invested in
      treating a patient. However, the residents did demonstrate a sunk-cost effect in
      evaluating non-medical situations. Thus, any advantage in decision making that is
      conferred by medical training appears to be domain specific.

PMID- 10414831
TI  - National health policies: sub-Saharan African case studies (1980-1990).
AB  - Four countries, Botswana, Cote d'Ivoire, Ghana and Zimbabwe, were chosen as cases
      to study the impact of national health policies on national health status in sub
      Saharan Africa. Through a conceptual framework that covers health problem
      identification, policy formulation and implementation procedures, the study
      examined national translations of Primary Health Care (PHC) and Health for All by
      the Year 2000 (HFA/2000) strategies. A series of government measures, taken
      between 1980-1986 for health policy development and implementation in these
      countries, were treated as policy determinants of national health outcomes for
      the period ending 1990. The impact of these determinants on national health
      status was then analyzed through a comparative description and documentation of
      observable patterns and trends in infant mortality rates (IMR), under-5 mortality
      rates (U5MR) and life expectancy. Policy guidelines from PHC and HFA/2000 were
      used in conjunction with the respective per capita Gross National Products to
      categorize the four cases. Based on these guidelines, Botswana was ranked high,
      both in terms of policy development and the level of economic development, while
      Zimbabwe ranked high in terms of policy development but relatively low in
      economic terms. Cote d'Ivoire ranked high on economic development but low with
      regard to its policy framework. Ghana was at the other end of the spectrum,
      ranking low both in terms of its policy development and its economic performance.
      The comparative analysis revealed that Botswana and Zimbabwe performed better
      than Cote d'Ivoire and Ghana on the three outcome indicators. Despite Cote
      d'Ivoire's superior level of economic development, its health status fell behind
      that of Zimbabwe and even Ghana. The study concluded that policies formulated and
      implemented in accordance with key PHC principles could account for improvements
      in national health status. Since the end of the study period (1990), there have
      been significant political changes in the sub-Saharan African region as a whole
      and in some of the case countries in particular. Political leadership has changed
      in Ghana and Cote d'Ivoire with some course corrections in Ghana's health plans.
      Health sector financing in the region has become more dependent on external
      donors. The World Bank leads the external donor community in promoting policy
      based lending. The complexity of a number of health problems has changed while
      the problems themselves remain the same as before. Essentially, building viable
      public health infrastructures to address basic public health needs must still be
      high on the agenda of action for most governments in the region. Thus,
      notwithstanding some course corrections and reasonable shifts in priorities, all
      the PHC principles are still applicable, indeed, much needed in the sub-Saharan
      African region. This study's findings, underscoring the fact that significant
      improvements in health are possible even where financial resources are limited,
      still hold true.

PMID- 10414832
TI  - HIV-related sexual risk assessment among Asian/Pacific Islander American women:
      an inductive model.
AB  - Current HIV/AIDS rates among Asian/Pacific Islander (A/PI) women in the United
      States are disproportionately low (CDC, 1998). However, there is evidence to
      suggest that risk for HIV is present, based upon studies on risk behaviors and
      markers for risk as well as demographic factors that may facilitate transmission
      among this population. Because a particular threat to A/PI women is heterosexual
      transmission, which accounts for nearly half of all cases (CDC, 1998), prevention
      efforts should focus on risk within sexual contexts and how such risk is assessed
      and acted upon. Using a qualitative methodology, the present study investigated
      how A/PI American women assess their HIV-related risk in sexual interactions.
      Based on extensive interview data, an inductive model of risk assessment was
      generated consisting of cultural and sexual risk schemata. Findings suggest the
      influence of cultural schemata on sexual risk schemata, which in turn influence
      whether condoms or HIV tests are requested. Specifically, the cultural values of
      reticence regarding sex, the accommodation of others and a traditional romantic
      ideal inhibit open discussion with partners about HIV as well as requests for
      safer sex behaviors. Instead, A/PI women tend to engage in non-explicit,
      inferential assessments of partners' risk, which may contribute to an illusory
      sense of control and safety. Consistent with previous studies on other groups of
      women, these findings further extend and elucidate theory and prevention
      strategies for this population.

PMID- 10414833
TI  - Occupational class and the probability of long-term limiting illness.
AB  - The central purpose of this paper is to investigate, using data from the Sample
      of Anonymised Records of the 1991 Census for Britain on over 80,000 male and over
      75,000 female employees between the ages of 41 and 67, the relationship between
      occupational class and health inequality. The specific aim of the investigation
      is to answer two questions. First, after controlling for non-class attributes,
      what was the contribution of occupational class to differences between the
      classes in the proportion of persons in them with a long-term limiting illness?
      ANSWER: a lot or very little depending on the classes that are being compared and
      whether the comparison is for men or for women. Second, how much of the
      inequality in the distribution, over the persons in the sample, in their
      probabilities of suffering from a long-term limiting illness was due to
      inequality between persons in the same occupation class (within-class inequality)
      and how much was due to inequality between persons in different occupational
      classes (between-class inequality)? ANSWER: for men, approximately one-quarter
      and, for women, approximately one-fifth of overall inequality in health status
      was the result of differences in occupational class.

PMID- 10414834
TI  - Goal-setting in clinical medicine.
AB  - The process of setting goals for medical care in the context of chronic disease
      has received little attention in the medical literature, despite the importance
      of goal-setting in the achievement of desired outcomes. Using qualitative
      research methods, this paper develops a theory of goal-setting in the care of
      patients with dementia. The theory posits several propositions. First, goals are
      generated from embedded values but are distinct from values. Goals vary based on
      specific circumstances and alternatives whereas values are person-specific and
      relatively stable in the face of changing circumstances. Second, goals are
      hierarchical in nature, with complex mappings between general and specific goals.
      Third, there are a number of factors that modify the goal-setting process, by
      affecting the generation of goals from values or the translation of general goals
      to specific goals. Modifying factors related to individuals include their degree
      of risk-taking, perceived self-efficacy, and acceptance of the disease. Disease
      factors that modify the goal-setting process include the urgency and
      irreversibility of the medical condition. Pertinent characteristics of the
      patient-family-clinician interaction include the level of participation, control,
      and trust among patients, family members, and clinicians. The research suggests
      that the goal-setting process in clinical medicine is complex, and the potential
      for disagreements regarding goals substantial. The nature of the goal-setting
      process suggests that explicit discussion of goals for care may be necessary to
      promote effective patient-family-clinician communication and adequate care
      planning.

PMID- 10414835
TI  - Pharmacy and herbal medicine in the US.
AB  - Herbal medicine is increasing in popularity in the United States. The market
      continues to grow, with a presence being established for commercially-prepared
      herbal products in community pharmacies throughout the nation. This survey was
      conducted to describe that presence in pharmacies and to describe pharmacists'
      perceptions of this product class. A response rate of 26.3% (n = 512) was
      achieved for a five-page mail survey sent to a geographically stratified random
      sample of community pharmacies in the United States. Approximately 73% of
      pharmacists responding indicated that their pharmacy carried commercially
      prepared herbal products. Attitudinal items were included to measure pharmacists'
      perceptions toward these products, as those perceptions have the potential to
      influence attitudes and subsequently behavior (such as clinical involvement with
      patients wishing to integrate herbal products into an existing regimen).
      Pharmacists, on average, did not believe that herbal products are well
      standardized, or that the products are well accepted by the Food and Drug
      Administration or the National Association of Boards of Pharmacy. Much potential
      exists for pharmacists to fill a role as information provider to patients who
      self-medicate with herbal medicines; must their perceptions of the product class
      be changed first?

PMID- 10414836
TI  - Effect of price and access on contraceptive use.
AB  - The Family Planning Program in Bangladesh has been very successful. The
      contraceptive prevalence rate (CPR) has increased from 13% in 1979 to 49% in
      1996. Now that the program has matured and demand for family planning has been
      created, the Ministry of Health and Family Welfare (MOHFW) of the Government of
      Bangladesh is concerned with increasing its financial sustainability. Options to
      increase financial sustainability include cost sharing and a gradual transition
      from doorstep to static clinic delivery of contraceptives. Many of these
      alternatives would involve additional travel time or charges for consumers, and
      it is important to estimate the effect that these additional prices would have on
      the use of contraception. The effect of economic constraints, such as cash price
      and access to services on contraceptive method use, the choice of contraceptive
      method and provider choice, has been analyzed, taking into account the
      socioeconomic factors that influence decision-making for individual family
      members. Two data sources have been used for this analysis: (1) a survey on use
      of contraception and (2) two baseline surveys of 1993 and 1994 in the two field
      sites of the MCH-FP Extension Project (Rural) of International Center for
      Diarrhoeal Disease Research, Bangladesh. No effect of cash prices was found on
      the probability of use of any contraceptive method, but clients were to a limited
      extent responsive to price in making choices about contraceptive methods and
      providers. In addition, couples were less likely to use contraception or choose
      methods if the travel time to fixed clinics was greater than 30 min.

PMID- 10414837
TI  - Production gains from health care: what should be included in cost-effectiveness
      analyses?
AB  - Recent literature has been concerned with the correct measurement of the
      'indirect costs and benefits' of health care as well as the issue of including
      these items in economic evaluations. This article considers the question of which
      'indirect benefits' to include in cost effectiveness analysis and cost utility
      analysis. Within the context of a collectively financed health scheme the
      relevant issues include not only the size of the net resource costs of providing
      health care but also which costs and benefits the society is prepared to consider
      in its assessment of health services. The strong preference for 'equal access for
      equal need' implies that some production gains may have to be disregarded in the
      social welfare function. We introduce the notion of socially relevant and
      socially irrelevant production gains. The analysis suggests that the magnitude of
      the socially relevant part of the production gains may vary between countries as
      it depends, first, upon differences in patients' potential contributions to the
      rest of society (tax rates), and second, the strength of preferences for equity.

PMID- 10414838
TI  - The referral process and urban health care in sub-Saharan Africa: the case of
      Lusaka, Zambia.
AB  - Much of the current reform of urban health systems in sub-Saharan Africa focuses
      upon the referral system between different levels of care. It is often assumed
      that patients are by-passing primary facilities which leads to congestion at
      hospital outpatient departments. Zambia is well advanced in its health sector
      reform and this case study from the capital, Lusaka, explores the patterns of
      health seeking behaviour of the urban population, the reasons behind health care
      choices, the functioning of the referral system and the users' evaluations of the
      care received. Data were collected across three levels of the system: the
      community, local health centres and the main hospital (both in- and out
      patients). Results showed those who by-passed health centres were doing so
      because they believed the hospital outpatient department to be cheaper and/or
      better supplied with drugs (not because they believed they would receive better
      technical care). Few users were given information about their diagnosis or reason
      for referral. The most striking result was the degree of unmet need for health
      services and the large number of individuals who were self-medicating due to lack
      of money rather than the minor nature of their illness. The current upgrading of
      urban health centres into 'reference centres' may provide a capacity for unmet
      need rather than decongesting the hospital outpatient department as originally
      intended.

PMID- 10414839
TI  - Power between evaluator and community: research relationships within New Mexico's
      healthier communities.
AB  - The relationship between evaluators and communities has been changing in the last
      two decades to a model of research 'with' the community, instead of research 'on'
      the community. This shift has paralleled increasing community demands for
      accountability and authority as community participation rhetoric has given way to
      words such as partnership, collaboration and community empowerment. Despite the
      rhetoric, there has been little reflection on the problematic and contradictory
      relationships between communities and researchers, specifically as related to
      their differing positions of power. This article provides a reflective
      examination of the contested power dynamics of the research relationship within a
      participatory evaluation process of the Healthier Communities initiative in New
      Mexico. An in-depth literature review of the philosophical principles and the
      complex realities of evaluations based on participatory, community-driven and
      post-modern inquiry precedes the case study. Without ongoing consideration of
      power issues, the article argues that evaluation design, implementation and
      utilization of findings will be compromised.

PMID- 10414840
TI  - Between intention and behavior: an application of community pharmacists'
      assessment of pharmaceutical care.
AB  - A new practice philosophy for pharmacists, pharmaceutical care, encourages
      pharmacists to ensure that medication-related health outcomes are optimized.
      However, its adoption by community pharmacists has been slow due to numerous
      barriers including the economic structure of retail pharmacy, interprofessional
      conflicts, information limitations, gaps in pharmacy training and uneven patient
      demand. The specific study objectives were to (1) describe self-efficacy,
      beliefs, evaluations and perceived behavioral control in the provision of
      pharmaceutical care, (2) quantify intention and behavior to provide
      pharmaceutical care in a period of two weeks and (3) examine the relationships
      between intention and behavior. A 20% sample of Alberta community pharmacists
      received an attitude survey followed in two weeks by a behavior survey. Both
      surveys were developed for this study. Of the 320 pharmacists receiving the
      attitude survey, 230 completed surveys were obtained (71.9%). The behavior survey
      was received from 182 of those completing the attitude survey (79.1%). A causal
      model was constructed predicting pharmaceutical care behavior/s from pharmacists'
      self-efficacy, beliefs, evaluations and behavioral control. Behavioral control
      exerted its effect upon behavior via three pathways and its direct effect on
      belief was strongest. The only direct predictor of behavior was self-efficacy.
      The chi2 measure indicated that the model was not a perfect fit (chi2 = 99.24, df
      = 67, p<0.006), but the goodness of fit index (0.931), adjusted goodness of fit
      index (0.876), and root mean squared error (0.067) fall within acceptable ranges.
      Thus, it appears that pharmaceutical care implementation programs which address
      individual factors singly in providing pharmaceutical care will not be
      successful. The control pharmacists' perceive over their patient care behaviors
      in their practice environment is critical. Programs which help pharmacists assess
      their work environment and determine strategies to impact or reconstruct their
      environments are required.

PMID- 10414841
TI  - Exploring the bio-psycho--social approach to premenstrual experiences.
AB  - A bio-psycho-social approach to the premenstrual syndrome suggests that cyclical
      hormonal changes are acknowledged and interpreted in light of the expectations
      and the attitudes acquired in the process of socialization. In this study,
      attitudes toward menstruation and premenstrual experiences of 229 Israeli
      students of different ethnic groups and gender role orientations were explored.
      The findings were consistent with previous reports: attitudes toward menstruation
      and premenstrual experiences were associated with exposure to premenstrual
      symptoms in women family members and negative messages during adolescence;
      respondents of a more traditional background perceived menstruation as relatively
      debilitating and bothersome but also a natural event and reported more severe
      experiences. However, models aimed at estimating the causal relationship
      indicated that attitudes toward menstruation depend on premenstrual experiences
      rather than predict them. The difficulties of investigating such reciprocal
      relationships of menstrual attitudes and premenstrual experiences cross
      culturally and longitudinally are discussed.

PMID- 10414842
TI  - Urban and rural suicide differentials in migrants and the Australian-born, New
      South Wales, Australia 1985--1994.
AB  - We estimated risk of suicide in adults in New South Wales (NSW) by sex, country
      of birth and rural/urban residence, after adjusting for age; we also examined
      youth suicide (age 15-24 years). The study population was the entire population
      of NSW, Australia, aged > or =15 years during the period 1985-1994. Poisson
      regression was used to examine the relationship between predictor variables and
      the risk of suicide, with the focus on migrant status and area of residence. A
      significantly higher risk of suicide was found in male migrants from Northern
      Europe and Eastern Europe/former USSR, compared to Australian-born males; a
      significantly lower suicide risk occurred in males from Southern Europe, the
      Middle East and Asia. In female migrants, those from UK/Eire, Northern Europe,
      Eastern Europe/former USSR and New Zealand exhibited a significantly higher risk
      of suicide compared to Australian-born females. A significantly lower risk of
      suicide occurred in females from the Middle East. Male migrants overall were at
      significantly lower risk of suicide than the Australian-born, while female
      migrants overall had a significantly higher risk of suicide than Australian-born
      females. Among migrant males overall, the rural-urban suicide risk differential
      was significantly higher for those living in non-metropolitan areas (RR = 1.9;
      95% CI: 1.7-2.1). Suicide risk was significantly higher in non-metropolitan male
      immigrants from the UK/Eire (RR = 1.4; 95% CI: 1.1-1.7), Southern Europe (RR =
      1.7; 95% CI: 1.2-2.4), Northern/Western Europe (1.5; 95% CI: 1.2-1.9), the Middle
      East (RR = 3.8; 95% CI: 1.9-7.8), New Zealand (RR = 1.4; 95% CI: 1.0-1.8) and
      'other' (RR = 2.6; 95% CI: 1.9-3.5), when compared to their urban counterparts.
      There was no statistically significant difference in suicide risk between rural
      and urban Australian-born males. For female suicide, significantly lower risk was
      found in female immigrants living in non-metropolitan areas who were from
      Northern/Western Europe (RR = 0.7; 95% CI: 0.4-0.96), as well as the Australian
      born (RR = 0.7; 95% CI: 0.6-0.8), when compared to their urban counterparts. The
      non-metropolitan/metropolitan relative risk for suicide in female migrants
      overall was not significantly different from one. Among male youth there was a
      significantly higher suicide risk in non-metropolitan areas, with a relative risk
      estimate of 1.4 for Australian-born youth (95% CI: 1.2-1.5) and 1.7 for migrant
      youth (95% CI: 1.2-2.4), when compared with metropolitan counterparts. We
      conclude that suicide among migrant males living in non-metropolitan areas
      accounts for most of the excess of male suicide in rural NSW, and the
      significantly lower risk of suicide for non-metropolitan Australian-born women
      does not apply to migrant women.

PMID- 10414843
TI  - Ecological pattern of first admitted schizophrenics in two German cities over 25
      years.
AB  - Ecological studies on the distribution of rates of first-admitted schizophrenics
      were carried out in Mannheim in 1965 and from 1974 to 1980. As the catchment area
      of the ABC Schizophrenia Study comprises the cities of Mannheim and Heidelberg,
      we were able to conduct a third ecological study for Mannheim and a first study
      for Heidelberg covering the years 1987 to 1989. High rates of schizophrenic
      residents are found in the inner districts of Mannheim and Heidelberg. This
      concentration has been stable over a period of 25 years for Mannheim. Subdividing
      the districts of Mannheim and Heidelberg into zones, only in Heidelberg and only
      for the second cross-section in Mannheim, the rates decreased constantly with
      increasing distance from the centre. Summing up the districts of Mannheim and
      Heidelberg in homogenous areas on the basis of economical and socio-demographic
      properties, high rates of schizophrenics were found in homogenous areas with poor
      and unfavourable living conditions. In Mannheim and Heidelberg, homogenous areas
      with the highest rates of schizophrenics are characterised by highly unfavourable
      living conditions, a high percentage of young men, people living alone, students,
      foreigners, people with a low level of education and a high
      immigration/emigration rate. The analysis on the individual level, i.e. in the
      biography of schizophrenics shows that processes of social drift and/or
      nonstarter take place long before first admission in the prodromal phase and the
      psychotic prephase of beginning schizophrenia. Probably, these selective
      processes like downward drift or nonstarting processes, lead to the migration of
      schizophrenics into unfavourable areas or schizophrenic residents staying in poor
      areas, while healthy residents leave these districts. Selective processes such as
      help seeking behaviour and access to the care system have no effect on the
      unequal distribution. In summary, a definite confirmation or refutation of one of
      the two causal hypotheses, 'social selection' vs. 'social causation', is not
      possible up to date, but the empirical results support the selective hypothesis
      for schizophrenic disorders.

PMID- 10414844
TI  - The sense of coherence, occupation and the risk of coronary heart disease in the
      Helsinki Heart Study.
AB  - The risk of coronary heart disease (CHD) was studied in 4405 Finnish middle-aged
      working men in different occupations according to their sense of coherence (SOC).
      The study design was prospective and the follow-up time was eight years. Clinical
      findings such as total cholesterol, systolic blood pressure and body-mass index
      showed differences when comparing blue and white collar workers. Lifestyle
      factors such as smoking also differed, but leisure time physical activity
      depended on SOC. In the white collar work environment the low SOC tertile had a
      high CHD incidence of 20.1 per 1000 person-years; the incidences in the medium
      and high SOC tertiles were 10.9 and 12.3, respectively. A similar effect was not
      observed in the blue collar work environment. There, contrary to theoretical
      expectations, the low SOC tertile had the lowest incidence of CHD. The difference
      in the CHD incidence pattern depended on the blue and white collar dichotomy and
      not on the branch (state agencies vs. industry). The SOC had a salutogenic effect
      among white collar workers, but failed to have any consequent effect on the
      health of blue collar workers. Further study is needed to look at the
      psychosocial factors among blue collar workers.

PMID- 10414845
TI  - Does employment improve the health of lone mothers? The ALSPAC Study Team. Avon
      Longitudinal Study of Pregnancy and Childhood.
AB  - In Britain the government is currently proposing legislation that will encourage
      welfare recipients to gain employment. A central tenet of this 'welfare to work'
      policy is that employment will not only reduce the poverty of welfare recipients,
      but also improve their health. This research assessed the extent to which the
      movement from 'welfare to work' is likely to benefit the mental and physical
      health of lone mothers with preschool children. The sample was 719 lone mothers
      and a comparison group of 8779 women with partners drawn from the Avon
      Longitudinal Study of Pregnancy and Childhood (ALSPAC). Data collected by self
      completion questionnaire at 33 months postpartum provided information about
      average weekly take home family income and the mother's employment status. The
      health outcomes measured were general well being, both minor and major depression
      (using the Edinburgh Postnatal Depression Scale), self report of respiratory
      symptoms (cough/cold, wheeze, influenza) from 18-33 months postpartum and self
      report of symptoms common in the childbearing years (backache, haemorrhoids) also
      from 18-33 months postpartum. Lone mothers who were not employed were the poorest
      group in the sample; 94% of this group (402) had a family income of less than
      pound sterling 200 per week, compared with 72% (188) of lone mothers who were
      employed, 25% (905) of partnered women who were not employed and 12% (466) of
      partnered women who were employed. Lone mothers were significantly more likely
      than women with partners to report poorer well being (chi2 = 11.7, df = 3, P =
      0.01), to have a major depressive disorder (chi2 = 92.6, df = 1, P = 0.0001) and
      to report wheeze (chi2 = 31.1, df = 1, P = 0.0001), but significantly less likely
      to report cough/cold (chi2 = 9.9, df = 1, P = 0.0001) or haemorrhoids (chi2 =
      16.6, df = 1, P = 0.0001). Lone mothers who were unemployed and living on less
      than pound sterling 100 per week were significantly more likely to be depressed
      (chi2 = 3.9, df = 1, P = 0.05) than those who were employed and living on pound
      sterling 200 or more per week, and significantly less likely to report cough/cold
      (chi2 = 3.8, df = 1, P = 0.05). Logistic regression analyses showed no
      significant independent association between employment and better health for lone
      mothers. Rather, when compared with lone mothers who were not working, those who
      were employed were more likely to report minor respiratory symptoms such as
      cough/cold (OR = 1.51, 95% CI = 1.00,2.31). Overall, the results suggested that
      the movement from 'welfare to work' is unlikely to improve the health of lone
      mothers.

PMID- 10414846
TI  - Social support at age 33: the influence of gender, employment status and social
      class.
AB  - This paper investigates the conceptualisation and operationalisation of social
      support and it's relationship to gender, employment status and social class.
      Clarification of these relationships is sought in order to better understand
      associations between social support and health. We used data from the 33-year
      survey of the 1958 British birth cohort study. Individual items and subscales of
      practical and emotional support were examined. In general, men had lower support
      than women and social classes IV and V had lower support than classes I and II.
      Emotional support, either from personal (for example, from friends or family), or
      combined with organisational sources of support (such as from a church or a
      financial institution), showed consistent gender and social class patterns. This
      suggests that emotional support is a robust concept across socio-demographic
      groups. Less consistent trends were found for practical support, in that socio
      demographic trends depended on how practical support was measured. In particular,
      it depended on whether both personal and organisational sources of support were
      examined. Gender differences in social support were large and might therefore be
      expected to contribute to gender differences in health, whereas social class
      differences in social support were modest, suggesting a minor explanatory role
      for this factor in accounting for inequalities in health.

PMID- 10414847
TI  - Morbidity and quality of life and the moderating effects of level of education in
      the elderly.
AB  - The moderating effect of level of education (as an indicator of socioeconomic
      status) on the associations between chronic medical morbidity and six domains of
      health-related quality of life (physical function, role function, social
      function, health perceptions, bodily pain and mental health) is studied in a
      large community-dwelling elderly sample (N = 5279). The results showed that
      health-related quality of life is substantially affected by chronic medical
      morbidity, and that level of education has weak, but significant unique
      contributions to physical function, social function, health perceptions, and
      mental health. We did not find substantial evidence for the differential
      vulnerability hypothesis. At best, low education might amplify the negative
      effects of the number of chronic medical conditions on mental health only, but
      this result was not confirmed in four specific disease groups.

PMID- 10414848
TI  - Morphological features of the minor salivary glands.
AB  - The minor salivary glands are important components of the oral cavity, present in
      most parts of the mouth, and their secretions directly bathe the tissues.
      Individual glands are usually in the submucosa between muscle fibres, and consist
      of groups of secretory endpieces made up of mucous acinar cells and serous or
      seromucous demilune cells. The ductal systems comprise intercalated ducts,
      intralobular ducts usually lacking basal striations, and excretory ducts opening
      directly through the mucosa Minor glands secrete highly glycosylated mucins,
      containing blood group determinants, and probably active in tissue lubrication
      and bacterial aggregation. They also secrete several antimicrobial proteins and
      immunoglobulins, and the lingual serous (von Ebner's) glands secrete digestive
      enzymes and proteins with possible taste perception functions. Minor gland
      morphology and function can conveniently be studied in the rat. There are
      substantial differences between major and minor salivary glands, as well as among
      the minor glands, in the nature and composition of their mucous and serous
      secretory products. The role of minor salivary glands in the function and defence
      of the oral cavity may be better understood as a result of new physiological and
      molecular methods applicable to samples of limited size and availability.

PMID- 10414849
TI  - The flow rate and composition of human labial gland saliva.
AB  - Since the flow rate of saliva from human labial salivary glands has usually been
      measured as the secretion from an area of labial mucosa as 0.05-4.8
      microl/cm2/min. The only data for single glands gives a comparable figure of 0.1
      microl/min/gland. There is no consensus on the effects of gustatory stimulation,
      gender or ageing, although most reports suggest that flow rate is not related to
      gender and ageing up to age 60. The main differences in composition between
      labial gland saliva and that from the major glands are the higher and variable
      sodium concentration, the very low phosphate and hydrogen carbonate
      concentrations, and the higher protein concentration despite low concentrations
      of amylase. The concentrations of IgA and blood group substances are notably
      higher in labial gland saliva. In Sjogren's syndrome and cystic fibrosis flow
      rates are decreased. Low rates of flow have been associated with a higher
      incidence of dental caries.

PMID- 10414850
TI  - Ion transport and signalling in human labial glands.
AB  - Recent reports characterizing the physiological properties of normal human labial
      acini are reviewed with particular emphasis on mechanisms related to fluid
      secretion. In contrast to the salivary glands of several experimental animals,
      human labial acinar cells do not appear to have a1-adrenergic receptors,
      substance P peptidergic receptors, or significant levels of Cl-/HCO3- exchange.
      Nor do they appear to secrete HCO3- in response to Ca2+ mobilizing stimuli. The
      data presently available indicates that fluid secretion by these glands is mainly
      under muscarinic control and is due to acinar Cl- secretion driven by a
      basolateral Na+ -K+ -2Cl- cotansporter.

PMID- 10414851
TI  - New concepts for the development of autoimmune exocrinopathy derived from studies
      with the NOD mouse model.
AB  - The non-obese diabetic (NOD) mouse is now recognized as an appropriate model to
      study autoimmune exocrinopathy prevalent in human Sjogren's syndrome patients.
      With increasing age, NOD mice undergo histopathological changes similar to human
      Sjogren's syndrome patients, but more importantly, exhibit the same clinical
      manifestation of declining exocrine tissue secretory function. Studies with the
      immunodeficient NOD-scid mouse have provided evidence for the temporal loss in
      the expression of several major salivary proteins and a decreased presence of
      acinar cells in salivary tissues. The diminished presence of acinar cells is
      accompanied by an increase in the enzymes associated with apoptosis in the
      absence of T- and B-lymphocytes. Despite these alterations, NOD-scid mice, unlike
      NOD mice, do not lose secretory function. Recent analyses of a second congenic
      NOD strain, the NOD.Igmnull, which lacks B-lymphocytes, indicate the histological
      presence of a T-cell infiltrate of the exocrine glands, increased caspace
      activity and induction of the biochemical alterations in protein expression
      observed in NOD and NOD-scid mice. NOD.Igmnull mice also do not lose secretory
      function, but can be manipulated to generate a reduced secretory response
      following the infusion of IgG fractions from autoimmune NOD mice or Sjogren's
      syndrome patients. These observations, in the absence of components of the
      adaptive arm of the immune system, have given rise to the concept that autoimmune
      exocrinopathy develops in two phases. The initial phase is lymphocyte independent
      and occurs as a consequence of an innate error in exocrine tissue homeostasis or
      differentiated function. The subsequent tissue specific immunological attack,
      generated in part by B-cell autoantibodies, is responsible for the loss of
      secretory function. Our preliminary observations in both NOD mice and Sjogren's
      syndrome patients is that antibody directed against the cell surface
      muscarinic/cholinergic receptors appears to play an important part in the onset
      of clinical disease.

PMID- 10414852
TI  - A scanning and transmission electron microscope study of the human minor salivary
      glands.
AB  - All human minor salivary glands, apart from the posterior deep lingual (von
      Ebner's) glands which were serous, contained a minor population of seromucous
      cells that increased from palatine and posterior superficial lingual (Weber's) to
      labial, anterior lingual (Blandin and Nuhn's) and buccal glands, in that order.
      Unlike the predominant mucous cells, whose structure was uniform, serous and
      seromucous cells exhibited, in each gland, peculiar cytological and
      cytoarchitectural characters.

PMID- 10414853
TI  - Immunocytochemical localisation of neuropeptide-containing nerve fibres in human
      labial glands.
AB  - Different neuropeptide-containing nerve fibers (vasoactive intestinal
      polypeptide, substance P, neuropeptide Y) and nitric oxide synthase (NOS)
      positive nerve fibers were investigated to clarify their role in the function of
      human labial glands using immunohisto- and immunocytochemical techniques. The
      distribution pattern of all immunoreactive nerve fibers was similar both in the
      control and in the Sjogren's syndrome specimens. A large number of thin varicose
      vasoactive intestinal polypeptide and NOS positive nerve fibers were seen around
      or in close contact with the acini. Some of the immunoreactive nerve fibers were
      associated with the salivary ducts and blood vessels. Substance P and
      neuropeptide Y immunoreactive nerve fibers were located mainly around the blood
      vessels. Immunocytochemistry demonstrated that some of the positive nerve fibers
      were in direct contact with the acini, blood vessels and with the lymphocytes.
      The gap between the membranes of immunoreactive nerve terminals and the target
      cells was 40 to 200 nm. The number of the nerve terminals in Sjogren's syndrome
      specimens was decreased and some degenerated axons were also found. These results
      suggest that these neuropeptides and nitric oxide might act as a neurotransmitter
      in the regulation of secretion and blood flow in the labial glands. These fibers
      might also alter the neuroimmunological processes, because the investigated
      neuropeptides are known to be immunoregulators.

PMID- 10414854
TI  - Purines, a new class of agonists in salivary glands?
AB  - The response of rat submandibular glands to extracellular purines was tested. In
      crude cellular suspensions, ATP increased the [Ca2+]i mostly by promoting uptake
      of extracellular calcium. ATP caused the pHi to drop, a response blocked by
      chloride channel inhibitors. ATP also inhibited the basal and isoproterenol
      stimulated activity of the Na+ -K+ -2Cl-cotransporter. These effects were
      reproduced by benzoyl-ATP, an agonist of ionotropic purinoceptors. In pure ductal
      suspensions, ATP activated a metabotropic P2Y1 purinergic receptor coupled to
      phospholipase C and opened a non-specific cation channel coupled to a P2X7
      receptor. Activation of these receptors stimulated a Ca2+ -dependent and a Ca2+ 
      independent phospholipase A2, the latter resulting in kallikrein secretion. We
      conclude that purinergic agonists can modulate the activity of both acinar and
      ductal phases of secretion. Activation of metabotropic receptors coupled to
      phospholipase C could lead to responses resembling those to muscarinic or
      adrenergic agonists. Activation of ionotropic receptors could stimulate new
      intracellular responses also involved in secretory function.

PMID- 10414855
TI  - Secretion from minor salivary glands following ablation of the major salivary
      glands in rats.
AB  - Since minor salivary glands are tiny and dispersed, ductal cannulation cannot be
      used when studying their function. The present study was devised to develop a
      method of measuring minor salivary gland function by excision of the major
      glands. Female rats (230-280 g) were anaesthetized with sodium pentobarbital.
      Ablation of the submandibular, sublingual and parotid glands was performed
      through a sagittal neck incision. Sham-operated rats served as controls. Groups
      of sialadenectomized animals were investigated immediately and after 1 week, 2
      weeks and 3 months. To study secretory function, the mouth was rinsed with 250
      microl water in every 5 min and protein and amylase concentrations were measured.
      After an initial 50 min of basal secretion pilocarpine (1 mg/kg, i.p.) was given.
      Bilateral ablation of both submandibular, sublingual and parotid glands led to a
      moderate loss of body weight and a considerable increase in water intake. No
      other obvious abnormality was observed for periods up to 90 days following
      surgery. We deduce that the minor glands secrete approximately 14 % of protein
      and 1% of amylase in whole saliva Secretion is maintained even after 90 days
      following removal of the major glands. Surgical removal of the major salivary
      glands allows the secretory function of the minor glands in rats to be studied in
      vivo.

PMID- 10414856
TI  - Cytokine expression in human labial minor salivary gland epithelial cells in
      health and disease.
AB  - Microdissection of biopsy material from labial minor salivary glands followed by
      RT-PCR demonstrates extensive production of cytokines IL-2, 1L-6, IL-10, TNF
      alpha, TGF-beta, and IFN-gamma in both normal glands and in glands affected by
      Sjogren's syndrome. Continuation of these studies should expand our knowledge of
      normal salivary gland function and the pathogenesis of Sjogren's syndrome.

PMID- 10414857
TI  - Expression of aquaporin 1 (AQP1) water channels in human labial salivary glands.
AB  - Aquaporin (AQP) water channels are widely expressed in the membranes of fluid
      transporting epithelia. Despite the fact that salivary glands are the site of
      considerable water movement, relatively little is known about the role of
      aquaporins in human salivary glands. We have examined the expression of AQP1 in
      human parotid, sublingual and labial salivary glands. Total RNA was extracted
      from glandular tissue obtained from surgery or biopsy. The presence of AQP1 mRNA
      was demonstrated in each of the three glands by RT-PCR using primers specifically
      designed for human AQP1. The PCR product from the labial gland RNA was further
      amplified with nested primers and the sequence confirmed by automated fluorescent
      DNA sequencing. The cleaned first PCR product from these glands was then used as
      a 32P-labelled hybridization probe in a Northern analysis which confirmed the
      presence of significant amounts of AQP1 transcript in all three glands. AQP1
      expression was also demonstrated in cryosections of human labial glands by
      immunohistochemistry using peroxidase-linked antibodies. Antibody labelling was
      most prominent in the capillaries but was also evident in the basal regions of
      the labial gland acini, and may therefore be associated with the serous demilunes
      which are believed to be a significant site of fluid movement.

PMID- 10414858
TI  - Study of saliva secretion and the salivary fluoride concentration of the human
      minor labial glands by a new method.
AB  - Unstimulated and stimulated flow rate from minor lower labial glands and the
      fluoride concentration of resting whole and labial saliva were measured over 15
      min using a novel method avoiding eversion of the lips. Resting salivary flow
      rate was measured as 1.09+/-0.44 microl/min/cm2 and stimulated flow rate as
      3.13+/-1.05 microl/min/cm2. Secretion rates were significantly (p<0.001)
      increased during periods of continuous speaking. The increase in secretion
      elicited by labial movements and speaking may result from mechanical stimulation
      and/or activity of myoepithelial cells. Fluoride concentrations in resting whole
      saliva and in unstimulated minor labial gland saliva were 0.066+/-0.048 and
      0.181+/-0.073 parts/10(6), respectively. The secretory capacity of the minor
      labial glands and the high F concentration in their secretions suggests a
      significant contribution to the F content of whole saliva. Our non-invasive
      method permits collection from the minor labial glands of a volume large enough
      for chemical analysis. It should prove useful for studying the effects of
      different secretory stimuli.

PMID- 10414859
TI  - Are salivary glands cell lines in culture a good model for purinergic receptors
      in salivary glands?
AB  - A major obstacle in studying the physiological and biochemical processes of
      salivary secretion is the lack of a good ductal cell line model. HSY, an
      immortalised cell line originating from human parotid gland intercalated ducts,
      provides a possible model for purinergic mechanisms in ductal cells. Unlike the
      biphasic dose response to ATP of isolated submandibular ductal cells, the rise in
      [Ca2+]i in HSY cells shows single Michaelis-Menten kinetics with an apparent Ka
      of 0.8 microM. Pre-incubation with thapsigargin inhibited the ATP induced [Ca2+]i
      rise. Both ATP (10 microM) and carbachol (100 microM) increased IP3 production.
      Intercalated duct cells may differentiate into acinar or ductal cells in response
      to appropriate stimuli from extracellular matrix We therefore attempted to induce
      a duct-like phenotype in the striated duct-derived HSY cells by growing them on
      microcarrier beads coated with type I collagen. In Ca-containing medium cells
      grown on all substrates showed similar responses to ATP. In contrast, in Ca-free
      medium, [Ca2+]i rose only slightly in cells grown on beads relative to those on
      glass. This probably resulted from reduced IP3 production. Carbachol also induced
      a much smaller increase in [Ca2+]i and less IP3 production in cells grown on
      Cytodex-3. The HSY response to purinergic stimuli by an increase in [Ca2+]i and
      IP3 means that they can be used to study the metabotropic purinergic pathway. The
      impairment in the HSY responses grown on Cytodex-3 can be used to probe
      phosposinositol signal transduction in salivary cells.

PMID- 10414860
TI  - Membrane stretch and salivary glands - facts and theories.
AB  - Cell shape in salivary glands is affected by mechanical forces. In the acini and
      ducts cell shape is modified by the contractions of the myoepithelial cells in
      both the secretory and ductal portions of the glands. At the organ level shape
      changes are due to muscle contraction during mastication, food intake and speech.
      All these factors may cause some degree of stretching of salivary cell membranes.
      Recent studies suggest that physical forces influence signal transduction, gene
      expression, secretory function, cell differentiation and proliferation. Here we
      overview membrane stretch-activated cellular events. Evidence from a variety of
      tissues suggests that mechanical forces may alter the properties of acinar cells
      leading to cytoskeletal reorganisation, changes in ion fluxes, modulation of
      secretory activity and subsequent release of transmitters such as ATP.
      Transmitters released from acinar cells may modulate the secretory activity of
      salivary tissue, and interact with classical regulatory pathways.

PMID- 10414861
TI  - Neutralizing capacity of antisera raised in horses and rabbits against Crotalus
      durissus terrificus (South American rattlesnake) venom and its main toxin,
      crotoxin.
AB  - Crotalus durissus terrificus (South American rattlesnake) venom possesses
      myotoxic and neurotoxic activities, both of which are also expressed by crotoxin,
      the principal toxin of this venom. We have investigated the ability of commercial
      equine antivenom and antivenoms raised in rabbits against C. d. terrificus venom
      and crotoxin to neutralize the physiological and morphological changes induced by
      this venom and crotoxin in electrically-stimulated phrenic nerve-diaphragm (PND)
      and extensor digitorum longus (EDL) preparations of mice. The time required to
      produce 50% neuromuscular blockade in the PND and EDL preparations was,
      respectively, 103+/-9 and 59+/-6 min for C. d. terrificus venom (10 microg/ml)
      and 75+/-9 and 110+/-7 min for crotoxin (10 microg/ml). The antivenoms dose
      dependently inhibited this neuromuscular activity of the venom and crotoxin. At a
      venom:antivenom ratio of 1:3, the rabbit antivenoms were as effective as the
      commercial equine antivenom. The creatine kinase (CK) concentrations in the organ
      bath containing EDL muscle were 290 and 1020 U/l following a 120 min exposure to
      C. d. terrificus venom and crotoxin, respectively. All of the antivenoms
      neutralized the release of CK by crotoxin, but were ineffective against C. d.
      terrificus venom. Histological analysis of the two preparations showed that
      rabbit anticrotoxin antivenom protected against the myotoxic action of C. d.
      terrificus venom and crotoxin better than the other antivenoms. We conclude that
      antisera raised in rabbits are better than equine antiserum in neutralizing the
      neurotoxic and myotoxic activities of C. d. terrificus venom and crotoxin.

PMID- 10414862
TI  - The first evidence of paralytic shellfish toxins in the fresh water
      cyanobacterium Cylindrospermopsis raciborskii, isolated from Brazil.
AB  - The blooms of toxic cyanobacteria (blue-green algae) are causing problems in many
      countries. During a screening of toxic freshwater cyanobacteria in Brazil, three
      strains isolated from the State of Sao Paulo were found toxic by the mouse
      bioassay. They all were identified as Cylindrospermopsis raciborskii by a close
      morphological examination. Extracts of cultured cells caused acute death to mice
      when injected intraperitoneally after developing neurotoxic symptoms which
      resembled to those caused by paralytic shellfish toxins. The analysis of the
      sample by HPLC-FLD postcolumn derivatization method for paralytic shellfish
      toxins resulted in the detection of several saxitoxin analogs. To avoid being
      misled by false peaks, the sample was reanalyzed after purification and also
      under the different postcolumn derivatizing conditions. Finally, the newly
      developed LC-MS method for paralytic shellfish toxins was applied to
      unambiguously identify the toxins. One isolate produced neosaxitoxin
      predominantly with saxitoxin as a minor component. The other two showed identical
      toxin profiles containing saxitoxin and gonyautoxins 2/3 isomers in the ratio of
      1:9. This is the first evidence of paralytic shellfish toxins in this species and
      also the occurrence of the toxin producing cyanobacterium in South American
      countries.

PMID- 10414863
TI  - Comparison of maitotoxin with thromboxane A2 in rabbit platelet activation.
AB  - Maitotoxin (MTX), a Ca2+ channel-activating marine toxin, caused shape change
      followed by aggregation in rabbit platelets, like U46619, a thromboxane A2
      analogue. Although both drugs failed to cause aggregation in the absence of
      external Ca2+, U46619, but not maitotoxin, elicited shape change in the absence
      of external Ca2+. The observations of platelets with a scanning electron
      microscope showed that both drugs caused contraction of platelets and extension
      of pseudopodia (shape change) followed by aggregation with a clot in the presence
      of Ca2+. It is noteworthy that long term exposure to MTX caused the lysis of
      platelets in the presence of Ca2+. While U46619 transiently increased the
      internal Ca2+ concentration ([Ca2+]i), maitotoxin slowly but irreversibly
      increased [Ca2+]i in an external Ca2(+)-dependent manner. MTX-induced
      phosphoinositide hydrolysis was totally dependent on the presence of external
      Ca2+, but U46619-induced phosphoinositide hydrolysis was still observed in the
      absence of external Ca2+. MTX-induced phosphoinositide hydrolysis was partly
      inhibited by SK&F96365, a voltage-independent Ca2+ channel antagonist, or by
      genistein, a tyrosine kinase inhibitor. MTX caused phosphorylation of tyrosine
      residues of several proteins, like U46619. Thus, MTX is similar to U46619 in
      functions of Ca2+ mobilization, phosphoinositide hydrolysis and tyrosine
      phosphorylation, but MTX-induced actions are strictly dependent on the presence
      of external Ca2+.

PMID- 10414864
TI  - Equinatoxins, pore-forming proteins from the sea anemone Actinia equina, belong
      to a multigene family.
AB  - The multigene family of equinatoxins, pore-forming proteins from sea anemone
      Actinia equina, has been studied at the protein and gene levels. We report the
      cDNA sequence of a new, sphingomyelin inhibited equinatoxin, EqtIV. The N
      terminal sequences of natural Eqt I and III were also determined, confirming two
      isoforms of EqtI, differing at position 13. The number of Eqt genes determined by
      Southern blot hybridization was found to be more than five, indicating that Eqts
      belong to a multigene family.

PMID- 10414865
TI  - Identification of bothrojaracin-like proteins in snake venoms from Bothrops
      species and Lachesis muta.
AB  - Bothrojaracin, a 27 kDa protein isolated from Bothrops jararaca venom, forms a
      non-covalent complex with thrombin, thus blocking its activity. We have
      previously identified a bothrojaracin-like protein in B. alternatus venom
      [Castro, H.C., Dutra, D.L.S., Oliveira-Carvalho, A.L., Zingali, R.B., 1998.
      Bothroalternin, an inhibitor of thrombin from the venom of Bothrops alternatus.
      Toxicon 36, 1903-1912]. In this report, we have examined snake venoms from six
      different Bothrops species (B. atrox, B. cotiara, B. jararacussu, B. moojeni and
      B. neuwiedi), from Lachesis muta and from Crotalus durissus terrificus for the
      presence of bothrojaracin-like proteins, which we define here as 27 kDa proteins
      that are immunologically related to bothrojaracin and that inhibit thrombin
      induced platelet aggregation. The immunological analysis of these venoms by
      different techniques indicated the existence of at least one protein recognized
      by anti-bothrojaracin serum in all venoms tested. Bothrojaracin-like proteins
      were purified from all crude venoms, except for C. d. terrificus, by a single
      step procedure using a thrombin affinity column (PPACK-thrombin-Sepharose).
      Retained material that inhibits thrombin-induced platelet aggregation was found
      in a different proportion in each species. Under non-reducing conditions, SDS
      PAGE of this material revealed several bands between 20-60 kDa; only those bands
      corresponding to 27 kDa were recognized by anti-bothrojaracin serum. ELISA
      confirmed the greater bothrojaracin immunoreactivity of proteins present in B.
      atrox and B. cotiara as compared to other Bothrops species. Smaller amounts of
      proteins related to bothrojaracin were found in L. muta venom and were absent
      from the venom of C. d. terrificus. Our results thus suggest that bothrojaracin
      like proteins are widely distributed among Bothrops genera.

PMID- 10414866
TI  - New methodology for the obtainment of antibothropic factors from the South
      American opossum (Didelphis marsupialis) and jararaca snake (Bothrops jararaca).
AB  - The antibothropic factor (ABF) from D. marsupialis was collected from perforated
      hollow plastic golf balls which were surgically implanted subcutaneously in
      anesthetized opossums, a technique originally described for the production of
      polyclonal antibodies. Two months after the implantation of the balls,
      approximately 15 ml of seromatous fluid from D. marsupialis (SFDm-50 mg total
      protein/ml) could be recovered monthly. Opossum serum as well as SFDm showed
      similar SDS-PAGE profiles and antihemorrhagic potencies against Bothrops jararaca
      snake venom (Bjv). The presence of ABF in SFDm was confirmed by immunoblotting,
      using rabbit polyclonal antibodies raised against ABF isolated from opossum
      serum. ABF isolated from SFDm or from serum by ion-exchange chromatography showed
      identical chromatographic and electrophoretic profiles. ABF fromboth sources
      displayed very similar antihemorrhagic and anticaseinolytic activities against
      Bjv. In the case of B. jararaca, polyethylene perforated tubes were inserted in
      the abdominal cavity and two months after implantation, approximately 4 ml of
      seromatous fluid from B. jararaca (SFBj-23 mg total protein/ml) were recovered.
      B.jararaca serum and SFBj showed the same native and SDS-PAGE band pattern. Both
      serum and SFBj inhibited Bjv hemorrhagic activity. We conclude that this new
      methodology is very suitable for continuously obtaining opossum ABF and SFBj, in
      large scale and in an easier way, avoiding animal suffering and eventual
      sacrifice.

PMID- 10414867
TI  - Effects of a centipede venom fraction on insect nervous system, a native Xenopus
      oocyte receptor and on an expressed Drosophila muscarinic receptor.
AB  - Centipede venoms are complex protein mixtures; very few is known about their
      pharmacological actions. Application of a Scolopendra sp. venom fraction (SC1) on
      the cockroach giant axon induced an increase in the leak current correlated with
      a decrease in the membrane resistance, suggesting the presence in SC1 of
      components opening non-specific pores in the axonal membrane. On a cockroach
      central cholinergic synapse, microinjection of SC1 induced a small transient
      depolarization of the postsynaptic membrane, followed by a slow stable
      depolarization and a drastic decrease in the evoked subthreshold excitatory
      postsynaptic potential amplitude. A pretreatment of the ganglion with atropine or
      scopolamine reduced the amplitude of the SC1-induced depolarizing wave,
      suggesting a possible cholinergic muscarinic target. On control Xenopus oocytes,
      SC1 induced an inward oscillatory Ca2(+)-dependent Cl- current mediated through
      the activation of native lysophosphatidic acid receptors (LPAr). Indeed,
      pretreatment of oocytes with 1 microM N-palmitoyl-tyrosine phosphoric acid, a
      selective competitive antagonist of LPAr, decreased responses to SC1 by 70%.
      Application of SC1 to oocytes expressing a cloned Drosophila muscarinic receptor
      (Dml) induced a biphasic response comprising: (1) a large fast Cl- current that
      was abolished by pretreatment with atropine and scopolamine and (2) a slow and
      small oscillating Cl- current corresponding to the response observed in control
      oocytes. These observations confirm the presence of muscarinic agonists in SCI
      and reveal their direct action on an insect muscarinic receptor subtype
      homologous to mammalian M1-M3 receptors.

PMID- 10414868
TI  - Bibliography of toxinology.

PMID- 10414869
TI  - Effects of interferons on proliferation and collagen synthesis of rat palatal
      wound fibroblasts.
AB  - The purpose was to select drugs that specifically reduce collagen synthesis by
      palatal granulation fibroblasts without affecting their proliferation.
      Granulation fibroblasts were obtained from 8-day-old palatal mucoperiosteal
      wounds and normal fibroblasts from palatal tissue of unwounded rats. Cultured
      cells were treated with interferon-alpha2b, interferon-beta and interferon-gamma
      (0, 100, 1000, and 10000 U/ml). Cell proliferation was measured by [3H]thymidine
      incorporation. Collagen synthesis and non-collagenous protein synthesis were
      determined from the incorporation of [3H]proline. None of the interferons
      significantly inhibited the proliferation of either type of fibroblasts.
      Interferon-alpha2b had no effect on the variables studied at the dosages used.
      Interferon-beta reduced collagen synthesis of granulation fibroblasts without
      affecting their non-collagenous protein synthesis or protein synthesis by normal
      fibroblasts. Interferon-gamma reduced collagen synthesis of both types of
      fibroblast and the non-collagenous protein synthesis of granulation fibroblasts.
      These data show that interferon-beta specifically reduces collagen synthesis by
      oral granulation fibroblasts without affecting normal palatal fibroblasts.

PMID- 10414870
TI  - Modulation by somatostatin of rat parotid salivary secretion stimulated by
      cholinergic, adrenergic and peptidergic agents.
AB  - Although it is well known that somatostatin (SRIF) modulates several digestive
      functions, there are only a few reports about its effect on the salivary glands.
      Here, the action of SRIF parotid secretion was studied, in vivo and in vitro, in
      male Wistar rats. In vivo SRIF infusion (35 microg/kg per hr) inhibited the
      parotid flow rate stimulated by methacholine, substance P and noradrenaline. The
      isoprenaline-stimulated flow rate was also decreased by SRIF, but only at highest
      dose of the secretory agent. Total protein and amylase secretion were studied.
      SRIF inhibited the total protein secretion stimulated by the above-mentioned
      agents, except that by isoprenaline. SRIF did not inhibit in vivo amylase
      secretion. In order to avoid flow-rate interference with total protein and
      amylase measurements, in vitro experiments were performed. SRIF (25 nM) strongly
      inhibited the total protein release stimulated by methacholine (5.1 microM),
      noradrenaline (19 microM), and substance P (10 microM). The inhibitory effect was
      not raised by the absence of calcium in the incubation medium. However, in vitro
      amylase release was not affected by SRIF. It was concluded that SRIF modulates
      rat parotid secretion stimulated by cholinergic, adrenergic and peptidergic
      agents, acting on any step in the calcium pathway.

PMID- 10414871
TI  - The role of passive muscle tensions in a three-dimensional dynamic model of the
      human jaw.
AB  - The role of passive muscle tensions in human jaw function are largely unknown. It
      seems reasonable to assume that passive muscle-tension properties are optimized
      for the multiple physiological tasks the jaw performs in vivo. However, the
      inaccessibility of the jaw muscles is a major obstacle to measuring their passive
      tensions, and understanding their effects. Computer modelling offers an
      alternative method for doing this. Here, a three-dimensional, dynamic model was
      used to predict active and passive jaw-muscle tensions during simulated postural
      rest, jaw opening and chewing. The model included a rigid mandible, two
      temporomandibular joints, multiple dental bite points, and an artificial food
      bolus located between the right first molars. It was driven by 18 Hill-type
      actuators representing nine pairs of jaw muscles. All anatomical forms, positions
      and properties used in the model were based on previously published, average
      values. Two states were stimulated, one in which all optimal lengths for the
      length-tension curves in the closing muscles were defined as their fibre
      component lengths when the incisor teeth were 2 mm apart (S2), and another in
      which the optimal lengths were set for a 12.0 mm interincisal separation (S12).
      At rest, the jaw attained 3.6 mm interincisal separation in S2, and 14.8 mm in
      S12. Activation of the inferior lateral pterygoid (ILP) and digastric (DG)
      muscles in various combinations always induced passive jaw-closer tensions, and
      compressive condylar loads. Maximum midline gape (from maximum bilateral co
      activation of DG and ILP) was 16.2 mm in S2, and 32.0 mm in S12. When both model
      states were driven with muscle patterns typical for human mastication,
      recognizable unilateral and vertical "chopping" chewing cycles were produced.
      Both states revealed condylar loading in the opening and closing phases of
      mastication. During unilateral chewing, compressive force on the working-side
      condyle exceeded that on the balancing side. In contrast, during the "chopping"
      cycle, loading on the balancing side was greater than that on the working side.
      In S2, chewing was limited in both vertical and lateral directions. These results
      suggest that the assumptions used in S12 more closely approximated human
      behaviour than those in S2. Despite its limitations, modelling appears to provide
      a useful conceptual framework for developing hypotheses regarding the role of
      muscle tensions during human jaw function.

PMID- 10414872
TI  - Effects of removing the negatively charged N-terminal region of the salivary
      acidic proline-rich proteins by human leucocyte elastase.
AB  - Human leucocyte elastase from inflammatory gingival crevicular exudates (gingival
      crevicular fluid) contacts saliva and saliva-coated tooth surfaces coronal to the
      gingival margin. Major components of saliva are the salivary acidic proline-rich
      proteins (PRPs). These acidic PRPs, via the numerous negatively charged amino
      acid residues located predominantly within their amino-terminal region, bind to
      the hydroxyapatite mineral of the tooth surface and become part of the salivary
      pellicle. Thus the potential for human leucocyte elastase-mediated removal of the
      negatively charged amino-terminal region of acidic PRP variants (PRP-1, PRP-2,
      PRP-3, PRP-4, PIF-s and PIF-f) was examined. It was determined that each of the
      acidic PRP variants was susceptible to fragmentation by human leucocyte elastase,
      in which the 16 amino-terminal segment was removed, leaving the respective
      residual fragment named as the transitional product (tr). The transitional
      products were termed PRP-1tr, PRP-2tr (PIF-str), PRP-3tr and PRP-4tr (PIF-ftr).
      Each of the residual transitional products of acidic PRP had an amino-terminal
      beginning with serine residue no. 17, determined by amino acid sequencing. When
      samples of human leucocyte elastase-treated acidic PRPs were placed on native
      polyacrylamide gels and electrophoresed, the respective transitional products
      moved more slowly than the parental acidic PRP molecules, reflecting the loss of
      a portion of the negatively charged section. In comparison to the acidic PRPs,
      the acidic PRP transitional products had markedly reduced binding to
      hydroxyapatite. The transitional products were resistant to further enzymatic
      digestion as a function of increased incubation time and appeared to exert an
      antihuman leucocyte elastase effect. However, when increased concentrations of
      human leucocyte elastase were incubated with the acidic PRP, a more extensive
      digestion occurred, leaving a residual peptide with an amino-terminal beginning
      with alanine residue no. 44. Interestingly, intact acidic PRPs if prebound to
      hydroxyapatite particles, resisted digestion by human leucocyte elastase. In
      summary, human leucocyte elastase was capable of digesting fluid-phase (unbound)
      acidic PRP in a manner that eliminated part of their negatively charged region,
      which subsequently reduced their binding to hydroxyapatite. High concentrations
      of human leucocyte elastase, arriving from inflammatory gingival crevicular
      exudates, may interrupt the normal binding of fluid-phase acidic PRPs to
      hydroxyapatite.

PMID- 10414873
TI  - The structure of the interstitial surfaces of the epithelial basement membranes
      of mouse oral mucosa, gingiva and tongue.
AB  - It is known that the gaps between epithelium and the underlying connective tissue
      usually occur between the epithelial cells and the basement membrane, resulting
      in exposure of the cellular surface of the lamina densa. After dithiothreitol
      separation, the epithelia of oral mucosa, gingiva, and tongue were mechanically
      peeled off from the underlying connective tissues. This treatment severed the
      connections between the basement membrane and the underlying connective tissue
      and the anchoring fibrils were pulled off from the collagen layer. In contrast,
      connections between the epithelial cells and basement membrane were preserved,
      resulting in exposure of the interstitial surfaces of the laminae densae.
      Scanning electron-microscopic observations of those interstitial surfaces were
      possible using the specimens prepared as above. The basement membranes of these
      three oral epithelia were morphologically the same not only by transmission but
      also by scanning electron microscopy. Scanning electron-microscopic observations
      revealed that their laminae densae were composed of fine fibrils and demonstrated
      three-dimensionally the projection of the anchoring fibrils from the laminae
      densae to the interstitial side. These findings coincide with those for epidermal
      basement membrane, which had already been observed with the same method.

PMID- 10414874
TI  - Serotonin in an antigen-induced arthritis of the rabbit temporomandibular joint.
AB  - The aim was to investigate the joint perfusate concentration of serotonin (5-HT)
      in antigen-induced monoarthritis of the rabbit temporomandibular joint (TMJ) and
      knee joint. Thirty adult male New Zealand White rabbits, of whom eight were first
      used as healthy controls, were divided into TMJ and knee arthritis groups.
      Unilateral arthritis was induced with ovalbumin intra-articularly and the
      contralateral joint was sham-induced. The joints were perfused with saline (flow
      rate, 0.05 ml/min; 10-min intervals during 50 min) 3 weeks later and the 5-HT
      concentration analysed. After the perfusion, the joints were evaluated
      histologically. The 5-HT concentration in the initial perfusate from the
      arthritic TMJ was higher than in both sham-induced and healthy control joints,
      and from the knee joint arthritis higher than in sham-induced joints. No
      histological difference in the arthritis was observed between the two groups.
      This study shows that the 5-HT concentration found immediately after puncture is
      increased in antigen-induced arthritis of the rabbit TMJ and knee joint.

PMID- 10414875
TI  - Cytokine-mediated stimulation of laminin expression and cell-growth arrest in a
      human submandibular gland duct-cell line (HSG).
AB  - Increased expression of laminin and various cytokines, including interferon-y
      (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) has been demonstrated in
      minor salivary glands from patients with Sjogren's syndrome. Previous reports
      state that exposure of a human salivary-gland cell line (HSG) to IFN-gamma
      results in cellular changes similar to those in vivo Sjogren's syndrome. To begin
      studies of the cause of increased laminin expression in salivary glands in
      Sjogren's syndrome and laminin's role in the pathological process, the effects of
      IFN-gamma on laminin expression and growth of HSG cells were examined here.
      Subconfluent cultures of HSG cells were treated or not with IFN-gamma (1000
      units/ml) for 1, 3 or 6 days. Immunoprecipitation showed that the expression of
      cell-associated laminin was significantly greater in IFN-gamma-treated cells at 3
      or 6 days than in untreated cells, while no significant differences in laminin
      counts precipitated from the media were evident among any of the IFN-gamma
      treated or untreated samples. Western blot analysis strongly suggested that this
      immunoprecipitated product is a dimer of the beta- and gamma-chains of laminin.
      Intracellular laminin was demonstrated immunocytochemically in a distinct,
      perinuclear pattern in both cytokine-treated and untreated cells. However, only
      faint staining for type IV collagen, and no staining for fibronectin were evident
      in untreated and cytokine-treated cells. An RNase protection assay showed only
      slight upregulation of the laminin beta-chain mRNA at 3 days, but no significant
      difference at 6 days of treatment. Taken together, these data suggest enhanced
      accumulation of a dimer of laminin beta- and gamma-chains in the cytoplasm of
      cytokine-treated HSG cells. However, mRNA for glyceraldehyde 3-phosphate
      dehydrogenase was significantly reduced at 6 days of treatment, suggestive of
      cytokine-mediated metabolic abnormalities. IFN-gamma treatment also resulted in
      significant reductions in cell numbers over time, in agreement with previous
      reports. Treatment of HSG cells for 3 days with IFN-gamma (1000 U/ml) and TNF
      alpha (20 U/ml) resulted in no significant changes in cell proliferation or
      laminin protein and/or mRNA species compared to cells treated with IFN-gamma
      alone. Karyotype analysis of HSG cells revealed human chromosomes with triploid
      chromosome numbers and rearrangements, characteristic of transformed cells. These
      data demonstrate that IFN-gamma increases the amount of intracellular laminin
      beta-gamma dimers while decreasing cell growth. Further studies are required to
      define an interaction between laminin expression and the growth and viability of
      HSG cells.

PMID- 10414876
TI  - Abnormal lipids and the acquired immunodeficiency syndrome: is there a problem
      and what should we do about it?
AB  - Recent research has shown abnormal lipids in acquired immunodeficiency syndrome
      (AIDS). In human immunodeficiency virus (HIV) infection hypocholesterolaemia,
      hypertriglyceridaemia and also low high density lipoprotein (HDL)-cholesterol
      have all been described. In addition, increased dense low density lipoprotein
      (LDL) particles and also lipoprotein (a) have been observed in some patients. The
      use of the protease inhibitors has been associated with diabetes mellitus and
      also features of insulin resistance. This article looks at these lipid
      abnormalities in detail and discusses possible therapeutic options that may be
      available, in order to address them.

PMID- 10414877
TI  - Changing cost of English HIV service provision 1996-1997. NPMS Steering Group.
      National Prospective Monitoring System.
AB  - The objectives of this study were to provide individual and population-based unit
      cost estimates of HIV treatment and care by stage of HIV infection for adults in
      England and estimate the financial impact of the use of combination
      antiretroviral therapy. Individual unit cost estimates were calculated, based on
      1997 activity data, and linked to the number of diagnosed HIV-infected
      individuals using statutory medical services by clinical stage of HIV infection
      in England during 1997 to obtain population-based cost estimates; these were
      compared with 1996 estimates. Most clinical guidelines now recommend the use of 3
      antiretroviral agents, but cost estimates for mono and dual therapy were included
      as baseline estimates. Baseline costs for treating AIDS patients with zidovudine
      (AZT) monotherapy were estimated at pound sterling 16,830 (95% CI 14,633-18,985)
      per patient-year which was substantially lower than the 1996 estimate; costs for
      asymptomatic individuals and people with symptomatic non-AIDS were pound sterling
      4450 (95% CI 3521-5612) and pound sterling 7289 (95% CI 6169-8386) per respective
      patient-year which did not differ substantially from 1996. The total annual
      population cost estimate for HIV service provision amounted to pound sterling 128
      million (95% CI pound sterling 109m to pound sterling 147m), if all patients with
      HIV disease were treated with AZT monotherapy only. For all eligible patients to
      be treated with 2 nucleoside reverse transcriptase inhibitors (NRTI) (AZT and
      didanosine (ddI) or zalcitabine (ddC)), cost estimates amounted to pound sterling
      161m (95% CI pound sterling 141m to pound sterling 181m), while for triple
      therapy, annual estimated expenditure amounted to pound sterling 185m (95% CI
      pound sterling 165m to pound sterling 206m) when a non-nucleoside reverse
      transcriptase inhibitor (NNRTI) (nevirapine) was included or pound sterling 205m
      (95% CI pound sterling 186m to pound sterling 235m) when a protease inhibitor was
      included. Compared with 1996 population-based cost estimates, the estimates for
      monotherapy decreased by 14%, by 11% for dual therapy, by 10% for triple therapy
      which included a NNRTI and by 9% if a protease inhibitor was used as part of a
      triple therapy regimen. Similarly, compared with 1996 estimates, the proportion
      of total costs attributable to treating asymptomatic individuals increased by 5%
      and 2-3% for people with symptomatic non-AIDS, while the proportion attributable
      for treating people with AIDS decreased by 8-9%.

PMID- 10414878
TI  - Short-term follow up of cervical squamous intraepithelial lesions associated with
      HIV and human papillomavirus infections in Africa.
AB  - A prospective study in gynaecology clinics was conducted in Abidjan, Cote
      d'Ivoire, to assess the short-term evolution of squamous intraepithelial lesions
      (SILs). Of 94 women with a cytological diagnosis of SIL, 38 were infected with
      HIV. The average follow-up period after the initial smear was 5 months. Detection
      of human papillomavirus (HPV) by polymerase chain reaction (PCR) was performed at
      both the time of enrolment and final follow-up smear. There were 39 cases of
      persistent SILs. HIV-positive women had a higher percentage of persistent SIL
      (76%) than HIV-negative women (18%, relative risk (RR)=4.3, 95% confidence
      interval (CI) = 2.4, 7.7). SILs were more frequent among women infected with HPV
      at the time of enrolment or with persistent HPV infection, but these associations
      disappeared after adjusting for HIV serostatus. Spontaneous regression of SILs
      commonly occurs in HIV-negative African women. HIV-infected women with cervical
      dyskaryosis require gynaecology follow-up.

PMID- 10414879
TI  - A randomized trial of interferon-alpha2a and zidovudine versus bleomycin and
      zidovudine for AIDS-related Kaposi's sarcoma. Swiss HIV Cohort Study.
AB  - The efficacy and toxicity of interferon-alpha2a (9MU/d) and bleomycin (15 mg
      every 2 weeks), each combined with zidovudine (2x250 mg/d), was compared in a
      randomized study in 26 men with progressing AIDS-related Kaposi's sarcoma (KS).
      The median CD4 count was 113/microl. Complete or partial response was achieved in
      one (8%) of 12 evaluable patients on interferon and in 2 (20%) of 10 patients on
      bleomycin (P = 0.43) during 4.7 and 5.3 months of treatment, respectively. The
      tolerability was comparable. During extended follow up, survival time was 24 and
      13 months in the interferon and bleomycin arm, respectively. In a multivariate
      Cox regression analysis, CD4 lymphocytes <200/microl (relative risk 3.74; 95% CI:
      1.30-10.8) and randomization to interferon (relative risk 0.37; 95% CI: 0.15
      0.90) were significantly predictive of mortality. New AIDS-related events
      occurred more frequently in patients who had received bleomycin. The antiviral
      activity of interferon-alpha or the chemotherapy-mediated increase in the risk
      for opportunistic infections may explain these differences.

PMID- 10414880
TI  - Patient-led partner referral enhances sexually transmitted disease service
      delivery in two towns in the Central African Republic.
AB  - In Bambari and Bria, 2 towns in the Central African Republic (CAR), we analysed a
      patient-led partner referral programme within enhanced sexually transmitted
      disease (STD) services. New (index) patients received syndromic management,
      counselling about notifying and treating contacts, and vouchers for distribution.
      From October 1993 to February 1996, 5232 and 4320 patient visits, of which 1814
      (35%) and 4320 (30%) were contact referral visits, were logged in Bambari and
      Bria, respectively. Vouchers were distributed for at least 90% of contacts. Index
      and contact patients had similar age and sex distributions. In both towns, having
      a spouse (Bambari: odds ratio [OR] 1.5, 95% confidence interval [CI] 1.4-1.7;
      Bria: OR 1.9, 95% CI 1.5-2.3) was a factor associated with successful referral of
      a partner. Successful referral was accomplished by both male and female patients.
      Appropriate counselling techniques and vouchers facilitated partner referral.
      Further research on how to reach casual partners would enhance STD control
      efforts using patient-led partner referral.

PMID- 10414881
TI  - Quality of life in patients with human immunodeficiency virus infection: impact
      of social support, coping style and hopelessness.
AB  - We aimed to determine whether the quality of life (QOL) in the patients infected
      with human immunodeficiency virus (HIV) infection was influenced by satisfaction
      with social support, coping style and hopelessness. One hundred and thirty-eight
      HIV-infected patients were prospectively studied in this multicentre,
      longitudinal study. The QOL was assessed by Medical Outcome Study Health Survey
      SF-36, social support by Sarason Social Support Questionnaire, hopelessness by
      Beck Hopelessness Scale, and coping by Billing and Moos Inventory of coping with
      illness. The QOL did not correlate with age, sex, race, HIV risk factor,
      education or marital status. Employment (P = 0.0001), higher income (P = 0.03),
      satisfaction with social support (P = 0.04), regardless of the source of that
      support, and problem-focused coping (P = 0.03) were associated with a
      significantly better QOL, while, emotion-focused coping (r = -0.19, P = 0.04),
      avoidant coping (r = 0.40, P = 0.0001), hopelessness (r = -0.64, P = 0.0001) and
      AIDS (P = 0.09) were predictors of poorer QOL. Physical functioning correlated
      positively with employment (P = 0.0001), and inversely with AIDS (P = 0.0002),
      hopelessness (P = 0.03), avoidant coping (P = 0.03), and age (P = 0.10). At 6
      months follow up, QOL score had changed in 20% of the patients; older age (P =
      0.01), and lesser satisfaction with social support (P = 0.15) were associated
      with a decline in QOL, while adherence with antiretroviral therapy (P = 0.006)
      was associated with an increase in QOL score. Seven of 138 patients died during
      follow up; these patients had significantly lower QOL at baseline than all other
      patients (P = 0.003). Interventions to alleviate hopelessness, maladaptive
      coping, and enhancement of satisfaction with social support may improve overall
      QOL in HIV-infected patients. Older patients with HIV were less satisfied with
      their social support, were more likely to utilize unhealthy coping styles, and
      experienced a greater decline in QOL over time.

PMID- 10414882
TI  - STD-related knowledge, beliefs and attitudes of Xhosa-speaking patients attending
      STD primary health-care clinics in South Africa.
AB  - The primary aim of this study was to describe patients at sexually transmitted
      disease (STD) clinics in Cape Town, South Africa, in terms of gender, education
      and age differences relative to their STD knowledge and beliefs, their condom
      use, as well as their attitudes towards condom use and their condom-use
      behaviour. The information was collected with a view to developing a health
      education intervention. Structured interviews were conducted with 2978 randomly
      sampled Xhosa-speaking STD clinic attenders about their knowledge, beliefs and
      practices regarding STDs and related behaviours. More males (75%) than females
      (25%) presented for STD treatment. The majority of patients (92%) were younger
      than 35 years. Female patients were found to be more aware than male patients of
      the sexual nature of STD transmission, valued personal autonomy in sexual
      behaviour and expressed a greater need to use condoms. Males perceived STD
      symptoms to be more serious, had more misconceptions about the cause of STDs and
      also more negative beliefs and attitudes towards condom use. Only 34.9% of the
      patients reported using condoms in the last 6 months while only 24.5% reported
      regular use. Those who reported condom use were more knowledgeable about the
      sexual transmission of STDs and the effects of STDs on the neonate. They also had
      fewer misconceptions about the causes of STDs and perceived STD symptoms to be
      more serious, attached greater value to personal autonomy in sexual behaviour and
      condom use and had more positive outcome expectancies of refusing sex than those
      who never used condoms. The data suggest that targeted interventions directed at
      males will have to address their inadequate knowledge regarding STDs in terms of
      transmission, causes, consequences, prevention and cure. Their negative beliefs
      and attitudes towards condoms will need special attention, especially in view of
      their multiple partner behaviour. Interventions directed at females will need to
      improve their knowledge regarding STD consequences, causes, recognition of
      symptoms as well as improve their knowledge of aspects of prevention and cure.
      All interventions must facilitate personal autonomy in decision making about
      sexual behaviour and condom use for both men and women, through skills
      development programmes that promote self-efficacy in the individual and instil a
      culture of mutual respect of such in the community.

PMID- 10414883
TI  - Evaluation of a rapid test for the detection of antibodies to human
      immunodeficiency virus type 1 and 2.
AB  - Hema-Strip HIV-1/2 is a one-step rapid test for the detection of anti-HIV-1/2
      antibodies in whole blood. The test requires no expensive equipment and the
      results are available within 10-15 min. Using 72 known HIV-1 positive samples and
      780 high-risk prisoners, the sensitivity and specificity of Hema-Strip HIV-1/2
      was found to be comparable to microparticle enzyme immunoassay (MEIA). The data
      also indicated that Hema-Strip HIV-1/2 is an effective alternate testing system
      to conventional ELISA where the use of ELISA is not suitable and the result of
      the HIV testing is needed urgently.

PMID- 10414884
TI  - Declining syphilis prevalence in pregnant women in Nairobi since 1995: another
      success story in the STD field?
AB  - Untreated maternal syphilis during pregnancy will cause adverse pregnancy
      outcomes in more than 60% of the infected women. In Nairobi, Kenya, the
      prevalence of syphilis in pregnant women of 2.9% in 1989, showed a rise to 6.5%
      in 1993, parallel to an increase of HIV-1 prevalence rates. Since the early
      1990s, decentralized STD/HIV prevention and control programmes, including a
      specific syphilis control programme, were developed in the public health
      facilities of Nairobi. Since 1992 the prevalence of syphilis in pregnant women
      has been monitored. This paper reports the findings of 81,311 pregnant women
      between 1994 and 1997. A total of 4244 women (5.3%) tested positive with
      prevalence rates of 7.2% (95% CI: 6.7-7.7) in 1994, 7.3% (95% CI: 6.9-7.7) in
      1995, 4.5% (95% CI: 4.3-4.8) in 1996 and 3.8% (95% CI: 3.6-4.0) in 1997. In
      conclusion, a marked decline in syphilis seroprevalence in pregnant women in
      Nairobi was observed since 1995-96 (P<0.0001, Chi-square test for trend) in
      contrast to upward trends reported between 1990 and 1994-95 in the same
      population.

PMID- 10414885
TI  - Low yield of chest radiography in screening for active pulmonary tuberculosis in
      HIV-infected patients in Hong Kong.
AB  - This study assessed the usefulness of routine chest radiography for detecting
      active pulmonary tuberculosis in persons infected with human immunodeficiency
      virus (HIV) without suggestive symptoms in Hong Kong. Tuberculosis is common in
      this locality and tuberculosis/HIV co-infection has been a frequent and
      significant problem. Records of patients attending the largest HIV clinic were
      reviewed. Three hundred and eleven routine chest radiographs were performed among
      191 HIV-infected patients with a total follow-up period of 792 person years. Of
      the 22 routine chest radiographs that had abnormalities in the lungs or hilar
      region, only one had led to the diagnosis of pulmonary tuberculosis. No patient
      with a normal chest radiograph was diagnosed to have tuberculosis within the
      following 2 months. The low yield (0.32%) suggests that routine chest radiography
      is not useful in screening for active pulmonary tuberculosis in asymptomatic HIV
      infected patients even in a locality where the tuberculosis rate is high.

PMID- 10414886
TI  - Diagnosis of disseminated Mycobacterium scrofulaceum infection in an AIDS patient
      using a continuously monitored culture system.

PMID- 10414887
TI  - Kaposi's sarcoma regression following treatment with a triple antiretroviral
      regimen containing nevirapine.

PMID- 10414889
TI  - Improving ultrasonographic diagnosis of prostate cancer with neural networks.
AB  - To improve ultrasonographic diagnosis of prostate cancer, the authors evaluated
      the performance of an optimized backpropagation artificial neural network (ANN)
      in predicting an outcome (cancer-not cancer) from recorded information on
      patients admitted for transrectal ultrasonography (TRUS) performed in our Center.
      A total of 442 cases with complete information were selected for the study. After
      preselecting 17 variables (age, PSA, previous clinical diagnosis, and 14
      ultrasonographic ones) through univariate analysis, a randomly selected subset of
      data (50%) was used to train ANNs, and the other subset (50%) was used to test
      the different models. The ANN achieved up to 81.82% of positive predictive value
      and up to 96.95% of negative predictive value vs. 67.18% and 90.97%,
      respectively, when compared with those obtained with logistic regression. Results
      and possible future practical applications are further discussed.

PMID- 10414888
TI  - Three months use of third-generation oral contraceptives does not affect artery
      wall properties.
AB  - In several studies, artery wall properties have been shown to differ between men
      and women. It has been hypothesized that these differences may result from
      hormonal influences but, in a previous study, we were unable to detect any
      influence of the menstrual cycle on artery wall properties. Therefore, we
      investigated the differences in artery wall properties, if any, between the
      menstrual cycle and the use of a third-generation oral contraceptive for 3
      months. We investigated the right common carotid (CCA) and femoral (CFA) arteries
      of normotensive young (18-25-y-old) women volunteers (n = 14). The arterial cross
      sectional distensibility and compliance coefficients were determined by means of
      a specially designed ultrasonic wall-tracking device and automatic brachial
      artery cuff blood-pressure measurements. The menstrual cycles and the cycles
      during oral contraceptive use (30 microg ethinylestradiol and 75 microg
      gestodene) were monitored by ultrasonographic evaluation and the assessment of
      plasma levels of 17beta-oestradiol and progesterone. The distensibility and cross
      sectional compliance coefficients of both the CCA and CFA did not differ
      significantly between the menstrual cycle and the use of oral contraceptives,
      despite different ovarian hormone levels. Brachial arterial blood pressure was
      also not affected. We conclude that 3 months use of a third-generation oral
      contraceptive does not influence the wall properties of peripheral arteries and
      cannot explain the observed difference between genders. The absence of a rise in
      blood pressure and the low androgenic profile of this specific oral contraceptive
      may have contributed to our findings.

PMID- 10414890
TI  - Artificial neural network analysis of common femoral artery Doppler shift
      signals: classification of proximal disease.
AB  - The aim of this study was to apply artificial neural networks (ANNs) to the
      problem of the diagnosis of aorto-iliac arterial disease on the basis of the
      profile of the common femoral artery (CFA) Doppler flow velocity waveform. The
      maximum frequency envelopes obtained from the CFA of 180 subjects were used to
      create sets of training and testing vectors for a back-propagation ANN. The ANN
      had three outputs: one representing the absence of significant aorto-iliac
      disease (i.e., < 50% diameter stenosis), one representing the presence of a
      hemodynamically significant aorto-iliac stenosis (i.e., 50-99% stenosis), and the
      other representing the presence of an aorto-iliac occlusion. After training, the
      ANN correctly classified 80% of "no significant disease" testing data, 45% of
      "significant stenosis" data and 85% of "occlusion" data. This work, thus,
      demonstrated the ability of an ANN to identify the severity of aorto-iliac
      disease from the CFA waveform. Although the ANN outperformed standard univariate
      methods and visual classification of the data, it would appear that further work
      is needed to increase the accuracy of the ANN to a clinically acceptable
      standard.

PMID- 10414891
TI  - Dynamic three-dimensional freehand echocardiography using raw digital ultrasound
      data.
AB  - In this paper, we present a new method for simple acquisition of dynamic three
      dimensional (3-D) ultrasound data. We used a magnetic position sensor device
      attached to the ultrasound probe for spatial location of the probe, which was
      slowly tilted in the transthoracic scanning position. The 3-D data were recorded
      in 10-20 s, and the analysis was performed on an external PC within 2 min after
      transferring the raw digital ultrasound data directly from the scanner. The
      spatial and temporal resolutions of the reconstruction were evaluated, and were
      superior to video-based 3-D systems. Examples of volume reconstructions with
      better than 7 ms temporal resolution are given. The raw data with Doppler
      measurements were used to reconstruct both blood and tissue velocity volumes. The
      velocity estimates were available for optimal visualization and for quantitative
      analysis. The freehand data reconstruction accuracy was tested by volume
      estimation of balloon phantoms, giving high correlation with true volumes.
      Results show in vivo 3-D reconstruction and visualization of mitral and aortic
      valve morphology and blood flow, and myocardial tissue velocity. We conclude that
      it was possible to construct multimodality 3-D data in a limited region of the
      human heart within one respiration cycle, with reconstruction errors smaller than
      the resolution of the original ultrasound beam, and with a temporal resolution of
      up to 150 frames per second.

PMID- 10414892
TI  - Bilateral cerebral emboli monitoring during extracorporeal circulation.
AB  - Microembolism generated during extracorporeal circulation is thought to be
      responsible for stroke and neuropsychological deficits. Before one can
      investigate the pathogenetic role in more detail, reproducible and reliable
      quantitative methods need to be developed. In several previous studies,
      microemboli detection was performed unilaterally. We questioned if this reflects
      the bihemispheric embolic load. In 42 patients undergoing coronary artery bypass
      grafting, bilateral embolus detection was performed during extracorporeal
      circulation. The side-to-side correlation of microembolus counts was strong
      (0.91), but there was a significant difference in number (p < 0.01) comparing
      left and right emboli. The side of higher embolus counts cannot be predicted in
      the individual because either side may show higher counts. Doubling the
      unilateral count may deviate from the bilateral count by as much as 51% in the
      individual patient. The total embolic load to the brain during extracorporeal
      circulation cannot be precisely predicted from unilateral transcranial insonation
      alone.

PMID- 10414893
TI  - Dependence of "apparent" magnitude on the time delay of cyclic variation of
      myocardial backscatter.
AB  - The goal of this study was to determine if the "apparent" magnitude of the cyclic
      variation, defined as the difference between the values of integrated backscatter
      at end-diastole and end-systole, was dependent on the corresponding time delay.
      We measured the cyclic variation in four myocardial segments of the parasternal
      short-axis view in 23 healthy subjects. The "apparent" magnitude, actual
      magnitude, and time delay were compared for each segment. Measured time delays
      were: 2.22+/-0.71 (lateral wall); 1.65+/-0.66 (inferior septum); and
      approximately 1.0 for the anterior septum and posterior wall. Segments exhibiting
      large time delays (> 1.0) resulted in a reversal in sign of the "apparent"
      magnitude of cyclic variation in one instance, and underestimated the true
      magnitude in both cases. Thus, estimates of the "apparent" magnitude of the
      cyclic variation are dependent on the associated time delay, whereas a properly
      defined magnitude is not.

PMID- 10414894
TI  - Persistent opacification of the left ventricle and myocardium with a new echo
      contrast agent.
AB  - Echo contrast agents with long survival times open up new fields of application
      in the investigation of tissue perfusion and cardiovascular function. The purpose
      of this study was to characterize the time-course of the opacification of the
      heart cavities and myocardium with a new long-lasting second-generation,
      phospholipid-based echo contrast agent containing perfluoropentane (BY963-C5F12),
      and to compare its contrast potency with that of air-filled phospholipid
      monolayer (BY963-air). Doses of 0.03 mL/kg, 0.08 mL/kg and 0.16 mL/kg of BY963
      air and BY963-C5F12 were administered intravenously to six conscious dogs
      weighing 25-36 kg. A transthoracic echocardiography was performed to evaluate
      peak intensity and area under the curve (AUC) from regions-of-interest placed in
      the right ventricle, left ventricle and left ventricular (LV) myocardium using
      acoustic densitometry. All injections were well tolerated, without wall-motion
      abnormalities or ECG changes. The LV cavity and myocardium were uniformly and
      well opacified for both echo contrast agents. However, at all administered doses,
      the contrast efficacy and duration were much more pronounced using BY963-C5F12
      than with BY963-air. For the myocardium, the average peak intensity increased
      from 11.9+/-2.8 to 15.0+/-2.7 (not significant) following injection of BY963-air
      and from 12.8+/-3.2 to 18.7+/-2.8 (p < 0.01) following IV administration of BY963
      C5F12; the latter corresponding to an increase in myocardial opacification of
      46%. In conclusion, these results show the high myocardial opacification of BY963
      C5F12 as compared to BY963-air. The simple incorporation of a perfluorocarbon gas
      into the phopholipid monolayer BY963 instead of air alters the acoustic
      properties of this contrast agent, resulting in qualitatively different
      application potentials for tissue opacification.

PMID- 10414896
TI  - Assessment of coronary stenoses by Doppler wires: a validation study using in
      vitro modeling and computer simulations.
AB  - The present study evaluates the use of intracoronary velocity measurements by
      Doppler guidewires for assessing coronary obstructions. In vitro experiments were
      performed in a flow model using acrylic phantoms of coronary stenoses with
      different configurations (stenosis area: 56%, 75% and 89%; stenosis length: 1 and
      5 mm; stenosis border: tapering or abrupt). Nonpulsatile laminar flow conditions
      of a test fluid were established at flow rates ranging from 0.5 to 2.0 mL/s to
      simulate baseline flow and flow after vasodilation. Peak Doppler velocity was
      measured proximal to, within and distal to the model stenoses. Computer
      simulations were employed to calculate radial flow profiles with and without a
      Doppler wire aligned with the vessel center. In 84 in vitro flow experiments,
      peak Doppler velocity correlated well with the average flow velocity as
      calculated from the actual flow rate and the vessel's cross-sectional area
      proximal to (r = 0.98, SEE = 1.4, p < 0.001) and within (r = 0.97, SEE = 16.4, p
      < 0.001) the stenosis. However, the ratio of calculated average velocity to
      Doppler-measured peak velocity was significantly different from 0.5, the expected
      value for a parabolic flow profile (0.76+/-0.08, 0.81+/-0.14; p < 0.001).
      Acceptable accuracy was found for the Doppler estimation of stenosis severity
      using the continuity equation (error: 0.9+/-1.2% and -4.6+/-3.5% for stenosis
      with a length of 5 mm and 1 mm, respectively). Doppler velocity reserve
      significantly underestimated the true flow reserve for the 56% and 75% stenoses
      (p < 0.01). Computer simulations demonstrated significant alterations of flow
      profiles by the wire, which explained the observed underestimation of the true
      flow reserve by the Doppler velocity reserve. Thus, Doppler guidewire
      measurements of intracoronary flow velocities are useful to assess the severity
      of coronary stenoses. However, the in vitro results and computer simulations
      indicate that guidewires alter the flow profile, so that Doppler velocity reserve
      may underestimate the true flow reserve.

PMID- 10414895
TI  - Color Doppler velocity accuracy proximal to regurgitant orifices: influence of
      orifice aspect ratio.
AB  - Many noninvasive methodologies used for the accurate evaluation of valvular
      regurgitation require precise velocity measurements from ultrasound instruments.
      Previous studies have indicated that velocity measurements from color Doppler
      (CD) instruments are susceptible to errors due to the interaction of the
      ultrasound beam and the proximal orifice flow field. This study examined the
      influence of high aspect ratio (AR) orifices on the CD velocity error. Center
      line velocity error distributions for orifices ranging from 7.07 to 78.5 mm2,
      varying in shape from circular to an AR = 8 ellipse, were evaluated using a
      numerical model of the ultrasound beam and the simulated regurgitant flow field.
      An in vitro study was also performed and confirmed the findings of the numerical
      model. The study showed that increasing AR does not significantly change the
      error characteristics. The study confirmed that orifice size is the dominant
      factor in the error distribution, and that corrections speculated for circular
      orifices can be extended to elliptical orifices without significant errors.

PMID- 10414897
TI  - Effect of catheter placement on 3-D velocity profiles in curved tubes resembling
      the human coronary system.
AB  - Novel measurement techniques based on intravenous ultrasound (IVUS) technology
      ('IVUS-Flowmetry') require the location of a catheter inside the coronary bed.
      The present study quantifies disturbances in the 3-D velocity profile induced by
      catheter placement inside a tube, applying computational fluid dynamics. Two
      curved, circular meshes (radius K = 0.025 m and K = 0.035 m) with and without a
      catheter inside the lumen were applied. The catheter was located at the inner
      curve, the outer curve and at the top position. Boundary conditions were: no slip
      on the wall, zero stress at the outlet, uniform inflow with entrance velocities
      of 0.1, 0.2 and 0.4 m/s. Curvature-associated centrifugal forces shifted the
      maximal velocity to the outer curve and introduced two symmetrical vortices.
      Additional catheter placement redistributed the 3-D axial velocity field away
      from the catheter, which was accompanied by the appearance of multiple low
      strength vortices. In addition, peak axial velocity increased, peak secondary
      velocities decreased, axial pressure drop increased and shear stress increased.
      Flow calculations simulated to resemble IVUS-based flowmetry changed by only 1%
      after considering secondary velocity. In conclusion, placement of a catheter
      inside a curved tube resembling the human coronary system changes the velocity
      field and reduces secondary patterns. The present study supports the usefulness
      of catheter-based flowmetry during resting flow conditions. During hyperemic flow
      conditions, flow measurements might be accompanied by large axial pressure drops
      because the catheter, itself, might act as a significant stenosis.

PMID- 10414898
TI  - Ultrasonic propagation in cancellous bone: a new stratified model.
AB  - The theoretical modeling of ultrasonic propagation in cancellous bone is
      pertinent to improving the ultrasonic diagnosis of osteoporosis. First, this
      paper reviews applications of Biot's theory to this problem. Next, a new approach
      is presented, based on an idealization of cancellous bone as a periodic array of
      bone-marrow layers. Schoenberg's theory is applied to this model to predict wave
      properties. Bovine bone samples were tested in vitro using pulses centered at 1
      MHz over various angles relative to the orientated cancellous structure. Two
      longitudinal modes (fast and slow waves) were observed for propagation parallel
      to the structure, but only one was observed for propagation normal to the
      structure. Angular-dependence of velocities was examined, and the fast wave was
      found to be strongly anisotropic. These results gave qualitative agreement with
      predictions of Schoenberg's theory. Although this new model is a simplification
      of the cancellous architecture, it has potential for future research.

PMID- 10414899
TI  - Computational methods for ultrasonic bone assessment.
AB  - Ultrasound has been proposed as a means to noninvasively assess bone and,
      particularly, bone strength and fracture risk. Although there has been some
      success in this application, there is still much that is unknown regarding the
      propagation of ultrasound through bone. Because strength and fracture risk are a
      function of both bone mineral density and architectural structure, this study was
      carried out to examine how architecture and density interact in ultrasound
      propagation. Due to the difficulties inherent in obtaining fresh bone specimens
      and associated architectural and density features, simulation methods were used
      to explore the interactions of ultrasound with bone. A sample of calcaneal
      trabecular bone was scanned with micro-CT and subjected to morphological image
      processing (erosions and dilations) operations to obtain a total of 15 three
      dimensional (3-D) data sets. Fifteen two-dimensional (2-D) slices obtained from
      the 3-D data sets were then analyzed to evaluate their respective architectures
      and densities. The architecture was characterized through the fabric feature, and
      the density was represented in terms of the bone volume fraction. Computer
      simulations of ultrasonic propagation through each of the 15 2-D bone slices were
      carried out, and the ultrasonic velocity and mean frequency of the received
      waveforms were evaluated. Results demonstrate that ultrasound propagation is
      affected by both density and architecture, although there was not a simple linear
      correlation between the relative degree of structural anisotropy with the
      ultrasound measurements. This study elucidates further aspects of propagation of
      ultrasound through bone, and demonstrates as well as the power of computational
      methods for ultrasound research in general and tissue and bone characterization
      in particular.

PMID- 10414900
TI  - Nonlinearity parameter for tissue-mimicking materials.
AB  - A finite amplitude insert-substitution method has been used to determine the
      ultrasonic nonlinearity parameter B/A of nine versions of water-based,
      macroscopically uniform ultrasonically tissue-mimicking (TM) nonfat and fat
      materials. In this method, the amplitude of the second harmonic following
      transmission through degassed distilled water with known B/A (B/A = 5.2) and the
      amplitude of the second harmonic following transmission through the unknown
      sample are measured. The ratio of these amplitudes allows calculation of the B/A
      of the sample. Measured B/A values of the nonfat materials range from 5.6 to 6.6.
      These values compare favorably with published values for nonfat soft tissues. In
      contrast, the measured B/A values for two tissue-mimicking fat materials are 9.8
      and 11.1; these two values represent the low and high end of B/A for most fresh
      fatty tissues. For comparison, B/A was measured for two commonly available
      uniform materials, corn oil and ethylene glycol, and the results are in good
      agreement with published values.

PMID- 10414901
TI  - Spectrogram enhancement algorithm: a soft thresholding-based approach.
AB  - Enhancing the spectrogram by denoising the Doppler ultrasound signal is a
      preliminary step, and important for further processing. Because the spectrogram
      may be based on the short-time fast Fourier transform (FFT) of the Doppler
      ultrasound signal, whose power spectrum density is time-varying, traditional
      denoising algorithms that simply optimize the mean-squared error are not
      appropriate, and they may exhibit considerable undesirable, noise-induced
      frequency components. A soft thresholding-based denoising algorithm is put
      forward in this paper, that achieves almost the minimax mean square error (MSE)
      over a wide range of function classes having norms measuring smoothness (i.e., it
      meets both the requirement of smoothness and MSE). Due to the importance of noise
      level estimation while applying this method, several robust L-estimators are
      compared and the median absolute deviation (MAD) method is chosen to estimate the
      noise level. The simulation study shows better performance of the later algorithm
      under various quantification measures, compared to the FFT thresholding and the
      hard thresholding wavelet method, and the results of clinical data also confirm
      it.

PMID- 10414902
TI  - Histological study of normal and tumor-bearing liver treated with focused
      ultrasound.
AB  - The purpose of this investigation was to study the tissue damage (including blood
      vessels) on both normal and tumor-bearing experimental livers and the course of
      liver repair after focused ultrasound (FUS) treatment using histological
      evaluation. A series of experiments were carried out in vivo. Tissue was treated
      using arrays of ultrasound exposures with a frequency of 1.7 MHz, in situ
      spatially averaged focal intensity (I(SAL) in situ) of 212-266 W/cm2
      (corresponding to in situ spatial peak intensity of 382-479 W/cm2), 5-10 s
      exposure duration and 1.5-3.0 mm exposure separation. Tissue specimens were
      examined using both light and electron microscopy. The damage to the blood vessel
      walls was studied. The results showed the existence of indirect tissue damage in
      both normal and tumor tissue that is outside of the treatment volume, due to
      disruption of the major blood vessels supplying the adjacent area. Evidence for
      liver regeneration was found 2 months after FUS treatment.

PMID- 10414903
TI  - Frequency filtering improves ultrasonic embolic signal detection.
AB  - Problems in detection of Doppler cerebral embolic signals primarily occur for
      embolic signals of low relative intensity. A characteristic feature of embolic
      signals is that the intensity increase is maximal over a narrow frequency band.
      Therefore, frequency filtering of the data might improve embolic signal relative
      intensity and detectability. We implemented an off-line finite impulse response
      filter in software running on a commercially available transcranial Doppler
      system, using the time-domain audio data as input. The range of the filter was
      chosen by placing a box around the embolic signal on the spectral display. One
      hundred consecutive embolic signals from patients with carotid stenosis were
      analyzed; all had been recorded by a bigate system and the signal was analyzed in
      both proximal and distal channels. There was a highly significant increase in
      embolic signal relative intensity following frequency filtering; mean (SD)
      proximal channel prefiltering 12.75 (4.83) dB, postfiltering 16.36 (4.93) dB;
      distal channel prefiltering 13.42 (4.98) dB, postfiltering 16.60 (5.11) dB, for
      both p < 0.001. Despite all embolic signals being audible and visible in at least
      one channel on the frequency spectral display, in 17 cases, the amplitude
      increase associated with the embolic signal could not be clearly seen in time
      domain data of one or both channels prior to filtering. Following frequency
      filtering, this was reduced to 5. Incorporation of such a frequency-filtering
      approach to an online system is likely to improve the sensitivity of online
      detection for embolic signals of low relative intensity.

PMID- 10414904
TI  - SieScape images.

PMID- 10414905
TI  - Immune ablation and stem cell transplantation for severe Evans syndrome and
      refractory thrombocytopenic purpura.

PMID- 10414906
TI  - Addition of high-dose Ara-C to the BMT conditioning regimen reduces leukemia
      relapse without an increase in toxicity.
AB  - The optimal conditioning regimen for allogeneic BMT for hematological
      malignancies is still to be determined. We used a conditioning regimen including
      high-dose Ara-C (HDAC)/CY/TBI for patients at high risk for leukemic relapse
      (regimen A, Ara-C 3 g/m2 every 12 h for six doses followed by CY 45 mg/kg for 2
      days and TBI 13.2 Gy in eight fractions) and a standard CY/TBI conditioning
      regimen for patients at low risk (regimen B, CY 60 mg/kg for 2 days and TBI 13.2
      Gy in eight fractions). We analyzed 55 patients treated with regimen A (group A)
      and 36 patients with regimen B (group B). Relapse rates (10.9% in group A, 2.9%
      in group B, P = 0.23), 5-year overall (53.2% in group A and 60.8% in group B, P =
      0.26) and disease-free (47.7% in group A and 60.8% in group B, P = 0.11) survival
      rates were not significantly different between these groups, although group A
      consisted of high-risk patients. Regimen-related toxicities were not
      significantly different between the two groups. This result suggests that adding
      HDAC to CY/TBI conditioning regimen may reduce leukemic relapse and improve
      survival without increasing regimen-related toxicities.

PMID- 10414907
TI  - Successful peripheral blood stem cell mobilization with etoposide (VP-16) in
      patients with relapsed or resistant lymphoma who failed cyclophosphamide
      mobilization.
AB  - High-dose chemotherapy (HDCT) followed by autologous blood stem cell
      transplantation is considered the treatment of choice for patients with relapsed
      or resistant aggressive non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD).
      However, several authors report failure of standard mobilization regimens in 29%
      to 56% of these patients making the completion of HDCT impossible and as a
      result, negatively influencing long-term outcome. Thus, effective new regimens
      for patients failing initial mobilization are needed. Here we report the results
      of using etoposide as a mobilizing agent in 16 patients with primary resistant or
      relapsed malignant lymphoma who had failed prior mobilization of peripheral blood
      stem cells (PBSC) with cyclophosphamide (4 g/m2) followed by G-CSF. The use of
      etoposide 500 mg/m2 (days 1-4) + G-CSF resulted in the successful collection of
      adequate numbers of PBSC with a median harvest of 3.6 x 10(6)/kg (range 2.2-12.6)
      CD34+ cells in all 16 patients. In 7/16 (44%) patients, the target yield of at
      least 2.0 x 10(6) CD34+ cells was harvested by a single apheresis and the maximum
      number of separations for all patients was two. No excessive toxicities appeared,
      allowing all patients to proceed to myeloablative chemotherapy. In addition,
      median peak values of circulating CD34+ cells were significantly higher after
      etoposide as compared to cyclophosphamide (49.2/microl vs 4.7/microl; P =
      0.0004). These results indicate that etoposide + G-CSF is a highly effective
      mobilization regimen in patients who have failed cyclophosphamide mobilization.

PMID- 10414908
TI  - Monitoring of CD34+ cells during leukapheresis allows a single, successful
      collection of hemopoietic progenitors in patients with low numbers of circulating
      stem cells.
AB  - We have studied a total of 188 patients with hematological malignancies,
      submitted to mobilization therapy with G-CSF associated or not with chemotherapy
      in order to: (1) establish the lower limit of circulating progenitor cells that
      allows the collection of 2 x 10(6) CD34+ cells/kg by a single leukapheresis,
      utilizing the instrument set on standard parameters; (2) evaluate whether the
      number and quality of CD34+ cells collected remain stable during leukapheresis;
      and (3) collect a sufficient number of circulating CD34+ cells by a single
      procedure in patients in whom such an approach would have been insufficient to
      reach the target with the instrument set on standard parameters. The
      retrospective analysis conducted in 85 patients showed that 19 circulating CD34+
      cells/microl represented the cut-off number capable of discriminating between
      patients who will require one or more apheresis to collect 2 x 10(6) CD34+
      cells/kg. The validity of this value was prospectively confirmed in 70 subsequent
      patients. Based on in vitro results that showed the stability in the number of
      CD34+ cells, the proportion of different CD34+ cell subpopulations and the
      clonogenic capacity of the stem cell compartment during leukapheresis both in the
      blood of the patients and in samples taken directly from the instrument, we have
      adapted the blood volume to be processed in 33 patients with <19 PB CD34+
      cells/microl. Stem cell collection was monitored during the leukapheresis and the
      procedure was prolonged for a time period estimated to be sufficient to reach the
      target number of CD34+ cells with a single procedure. The median increment of the
      total blood volume processed, calculated from the volume set automatically by the
      instrument was 25.2%, with a median of 3.3-fold total blood volume processed. In
      all cases, a sufficient CD34+ cell collection was completed in a single
      procedure. After autograft, the pattern of blood reconstitution was similar to
      that of all the other patients.

PMID- 10414909
TI  - Factors predicting engraftment of autologous blood stem cells: CD34+ subsets
      inferior to the total CD34+ cell dose.
AB  - Data were analyzed on 178 consecutive patients (median age 43 years) who
      underwent autologous blood stem cell transplantation (ABSCT) at a single
      institution to determine if CD34+ subsets (CD34+38-, CD34+33-, CD34+33+,
      CD34+41+) or various clinical factors affect hematopoietic engraftment
      independent of the total CD34+ cell dose/kg. Using Cox proportional hazards
      models, the factors independently associated with rapid neutrophil engraftment
      were higher CD34+ dose/kg, use of G-CSF post-ABSCT, and conditioning regimen
      (single-agent melphalan +/- TBI slower). Factors independently associated with
      rapid platelet engraftment were higher CD34+ cell dose/kg, higher ratio of
      CD34+33-/total CD34+ cells infused, conditioning regimen (mitoxantrone,
      vinblastine, cyclophosphamide faster), and no CD34+ cell selection of the
      autograft. The CD34+ cell selection process seemed to deplete CD34+41+ cells to a
      greater extent than total CD34+ cells which may explain our observation that it
      resulted in slower platelet engraftment. In conclusion, the total CD34+ dose/kg
      was a better predictor of hematopoietic engraftment following ABSCT than the dose
      of any CD34+ subset. Platelet engraftment, however, was also influenced by the
      ratio of CD34+33-/total CD34+ cells for unmanipulated autografts, and possibly by
      the CD34+41+ dose for autografts manipulated by CD34+ selection. The use of CD34+
      subsets requires further investigation in predicting engraftment of autografts
      which undergo ex vivo manipulation.

PMID- 10414910
TI  - Optimal timing of G-CSF administration after CD34+ immunoselected peripheral
      blood progenitor cell transplantation.
AB  - G-CSF accelerates neutrophil recovery after autologous peripheral blood
      progenitor cell transplantation (aPBPCT), although the optimal timing for its
      administration is currently unknown. In order to establish the role and the
      optimal timing of administration of G-CSF after immunoselected CD34+ aPBPCT, we
      analyzed the data from 21 consecutive patients affected by haematological
      malignancies. Patients were randomized into three groups according to G-CSF
      administration after transplantation: day +1 (group B); day +7 (group C) or no G
      CSF (group A). Serum G-CSF level was evaluated until engraftment. The CD34+ cell
      dose reinfused was similar (P = 0.48). G-CSF significantly reduced time to
      recovery of PMN >0.5 x 10(9)/l (11 vs 14 vs 20.5 days) (P= 0.00046); >1.0 x
      10(9)/l (12 vs 15 vs 22) (P = 0.001). No difference was observed in the number of
      days with PMN <0.1 x 10(9)/l (5.5 vs 7 vs 8 days). Platelet count >50 x 10(9)/l
      and >100 x 10(9)/l, reticulocytes >1%, length of hospitalization, non
      prophylactic antibiotic therapy, fever, incidence of sepsis and transfusion
      support did not differ. Early or delayed G-CSF after immunoselected CD34+ aPBPCT
      significantly accelerated PMN recovery but did not reduce the amount of
      supportive treatment or the duration of hospitalization. Delaying the initiation
      of G-CSF did not reduce the length of treatment (11.5 vs 12 days). Early or
      delayed G-CSF administration resulted in G-CSF peak serum levels 7 (early)-12
      (delayed)-fold greater than an endogenous response to neutropenia.

PMID- 10414911
TI  - Hematopoietic growth factor after autologous peripheral blood transplantation:
      comparison of G-CSF and GM-CSF.
AB  - Autologous peripheral blood stem cell (PBSC) transplantation results in rapid
      hematologic recovery when sufficient numbers of CD34+ cells/kg are infused.
      Recent studies suggest that filgrastim (G-CSF) administration following
      transplantation leads to more rapid neutrophil recovery and lower total
      transplant costs. This study compares the use of G-CSF (5 microg/kg/day) with
      sargramostim (GM-CSF) 500 microg/day from day 0 until neutrophil recovery (ANC
      >1500/mm3) in patients with breast cancer or myeloma who had PBSC mobilized with
      the combination of cyclophosphamide, etoposide, and G-CSF. Twenty patients (13
      breast cancer and seven myeloma) received GM-CSF and 26 patients (14 breast
      cancer and 12 myeloma) received G-CSF. The patients were comparable for age and
      stage of disease, and received stem cell grafts that were not significantly
      different (CD34+ x 10(6)/kg was 12.5 +/- 11.1 (mean +/- s.d.) for GM-CSF and 19.8
      +/- 18.5 for G-CSF; P = 0.10). The use of red cells (2.8 vs 2.3 units), and
      platelet transfusions (2.5 vs 3.1) was similar for the two groups, as was the use
      of intravenous antibiotics (4.3 vs 4.6 days) and the number of days with
      temperature >38.3 degrees C (2.3 vs 1.8). Platelet recovery was also similar in
      both groups (platelets >50,000/mm3 reached after 11.8 vs 14.9 days). The recovery
      of neutrophils, however, was faster using G-CSF. ANC >500/mm3 and >1000/mm3 were
      reached in the GM-CSF group at 10.5 +/- 1.5 and 11.0 +/- 1.7 days, respectively,
      whereas with G-CSF only 8.8 +/- 1.2 and 8.9 +/- 2.2 days were required (P <
      0.001). As a result, patients given G-CSF received fewer injections than the GM
      CSF patients (10.9 vs 12.3). Resource utilization immediately attributable to the
      use of growth factors and the duration of pancytopenia, excluding
      hospitalization, were similar for the two groups. This study suggests that
      neutrophil recovery occurs more quickly following autologous PBSC transplant
      using G-CSF in comparison to GM-CSF, but the difference is not extensive enough
      to result in lower total cost.

PMID- 10414912
TI  - Allogeneic bone marrow transplantation vs chemotherapy for the treatment of
      childhood acute lymphoblastic leukaemia in second complete remission (revisited
      10 years on).
AB  - In 1989 we carried out a trial comparing allogeneic BMT to chemotherapy (CT) in
      76 children with relapsed acute lymphoblastic leukaemia (ALL). Ten years on we
      have clinically revised outcome to firmly establish the role of each treatment,
      to analyse the importance of length of first remission and to provide long-term
      actuarial results for disease-free survival (DFS) and relapse rate in each group.
      For 21 patients within the transplantation group, probability of DFS and relapse
      are 42.8 +/- 10.8% and 40.2 +/- 11.7% (s.e.), respectively. In the chemotherapy
      group, probability of DFS is 10.0 +/- 4.74% (P = 0.001) and probability of
      relapse 87.5 +/- 5.2% (P = 0.0004). These results strongly reflect those at
      initial analysis, confirming a key role of BMT in the management of ALL in second
      remission. Moreover, on univariate analysis only two factors influenced DFS:
      treatment group and length of first complete remission (less or more than 30
      months from first CR). Thus, it seems clear that the best therapeutic option in
      early relapse is BMT, whereas DFS in late relapse is at the limit of significance
      (P = 0.07), with a higher relapse rate in the CT group. Although encouraging
      results using intensified rotational combination chemotherapy have been
      published, prospective randomised studies are needed to assess with certainty the
      best therapeutic option in these patients.

PMID- 10414913
TI  - Beta2-microglobulin and bone marrow plasma cell involvement predict complete
      responders among patients undergoing blood cell transplantation for myeloma.
AB  - We studied the prognostic value of clinical and laboratory variables, measured
      before blood cell transplantation, in predicting complete response among patients
      undergoing autologous blood cell transplantation for relapsed or primary
      refractory myeloma. Sixty-seven patients who underwent transplantation for
      relapsed or primary refractory myeloma were studied. The overall response rate
      was 90%, and the complete response rate was 33%. Low beta2-microglobulin (< or
      =2.7 mg/l) was associated with a significantly better complete response rate
      compared with high levels (54 vs 19%, P = 0.002). Similarly, the complete
      response rate was 39% when the bone marrow plasma cell percentage was low (<40%)
      and 21% with greater involvement (P = 0.04). Complete response rate was 50% when
      beta2-microglobulin and bone marrow plasma cell percentage were low, 36% if
      either was high, and 12% when both were high (P = 0.01). Median survival measured
      from initial diagnosis of myeloma was 51 months. Overall survival after
      transplantation was better among responders who achieved complete response than
      those who did not: median survival, 24 vs 11 months, P = 0.04 (log-rank) and
      0.009 (Gehan-Wilcoxon). Attainment of a complete response independently predicted
      better survival in a multivariate analysis. beta2-Microglobulin and bone marrow
      plasma cell percentage predict complete responders among patients undergoing
      transplantation for myeloma.

PMID- 10414914
TI  - Autologous stem cell transplantation for relapsed and primary refractory myeloma.
AB  - The aim of this study was to evaluate the effectiveness of autologous stem cell
      transplantation for patients with relapsed or primary chemotherapy-refractory
      myeloma. Seventy-five patients, 50 men and 25 women, ages 33-68 years (median, 53
      years), who underwent transplantation for relapsed or primary refractory myeloma
      were studied. Patients underwent transplantation 5-88 months (median, 23 months)
      after diagnosis of myeloma. The time to transplantation was significantly shorter
      in patients with refractory disease than for those with relapsed myeloma (median,
      8 and 32 months, respectively; P < 0.001). Patients with primary refractory
      myeloma had a significantly lower plasma cell labeling index than those with
      relapsed disease (P = 0.008). There were no differences in overall and complete
      response rates between patients with primary refractory and relapsed disease. The
      median survival of the entire cohort from diagnosis was 53 months. Overall
      survival from transplantation among patients with relapsed myeloma receiving
      therapy, relapsed myeloma off therapy, and primary refractory myeloma was
      significantly different (P = 0.04), with median times of 12, 21 and 30 months,
      respectively. Progression-free survival also was different (P < 0.001), with
      median times of 7, 13, and 26 months, respectively. We conclude that overall and
      progression-free survival in patients with primary refractory myeloma appear
      better than in patients with relapsed disease and need further study.

PMID- 10414915
TI  - Analysis of feasibility of myeloablative therapy and autologous peripheral stem
      cell (PBSC) transplantation in the elderly: an interim report.
AB  - An interim report evaluating the feasibility of myeloablative therapy followed by
      peripheral blood stem cell (PBSC) autotransplant in patients aged >60 years is
      presented. In the last 2 years 19 patients >60 years old with several oncological
      conditions, mostly hematological, underwent PBSC autotransplant either as salvage
      therapy following relapse or resistance to conventional treatment, or as
      consolidating therapy as a part of a well defined protocol. There were 13 males
      and six females; the mean age was 66.9 years (range 61-76 years); nine patients
      had resistant or relapsed lymphoma, six myeloma, two acute leukemia, one
      Waldenstrom's disease and one lung cancer. Myeloablative schemes included BEAM
      exclusively for lymphomas, busulfan and melphalan (Bu-MPH) mainly for myeloma,
      busulfan and cyclophosphamide (Bu-CTX) for lymphomas and leukemia and VP-16 and
      CTX for lung cancer. Mobilization of CD34+ cells was achieved in all patients
      with the combination of high-dose CTX and G-CSF with collections between 2.83 to
      19.04 x 10(6)/kg (mean 7.1). All patients engrafted with a median time for
      recovery of PMN (>0.5 x 10(3)/microl) of 10 days (range 8-12 days) and for PLT
      (>20 x 10(3)/microl) of 12 days (range 10-17 days). Major responses were obtained
      in 15 of 16 patients evaluable for response and eight patients entered CR;
      overall eight patients are in CR, five are alive with disease, five are dead from
      disease progression and one is dead because of congestive heart failure 7 months
      following PBSC autotransplant. No early deaths following the procedure occurred;
      major side-effects were grade I-II mucositis (58%), fever with documented sepsis
      (10%), pneumonia (5%), cardiac, renal and liver toxicity (5%). Cardiac function
      was evaluated before and after myeloablative therapy by VEF in all patients; no
      significant modifications were necessary. In conclusion, our experience
      demonstrates that myeloablative therapies in older selected patients can be
      feasible; the feasibility of introducing PBSC autotransplantation following
      myeloablative therapy as a front-line treatment in patients aged >60 years, needs
      accurate guide lines for selection of appropriate patients.

PMID- 10414917
TI  - A metalloproteinase inhibitor prevents acute graft-versus-host disease in mice
      after bone marrow transplantation.
AB  - Tumor necrosis factor (TNF) and Fas ligand (FasL) have been implicated in the
      pathogenesis of graft-versus-host disease (GVHD), which is a major complication
      after allogeneic bone marrow transplantation. We have examined the ameliorating
      effect of a metalloproteinase inhibitor (KB-R7785) that inhibits TNF-alpha and
      FasL release in a murine acute GVHD model after bone marrow transplantation.
      Administration of KB-R7785 to irradiated (BALB/c x C57BL/6) F1 mice that received
      C57BL/6 bone marrow cells and spleen cells reduced the mortality and weight loss
      in association with minimal signs of GVHD pathology in the liver, intestine, and
      hematopoietic tissues. The KB-R7785 treatment did not affect hematopoietic
      reconstitution by donor cells. Therefore, KB-R7785 could be a potent therapeutic
      agent for GVHD after bone marrow transplantation.

PMID- 10414916
TI  - Peripheral blood stem cell transplantation as an alternative to autologous marrow
      transplantation in the treatment of acute myeloid leukemia?
AB  - The clinical use of autologous marrow transplantation in acute myeloid leukemia
      (AML) has been hampered by the inability to collect adequate numbers of cells
      after remission induction chemotherapy and the notably delayed hematopoietic
      regeneration following autograft reinfusion. Here we present a study in which the
      feasibility of mobilizing stem cells was investigated in newly diagnosed AML.
      Among 96 AML patients, 76 patients (79%) entered complete remission. Mobilization
      was undertaken with low dose and high dose schedules of G-CSF in 63 patients, and
      54 patients (87%) were leukapheresed. A median of 2.0 x 10(6) CD34+ cells/kg
      (range 0.1-72.0) was obtained in a median of three leukaphereses following a low
      dose G-CSF schedule (150 microg/m2) during an average of 20 days. Higher dose
      regimens of G-CSF (450 microg/m2 and 600 microg/m2) given during an average of 11
      days resulted in 28 patients in a yield of 3.6 x 10(6) CD34+ cells/kg (range 0
      60.3) also obtained following three leukaphereses. The low dose and high dose
      schedules of G-CSF permitted the collection of 2 x 10(6) CD34-positive cells in
      46% and 79% of cases respectively (P = 0.01). Twenty-eight patients were
      transplanted with a peripheral blood stem cell (PBSC) graft and hemopoietic
      repopulation was compared with the results of a previous study with autologous
      bone marrow. Recovery of granulocytes (>0.5 x 10(9)/l, 17 vs 37 days) and
      platelets (>20 x 10(9)/l; 26 vs 96 days) was significantly faster after
      peripheral stem cell transplantation compared to autologous bone marrow
      transplantation. These results demonstrate the feasibility of PBSCT in the
      majority of cases with AML and the potential advantage of this approach with
      respect to hemopoietic recovery.

PMID- 10414918
TI  - Tacrolimus for prevention of graft-versus-host disease after mismatched unrelated
      donor cord blood transplantation.
AB  - Ten children with hematologic malignancies or a storage disease underwent
      transplantation using cord blood cells from an unrelated donor mismatched for 1
      (n = 7) or 2 (n = 3) HLA antigens. The median total nucleated cell dose was 4.0
      (range, 2.2-7.1) x 10(7)/kg. GVHD prophylaxis consisted of tacrolimus dose
      adjusted to maintain a whole blood level of 5-15 ng/ml with or without
      methotrexate 5 mg/m2 i.v. on days 1, 3, 6 and 11. Corticosteroids were not
      administered prophylactically. Median follow-up is 12 months (range, 5-28
      months). One patient had autologous recovery and subsequently relapsed 153 days
      post transplant. For the remainder of the patients, the median time to an ANC
      >0.5 x 10(9)/l was 21 days (range, 19-38 days), and the median time to platelets
      >20 x 10(9)/l was 39 days (range, 21-97 days). The actuarial risk of grade 2 GVHD
      was 77% (95% CI, 49-100%), and no patient had grades 3-4 GVHD. Two patients
      developed chronic GVHD. The survival rate is 90% (95% CI, 81-100%). The
      combination of tacrolimus and minidose methotrexate is active for the prevention
      of severe but not moderate acute GVHD after mismatched unrelated donor cord blood
      transplantation.

PMID- 10414919
TI  - Immunohistochemical detection of breast cancer cells in paired peripheral blood
      progenitor cell specimens collected after cytokine or cytokine and
      myelosuppressive chemotherapy.
AB  - Mobilized peripheral blood progenitor cells (PBPC) from 30 patients with advanced
      breast cancer were studied for the presence of tumor cell contamination using a
      highly sensitive immunohistochemical technique with the capacity to detect one
      tumor cell in one million mononuclear cells. Aliquots of PBPC were obtained after
      4 days of G-CSF and/or GM-CSF and again during G-CSF-stimulated recovery from
      myelosuppressive doses of cyclophosphamide. The overall incidence of tumor cell
      contamination was 23%, occurring in PBPC specimens from seven of 30 patients. All
      four cases in which tumor cells were detected after mobilization with cytokine
      alone also had tumor cells detected in PBPCs collected following chemotherapy and
      G-CSF. There were three cases in which malignant contamination was detected only
      in the specimens collected after cyclophosphamide. There was a greater frequency
      of tumor cell contamination in aphereses performed during G-CSF-stimulated
      recovery from cyclophosphamide than in collections primed by cytokine alone (13%
      vs 23%; P = 0.08), although this did not reach statistical significance. This
      trend suggests that collection of PBPC during cytokine-stimulated recovery from
      myelosuppressive chemotherapy may be associated with a greater risk of
      contamination with malignant cells than apheresis during mobilization with
      cytokines in the steady state.

PMID- 10414920
TI  - Clinical use of streptolysin-O to facilitate antisense oligodeoxyribonucleotide
      delivery for purging autografts in chronic myeloid leukaemia.
AB  - Antisense oligodeoxyribonucleotides (ODN) targeted against the breakpoint in BCR
      ABL mRNA will specifically decrease BCR-ABL mRNA, provided cells are first
      permeabilised with streptolysin-O (SL-O). We used 18-mer chimeric
      methylphosphonodiester: phosphodiester linked (4-9-4) ODN complementary to 9
      bases either side of the BCR-ABL junction to purge harvests ex vivo in three CML
      patients who remained completely Ph positive after multiple chemotherapy courses.
      After CD34+ cell selection and SL-O permeabilisation, harvests were purged with
      20 microM ODN. After purging, all individual CFU-GM colonies grown from the two
      b3a2 breakpoint cases remained positive for BCR-ABL mRNA. In contrast, all 24
      colonies grown from the b2a2 breakpoint case were BCR-ABL mRNA negative. Patients
      were conditioned with busulphan 16 mg/kg. The initial post-transplant course was
      uneventful, although the time to return to 0.5 x 10(9)/l neutrophils was slow at
      25-51 days. Both chronic phase patients remain in haematological remission at
      +724 and +610 days, although each has cytogenetic evidence of relapse. The b2a2
      accelerated phase patient died of myeloid blast transformation at day +91. The
      present SL-O-facilitated ODN purging strategy appears to be without significant
      toxicity, and offers considerable improvements in ODN delivery to the cytosol.

PMID- 10414921
TI  - Toxicities after peripheral blood progenitor cell transplantation for lymphoid
      malignancies: analysis of 300 cases in a single institution.
AB  - Two hundred and seventy-seven consecutive patients with non-Hodgkin's lymphoma (n
      = 207), Hodgkin's disease (n = 27) and multiple myeloma (n = 43) were intensified
      from October 1989 until April 1997 and received unmanipulated PBPC transplants.
      Twenty-three patients received a double intensification, out of a total of 300
      PBPC transplantations analyzed. Conditioning regimens consisted of total body
      irradiation (TBI)-containing regimens (n = 141), BEAM (n = 104), high-dose
      melphalan (n = 26), ICE (n = 23) or other regimens (n = 6). Eighty-four percent
      of the patients (119/142) evaluable for long-term hematological reconstitution
      beyond 180 days achieved normal trilineage blood counts. Abnormal hematological
      parameters were associated with low numbers of CD34+ cells re-infused and with
      prior exposure to fludarabine. The 100-day and long-term treatment-related
      mortality rates were 4% and 4%, respectively. Late complications and treatment
      related toxicities were influenced by disease history, use of TBI and exposure to
      fludarabine. Patients older than 60 years did not have greater toxicities or more
      frequent treatment-related deaths. This analysis suggests that while leading to a
      limited morbidity and a low mortality rate, intensive chemotherapy with PBPC
      transplantation still remains a procedure leading to significant short- and long
      term toxicities. Better recognition of the risk factors associated with these
      complications might allow a further decrease in their incidence.

PMID- 10414922
TI  - Herpes zoster ophthalmicus following bone marrow transplantation in children.
AB  - Varicella zoster virus (VZV) infection is a frequent complication following bone
      marrow transplantation (BMT). Involvement of the ophthalmic division of the
      trigeminal nerve, herpes zoster ophthalmicus (HZO), can result in significant and
      potentially vision-threatening ocular complications. We report the frequency and
      characteristics of HZO following BMT, including the timing of infection,
      treatment, ocular complications, and visual outcome. Between 1983 and 1997, 572
      patients underwent BMT and seven children developed HZO at a median of 150 days
      following transplantation. All but one of the children had undergone allogeneic
      BMT. All of the children were treated with acyclovir after onset of the rash but
      none had received prophylactic therapy. All seven children developed ocular
      complications within the first 4 weeks following the onset of the dermatomal rash
      but none reported any symptoms during this period. Complications included
      keratitis in six, anterior uveitis in three and scleritis in one. Keratitis was
      an early complication developing within the first 4 weeks, while anterior uveitis
      and scleritis occurred later in the course of the disease. The high frequency of
      ocular complications and lack of symptoms in children with HZO following BMT
      suggests that early ophthalmologic evaluation is warranted in this group of
      patients. Prompt diagnosis and treatment of ocular complications is essential in
      the prevention of acute and long-term ocular sequelae in these children.

PMID- 10414923
TI  - Successful treatment of advanced natural killer cell lymphoma with high-dose
      chemotherapy and syngeneic peripheral blood stem cell transplantation.
AB  - CD56+ angiocentric lymphoma has currently been recognized as a distinct clinical
      entity which is the prototype of the putative NK cell lymphomas. A 16-year-old
      Japanese girl with advanced CD56+ angiocentric lymphoma received high-dose
      chemotherapy supported with syngeneic peripheral blood stem cell transplantation
      (PBSCT). Prior to syngeneic PBSCT, she received six cycles of conventional
      chemotherapy before transplantation, resulting in a partial response. PBSC were
      mobilized with granulocyte colony-stimulating factor (G-CSF) and collected from
      her identical twin. High-dose cyclophosphamide, MCNU, etoposide, and carboplatin
      were used for pretransplant conditioning. Syngeneic PBSCT was well tolerated. She
      achieved complete remission and is now surviving in continuous complete remission
      for more than 30 months after syngeneic PBSCT. Thus, marrow-ablative chemotherapy
      facilitated by autologous or allogeneic PBSCT should be considered as part of the
      primary therapy for poor prognosis NK cell lymphomas.

PMID- 10414925
TI  - Adverse drug reactions associated with the administration of amphotericin B lipid
      complex (Abelcet)

PMID- 10414924
TI  - Post-mortem incidental finding of cytomegalovirus oophoritis after an allogeneic
      stem cell transplant.
AB  - Cytomegalovirus (CMV) disease is a common and serious complication of allogeneic
      stem cell transplantation (SCT). Its two most frequent manifestations are
      interstitial pneumonitis and gastroenteritis. We describe here the first reported
      case of CMV ovarian infection in an allo-SCT recipient. This patient was included
      in a clinical trial of high-dose chemotherapy (HDCT) with HLA-matched peripheral
      SCT for metastatic breast cancer. She expired 53 days after transplantation from
      organ failure unrelated to her CMV oophoritis.

PMID- 10414926
TI  - Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9
      cells.
AB  - Intracellular mechanisms through which insulin inhibits glucagon secretion remain
      to be elucidated in glucagon secreting cells. In this study, we confirmed that,
      in In-R1-G9 cells, a pancreatic alpha cell line, insulin stimulated
      phosphorylation of insulin receptor substrate-1 (IRS-1) and activated
      phosphatidylinositol 3-kinase (PI3-kinase). We further studied, using wortmannin,
      an inhibitor of PI3-kinase, whether the inhibitory effect of insulin on glucagon
      secretion was mediated through PI3-kinase pathway in these cells. In static
      incubation studies, insulin significantly inhibited glucagon secretion at 2, 6
      and 12 h, which was completely abolished by pretreatment with wortmannin. In
      perifusion studies, insulin significantly suppressed glucagon secretion after 10
      min, which was also blocked by wortmannin. Insulin also reduced glucagon mRNA at
      6 and 12 h but not at 2 h. Wortmannin also abolished insulin-induced reduction of
      glucagon mRNA. Insulin increased the amount of 85 kDa subunit of PI3-kinase in
      plasma membrane fraction (PM), with a reciprocal decrease of the kinase in
      cytosol fraction (CY). Insulin also increased PI3-kinase activity in PM, but not
      in CY. Our results suggest that insulin suppressed glucagon secretion by
      inhibiting glucagon release and gene expression. Both actions were mediated by
      activation of PI3-kinase. Recruitment and activation of PI3-kinase in plasma
      membrane might be relevant at least in part to insulin-induced inhibition of
      glucagon release.

PMID- 10414927
TI  - Beneficial effect of thyrotropin-releasing hormone on neuropathy in diabetic
      rats.
AB  - Thyrotropin releasing hormone (TRH) is therapeutically effective in experimental
      and clinical spinal injury. The effects of TRH on diabetic neuropathy are not
      known. The aim of the present study was to investigate the electrophysiological
      effects of TRH in the streptozotocin diabetic rats. Three groups of rats were
      studied, non-diabetic control (n = 10), diabetic controls (n = 8), and TRH
      treated diabetic rats (n = 9). Administration of TRH or saline and
      electrophysiological measurements were performed 4 weeks after induction of
      diabetes. TRH was given intraperitoneally in a dose of 600 microg (3 ml). Nerve
      conduction velocity (NCV), measured in caudal nerve, and N1 latency of
      somatosensory evoked potentials (SEP) were measured 75 min after injection of TRH
      or serum saline. SEP latencies were 28.1 +/- 0.6, 29.4 +/- 0.8, 27.8 +/- 1.1 ms,
      in normal, diabetic and diabetic TRH-treated groups, and NCV values were 28.1 +/-
      0.8, 23.8 +/- 0.4, and 27.9 +/- 0.7 m/s respectively. NCV was significantly
      reduced in the diabetic group compared to normals (P < 0.05). but then improved
      by TRH treatment (P < 0.05). Our findings suggest that TRH has an acute effect on
      peripheral neuropathy in experimental streptozotocin diabetes in the rat.

PMID- 10414928
TI  - W-5 and quin 2-AM reverse the inhibitory effect of insulin on lipolysis due to
      dibutyryl cAMP.
AB  - The effects of W-5, a weak calmodulin antagonist, and quin 2-AM, a cell permeant
      calcium chelator, on lipolysis and antilipolytic activity of insulin were studied
      in isolated rat adipocytes. We have previously shown that W-7, a strong
      calmodulin antagonist, suppresses the inhibitory effect of insulin on lipolysis
      due to dibutyryl cAMP (Bt2cAMP) in a dose-dependent manner [H. Goko, A. Matsuoka,
      Diabetes Res. Clin. Prac. 19 (1993) 177-181] and verapamil, a calcium antagonist,
      potentiates lipolysis due to Bt2cAMP. Like W-7, W-5 suppressed the antilipolytic
      action of insulin on lipolysis due to Bt2cAMP in a dose-dependent manner.
      However, when lipolysis was potentiated with 3-isobutyryl-1-methylxanthine
      (IBMX), W-5 did not suppress the antilipolytic action of insulin. At the same
      time, like verapamil, W-5 also potentiated lipolysis due to Bt2cAMP in a dose
      dependent manner. Thus W-5 has the pharmaceutical effects of both W-7 and
      verapamil. The chelation of intracellular Ca2+ in adipocytes with quin 2-AM also
      produced a dose-dependent potentiation of lipolysis due to Bt2cAMP and
      suppression of the antilipolytic action of insulin on lipolysis due to Bt2cAMP.
      These effects of quin 2-AM are the same as those of W-5. Therefore, our results
      suggest that the cytoplasmic Ca2+ plays a pivotal role in mediating the
      potentiation of lipolysis and antilipolytic action of insulin when lipolysis is
      induced by Bt2cAMP in rat adipocytes and that W-5 appears to exert its
      pharmaceutical effects through the inhibition of intracellular calcium-dependent
      steps other than calmodulin.

PMID- 10414929
TI  - Pioglitazone prevents mice from multiple low-dose streptozotocin-induced
      insulitis and diabetes.
AB  - Macrophage infiltration into pancreatic islets is thought to be an initial event
      inducing insulitis in the development of type 1 diabetes. Thiazolidinedione is a
      direct ligand for peroxisome proliferator-activated receptor-gamma, recently
      reported to inhibit macrophage activation, including cytokine production and type
      2 nitric oxide synthase expression. We investigated the effect of pioglitazone, a
      thiazolidinedione compound, on the development of multiple low-dose
      streptozotocin (MLDS)-induced autoimmune diabetes in mice. CD-1 mice
      intraperitoneally injected with five daily sub-diabetogenic doses (30 or 40 mg/kg
      body weight) of streptozotocin developed mononuclear cell infiltration in and
      around islets, followed by hyperglycemia. Oral administration of pioglitazone
      (0.01% food admixture) from 7 days before the first streptozotocin injection
      prevented or delayed the development of diabetes induced by MLDS. Histologically,
      pioglitazone blocked the infiltration of mononuclear cells into islets in MLDS
      mice. Peritoneal macrophages from MLDS mice at day-7 produced significantly large
      amount of nitric oxide compared with those from control mice. Such activation of
      peritoneal macrophages was not observed in pioglitazone-treated MLDS mice. These
      findings suggest that pioglitazone blocks the autoimmune process in the
      development of MLDS diabetes, partly by inhibiting the macrophage activation.

PMID- 10414930
TI  - Prevalence of sexual disorders in a selection-free diabetic population (JEVIN).
AB  - There is an extensive literature on sexual disorders among diabetic patients, but
      a shortage of studies on their prevalence in selection-free populations. In the
      present trial (JEVIN), 90% of all insulin-treated diabetic patients (IDDM/NIDDM,
      n = 127/117) aged 16-60 years and living in the city of Jena (100247 inhabitants)
      were studied. Each subject underwent a structured interview followed by a
      clinical and laboratory examination. The prevalence of sexual disorders was 32%
      in IDDM and 46% in NIDDM male patients. Patients with sexual disorders were older
      (IDDM 47.5 +/- 9.8 vs. 37.7 +/- 11.6, P = 0.0004; NIDDM 53.4 +/- 4.3 vs. 49.5 +/-
      8.2 years, P = 0.04) and had longer diabetes duration (IDDM 23.1 +/- 13.8 vs.
      13.5 +/- 11.1, P = 0.001; NIDDM 12.4 +/- 7.5 vs. 8.4 +/- 5.8 years, P = 0.03)
      than patients without sexual disorders. There were no significant differences (P
      < 0.05) between the groups as regards HbA1c, body-mass index and insulin dose/kg
      body weight. The prevalence of diabetes long-term complications in men with
      versus men without sexual disorders (IDDM/NIDDM): retinopathy, 65/53% vs. 50/18%
      (P = 0.34/0.03); neuropathy, 58/48% vs. 9/34% (P = 0.001/0.47); nephropathy,
      65/50% vs. 12/36% (P = 0.001/0.45). In addition, all the patients completed
      standardized questionnaires according to Bradley et al. and Lewis et al. to
      assess quality of life and treatment satisfaction, and one question concerning
      sexual disorders. The quality of life of IDDM patients with sexual disorders was
      lower than that of patients without sexual disorders (42.2 +/- 11.4 vs. 54.2 +/-
      8.5, P = 0.0005), but there were no differences (P < 0.05) in NIDDM patients. In
      women, the prevalence of sexual disorders was 18/42% in IDDM and NIDDM. Comparing
      these data with the literature and with reports from healthy controls, mostly
      there is clearly an underestimation of the prevalence of sexual disorders in
      diabetic populations. Physicians must make more efforts to detect and treat
      sexual disorders, which may result in an improvement of patients' quality of
      life.

PMID- 10414931
TI  - Diabetes management: shared care or shared neglect.
AB  - Shared care is increasingly being advocated as a way of managing patients with
      diabetes. While this approach has been supported by clinical trials, the success
      of shared care in 'real life' is not well established. If health care
      professionals leave undone what they think is done by others, shared care can
      become neglected care. Follow up of 200 'shared care' patients who had been
      referred to the Royal Prince Alfred Diabetes Centre, Sydney, Australia on two or
      more occasions between October 1995 and September 1998 showed that the majority
      of specialist recommendations regarding metabolic control (76%), referral to an
      ophthalmologist (73%) and blood pressure treatment (76%) had been implemented by
      the primary care physician; however, they were less likely to implement
      recommendations regarding lipid treatment (55%). The median HbA1c (7.6% vs. 8.4%;
      P = 0.04), cholesterol (5.6 vs. 6.8 mmol/l; P = 0.0005) and triglyceride (2.0 vs.
      2.8 mmol/l; P = 0.05) levels for patients in whom recommendations had been
      implemented were significantly lower at the time of second referral. Doctors
      registered with the Diabetes Shared Care Programme and those who wrote longer
      letters were more likely to implement recommendations than their counterparts
      (87.2%, versus 70.9%; chi2 = 4.12, 1 df; P = 0.04 and 56 words (inter-quartile
      range (IQR): 36-71) versus 45 words (IQR: 23-59); P = 0.02, respectively). It
      therefore appears that diabetes care can be well provided by a shared care
      approach. However, further monitoring of different shared care models is
      warranted.

PMID- 10414932
TI  - Heterogeneous relationship of early insulin response and fasting insulin level
      with development of non-insulin-dependent diabetes mellitus in non-diabetic
      Japanese subjects with or without obesity.
AB  - The aim of this study was to investigate the association of insulin secretion and
      insulin resistance with the development of non-insulin-dependent diabetes
      mellitus (NIDDM) in obese (body mass index (BMI) > or = 25 kg/m2) and non-obese
      Japanese. Subjects were selected from persons participating a health survey, and
      a 100 g oral glucose tolerant test was performed. A total of 1604 non-diabetic
      subjects were followed for 2-8 years (mean 4.5 years). The fasting insulin level
      and the homeostasis model insulin resistance index (HOMA-R = fasting glucose
      [mmol/l] x fasting insulin [microU/ml]/22.5) were used as the index of insulin
      resistance, and insulinogenic index (the ratio of increment of insulin to that of
      blood glucose 30 min after glucose load) as a measure of early insulin response.
      Cox's proportional hazards analysis in the whole group showed that BMI, fasting
      blood glucose (FBG) and 2-h blood glucose (2-h BG) were positive predictors, and
      age and insulinogenic index were negative predictors of diabetes. Sex, family
      history, fasting insulin level and HOMA-R were not predictive of developing
      diabetes. In subgroup analysis, the same variables as in the whole group were
      predictors in non-obese, whereas only FBG and 2-h BG predicted diabetes in obese
      subjects. Fasting insulin level and HOMA-R were not predictive of diabetes both
      in non-obese and obese subjects. Eleven obese subjects, who developed diabetes
      despite a normal initial insulinogenic index, had significantly higher BMI,
      fasting insulin level and HOMA-R, compared with 258 obese subjects who did not
      develop diabetes. We conclude that most cases of diabetes in Japanese begin with
      decreased insulin secretion, but a small group of diabetes patients may start
      with insulin resistance, especially obese subjects.

PMID- 10414933
TI  - Analysis and a long-term follow up of ketosis-onset Japanese NIDDM patients.
AB  - It has been reported that excessive intake of sugar-containing soft drinks
      results in diabetic ketoacidosis (DKA) or ketosis (DK) in obese patients with non
      insulin dependent diabetes mellitus (NIDDM). We describe the clinical
      characteristics and results of long-term follow-up for 24 newly-diagnosed
      patients with acute-onset NIDDM presenting with DKA or DK. A history of excessive
      intake of sugar-containing soft drinks was found in 19 (Group A); serious non
      diabetic illnesses were found in 5 (Group B). The range of patient ages in Group
      A was 16 to 57 years while all patients in Group B were 60 years or older. In
      Group A, no patient was positive for autoantibodies, specific HLAs for Japanese
      insulin dependent diabetes mellitus, or mutation of the beta-3-adrenergic
      receptor gene. The body mass indices (BMIs) at onset and admission and serum C
      peptide immunoreactivities at admission and discharge were significantly higher
      in patients in Group A than in patients Group B. In conclusion, we reconfirmed
      that excessive intake of sugar-containing soft drinks is one of the contributing
      factors in DKA or DK-onset NIDDM patients. We found no autoimmune mechanism
      involved in the pathogenesis and that a polymorphism in the beta-3-adrenergic
      receptor gene could be associated with the development of soft-drink ketosis.

PMID- 10414934
TI  - Vascular cell adhesion molecule-1 expression in the renal interstitium of
      diabetic KKAy mice.
AB  - To investigate the mechanism of interstitial inflammation in diabetic
      nephropathy, we used spontaneously diabetic KKAy mice. Twelve KKAy mice were
      divided into two groups; six mice were fed standard mouse chow ad libitum and six
      mice were placed on a diet (i.e. they received the same amount of chow as six
      control C57BL mice). Diabetic KKAy mice developed hypercholesterolemia and
      albuminuria. Animals were killed at 16 weeks of age and renal tissues were
      immunostained for vascular cell adhesion molecule-1 (VCAM-1). In diabetic KKAy
      mice, the renal interstitium was infiltrated by monocytes, lymphocytes, plasma
      cells, and other cells. The walls of venules near the infiltrating cells were
      more intensely stained for VCAM-1 when compared with other sites. In contrast,
      the VCAM-1 staining of arterioles and peritubular capillaries was not
      significantly increased. There was weak VCAM-1 staining of the infiltrating
      cells, including lymphocytes, monocytes, and other cells. Electron microscopy
      demonstrated immunolabeling for VCAM-1 on the cell surface and in the cytoplasm
      of both infiltrating cells and vascular endothelial cells. In KKAy mice placed on
      a diet, there was less staining for VCAM-1 and cellular infiltration was also
      decreased. Thus, increased expression of VCAM-1 by the endothelial cells of
      venules and VCAM-1 expression by infiltrating cells were demonstrated in the
      interstitium of kidneys from diabetic mice. These results suggest that increased
      expression of VCAM-1 by endothelial cells and infiltrating cells contributes to
      interstitial inflammation in diabetic nephropathy.

PMID- 10414935
TI  - Physical and psychological well-being in adults with Type 1 diabetes.
AB  - The physical and psychological well-being of adults with Type 1 (insulin
      dependent) diabetes (n = 397) were investigated using a series of questionnaires,
      including the Medical Outcomes Survey SF36. Development of diabetes complications
      and glycaemic control (glyated haemoglobin) were also measured. Results showed
      that older individuals, those with complications, women, the less physically
      active and those on lower incomes, were more likely to experience a poorer
      quality of life. Those who reported at least one hypoglycaemic episode per month
      also had poorer quality of life. This study, whilst confirming earlier work
      showing an association between quality of life and diabetes complications,
      demonstrates that other factors may also be important. Of particular interest is
      the association with hypoglycaemia, which has implications for diabetes care.
      Given the importance of reducing blood glucose levels in order to avoid
      complications, this focus in patient care may overlook the subsequent impact on
      quality of life.

PMID- 10414936
TI  - Diagnostic criteria for diabetes mellitus and other categories of glucose
      intolerance: 1997 criteria by the Expert Committee on the Diagnosis and
      Classification of Diabetes Mellitus (ADA), 1998 WHO consultation criteria, and
      1985 WHO criteria. World Health Organization.
AB  - To compare 1997 ADA diagnostic criteria for diabetes mellitus and other
      categories of glucose intolerance/1998 WHO Consultation criteria versus 1985 WHO
      criteria, we analyzed data from a 75-g oral glucose tolerance test (OGTT)
      performed on 1051 high-risk subjects without medical history of diabetes at
      Diabetes Screening Clinic, Ramathibodi Hospital, Thailand. There were 372 males
      and 679 females, aged (mean +/- S.D.) = 50.3 +/- 12.55 years, BMI = 25.62 +/-
      4.39 kg/m2. If fasting plasma glucose (FPG) was used as recently recommended then
      54.1, 20.4, and 25.5% of cases were classified as normal, impaired fasting
      glucose (IFG), and diabetic, respectively. In diagnosing diabetes using a full
      OGTT based on the 1985 WHO criteria as the reference test, FPG > or = 7 mmol/l
      had a sensitivity of 57.7%, specificity of 97.4%, positive predictive value of
      94.0%, and negative predictive value of 76.4%; 53.7% of subjects with IFG had 2-h
      plasma glucose > or = 11.1 mmol/l. The 1997 ADA/1998 WHO Consultation criteria
      and 1985 WHO criteria for a full OGTT yield similar overall results. FPG ( > or =
      7 mmol/l) was not sensitive for diagnosing diabetes. Moreover, about half of the
      subjects with IFG were actually diabetic. Therefore, OGTT remains a valuable test
      in diagnosing diabetes and classifying various categories of glucose intolerance.

PMID- 10414937
TI  - Insulin action and fibrinolysis influenced by vitamin E in obese Type 2 diabetes
      mellitus.
AB  - Increased oxidative stress, hypofibrinolysis and insulin resistance are present
      in obese Type 2 diabetic patients. It is supposed that treatment with antioxidant
      alpha-tocopherol (vitamin E) could not only decrease free radical production, but
      also ameliorate insulin action. We evaluated the effect of 3 months
      administration of vitamin E (600 mg daily) on insulin action examined by
      hyperinsulinemic clamp in 11 obese Type 2 diabetic patients. Oxidative stress and
      fibrinolysis were also determined. The administration of vitamin E caused a
      decrease of glucose disposal rate (26.6 +/- 9.5 vs 21.3 +/- 7.5 micromol/kg/min,
      P < 0.02) and of metabolic clearance rate of glucose (3.7 +/- 1.6 vs 2.9 +/- 0.8
      ml/kg/min. P < 0.02). A decrease of insulin receptor number was observed on
      erythrocytes after vitamin E (284 +/- 84 vs 171 +/- 59 pmol/l, P < 0.01).
      Significantly higher plasma malondialdehyde (MDA) concentration documented an
      increased oxidative stress in diabetic patients as compared with healthy persons
      (3.13 +/- 0.68 vs 1.89 +/- 0.18 micromol/l, P<0.001). An inverse relationship was
      found between MDA concentration and insulin sensitivity expressed by glucose
      disposal rate (r = -0.73). Vitamin E further worsened the hypofibrinolysis
      documented by a decrease of tissue plasminogen activator (P < 0.01) without
      changes in its inhibitor PAI-1. In conclusion. our results demonstrate that
      higher doses of vitamin E may further deteriorate insulin action and fibrinolysis
      in obese Type 2 diabetic patients.

PMID- 10414938
TI  - Microalbuminuria is closely related to diabetic macroangiopathy.
AB  - To investigate whether urinary excretion of transferrin (uTf) and albumin (uAlb)
      is related to diabetic macroangiopathy, we compared the levels of uTf and uAlb
      between ischemic heart disease (IHD) group and non-IHD group in patients with non
      insulin-dependent diabetes mellitus. The patients (n = 102) without
      macroproteinuria were enrolled in the present study. Firstly, we divided the
      subjects into the two groups, IHD group (n = 16) and non-IHD group (n = 86),
      according to findings of ischemic changes on electrocardiogram. The levels of uTf
      and uAlb in IHD group were 3.9 +/- 0.9 and 40.6 +/- 9.7 (mean +/- S.E.M.) mg/g
      Creatinine, respectively. These values were significantly (P < 0.01) higher than
      those of non-IHD group (1.8 +/- 0.2 for uTf and 19.6 +/- 1.8 for uAlb). There was
      no significance in the levels of HbA1c, blood pressure, plasma lipids, and
      diabetic duration between the two groups. Secondly, we divided the subjects by
      the levels of uTf and uAlb. The frequency of IHD in the group (n = 22, 36.4%)
      with microalbuminuria and microtransferrinuria was significantly (P <0.03) higher
      than those (n = 38, 10.5%) with normoalbuninuria and microtransferrinuria, and
      also significantly (P < 0.02) higher than those (n = 42, 9.5%) with
      normoalbuminuria and normotransferrinuria. We concluded that the measurement of
      uAlb is important when approaching diabetic macroangiopathy.

PMID- 10414939
TI  - Polymorphism of the beta3-adrenergic receptor gene and weight gain in pregnant
      diabetic women.
AB  - Inappropriate body weight gain during pregnancy has critical effects on the
      outcome for both mother and fetus. Therefore, body weight gain is an important
      issue in the management of pregnancy in women with diabetes. A Trp64Arg
      substitution in the beta3-AR gene has been reported to be associated with body
      weight gain and obesity in non-insulin-dependent diabetes mellitus (NIDDM)
      subjects. The aim of this study was to elucidate the contribution of the beta3-AR
      gene to body weight gain during pregnancy in subjects with diabetes. We analyzed
      199 diabetic patients (NIDDM/IDDM; 131/68) and patient data was obtained from the
      first delivery of each individual. The mean age at diagnosis of diabetes was 22.9
      +/- 7.5 years (mean +/- S.D.) and the mean age at delivery was 29.8 +/- 4.5
      years. A polymorphism of the beta3-AR gene was detected by PCR-RFLP using Bst OI,
      which recognizes a Trp64Arg substitution. The frequency of the Trp64Arg allele
      was 0.15 in NIDDM and 0.17 in IDDM. Among the NIDDM subjects, excess weight gain
      during pregnancy, as defined by maximum BMI during pregnancy minus basal BMI
      before pregnancy exceeding five, was observed in 12.2% of the wild-type patients,
      19.2% of heterozygotes and 28.6% of homozygotes. Homozygous subjects with NIDDM
      tended to show excess weight gain during pregnancy, however, this trend did not
      reach significance. None of the IDDM homozygotes showed excess weight gain. From
      our study, this beta3-AR gene polymorphism cannot be excluded as a contributing
      factor to excess weight gain during pregnancy in NIDDM subjects.

PMID- 10414940
TI  - Pakistan National Diabetes Survey: prevalence of glucose intolerance and
      associated factors in Baluchistan province.
AB  - The prevalence of diabetes mellitus (DM) and impaired glucose tolerance (IGT) and
      their relationship to age and obesity was estimated in a population-based survey
      in urban and rural areas in Baluchistan province, Pakistan. Cluster sampling of
      834 adults (260 men, 574 women) in the urban and 570 adults (175 men, 395 women)
      in the rural areas was carried out. Oral glucose tolerance tests were performed
      in adults aged 25 years and above. Diagnosis of diabetes and IGT was according to
      the World Health Organization (WHO) criteria. The overall prevalence of diabetes
      and IGT in both sexes was 10.8 and 11.9% (urban) versus 6.5 and 11.2% (rural),
      respectively. The crude prevalence of diabetes in the urban versus rural area was
      11.1% in men and 10.6% in women versus 10.3% in men and 4.8% in women. As against
      this IGT was found in 6.5% of men and 14.3% of women in the urban area and 7.4%
      of men and 13.0% of women in the rural setting. The major risk factors associated
      with diabetes were age, positive family history (F/H) of diabetes and obesity.
      Central obesity was more strongly associated with diabetes in women than men.

PMID- 10414941
TI  - High prevalence of impaired fasting glucose and type 2 diabetes mellitus in
      Penghu Islets, Taiwan: evidence of a rapidly emerging epidemic?
AB  - The purpose of this study was to estimate the prevalence of type 2 diabetes and
      impaired fasting glucose (IFG) in Penghu, Taiwan and compare these estimates with
      those of the US (NHANES III). Diabetes and IFG (American Diabetes Association
      criteria, 1997) were assessed among a stratified random sample of 2500 residents
      of Penghu Islands, Taiwan. The prevalence (age-adjusted to world adult
      population) of diabetes and IFG were 16.8% (95% CI 15.0-18.6) and 21.0% (95% CI
      19.0-23.0), respectively, among Penghu Islanders in Taiwan. Age sex-specific
      diabetes prevalence ranged from 10.0% in men aged 40-49 years to 29.4% in women
      aged 60-69 years. Prevalence of IFG ranged from 14.7% in women aged 40-49 years
      to 30.7% in men aged 50-59 years. Age, body mass index (BMI), and family history
      of diabetes were each independently associated with both diabetes and IFG. In
      addition, female gender, apolipoprotein B and triglyceride concentrations were
      associated with diabetes, and hypertension and apolipoprotein B concentration
      with IFG. Among persons > or = 40 years in Penghu, Taiwan, the prevalence of
      diabetes is up to a third higher and the prevalence of IFG is up to three times
      higher than comparably aged Americans, despite their having a mean BMI 2.2-3.2
      kg/m2 lower than Americans. The alarmingly high prevalence of IFG in Taiwan may
      indicate an emerging diabetes epidemic.

PMID- 10414942
TI  - Emphysematous pyelonephritis: case report and review of the literature.
AB  - Emphysematous pyelonephritis (EP), a rare necrotizing infection of the upper
      urinary tract, is a life-threatening complication of patients with diabetes
      mellitus. A case of EP is described where the diagnosis was delayed for 36 h and
      the patient died notwithstanding aggressive medical and surgical intervention.
      The demonstration of gas in the renal structures is pathognomonic of EP. Because
      early diagnosis and aggressive medical and surgical management is imperative for
      recovery, we recommend plain abdominal radiographs as a minimal screening tool
      for all diabetic patients who present to hospital with a presumptive
      pyelonephritis. The diagnosis should also be considered in patients who failed
      appropriate medical therapy.

PMID- 10414943
TI  - Reversal of multidrug resistance in hematological malignancies.

PMID- 10414944
TI  - Renal failure and multiple myeloma: pathogenesis and treatment of renal failure
      and management of underlying myeloma.
AB  - Renal impairment is a common complication of multiple myeloma occuring in 50% of
      patients at some stage in their disease. Pathogenesis is multifactorial.
      Nephrotoxic manifestations of monoclonal immunoglobulin overexpression include
      the 'myeloma kidney', light chain deposition disease, AL amyloid, plasma cell
      infiltration and glomerulonephritis. Other factors, such as hypercalcaemia,
      hyperuricaemia, infection, hyperviscocity and nephrotoxic drugs can precipitate
      or exacerbate acute and chronic renal failure. Aggressive treatment has
      dramatically improved outcome in patients who present with acute or acute-on
      chronic renal failure. Dialysis has become an accepted treatment acutely and in
      end stage renal disease due to myeloma. Conventional therapy with melphalan and
      prednisolone is still advocated for elderly patients. However, renal failure is
      not a contraindication to aggressive cytoreduction, stem cell collection, double
      hemibody radiotherapy and autologous transplantation in those otherwise fit to
      tolerate these procedures. Prognosis is primarily determined by the response of
      the myeloma clone to chemotherapy. Outcome in chemosensitive patients approaches
      that of patients with equivalent disease stage without renal dysfunction.

PMID- 10414945
TI  - Microbiology confirmatory tests for blood donors.
AB  - Blood donations collected in Scotland are currently screened for the presence of
      HBsAg, anti-HIV 1 + 2, anti-HCV and syphilis antibodies. Approximately 1% of all
      donations are found to repeatedly react to one of these four markers on screening
      but very few represent true infection. These samples must be sent to the
      designated confirmatory laboratory whose main role is to identify the true
      positive amongst a sea of 'false positives'. A battery of tests is used for this
      purpose, usually applied in a defined sequence. The use of such 'confirmatory
      algorithms' for each marker has been developed by most countries over the years
      and is now essential to the confirmatory process. The advent of gene
      amplification techniques such as PCR for initially pooled and eventually single
      donation testing will be the next challenge for confirmatory laboratories and
      will demand standards of confirmation as accurate as currently performed with the
      present serological markers.

PMID- 10414946
TI  - Molecular approaches to the detection and monitoring of chronic myeloid leukemia:
      theory and practice.

PMID- 10414947
TI  - Serial evaluation of patients with brain tumors using volume MRI and 3D 1H MRSI.
AB  - Patients with brain tumors are routinely monitored for tumor progression and
      response to therapy using magnetic resonance imaging (MRI). Although serial
      changes in gadolinium enhancing lesions provide valuable information for making
      treatment decisions, they do not address the fate of non-enhancing lesions and
      are unable to distinguish treatment induced necrosis from residual or recurrent
      tumor. The introduction of a non-invasive methodology, which could identify an
      active tumor more reliably, would have a major impact upon patient care and
      evaluation of new therapies. There is now compelling evidence that magnetic
      resonance spectroscopic imaging (MRSI) can provide such information as an add-on
      to a conventional MRI examination. We discuss data acquisition and analysis
      procedures which are required to perform such serial MRI-MRSI examinations and
      compare their results with data from histology, contrast enhanced MRI, MR
      cerebral blood volume imaging and FDG-PET. Applications to the serial assessment
      of response to therapy are illustrated by considering populations of patients
      being treated with brachytherapy and gamma knife radiosurgery.

PMID- 10414948
TI  - Inflammatory granulomas: evaluation with proton MRS.
AB  - Intracranial inflammatory lesions consisting mainly of tuberculomas (n = 28),
      neurocysticercosis (NCC) (n = 10), and non-specific inflammatory granulomas (IG)
      (n = 22) were evaluated with proton MRS. Water-suppressed proton spectra were
      acquired from 60 patients using the STEAM sequence with an echo time of 135 ms
      and metabolite ratios determined from the spectra. Student's paired t-test and
      chi2-test were used to analyse the data. Statistically significant differences
      were observed for the following ratios between the three patient categories: NAA/
      Cr (p < 0.0001), NAA/Cho (p = 0.001) and Cr/Cho (p = 0.02) for the non-specific
      IG and NCC, NAA/Cho (p = 0.03) for non-specific IG and tuberculoma, and NAA/Cr (p
      < 0.0001) for NCC and tuberculoma. While lipids were seen in 86% of the
      tuberculomas, they were observed in only 20% of the NCCs (chi2 = 6.81, p =
      0.009), and 21% of the non-specific IGs (chi2 = 10.75, p = 0.0001). While the
      presence of lipid can be used for differentiating tuberculomas from both non
      specific IG and NCC, the extremely low levels of metabolites together with a poor
      signal/noise ratio could itself act as a marker for NCC.

PMID- 10414950
TI  - Differences in metabolism of 5-fluorouracil and 5-fluorouridine and regulation by
      glucosamine in human colon cancer multicell tumor spheroids.
AB  - Glucosamine (GlcN) modulates fluoropyrimidine metabolism and enhances
      cytotoxicity of 5-fluorouridine (FUrd), but not of 5-fluorouracil (FUra), in
      human tumor models. To elucidate the underlying metabolic differences between
      FUra and FUrd, by the use of 19F and 31P NMR spectroscopy we studied these drugs
      in multicell tumor spheroids (MTS) formed by human colon carcinoma cells HT-29.
      This experimental system allowed detailed kinetic measurements of anabolic
      intracellular phosphates and fluorophosphates over periods of up to 2 days. Time
      dependent NMR data were reduced and interpreted by the use of nonlinear
      compartmental models which yielded numerical values for the empirical rate
      constants characterizing mass transfer among the compartments. An analysis of
      these rate constants indicated qualitative and quantitative differences in the
      metabolism of FUra and FUrd and in the effects of GlcN on these drugs. The
      enhanced generation of FUDP-hexoses was a predicted effect of GlcN, but inhibited
      formation of fluorouridine diphosphates and fluorouridine triphosphates in FUra
      treated MTS, and the magnitude of stimulation of fluoropyrimidine incorporation
      into macromolecules in FUrd-treated MTS were not predicted.

PMID- 10414949
TI  - On the inhibition of hepatic glycogenolysis by fructose. A 31P-NMR study in
      perfused rat liver using the fructose analogue 2,5-anhydro-D-mannitol.
AB  - Inhibition of hormone-stimulated hepatic glycogenolysis by fructose (Fru) has
      been attributed to accumulation of the competitive inhibitor Fru1P and/or to the
      associated depletion of the substrate phosphate (Pi). To evaluate the relative
      importance of either factor, we used the Fru analogue 2,5-anhydro-D-mannitol
      (aHMol). This analogue is avidly phosphorylated, traps Pi, and inhibits hormone
      stimulated glycogenolysis, but it is not a gluconeogenic substrate, and hence
      does not confound glycogenolytic glucose production. Livers were continuously
      perfused with dibutyryl-cAMP (100 microM) to clamp phosphorylase in its fully
      activated a form. We administered aHMol (3.8 mM), and studied changes in
      glycogenolysis (glucose, lactate and pyruvate output) and in cytosolic Pi and
      phosphomonoester (PME), using in situ 31P-NMR spectroscopy (n = 4). Lobes of
      seven livers perfused outside the magnet were extracted for evaluation, by high
      resolution 31P-NMR, of the evolution of aHMol1P and of aHMol(1,6)P2. After
      addition of aHMol, both glycogenolysis and the NMR Pi signal dropped
      precipitously, while the PME signal rose continuously and was almost entirely
      composed of aHMol1P. Inhibition of glycogenolysis in excess of the drop in Pi
      could be explained by continuing accumulation of aHMol1P. A subsequent block of
      mitochondrial ATP synthesis by KCN (1 mM) caused a rapid increase of Pi. Despite
      recovery of Pi to values exceeding control levels, glycogenolysis only recovered
      partially, attesting to the Pi-dependence of glycogenolysis, but also to
      inhibition by aHMol phosphorylation products. However, KCN resulted in conversion
      of the major part of aHMol1P into aHMol(1,6)P2. Residual inhibition of
      glycogenolysis was due to aHMol1P. Indeed, the subsequent withdrawal of aHMol
      caused a further gradual decrease in the proportion of aHMol1P (being converted
      into aHMol(1,6)P2, in the absence of de novo aHMol1P synthesis), and this
      resulted in a gradual de-inhibition of glycogenolysis, in the absence of marked
      changes in Pi. Glycogenolytic rates were consistently predicted by a model
      assuming non-saturated Pi kinetics and competition by aHMol1P exclusively: In
      conclusion, limited Pi availability and the presence of competitive inhibitors
      are decisive factors in the control of the in situ catalytic potential of
      phosphorylase a.

PMID- 10414951
TI  - Current awareness in NMR in biomedicine.

PMID- 10414952
TI  - Coordinated transcriptional regulation of the unc-25 glutamic acid decarboxylase
      and the unc-47 GABA vesicular transporter by the Caenorhabditis elegans UNC-30
      homeodomain protein.
AB  - An important aspect of the specification of neuronal fate is the choice of
      neurotransmitter. In Caenorhabditis elegans the neurotransmitter GABA is
      synthesized by the UNC-25 glutamic acid decarboxylase (GAD) and packaged into
      synaptic vesicles by the UNC-47 transporter. Both unc-25 and unc-47 are expressed
      in 26 GABAergic neurons of five different types. Previously, we have identified
      that the unc-30 homeobox gene controls the fate of 19 type D GABAergic neurons.
      We report here that the UNC-30 homeodomain protein transcriptionally regulates
      the expression of unc-25 and unc-47 in the 19 type D neurons. UNC-30 bound to the
      unc-25 and unc-47 promoters sequence-specifically. Mutations in the UNC-30
      binding sites of the unc-25 and unc-47 promoters abolished the expression of
      reporter genes in the D neurons. The ectopic expression of UNC-30 induced the
      ectopic expression of reporter genes driven by the wild-type unc-25 and unc-47
      promoters. Our data establish a mechanism for cell type-specific transcriptional
      coregulation of genes required for the synthesis and packaging of the
      neurotransmitter GABA.

PMID- 10414953
TI  - Caspase-dependent and -independent death of camptothecin-treated embryonic
      cortical neurons.
AB  - This study investigates the mechanisms underlying death of cultured embryonic
      cortical neurons exposed to the DNA-damaging agent camptothecin and in particular
      the interdependence of the roles of cyclin-dependent kinases (Cdks), caspases,
      and mitochondrial function. Camptothecin evokes rapid neuronal death that
      exhibits nuclear features of apoptosis. This death is accompanied by loss of
      cytochrome c and mitochondrial transmembrane potential as well as by induction of
      caspase-3-like activity and caspase-2 processing. The Cdk inhibitor flavopiridol
      provides long-term rescue from death and prevents loss of cytochrome c and
      mitochondrial transmembrane potential as well as caspase activation and
      processing. General caspase inhibitors rescue neurons from this rapid apoptotic
      death but do not prevent them from undergoing delayed death in which nuclear
      features of apoptosis are absent. Moreover, the caspase inhibitors do not affect
      early cytochrome c release and delay but do not prevent the loss of transmembrane
      potential. Agents that directly disrupt mitochondrial function without inducing
      cytochrome c release lead to a caspase-independent death. These observations
      favor a model in which (1) DNA damage leads to Cdk activation, which lies
      upstream of release of cytochrome c and caspase activation; (2) cytochrome c
      release is caspase-independent and may occur upstream of caspase activation; (3)
      early apoptotic death requires caspases; and (4) delayed nonapoptotic death that
      occurs in the presence of caspase inhibitors is a consequence of prolonged loss
      of mitochondrial function. These findings shed light on the mechanisms by which
      DNA damage kills neurons and raise questions regarding the general utility of
      caspase inhibitors as neurotherapeutic agents.

PMID- 10414954
TI  - Exacerbation of damage and altered NF-kappaB activation in mice lacking tumor
      necrosis factor receptors after traumatic brain injury.
AB  - Tumor necrosis factor alpha (TNFalpha) is widely expressed in both neurons and
      glia and has been shown to be upregulated after traumatic brain injury (TBI).
      TNFalpha receptor activation results in activation of the transcription factor
      nuclear factor kappaB (NF-kappaB), which may serve an antiapoptotic role via the
      induction of target genes manganese superoxide dismutase (MnSOD) and/or
      calbindin. In the present study, we used a controlled cortical impact model of
      TBI with pertinent lines of transgenic mice to combine both morphological
      characterization and molecular analysis to elucidate the role of TNFalpha after
      TBI. Measurements of both the lesion volume and the blood-brain barrier breach
      indicated exacerbations in mice rendered genetically deficient in both the p55
      and p75 TNFalpha receptors (TNFR-KO) compared with wild-type animals.
      Additionally, animals genetically altered to overexpress MnSOD showed a
      significant decrease in lesion volume compared with that of control littermates,
      whereas no alterations were observed in mice lacking the calcium-binding protein
      calbindin D28k. Analysis of NF-kappaB activation and relative levels of MnSOD
      revealed delayed responses in the injured cortex of TNFR-KO animals compared with
      wild-type animals, implying that endogenous TNFalpha may be neuroprotective after
      TBI.

PMID- 10414955
TI  - Contributions of residual calcium to fast synaptic transmission.
AB  - Fast neurotransmitter release is driven by high calcium (10-100 microM) near open
      channels (Ca(local)), followed by a much smaller (<1 microM), longer-lasting
      residual calcium (Ca(res)). The most prominent component of release, phasic
      release, lasts several milliseconds and is thought to be triggered by Ca(local).
      A transient tail of release then continues over the next 20 msec at 1-10% of peak
      rates. This transient component of release, which we refer to as TR, is poorly
      understood, and there is conflicting evidence regarding the role of Ca(local) and
      Ca(res) in its generation. We used optical methods to monitor Ca(res) and whole
      cell voltage-clamp recordings to study TR at synapses between granule cells and
      stellate cells in rat cerebellar slices. After stimulation the probability of
      release is elevated greatly, peaking at 500 microseconds and then slowly
      declining to prestimulus levels after tens of milliseconds. After speeding the
      decay of Ca(res) levels with EGTA, release is confined to a 3 msec interval, and
      TR is eliminated. Thus, we find that Ca(res) accounts for a transient tail of
      release on the millisecond time scale that helps to shape the average synaptic
      current and accounts for at least 20% of the synaptic charge in the 20 msec
      interval after stimulation. Ca(res)-dependent TR is likely to contribute
      significantly to fast synaptic transmission under physiological conditions,
      particularly during high-frequency bursts that elevate Ca(res).

PMID- 10414956
TI  - Myosin VIIa participates in opsin transport through the photoreceptor cilium.
AB  - Two types of Usher syndrome, a blindness-deafness disorder, result from mutations
      in the myosin VIIa gene. As for most other unconventional myosins, little is
      known about the function or functions of myosin VIIa. Here, we studied the
      photoreceptor cells of mice with mutant myosin VIIa by electron immunomicroscopy
      and microscopic autoradiography. We found evidence that myosin VIIa functions in
      the connecting cilium of each photoreceptor cell and participates in the
      transport of opsin through this structure. These findings provide the first
      direct evidence that opsin travels along the connecting cilium en route to the
      outer segment. They demonstrate that a myosin may function in a cilium and
      suggest that abnormal opsin transport might contribute to blindness in Usher
      syndrome.

PMID- 10414957
TI  - Demonstration of a coupled metabolism-efflux process at the choroid plexus as a
      mechanism of brain protection toward xenobiotics.
AB  - Brain homeostasis depends on the composition of both brain interstitial fluid and
      CSF. Whereas the former is largely controlled by the blood-brain barrier, the
      latter is regulated by a highly specialized blood-CSF interface, the choroid
      plexus epithelium, which acts either by controlling the influx of blood-borne
      compounds, or by clearing deleterious molecules and metabolites from CSF. To
      investigate mechanisms of brain protection at the choroid plexus, the blood-CSF
      barrier was reconstituted in vitro by culturing epithelial cells isolated from
      newborn rat choroid plexuses of either the fourth or the lateral ventricle. The
      cells grown in primary culture on semipermeable membranes established a pure
      polarized monolayer displaying structural and functional barrier features, (tight
      junctions, high electric resistance, low permeability to paracellular markers)
      and maintaining tissue-specific markers (transthyretin) and specific transporters
      for micronutriments (amino acids, nucleosides). In particular, the high enzymatic
      drug metabolism capacity of choroid plexus was preserved in the in vitro blood
      CSF interface. Using this model, we demonstrated that choroid plexuses can act as
      an absolute blood-CSF barrier toward 1-naphthol, a cytotoxic, lipophilic model
      compound, by a coupled metabolism-efflux mechanism. This compound was metabolized
      in situ via uridine diphosphate glururonosyltransferase-catalyzed conjugation,
      and the cellular efflux of the glucurono-conjugate was mediated by a transporter
      predominantly located at the basolateral, i.e., blood-facing membrane. The
      transport process was temperature-dependent, probenecid-sensitive, and recognized
      other glucuronides. Efflux of 1-naphthol metabolite was inhibited by
      intracellular glutathione S-conjugates. This metabolism-polarized efflux process
      adds a new facet to the understanding of the protective functions of choroid
      plexuses.

PMID- 10414958
TI  - L-proline and L-pipecolate induce enkephalin-sensitive currents in human
      embryonic kidney 293 cells transfected with the high-affinity mammalian brain L
      proline transporter.
AB  - The high-affinity mammalian brain L-proline transporter (PROT) belongs to the
      GAT1 gene family, which includes Na- and Cl-dependent plasma membrane carriers
      for neurotransmitters, osmolites, and metabolites. These transporters couple
      substrate flux to transmembrane electrochemical gradients, particularly the Na
      gradient. In the nervous system, transporters clear synapses and help to
      replenish transmitters in nerve terminals. The localization of PROT to specific
      excitatory terminals in rat forebrain suggests a role for this carrier in
      excitatory transmission (). We investigated the voltage regulation and
      electrogenicity of this novel transporter, using human embryonic kidney (HEK) 293
      cells stably transfected with rat PROT cDNA. In physiological solutions between 
      140 and -40 mV, L-proline (PRO) and its six-member ring congener L-pipecolate
      (PIP) induced inward current. The current-voltage relationship and the variance
      of current fluctuations were similar for PRO- and PIP-induced current, and the
      ratio of induced variance to the mean current ranged from 20 to 60 fA. Des-Tyr
      Leu-enkephalin (GGFL), a competitive peptide inhibitor of PROT, reduced the rat
      PROT-associated current to control levels. GGFL alone did not elicit currents,
      and the GGFL-sensitive substrate-induced current was absent in nontransfected
      cells. Finally, GGFL inhibited PROT-mediated transport only when applied to the
      extracellular face of PROT. These data suggest that (1) PROT uptake is
      electrogenic, (2) individual transporter currents are voltage-independent, and
      (3) GGFL is a nonsubstrate inhibitor that interacts either with an extracellular
      domain of PROT or in an externally accessible pore.

PMID- 10414959
TI  - Nicotinic receptor assembly requires multiple regions throughout the gamma
      subunit.
AB  - Assembly of ionotropic neurotransmitter receptors typified by acetylcholine
      receptors (AChRs) is thought to be directed by an N-terminal extracellular domain
      of a subunit. Consistent with this hypothesis, chimeras with the delta subunit N
      terminal domain fused to the rest of the gamma subunit can substitute for delta,
      but not gamma, subunits during AChR assembly. However, chimeras with the gamma
      subunit N-terminal domain fused to the rest of the delta subunit cannot
      substitute for gamma or delta subunits during assembly. Furthermore, expression
      of this chimera with the four wild-type subunits prevents the formation of alpha
      bungarotoxin (Bgt) binding sites. Instead of AChR pentamers, complexes are
      assembled containing only the chimera and either alpha or beta subunits. Based on
      the results of additional gamma-delta chimeras, there are at least two different
      regions within the C-terminal half of the chimera required for the dominant
      negative effect. Our results indicate that the N-terminal domain of the gamma
      subunit mediates the initial subunit associations, whereas signals in the C
      terminal half of the subunit are required for subsequent subunit interactions.

PMID- 10414960
TI  - Two actions of calcium regulate the supply of releasable vesicles at the ribbon
      synapse of retinal bipolar cells.
AB  - Ribbon synapses of sensory neurons are able to sustain high rates of exocytosis
      in response to maintained depolarization, but it is not known how this is
      achieved. Using the capacitance technique, we have found that Ca(2+) regulates
      the supply of releasable vesicles at the ribbon synapse of depolarizing bipolar
      cells from the retina of goldfish. Ca(2+) had two actions that could be
      differentiated by introduction of the Ca(2+) chelator EGTA; one action stimulated
      refilling of the rapidly releasable pool of vesicles from a reserve pool, and a
      second action stimulated recruitment of vesicles to the reserve pool. The
      capacity of the reserve pool was approximately 3500 vesicles, which is similar to
      the number that can attach to the ribbons. These results suggest that continuous
      exocytosis at ribbon synapses is maintained by the Ca(2+)-dependent translocation
      of vesicles from the cytoplasm, through the ribbon, to release sites on the
      plasma membrane.

PMID- 10414961
TI  - Conformational ensembles: the role of neuropeptide structures in receptor
      binding.
AB  - Conformational properties of several similar FMRFamide-like neuropeptides from
      mollusks were investigated by nuclear magnetic resonance (NMR) spectroscopy. It
      was found that amino acid substitutions in the N-terminal variable regions of the
      peptides had dramatic effects on the populations of reverse turns in solution.
      The populations of turns, as measured by two independent NMR parameters, were
      found to be highly correlated (r(2) = 0.93 and 0. 82) with IC(50) values using
      receptor membrane preparations from Helix aspersa (Payza, 1987; Payza et al.,
      1989). These results suggest that the amount of turn in the free peptide can
      influence the receptor binding affinities of that peptide. On the basis of these
      observations, a model was developed in which only a single species from a
      conformational ensemble of an unbound peptide will bind to a particular receptor.
      Thus, the conformational ensemble reduces the effective concentration of a
      particular peptide with respect to a particular receptor.

PMID- 10414962
TI  - Pituitary adenylate cyclase-activating polypeptide activates a phospholipase C
      dependent signal pathway in chick ciliary ganglion neurons that selectively
      inhibits alpha7-containing nicotinic receptors.
AB  - Neuropeptide receptors couple via G-proteins to two principal signaling pathways
      that elevate cAMP through adenylate cyclase (AC) or mobilize intracellular Ca(2+)
      through phospholipase C (PLC)-stimulated inositol phosphate (IP) turnover and
      production of inositol 1,4,5-trisphosphate (IP(3)). We showed previously that
      high-affinity receptors for pituitary adenylate cyclase-activating polypeptide
      (PACAP) are present on chick ciliary ganglion neurons and that receptor
      occupation increases cAMP production, resulting in enhanced acetylcholine
      sensitivity. After we suppressed AC activity and cAMP production with 2'-5'
      dideoxyadenosine, however, PACAP no longer increased acetylcholine sensitivity
      but instead reduced it, suggesting that an AC-independent signal pathway
      activated by PACAP inhibits some nicotinic acetylcholine receptors (AChRs). We
      now use fast-perfusion, imaging, and biochemical methods to identify the AChRs
      modulated by PACAP and to characterize the signal pathway responsible for their
      inhibition. Without previous AC block, both the rapidly desensitizing, alpha
      bungarotoxin (alphaBgt)-sensitive alpha7-AChRs and the slowly desensitizing,
      alphaBgt-insensitive alpha3*-AChRs on the neurons were potentiated by PACAP.
      After AC blockade, however, PACAP inhibited alpha7-AChRs but left alpha3*-AChRs
      unaffected. The selective inhibition of alpha7-AChRs appeared to use a PLC
      signaling pathway because it was not seen after lowering PLC activity or
      buffering intracellular Ca(2+) and was mimicked by dialyzing neurons with an
      IP(3) receptor agonist. PACAP also induced IP turnover and increased [Ca(2+)](i)
      assessed directly with Fluo-3AM imaging. Given our previous findings that PACAP
      receptors couple to AC, the present results demonstrate a remarkable ability of a
      single neuropeptide to activate two signaling pathways and in so doing
      selectively regulate two classes of downstream ion channel targets.

PMID- 10414963
TI  - Expression and branch-specific export of mRNA are regulated by synapse formation
      and interaction with specific postsynaptic targets.
AB  - Mechanosensory neurons (SNs) of Aplysia form synapses in culture with some
      targets (L7), but not others (L11), even when a SN is plated with both targets.
      We examined whether branch-specific net export of mRNA encoding synapse-specific
      molecules might contribute to branch-specific synapse formation. Single-cell RT
      PCR was used to assay levels of mRNA encoding the SN-specific neuropeptide
      (sensorin A) and other transcripts in cell bodies and neuritic processes of SNs
      cultured alone or with synaptic targets. Some mRNAs are exported to neurites, but
      not others. Sensorin A mRNA is detected only in SN cell bodies and neurites, and
      expression levels correlate with the strength of the synaptic connections formed
      with L7 after 4 d in culture. After 4 d, more sensorin A transcripts are detected
      in SN neurites contacting L7 than in SN neurites contacting L11. The differential
      expression at 4 d is found even when a single SN contacts both targets
      simultaneously. By contrast, no significant difference in expression is detected
      in SN neurites contacting L7 versus L11 after 1 d of coculture. The results
      suggest that interaction and synapse formation with a specific target lead to a
      time-dependent change in the branch-specific accumulation of sensorin A mRNA in
      SNs. Because local protein synthesis at synaptic sites might contribute to
      synaptic function or plasticity, the results suggest that branch-specific
      targeting of mRNA encoding synapse-related molecules may contribute to the
      formation of specific synapses.

PMID- 10414965
TI  - Identification of amino acid residues within GABA(A) receptor beta subunits that
      mediate both homomeric and heteromeric receptor expression.
AB  - GABA(A) receptors are believed to be heteropentamers that can be constructed from
      six subunit classes: alpha(1-6), beta(1-4), gamma(1-3), delta, epsilon, and pi.
      Given that individual neurons often express multiple receptor subunits, it is
      important to understand how these receptors assemble. To determine which domains
      of receptor subunits control assembly, we have exploited the differing
      capabilities of the beta2 and beta3 subunits to form functional cell surface
      homomeric receptors. Using a chimeric approach, we have identified four amino
      acids in the N-terminal domain of the beta3 subunit that mediate functional cell
      surface expression of this subunit compared with beta2, which is retained within
      the endoplasmic reticulum. Substitution of these four amino acids-glycine 171,
      lysine 173, glutamate 179, and arginine 180-into the beta2 subunit was sufficient
      to enable the beta2 subunit to homo-oligomerize. The effect of this putative
      "assembly signal" on the production of heteromeric receptors composed of
      alphabeta and betagamma subunits was also analyzed. This signal was not critical
      for the formation of receptors composed of either alpha1beta2 or alpha1beta3
      subunits, suggesting that mutation of these residues did not disrupt subunit
      folding. However, this signal was important in the formation of betagamma2
      receptors. These residues did not seem to affect the initial association of beta2
      and gamma2 subunits but appeared to be important for the subsequent production of
      functional receptors. Our studies identify, for the first time, key residues
      within the N-terminal domains of receptor beta subunits that mediate the
      selective assembly of GABA(A) receptors.

PMID- 10414966
TI  - Depolarization-induced mitochondrial Ca accumulation in sympathetic neurons:
      spatial and temporal characteristics.
AB  - Several lines of evidence suggest that neuronal mitochondria accumulate calcium
      when the cytosolic free Ca(2+) concentration ([Ca(2+)](i)) is elevated to levels
      approaching approximately 500 nM, but the spatial, temporal, and quantitative
      characteristics of net mitochondrial Ca uptake during stimulus-evoked [Ca(2+)](i)
      elevations are not well understood. Here, we report direct measurements of
      depolarization-induced changes in intramitochondrial total Ca concentration
      ([Ca](mito)) obtained by x-ray microanalysis of rapidly frozen neurons from frog
      sympathetic ganglia. Unstimulated control cells exhibited undetectably low
      [Ca](mito), but high K(+) depolarization (50 mM, 45 sec), which elevates
      [Ca(2+)](i) to approximately 600 nM, increased [Ca](mito) to 13.0 +/- 1.5 mmol/kg
      dry weight; this increase was abolished by carbonyl cyanide p-(trifluoromethoxy)
      phenylhydrazone (FCCP). The elevation of [Ca](mito) was a function of both
      depolarization strength and duration. After repolarization, [Ca](mito) recovered
      to prestimulation levels with a time course that paralleled the decline in
      [Ca(2+)](i). Depolarization-induced increases in [Ca](mito) were spatially
      heterogeneous. At the level of single mitochondria, [Ca](mito) elevations
      depended on proximity to the plasma membrane, consistent with predictions of a
      diffusion model that considers radial [Ca(2+)](i) gradients that exist early
      during depolarization. Within individual mitochondria, Ca was concentrated in
      small, discrete sites, possibly reflecting a high-capacity intramitochondrial Ca
      storage mechanism. These findings demonstrate that in situ Ca accumulation by
      mitochondria, now directly identified as the structural correlate of the "FCCP
      sensitive store, " is robust, reversible, graded with stimulus strength and
      duration, and dependent on spatial location.

PMID- 10414964
TI  - L-Type Ca(2+) channels are essential for glutamate-mediated CREB phosphorylation
      and c-fos gene expression in striatal neurons.
AB  - The second messenger pathways linking receptor activation at the membrane to
      changes in the nucleus are just beginning to be unraveled in neurons. The work
      presented here attempts to identify in striatal neurons the pathways that mediate
      cAMP response element-binding protein (CREB) phosphorylation and gene expression
      in response to NMDA receptor activation. We investigated the phosphorylation of
      the transcription factor CREB, the expression of the immediate early gene c-fos,
      and the induction of a transfected reporter gene under the transcriptional
      control of CREB after stimulation of ionotropic glutamate receptors. We found
      that neither AMPA/kainate receptors nor NMDA receptors were able to stimulate
      independently a second messenger pathway that led to CREB phosphorylation or c
      fos gene expression. Instead, we saw a consecutive pathway from AMPA/kainate
      receptors to NMDA receptors and from NMDA receptors to L-type Ca(2+) channels.
      AMPA/kainate receptors were involved in relieving the Mg(2+) block of NMDA
      receptors, and NMDA receptors triggered the opening of L-type Ca(2+) channels.
      The second messenger pathway that activates CREB phosphorylation and c-fos gene
      expression is likely activated by Ca(2+) entry through L-type Ca(2+) channels. We
      conclude that in primary striatal neurons glutamate-mediated signal transduction
      is dependent on functional L-type Ca(2+) channels.

PMID- 10414967
TI  - Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen
      receptors.
AB  - We have shown that physiological levels of estradiol exert profound protective
      effects on the cerebral cortex in ischemia induced by permanent middle cerebral
      artery occlusion. The major goal of this study was to begin to elucidate
      potential mechanisms of estradiol action in injury. Bcl-2 is a proto-oncogene
      that promotes cell survival in a variety of tissues including the brain. Because
      estradiol is known to promote cell survival via Bcl-2 in non-neural tissues, we
      tested the hypothesis that estradiol decreases cell death by influencing bcl-2
      expression in ischemic brain injury. Furthermore, because estradiol may protect
      the brain through estrogen receptor-mediated mechanisms, we examined expression
      of both receptor subtypes ERalpha and ERbeta in the normal and injured brain. We
      analyzed gene expression by RT-PCR in microdissected regions of the cerebral
      cortex obtained from injured and sham female rats treated with estradiol or oil.
      We found that estradiol prevented the injury-induced downregulation of bcl-2
      expression. This effect was specific to bcl-2, as expression of other members of
      the bcl-2 family (bax, bcl-x(L), bcl-x(S), and bad) was unaffected by estradiol
      treatment. We also found that estrogen receptors were differentially modulated in
      injury, with ERbeta expression paralleling bcl-2 expression. Finally, we provide
      the first evidence of functional ERbeta protein that is capable of binding ligand
      within the region of the cortex where estradiol-mediated neuroprotection was
      observed in cerebral ischemia. These findings indicate that estradiol modulates
      the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that
      estrogen receptors may be involved in hormone-mediated neuroprotection.

PMID- 10414968
TI  - Delayed rectifier currents in rat globus pallidus neurons are attributable to
      Kv2.1 and Kv3.1/3.2 K(+) channels.
AB  - The symptoms of Parkinson disease are thought to result in part from increased
      burst activity in globus pallidus neurons. To gain a better understanding of the
      factors governing this activity, we studied delayed rectifier K(+) conductances
      in acutely isolated rat globus pallidus (GP) neurons, using whole-cell voltage
      clamp and single-cell RT-PCR techniques. From a holding potential of -40 mV,
      depolarizing voltage steps in identified GP neurons evoked slowly inactivating
      K(+) currents. Analysis of the tail currents revealed rapidly and slowly
      deactivating currents of similar amplitude. The fast component of the current
      deactivated with a time constant of 11. 1 +/- 0.8 msec at -40 mV and was blocked
      by micromolar concentrations of 4-AP and TEA (K(D) approximately 140 microM). The
      slow component of the current deactivated with a time constant of 89 +/- 10
      microseconds at -40 mV and was less sensitive to TEA (K(D) = 0.8 mM) and 4-AP
      (K(D) approximately 6 mM). Organic antagonists of Kv1 family channels had little
      or no effect on somatic currents. These properties are consistent with the
      hypothesis that the rapidly deactivating current is attributable to Kv3.1/3.2
      channels and the slowly deactivating current to Kv2.1-containing channels.
      Semiquantitative single-cell RT-PCR analysis of Kv3 and Kv2 family mRNAs
      supported this conclusion. An alteration in the balance of these two channel
      types could underlie the emergence of burst firing after dopamine-depleting
      lesions.

PMID- 10414969
TI  - Roles of rapsyn and agrin in interaction of postsynaptic proteins with
      acetylcholine receptors.
AB  - At the neuromuscular junction, aggregates of acetylcholine receptors (AChRs) are
      anchored in the muscle membrane by association with rapsyn and other postsynaptic
      proteins. We have investigated the interactions between the AChR and these
      proteins in cultured C2 myotubes before and after treatment with agrin, a nerve
      derived protein that induces AChRs to cluster. When AChRs were isolated from
      detergent extracts of untreated C2 myotubes, they were associated with rapsyn
      and, to a lesser degree, with utrophin, beta-dystroglycan, MuSK, and src-related
      kinases, but not with syntrophin. Treatment with agrin increased the association
      of AChRs with MuSK, a receptor tyrosine kinase that forms part of the agrin
      receptor complex, without affecting other interactions. Analysis of rapsyn
      deficient myotubes, which do not form protein clusters in response to agrin,
      revealed that rapsyn is required for association of the AChR with utrophin and
      beta-dystroglycan, and for the agrin-induced increase in association with MuSK,
      but not for constitutive interactions with MuSK and src-related kinases. In
      rapsyn -/- myotubes, agrin caused normal tyrosine phosphorylation of AChR
      associated and total MuSK, whereas phosphorylation of the AChR beta subunit, both
      constitutive and agrin-induced, was strongly reduced. These results show first
      that aneural myotubes contain preassembled AChR protein complexes that may
      function in the assembly of the postsynaptic apparatus, and second that rapsyn,
      in addition to its role in AChR phosphorylation, mediates selected protein
      interactions with the AChR and serves as a link between the AChR and the
      dystrophin/utrophin glycoprotein complex.

PMID- 10414970
TI  - Local presentation of substrate molecules directs axon specification by cultured
      hippocampal neurons.
AB  - Axon specification is a crucial, early step in neuronal development, but little
      is known about how this event is controlled in vivo. To test the hypothesis that
      local presentation of growth-promoting molecules can direct axon specification,
      we cultured hippocampal neurons on substrates patterned with stripes of poly-L
      lysine and either laminin (LN) or the neuron-glia cell adhesion molecule (NgCAM).
      Although undifferentiated neurites contacted both substrates equally, axons
      formed preferentially on LN or NgCAM. Time-lapse studies revealed that changes in
      the growth pattern of a cell indicative of axon specification began almost
      immediately after the growth cone of one of the neurites of the cell contacted LN
      or NgCAM. When cells were plated on alternating stripes of LN and NgCAM, cells
      with their somata on LN usually formed axons on NgCAM, whereas those with somata
      on NgCAM preferentially formed axons on LN. This suggests that the change from
      one axon-promoting substrate to another also provides a signal sufficient to
      specify the axon. These results demonstrate that contact with preferred substrate
      molecules can govern which neurite becomes the axon and thus direct the
      development of neuronal polarity.

PMID- 10414971
TI  - Correlation of miniature synaptic activity and evoked release probability in
      cultures of cortical neurons.
AB  - Spontaneous miniature synaptic activity is caused by action potential (AP)
      independent release of transmitter vesicles and is regulated at the level of
      single synapses. In cultured cortical neurons we have used this spontaneous
      vesicle turnover to load the styryl dye FM1-43 into synapses with high rates of
      miniature synaptic activity. Automated selection procedures restricted analysis
      to synapses with sufficient levels of miniature activity-mediated FM1-43 uptake.
      After FM1-43 loading, vesicular FM1-43 release in response to AP stimulation was
      recorded at single synapses as a measure of release probability. We find that
      synapses with high rates of miniature activity possess significantly enhanced
      evoked release rates compared with a control population. Because the difference
      in release rates between the two populations is [Ca(2+)](o)-dependent, it is most
      likely caused by a difference in release probability. Within the subpopulation of
      synapses with high miniature activity, we find that the probabilities for
      miniature and AP-evoked release are correlated at single synaptic sites.
      Furthermore, the degree of miniature synaptic activity is correlated with the
      vesicle pool size. These findings suggest that both evoked and miniature
      vesicular release are regulated in parallel and that the frequency of miniature
      synaptic activity can be used as an indicator for evoked release efficacy.

PMID- 10414972
TI  - Glutamate release through volume-activated channels during spreading depression.
AB  - Volume-sensitive organic anion channels (VSOACs) in astrocytes are activated by
      cell swelling and are permeable to organic anions, such as glutamate and taurine.
      We have examined the release of glutamate through VSOACs during the propagation
      of spreading depression (SD). SD was induced by bath application of ouabain in
      hippocampal brain slices and was monitored by imaging intrinsic optical signals,
      a technique that provides a measure of cellular swelling. The onset of SD was
      associated with increased light transmittance, confirming previous studies that
      cellular swelling occurs during SD. NMDA receptor antagonists, either
      noncompetitive (MK-801, 10-50 microM) or competitive (CGS-17355, 100 microM),
      reduced the rate of propagation of SD, indicating that glutamate release
      contributes to SD onset. SD still occurred in zero Ca(2+)-EGTA (0-Ca(2+)-EGTA)
      solution, a manipulation that depresses synaptic transmission. HPLC measurements
      indicated that, even in this solution, there was significant glutamate release.
      Two lines of experiments indicated that glutamate was released through VSOACs
      during SD. First, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), a blocker
      of VSOACs, depressed the rate of propagation of SD in a manner similar to NMDA
      antagonists. Second, NPPB inhibited the release of glutamate during SD in 0
      Ca(2+)-EGTA external solution. These results indicate that cellular swelling
      during SD causes the activation of VSOACs and the release of glutamate by
      permeation through this channel. Cellular swelling is a result of neuronal
      activity and is observed during excitotoxicity. Therefore, glutamate release from
      VSOAC activation could occur under conditions of cell swelling and contribute to
      excitotoxic damage.

PMID- 10414973
TI  - Bcl-2 overexpression does not protect neurons from mutant neurofilament-mediated
      motor neuron degeneration.
AB  - Transgenic mice with a point mutation in the light neurofilament gene develop
      amyotrophic lateral sclerosis-like motor neuron disease characterized by
      selective spinal motor neuron loss, neurofilamentous accumulations, and severe
      muscle atrophy. To test whether the large motor neurons at risk in this disease
      could be protected from mutant neurofilament-mediated killing, these mice were
      bred to mice overexpressing the human Bcl-2 proto-oncogene. Elevated levels of
      Bcl-2 increased the numbers of motor and sensory axons surviving after the
      developmental period of naturally occurring cell death but did not greatly reduce
      the number of degenerating axons or protect the large motor neurons from mutant
      neurofilament-mediated death.

PMID- 10414975
TI  - Gp-41-mediated astrocyte inducible nitric oxide synthase mRNA expression:
      involvement of interleukin-1beta production by microglia.
AB  - Mechanisms underlying human immunodeficiency virus-1 encephalopathy are not
      completely known; however, recent studies suggest that the viral protein gp41 may
      be neurotoxic via activation of inducible nitric oxide synthase (iNOS) in glial
      cells. In the present study, we investigated the NO-generating activity of
      primary human fetal astrocytes in response to gp41 and the relationship to
      microglial cell production of interleukin-1 (IL-1). Gp41 failed to trigger iNOS
      mRNA expression in highly enriched (>99%) astrocyte or microglial cell cultures.
      However, gp41-treated microglia released a factor(s) that triggered iNOS mRNA
      expression and NO production in astrocytes. Because IL-1 receptor antagonist
      protein blocked gp41-induced NO production, a pivotal role was suggested for
      microglial cell IL-1 production in astrocyte iNOS expression. Also, gp41 induced
      IL-1beta mRNA expression and IL-1 production in microglial cell but not astrocyte
      cultures. Using specific inhibitors, we found that gp41-induced IL-1beta
      production in microglia was mediated via a signaling pathway involving protein
      tyrosine kinase. These data support the hypothesis that gp41 induces astrocyte NO
      production indirectly by triggering upregulation of microglial cell IL-1
      expression.

PMID- 10414974
TI  - A novel neuron-enriched homolog of the erythrocyte membrane cytoskeletal protein
      4.1.
AB  - We report the molecular cloning and characterization of 4.1N, a novel neuronal
      homolog of the erythrocyte membrane cytoskeletal protein 4.1 (4.1R). The 879
      amino acid protein shares 70, 36, and 46% identity with 4.1R in the defined
      membrane-binding, spectrin-actin-binding, and C-terminal domains, respectively.
      4.1N is expressed in almost all central and peripheral neurons of the body and is
      detected in embryonic neurons at the earliest stage of postmitotic
      differentiation. Like 4.1R, 4.1N has multiple splice forms as evidenced by PCR
      and Western analysis. Whereas the predominant 4.1N isoform identified in brain is
      approximately 135 kDa, a smaller 100 kDa isoform is enriched in peripheral
      tissues. Immunohistochemical studies using a polyclonal 4.1N antibody revealed
      several patterns of neuronal staining, with localizations in the neuronal cell
      body, dendrites, and axons. In certain neuronal locations, including the granule
      cell layers of the cerebellum and dentate gyrus, a distinct punctate-staining
      pattern was observed consistent with a synaptic localization. In primary
      hippocampal cultures, mouse 4.1N is enriched at the discrete sites of synaptic
      contact, colocalizing with the postsynaptic density protein of 95 kDa (a
      postsynaptic marker) and glutamate receptor type 1 (an excitatory postsynaptic
      marker). By analogy with the roles of 4.1R in red blood cells, 4.1N may function
      to confer stability and plasticity to the neuronal membrane via interactions with
      multiple binding partners, including the spectrin-actin-based cytoskeleton,
      integral membrane channels and receptors, and membrane-associated guanylate
      kinases.

PMID- 10414976
TI  - Ultrastructural localization of the alpha4-subunit of the neuronal acetylcholine
      nicotinic receptor in the rat substantia nigra.
AB  - The distribution of the alpha4-subunit of the neuronal nicotinic acetylcholine
      receptor (nAChR) in the rat brain was examined at light and electron microscopy
      levels using immunohistochemical staining. In the present study we demonstrate
      the specificity, in both tissue homogenates and brain sections, of a polyclonal
      antibody raised against the rat nAChR alpha4-subunit. The characterization of
      this antibody involved: (1) Western blot analysis of rat brain homogenates and
      membrane extracts from cells previously transfected with diverse combinations of
      neuronal nAChR subunits, and (2) immunohistochemistry using transfected cells and
      rat brain tissue. At the light microscope level, the alpha4-subunit-like
      immunoreactivity (LI) was widely distributed in the rat brain and matched the
      distribution of the alpha4-subunit transcripts observed previously by in situ
      hybridization. Strong immunohistochemical labeling was detected in the
      mesencephalic dopaminergic nuclei. The nAChRs in this region are thought to be
      responsible for the modulation of dopaminergic transmission. The neurotransmitter
      identity of alpha4-immunolabeled neurons in the substantia nigra pars compacta
      (SNpc) and the ventral tegmental area was thus assessed by investigating the
      possible colocalization of the nAChR alpha4-subunit with tyrosine hydroxylase
      using confocal microscopy. The double labeling experiments unambiguously
      indicated that the alpha4-subunit-LI is present in dopaminergic neurons. At the
      electron microscope level, the neurons in the SNpc exhibited alpha4-subunit-LI in
      association with a minority of postsynaptic densities, suggesting that the alpha4
      subunit may be a component of functional nAChRs mediating synaptic transmission
      between midbrain cholinergic neurons and mesencephalic dopaminergic neurons.

PMID- 10414977
TI  - Group I metabotropic glutamate receptors at GABAergic synapses in monkeys.
AB  - Recent data showed that group I metabotropic glutamate receptors (mGluRs) are
      located perisynaptic to the postsynaptic specializations of asymmetric
      glutamatergic synapses in the cerebellum and hippocampus in rats. In the present
      study, we used immunogold labeling to elucidate the subsynaptic localization of
      group I mGluRs (mGluR1a and mGluR5) in the internal and external segments of the
      globus pallidus in monkeys. In contrast to hippocampal and cerebellar neurons,
      which receive massive glutamatergic inputs, dendrites of pallidal neurons are
      covered with GABAergic boutons from the striatum intermingled with a small
      proportion of glutamatergic terminals arising largely from the subthalamic
      nucleus. In line with previous data, mGluR1a and mGluR5 immunoreactivity was
      found at the edge of the postsynaptic specializations of asymmetric synapses
      established by subthalamic-like boutons in the monkey pallidum. However, a large
      proportion of gold particles were also seen in the main body of the postsynaptic
      specializations of symmetric synapses formed by striatal GABAergic terminals.
      These data raise questions about the possible sources of activation of these
      receptors and the potential roles of group I mGluRs in modulating GABAergic
      neurotransmission at striatopallidal synapses.

PMID- 10414978
TI  - Isolectin B(4)-positive and -negative nociceptors are functionally distinct.
AB  - Small-diameter sensory neurons that are primarily nociceptors can be divided
      neurochemically into two populations: isolectin B(4) (IB(4))-positive
      nonpeptidergic neurons, and IB(4)-negative peptidergic neurons. It has been shown
      that IB(4)-positive neurons depend on glial-derived neurotrophic factor (GDNF),
      whereas IB(4)-negative neurons depend on NGF for survival during postnatal
      development (Molliver et al., 1997). Furthermore, these two populations of
      nociceptors terminate in distinct regions of the superficial spinal cord. To
      date, however, no evidence exists that indicates whether these two groups of
      nociceptors have distinct functional roles in the process of nociception (Snider
      and McMahon, 1998). To search for functional differences, we performed whole-cell
      voltage and current-clamp recordings on acutely isolated adult mouse dorsal root
      ganglion neurons that were labeled with fluorescent IB(4). We found that IB(4)
      positive neurons have longer-duration action potentials, higher densities of TTX
      resistant sodium currents, and smaller noxious heat-activated currents than IB(4)
      negative neurons. Furthermore, we show that NGF, but not GDNF, directly increases
      the number of neurons that respond to noxious heat. The different
      electrophysiological properties expressed by IB(4)-positive and -negative small
      neurons, including their different heat sensitivities, indicates that they may
      relay distinct aspects of noxious stimuli both acutely and after injury in vivo.

PMID- 10414979
TI  - Proline-rich synapse-associated protein-1/cortactin binding protein 1
      (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic
      density.
AB  - The postsynaptic density (PSD) is crucially involved in the structural and
      functional organization of the postsynaptic neurotransmitter reception apparatus.
      Using antisera against rat brain synaptic junctional protein preparations, we
      isolated cDNAs coding for proline-rich synapse-associated protein-1 (ProSAP1), a
      PDZ-domain protein. This protein was found to be identical to the recently
      described cortactin-binding protein-1 (CortBP1). Homology screening identified a
      related protein, ProSAP2. Specific antisera raised against a C-terminal fusion
      construct and a central part of ProSAP1 detect a cluster of immunoreactive bands
      of 180 kDa in the particulate fraction of rat brain homogenates that copurify
      with the PSD fraction. Transcripts and immunoreactivity are widely distributed in
      the brain and are upregulated during the period of synapse formation in the
      brain. In addition, two short N-terminal insertions are detected; they are
      differentially regulated during brain development. Confocal microscopy of
      hippocampal neurons showed that ProSAP1 is predominantly localized in synapses,
      and immunoelectron microscopy in situ revealed a strong association with PSDs of
      hippocampal excitatory synapses. The accumulation of ProSAP1 at synaptic
      structures was analyzed in the developing cerebral cortex. During early postnatal
      development, strong immunoreactivity is detectable in neurites and somata,
      whereas from postnatal day 10 (P10) onward a punctate staining is observed. At
      the ultrastructural level, the immunoreactivity accumulates at developing PSDs
      starting from P8. Both interaction with the actin-binding protein cortactin and
      early appearance at postsynaptic sites suggest that ProSAP1/CortBP1 may be
      involved in the assembly of the PSD during neuronal differentiation.

PMID- 10414980
TI  - Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO
      1 domain-containing protein that interacts with the cytoplasmic domain of
      neuropilin-1.
AB  - Neuropilin-1 (Npn-1), a receptor for semaphorin III, mediates the guidance of
      growth cones on extending neurites. The molecular mechanism of Npn-1 signaling
      remains unclear. We have used a yeast two-hybrid system to isolate a protein that
      interacts with the cytoplasmic domain of Npn-1. This Npn-1-interacting protein
      (NIP) contains a central PSD-95/Dlg/ZO-1 (PDZ) domain and a C-terminal acyl
      carrier protein domain. The physiological interaction of Npn-1 and NIP is
      supported by co-immunoprecipitation of these two proteins in extracts from a
      heterologous expression system and from a native tissue. The C-terminal three
      amino acids of Npn-1 (S-E-A-COOH), which is conserved from Xenopus to human, is
      responsible for interaction with the PDZ domain-containing C-terminal two-thirds
      of NIP. NIP as well as Npn-1 are broadly expressed in mice as assayed by Northern
      and Western analysis. Immunohistochemistry and in situ hybridization experiments
      revealed that NIP expression overlaps with that of Npn-1. NIP has been
      independently cloned as RGS-GAIP-interacting protein (GIPC), where it was
      identified by virtue of its interaction with the C terminus of RGS-GAIP and
      suggested to participate in clathrin-coated vesicular trafficking. We suggest
      that NIP and GIPC may participate in regulation of Npn-1-mediated signaling as a
      molecular adapter that couples Npn-1 to membrane trafficking machinery in the
      dynamic axon growth cone.

PMID- 10414981
TI  - Association of AMPA receptors with a subset of glutamate receptor-interacting
      protein in vivo.
AB  - The NMDA and AMPA classes of ionotropic glutamate receptors are concentrated at
      postsynaptic sites in excitatory synapses. NMDA receptors interact via their NR2
      subunits with PSD-95/SAP90 family proteins, whereas AMPA receptors bind via their
      GluR2/3 subunits to glutamate receptor-interacting protein (GRIP), AMPA receptor
      binding protein (ABP), and protein interacting with C kinase 1 (PICK1). We report
      here a novel cDNA (termed ABP-L/GRIP2) that is virtually identical to ABP except
      for additional GRIP-like sequences at the N-terminal and C-terminal ends. Like
      GRIP (which we now term GRIP1), ABP-L/GRIP2 contains a seventh PDZ domain at its
      C terminus. Using antibodies that recognize both these proteins, we examined the
      subcellular localization of GRIP1 and ABP-L/GRIP2 (collectively termed GRIP) and
      their biochemical association with AMPA receptors. Immunogold electron microscopy
      revealed the presence of GRIP at excitatory synapses and also at nonsynaptic
      membranes and within intracellular compartments. The association of native GRIP
      and AMPA receptors was confirmed biochemically by coimmunoprecipitation from rat
      brain extracts. A majority of detergent-extractable GluR2/3 was complexed with
      GRIP in the brain. However, only approximately half of GRIP was associated with
      AMPA receptors. Unexpectedly, immunocytochemistry of cultured hippocampal neurons
      and rat brain at the light microscopic level showed enrichment of GRIP in
      GABAergic neurons and in GABAergic nerve terminals. Thus GRIP is associated with
      inhibitory as well as excitatory synapses. Collectively, these findings support a
      role for GRIP in the synaptic anchoring of AMPA receptors but also suggest that
      GRIP has additional functions unrelated to the binding of AMPA receptors.

PMID- 10414982
TI  - Caveolin-3 upregulation activates beta-secretase-mediated cleavage of the amyloid
      precursor protein in Alzheimer's disease.
AB  - Here, we investigate the involvement of caveolins in the pathophysiology of
      Alzheimer's disease (AD). We show dramatic upregulation of caveolin-3
      immunoreactivity in astroglial cells surrounding senile plaques in brain tissue
      sections from authentic AD patients and an established transgenic mouse model of
      AD. In addition, we find that caveolin-3 physically interacts and biochemically
      colocalizes with amyloid precursor protein (APP) both in vivo and in vitro.
      Interestingly, recombinant overexpression of caveolin-3 in cultured cells
      stimulated beta-secretase-mediated processing of APP. Immunoreactivities of APP
      and presenilins were concomitantly increased in caveolin-3-positive astrocytes.
      Because the presenilins also form a physical complex with caveolin-3, caveolin-3
      may provide a common platform for APP and the presenilins to associate in
      astrocytes. In AD, augmented expression of caveolin-3 and presenilins in reactive
      astrocytes may alter APP processing, leading to the overproduction of its toxic
      amyloid metabolites.

PMID- 10414983
TI  - Autoregulatory sequences are revealed by complex stability screening of the mouse
      brn-3.0 locus.
AB  - The POU-IV or Brn-3 class of transcription factors exhibit conserved structure,
      DNA-binding properties, and expression in specific subclasses of neurons across
      widely diverged species. In the mouse CNS, Brn-3.0 expression characterizes
      specific neurons from neurogenesis through the life of the cell. This
      irreversible activation of expression suggests positive autoregulation. To search
      for cis-acting elements that could mediate autoregulation we used a novel method,
      complex stability screening, which we applied to rapidly identify functional Brn
      3.0 recognition sites within a large genomic region encompassing the mouse brn
      3.0 locus. This method is based on the observation that the kinetic stability of
      Brn-3.0 complexes with specific DNA sequences, as measured by their dissociation
      half-lives, is highly correlated with the ability of those sequences to mediate
      transcriptional activation by Brn-3.0. The principal Brn-3.0 autoregulatory
      region lies approximately 5 kb upstream from the Brn-3.0 transcription start site
      and contains multiple Brn-3.0-binding sites that strongly resemble the optimal
      binding site for this protein class. This region also mediates transactivation by
      the closely related protein Brn-3.2, suggesting a regulatory cascade of POU
      proteins in specific neurons in which Brn-3.2 expression precedes Brn-3.0.

PMID- 10414985
TI  - The contribution of color to motion processing in Macaque middle temporal area.
AB  - The chromatic properties of an image yield strong cues for object boundaries and
      thus hold the potential to facilitate the detection of object motion. The extent
      to which cortical motion detectors exploit chromatic information, however,
      remains a matter of debate. To address this further, we quantified the strength
      of chromatic input to directionally selective neurons in the middle temporal area
      (MT) of macaque cerebral cortex using an equivalent luminance contrast (EqLC)
      paradigm. This paradigm, in which two sinusoidal gratings, one heterochromatic
      and the other achromatic, are superimposed and moved in opposite directions,
      allows the sensitivity of motion detectors to heterochromatic stimuli to be
      quantified and expressed relative to the benchmark of sensitivity for a luminance
      defined stimulus. The results of these experiments demonstrate that the chromatic
      contrast in a moving red-green heterochromatic grating strongly influences
      directional responses in MT when the luminance contrast in that same grating is
      relatively low; for such stimuli, EqLC is at least 5%. When luminance contrast is
      added to the heterochromatic grating, however, EqLC wanes sharply and becomes
      negative (-4%) when luminance contrast is sufficiently high (>17-23%). Thus, the
      chromatic properties of an object appear to confer little or no benefit to motion
      processing by MT neurons when sufficient luminance contrast concurrently exists.
      These data support a simple model in which chromatic motion processing in MT is
      almost exclusively determined by magnocellular input. Additionally, a comparison
      of neuronal and psychophysical data suggests that MT may not be the sole
      contributor to the perceptual experience elicited by motion of heterochromatic
      patterns, or that only a subset of MT neurons serve this function.

PMID- 10414984
TI  - Selective regulation of trkC expression by NT3 in the developing peripheral
      nervous system.
AB  - We have studied the influence of neurotrophin-3 (NT3) on the expression of its
      receptor tyrosine kinase, trkC, in embryonic mice. The expression of trkC
      transcripts encoding full-length and kinase-deficient receptors was almost
      entirely restricted to neurons in the trigeminal ganglion and increased markedly
      throughout development. In NT3(+/-) embryos, the level of trkC mRNA in the
      trigeminal ganglion was much lower than that in wild-type embryos, although there
      was no significant reduction in the total number of neurons in the ganglion. This
      demonstrates that endogenous NT3 regulates trkC expression in trigeminal neurons
      independently of changes in population size. In NT3(-/-) embryos, the number of
      neurons in the trigeminal ganglion was much lower than in wild-type embryos, and
      there was a further reduction in the mean neuronal level of trkC mRNA. Direct
      regulation of trkC mRNA expression in cultured trigeminal neurons was also
      observed, although the finding that trkC mRNA levels were sustained better in
      explant cultures than in dissociated cultures irrespective of the presence of NT3
      suggests that trkC mRNA expression is regulated by additional factors within the
      ganglion. In contrast to trigeminal neurons, the level of trkC mRNA was sustained
      at normal levels in neurons of the sympathetic chain of NT3(-/-) embryos and was
      not increased by NT3 in sympathetic neuron cultures. TrkC mRNA expression in
      developing cutaneous tissues was also unaffected by the NT3 null mutation. In
      summary, our findings provide the first clear evidence that the expression of a
      trk receptor, tyrosine kinase, is regulated by physiological levels of its ligand
      in vivo and show that regulation by NT3 is cell type-specific.

PMID- 10414986
TI  - Evidence for tonic activation of NK-1 receptors during the second phase of the
      formalin test in the Rat.
AB  - Behavioral, electrophysiological, and autoradiographic experiments were done to
      study the second nociceptive phase in the formalin test. In initial experiments,
      this second phase was attenuated by 1-10 mg of the NK-1 receptor antagonist CP
      99,994, given subcutaneously 10, 30, or 60 min before formalin (n = 8-10) and by
      20 microgram given intrathecally 20 min after formalin (n = 13); the inactive
      isomer CP-100,263 was ineffective. In electrophysiological experiments on single
      dorsal horn neurons in vivo, the excitatory responses to subcutaneous formalin
      injection (50 microliter, 2.5%) were attenuated by subsequent intravenously
      administration of the NK-1 receptor antagonist CP-96,345 (0.5 mg/kg; n = 8),
      given 35-40 min after formalin, but not by the inactive enantiomer CP-96,344 (0.5
      mg/kg; n = 9). Finally, autoradiographic binding of exogenous [(125)I]BH
      substance P in the lumbar cord was reduced at 5 and 25 min after formalin (50
      microliter, 1 or 5%), with an intermediate level of reduction at 12 min. These
      data are interpreted as evidence that the second phase of nociceptive scores in
      the formalin test is attributable at least partially to tonic activation of NK-1
      receptors at the spinal level, whether because of a temporally limited release of
      substance P, for example only during the first phase, but a slow removal or
      breakdown of substance P, or, more likely, because of tonic release from primary
      afferents throughout the second phase. Irrespective of the mechanism, it can be
      concluded that at least some of the persistent nociceptive effects associated
      with peripheral inflammation, or at least those provoked by subcutaneous
      injection of formalin, are mediated via continuous activation of NK-1 receptors
      at the level of the spinal dorsal horn; this may relate directly to mechanisms
      underlying prolonged nociceptive pains in humans.

PMID- 10414987
TI  - Smell and taste perception in Drosophila melanogaster larva: toxin expression
      studies in chemosensory neurons.
AB  - GAL4-driven targeted expression of tetanus toxin light chain (UAS-TeTxLC) in a
      subset of chemosensory neurons of the larval antennomaxillary complex (AMC) and
      pharynx causes abnormal chemosensory behavior in Drosophila melanogaster.
      Consistent with strongest staining in the dorsal organ (DO), the presumed
      olfactory organ of the AMC, tetanus toxin-expressing larvae subjected to an
      olfactory preference assay show anosmic behavior to most volatile substances
      tested. Furthermore, we observed reduced responses to sodium chloride, fructose,
      and sucrose in gustatory plate assays. Surprisingly, the entire subset of labeled
      sensory neurons from the terminal (maxillary) organ (TO) of the AMC was found to
      project via the antennal nerve to the larval antennal lobe region. The maxillary
      nerve remained completely unstained. Hence, a subset of neurons from the TO
      builds an anatomical entity with projections from the DO. Our results suggest
      that the AMC contains both olfactory and gustatory sensilla, and that the DO is
      the main olfactory organ in larvae.

PMID- 10414988
TI  - Orbitofrontal cortex and representation of incentive value in associative
      learning.
AB  - Clinical evidence indicates that damage to ventromedial prefrontal cortex
      disrupts goal-directed actions that are guided by motivational and emotional
      factors. As a consequence, patients with such damage characteristically engage in
      maladaptive behaviors. Other research has shown that neurons in the corresponding
      orbital region of prefrontal cortex in laboratory animals encode information
      regarding the incentive properties of goals or expected events. The present study
      investigates the effect of neurotoxic orbitofrontal cortex (OFC) lesions in the
      rat on responses that are normally influenced by associations between a
      conditioned stimulus (CS) and the incentive value of reinforcement. Rats were
      first trained to associate a visual CS with delivery of food pellets to a food
      cup. As a consequence of learning, rats approached the food cup during the CS in
      anticipation of reinforcement. In a second training phase, injection of LiCl
      followed consumption of the food unconditioned stimulus (US) in the home cage, a
      procedure used to alter the incentive value of the US. Subsequently, rats were
      returned to the conditioning chamber, and their responding to the CS in the
      absence of the food US was tested. Lesions of OFC did not affect either the
      initial acquisition of a conditioned response to the light CS in the first
      training phase or taste aversion learning in the second training phase. In the
      test for devaluation, however, OFC rats exhibited no change in conditioned
      responding to the visual CS. This outcome contrasts with the behavior of control
      rats; after devaluation of the US a significant decrease occurred in approach to
      the food cup during presentation of the CS. The results reveal an inability of a
      cue to access representational information about the incentive value of
      associated reinforcement after OFC damage.

PMID- 10414990
TI  - Attenuation of emotional and nonemotional memories after their reactivation: role
      of beta adrenergic receptors.
AB  - A memory trace in its active state is susceptible to interference by amnesic
      agents, such as hypothermia and electroconvulsive shock, and by NMDA receptor
      antagonists, suggesting that a time-dependent consolidation process occurs each
      time a memory is reactivated. The role of beta noradrenergic receptors in
      reconsolidation in rats was examined in both a positively reinforced radial maze
      task and a footshock-reinforced conditioned emotional response task. For the
      former, rats were trained over several days in a spatial reference memory task
      and received a single reactivation trial followed by propranolol. A temporally
      graded impairment was observed when propranolol treatment occurred after the
      memory reactivation trial. In the emotional task, memory impairing effects of
      propranolol were greater when the drug was administered after a reactivation
      trial than when administered immediately after the initial training. These
      results suggest that reactivation of memory triggers a beta receptor-dependent
      cascade of intracellular events, recapitulating that which occurs during initial
      postacquisition consolidation, thus permitting reorganization of the existing
      memory as a function of new information in the retrieval environment. This
      remarkable lability of an active memory trace provides a new basis for
      pharmacotherapeutic intervention in such syndromes as Posttraumatic Stress
      Disorder. beta adrenoreceptor antagonists may be promising pharmacological agents
      for attenuating debilitating memories at the time of their controlled
      reactivation.

PMID- 10414989
TI  - Basolateral amygdala is involved in modulating consolidation of memory for
      classical fear conditioning.
AB  - Previous findings indicate that the basolateral amygdala complex of nuclei (BLC)
      is involved in modulating (i.e., enhancing or impairing) memory consolidation for
      aversive training such as inhibitory avoidance. The present study examined
      whether the BLC also modulates the consolidation of memory for classical fear
      conditioning in which a specific context is paired with footshock. Adult male
      rats with bilateral cannulae targeting the BLC were allowed, first, to habituate
      in a Y maze that had differently shaped and textured arms. On the next day the
      rats were placed in one maze arm (shock arm), and they received four unsignaled
      footshocks. In Experiment 1, immediately after the training some rats received
      BLC inactivation with lidocaine (10 microgram/0.2 microliter per side), and
      control rats received buffered saline. In Experiment 2, rats received immediate
      post-training intra-BLC infusions of the muscarinic receptor agonist oxotremorine
      (10 ng/0.2 microliter per side) or saline. On a 24 hr retention test each rat was
      placed in a "safe" arm of the maze and allowed to access all maze arms. Lidocaine
      treated rats had impaired memory for the classical fear conditioning when they
      were compared with the saline-treated controls: they spent less time freezing,
      entered the shock arm more readily and more often, and spent more time in it. In
      contrast, oxotremorine-treated rats had a stronger memory for the context
      footshock association as assessed by all measures of memory. Thus, post-training
      treatments affecting BLC function modulate memory for Pavlovian contextual fear
      conditioning in a manner similar to that found with other types of training.

PMID- 10414991
TI  - Presynaptic regulation of glutamate release in the ventral tegmental area during
      morphine withdrawal.
AB  - The regulation of glutamate (Glu) release from the excitatory input to dopamine
      cells in the ventral tegmental area (VTA) during acute withdrawal from morphine
      was studied in slices from animals treated for 6-7 d with morphine. EPSCs were
      inhibited by opioid agonists acting at micro-subtype receptors but not by
      selective delta- or kappa-subtype agonists. The opioid inhibition was reduced by
      65% with the potassium channel blocker 4-aminopyridine (4-AP; 100 microM) and a
      12-lipoxygenase inhibitor, baicalein (5 microM), suggesting that opioids acted
      via a transduction pathway involving activation of a voltage-dependent potassium
      conductance by lipoxygenase metabolites as has been shown in the periaqueductal
      gray (). During withdrawal, neither the potency nor the efficacy of D-Ala-Met
      enkephalin-Gly-ol (DAMGO) were changed; however, the blockade of micro-opioid
      inhibition by both 4-AP and baicalein was reduced. In addition, the potency of
      baclofen to depress EPSCs by GABA-B receptors and the effects of the GABA-uptake
      inhibitor NO-711 (10 microM) were increased in withdrawn rats. Finally, group 2
      (but not group 4 or 1) metabotropic glutamate receptor-mediated presynaptic
      inhibition was also enhanced in morphine-withdrawn rats. These results suggest
      that one of the consequences of withdrawal from chronic morphine is an enhanced
      presynaptic inhibition of the excitatory inputs to the dopamine cells of the VTA.
      Inhibition of glutamate release during acute withdrawal would add to the
      inhibition of dopamine cells that is mediated by an augmented release of GABA ().

PMID- 10414992
TI  - Pituitary adenylate cyclase activating peptide phase shifts circadian rhythms in
      a manner similar to light.
AB  - The endogenous circadian pacemaker in mammals is located in the suprachiasmatic
      nuclei (SCN) of the hypothalamus. Various cues can reset circadian rhythm phase,
      thereby entraining the internal rhythm to the environmental cycle, and these
      effects can be investigated using an in vitro method to measure phase shifts of
      the SCN. Although pituitary adenylate cyclase activating peptide (PACAP) is
      localized in retinal inputs to the SCN, it has been reported to alter clock phase
      only during the subjective day (Hannibal et al., 1997), whereas light alters
      phase only in the subjective night. In this study we show that PACAP can reset
      the clock in the photic pattern during the subjective night when applied in 10 pM
      to 1 nM doses. This appears to be mediated via a glutamatergic mechanism,
      possibly by potentiation of NMDA currents as is seen at 10-100 pM. Given at
      higher doses (>10 nM), PACAP shifts in the subjective day, apparently via
      activation of adenylate cyclase and increased intracellular cAMP. These results
      indicate dose and phase specificity of the effects of PACAP, and a new role as a
      transmitter in the retinohypothalamic tract.

PMID- 10414993
TI  - Striatal preproenkephalin gene expression is upregulated in acute but not chronic
      parkinsonian monkeys: implications for the contribution of the indirect
      striatopallidal circuit to parkinsonian symptomatology.
AB  - This study examined the extent of striatal dopamine (DA) denervation and
      coincident expression of preproenkephalin (PPE) mRNA in monkeys made parkinsonian
      by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. Some
      animals (n = 4) became moderately parkinsonian after receiving large doses of
      MPTP over short periods of time and were symptomatic for only a short period of
      time (1-3 months; acute parkinsonian group). Other animals became moderately
      parkinsonian after receiving either escalating doses of MPTP over long periods (4
      6 months; n = 5) or a high dose of MPTP over a short period (<1 month; n = 1) and
      remained symptomatic for an extended period (>8 months; chronic parkinsonian
      group). Despite similar symptomatology and similar degrees of striatal DA
      denervation at the time of their deaths, only acute parkinsonian animals had
      significantly increased PPE expression in sensorimotor striatal regions. PPE
      expression in chronic parkinsonian animals was either not changed or
      significantly decreased in most striatal regions. These findings suggest that the
      duration and not the extent of striatal DA denervation is a critical factor in
      modulating changes in striatal PPE expression. Furthermore, these results
      question the role of increased activity in the enkephalin-containing indirect
      striatopallidal pathway in the expression of parkinsonian symptoms.

PMID- 10414994
TI  - Coordination of fast and slow rhythmic neuronal circuits.
AB  - Interactions among rhythmically active neuronal circuits that oscillate at
      different frequencies are important for generating complex behaviors, yet little
      is known about the underlying cellular mechanisms. We addressed this issue in the
      crab stomatogastric ganglion (STG), which contains two distinct but interacting
      circuits. These circuits generate the gastric mill rhythm (cycle period,
      approximately 10 sec) and the pyloric rhythm (cycle period, approximately 1 sec).
      When the identified modulatory projection neuron named modulatory commissural
      neuron 1 (MCN1) is activated, the gastric mill motor pattern is generated by
      interactions among MCN1 and two STG neurons [the lateral gastric (LG) neuron and
      interneuron 1]. We show that, during MCN1 stimulation, an identified synapse from
      the pyloric circuit onto the gastric mill circuit is pivotal for determining the
      gastric mill cycle period and the gastric-pyloric rhythm coordination. To examine
      the role of this intercircuit synapse, we replaced it with a computational
      equivalent via the dynamic-clamp technique. This enabled us to manipulate better
      the timing and strength of this synapse. We found this synapse to be necessary
      for production of the normal gastric mill cycle period. The synapse acts, during
      each LG neuron interburst, to boost rhythmically the influence of the modulatory
      input from MCN1 to LG and thereby to hasten LG neuron burst onset. The two
      rhythms become coordinated because LG burst onset occurs with a constant latency
      after the onset of the triggering pyloric input. These results indicate that
      intercircuit synapses can enable an oscillatory circuit to control the speed of a
      slower oscillatory circuit, as well as provide a mechanism for intercircuit
      coordination.

PMID- 10414995
TI  - Excitotoxic septal lesions result in spatial memory deficits and altered
      flexibility of hippocampal single-unit representations.
AB  - The septal nuclei are reciprocally connected with the hippocampal formation and
      contribute importantly to spatial and memory processing. Using excitotoxic
      lesions of the septal area, we investigated whether neurodegeneration in
      subcortical projections to hippocampus can compromise flexible information
      processing by hippocampal single units. In agreement with the mild effects of
      excitotoxic septal lesions on hippocampal physiology compared with fimbria-fornix
      lesions and septal inactivation, we observed limited lesion effects on single
      unit activity. The location specificity of hippocampal complex spike cells
      remained unchanged, but a less reliable location-dependent discharge was observed
      in experimental animals with a pronounced postoperative working memory deficit.
      Testing in the absence of ambient illumination and in a new environment revealed
      that the spatial correlates of complex spike cells in lesioned animals may rely
      on a more limited set of sensory cues. Altered sensory cues resulted in a
      significantly different response pattern between the control and lesion group in
      the new environment, a situation that normally results in place field
      reorganization. Such a group difference was not observed during dark testing, a
      condition in which place field reorganization is less prominent. A contribution
      of hippocampal interneurons to the observed alterations in the spatial properties
      of the principal cells was suggested by decreased theta modulation in the
      lesioned group. Because excitotoxic lesions result in memory deficits that
      resemble age-related memory problems in the absence of age-related degenerative
      processes, we suggest that septal neurodegeneration could directly contribute to
      those behavioral changes with advanced age that correlate with functional
      alterations in the hippocampal formation.

PMID- 10414996
TI  - The anterior thalamic head-direction signal is abolished by bilateral but not
      unilateral lesions of the lateral mammillary nucleus.
AB  - Head-direction (HD) cells are neurons that signal a rat's directional heading in
      the horizontal plane. Evidence suggests that the lateral mammillary nucleus (LMN)
      may play an important role in generating the HD signal. Here, we examined the
      role of LMN in the HD circuit by comparing the effects of unilateral and
      bilateral LMN lesions on the activity of HD cells in the anterodorsal thalamus
      (AD). HD cells were recorded from AD in freely behaving rats. In the middle of
      the recording session, the rat received either bilateral or unilateral lesions of
      LMN. Immediately after the lesion, we continued recording the same HD cell in AD
      that had been recorded before the lesion. Additional cells were recorded from
      lesioned animals for up to 3 weeks after the lesion. We found that bilateral
      lesions of LMN permanently abolish HD cells in AD. After bilateral lesions, AD
      exhibits unusual rhythmic oscillations and velocity-correlated spike activity.
      Unilateral lesions of LMN did not abolish HD cells in AD. After unilateral
      lesions, the firing properties of HD cells in AD become more similar to those of
      HD cells in the intact hemisphere of LMN. We discuss the implications of these
      findings for understanding the role of LMN in the HD circuit.

PMID- 10414997
TI  - Independent and overlapping effects of corticosterone and testosterone on
      corticotropin-releasing hormone and arginine vasopressin mRNA expression in the
      paraventricular nucleus of the hypothalamus and stress-induced
      adrenocorticotropic hormone release.
AB  - Adrenocorticotropin (ACTH) release is regulated by both glucocorticoids and
      androgens; however, the precise interactions are unclear. We have controlled
      circulating corticosterone (B) and testosterone (T) by adrenalectomy (ADX) +/- B
      replacement and gonadectomy (GDX) +/- T replacement, comparing these to sham
      operated groups. We hoped to reveal how and where these neuroendocrine systems
      interact to affect resting and stress-induced ACTH secretion. ADX responses. In
      gonadal-intact rats, ADX increased corticotropin-releasing factor (CRH) and
      vasopressin (AVP) mRNA in hypothalamic parvocellular paraventricular nuclei (PVN)
      and ACTH in pituitary and plasma. B restored these toward normal. GDX blocked the
      increase in AVP but not CRH mRNA and reduced plasma, but not pituitary ACTH in
      ADX rats. GDX+T restored increased AVP mRNA in ADX rats, although plasma ACTH
      remained decreased. Stress responses. Restraint-induced ACTH responses were
      elevated in ADX gonadally intact rats, and B reduced these toward normal. GDX in
      adrenal-intact and ADX+B rats increased ACTH responses. Without B, T did not
      affect ACTH; together with B, T restored ACTH responses to normal. The magnitude
      of ACTH responses to stress was paralleled by similar effects on the number of c
      fos staining neurons in the hypophysiotropic PVN. We conclude that gonadal
      regulation of ACTH responses to ADX is determined by T dependent effects on AVP
      biosynthesis, whereas CRH biosynthesis is B-dependent. Stress-induced ACTH
      release is not explained by B and T interactions at the PVN, but is determined by
      B- and T-dependent changes in drive to PVN motorneurons.

PMID- 10414999
TI  - A GABAergic, strongly inhibitory projection to a thalamic nucleus in the zebra
      finch song system.
AB  - The anterior forebrain pathway (AFP) of the oscine song system is essential for
      song learning but not song production. Most cells recorded in this serially
      connected pathway show increased firing in response to song playback, suggesting
      largely excitatory connections among AFP nuclei. However, the neurons forming a
      key projection in this pathway, from area X to the medial nucleus of the
      dorsolateral thalamus (DLM), express glutamic acid decarboxylase in their somata
      and terminals, suggesting an inhibitory connection. To investigate the firing
      properties of DLM neurons and the functional influence of area X afferents in
      DLM, we made whole-cell recordings from DLM neurons in brain slices from adult
      male zebra finches. Most cells had intrinsic properties closely resembling those
      of mammalian thalamocortical cells, including a low-threshold Ca(2+) spike and
      time-dependent, hyperpolarization-activated inward rectification. Activation of
      afferents from area X evoked a strong, all-or-none IPSP whose amplitude and
      latency were unchanged by application of glutamate antagonists, consistent with a
      monosynaptic contact. The IPSP had a reversal potential near -70 mV and was
      blocked by the GABA(A) receptor antagonist bicuculline methiodide. Post
      inhibitory rebound firing occurred in DLM neurons with a delay near 50 msec.
      Strong inhibition can combine with the intrinsic properties of DLM neurons to
      allow signaling on disinhibition. Our data are consistent with the hypothesis
      that the AFP corresponds to the mammalian corticobasal ganglia-thalamocortical
      loop. The similar functional properties of avian and mammalian thalamic neurons
      suggest conserved forebrain mechanisms of sensorimotor information processing
      across vertebrate taxa.

PMID- 10414998
TI  - Glutamate inhibits thalamic reticular neurons.
AB  - Activation of metabotropic glutamate receptors (mGluRs) can result in long
      lasting modulation of neuronal excitability. Multiple mGluR subtypes are
      localized within the rat thalamic reticular nucleus (TRN), and we have examined
      the effects of activating these different receptor subtypes on the excitability
      of these neurons using an in vitro slice preparation. Typical of most mGluR
      sensitive preparations, the general mGluR agonist, (+/-)-1-aminocyclopentane
      trans-1,3-dicarboxylic acid (ACPD) produced a robust, long-lasting excitatory
      response. Surprisingly, ACPD produced a membrane hyperpolarization in some
      neurons. Using selective mGluR agonists, we found that activation of group II
      mGluRs produces the hyperpolarization, whereas the depolarization is mediated by
      group I mGluRs. While the polarity of the postsynaptic response
      (hyperpolarization vs depolarization) was dependent on the mGluR subtype
      activated, both actions appear to result from modification of a linear K(+)
      conductance. The inhibitory action of Glutamate, via group II mGluRs, provides an
      avenue for a disinhibitory effect that could have interesting consequences upon a
      well-investigated, model neuronal circuit, turning its assumed functional role
      upside down.

PMID- 10415000
TI  - Monoamine control of the pacemaker kernel and cycle frequency in the lobster
      pyloric network.
AB  - The monoamines dopamine (DA), serotonin (5HT), and octopamine (Oct) can each
      sculpt a unique motor pattern from the pyloric network in the stomatogastric
      ganglion (STG) of the spiny lobster Panulirus interruptus. In this paper we
      investigate the contribution of individual network components in determining the
      specific amine-induced cycle frequency. We used photoinactivation of identified
      neurons and pharmacological blockade of synapses to isolate the anterior burster
      (AB) and pyloric dilator (PD) neurons. Bath application of DA, 5HT, or Oct
      enhanced cycle frequency in an isolated AB neuron, with DA generating the most
      rapid oscillations and Oct the slowest. When an AB-PD or AB-2xPD subnetworks were
      tested, DA often reduced the ongoing cycle frequency, whereas 5HT and Oct both
      evoked similar accelerations in cycle frequency. However, in the intact pyloric
      network, both DA and Oct either reduced or did not alter the cycle frequency,
      whereas 5HT continued to enhance the cycle frequency as before. Our results show
      that the major target of 5HT in altering the pyloric cycle frequency is the AB
      neuron, whereas DA's effects on the AB-2xPD subnetwork are critical in
      understanding its modulation of the cycle frequency. Octopamine's effects on
      cycle frequency require an understanding of its modulation of the feedback
      inhibition to the AB-PD group from the lateral pyloric neuron, which constrains
      the pacemaker group to oscillate more slowly than it would alone. We have thus
      demonstrated that the relative importance of the different network components in
      determining the final cycle frequency is not fixed but can vary under different
      modulatory conditions.

PMID- 10415001
TI  - Cutting edge: RANTES regulates Fas ligand expression and killing by HIV-specific
      CD8 cytotoxic T cells.
AB  - Based on the previous observation that RANTES mediates the cytotoxic activity of
      human HIV-specific CD8+ T cells via the chemokine receptor CCR3, we studied the
      effect of this chemokine on different effector CD8+ cytolytic cells requiring
      Fas/Fas ligand (FasL) or perforin-dependent pathway. In CTLs derived from PBMCs
      of HIV-infected patients, both the spontaneous and the RANTES-induced
      cytotoxicity were inhibited by anti-FasL neutralizing Abs. In contrast,
      allogeneic CTLs or NK cells killing through perforin were not affected by RANTES
      and anti-FasL Ab. Accordingly, RANTES enhanced the expression of FasL in a
      concentration- and time-dependent manner in HIV-specific CTLs, whereas anti
      RANTES Ab decreased markedly FasL expression. Finally, cell surface expression of
      FasL protein in HIV-specific CTLs was also up-regulated by eotaxin, a selective
      ligand for CCR3. Our observations show that the action of RANTES via CCR3 is
      necessary to regulate FasL expression on HIV-specific CD8+ T cells that kill
      through the Fas/FasL pathway.

PMID- 10415004
TI  - Cutting edge: HIV-1 Tat protein differentially modulates the B cell response of
      naive, memory, and germinal center B cells.
AB  - Critical steps of B cell differentiation occur within lymphoid organs that are
      also major sites of HIV-1 replication. Because Tat can be released by infected
      cells, we investigated whether extracellular HIV-1 Tat modulates cell
      proliferation of B cells at critical stages of their differentiation. Here we
      show that extracellular Tat inhibited the proliferation of B cell receptor
      triggered naive and memory B cells by >80% but had no effect on their CD40 mAb
      and IL-4-mediated proliferation. In striking contrast, Tat doubled the germinal
      center B cell proliferation induced by CD40 mAb and IL-4. These effects were dose
      dependent and required the addition of Tat at the initiation of the culture,
      suggesting that Tat acts on early stages of cell cycle progression. By its
      effects on B cell subsets, Tat might directly affect the normal B cell
      differentiation process in HIV-positive patients and favor the occurrence of AIDS
      associated B cell lymphomas.

PMID- 10415003
TI  - Cutting edge: myelin basic protein-specific cytotoxic T cell tolerance is
      maintained in vivo by a single dominant epitope in H-2k mice.
AB  - Multiple sclerosis (MS) is believed to be an autoimmune disease mediated by T
      cells specific for CNS Ags. MS lesions contain both CD4+ and CD8+ T lymphocytes.
      The contribution of CD4+ T cells to CNS autoimmune disease has been extensively
      studied in an animal model of MS, experimental autoimmune encephalomyelitis.
      However, little is known about the role of autoreactive CD8+ cytotoxic T cells in
      MS or experimental autoimmune encephalomyelitis. We demonstrate here that myelin
      basic protein (MBP) is processed in vivo by the MHC class I pathway leading to a
      MBP79-87/Kk complex. The recognition of this complex by MBP-specific cytotoxic T
      cells leads to a high degree of tolerance in vivo. This study is the first to
      show that the pool of self-reactive lymphocytes specific for MBP contain MHC
      class I-restricted T cells whose response is regulated in vivo by the induction
      of tolerance.

PMID- 10415002
TI  - Cutting edge: extracellular signal-regulated kinase activates syk: a new
      potential feedback regulation of Fc epsilon receptor signaling.
AB  - The protein tyrosine kinase Syk is an essential element in several cascades
      coupling Ag receptors to cell responses. Syk and the mitogen-activated protein
      kinase extracellular signal-regulated kinase 1 (ERK1) were found to form a tight
      complex in both resting and Ag-stimulated rat mucosal-type mast cells (rat
      basophilic leukemia 2H3 cell line RBL-2H3). A direct serine phosphorylation and
      activation of Syk by ERK was observed in in vitro experiments. Moreover the
      mitogen-activated protein kinase/extracellular signal-regulated protein kinase
      (ERK) kinase (MEK) inhibitors markedly decreased the Ag-induced phosphorylation
      of the tyrosyl residues of Syk and its activation as well as suppressed the
      degranulation of the cells. These results suggest a positive feedback regulation
      of Syk by ERK in the cascade coupling the type 1 Fc epsilon receptor to the
      secretory response of mast cells; hence, the existence of a novel type of cross
      talk between protein serine/threonine kinases and protein tyrosine kinases is
      suggested.

PMID- 10415005
TI  - Cutting edge: CD40 ligand is a limiting factor in the humoral response to T cell
      dependent antigens.
AB  - CD40 ligand (CD40L) plays a crucial role in T cell-dependent B cell responses,
      but whether its abundance is a limiting factor in their development is unclear.
      This question was addressed in transgenic mice expressing the murine CD40L gene
      under the control of the IL-2-promoter (CD40Ltg+). The fraction of activated T
      cells from the CD40Ltg+ mice with detectable levels of surface CD40L was modestly
      greater (1.1- to 2-fold) than littermate controls and paralleled an approximately
      1.8-fold increase in CD40L mRNA abundance. In response to trinitrophenol (TNP)
      keyhole limpet hemocyanin and tetanus/diphtheria vaccine, CD40Ltg+ mice developed
      higher titers of high-affinity IgG and IgG1 Ab than wild-type mice. In contrast,
      the Ab response of CD40Ltg+ and control mice was similar in response to the T
      independent Ag TNP-Ficoll. These results suggest that a modest increment in
      expression of CD40L accelerates the development of T-dependent responses, and
      that CD40L plays a limiting role in the induction of high-affinity Ab and Ab
      class switching.

PMID- 10415006
TI  - Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell
      autonomous.
AB  - Mice deficient for the expression of CTLA-4 develop a lethal lymphoproliferative
      syndrome and multiorgan inflammation leading to death at about 4 wk of age. Here
      we show that RAG2-deficient mice reconstituted with CTLA-4-deficient bone marrow
      do not develop a lymphoproliferative syndrome despite lymphocyte infiltration
      mainly into pericardium and liver. Moreover, RAG2-deficient mice reconstituted
      with a mixture of normal and CTLA-4-deficient bone marrow remain healthy and do
      not develop any disease. Thus, the lethal disease observed in CTLA-4-deficient
      mice is not T cell autonomous and can be prevented by factors produced by normal
      T cells.

PMID- 10415007
TI  - CD28, IL-2-independent costimulatory pathways for CD8 T lymphocyte activation.
AB  - We investigate, here, the mechanism of the costimulatory signals for CD8 T cell
      activation and confirm that costimulation signals via CD28 do not appear to be
      required to initiate proliferation, but provide survival signals for CD8 T cells
      activated by TCR ligation. We show also that IL-6 and TNF-alpha can provide
      alternative costimulatory survival signals. IL-6 and TNF-alpha costimulate naive
      CD8 T cells cultured on plate-bound anti-CD3 in the absence of CD28 ligation.
      They act directly on sorted CD8-positive T cells. They also costimulate naive CD8
      T cells from Rag-2-deficient mice, bearing transgenic TCRs for HY, which lack
      memory cells, a potential source of IL-2 secretion upon activation. IL-6 and TNF
      alpha provide costimulation to naive CD8 T cells from CD28, IL-2, or IL-2Ralpha
      deficient mice, and thus function in the absence of the B7-CD28 and IL-2
      costimulatory pathways. The CD8 T cell generated via the anti-CD3 plus IL-6 and
      TNF-alpha pathway have effector function in that they express strong cytolytic
      activity on Ag-specific targets. They secrete only very small amounts of any of
      the cytokines tested upon restimulation with peptide-loaded APC. The ability of
      the naive CD8 T cells to respond to TCR ligation and costimulatory signals from
      IL-6 and TNF-alpha provides a novel pathway that can substitute for signals from
      CD4 helper cells or professional APC. This may be significant in the response to
      viral Ags, which can be potentially expressed on the surface of any class I MHC
      expressing cell.

PMID- 10415008
TI  - Nickel allergy in mice: enhanced sensitization capacity of nickel at higher
      oxidation states.
AB  - Attempts to induce contact hypersensitivity to nickel in mice using, e.g.,
      Ni(II)Cl2 often failed. Here, we report that sensitization was achieved by
      injecting Ni(II)Cl2 in combination with either CFA or an irritant, such as SDS
      and PMA, or IL-12, or by administering nickel at higher oxidation states, i.e.,
      Ni(III) and Ni(IV). Although Ni(II), given alone, was ineffective in T cell
      priming, it sufficed for eliciting recall responses in vivo and in vitro,
      suggesting that Ni(II) is able to provide an effective signal 1 for T cell
      activation, but is unable to provide an adequate signal 2 for priming.
      Immunization of mice with nickel-binding proteins pretreated with Ni(IV), but not
      with Ni(II), allowed them to generate nickel-specific CD4+ T cell hybridomas.
      Ni(II) sufficed for restimulation of T cell hybridomas; in this and other aspects
      as well, the hybridomas resembled the nickel-specific human T cell clones
      reported in the literature. Interestingly, restimulation of hybridomas did not
      require the original Ni(IV)-protein complex used for priming, suggesting either
      that the nickel ions underwent ligand exchange toward unknown self proteins or
      peptides or that nickel recognition by the TCR is carrier-independent. In
      conclusion, we found that Ni(III) and Ni(IV), but not Ni(II) alone, were able to
      sensitize naive T cells. Since both Ni(III) and Ni(IV) can be generated from
      Ni(II) by reactive oxygen species, released during inflammation, our findings
      might explain why in humans nickel contact dermatitis develops much more readily
      in irritated than in normal skin.

PMID- 10415009
TI  - A soluble form of IL-13 receptor alpha 1 promotes IgG2a and IgG2b production by
      murine germinal center B cells.
AB  - A functional IL-13R involves at least two cell surface proteins, the IL-13R alpha
      1 and IL-4R alpha. Using a soluble form of the murine IL-13R alpha 1 (sIL-13R),
      we reveal several novel features of this system. The sIL-13R promotes
      proliferation and augmentation of Ag-specific IgM, IgG2a, and IgG2b production by
      murine germinal center (GC) B cells in vitro. These effects were enhanced by CD40
      signaling and were not inhibited by an anti-IL4R alpha mAb, a result suggesting
      other ligands. In GC cell cultures, sIL-13R also promoted IL-6 production, and
      interestingly, sIL-13R-induced IgG2a and IgG2b augmentation was absent in GC
      cells isolated from IL-6-deficient mice. Furthermore, the effects of the sIL-13R
      molecule were inhibited in the presence of an anti-IL-13 mAb, and preincubation
      of GC cells with IL-13 enhanced the sIL-13R-mediated effects. When sIL-13R was
      injected into mice, it served as an adjuvant-promoting production to varying
      degrees of IgM and IgG isotypes. We thus propose that IL-13R alpha 1 is a
      molecule involved in B cell differentiation, using a mechanism that may involve
      regulation of IL-6-responsive elements. Taken together, our data reveal
      previously unknown activities as well as suggest that the ligand for the sIL-13R
      might be a component of the IL-13R complex or a counterstructure yet to be
      defined.

PMID- 10415010
TI  - Th cells and Th2 responses can develop in the absence of MHC class II-CD4
      interactions.
AB  - In this paper, we address the question whether CD4 and MHC class II expression
      are necessary for the development of the T helper lineage during thymocyte
      maturation and for activation-induced Th2 responses. To bypass the CD4-MHC class
      II interaction requirements for positive selection and activation, we used mice
      that are doubly transgenic for CD8 and for the MHC class I-restricted TCR F5.
      This transgene combination leads to MHC class I-dependent maturation of CD4
      lineage cells. Upon activation, these CD4 lineage T cells secrete IL-4 and give
      help to B cells but show no cytotoxic activity. Remarkably, neither MHC class II
      nor CD4 expression are necessary for the generation and helper functions of these
      cells. This suggests that under normal conditions, coreceptor-MHC interactions
      are necessary to ensure the canonical combinations of coreceptor and function in
      developing thymocytes, but that they do not determine functional commitment. Our
      results also imply that expression of the CD4 gene does not influence, but is
      merely associated with the decision to establish the T helper program. In
      addition, we show that activation through TCR-MHC class I interactions can induce
      Th2 responses independently of CD4 and MHC class II expression.

PMID- 10415011
TI  - Th1 cytokines and NK cells participate in the development of murine syngeneic
      graft-versus-host disease.
AB  - Syngeneic graft-vs-host disease (SGVHD) is induced by reconstituting lethally
      irradiated mice with syngeneic bone marrow cells followed by a short course of
      therapy with the immunosuppressive agent cyclosporine A. Following cessation of
      cyclosporine A therapy, animals develop clinical symptoms of SGVHD: weight loss,
      runting, and diarrhea. While it has been suggested that T cells are responsible
      for the induction and effector phases of SGVHD, the role of nonspecific effector
      cells and cytokine mediators has yet to be examined in the disease process. Mice
      with SGVHD had increased levels of message for IL-12p40, IFN-gamma, and TNF-alpha
      in the target organs of SGVHD as compared with transplant controls and
      asymptomatic cyclosporine A-treated mice. Concomitant with the increase in Th1
      cytokines was an enhanced cellular infiltrate in the target organs of SGVHD mice
      as determined by histological analysis. To directly examine the role of IL-12 in
      the development of SGVHD, in vivo neutralization of IL-12 was performed.
      Treatment of mice with Abs to IL-12 inhibited SGVHD-mediated tissue pathology and
      mortality. Because IL-12 has been shown to activate both T cells and NK cells to
      secrete IFN-gamma and to become more cytolytic, studies were initiated to
      ascertain which lymphocyte populations play a role in the development of murine
      SGVHD. Depletion of NK cells inhibited clinical symptoms of SGVHD. In contrast, T
      cell depletion did not alter the disease process. Therefore, these findings
      collectively demonstrate a role for IL-12 and NK cells in the effector phase of
      murine SGVHD.

PMID- 10415012
TI  - Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of
      autoimmune diabetes at late stages of disease is epitope dependent.
AB  - Peptide-based immunotherapy is one strategy by which to selectively suppress the
      T cell-mediated destruction of beta cells and treat insulin-dependent diabetes
      mellitus (IDDM). Here, we investigated whether a panel of T cell epitopes derived
      from the beta cell autoantigen glutamic acid decarboxylase 65 (GAD65) differ in
      their capacity to induce Th2 cell function in nonobese diabetic (NOD) mice and in
      turn prevent overt IDDM at different preclinical stages of disease development.
      The panel consists of GAD65-specific peptides spanning aa 217-236 (p217), 247-265
      (p247), 290-309 (p290), and 524-543 (p524). Our studies revealed that all of the
      peptides effectively prevented insulitis and diabetes when administered to NOD
      mice before the onset of insulitis. In contrast, only a mixture of p217 and p290
      prevented progression of insulitis and overt IDDM in NOD mice exhibiting
      extensive beta cell autoimmunity. Immunization with the GAD65-specific peptides
      did not block IDDM development in NOD mice deficient in IL-4 expression. These
      findings demonstrate that GAD65-specific peptide immunotherapy effectively
      suppresses progression to overt IDDM, requires the production of IL-4, and is
      dependent on the epitope targeted and the extent of preexisting beta cell
      autoimmunity in the recipient.

PMID- 10415014
TI  - Fas is expressed early in human thymocyte development but does not transmit an
      apoptotic signal.
AB  - We investigated the expression and function of Fas on human thymocytes prepared
      from fetal and pediatric tissue specimens and from SCID-hu Thy/Liv grafts. Unlike
      mouse thymocytes, human thymocytes exhibited a pattern of Fas expression skewed
      to immature cells, in that the highest expression was seen on double negative
      thymocytes and on intrathymic T progenitor cells. Fas expression was intermediate
      on double positive human thymocytes, and low or negative on mature single
      positive CD4 and CD8 medullary thymocytes. In spite of this relatively abundant
      surface expression, cross-linking of Fas with agonist mAb was incapable of
      triggering an apoptotic signal in human thymocytes. Apoptotic signaling was not
      enhanced by treatment with cycloheximide, nor by restoring a cosignaling milieu
      by addition of thymic stromal cells. Mouse thymocytes were induced to apoptosis
      by cross-linked recombinant soluble human Fas ligand both in vitro and in vivo,
      though human thymocytes were also resistant to this mode of receptor ligation.
      Membrane-bound Fas ligand also induced apoptotic death in murine thymocytes but
      not in human thymocytes. Human thymocytes were as sensitive as Jurkat cells,
      however, to apoptosis induced by TNF-alpha, suggesting that these cells have a
      signaling defect before activation of the earliest caspases. These data
      demonstrate a durable and specific resistance of human thymocytes to apoptosis
      induced through Fas receptor engagement, and reveal significant species-specific
      differences in the biology of thymocyte-programmed cell death.

PMID- 10415013
TI  - CpG oligodeoxynucleotides down-regulate macrophage class II MHC antigen
      processing.
AB  - Unmethylated CpG motifs in bacterial DNA or short oligodeoxynucleotides (ODN)
      stimulate cells of the immune system and provide adjuvant activity. CpG DNA
      directly activates macrophages to secrete IL-12 and TNF-alpha and increases
      transcription of various genes, but its effects on macrophage Ag processing
      remain uncertain. The effects of CpG ODN on class II MHC (MHC-II) Ag processing
      and presentation were examined using peritoneal macrophages that were cultured
      for 18 h with CpG ODN and then pulsed with protein Ags. T cell hybridomas were
      used to detect presentation of specific peptide:MHC-II complexes. Both CpG ODN
      and LPS inhibited processing of bovine RNase and hen egg lysozyme. Presentation
      of exogenous peptides was inhibited to a lesser degree. Treatment of macrophages
      for 18 h with CpG ODN decreased surface MHC-II expression, as measured by flow
      cytometry. Furthermore, Northern blot analysis revealed that treatment with CpG
      ODN decreased I-Ak mRNA. Endocytosis by macrophages, as measured by uptake of
      fluorescent dextran, was not altered by treatment with CpG ODN. The inhibitory
      effect of CpG ODN on Ag processing was seen after prolonged (18 h) treatment of
      macrophages, but not after short treatment (e.g., 2 h) with CpG ODN and protein
      Ag. Enhancement of macrophage Ag processing was not seen at any time point of CpG
      ODN exposure, in contrast to data from other studies with dendritic cells. In
      summary, exposure of macrophages to CpG ODN results in a decrease in macrophage
      Ag processing and presentation, which is largely mediated by a decrease in
      synthesis of MHC-II molecules.

PMID- 10415015
TI  - Peptide dose, affinity, and time of differentiation can contribute to the Th1/Th2
      cytokine balance.
AB  - Opposing viewpoints exist regarding how Ag dose and affinity modulate Th1/Th2
      differentiation, with data suggesting that both high and low level stimulation
      favors Th2 responses. With transgenic T cells bearing a single TCR, we present
      novel data, using peptides differing in affinity for the TCR, that show that the
      time period of differentiation can determine whether Th1 or Th2 responses
      predominate as the level of initial stimulation is altered. Over the short term,
      IFN-gamma-producing cells were induced by lower levels of stimulation than IL-4
      producing cells, although optimal induction of both was seen with the same high
      level of stimulation. Over the long term, however, high doses of high affinity
      peptides led selectively to IFN-gamma-secreting cells, whereas IL-4- and IL-5
      secreting cells predominated with lower levels of initial signaling, brought
      about by moderate doses of high affinity peptides. In contrast, too low a level
      of stimulation at the naive T cell stage, with low affinity peptides at any
      concentration, promoted only IL-2-secreting effectors or was not sufficient for
      long term T cell survival. These results demonstrate that the level of signaling
      achieved through the TCR is intimately associated with the induction of distinct
      cytokine-secreting T cells. We show that dose, affinity, time over which
      differentiation occurs, and initial production of IL-4 and IFN-gamma all can
      contribute to which T cell subset will predominate. Furthermore, these data
      reconcile the two opposing views on the effects of dose and affinity and provide
      a unifying model of Th1/Th2 differentiation based on strength of signaling and
      length of response.

PMID- 10415016
TI  - Expression of L-selectin on Th1 cells is regulated by IL-12.
AB  - L-selectin has become established as a key molecule in the recirculation of naive
      T cells from the blood to peripheral lymph nodes, yet little is known about its
      role in the migration of effector or memory cells. While differentiating naive
      CD4+ T cells into Th1 and Th2 subsets in vitro, it was noted that L-selectin
      levels were maintained on the Th1 subset of cells. The expression of L-selectin
      on the Th1 cells appeared to be dependent on the presence of IL-12. Th2 cells,
      differentiated in the absence of IL-12, failed to maintain L-selectin expression.
      Coculture with IL-12, IL-18, IL-4, TNF-alpha, or IFN-alpha, -beta, or -gamma
      demonstrated a dependence on IL-12 alone for L-selectin expression. In addition,
      the inclusion of heat-killed Listeria monocytogenes in the cultures also
      maintained L-selectin expression on the Th1 cells. In all cultures, the
      maintenance of L-selectin on the T cell surface could be blocked by the inclusion
      of anti-IL-12 Abs. Analysis of the mRNA levels for L-selectin in T cells,
      differentiated in the presence or absence of IL-12, showed that the cytokine
      appears to exert its effect on L-selectin at the transcriptional level. Given the
      key role played by IL-12 in the differentiation of naive T cells into the Th1
      subset, the observation that IL-12 can also regulate L-selectin expression has
      implications for the migration of Th1 effector cells both through the lymphatic
      system and to sites of inflammation.

PMID- 10415017
TI  - Functional similarity and differences between selection-independent CD4-CD8-
      alphabeta T cells and positively selected CD8 T cells expressing the same TCR and
      the induction of anergy in CD4-CD8- alphabeta T cells in antigen-expressing mice.
AB  - In TCR-alphabeta transgenic mice, CD4-CD8- TCR-alphabeta+ (alphabeta DN) cells
      arise in the absence of positively selecting MHC molecules and are resistant to
      clonal deletion in Ag-expressing mice. In this study the activation requirements
      and functional properties of alphabeta double-negative (DN) cells were compared
      with those of positively selected CD8+ cells expressing equivalent levels of the
      same MHC class I-restricted transgenic TCR. We found that positively selected
      CD8+ cells required a lower density of the antigenic ligand for optimal
      proliferative responses compared with alphabeta DN cells derived from
      nonpositively selecting mice. However, when the CD8 coreceptor on CD8+ cells was
      blocked with an anti-CD8 mAb, both alphabeta DN and CD8+ cells exhibited the same
      dose-response curve to the antigenic ligand and the same dependence on CD28/B7
      costimulation. Positively selected CD8+ cells also differed from alphabeta DN
      cells in that they differentiated into more efficient killers and IL-2 producers
      after Ag stimulation, even after CD8 blockade. However, Ag-activated alphabeta DN
      and CD8+ cells were equally efficient in producing IFN-gamma, suggesting that
      this functional property is independent of positive selection. We also found that
      alphabeta DN cells recovered from the lymph nodes of Ag-expressing mice were
      functionally anergic. This anergic state was associated with defective
      proliferation and IL-2 production in response to Ag stimulation. These
      observations indicate that alphabeta DN cells can be anergized in vivo by
      physiological levels of the antigenic ligand.

PMID- 10415018
TI  - IL-18 inhibits diabetes development in nonobese diabetic mice by
      counterregulation of Th1-dependent destructive insulitis.
AB  - The development of type 1 diabetes in animal models is T cell and macrophage
      dependent. Islet inflammation begins as peripheral benign Th2 type insulitis and
      progresses to destructive Th1 type insulitis, which is driven by the innate
      immune system via secretion of IL-12 and IL-18. We now report that daily
      application of IL-18 to diabetes-prone female nonobese diabetic mice, starting at
      10 wk of age, suppresses diabetes development (p < 0.001, 65% in sham-treated
      animals vs 33% in IL-18-treated animals by 140 days of age). In IL-18-treated
      animals, we detected significantly lower intraislet infiltration (p < 0.05) and
      concomitantly an impaired progression from Th2 insulitis to Th1-dependent
      insulitis, as evidenced from IFN-gamma and IL-10 mRNA levels in tissue. The
      deficient progression was probably due to lesser mRNA expression of the Th1
      driving cytokines IL-12 and IL-18 by the innate immune system (p < 0.05).
      Furthermore, the mRNA expression of inducible NO synthase, a marker of
      destructive insulitis, was also not up-regulated in the IL-18-treated group. IL
      18 did not exert its effect at the levels of islet cells. Cultivation of islets
      with IL-18 affected NO production or mitochondrial activity and did not protect
      from the toxicity mediated by IL-1beta, TNF-alpha, and IFN-gamma. In conclusion,
      we show for the first time that administration of IL-18, a mediator of the innate
      immune system, suppresses autoimmune diabetes in nonobese diabetic mice by
      targeting the Th1/Th2 balance of inflammatory immune reactivity in the pancreas.

PMID- 10415019
TI  - HIV type 1 Nef protein is a viral factor for leukocyte recruitment into the
      central nervous system.
AB  - Recombinant HIV-1 Nef protein, but not Tat, gp120, and gp160, provoked leukocyte
      recruitment into the CNS in a rat model. The strong reduction of bioactivity by
      heat treatment of Nef, and the blocking effect of the mAb 2H12, which recognizes
      the carboxy-terminal amino acid (aa) residues 171-190 (but not of mAb 3E6, an
      anti-Nef Ab of the same isotype, which maps the aa sequence 168-175, as well as a
      mixture of mAbs to CD4) provided evidence for the specificity of the observed Nef
      effects. Using a modified Boyden chamber technique, Nef exhibited chemotactic
      activity on mononuclear cells in vitro. Coadministration of the anti-Nef mAb
      2H12, as well as treatment of Nef by heat inhibited Nef-induced chemotaxis.
      Besides soluble Nef, chemotaxis was also induced by a Nef-expressing human
      astrocytoma cell line, but not by control cells. These data suggest a direct
      chemotactic activity of soluble Nef. The detection of elevated levels of IL-6,
      TNF-alpha, and IFN-gamma in rat cerebrospinal fluid 6 h after intracisternal Nef
      injection hint at the additional involvement of indirect mechanisms in Nef
      induced leukocyte migration into rat CNS. These data propose a mechanism by which
      HIV-1 Nef protein may be essential for AIDS neuropathogenesis, as a mediator of
      the recruitment of leukocytes that may serve as vehicles of the virus and
      perpetrators for disease through their production of neurotoxins.

PMID- 10415020
TI  - Simultaneous activation of T cells and accessory cells by a new class of intact
      bispecific antibody results in efficient tumor cell killing.
AB  - Bispecific Abs (bsAb) are promising immunological tools for the elimination of
      tumor cells in minimal residual disease situations. In principle, they target an
      Ag on tumor cells and recruit one class of effector cell. Because immune
      reactions in vivo are more complex and are mediated by different classes of
      effector cell, we argue that conventional bsAb might not yield optimal immune
      responses at the tumor site. We therefore constructed a bsAb that combines the
      two potent effector subclasses mouse IgG2a and rat IgG2b. This bispecific
      molecule not only recruits T cells via its one binding arm, but simultaneously
      activates FcgammaR+ accessory cells via its Fc region. We demonstrate here that
      the activation of both T lymphocytes and accessory cells leads to production of
      immunomodulating cytokines like IL-1beta, IL-2, IL-6, IL-12, and DC-CK1. Thus
      this new class of bsAb elicits excellent antitumor activity in vitro even without
      the addition of exogenous IL-2, and therefore represents a totally self
      supporting system.

PMID- 10415021
TI  - On the lifespan of virgin T lymphocytes.
AB  - To study the lifespan of virgin T lymphocytes, we removed the thymus from adult
      female mice and then, at various times afterward, tested their ability to mount
      an immune response to a newly encountered Ag, the male Ag H-Y. We found that
      unprimed thymectomized mice were able to generate a primary response to H-Y for
      some time after thymectomy but lost this ability at approximately 6 mo. In
      contrast, mice that were primed to H-Y just after thymectomy continued to display
      immunological memory to H-Y for >1 year. These experiments show that primary
      immune responses disappear in the absence of a thymus.

PMID- 10415022
TI  - Requirements for signal delivery through CD44: analysis using CD44-Fas chimeric
      proteins.
AB  - CD44 is a transmembrane glycoprotein involved in various cell adhesion events,
      including lymphocyte migration, early hemopoiesis, and tumor metastasis. To
      examine the requirements of CD44 for signal delivery through the extracellular
      domain, we constructed a chimeric CD44 protein fused to the intracellular domain
      of Fas on its C-terminus. In cells expressing the CD44-Fas fusion protein,
      apoptosis could be induced by treatment with certain anti-CD44 mAbs alone,
      especially those recognizing the epitope group d, which has been previously shown
      to play a role in ligand binding, indicating that ligation of a specific region
      of the CD44 extracellular domain results in signal delivery. Of note was that
      appropriate ligation of the epitope h also resulted in the generation of
      apoptotic signal, although this region was not thought to be involved in ligand
      binding. In contrast, the so-called blocking anti-CD44 mAbs (epitope group f)
      that can abrogate the binding of hyaluronate (HA) failed to induce apoptosis even
      after further cross-linking with the secondary Ab, indicating that a mere mAb
      induced oligomerization of the chimeric proteins is insufficient for signal
      generation. However, these blocking mAbs were instead capable of inhibiting
      apoptosis induced by nonblocking mAb (epitope group h). Furthermore, a chimeric
      protein bearing a mutation in the HA binding domain and hence lacking the ability
      to recognize HA was incapable of mediating the mAb-induced apoptosis, suggesting
      that the functional integrity of the HA binding domain is crucial to the signal
      generation in CD44.

PMID- 10415023
TI  - Distinct in vivo and in vitro cytokine profiles of draining lymph node cells in
      acute and chronic phases of contact hypersensitivity: importance of a type 2
      cytokine-rich cutaneous milieu for the development of an early-type response in
      the chronic phase.
AB  - Although regional lymph nodes (LN) have been extensively studied as rich sources
      of effector T cells in contact hypersensitivity (CH), it remains unknown whether
      T cell responses in the LN reflect those in effector skin sites. We previously
      showed that repeated elicitation of CH results in a shift in the time course of
      Ag-specific CH from a delayed-type hypersensitivity response to an early-type
      response, a reflection of a shift in cutaneous cytokine expression from a type 1
      to a type 2 profile. To investigate whether repeated elicitation of CH could also
      drive T cell development to the type 2 phenotype in the regional draining LN,
      sequential cytokine gene expression after hapten application was assessed during
      both the acute and the chronic phase of CH. In the draining LN the shift to type
      2 cytokine production was also observed, but more mixed patterns of responses
      were induced than in the corresponding skin sites. The chronic LN cells (LNC),
      when stimulated in vitro, produced markedly lower levels of type 1 cytokines and
      higher levels of type 2 cytokines than the acute LNC. A successful passive
      transfer of an early-type response by the LNC was only induced in the recipient
      mice when the skin sites chronically treated with hapten were elicited. These
      results indicate that an early-type response by regional LNC would take place
      only in a milieu with sufficient levels of type 2 cytokines.

PMID- 10415025
TI  - Direct suppression of TCR-mediated activation of extracellular signal-regulated
      kinase by leukocyte protein tyrosine phosphatase, a tyrosine-specific
      phosphatase.
AB  - Leukocyte protein tyrosine phosphatase (LC-PTP)/hemopoietic PTP is a human
      cytoplasmic PTP that is predominantly expressed in the hemopoietic cells.
      Recently, it was reported that hemopoietic PTP inhibited TCR-mediated signal
      transduction. However, the precise mechanism of the inhibition was not
      identified. Here we report that extracellular signal-regulated kinase (ERK) is
      the direct target of LC-PTP. LC-PTP dephosphorylated ERK2 in vitro. Expression of
      wild-type LC-PTP in 293T cells suppressed the phosphorylation of ERK2 by a mutant
      MEK1, which was constitutively active regardless of upstream activation signals.
      No suppression of the phosphorylation was observed by LC-PTPCS, a catalytically
      inactive mutant. In Jurkat cells, LC-PTP suppressed the ERK and p38 mitogen
      activated protein kinase cascades. LC-PTP and LC-PTPCS made complexes with ERK1,
      ERK2, and p38alpha, but not with the gain-of-function sevenmaker ERK2 mutant
      (D321N). A small deletion (aa 1-46) in the N-terminal portion of LC-PTP or Arg to
      Ala substitutions at aa 41 and 42 resulted in the loss of ERK binding activity.
      These LC-PTP mutants revealed little inhibition of the ERK cascade activated by
      TCR cross-linking. On the other hand, the wild-type LC-PTP did not suppress the
      phosphorylation of sevenmaker ERK2 mutant. Thus, the complex formation of LC-PTP
      with ERK is the essential mechanism for the suppression. Taken collectively,
      these results indicate that LC-PTP suppresses mitogen-activated protein kinase
      directly in vivo.

PMID- 10415024
TI  - Activated human T cells release bioactive Fas ligand and APO2 ligand in
      microvesicles.
AB  - Activation-induced cell death is a process by which overactivated T cells are
      eliminated, thus preventing potential autoimmune attacks. Two known mediators of
      activation-induced cell death are Fas(CD95) ligand (FasL) and APO2 ligand
      (APO2L)/TNF-related apoptosis-inducing ligand (TRAIL). We show here that upon
      mitogenic stimulation, bioactive FasL and APO2L are released from the T cell
      leukemia Jurkat and from normal human T cell blasts as intact, nonproteolyzed
      proteins associated with a particulate, ultracentrifugable fraction. We have
      characterized this fraction as microvesicles of 100-200 nm in diameter. These
      microvesicles are released from Jurkat and T cell blasts shortly (</=1 h) after
      PHA stimulation, well before the cell enters apoptosis. FasL- and APO2L
      containing vesicles are also present in supernatants from PHA-activated fresh
      human PBMC. These observations provide the basis for a new and efficient
      mechanism for the rapid induction of autocrine or paracrine cell death during
      immune regulation.

PMID- 10415026
TI  - Synergistic action of fms-like tyrosine kinase 3 ligand and CD40 ligand in the
      induction of dendritic cells and generation of antitumor immunity in vivo.
AB  - Daily treatment of mice with fms-like tyrosine kinase 3 ligand (Flt3L) leads to a
      significant increase in the number of dendritic cells and induces antitumor
      immunity. Here, we show that Flt3L and CD40 ligand (CD40L) synergize in the
      generation of immune responses against two poorly immunogenic tumors, leading to
      complete tumor rejection in a high proportion of mice. Rechallenge of the Flt3L +
      CD40L-treated mice with the immunizing tumor resulted in complete inhibition of
      tumor growth, indicating that these animals had developed long-lasting antitumor
      immunity. In addition, we demonstrate that endogenous CD40L plays a critical role
      in antitumor immunity, since blockade of CD40-CD40L interactions in vivo prevents
      the generation of antitumor immunity in therapeutic and vaccination protocols.
      Dendritic cells generated in mice treated with Flt3L alone or in combination with
      CD40L were equally potent in stimulating allogeneic T cells and expressed similar
      levels of MHC class II, CD80, and CD86. However, mice treated with Flt3L + CD40L
      had significantly more dendritic cells than mice treated with either of the
      cytokines alone, suggesting that CD40L promotes the proliferation and/or survival
      of dendritic cells generated by Flt3L treatment. Dendritic cells generated in
      this manner are likely to be involved in the priming of antitumor immune
      responses.

PMID- 10415027
TI  - Critical role of costimulation in the activation of naive antigen-specific TCR
      transgenic CD8+ T cells in vitro.
AB  - The influence of costimulation on the activation of naive CD8+ T cells and
      thymocytes was studied in vitro using H-Y-specific TCR-transgenic mice and H-Y
      antigenic peptide. Using a variety of physiological APC types, the activation of
      naive CD8+ T cells depended strictly on costimulation, which could not be
      substituted by high epitope density. T cell activation is known to be regulated
      by the interactions between CD86/CD80 and CD28/CD152, although it remains unclear
      whether the B7 isoforms have distinct roles. Addition of soluble anti-CD86 Ab led
      to profound inhibition of T cell reactivity, further confirming the importance of
      costimulation in naive CD8+ T cell activation. Finally, TCR engagement in the
      absence of costimulation had no effect on the subsequent reactivity of peripheral
      naive transgenic CD8+ T cells, but induced nonresponsiveness in mature CD8+
      transgenic thymocytes. Collectively, these results demonstrate the importance of
      costimulation for naive CD8+ T cell activation, suggest that CD80 and CD86 can
      mediate opposing effects, possibly due to differential interaction with CD152 and
      CD28, and indicate differences in the sensitivity of immature vs mature CD8+ T
      cells to the induction of nonresponsiveness following costimulation-deficient Ag
      presentation.

PMID- 10415029
TI  - Primed T cells are more resistant to Fas-mediated activation-induced cell death
      than naive T cells.
AB  - Memory T cells respond in several functionally different ways from naive T cells
      and thus function as efficient effector cells. In this study we showed that
      primed T cells were more resistant to Fas-mediated activation-induced cell death
      (AICD) than naive T cells using OVA-specific TCR transgenic DO10 mice and Fas
      deficient DO10 lpr/lpr mice. We found that apoptosis was efficiently induced in
      activated naive T cells at 48 and 72 h after Ag restimulation (OVA peptide; 0.3
      and 3 microM), whereas apoptosis was not significantly increased in activated
      primed T cells at 24-72 h after Ag restimulation. We further showed that the
      resistance to AICD in primed T cells was due to the decreased sensitivity to
      apoptosis induced by Fas-mediated signals, but TCR-mediated signaling equally
      activated both naive and primed T cells to induce Fas and Fas ligand expressions.
      Furthermore, we demonstrated that primed T cells expressed higher levels of Fas
      associated death domain-like IL-1beta-converting enzyme inhibitory protein
      (FLIP), an inhibitor of Fas-mediated apoptosis, at 24-48 h after Ag restimulation
      than naive T cells. In addition, Bcl-2 expression was equally observed between
      activated naive and primed T cells after Ag restimulation. Thus, these results
      indicate that naive T cells are sensitive to Fas-mediated AICD and are easily
      deleted by Ag restimulation, while primed/memory T cells express higher levels of
      FLIP after Ag restimulation, are resistant to Fas-mediated AICD, and thus
      function as efficient effector cells for a longer period.

PMID- 10415028
TI  - A monoclonal antibody reactive with a 40-kDa molecule on fetal thymocytes and
      tumor cells blocks proliferation and stimulates aggregation and apoptosis.
AB  - E710.2.3 is a murine thymic lymphoma cell line with an immature phenotype (CD4
      CD8-) that proliferates in response to thymocytes or PMA when cultured at low
      density and proliferates spontaneously when grown at high density. To identify
      functional molecules on this cell line, we screened for mAbs that could block its
      proliferation. A hamster mAb, DMF10.62.3, inhibited the spontaneous, thymocyte
      induced, and PMA-stimulated proliferation of E710.2.3 in vitro and induced these
      cells to undergo apoptosis. The mAb also caused homotypic aggregation of
      E710.2.3, which was inhibited by cytochalasin B, trifluoperazine, a combination
      of sodium azide and 2-deoxyglucose, EDTA, incubation at 4 degrees C, or treatment
      with paraformaldehyde. The DMF10 62.3 mAb stained a number of immortalized murine
      and human cell lines and, where tested, blocked their proliferation and caused
      death to varying extents by apoptosis. The molecule recognized by the mAb
      DMF10.62.3 was expressed on day 14 fetal thymus Thy1.2-positive cells. However,
      it was not detected on adult murine thymocytes, splenocytes, or bone marrow cells
      or on splenic LPS-activated B cells or Con A-activated T cells. The Ab
      immunoprecipitated a 40-kDa molecule from E710.2.3 that was not
      glycosylphosphatidylinositol linked. The data suggest that the molecule
      recognized by DMF62.3 is a novel cell surface molecule that may be involved in
      cell proliferation and/or cell death.

PMID- 10415030
TI  - CD45 negatively regulates lyn activity by dephosphorylating both positive and
      negative regulatory tyrosine residues in immature B cells.
AB  - Using CD45-deficient clones from the immature B cell line, WEHI-231, we
      previously demonstrated that CD45 selectively dephosphorylates the Src-family
      protein tyrosine kinase Lyn and inhibits its kinase activity. To further define
      the mechanisms of CD45 action on Lyn, we metabolically labeled Lyn from CD45
      positive and -negative WEHI-231 cells and analyzed cyanogen bromide fragments by
      SDS-PAGE analysis. Phosphoamino acid analysis confirmed that Lyn is tyrosine
      phosphorylated with little serine or threonine phosphorylation. In CD45-negative
      cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell
      Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment
      containing the positive regulatory site (Tyr397), as assessed by its size and its
      phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated
      by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal
      negative regulatory site (Tyr508). CD45 was also shown to dephosphorylate
      autophosphorylated Lyn in vitro. Thus, CD45 dephosphorylates not only the
      negative but also the positive regulatory tyrosine residues of Lyn. Furthermore,
      coimmunoprecipitations using anti-Igalpha Ab demonstrated that Lyn associated
      with the resting BCR was constitutively phosphorylated and activated in CD45
      negative cells. In the parental cells, both regulatory sites were phosphorylated
      on BCR ligation. Taken collectively, these results suggest that CD45 keeps both
      BCR-associated and total cytoplasmic pools of Lyn in an inactive state, and a
      mechanism by which Lyn is activated by relative reduction of CD45 effect may be
      operative on BCR ligation.

PMID- 10415031
TI  - Thymus-derived glucocorticoids set the thresholds for thymocyte selection by
      inhibiting TCR-mediated thymocyte activation.
AB  - Selection processes in the thymus eliminate nonfunctional or harmful T cells and
      allow the survival of those cells with the potential to recognize Ag in
      association with self-MHC-encoded molecules (Ag/MHC). We have previously
      demonstrated that thymus-derived glucocorticoids antagonize TCR-mediated
      deletion, suggesting a role for endogenous thymic glucocorticoids in promoting
      survival of thymocytes following TCR engagement. Consistent with this hypothesis,
      we now show that inhibition of thymus glucocorticoid biosynthesis causes an
      increase in thymocyte apoptosis and a decrease in recovery that are directly
      proportional to the number of MHC-encoded molecules present and, therefore, the
      number of ligands available for TCR recognition. Expression of CD5 on CD4+CD8+
      thymocytes, an indicator of TCR-mediated activation, increased in a TCR- and MHC
      dependent manner when corticosteroid production or responsiveness was decreased.
      These results indicate that thymus-derived glucocorticoids determine where the
      window of thymocyte selection occurs in the TCR avidity spectrum by dampening the
      biological consequences of TCR occupancy and reveal that glucocorticoids mask the
      high percentage of self-Ag/MHC-reactive thymocytes that exist in the preselection
      repertoire.

PMID- 10415032
TI  - TCR alpha beta-independent CD28 signaling and costimulation require non-CD4
      associated Lck.
AB  - Whether the sequelae of signals generated through CD28 either directly or in
      circumstances of costimulation require proximal events mediated by p56lck remains
      contentious. We demonstrate that CD4-, but not CD4+ clonal variants respond to
      CD28-specific mAb with both early and late indicators of activation. Forced
      expression of A418/A420-mutated CD4 or wild-type CD4 in the CD4- variant
      recapitulated the CD28-mediated responses of the CD4- and CD4+ variants,
      respectively. The implicated involvement of non-CD4-associated Lck is formally
      demonstrated by overexpressing S20/S23 Lck or wild-type Lck in CD4+ variants. The
      former, but not latter, rescues direct CD28 signaling, and supports
      costimulation. The results demonstrate that constitutive levels of non-CD4
      associated Lck functionally limit CD28-mediated signaling.

PMID- 10415033
TI  - On the role of feedback in promoting conflicting goals of the adaptive immune
      system.
AB  - We explored here the implications of two premises. 1) In their response over days
      or weeks to pathogen invasion, cells of the immune system combine several
      overlapping and perhaps contradictory goals. 2) The immune system has ways to
      monitor progress toward these goals via receptors that bind chemicals whose
      concentrations are related to such progress. We illustrate with simple
      mathematical models how such monitoring can lead to feedbacks that improve the
      efficiency of a given effector type in accomplishing its specialized task, and
      also how feedbacks can shift the balance among a variety of effectors toward a
      preponderance of the more effective. Specific suggestions are given for feedback
      molecules.

PMID- 10415034
TI  - Multiple deficiencies underlie NK cell inactivity in lymphotoxin-alpha gene
      targeted mice.
AB  - We have evaluated the NK cell antitumor activity in lymphotoxin (LT)-deficient
      mice. Both NK cell-mediated tumor rejection and protection from experimental
      metastases were significantly compromised in LT-alpha-deficient mice. Analysis of
      LT-alpha-deficient mice revealed that the absolute number of alphabetaTCR- NK1.1+
      NK cells was reduced in bone marrow and thymus, but with overall proportional
      decreases in other hemopoietic organs. In addition, the antitumor potential of
      alphabetaTCR- NK1.1+ cells, as determined by their lytic capacity and perforin
      expression, was reduced 1.5- to 3-fold in LT-alpha-deficient mice, as compared
      with wild-type mice. Combined defects in NK cell development and effector
      function contribute to compromised NK cell antitumor function in LT-alpha
      deficient mice.

PMID- 10415035
TI  - Human blood dendritic cell-like B cells isolated by the 5G9 monoclonal antibody
      reactive with a novel 220-kDa antigen.
AB  - We developed a murine IgG1 mAb, 5G9, following immunization of a BALB/c mouse
      with Daudi cells. By immunoprecipitation, 5G9 reacted with a 220-kDa Ag on Daudi
      cells, which reduced to four subunits (55, 65, 80, and 85 kDa). mAb 5G9 bound to
      40-60% of peripheral blood B cells, weakly reacted with monocytes and
      granulocytes, and did not bind to erythrocytes, platelets, T cells, or NK cells.
      mAb 5G9 brightly stained scattered cells in human tonsil sections, which appeared
      to be dendritic cells (DC) by morphology. mAb 5G9 also stained scattered cells in
      cytospin slides of monocyte-derived DC with long, thin, beaded membrane
      processes, morphologically distinct from other monocyte-derived DC. Positive
      selection of blood mononuclear cells with mAb 5G9 and sheep anti-mouse IgG
      Dynabeads demonstrated an enriched population of DC. By flow cytometry analysis,
      these cells were CD19, CD20, CD22, CD40, CD44, CD83, CD86, IgD, and HLA-Dr
      positive and either kappa- or lambda-L chain positive. They did not express CD3,
      CD4, CD5, CD10, CD11b, CD13, CD25, CD56, CD14, CD33, or CD64. Isolated 5G9+ cells
      were potent APCs in allogeneic MLR, compared with 5G9- PBMC, 5G9- B cells,
      monocytes, and monocytes cultured in IL-4 and GM-CSF for 24 h. mAb 5G9 defines a
      novel peripheral blood cell with B cell phenotype and DC morphology and function:
      DC-like B cells. The significance of this cell in immune responses requires
      further study.

PMID- 10415036
TI  - Regulation of human intestinal intraepithelial lymphocyte cytolytic function by
      biliary glycoprotein (CD66a).
AB  - Human small intestinal intraepithelial lymphocytes (iIEL) are a unique population
      of CD8alphabeta+ TCR-alphabeta+ but CD28- T lymphocytes that may function in
      intestinal epithelial cell immunosurveillance. In an attempt to define novel cell
      surface molecules involved in iIEL function, we raised several mAbs against
      activated iIELs derived from the small intestine that recognized an Ag on
      activated, but not resting, iIELs. Using expression cloning and binding studies
      with Fc fusion proteins and transfectants, the cognate Ag of these mAbs was
      identified as the N domain of biliary glycoprotein (CD66a), a carcinoembryonic Ag
      related molecule that contains an immune receptor tyrosine-based inhibitory
      motif. Functionally, these mAbs inhibited the anti-CD3-directed and lymphokine
      activated killer activity of the P815 cell line by iIELs derived from the human
      small intestine. These studies indicate that the expression of biliary
      glycoprotein on activated human iIELs and, potentially, other mucosal T
      lymphocytes is involved in the down-regulation of cytolytic function.

PMID- 10415037
TI  - B cell responses to a peptide epitope. VIII. Immune complex-mediated regulation
      of memory B cell generation within germinal centers.
AB  - Using an in vivo reconstitution assay, we examine here the role of immune
      complexes in both formation of germinal centers (GC) and processes that occur
      subsequently within. The presence of Ag, as immune complexes, was found not to
      constitute a limiting requirement for the initiation of GC formation. No
      detrimental effect either on numbers or sizes of the resulting GC was observed
      when Ag-containing immune complexes were omitted during reconstitution. Thus,
      both recruitment and proliferation of Ag-activated B cells within GC appear not
      to be limited by Ag concentrations. In contrast, the presence of immune complexes
      was observed to be obligatory for the generation of Ag-specific memory B cells.
      This optimally required immune complexes to be constituted by IgG-class Abs with
      epitope specificities that were homologous to those of the GC B cells. The GC
      reaction was also found to be characterized by an enhancement of Ab specificity
      for the homologous epitope. Although some improvement in specificity was noted in
      recall responses from immune complex-deficient GC, the presence of appropriate
      immune complexes served to further optimize the outcome. Here again, isotype and
      epitope-specificity of the Ab constituent in immune complexes proved to be
      important.

PMID- 10415038
TI  - Nasal-associated lymphoid tissue: phenotypic and functional evidence for the
      primary role of peripheral node addressin in naive lymphocyte adhesion to high
      endothelial venules in a mucosal site.
AB  - Nasal-associated lymphoid tissue (NALT), a mucosal inductive site for the upper
      respiratory tract, is important for the development of mucosal immunity locally
      and distally to intranasally introduced Ag. To more fully understand the
      induction of nasal mucosal immunity, we investigated the addressins that allow
      for lymphocyte trafficking to this tissue. To investigate the addressins
      responsible for naive lymphocyte binding, immunofluorescent and immunoperoxidase
      staining of frozen NALT sections were performed using anti-mucosal addressin cell
      adhesion molecule-1 (MAdCAM-1), anti-peripheral node addressin (PNAd), and anti
      VCAM-1 mAbs. All NALT high endothelial venules (HEV) expressed PNAd, either
      associated with MAdCAM-1 or alone, whereas NALT follicular dendritic cells
      expressed both MAdCAM-1 and VCAM-1. These expression profiles were distinct from
      those of the gut mucosal inductive site, Peyer's patches (PP). The functionality
      of NALT HEV was determined using a Stamper-Woodruff ex vivo assay. The anti-L
      selectin MEL-14 mAb blocked >90% of naive lymphocyte binding to NALT HEV, whereas
      the anti-MAdCAM-1 mAb, which blocks almost all naive lymphocyte binding to PP,
      minimally blocked binding to NALT HEV. NALT lymphocytes exhibited a unique L
      selectin expression profile, differing from both PP and peripheral lymph nodes.
      Finally, NALT HEV were found in increased amounts in the B cell zones, unlike PP
      HEV. These results suggest that NALT is distinct from the intestinal PP, that
      initial naive lymphocyte binding to NALT HEV involves predominantly L-selectin
      and PNAd rather than alpha4beta7-MAdCAM-1 interactions, and that MAdCAM-1 and
      VCAM-1 expressed by NALT follicular dendritic cells may play an important role in
      lymphocyte recruitment and retention.

PMID- 10415039
TI  - Inhibition of autoimmune T cell responses in the DA rat by bone marrow-derived NK
      cells in vitro: implications for autoimmunity.
AB  - Regulation of the immune response is critical to homeostasis. While innate
      immunity can influence the development of adaptive immune responses, its role in
      regulation is less well understood. Recently, NK cells have been implicated in
      the control of experimental autoimmune encephalomyelitis, an animal model for
      multiple sclerosis. In this report, we show that rat bone marrow-derived NK cells
      exhibited potent inhibitory effects on T cell proliferation to both Con A as well
      as the central nervous system Ag myelin basic protein. There was also a
      significant decrease in both IFN-gamma and IL-10 production in vitro, whereas
      levels of the beta-chemokine monocyte chemoattractant protein-1 were
      significantly elevated. Flow cytometry studies suggest that the NK cells may play
      an important role in regulating both normal and autoimmune T cell responses by
      exerting a direct effect on activated, autoantigen-specific T cells.

PMID- 10415041
TI  - A CD1a+/CD11c+ subset of human blood dendritic cells is a direct precursor of
      Langerhans cells.
AB  - Based on the relative expression of CD11c and CD1a, we have identified three
      fractions of dendritic cells (DCs) in human peripheral blood, including a direct
      precursor of Langerhans cells (LCs). The first two fractions were CD11c+ DCs,
      comprised of a major CD1a+/CD11c+ population (fraction 1), and a minor CD1a
      /CD11c+ component (fraction 2). Both CD11c+ fractions displayed a monocyte-like
      morphology, endocytosed FITC-dextran, expressed CD45RO and myeloid markers such
      as CD13 and CD33, and possessed the receptor for GM-CSF. The third fraction was
      comprised of CD1a-/CD11c- DCs (fraction 3) and resembled plasmacytoid T cells.
      These did not uptake FITC-dextran, were negative for myeloid markers (CD13/CD33),
      and expressed CD45RA and a high level of IL-3Ralpha, but not GM-CSF receptors.
      After culture with IL-3, fraction 3 acquired the characteristics of mature DCs;
      however, the expression of CD62L (lymph node-homing molecules) remained
      unchanged, indicating that fraction 3 can be a precursor pool for previously
      described plasmacytoid T cells in lymphoid organs. Strikingly, the CD1a+/CD11c+
      DCs (fraction 1) quickly acquired LC characteristics when cultured in the
      presence of GM-CSF + IL-4 + TGF-beta1. Thus, E-cadherin, Langerin, and Lag Ag
      were expressed within 1 day of culture, and typical Birbeck granules were
      observed. In contrast, neither CD1a-/CD11c+ (fraction 2) nor CD1a-/CD11c-
      (fraction 3) cells had the capacity to differentiate into LCs. Furthermore, CD14+
      monocytes only expressed E-cadherin, but lacked the other LC markers after
      culture in these cytokines. Therefore, CD1a+/CD11c+ DCs are the direct precursors
      of LCs in peripheral blood.

PMID- 10415040
TI  - Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and
      targets immature dendritic cell precursors to enhance antigen uptake.
AB  - Previously, we reported that killing tumor cells in vivo with the HSV thymidine
      kinase/ganciclovir system generates potent antitumor immunity, determined in part
      by the mechanism by which the cells die and by the levels of inducible heat shock
      protein (hsp) expression induced during the process of cell death. Here, we show
      that induction of hsp70 expression induces an infiltrate of T cells, macrophages,
      and predominantly dendritic cells (DCs) into the tumors as well as an
      intratumoral profile of Th1 cytokine expression (IFN-gamma, TNF-alpha, and IL-12)
      and enhances immunogenicity via a T cell-mediated mechanism. In addition, the
      protection conferred by hsp70 is both tumor and cell specific. We also
      demonstrate that hsp70 targets immature APC to make them significantly more able
      to capture Ags. This is likely to optimize cross-priming of the infiltrating APC
      with tumor Ags, which are simultaneously being released by the dying cells. In
      addition, using an Myc epitope-tagged hsp70 expression vector, we present
      evidence that hsp70 released from dying tumor cells is taken up directly into DCs
      and may, therefore, be involved in direct chaperoning of Ags into DCs. Taken
      together, our data suggest that hsp70 induction serves to signal the immune
      system of the presence of an immunologically relevant (dangerous) situation
      against which an immune reaction should be raised.

PMID- 10415042
TI  - IL-10 transgenic mice present a defect in T cell development reminiscent of SCID
      patients.
AB  - To analyze the effect of IL-10 overexpressed by APCs as observed in some SCID
      patients, we have expressed the human IL-10 cDNA under the control of the murine
      MHC class II promoter in transgenic mice. Similar to SCID patients, these mice
      presented a defect in T cell maturation characterized by a rapid thymic aplasia
      that started after birth. The blockage in T cell maturation was strictly
      restricted to TCR-alpha beta T cells as the absolute number of thymic dendritic,
      TCR-gamma delta and NK1.1 T cells were equivalent to control littermates.
      Crossing IL-10 transgenic mice with TCR transgenic mice or treatment with
      staphylococcal enterotoxin B showed that the defect was not related to the
      impairment of positive or negative selection. However, repopulating of IL-10
      transgenic mouse-fetal thymic organ culture with different stages of triple
      negative T cells isolated from control mice showed that the blockage occurred
      specifically at the pre-T cell stage and was reverted by treatment with blocking
      anti-IL-10 mAbs. These results demonstrate that IL-10 regulates T cell maturation
      and that dysregulation of IL-10 expression can lead to severe T cell
      immunodeficiency.

PMID- 10415043
TI  - Transactivation of classical and nonclassical HLA class I genes through the IFN
      stimulated response element.
AB  - The IFN-stimulated response element (ISRE) is an important conserved cis-acting
      regulatory element in the promoter of MHC class I genes, but displays
      considerable locus-specific nucleotide variation. In this report, the putative
      ISREs of classical and nonclassical HLA class I genes were investigated for their
      contribution to MHC class I transactivation. It is shown that IFN-gamma induced
      MHC class I transactivation through the ISRE of HLA-A, HLA-B, HLA-C, and HLA-F.
      This is congruent with the binding of IFN regulatory factor-1 to the ISREs of
      these loci upon IFN-gamma treatment. Sp1 was shown to bind to the CG-rich
      sequences in the ISRE regions of HLA-B, HLA-C, and HLA-G. The putative E box 5'
      of the ISRE in most HLA-B alleles was shown to bind the upstream stimulatory
      factors (USF) 1 and 2. The Sp1 and USF binding sites did not influence IFN-gamma
      induced transactivation. However, the USF binding site played a suppressive role
      in the constitutive expression of HLA-B. The locus-specific transcriptional
      control through the ISRE could be an important mechanism in the differential
      regulation of classical and nonclassical MHC class I expression, which determines
      adequate Ag presentation upon pathogenic challenge.

PMID- 10415044
TI  - TNF-alpha suppresses IFN-gamma-induced MHC class II expression in HT1080 cells by
      destabilizing class II trans-activator mRNA.
AB  - Precise regulation of MHC class II gene expression is crucial for development and
      function of the immune system. Class II trans-activator (CIITA) has been shown to
      be required for constitutive and IFN-gamma-induced MHC class II transcription.
      TNF-alpha is commonly coexpressed with IFN-gamma during immune-mediated
      inflammatory responses and modulates IFN-gamma-stimulated MHC class II
      expression. The effect of TNF-alpha on MHC class II expression depends on cell
      type and cellular differentiation state. We show here that TNF-alpha suppresses
      IFN-gamma-induced CIITA mRNA accumulation, resulting in decreased MHC class II
      expression in human fibrosarcoma HT1080 cells. TNF-alpha also inhibits CIITA mRNA
      accumulation and protein expression in a tetracycline-regulated system without
      affecting promoter activity. CIITA mRNA, regulated by either IFN-gamma or
      tetracycline, was destabilized in the presence of TNF-alpha, suggesting that TNF
      alpha utilizes a distinct mechanism to suppress MHC class II expression in HT1080
      cells. Consistent with this interpretation, TNF-alpha blocked IFN-gamma-induced
      CIITA and MHC class II expression in mutant cells that are unresponsive to TGF
      beta or IFN-beta. This is the first instance in which MHC class II expression is
      inhibited by destabilizing CIITA mRNA.

PMID- 10415045
TI  - A novel CD8 T cell-restricted CD45RB epitope shared by CD43 is differentially
      affected by glycosylation.
AB  - The mAb 1B11 has been characterized as recognizing the activation-associated
      glycoform of murine CD43, a heavily O-glycosylated protein implicated in
      leukocyte homing. When hemopoietic cells from CD43-/- mice were stained with
      1B11, CD43-independent binding of 1B11 was observed on peripheral CD8 T cells and
      at low levels on thymocytes, while no binding was detected on CD4 T cells, B
      cells, or bone marrow cells. Levels of 1B11 staining were comparable in lymph
      node CD8+ T cells from both CD43-/- mice and CD43+/+ mice. We sought to identify
      the CD43-independent target of 1B11 expressed on CD8 T cells. Previous work had
      demonstrated that neuraminidase treatment of lymph node cells (LNC) enhanced 1B11
      binding on CD43+/+ LNC; this enhancement was also observed in CD43-/- LNC. We
      show that neuraminidase-enhanced 1B11 binding in CD43-/- LNC and EL4 thymoma
      cells is CD43 independent and that 1B11 detects a novel target of apparent mass
      of approximately 200 kDa identified as a hyposialylated form of CD45RB
      preferentially expressed on peripheral CD8, but not CD4, T cells. Our data also
      show that the recognition of CD43 and CD45RB by 1B11 is differentially affected
      by O-linked glycosylation and sialic acid. Whereas 1B11 recognition of CD43 on
      activated T cells required both core 2 O-glycan branching and sialic acid, 1B11
      recognition of CD45 only occurred in the absence of both core 2 glycosylation and
      sialic acid.

PMID- 10415046
TI  - Th1 T cell responses to HIV-1 Gag protein delivered by a Listeria monocytogenes
      vaccine are similar to those induced by endogenous listerial antigens.
AB  - Listeria monocytogenes is a facultative intracellular bacterium that lives and
      grows in the cytoplasm of the host cell. The hallmark of a listerial infection is
      a cell-mediated immune response to its own secreted virulence factors. Thus, L.
      monocytogenes vaccines engineered to secrete HIV proteins may be ideal vectors
      for boosting cellular immune responses against HIV. Using strains of L.
      monocytogenes that stably express and secrete HIV Gag (Lm-Gag) to deliver this Ag
      to the immune system, we have previously shown strong MHC class I-restricted
      cytotoxic T cell responses to this protein. In this study, we examine MHC class
      II-restricted T cell responses to HIV-Gag delivered by Lm-Gag. We demonstrate the
      induction of CD4+ T cells that are HIV-Gag specific and identify three epitopes
      in two strains of mice, BALB/c (H-2d) and C57BL/6 (H-2b), two of which are both H
      2d and H-2b restricted, but are not immunodominant for both haplotypes. In
      addition, we show that the CD4+ T cells induced are of the Th1 phenotype that
      produce IFN-gamma at levels similar to CD4+ T cells induced to endogenous
      listerial Ags. These studies suggest that chromosomally modified strains of L.
      monocytogenes may be useful as vaccine vectors for the induction of Th1 T cell
      responses against HIV.

PMID- 10415048
TI  - Protective immune responses induced by vaccination with an expression genomic
      library of Leishmania major.
AB  - To develop an effective vaccine against the intracellular protozoan parasite
      Leishmania spp., we investigated the feasibility of expression library
      immunization (ELI) in the mouse. Genomic expression libraries of L. major were
      constructed and used to immunize mice. One of the three libraries (L1, with 10(5)
      clones) induced a significant protective immune response and delayed the onset of
      lesion development in highly susceptible BALB/c mice after i.m. immunization,
      compared with control mice immunized with the empty vector (EV). L1 was then
      divided into five sublibraries of approximately 2 x 10(4) clones each. Mice
      immunized with one of the sublibraries (SL1A) developed an even stronger
      protective effect than that induced by L1. SL1A was further divided into 20
      sublibraries (SL2) of approximately 10(3) clones each. One of the SL2 libraries
      (SL2G) induced a strong protective effect against L. major infection. In direct
      comparative studies, the protective effect of the sublibraries was in the order
      of SL2G > SL1A > L1. Lymphoid cells from mice vaccinated with SL2G produced more
      IFN-gamma and NO, compared with cells from control mice injected with EV. Serum
      from the vaccinated mice also contained more parasite-specific IgG2a Ab, compared
      with controls. Therefore, these data demonstrate that ELI is feasible against
      this complex intracellular parasitic infection, by preferentially inducing the
      development of Th1 responses. Furthermore, by sequential division of the
      libraries, this approach may be used to enrich and identify protective genes for
      effective gene vaccination against other parasitic infections.

PMID- 10415047
TI  - NF-kappa B is a central regulator of the intestinal epithelial cell innate immune
      response induced by infection with enteroinvasive bacteria.
AB  - Human intestinal epithelial cells up-regulate the expression of an inflammatory
      gene program in response to infection with a spectrum of different strains of
      enteroinvasive bacteria. The conserved nature of this program suggested that
      diverse signals, which are activated by enteroinvasive bacteria, can be
      integrated into a common signaling pathway that activates a set of
      proinflammatory genes in infected host cells. Human intestinal epithelial cell
      lines, HT-29, Caco-2, and T84, were infected with invasive bacteria that use
      different strategies to induce their uptake and have different intracellular
      localizations (i.e., Salmonella dublin, enteroinvasive Escherichia coli, or
      Yersinia enterocolitica). Infection with each of these bacteria resulted in the
      activation of TNF receptor associated factors, two recently described serine
      kinases, I kappa B kinase (IKK) alpha and IKK beta, and increased NF-kappa B DNA
      binding activity. This was paralleled by partial degradation of I kappa B alpha
      and I kappa B epsilon in bacteria-infected Caco-2 cells. Mutant proteins that act
      as superrepressors of IKK beta and I kappa B alpha inhibited the up-regulated
      transcription and expression of downstream targets genes of NF-kappa B that are
      key components of the epithelial inflammatory gene program (i.e., IL-8, growth
      related oncogene-alpha, monocyte chemoattractant protein-1, TNF-alpha,
      cyclooxygenase-2, nitric oxide synthase-2, ICAM-1) activated by those
      enteroinvasive bacteria. These studies position NF-kappa B as a central regulator
      of the epithelial cell innate immune response to infection with enteroinvasive
      bacteria.

PMID- 10415049
TI  - Human NK cells express endothelial nitric oxide synthase, and nitric oxide
      protects them from activation-induced cell death by regulating expression of TNF
      alpha.
AB  - Although NO appears important in rodent immune responses, its involvement in the
      human immune system is unclear. We report that human NK cells express
      constitutive endothelial NO synthase mRNA and protein, but not detectable levels
      of inducible NO synthase. They produce NO following activation by coculture with
      target cells or cross-linking with anti-CD16 mAb, and production is increased in
      the presence of IL-2. N-monomethyl-L-arginine (L-NMA), a NOS inhibitor, partially
      inhibited NK cell lysis of four different target cells (<40% inhibition at 500
      microM L-NMA), but not granule release following coculture with target cells, or
      Fas ligand induction following cross-linking with anti-CD16 mAb. However, L-NMA
      augmented apoptosis of NK cells induced by activation through CD16 ligation or
      coculture with K562. An NO donor, S-nitroso-N-acetylpenicillamine (SNAP),
      suppressed apoptosis of NK cells induced by CD16 cross-linking or coculture with
      target cells, suggesting that endogenous NO production is involved in protection
      of NK cells from activation-induced apoptosis, thereby maintaining NK activity.
      SNAP also suppressed, and L-NMA enhanced, expression of TNF-alpha, reported to be
      involved in activation-induced NK cell death, in response to CD16 cross-linking.
      Suppression of anti-CD16-induced apoptosis by SNAP was reversed by the addition
      of rTNF-alpha. DNA-binding activity of the transcription factor, NF-AT, which is
      involved in TNF-alpha induction upon ligation of CD16, was inhibited by SNAP and
      enhanced by L-NMA. Our results suggest that down-regulation of TNF-alpha
      expression, possibly due to suppression of NF-AT activation, is a mechanism by
      which endogenous NO protects NK cells from activation-induced apoptosis, and
      maintains lytic capacity.

PMID- 10415050
TI  - Apparent MHC-independent stimulation of CD8+ T cells in vivo during latent murine
      gammaherpesvirus infection.
AB  - Like EBV-infected humans with infectious mononucleosis, mice infected with the
      rodent gammaherpesvirus MHV-68 develop a profound increase in the number of CD8+
      T cells in the circulation. In the mouse model, this lymphocytosis consists of
      highly activated CD8+ T cells strikingly biased toward V beta 4 TCR expression.
      Moreover, this expansion of V beta 4+CD8+ T cells does not depend on the MHC
      haplotype of the infected animal. Using a panel of lacZ-inducible T cell
      hybridomas, we have detected V beta 4-specific T cell stimulatory activity in the
      spleens of MHV-68-infected mice. We show that the appearance and quantity of this
      activity correlate with the establishment and magnitude of latent viral
      infection. Furthermore, on the basis of Ab blocking studies as well as
      experiments with MHC class II, beta2-microglobulin (beta2m) and TAP1 knockout
      mice, the V beta 4-specific T cell stimulatory activity does not appear to depend
      on conventional presentation by classical MHC class I or class II molecules.
      Taken together, the data indicate that during latent infection, MHV-68 may
      express a T cell ligand that differs fundamentally from both conventional peptide
      Ags and classical viral superantigens.

PMID- 10415052
TI  - Increased susceptibility of TNF-alpha lymphotoxin-alpha double knockout mice to
      systemic candidiasis through impaired recruitment of neutrophils and phagocytosis
      of Candida albicans.
AB  - TNF-alpha and lymphotoxin-alpha (LT) are members of the TNF family, and these
      cytokines play crucial roles in the defense against infection with Candida
      albicans. The aim of the present study was to investigate the role of endogenous
      TNF and LT during disseminated candidiasis in TNF-/-LT-/- knockout mice. The TNF-
      and LT-deficient animals had a significantly increased mortality following C.
      albicans infection compared with control mice, and this was due to a 10- to 1000
      fold increased outgrowth of the yeast in their organs. No differences between TNF
      /-LT-/- mice and TNF+/+LT+/+ were observed when mice were rendered neutropenic,
      suggesting that activation of neutrophils mediates the beneficial effects of
      endogenous TNF and LT. Histopathology of the organs, combined with neutrophil
      recruitment experiments, showed a dramatic delay in the neutrophil recruitment at
      the sites of Candida infection in the TNF-/-LT-/- mice. Moreover, the neutrophils
      of deficient animals were less potent to phagocytize Candida blastospores than
      control neutrophils. In contrast, the killing of Candida and the oxygen radical
      production did not differ between neutrophils of TNF-/-LT-/- and TNF+/+LT+/+
      mice. Peak circulating IL-6 was significantly higher in TNF-/-LT-/- mice during
      infection. Peritoneal macrophages of TNF-/-LT-/- mice did not produce TNF, and
      synthesized significantly lower amounts of IL-1alpha, IL-1beta, IL-6, and
      macrophage-inflammatory protein-1alpha than macrophages of TNF+/+LT+/+ animals
      did. In conclusion, endogenous TNF and/or LT contribute to host resistance to
      disseminated candidiasis, and their absence in TNF-/-LT-/- mice renders the
      animals susceptible through impaired recruitment of neutrophils and impaired
      phagocytosis of C. albicans.

PMID- 10415051
TI  - Cellular immune responses are essential for the development of Helicobacter felis
      associated gastric pathology.
AB  - The bacteria Helicobacter pylori is a major human pathogen that infects over half
      of the world's population. Infection initiates a series of changes in the gastric
      mucosa, beginning with atrophic gastritis and leading in some patients to peptic
      ulcer disease, mucosa-associated lymphomas, and gastric adenocarcinoma. Although
      this cascade of events clearly occurs, little is known about the role of the host
      immune response in disease progression. We have utilized the C57BL/6 Helicobacter
      felis mouse model to critically analyze the role of the adaptive immune response
      in the development of Helicobacter-associated gastric pathology. Infection of B
      and T cell-deficient RAG-1-/- mice or T cell-deficient TCRbetadelta-/- mice with
      H. felis resulted in high levels of colonization, but no detectable gastric
      pathology. Conversely, infection of B cell-deficient microMT mice resulted in
      severe gastric alterations identical with those seen in immunocompetent C57BL/6
      infected mice, including gastric mucosal hyperplasia and intestinal metaplasia.
      These results demonstrate that the host T cell response is a critical mediator of
      Helicobacter-associated gastric pathology, and that B cells and their secreted
      Abs are not the effectors of the immune-mediated gastric pathology seen after H.
      felis infection. These results indicate that in addition to specific Helicobacter
      virulence factors, the host immune response is an important determinant of
      Helicobacter-associated disease.

PMID- 10415053
TI  - Infection of HIV-1 transgenic mice with Mycobacterium avium induces the
      expression of infectious virus selectively from a Mac-1-positive host cell
      population.
AB  - Infection of HIV-1-transgenic mice with Mycobacterium avium, a common
      opportunistic pathogen in AIDS patients, was shown to result in increased tissue
      expression of viral specific transcripts. Moreover, by coculturing splenocytes
      from the transgenic animals with human T cells it was possible to demonstrate
      that the elevation in HIV-1 mRNA triggered by M. avium infection reflects
      increased production of infectious virions. Viral immune activation was also
      shown to correlate with a marked elevation of p24 in supernatants of ex vivo
      cultured tissues and, more importantly, in systemic increases in the HIV-1
      protein in plasma. Interestingly, these tissue and systemic p24 responses were
      found to be differentially regulated. Thus, while in vitro p24 production by
      cultured splenocytes increased concurrently with bacterial loads during the first
      6 wk of infection, levels of the Ag in plasma actually decreased. In situ
      localization experiments together with FACS analysis of HIV-1-expressing
      splenocytes indicated that virus production is restricted largely to cells of the
      monocyte/macrophage lineage. Indeed, in vitro p24 expression by cells from
      noninfected transgenic mice was up-regulated by polyclonal stimulation of
      macrophages but not T cells. Together these results underscore the importance of
      the macrophage reservoir in persistent virus expression and establish a
      convenient and relevant animal model for studying the factors responsible for
      immune activation of HIV-1 induced by mycobacterial as well as other common
      coinfections encountered by AIDS patients.

PMID- 10415054
TI  - Adenovirus-induced liver pathology is mediated through TNF receptors I and II but
      is independent of TNF or lymphotoxin.
AB  - Mice infected with an adenovirus mutant in which the E3 region is deleted,
      including TNF-resistance genes, develop fatal liver pathology within 3-4 days
      after infection. At least 10-fold more wild-type virus was needed to cause
      comparable pathology. These results indicate that the E3 region is critically
      involved in modulating the pathogenesis of adenovirus infection and that TNF may
      play a role in liver damage. To explore the latter possibility, the course of
      disease was examined in infected mice lacking TNFR-I and/or TNFRII, TNF only, or
      both TNF and lymphotoxin-alpha. Only mice lacking both TNFRI and TNFRII were
      protected from the lethal affects of the mutant adenovirus. Mice deficient in TNF
      or TNF and lymphotoxin-alpha displayed the fatal pathology. This outcome is
      consistent with the existence of another related ligand that binds TNFRI/II to
      mediate liver damage during infection with this mutant.

PMID- 10415055
TI  - Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following
      anti-TNF-alpha therapy in rheumatoid arthritis.
AB  - Treatment with a chimeric mAb to TNF-alpha has been shown to suppress
      inflammation and improve patient well-being in rheumatoid arthritis (RA), but the
      mechanisms of action of such treatment have not been fully explored. Here we show
      that in vivo administration of anti-TNF-alpha Ab, using a longitudinal analysis,
      results in the rapid down-regulation of a spectrum of cytokines, cytokine
      inhibitors, and acute-phase proteins. Marked diurnal variation in the serum
      levels of some of these were detected. These results were consistent with the
      concept of a cytokine-dependent cytokine cascade, and the degree of clinical
      benefit noted after anti-TNF-alpha therapy is probably due to the reduction in
      many proinflammatory mediators apart from TNF-alpha, such as IL-6, which reached
      normal levels within 24 h. Serum levels of cytokine inhibitors such as soluble
      p75 and p55 TNFR were reduced as was IL-1 receptor antagonist. Reductions in
      acute-phase proteins occurred after serum IL-6 fell and included serum amyloid A,
      haptoglobin, and fibrinogen. The latter reduction could be of importance, as it
      is a risk factor for atherosclerosis, which is augmented in RA patients.

PMID- 10415056
TI  - IL-12 is dysregulated in macrophages from IRF-1 and IRF-2 knockout mice.
AB  - Macrophages derived from IFN-regulatory factor-1 (IRF-1) and IRF-2 knockout (-/-)
      and wild-type (+/+) mice were utilized to examine the role of these transcription
      factors in the regulation of IL-12 mRNA and protein expression. Induction of IL
      12 p40 mRNA by LPS was markedly diminished in both IRF-1(-/-) and IRF-2(-/-)
      macrophages. In contrast, IRF-1(-/-), but not IRF-2(-/-), macrophages exhibited
      impaired LPS-induced IL-12 p35 mRNA expression. The ability of IFN-gamma to
      augment LPS-induced IL-12 p40 mRNA further when both stimuli were present
      simultaneously was significantly diminished in both IRF-1(-/-) and IRF-2(-/-)
      macrophages, with the most profound impairment observed for IRF-1(-/-)
      macrophages. Reductions in IL-12 mRNA expression after stimulation with LPS or
      LPS plus IFN-gamma were accompanied by substantial reductions in IL-12 p40 and IL
      12 p70 protein in both IRF-1(-/-) and IRF-2(-/-) macrophages. Priming IRF-1(-/-)
      and IRF-2(-/-) macrophages with IFN-gamma for 24 h before LPS treatment partially
      restored impaired IL-12 mRNA and protein production in both IRF-1(-/-) and IRF-2(
      /-) macrophages. Depressed IL-12 levels were paralleled by significant reductions
      in IFN-gamma mRNA expression in IRF-1(-/-) and IRF-2(-/-) macrophages. These
      results indicate that both IRF-1 and IRF-2 are critical transcription factors in
      the regulation of macrophage IL-12 and consequently IFN-gamma production.

PMID- 10415057
TI  - Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and
      in vivo.
AB  - The host response to Gram-negative LPS is characterized by an influx of
      inflammatory cells into host tissues, which is mediated, in part, by localized
      production of chemokines. The expression and function of chemokines in vivo
      appears to be highly selective, though the molecular mechanisms responsible are
      not well understood. All CXC (IFN-gamma-inducible protein (IP-10), macrophage
      inflammatory protein (MIP)-2, and KC) and CC (JE/monocyte chemoattractant protein
      (MCP)-1, MCP-5, MIP-1alpha, MIP-1beta, and RANTES) chemokine genes evaluated were
      sensitive to stimulation by LPS in vitro and in vivo. While IL-10 suppressed the
      expression of all LPS-induced chemokine genes evaluated in vitro, treatment with
      IFN-gamma selectively induced IP-10 and MCP-5 mRNAs, but inhibited LPS-induced
      MIP-2, KC, JE/MCP-1, MIP-1alpha, and MIP-1beta mRNA and/or protein. Like the
      response to IFN-gamma, LPS-mediated induction of IP-10 and MCP-5 was Stat1
      dependent. Interestingly, only the IFN-gamma-mediated suppression of LPS-induced
      KC gene expression was IFN regulatory factor-2 dependent. Treatment of mice with
      LPS in vivo also induced high levels of chemokine mRNA in the liver and lung,
      with a concomitant increase in circulating protein. Hepatic expression of MIP
      1alpha, MIP-1beta, RANTES, and MCP-5 mRNAs were dramatically reduced in Kupffer
      cell-depleted mice, while IP-10, KC, MIP-2, and MCP-1 were unaffected or
      enhanced. These findings indicate that selective regulation of chemokine
      expression in vivo may result from differential response of macrophages to pro-
      and antiinflammatory stimuli and to cell type-specific patterns of stimulus
      sensitivity. Moreover, the data suggest that individual chemokine genes are
      differentially regulated in response to LPS, suggesting unique roles during the
      sepsis cascade.

PMID- 10415058
TI  - Glucocorticosteroids inhibit mRNA expression for eotaxin, eotaxin-2, and monocyte
      chemotactic protein-4 in human airway inflammation with eosinophilia.
AB  - How eosinophils are preferentially recruited to inflammatory sites remains
      elusive, but increasing evidence suggests that chemokines that bind to the CCR3
      participate in this process. In this study, we investigated the transcript levels
      and chemotactic activity of CCR3-binding chemokines in nasal polyps, a disorder
      often showing prominent eosinophilia. We found that mRNA expression for eotaxin,
      eotaxin-2, and monocyte-chemotactic protein-4 was significantly increased in
      nasal polyps compared with turbinate mucosa from the same patients, or
      histologically normal nasal mucosa from control subjects. Interestingly, the
      novel CCR3-specific chemokine, eotaxin-2, showed the highest transcript levels.
      Consistent with these mRNA data, polyp tissue fluid exhibited strong chemotactic
      activity for eosinophils that was significantly inhibited by a blocking Ab
      against CCR3. When patients were treated systemically with glucocorticosteroids,
      the mRNA levels in the polyps were reduced to that found in turbinate mucosa for
      all chemokines. Together, these findings suggested an important role for CCR3
      binding chemokines in eosinophil recruitment to nasal polyps. Such chemokines,
      therefore, most likely contribute significantly in the pathogenesis of eosinophil
      related disorders; and the reduced chemokine expression observed after steroid
      treatment might reflect, at least in part, how steroids inhibit tissue
      accumulation of eosinophils.

PMID- 10415059
TI  - Lipid-DNA complexes induce potent activation of innate immune responses and
      antitumor activity when administered intravenously.
AB  - Cationic lipid-DNA complexes (CLDC) are reported to be safe and effective for
      systemic gene delivery, particularly to the lungs. However, we observed that i.v.
      injection of CLDC induced immunologic effects not previously reported. We found
      that even very low doses of CLDC administered i.v. induced marked systemic immune
      activation. This response included strong up-regulation of CD69 expression on
      multiple cell types and systemic release of high levels of Th1 cytokines, from
      both lung and spleen mononuclear cells. CLDC were much more potent immune
      activators on a per weight basis than either LPS or poly(I:C). The remarkable
      potency of CLDC appeared to result from enhancement of the immune stimulatory
      properties of DNA, since cationic lipids alone were without immune stimulatory
      activity. Systemic treatment with CLDC controlled tumor growth and significantly
      prolonged survival times in mice with metastatic pulmonary tumors. NK cells
      accumulated to high levels in the lungs of CLDC-treated mice, were functionally
      activated, and released high levels of IFN-gamma. The antitumor activity induced
      by CLDC injection was dependent on both NK cells and IFN-gamma. Thus, DNA
      complexed to cationic liposomes becomes highly immunostimulatory and capable of
      inducing strong antitumor activity when administered systemically.

PMID- 10415060
TI  - Evidence that beta cell death in the nonobese diabetic mouse is Fas independent.
AB  - Recent studies suggest that Fas expression on pancreatic beta cells may be
      important in the development of autoimmune diabetes in the nonobese diabetic
      (NOD) mouse. To address this, pancreatic islets from NOD mice were analyzed by
      flow cytometry to directly identify which cells express Fas and Fas ligand (FasL)
      ex vivo and after in vitro culture with cytokines. Fas expression was not
      detected on beta cells isolated from young (35 days) NOD mice. In vitro,
      incubation of NOD mouse islets with both IL-1 and IFN-gamma was required to
      achieve sufficient Fas expression and sensitivity for islets to be susceptible to
      lysis by soluble FasL. In islets isolated from older (>/=125 days) NOD mice, Fas
      expression was detected on a limited number of beta cells (1-5%). FasL was not
      detected on beta cells from either NOD or Fas-deficient MRLlpr/lpr islets. Also,
      both NOD and MRLlpr/lpr islets were equally susceptible to cytokine-induced cell
      death. This eliminates the possibility that cytokine-treated murine islet cells
      commit "suicide" due to simultaneous expression of Fas and FasL. Last, we show
      that NO is not required for cytokine-induced Fas expression and Fas-mediated
      apoptosis of islet cells. These findings indicate that beta cells can be killed
      by Fas-dependent cytotoxicity; however, our results raise further doubts about
      the clinical significance of Fas-mediated beta cell destruction because few Fas
      positive cells were isolated immediately before the development of diabetes.

PMID- 10415061
TI  - Generation of nitric oxide by the inducible nitric oxide synthase protects gamma
      delta T cells from Mycobacterium tuberculosis-induced apoptosis.
AB  - Gamma delta T cells are early recruited into mycobacterial lesions. Upon
      microbial Ag recognition, gamma delta cells secrete cytokines and chemokines and
      undergo apoptosis via CD95/CD95 ligand (CD95L) interaction, possibly influencing
      the outcome of infection and the characteristics of the disease. In this paper we
      show that activated phagocytes acquire, upon challenge with Mycobacterium
      tuberculosis, the ability to inhibit M. tuberculosis-induced gamma delta cell
      apoptosis. Apoptosis protection was due to NO because it correlated with NO
      synthase (NOS)-2 induction and activity in scavenger cells and was abrogated by
      NOS inhibitors. Furthermore, the NO donor S-nitrosoacetylpenicillamine mimicked
      the effect of enzyme induction. NO left unaffected the expression of CD95 and
      CD95L, suggesting interference with an event ensuing CD95/CD95L interaction. NO
      was found to interfere with the intracellular accumulation of ceramide and the
      activation of caspases, which were involved in gamma delta T cells apoptosis
      after M. tuberculosis recognition. We propose that NO generated by infected
      macrophages determines the life span and therefore the function of lymphocytes at
      the infection site, thus linking innate and adaptive immunity.

PMID- 10415062
TI  - Essential role of T cell NF-kappa B activation in collagen-induced arthritis.
AB  - NF-kappa B/Rel proteins are ubiquitous transcription factors that are activated
      by proinflammatory signals or engagement of Ag receptors. To study the role of NF
      kappa B/Rel signaling in T lymphocytes during autoimmune disease, we investigated
      type II collagen-induced arthritis (CIA) in transgenic mice expressing a
      constitutive inhibitor of NF-kappa B/Rel (I kappa B alpha(Delta N)) in the T
      lineage. Expression of the I kappa B alpha(Delta N) transgene was persistently
      high in adult peripheral lymphoid organs and undetectable in T cell-depleted
      splenocytes, suggesting the expression of the transgene is restricted to the T
      lineage. The incidence and severity of CIA were decreased significantly in these
      I kappa B alpha(Delta N) transgenic mice compared with nontransgenic littermates.
      Inhibition of CIA was not due solely to a decrease in their CD8+ population
      because transfer of wild-type CD8+ cells into transgenic mice failed to restore
      disease susceptibility. Protection against disease was associated with a moderate
      decrease in clonal expansion and a profound and persistent decrease in Ag-induced
      IFN-gamma production in vivo. Consistent with decreased level of anti-type II
      collagen-specific Abs and IFN-gamma, serum levels of IgG2a anti-CII Abs were
      significantly reduced. However, anti-CII-specific IgG1 levels were normal,
      indicating that some aspects of T cell help were unaffected. Taken together,
      these results suggest that inhibition of NF-kappa B in T cells impairs CIA
      development in vivo through decreases in type 1 T cell-dependent responses.

PMID- 10415063
TI  - Involvement of distinct cellular compartments in the abnormal lymphoid
      organogenesis in lymphotoxin-alpha-deficient mice and alymphoplasia (aly) mice
      defined by the chimeric analysis.
AB  - Both lymphotoxin-alpha (LTalpha)-deficient mice and alymphoplasia (aly) mice, a
      natural mutant strain, manifest a quite similar phenotype: lack of lymph nodes
      (LN) and Peyer's patches (PP), with disturbed spleen architecture. The mechanisms
      underlying the defective lymphoid organogenesis in these mice were investigated
      by generating aggregation chimeras; ex vivo fused morulae were implanted into
      pseudo-pregnant host females and allowed to develop to term. Chimeric mice
      between LTalpha-deficient mice and wild-type mice restored LN and PP almost
      completely, suggesting that LTalpha expressed by circulating bone marrow-derived
      cells is essential for lymphoid organogenesis as well as for organization of
      spleen architecture. By contrast, chimeric mice between aly mice and wild-type
      mice showed only limited restoration of LN and PP. This suggests that the
      putative aly gene product does not act as a circulating ligand for lymphoid
      organogenesis, like LTalpha. Rather, abnormal development of lymphoid organs in
      aly mice seems most likely due to the defective development of the incipient
      stromal cells of the LN and PP. Supporting this hypothesis, up-regulation of VCAM
      1 on aly mouse embryonic fibroblasts by signals through LTbetaR, which is
      exclusively expressed by nonlymphoid cells, was disturbed. These studies
      demonstrate that LTalpha and the putative aly gene product together control
      lymphoid organogenesis with a close mechanistic relationship in their biochemical
      pathways through governing the distinct cellular compartments, the former acting
      as a circulating ligand and the latter as a LTbetaR-signaling molecule expressed
      by the stroma of the lymphoid organs.

PMID- 10415064
TI  - Lymphocyte adhesion to epithelia and endothelia mediated by the lymphocyte
      endothelial-epithelial cell adhesion molecule glycoprotein.
AB  - Upon encountering the relevant vascular bed, lymphocytes attach to endothelial
      adhesion molecules, transmigrate out of circulation, and localize within tissues.
      Lymphocytes may then be retained at microanatomic sites, as in tissues, or they
      may continue to migrate to the lymphatics and recirculate in the blood.
      Lymphocytes also interact transiently, but with high avidity, with target cells
      or APC that are infected with microbes or have taken up exogenous foreign Ags.
      This array of adhesive capabilities is mediated by the selective expression of
      lymphocyte adhesion molecules. Here, we developed the 6F10 mAb, which recognizes
      a cell surface glycoprotein designated lymphocyte endothelial-epithelial cell
      adhesion molecule (LEEP-CAM), that is distinct in biochemical characteristics and
      distribution of expression from other molecules known to play a role in
      lymphocyte adhesion. LEEP-CAM is expressed on particular epithelia, including the
      suprabasal region of the epidermis, the basal layer of bronchial and breast
      epithelia, and throughout the tonsillar and vaginal epithelia. Yet, it is absent
      from intestinal and renal epithelia. Interestingly, it is expressed also on
      vascular endothelium, especially high endothelial venules (HEV) in lymphoid
      organs, such as tonsil and appendix. The anti-LEEP-CAM mAb specifically blocked T
      and B lymphocyte adhesion to monolayers of epithelial cells and to vascular
      endothelial cells in static cell-to-cell binding assays by approximately 40-60%
      when compared with control mAbs. These data suggest a role for this newly
      identified molecule in lymphocyte binding to endothelium, as well as adhesive
      interactions within selected epithelia.

PMID- 10415065
TI  - A novel human CC chemokine, eotaxin-3, which is expressed in IL-4-stimulated
      vascular endothelial cells, exhibits potent activity toward eosinophils.
AB  - IL-4 has been shown to be involved in the accumulation of leukocytes, especially
      eosinophils, at sites of inflammation by acting on vascular endothelial cells. To
      identify novel molecules involved in the IL-4-dependent eosinophil extravasation,
      cDNA prepared from HUVEC stimulated with IL-4 was subjected to differential
      display analysis, which revealed a novel CC chemokine designated as eotaxin-3.
      The human eotaxin-3 gene has been localized to chromosome 7q11.2, unlike most
      other CC chemokine genes. The predicted mature protein of 71 aa showed 27-42%
      identity to other human CC chemokines. The recombinant protein induced a
      transient increase in the cytosolic Ca2+ concentration and in vitro chemotaxis on
      eosinophils. Furthermore, in cynomolgus monkeys, the accumulation of eosinophils
      was observed at the sites where the protein was injected. Eotaxin-3 inhibited the
      binding of 125I-eotaxin, but not 125I-macrophage inflammatory protein-1alpha, to
      eosinophils and acted on cell lines transfected with CCR-3, suggesting that
      eotaxin-3 recognized CCR-3. IL-13 as well as IL-4 up-regulated eotaxin-3 mRNA in
      HUVEC, whereas neither TNF-alpha, IL-1beta, IFN-gamma, nor TNF-alpha plus IFN
      gamma did. The expression profile of eotaxin-3 is different from those of
      eotaxin, RANTES, and monocyte chemoattractant protein-4, which are potent
      eosinophil-selective chemoattractants and are induced by either TNF-alpha or TNF
      alpha plus IFN-gamma. These results suggest that eotaxin-3 may contribute to the
      eosinophil accumulation in atopic diseases.

PMID- 10415066
TI  - Activation of mitogen-activated protein kinase regulates eotaxin-induced
      eosinophil migration.
AB  - Eotaxin is a potent eosinophil chemoattractant that plays an important role in
      regulating eosinophil tissue levels both in healthy individuals and in diseases
      associated with significant eosinophil infiltrates, such as the allergic
      inflammation observed in asthma. Here, we demonstrate that treatment of
      eosinophils with eotaxin induces the phosphorylation of the mitogen-activated
      protein kinases (MAPKs) p42 and p44, leading to kinase activation. Blockade of
      MAPK activation by the MAPK kinase inhibitor PD98059 leads to a dramatic decrease
      in eotaxin-induced eosinophil rolling in vivo and chemotaxis in vitro. This
      blockade in the leukocyte migration process is consistent with the observed
      inhibition of actin polymerization and rearrangement within the eosinophil
      following treatment with MAPK inhibitor. It is suggested, therefore, that the
      intrinsic mechanism of eotaxin-induced eosinophil rolling and migration involves
      activation of the p42/p44 MAPK, possibly through regulation of the cytoskeletal
      rearrangements necessary for chemotaxis.

PMID- 10415067
TI  - Evidence for the involvement of CD44 in endothelial cell injury and induction of
      vascular leak syndrome by IL-2.
AB  - At sites of chronic inflammation seen during infections, autoimmunity, graft-vs
      host response, and cytokine therapy, endothelial cell injury is known to occur,
      the exact mechanism of which is unknown. In the current study we used IL-2
      induced vascular leak syndrome (VLS) as a model to investigate whether cytotoxic
      lymphocytes use CD44 in mediating endothelial cell injury. Administration of IL-2
      to wild-type mice triggered significant VLS in the lungs and liver. In contrast,
      in CD44 knockout (KO) mice, IL-2-induced VLS was markedly reduced in the lungs
      and liver. IL-2-treated wild-type and CD44 KO mice had similar levels of
      perivascular infiltration with lymphocytes in the lungs and liver. This suggested
      that the decrease in VLS seen in CD44 KO mice was not due to the inability of
      lymphocytes to migrate to these organs. Ultrastructural studies demonstrated
      extensive endothelial cell damage in the lungs and liver of IL-2-treated wild
      type, but not CD44 KO, mice. Moreover, CD44-KO mice exhibited a marked decrease
      in IL-2-induced lymphokine-activated killer cell activity. The induction of VLS
      was dependent on the expression of CD44 on immune cells rather than endothelial
      cells because adoptive transfer of CD44+, but not CD44- spleen cells along with
      IL-2 into CD44 KO mice triggered VLS. The IL-2-induced VLS was blocked by
      administration of F(ab')2 of Abs against CD44. The current study demonstrates
      that CD44 plays a key role in endothelial cell injury. Blocking CD44 in vivo may
      offer a novel therapeutic approach to prevent endothelial cell injury by
      cytotoxic lymphocytes in a variety of clinical disease models.

PMID- 10415068
TI  - Characterization of fractalkine in rat brain cells: migratory and activation
      signals for CX3CR-1-expressing microglia.
AB  - Molecular analyses of the chemokine fractalkine and its receptor CX3C-R1 in the
      rat brain have revealed a striking polarization: fractalkine is expressed
      constitutively in neurons and is up-regulated by TNF-alpha and IL-1beta in
      astrocytes. Expression of its specific receptor, CX3C-R1, is restricted to
      astrocytes and microglia. We have analyzed the functional correlates of this
      expression and demonstrate that fractalkine induces microglial cell migration and
      activation. However, the activity of this chemokine on astrocytes may also be
      highly relevant in inducing astrocyte-microglia cell interactions through
      cytokine/mediator release leading to microglial activation.

PMID- 10415069
TI  - Chemokine receptor expression and signaling in macaque and human fetal neurons
      and astrocytes: implications for the neuropathogenesis of AIDS.
AB  - Chemokines are believed to play a role in the neuropathogenesis of AIDS through
      their recruitment of neurotoxin-secreting, virally infected leukocytes into the
      CNS. Levels of chemokines are elevated in brains of patients and macaques with
      HIV/SIV-induced encephalitis. The chemokine receptors CCR3, CCR5, and CXCR4 are
      found on subpopulations of neurons in the cortex of human and macaque brain. We
      have developed an in vitro system using both macaque and human fetal neurons and
      astrocytes to further investigate the roles of these receptors in neuronal
      response to inflammation. Here we report the presence of functional HIV/SIV
      coreceptors CCR3, CCR5, and CXCR4 on fetal human and macaque neurons and CCR5 and
      CXCR4 on astrocytes immediately ex vivo and after several weeks in culture.
      Confocal imaging of immunostained neurons demonstrated different patterns of
      distribution for these receptors, which may have functional implications.
      Chemokine receptors were shown to respond to their appropriate chemokine ligands
      with increases in intracellular calcium that, in the case of neurons, required
      predepolarization with KCl. These responses were blocked by neutralizing
      chemokine receptor in mAbs. Pretreatment of neural cells with pertussis toxin
      abolished responses to stromal-derived factor-1alpha, macrophage inflammatory
      protein-1beta, and RANTES, indicating coupling of CCR5 and CXCR4 to a Gialpha
      protein, as in leukocytes. Cultured macaque neurons demonstrated calcium flux
      response to treatment with recombinant SIVmac239 envelope protein, suggesting a
      mechanism by which viral envelope could affect neuronal function in SIV
      infection. The presence of functional chemokine receptors on neurons and
      astrocytes suggests that chemokines could serve to link inflammatory and neuronal
      responses.

PMID- 10415070
TI  - Differential susceptibilities to chronic beryllium disease contributed by
      different Glu69 HLA-DPB1 and -DPA1 alleles.
AB  - Chronic beryllium disease (CBD) is associated with the allelic substitution of a
      Glu69 in the HLA-DPB1 gene. Although up to 97% of CBD patients may have the Glu69
      marker, about 30-45% of beryllium-exposed, unaffected individuals carry the same
      marker. Because CBD occurs in only 1-6% of exposed workers, the presence of Glu69
      does not appear to be the sole genetic factor underlying the disease development.
      Using two rounds of direct automated DNA sequencing to precisely assign HLA-DPB1
      haplotypes, we have discovered highly significant Glu69-containing allele
      frequency differences between the CBD patients and a beryllium-exposed,
      nondiseased control group. Individuals with DPB1 Glu69 in both alleles were
      almost exclusively found in the CBD group (6/20) vs the control group (1/75).
      Whereas most Glu69 carriers from the control group had a DPB1 allele *0201 (68%),
      most Glu69 carriers from the CBD group had a non-*0201 DPB1 Glu69-carrying allele
      (84%). The DPB1 allele *0201 was almost exclusively (29/30) associated with DPA1
      *01 alleles, while the non-*0201 Glu69-containing DPB1 alleles were closely
      associated with DPA1 *02 alleles (26/29). Relatively rare Glu69-containing
      alleles *1701, *0901, and *1001 had extremely high frequencies in the CBD group
      (50%), as compared with the control group (6.7%). Therefore, the most common
      Glu69-containing DPB1 allele, *0201, does not seem to be a major disease allele.
      The results suggest that it is not the mere presence of Glu69, per se, but
      specific Glu69-containing alleles and their copy number (homozygous or
      heterozygous) that confer the greatest susceptibility to CBD in exposed
      individuals.

PMID- 10415071
TI  - An immunoadhesin incorporating the molecule OX-2 is a potent immunosuppressant
      that prolongs allo- and xenograft survival.
AB  - We have established that, in mice receiving donor-specific immunization by the
      portal vein, the increased graft survival seen is associated with the increased
      expression of a molecule (OX-2) on a subpopulation of dendritic cells (DC), and
      polarization of cytokine production to type 2 cytokines on Ag-specific
      restimulation of cells from these mice. Furthermore, infusion of a mAb to OX-2
      blocks both the increased graft survival and the altered cytokine production
      seen. We have constructed an immunoadhesin in which the extracellular domain of
      OX-2 is linked to the murine IgG2a Fc region, and we have expressed this molecule
      (OX-2:Fc) in a eukaryotic (baculovirus) expression system. Incubation of
      lymphocytes with 50 ng/ml OX-2:Fc inhibits a primary mixed lymphocyte reaction in
      vitro, as assayed by proliferation and induction of cytotoxic T cells, and also
      alters cytokine production with decreased IL-2 (IFN-gamma) production and
      increased IL-4 (IL-10) production. Similarly, in vivo infusion of OX-2:Fc
      promotes increased allo- and xenograft (both skin and renal grafts) survival and
      decreases the Ab response to sheep erythrocytes. Our data suggest this molecule
      might have clinical importance in allo- and xenotransplantation.

PMID- 10415072
TI  - Identification of T cell determinants on human type II collagen recognized by HLA
      DQ8 and HLA-DQ6 transgenic mice.
AB  - HLA-DQA1*0301 and HLA-DQB1*0302 genes encoding the HLA-DQ8 molecule and HLA
      DQA1*0103 and HLA-DQB1*0601 genes encoding the HLA-DQ6 molecule were introduced
      into H-2Abetao knockout mice. Three lines of transgenic mice were established:
      HLA-DQ8, HLA-DQ6, and HLA-DQ8beta6alpha. HLA-DQ8 mice are susceptible to collagen
      induced arthritis, while HLA-DQ6 mice are resistant. HLA-DQ8beta6alpha mice
      develop polychrondritis in addition to arthritis. Transgenic mice were primed and
      challenged with individual synthetic peptides representing human type II
      collagen. A total of 101 synthetic peptides were tested in each transgenic line
      of mice. HLA-DQ8 mice responded to 15 synthetic peptides representing all
      cyanogen bromide fragments. In contrast, HLA-DQ6 mice responded to a subset of
      the peptides recognized by HLA-DQ8 T cells. HLA-DQ8beta6alpha mice, although
      exhibiting diminished responses to the majority of HLA-DQ8-restricted
      determinants, elicited enhanced responses to two peptides. In addition, HLA
      DQ8beta6alpha mice respond to two unique peptide determinants contained within
      cyanogen bromide fragments CB10 and CB11 showing the significance of mixed
      isotype dimers in the immune response. The determinants recognized by the HLA-DQ
      transgenic mice are distinct from those previously identified using conventional
      laboratory mice. These results suggest that human class II transgenic mice offer
      a means of identifying human class II-restricted epitopes associated with
      potential human autoantigens.

PMID- 10415073
TI  - Normal immune function of monocyte-derived dendritic cells from HIV-infected
      individuals: implications for immunotherapy.
AB  - Dendritic cells (DC) are the most potent cells involved in the generation of
      primary and secondary immune responses. To assess the feasibility of using
      autologous DC as immunotherapy for HIV disease, we analyzed a variety of immune
      parameters using DC isolated from HIV-infected (HIV+) individuals, as well as DC
      obtained from HIV-uninfected (HIV-) individuals infected in vitro with HIV. After
      stimulation with recombinant CD40 ligand (CD40LT), cytokine and beta-chemokine
      production were similar by DC from HIV- donors infected in vitro with the CCR5
      using HIV Ba-L strain (n = 8) compared with uninfected DC from the same donors.
      Production of beta-chemokines, but not of cytokines, was increased by a CXCR4
      using IIIB strain-infected DC (n = 7). Stimulation of HIV-infected DC with CD40LT
      decreased infection in Ba-L-infected DC, but had no effect on IIIB-infected DC.
      Consistent with this finding, CD40LT down-regulated CCR5 and up-regulated CXCR4
      expression on DC. Monocyte-derived DC were also propagated from 15 HIV+ and 13
      HIV- donors. They exhibited similar expression of costimulatory molecules and
      produced similar amounts of IL-12, IL-10, and beta-chemokines, following
      stimulation. By contrast, stimulated PBMC from HIV+ patients exhibited decreased
      IL-12 and increased IL-10 production. In summary, phenotype, cytokine secretion,
      and beta-chemokine production by DC from HIV+ individuals were normal. These
      cells may prove useful in boosting cellular immune responses in HIV+ individuals.

PMID- 10415074
TI  - Differential presentation of glutamic acid decarboxylase 65 (GAD65) T cell
      epitopes among HLA-DRB1*0401-positive individuals.
AB  - Glutamic acid decarboxylase 65 (GAD65) is one of the major autoantigens in type 1
      diabetes. We investigated whether there is variation in the processing of GAD65
      epitopes between individuals with similar HLA backgrounds and whether the
      processing characteristics of certain immunogenic epitopes are different in
      distinct APC subpopulations. Using DR401-restricted T cell hybridomas specific
      for two immunogenic GAD65 epitopes (115-127 and 274-286), we demonstrate an
      epitope-specific presentation pattern in human B-lymphoblastoid cell lines (B
      LCL). When pulsed with the GAD protein, some DRB1*0401-positive B-LCL, which
      presented GAD65 274-286 epitope efficiently, were unable to present the GAD65 115
      127 epitope. However, all B-LCL presented synthetic peptides corresponding to
      either GAD epitope. In addition, when pulsed with human serum albumin, all cell
      lines gave equal stimulation of a DR4-restricted human serum albumin-specific T
      hybridoma. GAD65-transfected cell lines displayed the same presentation
      phenotype, showing that lack of the presentation of the 115-127 epitope was not
      due to inefficient uptake of the protein. Blood mononuclear adherent cells, B
      cells, or dendritic cells derived from the same individual displayed the same
      presentation pattern as observed in B cell lines, suggesting that the defect most
      likely is genetically determined. Therefore, individual differences in Ag
      processing may result in the presentation of distinct set of peptides derived
      from an autoantigen such as GAD65. This may be an important mechanism for the
      deviation of the immune response either into a regulatory pathway or into an
      inflammatory autoimmune reactivity.

PMID- 10415075
TI  - Abnormal NF-kappa B activity in T lymphocytes from patients with systemic lupus
      erythematosus is associated with decreased p65-RelA protein expression.
AB  - Numerous cellular and biochemical abnormalities in immune regulation have been
      described in patients with systemic lupus erythematosus (SLE), including surface
      Ag receptor-initiated signaling events and lymphokine production. Because NF
      kappa B contributes to the transcription of numerous inflammatory genes and has
      been shown to be a molecular target of antiinflammatory drugs, we sought to
      characterize the functional role of the NF-kappa B protein complex in lupus T
      cells. Freshly isolated T cells from lupus patients, rheumatoid arthritis (RA)
      patients, and normal individuals were activated physiologically via the TCR with
      anti-CD3 and anti-CD28 Abs to assess proximal membrane signaling, and with PMA
      and a calcium ionophore (A23187) to bypass membrane-mediated signaling events. We
      measured the NF-kappa B binding activity in nuclear extracts by gel shift
      analysis. When compared with normal cells, the activation of NF-kappa B activity
      in SLE patients was significantly decreased in SLE, but not in RA, patients. NF
      kappa B binding activity was absent in several SLE patients who were not
      receiving any medication, including corticosteroids. Also, NF-kappa B activity
      remained absent in follow-up studies. In supershift experiments using specific
      Abs, we showed that, in the group of SLE patients who displayed undetectable NF
      kappa B activity, p65 complexes were not formed. Finally, immunoblot analysis of
      nuclear extracts showed decreased or absent p65 protein levels. As p65 complexes
      are transcriptionally active in comparison to the p50 homodimer, this novel
      finding may provide insight on the origin of abnormal cytokine or other gene
      transcription in SLE patients.

PMID- 10415076
TI  - Impact of cytokine administration on the generation of antitumor reactivity in
      patients with metastatic melanoma receiving a peptide vaccine.
AB  - Patients with metastatic melanoma were immunized with an immunodominant peptide
      derived from the gp100 melanoma-melanocyte differentiation Ag that was modified
      to increase binding to HLA-A+0201. A total of 10 of 11 patients who received the
      g209-2M peptide alone developed precursors reactive with the native g209 peptide,
      compared with only 5 of 16 patients who received g209-2M peptide plus IL-2 (p2 =
      0.005). Peptide reactivity closely correlated with the recognition of HLA-A+0201
      melanoma cells (p < 0. 001). The decrease in immune reactivity when peptide was
      administered with IL-2 appeared specific for the immunizing peptide, since
      reactivity to an influenza peptide resulting from prior exposure was not
      affected. Preexisting antitumor precursors did not decrease when peptide plus IL
      2 was administered. The administration of GM-CSF or IL-12 also resulted in a
      decrease in circulating precursors compared with the administration of peptide
      alone, though not as great a decrease as that seen with IL-2. Immunization with
      peptide plus IL-2 did, however, appear to have clinical impact since 6 of the 16
      patients (38%) that received peptide plus IL-2 had objective cancer regressions.
      It thus appeared possible that immunization with peptide plus IL-2 resulted in
      sequestering or apoptotic destruction of newly activated immune cells at the
      tumor site. These represent the first detailed studies of the impact of
      immunization with tumor peptides in conjunction with a variety of cytokines in
      patients with metastatic cancer.

PMID- 10415077
TI  - Pancreatic IL-4 expression results in islet-reactive Th2 cells that inhibit
      diabetogenic lymphocytes in the nonobese diabetic mouse.
AB  - When immunological tolerance breaks down, autoimmune destruction of insulin
      producing beta cells in the pancreas can cause insulin-dependent diabetes
      mellitus. We previously showed that transgenic nonobese diabetic (NOD) mice
      expressing IL-4 in the pancreas (NOD-IL-4 mice) were protected from insulitis and
      diabetes. Here we have characterized the avoidance of pathological autoimmunity
      in these mice. The absence of disease did not result from a lack of T cell
      priming, because T cells responding to dominant islet Ags were present. These
      islet Ag-specific T cells displayed a Th2 phenotype, indicating that Th2
      responses could account for the observed tolerance. Interestingly, islet Ag
      specific Th1 T cells were present and found to be functional, because
      neutralization of the Th2 effector cytokines IL-4 and IL-10 resulted in diabetes.
      Histological examination revealed that NOD-IL-4 splenocytes inhibited
      diabetogenic T cells in cotransfer experiments by limiting insulitis and delaying
      diabetes. Neutralization of IL-4 in this system abrogated the ability of NOD-IL-4
      splenocytes to delay the onset of diabetes. These results indicate that IL-4
      expressed in the islets does not prevent the generation of pathogenic islet
      responses but induces islet Ag-specific Th2 T cells that block the action of
      diabetogenic T cells in the pancreas.

PMID- 10415078
TI  - Blockade of CD28 during in vitro activation of encephalitogenic T cells or after
      disease onset ameliorates experimental autoimmune encephalomyelitis.
AB  - Previous studies have shown complex roles for the B7 receptors in providing both
      positive and negative regulation of experimental autoimmune encephalomyelitis
      (EAE). B7 blockade can ameliorate clinical EAE by indirectly interfering with
      CD28 signaling. However, B7 blockade can also result in disease exacerbation,
      presumably by interfering with regulatory B7:CTLA-4 interactions. Therefore, we
      have directly targeted T cell CD28 with specific mAbs both during initial Ag
      priming and after the onset of clinical signs of EAE. We found that CD28 blockade
      ameliorated EAE during the efferent and afferent limbs of the immune response.
      Disease amelioration at disease onset was associated with suppression of TNF
      alpha production. Finally, Ab blockade of T cell CD28 during the first disease
      episode resulted in significant attenuation of the subsequent disease course,
      with no significant relapses. In contrast to previous studies targeting APC B7
      with CTLA4-Ig, reagents targeting CD28 can block ongoing disease. Therefore, the
      present results suggest a clinically relevant therapeutic scenario for human
      diseases, such as multiple sclerosis.

PMID- 10415079
TI  - Gas chromatographic-mass spectrometric detection of S-nitroso-cysteine and S
      nitroso-glutathione.
AB  - A gas chromatographic-mass spectrometric (GC-MS) method is described for the
      quantitative determination of the S-nitroso compounds S-nitroso-cysteine (SNC)
      and S-nitroso-glutathione (GSNO) using their (15)N-labeled analogs, i.e., S(15)NC
      and GS(15)NO, as internal standards. The method is based on the specific
      conversion by HgCl(2) of the unlabeled and (15)N-labeled S-nitroso groups to
      nitrite and (15)N-nitrite, respectively, and their conversion to the
      pentafluorobenzyl derivatives. The method was applied to quantify GS(15)NO formed
      in the cytosol of washed human erythrocytes incubated with S(15)NC. Combination
      of high-performance liquid chromatography with GC-MS allowed specific and
      accurate quantification of SNC and GSNO externally added to human plasma
      ultrafiltrate (range 0-10 microM). Method accuracy and precision for SNC and GSNO
      were close to 100 and below 9%, respectively. As little as 0.1 nM GS(15)NO
      corresponding to 30 amol of (15)N-nitrite injected onto the column was precisely
      detected by the method.

PMID- 10415080
TI  - Automated kinetic exclusion assays to quantify protein binding interactions in
      homogeneous solution.
AB  - A method was developed for the quantification of protein-ligand interactions in
      which the free protein present in homogeneous reaction mixtures was separated and
      quantified using a KinExA immunoassay instrument. Separation was achieved by
      rapid percolation of the reaction mixture over a column of microbeads whose
      surfaces were coated with an immobilized form of the ligand. The protein thus
      captured was quantified using a fluorescently labeled anti-protein antibody. The
      features of this new method were illustrated using a model system in which each
      of the principal reagents was covalently labeled with a different fluorescent
      molecule: mouse monoclonal anti-biotin primary antibody (fluorescein), biotin (B
      phycoerythrin), and goat anti-mouse polyclonal secondary antibody
      (indodicarbocyanin). Values for the equilibrium and kinetic rate constants for
      the binding between the anti-biotin antibody and biotin conjugated with B
      phycoerythrin were determined and shown to be independent of whether the
      fluorescent label was located on the primary or secondary antibody. Equilibrium
      binding experiments conducted with (F(AB))(2) and corresponding F(AB) fragments
      showed that the valency of the binding protein had no influence on the value of
      the dissociation constant. The values of the equilibrium and rate constants
      obtained by this new method are those for the binding reaction in homogeneous
      solution; the immobilized ligand is only a tool exploited for the separation and
      quantification of the free protein.

PMID- 10415081
TI  - Serum-free culture conditions for analysis of secretory proteinases during
      myogenic differentiation of mouse C2C12 myoblasts.
AB  - We have been studying extracellular proteins such as proteinases and attachment
      factors under serum-free culture conditions. A number of studies on myogenesis
      using an in vitro culture system have reported that proteinases and ECM
      components play significant roles in muscle differentiation. However, most of the
      studies were performed in the presence of serum. Serum is abundant in the
      aforementioned proteins and its use in serum-free culture affects many cellular
      functions significantly. In this study, we tried to establish serum-free culture
      conditions for analyzing extracellular proteins involved in mouse myogenic
      differentiation. By evaluating media, supplements, and procedure of cell
      inoculation under serum-free conditions and by comparing the resultant conditions
      with conventional conditions on differentiated characteristics of the cells, it
      was revealed that serum-free Dulbecco's modified Eagle's medium/Ham's F-12 plus
      insulin more efficiently supported myogenesis morphologically and biochemically
      than conventional 2% horse serum-containing culture and that secretory
      proteinases obtained from our serum-free culture were different from those
      obtained utilizing conventional serum-free cultures in their activities and
      patterns. Since our serum-free medium consists of simple components, the medium
      is low cost and easy to prepare. Furthermore, the results suggest that our
      culture conditions are superior to conventional conditions biochemically and
      morphologically and will provide more precise and accurate information on
      extracellular proteins involved in myogenesis.

PMID- 10415082
TI  - Assay of dihydrofolate reductase activity by monitoring tetrahydrofolate using
      high-performance liquid chromatography with electrochemical detection.
AB  - We developed a method to determine dihydrofolate reductase (DHFR) activity at pH
      7.4 (37 degrees C) by monitoring its product, tetrahydrofolate (H(4)folate),
      using HPLC with electrochemical detection. After the assay mixture was
      deproteinized by 0.5 M perchloric acid, the H(4)folate concentration was
      measured. Using sodium ascorbate at 20 mM, H(4)folate was stable in our assay
      system. The enzyme activity was also stable. The detection limit of this method
      was less than 1 nM of H(4)folate in the enzyme assay system, which was 1/100
      lower than those for the NADPH-spectrophotometric assay, which is commonly used
      for analysis of DHFR activity. This value of 1 nM allowed us to control the
      conversion from dihydrofolate (H(2)folate) to H(4)folate less than 10% of initial
      substrate concentrations during assay, when we used a concentration around K(m)
      values reported for DHFR from various sources. The rate of reduction showed a
      linearity at concentrations around the K(m). The reduction rate must be evaluated
      exactly around the K(m), in order to obtain an accurate profile of Michaelis
      Menten kinetics. This assay method has a sensitivity high enough to determine the
      reduction rate at H(2)folate concentrations around K(m). In addition, the assay
      procedure is very simple. Therefore, our method may be useful for studying DHFR.

PMID- 10415083
TI  - Functional analysis of native and recombinant ion channels using a high-capacity
      nonradioactive rubidium efflux assay.
AB  - A nonradioactive cell-based rubidium (Rb(+)) efflux assay for functional analysis
      of native and recombinant ion channels has been developed. Cells are first loaded
      with rubidium, a tracer for potassium, and after channel activation, rubidium
      distribution between intracellular and extracellular space is determined by
      atomic absorption spectroscopy. The relative amount of rubidium in the cell
      supernatant is a direct measure of channel activity. The broad utility of the
      method is demonstrated by analysis of a range of different ion channels. Ligand
      gated ion channels like nicotinic acetylcholine receptors and purinergic P2X
      receptors were studied in native PC-12 cells. Calcium-activated potassium
      channels were analyzed in native (small-conductance calcium-activated potassium
      channel, SK(Ca)) as well as recombinant cell lines (large-conductance calcium
      activated potassium channel, BK(Ca)). Also recombinant voltage-gated potassium
      channels (Kv1.1, Kv1.4) were amenable to this functional analysis. The method is
      particularly useful for identification of ion channel modulators in drug
      discovery since it allows functional analysis with high capacity.

PMID- 10415084
TI  - Mutation detection by denaturing DNA chromatography using fluorescently labeled
      polymerase chain reaction products.
AB  - A specialized form of ion-pair reversed-phase high-performance liquid
      chromatography is gaining widespread application in mutation detection for single
      nucleotide polymorphisms (SNP). The technique relies on temperature-modulated
      heteroduplex analysis (TMHA) by chromatographic separation of partially denatured
      DNA heteroduplexes from homoduplexes. Here, we demonstrate that fluorescent
      labeling is compatible with mutation analysis by this form of DNA chromatography
      and offers advantages over the use of unlabeled DNA fragments. Uniform labeling
      of wild-type and mutant alleles for TMHA yields peak patterns identical to
      unlabeled fragments. However, fluorescent labels increase retention times but do
      not influence resolution of heteroduplexes from homoduplexes. They increase
      sensitivity and decrease the amount of DNA required for analysis; e.g., in the
      case presented here, one allele can be detected in the presence of a 500-fold
      excess of another allele. Furthermore, allele-specific wild-type probes,
      fluorescently labeled on one strand only, make it possible to selectively monitor
      specific homoduplexes and wild-type/mutant heteroduplexes. This, in combination
      with an internal homoduplex standard, greatly reduces the complexity of
      fluorescence chromatograms compared with chromatograms recorded in the UV. These
      simplified chromatograms, in which only the internal homoduplex standard and the
      labeled heteroduplex are detected in the presence of a mutation, greatly
      facilitate the detection and identification of mutant alleles.

PMID- 10415085
TI  - High sensitivity immunoassays using particulate fluorescent labels.
AB  - The use of polystyrene fluorescent microspheres as sensitive labels in direct
      detection (not enzymatically amplified) heterogeneous equilibrium "sandwich"
      immunoassays in 96-well plates is described. With mouse IgG as a model antigen, a
      fluorescent particulate label is more sensitive than a corresponding soluble
      reporter. The limit of detection of mouse IgG in the multiparametrically
      optimized assay was 0.2 ng/ml (7.6 x 10(8) antigens/ml) for the particulate
      reporter and 50 ng/ml (1.9 x 10(11) antigens/ml) for the soluble reporter. The
      sensitivities of assays using the particulate label were dependent on the surface
      densities of the capture and reporter antibodies and the concentration of
      reporter beads. Sensitivity was improved by adding the preformed reporter
      antibody/fluorescent microsphere complex to trapped antigen on the well surfaces
      instead of sequentially adding the reporter antibody and then the fluorescent
      microspheres. Maximal (equilibrium) binding of the particulate reporter to
      captured antigen occurred after 20 h with a concentration of 1.4 x 10(9) reporter
      beads/ml. Thus, particulate fluorescent labels provide high sensitivity in direct
      detection immunoassays.

PMID- 10415086
TI  - Transfection-mediated cell-cycle signaling: considerations for transient
      transfection-based cell-cycle studies.
AB  - Transient transfection of recombinant genes into cells is a commonly used
      approach for analyzing cell-cycle- and/or apoptotic-related activities of cell
      cycle control proteins. In this approach, information regarding the functional
      consequence of expressing a recombinant protein transiently is garnered by
      comparing against results obtained from cells which are transfected with either a
      control expression plasmid and/or with mutant expression plasmids. In general
      however, little attention is paid to whether the transfection procedure itself
      influences these experiments. Using the calcium phosphate transfection method, we
      show that the introduction of DNA into cells induces signaling of the cell-cycle
      control machinery. In Hela cells, a transient increase in G0/G1 cells is observed
      8 h after transfection. Furthermore, the introduction of DNA into several cell
      lines induces apoptosis. Transfection-mediated apoptosis can be elicited through
      a p53-independent mechanism, suggesting the possible extrapolation to many tumor
      cell lines. Last, we show that due to a likely cell-cycle-specific entry of
      marker genes into the nucleus, a highly biased cell-cycle distribution is
      observed in successfully transfected cells at early times following transfection.
      The importance of these issues in the interpretation as well as the design of
      transient transfection-based cell-cycle experiments is discussed.

PMID- 10415087
TI  - Determination of ligand binding affinities for endogenous seven-transmembrane
      receptors using fluorometric microvolume assay technology.
AB  - We have developed a fluorescence-based mix and read method for the quantitative
      determination of receptor-ligand binding interactions. This method was used to
      determine IC(50) values for peptide ligands of two endogenous seven-transmembrane
      receptors that are expressed in cultured human cancer cells. Substance P,
      neurokinin A, and galanin were labeled with Cy5 and were shown to retain their
      native binding affinities. The cell-associated fluorescence was quantified using
      a fluorometric microvolume assay technology (FMAT) scanner that was designed to
      perform high-throughput screening assays in multiwell plates with no wash steps.
      The binding of fluorescently labeled substance P and neurokinin A was tested on
      the human astrocytoma cell line UC11 that expresses endogenous NK(1) receptor.
      Galanin binding was measured on endogenous galanin type 1 receptors in the Bowes
      neuroblastoma cell line. IC(50) values were determined for substance P,
      neurokinin A, and galanin and were found to correspond well with reported values
      from radioligand binding determinations. To demonstrate FMAT as instrumentation
      for high-throughput screening, it was utilized to successfully identify
      individual wells in a 96-well plate in which Cy5-substance P binding in UC11
      cells was competed with unlabeled substance P. In addition, we developed a two
      color multiplex assay in which cells individually expressing neuropeptide Y and
      substance P receptors were mixed in the same well. In this assay, the fluorescent
      ligands substance P and neuropeptide Y bound only to their respective cell types
      and binding was specifically competed. Therefore, two different seven
      transmembrane receptor targets can be tested in one screen to minimize reagent
      consumption and increase throughput.

PMID- 10415088
TI  - Measurement of firefly luciferase reporter gene activity from cells and lysates
      using Escherichia coli arsenite and mercury sensors.
AB  - The structural gene encoding firefly luciferase from Photinus pyralis is a widely
      used reporter both in traditional monitoring of gene expression and in bacterial
      sensors. Its activity can be detected from living cells (in vivo) without
      disruption or from cell-free lysate (in vitro). We compared the two measurement
      methods by using an overall toxicity detecting strain Escherichia coli
      MC1061(pCSS810), a mercury-sensing strain E. coli MC1061(pTOO11), and two new
      arsenic sensor strains MC1061(pTOO31) and AW3110(pTOO31) which were constructed
      for this study. Plasmid pTOO31 was constructed by inserting the ars promoter and
      the arsR gene from plasmid R773 to control firefly luciferase gene expression.
      Both in vivo and in vitro methods correlated well with the strains tested
      [correlation coefficients R = 0.99484 and 0.99834] and gave highly comparable
      results with standard solutions of arsenite or mercury ions and from six
      environmental water samples spiked with the ions. Use of the in vivo method
      resulted in lower variation between replicates of the same sample (CVs ranging
      from 3.9 to 7.2%) and also between different samples (from 8.6 to 25.9%) compared
      to the in vitro method (CVs ranging from 8.6 to 17.8% for replicates and from
      13.1 to 36.3% for different samples).

PMID- 10415089
TI  - Sedimentation equilibrium analysis of interference optical data by systematic
      noise decomposition.
AB  - An analytical method is described for removal of systematic signal offsets from
      interference optical data of sedimentation equilibrium gradients. It is
      demonstrated that the time-invariant signal contributions can be extracted from
      hydrodynamic modeling of interference profiles acquired during the approach to
      sedimentation equilibrium. This method is based on a technique for the explicit
      algebraic calculation of time-invariant noise components from sedimentation data,
      recently described for the direct modeling of sedimentation velocity experiments
      (P. Schuck and B. Demeler, Biophys. J. 76, 2288-2296, 1999). The calculated
      systematic signal offset is very well defined by the experimental data, stable
      over time, and its calculation is robust and to a large extent independent of the
      hydrodynamic model. The calculated time-invariant signal can be used to reduce
      the systematic errors in the measured sedimentation equilibrium profiles by more
      than an order of magnitude. It is shown that the resulting net equilibrium fringe
      profiles after subtraction of the time-invariant noise component allow
      equilibrium analyses consistent with those obtained from absorbance profiles.
      However, due to a higher dynamic range and the higher number of data points, the
      parameters derived from the net interference analysis can exhibit significantly
      improved precision. The presented study demonstrates the feasibility and
      potential of this analytical method for full exploitation of the remarkable
      precision of the interference optical data acquisition system, allowing
      sedimentation equilibrium experiments at loading concentrations below 0.05 mg/ml.

PMID- 10415090
TI  - Measurement of urinary F(2)-isoprostanes as markers of in vivo lipid peroxidation
      A comparison of enzyme immunoassay with gas chromatography/mass spectrometry.
AB  - This study aimed at comparing the two most commonly utilized methods for
      measuring urinary F(2)-isoprostanes, currently considered one of the best
      available markers of in vivo lipid peroxidation. The F(2)-isoprostanes were
      measured in 24-h urine samples from 14 male subjects using electron capture
      negative ionization gas chromatography-mass spectrometry (ECNI-GCMS) with 8-iso
      PGF(2alpha)-d(4) as an internal standard and compared with levels obtained using
      an enzyme immunoassay (EIA, 8-iso-PGF(2alpha) kit, Cayman Chemical Co.). The
      methods were compared using Pearson correlation coefficients, and Bland-Altman
      plots were constructed for the difference in F(2)-isoprostane against the average
      F(2)-isoprostane measured by either method. Weighted least-products regression
      was used to determine fixed bias (where there is a consistent difference between
      the methods) and proportional bias (where one method gives values higher or lower
      than the other method by an amount proportional to the size of the measurement).
      The correlation between F(2)-isoprostane levels obtained using EIA and GCMS
      methods, although significant, was poor (r = 0.628, P < 0.02). Comparison of the
      methods using the Bland-Altman analysis showed that there were wide limits of
      agreement between the two methods with only 28% of the values falling within the
      95% confidence limits for the difference. The GCMS gave higher values with a mean
      difference of 298.1 pM (636.6, -40.2; P = 0.079), and a near significant linear
      association between the differences and the mean F(2)-isoprostane level (r = 
      0.559, P = 0.05). Weighted least-product regression analysis confirmed the
      presence of both significant fixed and proportional bias with the EIA giving
      lower levels of F(2)-isoprostanes at low concentrations and higher levels at
      higher concentrations. The cross-reactivity in the EIA of 8-iso-15(R)-PGF(2alpha)
      and 9beta-PGF(2alpha) which coelute with the F(2)-isoprostane peak measured by
      GCMS was very low, 0.2 and 0.1%, respectively. The proportional bias observed
      between the methods may in part be due to differences in the relative amounts of
      8-iso-15(R)-PGF(2alpha), 9beta-PGF(2alpha), and 8-iso-PGF(2alpha) with increasing
      lipid peroxidation. This study shows that the measurements of F(2)-isoprostanes
      by EIA and GCMS are not equivalent. Therefore, comparison of levels derived using
      a GCMS method which estimates concentration from a peak encompassing a number of
      F(2)-isoprostane isomers, and levels derived from enzyme immunoassay measuring a
      specific isoprostane, may be inappropriate.

PMID- 10415091
TI  - An enzyme-linked immunosorbent assay for the association of the catalytic domain
      of diphthamide-specific ribosyltransferases to eukaryotic elongation factor-2.
AB  - The X-ray structure of the catalytic domain of Pseudomonas aeruginosa exotoxin A
      (PE24) has recently been solved to high resolution, facilitating studies on the
      interaction of PE24 with its target substrate, eukaryotic elongation factor-2
      (eEF-2). PE24 exhibits mono-ADP-ribosyltransferase (ADPRT) activity in a
      mechanism that has been proposed to feature a nucleophilic attack by the
      diphthamide residue (nucleophile) of eEF-2 on the C-1 of the nicotinamide ribose
      of NAD(+). The interaction of wheat germ eEF-2 with PE24 was studied by employing
      an enzyme-linked immunosorbent assay (ELISA), devised to assess protein-protein
      interactions. It was shown that the proteins associate with each other only in
      the presence of the enzyme's nucleotide substrate, NAD(+), and exhibit a dose
      dependent association that is saturable. The apparent dissociation constant
      (K(d)) for this protein-protein interaction is 50 nM and is salt-dependent. The
      association is maximal at low ionic strength and is progressively weaker at
      higher salt concentrations, which corroborates previous findings on the salt
      dependence of ADPRT activity for this toxin. This finding suggests that the
      sensitivity of ADPRT activity toward high salt resides in the interaction between
      the catalytic domain of the toxin and eEF-2. A major product of the
      glycohydrolase activity of PE24, nicotinamide, inhibits the binding between PE24
      and eEF-2 with an ID(50) of 20 microM. The naturally occurring, noncatalytic
      mutant of PE24, H426Y, did not bind eEF-2 in the ELISA, verifying that His 426 is
      located at the center of the eEF-2 binding site within ETA.

PMID- 10415092
TI  - Enzymatic synthesis and purification of [(3)H]uridine diphosphate galacturonic
      acid for use in studying Golgi-localized transporters.
AB  - Uridine 5'-diphosphate galacturonic acid (UDP-GalA) is a substrate for the
      galacturonosyltransferases that synthesize the three pectic polysaccharides
      homogalacturonan, rhamnogalacturonan I, and rhamnogalacturonan II. Pectin
      synthesis occurs in the Golgi and it is hypothesized that UDP-GalA is transported
      into the lumen of the Golgi by membrane-localized transporters. To study the
      transport and metabolism of UDP-GalA in the Golgi, UDP-GalA labeled in the
      uridine moiety is required. Here we present a high-yield method for the synthesis
      of [(3)H]UDP-GalA from [(3)H]UTP and Glc-1-P by sequential reactions catalyzed by
      UDP-Glc pyrophosphorylase, UDP-Glc dehydrogenase, and UDP-GlcA-4-epimerase and
      the separation of the reaction products over a Dionex CarboPac PA1 anion-exchange
      column using high-performance anion-exchange chromatography (HPAEC).
      Approximately half of the [(3)H]UTP was converted into [(3)H]UDP-GalA and the
      remaining 50% was recovered as [(3)H]UDP-GlcA. Both products were purified and
      the identity of the [(3)H]UDP-GalA was confirmed by its conversion into [(3)H]UDP
      GlcA by UDP-GlcA-4-epimerase. The enzymatic synthesis of diverse nucleotide
      sugars radiolabeled in the nucleotide by the use of nucleotide-converting
      enzymes, combined with the high-resolution separation of the nucleotide sugars
      and their purification by HPAEC, can provide unique substrates required for the
      study of diverse nucleotide sugar transporters.

PMID- 10415093
TI  - Analysis of cyclic and acyclic analogs of retinol, retinoic acid, and retinal by
      laser desorption ionization-, matrix-assisted laser desorption ionization-mass
      spectrometry, and UV/Vis spectroscopy.
AB  - Laser desorption ionization (LDI)- and matrix-assisted laser desorption
      ionization (MALDI)-mass spectrometry (LDI-MS, MALDI-MS) at 337-nm laser
      wavelength were used to analyze retinol (vitamin A), retinoic acid, and retinal
      and their analogs 3-hydroxyretinol, 3-hydroxyretinoic acid, 3-hydroxyretinal, 4
      oxoretinol, 4-oxoretinoic acid, 4-oxoretinal, 3,4-didehydroretinol (vitamin
      A(2)), 3,4-didehydroretinoic acid, 3,4-didehydroretinal, acycloretinol,
      acycloretinoic acid, and acycloretinal. The compounds exhibit sufficient
      ionizability which allows to obtain mass spectra by LDI which are similar in
      quality to those obtained by MALDI. Mass spectra were recorded with a linear time
      of-flight (TOF) instrument or a reflectron-type (RETOF) instrument in positive
      ion mode. Under the conditions of LDI-MS the compounds form abundant radical
      molecular ions (M+*), whereas in the MALDI mass spectra abundant protonated
      molecular ions ([M + H]+) are observed. Characteristic fragment ions provide
      additional structural information. High-performance liquid chromatography (HPLC)
      coupled with UV/Vis photodiode detection was used to assist in retinoid
      characterization. Synthesis of 3-hydroxyretinal, 4-oxoretinal, and acycloretinal
      was performed by oxidative cleavage of the all-trans-carotenoids of zeaxanthin,
      canthaxanthin, and lycopene.

PMID- 10415094
TI  - A fluorometric assay for cyclic guanosine 3',5'-monophosphate incorporating a Sep
      Pak cartridge and enzymatic cycling.
AB  - We developed a sensitive and nonradioactive fluorometric assay for cyclic
      guanosine 3',5'-monophosphate (cGMP). Guanine nucleotides except cGMP were
      enzymatically phosphorylated to GTP. cGMP, absorbed into a Sep-Pak amino propyl
      cartridge, was eluted separately from GTP. Purified cGMP was enzymatically
      converted to GTP, which was applied to the GTP-GDP cycle using succinic
      thiokinase and pyruvate kinase. When pyruvic acid produced by the GTP-GDP cycle
      was reduced by lactate dehydrogenase, a reduced form of nicotinamide adenine
      dinucleotide (NADH) was equivalently oxidized to NAD(+). NAD(+) was further
      converted into fluorescent compound, which was excited at 370 nm and emitted
      fluorescence at 460 nm, by a strong alkali. When 20 nmol NADH was used for this
      assay, the calibration curve over 50 to 500 fmol cGMP became sufficiently linear.
      The detection limit for cGMP was ca. 5 fmol (signal to noise ratio >3). Using
      this assay, we confirmed that the cGMP content in the left atrial strip of dog
      was changed from 11.4 +/- 3.8 to 19.3 +/- 2.6 fmol/mg wet wt of tissue (mean +/-
      SE, n = 6) by electrical driving at 1 Hz. Carbachol (1 microM) further increased
      the cGMP to 45.6 +/- 9.2 fmol/mg wet wt of tissue. From these results, it is
      suggested that this novel assay for cGMP is highly sensitive and can be applied
      to various biological samples.

PMID- 10415095
TI  - A radiochemical assay for beta-ureidopropionase using radiolabeled N-carbamyl
      beta-alanine obtained via hydrolysis of [2-(14)C]5, 6-dihydrouracil.
AB  - A radiochemical assay was developed to measure the activity of beta
      ureidopropionase in human liver homogenates which is based on the detection of
      the reaction product (14)CO(2) by liquid scintillation counting. Radiolabeled N
      carbamyl-beta-alanine was prepared within 15 min by a simple hydrolysis of [2
      (14)C]5, 6-dihydrouracil under alkaline conditions at 37 degrees C. The enzymatic
      reaction proved to be linear with time up to at least 3.5 h and protein
      concentrations up to at least 1 mg/ml. Human beta-ureidopropionase obeyed
      Michaelis-Menten kinetics with an apparent Km for N-carbamyl-beta-alanine of 15.5
      +/- 1.9 microM. The assay proved to be very accurate and sensitive with an
      intraassay coefficient of variation of 2% and a detection limit of 28 pmol for
      the product CO(2).

PMID- 10415096
TI  - Detection of DNA in agarose gels using berberine and Mordant Yellow 3R.
AB  - A nontoxic and simple staining method for the detection of DNA in agarose gels is
      described. After eletrophoretic separation, the gels were stained with 5
      microg/ml of berberine (BB) prepared in distilled water and then the gels were
      soaked in 20 microg/ml of aqueous Mordant Yellow 3R (MY3R) solution. Employment
      of MY3R as a counterion dye efficiently quenched unwanted background fluorescence
      of BB. This method can detect as little as 10 ng of plasma membrane H(+)-ATPase
      cDNA obtained from Arabidopsis thaliana L. (AHA1, 3.2 kb) under a long wavelength
      of UV irradiation (366 nm) within 1 h.

PMID- 10415097
TI  - The kinetics of S-transnitrosation--a reversible second-order reaction.
AB  - Transnitrosation between thiols and S-nitrosothiols has been suggested to be a
      mechanism of signal transduction. This kinetics of such reactions fit well to a
      reversible second-order model. Parameters derived from this model give both the
      forward and reverse rate constants and the equilibrium position at physiological
      temperature and pH. In addition, methods are shown for calculating the
      equilibrium distribution of the nitrosyl function group in mixtures of up to
      three thiols.

PMID- 10415098
TI  - Characterization of a temperature-sensitive mutant of a ubiquitin-conjugating
      enzyme and its use as a heat-inducible degradation signal.
AB  - The ubiquitin/proteasome pathway is a highly conserved mechanism of proteolysis
      in all eukaryotes. Ubiquitin (Ub) is conjugated to proteolytic substrates through
      the sequential action of ubiquitin-activating (E1/Uba) and ubiquitin-conjugating
      (E2/Ubc) enzymes. The mechanism of substrate recognition and ubiquitination is an
      area of active investigation, and we have begun a site-directed mutagenesis
      approach to define the biochemical and biophysical properties of ubiquitin
      conjugating enzymes. We have characterized a specific mutation in Ubc4
      (Ubc4(P62S)) which was previously shown to cause a temperature-sensitive growth
      defect in several other Ubc's. Ubc4(P62S) was rapidly degraded in vivo,
      contributing to the loss of function. However, reconstitution experiments
      revealed that the catalytic activity of Ubc4(P62S) was reversibly inactivated at
      37 degrees C, demonstrating that the primary defect of Ubc4(P62S) is its
      inability to form a ubiquitin thioester bond at high temperature. The in vivo
      defect is compounded by increased susceptibility of Ubc4(P62S) to degradation by
      the ubiquitin/proteasome pathway. We have exploited the temperature-dependent
      degradation of the P62S mutant to destabilize an otherwise stable test protein
      (glutathione S-transferase). The use of this mutant may provide a useful cis
      acting temperature-inducible degradation signal.

PMID- 10415099
TI  - Preparation of insoluble transmembrane peptides: glycophorin-A, prion (110-137),
      and FGFR (368-397).
AB  - A general procedure for the reliable preparation of large quantities of insoluble
      transmembrane peptides has been developed. Optimal couplings were obtained during
      synthesis by using high-temperature couplings in conjunction with O-(7
      azabenzotriazol-1-yl)-1,1,3, 3-tetramethyluronium hexafluorophosphate (HATU)
      activation. Improved purification schemes were developed that use reverse- phase
      HPLC on a C1 column and elution with a 2:1 mixture of 1-propanol:1-butanol. Using
      these methods three very different transmembrane peptides all longer than 25
      amino acids have been prepared: glycophorin-A, prion (110-137), and fibroblast
      growth factor receptor (368-397).

PMID- 10415100
TI  - Oligonucleotide stimulators allow complete cleavage of agarose-embedded DNA by
      particular type II restriction endonucleases.

PMID- 10415101
TI  - A cosmid system for the analysis of lytic replication of Epstein-Barr virus.

PMID- 10415102
TI  - Improved ligation-mediated polymerase chain reaction of GC-rich transcriptional
      control regions.

PMID- 10415103
TI  - Field inversion gel electrophoresis for apolipoprotein(a) genotyping.

PMID- 10415104
TI  - Inhibition studies on the metallo-beta-lactamase L1 from Stenotrophomonas
      maltophilia.
AB  - In an effort to identify a competitive inhibitor that can be used in future
      spectroscopic and crystallographic studies and to better understand the
      interaction of a mercaptoacetic acid-thiolester-containing compound with metallo
      beta-lactamase L1 from Stenotrophomonas maltophilia, inhibition studies using two
      thiol-containing compounds were conducted. N-(2'-Mercaptoethyl)-2-phenylacetamide
      is a competitive inhibitor of L1 with a K(i) of 50 +/- 3 microM, and this
      compound is not a time-dependent inactivator of L1. N-Benzylacetyl-d
      alanylthioacetic acid is a competitive inhibitor of L1 with a K(i) of 1.6 +/- 0.3
      microM. Matrix-assisted laser desorption ionization time-of-flight mass
      spectrometric studies revealed that 2 mol of mercaptoacetate covalently bind to
      L1 upon incubation of the enzyme with N-benzylacetyl-d-alanylthioacetic acid;
      however, this covalently modified enzyme has the same activity as wild-type L1.
      Last, inhibition studies were used to demonstrate that 4-morpholinoethanesulfonic
      acid does not inhibit L1, even at concentrations up to 300 mM. This work
      identifies two possible competitive inhibitors which can be used in future
      structural studies and further demonstrates inhibitory heterogeneity among the
      metallo-beta-lactamases.

PMID- 10415106
TI  - Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic
      regulation.
AB  - An orphan nuclear receptor, termed the pregnane X receptor (PXR), has recently
      been cloned from mouse and human and defines a novel steroid signaling pathway
      (Cell 92, 73-82, 1998; Proc. Natl. Acad. Sci. USA 95, 12208-122313, 1998).
      Transient cotransfection experiments demonstrate that the PXR responds to
      structurally dissimilar compounds and confers the induction of cytochrome P4503A
      (CYP3A), a subfamily of enzymes that involve the metabolism of two-thirds of
      drugs and other xenobiotics. In this report, we describe the molecular cloning,
      tissue distribution, and xenobiotic regulation of a rat PXR designated rPXR-1.
      rPXR-1 exhibits a 95% sequence identity with the mouse PXR, but only 79% identity
      with the human PXR, providing the molecular basis that rats and mice have a
      similar CYP3A induction profile but differ from humans. rPXR-1 gene was expressed
      abundantly in liver, intestine, and, to a lesser extent, kidney, lung, and
      stomach. The tissue distribution and the relative abundance of rPXR-1 mRNA among
      these tissues resemble those of CYP3A, suggesting that PXR is important not only
      for induction but also for constitutive expression of these enzymes. Xenobiotics
      known to induce liver microsomal enzymes showed differential effects on the rPXR
      1 expression as determined by Northern blot analysis. Dexamethasone, for example,
      increased the accumulation of rPXR-1 mRNA, whereas troleandomycin slightly
      suppressed it. Compounds that increase PXR expression (inducers) and compounds
      that interact with PXR (ligands) likely have synergistic effects on CYP3A
      induction, which provides a novel molecular explanation for drug-drug
      interactions.

PMID- 10415105
TI  - Purification and N-terminal amino acid sequence of sheep neutrophil cathepsin G
      and elastase.
AB  - Sheep cathepsin G (CG) and neutrophil elastase (NE) were isolated from a crude
      leukocyte membrane preparation by elastin-Sepharose 4B and CM-Sepharose 4B
      chromatography, followed by native preparative PAGE. The N-termini of CG and NE
      were sequenced to 24 and 20 residues, showing 96 and 85% identity with human CG
      and NE, respectively. During SDS-PAGE, sheep CG and NE migrated parallel to human
      CG and NE and have apparent molecular masses of 28 and 26 kDa, respectively.
      Following incubation of sheep CG and NE with human alpha(1)-antichymotrypsin and
      alpha(1)-proteinase inhibitor, complexes with apparent molecular masses of 89 and
      81 kDa respectively were observed by SDS-PAGE. Polyclonal antibodies to human CG
      and NE cross-reacted with purified sheep CG and NE, respectively. These results
      indicate that sheep neutrophils contain CG and elastase that are analogous to
      human CG and NE in terms of molecular mass, reactivity with endogenous
      inhibitors, immunocross-reactivity, and N-terminal sequence.

PMID- 10415107
TI  - Diffusion of peroxynitrite in the presence of carbon dioxide.
AB  - Peroxynitrite, the reactive species formed in vivo by the reaction of nitric
      oxide with superoxide anion, is capable of diffusing across erythrocyte membranes
      via anion channels and passive diffusion (A. Denicola, J. M. Souza, and R. Radi,
      Proc. Natl. Acad. Sci. USA 95, 3566-3571, 1998). However, peroxynitrite diffusion
      could be limited by extracellular targets, with the reaction with CO(2) (k(2) =
      4.6 x 10(4) at 37 degrees C and pH 7.4) the most relevant. Herein, we studied the
      influence of physiological concentrations of CO(2) on peroxynitrite diffusion
      across intact red blood cells. The presence of CO(2) inhibited the oxidation of
      intracellular oxyhemoglobin by externally added peroxynitrite. However, the
      inhibition by CO(2) decreased at increasing red blood cell densities. At 45%
      hematocrit, 1.3 mM CO(2) (in equilibrium with 24 mM bicarbonate, at pH 7.4 and 25
      degrees C) only inhibited 30% of intracellular oxyhemoglobin oxidation. This
      partial inhibition was also observed in red blood cells pretreated with the anion
      exchanger inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, ruling
      out a competition between peroxynitrite and bicarbonate for the transport through
      the anion channel. A theoretical model was developed to estimate the diffusion
      distance and half-life of extracellular peroxynitrite before reacting with
      intracellular oxyhemoglobin, at different red blood cell densities, and in the
      presence or absence of CO(2). The theoretical model correlated well with the
      experimental data. Our results indicate that, even in the presence of CO(2),
      peroxynitrite is able to diffuse and reach the inside of the erythrocyte.

PMID- 10415109
TI  - Inhibitory effect of the kinase inhibitor chelerythrine on acetylcholine-induced
      current in PC12 cells.
AB  - In order to analyze the effect of protein kinase C(PKC) on nicotinic
      acetylcholine receptor in pheochromocytoma (PC12) cells by the whole-cell clamp
      technique, chelerythrine, a well-known inhibitor of PKC, was used to investigate
      the influence of PKC on acetylcholine (ACh)-induced current. When cells were
      preincubated with chelerythrine (0.1-10 microM) for 5 min, an inhibitory effect
      of chelerythrine on the peak of ACh-induced current was found. This effect was
      concentration-dependent, voltage-independent, and time-dependent within 1-6 min
      and reversible. However, intracellular dialysis with 0.1-5 microM PKCI 19-31, a
      specific pseudosubstrate PKC inhibitor, did not affect the inhibitory effect of
      chelerythrine. These results suggest that chelerythrine has an inhibitory effect
      on ACh-induced current in PC12 cells and that this effect is independent of its
      inhibition on PKC, may represent a new pharmacological effect of chelerythrine,
      and is mediated by an alternative mechanism.

PMID- 10415108
TI  - Role of estradiol receptor-alpha in differential expression of 2,3,7, 8
      tetrachlorodibenzo-p-dioxin-inducible genes in the RL95-2 and KLE human
      endometrial cancer cell lines.
AB  - The present study was conducted to investigate the mechanism of the response of
      human uterine endometrial carcinoma cells, RL95-2 and KLE, to 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD). RL95-2 cells were highly responsive to TCDD
      in terms of cytochrome P4501A1 (CYP1A1), cytochrome P4501B1 (CYP1B1), and
      plasminogen activator inhibitor-2 (PAI-2), whereas KLE cells showed little
      stimulatory effects only at high doses. Neither showed any growth inhibition upon
      exposure to TCDD. KLE cells expressed higher levels of aryl hydrocarbon receptor
      (AhR) than RL95-2 and gel mobility shift assay also identified more liganded AhR
      ARNT complex bound to xenobiotic response elements (XRE). TCDD had no
      downregulatory effects on the expression of either AhR or the estradiol receptor
      (ER). Though both cell types expressed ER-alpha almost equally,
      immunofluorescence demonstrated a defect in its nuclear translocation in KLE
      cells where ER-alpha was mainly cytoplasmic and estradiol-17beta (E(2)) was
      unable to translocate it to the nucleus. However, both cells were nonresponsive
      to E(2) in terms of transcriptional activation and transient expression of normal
      ER-alpha restored the E(2) responsiveness. Transient expression of ER-alpha in
      KLE cells also restored its responsiveness to TCDD on transcriptional activation.
      Collectively, these results indicate that ER-alpha acts as a positive modulator
      in regulation of the TCDD-inducible genes.

PMID- 10415110
TI  - Regulation of 12-lipoxygenase in rat intestinal epithelial cells during
      differentiation and apoptosis induced by sodium butyrate.
AB  - We evaluated the expression and activity of rat 12-lipoxygenase (LO) in rat
      intestinal epithelial (RIE) cells during apoptosis and cell differentiation.
      Sodium butyrate (NaBT) treatment induced wild-type RIE (W-RIE) cells to undergo
      differentiation and apoptosis. Alkaline phosphatase (ALP) activity, a marker of
      cell differentiation, and DNA fragmentation, an index of apoptosis, were
      increased by NaBT treatment. Arachidonic acid was metabolized primarily to 12
      hydroxyeicosatetraenoic acid (HETE) suggesting induction of 12-LO activity. In
      contrast, sense-RIE (S-RIE) cells engineered to overexpress COX-2 were resistant
      to apoptosis by treatment with 5 mM NaBT and NaBT did not induce 12-LO activity.
      The upregulation of 12-LO expression by NaBT in W-RIE cells was confirmed at both
      the transcriptional and translational level but 12-LO was undetectable in S-RIE
      cells following NaBT treatment. The expression of 12-LO mRNA in W-RIE cells
      occurs as early as 6 h after treatment and reaches maximum expression at 24 h
      following treatment. This inducible 12-LO was isolated by RT-PCR and identified
      as rat "leukocyte-type" 12-LO. The level of 12-LO expression in W-RIE cells was
      dependent on the concentration of NaBT and appears to reflect the extent of cell
      differentiation. NDGA, a lipoxygenase inhibitor, attenuated induction of ALP
      activity by NaBT treatment of W-RIE cells. These observations suggested that 12
      LO is regulated by treatment with NaBT and is associated with cell
      differentiation in rat intestinal epithelial cells.

PMID- 10415111
TI  - Characterization of alpha-L-rhamnosidase of Bacillus sp. GL1 responsible for the
      complete depolymerization of gellan.
AB  - A bacterium, Bacillus sp. GL1, depolymerizes a heteropolysaccharide (gellan) to a
      tetrasaccharide (unsaturated glucuronyl-glucosyl-rhamnosyl-glucose) by
      extracellular gellan lyase. The resultant tetrasaccharide was degraded to the
      constituent monosaccharides by subsequent reactions of unsaturated glucuronyl
      hydrolase, beta-d-glucosidase, and alpha-l-rhamnosidase. alpha-l-Rhamnosidase was
      substantially induced in the bacterial cells when grown in a medium containing
      gellan as a carbon source. The purified enzyme from the cells was a monomer with
      a molecular mass of about 100 kDa and was most active at pH 7.0 and 50 degrees C.
      The enzyme acted on the gellan-degrading product (rhamnosyl-glucose) formed after
      successive reactions catalyzed by gellan lyase, unsaturated-glucuronyl hydrolase
      and beta-d-glucosidase, and released rhamnose from the disaccharide. Therefore,
      the alpha-l-rhamnosidase is found to be responsible as the final enzyme for the
      complete depolymerization of gellan.

PMID- 10415112
TI  - Activity and conformation changes of Chinese hamster dihydrofolate reductase in
      reverse micelles.
AB  - Changes in the activity and conformation of Chinese hamster dihydrofolate
      reductase (ch-DHFR) were studied in reverse micelles of cetyltrimethylammonium
      bromide (CTAB) and dodecylammonium butyrate (DAB) at various water contents and
      denaturant concentrations. The ch-DHFR entrapped in CTAB and DAB reverse micelles
      shows very low activity at a lower ratio of water to surfactant (omega(0)). The
      activity was enhanced in the presence of low concentrations of guanidine
      hydrochloride. Emission fluorescence spectra of ch-DHFR in aqueous medium and in
      reverse micelles in the presence of low concentrations of denaturants were
      compared. Only a slight change in emission intensity of ch-DHFR accompanies
      enzyme activation in the presence of low concentrations of guanidine
      hydrochloride in CTAB and DAB reverse micelles. There was no detectable change in
      the average diameters of CTAB and DAB reverse micelles in the presence of low
      concentrations of denaturants measured by laser light scattering, indicating that
      the enzyme activation in the presence of denaturant is not due to a size change
      in the reverse micelles. Our results suggest that the reduced activity of ch-DHFR
      in reverse micelles at low omega(0) is due to the restrictions in enzyme
      conformation caused by an environment with low water content. The reduction in
      enzyme activity was restored by the presence of low concentrations of denaturant
      or increased water content, indicating that conformation flexibility is important
      for full expression of enzyme activity.

PMID- 10415113
TI  - adapt78, a stress-inducible mRNA, is related to the glucose-regulated protein
      family of genes.
AB  - We have recently reported a new oxidant- and calcium-inducible mRNA, adapt78,
      from hamster HA-1 cells. The adapt78 mRNA is induced in HA-1 cells under
      conditions where a protective adaptive response is observed and contains a
      translatable open reading frame whose protein product shows strong homology to a
      human sequence. Computer analysis of the predicted Adapt78 protein sequence also
      revealed a stretch of amino acids homologous to a portion of the glucose
      regulated protein78 (Grp78). Based on this homology, we tested the hypothesis
      that adapt78 may be a new member of the grp gene family. Toward this, we assessed
      the modulation of adapt78 mRNA by stress agents known to induce grp78. In HA-1
      cells, adapt78 mRNA was induced by the calcium ionophore A23187, 2-deoxyglucose,
      brefeldin A, tunicamycin, thapsigargin, and cyclopiazonic acid, with thapsigargin
      being the most potent inducer (7.3-fold). As expected, grp78 mRNA was also
      induced by these agents in our model system. In contrast, heat shock treatment
      produced little if any modulation of either grp78 or adapt78. Differences were
      also observed, as adapt78 mRNA but not grp78 mRNA was induced by 160 microM
      hydrogen peroxide, and adapt78 demonstrated earlier induction kinetics for
      certain agents compared with grp78. adapt78 mRNA was also found to be induced in
      several different human cell lines. A23187 had the strongest effect on adapt78
      mRNA levels in human cells, inducing greater than 20-fold in all human cell
      cultures tested. Furthermore, in vitro transcription translation of human adapt78
      cDNA produced an Adapt78 protein product. We conclude that adapt78 may be a new
      member of the grp family of genes and may represent an early response grp that
      complements the actions of grp78 and grp94.

PMID- 10415114
TI  - Photoaffinity labeling of the aglycon binding site of the recombinant human liver
      UDP-glucuronosyltransferase UGT1A6 with 7-azido-4-methylcoumarin.
AB  - 7-Azido-4-methylcoumarin (AzMC) is a fluorescent photoactive compound
      structurally related to 4-methylumbelliferone (4-MU), a marker substrate of the
      human liver recombinant UDP-glucuronosyltransferase (UGT) 1A6. AzMC was
      synthesized and utilized to label the substrate binding site of UGT1A6. AzMC
      exhibits a fluorescence spectrum with maximum excitation and emission wavelengths
      of 380 and 442 nm, respectively. Upon irradiation, the probe irreversibly
      inhibited glucuronidation activity measured with para-nitrophenol (pNP) as
      substrate and interacted with UGT1A6 according to a saturable process indicative
      of reversible binding before covalent incorporation of the photoaffinity label.
      This inhibition was both time and concentration dependent and led to the
      calculation of an inhibition constant, k(2) = 0.113 mM min(-1), and dissociation
      constant, K(d) = 2.89 mM, for the reaction. Partial photoinactivation of UGT1A6
      with AzMC revealed that the probe decreased the apparent V(max) of the pNP
      glucuronidation reaction, but not the K(m). Moreover, inhibition was partially
      prevented by 1-naphthol, a surrogate substrate for the enzyme, or by
      preincubation with an active-site directed inhibitor, 5'-O-[[(2-decanoylamino-3
      phenyl-propyloxycarbonyl)amino]-su lfonyl]-2 ',3'-O-isopropylideneuridine. In
      contrast, UDP-glucuronic acid (UDP-GlcUA) did not have any protective effect
      against photoinactivation and AzMC did not affect the photoaffinity labeling of
      UGT1A6 by 5-[beta-(32)P]N(3)UDP-GlcUA, a photoaffinity analog of UDP-GlcUA.
      Additionally, in the absence of irradiation, AzMC was found to be a competitive
      inhibitor of 4MU glucuronidation. Collectively, these results strongly indicate
      that AzMC specifically binds to the UGT1A6 aglycon binding site. Amino acid
      alignment of phenol-binding proteins revealed a conserved motif, YXXXKXXPXP. It
      is possible that this motif is involved in phenol binding to UGT1A6 and other
      phenol-accepting proteins.

PMID- 10415115
TI  - Subunit compositions and catalytic properties of proteasomes from developmental
      temperature- sensitive mutants of Drosophila melanogaster.
AB  - Two dominant temperature-sensitive (DTS) Drosophila mutants are missense
      mutations of proteasome genes encoding beta-type subunits beta6/C5 (DTS5) and
      beta2/Z (DTS7). At nonpermissive temperature (29 degrees C), heterozygotes
      (DTS5/+ and DTS7/+) develop normally until metamorphosis; pupae fail to mature
      and die before eclosion. Proteasomes were purified from wild-type (WT) and
      heterozygous adult flies raised at permissive temperature (25 degrees C). Two
      dimensional gel electrophoresis separated at least 28 proteins, 13 of which were
      identified with monospecific antibodies to alpha6/C2 (five species), alpha2/C3
      (three species), alpha7/C8 (three species), alpha5/zeta, and beta1/Y subunits.
      Both quantitative and qualitative differences were observed between WT and DTS/+
      proteasomes, with DTS5/+ deviating more from WT than DTS7/+ proteasomes. In
      DTS5/+ there was a shift to more acidic species of C2 and C3 and a shift to less
      acidic species of 32-kDa subunits (#3-#7) recognized by an anti-alpha subunit
      monoclonal antibody (MCP222) and were losses of two 32-kDa subunits (#2 and #3),
      decreases in Y (25 kDa; 2-fold) and 31-kDa (#9; 2-fold) subunits, and increases
      in 52-kDa (#1; 1.9-fold) and 24-kDa (#13; 2.3-fold) subunits. In DTS7/+ there was
      a less pronounced shift to acidic species of C3 and no pI shift in C2 species and
      subunits #3-#7 and were decreases in #9 (2.5-fold) and #14 (3-fold) and a loss of
      #2. The three C8 species were similar between WT, DTS5/+, and DTS7/+ proteasomes.
      Qualitatively, the most dramatic difference was the appearance of a new 24-kDa
      subunit (#16) in DTS/+ preparations, with about a 14-fold greater amount of #16
      in DTS7/+ than in DTS5/+ proteasomes. Catalytically, WT and DTS/+ proteasomes had
      similar peptidase activities, although the DTS/+ proteasomes were slightly more
      sensitive to SDS and elevated temperatures in vitro. The incorporation of DTS
      subunits apparently altered proteasome assembly and/or processing at permissive
      temperature with little effect on catalytic activities. These data suggest that
      at nonpermissive temperature, assembly/processing is more severely affected,
      producing DTS-containing complexes that lack functions essential for cellular
      proliferation and differentiation at metamorphosis.

PMID- 10415116
TI  - Protein crosslinking by the Maillard reaction: dicarbonyl-derived imidazolium
      crosslinks in aging and diabetes.
AB  - alpha-Dicarbonyl compounds that arise from various metabolic pathways react with
      proteins to form a variety of adducts in a reaction known as the Maillard
      reaction. These adducts are collectively known as advanced glycation end products
      or AGEs. Methylglyoxal (MG) and glyoxal (GXL) are two such dicarbonyls. They
      react with proteins to produce lysine-lysine imidazolium crosslinking AGEs. The
      imidazolium crosslinks derived from MG (MOLD-methylglyoxal-lysine dimer) and GXL
      (GOLD-glyoxal-lysine dimer) are present in human tissue proteins. In this study,
      we report an HPLC method for the simultaneous quantification of GOLD and MOLD in
      biological specimens. The method consists of reverse-phase HPLC of acid
      hydrolyzed proteins, collection of eluate-containing imidazoliums,
      phenylisothiocyanate derivatization, followed by a second reverse-phase HPLC.
      This method was linear for both the imidazolium compounds in the range of 0.5-300
      pmol. The levels of GOLD and MOLD in aging lenses (20 to 80 years) were trace-8.4
      pmol and 15-93 pmol per milligram of protein, respectively. Cataractous lenses
      showed significantly higher levels of both GOLD and MOLD (mean +/- SD, 14.5 +/-
      1.8 and 141 +/- 18.4 pmol per milligram of protein, P < 0.05). Brunescent lenses
      had the highest levels of imidazolium crosslinks (GOLD, 18.36 +/- 2.5; and MOLD,
      179. 2 +/- 32.3 pmol per milligram of protein, P < 0.05). The GOLD and MOLD
      levels were higher in diabetic plasma proteins when compared to that of normal
      (GOLD, 17.5 +/- 6.34 pmol per milligram of protein vs 43.5 +/- 15.96 pmol per
      milligram of protein; and MOLD, 172.5 +/- 32. 53 pmol per milligram of protein vs
      273 +/- 62.67 pmol per milligram of protein, P < 0.05). GOLD and MOLD are
      significant in terms of tissue damage in aging and diabetes because they
      represent protein crosslinking by compounds that are major precursors of AGEs.
      Our method can be used for quantification of imidazolium crosslinks in tissue
      proteins to assess alpha-dicarbonyl-mediated protein damage in vivo.

PMID- 10415117
TI  - Correlation between polymerizability and conformation in scallop beta-like actin
      and rabbit skeletal muscle alpha-actin.
AB  - In order to investigate the structural basis for functional differences among
      actin isoforms, we have compared the polymerization properties and conformations
      of scallop adductor muscle beta-like actin and rabbit skeletal muscle alpha
      actin. Polymerization of scallop Ca(2+)-actin was slower than that of skeletal
      muscle Ca(2+)-actin. Cleavage of the actin polypeptide chain between Gly-42 and
      Val-43 with Escherichia coli protease ECP 32 impaired the polymerization of
      scallop Mg(2+)-actin to a greater extent than skeletal muscle Mg(2+)-actin. When
      monomeric scallop and skeletal muscle Ca(2+)-actins were subjected to limited
      proteolysis with trypsin, subtilisin, or ECP 32, no differences in the
      conformation of actin subdomain 2 were detected. At the same time, local
      differences in the conformations of scallop and skeletal muscle actin subdomains
      1 were revealed as intrinsic fluorescence differences. Replacement of tightly
      bound Ca(2+) with Mg(2+) resulted in more extensive proteolysis of segment 61-69
      of scallop actin than in the case of skeletal muscle actin. Furthermore, segment
      61-69 was more accessible to proteolysis with subtilisin in polymerized scallop
      Ca(2+)-actin than in polymerized skeletal muscle Ca(2+)-actin, indicating that,
      in the polymeric form, the nucleotide-containing cleft is in a more open
      conformation in beta-like scallop actin than in skeletal muscle alpha-actin. We
      suggest that this difference between scallop and skeletal muscle actins is due to
      a less efficient shift of scallop actin subdomain 2 to the position it has in the
      polymer. The possible consequences of amino acid substitutions in actin subdomain
      1 in the allosteric regulation of the actin cleft, and hence in the different
      stabilities of polymers formed by different actins, are discussed.

PMID- 10415118
TI  - Effect of exercise duration on characteristics of mitochondrial population from
      rat liver.
AB  - Young male rats were sacrificed either at rest or immediately after a single bout
      of swimming lasting either 5 or 8 h. Mitochondrial population, obtained by
      centrifugation (10,000g for 10 min) from liver homogenates freed from debris and
      nuclei, was resolved by differential centrifugation into three fractions.
      Homogenates and mitochondrial preparations were examined for their protein
      content, oxidative capacity (by cytochrome oxidase activity), peroxidative
      processes (by thiobarbituric acid reactive substance and hydroperoxide levels),
      antioxidant status (by reduced glutathione and vitamin E levels and whole
      antioxidant capacity), and susceptibility to in vitro oxidative stress. In all
      groups, the antioxidant level was smaller and oxidative capacity, lipid
      peroxidation, and susceptibility to oxidants were greater in the heavy
      mitochondrial fraction. Exercise of shorter duration did not significantly affect
      most of the parameters; only the resulting homogenate glutathione level and
      susceptibility to oxidative stress decreased and increased, respectively,
      compared with control values. In contrast, more prolonged exercise was associated
      with increased lipid peroxidation and susceptibility to oxidative stress and
      decreased antioxidant levels in all preparations. The contribution of each
      fraction to the whole mitochondrial population was also modified in that the
      heavy fraction decreased and light fractions increased. These results suggest
      that liver antioxidant defence systems are able to withstand oxidative challenge
      due to low-intensity exercise of moderate duration. In contrast, the free radical
      production associated with long-lasting exercise causes oxidative injury in
      cellular components and in particular induces protein degradation in the heavy
      mitochondrial fraction characterized by higher susceptibility to oxidative
      stress.

PMID- 10415119
TI  - Biosynthesis of cyanogenic glucosides in Triglochin maritima and the involvement
      of cytochrome P450 enzymes.
AB  - The biosynthesis of the two cyanogenic glucosides, taxiphyllin and triglochinin,
      in Triglochin maritima (seaside arrow grass) has been studied using undialyzed
      microsomal preparations from flowers and fruits. Tyrosine was converted to p
      hydroxymandelonitrile with V(max) and K(m) values of 36 nmol mg(-1) g(-1) fresh
      weight and 0.14 mM, respectively. p-Hydroxyphenylacetaldoxime and p
      hydroxyphenylacetonitrile accumulated as intermediates in the reaction mixtures.
      Using radiolabeled tyrosine as substrate, the radiolabel was easily trapped in p
      hydroxyphenylacetaldoxime and p-hydroxyphenylacetonitrile when these were added
      as unlabeled compounds. p-Hydroxyphenylacetaldoxime was the only product obtained
      using microsomes prepared from green leaves or dialyzed microsomes prepared from
      flowers and fruits. These data contrast earlier reports (Hosel and Nahrstedt,
      Arch. Biochem. Biophys. 203, 753-757, 1980; and Cutler et al., J. Biol. Chem.
      256, 4253-4258, 1981) where p-hydroxyphenylacetaldoxime was found not to
      accumulate. All steps in the conversion of tyrosine to p-hydroxymandelonitrile
      were found to be catalyzed by cytochrome P450 enzymes as documented by
      photoreversible carbon monoxide inhibition, inhibition by antibodies toward NADPH
      cytochrome P450 oxidoreductase, and by cytochrome P450 inhibitors. We hypothesize
      that cyanogenic glucoside synthesis in T. maritima is catalyzed by
      multifunctional cytochrome P450 enzymes similar to CYP79A1 and CYP71E1 in Sorghum
      bicolor except that the homolog to CYP71E1 in T. maritima exhibits a less tight
      binding of p-hydroxyphenylacetonitrile, thus permitting the release of this
      intermediate and its conversion into triglochinin.

PMID- 10415120
TI  - Modification of leukotriene A(4) hydrolase/aminopeptidase by sulfhydryl-blocking
      reagents: differential effects on dual enzyme activities by methyl-methane
      thiosulfonate.
AB  - The presence of a cysteine residue at or near the active site of leukotriene A(4)
      hydrolase (EC 3.3.2.6) was suggested by inactivation of the enzyme with
      sulfhydryl-blocking reagents and by protection against inactivation afforded by
      substrates and competitive inhibitors. The aminopeptidase activity was more
      susceptible to inactivation than the epoxide hydrolase activity. The sulfhydryl
      modifying reagent methyl-methane thiosulfonate reacted with one thiol as judged
      by kinetic data and titration with 5, 5'-dithiobis-2-nitrobenzoate. Inactivation
      was a time- and dose-dependent process of apparent pseudo-first-order and maximal
      at 80-85%. The inactivation rate was nonsaturable and strongly influenced by ion
      strength. The second-order rate constant increased from 0.9 to 4.3 M(-1) s(-1) in
      the presence of 0.2 M NaCl. Albumin, a stimulator of the aminopeptidase activity,
      increased apparent inactivation rates by shifting pK(a) for the modification from
      8.2 to 7.8. The inactivated enzyme partially regained activity upon treatment
      with beta-mercaptoethanol. Peptide substrates and competitive inhibitors
      protected against inactivation. Bestatin, a competitive inhibitor, afforded
      complete protection with a K(D) = 0.15 microM, similar to K(i) = 0.17 microM for
      inhibition of peptidase activity. Treated enzyme had an unchanged K(m) but a
      reduced V(max). The epoxide hydrolase activity was only weakly affected by methyl
      methane thiosulfonate with a maximal inactivation of 15-20% after prolonged
      treatment. Pretreatment of leukotriene A(4) hydrolase with the reagent did not
      protect against mechanism-based inactivation by its lipid substrate, leukotriene
      A(4). On the other hand, leukotriene B(4) was a competitive inhibitor of
      aminopeptidase activity and protected against modification by methyl-methane
      thiosulfonate. Our results suggest the presence of a cysteine at or close to
      subsite S'(1) of the active site of leukotriene A(4) hydrolase and that
      modification of this residue interferes with the function of the aminopeptidase
      activity, but not the epoxide hydrolase activity. This is the first report to
      distinguish the two catalytic activities of leukotriene A(4) hydrolase by
      chemical means.

PMID- 10415121
TI  - In vitro processing of the human alkyl-dihydroxyacetonephosphate synthase
      precursor.
AB  - Alkyl-dihydroxyacetonephosphate synthase, a peroxisomal enzyme involved in the
      biosynthesis of ether phospholipids, is synthesized with a cleavable N-terminal
      presequence containing the peroxisomal targeting signal type 2. The human alkyl
      dihydroxyacetonephosphate synthase precursor produced in vitro or expressed in
      Escherichia coli could be processed to a lower molecular weight protein by
      incubation at 37 degrees C with a guinea pig liver fraction, enriched in
      mitochondria, lysosomes, and peroxisomes. This lower molecular weight protein was
      identified as the mature human alkyl-dihydroxyacetonephosphate synthase by
      radiosequencing, indicating that the processing protease is present in this
      organellar fraction. Characterization of the processing protease indicated that
      it is a cysteine protease with a pH optimum of 6.5. Furthermore, it was
      demonstrated that exogenously added pre-alkyl-dihydroxyacetonephosphate synthase
      was imported and processed in purified peroxisomes in vitro. Processing of alkyl
      dihydroxyacetonephosphate synthase did not increase the activity of the enzyme.
      This indicates that the presence of the presequence does not affect the activity
      of the enzyme.

PMID- 10415123
TI  - Escherichia coli membrane fluidity as detected by excimerization of
      dipyrenylpropane: sensitivity to the bacterial fatty acid profile.
AB  - A coordinated study of membrane fluidity and fatty acid composition has been
      carried out in Escherichia coli W3110. The lipid acyl chain profile of the
      bacteria, altered by growing cells in steady state at 30, 37, 42, or 45 degrees
      C, was determined by gas chromatography of the fatty acid methyl esters. In
      parallel experiments, total membranes obtained from cells of the above-mentioned
      cultures were labeled with dipyrenylpropane and their relative fluidity was
      measured on the basis of the excimer to monomer fluorescence intensity ratio of
      the fluorophore. It has been found that, at constant assay temperature, fluidity
      determined with dipyrenylpropane decreases gradually with the growth temperature
      increment, from 30 to 45 degrees C. Interestingly, when fatty acid composition is
      taken into account, fluidity increases linearly in the range under study, with
      the proportion of unsaturated fatty acyl chains, both variables being highly
      correlated (0.924 </= r(2) </= 0.996). Our results show that dipyrenylpropane is
      a reliable and quantitative indicator of changes in membrane fluidity, driven by
      modifications in the acyl chain composition of bacterial lipids.

PMID- 10415124
TI  - Mutant PTR1 proteins from Leishmania tarentolae: comparative kinetic properties
      and active-site labeling.
AB  - PTR1, the gene promoting MTX resistance following gene amplification or DNA
      transfection in Leishmania tarentolae and selected mutants, has been cloned and
      heavily overexpressed (>100 mg/liter) in Escherichia coli strain BL21 (DE3).
      Protein has been purified, essentially to homogeneity, in two steps, via ammonium
      sulfate precipitation and chromatography on DEAE-Trisacryl. The active proteins
      are tetramers and display optimal pteridine reductase activity at pH 6.0 using
      biopterin as substrate and NADPH as the reduced dinucleotide cofactor. 2,4
      Diaminopteridine substrate analogues are strong competitive inhibitors (K(i)
      approximately 38 --> 3 nM) against the pterin substrate and both NADP(+) and
      folate are inhibitors although somewhat weaker. Dihydropteridines are poor
      substrates compared to the fully oxidized pteridine. Kinetic analysis affords the
      usual Michaelis constants and in addition shows that inhibition by NADP(+) allows
      the formation of ternary nonproductive complexes with folate. The kinetic results
      are consistent with a sequential ordered bi-bi kinetic mechanism in which first
      NADPH and then pteridine bind to the free enzyme. Sequence comparisons suggest
      that PTR1 belongs to the short-chain dehydrogenase/reductase (SDR) family
      containing an amino-terminal glycine-rich dinucleotide binding site plus a
      catalytic Y(Xaa)(3)K motif. In accord with this observation, the mutants K16A,
      Y37D, and R39A and the double mutants K17A:R39A and Y37D:R39A all show a two- to
      threefold lower binding affinity for NADPH and exhibit low or zero activity. Two
      Y(Xaa)(3)K regions are present in wild-type PTR1 at 152 and 194. Only Y194F gives
      protein with zero activity. This observation coupled with affinity labeling of
      PTR1 by oNADP(+) (2', 3'-dialdehyde derivative of NADP(+)) followed by NaBH(4)
      reduction, V8 protease digestion, and mass spectral analysis suggests that the
      motif participating in catalysis is that at 194. The mutation K198Q eliminates
      inactivation by oNADP(+) supporting the hypothesis that K198 is associated with
      nucleotide orientation, as has been demonstrated for similar lysine residues in
      other members of the SDR family.

PMID- 10415122
TI  - Direct interaction of STAT4 with the IL-12 receptor.
AB  - Signal transduction by interleukin-12 (IL-12) requires phosphorylation and
      activation of STAT4. Direct interaction of the SH2 domain of STAT4 with a
      phosphotyrosine residue in the IL-12 receptor has been proposed to be required
      for the subsequent STAT4 phosphorylation. The IL-12 receptor beta2 subunit
      contains three tyrosine residues in its cytoplasmic domain. To test the
      hypothesis that one of these tyrosines is involved in binding STAT4,
      phosphopeptides were synthesized according to the amino acid sequences
      surrounding each of these tyrosine residues. Only the phosphopeptide containing
      pTyr800 strongly bound to STAT4 in a cell-free binding assay. When this
      phosphopeptide was introduced into TALL-104 cells, it blocked IL-12-induced STAT4
      phosphorylation by competing with the IL-12 receptor for binding to STAT4. A
      series of alanine replacements was performed in this phosphopeptide to elucidate
      which amino acids surrounding the pTyr800 residue are critical for STAT4 binding.
      To summarize, the site on the IL-12 receptor which binds STAT4 can be described
      as -T-X-X-G-pY(800)-L-, where the core G-pY(800)-L motif is critical for the
      binding; the threonine at the pY-4 position has only a minor contribution and X
      represents amino acids not critical for the binding. These results demonstrate
      that only a small region of the IL-12 receptor is critically involved in binding
      STAT4 and suggest the feasibility that small molecule inhibitors could be
      identified which interfere with IL-12 signal transduction for treatment of
      autoimmune diseases.

PMID- 10415126
TI  - Regiospecific cytochrome P450 limonene hydroxylases from mint (Mentha) species:
      cDNA isolation, characterization, and functional expression of (-)-4S-limonene-3
      hydroxylase and (-)-4S-limonene-6-hydroxylase.
AB  - The oxygenation pattern of the cyclic monoterpenoids of commercial mint (Mentha)
      species is determined by regiospecific cytochrome P450-catalyzed hydroxylation of
      the common olefinic precursor (-)-4S-limonene. In peppermint (Mentha x piperita),
      C3-allylic hydroxylation leads to (-)-trans-isopiperitenol, whereas in spearmint,
      C6-allylic hydroxylation leads to (-)-trans-carveol. The microsomal limonene-6
      hydroxylase was purified from the oil glands of spearmint, and amino acid
      sequences from the homogeneous enzyme were used to design PCR primers with which
      a 500-bp amplicon was prepared. This nondegenerate probe was employed to screen a
      spearmint oil gland cDNA library from which the corresponding full-length cDNA
      was isolated and subsequently confirmed as the C6-hydroxylase by functional
      expression using the baculovirus-Spodoptera system. The probe was also utilized
      to isolate two closely related full-length cDNA species from a peppermint oil
      gland cDNA library which were confirmed as the limonene-3-hydroxylase by
      functional expression as before. Deduced sequence analysis of these regiospecific
      cytochrome P450 monooxygenases indicates that both enzymes bear a typical amino
      terminal membrane anchor, consistent with the microsomal location of the native
      forms, exhibit calculated molecular weights of 56,149 (spearmint) and about
      56,560 (peppermint), and are very similar in primary sequence (70% identity and
      85% similarity). The availability of these regiochemically distinct, yet very
      closely related, recombinant hydroxylases and their corresponding genes provides
      a unique model system for understanding structure-function relationships in
      cytochrome P450 substrate binding and catalysis, and a means for transgenic
      manipulation of monoterpene biosynthetic pathways in plants.

PMID- 10415125
TI  - Identification of specific residues involved in substrate discrimination in two
      plant O-methyltransferases.
AB  - Among the large number of plant O-methyltransferases that are involved in
      secondary metabolism, only a few have been enzymatically characterized, and
      little information is available on the structure of their substrate binding site
      and the mechanism which determines their substrate specificity and methylation
      regiospecificity. We have previously reported the isolation of two O
      methyltransferases, S-adenosyl-l-methionine:(iso)eugenol O-methyltransferase
      (IEMT) and S-adenosyl-l-methionine:caffeic acid O-methyltransferase (COMT) from
      Clarkia breweri, an annual plant from California. While IEMT and COMT (which
      methylate eugenol/isoeugenol and caffeic acid/5-hydroxyferulic acid,
      respectively) share 83% identity at the amino acid level, they have distinct
      substrate specificity and methylation regiospecificity. We report here that seven
      amino acids play a critical role in discriminating between eugenol/isoeugenol and
      caffeic acid/5-hydroxyferulic acid. When these amino acids in IEMT were replaced
      by the corresponding residues of COMT, the hybrid protein showed activity only
      with caffeic acid/5-hydroxyferulic acid. Conversely, when these amino acids in
      COMT were replaced by corresponding IEMT residues, the hybrid protein had
      activity only with eugenol/isoeugenol. These results provide strong evidence that
      O-methyltransferase substrate preference could be determined by a few amino acid
      residues and that new OMTs with different substrate specificity could begin to
      evolve from an existing OMT by mutation of a few amino acids. Phylogenetic
      analysis confirms that C. breweri IEMT evolved recently from COMT.

PMID- 10415127
TI  - His(15) of subunit a of the Escherichia coli ATP synthase is important for the
      structure or assembly of the membrane sector F(o).
AB  - Approximately 37 amino acids at the amino-terminus of subunit a of the
      Escherichia coli ATP synthase are found localized to the periplasm. Results
      indicate that a single amino acid substitution, H15D, disrupts assembly of
      subunit a and causes a loss of ATP synthase function. In this study, a conserved
      region of nine amino acids, 11-19, was initially mutagenized randomly, generating
      no mutants that could grow on succinate-minimal medium. Subsequent mutagenesis,
      confined to residues His(14), His(15), and Asn(17), indicated that constructs
      containing H15D were the most deleterious. Four single mutants were constructed
      and analyzed: H15A, H14D, H15A, and H15D. Only H15D was significantly impaired,
      with respect to ATP-driven proton translocation, passive proton permeability
      through F(o), and sensitivity of membrane-bound ATPase to DCCD. Immunoblot
      analysis indicated very low levels of subunit a from H15D. Cysteine mutations
      were constructed at positions 14, 15, 17, and 18. Residues 14, 15, and 17 were
      shown to be accessible in the periplasmic space, while residue 18 was not,
      indicating that this region was stably folded. While both His(14) and His(15) are
      conserved among a group of bacteria, results presented here indicate that they
      are not equivalent, and that a specific role for His(15) in the assembly or
      structure of the ATP synthase is supported.

PMID- 10415128
TI  - Small and large unilamellar vesicle membranes as model system for bile acid
      diffusion in hepatocytes.
AB  - Uptake of bile acids into the liver cell occurs via active transport or passive
      diffusion. In a model system, passive diffusion was studied in liposomes using
      pyranine fluorescence. Rate constants for the diffusion of diverse more polar or
      more apolar bile acids were examined. Hydrophobic lithocholic acid (LCA) revealed
      a maximal rate constant of 0.057 s(-1); with the polar ursodeoxycholic acid
      (UDCA), the value was 0.019 s(-1). UDCA (3 mol%) effectively decreased the rate
      constant of 0.1 mM chenodeoxycholic acid (CDCA), whereas cholesterol reached a
      similar decrease only between 5 and 10 mol%. At higher concentrations of CDCA
      (above 1 mM) or LCA (0.3-0.4 mM), breaking up of liposomal structure was
      confirmed by light-scattering decrease and increase of carboxyfluorescein
      fluorescence. Changes in lipid composition of phosphatidylcholine (PC)- small
      unilamellar vesicles (SUVs) or large unilamellar vesicles (LUVs) also caused
      decreasing rate constants. For a cardiolipin (CL):PC ratio of 1:20 the CDCA (0.1
      mM) rate constant was 71% lower (0.015 s(-1)) and for a sphingomyelin (SM):PC
      ratio of 2:1 the rate constant was 50% lower (0.026 s(-1)). Changes in membrane
      fluidity were detected using membrane anisotropy measurements with the 1,6
      diphenyl-1,3, 5-hexatriene (DPH) method. Membrane fluidity was reduced with
      cholesterol- but not with CL- or SM-containing SUVs (ratio: cholesterol, CL,
      SM:PC of 1:5). This model system is currently used for the analysis of more
      complex lipid vesicles resembling the plasma/hepatocyte membrane, which is either
      stabilized or destabilized by appropriate conditions. The results should become
      clinically relevant.

PMID- 10415129
TI  - Phosphorylation of P'(1) serine inhibits peptide bond sensitivity to
      Staphylococcus aureus V8 protease.

PMID- 10415130
TI  - Child age and planum temporale asymmetry.
AB  - Investigations using in vivo magnetic resonance (MR) morphometry have shown that
      left-right asymmetry of the planum temporale (PT) is a structural correlate of
      hemispheric functional asymmetries in adult humans (e.g., handedness, language
      representation). Postmortem studies of brains of fetuses and newborns have
      demonstrated that PT asymmetry becomes visible as early as in the last
      gestational trimester. The same studies could not clarify when the full (adult)
      degree of PT asymmetry is reached during brain development and whether this
      process may be influenced by functional specialization during childhood. We
      examined 61 neuropsychiatrically normal right-handed children aged 3 to 14 years
      (mean age +/-SD, 8.4 +/- 2. 7 years; cross-sectional study). MR morphometry
      showed no change in PT or planum parietale asymmetry with increasing age or brain
      volume. An unexpected gender difference of unknown significance emerged, with
      girls displaying a stronger leftward PT asymmetry, independently of age. For the
      age range studied, the results suggest that functional differentiation follows a
      structural asymmetry that is already "preset."

PMID- 10415131
TI  - Quantitative and qualitative hemispheric asymmetry for processing Japanese kana.
AB  - Native Japanese speakers identified three-letter kana stimuli presented to the
      left visual field and right hemisphere (LVF/RH), to the right visual field and
      left hemisphere (RVF/LH), or to both visual fields and hemispheres simultaneously
      (BILATERAL trials). There were fewer errors on RVF/LH and BILATERAL trials than
      on LVF/RH trials. Qualitative analysis of error patterns indicated that there
      were many fewer errors of first-letter identification than of last-letter
      identification, suggesting top-to-bottom scanning of the kana characters. In
      contrast to similar studies presenting nonword letter trigrams to native English
      speakers, qualitative error patterns were identical for the three visual field
      conditions. Taken together with the results of earlier studies, the results of
      the present experiment indicate that the ubiquitous RVF/LH advantage reflects a
      left-hemisphere superiority for phonetic processing that generalizes across
      specific languages. At the same time, qualitative aspects of hemispheric
      asymmetry differ from one language to the next and may depend on such things as
      the way in which individual characters map onto the pronunciation of words and
      nonwords.

PMID- 10415132
TI  - Cognitive processing of drawing abilities.
AB  - This critical review examines constructional apraxia from a cognitive
      neuropsychological perspective. To our knowledge, van Sommers (1989) is the only
      researcher to present a global cognitive model of drawing abilities. He organizes
      it into two hierarchical systems: Marr's model of visual perception and a graphic
      production system. The latter comprises four hierarchically organized components:
      depiction decisions, production strategy, contingent planning, and articulatory
      and economic constraints. Van Sommers' model will be discussed in light of other
      models and on the basis of empirical neuropsychological studies (Farah, 1984;
      Kosslyn & Koenig, 1992; Roncato, Sartori, Masterson, & Rumiati, 1987; van
      Sommers, 1989). We find that: (1) the Kosslyn and Koenig visual perception model
      describes more accurately the perceptual components underlying copying than the
      visual perception system of van Sommers' drawing model, (2) Van Sommers'
      arguments in favor of a depiction processing as opposed to visual imagery are not
      convincing, (3) Van Sommers' assumption that a production strategy is a component
      is unclear, and (4) articulatory and economic constraints are not cognitive
      components, but constraints imposed during action programming. This literature
      review leads to a discussion of future research topics and the specificity of
      constructional apraxia.

PMID- 10415133
TI  - Cerebral hemispheric mechanisms linking ambiguous word meaning retrieval and
      creativity.
AB  - The deferral of ambiguity resolution has been thought to be an important
      component of creativity. The time course of priming of dominant and subordinate
      meanings of ambiguous words was investigated using a divided visual field priming
      paradigm with subjects that varied on a measure of creativity. The Wallach-Kogan
      similarities subtest was used to group 72 subjects into three levels of verbal
      creativity to compare their performance on the ambiguity resolution task (Burgess
      & Simpson, 1988a). Results suggest that both the left and right hemispheres
      contribute to the maintenance of multiple word meanings in highly creative
      subjects, while less creative subjects show sustained subordinate priming only in
      the right hemisphere or no sustained subordinate priming. These results support
      an interactive, collaborative theory of verbal creativity (Bogen & Bogen, 1969)
      and suggest that there are important individual differences that expand on the
      basic time course model of hemispheric processing (Burgess & Simpson, 1988a).

PMID- 10415134
TI  - Cerebral organization of motor programming and verbal processing as a function of
      degree of hand preference and familial sinistrality.
AB  - Seventy-six right- and left-handed subjects responded to monaurally presented
      verbal stimuli (CVs) using their right and left hands on separate occasions. Both
      degree of hand preference and familial sinistrality (FS) were taken into account.
      It was found that, contrary to expectation, the manual response interfered with
      the verbal perception task, but only in the consistent strong handers. The
      pattern of interference suggests that those with a consistent hand preference
      (right or left) have general motor programming in the left hemisphere. Those with
      an inconsistent strong hand preference probably have some degree of general motor
      programming in both hemispheres. No effect for FS was found for the
      lateralization of verbal processing or general motor programming.

PMID- 10415135
TI  - In vitro expansion of a multipotent population of human neural progenitor cells.
AB  - The isolation and expansion of human neural progenitor cells have important
      potential clinical applications, because these cells may be used as graft
      material in cell therapies to regenerate tissue and/or function in patients with
      central nervous system (CNS) disorders. This paper describes a continuously
      dividing multipotent population of progenitor cells in the human embryonic
      forebrain that can be propagated in vitro. These cells can be maintained and
      expanded using a serum-free defined medium containing basic fibroblast growth
      factor (bFGF), leukemia inhibitory factor (LIF), and epidermal growth factor
      (EGF). Using these three factors, the cell cultures expand and remain multipotent
      for at least 1 year in vitro. This period of expansion results in a 10(7)-fold
      increase of this heterogeneous population of cells. Upon differentiation, they
      form neurons, astrocytes, and oligodendrocytes, the three main phenotypes in the
      CNS. Moreover, GABA-immunoreactive and tyrosine hydroxylase-immunoreactive
      neurons can be identified. These results demonstrate the feasibility of long-term
      in vitro expansion of human neural progenitor cells. The advantages of such a
      population of neural precursors for allogeneic transplantation include the
      ability to provide an expandable, well-characterized, defined cell source which
      can form specific neuronal or glial subtypes.

PMID- 10415137
TI  - Magnetically aligned collagen gel filling a collagen nerve guide improves
      peripheral nerve regeneration.
AB  - Bioresorbable collagen nerve guides filled with either magnetically aligned type
      I collagen gel or control collagen gel were implanted into 4- or 6-mm surgical
      gaps created in the sciatic nerve of mice and explanted 30 and 60 days
      postoperation (dpo) for histological and immunohistochemical evaluation. The
      hypothesis was that contact guidance of regenerating axons and/or invading
      nonneuronal cells to the longitudinally aligned collagen fibrils would improve
      nerve regeneration. The criterion for regeneration was observation of
      regenerating myelinated fibers distal to the nerve guide. Consistent with
      previous studies showing poor regeneration in 6-mm gaps at 60 dpo with
      entubulation repair, only one of six mice exhibited regeneration with control
      collagen gel. In contrast, four of four mice exhibited regeneration with
      magnetically aligned collagen gel, including the appearance of nerve fascicle
      formation. The numbers of myelinated fibers were less than the uninjured nerve in
      all groups, however, which may have been due to rapid resorption of the nerve
      guides. An attempt to increase the stability of the collagen gel, and thereby the
      directional information presented by the aligned collagen fibrils, by
      crosslinking the collagen with ribose before implantation proved detrimental for
      regeneration.

PMID- 10415136
TI  - Innervation and properties of the rat FDSBQ muscle: an animal model to evaluate
      voluntary muscle strength after incomplete spinal cord injury.
AB  - Muscles innervated from spinal segments close to the site of a human spinal cord
      injury are often under voluntary control but are weak because they are partially
      paralyzed and partially denervated. Our objective was to develop an animal model
      of this clinical condition to evaluate strategies to improve voluntary muscle
      strength. To do so, we examined the spinal and peripheral innervation of the
      flexor digitorum superficialis brevis quinti (FDSBQ) muscle of the rat foot,
      characterized the muscle and motor unit properties, and located the FDSBQ
      motoneurons. Retrograde labeled motoneurons were in L4 to L6 spinal cord.
      Unilateral stimulation of L4 to S1 ventral roots and recording of evoked force
      showed that FDSBQ motor axons exited via two ventral roots (L5 and L6 or L6 and
      S1) in 38% of rats and via one ventral root in 62% of rats. FDSBQ motor axons
      traveled via two peripheral nerves, the lateral plantar (76% of axons) and sural
      nerves (24%). Each ventral root contributed motor axons to each nerve branch.
      Thus, by combining conduction block of one peripheral nerve to induce partial
      muscle paralysis and ventral root section to induce partial denervation, it is
      possible to produce in one rat muscle the consequences of many human cervical
      spinal cord injuries. FDSBQ muscles and motor units were mainly fast-twitch,
      fatigable, and composed of fast-type muscle fibers. The narrow range of motor
      unit forces (1-13 mN), the low mean twitch force (5.1 +/- 0.3 mN), and the large
      number of motoneurons (31 +/- 4) suggest that rat FDSBQ muscle is a good model of
      distal human musculature which is frequently influenced by spinal cord injury. We
      conclude that the FDSBQ muscle and its innervation provide a useful animal model
      in which to study the consequences of many spinal cord injuries which spare some
      descending inputs but also induce substantial motoneuron death near the lesion.

PMID- 10415138
TI  - Cerebellar allografts survive and transiently alleviate ataxia in a transgenic
      model of spinocerebellar ataxia type-1.
AB  - Spinocerebellar ataxia type 1 (SCA-1) is one of several neurodegenerative
      diseases, including Huntington's disease, spinobulbar muscular atrophy,
      dentatorubral-pallidoluysian atrophy, and SCA-2, SCA-3, SCA-6, and SCA-7, each
      caused by an expanded number of CAG repeats in the coding region of their
      respective genes. The mechanism by which the resulting proteins are pathogenic is
      unknown. Clinical trials of neural transplants in Huntington's disease patients
      are under way. While initial reports are encouraging, definitive evidence of
      graft survival in patients despite the ongoing disease process is not possible
      with current imaging techniques. Transplants in primates have shown long-term
      survival of striatal grafts and recovery of function, but have used lesioning to
      model Huntington's phenotypically. Studies of striatal grafts in a transgenic
      mouse model of Huntington's have not yet shown a behavioral benefit. We describe
      a behavioral benefit of cerebellar grafts in a transgenic model of SCA-1 in which
      the ataxic phenotype results from expression of an expanded ataxin-1 protein.
      Mice were transplanted at an age when their ataxic phenotype is just becoming
      evident. Compared with sham-operated littermates, grafted mice showed better
      performance on multiple behavioral tests of cerebellar function. Differences
      persisted for 10 to 12 weeks posttransplant, after which there was a progressive
      decline in motor performance. At 20 weeks postsurgery, donor Purkinje cell
      survival was evident in 9 of 12 graft recipients. These results indicate that
      transplants can have behavioral benefits and grafts can survive long-term despite
      the ongoing pathological process in a brain actively expressing an expanded
      polyglutamine protein.

PMID- 10415139
TI  - Lysosomal protease inhibitors induce meganeurites and tangle-like structures in
      entorhinohippocampal regions vulnerable to Alzheimer's disease.
AB  - Lysosomal protease inhibitors induce signs of human brain aging in rat
      hippocampal slices. The present studies tested if they (1) also cause
      neurofibrillary tangles and (2) reproduce regional patterns of pathology found in
      Alzheimer's disease (AD). Slices of hippocampus plus retrohippocampal cortex were
      prepared from rats at postnatal days 6-7 and maintained for 2-5 weeks. In
      agreement with earlier studies, 6- to 12-day infusions of selective (ZPAD) or
      generalized (chloroquine) inhibitors of lysosomal proteases generated
      meganeurites of the type found in aged human cortex. Surveys and quantitative
      analyses established that the meganeurites developed almost exclusively in AD
      vulnerable regions. Antibodies against the phosphorylated tau protein in
      neurofibrillary tangles labeled thick filaments running through neurons in the
      superficial layers of entorhinal cortex in 6-day ZPAD-treated slices. The general
      appearance of the stained structures resembled that of early stage tangles. More
      mature tangle-like profiles were found at a number of sites after longer
      incubations; these were threefold more frequent in the superficial (AD
      vulnerable) than in the deep layers of the entorhinal cortex. Immunoblots
      indicated that essentially all phosphorylated tau labeling in the slices involved
      approximately 29-kDa fragments of the native isoforms. These findings establish
      that lysosomal dysfunction triggers the parallel formation of meganeurites and
      tangles with the regional distribution of both effects reflecting that for AD
      vulnerability.

PMID- 10415140
TI  - The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's
      disease from normal and pathologic aging.
AB  - The abundance and solubility of Abeta peptides are critical determinants of
      amyloidosis in Alzheimer's disease (AD). Hence, we compared levels of total
      soluble, insoluble, and total Abeta1-40 and Abeta1-42 in AD brains with those in
      age-matched normal and pathologic aging brains using a sandwich enzyme-linked
      immunosorbent assay (ELISA). Since the measurement of Abeta1-40 and Abeta1-42
      depends critically on the specificity of the monoclonal antibodies used in the
      sandwich ELISA, we first demonstrated that each assay is specific for Abeta1-40
      or Abeta1-42 and the levels of these peptides are not affected by the amyloid
      precursor protein in the brain extracts. Thus, this sandwich ELISA enabled us to
      show that the average levels of total cortical soluble and insoluble Abeta1-40
      and Abeta1-42 were highest in AD, lowest in normal aging, and intermediate in
      pathologic aging. Remarkably, the average levels of insoluble Abeta1-40 were
      increased 20-fold while the average levels of insoluble Abeta1-42 were increased
      only 2-fold in the AD brains compared to pathologic aging brains. Further, the
      soluble pools of Abeta1-40 and Abeta1-42 were the largest fractions of total
      Abeta in the normal brain (i.e., 50 and 23%, respectively), but they were the
      smallest in the AD brain (i.e., 2.7 and 0.7%, respectively) and intermediate
      (i.e., 8 and 0.8%, respectively) in pathologic aging brains. Thus, our data
      suggest that pathologic aging is a transition state between normal aging and AD.
      More importantly, our findings imply that a progressive shift of brain Abeta1-40
      and Abeta1-42 from soluble to insoluble pools and a profound increase in the
      levels of insoluble Abeta1-40 plays mechanistic roles in the onset and/or
      progression of AD.

PMID- 10415141
TI  - Guided neurite elongation and schwann cell invasion into magnetically aligned
      collagen in simulated peripheral nerve regeneration.
AB  - High-strength magnetic fields were used to align collagen gel formed into 4-mm
      diameter rods during the self-assembly of type I collagen monomers into fibrils.
      We developed an in vitro assay to study neurite elongation into the magnetically
      aligned collagen gel rods from dorsal root ganglia (DRG) explants placed onto one
      end of the rods. The depth of neurite elongation from chick embryo DRG neurons
      into these rods was found to be substantially greater than that observed in
      controls and increased with an increase in magnetic field strength, as did the
      collagen gel rod birefringence, indicative of collagen fibril alignment along the
      rod axis. Moreover, the axial bias of neurite elongation became more pronounced
      with an increase in magnetic field strength, presumably due to a contact guidance
      response of growth cones at the neurite tips. Coinvasion of Schwann cells from
      neonatal rat DRG was also studied in these assays using double immunolabeling. In
      the absence of serum, Schwann cells were highly associated with, and often
      trailed, elongating neurites. In the presence of serum, Schwann cells showed
      significantly higher rates of invasion and formed axially aligned chords
      reminiscent of bands of Bungner. These results may translate into an improved
      method of entubulation repair of transected peripheral nerves by directing and
      stimulating axonal growth through a tube filled with magnetically aligned
      collagen gel.

PMID- 10415142
TI  - Depletion of hematogenous macrophages promotes partial hindlimb recovery and
      neuroanatomical repair after experimental spinal cord injury.
AB  - Traumatic injury to the spinal cord initiates a series of destructive cellular
      processes which accentuate tissue damage at and beyond the original site of
      trauma. The cellular inflammatory response has been implicated as one mechanism
      of secondary degeneration. Of the various leukocytes present in the spinal cord
      after injury, macrophages predominate. Through the release of chemicals and
      enzymes involved in host defense, macrophages can damage neurons and glia.
      However, macrophages are also essential for the reconstruction of injured
      tissues. This apparent dichotomy in macrophage function is further complicated by
      the overlapping influences of resident microglial-derived macrophages and those
      phagocytes that are derived from peripheral sources. To clarify the role
      macrophages play in posttraumatic secondary degeneration, we selectively depleted
      peripheral macrophages in spinal-injured rats during a time when inflammation has
      been shown to be maximal. Standardized behavioral and neuropathological analyses
      (open-field locomotor function, morphometric analysis of the injured spinal cord)
      were used to evaluate the efficacy of this treatment. Beginning 24 h after injury
      and then again at days 3 and 6 postinjury, spinal cord-injured rats received
      intravenous injections of liposome-encapsulated clodronate to deplete peripheral
      macrophages. Within the spinal cords of rats treated in this fashion, macrophage
      infiltration was significantly reduced at the site of impact. These animals
      showed marked improvement in hindlimb usage during overground locomotion.
      Behavioral recovery was paralleled by a significant preservation of myelinated
      axons, decreased cavitation in the rostrocaudal axis of the spinal cord, and
      enhanced sprouting and/or regeneration of axons at the site of injury. These data
      implicate hematogenous (blood-derived) macrophages as effectors of acute
      secondary injury. Furthermore, given the selective nature of the depletion
      regimen and its proven efficacy when administered after injury, cell-specific
      immunomodulation may prove useful as an adjunct therapy after spinal cord injury.

PMID- 10415143
TI  - Nitric oxide synthase inhibition delays axonal degeneration and promotes the
      survival of axotomized retinal ganglion cells.
AB  - Nitric oxide (NO) synthesized by inducible nitric oxide synthase (iNOS) has been
      implicated in neuronal cytotoxicity following trauma to the central nervous
      system. The aim of the present study was to examine the role of NO in mediating
      axotomy-induced retinal ganglion cell (RGC) death. We observed increases in iNOS
      expression by microglia and Muller cells in the retina after optic nerve
      transection. This was paralleled by the induced expression of constitutive NOS
      (cNOS) in RGCs which do not normally express this enzyme. In order to determine
      if NO is cytotoxic to axotomized RGCs, the nonspecific NOS inhibitors Nomega
      nitro-L-arginine (NOLA) or N-nitro-L-arginine methyl ester (L-NAME) were
      delivered to the vitreous chamber by intraocular injections. Both NOLA and L-NAME
      significantly enhanced RGC survival at 7, 10, and 14 days postaxotomy. The
      separate contributions of iNOS and cNOS to RGC degeneration were examined with
      intraocular injections of the specific iNOS inhibitor L-N(6)-(I-iminoethyl)lysine
      hydrochloride or the specific cNOS inhibitor L-thiocitrulline. Our results
      suggest that cNOS plays a greater role in RGC degeneration than iNOS. In addition
      to enhancing RGC survival, NOS inhibitors delayed the retrograde degeneration of
      RGC axons after axotomy. We conclude that NO synthesized by retinal iNOS and cNOS
      plays a major role in RGC death and retrograde axonal degeneration following
      axotomy.

PMID- 10415144
TI  - The effects of FK506 on dorsal column axons following spinal cord injury in adult
      rats: neuroprotection and local regeneration.
AB  - There is considerable evidence that immunophilin ligands can promote the
      regeneration of axons in peripheral nerves and act as neuroprotective agents in
      the CNS. We have examined the effects of FK506 and GPI 1046 on the responses to
      partial transection of ascending spinal dorsal column axons at T9, in some cases
      combined with crush of one sciatic nerve. FK506 (0.5 or 2.0 mg/kg) and GPI 1046
      (10 or 40 mg/kg) was administered subcutaneously immediately after surgery and
      five times a week thereafter. Some animals received methylprednisolone (MP) (two
      subcutaneous doses of 30 mg/kg) in addition to, or instead of, FK506. After
      survival times of 1-12 weeks, dorsal column axons were labeled
      transganglionically with cholera toxin B-HRP. There was massive axonal sprouting
      at the lesion sites in animals with sciatic nerve injury and immunophilin ligand
      treatment. In FK506-treated animals a few severed sensory axons regenerated for
      up to 10 mm rostral to the lesion. Of greater significance, 30% of 71 FK506
      treated animals had spared axons in the dorsal column, extending to the nucleus
      gracilis, versus 8% of 50 control animals (P < 0.05), showing that FK506 reduces
      the likelihood of axonal destruction due to secondary injury. A combination of
      FK506 and MP afforded greater protection than MP alone (P < 0.05), but axonal
      survival was not affected by sciatic nerve crush, dose of FK506, or survival time
      after injury. GPI 1046 (n = 11) did not promote axonal survival. Thus FK506
      protects axons from secondary injury following spinal cord trauma, and in this
      experimental model, its neuroprotective effect is greater than that of MP.

PMID- 10415146
TI  - Alzheimer's disease and down syndrome: from meiosis to dementia.
AB  - Several molecular and clinical similarities have been detected in Alzheimer's
      disease (AD) and Down syndrome (DS). The most remarkable feature is abnormal
      accumulation of beta-amyloid in the brains of both individuals affected with AD
      and aging DS patients followed by dementia. In addition, AD patients exhibit
      dermatoglyphic patterns similar to those in DS, and late maternal age is a risk
      factor in both diseases. AD and DS could be related genetically because AD
      families exhibit a higher rate of DS cases and vice versa. Although numerous
      discoveries have been made in the elucidation of the etiopathogenic factors in AD
      and DS, little progress has been achieved in understanding the origin of the
      common features of the two diseases. This article reviews clinical and molecular
      similarities in DS and AD and also chromosome 21 studies in both diseases. A new
      hypothesis explaining the association between AD and DS is suggested, and this
      hypothesis is based on the poorly understood molecular phenomenon of aberrant
      meiotic recombination. Aberration in meiotic recombination has been consistently
      detected in chromosomal diseases including trisomy 21 and sex chromosomes. There
      are no studies dedicated to meiotic recombination in genetic diseases; however,
      evidence for disturbed recombination has been documented in several neurological
      diseases such as Huntington's disease, myotonic dystrophy, and fragile X
      syndrome. Interestingly, the rate of trisomic XXY children born to mothers
      transmitting fragile X mutation is higher than expected. This finding suggests
      that AD could be associated with DS in a similar way to which fragile X syndrome
      is related to trisomy of sex chromosomes. Based on analogy with fragile X
      syndrome, it can be predicted that AD should demonstrate aberrant meiotic
      recombination in chromosome 21, most likely in the region D21S1/S11-D21S16 which
      is linked to early onset familial AD. Based on the same rationale, different
      patterns of meiotic recombination in the nondisjunct chromosome 21 within DS
      patients grouped according to the concomitant disease are predicted.

PMID- 10415145
TI  - The effects of mitotic inhibition on the spinal cord response to the superimposed
      injuries of spinal cord hemisection and peripheral axotomy.
AB  - The present study was carried out to test the hypothesis that dividing microglia
      are responsible for the depression of crossed phrenic nerve activity documented
      at 2 weeks postphrenicotomy in an injury model which superimposes the effects of
      spinal cord injury on peripheral axotomy. Crossed phenic nerve activity is
      defined as the respiratory activity recorded from the phrenic nerve during the
      crossed phrenic phenomenon (CPP) which is a respiratory reflex induced by
      respiratory stress following an ispsilateral spinal cord hemisection. Young adult
      female Sprague-Dawley rats were subjected to left intrathoracic phrenicotomies.
      Cytarabine (Cyt-A, a powerful antimitotic drug) or saline-filled miniosmotic
      pumps were then implanted into the cisterna magna and 2 weeks were allowed to
      pass at which time the CPP was induced by a left C2 spinal cord hemisection and
      transection of the contralateral phrenic nerve. Control studies including
      bromodeoxyuridine labeling of mitotic cells and a triple immunofluorescent
      protocol were carried out to verify that microglial cells were the primary cell
      type undergoing mitosis in the current injury model and that Cyt-A completely
      inhibited cellular proliferation. Quantitative electrophysiological analysis of
      crossed phrenic nerve activity showed that there is a statistically significant
      depression of activity at 2 weeks postphrenicotomy when animals were infused with
      saline compared to controls. Crossed phrenic nerve activity levels were not
      significantly different, however, from control levels when 2-week
      postphrenicotomized rats were infused with Cyt-A. Immunofluorescent studies
      showed that the majority of cells dividing in response to phrenicotomy were
      microglia. Furthermore, there were no astrocytes seen dividing at any time. From
      the results, we conclude that activated microglial cells may be responsible for
      the depression in crossed phrenic activity normally seen 2 weeks
      postphrenicotomy. Further, the activation of microglia may be related to the
      astrocytic response to injury. The activated microglial cell may be acting as a
      coordinator of various aspects of the injury response. Alternatively, the
      activation of microglia may be a necessary step in the cascade of multiple events
      that take place in the spinal cord after injury.

PMID- 10415147
TI  - Nicotine alone and in combination with L-DOPA methyl ester or the D(2) agonist N
      0923 in MPTP-induced chronic hemiparkinsonian monkeys.
AB  - Nicotine, the soluble methyl ester of L-DOPA, and the D(2) agonist N-0923 were
      given alone and in combination im to five hemiparkinsonian monkeys. Daily
      nicotine in doses of 32-320 micrograms/kg for 6 days each, surprisingly, had
      slight effects on motor activity. When combined with N-0923, nicotine did not
      further enhance its effects. However, L-DOPA methyl ester plus nicotine produced
      greater contraversive circling than L-DOPA methyl ester plus 0.9% NaCl. Similar
      effects were obtained on significant motor movements of both the affected
      (contralateral) and normal (ipsilateral) arm and hand. The results indicate that
      nicotine is synergistic with l-DOPA methyl ester, but not with the postsynaptic
      D(2) agonist N-0923.

PMID- 10415148
TI  - Methionine adenosyltransferase activity in erythrocytes and spinal cord of
      patients with sporadic amyotrophic lateral sclerosis.
AB  - The role of transmethylation mechanisms in the etiology of amyotrophic lateral
      sclerosis (ALS) is hitherto unexplored. The activity of L-methionine S
      adenosyltransferase (MAT), a regulatory enzyme of S-adenosylmethionine
      biosynthesis, was investigated in erythrocytes of 21 patients with ALS, spinal
      cord specimens of 7 ALS patients, and matched controls. In ALS patients the
      activity of MAT in erythrocytes was sex-dependent. In comparison with controls,
      the male group presented a 33% higher V(max) (P < 0.05) and a 41% decrease in the
      affinity of MAT for methionine (K(m), P < 0.05). The type of ALS onset (limb or
      bulbar), age, or duration of the disease did not influence erythrocyte MAT
      activity. In the spinal cord, the activity of MAT was homogeneously distributed
      through dorsal horn, ventral horn, and white matter. Comparisons between data
      from controls and ALS patients and analysis of sex effect showed no significant
      differences. The kinetic difference of erythrocyte MAT in the male group of ALS
      patients might be interesting to explore since it is well known that there is a
      male predominance of 1.5 to 2. 5:1 in ALS.

PMID- 10415149
TI  - Overproduction of Cu/Zn-superoxide dismutase or Bcl-2 prevents the brain
      mitochondrial respiratory dysfunction induced by glutathione depletion.
AB  - Recent work has focused attention on the role of oxidative stress in various
      acute and chronic neurodegenerative diseases. Low concentrations of the powerful
      antioxidant glutathione (GSH) and impaired brain energy metabolism, particularly
      in the substantia nigra, are key features of Parkinson's disease (PD). The main
      goal of this study was to better characterize the deleterious effects of brain
      GSH depletion on mitochondrial function. We depleted GSH in the brains of newborn
      wild-type (WT) and transgenic (Tg) mice overproducing either human Cu/Zn
      superoxide dismutase (h-CuZnSOD) or human Bcl2 (h-Bcl-2), by subcutaneous
      injection of l-buthionine sulfoximine (BSO), a specific inhibitor of gamma
      glutamylcysteine synthetase. GSH was 97% depleted in brain homogenates and 90%
      depleted in brain mitochondria for both WT and Tg mice. This depletion of brain
      GSH led to a decrease in the activity of the GSH-dependent antioxidant enzyme
      glutathione peroxidase, both in WT and in Tg animals. BSO treatment decreased the
      activities of respiratory complexes I, II, and IV in the brain homogenates of WT
      mice. BSO-treated h-CuZnSOD or h-Bcl-2 Tg mice had no respiratory chain
      deficiencies. Thus, brain GSH depletion leads to the impairment of mitochondrial
      respiratory chain activity. The protection of mitochondrial respiratory function
      by overproduction of Bcl-2 may result from a decrease in the generation of
      reactive oxygen species (ROS) or lipid peroxidation. The protection of
      mitochondria by overproduction of CuZnSOD is consistent with the involvement of
      superoxide or superoxide-derived ROS in the mitochondrial dysfunction caused by
      brain GSH depletion. This study demonstrates that the antioxidant balance is
      critical for maintenance of brain mitochondrial function, and its disruption may
      contribute to the pathogenesis of PD.

PMID- 10415150
TI  - Morphological development of beta(1-40) amyloid fibrils.
AB  - The Alzheimer's disease-related peptide beta(1-40) amyloid self-associates to
      form fibrils exhibiting a morphology characteristic of amyloidogenic proteins.
      The mechanism of this fibrillization process has yet to be fully elucidated. In
      this study we have immobilized the beta(1-40) amyloid to flat gold surfaces using
      thiol-based self-assembled monolayers. Atomic force microscopy reveals the
      presence of spherical units of beta(1-40) amyloid immediately following the
      initiation of fibrillization. Short fibrillar structures, termed nascent fibrils,
      which appear to be formed by the association of these units are also present at
      this time point. At later time points extended, branching networks of fibrils are
      observed. Some fibrils exhibit a more beaded appearance and greater axial
      periodicity than others. No nascent fibrils are seen to be present. We believe
      that these data identify an early fibril structure which could act as an
      intermediate in beta-amyloid fibrillization. The oligomeric units of which these
      nascent fibrils are comprised are also determined.

PMID- 10415151
TI  - Postischemic hypothermia and IL-10 treatment provide long-lasting neuroprotection
      of CA1 hippocampus following transient global ischemia in rats.
AB  - Experimental studies have demonstrated that postischemic therapeutic
      interventions may delay rather than provide long-lasting neuroprotection. The
      purpose of this study was to determine whether mild hypothermia (33-34 degrees C)
      combined with the anti-inflammatory cytokine interleukin-10 (IL-10) would protect
      the CA1 hippocampus 2 months after ischemia. Rats were subjected to 12.5 min of
      normothermic (37 degrees C) forebrain ischemia by two-vessel occlusion followed
      immediately by: (a) 4 h of normothermic (37 degrees C) reperfusion (n = 5); (b) 4
      h of postischemic hypothermia (33-34 degrees C) (n = 5); (c) 4 h of normothermia
      plus IL-10 (5 micrograms) treatment 30 min after ischemia and at 3 days (n = 5);
      or (d) 4 h of hypothermia plus IL-10 treatment (n = 5). Rats survived for 2
      months and were perfusion fixed for quantitative histopathological assessment of
      CA1 hippocampus. Postischemic normothermia and hypothermia, as well as
      normothermia plus IL-10 treatment led to severe damage of the CA1 hippocampus. In
      contrast, the combined treatment of hypothermia with IL-10 treatment improved
      overall neuronal survival by 49% compared to normothermic ischemia (P < 0.01).
      These data emphasize the detrimental consequences of secondary inflammatory
      responses on ischemic neuronal damage after transient global ischemia. In
      postinjury settings where restricted durations of mild hypothermia can be
      induced, anti-inflammatory treatments, including IL-10, may promote chronic
      neuroprotection.

PMID- 10415152
TI  - Reduced high-affinity agonist binding at the M(1) muscarinic receptor in
      Alzheimer's disease brain: differential sensitivity to agonists and divalent
      cations.
AB  - M(1) muscarinic acetylcholine receptor (M(1)AchR)-G protein coupling, as measured
      by high-affinity agonist binding, was examined in membranes prepared from
      postmortem human temporal cortex (Brodmann area 38) from individuals with
      Alzheimer's disease (AD, n = 8) and age-matched controls (n = 6). Binding
      competitions between the M(1)AchR-selective antagonist [(3)H]pirenzepine
      ([(3)H]PZ) and muscarinic agonists carbachol, acetylcholine, oxotremorine, and
      oxotremorine M were conducted. In the presence of 1 mM MgCl(2), the inhibition of
      [(3)H]PZ binding by carbachol, acetylcholine, or oxotremorine M was best
      described by a two-affinity state model for control and AD cases, while
      oxotremorine binding affinity was best fit to a single-state model. Although both
      control and AD groups had similar K(D) values for the high- and low-affinity
      agonist binding sites, the proportion of M(1)AchRs exhibiting high affinity for
      carbachol and acetylcholine was reduced by 48 and 33%, respectively, in AD
      membranes relative to controls (P < 0.05). No changes in the binding of the
      oxotremorine M or oxotremorine were noted. The nonhydrolyzable guanine nucleotide
      GppNHp (100 microM) reduced the proportion of M(1)AchRs with high affinity for
      agonists in both control and AD membranes. Substitution of 1 mM MnCl(2) for
      MgCl(2) restored high-affinity carbachol binding at the M(1)AchR in AD membranes
      similar to that seen in controls. In the presence of 1 mM MnCl(2), agonist
      binding in controls did not differ from 1 mM MgCl(2). In the absence of cations
      (1 mM EDTA), no differences between control and AD M(1)AchR carbachol binding
      were observed. Thus, the loss of high-affinity agonist binding at the M(1)AchR in
      AD is dependent on the agonist and cation studied.

PMID- 10415153
TI  - IL-6 deficiency causes enhanced pathology in Twitcher (globoid cell
      leukodystrophy) mice.
AB  - The expression of IL-6 is greatly enhanced in the twitcher mouse (S. M. LeVine
      and D. C. Brown, 1997, J. Neuroimmunol. 73, 47-56), which is an authentic animal
      model of globoid cell leukodystrophy (Krabbe's disease). In order to investigate
      the role of IL-6 in this disease, twitcher/IL-6-deficient mice were generated and
      the pathology was compared between them and regular twitcher mice. Twitcher/IL-6
      deficient mice had a more severe disease than regular twitcher mice: they had an
      earlier onset day of twitching, a greater number of PAS-positive cells, a greater
      susceptibility to LPS, an exaggerated gliotic response around some vessels, an
      elevated level of TNF-alpha, and a compromised blood-brain barrier, which was
      evaluated by three independent measures. This latter finding indicates that IL-6
      plays a role in maintaining the integrity of the BBB, and it raises the
      possibility that IL-6 functions in a similar manner in other diseases of the CNS.
      LPS was found to greatly shorten the life of twitcher and twitcher/IL-6-deficient
      mice compared to genotyped-matched saline-injected mice. This result indicates
      that a proinflammatory condition can exacerbate an underlying CNS pathology,
      which could help explain why some leukodystrophy patients display their initial
      symptoms following a fever or blow to the head.

PMID- 10415154
TI  - Entorhinal cortex beta-amyloid load in individuals with mild cognitive
      impairment.
AB  - The deposition of beta-amyloid within the entorhinal cortex (EC) may play a key
      role in the development of mild cognitive impairment (MCI) in the elderly. To
      examine the relationship of beta-amyloid deposition to MCI, EC tissue
      immunostained for this protein was quantitated from a cohort of aged Catholic
      religious clergy with a clinical diagnosis of MCI and compared to those with no
      cognitive impairment (NCI) and Alzheimer's disease (AD). beta-amyloid staining
      was seen in 12 of the 20 NCI, in 10 of 12 MCI, and in all 12 AD cases within the
      EC. beta-amyloid immunoreactivity displayed two patterns within the EC: (1) a
      crescent-shaped band within layers 3-4 or (2) bilaminar staining mainly within
      layers 2-3 and 5-6. Ten cases failed to display any detectable beta-amyloid
      imunoreactivity. Despite the heterogeneity of beta-amyloid loads within the
      clinical groups, decomposing an analysis of variance revealed a significant
      difference across groups in mean beta-amyloid load within the EC based upon a
      linear trend analysis. Multiple comparisons testing revealed that NCI individuals
      had a significantly lower mean beta-amyloid load (1.32) than AD individuals
      (4.55). The MCI individuals had a mean intermediate (2.60) load between NCI and
      AD, but not statistically distinguishable from the mean for either NCI or AD.
      Spearman rank correlation showed a trend for decreasing MMSE with increasing
      amyloid load that failed to reach statistical significance. Since many NCI cases
      displayed beta-amyloid loads equal to or greater than that seen in some MCI and
      some AD cases, it is mostly likely that deposition of this protein is not the
      sole pathogenic event underlying cognitive impairment in the elderly.

PMID- 10415155
TI  - Vulnerability of the dentate gyrus to aging and intracerebroventricular
      administration of kainic acid.
AB  - The hippocampal formation is highly vulnerable to the aging process,
      demonstrating functional alterations in circuitry with aging. Aging may also
      change the sensitivity of the hippocampal formation to excitotoxic lesions. In
      this study, using young adult, middle aged, and aged Fischer 344 rats, we
      evaluated morphometric changes in the dentate gyrus as a function of age and also
      in response to an administration of an excitotoxin (kainic acid) into the right
      lateral ventricle. The dentate gyrus was measured for changes in the area of
      dentate hilus and the dentate granule cell layer, alterations in the width of the
      dentate granule cell layer, and degree of dentate hilar cell loss. With aging,
      the hilar area increased in size while the area and width of the dentate granule
      cell layer remained constant. However, the most striking change with aging was a
      significant reduction in the number of dentate hilar neurons.
      Intracerebroventricular kainic acid produced consistent lesions in the entire
      ipsilateral CA3 region, and the size of CA3 lesion was identical in all three
      ages of animals. Following the lesion, areas of both the dentate hilus and the
      granule cell layer were significantly decreased in only young adult and middle
      aged animals whereas the width of the dentate granule cell layer was
      significantly increased only in the middle aged group. In contrast, dentate hilar
      neurons were significantly reduced in all ages of animals with the maximum
      reductions in neuron number observed in the aged group. Thus, aging in the
      dentate gyrus is characterized by a significantly decreased number of dentate
      hilar neurons and also a significantly increased susceptibility of dentate hilar
      neurons to excitotoxic damage.

PMID- 10415158
TI  - Georgetown University Medical Center: Lombardi Cancer Center.

PMID- 10415156
TI  - Expression of neurturin, GDNF, and GDNF family-receptor mRNA in the developing
      and mature mouse.
AB  - The GDNF family of neurotrophic factors currently has four members: neurturin
      (NRTN), glial cell line-derived neurotrophic factor (GDNF), persephin, and
      artemin. These proteins are potent survival factors for several populations of
      central and peripheral neurons. The receptors for these factors are complexes
      that include the Ret tyrosine kinase receptor and a GPI-linked, ligand-binding
      component called GDNF family receptor alpha 1-4 (GFRalpha1-4). We have used in
      situ hybridization to study the mRNA expression of NRTN, GDNF, Ret, GFRalpha1,
      and GFRalpha2 during embryonic development and in the adult mouse. GDNF receptors
      were prominently expressed during embryonic development in the nervous system,
      the urogenital system, the digestive system, the respiratory system, and in
      developing skin, bone, muscle, and endocrine glands. In some regions, incomplete
      receptor complexes were expressed suggesting that other, as yet unidentified,
      receptor components exist or that receptor complexes are formed in trans. NRTN
      and GDNF were expressed in many trigeminal targets during embryonic development
      including the nasal epithelium, the teeth, and the whisker follicles. NRTN and
      GDNF were also expressed in the developing limbs and urogenital system. In the
      embryo, GDNF factors and receptors were expressed at several sites of
      mesenchyme/epithelial induction, including the kidney, tooth, and submandibular
      gland. This expression pattern is consistent with the possibility that the GDNF
      factors function in inductive processes during embryonic development and with the
      recently discovered role of NRTN as a necessary trophic factor for the
      development of some parasympathetic neurons. In the mature animal, receptor
      expression was more limited than in the embryo. In the adult mouse, NRTN was most
      prominently expressed in the gut, prostate testicle, and oviduct; GDNF was most
      prominently expressed in the ovary.

PMID- 10415157
TI  - Activated astrocytes display increased 5-HT2a receptor expression in pathological
      states.
AB  - In human brain tissues from patients dying with cerebral infarction, hypertensive
      encephalopathy, Alzheimer's disease, Huntington's disease, frontotemporal
      dementia, and Creutzfeldt-Jakob disease there is an activation of astrocytes.
      Such activated astrocytes display GFAP and strong 5-HT(2A), but not 5-HT(2B) or 5
      HT(2C), receptor immunoreactivity; this 5-HT(2A) reaction has not been observed
      in normal, nonactivated astrocytes. It is suggested that an up-regulation of 5
      HT(2A) receptors may be part of an early response reaction in astrocytes,
      possibly designed to maintain homeostasis or to induce secondary message pathways
      involving trophic factors or glycogenolysis.

PMID- 10415159
TI  - Natural responses to unnatural materials: A molecular mechanism for foreign body
      reactions.

PMID- 10415161
TI  - Regulation of macrophage migration inhibitory factor (MIF) expression by glucose
      and insulin in adipocytes in vitro.
AB  - BACKGROUND: It has been reported that macrophage migration inhibitory factor
      (MIF) stimulated insulin secretion from pancreatic islet beta-cells in an
      autocrine manner, which suggests its pivotal role in the glucose metabolism.
      According to this finding, we evaluated MIF expression in cultured adipocytes and
      epididymal fat pads of obese and diabetic rats to investigate its role in adipose
      tissue. MATERIALS AND METHODS: The murine adipocyte cell line 3T3-L1 was used to
      examine MIF mRNA expression and production of MIF protein in response to various
      concentrations of glucose and insulin. Epididymal fat pads of Otsuka Long-Evans
      Tokushima fatty (OLETF) and Wistar fatty rats, animal models of obesity and
      diabetes, were subjected to Northern blot analysis to determine MIF mRNA levels.
      RESULTS: MIF mRNA of 3T3-L1 adipocytes was up-regulated by costimulation with
      glucose and insulin. Intracellular MIF content was significantly increased by
      stimulation, whereas its content in the culture medium was decreased. When the
      cells were treated with cytochalasin B, MIF secretion in the medium was
      increased. Pioglitazone significantly increased MIF content in the culture medium
      of 3T3-L1 cells. However, MIF mRNA expression of both epididymal fat pads of
      OLETF and Wistar fatty rats was down-regulated despite a high plasma glucose
      level. The plasma MIF level of Wistar fatty rats was significantly increased by
      treatment with pioglitazone. CONCLUSION: We show here that the intracellular
      glucose level is critical to determining the MIF mRNA level as well as its
      protein content in adipose tissue. MIF is known to play an important role in
      glucose metabolism as a positive regulator of insulin secretion. In this context,
      it is conceivable that MIF may affect the pathophysiology of obesity and
      diabetes.

PMID- 10415162
TI  - Loss of NF-kappaB activity during cerebral ischemia and TNF cytotoxicity.
AB  - Recent evidence implicates tumor necrosis factor (TNF), a cytokine with both
      cytotoxic and cytoprotective activities, in the pathogenesis of cerebral
      ischemia. The development of TNF cytotoxicity is dependent upon the balance
      between the activities of intracellular signaling pathways that mediate either
      apoptotic or anti-apoptotic effects. One critical protective signaling mechanism
      is the activation of nuclear factor (NF)-kappaB, a ubiquitous transcription
      factor that regulates expression of anti-apoptotic gene products. Here we show
      the distribution and kinetics of NF-kappaB activation and the correlation between
      loss of NF-kappaB activity, TNF up-regulation, and apoptosis in a standardized
      rat model of focal cerebral ischemia. We observed a rapid and progressive
      ischemia-induced loss of p65 immunoreactivity within the ischemic core and nearby
      penumbra. These findings were confirmed by Western blot analysis of nuclear
      extracts and by electrophoretic mobility shift assay. The anatomical area of
      suppressed NF-kappaB activity overlapped significantly with the zones of TNF
      overexpression and apoptosis. Loss of NF-kappaB activity and increased TNF
      expression preceded the onset of cell death. Direct evidence that loss of NF
      kappaB activity can sensitize brain cells to TNF cytotoxicity was obtained in
      vitro by co-administration of MG-132, an inhibitor of NF-kappaB activation, and
      TNF to neuronal-like and glial-like cell cultures. Inhibition of NF-kappaB
      significantly increased the sensitivity of these cultures to TNF cytotoxicity,
      indicating that the observed loss of neuronal NF-kappaB activity during cerebral
      ischemia can participate in the development of TNF-induced cytotoxicity.

PMID- 10415163
TI  - TNF-alpha induces actin cytoskeleton reorganization in glomerular epithelial
      cells involving tyrosine phosphorylation of paxillin and focal adhesion kinase.
AB  - Glomerular permeability for macromolecules depends partially on proper attachment
      of the glomerular epithelial cells (GEC) to the glomerular basement membrane
      (GBM). The latter requires integrity of the actin cytoskeleton, which in turn is
      regulated by specific actin-associated proteins. Since several glomerulopathies
      characterized by heavy proteinuria are associated with increased glomerular tumor
      necrosis factor alpha (TNF-alpha) expression, we studied the interaction of TNF
      alpha with the actin cytoskeleton of cultured rat GEC. Incubation of GEC with 10
      ng/ml TNF-alpha for variable time periods ranging from 15 min to 24 hr
      demonstrated a marked accentuation and redistribution of actin microfilaments, as
      shown by direct fluorescence analysis and confocal laser scanning microscopy.
      Quantitative biochemical determination of the G/total-actin ratio confirmed the
      above observations. Indeed, this ratio was significantly reduced, indicating
      substantial polymerization of G-actin and formation of F-actin. Concurrently, TNF
      alpha rapidly induced tyrosine phosphorylation of both paxillin and focal
      adhesion kinase, without affecting the expression levels of these two proteins.
      In addition, tyrosine phosphorylation of vinculin became evident, indicating
      involvement of this focal adhesion marker in the observed actin reorganization.
      Inhibition of tyrosine phosphorylation by genistein prevented the reorganization
      of the actin cytoskeleton by TNF-alpha. We conclude that TNF-alpha induces
      substantial reorganization of actin cytoskeleton and focal adhesions. These
      effects occur simultaneously, with a prompt TNF-alpha-induced tyrosine
      phosphorylation of paxillin and focal adhesion kinase, indicating that these
      proteins, known to regulate actin polymerization and formation of focal
      adhesions, may be directly involved in the mechanism controlling the observed
      actin redistribution. These findings suggest that the observed TNF-alpha-actin
      cytoskeleton interactions may relate to the pathogenesis of glomerulopathies with
      heavy proteinuria, in which increased glomerular expression of TNF-alpha is
      associated with disturbances in the attachment of podocytes to the GBM.

PMID- 10415164
TI  - Detection of noncarboxymethyllysine and carboxymethyllysine advanced glycation
      end products (AGE) in serum of diabetic patients.
AB  - BACKGROUND: The advanced stage of the Maillard reaction, which leads to the
      formation of advanced glycation end products (AGE), plays an important role in
      the pathogenesis of angiopathy in diabetic patients and in the aging process.
      N(epsilon)-(carboxymethyl)lysine (CML) is thought to be an important epitope for
      many of currently available AGE antibodies. However, recent findings have
      indicated that a major source of CML may be by pathways other than glycation. A
      distinction between CML and non-CML AGE may increase our understanding of AGE
      formation in vivo. In the present study, we prepared antibodies directed against
      CML and non-CML AGE. MATERIALS AND METHODS: AGE-rabbit serum albumin prepared by
      4, 8, and 12 weeks of incubation with glucose was used to immunize rabbits, and a
      high-titer AGE-specific antiserum was obtained without affinity for the carrier
      protein. To separate CML and non-CML AGE antibodies, the anti-AGE antiserum was
      subjected to affinity chromatography on a column coupled with AGE-BSA and CML
      BSA. Two different antibodies were obtained, one reacting specifically with CML
      and the other reacting with non-CML AGE. Circulating levels of CML and non-CML
      AGE were measured in 66 type 2 diabetic patients without uremia by means of the
      competitive ELISA. Size distribution and clearance by hemodialysis detected by
      non-CML AGE and CML were assessed in serum from diabetic patients on
      hemodialysis. RESULTS: The serum non-CML AGE level in type 2 diabetic patients
      was significantly correlated with the mean fasting blood glucose level over the
      previous 2 months (r = 0.498, p < 0.0001) or the previous 1 month (r = 0.446, p =
      0. 0002) and with HbA(1c) (r = 0.375, p = 0.0019), but the CML AGE level was not
      correlated with these clinical parameters. The CML and non-CML AGE were detected
      as four peaks with apparent molecular weights of 200, 65, 1.15, and 0.85 kD. The
      hemodialysis treatment did not affect the high-molecular-weight protein
      fractions. Although the low-molecular-weight peptide fractions (absorbance at 280
      nm and fluorescence) were decreased by hemodialysis, there was no difference
      before and after dialysis in the non-CML AGE- and CML-peptide fractions (1.15 and
      0.85 kD fractions). CONCLUSIONS: We propose that both CML and non-CML AGE are
      present in the blood and that non-CML AGE rather than CML AGE should be more
      closely evaluated when investigating the pathophysiology of AGE-related diseases.

PMID- 10415167
TI  - Mechanisms of dominance: coexistence of picocyanobacterial genotypes in a
      freshwater ecosystem 
AB  - The autotrophic picoplankton of the pelagic zone of the mesotrophic Lake
      Constance is dominated by phycoerythrin-rich unicellular cyanobacteria
      phylogenetically related to the marine Synechococcus and Prochlorococcus cluster.
      In Lake Constance, the abundance of picocyanobacteria shows a recurrent pattern
      of seasonal variations. Evidence of diverse subpopulations was obtained by
      electron-microscopic examination of natural water samples and isolated strains
      that unveiled different surface structures of picocyanobacteria. Further evidence
      was obtained by DNA analysis of 26 clonal isolates representing 12 different
      genotypes. Variations in light and nutrient supply revealed distinct abilities of
      the genetically different strains to cope with these stress situations.
      Furthermore, cultured heterotrophic nanoflagellates exhibited differential
      feeding preferences for certain Synechococcus strains. The findings imply that
      growth and loss rates of the natural cyanobacterial community may be influenced
      by its genetic composition. Phylogenetic analyses of isolated strains indicated
      that the physiological diversification of pelagic Synechococcus spp. has occurred
      during a recent adaptive radiation. An example for genetic mechanisms underlying
      physiological diversification is indicated by mobile DNA elements found in a
      Synechocystis strain also isolated from the pelagic zone of Lake Constance. The
      observations suggest that dominance of Synechococcus spp. was achieved by
      evolutionary adaptation and coexistence of numerous genotypes generating a
      physiologically highly diversified population.

PMID- 10415165
TI  - Differences in proteinase K resistance and neuronal deposition of abnormal prion
      proteins characterize bovine spongiform encephalopathy (BSE) and scrapie strains.
AB  - Prion diseases are associated with the accumulation of an abnormal isoform of
      host-encoded prion protein (PrP(Sc)). A number of prion strains can be
      distinguished by "glycotyping" analysis of the respective deposited PrP(Sc)
      compound. In this study, the long-term proteinase K resistance, the molecular
      mass, and the localization of PrP(Sc) deposits derived from conventional and
      transgenic mice inoculated with 11 different BSE and scrapie strains or isolates
      were examined. Differences were found in the long-term proteinase K resistance
      (50 microg/ml at 37 degrees C) of PrP(Sc). For example, scrapie strain Chandler
      or PrP(Sc) derived from field BSE isolates were destroyed after 6 hr of exposure,
      whereas PrP(Sc) of strains 87V and ME7 and of the Hessen1 isolate were extremely
      resistant to proteolytic cleavage. Nonglycosylated, proteinase K-treated PrP(Sc)
      of BSE isolates and of scrapie strain 87V exhibited a 1-2 kD lower molecular mass
      than PrP(Sc) derived from all other scrapie strains and isolates. With the
      exception of strain 87V, PrP(Sc) was generally deposited in the cerebrum,
      cerebellum, and brain stem of different mouse lines at comparable levels. Long
      term proteinase resistance, molecular mass, and the analysis of PrP(Sc)
      deposition therefore provide useful criteria in discriminating prion strains and
      isolates (e.g., BSE and 87V) that are otherwise indistinguishable by the PrP(Sc)
      "glycotyping" technique.

PMID- 10415168
TI  - Two modes of sulfite oxidation in the extremely thermophilic and acidophilic
      archaeon acidianus ambivalens 
AB  - Sulfite-oxidizing enzyme activities were analyzed in cell-free extracts of
      aerobically grown cells of Acidianus ambivalens, an extremely thermophilic and
      chemolithoautotrophic archaeon. In the membrane and cytoplasmic fractions, two
      distinct enzyme activities were found. In the membrane fraction, a
      sulfite:acceptor oxidoreductase activity was found [530 mU (mg protein)(-1);
      apparent K(m) for sulfite, 3.6 mM]. In the cytoplasmic fraction the following
      enzyme activities were found and are indicative of an oxidative adenylylsulfate
      pathway: adenylylsulfate reductase [138 mU (mg protein)(-1)],
      adenylylsulfate:phosphate adenyltransferase ["ADP sulfurylase"; 86 mU (mg
      protein)(-1)], adenylate kinase [650 mU (mg protein)(-1)], and rhodanese
      [thiosulfate sulfur transferase, 9.2 mU (mg protein)(-1)]. In addition, 5',5"'
      P(1),P(4)-di(adenosine-5') tetraphosphate (Ap(4)A) synthase and Ap(4)A
      pyrophosphohydrolase activities were detected.

PMID- 10415169
TI  - Specific detection of different phylogenetic groups of chemocline bacteria based
      on PCR and denaturing gradient gel electrophoresis of 16S rRNA gene fragments.
AB  - Specific amplification of 16S rRNA gene fragments in combination with denaturing
      gradient gel electrophoresis (DGGE) was used to generate fingerprints of
      Chromatiaceae, green sulfur bacteria, Desulfovibrionaceae, and beta
      Proteobacteria. Sequencing of the gene fragments confirmed that each primer pair
      was highly specific for the respective phylogenetic group. Applying the new
      primer sets, the bacterial diversity in the chemoclines of a eutrophic freshwater
      lake, a saline meromictic lake, and a laminated marine sediment was investigated.
      Compared to a conventional bacterial primer pair, a higher number of discrete
      DGGE bands was generated using our specific primer pairs. With one exception, all
      15 bands tested yielded reliable 16S rRNA gene sequences. The highest diversity
      was found within the chemocline microbial community of the eutrophic freshwater
      lake. Sequence comparison revealed that the six sequences of Chromatiaceae and
      green sulfur bacteria detected in this habitat all represent distinct and
      previously unknown phylotypes. The lowest diversity of phylotypes was detected in
      the chemocline of the meromictic saline lake, which yielded only one sequence
      each of the Chromatiaceae, beta-2-Proteobacteria, and Desulfovibrionaceae, and no
      sequences of green sulfur bacteria. The newly developed primer sets are useful
      for the detection of previously unknown phylotypes, for the comparison of the
      microbial diversity between different natural habitats, and especially for the
      rapid monitoring of enrichments of unknown bacterial species.

PMID- 10415170
TI  - Thermococcus waiotapuensis sp. nov., an extremely thermophilic archaeon isolated
      from a freshwater hot spring.
AB  - An extremely thermophilic, sulfur-dependent archaeon, strain WT1, was isolated
      from a freshwater hot spring in the Lake Taupo area of North Island, New Zealand.
      The cells are flagellated, strictly anaerobic cocci that grow optimally at 85
      degrees C and 5.4 g NaCl l(-1). The strain grows heterotrophically on complex
      proteinaceous substrates or on appropriate salts plus amino acid mixtures and is
      also able to utilize maltose, starch, and pyruvate. Elemental sulfur could be
      replaced by cystine or thioglycollate. The range of temperatures allowing growth
      is from 60 to 90 degrees C; the pH supporting growth ranges from 5 to 8 (optimum,
      pH 7). Strain WT1 grew in a defined medium containing amino acids as the sole
      carbon and energy sources. The required amino acids were: Arg, His, Ile, Leu,
      Phe, Ser, Thr, Trp, Tyr, and Val. Strain WT1 showed sensitivity to rifampicin.
      DNA G+C content was 50.4 mol%. Phylogenetic analysis of the sequence encoding the
      16S rRNA gene indicated that this isolate is a member of the Thermococcales.
      DNA/DNA hybridization studies revealed no similarity to several species of
      Thermococcus and Pyrococcus, with the exception of Thermococcus zilligii. Based
      on the reported results, we propose strain WT1 as a new species to be named
      Thermococcus waiotapuensis sp. nov.

PMID- 10415171
TI  - Antibody responses against flagellin in mice orally immunized with attenuated
      Salmonella vaccine strains.
AB  - Salmonella fIagellin has been repeatedly used as a carrier for heterologous
      peptide epitopes either as a parenterally delivered purified antigen or as a
      parenterally/orally-administered, flagellated, live, attenuated vaccine.
      Nonetheless, the ability to induce specific antibody responses against the
      flagellin moiety, fused or not with heterologous peptide, has not usually been
      reported in mice orally inoculated with a live, attenuated, flagellated
      Salmonella strain. In this work we evaluated the immunogenicity of flagellin in
      mice following oral inoculation with an aroA Salmonella enterica serovar Dublin
      SL5929 strain, which expressed plasmid-encoded recombinant hybrid flagellin fused
      to the CTP3 epitope (amino acids 50-64) of cholera toxin B-subunit. In contrast
      to parenterally immunized mice, no significant CTP3- or flagellin-specific
      antibody responses either in sera (IgG) or feces (IgA) were detected following
      repeated oral delivery of the recombinant Salmonella strain to C57BL/6 mice.
      Similarly, flagellin-specific antibody responses were also not detected in mice
      immunized with strain SL5930, which expressed a nonhybrid flagellin. The lack of
      flagellin-specific antibody responses was not associated with deficient Peyer
      patch colonization or spleen invasion. Moreover, stabilization of the flagellin
      coding gene by integration into the host chromosome did not significantly improve
      flagellin-specific antibody responses following administration by the oral route.
      Taken together, these results suggest that flagellin does not represent an
      efficient peptide carrier for activation of antibody responses in mice orally
      immunized with live, attenuated Salmonella strains.

PMID- 10415172
TI  - Characterization of the molybdate transport system ModABC of Staphylococcus
      carnosus.
AB  - Transposon mutagenesis of Staphylococcus carnosus led to the identification of
      three genes, modABC, which encode an ABC transporter that is involved in
      molybdate transport. It was shown by [14C]palmitate labeling that ModA represents
      a lipoprotein that in gram-positive bacteria is the counterpart of the
      periplasmic binding proteins of gram-negative organisms. The sequence
      characteristics identify ModB as the integral-membrane, channel-forming protein
      and ModC as the ATP-binding energizer for the transport system. Mutants defective
      in modABC had only 0.4% of the wild-type nitrate reductase activity. Molybdate at
      a non-physiologically high concentration (100 microM) fully restored nitrate
      reductase activity, suggesting that at least one other system is able to
      transport molybdate, but with lower affinity. The expression of modA (and most
      likely of modBC) was independent of oxygen and nitrate. To date, there are no
      indications for molybdate-specific regulation of modABC expression since in a
      modB mutant, modA expression was unchanged in comparison to the wild-type.

PMID- 10415173
TI  - Chlorobium ferrooxidans sp. nov., a phototrophic green sulfur bacterium that
      oxidizes ferrous iron in coculture with a "Geospirillum" sp. strain.
AB  - A green phototrophic bacterium was enriched with ferrous iron as sole electron
      donor and was isolated in defined coculture with a spirilloid chemoheterotrophic
      bacterium. The coculture oxidized ferrous iron to ferric iron with stoichiometric
      formation of cell mass from carbon dioxide. Sulfide, thiosulfate, or elemental
      sulfur was not used as electron donor in the light. Hydrogen or acetate in the
      presence of ferrous iron increased the cell yield of the phototrophic partner,
      and hydrogen could also be used as sole electron source. Complexed ferric iron
      was slowly reduced to ferrous iron in the dark, with hydrogen as electron source.
      Similar to Chlorobium limicola, the phototrophic bacterium contained
      bacteriochlorophyll c and chlorobactene as photosynthetic pigments, and also
      resembled representatives of this species morphologically. On the basis of 16S
      rRNA sequence comparisons, this organism clusters with Chlorobium,
      Prosthecochloris, and Pelodictyon species within the green sulfur bacteria
      phylum. Since the phototrophic partner in the coculture KoFox is only moderately
      related to the other members of the cluster, it is proposed as a new species,
      Chlorobium ferrooxidans. The chemoheterotrophic partner bacterium, strain KoFum,
      was isolated in pure culture with fumarate as sole substrate. The strain was
      identified as a member of the epsilon-subclass of the Proteobacteria closely
      related to "Geospirillum arsenophilum" on the basis of physiological properties
      and 16S rRNA sequence comparison. The "Geospirillum" strain was present in the
      coculture only in low numbers. It fermented fumarate, aspartate, malate, or
      pyruvate to acetate, succinate, and carbon dioxide, and could reduce nitrate to
      dinitrogen gas. It was not involved in ferrous iron oxidation but possibly
      provided a thus far unidentified growth factor to the phototrophic partner.

PMID- 10415174
TI  - Fractionation of sulfur isotopes during dissimilatory reduction of sulfate by a
      thermophilic gram-negative bacterium at 60 degrees C 
AB  - Sulfur isotope ((34)S/(32)S) fractionation during reduction of dissolved sulfate
      was investigated with a growing batch culture of a thermophilic, gram-negative,
      sulfate-reducing bacterium (strain MT-96) at 60 degrees C. The completely
      oxidizing strain was isolated from geothermally heated sediments of a shallow
      water hydrothermal vent in the Mediterranean Sea. The hydrogen sulfide produced
      in the experiments was enriched in (32)S by approximately 19 per thousand as
      compared to sulfate, which indicates that stable isotope discrimination by this
      thermophile is within the range found previously for mesophilic sulfate-reducing
      bacteria, and only slightly higher than that observed for the thermophilic gram
      positive Desulfotomaculum nigrificans.

PMID- 10415177
TI  - Low-dose spiral CT: applicability to paediatric chest imaging.
AB  - BACKGROUND: Spiral CT of the chest is an imaging technique with unequivocal
      indications and proven higher sensitivity and specificity than conventional chest
      X-rays. However, particularly in children, attempts should be made to reduce
      radiation exposure to a minimum. OBJECTIVE. To evaluate whether a low-dose
      technique in spiral CT scanning results in adequate diagnostic information.
      MATERIALS AND METHODS: In a prospective study, 27 children (range 3 weeks to 14
      years, mean 7 years) underwent a low-dose CT examination of the chest for various
      indications. The tube energy was 12.5 mAs (n = 5), 25 mAs (n = 17), 50 mAs (n =
      3), or 75 mAs (n = 2) per slice. Two radiologists evaluated, in consensus, the CT
      scans with respect to their diagnostic value and comparison was made with 20
      standard-dose chest CT examinations of adults (175 mAs per slice, mean age 56
      years) with respect to technical image quality (noise and artefacts). In a second
      part of the study, dose measurements were carried out by means of exposing
      thermoluminescent dosimeters attached to a water/air phantom simulating a child's
      chest. RESULTS: All low-dose CT scans were of diagnostic image quality and no
      additional studies were necessary. The average image noise was significantly
      higher than in standard-dose CT examinations (SD 39.5 compared with 12.5 for
      unenhanced soft tissue, P < 0.01), but did not hinder accurate diagnosis.
      Artefacts were exclusively due to patient motion. Radiation exposure per slice
      was approx. 4 mGy at 25 mAs and 34 mGy at 250 mAs, regardless of slice thickness.
      CONCLUSIONS: For all indications in paediatric CT scanning of the chest, low-dose
      technique provides adequate image quality without loss of diagnostic information.
      The radiation exposure is approximately 5-20 % of a standard-dose CT.

PMID- 10415178
TI  - Pilot study of noninvasive detection of venous occlusions from central venous
      access devices in children treated for acute lymphoblastic leukemia.
AB  - BACKGROUND: Survivors of childhood acute lymphocytic leukemia (ALL) are at risk
      of venous occlusion induced by central venous access devices (CVADs). A
      sensitive, noninvasive screening technique to identify the magnitude of this
      problem is needed. Ultrasound (US) cannot always adequately image the innominate
      veins or the superior vena cava. Magnetic resonance angiography (MRA) can be
      noninvasive and may be useful for screening these patients. OBJECTIVE: We
      examined the suitability of US and MRA to identify venous occlusion. MATERIALS
      AND METHODS: We used MRA and ultrasound to examine 11 pediatric patients
      previously treated for ALL. CVADs had been in place a median of 2.5 years (range,
      0.4-2.8 years) and removed a median of 2.1 years (range, 0.6-2.9 years)
      previously. We also performed 2D time-of-flight magnetic resonance angiography
      (TOF MRA) on two healthy young adult women with no history of venous abnormality
      or CVAD use. RESULTS: MRA suggested central venous abnormalities in 8 of the 11
      ALL survivors and in both healthy control subjects. US results were negative in
      all 11 survivors. CONCLUSION: Further investigation is warranted to develop a
      sensitive and specific noninvasive method for identifying venous occlusion caused
      by prior CVAD use. Such a method would allow prospective studies of this
      complication in pediatric ALL survivors.

PMID- 10415179
TI  - Fluoroscopy-guided retrieval of a sheared endotracheal stylet sheath from the
      tracheobronchial tree in a premature infant.
AB  - Endotracheal intubation of premature infants with respiratory distress is a
      commonly performed procedure in the neonatal intensive care unit. We report a
      rare complication of this procedure, shearing of the plastic sheath that is
      bonded to and surrounds the stylet used to assist intubation and lodging of the
      sheared stylet in the tracheobronchial tree of a small premature infant. We
      suggest a method for removing the plastic foreign body using fluoroscopy and an
      Amplatz gooseneck snare directed through the existing endotracheal tube, a
      technique not previously reported.

PMID- 10415180
TI  - Meandering right pulmonary vein: a case of scimitar variant.
AB  - We report a healthy, asymptomatic 15-year-old girl with a meandering right
      pulmonary vein draining to the left atrium. A meandering pulmonary vein may or
      may not be associated with the scimitar syndrome. The differential diagnosis with
      the scimitar syndrome and other forms of scimitar variants is discussed.

PMID- 10415181
TI  - Reversible MRI abnormalities in an unusual paediatric presentation of Wernicke's
      encephalopathy.
AB  - BACKGROUND: We report an unusual paediatric presentation of acute Wernicke's
      encephalopathy in a 12-year-old boy affected by chronic gastrointestinal disease.
      MRI demonstrated, in addition to the typical diencephalic and mesencephalic
      signal abnormalities on T2-weighted images, enhancement of the mammillary bodies
      and the floor of the hypothalamus. MATERIALS AND METHODS: Following parenteral
      administration of thiamine for 4 days, the patient recovered from his
      neurological deficits and on follow-up enhanced MRI 1 month later, no signal
      abnormalities were found nor was there diencephalic or mesencephalic atrophy, as
      is usual in the chronic phase of the disease. RESULTS: MRI provides crucial
      information in the diagnosis of Wernicke's encephalopathy, either in the acute or
      chronic phases of the disease. CONCLUSION: Our report provides an additional clue
      for recognition of the acute phase of the disease; enhancement of the floor of
      the hypothalamus has not previously been described despite its recorded
      involvement at autopsy.

PMID- 10415182
TI  - Commentary 

PMID- 10415183
TI  - Aplasia of right internal carotid artery and hypopituitarism.
AB  - BACKGROUND: The pathogenesis of congenital hypopituitarism is unknown in many
      cases. OBJECTIVE: We report a case of congenital pan-anterior hypopituitarism in
      association with a complex vascular abnormality involving the central nervous
      system, nasal pyriform aperture stenosis, and a single central maxillary incisor.
      MATERIALS AND METHODS: MRI and MRA were used to define this patient's complex
      vascular anomaly. RESULTS: The vascular abnormality consists of absence of the
      right common carotid artery, the right internal carotid artery, the A1 segment of
      the right anterior cerebral artery, the anterior communicating artery, and
      partial absence of the M1 segment of the right middle cerebral artery.
      CONCLUSION: This unusual vascular anomaly may contribute to the pathogenesis of
      some cases of congenital hypopituitarism and related midline abnormalities, or
      may result from a common defect that causes pituitary insufficiency.

PMID- 10415184
TI  - Cerebellar vermis diameter at cranial sonography for assessing gestational age in
      low-birth-weight infants.
AB  - BACKGROUND: Clinical assessment of gestational age for very-low-birth-weight
      infants is often inaccurate. Survival rates are more dependent on gestational age
      than on the birth weight. OBJECTIVE: To assess whether cerebellar vermis diameter
      might predict gestational age in infants under 2,000 g and/or under 32 weeks'
      gestation. MATERIALS AND METHODS: We carried out a retrospective review of the
      hard-copy images of midline sagittal views of the cerebellum obtained at cranial
      sonography, performed via the anterior or posterior fontanelle, in 518 infants
      admitted to a regional neonatal intensive care unit between June 1991 and
      November 1996. The vermis diameter was measured from the base of the fourth
      ventricle to the junction of folium and tuber vermis. We generated regression
      equations for estimating gestational age from vermis diameter, and from vermis
      diameter and birth weight, for the 86 infants of known gestational age (less than
      32 weeks), with birth weight under 2,000 g and who had scans carried out within 1
      week of birth. RESULTS: Measurement of cerebellar vermis diameter alone allowed
      prediction of gestational age to +/- 1.53 weeks using a 68 % prediction interval,
      or +/- 3.0 weeks using a 95 % prediction interval. Gender was not significant in
      the regression analysis. CONCLUSION: Cerebellar vermis diameter predicts
      gestational age with slightly more precision than the new Ballard score.

PMID- 10415185
TI  - Cerebral sinovenous thrombosis in the idiopathic hypereosinophilic syndrome in
      childhood.
AB  - The idiopathic hypereosinophilic syndrome (HES) is a leukoproliferative disorder
      marked by a sustained overproduction of eosinophils and a distinct predilection
      to damage specific organs, especially the cardiovascular system. It is primarily
      a disease of middle-aged people. Occasional cases have been encountered in
      children. We report a case of an 11-year-old boy affected by idiopathic HES with
      an unusual rapidly fatal course. In addition to eosinophilic cellulitis, cerebral
      straight and superior sagittal sinus vein thrombosis (CVT) was evident on cranial
      CT. In our review of the English literature we were unable to find an association
      between idiopathic HES and CVT.

PMID- 10415186
TI  - Sonographic appearance of omental infarction in children.
AB  - BACKGROUND: Omental infarction has been previously reported in the adult surgical
      and imaging literature; however, the imaging features of this entity in children
      have received little attention. OBJECTIVE: The purpose of our study was to
      identify the sonographic features of omental infarction in nine children who had
      preoperative sonography and surgically proven omental infarction. MATERIALS AND
      METHODS: Sonographic images were reviewed and correlated with clinical
      information obtained from the patients' medical records, including clinical
      presentation, operative notes, and pathology reports. RESULTS: In seven of the
      children, sonography demonstrated a focal area of moderately increased
      echogenicity in the omental fat in the right abdomen (a previously described
      finding in omental infarction). This was an isolated finding in four of these
      cases. In the three cases where this was not an isolated finding, the more
      complex sonographic appearance led to incorrect preoperative imaging diagnoses.
      This finding of increased echogenicity in the omental fat was not present in the
      two remaining patients. CONCLUSION: Our study confirms that foci of moderately
      increased echogenicity in the omentum of the right abdomen, a sonographic finding
      described in omental infarction in a large series in adults (and in a single
      prior case report in children), can be seen in children as well. However,
      although this is a relatively unique finding, it may be absent in some cases or
      may be seen in conjunction with other sonographic findings which may preclude the
      correct preoperative sonographic diagnosis.

PMID- 10415187
TI  - Duodenum inversum mimicking mesenteric artery syndrome.
AB  - BACKGROUND: Duodenum inversum is an often unrecognized anomaly of duodenal
      rotation/fixation at upper gastrointestinal (UGI) contrast study because the
      duodenojejunal junction appears normally located. OBJECTIVE: This anomaly is
      important to diagnose because it may result in obstructive gastrointestinal
      symptoms. CONCLUSION: We describe a case of duodenum inversum mimicking superior
      mesenteric artery (SMA) syndrome that improved after surgical therapy.

PMID- 10415188
TI  - Popliteal cysts in children: prevalence, appearance and associated findings at MR
      imaging.
AB  - OBJECTIVE: The purpose of this study was to determine the prevalence of Baker's
      cysts on MR images in a paediatric orthopaedic population, to investigate the
      association of Baker's cyst with joint fluid and joint disorders in children, and
      to compare the MR appearance of Baker's cysts in children with that previously
      reported in adults. MATERIALS AND METHODS: Reports from 393 MR studies of the
      knee performed in children aged from 1 to 17 years were retrospectively reviewed
      for the presence of a Baker's cyst, joint effusion, meniscal tear, anterior
      cruciate ligament tear, or any other joint disorder. RESULTS: A Baker's cyst was
      identified in 6.3 % (25/393) of patients. The MR images and clinical charts of
      patients with a Baker's cyst were reviewed. None of the 25 patients with a
      Baker's cyst had an associated anterior cruciate ligament tear or meniscal tear.
      Two patients had osteochondritis dissecans and two others had synovial disease
      (infection and juvenile rheumatoid arthritis). Joint fluid was demonstrated in 16
      % (4/25) of patients with a Baker's cyst. There was no statistically significant
      association between presence of a Baker's cyst and presence of joint fluid.
      CONCLUSIONS: Baker's cyst is less prevalent in a paediatric orthopaedic
      population than in an adult population. In children, it seems that Baker's cyst
      is seldom associated with joint fluid, meniscal tear, or anterior cruciate
      ligament tear. On MR images, a communication between the Baker's cyst and the
      joint was not demonstrated in any of the patients. In addition, the presence of
      debris and cyst leakage was not observed.

PMID- 10415189
TI  - Accessory soleus muscle: a case report and review of the literature.
AB  - Accessory soleus muscle is a rare condition which presents as a soft-tissue mass
      medial to the calcaneum and distal Achilles tendon. Though congenital in origin,
      it manifests in the second and third decades of life as a soft-tissue mass due to
      muscle hypertrophy. Patients may be asymptomatic or present with a painful ankle
      mass. It is important to be aware of this condition when interpreting CT or MRI
      of the ankle, which show characteristic findings of a normal muscle in an
      abnormal location.

PMID- 10415190
TI  - Congenital hemihypertrophy and epithelioid haemangioendothelioma in a 10-year-old
      boy: a case report.
AB  - Epithelioid haemangioendothelioma has not been previously described in a patient
      with congenital hemihypertrophy and diabetes mellitus. Hepatic nodules were
      incidentally discovered on a routine US examination searching for known
      associated abnormalities. Pulmonary nodules were present on chest X-ray and CT of
      the lungs. The diagnosis was confirmed by open biopsy of a hepatic nodule.
      Despite significant disease progression the patient remains symptom free.

PMID- 10415191
TI  - Power Doppler evaluation of joint effusions: investigation in a rabbit model.
AB  - OBJECTIVE: To study the power Doppler findings of septic arthritis and
      noninfectious synovitis in an animal model. MATERIALS AND METHODS: The right
      knees of 10 rabbits were inoculated with an aqueous suspension of Staphylococcus
      aureus. The right knees of 5 rabbits were injected with talc suspension. The
      right knees of 5 rabbits were injected with saline. All 20 left knees were
      injected with saline. Serial power Doppler images were obtained using constant
      imaging parameters. Images were reviewed by blinded observers who assessed for
      increased power Doppler signal. RESULTS: All 10 knees inoculated with S. aureus
      developed septic arthritis. Each infected rabbit knee demonstrated increased
      signal on power Doppler on at least one examination, ranging from 1-6 days after
      inoculation. Only 23 of 45 examinations of infected knees were unequivocally
      positive by power Doppler on examinations performed 1 to 6 days after
      inoculation. No knee with talc synovitis demonstrated increased power Doppler
      signal. No control knee demonstrated increased power Doppler signal. CONCLUSION:
      Increased power Doppler signal may be seen with septic arthritis; however, its
      intensity and timing may vary from subject to subject. A normal power Doppler
      examination does not exclude septic arthritis.

PMID- 10415192
TI  - Renal calculi in children: imaging features that lead to diagnoses: a pictorial
      essay.

PMID- 10415193
TI  - Indium-111-oxine labeled leukocyte uptake in Ki-1-positive anaplastic large cell
      lymphoma.
AB  - Indium-111-oxine labeled leukocyte ((111)In-WBC) scintigraphy is well known for
      its ability to localize in areas of active infection, but not in areas of
      lymphomatous involvement. We present a case of Ki-1-positive anaplastic large
      cell lymphoma that was initially thought to be a case of multifocal osteomyelitis
      because of positive uptake on a (111)In-WBC scan. The areas of abnormal uptake on
      the indium scan were demonstrated histopathologically to be sites of lymphomatous
      involvement in bone.

PMID- 10415194
TI  - Orbital myositis due to Kawasaki's disease.
AB  - Kawasaki's disease is an inflammatory syndrome of young children that affects
      multiple organ systems. The most common ophthalmologic manifestations of
      Kawasaki's disease are bilateral conjunctival injection and nongranulomatous
      iridocyclitis. To our knowledge, this patient is the first with Kawasaki's
      disease to demonstrate extraocular muscle palsy and orbital myositis.

PMID- 10415195
TI  - Risk and benefit in paediatric radiology.
AB  - An investigation requiring the use of ionising radiation can be justified by
      showing that its benefits are likely to exceed its risks. The risks can be
      estimated from the effective dose by using the system recommended by the
      International Commission on Radiological Protection. The benefits of
      investigations in paediatric radiology are currently unquantified. We can assume
      that some tests have potential benefits so large that further evaluation is
      unnecessary. Others have a maximum potential benefit so low that they can be
      discarded. For most investigations, however, research into the magnitude of
      benefit to the patient is required in order to establish that it is greater than
      the magnitude of the radiation risk.

PMID- 10415196
TI  - Barrett's esophagus in a teenager with a ringed esophagus.

PMID- 10415198
TI  - Endoscopic surgery: innovation versus evaluation-introduction.

PMID- 10415197
TI  - Fracture dislocation of the sacro-coccygeal joint: MRI evaluation.

PMID- 10415199
TI  - Endoscopic surgery: the history, the pioneers.
AB  - The introduction of endoscopy into surgical practice is one of the biggest
      success stories in the history of medicine. Endoscopy has its roots in the
      nineteenth century and was initially developed by urologists and internists.
      During the 1960s and 1970s gynecologists took the lead in the development of
      endoscopic surgery while most of the surgical community continued to ignore the
      possibilities of the new technique. This was due in part to the introduction of
      ever more sophisticated drugs, the impressive results of intensive care medicine,
      and advances in anesthesia, which led to the development of more radical and
      extensive operations, or "major surgery." The idea that large problems require
      large incisions so deeply dominated surgical thinking that there was little room
      to appreciate the advances of "key-hole" surgery. Working against this current,
      some general surgeons took up the challenge. In 1976 the Surgical Study Group on
      Endoscopy and Ultrasound (CAES) was formed in Hamburg. Five years later, on the
      other side of the Atlantic, the Society of American Gastrointestinal Endoscopic
      Surgeons (SAGES) was called into being. In 1987 the first issue of the journal
      Surgical Endoscopy was published, and the following year the First World Congress
      on Surgical Endoscopy took place in Berlin. The sweeping success of the
      "laparoscopic revolution" (1989-1990) marked the end of traditional open surgery
      and encouraged surgeons to consider new perspectives. By the 1990s the
      breakthrough had been accomplished: endoscopy was incorporated into surgical
      thinking.

PMID- 10415200
TI  - First step: the idea.
AB  - It is a fact that without ideas there is nothing. Without ideas and without
      innovations there is nothing to test. An interesting, often asked question is:
      How are ideas, innovations born? It is surely correct that people giving birth to
      ideas have special characteristics. These creative people are different but still
      have many, maybe essential, characteristics in common. They are open-minded.
      Abnormality is interesting for them. They are highly emotional, passionate. They
      are intelligent and naive at the same time. They are often like children but they
      also are determined and enjoy their lives. It is a fact that an idea, once born,
      does not always attain fruition; place, time, social environment, and society
      have to fit. The domain has to be prepared for it. The true pioneer is the one
      who has seen the beginning to a certain degree but also brings the new idea to
      the public, places it on the agenda, accompanies it with positive skepticism, and
      most of all carries it over the "finishing line." Giving birth to an idea is an
      important step. Testing the idea regarding its effectivity is a necessity. Since
      Decartes, in our Western way of thinking, we have a systematic methodic
      procedure. The idea is expressed in a hypothesis. Here the hypothesis is:
      "Endoscopic surgery supplies more comfort and means less trauma at the same or
      greater safety." This is the idea, the dream, the hypothesis. In concrete terms
      it means less pestering, less pain, less fatigue, and in general a quicker return
      to daily life during the pre- and postoperative course. Less trauma means less
      stress response of the body; these are the true endpoints. In the long run,
      endoscopic surgery means-this being the unproved prerequisite-physical integrity,
      less immunosuppression, and last but not least consideration of the abdominal
      wall (in concrete terms, fewer incisional hernias). Thus the relevant endpoints
      have been formulated by the concrete terms of the hypothesis. This makes clear
      that comfort relates to-and this is for the first time-"soft" data. This is the
      true revolution. For me this is a true change of paradigm. Here a few important
      problems become evident. In the first place, a solution must be found-with the
      intention of reality and coolness-for the problem of comparing "soft" and "hard"
      data. With this problem it must be clear that subjective endpoints strongly
      depend on social and cultural circumstances and are probably influenced more by
      these factors than by the endoscopic surgery itself. The placebo effect must also
      be considered. Up to 50% of the subjective endpoints are due to the placebo
      effect, especially with surgery. For example, pain and return to work depend
      heavily on socioeconomic aspects and the placebo effect. In summary, the first
      step is the idea; the second step is testing the idea for effectiveness.
      Endoscopic surgery as a patient-friendly treatment is the idea, the hypothesis.
      This hypothesis must be tested according to our present standard of methodology.
      In addition to the "conventional" endpoints (negative events), the comfort of the
      patient is the true endpoint of patient-friendly surgery-endoscopic surgery.

PMID- 10415201
TI  - Second step: testing-outcome measurements.
AB  - Despite worldwide enthusiasm for endoscopic surgery, this new technology is now
      on the top of McKinlay's "product life circle curve." Critical questions are
      being asked about its benefits and burdens, but the concepts applied and the
      methodologies used for technology assessment are in a similar position as
      endoscopic surgery and need a critical evaluation. (1) There are incorrect and
      outdated concepts for the scientific basis of surgery (surgical theory) including
      the basic sciences involved; biomedicine still dominates, but assessment of
      outcome after operations is no longer possible without clinical epidemiology and
      social psychology. (2) Based on an outdated scientific theory for surgery, an
      outdated concept of disease is still propagated. It is denoted as mechanical and
      is based solely on biomedicine. Human subjects are reduced to biologic machines,
      and outcomes measurement excludes most dimensions of functioning and well-being.
      To achieve a valid result for outcome measures, a hermeneutic approach must be
      combined with the mechanical approach. (3) Based on an outdated model of disease,
      the outcomes used in endoscopic surgery rely too much on traditional measures,
      such as mortality rate, complication rate, hospital stay, and especially an
      endless list of biochemical mediators. Their alterations during the perioperative
      period have not yet been shown to be related to clinical or hermeneutic outcomes.
      A new method of assessment for clinical trials in endoscopic surgery and for
      other surgical problems is outlined, such as for surgical infections and for
      surgical oncology. It includes an index of recovery and objective health status
      assessed by the doctor, a quality-of-life self-report by the patient, and the
      true endpoint concept as a critical weighting of both types of outcome by
      patients and doctors.

PMID- 10415202
TI  - Socioeconomic aspects.
AB  - Most surgeons conceptualize "surgical advance" as the introduction of a new
      operative technique or the presentation of a technologic breakthrough. However,
      the true landmark innovations of the past decade, with regard to effecting
      surgical health care delivery, have been the impact of economics and sociology in
      determining the profession's future. In the past, the surgeon's primary interests
      revolved around the art and science of surgery, and socioeconomic issues were
      deemed of secondary importance. Consequently, few of the investigations into
      "surgical socioeconomics" were conducted by surgeons, and the surgical
      establishment was more than mildly apathetic toward such social science research.
      All of this has changed, and it is now evident that there is an overwhelming need
      for surgeons to incorporate an understanding of sociologic and economic
      conditions into their clinical thinking. Basic tenets of surgical socioeconomics
      are presented, and their impact on various clinical situations is discussed.

PMID- 10415203
TI  - Ethical problems in surgery: innovation leading to unforeseen complications.
AB  - A hypothetical case that involves a surgical innovation is used to illustrate
      three ethical issues in surgery: the profound trust that vulnerable patients feel
      toward their surgeons, even when they innovate; the disequilibrating effect of
      new procedures on traditional safeguards of surgical competence; and the need for
      a systematic approach to the evaluation of new surgical procedures.

PMID- 10415204
TI  - Evidence-based surgery: A passing fad?
AB  - Recent years have witnessed the development of a new movement within health care:
      the promotion of "evidence-based medicine" (EBM). EBM is about integrating
      individual clinical expertise and the best external evidence derived from
      scientific research. Advocates claim that much medical practice is based too much
      on opinion and experience and insufficiently on research evidence. Their approach
      would increase the quality of care and its efficiency. This paper describes the
      principal steps in the evidence-based approach-systematic reviews of the
      literature and meta-analyses-and its shortcomings in surgery. These include the
      reliance of EBM on randomized trials, the lack of generalizability of scientific
      evidence to individual patients, the lack of attention to third party interests,
      the threat to the "art" of medicine, and the dangers of an oversimplistic
      approach. Although EBM clearly has a place, it does not have all the answers.

PMID- 10415205
TI  - CO(2) pneumoperitoneum: what we know and what we need to know.
AB  - The development of the laparoscopic technique in surgery was so overwhelming that
      scientific evaluation could not keep in step. While investigators were still
      discussing the effects of the pneumoperitoneum on the healthy organism,
      laparoscopy was already performed in patients with an acute abdomen due to trauma
      or disease. Therefore, there is an urgent need of further experimental and
      clinical studies with relevant endpoints to gain external evidence concerning the
      benefits of diagnostic or therapeutic laparoscopy for critically ill patients. In
      experiments with pigs we have shown that even in a healthy organism perfusion and
      energy metabolism of the small bowel is impaired by a pneumoperitoneum with
      carbon dioxide. Under the conditions of a systemic inflammatory response syndrome
      induced by infusion of endotoxin, the negative effects of the pneumoperitoneum
      were significantly amplified. Furthermore, we found that the increased
      intracranial pressure as caused by a head injury was further enhanced during a
      pneumoperitoneum but not by the alternative method of mechanical wall retraction.
      The current literature dealing with the effects of a pneumoperitoneum in
      critically ill patients is still controversial. Our data support the results of
      those authors who hold the opinion that creating a pneumoperitoneum in patients
      with acute abdominal problems means an additional serious burden that in single
      cases may lead to a disaster. As evidence is lacking, the current extension of
      laparoscopy into the field of intensive care medicine is still a human experiment
      that must be performed with high responsibility, extensive monitoring, and
      according to the rules of a clinical study.

PMID- 10415206
TI  - Surgical stress response: does endoscopic surgery confer an advantage?
AB  - "Open" surgical procedures are followed by profound changes in endocrine
      metabolic function and various host defense mechanisms, impaired pulmonary
      function, and hypoxemia. These physiologic changes are supposed to be involved in
      the pathogenesis of postoperative morbidity. Endoscopic surgery, mostly studied
      during laparoscopy, when compared with similar open operations, has no important
      effects on classic endocrine metabolic responses but may slightly reduce
      inflammatory responses and various immune functions, although the data are not
      consistent. In contrast, most data show improvement of postoperative pulmonary
      function and less hypoxemia with endoscopic operation. The slight modification of
      surgical stress responses by endoscopic surgery is in contrast to the common,
      though not universal, demonstration of less pain, shorter hospital stay, and less
      morbidity after endoscopic surgery. In conclusion, endoscopic surgery has so far
      not been demonstrated to have important modifying effects on classic endocrine
      metabolic responses and only a slight inhibitory effect on various inflammatory
      responses, but with improved pulmonary function and less hypoxemia. More data are
      needed from major operations where differences are more likely to be found. The
      clinical consequences of these findings in relation to all over surgical outcome
      remain to be defined, but effective pain treatment, stress reduction by other
      techniques, and provision of an active rehabilitation program with early
      mobilization and oral feeding may be more important than the choice between an
      endoscopic technique versus "open" operation per se to improve outcome.

PMID- 10415207
TI  - Endoscopic surgery: fit for malignancy?
AB  - Neither experimental nor clinical data confirm the repeatedly published opinion
      that video-endoscopic surgery promotes tumor growth or the occurrence of
      implantation metastases in cancer patients. On the contrary, alterations due to
      pneumoperitoneum by the application of different gases, pressures, and
      temperatures might provide the basis for a new therapeutic approach to cancer
      surgery. Oncologically adequate resections defined by such terms as "no touch
      isolation" and "monobloc resection" can be performed video-endoscopically in a
      variety of intraabdominally or intrathoracically located cancers if a
      standardized technique is used. The benefit of video-endoscopic surgery is
      limited in large tumors, especially if they have reached the organ surface. There
      is still a major deficit in the clinical evaluation of video-endoscopic
      interventions in most oncologic diseases. Randomized studies comparing video
      endoscopic and conventional surgery have been reported only for the resection of
      colorectal carcinoma. They show that laparoscopic resections can be performed
      with a minimum of postoperative complications to the same extent as conventional
      resections and offer several advantages during the early postoperative period. No
      reliable data from comparative trials are as yet available on the long-term
      results.

PMID- 10415208
TI  - Endoscopic surgery: what has passed the test?
AB  - The use of endoscopic surgery has increased in gastrointestinal surgery since the
      introduction of laparoscopic cholecystectomy. It was the aim of this study to
      investigate the impact of endoscopic procedures in 1998. Laparoscopic
      cholecystectomy, fundoplication, repair of perforated peptic ulcer, gastric
      banding procedure, sigmoid resection for diverticulitis, and ileal pouch-anal
      anastomosis were investigated using techniques of technology assessment.
      Feasibility, efficacy, and effectiveness were used to evaluate the different
      types of operation. The statements were graded by three categories of evidence.
      Laparoscopic cholecystectomy and fundoplication have passed the test.
      Laparoscopic repair of perforated duodenal ulcer, gastric banding for morbid
      obesity, and sigmoid resection for diverticulitis are feasible and efficient but
      not effective today. Laparoscopy-assisted ileal pouch-anal anastomosis has been
      shown to be feasible but is not yet efficient and effective.

PMID- 10415209
TI  - Endoscopic surgery: ideal for endocrine surgery?
AB  - The laparoscopic approach of endocrine tumors is recent, the first reported
      resection of an adrenal gland in 1992. It represents a revolution in endocrine
      surgery equivalent to that observed in general surgery after the first
      cholecystectomy was performed in 1987. This new approach needs evaluation in
      terms of feasibility, indications, safety, and surgical procedure to define its
      potential advantages. The surgical technique and operative approaches of
      laparoscopic adrenalectomies are at the present time well defined and mostly
      accepted. Pancreatic approaches and resections, thyroidectomies, and
      parathyroidectomies are more confidential and performed only by rare teams.
      Nevertheless, the development of this technique is ineluctable. The spread of
      this technique, partly due to the increased quality of the technologies
      available, especially cameras, encounter a major brake that limits its
      generalization: If general surgeons commonly perform laparoscopy in their daily
      practice, they treat few patients presenting endocrine disorders. On the other
      hand, endocrine surgeons to whom many patients are referred do not have regular
      videoscopic practice. Endocrine surgery benefit few patients for these reasons.
      An analysis of the present state of the art allows us to imagine the evolution
      and future of videoscopic endocrine surgery.

PMID- 10415210
TI  - Laparoscopic versus open appendectomy: time to decide.
AB  - Although widely practiced, laparoscopic appendectomy (LA) has not met with
      universal approval. Several controlled trials have been conducted, some in favor,
      others not. The goal of this review was to ascertain (1) if laparoscopy was
      capable of improving the diagnostic and therapeutic difficulties encountered
      during open appendectomy (OA) and (2) if the introduction of laparoscopy in the
      overall management of acute appendicitis has changed anything in practice.
      Analysis and criticism of 17 controlled studies (nearly 1800 patients) on
      laparoscopic appendectomy and 2 randomized studies dealing with diagnostic
      laparoscopy are reported. Because of the questionable quality of randomized
      controlled trials (number of patients, exclusions, withdrawals, blinding,
      intention-to-treat analysis), publication biases, local practice variations
      (hospital stay, rate of enrollment), results regarding analgesia requirements,
      return to activity and work, duration of hospital stay, outcome, follow-up, and
      antibiotic prophylaxis the studies must be interpreted with caution. The real
      world of appendicitis probably differs greatly from the atmosphere under which
      controlled trials comparing LA and OA have been performed. Statistical
      significance is contrary to the clinical significance of the results.
      Consistently longer operating times [the difference ranging from 8 minutes (NS)
      to 29 minutes (p < 0.0001)], a minimal reduction in hospital stay [0. 1 day (NS)
      to 2.1 days (p < 0.007)], and, somewhat more controversial, an earlier return to
      normal activity were reported for LA. Data on analgesic requirements were
      confusing, but wound complications were more frequent after OA [pooled odds ratio
      for 10 studies: 2.6 (95% CI 1.3-5.2)]. Unsolved problems include national
      behavioral problems, age and experience of operating surgeons (LA or OA), and
      emergency conditions (availability of staff, instruments). Results of cost
      analysis vary according to the standpoint of disease, the patient, the surgeon,
      the treatment center, industry, and society. Three questions remain: Because of
      the competition of LA versus OA, OA has improved greatly. Can it be improved any
      more? Is there a place or need for further randomized controlled trials? Should
      we not conclude once and for all that LA is out?

PMID- 10415211
TI  - Disasters of endoscopic surgery and how to avoid them: error analysis.
AB  - For every innovation there are two sides to consider. For endoscopic surgery the
      positive side is more comfort for the patient, and the negative side is new
      complications, even disasters, such as injuries to organs (e.g., the bowel),
      vessels, and the common bile duct. These disasters are rare and seldom reported
      in the scientific world, as at conferences, at symposiums, and in publications.
      Today there are many methods for testing an innovation (controlled clinical
      trials, consensus conferences, audits, and confidential inquiries). Reporting
      "complications," however, does not help to avoid them. We need real methods for
      avoiding negative failures. The failure analysis is the method of choice in
      industry. If an airplane crashes, error analysis starts immediately. Humans make
      errors, and making errors means punishment. Failure analysis means rigorously and
      objectively investigating a clinical situation to find clinical relevant
      information for avoiding these negative events in the future. Error analysis has
      four important steps: (1) What was the clinical situation? (2) What has happened?
      (3) Most important: Why did it happen? (4) How do we avoid the negative event or
      disaster in the future. Error analysis has decisive advantages. It is easy to
      perform; it supplies clinically relevant information to help avoid it; and there
      is no need for money. It can be done everywhere; and the information is available
      in a short time. The other side of the coin is that error analysis is of course
      retrospective, it may not be objective, and most important it will probably have
      legal consequences. To be more effective in medicine and surgery we must handle
      our errors using a different approach. According to Sir Karl Popper: "The
      consituation is that we have to learn from our errors. To cover up failure is
      therefore the biggest intellectual sin.

PMID- 10415212
TI  - Pregnancy: A contraindication?
AB  - According to David L. Sackett evidence-based medicine is the conscientious,
      explicit, and judicious use of current best evidence when making decisions about
      the care of individual patients. It means integrating individual clinical
      expertise with the best available external evidence from systematic research. On
      the basis of this idea in medicine the following communication summarizes and
      evaluates current statements and literature on laparoscopic surgery during
      pregnancy. The topic is an example for excellent individual clinical performance
      on one hand, as gynecologists have perform laparoscopic procedures during
      pregnancy for decades. On the other hand, pregnancy is considered to be a
      contraindication for laparoscopic surgery by clinicians, because no excellent
      external evidence from systematic research is available. To find an answer to the
      question of whether pregnancy is a contraindication for laparoscopic surgery we
      performed a literature search and gained information by conducting interviews
      with several experts in gynecology and endoscopic operations. We concluded that
      there are almost no "scientific" data about endoscopic surgery during pregnancy,
      but gynecologists representing the "real world" seem to have no fear of the
      procedure for their patients. Between the two extremes, performing laparoscopic
      operations during pregnancy might be advantageous for maximal patient-friendly
      surgery, but considering pregnancy as a contraindication for the laparoscopic
      approach might be the safer treatment. The reader may decide that the subject on
      endoscopic surgery in pregnancy is still open.

PMID- 10415213
TI  - Laparoscopic surgery: A pioneer's point of view.
AB  - For a surgeon who performed some of the first laparoscopic cholecystectomies,
      laparoscopic surgery is undoubtedly the main revolution in the last decade of
      this century. It is impossible not to be fascinated by the extraordinary changes
      introduced in our profession in less than 10 years. However, looking back in
      history, one realizes that laparoscopy is but one of those leaps forward that
      have always punctuated the evolution of our profession. Since the last century we
      have witnessed the advent of painless surgery, infectionless surgery,
      reconstructive surgery, microsurgery, surgery under extracorporeal circulation,
      organ replacement, and so on. We are in the time of scarless surgery, with no
      lengthy postoperative handicap. Maybe tomorrow will see surgery performed by
      remote-controlled robots and surgery at the molecule level. The laparoscopic
      revolution is particularly important because for the first time surgery no longer
      involves any physical contact between the surgeon's hand and the patient. Let us
      hope that this will not lead to total absence of a human relationship in the
      surgical operation. To avoid this possibility we must remain resolutely involved
      in the development of laparoscopic surgery; we must keep our minds open to the
      future advances of science and technology and integrate them in our operative
      procedures.

PMID- 10415214
TI  - Referred pain to the ipsilateral forehead and orbit: An unusual phenomenon during
      bronchial artery embolization.
AB  - PURPOSE: We report an unusual pattern of referred pain to the ipsilateral
      forehead and orbit observed during bronchial artery embolization (BAE) for
      massive hemoptysis due to pulmonary tuberculosis (TB) and postulate possible
      neural mechanisms for its occurrence. METHODS: Seven men, from a series of 194
      patients (171 men, 23 women) undergoing BAE (right bronchial artery 4, left 3)
      with gelatin sponge for control of massive hemoptysis due to pulmonary TB form
      the subject of this report. RESULTS: Embolization was successful in achieving
      control of hemoptysis in these patients and there were no complications following
      the embolization. Transient, moderately severe, ipsilateral supraorbital and/or
      retroorbital pain occurred only during the injection of the gelatin sponge
      contrast mixture into the bronchial artery. The pain did not occur during the
      injection of heparinized saline or ionic contrast medium. CONCLUSIONS: Referred
      pain during BAE is an unusual phenomenon. Acute vessel distension triggering
      visceral sensations is probably the causative mechanism. Sympathetic afferents
      from the bronchi coursing through the posterior pulmonary plexus eventually pass
      to the trigeminal ganglion via the carotid sympathetic chain. The ophthalmic and
      maxillary divisions of the trigeminal nerve then mediate pain sensation to the
      ipsilateral forehead and orbit. Similarly, parasympathetic afferents from the
      pulmonary plexus crossing the nucleus of the spinal tract of the trigeminal nerve
      may be responsible for interexchange of impulses to the neurons in this nucleus.
      Sensory fibers of the ophthalmic and maxillary nerves relaying in this nucleus
      are then involved in this pain being referred to the forehead and orbit.

PMID- 10415215
TI  - Primary stent placement for recanalization of iliac artery occlusions: using a
      self-expanding spiral stent.
AB  - PURPOSE: To report the clinical results for recanalizations of an occluded iliac
      artery by a self-expanding spiral stent. METHODS: We attempted to recanalize 36
      iliac artery occlusions in 34 patients [33 men, 1 woman, aged 51-75 years
      (average 61.6 years)]. The average lesion length was 6.92 cm (range 1-14 cm). The
      patients' chief complaints were intermittent claudication and resting pain.
      Fontaine classification was assigned before and after the procedure. Technical
      and clinical success were also analyzed. RESULTS: Forty-five stents were
      successfully deployed in 34 patients. All 36 lesions (13 in the external iliac
      artery, 12 in the common iliac artery, and 11 in both) were patently recanalized
      on angiography. The follow-up period ranged from 6 months to 36 months (mean 11.9
      months). Fourteen stents (39%) with incomplete expansion were dilated with a
      balloon catheter. Good technical (100%) and clinical (94%) results were obtained.
      The only complication was one hematoma at the puncture site. Reocclusions were
      noted in two lesions (5%) at 1 week and 15 months, respectively. CONCLUSION: A
      self-expanding spiral stent is a safe and effective device for recanalization of
      an iliac artery occlusion as the primary stent without any previous intervention.

PMID- 10415216
TI  - Percutaneous transluminal angioplasty of peripheral bypass stenoses.
AB  - PURPOSE: To assess the success of percutaneous transluminal angioplasty (PTA) in
      treating peripheral bypass stenoses. METHODS: Patients who received a
      femoropopliteal or femorocrural bypass graft for limb ischemia were included in a
      duplex surveillance program. If duplex ultrasound revealed a short (<2 cm) severe
      (peak systolic velocity ratio >/= 4.5) stenosis, patients were scheduled for
      arteriography and PTA. Fifty-eight peripheral bypass stenoses in 39 grafts in 37
      patients were treated with PTA. The cumulative primary patency of treated
      stenoses was calculated. RESULTS: During the first year after PTA 31 (53%)
      treated lesions remained patent, 15 (26%) lesions restenosed at a median interval
      of 5.0 (range 1-12) months and 4 (7%) bypasses occluded. The cumulative primary
      patency of 58 treated graft stenoses at 1 year was 60% [95% confidence interval
      (CI) 46%-74%] and 55% (95% CI 41%-70%) at 2 years. Graft body stenoses showed a
      better 2-year cumulative primary patency (86%; 95% CI 68%-100%) compared with
      juxta-anastomotic lesions (45%; 95% CI 29%-62%; p < 0.05). CONCLUSION: PTA is
      justifiable as the initial treatment of peripheral bypass stenoses. Nevertheless,
      the restenosis rate is rather high, especially in juxta-anastomotic lesions.
      Continuation of duplex surveillance after PTA and timely reintervention is
      recommended.

PMID- 10415217
TI  - Efficacy and complications of the Gianturco-Z tracheobronchial stent for
      malignant airway stenosis.
AB  - PURPOSE: To describe our experience using the Gianturco Z-stent (G-Z stent) for
      the management of malignant tracheobronchial stenosis, with special reference to
      complications. METHODS: Thirty-six stents were used in 22 patients with 28
      lesions. Thirteen patients were grade 5 according to the Hugh-Jones
      classification. The technical success rates, follow-up results, and complications
      were reviewed on the basis of the patients' charts and radiographs. RESULTS: All
      stents were successfully placed in the ideal position without procedure-related
      complications. After the procedure, respiratory status improved in 95% (21/22) of
      patients, and performance status improved in 77% (17/22). Mean survival after
      stent placement was 15 weeks. Four patients suffered from increased thick
      secretions requiring multiple suctioning and aspiration by bronchoscopy. One of
      these patients died from asphyxiation 2 weeks after placement. Stent disruption
      and/or migration was observed in six patients. Of these six, four experienced
      life-threatening hemoptysis; all four had received aggressive anticancer
      treatment. CONCLUSION: G-Z stents are useful for palliation of malignant
      tracheobronchial obstruction. However, complications of stent strut fracture and
      migration give cause for concern.

PMID- 10415218
TI  - Hepatic chemoembolization: effect of intraarterial lidocaine on pain and
      postprocedure recovery.
AB  - PURPOSE: To determine if intraarterial lidocaine reduces pain during and after
      chemoembolization, and whether it influences postprocedure recovery. METHODS: Two
      patient cohorts undergoing selective hepatic chemoembolization were compared.
      Chemoembolization was performed without lidocaine (control group) in 27 patients
      and intraarterial lidocaine was used (lidocaine group) in 29 similar patients.
      Objective changes in patient management were assessed. Pain reduction in 31 more
      procedures with lidocaine (total 60) was assessed and related to tumor type.
      RESULTS: During chemoembolization, intraarterial lidocaine reduced the need for
      additional intravenous analgesics from 69% to 19%. After chemoembolization the
      mean Dilaudid dose in the first 24 hr was reduced from 9.5 mg to 4.15 mg;
      accordingly, the mean length of hospital stay was reduced from 67.5 to 53.5 hr.
      During the day of chemoembolization, the mean oral fluid intake increased from
      420 ml (control group) to 487 ml (lidocaine group); the percentage of patients
      taking solid food on the day of chemoembolization increased from 3% to 43%.
      CONCLUSION: Intraarterial lidocaine during chemoembolization reduces the severity
      and duration of pain after chemoembolization resulting in faster recovery thus
      reducing the length of hospitalization.

PMID- 10415219
TI  - Recurrent TIPS failure associated with biliary fistulae: treatment with PTFE
      covered stents.
AB  - PURPOSE: To evaluate the efficacy of covered stents for the treatment of
      transjugular intrahepatic portosystemic shunt (TIPS) obstruction in human
      subjects with identified or suspected biliary fistulae. METHODS: Five patients
      were treated for early failure of TIPS revisions. All had mid-shunt thrombus, and
      four of these had demonstrable biliary fistulae. Three patients also propagated
      thrombus into the native portal venous system and required thrombolysis. TIPS
      were revised in four patients using a custom-made polytetrafluoroethylene (PTFE)
      covered Wallstent, and in one patient using a custom-made PTFE-covered Gianturco
      Z-stent. RESULTS: All identified biliary fistulae were successfully sealed. All
      five patients maintained patency and function of the TIPS during follow-up
      ranging from 2 days to 21 months (mean 8.4 months). No patient has required
      additional revision. Thrombosis of the native portal venous system was treated
      with partial success by mechanical thrombolysis. CONCLUSION: Early and recurrent
      failure of TIPS with mid-shunt thrombosis, which may be associated with biliary
      fistulae, can be successfully treated using covered stents. Stent-graft revision
      appears to be safe, effective, and potentially durable.

PMID- 10415221
TI  - Interventional radiologic treatment for idiopathic portal hypertension.
AB  - PURPOSE: To evaluate the usefulness of interventional radiological treatment for
      idiopathic portal hypertension. METHODS: Between 1995 and 1998, we performed an
      interventional radiological treatment in five patients with idiopathic portal
      hypertension, four of whom had refused surgery and one of whom had undergone
      surgery. Three patients with gastroesophageal varices (GEV) were treated by
      partial splenic embolization (PSE), one patient with esophageal varices (EV) and
      massive ascites by transjugular intrahepatic portosytemic shunt (TIPS) and PSE,
      and one patient with GEV by percutaneous transhepatic obliteration (PTO). Midterm
      results were analyzed in terms of the effect on esophageal and/or gastric
      varices. RESULTS: In one woman with severe GEV who underwent three sessions of
      PSE, there was endoscopic confirmation that the GEV had disappeared. In one man
      his EV shrunk markedly after two sessions of PSE. In two patients slight
      reduction of the EV was obtained with one application of PSE combined with
      endoscopic variceal ligation therapy. PTO for GV in one patient resulted in good
      control of the varices. All patients have survived for 16-42 months since the
      first interventional treatment, and varices are well controlled. CONCLUSION:
      Interventional radiological treatment is effective for patients with idiopathic
      portal hypertension, whether or not they have undergone surgery.

PMID- 10415220
TI  - Primary implantation of polyester-covered stent-grafts for transjugular
      intrahepatic portosystemic stent shunts (TIPSS): A pilot study.
AB  - PURPOSE: To investigate whether placement of a polyester-covered stent-graft
      increases the primary patency of transjugular intrahepatic portosystemic stent
      shunts (TIPSS). METHODS: Between 1995 and 1997 Cragg Endopro or Passager MIBS
      stent-grafts were used for the creation of TIPSS in eight male patients, 35-59
      years of age (mean 48 years). All patients suffered from recurrent variceal
      bleeding and/or refractory ascites due to liver cirrhosis. Seven stent-grafts
      were dilated to a diameter of 10 mm, one to 12 mm. Follow-up was performed with
      duplex ultrasound, clinical assessment, and angiography. RESULTS: The technical
      success rate for creation of a TIPSS was 100%. The mean portosystemic pressure
      gradient decreased from 25 mmHg to 12 mmHg. In seven of eight patients TIPSS
      dysfunction occurred between 2 days and 3 years after stent-graft placement. In
      one patient the TIPSS is still primarily patent (224 days after creation). The
      secondary patency rates are 31 days to 3 years. CONCLUSION: The primary use of
      polyester-covered stent-grafts for TIPSS did not increase primary patency rates
      in our small series.

PMID- 10415222
TI  - Embolization of the vasa recta in acute lower gastrointestinal hemorrhage: A
      report of five cases.
AB  - PURPOSE: To present our preliminary experience in embolization of the vasa recta
      in acute gastrointestinal hemorrhage. METHODS: In four of five patients with
      acute gastrointestinal hemorrhage superselective embolization of the vasa recta
      was performed. In one patient in whom superselective catheterization of the
      bleeding vas rectum was technically impossible, the origin of this vessel was
      embolized at the level of the terminal arcade. The following embolization
      materials were used: microcoils and polyvinyl alcohol particles (355-500 microm),
      n = 2; microcoils only, n = 2; Gelfoam particles, n = 1. RESULTS: Bleeding was
      found in two patients in the small bowel (jejunum and ileum) and in three
      patients in the colon. Immediate hemostasis was achieved in all patients. No
      signs of ischemia or infarction were observed after intervention. CONCLUSIONS:
      Superselective embolization of the vasa recta proved efficient and safe in our
      small patient group. Advantages of this technique are reduction of the embolized
      area to a minimum and direct control of hemostasis.

PMID- 10415224
TI  - Coil embolization of arterioportal fistula that developed after partial
      gastrectomy.
AB  - A 51-year-old man suffered from bleeding esophageal varices. He had undergone
      partial gastrectomy for gastric cancer 1 year before. An extrahepatic
      arterioportal fistula and resultant portal hypertension were found. We
      successfully performed transarterial embolization of the fistula using stainless
      steel coils. Portal hypertension improved dramatically.

PMID- 10415223
TI  - Pulmonary hemorrhage: imaging with a new magnetic resonance blood pool agent in
      conjunction with breathheld three-dimensional magnetic resonance angiography.
AB  - PURPOSE: To describe the three-dimensional magnetic resonance angiography (3D
      MRA) imaging appearance of the pulmonary arteries following administration of a
      superparamagnetic iron oxide blood pool agent to human volunteers, and to
      demonstrate in an animal model (pigs) how this technique can be used to detect
      pulmonary parenchymal hemorrhage. METHODS: Two volunteers were examined following
      the intravenous administration of a superparamagnetic iron oxide blood pool agent
      (NC100150 Injection, Nycomed Amersham Imaging, Wayne, PA, USA). T1-weighted 3D
      gradient recalled echo (GRE) image sets (TR/TE 5.1/1.4 msec, flip angle 30
      degrees ) were acquired breath-held over 24 sec. To assess the detectability of
      pulmonary bleeding with intravascular MR contrast, pulmonary parenchymal injuries
      were created in two animals under general anesthesia, and fast T1-weighted 3D GRE
      image sets collected before and after the injury. RESULTS: Administration of the
      intravascular contrast in the two volunteers resulted in selective enhancement of
      the pulmonary vasculature permitting complete visualization and excellent
      delineation of central, segmental, and subsegmental arteries. Following
      iatrogenic injury in the two animals, pulmonary hemorrhage was readily detected
      on the 3D image sets. CONCLUSION: The data presented illustrate that ultrafast 3D
      GRE MR imaging in conjunction with an intravenously administered intravascular
      blood pool agent can be used to perform high-quality pulmonary MRA as well as to
      detect pulmonary hemorrhage.

PMID- 10415225
TI  - Emergent right coronary artery thrombectomy with a jet aspiration thrombectomy
      catheter.
AB  - A saline-jet aspiration thrombectomy (JAT) catheter was used in a patient with
      acute myocardial infarction. A right coronary arteriogram showed complete
      thrombotic occlusion at the proximal segment. With this catheter the thrombus was
      removed without complications in 5 sec. The patient underwent percutaneous
      transluminal coronary angioplasty and placement of a Palmaz-Schatz stent after
      successful thrombectomy. Thrombectomy with a JAT catheter was very useful in this
      patient.

PMID- 10415226
TI  - Percutaneous transhepatic catheterization of the portal vein: A combined CT- and
      fluoroscopy-guided technique.
AB  - Combined CT- and fluoroscopy-guided transhepatic portal vein catheterization was
      performed in 44 patients selected for pancreatic islet cell transplantation. The
      method allowed catheterization with a single puncture attempt in 39 patients. In
      four patients two attempts and in one patient four attempts were necessary. One
      minor hematoma of the liver capsule occurred that required no further treatment.
      Compared with other methods the average number of puncture attempts was reduced.

PMID- 10415227
TI  - Stabilization of a percutaneously implanted port catheter system for hepatic
      artery chemotherapy infusion.
AB  - A port catheter system for hepatic artery infusion chemotherapy was implanted
      percutaneously via the left subclavian artery in 41 patients for treatment of
      unresectable liver metastases. The catheter tip was inserted into the
      gastroduodenal artery (GDA), the end hole was occluded with a guidewire fragment,
      and a side-hole for infusion was positioned at the bifurcation of the proper
      hepatic artery and the GDA. The GDA was embolized with steel coils around the
      infusion catheter tip via a transfemoral catheter. This procedure is designed to
      reduce the incidence of hepatic artery occlusion and infusion catheter
      dislocation.

PMID- 10415228
TI  - Focal fatty infiltration in the posterior aspect of hepatic segment IV associated
      with aberrant pancreaticoduodenal venous drainage.

PMID- 10415230
TI  - Announcements 

PMID- 10415229
TI  - Re: Intrahepatic portosystemic shunt.

PMID- 10415231
TI  - MRI - from basic knowledge to advanced strategies: hardware.
AB  - There have been remarkable advances in the hardware used for nuclear magnetic
      resonance imaging scanners. These advances have enabled an extraordinary range of
      sophisticated magnetic resonance MR sequences to be performed routinely. This
      paper focuses on the following particular aspects: (a) Magnet system. Advances in
      magnet technology have allowed superconducting magnets which are low maintenance
      and have excellent homogeneity and very small stray field footprints. (b)
      Gradient system. Optimisation of gradient design has allowed gradient coils which
      provide excellent field for spatial encoding, have reduced diameter and have
      technology to minimise the effects of eddy currents. These coils can now
      routinely provide the strength and switching rate required by modern imaging
      methods. (c) Radio-frequency (RF) system. The advances in digital electronics can
      now provide RF electronics which have low noise characteristics, high accuracy
      and improved stability, which are all essential to the formation of excellent
      images. The use of surface coils has increased with the availability of phased
      array systems, which are ideal for spinal work. (d) Computer system. The largest
      advance in technology has been in the supporting computer hardware which is now
      affordable, reliable and with performance to match the processing requirements
      demanded by present imaging sequences.

PMID- 10415232
TI  - K-space sampling strategies.
AB  - The k-space algorithm offers a comprehensive way for classification and
      understanding of the imaging properties of all commonly used MR sequences. This
      presentation describes the basic concepts of k-space and its most relevant
      properties for MR imaging. The ramifications of k-space sampling is discussed for
      the most commonly used groups of MR sequences including gradient-echo techniques,
      echo-planar imaging, spin echo, and rapid acquisition relation enhanced imaging
      (e. g., turbo spin echo, fast spin echo). In addition, the basic problems and
      properties of sequences based on non-rectilinear k-space sampling, such as spiral
      imaging, are discussed. Their artifact behavior is significantly different from
      rectilinear scans, which project all imperfections along the phase-encoding
      directions, whereas the artifact produced by spirals are more complex and not
      always easily recognizable as such. An understanding of the k-space sampling
      offers important insight into the basic properties of a given sequence regarding
      signal-to-noise ratio, image distortion, resolution and contrast. It is
      demonstrated that the ultimate limitation in imaging speed is given by the loss
      of signal-to-noise ratio inherent to faster data sampling.

PMID- 10415233
TI  - Contrast mechanisms in MR imaging.
AB  - This paper is a brief introduction to tissue-specific parameters and the
      utilization of various MR imaging sequences to display these parameters in order
      to differentiate normal from pathologic tissue and function. The three dominant
      tissue-specific parameters discussed are proton density, longitudinal relaxation
      time T1, and transverse relaxation time T2. For the utilization of gradient-echo
      sequences, transverse relaxation time T2(*) is introduced, more dependent on the
      environment or tissue interfaces than on the tissue itself. Another tissue
      specific parameter is the concentration of macromolecules and their hydration
      layers as targeted with magnetization transfer imaging. Still another tissue
      specific parameter is the chemical environment. Functional parameters that
      influence the contrast are diffusion, perfusion, flow, or motion. The sequence
      related utilization of these tissue-specific parameters start with magnetization
      preparation as in spectral suppression of fat signal, relaxation-dependent
      elimination of fat or cerebrospinal fluid (CSF) signal, simple inversion pulse,
      magnetization transfer saturation, or diffusion weighting. Possible contrast
      mechanisms for the tissue-specific parameters are discussed for each of the
      commonly used sequences, whether of spin-echo type or of gradient-echo type, with
      or without magnetization preparation, conventional single-echo acquisition, or
      contemporary multiecho acquisition.

PMID- 10415234
TI  - MR imaging of the brain: tumors.
AB  - The radiologic modality that most likely provides the imaging information needed
      in a patient suspected of having a brain tumor is MR imaging. A brain tumor can
      be reliably ruled out if the MR examination is performed properly and experts
      interpret the results as negative. If there is a tumor, however, its exact
      location and topography must be determined. Important for therapy and prognosis
      are also tumor properties such as histologic type and grade, as well as effects
      on adjacent brain structures. Although potentially a noninvasive method of in
      vivo neuropathology, MR is still far from being sufficiently specific, as
      dissimilar lesions may look the same despite the use of refined imaging
      protocols. The evolution of MR imaging continues, however, making further
      methodologic improvement likely. Presently, advanced methods, such as diffusion-
      and perfusion-weighted MR imaging, functional MR imaging, neuronavigation based
      on MR imaging data, and the use of MR imaging during surgery (intraoperative MR
      imaging), influence the way patients are treated. Likewise, follow-up imaging
      (monitoring) of tumor patients by MR has become more effective, and experience
      has shown how to distinguish reactive changes from recurrent tumor. In the
      future, MR imaging may gain importance in the development of novel therapeutic
      concepts.

PMID- 10415235
TI  - MRI of non-ischemic vascular disease: aneurysms and vascular malformations.
AB  - Due to flow-void phenomena, MRI is of great value in the demonstration of
      cerebral aneurysms and vascular malformations as well as of related parenchymal
      changes and hemorrhagic complications. Magnetic resonance angiography can produce
      vascular images which are of importance in the diagnosis and follow-up of the
      lesions.

PMID- 10415236
TI  - MR imaging of the brain: metabolic and toxic white matter diseases.
AB  - Metabolic disorders of the brain are rare, complex and confusing. The diagnostic
      modality of choice nowadays is MRI. The high diagnostic sensitivity, however, is
      coupled with a lack of specificity and usually results in the depiction of
      similar appearing but clinically diverse white matter processes. For this reason
      it is essential to perform the MRI as early as possible during the course of the
      disease and to keep in close contact to the referring clinician to optimize image
      interpretation. Another precondition is to know the natural course of brain
      myelination and to know how this appears on the individual MR machine with
      different parameters. In some diseases like phenylketonuria MRI seems to be an
      excellent tool to monitor dietary treatment and patient compliance. In patients
      after radio- and / or chemotherapy MRI reveals the radiation induced
      leucencephalopathy and can usually differentiate between a recurrent malignancy.

PMID- 10415237
TI  - Spinal infection.
AB  - Spinal infection is a significant cause of morbidity. Despite advances in
      antibiotic treatment regimens, the incidence is not decreasing due at least in
      part to an increase in 'at-risk' populations, namely the elderly and the
      immunocompromised. Prompt diagnosis is greatly facilitated by early and
      appropriate imaging techniques together with microbiological assessment following
      culture from blood, needle aspirate and biopsy material. This article gives an
      overview of imaging of spinal infection with an emphasis on MR imaging, which has
      greatly contributed to early diagnosis, thus allowing implementation of timely
      appropriate treatment.

PMID- 10415238
TI  - Rare bone infections "excluding the spine".
AB  - Bone infections are usually due to haematogenous spread from distant infected
      organs. Spread of local sepsis or contamination of open wounds are less frequent
      routes of infection. The commonest cause of osteomyelitis is Staphylococcus
      aureus. The term rare bone infections refers to diseases where only a few percent
      affect bone or diseases which are essentially rare; these include bacteria,
      fungi, parasites and non-specific conditions. Common examples are tuberculosis,
      salmonellosis, brucellosis, hydatidosis, madura, actinomycosis, aspergillosis and
      American fungal infections. Certain bone infections have become exceedingly rare,
      particularly atypical mycobacteria, viral embryopathies and spirochaetes. Rare
      bone infections are encountered in many parts of the world commonly in the
      tropics and in the U. S. Immunocompromise and ease of travel can lead to
      increased incidence. A high index of clinical suspicion is necessary for
      diagnosis. Specific laboratory diagnosis is not always possible. Radiographs,
      computed tomography, isotope studies and magnetic resonance are useful but may
      not make the diagnosis. Aspiration or biopsy is necessary. Rare bone infections
      may simulate non-infective bone lesions.

PMID- 10415239
TI  - Sports-related muscle injuries of the lower extremity: MR imaging appearances.
AB  - Sports-related injuries of the lower extremity are frequent. Before magnetic
      resonance (MR) imaging was available, ultrasound, radionuclide scintigraphy and
      computed tomography were used to evaluate muscle trauma. Although relatively
      inexpensive, these imaging modalities are limited by their low specificity. The
      high degree of soft tissue contrast and multiplanar capability of MR imaging,
      allow direct visualization as well as characterization of traumatic muscle
      lesions. This pictorial review highlights the spectrum of traumatic muscle
      lesions on MRI, with emphasis on its typical appearances.

PMID- 10415240
TI  - Systemic mastocytosis: MRI of bone marrow involvement.
AB  - Systemic mastocytosis (SM) is an abnormal proliferation of mast cells, located in
      different structures: skin, bone marrow, spleen, liver and lymph nodes. Magnetic
      resonance imaging was prospectively performed in ten patients diagnosed by bone
      marrow biopsy in order to describe the different patterns of bone marrow
      involvement. Coronal T1-weighted spin-echo images were obtained in vertebral,
      pelvic, humeral and femoral bones. Depending on the extension of the cell
      infiltration, three patterns of bone marrow involvement were used: normal/no
      involvement (N), non-homogeneous (NH) and homogeneous (H). All ten patients
      presented bone infiltration. The patterns observed were: spine (50 % NH, 50 % H),
      pelvis (70 % NH), humerus 100(NH) and femur 40 % (NH). T1-weighted MR imaging is
      a sensitive technique for detecting marrow abnormalities in patients with
      systemic mastocytosis. There is no correlation between percentage of mast cells
      in bone marrow biopsy and extent or pattern of bone marrow involvement.

PMID- 10415241
TI  - Unusual manifestation of an osteoid osteoma of the capitate.
AB  - A case of osteoid osteoma of the capitate in a 29-year-old male is reported. The
      patient suffered from unspecific clinical findings and a 3-year history of
      uncharacteristic wrist pain. Conventional radiographs of the wrist revealed a
      circumscribed sclerosis in the proximal part of the capitate bone beside a
      diffuse demineralisation of the carpal bones. Magnetic resonance imaging
      demonstrated a circumscribed, tumorous lesion with marked enhancement after IV
      administration of contrast agent and a highly calcified nidus, which was sharply
      demarcated by a small rim of granulation tissue from the surrounding spongious
      bone. Based on MRI findings, the diagnosis of an osteoid osteoma was established
      and confirmed after operation and histologic analysis.

PMID- 10415242
TI  - Primary soft tissue hydatid disease: report of two cases with MRI
      characteristics.
AB  - Hydatid disease of the soft tissues forms a rare mass lesion of the extremities.
      Two cases of primary hydatid disease in soft tissues are presented with MR
      imaging findings. A cystic mass with multiloculated or multicystic appearance was
      identified on MR images in both cases. The lesions were surrounded by a rim with
      two layers representing a collageneous and a vascularized pericyst. The contrast
      enhanced images demonstrated the vascularized component of the wall clearly in
      the first case. In diagnosis of hydatid disease and in its differentiation from
      other cystic lesions of the extremities, we think that the described MR
      appearances can be used confidently.

PMID- 10415243
TI  - Calcific tendinitis of the gluteus maximus tendon: CT findings.
AB  - Two cases of calcific tendinitis of gluteus maximus muscle are presented. The CT
      findings, including amorphous calcification without soft tissue mass and possible
      cortical erosion at the femoral enthesis of the gluteus maximus muscle, are
      highly suggestive of calcific tendinitis at this unusual but classical location.
      Ossifying entheses with well-defined cortical defect are frequent at the femoral
      insertion of the gluteus maximus muscle in asymptomatic subjects and must be
      differentiated from a real cortical erosion sometimes associated with these
      calcific tendinitis.

PMID- 10415244
TI  - MR mammography: influence of menstrual cycle on the dynamic contrast enhancement
      of fibrocystic disease.
AB  - Magnetic resonance mammography (MRM) provides data regarding the nature of
      tumours based on contrast medium dynamics; fibrocystic changes in the breast,
      however, may lead to false-positive results. This study investigated whether the
      contrast medium dynamics of fibrocystic changes are dependent on the menstrual
      cycle. Twenty-four patients with palpable lumps but normal mammographies and
      ultrasound studies were examined. The MRM technique was performed during the
      first and second part of the menstrual cycle using a FLASH 3D sequence, both
      native and at 1, 2, 3 and 8 min after intravenous application of 0.15 mmol/kg
      body weight of gadodiamide. The calculated time-intensity curves were evaluated
      based on the following criteria: early percentage of contrast medium uptake in
      relation to the native value; formation of a plateau phenomenon after the second
      minute; the point of maximal contrast medium uptake; and calculation of the
      contrast enhancing index. During the second half of the menstrual cycle, a
      generally greater contrast medium uptake was observed. Nevertheless, when further
      diagnostic criteria, such as continuous contrast medium increase as a function of
      time, were considered, there was no increased rate of false-positive findings.
      The phase of the menstrual cycle may affect the specificity of the examination,
      if only the quantitative contrast medium uptake and the percentage of contrast
      medium uptake in the first 2 min are considered. A control MRM during the other
      half of the cycle may then be indicated and additional diagnostic criteria may
      improve specificity.

PMID- 10415245
TI  - Metastases to the breast from rhabdomyosarcoma: appearances on MRI.
AB  - The authors report a case of blood-borne bilateral metastatic breast disease of
      alveolar rhabdomyosarcoma (RMS) in a 21-year-old patient. The possibilities of
      mammography, ultrasound, and MRI in the early detection of breast metastases and
      their appearance on these modalities are discussed. Whereas mammography rendered
      no additional information due to dense breast parenchyma and ultrasound showed
      only a solitary tumor without definite criteria of malignancy, multifocal
      bilateral spread was verified with MRI and early ring-like enhancement suggested
      malignancy. Therefore, we conclude that MRI may provide useful information in
      evaluating patients with sarcomas, even when there is no clinical evidence for
      metastatic disease of the breast.

PMID- 10415246
TI  - Multifocal bone tuberculosis presenting as a breast mass: CT and MRI findings.
AB  - Chest wall involvement is an uncommon manifestation of musculoskeletal
      tuberculosis. We present computed tomography and magnetic resonance imaging
      findings in a case with multifocal musculoskeletal tuberculosis presenting as a
      breast mass. These radiological modalities are not diagnostic without
      histopathological confirmation, but they are valuable guides to surgery in
      defining the extent of disease involvement.

PMID- 10415247
TI  - Extra-abdominal desmoid mimicking malignant male breast tumor.
AB  - A rare case of extra-abdominal desmoid tumor is reported. A palpable mass was
      detected in the right breast of a 47-year-old man. Mammography showed a stellate
      mass without calcification, and breast ultrasound examination revealed a solid,
      inhomogeneous, non-calcified lesion. The result of cytological examination of the
      fine-needle aspiration biopsy specimen was equivocal. Histology of the surgical
      specimen showed extra-abdominal desmoid tumor. Extra-abdominal presentation of
      this semimalignant tumor is rare and may mimic malignant breast tumor.
      Differential diagnosis is difficult and usually based on the result of the
      histological examination.

PMID- 10415248
TI  - Self-expanding metallic stents in the management of pyloric dysfunction after
      gastric pull-up operations.
AB  - The purpose of this paper is to report the use and benefits of self-expanding
      metallic stents employed in pyloric dysfunction. Four patients treated with
      oesophagectomy and gastric pull-up for oesophageal carcinoma failed to respond to
      balloon dilatation for pyloric dysfunction. Three of the patients were thought to
      have residual tumour at sites remote from the pylorus prior to stenting, but the
      fourth, who had undergone surgery 8 years previously, was thought to be cured.
      All were treated with self-expanding metallic stents. All four patients responded
      well with resolution of their symptoms. Over a mean follow-up of 6 months there
      has been no recurrence of symptoms. Stent insertion represents a potentially
      valuable method of treatment in patients with post-surgical pyloric dysfunction
      in whom simple balloon dilatation has failed.

PMID- 10415249
TI  - Intrahepatic arterioportal shunt: helical CT findings.
AB  - The purpose of this study was to characterize the appearance of intrahepatic
      arterioportal shunts (APS) on two-phase helical CT, with emphasis on the
      importance of the hepatic arterial-dominant phase (HAP) to demonstrate perfusion
      disorders. We review eight cases of APS diagnosed by helical CT in our
      institution from January 1996 to March 1997 and describe the CT findings that
      established diagnosis. Five of them were confirmed by angiography. In seven (87.
      5 %) cases of APS we found early enhancement of the peripheral portal branches
      during the HAP of helical CT, whereas the superior mesenteric and splenic veins
      remained unenhanced. In five (62.5 %) cases of APS, transient, peripheral,
      triangular parenchymal enhancement was depicted during the HAP of helical CT; in
      four of these cases there was associated early enhancement of the portal
      branches. Helical CT can show perfusion alterations that might remain undiagnosed
      with conventional CT. An understanding of the hemodynamic changes that occur in
      APS can help in the interpretation of focal transient hepatic parenchymal
      enhancement and to differentiate APS from hypervascular tumors. We believe that
      the helical CT findings described herein are characteristic enough to suggest the
      diagnosis of APS.

PMID- 10415250
TI  - Presinusoidal portal hypertension does not affect hepatic artery resistance
      index.
AB  - We aimed to determine the mean hepatic artery resistance index (RI) in
      presinusoidal portal hypertension and to compare the values with those in
      sinusoidal portal hypertension. The hepatic artery RIs of 11 patients with
      presinusoidal portal hypertension, 12 patients with sinusoidal portal
      hypertension and 16 healthy subjects were examined with duplex Doppler
      ultrasound. Mean hepatic artery RIs of three groups were compared. In patients
      with presinusoidal portal hypertension, mean RI in the hepatic artery (0.63 +/-
      0.06) was significantly lower (p < 0.05) than that in the patients with
      sinusoidal portal hypertension (0.73 +/- 0.03). There was no significant
      difference (p > 0.05) in the mean RIs of the hepatic artery between the patients
      with presinusoidal portal hypertension (0.63 +/- 0.06) and the controls (0.67 +/-
      0.05). Mean RI value in patients with sinusoidal portal hypertension (0.73 +/-
      0.03) was significantly higher (p < 0.05) than the mean values in the control
      group (0.67 +/- 0.05). Hepatic arterial resistance does not change in
      presinusoidal portal hypertension, whereas it increases in sinusoidal portal
      hypertension. However, there are some overlaps in the RI values which raise
      difficulties in the differentiation of these two forms of portal hypertension.

PMID- 10415252
TI  - Xanthogranulomatous cholecystitis associated with a xanthogranulomatous
      pseudotumour on the left diaphragm.
AB  - We present a case of xanthogranulomatous cholecystitis associated with a
      xanthogranulomatous vegetation on the left diaphragm with breakthrough into the
      thoracic cavity. A similar case has not previously been reported.

PMID- 10415251
TI  - Do magnesium ions influence barium mucosal coating of the large bowel?
AB  - The aim of the present study was to verify whether the presence of magnesium in
      the colon lumen at the time of the double-contrast barium enema (DCBE)
      examination changes the quality of barium mucosal coating. The two members of 38
      pairs of patients undergoing DCBE with a standardised technique were randomly
      subjected to bowel preparation with sennosides and magnesium sulphate, or
      sennosides and sodium sulphate. Mucosal coating, residual fluid and colon
      cleansing were assessed independently by three radiologists. The null hypothesis
      was tested by means of Wilcoxon's signed-rank test. Barium mucosal coating was
      judged to be better in the members to whom magnesium sulphate was administered (p
      = 0.0007). There was no difference in the amount of residual fluids (p = 0.3198).
      Colon cleansing was judged to be better in the members to whom sodium sulphate
      was administered (p = 0.0166). These results demonstrate, in a simple way, that
      magnesium ions increase barium coating of the colon mucosa in vivo. The
      underlying mechanisms (increase in viscosity of barium suspension through water
      subtraction owing to the hydrophilism of magnesium ions, or interactions with the
      polysaccharide additives) need further investigation. A first clinical
      application could be the integration of magnesium ions in a newly designed
      isotonic electrolyte solution containing polyethylene glycol for the oral colon
      wash-out.

PMID- 10415253
TI  - Placement of Palmaz stents in malignant duodenal stenosis through a cutaneous
      fistula.
AB  - This is the first report of palliative percutaneous treatment of a malignant
      duodenal stenosis due to cancer of the pancreatic head with Palmaz stents. A 65
      year-old male with a malignant tumour of the pancreatic head developed an abscess
      with fistular communication to the cutis. In the subsequent course of the
      disease, tumour growth led to a severe duodenal stenosis. To dilate the tumorous
      stenosis, three Palmaz stents were introduced coaxially into the duodenum
      percutaneously, via the preexisting fistula. A technique to pass an almost 90
      degrees kink is described. Symptomatic malignant duodenal stenosis was treated by
      insertion of three Palmaz stents. Due to their accurately controlled passive
      expansion at the level of the stenosis, and the resulting good adaptation to the
      individual anatomical situation, they were suitable for application in the
      duodenum.

PMID- 10415254
TI  - Biliary-enteric fistulas: report of five cases and review of the literature.
AB  - Internal biliary fistulas (IBF) are seen rarely. Because the symptoms and signs
      of IBF are not specific and the diagnosis is not suspected, these patients are
      commonly investigated with plain abdominal films (PAF), ultrasonography (US),
      upper gastrointestinal series (UGIS), barium enema (BE), and computed tomography
      (CT), but not always with endoscopic retrograde cholangiopancreatography (ERCP).
      The purposes of this article are (a) to attract attention of radiologists to
      presumptive findings of IBF, so as not to misdiagnose this unsuspected and rare
      disease, and (b) review of the literature while presenting radiologic features of
      our cases. Five cases of IBFs in which extrahepatic biliary tree communicating
      with duodenum (four cases) and colon (one case) are reported. Diagnostic work-up
      of cases were done by PAF, US, UGIS, BE, and CT. Aerobilia, which cannot be
      explained using other means, ectopic gallstone and small bowel dilatation,
      nonvisualization of the gallbladder despite no history of cholecystectomy, and
      thick-walled shrunken gallbladder adherent to neighboring organs were suggestive
      findings of IBF in our study. Knowledge of imaging findings suggestive of IBF and
      a high index of suspicion increase the diagnostic rate of IBFs.

PMID- 10415256
TI  - PACS workstation respecification: display, data flow, system integration, and
      environmental issues, derived from analysis of the Conquest Hospital pre-DICOM
      PACS experience.
AB  - This paper is based on 4 years of practical experience with a developmental pre-
      Digital Imaging and Communications in Medicine (DICOM) picture archiving and
      communication system (PACS) plus analysis from the respecification study data for
      a DICOM/HTML PACS replacement. High-performance, but economic, workstations are
      required within PACS for radiologists to rapidly and accurately report images.
      For economic reasons such workstations should utilise standard landscape
      orientation monitors. They must have full Radiology Information System (RIS)
      integrated reporting functionality to optimise radiologists' work. The
      workstations must also be capable of displaying request data and both new and
      associated old images and image reports from multiple modalities. All images
      should be imported as "folders" according to semi-intelligent "knowledge table"
      based DICOM 3.0 standard Worklist control exerted by image management servers.
      This information can be obtained by relevant image lists and decision charts. A
      description of an optimal standard monitor workstation environment and related
      issues based on experience and literature review is given.

PMID- 10415255
TI  - PACS: the silent revolution.
AB  - More than 15 years ago the idea of a Picture Archiving and Communication System
      (PACS) and a filmless hospital was created. In a PACS environment images are
      acquired, read, communicated and stored digitally. After many years of
      unsuccessful attempts and prototype installations, the necessary hardware
      components for a successful PACS installation are now readily available. However,
      software development is still lagging behind. Only very recently, software
      developers have realized that it is not sufficient for PACS software to store,
      communicate and display images, but that PACS software should effectively support
      the radiologist in the task of interpreting and communicating imaging findings
      through context-dependent default display arrangements, work-flow management,
      radiological and hospital information systems integration, and computer-assisted
      diagnosis. This review examines hard- and software requirements for efficient
      PACS operation, analyses costs and benefits, and discusses future developments.

PMID- 10415258
TI  - Maximal thickness of the normal human pericardium assessed by electron-beam
      computed tomography.
AB  - The purpose of this study was to determine the maximal value of normal
      pericardial thickness with an electron-beam computed tomography unit allowing
      fast scan times of 100 ms to reduce cardiac motion artifacts. Electron-beam
      computed tomography was performed in 260 patients with hypercholesterolemia
      and/or hypertension, as these pathologies have no effect on pericardial
      thickness. The pixel size was 0.5 mm. Measurements could be performed in front of
      the right ventricle, the right atrioventricular groove, the right atrium, the
      left ventricle, and the interventricular groove. Maximal thickness of normal
      pericardium was defined at the 95th percentile. Inter-observer and intra-observer
      reproducibility studies were assessed from additional CT scans by the Bland and
      Altman method [24]. The maximal thickness of the normal pericardium was 2 mm for
      95 % of cases. For the reproducibility studies, there was no significant
      relationship between the inter-observer and intra-observer measurements, but all
      pericardial thickness measurements were </= 1.6 mm. Using electron-beam computed
      tomography, which assists in decreasing substantially cardiac motion artifacts,
      the threshold of detection of thickened pericardium is statistically established
      as being 2 mm for 95 % of the patients with hypercholesterolemia and/or
      hypertension. However, the spatial resolution available prevents a reproducible
      measure of the real thickness of thin pericardium.

PMID- 10415257
TI  - World Wide Web and Internet: applications for radiologists.
AB  - Global exchange of information is one of the major sources of scientific progress
      in medicine. For management of the rapidly growing body of medical information,
      computers and their applications have become an indispensable scientific tool.
      Approximately 36 million computer users are part of a worldwide network called
      the Internet or "information highway" and have created a new infrastructure to
      promote rapid and efficient access to medical, and thus also to radiological,
      information. With the establishment of the World Wide Web (WWW) by a consortium
      of computer users who used a standardized, nonproprietary syntax termed HyperText
      Markup Language (HTML) for composing documents, it has become possible to provide
      interactive multimedia presentations to a wide audience. The extensive use of
      images in radiology makes education, worldwide consultation (review) and
      scientific presentation via the Internet a major beneficiary of this technical
      development. This is possible, since both information (text) as well as medical
      images can be transported via the Internet. Presently, the Internet offers an
      extensive database for radiologists. Since many radiologists and physicians have
      to be considered "Internet novices" and, hence, cannot yet avail themselves of
      the broad spectrum of the Internet, the aim of this article is to present a
      general introduction to the WWW/Internet and its applications for radiologists.
      All Internet sites mentioned in this article can be found at the following
      Internet address: http://www.univie.ac. at/radio/radio.html (Department of
      Radiology, University of Vienna)

PMID- 10415259
TI  - Exogenous lipoid pneumonia: HRCT, MR, and pathologic findings.
AB  - The objective of this study was to describe high-resolution CT (HRCT) and MR
      findings of exogenous lipoid pneumonia and to correlate them with pathologic
      findings. A retrospective review of the medical records of our institution
      revealed seven patients with a diagnosis of lipoid pneumonia based on clinical
      data, chest films, bronchoalveolar lavage, and follow-up. Both HRCT and MR
      imaging were reviewed by two readers. Pathologic examination of the resected
      specimen or surgical biopsies were also reviewed in the four available cases. The
      HRCT findings were pulmonary consolidations (n = 6) with fatty (n = 3) or
      unspecific but low attenuation values (n = 3), areas of ground-glass opacities (n
      = 5), septal lines, and centrilobular interstitial thickening (n = 5). In five of
      the seven cases, a crazy-paving pattern of various spread was also present,
      either isolated (n = 1) or surrounding a pulmonary consolidation. In two cases
      traction bronchiectasis and cystic changes consistent with fibrosis were seen. At
      MR imaging (n = 2) a pulmonary consolidation of high signal intensity on T1
      weighted image consistent with lipid content was present in one case. Pathologic
      examination (n = 4) showed the coexistence of lobules with lesions of various
      ages, sometimes in contiguous lobules, within the same patient. Recent lesions
      were those with alveolar fill-in by spumous macrophages and almost normal
      alveolar walls and septae. In more advanced lesions, lobules were filled in with
      larger vacuoles often surrounded by inflammatory infiltrates of alveolar walls,
      bronchiolar walls, and septa. The oldest lesions were characterized by fibrosis
      and parenchymal distortion around large lipid-containing vacuoles. The HRCT
      findings reflect pathologic findings in exogenous lipoid pneumonia. Although non
      specific, consolidation areas of low attenuation values and crazy-paving pattern
      are frequently associated in exogenous lipoid pneumonia and are indicative of the
      diagnosis.

PMID- 10415260
TI  - Evaluation of sleep apnea syndrome with low-field magnetic resonance fluoroscopy.
AB  - The aim of this study was to assess the upper airway status of sleep apnea
      syndrome (SAS) patients with low-field MR fluoroscopy. Twenty patients with
      clinically diagnosed SAS underwent upper airway monitoring using MR fluoroscopy
      for 5 min while awake and for 30 min while asleep. A 0.064-T permanent-magnet MR
      imaging system was used for the study. No patients required any sedative drugs
      because of the very small gradient noise, except in one case. No occlusion was
      observed while patients were awake. Nine patients showed repeated occlusion at
      retropalatal (Rp) pharynx, whereas 11 demonstrated both simple Rp occlusion and
      combined retropalato-retroglossal (Rp + Rg) occlusions (complex occlusion). The
      mean frequency of occlusion in complex cases was significantly higher than that
      in simple Rp cases (p < 0.05). Low-field MR fluoroscopy was useful in determining
      the occlusion level while asleep in patients with SAS because of its quiet gantry
      and long-term monitoring capability. The MR fluoroscopy technique should prove to
      be a valuable clinical tool for the diagnosis and for determining the appropriate
      therapy in patients with SAS.

PMID- 10415261
TI  - Cellulose granulomatosis of the lungs.
AB  - Chest radiographs and high-resolution chest CT scans were performed in a 30-year
      old man with a history of intravenous drug abuse and diffuse micronodular
      infiltrates. Transbronchial biopsy gave a diagnosis of cellulose granulomatosis
      of the lung. Cellulose granulomatosis should be considered in the differential
      diagnosis of pulmonary interstitial disease, especially in the setting of
      intravenous drug abuse.

PMID- 10415262
TI  - Inflammatory myofibroblastic tumor of the lung (inflammatory pseudotumor):
      uncommon cause of solitary pulmonary nodule.
AB  - Lung inflammatory myofibroblastic tumor is an uncommon cause of solitary lung
      nodule (0.7 % of lung tumors). The principal site of inflammatory pseudotumor is
      the lung, but it can also occur elsewhere in various organs. Although benign,
      they may be locally very aggressive. Recurrent and multifocal forms have been
      described. Since they are likely to mimic malignant neoplasms, accurate
      histopathologic diagnosis is necessary in order to guide appropriate surgical
      excision and avoid aggressive treatments. We report a case of lung involvement in
      a young adult with radiologic and pathologic correlations.

PMID- 10415263
TI  - Endovaginal color Doppler sonographic evaluation of ectopic pregnancy in women
      after in vitro fertilization and embryo transfer.
AB  - The aim of this study was to evaluate the value of endovaginal color Doppler
      ultrasonography in the early diagnosis of ectopic pregnancy in women after in
      vitro fertilization and embryo transfer, and to correlate the sonographic
      findings with ss-hCG serum levels. Thirty-five patients had proven ectopic
      pregnancies and 4 other patients had heterotopic pregnancies. The diagnosis was
      disclosed correctly in all cases by endovaginal color Doppler US by identifying
      an adnexal mass with placental flow and a nongravid uterus called a "cold
      uterus". An intrauterine sac with "double ring sign" was found in all normal
      intrauterine pregnancies when the hCG levels exceeded 1000 IU/l but in none of
      the patients with ectopic pregnancy (EP). These findings suggest the efficacy of
      the discriminatory hCG serum level of 1000 IU/l in the investigation of EP. In
      conclusion, this study describes the diagnostic importance of transvaginal color
      Doppler US in correlation with hCG serum levels in the early detection of EP
      avoiding life-threatening complications and improving patient outcome.

PMID- 10415265
TI  - Castleman disease: CT and MR imaging features of a retroperitoneal location in
      association with paraneoplastic pemphigus.
AB  - We describe the CT and MRI features of a case of Castleman disease which was
      unusual by both its retroperitoneal location and its association with
      paraneoplastic pemphigus.

PMID- 10415264
TI  - MR imaging of non-squamous vaginal tumors.
AB  - We reviewed the MR images and pathologic findings of five cases of primary
      vaginal neoplasms of non-squamous origin. Histologic types consisted one case
      each of adenocarcinoma, adenosarcoma, melanoma, lymphoma, and neurilemoma.
      Magnetic resonance imaging was found useful for evaluating the type and the
      extension of vaginal tumors.

PMID- 10415266
TI  - High-resolution ultrasound evaluation of internal jugular venous valves.
AB  - Although the presence of valves in the distal portion of the internal jugular
      veins has been widely described by anatomists and pathologists, their existence
      remains underscored in the medical literature. We set out to demonstrate their
      sonographic aspect and to evaluate their morphology, location and prevalence.
      Seventy-five cadavers were evaluated for the presence and aspect of such valves
      through neck dissections. Concurrent evaluation of the sonographic character of
      these structures was performed in another cohort of 75 adults. Valves of the
      distal portion of the internal jugular veins were found in 93 % of the cadaveric
      studies. Ultrasonography easily demonstrated the valve leaflets in 87 % of
      patients; all were observed in the distal portion of the internal jugular (IJ)
      veins. Sixty percent were bilateral with the majority of unilateral veins found
      on the right side. High-resolution ultrasonography easily demonstrates valves in
      the distal portion of the IJ veins which are present in the great majority of
      persons. Their evaluation may be of use in percutaneous procedures using this
      venous access.

PMID- 10415267
TI  - Pseudoaneurysm of the abdominal aorta: evaluation with virtual angioscopy of
      spiral-CT data sets.
AB  - We describe a case of graft-related pseudoaneurysm of the abdominal aorta
      evaluated with spiral CT and DSA. Spiral CT data sets were processed to obtain
      surface-rendered internal views (virtual angioscopy, VA) of the graft and the
      pseudoaneurysm, and to demonstrate from inside the lumen the site of dehiscence.
      A jet flow phenomenon inside the pseudoaneurysm was observed at DSA. Spiral-CT
      axial images, multiplanar volume reconstructions with maximum intensity
      projections, and shaded surface display showed the site of rupture. The VA
      findings were: (a) from inside the graft lumen, the evidence of a communication
      canal between the graft and the pseudoaneurysm; and (b) from inside the
      pseudoaneurysm, the presence of a jet flow. The VA findings showed good
      correlation with those obtained with the other imaging techniques.

PMID- 10415268
TI  - Life-threatening spontaneous psoas haematoma treated by transcatheter arterial
      embolization.
AB  - We report two cases of large spontaneous psoas haematoma in patients on
      anticoagulant therapy. Active bleeding was well demonstrated on spiral CT.
      Transcatheter arterial embolization was used successfully to stop bleeding. The
      diagnostic strategy, the relevance of spiral computed tomography and our
      therapeutic approach to this complication are discussed.

PMID- 10415270
TI  - Malignant fibrous histiocytoma of the jejunum.

PMID- 10415269
TI  - Low-grade transitional cell carcinoma of the renal pelvis: evolution over 16
      years.

PMID- 10415271
TI  - Serosal metastasis presenting as a cutaneous mass.

PMID- 10415273
TI  - Lubos Vyhnanek (1928-1999) 

PMID- 10415272
TI  - Quiz case of the month. Infertility work-up. Diagnosis: bilateral testicular
      microlithiasis.

PMID- 10415274
TI  - Babies born with major disabilities.

PMID- 10415276
TI  - Babies born with major disabilities: the medical-legal interface.
AB  - This article explores some of the legal and medical issues that confront doctors,
      lawyers, ethicists, and families when faced with the problems of a baby born with
      one or more major disabilities. Attitudes vary widely, and these are emphasised
      by cultural and social aspects in different parts of the world. Although the
      legal issues vary, in a large number of countries there appears to be less
      variation than with the medical issues.

PMID- 10415275
TI  - Ethical considerations in prenatal surgical consultation.
AB  - When pediatric surgeons counsel the prospective parents of a fetus with a major
      congenital anomaly, medical and ethical issues may arise in one or more contexts.
      There may be: (1) issues concerning the possibility of in-utero intervention or
      termination of pregnancy; (2) issues surrounding the timing, location and mode of
      delivery; and (3) issues concerning possible operative interventions after the
      birth. The virtues of compassion, honesty, and integrity should guide the surgeon
      in helping the parents confront the diagnosis of a fetal malformation. The
      ethical principles that inform the prenatal consultation should include respect
      for autonomy, reproductive freedom, beneficence, and justice. Ethical conflict
      may develop if the pregnant woman chooses a course of action that is inconsistent
      with traditional pediatric surgical recommendations.

PMID- 10415277
TI  - The relationship between ethics and phronesis.
AB  - The management of a baby born with a major disability presents one of the most
      significant ethical problems faced at the end of the second millenium. These
      problems concern the individual baby and its family, but society as a whole is
      and must be involved in their resolution. This article explores these issues as
      they impact on the contemporary surgeon confronted with changing medical,
      technical, and ethical considerations.

PMID- 10415278
TI  - Conservative treatment of caustic esophageal injuries in children: 20 years of
      experience.
AB  - The authors present their experience in the medical treatment of 1, 296 caustic
      esophageal injuries in children over the last 20 years in two study groups, one
      comprising the period up to 1989 and the other 1990 to 1996, comparing the
      different treatments used in each group. The treatment was based fundamentally on
      dilatations with anterograde mercury bougies, Savary bougies, or retrograde
      thread-guided bougies with gastrostomy. Pneumatic balloons or stenting procedures
      have also been employed in the last 3 years. Early fiberendoscopy was used
      systematically in the second group, which provides a more accurate evaluation of
      the esophageal lesions. Antibiotic coverage was done systematically during the
      first 10 days in all serious cases, while steroids were employed routinely only
      in the last 3 years. The results were similar in both groups, with a dilatation
      average of 32 in the first and 30 in the second group and an initial dilatation
      interval of 3 to 4 weeks in both. Using updated exploration and dilatation
      techniques, we drastically reduced the number of gastrostomies needed for
      retrograde thread-guided dilatations from 51 in the first group to 5 in the
      second, consequently improving the patients' life quality. There was no mortality
      and only five esophageal perforations, which did not require surgical treatment.

PMID- 10415279
TI  - Cystic adenomatoid malformation of the lung: neonatal management of 21 cases.
AB  - Currently, congenital cystic adenomatoid malformation of the lung (CCAM) is often
      diagnosed antenatally by ultrasound, allowing prompt and appropriate medical and
      surgical management after birth. The authors report 21 cases of CCAM admitted
      from 1988 to 1997 to a neonatal intensive care unit and treated by high-frequency
      oscillation (HFO) and early surgery. Six infants developed respiratory distress,
      of whom 4 required ventilation by HFO. HFO was also the mode of ventilation used
      in all cases except 1 during the perioperative period. There was no death from
      respiratory failure. The authors emphasize the usefulness of antenatal diagnosis,
      the efficiency of HFO in cases with severe respiratory failure, and well
      tolerated early surgery.

PMID- 10415280
TI  - Long-term outcome of congenital cystic adenomatoid malformation.
AB  - To determine the long-term outcome of congenital cystic adenomatoid malformation
      (CCAM), the records of all patients with CCAM treated in three Hungarian
      paediatric surgical centers between 1977 and 1996 were reviewed. Patients were
      followed for up to 20 years following diagnosis and treatment. In 20 patients
      CCAM was diagnosed postnatally and in 3 prenatally. Biodata including the
      operative procedures are presented. Follow-up findings between 18 months and 20
      years after diagnosis showed better height and weight growth in patients operated
      upon in later childhood compared with those operated upon in infancy. The older
      the patient at the time of diagnosis, the better was the long-term outcome.

PMID- 10415281
TI  - Congenital pouch colon in females.
AB  - From January 1995 to March 1998, congenital pouch colon (CPC) with anorectal
      agenesis was diagnosed in ten girls who were classified into four groups based on
      the length of normal colon proximal to the colonic pouch. Of six girls with
      little or no normal colon, one had a cloacal anomaly while five had a colovesical
      or colovestibular fistula along with a completely bifid uterus and cervix and a
      septate vagina. Initial surgery consisted of ligation of the fistula and subtotal
      pouch excision with tubularization of the remaining colon in four girls,
      ileostomy after excision of a gangrenous pouch in one, and window colostomy in
      another. None of the patients had a sacral abnormality or associated major
      malformation. Definitive surgery using the posterior sagittal approach consisted
      of a pull-through of the tubularized colon in three girls (including one in whom
      one-stage cloacal reconstruction was performed), the ileum in one, and the
      proximal colon in another. The four girls with a longer length of normal colon
      had an associated vestibular fistula. In these, a colostomy was constructed just
      proximal to the pouch with definitive surgery in two patients consisting of
      excision of the pouch and pull-through of the proximal colon. Definitive surgery
      was well tolerated in all seven patients. The embryogenesis of this condition and
      the related genitourinary tract abnormalities are discussed.

PMID- 10415282
TI  - Comparison of results of laparoscopic and open antegrade continence enema
      procedures.
AB  - Several modifications of the Malone antegrade continence enema (ACE) procedure
      have now been reported. In this study we have compared the results of our
      experience with the laparoscopic appendicostomy (LACE procedure) with the
      published results of previously described open ACE procedures. Children who had
      the LACE procedure at our institutions were reviewed. Intra- and postoperative
      problems were identified by review of hospital case notes and from a
      questionnaire completed by the children's caregivers. These results were compared
      with the reported results of the original Malone procedure, the Pena
      modification, and the open appendicostomy as described by Wilcox. Since 1994, 30
      children have had LACE procedures performed at our institutions. Two have
      required conversion to an open procedure because of difficulty locating the
      appendix. The stoma is being used for regular antegrade colonic washouts in 29 of
      the 30, compared with 19 of 31 in Malone's series and 16 of 20 in Pena's.
      Improvement in soiling has been achieved in 27 (90%) of our patients, 15 of whom
      are completely clean, a rate similar to that of the other types of procedure (61%
      78%). Stenosis of the stoma has occurred in 8 children (27%), compared with rates
      of 10%-33% in other series. Stomal leakage has been troublesome for 2 (6.7%),
      compared with leak rates between 5.6% and 15% in other series. The LACE procedure
      is technically the simplest. The laparoscopic approach to the ACE procedure
      appears to be a simpler and safe alternative to previously described methods. It
      causes minimal morbidity, has a high long-term viability rate, and resulted in
      improved control of soiling in 90% of the children with faecal incontinence in
      whom it has been employed.

PMID- 10415283
TI  - The role of minimal surgery with renal preservation in abnormal complete duplex
      systems.
AB  - Among 36 children, mostly less than 1 year of age, referred for a complete duplex
      system anomaly, 18 were diagnosed before birth by obstetrical ultrasonography
      where a diagnosis of dilated upper urinary tract was the most frequent report; in
      the remaining cases urinary tract infection was the main presenting symptom. Five
      children had bilateral anomalies. Principal diagnoses associated with the
      complete duplex system were: 18 ureteroceles (UC) (11 extravesical [EUC] with
      bladder-neck or urethral extension, 7 intravesical [IUC]), 5 ectopic ureters
      without UC and 28 lower-polar vesicoureteral reflux (VUR) associated in 6 with
      upper polar VUR. The initial assessment was based on a voiding cystogram and
      radionuclide scan. Renal-polar function was severely impaired when major ureteral
      ectopia or severe primary reflux was present. Primary surgery was performed in 8
      patients, demolitive in 4 (3 upper-polar nephrectomies, 1 nephrectomy) and
      reconstructive in 4 (duplex en-bloc reimplantation); staged management with
      minimal endoscopic incision was undertaken in 15 UCs (9 EUCs and 6 IUCs).
      Expectant management was elected in all cases of mild primary, single, or double
      VUR not associated with UC and was followed by spontaneous reduction in one-half
      of the cases. Secondary VUR complicated endoscopic incision in 2 of 6 IUCs and 5
      of 9 EUCs; a certain degree of functional improvement after decompression could
      be observed in all IUCs versus only 2 EUCs. Twenty-one patients requested
      secondary surgery; 17 needed an open intravesical procedure for ureteral
      reimplantation, combined in 8 with UC excision and bladder-floor reconstruction
      and in 5 with upper-pole nephrectomy. A nephrectomy was required in 4 cases. All
      primary or secondary demolitive procedures involved 9 of 11 EUCs extravesical and
      2 of 5 ectopic ureters. EUCs and ureteral ectopia were associated with severe
      renal-polar damage, and function was rarely affected by primary decompressive
      procedures even in prenatally detected, uninfected cases. Endoscopic incision of
      EUCs was frequently followed by secondary VUR, which made secondary intravesical
      operations more complex. For these reasons, primary elective resection of a
      dysplastic upper pole is preferable in most cases to temporary decompressive
      measures. Conservative surgery is always indicated in IUC, which may benefit from
      endoscopic decompression. Isolated VUR involving the lower pole of a completely
      duplicated system may respond to expectant management in a significant number of
      cases.

PMID- 10415285
TI  - Acute scrotal pain in children: results of 543 surgical explorations.
AB  - A total of 543 boys suffering from acute scrotal pain underwent emergency surgery
      between 1986 and 1996. Of these, 91 had a testicular torsion (TT) (16.8%) and 250
      had an appendage torsion (AT) (46%). The cause varied with patient age, with most
      TTs in newborns and boys of 15 years and most ATs in 10-11-year-olds; 21.5% were
      operated upon within 6 h of the onset of pain and 69.2% within 24 h. Most stayed
      in hospital for less than 24 h. Pre-surgical examination identified no criterion
      for excluding TT. We therefore believe that all children complaining of acute
      scrotal pain should undergo surgery. As release of an inflamed AT reduces pain,
      three-fourths of the children benefited directly from surgery.

PMID- 10415284
TI  - Ureteric tunnel incision in the fetal pig: a model for non-obstructive prenatal
      vesicoureteric reflux.
AB  - The understanding of vesicoureteric reflux (VUR) continues to improve,
      particularly as the renal tract can now be assessed prenatally. To further study
      the evolution of fetal renal changes, we studied two neonatal piglets that had
      undergone midgestation ureteric tunnel ablation. Dilatation of the pelvicalyceal
      system was seen radiologically and macroscopically in all three kidneys into
      which VUR had been created. Despite the study being marred by poor fetal
      survival, the results indicate that the model should be developed further to
      explore what appears to be an interrelationship between VUR and renal parenchymal
      changes in utero.

PMID- 10415286
TI  - Urodynamic evaluation in boys treated for posterior urethral valves.
AB  - This study describes the urodynamic findings in 22 patients with posterior
      urethral valves and discusses their association with urinary incontinence, age,
      mode of primary treatment, renal function, and changes in the upper tracts. The
      patients' ages ranged from 3 to 26 years and 27% were either adolescents or
      older. The urodynamic findings were categorized into 5 main patterns, although
      mixed patterns were also observed; (1) normal capacity and compliance with normal
      detrusor contractility (2/22 patients, 9.1%); (2) small-capacity, hypocompliant
      bladder (8/22 patients, 36.4%); (3) unstable bladder (2/22 patients, 9.1%); (4)
      large-capacity, hypotonic bladder with decreased detrusor contractility (2/22
      patients, 9.1%); and (5) normal capacity and compliance but with decreased
      detrusor contractility (8/22 patients, 36.4%). More than one-half of the patients
      (57.1%) evacuated their bladders incompletely, and this seemed to be associated
      with post-treatment episodes of urinary-tract infection. The commonest symptom
      was daytime frequency, urgency, and leak with nocturnal enuresis, which
      urodynamically correlated with a small-capacity, hypocompliant or unstable
      bladder or to incomplete evacuation of the bladder, leading to significant post
      void residue. Significant detrusor dysfunction was identified in 2 asymptomatic
      patients as well, emphasizing the need to perform a routine urodynamic work-up on
      all valve patients. Urodynamic properties seemed to be associated with age.
      Small, hypocompliant, and unstable bladders were almost always seen in
      prepubertal boys and in the first 5 years following undiversion, whereas large,
      hypotonic bladders with impaired contractility were seen in post-pubertal boys.
      While the current policy is to avoid high diversion, data in this study suggest
      that disorders of detrusor capacity, compliance, and contractility exist in
      children treated by primary valve ablation and vesicostomy and that abnormal
      detrusor dynamics seem to be a reflection of inherent developmental detrusor
      dysfunction consequent to congenital infravesical obstruction.

PMID- 10415287
TI  - Changing pattern of osteomyelitis in infants and children.
AB  - A retrospective analysis of 332 children with osteomyelitis (OM), managed from
      1966 to 1996, was undertaken to evaluate etiology, clinical course and treatment
      results. In 64% of all patients positive bacterial cultures were obtained,
      Staphylococcus aureus, streptococci, pneumococci, and Haemophilus influenzae were
      the most frequently cultured pathogens. In two-thirds of the cases long bones
      (femur, tibia, humerus) were affected. Osteoarthritis or suppurative arthritis
      was evident in 27%; 32 of 170 (19%) re-evaluated patients had moderate or severe
      sequelae. Risk factors for an unfavorable course were the onset of disease in
      early infancy, suppurative arthritis, and an affected epiphysis. Suppurative
      arthritis, in particular, needs early evacuation to prevent sequelae. In recent
      years we observed an increasing number of patients presenting with atypical forms
      of OM. Since 1989 10 patients were considered to have chronic recurrent
      multifocal OM (CRMO). In 6 of them the clavicle was involved; their ages ranged
      from 3 to 14 years. The erythrocyte sedimentation rate was elevated (median 48,
      range 9-110 mm), while other inflammatory parameters like C-reactive protein
      (median 9, range <5-85 mg/l) or leucocyte count were slightly elevated or normal.
      Histopathology was stage-dependent, with a predominance of lymphoplasmacellular
      infiltration. A nonbacterial origin of CRMO is probable but not proven.
      Histopathology is not suitable for differentiation between bacterial and
      nonbacterial forms of bone inflammation.

PMID- 10415288
TI  - A case of Down's syndrome associated with progressive extradural neuroblastoma.
AB  - We describe a case of Down's syndrome associated with progressive extradural
      neuroblastoma. Postmortem aspiration of the bone marrow revealed diffuse
      infiltration by tumor cells, in which trisomy 21 was found by fluorescence in
      hybridization in situ.

PMID- 10415289
TI  - Primary anastomosis in esophageal atresia type I without a gap.
AB  - This paper reports the case of an infant born with type I esophageal atresia (EA)
      associated with duodenal atresia (DA). The critical condition of the patient
      necessitated an exploratory laparotomy, which revealed severe dilatation of the
      stomach and duodenum. The routine procedure for repairing type I EA is a delayed
      primary anastomosis after 10 weeks of age because of the long gap between the two
      esophageal segments. In our case, due to the concomitant DA, the lower pouch was
      long enough to allow primary neonatal anastomosis. A radiograph taken with a
      Hegar dilator in the lower segment via the gastrostomy confirmed this suspicion,
      and the baby underwent a thoracotomy and primary anastomosis between the
      esophageal pouches. The authors propose the possibility of primary esophageal
      anastomosis in similar cases.

PMID- 10415290
TI  - Ectopia hepatica extrathoracica nuda associated with amelia and pulmonary
      agenesis.
AB  - A neonate with a constellation of unusual congenital deformities associated with
      pulmonary agenesis is reported.

PMID- 10415291
TI  - Pulmonary blastoma: diagnostic and therapeutic aspects.
AB  - Pulmonary blastoma (PB) is an extremely uncommon intrathoracic neoplasm in
      children. It accounts for 0.5% of all primary malignant tumors of the lung, and
      20%-25% of the cases present in childhood. A new case of PB in a 3-year-old girl
      is discussed with special emphasis on diagnosis and treatment. The authors point
      out that the possibility of a primary lung tumor should be considered for any
      childhood cases with intractable signs and symptoms of a space-occupying lesion.
      A primary lung malignancy should not be excluded only on the basis of the
      patient's age, and childhood lung disorders should receive the same detailed and
      vigorous diagnostic evaluation and appropriate treatment given to adults.

PMID- 10415292
TI  - Button battery ingestion: a solution to a management dilemma.
AB  - There is a dilemma in the management of ingested intact button batteries in the
      gastrointestinal (GI) tract distal to the oesophagus: whether to do an emergency
      laparotomy or to adopt a wait-and-watch policy. In this case report an effective,
      safe, and quick method of GI lavage was used and a button battery was expelled
      successfully from the stomach without resorting to laparotomy or endoscopy.

PMID- 10415294
TI  - Inflammatory pseudotumor of the diaphragm.
AB  - A 5-year-old-boy presented with a right pleural effusion and fever. A tumorous
      mass was located between the right lung and the liver. The boy underwent a right
      thoracotomy with excision of the tumor and the adherent parts of the right
      hemidiaphragm. Histology and immunohistochemistry showed an inflammatory
      pseudotumor of the diaphragm. This is the first reported case of an inflammatory
      pseudotumor in this location. A brief review of the heterogeneous theories about
      the pathogenesis and the different therapeutic regimens for this rare neoplastic
      entity are discussed.

PMID- 10415293
TI  - Recurrent vomiting after successful pyloromyotomy.
AB  - Persistent vomiting after pyloromyotomy is rare. We report the case of a boy with
      recurrent vomiting after a successful pyloromyotomy, who required
      repyloromyotomy.

PMID- 10415295
TI  - Intestinal ulceration, obstruction, and haemorrhage in congenital syphilis.
AB  - Intestinal obstruction and bleeding are uncommon complications of congenital
      syphilis (CS). A VDRL-positive infant developed incomplete intestinal obstruction
      and rectal bleeding. Despite conservative management, his symptoms continued. At
      laparotomy, terminal ileal inflammation and stenosis were demonstrated. He
      underwent ileal resection and primary end-to-end anastomosis with resolution of
      his symptoms. Histopathological examination demonstrated heavy plasmacytic
      infiltration of the lamina propria and submucosa with ulceration of the mucosa,
      consistent with syphilitic ileitis. This report documents for the first time
      bleeding from ileal ulcers associated with intestinal obstruction in CS and
      highlights an unusual presentation of the disease.

PMID- 10415296
TI  - An accessory lobe of the liver disturbing closure of the umbilical ring.
AB  - The authors report a small omphalocele involving an accessory lobe of the liver
      (ALL) embedded in a cranial portion of the amniotic sac. The pedicle of liver
      tissue was markedly elongated. In this case, it was reasonable to assume that the
      ALL was formed during development of the embryonic body-wall folds and disturbed
      complete closure of the umbilical ring. Surgical resection of the ALL was
      performed to avoid its postoperative torsion. The pertinent literature is also
      reviewed.

PMID- 10415297
TI  - Recanalization of a portal-vein thrombosis and partial resolution of biliary
      cirrhosis following cholecystectomy for cholelithiasis in an infant.
AB  - Cholelithiasis in infants and children is unusual and is reputedly associated
      with underlying hemolytic disorders, total parenteral nutrition, ileal disease,
      and congenital anomalies of the biliary tree. We report a case of cholecystitis
      with pigmented stones in a 3-month-old infant associated with portal vein
      thrombosis (PVT) and biliary cirrhosis without the above-mentioned causes.
      Recanalization of the PV and partial resolution of the cirrhosis was observed
      following cholecystectomy. To our knowledge, cholelithiasis associated with PVT
      and cirrhosis in an infant has not been reported in the literature.

PMID- 10415298
TI  - Spontaneous biliary perforation and necrotizing enterocolitis.
AB  - A case of spontaneous bile-duct perforation in a 5-month-old boy with a history
      of necrotizing enterocolitis in his 1st week of life is reported. To our
      knowledge, this is the second case reported with such an antecedent, supporting a
      vascular etiology for some cases of spontaneous biliary perforation.

PMID- 10415299
TI  - Different types of congenital biliary dilatation in dizygotic twins.
AB  - A pair of dizygotic twins who were both found to have congenital biliary
      dilatation, but of different types, is reported. This case is of academic
      interest from an etiologic point of view.

PMID- 10415300
TI  - Profuse lower gastrointestinal haemorrhage as an indication for surgery in
      necrotising enterocolitis.
AB  - An infant developed massive lower gastrointestinal haemorrhage secondary to
      necrotising enterocolitis after cardiac surgery. The haemorrhage was only
      controlled following a colectomy.

PMID- 10415301
TI  - Ileosigmoid knotting in a 6-year-old child.
AB  - Ileosigmoid knotting occurs when the ileum wraps around the base of an elongated
      sigmoid colon, thus producing two closed-loop obstructions with the possibility
      of ischemia and necrosis of either the ileum or sigmoid colon. It occurs more
      commonly in African, Asian, and Middle Eastern countries, although there have
      been three Americans previously reported with this problem. The 6-year-old child
      presented here is the youngest person ever reported with ileosigmoid knotting.

PMID- 10415302
TI  - A case of incomplete Currarino triad with malignant transformation.
AB  - A case of an incomplete Currarino triad is reported. The baby underwent an
      emergency laparotomy due to a life-threatening intestinal obstruction caused by
      severe rectal stenosis. During the posterosagittal anorectoplasty (PSARP), a
      presacral teratoma was identified and resected. The tumor recurred three times;
      she initially responded to chemotherapy, but nonetheless died at the age of 4
      years. In cases with evidence of anorectal stenosis, a presacral mass should be
      suspected. PSARP is the best choice of treatment for both the anorectal anomaly
      and excision of the presacral mass. The presacral region should be followed up
      closely for recurrence of the tumor.

PMID- 10415303
TI  - Handlebar hernia: case report and review of pediatric cases.
AB  - The authors describe a rare case of handlebar hernia in a 9-year-old-boy. All
      layers of his abdominal wall were disrupted by a fall on a bicycle; however, his
      skin and intra-abdominal organs were completely intact. Computed tomography
      demonstrated subcutaneous intestinal loops protruding through the rent. Surgical
      repair was performed, and his postoperative course was uneventful.

PMID- 10415304
TI  - Ureterocystoplasty in a patient with a single kidney.
AB  - Ureterocystoplasty (UCP) has now been widely used for bladder augmentation, with
      and without unilateral nephrectomy. Many techniques have been described to
      incorporate portions of the upper renal tract, but none have yet described UCP in
      a child with unilateral renal agenesis.

PMID- 10415305
TI  - Bladder agenesis with urometrocolpos.
AB  - A 20-day-old female presented in acute renal failure with an absent bladder and
      vaginal atresia. The right ureter opened into the uterus, resulting in a
      urometrocolpos, and the left ureter opened through a stenotic opening into the
      introitus. The literature is reviewed for reported cases and the embryo-pathology
      of bladder agenesis is discussed.

PMID- 10415306
TI  - Cloacal malformation with solitary crossed renal ectopia and single-system
      vaginal ectopic ureter.
AB  - A patient with a cloacal malformation and hydrocolpos underwent a colostomy and
      vaginostomy in the neonatal period and total reconstruction at 7 months of age.
      Associated upper-urinary-tract abnormalities included solitary crossed left renal
      ectopia and a non-functioning right kidney with a single-system vaginal ectopic
      ureter.

PMID- 10415307
TI  - Duplication of the urethra.
AB  - Accessory urethra or duplication of the urethra is a rare anomaly. The vast
      majority occur in the sagittal plane; however, collateral or side-by-side
      duplications in the absence of bladder duplication also exist. We report six
      cases of urethral duplications. The mode of presentation and the importance of
      complete examination are discussed.

PMID- 10415308
TI  - Covered exstrophy with incomplete duplication of the bladder.
AB  - A rare exstrophy variant in a 1(1/2)-year-old girl is reported. The child had a
      wide, scar-like lesion over the lower central abdomen with divarication of the
      recti and a spread symphysis pubis. The underlying bladder was divided into two
      unequal chambers by a complete sagittal septum with only the right chamber
      communicating with the single urethra and the left draining by a vesicocutaneous
      fistula. Both kidneys were normal. The clitoris was bifid and the anus anteriorly
      placed. Preliminary surgical management consisted of dissection of the bladder
      from its prevesical covering, excision of the sagittal septum, and
      cystocystostomy. Postoperatively, the child had normal urinary continence. The
      literature is reviewed with special reference to the various forms of duplicate
      exstrophy.

PMID- 10415309
TI  - Congenital scaphoid megalourethra associated with posterior urethral valves.
AB  - Megalourethra is a very rare mesenchymal congenital anomaly and its association
      with posterior urethral valves is still rarer. We hereby present such a rare
      combination and discuss its etiopatho-genesis

PMID- 10415310
TI  - Borderline phylloides tumor in an 11-year-old girl.
AB  - Phylloides tumor is an uncommon breast tumor in children. Only a few cases have
      been reported in the literature. A case of borderline phylloides tumor in an 11
      year-old girl is described.

PMID- 10415311
TI  - Giant intra-abdominal cyst in a 13-year-old girl.
AB  - A case of a massive unilocular intra-abdominal cyst arising in a 13-year-old girl
      is presented. This appeared to be a foregut duplication cyst of gastric origin,
      and thus one of the largest recorded in the literature.

PMID- 10415312
TI  - Small-cell carcinoma of the ovary of the hypercalcemic type in an 8-year-old
      girl.
AB  - Tumors of the ovary in girls represent about 80% of pediatric genital tumors;
      approximately 30% of these tumors are malignant. The risk of malignancy increases
      with decreasing age. The most frequent finding is a teratoma; other tumors are
      rare. Small-cell carcinoma (SCCO) of the ovary is extremely rare, occurring
      mostly in young women. We present an 8-year-old girl with a SCCO of the
      hypercalcemic type. The findings and treatment are discussed with emphasis on the
      poor prognosis in these patients, even in stage 1 disease. The current literature
      is reviewed.

PMID- 10415313
TI  - Enlargement and maturation in benign cystic ovarian teratoma.
AB  - This is a report of a 13(1/2) year old girl with bilateral benign cystic ovarian
      teratomas (BCOT). The clinical presentation was with an abdominal mass and an
      abdominal X-ray film confirmed the mass which contained teeth. Previous abdominal
      X-ray at 3 and 10 years of age had not shown any abnormality. The clinical
      features and the radiological findings indicated that the BCOT had enlarged and
      matured during the period of follow-up.

PMID- 10415314
TI  - Chondromatosis of the ankle joint (Reichel syndrome).
AB  - A case of chondromatosis of the upper ankle joint in childhood is described. It
      is a monoarticular disease with a good prognosis, frequently without known prior
      trauma or inflammation, although often free fragments of cartilage are seen in
      the joint cavities. It originates from the synovium of the joint, and is known in
      the literature as Reichel syndrome.

PMID- 10415315
TI  - Unusual vascular dysplasia presenting as an intra-abdominal catastrophe.
AB  - A case of severe, generalised vascular dysplasia presenting as an intra-abdominal
      catastrophe is reported. Associated clinical features included cutis marmorata
      telangiectatica congenita, congenital glaucoma, hypertension, and focal fits. The
      case has been reported in view of its rarity and nature of presentation.

PMID- 10415316
TI  - Use of a plastic hemoderivative bag in the treatment of gastroschisis.
AB  - The authors report their experience with the use of a polyvinyl chloride (PVC)
      bag for blood-derivative transfer as a prosthesis for the creation of a silo for
      surgical treatment of gastroschisis (GS) in seven newborn infants. The bag is
      sterile, impermeable to micro-organisms, transparent, flexible, resistant,
      internally smooth, does not adhere to the bowel loops, readily available, and
      inexpensive, properties that make it an excellent alternative as a prosthesis for
      staged surgical treatment of congenital anomalies of the abdominal wall such as
      GS and omphalocele. The importance of a multidisciplinary team for the care of
      newborns with GS is also emphasized for a good postoperative outcome.

PMID- 10415317
TI  - Modified Duhamel operation using a newly designed crushing clamp.
AB  - A newly designed crushing clamp that is suitable for use in the modified Duhamel
      operation for Hirschsprung's disease but costs much less than a stapling device
      is presented.

PMID- 10415318
TI  - Webbed penis.
AB  - A simpler technique to correct the webbed penis is described and the literature
      discussed.

PMID- 10415319
TI  - Endoscopic treatment of recurrent tracheo-oesophageal fistulae: the optimal
      technique.

PMID- 10415320
TI  - Visualisation of the inferior pouch in oesophageal atresia without fistula.

PMID- 10415321
TI  - Scroto-peritoneal port for laparoscopic orchidopexy.

PMID- 10415322
TI  - Vulva formation in Pristionchus pacificus relies on continuous gonadal induction.
AB  - One of the best known features of vulva development in Caenorhabditis elegans is
      the induction of vulval precursor cells by the gonadal anchor cell. Induction is
      crucial for the initiation of pattern formation within the C. elegans vulva
      equivalence group, and it is therefore surprising to find that this aspect of
      vulva formation, in particular, varies greatly among nematodes. In some species
      which form vulvae in the posterior body region, no gonadal signal is necessary
      for vulva induction. In other nematodes, such as Panagrolaimus, Oscheius, and
      Rhabditella, vulva formation depends on two temporally distinct gonadal
      inductions which specify the different cell fates. Here we report our analysis of
      vulva induction in Pristionchus pacificus, a species which has recently been used
      as a genetic system to analyze the evolution of vulva development. Cell ablation
      studies in P. pacificus show that another mode of vulva induction exists. P.
      pacificus vulva formation depends on a continuous gonadal induction that starts
      several hours after hatching and continues until the birth of the anchor cell,
      some 20 h later. Mutations defective in gonadal induction result in the absence
      of vulva differentiation, suggesting that only one signaling system is involved
      in the gonadal-epidermal interaction. This new mode adds further to the great
      variety of gonadal inductions among nematode species.

PMID- 10415323
TI  - Homeotic gene expression in the wild-type and a homeotic mutant of the moth
      Manduca sexta.
AB  - Antibodies were used to examine the expression patterns of Antennapedia (Antp),
      Ultrabithorax (Ubx), Ubx and abdominal-A combined (Ubx/abd-A), and Distalless
      (Dll) in the embryos of the moth Manduca sexta. We found that the spatial and
      temporal pattern of Antp expression in Manduca was correlated with the anterior
      migration of two patches of epithelium that include the anterior-most tracheal
      pits, and with the development of functional spiracles. Ubx expression showed an
      intricate pattern which suggests complex regulation during development.
      Throughout Manduca embryogenesis the expression of Ubx/Abd-A and Dll was similar
      to that reported for other insects. However, there was no apparent reduction in
      Ubx/Abd-A expression in the Manduca abdominal proleg primordia that expressed
      Dll. The expression of these four proteins was also examined in embryos of the
      Manduca homozygous homeotic mutant Octopod (Octo). The Octo mutation results in
      the transformation of A1 and A2 in the anterior direction, with homeotic legs
      appearing on A1 and occasionally A2. Our results suggest that in Octo animals
      there is a reduction in the level of Ubx protein expression throughout its
      domain. Based on homeotic gene expression in wild-type and mutant Manduca and in
      other insects, we discuss potential roles of homeotic genes in insect
      morphological evolution.

PMID- 10415324
TI  - Axial variation in the threespine stickleback: relationship to Hox gene
      expression.
AB  - Despite mounting evidence that key developmental regulator genes are involved in
      significant macroevolutionary changes, there have been few studies demonstrating
      the functional significance of variation in such genes for the generation of
      population-level variation. In this study we examined and compared the expression
      domains of three Hox gene homeobox sequences in embryos derived from two
      morphologically distinct populations of the threespine stickleback, Gasterosteus
      aculeatus. We found within-population variation in the location of anterior
      limits, particularly in more 5' Hox genes whose anterior expression domains
      showed graded distributions of transcripts over several somites. However, despite
      considerable and statistically significant differences in the anteroposterior
      pattern of the axial and median skeletons between the two stickleback
      populations, this phenotypic variation was not found to be correlated with any of
      the variation in Hox gene expression. The possible functional significance of the
      combinatorial Hox code in fish species is discussed with respect to the buffering
      of development in fluctuating environments, and it is argued that population and
      quantitative genetic perspectives should also be taken into account in
      considering the function and evolution of Hox genes.

PMID- 10415325
TI  - Expression patterns of threespine stickleback hox genes and insights into the
      evolution of the vertebrate body axis.
AB  - Understanding the patterning mechanisms that operate to promote differentiation
      of individual segments along the main body axis is an important goal of both
      developmental and evolutionary biology. In order to gain a better insight into
      the role of Hox genes in generating diversity of axial plans seen in vertebrates,
      we have cloned 11 homeobox sequences from an acanthopterygian teleost, the
      threespine stickleback, and analyzed the expression of 7 of these during
      embryogenesis. Transcripts are observed in a variety of tissues, including the
      neural tube, paraxial mesoderm, lateral plate mesoderm, pectoral fins, pronephric
      ducts, as well as some neural crest-derived structures. Anterior limits of
      expression in the central nervous system and paraxial mesoderm exhibited both
      similarities and differences to those of mouse and zebrafish homologs. In both
      stickleback and zebrafish embryos expression limits within the paraxial mesoderm
      were detected only within the trunk region in which ribs are attached to all
      vertebrae. The finding of this pattern in two divergent teleosts as well as in
      various tetrapod species supports the hypothesis that a Hox precode was present
      prior to the divergence of ray-finned and lobe-finned fishes and was subsequently
      used to generate different types of vertebrae in tetrapods. We also describe a
      dynamic pattern of expression of several stickleback Hox genes associated with
      the development of the caudal paraxial mesoderm, which suggests uncoupling of the
      process of segmentation from segmental identity determination. We propose that in
      fishes the patterning of the tail region is under the control of a separate
      mechanism from the trunk, which utilizes Hox genes in a different manner.

PMID- 10415326
TI  - Gene expression patterns associated with suppression of odontogenesis in mouse
      and vole diastema regions.
AB  - Rodents have a toothless diastema region between the incisor and molar teeth
      which may contain rudimentary tooth germs. We found in upper diastema region of
      the mouse (Mus musculus) three small tooth germs which developed into early bud
      stage before their apoptotic removal, while the sibling vole (Microtus
      rossiaemeridionalis) had only a single but larger tooth germ in this region, and
      this developed into late bud stage before regressing apoptotically. To analyze
      the genetic mechanisms of the developmental arrest of the rudimentary tooth germs
      we compared the expression patterns of several developmental regulatory genes
      (Bmp2, Bmp4, Fgf4, Fgf8, Lef1, Msx1, Msx2, p21, Pitx2, Pax9 and Shh) between
      molars and diastema buds of mice and voles. In diastema tooth buds the expression
      of all the genes differed from that of molars. The gene expression patterns
      suggest that the odontogenic program consists of partially independent signaling
      cascades which define the exact location of the tooth germ, initiate epithelial
      budding, and transfer the odontogenic potential from the epithelium to the
      underlying mesenchyma. Although the diastema regions of the two species differed,
      in both species the earliest difference that we found was weaker expression of
      mesenchymal Pax9 in the diastema region than in molar and incisor regions at the
      dental lamina stage. However, based on earlier tissue recombination experiments
      it is conceivable that the developmental arrest is determined by the early oral
      epithelium.

PMID- 10415327
TI  - Characterization of three genes, AKAP84, BAW and WSB1, located 3' to the
      neurofibromatosis type 1 locus in Fugu rubripes.
AB  - Sequence analysis of cosmid clones was instrumental to identify three genes in
      the region flanking the Fugu rubripes NF1 gene in the 3' direction: the AKAP84
      gene (A-kinase anchor protein 84), the WSB1 gene (WD-40-repeat protein with a
      SOCS box) and the BAW gene of yet unknown function located between the AKAP84 and
      the WSB1 genes. The human homologues of these genes are not located in the
      immediate vicinity of the NF1 gene at 17q11.2. Although synteny of the NF1,
      AKAP84, BAW and WSB1 genes is conserved between Fugu and human, the gene order is
      not conserved, and more than a simple inversion would have been necessary to
      explain the difference in gene order. The mammalian homologue of the Fugu BAW
      gene or protein has not yet been characterized. As deduced from the respective
      cDNAs, the Fugu AKAP84, WSB1 and BAW proteins vary concerning the overall degree
      of similarity to their mammalian counterparts. Whereas the overall similarity of
      AKAP84 between Fugu and mouse is low, three regions of known functional
      importance show considerable conservation. These are the N-terminal anchoring
      domain mediating the insertion of AKAP84 in the outer mitochondrial membrane, the
      binding site of the regulatory subunit (RI or RII) of protein kinase A, and the C
      terminal domain present in the alternatively spliced isoform AKAP121 with an
      hnRNP K homology domain involved in RNA binding. A higher overall similarity of
      deduced protein sequences between Fugu and mouse was observed comparing the BAW
      gene products (74.1%) and the WSB1 proteins (77.2%).

PMID- 10415328
TI  - Sequence and expression analysis of a novel Xenopus laevis cDNA that encodes a
      protein similar to bacterial and chloroplast ribosomal protein L24.
AB  - We report here the cloning and the characterization of a Xenopus laevis cDNA that
      encodes a basic protein of 276 amino acids with a central core region, which
      shows a substantial degree of homology to bacterial and chloroplast ribosomal
      protein L24, and additional diverged N- and C-terminal polypeptide extensions.
      The N-terminal extension displays similarities to the mitochondrial targetting
      sequence, thereby suggesting that the cDNA probably codes for a mitochondrial
      ribosomal protein. Although the gene was expressed ubiquitously, at fairly
      constant levels, during embryogenesis, the abundance of the transcripts in the
      different tissues varies with the mRNA levels in the kidney, adipose tissue,
      muscle and liver being greater than that present in the brain, heart, ovary and
      lung.

PMID- 10415329
TI  - Cloning, gene expression, and characterization of CP27, a novel gene in mouse
      embryogenesis.
AB  - We report the full-length sequencing, tissue-specific expression, and
      immunolocalization of cp27, a novel gene in mouse embryogenesis. The cp27 gene
      was isolated and cloned from a mouse E11 lambdagt11 library using a peptide
      antibody that recognized a distinct expression pattern in mouse craniofacial
      development. The cp27 gene contains an open reading frame of 295 amino acids
      corresponding to a predicted molecular mass of 33kDa. On Western blots, a
      polyclonal antibody against CP27 detected a single epitope at 27kDa. The putative
      CP27 protein has an isoelectric point of 4.75 and features a distinct helix-loop
      helix structure according to prediction algorithms. We have cloned the human cp27
      gene and mapped it to a locus on the human chromosome 16 which is in proximity to
      several loci associated with inherited craniofacial diseases such as fanconi
      anemia type A. Northern blot analysis of RNA from multiple mouse tissues
      demonstrated high levels of expression in developing mouse teeth, heart, lung,
      and liver of a single transcript of approx. 1. 8kbp. In situ hybridization using
      a radioactive RNA probe resulted in distinct signals in the developing
      neuroepithelium, cerebellum, heart, lung, liver, teeth, salivary glands, and
      periosteum of developing bones. Immunohistochemical staining of developing mouse
      tissues detected epitopes specific for CP27 in the mesenchyme surrounding the
      primary brain vesicles, in basement membranes, in the periosteum, in salivary
      glands, and in the stellate reticulum of teeth. Thus, CP27 represents a unique
      gene product involved in mouse embryogenesis.

PMID- 10415330
TI  - Statistical aspects of genetic mapping in autopolyploids.
AB  - Many plant species of agriculture importance are polyploid, having more than two
      copies of each chromosome per cell. In this paper, we describe statistical
      methods for genetic map construction in autopolyploid species with particular
      reference to the use of molecular markers. The first step is to determine the
      dosage of each DNA fragment (electrophoretic band) from its segregation ratio.
      Fragments present in a single dose can be used to construct framework maps for
      individual chromosomes. Fragments present in multiple doses can often be used to
      link the single chromosome maps into homologous groups and provide additional
      ordering information. Marker phenotype probabilities were calculated for pairs of
      markers arranged in different configurations among the homologous chromosomes.
      These probabilities were used to compute a maximum likelihood estimator of the
      recombination fraction between pairs of markers. A likelihood ratio test for
      linkage of multidose markers was derived. The information provided by each
      configuration and power and sample size considerations are also discussed. A set
      of 294 RFLP markers scored on 90 plants of the species Saccharum spontaneum L.
      was used to illustrate the construction of an autopolyploid map. Previous studies
      conducted on the same data revealed that this species of sugar cane is an
      autooctaploid with 64 chromosomes arranged into eight homologous groups. The
      methodology described permitted consolidation of 54 linkage groups into ten
      homologous groups.

PMID- 10415331
TI  - Transcript map of the human chromosome Xq11-Xq21 region: localization of 33 novel
      genes and one pseudogene.
AB  - The human Xq11-Xq21.3 region has been implicated in several inherited disorders
      including dystonia-parkinsonism (DYT3), sideroblastic anemia and several specific
      and non-specific forms of mental retardation (MR) syndromes. As part of a
      positional cloning effort to identify MR genes, we have generated a YAC-based
      transcript map. We first constructed a YAC/STS framework by extending previously
      published contigs. This framework map consists of a minimal set of 119 clones,
      covering approximately 20 Megabases (Mb) and allowing the precise ordering of 71
      STSs between DXS136 and DXS472. This YAC contig was then used to define the
      positions of genes and expressed sequence tags (ESTs) assigned to the Xcen-Xq21.3
      region. In addition to the genes previously localized to this part of the X
      chromosome, 18 transcription units corresponding to additional known genes or
      gene family members, one pseudogene and 15 novel transcripts were mapped. This
      transcriptional map incorporates 51 transcription units and provides a useful
      resource of candidate genes for some of the disorders assigned to this region of
      the X chromosome.

PMID- 10415332
TI  - Rat endozepine-like peptide (ELP): cDNA cloning, genomic organization and tissue
      specific expression.
AB  - A cDNA encoding the rat homolog of the previously characterized murine endozepine
      like peptide (ELP) was isolated by a PCR cloning strategy. Sequence comparison
      with the murine cDNA sequence revealed a conservation of the ELP primary
      structure between both rodent species with minor amino acid exchanges. We
      investigated the genomic organization of the rat ELP gene by genomic PCR. This
      indicated the presence of a single short intron of 451bp interrupting the 5'
      untranslated region. Tissue-dependent ELP expression was determined by Northern
      hybridization and semiquantitative RT-PCR. Northern hybridization showed an ELP
      specific transcript in both the male and the female gonad, but the level of
      ovarian ELP transcription was considerably lower than in the testis. RT-PCR
      analysis demonstrated a low and varying level of ELP background expression in all
      examined tissues. In contrast to the closely related ACBP gene, ELP shows a
      different genomic organization and a more regulated expression pattern, and may
      exert a specific function as a gonadal acyl-CoA pool former and transporter.

PMID- 10415333
TI  - Molecular cloning and characterization of splice variants of human RAD50 gene.
AB  - In this report, splice variants of human RAD50 (hRAD50) were cloned and
      characterized. A Northern blot survey identified two transcripts that hybridized
      to a hRAD50 cDNA clone, an upper faint band (5.9kb) and lower dense band (4.6kb).
      cDNA clones (hRAD50-2, 4.6kb) encompassing the entire hRAD50 transcript but
      having a shorter 3'-untranslated region (3'UTR) than the previously reported
      hRAD50-1 cDNA (5.9kb; Dolganov, G.M., Maser, R.S., Novikov, A., Tosto, L., Chong,
      S., Bressan, D.A., Petrini, J.H.J., 1996. Human Rad50 is physically associated
      with human Mre11: Identification of a conserved multiprotein complex implicated
      in recombinational DNA repair. Mol. Cell. Biol. 16, 4832-4841.) were isolated.
      The presence of AU-rich sequences in the 3'UTR of hRAD50-1, which define mRNA
      instability and Northern results, suggest that hRAD50-2 is the major transcript
      of hRAD50. A third alternative splice variant that lacks the ATP-binding domain
      was also identified (hRAD50-3, approximately 4.5kb). Expression of hRAD50-3
      transcript was detected in all tissues examined by RT-PCR (reverse transcriptase
      polymerase chain reaction) and nested DNA-PCR analyses. Expression of hRAD50
      partially rescued the MMS (methyl methanesulfonate)-sensitive phenotype in rad50
      mutant yeast, whereas hRAD50-3 did not show complementation. These data suggest
      that the hRAD50-3 does not repair DNA double-strand breaks most likely due to its
      inability to bind ATP, and to bind damaged DNA. The existence of these
      alternative splice forms is potentially important in regulation of the biological
      activity of the DNA recombinational repair gene, hRAD50.

PMID- 10415334
TI  - A GC-box is required for expression of the human vimentin gene.
AB  - Vimentin is an intermediate filament protein normally expressed in cells of
      mesenchymal origin. The promoter of the human vimentin gene (-1416 to +73) was
      shown to contain two positive-acting regions, separated by a negative region, and
      at least eight GC-boxes as determined by sequence homology (Rittling, S.R.,
      Baserga, R., 1987. Mol. Cell. Biol. 7, 3908-3915). We have analyzed the region 
      900 to +41 for protein binding by in vivo footprinting experiments using ligation
      mediated PCR. For the various GC-boxes, we detect protein binding only to that GC
      box (at position -64 and -55) closest to the transcriptional start site.
      Transient transfection assays of various vimentin 5'-end fragments and mutations
      thereof fused to the reporter gene cat indicate that this sequence is
      indispensable for promoter function regardless of the inclusion of upstream DNA
      sequences. In vitro binding studies confirm that this region binds protein
      specifically. We suggest that this GC-box and its binding factor are required for
      regulated expression of the human vimentin gene.

PMID- 10415335
TI  - The ATPase subunit 6 gene sequence predicts that RNA editing is conserved between
      lizard- and human-infecting Leishmania.
AB  - Here we investigate the similarities in the kinetoplastid RNA editing process
      between human- and lizard-infecting Leishmania species. We present the sequence
      of the maxicircle-encoded ATPase subunit 6 gene from L. (V.) panamensis, L. (L.)
      mexicana and L. (L.) donovani species of human-infecting Leishmania. These
      represent the first available sequences of this gene from Leishmania species
      other than the lizard-infecting L. tarentolae. The gene sequences are highly
      conserved, both over the edited and unedited parts of the gene, implying that the
      RNA editing process is likely to be highly conserved between Leishmania species.
      Indeed, the first editing domain is absolutely conserved in all three Leishmania
      species studied and L. tarentolae. A phylogeny based on part of the ATPase
      subunit 6 gene placed the lizard-infecting Leishmania within the monophyletic
      Leishmania genus, supporting previous data which suggest that lizard- and human
      infecting Leishmania species are closely related.

PMID- 10415336
TI  - PTEN transcriptionally modulates c-myc gene expression in human breast carcinoma
      cells and is involved in cell growth regulation.
AB  - A novel tumor suppressor gene, PTEN, has recently been identified at chromosome
      10q23, which is inactivated in a number of different tumor types including breast
      cancer. An investigation of the functional role suggested that PTEN
      transcriptionally represses both exogenous and endogenous c-myc expressions in
      human breast carcinoma cells. PTEN, when ectopically expressed in human breast
      carcinoma cells, exhibited an inhibition of phosphorylation of both activating
      residues of protein kinase B (PKB)/AKT at Ser-473 and Thr-308 without any
      significant alteration of AKT expression. Furthermore, introduction of PTEN into
      human breast carcinoma cells induced apoptotic cell death and inhibited cell
      growth and tumor formation in nude mice. Taken together, our data suggest that
      PTEN acts as a transcriptional repressor, inhibits the AKT-mediated cell survival
      signaling pathway, and negatively regulates human breast carcinoma cell growth.
      These results further emphasize the potential of PTEN as a gene therapeutic
      agent.

PMID- 10415337
TI  - Identification of a novel gene encoding a p53-associated protein.
AB  - p53 exerts important physiological functions in cell-cycle control, gene
      regulation, cell differentiation, apoptosis and tumor suppression by interacting
      with many cellular proteins. Using the yeast two-hybrid system, we screened a
      HeLa cDNA library and identified a novel gene encoding a p53-binding protein
      (p53BP3). The full-length cDNA of p53BP3 was isolated from a HeLalambdagt10 cDNA
      library. This predicted protein was composed of 815 amino acids. Sequence
      analysis indicated that p53BP3 contained two bipartite nuclear localization
      signals and was confirmed to be a nuclear protein. FISH mapping results showed
      that this novel gene was located at human chromosome 12, region p11.2-p12.1.
      Northern blot analysis suggested that p53BP3 was broadly expressed in human
      tissues. A further study showed that p53BP3 had a homologue in mouse.

PMID- 10415338
TI  - Context-dependent Taq-polymerase-mediated nucleotide alterations, as revealed by
      direct sequencing of the ZNF189 gene: implications for mutation detection.
AB  - We have recently reported on the genetic organisation of a novel Kruppel-like
      zinc finger, ZNF189, located to 9q22-q31. In that study we found no mutations in
      the coding sequence when using ZNF189 as a candidate gene for sporadic basal cell
      cancer and squamous cell cancer. Here, by direct sequencing of the proximal
      promotor of ZNF189, mutations were found to appear in a small hot-spot region in
      over 50% of analysed tumour samples, the majority being G to A substitutions. The
      hot-spot region spans a 24bp G-rich region. Repeated analyses of the original
      sample lysates fail to confirm each of these mutations; and frequently new
      mutations appear at neighbouring positions. Subsequent analysis with serial
      dilutions of genomic DNA and a cosmid harbouring the wild-type ZNF189 gene
      demonstrate that these sequence-specific alterations arise in the outer PCR
      amplification when 50 copies or less of template are used. Although the mechanism
      of how these context-specific alterations arise is not proven, the results
      demonstrate a previously unreported type of PCR-mediated sequence-specific
      alteration that easily could have been interpreted as being of clinical
      relevance. The phenomena observed show that mutations detected by direct
      sequencing can be caused by PCR-introduced alterations. Consequently, this should
      be of general caution in mutation analysis of disease gene candidates when using
      small amounts of template, such as microdissected biopsies.

PMID- 10415340
TI  - Fungal proteinase expression in the interaction of the plant pathogen Magnaporthe
      poae with its host.
AB  - Infection by pathogenic fungi involves breaching the outer layer of the host by
      either mechanical or enzymatic means. Subtilisin-like proteinases are considered
      to be important in the infection process of entomopathogenic, nematophagous, and
      mycoparasitic fungi. Little is known regarding the expression of such proteinases
      by plant pathogenic fungi. Magnaporthe poae, a fungal pathogen of Kentucky
      bluegrass, expressed a subtilisin-like proteinase, proteinase Mp1, in the
      infected roots. Antibody was produced against the purified enzyme. From
      immunoblot analysis, expression of the proteinase in infected roots correlated
      with increasing severity of disease symptoms. Sequence analysis of a genomic
      clone indicated proteinase Mp1 was homologous to other fungal subtilisin-like
      proteinases. DNA gel blot analysis indicated proteinase Mp1 was encoded by a
      small gene family.

PMID- 10415339
TI  - Cloning and gene structure of rat phosphatidylcholine transfer protein, Pctp.
AB  - Phosphatidylcholine transfer protein (PC-TP) is a cytosolic lipid transfer
      protein that promotes intermembrane transfer of phosphatidylcholines but no other
      phospholipids. Although its physiological function remains unknown,
      phosphatidylcholine transfer protein is enriched in liver and evidence from model
      systems suggests a role in hepatocellular selection and transport of biliary
      phospholipids. To facilitate in vivo studies, a cDNA encoding rat PC-TP was
      cloned by library screening and 5'-rapid amplification of cDNA ends. Genomic
      cloning demonstrated the rat Pctp gene spans 10. 8kb and is comprised of six
      exons. The putative transcription initiation site was identified 50bp upstream of
      the translation initiation site. Nucleotide sequence analysis of the 5'-flanking
      region revealed a CAAT- but no TATA-box. Transient transfection of a series of 5'
      deleted Pctp-promoter-firefly luciferase constructs into Reuber H35 rat hepatoma
      cells, which express Pctp mRNA, and Gunn rat fibroblasts, which do not, suggest
      that cis-acting elements in a 637bp promoter region contribute to enhanced
      expression of PC-TP in liver.

PMID- 10415341
TI  - The mitochondrial Pylaiella littoralis nad11 gene contains only the N-terminal
      FeS-binding domain.
AB  - We describe a nad11 gene located on the mitochondrial genome of the brown alga
      Pylaiella littoralis. This gene is cotranscribed with other neighbouring nad
      genes. It encodes the first domain only of the Nad11 polypeptide, i.e. a 23-kDa,
      FeS-binding domain instead of the usual 75/80-kDa protein found in the
      mitochondrial or alpha-proteobacterial complex I enzymes. The second domain of
      the protein, of unknown function, seems to be entirely missing in this alga.
      Cyanobacteria, beta-proteobacteria and actinomycetes also feature small
      homologous genes, known as hoxU, and it has been suggested that these could
      function in complex I of cyanobacteria. These observations indicate that complex
      I can probably function with the first domain only of the 75-kDa protein. P.
      littoralis represents the first such example within the alpha
      proteobacterial/mitochondrial lineage.

PMID- 10415342
TI  - Protein-tyrosine phosphatases in development.
AB  - One of the most important mechanisms of eukaryotic signalling is protein
      phosphorylation on tyrosine residues, which plays a pivotal role in development
      by regulating cell proliferation, differentiation and migration. Cellular
      phosphotyrosine (P.Tyr) levels are regulated by the antagonistic activities of
      the protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs). We
      have good insight into the function of PTKs at the molecular level and into the
      role of PTK-mediated signalling in development. Intuitively, PTPs and PTKs are
      equally important in development. Over the past decade, much emphasis has been
      placed on elucidation of the function of PTPs, which has led to good insights
      into the mechanism of PTP-mediated dephosphorylation. Although still relatively
      little is known about the role of PTPs in cell signalling and development,
      evidence is now emerging that several PTPs are crucial for proper development.
      Here I will introduce PTP-mediated signalling and discuss recent findings
      regarding the function of PTPs in development.

PMID- 10415343
TI  - The BMP-related protein radar: a maintenance factor for dorsal neuroectoderm
      cells?
AB  - We have previously cloned several members of the TGF-beta superfamily of growth
      factors in zebrafish, one of which, Radar, belongs to the Dpp-Vg1-related (DVR)
      subgroup, with highest homology to GDF6. The pattern of expression of Radar
      suggested a possible involvement in several induction steps during embryogenesis
      including in the dorsal neural tube, red blood cells, the dorsal fin and the
      retina. We have analyzed the pattern of expression of Radar in comparison with
      that of a marker of dorsal neural tube structures, msxC and show that Radar and
      msxC are expressed in similar and/or adjacent tissues throughout embryogenesis.
      In order to demonstrate a functional relationship between these two proteins, we
      have generated a full-length cDNA for Radar and shown that Radar overexpression
      by DNA injection maintains expression of msxC in tissues where it is normally
      expressed then turned off, in particular in the dorsal neurectoderm. Study of the
      phenotype of a mutant carrying a deletion of Radar shows a loss of identity and
      death of the cells of the dorsal neural tube. Taken together these results
      suggest that Radar could be involved in maintaining the identity of cells of the
      dorsal-most neural tube and of at least a subset of neural crest cells.

PMID- 10415344
TI  - Heat shock produces periodic somitic disturbances in the zebrafish embryo.
AB  - Environmental influences are known to produce segmental defects in a variety of
      organisms. In this paper we report upon segmental aberrations produced by brief
      heat shocks delivered to developing zebrafish embryos. The initial defects in the
      segmental pattern of somitic boundaries and motoneuron axon outgrowth were
      usually observed five somites caudal to the somite which was forming at the time
      of heat shock application. Segmental defects in zebrafish embryos exposed to a
      single heat shock treatment can occur in a periodic pattern similar to the
      multiple disturbances observed to occur in chick embryos. These data are
      discussed with regard to models involving cell cycle synchrony or 'clock and
      wavefront' schemes in the process of somitogenesis.

PMID- 10415345
TI  - Efficient gene-specific expression of cre recombinase in the mouse embryo by
      targeted insertion of a novel IRES-Cre cassette into endogenous loci.
AB  - Site specific recombinases have provided the experimental strategy necessary to
      modulate the expression of gene products in the mouse embryo. In this study we
      have exploited Cre recombinase to develop a widely applicable cell marking system
      which functions efficiently even at early post-implantation embryonic stages.
      Importantly, the techniques and reagents derived in this study are generally
      applicable to any recombinase driven approach, including strategies to temporally
      and spatially modulate endogenous or ectopic gene expression in the embryo. The
      cell marking scheme has two essential components which were derived as separate
      mouse lines. The first line carries a universal conditional lacZ reporter (UCR)
      locus which was prepared by using gene targeting in a novel approach to modify a
      ubiquitously expressed retroviral lacZ promoter trap insertion. The UCR locus is
      silent until it undergoes a Cre mediated DNA rearrangement to restore lacZ
      expression. To generate the Cre expressing allele, we outline a flexible strategy
      which requires the introduction of a novel IRES-Cre cassette into exon sequence
      of an endogenous locus by gene targeting. We successfully demonstrate this
      approach by generating a Cre expressing allele of the EphA2 gene, an Eph receptor
      protein tyrosine kinase expressed early in development. Analysis of double
      heterozygote embryos clearly demonstrates that Cre recombinase is expressed in
      vivo from the EphA2 IRES-Cre allele, and that the conditional reporter locus is
      efficiently restored in EphA2-expressing cells as early as 7.5 dpc. This cell
      marking experiment establishes the feasibility of expressing Cre recombinase from
      a single copy allele in the embryo and demonstrates the utility of the
      conditional reporter mouse which can be used in the analysis of any Cre
      expressing allele.

PMID- 10415346
TI  - The forkhead gene FH1 is involved in evolutionary modification of the ascidian
      tadpole larva.
AB  - The forkhead gene FH1 encodes a HNF-3beta protein required for gastrulation and
      development of chordate features in the ascidian tadpole larva. Although most
      ascidian species develop via a tadpole larva, the conventional larva has
      regressed into an anural (tailless) larva in some species. Molgula oculata (the
      tailed species) exhibits a tadpole larva with chordate features (a dorsal neural
      sensory organ or otolith, a notochord, striated muscle cells, and a tail),
      whereas its sister species Molgula occulta (the tailless species) has evolved an
      anural larva, which has lost these features. Here we examine the role of FH1 in
      modifying the larval body plan in the tailless species. We also examine FH1
      function in tailless speciesxtailed species hybrids, in which the otolith,
      notochord, and tail are restored. The FH1 gene is expressed primarily in the
      presumptive endoderm and notochord cells during gastrulation, neurulation, and
      larval axis formation in both species and hybrids. In the tailless species, FH1
      expression is down-regulated after neurulation in concert with arrested otolith,
      notochord, and tail development. The FH1 expression pattern characteristic of the
      tailed species is restored in hybrid embryos prior to the development of chordate
      larval features. Antisense oligodeoxynucleotides (ODNs) shown previously to
      disrupt FH1 function were used to compare the developmental roles of this gene in
      both species and hybrids. As described previously, antisense FH1 ODNs inhibited
      endoderm invagination during gastrulation, notochord extension, and larval tail
      formation in the tailed species. Antisense FH1 ODNs also affected gastrulation in
      the tailless species, although the effects were less severe than in the tailed
      species, and an anural larva was formed. In hybrid embryos, antisense FH1 ODNs
      blocked restoration of the otolith, notochord, and tail, reverting the larva back
      to the anural state. The results suggest that changes in FH1 expression are
      involved in re-organizing the tadpole larva during the evolution of anural
      development.

PMID- 10415347
TI  - Local signals in the chick limb bud can override myoblast lineage commitment:
      induction of slow myosin heavy chain in fast myoblasts.
AB  - Patterning of fast and slow muscle fibres in limbs is regulated by signals from
      non-muscle cells. Myoblast lineage has, however, also been implicated in fibre
      type patterning. Here we test a founder cell hypothesis for the role of myoblast
      lineage, by implanting characterized fast and slow mouse myoblast clones into
      chick limb buds. In culture, late foetal mouse myoblast clones are committed to a
      probability (range 0-0.92) of slow myosin heavy chain (MyHC) expression. In
      contrast, when implanted into chick limbs, fast mouse myoblast clones express
      myosin characteristic of their new environment, without fusion to chick muscle
      cells and in the absence of innervation. Therefore, local signals exist within
      the chick limb bud during primary myogenesis that can override intrinsic
      commitment of at least some myoblasts, and induce slow MyHC.

PMID- 10415348
TI  - Skeletal dysplasias, growth retardation, reduced postnatal survival, and impaired
      fertility in mice lacking the SNF2/SWI2 family member ETL1.
AB  - The mouse Etl1 gene encodes a nuclear protein belonging to the rapidly growing
      SNF2/SWI2 family. Members of this family are related to helicases and nucleic
      acid-dependent ATPases and have functions in essential cellular processes such as
      transcriptional regulation, maintenance of chromosome stability and various
      aspects of DNA repair. The ETL1 protein is expressed from the two-cell stage
      onwards, throughout embryogenesis in a dynamic pattern with particularly high
      levels in the thymus, epithelia and the nervous system and in most adult tissues.
      As a first step to address the role of ETL1 in cells and during development, we
      inactivated the gene by homologous recombination. ES cells and mice lacking
      detectable ETL1 protein were viable, indicating that ETL1 is not essential for
      cell survival or for embryonic development. However, mutant mice showed retarded
      growth, peri/post natal lethality, reduced fertility and various defects in the
      sternum and vertebral column. Expressivity and penetrance of all observed
      phenotypes were influenced by the genetic background. Isogenic 129Sv(Pas) mice
      lacking ETL1 had a severely reduced thoracic volume, which might lead to
      respiratory failure and could account for the high incidence of perinatal death
      on this genetic background.

PMID- 10415349
TI  - Mesoderm patterning and somite formation during node regression: differential
      effects of chordin and noggin.
AB  - In Xenopus, one of the properties defining Spemann's organizer is its ability to
      dorsalise the mesoderm. When placed ajacent to prospective lateral/ventral
      mesoderm (blood, mesenchyme), the organizer causes these cells to adopt a more
      axial/dorsal fate (muscle). It seems likely that a similar property patterns the
      primitive streak of higher vertebrate embryos, but this has not yet been
      demonstrated clearly. Using quail/chick chimaeras and a panel of molecular
      markers, we show that Hensen's node (the amniote organizer) can induce posterior
      primitive streak (prospective lateral plate) to form somites (but not notochord)
      at the early neurula stage. We tested two BMP antagonists, noggin and chordin
      (both of which are expressed in the organizer), for their ability to generate
      somites and intermediate mesoderm from posterior streak, and find that noggin,
      but not chordin, can do this. Conversely, earlier in development, chordin can
      induce an ectopic primitive streak much more effectively than noggin, while
      neither BMP antagonist can induce neural tissue from extraembryonic epiblast.
      Neurulation is accompanied by regression of the node, which brings the
      prospective somite territory into a region expressing BMP-2, -4 and -7. One
      function of noggin at this stage may be to protect the prospective somite cells
      from the inhibitory action of BMPs. Our results suggest that the two BMP
      antagonists, noggin and chordin, may serve different functions during early
      stages of amniote development.

PMID- 10415350
TI  - A conserved 30 base pair element in the Wnt-5a promoter is sufficient both to
      drive its' early embryonic expression and to mediate its' repression by otx2.
AB  - We have characterised a short (30 base pair) element from the Xenopus Wnt-5a
      promoter which is nearly identical to one located in the human Wnt-5a promoter,
      and has the same position relative to the transcription start site. When placed
      in front of a LacZ gene, this element can reproduce the same expression pattern
      observed for Wnt-5a at the late gastrula stage. Further we show that gastrula
      stage Wnt-5a expression is repressed by otx2, something which is reflected by the
      mutually exclusive expression patterns of these two genes. The isolated promoter
      sequence contains an OTX- consensus binding site and its' activity in embryos is
      repressed by ectopically expressed otx2.

PMID- 10415351
TI  - Role of polysialic acid on outgrowth of rat olfactory receptor neurons.
AB  - Towards elucidating the role of polysialic acid (PSA) in developing olfactory
      neuron of the rat, we injected neuraminidase (endo-N) into the olfactory nerve
      pathway under whole embryo culture, then employed immunohistochemistry to (i)
      detect expression of highly sialylated neural cell adhesion molecules (NCAM-H)
      and (ii) identify olfactory neurons via anti-microtubule-associated protein 1B
      (MAP1B) antibody. Olfactory axonal outgrowth from basal lamina occurred at the 31
      somite stage and reached the olfactory bulb primordium at the 42-somite stage,
      being coincident with the timing and expression of NCAM-H immunoreactivity.
      Enzymatic removal of PSA by endo-N remarkably affected developmental processes of
      axonal outgrowth, extension, and pathfinding, i.e. individual axons appeared to
      have become stuck in the mesenchyme. Results indicate that PSA is critically
      involved with anti-adhesion cues associated with individual axonal growth during
      olfactory system development.

PMID- 10415352
TI  - The actin cytoskeleton is required for maintenance of posterior pole plasm
      components in the Drosophila embryo.
AB  - Localization of mRNAs is one of many aspects of cellular organization that
      requires the cytoskeleton. In Drosophila, microtubules are known to be required
      for correct localization of developmentally important mRNAs and proteins during
      oogenesis; however, the role of the actin cytoskeleton in localization is less
      clear. Furthermore, it is not known whether either of these cytoskeletal systems
      are necessary for maintenance of RNA localization in the early embryo. We have
      examined the contribution of the actin and microtubule cytoskeletons to
      maintenance of RNA and protein localization in the early Drosophila embryo. We
      have found that while microtubules are not necessary, the actin cytoskeleton is
      needed for stable association of nanos, oskar, germ cell-less and cyclin B mRNAs
      and Oskar and Vasa proteins at the posterior pole in the early embryo. In
      contrast, bicoid RNA, which is located at the anterior pole, does not require
      either cytoskeletal system to remain at the anterior.

PMID- 10415353
TI  - Antagonist activity of DWnt-4 and wingless in the Drosophila embryonic ventral
      ectoderm and in heterologous Xenopus assays.
AB  - Wnt genes encode secreted signalling molecules involved in a number of basic
      developmental processes. In Drosophila, wingless and DWnt-4 are two physically
      clustered Wnt genes, which are transcribed in overlapping patterns during
      embryogenesis and, in several instances, are controlled by the same regulatory
      molecules. To address the question of the functional relationship of wingless and
      DWnt-4, we analysed how embryonic cells respond when they are exposed,
      simultaneously or not, to the encoded Wnt signals. We show that DWnt-4 has the
      capacity to antagonise Wingless signalling both in the Drosophila ventral
      epidermis and in a heterologous system, the Xenopus embryo. We provide evidence
      that DWnt-4 inhibits the Wingless/Wnt-1 signalling pathway upstream of the
      activation of transcriptional targets. This is the first report that antagonising
      Wnt signals exist in Drosophila.

PMID- 10415354
TI  - Promoter activity of the zebrafish bhikhari retroelement requires an intact
      activin signaling pathway.
AB  - We have investigated mesoderm induction in zebrafish employing the zebrafish LTR
      retroelement bhikhari (bik). bik elements are transcribed in all early
      mesendodermal cells. This expression pattern is generated by a promoter located
      in the U3 region of the LTR. We show that bik is activated through the
      activin/Vg1 signaling pathway in an immediate early fashion. This activation
      critically depends on a sequence motif that occurs among others also in the
      Xenopus Mix2 activin response element (ARE). It has been shown that the Mix2 ARE
      binds FAST- 1, which complexes with Smad proteins to form a multi-protein
      complex. We confirm that also the bik ARE can be bound by FAST-1 in vitro. In
      animal cap experiments we demonstrate that this binding site is required for
      activin-induced transcriptional activation mediated by FAST and Smad-type
      proteins.

PMID- 10415355
TI  - Zebrafish zic1 expression in brain and somites is affected by BMP and hedgehog
      signalling.
AB  - Here we report the expression of the zebrafish zic1 gene, also known as opl, a
      homologue to other vertebrate Zic genes and the Drosophila odd-paired gene. zic1
      expression starts during epiboly stages in lateral parts of the neural plate and
      eventually comes to lie in dorsal regions of the developing brain following the
      morphogenetic movements of neural tube formation. To address the question whether
      BMP2 signalling affects the extent of zic1 expression, we analysed swirl and
      chordino mutant embryos. Expanded Zic1 expression in swirl and reduced expression
      in chordino as well as in bmp2 injected embryos suggest that BMP2 and its
      antagonists define the extent of zic1 expression in the neural plate. By
      searching for factors responsible for the dorsal restriction of Zic1 expression,
      we found zic1 expression is eliminated in sonic hedgehog (shh) injected embryos.
      The most rostral expression however is not affected by Shh suggesting that Shh
      plays a different role in dorso-ventral patterning of the future telencephalon.
      During somitogenesis zic1 is expressed in the dorsal most part of the developing
      somites. Here zic1 marks cells that are distinct from the main adaxial somite
      portion, the future myomere. zic1 expression in the somites is expanded in swirl
      but reduced in shh injected embryos, suggesting these factors have opposing
      activity in dorsoventral patterning of the somites. Later, a growing mass of zic1
      expressing cells occurs in a dorsal mesenchyme that eventually invades the dorsal
      fin fold, suggesting a somitic contribution to the dorsal fin mesenchyme.

PMID- 10415356
TI  - cSix4, a member of the six gene family of transcription factors, is expressed
      during placode and somite development.
AB  - We describe the expression pattern of cSix4, a chick homologue of the murine
      Six4/AREC3 gene. cSix4 transcripts are detected at gastrula stages in the
      blastoderm surrounding the developing axial midline. As the neural plate begins
      to form cSix4 mRNA is detected in a crescent-shaped band, which surrounds the
      anterior developing neural plate and corresponds to the presumptive placode
      region. This expression is maintained in all the placodes (olfactory, optic,
      neural and otic) as they develop but with different characteristics. Further,
      abundant expression of cSix4 was localised to the paraxial mesoderm and the
      entire developing somites, becoming restricted first to their dorsal portion,
      then to the dermomyotome and finally to the myotome. cSix4 expression is
      maintained in the developing and adult muscular tissue. Additional sites of cSix4
      expression are the presumptive and developing limb buds, the notochord,
      trigeminal ganglia, cells of the spinal cord, particularly the motor neurones,
      the dorsal root ganglia, the neural retina, as well as the epithelial component
      of the developing kidney.

PMID- 10415357
TI  - Expression of Fgfr2 in the early mouse embryo indicates its involvement in
      preimplantation development.
AB  - We report that the IIIc transcriptional alternative of Fgfr2 is transcribed in
      the unfertilized egg and that during early zygotic transcription, messages
      encoded by both Fgfr2 alternatives (IIIc and IIIb) are present. The Fgfr2 protein
      was first detected in peripheral blastomeres of compacted morulae. Trophectoderm
      specificity of Fgfr2 became obvious in the early blastocyst and with maturation
      its localization underwent further specification, Fgfr2 concentration increased
      at the abembryonic pole and decreased at the embryonic pole. Moreover Fgfr2
      expression became markedly asymmetrical along the animal-vegetal axis of the
      mature blastocyst. Our observations indicate a role for Fgfr2 in trophectoderm
      growth and specification and in the orientation and polarity of the
      preimplantation conceptus.

PMID- 10415358
TI  - Hey genes: a novel subfamily of hairy- and Enhancer of split related genes
      specifically expressed during mouse embryogenesis.
AB  - We have identified a novel subfamily of mammalian hairy/Enhancer of split
      (E(spl))-related basic helix-loop-helix (bHLH) genes together with a putative
      Drosophila homologue. While hairy/E(spl) proteins are characterized by an
      invariant proline residue in the basic domain and a carboxyterminal groucho
      binding WRPW motif, our genes encode a carboxyterminal KPYRPWG sequence and were
      thus designated as Hey genes (Hairy/E(spl)-related with YRPW motif). Furthermore,
      they bear a unique C-terminal TE(I/V)GAF motif and the characteristic proline is
      changed in all Hey family members to glycine. RNA in situ hybridization analysis
      revealed specific expression of Hey1 during development of the nervous system,
      the somites, the heart and the craniofacial region. Hey2 is similarly expressed
      in the somites whereas it shows a complementary expression in the heart, the
      craniofacial region and the nervous system. The diversity of expression patterns
      implies unique functions in neurogenesis, somitogenesis and organogenesis.

PMID- 10415360
TI  - Embryonic expression of the human GATA-3 gene.
AB  - The spatial and temporal analysis of GATA-3 expression pattern in the human
      embryo revealed its expression in new anatomical sites. These include the
      endoderm of the primitive foregut, pharynx and allantois, the branchial arches
      and the mesenchymal cells surrounding the stomach and dorsal aorta. On the other
      hand, human (h) GATA-3 expression in the central nervous system, somites and
      embryonic kidney confirms the tissue specificity of this gene throughout
      vertebrate evolution.

PMID- 10415359
TI  - Expression of the Nkx3.1 homobox gene during pre and postnatal development.
AB  - We report here the expression pattern of Nkx3.1, a murine homolog of Drosophila
      bagpipe, in different stages of embryos and in neonates. Nkx3.1 was expressed in
      paraxial mesoderm at day 7.5 p.c., in the somite by day 8.0 p.c. and in a subset
      of vascular smooth muscle cells by day 9.5 p.c. In later stage embryos and
      neonates, Nkx3.1 was expressed in subpopulations of epithelial cells,
      particularly in epithelial outgrowths. Nkx3.1 was also expressed in restricted
      regions of the central nervous system.

PMID- 10415361
TI  - Expression of Fgf4 during early development of the chick embryo.
AB  - Fibroblast growth factor 4 (Fgf4) has been implicated as a regulator of mesoderm
      formation, posteriorisation, neural induction and neural patterning. Much of the
      evidence for this derives from studies in which exogenous FGF4 is applied to
      avian embryos. We have therefore examined expression of endogenous Fgf4 mRNA in
      the developing chick embryo at stages when these processes are occurring.
      Expression was detected in the primitive streak from the onset of gastrulation.
      Notably, transient expression of transcripts was found in head process cells at
      the onset of neural plate formation and regionalisation. Later, mRNA was detected
      in the presumptive posterior hindbrain and within the ventral midbrain. Fgf4 mRNA
      was also found in paraxial mesoderm underlying the posterior hindbrain, somites,
      branchial arches, limb buds and the tail bud.

PMID- 10415362
TI  - Identification of chick rax/rx genes with overlapping patterns of expression
      during early eye and brain development.
AB  - We have isolated chick rax/rx cDNAs, cRaxL (chick Rax/Rx-like) and cRax, (chick
      Rax) and examined their expression patterns during early eye and brain
      development. The cRaxL cDNA encodes a 228 amino acid protein that is most closely
      related to the zebrafish Rx1 and Rx2. The cRax cDNA encodes a 317 amino acid
      protein, which shares higher homology with the Xenopus Rx. In addition to the
      homeodomain, the octapeptide and paired tail domains are conserved between the
      cRax and other vertebrate Rax/Rx, while cRaxL lacks the octapeptide containing N
      terminal region which is conserved among all other members of the rax/rx gene
      family identified so far. The chick rax/rx genes are expressed in overlapping
      domains in the anterior neural ectoderm which corresponds to the forebrain and
      retina field, and later in the optic vesicle. cRax mRNA can be detected earlier
      than cRaxL prior to the formation of the notochord and its expression domain
      appears broader than that of cRaxL.

PMID- 10415363
TI  - Expression of Wnt signalling pathway genes during tooth development.
AB  - We have carried out comparative in situ hybridisation analysis of six Wnt genes
      Wnts-3, -4, -5a, -6, -7b, and 10b together with Wnt receptor MFz6 and receptor
      agonist/antagonists MFrzb1 and Mfrp2 during murine odontogenesis from the
      earliest formation of the epithelial thickening to the early bell stage.
      Expression of Wnt-4, Wnt-6, and one Wnt receptor MFz6 was observed in the facial,
      oral and dental epithelium. Wnt10b was localised specifically to the presumptive
      dental epithelium. Wnts-3 and -7b were expressed in oral epithelium but showed no
      expression in the presumptive dental epithelium. Wnt-3 also showed no expression
      in the epithelial cells of the molar bud stage tooth germs, but showed restricted
      expression in the enamel knots which are signalling centres believed to be
      involved in regulating tooth shape. Wnts -6, -10b and MFz6 were also detected in
      the primary and secondary enamel knots. Wnt-5a and agonist/antagonists MFrzb1 and
      Mfrp2 were expressed in a graded proximo-distal (P-D) manner in mesenchymal cells
      during the early stages of tooth development with no overlying expression in the
      oral or dental epithelium. Wnt-5a and MFrzb1 show strong expression in the dental
      papilla mesenchyme.

PMID- 10415364
TI  - Cyclic AMP increases hydroxyindole-O-methyltransferase mRNA levels in the chicken
      pineal gland, but is not required for circadian rhythmicity of this transcript.
AB  - Hydroxyindole-O-methyltransferase (HIOMT) plays an important role as the final
      enzyme in the synthesis of melatonin. In the chicken pineal gland, HIOMT mRNA
      concentration exhibits a circadian rhythm with a threefold peak at midday. The
      present study sought to evaluate the possible role of cyclic AMP in this
      transcriptional rhythm. In cultured pineal glands from 4-day-old chicks, cyclic
      AMP analogs and the adenylate cyclase activator, forskolin, increased HIOMT mRNA
      levels twofold to threefold in a dose-dependent manner. Vasoactive intestinal
      polypeptide increased HIOMT mRNA levels by 50%. Actinomycin-D chase experiments
      indicated that cyclic AMP did not affect the stability of HIOMT mRNA, thus
      providing indirect evidence that the effect of cyclic AMP was exerted at
      transcriptional level. In cultured pineal glands from 11 days embryos, HIOMT mRNA
      levels failed to respond to cyclic AMP. However, a daily rhythm of HIOMT mRNA,
      with an endogenous component in constant darkness was clearly observed at this
      developmental stage. This observation indicates that cyclic AMP is not required
      for circadian rhythmicity of HIOMT gene transcription.

PMID- 10415366
TI  - The association of metalloendopeptidase EC 3.4.24.15 at the extracellular surface
      of the AtT-20 cell plasma membrane.
AB  - Endopeptidase EC 3.4.24.15 (EP24.15) is a soluble, neuropeptide-degrading
      metalloenzyme, widely expressed in the brain, pituitary and gonads. For the
      physiological metabolism of neuropeptides, the enzyme should be located
      extracellularly, either associated with the plasma membrane or in the
      extracellular milieu. Western immunoblot analyses of crude cytosolic and post
      nuclear membrane fractions prepared by differential centrifugation revealed a
      slightly smaller molecular mass ( approximately 2 kDa) for EP24.15 in the post
      nuclear membrane fraction. This smaller EP24.15 species was also present in an
      enriched fraction of plasma membrane prepared by Percoll gradient centrifugation.
      To ascertain whether EP24.15 is associated with the extracellular surface of
      plasma membrane, two sets of experiments were carried out. First, Western
      immunoblot analysis of AtT-20 cells treated with the membrane-impermeable, thiol
      cleavable cross-linker, 3, 3'-dithio-bis(sulpho-succinimidyl-propionate) (DTSSP),
      indicated an extracellular membrane association. After cross-linking and thiol
      reduction, a distinct band corresponding to EP24.15 was significantly diminished
      under non-reducing conditions. Second, immunocytochemical studies performed at 4
      degrees C on non-permeabilized AtT-20 cells (i.e., non-fixed to prevent antibody
      internalization), indicated that EP24.15 was expressed on the surface of the AtT
      20 cells. We furthermore determined that EP24.15 enzymatic activity is present on
      the extracellular surface of the cell discernable from the secreted enzyme. These
      results suggest that the EP24.15 is associated with the extracellular surface of
      the AtT-20 cell plasma membrane and is enzymatically active. Taken together, the
      results are consistent with a putative role in the degradation of neuropeptides
      acting at the external cell surface.

PMID- 10415367
TI  - Aluminum-induced degeneration of astrocytes occurs via apoptosis and results in
      neuronal death.
AB  - The mechanisms by which aluminum interacts with the nervous system are only
      partly understood. In this study, we used cultured astrocytes and neurons to
      investigate the effects of long exposures to aluminum (1 mM). We found that
      aluminum accumulated both in neurons and astrocytes. After 8-12 days exposure,
      aluminum caused strong changes in the morphology of astrocytes including
      shrinkage of cell bodies and retraction of processes. Exposures over 15-18 days
      reduced astrocytes viability by 50%. Aluminum-induced degeneration of astrocytes
      involved the DNA fragmentation characteristic of apoptosis, and staining of
      aluminum-treated astrocytes with the DNA-binding fluorochrome Hoeschst 33258
      revealed the typical apoptotic condensation and fragmentation of chromatin.
      Aluminum was also found to be neurotoxic, causing first (4-6 days) abnormal
      clustering and aggregation, and later (8-12 days) neuronal death. Interestingly,
      aluminum neurotoxicity occurred in neuroglial cultures containing approximately
      10% astrocytes but not in near-pure neuronal cultures containing only 1%
      astrocytes. Staining of co-cultured cells with Hoeschst 33258 showed apoptotic
      condensation and fragmentation of chromatin in aluminum-treated astrocytes but
      not in co-cultured neurons. Our study demonstrates that aluminum can induce the
      apoptotic degeneration of astrocytes, and that this toxicity is critical in
      determining neuronal degeneration and death. Aluminum-mediated apoptosis of
      cultured astrocytes may be also a valuable model system to study the mechanisms
      underlying apoptosis in glial cells.

PMID- 10415365
TI  - Ketanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase
      A.
AB  - Mice deficient in monoamine oxidase A (MAO A) have elevated brain levels of 5-HT
      and manifest enhanced aggression. We used these mice as a model to study the role
      of 5-HT in aggression. Our results show that ketanserin and tetrabenazine (TBZ)
      strikingly abolished the aggressive behavior of MAO A-deficient mice. The anti
      aggressive effect of ketanserin may be primarily mediated by 5-HT(2A) receptors.
      Another specific 5-HT(2A) antagonist, [R-(+)-a-(2, 3-dimethoxyphenyl)-1-[2-(4
      fluorophenylethyl)]-4-piperidine-methan ol (MDL 100907), also blocks the
      aggression of mutant mice but was less dramatic. Ketanserin and TBZ are both
      antagonists of the vesicular monoamine transporter (VMAT2). The anti-aggressive
      effect of TBZ and part of the effect of ketanserin may be mediated by the VMAT2.
      Using radioligand binding and autoradiography, we also showed that the numbers of
      VMAT2, 5-HT(1A), 5-HT(2A) and 5-HT(2C) sites are decreased in brains of mutant
      mice, which may reflect down-regulation by excess 5-HT. This study suggests that
      ketanserin and TBZ may be developed as novel anti-aggressive agents.

PMID- 10415368
TI  - Endogenous morphine levels increase in molluscan neural and immune tissues after
      physical trauma.
AB  - The aim of this study was to demonstrate by biochemical and immunocytochemical
      methods the presence of endogenous morphine in nervous and immune tissues of the
      freshwater snail, Planorbarius corneus. High performance liquid chromatography
      (HPLC) coupled to electrochemical detection performed on tissues from control
      snails, revealed that the CNS contains 6.20+/-2.0 pmol/g of the alkaloid, the
      foot tissue contains a much lower level, 0.30+/-0.03 pmol/g, whilst morphine is
      not detected in the hemolymph and hepatopancreas. In specimens that were
      traumatized, we detected a significant rise of the CNS morphine level 24 h later
      (43.7+/-5.2 pmol/g) and an initial decrease after 48 h (19.3+/-4.6 pmol/g). At
      the same times, we found the appearance of the opiate in the hemolymph (0.38+/
      0.04 pmol/ml and 0.12+/-0.03 pmol/ml) but not in the hepatopancreas. Using
      indirect immunocytochemistry, a morphine-like molecule was localized to a number
      of neurons and a type of glial cell in the CNS, to some immunocytes in the
      hemolymph and to amoebocytes in the foot, as well as to fibers in the aorta wall.
      Simultaneously to the rise of morphine biochemical level following trauma,
      morphine-like immunoreactivity (MIR) increased in both intensity and the number
      of structures responding positively, i.e., neurons and fiber terminals. In
      another mollusc, the mussel Mytilus galloprovincialis, the same pattern of
      enhanced MIR was found after trauma. Taken together, the data suggest the
      presence of a morphinergic signaling in invertebrate neural and immune processes
      resembling those of classical messenger systems and an involvement in trauma
      response.

PMID- 10415369
TI  - The immunosuppressants cyclosporin A and FK506 equally ameliorate brain damage
      due to 30-min middle cerebral artery occlusion in hyperglycemic rats.
AB  - In the present experiments, we compared the anti-ischemic effects of the
      immunosuppressants cyclosporin A (CsA) and FK506 in hyperglycemic animals
      subjected to 30 min of middle cerebral artery (MCA) occlusion. Both
      immunosuppressants were given as pre-treatment, the effect of treatment being
      evaluated by 2,3, 5-triphenyltetrazolium (TTC) staining after 3 days of recovery.
      Both FK506 and CsA reduced the infarct volume to less than 1/3 of control. In
      spite of CsA's known effect as a blocker of the mitochondrial transition (MPT)
      pore, it failed to give a more robust effect than FK506. If anything, FK506,
      which lacks an effect on the MPT pore, had a more pronounced anti-ischemic
      effect. We conclude that, in this model of infarction, an MPT may not play a
      major pathogenetic role.

PMID- 10415370
TI  - Haloperidol induces Fos expression in the globus pallidus and substantia nigra of
      cynomolgus monkeys.
AB  - Systemic injections of the dopamine antagonist haloperidol (0.1-2.5 mg/kg)
      induced a dose dependent increase in Fos-like immunoreactivity (FLI) in the
      internal segment of the globus pallidus (GPi) and in the substantia nigra (SN) of
      cynomolgus monkeys. These findings are consistent with models of basal ganglia
      organization which predict that blockade of dopamine receptors should result in a
      disinhibition of cells in these structures. In the GPi, labeling was most
      pronounced along the ventral, lateral and medial borders of the nucleus and none
      of the pallidal cells expressing FLI were immunopositive for choline
      acetyltransferase. In the SN, immunoreactive nuclei were concentrated in the pars
      reticulata and the majority of labeled nigral neurons did not display tyrosine
      hydroxylase-like immunoreactivity. A small number of cells displaying FLI were
      also observed in the external pallidal segment, but no labeling was seen in the
      subthalamic nucleus. These findings indicate that blockade of dopamine receptors
      induces a characteristic pattern of Fos expression in the primate brain which
      strongly resembles that previously reported in rodents.

PMID- 10415371
TI  - The trophic factors S-100beta and basic fibroblast growth factor are increased in
      the forebrain reactive astrocytes of adult callosotomized rat.
AB  - S-100 is a calcium-binding protein that is predominantly found in astrocytes of
      the central nervous system. In the present study, we investigated the temporal
      and spatial changes of S-100beta immunoreactivity after a stereotaxic mechanical
      lesion of the adult rat corpus callosum performed with an adjustable wire knife.
      Rats were killed 7, 14 and 28 days after surgery. S-100beta immunoreactivity was
      found within the cytoplasm and processes of quiescent putative astrocytes that
      were observed throughout the gray and white matters of the forebrain of sham
      operated rats. Following callosotomy, the S-100beta immunoreactive profiles
      showed increased size and thick processes, as well as increased amount of S
      100beta immunoreactivity. Unbiased stereologic analysis revealed a sustained and
      widespread increase of the Areal Fraction of S-100beta immunoreactive profiles in
      the medial and lateral regions of the white matter of callosotomized rats at the
      studied time-intervals. In the cerebral cortex of callosotomized rats, the
      estimated total number of S-100beta immunoreactive profiles was also increased 7
      and 14 days after the lesion. Since the cellular and temporal changes in S
      100beta immunoreactivity were closely similar to those described for basic
      fibroblast growth factor (bFGF) following brain lesions, we co-localized the S
      100beta and bFGF immunoreactivities after callosotomy. bFGF immunoreactivity was
      found in the nuclei of S-100beta immunoreactive glial profiles throughout the
      forebrain regions of the sham-operated rats. bFGF immunoreactivity was increased
      in the nuclei of reactive S-100beta immunoreactive putative astrocytes in the
      forebrain white matter and in the cerebral cortex of callosotomized rats. These
      results indicate that after transection of the corpus callosum of adult rats, the
      reactive astrocytes may exert paracrine trophic actions through S-100beta and
      bFGF. Interactions between S-100beta and bFGF may be relevant to the events
      related to neuronal maintenance and repair following brain injury.

PMID- 10415372
TI  - Quantitative analyses of neurons projecting to primary motor cortex zones
      controlling limb movements in the rat.
AB  - The objective was to determine if projections of single neurons to primary motor
      cortex preferentially terminate in several efferent zones that could form
      synergies for the execution of limb movements. Intracortical microstimulation was
      used to identify zones evoking hip flexion (HF), elbow flexion (EF), and both
      plantarflexion (PF) and dorsiflexion (DF) about the ankle. Histological
      examination showed that the zones from which some movements were evoked extended
      beyond the agranular cortex into granular cortex. Fluorogold, Fast blue, and
      propridium iodide or rhodamine-labeled dextran were injected into three of these
      four efferent zones in each rat. There was a virtual absence of multiple-labeled
      cells despite having an intermingling of different-colored cells of which 15% in
      frontal cortex were less than 1.2 mm away from a neighboring neuron that
      projected to a different efferent zone. This suggests that single neurons
      projecting to the motor cortex do not hard-wire specific synergies but rather
      project to single efferent zones in order to offer the greatest degree of freedom
      for the generation of movements. The distribution of ventral posterolateral and
      ventrolateral thalamic nucleus labeling depended on whether the injections were
      in granular or agranular cortex. Conversely, frontal cortex projections to motor
      efferent zones were made irrespective of their location in either granular or
      agranular cortex and thereby supporting their presumed role in the control of
      movements. Hindlimb motor cortex injections yielded retrograde labeling that
      extended into the more localised distribution of frontal cortex neurons
      retrogradely labeled from forelimb injections. This may allow hindlimb movements
      to be synchronized by forelimb movements during walking on challenging terrain.

PMID- 10415373
TI  - Induced hypertension treatment to improve cerebral ischemic injury after
      transient forebrain ischemia.
AB  - The effect of induced hypertension treatment on cerebral ischemia is still
      controversial. We investigated the preferred blood pressure manipulation level
      and pressor agent required to reduce cerebral ischemic injury following transient
      forebrain ischemia induced by bilateral occlusion of the common carotid arteries
      in anesthetized gerbils. Following 60-min cerebral ischemia, we evaluated the
      preferred blood pressure manipulation level and pressor agent required to treat
      cerebral ischemic injury after reperfusion by examining the effects of different
      levels of mean arterial blood pressure (MABP), increased with phenylephrine or
      angiotensin II or decreased by blood withdrawal, on cerebral blood flow (CBF),
      survival ratio, cerebral edema, and brain energy metabolism following transient
      forebrain ischemia in gerbils. Mild phenylephrine-induced hypertension treatment
      (21+/-4 mmHg) during post-cerebral ischemia-reperfusion improved the survival
      ratio and reduced cerebral edema, which was also associated with an increase in
      local CBF and a recovery of brain energy metabolism. However, intense
      phenylephrine-induced hypertension, angiotensin II-induced hypertension, or
      hypotension worsen the survival rate and produced extra cerebral edema, that were
      also associated with deterioration of brain energy metabolism. These results
      demonstrate that a mild induced hypertension with phenylephrine (21+/-4 mmHg
      above the baseline level) results in reduction of the cerebral edema and improves
      the survival ratio and brain energy metabolism. Furthermore, angiotensin II may
      have neurotoxic effect to use as the pressor agent for induced hypertension after
      cerebral ischemia.

PMID- 10415374
TI  - In vitro responses of neurons in the periaqueductal gray to hypoxia and
      hypercapnia.
AB  - Hypoxia-sensitive neurons in the caudal hypothalamus (CH) have been shown to
      project to the periaqueductal gray (PAG) which, in turn, sends descending
      projections to an area of the ventrolateral medulla (VLM) containing neurons
      inherently excited by hypoxia. The purpose of this study was to determine if
      neurons in the PAG are excited by hypoxia or hypercapnia in an in vitro
      environment. Extracellular responses to hypoxia and hypercapnia of neurons
      located throughout the PAG were recorded in a rat brain slice (400-500 microm
      thick) preparation. Hypoxic (10% O(2)/5% CO(2)/85% N(2)) and hypercapnic (7%
      CO(2)/93% O(2)) stimuli were delivered to the tissue through gas bubbled into the
      brain slice chamber. A majority (39 of 53) of the neurons tested responded to
      hypoxia. Of these neurons, 92% responded to hypoxia with an increase in firing
      rate. Neurons in the dorsolateral/lateral regions increased firing rates to a
      greater extent than neurons located in ventrolateral regions. All neurons tested
      (n=6) also responded to hypoxia after perfusion of the tissue with a low
      Ca(2+)/high Mg(2+) solution to block classic synaptic transmission. Only a small
      proportion (7/33) of neurons tested responded to hypercapnia. These findings
      indicate that neurons in the periaqueductal gray region of the brain have an
      inherent responsiveness to hypoxia and, thus, may contribute to the overall
      coordination of cardiorespiratory responses to systemic hypoxia.

PMID- 10415375
TI  - Chronic administration of morphine alters immediate-early gene expression in the
      forebrain of post-dependent rats.
AB  - Previous studies from this laboratory have demonstrated that acute, systemic
      administration of morphine results in an induction of the immediate-early gene
      (IEG) proteins, c-Fos and Jun-B, in the dorsomedial portion of the rat caudate
      putamen (CPu). These studies have also shown that morphine can induce c-Fos in
      the central medial nucleus of the thalamus (CM). To determine whether this
      response is altered in post-dependent rats, twice-daily injections of an
      ascending dose of morphine were administered for 5 days, followed by a withdrawal
      period of 7 or 14 days. A challenge injection of morphine (10 mg/kg) was
      administered on the last day of withdrawal. As compared to an acute dose of
      morphine in a naive animal, the induction of c-Fos was increased in the
      dorsolateral CPu following challenge injection at 7 days, but not at 14 days.
      Induction of c-Fos in the CM following the challenge injection was blunted
      following 7 day, but not at 14 days, of withdrawal. An increase in the IEG
      protein, Jun-B, was also seen following 7 but not 14 days of withdrawal in both
      the dorsomedial and dorsolateral CPu. These findings demonstrate that a chronic
      treatment of morphine can result in altered patterns of IEG expression upon
      challenge with acute morphine, in a time-dependent manner, within the rat CPu and
      CM.

PMID- 10415376
TI  - Differential regulation of major histocompatibility complex class II expression
      and nitric oxide release by beta-amyloid in rat astrocyte and microglia.
AB  - Astrocytes and microglial cells were examined for expression of two
      immunologically important molecules, major histocompatibility complex class II
      (MHC-II) and nitric oxide (NO) following treatment with IFN-gamma and beta
      amyloid (betaA) peptides, betaA(1-42) and betaA(25-35). IFN-gamma is a potent
      inducer of both MHC-II gene expression and NO production. The induction of MHC-II
      was inhibited by both betaA peptides in astrocytes but they had little or no
      effect in microglia. betaA peptides had no effect on NO release in astrocytes but
      on microglia betaA(1-42) synergistically induced NO release with IFN-gamma.
      Transient transfection of astrocytes with 5' deletional mutants of MHC-II IAalpha
      promoter linked to the chloramphenicol acetyl transferase reporter gene (IAalpha
      CAT), demonstrated that betaA acts at the transcriptional level to downregulate
      IFN-gamma induced MHC-II gene expression in astrocytes. In previous studies, the
      induction of MHC-II on glial cells were suggested to be involved in the
      pathogenesis of neurodegenerative diseases and MHC-II(+) microglial cells were
      observed at much higher frequency than astrocytes. This study provides
      information on the regulation of the MHC-II gene expression in astrocytes and in
      microglial cells by betaA and this pathway may be critically involved in the
      immune/inflammatory regulation within the central nervous system.

PMID- 10415377
TI  - Autoreceptors remain functional after prolonged treatment with a serotonin
      reuptake inhibitor.
AB  - Serotonin (5-hydroxytryptamine, 5-HT) autoreceptors may desensitize during
      prolonged administration of antidepressant drugs. If autoreceptors desensitize,
      their inhibitory influence on extracellular 5-HT should be attenuated. To test
      this hypothesis, the selective serotonin reuptake inhibitor (SSRI) citalopram (10
      mg kg(-1), s.c., b.i.d.) or saline was administered for 14 days to rats. After a
      24-h washout period, rats were anesthetized, and implanted with dialysis probes
      for determination of 5-HT in the frontal cortex (FCx) and dorsal hippocampus
      (DH). In response to citalopram (5 mg kg(-1), s.c.) challenge, there were
      moderate increases in 5-HT in the FCx and DH of both the chronic citalopram and
      saline pretreatment groups. After subsequent administration of the 5-HT(1A/1B)
      autoreceptor antagonist, (-)-penbutolol, there were further increases in 5-HT in
      the FCx and DH of the saline pretreatment group. Moreover, contrary to the
      expected effect if autoreceptors were desensitized, the potentiation produced by
      (-)-penbutolol was greater in the FCx and DH of the chronic citalopram group as
      compared to rats pretreated with saline. These results suggest that autoreceptors
      still restrain the increase in 5-HT produced by an SSRI after prolonged
      administration.

PMID- 10415379
TI  - Effects of orphanin FQ on endomorphin-1 induced analgesia.
AB  - Orphanin FQ (also known as nociceptin) is a 17-amino-acid peptide which acts as a
      potent endogenous agonist of the orphan opioid receptor-like (ORL1) receptor.
      Endomorphin-1, a 4-amino-acid peptide discovered recently, is a potent and
      selective endogenous agonist for the mu-opiate receptor. In the present study,
      the effect of OFQ or/and endomorphin-1 on the response to noxious thermal stimuli
      was observed using the tail-flick test in rats. Intracerebroventricular (i.c.v.)
      administration of OFQ (1, 5 microg) could shorten tail-flick latency; In
      contrast, intrathecal (i.t.) administration of OFQ (1, 2 or 10 microg) could
      increase the latency; i.c.v. (1, 2, 5 microg) or i.t. (0.2, 2, 5 microg)
      administration of endomorphin-1 dose-dependently increased the latency,
      indicating an analgesic effect. Furthermore, OFQ (0.1-5 microg) when
      intraventricularly injected together with endomorphin-1 (5 microg), could dose
      dependently reverse the analgesia induced by the latter. On the contrary, OFQ (1
      microg) intrathecally injected together with endomorphin-1 (0.2 microg) could
      further increase the tail-flick latency. The results showed that OFQ at the
      supraspinal level produces hyperalgesia and is antagonistic to endomorphin-1,
      while at the spinal level it produces analgesia and is synergic with endomorphin
      1. Different interaction mechanism between OFQ and endomorphin-1 in the brain and
      the spinal cord is thus suggested.

PMID- 10415378
TI  - Ascorbic acid is neuroprotective against global ischaemia in striatum but not
      hippocampus: histological and voltammetric data.
AB  - Following reports that ascorbic acid (AA) blocks NMDA receptors, we examined its
      possible neuroprotective properties in vivo (gerbil bilateral carotid artery
      occlusion model: BCAO) and in vitro (ischaemia-induced dopamine (DA) release in
      brain slices). Five minutes of BCAO caused substantial cell loss of 90-95% and 40
      50% in gerbil CA1 hippocampus and striatum, respectively, measured in
      haematoxylin and eosin-stained sections, 5 days post-insult. AA (500 mg kg(-1)
      day(-1) i.p. for 312 days, first dose 1 h before occlusion) significantly
      (P<0.05) reduced striatal cell loss (from 40 to 13%) while only reducing CA1 cell
      loss from 95 to 88%. A lower dose (250 mg kg(-1) day(-1) i.p. for 312 days) was
      ineffective in either region. AA (750 mg kg(-1) day(-1) i.p. for 312 days) caused
      significant striatal protection (cell loss reduced from 49 to 20%) if treatment
      was initiated 1 h before occlusion. Initiation of treatment immediately post
      occlusion did not cause significant protection. Neither treatment regime
      protected CA1 hippocampus. In separate experiments we examined the effect of AA
      on DA release, monitored by voltammetry, in an in vitro model of striatal
      ischaemia. Four DA release variables were measured: T(on)--time from initiation
      of ischaemia to the onset of DA release, T(pk)--the time from onset of DA release
      to maximum, deltaDA/deltat--the mean rate of DA release and [DA](max)-- the
      maximum extracellular DA concentration. Control values in drug-naive slices were:
      T(on)=193+/-8 s, T(pk) = 24 +/- 4 s, [DA](max) = 69 +/- 6 microM and
      deltaDA/deltat = 4.2 +/- 0.7 microM s(-1) (means+/-S.E.M., n=15). 212 h
      pretreatment with AA (0.4 to 10 mM) did not affect T(on) or [DA](max) but
      increased T(pk) and decreased deltaDA/deltat (P<0.05) with an EC50 of 1.66 mM.
      NMDA (100 microM) shortened T(on). N-ethylmaleimide (20 microM) had no effect on
      the response to AA but potentiated the action of NMDA on T(on). AA (2 or 10 mM)
      had no effect on the response to NMDA. We conclude that AA is neuroprotective
      against global ischaemia in the striatum and that some of this action may be due
      to attenuation of ischaemia-induced DA release. This action is mediated neither
      by blockade of the NMDA receptor nor modulation of its redox status.

PMID- 10415380
TI  - Distribution of neurturin mRNA and immunoreactivity in the peripheral tissues of
      adult rats.
AB  - Neurturin (NTN) is a recently discovered neurotrophic factor related to glial
      cell line-derived neurotrophic factor (GDNF) and has a wide spectrum of
      biological roles in different types of neurons in the central and peripheral
      nervous systems. However, information on its expression in peripheral tissues has
      been limited, and there is no information on its peptide distribution. As a step
      to examine its role and action mechanisms in neuronal and non-neuronal cells in
      the periphery, the present study investigated the distribution patterns of its
      mRNA and peptide in some major peripheral organs of adult rats by in situ
      hybridization and immunohistochemistry. A widespread expression of NTN mRNA was
      found in the selected organs of various systems, with a high level in pituitary
      intermediate lobe, intestine, salivary gland, and testis, and a moderate level in
      ovary, adrenal gland, kidney, thyroid, and spleen. NTN peptide was also present
      in the peripheral organs studied, with its distribution corresponding to that of
      mRNA. In conclusion, NTN is expressed widely in many regionally well-defined
      cellular systems in various peripheral tissues, suggesting that NTN may act as a
      target-derived neurotrophic factor for innervating neurons and may have
      maintenance functions in non-neuronal cells of these adult organs.

PMID- 10415381
TI  - Deprivation of endogenous brain-derived neurotrophic factor results in impairment
      of spatial learning and memory in adult rats.
AB  - Brain-derived neurotrophic factor (BDNF) is abundantly expressed in the
      hippocampus and cerebral cortex and is involved in synaptic plasticity and long
      term potentiation (LTP). The present study was under taken to investigate whether
      endogenous BDNF was required for spatial learning and memory in a rat model.
      Antibodies to BDNF (anti-BDNF, n=7) or control immunoglobulin G (control, n=6)
      were delivered into the rat brain continuously for 7 days with an osmotic pump.
      The rats were then subjected to a battery of behavioral tests. The results show
      that the average escape latencies in the BDNF antibody treated group were
      dramatically longer than those of the control (F=13.3, p<0.001). The rats treated
      with control IgG swam for a significantly longer distance in the P quadrant
      (where the escape plane had been placed) compared with the other three quadrants
      (p<0.05). In contrast, anti-BDNF-treated rats swam an equivalent distance in all
      four quadrants. The average percentage of swimming distance in the P quadrant by
      anti-BDNF-treated rats was much less than that by control IgG treated rats
      (p<0.001). These results suggest that endogenous BDNF is required for spatial
      learning and memory in adult rats.

PMID- 10415382
TI  - Reorganization of area 5 neuron activity in trained deafferented monkeys.
AB  - A command function is attributable to certain area 5 neurons which clearly fire
      before movement in trained monkey. Statistical analysis allowed us to define two
      categories of spontaneous firing mode for these cells: type I which exhibits a
      random pattern of discharge (14%), and type II displaying markedly "bursty
      firing". After deafferentation, both categories were still observed in the same
      proportion. However, the discharge pattern and frequency in type II cells
      remained altered for 5 months. This paralleled rises in neural latency response
      (RS) and reaction time (RT). Beginning the 6th month, there was a progressive
      reorganization of the spontaneous activity along with normalization of RS and RT.
      Our results support the idea that an enhancement of the excitability of these
      area 5 neurons, initially depressed by the suppression of sensory inputs, occurs
      over time. This sensitivity gain could be due to neural network rearrangements
      induced by repetitive operant solicitation.

PMID- 10415383
TI  - Platelet-activating factor stimulation of p125(FAK) and p130(Cas) tyrosine
      phosphorylation in brain.
AB  - The effect of platelet-activating factor (PAF) on protein tyrosine
      phosphorylation was studied in rat brain slices. PAF induced a time- and
      concentration-dependent increase in tyrosine phosphorylation of a doublet of
      approximately 125 kDa. These proteins were identified by immunoprecipitation as
      p125(FAK) and p130(Cas), using monoclonal antibodies. This effect was mediated by
      PAF receptors, as shown by its inhibition by the action of a PAF antagonist. The
      tyrosine phosphorylation evoked by PAF was dependent, at least in part, on
      external calcium. The involvement of protein kinase C was demonstrated by the
      synergistic effect of TPA on PAF-stimulated tyrosine phosphorylation. The finding
      that PAF stimulates tyrosine phosphorylation of both focal adhesion protein
      p125(FAK) and p130(Cas) suggests that PAF might modulate the integrin mediated
      signal transduction in the brain.

PMID- 10415384
TI  - Hypoprolactinemic rats under conditions of constant darkness or constant light.
      Effects on the sleep-wake cycle, cerebral temperature and sulfatoxymelatonin
      levels.
AB  - In genetic hypoprolactinemic rats under light-dark (LD) conditions, the circadian
      rhythms of slow-wave (SWS) and paradoxical (PS) sleep display an alteration of
      their phase relationship. The aim of our study was to investigate the effects of
      constant darkness (DD) or constant light (LL) on the daily distribution and
      amounts of sleep-wake stages, cerebral temperature and concentrations of the
      urinary melatonin metabolite, 6-sulfatoxymelatonin, in prolactin-deficient rats.
      After 3 weeks of DD, the SWS period was 24 h 8+/-6 min and the acrophase occurred
      at 15:44+/-1:35, while for PS, the period was more stable than during LD (24 h
      10+/-8 min vs. 24 h 55+/-43 min) and the acrophase occurred at 16:44+/-1:54.
      Under LL conditions, circadian sleep rhythms persisted during the first 3 days,
      then completely disappeared during the third week, to be replaced by ultradian
      rhythms (period of 4-6 h). Time-series analysis showed that the two sleep states
      became synchronous as early as the second day under constant conditions. The
      total amount of PS was increased under both conditions (LL and DD) at the expense
      of duration of waking. Under LD and constant conditions, the pattern of changes
      in cerebral temperature was similar to that for wakefulness (W).
      Sulfatoxymelatonin was rhythmically secreted under both LD and DD conditions,
      whereas, under LL conditions, its rhythm was abolished. The results show that, in
      IPL rats in the absence of a zeitgeber, the PS and SWS rhythms recover a
      synchronous phase relationship and PS amounts are increased.

PMID- 10415385
TI  - Epileptiform activity generated by endogenous acetylcholine during blockade of
      GABAergic inhibition in immature and adult rat hippocampus.
AB  - We tested the effects of the acetylcholinesterase inhibitor eserine (10 microM),
      an indicator of the activity of endogenous ACh, on the generation of epileptiform
      discharges during blockade of inhibitory GABA(A)-mediated potentials by
      bicuculline (10 microM), in the CA3 area of hippocampal slices from postnatal
      days 4-20 (P4-P20) immature and adult rats. Eserine provoked or significantly
      increased the frequency of spontaneous synchronous epileptiform discharges, in
      6/22 (27%) P4-P10 slices, 34/35 P11-P20 slices and 18/18 adult slices, an
      epileptogenic effect. In immature slices, spontaneous discharges showed a stable
      frequency throughout perfusion with eserine, while in 5/11 adult slices an
      initial fast frequency was followed by a slower steady-state one. The cholinergic
      agonist carbachol (CCh, 25 microM) provoked only transient or no spontaneous
      synchronous discharges in adult slices (n=8), thus suggesting that massive
      activation of cholinergic receptors may lead to suppression of epileptiform
      activity in adult brain. Stimulus-induced excitatory CA3 responses, were
      depressed by eserine in approximately half of 20 P4-P10, 45 P11-P20 and 11 adult
      slices. The depression consisted of a decrease in the amplitude, duration, and
      number of population spikes of the field potentials by about 30%, a minor
      neuroprotective effect, which did not change with maturation. The different
      developmental profiles of the epileptogenic and neuroprotective effects of
      endogenous ACh suggest that they are mediated by different mechanisms. These
      experiments demonstrate that, endogenous ACh is sufficient to induce
      epileptogenesis during a decrease or failure of GABAergic inhibition, in both
      >/=P10 immature and in adult hippocampus. We therefore suggest that clinical or
      behavioral conditions which raise the concentration of endogenous ACh may lower
      the threshold to seizures.

PMID- 10415386
TI  - Involvement of dopamine D(1) and D(2) receptors in the ethanol-associated place
      preference in rats exposed to conditioned fear stress.
AB  - The present study was designed to investigate: (1) the involvement of dopamine
      D(1) and D(2) receptors, and (2) the roles of these receptors and endogenous
      opioid systems (endorphinergic and enkephalinergic systems) in the ethanol
      induced place preference in rats exposed to conditioned fear stress using the
      conditioned place preference paradigm. The administration of ethanol (300 mg/kg,
      i.p.) induced a significant place preference. The selective D(1) receptor
      antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H3
      benzazepine)hydrochloride (SCH23390; 0.01 and 0.03 mg/kg, s.c.) and the selective
      D(2) receptor antagonist S(-)-5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)
      methyl]-2- methoxybenzamide (sulpiride; 20 and 40 mg/kg, s.c.) significantly
      attenuated the ethanol-induced place preference. The administration of ethanol
      (75 mg/kg, i.p.) tended to produce a place preference, but this effect was not
      significant. SCH23390 (0.03 mg/kg, s.c.) and sulpiride (40 mg/kg, s.c.)
      significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced
      place preference produced by the mu-opioid receptor agonist morphine (0.1 mg/kg,
      s.c.). In addition, SCH23390 (0.03 mg/kg, s.c.) also significantly attenuated the
      enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by
      the selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)
      1,2,3,4,4a,5,12, 12aalpha-octahydroquinolino[2,3,3,-g]isoquinoline (TAN-67; 20
      mg/kg, s.c.). On the other hand, sulpiride (40 mg/kg) had no significant effect
      on the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference
      produced by TAN-67. These results suggest that D(1) and D(2) receptors may be
      involved in the rewarding mechanism of ethanol under psychological stress. In
      addition, D(1) receptors may participate in the rewarding effect of ethanol
      modulated by the activation of mu- and delta-opioid receptors, whereas D(2)
      receptors may participate in the rewarding effect of ethanol modulated by the
      activation of mu-opioid receptors, but not in that modulated by the activation of
      delta-opioid receptors.

PMID- 10415387
TI  - Mucus of the human olfactory epithelium contains the insulin-like growth factor-I
      system which is altered in some neurodegenerative diseases.
AB  - Growth factors are believed to be involved in the mitotic regulation of the
      animal olfactory epithelium (OE). We investigated mucus covering the human OE
      area to see if it contained the insulin-like growth factor-I (IGF-I) and its
      binding proteins (IGFBPs) and to examine their behaviour in neurodegenerative
      diseases. Thirty patients with idiopathic late onset cerebellar ataxia (ILOCA),
      Parkinson's disease, and amyotrophic lateral sclerosis (ALS) and 30 age- and sex
      matched healthy subjects were studied. In 10 controls, we also analyzed the mucus
      of the respiratory mucosa of the nose and tears. We detected IGF-I in the mucus
      covering the OE and Western ligand blot analysis (WLB) showed IGFBPs with an
      apparent Mr of 41, 500/38,500, 34,000 and 24,000, which were immunoprecipitated
      by specific antisera to IGFBP-3, -2 and -4, respectively. Their levels were
      higher than those observed in the respiratory mucosa of the nose or in tears.
      Mucus of the OE of the patients contained significantly reduced levels of IGF-I
      in comparison with those of controls. The intensity of all the IGFBPs-related
      bands were reduced in the ILOCA, while the remaining patients had a loss in the
      amounts of IGFBP-3. Plasma IGF-I and IGFBPs levels were similar in patients and
      controls. In conclusion, our data show that mucus covering the human OE contains
      IGF-I and IGFBPs, suggesting that these factors have a role in the activity of
      the OE. The amounts are reduced in the patients' mucus, possibly reflecting a
      dysfunction of the OE itself.

PMID- 10415389
TI  - Hand preference and transcranial magnetic stimulation asymmetry of cortical motor
      representation.
AB  - Human handedness may be associated with asymmetry in the corticospinal motor
      system. Previous studies measuring the threshold for eliciting motor evoked
      potentials (MEPs) to transcranial magnetic stimulation (TMS) have provided
      evidence consistent with this hypothesis. However, TMS asymmetry observed in
      previous studies may have reflected cortical or spinal differences. We therefore
      undertook this investigation to test the hypothesis that handedness is associated
      with asymmetry in cortical motor representations. We used TMS to map
      contralateral cortical motor representations of the right and left abductor
      pollicis brevis (APB) and flexor carpi radialis (FCR) muscles in nine normal
      subjects (three left-handed). Using focal stimulation with a figure-of-8 shaped
      magnetic coil, we found no differences in MEP threshold or MEP size between the
      preferred and the nonpreferred hand. However, we observed that the number of
      scalp stimulation sites eliciting MEPs was statistically greater for APB and FCR
      muscles of the preferred limb. We found significant asymmetry between right
      handed and left-handed subjects, such that in right-handers, the representation
      of the right APB was larger than that of the left APB, but in left-handers the
      representation of right APB was smaller than that of the left APB. These results
      suggest that handedness is associated with asymmetry in cortical motor
      representation.

PMID- 10415388
TI  - Nociceptin/orphanin FQ dilates pial arteries by K(ATP) and K(ca) channel
      activation.
AB  - Nociceptin/orphanin FQ (NOC/oFQ) is a recently discovered endogenous ligand for
      the opioid like receptor, ORL-1. In the piglet, cGMP activates the ATP sensitive
      (K(ATP)) while cAMP activates both the K(ATP) and the calcium sensitive (K(ca))
      K(+) channel to elicit vasodilation. The present study was designed to
      characterize the role of cGMP, cAMP, K(ATP), and K(ca) channel activation in
      NOC/oFQ-induced pial artery dilation in newborn pigs equipped with a closed
      cranial window. NOC/oFQ (10(-8), 10(-6) M) induced pial arteriole dilation was
      decreased by the protein kinase A inhibitor Rp 8-Br cAMPs (16+/-1 and 30+/-1 vs.
      5+/-1 and 10+/-1%). NOC/oFQ dilation was associated with elevated CSF cAMP
      (1037+/-58 vs. 1919+/-209 fmol/ml for control and 10(-6) M NOC/oFQ).
      Glibenclamide and iberiotoxin, K(ATP) and K(ca) channel antagonists, attenuated
      NOC/oFQ induced dilation (15+/-1 and 28+/-1 vs. 10+/-1 and 19+/-1% before and
      after iberiotoxin). In contrast, the nitric oxide synthase inhibitor, L-NNA, and
      the protein kinase G inhibitor, Rp 8-Br cGMPs had no effect on NOC/oFQ dilation
      while such dilation was not associated with a change in CSF cGMP. The putative
      ORL-1 receptor antagonist [F/G] NOC/oFQ (1-13)-NH(2) blocked NOC/oFQ dilation
      while responses were unchanged after naloxone (17+/-1 and 30+/-2 vs. 3+/-1 and
      5+/-1%, before and after [F/G] NOC/oFQ (1-13)-NH(2)). Dilation to other opioids
      (e.g., methionine enkephalin) was unchanged by [F/G] NOC/oFQ (1-13)-NH(2). These
      data show that NOC/oFQ elicits pial artery dilation, at least in part, via cAMP,
      K(ATP), and K(ca) channel dependent mechanisms. These data suggest that such a
      mechanism involves the sequential release of cAMP and subsequent K(ATP) and K(ca)
      channel activation.

PMID- 10415390
TI  - Effects of chronic lesions of the anteroventral third ventricle region on
      baroreceptor reflex function in conscious rats.
AB  - This study determined baroreceptor reflex (BR) function in conscious rats which
      had received sham or electrolytic lesions of the anteroventral third ventricle
      (AV3V) 54-56 days previously. Resting mean arterial pressure (MAP) and heart rate
      (HR) values of the AV3V-lesion rats were similar to those of sham-lesion rats
      (P>0.05 for both comparisons). The sensitivity of the BR-mediated tachycardia in
      AV3V-lesion was greater than in sham-lesion rats (-9. 92+/-1.00 vs. -4.54+/-0.45
      bpm/mmHg, P<0.05). The sensitivity of the BR-mediated bradycardia in AV3V-lesion
      rats was also greater than in rats with sham lesions (-3.56+/-0.38 vs. -2.06+/
      0.42 bpm/mmHg, P<0. 05). The AV3V lesions did not affect other BR parameters.
      These findings demonstrate that chronic lesions of the AV3V region increase the
      sensitivity of the baroreceptor HR reflex in conscious rats.

PMID- 10415391
TI  - A single intrathecal injection of GABA permanently reverses neuropathic pain
      after nerve injury.
AB  - To investigate whether neuropathic pain is sensitive to spinal GABA levels, GABA
      was injected intrathecally after nerve injury and sensory behaviors were
      evaluated. Both thermal and tactile hypersensitivities were permanently reversed
      at the highest doses of GABA. However, if GABA was injected any later than 2-3
      weeks after nerve injury, it was ineffective to prevent such hypersensitivity.
      This suggests that altered spinal GABA levels contribute to the induction phase
      of chronic neuropathic pain and that early intervention to restore GABA may
      prevent the development of that pain.

PMID- 10415392
TI  - Response of amygdalar norepinephrine to footshock and GABAergic drugs using in
      vivo microdialysis and HPLC.
AB  - These studies used in vivo microdialysis and high-performance liquid
      chromatography (HPLC) to examine levels of norepinephrine (NE) within the
      amygdala in response to both footshock and GABAergic compounds. In Experiment 1,
      microdialysis probes were inserted into a previously implanted guide cannula
      aimed at the amygdala and the level of NE was examined in response to footshock.
      A 0.55 mA (2 s) footshock induced a significant increase in NE levels when the
      microdialysis probe was located within the amygdala; levels of NE did not differ
      from baseline in rats with microdialysis probes located outside the amygdala.
      Experiment 2 examined the effects of the GABAergic antagonist, picrotoxin, the
      GABAergic agonist, muscimol, and saline on NE levels in the amygdala. Rats
      treated systemically with picrotoxin showed a dramatic increase in levels of NE
      within the amygdala. In contrast, systemic injection of muscimol resulted in
      decreased levels of NE. These findings are consistent with the hypothesis that
      drugs that are capable of modulating memory do so by altering levels of NE within
      the amygdala.

PMID- 10415393
TI  - Nitric oxide modulates the release of serotonin in the rat hypothalamus.
AB  - To investigate the effect of nitric oxide (NO) on the release of serotonin and
      its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), the posterior
      hypothalamus of the conscious rat was superfused through a push-pull cannula with
      drugs which either liberate NO, or inhibit NO synthase (NOS). The NO donors,
      linsidomine, diethylamine/nitric oxide (DEA/NO), S-nitroso-N-acetylpenicillamine
      (SNAP), S-nitroso-glutathione (SNOG) and sodium nitroprusside influenced the
      release of serotonin in a biphasic way. Low concentrations of drugs diminished,
      while higher concentrations of these compounds enhanced the outflow of serotonin.
      The NOS inhibitors N(G)-methyl-L-arginine methyl ester (L-NAME) and 7
      nitroindazole (7-NINA) enhanced the serotonin release. A high concentration of L
      NAME slightly diminished the outflow of serotonin. Inhibition of the guanylyl
      cyclase by oxodiazolo[4, 3]quinoxaline-one (ODQ) abolished the changes in
      serotonin outflow induced by both low and high concentrations of linsidomine. The
      extracellular concentration of the 5-HIAA was not influenced by the compounds
      used. These data suggest that endogenous NO modulates the release of serotonin in
      a biphasic and cGMP-dependent way.

PMID- 10415394
TI  - Inhibition of protein kinase A phase delays the mammalian circadian clock.
AB  - The suprachiasmatic nuclei (SCN) contain the mammalian circadian clock whose
      rhythm of firing rate can be recorded in vitro for several days. Application of a
      protein kinase A (PKA) inhibitor onto the SCN at Zeitgeber time (ZT) 10 on the
      first day in vitro phase delayed the rhythm of firing rate expressed by SCN
      neurons on the subsequent day in vitro. Application of the inhibitor (Rp-cAMPS)
      at other circadian phases did not phase shift the rhythm. These results suggest
      that during approximately 1 h in the late subjective day the presence and
      activity of PKA plays a role in setting the phase of the mammalian circadian
      clock.

PMID- 10415395
TI  - Stereological evaluation of substantia nigra cell number in normal and
      hemispherectomized monkeys.
AB  - The assessment of the anatomical consequences of cortical lesions on subcortical
      visual relays is necessary to further understand residual visual capacities.
      Unbiased stereological techniques were used to evaluate cell numbers in the
      substantia nigra (SN), a structure involved in the control of saccadic eye
      movements. Cell numbers were very similar in the ipsi- and contralateral SN of
      the hemispherectomized animal (329,926 vs. 310,248). These numbers are close to
      what was observed in the normal monkey (300,130 and 320, 859). In one case, part
      of the striatum was lesioned in addition to the cerebral hemisphere. Noticeable
      effects were observed in the SN ipsilateral to the cortical lesion: volume was
      reduced by 30.5% while the number of neurons, compared to the contralateral side,
      dropped by 43.2% (186,644 vs. 328,757). These results suggest that due to its
      anatomical sparing following hemispherectomy the SN, in addition to other
      subcortical structures, is in a prime position to modulate the spared saccadic
      behaviors seen after massive cortical injuries.

PMID- 10415396
TI  - P- and E-selectin-deficient mice are susceptible to cerebral ischemia-reperfusion
      injury.
AB  - We examined brain sections from P- and E-selectin-deficient mice (-/-) and their
      nontransgenic littermates (+/+) after focal cerebral ischemia and reperfusion
      (I/R) tissue injury. There was no difference in the subsequent infarct volume
      after 3 h of ischemia and 21 h of reperfusion. These data indicate that selectin
      independent mechanisms mediate tissue injury after a prolonged period of
      transient focal ischemia.

PMID- 10415397
TI  - Regional distribution of a novel calcium/calmodulin-dependent protein kinase mRNA
      in the rat brain.
AB  - The regional distribution of a novel Ca(2+)/calmodulin-dependent protein kinase
      (CaMK-VI) was examined in the adult rat brain by in situ hybridization. High
      levels of CaMK-VI mRNA were detected in the hippocampus, piriform cortex and
      habenula, moderate levels in different thalamic nuclei and cerebral cortex, and
      low levels in the frontal and parietal cortex. This discrete distribution pattern
      suggests an important role for CaMK-VI in limbic brain regions.

PMID- 10415399
TI  - Ectopic substance P-immunoreactive boutons are preferentially presynaptic to
      neurokinin-1 receptor immunoreactive dendrites in the spinal white matter of
      transgenic mice.
AB  - A recent immunocytochemical study has shown that substance P (SP) preferentially
      innervates targets expressing the neurokinin-1 receptor (NK-1r) in the
      superficial spinal dorsal horn of the rat. Based on these findings, we decided to
      further investigate the relationship between SP and the NK-1r in a transgenic
      mouse model in which SP fibres are ectopically located. Double-labelling
      immunocytochemistry at both the light and electron microscopic levels was
      performed to study the association between SP and the NK-1r in the spinal white
      matter of both control and transgenic mice. Light microscopy revealed NK-1r
      immunoreactive (IR) dendrites in the white matter of the dorsolateral funiculus
      in both control and transgenic mice. In transgenic mice, but not in controls, SP
      IR fibres were observed in close proximity to the NK-1r-IR dendrites in the white
      matter. At the ultrastructural level, SP-IR boutons were apposed to NK-1r-IR
      dendrites in the dorsolateral funiculus of transgenic mice, and a synapse was
      frequently observed as well. These results indicate that, even in conditions in
      which SP fibres are ectopically located, they still preferentially innervate
      targets expressing the NK-1r.

PMID- 10415400
TI  - Noradrenergic and serotonergic projections to the superior olive: potential for
      modulation of olivocochlear neurons.
AB  - The distribution and density of noradrenergic (NA) and serotonergic (5-HT)
      varicosities in the superior olive (SO) and periolivary region (PO) and their
      relationship to olivocochlear neurons was studied. Antibodies against 5-HT and
      the NA precursor enzyme dopamine beta-hydroxylase were utilized to examine the
      density of innervation of SO and PO. To determine the relationship of these
      varicosities to efferent neurons projecting to the cochlea, olivocochlear neurons
      were retrogradely labeled with biotinylated dextranamine (BDA). NA and 5-HT
      varicosities were found adjacent to labeled olivocochlear neuron cell bodies and
      dendrites. More than 50% of labeled medial olivocochlear (MOC) neurons showed
      likely contact with NA varicosities and more than 90% of labeled MOC neurons with
      5-HT varicosities. There was no apparent difference in the number of lateral
      olivocochlear (LOC) neurons in close proximity to NA and 5-HT varicosities versus
      MOCs in close proximity to NA and 5-HT varicosities. Our results suggest that the
      NA and 5-HT systems are in a position to modulate auditory brainstem processing.
      The specific relationship of NA and 5-HT varicosities to olivocochlear neurons
      suggests that one possible level of modulation is prior to signal transduction.

PMID- 10415398
TI  - Expression of the activin axis and neuronal rescue effects of recombinant activin
      A following hypoxic-ischemic brain injury in the infant rat.
AB  - Neurotrophic factors are induced in the brain in response to injury and may
      restrict the extent of neuronal loss and facilitate recovery. We have previously
      reported a strong neuronal induction of activin betaA subunit mRNA expression
      after a hypoxic-ischemic (HI) injury in the rat brain. Here, we further extended
      our studies to examine a role for the activin inhibitory binding protein,
      follistatin after injury and also to determine the potential of activin as a
      neuronal rescue agent. Ribonuclease protection assay (RPA) was used to quantify
      the time course of the mRNA expression of activin betaA subunit and follistatin,
      following a 60-min HI brain injury. Activin betaA subunit mRNA level increased in
      the contralateral hemisphere 5 h after injury and returned to normal at 10 h post
      injury. In contrast, follistatin mRNA levels decreased in the same hemisphere at
      5 and 10 h after injury. The effect of intracerebroventrically (i. c.v.)
      administered recombinant human activin A or its antagonist, inhibin A, on
      neuronal death after a 15-min HI brain injury was determined for a number of
      brain regions. One microgram activin A (n=23) reduced the neuronal loss in the
      hippocampal CA1/2 region, dorsolateral striatum but not in the parietal cortex.
      In contrast, 1 microg of inhibin A (n=18) did not have a significant effect on
      the extent of neuronal loss in any of the affected regions. This pattern of
      neuroprotection was consistent with the distribution of immunoreactivity for the
      activin receptor type II subunit. These results demonstrate that activin A, but
      not its functional antagonist inhibin A, can enhance the survival of injured
      hippocampal and striatal neurons. Since follistatin is thought to exert a
      neutralising effect on activin A activity, the down-regulation of follistatin
      expression post injury may be allowing activin A to become more accessible to
      neurons after injury. Overall, these results suggest a role of the activin axis
      in modulating the survival of specific populations of injured neurons.

PMID- 10415401
TI  - Bladder and urethral pressures evoked by microstimulation of the sacral spinal
      cord in cats.
AB  - Experiments were conducted to measure the bladder and urethral pressures evoked
      by intraspinal microstimulation of the sacral segments (S1-S2) in neurologically
      intact, chloralose anesthetized adult male cats. The bladder pressure was
      measured with a superpubic catheter and the urethral pressure was measured
      simultaneously at the level of the urethral sphincter and at the level of the
      penis using a two-element micromanometer. Intraspinal stimuli (typically 1 s, 20
      Hz, 100 microA, 100 microseconds) were applied with activated iridium microwire
      electrodes in ipsilateral segments and intersegmental boundaries with a 250
      micrometer mediolateral resolution and a 200 micrometer dorsoventral resolution.
      Increases in bladder pressures were generated by microstimulation in the
      intermediolateral region, in the lateral and ventrolateral ventral horn, and
      around the central canal. Simultaneous increases in urethral pressure were evoked
      by microstimulation in the ventrolateral ventral horn, but not at the other
      locations. Small reductions in urethral pressure (<10 cm H(2)O) were evoked at
      locations in the intermediate laminae and around the central canal. The magnitude
      of these pressure reductions was weakly dependent on the stimulus parameters.
      Stimulation around the central canal produced bladder contractions with either no
      change or a reduction in urethral pressure and voiding of small amounts of fluid.
      These results demonstrate that regions are present in the spinal intact
      anesthetized cat where microstimulation generates selective contraction of the
      bladder without increases in urethral pressure and that regions are present where
      microstimulation generates small reductions in urethral pressure.

PMID- 10415402
TI  - Systemically administered alpha-melanocyte-stimulating peptides inhibit NF-kappaB
      activation in experimental brain inflammation.
AB  - The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) and its C
      terminal tripeptide alpha-MSH11-13 modulate production of proinflammatory
      cytokines and inhibit inflammation. We examined whether systemic alpha-MSH and
      alpha-MSH11-13 inhibit activation of the nuclear transcription factor, nuclear
      factor kappa B (NF-kappaB), a factor that is essential to expression of
      proinflammatory cytokines, in experimental murine brain inflammation induced by
      lipopolysaccharide. Electrophoretic mobility shift assays of nuclear extracts
      demonstrated that parenteral alpha-MSH inhibited NF-kappaB activation. Western
      blot analysis revealed that this inhibition was linked to alpha-MSH-induced
      preservation of expression of IkappaBalpha protein in the brain. The effects of
      alpha-MSH on NF-kappaB and IkappaBalpha were paralleled by pretreatment with
      alpha-MSH11-13. Similar effects of the two peptides were observed in mice with
      nonfunctional melanocortin 1 receptors (MC1R), ruling out the possibility that
      this receptor subtype is essential to the influence on NF-kappaB. These findings
      indicate that alpha-MSH peptides given systemically can inhibit NF-kappaB
      activation induced in acute brain inflammation even in the absence of MC1R.

PMID- 10415403
TI  - A behavioral and neuroanatomical assessment of an inbred substrain of 129 mice
      with behavioral comparisons to C57BL/6J mice.
AB  - The inbred 129 substrains have been characterized as poor learners that display
      hypoplasia of the corpus callosum. However, they are used extensively as a source
      of embryonic stem (ES) cells for creating mice carrying altered copies of a
      targeted gene ('knockout mice'). The present research investigated callosal
      agenesis and behavior in the 129/SvEvTac substrain and compared their behavior to
      that of C57BL/6J mice. In addition, the degree to which callosal agenesis
      affected behavior was assessed. Nearly 80% of 129/SvEvTac mice in the current
      sample exhibited callosal hypoplasia, although this was not subsequently found to
      be associated with any measure of cognition. They learned the Morris maze and a
      non-spatial pattern discrimination task, though at a level inferior to C57BL/6J
      mice. They were unable to learn shuttlebox avoidance or the Lashley III maze. The
      only measure on which they performed better than C57BL/6J mice was a simple water
      escape task. Thus, 129/SvEvTac mice, in addition to displaying aberrant
      neuroanatomy, perform poorly on many behavioral tasks, resulting in potential
      interpretational difficulties.

PMID- 10415404
TI  - Neuronal age influences the response to neurite outgrowth inhibitory activity in
      the central and peripheral nervous systems.
AB  - Axonal regeneration is abortive in the central nervous system (CNS) of adult
      mammals, but readily occurs in the injured peripheral nervous system (PNS).
      Recent experiments indicate an important role for both intrinsic neuronal
      features and extrinsic substrate properties in determining the propensity for
      axonal regrowth. In particular, certain components of adult mammalian CNS myelin
      have been shown to exert a strong inhibitory influence on neurite outgrowth. To
      determine whether the potent neurite outgrowth inhibitory activity found in CNS
      myelin may also be present in PNS myelin and to study the influence of neuronal
      age on neurite outgrowth, we used a cryoculture assay in which dissociated rat
      dorsal root ganglion (DRG) neurons of different ages were challenged to extend
      neurites on fractionated myelin and cryostat sections from the PNS (sciatic nerve
      and myelin-free degenerated sciatic nerve) and CNS (optic nerve) of adult rats.
      The CNS environment of the optic nerve did not support E17 to P8 DRG neurite
      adhesion or outgrowth. E17 DRG neurons, unlike their older counterparts, however,
      were able to attach and extend neurites onto normal sciatic nerve and onto
      purified PNS myelin. In contrast, a vigorous neurite outgrowth response from all
      the ages tested was observed on the myelin-free degenerated sciatic nerve. These
      results indicate that PNS myelin is a potent inhibitor of neurite outgrowth and
      that DRG neuronal age plays an important role in determining the propensity for
      neurite outgrowth and regenerative response on inhibitory PNS and CNS substrata.

PMID- 10415405
TI  - Nitric oxide is involved in anoxic preconditioning neuroprotection in rat
      hippocampal slices.
AB  - Sublethal anoxia/ischemia protects against subsequent damaging insults in intact
      brain or hippocampal slices. To help further understand mechanisms underlying
      anoxic/ischemic preconditioning, we tested three hypotheses which were that: (a)
      anoxic preconditioning (APC) improves electrical recovery in rat hippocampal
      slices; (b) anoxic preconditioning requires nitric oxide (NO); and (c) anoxic
      preconditioning blocks mitochondrial dysfunction that occurs following re
      oxygenation after anoxia. Control hippocampal slices underwent a single 'test'
      anoxic insult. Experimental slices were preconditioned by 3 short anoxic insults
      prior to the 'test' insult. Evoked potentials (EPs), and NADH redox status were
      recorded prior to, during and after preconditioning and/or 'test' anoxic insults.
      To examine the role of NO, studies sought to determine whether APC could be
      produced by the NO donor, DEA/NO, and whether APC could be inhibited by NO
      synthase (NOS) inhibitor (7-nitroindazole). EP amplitudes recovered significantly
      better after reoxygenation in preconditioned slices and after NO-emulated
      preconditioning (90.0+/-17.7% and 90.0+/-21.3%, respectively, n=9, ** p<0.01, vs.
      17.0+/-7.9%, n=9, in control slices). Inhibition of NOS blocked APC protection
      (6.8+/-6.8%, n=9). The intensity of NADH hyperoxidation was not significantly
      different among groups following 'test' anoxia. These data confirm that
      preconditioning by anoxia improves electrical recovery after anoxia in
      hippocampal slices. Evidence supports that NO from constitutive hippocampal NOS
      may be involved in the neuroprotection afforded by preconditioning by a mechanism
      that does not change the apparent mitochondrial hyperoxidation after anoxia.

PMID- 10415406
TI  - Immunohistochemical detection of oxidative DNA damage induced by ischemia
      reperfusion insults in gerbil hippocampus in vivo.
AB  - There is much evidence to suggest that ischemic injury occurs during the
      reperfusion phase of ischemia-reperfusion insults, and that the injury may be due
      to reactive-oxygen-species (ROS)-mediated oxidative events, including lipid
      peroxidation and DNA damage. However, oxidative DNA damage has until now not been
      examined in situ. In the present study, we report for the first time observation
      of cell type- and region-specific oxidative DNA damages in 5 min transient
      ischemic model by immunohistochemical methods, using monoclonal antibody against
      8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative DNA product. The cell types
      containing 8-OHdG immunoreactivity were neurons, glia and endothelial cells in
      the hippocampus. The 8-OHdG immunoreactivity was present in the nucleus but not
      the cytoplasm of these cells. The level of 8-OHdG in CA1 increased significantly
      (P<0.05) at the end of 30 min after ischemia, but there was no increase within
      CA2 and CA3 areas. The 8-OHdG levels in the hippocampus increased significantly
      (about fourfold) after 3 h of reperfusion and remained significantly (P<0.01)
      elevated for at least 12 h. At 4 days after ischemia, 8-OHdG levels in the CA2
      and CA3 areas decreased to levels of the sham without neuronal loss, while
      disappearance of 8-OHdG immunoreactivity in the CA1 coincided with neuronal death
      in this area. These findings strongly suggest that ischemia-induced DNA damage
      evolves temporally and spatially, and that oxidative DNA damage may be involved
      in delayed neuronal death in the CA1 region.

PMID- 10415407
TI  - Identification of differently timed motor components of conditioned blink
      responses.
AB  - Electromyographic recordings were made from the orbicularis oculi muscles of cats
      in order to identify differently timed motor components of conditioned eye blink
      responses (CRs). Conditioning was established rapidly by pairing electrical
      stimulation of the hypothalamus (HS) with a click conditioned stimulus (CS) and a
      glabella tap unconditioned stimulus (US). Analysis of the EMG responses disclosed
      five different motor components of the CR that could be distinguished and
      characterized according to their latencies of occurrence. Four were associated
      with an increase in EMG activity elicited by the CS (16-48 ms, alpha(1); 48-80
      ms, alpha(2); 80 to 120 ms, beta; >/=120 ms, gamma), and one was associated with
      a decrease in activity (16 to 60 ms, alpha(i)). Analysis of the amplitudes of the
      different components of the CR during the course of conditioning and extinction
      disclosed that short latency, alpha(1) components of the CRs were acquired and
      extinguished in a manner equivalent to longer latency components of the CRs. The
      observations supported the hypothesis that short and long latency components of
      blink responses represented comparable rather than substantially different forms
      of Pavlovian conditioning. The alpha(2) response was present before conditioning
      began, and increased with other components after conditioning. The alpha(i)
      response component was also observed prior to conditioning, and represents a
      previously undetected, inhibitory consequence of presenting weak (70 dB) acoustic
      stimuli. It could play a role in conditioned inhibition, latent inhibition and
      blocking as well as suppression of the conditioned motor response during
      extinction.

PMID- 10415408
TI  - Effects of testosterone on neuronal nitric oxide synthase and tyrosine
      hydroxylase.
AB  - Male rat copulatory ability decreases dramatically following castration. This may
      be due in part to the impairment of medial preoptic area (MPOA) dopamine (DA)
      release. Previous studies showed that extracellular DA levels in the MPOA of
      castrates were lower than in intact males, both during basal conditions and in
      the presence of a receptive female. However, tissue levels of DA in the MPOA were
      higher in castrates than in intact males, suggesting that DA synthesis may be
      normal or increased in castrates, but that release may be compromised. The
      current study found that neither long term (2 months) nor short term (2 weeks)
      castration had any effect on the number of neurons in the DA A(14) area that were
      immunoreactive (ir) for tyrosine hydroxylase (TH), the rate limiting enzyme for
      DA synthesis. Therefore, castration may not affect DA synthesis in the MPOA.
      Tissue levels of neurotransmitter reflect release, as well as synthesis. We
      previously reported that nitric oxide (NO) may increase DA release in the MPOA.
      The present study tested whether castration affected the number of NO producing
      cells in the MPOA. Long term, but not short term, castration significantly
      decreased the number of NADPH-d (nicotinamide adenine dinucleotide phosphate
      diaphorase) positive neurons and brain nitric oxide synthase immunoreactive (bNOS
      ir) neurons in the medial preoptic nucleus (MPN). This suggests that in gonadally
      intact animals testosterone may activate NOS, which increases the production of
      NO. Long or short term castration had no effect on the numbers of bNOS-ir neurons
      in the paraventricular nucleus (PVN) or medial amygdala. However, short term
      castration decreased bNOS-ir neurons in the bed nucleus of stria terminalis
      (BNST). Thus, one means by which testosterone promotes male sexual behavior may
      be by increasing production of NO in the MPOA, which increases local DA release.

PMID- 10415409
TI  - The role of dorsal striatal GABA(A) receptors in dopamine agonist-induced
      behavior and neuropeptide gene expression.
AB  - The purpose of this study was to investigate whether GABA(A) receptors in the
      dorsal striatum regulate basal or stimulant-induced behaviors. Correspondingly,
      the question of possible GABA(A) receptor control of neuropeptide mRNA expression
      in nigrostriatal neurons was addressed. The GABA(A) receptor antagonist,
      bicuculline, was unilaterally or bilaterally microinjected into the dorsal
      striatum of rats in a series of 3 studies. In the first study, unilateral
      administration of 10-50 ng/microliter of bicuculline did not alter behavior.
      However, 250 ng/microliter bicuculline produced motor dyskinesias and/or
      seizures. In the second study, 100 ng/microliter bicuculline administered
      unilaterally prior to saline or amphetamine treatment, produced mild twitching in
      61% of rats but did not affect amphetamine (2.5 mg/kg, i.p.)-induced behavioral
      activity, specifically rearing and sniffing. In the third study, 75 ng/microliter
      of bicuculline was administered unilaterally or bilaterally into the striatum in
      two separate experiments. Administration of bicuculline either unilaterally or
      bilaterally produced mild transient twitching of the forelimbs but did not affect
      behaviors induced by the selective D(1) receptor agonist SKF-82958 (0.5 mg/kg,
      s.c.). Three hours after unilateral bicuculline administration, the brains were
      removed and processed for quantitative in situ hybridization. Bicuculline did not
      significantly affect the basal or SKF-82958-induced increase in preprodynorphin
      or substance P mRNA expression in striatonigral neurons on the side of injection.
      These data suggest that blockade of GABA(A) receptors in the dorsal striatum does
      not affect dopamine agonist-stimulated behaviors or neuropeptide mRNA expression
      in striatonigral neurons in the rat striatum.

PMID- 10415410
TI  - Retina-derived microglial cells induce photoreceptor cell death in vitro.
AB  - In animals with retinal degeneration, the presence of activated microglial cells
      in the outer retina during the early stages of injury suggests that they may be
      involved in the ensuing photoreceptor cell death. In the following study, we
      investigated the effects of rat retina-derived microglial cells on a
      photoreceptor cell line (661w) using cell culture techniques. The difficulty of
      obtaining pure populations of photoreceptor cells necessitated our use of the
      661w photoreceptor cells generated from retinas of transgenic mice. 661w Cells
      were incubated for 24-48 h in basal medium or basal medium conditioned by
      activated microglial cells (MGCM) or Muller cells (MCCM), and tested for cell
      death using lactate dehydrogenase (LDH) assay. The induction of apoptosis in the
      661w cells by MGCM was investigated using Terminal deoxynucleotidyl Transferase
      (TdT)-mediated dUTP nick-end labeling (TUNEL) and DNA laddering. Treatment of
      661w cells with MGCM for 48 h resulted in approximately 73% of cells dead as
      compared with 19-20% of cells grown in either basal medium or MCCM. Serum
      supplementation or pretreatment with heat did not abolish the cytotoxicity of
      MGCM. More TUNEL-positive cells were observed in MGCM-treated cultures as
      compared with those in basal medium. Bands in multiples of approximately 180 bp
      formed DNA ladders in MGCM-treated but not in basal medium-treated samples. Our
      study shows that microglial cells release soluble product(s) that induce
      degeneration of cultured photoreceptor cells. Moreover, the mechanism of
      microglia-induced photoreceptor cell death may involve apoptosis similar to that
      observed in animals with retinal degeneration.

PMID- 10415411
TI  - Severe learning impairment caused by combined immunotoxic lesion of the
      cholinergic projections to the cortex and hippocampus in monkeys.
AB  - Monkeys with immunotoxic lesions of both the basal nucleus of Meynert and the
      vertical limb of the diagonal band of Broca (NBM+VDB) lost cholinergic
      innervation throughout the cortex and hippocampus. They were impaired at learning
      discriminations between objects differing in either few, or many, attributes and
      at learning visuospatial conditional discriminations. Monkeys with immunotoxic
      lesions of the NBM lost cholinergic innervation of the neocortex only. Initially,
      they were unable to learn a simple visual discrimination where the stimuli
      differed in a limited number of attributes but they were unimpaired at learning
      discriminations between objects that differed in more attributes. They were
      mildly impaired at learning a visuospatial conditional task. The impairment
      exhibited by monkeys with lesions of the NBM alone ameliorated with time but that
      following NBM+VDB lesions did not. Previous experiments have shown that monkeys
      with immunotoxic lesions of the VDB alone are impaired at learning visuospatial
      conditional discriminations but are unimpaired at learning simple visual
      discriminations. When monkeys with NBM lesions were given excitotoxic lesions of
      the CA1 field of the hippocampus the learning impairment on discriminations
      between objects which differed in few attributes was reinstated. Pretreatment
      with a cholinergic agonist improved learning ability on visual discrimination
      learning in all monkeys but this improvement was significantly greater in monkeys
      with lesions of the NBM. On conditional discrimination learning, which is
      particularly sensitive to hippocampal damage, pilocarpine produced a significant
      improvement in monkeys with NBM+VDB lesions (where the hippocampal dysfunction
      was cholinergic) but not in monkeys with NBM+CA1 lesions (where the hippocampal
      damage was structural).

PMID- 10415412
TI  - Biphasic expression of TGF-beta1 mRNA in the rat brain following permanent
      occlusion of the middle cerebral artery.
AB  - Two patterns of transforming growth factor-beta1 (TGF-beta1) expression were
      identified in brains of normotensive rats following permanent occlusion of the
      middle cerebral artery (MCAO). First, a relative increase of TGF-beta1 mRNA by
      37% was found at 12 h after MCAO in the ipsilateral cingulate cortex as compared
      to the homotopic contralateral region. The cingulate cortex is located distant
      from the ischemic territory. Treatment with the glutamate receptor antagonists MK
      801 and NBQX did not reduce this expression (34% and 26% increase, respectively).
      Therefore, peri-infarct depolarization waves were probably not responsible for
      induction. Secondly, an increase of TGF-beta1 mRNA by 116% was found at 7 days
      after MCAO within infarcted tissue. This expression was not reduced by the
      glutamate receptor antagonists MK-801 (increase 140%) and NBQX (increase 137%),
      either. TGF-beta1 mRNA expression in the cingulate cortex at 12 h after MCAO is
      possibly mediated by neurons and astroglia and may support cell survival.
      Expression in the infarcted tissue at 7 days after MCAO is most likely related to
      the invasion of monocytes and may be involved in the downregulation of
      inflammatory events, in neoangiogenesis, and in formation of a glial scar around
      the infarct.

PMID- 10415413
TI  - Perinatal elevation of hypothalamic insulin, acquired malformation of
      hypothalamic galaninergic neurons, and syndrome x-like alterations in adulthood
      of neonatally overfed rats.
AB  - Overnutrition during critical developmental periods is suggested to be a risk
      factor for obesity and associated metabolic disorders in later life. Underlying
      mechanisms are unknown. Neuropeptides are essentially involved in the central
      nervous regulation of body weight. For instance, hypothalamic galanin (GAL) is a
      stimulator of food intake and body weight gain. To investigate long-term
      consequences of early postnatal overfeeding, the normal litter size of Wistar
      rats (n=10; controls) was reduced from day 3 to day 21 of life to only 3 pups per
      mother (small litters, SL; overnutrition). Throughout life, SL rats displayed
      hyperphagia (p<0.01), overweight (p<0.0001), hyperinsulinemia (p<0.01), impaired
      glucose tolerance (p<0.001), elevated triglycerides (p<0.001), and an increased
      systolic blood pressure (p<0.05). In adulthood, an increase of GAL-neurons in the
      arcuate hypothalamic nucleus (ARC) was found (p<0.001), positively correlated to
      body weight (p<0.001). A second experiment revealed hyperinsulinemia (p<0.001)
      and increased hypothalamic insulin levels (p<0.05) in SL rats during early
      postnatal life. Already on day 21 of life, i.e., at the end of the critical
      hypothalamic differentiation period, in SL rats the number of GAL-neurons was
      increased in the ARC (p<0.001), showing a positive correlation to body weight and
      insulin (p<0.05). In conclusion, neonatally acquired persisting malformation of
      hypothalamic galaninergic neurons, induced by early overfeeding and
      hyperinsulinism, might promote the development of overweight and syndrome X-like
      alterations during life.

PMID- 10415414
TI  - Reduced signal complexity of intracellular recordings: a precursor for
      epileptiform activity?
AB  - Recent studies have shown that time windowed extraction of nonlinear parameters
      like an effective correlation dimension from intracranially recorded EEG of
      epileptic patients often allows to detect and identify an unequivocal "pre-ictal
      phase" preceding an epileptic seizure. In another study, however, such an
      anticipation could not be made. These conflicting findings may indicate that
      observed changes in nonlinear parameters probably depend on the type of
      elementary mechanisms underlying epileptic processes and/or the spatial
      distribution of neurons primarily involved in generation of epileptiform
      discharges. To test the existence of such dependencies, the transition from
      normal to epileptiform activity (EA) of CA3-neurons in hippocampal slices was
      analyzed in four epilepsy models, using a time windowed computation of an
      effective correlation dimension. Indeed, in xanthine and penicillin models,
      signal complexity in intracellular recordings was reduced before manifestation of
      paroxysmal depolarization shifts (PDS), whereas a preceding loss of complexity
      was missing in low-magnesium and veratridine models. These findings indicate that
      interictal-like EA is predictable only in some epilepsy models.

PMID- 10415415
TI  - Effects of bilateral electrical stimulation of the ventral pallidum on acoustic
      startle.
AB  - The ventral pallidum (VP) is believed to occupy a critical position between the
      limbic and the motor systems, for transferring motive information into motor
      commands. To estimate the time course of signaling from the VP to motor outputs,
      in the present study we examined the effects of bilateral electrical stimulation
      of the VP on the acoustic startle reflex in awake rats. When the interstimulus
      interval (ISI) between VP stimulation and acoustic stimulation was shorter than 5
      ms, VP stimulation potentiated acoustic startle. When the ISI was longer than 5
      ms, VP stimulation inhibited acoustic startle over a large range of ISIs with the
      maximum inhibition at ISIs between 15 and 25 ms. In contrast, bilateral
      electrical stimulation of the amygdala did not have a significant inhibitory
      effect on acoustic startle, but strongly augmented acoustic startle at shorter
      ISIs (0-10 ms). Compared to unilateral electrical stimulation of the inferior
      colliculus (IC), bilateral stimulation of the VP gave rise to a rightward shift
      of the ISI curve, indicating that the neural pathways conveying the inhibitory
      influence from the VP to the acoustic startle circuit are longer than those from
      the IC.

PMID- 10415416
TI  - Time-dependent alterations in NOS1 immunoreactivity in feline pudendal
      motoneurons following retrograde axonal transport of diphtheria toxin.
AB  - Neuronal nitric oxide synthase immunoreactivity (NOS1-ir) in sacral somatic motor
      neurons of normal adult cats was compared with NOS1-ir in cats surviving 1 to 10
      weeks after injection of the ADP-ribosylating protein diphtheria toxin (DTX) into
      one-half of the external anal sphincter. Levels of immunostaining were measured
      by microdensitometry. In non-operated cats, 60% of motor neurons in the
      ventrolateral (VL) and Onuf's nucleus (ON) showed high levels of NOS1-ir with
      lower NOS1-ir in 40%. Intramuscular injection of DTX caused cytopathology in
      motoneurons in ON, but not in VL with onset at 1 week, and regression by 10
      weeks. Immunocytochemistry and microdensitometry disclosed an associated rise in
      levels of NOS1-ir in both the ipsilateral and contralateral ON at 1 week, which
      persisted up to 4 weeks, but reduced to normality by 10 weeks. Simultaneous
      neuronal swelling in ON precluded raised staining intensity being an artifact of
      neuronal atrophy. Despite restriction of cytopathology to ON, motoneurons in VL
      also exhibited acute elevation with subsequent normalisation of NOS1-ir over an
      identical time-course. Conclusions. Since DTX inhibits protein synthesis, (i)
      activation of NOS1 in acute toxicity probably reflects raised intracellular
      calcium due to loss of calcium homeostasis; (ii) the bilateral response in ON may
      indicate uptake of DTX by contralateral pudendal axons crossing the sphincter
      midline; and (iii) raised NOS1-ir in VL indicates a wider response in nuclei
      synaptically coupled to ON. Recovery of neuronal morphology and normalisation of
      NOS1-ir in sublethal toxicity contrast with the protracted elevation of NOS1-ir
      reported by others following axonal lesions associated with neuronal death and
      muscle target deprivation.

PMID- 10415417
TI  - Involvement of glutamate release in substance P-induced phase delays of
      suprachiasmatic neuron activity rhythm in vitro.
AB  - The suprachiasmatic nucleus (SCN) has been identified as a mammalian circadian
      rhythm clock. Treatment with substance P (SP) at zeitgeber time 13-14 produced
      phase delays of circadian rhythm in spontaneous neural activity in SCN neurons in
      vitro. SP-induced phase delays are blocked by treatment with not only SP receptor
      antagonist, spantide, but N-methyl-D-aspartate receptor antagonist, MK-801. In
      the biochemical experiment, we demonstrated that SP-induced glutamate release
      from the SCN slices was observed by the high-performance liquid chromatography
      assay. The present results suggest that glutamate release may be involved in SP
      induced phase delays.

PMID- 10415419
TI  - Noradrenaline and serotonin levels in the guinea pig hippocampus following
      unilateral vestibular deafferentation.
AB  - Recent evidence indicates that the hippocampus uses input from the vestibular
      system in order to accomplish its spatial computational functions. At present,
      there are few data on the neurochemical basis of the interactions between the
      vestibular system and the hippocampus. The aim of this study was to determine
      levels of noradrenaline (NA), serotonin (5-HT) and the 5-HT metabolite, 5
      hydroxyindoleacetic acid (5-HIAA), in the CA1, CA2 and dentate gyrus (DG) regions
      of the ipsilateral and contralateral hippocampi, at 10 h following
      deafferentation of the peripheral vestibular nerve (UVD) in guinea pig, using
      high-performance liquid chromatography (HPLC) with electrochemical detection
      (ECD). There were no significant differences in NA levels in the ipsilateral or
      contralateral CA1 following UVD. However, there was a significant increase in NA
      levels in the contralateral CA2 following UVD, compared to both the sham and
      intact anesthetic control conditions (p<0.05). No such change was seen in the
      ipsilateral CA2. In the contralateral DG, there was a significant increase in NA
      levels in both the UVD and sham conditions, compared to the intact anesthetic
      controls (p<0.05). No significant changes in 5-HT or 5-HIAA levels were seen in
      the ipsilateral or contralateral CA1, CA2 or DG following UVD. This study
      provides the first evidence that UVD may cause an increase in NA levels in the
      CA2 region of the contralateral hippocampus.

PMID- 10415418
TI  - Effects of prenatal cocaine exposure on amphetamine-induced dopamine release in
      the caudate nucleus of the adult rabbit.
AB  - Acute amphetamine (AMPH) challenge has been used to probe the neurochemical and
      behavioral integrity of dopaminergic neurons under various conditions including
      prenatal cocaine exposure. In this study, we employed in vivo microdialysis to
      examine the effects of prenatal cocaine exposure on AMPH-induced dopamine (DA)
      release in the caudate nucleus of the awake adult rabbit. Pregnant rabbits were
      given intravenous injections of either saline or cocaine (4 mg/kg) twice a day
      from gestational day 8 (G8) through G29. Microdialysis was performed in adult
      saline and cocaine progeny at approximately postnatal day 70 (P70). There were no
      significant differences between cocaine and saline progeny in their basal
      concentrations of DA or its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC)
      and homovanillic acid (HVA). AMPH (5 mg/kg, i.v.) significantly increased
      extracellular DA in the caudate of both groups. However, AMPH-induced DA release
      was 2 to 3-fold greater in cocaine progeny than in the saline controls. Although,
      DOPAC decreased in both groups following AMPH injection, there was no significant
      group effect. In addition, there were no significant changes in concentrations of
      HVA. AMPH is known to release DA by a mechanism of exchange diffusion via the
      presynaptic DA transporter (DAT). Therefore, we examined the binding of [(3)H]WIN
      35,428 to membrane fractions prepared from fresh caudate tissue to determine
      whether prenatal exposure to cocaine had altered the density (B(max)) or affinity
      (K(d)) of the DAT. While the B(max) for [(3)H]WIN 35,428 binding increased 3-fold
      between P3 and P120, there were no significant differences between saline and
      cocaine progeny at any age examined. The K(d) for [(3)H]WIN 35,428 binding did
      not change with postnatal age and did not differ between cocaine and saline
      progeny. These findings suggest that prenatal exposure to cocaine produces a long
      term increase in the size of the presynaptic, AMPH releasable, cytoplasmic pool
      of DA.

PMID- 10415420
TI  - Feline immunodeficiency virus envelope protein (FIVgp120) causes
      electrophysiological alterations in rats.
AB  - Close to 20% of the patients infected with the AIDS virus develops neurological
      deficit; eventhough HIV does not invade neurons. Consistently with the
      neurological deficit, HIV(+) subjects show abnormalities in brainstem auditory
      and visual evoked potentials (BSAEP and VEP) and in sleep patterns. The HIV
      derived glycoprotein 120 has been postulated as a neurotoxic; therefore, it may
      be playing a crucial role in the generation of BSAEP and VEP, as well as in sleep
      disturbances. To study the role of the virus-derived proteins on the development
      of these electrophysiological signals' alterations, we have used the feline
      immunodeficiency virus (FIV)-derived gp120 and evaluated the changes in these
      electrophysiological signals. We employed 15 adult male Sprague-Dawley rats (250
      350 g), chronically implanted for evoked potential and sleep recordings. Results
      showed that the i.c.v. administration of FIVgp120 (5 ng/10 microliter) produces
      changes in the latency of both cortical auditory evoked potentials (CAEPs) and
      VEPs and a decrease in both REM sleep and SWS. These data support the notion that
      FIVgp120 is neurotoxic to the central nervous system of cats and rats and that
      this protein suffices to cause electrophysiological alterations. In addition, it
      suggests that a similar effect may be occurring in humans as a result of
      HIVgp120's neurotoxic effects.

PMID- 10415421
TI  - Periventricular anteroventral third ventricle lesions diminish the pressor
      response produced by systemic injection of the N-methyl-D-aspartate receptor
      antagonist MK-801.
AB  - This study examined whether electrolytic ablation of the periventricular
      anteroventral third ventricle (AV3V) would affect the increases in mean arterial
      blood pressure (MAP) and heart rate (HR) in conscious rats produced by systemic
      injection of the centrally acting N-methyl-D-aspartate (NMDA) receptor ion
      channel blocker, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10
      imine (MK-801; 250 microgram/kg, i.v.). MK-801 produced a smaller increase in MAP
      in rats with AV3V lesions than in sham-lesion rats (+36+/-2% vs. +52+/-5%,
      respectively, P<0.05). In contrast, MK-801 produced similar increases in HR in
      the AV3V- and sham-lesion rats (+28+/-3% vs. +22+/-4%, respectively, P>0.05).
      These findings demonstrate that the MK-801-induced pressor response is dependent
      upon the integrity of the AV3V region, whereas the MK-801-induced tachycardia is
      not.

PMID- 10415422
TI  - Kainic acid-induced inducible cyclooxygenase and c-Jun phosphorylation in the rat
      hippocampal formation.
AB  - Inducible cyclooxygenase (COX-2) was transiently induced in the neurons
      throughout the entire hippocampus between 6 and 24 h after injection of kainic
      acid (KA). The induction of COX-2 correlated more closely with the induction of c
      Jun than with that of c-Fos. Phosphorylated c-Jun was induced 6-12 h after in the
      CA3 pyramidal neurons, which undergo apoptosis. Almost all of neurons with
      phosphorylated c-Jun were colocalized with COX-2. These results suggest that COX
      2 and c-Jun phosphorylation may participate in KA-induced neurodegeneration.

PMID- 10415423
TI  - Prolactin receptor localization to the area postrema.
AB  - The area postrema, which lacks a blood-brain barrier, was examined for the
      presence of prolactin receptors, which would render it a potential site for
      vascular prolactin to directly interact with neuronal elements. Using an in vitro
      autoradiographic technique, frozen sections of New Zealand white rabbit medulla
      were incubated with radiolabelled ovine prolactin alone (total binding) or
      radiolabelled ovine prolactin in the presence of excess unlabelled ovine
      prolactin (non-specific binding). The specificity of the binding was also
      assessed using excess unlabelled human prolactin or ovine LH. While excess
      unlabelled ovine and human prolactin caused a statistically significant reduction
      in radio labeled prolactin binding, unlabelled LH was without effect. Results
      reveal the presence of specific prolactin binding sites within the area postrema,
      a previously unknown prolactin target area of the CNS.

PMID- 10415424
TI  - Orphanin FQ, a novel neuropeptide with anti-stress-like activity.
AB  - Potential anxiolytic-like properties of intracerebroventricular (i.c. v.)
      infusion of orphanin FQ (OFQ), a recently discovered neuropeptide, were
      investigated in the mouse defense test battery, a well-validated anxiolytic
      screening test. In this model, Swiss mice are directly confronted with a natural
      threat (a rat) as well as situations associated with this threat. Primary
      measures taken during and after rat confrontation were flight, risk assessment,
      defensive attack and escape attempts. Unlike the anxiolytic drug diazepam (3-10
      microgram/5 microliter, i.c.v.), which affected all defensive responses, OFQ (0.3
      3 nM/5 microliter) only clearly reduced defensive upright postures and biting
      reactions. Subjects displayed these latter defensive behaviors upon forced
      contact with the threat stimulus, a situation which is considered to be highly
      stressful. These results suggest that the OFQ system may not be primarily
      involved in anxiety-related responses including cognitive aspects (i. e., risk
      assessment), while it may play a role in the adaptative responses to unavoidable
      or extreme stress stimuli.

PMID- 10415425
TI  - Lack of cortico-striatal projections from the primary auditory cortex in the
      squirrel monkey.
AB  - The projections of the superior temporal gyrus to the caudate nucleus were
      studied in 10 squirrel monkeys (Saimiri sciureus). It was found that the primary
      auditory cortex lacks direct connections with the caudate nucleus as well as the
      putamen. Areas RL and T1 of Burton and Jones, bordering the primary auditory
      cortex laterally, show a moderate projection to the body and tail of the caudate
      nucleus; area T2, bordering areas RL and T1, shows an extensive projection into
      the head, body and tail. A comparison of the temporo-caudate projections of the
      monkey with those of rodents and carnivores suggests that primary and secondary
      auditory cortices differ in their connections in primates more than in other
      mammals, pointing to a greater functional differentiation of these areas in
      primates.

PMID- 10415426
TI  - Serotonin 5-HT(1B/1D) agonist-stimulated [(35)S]GTPgammaS binding in rat and
      guinea pig striatal membranes.
AB  - Serotonin (5-hydroxytryptamine; 5-HT) receptor ligands were used to assess
      agonist-stimulated [(35)S]GTPgammaS binding in rat and guinea pig striatal
      membranes. The assay contained 45-60 microgram protein, 300 microM GDP and 0.1 nM
      [(35)S]GTPgammaS, incubated at 37 degrees C for 20 min. The non-selective
      agonists 5-HT, 5-CT (5-carboxyamidotryptamine), and L-694,247, and the selective
      5-HT(1B) receptor agonist CP 93,129 produced concentration-dependent increases in
      [(35)S]GTPgammaS binding in rat striatum, whereas the selective 5-HT(1A) receptor
      agonist R(+)-8-OH-DPAT [R(+)-8-hydroxy-2-(di-n-propylamino)tetralin] was
      inactive. Cyanopindolol, a 5-HT(1A/1B) receptor antagonist, completely blocked
      the effect of 5-HT. Methiothepin, yohimbine and cyanopindolol also blocked 5-CT
      stimulated [(35)S]GTPgammaS binding with the following rank order of potency:
      cyanopindolol >/= methiothepin >>> yohimbine, consistent with rat 5-HT(1B)
      receptor pharmacology. Neither cyanopindolol nor methiothepin altered basal
      [(35)S]GTPgammaS binding by themselves while yohimbine had weak partial agonist
      activity. Furthermore, cyanopindolol shifted the 5-CT concentration-response
      curve rightward, increasing the EC(50) and decreasing the maximal response, but
      did not affect L-694, 247-stimulated [(35)S]GTPgammaS binding. The ability of
      cyanopindolol or spiperone (a 5-HT(1A/1D) receptor antagonist) to alter CP 93,129
      stimulated [(35)S]GTPgammaS binding was determined. Cyanopindolol produced a
      rightward shift in the CP 93,129 concentration-response curve, while spiperone
      had no affect. Finally, in guinea pig striatum and hippocampus, L-694,247
      produced a concentration dependent increase in [(35)S]GTPgammaS binding. In
      conclusion, these studies indicate that 5-HT(1B) receptor function can be
      assessed using agonist-stimulated [(35)S]GTPgammaS binding in rat striatal
      membranes using CP 93,129, 5-HT or 5-CT, but not L-694, 247.

PMID- 10415427
TI  - Oxidative stress induced by MPTP and MPP(+): selective vulnerability of cultured
      mouse astrocytes.
AB  - Oxidative stress has been implicated in the pathogenesis of Parkinson's disease.
      In the present study, reactive oxygen species (ROS) formation and antioxidant
      enzyme superoxide dismutase (SOD) activities were examined in cultured cortical,
      striatal and mesencephalic mouse astrocytes after 1-methyl-4-phenyl-1,2,3, 6
      tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP(+)) treatment.
      Linear regression analysis showed that control mesencephalic (slope
      coefficient=0.01) astrocytes had a three-fold (F-test, p<0.05) greater rate of
      change in ROS production when compared to cortical (0.003) or striatal (0.003)
      astrocytes. However, when treated with 500 microM MPTP for 120 min, mesencephalic
      and striatal astrocytes demonstrated a decreased and increased rate of change in
      ROS production respectively. On the other hand, when treated with 10 microM
      MPP(+), a significant increase in the rate of change in ROS formation was
      observed in both mesencephalic and striatal astrocytes, with mesencephalic
      astrocytes producing a four-fold greater increase when compared to striatal
      astrocytes. Cortical astrocytes did not show any significant changes in ROS
      production when treated with MPTP or MPP(+). When astrocytes were treated with
      MPTP over a 24 h period, striatal astrocytes demonstrated significant increases
      in SOD activity to 12 h, followed by a return towards control levels after 8 h
      treatment. In contrast, mesencephalic astrocytes showed trends for a decrease in
      SOD production as well as a significant decrease in ATP levels by 24 h MPTP
      treatment. The present results suggested that mesencephalic astrocytes are more
      vulnerable to oxidative stress when compared to striatal astrocytes, given their
      greater rates of ROS production at basal and MPP(+) conditions. Striatal
      astrocytes, on the other hand, may have a more protective capacity against
      oxidative stress by producing greater SOD activities.

PMID- 10415428
TI  - Preischemic blood glucose supply to the brain modulates HSP(72) synthesis and
      neuronal damage in gerbils.
AB  - Preischemic hyperglycemia is known to aggravate brain damage caused by transient
      forebrain ischemia. Because heat shock proteins (HSPs) 72 have been proposed to
      play a protective role against ischemic neuronal injury, we studied the HSP(72)
      mRNA expression and protein synthesis in gerbils subjected to 10 min bilateral
      carotid occlusion under normoglycemic, hyperglycemic and fasting conditions.
      HSP(72) mRNA expression and HSP(72) synthesis were studied using in situ
      hybridization and immunostaining, respectively. After 8 h of blood recirculation,
      HSP(72) mRNAs were expressed in all the hippocampal subfields of the three
      different groups, with higher expression in the hyperglycemic gerbils. After 48 h
      of reperfusion, HSP(72) mRNAs had almost completely disappeared in the hyper- and
      normoglycemic groups, and were more strongly expressed in the CA(1) neurons of
      the fasted group. At this time, fasted gerbils exhibited intense HSP(72)
      immunoreactivity in the CA(1), whereas an absence of immunoreactivity was
      observed in that area in the other groups. Finally, ischemia was also associated
      with marked astrocytic activation, as evidenced by GFAP immunostaining. Overall
      results indicate that preischemic differences in blood glucose supply to the
      brain are related to HSP(72) mRNA expression (in terms of duration) and to
      HSP(72) protein induction (in terms of intensity) in the vulnerable CA(1) neurons
      of the hippocampus. Ability of CA(1) neurons to synthesize HSP(72) proteins was
      associated with higher neuronal survival in the fasted group after 48 h of
      reflow, suggesting a protective role of HSP(72), even though evaluation of
      neuronal damage at 7 days indicated that neuronal death was mainly delayed in the
      time.

PMID- 10415429
TI  - Internal hazards: baseline DNA damage by endogenous products of normal
      metabolism.
AB  - Recent improvements in the ability to detect chemically modified bases in DNA
      have revealed that not only does the genetic material incur damage by foreign
      chemicals, but that it also sustains injury by reactive products of normal
      physiological processes. This review summarises current understanding of the DNA
      damaging potential of various substances of endogenous origin, including
      oxidants, lipid peroxidation products, alkylating agents, estrogens, chlorinating
      agents, reactive nitrogen species, and certain intermediates of various metabolic
      pathways. The strengths and weaknesses of the existing database for DNA damage by
      each class of substance are discussed, as are future strategies for resolving the
      difficult question of whether endogenous chemicals are significant contributors
      to spontaneous mutagenesis and cancer development in vivo.

PMID- 10415431
TI  - Pyrrolizidine alkaloids in human diet.
AB  - Pyrrolizidine alkaloids are the leading plant toxins associated with disease in
      humans and animals. Upon ingestion, metabolic activation in liver converts the
      parent compounds into highly reactive electrophiles capable of reacting with
      cellular macromolecules forming adducts which may initiate acute or chronic
      toxicity. The pyrrolizidine alkaloids present a serious health risk to human
      populations that may be exposed to them through contamination of foodstuffs or
      when plants containing them are consumed as medicinal herbs. Some pyrrolizidine
      alkaloids (PA) adducts are persistent in animal tissue and the metabolites may be
      re-released and cause damage long after the initial period of ingestion. PAs are
      also known to act as teratogens and abortifacients. Chronic ingestion of plants
      containing PAs has also led to cancer in experimental animals and metabolites of
      several PAs have been shown to be mutagenic in the Salmonella
      typhimurium/mammalian microsome system. However, no clinical association has yet
      been found between human cancer and exposure to PAs. Based on the extensive
      reports on the outcome of human exposure available in the literature, we conclude
      that while humans face the risk of veno-occlusive disease and childhood cirrhosis
      PAs are not carcinogenic to humans.

PMID- 10415430
TI  - Oxygen and nitrogen are pro-carcinogens. Damage to DNA by reactive oxygen,
      chlorine and nitrogen species: measurement, mechanism and the effects of
      nutrition.
AB  - Humans are exposed to many carcinogens, but the most significant may be the
      reactive species derived from metabolism of oxygen and nitrogen. Nitric oxide
      seems unlikely to damage DNA directly, but nitrous acid produces deamination and
      peroxynitrite leads to both deamination and nitration. Scavenging of reactive
      nitrogen species generated in the stomach may be an important role of flavonoids,
      flavonoids and other plant-derived phenolic compounds. Different reactive oxygen
      species produce different patterns of damage to DNA bases, e.g., such patterns
      have been used to implicate hydroxyl radical as the ultimate agent in H(2)O(2)
      induced DNA damage. Levels of steady-state DNA damage in vivo are consistent with
      the concept that such damage is a major contributor to the age-related
      development of cancer and so such damage can be used as a biomarker to study the
      effects of diet or dietary supplements on risk of cancer development, provided
      that reliable assays are available. Methodological questions addressed in this
      article include the validity of measuring 8-hydroxydeoxyguanosine (8OHdG) in
      cellular DNA or in urine as a biomarker of DNA damage, the extent of artifact
      formation during analysis of oxidative DNA damage by gas chromatography-mass
      spectrometry and the levels of oxidative damage in mitochondrial DNA.

PMID- 10415432
TI  - Bracken carcinogens in the human diet.
AB  - The ubiquitous bracken fern (genus Pteridium) is the only higher plant known to
      cause cancer naturally in animals. In addition to the well-recognized syndromes
      of thiamine deficiency, acute haemorrhage associated with myeloid aplasia and
      blindness due to retinal degeneration, it causes neoplasia of the urinary bladder
      and in some circumstances, of the upper gut. In addition, it has been shown to
      cause neoplasia in a wide range of tissues in many experimental species. The
      major carcinogen (and the cause of the retinal degeneration and the myeloid
      aplasia) has been shown to be ptaquiloside (PT), a norsesquiterpene glucoside
      that can be present in bracken in extraordinary concentrations, up to 13 000 ppm.
      The highest concentrations were found in the crosiers and young unfolding fronds.
      The mutagenicity, clastogenicity, teratogenicity and carcinogenicity have been
      convincingly demonstrated. Under alkaline conditions the loss of the glucose
      gives rise to the formation of a dienone intermediate which possesses a highly
      reactive cyclopropyl ring capable of reacting with cellular macromolecules. PT
      has been shown to alkylate DNA at N3 of adenines in the minor groove,
      preferentially in 5'-TAG and 3'-A in 5'-AA-3' sequences. It also alkylates N7
      guanines in the major groove occurring in 5'-TG sequences. It is believed that
      these alkylations lead to mismatch repair and subsequent mutations in particular
      proto-oncogenes. Recently a rat model of carcinogenesis has been established
      using intravenously (iv) administered PT. Some epidemiological evidence has
      indicated higher risk of cancer in people who consume bracken crosiers, people
      who consume milk of cows feeding on bracken and those who live in bracken
      infested areas. PT has been found in the milk of cows fed on bracken fern
      experimentally and the milk of bracken-fed cows has been shown to cause cancer in
      rats. PT carcinogenesis presents an excellent model of environmental and
      experimental carcinogenesis.

PMID- 10415433
TI  - Fumonisin contamination of food: progress in development of biomarkers to better
      assess human health risks.
AB  - Fumonisins, fungal toxins produced by Fusarium moniliforme, contaminate maize
      based foods and feeds throughout the world. They cause liver and kidney toxicity
      in animals in addition to leukoencephalomalacia in horses and pulmonary edema in
      pigs. Fumonisin B(1) is carcinogenic in rats and mice. Ecological studies have
      linked consumption of fumonisin contaminated maize with oesophageal cancer in
      human populations in South Africa and China. This review discusses the potential
      health risks for people exposed to the fumonisins, and describes how mechanistic
      studies of toxicity in animal models have allowed the development of putative
      biomarkers of fumonisin exposure at the individual level. The requirements for an
      applicable biomarker include sample availability as well as a high specificity
      and sensitivity for the exposure of interest. Most environmental toxic insults
      involve complex exposures both to other toxins and to infections; these
      confounding factors need to be considered in assessing both the validity of the
      biomarker and the exposure-disease associations. Fumonisins can be detected in
      the urine of animals in feeding studies but the sensitivity of the current
      methodology means only highly exposed people could be monitored. Mechanistic
      studies indicate that ceramide synthase, an enzyme involved in sphingolipid
      synthesis, is one cellular target for fumonisin toxicity and carcinogenicity, and
      this disruption to sphingolipid metabolism increases the ratio of two sphingoid
      precursors, sphinganine and sphingosine. The altered ratio has been observed in
      tissues, serum and urine for a number of animal models suggesting it as a good
      candidate marker of fumonisin exposure. Despite development of analytical methods
      to measure this biomarker there have been no studies to date correlating it to
      fumonisin intake in people. Given the toxic effects of fumonisins in animals and
      the widespread human exposure, which has been calculated to reach 440 micrograms
      kg(-1) body weight day(-1) in a population consuming high quantities (460 g day(
      1)) of contaminated maize, then the development of biomarkers and their
      application in epidemiological studies should be a priority for research on these
      toxins.

PMID- 10415434
TI  - Dietary fibres may protect or enhance carcinogenesis.
AB  - Dietary fibre (DF) is widely considered to protect against cancer, especially
      colorectal cancer. However, a large prospective epidemiological study has shown
      no apparent effect of DF intake on the development of colorectal cancer. We
      suggest that this may be because the term DF represents a wide range of
      materials, some able to protect, but some able to enhance carcinogenesis. This is
      consistent with data from animal carcinogenesis experiments. Most of the DF in
      western diets is in the form of plant cell walls, but these vary in their
      composition and it is unlikely that all types are protective. The few data
      available indicate that plant cell walls containing suberin or lignin may be the
      most protective, although they are present in only small amounts in food plants.
      DFs are also added to foods. These include components obtained from plant cell
      walls, such as pectins, as well as soluble DFs from other sources. In general,
      animal carcinogenesis experiments indicate that soluble DFs do not protect and
      some may enhance carcinogenesis. Few human intervention studies have been done on
      DF or sources of DF, with the exception of wheat bran, a good source of DF, which
      has been shown to protect. Possible mechanisms whereby DF may enhance
      carcinogenesis are discussed. In addition to DFs, resistant starches and non
      digestible oligosaccharides are added to foods; these, like DF, escape digestion
      in the small intestine. However, so far only a few animal carcinogenesis
      experiments have been reported using these materials, and no human intervention
      studies. We believe caution should be exercised in the addition of such materials
      to food.

PMID- 10415435
TI  - Dietary fat and carcinogenesis.
AB  - Epidemiologic investigations have suggested a relationship between dietary fat
      intake and various types of cancer incidences. Furthermore, epidemiologic studies
      as well as studies with animal models have demonstrated that not only the amount
      but also the type of fat consumed is important. At present, the mechanism by
      which dietary fat modulates carcinogenesis has not been elucidated. The effects
      of dietary fat on the development of tumours have been summarized in the present
      review with emphasis on colorectal, pancreas, breast and prostate cancer. It is
      concluded that influence on synthesis of prostaglandins and leukotrienes may be
      the universal mechanism by which dietary fats modulate carcinogenesis.

PMID- 10415436
TI  - N-Nitroso compounds in the diet.
AB  - N-Nitroso compounds were known almost 40 years ago to be present in food treated
      with sodium nitrite, which made fish meal hepatotoxic to animals through
      formation of nitrosodimethylamine (NDMA). Since that time, N-nitroso compounds
      have been shown in animal experiments to be the most broadly acting and the most
      potent group of carcinogens. The key role of nitrite and nitrogen oxides in
      forming N-nitroso compounds by interaction with secondary and tertiary amino
      compounds has led to the examination worldwide of foods for the presence of N
      nitroso compounds, which have been found almost exclusively in those foods
      containing nitrite or which have become exposed to nitrogen oxides. Among these
      are cured meats, especially bacon-and especially when cooked; concentrations of
      100 micrograms kg(-1) have been found or, more usually, near 10 micrograms kg(
      1). This would correspond to consumption of 1 microgram of NDMA in a 100-g
      portion. Much higher concentrations of NDMA (but lower ones of other
      nitrosamines) have been found in Japanese smoked and cured fish (more than 100
      micrograms kg(-1)). Beer is one source of NDMA, in which as much as 70 micrograms
      l(-1) has been reported in some types of German beer, although usual levels are
      much lower (10 or 5 micrograms l(-1)); this could mean a considerable intake for
      a heavy beer drinker of several liters per day. Levels of nitrosamines have been
      declining during the past three decades, concurrent with a lowering of the
      nitrite used in food and greater control of exposure of malt to nitrogen oxides
      in beer making. There have been declines of N-nitroso compound concentrations in
      many foods during the past two decades. The small amounts of nitrosamines in food
      are nonetheless significant because of the possibility-even likelihood-that
      humans are more sensitive to these carcinogens than are laboratory rodents.
      Although it is probable that alkylnitrosamides (which induce brain tumors in
      rodents) are present in cured meats and other potentially nitrosated products in
      spite of much searching, there has been only limited indirect evidence of their
      presence.

PMID- 10415437
TI  - Polycyclic aromatic hydrocarbons in the diet.
AB  - Polycyclic aromatic hydrocarbons (PAHs), of which benzo[a]pyrene is the most
      commonly studied and measured, are formed by the incomplete combustion of organic
      matter. They are widely distributed in the environment and human exposure to them
      is unavoidable. A number of them, such as benzo[a]pyrene, are carcinogenic and
      mutagenic, and they are widely believed to make a substantial contribution to the
      overall burden of cancer in humans. Their presence in the environment is
      reflected in their presence at detectable levels in many types of uncooked food.
      In addition, cooking processes can generate PAHs in food. PAHs can also be formed
      during the curing and processing of raw food prior to cooking. Several studies
      have been carried out to determine the levels of exposure to PAHs from
      representative human diets, and the proportion of the overall burden of
      environmental exposure to PAHs that is attributable to the diet. In most cases,
      it is concluded that diet is the major source of human exposure to PAHs. The
      major dietary sources of PAHs are cereals and vegetables, rather than meat,
      except where there is high consumption of meat cooked over an open flame. More
      recently, biomonitoring procedures have been developed to assess human exposure
      to PAHs and these have also indicated that diet is a major source of exposure.
      Exposure to nitro-PAHs through food consumption appears to be very low.

PMID- 10415438
TI  - Factors determining dietary intakes of heterocyclic amines in cooked foods.
AB  - The identification of heterocyclic amines (HCAs) in cooked foods has focused
      attention on the potential health effects from their consumption in the diet.
      Recent studies have estimated daily dietary intakes of HCAs that vary 10-fold and
      implicated different cooked meats as the prime source of HCAs in the diet. These
      varied estimates can be attributed to the different dietary assessment methods
      used in these studies, as well as the different levels of HCAs ascribed to the
      most commonly consumed cooked meats. Epidemiological studies utilizing
      information on dietary practice and food intake have found higher risks for
      several cancers among individuals consuming the highest levels of HCAs. These
      studies have highlighted the importance of using information on cooking methods
      in addition to food intake to accurately estimate dietary exposure to HCAs.

PMID- 10415439
TI  - Are metals dietary carcinogens?
AB  - Humans have been in contact with metals almost since the beginning of our
      existence. In fact, one cannot even think on human evolution without considering
      the great role played by metals in mankind's development. Metals are common
      moieties of molecules involved in a wide variety of biological processes, and
      hence are found in virtually all living organisms. Some metals are essential for
      human nutrition; others are found as contaminants in foodstuffs. One feature of
      the normal human diet which is frequently found is the simultaneous presence of
      both essential and toxic metals. Other factors important in the risk-evaluation
      analysis of metals are their pharmacokinetics, interactions among them and with
      other major components of the diet, and, especially, the great differences in the
      dietary habits of different populations and in the regional distribution of
      metals. In attempting to understand the role which dietary metals could play in
      human carcinogenesis, we found that the many factors involved and the lack of
      specific information made it difficult to reach firm conclusions on the hazards
      of dietary metals. We hope that this paper will raise the interest of genetic
      toxicologists in the subject and will consequently facilitate a risk analysis of
      the carcinogenic potential of dietary metals.

PMID- 10415441
TI  - Genetic engineering of crops as potential source of genetic hazard in the human
      diet.
AB  - The benefits of genetic engineering of crop plants to improve the reliability and
      quality of the world food supply have been contrasted with public concerns raised
      about the food safety of the resulting products. Debates have concentrated on the
      possible unforeseen risks associated with the accumulation of new metabolites in
      crop plants that may contribute to toxins, allergens and genetic hazards in the
      human diet. This review examines the various molecular and biochemical mechanisms
      by which new hazards may appear in foods as a direct consequence of genetic
      engineering in crop plants. Such hazards may arise from the expression products
      of the inserted genes, secondary or pleiotropic effects of transgene expression,
      and random insertional mutagenic effects resulting from transgene integration
      into plant genomes. However, when traditional plant breeding is evaluated in the
      same context, these mechanisms are no different from those that have been widely
      accepted from the past use of new cultivars in agriculture. The risks associated
      with the introduction of new genes via genetic engineering must be considered
      alongside the common breeding practice of introgressing large fragments of
      chromatin from related wild species into crop cultivars. The large proportion of
      such introgressed DNA involves genes of unknown function linked to the trait of
      interest such as pest or disease resistance. In this context, the potential risks
      of introducing new food hazards from the applications of genetic engineering are
      no different from the risks that might be anticipated from genetic manipulation
      of crops via traditional breeding. In many respects, the precise manner in which
      genetic engineering can control the nature and expression of the transferred DNA
      offers greater confidence for producing the desired outcome compared with
      traditional breeding.

PMID- 10415440
TI  - A survey of EPA/OPP and open literature on selected pesticide chemicals. II.
      Mutagenicity and carcinogenicity of selected chloroacetanilides and related
      compounds.
AB  - With this effort, we continue our examination of data on selected pesticide
      chemicals and their related analogues that have been presented to the U.S.
      Environmental Protection Agency's (USEPA's) Office of Pesticide Programs (OPP).
      This report focuses on a group of selected chloroacetanilides and a few related
      compounds. As part of the registration process for pesticidal chemicals,
      interested parties (registrants) must submit toxicity information to support the
      registration including both mutagenicity and carcinogenicity data. Although this
      information is available to the public via Freedom of Information (FOI) requests
      to the OPP, publication in the scientific literature allows greater dissemination
      and examination of the data. For this Special Issue, graphic profiles have been
      prepared of the mutagenicity and carcinogenicity data available in the
      submissions to OPP. Also, a discussion is presented about how toxicity data are
      used to help establish tolerances (limits of pesticide residues in foods). The
      mutagenicity results submitted by registrants are supplemented by data on these
      chemicals from the open literature to provide a full perspective of their genetic
      toxicology. The group of chloroacetanilides reviewed here display a consistent
      pattern of mutagenic activity, probably mediated via metabolites. This mutagenic
      activity is a mechanistically plausible factor in the development of tumors seen
      in experimental animals exposed to this class of chemicals.

PMID- 10415442
TI  - The anti-carcinogenic effects of dietary restriction: mechanisms and future
      directions.

PMID- 10415443
TI  - Carcinogens in the diet vs. overnutrition. Individual dietary habits,
      malnutrition, and genetic susceptibility modify carcinogenic potency and cancer
      risk.
AB  - Chemical carcinogens in the diet cannot explain the cancer incidence attributed
      by epidemiologists to dietary factors when the calculation is based on average
      exposure levels and conservative estimates of carcinogenic potencies. In a
      previous review, the discrepancy was explained primarily by overnutrition to
      which a carcinogenic potency was assigned from dietary restriction experiments
      and the associated reduction in spontaneous tumor incidence (W.K. Lutz and J.
      Schlatter, Chemical carcinogens and overnutrition in diet-related cancer,
      Carcinogenesis 13 [1992] 2211-2216). Here, additional aspects are introduced.
      They focus on using individual rather than averaged data, both for exposure and
      susceptibility. First, under conditions of a sublinear (convex) dose-response,
      the cancer incidence obtained by using an average exposure level is lower than if
      individual exposure levels associated with particular dietary habits are taken
      into account. Second, carcinogenic factors, including those unrelated to the diet
      (e.g., smoking), can act synergistically. Third, the potency of dietary
      carcinogens is increased under conditions of malnutrition in the sense of a
      deficiency of protective factors, such as those available with fruits,
      vegetables, and fibers. Quantitatively, this aspect may be particularly important
      because it simultaneously increases the efficacy of a multitude of carcinogens.
      It is concluded that chemical carcinogens could be as important as overnutrition
      for diet-related cancer.

PMID- 10415444
TI  - The role of biotransformation in dietary (anti)carcinogenesis.
AB  - The fact that dietary compounds influence the susceptibility of human beings to
      cancer, is widely accepted. One of the possible mechanisms that is responsible
      for these (anti)carcinogenic effects is that dietary constituents may modulate
      biotransformation enzymes, thereby affecting the (anti)carcinogenic potential of
      other compounds. This ambiguous theme is the basis for the present paper. The
      possible effects of enzymatic bioactivation and detoxification of dietary
      constituents are discussed using two representative examples of phase I and phase
      II biotransformation enzymes i.e., cytochrome P450 and glutathione S-transferase.
      Furthermore, the impact of genetic polymorphisms of these two enzyme systems is
      considered. Although it is very difficult on the basis of the enzyme inducing or
      inhibiting properties of dietary compounds, especially to characterize them as
      anticarcinogenic, for certain constituents it is acknowledged that they have
      anticarcinogenic properties. As such, this provides for an important mechanistic
      substantiation of the established cancer chemopreventive effect of a diet rich in
      fruits and vegetables.

PMID- 10415445
TI  - [Basic examination of hepatitis C virus (HCV) core protein quantitative method
      and the clinical significance in during the follow-up of the patients after
      interferon treatment].
AB  - We evaluated the basic efficacy and clinical usefulness of "Imucheck F-HCV Ag
      core(KOKUSAI)" (Ag-Core). This kit has been developed using monoclonal antibodies
      against hepatitis C virus (HCV) core protein. This character is different from RT
      PCR assay or branched DNA assay, which have been developed for the detection of
      HCV-RNA. The reproducibility of Ag-Core assay was supported by vigorous mixture
      of reagents during the manual pretreatment of samples. The correlation between Ag
      Core assay and Amplicor HCV (RT-PCR) assay was relatively good (correlation
      coefficient: r was 0.735 and the qualitative accordance rate was 96.6%). The
      change of viral load during the IFN-alpha treatment was also in good accordance
      between the values determined by Ag-Core and Amplicor-HCV assay. Since it is
      simple, cheaper and faster than the Amplicor-HCV assay. Quantitation of HCV core
      protein by the Ag-Core assay is useful for monitoring the therapeutic efficacy of
      IFN-alpha treatment.

PMID- 10415446
TI  - The effects of the extension of transit times on qualitative and quantitative
      bacterial culture after clinical sampling.
AB  - The effects of the extension of transit times on qualitative and quantitative
      bacterial culture after clinical sampling were investigated with the clinical
      samples, using the bacterial flora from the cancer portion inside the uterine
      cervix in 25 patients with the uterine cervical cancer. In the qualitative
      bacterial study, the strains of both aerobic and anaerobic bacteria detected were
      rather preserved for 6 hours after clinical sampling and decreased in a time
      dependent manner in the samples of more than 6 hours after clinical sampling. In
      particular, number of anaerobic bacterial species detected remarkably decreased
      in the samples of more than 12 hours after clinical sampling. Therefore, prompt
      bacterial culture after clinical sampling, possibly within 6 hours after clinical
      sampling, may be crucial in order to detect most probable pathogenic anaerobic
      bacteria, particularly when anaerobic infection is suspected. In the quantitative
      bacterial study, the quantity of bacteria detected were rather preserved for 3
      hours after clinical sampling and decreased in a time-dependent manner in the
      samples of more than 3 hours after clinical sampling. Therefore, quantitative
      bacterial culture should be performed within 3 hours after clinical sampling.

PMID- 10415447
TI  - [Laboratory-based evaluation of DainaScreen TPAb to detect specific antibodies
      against Treponema pallidum].
AB  - A newly developed immunochromatography assay, DainaScreen TPAb (Dainabot, Tokyo),
      to detect antibodies specific to Treponema pallidum was evaluated. When we tested
      serum and plasma samples of Syphilis Mixed Titer Performance Panel PSS201 (Boston
      Biomedica, Inc. , Bridgewater, MA, U.S.A.), all the test results obtained by
      DainaScreen TPAb were comparable to those determined by fluorescent treponemal
      antibody absorption test (FTA-ABS). Both within-run and day-to-day variation
      tests were highly precise, and no discrepant interpretation was obtained by the
      different medical technicians performed. Also, the testings of whole blood and
      plasma for individual samples gave same interpretations. The minimum detectable
      antibody titer was equal to that of Mediace TPLA (Sekisui Chemicals, Osaka)
      determined by Behring Nephelometer Analyzer (Dade Behring, Marburg, Germany). All
      the test results by DainaScreen TPAb for clinical serum samples were comparable
      to those by Mediace TPLA. With these results, we can conclude that DainaScreen
      TPAb is a rapid, practical and easy-to-perform alternative to detect antibodies
      specific to Treponema pallidum, in particular as being a point-of-care testing.

PMID- 10415448
TI  - [A trial of rapid assay of identification and susceptibility test of bacteria
      detected from blood culture by using VITEK AMS].
AB  - For rapid identification and susceptibility test of bacteria detected from
      bottles of blood culture, we tried a direct method that adjusted bacterial fluid
      by one time centrifugalization. Identification and susceptibility test were done
      using VITEK AMS. A result of having compared direct method with a standard method
      inspected from a colony of medium, an agreement rate was 82.1% of gram negative
      bacilli, 64.0% of gram positive cocci, 100% of yeast in identification test. In
      the same way, an agreement rate was 98.0% of gram negative bacilli, 97.2% of gram
      positive cocci in susceptibility test. The appearance rate of very major error
      was 0. 7% in gram negative bacilli, and 2.8% in gram positive cocci. As for this
      method, operation is simple, but it is necessary for confirmed examination in a
      kind of bacteria. But agreement rate with a standard method is high, direct
      method is useful to select an appropriate antibiotic until reporting of the last
      test result of bacteria.

PMID- 10415449
TI  - [Evaluation of COBAS CORE anti-HIV-1/HIV-2 EIA DAGS for the detection of
      antibodies to HIV by COBAS CORE].
AB  - COBAS CORE Anti-HIV-1/HIV-2 EIA DAGS (CORE HIV-1/2) for the detection of
      antibodies to HIV-1 and HIV-2 was evaluated by a fully automated immunoassay
      system, COBAS CORE II (Roche Diagnostics K.K.). The sensitivity of CORE HIV-1/2
      was assessed in comparison with PA1/2, Enzygnost, VIDAS and AxSYM by testing
      serial two-fold dilutions of HIV-1 and HIV-2 sera. CORE HIV-1/2 showed the
      highest sensitivity than other methods. The agreements of the results of anti-HIV
      antibodies determinations between the CORE HIV-1/2 and other methods, PA1/2,
      Enzygnost, VIDAS, and AxSYM, were 99.4%, 100%, 100%, and 99.7%, respectively in
      the tests for anti-HIV-1 antibody. In the tests for anti-HIV-2, all results were
      agreed at 100%. Discrepant samples which showed a negative by CORE HIV-1/2 and a
      positive by PA1/2 and AxSYM were clearly negative of anti-HIV-1 antibody by p24
      ACA, PCR, Western blot, and continuous clinical studies. This assay showed
      excellent coefficients of variation for both within-run and day to day precision.
      The determination of anti-HIV antibodies was not interfered with hemoglobin,
      bilirubin, and chylemia. We conclude that the excellent specificity and
      sensitivity of the CORE HIV-1/2 make the CORE HIV-1/2 a suitable method for
      diagnosis of HIV-1 and HIV-2 infections in clinical laboratories.

PMID- 10415450
TI  - Is another mannose receptor-like lectin present in retinal pigment epithelium?
AB  - PURPOSE: This study was designed to investigate the presence of the secretory
      phospholipase A2 receptor in RPE, a protein closely related to the phagocytic
      mannose receptor. METHODS: Proteins from cultured rat, pig, and human RPE were
      separated by SDS-PAGE and immunoblotted with a polyclonal guinea pig sPLA2
      receptor antibody. RT-PCR was performed on rat and pig RPE samples using primers
      designed from published rat pancreatic sPLA2 receptor sequences. RESULTS: The
      sPLA2 receptor protein was not detected in rat, pig, or human RPE by immunoblots.
      Additionally, message for this receptor was not detected in rat or pig RPE.
      CONCLUSIONS: With these techniques, these data demonstrate that the sPLA2
      receptor is undetectable in the RPE.

PMID- 10415451
TI  - Components responsible for the surface tension of human tears.
AB  - PURPOSE: It was previously thought that the surface tension of tears was due to
      dissolved mucin, but it has recently been shown that very little mucin is
      present. The surface tensions of solutions of commercial mucin, lysozyme,
      lactoferrin or secretory IgA are all higher than that of tears. The influence of
      tear lipocalin and lipids remained to be tested. METHODS: Surface tension was
      determined by a micro-method on pooled intact stimulated human tears, and
      following extraction with lipid solvents. The extracted material was also added
      back, as was a variety of lipid standards (phospholipids, glycolipids, sterols,
      etc.). TLC and GLC were used in partial identification of the extract. Another
      lipocalin, bovine beta-lactoglobulin, was also tested alone and mixed with tear
      lipids, model lipids, or model tear proteins. RESULTS: Intact tears had a surface
      tension of 42-46 mN/m, but after lipid extraction this rose to 53-55.5 mN/m.
      Addition of lipids to the delipidised tear fluid gave a range of tensions from 42
      to 49 mN/m, with the greatest effects shown by phospholipids
      (phosphatidylcholine, sphingomyelin), but full recovery was only achieved by
      using the extracted lipid material. Human meibomian oil was less effective. The
      GLC peak profile of the extract was markedly different from meibomian oil, and
      the TLC pattern was consistent with the presence of glycolipids. CONCLUSIONS: The
      surface tension of tears is due to a complex of tear lipocalin with a polar lipid
      fraction extractable from tears by lipid solvents and different from meibomian
      lipid. Lipocalin and this lipid fraction may be secreted together by the lacrimal
      gland.

PMID- 10415452
TI  - Lactoferrin increases the susceptibility of S. epidermidis biofilms to lysozyme
      and vancomycin.
AB  - PURPOSE: The tear cationic protein lactoferrin increases the activity of various
      antimicrobial agents against suspended bacterial cultures including
      Staphylococcus epidermidis, the predominant causative agent of intraocular lens
      biofilm infections. We investigated the ability of lactoferrin to enhance the
      activity of vancomycin and lysozyme against biofilms of a clinical S. epidermidis
      isolate. METHODS: Biofilms were prepared on soft contact lenses and cells
      released from the biofilm surface were collected from the surrounding broth. The
      minimum inhibitory concentration (MIC) and minimum bactericidal concentration
      (MBC) against the intact biofilm, released cells and suspended bacteria were
      evaluated using vancomycin with and without lactoferrin. RESULTS: Lactoferrin
      induced a two-fold reduction in the MBC of vancomycin for biofilm (p < 0.01) and
      biofilm-released cells from 64 microg/ml to 32 microg/ml and similarly decreased
      the MIC for biofilm-released cells (p < 0.01) from 32 microg/ml to 16 microg/ml.
      With or without lactoferrin, the MIC of vancomycin for suspended cells (2 and 4
      microg/ml respectively) was less (p < 0.01) than that of both the biofilm (32 and
      32 microg/ml) and biofilm-released cells (16 and 32 microg/ml). Lactoferrin did
      not reduce the MIC of lysozyme, but, at a lysozyme concentration of 16 mg/ml, did
      significantly (p < 0.05) reduce the number of viable biofilm and biofilm-released
      cells. CONCLUSIONS: Lactoferrin displays potential as an adjunctive agent to
      vancomycin in the treatment of S. epidermidis biofilm infections, such as
      endophthalmitis, associated with intraocular lenses.

PMID- 10415453
TI  - Anti VLA-4 monoclonal antibody inhibits eosinophil infiltration in allergic
      conjunctivitis model of guinea pig.
AB  - PURPOSE: To determine the contribution of very late activation antigen-4 (VLA-4)
      molecule to eosinophil infiltration into the conjunctiva in an actively
      sensitized allergic conjunctivitis model of guinea pig, effects of a monoclonal
      antibody against VLA-4 was examined in vivo. METHODS: A rat anti-mouse VLA-4 mAb
      (PS 2. 3), which cross-reacts with guinea pig VLA-4, inhibited the adhesion and
      transmigration of guinea pig eosinophils to /through human umbilical vein
      endothelial cells (HUVEC) in vitro. Hartley guinea pigs were actively sensitized
      by intraperitoneal injection of ovalbumin with aluminum hydroxide. Two weeks
      later, 2.5% ovalbumin was dropped into the eye for the antigen challenge. In the
      treatment group, 4 mg/kg (body weight) of the anti VLA-4 mAb (PS2.3), and in the
      control group, the same amount of a control Ab was intraperitoneally injected
      respectively at 4 hours before the antigen challenge. From both groups, the
      eyelids and eyeballs were excised at 2, 4, 10, and 24 hours after the antigen
      challenge, fixed, stained with Hansel solution and the number of the infiltrating
      eosinophils in the conjunctiva was counted. RESULTS: In the control group,
      infiltration of eosinophils to the conjunctiva increased with time, peaked at 12
      hours, and then gradually decreased until 24 hours after the antigen challenge.
      In the anti VLA4-mAb treated group, eosinophil infiltration was almost completely
      inhibited at least until 24 hours after the antigen challenge. CONCLUSION: VLA-4
      molecule was elucidated to play a critical roll in the eosinophil infiltration in
      experimentally-induced allergic conjunctivitis model of guinea pig.

PMID- 10415454
TI  - Complement defects in aged mice compromise phagocytosis of Pseudomonas
      aeruginosa.
AB  - PURPOSE: The role of complement in phagocytosis and killing of P. aeruginosa was
      examined using serum from aged vs young donor mice. METHODS: Phagocytosis,
      complement hemolytic and microbicidal assays were used. RESULTS: Serum from young
      donor mice contained a heat-labile factor which significantly enhanced phagocytic
      activity of cells from young mice compared with similarly treated aged donor
      serum. Use of cobra venom factor (CVF) to destroy C3 and the terminal complement
      components in serum from young or aged donor mice also significantly decreased
      the phagocytic activity of young cells. EGTA treatment of young or aged donor
      serum, to activate the alternative pathway and selectively inhibit activation of
      the classical pathway, resulted in a significant decrease in phagocytosis by
      young cells in the presence of donor serum from either group. Alternative pathway
      mediated hemolysis also was measured and was significantly reduced in aged vs
      young donor serum. PMN microbicidal activity was tested using cells from young
      mice in the presence of aged vs young donor serum, but no significant differences
      were noted. CONCLUSION: These data provide evidence that defects in the
      alternative pathway of complement in the serum of aged animals lead to decreased
      phagocytic activity of cells from young mice, but not impaired bacterial killing.

PMID- 10415455
TI  - Oxidation enhances calpain-induced turbidity in young rat lenses.
AB  - PURPOSE: To determine if oxidation enhances turbidity after proteolysis of rat
      lens crystallins by the calcium-activated protease calpain (EC 3.4.22.17).
      METHODS: Total soluble proteins from young rat lens were hydrolyzed for 24 hr by
      endogenous lens calpain, and the proteins were further incubated with the oxidant
      diamide for up to 7 days. Turbidity was measured daily at 405 nm. To measure
      proteolysis and turbidity in cultured lenses, rat lenses were cultured for 6 days
      in low calcium medium and diamide. The lenses were then photographed to assess
      transmission of light. SDS-PAGE and immunoblotting assessed proteolysis of
      crystallins, alpha-spectrin, and activation of calpain. RESULTS: Appreciable in
      vitro turbidity occurred in soluble proteins from young rat lenses after
      proteolysis of crystallins by endogenous calpain. Calpain inhibitor E64, or anti
      oxidants DTE and GSH, inhibited this turbidity. On the other hand, the oxidant
      diamide markedly enhanced calpain-induced turbidity. Cultured rat lenses showed
      elevated intralenticular calcium and proteolysis of crystallins by calpain, but
      no nuclear cataract. Addition of diamide to the culture medium caused development
      of nuclear cataract. CONCLUSIONS: Diamide enhanced turbidity only when
      crystallins were proteolyzed. Oxidation may be one of the factors promoting light
      scatter and insolubilization after proteolysis. These data are consistent with
      the hypothesis that proteolysis of crystallins from young rat lens may expose
      cysteine residues, which are then oxidized, become insoluble and scatter light.

PMID- 10415456
TI  - Model of human refractive error development.
AB  - PURPOSE: To construct a model of refractive error development that can account
      for the different interactive mechanisms and time courses of refractive error in
      the hyperope (HYP), emmetrope (EMM), early-onset myope (EOM), and late-onset
      myope (LOM) over the first 30 years of life. METHODS: First, a baseline short
      term (1 mo.) simulation of a previously developed nearwork-induced transient
      myopia (NITM) model was performed under both far- and near-viewing paradigms to
      obtain the critical relationships between AErms and refractive error for the four
      refractive groups. Then, two control pathways were added to the NITM model. The
      genetically-controlled pathway was associated with the long-term growth of the
      cornea, lens, and the eyeball. The environmentally-controlled pathway was
      associated with retinal-defocus during nearwork, wherein the root mean square
      (rms) of the accommodative error (AE) above a threshold level resulted in an
      increase in axial length of the eyeball. The thresholds for defocus-induced axial
      length change were empirically determined to correspond to the differential
      susceptibility in the four refractive groups. The combination of effects from the
      two pathways produced the overall refractive error. The relationship between
      AErms and refractive error was combined with the two control pathways for the
      long-term simulations (30 yrs: the initial 15 yrs using a far-viewing paradigm
      followed by an additional 15 yrs using a near-viewing paradigm) to quantify
      refractive error development as related to daily nearwork activity in the four
      refractive groups. RESULTS: All refractive groups began early in life with a
      genetically-determined hyperopic refractive error. The HYP had the lowest
      susceptibility or highest threshold to retinal defocus effects, and remained at a
      hyperopic level. The EMM exhibited a relative myopic shift in the first 2 years
      to become and remain at emmetropia. In the myopic groups, the EOM exhibited both
      a genetically-controlled component (starting 2 years of age) and a defocus
      induced component (starting at 15 years of age), whereas the LOM manifested only
      a defocus-induced factor (starting at 15 years of age) in the development of
      myopia. In addition, simulations indicated that emmetropization occurred only for
      "induced" refractive error that was less than 0.5 D, which was consistent with
      the non-monotonic relationship between AErms and refractive error, wherein the
      minimum AErms occurred at 0.5 D. CONCLUSIONS: The model showed that both genetic
      and defocus-induced environmental factors play important roles in the development
      of refractive error in the different refractive groups. The model also provides a
      framework for further detailed quantitative analysis of the processes of
      refractive error development and emmetropization.

PMID- 10415457
TI  - Suppression of experimental corneal angiogenesis by focal X-ray irradiation.
AB  - PURPOSE: To investigate the effect of focal X-ray irradiation on experimental
      corneal angiogenesis in the rabbit. METHODS: A gelatin hydrogel sheet impregnated
      with basic fibroblast growth factor was implanted into the corneal stroma of
      rabbits; this induced corneal angiogenesis. After the first sign of corneal
      angiogenesis was noted, the corneal region was irradiated with a dose of 10 Gy or
      20 Gy. The control rabbits received no irradiation. The eyes were examined by
      slitlamp biomicroscopy and photographed, over a period of 28 days. The maximum
      length and total surface area of corneal angiogenesis were quantified by
      computerized image analysis. RESULTS: Corneal angiogenesis was noted on day 3
      following implantation of the hydrogel sheet. In the rabbits irradiated with 10
      Gy, the maximum length and total surface area of corneal angiogenesis were both
      significantly lower on day 4 and 7 following irradiation, compared to the
      respective measurement in the controls. In the rabbits irradiated with 20 Gy, the
      maximum length and total surface area of corneal angiogenesis were significantly
      lower between days 4 and 21, and between days 4 and 14, respectively, compared to
      the respective measurement in the controls. CONCLUSIONS: Focal X-ray irradiation
      to the corneal region suppressed corneal angiogenesis in a dose-dependent manner.
      Focal X-ray irradiation may be beneficial in treating ocular angiogenesis.

PMID- 10415458
TI  - Susceptibility of retinal ganglion cells to excitotoxicity depends on soma size
      and retinal eccentricity.
AB  - PURPOSE: This study was undertaken to determine if retinal ganglion cell
      sensitivity to intraocular N-methyl-D-aspartate or kainate injections varied as a
      function of retinal location (eccentricity) or cell soma size. METHODS: Rat
      retinal ganglion cells surviving intraocular N-methyl-D-aspartate or intraocular
      kainate induced lesions were retrogradely labeled with horseradish peroxidase and
      analyzed using an image analysis system. Control animals were retrogradely
      labeled after vehicle injection only. Cell counting was performed at 48 sampling
      points over the entire retina and represented a total area of 1.92 mm2 per
      retina. RESULTS: Larger cells were more sensitive to kainate than to N-methyl-D
      aspartate excitotoxicity; smaller cells more vulnerable to N-methyl-D-aspartate
      excitotoxicity. Further from the optic nerve, more smaller cells survived kainate
      administration. After N-methyl-D-aspartate administration, larger cells survived
      most, noticeably in the central retina. CONCLUSIONS: Our results suggest that
      loss of retinal ganglion cells after N-methyl-D-aspartate or kainate
      administration affects distinct populations of retinal ganglion cells, dependent
      upon soma size and retinal location. The mechanism by which certain classes of
      cells survive or succumb to such insults has yet to be determined.

PMID- 10415459
TI  - Nuclear targeting of plasmid DNA in human corneal cells.
AB  - PURPOSE: To characterize the mechanisms of plasmid DNA nuclear localization in
      primary cultures of human corneal epithelial cells and keratocytes. METHODS:
      Purified, supercoiled plasmid DNA was microinjected into the cytoplasm of human
      corneal epithelial cells and keratocytes that had been established from donor
      corneas two to three passages previously, and localized 8 hours later by in situ
      hybridization. To confirm the sequence-specificity of nuclear import observed in
      microinjected cells, liposome-mediated transient transfection experiments also
      were performed on human corneal epithelial cell and keratocyte cultures. RESULTS:
      Primary cultures of human corneal epithelial cells and keratocytes have the
      capacity to transport plasmid DNA from the cytoplasm to the nucleus in the
      absence of cell division. This transport activity is sequence-dependent requiring
      portions of the simian virus 40 (SV40) early promoter and enhancer. The majority
      of this nuclear transport activity resides within the enhancer domain of the SV40
      DNA, a region rich in transcription factor binding sites. This DNA nuclear import
      sequence also manifested itself in liposome-mediated transfection experiments,
      causing a greater than 2-fold increase in reporter gene expression in human
      corneal cells in a beta-galactosidase-expressing vector and up to a 1000-fold
      increase in a luciferase-expressing vector when compared to similar expression
      plasmids lacking the sequence. CONCLUSION: These results demonstrate that
      primary, non-transformed human corneal epithelial cells and keratocytes display
      sequence-specific nuclear import of plasmid DNA in the absence of mitosis. The
      small sequence that mediates nuclear localization of plasmids is active both in
      microinjected and cationic liposome transfected cells, and leads to increased
      gene expression. Thus, inclusion of this DNA sequence into non-viral vectors
      should improve the efficiency of ocular gene transfer in vivo.

PMID- 10415461
TI  - Sequence and location of SIX3, a homeobox gene expressed in the human eye.
AB  - Mouse Six3 is a homeobox gene expressed almost exclusively in the developing
      retina, lens, hypothalamus, and pituitary. It belongs to the same family as sine
      oculis, a Drosophila regulatory gene that encodes a transcription factor
      essential for eye development. The optix gene is its closest known Drosophila
      homologue, with a homeodomain that is 95% identical in sequence to the Six3
      protein. We have isolated the homologous human gene, SIX3, which is expressed in
      the adult retina and encodes a 332 amino acid protein that is 98% identical to
      its mouse counterpart. The SIX3 protein coding region is interrupted by a single
      intron located just downstream of the homeobox. A surprising feature of the SIX3
      gene is a 533 nucleotide 5' untranslated region that contains long polypyrimidine
      tracts with 96% identity to mouse Six3. We have used in-situ hybridization to map
      SIX3 to 2p21-p22, a site that is syntenic with the Six3 region of mouse
      chromosome 17. Large heterozygous deletions associated with human
      holoprosencephaly type 2 have been previously mapped to 2p21, opening the
      possibility that SIX3 could be involved in the development of midline structures
      of the head. Alternatively, the expression pattern of mouse Six3 suggests that
      human SIX3 could be involved in disorders of eye and pituitary development.

PMID- 10415460
TI  - Murine endotoxin-induced uveitis, but not immune complex-induced uveitis, is
      dependent on the IL-8 receptor homolog.
AB  - PURPOSE: To determine the roles of the murine interleukin-8 receptor homolog (mIL
      8Rh, neutrophil chemokine CXC receptor 2) and macrophage inflammatory protein
      1alpha (MIP-1alpha, a CC chemokine) in two eye inflammation models: endotoxin
      induced uveitis (EIU) and immune complex-induced uveitis (reverse passive Arthus
      reaction (RPAR) uveitis). METHODS: For the EIU model, 250 ng E.coli endotoxin was
      injected into the vitreous of mIL-8Rh-/- mice or heterozygous littermate mIL
      8Rh+/- controls and into MIP-1alpha-/- mice or congenic MIP-1alpha+/+ controls.
      Eyes were harvested after 24 h for histologic characterization of infiltrating
      cells and IL-6 bioassays. For the RPAR model, mouse antiserum against human serum
      albumin (HSA) was injected into the vitreous of mIL-8Rh-/-, mIL-8Rh+/-, MIP
      1alpha-/-, and MIP-1alpha+/+ mice. Twenty-four hours later, animals were
      challenged with intravenous HSA. Eyes were harvested after 4 h for analysis.
      RESULTS: RPAR resulted in the deposition of immune complexes at the ciliary area
      and iris with the subsequent development of uveitis. Genetic deficiency of mIL
      8Rh reduced the median number of infiltrating cells in EIU by 63% (p < 0.01) but
      had no effect on RPAR-induced inflammation. In the EIU model, macrophages
      comprised a much higher percentage (45%) of infiltrating cells in mice lacking
      mIL-8Rh than in controls (17%). Loss of the MIP-1alpha gene had no apparent
      effect on RPAR uveitis and a 39% reduction of infiltrating cells in EIU that was
      not statistically significant. IL-6 activity in aqueous humor was much less in
      mice with RPAR uveitis than in those with EIU. Neither gene deletion had a
      significant impact on IL-6 levels in either disease model. CONCLUSIONS:
      Chemokines acting via mIL-8Rh have a significant role in the induction of
      neutrophil infiltration during EIU but not during RPAR uveitis. MIP-1alpha is not
      critical for either EIU or RPAR-induced uveitis. The differential dependence on
      IL-8-like chemokines is in accord with the two forms ofuveitis having different
      etiologies and, therefore, potentially different optimal therapies.

PMID- 10415462
TI  - Multifocal osteosarcoma following retinoblastoma.
AB  - Three survivors of retinoblastoma, one with hereditary bilateral and two with
      nonhereditary (spontaneous) unilateral disease, developed multifocal
      osteosarcoma. For one patient, unilateral retinoblastoma was followed by
      primitive neuroepithelioma at age 13 years. Multifocal chondroblastic
      osteosarcoma represented the patient's third malignant neoplasm. The course of
      multifocal osteosarcoma in these three patients compares to that of multifocal
      osteosarcoma which presents de novo in other patients without prior
      retinoblastoma.

PMID- 10415463
TI  - Intraocular carboplatin concentrations following intravenous administration for
      human intraocular retinoblastoma.
AB  - Previous studies of the penetration of carboplatin into the vitreous have
      depended on unaffected animals or on animal models for other cancers. The
      objective of this study was to determine the intraocular levels of carboplatin
      following intravenous administration of carboplatin in the treatment of human
      intraocular retinoblastoma. Eight patients with bilateral intraocular
      retinoblastoma were treated in a consistent fashion with intravenous carboplatin.
      One additional patient was similarly treated, but enucleated one month later.
      Samples were taken from those nine eyes after enucleation one to two hours after
      the administration of 18.7 mg/kg (560 mg/m( 2) for patients more than 12 kg) of
      intravenous carboplatin, and carboplatin concentrations in the aqueous and
      vitreous were then measured by atomic absorption spectrometry. The mean
      concentration measured in the aqueous was 5.13 microg/ml and in the vitreous 4.05
      microg/ml, and vitreal concentrations were an average of 80% of aqueous
      concentrations. In one patient, a vitreous concentration of carboplatin was
      detected after an interval of one month that was 10% of the levels found in the
      samples enucleated one hour post-administration. These concentrations are much
      higher than previous animal studies would predict, and are similar to levels
      measured in unaffected animals when the drug is given after the use of
      cryotherapy. The concentration also approaches levels previously shown to be
      toxic to the retina. This elevation in carboplatin concentration may be due to
      disruption of the blood-vitreous barrier by active tumor.

PMID- 10415464
TI  - A Colombian family with X-linked juvenile retinoschisis with three affected
      females finding of a frameshift mutation.
AB  - X-linked retinoschisis (XLRS) is a vitreoretinal disease responsible for most
      cases of juvenile macular degeneration in males. Retinoschisis carrier females
      generally manifest no pathological symptoms. However, a large affected family
      from Colombia presented three affected females with typical RS phenotype similar
      to their 27 affected male relatives. Fundus examination as well as
      electroretinograms (ERG) indicate that the disease in these three affected
      females is as severe as in their affected male counterparts. DNA sequence
      analysis of the XLRS1 gene in the affected members of this family indicates a
      single base (G) deletion at the 639 base position (639delG). This deletion causes
      a frameshift during translation and results in a larger (235 amino acids) than
      normal peptide (224 amino acids) with grossly altered discoidin domain, which is
      considered critical for the cellular function of the protein. The co-segregation
      of this gene mutation with the RS phenotype and the RS carrier status as well as
      its complete absence in normal controls indicates that this genetic change is
      responsible for the RS pathology in this family. This (639delG) is a novel RS
      mutation and reported here for the first time. Furthermore, the analysis of the
      three affected females indicates that the RS pathology in affected females (a
      very rare occurrence) is due to XLRS1 mutations carried on both of their X
      chromosomes.

PMID- 10415465
TI  - Optic disc elevation in Down syndrome.
AB  - BACKGROUND: Optic disc elevation associated with Down syndrome is an uncommon
      phenomenon and raises the suspicion of an intracranial space-occupying lesion,
      thus necessitating the consideration of invasive and noninvasive investigations.
      METHOD OF STUDY: Four patients with Down syndrome and optic disc elevation
      without an underlying intracranial pathology are reported. Thorough
      ophthalmological and neuroradiological investigations were performed on each
      patient. Mild hyperopia occurred in three patients and myopia in one.
      CONCLUSIONS: We believe that in most Down syndrome patients with disc elevation,
      fluorescein angiography and/or clinical follow-up may be sufficient.

PMID- 10415466
TI  - Marked increase in flow velocities during deep expiration: A duplex Doppler sign
      of celiac artery compression syndrome.
AB  - Symptoms of chronic mesenteric ischemia develop when the celiac artery is
      constricted by the median arcuate ligament of the diaphragm. Lateral aortography
      is the primary modality for diagnosing ligamentous compression of the celiac
      artery. However, duplex Doppler sonography performed during deep expiration can
      cause a marked increase in flow velocities at the compressed region of the celiac
      artery and suggest the diagnosis of celiac arterial constriction due to the
      diaphragmatic ligament.

PMID- 10415467
TI  - Late in-stent restenosis of the abdominal aorta in a patient with Takayasu's
      arteritis and related pathology.
AB  - This report describes an in-stent restenosis of the infrarenal aorta in a patient
      with Takayasu's arteritis in a nonactive state. A 10-mm-diameter Wallstent had
      been deployed 42 months previously. The stented restenosed segment was replaced
      by a surgical graft. Histopathological examination of the excised aortic segment
      showed a thin layer of fibrocellular neointima and massive organized and
      calcified thrombus. To our knowledge, this is the first histopathological report
      of a late in-stent restenosis of the abdominal aorta in Takayasu's arteritis.

PMID- 10415469
TI  - Chance favors the prepared genome.
AB  - Most descriptions of mutation have emphasized its negative consequences, and
      randomness with respect to biological function. This book seeks to balance the
      discussion by emphasizing mechanisms that both diversify the genome and increase
      the probability that a genome's descendants will survive. This chapter provides a
      framework for, and overview of, the diverse contributions to this book; these
      contributions will be stimulating companions, well into the 21st Century, as we
      work to comprehend the information contained in genomic databases. Genomes that
      encode "better" amino acid sequences are at a selective advantage. Genomes that
      generate diversity also are at an advantage to the extent that they can navigate
      efficiently through the space of possible sequence changes. Biochemical systems
      that tend to increase the ratio of useful to destructive genetic change may
      harness preexisting information (horizontal gene transfer, DNA translocation
      and/or DNA duplication), focus the location, timing, and extent of genetic
      change, adjust the dynamic range of a gene's activity, and/or sample regulatory
      connections between sites distributed across the genome. Rejecting entirely
      random genetic variation as the substrate of genome evolution is not a
      refutation, but rather provides a deeper understanding, of the theory of natural
      selection of Darwin and Wallace. The fittest molecular strategies survive, along
      with descendants of the genomes that encode them.

PMID- 10415468
TI  - Treatment of popliteal artery aneurysms with uncovered Wallstents.
AB  - We report two patients with acutely thrombosed popliteal artery aneurysms that
      were successfully treated with a combination of thrombolytic therapy and
      placement of noncovered Wallstents.

PMID- 10415470
TI  - Genome system architecture and natural genetic engineering in evolution.
AB  - Molecular genetics teaches three lessons relevant to the nature of genetic change
      during evolution: (1) Genomes are organized as hierarchies of composite systems
      (multidomain protein-coding sequences; functional loci made up of regulatory,
      coding, processing, and intervening sequences; and multilocus regulons and
      replicons) interconnected and organized into specific "system architectures" by
      repetitive DNA elements. (2) Genetic change often occurs via natural genetic
      engineering systems (cellular biochemical functions, such as recombination
      complexes, topoisomerases, and mobile elements, capable of altering DNA sequence
      information and joining together different genomic components). (3) The activity
      of natural genetic systems is regulated by cellular control circuits with respect
      to the timing, activity levels, and specificities of DNA rearrangements (e.g.,
      adaptive mutation, Ty element mobility, and P factor insertions). These three
      lessons provide plausible molecular explanations for the episodic, multiple,
      nonrandom DNA rearrangements needed to account for the evolution of novel genomic
      system architectures and complex multilocus adaptations. This molecular genetic
      perspective places evolutionary change in the biologically responsive context of
      cellular biochemistry.

PMID- 10415471
TI  - Involvement of gene products in bacterial evolution.
AB  - Three strategies of different quality contribute in parallel to the natural
      formation of genetic variants in bacteria: (1) small local alterations of DNA
      sequences; (2) recombinational reshuffling of segments of the genome; and (3)
      acquisition of DNA sequences by horizontal gene transfer. Key enzymes involved in
      these processes often act as variation generators by making use of structural
      flexibilities of biological macromolecules and of the effect of random encounter.
      In the theory of molecular evolution, genetic determinants of variation
      generators as well as of modulators of the frequency of genetic variation are
      defined as evolutionary genes. This postulate is consistent with the notion that
      spontaneous mutagenesis is in general not adaptive and that the direction of
      evolution depends on natural selection exerted on populations of genetic
      variants.

PMID- 10415472
TI  - Palindromic DNA and genome stability. Further studies.
AB  - Unusual DNA structures promote genetic instability. One such example is hairpin
      DNA, which can form from palindromic sequences and triplet repeats, and is also a
      characteristic intermediate in V(D)J recombination. We previously found that a
      large 15.3-kb palindrome that was introduced as a transgene into the mouse
      germline was highly unstable. Although it could be transmitted, the transgene was
      found to be rearranged in up to 56% of the progeny, and rearrangement events
      often involved deletion at the center of symmetry. Here, the fine structure of
      centrally deleted palindromes was sampled by analysis of recombinant junctions
      isolated from testes DNA, providing further evidence for a model, previously
      proposed, that accounts for such deletions on the basis of a hairpin-tip nicking
      activity. In addition to central deletions, gene conversion events were also
      elevated in the transgenic palindrome. We have now analyzed instability in two
      mouse sublines in which (as a result of inversion) the transgenic palindrome had
      been shortened to 4.2 kb. In these sublines, the transgene was still subject to
      both rearrangement and gene conversion events at a high frequency, similar to the
      original 15.3-kb palindrome. Recombination was not limited to the sequences
      constituting the inverted repeat, but was seen to include sequences lying outside
      the palindrome. As discussed, the salient feature in all of these observations, a
      high level of genetic change associated with palindromic DNA, underscores the
      significance of hairpin DNA and hairpin-tip nicking in genome stability.

PMID- 10415473
TI  - Evolution of immunoglobulin and T-cell receptor gene assembly.

PMID- 10415474
TI  - Mobile gene cassettes and integrons in evolution.
AB  - Integrons and the site-specific recombination systems encoded by them provide a
      simple mechanism for the addition of new genes to bacterial chromosomes. Although
      there is substantial divergence among the four known integron-encoded integrases,
      they all recognize the recombination sites, known as 59-base elements, that are
      associated with genes that are packaged in gene cassettes. In contrast, the
      integron-associated recombination sites, attl sites, are preferentially
      recognized by the cognate integrase.

PMID- 10415475
TI  - Evolutionary genomics of vertebrates and its implications.
AB  - The discovery that the vertebrate genomes of warm-blooded vertebrates are mosaics
      of isochores, long DNA segments homogeneous in base composition, yet belonging to
      families covering a broad spectrum of GC levels, has led to two major
      observations. The first is that gene density is strikingly non-uniform in the
      genome of all vertebrates, gene concentration increasing with increasing GC
      levels. (Although the genomes of cold-blooded vertebrates are characterized by
      smaller compositional heterogeneities than those of warm-blooded vertebrates and
      high GC levels are not attained, their gene distribution is basically similar to
      that of warm-blooded vertebrates.) The second observation is that the GC-richest
      and gene-richest isochores underwent a compositional transition (characterized by
      a strong increase in GC level) between cold- and warm-blooded vertebrates.
      Evidence to be discussed favors the idea that this compositional transition and
      the ensuing highly heterogeneous compositional pattern was due to, and was
      maintained by, natural selection.

PMID- 10415476
TI  - The distribution of rates of spontaneous mutation over viruses, prokaryotes, and
      eukaryotes.
AB  - Although mutation has chaotic aspects, spontaneous mutation rates assume certain
      characteristic values when expressed per genome per genome duplication. The rate
      among lytic RNA viruses is roughly 1, while the rate among retroelements is
      roughly 0.2. The rate among viral and cellular microbes with DNA chromosomes is
      close to 0.0034. Mutation rates among higher eukaryotes, estimated from specific
      locus studies, vary greatly. Most of this variation can be suppressed if the
      rates are expressed per cell division instead of per sexual generation, and if
      the genome size is taken to be only a little larger than the sum of the protein
      encoding sequences; then, the mutation rate is roughly 0.01. The reasons for
      different characteristic mutation rates among different organism groups remain
      mysterious and pose a substantial challenge to students of evolution.

PMID- 10415477
TI  - Fidelity of retrotransposon replication.
AB  - Ty1, the genetically tractable retrotransposable element found in the yeast
      Saccharomyces cerevisiae, closely resembles vertebrate retroviruses both in
      structure and in mechanism of replication. By direct sequence analysis, we
      examined the rate and spectrum of new mutations appearing during a single cycle
      of Ty1 replication. The rate of new mutations was comparable to those seen for
      replicating retroviruses. All observed changes were base substitutions, and their
      location suggested that template ends may be hot spots for generating these
      mutations. To test this, we developed methods to examine, at the nucleotide
      level, the end structure of the expected Ty1 replication intermediates. Our
      results demonstrate that Ty1 reverse transcriptase can add terminal non-templated
      bases in vivo during each step in replication. Furthermore, Ty1 RNAse H creates
      multiple template ends by imprecisely cleaving RNA. This expands the range of
      sites of subsequent non-templated base addition. Finally, on reaching template
      ends, Ty1 reverse transcriptase can strand transfer to inappropriate templates.
      Taken together, these mutagenic mechanisms may influence the evolution of
      particular regions of the Ty1 genome and serve as a mechanism to regulate the
      overall level of Ty1 transposition in its host cell.

PMID- 10415478
TI  - RNA processing in evolution. The logic of soft-wired genomes.
AB  - Direct read-out of information from DNA into RNA allows the genome to be
      faithfully reproduced in RNA. This outcome occurs in what may be called "hard
      wired" organisms. On the other hand, in what we refer to as "soft-wired"
      organisms, RNA is processed extensively, allowing a number of different messages
      to be produced from the same gene. As a consequence, the nucleotide sequences
      present in RNA (referred to here as the ribotype) differ from those present in
      DNA (the genotype). In soft-wired organisms, RNA processing can be thought of as
      a series of steps, one or more of which have two mutually exclusive outcomes: a
      "default" outcome and an "alternative" outcome. In the presence of appropriate
      regulatory signals, the RNA is processed using the alternative pathway, while the
      default pathway is used in their absence. The setup is functionally equivalent to
      that found in binary "logic gates." In both cases, "logical operations" are
      implemented by using regulatory signals to establish a conditional relationship
      between input and output and can be described using the Boolean operators AND,
      OR, and NOT. In the case of RNA processing events, the outcomes can be used
      either to directly regulate cellular responses or to control other RNA processing
      events. In the latter case, "networks" are established that make processing of
      one RNA contingent on another. Such networks allow cells to respond to their
      surroundings by changing the connectivity between different RNA processing
      events, using RNA as a substrate to compute an appropriate response. As such
      logical operations impact phenotype, they are subject to natural selection.
      Through reverse transcription, successful outcomes can be incorporated into the
      genome.

PMID- 10415480
TI  - Evolution of evolvability.
AB  - Genomic sequence data provide evidence for a common origin of life and for its
      evolution by genetic variation via mutation and recombination. This paper
      discusses the fundamental dialectic paradigm of evolution--stability versus
      variability--at the crossroads of molecular genetics, population genetics,
      ecology, and the emerging science of experimental evolution. Experimental
      evolution of molecules, viruses, and bacteria can be used not only to test some
      basic evolutionary hypotheses but also to create new organisms for applications
      in biotechnology, agriculture, and medicine.

PMID- 10415481
TI  - Predictability of mutant sequences. Relationships between mutational mechanisms
      and mutant specificity.
AB  - Spontaneous mutations are rare and are produced by multiple biochemical
      mechanisms. Nonetheless, studies of these mechanisms have revealed striking
      examples in which mutational specificity can be regularly related to a
      characteristic of the surrounding DNA sequence and/or the enzymes participating
      in mutagenesis. Thus, to an increasing degree the DNA sequences of mutants are
      "predictable." This report considers some examples of predictable sequence
      changes, evidence for their contribution to mutagenesis in populations, and how
      the predictability of mutant sequences may be useful to improve our
      interpretation of the molecular course of evolution from DNA sequence
      comparisons.

PMID- 10415479
TI  - Mechanisms of mutation in nondividing cells. Insights from the study of adaptive
      mutation in Escherichia coli.
AB  - When populations of cells are subjected to nonlethal selection, mutations arise
      in the absence of cell division, a phenomenon that has been called "adaptive
      mutation." In a strain of Escherichia coli that cannot metabolize lactose (Lac-)
      but that reverts to lactose utilization (Lac+) when lactose is its sole energy
      and carbon source, the mutational process consists of two components. (1) A
      highly efficient, recombination-dependent mechanism giving rise to mutations on
      the F' episome that carries the Lac- allele; and (2) a less efficient, unknown
      mechanism giving rise to mutations elsewhere in the genome. Both selected and
      nonselected mutations arise in the Lac- population, but nonselected mutations are
      enriched in Lac+ mutants, suggesting that some Lac+ cells have passed though a
      transient period of increased mutation. These results have several evolutionary
      implications. (1) DNA synthesis initiated by recombination could be an important
      source of spontaneous mutation, particularly in cells that are not undergoing
      genomic replication. (2) The highly active mutational mechanism on the episome
      could be important in the horizontal transfer of variant alleles among species
      that carry and exchange conjugal plasmids. (3) A sub-population of cells in a
      state of transient mutation could be a source of multiple variant alleles and
      could provide a mechanism for rapid adaptive evolution under adverse conditions.

PMID- 10415482
TI  - DNA-directed mutations. Leading and lagging strand specificity.
AB  - The fidelity of replication has evolved to reproduce B-form DNA accurately, while
      allowing a low frequency of mutation. The fidelity of replication can be
      compromised, however, by defined order sequence DNA (dosDNA) that can adopt
      unusual or non B-DNA conformations. These alternative DNA conformations,
      including hairpins, cruciforms, triplex DNAs, and slipped-strand structures, may
      affect enzyme-template interactions that potentially lead to mutations. To
      analyze the effect of dosDNA elements on spontaneous mutagenesis, various
      mutational inserts containing inverted repeats or direct repeats were cloned in a
      plasmid containing a unidirectional origin of replication and a selectable marker
      for the mutation. This system allows for analysis of mutational events that are
      specific for the leading or lagging strands during DNA replication in Escherichia
      coli. Deletions between direct repeats, involving misalignment stabilized by DNA
      secondary structure, occurred preferentially on the lagging strand.
      Intermolecular strand switch events, correcting quasipalindromes to perfect
      inverted repeats, occurred preferentially during replication of the leading
      strand.

PMID- 10415483
TI  - Evolution of the U-insertion/deletion RNA editing in mitochondria of
      kinetoplastid protozoa.

PMID- 10415484
TI  - Immunoglobulin switch recombination may occur by a DNA end-joining mechanism.
AB  - Immunoglobulin switch recombination is a specialized recombination event that
      occurs exclusively in B lymphocytes and is focused on tandemly repetitive DNA
      sequences called switch regions. Switch recombination occurs as an
      intrachromosomal deletion event in which the deleted genetic material is excised
      as a circle. Although the developmental profile of this recombination event is
      well characterized, the underlying mechanism for switch recombination is poorly
      understood. Recent studies detected the presence of double strand breaks in
      switch DNA and the dependency of switching on the Ku and DNA-dependent protein
      kinase proteins which are involved in repair of double strand breaks by
      nonhomologous end-joining. Taken together these findings strongly suggest that
      switch recombination is a specialized recombination system that occurs through a
      DNA end-joining mechanism.

PMID- 10415485
TI  - Transgenic and mutational analyses of meiotic recombination in mice.

PMID- 10415486
TI  - Speciation of cone snails and interspecific hyperdivergence of their venom
      peptides. Potential evolutionary significance of introns.
AB  - All 500 species of cone snails (Conus) are venomous predators. From a
      biochemical/genetic perspective, differences among Conus species may be based on
      the 50-200 different peptides in the venom of each species. Venom is used for
      prey capture as well as for interactions with predators and competitors. The
      venom of every species has its own distinct complement of peptides. Some of the
      interspecific divergence observed in venom peptides can be explained by
      differential expression of venom peptide superfamilies in different species and
      of peptide superfamily branching in various Conus lineages into pharmacologic
      groups with different targeting specificity. However, the striking interspecific
      divergence of peptide sequences is the dominant factor in the differences
      observed between venoms. The small venom peptides (typically 10-35 amino acids in
      length) are processed from larger prepropeptide precursors (ca. 100 amino acids).
      If interspecific comparisons are made between homologous prepropeptides, the
      three different regions of a Conus peptide precursor (signal sequence, pro
      region, mature peptide) are found to have diverged at remarkably different rates.
      Analysis of synonymous and nonsynonymous substitution rates for the different
      segments of a prepropeptide suggests that mutation frequency varies by over an
      order of magnitude across the segments, with the mature toxin region undergoing
      the highest rate. The three sections of the prepropeptide which exhibit
      apparently different mutation rates are separated by introns. This striking
      segment-specific rate of divergence of Conus prepropeptides suggests a role for
      introns in evolution: exons separated by introns have the potential to evolve
      very different mutation rates. Plausible mechanisms that could underlie differing
      mutational frequency in the different exons of a gene are discussed.

PMID- 10415487
TI  - Evolution of chordate hox gene clusters.
AB  - In this article, we consider the role of the Hox genes in chordate and vertebrate
      evolution from the viewpoints of molecular and developmental evolution. Models of
      Hox cluster duplication are considered with emphasis on a threefold duplication
      model. We also show that cluster duplication is consistent with a
      semiconservative model of duplication, where following duplication, one daughter
      cluster remains unmodified, while the other diverges and assumes a new
      architecture and presumably new functions. Evidence is reviewed, suggesting that
      Hox gene enhancers have played an important role in body plan evolution. Finally,
      we contrast the invertebrates and vertebrates in terms of genome and Hox cluster
      duplication which are present in the latter, but not the former. We question
      whether gene duplication has been important in vertebrates for the introduction
      of novel features such as limbs, a urogenital system, and specialized
      neuromuscular interactions.

PMID- 10415488
TI  - Transposable elements as a molecular evolutionary force.
AB  - This essay addresses the paradoxes of the complex and highly redundant genomes.
      The central theses developed are that: (1) the distinctive feature of complex
      genomes is the existence of epigenetic mechanisms that permit extremely high
      levels of both tandem and dispersed redundancy; (2) the special contribution of
      transposable elements is to modularize the genome; and (3) the labilizing forces
      of recombination and transposition are just barely contained, giving a dynamic
      genetic system of ever increasing complexity that verges on the chaotic.

PMID- 10415489
TI  - Floricultural traits and transposable elements in the Japanese and common morning
      glories.
AB  - The Japanese morning glory has an extensive history of genetic studies and over
      200 different spontaneous mutant lines have been described. Of these, we
      identified that two mutable alleles, flecked and speckled, for flower
      variegations are caused by integration of transposable elements, belonging to the
      En/Spm family, into the DFR-B and CHI genes for flower pigmentation,
      respectively. The mutable flaked allele of the common morning glory bearing
      variegated flowers is caused by insertion of a new transposable element, Tip100,
      into one of the CHS genes for pigmentation and that Tip100 belongs to the Ac/Ds
      family. These results are discussed with regard to spontaneous transposon
      mutagenesis and generation of floricultural traits of morning glories.

PMID- 10415490
TI  - Mechanisms of genome-wide hypermutation in stationary phase.
AB  - Stationary-phase mutation (a subset of which was previously called adaptive
      mutation) occurs in apparently nondividing, stationary-phase cells exposed to a
      nonlethal genetic selection. In one experimental system, stationary-phase
      reversion of an Escherichia coli F'-borne lac frameshift mutation occurs by a
      novel molecular mechanism that requires homologous recombination functions of the
      RecBCD system. Chromosomal mutations at multiple loci are detected more
      frequently in Lac+ stationary-phase revertants than in cells that were also
      exposed to selection but did not become Lac+. Thus, mutating cells represent a
      subpopulation that experiences hypermutation throughout the genome. This paper
      summarizes current knowledge regarding stationary-phase mutation in the lac
      system. Hypotheses for the mechanism of chromosomal hypermutation are discussed,
      and data are presented that exclude one hypothetical mechanism in which
      chromosomal mutations result from Hfr formation.

PMID- 10415491
TI  - Dynamic evolution of genomes and the concept of genome space.
AB  - A new era in the elucidation of genome evolution has been heralded with the
      availability of numerous genome sequences. With these data, it has been possible
      to study evolutionary processes at a greater level of detail in order to
      characterize features such as gene shuffling, genome rearrangements, base bias
      composition, and horizontal gene transfer. In this paper, we discuss the
      evolutionary implications of significant rearrangements within genomes as well as
      characteristic genomic regions that have been conserved across genomes. This is
      based on our analysis of orthologous and paralogous genes. We argue that genome
      plasticity has most likely contributed substantially to the dynamic evolution of
      genomes. We also describe the characteristic mosaic features of an archaea genome
      that is comprised of both bacterial and eukaryal elements. Here we investigate
      base compositional differences as well as the similarity of this species' genes
      to either bacteria or eukarya. We conclude that these features can be largely
      explained by the mechanism of horizontal gene transfer. Finally, we introduce the
      concept of genome space which is defined as the entire set of genomes of all
      living organisms. We explain its usefulness to describe as well as to gain deeper
      insight into the general features of the dynamic genomic evolutionary process.

PMID- 10415492
TI  - Evolution of DNA organization in hypotrichous ciliates.
AB  - Profound changes have been introduced into the germline (micronuclear) and
      somatic (macronuclear) genomes of hypotrichous ciliates during evolution. First,
      multiple, short, unique, noncoding sequences, called IESs, have been inserted
      into micronuclear genes. IESs are spliced out of each gene, and the gene
      segments, called MDSs, are ligated during conversion of the micronuclear genome
      to a macronuclear genome after cell mating. The IESs in a particular gene can
      change dramatically in number, position, length, and sequence during speciation.
      Once inserted, IESs can shift along the DNA of a gene 1 or 2 bp at a time by a
      mutational mechanism that does not alter the coding sequence of the gene. Second,
      the MDSs in the same genes have been rearranged into random or nonrandom,
      scrambled disorder. The origin of nonrandom scrambling patterns can be explained
      by a model of simultaneous insertion of multiple IESs into a germline gene during
      evolution. Subsequent recombinations among the IESs may change the MDS
      arrangement from a nonrandomly scrambled to a randomly scrambled pattern,
      including inversions of MDSs. Third, during the conversion of a micronucleus to a
      macronucleus after cell mating, MDSs are ligated in the unscrambled, orthodox
      order in association with IES excision, and the genes are then removed from the
      chromosomes as individual, short DNA molecules. These gene-size molecules are
      amplified many-fold to produce a mature macronucleus. All of these phenomena
      attest to a remarkable fluidity of the hypotrich genome both over evolutionary
      time and in the conversion of a germline genome to a somatic genome. The
      significance of this fluidity for the life and evolution of these organisms is
      still obscure. Recombination among IESs could shuffle MDSs and facilitate faster
      evolution of new genes.

PMID- 10415493
TI  - Detecting alien genes in bacterial genomes.
AB  - We present new methods for calculating codon bias of a group of genes or an
      individual gene relative to a standard gene class. This method is suitable for
      identifying alien (e.g., horizontally transferred) and highly expressed genes. In
      yeast and several bacterial genomes, highly expressed genes typically include
      ribosomal protein genes, elongation factors, chaperonins (heat shock proteins),
      and a subset of genes involved in glycolysis generally essential in exponential
      growth. Highly expressed genes of the Synechocystis genome feature several
      photosystem II genes, and highly expressed genes in several methanogens
      (Methanococcus jannaschii, M. thermoautotrophicum) are essential for
      methanogenesis. Alien genes mostly consist of ORFs of unknown function,
      transposases, prophage genes, and restriction/modification enzymes. Notably,
      nuclear ribosomal proteins of yeast are highly expressed, whereas mitochondrial
      ribosomal protein genes appear to be alien genes. Alien genes often occur in
      clusters, suggesting in these cases that transfer events entail several genes.

PMID- 10415494
TI  - Elucidating sequence codes: three codes for evolution.
AB  - The sequences are related to evolution in several ways. First, they carry traces
      of a distant past. Two sequence features point to the earliest sequence
      organization. The universal hidden GCU-periodical pattern in mRNA suggests the
      earliest codons: GCU and its nine-point-change derivatives. They code for seven
      amino acids that by several criteria are also the oldest. Together it makes the
      earliest form of the triplet code, still recognizable in the extant sequences.
      Another feature present in the sequences, apparently, since separation of
      prokaryotes and eukaryotes, is hidden genome segmentation. Both protein-coding
      and noncoding sequences appear to have been formed by fusion of standard size
      units, about 360 bp (120 aa) in eukaryotes and 450 bp (150 aa) in prokaryotes.
      Presumably, the units have been functioning at some stage of evolution as
      autonomous single-gene size elements. There are sequence designs that promote
      evolution. One such design suitable for fast adaptation is the tandem repetition
      of identical sequences, so that their copy numbers in the repeat arrays would
      modulate (tune) the expression of nearby genes. The tandem repeat expansion
      diseases illustrate this mechanism in a dramatic way: overtuning of the
      respective gene expression leads to the disease.

PMID- 10415495
TI  - Evolution of gene scrambling in ciliate micronuclear genes.

PMID- 10415496
TI  - Protein binding to meiotic recombination hotspots in mouse testis.

PMID- 10415497
TI  - Homologous recombination and sex as a strategy against selfish genes attacking
      the genome.

PMID- 10415498
TI  - Random amplified polymorphic DNA analysis of Ustilago violacea.
AB  - Isolates of the two mating type strains of the basidiomycete phytopathogen
      Ustilago violacea (Pers.) Roussel [a.k.a Microbotryum violaceum (Pers.:Pers.)
      Deml and Oberw] are restricted in their host range to one or a few species of
      Caryophyllaceae (Pinks). Molecular genetics maps in this species are commonly
      constructed by analyzing the segregation of restriction fragment length
      polymorphisms (RFLPs) among the progeny of a sexual cross and more recently
      through electrophoretic karyotypes and chromosomal polymorphism using CHEF gel
      analysis. However, currently, polymorphisms in genomic fingerprints generated by
      arbitrarily primed polymerase chain reaction (PCR) can distinguish between
      strains of almost any organism, which is useful in genetic mapping. The objective
      of this project was to use PCR technology, 40 Operon 10-mer primers, and 5 simple
      sequence repeat (SSR) primers, designed on microsatellite sequences to determine
      their efficiency in detecting intraspecific differences between the genomic DNA
      of the two mating type strains of U. violacea (a1 and a2). Polymorphism in the
      banding patterns of the DNA samples was detected after PCR and electrophoresis in
      1.4% agarose gels. This polymorphic intraspecific variation will be utilized to
      detect cryptic and trans-active transposable elements in U. violacea.

PMID- 10415499
TI  - Human chromosome 21. Why 40 Mb?

PMID- 10415500
TI  - Sequence patterns observed in 5' flanking regions of primate Alu elements.
AB  - Retrotransposons have generally been known to integrate randomly into host
      genomes. Jurka, however, showed some consensus sequence patterns at insertion
      sites of some mammalian retrotransposons and proposed enzymatic involvement that
      mediates integration. Jurka used about 400 complete human Alu and rodent ID
      sequences which retain full length with identical flanking sequences at both
      ends. In our study, more than 25,000 Alu sequences longer than 250 bp were used
      for comprehensive analysis to identify any consensus sequence(s) preceding the 5'
      end of Alu elements. "Entropy" at each nucleotide position within 500 bases of
      the 5' Alu end was computed. Significant drop of entropy was observed between
      position -20 and -10 of the 5' end of Alu, suggesting the existence of certain
      consensus sequence(s) in the region. Frequencies of all possible triplets (total
      of 64) were measured in the same region. Observation that frequencies of triplets
      "aaa," "taa," and "tta" in the 5' flanking sequences were high is consistent with
      Jurka. However, frequencies of triplets "att" and "aca" were also significantly
      high, which are not the primary candidates for nick site in Jurka.

PMID- 10415501
TI  - EXO1 of Saccharomyces cerevisiae functions in mutagenesis during double-strand
      break repair.

PMID- 10415502
TI  - Contingency loci, mutator alleles, and their interactions. Synergistic strategies
      for microbial evolution and adaptation in pathogenesis.

PMID- 10415503
TI  - Specificity of transcription-enhanced mutations.

PMID- 10415504
TI  - E. coli RNA polymerase bypass of DNA base damage. Mutagenesis at the level of
      transcription.

PMID- 10415505
TI  - Gonad recruitment of carboxylesterase genes during evolution of the reproductive
      system. Conserved male-specific overexpression in mussels, fruitflies, and
      mammals.

PMID- 10415506
TI  - Mutagenesis patterns in a tRNA mutation marker gene altered to include repetitive
      sequence replicated in mutS E. coli.

PMID- 10415507
TI  - Modeling selection for adjustable genes based on simple sequence repeats.

PMID- 10415509
TI  - Protein salvage by directed evolution. Functional restoration of a defective
      lysozyme mutant.

PMID- 10415508
TI  - Directed evolution of mesophilic enzymes into their thermophilic counterparts.

PMID- 10415510
TI  - Is the genetic code really a frozen accident? New evidence from in vitro
      selection.

PMID- 10415511
TI  - The linguistics of DNA: words, sentences, grammar, phonetics, and semantics.

PMID- 10415512
TI  - Is there a link between mutation rates and the stringent response in Bacillus
      subtilis?

PMID- 10415513
TI  - Does the fountain epitope model's rhythmic hydropathy continuum pattern satisfy
      the requirements of a nucleic acid meta-code or protein meta-form?

PMID- 10415514
TI  - A comparative genomics approach to DNA asymmetry.

PMID- 10415515
TI  - Cardiac hypertrophy: signal transduction, transcriptional adaptation, and altered
      growth control.
AB  - Cardiac hypertrophy results from the enlargement of cardiac muscle and fibroblast
      cells. This abnormal pattern of growth can be elicited by a number of
      hypertrophic agents, such as cytokines and hormones that participate in normal
      cell-cell signaling events during development. Under conditions yet to be
      defined, these same signaling molecules can cause hypertrophy of the heart.
      Intracellular signal transduction pathways appear to be the prime means by which
      the hypertrophic signal is transduced in cardiomyocytes. There is no evidence
      that the signal transduction pathways in hypertrophic cardiomyocytes differ from
      those of normal cardiomyocytes. Perhaps the signal itself is aberrant, mistimed,
      misplaced, or occurring at non-physiological concentrations. Alternatively, as a
      quiescent cell, the cardiomyocyte may not be able to respond completely to a
      growth signal by turning on its proliferative machinery. Three avenues of
      research are described: (1) the study of the upregulation of the cardiac MLC-2
      gene, (2) STAT proteins and activation of angiotensin II, and (3) hypertrophy as
      a perturbation of cell cycle controls.

PMID- 10415516
TI  - The ins and outs of caveolar signaling. m2 muscarinic cholinergic receptors and
      eNOS activation versus neuregulin and ErbB4 signaling in cardiac myocytes.
AB  - Endothelial cells constitutively express the NOS isoform eNOS, which generates NO
      in response to specific extracellular signals to regulate vascular smooth muscle
      tone, vascular permeability, and platelet adhesion, among other actions. In
      addition to coronary vascular and endocardial endothelium, both atrial and
      ventricular myocytes express eNOS, the activation of which is also dependent on
      specific intracellular and extracellular signals. eNOS is targeted in cardiac
      myocytes to caveolae in plasma membranes and, in the case of cardiac myocytes,
      possibly T-tubular membranes as well. eNOS targeting to caveolae in cardiac
      myocytes requires co-translational myristoylation and subsequent palmitoylation
      for efficient targeting of the enzyme to the specialized lipid microdomains
      characteristic of caveolae. Although eNOS also contains a caveolin binding motif,
      this is insufficient for correct targeting of eNOS to caveolae. Recent evidence
      obtained from ventricular myocytes of mice with targeted disruption of the eNOS
      gene indicates that the lack of functional eNOS interrupts muscarinic cholinergic
      control of ICa-L in these cells. eNOS-/- mice are hypertensive and develop
      cardiac hypertrophy as they age, and these animals also exhibit an accelerated
      degree of vascular remodeling in response to injury. Reconstitution experiments
      confirm both the essential role of eNOS in coupling m2 AchR signaling to the
      control of ICa-L and myocyte automaticity and the importance of eNOS subcellular
      localization within caveolae in mediating this signal transduction pathway. It
      appears that translocation into caveolae is essential for signaling. However,
      this is not the case with all receptors associated with caveolae.

PMID- 10415517
TI  - Amplification of angiotensin II signaling in cardiac myocytes by adenovirus
      mediated overexpression of the AT1 receptor.
AB  - Low levels of AT1 receptor can make studying the growth-related signal
      transduction events mediated by this angiotensin II receptor in cardiac myocytes
      technically difficult. The purpose of the present study was to establish whether
      an adenovirus expression system could be used to increase the number of plasma
      membrane AT1 receptors in neonatal rat ventricular myocytes, thereby amplifying
      the signaling pathways activated by this receptor. Cardiac myocytes infected with
      adenovirus expressing the AT1 receptor exhibited increased ligand binding. The
      overexpressed receptor appeared to function like the endogenous receptor, in
      regard to agonist-induced internalization, as well as coupling to MAPK activation
      and protein tyrosine phosphorylation events. In addition, adenovirus-mediated
      overexpression of the AT1 receptor resulted in the amplification of angiotensin
      II intracellular signaling. In conclusion, adenovirus-mediated overexpression of
      angiotensin II receptors appears to be a useful strategy for studying the signal
      transduction events activated by this hormone in cardiac myocytes and for
      unraveling the molecular means by which this receptor type couples to a
      hypertrophic pattern of growth and gene expression.

PMID- 10415519
TI  - The molecular mechanism of cardiac hypertrophy and failure.
AB  - Mechanical stretch induced by high blood pressure is an initial factor leading to
      cardiac hypertrophy. In an in vivo study, an angiotensin II (AngII) type 1
      receptor antagonist TCV116 reduced left ventricular (LV) weight, LV wall
      thickness, transverse myocyte diameter, relative amount of V3 myosin heavy chain,
      and interstitial fibrosis, while treatment with hydralazine did not. In an in
      vitro study using cultured cardiomyocytes, mechanical stretch activated second
      messengers such as mitogen-activated protein (MAP) kinase, followed by increased
      protein synthesis. Additionally, in the stretch-conditioned medium AngII and
      endothelin-1 concentrations were increased. Furthermore, the Na+/H+ exchanger
      activated by mechanical stretch modulated the hypertrophic responses of
      cardiomyocytes. The pathways leading to MAP kinase activation differed between
      cell types. In cardiac fibroblasts AngII activated MAP kinase via G beta gamma
      subunit of Gi, Src, Shc, Grb2, and Ras, whereas Gq and protein kinase C were
      critical in cardiomyocytes.

PMID- 10415520
TI  - Oxygen free radical signaling in ischemic preconditioning.
AB  - This review will focus on the free radical signaling mechanism of
      preconditioning. The results from our laboratory as well as studies from other
      laboratories suggest that reactive oxygen species function as second messenger
      during myocardial adaptation to ischemia. This review provides evidence for the
      first time that tyrosine kinase and MAP kinases are the targets for reactive
      oxygen species generated in the preconditioned myocardium. The finding that p38
      MAP kinase might be upstream of NF kappa B further supports our previous reports
      that MAPKAP kinase 2 could be the most likely link between the preconditioning
      and adaptation mediated by gene expression. p38 activation appears to be an
      important step in the translocation and activation of the nuclear transcription
      factor NF kappa B, which in turn may be involved in the induction of the
      expression of a variety of stress-inducible genes.

PMID- 10415518
TI  - Mitochondrial ATP-dependent potassium channels. Viable candidate effectors of
      ischemic preconditioning.
AB  - Pharmacological evidence has implicated ATP-dependent potassium (KATP) channels
      in the mechanism of ischemic preconditioning; however, the effects of sarcolemmal
      KATP channels on excitability cannot account for the protection. KATP channels
      also exist in mitochondrial inner membrane. To test whether such channels play a
      role in cardioprotection, we simultaneously measured flavoprotein fluorescence,
      an index of mitochondrial redox state, and sarcolemmal KATP currents in intact
      rabbit ventricular myocytes. Our results show that diazoxide, a KATP channel
      opener, induced reversible oxidation of flavoproteins, but did not activate
      sarcolemmal KATP channels. This effect of diazoxide was blocked by 5
      hydroxydecanoic acid (5-HD). We further verified that 5-HD is a selective blocker
      of the mitochondrial KATP channels. These methods have enabled us to demonstrate
      that the activity of mitochondrial KATP channels can be regulated by protein
      kinase C. In a cellular model of simulated ischemia, inclusion of diazoxide
      decreased the rate of cell death to about half of that in control. Such
      protection is inhibited by 5-HD. In conclusion, our results demonstrate that
      diazoxide targets mitochondrial but not sarcolemmal KATP channels, and imply that
      mitochondrial KATP channels may mediate preconditioning.

PMID- 10415521
TI  - Small heat shock proteins and protection against injury.
AB  - The small heat shock proteins alpha B crystallin and HSP27 exert a protective
      effect in response to simulated ischemia. A model is proposed whereby proteins
      not in their final folding state bind to the outside of the large oligomeric
      small heat shock protein complexes thus finding a safe haven during ischemia.
      After the ischemia is resolved, these proteins may be released and, with the help
      of HSP70, are shuttled to a productive refolding pathway resulting in proteins in
      their final folding state, which can assume their normal activity in cells
      recovered from ischemic injury.

PMID- 10415522
TI  - Inhibition of myocardial TNF-alpha production by heat shock. A potential
      mechanism of stress-induced cardioprotection against postischemic dysfunction.
AB  - Overproduction of tumor necrosis factor-alpha (TNF-alpha) contributes to cardiac
      dysfunction associated with systemic or myocardial stress, such as endotoxemia
      and myocardial ischemia/reperfusion (I/R). Heat shock has been demonstrated to
      enhance cardiac functional resistance to I/R. However, the protective mechanisms
      remain unclear. The purpose of this study was to determine: (1) whether cardiac
      macrophages express heat shock protein 72 (HSP72) after heat shock, (2) whether
      induced cardiac HSP72 suppresses myocardial TNF-alpha production during I/R, and
      (3) whether preservation of postischemic myocardial function by heat shock is
      correlated with attenuated TNF-alpha production during I/R. Rats were subjected
      to heat shock (42 degrees C for 15 min) and 24 h recovery. Immunoblotting
      confirmed the expression of cardiac HSP72. Immunofluorescent staining detected
      HSP72 in cardiac interstitial cells including resident macrophages rather than
      myocytes. Global I/R caused a significant increase in myocardial TNF-alpha. The
      increase in myocardial TNF-alpha was blunted by prior heat shock and the reduced
      myocardial TNF-alpha level was correlated with improved cardiac functional
      recovery. This study demonstrates for the first time that heat shock induces
      HSP72 in cardiac resident macrophages and inhibits myocardial TNF-alpha
      production during I/R. These observations suggest that inhibition of myocardial
      TNF-alpha production may be a mechanism by which HSP72 protects the heart against
      postischemic dysfunction.

PMID- 10415523
TI  - Cardiac adaptation to ischemia-reperfusion injury.
AB  - Acute myocardial ischemia initiates a cascade of cellular events that lead to
      irreversible injury. We previously described the transient nature of heat-shock
      induced cardioprotection; treatment with a catalase inhibitor abolished the
      cytoprotective actions without affecting expression levels of HSP71. Repeated,
      transient ischemic episodes augment the ischemic tolerance of affected myocardium
      but the fundamental cytoprotective mechanism(s) for both "early" and "delayed"
      preconditioning remains unclear. Increased cellular induction of protooncogenes,
      heat shock genes, and downstream effector proteins might play critical roles in
      the cytoprotection afforded by delayed preconditioning. We measured c-fos, c-jun,
      c-myc, and hsp70 induction in preconditioned (2 x 5-min ischemia/10-min
      reperfusion) and control rabbit hearts that either underwent 30- or 120-min
      coronary occlusion and 60-min reperfusion, or did not undergo subsequent
      sustained ischemia; the latter hearts were allowed to recover for 0, 1, 3, 6, 24,
      48, 72, or 96 hours. Both c-fos and c-jun in ischemic tissue were strongly
      induced by ischemia-reperfusion injury and preconditioning pretreatment. However,
      expression levels diminished significantly by 1-h reperfusion and remained
      depressed during the 96-h recovery period. Hsp70 (inducible) mRNA expression
      levels were highest primarily in ischemic myocardium after 6-h recovery post
      preconditioning; Hsp70 levels in ischemic myocardium were slightly stronger after
      48-h recovery but subsequently diminished to barely detectable levels by 96-h
      post-preconditioning. Induction of c-fos and c-jun preceded that of Hsp70. These
      findings support the concept that upregulation of immediate early genes and heat
      shock genes plays an important role in myocardial adaptation to acute ischemic
      stress.

PMID- 10415524
TI  - Subcellular remodeling and heart dysfunction in cardiac hypertrophy due to
      pressure overload.
AB  - Rats were treated with etomoxir, an inhibitor of palmitoyltransferase-1, to
      examine the role of a shift in myocardial metabolism in cardiac hypertrophy.
      Pressure overload was induced by abdominal aorta banding for 8 weeks. Sham
      operated animals served as control. Left ventricular dysfunction, as reflected by
      decreased LVDP, +dP/dt, -dP/dt, and elevated LVEDP in the pressure overloaded
      animals, was improved by treatment with etomoxir. Cardiac hypertrophy in pressure
      overload rats decreased the sarcoplasmic reticular (SR) Ca2+ uptake and Ca2+
      release as well as myofibrillar Ca(2+)-stimulated ATPase and myosin Ca(2+)-ATPase
      activities; these changes were attenuated by treatment with etomoxir. Steady
      state mRNA levels for alpha- and beta-myosin heavy chains, SR Ca(2+)-pump, and
      protein content of SR Ca(2+)-pump were reduced in hypertrophied hearts; these
      alterations were prevented by etomoxir treatment. The results indicate that
      modification of changes in myocardial metabolism by etomoxir may prevent
      remodeling of myofibrils and SR membrane and thereby improve cardiac function in
      hypertrophied heart.

PMID- 10415525
TI  - In vitro analysis of SERCA2 gene regulation in hypertrophic cardiomyocytes and
      increasing transfection efficiency by gene-gun biolistics.
AB  - The transcriptional downregulation of the SERCA2 gene is studied using neonatal
      rat cardiomyocytes stimulated with endothelin-1 to induce hypertrophy. Liposome
      based transfection of cells with a 1.9 kb SERCA2 promoter fragment directed
      expression of a reporter gene identical to the downregulation of genomic SERCA2
      expression by endothelin-1. Results of a new gene gun technology for transient
      transfection of cardiomyocytes with a RSV-beta-galactosidase construct are
      reported. This new method for propelling DNA-coated gold beads into
      cardiomyocytes is extremely suitable for directly testing promoter/reporter gene
      DNA constructs since the transfection efficiency (approximately 10%) appears to
      be higher than traditional transfection methods.

PMID- 10415526
TI  - Myocardial response to stress in cardiac hypertrophy and heart failure: effect of
      antihypertensive drugs.
AB  - The myocardium's response to increased stress or load is not stereotyped.
      Differences have been observed in the heart's molecular composition and
      performance characteristics when exposed to stress. Myosin isoforms gradually
      change during development of hypertrophy, whereas collagen levels change only
      during the chronic phase of hypertrophy. Cardiac hypertrophy can regress if
      treated with antihypertensive drugs, but the myocardium of the post-hypertrophic
      heart no longer has the same composition as it did before hypertrophy. In rat
      studies of the effects of antihypertensive drugs on cardiac functional reserve,
      captopril showed a regression of hypertrophy associated with a lower baseline
      stroke volume and, after dobutamine stress, a dose-dependent rise in stroke
      volume. In untreated rates captopril showed no change in stroke volume. In
      hydralazine-treated rats, there was no change in reserve after dobutamine stress,
      whereas propranolol treatment resulted in partial regression and a slight change
      in stroke volume. Overall, our data suggests that development of hypertension and
      hypertrophy plays a role in changes in the molecular structure of the myocardium,
      especially during the chronic phase of hypertrophy and heart failure. This
      complex process cannot be explained by one factor but involves a combination of
      factors. Identification of each factor would be of importance for the development
      of appropriate therapeutic agents.

PMID- 10415527
TI  - Oxidized LDL and atherogenesis.
AB  - A brief review of recent findings regarding the role of oxidized low-density
      lipoproteins (Ox-LDL) in atherogenesis. Lipid peroxidation and oxidative damage
      to LDL make arteries susceptible to chronic inflammation, which is known to cause
      alterations in arterial gene expression and promote lesion development. Treatment
      protocols implementing antioxidants for preventing cardiovascular diseases are
      suggested.

PMID- 10415528
TI  - Effect of antioxidant trace elements on the response of cardiac tissue to
      oxidative stress.
AB  - It is now well established that several trace elements, because of their
      involvement in the catalytic activity and spatial conformation of antioxidant
      enzymes, may contribute to the prevention of oxidative stress such as occurs upon
      reperfusion of ischemic tissue. The aim of this paper is (1) to review the role
      of these trace elements (Cu, Mn, Se, and Zn) in antioxidant cellular defenses in
      the course of post-ischemic reperfusion of cardiac tissue, (2) to provide
      experimental data suggesting that variations in trace element dietary intake may
      modulate the vulnerability of cardiac tissue to ischemia-reperfusion, and (3) to
      discuss in more detail the effect of Mn ions, which seem to play a special
      protective role against reperfusion injury. Some results obtained from
      experiments in animal models of myocardial reperfusion have shown that the
      dietary intake of such trace elements can modulate cardiac activity of
      antioxidant enzymes and, consequently, the degree of reperfusion damage. In
      addition, experimental data on the protective effects of an acute treatment with
      Mn are presented. Finally, experimental evidence on the protective role of salen
      Mn complexes, which exhibit catalytic SOD- and CAT-like activities against
      reperfusion injury, are described. These complexes should be of considerable
      interest in clinical conditions.

PMID- 10415529
TI  - Apoptosis in isolated adult cardiomyocytes exposed to adriamycin.
AB  - Adriamycin (doxorubicin) is a highly potent antineoplastic agent, but its use is
      limited by the risk of developing cardiomyopathy and congestive heart failure.
      Available evidence suggests that adriamycin-induced congestive heart failure is
      mediated by oxidative stress. We examined the possibility of adriamycin-induced
      apoptosis in isolated adult rat cardiomyocytes and its inhibition by trolox, a
      water-soluble antioxidant. Cardiomyocytes isolated from rat hearts were exposed
      to 20 microM adriamycin for 1 h and examined at different post-treatment
      durations (0-23 h). Adriamycin caused a significant decrease in rod-shaped cells
      and an increase in round cells. Both Hoechst 33258 staining and TUNEL assay
      revealed a significantly increased number of apoptotic myocytes and nucleosomal
      fragmentation upon exposure to adriamycin. In agarose gel electrophoresis, DNA
      laddering was found to be more intense in adriamycin-exposed myocytes. A bright
      smear at the leading edge of the gels suggested indiscriminate fragmentation of
      DNA and myocyte necrosis by adriamycin. Both types of DNA degradations due to
      adriamycin were significantly reduced by trolox. We suggest that adriamycin
      induced cell death involves both apoptosis and necrosis and these may be mediated
      by oxidative stress.

PMID- 10415530
TI  - Physical exercise and antioxidant defenses in the heart.
AB  - Cardiac muscle relies highly on aerobic metabolism. Heart muscle has a high
      oxygen uptake at resting conditions, which increases many fold during exhaustive
      physical exercise. Such a high rate of oxidative metabolism is often associated
      with enhanced production of reactive oxygen metabolites. A single bout of
      strenuous exercise has been demonstrated to induce oxidative damage in heart.
      Such oxidant insult may lead to adaptive responses and strengthen antioxidant
      defenses in the heart tissue. Endurance exercise training has indeed been shown
      to upregulate heart tissue antioxidant defenses. Recently, we have observed that
      even predominantly anaerobic sprint training regimens may enhance cardiac
      antioxidant defenses. Regular physical exercise may beneficially influence
      cardiac antioxidant defenses and promote overall cardiac function.

PMID- 10415531
TI  - New insights into cardioprotection by ischemic preconditioning and other forms of
      stress.
AB  - Ischemic preconditioning has not only received wide attention in heart research,
      but has also been a topic of extensive studies involving other organs. In several
      of these studies, it has been shown that in spite of differences in the endpoints
      used to assess protection, the same mediators as in myocardial ischemic
      preconditioning may be involved. However, several of the putative mediators do
      not require ischemia to become activated. This has guided us and others to
      investigate whether the myocardium can also be protected by brief ischemia in
      other organs and whether other non-pharmacological forms of stress, which do not
      produce ischemia but are capable of activating these potential mediators, are
      also cardioprotective.

PMID- 10415532
TI  - Cellular mechanisms of infarct size reduction with ischemic preconditioning. Role
      of calcium?
AB  - Brief episodes of ischemia protect or "precondition" the heart and reduce infarct
      size caused by a subsequent sustained ischemic insult. Despite a decade of
      intensive investigation, the cellular mechanism(s) responsible for this
      paradoxical protection remain poorly understood. In this review, we focus on the
      emerging concept that alterations in intracellular calcium homeostasis may
      participate in either triggering and/or mediating infarct size reduction with
      preconditioning.

PMID- 10415533
TI  - Role of KATP channel in heat shock and pharmacological preconditioning.
AB  - Heat shock (HS) and 4-monophosphoryl lipid A (MLA, a non-toxic analogue of
      endotoxin) protects the myocardium against ischemia-reperfusion injury. We
      studied the involvement of ATP-sensitive potassium channel (KATP channel) in
      ischemic protection induced by these stimuli. Anesthetized rabbits were
      preconditioned with either HS (by raising temperature to 42 degrees C for 15 min)
      or intravenous pretreatment with MLA (35 micrograms/kg). After 24 h, animals were
      re-anesthetized and subjected to 30-min regional ischemia followed by 180-min
      reperfusion (I/R). KATP channel blockers glibenclamide and/or 5-hydroxydecanoate
      (5-HD) were used to inhibit channel function. The 72 kD heat shock protein (HSP
      72) was measured by Western blots. HS produced a marked reduction in infarct size
      (39.4 +/- 8.1% to 14.3 +/- 2.5%, p < 0.05) that was abolished by glibenclamide
      (42.3 +/- 3.2%) and 5-HD (33.7 +/- 4.8%) when given before I/R. These drugs
      failed to block HS protection when given before HS. Expression of HSP-72 was
      increased in all HS groups as compared to non-HS groups in both glibenclamide and
      5-HD-treated rabbits. Similarly, pretreatment with MLA reduced infarct size from
      40 +/- 8.6% to 15.1 +/- 1.5% (p < 0.05). The infarct size increased to 51.9 +/-
      5.8 with 5-HD in MLA-treated rabbits. 5-HD did not alter infarct size
      significantly when given in vehicle-treated control rabbits. These data suggest
      that HS and MLA exert their anti-ischemic effect through activation of KATP
      channel.

PMID- 10415534
TI  - Pharmacologic enhancement of tolerance to ischemic cardiac stress using
      monophosphoryl lipid A. A comparison with antecedent ischemia.
AB  - In comparison with ischemic preconditioning, MLA-mediated cardioprotection seems
      to show numerous common features. Like ischemia, MLA induces a first and second
      window (biphasic profile) of heightened tolerance to ischemia. As with delayed
      ischemic preconditioning, MLA protects against infarction, stunning, and
      arrhythmias associated with ischemia-reperfusion. In contrast with acute ischemic
      preconditioning, MLA reduces infarction and stunning. A role has been
      demonstrated for nitric oxide synthase and KATP channel activation in the
      mechanism of delayed preconditioning induced by ischemia and by MLA. Regarding
      acute preconditioning, kinase and KATP channel activation have been implicated as
      involved in the mechanism of ischemic preconditioning and also in MLA
      cardioprotection. Use of MLA or related compounds as cardioprotectants may
      represent a method for inducing acute tolerance to ischemia-reperfusion injury
      manifested as infarction or stunning, with the added benefit of a sustained
      delayed cardioprotective state being achieved.

PMID- 10415535
TI  - Adaptation to chronic hypoxia confers tolerance to subsequent myocardial ischemia
      by increased nitric oxide production.
AB  - Chronic exposure to hypoxia from birth increased the tolerance of the rabbit
      heart to subsequent ischemia compared with age-matched normoxic controls. The
      nitric oxide donor GSNO increased recovery of post-ischemic function in normoxic
      hearts to values not different from hypoxic controls, but had no effect on
      hypoxic hearts. The nitric oxide synthase inhibitors L-NAME and L-NMA abolished
      the cardioprotective effect of hypoxia. Message and catalytic activity for
      constitutive nitric oxide synthase as well as nitrite, nitrate, and cGMP levels
      were elevated in hypoxic hearts. Inducible nitric oxide synthase was not detected
      in normoxic or chronically hypoxic hearts. Increased tolerance to ischemia in
      rabbit hearts adapted to chronic hypoxia is associated with increased expression
      of constitutive nitric oxide synthase.

PMID- 10415536
TI  - Metabolic changes in the normal and hypoxic neonatal myocardium.
AB  - Hypoxia is characterized by inadequate oxygen delivery to the myocardium with a
      resulting imbalance between oxygen demand and energy supply. Several adaptive
      mechanisms occur to preserve myocardial survival during hypoxia. These include
      both short- and long-term mechanisms, which serve to achieve a new balance
      between myocardial oxygen demand and energy production. Short-term adaptation
      includes downregulation of myocardial function along with upregulation of energy
      production via anaerobic glycolysis following an increase in glucose uptake and
      glycogen breakdown. Long-term adaptation includes genetic reprogramming of key
      glycolytic enzymes. Thus, the initial decline in high-energy phosphates following
      hypoxia is accompanied by a decrease in myocardial contractility and myocardial
      energy requirements are subsequently met by ATP supplied from anaerobic
      glycolysis. Thus, a downregulation in cardiac function and/or enhanced energy
      production via anaerobic glycolysis are the major mechanisms promoting myocardial
      survival during hypoxia. In contrast to the aforementioned metabolic changes
      occurring in adult myocardium, the effects of chronic hypoxia on neonatal
      myocardial metabolism remain undefined. Studies from our laboratory using a novel
      neonatal piglet model of chronic hypoxia have shown a shift in cardiac myocyte
      substrate utilization towards the newborn state with a preference for glucose
      utilization. We have also shown, using this same model, that chronically hypoxic
      neonatal hearts were more tolerant to ischemia than non-hypoxic hearts. This
      ischemic tolerance is likely due to adaptive metabolic changes in the chronically
      hypoxic hearts, such as increased anaerobic glycolysis and glycogen breakdown.

PMID- 10415538
TI  - Activity of cytochrome c oxidase in the right and left ventricular myocardium of
      male and female rats exposed to intermittent high altitude hypoxia.
AB  - The aim of the present study was to compare the capacity of the oxidative
      metabolism (total activity of cytochrome c oxidase, COX) in the right and left
      ventricular myocardium of adult rats exposed to intermittent high altitude (IHA)
      hypoxia simulated in a barochamber (5,000 m, 8 h/day, 5 days/wk, for a total of
      32 exposures). In male and female rats, IHA induced significant increases of the
      right ventricular (RV) weight and protein content, whereas left ventricular (LV)
      weight and protein content remained unaffected. Consequently, the RV/LV ratio in
      both sexes markedly increased. Similarly, IHA induced an increase of the total
      activity of COX in RV in both sexes. The specific activities of COX in homogenate
      as well as in isolated mitochondria were not changed in IHA-exposed animals,
      which indicates that the increase of total activity of COX is proportional to the
      increase of total protein content and RV weight.

PMID- 10415537
TI  - Regulation of cardiovascular development and physiology by hypoxia-inducible
      factor 1.
AB  - Hypoxia is an essential pathophysiologic component of ischemic cardiovascular
      disease. A better understanding of the molecular mechanisms underlying adaptive
      responses to hypoxia may lead to novel therapeutic strategies. Hypoxia-inducible
      factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS domain
      transcription factor that mediates changes in gene expression in response to
      changes in O2 concentration. Genes that are transcriptionally activated by HIF-1
      in hypoxic cells encode proteins that increase O2 delivery or allow metabolic
      adaptation to limited O2 availability. HIF-1 target genes include those encoding
      vascular endothelial growth factor (VEGF), erythropoietin, glucose transporters,
      and glycolytic enzymes. In anemic fetal sheep, increased myocardial
      vascularization was associated with concomitant increases in the expression of
      HIF-1 and VEGF. Expression of HIF-1 target genes was not induced by hypoxia in
      embryonic stem cells lacking expression of the O2-regulated HIF-1 alpha subunit.
      Mouse embryos lacking HIF-1 alpha expression arrested in their development by
      E9.0 and died by E10.5 with cardiovascular malformations and massive cell death
      throughout the embryo. These studies indicate that HIF-1 functions as a master
      regulator of O2 homeostasis that controls the establishment of essential
      physiologic systems during embryogenesis as well as their subsequent utilization
      during fetal and postnatal life.

PMID- 10415539
TI  - Quantitative analysis of collagens and fibronectin expression in human right
      ventricular hypertrophy.
AB  - One of the main features in human tetralogy of Fallot (TF) is right ventricular
      hypertrophy (RVH) due to pressure (sub-pulmonary stenosis) and volume overload
      (ventricular septal defect). Currently, primary correction at a young age is the
      treatment of choice. To unravel the role of extracellular matrix in RVH, we
      examined myocardial expression of collagens and fibronectin in TF patients with
      primary correction (TF1, age 0.7 +/- 0.2 yr.), secondary surgery (TF2, age 36.9
      +/- 4.6 yr), and in age-matched control patients. Sirius red staining quantified
      by video imaging showed significantly increased interstitial staining for
      collagens in both TF1 and TF2 groups as compared to respective controls.
      Fibronectin was expressed in extracellular spaces, perivascular regions, and in
      some cardiomyocytes. Quantitative analysis of fibronectin revealed increased
      expression in only TF1 group as compared to respective control. Our results
      indicate an increased amount of myocardial extracellular matrix deposition as a
      sign of fibrosis during RVH in patients with TF.

PMID- 10415540
TI  - Interaction of bradykinin with angiotensin, prostacyclin, and nitric oxide in
      myocardial preservation.
AB  - This review focuses on the importance of bradykinin in myocardial preservation
      during ischemic arrest. Bradykinin is released from the heart spontaneously in
      response to ischemic stress, which may be viewed as a survival signal of the
      heart against ischemia. Bradykinin appears to function as a signaling molecule by
      controlling the release of other intracellular modulators, such as prostacyclins
      and nitric oxide, which also exert beneficial effects on the ischemic myocardium.

PMID- 10415541
TI  - Alternatives for myocardial protection: adenosine-enhanced ischemic
      preconditioning.
AB  - Intrinsic to the development of new myoprotective protocols for use in cardiac
      surgery are the requirements of new protocols to be equal to or better than
      conventional cardioplegia in providing for enhanced post-ischemic functional
      recovery and decreased myocardial infarct size. Our data suggest that adenosine
      enhanced ischemic preconditioning, in which a bolus injection of adenosine to the
      myocardium is used coincident with ischemic preconditioning, meets these
      requirements, providing equal cardioprotection as that of cold blood
      cardioplegia, significantly decreasing myocardial infarct size and significantly
      enhancing post-ischemic myocardial functional recovery in both the isolated
      perfused rabbit heart and in the in situ blood-perfused sheep heart. These
      results further suggest that adenosine-enhanced ischemic preconditioning may
      provide an effective, alternative myocardial protective protocol to reduce the
      morbidity and mortality in cardiac surgery.

PMID- 10415543
TI  - Surgical stress and the heat shock response: in vivo models of stress
      conditioning.
AB  - All forms of surgical therapy are stressful and injurious. The majority of
      surgical procedures are performed electively and provide an opportunity to
      condition the patient before surgery to maximize outcome. We have successfully
      protected the spinal cord and kidneys from warm ischemia-reperfusion injury with
      whole-body heat shock (42.5 degrees C, 15 min, HS) and recovery (37 degrees C, 6
      8 h) before acute aortic occlusion. Control rabbits experienced an 88% incidence
      of paralysis (7/8) after acute spinal cord ischemia, while HS-pretreated animals
      never became paralyzed (0/9, p < 0.001). Control pig kidneys showed partial
      function (4/8 survival) after 90-min warm ischemia, while HS-pretreated kidneys
      always functioned (8/8 survival, p < 0.04). A positive temporal association was
      made between the HS-associated functional protection and the enhanced expression
      of inducible HSP70. The induction of the heat-shock response (cellular stress
      response) to protect tissues from lethal acute ischemia-reperfusion injury could
      be employed in a wide range of medical and surgical settings.

PMID- 10415542
TI  - Optimal myocardial preconditioning in humans.
AB  - We developed a model of ischemia and reperfusion (I and R) in human ventricular
      myocytes (CM). CM injury and metabolics were studied after various interventions:
      endogenous preconditioning (PC) with anoxia, hypoxia, and anoxic or hypoxic
      supernatants; endogenous PC with or without SPT or adenosine deaminase; and
      exogenous adenosine PC before, during, or after I or continuously, with or
      without SPT. To assess the clinical implications of PC and the possible mediating
      effects of adenosine, patients undergoing elective coronary bypass surgery (CABG)
      received either a high or low dose of adenosine. Patients not receiving adenosine
      served as controls. Adenosine levels, high-energy phosphate levels, the metabolic
      parameters were evaluated from blood samples and left ventricular biopsy samples.
      Our cellular model studies indicated that preconditioning conferred protection to
      human CM via an adenosine-mediated pathway. Adenosine simulated PC without a fall
      in ATP. Adenosine administered to patients during CABG stimulated myocardial
      metabolism while preventing the degradation of high energy phosphates. A
      prospective randomized trial of adenosine administered to high-risk patients for
      myocardial protection is required.

PMID- 10415544
TI  - The role of the myocardial sodium-hydrogen exchanger in mediating ischemic and
      reperfusion injury. From amiloride to cariporide.
AB  - There is convincing evidence that the Na-H exchanger (NHE) plays a pivotal role
      in mediating tissue injury during ischemia and reperfusion. Extensive studies
      with NHE inhibitors have consistently shown protective effects against ischemic
      and reperfusion injury in a large variety of experimental models and animal
      species, particularly in terms of attenuating contractile dysfunction. These
      protective effects of NHE inhibition appear to be superior to other strategies,
      including ischemic preconditioning. Such studies have contributed greatly to the
      overwhelming evidence that NHE activation mediates ischemic and reperfusion
      injury. The NHE inhibitor HOE 642 (cariporide) is currently undergoing clinical
      evaluation in high-risk cardiac patients. Moreover, there is now emerging
      evidence that NHE may be involved in mediating cardiotoxicity directly produced
      by various ischemic metabolites such as lipid amphiphiles or reactive oxygen
      species. NHE inhibition also attenuates apoptosis in the ischemic myocardium, a
      process that may be of importance in the subsequent development of postinfarction
      heart failure. In conclusion, NHE represents an important adaptive process in
      response to intracellular acidosis that results in a paradoxical contribution to
      cardiac tissue injury.

PMID- 10415545
TI  - Regulation of cardiac sarcolemmal Na+/H+ exchanger activity by endogenous
      ligands. Relevance to ischemia.
AB  - The cardiac sarcolemmal Na+/H+ exchanger (NHE) extrudes one H+ in exchange for
      one Na+ entering the myocyte, utilizing for its driving force the inwardly
      directed Na+ gradient that is maintained by the Na+/K+ ATPase. The exchanger is
      quiescent at physiological values of intracellular pH but becomes activated in
      response to intracellular acidosis. Recent evidence suggests that a variety of
      extracellular signals (e.g., adrenergic agonists, thrombin, and endothelin) also
      modulate sarcolemmal NHE activity by altering its sensitivity to intracellular
      H+. Since sarcolemmal NHE activity is believed to be an important determinant of
      the extent of myocardial injury during ischemia and reperfusion, regulation of
      exchanger activity by endogenous ligands associated with ischemia is likely to be
      of pathophysiological importance.

PMID- 10415546
TI  - Na+/H+ exchangers. Molecular diversity and relevance to heart.
AB  - During the last several years, significant advances have been made in our
      understanding of the molecular, cellular, and physiological diversity of
      mammalian Na+/H+ exchangers. This transporter forms a multigene family of at
      least six members (NHE1-NHE6) that share approximately 20-60% amino acid
      identity. NHE1 is the most predominant isoform expressed in heart and it
      contributes significantly to myocardial pHi homeostasis, which is important for
      maintaining contractility. However, hyperactivation of NHE1 during episodes of
      cardiac ischemia and reperfusion disrupts the intracellular ion balance, leading
      to cardiac dysfunction and damage in several animal models, but which can be
      prevented by pharmacological antagonists of NHE1. Molecular studies have
      indicated that the predicted transmembrane segments M4 and M9 contain several
      residues involved in drug sensitivity. Molecular dissection of the drug binding
      region should facilitate the rational design of more potent and isoform-specific
      drugs that may provide therapeutic benefit in the prevention of cardiac ischemia
      and reperfusion injuries.

PMID- 10415548
TI  - Nitric oxide prevents myoglobin/tert-butyl hydroperoxide-induced inhibition of
      Ca2+ transport in skeletal and cardiac sarcoplasmic reticulum.
AB  - Interaction of hydrogen peroxide or organic hydroperoxides with hemoproteins is
      known to produce oxoferryl hemoprotein species that act as very potent oxidants.
      Since skeletal and cardiac muscle cells contain high concentrations of myoglobin
      this reaction may be an important mechanism of initiation or enhancement of
      oxidative stress, which may impair their Ca2+ transport systems. Using skeletal
      and cardiac sarcoplasmic reticulum (SR) vesicles, we demonstrated by EPR the
      formation of alkoxyl radicals and protein-centered peroxyl radicals in the
      presence of myoglobin (Mb) and tert-butyl hydroperoxide (t-BuOOH). The low
      temperature EPR signal of the radicals was characterized by major feature at g =
      2.016 and a shoulder at g = 2.036. In the presence of SR vesicles, the magnitude
      of the protein-centered peroxyl radical signal decreased, suggesting that the
      radicals were involved in oxidative modification of SR membranes. This was
      accompanied by SR membrane oxidative damage, as evidenced by accumulation of 2
      thiobarbituric acid-reactive substances (TBARS) and the inhibition of Ca2+
      transport. We have shown that nitric oxide (NO), reacting with redox-active heme
      iron, can prevent peroxyl radical formation activated by Mb/t-BuOOH. Incubation
      of SR membranes with an NO donor, PAPA/NO (a non-thiol compound that releases NO)
      at 200-500 microM completely prevented the t-BuOOH-dependent production of
      peroxyl radicals and formation of TBARS, and thus protected against oxidative
      inhibition of Ca2+ transport.

PMID- 10415547
TI  - Nitric oxide and the vascular endothelium in myocardial ischemia-reperfusion
      injury.
AB  - The normal coronary vascular endothelium (VE) tonically releases nitric oxide
      (NO) by converting L-arginine to citrulline by a constitutive NO synthase.
      Reperfusion after myocardial ischemia reduces basal and stimulated release of NO.
      This "vascular reperfusion injury" is mediated largely by neutrophils (PMN)
      through specific interactions between adhesion molecules on the endothelium and
      the PMN, an interaction that precedes myocyte injury. NO inhibits the PMN
      mediated reperfusion injury by direct effects on both the PMN and the vascular
      endothelium. Cardioprotective strategies include augmentation of endogenous NO by
      the precursor L-arginine and the administration of exogenous NO donors at the
      time of perfusion, which (1) attenuates PMN adherence to the coronary artery and
      venous endothelium, (2) reduces PMN-mediated endothelial dysfunction, (3) reduces
      PMN accumulation in the area at risk, and (4) reduces infarct size. Hence, NO
      represents a powerful therapeutic tool with which to attenuate the consequences
      of ischemia-reperfusion injury on vascular injury and infarction.

PMID- 10415549
TI  - Role for NADPH/NADH oxidase in the modulation of vascular tone.
AB  - The endothelium modulates vascular tone by producing vasodilator and
      vasconstrictor substances. Of these, the best characterized and potentially most
      important are nitric oxide (NO.) and O2-.. These small molecules exhibit opposing
      effects on vascular tone and chemically react with each other in a fashion that
      negates their individual effects and leads to the production of potentially toxic
      substances, such as peroxynitrite (ONOO-). These dynamic interactions may likely
      have important implications, altering not only tissue perfusion but also
      contributing to the process of atherosclerosis. The precise O2-. source within
      vascular tissue remains to be determined. Recent work demonstrated that in
      endothelial cells as well as in vascular smooth muscle cells, a membrane
      associated NAD(P)H-dependent oxidase represents the most significant O2-. source.
      Interestingly, this oxidase is activated upon stimulation with angiotension II,
      suggesting that under all conditions of an activated circulating and/or local
      renin-angiotensin system endothelial dysfunction secondary to increased vascular
      O2-. production is expected.

PMID- 10415550
TI  - Differential regulation of apoptosis by ischemia-reperfusion and ischemic
      adaptation.
AB  - Ischemia and reperfusion injure the heart, as manifested by myocardial
      infarction, postischemic ventricular functional dysfunctions, arrhythmias, and
      cardiomyocyte apoptosis. Hearts can be adapted to ischemic-reperfusion injury by
      subjecting them to non-lethal cyclic episodes of short-term ischemia and
      reperfusion. The adapted myocardium becomes resistant to subsequent lethal
      ischemic injury. Reactive oxygen species and oxidative stress play crucial roles
      in the pathophysiology of ischemic-reperfusion injury. The adapted hearts, when
      subjected to subsequent ischemia and reperfusion, generate a reduced amount of
      oxygen free radicals compared to the nonadapted hearts. The number of
      cardiomyocytes undergoing apoptotic cell death is reduced in the adapted hearts
      subjected to ischemia and reperfusion. In concert, the adapted myocardium is
      associated with increased antioxidant gene Bcl-2, increased binding activity of
      the nuclear transcription factor NF kappa B, and reduced binding activity of AP-1
      compared to nonadapted hearts. Yet when nonadapted hearts are subjected to
      ischemia and reperfusion, Bcl-2 is down-regulated while NF kappa B is moderately
      upregulated and AP-1 is significantly upregulated.

PMID- 10415551
TI  - Apoptosis in myocardial ischemia-reperfusion.
AB  - The signal transduction pathways by which ischemia-reperfusion leads to apoptosis
      may involve the JNK pathway, ceramide generation, and inhibition of protective
      PKC pathways. The biochemical events associated with apoptosis include
      mitochondrial inactivation, cytochrome c dislocation, caspase activation, and
      cytoplasmic acidification. Through the concerted efforts of multiple classes of
      enzymes, apoptosis is accomplished, resulting in the death of a cell in which
      potentially transforming oncogenes have been degraded and inflammatory contents
      are contained within the plasma membrane until the fragments can be ingested by
      phagocytes. This non-inflammatory mode of cell death permits tissue remodeling
      with minimal scar formation, and so is preferable to necrotic cell death. The
      distinction between apoptosis and necrosis, which implies different mechanisms of
      cell death, is blurred in the case of a pathologic insult such as ischemia
      reperfusion. It is suggested that it is more useful to view cell death in the
      context of whether or not it can be prevented.

PMID- 10415552
TI  - Stress signal to survival and apoptosis.
AB  - This investigation focused on whether apoptosis can be observed in some heart
      diseases. Apoptosis was examined immunochemically using monoclonal antibodies
      such as p53, Bcl-2 and cyclin E, A, and B1 in parallel with flow cytometry. Left
      ventricular myocardium was obtained at autopsy from 40 patients with acute
      myocarditis (AM; N = 10, 6 males, 4 females, mean age 56 +/- 13 years), chronic
      myocarditis (CM; N = 10, 5 males, 5 females, mean age 48 +/- 16 years), dilated
      cardiomyopathy (DCM; N = 10, 7 males, 3 females, mean age 60 +/- 11 years), and
      no heart disease (Cont; N = 10, 5 males, 5 females, mean age 63 +/- 14 years).
      Cell cycle analysis of myocytes by flow cytometry revealed that the relative
      content of G2M phase in acute myocarditis was far higher than those in other
      heart diseases (AM, 12.3 +/- 3.7%; CM, 5.2 +/- 4.5%; DCM, 6.3 +/- 4.0%; Cont, 3.4
      +/- 1.8%; Mean +/- SD). Expression of p53 was observed mainly in myocytes from
      chronic myocarditis. Expression of Bcl-2, on the other hand, was detected in
      myocytes from acute myocarditis. Results suggest that apoptosis may play some
      role in the repairing process of myocardial inflammation.

PMID- 10415553
TI  - Bioartificial organs. Risks and requirements.

PMID- 10415554
TI  - Control of complement activities for immunoisolation.
AB  - Immunoisolation of cells by semipermeable membranes is a most promising approach
      to transplant xenogeneic cells. Although membranes which allow
      xenotransplantation have been reported, ambiguity remains as to their long term
      effectiveness. In this review, we would like to reconsider the immuno-isolative
      effectiveness of membranes reported from the standpoint of permeability and
      present our strategy to prepare membranes that can realize long-term functioning
      of xenograft. There are distinct different types of semi-permeable membranes,
      hydrogel membranes and ultrafiltration membranes. Studies on their permeability
      indicated that neither of these membranes effectively fractionate solutes on the
      basis of molecular size under a diffusion-controlled process, nor thus can they
      immuno-isolate xenograft for a long time. Humoral immunity including antibodies
      and complement proteins is suspected of playing a major role in the rejection of
      xenografts. Control of complement cytolytic activities, not antibody permeation,
      may be a key factor determining the fate of the xenograft enclosed in membranes.
      We found that the microbead containing poly(styrene sulfonic acid) can consume
      complement cytolytic activities and thus can effectively protect xenogeneic
      islets of Langerhans in diabetic mice from the humoral immunity.

PMID- 10415555
TI  - Designing biomaterials to direct biological responses.
AB  - We have set forth a design strategy for creating biomimetic materials that direct
      the formation of tissue surrounding implants or regeneration within porous
      scaffolds. Our studies have established that heterogeneous mimetic peptide
      surfaces (MPS) containing both the -RGD- (cell-binding) and-FHRRIKA- (putative
      heparin-binding) peptides, unique to BSP, in the ratio of 75:25 (MPS II) or 50:50
      (MPS III) proved to be more biologically relevant and specific for RCO cell
      function. The initial response of human osteoblast-like cells to these surfaces
      was mediated by the collagen (alpha 2 beta 1) and vitronectin receptors (alpha v
      beta 3), whereas the vitronectin receptor alone dominated longer-term events (>
      30 min). MPS II and III surfaces enhanced cell spreading and long-term events
      such as mineralization of the extracellular matrix compared to homogenous peptide
      surfaces and controls. Furthermore, extensive mineralization of the ECM deposited
      by RCOs occurred when the peptide was coupled to an interfacial interpenetrating
      polymer network (IPN) that resisted protein deposition (i.e., non-specific
      adsorption) and fouling. Work on thermo-reversible P(NIPAAm-co-AAc) hydrogels
      demonstrated the ability to create materials that can be delivered to the body in
      a minimally invasive manner and support tissue regeneration. These hydrogels can
      be modified to incorporate biofunctional components such as the biomimetic
      peptides, theoretically enhancing their ability to foster tissue regeneration.
      These results suggest that biomaterials can be engineered to mimic ECM components
      of bone (e.g., various organs) by grafting peptides in the appropriate ratios of
      the cell and heparin-binding domains, and ultimately modulate the expression of
      the osteoblast cell phenotype. Approaches similar to the one presented in this
      work can be used to design materials for hybrid artificial organs and other
      tissues.

PMID- 10415556
TI  - New microcapsules based on oligoelectrolyte complexation.
AB  - A new one-step microencapsulation procedure has been developed. For the
      alginate/oligochitosan system the molar mass of the chitosan is a key parameter
      in the formation of stable, elastic capsules with high modulus. Furthermore, the
      selection of an optimum molar mass provides an additional degree of freedom,
      permitting the simultaneous regulation of mechanical properties and permeability
      without the need for multicomponent organic-inorganic chemistries as have been
      previously employed. The effects of molar mass of chitosan, its concentration,
      the alginate molar mass and its metal salt on the preparation, physical
      properties, and release characteristics of the capsules have been studied.

PMID- 10415557
TI  - Development of cellulose sulfate-based polyelectrolyte complex microcapsules for
      medical applications.
AB  - Microencapsulation, as a tool for immunoisolation for allogenic or xenogenic
      implants, is a rapidly growing field. However most of the approaches are based on
      alginate/polylysine capsules, despite this system's obvious disadvantages such as
      its pyrogenicity. Here we report a different encapsulation system based on sodium
      cellulose sulfate and polydiallyldimethyl ammonium chloride for the encapsulation
      of mammalian cells. We have characterized this system regarding capsule
      formation, strength and size of the capsules as well as viability of the cells
      after encapsulation. In addition, we demonstrate the efficacy of these capsules
      as a "microfactory" in vitro and in vivo. Using encapsulated hybridoma cells we
      were able to demonstrate long-term release of antibodies up to four months in
      vivo. In another application we could show the therapeutic relevance of
      encapsulated genetically modified cells as an in vivo activation center for
      cytostatic drugs during tumor therapy.

PMID- 10415559
TI  - Artificial cells, encapsulation, and immobilization.
AB  - The basic principles of artificial cells, encapsulation and immobilization form
      the basis for a number of bioartificial organs. Hemoperfusion based on
      encapsulated adsorbent has been in routine clinical uses for many years to remove
      toxins or drugs from the circulating blood. Blood substitutes based on
      crosslinked hemoglobin or encapsulated hemoglobin are being developed and tested
      in phase II and Phase III clinical trials. Enzyme therapy using microencapsulated
      enzymes have been studied in animal studies and in a preliminary human study.
      Encapsulation or other ways of immobilization of cells are being developed
      extensively by many groups. This includes the encapsulation or immobilization of
      islets, hepatocytes and genetically engineered cells.

PMID- 10415558
TI  - Radiation sterilization of a bifunctional cement formulation of hydroxilapatite
      plaster-polymers.
AB  - A sterilization method based on the use of gamma ionizing radiation was applied
      to a cement formulation of hydroxilapatite, plaster and polymers to be used in
      bone restorations in dental, aesthetic, and neurological surgery. After the
      cement was exposed to a dose of 21.5 kGy it reached the sterility assurance level
      which was necessary for its employment in surgical applications as specified by
      International Standard ISO ordinate 11137: Radiation Sterilization of Health Care
      Products. No variation in the initial cement composition or processing
      parameters, such as working or setting time and molding quality was observed due
      to sterilization. Its characteristics as a drug delivery system were also not
      affected. Therefore, radiation sterilization provides a feasible alternative to
      conventional sterilization methods such as dry/wet heat and ethylene oxide.

PMID- 10415560
TI  - Physico-chemical and mass transfer considerations in microencapsulation.
AB  - To gain better insight into mass transfer problems in encapsulated cell systems
      requires a combination of experimental investigations and mathematical modeling.
      Specific mass transfer studies are reviewed including oxygen transfer in
      immobilized animal cell culture bioreactors, modeling of polymer droplet
      formation and encapsulated animal cell growth, and growth of somatic tissue
      encapsulated in alginate using electrostatics. Special emphasis is given to
      electrostatic droplet generation for cell immobilization.

PMID- 10415561
TI  - In situ electrochemical oxygen generation with an immunoisolation device.
AB  - The viability and function of transplanted tissue encapsulated in immunobarrier
      devices is subject to oxygen transport limitation. In this study, we have
      designed and used an in situ electrochemical oxygen generator which decomposes
      water electrolyticaly to provide oxygen to the adjacent planer immunobarrier
      diffusion chamber. The rate of oxygen generation, which increases linearly with
      electrical current, was accurately controlled. A theoretical model of oxygen
      diffusion was also developed and was used to calculate the oxygen profiles in
      some of the experimental systems. In vitro culture experiments were carried out
      with beta TC3 cells encapsulated in titanium ring devices. The growth and
      viability of cells with or without in situ oxygen generation was studied. We
      found that under otherwise similar culturing conditions, the thickness of the
      cell layer and the viability of cells was the highest in devices cultured in
      stirred media with oxygen generation, even though the thickness had not reached
      the theoretically predicted value, and lowest in those unstirred and without
      oxygen generation.

PMID- 10415562
TI  - Conformal coating of small particles and cell aggregates at a liquid-liquid
      interface.
AB  - Polymer encapsulation of allogeneic or xenogeneic tissue is under active
      investigation as a means of isolating transplanted cells, such as pancreatic
      islets, from the immune system. We report here a method for coating small
      particles and cell aggregates with a very thin water insoluble hydroxyethyl
      methacrylate-methyl methacrylate (HEMA-MMA) membrane that conforms to the shape
      of the aggregate, and minimizes the polymer's contribution to the total
      transplant volume. Cell aggregates were coated at a liquid-liquid interface of a
      discontinuous density gradient composed of both aqueous and organic liquids. By
      increasing the viscosity difference and decreasing the density difference between
      the two liquids of the coating interface, coatings from approximately 1 to 15
      microns thick were formed. Aggregates of HepG2 cells and pancreatic islets were
      coated and remained viable.

PMID- 10415563
TI  - New multicomponent capsules for immunoisolation.
AB  - A new generation of microcapsules based on the use of oligomers which participate
      in polyelectrolyte complexation reactions has been developed. These freeze-thaw
      stable capsules have been applied as a bioartificial pancreas and have resulted
      in normoglycemia for periods of six months in concordant xenotransplantations.
      The new chemistry permits the control of permeability and mechanical properties
      over a wide range and can be adapted both to microcapsule and hollow fiber
      geometries rendering it a robust tool for encapsulation in general. Methods, and
      metrics, for the characterization of the mechanical properties and permeability
      of microcapsules are presented.

PMID- 10415564
TI  - Encapsulation for somatic gene therapy.
AB  - With the human genome project approaching its completion date of 2005, gene-based
      technology will play an increasingly important role in health-care delivery. Non
      autologous somatic gene therapy is a novel application in which non-autologous
      cell lines engineered to secrete a recombinant protein are enclosed within
      immunoisolation devices and implanted into all patients requiring the same
      product for therapy. The development of this technology requires a multi
      disciplinary effort towards optimization of the biomaterial used to manufacture
      the implantable devices and selection of the appropriate cell lines for
      enclosure. The efficacy of this technology is illustrated in the treatment of
      dwarfism and lysosomal storage disease in murine models. The potential of a safe
      and cost-effective gene-based delivery method should have wide applications in
      treating both classical genetic disorders and non-Mendelian diseases.

PMID- 10415565
TI  - Review--the use of immunosuppressive agents to prevent neutralizing antibodies
      against a transgene product.
AB  - A potential obstacle to successful gene therapy for some patients is the in vivo
      production of neutralizing antibodies against the recombinant therapeutic product
      delivered. This is a problem inherent to all gene therapy methods, regardless of
      the vector used to deliver the protein. This clinical situation can be mimicked
      in animal models by delivering a foreign protein (i.e., a human protein) to the
      animal to provoke anti-human protein antibody production. The efficacy of
      different immunosuppressive treatments to inhibit the development of neutralizing
      antibodies can then be investigated. The immunosuppressive agents examined here
      include drugs (e.g., cyclophosphamide, FK506), cytokines (e.g., interferon-gamma,
      interleukin-12), and monoclonal antibodies (e.g., anti-CD4, anti-gp39, CTLA4-Ig).
      It has been found that a high level of antibody suppression is necessary to allow
      prolonged delivery of a foreign protein. Immunosuppressive agents capable of this
      high level of suppression will be important adjuncts to prevent treatment
      failures in situations where patients are at risk of developing neutralizing
      antibodies.

PMID- 10415566
TI  - Potential application of neonatal porcine islets as treatment for type 1
      diabetes: a review.
AB  - Islet transplantation has been shown to be a viable option for treating patients
      with type 1 diabetes. However, widespread clinical application of this treatment
      will necessitate an alternative source of insulin-producing tissue. Porcine
      pancreata may be a potential source of islets since pigs are inexpensive, readily
      available, and exhibit morphological and physiological characteristics comparable
      to humans. Recently, we developed a simple, standardized procedure for isolating
      large numbers of neonatal porcine islets with a reproducible and defined cellular
      composition. Following nine days of in vitro culture, tissue from one neonatal
      pig pancreas yielded approximately 50,000 islet cell aggregates, consisting of
      primarily epithelial cells (57%) and pancreatic endocrine cells (35%). In
      addition, neonatal porcine islets were responsive to glucose challenge in vitro
      and were capable of correcting hyperglycemia in alloxan-induced diabetic nude
      mice. Although neonatal porcine islets constitute an attractive alternative
      source of insulin-producing tissue for clinical transplantation, many aspects
      such as the immunological responses to these tissue and the latent period (2 to 8
      weeks) between transplantation of these islets and the reversal of hyperglycemia
      need further investigation. This article discusses these issues and presents
      possible solutions to problems that may hinder the potential application of
      neonatal porcine islets for transplantation into patients with type 1 diabetes.

PMID- 10415567
TI  - Clinical islet transplantation: a review.
AB  - For decades, the inability of insulin therapy to physiologically control glycemia
      in type I diabetic patients has motivated the search for insulin-delivering
      grafts. Islet autotransplantation is such a therapeutic approach to prevent
      diabetes mellitus following a major pancreatectomy, whereas allotransplantation
      is generally prescribed for type I diabetic patients with a functional solid
      organ graft, or for patients awaiting one. As of today, over 150 patients have
      been autotransplanted world-wide, following total or subtotal pancreatectomy,
      permitting an insulin-independence in nearly 40% of patients. Furthermore, more
      than 350 islet allotransplantations have been performed. Recent results show
      improved metabolic control in over 50% of cases and insulin-independence in
      approximately 20%. This chapter presents a literature review including
      preliminary human islet transplantation data from the University of Geneva.

PMID- 10415568
TI  - Islet cryopreservation protocols.
AB  - Low temperature banking of islets has facilitated ongoing clinical trials,
      allowing for the collection and long-term storage of islets during which
      viability and sterility assessment can be carried out. Islets from most species
      of animals have been cryopreserved using various freeze-thaw protocols; however,
      the best to date is slow cooling to -40 degrees C and rapid thawing from -196
      degrees C. If one carefully follows the three distinct steps of freezing and
      thawing human islets can be successfully cryopreserved, allowing for the
      establishment of a low temperature bank with diverse HLA (Human Leukocyte
      Antigen) and ABO phenotypes. Using a combination of fresh and cryopreserved
      islets to transplant type I diabetic patients, long-term insulin independence has
      been obtained.

PMID- 10415569
TI  - Bioartificial pancreas: alternative supply of insulin-secreting cells.
AB  - In this study, insulin secretion function of INS-1 cells immunoisolated in
      microcapsules was evaluated. Following encapsulation, the immunoisolated INS-1
      cells continued to propagate and flourish within the microcapsules during the
      entire two-month in vitro incubation period. The insulin secretion from
      encapsulated INS-1 cells following seven days of in vitro culture increased from
      1.6 +/- 0.2 ng/2h/10(6) cells in a glucose-free medium to 11.5 +/- 2.1
      ng/2h/10(6) cells at 16.7 mM glucose. In vivo, transplants of 1.2 x 10(7) cells
      into each of six diabetic C57BL/6 mice resulted in the restoration of
      normoglycemia in all graft recipients for up to 60 days post transplantation.
      Most capsules recovered from two animals 30 days post transplantation were free
      of cell overgrowth and physically intact. Immunostaining for insulin of the cells
      within the recovered capsules clearly indicated the presence of insulin. The
      presented data demonstrate the potential use of an immunoisolated beta-cell line
      for the treatment of diabetes.

PMID- 10415571
TI  - Evaluation of graft-host response for various tissue sources and animal models.
AB  - The efficacy of pancreatic islet transplants in correcting hyperglycemia and
      slowing the progression of complications in diabetics has been confirmed by many
      experimental and clinical studies. Unfortunately, the availability of human
      islets is extremely limited and, therefore, treatment of large numbers of human
      diabetic patients will almost certainly require either the use of islets
      harvested from animals (xenografts) or the use of insulin-secreting genetically
      modified cells of either human or animal origin. There is currently no effective
      regimen which will allow long-term survival of xenogeneic islets from widely
      unrelated donor-recipient combinations, such as pig-to-rodent, pig-to-dog, or pig
      to-primate. There is considerable interest in the development of immunoisolation
      techniques for protection of donor islets. However, most materials used in
      immunoisolation devices are relatively bio-incompatible. Poly-L-lysine-alginate
      microcapsules are biocompatible and provide an optimal geometry for transmembrane
      diffusion of insulin and nutrients. Microcapsules allow long-term survival of
      xenogeneic islets in diabetic rodents or dogs with induced diabetes. However,
      mice and rats with spontaneous diabetes destroy encapsulated islet grafts within
      2 to 3 weeks. Biopsies reveal large numbers of macrophages, immunoglobulins and
      limited numbers of helper and cytotoxic T-cells in the peri-microcapsule
      environment of the peritoneal cavity. Cytokines have been identified in
      peritoneal fluid from mice with islet grafts and may play a role in encapsulated
      islet destruction. Targeted immunomodulation by treatment of recipients with
      either anti-helper T-cell antibodies, or fusion proteins which block
      costimulatory interactions between antigen presenting cells and host T-cells have
      demonstrated synergy in significant prolongation of encapsulated islet xenograft
      survival in NOD mice with spontaneous diabetes. Technical improvements in
      microcapsule design also have contributed to prolonged graft survival. "Double
      wall" microencapsulation provides a more durable microcapsule and islet
      pretreatment prior to encapsulation reduces the frequency of defective capsules
      with islets entrapped in the membrane. Long-term durability of encapsulated islet
      grafts remains a concern and further improvements in microcapsule design are a
      prerequisite to clinical trials.

PMID- 10415570
TI  - Transplantation of pancreatic islets contained in minimal volume microcapsules in
      diabetic high mammalians.
AB  - To minimize technical problems relating to excessive size (600-800 mu in
      diameter) of standard alginate microcapsules (CSM) for pancreatic islet graft
      immunoisolation, we have developed two novel minimal volume, chemically
      identical, capsule prototypes (MVC): 1) coherent microcapsules (CM), and 2)
      medium-size microcapsules (300-400 mu, MSM). CM, which envelop each individual
      islet within a thin alginate hydrogel cast, are prepared by emulsification,
      whereas MSM are made by atomizing the islet-alginate suspension through a special
      microdroplet generator. Upon graft into diabetic rodents, CM have shown to
      immunoprotect both allo- and xenogeneic nondiscordant islets, and restored
      normoglycemia. In higher mammals, at subtherapeutic doses, CM fully
      immunoprotected islet allografts (pig-->pig), but only temporarily xenografts
      (dog-->pig). We then used MSM to immunoisolate canine islet allografts in the
      peritoneal cavity of dogs with spontaneous insulin-dependent diabetes. Of three
      grafted dogs, two showed full remission of hyperglycemia with insulin withdrawal.
      MSM could represent an intermediate solution between CSM and CM for peritoneal
      immunoisolated islet transplants.

PMID- 10415572
TI  - Antigen presentation pathways for immunity to islet transplants. Relevance to
      immunoisolation.
AB  - Tremendous advances have been made over the past several years in the development
      of diverse biocompatible materials and structural designs for the implantation of
      immunoisolated cells and tissues. This area of bioengineering has clear
      application to insulin-dependent diabetes for which the implantation of micro- or
      macroencapsulated pancreatic islets or surrogate beta cells has great potential
      therapeutic benefit. This discussion concentrates on three antigen-specific
      immunologic processes that impede the application of islet transplantation as a
      therapy for insulin-dependent diabetes: (1) Allograft immunity, (2) Xenograft
      immunity, and (3) Autoimmune pathogenesis of Type I diabetes. Special emphasis is
      placed on the potential impact of these immune pathways on immunoisolated
      tissues.

PMID- 10415573
TI  - Factors in xenograft rejection.
AB  - Important mechanisms underlying immediate xenograft loss by hyperacute rejection
      (HAR), in the pig-to-primate combination, have been recently delineated. There
      are now several proposed therapies that deal with the problem of complement
      activation and xenoreactive natural antibody (XNA) binding to the vasculature
      that have been shown to prevent HAR. However, vascularized xenografts are still
      lost, typically within days, by delayed xenograft rejection (DXR), alternatively
      known as acute vascular rejection (AVR). This process is characterized by
      endothelial cell (EC) perturbation, localization of XNA within the graft
      vasculature, host NK cell and monocyte activation with platelet sequestration and
      vascular thrombosis. Alternative immunosuppressive strategies, additive anti
      complement therapies with the control of any resulting EC activation processes
      and induction of protective responses have been proposed to ameliorate this
      pathological process. In addition, several potentially important molecular
      incompatibilities between activated human coagulation factors and the natural
      anticoagulants expressed on porcine EC have been noted. Such incompatibilities
      may be analogous to cross-species alterations in the function of complement
      regulatory proteins important in HAR. Disordered thromboregulation is potentially
      relevant to the progression of inflammatory events in DXR and the disseminated
      intravascular coagulation seen in primate recipients of porcine renal xenografts.
      We have recently demonstrated the inability of porcine tissue factor pathway
      inhibitor (TFPI) to adequately neutralize human factor Xa (FXa), the aberrant
      activation of both human prothrombin and FXa by porcine EC and the failure of the
      porcine natural anticoagulant, thrombomodulin to bind human thrombin and hence
      activate human protein C. The enhanced potential of porcine von Willebrand factor
      to associate with human platelet GPIb has been demonstrated to be dependent upon
      the isolated A1 domain of von Willebrand factor. In addition, the loss of TFPI
      and vascular ATPDase/CD39 activity following EC activation responses would
      potentiate any procoagulant changes within the xenograft. These developments
      could exacerbate vascular damage from whatever cause and enhance the activation
      of platelets and coagulation pathways within xenografts resulting in graft
      infarction and loss. Analysis of these and the other putative factors underlying
      DXR should lead to the development and testing of genetic approaches that, in
      conjunction with selected pharmacological means, may further prolong xenograft
      survival to a clinically relevant extent.

PMID- 10415574
TI  - Encapsulated, genetically engineered cells, secreting glucagon-like peptide-1 for
      the treatment of non-insulin-dependent diabetes mellitus.
AB  - Non-insulin-dependent, or type II, diabetes mellitus is characterized by a
      progressive impairment of glucose-induced insulin secretion by pancreatic beta
      cells and by a relative decreased sensitivity of target tissues to the action of
      this hormone. About one third of type II diabetic patients are treated with oral
      hypoglycemic agents to stimulate insulin secretion. These drugs however risk
      inducing hypoglycemia and, over time, lose their efficacy. An alternative
      treatment is the use of glucagon-like peptide-1 (GLP-1), a gut peptidic hormone
      with a strong insulinotropic activity. Its activity depends of the presence of
      normal blood glucose concentrations and therefore does not risk inducing
      hypoglycemia. GLP-1 can correct hyperglycemia in diabetic patients, even in those
      no longer responding to hypoglycemic agents. Because it is a peptide, GLP-1 must
      be administered by injection; this may prevent its wide therapeutic use. Here we
      propose to use cell lines genetically engineered to secrete a mutant form of GLP
      1 which has a longer half-life in vivo but which is as potent as the wild-type
      peptide. The genetically engineered cells are then encapsulated in semi-permeable
      hollow fibers for implantation in diabetic hosts for constant, long-term, in situ
      delivery of the peptide. This approach may be a novel therapy for type II
      diabetes.

PMID- 10415575
TI  - Genetically engineered pancreatic beta-cell lines for cell therapy of diabetes.
AB  - The optimal treatment of insulin-dependent diabetes mellitus (IDDM), which is
      caused by the autoimmune destruction of pancreatic islet beta cells, would
      require the regulated delivery of insulin by transplantation of functional beta
      cells. beta-cell transplantation has so far been restricted by the scarcity of
      human islet donors. This shortage would be alleviated by the development of
      differentiated beta-cell lines, which could provide an abundant and well
      characterized source of beta cells for transplantation. Using conditional
      transformation approaches, our laboratory has generated continuous beta-cell
      lines from transgenic mice. These cells produce insulin amounts comparable to
      those of normal islets and release insulin in response to physiological stimuli.
      Cell replication in these beta cells can be tightly controlled both in culture
      and in vivo, allowing regulation of cell number and cell differentiation. Another
      challenge to cell therapy of IDDM is the protection of transplanted cells from
      immunological rejection and recurring autoimmunity. By employing adenovirus genes
      which downregulate antigen presentation and increase cell resistance to
      cytokines, beta-cell transplantation across allogeneic barriers was achieved
      without immunosuppression. In principle, similar beta-cell lines can be derived
      from isolated human islets using viral vectors to deliver conditionally regulated
      transforming and immunomodulatory genes into beta cells. The combination of these
      approaches with immunoisolation devices holds the promise of a widely available
      cell therapy for treatment of IDDM in the near future.

PMID- 10415576
TI  - Re-engineering the functions of a terminally differentiated epithelial cell in
      vivo.
AB  - Because of their easy access, and important role in oral homeostasis, mammalian
      salivary glands provide a unique site for addressing key issues and problems in
      tissue engineering. This manuscript reviews studies by us in three major
      directions involving re-engineering functions of salivary epithelial cells. Using
      adenoviral-mediated gene transfer in vivo, we show approaches to i) repair
      damaged, hypofunctional glands and ii) redesign secretory functions to include
      endocrine as well as exocrine pathways. The third series of studies show our
      general approach to develop an artificial salivary gland for clinical situations
      in which all glandular tissue has been lost.

PMID- 10415578
TI  - Overview of extracorporeal liver support systems and clinical results.
AB  - Patients with acute liver failure (ALF) continue to have an almost 50% mortality
      rate despite improvements associated with the use of orthotopic liver
      transplantation (OLT). Numerous ex vivo methods have been developed in attempts
      to improve patient survival. These methods can be divided into three groups:
      detoxification (e.g., dialysis, charcoal adsorption, plasma exchange), which only
      provides excretory function; ex vivo liver perfusion (e.g., whole organ or tissue
      perfusion), which provides some metabolic function; and bioartificial or cell
      based systems, which combine elements of the first two methods. Clinical trials
      have shown minimal efficacy of the various detoxification methods in terms of ALF
      patient survival, while the relative success of OLT has shown the importance of
      providing metabolic as well as excretory functions. Attempts to provide those
      additional functions with ex vivo tissue perfusion have been fraught with
      complications such as clotting and acute tissue rejection, leading to the
      conceptual development of cell-based bioreactor systems. A number of these
      bioartificial systems have been clinically evaluated, and the preliminary patient
      survival rates have encouraged further work in this area.

PMID- 10415577
TI  - Reverse engineering of bioadhesion in marine mussels.
AB  - Marine mussels (Mytilus) are experts at bonding to a variety of solid surfaces in
      a wet, saline and turbulent environment. Bonding is rapid, permanent, versatile
      and protein-based. In mussels, adhesive bonding takes the form of a byssus--a
      bundle of extracorporeal threads--each connected to living tissues of the animal
      at one end and secured by an adhesive plaque at the other. We have investigated
      the composition and formation of byssal plaques and threads with the hope of
      discovering technologically relevant innovations in chemistry and materials
      science. All proteins isolated from the byssus to date share the quality of
      containing the unusual amino acid, 3,4-dihydroxyphenylalanine. This residue
      appears to have a dual functionality with significant consequences for adsorption
      and cohesion. On the one hand, it forms a diverse array of weaker molecular
      interactions such as metal chelates, H-bonds, and pi-cations: these appear to
      dominate in surface behavior (adsorption). On the other hand, 3,4
      dihydroxyphenylalanine and its redox couple, dopaquinone, can mediate formation
      of covalent cross-links among byssal proteins (cohesion). One of the challenges
      in making functional biomimetic versions of byssal adhesion is to understand how
      these two reactivities are balanced.

PMID- 10415579
TI  - Bioreactors for hybrid liver support: historical aspects and novel designs.
AB  - A novel bioreactor construction has been designed for the utilization of
      hepatocytes and sinusoidal endothelial cells. The reactor is based on capillaries
      for hepatocyte aggregate immobilization. Three separate capillary membrane
      systems, each permitting a different function are woven in order to create a
      three dimensional network. Cells are perfused via independent capillary membrane
      compartments. Decentralized oxygen supply and carbon dioxide removal with low
      gradients are possible. The use of identical parallel units to supply hepatocytes
      facilitates scale up. In vitro studies demonstrate long-term external metabolic
      function in primary isolated hepatocytes within bioreactors. These systems are
      capable of supporting essential liver functions. Animal experiments have verified
      the possibility of scaling-up the bioreactors for clinical treatment. However,
      since there is no reliable animal model for investigation of the treatment of
      acute liver failure, the promising results obtained from these studies have
      limited relevance. The small number of clinical studies performed so far is not
      sufficient to reach conclusions about improvements in the therapy of acute liver
      failure. Although important progress has been made in the development of these
      systems, various hepatocyte culture models and bioreactor constructions are being
      discussed in the literature, which indicates competition in this field of medical
      research. An overview, which emphasizes the development of hepatocyte culture
      models for bioreactors, subsequent in vitro studies, animal studies, and clinical
      application, is also provided.

PMID- 10415581
TI  - Three-dimensional in vitro cell culture leads to a marked upregulation of cell
      function in human hepatocyte cell lines--an important tool for the development of
      a bioartificial liver machine.
AB  - Upregulating hepatocyte function in proliferating human liver cell lines could
      provide cells for a bio-artificial liver. Ideally, a means of mimicking the
      biological extracellular matrix with a relatively inert, bio-compatible matrix is
      required. Alginate encapsulation of primary hepatocytes is biocompatible. This
      study aimed to characterize cells grown in a 3D configuration in alginate. A
      human-derived liver cell line encapsulated in 1% alginate was assessed for
      synthetic and detoxification functions. Secreted proteins measured (e.g.,
      albumin, fibrinogen, alpha-1-antitrypsin etc.) were increased in alginate
      compared with monolayers. Cytochrome P450 1A1 activity increased three- to
      fourfold, whilst urea synthesis, undetectable in monolayer cultures, was
      synthesized by cells in alginate at levels approaching in vivo production. TEM
      revealed good ultrastructure reminiscent of normal hepatocytes. Alginate promotes
      3D colonies of proliferating cells with upregulated liver functions. Rapid
      recovery of function of cryopreserved cells (< 18 h) provides added advantages
      for this system to support the biological component of an artificial liver for
      patients with fulminant hepatic failure.

PMID- 10415580
TI  - Novel bioartificial liver support system: preclinical evaluation.
AB  - Preclinical safety and efficacy evaluation of a novel bioartificial liver support
      system (BLSS) was conducted using a D-galactosamine canine liver failure model.
      The BLSS houses a suspension of porcine hepatocytes in a hollow fiber cartridge
      with the hepatocytes on one side of the membrane and whole blood flowing on the
      other. Porcine hepatocytes harvested by a collagenase digestion technique were
      infused into the hollow fiber cartridge and incubated for 16 to 24 hours prior to
      use. Fifteen purpose-bred male hounds, 1-3 years old, 25-30 kg, were administered
      a lethal dose, 1.5 g/kg, of D-galactosamine. The animals were divided into three
      treatment groups: (1b) no BLSS treatment (n = 6); (2b) BLSS treatment starting at
      24-26 h post D-galactosamine (n = 5); and (2c) BLSS treatment starting at 16-18 h
      post D-galactosamine (n = 4). While maintained under isoflurane anesthesia,
      canine supportive care was guided by electrolyte and invasive physiologic
      monitoring consisting of arterial pressure, central venous pressure, extradural
      intracranial pressure (ICP), pulmonary artery pressure, urinary catheter, and end
      tidal CO2. All animals were treated until death or death-equivalent (inability to
      sustain systolic blood pressure > 80 mmHg for 20 minutes despite massive fluid
      resuscitation and/or dopamine administration), or euthanized at 60 hours. All
      animals developed evidence of liver failure at 12-24 hours as evidenced by blood
      pressure lability, elevated ICP, marked hepatocellular enzyme elevation with
      microscopic massive hepatocyte necrosis and cerebral edema, elevated prothrombin
      time, and metabolic acidosis. Groups 2b and 2c marginally prolong survival
      compared with Group 1b (pairwise log rank censored survival time analysis, p =
      0.096 and p = 0.064, respectively). Since survival times for Groups 2b and 2c are
      not significantly different (p = 0.694), the groups were combined for further
      statistical analysis. Survival times for the combined active treatment Groups 2b
      and 2c are significantly prolonged versus Group 1b (p = 0.047). These results
      suggest the novel BLSS reported here can have a significant impact on the course
      of liver failure in the D-galactosamine canine liver failure model. The BLSS is
      ready for Phase I safety evaluation in a clinical setting.

PMID- 10415582
TI  - Cultivation and characterization of a new immortalized human hepatocyte cell
      line, HepZ, for use in an artificial liver support system.
AB  - The new human hepatocyte cell line HepZ was investigated with regard to use it
      for a mass cell cultivation. The cells were originally derived from a human liver
      biopsy and immortalized through lipofectamine-mediated transfection of albumin
      promotor-regulated antisense constructions against the negative controlling cell
      cycle proteins Rb and p53 (pAlb asRb, pAIb asp53). Furthermore, plasmids
      including genes coding for the cellular transcription factor E2F and D1 cyclin
      (pCMV E2F, pSV2neo D1) were cotransfected to overcome the G1-restriction point.
      Cell cultivation was performed in a 2-liter bioreactor with a working volume of 1
      liter. With CultiSpher G microcarriers used in a concentration of 3 g/l a maximal
      density of 7.1 x 10(6) cells/ml was achieved in a cultivation period of 20 days.
      The cells exhibited a maximal specific growth rate of 1.0 per day in the first 4
      days. After 9 days of cultivation the stationary growth phase was reached with an
      average cell density of 5.5 x 10(6) cells/ml. The viability status of the culture
      was determined indirectly by measuring of the lactate dehydrogenase activity
      (LDH) at 37 degrees C. During the growth phase the activity rose slightly up to a
      value of 200 U/l. The cells were flat after first attachment on the gelatine
      microcarriers and spherical after growing into the three-dimensional inner matrix
      -both of which characteristics were verified by scanning electron microscopy
      (SEM) and transmission electron microscopy (TEM). The liver-specific cytochrome
      P450 activity was challenged with a pulse of 7 micrograms/ml lidocaine at a cell
      density of 4.5 x 10(6) cells/ml. After an induction period of 3 days with 50
      micrograms/ml of phenobarbital, 26 ng/ml MEGX were generated within one day
      compared to 5 ng/ml without induction. The new cell line HepZ has proven to
      retain liver-specific qualities and to be appropriate for mass cell cultivation
      for bioartificial devices.

PMID- 10415584
TI  - Tissue engineering of bone in the craniofacial complex.
AB  - Tissue engineered therapies to regenerate bone in the craniofacial complex will
      probably include combinations of BMP-like molecules, a BMP-responsive set of
      cells (both endogenous and exogenous), and packaging in a surgically convenient
      format. In this report we have described our work with OPCs, BMP, and polymer:
      components suitable for tissue engineering.

PMID- 10415583
TI  - rhBMP-collagen sponges as osteoinductive devices: effects of in vitro sponge
      characteristics and protein pI on in vivo rhBMP pharmacokinetics.
AB  - Osteoinductive devices, comprised of biodegradable collagen scaffolds and
      recombinant human Bone Morphogenetic Proteins (rhBMPs), are being currently
      pursued for local bone induction. To better understand the biological performance
      of such devices, we have carried out a series of studies to investigate the
      effects of sponge properties and protein structural features on the
      pharmacokinetics of implanted rhBMPs. The results indicated little dependence of
      the rhBMP-2 pharmacokinetics on the in vitro determined sponge properties. The
      protein isoelectric point (pI), on the other hand, was found to significantly
      affect the initial implant retention of rhBMPs, but not the subsequent
      pharmacokinetics. A 100-fold difference in the implant-retained dose could be
      observed depending on the type of rhBMP implanted. We conclude that protein
      structural features are important variables controlling in vivo pharmacokinetics
      of rhBMPs, and possibly the osteoinductive potency of the devices.

PMID- 10415585
TI  - Computer controlled bioreactor for large-scale production of cultured skin
      grafts.
AB  - KERATOR--an automated membrane bioreactor--was developed to produce Autologous
      Wound Dressing (AWD) at significantly reduced cost and time of transplantation
      down to two weeks time. At the same time, the risk of human error is largely
      eliminated. The computer-controlled reactor is modular, allowing the production
      of up to 0.5 m2 AWD at one time. A special feature of the reactor is a
      hydrophilic polymeric support membrane on which the human keratinocytes attach
      and proliferate. Recently developed serum-free medium is used to culture
      keratinocytes as a monolayer without a feeder layer of murine fibroblasts. The
      use of composite skin grafts consisting of a subconfluent keratinocyte layer on a
      polymeric support film is a very promising method for skin transplantation owing
      to the high activity of non-differentiated keratinocyte cells and reduction of
      the time needed to prepare the skin grafts. A microscopic video system with image
      analysis was developed for on-line monitoring of the cell growth and morphology
      in the KERATOR. The computer uses the obtained information to control medium
      change and to predict the end of cultivation.

PMID- 10415586
TI  - A method for tissue engineering of cartilage by cell seeding on bioresorbable
      scaffolds.
AB  - This chapter describes a method for the in vitro generation of a 3-dimensional
      cartilage matrix from articular chondrocytes seeded onto a bioresorbable
      polymeric scaffold. This particular growth system was chosen for the subject of
      this chapter owing to the relative simplicity of the methods required and the
      ease with which the necessary materials can be obtained. The tissue produced
      using this protocol is a cellular, metabolically active hyaline-like matrix,
      containing the major cartilage constituents: sulfated proteoglycan, collagen type
      II, and water. It serves as a useful in vitro tool for studying the influence of
      various mechanical and chemical factors on cartilage metabolism, as well as
      providing an implantable material for in vivo cartilage repair studies.

PMID- 10415587
TI  - Bioreactor development for tissue-engineered cartilage.
AB  - The development of tissue engineered cartilage is emerging as a potential
      treatment for the repair of cartilage defects. By seeding chondrocytes onto poly
      glycolic acid (PGA) biodegradable scaffolds within a convective-flow bioreactor,
      the synthesis of tissue-engineered articular cartilage has been recently
      demonstrated. The ability to cultivate and manipulate this cell-polymer construct
      to possess specific dimensions, as well as biochemical and biomechanical
      properties is critical for potential application as an in vivo therapy of damaged
      articular surfaces. Bioreactor design requirements for stages from research to
      development to commercialization are discussed. Advantages and limitations to
      various bioreactor designs are critiqued. These studies illustrate the ability to
      synthesize tissue-engineered cartilage under convective-flow conditions for
      potential human tissue repair.

PMID- 10415588
TI  - Neuroendocrine immune basis of the rheumatic diseases.

PMID- 10415589
TI  - Stress, corticotropin-releasing hormone, glucocorticoids, and the
      immune/inflammatory response: acute and chronic effects.
AB  - Corticotropin-releasing hormone (CRH) influences the immune system indirectly,
      through activation of the hypothalamic-pituitary-adrenal axis and sympathetic
      system, and directly, through local modulatory actions of peripheral (immune)
      CRH. We recently demonstrated that catecholamines and histamine potently
      inhibited interleukin (IL)-12 and stimulated IL-10, whereas glucocorticoids
      suppressed IL-12, but did not affect IL-10 production ex vivo. Thus, both
      glucocorticoids and catecholamines, the end products of the stress system, and
      histamine, a product of activated mast cells, may selectively suppress cellular
      immunity and favor humoral immune responses. We localized immunoreactive CRH in
      experimental carrageenin-induced aseptic inflammation and, in humans, in inflamed
      tissues from patients with several autoimmune disease. In addition, we
      demonstrated that CRH activated mast cells via a CRH receptor type 1-dependent
      mechanism, leading to release of histamine and hence vasodilatation and increased
      vascular permeability. Thus, activation of the stress system, through direct and
      indirect effects of CRH, may influence the susceptibility of an individual to
      certain autoimmune, allergic, infectious or neoplastic diseases. Antalarmin, a
      novel nonpeptide CRH antagonist, prevented several proinflammatory effects of
      CRH, thus revealing its therapeutic potential in some forms of inflammation.

PMID- 10415591
TI  - Macrophages as effectors of the immunoendocrinologic interactions in autoimmune
      rheumatic diseases.
AB  - An intricate balance between soluble mediators, released by activated cells of
      the immune/inflammatory systems, and products of the neuroendocrine system is
      implicated in the presence of an autoimmune rheumatic disease.
      Monocytes/macrophages contribute to autoimmune events in rheumatic diseases, such
      as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), mainly acting
      as antigen-processing and presenting cells in the presence of an autoimmune
      rheumatic disease. Clinical symptoms such as morning stiffness and gelling, at
      least in RA, that peak during the late night and early morning, are consistent
      with the hypothesis that the immune function of activated cells (i.e., Th1 cells
      and monocytes/macrophages) and their mediators (cytokines and reactive oxygen
      intermediates) is increased at these times in relation to neuroendocrine pathway
      rhythmicity. Therefore, monocytes/macrophages seem to be the "link" between the
      steroid hormone environment (i.e., gonadal hormones) and the immune response
      effectors. If gonadal hormones, along with cytotoxic agents, do modulate
      macrophage apoptosis, such an approach might offer an important pathway to the
      control of autoimmune diseases. In conclusion, on the basis of a more complete
      understanding of macrophage effector and immunoregulatory activities, on both a
      local and systemic level, new hopes arise from the possible development of more
      sophisticated antimacrophage treatments for the management of autoimmune
      rheumatic diseases.

PMID- 10415590
TI  - Hormonal regulation of tumor necrosis factor-alpha, interleukin-12 and
      interleukin-10 production by activated macrophages. A disease-modifying mechanism
      in rheumatoid arthritis and systemic lupus erythematosus?
AB  - Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) frequently
      develop and progress in settings in which sympathoadrenomedullary and gonadal
      hormone levels are changing, e.g., during pregnancy, postpartum period,
      menopause, estrogen administration. This paper addresses the view that adrenal
      and gonadal hormonal deficiency facilitates excessive macrophage production of
      TNF-alpha and IL-12 that characterizes RA, whereas excessive estrogen action is
      suggested to play an essential role in the production of IL-10 in patients with
      SLE. Disease activity in SLE, in contrast to RA, appears to be associated with
      high-level production of IL-10, relative to the proinflammatory cytokines, TNF
      alpha and IL-12. Accumulating data suggest that novel therapeutic approaches may
      ultimately be developed from continued investigation of the role of the
      neuroendocrine factors in RA and SLE.

PMID- 10415592
TI  - Differential effects of psychological and immunological challenge on the
      hypothalamo-pituitary-adrenal axis function in adjuvant-induced arthritis.
AB  - Inability to mount a suitable glucocorticoid response to a stressor can be life
      threatening. Rats with hind-paw inflammation, associated with the development of
      adjuvant-induced arthritis (AA), are unable to mount a hypothalamo-pituitary
      adrenal (HPA) axis response to acute stress. In the present study we have
      compared the effects of acute psychological stress (noise) and acute
      immunological challenge (lipopolysaccharide [LPS] injection), on the activation
      of the HPA axis in rats with the chronic inflammatory stress of AA. We conclude
      that the increase in HPA axis activity in AA is principally due to an increase in
      corticosterone pulse frequency and not to any alteration in pulse magnitude. The
      lack of response to acute stress can be accounted for by the increase in pulse
      frequency and the associated refractory period following each pulse, producing
      dramatic but specific changes in basal HPA function. These changes may account
      for the loss of responsiveness to acute stress, but not to acute immunological
      challenge, because the HPA axis is able to respond to LPS in male rats with AA.
      However, there appears to be an impaired adrenal responsiveness in female rats
      with AA that is not inherent, but occurs as a consequence of the development of
      inflammation.

PMID- 10415594
TI  - Emerging concepts for sexual predilection in the disease systemic lupus
      erythematosus.

PMID- 10415593
TI  - Perturbations of hypothalamic-pituitary-gonadal axis and adrenal androgen
      functions in rheumatoid arthritis: an odyssey of hormonal relationships to the
      disease.
AB  - Rheumatoid arthritis (RA) is a heterogeneous disease with a diverse spectrum of
      manifestations and course of illness. Multiple factors are believed to contribute
      to its etiology. Nevertheless, consistent features are observed across
      populations, which include (1) increased familial or immunogenetic risk in
      younger-onset disease; (2) female predisposition, particularly during child
      bearing ages; (3) predictable clinical improvement during pregnancy and worsening
      postpartum; and (4) increased incidence with aging, which suggest that hormonal
      factors influence the disease. In 1974, serum was prospectively obtained from pre
      RA cases, 4 to 20 (mean = 12.0) years prior to onset of disease and concurrently
      from controls (CN) matched (4 CN per 1 RA) on age (+/- 2 years), race (all
      Caucasians), and entry menopausal status (EMS). CN have no known rheumatic
      disease. Pre-RA were divided into subgroups, according to EMS, i.e.,
      premenopausal vs. non-premenopausal (peri- or post-menopausal), and either age at
      entry in 1974 or age at onset of RA. For example, one 3-way subgrouping includes:
      I. Entry premenopausal and RA onset < age 50 years; II. Entry premenopausal and
      RA onset age 50+ years, and III. Entry postmenopausal. The 11 youngest pre-RA (I)
      had a mean entry age of 29 years and RA onset of 41 years. An alternative 4-way
      subgrouping (a, b, c, d) divided the female subjects into premenopausal (last
      menstrual period [LMP], 0-31 days) and non-premenopausal major groups, as well as
      younger vs. older subgroups within the major EMS categories. The younger
      premenopausal women in each subgrouping system, that is, I or a, overlap almost
      entirely. Assays (RIA) of the major sex hormones were performed, e.g.,
      luteinizing hormone (LH); follicle stimulating (FSH); estradiol (E2);
      progesterone (P4); and total testosterone (T); as well as adrenal hormones,
      including androstenendione (A4); dehydroepiandrosterone (DHEA); its sulfate
      (DHEAS); and cortisol (C). A significantly lower entry mean serum DHEAS level
      (mumol/L) was found in the pre-RA subgroup I, than in the 43 CN (2.14 +/- 0.47
      vs. 3.62 +/- 0.37, respectively, (p = 0.033). The 25 older pre-RA and 100 CN
      (subgroups II and III) showed close mean DHEAS levels (1.89 +/- 0.30 and 1.94 +/-
      0.14, respectively, p = 0.45). The serum DHEAS levels in pre-RA vs. CN subgroups
      were validated in a second reference laboratory. Also, the youngest pre-RA
      subgroup (I) showed a significant dissociation between entry serum DHEAS and
      cortisol levels (r = -0.660, p = 0.027), which differed (p = 0.017) from its
      matched CN, and from the older pre-RA (p = 0.004). Analyses of results based upon
      subgroupings by EMS and entry age (a, b, c, d) showed similar results. No
      significant differences were found between pre-RA and CN groups in levels of
      serum cortisol, other adrenal steroids, or the sex hormones assayed. In a sample
      of younger premenopausal women, significantly low serum DHEAS levels were found 4
      to 20 years prior to onset of RA. Dissociation of serum cortisol and DHEAS levels
      was also found in the youngest, but not older, pre-RA subjects. The data suggest
      that subtle adrenal cortical dysfunction, manifested mainly by adrenal androgen
      (AA) deficiency, may either predispose to younger-onset RA or be a long-term
      marker in a minority subgroup of women.

PMID- 10415595
TI  - Neuroendocrine immune features of pediatric inflammatory rheumatic diseases.
AB  - Juvenile rheumatoid arthritis (JRA) and juvenile systemic lupus erythematosus
      (JSLE) are the most common autoimmune rheumatic diseases in children associated
      with high levels of autoantibodies and immune reactivity. JRA and JSLE are more
      common in girls. Disease activity is worse in the morning, improves during the
      daytime and worsens at night suggesting that neuroendocrine immune mechanisms are
      involved in disease pathophysiology. Adult patients with RA and SLE have
      excessive levels of prolactin (PL) while cortisol (CS) production is down
      regulated for the degree of ongoing inflammation. PL has potent proinflammatory
      properties. Normal to low levels of cortisol have been observed in children with
      active JRA despite the high serum levels of IL-6, IL-1 beta, and TNF-alpha, which
      activate the hypothalamic-pituitary-adrenal axis (HPA). The CS levels are in fact
      subnormal because inflammatory stress activates the HPA. Normal serum PL levels
      were seen in children with JRA, most of whom were not active with higher levels
      in those with active ANA +ve JRA complicated by uveitis. A trend toward high PL
      levels was seen in 33 children with JSLE. High serum PL levels are seen in
      patients with active juvenile ankylosing spondylitis (JAS) only. Growth
      retardation is a feature of JRA. Patients with JRA have low to normal levels of
      growth hormone (GH) and low levels of insulin-like growth factor 1 (IGF-1). IGF-1
      mediates the effects of GH. The observation of low IGF-1 in JRA raises the
      therapeutic possibility with IGF-1. Overall, high levels of follicle stimulating
      hormone and luteinizing hormone are found in children with JSLE while the levels
      in JRA tend to be normal. Testosterone levels are low in patients with JRA. No
      significant differences in estrogen levels have been found between patients with
      JRA and those with JSLE and matched controls. There is evidence that the
      autonomic nervous function is defective in patients with JRA.

PMID- 10415596
TI  - Desmopressin, ovine CRH, and low-dose ACTH tests: tools for the study of the
      hypothalamic-pituitary-adrenal axis in premenopausal rheumatoid arthritis
      patients.

PMID- 10415597
TI  - Circadian abnormalities of natural killer cell activity in rheumatoid arthritis.

PMID- 10415598
TI  - Immunological properties of dehydroepiandrosterone, its conjugates, and
      metabolites.
AB  - The immunological response to the administration of various C-19 steroids has
      been of increasing interest. Although the action of dehydroepiandrosterone has
      been studied, the responses to its metabolites have not been explored. In the
      present study the ability of dehydroepiandrosterone, its conjugates, and
      metabolites to oppose the anti-inflammatory action of glucocorticoids on the
      inflammatory response to 2,4-dinitrochlorobenzene in the sensitized mouse was
      examined. A clear difference was seen between the antiglucocorticoid activity of
      dehydroepiandrosterone, its conjugates, and its 5 beta-metabolites on the one
      hand and the planar 5 alpha- and delta 4-metabolites, which were devoid of
      antiglucocorticoid activity. The mechanism of this antiglucocorticoid activity
      remains to be established.

PMID- 10415599
TI  - Sex hormones and glucocorticoids: interactions with the immune system.
AB  - Gender and sex hormones exert powerful effects in the susceptibility and
      progression of numerous human and experimental autoimmune diseases. This has been
      attributed to direct immunological effects of sex hormones that impact a clear
      gender dimorphism on the immune system. Globally, estrogens depress T cell
      dependent immune function and diseases, but enhance antibody production and
      aggravate B cell-dependent diseases. Androgens suppress both T-cell and B-cell
      immune responses and virtually always result in the suppression of disease
      expression. Defects in the hypothalamic-pituitary-adrenal (HPA) axis have been
      proposed to play an important role in the pathogenesis of autoimmune diseases.
      Glucocorticoid response to stress, including immune challenge, is strongly
      inhibited by androgens and enhanced by estrogens. Complex three-way interactions
      between these systems appear to be involved in gender dimorphism of the immune
      system. This paper reviews the mechanisms involved in interactions between sex
      steroids and the HPA axis, addresses the possibility of similar interactions on
      immunocompetent cells, and explores an integrated perspective of the impact of
      these interplays on the immune system.

PMID- 10415600
TI  - Prolactin and neuroimmunomodulation: in vitro and in vivo observations.
AB  - Prolactin (PL) is a mammotropic neuropeptide produced by the pituitary and
      extrapituitary cells existing as several isoforms and belongs to the growth and
      lactogenic hormone family, which includes growth hormone and placental lactogens.
      The secretion of pituitary PL is under hypothalamic control. The cytokines IL-1,
      IL-2, and IL-6 also stimulate production, while IFN-gamma and endothelin-3 are
      inhibitory. PL exerts its effects via PL receptors (PLr) which exist as three
      isoforms. PL regulates reproduction, osmoregulation, and behavior and has potent
      immunomodulatory effects. PL is structurally related to members of the
      cytokine/hematopoietic family such as erythropoietin, GM-CSF, growth hormone, and
      IL-2 to IL-7. The PLr is a member of the cytokine/hematopoietic receptor family.
      Interaction of PL with PLr activates the Jak kinases which phosphorylate latent
      STAT proteins resulting in the activation of transcription. PL counteracts the
      effects of corticosteroids by enhancing Th1 cellular responses. Perturbations of
      PL physiology have significant immunologic effects. Hypoprolactinemia impairs
      immune function while hyperprolactinemia enhances active systemic lupus
      erythematosus, Reiter's disease, juvenile and adult rheumatoid arthritis (RA),
      autoimmune thyroiditis, multiple sclerosis, and cardiac allograft rejection. PL
      gene polymorphisms have now been shown to be linked to RA. Thus, manipulation of
      PL may have significant clinical utility. Further study of the relationship of
      the PL/PLr complex, other hormones, and the immune system will provide further
      insights into the potential therapeutic utility of this complex in immune
      diseases.

PMID- 10415601
TI  - Sex hormones and pregnancy in rheumatoid arthritis and systemic lupus
      erythematosus.
AB  - Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are autoimmune
      disorders with a preponderance in females. RA and SLE differ in their response to
      sex hormones. Disease development of RA is mitigated by estrogen and pregnancy
      whereas SLE tends to flare during pregnancy and in response to estrogen.
      Pregnancy improves the symptoms of RA in about 75% of pregnant patients, but
      relapses within six months postpartum in 90% of cases. RA is regarded as a T cell
      mediated and TH1 immune response-driven disease. Pregnancy induces a shift from
      TH1 to TH2 immune response, increasing the anti-inflammatory cytokines IL-4 and
      IL-10, which may contribute to gestational amelioration of RA. Prospective
      studies of SLE pregnancies indicate that about 50% of patients experience a
      flare, however, with no permanent aggravation of the disease. Lupus nephritis,
      presence of antiphospholipid antibodies, and a previous history of pregnancy loss
      increase the risk of complications during pregnancy and fetal loss. The marked
      increase of estrogen and progesterone during pregnancy seems to enhance some of
      the manifestations of SLE. The shift to a TH2 immune response may trigger SLE
      manifestations that are dependent on humoral immune responses such as lupus
      nephritis. Another factor stimulating immune responses is the pituitary hormone
      prolactin, which has been found elevated in SLE patients of both sexes and
      correlated to disease activity in several studies. The hyperprolactinemia of
      lactation seems to influence postpartum behavior of SLE as well as RA.

PMID- 10415602
TI  - Levels of dehydroepiandrosterone sulfate in female patients with early stage of
      rheumatoid arthritis.

PMID- 10415603
TI  - Gender differences in adrenal and gonadal responses to inflammatory aggression.

PMID- 10415604
TI  - Dehydroepiandrosterone sulfate in patients with rheumatoid arthritis.

PMID- 10415605
TI  - Basal and after-stimuli test for prolactinemia in systemic lupus erythematosus.

PMID- 10415606
TI  - Association between anticardiolipin antibody positivity and increased 17-beta
      estradiol levels in premenopausal women with rheumatoid arthritis.

PMID- 10415607
TI  - Immune regulatory properties of corticosteroids: prednisone induces apoptosis of
      human T lymphocytes following the CD3 down-regulation.
AB  - Glucocorticoid hormones (GCH) induce apoptosis in PHA-primed peripheral blood T
      lymphocytes (PBL) and down-regulate membrane-bound proteins involved in the
      immune response. We have analyzed whether GCH are able to affect the expression
      of the TCR-associated molecules CD3, CD4, and CD8 on PBL-PHA, and whether the
      modulation of those receptors is related to the GCH-driven apoptosis of the PBL
      PHA. Lymphocytes were cultured with PHA or with PHA plus prednisone (PDN) 10(-3),
      10(-6), and 10(-9) M. Then expression of CD2, CD3, CD4, CD8, and CD56 antigens
      was studied by cytofluorimetric assay using propidium iodide (PI) staining and
      annexin procedure, and by gel electrophoresis of low molecular weight DNA. PDN,
      at a pharmacological concentration (10(-6) M), was able to inhibit the CD3
      expression on T cells. The kinetics of CD3 decrement and of apoptosis show that
      the down-regulation of CD3 molecules precedes DNA fragmentation and that the
      cells lacking CD3 are those prone to PDN-induced apoptosis. The inhibition of CD3
      is not related to a transcriptional or posttranscriptional phenomenon, because
      both PBL-PHA and PBL-PHA-PDN expressed the same amount of intracytoplasmic CD3
      molecule. PDN also induced a down-regulation of the CD4 and CD8 molecules that
      resulted sooner in more intense CD8. In vitro PDN is able to induce apoptosis in
      PBL-PHA through a down-regulation of CD3 molecules.

PMID- 10415608
TI  - Endocrine end-points in rheumatoid arthritis.
AB  - Our previous studies are reviewed and at the same time preliminary experimental
      observation to the topic of endocrine end-points in autoimmune disease is
      introduced. To this end, we have used rheumatoid arthritis (RA), including
      synovial fluids and primary cultures of synovial macrophages, as a model system
      in order to investigate (a) expression and subcellular localization of high
      affinity sites of steroid binding in immune effector cells; (b) steroid metabolic
      profiles in both male and female RA patients, as compared to healthy subjects;
      and (c) activities of key steroid enzymes that govern intratissue accumulation of
      sex hormones. In RA tissues and cells, the concurrent evidence for (1) androgen
      and/or estrogen receptors, (2) high concentrations of biologically active
      steroids, (3) key enzymes of steroid metabolism, and (4) significant changes of
      estrogen to androgen ratio, all strongly suggests that individual immune cells,
      including synovial macrophages, may behave as steroid-sensitive cells, namely,
      they may represent a target for sex steroids, supporting the hypothesis of a
      potential endocrine regulation of the immune response also in RA disease. In this
      respect, definition of several endocrine end-points may have important
      implications for the treatment of rheumatic disease and other immunological
      disorders.

PMID- 10415609
TI  - Possible differences in the mechanism(s) of action of different glucocorticoid
      hormone compounds.
AB  - Different glucocorticoid hormones (GCH) show differences in the intensity and in
      the kinetics of their immunomodulating activity. The mechanism(s) of action of
      GCH is under investigation, but is has been noted that they exert immune activity
      via the genomic pathway. We have studied the effects of prednisone (PDN),
      deflazacort (DFC), and dexamethasone (DXM) on the production of cytokines (IL-2,
      IL-6, TNF-alpha, IL-10) by peripheral T lymphocytes, and the effects on the
      inhibition of NF-kB DNA binding activity by activated Jurkat cell line. The data
      obtained show that the three GCH molecules exert an immunosuppression on cytokine
      production by T lymphocytes and a strong decrease in the nuclear translocation of
      NF-kB in Jurkat cells; moreover, (a) not all the cytokines investigated were
      affected, and not with the same intensity, by the three GCH and (b) DXM inhibited
      the binding activity of NF-kB less than that of DFC and PDN. These data are in
      agreement with the concept that different GCH compounds might differ in their
      binding and affinity properties, tissue-specific metabolism, and interaction with
      transcription factor.

PMID- 10415610
TI  - Influence of corticosteroids on neutrophils, lymphocytes, their subsets, and T
      cell activity markers in patients with active rheumatoid arthritis, compared to
      healthy controls.

PMID- 10415611
TI  - Expression of chemokine receptors in the rat brain.
AB  - Human immunodeficiency virus (HIV-1) infects the brain and causes a progressive
      encephalopathy in 20 to 30% of infected children and adults called AIDS dementia
      complex. Evidence from in vitro and in vivo studies suggests a role for the viral
      envelope glycoprotein gp120, as a mediator of neurotoxicity. However, the site of
      interaction of gp120 with neurons and astrocytes to mediate neuronal death is
      still unknown. Recently the chemokine receptors, CCR5 and CXCR4, have been
      identified as co-receptors together with CD4 for HIV-1 entry into the target
      cells, suggesting a possible role for these receptors in the pathogenesis of the
      HIV-1 infection in the brain. Here we report the expression of CCR5 and CXCR4 in
      many different rat brain areas. We also found both receptors in cultured type I
      astrocytes demonstrating that glial cells may represent an important target for
      chemokines in vivo. Indeed, the functional capacity of CXCR4 receptor in
      astrocytes was demonstrated showing that SDF 1 alpha induced an increase of
      intracellular calcium concentration.

PMID- 10415612
TI  - Modulation by cytokines of glucocorticoid action.
AB  - Glucocorticoids (GC) are potent modulators of the inflammatory response. Their
      effects serve to down-regulate the inflammatory response and are mediated by
      genomic pathways that follow the interaction with specific receptors
      (glucocorticoid receptors, GR). Interleukin (IL)-1, IL-2, and IL-6 are able to
      increase GC secretion by enhancing synthesis and release of CRH and ACTH.
      Cytokine effects upon steroidogenesis also occur at the adrenal level. The role
      of cytokines as modulators of GR has received scarce attention. IL-1 has been
      shown to up-regulate GR mRNA expression in hypothalamic CRH secreting cells. On
      the other hand, macrophage migration inhibitory factor (MIF), a T-cell product
      inducible by inflammatory substances including other cytokines, counterregulates
      GC action within the immune system. Besides immunocytes and neurons, bone cells
      are a sensitive target for GC and cytokines. We have found that IL-2 and IL-6 up
      regulate remarkably the number of GR binding sites and the expression of GR mRNA
      in peripheral blood mononuclear cells and in osteoblast-like Saos-2 cells.
      Available data suggest that inflammatory cytokines have both direct and indirect
      effects on GC action at the target level. Autocrine-induced transcription of GR
      in immunocytes and/or osteoblasts could be a mechanism that restrains excess
      cytokine production.

PMID- 10415613
TI  - Possible pathogenetic relevance of interleukin-1 beta in "destructive" organ
      specific autoimmune disease (Hashimoto's thyroiditis).
AB  - Thyroid follicular cells (TFC) abundantly express a variety of immunologically
      relevant surface molecules in Hashimoto's thyroiditis (HT), for example, MHC
      antigens and adhesion molecules such as ICAM-1. Cytokines produced by
      infiltrating type 1 helper and cytotoxic T cells are importantly involved in de
      novo expression or up-regulation of such molecules. We recently demonstrated that
      TFC from HT patients almost invariably bear on their surface two additive
      functional molecules: Fas/Apo1/CD95, an important participant in apoptosis, and
      B7.1, a member of a family of "co-stimulatory" molecules that are crucial for
      efficient antigen presentation. To date, 12 out of 14 surgical HT thyroid
      specimens that we studied by immunohistochemistry showed B7.1-positive TFC, and
      all showed Fas-positive TFC, different from Graves' disease (GD) or nonautoimmune
      specimens. We have investigated the role of a number of cytokines (IL-1 beta, TNF
      alpha, IL-4, IL-6, IL-10, IL-12, TGF-beta 1, IFN-gamma) in regulating B7.1 and
      Fas expression. The experiments were performed by immunofluorescence flow
      cytometry on TFC purified from nontoxic goiter specimens which were Fas- and B7.1
      negative at baseline, and one B7.1/Fas-positive HT specimen. IFN-gamma (500 U/mL)
      and TNF-alpha (200 ng/mL) were unable to induce de novo expression of B7.1 or Fas
      on cultured TFC. At higher doses (2000 U/mL and 800 ng/mL, respectively), they
      were unable to induce B7.1, but potentiated the spontaneous expression of Fas.
      Type 2 cytokines (IL-4 and IL-10) were unable to induce Fas or B7.1 on TFC at
      all, or to down-regulate Fas or B7.1 when expressed. On the other hand, IL-1 beta
      was the only cytokine able to induce Fas expression on Fas-negative TFC at doses
      ranging from 100 to 1000 pg/mL. Moreover, at a dose of 400 pg/mL, it was also
      able to induce B7.1. We demonstrated by immunohistochemistry that IL-1 beta is
      abundantly present on HT thyroids, including follicular structures. It is
      conceivable that IFN-gamma, or other cytokines secreted by infiltrating T
      lymphocytes, are able to promote IL-1 beta secretion by TFC. In conclusion, a
      crucial role of IL-1 beta in "destructive" organ-specific autoimmunity may be
      suggested both for the perpetuation of the autoimmune reaction (induction of
      efficient autoantigen presentation by TFC, via co-stimulatory molecules) and in
      induction of tissue damage via "suicide" Fas/FasL-mediated TFC interaction.

PMID- 10415614
TI  - Chronic administration of UK-114, a multifunctional emerging protein, modulates
      the Th1/Th2 cytokine pattern and experimental autoimmune diseases.
AB  - UK-114 is a 14-kDa ubiquitous protein recently sequenced by several groups
      throughout the world. Its activity ranges from being a tumor antigen, a protein
      synthesis inhibitor or a specific mu-calpain activator. UK-114 shows structural
      homologies also with proteins of the MHC-1 binding proteins, and heat shock
      proteins (HSPs). We investigated the possible effects of UK-114 on T helper cells
      cytokine profile and the development and progression of experimental autoimmune
      diseases. Homogeneous recombinant UK-114 was used in all experiments. Treatment
      of Balb/c male mice for two weeks resulted in the increase of IL-4, and the
      decrease of TNF-alpha, IFN-gamma, and IL-2 release from stimulated splenocytes,
      suggesting that UK-114 modulates the Th1/Th2 cytokine profile toward Th2. Similar
      to that observed with HSP60/65, a single pretreatment of Lewis rats with UK-114
      significantly blunted the development of adjuvant-induced arthritis, whereas
      chronic treatment of 4-week-old female NOD mice dose dependently inhibited the
      development of diabetes.

PMID- 10415615
TI  - IL-15/IL-15R alpha intracellular trafficking in human cells and protection from
      apoptosis.
AB  - IL-15 is an immunostimulatory cytokine sharing with IL-2 the IL-2R beta gamma
      complex. In vivo, IL-15 detection in synovial fluids has been associated with the
      development of rheumatoid arthritis. A debate exists as to whether IL-15 has the
      potential to be secreted in meaningful amounts or to act as a pericellular
      cytokine. Our data show (1) the presence of two IL-15 isoforms displaying signal
      peptides of different length and the capacity to be secreted restricted to the
      isoform bearing the longer one; (2) in cells expressing the two isoforms, the
      existence of different nuclear localization and intracellular trafficking of IL
      15 and IL-15R alpha; and (3) an intercellular microcirculation of IL-15, not
      detectable with ELISA kits, but displaying a role as an anti-apoptotic factor
      able to induce the deflection of the TNFR associated factor 2 (TRAF) to IL-15R
      alpha. Our data point to a juxtacrine mechanism of action of IL-15 and suggest a
      role for IL-15/IL-15R alpha in the regulation of apoptosis.

PMID- 10415616
TI  - Melatonin influences interleukin-12 and nitric oxide production by primary
      cultures of rheumatoid synovial macrophages and THP-1 cells.
AB  - Because some of the clinical symptoms related to rheumatoid arthritis (RA)
      synovitis, such as joint morning stiffness and gelling, might be related to the
      effects exerted by the diurnal rhythmicity of the neurohormone melatonin (MLT) on
      synovial immune cell activation, we decided to evaluate the influence of MLT on
      the production of IL-12 and nitric oxide (NO) on primary cultures of RA synovial
      macrophages. Synovial macrophages were also prestimulated with lipopolysaccaride
      (LPS). Results were compared with those obtained on cultured human myeloid
      monocytic cells (THP-1). A significant increase in IL-12 (p = 0.01) was found in
      media of MLT-stimulated synovial macrophages versus RMPI-treated synovial
      macrophage controls. Interestingly, a significant decrease of IL-12 (p < 0.0001)
      was observed in media of synovial macrophages previously activated with LPS and
      then treated with MLT, when compared to synovial macrophages treated with LPS
      alone. A significant increase in NO levels (p = 0.01) was found in MLT-stimulated
      synovial macrophages versus RMPI-treated synovial macrophage controls.
      Interestingly, a nonsignificant increase of NO levels was observed in media of
      synovial macrophages previously activated with LPS and then treated with MLT,
      when compared to cynovial macrophages treated with LPS alone. Finally, a
      significant increase in IL-12 (p = 0.03) and NO (p = 0.002) concentrations was
      observed in media of MLT-stimulated THP-1 cells versus RMPI-treated controls. Our
      results therefore show that MLT induces IL-12 secretion and NO production by
      unstimulated cultured RA synovial macrophages and human monocytic myeloid THP-1
      cells. The unexpected and opposite effects on IL-12 and NO production in RA
      synovial macrophages treated with LPS may be related to dose-dependent mechanisms
      exerted by MLT or to altered cell priming in RA macrophages; these are matters of
      our further research. This study strongly supports the role of MLT in immune
      response modulation and in particular suggests a close relationship between
      diurnal rhythmicity of neuroendocrine pathways, cytokine and reactive oxygen
      intermediate production by monocyte/macrophages, and synovial arthritis
      symptomatology, at least in RA.

PMID- 10415617
TI  - Concentration of cortisol in the synovial fluid of patients with untreated
      rheumatoid arthritis. Relation to in vitro IL-8 production by synovial
      mononuclear cells.

PMID- 10415618
TI  - Preliminary data suggesting production of interleukin-12 by rat Leydig cells
      cultured in vitro.

PMID- 10415619
TI  - Interactions between prolactin and the proinflammatory cytokine network in
      juvenile chronic arthritis.

PMID- 10415620
TI  - In vitro superfusion method to study nerve-immune cell interactions in human
      synovial membrane in long-standing rheumatoid arthritis or osteoarthritis.
AB  - Reports on patients with hemiparalysis indicate the importance of the nervous
      system for the pathophysiology of rheumatoid arthritis (RA) or osteoarthritis
      (OA). Norepinephrine (NE) and opioids seem to be more antiinflammatory
      neurotransmitters whereas substance P is proinflammatory. The study aimed to
      investigate the direct noradrenergic nerve-immune cell interaction in human
      synovial membrane. We used a recently developed superfusion technique with
      electrical stimulation of synovial membrane to elicit local NE from synovial
      membrane slices. The readout parameter of synovial immune cells was interleukin-6
      (IL-6). IL-6 was spontaneously secreted from RA and OA synovial membranes.
      Electrical field stimulation intensively reduced IL-6 secretion. In patients with
      OA or RA, this electrically induced reduction of IL-6 secretion was not
      significantly changed by alpha- or beta-adrenergic antagonists. The study
      demonstrates that local endogenous NE seem to play a minor role, which may be due
      to a depletion of NE or loss of noradrenergic fibers during chronic RA and OA.

PMID- 10415621
TI  - Effects of stress on susceptibility and severity of inflammation in adjuvant
      induced arthritis.
AB  - We have utilized the open field and learned helplessness (LH) models of
      psychological stress to determine whether a differential response to stress can
      affect the severity of adjuvant-induced arthritis (AA) within a single rat
      strain. In response to open field stress, the corticosterone response of the low
      emotivity rats was significantly lower than that of the high emotivity rats. In
      spite of the differential corticosterone response to stress, no significant
      difference was found in paw volumes between the AA high and low emotivity groups.
      In another study, rats were subjected to a learned LH paradigm and separated into
      two groups based on failed (LH+) or successful (LH-) avoidance. Plasma
      corticosterone levels in response to avoidable foot shock in the LH- rats were
      significantly greater than in the LH+ group. Following injection with adjuvant,
      paw inflammation occurred earlier and was more severe in the LH- rats compared to
      the LH+ group. These data show that rats with a greater tendency to avoid foot
      shock have more severe inflammation, despite having a greater corticosterone
      response to stress. We conclude that an increased corticosterone response to
      stress does not affect susceptibility to or severity of inflammation in AA.
      Indeed, in the LH model a more robust response to stress is associated with
      increased inflammation and earlier onset of the disease.

PMID- 10415622
TI  - Disease activity related catecholamine response of lymphocytes from patients with
      rheumatoid arthritis.
AB  - In patients with chronic rheumatic diseases, a decreased density of beta 2
      adrenergic receptors (beta 2R) on peripheral blood mononuclear cells (PBMC) could
      be demonstrated negatively correlating with various disease activity parameters.
      The aim of the present study was to determine the impact of this decrease on
      catecholamine response of PBMC from patients with rheumatoid arthritis (RA) in
      vitro. PBMC from 17 patients with RA and 6 healthy blood donors (HD) were
      investigated. The effects of epinephrine (E) and norepinephrine (NE) on PBMC
      proliferation were studied using cells activated with phytohemagglutinin (PHA)
      and monoclonal anti-CD3-antibodies (OKT3), respectively. The results revealed
      that lymphocytes of patients with RA showed a significantly reduced influence of
      catecholamines on PBMC function. In RA patients with high disease activity only,
      a shift to alpha 1-adrenergic-mediated catecholamine effects upon PBMC reactivity
      could be observed. The study demonstrates the intricate relationship between PBMC
      reactivity and catecholamine effects that is mediated via alpha- and beta
      adrenergic receptors due to disease activity. In this respect the altered
      catecholamine response of PBMC from patients with RA may contribute to the
      pathogenic process of RA.

PMID- 10415623
TI  - Nitric oxide modulates Leydig cell function in vitro: is this a way of
      communication between the immune and endocrine system in the testis?

PMID- 10415624
TI  - Expression of mRNA encoding muscarinic receptor subtypes in neutrophils of
      patients with rheumatoid arthritis.

PMID- 10415625
TI  - Hypothalamic beta-endorphin concentrations are decreased in animal models of
      autoimmune disease.

PMID- 10415626
TI  - Intracellular cAMP and beta 2-adrenergic receptors on CD19+ lymphocytes in
      patients with rheumatoid arthritis.

PMID- 10415627
TI  - Androgens and dry eye in Sjogren's syndrome.
AB  - Sjogren's syndrome is an extremely complex and currently incurable autoimmune
      disorder, which occurs primarily in females, and is associated with lacrimal
      gland inflammation, meibomian gland dysfunction, and severe dry eye. We
      hypothesize that androgen deficiency, which reportedly occurs in primary and
      secondary Sjogren's syndrome (e.g., systemic lupus erythematosus, rheumatoid
      arthritis), is a critical etiologic factor in the pathogenesis of dry eye
      syndromes. We further hypothesize that androgen treatment to the ocular surface
      will promote both lacrimal and meibomian gland function and alleviate both
      "aqueous-deficient" and "evaporative" dry eye. Our results demonstrate that
      androgens regulate both lacrimal and meibomian gland function, and suggest that
      topical androgen administration may serve as a safe and effective therapy for the
      treatment of dry eye in Sjogren's syndrome.

PMID- 10415628
TI  - Hormonal pertubations in fibromyalgia syndrome.
AB  - The symptomatology characterizing fibromyalgia (FM) comprises three systems: the
      musculoskeletal system with widespread muscular pain, neuroendocrine disorders,
      and psychological distress including depression. Though the most prominent
      symptom of FM is pain in defined points of the musculoskeletal system, the
      numerous other somatoform and psychological disorders suppose a common primary
      disturbance which we consider to originate within higher levels of the central
      nervous system. Recent studies of the entire endocrine profile of FM patients
      following a simultaneous challenge of the hypophysis with corticotropin-releasing
      hormone (CRH), thyrotropin-releasing hormone, growth hormone-releasing hormone,
      and luteinizing hormone-releasing hormone support the hypothesis that an elevated
      activity of CRH neurons determines not only many symptoms of FM but may also
      cause the deviations observed in the other hormonal axes. Hypothalamic CRH
      neurons thus may play a key role not only in "resetting" the various endocrine
      loops but possibly also nociceptive and psychological mechanisms as well.

PMID- 10415629
TI  - Androgens and ankylosing spondylitis: a role in the pathogenesis?
AB  - The frequency and severity of ankylosing spondylitis (AS) show a male
      preponderance, and androgenic steroids have been implicated in its etiology. Some
      reports have indicated that serum androgen levels are slightly elevated relative
      to estrogen levels in patients with AS as compared to controls. In more recent
      studies, however, serum testosterone, 17 beta-estradiol, and androstenedione
      levels did not significantly differ between AS patients and controls. Moreover,
      testosterone levels measured directly in serum can be spuriously elevated,
      especially in patients using phenylbutazone. Elevated serum levels of the adrenal
      steroids 17 alpha-hydroxyprogesterone and dehydroepiandrosterone (DHEA) sulfate
      have been found in patients with AS. These elevations might be explained by
      partial 11 beta- or 21-hydroxylase deficiencies, but may also be secondary to an
      enhanced stress response. In vitro studies as well as studies in animals and
      humans indicate that DHEA enhanced, and 17 beta-estradiol and progesterone
      inhibit, the cell-mediated immune response, which may play a role in the
      pathogenesis of AS. Oral estrogen therapy in female patients and human chorionic
      gonadotrophin injections in male patients with AS, increased the 17 beta
      estradiol/testosterone ratio and resulted in a moderate clinical improvement. In
      conclusion, serum testosterone levels are not elevated in patients with AS.
      Therefore testosterone probably has no role in the perpetuation of long-standing
      AS and provides no basis for antiandrogenic treatment. Cross-sectional case
      control studies, however, cannot clearly distinguish etiological factors from
      secondary disease effects, especially when blood sampling occurs many years after
      the onset of AS. Consequently, the role of sex steroids in the pathogenesis is
      still insufficiently elucidated.

PMID- 10415630
TI  - Can we use steroid hormones to immunomodulate rheumatic diseases? Rheumatoid
      arthritis as an example.
AB  - This review discusses the available clinical trials in which steroids have been
      used in the (adjuvant) treatment of rheumatoid arthritis. Glucocorticosteroids
      have a positive effect on symptoms and signs of inflammation, but probably not on
      structural damage. Therefore glucocorticosteroids should be used as part of a
      long-term treatment strategy, including disease modifying drugs. Preventive
      measures regarding osteoporosis and peptic ulcer disease are now possible, and an
      active screening for potential adverse effects is advisable. The benefit of
      adjuvant treatment with sex hormones is limited. Estrogens have a slight positive
      effect in postmenopausal women on disease activity and bone mass. Androgens have
      a slight positive effect in men and postmenopausal women, especially on general
      well-being and bone mass.

PMID- 10415631
TI  - Hyperprolactinemia, uveitis, and systemic lupus erythematosus: clinical
      immunological correlation.

PMID- 10415632
TI  - Antiphospholipid antibodies and pregnancy.

PMID- 10415633
TI  - Gender-related analysis of thrombopoietic cytokine pattern in patients with
      immune thrombocytopenic purpura.

PMID- 10415634
TI  - Androgenizing effects of cyclosporin A in rheumatoid arthritis.
AB  - In order to determine the influence of CsA on whole peripheral androgen
      metabolism, we evaluated 14 patients with RA over a period of 12 months. Patients
      were treated with low-dose CsA (2.5-3.5 mg/kg/day). Other drugs influencing
      androgen metabolism were excluded. Plasma levels of Test and of 5 alpha
      androstane-3 alpha, 17 beta-diol glucuronide (Adiol-G), an important peripheral
      Test metabolite, were analyzed. Each patient was monthly examined for the first
      three months, and thereafter every three months. At each visit, the number of
      swollen and tender joints, as well as the visual analogic scale of pain, were
      evaluated. The laboratory parameters of RA activity (ESR, CRP, Hb) were also
      monitored, along with some safety serological indexes. Statistical analysis was
      performed by using nonparametrical tests. After 12 months of treatment, an
      evident increase in mean plasma Adiol-G concentration was observed in patients of
      both sexes (women's basal levels +/- SE = 2.89 +/- 0.58 ng/mL vs. 12 months =
      5.71 +/- 1.33 ng/mL; men's basal levels = 4.87 +/- 0.91 vs. 9.20 +/- 0.68,
      respectively) (p < 0.001). The increase was already statistically significant
      after 4-5 weeks of treatment in male patients (p < 0.01) and after 12-14 weeks in
      female patients (p < 0.05). All the patients experienced the side effect of a low
      degree hypertrichosis after a mean period of 4-8 weeks. Concerning clinical
      parameters, a significant improvement (p < 0.05) of the number of swollen and
      tender joints was observed after 12 months, as well as a reduction of CRP levels.
      No statistically significant correlation between hormonal levels and clinical or
      laboratory indexes of disease activity was observed. In conclusion, the
      appearance of a dose-related hypertrichosis and the increase in plasma androgen
      metabolites (Adiol-G) in CsA-treated patients should be regarded as possible
      markers of the influence of CsA on peripheral androgen metabolism, at the level
      of target cells and tissues.

PMID- 10415635
TI  - Field research on the relationship between stress and disease activity in
      rheumatoid arthritis.
AB  - We review empirical evidence from two field studies for the role of stressful
      life events in disease flare-ups among patients with rheumatoid arthritis (RA).
      RA patients were expected to be more vulnerable psychologically, and
      physiologically, to stressful events in their everyday lives than other arthritis
      patients without an autoimmune disease. Findings from two studies are reviewed
      both for their substantive contribution, but also to provide guidance on
      measurement issues in future field research of this kind. One study included 41
      patients with RA, who were interviewed weekly and called to a clinic for blood
      work and joint examinations when their levels of interpersonal stress increased
      significantly. A second study used a similar design but included comparison
      samples of patients with osteoarthritis (OA) and healthy controls of similar age
      and the same gender as the RA sample. The findings provided support for the
      proposition that interpersonal stressors are predictive of increases in disease
      activity. Not all RA patients, however, showed these relationships, and there was
      evidence that some participants with OA who were depressed also showed higher
      disease activity following interpersonal stressors. Significant individual
      differences in the stress-disease relationship were uncovered that deserve
      greater attention in future studies. Important improvements in the assessment of
      stressful events and refinements in panel study design are also presented as
      guides to research on the role of stress in disease processes.

PMID- 10415636
TI  - Stress and immune dysfunction in Gulf War veterans.
AB  - The role of stress and immunological abnormalities, as well as the neuroendocrine
      regulation of these two variables, in illnesses in Gulf War veterans (GWVs) is
      unknown. Many GWV patients complain of skin and joint problems, that is,
      disorders that may have a common immunological basis. Post-traumatic stress
      disorder (PTSD), an anxiety disorder associated with chronic stress, is diagnosed
      in approximately 10% of the Alabama GWVs. Chronic stress can lead to a reduced
      capacity to resist disease. Recent work suggests that a dysregulated balance of
      cytokines produced by T helper cells of the immune system can play a significant
      role in stress-related illnesses. Indeed, a balanced immune response (cell
      mediated and humoral immunity) is an important defense mechanism, and cytokines
      can regulate this balance. It is therefore plausible that stress-induced changes
      in hormones (such as cortisol and catecholamines) and cytokines, both of which
      have been implicated in altering levels of cellular or humoral immunity, may play
      a role in GWV illnesses.

PMID- 10415638
TI  - Sex hormones modulate inflammatory mediators produced by macrophages.

PMID- 10415637
TI  - Rheumatoid arthritis, personality, stress response style, and coping with
      illness. A preliminary survey.
AB  - Rheumatoid arthritis (RA) is an inflammatory chronic disease with an autoimmune
      pathogenesis and a complex multifactorial etiology. Various factors such as
      immunogenetic determinants, sex, age, and stress play an important role. The
      relationship between stress and RA is still unclear and undefined; however,
      various lines of research are developing in order to evaluate environmental,
      psychologic, and biologic stressors as predisposing factors. The aim of our study
      was to evaluate whether stress-related psychologic factors and personality
      disorders might be involved in the development of RA, by using a psychometric
      investigation-methodology in a series of patients. Fifteen in- and outpatients
      underwent a clinical interview and other specific psychometric tests. Macro- and
      microstressful life-events preceded RA onset in 86% of the cases. Sixty percent
      of the patients showed a correlation between flare-ups of the disease and
      appearance of microevents. Forty percent of the patients showed an obsessive
      compulsive personality disorder (OCPD), 40% showed a borderline personality
      disorder (BPD), 7% showed a schizoid and a dependent disorder. Only 13% of the
      patients showed no personality disorders. Among the BPD group we also detected
      alexithymia. Our results should be considered as preliminary; on the other hand,
      the high prevalence of major life-events preceding the onset of RA and the
      presence of personality disorders support the role of the altered stress response
      system as an important pathogenetic factor and will be a matter of further
      studies.

PMID- 10415639
TI  - Advancing from the ventral striatum to the extended amygdala. Implications for
      neuropsychiatry and drug abuse. Introduction.

PMID- 10415640
TI  - The concepts of the ventral striatopallidal system and extended amygdala.
AB  - The concepts of the ventral striatopallidal system and extended amygdala have
      significantly improved our understanding of basal forebrain organization. As a
      result of these and other advances during the last twenty years, many of the most
      prominent basal forebrain structures, including the nucleus accumbens, olfactory
      tubercle, and amygdaloid body, have all but lost their relevance as independent
      functional anatomical units. In order to appreciate the distinct differences that
      exist between the ventral striatopallidal system and the extended amygdala, and
      as a way of explaining the choice of the terms ventral striatopallidal system and
      extended amygdala, we will review the discovery and subsequent elaboration of
      these two systems. On the background of these discussions, we will then proceed
      to dispel some recently published misgivings regarding the usefulness of the
      extended amygdaloid concept.

PMID- 10415641
TI  - The concept of the ventral striatum in nonhuman primates.
AB  - The concept of the ventral striatum was first put forth by Heimer and Wilson to
      describe the extension of basal ganglia elements into the olfactory tubercle. The
      ventral striatum includes the conventional nucleus accumbens, which has been
      closely associated with reward and motivation. This paper uses the afferent
      connections to the ventral striatum to define this region in monkeys. Furthermore
      the shell and core subterritories are discussed with respect to their
      histochemistry and specific connections.

PMID- 10415642
TI  - Convergence and segregation of ventral striatal inputs and outputs.
AB  - The ventral striatum, which prominently includes the nucleus accumbens (Acb), is
      a heterogeneous area. Within the Acb of rats, a peripherally located shell and a
      centrally situated core can be recognized that have different connectional,
      neurochemical, and functional identities. Although the Acb core resembles in many
      respects the dorsally adjacent caudate-putamen complex in its striatal character,
      the Acb shell has, in addition to striatal features, a more diverse array of
      neurochemical characteristics, and afferent and efferent connections. Inputs and
      outputs of the Acb, in particular of the shell, are inhomogeneously distributed,
      resulting in a mosaical arrangement of concentrations of afferent fibers and
      terminals and clusters of output neurons. To determine the precise relationships
      between the distributional patterns of various afferents (e.g., from the
      prefrontal cortex, the basal amygdaloid complex, the hippocampal formation, and
      the midline/intralaminar thalamic nuclei) and efferents to the ventral pallidum
      and mesencephalon, neuroanatomical anterograde and retrograde tracing experiments
      were carried out. The results of the double anterograde, double retrograde, and
      anterograde/retrograde tracing experiments indicate that various parts of the
      shell (dorsomedial, ventromedial, ventral, and lateral) and the core (medial and
      lateral) have different input-output characteristics. Furthermore, within these
      Acb regions, various populations of neurons can be identified, arranged in a
      cluster-like fashion, onto which specific sets of afferents converge and that
      project to particular output stations, distinct from the input-output
      relationships of neighboring, cluster-like neuronal populations. These results
      support the idea that the nucleus accumbens may consist of a collection of
      neuronal ensembles with different input-output relationships and, presumably,
      different functional characteristics.

PMID- 10415643
TI  - Involvement of the pallidal-thalamocortical circuit in adaptive behavior.
AB  - Interconnections among the ventral mesencephalon, nucleus accumbens, and ventral
      pallidum are critical in the initiation of adaptive behavioral responses to
      environmental stimuli. Within this circuit are two highly topographically
      organized subcircuits that are differentially interconnected with limbic and
      motor circuitry in the brain. However, there is not a great deal of anatomical
      interconnection between the limbic and motor subcircuits. A polysynaptic
      connection between the two subcircuits involves projections from the limbic
      ventral pallidum to the mediodorsal thalamus to the prefrontal cortex back to the
      motor regions of the nucleus accumbens. In the present report we show that this
      connection is critical in the expression of motor behavior elicited by opioids
      and the capacity of a rat to perform in a task requiring spatial working memory.

PMID- 10415644
TI  - Functional specificity of ventral striatal compartments in appetitive behaviors.
AB  - The nucleus accumbens and its associated circuitry subserve behaviors linked to
      natural or biological rewards, such as feeding, drinking, sex, exploration, and
      appetitive learning. We have investigated the functional role of neurotransmitter
      and intracellular transduction mechanisms in behaviors subserved by the core and
      shell subsystems within the accumbens. Local infusion of the selective NMDA
      antagonist, AP-5, into the accumbens core, but not the shell, completely blocked
      acquisition of a bar-press response for food in hungry rats. This effect was
      apparent only when infused during the early stages of learning. We have also
      recently shown that infusion of certain protein kinase inhibitors into the core
      also impairs learning in the same paradigm. These results suggest that plasticity
      related mechanisms within the accumbens core, involving glutamate-linked
      intracellular second messengers, are important for response-reinforcement
      learning. In contrast to the core, which primarily connects to somatic motor
      output systems, the shell is more intimately linked to viscero-endocrine effector
      systems. We have shown that both AMPA and GABA receptors within the medial shell
      (but not the core) are critically involved in controlling the brain's feeding
      pathways, via activation of the lateral hypothalamus (LH). This effect is blocked
      by local inhibition of the LH in double-cannulae experiments and also strongly
      and selectively activates Fos expression in the LH. These results provide a newly
      emerging picture of the differentiated functions of this forebrain region and
      suggest an integrated role in the elaboration of adaptive motor actions.

PMID- 10415645
TI  - Mesolimbic neuronal activity across behavioral states.
AB  - A goal of neurophysiology of the mesolimbic system is to determine the activity
      patterns within the regions in the prefrontal cortex, ventral neostriatum, and
      amygdala that regulate behavioral patterns to seek rewards. A new technology has
      been introduced in which arrays of microwires are implanted in different brain
      regions while activity patterns of ensembles of neurons are recorded for long
      periods of time during freely moving behaviors. Multichannel instrumentation and
      software is used for data acquisition and analysis. An initial hypothesis was
      that neural signals would be encountered in the nucleus accumbens and associated
      regions specifically related to reward. However, an initial study of neural
      activity and behavioral patterns during a simple lever press for intravenous
      cocaine (1 mg/kg) revealed that phasic excitatory or inhibitory neural activity
      patterns often appear prior to the reward phase. Individual neurons throughout
      the mesolimbic system appear to code information specific to sensory and motor
      events, tones, or lever presses in the chain of tasks leading to all rewards so
      far studied. Different spatial temporal patterns also appear within the same
      neural populations, as reward is changed from injected cocaine to heroin, from
      ingested pure water to ethanol in water or sucrose. Overall, patterns of activity
      for each neuron are found to shift dynamically during the operant task as changes
      are made in the target reward. Significant shifts in activity of mesolimbic
      neurons that are unrelated to specific sensory-motor events also appear during
      complex sessions, such as during a bout of ethanol consumption to reach satiation
      or during progressive ratio tasks with increasing difficulty. An emerging
      hypothesis is that some candidate neural elements in the mesolimbic system code
      the anticipated reward, whereas others serve internal logic functions of
      motivation that mediate extinction or resumption of specific goal-directed
      behaviors.

PMID- 10415646
TI  - Functional-anatomical implications of the nucleus accumbens core and shell
      subterritories.
AB  - The nucleus accumbens, a major part of the ventral striatum, comprises numerous
      subterritories and compartments, of which the core and shell appear to be
      dominant. Shell exhibits greater chemical neuroanatomical diversity than core and
      is rather directly connected to it by a robust, feed-forward, striatopallido
      thalamocortico-striatal pathway. Shell and extended amygdala share afferents, but
      the two are distinguished by their outputs, strongly toward cortex for shell and
      descendent toward brain stem effector sites for extended amygdala. Shell responds
      independently to stimulation by excitatory amino acids and dopamine, which are
      more mutually permissive in the core. Accordingly, the shell responds to a broad
      variety of physiological and pharmacological stimuli, including psychomotor and
      opioid drugs. Whereas locomotion and oro-facial movements are elicitable from the
      shell, lesions and blockade of EAA transmission in the core reduce locomotion. It
      is hypothesized that core-shell has a feed-forward functional organization.

PMID- 10415647
TI  - Regulation of neurotransmitter interactions in the ventral striatum.
AB  - Transsynaptic activation of neuronal circuits originating in the basal forebrain
      contributes to psychostimulant-evoked dopamine and glutamate release and
      consequent changes in medium spiny neuronal gene expression in the ventral
      striatum. New evidence from microdialysis studies indicates that amphetamine
      induced dopamine and glutamate release in vivo is partially calcium dependent.
      The calcium-dependent component is totally blocked by a kappa opioid receptor
      agonist, indicating that endogenous opioids may regulate dopamine-glutamate
      interactions in the ventral striatum. Further, muscarinic receptor blockade
      increases, and muscarinic receptor stimulation decreases, dialysate glutamate
      levels in the striatum. Pre- and postsynaptic muscarinic receptors contribute to
      the ability of the muscarinic antagonist, scopolamine, to augment D1 receptor
      stimulated immediate early and neuropeptide gene expression. Moreover,
      scopolamine prevents a D2 antagonist from blocking D1 agonist-induced gene
      expression, indicating that activation of cholinergic interneurons contributes to
      D1/D2 interactions in the striatum. Thus, transsynaptic activity and presynaptic
      muscarinic and kappa opioid receptors regulate dopamine and glutamate
      interactions that switch on and off multiple intracellular signaling cascades.
      Changes in immediate early and neuropeptide gene expression that result from
      activation of these cascades are mediated by such nuclear transcription factors
      as phosphorylated cyclase response element-binding protein. In addition, a novel
      signaling pathway involving the RAR/RXR nuclear hormone receptor complex is
      implicated in the control of dopamine receptor and neuropeptide gene expression
      in the striatum.

PMID- 10415648
TI  - The synaptic framework for chemical signaling in nucleus accumbens.
AB  - Our knowledge of the organization of the nucleus accumbens has been greatly
      advanced in the last two decades, but only now are we beginning to understand the
      complex neural circuitry that underlies the mix of behaviors attributed to this
      nucleus. Superimposed on the neurochemically defined territories of the shell and
      core are four or more conduits for information flow. Each of these behaviorally
      relevant pathways can be characterized by the spatial distribution of inputs to
      its central unit: the GABAergic projection neuron, a spiny cell that also
      contains the opioid peptides, enkephalin or dynorphin. In this review, current
      models of accumbal circuits will be examined and, with the aid of recent
      anatomical findings, further extended to shed light on how functionally diverse
      information is processed in this nucleus. However complex, accumbal wiring is not
      fixed, and, as we will show, psychostimulants, dopamine-deleting lesions, and
      chronic blockade of dopaminergic receptors can alter the anatomical substrate,
      synaptology, and neurotrophic factors that govern circuits through the shell and
      core.

PMID- 10415649
TI  - Modulation of cell firing in the nucleus accumbens.
AB  - Pennartz et al. have proposed that functions of the nucleus accumbens (NA) are
      subserved by the activity of ensembles of neurons rather than by an overall
      neuronal activation. Indeed, the NA is a site of convergence for a large number
      of inputs from limbic structures that may modulate the flow of prefrontal
      cortical information and contribute to defining such ensembles, as exemplified in
      the ability of hippocampal input to gate cortical throughput in the nucleus
      accumbens. NA neurons exhibit a bistable membrane potential, characterized by a
      very negative resting membrane potential (down state), periodically interrupted
      by plateau depolarizations (up state), during which the cells may fire in
      response to cortical inputs. A dynamic ensemble can be the result of a
      distributed set of neurons in their up state, determined by the moment-to-moment
      changes in the spatial distribution of hippocampal inputs responsible for
      transitions to the up state. Ensembles may change as an adaptation to the
      contextual information provided by the hippocampal input. Furthermore, for
      dynamic ensembles to be functionally relevant, the model calls for near
      synchronous transitions to the up state in a group of neurons. This can be
      accomplished by the cell-to-cell transfer of information via gap junctions, a
      mechanism that can allow for a transfer of slow electrical signals, including
      "up" events between coupled cells. Furthermore, gap junction permeability is
      tightly modulated by a number of factors, including levels of dopamine and nitric
      oxide, and cortical inputs, allowing for fine-tuning of this synchronization of
      up events. The continuous selection of such dynamic ensembles in the NA may be
      disputed in schizophrenia, resulting in an inappropriate level of activity of
      thalamocortical systems.

PMID- 10415650
TI  - Opioid modulation of ventral pallidal inputs.
AB  - While the ventral pallidum (VP) is known to be important in relaying information
      between the nucleus accumbens and target structures, it has become clear that
      substantial information processing occurs within the VP. We evaluated the
      possibility that opioid modulation of other transmitters contained in VP
      afferents is involved in this process. Initially, we demonstrated that opioids
      hyperpolarized VP neurons in vitro and suppressed spontaneous firing in vivo. The
      ability of opioids to modulate other transmitters was determined using
      microiontophoretically applied ligands and extracellular recordings of VP neurons
      from chloral hydrate-anesthetized rats. With neurons that responded to
      iontophoresed opioid agonists, the ejection current was reduced to a level that
      was below that necessary to alter spontaneous firing. This "subthreshold" current
      was used to determine the ability of mu opioid receptor (microR) agonists to
      alter VP responses to endogenous (released by electrical activation of afferents)
      and exogenous (iontophoretically applied) transmitters. microR agonists decreased
      the variability and enhanced the acuity (e.g., "signal-to-noise" relationship) of
      VP responses to activation of glutamatergic inputs from the prefrontal cortex and
      amygdala. By contrast, microR agonists attenuated both the slow excitatory
      responses to substance P and GABA-induced inhibitions that resulted from
      activating the nucleus accumbens. Subthreshold opioids also attenuated inhibitory
      responses to stimulating midbrain dopaminergic cells. These results suggest that
      a consequence of opioid transmission in the VP is to negate the influence of some
      afferents (e.g., midbrain dopamine and accumbal GABA and substance P) while
      selectively potentiating the efficacy of others (e.g., cortical and amygdaloid
      glutamate). Interpreted in the context of opiate abuse, microR opioids in the VP
      may serve to diminish the influence of reinforcement (ventral tegmental area and
      nucleus accumbens) in the transduction of cognition (prefrontal cortex) and
      affect (amygdala) into behavior. This may contribute to drug craving that occurs
      even in the absence of reward.

PMID- 10415651
TI  - Cross-species studies of sensorimotor gating of the startle reflex.
AB  - Sensorimotor gating of the startle reflex can be assessed across species, using
      similar stimuli to elicit comparable response characteristics. As measured by
      prepulse inhibition (PPI), gating is reduced in patients with some
      neuropsychiatric disorders, and in rats after manipulations of limbic cortex,
      striatum, pallidum, or pontine tegmentum. This limbic "CSPP" circuitry can be
      studied in rats to reveal the neurochemical and neuroanatomical substrates
      regulating PPI at a high level of resolution. This detailed circuit information
      is used as a "blueprint" to identify substrates that may lead to PPI deficits in
      psychiatric-disordered humans. Some human disorders with identifiable, localized
      lesions in CSPP circuitry, for example, Huntington's disease, provide direct
      validation for this cross-species model. Studies have begun to assess the
      pharmacological homology of PPI across species, as an initial step towards
      translating detailed neural circuit information from rats to humans. These
      initial studies suggest the possibility that the effects of dopaminergic
      (DAergic) drugs on PPI (reducing PPI) may be homologous across species; nicotinic
      drugs may also produce similar effects on PPI across species (increasing PPI). By
      contrast, the effects of glutamatergic and serotonergic drugs may exhibit
      disparate effects on PPI across species. The use of DAergic agonists in human
      studies is complicated by their significant side effects, but new studies
      demonstrate that several "human friendly" direct DA agonists disrupt PPI in rats
      and are thus good candidates for further studies of the cross-species homology of
      the DAergic regulation of PPI. In this manner, PPI can be used to probe the
      sensitivity of DAergic systems, and perhaps other CSPP elements, across normal
      and neuropsychiatric-disordered populations.

PMID- 10415652
TI  - The intrinsic organization of the central extended amygdala.
AB  - The central component of the extended amygdala (CEA) comprises the central
      amygdaloid nucleus (Ce), the dorsal substantia innominata (SI), and the bed
      nucleus of the stria terminalis (BNST). Anatomical studies have suggested the
      presence of an intrinsic system of GABAergic neurons that not only connects
      homologous subareas of the Ce, SI, and BNST but that also acts as an interface
      between sensory afferents and brain stem-projecting neurons. CEA outputs, with a
      few exceptions, arise from separate populations of neurons, but all, including
      GABAergic neurons themselves, are heavily innervated by GABAergic terminals.
      GABAergic neurons may serve to integrate output activity of the CEA, though
      GABAergic neurons form a heterogeneous population whose differential intrinsic
      connections appear related to their peptide content. Afferents from the
      dysgranular insular cortex and lateral parabrachial complex preferentially
      innervate GABAergic neurons, suggesting these neurons may also integrate afferent
      activity. Afferents from the basolateral amygdala (BL) appear to innervate both
      output neurons and intrinsic GABAergic neurons. Evidence will be presented to
      show that BL afferents form synaptic complexes with cortical, GABAergic, and TH
      immunoreactive terminal boutons on GABAergic dendritic spines. These complexes
      may be a key element in control of CEA output activity.

PMID- 10415653
TI  - The medial extended amygdala in male reproductive behavior. A node in the
      mammalian social behavior network.
AB  - Hormonal and chemosensory signals regulate social behaviors in a wide variety of
      mammals. In the male Syrian hamster, these signals are integrated in nuclei of
      the medial extended amygdala, where olfactory and vomeronasal system transmission
      is modulated by populations of androgen- and estrogen-sensitive neurons. Evidence
      from behavioral changes following lesions and from immediate early gene
      expression supports the hypothesis that the medial extended amygdala and medial
      preoptic area belong to a circuit that functions selectively in male sexual
      behavior. However, accumulated behavioral, neuroanatomical, and neuroendocrine
      data in hamsters, other rodents, and other mammals indicate that this circuit is
      embedded in a larger integrated network that controls not only male mating
      behavior, but female sexual behavior, parental behavior, and various forms of
      aggression. In this context, perhaps an individual animal's social responses can
      be more easily understood as a repertoire of closely interrelated, hormone
      regulated behaviors, shaped by development and experience and modulated acutely
      by the environmental signals and the hormonal milieu of the brain.

PMID- 10415654
TI  - The extended amygdala and salt appetite.
AB  - Both chemo- and mechanosensitive receptors are involved in detecting changes in
      the signals that reflect the status of body fluids and of blood pressure. These
      receptors are located in the systemic circulatory system and in the sensory
      circumventricular organs of the brain. Under conditions of body fluid deficit or
      of marked changes in fluid distribution, multiple inputs derived from these
      humoral and neural receptors converge on key areas of the brain where the
      information is integrated. The result of this central processing is the
      mobilization of homeostatic behaviors (thirst and salt appetite), hormone
      release, autonomic changes, and cardiovascular adjustments. This review discusses
      the current understanding of the nature and role of the central and systemic
      receptors involved in the facilitation and inhibition of thirst and salt appetite
      and on particular components of the central neural network that receive and
      process input derived from fluid- and cardiovascular-related sensory systems.
      Special attention is paid to the structures of the lamina terminalis, the area
      postrema, the lateral parabrachial nucleus, and their association with the
      central nucleus of the amygdala and the bed nucleus of the stria terminalis in
      controlling the behaviors that participate in maintaining body fluid and
      cardiovascular homeostasis.

PMID- 10415655
TI  - The extended amygdala: are the central nucleus of the amygdala and the bed
      nucleus of the stria terminalis differentially involved in fear versus anxiety?
AB  - Although there is a close correspondence between fear and anxiety, and the study
      of fear in animals has been extremely valuable for understanding the neural basis
      of anxiety, it is also clear that a richer animal model of human anxiety
      disorders would include measures of both stimulus-specific fear and something
      less stimulus specific, more akin to anxiety. Patients with posttraumatic stress
      syndrome seem to show normal fear reactions but abnormal anxiety measured with
      the acoustic startle reflex. Studies in rats, also using the startle reflex,
      indicate that highly processed explicit cue information (lights, tones) activates
      the central nucleus of the amygdala, which projects to and modulates the acoustic
      startle pathway in the brain stem. Less explicit information, such as that
      produced by exposure to a threatening environment or by intraventricular
      administration of corticotropin-releasing hormone, may activate another part of
      the extended amygdala, the bed nucleus of the stria terminalis, which also
      projects to the startle pathway. Because this information may be less specific
      and of long duration, activation of the bed nucleus of the stria terminalis may
      mediate anxiety, whereas activation of the central nucleus of the amygdala may
      mediate stimulus-specific fear.

PMID- 10415656
TI  - Brain and sexual behavior.
AB  - This chapter will give personal accounts of the neural basis of male rat sexual
      behavior from two somewhat different perspectives, one tilted towards
      neuroanatomy (K.L.), and one tilted towards monoaminergic pharmacology (S.A.).
      Both perspectives were strongly influenced by the Zeitgeist, the former
      imperceptibly merging into the latter as relations between the neural substrate
      for monoaminergic neurotransmission was elucidated.

PMID- 10415657
TI  - Cortical afferents to the extended amygdala.
AB  - The projections of the cerebral cortex to the extended amygdala were studied in
      the rat using anterograde and retrograde tract-tracing techniques. Most cortical
      areas with strong projections to the extended amygdala preferentially targeted
      either the medial extended amygdala (including the medial amygdalar nucleus,
      ventromedial substantia innominata, and the medial part of the bed nucleus the
      stria terminalis) or the central extended amygdala (including the central
      amygdalar nucleus, dorsolateral substantia innominata, and the lateral part of
      the bed nucleus of the stria terminalis). Some cortical areas, however, had equal
      projections to both medial and central portions. The main areas projecting
      preferentially to the medial extended amygdala were the ventral subiculum,
      infralimbic cortex, ventral agranular insular area, and the rostral part of the
      ventrolateral entorhinal area. The main areas projecting preferentially to the
      central extended amygdala were the prefrontal cortex, viscerosensory and
      somatosensory portions of the insular cortex, and the amygdalopiriform
      transitional area. It is suggested that these cortical inputs may be important
      for cognitive, mnemonic, and affective aspects of emotional and motivated
      behavior.

PMID- 10415658
TI  - The basal forebrain corticopetal system revisited.
AB  - The medial septum, diagonal bands, ventral pallidum, substantia innominata,
      globus pallidus, and internal capsule contain a heterogeneous population of
      neurons, including cholinergic and noncholinergic (mostly GABA containing),
      corticopetal projection neurons, and interneurons. This highly complex brain
      region, which constitutes a significant part of the basal forebrain has been
      implicated in attention, motivation, learning, as well as in a number of
      neuropsychiatric disorders, such as Alzheimer's disease, Parkinson's disease, and
      schizophrenia. Part of the difficulty in understanding the functions of the basal
      forebrain, as well as the aberrant information-processing characteristics of
      these disease states lies in the fact that the organizational principles of this
      brain area remained largely elusive. On the basis of new anatomical data, it is
      proposed that a large part of the basal forebrain corticopetal system be
      organized into longitudinal bands. Considering the topographic organization of
      cortical afferents to different divisions of the prefrontal cortex and a similar
      topographic projection of these prefrontal areas to basal forebrain regions, it
      is suggested that several functionally segregated cortico-prefronto-basal
      forebrain-cortical circuits exist. It is envisaged that such specific
      "triangular" circuits could amplify selective attentional processing in posterior
      sensory cortical areas.

PMID- 10415660
TI  - Prefrontal cortical networks related to visceral function and mood.
AB  - At least twenty-two architectonic areas can be distinguished within the orbital
      and medial prefrontal cortex (OMPFC). Although each of these areas has a distinct
      structure and connections, they can be grouped into two "networks," defined by
      cortico-cortical connections that primarily interconnect areas within each
      network. The networks also have different connections to the striatum, medial
      thalamus, and other brain regions. The orbital network consists of most of the
      areas in the orbital cortex. It receives several sensory inputs (olfactory,
      gustatory, visceral afferent, somatic sensory, and visual) that appear to be
      related to feeding. It also receives many limbic inputs from the amygdala,
      entorhinal and perirhinal cortex, and subiculum, including a specific projection
      from the ventrolateral part of the basal amygdaloid nucleus. The orbital network
      may therefore serve as a substrate to integrate viscerosensory information with
      affective signals. The medial network consists of areas on the medial frontal
      surface together with a few select areas in the orbital cortex. These areas have
      few direct sensory inputs, and their limbic inputs are somewhat different than
      those to the orbital network (e.g., from the ventromedial part of the basal
      amygdaloid nucleus). However, they provide the major output from the OMPFC to the
      hypothalamus and brain stem (especially the periaqueductal gray). The medial
      network may therefore serve as a visceromotor system to provide frontal cortical
      influence over autonomic and endocrine function. Connections between the networks
      presumably allow information flow from viscerosensory to visceromotor systems. In
      addition to a probable role in eating behavior, this system appears to be
      involved in guiding behavior and regulation of mood. Lesions of the ventromedial
      prefrontal cortex result in sociopathic behavior and difficulty in making
      appropriate choices, whereas functional imaging studies indicate that subjects
      with unipolar and bipolar depression have abnormal activity in medial and orbital
      prefrontal areas. Many of these areas also show volume changes and decreased
      glial number and density in mood-disordered subjects.

PMID- 10415659
TI  - Basal forebrain afferent projections modulating cortical acetylcholine,
      attention, and implications for neuropsychiatric disorders.
AB  - Cortical acetylcholine (ACh) mediates the detection, selection, and processing of
      stimuli and associations, and the allocation of processing resources for these
      attentional functions. For example, loss of cortical cholinergic inputs impairs
      the performance of rats in tasks designed to assess sustained or divided
      attention. Intrabasalis infusions of benzodiazepine receptor (BZR) agonists block
      increases in cortical ACh efflux and impair attentional abilities. Studies on the
      regulation of cortical ACh efflux by nucleus accumbens (NAC) dopamine (DA)
      demonstrate that increases in cortical ACh efflux are attenuated by intra
      accumbens administration of D1 and, more potently, D2 receptor antagonists. These
      and other data support the hypothesis that NAC DA, via GABAergic projections to
      the basal forebrain, controls the excitability of basal forebrain cholinergic
      neurons. As increases in NAC DA have been hypothesized to represent a major
      neuronal mediator of schizophrenia and the compulsive use of addictive drugs, the
      data predict that the abnormal regulation of cortical ACh release represents a
      crucial neuronal mechanism mediating the cognitive components of these
      psychopathological disorders.

PMID- 10415661
TI  - Functions of the amygdala and related forebrain areas in attention and cognition.
AB  - This paper will concentrate on two features of the systems described by Alheid
      and Heimer that have influenced research in our laboratory in recent years. In
      the first part, we describe our findings on a representational function of the
      amygdaloid basolateral complex that appears to depend on its interconnections
      with the prefrontal cortex. In the second part, we describe progress assessing
      the function of magnocellular corticopetal neurons within the basal forebrain and
      the strong input to this system from the central amygdaloid group. These lines of
      behavioral research have revealed that sub-systems in the basal forebrain and
      amygdala serve adaptive functions beyond the domains of motivation and emotion to
      include attention and cognition.

PMID- 10415662
TI  - Associative processes in addiction and reward. The role of amygdala-ventral
      striatal subsystems.
AB  - Only recently have the functional implications of the organization of the ventral
      striatum, amygdala, and related limbic-cortical structures, and their
      neuroanatomical interactions begun to be clarified. Processes of activation and
      reward have long been associated with the NAcc and its dopamine innervation, but
      the precise relationships between these constructs have remained elusive. We have
      sought to enrich our understanding of the special role of the ventral striatum in
      coordinating the contribution of different functional subsystems to confer
      flexibility, as well as coherence and vigor, to goal-directed behavior, through
      different forms of associative learning. Such appetitive behavior comprises many
      subcomponents, some of which we have isolated in these experiments to reveal
      that, not surprisingly, the mechanisms by which an animal sequences responding to
      reach a goal are complex. The data reveal how the different components, pavlovian
      approach (or sign-tracking), conditioned reinforcement (whereby pavlovian stimuli
      control goal-directed action), and also more general response-invigorating
      processes (often called "activation," "stress," or "drive") may be integrated
      within the ventral striatum through convergent interactions of the amygdala,
      other limbic cortical structures, and the mesolimbic dopamine system to produce
      coherent behavior. The position is probably not far different when considering
      aversively motivated behavior. Although it may be necessary to employ simplified,
      even abstract, paradigms for isolating these mechanisms, their concerted action
      can readily be appreciated in an adaptive, functional setting, such as the
      responding by rats for intravenous cocaine under a second-order schedule of
      reinforcement. Here, the interactions of primary reinforcement, psychomotor
      activation, pavlovian conditioning, and the control that drug cues exert over the
      integrated drug-seeking response can be seen to operate both serially and
      concurrently. The power of our analytic techniques for understanding complex
      motivated behavior has been evident for some time. However, the crucial point is
      that we are now able to map these components with increasing certainty onto
      discrete amygdaloid, and other limbic cortical-ventral striatal subsystems. The
      neural dissection of these mechanisms also serves an important theoretical
      purpose in helping to validate the various hypothetical constructs and further
      developing theory. Major challenges remain, not the least of which is an
      understanding of the operation of the ventral striatum together with its
      dopaminergic innervation and its interactions with the basolateral amygdala,
      hippocampal formation, and prefrontal cortex at a more mechanistic, neuronal
      level.

PMID- 10415663
TI  - Functional and anatomical relationships among the amygdala, basal forebrain,
      ventral striatum, and cortex. An integrative discussion.
AB  - Two recent papers have questioned the concept of the amygdala as a functional and
      anatomically separate entity. Swanson and Petrovich go so far as to state that
      "the amygdala is neither a structural nor a functional unit." This novel concept
      is derived from the fact that the amygdala is a structure whose anatomical
      connections and neurochemical features are more strongly interrelated to adjacent
      parts of the temporal lobe and basal forebrain than to unique characteristics of
      its own. This is an emerging hypothetical concept of the "amygdala" that seems to
      repeat itself in many parts of this volume and merits further examination in the
      future. The basal forebrain and cortical circuitry described here seem to be
      critical for a set of behaviors/processes that could be collectively described as
      cognitive-emotive. For example, this would include arousal, attention, sensory
      processing, reinforcement, and finally associative learning, decision making, and
      memory. Collectively this circuitry influences the emotional, motivational, and
      cognitive state of an organism. More and more studies are demonstrating that
      small and localized manipulations of the brain can result in equally subtle and
      specific deficits that are associated with definable parts of the anatomical
      circuitry, neurotransmitters, and receptors of basal forebrain structures. These
      studies have been guided and influenced by the refined neuroanatomical and
      neurochemical investigations of Lennart Heimer and his colleagues.
      Interpretations of these studies are beginning to uncover distinct deficits that
      suggest explanations and potential treatments for many psychiatric and
      pathological degenerative disorders.

PMID- 10415664
TI  - The role of the striatopallidal and extended amygdala systems in drug addiction.
AB  - Evidence suggests that the acute reinforcing actions of drugs of abuse may be
      mediated by specific elements of the striatopallidal and extended amygdala
      systems. These include the shell of the nucleus accumbens, the central nucleus of
      the amygdala, and the sublenticular extended amygdala. Chronic administration of
      drugs of abuse, including cocaine, amphetamines, nicotine, alcohol, and
      tetrahydrocannabinol leads to an increasing dysregulation of brain reward systems
      that is characterized by decreases in reward function. Withdrawal from chronic
      administration of cocaine, amphetamine, nicotine, alcohol, and
      tetrahydrocannabinol raises thresholds for brain stimulation reward.
      Neurochemical elements in the extended amygdala may mediate these changes,
      including decreases in dopamine and serotonin neurotransmission in the nucleus
      accumbens and increases in the brain-stress neurotransmitter, corticotropin
      releasing factor, in the central nucleus of the amygdala. The combination of
      decreases in function of neurotransmitters involved in the positive-reinforcing
      properties of drugs of abuse with recruitment of brain-stress systems within the
      extended amygdala provides a powerful mechanism for allostatic changes in hedonic
      set point that can lead to the compulsive drug-seeking and drug-taking behavior
      characteristic of addiction.

PMID- 10415665
TI  - Drug addiction as a disorder of associative learning. Role of nucleus accumbens
      shell/extended amygdala dopamine.
AB  - Conventional reinforcers phasically stimulate dopamine transmission in the
      nucleus accumbens shell. This property undergoes one-trial habituation consistent
      with a role of nucleus accumbens shell dopamine in associative learning.
      Experimental studies with place- and taste-conditioning paradigms confirm this
      role. Addictive drugs share with conventional reinforcers the property of
      stimulating dopamine transmission in the nucleus accumbens shell. This response,
      however, undergoes one-trial habituation in the case of conventional reinforcers
      but not of drugs. Resistance to habituation allows drugs to repetitively activate
      dopamine transmission in the shell upon repeated self-administration. This
      process abnormally facilitates associative learning, leading to the attribution
      of excessive motivational value to discrete stimuli or contexts predictive of
      drug availability. Addiction is therefore the expression of the excessive control
      over behavior acquired by drug-related stimuli as a result of abnormal
      strenghtening of stimulus-drug contingencies by nondecremental drug-induced
      stimulation of dopamine transmission in the nucleus accumbens shell.

PMID- 10415666
TI  - The bed nucleus of the stria terminalis. A target site for noradrenergic actions
      in opiate withdrawal.
AB  - Hyperactivity of brain norepinephrine (NE) systems has long been implicated in
      mechanisms of opiate withdrawal (OW). However, little is known about where
      elevated NE may act to promote OW. Here we report that the bed nucleus of the
      stria terminalis (BNST), the densest NE target in the brain, is critical for NE
      actions in OW. (1) Many BNST neurons become Fos+ after OW. Pretreatment with the
      beta antagonist, propranolol, markedly reduces OW symptoms and the number of Fos+
      cells in the BNST. (2) Numerous neurons in the nucleus tractus solitarius (A2
      neurons) and the A1 cell group are triple labeled for tyrosine hydroxylase, a
      retrograde tracer from the BNST, and Fos after OW, revealing numerous NE neurons
      that project to the BNST from the medulla that are stimulated by OW. Fewer such
      triple-labeled neurons were found in the locus caeruleus. (3) Behavioral studies
      reveal that local microinjections of selective beta-adrenergic antagonists into
      the BNST attenuate OW symptoms. In particular, withdrawal-induced place aversion
      is abolished by bilateral microinjection of a cocktail of selective beta 1
      (betaxolol) plus the beta 2 (ICI 181,555) antagonists (1.0 nmol each/0.5 microL
      per side) into the BNST. Similar results were obtained with neurochemically
      selective lesions of the ventral ascending NE bundle, the pathway for A1 and A2
      projections to the BNST. Similar lesions of the dorsal NE bundle of projections
      from the locus caeruleus had no effect on either aversive or somatic withdrawal
      symptoms. Together, these results indicate that beta-receptor activation in the
      BNST is critical for aversive withdrawal symptoms, and that A1 and A2 neurons in
      the medulla are the source of this critical NE.

PMID- 10415667
TI  - The role of dopamine, dynorphin, and CART systems in the ventral striatum and
      amygdala in cocaine abuse.
AB  - Disturbance of the mesolimbic dopamine system has long been hypothesized for the
      underlying neurobiology of cocaine addiction. Recently, increased attention has
      been directed towards the opioid neuropeptide system, in particular dynorphin;
      inasmuch as opioid peptide-containing neurons are regulated by dopamine, these
      peptides have potent effects on mood and reward, and cocaine consistently
      modulates dynorphin activity. Our experiments have been directed towards
      characterizing the specific alterations of dopamine and dynorphin systems during
      different stages following cocaine administration, as well as assessing the
      contribution of nucleus accumbens and amygdala dopamine levels to cocaine-intake
      behavior. We have used the techniques of in vivo microdialysis to measure and
      manipulate extracellular concentrations of dopamine in animals that self
      administer cocaine, and in situ hybridization to study mRNA expression levels of
      prodynorphin and dopamine receptors. It is clear from these studies that
      different stages of the cocaine use cycle are characterized by distinct patterns
      of prodynorphin and dopamine D1 mRNA expression levels. Moreover, cocaine-intake
      behavior is sensitive to very specific concentrations of dopamine in the nucleus
      accumbens as well as in the amygdala. Recently, the CART (cocaine and amphetamine
      regulated transcript) peptide was proposed as a novel target for the actions of
      psychostimulant drugs. We have noted differences between male and female rats in
      the mesolimbic mRNA expression of CART that might be relevant for gender
      differences apparent in drug abuse.

PMID- 10415668
TI  - D3 dopamine and kappa opioid receptor alterations in human brain of cocaine
      overdose victims.
AB  - Cocaine is thought to be addictive because chronic use leads to molecular
      adaptations within the mesolimbic dopamine (DA) circuitry, which affects
      motivated behavior and emotion. Although the reinforcing effects of cocaine are
      mediated primarily by blockade of DA uptake, reciprocal signaling between DA and
      endogenous opioids has important implications for understanding cocaine
      dependence. We have used in vitro autoradiography and ligand binding to map D3 DA
      and kappa opioid receptors in the human brains of cocaine-overdose victims. The
      number of D3 binding sites was increased one-to threefold over the nucleus
      accumbens and ventromedial sectors of the caudate and putamen from cocaine
      overdose victims, as compared to age-matched and drug-free control subjects. D3
      receptor/cyclophilin mRNA ratios in the nucleus accumbens were increased sixfold
      in cocaine-overdose victims over control values, suggesting that cocaine exposure
      also affects the expression of D3 receptor mRNA. The number of kappa opioid
      receptors in the nucleus accumbens and other corticolimbic areas from cocaine
      fatalities was increased twofold as compared to control values. Cocaine-overdose
      victims exhibiting preterminal excited delirium had a selective upregulation of
      kappa receptors measured also in the amygdala. Understanding the complex
      regulatory profiles of DA and opioid synaptic markers that occur with chronic
      misuse of cocaine may suggest multitarget strategies for treating cocaine
      dependence.

PMID- 10415669
TI  - Functional magnetic resonance imaging of brain reward circuitry in the human.
AB  - To produce behavior, motivational states necessitate at least three fundamental
      operations, including (1) selection of objectives focused on goal-objects, (2)
      compilation of goal-object information, and (3) determination of physical plans
      for securing goal-objects. The second of these general operations has been
      theorized to involve three subprocesses: (a) feature detection and other
      perceptual processing of putative goal-object "rewards," (b) valuation of goal
      object worth in the context of potential hedonic deficit states, and (c)
      extraction of incidence and temporal data regarding the goal-object. A number of
      subcortical brain regions appear to be involved in these three informational
      subprocesses, in particular, the amygdala, sublenticular extended amygdala (SLEA)
      of the basal forebrain, and nucleus accumbens/subcallosal cortex (NAc/SCC).
      Components of the amygdala, SLEA, and NAc/SCC together constitute the larger
      anatomic structure of the extended amygdala. Functional magnetic resonance
      imaging (fMRI) studies of humans have recently begun to localize these
      subcortical regions within the extended amygdala during specific experimental
      conditions. In this manuscript, two human cocaine- infusion studies and one
      cognitive psychology experiment are reviewed in relation to their pattern of fMRI
      activation within regions of the extended amygdala. Activation in the NAc/SCC, in
      particular, is evaluated in relation to a hypothesis that one function of the
      NAc/SCC and associated brain regions is the evaluation of goal-object incidence
      data for the computation of conditional probabilities regarding goal-object
      availability. Further work is warranted to test hypothesized functions for all
      regions within the extended amygdala and integrate them toward an understanding
      of motivated behavior.

PMID- 10415670
TI  - Epilepsy, schizophrenia, and the extended amygdala.
AB  - Propagation and prolongation of rapid neuronal discharge underlies the
      epilepsies. However, episodic focal rapid neuronal discharges limited to discrete
      nuclei and pathways of the amygdala-hippocampal-septal-hypothalamic networks are
      the language of physiologic message systems for endocrine regulation and
      reproductive activities vital to the survival of the organism and the species. To
      prevent prolongation and propagation of physiologic pulsed excitation to areas
      outside specific networks and resultant epileptic seizures, these discharges must
      be limited in extent and time by powerful inhibitory processes. The nucleus
      accumbens, a unit of the extended amygdala, and the monoamines and GABA are
      components of the inhibitory networks that restrict physiologic rapid discharge
      in duration and in location. In parallel to the relationship of excessive
      neuronal excitation to epilepsy, evidence will be presented that excessive
      inhibition via one or more components of these inhibitory networks or diminished
      excitation underlies development of some psychoses, including schizophrenia.

PMID- 10415671
TI  - Mesolimbic activity associated with psychosis in schizophrenia. Symptom-specific
      PET studies.
AB  - Hallucinations and paranoid delusions are prominent among the positive symptoms
      of schizophrenia. Such psychotic symptoms are notable for their aberrant
      representations of, and relation to, the external world and for the
      emotional/motivational valence associated with the representations. As mesolimbic
      structures, including the amygdala and ventral striatum, are thought to play a
      significant role in imparting emotional valence to external stimuli, we here
      examine the mesolimbic findings of H215O PET studies designed to probe the
      functional neuroanatomy of psychosis. Patients with schizophrenia (including
      those with active hallucinations, those with active paranoid delusions, and those
      without active positive symptoms at the time of scanning) and healthy control
      subjects were studied. An event-related PET paradigm was used to identify the
      neural correlates of hallucinations, and a modified emotional stroop paradigm
      (with threat versus neutral words) was used to test the hypothesis that paranoid
      patients would have increased mesolimbic activity in response to threat, and even
      in response to neutral stimuli. The findings suggest that the positive psychotic
      symptoms of hallucinations and delusions share similar functional neuroanatomical
      features of increased mesotemporal and ventral striatal activity in the setting
      of decreased prefrontal activity. The pattern is evident even in a neutral
      context, unlike the case for normal subjects, who show such features only in
      response to threat. The implications of these findings for a pathophysiology of
      psychosis will be discussed in the context of the behavioral neuroanatomical
      literature in animals and humans.

PMID- 10415672
TI  - Ventromedial temporal lobe pathology in dementia, brain trauma, and
      schizophrenia.
AB  - The ventromedial temporal area contains numerous anatomical structures
      collectively or selectively involved in a wide range of neurological and
      psychiatric disorders. Collective involvement is exemplified best by Alzheimer's
      disease where a host of anatomical structures and a host of cognitive and
      behavioral changes are manifested. Selective disease of the amygdala can yield
      deficits in the ability to judge and evaluate emotional expressions. While memory
      functions are nearly synonymous with the concept of ventromedial temporal area,
      they overshadow other functions associated with the diverse anatomical structures
      in this part of the brain. For example, it could be argued that in addition to
      output directed toward the hippocampal formation, the output of the ventromedial
      temporal area is equally strong to the ventral striatopallidal system of the
      basal forebrain. Denervation of these structures could be associated with the
      behavioral changes that occur in tandem with the memory-related changes of
      ventromedial temporal lobe pathology. Here we explore the anatomical and
      pathological correlate associated with ventromedial temporal area pathology and
      consider how these may impact on ventral striatopallidal conceptualizations. We
      conclude that ventromedial temporal area pathology deprives the basal forebrain
      of multimodal association information from the endstages of corticocortical
      sensory processing. This endstage information carries with it an analysis of real
      time sensory awareness, historical-time or past sensory experiences, and
      decisions from hippocampal output structures regarding relevancy and novelty. In
      this sense, basal forebrain structures are in a unique position to regulate
      behavioral responses to a wide range of stimuli and to organize appropriate
      emotional, motor, autonomic, and endocrine responses to them.

PMID- 10415673
TI  - D3 receptors and the actions of neuroleptics in the ventral striatopallidal
      system of schizophrenics.
AB  - The mesolimbic dopamine (DA) system and an important target receptor, the D3
      receptor, have been implicated in schizophrenia. We have identified, using non
      radioactive in situ hybridization histochemistry, that D3 mRNA-positive neurons
      are highly concentrated in the ventral striatum, efferents of the ventral
      striatum (globus pallidus internal, ventral palladium, substantia nigra pars
      reticulata), and in regions projecting to the ventral striatum (medial dorsal
      thalamus, nucleus basalis, extended amygdala). D3 receptors are also highly
      enriched in the "limbic" striatal-pallidal-thalamic loop, exhibiting segregation
      from the D2 receptor-enriched "motor loop." This supports data developed in rats
      showing that the D3 receptor is a target of the mesolimbic DA system that can
      modulate the limbic striatal-palladial-thalamic loop. However, D2 and D3
      receptors and their mRNAs are co-localized in many sensory regions (lateral and
      medial geniculate nuclei, basolateral and basomedial amygdala, regions of
      thalamus), suggesting mechanisms of cross-talk. We have also demonstrated that
      there are 45% elevations in D3 receptor number in ventral striatal neurons and
      their striatopalladial targets in schizophrenics that is reduced by concurrent
      antipsychotic treatment. Chronic haloperidol treatment to rats for 6 months with
      a 2-month withdrawal does not result in elevated D3 receptor number. We
      hypothesize that antipsychotic treatment via D3 receptors returns balance to
      limbic efferents of the ventral striatum. We established that early neonatal
      damage to the nigrostriatal DA system in rats produces characteristic adaptations
      in the pre- and post-synaptic components of the mesolimbic DA system that can
      provide a model to explore regulation by antipsychotics. This includes elevated
      release of DA from the mesolimbic DA terminals, elevated D3 receptor mRNA in the
      Islands of Calleja and nucleus accumbens, and enhanced behavioral response to
      psychostimulants.

PMID- 10415675
TI  - On some clinical implications of the ventral striatum and the extended amygdala.
      Investigations of aggression.
AB  - In this paper, we have first reviewed the animal studies which suggest an
      association between the amygdala and aggressive behavior. This is followed by a
      review of the literature of aggression in epilepsy, emphasizing the less
      controversial peri-ictal aggressions, with the more controversial assertion that
      temporal lobe epilepsy in particular is associated with an increase in interictal
      aggression. We then go on to describe the results of some investigations using
      the MRI to examine amygdala pathology in a group of patients presenting with
      affective aggression in comparison with a control group. The main findings are
      that the patients with aggression tend to have lower IQs and more psychopathology
      than the control group. There is no difference in amygdala T2 and volumetric
      assessments between the groups, but a subgroup of patients are defined with
      aggression, left-sided amygdala atrophy, and a history of encephalitis.

PMID- 10415674
TI  - Prefrontal cortical-amygdalar metabolism in major depression.
AB  - Functional neuroimaging studies of the anatomical correlates of familial major
      depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities
      of resting blood flow (BF) and glucose metabolism in depression in the amygdala
      and the orbital and medial prefrontal cortical (PFC) areas that are extensively
      connected with the amygdala. The amygdala metabolism in MDD and BD is positively
      correlated with both depression severity and "stressed" plasma cortisol
      concentrations measured during scanning. During antidepressant drug treatment,
      the mean amygdala metabolism decreases in treatment responders, and the
      persistence of elevated amygdala metabolism during remission is associated with a
      high risk for the development of depressive relapse. The orbital C metabolism is
      also abnormally elevated during depression, but is negatively correlated with
      both depression severity and amygdala metabolism, suggesting that this structure
      may be activated as a compensatory mechanism to modulate amygdala activity or
      amygdala-driven emotional responses. The posterior orbital C and anterior
      cingulate C ventral to the genu of the corpus callosum (subgenual PFC) have more
      recently been shown in morphometric MRI and/or post mortem histopathological
      studies to have reduced grey matter volume and reduced glial cell numbers (with
      no equivalent loss of neurons) in familial MDD and BD. These data suggest a
      neural model in which dysfunction of limbic PFC structures impairs the modulation
      of the amygdala, leading to abnormal processing of emotional stimuli.
      Antidepressant drugs may compensate for this dysfunction by inhibiting
      pathological limbic activity.

PMID- 10415676
TI  - The interstitial nucleus of the posterior limb of the anterior commissure: a
      novel layer of the central division of extended amygdala.

PMID- 10415677
TI  - Projections of the amygdalopiriform transition area (APir). A PHA-L study in the
      rat.

PMID- 10415678
TI  - The ventral striatum of the Syrian hamster.

PMID- 10415679
TI  - Afferent connections to the ventral striatum from the medial prefrontal cortex
      (area 25) and the thalamic nuclei in the macaque monkey.
AB  - The ventral striatal inputs in the macaque monkey were studied in relation to the
      connections from the orbitofrontal cortex, focusing on the infralimbic area (IL
      or area 25), thalamic nuclei and the vagal-solitary nuclear complex (NTS-X). The
      IL projects to more restricted parts of the ventral striatum (shell and core of
      nucleus accumbens, Acb; ventricular margin of caudate nucleus, CN), whereas the
      striatal projections of the prelimbic area (PL) are more extended than those of
      IL. The dorsal midline nuclei project densley to area 13, agranular insular
      cortex (Ia), and Acb. The nucleus ventralis anterior pars magnocellularis (VAmc)
      projects to the IL, perigenual area and to the region of CN between the limbic
      and association striatum with partial overlapping, and seems to play a role as an
      interface between the limbic and motor systems. The distribution pattern of
      retrogradely labeled neurons was similar in the midline-intralaminar thalamic
      nuclei following injections in the IL and ventral striatum.

PMID- 10415680
TI  - Expression of enkephalin in pallido-striatal neurons.

PMID- 10415681
TI  - Terminals from the rat prefrontal cortex synapse on mesoaccumbens VTA neurons.

PMID- 10415682
TI  - Dopamine D4 receptors are strategically localized for primary involvement in the
      presynaptic effects of dopamine in the rat nucleus accumbens shell.

PMID- 10415683
TI  - Glutamatergic modulation of subcortical motor and limbic circuits.

PMID- 10415684
TI  - Modulation of ventral tegmental area dopamine cell activity by the ventral
      subiculum and entorhinal cortex.

PMID- 10415685
TI  - Electrophysiological properties of anatomically identified ventral pallidal
      neurons in rat brain slices.

PMID- 10415686
TI  - Neurons of the bed nucleus of the stria terminalis (BNST). Electrophysiological
      properties and their response to serotonin.

PMID- 10415688
TI  - Antidepressants and atypical neuroleptics induce Fos-like immunoreactivity in the
      central extended amygdala.

PMID- 10415687
TI  - Distribution of [3H]citalopram binding sites in the nonhuman primate brain.

PMID- 10415689
TI  - Stimulation of dopamine release in the bed nucleus of stria terminalis. A trait
      of atypical antipsychotics?

PMID- 10415690
TI  - Involvement of the ventral pallidum in working memory tasks with or without a
      delay.

PMID- 10415692
TI  - Disrupted and undisruptable latent inhibition following shell and core lesions.

PMID- 10415691
TI  - NMDA glutamatergic blockade of nucleus accumbens disrupts acquisition but not
      consolidation in a passive avoidance task.

PMID- 10415693
TI  - Freezing behavior in BNST-lesioned Wistar rats.

PMID- 10415694
TI  - A functional role for dopamine transmission in the amygdala during conditioned
      fear.

PMID- 10415695
TI  - Effect of amygdala kindling on emotional behavior and benzodiazepine receptor
      binding in rats.

PMID- 10415696
TI  - Does chronic activity-stress produce hippocampal atrophy and basal forebrain
      lesions? A preliminary analysis.

PMID- 10415697
TI  - Role of the basolateral amygdala in panic disorder.

PMID- 10415698
TI  - Changes in nociceptive and anxiolytic responses following herpes virus-mediated
      preproenkephalin overexpression in rat amygdala are naloxone-reversible and
      transient.
AB  - These results using herpes virus-mediated gene transfer to overexpress enkephalin
      in the amygdala support the role of amygdalar opioids in the anxiolytic actions
      of benzodiazepines and supraspinal nociception (see ref. 1). These studies also
      demonstrate the usefulness of recombinant herpes virus in evaluating the role of
      single gene products within specific brain sites in pharmacological responses and
      complex behaviors.

PMID- 10415699
TI  - Enduring neurochemical effects of early maternal separation on limbic structures.

PMID- 10415700
TI  - Prenatal stress-induced modifications of neuronal nitric oxide synthase in
      amygdala and medial preoptic area.

PMID- 10415701
TI  - Amygdaloid and hippocampal beta-adrenoceptors in the olfactory bulbectomy
      syndrome: effects of desipramine.

PMID- 10415703
TI  - Pattern of disturbance of different ventral frontal functions in organic
      depression.

PMID- 10415702
TI  - Cholinergic, M1 receptors in the nucleus accumbens mediate behavioral depression.
      A possible downstream target for fluoxetine.

PMID- 10415704
TI  - Phasic accumbal firing may contribute to the regulation of drug taking during
      intravenous cocaine self-administration sessions.

PMID- 10415705
TI  - Cocaine is self-administered into the shell region of the nucleus accumbens in
      Wistar rats.

PMID- 10415707
TI  - Cocaine-seeking behavior and Fos expression in the amygdala produced by cocaine
      or a cocaine self-administration environment.

PMID- 10415706
TI  - Involvement of acetylcholine in the nucleus accumbens in cocaine reinforcement.

PMID- 10415708
TI  - Differences in receptor system participation between nicotine- and cocaine
      induced dopamine overflow in nucleus accumbens.

PMID- 10415709
TI  - Modulation of cocaine-induced sensitization by kappa-opioid receptor agonists.
      Role of the nucleus accumbens and medial prefrontal cortex.

PMID- 10415710
TI  - SPECT following intravenous procaine in cocaine addiction.

PMID- 10415711
TI  - A multicomponent learning model of drug abuse. Drug taking and craving may
      involve separate brain circuits underlying instrumental and classical
      conditioning, respectively.

PMID- 10415712
TI  - Mesoaccumbens dopamine and the self-administration of amphetamine.

PMID- 10415713
TI  - Amphetamine microinfusion in the dorso-ventral axis of the prefrontal cortex
      differentially modulates dopamine neurotransmission in the shell-core
      subterritories of the nucleus accumbens.

PMID- 10415714
TI  - Amphetamine injections into the nucleus accumbens enhance the reward of
      stimulation of the subiculum.

PMID- 10415715
TI  - Asymmetrical effects of ethanol in basal ganglia aldehyde dehydrogenase activity.

PMID- 10415717
TI  - Role of matrix metalloproteinases and their inhibition in cutaneous wound healing
      and allergic contact hypersensitivity.
AB  - Normal wounds can heal by secondary intention (epidermal migration to cover a
      denuded surface) or by approximation of the wound edges (e.g., suturing). In
      healing by secondary intention, epidermis-derived MMPs are important.
      Keratinocyte migration begins within 3-6 hr post injury, as basal cells detach
      from underlying basal lamina and encounter a dermal substratum rich in type I
      collagen. Cell contact with type I collagen in vitro stimulates collagenase-1
      expression, which is mediated by the alpha 2 beta 1 integrin, the major
      keratinocyte collagen-binding receptor. Collagenase-1 activity alone is necessary
      and sufficient for keratinocyte migration over a collagen subsurface.
      Stromelysins-1 and -2 are also found in the epidermis of normal acute wounds.
      Stromelysin-2 co-localizes with collagenase-1 and may facilitate cell migration
      over non-collagenous matrices of the dermis. In contrast, stromelysin-1 is
      expressed by keratinocytes behind the migrating front and which remain on basal
      lamina, i.e., the proliferative cell population. Studies with stromelysin-1
      deficient mice that suggest this MMP plays a role in keratinocyte detachment from
      underlying basement membrane to initiate cell migration. In chronic ulcers, MMP
      levels are markedly elevated, in contrast to their precise temporal and spatial
      expression in acute wounds. Both collagenase-1 and stromelysin-1 are found in
      fibroblasts underlying the nonhealing epithelium, and stromelysin-1 expression is
      especially prominent. Two key questions underlie the use of MMP inhibitors and
      wound healing: (1) will these agents impair normal reepithelialization in wounds
      that heal by secondary intention; and (2) can MMP inhibitors be effective therapy
      for chronic ulcers? The answer to neither is known. Batimastat and marimastat
      appear not to interfere with normal wound healing, but only in sutured surgical
      wounds, a situation in which MMP expression has practically no role. We also show
      the first example of an in vivo immune response, contact hypersensitivity, which
      is dependent upon MMP activity. Using gene-deficient mice, we demonstrate that
      stromylysin-1 (MMP-3) is required for sensitization, whereas gelatinase B (MMP-9)
      is required for timely resolution of the reaction to antigenic challenge.

PMID- 10415716
TI  - Engineering of selective TIMPs.
AB  - Differences in proteinase susceptibility between free TIMP-1 and the TIMP-1-MMP-3
      complex and mutagenesis studies suggested that the residues around the disulfide
      bond between Cys1 and Cys70 in TIMP-1 may interact with MMPs. The crystal
      structure of the complex between TIMP-1 and the catalytic domain of MMP-3 has
      revealed that the alpha-amino group of Cys1 bidentately chelates the catalytic
      zinc of MMP-3 and the Thr2 side chain occupies the S1' pocket. Generation of the
      N-terminal domain of TIMP-1 (N-TIMP-1) variants with 15 different amino acid
      substitutions for Thr2 has indicated that the nature of the side chain of residue
      2 has a major effect on the affinity of N-TIMP-1 for three different MMPs (MMPs
      1, -2 and -3). The results also demonstrate that the mode of binding of N-TIMP-1
      residue 2 differs from the binding of the P1' residue of a peptide substrate.

PMID- 10415718
TI  - Evaluation of some newer matrix metalloproteinases.
AB  - Recombinant protein expression techniques have been utilized to facilitate the
      biochemical and cell biological characterization of human matrix
      metalloproteinases (MMPs). The importance of the membrane type 1 MMP (MMP 14) in
      the regulation of pericellular proteolysis, either directly or through the
      activation of MMP-2, MMP-9, and MMP-13 has been identified. Studies on an in
      vitro chondrocyte-like cell and an in vivo cartilage repair model indicated that
      such MT1 MMP-regulated activation cascades are physiologically feasible. MMP19
      shows a limited sequence identity with other MMPs and may represent a novel
      subclass. However, analysis of the recombinant protein identified a number of
      biochemical properties typical of the MMP family.

PMID- 10415719
TI  - The next generation of MMP inhibitors. Design and synthesis.
AB  - Since their inception during the eighties, MMP inhibitors (MMPIs) have gone
      through several cycles of metamorphosis. The design of early MMPIs was based on
      the cleavage site of peptide substrates. The second generation contained a
      substituted succinate scaffold (e.g., marimastat) coupled to a modified amino
      acid residue. The lower molecular weight analogs with multiple substitution
      possibilities produced a series of MMP inhibitors with varying degrees of
      selectivity for various MMPs. The introduction of sulfonamides in the midnineties
      added a new dimension to this field. The simplicity of synthesis coupled with
      high potency (e.g., CGS-27023A, AG-3340) produced a number of clinical
      candidates. This review highlights some of the key features that contributed to
      the discovery of this novel series of MMP inhibitors.

PMID- 10415722
TI  - Aggrecanase. A target for the design of inhibitors of cartilage degradation.
AB  - In arthritic diseases there is a gradual erosion of cartilage that leads to a
      loss of joint function. Aggrecan, which provides cartilage with its properties of
      compressibility and elasticity, is the first matrix component to undergo
      measurable loss in arthritis. This loss of aggrecan appears to be due to an
      increased rate of degradation, that can be attributed to proteolytic cleavage of
      the core protein within the interglobular domain (IGD). Two major sites of
      cleavage have been identified within the IGD. One, between the amino acids Asn341
      Phe342, where the matrix metalloproteinases (MMPs) have been shown to clip; and
      the other, between Glu373-Ala374, which is attributed to a novel protease,
      "aggrecanase." We have generated aggrecanase in conditioned media from IL-1
      stimulated bovine nasal cartilage and have used an enzymatic assay to evaluate
      this proteinase activity. In these studies we follow the generation of
      aggrecanase and MMPs in response to IL-1 in this system and examine the
      contribution of these enzymes in aggrecan degredation. Our data suggest that
      aggrecanase is a key enzyme in cartilage aggrecan degradation that represents a
      novel target for cartilage protection therapy in arthritis.

PMID- 10415720
TI  - Design and synthetic considerations of matrix metalloproteinase inhibitors.
AB  - Experimental evidence confirms that the matrix metalloproteinases (MMPs) play a
      fundamental role in a wide variety of pathologic conditions that involve
      connective tissue destruction including osteoarthritis and rheumatoid arthritis,
      tumor metastasis and angiogenesis, corneal ulceration, multiple sclerosis,
      periodontal disease, and atherosclerosis. Modulation of MMP regulation is
      possible at several biochemical sites, but direct inhibition of enzyme action
      provides a particularly attractive target for therapeutic intervention.
      Hypotheses concerning inhibition of specific MMP(s) with respect to disease
      target and/or side-effect profile have emerged. Examples are presented of recent
      advances in medicinal chemistry approaches to the design of matrix
      metalloproteinase inhibitors (MMPIs), approaches that address structural
      requirements and that influence potency, selectivity, and bioavailability. Two
      important approaches to the design, synthesis, and biological evaluation of MMPIs
      are highlighted: (1) the invention of alternatives to hydroxamic acid zinc
      chelators and (2) the construction of nonpeptide scaffolds. One current example
      in each of these two approaches from our own work is described.

PMID- 10415721
TI  - Insights into MMP-TIMP interactions.
AB  - The proteolytic activity of the matrix metalloproteinases (MMPs) involved in
      extracellular matrix degradation must be precisely regulated by their endogenous
      protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs).
      Disruption of this balance can result in serious diseases such as arthritis and
      tumor growth and metastasis. Knowledge of the tertiary structures of the proteins
      involved in such processes is crucial for understanding their functional
      properties and to interfere with associated dysfunctions. Within the last few
      years, several three-dimensional structures have been determined showing the
      domain organization, the polypeptide fold, and the main specificity determinants
      of the MMPs. Complexes of the catalytic MMP domains with various synthetic
      inhibitors enabled the structure-based design and improvement of high-affinity
      ligands, which might be elaborated into drugs. Very recently, structural
      information also became available for some TIMP structures and MMP-TIMP
      complexes, and these new data elucidated important structural features that
      govern the enzyme-inhibitor interaction.

PMID- 10415723
TI  - Tissue inhibitors of matrix metalloproteinases in cancer.
AB  - Tissue inhibitors of metalloproteinases (TIMPs) play a key regulatory role in the
      homeostasis of the extracellular matrix (ECM) by controlling the activity of
      matrix metalloproteinases (MMPs). Some TIMPs have a second function as well,
      unrelated to their antiMMP activity, which affects cell proliferation and
      survival. The role of these inhibitors in cancer has been the subject of
      extensive investigations that have examined their biological activity in tumor
      growth, invasion, metastasis and angiogenesis, as well as their potential use in
      the diagnosis and treatment of human cancer.

PMID- 10415724
TI  - The regulation of MMPs and TIMPs in cartilage turnover.
AB  - The treatment of cartilage with mediators initiates the breakdown of proteoglycan
      followed by collagen. This is accompanied by the modulation of different
      proteinases and inhibitors that include members of the MMP family and TIMPs. We
      have evidence that a chondrocyte membrane-associated metalloproteinase cleaves
      aggrecan. This activity is rapidly induced after stimulation with IL-1 and OSM
      and is not inhibited by TIMPs-1 and -2 but is inhibited by synthetic MMP
      inhibitors. This same combination of cytokines also upregulates the collagenases
      with the subsequent release of collagen fragments, and there is a close
      correlation between the amount of collagen released and collagenase activity
      produced. Collagen release can be prevented after treatment with specific
      inhibitors of MAP kinases, inhibitors of MMP transcription, synthetic
      metalloproteinase inhibitors, TIMPs and treatment of cartilage with agents that
      upregulate TIMPs. The results from bovine cartilage culture models show that
      collagen release occurs when TIMP levels are low, collagenases are upregulated
      and then subsequently activated.

PMID- 10415725
TI  - Scientific basis of a matrix metalloproteinase-8 specific chair-side test for
      monitoring periodontal and peri-implant health and disease.
AB  - Matrix metalloproteinases (MMPs), especially collagenase-2 (MMP-8), are key
      mediators of irreversible tissue destruction associated with periodontitis and
      peri-implantitis. MMP-8 is known to exist in elevated amounts and in active form
      in the gingival crevicular fluid (GCF) and peri-implant sulcular fluid (PISF)
      from progressing periodontitis and peri-implantitis lesions and sites,
      respectively. (Sorsa et al. Ann. N.Y. Acad. Sci. 737: 112-131 [1994]; Teronen et
      al. J. Dent. Res. 76: 1529-1537 [1997]). We have developed monoclonal antibodies
      to MMP-8 (Hanemaaijer et al. J. Biol. Chem. 272: 31504-31509 [1997]) that can be
      used in a chair-side dipstick test to monitor the course and treatment of
      periodontitis and peri-implantitis. Monoclonal and polyclonal antibody tests for
      MMP-8 coincided with the classical functional collagenase activity test from GCF
      and PISF (Sorsa et al. J. Periodont. Res. 22: 386-393 [1988]) in periodontal and
      peri-implant health and disease. In future a chair-side functional and/or
      immunological MMP-test can be useful to diagnose and monitor periodontal and peri
      implant disease and health.

PMID- 10415726
TI  - MMP-9 activity in urine from patients with various tumors, as measured by a novel
      MMP activity assay using modified urokinase as a substrate.
AB  - Matrix metalloproteinases (MMPs) play an important role in many pathologic
      processes, but their activities are difficult to determine since no simple
      specific and/or chromogenic substrate exists. We have developed a novel MMP
      activity assay using a modified urokinase as a substrate. Protein engineering
      enabled the plasmin activation site in this urokinase to be substituted by a
      specific activation site recognized by MMPs. In this way the MMP activity can be
      monitored via urokinase activity as measured by a simple chromogenic assay. The
      assay was made specific for MMP-9 by a capture step using MMP-9-specific
      antibodies that do not interfere with MMP-activity. This assay monitors the
      amount of active enzyme as well as the latent, but potentially active proform.
      Using this assay the levels of MMP-9 were investigated in urine from patients
      with various kinds of carcinoma. High levels of both active and latent MMP-9 were
      detected in urine from patients with carcinoma of the bladder, whereas hardly any
      activity was observed in urine from healthy controls. MMP-9 in urine was present
      in its intact form. Surprisingly, MMP-9 was also increased in the urine of
      patients with nonurogenital carcinoma. Therefore, measurement of urinary MMP-9
      activity levels may be a convenient diagnostic tool for various types of
      carcinoma.

PMID- 10415727
TI  - Fluorogenic MMP activity assay for plasma including MMPs complexed to alpha 2
      macroglobulin.
AB  - Elevated MMP activities are implicated in tissue degradation in, e.g., arthritis
      and cancer. The present study was designed to measure MMP enzyme activity in
      plasma. Free active MMP is unlikely to be present in plasma: upon entering the
      circulation, active MMP is expected to be captured by the proteinase inhibitor
      alpha 2-macroglobulin (alpha 2M). Reconstituted MMP-13/alpha 2M complex was
      unable to degrade collagen (MW 300,000) in contrast to the low-molecular-weight
      fluorogenic substrate (MW < 1500). Limited access of high-MW substrates to the
      active site of MMPs captured by alpha 2M presents the most likely explanation.
      Consistently, the high-MW inhibitor TIMP (MW approximately 28,000) was unable to
      inhibit MMP/alpha 2M enzyme activity, whereas the low-MW inhibitor BB94 (MW
      approximately 500) effectively suppressed enzyme activity. By using fluorogenic
      substrates with Dabcyl/Fluorescein as quencher/fluorophore combin-ation,
      sensitive MMP-activity assays in plasma were achieved. Spiking of active MMP-13
      and MMP-13/alpha 2M complex, and inhibitor studies with TIMP-1 and BB94,
      indicated that active MMPs are efficiently captured by alpha 2M in plasma. MMP
      activity was even detected in control plasma, and was significantly increased in
      plasma from rheumatoid arthritis patients.

PMID- 10415728
TI  - MMP inhibition in abdominal aortic aneurysms. Rationale for a prospective
      randomized clinical trial.
AB  - Abdominal aortic aneurysms (AAAs) represent a chronic degenerative condition
      associated with a life-threatening risk of rupture. The evolution of AAAs is
      thought to involve the progressive degradation of aortic wall elastin and
      collagen, and increased local production of several matrix metallo-proteinases
      (MMPs) has been implicated in this process. We have previously shown that
      tetracycline derivatives and other MMP inhibitors suppress aneurysm development
      in experimental animal models of AAA. Doxycycline also reduces the expression of
      MMP-2 and MMP-9 by human vascular wall cell types and by AAA tissue explants in
      vitro. To determine whether this strategy might have a role in the clinical
      management of small AAA, we examined the effect of doxycycline on aortic wall MMP
      expression in vivo. Patients were treated with doxycycline (100 mg p.o. bid) for
      7 days prior to elective AAA repair, and aneurysm tissues were obtained at the
      time of surgery (n = 5). Tissues obtained from an equal number of untreated
      patients with AAA were used for comparison. By reverse transcription-polymerase
      chain reaction and Southern blot analysis, MMP-2 and MMP-9 were both found to be
      abundantly expressed in the aneurysm wall. Preoperative treatment with
      doxycycline was associated with a 3-fold reduction in aortic wall expression of
      MMP-2 and a 4-fold reduction in MMP-9 (p < 0.05 compared to untreated AAA). These
      preliminary results suggest that even short-term treatment with doxycycline can
      suppress MMP expression within human AAA tissues. Given its pleiotropic effects
      as an MMP inhibitor, doxycycline may be particularly effective in suppressing
      aortic wall connective tissue degradation. While it remains to be determined
      whether MMP inhibition will have a clinically significant impact on aneurysm
      expansion, it is expected that this question can be resolved by a properly
      designed prospective randomized clinical trial.

PMID- 10415729
TI  - Effect of matrix metalloproteinase inhibition on progression of atherosclerosis
      and aneurysm in LDL receptor-deficient mice overexpressing MMP-3, MMP-12, and MMP
      13 and on restenosis in rats after balloon injury.
AB  - The broad-spectrum MMP inhibitor CGS 27023A was tested to determine its potential
      as a therapy for atherosclerosis, aneurysm, and restenosis. LDL receptor
      deficient (LDLr -/-) mice fed a high-fat, cholic acid-enriched diet for 16 weeks
      developed advanced aortic atherosclerosis with destruction of elastic lamina and
      ectasia in the media underlying complex plaques. Lesion formation correlated with
      a 4.6- to 21.7-fold increase in MMP-3, -12, and -13 expression. Treatment with
      CGS 27023A (p.o., b.i.d. at 50 mg/kg) had no effect on the extent of aortic
      atherosclerosis (36 +/- 4% versus 30 +/- 2% in controls), but both aortic medial
      elastin destruction and ectasia grade were significantly reduced (38% and 36%,
      respectively, p < 0.05). In the rat ballooned-carotid-artery model, CGS 27023A
      (12.5 mg/kg/day via osmotic minipump) reduced smooth muscle cell migration at 4
      days by 83% (p < 0.001). Intimal lesions were reduced by 85% at 7 days (p <
      0.001), but intimal smooth muscle proliferation was unaffected, and inhibitory
      efficacy was lost with time. At 12 days, intimal lesion reduction was less potent
      (52%, p < 0.01). At 3 and 6 weeks, reductions of 11% and 4%, respectively, were
      not significant. This demonstrates that it is essential to include late time
      points when the ballooned-carotid-artery model is employed to ensure that lesion
      size does not "catch up" when a compound solely inhibits smooth muscle cell
      migration. In summary, MMP inhibitor therapy delayed but did not prevent intimal
      lesions, thereby demonstrating little promise to prevent restenosis. In contrast,
      MMP inhibitor therapy may prove useful to retard progression of aneurysm.

PMID- 10415730
TI  - Treatment of osteoporosis with MMP inhibitors.
AB  - In the current study, we examined the effects of minocycline on the osteopenia of
      ovariectomized (OVX) aged rats using the marrow ablation model. This injury
      induces rapid bone formation followed by bone resorption in the marrow cavity.
      Old female rats were randomly divided into five groups: sham, OVX, OVX +
      minocycline (5-15 mg/day, orally), OVX + 17 beta-estradiol (25 micrograms/day,
      subcutaneously), and OVX + both agents. Rats were OVX, treated with minocycline
      and/or estrogen, followed by marrow ablation. Bone samples were collected 16 days
      post-marrow ablation. X-ray radiography of bones operated on showed that
      treatment of OVX old rats with minocycline increased bone mass in diaphyseal
      region. Diaphyseal bone mineral density (BMD) was measured by DEXA scan.
      Diaphyseal BMD of OVX rats was increased 17-25% by treatment with 5-15 mg of
      minocycline or 17 beta-estradiol. The effects of minocycline and estrogen
      treatments on the expression of osteoblast and osteoclast markers were also
      examined. Northern and dot blot analysis of RNA samples showed that treatment of
      OVX aged rats with minocycline increased the expression of type I collagen (COL
      I) (49%) and decreased that of interleukin-6 (IL-6) (31%). In contrast, estrogen
      treatment decreased the expression of interleukin-6 (IL-6) (39%), carbonic
      anhydrase II (CA II) (36%), and osteopontin (OP) (37%). Neither minocycline nor
      17 beta-estradiol had an effect on the expression of osteocalcin (OC) and
      alkaline phosphatase (AP). To elucidate the mechanism by which minocycline
      prevented the loss of bone in OVX aged rats, we examined the colony-formation
      potential of bone marrow stromal cells in ex vivo cultures. Minocycline
      stimulated the colony-forming efficiency of marrow stromal cells derived from old
      animals. We have therefore concluded that the modest increase in BMD noted in OVX
      aged rats, in response to minocycline treatment, may be due to a change in bone
      remodeling that favors bone formation; and the anabolic effect of minocycline is
      likely due to its effect on the expression of COL I and/or the metabolism of
      osteoprogenitor cells.

PMID- 10415731
TI  - Clinical trials of a stromelysin inhibitor. Osteoarthritis, matrix
      metalloproteinase inhibition, cartilage loss, surrogate markers, and clinical
      implications.
AB  - Long-term trials with BAY 12-9566, a stromelysin inhibitor, have been initiated
      in osteoarthritis. Validation of the long-term, clinical relevance of early
      markers has to be tested in these and other trials. Detection of the slowing of
      cartilage loss (as gauged by measures of joint space narrowing and by other
      techniques, such as MRI) remains to be proven, but now may be possible in
      intervention trials.

PMID- 10415732
TI  - Experimental models to identify antimetastatic drugs: are we there yet? A
      position paper.

PMID- 10415734
TI  - Preclinical and clinical studies of MMP inhibitors in cancer.
AB  - The role of matrix metalloproteinases in tumor angiogenesis and growth is now
      well recognized for models of both human and animal cancer. Clinical studies
      currently under way with the prototype matrix metalloproteinase inhibitor,
      marimastat, will establish whether inhibitors of these enzymes are of benefit in
      the treatment of different types of human cancer. On chronic therapy in humans,
      marimastat induces a reversible tendinitis that can also be detected in certain
      animal species. This paper compares the ability of broad-spectrum and various
      types of selective matrix metalloproteinase inhibitors to induce tendinitis and
      to exhibit anticancer effects in an animal cancer model. Under conditions in
      which both systemic exposure and inhibitor potency are controlled, selective
      inhibitors are less pro-tendinitic, but are weaker anticancer agents than broad
      spectrum agents such as marimastat. The clinical relevance of these findings is
      discussed.

PMID- 10415733
TI  - Measurement of matrix metalloproteinases and tissue inhibitors of
      metalloproteinases in blood and tissues. Clinical and experimental applications.
AB  - The balance between production and activation of MMPs and their inhibition by
      TIMPs is a crucial aspect of cancer invasion and metastasis. On the basis of the
      concept that MMPs synthesized in tissues seep into the bloodstream, we have
      examined MMP levels in the plasma of patients with cancer. In colorectal, breast,
      prostate, and bladder cancer, most patients with aggressive disease have
      increased plasma levels of gelatinase B. In patients with advanced colorectal
      cancer, high levels of either gelatinase B or TIMP complex were associated with
      shortened survival. We propose that these assays may be clinically useful in
      characterizing metastatic potential in selected kinds of cancer. In rheumatoid
      arthritis and systemic lupus erythematosus (SLE), serum and plasma levels of
      stromelysin-1 were approximately 3-5-fold increased. Fluctuating serum
      stromelysin-1 levels in SLE did not correspond with change in disease activity.
      In SLE, stromelysin-1 may be a component of the chronic tissue repair process
      rather than being responsible for inciting tissue damage. On the basis of these
      observations, we conclude that measurement of plasma/serum MMP and TIMP levels
      may provide important data for selecting and following patients considered for
      treatment with drugs that interfere with MMP activity.

PMID- 10415735
TI  - Broad antitumor and antiangiogenic activities of AG3340, a potent and selective
      MMP inhibitor undergoing advanced oncology clinical trials.
AB  - We studied AG3340, a potent metalloproteinase (MMP) inhibitor with pM affinities
      for inhibiting gelatinases (MMP-2 and -9), MT-MMP-1 (MMP-14), and collagenase-3
      (MMP-13) in many tumor models. AG3340 produced dose-dependent pharmacokinetics
      and was well tolerated after intraperitoneal (i.p.) and oral dosing in mice.
      Across human tumor models, AG3340 produced profound tumor growth delays when
      dosing began early or late after tumor implantation, although all established
      tumor types did not respond to AG3340. A dose-response relationship was explored
      in three models: COLO-320DM colon, MV522 lung, and MDA-MB-435 breast. Dose
      dependent inhibitions of tumor growth (over 12.5-200 mg/kg given twice daily,
      b.i.d.) were observed in the colon and lung models; and in a third (breast),
      maximal inhibitions were produced by the lowest dose of AG3340 (50 mg/kg, b.i.d.)
      that was tested. In another model, AG3340 (100 mg/kg, once daily, i.p.) markedly
      inhibited U87 glioma growth and increased animal survival. AG3340 also inhibited
      tumor growth and increased the survival of nude mice bearing androgen-independent
      PC-3 prostatic tumors. In a sixth model, KKLS gastric, AG3340 did not inhibit
      tumor growth but potentiated the efficacy of Taxol. Importantly, AG3340 markedly
      decreased tumor angiogenesis (as assessed by CD-31 staining) and cell
      proliferation (as assessed by bromodeoxyuridine incorporation), and increased
      tumor necrosis and apoptosis (as assessed by hematoxylin and eosin and TUNEL
      staining). These effects were model dependent, but angiogenesis was commonly
      inhibited. AG3340 had a superior therapeutic index to the cytotoxic agents,
      carboplatin and Taxol, in the MV522 lung cancer model. In combination, AG3340
      enhanced the efficacy of these cytotoxic agents without altering drug tolerance.
      Additionally, AG3340 decreased the number of murine melanoma (B16-F10) lesions
      arising in the lung in an intravenous metastasis model when given in combination
      with carboplatin or Taxol. These studies directly support the use of AG3340 in
      front-line combination chemotherapy in ongoing clinical trials in patients with
      advanced malignancies of the lung and prostate.

PMID- 10415736
TI  - MMP inhibition in prostate cancer.
AB  - Matrix metalloproteinases (MMPs) play a significant role during the development
      and metastasis of prostate cancer (CaP). CaP cells secrete high levels of MMPs
      and low levels of endogenous MMP inhibitors (TIMPs), thus creating an excess
      balance of MMPs. Established CaP cell lines that express high levels of MMPs
      frequently metastasize to the bone and the lungs. Drugs such as Taxol and
      alendronate that reduce cell motility and calcium metabolism reduce bony
      metastasis of xenografted CaP tumors. We tested several synthetic, nontoxic
      inhibitors of MMPs that can be administered orally, including doxycycline (DC)
      and chemically modified tetracyclines (CMTs) on CaP cells in vitro and on a rat
      CaP model in vivo. Among several anti-MMP agents tested, CMT-3 (6-deoxy, 6
      demethyl,4-de-dimethylamino tetracycline) showed highest activity against CaP
      cell invasion and cell proliferation. Micromolar concentration of CMT-3 and DC
      inhibited both the secretion and activity of MMPs by CaP cells. When tested for
      in vivo efficacy in the Dunning rat CaP model by daily oral gavage, CMT-3 and DC
      both reduced the lung metastases (> 50%). CMT-3, but not DC, inhibited tumor
      incidence (55 +/- 9%) and also reduced the tumor growth rate (27 +/- 9.3%). More
      significantly, the drugs showed minimum systemic toxicity. Ongoing studies
      indicate that CMT-3 may inhibit the skeletal metastases of CaP cells and delay
      the onset of paraplegia due to lumbar metastases. These preclinical studies
      provide the basis for clinical trials of CMT-3 for the treatment of metastatic
      disease.

PMID- 10415737
TI  - A chemically modified nonantimicrobial tetracycline (CMT-8) inhibits gingival
      matrix metalloproteinases, periodontal breakdown, and extra-oral bone loss in
      ovariectomized rats.
AB  - Estrogen deficiency in the postmenopausal (PM) female is the major cause of
      osteoporosis and may contribute to increased periodontal disease, including
      alveolar bone loss, seen in these women. In the current study, an animal model of
      PM osteoporosis, the OVX adult female rat, was studied to determine: (i) the
      relationship between periodontal breakdown and skeletal bone loss, and (ii) the
      effect of CMT-8 on gingival collagenase and bone loss. OVX rats were daily
      gavaged with CMT-8 (1, 2, or 5 mg/rat) for 28 or 90 days; non-OVX rats and those
      gavaged with vehicle alone served as controls. Elevated collagenase activity,
      assessed using [3H-methyl] collagen as substrate in the presence or absence of
      APMA, was seen in the gingiva of the OVX rats, and CMT-8 therapy suppressed this
      effect. Western blot revealed a similar pattern for MMP-8 and MMP-13
      concentrations. The changes in the gingival collagenase activity paralleled
      changes in periodontal bone loss, which, in turn, reflected trabecular bone
      density changes. Preliminary studies on PM humans administered sub-antimicrobial
      tetracycline as a matrix metalloproteinase inhibitor are under way.

PMID- 10415738
TI  - MMP-mediated events in diabetes.
AB  - Both Type I and Type II diabetes mellitus (DM) have been associated with
      unusually aggressive periodontitis. Accordingly, rat models of both types of DM
      were used to study (i) mechanisms mediating this systemic/local interaction and
      (ii) new pharmacologic approaches involving a series of chemically modified
      tetracyclines (CMTs) that have lost their antimicrobial but retained their host
      modulating (e.g., MMP-inhibitory) properties. In vitro experiments on tissues
      from Type I DM rats demonstrated that several of these CMTs were better matrix
      metalloproteinase (MMP) inhibitors than was antibacterial doxycycline (doxy),
      except for CMT-5, which, unlike the other MMP inhibitors, was found not to react
      with zinc. Data from in vivo studies on the same rat model generally supported
      the relative efficacy of these compounds: the CMTs and doxy were found to inhibit
      MMP activity, enzyme expression, and alveolar bone loss. To examine other long
      term complications such as nephropathy and retinopathy, a Type II (ZDF) model of
      DM was studied. Treatment of these DM rats with CMT-8 produced a 37% (p < 0.05),
      93% (p < 0.001), and 50% (p < 0.01) reduction in the incidence of cataract
      development, proteinuria, and tooth loss, respectively; whereas the doxy-treated
      ZDF rats showed little or no effect on these parameters. CMT treatment decreased
      mortality of the Type II ZDF diabetic animals, clearly indicating that CMTs, but
      not commercially available antibiotic tetracyclines (TCs), may have therapeutic
      applications for the long-term management of diabetes.

PMID- 10415739
TI  - Clinical trials of a matrix metalloproteinase inhibitor in human periodontal
      disease. SDD Clinical Research Team.
AB  - After demonstration by Golub et al. of the ability of the tetracyclines to
      inhibit elevated collagenolytic activity in animal models of periodontal
      diseases, a clinical development program was initiated to demonstrate the
      potential of a subantimicrobial dose of doxycycline (SDD) to augment and maintain
      the improvements in clinical parameters of adult periodontitis (AP) afforded by
      conventional nonsurgical periodontal therapy. Clinical trials were carried out in
      which a number of different SDD dosing regimens and placebo were compared in
      patients administered a variety of adjunctive nonsurgical therapies. Measured
      parameters included levels of collagenase activity in gingival crevicular fluid
      (GCF) and gingival specimens, clinical attachment levels (cALv), probing pocket
      depths (PD), bleeding on probing (BOP), and subtraction radiographic measurements
      of alveolar bone height. When used as an adjunct to either scaling and root
      planing or supragingival scaling and dental prophylaxis, SDD was shown to reduce
      collagenase levels in both GCF and gingival biopsies, to augment and maintain
      cALv gains and PD reductions, to reduce BOP, and to prevent loss of alveolar bone
      height. These clinical responses arose in the absence of any significant effects
      on the subgingival microflora and without evidence of an increase in the
      incidence or severity of adverse reactions relative to the control groups. It is
      proposed that one of the mechanisms of action of SDD is as an inhibitor of
      pathologically elevated MMPs, including neutrophil and bone cell collagenases
      (MMP-8 and MMP-13), which are associated with the host response in chronic AP,
      and that SDD provides a novel systemic approach to the management of AP.

PMID- 10415740
TI  - Effects of chemically modified tetracycline, CMT-8, on bone loss and osteoclast
      structure and function in osteoporotic states.
AB  - We examined the effects of a nonantimicrobial tetracycline analogue, CMT-8, on
      bone loss and osteoclasts in ovariectomized (OVX) rats. Three-month-old female
      rats were OVX, and, one week later, distributed into three groups: sham-operated
      non-OVX controls, untreated OVX controls, and CMT-8-treated OVX rats. After 145
      days of daily drug administration (p.o.), the femurs were dissected and examined
      histologically. Ovariectomy markedly decreased trabecular and cortical bone
      volume in the metaphyses compared to sham-operated controls. Treating the OVX
      rats with CMT-8 produced a significant inhibition of trabecular and cortical bone
      loss and induced new bone formation, in which connectivity of the trabecular
      struts was increased by bridging the adjacent longitudinal bone trabeculae.
      Ultrastructurally, CMT-8 reduced ruffled border formation in osteoclasts, while
      it caused no structural impairment in osteoblasts. To further evaluate the
      effects of CMT-8 on the resorbing activity of osteoclasts, osteoclasts were
      cultured on dentine slices pretreated with CMT-8 at concentrations of 2, 10, or
      50 micrograms/ml, and resorption lacuna formation on the dentine surface was
      found to be reduced, dose-dependently, by the bound CMT-8. Our results suggest
      that CMT-8 therapy effectively inhibits post-ovariectomy bone loss not only by
      inducing new bone formation, but also by inhibiting osteoclastic bone resorption,
      and that CMT-8 binding to bone may provide a prolonged release delivery of this
      anti-resorptive therapy.

PMID- 10415741
TI  - Specialized surface protrusions of invasive cells, invadopodia and lamellipodia,
      have differential MT1-MMP, MMP-2, and TIMP-2 localization.
AB  - Surface protrusions, invadopodia, and analogous lamellipodia at the leading edge
      of an invasive cell, which make contact with the underlying extracellular matrix
      (ECM), are the main motor for cellular locomotion and invasion. Previous studies
      have demonstrated that invadopodia, but not lamellipodia, are sites of ECM
      degradation on the cell surface. Such degradative activity is in part due to the
      localization of latent matrix metalloproteinase-2 (MMP-2) and membrane type-1 MMP
      (MT1-MMP) to invadopodia, where MMP activation occurs. Although lamellipodia
      exhibit similar structure and mobility to invadopodia, lamellipodia, by virtue of
      their location at the cellular periphery, are readily accessible to the soluble
      tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and blood-borne
      inhibitors. We show here that TIMP-2 co-localizes with MT1-MMP and MMP-2 at
      lamellipodia but not with that of invadopodia. Thus, the MMP-TIMP localization at
      lamellipodia may be a key mechanism for the regulation of MMP activation on the
      cell surface, which in turn governs expression of the cell-invasive phenotype.

PMID- 10415742
TI  - Activation of proMMP-9 by a plasmin/MMP-3 cascade in a tumor cell model.
      Regulation by tissue inhibitors of metalloproteinases.
AB  - To examine MMP-9 activation in a cellular setting we employed cultures of human
      tumor cells that were induced to produce MMP-9 over a 200-fold concentration
      range (0.03 to 8.1 nM). The secreted levels of TIMPs in all the induced cultures
      remain relatively constant at 1-4 nM. Quantitation of the zymogen/active enzyme
      status of MMP-9 in the cultures indicates that even in the presence of potential
      activators, the molar ratio of endogenous MMP-9 to TIMP dictates whether proMMP-9
      activation can progress. When the MMP-9/TIMP ratio exceeds 1.0, MMP-9 activation
      progresses, but only via an interacting protease cascade involving plasmin and
      stromelysin 1 (MMP-3). Plasmin, generated by the endogenous plasminogen activator
      (uPA), is not an efficient activator of proMMP-9. Plasmin, however, is very
      efficient at generating active MMP-3 from exogenously added proMMP-3. The
      activated MMP-3, when its concentration exceeds that to TIMP, becomes a potent
      activator of proMMP-9. Addition to the cultures of already-activated MMP-3
      relinquishes the requirement for plasminogen and proMMP-3 additions and results
      in direct activation of the endogenous proMMP-9. The activated MMP-9 enhances the
      invasive phenotype of the cultured cells as their ability to transverse basement
      membrane is significantly increased following zymogen activation. That this
      enhanced tissue remodeling capability is due to the activation of MMP-9 is
      demonstrated through the use of a specific anti-MMP-9-blocking monoclonal
      antibody.

PMID- 10415743
TI  - Matrix metalloproteinase inhibition. From the Jurassic to the third millennium.
AB  - A brief historical introduction to the matrix metalloproteinase (MMP) field,
      which began in 1962, is followed by an overview of the inhibition of these
      proteases by natural inhibitors such as alpha 2 macroglobulin and the TIMPs
      (tissue inhibitors of metalloproteinases) and by synthetic inhibitors, which are
      largely chelating agents. The latter include thiol, alkylcarbonyl, phosponamidate
      and hydroxamate compounds, as well as the tetracyclines. A review of the most
      recent progress concludes with prognostications as to where the field may be
      going next.

PMID- 10415745
TI  - Thirty-six years in the clinic without an MMP inhibitor. What hath collagenase
      wrought?
AB  - Vertebrate collagenase was discovered in 1962, and within a few short years,
      several inhibitors had been identified. At one time or another, virtually every
      major drug company has had an MMP inhibitor program, but in 1999, there is only
      one such product on the market. With a potential market for lifelong therapy in
      rheumatoid arthritis, osteoarthritis, periodontal disease, osteoporosis, and
      cancer, this is certainly puzzling. The problem is that the chemistry appears to
      have outstripped the biology. In vitro, there are many inhibitors with nanomolar
      or picomolar efficacy, but in vivo efficacy in animal models does not always
      follow. There is also a conceptual problem regarding broad-spectrum vs. highly
      specific inhibitors. Designing human trials to demonstrate MMP inhibition and
      clinical efficacy is a daunting problem, especially if one seeks to distinguish
      anti-MMP activity from anti-inflammatory effect. Adult periodontal disease may be
      the best available human disease model for development of an MMPI.

PMID- 10415744
TI  - C-telopeptide pyridinoline cross-links. Sensitive indicators of periodontal
      tissue destruction.
AB  - C-telopeptides and related pyridinoline cross-links of bone Type I collagen are
      sensitive markers of bone resorption in osteolytic diseases such as osteoporosis
      and osteoarthritis. We have studied the release of C-telopeptide pyridinoline
      crosslinks of Type I collagen as measures of bone destruction in periodontal
      disease. Studies in preclinical animal models and humans have demonstrated the
      relationship between radiographic bone loss and crevicular fluid C-telopeptide
      levels. We have recently found that C-telopeptide levels correlate strongly with
      microbial pathogens associated with periodontitis and around endosseous dental
      implants. Host-modulation of bone-related collagen breakdown has been shown by
      studies in humans demonstrating that MMP inhibition blocks tissue destruction and
      release of C-telopeptides in patients with active periodontal disease.

PMID- 10415746
TI  - Physical and biological regulation of proteoglycan turnover around chondrocytes
      in cartilage explants. Implications for tissue degradation and repair.
AB  - The development of clinical strategies for cartilage repair and inhibition of
      matrix degradation may be facilitated by a better understanding of (1) the
      chondrocyte phenotype in the context of a damaged extracellular matrix, and (2)
      the roles of biochemical and biomechanical pathways by which matrix metabolism is
      mediated. Using methods of quantitative autoradiography, we examined the cell
      length scale patterns of proteoglycan deposition and turnover in the cell
      associated matrices of chondrocytes in adult bovine and calf cartilage explants.
      Results highlight a rapid turnover in the pericellular matrix, which may indicate
      spatial organization of PG metabolic pools, and specific biomechanical roles for
      different matrix regions. Subsequent to injurious compression of calf explants,
      which resulted in grossly visible tissue cracks and caused a decrease in the
      number of viable chondrocytes within explants, cell-mediated matrix catabolic
      processes appeared to increase, resulting in apparently increased rates of
      proteoglycan turnover around active cells. Furthermore, the influences of cell
      stimulatory factors such as IL-1 beta appeared to be delayed in their effects
      subsequent to injurious compression, suggesting interactions between
      biomechanical and biochemical pathways of PG degradation. These results may
      provide a useful reference point in the development of in vitro models for
      cartilage injury and disease, and hint at possible new approaches in the
      development of cartilage repair strategies.

PMID- 10415747
TI  - Adamalysins. A family of metzincins including TNF-alpha converting enzyme (TACE).
AB  - The adamalysins are a family of proteins in the metzincin superfamily of
      metalloproteases, which also includes the matrix metalloproteinases. There are
      two subfamilies of adamalysins: the snake venom metalloproteases (SVMPs) and the
      ADAMs (proteins containing a disintegrin and metalloprotease domain). At least 23
      ADAMs have been identified to date. The ADAMs are expressed by a wide variety of
      cell types, and are involved in functions as diverse as sperm-egg binding,
      myotube formation, neurogenesis, and proteolytic processing of cell surface
      proteins. An overview of the ADAM family and their functions will be presented.
      TACE is a unique member of the ADAM family that cleaves membrane-bound TNF-alpha
      to generate soluble TNF-alpha. Mice lacking proteolytically active TACE have been
      generated and characterized. The TACE knock-out results in perinatal lethality.
      Cells from the TACE-deficient mice release 80-90% less soluble TNF-alpha than do
      wild-type cells. Irradiated mice that are reconstituted with TACE knock-out
      hematopoeitic stem cells have markedly reduced levels of serum TNF-alpha
      following LPS challenge, compared to irradiated mice reconstituted with wild-type
      cells, suggesting that TACE is the major TNF-alpha converting enzyme in vivo.
      TACE-deficient cells are compromised in the generation of other soluble proteins
      that are produced as the result of cleavage of a membrane precursor form,
      suggesting that TACE is involved in multiple shedding events.

PMID- 10415749
TI  - Retinoid-mediated suppression of tumor invasion and matrix metalloproteinase
      synthesis.
AB  - Cancer mortality usually results from the tumor invading the local environment
      and metastasizing to vital organs, e.g. liver, lung, and brain. Degradation of
      the extracellular matrix is, therefore, the sine qua non of tumor cell invasion.
      this degradation is mediated mainly by MMPs, and thus, inhibition of MMP
      synthesis is a target for anticancer agents. Tumor cells must traverse both the
      basement membrane (type IV collagen) and the interstitial stroma (type I
      collagen). Therefore, we used scanning electron microscopy to examine the
      invasive behavior of several aggressive tumor cell lines, A2058 melanoma cells,
      and SCC and FaDu squamous cell carcinomas through these matrices; and we
      monitored the ability of all-trans retinoic acid and several RAR-specific ligands
      to block invasion. We demonstrate that several retinoids, which are specific RAR
      alpha, beta, or gamma agonists/antagonists, selectively inhibited MMP synthesis
      in the three tumor cell lines. However, there was not a common pattern of MMP
      inhibition by a particular retinoid. For instance, a RAR alpha antagonist
      suppressed MMP-1 and MMP-2 synthesis in the melanoma cell line, but not in the
      FaDu or SCC-25 cells. On the other hand, synthesis of MMP-1 and MMP-9 by the FaDu
      cells was affected hardly at all, while a RAR gamma antagonist reduced the levels
      of MMP-2. Only all-trans retinoic acid reduced MMP-1 synthesis in these cells. We
      postulate that the differences may be related to a differential pattern of RAR
      expression in each of these cells, and that the RARs expressed by each cell line
      may not be targets of these RAR specific compounds. All-trans retinoic acid is a
      pan ligand, binding to all three RARs and, therefore, may modulate gene
      expression more generally. We conclude that the power of these new ligands lies
      in their specificity, which can be directed towards modulating expression of
      certain RARs and, thus, of certain MMPs. By blocking MMP synthesis, retinoids may
      be effective in cancer therapy by decreasing tumor invasiveness.

PMID- 10415748
TI  - MMP inhibition and downregulation by bisphosphonates.
AB  - Bisphosphonates are a group of drugs capable of inhibiting bone resorption, and
      are thus used for the treatment of bone diseases, such as Paget's disease,
      osteoporosis, and for bone metastases of malignant tumors. Their primary cellular
      target is considered to be the osteoclast. The molecular mechanisms responsible
      for the downregulation of bone resorption by bisphosphonates have remain unclear.
      We have discovered that various matrix metalloproteinases (MMPs) are inhibited in
      vitro by several bisphosphonates. This novel finding may, in part, explain the
      efficacy of bisphosphonates in their current indications in humans. In enzyme
      activity tests using purified and recombinant enzymes, we have observed the
      inhibition of MMP-1, -2, -3, -7, -8, -9, -12, -13, and -14 by clondronate,
      alendronate, pamidronate, zolendronate, nedrinate, and clodrinate. The IC50s
      range from 50 to 150 microM. We have also shown that clodronate can downregulate
      the expression of MT1-MMP protein and mRNA in several cell lines. Additionally,
      several bisphosphonates decrease the degree of invasion of malignant melanoma
      (C8161) and fibrosarcoma (HT1080) cells through artificial basement membrane
      (Matrigel) in cell cultures at IC50s of 50-150 microM and below. Having low
      toxicity and proven to be well tolerated after several years in human use,
      bisphosphonates have the potential to become one of the main MMP-inhibitors for
      MMP-related human soft and hard tissue-destructive diseases in the near future.

PMID- 10415750
TI  - Determination of gelatinase-A (MMP-2) activity using a novel immunocapture assay.

PMID- 10415751
TI  - Analytical aspects regarding the measurement of metalloproteinases.

PMID- 10415752
TI  - Hyper-resistance to infection in TIMP-1-deficient mice is neutrophil dependent
      but not immune cell autonomous.

PMID- 10415753
TI  - Shed membrane vesicles and selective localization of gelatinases and MMP-9/TIMP-1
      complexes.

PMID- 10415754
TI  - Tissue inhibitor of metalloproteinase-1 is not an acute-phase protein.

PMID- 10415755
TI  - Regulation of TIMP-1 expression by hypoxia in kidney fibroblasts.

PMID- 10415756
TI  - Induction of human tissue inhibitor of metalloproteinase-1 gene expression by all
      trans retinoic acid in combination with basic fibroblast growth factor involves
      both p42/44 and p38 MAP kinases.

PMID- 10415757
TI  - Transcriptional regulation of the human tissue inhibitor of metalloproteinases-1:
      mapping transcriptional control in intron-1.

PMID- 10415758
TI  - Balance between MMP-9 and TIMP-1 expressed by human bronchial epithelial cells:
      relevance to asthma.

PMID- 10415759
TI  - Use of encapsulated cells secreting murine TIMP-2 ameliorates collagen-induced
      arthritis in mice.

PMID- 10415760
TI  - TIMP-1 and TIMP-2 perform different functions in vivo.

PMID- 10415761
TI  - Tissue inhibitor of metalloproteinase-2 induces apoptosis in human T lymphocytes.

PMID- 10415762
TI  - Analysis of the interaction of TIMP-2 and MMPs: engineering the changes.

PMID- 10415763
TI  - Murine TIMP-2 gene-targeted mutation.

PMID- 10415764
TI  - The expression of TIMP-3 in hepatoma cell lines.

PMID- 10415765
TI  - In situ activity of gelatinases during Lewis lung carcinoma progression.

PMID- 10415766
TI  - Targeting matrix metalloproteinases in human prostate cancer.

PMID- 10415767
TI  - Expression of matrix metalloproteinases in gastric carcinoma and possibility of
      clinical application of matrix metalloproteinase inhibitor in vivo.

PMID- 10415768
TI  - Metalloproteinases and tissue inhibitors of matrix-metalloproteinases in plasma
      of patients with prostate cancer and in prostate cancer tissue.

PMID- 10415769
TI  - MMP inhibition reduces intimal hyperplasia in a human vein graft stenosis model.

PMID- 10415770
TI  - Increased MMP-9 activity in acute carotid plaques: therapeutic avenues to prevent
      stroke.

PMID- 10415771
TI  - Enhanced expression of matrix metalloproteinase-3, -12, and -13 mRNAs in the
      aortas of apolipoprotein E-deficient mice with advanced atherosclerosis.

PMID- 10415773
TI  - Modulation of matrix metalloproteinases in trophoblast cell lines.

PMID- 10415772
TI  - Defects in matrix metalloproteinase inhibitory stoichiometry and selective MMP
      induction in patients with nonischemic or ischemic dilated cardiomyopathy.

PMID- 10415774
TI  - Effect of relaxin on tissue inhibitor of metalloproteinase-1 and -2 in the
      porcine uterus and cervix.

PMID- 10415775
TI  - Matrix metalloproteinases exhibit different expression patterns in inflammatory
      demyelinating diseases of the central and peripheral nervous system.

PMID- 10415777
TI  - Chemokine-induced extravasation of MonoMac 6 cells: chemotaxis and MMP activity.

PMID- 10415776
TI  - Matrix metalloproteinases in sterile corneal melts.

PMID- 10415778
TI  - Elevated plasma gelatinase A (MMP-2) activity is associated with quiescent
      Crohn's Disease.

PMID- 10415779
TI  - Regulation of matrix metalloproteinases in human intestinal mucosa.

PMID- 10415780
TI  - MMP-13 and MMP-1 expression in tissues of normal articular joints.

PMID- 10415781
TI  - Expression and localization of TIMP-1, TIMP-2, MMP-13, MMP-2, and MMP-9 in early
      and advanced experimental lung silicosis.

PMID- 10415782
TI  - Type II collagen peptide release from rabbit articular cartilage.

PMID- 10415783
TI  - Inhibition of articular cartilage degradation in culture by a novel nonpeptidic
      matrix metalloproteinase inhibitor.

PMID- 10415784
TI  - Collagen-PVP decreases collagen turnover in synovial tissue cultures from
      rheumatoid arthritis patients.

PMID- 10415785
TI  - Matrix metalloproteinase inhibitors block osteoclastic resorption of calvarial
      bone but not the resorption of long bone.

PMID- 10415786
TI  - Matrix metalloproteinase inhibitor CGS 27023A protects COMP and proteoglycan in
      the bovine articular cartilage but not the release of their fragments from
      cartilage after prolonged stimulation in vitro with IL-1 alpha.

PMID- 10415787
TI  - Modulation of the synthesis and activation of matrix metalloproteinases in IL-1
      treated chondrocytes by antirheumatic drugs.

PMID- 10415788
TI  - Effects of 1 alpha,25dihydroxyvitaminD3 on matrix metalloproteinase expression by
      rheumatoid synovial cells and articular chondrocytes in vitro.

PMID- 10415789
TI  - Synovial cytokine and growth factor regulation of MMPs/TIMPs: implications for
      erosions and angiogenesis in early rheumatoid and psoriatic arthritis patients.

PMID- 10415790
TI  - Development and application of a microplate assay method for the mass screening
      of MMP inhibitors.

PMID- 10415791
TI  - Heparin and fragments modulate the expression of collagen-degrading enzymes
      (matrix metalloproteinases 1 and 2) by human gingival fibroblasts.

PMID- 10415792
TI  - Inhibition of matrix metalloproteinases by tea catechins and related polyphenols.

PMID- 10415793
TI  - The citrus flavonoid nobiletin suppresses the production and gene expression of
      matrix metalloproteinases-9/gelatinase B in rabbit synovial cells.

PMID- 10415794
TI  - Gelastatins, new inhibitors of matrix metalloproteinases from Westerdykella
      multispora F50733.

PMID- 10415795
TI  - Human metalloproteinase-1 (collagenase-1) is a tumor suppressor protein p53
      target gene.

PMID- 10415796
TI  - Interaction between stromal cells and tumor cells induces chemoresistance and
      matrix metalloproteinase secretion.

PMID- 10415797
TI  - Inhibition of gelatinase A by oleic acid.

PMID- 10415798
TI  - Attenuation of oxidant-induced lung injury by the synthetic matrix
      metalloproteinase inhibitor BB-3103.

PMID- 10415799
TI  - Influence of putative antiinvasive agents on matrix metalloproteinase secretion
      by human neoplastic glia in vitro.

PMID- 10415800
TI  - Effect of a matrix metalloproteinase inhibitor (BB-1101) on nerve regeneration.

PMID- 10415801
TI  - Selective inhibition of collagenase-1, gelatinase A, and gelatinase B by
      chemotherapeutic agents.

PMID- 10415802
TI  - Meloxicam and indomethacin activity on human matrix metalloproteinases in
      synovial fluid.

PMID- 10415803
TI  - Non-antimicrobial and antimicrobial tetracyclines inhibit IL-6 expression in
      murine osteoblasts.

PMID- 10415805
TI  - MMP inhibition by chemically modified tetracycline-3 (CMT-3) in equine pulmonary
      epithelial lining fluid.

PMID- 10415804
TI  - CMT-8/clodronate combination therapy synergistically inhibits alveolar bone loss
      in LPS-induced periodontitis.

PMID- 10415806
TI  - CMT-3, a chemically modified tetracycline, inhibits bony metastases and delays
      the development of paraplegia in a rat model of prostate cancer.

PMID- 10415807
TI  - Collagenase-2 and -3 are inhibited by doxycycline in the chronically inflamed
      lung in bronchiectasis.

PMID- 10415808
TI  - The effect of MMP inhibitor metastat on fissure caries progression in rats.

PMID- 10415810
TI  - TNF-alpha-converting enzyme activity in colonic biopsy specimens from patients
      with inflammatory bowel disease revealed by mRNA and in vitro assay.

PMID- 10415809
TI  - Tetracycline derivative CMT-3 inhibits cytokine production, degranulation, and
      proliferation in cultured mouse and human mast cells.

PMID- 10415811
TI  - MMPs are IGFBP-degrading proteinases: implications for cell proliferation and
      tissue growth.

PMID- 10415812
TI  - Phosphonate inhibitors of adamalysin II and matrix metalloproteinases.

PMID- 10415813
TI  - Roles of MT1-MMP in the regulation of cell surface proteolysis.

PMID- 10415814
TI  - Transient increase of intracellular cAMP by heat shock initiates the suppression
      of MT1-MMP production in tumor cells.

PMID- 10415815
TI  - The 9-kDa N-terminal propeptide domain of MT1-MMP is required for the activation
      of progelatinase A.

PMID- 10415816
TI  - Cell type-specific involvement of furin in membrane type 1 matrix
      metalloproteinase-mediated progelatinase A activation.

PMID- 10415817
TI  - High fructose-fed rats: a model of glomerulosclerosis involving the renin
      angiotensin system and renal gelatinases.

PMID- 10415818
TI  - Wound healing in aged normal and ovariectomized rats: effects of chemically
      modified doxycycline (CMT-8) on MMP expression and collagen synthesis.

PMID- 10415819
TI  - Therapeutic options in small abdominal aneurysms: the role of in vitro studies.

PMID- 10415820
TI  - Inhibition of the metalloproteinase domain of mouse TACE.

PMID- 10415821
TI  - The effects of sustained elevated levels of circulating tissue inhibitor of
      metalloproteinases-1 on the development of breast cancer in mice.

PMID- 10415822
TI  - Macrophage-specific expression of human collagenase (MMP-1) in transgenic mice.

PMID- 10415823
TI  - TIMP-4 is regulated by vascular injury in rats.

PMID- 10415824
TI  - In vivo adenoviral gene transfer of TIMP-1 after vascular injury reduces
      neointimal formation.

PMID- 10415825
TI  - Paradoxical stimulation of matrix metalloproteinase-9 expression in HT1080 cells
      by a broad-spectrum hydroxamate-based matrix metalloproteinase inhibitor.

PMID- 10415826
TI  - Identification of the TIMP-2 binding site on the gelatinase A hemopexin C-domain
      by site-directed mutagenesis and the yeast two-hybrid system.

PMID- 10415827
TI  - Alternating oscillations and chaos in a model of two coupled biochemical
      oscillators driving successive phases of the cell cycle.
AB  - The animal cell cycle is controlled by the periodic variation of two cyclin
      dependent protein kinases, cdk1 and cdk2, which govern the entry into the M
      (mitosis) and S (DNA replication) phases, respectively. The ordered progression
      between these phases is achieved thanks to the existence of checkpoint mechanisms
      based on mutual inhibition of these processes. Here we study a simple theoretical
      model for oscillations in cdk1 and cdk2 activity, involving mutual inhibition of
      the two oscillators. Each minimal oscillator is described by a three-variable
      cascade involving a cdk, together with the associated cyclin and cyclin-degrading
      enzyme. The dynamics of this skeleton model of coupled oscillators is determined
      as a function of the strength of their mutual inhibition. The most common mode of
      dynamic behavior, obtained under conditions of strong mutual inhibition, is that
      of alternating oscillations in cdk1 and cdk2, which correspond to the
      physiological situation of the ordered recurrence of the M and S phases. In
      addition, for weaker inhibition we obtain evidence for a variety of dynamic
      phenomena such as complex periodic oscillations, chaos, and the coexistence
      between multiple periodic or chaotic attractors. We discuss the conditions of
      occurrence of these various modes of oscillatory behavior, as well as their
      possible physiological significance.

PMID- 10415828
TI  - Self organization in synthetic polymeric systems.

PMID- 10415829
TI  - Relevance of the protein-lipid interaction on the functioning of the bacterial
      reaction center.

PMID- 10415830
TI  - Time-dependent properties of isotactic polypropylene fibers.

PMID- 10415831
TI  - Suspended life in biological systems. Fragility and complexity.

PMID- 10415832
TI  - Coupling of erratic Belousov-Zhabotinsky oscillators observed by
      spectrophotometric measure.

PMID- 10415833
TI  - Complexity at the molecular level. A dynamic view of biomolecules obtained by
      NMR.

PMID- 10415834
TI  - Thermodynamics of extremely diluted aqueous solutions.

PMID- 10415835
TI  - Linear and nonlinear properties of heart rate variability: influence of obesity.

PMID- 10415837
TI  - Recurrence quantification analysis in molecular dynamics.

PMID- 10415836
TI  - Fractal analysis in human pathology.

PMID- 10415839
TI  - Complex rotational dynamics of the Cu(II)-bleomycin system in mobile and viscous
      media.

PMID- 10415838
TI  - Photodegradation of organic waste coupling hydrogenase and titanium dioxide.
AB  - In this work the results of the study on the degradation of dairy waste and
      lactose with use of titanium dioxide (TiO2), as photocatalyst, are presented. The
      ability of TiO2 to degrade dairy waste is compared either in the presence of
      molecular oxygen or of a bacterial hydrogenase as electron acceptor. The enzyme
      mediated H2 production rates or the O2 consumption rates are used to measure
      electron donor degradation. The results obtained clearly indicate that dairy
      waste can be degraded by the TiO2 photocatalyst. Proteins present in the dairy
      waste have a strong inhibitory effect on the degradation process. Indeed lactose
      alone can easily be degraded. When the protein extract obtained from the dairy
      waste was added to the lactose solution, the reaction for both electron
      acceptors, hydrogenase and oxygen, was inhibited. When the dairy waste solutions
      were diluted, there was a positive effect on the reaction rate. This was
      particularly true in the case of hydrogenase, and to a lesser extent in the case
      of oxygen acceptor. The reduction of the pH from 8 to 6 also increased H2
      production when the enzyme was used.

PMID- 10415840
TI  - On crystallization kinetics of polytetrafluoroethylene.

PMID- 10415841
TI  - Conformational chaos of an elastin-related peptide in aqueous solution.

PMID- 10415842
TI  - Vanadium uptake by yeasts.

PMID- 10415843
TI  - Fish exclusion and PCB bioaccumulation in Bear Creek, east Tennessee.

PMID- 10415844
TI  - Relations between energy consumption and air quality in an urban environment:
      spatial scenarios of emission reduction.

PMID- 10415845
TI  - Gene expression in pancreatic adenocarcinoma.
AB  - Both acinar and duct cell-specific gene products are expressed by pancreatic
      adenocarcinoma. In order to begin to understand the mechanisms by which genes of
      both cell types are expressed in pancreatic adenocarcinoma, an understanding of
      the underlying transcription factors is important. PDX1 plays an important role
      in the development of the pancreas and is also expressed in the adult pancreas;
      it is known to be involved in the regulation of expression of both acinar and
      islet cell-specific gene products. We have examined pancreatic adenocarcinoma
      cell lines and have determined that they also express PDX1, making it a candidate
      transcription factor for the abnormal regulation of these acinar and duc cell
      gene products.

PMID- 10415846
TI  - Carbonic anhydrase in human pancreas: hypotheses for the pathophysiological roles
      of CA isozymes.
AB  - Among more than ten isozymes of the carbonic anhydrase (CA) family, only
      cytoplasmic CA II and membrane-bound CA IX have been reported to be expressed in
      human pancreas. To study the mRNA expression of CA isozymes in human pancreas,
      reverse transcriptase-polymerase chain reaction (RT-PCR)-Southern blot analysis
      and cDNA sequencing following RT-PCR were employed. CA II, IV, VI, IX, and XII
      were clearly identified in polyA+ RNA from normal human pancreas by RT-PCR
      Southern blotting. Results with cultured pancreatic tumor cell, lines suggest
      that CA II, IV, IX, and XII are expressed in the ductal cells, and CA VI is
      expressed in the acinar cells. We propose a hypothesis for the pathophysiological
      function of CA isozymes in human pancreas; (1) the intraluminal CA isozymes (CA
      IV, VI, and possibly XII) form a mutually complementary system with cytoplasmic
      CA II to regulate the luminal pH of the pancreatic duct system and work as a self
      defense mechanism against pancreatitis; (2) CA II and other CA isozymes play a
      pathological role in the autoimmune process of idiopathic chronic pancreatitis.

PMID- 10415847
TI  - The duct cell in cystic fibrosis.
AB  - The pancreatic duct cell is central to the etiology of cystic fibrosis (CF) and
      is the site where pathology commences in utero. We have evaluated expression of
      the cystic fibrosis transmembrane conductance regulator gene (CFTR) through human
      development and shown it to be expressed from the early mid-trimester, with
      highest levels in the most distal portion of the developing duct system and in
      centroacinar cells. The precise cause of pancreatic destruction in CF is thought
      to be the obstruction of pancreatic ducts with inspissated secretions. We have
      shown that the MUC6 mucin is a significant component of the material that
      obstructs the ducts and that the MUC6 gene shows a very similar pattern of
      expression to that of CFTR in the developing pancreas. These observations provide
      a starting point for investigating how mutations in CFTR lead to obstruction of
      the pancreatic ducts in CF.

PMID- 10415849
TI  - Proteins expressed by pancreatic duct cells and their relatives.
AB  - Significant progress has been made in the characterization of the structure and
      function of pancreatic ductal cells. Our understanding at this point in time
      extends to knowledge of specific molecules that provide for the structural
      composition of the ductal cells, their interactions with the local environment,
      and the regulation of their growth and properties of differentiation. Knowledge
      of the molecular composition and structure of the secretory products of
      epithelial cells in the pancreas also has increased so that we now understand the
      individual contributions of several secretory products to the overall function of
      pancreatic juice. Further study of these parameters will give us important
      insight into the normal function of the ductal cells and into how these processes
      are altered during the development and progression of diseases of the pancreas
      such as pancreatitis and cancer.

PMID- 10415848
TI  - Tumor suppressor gene Smad4/DPC4, its downstream target genes, and regulation of
      cell cycle.
AB  - The tumor suppressor gene deleted in pancreatic cancer locus 4 (Smad4/DPC4) is
      inactivated in about 50% of pancreatic adenocarcinomas. The role of DPC4 in the
      transforming growth factor-beta (TGF-beta) receptor-mediated signal transduction
      cascade in human pancreatic, colon, and breast carcinoma cell lines has been
      investigated by a number of laboratories. The results demonstrate that Smad4/DPC4
      protein functions as a key transcription factor required in regulation of TGF
      beta inducible gene expression and subsequent growth inhibition. Many
      transcription regulators that are involved in cell growth, differentiation, and
      oncogenesis have been identified and cloned. Yet paradoxically, it is much more
      difficult to identify the important downstream target genes responsible for the
      biological effects elicited by these transcription factors. Although numerous
      attempts have been made and different approaches have been used to identify the
      target genes, only limited success has been achieved. Our data show that p21waf1
      is one of the Smad4/DPC4-regulated downstream target genes and suggest that
      overexpression of the Smad4/DPC4 gene can bypass TGF-beta receptor activation and
      reestablish one of the key regulatory controls of cell proliferation.
      Identification of the Smad-regulated downstream target genes responsible for
      diverse biological processes that they control will extend our understanding of
      the mechanism for cell cycle regulation and cell differentiation.

PMID- 10415851
TI  - Hyperplastic and metaplastic changes in pancreatic ducts: nomenclature and
      preneoplastic potential.

PMID- 10415850
TI  - Immortalized pancreatic duct cells in vitro and in vivo.
AB  - Although pancreatic adenocarcinoma has become one of the best characterized
      malignant diseases, severe diagnostic and therapeutic problems are still
      associated with this disease. The establishment of a molecular model of
      pancreatic carcinogenesis may provide tools that could result in earlier
      diagnosis of this disease and, in turn, improves prognosis. Since pancreatic
      adenocarcinoma seems to originate in epithelial cells in the pancreatic ducts,
      cultivation of native pancreatic duct epithelial cells (PDEC) is the initial step
      in the establishment of an in vitro model of pancreatic carcinogenesis. As these
      native cells survive only a short period in culture, the aim of this study was to
      establish a stable pancreatic duct cell line by immortalization with the SV40
      large T antigen. Furthermore, initial steps in pancreatic carcinogenesis should
      possibly be imitated by additional transfections of mutated ki-ras and/or mutated
      p53 genes. By optimization of the isolation protocol and the culture medium,
      yield as well as proliferative activity of isolated PDEC was increased
      considerably. Transfection of SV40 large T antigen resulted in an increase in the
      proliferative lifetime of the isolated cells, but no real immortal phenotype was
      obtained. Moreover, one step in the transformation from the normal to the
      malignant phenotype was imitated successfully by additional transfection of
      mutated ki-ras.

PMID- 10415852
TI  - Molecular pathology of invasive carcinoma.
AB  - Abnormalities of several oncogenes and tumor suppressor genes have been
      identified in carcinomas of the pancreas during the last decade, and multiple
      genetic changes have been demonstrated in individual carcinomas. The variety of
      genetic changes suggests that multiple etiologic factors contribute to
      carcinogenesis in the pancreas. Several of these changes are characteristically
      found in specific types of tumors, suggesting that different causes and molecular
      mechanisms are involved. One example is the loss of heterozygosity at the von
      Hippel-Lindau (VHL) gene locus in both wild type and hereditary serous
      cystadenomas, and another is the virtual absence of K-ras mutation and p53
      abnormalities in acinar cell carcinomas, whereas both are frequently found in
      ductal adenocarcinomas. Multiple lines of evidence place K-ras mutation very
      early and loss of p53 and p16 as late events during ductal cell carcinogenesis.
      The timing and order of other genetic changes such as loss of the DPC4 tumor
      suppressor function is less certain.

PMID- 10415853
TI  - Hollow-spheres: a new model for analyses of differentiation of pancreatic duct
      epithelial cells.
AB  - We discovered a unique feature of a subclone of the pancreatic carcinoma cell
      line A818. A818-1-derived hollow-spheres developed under three-dimensional growth
      conditions. Hollow-spheres consist of a single layer of 50-200 epithelial cells
      surrounding an inner lumen. In contrast to A818-1, the subclone A818-4 and all
      other pancreatic tumor cell lines tested (n = 5), formed spheroids as the only
      three-dimensional phenotype. A dramatically reduced proliferation rate compared
      to the corresponding monolayer was observed in hollow-spheres when
      bromodeoxyuridine (BrdU) incorporation was measured. This finding was confirmed
      by immunostaining using the MIB-1 antibody. Mechanically disrupted hollow-spheres
      not only attached but also grew as monolayer with the same doubling time as the
      founder cells. Hollow-spheres developed in fetal calf serum (FCS) containing RPMI
      1640 medium without additionally added cytokines. A818-1 hollow-sphere formation
      and integrity was influenced by interferon-gamma. Tumor necrosis factor-alpha
      (TNF-alpha) led to cell death. Exogenously added hepatocyte growth factor (HGF)
      showed no effect neither on hollow-sphere formation nor on the integrity of
      completely developed hollow-spheres. Moreover, no changes were observed when
      cells were treated with a neutralizing antibody for HGF. Interestingly, hollow
      spheres showed intensive immunoreactivity for the HGF-receptor (c-met) and its
      ligand (HGF). Immunostaining for the biliary glycoprotein (BGP), the non-specific
      cross-reacting antigen 95 (NCA95) and beta-catenin revealed a polar organization
      of hollow-spheres. Immunhistochemically, hollow-spheres were negative for the
      carcinoembryonic antigen (CEA). When hollow-spheres were embedded into matrigel,
      duct-like tubes grew out. Taken together, A818-1 hollow-spheres resemble normally
      differentiated duct-like structures and will serve as an excellent model to study
      differentiation of human pancreatic epithelial cells.

PMID- 10415854
TI  - Sp1 and its likes: biochemical and functional predictions for a growing family of
      zinc finger transcription factors.
AB  - The discovery and functional characterization of Sp1 as a GC-rich binding zinc
      finger protein provided a useful paradigm for understanding mechanisms mediating
      transcriptional activation in eukaryotic cells. This early paradigm suggested
      that promoters carrying GC-rich sequences are activated by Sp1 through its
      interaction with proteins from the basal transcriptional machinery to upregulate
      gene expression. Since the time of this seminal work, studies from several
      laboratories have led to the discovery of many Sp1-like transcription factors
      containing highly homologous DNA binding motifs that bind to similar sequences.
      Consequently, this knowledge poses many important questions regarding whether
      these related proteins have similar or antagonistic biochemical and functional
      properties to Sp1. The goal of this article is to use available database
      information and recent experimental evidence to describe the current repertoire
      of Sp1-like zinc finger transcription factors in mammalian cells. Furthermore, we
      discuss structural and functional studies that reveal that these proteins may
      share a role in morphogenetic pathways. Altogether, this information is aimed at
      better understanding how this growing family of transcription factors work to
      regulate gene expression and morphogenesis.

PMID- 10415855
TI  - Orthotopic models of human pancreatic cancer.
AB  - Orthotopic transplantation of solid tumor fragments of human tumors in nude mice
      reproduces their pattern of local growth and distal dissemination. While
      lymphatic, hepatic or peritoneal dissemination can be reproduced, perineural
      invasion is absent. Early passages (less than 3) of xenografts show a high degree
      of stability regarding K-ras, p53 and p16 gene status. On the other hand,
      advanced passages of tumors acquire additional alterations in the p15 and Smad4
      genes. Mutations in K-ras, p53, p15 and Smad4 genes can be acquired, in this
      model system, in the more advanced stages of pancreatic tumor dissemination.
      Finally, it is also possible to standardize local growth of these tumors as well
      as its dissemination pattern giving us a preclinical tool to evaluate the
      anticancer activity of new drugs.

PMID- 10415856
TI  - Growth factors and cytokines in pancreatic carcinogenesis.
AB  - Pancreatic cancer is a deadly disease challenging basic and clinical researchers
      alike in characterizing its pathobiology and finding better treatment options. A
      number of molecular alterations including gene mutations such as k-ras, p53, and
      Smad4 and aberrant expression of a variety of genes have been identified in
      recent years. This review focuses on two families of growth factors and growth
      factor receptors which are representative for the molecular alterations observed
      in pancreatic cancer: the transforming growth factor-beta superfamily of serine
      threonine kinase receptors and their ligands, which usually act as negative
      growth regulators, and the epidermal growth factor receptor family and their
      ligands, which have the potential to act as growth promoters in pancreatic
      cancer. In addition, we will discuss the role of the cytokines TNF-alpha, IFN
      gamma, and IL-6 and its effects on pancreatic cancer cell proliferation in vitro
      and in vivo. Pancreatic cancer cell biology consists of complex interactions of
      various factors, and a better understanding of the molecular pathogenesis of this
      disorder might lead to better treatment strategies in the near future.

PMID- 10415857
TI  - Strategies for the detection of disease genes in pancreatic cancer.
AB  - The present review summarizes our strategies aimed at identifying and
      characterizing genetic alterations occurring at the transcriptional and
      chromosomal level in pancreatic cancer. To study transcriptional alterations we
      have used a number of techniques including modified versions of differential
      hybridizations and cDNA RDA (representational difference analysis). These
      approaches have led to the identification of more than 500 genes with
      differential expression in pancreatic cancer. To study chromosomal aberrations
      occurring in pancreatic cancer tissues we used comparative genomic hybridization
      (CGH). This allowed the identification of a number of chromosomal regions
      containing putative tumor suppressor genes or oncogenes. Genes isolated in both
      approaches represent potential new disease genes for pancreatic cancer and are at
      present being characterized by individual or serial analysis.

PMID- 10415858
TI  - p22/PRG1: a novel early response gene in pancreatic cancer cells regulated by p53
      and NF kappa B.

PMID- 10415860
TI  - Differentially expressed genes in normal and tumor pancreatic tissue.

PMID- 10415859
TI  - Protein tyrosine dephosphorylation and the maintenance of cell adhesions in the
      pancreas.
AB  - Cell-cell contacts are important regulatory elements in tissue development, organ
      morphogenesis and malignant tumor invasion. In recent in vivo studies we have
      identified the members of the cadherin/catenin family of cell adhesion proteins
      that are differentially expressed in the pancreas and have determined their cell
      biological dynamics during dissociation and repair of adherens junctions. To
      further characterize these events, epithelial cell culture systems were used and
      a number of type II protein tyrosine phosphatases (PTPs) were found to colocalize
      and interact with the cadherin/catenin complex. These observations suggest that
      tyrosine dephosphorylation in general and PTPs in particular are involved in cell
      contact formation. Our most recent experiments indicate 1) that inhibition of
      PTPs alone dissociates pancreatic adherens junctions, 2) that cytosolic and
      transmembrane PTPs are differentially expressed in acinar cells, and 3) that a
      subset of them can associate with proteins of the cadherin/catenin complex at
      pancreatic cell-cell adhesions.

PMID- 10415861
TI  - Typing of leukocytes in pancreatic tissue surrounding human pancreatic carcinoma.

PMID- 10415862
TI  - Apoptotic molecules in pancreatic carcinoma cell lines.

PMID- 10415863
TI  - Genomic anomalies in pancreatic tumors other than common adenocarcinoma.
AB  - In recent years enormous advances have been made in the understanding of the
      molecular mechanisms governing pancreatic ductal adenocarcinoma. However, little
      is known about other pancreatic neoplasms, which include intraductal papillary
      mucinous (IPMT), serous cystic (SCT), mucinous cystic (MCT), solid
      pseudopapillary (SPT), acinar and islet cell tumors. In addition, the study of
      tumors grouped under the unfortunate term of periampullary cancers will help
      distinguish the pathogenetic features of these neoplasms, often confused with
      pancreatic head neoplasms. The available data suggest that the less common
      pancreatic tumor types do not generally follow the same molecular pathway as the
      more common ductal carcinoma. IPMT seems to contain chromosomal anomalies similar
      to those found in ductal cancers, whereas papilla of Vater and duodenal cancers
      show genetic anomalies resembling those of gastrointestinal malignancies. The
      application of genome-wide screening techniques to these less common pancreatic
      tumors will undoubtedly play a central role in unraveling the complexity behind
      their pathology.

PMID- 10415864
TI  - Pancreatic cancer: development of a unifying etiologic concept.
AB  - Our knowledge of the etiology of all forms of cancer including pancreatic cancer
      has improved dramatically in the second half of this century. The current model
      describes a gradual change from a normal pancreatic cell to a fully malignant
      cell requiring several stages with gradual and progressive alterations appearing
      at the genetic and the tissue level. Although there are many germ line diseases
      that are associated with pancreatic cancer it is probable that inherited diseases
      account for only about 10% of the total burden of pancreatic cancer. Avoidance of
      smoking and dietary modification are the current best strategies for reducing the
      risk of this tumor. In addition, newer molecular techniques and imaging
      procedures should provide clinicians with the ability to detect pancreatic cancer
      at an early, potentially curable stage.

PMID- 10415865
TI  - Hereditary pancreatitis and pancreatic carcinoma.
AB  - Few risk factors for pancreatic cancer have emerged except for chronic
      pancreatitis. Recently, hereditary pancreatitis was estimated to carry a
      standardized incidence ratio of 53, a risk about 25 times higher than smoking. A
      review of the ongoing hereditary pancreatitis study of the Midwest Multicenter
      Pancreatic Study Group suggests that the risk of pancreatic cancer is related to
      long-standing pancreatitis rather than to the cationic trypsinogen mutations. No
      recommendations can be made on screening patients with hereditary pancreatitis
      for pancreatic cancer at this time. However, prospective data, serum, and
      pancreatic juice should be collected and banked on consenting patients at risk as
      part of prospective, multicenter trials so that evidence-based recommendations
      for hereditary pancreatitis and other types of chronic pancreatitis can be made
      in the future.

PMID- 10415866
TI  - Ki-ras oncogene mutations in chronic pancreatitis: which discriminating ability
      for malignant potential?
AB  - Ki-ras mutations are found in the majority of pancreatic adenocarcinomas (85
      100%). Ki-ras analysis was increasingly used in ERCP samples in order to
      differentiate between chronic pancreatitis and pancreatic cancer. However, its
      sensitivity was recently reported to be low due to a high prevalence of ras
      mutations in patients with chronic pancreatitis (25-37%). Detection of Ki-ras
      mutations in microdissected pancreata confirmed their high frequency (55-83%) in
      pancreatic intraductal lesions (PILs) observed in chronic pancreatitis specimens
      and in the vicinity of invasive pancreatic carcinoma. There is now molecular
      evidence that PILs can be precursors of invasive carcinoma, since they can harbor
      genetic alterations identical to those of the adjacent carcinoma. Similarly, we
      observed 2 patients with chronic pancreatitis who developed pancreatic cancer 18
      and 24 months after the evidence of Ki-ras mutations in pancreatic brushings.
      However, besides these findings, ras mutations were also identified in
      nondiseased pancreata coming from autopsy series. The current data on ras
      analysis in pancreatic juice and brushings or in microdissected pancreata suggest
      that PILs with Ki-ras mutations do not inevitably lead toward invasive carcinoma.
      Ki-ras mutations probably have a low discriminating ability for malignant
      potential and their detection in pancreatic juice is not justified routinely for
      differentiating between benign and malignant pancreatic diseases. However,
      prospective follow-up of patients with chronic pancreatitis harboring a mutant
      ras is probably of major interest by combining the search for other genetic
      markers that have the ability to characterize patients with the greater risk of
      malignant transformation.

PMID- 10415867
TI  - Acinar-ductal-carcinoma sequence in transforming growth factor-alpha transgenic
      mice.
AB  - Transgenic mice overexpressing transforming growth factor-alpha (TGF-alpha)
      display an expansion of intrapancreatic fibroblasts and a progressive
      accumulation of extracellular matrix. This massive fibrosis is associated with an
      increase in pancreatic size and weight. In parallel, tubular complexes appear
      that are composed of acinar cells with a decreased height. These acinar cell lose
      zymogen granules and become transitional cells, which subsequently gain duct cell
      features. In animals older than one year dysplastic lesions develop, which
      originate from tubular complexes. Occasionally these dysplastic foci transform to
      papillary and cystic pancreatic carcinoma. These tumors are positive for the duct
      specific antigen Duct-1 and carbonic anhydrase activity indicative of ductal
      differentiation. Tumors overexpress the epidermal growth factor (EGF)-receptor
      and p53, but lack K-ras mutations. These data suggest an acinar-ductal-carcinoma
      sequence in TGF-alpha transgenic mice.

PMID- 10415868
TI  - The course of pancreatic fibrosis induced by dibutyltin dichloride (DBTC).
AB  - In summary, in addition to an acute interstitial pancreatitis the organotin
      compound DBTC induced a pancreatic fibrosis in rats. The course of the pancreatic
      fibrosis was studied 2-36 weeks after single i.v. treatment of rats with 6 or 8
      mg/kg DBTC. The pancreatic fibrosis induced by DBTC differs from other
      experimental models of acute pancreatitis. Extensive infiltration by mononuclear
      cells is present in fibrotic areas without pancreatic atrophy or lipomatosis. The
      presence of chronic inflammatory lesions characterized by the destruction of
      exocrine parenchyma and fibrosis and in the later stages the endocrine
      parenchyma, indicate a chronic pancreatitis. In completion of the experimental
      model of the DBTC-induced acute interstitial pancreatitis in rats, the described
      late fibrotic effects on rat pancreas may be used as an experimental model of
      chronic pancreatitis.

PMID- 10415869
TI  - CD44, bFGF and hyaluronan in human pancreatic cancer cell lines.

PMID- 10415870
TI  - Immunological escape mechanisms in pancreatic carcinoma.
AB  - Malignancies have developed several strategies to evade immune surveillance. We
      have investigated pancreatic cancer cell lines and pancreatic cancer surgical
      specimens to evaluate possibilities of tumor escape in the Fas system, and local
      immune suppression. Despite Fas expression the majority of cell lines was
      resistant to Fas-mediated apoptosis. The Fas-associated phosphatase-1 is a strong
      candidate to confer Fas resistance in pancreatic cancer cells. In addition, all
      investigated pancreatic cancer cell lines and cancer specimens expressed Fas
      ligand. Fas ligand was functional in cancer cell lines as shown by coculture
      assays of pancreatic cancer cell lines with Jurkat cells as targets. Additional
      local immune suppression was demonstrated by loss of T-cell receptor/CD3-zeta
      chain of pancreatic cancer infiltrating T-lymphocytes. We conclude that these
      tumor escape mechanisms may contribute to the poor prognosis of pancreatic cancer
      but also represent targets for new treatment modalities.

PMID- 10415871
TI  - The novel Trk receptor tyrosine kinase inhibitor CEP-701 (KT-5555) exhibits
      antitumor efficacy against human pancreatic carcinoma (Panc1) xenograft growth
      and in vivo invasiveness.
AB  - The survival rate for patients with pancreatic ductal adenocarcinoma (PDAC) is
      among the poorest for all cancers. The factors that contribute to this poor
      prognosis are lack of effective early detection, high rate of metastases and a
      generally refractory response to available treatment modalities. The most
      commonly used treatment methods--chemotherapy and radiation therapy--are mainly
      used for symptom palliation, with surgery being the only "curative" treatment
      option. The use of combinations of treatment modalities is the only therapy
      available to patients with locally advanced disease or that which is surgically
      unresectable. These options are still not sufficient to increase patient survival
      time significantly. The aggressive behavior and poor prognosis of this cancer is
      associated with an increased expression of many growth factors and their cognate
      receptors. We have demonstrated previously the aberrant expression of the Trk
      receptors (Trks A, B, and C) in PDAC specimens and human PDAC-derived cell lines
      and a biphasic, dose-dependent response of specific neurotrophic agents on the in
      vitro invasiveness of PDAC cells. Based on these data we have evaluated the
      therapeutic potential of inhibiting neurotrophin-Trk interactions using a
      selective Trk tyrosine kinase inhibitor (CEP-701) on subcutaneous (s.c.) and
      tracheal xenografts derived from the poorly differentiated PDAC cell line, Panc1.
      We demonstrate that CEP-701 administration at 10 mg/kg s.c. BID for 21 days
      inhibited tumor growth of the Panc1 s.c. xenografts in a statistically
      significant manner (p < 0.01) compared to vehicle controls, in the absence of
      morbidity and mortality. A T/C value of 25% was observed for CEP-701-treated s.c.
      xenografts. In addition, CEP-701 administration inhibited tumor cell invasion in
      the s.c. tracheal xenograft model of in vivo invasiveness. Taken together, these
      data suggest that further studies are warranted to evaluate CEP-701 as a
      potential therapeutic agent in the treatment of PDAC.

PMID- 10415872
TI  - Single-chain antibodies in pancreatic cancer.
AB  - Pancreatic cancer is a therapeutic challenge for surgical and medical oncology.
      Development of specific molecular tracers for the diagnosis and treatment of this
      lethal cancer has been one of our major goals. Monoclonal antibodies (MAbs) have
      been successfully used as selective carriers for delivering radionuclides, toxins
      or cytotoxic drugs to malignant cell populations; therefore, monoclonal antibody
      technology has led to a significant amount of research into optimizing targeted
      therapy. This targeted therapy results in the selective concentration of
      cytotoxic agents or radionuclides in tumors and should lessen the toxicity to
      normal tissues, which would normally limit the dosage and effectiveness of
      systemically administered drugs. The MAb CC49 reacts with a unique disaccharide,
      Sialyl-Tn, present on tumor-associated mucin (TAG-72) expressed by a majority of
      human adenocarcinomas. The unique Sialyl-Tn epitope has provided a potential
      target for immunotherapy of cancer. A single chain Fv (scFv) recombinant protein
      from CC49 MAb was prepared by engineering the DNA fragments for coding heavy
      chain and light-chain variable regions with an appropriate oligonucleotide
      linker. scFv molecules, when compared to intact MAbs and the more conventional
      enzymatically derived F(ab')2 and Fab' fragments, offer several advantages as
      carriers for the selective delivery of radionuclides to tumors. The divalent
      antibody fragments (sc(Fv)2 or (scFv)2) display an affinity constant similar to
      that of the intact CC49 IgG and are stable with storage, and after radiolabeling.
      In preclinical studies, both the covalent and the non-covalent dimeric scFvs
      exhibit excellent tumor targeting properties with characteristics similar to
      those of the monomer, e.g., the rapid blood clearance, low kidney uptake and
      small size suitable for rapid penetration through tumor tissue. Increased tumor
      targeting of the dimers are probably due to their increased functional affinity
      attributable to valency, coupled with their higher molecular weight and fewer
      interactions with normal organs. These properties make these constructs superior
      to monovalent CC49 scFv. The relatively high tumor uptake, the in vitro and in
      vivo targeting specificity, and the stability in storage demonstrated by the
      dimeric CC49 sc(Fv)2 makes it a promising delivery vehicle for therapeutic
      applications in pancreatic cancer.

PMID- 10415873
TI  - p53 in relation to therapeutic outcome of locoregional chemotherapy in pancreatic
      cancer.
AB  - Since celiac artery infusion (CAI) led to an increase in survival in palliative
      chemotherapy in pancreatic cancer, we treated 26 patients with adjuvant CAI
      following resection for advanced pancreatic cancer. Catheters were placed
      angiographically into the celiac artery and remained there for five consecutive
      days. One cycle of chemotherapy consisted of mitoxantrone, 5-fluorouracil (5-FU),
      folinic acid, and cis-platinum. This treatment was repeated five times in monthly
      intervals. Median survival times in patients who received CAI are 21 months for
      all patients, whereas in patients who did not receive adjuvant treatment median
      survival is 10.5 months. In all patients p53 expression of the carcinomas was
      determined by immunohistochemistry. In 11/26 patients a p53 overexpression was
      observed. Although p53 overexpression turned out to be associated with poor
      prognosis in the patients who underwent adjuvant regional cancer treatment, p53
      is not a sufficient prognostic parameter in pancreatic carcinoma, since p53
      overexpression was more frequent in undifferentiated tumors and in palliative
      resected tumors.

PMID- 10415874
TI  - The matrix metalloproteinases and their inhibitors in the treatment of pancreatic
      cancer.
AB  - Matrix metalloproteinases (MMPs) are a family of zinc-containing proteolytic
      enzymes that break down extracellular matrix proteins (ECM) in physiological and
      pathological conditions. Disruption in the tight control of MMP metabolism occurs
      in cancer, resulting in excessive destruction of the ECM, neovascularization,
      tumor spread and metastases. Recent studies have shown that overexpression of
      MMPs is associated with poor prognosis. Several MMP inhibitors have been
      developed and preclinical trials have confirmed a reduction in tumor spread and
      metastases. Marimastat is a broad spectrum inhibitor, and recent published
      results shows the drug is well tolerated in patients with advanced cancer. Phase
      II studies which have used marimistat alone or in combination with other
      cytotoxic agents, have produced encouraging results with improved survival. Phase
      III trials are now underway for the use of marimastat in advanced pancreatic
      cancer and as an adjuvant therapy in patients following resection of pancreatic
      cancer.

PMID- 10415875
TI  - Exocrine pancreatic function following pancreatectomy.
AB  - Pancreatic exocrine insufficiency can follow major pancreatic resection and
      result in the malabsorption of fat, causing symptoms of steatorrhea, abdominal
      pain and weight loss. The extent of malabsorption will depend on the original
      disease process and the type and extent of surgical resection. The steatorrhea
      can be severe and difficult to control, and patients may require high doses of
      pancreatic enzyme supplements. There have been few studies that have looked at
      the treatment of steatorrhea postpancreatectomy, and very few randomized studies.
      Results of the latter have demonstrated that after treatment with oral pancreatic
      supplements over a third of postpancreatectomy patients still have significant
      levels of steatorrhea. These results show that even using the best available
      agents the complete elimination of steatorrhea following major pancreatic
      resection is not possible at the present time. This indicates a need for further
      effective therapies.

PMID- 10415876
TI  - Genetic prodrug activation therapy for pancreatic cancer.

PMID- 10415877
TI  - Characterization of a human cell clone expressing cytochrome P450 for safe use in
      human somatic cell therapy.
AB  - We have previously demonstrated the therapeutic effect and efficacy of
      implantation of cells genetically modified to express cytochrome P450 2B1 in a
      nude mouse tumor model. The cells are encapsulated in polymerized cellulose
      sulphate and injected into preformed tumors. Upon administration of ifosfamide,
      the P450 enzyme converts the ifosfamide into antitumorigenic toxic metabolites at
      the site required, thereby significantly reducing tumor burden. Feline kidney
      epithelial cells were chosen for these studies, because they are easy to culture
      and can readily be transfected. However, these cells are not suitable for
      eventual use in human patients, since they are known to express endogenous
      retroviruses that are able to infect mammalian cells. They thus represent a
      safety risk. Here we describe the establishment of a human cell line that has
      been genetically modified to express the same cytochrome P450 construct and their
      characterization. The usefulness of mitomycin C treatment, both to protect the
      cells from the toxic metabolites that they produce and to incapacitate these
      cells from replicating, should they escape from the capsules, has also been
      investigated.

PMID- 10415878
TI  - Injection of encapsulated cells producing an ifosfamide-activating cytochrome
      P450 for targeted chemotherapy to pancreatic tumors.
AB  - The prognosis of pancreatic cancer is poor, and current medical treatment is
      mostly ineffective. The aim of this study was to design a new treatment modality
      in an animal model system. We describe here a novel treatment strategy employing
      a mouse model system for pancreatic carcinoma. Embryonal kidney epithelial cells
      were genetically modified to express the cytochrome P450 subenzyme 2B1 under the
      control of a cytomegalovirus (CMV) immediate early promoter. This CYP2B1 gene
      converts ifosfamide to its active cytotoxic compounds, phosphoramide mustard,
      which alkylates DNA, and acrolein, which alkylates proteins. The cells were then
      encapsulated in a cellulose sulphate formulation and implanted into
      preestablished tumors derived from a human pancreatic tumor cell line.
      Intraperitoneal administration of low-dose ifosfamide to tumor bearing mice that
      received the encapsulated cells results in partial or even complete tumor
      ablation. Such an in situ chemotherapy strategy utilizing genetically modified
      cells in an immunoprotected environment may prove useful for solid tumor therapy
      in man.

PMID- 10415879
TI  - Ablation of tumor cells in vivo by direct injection of HSV-thymidine kinase
      retroviral vector and ganciclovir therapy.
AB  - The introduction of therapeutic genes into proliferating tumor cells in vivo by
      direct intralesional injection of retroviral vectors can provide an effective and
      valuable approach for the treatment of a variety of solid tumor types. Efficient
      transduction of tumor cells in situ by direct injection was demonstrated using a
      retroviral vector containing the beta-galactosidase (beta-gal) gene. Ablation
      therapy in vivo was demonstrated using a retroviral vector containing the Herpes
      simplex virus thymidine kinase gene (HSV-TK) to deliver the TK gene into the
      murine colorectal tumor cell line CT26. Ablation of CT26 tumor cells in situ was
      achieved by directly injecting high-titer HSV-TK retroviral vector preparations
      into the site of tumor cell inoculation followed by intraperitoneal (i.p.)
      delivery of ganciclovir (GCV). This gene therapy strategy demonstrated a markedly
      lower rate of tumor progression, with several complete regressions, compared to
      animals in control groups. We also demonstrated that resistance to subsequent
      challenges with unmodified CT26 cells and an enhanced cellular immune response is
      associated with tumor regression in immunocompetent animals. Our results
      demonstrate the feasibility of direct in situ administration of HSV-TK retroviral
      vectors for the treatment of cancer and suggest that a cellular immune response
      may be elicited by this therapy.

PMID- 10415880
TI  - Enhanced retroviral transduction efficiency of pancreatic tumor cell lines using
      different envelope glycoproteins.

PMID- 10415881
TI  - Construction of recombinant retroviruses expressing mutated k-ras or mutated p53
      genes.

PMID- 10415882
TI  - Intraarterial instillation of microencapsulated cells in the pancreatic arteries
      in pig.

PMID- 10415883
TI  - Genetics session: the human genome. Prognostications and predispositions.

PMID- 10415884
TI  - Of genes and genomes.

PMID- 10415885
TI  - The human genome project and the future of medicine.

PMID- 10415886
TI  - Neuroscience session: intelligence--the origin and substrate of thinking.
      Introduction to the session.

PMID- 10415887
TI  - Building a picture of the brain.

PMID- 10415888
TI  - The importance of being well placed and having the right connections.

PMID- 10415889
TI  - Modern phrenology: maps of human cortical function.

PMID- 10415890
TI  - How the mind works.

PMID- 10415891
TI  - Imidazoline receptor antisera-selected cDNA clone and mRNA distribution.
AB  - A novel cDNA, designated Imidazoline Receptor Antisera-Selected cDNA-1 (iras-1),
      encodes a 167-kD protein. Two of its predicted peptides (42-43 kD) are
      immunologically consistent with a previously reported 1(1)-imidazoline binding
      protein. In the present study, two forms of iras mRNA (6.0 and 9.5 kb) were
      quantified across fresh rat tissues. Highest levels were found in brain (almost
      exclusively 6.0 kb in size), followed by liver and lung (9.5 > or = 6.0 kb iras
      mRNA), kidney (6.0 > 9.5 kb), heart (6.0 kb), spleen (6.0 > or = 9.5 kb), testes
      (6.0 > 9.5 kb), and skeletal muscle (6.0 > 9.5 kb). A correlation exists (p =
      0.71, p = 0.05) between total (6.0 + 9.5 kb) iras mRNA and I1 BMAX values across
      rat tissues, corrected for housekeeping gene expression. Thus, total iras mRNA
      appears to be roughly proportional to the density of I1-imidazoline binding
      sites.

PMID- 10415892
TI  - Pharmacologic characterization of imidazoline receptor proteins identified by
      immunologic techniques and other methods.
AB  - Biochemical and pharmacologic evidence supports the heterogeneous nature of
      imidazoline receptors (IRs). However, only monoamine oxidase (MAO) (55- and 61
      kD) isozymes have been identified as imidazoline binding site-containing
      proteins. Idazoxan-binding proteins of approximately 70- and approximately 45-kD
      of unknown amino acid sequences have been isolated from chromaffin cells and rat
      brain, respectively. Other proteins of approximately 27-30 to > 80 kD have been
      visualized by immunologic and photoaffinity labeling techniques in different
      tissues and species. The specific antiserum that recognizes the approximately 70
      , approximately 45-, and approximately 29-kD IR proteins, but not MAO, was used
      to quantitate these proteins in the rat brain cortex. Treatments (7 days) with
      the I2-selective imidazoline drugs idazoxan (10 mg/kg), cirazoline (1 mg/kg), and
      LSL 60101 ([2-(2-benzofuranyl) imidazole; 10 mg/kg]) induced differential changes
      in these proteins: levels of the approximately 29-kD IR were increased by
      idazoxan and LSL 60101 (23%), levels of the approximately 45-kD protein only by
      cirazoline (44%), and those of the approximately 66-kD protein only by idazoxan
      (50%). These treatments also increased the densities of [3H]-idazoxan (I2)
      binding sites (32-42%). Chronic treatment with efaroxan, RX821002, and yohimbine
      (10 mg/kg), which possess very low affinity for I2-IRs, did not alter either
      their immunoreactivities or the density of I2 sites. Chronic treatment with MAO
      inhibitors clorgyline and phenelzine (10 mg/kg) and acute treatment with EEDQ
      (1.6 mg/kg, 6 h) induced decreases in the levels of these IR proteins (17-47%)
      and I2 sites (31-57%). Significant correlations were found when the mean
      percentage changes in immunoreactivity of IR proteins were related to the mean
      percentage changes in the density of I2 sites after treatment with the foregoing
      drug (r = 0.92, r = 0.69, and r = 0.75 for the approximately 29-, approximately
      45-, and approximately 66-kD proteins, respectively). These results indicate that
      in the rat cerebral cortex, the I2 sites labeled by [3H]idazoxan are
      heterogeneous and that the related immunoreactive IR proteins contribute
      differently to the modulation of I2 sites after drug treatment.

PMID- 10415893
TI  - Imidazoline binding domains on MAO-B. Localization and accessibility.
AB  - Various imidazoline and guanidinium derivatives elicit diverse cellular responses
      in both peripheral tissues and the central nervous system that are often
      difficult to attribute to known receptor signaling systems. Such molecules also
      exhibit high affinity for membrane proteins (imidazoline binding sites) that are
      distinct from receptors for known hormones and recognize endogenous bioactive
      substance(s) that mimic some of the effects of these compounds. These
      observations suggest a previously uncharacterized cell signaling system. However,
      limited information on the identity and functionality of this family of
      imidazoline binding sites has hampered the full understanding of this system.
      Unexpectedly and of particular significance, recent data indicate that two
      members of the family of imidazoline binding proteins are identical to the A and
      B isoforms of monoamine oxidase (MAO). The imidazoline binding domain on MAO is
      distinct from the enzyme active site that recognizes the mechanism-based
      inhibitors such as pargyline and deprenyl and is not equally accessible in all
      tissues.

PMID- 10415894
TI  - Relationship between I2 imidazoline binding sites and monoamine oxidase B in
      liver.
AB  - Biochemical and pharmacologic studies suggest that I2 imidazoline binding sites
      (I2BS) represent a heterogeneous family of membrane proteins. Indeed, the
      imidazoline binding sites located on monoamine oxidases (MAO) A and B display
      different pharmacologic properties. Recent results suggest that in liver and
      brain, I2BS may be located on proteins distinct from MAOs. The following
      observations indicate that in liver and brain, [3H]idazoxan binds exclusively to
      I2BS located on MAO-B: (1) size exclusion chromatography of digitonin-solubilized
      preparations from rabbit and human liver showed that [3H]idazoxan-specific
      binding eluted only in two peaks (approximately 175,000 and approximately 100,000
      Da, corresponding to 90% and 10% of the recovered [3H]idazoxan binding) which
      also contained MAOs as determined by [14C]tyramine oxidation and Western blot
      analysis; (2) according to previous results obtained in various human and rat
      tissues, experiments performed in mice liver and brain showed that idazoxan was a
      potent inhibitor of [125I]-AZIPI photoincorporation to MAO-B but not to MAO-A;
      (3) in MAO-deficient transgenic mice, [3H]idazoxan binding to liver and brain
      membranes was completely abolished in MAO-B knockout mice and was not affected in
      MAO-A knockout mice. Together, these results show that in both liver and brain,
      I2BS are located exclusively on MAO-B. The imidazoline binding site on MAO-A,
      which photoincorporates [125I]-AZIPI and displays a low affinity for idazoxan,
      may not belong to the family of the I2 imidazoline binding sites.

PMID- 10415895
TI  - The I1-imidazoline receptor and its cellular signaling pathways.
AB  - Two primary questions are addressed. First, do I1-imidazoline binding sites
      fulfill all the essential criteria for identification as a true receptor? Second,
      what are the cellular signaling pathways coupled to this novel receptor? I1
      imidazoline binding sites show specificity in binding assays, linkage to
      physiologic functions, appropriate anatomic, and cellular and subcellular
      localization. Most important, binding affinities correlate with functional drug
      responses. I1-imidazoline binding sites meet several additional criteria
      identified with functional receptors: they show physiologic regulation and
      endogenous ligands and, most crucially, are coupled to cellular signaling events.
      A series of studies have identified cellular events triggered by I1-imidazoline
      receptor occupancy. This receptor is not coupled to conventional pathways
      downstream of heterotrimeric G-proteins, such as activation or inhibition of
      adenylyl or guanylyl cyclases, stimulation of inositol phospholipid hydrolysis,
      or induction of rapid calcium fluxes. The I1-imidazoline receptor is coupled to
      choline phospholipid hydrolysis, leading to the generation of diacylglyceride,
      arachidonic acid, and eicosanoids. Additional cellular responses include
      inhibition of Na+/H+ exchange and induction of genes for catecholamine synthetic
      enzymes. The signaling pathways linked to the I1-imidazoline receptor are similar
      to those of the interleukin family, implying that I1-receptors may belong to the
      family of neurocytokine receptors.

PMID- 10415896
TI  - Coexpression of imidazoline receptors and alpha 2-adrenoceptors in neuroglial
      cell line NG 108,15.

PMID- 10415897
TI  - Transfected cells expressing the three subtypes of alpha 2-adrenergic receptors
      lack I1-imidazoline binding sites.

PMID- 10415898
TI  - Lack of effect of reserpine on immunoreactive imidazoline receptor proteins in
      rat brain.

PMID- 10415899
TI  - Agmatine: an endogenous ligand at imidazoline receptors is a novel
      neurotransmitter.
AB  - Agmatine, an amine and organic cation, is an endogenous ligand at alpha 2
      adrenergic and imidazoline (I-) receptors, to which it binds with high affinity.
      In addition, agmatine has properties of an endogenous neurotransmitter. Thus,
      agmatine (a) is locally synthesized in brain by a specific enzyme, arginine
      decarboxylase; (b) is stored in a large number of neurons with selective
      distribution in the CNS; (c) is associated with small vesicles in axon terminals
      that, at least in hippocampus, make synaptic asymmetric (excitatory) synapses on
      pyramidal cells; (d) is released from synaptosomes in a Ca(2+)-dependent manner;
      (e) can be enzymatically degraded by agmatinase in synaptosomes; (f) can be
      inactivated by selective reuptake; (g) blocks the ligand-gated NMDA receptor
      channel at sites distinct from ligand-binding and polyamine sites; and (h) has
      systemic actions when administered intraventricularly. Additionally, (i) agmatine
      is a precursor of brain putrescine and, hence, of higher polyamines, and (j) it
      competitively inhibits the activity of all isozymes of nitric oxide synthase.
      Agmatine meets most criteria to establish it as a novel
      neurotransmitter/neuromodulator in the CNS. However, agmatine differs from forms
      of clonidine displacing system with respect to distribution, bioactivity, and
      capacity to interact with antibodies raised to imidazoline-like drugs. Thus,
      there are multiple endogenous ligands of the imidazoline receptors, one of which
      is agmatine.

PMID- 10415900
TI  - Novel selective compounds for the investigation of imidazoline receptors.
AB  - Over several years our group has sought to synthesize and identify selective
      ligands for imidazoline (I) receptors, in particular the I2 binding site. As a
      consequence, [3H]2-(2-benzofuranyl)-2-imidazoline (2BFI) has proved extremely
      useful for binding and autoradiographic studies. More recently we have
      synthesized a BU series of compounds and examined these for their affinities for
      both I1 and I2 binding sites. BU224 (2-(4,5-dihydroimidaz-2-yl)-quinoline) shows
      high affinity for I2 receptors with a Ki of 2.1 nM. BU226 (2-(4,5-dihydroimidaz-2
      yl)-isoquinoline) demonstrated slightly higher affinity (Ki 1.4 nM) for I2
      receptors, but overall BU224 displayed greater selectivity for I2 over I1
      receptors (832-fold) than BU226 (380-fold). Both compounds showed low (microM)
      affinity for alpha 2-adrenoceptors. Given BU224's ability to cross the blood
      brain barrier, we predict that its in vivo effects are likely to be mediated via
      I2 receptors. Brain dialysis revealed BU224 to dose dependently (0-20 mg/kg i.p.)
      elevate basal noradrenaline in rat frontal cortex and basal dopamine in striatum.
      In a rat model of opiate withdrawal, behavioral studies showed that BU224 (10
      mg/kg, s.c.) was able to reduce acute weight loss and diarrhea, but not the
      number of wet dog shakes associated with the withdrawal syndrome.

PMID- 10415901
TI  - Comparison of crude methanolic CDS extracts from various tissues.

PMID- 10415902
TI  - Effects of agmatine on the cardiovascular system of spontaneously hypertensive
      rats.

PMID- 10415903
TI  - An unexpected central hypertensive effect of the new imidazoline compound
      benazoline.

PMID- 10415904
TI  - Structure of new imidazoline derivatives and their cardiovascular effect in rats.

PMID- 10415905
TI  - Pentamidine is a potent inhibitor of [3H]idazoxan binding to imidazoline I2
      receptors.

PMID- 10415906
TI  - Inhibition of central monoamine oxidase by imidazoline2 site-selective ligands.

PMID- 10415907
TI  - Binding of tracizolines to the imidazoline receptor. Role of lipophilicity in
      quantitative structure-activity relationship models.

PMID- 10415908
TI  - Identification of human I1 receptors and their relationship to alpha 2
      adrenoceptors.
AB  - I1 imidazoline receptors (I1R) were defined as receptors insensitive to
      catecholamines and highly sensitive to [3H]clonidine and analogs. By contrast,
      the I2R subtype is more sensitive to [3H]idazoxan. [3H]clonidine and [3H]idazoxan
      imidazoline specific binding sites (IBS) have been detected in crude human
      membranes. Pharmacologic characterization by binding assays clearly
      differentiates IBS from alpha 2-adrenoceptors, whereas differences between
      [3H]clonidine and [3H]idazoxan IBS are less clear in crude preparations. In fact,
      only moderate affinity for [3H]clonidine was detectable in such preparations.
      However, purification procedures allowed detection of high affinity [3H]clonidine
      IBS in the human brain, corresponding to the I1R. Difficulties in the
      characterization of the I1R in crude membranes are due to multiple factors
      including heterogeneity of IBS, their low Bmax value, the existence of allosteric
      modulation, and possibly the presence of natural binding inhibitors. Immunologic
      studies with specific anti-idiotypic antibodies revealed a 43-kD protein as the
      best candidate for I1R as binding activity coincides with immunodetection. No
      cross-reaction was found with anti-monoamine oxidase (MAO) A/B antibodies and the
      43-kD protein, ruling out the possibility of this protein being an MAO-associated
      I2R. Neither anti-alpha 2A- nor anti-alpha 2B-specific antibodies were able to
      immunodetect the 43-kD protein in crude membrane preparations or in purified
      fractions. These results and further biochemical characterization (pHi, N
      glycosylation) of the 43-kD protein definitely assessed that human brain I1R and
      alpha 2-adrenoceptors clearly differ physically. However, coexpression of I1R and
      alpha 2-adrenoceptors in synaptic plasma membranes of the bovine brainstem
      reinforce the possibility of a functional relationship between the two types of
      receptor.

PMID- 10415909
TI  - Identification of I1 and I2 imidazoline receptors in striatum membranes from
      different species.
AB  - The alpha 2-adrenergic agonist [3H]clonidine and antagonist [3H]idazoxan also
      label I1 and I2 imidazoline receptors in striatum membranes. They are
      investigated here in striata from the dog, rat, mouse, rabbit, calf, monkey, and
      human. I1 receptors were barely detected in the dog, rat, and mouse and only
      further examined by competition binding experiments in calf, rabbit, and human.
      I2 receptors were further examined in all species. The centrally acting
      vasodilators clonidine and rilmenidine were more potent than moxonidine at the I1
      receptors. They displayed low potency for the I2 receptors in all species except
      the rat. In all species examined, the nonsubstituted imidazoline derivatives
      idazoxan and RX801077 displayed high affinity for the I1 and I2 receptors.
      Conversely, both stereoisomers of the alkoxy-substituted imidazoline-derivative
      efaroxan displayed low affinity. The matching binding characteristics of these
      compounds further stress the structural similarity of the ligand binding sites of
      I1 and I2 receptors.

PMID- 10415910
TI  - Pharmacologic and molecular discrimination of I2-imidazoline receptor subtypes.
AB  - I2-imidazoline receptors (I2-IR) are characterized by their high affinity for
      imidazolines and guanidines and medium affinity for imidazolidines. The
      differential recognition of I2-IR by amiloride led to subtype these sites as
      amiloride-sensitive (I2A-IR) and amiloride-insensitive (I2B-IR). I2-IR labeled
      with [3H]idazoxan or [3H]2-BFI in the rabbit cerebral cortex (I2A-IR) displayed
      higher affinities for amiloride and amiloride analogs than in the rat cerebral
      cortex (I2B-IR). Other drugs tested displayed biphasic curves in competition
      experiments, indicating the existence of high and low affinity sites for both I2
      IR subtypes. The drugs (+)- and (-)-medetomidine, bromoxidine, moxonidine, and
      clorgyline were more potent on the high and/or low affinity sites of I2B-IR than
      on I2A-IR. Preincubation (30 min at 25 degrees C) with 10(-6) M
      isothiocyanatobenzyl imidazoline (IBI) or with 10(-6) M clorgyline reduced by 40%
      and 26%, respectively, the binding of [3H]2-BFI to I2B-IR, but it did not alter
      the binding of the radioligand to I2A-IR. These results indicated that the I2-IR
      subtypes differ in their pharmacologic profiles and in the nature of the
      imidazoline binding site involved in clorgyline and IBI alkylation. In rat
      cortical membranes, western blot detection of immunoreactive imidazoline receptor
      proteins revealed a double band of approximately 29/30 kD and three less intense
      bands of approximately 45, approximately 66, and approximately 85 kD. In rabbit
      cortical membranes the antibody detected proteins of approximately 30,
      approximately 57, approximately 66, and approximately 85 kD. It is suggested that
      I2-IR may be related to more than one receptor protein and that I2-IR subtypes
      differ in the nature of the proteins implicated.

PMID- 10415912
TI  - Presynaptic imidazoline receptors. New developments in characterization and
      classification.
AB  - Presynaptic imidazoline receptors (IRs) which inhibit norepinephrine (NE) release
      from sympathetic nerve endings have been identified in cardiovascular tissue of
      man, rabbit, rat, and guinea pig. They do not belong to one of the classical
      presynaptic inhibitory receptor classes such as alpha 2-adrenoceptors or H3
      histamine receptors, and there is also no relation to I1- and I2-imidazoline
      binding sites. Segments of human right atrial appendages preincubated with [3H]NE
      were used to determine unknown pharmacologic properties of the presynaptic IRs.
      In the presence of 1 microM rauwolscine, S23230, the (-)-enantiomer of the
      racemic oxazoline derivative S22687 (5-(2(methyl-phenoxy-methyl)-1,3-oxazoline-2
      yl)amine) exhibited low potency in inhibiting the electrically evoked [3H]NE
      release (pIC30% = 4.96), whereas the (+)-enantiomer S23229 and the racemate
      S22687 were ineffective. The IR-mediated inhibitory effect of the imidazoline BDF
      6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline) and the guanidine
      aganodine on evoked [3H]NE release from sympathetic nerves in human atrial
      appendages was counteracted by rauwolscine (with very low potency) and by the
      cannabinoid CB1-receptor antagonist SR141715A (N-[piperdin-1-yl]-5-[4
      chlorophenyl]-2,4-dichlorophenyl]-4- methyl-1H-pyrazole-3-carboxamide). The
      inhibitory effect of moxonidine on evoked [3H]NE release (which is exclusively
      mediated via activation of alpha 2-autoreceptors) was antagonized with high
      potency by rauwolscine, but not by SR141716A. The cannabinoid CB1 receptor
      agonists CP55,940([(-)-Cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl] -trans-4-
      (3-hydroxy-propyl)cyclohexane]) and anandamide inhibited evoked [3H]NE release.
      Inhibition by CP55,940 and anandamide was abolished by 1 microM SR141716A as well
      as by 30 microM rauwolscine. In radioligand binding experiments on membranes from
      human atrial appendages (alpha 2- and sigma-binding sites were masked),
      cannabinoid receptor ligands and IR agonists displaced the radiolabeled guanidine
      derivative [3H]DTG (1,3-di-o-tolyguanidine, an agonist at presynaptic IRs) from
      its binding sites. Comparison of the potencies of these drugs determined in the
      competition experiments with [3H]DTG with those in inhibiting NE release via
      activation of the presynaptic IRs in the same tissue revealed a correlation. The
      present results suggest, e.g., that the presynaptic IRs may have certain binding
      domains in common with presynaptic cannabinoid receptors or that both receptors
      are different proteins which interact with each other in an unknown manner.

PMID- 10415911
TI  - Identification of imidazoline-receptor binding sites in cortex and medulla of the
      bovine adrenal gland. Colocalization with MAO-A and MAO-B.
AB  - The distribution and relative densities of imidazoline-receptor binding sites (I
      RBS) in bovine adrenal gland were determined using [3H]clonidine, [3H]2-(2
      benzofuranyl)-2-imidazoline ([3H]2-BFI), and [3H]rilmenidine. In light of strong
      evidence that I-RBS and monoamine amine oxidase enzymes are linked, the selective
      radioligands [3H]RO41-1049 and [3H]RO19-6327 were used to label the distribution
      of MAO-A and -B enzymes, respectively. [3H]Clonidine (12 nM) labeled sites in two
      discrete regions of the bovine adrenal gland, the zona glomerulosa (39 +/- 7
      fmol/mg tissue equivalent) and inner medulla (34 +/- 1 fmol/mg tissue). Binding
      was nonadrenergic (i.e., not inhibited by 100 nM methoxyidazoxan) and inhibited
      by 60-70% by 100 nM 2-BFI, the selective I2-RBS, suggesting binding predominantly
      to an I2-RBS. [3H]2-BFI (5 nM), the selective I2-RBS ligand, also labeled a high
      density of binding sites in the zona glomerulosa (57 +/- 9 fmol/mg) and
      chromaffin cells in the inner medulla (53 +/- 4 fmol/mg). These sites, however,
      were insensitive to clonidine (100 nM). By contrast, [3H]rilmenidine (40 nM)
      labeled I-RBS in all regions of the adrenal gland, that is, the zonae glomerulosa
      (59 +/- 10 fmol/mg), fasciculata (78 +/- 10 fmol/mg) and reticularis (63 +/- 7
      fmol/mg), and outer and inner medullary chromaffin cells (42 +/- 1 and 55 +/- 2
      fmol/mg, respectively). Binding to sites in the zona glomerulosa was partially
      inhibited (16%) by 100 nM 2-BFI. These results are consistent with previous
      studies indicating that [3H]rilmenidine labels an I2-RBS and additional I-RBS in
      rat brain and kidney. The distribution of [3H]RO19-6327 (5 nM) binding resembled
      that of [3H]2-BFI and [3H]clonidine binding with high densities of MAO-B enzyme
      located in the zona glomerulosa and chromaffin cells of the inner medulla (55 +/-
      7 and 76 +/- 6 fmol/mg tissue, respectively), suggesting the colocalization of
      MAO-B enzyme with I2-RBS. [3H]RO41-1049 (20 nM) binding to MAO-A was highest in
      the zona reticularis (196 +/- 7 fmol/mg tissue) compared to the zonae glomerulosa
      and fasciculata (90 +/- 12 and 116 +/- 14 fmol/mg tissue) and inner medulla (149
      +/- 38 fmol/mg tissue). Although the existence of I-RBS in bovine adrenal
      chromaffin cells is well established, this is the first description of I-RBS in
      the adrenal cortex. Further investigations are now required to determine whether
      imidazolines can affect adrenal function via actions at these sites.

PMID- 10415913
TI  - Evidence for presynaptic high affinity imidazoline-specific binding sites in the
      bovine brainstem.

PMID- 10415914
TI  - Imidazoline (I2) binding sites in chicken brain.

PMID- 10415915
TI  - Binding of the imidazoline ligand 3H-2-benzofuranyl-2-imidazoline (BFI) to human
      brain and platelets. Potentiation by tranylcypromine and role of MAO isoforms.

PMID- 10415916
TI  - I2-imidazoline receptors in platelets of patients with Parkinson's disease and
      Alzheimer's type dementia.

PMID- 10415917
TI  - Densities of I2-imidazoline receptors, imidazoline receptor proteins, and MAO-B
      sites in human gliomas and pituitary adenomas.

PMID- 10415918
TI  - Autoradiography of I2 receptors in frog brain.

PMID- 10415920
TI  - Imidazolines and pancreatic hormone secretion.
AB  - A range of imidazoline derivatives are known to be effective stimulators of
      insulin secretion, and this response correlates with closure of ATP-sensitive
      potassium channels in the pancreatic beta-cell. However, mounting evidence
      indicates that potassium channel blockade may form only part of the mechanism by
      which imidazolines exert their effects on insulin secretion. Additionally, it
      remains unclear whether members of this class of drugs can bind directly to
      potassium channel components and whether occupation of a single binding site
      accounts for their functional activity. This review considers recent developments
      in the field and highlights evidence that does not fit readily with the concept
      that a single mechanism of action is sufficient to mediate the effects of
      imidazolines on pancreatic hormone secretion.

PMID- 10415919
TI  - Endogenous indoleamines demonstrate moderate affinity for I2 binding sites.

PMID- 10415921
TI  - Imidazolines and the pancreatic B-cell. Actions and binding sites.
AB  - Stimulation of insulin secretion by imidazoline compounds displays variable
      characteristics. Phentolamine (10-100 microM) increased secretion of perifused
      mouse islets at nonstimulatory glucose concentrations (5 mM) and even in the
      absence of glucose. Idazoxan (20-100 microM) elicited a moderate increase in
      insulin secretion, which required the presence of a stimulatory glucose
      concentration (10 mM). Phentolamine is therefore a stimulator of secretion in its
      own right, whereas idazoxan may be termed an enhancer of secretion. Both
      compounds inhibited the activity of ATP-dependent K+ channels in inside-out
      patches from B-cells; however, idazoxan achieved only an incomplete block. Both
      compounds depolarized the B-cell plasma membrane to an extent that permitted the
      opening of voltage-dependent Ca2+ channels (-40 to -30 mV). An increase in
      cytoplasmic Ca2+ concentration was induced by phentolamine and much less so by
      idazoxan. Activation of protein kinase C, a possible mechanism to amplify Ca(2+)
      induced secretion, could not be verified for phentolamine. It thus appears that
      stimulation of insulin secretion by phentolamine is due to its blocking effect on
      KATP channels, which may be the correlate of non-adrenergic imidazoline binding
      sites which were characterized in insulin-secreting HIT cells. Whether incomplete
      closure of KATP channels by idazoxan or additional effects are responsible for
      the requirement of high glucose to stimulate secretion remains to be clarified.

PMID- 10415922
TI  - Different modes of action of the imidazoline compound RX871024 in pancreatic beta
      cells. Blocking of K+ channels, mobilization of Ca2+ from endoplasmic reticulum,
      and interaction with exocytotic machinery.
AB  - The imidazoline compound RX871024 glucose-dependently potentiates the release of
      insulin in pancreatic islets and beta-cell lines. This activity of the compound
      is not related to its action by stimulating alpha 2-adrenoceptors and I1- and I2
      imidazoline receptors. There are at least three modes of action of RX871024 in
      beta-cells: (1) RX871024 blocks the ATP-dependent, Ca(2+)-activated, and delayed
      rectifier K+ channel activity; (2) RX871024 causes mobilization of Ca2+ from
      thapsigargin-sensitive intracellular stores, the effect probably controlled by
      cytochrome P450; and (3) the stimulatory activity of RX871024 on insulin release
      involves interaction of the compound with the exocytotic machinery, unrelated to
      the changes in membrane potential and cytoplasmic-free Ca2+ concentration,
      whereas protein phosphorylation plays an important role in this process. The
      maximal insulinotropic effect of RX871024 is much higher than that of the
      sulfonylurea glibenclamide. RX871024 stimulates insulin release and normalizes
      blood glucose levels in rats in vivo without affecting blood pressure and heart
      rate.

PMID- 10415923
TI  - Mechanism of the sympathoinhibition produced by the clonidine-like drugs
      rilmenidine and moxonidine.
AB  - The mechanism of the sympathoinhibition produced by two new derivatives of
      clonidine, rilmenidine and moxonidine, was studied. One aim was to determine the
      receptor responsible for the central sympathoinhibition by these drugs.
      Rilmenidine and moxonidine were injected into the cisterna cerebellomedullaris.
      They decreased blood pressure and the plasma noradrenaline concentration. After
      rilmenidine and moxonidine, two selective alpha 2-adrenoceptor antagonists
      (devoid of affinity for I1 binding sites), yohimbine and SK&F86466, were given
      intracisternally. They completely counteracted the hypotensive effects of
      rilmenidine and moxonidine, indicating that alpha 2-adrenoceptors are involved in
      the central sympathoinhibition produced by these drugs. The other aim was to
      determine if peripheral presynaptic inhibition of noradrenaline release from
      postganglionic sympathetic neurons contributes to the overall reduction of
      sympathetic tone. Rilmenidine and moxonidine were injected i.v. in pithed rabbits
      with electrically stimulated sympathetic outflow. They dose-dependently lowered
      blood pressure and the plasma noradrenaline concentration and inhibited
      stimulation-evoked cardioacceleration. Moreover, the doses necessary for these
      peripheral effects were identical to the doses that reduce the sympathetic nerve
      firing rate and blood pressure in conscious rabbits. These observations indicate
      that peripheral presynaptic inhibition of noradrenaline release from
      postganglionic sympathetic neurons contributes to the overall reduction of
      sympathetic tone produced by rilmenidine and moxonidine in intact animals.

PMID- 10415924
TI  - Gene substitution/knockout to delineate the role of alpha 2-adrenoceptor subtypes
      in mediating central effects of catecholamines and imidazolines.
AB  - Adrenergic receptors form the interface between the sympathetic nervous system
      and the cardiovascular system as well as many endocrine and parenchymal tissues.
      For the three alpha 2-adrenergic receptors (alpha 2A, alpha 2B, and alpha 2C),
      genetic mouse models have been developed that can be used to elucidate the
      physiologic function of each receptor subtype in vivo. Different strategies for
      homologous recombination in embryonic stem cells were applied to generate lines
      of mice with gene knockouts of the individual alpha 2-receptor subtypes (alpha 2A
      KO, alpha 2B-KO, and alpha 2C-KO) or with a substitution of a mutant receptor at
      the wild-type locus (alpha 2-D79N). In these transgenic mice, the cardiovascular
      effects of alpha 2-agonists and imidazoline receptor agonists were tested.
      Stimulation of alpha 2B receptors in vascular smooth muscle produces hypertension
      and counteracts the clinically beneficial hypotensive effect of stimulating alpha
      2A receptors in the central nervous system.

PMID- 10415925
TI  - Participation of imidazoline receptors and alpha(2-)-adrenoceptors in the central
      hypotensive effects of imidazoline-like drugs.
AB  - The central hypotensive effect of imidazoline-like drugs (IMs) involves non
      adrenergic imidazoline receptors (IRs). IMs cause hypotension irrespective of
      their affinity and selectivity for one or the other alpha-adrenoceptor subtypes.
      LNP 509, which binds to I1Rs (Ki = 5.10(-7) M) but roughly not to alpha 2
      adrenoceptors (A2Rs) (Ki > 10(-5) M), causes hypotension when injected alone into
      the brainstem. As far as hybrid drugs, that is, those with mixed binding profiles
      (I1/alpha 2), are concerned, a significant correlation was reported between their
      central hypotensive effect and their affinity for IRs. Imidazoline antagonists
      such as idazoxan competitively antagonized the centrally induced hypotensive
      effect of IMs. Yohimbine, an A2Rs antagonist, blocks the hypotensive effect of
      hybrids but usually in a noncompetitive manner. Mutation of A2Rs prevented the
      hypotensive effects of drugs highly selective for A2Rs, but also that of hybrids
      such as clonidine. These data indicate that triggering of the hypotensive effects
      of IMs (1) needs implication of IRs; (2) appears to be facilitated by additional
      activation of A2Rs; and (3) requires integrity of A2Rs along the sympathetic
      pathways.

PMID- 10415926
TI  - Central imidazoline- and alpha 2-receptors involved in the cardiovascular actions
      of centrally acting antihypertensive agents.
AB  - There has been a continuing and yet unresolved debate concerning the existence
      and contribution of imidazoline receptors to the antihypertensive actions of
      clonidine-like agents. Studies from our laboratory have examined the importance
      of imidazoline receptors and alpha 2-adrenoceptors in the mechanism of action of
      centrally acting antihypertensive drugs. We used conscious rabbits and
      imidazoline and specific alpha 2-adrenoceptor antagonists to show that second
      generation agents rilmenidine and moxonidine act preferentially through
      imidazoline receptors but that alpha 2-adrenoceptors are important for the
      hypotension produced by clonidine and alpha-methyldopa. Using microinjections of
      the imidazoline antagonists into the rostral ventrolateral medulla (RVLM) of
      anesthetized rabbits we confirmed the generally held view that this is the major
      site of sympathoinhibitory actions of centrally acting antihypertensive agents.
      However, we also found that alpha 2-adrenoceptors are present in this nucleus and
      appear to be activated as a consequence of imidazoline receptor activation. In
      recent studies using a noradrenergic neurotoxin microinjected into the RVLM we
      found that this treatment selectively blocked the actions of moxonidine but did
      not affect the level of imidazole proteins, suggesting that I1-imidazoline
      receptors may be located presynaptic to the noradrenergic terminal. By contrast,
      clonidine acts directly on the alpha 2-adrenoceptors perhaps located on cell
      bodies in the nucleus. In conclusion, our studies suggest that imidazoline
      receptors and alpha 2-adrenoceptors within the RVLM are important for the
      antihypertensive actions of clonidine-like drugs.

PMID- 10415928
TI  - Importance of imidazoline receptors in the cardiovascular responses of clonidine
      in sinoaortic denervated rats.

PMID- 10415927
TI  - alpha 2A-adrenoceptors, not I1-imidazoline receptors, mediate the hypotensive
      effects of rilmenidine and moxonidine in conscious mice. In vivo and in vitro
      studies.

PMID- 10415929
TI  - Influence of sinoaortic barodenervation on the hypotensive effects of imidazoline
      like drugs in stroke-prone spontaneously hypertensive rats.

PMID- 10415930
TI  - Dissociation of the effects of intramedullary monoamine neurotoxins on the
      hypotensive action of moxonidine and on immunodetected imidazoline and alpha 2
      receptor proteins.

PMID- 10415931
TI  - Novel targets and techniques in imidazoline receptor research.
AB  - Imidazoline binding sites are now generally accepted as being receptors. Despite
      this acceptance, the molecular structure and signal transduction mechanisms of
      these receptors are still poorly understood. The I1-imidazoline binding site (I1
      receptor) is localized to the plasma membrane, but it is not clear if this
      represents a conventional receptor. It is also not clear if there are multiple
      forms of the I1-receptor. The signal transduction mechanisms of I1-receptors are
      similarly unclear, but much progress has been made. Evidence clearly indicates
      that ligands with high affinity for I1-receptors stimulate a novel signal
      transduction pathway, phosphatidylcholine-selective phospholipase C, in the rat
      adrenal medullary tumor cell line PC-12. However, this may not be the case in all
      cell types as microphysiometry, a novel technique for determining cellular
      activation, could not detect receptor activation in cultured bovine adrenal
      medullary cells exposed to a number of imidazolines considered to be agonists at
      the I1-receptor. This suggests that there is no I1-receptor-mediated stimulation
      of phosphatidylcholine-specific phospholipase C in these cells. By contrast,
      nicotine-stimulated increases in ion entry were blocked by clonidine. Ion
      channels have been suggested as another possible I1-imidazoline "receptor" family
      and may represent the low affinity I1-receptor. I1-Receptor ligands can be shown
      to bind to, or block, the following members of the ligand-gated ion channel super
      family, the 5HT3, K+ATP, NMDA, and nicotinic acetylcholine receptors. The site of
      action appears to be the phencyclidine binding site in these channels, but other
      possibilities cannot be excluded. Molecular modeling suggests that I1-receptor
      selective ligands share a common three-dimensional structure with phencyclidine,
      providing a basis for these actions. This suggests that a phencyclidine-binding
      site motif may represent a novel site of action for I1-receptor ligands and that
      searches for receptors based on this motif may reveal novel imidazoline
      "receptors."

PMID- 10415932
TI  - Modulation of MAO activity by imidazoline and guanidine derivatives.
AB  - I2-binding sites (I2-BS) are attributed to be a regulative site on monoamine
      oxidase (MAO). The in vivo and in vitro effects of various imidazoline and
      guanidine derivatives on MAO activity and on mitochondrial respiration were
      studied. Substances with high affinity for I2-BS (antazoline, idazoxan, and
      cirazoline: IC50 = 20.3, 33.8, and 43.4 microM) had a stronger inhibitory effect
      on MAO activity than did I1-ligands (efaroxan, rilmenidine, clonidine, and
      moxonidine: IC50 = 277, 801, 1,224, and > 10,000 microM). Substances with the
      highest inhibitory effects were BDF8082 (IC50 = 1.7 microM) and 2-(2
      benzofuranyl)-2-imidazoline (BFI; IC50 = 4.0 microM). The enzyme is inhibited
      noncompetitively and is reversible, because its activity is completely or
      partially restored after dialysis. Agmatine, the putative endogenous ligand for
      IBS, also decreased MAO activity (IC50 = 168 microM), whereas its precursor, L
      arginine, and its metabolite, putrescine, had no effects. In vitro inhibition of
      MAO and mitochondrial respiration by the IBS-ligands tested could not be
      correlated, suggesting no link between the function of the inner and outer
      mitochondrial membrane. MAO activity in vivo was significantly reduced only by
      pargyline (-95%), BDF8082 (-68%), BFI (-43%), and 1-(m-chlorophenyl)-biguanide (
      28%). Catecholamine content of livers obtained from animals treated with
      different IBS-ligands was consequently increased. In conclusion, the strong
      inhibitory effects of I2 selective imidazoline ligands confirm the existence of
      I2-BS as a regulatory site on MAO.

PMID- 10415933
TI  - Imidazoline recognition sites and stomach function.
AB  - Radioligand binding experiments carried out in cell membranes from rat and human
      stomach revealed the existence of non-adrenoceptor [3H]clonidine and [3H]idazoxan
      binding sites and of [3H]DTG (1,2-di-(2-tolyl)guanidine) binding sites. In rat
      stomach, specific binding was inhibited by imidazolines and guanidines and by non
      imidazoline sigma-site ligands, respectively, at different rank orders of
      affinity, suggesting the existence of non-I1/non-I2 [3H]clonidine binding sites,
      I2-imidazoline binding sites as well as sigma 2-like-sites. These sites are not
      directly related to a postsynaptic contractile effect on rat gastric smooth
      muscle or to acid release from isolated gastric glands. Finally, we demonstrated
      that the gastric pathogen Helicobacter pylori is able to form and to release the
      endogenous imidazoline receptor ligand agmatine and that considerable amounts of
      agmatine are present in human gastric juice. The quantities of agmatine were
      higher in gastric juice from H. pylori-positive than H. pylori-negative patients.

PMID- 10415934
TI  - Peripheral and central imidazoline receptor-mediated natriuresis in the rat.
AB  - On the basis of both radioligand and functional studies, the existence of a novel
      receptor that was unique from the alpha 2-adrenoceptor has become evident. Our
      initial studies contrasted the function of I1 imidazoline receptor agonists with
      that of purported alpha 2-adrenoceptor agonists in the kidney. The mechanism by
      which urine flow increased (osmolar vs free water clearance) as well as the
      effects of idazoxan, rauwolscine, a V2 vasopressin receptor antagonist,
      indomethacin pretreatment, and one-kidney one clip hypertension in rats were
      different following moxonidine when compared to an alpha 2-adrenoceptor agonist.
      This indicated two separate receptor systems. Subsequent studies determined that
      i.c.v. administration of moxonidine would also increase the urine flow rate by
      increasing osmolar clearance. This response to i.c.v. moxonidine differed from
      the response of an alpha 2-adrenoceptor agonist administered i.c.v.. Moreover,
      this effect of i.c.v. moxonidine was unique from that observed following the
      intrarenal infusion of moxonidine (Fig. 2). Denervation, intravenous prazosin,
      and i.c.v. idazoxan selectively blocked the effects of i.c.v. moxonidine.
      Intravenous idazoxan selectively blocked the response to intrarenal infusion of
      moxonidine. On the basis of the response to i.c.v. moxonidine in SH rats, the
      site(s) and/or receptor(s) responsible for blood pressure lowering were altered
      and those for increasing sodium excretion appear to be inactive. The significance
      of the findings in long-term regulation of blood pressure remain to be
      determined.

PMID- 10415935
TI  - Effects of imidazoline drugs on tyrosine and tryptophan hydroxylase activity in
      rat brain in vivo.

PMID- 10415936
TI  - Attenuation of tolerance to opioid-induced antinociception by idazoxan and other
      I2-ligands.

PMID- 10415937
TI  - Effects of 2-(2-benzofuranyl)-2-imidazoline (2-BFI) on dopamine synthesis in rat
      striatum in vivo.

PMID- 10415938
TI  - Imidazoline-induced inhibition of firing rate of 5-HT neurons in rat dorsal raphe
      by modulation of extracellular 5-HT levels.

PMID- 10415939
TI  - Behavioral effects of RS-45041-190, a selective I2 imidazoline ligand, in rats.

PMID- 10415941
TI  - Localization of the diuretic effect of moxonidine in the nephron by micropuncture
      experiments in anesthetized rats.

PMID- 10415940
TI  - Moxonidine acting centrally inhibits airway reflex responses.
AB  - We examined the role of I1-imidazoline (I1-IR) receptors in control of airway
      function, by testing the effects of systemic administration of the I1-IR agonist
      moxonidine on reflex responses of tracheal smooth muscle (TSM) tone to either
      lung deflation or mechanical stimulation of intrapulmonary rapidly adapting
      receptors. Experiments were performed in either alpha-chloralose anesthetized or
      decorticate, paralyzed, and mechanically ventilated beagle dogs. Moxonidine (10
      100 micrograms/kg) administered via three different routes (femoral vein,
      muscular branch of superior thyroid artery, and vertebral artery) attenuated TSM
      responses to stimulation of airway sensory nerve fibers by two different ways and
      caused a decrease in arterial pressure and heart rate. These effects were dose
      dependent and were significantly reversed by efaroxan (an I1-IR and alpha 2
      adrenergic blocker) administered via the vertebral artery. Intravertebral
      efaroxan abolished the hemodynamic effects of moxonidine. Intravenous moxonidine
      (10-100 micrograms/kg) did not alter airway smooth muscle responses to electrical
      stimulation of the peripheral vagus nerve. In addition, in vitro moxonidine (1
      100 micrograms/ml) had no effect on contractile responses to increasing doses of
      acetylcholine. These findings indicate that moxonidine may act at a central site
      to suppress reflex airway constriction, even when given into the systemic
      circulation. Given the presence of I1-IR sites and alpha 2-adrenergic receptors
      in brain regions participating in airway reflexes, these receptor classes may be
      involved in brainstem control of the cholinergic outflow to the airways.

PMID- 10415942
TI  - The renal actions of moxonidine are mediated by atrial natriuretic peptide and
      involve the opioid receptors.

PMID- 10415943
TI  - Peripheral and central effects of naphazoline on ocular hydrodynamics.
      Involvement of imidazoline receptors, ANP, and Gi proteins.

PMID- 10415944
TI  - Imidazoline receptors and human brain disorders.
AB  - Major depression, opioid addiction, neurodegenerative diseases, and glial tumors
      are associated with disturbances of imidazoline receptors (IR) in the human
      brain. In depression, the level of a 45-kD IR protein (putative I1-IR) is
      increased in the brain of suicide victims (51%) and in platelets of depressed
      patients (40%). The density of platelet I1-IR ([125I]-p-iodoclonidine binding) is
      also increased in depression (135%). The 29/30-kD IR protein (putative I2B-IR) is
      downregulated (19%) in suicide victims in parallel with a reduction (40%) in the
      density of I2B-IR ([3H]idazoxan binding). Antidepressant drugs induce
      downregulation of 45-kD IR protein and I1-sites in platelets of depressed
      patients and upregulation of I2-sites in rat brain. The densities of I2B-IR and
      the related 29/30-kD IR protein are decreased (39% and 28%) in the brain of
      heroin addicts. The density of I2B-IR is increased in Alzheimer's disease (63%)
      and decreased in Huntington's disease (56%). Brain I2B-IR is not altered in
      Parkinson's disease. The level of I2-IR in glial tumors is increased (two
      fivefold) in parallel with the abundance of the related 29/30-kD IR protein
      (39%), whereas the level of 45-kD IR protein is decreased (39%). The possible
      functional relevance of these findings in the context of the pathogenesis of
      these disorders remains to be elucidated.

PMID- 10415945
TI  - Anti-proliferative and anti-inflammatory actions of imidazoline agents. Are
      imidazoline receptors involved?
AB  - We have shown that cultured vascular smooth muscle cells (VSMC) and brain
      astroglial cells express I-receptors of the I2 subtype. While imidazoline agents
      are anti-proliferative in smooth muscle cells, they increase the expression of
      glial fibrillary acidic protein (GFAP) in astrocytes. Because increases in GFAP
      suppress the induction of calcium-independent, inducible nitric oxide synthase
      (NOS-2), we measured whether idazoxan and related imidazolines and agmatine would
      also suppress the expression of NOS-2. Cultured astrocytes and macrophages, RAW
      264.7 cell line, were incubated with lipopolysaccharide (LPS, 1 microgram/ml) or
      cytokine mixture in the presence of 1-100 microM of idazoxan, agmatine, or other
      imidazoline agents. Idazoxan potently (IC50 10 microM) decreased the activity of
      NOS-2 in astrocytes, but was less potent in RAW 264.7 cells. By contrast,
      agmatine was most potent in RAW 264.7 cells (IC50, 10 microM) but less potent in
      glial cells and VSMC. Both idazoxan and agmatine decreased the activity of NOS-2
      by reducing the levels of enzyme protein as measured by immunoblot and
      immunocytochemistry. No specific binding of [3H]-idazoxan was observed in RAW
      264.7 cell membranes. We conclude that idazoxan, agmatine, and selected
      imidazoline agents inhibit the expression of NOS-2 and proliferation in primary
      glial cells and VSMC. While the antiproliferative actions appear mediated by I
      receptors of the I2 type, the anti-inflammatory response is probably not mediated
      by I-receptors but possibly by direct actions on signal transduction enzymes.

PMID- 10415946
TI  - Central I1-imidazoline receptors as targets of centrally acting antihypertensive
      drugs. Clinical pharmacology of moxonidine and rilmenidine.
AB  - Moxonidine and rilmenidine are moderately selective I1-receptor stimulants. The
      imidazoline (I1) agonists cause peripheral sympathoinhibition, triggered at the
      level of central nervous imidazoline receptors. Imidazoline receptor stimulants
      are effective antihypertensive agents with a hemodynamic profile that is
      attractive from a pathophysiologic point of view. The antihypertensive activity
      of these agents is caused by vasodilatation and reduced peripheral vascular
      resistance. Left ventricular end-diastolic and end-systolic volume is reduced,
      whereas heart rate, stroke volume, cardiac output, and pulmonary artery pressures
      are largely unchanged. Long-term left ventricular hypertrophy is reduced. Both
      drugs, when applied in a once-daily dosage schedule, appear to control
      hypertension in most patients. Both drugs have been compared with representative
      agents from the major classes of antihypertensive drugs in controlled trials and
      found to be equally effective in blood pressure control. The incidence and
      severity of side effects are lower than those for clonidine, particularly with
      respect to sedation. A rebound (withdrawal) phenomenon has so far not been
      reported for moxonidine and rilmenidine. Therefore, I1-receptor stimulants offer
      the possibility of developing centrally acting agents with a better side-effect
      profile than do the classic alpha 2-adrenoceptor stimulants.

PMID- 10415947
TI  - Excess catecholamine syndrome. Pathophysiology and therapy.
AB  - In addition to genetic factors, lifestyle has a predominant influence on primary
      hypertension and noninsulin-dependent diabetic mellitus (NIDDM). We initiated
      studies using radiotelemetry for characterizing molecular events linked with
      excess calorie intake and psychologic stress. An increased calorie intake was
      associated with raised (p < 0.05) systolic and diastolic blood pressure as well
      as heart rate independent of day-night cycle. Sympathetic activity was in excess
      when related to the unchanged motility. The hyperkinetic hypertension is expected
      to result in adverse remodeling of resistance vessels and to aggravate insulin
      resistance. To examine adverse effects of psychological stress, rats were
      subjected to intermittent food pellet feeding. Urinary catecholamines and cardiac
      norepinephrine stores were increased (p < 0.05). The depressed (p < 0.05) rate of
      Ca2+ uptake of sarcoplasmic reticulum is expected to contribute to cellular Ca2+
      overload. These lifestyle influences strengthen the notion of an excess
      catecholamine syndrome which requires selective reduction of sympathetic outflow
      of the brain by I1-receptor agonists.

PMID- 10415948
TI  - Plasma agmatine and platelet imidazoline receptors in depression.
AB  - Plasma agmatine concentrations are elevated significantly in depressed patients
      compared to healthy controls. Treatment with the antidepressant bupropion
      normalized plasma agmatine levels. Correlational evidence is presented that a
      change in plasma agmatine levels may lead to similar changes in platelet I1
      imidazoline receptors.

PMID- 10415949
TI  - Protection by imidazol(ine) compounds of L-glutamate neurotoxicity through NMDA
      receptor blockade.

PMID- 10415985
TI  - Spiritual psychotherapy.
AB  - The author proposes the practice of spiritual psychotherapy, which transcends but
      does not preclude traditional modalities or strategies of treatment. The terms
      soul and spirit are distinguished as different transpersonal abstractions, yet
      are inextricably linked. The former aims at revealing the mystery of relatedness
      and intimacy in everyday life, the latter at finding the divine in universal
      life. For the spiritual therapist, these concepts are applied to a therapeutic
      context of care and compassion--which means love and belief beyond oneself. More
      specifically, the way to soulfulness requires Love of Others, Love of Work, and
      Love of Belonging, whereas the way to spirituality requires Belief in the Sacred,
      Belief in Unity, and Belief in Transformation. By cultivating a soulful and
      spiritual existence, thus conducting one's clinical practice on the basis of
      these six tenets of transcendence, the therapist can guide the patient to reach
      his or her own authentic self.

PMID- 10415986
TI  - Sign-language interpretation in psychotherapy with deaf patients.
AB  - Sporadic encounters with deaf patients seeking psychotherapy present a challenge
      to general clinicians outside of specialized services for the deaf. Skills for
      working with people who do not share one's own language mode and culture are not
      routinely taught in most training programs, so clinicians may be unprepared when
      they first encounter a deaf patient. While it would be ideal to be able to match
      deaf patients with therapists fluent in their preferred language mode, this is
      often not feasible in smaller centers. Working with a trained professional sign
      language interpreter can be a productive alternative, as long as patient,
      therapist, and interpreter understand and are comfortable with the process. Peer
      reviewed literature on sign language interpretation in psychotherapy is sparse,
      but some practical guidelines can be gleaned from it and supplemented by
      information provided by the deaf community through the Internet. This paper arose
      from one psychiatric resident's first experience of psychotherapy working with a
      sign-language interpreter, and summarizes the literature search that resulted
      from a quest for understanding of deaf culture and experience, of the unique
      characteristics of sign language, and of the effects on the therapeutic
      relationship of the presence of the interpreter.

PMID- 10415987
TI  - An infant's experience as a selfobject.
AB  - Exploration of the clinical literature shows an awareness that an infant's
      experience as a selfobject often is traumatic, but if there is an experience of
      mutuality, the trauma might be avoided. Where such mutuality does not occur, an
      infant's experience of constantly repairing a depressed parent, or of being
      blamed, abused or having an identity imposed by a parent, leads to exhaustion
      and/or traumatization. Kohut's paradigmatic case of Mr. Z is presented as an
      example of the distressful effects of being a selfobject (of idealization) for a
      mother. Patients who were traumatized as infants by functioning as a selfobject
      for a parent often present for psychotherapy seeking an archaic form of twinship
      that recreates the infant-parent traumatizing relationship by imposing on the
      therapist the function that had been imposed on them as infants. Until this
      archaic twinship is empathically understood, accepted and explored with the
      patient, the lasting effects of the traumatization are not resolved.

PMID- 10415988
TI  - The use of metaphors by the "ambulatory inpatients" of the managed care era.
AB  - An important effect of managed care is keeping partially decompensated patients
      out of the hospital, for this is the single most decisive factor in cutting the
      costs of psychiatric services. It is proposed that discharging sicker patients
      from inpatient units and denying admission to poorly compensated patients poses
      new challenges to their outpatient therapists. This calls for new, refined
      psychotherapeutic skills, especially around the development of a therapeutic
      alliance. Patient communications in the form of metaphors may help the clinician
      understand the patient's conflicts while avoiding excessive anxiety that might
      accompany more direct communications. Recognizing the meaning of the metaphor and
      working with it can keep the patient from regressing and assist in the formation
      of a therapeutic alliance. This statement is examined in a number of clinical
      examples. The similarities and differences between metaphors and dreams,
      symptoms, and the transference are discussed.

PMID- 10415989
TI  - Status enhancement: a further path to therapeutic change.
AB  - Historically, psychotherapists have targeted change efforts primarily on clients'
      behaviors, beliefs, unconscious conflicts, and patterns of interaction with
      significant others. The present article explores a further, and very powerful,
      path to change: that of bringing about changes in the client's status.

PMID- 10415990
TI  - Don't ask questions: a psychotherapeutic strategy for treatment of involuntary
      clients.
AB  - This article puts forth the proposition that asking questions is detrimental to
      successful therapy with unwilling clients. The utility of three commonly used
      approaches is examined by asking. Does continuing questioning impede therapy with
      involuntary clients? Are therapists asking questions primarily as a means of
      coping personally with sullen and silent, or angry and abrasive client behavior?
      Is it correct to assume that asking "why" is a particularly poor therapy
      intervention because it brings therapists and clients into a futile search for
      causation of behaviors? It is recommended that statements, instead of questions,
      should be introduced as the preferred therapeutic modality with reluctant and
      unwilling clients.

PMID- 10415991
TI  - A verified case of recovered memories of sexual abuse.
AB  - A case is presented that shows verifiable evidence of repression at work. Rachel,
      a 40-year-old woman with no history of mental illness and ten years of exemplary
      professional work, recovers memories of childhood sexual abuse by her father
      through a call from her youth pastor in whom she had confided as an adolescent.
      This reminder triggered a severe depression, suicidal action, and the need for
      hospitalization. Rachel's older sister, herself an abuse victim, had witnessed
      the abuse, yet Rachel had no memory of the events. No apparent causes of false
      memories are present, so a different mechanism than forgetting must have been at
      work.

PMID- 10415992
TI  - Intergenerational transmission of trauma: recent contributions from the
      literature of family systems approaches to treatment.

PMID- 10415993
TI  - Understanding empathy and related phenomena.
AB  - Over a period of time, the author arrived at a few tentative postulates
      concerning empathy and related processes based on some of his experiences and
      observations. The central theme of these postulates is, firstly, that
      interpersonal interaction is an interaction of the personal-space fields.
      Secondly, empathy, therapeutic benefit, and the professional stress are all
      related to the same process of interpersonal interaction. This interaction takes
      place as an enmeshment of personal spaces of the interacting individuals, and
      involves transfer of a wide range of information in the affective, cognitive, and
      other areas. This is because the personal spaces have fieldlike qualities
      analogous to what Kurt Lewin described. Thus, such phenomena as empathy,
      therapeutic benefit, professional stress are all consequences of the same
      process. It is possible to substantiate these postulates by diverse evidences in
      the published literature. The natural consequences of such an interpersonal
      interaction are empathic understanding, transfer of mood states (like hope,
      distress or expectancy), affective states (like anxiety, sadness, anger or
      hostility), ideas, images and even attitudes and values, etc. This phenomenon of
      transfer can explain such processes as therapeutic benefit in individual and
      group settings, professional stress, shared delusions, and even experimenter
      bias. Whether one becomes aware of such transferred information or not depends
      upon the intent and sensitivity of the participants.

PMID- 10415994
TI  - Dream and suicide. 1948.

PMID- 10415995
TI  - Emil A. Gutheil, M.D.: "dream and suicide"

PMID- 10415996
TI  - Stem cell transplant at home: glimpse of the future.

PMID- 10415997
TI  - Antisense--time to shoot the messenger.

PMID- 10415998
TI  - Redefining the therapeutic goals in chronic lymphocytic leukemia: towards an
      evidence-based, risk-adapted therapy.

PMID- 10415999
TI  - At home management of aplastic phase following high-dose chemotherapy with stem
      cell rescue for hematological and non-hematological malignancies.
AB  - BACKGROUND: After high-dose chemotherapy with autologous stem-cell support long
      hospital stays in the aplastic phase are expensive, lead to increased risk of
      hospital infections and to increasing pressure on available hospital beds. We
      developed a home care regimen that allows patients to be at home for most of the
      aplastic period, without daily hospital visits. PATIENTS AND METHODS: Between
      October 1995 and December 1997, transfer of supportive care to the home setting
      took place in three phases for patients undergoing high-dose chemotherapy with
      stem-cell transplant for malignant lymphoma (one course of BEAM), breast cancer
      or germ-cell cancer (three courses of tCTC). In the inpatient cohort, the
      supportive care designed for at home use was administered in the hospital until
      neutrophile recovery to 0.5 x 10(9)/l. In the second, outpatient cohort, patients
      were discharged the day after stem-cell reinfusion but the supportive care was
      delivered daily in hospital. The third, home care cohort, consisted of patients
      who were discharged the day after stemcell reinfusion, after which specialized
      home care professionals delivered all supportive care including transfusions and
      parenteral antibiotics at home, with once weekly check-up in hospital by the
      transplant physician. RESULTS: Forty-two patients were treated with 81 cycles of
      high-dose chemotherapy (11, 18 and 13 patients and 17, 40 and 24 courses in the
      inpatient, outpatient and home care cohorts respectively). Inpatients were
      hospitalized in the aplastic phase for a median of 14 days. Patients in the
      outpatient cohort were at home in the aplastic phase for a median of six days
      (with a median of six days in hospital), and in the home care cohort for a median
      of 10 days (with a median of 1.5 days in hospital). Unscheduled readmissions and
      hospital visits were frequent in the outpatient and home care cohorts, mostly due
      to fever, central indwelling catheter malfunctioning or chemotherapy-related
      toxicity. However, patients could usually be discharged again after observation
      and treatment. No infectious deaths or unexpected emergencies occurred in the
      outpatient or home care cohort. Neither was there any suggestion of an increased
      number of fevers, infections, or other complications. CONCLUSIONS: At home
      management in the aplastic phase after high-dose chemotherapy and stemcell
      transplant by community-based professionals is feasible without signs of
      increased toxicity or infections.

PMID- 10416000
TI  - Dose-escalation of CHOP in non-Hodgkin's lymphoma.
AB  - BACKGROUND: CHOP is considered to be the gold standard for patients with
      histologically aggressive non-Hodgkin's lymphoma both in limited and advanced
      stages. In order to determine the maximum tolerable dose of an intensified CHOP
      regimen, a dose-escalation study of CHOP (cyclophosphamide, doxorubicin,
      vincristine, and prednisone) in patients with non-Hodgkin's lymphoma (NHL) was
      started. PATIENTS AND METHODS: With an increased fixed dose of doxorubicin at 75
      mg/m2 instead of 50 mg/m2 on day 1 and standard doses of vincristine (1.4 mg/m2
      on day 1) and prednisone (100 mg day 1 through 5), cyclophosphamide dose was
      escalated by increments of 250 mg/m2 in consecutive cohorts of at least three
      patients starting from 1000 mg/m2. Granulocyte-colony stimulating factor (G-CSF)
      support was added to the regimen starting from the dose-level inducing grade 4
      neutropenia lasting more than five days in two patients. Dose limiting toxicity
      was defined as either the dose inducing grade 4 neutropenia lasting more than
      seven days despite the use of G-CSF, or grade 3-4 thrombocytopenia lasting more
      than seven days, or any grade 4 non-hematological toxicity other than alopecia.
      The dose-level below the one inducing dose-limiting toxicity was defined as
      maximum tolerable dose. All patients were treated on an outpatient basis. Dose
      intensity parameters for single agent doxorubicin and cyclophosphamide as well as
      for the whole regimen were evaluated. RESULTS: Eighty-seven patients are
      evaluable over a four-year study period. At 1750 mg/m2 dose-level, G-CSF was
      added to the regimen according to described criteria. At the cyclophosphamide
      dose of 3000 mg/m2, dose-limiting hematological toxicity occurred in two
      patients, with one grade 4 thrombocytopenia and neutropenia and one grade 4
      neutropenia lasting more than seven days. Thus, cyclophosphamide dose of 2750
      mg/m2 was defined as maximum tolerable dose. CONCLUSIONS: CHOP intensification of
      approximately 1.8 times that of the standard regimen is feasible and safely
      administered on an outpatient basis with G-CSF support. Further investigation on
      the role of dose-intensity in the outcome of NHL should focus on the comparison
      of intensified CHOP regimen and standard CHOP or high-dose chemotherapy.

PMID- 10416002
TI  - The high-dose sequential (Milan) chemotherapy/PBSC transplantation regimen for
      patients with lymphoma is not cardiotoxic.
AB  - BACKGROUND: The high-dose sequential (HDS) regimen developed in Milan for high
      grade lymphomas is very active, but its toxicities are still partly unknown. We
      evaluated prospectively by doppler-echocardiography the cardiotoxicity of this
      treatment. PATIENTS AND METHODS: Over seven weeks, 20 patients received a
      sequence of cyclophosphamide, methotrexate, etoposide, mitoxantrone and
      melphalan, each at its maximum tolerable dose, and the latter in conjunction with
      autologous peripheral stem-cell transplantation. Echocardiography was performed
      at baseline, before administration of mitoxantrone and 2, 6 and 12 months after
      transplantation. The following parameters of the left ventricular systolic and
      diastolic functions were determined: end diastolic (LVD) and end systolic (LVS)
      dimensions, the ejection fraction (EF), and the Doppler derived diastolic
      parameters: peak velocity of the early (E) and late (A) transmitral flow, the E:A
      ratio, deceleration time of the E wave (DT) and isovolumetric relaxation time
      (IVRT). A group of 20 normal volunteers served as control. RESULTS: At baseline,
      in comparison to controls, the patients had altered diastolic function
      (diminished E:A ratio) and, although still within the normal range, a slightly
      reduced systolic function (EF). During treatment or in the course of follow-up
      none of the patients showed clinical signs or symptoms of cardiac failure, nor
      significant changes of systolic or diastolic parameters, apart from a transient
      increase in the E:A ratio after the first three chemotherapy cycles (from 1.14 to
      1.37, P < 0.05). The EF remained constant during, and up to six months after,
      transplantation, decreasing only slightly after one year (from 62% to 59%, P <
      0.05). Using analysis of covariance we showed that the major determinants of
      baseline cardiac function and of its evolution over time were patient age and
      gender, with previous treatment with anthracyclines having a minor role.
      CONCLUSIONS: The HDS chemotherapy regimen produced no significant sign of
      cardiotoxicity up to one year after transplantation in patients with normal
      baseline cardiac function and no history of cardiac disease, pretreated with up
      to 550 mg/m2 of doxorubicin.

PMID- 10416001
TI  - Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for
      allogeneic transplantation for high-risk malignant lymphoma.
AB  - BACKGROUND: The combination of carmustine, etoposide, cytarabine and melphalan
      (BEAM) is an effective autologous transplantation preparative regimen for
      lymphoma and has little toxicity, but the feasibility and tolerance of BEAM as a
      preparative regimen for allogeneic transplantation has not been established.
      PATIENTS AND METHODS: Thirty adults with primary refractory or recurrent
      intermediate- or low-grade lymphoma were treated on a prospective phase II study
      with carmustine 300 mg/m2 i.v. day -6, etoposide 200 mg/m2 i.v. followed by
      cytarabine 200 mg/m2 i.v. twice daily days -5 to -2, melphalan 140 mg/m2 i.v. day
      -1, and marrow or blood stem cells from an HLA-identical donor on day 0.
      Tacrolimus and methotrexate were used to prevent graft-vs.-host disease (GVHD).
      RESULTS: Median time from transplantation was 20 mos (range 6-32 months). Median
      maximal regimen-related toxicity grade was 2, and four patients (13%) had a grade
      3-4 regimen-related toxicity. Two patients had idiopathic interstitial
      pneumonitis. One patient had primary graft failure, and a second had autologous
      reconstitution documented at three months posttransplant. Grades 2-4 acute GVHD
      occurred in 31%, grades 3-4 in 16%, and chronic GVHD in 54%. Day-100 survival was
      70%. Twenty-three patients achieved a complete response. The two-year relapse
      rate was 23%, survival was 48%, and disease-free survival (DFS) was 42%.
      CONCLUSIONS: BEAM supports engraftment of allogeneic transplants and is a
      tolerable preparative regimen for allogeneic transplantation for lymphoma.

PMID- 10416004
TI  - Front-line treatment of metastatic breast cancer with docetaxel and epirubicin: a
      multicenter dose-escalation study. The Greek Breast Cancer Cooperative Group
      (GBCCG).
AB  - PURPOSE: To determine the maximum tolerable dose (MTD) and the dose-limiting
      toxicity (DLT) of docetaxel (D) in combination with epirubicin (Epi) in patients
      with advanced breast cancer. PATIENTS AND METHODS: Forty-seven chemotherapy-naive
      metastatic breast cancer patients aged < 75 years with PS (WHO) 0-2 and adequate
      bone marrow, renal, liver and cardiac function, were enrolled in the study. Epi
      was given as a five-min bolus i.v. infusion on day 1 (d1) in escalated doses with
      increments of 10 mg/m2; D was given in a one-hour infusion after appropriate
      premedication on either day 1 or on day 2 in escalated doses with increments of
      10 mg/m2. The patients' median age was 60 years, 42 (89%) had a PS (WHO) 0-1, 16
      (34%) were premenopausal and 25 (53%) had visceral disease. RESULTS: When the two
      drugs were given on the same day, the MTD1 was reached at the doses of Epi 60
      mg/m2 and D 80 mg/m2; administration of G-CSF could not result in a dose
      intensification. When the drugs were given on two consecutive days, the MTD2 was
      reached at the doses of Epi 80 mg/m2 (d1) and D 90 mg/m2 (d2). The dose-limiting
      events were febrile neutropenia and grade 4 neutropenia, which developed in 30
      (64%) patients during the study; among 227 delivered cycles grade 3-4 neutropenia
      occurred in 64 (28%) cycles but only 22 (10%) of them were complicated by fever.
      There were no septic deaths. Grade 1-2 neurosensory toxicity occurred in nine
      (19%) patients, mild edema in eight (17%) and allergic reactions in five (11%).
      Four (9%) patients presented a greater than 10% decrease of LVEF and treatment
      discontinuation was required in two of them; none of the patients developed
      congestive heart failure. Nevertheless, one patient suddenly died 10 days after
      treatment initiation of myocardial ischemia, and this death is considered
      treatment-related. Five (14.7%) complete and thirteen (38.2%) partial responses
      (ORR: 53.9%; 95% confidence interval: 36.1%-69.7%) were observed in 34 evaluable
      patients. Ten (29.4%) and six (17.6%) patients had stable and progressive
      disease, respectively. The median duration of response and time to tumor
      progression were five and seven months, respectively. The median survival has not
      yet been reached. CONCLUSIONS: The combination of epirubicin and docetaxel is a
      feasible and well tolerated regimen, but the MTD depends on the administration
      schedule of the drugs.

PMID- 10416005
TI  - Dose-finding study of docetaxel and doxorubicin in first-line treatment of
      patients with metastatic breast cancer.
AB  - PURPOSE: To determine the maximum tolerated dose (MTD), the dose-limiting
      toxicity (DLT) and the recommended dose of docetaxel in combination with
      doxorubicin, and to evaluate the activity in patients with advanced breast
      cancer. PATIENTS AND METHODS: Forty-two women with untreated metastatic breast
      cancer (79% with visceral metastases; 52% with prior adjuvant anthracycline
      therapy) were treated with doxorubicin (40-60 mg/m2) i.v. bolus followed one hour
      later by docetaxel (50-85 mg/m2) one-hour i.v. infusion every three weeks,
      without G-CSF support. RESULTS: The MTD occurred at the dose level combining 85
      mg/m2 of docetaxel and 50 mg/m2 of doxorubicin, with the DLT being neutropenic
      sepsis. Neutropenia and/or its complications were manageable and no grade 3-4 or
      severe non-hematological toxicities were observed. Fluid retention was frequent
      but never severe. With a median cumulative dose of doxorubicin of 392 mg/m2 (240
      559 mg/m2) and a median follow-up time of 29 months (9(+)-41), no congestive
      heart failure was observed. High activity was observed at all dose levels,
      particularly the last four, with a response rate of 81% (95% confidence interval
      (95% CI): 62.5-92.5). Median time to progression was 46 weeks (6(+)-62). Two-year
      survival was 66%, and median survival has not yet been reached. CONCLUSIONS:
      Docetaxel-doxorubicin is feasible, safe and highly active. The incidence of
      febrile neutropenia without G-CSF requires careful monitoring but is acceptable
      in this setting. There does not appear to be an increase in the cardiac toxicity
      of doxorubicin. The recommended doses is either docetaxel 75 mg/m2 and
      doxorubicin 50 mg/m2 or docetaxel 60 mg/m2 and doxorubicin 60 mg/m2, administered
      every three weeks.

PMID- 10416003
TI  - Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in
      patients with advanced breast cancer.
AB  - BACKGROUND: Anthracyclines and taxanes are the most active drugs against breast
      cancer and the search after their optimal combination is under intensive
      investigation in both the advanced and early disease settings. A dose-finding
      study of epidoxorubicin (E) and docetaxel (D) was conducted in advanced breast
      cancer (ABC) to define the maximum tolerated dose (MTD) of the combination with
      and without granulocyte colony-stimulating factor (G-CSF) support and to
      characterise its toxicity and activity profile. PATIENTS AND METHODS: Forty-two
      patients who received neither palliative chemotherapy nor adjuvant anthracyclines
      (55% with dominant visceral disease and 66% with > or = 2 sites involved) with
      measurable/evaluable lesions, were treated at four dose levels starting from E 75
      mg/m2 and D 75 mg/m2 to E 120 mg/m2 and D 85 mg/m2. A maximum of four cycles of
      the combination was given every three weeks and four additional cycles of single
      agent D were allowed in responding patients. Cardiac function was monitored at
      baseline and at every second course by echocardiography. RESULTS: Febrile
      neutropenia (two patients) and prolonged, severe neutropenia (absolute neutrophil
      count (ANC) < 0.1 x 10(9)/l for more than three days; one patient) defined the
      MTD of the combination without G-CSF support at E 90 mg/m2 and D 75 mg/m2. G-CSF
      was then routinely administered from the subsequent dose level of E 120 mg/m2 and
      D 75 mg/m2. The MTD with G-CSF support was established at E 120 mg/m2 and D 85
      mg/m2 (one patient with neutropenic fever together with failure of ANC recovery
      at day 21, three patients with ANC less than 0.1 x 10(9)/l for more than three
      days, one patient with both and one patient with grade 4 thrombocytopenia and
      toxic death from typhlitis while neutropenic). No severe neurotoxicity,
      mucositis, or fluid retention were observed and there were no clinical signs of
      cardiotoxicity. Antitumor activity was not a primary endpoint of the study: the
      overall response rate (ORR) in 40 evaluable patients was 60% (95% confidence
      interval: 43%-75%, 58% in liver disease, 84% in soft tissue) with no apparent
      dose-related effect. After a median follow-up of 19 months (range 2-30+), the
      overall time to progression (TTP) in nine patients without maintenance hormonal
      therapy was five months. CONCLUSIONS: The combination of E and D proved to be an
      effective and safe regimen in poor- prognosis patients with ABC. G-CSF support
      allowed higher doses to be delivered safely but dose escalation did not translate
      into improved response rates (RR). The MTD without growth factors support was
      used, in a phase II trial, which also included patients with previous
      anthracycline-containing adjuvant regimens.

PMID- 10416006
TI  - Standard- and high-dose etoposide, ifosfamide, carboplatin, and epirubicin in 100
      patients with small-cell lung cancer: a mature follow-up report.
AB  - BACKGROUND: We conducted a phase I-II trial to assess the feasibility and
      activity of a combination chemotherapy regimen with etoposide, ifosfamide,
      cisplatin or carboplatin, and epirubicin in limited-disease (LD, stages I-IIIB)
      and extensive-stage (ED, stage IV) small-cell lung cancer (SCLC). PATIENTS AND
      METHODS: Standard-dose chemotherapy (SDC) consisting of etoposide (500 mg/m2),
      ifosfamide (4000 mg/m2), cisplatin (50 mg/m2) and epirubicin (50 mg/m2) (VIP-E),
      followed by granulocyte colony-stimulating factor (G-CSF), was given to 100
      patients with SCLC. Thirty patients with qualifying responses to VIP-E proceeded
      to high-dose chemotherapy (HDC) with autologous peripheral blood stem-cell
      transplantation (PBSCT) after etoposide (1,500 mg/m2), ifosfamide (12,000 mg/m2),
      carboplatin (750 mg/m2) and epirubicin (150 mg/m2) (VIC-E) conditioning. RESULTS
      OF STANDARD-DOSE VIP-E: Ninety-seven patients were evaluable for response. The
      objective response rate was 81% in LD SCLC (33% CR, 48% PR; excluding patients in
      surgical CR) and 77% in ED SCLC (18% CR, 58% PR). The treatment-related mortality
      (TRM) of SDC was 2%. Two additional patients in CR from their SCLC developed
      secondary non-small-cell lung cancers (NSCLC), and both were cured by surgery.
      The median survival was 19 months in LD SCLC and 6 months in ED SCLC. The five
      year survivals were 36% in LD and 0% in ED SCLC. RESULTS OF HIGH-DOSE VIC-E: HDC
      was feasible in 16% of ED-, and 58% of LD-patients. All HDC patients (n = 30)
      improved or maintained prior responses. Four patients died of early treatment
      related complications (TRM 13%). Two additional patients in CR from their SCLC
      developed secondary malignancies (esophageal cancer, secondary chronic
      myelogenous leukemia). The median survivals were 26 months in LD SCLC, and 8
      months in ED SCLC. The five-year survival was 50% in LD and 0% in ED SCLC.
      CONCLUSIONS: Despite high response rates, survival after VIP-E SDC and VIC-E HDC
      in patients with ED SCLC is not superior to that achieved with less toxic
      traditional regimens. The high five-year survival rates achieved with these
      protocols in LD SCLC probably reflect both patient selection (high proportion of
      patients with prior surgical resection) and the high activity of our chemotherapy
      regimen in combination with radiotherapy. A study comparing protocols using
      simultaneous radiation therapy and chemotherapy, and other dose-escalated forms
      of SDC with HDC is needed to further define the role of this treatment modality
      in SCLC. Given the high rate of secondary malignancies observed in patients in CR
      > 2 years in our study, close follow-up and early treatment of these neoplasms
      may contribute to maintaining overall survival in patients with SCLC.

PMID- 10416007
TI  - Chemotherapy in carcinomas of unknown primary site: a high-dose intensity policy.
AB  - BACKGROUND: Unknown primary tumors are highly malignant diseases which portend a
      dire prognosis. We designed a prospective high dose-intensity policy with the aim
      of improving the results obtained with conventional chemotherapy. PATIENTS AND
      METHODS: Chemotherapy regimens were determined according to clinical features. In
      patients younger than 61 years with an ECOG performance status of 0 or 1, poorly
      differentiated adenocarcinoma or poorly differentiated carcinoma, and no evidence
      of brain or bone marrow involvement (group A), the treatment plan included four
      sequential high-dose courses with hematopoietic progenitor cell and growth factor
      support. Peripheral blood progenitor cells were collected by apheresis as the
      leukocyte counts recovered from the nadir induced by the first cycle of
      chemotherapy (doxorubicin 75 mg/m2, cyclophosphamide 6000 mg/m2). Patients then
      received two cycles of etoposide (800 mg/m2) and carboplatin (900 mg/m2)
      separated by one cycle of doxorubicin (75 mg/m2) and cyclophosphamide (3000
      mg/m2). G-CSF (5 micrograms/kg/d) was given until engraftment. It was planned
      that cycles would be delivered every three weeks. The remaining patients (group
      B) received alternative cycles of AC (doxorubicin 50 mg/m2, cyclophosphamide 1000
      mg/m2) and EP (etoposide 300 mg/m2, cisplatin 100 mg/m2). Cycles were given at
      two-week intervals with GM-CSF support (5 micrograms/kg/d) from day 4 to day 10.
      Patients without measurable lesions were included, since the major endpoint was
      survival. RESULTS: Sixty patients entered the study. Twenty patients were
      assigned to group A and 40 patients to group B. In group A, 5 of 12 patients with
      measurable lesions (42%; 95% confidence interval (95% CI): 22%-62%) achieved
      major responses to chemotherapy, including one complete response. The duration of
      the overall median survival was 11 months. In group B, a major response was
      observed in 12 (39%; 95% CI: 28%-50%) of 31 patients with measurable lesions,
      including three complete responses. The overall median survival was 8 months.
      Hematological toxicities were noteworthy in both groups. Two toxic deaths
      occurred in group B. CONCLUSION: Using these doses and schedules of chemotherapy,
      a high-dose intensity policy does not appear to improve the outcome of patients
      with carcinoma of unknown primary site. Alternative studies dealing with new
      drugs are required.

PMID- 10416008
TI  - Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion
      formulation in patients with refractory or relapsed acute leukemia.
AB  - PURPOSE: Topoisomerase I inhibitors have shown promising anti leukemic activity
      in acute myelogenous leukemia (AML) and myelodysplastic syndrome. In this phase I
      study, we investigated the toxicity profile, pharmacokinetics, and activity of a
      prolonged continuous infusion schedule of the colloidal dispersion formulation of
      9-amino-camptothecin (9-AC/CD) in patients with acute leukemia. PATIENTS AND
      METHODS: Patients with refractory or relapsed AML, acute lymphocytic leukemia
      (ALL) or chronic myelogenous leukemia in blastic phase (CML-BP) were included in
      the study. Eligibility criteria were age greater than 15 years, performance
      status of 2 or better, creatinine < 1.5 mg/dl, and bilirubin < 1.5 mg/dl. 9-AC/CD
      was given as a continuous intravenous infusion over seven days every three to
      four weeks. The starting dose was 0.2 mg/m2/d (1.4 mg/m2/course). Courses were
      given every three to four weeks according to toxicity and anti leukemic efficacy.
      This phase I study used the classical 3 + 3 design. The dose was escalated by 50%
      until grade I toxicity was observed, and then by 30% to 35% until the dose
      limiting toxicity was defined. At the maximal tolerated dose (MTD), 8 to 10
      patients were planned to be treated to better define the toxicity and early
      activity profiles. RESULTS: Thirty-nine patients (AML thirty-six patients; ALL
      two patients; CML-BP one patient), median age 56 years, were treated. Severe
      mucositis was the dose limiting toxicity; it occurred in three of six patients
      treated at a dose of 1.6 mg/m2/d. The MTD was defined as 1.4 mg/m2/day by the
      phase I design. Upon expansion of the number of patients, 3 of 10 patients had
      grade 4 mucositis and 1 of 10 patients had grade 3 diarrhea. Nausea and vomiting
      were uncommon. No complete or partial remission was observed in 37 evaluable
      patients. However, 9-AC/CD exhibited antileukemic activity, as reflected by the
      finding of marrow hypoplasia on day 14 in 46% of the patients. Average steady
      state concentration of 9-AC lactone was close to 10 nmol/l, and the of 9-AC
      lactone area under curve (AUC) was 1409 +/- 705 nmol/l. hr. CONCLUSION: The MTD
      of 9-AC/CD given as a seven-day continuous infusion was 1.4 mg/m2/d (9.8
      mg/m2/course) in patients with acute leukemia. This represents three to fourfold
      dose escalation compared with the MTD of 9-AC given as shorter continuous
      infusion (three days) in patients with solid tumors. Future studies will
      determine the activity of prolonged administration of 9-AC/CD in patients with
      better prognosis acute leukemia.

PMID- 10416009
TI  - Synchronous inflammatory breast cancer and advanced ovarian carcinoma: a case
      with prolonged disease-free survival.
AB  - Despite the known association of these malignancies, the incidence of a
      synchronous presentation of breast and ovarian cancer is low, and the current
      literature does not address an approach to this clinical problem directly. We
      report a greater than 2.5 year disease-free survival in a patient treated for
      synchronous stage IIIB inflammatory breast cancer and stage IIIC epithelial
      ovarian cancer. The prolonged disease-free survival in our case may provide some
      guidance in this unusual clinical situation.

PMID- 10416010
TI  - The metalloproteinase inhibitor batimastat (BB-94) causes cell cycle phase
      perturbations in ovarian cancer cells.

PMID- 10416011
TI  - ESHAP is an active regimen for relapsing Hodgkin's disease.
AB  - BACKGROUND: Refractory or relapsing Hodgkin's disease is associated with a poor
      prognosis. There is no widely accepted salvage chemotherapy regimen for these
      patients. However, the addition of high-dose chemotherapy followed by autologous
      hematopoietic transplantation (AHT) has proven of benefit to them. A prospective
      clinical trial was carried out to evaluate the efficacy and toxicity of ESHAP
      (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin). PATIENTS
      AND METHODS: Twenty-two patients with refractory (5) or relapsing Hodgkin's
      disease (17) were entered and scheduled to receive three courses of ESHAP.
      Patients suitable for AHT were then given high-dose chemotherapy with CBV
      (cyclophosphamide, carmustine, and etoposide) plus AHT, whereas responding, non
      AHT-suitable patients completed six ESHAP courses. RESULTS: Nine patients
      achieved complete responses and seven partial responses (overall response rate
      73%) with ESHAP. Grade 3-4 myelotoxicity was seen in 13 patients (59%). Nine
      patients received CBV plus AHT. At a median follow-up time of 50 months (range 6
      96), seven patients (32%) are alive and disease-free. Three patients died of
      toxic effects of ESHAP (1) or CBV (2). Actuarial overall survival and disease
      free survival were 35% and 27% at three years. CONCLUSIONS: ESHAP is an active
      regimen for relapsing Hodgkin's disease, with myelosuppression as its dose
      limiting toxicity. An increased risk of treatment-related mortality when it is
      combined with high-dose chemotherapy can not be ruled out.

PMID- 10416012
TI  - High-dose paclitaxel plus G-CSF for malignant mesothelioma: CALGB phase II study
      9234.
AB  - BACKGROUND: New agents with activity in mesothelioma are sorely needed. The
      Cancer and Leukemia Group B (CALGB) therefore performed a phase II study of high
      dose paclitaxel in patients with malignant mesothelioma who had no prior
      chemotherapy. PATIENTS AND METHODS: Thirty-five patients accrued to this multi
      institutional phase II study of paclitaxel given as a 24-hour infusion at 250
      mg/m2 every three weeks plus filgrastim (G-CSF) 300 mcg subcutaneously days 3-18.
      RESULTS: There were three (9%) regressions of evaluable disease. The median
      survival was five months (95% confidence interval (95% CI): 1.9-9.6 months), the
      one-year survival rate was 14% and the two-year survival rate was 6%. Toxicity
      was tolerable with one death from pneumonia (without neutropenia) on day 18 and a
      23% rate of grade 4 granulocytopenia. CONCLUSIONS: The level of activity seen
      with paclitaxel is similar to that seen in other CALGB trials of the single
      agents carboplatin, trimetrexate and 5-azacytidine. Future studies of of
      paclitaxel (at lower doses) in combination with synergistic agents could be
      considered.

PMID- 10416013
TI  - Phase I study of the sequential administration of edatrexate and paclitaxel in
      patients with advanced solid tumors.
AB  - BACKGROUND: The antifolate edatrexate and the microtubule-stabilizing agent
      paclitaxel have both demonstrated single-agent activity in lung and breast
      cancer. In vitro, the sequential combination of edatrexate followed by paclitaxel
      produced synergistic antitumor effects. This trial was designed to find the
      maximum tolerated doses of edatrexate and paclitaxel when given every two weeks
      utilizing this sequential schedule. PATIENTS AND METHODS: Thirty-four patients
      with solid tumors received edatrexate intravenously on days 1 and 15 and
      paclitaxel intravenously as a three-hour infusion on days 2 and 16 of each 28-day
      cycle. Edatrexate was escalated from 40 to 120 mg/m2 and the paclitaxel dose
      fixed at 135 mg/m2. When the maximum-tolerated dose was not reached, edatrexate
      was fixed at 120 mg/m2 and paclitaxel escalated to 175 and 210 mg/m2. RESULTS:
      All 34 patients were assessable. The maximum tolerated doses were 120 mg/m2 of
      edatrexate and 210 mg/m2 of paclitaxel. Grade 3 myalgia, peripheral neuropathy,
      leukopenia, and an infusion-related reaction occurred. Eight patients with non
      small-cell lung cancer and one with bladder cancer achieved major objective
      responses. CONCLUSIONS: The recommended phase II doses are 120 mg/m2 of
      edatrexate days 1 and 15 and 175 mg/m2 of paclitaxel as a three-hour infusion
      days 2 and 16 of a 28 day cycle. These results warrant phase II trials of the
      combination leading to phase III studies comparing the two drugs to a single
      agent to confirm the preclinical evidence of synergy.

PMID- 10416014
TI  - Standard- and high-dose etoposide, ifosfamide, carboplatin, and epirubicin in 107
      patients with non-small-cell lung cancer: a mature follow-up report.
AB  - BACKGROUND: We conducted a phase I-II trial to assess the activity of standard
      dose (SDC) and high-dose chemotherapy (HDC) with etoposide, ifosfamide,
      cis/carboplatin, and epirubicin (VIP-E, VIC-E) in 107 patients with limited-stage
      (LS, stage I-IIIB) and extensive stage (ES, stage IV) non-small-cell lung cancer
      (NSCLC). PATIENTS AND METHODS: Updated results of a previously published trial
      are presented. RESULTS: Response rates and survival after VIP-E were comparable
      to those of other standard-dose combination chemotherapies in NSCLC. Treatment
      related mortality (TRM) in SDC was 3% in LS-NSCLC, and 8% in ES-NSCLC. TRM was 4%
      in patients selected for HDC by response rate and performance score. Five-year
      survival in LS-NSCLC was 12% after SDC, and 18% after HDC; it was 0% for both
      treatment protocols in ES-NSCLC. CONCLUSIONS: The activity of VIP-E SDC and VIC-E
      HDC is not superior to that of established protocols in the treatment of NSCLC.
      In view of the toxicity and TRM associated with this protocol, less aggressive
      regimens should be preferred for most patients. Whether selected patients with
      chemosensitive disease could benefit from VIP-E SDC and/or VIC-E HDC in an
      adjuvant or neo-adjuvant setting could not be determined within the scope of this
      study.

PMID- 10416015
TI  - A new approach to safeguard high standards and cost containment of stem cell
      transplantation in Germany.

PMID- 10416016
TI  - Gemcitabine: a real major advance?

PMID- 10416017
TI  - Anaphylaxis after oxaliplatin.

PMID- 10416018
TI  - Energy transduction function of the quinone reactions in cytochrome bc complexes.
AB  - Cytochrome bc1, a multi-subunit integral membrane protein complex found in
      mammalian mitochondria, plays a central role in the transfer of electrons and
      protons generated by the oxidation of ubiquinol. According to the classical
      chemiosmotic theory, quinones shuttle protons across the hydrophobic membrane
      bilayer with the net result of H+ transfer to the aqueous side and generation of
      an electrochemical proton gradient. Recently, high-resolution structures of the
      mitochondrial bc1 complex showed quinone binding sites at one of the
      transmembrane helices of cytochrome b, and two potentially protonatable histidine
      residues on the Rieske iron-sulfur protein. The modern biochemical refinements of
      the original chemiosmotic theory require electron and proton transfer from
      quinones to particular residues/redox centers of integral membrane proteins and
      subsequent transfer of H+ to the bulk aqueous phase outside the membrane.

PMID- 10416019
TI  - Localization and mobility of coenzyme Q in lipid bilayers and membranes.
AB  - We have studied the mobility of coenzyme Q (CoQ) in lipid bilayers and
      mitochondrial membranes in relation to the control of electron transfer
      activities. A molecular dynamics computer simulation in the vacuum yielded a
      folded structure for CoQ10, with a length of only 21 A. Using this information we
      were able to calculate diffusion coefficients in the range of 10(-6) cm2/s in
      good agreement with those found experimentally by fluorescence quenching of
      pyrene derivatives. To investigate if CoQ diffusion may represent the rate
      limiting step of electron transfer, we reconstituted complexes I and III and
      assayed the resulting NADH-cytochrome c reductase activity in presence of
      different CoQ10 levels and at different distances between complexes; the
      experimental turnovers were higher than the collision frequencies calculated
      using diffusion coefficients of 10(-9) cm2/s but compatible with values found by
      us by fluorescence quenching. Since the experimental turnovers are independent of
      the distance between complexes, we conclude that CoQ diffusion is not rate
      limiting for electron transfer.

PMID- 10416020
TI  - Proton translocation in the respiratory chain involving ubiquinone--a
      hypothetical semiquinone switch mechanism for complex I.
AB  - The protonmotive Q-cycle is the generally accepted reaction scheme of the
      cytochrome bc1 complex of the respiratory chain. It employs the redox-dependent
      protonation and deprotonation of ubiquinone (coenzyme Q10) to translocate protons
      across the inner mitochondrial or bacterial plasma membrane. The requirements for
      the operation of a similar mechanism in proton translocating NADH:ubiquinone
      oxidoreductase (complex I) and the specific roles of the 'Rieske' iron-sulfur
      center in the cytochrome bc1 complex and iron-sulfur center N-2 in complex I are
      discussed. Recent results suggest that there is only one ubiquinone-reactive site
      in complex I which seems to exclude a classical Q-cycle type mechanism.
      Therefore, a "semiquinone switch" mechanism is proposed involving one tightly
      bound and one substrate quinone. It is based on the same principles as a Q-cycle,
      but is a localized rather than a ligand conduction type mechanism.

PMID- 10416021
TI  - Structure and reaction mechanisms of multifunctional mitochondrial cytochrome bc1
      complex.
AB  - The cytochrome bc1 complex from bovine heart mitochondria is a multi-functional
      enzyme complex. In addition to electron and proton transfer activity, the complex
      also processes an activatable peptidase activity and a superoxide generating
      activity. The crystal structure of the complex exists as a closely interacting
      functional dimer. There are 13 transmembrane helices in each monomer, eight of
      which belong to cytochrome b, and five of which belong to cytochrome c1, Rieske
      iron-sulfur protein (ISP), subunits 7, 10 and 11, one each. The distances of 21 A
      between bL heme and bH heme and of 27 A between bL heme and the iron-sulfur
      cluster (FeS), accommodate well the observed fast electron transfers between the
      involved redox centers. However, the distance of 31 A between heme c1 and FeS,
      makes it difficult to explain the high electron transfer rate between them. 3D
      structural analyses of the bc1 complexes co-crystallized with the Qu site
      inhibitors suggest that the extramembrane domain of the ISP may undergo
      substantial movement during the catalytic cycle of the complex. This suggestion
      is further supported by the decreased in the cytochrome bc1 complex activity and
      the increased in activation energy for mutants with increased rigidity in the
      neck region of ISP.

PMID- 10416022
TI  - Metabolism of coenzyme Q10: biliary and urinary excretion study in guinea pigs.
AB  - Biliary and urinary metabolites were examined after intravenous administration of
      14C-coenzyme Q10 (14C-CoQ) to guinea pigs. Cumulative recovery of administered
      radioactivity for up to 8 hours by bile drainage was 4.8%. The greater part of
      radioactivity was detected in conjugate form. After hydrolyzing with beta
      glucuronidase, aglycone fragments were subjected to methylation and reductive
      acetylation. The main metabolite was demonstrated to be Q acid-1 1,4-hydroquinone
      diacetate methyl ester (M-1) on HPLC. Then, the main metabolite was assumed to be
      glucuronide of 2,3-dimethoxy-5-methyl-6-(3'-methyl-5'-carboxy-2'-pentenyl)-1, 4
      benzohydroquinone [Q acid-I hydroquinone]. The cumulative urinary recovery of the
      administered radioactivity over 48 hours was 8.3%. The labeled samples were
      treated similarly to bile. The urinary metabolites of CoQ10 consisted of
      unconjugated and conjugated forms. Lyophilized urine was treated as a bile sample
      and analyzed. The two major metabolites were assigned to be M-1 and Q acid-II 1,4
      hydroquinone diacetate methyl ester (M-2). Then, the two metabolites were assumed
      to be composed of Q acid-I and 2,3-dimethoxy-5-methyl-6-(3'-carboxypropyl)-1,4
      benzoquinone (Q acid-II) in free and corresponding hydroquinone conjugate forms.
      To investigate the effect of exogenous labeled CoQ10 on unlabeled CoQ10
      (endogenous) metabolites in urine, simultaneous quantitative determination was
      performed using deuterium labeled CoQ10 (CoQ10-d5). Urine collected over a 72
      hour period after intravenous administration of CoQ10-d5 was processed similarly
      to that described above and two derivatized metabolites (M-1 and M-2) were
      quantified by gas chromatography-mass fragmentography with the multi-ion
      detection method. The analytical results showed that the addition of exogenous
      labeled CoQ10 did not influence the metabolism (or breakdown) of unlabeled
      (endogenous) CoQ10.

PMID- 10416023
TI  - Characterization of Saccharomyces cerevisiae ubiquinone-deficient mutants.
AB  - Ubiquinol (QH2) is a lipid-soluble molecule that participates in cellular redox
      reactions. Previous studies have shown that yeast mutants lacking QH2 are
      hypersensitive to treatment with polyunsaturated fatty acids (PUFAs) indicating
      that QH2 can function as an antioxidant in vivo. In this study the effect of 1 mM
      linolenic acid on levels of Q6 and Q6H2 is assessed in both wild-type and
      respiration-deficient (atp2 delta) strains. The response of Q-deficient mutants
      to other forms of oxidative stress is further characterized to define those
      conditions where QH2 acts as an antioxidant. Endogenous antioxidant defense
      systems were also assessed in wild-type, Q-deficient, and atp2 delta strains.
      Superoxide dismutase (SOD) activity decreased and catalase activity increased in
      both Q-deficient and atp2 delta mutants compared to wild-type cells, suggesting
      that such changes result from the loss of respiration rather than the lack of Q.

PMID- 10416024
TI  - Induction of endogenous coenzyme Q biosynthesis by administration of peroxisomal
      inducers.
AB  - A large number of chemical compounds have been identified which cause peroxisomal
      proliferation and induce a number of enzymes, mainly those participating in lipid
      metabolism. Administration of these drugs/chemicals to rats increased coenzyme Q
      levels in the blood and most of the organs. Levels were raised in all cellular
      membranes of such organs. The extent of induction of this lipid was 8-fold in
      young animals but decreased during aging and was absent at 1.5 year of age. One
      of the regulating factors of the mevalonate pathway is farnesol, which is
      produced by dephosphorylation of farnesyl-PP and eliminated by phosphorylation
      including two kinases. Future research will involve a search for modified
      intermediary metabolites, which increase coenzyme Q synthesis and thereby
      efficiently elevate the level of this lipid in conditions of deficiency.

PMID- 10416025
TI  - Dynamics of antioxidant action of ubiquinol: a reappraisal.
AB  - The dynamics of action of ubiquinol as an antioxidant against lipid peroxidation
      was reinvestigated and compared with that of alpha-tocopherol. It was found that
      ubiquinol was 2.5 and 1.9 times more reactive than alpha-tocopherol toward
      phenoxyl and peroxyl radicals, respectively, at 25 degrees C in ethanol and that
      it was capable of donating two hydrogen atoms toward oxygen radicals but that the
      apparent stoichiometric number decreased in the inhibition of lipid peroxidation,
      to even smaller than 1, due to its autoxidation. The autoxidation of ubiquinol
      proceeded even in the micelles and liposomal membranes in aqueous dispersions as
      well as in organic homogeneous solution. The apparent antioxidant activity of
      ubiquinol was smaller than that of alpha-tocopherol against lipid peroxidation in
      organic solution as judged from either rate of oxidation or duration of
      inhibition period. They exerted similar antioxidant potency against lipid
      peroxidation in the membranes and micelles in aqueous dispersions. The
      combination of ubiquinol and alpha-tocopherol was suggested to be effective.

PMID- 10416026
TI  - Expansion of antioxidant function of vitamin E by coenzyme Q.

PMID- 10416027
TI  - Critical aspects of the antioxidant function of coenzyme Q in biomembranes.
AB  - Coenzyme Q (ubiquinone, UQ) is increasingly considered as a significant natural
      antioxidant, which protects biomembranes in concert with alpha-tocopherol. In
      vitro experiments demonstrated that reduced UQ (ubiquinol) can improve the chain
      breaking activities of alpha-tocopherol by recycling the antioxidant-derived
      reaction product, the chromanoxyl radical, to the native antioxidant. Less
      attention, however, was devoted to the antioxidant-derived reaction products of
      reduced UQ. Although both alpha-tocopherol and ubiquinol were found to be equally
      effective in scavenging chain-propagating lipid radicals. alpha-tocopherol
      protected lipid membranes from lipid peroxidation more efficiently than
      ubiquinol. The present study not only provides data which document this
      discrepancy but also contributes experimental data on the existence of ubiquinol
      derived pro-oxidants, which give an explanation of this phenomenon.

PMID- 10416028
TI  - Protective role of ubiquinone in vitamin E and selenium-deficient plasma
      membranes.
AB  - We have studied the effects of dietary depletion of vitamin E and selenium on
      endogenous ubiquinone-dependent antioxidant system. Deficiency induced an
      increase in both coenzyme Q9 and Q10 in liver tissue, reaching a maximum between
      4 and 7 weeks of deficient diet consumption. Cytochrome b5 reductase polypeptide
      was also enriched in membranes after 5 weeks of deficient diet consumption.
      Substantial DT-diaphorase activity was found in deficient, but not in control
      plasma membranes. Deficient membranes were very sensitive to lipid peroxidation,
      although a great protection was observed after incubation with NAD(P)H. Our
      results show that liver cells can boost endogenous ubiquinone-dependent
      protective mechanisms in response to deficiency in vitamin E and selenium.

PMID- 10416029
TI  - Role of plasma membrane coenzyme Q on the regulation of apoptosis.
AB  - Serum withdrawal is a model to study the mechanisms involved in the induction of
      apoptosis caused by mild oxidative stress. Apoptosis induced by growth factors
      removal was prevented by the external addition of antioxidants such as ascorbate,
      alpha-tocopherol and coenzyme Q (CoQ). CoQ is a lipophilic antioxidant which
      prevents oxidative stress and participates in the regeneration of alpha
      tocopherol and ascorbate in the plasma membrane. We have found an inverse
      relationship between CoQ content in plasma membrane and lipid peroxidation rates
      in leukaemic cells. CoQ10 addition to serum-free culture media prevented both
      lipid peroxidation and cell death. Also, CoQ10 addition decreased ceramide
      release after serum withdrawal by inhibition of magnesium-dependent plasma
      membrane neutral-sphingomyelinase. Moreover, CoQ10 addition partially blocked
      activation of CPP32/caspase-3. These results suggest CoQ of the plasma membrane
      as a regulator of initiation phase of oxidative stress-mediated serum withdrawal
      induced apoptosis.

PMID- 10416030
TI  - A multifunctional hydroquinone oxidase of the external cell surface and sera.
AB  - A multifunctional cell surface protein with NADH oxidase (NOX) activity and
      capable of oxidizing hydroquinones is located at the exterior of the cell and is
      shed in soluble form into sera. The oxidase appears to function as a terminal
      oxidase of a trans plasma membrane electron transport chain consisting of a
      NAD(P)H-ubiquinone reductase at the cytosolic membrane surface, possibly a b-type
      cytochrome, ubiquinone and the oxidase. Hyperactivity or conditions that
      interrupt ordered 2H+ + 2e- transport from NAD(P)H or hydroquinone to molecular
      oxygen and other acceptors at the external cell surface may result in the
      generation of superoxide. The latter may serve to propagate aging-related redox
      changes both to adjacent cells and circulating blood components. A circulating
      NOX activity form associated with aging and the reduction of cytochrome c by sera
      of aged patients that is partially inhibited by ubiquinone are described.

PMID- 10416031
TI  - Cytosolic NADPH-UQ reductase, the enzyme responsible for cellular ubiquinone
      redox cycle as an endogenous antioxidant in the rat liver.
AB  - Cellular ubiquinone (UQ) is expected to act as an endogenous antioxidant against
      oxidative stress. To confirm this, UQ-reductases which are necessary to
      regenerate ubiquinol (UQH2) were investigated in rat tissue, and a novel NADPH
      dependent UQ (NADPH-UQ) reductase was found in cytosol. The cytosolic NADPH-UQ
      reductase activity accounted for more than 80% of UQ-10 reduction by the rat
      liver homogenate in the presence of NADPH. Furthermore, the NADPH-UQ reductase
      activities in various tissues were correlated to the redox states of UQ in the
      corresponding tissues. Rat liver cytosol with NADPH protected lecithin liposomes
      containing UQ-10, as well as UQH2-10 from AMVN (2,2'-azobis(2,4
      dimethylvaleronitrile))-induced lipid peroxidation. The enzyme purified from rat
      liver cytosol, reduced UQ-10 in lecithin liposomes at approximately the same rate
      as did cytosol. These results supported that cytosolic NADPH-UQ reductase is the
      enzyme responsible for nonmitochondrial UQ reduction acting as an endogenous
      antioxidant against oxidative stress. The antioxidant role of the UQ redox cycle
      and NADPH-UQ reductase was discussed in relation to other cellular NADPH
      dependent antioxidant enzymes.

PMID- 10416032
TI  - Mitochondrial coenzyme Q content and aging.
AB  - The main objective of this study was to determine the nature of the relationship
      between aging and mitochondrial coenzyme Q (CoQ) content. Mitochondria in the
      heart, skeletal muscle, kidney and brain of the mouse varied in both the amount
      of total CoQ (CoQ9 + CoQ10) content as well as in the ratio of the CoQ9 to CoQ10.
      CoQ content declined with age only in the skeletal muscle. Caloric restriction
      (CR) resulted in an increase in the amount of CoQ9 in skeletal muscle
      mitochondria. This effect was partially reversible upon termination of the
      caloric restriction regimen. Results suggest that a decrease in mitochondrial CoQ
      content is an integral aspect of aging in skeletal muscle.

PMID- 10416034
TI  - Plasma ubiquinol-10 as a marker for disease: is the assay worthwhile?
AB  - Ubiquinol-10 and ubiquinone-10 were measured in plasma of patients with several
      pathologies known to be associated with increased oxidative stress. Plasma
      ubiquinol-10, expressed as a percentage of total ubiquinol-10 + ubiquinone-10,
      was found to be significantly lower in hyperlipidaemic patients and in patients
      with liver diseases than in age-matched control subjects. In contrast, no
      decrease in ubiquinol-10 was detected in plasma of patients with coronary heart
      disease and Alzheimer's disease. Except for ubiquinol-10, no other lipophilic
      antioxidant was found to be decreased in patients with liver diseases. These data
      suggest that the level of ubiquinol-10 in human plasma may serve as a marker for
      liver dysfunction, reflecting its diminished reduction by the liver rather than
      increased consumption by oxidants.

PMID- 10416033
TI  - A role for reduced coenzyme Q in atherosclerosis?
AB  - Substantial evidence implicates oxidative modification of low density lipoprotein
      (LDL) as an important event contributing to atherogenesis. As a result, the
      elucidation of the molecular mechanisms by which LDL is oxidized and how such
      oxidation is prevented by antioxidants has been a significant research focus.
      Studies on the antioxidation of LDL lipids have focused primarily on alpha
      tocopherol (alpha-TOH), biologically and chemically the most active form of
      vitamin E and quantitatively the major lipid-soluble antioxidant in extracts
      prepared from human LDL. In addition to alpha-TOH, plasma LDL also contains low
      levels of ubiquinol-10 (CoQ10H2; the reduced form of coenzyme Q10). Recent
      studies have shown that in oxidizing plasma lipoproteins alpha-TOH can exhibit
      anti- or pro-oxidant activities for the lipoprotein's lipids exposed to a vast
      array of oxidants. This article reviews the molecular action of alpha-TOH in LDL
      undergoing "mild" radical-initiated lipid peroxidation, and discusses how small
      levels of CoQ10H2 can represent an efficient antioxidant defence for lipoprotein
      lipids. We also comment on the levels alpha-TOH, CoQ10H2 and lipid oxidation
      products in the intima of patients with coronary artery disease and report on
      preliminary studies examining the effect of coenzyme Q10 supplementation on
      atherogenesis in apolipoprotein E knockout mice.

PMID- 10416035
TI  - Distribution of antioxidants among blood components and lipoproteins:
      significance of lipids/CoQ10 ratio as a possible marker of increased risk for
      atherosclerosis.
AB  - Total CoQ10 levels were evaluated in whole blood and in plasma obtained from a
      group of 83 healthy donors. Extraction with light petroleum ether/methanol was
      more efficient, for whole blood, than the extraction which is often used for
      plasma and serum, i.e., ethanol hexane. An excellent correlation was present
      between plasma CoQ10 and whole blood CoQ10. CoQ10 is mainly associated with
      plasma rather than with cellular components. Positive, significant correlations
      were found between the LDL-chol/CoQ10 ratio and the total-chol/HDL-chol ratio,
      which is usually considered a risk factor for atherosclerosis. The proportion of
      CoQ10 carried by LDL was 58 +/- 10%, while the amount carried by HDL was 26 +/-
      8%. In VLDL + IDL CoQ10 was 16 +/- 8%. The content of CoQ10 in single classes of
      lipoproteins is strictly correlated with CoQ10 plasma concentration. In a
      parallel study conducted on a population of diabetic patients (one IDDM group and
      one NIDDM) CoQ10 plasma levels were generally higher compared to the control
      group, also when normalised to total cholesterol. In particular the LDL fraction
      showed a CoQ10/chol ratio higher in NIDDM but not in IDDM patients, compared to
      controls. The CoQ10/triglycerides ratio was lower in NIDDM respect to controls
      and even lower in IDDM patients.

PMID- 10416036
TI  - Plasma ubiquinone to ubiquinol ratio in patients with hepatitis, cirrhosis, and
      hepatoma, and in patients treated with percutaneous transluminal coronary
      reperfusion.
AB  - To assess the degree of oxidative stress, we measured plasma ubiquinone-10
      percentage (%CoQ-10) in total amounts of ubiquinone-10 in patients with chronic
      active hepatitis, liver cirrhosis, and hepatocellular carcinoma, and in age
      matched control subjects, %CoQ-10 values were 12.9 +/- 10.3 (n = 28), 10.6 +/-
      6.8 (n = 28), 18.9 +/- 11.1 (n = 20), and 6.4 +/- 3.3 (n = 16), respectively,
      showing a significant increase in oxidative stress in patient groups as compared
      to control subjects. There were no differences in total amounts of ubiquinone-10
      and ubiquinol-10 among the four groups. We next measured %CoQ-10 in plasmas
      obtained from nine patients treated with percutaneous transluminal coronary
      angioplasty (PTCA). Plasmas were collected when hospitalized, and at the time (0,
      4, 8, 12, 16, and 20 hr, and 1, 2, 3, 4, and 7 days) after the PTCA. %CoQ-10
      values before and right after PTCA were 9.9 +/- 2.8 and 11.4 +/- 2.0,
      respectively, reached a maximum (20-45) at 1 or 2 days later, and decreased to
      7.9 +/- 2.7 at 7 days after PTCA, indicating an increase in oxidative stress in
      patients during coronary reperfusion.

PMID- 10416037
TI  - Quinone analogs prevent enzymes targeted in Friedreich ataxia from iron-induced
      injury in vitro.

PMID- 10416038
TI  - Improved brain and muscle mitochondrial respiration with CoQ. An in vivo study by
      31P-MR spectroscopy in patients with mitochondrial cytopathies.
AB  - We used in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) to study the
      effect of CoQ10 on the efficiency of brain and skeletal muscle mitochondrial
      respiration in ten patients with mitochondrial cytopathies. Before CoQ, brain
      [PCr] was remarkably lower in patients than in controls, while [Pi] and [ADP]
      were higher. Brain cytosolic free [Mg2+] and delta G of ATP hydrolysis were also
      abnormal in all patients. MRS also revealed abnormal mitochondrial function in
      the skeletal muscles of all patients, as shown by a decreased rate of PCr
      recovery from exercise. After six-months of treatment with CoQ (150 mg/day), all
      brain MRS-measurable variables as well as the rate of muscle mitochondrial
      respiration were remarkably improved in all patients. These in vivo findings show
      that treatment with CoQ in patients with mitochondrial cytopathies improves
      mitochondrial respiration in both brain and skeletal muscles, and are consistent
      with Lenaz's view that increased CoQ concentration in the mitochondrial membrane
      increases the efficiency of oxidative phosphorylation independently of enzyme
      deficit.

PMID- 10416039
TI  - Coenzyme Q10 administration and its potential for treatment of neurodegenerative
      diseases.
AB  - Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport chain as
      well as an important antioxidant. Previous studies have suggested that it may
      exert therapeutic effects in patients with known mitochondrial disorders. We
      investigated whether it can exert neuroprotective effects in a variety of animal
      models. We have demonstrated that CoQ10 can protect against striatal lesions
      produced by both malonate and 3-nitropropionic acid. It also protects against
      MPTP toxicity in mice. It extended survival in a transgenic mouse model of
      amyotrophic lateral sclerosis. We demonstrated that oral administration can
      increase plasma levels in patients with Parkinson's disease. Oral administration
      of CoQ10 significantly decreased elevated lactate levels in patients with
      Huntington's disease. These studies therefore raise the prospect that
      administration of CoQ10 may be useful for the treatment of neurodegenerative
      diseases.

PMID- 10416040
TI  - A possible role of coenzyme Q10 in the etiology and treatment of Parkinson's
      disease.
AB  - Parkinson's disease (PD) is a degenerative neurological disorder. Recent studies
      have demonstrated reduced activity of complex I of the electron transport chain
      in brain and platelets from patients with PD. Platelet mitochondria from
      parkinsonian patients were found to have lower levels of coenzyme Q10 (CoQ10)
      than mitochondria from age/sex-matched controls. There was a strong correlation
      between the levels of CoQ10 and the activities of complexes I and II/III. Oral
      CoQ10 was found to protect the nigrostriatal dopaminergic system in one-year-old
      mice treated with MPTP, a toxin injurious to the nigrostriatal dopaminergic
      system. We further found that oral CoQ10 was well absorbed in parkinsonian
      patients and caused a trend toward increased complex I activity. These data
      suggest that CoQ10 may play a role in cellular dysfunction found in PD and may be
      a potential protective agent for parkinsonian patients.

PMID- 10416041
TI  - Overview of the use of CoQ10 in cardiovascular disease.
AB  - The clinical experience in cardiology with CoQ10 includes studies on congestive
      heart failure, ischemic heart disease, hypertensive heart disease, diastolic
      dysfunction of the left ventricle, and reperfusion injury as it relates to
      coronary artery bypass graft surgery. The CoQ10-lowering effect of HMG-CoA
      reductase inhibitors and the potential adverse consequences are of growing
      concern. Supplemental CoQ10 alters the natural history of cardiovascular
      illnesses and has the potential for prevention of cardiovascular disease through
      the inhibition of LDL cholesterol oxidation and by the maintenance of optimal
      cellular and mitochondrial function throughout the ravages of time and internal
      and external stresses. The attainment of higher blood levels of CoQ10 (> 3.5
      micrograms/ml) with the use of higher doses of CoQ10 appears to enhance both the
      magnitude and rate of clinical improvement. In this communication, 34 controlled
      trials and several open-label and long-term studies on the clinical effects of
      CoQ10 in cardiovascular diseases are reviewed.

PMID- 10416042
TI  - Coenzyme Q10 treatment in serious heart failure.
AB  - Several noninvasive studies have shown the effect on heart failure of treatment
      with coenzyme Q10. In order to confirm this by invasive methods we studied 22
      patients with mean left ventricular (LV) ejection fraction 26%, mean LV internal
      diameter 71 mm and in NYHA class 2-3. The patients received coenzyme Q10 100 mg
      twice daily or placebo for 12 weeks in a randomized double-blinded placebo
      controlled investigation. Before and after the treatment period, a right heart
      catheterisation was done including a 3 minute exercise test. The stroke index at
      rest and work improved significantly, the pulmonary artery pressure at rest and
      work decreased (significantly at rest), and the pulmonary capillary wedge
      pressure at rest and work decreased (significantly at 1 min work). These results
      suggest improvement in LV performance. Patients with congestive heart failure may
      thus benefit from adjunctive treatment with coenzyme Q10.

PMID- 10416043
TI  - Coenzyme Q10 improves the tolerance of the senescent myocardium to aerobic and
      ischemic stress: studies in rats and in human atrial tissue.
AB  - The inferior recovery of cardiac function after interventional cardiac procedures
      in elderly patients compared to younger patients suggests that the aged
      myocardium is more sensitive to stress. We report two studies that demonstrate an
      age-related deficit in myocardial performance after aerobic and ischemic stress
      and the capacity of CoQ10 treatment to correct age-specific diminished recovery
      of function. In Study 1 the functional recovery of young (4 mo) and senescent (35
      mo) isolated working rat hearts after aerobic stress produced by rapid electrical
      pacing was examined. After pacing, the senescent hearts, compared to young,
      showed reduced recovery of pre-stress work performance. CoQ10 pretreatment (daily
      intraperitoneal injections of 4 mg/kg CoQ10 for 6 weeks) in senescent hearts
      improved their recovery to match that of young hearts. Study 2 tested whether the
      capacity of human atrial trabeculae (obtained during surgery) to recover
      contractile function, following ischemic stress in vitro (60 min), is decreased
      with age and whether this decrease can be reversed by CoQ10. Trabeculae from
      older individuals (> or = 70 yr) showed reduced recovery of developed force after
      simulated ischemia compared to younger counterparts (< 70 yr). Notably, this age
      associated effect was prevented in trabeculae pretreated in vitro (30 min at 24
      degrees C) with CoQ10 (400 MicroM). We measured significantly lower CoQ10 content
      in trabeculae from > or = 70 yr patients. In vitro pretreatment raised trabecular
      CoQ10 content to similar levels in all groups. We conclude that, compared to
      younger counterparts, the senescent myocardium of rats and humans has a reduced
      capacity to tolerate ischemic or aerobic stress and recover pre-stress
      contractile performance, however, this reduction is attenuated by CoQ10
      pretreatment.

PMID- 10416044
TI  - Coenzyme Q10 depletion and mitochondrial energy disturbances in rejection
      development in patients after heart transplantation.
AB  - Sixty endomyocardial biopsies (EMB) and whole blood or plasma samples from 34
      patients after heart transplantation (HTx-pts) were studied. Acute rejection of
      the transplanted heart was histologically graded as: 0 (without), 0-1
      (incipient), 1 (mild), 2 (moderate). The level of coenzyme Q10 (CoQ10) in 28 EMB
      was estimated by HPLC. Mitochondrial respiratory chain function and energy
      production were measured in 60 EMB. This study is the first report showing a
      correlation between: (a) histological signs of rejection in the human
      transplanted heart and (b) CoQ10 level of EMB, CoQ10 blood level, and
      mitochondrial bioenergetic processes: inhibition in FAD-part, but not in NAD-part
      of respiratory chain. In all patients after heart transplantation (HTx-pts) the
      dynamic balance between total antioxidant status and degree of oxidative stress
      was disturbed. CONCLUSIONS: CoQ10 level and mitochondrial bioenergetic functions
      of EMB contribute to the explanation of pathobiochemical mechanisms of origin and
      development rejection of human transplanted heart. We suppose that estimation of
      EMB CoQ10 level could be used as a bioenergetic marker of rejection development
      in human transplanted heart. CoQ10 therapy could contribute to the prevention of
      rejection of the transplanted heart.

PMID- 10416045
TI  - Bioenergetic effect of liposomal coenzyme Q10 on myocardial ischemia reperfusion
      injury.
AB  - The antioxidant and bioenergetic effects of CoQ10 are well known but its clinical
      utility is limited by the requirement for enteral administration. A newly
      developed liposomal CoQ10 (CoQ) is water soluble and capable of intravenous
      administration. The purpose of this study is to determine the mechanism by which
      acute administration CoQ protects myocardium from reperfusion (Rp) injury. Rats
      were pretreated with CoQ 10 mg/kg i.v. 30 min prior to the experiment. Control
      rats were pretreated with liposome only. Hearts were excised and subjected to
      equilibration, 25 min of normothermic ischemia and 40 min of Rp on a Langendorff
      apparatus. At end Rp, CoQ hearts recovered 74 +/- 5% of their DP vs. 50 +/- 9% in
      control (p < 0.05). Aerobic efficiency was maintained (0.66 +/- 0.02 vs. control,
      0.5 +/- 0.04, p < 0.003) and CoQ hearts lost less CK activity vs. control (p <
      0.02). PCr and ATP were higher than control (p < 0.05, 0.02, respectively).
      Results show that i.v. CoQ improves recovery of function, aerobic efficiency, CK
      activity, and recovery of PCr and ATP after Rp. This suggests that acute
      administration of liposomal CoQ improves myocardial tolerance to I/R via its role
      as an antioxidant as well as improving oxygen utilization and high energy
      phosphate production.

PMID- 10416046
TI  - The effect of coenzyme Q10 administration on metabolic control in patients with
      type 2 diabetes mellitus.
AB  - A possible relationship between the pathogenesis of type 2 diabetes and coenzyme
      Q10 (CoQ10) deficiency has been proposed. The aim of this study was to assess the
      effect of CoQ10 on metabolic control in 23 type 2 diabetic patients in a
      randomized, placebo-controlled trial. Treatment with CoQ10 100 mg bid caused a
      more than 3-fold rise in serum CoQ10 concentration (p < 0.001). No correlation
      was observed between serum CoQ10 concentration and metabolic control. No
      significant changes in metabolic parameters were observed during CoQ10
      supplementation. The treatment was well tolerated and did not interfere with
      glycemic control, therefore CoQ10 may be used as adjunctive therapy in patients
      with associated cardiovascular diseases.

PMID- 10416048
TI  - Monounsaturated diet lowers LDL oxidisability in type IIb and type IV
      dyslipidemia without affecting coenzyme Q10 and vitamin E contents.
AB  - The purpose of the present study was to evaluate the effects of MUFA vs PUFA
      enriched diets on the plasma and LDL lipid profile and antioxidant contents in
      mild hypercholesterolemic and triglyceridemic subjects. The study was divided in
      two consecutive diet periods. Two groups of 11 dyslipidemic patients each (type
      IIb and type IV) were recruited and during the first period (lasting four weeks)
      received a linoleic rich diet while during the following four weeks took an
      oleate rich diet. Both groups showed no significant changes in cholesterol and TG
      concentration either in plasma or in LDL. Coenzyme Q10 and vitamin E were also
      unaffected by the dietary treatments. LDL proneness to be oxidatively modified
      increased after dietary PUFA administration and markedly decreased following the
      virgin olive oil enriched diet. In fact, LDL from hypertrigliceridemic subjects
      on a oleate-enriched diet displayed a 26% (p < 0.05) longer lag-phase in
      conjugated dienes generation than during linoleate-enriched diet and at
      recruitment. In hypercholesterolemic subjects similar results were obtained: the
      lag-phase was 28% longer after MUFA diet that after PUFA diet. No differences
      were found in the maximum propagation rate and maximum concentration of
      conjugated dienes among dietary periods and at recruitment. Since we found that
      the vit. E and CoQ10 levels in plasma and in LDL particles remained unchanged
      during the course of the study, we may conclude that LDL proneness to undergo
      oxidative modifications is mainly the result of compositional change due to the
      enrichment from the different diets of the relative fats.

PMID- 10416049
TI  - Olive oil supplemented with vitamin E affects mitochondrial coenzyme Q levels in
      liver of rats after an oxidative stress induced by adriamycin.
AB  - In this study we have evaluated the supplementation of olive oil with vitamin E
      on coenzyme Q concentration and lipid peroxidation in rat liver mitochondrial
      membranes. Four groups of rats were fed on virgin olive, olive plus 200 mg/kg of
      vitamin E or sunflower oils as lipid dietary source. To provoke an oxidative
      stress rats were administered intraperitoneally 10 mg/kg/day of adriamycin the
      last two days of the experiment. Animals fed on olive oil plus vitamin E had
      significantly higher coenzyme Q and vitamin E levels but a lower mitochondrial
      hydroperoxide concentration than rats fed on olive oil. Retinol levels were not
      affected, by either different diets or adriamycin treatment. In conclusion, an
      increase in coenzyme Q and alpha-tocopherol in these membranes can be a basis for
      protection against oxidation and improvement in antioxidant capacity.

PMID- 10416047
TI  - High serum coenzyme Q10, positively correlated with age, selenium and
      cholesterol, in Inuit of Greenland. A pilot study.
AB  - Greenlanders (Eskimos) have low prevalence of ischaemic heart disease, partly
      explained by a lower extent of atherosclerosis and a low n-6/n-3 ratio of
      polyunsaturated fatty acids. As atherosclerosis is also a result of oxidative
      stress, the total antioxidative readiness could have a substantial impact. From a
      health survey we chose the subpopulation from the most remote area, where the
      traditional Greenlandic diet with high intake of sea mammals and fish
      predominates. The mean (SD) of S-CoQ10 in males was 1.495 (0.529) nmol/ml and
      1.421 (0.629) nmol/ml in females, significantly higher (p < 0.001) compared to a
      Danish population. In a linear multiple regression model the S-CoQ10 level is
      significantly positively associated with age and S-selenium in males, and S-total
      cholesterol in females. The high level of CoQ10 in Greenlanders probably reflects
      diet, since no bioaccumulation takes place, and it could probably be a
      substantial part of the antioxidative defense.

PMID- 10416050
TI  - Virgin olive oil and coenzyme Q10 protect heart mitochondria from peroxidative
      damage during aging.
AB  - The mitochondrial theory of aging suggests that this phenomenon is the
      consequence of random somatic mutations in mitochondrial DNA, induced by long
      term exposure to free radical attack. There are two potential dietary means of
      delaying the effects of free radicals on cellular aging, i.e., enrichment of
      mitochondrial membranes with monounsaturated fatty acids and supplementation with
      antioxidants. We have performed a preliminary study on male rats, 6 or 12 month
      old, fed with diets differing in the nature of the fat (virgin olive oil or
      sunflower oil) and/or with antioxidant supplementation (coenzyme Q10), analysing
      hydroperoxide and coenzyme Q9 and Q10 in heart mitochondria. Preliminary results
      allow us to conclude that the CoQ10 dietetic supplementation as well as the
      enrichment of the cellular membranes with monounsaturated fatty acids,
      successfully protect mitochondrial membranes from aged rats against the free
      radical insult.

PMID- 10416051
TI  - Protective effect of exogenous coenzyme Q in rats subjected to partial hepatic
      ischemia and reperfusion.
AB  - In a surgical model of liver ischemia lipid peroxidation occurs, as shown by
      increase of lipid peroxidation end products, endogenous CoQ9 is oxidized and
      mitochondrial respiration is lowered; however, pre-treatment of the rats by i.p.
      injection of CoQ10 for 14 days normalizes the above parameters, presumably by way
      of the observed high extent of reduction of the incorporated quinone; moreover,
      liver homogenates of the CoQ10-treated rats are more resistant than those of non
      treated rats to oxidative stress induced by an azido free radical initiator. This
      preliminary study suggests that CoQ10 pre-treatment can be of beneficial effect
      against oxidative damage during liver surgery transplantation.

PMID- 10416052
TI  - Coenzyme Q10 administration increases antibody titer in hepatitis B vaccinated
      volunteers--a single blind placebo-controlled and randomized clinical study.
AB  - Persons involved in the study, 21 per treatment arm, were consuming ubiquinone
      (Q10), 90 mg/day, 180 mg/day or placebo, for two weeks prior to hepatitis B
      vaccination. After 30 days this vaccination was repeated. Q10 was given as soft
      gelatin capsules containing 30 mg each. The consumption was continued throughout
      the study conducted for 90 days. Clinical observations and laboratory tests were
      performed throughout the study and no adverse effects were observed in any of the
      groups. Already after 30 days the two groups receiving Q10 showed a slightly
      titer of antibodies to hepatitis B surface antigen then the placebo group. This
      difference escalated and the immunopotentiating effect of Q10 was even more clear
      cut in the residual part of the study. In addition, a dose response did also seem
      to be present when comparing the 90 mg group with the 180 mg group. Statistics
      revealed that Q10 in the dose 180 mg/day is able to increase antibody response in
      vivo in humans vaccinated against hepatitis B with up to 57% (p = 0.011).

PMID- 10416053
TI  - Clinical implications of the correlation between coenzyme Q10 and vitamin B6
      status.
AB  - The endogenous biosynthesis of the quinone nucleus of coenzyme Q10 (CoQ10) from
      tyrosine is dependent on adequate vitamin B6 nutriture. Lowered blood and tissue
      levels of CoQ10 have been observed in a number of clinical conditions. Many of
      these clinical conditions are most prevalent among the elderly. Kalen et al. have
      shown that blood levels of CoQ10 decline with age. Similarly, Kant et al. have
      shown that indicators of vitamin B6 status also decline with age. Blood samples
      were collected from 29 patients who were not currently being supplemented with
      either CoQ10 or vitamin B6. Mean CoQ10 concentrations was 1.1 +/- 0.3
      micrograms/ml of blood. Mean specific activities of EGOT was 0.30 +/- 0.13 mumol
      pyruvate/hr/10(8) erythrocytes and the mean percent saturation of EGOT with PLP
      was 78.2 +/- 13.9%. Means for all parameters were within normal ranges. Strong
      positive correlation was found between CoQ10 and the specific activity of EGOT (r
      = 0.5787, p < 0.001) and between CoQ10 and the percent saturation of EGOT with
      PLP (r = 0.4174, p < 0.024). Studies are currently in progress to determine the
      effect of supplementation with vitamin B6 of blood CoQ10 levels. It appears
      prudent to recommend that patients receiving supplemental CoQ10 be concurrently
      supplemented with vitamin B6 to provide for better endogenous synthesis of CoQ10
      along with the exogenous CoQ10.

PMID- 10416054
TI  - CoQ10: could it have a role in cancer management?
AB  - Coenzyme Q10 or ubiquinone has been shown to have both anti-cancer and immune
      system enhancing properties when tested in animals. Preliminary results reported
      here suggest that it might inhibit tumour-associated cytokines. Clinical studies
      conducted with combination therapies of CoQ10 and other antioxidants are ongoing,
      but the results are difficult evaluate owing to the lack of proper control groups
      and of initial randomisation. Also on the basis of some anti-cancer effects of
      antioxidants reported in literature, further animal studies and a proper clinical
      trial of coenzyme Q10 in cancer patients are needed.

PMID- 10416055
TI  - Coenzyme Q10, a cutaneous antioxidant and energizer.
AB  - The processes of aging and photoaging are associated with an increase in cellular
      oxidation. This may be in part due to a decline in the levels of the endogenous
      cellular antioxidant coenzyme Q10 (ubiquinone, CoQ10). Therefore, we have
      investigated whether topical application of CoQ10 has the beneficial effect of
      preventing photoaging. We were able to demonstrate that CoQ10 penetrated into the
      viable layers of the epidermis and reduce the level of oxidation measured by weak
      photon emission. Furthermore, a reduction in wrinkle depth following CoQ10
      application was also shown. CoQ10 was determined to be effective against UVA
      mediated oxidative stress in human keratinocytes in terms of thiol depletion,
      activation of specific phosphotyrosine kinases and prevention of oxidative DNA
      damage. CoQ10 was also able to significantly suppress the expression of
      collagenase in human dermal fibroblasts following UVA irradiation. These results
      indicate that CoQ10 has the efficacy to prevent many of the detrimental effects
      of photoaging.

PMID- 10416056
TI  - High-performance liquid chromatography study on effects of permanent wave, dye
      and decolorant treatments on methamphetamine and amphetamine in hair.
AB  - Black hairs that had been removed from a methamphetamine (MA) addict were treated
      with permanent wave, dye or decolorant liquids, and MA and amphetamine (AP) were
      quantified by a high-performance liquid chromatography/chemiluminescence
      detection method. The concentrations of MA and AP in the hair decreased
      significantly in all cases. Both MA and AP were stable in the permanent wave
      treatments, but not stable in the dye or decolorant treatments. As possible
      reasons for the decrease, the elution of MA and AP from hair in the permanent
      wave treatment, and the degradation of MA and AP in the dye or decolorant
      treatments might be considered. These results suggested that treatments of hair
      with permanent wave, dye or decolorant liquids interfered with determination of
      MA and AP in hair.

PMID- 10416057
TI  - Determination of unbound drug concentration and protein-drug binding fraction in
      plasma.
AB  - The aim of this work was to provide a short overview of existing methods for the
      determination of free drug concentration and protein-drug binding fraction in
      plasma. Various methods have been described in terms of principles, evaluation of
      methods, and applications in recent years, with an emphasis on the
      chromatographic method, i.e. high-performance frontal analysis (HPFA).

PMID- 10416059
TI  - Rapid high-performance liquid chromatographic determination of cefepime in human
      plasma.
AB  - A simple, rapid and reproducible high-performance liquid chromatographic method
      for the quantitative determination of cefepime in human plasma was developed.
      Ceftazidime was used as internal standard. Chromatography was performed on a
      reversed-phase encapped column (Hypersil BDS C18). The samples, after protein
      precipitation, were eluted with a mobile phase of acetonitrile-acetate buffer, pH
      4 (2.8:97.2, v/v). The detection wavelength was 254 nm. The limit of quantitation
      of cefepime was 0.5 microgram/mL and only 0.5 mL of plasma sample was required
      for the determination. The average cefepime recoveries over a concentration range
      of 0.5-500 micrograms/mL ranged from 98 to 104%. Precision and accuracy did not
      exceed 5%.

PMID- 10416058
TI  - Bilirubin-human serum albumin interaction monitored by capillary zone
      electrophoresis.
AB  - Capillary zone electrophoresis was used to monitor the interaction between
      bilirubin and human serum albumin. Cord blood serum samples were injected
      directly into an uncoated fused-silica capillary (30 cm x 50 microns i.d.) and
      separation was accomplished within 4 min without extensive sample pretreatment.
      The most suitable running buffer to separate free bilirubin from albumin bound
      bilirubin was found to contain 1.0 mmol/L EDTA, 5% acetonitrile and 15 mmol/L
      phosphate with pH adjusted to 8.4. Approximately two bilirubin dianions could be
      bound per human serum albumin molecule in the cord blood serum. The binding
      constant was estimated to be 1.1 x 10(5) (L/mol) at 25 degrees C and pH 8.4. The
      peak area ratio of free bilirubin to total bilirubin can be used to determine the
      bilirubin binding capacity of cord blood serum for the concentration range of
      total bilirubin from 204 to 340 mumol/L using 1:5 diluted cord blood seras.

PMID- 10416060
TI  - Direct enantiomeric resolution of some 2-arylpropionic acids using (-)-brucine
      impregnated thin-layer chromatography.
AB  - Direct enantioseparation of (+/-)-ibuprofen and (+/-)-flurbiprofen was achieved
      by two-dimensional thin-layer chromatography on silica gel plates impregnated
      with optically pure (-)-brucine as chiral selector. The solvent systems that were
      successful in resolving both the compounds were acetonitrile-methanol (16:3 v/v)
      for the first dimension and acetonitrile-methanol-water (16:3:0.4, v/v) for the
      second dimension. Iodine vapour was used for detection; the detection limit for
      both (+/-)-ibuprofen and (+/-)-flurbiprofen was 0.1 microgram.

PMID- 10416061
TI  - Determination of fluoroquinolone residues in animal tissues by liquid
      chromatography.
AB  - A simple liquid chromatographic (LC) method was developed for the determination
      of fluoroquinolones (ciprofloxacin, difloxacin, enrofloxacin and sarafloxacin) in
      animal tissues. Isolation of fluoroquinolones from biological matrices was
      performed with 5% trichloroacetic acid-acetonitrile (7:3) solution. For clean-up,
      solid-phase extraction with an SDBI (styrene-divinylobenzene) cartridge was used.
      LC analyses were performed with analytical column (LiChrospher 100 RP-8 5
      microns) and mobile phase (0.025 M o-phosphoric acid-acetonitrile 70:30, v/v) in
      ion-pair mode. The whole procedure was validated in intra- and inter-assay
      reproducibility and accuracy determination by simultaneously assaying of muscle,
      liver and kidney samples supplemented with fluoroquinolones at the level of 30
      and 60 ng/g, respectively. The statistical evaluation demonstrates high absolute
      recovery (> 80%) and low coefficient of variation (< 10%) for all analysed
      samples. The detection limits for fluoroquinolones were 5 ng/g in muscle, liver
      and kidney samples.

PMID- 10416062
TI  - Liquid chromatographic bioanalytical determination of ropivacaine, bupivacaine
      and major metabolites.
AB  - Bioanalytical methods for the determination of ropivacaine, bupivacaine and their
      major metabolites in urine and blood plasma are presented. Ropivacaine is a new
      local anaesthetic drug mainly used for surgery and for postoperative pain relief.
      The samples are hydrolysed and cleaned using solid-phase extraction and analysed
      using ion-pair reversed-phase liquid chromatography with gradient elution. The
      analytes are detected using UV at 210 nm. The methods are highly selective and
      the limits of quantification were 1 microM in urine and 0.1 microM in plasma,
      respectively. The between-day variance was generally below 3% (RSD).

PMID- 10416063
TI  - Simultaneous measurement of dopamine, serotonin, their metabolites and tryptophan
      in mouse brain homogenates by high-performance liquid chromatography with dual
      coulometric detection.
AB  - A new rapid and sensitive high-performance liquid chromatography (HPLC) method
      for the simultaneous determination of dopamine, 3,4-dihydroxyphenylacetic acid
      (DOPAC), 3-methoxytyramine, 5-hydroxytryptamine (serotonin), 5
      hydroxyindoleacetic acid (5-HIAA), homovanillic acid and tryptophan has been
      developed and applied to mouse frontal cortex, caudate nucleus and dorsal raphe
      assays. A dual coulometric detector was used with detection at +0.25 and +0.55 V,
      which allowed the determination of tryptophan. Detection limits for all compounds
      (0.8-9.0 pg per injection, depending on the compounds) were useful for this
      application. Owing to great sensitivity of the method, the brain tissue samples
      can be very small, less than 2 mg. Linearity of standards was excellent (r >
      0.999 in all cases). Intraday and interday precisions for samples analytes were
      generally acceptable (intraday assay CV < 8.7% and interday assay CV < 7.0%
      except for DOPAC and 5-HIAA, which was 11.4% for the low concentrations). Average
      recoveries of standard additions to sample analytes were > 90%. Attention was
      paid to stability of standard and sample analytes when stored at +4 degrees C or
      at -70 degrees C with two different homogenizing agents (0.1 M HClO4 with 10(-7)
      M ascorbic acid and 0.05 M HClO4 without ascorbic acid). This simple, rapid and
      efficient method can be used as a basic research tool for modification of brain
      neurotransmitters in experimental pharmacological protocols for following
      psychotropic drug treatments in animals.

PMID- 10416064
TI  - Chromatographic assay and pharmacokinetic studies of propofol in human serum.
AB  - A high-performance liquid chromatographic system with automated precolumn
      extraction was developed for the determination of propofol in human serum.
      Propofol of directly injected serum sample was enriched on a protein-coated mu
      Bondapak phenyl precolumn while serum constituents such as proteins and salts
      were eluted to waste. Thereafter, using an on-line column-switching system, the
      drug was quantitatively transferred and separated on a second analytical column
      followed by spectrophotometric determination at 270 nm. Good precision, accuracy
      and linearity were obtained over a range of 30-3000 ng/mL propofol in human
      serum. The developed method proved to be fast, simple, reproducible, reliable and
      therefore convenient for propofol monitoring from serum. The recovery of propofol
      in serum samples from the lowest to the highest concentration ranged from 96.84
      to 100.16% (n = 5). The assay was applied to study the pharmacokinetic of the
      drug in six women undergoing elective caesarean section under general anaesthesia
      induced with a single intravenous bolus dose of propofol (2.5 mg/kg).

PMID- 10416065
TI  - Experimental model for optimization of hydrophobic interaction: chromatographic
      purification of glucagon.
AB  - The chromatographic behavior of the components of glucagon-containing material
      from bovine pancreas by hydrophobic interaction on Amberlite XAD-7 was
      investigated. The effect of initial ionic strength and pH of the mobile phase on
      selectivity was quantitatively determined. The data, obtained from 56
      experiments, were used for modeling and the corresponding management of the
      purification process. The purified glucagon is of very high quality: total
      impurities are not more than 1.7% as determined by analytical HPLC. The
      biological activity is 1.08 IU/mg, calculated for dry substance.

PMID- 10416066
TI  - Validation of a high-performance liquid chromatography assay for quantification
      of caffeine and paraxanthine in human serum in the context of CYP1A2 phenotyping.
AB  - In this study the validation of a reversed-phase high-performance liquid
      chromatography (HPLC) method, with UV-detection, for both caffeine and
      paraxanthine in human serum is described. This method is feasible for cytochrome
      P450 1A2 (CYP1A2) phenotyping, according to the results of a pilot study. With
      this HPLC method caffeine and paraxanthine can be determined selectively and
      specifically. In the expected concentration range, caffeine recoveries were 98
      108% (within-run variation 4.0-6.4%, between-run variation 6.4-8.8%),
      paraxanthine recoveries were 96.6-97.5% (within-run variation 5.0-7.2%, between
      run variation 7.2-10.8%). The limits of detection for caffeine and paraxanthine
      using this HPLC system were 0.3 and 0.1 mg/L, respectively. Linear calibration
      curves for both caffeine and paraxanthine were obtained in the concentration
      range 0.5-30 mg/L (r > 0.9999. Serum samples were stable for a week, when stored
      at -20 and +4 degrees C.

PMID- 10416067
TI  - Intubation not for guinea pigs.

PMID- 10416068
TI  - Cow level sampling factors affecting analysis and interpretation of milk urea
      concentrations in 2 dairy herds.
AB  - The goals of this study were to determine the influence of the variations among
      udder quarters, the somatic cell count, the time of sampling during the day,
      sample conservation, and centrifugation on milk urea (UREA) concentrations, and
      to propose a sample collection procedure for herds that are not on a Dairy Herd
      Improvement (DHI) program. Forty cows from 2 herds with different feeding
      practices were randomly selected. The quarter sampled and the somatic cell count
      did not significantly influence UREA concentrations. Milk urea concentrations
      were highest in the morning. The diurnal pattern was not influenced by intrinsic
      factors like parity, days postpartum, or daily milk yield. The UREA
      concentrations were significantly higher after refrigeration for one week (mean
      UREA change = +0.41 +/- 0.24 mmol/L, P = 0.0001) and freezing for one month (mean
      UREA change = +1.52 +/- 1.25 mmol/L, P = 0.0001). Urea concentrations were
      slightly higher in lactoserum than in whole milk (mean UREA difference = +0.17 +/
      0.24 mmol/L, P = 0.0001). Although this study included only 2 herds and does not
      allow extrapolation, differences were found in the diurnal pattern of UREA in
      these 2 herds, which possibly reflect differences in feeding strategy. With
      consideration of these results, a 6-point sampling procedure for herds that are
      not on a DHI program is proposed.

PMID- 10416069
TI  - Hematology and serum chemistry of captive juvenile double-crested cormorants
      (Phalacrocorax auritus).
AB  - Hematologic and serum chemical values were obtained for double-crested cormorants
      (Phalacrocorax auritus) to improve clinical diagnosis of disease in this species.
      Blood samples were collected from 20 captive double-crested cormorants at 4 to 6
      weeks of age. Hematocrit and leukocyte concentrations were determined in
      heparinized blood. Concentrations of sodium, potassium, chloride, bicarbonate,
      calcium, phosphorus, creatinine, glucose, uric acid, total protein, and albumin,
      and the activity levels of alkaline phosphatase, creatinine kinase, and aspartate
      aminotransferase were determined in serum. Total leukocyte concentrations in
      these double-crested cormorants were higher than the limited ranges reported for
      cormorants of other species, possibly due to subclinical infection with the liver
      trematode Amphimerus elongatus, and to differences in species and age.

PMID- 10416070
TI  - An unusual congenital abnormality.

PMID- 10416071
TI  - Profound postanesthetic hypoglycemia attributable to glucocorticoid deficiency in
      2 dogs.
AB  - Glucocorticoid deficiency was diagnosed as the cause of severe postanesthetic
      hypoglycemia in 2 dogs. Prior signs of systemic illness were not described in
      either dog; however, preoperative hematologic findings were consistent with
      glucocorticoid deficiency. Fasting hypoglycemia is a possible complication of
      chronic adrenal insufficiency primarily because of impaired gluconeogenesis.

PMID- 10416072
TI  - Staphylococcus intermedius cellulitis and toxic shock in a dog.
AB  - A Labrador retriever was examined for sudden lameness and cellulitis of the right
      forelimb. Bacterial culture of the dermis yielded a large number of
      Staphylococcus intermedius. The association of this bacterium with toxic shock is
      discussed.

PMID- 10416073
TI  - Factor VII deficiency in a mixed breed dog.
AB  - Abnormal bleeding following routine orchectomy of a 5-month-old mixed breed was
      determined to be due to factor VII deficiency. Although pedigree information was
      unavailable, failure to respond to vitamin K therapy and the absence of a plasma
      coagulation inhibitor suggested that the factor VII deficiency was likely
      inherited rather than acquired.

PMID- 10416074
TI  - Listeriosis in a Holstein cow.
AB  - Bovine listeriosis is a sporadie bacterial infection most commonly manifested by
      encephalitis or meningoencephalitis in adult animals. Cattle fed poorly fermented
      haylage or corn silage are at increased risk. Mortality is high without early
      antibiotic and supportive therapy. Listeria monocytogenes can affect many species
      and is a public health concern.

PMID- 10416075
TI  - [Report on the state of animal sanitation in Canada].

PMID- 10416076
TI  - Yield--merge ahead!

PMID- 10416077
TI  - Diagnostic ophthalmology.

PMID- 10416078
TI  - [Optimization of therapy. News in oncology and in management of infectious
      diseases].

PMID- 10416079
TI  - MRI findings in lumbar puncture headache syndrome: abnormal dural-meningeal and
      dural venous sinus enhancement.
AB  - Intracranial hypotension (IH) is a treatable cause of persistent headaches.
      Persistent cerebrospinal fluid (CSF) leak at a lumbar puncture (LP) site may
      cause IH. We present postcontrast MRI of a patient with post-lumbar-puncture
      headache (LPHA) showing abnormal, intense, diffuse, symmetric, contiguous dural
      meningeal (pachymeningeal) enhancement of the supratentorial and infratentorial
      intracranial dura, including convexities, interhemispheric fissure, tentorium,
      and falx. MRI also showed abnormal dural venous sinus enhancement, a new finding
      in LPHA, suggesting compensatory venous expansion. Thus, IH and venodilatation
      may play a role in the development of LPHA.

PMID- 10416080
TI  - Value of CT angiography in the evaluation of a peripheral anterior inferior
      cerebellar artery aneurysm: case report.
AB  - We report a case of a peripheral anterior inferior cerebellar artery (AICA)
      aneurysm in a 66-year-old woman. Computed tomography angiography (CTA)
      demonstrated a saccular aneurysm in the left AICA. A subsequent vertebral digital
      subtraction angiography using our standard injection technique failed to
      demonstrate the aneurysm. However, the aneurysm was visualized on a follow-up
      injection performed with an increased contrast dose and injection rate. CTA
      proved to be critical in the detection of this aneurysm which could have been
      easily overlooked on a conventional angiogram.

PMID- 10416081
TI  - Intrapericardial bronchogenic cyst: assessment with magnetic resonance imaging
      and transesophageal echocardiography.

PMID- 10416082
TI  - Metallic artifacts of coronary and iliac arteries stents in MR angiography and
      contrast-enhanced CT.
AB  - Metallic artifacts of intravascular stents were assessed with MR angiography and
      contrast-enhanced spiral CT. Stainless steel showed less metal artifact than
      tantalum stent in CT. Metallic artifact in coronary and iliac arteries treated
      with tantalum stent was not remarkable in MR angiography. Contrast-enhanced CT
      might be preferable to assess patency of arteries treated with stainless steel
      stent. while MR angiography was useful in depicting intraluminal signal in
      tantalum stent.

PMID- 10416083
TI  - Multiple nodular metastases in mesenteric panniculitis by uterine papillary
      serous adenocarcinoma (UPSC): CT appearance of a case.
AB  - Intra-abdominal panniculitis is a thickening of the mesentery of the small/large
      intestine due to infiltration of lipid-laden macrophages associated with a
      variable amount of fibrosis. This condition is rarely associated with malignant
      neoplasms. We report the computed tomography (CT) findings of a patient treated
      for uterine papillary serous adenocarcinoma (UPSC). She had mesenteric
      panniculitis where metastatic tumor nodules implanted. This was the only
      intraperitoneal recurrence. To our knowledge, no such finding has been reported
      in the gynecologic and radiologic literature to date. On CT images, the
      differential diagnosis is with cystic dilatations of mesenteric lymph vessels.

PMID- 10416084
TI  - Pedunculated exogastric leiomyosarcoma: case report and brief literature review.
AB  - A case report and review of the literature on pedunculated exogastric
      leiomyosarcomas are presented. Although about one-fourth of the stromal tumors
      (common leiomyomas and leiomyosarcomas) of the stomach grow in an exogastric
      configuration, pedunculated exogastric leiomyosarcomas are extremely rare. At
      present there is no evidence of intraperitoneal seeding from exogastric
      leiomyosarcomas. Consequently, a local resection with an adequate margin is
      sufficient when no invasion to the adjacent structures, is observed.

PMID- 10416085
TI  - Inferior vena cava hypoplasia with intrahepatic venous continuation: sonographic,
      angiographic and MR features including MR angiography.
AB  - In cases of inborn or acquired obstacles on the inferior vena cava (IVC), the
      derived blood flow usually goes through collaterals in the azygos or the
      hemiazygos venous systems. Exceptionally, a collateral pathway through the portal
      system or through an anastomosis in between hepatic veins, shunting the IVC
      interruption, is encountered. In the present paper, the authors describe the
      fortuitous discovery of a IVC hypoplasia in its retrohepatic segment. MR
      venography, correlated with fluoroscopic angiography, clearly depicted an
      intrahepatic collateral circulation consisting of a double aneurysmal
      communication between an inferior right hepatic vein and the main right hepatic
      vein.

PMID- 10416086
TI  - Interventional radiology in percutaneous management of bile duct obstruction:
      biliary drainage through a spontaneous common hepatic duct-duodenal fistula.
AB  - Bile duct injuries are a serious complication of biliary surgery. We report a
      case of benign obstruction of the common hepatic duct associated with common
      hepatic duct-duodenal spontaneous fistula following complex surgical
      intervention. We managed percutaneously the fistula with balloon dilatation and
      long-term stenting, as the fistula allowed biliary flow in the duodenum. We
      avoided reintervention preserving biliary flow, with good clinical results after
      a follow-up of a 3 years. We emphasize the role of a clinically focused approach
      to percutaneous management of complications following biliary surgery.

PMID- 10416087
TI  - Optimal scan delay of arterial phase scanning of hepatic CT using a real-time
      image reconstruction system.
AB  - To optimize scan delay of arterial phase scanning of hepatic CT, 30 patients
      suspected of having HCC were examined using real-time image reconstruction
      technology (SureStart). In all cases, SureStart was successful. Despite the low
      dose, these images allowed adequate visualization of the abdominal aorta. The
      mean delay from the initiation of contrast administration to the beginning of
      arterial phase scanning was 29.6 +/- 5.2 sec (mean +/- SD; range, 22-51 sec).

PMID- 10416088
TI  - Hemangioendothelioma of the spleen: imaging findings at color Doppler, US, and
      CT.
AB  - The ultrasonographic, color Doppler, and computed tomography findings of an
      unusual vascular primary tumor of the spleen are reported. A brief clinical and
      histopathological analysis of this entity is discussed and the differential
      diagnosis of other primary lesions of the spleen is attempted.

PMID- 10416089
TI  - Collecting duct carcinoma arising in a solitary kidney: imaging findings.
AB  - Collecting duct carcinoma is an aggressive malignancy derived from the renal
      medulla. Imaging features suggestive of this diagnosis include a medullary
      origin, hypovascularity, and an infiltrative growth pattern. A case of collecting
      duct carcinoma with unsuspected contralateral renal agenesis is presented.

PMID- 10416090
TI  - Correlation of gallium-67 SPECT and CT findings in primary gynecologic lymphoma.
AB  - Primary gynecologic malignant lymphomas are rare and gallium (Ga)-67 imaging has
      proven to be useful to differentiate viable lymphoma from fibrotic or necrotic
      tissue. Computed tomographic (CT) scan is often used in initial localization and
      staging of the lymphoma. In this study, we retrospectively analyzed the findings
      of Ga-67 single photon emission computed tomography (SPECT) correlated with those
      of CT scan for staging initial disease and also differentiation between active
      lymphoma and post-treatment changes in the follow-up studies.

PMID- 10416092
TI  - Meniscal cysts causing bone erosion: retrospective analysis of seven cases.
AB  - Meniscal cysts of the knee are common and well evaluated by magnetic resonance
      (MR) imaging, a method that also reveals the frequently associated meniscal tear.
      Diagnosis of meniscal cysts with routine radiography is difficult, although bone
      erosions are reported as a very rare manifestation of such cysts. Our
      retrospective study describes seven patients in whom meniscal cysts were
      associated with adjacent erosion of bone.

PMID- 10416091
TI  - Spinal involvement of hematopoietic malignancies and metastasis: differentiation
      using MR imaging.
AB  - The purpose of this study was to determine the usefulness of magnetic resonance
      imaging (MRI) for distinguishing spinal involvement of hematopoietic malignancies
      (lymphoma, leukemia, and multiple myeloma) from metastasis. 62 spinal MRIs were
      obtained in 60 patients with hematopoietic malignancies (n = 24) and metastasis
      (n = 36) in clinically and pathologically proven cases. MRI findings were
      evaluated in each group of patients for the pattern of involvement, signal change
      of vertebral body, location of paraspinal mass formation, location of epidural
      mass formation, cortical destruction, contour change, and compression fracture.
      Diffuse involvements were more commonly seen in hematopoietic malignancies than
      in metastasis (p < 0.05). Signal change confined to anterior element was seen in
      9 metastasis but was not seen in hematopoietic malignancies. Cortical
      destructions were more commonly seen in metastasis than in hematopoietic
      malignancies (p < 0.05). Other findings did not show any statistical significance
      in both groups. MRI findings such as diffuse involvement, posterior epidural mass
      formation, and cortical destruction were useful to distinguish spinal involvement
      of hematopoietic malignancies and metastasis.

PMID- 10416093
TI  - Acute or subacute cranial computed tomography findings in patients with
      congenital lactic acidemia.
AB  - Two patients with congenital lactic acidemia of unknown etiology developed
      striking and extensive cranial computed tomography abnormalities of acute or
      subacute onset. In addition to Leigh syndrome and MELAS (mitochondrial
      encephalomyopathy, lactic acidosis, and stroke-like episodes), other lactic
      acidemia disorders may produce evolving cerebral radiographic abnormalities. An
      aggressive effort should be made in such patients to obtain a specific diagnosis
      through biochemical and molecular genetic studies.

PMID- 10416094
TI  - Late cognitive effects of early treatment with phenobarbital.
AB  - We previously reported that IQ was significantly lowered in a group of toddler
      aged children randomly assigned to receive phenobarbital or placebo for febrile
      seizures and there was no difference in the febrile seizure recurrence rate. We
      retested these children 3-5 years later, after they had entered school, to
      determine whether those effects persisted over the longer term and whether later
      school performance might be affected. On follow-up testing of 139 (of the
      original n = 217) Western Washington children who had experienced febrile
      seizures, we found that the phenobarbital group scored significantly lower than
      the placebo group on the Wide Range Achievement Test (WRAT-R) reading achievement
      standard score (87.6 vs 95.6; p = 0.007). There was a nonsignificant mean
      difference of 3.71 IQ points on the Stanford-Binet, with the phenobarbital
      treated group scoring lower (102.2 vs 105.7; p = 0.09). There were five children
      in our sample with afebrile seizures during the 5-year period after the end of
      the medication trial. Two had been assigned to phenobarbital, and three had been
      in the placebo group. We conclude there may be a long-term adverse cognitive
      effect of phenobarbital on the developmental skills (language/verbal) being
      acquired during the period of treatment and no beneficial effect on the rate of
      febrile seizure recurrences or later nonfebrile seizures.

PMID- 10416095
TI  - Chest radiographs in the pediatric emergency department for children < or = 18
      months of age with wheezing.
AB  - There are no widely accepted predictors of pneumonia in wheezing infants and
      toddlers who present to the emergency department (ED). A 10-month retrospective
      review of ED visits of wheezing children < or = 18 months of age revealed the
      following chest radiograph (CXR) results: normal (21%), findings consistent with
      uncomplicated bronchiolitis or asthma (61%), focal infiltrates (18%), and other
      abnormalities (< 1%). Patients with focal infiltrates on CXR were more likely to
      have the following: a history of fever (p = 0.03, OR 2.1, 95% CI 1.0, 4.4),
      temperature > or = 38.4 degrees (p = 0.01, OR 2.5, 95% CI 1.1, 5.8) or crackles
      on examination (p < 0.0005, OR 3.9, 95% CI 1.7, 9.0). Selective use of CXRs has
      the potential to save health care dollars and limit unnecessary radiation.

PMID- 10416097
TI  - Home schooled children: a pediatric perspective.
AB  - To explore the attitudes and self-assessed knowledge of pediatricians regarding
      home schooling and determine whether practices provide preventive services
      typically rendered by the school system, we surveyed pediatricians in Wisconsin
      and Maryland (high versus low rates of home schooling, respectively). Of the 598
      (53%) responding, only 18% supported home schooling. They judged home-schooled
      children to perform at an average (58%) or below average (12%) level on
      standardized tests and regarded them to be less mature than their peers (51%).
      These opinions differ from studies published in the educational literature. Many
      practitioners do not perform routine vision (18%) or hearing (83%) screens or
      monitor for overdue immunizations (71%). As pediatricians and child advocates, we
      need to become more knowledgeable about home schooling and provide preventive
      services for these children.

PMID- 10416096
TI  - Back pain in children who present to the emergency department.
AB  - The purpose of this study was to identify the causes and epidemiology of back
      pain in children who present to the emergency department. All children who
      presented to an urban pediatric emergency department (ED) during a 1-year period
      with the chief complaint of back pain were examined and evaluated with a uniform
      questionnaire. This was completed at the time of the ED visit in 48%, and within
      48 hours in 52%. During a 1-year period, 225 children with a complaint of back
      pain were evaluated. The mean age was 11.9 +/- 4 years and 60% were female. Onset
      was acute (< or = 2 days) in 59%, and chronic (> or = 4 weeks) in only 11.6%.
      Pain awakened children from sleep in 47%, and caused 52% to miss school or work.
      The most common diagnoses were direct trauma (25%), muscle strain (24%), sickle
      cell crises (13%), idiopathic (13%), urinary tract infection (5%), and viral
      syndrome (4%). Radiographs of the back were rarely helpful. About 5% required
      hospital admission; one half of these were attributed to sickle cell crises. We
      conclude that back pain is an uncommon reason for children to present to an
      emergency department. When present, pediatric back pain is most often
      musculoskeletal, associated with an acute infectious illness or a traumatic
      event. Although the etiology is rarely serious, back pain often affects the daily
      activities of symptomatic children.

PMID- 10416098
TI  - Neonatal pelvic mass. Neonatal ovarian torsion.

PMID- 10416099
TI  - Invasive group A streptococcal disease in children.

PMID- 10416101
TI  - Eikenella corrodens: a rare pathogen in a polymicrobial hepatic abscess in an
      adolescent.

PMID- 10416100
TI  - Long-term ocular complication of Stevens-Johnson syndrome.

PMID- 10416102
TI  - Safety of gentamicin administered by intravenous bolus in the nursery.

PMID- 10416103
TI  - Abnormal calcification on plain radiographs of the abdomen.
AB  - The purpose of this pictorial review is to facilitate recognition and
      understanding of calcifications seen on conventional radiographs of the abdomen.
      Calcifications can be categorized by organ system and location in the abdomen.
      Both common and rare calcifications in the urinary tract, liver, gallbladder,
      spleen, pancreas, adrenal glands, digestive tract, genital tract, peritoneal
      cavity, and retroperitoneum are illustrated. Abnormal calcifications in the
      urinary tract are subcategorized by kidneys, ureters, bladder, and urethra. The
      density, shape, size, margins, pattern, position, and mobility of calcifications
      are emphasized for differential diagnoses.

PMID- 10416104
TI  - [The liver and brucellosis].

PMID- 10416105
TI  - [Hepatocyte dysplasia: pre- or peri-neoplastic lesion?].

PMID- 10416106
TI  - [Risk factors of contamination by hepatitis C virus. Case-control study in the
      general population].
AB  - In 30% of patients with hepatitis C virus, the source of infection is unknown.
      OBJECTIVE: To identify the risk factors of infection by hepatitis C virus in a
      case-control study. METHODS: Cases had positive hepatitis C virus serology, and
      were living in Fecamp (Normandy, France). Controls (2 for each case) were age and
      sex-matched subjects with negative hepatitis C virus serology, living in Fecamp.
      Demographic, medical, professional, and environmental data were collected.
      Statistical analysis included chi 2 or Fisher's exact test and multiple logistic
      regression. RESULTS: The risk factors of hepatitis C virus by univariate analysis
      were: history of transfusion, high number of sexual partners, hepatitis C virus
      infection in a relative, history of digestive or genitourinary surgery, an
      invasive medical procedure, digestive endoscopy, biopsy, lumbar or pleural
      puncture, medical care after an accident, injections, multiple deliveries or
      abortion. Risk factors of hepatitis C virus infection by multivariate analysis:
      hepatitis C virus infection in a relative (Odds ratio: 4.58), history of
      transfusion (Odds ratio: 2.32), of a surgical procedure (Odds ratio: 2.50), of
      medical care after an accident (Odds ratio: 1.51), of injections (Odds ratio:
      2.24). CONCLUSION: Our results suggest the possible nosocomial transmission of
      hepatitis C virus. Intrafamilial transmission is also possible.

PMID- 10416107
TI  - [Fall in the seroprevalence of hepatitis A in French youth].
AB  - OBJECTIVE: An anti-hepatitis A virus seroprevalence survey was performed in 1997
      in 1052 French army recruits (mean age: 21.2 years). To describe epidemiological
      trends, the current pattern was compared to previous results obtained by similar
      methods in 1985, 1990 and 1993. RESULTS: In 1997, overall anti-hepatitis A virus
      seroprevalence was 11.5%. The greatest risk factor of hepatitis A infection was
      related to travel in intermediate or highly endemic areas for hepatitis A virus:
      46% of overseas residents (odds ratio = 10.3), 28% of recruits who had travelled
      in developing countries (odds ratio = 3.7) and 7.65% of French living in
      industrialised countries are anti-hepatitis A virus antibody positive. Moreover,
      seroprevalence was higher in subjects with a history of icteria (adjusted odds
      ratio = 3.5) and families with at least 3 children (adjusted odds ratio = 3). No
      association was found with drinking water, socioeconomic status such as
      baccalaureat degree, or parents profession. The seroepidemiological shift of
      hepatitis A, as assessed in three previous studies, shows a marked decrease of
      20% in 12 years from 30.4% in 1985, to 21.3% in 1990, to 16.3% in 1993, and to
      11.5% in 1997. The decrease in the prevalence of anti-hepatitis A virus was more
      marked in young adults who had never travelled in endemic countries (decrease of
      20%) than those who had visited or lived in developing countries (decrease of
      10%). CONCLUSION: Although France is not highly endemic for hepatitis A thanks to
      improved hygiene and housing conditions over the past 20 years, a pattern of
      intermediate endemicity was seen in French overseas areas in which the risk of
      outbreaks of hepatitis A was higher. The decrease in anti-hepatitis A virus
      seroprevalence in French youth can be used to draft a public health policy for
      hepatitis A control.

PMID- 10416109
TI  - [Are endoscopic treatments of pain during chronic pancreatitis justified].

PMID- 10416108
TI  - [Prophylactic vaccination against hepatitis B: present and future].

PMID- 10416110
TI  - [Pancreatic intubation by endoscopy in chronic calcifying pancreatitis].
AB  - BACKGROUND: The aim of our study was to assess the efficacy of endoscopic
      pancreatic stenting on pain and frequency of acute pancreatitis in patients with
      calcifying chronic pancreatitis. PATIENTS: Between 1987 and 1996, 70 patients
      underwent endoscopic management for calcifying chronic pancreatitis. RESULTS:
      Endoscopic stent placement was successful in 59 patients (85%). 46 patients were
      followed for a mean duration of 29 +/- 26.4 months after stent removal. The
      presence of pancreatic pseudocysts in 26 patients appeared to modify pain
      improvement rate but did not influence the decrease in the frequency of acute
      pancreatitis. An improvement of pancreatic pain occurred at the end of stenting
      and after removal of the stent in respectively 44% and 38% of the patients
      without pseudocysts and in 85% (P < 0.02) and 65% of the patients presenting with
      pancreatic pseudocysts. Before stenting, 43/70 (61%) patients had at least two
      episodes of acute pancreatitis. After removal of the stent, only 5/46 (11%) had
      one episode of acute pancreatitis. Improvement of weight loss and diabetes was
      observed in respectively 28 cases (52%), 7 cases (39%) at the end of pancreatic
      stenting and was still persisting in 21 (51%) and 5 cases (26%) after removal of
      the stent. CONCLUSION: After pancreatic stenting, the improvement of pain appears
      to be moderate in the absence of pancreatic pseudocyst. Nevertheless, the
      improvement of pain is maintained after stent removal. Moreover, the frequency of
      acute pancreatitis is significantly decreased after pancreatic stenting.

PMID- 10416111
TI  - [Excluded rectum during Crohn's diseases: what is the risk of dysplasia?].
AB  - OBJECTIVES: An excluded rectum may be at risk of carcinoma in the course of
      Crohn's disease. Surveillance of patients requires detection of dysplasia. The
      aim of our study was to determine the frequency of dysplasia from secondary
      proctectomy specimens in active rectal Crohn's disease. METHODS: Twenty three
      patients (13 women and 10 men, median age 38 years) were studied. The median
      duration of rectal exclusion was four years. Detection of dysplasia relied upon
      histopathology. Immunohistochemistry with MIB-1 (Ki-67) and anti-p53 (clone DO7)
      antibodies was performed as well. RESULTS: Frequency of dysplasia was 30%. This
      was low grade dysplasia, focally observed in proctectomy specimens. MIB-1 was
      positive on 46% of dysplastic cells. There was no expression of p53 protein.
      CONCLUSIONS: These results must be taken into account for decision of secondary
      proctectomy, in patients having an excluded rectum for Crohn's disease, when
      ileorectal anastomosis is not possible. Rectal endoscopic surveillance is
      advisable with multiple biopsies according to focal distribution of dysplasia.

PMID- 10416112
TI  - [Cost of early management of chronic inflammatory intestinal disease].
AB  - OBJECTIVES: The aim of this study was to assess the cost of the first management
      of inflammatory bowel disease (IBD) from the onset of first symptoms until 6
      weeks after the diagnosis. This cost was calculated in French francs (FF) for all
      IBD and namely for Crohn's disease (CD), ulcerative colitis (UC), and ulcerative
      proctitis (UP). MATERIAL AND METHODS: Data concerning 258 patients were collected
      by the mean of a standardized questionnaire from 3 different sources: the
      patient, his general practitioner, and his gastroenterologist. RESULTS: Two
      hundred and fifty eight patients were included: 144 CD (55.8%), 76 UC (29.5%), 30
      UP (11.6%), and 8 chronic unclassifiable colitis (CUC) (3.1%). The mean direct
      costs of the diagnosis (m +/- SD) were 23,116 +/- 40,820 FF for CD, 10,628 +/-
      17,316 FF for UC and 3,451 +/- 2,743 FF for UP. Although unplanned
      hospitalizations occurred in only 38% of the patients (98/258), they represented
      the 3/4 of the mean costs: 78.2% for CD and 64% for UC. Indirect costs generated
      by days off work were 4,719 +/- 6,610 FF for CD, 2,996 +/- 6,897 FF for UC and
      1,230 +/- 3,622 FF for UP. CONCLUSION: The first management of a patient with CD
      was twice more expensive than the one with UC and 6.5 times than the one with UP.

PMID- 10416113
TI  - [Quality of life in patients with colorectal cancer].

PMID- 10416114
TI  - [What can be done for digestive cancer in 1999? Recommendations of the French
      Foundation of Digestive Cancer (1st Part)].

PMID- 10416115
TI  - [Hepatic brucelloma: 2 cases and a review of the literature].
AB  - We report two new cases of hepatic brucelloma in addition to the 22 previously
      reported cases in the literature. Our analysis of these cases reveals certain
      characteristics. Hepatic brucelloma is a rare localization that follows
      previously undetected acute brucellosis. Brucelloma is a result of caseification
      of a granulomatous reaction induced by persistent Brucella in macrophages.
      Clinical manifestations can mimic malignant liver tumors or pyogenic, amebic
      liver abscess. Diagnosis is based on the association of characteristic imaging
      features (central calcification and peripheral necrotic areas), positive serology
      and hepatic granulomas. Brucella is rarely isolated in the blood or liver.
      Awareness of this clinical variant can prevent unnecessary laparotomy. Treatment
      should begin with rifampicine (900 mg per day) and doxycyclin (200 mg per day)
      for 3 months. If medical treatment is unsuccessful, percutaneous or surgical
      drainage should be performed. A cure should be achieved in all cases.

PMID- 10416116
TI  - [Reoperation for recurrent cholangitis due to a defect in the hepatico-jejunal
      anastomosis].
AB  - We report three cases of postoperative recurrent cholangitis due to a defective
      hepaticojejunal anastomosis. Causal diseases were alveolar echinococcosis of the
      liver, alcoholic chronic pancreatitis, liver colorectal metastases. Clinical
      presentation included major cholestasis and cachexia. Imaging explorations showed
      that cholangitis was due to an inversion of the Roux-en-Y jejunal loop which had
      been disposed in a wrong position. Clinical improvement was remarkable after
      reoperation and replacement of the defective loop in the right position. This
      exceptional cause of postoperative cholangitis after Roux-en-Y hepaticojejunal
      anastomosis must be identified and treated by prompt restorative surgery.

PMID- 10416117
TI  - [Rectal leiomyosarcoma. 4 new cases].
AB  - We report four cases of leiomyosarcoma of the rectum suspected by endoscopic
      ultrasonography. Three patients were treated by local excision and one by
      abdominoperineal resection. An excision of the mass via a Kraske's approach was
      used. Leiomyosarcoma confined to the rectum wall can be treated by local
      excision. Endosonography can provide exact estimation of the lesion and is of
      great value in selecting the appropriate treatment. The treatment is surgical
      excision with wide margins. The histological stage and the presence or absence of
      metastases determine the therapeutic. Two patients in our series underwent
      radiation therapy. Chemotherapeutic agents including doxorubicin have had
      beneficial effect on recurrence or survival, only for higher grade sarcomas.

PMID- 10416118
TI  - [Malignant pancreatic non-hodgkin's lymphoma manifesting as severe acute
      pancreatitis].
AB  - Primary non-Hodgkin's lymphoma of the pancreas is a rare disease. Its diagnosis
      is difficult without histological examination. In fact, clinical and imaging
      findings are not pathognomonic. Acute pancreatitis associated with pancreatic
      lymphoma is extremely rare. We have found only 7 case reports in literature. We
      report herein a new case of pancreatic lymphoma which was revealed by a severe
      pancreatitis.

PMID- 10416119
TI  - [Regression of Polycythemia and elevated serum erythropoietin after resection of
      hepatocellular carcinoma].

PMID- 10416120
TI  - [Gait disorders secondary to azathioprine treatment in 2 patients with Crohn's
      disease].

PMID- 10416121
TI  - [Cystic epidermoid carcinoma of the pancreas].

PMID- 10416122
TI  - [Pancreatic localization of Castleman's tumor].

PMID- 10416123
TI  - [Pancreatic metastasis of a renal adenocarcinoma manifesting as steatorrhea].

PMID- 10416124
TI  - [Treatment of chronic hepatitis C: interferon alpha-2b alone or in combination
      with ribavirin].

PMID- 10416125
TI  - [Is PPAR-gamma (peroxisome proliferator-activated receptor-gamma) implicated in
      the negative regulation of monocyte-macrophage activity?].

PMID- 10416126
TI  - Induction of intracellular arginase activity does not diminish the capacity of
      macrophages to produce nitric oxide in vitro.
AB  - The hypothesis was tested that induction of arginase expression in macrophages (M
      phi) diminishes nitric oxide (NO) synthesis due to intracellular competition
      between arginase and inducible nitric oxide synthase (iNOS) for L-arginine (L
      arg). Murine M phi cell lines and bone marrow-derived M phi (BMM) were stimulated
      to express either iNOS or arginase or to co-express these two enzymes. The
      response pattern obtained was complex but allowed the following conclusions: (i)
      iNOS and arginase are differentially regulated. (ii) High intracellular arginase
      levels do not limit the capacity of M phi to synthesize NO even when the L-arg
      concentration in the culture medium is lowered to physiological levels. (iii)
      Arginase levels in BMM pre-exposed to either M phi colony-stimulating factor (M
      CSF) or granulocyte-M phi colony-stimulating factor (GM-CSF) differ markedly, but
      iNOS expression and NO synthesis by the two BMM types is similar. (iv) Regulation
      of iNOS and arginase differs between primary murine bone marrow M phi and murine
      M phi cell lines. (v) Arginase activity appears to be inhibited during high
      output NO synthesis. Taken together, our results show that NO production by M phi
      is not compromised by conditions that increase intracellular arginase activity.

PMID- 10416128
TI  - Monoclonal autoantibodies from patients with autoimmune diseases: synovial fluid
      B lymphocytes of a patient with rheumatoid arthritis produced an IgG lambda
      antibody recognizing J-sequences of Ig kappa chains in a conformation-dependent
      way.
AB  - Synovial fluid B cells from a patient with seronegative rheumatoid arthritis were
      immortalized by electrofusion. The specificity of clone FKN-E12 (IgG1 lambda) was
      analysed by screening a phage display random peptide library. One heptamer
      sequence was identified (RASFp1 = HLTFGPG). Three human IgG kappa antibodies
      contained a highly homologous sequence (xLTFGPG) at the junction of V- and J
      regions. Homologies were also found in distinct humans (J kappa 3, J kappa 4) and
      murine (J kappa 5) J kappa-sequences (TFGPG, LTFGxG), and to a lower degree in
      all remaining J kappa-sequences (TFGxG). Binding and binding inhibition assays
      showed that FKN-E12 bound to kappa light chains tested in a conformation
      dependent way: it reacted only with IgG kappa or IgA kappa chains adhered to a
      plastic surface, but not in soluble form. In conclusion, FKN-E12 detects a
      conformational epitope on probably all kappa light chains, which could be
      definded by screening a phage library displaying linear epitopes.

PMID- 10416127
TI  - Expression of surface antigens during the differentiation of human dendritic
      cells vs macrophages from blood monocytes in vitro.
AB  - High expression of MHC antigens and adhesion/costimulation molecules is
      considered as one of the major characteristics qualifying macrophages (M) and
      dendritic cells (DC) as professional antigen presenting cells. Since accessory
      activity of M is known to be weaker than that of DC but both M or DC can
      differentiate from blood monocytes (MO) depending on culture conditions (i.e. GM
      CSF vs GM-CSF/IL-4), we investigated the kinetics of expression of MHC antigens
      and several adhesion/costimulation molecules during the differentiation of DC or
      M from blood MO. Blood MO cultured with GM-CSF consistently induced M that showed
      adherence to plastic and CD14 expression. In contrast, MO cultured with GM-CSF/IL
      4 rapidly became nonadherent, acquired DC morphology and lost CD14 expression. M
      but not DC proliferated as demonstrated by [H3]thymidine incorporation. MHC Class
      I was highly expressed in both M and DC. In contrast, MHC Class II molecules were
      significantly higher on DC compared to M. CD80 was upregulated on both DC and M
      but only on a subset of cells. CD80 expression peaked at day 3 on M and declined
      thereafter, while on DC expression increased significantly until day 10. CD86 was
      upregulated on the majority of DC and M. However, while M maintained stable
      expression of CD86 after day 3, DC progressively upregulated CD86 throughout the
      culture period. CD1a expression was initially low in both cell types and peaked
      at day 3 in M declining thereafter, while expression remained stable on DC until
      day 10. ICAM-1 expression was significantly upregulated on M when compared to DC
      at day 3. However, on M, ICAM-1 expression became undetectable by day 5 while on
      DC it increased through day 10. Similarly, CD40 was transiently expressed on M
      until day 5, while on DC it continuously increased until day 10. Finally, in
      contrast to other antigens, LFA-3 was always more strongly expressed on M than DC
      at all culture periods. Taken together, these data suggest that M showed a rapid
      but transient upregulation in the expression of adhesion/costimulation molecules,
      suggesting that maximal accessory ability is reached by M at an earlier time
      point than DC. Significant differences in surface antigen expression DC vs M were
      recognizable for MHC class II, CD86, CD80, CD1a, CD40 and ICAM-1. Specifically,
      major differences occurred for MHC class II, CD86, CD40 and ICAM-1. Therefore,
      the higher accessory ability of DC compared to M in naive T cell priming may be
      related to qualitative and quantitative differences in expression of these
      immunologically important surface molecules.

PMID- 10416129
TI  - Persistent tolerance induced after portal venous injection of allogeneic cells
      plus cyclophosphamide treatment.
AB  - The injection of allogeneic cells via the portal vein (p.v.) is known to reduce
      responses to donor-alloantigens. In the present study, we have obtained
      persistent tolerance across Mls and multiple minor histocompatibility complexes
      by p.v. preimmunization followed by the administration of cyclophosphamide (CY).
      A hundred percent survival of (BALB/c x DBA/2)F1 (CDF1) skin grafts for more than
      200 days was observed when BALB/c mice were preimmunized with spleen cells of
      CDF1 (3 x 10(7)) via the p.v. and administered 300 mg/Kg CY 2 days after the p.v.
      injection. Comparable survival of the skin graft was observed when bone marrow
      cells instead of spleen cells were p.v. preimmunized. However, the survival rate
      was significantly decreased when LPS-stimulated blastic cells were p.v.
      preimmunized. Microchimerism has been observed in the liver, thymus, bone marrow
      and peripheral blood of recipients. V beta 6+ cells decreased in CD4+ cells of
      recipients of the p.v. preimmunization plus CY treatment. However, there was no
      difference in the decrease in V beta 6+ cells between recipients accepting the
      CDF1 skin grafts and recipients that had rejected the skin grafts. Furthermore,
      no intrathymic depletion of the V beta 6+ cells was observed. From these results,
      it is suggested that, rather than clonal deletion, other mechanisms such as
      clonal anergy or suppression may be involved in the induction of persistent
      tolerance after the p.v. preimmunization plus CY treatment.

PMID- 10416130
TI  - Increased cortisol levels in human umbilical cord blood inhibit interferon alpha
      production of neonates.
AB  - Immunosuppressive effects of corticosteroids are generally known, but the
      mechanisms influencing the immune system are poorly understood. However, a
      correlation between cortisol levels and cytokine production has been reported by
      several investigators. In the present study we determined cortisol concentrations
      in human umbilical cord blood. Cord blood samples from healthy and normal term
      infants born by vaginal delivery and blood samples from healthy adult donors,
      respectively, were analysed. Our data revealed significantly increased cortisol
      levels in cord blood. In contrast, samples derived from infants born by caesarian
      section seem to be normal. Further experiments were performed to analyse the
      influence of cortisol on the production of interferon (IFN) alpha. Therefore,
      peripheral blood mononuclear cells (PBMC) were separated from peripheral blood of
      healthy adult volunteers. Cortisol was added to a final concentration of 30
      micrograms/dl as measured in cord blood. Following stimulation with Newcastle
      disease virus (NDV) the IFN-alpha release was 50 to 60% reduced compared to
      untreated controls. These data suggest that increased levels of cortisol in cord
      blood might influence the IFN-alpha response of newborns. We propose that
      cortisol levels increase transiently after birth and may alter several
      physiological as well as immunological reactions. Since cord blood is commonly
      used to investigate features of the neonatal immune system, different behaviour
      as a result of temporarily increased cortisol concentrations should be
      considered.

PMID- 10416131
TI  - Characterization of the human leukocyte GPI-anchored glycoprotein CDw108 and its
      relation to other similar molecules.
AB  - The CDw108 glycoprotein is expressed on the surface of some leukemic cell lines,
      erythrocytes and on activated lymphocytes. Its surface expression is rapidly
      upregulated following various activating stimuli (PHA, PWM, Con A, PMA, anti-CD3)
      and subsequently gradually decreases. The molecule is anchored in the membrane
      via glycosylphosphatidylinositol (GPI) moiety, it has molecular mass of 75-80 kDa
      and pI of 5.0-5.5. Endoglycosidase F and H reduce its apparent size as determined
      by SDS PAGE by approx. 15 and 22 kDa, respectively. It is a component of large,
      detergent-resistant GPI-complexes associated with protein kinases. In addition to
      the previously described identity of CDw108 with the JMH blood group antigen, we
      demonstrate here its identity to the previously described glycoprotein recognized
      by monoclonal antibodies H105 and KS.2, and exclude its identity with another GPI
      anchored glycoprotein of similar size, melanotransferrin (gp97).

PMID- 10416132
TI  - Relative abilities of 4-1BB (CD137) and CD28 to co-stimulate the response of
      cytokine deflected Th1 and Th2 cells.
AB  - In this report we show that allo-stimulated naive CD4+ cells when cultured in IL
      2, IFN-gamma, IL-12 and anti-IL-4 differentiated into Th1 cells expressing very
      low amounts of 4-1BB molecule, but high amounts of CD28. By contrast, allo
      stimulated naive CD4+ cells cultured in the presence of exogenous IL-2, IL-10, IL
      4 and anti-INF-gamma evolved into Th2 expressing high amounts of both 4-1BB and
      CD28. Various Th1/Th2 clones derived from limiting dilution also exhibited
      similar expression pattern. This differential expression of co-stimulatory
      molecules on Th subsets account for the ability of 4-1BB to trigger both the
      proliferation and production of IL-4 by Th2 cells only and for the ability of
      CD28 to trigger proliferation and typical secretion in both Th1 and Th2 cells.

PMID- 10416133
TI  - Oral tolerance by a high dose OVA in BALB/c mice is more pronounced and
      persistent in Th2-mediated immune responses than in Th1 responses.
AB  - Oral administration of antigen induces an antigen-specific immunologic tolerance
      and many studies are being carried out to apply this phenomenon to the treatment
      of autoimmune diseases. In this study, we investigated long-term Th1 and Th2
      tolerance in mice given a high dose of orally administered Ovalbumin (OVA).
      Feeding OVA to BALB/c mice suppressed OVA-specific IgG response and the degree of
      inhibition was dose-dependent in the range of 2.5-250 mg. Moreover, the state of
      tolerance established by prior feeding of high dose of OVA was present after 26
      weeks. Interestingly, even though both Th subsets were tolerized significantly
      for a short period, the tolerizing effect was more pronounced and persistent in
      Th2-mediated immune responses. Thus we speculate that oral administration of a
      single high dose of OVA induces Th1- and Th2-tolerance by different mechanisms.
      Our findings could be important in the development of therapeutics for the
      treatment of autoimmune disease and allergy.

PMID- 10416134
TI  - Basidiolipids from Agaricus are novel immune adjuvants.
AB  - The primary aim of the present study was to compare the immune adjuvanticity of
      two different groups of glycolipids, i.e., the newly discovered basidiolipids
      from Basidiomycete mushrooms (Bl-1, Bl-2, Bl-3, and Bl-4), and saponin fractions
      from Quillaja saponaria. The basidiolipids, though with differential
      effectiveness of the Bl-components, stimulated the expression of serum immune
      globulins in mice that recognized co-injected antigens, bovine serum albumin
      (BSA) or a keyhole-limpet hemocyanin-ganglioside Gfpt1 conjugate (KLH-Gfpt1),
      respectively. The immune adjuvanticity of the basidiolipids was comparable to
      that of acidic (QAS2, QAS5, QAS10), and novel neutral (QNS1, QNS2, QNS3) saponin
      compounds isolated and purified from Quillaja saponaria bark bulk material.
      Basidiolipids, as well as, the Q. saponin fractions were only marginally
      antigenic. MPL-A, by contrast, a comparable immune adjuvant, stimulated the
      expression of specific antibodies that recognized this glycophospholipid.
      Different from the Q. saponins with restricted toxicity, the basidiolipids
      displayed no toxic or hemolytic properties.

PMID- 10416135
TI  - Early rheumatoid arthritis is associated with diminished numbers of TH1 cells in
      stimulated peripheral blood.
AB  - Rheumatoid arthritis (RA) has been associated with an altered TH1/TH2 balance.
      Here we present first results with a technique to quantitate stimulated TH1 and
      TH2 subsets in whole blood by means of cytofluorimetric detection of
      intracytoplasmic TH1 and TH2 cytokines. A group of 10 patients suffering from
      initial stages of RA exhibited a significantly reduced percentage of TH1 cells
      (11.0 +/- 2.0%) in the peripheral blood as compared to 13 healthy, age matched
      controls (28.8 +/- 2.0%). The TH2 response, as determined by intracellular
      expression of IL-4, remained unchanged. The data may indicate a defect in the TH0
      TH1 differentiation or/and a selective trapping of TH1 cells into the affected
      joints.

PMID- 10416136
TI  - Longitudinal study of antibody reactivity against HIV-1 envelope and a peptide
      representing a conserved site on Gp41 in HIV-1-infected patients.
AB  - This study was designed to distinguish between antibodies in HIV-1-infected
      patients directed against epitopes accessible on the native HIV-1 envelope (Env)
      complex and non-native Env epitopes. Peptide p#13 (Env. aa642-673) containing the
      neutralising 2F5 epitope and recombinant soluble glycoprotein 160 (rsgp160) were
      used in ELISA to determine the antibody (Ab) reactivity in sera of 116 HIV-1
      infected individuals and 18 HIV negative controls. The reactivity of sera
      classified CDC stage C against p#13 was significantly decreased in comparison to
      stage A sera, while staying constant against rsgp160. Accordingly, in 6 out of 8
      individual patients tested over time the response against p#13 was declining at
      later time points of infection. The reactivity of patients' sera against p#13
      corresponded directly to the recognition of infected T cells and largely also to
      the CD4 cell count. The causal relationships of these phenomena are not clear. It
      is conceivable that antibodies against epitopes on HIV are lost or escape mutants
      arise and consequently control of HIV is lost and virus load increases as it is
      known for CDC stage C. Alternatively, increasing virus load may affect B cells
      recognising native Env epitopes and turn antibody production down by some
      mechanism. In this latter scenario helper T cells might have a critical role.

PMID- 10416137
TI  - [Pregnancy and scuba diving: what precautions?].
AB  - Scuba diving is a leisure activity increasingly popular amongst women. Many women
      are concerned about the risks associated with diving and a known or planned
      pregnancy. In order to advise these young women, we have reviewed the literature
      concerning women and diving as well as animal studies on the subject. The
      different international federations and the Undersea and Hyperbaric Medical
      Society advise against scuba diving for pregnant women or those planning a
      pregnancy, but no randomized trials or trials provide a solid scientific basis.
      The fetal circulation is characterized by the exclusion of the pulmonary
      circulation by 2 right to left shunts. As the lung appears to act as a filter
      against the progression of micro-bubbles to the main circulation, the fetus may
      be therefore particularly exposed to gas emboli. However, the placenta could play
      this role in certain animal species. Nitrox diving appears to be particularly
      promising, but studies on the subject are still insufficient to recommend it for
      pregnant women.

PMID- 10416138
TI  - [Hysterectomy for a benign lesion: can the vaginal route be used in all cases?].
AB  - OBJECTIVE: To determine which factors indicate the vaginal route cannot be used
      for hysterectomy and study the morbidity of this technique in comparison with the
      abdominal route. METHODS: A retrospective study was conducted in 682 patients who
      underwent hysterectomy for benign lesions between 1992 and 1996. Genital
      prolapses and/or urinary incontinence accounted for 31% of the indications. Mean
      patient age was 50 years. There were 75 nulliparous patients and 27% of all
      patients had a pelvic history (including cesarean section) which might compromise
      vaginal hysterectomy. RESULTS: Hysterectomy was performed via the abdominal route
      in 39.7% of the cases and via the vaginal route in 60.3% including 5.7% with
      laparoscopic assistance. Factors which dictated the abdominal route were: large
      size of the uterus (47%), pelvic background (30%), tubo-ovarian pathology (6%),
      multiple elements (6%), unknown (11%). Operation time depended on the surgical
      route, parity, pelvic background and associated techniques (prolapse,
      oophorosalpingectomy, uterine segmentation). Morbidity was very low and the same
      for both routes: 1.8% operative accidents (mainly bladder wounds), 1%
      reoperation, only one case of thromboembolism and less than 0.5% postoperative
      fever. DISCUSSION: There is no absolute contraindication to vaginal hysterectomy.
      It would appear unreasonable to an unexperienced surgeon to use the vaginal route
      for a fixed uterus with an estimated weight over 400 g in nulliparous patients
      with a pelvic background. In a department with vaginal training, 84% of all
      hysterectomies could be performed by vaginal route, because half of the
      indications for the abdominal route are excessive or a matter for laparoscopic
      assistance.

PMID- 10416140
TI  - [Clinical importance of fetal pulse oximetry. II. Comparative predictive values
      of oximetry and scalp pH. Multicenter study].
AB  - OBJECTIVE: To compare the predictive value of intrapartum fetal pulse oximetry to
      that of fetal blood analysis for an abnormal neonatal outcome in case of abnormal
      fetal heart rate (FHR). STUDY DESIGN: A prospective multicenter observational
      study, from June 1994 to November 1995. Fetal oxygen saturation was continuously
      recorded using a Nellcor N-400 fetal pulse oximeter in case of abnormal FHR
      during labor. Simultaneous readings of fetal oxygen saturation and fetal blood
      analysis obtained before birth, i.e. either at full dilatation, or before
      cesarean section when indicated, were compared with the neonatal status. The
      criteria for an abnormal neonatal outcome were 1) an umbilical arterial blood pH
      < or = 7.15 and 2) a combined variable including: 5 min. Apgar score < or = 7,
      umbilical arterial pH < or = 7.15, secondary respiratory distress, transfer in a
      neonatal care unit, or neonatal death. RESULTS: At a 7.20 threshold for fetal
      scalp pH, and 30% for fetal oxygen saturation (i.e. the tenth centile in the
      study population), the predictive value of fetal pulse oximetry was similar to
      that of fetal blood analysis for an arterial umbilical pH < or = 7.15, and for an
      abnormal neonatal outcome (positive predictive value 56% vs 55%, negative
      predictive value 81% vs 82%, sensitivity 29% vs 35%, and specificity 93% vs 91%
      respectively). The receiver operating curve showed similar performance of either
      technique for cut-off values < or = 7.20 for fetal blood pH and < or = 30% for
      fetal oxygen saturation, whereas fetal pulse oximetry became superior at higher
      thresholds. CONCLUSION: The predictive value of intrapartum fetal pulse oximetry
      can be favorably compared with that of fetal blood analysis. Randomized
      controlled management trials can now be performed to assess potential clinical
      benefits of this new tool.

PMID- 10416139
TI  - [Comparison of contrast hysterosonography and transvaginal ultrasonography for
      uterus imaging].
AB  - AIM OF THE STUDY: To evaluate the efficacy of transvaginal sonography and saline
      infusion hysterosonography, as imaging tools, for the diagnosis of uterine
      abnormalities. METHODS: Two hundred seventy five patients were examined using
      transvaginal sonography (TVS) and saline infusion sonography (SIS), and the
      results were compared. RESULTS: Saline infusion sonography was performed in 88.4%
      of the cases. The most frequent cause of SIS failure was the presence of a
      stenotic cervix. In case of normal TVS, SIS allowed to visualize a polypoid
      lesion that was not demonstrated by TVS in 20.4% of the cases (n = 29/142).
      Saline infusion sonography confirmed the diagnosis of focal lesion suspected
      after TVS in all cases (n = 36). Finally, the localization of intramyometrial or
      submucous myomas was improved by SIS: myomas diagnosed by TVS as intramyometrial
      were demonstrated by SIS to be submucous in 41% of the cases (n = 23/56).
      CONCLUSIONS: Our results confirm that saline infusion sonography is a useful
      complementary tool for transvaginal sonography in the diagnosis of focal
      endometrial lesions and for the localization of fibromyomas.

PMID- 10416141
TI  - [Maternal and neonatal prognosis after a prolonged second stage of labor].
AB  - The purpose of this study was to evaluate the neonatal and maternal outcome after
      a prolonged second stage of labor. We compared a study group of 751 women, who
      delivered after a prolonged second stage (mean: 189 minutes) with a control group
      of 5241 women, who delivered spontaneously after a short second stage (mean: 19
      minutes). In the study group different factors were significantly associated with
      a prolonged second stage: primiparity, higher birth weight and occiput posterior
      position. If no arbitrary limit for the second stage of labor is used, the
      presentation will progress in 70% of cases and 90% of women will delivery
      vaginally. The high rate forceps delivery slightly increases maternal morbidity.
      In spite of lower umbilical pH and five-minute Apgar scores, neonatal morbidity
      and mortality were not increased.

PMID- 10416142
TI  - [Utilization of a pedicled labial flap, single or double face, for the management
      of post-obstetric urethral damage].
AB  - Reported here is our experience with a single or double-face new procedure using
      a pedicled labial flap for urethral reconstruction in patients treated for
      extensive urethral damage after obstetrical injury. Between January 1992 to July
      1997, 56 cases of urethral damage on African female patients, with an average age
      of 18 years old, were treated by pedicled labial urethroplasty. This procedure
      was done by using a single or double-face pedicled flap obtained from the major
      or minor labia. The flap was then introduced as in a tunnel beneath the vaginal
      epithelium reaching the damaged urethra. A variety of techniques were proposed:
      patch for sufficient lengthening (27 cases), tubularized flap allowing complete
      reconstruction of the urethra (18 cases) and the double-face urethroplasty (11
      cases). Good quality urine continence was obtained by using the sub urethral
      Martius'sling procedure. In 11 cases, we combined the treatment with a
      colposuspension procedure. The average follow-up was 23 months (ranging from 5 to
      47 months). The global success was 82% (52 patients treated). Recovery of normal
      miction and absence of urinary leak was obtained in 36 cases (69%). While 7
      moderate failures occurred (13%), 9 cases were considered complete failures
      (17%). In view of the high success rate, we consider that the one-stage procedure
      by the use of a single or double face pedicled labial flap is a choice treatment
      and highly suitable for the management of extensive urethral cervical damage
      after obstetrical injury.

PMID- 10416143
TI  - [Migration of an intrauterine device into the bladder. Report of a case].
AB  - PURPOSE: We report an uncommon case of a bladder lithiasis arising from an
      intrauterine device (i.u.d.). CASE REPORT: A female patient with i.u.d. for 13
      years consulted for frequent episodes of cystitis. Patient evaluation
      demonstrated a bladder stone. RESULTS: Treatment was cystolithotomy, which
      dislodged two stones. One stone was attached to the IUD. CONCLUSION: Bladder
      calculus arising from an IUD is very rare. We review the literature.

PMID- 10416144
TI  - [Uterine leiomyoma in a patient with Rokitansky-Kuster-Hauser syndrome. Report of
      a case].
AB  - We report the discovery of a leiomyoma which developed from a fibrous myometrial
      band in a woman with Rokitansky-Kuster-Hauser syndrome. This localization is
      exceptional. The diagnosis was suspected at physical examination and pelvic
      ultrasonography and laparoscopy. Histology confirmed leiomyoma.

PMID- 10416145
TI  - [Rupture of a splenic artery aneurysm during pregnancy. Report of a case].
AB  - Splenic artery aneurysm rupture during pregnancy is a rare but serious condition.
      The clinical presentation associates abdominal pain, hypotension and anemia that
      can mimic uterine rupture or abruptio placentae. An emergency cesarean section
      and splenectomy are necessary.

PMID- 10416146
TI  - [Teaching resources of a hospital Gynecology-Obstetrics service. Review of the
      literature and practical applications].
AB  - OBJECTIVES: To summarize the methods encountered in a gynecological department
      for teaching medical students. STUDY: Review of the Medline literature underlying
      the benefits and disadvantages of each method using the issues of the modern
      theories of teaching. RESULTS: All the methods are helpful for learning, with
      different and complementary objectives. Students can constitute a set of skills
      using a teaching program containing clear objectives and evaluation on which the
      future medical practice will be based. CONCLUSION: Students have immediate
      benefits from an active clinical learning involving them and are prepared to the
      Continued Medical Education.

PMID- 10416147
TI  - [Carriage and genital pneumococcal infections in the pregnancy woman: a major
      risk for the infant].

PMID- 10416148
TI  - Tracing craniosynostosis to its developmental stage through bone center
      displacement.
AB  - In metopic and coronal suture synostosis, the involved bone centers are
      abnormally situated just next to the affected suture. Bone centers are the
      starting point of ossification during embryogenesis from which bone growth
      spreads radially. In this paper, we describe a similar observation for sagittal
      suture synostosis, with both parietal bone centers located almost completely
      cranially. The (reduced) distance between the bone centers of a synostotic suture
      reflects the time during embryogenesis at which fusion took place. We suggest
      that in craniosynostosis the bone centers arise in their normal position, and
      initial outgrowth is undisturbed until the bone fronts meet. It is during this
      developmental stage that fusion occurs instead of suture formation. Due to the
      fusion, growth can only occur at the free bony rims from then on. The bone
      centers remain located at a fixed distance from one another in the middle of the
      fused bones, becoming relatively more displaced with time. This implies that the
      distance between the involved bone centers directly indicates the developmental
      period during which sutural growth was arrested. The same phenomenon of bone
      center displacement is found in types of craniosynostosis with and without
      fibroblast growth factor receptor (FGFR) or TWIST gene mutations.

PMID- 10416149
TI  - Positional changes of the frontoparietal ossification centers in perinatal
      craniosynostotic rabbits.
AB  - It has been suggested that craniosynostosis is caused by abnormally located
      ossification centers (i.e., bony tubers) in the developing skull prior to suture
      formation [Mathijssen et al., 1996, 1997]. The present study was designed to test
      this hypothesis in a rabbit model of human familial, nonsyndromic coronal suture
      (CS) synostosis. Calvariae were taken from 99 New Zealand White rabbit perinates
      (55 normal controls, 15 with delayed-onset CS synostosis, and 29 with bilateral
      or unilateral CS synostosis), ranging in age from 23 to 34 days postconception
      (synostosis occurs at approximately 23 days in this model). Frontoparietal,
      interfrontal, and interparietal ossification center distances were obtained using
      a Wild microscope with camera lucida attachment and a 2-D computer digitization
      technique. Linear regression analysis was used to compare age-related changes in
      the perinatal ossification centers among groups. Results revealed that
      frontoparietal ossification center regression line slopes had similar start
      points (24-day intercepts) with significantly (P < 0.05) diverging slopes over
      time. Normal and delayed-onset ossification center distance increased more
      rapidly than in synostosed perinates. No significant (P > 0.05) differences were
      noted in regression line slopes among groups for interparietal or interfrontal
      ossification center distances. Results demonstrated that, in synostosed
      perinates, frontoparietal ossification center location was similar to normals
      around the time of synostosis and became displaced later. These findings suggest
      that ossification center (i.e., bony tuber) displacement seen in infants with
      craniosynostosis is probably a secondary and compensatory, postsynostotic change
      and not a primary causal factor of synostosis in this rabbit model.

PMID- 10416150
TI  - Anomalies of craniofacial skeleton and teeth in cleidocranial dysplasia.
AB  - Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia
      (CCD) in man. Recently, a mouse model of CCD has been generated (Cbfal +/-)
      [Komori et al., 1997], and disturbances of osteoclast differentiation have been
      documented. It has been shown that these animals exhibit hypoplastic clavicles
      and nasal bones, and retarded ossification of parietal, interparietal, and
      supraoccipital bones. Humans with CCD show all these features, including severely
      retarded ossification of the cranial base, strongly suggesting that both
      intramembranous ossification and endochondral ossification are affected. In
      addition, CCD patients have multiple supernumerary teeth and delayed tooth
      eruption. The present report presents 3D reconstructions of computerised
      tomography (CT) scans of the craniofacial region of a CCD boy examined at both 1
      and 7 years of age. The anomalies in craniofacial skeleton and teeth are analysed
      and compared to the findings of our previous clinical studies and to the findings
      in the animal model. Based on the available information, we suggest that
      osteoblast, osteoclast, and dentinoclast differentiation may be disturbed in CCD.

PMID- 10416152
TI  - Soft tissue thin-plate spline analysis of pre-pubertal Korean and European
      Americans with untreated Angle's Class III malocclusions.
AB  - The purpose of this study was to assess soft tissue facial matrices in subjects
      of diverse ethnic origins with underlying dentoskeletal malocclusions. Pre
      treatment lateral cephalographs of 71 Korean and 70 European-American children
      aged between 5 and 11 years with Angle's Class III malocclusions were traced, and
      12 homologous, soft tissue landmarks digitized. Comparing mean Korean and
      European-American Class III soft tissue profiles, Procrustes analysis established
      statistical difference (P < 0.001) between the configurations, and this
      difference was also true at all seven age groups tested (P < 0.001). Comparing
      the overall European-American and Korean transformation, thin-plate spline
      analysis indicated that both affine and non-affine transformations contribute
      towards the total spline (deformation) of the averaged Class III soft tissue
      configurations. For non-affine transformations, partial warp (PW) 8 had the
      highest magnitude, indicating large-scale deformations visualized as labio-mental
      protrusion, predominantly. In addition, PW9, PW4, and PW5 also had high
      magnitudes, demonstrating labio-mental vertical compression and antero-posterior
      compression of the lower labio-mental soft tissues. Thus, Korean children with
      Class III malocclusions demonstrate antero-posterior and vertical deformations of
      the labio-mental soft tissue complex with respect to their European-American
      counterparts. Morphological heterogeneity of the soft tissue integument in
      subjects of diverse ethnic origin may obscure the underlying skeletal morphology,
      but the soft tissue integument appears to have minimal ontogenetic association
      with Class III malocclusions.

PMID- 10416151
TI  - A comparison of the craniofacial morphology in 2-month-old unoperated infants
      with unilateral complete cleft lip and palate, and unilateral incomplete cleft
      lip.
AB  - This paper reports a cephalometric analysis of the craniofacial morphology in
      infants with unoperated unilateral complete cleft lip and palate (UCCLP) and
      unoperated unilateral incomplete cleft lip (UICL). The purpose of the study was
      to determine the nature and extent of the craniofacial deviations in UCCLP as
      compared to the morphology in UICL, which has previously been shown to be close
      to normal. The samples comprised 82 infants with UCCLP (58 males and 24 females)
      and 75 with UICL (48 males and 27 females). The mean age was about 2 months in
      both groups. The cephalometric analysis of craniofacial morphology included the
      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. The most
      pronounced deviations in the UCCLP group were observed in the maxillary complex
      and the mandible. The most striking findings were: markedly increased width of
      the maxilla, a short mandible, and bimaxillary retrognathia except for the
      premaxillary area, which was relatively protruding and asymmetric. The study did
      not support the hypothesis previously suggested in the literature that cleft lip
      and palate is a craniofacial anomaly as size and shape of the calvaria and
      cranial base were found to be normal. The etiology of cleft lip and palate is
      still incompletely understood. Based on the present study, we suggest that facial
      type may be a liability factor that could represent a developmental threshold
      increasing the probability of cleft lip and palate.

PMID- 10416153
TI  - Craniofacial growth in a whole rat head transplant: how does a non-functional
      head grow?
AB  - To evaluate factors intrinsic to the regulation of craniofacial bone growth, we
      have developed a new experimental model in which the whole head of an infant rat
      is transplanted to the body of an isohistogenic rat by means of microvascular
      anastomosis. In our model, the transplanted head has neither scars nor any moving
      soft tissue that could modify growth around facial bones. Using this model, we
      evaluated the growth pattern of the craniofacial complex by means of serial
      roentgenographic cephalometrics. Ten transplantations were performed using 10-day
      old rats as donors and 8-week-old rats as recipients. Cephalograms were taken
      from the lateral direction at 10, 20, 30, and 40 days after transplantation.
      Several reference points were selected to analyze the growth pattern. In the
      present study, we conclude that the size and form of the bony complex are mainly
      determined genetically. There is craniofacial skeletal growth in the absence of
      muscle function and brain growth. Further, both the nasal cartilage and the
      sutures appear to be autonomous growth centers having intrinsic growth potential.
      Genetic or epigenetic information plays an important role at the skeletal level,
      but it also affects the muscles through the medium of the muscular tonus
      responsible for posture and other related phenomena.

PMID- 10416154
TI  - Remodeling of the sagittal suture in osteopetrotic (op/op) mice associated with
      cranial flat bone growth.
AB  - It is well known that cranial flat bone experiences growth and development at the
      sutural interface, which is regarded as a neutral zone to control mechanical
      stimuli. In osteopetrotic (op/op) mice, meanwhile, cranial deformation is
      produced by the deficiency of osteoclasts and the subsequent defect of bone
      resorption. It would be a reasonable assumption that such disturbance in bone
      remodeling affects sutural modification and the relevant cranial flat bone
      development. The present study was thus conducted to examine histological
      features of the sagittal sutures in op/op mice, with special reference to the
      relevant bone remodeling. The sagittal sutures in 10-, 15-, 30-, and 60-day-old
      normal and op/op mice were observed microscopically. Furthermore, osteoclastic
      activity was evaluated on the sections stained with tartrate-resistant acid
      phosphatase (TRAP). The sutures of 15-day-old op/op mice showed stenosis and
      synostosis, and less-developed collagen fibers associated with an irregular
      arrangement of fibroblasts, whereas these changes were rarely found in normal
      mice. Osteoclasts were hardly detected in the parietal bones around the sutures
      of op/op mice, although the number was numerous in normal mice. These results
      emphasize that congenital deficiency in osteoclast produces unbalanced bone
      remodeling at the sutural interface and on the surfaces of the cranial bones,
      which is assumed to be closely related to cranial bone deformity in op/op mice.

PMID- 10416155
TI  - Lack of the bone remodeling in osteopetrotic (op/op) mice associated with
      microdontia.
AB  - Osteopetrosis is an inherited metabolic disease characterized by an excessive
      accumulation of bone. This is associated with an osteoclast deficiency.
      Osteopetrosis is always accompanied by the failure and/or delay of tooth
      eruption. The present study was conducted to examine in detail the morphological
      and histological changes of growth of the third molars in the osteopetrosis
      (op/op) mouse. At the age of 10 days, normal and op/op mice showed no detectable
      difference in the shape of the third molar follicles. However, the third molars
      in the op/op mouse became obscured by the proliferation of neighboring bone
      trabeculae. Moreover, no tartrate-resistant acid phosphatase-positive cells were
      detected on the bone surfaces of 10-day-old op/op mice. Ankylosis between the
      root dentin and proliferating bone trabeculae was a common feature in the 20- and
      30-day-old op/op mice. The third molars erupted into the oral cavity before the
      age of 30 days in normal mice, and the crowns, roots, and periodontal ligaments
      appeared well developed. Throughout the experiment, it seemed that the primary
      cause of the microdontia and ankylosis of the developing root in the mutant mouse
      was a deficiency of osteoclasts, with attendant lack of bone remodeling.

PMID- 10416156
TI  - Detection of specific sugars in dairy process samples using multivariate curve
      resolution.
AB  - Dairy process monitoring by application of multivariate curve resolution using
      alternating least squares is presented. Alternating least squares was used for
      resolving Fourier transform infrared spectral data from a dairy batch process in
      which lactose is enzymatically hydrolyzed to glucose and galactose. It was
      possible to extract four compounds (fat, lactose, and two other sugar components)
      from the spectral data obtained from nine process runs. Subsequently, the pure
      spectra obtained in this way were used to monitor the content of these compounds
      in two new process runs. In this way, alternating least squares made it possible
      to follow the hydrolysis process by Fourier transform infrared spectroscopy
      without the need for reference analyses. When the results were correlated to
      reference results for lactose, the accuracy was similar to that obtained when a
      partial least squares regression was performed on the same data; lactose
      correlation was 0.980 when alternating least squares was used and was 0.987 when
      partial least squares was used.

PMID- 10416157
TI  - Evaluation of cheddar cheese as a food carrier for delivery of a probiotic strain
      to the gastrointestinal tract.
AB  - Cheddar cheese was evaluated as a food carrier for the delivery of viable
      microorganisms of Enterococcus faecium (Fargo 688; Quest Int., Naarden, The
      Netherlands) to the gastrointestinal tract. This strain had previously been shown
      to possess properties required of a probiotic microorganism including the ability
      to relieve irritable bowel syndrome. The strain was found to survive to high
      numbers in Cheddar cheese during ripening at 8 degrees C for 15 mo (4 x 10(8)
      cfu/g) and in yogurt during storage at 4 degrees C for 21 d (4 x 10(7) cfu/g). In
      an in vitro model system, Cheddar cheese was found to have a greater protective
      effect than yogurt upon exposure of the probiotic culture to porcine gastric
      juice at pH 2. Subsequently, a feeding trial involving 8 pigs per group was
      performed in which a rifampicin-resistant variant of the probiotic strain was fed
      for 21 d at a mean daily intake of 1.3 x 10(10) cfu/d from Cheddar cheese or 3.7
      x 10(9) cfu/d from yogurt. During the feeding period, Cheddar cheese yielded a
      significantly higher mean fecal probiotic count (2 x 10(6) cfu/g of feces) than
      did yogurt (5.2 x 10(5) cfu/g of feces). These data indicate that mature Cheddar
      cheese compares very favorably with fresh yogurt as a delivery system for viable
      probiotic microorganisms to the gastrointestinal tract.

PMID- 10416158
TI  - Purification and characterization of an antihypertensive peptide from a yogurt
      like product fermented by Lactobacillus helveticus CPN4.
AB  - Whey peptides in a yogurt-like product fermented by Lactobacillus helveticus CPN4
      were fractionated by a Sep-pak C-18 cartridge followed by two-step reverse-phase
      HPLC. The antihypertensive activity was measured by systolic blood pressure in
      spontaneously hypertensive rats after oral administration of each fraction. Five
      major peptides in the final fraction were further purified by reverse-phase HPLC
      and were measured for these antihypertensive activities in spontaneously
      hypertensive rats. The only peptide in the final fraction that showed strong
      antihypertensive activity had a sequence of Tyr-Pro, which is found in alpha s1
      casein (CN), beta-CN, and kappa-CN. The synthetic peptide Tyr-Pro yielded
      significant antihypertensive activity from 2 to 8 h after oral administration of
      1 mg of peptide/kg of body weight, and the effect was maximal at 6 h after oral
      administration. The antihypertensive effect of the peptide was dependent on the
      peptide dosage from 0.1 to 10 mg of peptide/kg of body weight. The concentration
      of Tyr-Pro peptide increased during fermentation and reached about 8.1
      micrograms/ml of whey in the pH 4.3 yogurt-like product. The antihypertensive
      peptide had a low inhibitory activity against angiotensin I-converting enzyme.
      The inhibition of 50% of the angiotensin I-converting enzyme (IC50) was 720
      microM.

PMID- 10416159
TI  - Effects of induced parturition and estradiol on feed intake, liver triglyceride
      concentration, and plasma metabolites of transition dairy cows.
AB  - The effect of induced parturition and estradiol on feed intake, liver
      triglyceride, plasma metabolites, and milk yield was evaluated in fifty-six
      Holstein cows and heifers. Cows were assigned to treatments on d 260 of gestation
      and were on trial until d 10 postpartum for measurement of dry matter intake
      (DMI), plasma metabolites, and liver triglyceride and until d 31 postpartum to
      measure milk yield. Fourteen animals per group (9 cows and 5 heifers) received
      either a placebo, 1 mg of fenprostalene, 50 mg of estradiol-17 beta benzoate, or
      both on d 276 of gestation. Cows that received fenprostalene consumed more dry
      matter (DM) for the last 8 d prepartum than did cows that did not receive
      fenprostalene (9.6 kg/d vs. 8.5 kg/d, respectively) but consumed less DM for the
      first 10 d postpartum (10.9 kg/d vs. 13.1 kg/d, respectively). Cows injected with
      estradiol-17 beta benzoate tended to consume less DM postpartum than did cows not
      injected with estradiol-17 beta benzoate (11.3 kg/d vs. 12.7 kg/d, respectively).
      There was no effect of treatment on milk yield; however, a fenprostalene by day
      interaction resulted from lower milk yield on d 3, 4, 5, 7, and 10 relative to
      calving in cows that received fenprostalene. Administration of fenprostalene
      resulted in a delay in the peak plasma nonesterified fatty acid (NEFA)
      concentration until 2 d after calving. Plasma glucose concentrations were
      greatest 1 d prior to calving for cows that received fenprostalene, whereas
      plasma glucose concentrations peaked on the day of calving for cows that did not
      receive fenprostalene. Liver triglyceride increased over time; however, there was
      no effect of treatment on liver triglyceride. Calving induction improved DMI for
      the last 8 d prepartum, but a concomitant decrease in liver triglyceride after
      calving did not result. Estradiol-17 beta benzoate had no effect on plasma
      metabolites or liver triglyceride, indicating that the physiological rise in
      estradiol prior to calving does not have a primary role in lipolysis or hepatic
      fatty acid metabolism in the dairy cow.

PMID- 10416160
TI  - Optimal replacement and insemination policies for Holstein cattle in the
      southeastern region of Brazil: the effect of selling animals for production.
AB  - Dynamic programming was used to determine optimal replacement and insemination
      policies for Holstein-Friesian cattle in the southeastern region of Brazil.
      Optimal insemination and replacement decisions were determined for two disposal
      alternatives: selling all cows exclusively for slaughter (A) or selling the cows
      either for slaughter or to other farmers for production (B). Disposal alternative
      B reflects the common practice among dairy farmers to sell some of their cows to
      other farmers at a higher price than the carcass price. In the model, cows were
      described in terms of lactation number, stage of lactation, calving interval, and
      milk produced during present and previous lactation. For disposal alternative A,
      the optimal average herd life was 54.9 mo, corresponding to annual replacement
      and voluntary culling rates of 21.8 and 4.1%, respectively. For disposal
      alternative B, the optimal average herd life was 44.0 mo, which corresponded to
      annual replacement and voluntary culling rates of 27.3 and 10.0%, respectively.
      In this case, from the total of voluntarily culled cows, 70% were sold to other
      farmers for production. Sensitivity analyses showed that changes in the disposal
      value of cows and replacement heifer prices strongly influenced the optimal
      insemination and replacement policy.

PMID- 10416161
TI  - Differential distribution of T lymphocyte subpopulations in the bovine mammary
      gland during lactation.
AB  - The existence and distribution of T lymphocyte subpopulations in the mammary
      parenchymal tissue of cows were immunohistochemically detailed during early
      lactation. CD2+, CD4+, and CD8+ T lymphocytes were localized primarily in the
      mammary parenchymal tissue. CD8+ T lymphocytes were predominant over CD4+ T
      lymphocytes and occurred in close contact with the alveolar epithelium and
      between epithelial cells in the central area of the upper mammary gland. CD4+ T
      lymphocytes were present in equal numbers in the epithelial and connective tissue
      area. Occasionally, both CD4+ and CD8+ T lymphocytes formed cell clusters in the
      interalveolar connective tissue. The ratio of CD4+ T lymphocytes to CD8+ T
      lymphocytes was less than 1.0 and was lower in the epithelial area than in the
      connective tissue. The distribution of CD4+ and CD8+ T lymphocytes was similar in
      the parenchymal tissue of the gland cistern. The observation that there is a
      preferential presence of CD8+ T lymphocytes in the epithelial area of the bovine
      mammary gland during early lactation might indicate that these cells participate
      in the maintenance of the integrity of the epithelium.

PMID- 10416162
TI  - Effect of bovine somatotropin on neutrophil functions and clinical symptoms
      during Streptococcus uberis mastitis.
AB  - The effect of recombinant bovine somatotropin (bST) on the chemiluminescence,
      diapedesis, and expression of adhesion receptors (CD11a, CD11b, CD18) of isolated
      polymorphonuclear leukocytes was studied. The plasma concentrations of insulin
      like growth factor-I (IGF-I), bST, cortisol, and alpha-lactalbumin were also
      monitored. In addition, general and local clinical symptoms and the
      differentiation of circulating leukocytes were also studied during experimentally
      induced Streptococcus uberis mastitis in cows. Ten cows were infected with 500
      cfu of S. uberis O140J in both left quarters. Five cows were subcutaneously
      treated with 500 mg of recombinant bST 7 d before and after infection, and 5
      control cows received the excipient. General (fever, tachycardia, inappetance,
      and depression) and local symptoms (swelling, pain, firmness, and flecks in milk)
      were more acute, severe, and longer-lasting in control cows. Treatment with bST
      had no effect on chemiluminescence and diapedesis of circulating
      polymorphonuclear leukocytes and no effect on the expression of adhesion
      receptors. Recombinant bST induced significantly higher IGF-I and bST
      concentrations in plasma. The leukopenia observed after infection was less
      pronounced in the bST-treated cows, and the number of circulating band
      neutrophils and metamyelocytes was significantly lower in the treated group. The
      concentration of cortisol did not differ between both groups, but the blood
      concentration of alpha-lactalbumin significantly increased in both groups from 6
      d after infection. These results showed that treatment with recombinant bST
      improves animal welfare by protecting the cows from severe local and general
      clinical symptoms during subsequent S. uberis mastitis, but that it has no effect
      on chemiluminescence, diapedesis, and the expression of adhesion receptors of
      circulating polymorphonuclear leukocytes.

PMID- 10416163
TI  - Milk yield, somatic cell counts, and risk of removal from the herd for dairy cows
      after covered teat canal injury.
AB  - The objective of this study was to evaluate milk yield, somatic cell count (SCC),
      and risk of removal of a cow from the herd after covered teat injury. Teat
      injuries were diagnosed and treated by using endoscopy. After treatment, teats
      were rested for 3 x 3 d. Eighty-one cows referred to the Veterinary Clinic
      Babenhausen were used for this study. Each cow was matched to three herdmates by
      breed, age, and calving date. Data on milk yield and SCC were available from the
      records of the Bavarian milk control board. Test day milk yields and lactational
      milk yields were equal for cows with covered teat injury and herdmates in the
      lactation when the injury was diagnosed and in the subsequent lactation. Calving
      interval in the year the injury was diagnosed and the time cows lived in the herd
      were also equal. However, covered teat injuries significantly increased test day
      SCC by 128,000 cells/ml of milk. These injuries also significantly increased the
      odds of subclinical mastitis (SCC > 100,000 on test day) and the odds of
      violating European milk shipping regulations (SCC > 400,000 on test day). Because
      increased SCC was significantly associated with decreased milk yield, cows may
      not have fully utilized their milk yield capacity after covered teat injury.

PMID- 10416165
TI  - Estimation of microbial nitrogen flow to the duodenum of cattle based on dry
      matter intake and diet composition.
AB  - The objectives of this study were: 1) to evaluate the National Research Council
      equation used to predict microbial N flow to the duodenum in lactating cows, and
      2) to determine whether improved equations could be developed by using dietary
      parameters used in the field. Treatment means from 55 trials with lactating and
      nonlactating cattle with duodenal cannulas were subjected to the backward
      elimination procedure of multiple regression. Variation within and among trials
      was accounted for by weighting the observations and including trial effects in
      all models. The equations to predict microbial N flow based on net energy for
      lactation (NEL) intake were different from the equation based on NEL intake used
      by the dairy National Research Council. Dry matter intake (DMI) estimated
      microbial N flow as well as did NEL intake, indicating that DMI drives
      predictions based on NEL intake. When multiple dietary factors [i.e., DMI;
      dietary percentages of crude protein, forage, and neutral detergent fiber; and
      all two-way interactions] were included, the resulting equation [microbial N
      (grams per day) = 16.1 + 22.9 x DMI (kilograms per day) - 0.365 x DMI2 - 1.74 x
      dietary neutral detergent fiber (percentage of dry matter)] tended to fit the
      data better than the equations based on NEL intake but not better than the
      equation based on DMI alone. The multiple-factor equation appeared to be the best
      overall equation for prediction; in contrast to the equation based on DMI, this
      equation is sensitive to diet composition. An asymptotic multiple-factor equation
      was developed, which may be more appropriate when extrapolating beyond the data
      range.

PMID- 10416164
TI  - Suckling reinitiated milk secretion in beef cows after an early postpartum hiatus
      of milking or suckling.
AB  - We determined whether milk secretion in beef cows could be reinitiated by renewed
      suckling after a hiatus from milking or suckling. Fifty-three Angus x Hereford
      cows were suckled ad libitum by their own calves for 13 to 18 d postpartum and
      then assigned to treatments for 4 wk in which cows were 1) neither milked nor
      suckled (weaned; n = 18), 2) milked 2 x daily (milked; n = 18), or 3) suckled by
      their own calves (suckled; n = 17). Thereafter, all calves (including earlier
      weaned calves) suckled their own dams until permanent weaning at 203 d of age,
      except when their dams were milked once after receiving (i.m.) 40 IU of oxytocin
      at reinitiation of suckling (0 wk) and again 1 and 5 wk later. Prolactin was
      increased in milked and suckled cows during 20 min after milking or suckling at
      the termination of treatments (0 wk). Concentrations of insulin-like growth
      factor-I were greater for weaned than suckled cows; milked cows had intermediate
      concentrations. At 0 wk, milk yield was greater for suckled than milked or weaned
      treatment cows. After 1 wk of renewed suckling, milk secretion of weaned
      treatment cows increased, and by 5 wk, composition of milk was normal, but yield
      was still reduced. We concluded that milk secretion was renewed by suckling in
      early postpartum cows after they were neither suckled nor milked for 4 wk.

PMID- 10416166
TI  - Effects of insulin and amino acids on milk protein concentration and yield from
      dairy cows.
AB  - Our study investigated the effect of insulin on the regulation of milk protein
      synthesis in well-fed cows (n = 4) with or without additional amino acids (AA).
      The design was a two-way crossed factorial with two 12-d periods involving
      abomasal infusions of either water or a mixture of casein (500 g/d) plus branched
      chain AA (88 g/d). During the last 4 d of each period a hyperinsulinemic
      euglycemic clamp was performed; insulin was infused at 1.0 microgram.kg of BW-1.h
      1 to increase circulating levels fourfold, and euglycemia was maintained by
      infusion of glucose. Cows were fed a diet formulated to exceed requirements for
      metabolizable energy and protein. During abomasal water infusion, the insulin
      clamp increased milk protein yields by 15% (+128 g/d); when combined with
      abomasal infusion of casein plus branched-chain AA, milk protein yield was
      increased by 25% (+213 g/d). These increases resulted from equivalent increases
      in milk protein concentration and milk yield. Concentrations of casein and whey
      proteins in milk were increased by insulin clamp treatments; however, there were
      no major changes in the relative proportions of individual casein and whey
      proteins. Plasma concentrations of essential AA were reduced (-33%) during the
      insulin clamp treatments; effects were most dramatic for the branched-chain AA (
      41%) and their keto acids (-45%). Results confirm the important regulatory role
      of the endocrine system in milk protein synthesis and demonstrate this potential
      to produce milk protein is not fully expressed.

PMID- 10416167
TI  - Lactation performance and fatty acid composition of milk from Holstein cows fed 0
      to 5% oleamide.
AB  - Diets containing 0 to 5% oleamide were fed to Holstein cows to determine linear
      or nonlinear responses to the fat supplement on lactation performance and milk
      fatty acid composition. Six rations containing concentrate, corn silage, and 0,
      1, 2, 3, 4, or 5% (dry matter basis) added oleamide were fed to six multiparous
      cows in a 6 x 6 Latin square for 2-wk periods. As the oleamide concentration in
      the ration increased from 0 to 5%, dry matter intake declined, fiber and dry
      matter digestibilities remained constant, and digestibilities of protein and
      fatty acids increased. Milk yield declined as dietary oleamide increased,
      although yield was not depressed numerically until oleamide exceeded 2% of the
      diet dry matter. The C18:1 concentration doubled in milk as oleamide in the diet
      increased from 0 to 5%. Ratios of C18:1 to C16:0 in milk fat were 0.56, 0.83,
      1.34, 1.53, and 1.73 for the diets supplemented with 0, 1, 2, 3, 4, and 5%
      oleamide, respectively. No amide was detected in milk samples taken from cows fed
      the 5% oleamide diet. Results show that intake of diets containing 2 to 3%
      oleamide substantially increased the milk C18:1:C16:0 ratio without greatly
      affecting milk yield or causing detectable amounts of amide in milk.

PMID- 10416168
TI  - Interaction of tallow and hay particle size on ruminal parameters.
AB  - Four nonlactating ruminally cannulated Holstein cows were used in a 4 x 4 Latin
      square experiment with 4 21-d periods to determine if the effects of dietary fat
      would be affected by hay particle length. Treatments consisted of two levels of
      tallow (0 and 5%) and two hay particle lengths (short-cut and long-cut) in a 2 x
      2 factorial. Diets contained alfalfa hay, corn silage, and concentrate [1:1:2,
      dry matter (DM) basis] fed as a total mixed ration (TMR) once per day. Samples of
      the 0 and 5% tallow TMR were ground and incubated in situ in polyester bags for
      24 and 48 h. Ruminal samples were taken on day 21 at 0800 h and at 2-h intervals
      until 1600 h. The total tract digestibilities of acid detergent fiber (ADF) and
      neutral detergent fiber (NDF) were not affected by tallow or by hay by tallow
      interactions. There was a trend for tallow to improve total tract digestibility
      of crude protein (CP) (70.2 vs. 74.7%). After 48 h of ruminal incubation, tallow
      significantly decreased the digestibilities of DM, ADF, and NDF. No hay length by
      tallow interactions for DM, NDF, ADF or CP digestibilities occurred after 24 or
      48 h. Tallow increased concentrations of propionate and decreased concentrations
      of acetate and valerate and the acetate-to-propionate ratio. Total volatile fatty
      acids increased when tallow was added to diets with short-cut hay, which suggests
      that when unprotected fat is added to diets with a high level of hay, a short-cut
      hay length may be advantageous. This result may be due to shorter rumen retention
      time of feed particles, which reduces the time for fatty acids to exert
      antimicrobial effects. Or, it may because the increased surface area of the hay
      particle provides more area for microbial attachment and increased fermentation.

PMID- 10416169
TI  - Nutrient content, dry matter yield, and species composition of cool-season
      pasture with management-intensive grazing.
AB  - The objective of this study was to determine changes in the nutrient content,
      available pasture, and species stand counts of cool season pastures during the
      grazing season. Four replicated pastures were flexibly subdivided into 18 to 36
      paddocks and grazed rotationally from late April to November in each of 2 yr.
      Steers were grazed with fresh pasture offered each 1 to 2 d, which resulted in
      rest periods for paddocks of 17 to 35 d. Samples used to determine the nutrient
      content of pasture forage dry matter (DM) were collected from two grazing rumen
      fistulated heifers that had empty, clean rumens at initiation of the sampling
      period. Mean stand counts in long-term established pastures for the grazing
      season were 24% legumes, 45% grasses, 8% grassy weeds, 10% bare ground, 11%
      broadleaf weeds, and 1% dung piles. Stand counts did not differ between years.
      Mean DM utilization of pasture per grazing cycle was 1103 kg/ha, and total DM
      temporal utilization per season was 6624 kg/ha, which was 35% of the pasture
      available for each grazing. Pasture content of neutral detergent fiber, crude
      protein, in situ digestible DM, and net energy for lactation did not differ
      between years but did differ among months of harvest: neutral detergent fiber
      decreased, crude protein and in situ digestible DM increased, and acid detergent
      fiber and estimated net energy for lactation remained relatively constant over
      the grazing season. The content of measured nutrients in ingested herbage did not
      differ among heifers sampled. These results indicate that individual cattle
      select similar quality diets from given pastures and nutrient differences
      occurred among months of sampling. Even though differences among months of season
      were statistically different, actual differences were small. Management-intensive
      grazing of pastures was uniform enough over season, and animal selectivity was
      strong enough over season to result in constant quality of consumed pasture.

PMID- 10416170
TI  - Effects of feeding virginiamycin and sodium bicarbonate to grazing lactating
      dairy cows.
AB  - The effects of virginiamycin, an agent active against Gram-positive lactic acid
      producing bacteria, and NaHCO3 on ruminal and fecal pH, rumen volatile fatty acid
      proportions, blood metabolites, and milk production and composition were
      assessed. This study was conducted over 28 d and involved 71 dairy cows that
      grazed predominantly ryegrass, oats, and clover, and that were fed 10 kg of
      concentrate pellets/d per head. The pellets contained (per kilogram) no dietary
      additive, 30 mg of virginiamycin, 20 g of NaHCO3, or 30 mg of virginiamycin and
      20 g of NaHCO3 on a DM basis. Ruminal pH tended to be higher in cows fed pellets
      containing virginiamycin (7.0 vs. 6.9; SED = 0.16). The results of in vitro
      incubation of ruminal fluid with glucose found the potential for L-lactic acid
      accumulation in ruminal fluid to be significantly lower in cows fed virginiamycin
      (15.5 vs. 35.3 mmol/L; SED = 2.98). Cows fed virginiamycin had significantly
      higher fecal pH (6.72 vs. 6.57; SED = 0.08) and produced more milk (23.94 vs.
      23.32 kg/d) and more lactose than those not fed virginiamycin. No effects of
      NaHCO3 on fecal pH, in vitro potential for L-lactic acid accumulation in ruminal
      fluid, or milk production were observed, but ruminal pH tended to be higher and
      ruminal acetate proportion was greater for cows fed NaHCO3. Milk fat and milk
      protein percentage did not differ significantly as a result of dietary treatment.
      These data suggest that the inclusion of virginiamycin in the diet will reduce L
      lactic acid accumulation in ruminal fluid and increase fecal pH in grazing dairy
      cattle fed concentrate supplements.

PMID- 10416171
TI  - Prediction of daily milk yields from a limited number of test days using test day
      models.
AB  - A data set of weekly milk yield records was used to compare different test day
      models for their ability to interpolate and extrapolate missing milk yields. The
      criteria to compare the models were 1) the (co)variance structure modeled
      compared with the observed (co)variance structure in the data and 2) mean square
      error of predictions of missing observations (MSEP), which compared the predicted
      value of a missing record to the known value of the record. The test day models
      used were LEG(m), which are Legendre polynomials with an order of fit of m, and
      EXP, which is an exponential lactation function. When fitting the LEG(m) models,
      criteria 1) and 2) generally improved with an increasing order of fit as
      expected. The model EXP, which contains three random regression coefficients, was
      between LEG(1) and LEG(2), which contain two and three coefficients,
      respectively. The improvement of the criteria with m in LEG(m) became negligible
      after LEG(5). Thus, a 5th order Legendre polynomial yields a good fit with a
      minimum number of parameters. Also, the correlation structure of milk yields
      among days in milk modeled by LEG(5) resembled the correlation structure that was
      observed in the data. However, the modeled variances at the end of lactation were
      larger than those observed in the data except when LEG(0) was used. Legendre
      polynomials with a fit less than five yielded correlation structures that clearly
      deviated from the observed correlations, especially in the case of LEG(0).
      Overall, LEG(5) is preferred to develop a genetic TDM for breeding value
      estimation.

PMID- 10416172
TI  - A covariance function for feed intake, live weight, and milk yield estimated
      using a random regression model.
AB  - To enable investigation of genetic variation during early lactation in heifers,
      multitrait covariance functions were used to describe genetic covariances among
      feed intake, live weight, and milk yield during the first 15 wk of lactation (n =
      628). Random regression models were used to estimate covariance functions for the
      additive genetic and permanent environmental effects. Fixed effects were date of
      the week that records were collected, a group effect, and week of lactation.
      Second or third order polynomials were sufficient to describe the additive
      genetic variation for milk yield, dry matter intake, and live weight during the
      first 15 wk of lactation. Estimates for the genetic covariance function
      demonstrated that a high milk yield is only moderately correlated with high feed
      intake (0.21) but is very strongly correlated to an increase of intake and a loss
      of live weight during the first 15 wk of lactation. Levels of weight and intake
      were correlated strongly (0.81). The reduced fit covariance function was used to
      estimate genetic correlations between traits at different lactation stages.
      Estimates for the genetic correlations between wk 1 and 15 were 0.62, 0.24, and
      0.79 for milk yield, dry matter intake, and live weight, respectively. Feed
      intake during early lactation was negatively correlated with milk yield, but feed
      intake during the later weeks was positively correlated with milk yield. The
      implication is that when selection is for a linear combination of milk yield,
      feed intake, and live weight (i.e., energy balance or efficiency), it is
      important to consider when each trait is measured during lactation.

PMID- 10416173
TI  - Variance caused by cytoplasmic line and sire by herd interaction effects for milk
      yield considering estimation bias.
AB  - A total of 138,869 lactation milk yields (305 d, milked twice daily, mature
      equivalent) from the first three parities of 68,063 New York Holstein cows were
      used to estimate variance components that were due to additive direct genetic
      effects, cow permanent environmental effects (cow within sire for sire model),
      sire by herd interaction effects, and cytoplasmic line effects. The original data
      were assigned to 10 random samples, which were each analyzed using an animal
      model and a sire model. From each sample of original data, 20 other samples were
      analyzed with levels assigned randomly to cytoplasmic and interaction effects
      (data with randomly simulated levels). Ten of those samples were analyzed with an
      animal model and 10 with a sire model. The models also included fixed effects of
      herd-year-seasons. For the animal model and sire model, average fractions of
      phenotypic variance and average standard errors were, respectively, for additive
      direct genetic effects 0.300 (0.029) and 0.228 (0.040) for original data and
      0.325 (0.025) and 0.262 (0.039) for data with randomly simulated levels. For cow
      permanent environmental effects the respective averages were 0.242 (0.024) and
      0.444 (0.014) for original data and 0.235 (0.025) and 0.492 (0.016) for data with
      randomly simulated levels. The averages for sire by herd interaction effects were
      0.015 (0.008) and 0.018 (0.007) for original data and 0.003 (0.007) and 0.004
      (0.009) for data with randomly simulated levels. For cytoplasmic line effects,
      the respective averages were 0.011 (0.007) and 0.043 (0.008) for original data
      and 0.003 (0.006) and 0.003 (0.007) for data with randomly simulated levels. The
      differences between estimates of variance components for original data and data
      with randomly simulated levels suggest that estimates of fractions of total
      variance caused by sire by herd interaction and cytoplasmic effects estimated
      with REML may be biased upward by 0.003 to 0.004.

PMID- 10416174
TI  - Deoxyribonucleic acid fingerprinting of Staphylococcus aureus from heifer mammary
      secretions and from horn flies.
AB  - Staphylococcus aureus isolated from heifer mammary secretions, streak canals, and
      horn flies (Haematobia irritans) were evaluated by randomly amplified polymorphic
      DNA fingerprinting. The relationship between DNA fingerprint patterns of S.
      aureus isolated from horn flies and S. aureus isolated from heifer mammary glands
      was examined. Amplified DNA fragments were visualized by agarose gel
      electrophoresis and were analyzed by densitometry. Analysis of DNA fingerprint
      patterns of 56 S. aureus isolates that were obtained from heifer mammary
      secretions or streak canals resulted in three distinct subtypes of S. aureus. Of
      these, 31 isolates (55%) belonged to subtype 1, 22 isolates (39%) belonged to
      subtype 2, and 3 (5%) belonged to subtype 3. Eight of 10 S. aureus isolates from
      horn flies belonged to subtype 1, and 2 isolates belonged to subtype 2. Thus, all
      of the S. aureus isolates from horn flies had DNA fingerprint patterns identical
      to the majority (95%) of S. aureus isolates from heifer mammary secretions or
      streak canals. In addition, 10 S. aureus isolates from multiparous cows from the
      same herd were examined by randomly amplified polymorphic DNA. All S. aureus
      isolates from multiparous cows belonged to subtype 3. Results of this study
      suggest that horn flies may play an important role in the transmission of S.
      aureus to nulligravid and primigravid heifers. Furthermore, this study
      demonstrates the usefulness of randomly amplified polymorphic DNA fingerprinting
      to distinguish between different subtypes of S. aureus and to draw
      epidemiological inferences from the information it provides.

PMID- 10416175
TI  - The potential of open learning in animal breeding.
AB  - Animal breeding education is presently facing many challenges. These include
      rapid changes in breeding knowledge and technology, resource and funding
      restrictions, and altering demographics of the learner and the animal breeding
      industry. These challenges can be met via an open learning educational format.
      This nontraditional approach is based on the needs of individual learners, not
      the interests of the teacher or the institution. An important feature of open
      learning is its appropriateness for the professional development audience.
      Delivery methods include interactive distance courses on the Web, computer
      assisted learning, and team-based study. The Canadian dairy breeding industry has
      expressed the need for ongoing professional development to understand and adopt
      new animal breeding technologies. The University of Guelph responded by
      delivering a series of animal breeding short courses (Executive Certificate
      Program in Animal Breeding) to industry decision makers in 1997. A version
      modified specifically for farmers and breeding industry personnel was offered in
      1998. Through the collaboration of experts from various agricultural institutions
      and the use of a learner-centered format, this professional development
      initiative was a pedagogical and financial success. This paper describes how the
      open learning approach differs from traditional university teaching. Using the
      University of Guelph example in animal breeding professional development, the
      framework for a successful open learning program will be examined. The best
      practices for effective adult education will also be identified and discussed
      within this case study.

PMID- 10416177
TI  - Reliability of McConnell's classification of patellar orientation in symptomatic
      and asymptomatic subjects.
AB  - STUDY DESIGN: Test-retest reliability study with blinded testers. OBJECTIVES: To
      determine the intratester reliability of the McConnell classification system and
      to determine whether the intertester reliability of this system would be improved
      by one-on-one training of the testers, increasing the variability and numbers of
      subjects, blinding the testers to the absence or presence of patellofemoral pain
      syndrome, and adhering to the McConnell classification system as it is taught in
      the "McConnell Patellofemoral Treatment Plan" continuing education course.
      BACKGROUND: The McConnell classification system is currently used by physical
      therapy clinicians to quantify static patellar orientation. The measurements
      generated from this system purportedly guide the therapist in the application of
      patellofemoral tape and in assessment of the efficacy of treatment interventions
      on changing patellar orientation. METHODS AND MEASURES: Fifty-six subjects (age
      range, 21-65 years) provided a total of 101 knees for assessment. Seventy-six
      knees did not produce symptoms. A researcher who did not participate in the
      measuring process determined that 17 subjects had patellofemoral pain syndrome in
      25 knees. Two testers concurrently measured static patellar orientation
      (anterior/posterior and medial/lateral tilt, medial/lateral glide, and patellar
      rotation) on subjects, using the McConnell classification system. Repeat measures
      were performed 3-7 days later. A kappa (kappa) statistic was used to assess the
      degree of agreement within each tester and between testers. RESULTS: The kappa
      coefficients for intratester reliability varied from -0.06 to 0.35. Intertester
      reliability ranged from -0.03 to 0.19. CONCLUSION: The McConnell classification
      system, in its current form, does not appear to be very reliable. Intratester
      reliability ranged from poor to fair, and intertester reliability was poor to
      slight. This system should not be used as a measurement tool or as a basis for
      treatment decisions.

PMID- 10416176
TI  - Criterion-related validity of a clinical measurement to determine the
      medial/lateral component of patellar orientation.
AB  - STUDY DESIGN: Repeated measures design using a sample of convenience. OBJECTIVE:
      To assess the criterion-related validity and intrarater reliability of a clinical
      measurement used for determining the medial/lateral position of the patella.
      BACKGROUND: Patellar taping is a common treatment for patellofemoral pain.
      Application of this intervention requires accurate assessment of patellar
      orientation; however, the validity of this clinical procedure has not been
      documented. METHODS AND MEASURES: Fourteen subjects (10 women, 4 men; average
      age, 41 +/- 16 years) were evaluated. Clinical assessment of medial/lateral
      patellar orientation using the technique described by McConnell was compared with
      the actual position of the patella as determined through magnetic resonance
      imaging (MRI). Imaging was done on 7 knees of 4 subjects who were asymptomatic
      and 11 knees of 10 subjects who were symptomatic. Both clinical and MRI
      assessments were made with the subjects supine, the knee extended, and the
      quadriceps relaxed. Agreement between the 2 techniques and the intrarater
      reliability of each measurement were quantified by means of the intraclass
      correlation coefficient (ICC). RESULTS: Both the clinical and MRI measures of
      medial/lateral patellar displacement were found to demonstrate good intrarater
      reliability (ICC = 0.91 and 0.85, respectively). The agreement between the
      clinical and MRI determinations of medial/lateral patellar position was poor (ICC
      = 0.44). The average amount of lateral patellar displacement as determined by the
      clinical method was more than twice that established through MRI. CONCLUSIONS:
      The clinical assessment of the medial/lateral position of the patella
      overestimates the true amount of lateral patellar displacement. A more valid
      clinical method of assessing the medial/lateral component of patellar orientation
      is necessary.

PMID- 10416179
TI  - Weight-bearing immobilization and early exercise treatment following a grade II
      lateral ankle sprain.
AB  - STUDY DESIGN: Case study. OBJECTIVES: To describe a protocol used in the
      rehabilitation of a grade II lateral ankle sprain, emphasizing brief
      immobilization with a removable boot, weight bearing as tolerated, and
      progression of early exercise. BACKGROUND: The optimum conservative treatment of
      severe grade II ankle sprains remains undefined. Short-term benefits of early
      mobilization have won favor over immobilization by casting; however, pain and
      ankle joint instability often linger. The timing of weight bearing as a variable
      that influences recovery has largely been ignored when either treatment is
      considered. METHODS AND MEASURES: The patient was a 17-year-old girl who had
      sustained a left ankle inversion sprain while playing high school basketball. The
      sprained ankle was placed in an immobilizer boot for 1 week, and weight bearing
      was encouraged. She received instructions for active exercise and for resistive
      exercise with elastic tubing. Volumetric and active range of motion measurements
      and gait observation provided indicators of rehabilitation progress. A digital
      inclinometer was used to measure active range of motion in the sagittal plane.
      Vertical ground reaction forces recorded with an instrumented treadmill
      documented gait symmetry. RESULTS: The patient responded well to the course of
      treatment, returning to full participation in basketball 2 weeks after the
      injury. The injured ankle had 29% (19 degrees) less active range of motion than
      the nonimpaired ankle at the beginning of physical therapy. The injured ankle
      also displaced 50 mL more water compared with the nonimpaired ankle at the start
      of treatment. Four weeks after beginning treatment, the sprained ankle had 4
      degrees less active range of motion and displaced 5 mL more water compared with
      the nonimpaired ankle. As a college athlete, the patient has remained free of
      subjective complaints of ankle pain, instability, and swelling. CONCLUSION:
      Weight-bearing immobilization combined with early exercise provided safe and
      effective treatment for this patient, who suffered a grade II lateral ankle
      sprain.

PMID- 10416180
TI  - Prospective study of changes in impairments and disabilities after anterior
      cruciate ligament reconstruction.
AB  - STUDY DESIGN: Single-group, repeated-measures prospective study. OBJECTIVES: To
      analyze changes in impairments and disabilities among patients with anterior
      cruciate ligament (ACL) reconstruction and to assess the relationships between
      the impairment and disability outcome measures from 3 months to 2 years following
      ACL reconstruction. BACKGROUND: Outcomes after ACL reconstruction can be
      categorized as impairments or disabilities. The relationship between impairments
      and disabilities may be crucial to understanding physical therapy interventions
      and predicting long-term outcome. METHODS AND MEASURES: Sixty patients who had
      undergone ACL reconstruction participated in the study. Impairment measures were
      range of motion, pain, knee-joint laxity, and muscle performance using isokinetic
      muscle tests. Disability measures were the Cincinnati knee score and lower limb
      performance using the triple-jump and stair-hop tests. Follow-up times were 3 and
      6 months and 1 and 2 years after surgery. RESULTS: The Cincinnati knee score
      results show significant improvement 1 year after surgery (84.2 +/- 13.6)
      compared with 6 months (76.8 +/- 13.7) and 3 months (67.4 +/- 16.3) after
      surgery. Quadriceps total work (percentage of normal leg) significantly improved
      2 years after surgery (92.6 +/- 14.1%) compared with 1 year after surgery (81.6
      +/- 16.8%). Between 37 and 75% of the variability in the Cincinnati knee score
      could be explained by variation in the impairment variables, and quadriceps
      muscle performance and pain were the most significant predictors of disability.
      Extension deficit and pain at 3 months were significantly related to the
      Cincinnati knee score at the 2-year follow-up. CONCLUSIONS: Up to 2 years may be
      needed to regain normal quadriceps muscle performance following ACL
      reconstruction. Pain and quadriceps muscle performance explained most of the
      variability in the Cincinnati knee score.

PMID- 10416181
TI  - Resistance properties of Thera-Band tubing during shoulder abduction exercise.
AB  - STUDY DESIGN: Single-group, repeated measures. OBJECTIVES: To investigate the
      relationship between tubing length and tubing tension for 6 colors of Thera-Band
      tubing (each color representing a different level of resistance) and to estimate
      the resistive shoulder torque provided during shoulder abduction exercise.
      BACKGROUND: Thera-Band tubing is popular for providing resistance in
      rehabilitation strengthening programs. Unfortunately, it is difficult to compare
      use of elastic tubing with other resistance training methods because no published
      data exist on how much resistance is being provided during exercise. METHODS AND
      MEASURES: Nine male and 6 female subjects (age, 25.9 +/- 3.6 years; height, 173
      +/- 10 cm) performed shoulder abduction, using 6 colors of tubing. A strain gauge
      attached at the fixed end of the tubing directly measured the tension generated
      during stretch. For each color of tubing, each subject momentarily held a
      position at 30 degrees, 60 degrees, 90 degrees, 120 degrees, and 150 degrees of
      abduction. Shoulder joint abduction, limb segment position, and tubing length
      were analyzed by means of the Peak Motion Measurement System. Simple linear
      regression equations predicted tubing tension from percent change in tubing
      length at the joint angle positions. A 2-way (5 x 6) repeated-measures ANOVA
      determined the mean differences in tubing tension across tubing colors at the
      shoulder abduction positions. RESULTS: Strong linear relationships were found for
      each tubing tension when referenced according to changes in tubing length.
      Significant differences in tension were found for the various colors of tubing.
      The resistive torque curves for each color tubing were similar to isotonic
      exercise. CONCLUSIONS: Thera-Band tubing provides linear resistance during
      shoulder abduction, but the resistive torque provided by the tubing mimics
      isotonic exercise.

PMID- 10416182
TI  - Foot pronation and patellofemoral joint function.

PMID- 10416183
TI  - Were the effects of a calf-stretching exercise measured?

PMID- 10416184
TI  - Periodic infectivity of Plasmodium gametocytes to the vector. A review.
AB  - Frank Hawking, in 1966 postulated that in synchronous malaria infections, the
      brief period of infectivity of gametocytes was timed to occur when the vector
      bites. Since this early work, numerous studies had contributed to confirm and
      explain this phenomenon with bird, rodent and primate Plasmodium. Data on the
      periodic production of gametocytes, the duration of their maturation, the effect
      of the schizogony on the infectivity and the circadian bioavailability of
      gametocytes provide some more informations on the periodic Plasmodium gametocyte
      infectivity to the vector. This paper is intended to be a review of contributions
      on the "Hawking phenomenon" and to summarize the principal causal hypotheses. The
      conclusion stresses the practical consequences for experimental studies and
      epidemiological surveys.

PMID- 10416185
TI  - The re-emergence of American visceral leishmaniasis in an old focus in Venezuela.
      II. Vectors and parasites.
AB  - As part of an epidemiological study in an old focus of American Visceral
      Leishmaniasis (AVL) in Venezuela (Guayabita, Aragua State), a longitudinal
      entomological survey (January 1993-June 1994) was carried out. A total of 3,239
      males and 6,043 females belonging to 11 phlebotomine sandfly species were
      collected. The two recognised vectors of AVL in the New World, Lutzomyia evansi
      and Lu. longipalpis were found to be sympatric. Lutzomyia evansi was the dominant
      species (86.4%), almost ten fold times more abundant than Lu. longipalpis
      (10.6%). The two species alternated seasonally: Lu evansi peaked at the end of
      the rainy season while Lu. longipalpis, almost virtually absent during such
      period, increased in the dry season. This species seems more greatly influenced
      by the temperature. Seven of 4,559 Lutzomyia evansi (0.15%) and one of 353 Lu.
      longipalpis (0.28%) were found positive for suprapyloric promastigotes. Using the
      polymerase chain reaction (PCR) with universal primers, all isolates were
      identified as Leishmania spp. Two cultures from Lu. evansi, IEVA/VE/93/UCNA-2 and
      IEVA/VE/93/UCNA-3, were established. k-DNA restriction analysis showed high
      homologies between these isolates and Leishmania chagasi. High hybridization
      signal with L. chagasi specific kDNA confirmed these results. These findings
      suggest that Lu. evansi may play a role as vector of visceral leishmaniasis in
      this area. The identity of the parasite carried by Lu. longipalpis needs to be
      confirmed.

PMID- 10416186
TI  - Secreted antigens of the amastigote and promastigote forms of Leishmania infantum
      inducing a humoral response in humans and dogs.
AB  - To study the antigens secreted by promastigote and amastigote forms of Leishmania
      infantum which are able to induce a humoral response in human patients and dogs,
      we have carried out immunoprecipitation assays with different supernatants of in
      vitro cultured parasites, metabolically labelled with [35S]methionine, using
      serum samples from human patients and dogs. In addition, some metabolic labelling
      experiments were performed daily during the in vitro culture parasite's life
      cycle to follow the time course excretion-secretion of parasitic antigens. The
      results demonstrated that the two different hosts developed an antibody response
      against secreted antigens of both stages of Leishmania infantum. Nevertheless,
      the humoral response directed against the excreted-secreted antigens of the
      promastigote forms was qualitatively and quantitatively different when we compare
      the human and the dog immune responses. On the other hand, when the excreted
      secreted antigens of the amastigote forms are immunoprecipitated with either
      human or canine immune serum, the humoral response is similar. In addition, the
      time course study showed that excretion-secretion of antigens was qualitatively
      and quantitatively modulated during the parasitic in vitro life cycle.

PMID- 10416187
TI  - Transglutaminase activity in equine strongyles and its potential role in growth
      and development.
AB  - Transglutaminases (E.C. 2.3.3.13) are a family of Ca(2+)-dependent enzymes that
      stabilize protein structure by catalyzing the formation of isopeptide bonds. A
      novel form of transglutaminase has been identified and characterized that seem to
      play an important role in growth, development, and molting in adult and larval
      stages of filarial nematodes. The aim of this study was to identify the
      ubiquitous nature of this enzyme in other nematodes and to measure its
      significance to larval growth, molting, and development. For this purpose, equine
      Strongylus spp. were used. Activity of this enzyme was identified in extracts of
      larvae and adults of Strongylus vulgaris, S. edentatus, Parascaris equorum and
      Cylicocyclus insigne. The significance of transglutaminase in the early growth
      and development of Strongylus vulgaris, S. edentatus and S. equinus was tested by
      adding specific inhibitors, monodansylcadaverine (MDC) or cystamine (CS), to in
      vitro cultures of third (L3) and fourth stage larvae (L4). The viability, molting
      and growth of these nematode species were affected by both inhibitors. Cystamine
      promoted abnormal development of Strongylus edentatus L3, resulting in an
      aberrant expansion of the anterior end. Addition of these inhibitors to cultures
      of L4 also reduced growth of the three species. The results indicated that
      transglutaminase is present in a wide array of nematode parasites and may be
      important in growth and development of their larval stages.

PMID- 10416188
TI  - [Reactions of cells of nasal and sinusoidal mucosa of goats and sheep naturally
      infected by Oestrus ovis Linne 1758 (Diptera: Oestridae)].
AB  - OEstrosis is a very common myiasis of sheep and goats in mediterranean and
      tropical countries. Goats are suitable hosts for OEstrus ovis but the parasitic
      burden remain lower than in sheep. Cellular responses (mucous and serous mast
      cells, eosinophis and globules leucocytes) were measured in 30 infected and 30
      non infected sheep and in 23 infected and 24 non infected goats. The presence of
      OEstrus ovis larvae led to an important inflammatory response in sheep and in
      goats as well. Furthermore, the intensity of the cellular response correlated
      with the larva burden, specially with globules leucocytes and eosinophils.
      Nevertheless, huge differences occurred between sheep and goats responses even in
      similar larval burden range. Infected sheep showed larger counts of mucous mast
      cells than goats, the differences were smaller in serous mast cells and
      eosinophils and no difference was detected in globules leucocytes
      (intraepithelial mast cells) counts between the two hosts species. These results
      were compared with those obtained in gastro-intestinal strongyles infections.

PMID- 10416189
TI  - Some coccidia from the gall-bladder and intestine of the teiid lizard Ameiva
      ameiva ameiva and the gecko Hemidactylus mabouia in north Brazil.
AB  - A study has been made of the endogenous development of two eimeriid Coccidia in
      the teiid lizard Ameiva ameiva, which were previously considered by Carini (1932)
      to be conspecific with Eimeria rochalimai and Eimeria boveroi Carini & Pinto,
      1926, described in the gecko Hemidactylus mabouia. It has been shown that this is
      not so, and the two parasites of A. ameiva have been named Choleoeimeria carinii
      n. sp. and Acroeimeria pintoi n. sp. A description is also given of the
      endogenous stages of the two eimeriid coccidians previously described in
      Hemidactylus mabouia. The one from the gall-bladder is renamed Choleoeimeria
      rochalimai (Carini & Pinto, 1926) nov. comb., and a redescription is made of
      Eimeria boveroi. The shortcomings of diagnosis based solely on morphology of the
      oocysts are discussed, particularly with regards the eimeriids of reptiles.

PMID- 10416190
TI  - [Neopsylla musseri n. sp. (Siphonaptera-Ctenophthalmidiae), a new flea from
      central Sulawesi (Indonesia)].
AB  - This flea is a montane flea, known from elevations of 1,700-2,300 m, that
      parasitizes endemic murid rodents. It represents a newly recorded genus and
      family of fleas for Sulawesi. Morphologically, the closest taxon to N. musseri n.
      sp. is N. sondaica Jordan, 1931 from Java; it is not closely related to N. luma
      Traub, 1954 from Borneo.

PMID- 10416191
TI  - In vitro culture of rediae of Echinostoma caproni.
AB  - Rediae of Echinostoma caproni (Egyptian strain) were dissected from Biomphalaria
      glabrata snails at intervals from 13-34 days post-exposure and co-cultured for up
      to 51 days with cells of the B. glabrata embryonic (Bge) cell line. Rediae
      readily ingested Bge cells and survived longer when co-cultured with cells than
      in cell-free cultures. Rediae released mostly motile cercariae throughout the
      observation period when in Bge medium and cells. Rediae cultured in 199 medium
      with Bge cells also produced progeny throughout most of the observation period.
      In the latter medium, progeny were much more likely to include rediae as well as
      cercariae. Some cercariae produced in vitro encysted as metacercariae. Rediae
      consumed cercariae released into culture but were not observed to attack one
      another or rediae of a different echinostome species.

PMID- 10416192
TI  - Comparison of a digestion-sedimentation technique with the Kato-Katz technique in
      the detection and quantification of S. mansoni eggs in light to moderate
      infections.
AB  - A comparison between a digestion-sedimentation technique (DST) and the Kato-Katz
      thick smear technique (KKT) in the detection and quantification of Schistosoma
      eggs in stool was carried out in 551 subjects. Specimen were collected one or two
      years after treatment with praziquantel from subjects living in a schistosomiasis
      endemic area of Mali. One hundred infections missed by the KKT were detected by
      the DST. Conversely, 35 infections missed by the DST were detected by the KKT
      (88% were light infections). More subjects were classified as lightly infected by
      the DST (p < 10(-3)) and more subjects were classified as moderately infected
      (101-400 epg) by the KKT (p = 0.02). The KKT produced higher counts than the DST
      among the youngest age group which was also the most infected. The principal
      advantage of the DST over the KKT was its better sensitivity to detect light
      infections resulting from a larger amount of stool processed.

PMID- 10416193
TI  - Survival and emergence of immature Anopheles arabiensis mosquitoes in market
      gardener wells in Dakar, Senegal.
AB  - Anopheles arabiensis is the unique species of the An. gambiae complex observed in
      the wells dug by market-gardeners in the Dakar area. In order to relate the
      numbers of immature stages and emerging adults mosquitoes, population
      measurements were performed in eight wells in which An. arabiensis was the only
      mosquito species. Mean density of immature stages was measured using two sampling
      methods, the dipping with a tray by giving 50 dips in each well, and the quadrat
      with a frame on 2 or 3 m2 in each well. The absolute number of emergent adults
      was obtained by collecting mosquitoes under net-trap covering entirely each
      wells. The dipping method was quicker and more operational than quadrat method.
      Density estimations of larvae at stage I to IV did not significantly differed
      using dipping or quadrat methods. On the contrary, pupal density was
      underestimated when measured by dipping. Mosquito nets placed over wells
      increased significantly emergence rate of adults, thus measurement of emerging
      mosquitoes was possible only the first day following the net putting up. The
      total number of immature stages in each well was significantly correlated with
      the number of emergent mosquitoes. The mean number of mosquitoes emerging daily
      from one well corresponded to 5% of the total number of immature stages. Stage
      distribution for larvae I to IV and pupae, estimated by quadrat, was respectively
      29%, 28%, 22%, 16% et 5% (total = 100%). Taking account the mean duration of
      various immature stages and the number of emerging mosquitoes by day, the
      equation of the survivorship curve from larval hatch (excluded) to emergence
      included was: y = 427.2-136.8 Log x. Therefore the mean mortality at immature
      stages was 80% i.e. an emerging rate of 20%. The results of this study,
      associated with those of previous ones, permit to evaluate the average
      productivity of malaria vectors in market-gardener wells in the Dakar area.

PMID- 10416195
TI  - About the authorship of Lutzomyia youngi (Diptera: Psychodidae)

PMID- 10416194
TI  - Detection of new Enterocytozoon genotypes in faecal samples of farm dogs and a
      cat.
AB  - The microsporidian species Enterocytozoon bieneusi had emerged as opportunistic
      pathogen in AIDS patients causing chronic diarrhoea and was found with high
      prevalences in faeces of asymptomatic pigs. Analysis of the ribosomal RNA gene
      internal transcribed spacer (rDNA ITS) had revealed that nine distinct but
      closely related genotypes occur in humans and in swine. Using primers that were
      designed to be specific for E. bieneusi, we obtained amplicons from the faecal
      samples of one from twelve cats and from three out of 36 farm dogs. Sequence
      analysis of the rDNA ITS, which is part of the diagnostic PCR product, revealed
      that the isolate from the cat is very closely related to the E. bieneusi
      genotypes of human or swine origin. The corresponding sequence of all three dog
      derived isolates were identical among each other and had a sequence similarity to
      known sequences of only 47.6-48.2%. In addition, part of the small subunit rRNA
      gene was amplified and sequenced from one dog-derived isolate revealing a
      similarity to known sequences of human-derived E. bieneusi of 96-98%.
      Enterocytozoon-like spores could be detected by light microscopy in one canine
      sample. Together with recent reports of detection of Enterocytozoon in
      environmental samples, our findings suggest that microsporidia of the genus.
      Enterocytozoon seem to be ubiquitous and consist of many genotypes in various
      naturally infected animal species.

PMID- 10416196
TI  - Rainfall is not a direct mortality factor for anopheline larvae.

PMID- 10416197
TI  - Effects of disease on milk production in the dairy cow: a review.
AB  - Estimates of milk losses consequent to dystocia, stillbirth, milk fever, retained
      placenta, metritis, cystic ovaries, ketosis, displaced abomasum and locomotor
      disorders were reviewed. Papers were selected if they provided quantitative
      estimates of losses based on data collected after 1965, with a sample size
      resulting in a minimum number of disease cases of 25. Thirty-five papers
      fulfilled the selection criteria. Milk losses were expressed in kg/day over the
      period under study to allow comparison of results. Milk fever and cystic ovaries
      were not associated with yield losses (six studies for each disease). Less than
      half of the studies found losses associated with dystocia, retained placenta, and
      metritis, with, respectively, five studies out of 13 (0.3-2.3 kg/day across the
      lactation), five studies out of 13 (0.8 kg/day across the lactation to 2.5 kg/day
      across 100 days in milk), and two studies out of 10 (0.4 kg/day across the
      lactation, and 2.3 kg/day across 119 days in milk). More than half of the studies
      found losses associated with stillbirth, clinical ketosis, ketosis evidenced by a
      diagnostic test, and locomotor disorders, with, respectively, three studies out
      of five (0.7-1.3 kg/day across the lactation), seven studies out of 11 (2.6-5.7
      kg/day short-term, and 1.2 kg/day across the lactation), five studies out of
      seven (1-7 kg/day on the day of diagnosis, and around 1 kg/day across 200 days in
      milk), and six studies out of 11 (0.3-3.3 kg/day across the lactation). All the
      five studies, investigating effects of displaced abomasum, found losses (3.5-10.9
      kg/day across 80 days in milk, or 0.8-2.5 kg/day across the lactation).

PMID- 10416198
TI  - A simulation model for studying the role of pre-slaughter factors on the exposure
      of beef carcasses to human microbial hazards.
AB  - A Monte Carlo simulation model was constructed for assessing the quantity of
      microbial hazards deposited on cattle carcasses under different pre-slaughter
      management regimens. The model permits comparison of industry-wide and abattoir
      based mitigation strategies and is suitable for studying pathogens such as
      Escherichia coli O157:H7 and Salmonella spp. Simulations are based on a
      hierarchical model structure that mimics important aspects of the cattle
      population prior to slaughter. Stochastic inputs were included so that
      uncertainty about important input assumptions (such as prevalence of a human
      pathogen in the live cattle-population) would be reflected in model output.
      Control options were built into the model to assess the benefit of having prior
      knowledge of animal or herd-of-origin pathogen status (obtained from the use of a
      diagnostic test). Similarly, a facility was included for assessing the benefit of
      re-ordering the slaughter sequence based on the extent of external faecal
      contamination. Model outputs were designed to evaluate the performance of an
      abattoir in a 1-day period and included outcomes such as the proportion of
      carcasses contaminated with a pathogen, the daily mean and selected percentiles
      of pathogen counts per carcass, and the position of the first infected animal in
      the slaughter run. A measure of the time rate of introduction of pathogen into
      the abattoir was provided by assessing the median, 5th percentile, and 95th
      percentile cumulative pathogen counts at 10 equidistant points within the
      slaughter run. Outputs can be graphically displayed as frequency distributions,
      probability densities, cumulative distributions or x-y plots. The model shows
      promise as an inexpensive method for evaluating pathogen control strategies such
      as those forming part of a Hazard Analysis and Critical Control Point (HACCP)
      system.

PMID- 10416199
TI  - Pre-slaughter control of Escherichia coli O157 in beef cattle: a simulation
      study.
AB  - A stochastic simulation model was used to assess the benefit of measures
      implemented in the pre-slaughter period that are aimed at reducing the
      contamination of beef carcasses with Shiga-like-toxin-producing Escherichia coli
      O157. The scenario studied was based on an abattoir processing approximately 1000
      head of lot-fed cattle per day. Input assumptions were described using
      probability distributions to reflect uncertainty in their true values. Control
      measures that were assessed were based on either a reduction in herd prevalence
      of infection, reduction in opportunity for cross-contamination in the processing
      plant by re-ordering of the slaughter queue, reduction of concentration of E.
      coli O157 in fresh faeces, or a reduction in the amount of faeces, mud and
      bedding ('tag') transferred from the hide to the carcass. Some control measures
      evaluated were hypothetical in nature and were included to assist with the
      planning of research priorities. Simulations suggested that the greatest
      potential impact is associated with vaccination and with an agent that reduces
      shedding E. coli O157 in faeces. Knowledge of herd-test results obtained by
      testing a sample of animals from the herd provides only a minor advantage in
      control programmes, although application of a rapid test to all animals in all
      lots might be of some benefit. Under most scenarios, there is ample opportunity
      for cross-contamination to occur within the slaughter plant as a result of early
      entry of cattle contaminated with E. coli O157. An industry-wide reduction in the
      amount of tag attached to hides and addition of a source of cattle having a
      prolonged average fasting time were not predicted to have a large impact on mean
      amount of carcass contamination with E. coli O157.

PMID- 10416200
TI  - Urinary biomarkers: roles in risk assessment to environmental and occupational
      nephrotoxins: monitoring of effects and evaluation of mechanisms of toxicity.

PMID- 10416202
TI  - Usefulness of biomarkers of exposure to inorganic mercury, lead, or cadmium in
      controlling occupational and environmental risks of nephrotoxicity.
AB  - A successful prevention of renal diseases induced by occupational or
      environmental exposure to toxic metals such as mercury (Hg), lead (Pb), or
      cadmium (Cd) largely relies on the capability to detect nephrotoxic effects at a
      stage when they are still reversible or at least not yet compromising renal
      function. The knowledge of dose-effect/response relations has been useful to
      control nephrotoxic effects of these metals through a "biological monitoring of
      exposure approach". Chronic occupational exposure to inorganic mercury (mainly
      mercury vapor) may result in renal alterations affecting both tubules and
      glomeruli. Most of the structural or functional renal changes become significant
      when urinary mercury (HgU) exceeds 50 micrograms Hg/g creatinine. However, a
      marked reduction of the urinary excretion of prostaglandin E2 was found at a HgU
      of 35 micrograms Hg/g creatinine. As renal changes evidenced in moderately
      exposed workers were not related to the duration of Hg exposure, it is believed
      that those changes are reversible and mainly the consequence of recently absorbed
      mercury. Thus, monitoring HgU is useful for controlling the nephrotoxic risk of
      overexposure to inorganic mercury; HgU should not exceed 50 micrograms Hg/g
      creatinine in order to prevent cytotoxic and functional renal effects. Several
      studies on Pb workers with blood lead concentrations (PbB) usually below 70
      micrograms Pb/dl have disclosed either no renal effects or subclinical changes of
      marginal or unknown health significance. Changes in urinary excretion+ of
      eicosanoids was not associated with deleterious consequences on either the
      glomerular filtration rate (GFR)--estimated from the creatinine clearance (C(Cr))
      -or renal hemodynamics if the workers' PbB was kept below 70 micrograms Pb/dL.
      The health significance of a slight renal hyperfiltration state in Pb workers is
      yet unknown. In terms of Pb body burden, a mean tibia Pb concentration of about
      60 micrograms Pb/g bone mineral (that is 5 to 10 times the average "normal"
      concentration corresponding to a cumulative PbB index of 900 micrograms Pb/dL x
      year) did not affect the GFR in male workers. This conclusion may not necessarily
      be extrapolated to the general population, as recent studies have disclosed
      inverse associations between PbB and GFR at low-level environmental Pb exposure.
      A 10-fold increase in PbB (e.g., from 4 to 40 micrograms Pb/dL) was associated
      with a reduction of 10-13 mL/min in the C(Cr) and the odds ratio of having
      impaired renal function (viz. C(Cr) < 5th percentile: 52 and 43 mL/min in men and
      women, respectively) was 3.8 (CI 1.4-10.4; p = 0.01). However, the causal
      implication of Pb in this association remains to be clarified. The Cd
      concentration in urine (CdU) has been proposed as an indirect biological
      indicator for Cd accumulation in the kidney. Several biomarkers for detecting
      nephrotoxic effects of Cd at different renal sites were studied in relation to
      CdU. In occupationally exposed males, the CdU thresholds for significant
      alterations of renal markers ranged, according to the marker, from 2.4 to 11.5
      micrograms Cd/g creatinine. A threshold of 10 micrograms Cd/g creatinine
      (corresponding to 200 micrograms Cd/g renal cortex: the critical Cd concentration
      in the kidney) is confirmed for the occurrence of low-molecular-mass proteinuria
      (functional effect) and subsequent loss of renal filtration reserve capacity. In
      workers, microproteinuria was found reversible when reduction or cessation of
      exposure occurred timely when tubular damage was still mild (beta(2)
      microglobulinuria < 1500 micrograms/g creatinine) and CdU had never exceeded 20
      micrograms Cd/g creatinine. As the predictive significance of other renal changes
      (biochemical or cytotoxic) is still unknown, it seems prudent to recommend that
      occupational exposure to Cd should not allow that CdU exceeds 5 micrograms Cd/g
      creatinine.(ABSTRACT TRUNCATED)

PMID- 10416201
TI  - Urinary biomarkers as indicators of renal disease.
AB  - Using modern technology, minute quantities of LMWP, prostanoids, growth factors,
      intra-renal and extra-renal enzymes can be measured in urine. Excretory patterns
      that are characteristic for site and mechanism of renal injury often can be
      found. It is possible to recognise urinary biomarker patterns that suggest the
      putative environmental nephrotoxin. Our own studies performed in subjects with
      low level occupational and environmental exposures in New Jersey confirm the
      pattern specificity and threshold effects for Cr, Hg and Pb. In addition, we have
      been able to show that increased NAG and IAP excretion following Pb exposure
      correlates with current (blood Pb) but not with the cumulative Pb burden (bone
      Pb). The relatively specific characteristic patterns of biomarker excretion are
      lost as renal failure progresses. Moreover, renal injury that results in tubular
      proteinuria may not progress to renal failure. Nevertheless, urine biomarkers can
      help to establish acceptable levels and identify the need for long term
      surveillance to ascertain when clinical renal disease may result.

PMID- 10416203
TI  - Biomedical testing of the kidney for persons exposed to hazardous substances in
      the environment.
AB  - To identify kidney injury and dysfunction among persons exposed to hazardous
      substances in the environment, a battery of biomarker tests has been identified
      for systematic public health use. The standardized use of tests for conducting
      field epidemiology studies was reviewed in a 1995 joint American-European
      workshop, and recommended tests were selected by the Agency for Toxic Substances
      and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention
      (CDC). These tests would be useful in conducting public health activities but are
      not recommended in a manner that would suggest changes in routine clinical
      practice. The tests selected include serum creatinine, urine analysis, urinary
      albumin, retinol-binding protein, N-acetyl-beta-D-glucosaminidase (NAG), alanine
      aminopeptidase (AAP), and osmolality. Urinary creatinine was also included to
      adjust for urine concentration. The tests were chosen for use not only in
      epidemiologic field studies but also clinically oriented population screening and
      case studies of persons exposed to hazardous substances at waste sites. Studies
      using the battery may address the relationship between kidney damage and
      dysfunction and exposures to hazardous substances, especially in susceptible
      populations including children. Also, longitudinal studies should be conducted to
      evaluate the long-term health implications of abnormal tests and to measure the
      tests' predictive value for renal injury. These studies could evaluate the
      continuum of renal dysfunction as expressed by persistent decrements in
      glomerular filtration to the development of end-stage renal disease.

PMID- 10416204
TI  - Risk assessment of nephrotoxicity of cadmium.
AB  - Cadmium as an environmental or occupational toxin has been well studied. Exposure
      can fairly easily be detected by analysis of cadmium in biological material.
      Different routes of cadmium uptake, such as via airborne particles, cigarette
      smoke or contaminated food, have been identified. Urinary concentrations
      associated with renal effects vary, depending on urinary marker of effect, and
      are as low as 2 micrograms cadmium/g creatinine. Different segments of the
      nephron are affected by cadmium. Urinary enzymes and serum derived proteins,
      mainly low-molecular weight proteins, as well as eicosanoids or
      glycosaminoglycans are among the tubular or glomerular markers of effect.
      Predisposing factors, such as smoking, dietary habits and low body iron stores
      have been described. It is concluded that even for low level cadmium exposure
      effects can be detected with sensitive diagnostic tools.

PMID- 10416205
TI  - The maturing kidney: development and susceptibility.
AB  - Kidney morphogenesis is accomplished by the coordinated interaction of molecular
      signals that culminate in the production of an organ that is architecturally and
      functionally ready for extrauterine, free life. In humans, nephrogenesis is
      completed before birth. However the kidney continues to mature both from a
      functional and anatomical point of view. Throughout its development, the kidney
      is susceptible to a variety of injurious agents. This brief review considers the
      basic mechanisms of kidney organogenesis and functional maturation. To illustrate
      some concepts, the renal alterations caused by interference with a normal
      regulatory system, the renin-angiotensin system is discussed.

PMID- 10416206
TI  - Urinary albumin excretion in children: factors related to elevated excretion in
      the United States population.
AB  - Past population studies have indicated a higher prevalence of high albumin
      excretion in children than in adults. In this study, NHANES III United States
      population data was analyzed to study factors associated with elevated albumin
      excretion in children 8 to 18 years of age. The analysis confirmed a higher
      prevalence of albumin values > 30 mg/g creatinine and > 200 mg/g creatinine in
      children than in adults, and indicated that girls are two to three times more
      likely to have albumin excretion above these levels than boys. Neither
      hypertension nor reported diabetes--major factors influencing albumin excretion
      in adults--accounted for the higher excretion levels in children. The higher
      excretion levels were not associated with prescription medications or a poor
      rating of the child's overall health status by a physician. The higher
      prevalences is influenced by puberty stage and is more likely to occur in
      children with lower than average body mass index, independent of the relationship
      with urine creatinine excretion. The increased prevalence of high albumin
      excretion is probably associated with normal development in children, but an
      increased susceptibility to chronic diseases in the future among the children
      with high excretion cannot be ruled out.

PMID- 10416208
TI  - Using urinary biomarkers to evaluate renal effects of a Cox-2 NSAID in
      volunteers.
AB  - We explored urinary biomarkers as an alternative for measuring the effect of an
      experimental COX-2 inhibitor on renal function in volunteers. Thirty male
      volunteers between the ages of 20-40 were enrolled and a COX-2 NSAID was given in
      a blinded design. The acute administration of an oral COX-2 NSAID resulted in a
      consistent increase in the urinary enzyme AAP at 2 hours. At 24 hours after COX-2
      NSAID administration values for most of the urinary biomarkers had returned to
      baseline suggesting that such effects are transient and without clinical
      significance in situations of acute administration.

PMID- 10416207
TI  - Early markers of nephrotoxicity: detection of children at risk from environmental
      pollution.
AB  - The current investigation is the largest to date concerned with the assessment of
      the value of different urinary biomarkers to detect nephrotoxic effects in
      children exposed to cadmium and lead. A battery of tests which had proved
      valuable in previous studies on men and women where used, together with a number
      of more recently developed biomarkers. No significant effect of sex and age were
      found but the location of the children (site) was important. The results
      indicated that there might have been variability in either the assay procedures
      or sample handling between the different sites. A small group of tests were found
      to be elevated following toxic exposure and should be used in future studies.
      However, there was considerable variation in the degree of exposure amongst the
      control groups from different countries and in the test groups. This made pooling
      of the data difficult but the study does highlight the way forward and
      demonstrates that children can be at risk from environmental exposure to toxins
      at a lower level than is acceptable for adults.

PMID- 10416209
TI  - FK506 nephrotoxicity.
AB  - Tacolimus (FK506) is a potent immunosuppressive agent with significant
      nephrotoxic properties. FK506 is complexed with an intracellular binding protein
      FKBP-12. Both the immunosuppressive and nephrotoxic effects may be linked to the
      inhibitory effect of this complex on calcineurin. The initial phase of FK506
      nephrotoxicity is associated with a reduction in renal blood flow and glomerular
      filtration rate. More significant microvascular injury may follow with
      endothelial damage. Tubular epithelial cell vacuolation, atrophy and
      micocalcification may be associated with the development of irreversible
      interstitial fibrosis. At times, mesangial cell proliferation adds to the
      glomerular abnormalities. These effects may be mediated by the inhibitory effect
      on calcineurin and its role in regulating cellular calcium channels. FK506
      stimulates several inflammatory cytokines, such as transforming growth factor
      beta, with potential deleterious effects. Also abnormalities in the
      reninangiotensin system, endothelin, renal prostaglandins, adrenergic receptors
      may all play a role in the nephrotoxic effects.

PMID- 10416211
TI  - Study design and data analysis in clinical and environmental models of
      nephrotoxicity.
AB  - Protocols for clinical studies of nephrotoxicity may include several elements.
      They include background information, study objectives, study design, data
      handling and analysis, organization and administration, and methods and
      definitions. Response variables used to indicate the development of clinically
      apparent renal disease should be clearly defined. Susceptibility factors such as
      diabetes, hypertension, cardiovascular disease, obesity, smoking history, and
      genetic factors may influence the development of renal disease and other health
      outcomes. These factors may also affect the pattern of abnormal biomarkers that
      appear during the development of renal disease. Some individuals who are normal
      by standard clinical criteria will be in various stages of disease development
      and will have abnormal biomarker levels. With all approaches, an adequate
      baseline assessment of biomarker values is critically important. Consistent
      findings among studies reinforce conclusions.

PMID- 10416210
TI  - Aquaporin-2 as a biomarker of distal renal tubular function using lithium as an
      experimental model.
AB  - Aquaporin-2 protein levels can be detected in the urine of normal of subjects if
      measured after fluid deprivation. By contrast, in patients with nephrogenic
      diabetes insipidus caused by mutations in the aquaporin-2 gene, urine aquaporin-2
      protein excretion cannot be detected. We propose that properly standardized
      measurements of urinary aquaporin-2 protein may provide a useful biomarker of
      distal tubular function in a variety of acquired conditions that impair
      concentrating ability including some nephrotoxic agents.

PMID- 10416212
TI  - Experimental studies on genetically determined susceptibility to mercury-induced
      autoimmune response.
AB  - Individual differences in susceptibility may be caused by genetical as well as
      external variables. In mice as well as rats, autoimmune response can be induced
      by mercury or gold. The present data demonstrates that the autoimmune response
      depends qualitatively on the H-2 haplotype. If a strain of mice does not have the
      susceptible haplotype, no autoimmunity will be induced. However, even among the
      responding strains significant differences were observed. A clear correlation
      exists between renal mercury deposition and the autoimmune response in
      susceptible strains of mice. There was a threshold for induction of the
      autoimmune response in genetically susceptible mice. When exposure was
      interrupted, the mercury deposition decreased as did the antinucleolar antibody
      titre. Thresholds exist within susceptible strains below which no autoimmune
      response is induced.

PMID- 10416213
TI  - The use of optical sensors to understand cellular interactions with renal cells.
AB  - Optical biosensor technology has revolutionized the assessment of receptor
      binding, enabling the characterization of low affinity interactions in real time.
      We report the application of the LAsys Optical Biosensor to the investigation of
      the affinity and specificity of the putative proximal tubular scavenging receptor
      for protein reabsorption and the specificity of AGE-modified protein interactions
      with primary human mesangial cells. Using the LLCPK cell line, the carboxy-methyl
      dextran cuvette surface and five different proteins (ranging in size and charge),
      we have shown that there is evidence to support the existence of a single
      scavenging receptor for all the proteins tested. The proteins competed with each
      other differing only in their relative binding affinity for the common receptor.
      We have also shown that human mesangial cells can bind to AGE-modified human
      serum albumin (AGE-HSA) immobilized onto the carboxylate surfaced planar cuvette
      and that binding can be inhibited using increasing concentrations of soluble AGE
      HSA. However, increasing concentrations of soluble Non-AGE modified HSA can also
      inhibit binding to a similar extent which implies that there is relatively little
      AGE-receptor (RAGE) expression on cultured primary human mesangial cells. These
      results demonstrate the exciting potential of this technology as a tool to
      explore cellular interactions with renal cells.

PMID- 10416214
TI  - Lessons learned from ischemic and cisplatin-induced nephrotoxicity in animals.
AB  - Following ischemic or nephrotoxic injury, the regenerating kidney assumes an
      earlier developmental stage and a less mature phenotype. Recovery involves the
      activation of a group of genes, including protooncogenes and growth factor genes
      that initiate and sustain cell growth. Inflammation also plays an important role
      in the recovery process as several of the changes in gene expression implicate
      the participation of the inflammatory cascade. Many of the changes in gene
      expression may eventually be reflected in the urine of the damaged kidney. By
      exploiting these changes in urine composition as a consequence of injury it
      should be possible to detect evidence of biologic effects of exposure and may
      yield predictions of eventual risk of serious damage to kidney.

PMID- 10416215
TI  - An animal model of chronic cyclosporine nephrotoxicity.
AB  - The development of a reproducible animal model that mimics CSA nephropathy in man
      has allowed the examination of the several proposed mechanisms of toxicity. While
      the precise mechanism remains to be defined, important clues have been provided
      and creative techniques for minimizing the adverse effects of this very valuable
      adjunct to transplant success have been identified.

PMID- 10416216
TI  - Exposure to hydrocarbons and renal disease: an experimental animal model.
AB  - The association between hydrocarbon exposure and chronic glomerulonephritis is
      still a controversial scientific issue. Recent epidemiological evidence suggests
      a role of exposure to hydrocarbons in the progression of glomerulonephritis
      towards chronic renal failure. The present experimental study on rats has been
      designed to assess the possible role of styrene in the progression of adriamycin
      (ADR) nephrosis, a well known model of renal fibrosis following nephrotic
      syndrome induced by ADR. Female Sprague-Dawley rats were exposed to styrene, 300
      ppm, 6 h/day, 5 days/week for 12 weeks (group 1); treated with ADR, 2 mg/Kg,
      i.v., twice on day 1 and day 15 of the study (group 2); Additional groups of
      animals received both the styrene and ADR treatments (group 3) or served as
      controls (group 4). The urinary excretion of total and single proteins (albumin,
      Retinol-Binding Protein (RBP), Clara Cell 16 Kd protein (CC16), fibronectin) was
      measured monthly, whereas histopathology and determinations requiring blood
      sampling were carried out at the end of the experiment. A progressive increase in
      total proteinuria, falling in the nephrotic range already by the 6th week was
      observed in ADR-treated groups. Styrene exposure caused up to a 3- to 5-fold
      increase as compared to controls. Co-exposure to ADR and styrene also resulted in
      a proteinuria much greater than that caused by ADR alone. The interactive effect
      of styrene and ADR was statistically significant for albuminuria and urinary
      fibronectin. A similar response was observed for glomerular filtration rate at
      the end of the experiment, styrene-exposed animals showing hyperfiltration as
      compared to their respective control group. At the end of the experiment,
      histopathological scoring for interstitial infiltration and fibrosis was also
      significantly higher in styrene-treated animals as compared to their respective
      control groups. In ADR-treated rats, low molecular weight proteinuria (l.m.w.p.)
      was only slightly affected, suggesting minimal tubular dysfunction associated
      with extensive tubular atrophy. However, styrene-exposed animals showed l.m.w.p.
      higher than their respective controls. In summary, in this animal model we were
      able to confirm both styrene-induced microproteinuria, mainly albuminuria and
      minor increases in l.m.w.p., observed among occupationally exposed workers and
      the role of hydrocarbon exposure as a factor accelerating the progression of
      renal disease suggested by epidemiological investigations in patients suffering
      from chronic renal disease. Whereas in rats exposed to styrene only,
      microproteinuria was stable over time and minor histopathological changes were
      noted at the end of the experiment, evidence of a role of solvent exposure in the
      progression of ADR nephropathy was obtained in terms of both renal dysfunction
      and interstitial fibrosis. The mechanistic basis of styrene-ADR interaction is
      unclear. However, experimental evidence is consistent with epidemiological
      findings suggesting the need to avoid solvent exposure in patients suffering from
      renal diseases.

PMID- 10416217
TI  - Human renal medullary interstitial cells and analgesic nephropathy.
AB  - The aim of this study was to investigate the effects of known papillotoxins using
      cultures of human renal interstital medullary cells (hRMIC). The culture of hMIC
      was based on the primary culture of human renal medullary explants, selective
      detachment of interstitial cells and selective overgrowth of these cells in a
      serum-rich medium after dilution cloning. The homogeneous population of cells
      obtained exhibited the characteristic morphological and functional
      characteristics of Type I interstitial cells, viz. stellate-shaped cells
      demonstrating numerous lipid droplets, abundant endoplasmic reticulum and
      mitochondria, fine filaments underlying the cell membrane and the production of
      extracellular matrix. Cytotoxicity studies using hMIC and known papillotoxins
      clearly demonstrated a reduction in cell viability that varied with bath exposure
      time and type of agent tested. While only phenylbutazone and mefenamic acid
      produced significant cytotoxicity after a 24 h incubation period, cell viability
      assessed using the MTT assay was only profoundly reduced by aspirin and
      paracetamol following sub-chronic exposure for 7 days. The rank order of
      cytotoxicity observed in hMIC was phenylbutazone > mefenamic acid > aspirin >
      paracetamol. The results demonstrate the potential of hMIC for investigating and
      defining the early cellular events in the pathogenesis of analgesic nephropathy.

PMID- 10416218
TI  - Review of the genetics of renal disease.
AB  - The results of many of human studies indicate that the genetics of the more
      common forms of renal disease are quite complex. There are indications that human
      renal disease may be both polygenic and heterogenic. There are several
      approaches. Some researchers studying small populations are collecting larger
      numbers of families with multiple affected individuals. Others are employing
      discordant sib-pair analysis. Also, trios (individual with renal disease and that
      individual's parents) have been suggested as a means of collecting larger numbers
      of people with renal disease. Another population of interest is the group
      susceptible to nephrotoxicity. At common doses of nephrotoxic drugs and common
      levels of exposure to environmental and occupational nephrotoxic substances, only
      a portion of those similarly exposed develop significant renal damage. This
      subset of individuals may have a genetic susceptibility to renal damage caused by
      toxic agents.

PMID- 10416219
TI  - Candidate gene analysis in African Americans with renal failure.
AB  - A search for renal failure genes is being conducted in African American sib pairs
      concordant for end-stage renal disease (ESRD) recruited predominantly from the
      dialysis population in the Southeastern United States. Family history data is
      being collected in patients from more than 250 individual dialysis units.
      Patients with polycystic kidney disease, Alport's Syndrome and confirmed urologic
      disease are excluded. The study employs a candidate gene strategy initially,
      followed by a genome-wide search for linkage between polymorphic markers and the
      phenotype "ESRD."

PMID- 10416220
TI  - SDS-electrophoresis of unconcentrated urine samples using a semi-automatic
      method.
AB  - The study of urinary proteins is an important tool in the screening and diagnosis
      of patients with renal impairment. Quantification of total proteins, although
      useful, can provide only limited information. Gel electrophoresis of urine
      samples may provide more detailed information.

PMID- 10416221
TI  - Biomarkers in occupational volatile organic chemical exposure.
AB  - Evidence exists that in certain groups of workers exposed to volatile organic
      chemicals, there is subclinical renal damage and dysfunction. Also, there is
      activation of biological mechanisms that are suggested links between volatile
      organic chemical exposure and renal disease. Notably, the workers studied are
      employed in factories where exposures are considered controlled, with on-site
      professional health and safety management. Recent studies continue to indicate an
      increased risk of renal disease in those exposed to volatile organic chemicals.

PMID- 10416223
TI  - Cell cycle events during renal injury.
AB  - Recovery from ischemic and nephrotoxic acute renal failure requires replacement
      of damaged tubule cells in order to restore the morphological and functional
      integrity of the renal epithelium. A more thorough understanding of the renal
      stress response and its molecular interactions with the cell cycle machinery will
      be important areas of biomarker research in nephrotoxicity. Many of these
      molecular targets should be detectable hopefully without resorting the invasive
      techniques.

PMID- 10416222
TI  - The use of lithium clearance measurements as an estimate of glomerulo-tubular
      function.
AB  - Lithium clearance measurements are based on the observation that lithium
      undergoes isoosmotic reabsorption in the proximal renal tubule to the same extent
      as salt and water, but undergoes neither reabsorption nor secretion elsewhere in
      the nephron. Consequently, lithium clearance values estimate the delivery of
      isoosmotic fluid to the loop of Henle and hence provide an assessment of proximal
      tubular reabsorption of isoosmotic fluid. If sodium clearance and urinary flow
      rate are also measured, then this allows the derivation of a number of parameters
      relating to both the absolute and relative renal handling of isoosmotic fluid in
      the proximal and distal regions of the kidney. Consequently, lithium clearance
      techniques can be used in both experimental and clinical studies to evaluate
      glomerulo-tubular function and provide information regarding the handling of
      sodium and water by the proximal and distal nephron in both health and disease.
      The use of lithium clearance measurements in the assessment of glomerulo-tubular
      function in patients treated with rIL2 for colorectal cancer is described and its
      application to both drug-induced toxicity and other disease states discussed.

PMID- 10416225
TI  - Urinary biomarkers: recommendations of the Joint European/United States Workshop
      for future research.
AB  - The session concluded on a positive note with enthusiasm on the part of
      participates to become involved in one of the proposed joint protocols. Left to
      be answered was whether or not individual urinary biomarkers can be tailored to
      be disease specific or will there always be a need for a panel of biomarkers to
      insure interpretable results? It was agreed that proposals for three studies
      would be prepared. The first study will take advantage of the fact that field
      studies are currently being organized by both European and American groups.
      European scientists are working with the World Health Organization to investigate
      lead exposure in a region of China. At the same time, scientists in the United
      States are implementing a surveillance program in a population exposed to lead
      and other heavy metals in Kellogg, Idaho. These efforts provide an excellent
      opportunity for the sharing of samples and the study of a biomarkers panel that
      would contain both standard and candidate biomarkers. It was agreed that the
      parties interested in participating would alert the workshop organizers. The
      second study will expand upon a protocol developed by Dr. Debroe that has as its
      subjects non-transplant patients being treated with cyclosporine. An additional
      complimentary study of tacrolimus (FK-506) nephrotoxicity will also be developed.
      This protocol will be designed to follow the loss of renal function with a
      urinary biomarkers panel. The third study will follow the lead of Dr. Safirstein
      who urged the consideration of Cisplatin nephrotoxicity as a singular model for
      analyzing the usefulness of various biomarkers as measures of both acute and
      chronic nephrotoxicity.

PMID- 10416224
TI  - Oxidant mechanisms in gentamicin nephrotoxicity.
AB  - Acute renal failure is a major complication of aminoglycoside antibiotics, which
      are widely used in the treatment of gram-negative infections. Sequential
      reduction of oxygen along the univalent pathway leads to the generation of
      superoxide anion, hydrogen peroxide, hydroxyl radical, and water. A large body of
      in vitro and in vivo evidence indicates that these partially reduced oxygen
      metabolites are important mediators of gentamicin nephrotoxicity. Gentamicin has
      been shown to enhance the generation of superoxide anion and hydrogen peroxide by
      renal cortical mitochondria. The interaction between superoxide anion and
      hydrogen peroxide in the presence of metal catalyst can lead to the generation of
      hydroxyl radical. Gentamicin has been shown to lead to release of iron from renal
      cortical mitochondria and to enhance generation of hydroxyl radical. These in
      vitro observations have been supported by in vivo studies in which scavengers of
      reactive oxygen metabolites and iron chelators have shown to be protective in
      gentamicin induced acute renal failure. There is evidence to suggest that studies
      may have broader implication in being relevant to other aminoglycosides including
      streptomycin and being applicable to other major toxicity of aminoglycoside such
      as ototoxicity.

PMID- 10416226
TI  - [Changes in neurotransmission systems after the injection of beta-amyloid protein
      beta (12-28) in the hypothalamus and anterior thalamus of the rat].
AB  - INTRODUCTION AND OBJECTIVE: Alzheimer's disease (AD) is a degenerative central
      nervous system disorder. The histopathologic features include senile plaques,
      which are composed primarily of insoluble aggregates of amyloid beta-protein (A
      beta). The purpose of this study was to analyse the effects of A beta on several
      neurotransmitter/neuromodulator systems as a possible model for the
      neuropathological changes that occur in AD. MATERIAL AND METHODS: Adult rats
      (Wistar, 200-300 g) received injections of A beta (12-28) (0.5 microliter-2
      microliters, 1 microgram-4 micrograms) into the hypothalamus (mammillary complex)
      and anterior thalamic nuclei (ATN). After a postinjection survival period of 3
      days-3 weeks the rats were perfused and the brains processed for the
      immunocytochemical localization of several neurochemicals markers. RESULTS AND
      CONCLUSIONS: Following injections of A beta into the mammillary nuclei and into
      ATN a significant decrease in fibres and terminal like-structures immunoreactive
      for ChAT were found in the cortex and hippocampus. Loss and degeneration of
      cholinergic neurons was also observed in the basal forebrain (medial septal
      nucleus, nuclei of the diagonal band of Broca and magnocellular nucleus of
      Meynert). A similar pattern of changes was also found in the glutamatergic
      system. Thus, injections of A beta into the mammillary nuclei caused a moderate
      loss of glutamate-immunoreactive neurons in the ATN and tegmental nuclei of
      Gudden, whereas injections of A beta into the ATN caused a moderate loss of
      glutamate-immunoreactive neurons in the retrosplenial cortex, hippocampus and
      mammillary nuclei. No significant changes were found in the GABAergic system. The
      alteration of certain neuropeptides, such us the somatostatin, is also a
      consistent finding. These results indicate the possibility that A beta in vivo
      caused alteration of different neurotransmitter/neuromodulator markers in the rat
      brain.

PMID- 10416227
TI  - [Epidemiology of acute cerebrovascular disease in Lleida from 1996 to 1997.
      Predictive factors of mortality at short and medium term].
AB  - INTRODUCTION: Given the great clinical relevance of the cerebrovascular disease,
      the incidence, nosology, vascular risk factors and factors predicting short and
      medium-term survival after stroke were evaluated in Lleida (Spain). PATIENTS AND
      METHODS: Five hundred forty-five consecutive patients with an acute stroke
      admitted to the Hospital Universitario Arnau de Vilanova during the period 1996
      1997 were evaluated. A descriptive epidemiological study and a multivariate
      logistic regression analysis of predictive factors of mortality at 1-month and 1
      year after the stroke were made. The latter provided a clinical scoring system
      for predicting survival. RESULTS: The incidence rate of stroke was 138.3/100,000
      inhabitants. Significant risk factors were hypertension and peripheral
      vasculopathy. There were 80.1% of ischemic and 19.9% of hemorrhagic strokes (p <
      0.001). A Glasgow scale < or = 7, hemianopsia and hemorraghic stroke were
      significant predictors of 1-month mortality, whereas age > or = 70 years,
      diabetes, atrial fibrillation and limb weakness decreased survival at 1 year.
      CONCLUSIONS: The incidence rate of stroke in Lleida is low respect to other
      studies in Spain. Simple clinical measures may help to establish a prognosis at
      short and medium-term.

PMID- 10416228
TI  - [Myasthenia gravis in patients over 50 years of age].
AB  - INTRODUCTION: A study was made in the Clinical Provincial Hospital for Surgical
      Teaching Saturnino Lora in Santiago de Cuba. A group of 23 patients over 50 years
      of age attended this centre and were treated for the onset of myasthenia gravis
      between January 1983 and December 1997. OBJECTIVE AND METHODS: To determine some
      of the clinical and evolutive characteristics of the disease such as: sex, age of
      onset, initial symptoms of the illness, clinical forms and also the different
      types of treatment used, evolution and mortality. RESULTS AND CONCLUSIONS: There
      was a clear predominance of men, the commonest age of onset was from sixty to
      seventy, the predominant clinical forms were generalized (mild or moderate), and
      the initial symptoms were ocular. The most commonly used treatment was by
      anticholinesterases and steroids. There is significant variability in the
      evolution of these patients. The larger group improved. However, there was high
      mortality, mainly in older men.

PMID- 10416229
TI  - [Use of multidimensional scale for parents of children aged 6 to 11 for the
      diagnosis of attention deficit with hyperactivity].
AB  - INTRODUCTION: The BASC is a multidimensional approach to evaluate the child
      behavior and it has been validated on the diagnosis of ADD/+H in North American
      children. OBJECTIVE: Validating BASC-PRS 6-11 on the diagnosis of ADD/+H.
      PATIENTS AND METHODS: We selected 25 male DSM IV-ADD/+H (combined type), 6 to 11
      years-old children, and 25 age, gender, and socioeconomic status matched
      controls. Mean ages of both groups 8.16 (1.5), schooling of controls 2.64 (1.4),
      and cases 2.6 (1.9). RESULTS: On the Clinical Scale ADD/+H children had
      significant (Anova p < 0.01) higher scores in hyperactivity, conduct problems,
      and attention problems. On the Adaptive Scale only significant differences on
      social skills and leadership were found, with lower score in the ADD/+H group. A
      crosstab analysis between group code and each rating variable transformed into
      categorical (0 and 1) variable, cut-off point = 85 percentile, found that the
      case children's parents qualified as clinically in higher risk the variables
      attention problems (OR = 24.4; 95% CI = 4.5-130), conduct problems (OR = 9.0; 95%
      CI = 1.7-46.9) and hyperactivity (OR = 6.8; 95% CI = 1.6-28.5) (p < 0.01). A
      discriminant analysis selected attention problems as discriminant function (p <
      0.0001). Classification capability 84% for each group. CONCLUSION: Our results
      proved the validity of the BASC-PRS 6-11 questionnaire for the screening
      diagnosis of ADD/+H children in a Spanish speaking population.

PMID- 10416231
TI  - [Spinocerebellar ataxia type VII (AEC 7). Report of a Spanish family with the
      disease].
AB  - INTRODUCTION: The dominant autosomic ataxias are a group of neurodegenerative
      disorders caused by expansion of a CAG triplet in different genes, found along
      the genome. The dominant autosomic ataxias present very varied clinical findings.
      However, genetic studies are being done to establish the genotype-phenotype
      relationship of the different autosomal dominant ataxias. CLINICAL CASE: A 50
      year old man had alterations in gait, dysarthria and visual changes (retinal
      degeneration). Study of the different genes known to be responsible for the
      dominant autosomic ataxias have an expansion of the superior CAG of more than 37
      repetitions of the gene SCA 7, whilst in the normal control population there are
      9-18 repetitions of this gene. Other members of the family had similar clinical
      findings, although the age of onset varied. One did not have retinal degeneration
      but did have expansion of the SCA 7 gene. CONCLUSIONS: The non-pathological range
      of SCA 7 in the Spanish population, according to our study, is between 9-18
      repetitions of triplet CAG, whilst in members of the patient's family they were
      over 37. The clinical findings, which were similar in all patients were found in
      all patients except for one, who did not have retinal degeneration. We observed
      the phenomenon of genetic anticipation in the family studied.

PMID- 10416230
TI  - [The use of ropinirol ++ as a treatment for restless leg syndrome].
AB  - INTRODUCTION: Restless legs is an unpleasant sensation in the calves that occurs
      when the individual is sitting or laying down, with an irresistible urge to move
      the legs. It has been know as a cause of insomnia. We have been using various
      drugs with a variety of effectiveness. Levodopa is now considered the drug of
      choice but drug tolerance is likely to develop the risk of drug dependence.
      Recently, a new drug was developed by Smithkline Beecham called ropinirol which
      principal indication is the treatment of initial phase of Parkinson's disease.
      PATIENTS AND METHODS: Base on the idea of the efficacy de la levodopa in patients
      with restless legs we administered 0.25 mg of ropinirol at bedtime to 15 of our
      patients diagnosed with restless legs syndrome. None of them had received
      positive results using the classic treatments during more than five years since
      they had developed this syndrome. Before the treatment was begun, we discontinued
      any medications relating to this illness. RESULTS: Beneficial effects were
      observed after the first administration and has continued until this time, 12
      months after the initial treatment. Efficacy was measure by using sleep
      questionnaires (Spiegel). With only a pill (0.25 mg) at the moment of laying down
      at bedtime reports a clear improvement in the symptoms, including reducing the
      periodic leg movements. CONCLUSION: That improvements continue without any
      secondary side effects and without appearing to have built up any tolerance for
      the medication. Further research is needed to investigate the long term efficacy
      and side effects of this new treatment, but at this moment is a valuable and
      satisfactory tool to treat restless legs syndromes.

PMID- 10416232
TI  - [Stroke in a child due to hemoglobinopathy AS].
AB  - INTRODUCTION: Falciform cell anaemia is a genetically determined
      haemoglobinopathy which in homozygote form (HbSS) is accompanied by neurological
      disorders in a quarter of the patients, mainly in the form of cerebral ischemia.
      Some authors consider the heterozygote (HbAS) form to be asymptomatic, although
      several such patients have been described with stroke. CLINICAL CASE: A white boy
      of 5 years of age had a cerebral infarct whilst travelling by car from his home
      town (222 meters above sea level) to the capital of the country (which is 2,600
      meters above sea level). During the journey he complained of headache, vomiting
      and the onset of right hemiplegia. Angio-MR and CT showed the characteristic
      features of an infarct. SPECT showed hypoperfusion of left frontal predominance
      and of the basal ganglia bilaterally, but with left-sided predominance.
      Electrophoresis studies of his haemoglobin showed the present of AS
      haemoglobinopathy. We present the results of investigations done and a review of
      the literature. CONCLUSIONS: AS haemoglobinopathy, together with hypoxia due to
      altitude and possibly slight dehydration, were probably the causes of our
      patient's cerebral infarct. We recommended electrophoresis of haemoglobin in all
      patients (especially children and young adults) who present with stroke.

PMID- 10416233
TI  - [Sotos syndrome associated with focal dystonia].
AB  - INTRODUCTION: Sotos syndrome is a form of infantile gigantism characterized by
      excessive body size from the time of birth, particular facies, acromegalic
      changes and signs of non-progressive cerebral involvement. The etiology is
      unknown. Diagnosis is based on somatometric data and the particular phenotype
      traits. Biochemical and endocrine studies are normal. Torticollis is a focal
      dystonia and therefore more common in adults. CLINICAL CASE: A 20 year old woman
      with macrosomic features since birth presented with: weight 104 kg, height 182
      cm; prognathism, hypertelorism, a broad over hanging forehead with a high hair
      line; large ears, hands and feet; torticollis towards the right with elevation
      and anteroversion of the right shoulder which caused symptomatic scoliosis. She
      was bradypsychic and rather slow in speech. The complementary tests done
      (cerebral and cervical CT and MR, bone gammography, evoked potentials, EMG-ENG,
      sural nerve biopsy, biopsy of skin and muscle, EEG and hormone and biochemistry
      studies) were normal. The torticollis was treated with botulinus toxin and
      improved considerably, as did the scoliosis. CONCLUSIONS: To date, dystonia has
      not been described in association with Sotos syndrome. This may be a causal
      association, or even perhaps hereditary, since the patient's mother had dystonia
      (in the form of blepharospasm).

PMID- 10416234
TI  - [Intraventricular hemorrhage due to the rupture of atherosclerotic dissecting
      aneurysm of the middle cerebral artery].
AB  - INTRODUCTION: We present a case of fusiform intracranial aneurysm where, apart
      from the unusual site, we draw attention to the form of clinical presentation,
      namely intraventricular haemorrhage. Clinical case. A 68 year-old-man with a
      history of smoking, hyperuricemia with seizures of gout treated with colchicine
      and allopurinol, and hypertension treated with captopril. Nine years previously
      he had a right capsulothalamic haematoma and presented (as a sequela of this) a
      left sensomotor deficit, with a good functional level. In December 1998 he was
      admitted for sudden onset of headache and deterioration of consciousness. He had
      right limb movements which were typical of decerebration and made intubation and
      mechanical ventilation necessary. Cerebral CT, with angiographic sequences,
      showed blood in the lateral ventricles and III ventricle, with ventricular
      dilation and a fusiform aneurysm of the left middle cerebral artery. In view of
      the neurological state of the patient, treatment of the aneurysm was postponed.
      After initial improvement, which permitted extubation, tetraparesia
      (predominantly right) and a pseudobulbar syndrome were seen. The patient had
      repeated respiratory infections and died from sepsis caused by Pseudomona
      aeruginosa (of respiratory origin) three months after admission. CONCLUSIONS:
      Fusiform intracranial aneurysms form 9% of all aneurysms. Localization to the
      middle cerebral artery is infrequent, the basilar trunk and internal carotid
      artery are commoner sites. In our case angio-CT was a useful non-invasive neuro
      radiological technique.

PMID- 10416235
TI  - [Epileptic seizures as the first sign of fibrous bone dysplasia].
AB  - INTRODUCTION: Fibrous bone dysplasia is an unusual disorder of the maturation of
      bone, seen as hyperostosis of the craniofacial bones and the diaphyses of long
      bones. Monostotic and polyostotic forms occur, depending on whether one or more
      bones are affected. The diagnosis is radiological (cranial CT or MR) or on morbid
      anatomy. The etiopathogenesis is not known. The association of epilepsy and
      monostotic fibrous bone dysplasia is rare. We present a case of monostotic
      fibrous bone dysplasia which presented with epileptic seizures. CLINICAL CASE: A
      28 year-old-woman had had undiagnosed epilepsy for 12 years. Neurological
      examination was normal and EEG findings non-specific. Cranial CT and MR suggested
      fibrous bone dysplasia. Since there was bilateral reduction of the visual fields,
      due to compression of both optic nerves, the affected bones were removed
      surgically. Anatomopathological study confirmed the diagnosis of fibrous bone
      dysplasia. CONCLUSIONS: The association between epilepsy and monostotic fibrous
      bone dysplasia is unusual. Epilepsy may be an initial symptom in asymptomatic
      fibrous bone dysplasia. The mechanism for the production of epileptic seizures
      may not be related to compression phenomena or local ischemia, but be secondary
      to alteration in the mechanism of cAMP as the second messenger of the cerebral
      cortex. Patients with fibrous bone dysplasia should undergo neurological
      examination to rule out local compression with minimal clinical findings.

PMID- 10416236
TI  - [Ischemic stroke of middle cerebral artery territory after the traumatic epidural
      hematoma].
AB  - INTRODUCTION: Epidural haematoma is a complication which may occur after
      apparently minor head injury. It may lead to the sudden onset, after a variable
      lucid interval, of transtentorial uncal hernia with consequent risk to life. If
      drainage is done early, the prognosis is excellent. CLINICAL CASE: We present a
      case of right parietal epidural haematoma in a 5 year-old-boy following a minor
      head injury, with no fracture of the skull. After a clear interval of 40 hours
      his consciousness deteriorated, there was right mydriasis and extension
      hypertonia of arms and legs. Following surgical removal there was evidence of an
      extensive cerebrovascular accident in the territory of the middle cerebral
      artery. CONCLUSIONS: Although they are infrequent, infarcts have been described
      in relation to epidural haematoma in all cerebral territories, predominantly in
      the distribution of the posterior cerebral artery. In the territory of the middle
      cerebral artery this may be due to traction and stenosis or occlusion of the
      small perforating branches, secondary to the displacement of midline cerebral
      structures or the space-occupying effect of epidural haematoma. All head
      injuries, including minor injuries mean a risk of serious hemorrhagic
      complications, the prognosis of which depends on the rapidity with which they are
      treated. GUIDELINES: Adapted to each centre are necessary for a common problem,
      usually without complications, but which may have unpredictably fatal results.
      Head injury is a dynamic process and therefore requires close clinical
      observation, which cannot be substituted by any complementary test.

PMID- 10416237
TI  - [Motor and mental complications in the long-term treatment of complicated
      Parkinson's disease with levodopa].
AB  - INTRODUCTION: The progression of Parkinson's disease and levodopa therapy leads
      to development of motor and psychic complications that cause serious limitations
      to the management of the advanced disease. DEVELOPMENT: This article reviews the
      current literature regarding the pathophysiology and the therapeutic approaches
      to the management of motor and psychic fluctuations in Parkinson's disease.
      CONCLUSIONS: 1. The most important risk factors for the development of motor
      fluctuations are the young age at onset and severity of Parkinson's disease, and
      duration and maximum dose of levodopa. 2. Pathophysiological data include the
      denervation of substantia nigra compacta and postsynaptic pharmacodynamic
      mechanisms, with a lesser contribution of pharmacokinetic factors. 3. The main
      therapeutic approaches include changes in the form of administration of levodopa,
      inhibitors of levodopa catabolism, and dopamine agonists. 4. A number of
      psychiatric symptoms, including depression, panic attacks, mania and cognitive
      impairment, can have a fluctuating course, coinciding with the motor
      fluctuations.

PMID- 10416238
TI  - [Clinical picture of neuroblast migratory disorders].
AB  - INTRODUCTION: Disturbances of neuroblast migration are prominent among the
      numerous causes of symptomatic epilepsy and of abnormal neurological development
      in children. DEVELOPMENT: Although their clinical manifestations are generally
      nonspecific with considerable overlap of symptoms and signs amongst the various
      disorders, the clinical picture of migratory disorders is continuously being
      redefined with greater precision and, in some cases, disorders of migration may
      be grouped into syndromes that are more easily diagnosed during life, in large
      part because of major advances in recent years in the technology of neuroimaging
      and in molecular genetics. It is therefore possible to study these patients in
      greater detail and over longer periods when detected early in life. CONCLUSIONS:
      I have reviewed the clinical manifestations of some of the defined disorders of
      neuroblast migration: lissencephaly-pachygyria types I and II, pachygyria,
      schizencephaly, polymicrogyria, special location heterotopia, for example,
      periventricular heterotopia and subcortical band heterotopia or 'double cortex'
      syndrome, the latter closely related to isolated lissencephaly type I.

PMID- 10416239
TI  - [Reibergrams: essential element in cerebrospinal fluid immunological analysis].
AB  - INTRODUCTION: The cerebrospinal fluid analysis is not displace on diagnosis of
      neurological disease in spite of the development of imaging techniques.
      DEVELOPMENT: Divulge the reibergrams as essential part of cerebrospinal fluid
      analysis. To perform a reibergram you have to quantify albumin, IgA, IgM and IgG
      in serum and cerebrospinal fluid. Then you have to calculate the quotients
      cerebrospinal fluid/serum and to plot the quotients in the reibergram. From the
      patterns you can have further information than single analyses. In contrast, the
      reibergram can yield the following information: about the intrathecal synthesis
      of immunoglobulins, CSF-blood barrier permeability and according to clinical data
      and symptoms can expect help in differential diagnosis by direct plausibilities
      or by suggesting the true diagnosis by pointing away from other diseases like
      opportunistic infections, neuro-tuberculosis and autoimmune inflammatory disease.
      It would be possible to detect an intrathecal tumour metastasis, monitoring
      efficacy of therapy and course of disease among others further knowledges.
      CONCLUSION: Reibergrams represent the best way to characterize blood
      cerebrospinal fluid barrier function and intrathecal synthesis of immunoglobulins
      on neurological disorders.

PMID- 10416240
TI  - [Diagnostic decision tree for the correct use of neuropsychological evaluation in
      head injury].
AB  - INTRODUCTION AND OBJECTIVE: We present a diagnostic decision tree for the correct
      use of neuropsychological evaluation techniques in head injury. Our aim is to
      avoid extensive, intensive use of unnecessary tests and measurements or lapses
      into diagnostic error which often accompany cognitive dysfunction when
      'superficial' 'undirected' studies are done. DEVELOPMENT: It is essential to
      select the neuropsychological, neuroconductal and psychosocial evaluation tests
      which are most suitable in each case and establish a reliable diagnosis of the
      functional, cognitive, emotional and psychosocial conditions of the patient. The
      decision tree for neuropsychological evaluation is a guide to assist
      professionals so that they may adequately examine the functional changes which
      can occur as a consequence of traumatic brain damage, adapted to each point in
      its evolution and taking into account factors which may influence
      neuropsychological evaluation. CONCLUSION: The evaluation of consequences of
      trauma includes evaluation of the gravity of the head injury, and the
      neuropsychological, neuroconductal and functional evaluation of the patient.

PMID- 10416241
TI  - [Atherosclerosis, cerebral ischemia and cellular inflammation].

PMID- 10416242
TI  - [Antiaggregant treatment: present and future].
AB  - OBJECTIVE: To present current information on the use of antiaggregant agents and
      the possibilities of their further development. DEVELOPMENT: Aspirin is an
      established treatment for the prevention of cerebrovascular accidents (CVA) in
      patients with transitory ischemic attacks (TIA) or minor CVA. This agent reduces
      the risk by 20%. Ticlopidine has a slightly greater antiaggregant effect than
      Aspirin, but has the disadvantage of being more expensive and having serious
      haematological effects such as thrombotic thrombocytopenic purpura. In
      combination with Aspirin, ticlopidine is valuable in maintaining coronary stents
      permeable. Dipyridamole, used in combination with Aspirin reduces the risk of CVA
      by 37% which is more than either drug used alone. Clopidogrel, chemically related
      to ticlopidine, has a slightly greater protective effect without the serious
      haematological side-effects of the latter. Use of Aspirin in CVA, alone or
      combined with subcutaneous heparin, is effective in the early secondary
      prevention of CVAs. Future development of antiaggregant treatment includes
      various aspects, such as the use of Aspirin in primary and secondary prevention
      of CVA, its value in combination with other antiaggregant, antithrombotic and
      neuroprotector agents. CONCLUSIONS: Antiaggregant agents have meant a great
      advance in the treatment of CVA. In view of the relatively modest degree of
      protection given by Aspirin, future strategies will probably include combining it
      with other antiaggregant agents, antithrombotic drugs and neuroprotectors.

PMID- 10416243
TI  - [Atherosclerosis and cerebral ischemia. A systemic process].
AB  - INTRODUCTION: Atherosclerosis is a systemic process involving all the arteries of
      the body. It is often silent, until its progression affects an organ causing a
      cerebral infarct, myocardial infarct or peripheral vascular disease. DEVELOPMENT:
      We consider three distinct aspects of this systemic involvement: the risk factors
      which are common to atherosclerosis at any site; previous alterations of other
      vascular regions apart from the current disorder, and the frequent presentation
      of a new site of vascular disorder, mainly coronary. The authors discuss the
      evolution of our understanding of cerebral ischaemia and the process of
      atherosclerosis. Atherosclerosis of the intracranial arteries leading to
      thrombosis was considered for many years to be the main cause of cerebral
      infarcts. However, this has been shown to be an unusual cause. The commonest
      cause has been found to be atheromatosis of the extracranial arteries leading to
      stenosis, ulceration or thrombosis. The aorta, the artery which is the first and
      most severely altered by the process of atherosclerosis, is often the cause of a
      cerebral infarct of unknown aetiology. The embolic etiology of cardiac origin is
      generally due to valvulopathies and disorders of rhythm and, less frequently, to
      myocardial ischaemia. CONCLUSION: Atherosclerosis of arteries of the limbs is an
      indicator of systemic atherosclerosis but not a common etiological factor of
      cerebral infarct.

PMID- 10416244
TI  - [Postmictional cervical infarct].

PMID- 10416245
TI  - [Application of the extended scale of degree of handicap to patients with
      multiple sclerosis in Santiago de Cuba].

PMID- 10416246
TI  - [Ethical implications in scientific work. Two recent publications].

PMID- 10416247
TI  - [A clinical study of tuberous sclerosis].

PMID- 10416248
TI  - Nasal hyperreactivity.
AB  - Nasal hyperreactivity is an important feature of allergic and non-allergic
      rhinitis. This paper reviews the possible mechanisms behind hyperreactivity.
      Distinct mechanisms may play a role in allergic rhinitis--an inflammatory disease
      -and non-allergic rhinitis, mainly a non-inflammatory disease. In allergic
      rhinitis, particularly in perennial allergic rhinitis, there is a close
      connection between allergic response and non-specific hyperreactivity. In non
      allergic rhinitis, a pathological entity comprising a heterogeneous series of
      diseases, understanding and measuring nasal hyperreactivity is much more
      difficult. A variety of methods to assess nasal hyperreactivity are available.
      Given the heterogeneity of mechanisms, the various patients groups and the lack
      of standardization in tests, it is not surprising that measurement of nasal
      hyperreactivity is not included in the diagnostic arsenal of the clinician.

PMID- 10416249
TI  - In vivo and in vitro effect of ozone and formaldehyde on human nasal mucociliary
      transport system.
AB  - The effect of ozone and formaldehyde on the nasal mucociliary transport system
      after short-term exposure was comparatively evaluated in human by using in vivo
      and in vitro test systems. Concentrations of ozone used were 10, 100, 500 and
      1000 micrograms/m3 of ozone and of formaldehyde 100, 500 and 5000 micrograms/m3.
      The in vivo effect of ozone was monitored by measuring the saccharin transport
      time before and two hours after exposure to ozone. The in vitro effect of ozone
      and formaldehyde was evaluated by quantifying the ciliary beat frequency (CBF) of
      isolated respiratory epithelial cells before and after one, two, and three hours
      of exposure. Control experiments were performed using synthetic air. Ozone had no
      effect on the human nasal mucociliary transport system under the conditions
      tested here. Neither in vivo nor in vitro any significant changes of saccharin
      transport time nor CBF were measured. In contrast, formaldehyde significantly
      reduced (67.1%) CBF at the highest dosis (2 hours, 5000 micrograms/m3). These
      results will be discussed according to the environmental impact of ozone and
      formaldehyde in air pollutants and compared to sulphur dioxide and nitric oxide,
      which were tested under similar conditions, and to results revealed from animal
      experiments.

PMID- 10416250
TI  - Aspiration flow optimized for nasal nitric oxide measurement.
AB  - The aim of the present study was to evaluate some of the factors which may
      influence the reliability of nasal NO measurements, and to optimize methods
      suitable for children and adults. Nasal nitric oxide (NO) output was determined
      by chemiluminescent analysis of aspirated samples in 16 adults and 6 children.
      With the velopharyngeal aperture closed, stable NO levels were obtained at flows
      ranging form 0.9 to 6.2 L/min. NO output averaged 401.0 +/- 145.4 nL/min./M2 in 6
      children, 338.2 +/- 92.3 in 7 adult females and 268.6 +/- 70.2 in 9 adult males.
      Nasal NO output was independent of flow provided a stable plateau of NO value was
      reached. In this study, the optimal range of flows was 3.2-5.2 L/min. in adults
      and 2.2-3.2 L/min. in children. This enables selection of the most favorable flow
      to be chosen for individual subjects and situations.

PMID- 10416251
TI  - The alteration of nasal resistance before and after local exposure to heated
      aerosol in perennial allergic rhinitis.
AB  - To determine the patho-physiological effects of heated vapour to the normal or
      allergic nasal mucosa, we measured the nasal resistance before and after a 10
      min. exposure of hyperthermal (43.0 degrees C) aerosol to the nasal mucosa in
      normal subjects and perennial allergic rhinitis patients. In the allergic
      patients the mean nasal resistances after hyperthermal stimulation were
      significantly higher than those resistances without stimulation, both in
      expiration or inspiration. No significant differences of nasal resistances in
      normal individuals during the whole schedule with and without heated aerosol
      stimulation were found on expiration or inspiration. The local heated aerosol
      exposure increases the nasal resistance in nasal allergic patients while in
      normal subjects no changes were found, and the reaction may have arisen from a
      non-specific hypersensitivity of the susceptible allergic nasal mucosa.

PMID- 10416253
TI  - Excision and replacement of nasal septum in aesthetic and functional nose
      surgery: setting criteria and establishing indications.
AB  - Despite the technical details of the excision and replacement of the nasal septum
      both in aesthetic and functional nasal surgery have been extensively reviewed, in
      the opinion of the authors a clear and precise definition of the indications of
      this technique is still lacking. A simplified classification of the nasal septum
      deformities, based on the site and the direction of the fracture or bending axis,
      is proposed to establish reproducible guidelines to nasal septum surgery. On the
      basis of this classification the post-operative results of 227 patients affected
      by obstructive nasal septum deviation were evaluated. The surgical treatment
      consisted of conservative septoplasty in 173 cases, while in 54 cases excision
      and replacement of the nasal septum were performed. A conservative tension
      release septoplasty was performed for horizontal fracture or angulation of the
      septum. The more radical excision/replacement surgical approach was preferred
      when a vertical angulation or bending axis was observed (vertical = normal to the
      maxillary ridge). Twenty persisting septal deviations were found at the one year
      post-operative follow-up. Nineteen of these were the outcome of 173 conservative
      septoplasty, while only one case with unsatisfactory results was the outcome of
      54 excision/replacement procedures. Seventeen out of 19 cases originally
      classified as horizontal deformity who presented at follow up with persisting
      septum deviation were reclassified as vertical. The reason for surgical failure
      must be probably identified in a preoperatory classification mistake where
      vertical deformities were erroneously evaluated horizontal and operated
      accordingly. The authors suggest excision/replacement of the nasal septum
      whenever its fracture or major bending axis is vertical.

PMID- 10416252
TI  - Videoendoscopic analysis of nasal steroid distribution.
AB  - Topical corticosteroids are one of the main pillars in the treatment of nasal
      polyps. The exact topography of their intranasal deposition has not yet been
      adequately visualised. The intranasal distribution of a 1% sodium fluorescein
      solution applied with original Pulmicort Topinasal (budesonide) metered pump
      bottles was analysed by videoendoscopy. The study group included eight healthy
      subjects and ten patients who had undergone endonasal sinus surgery.
      Videoendoscopy was performed in the study group within the first minute after
      application of the fluorescein solution. Additionally the deposition pattern of
      Pulmicort Topinasal was analyzed using a nasal model. The examination showed that
      the majority of the substance is deposited on the anterior portion of the nasal
      septum and the head of the inferior turbinate. Only a small fraction actually
      reaches the middle meatus. The distribution is improved by application during the
      decongested phase of the nasal cycle, after use of vasoconstricting nasal drops
      and maintaining a spraying angle of 45 degrees upwards. The development of new
      delivery techniques and systems could improve the efficacy of intranasally
      administered corticosteroids and reduce the complication rate.

PMID- 10416254
TI  - Experiences with endonasal surgery in angiofibroma.
AB  - Surgery is the most common treatment for angiofibromas, but the approach is still
      a major point of discussion. Five cases of angiofibroma with typical localisation
      were treated surgically by an endonasal approach at the Fulda Academic Teaching
      Hospital from 1994 to 1997. This article presents an analysis of the clinical
      findings, computer tomography and magnetic resonance imaging, preoperative
      embolization, operative technique and complications. Endoscopic and radiologic
      follow-up ranging from 5 to 39 months excluded any residual tumour or recurrence.
      The endonasal microendoscopic approach with adequate preoperative embolization
      should be considered as an useful technique for removing tumours with
      considerable size without using an external incision.

PMID- 10416255
TI  - Negative pressure suction in nasal septum surgery.
AB  - Operations for the correction of septal deviations are among the most common in
      otorhinolaryngology. Several approaches and techniques have been proposed, for
      securing the mucoperichondrial flap back in place. A new method of stabilizing
      the septum by applying a negative pressure suction tube, without the insertion of
      any kind of packing, is described. The advantages of the negative pressure
      suction are that the patient can breathe through the nose immediately after the
      operation, there is no pressure sensation and the pain, if any, is reduced, there
      is no epiphora, no skin edema and the patient feels very comfortable. Risks for
      complications are minimal.

PMID- 10416256
TI  - A reliable absorbable intranasal bolster for proper maintenance of fractured
      nasal bone position.
AB  - The maintenance of comminuted or otherwise unstable nasal bones in proper
      position following adequate operative reduction, may, on occasion, be a
      frustrating experience for both the patient and the surgeon. Migration of the
      fragments may compromise the aesthetic and functional results of well executed
      corrective nasal surgery. In this article, we will outline our successful,
      inexpensive approach to this occasionally challenging problem utilising an
      absorbable intranasal customised Surgicel bolster.

PMID- 10416257
TI  - Concha bullosa pyocele--undiagnosed for 3 years.
AB  - We report a rare case of post-traumatic concha bullosa pyocele in a diabetic
      teenager that has gone undiagnosed for 3 years. The clinical findings,
      radiological features and management are discussed. The literature is reviewed.

PMID- 10416258
TI  - Acquired immune deficiency syndrome (AIDS) presenting as a nasal septal
      perforation.
AB  - Patients infected with the Human Immunodeficiency Virus (HIV) and those with AIDS
      may present with many head and neck manifestations. We report a case of an
      undiagnosed HIV positive male who presented with symptoms due to a nasal septal
      perforation, and rapidly developed AIDS. The histopathology of the perforation
      margins revealed active chronic inflammation with no evidence of neoplasia or
      granuloma. No viral or fungal infection was demonstrable on immunological testing
      and fungal stain. This is the first reported case of a patient developing AIDS
      presenting with a nasal septal perforation.

PMID- 10416259
TI  - The duration of non-rodent toxicity studies for pharmaceuticals. International
      Conference on Harmonication (ICH).
AB  - At the present time, there are no uniform standards for the duration of non
      rodent chronic toxicity studies. The European Union (EU) requires a 6-month non
      rodent study. In Japan, a 6-month study is sufficient for most, but not all,
      compounds. The U.S. Food and Drug Administration (FDA) maintains its standard
      duration of 12 months for non-rodents, with 6-month studies accepted for some
      clinical indications on a case-by-case basis. To achieve harmonization on the
      duration of non-rodent toxicity studies, each member regulatory region (EU, U.S.,
      and Japan) of the International Conference on Harmonization (ICH) collected non
      rodent studies with significant new toxicological findings that had occurred
      after 6 months. An ICH expert working group was organized that included
      representatives from the regulatory authorities of each ICH region, to jointly
      review all available case studies for the purpose of arriving at a consensus on
      the best duration time for non-rodent toxicity studies. Eighteen case studies
      were identified and evaluated (16 original cases plus 2 additional FDA cases);
      most of the toxicities identified fell into the following categories: (1)
      toxicities identified at 6 months; (2) toxicities observed at 12 months, which
      were absent or considered isolated and not noteworthy findings at 6 months; (3)
      drug-related deaths or morbidity that occurred between 6 and 12 months, with a
      pattern of toxicity that permitted the interpolation of findings to an
      intermediate interval between 6 and 12 months; and (4) a shift in the dose
      response for toxicity with increasing duration of drug exposure. Of the 18 cases
      evaluated, 11 supported a study-duration of 9-12 months, 4 supported a duration
      of 12 months, and the 3 remaining cases indicated that a 6-month study would be
      adequate. The working group concluded that there was sufficient evidence to
      support a harmonized 9-month duration for non-rodent toxicity studies, which
      would be applicable for most categories of pharmaceuticals.

PMID- 10416261
TI  - An observation: role of the M.D., Ph.D. in science.

PMID- 10416260
TI  - Concise review of the glutathione S-transferases and their significance to
      toxicology.

PMID- 10416262
TI  - Rodent tumors of urinary bladder, renal cortex, and thyroid gland in IARC
      Monographs evaluations of carcinogenic risk to humans.

PMID- 10416263
TI  - Quantitative evaluation of alternative mechanisms of blood and testes disposition
      of di(2-ethylhexyl) phthalate and mono(2-ethylhexyl) phthalate in rats.
AB  - Di(2-ethylhexyl) phthalate (DEHP), a commercially important plasticizer, induces
      testicular toxicity in laboratory animals at high doses. After oral exposure,
      most of the DEHP is rapidly metabolized in the gut to mono(2-ethylhexyl)
      phthalate (MEHP), which is the active metabolite for induction of testicular
      toxicity. To quantify the testes dose of MEHP with various routes of exposure and
      dose levels, we developed a physiologically based pharmacokinetic (PBPK) model
      for DEHP and MEHP in rats. Tissue:blood partition coefficients for DEHP were
      estimated from the n-octanol: water partition coefficient, while partition
      coefficients for MEHP were determined experimentally using a vial equilibration
      technique. All other parameters were either found in the literature or estimated
      from blood or tissue levels following oral or intravenous exposure to DEHP or
      MEHP. A flow-limited model failed to adequately simulate the available data.
      Alternative plausible mechanisms were explored, including diffusion-limited
      membrane transport, enterohepatic circulation, and MEHP ionization (pH-trapping
      model). In the pH-trapping model, only nonionized MEHP is free to become
      partitioned into the tissues, where it is equilibrated and trapped as ionized
      MEHP until it is deionized and released. All three alternative models
      significantly improved predictions of DEHP and MEHP blood concentrations over the
      flow-limited model predictions. The pH-trapping model gave the best predictions
      with the largest value of the log likelihood function. Predicted MEHP blood and
      testes concentrations were compared to measured concentrations in juvenile rats
      to validate the pH-trapping model. Thus, MEHP ionization may be an important
      mechanism of MEHP blood and testes disposition in rats.

PMID- 10416264
TI  - Quantitative and qualitative differences in the metabolism of 14C-1,3-butadiene
      in rats and mice: relevance to cancer susceptibility.
AB  - 1,3-Butadiene (butadiene) is a potent carcinogen in mice, but not in rats.
      Metabolic studies may provide an explanation of these species differences and
      their relevance to humans. Male Sprague-Dawley rats and B6C3F1 mice were exposed
      for 6 h to 200 ppm [2,3-14C]-butadiene (specific radioactivity [sa] 20 mCi/mmol)
      in a Cannon nose-only system. Radioactivity in urine, feces, exhaled volatiles
      and 14C-CO2 were measured during and up to 42 h after exposure. The total uptake
      of butadiene by rats and mice under these experimental conditions was 0.19 and
      0.38 mmol (equivalent to 3.8 and 7.5 mCi) per kg body weight, respectively. In
      the rat, 40% of the recovered radioactivity was exhaled as 14C-CO2, 70% of which
      was trapped during the 6-h exposure period. In contrast, only 6% was exhaled as
      14C-CO2 by mice, 3% during the 6-h exposure and 97% in the 42 h following
      cessation of exposure. The formation of 14C-CO2 from [2,3-14C]-labeled butadiene
      indicated a ready biodegradability of butadiene. Radioactivity excreted in urine
      accounted for 42% of the recovered radioactivity from rats and 71% from mice.
      Small amounts of radioactivity were recovered in feces, exhaled volatiles and
      carcasses. Although there was a large measure of commonality, the exposure to
      butadiene also led to the formation of different metabolites in rats and mice.
      These metabolites were not found after administration of [4-14C]-1,2-epoxy-3
      butene to animals by i.p. injection. The results show that the species
      differences in the metabolism of butadiene are not simply confined to the
      quantitative formation of epoxides, but also reflect a species-dependent
      selection of metabolic pathways. No metabolites other than those formed via an
      epoxide intermediate were identified in the urine of rats or mice after exposure
      to 14C-butadiene. These findings may have relevance for the prediction of
      butadiene toxicity and provide a basis for a revision of the existing
      physiologically based pharmacokinetic models.

PMID- 10416265
TI  - Evidence for site-specific bioactivation of alachlor in the olfactory mucosa of
      the Long-Evans rat.
AB  - Alachlor (2-chloro-2',6'-diethyl-N-[methoxymethyl]-acetanilide) is a restricted
      use chloracetanilide herbicide which has been shown previously to produce a dose
      dependent incidence of olfactory mucosal tumors in rats following chronic dietary
      exposure. However, the mechanism of alachlor carcinogenicity is poorly
      understood. Alachlor was administered i.p. to male Long-Evans rats for up to 28
      days at doses that are carcinogenic in chronic studies in order to study
      olfactory lesion development and alterations in cell proliferation. Neither
      treatment-related olfactory mucosal lesions nor regenerative cell proliferation,
      as assessed with BrdU labeling, was detected. In vitro genotoxicity studies using
      Salmonella typhimurium strain TA100 showed that alachlor was non-mutagenic in the
      absence of metabolic activation. When pre-incubated with an olfactory mucosal S9
      activation system, alachlor induced a weak, dose-dependent mutagenic response at
      500-1250 micrograms/plate, with toxicity at higher doses. In contrast, an S9
      activation system derived from nasal respiratory mucosa, the tissue physically
      juxtaposed with the olfactory mucosa but reportedly not susceptible to alachlor
      induced tumors, did not produce a mutagenic response for alachlor or the positive
      control. Thus, this result suggested site-specificity of alachlor activation
      consistent with the target site of carcinogenicity. The mutagenicity of alachlor
      to Salmonella, in the presence of an olfactory mucosal-activating system, was
      confirmed by a limited positive response in the mouse lymphoma assay. Here there
      were increases in small colony mutants (indicative of chromosomal effects) as
      well as large colony mutants (which reflect gene mutations). This study suggests
      that target tissue bioactivation of alachlor results in the formation of one or
      more mutagenic metabolite(s), which may be critical in alachlor-induced nasal
      tumorigenesis.

PMID- 10416266
TI  - Optimal design for a study of butadiene toxicokinetics in humans.
AB  - The derivation of the optimal design for an upcoming toxicokinetic study of
      butadiene in humans is presented. The specific goal of the planned study is to
      obtain a precise estimate of butadiene metabolic clearance for each study
      subject, together with a good characterization of its population variance. We
      used a two-compartment toxicokinetic model, imbedded in a hierarchical population
      model of variability, in conjunction with a preliminary set of butadiene kinetic
      data in humans, as a basis for design optimization. Optimization was performed
      using Monte Carlo simulations. Candidate designs differed in the number and
      timing of exhaled air samples to be collected. Simulations indicated that only 10
      air samples should be necessary to obtain a coefficient of variation of 15% for
      the estimated clearance rate, if the timing of those samples is properly chosen.
      Optimal sampling times were found to closely bracket the end of exposure. This
      efficient design will allow the recruitment of more subjects in the study, in
      particular to match prescribed levels of accuracy in the estimate of the
      population variance of the butadiene metabolic rate constant. The techniques
      presented here have general applicability to the design of human and animal
      toxicology studies.

PMID- 10416267
TI  - The effect of inhibition of aldehyde dehydrogenase on nasal uptake of inspired
      acetaldehyde.
AB  - At exposure concentrations of 750 ppm or more, acetaldehyde is a rodent
      inhalation carcinogen that induces nasal tumors. Aldehyde dehydrogenase (ALDH) is
      thought to be an important detoxifying enzyme for aldehydes. Although nasal
      tissues express ALDH, the importance of this enzyme relative to delivered dosage
      rates at high-inspired concentrations is not well defined. To provide such
      information, uptake of inspired acetaldehyde was measured at an inspiratory flow
      rate that approximated the minute ventilation rate in the surgically isolated
      nasal cavity of F 344 rats pretreated with either saline (control) or the ALDH
      inhibitor, cyanamide (10 mg/kg s.c.). ALDH activities (substrate concentration 3
      times the K(m)) in anterior (respiratory mucosa) and posterior (olfactory mucosa)
      nasal tissues averaged 160 and 210 nmol/min), respectively, in control animals
      (total activity 370 nmol/min), compared to 60 and 80 nmol/min, respectively, in
      cyanamide-pretreated rats (p < 0.05), indicating that approximately 60%
      inhibition was obtained. Nasal uptake was measured at 3 inspired concentrations:
      10, 300, and 1500 ppm. At these concentrations, acetaldehyde uptake efficiency
      averaged 54, 37, and 34% in saline-pretreated rats, respectively (p < 0.05). In
      absolute terms, the delivered dosage rates at these exposure concentrations
      averaged 21, 420, and 1990 nmol/min. The concentration dependence on uptake
      suggests a saturable process was involved. At inspired concentrations of 300 ppm
      or more, the delivered dosage rates exceeded the measured specific activity for
      nasal ALDH of 370 nmol/min. Cyanamide pretreatment abolished the concentration
      dependence. Specifically, uptake efficiencies in cyanamide-pretreated rats
      averaged 30, 27, and 31% at inspired concentrations of 10, 300, and 1500 ppm,
      respectively (p > 0.05); delivered dosage rates were 12, 310, and 1780 nmol/min.
      Thus, cyanamide pretreatment reduced nasal-delivered dosage rates at inspired
      concentrations of 10, 300, and 1500 ppm, respectively by 9, 110, and 210
      nmol/min, values that correspond well with the total nasal ALDH activity of 370
      nmol/min. In toto, these results suggest that inspired acetaldehyde is
      metabolized in situ by ALDH, but at exposure concentrations of 300 ppm or
      greater, the delivered dosage rate may equal or exceed the capacity of this
      enzyme.

PMID- 10416268
TI  - Polycyclic aromatic hydrocarbons with bay-like regions inhibited gap junctional
      intercellular communication and stimulated MAPK activity.
AB  - Many polycyclic aromatic hydrocarbons (PAHs) are known carcinogens. A
      considerable amount of research has been devoted to predicting the genotoxic,
      tumor-initiating potential of PAHs based on chemical structure. However,
      information on the correlation of structure with the non-genetoxic, epigenetic
      events of tumor promotion is sparse. PAHs containing a bay or bay-like region
      were shown to be potent inhibitors of gap-junctional intercellular communication
      (GJIC), an epigenetic event involved in the removal of an initiated cell from
      growth suppression. We tested the epigenetic toxicity of PAHs containing bay-like
      regions by comparing the effects of methylated vs. chlorinated isomers of
      anthracene on the temporal activation of mitogen-activated protein kinase (MAPK)
      and the regulation of GJIC. Specifically, we used anthracene, 1-methylanthracene,
      2-methylanthracene, 9-methylanthracene, 9,10-dimethylanthracene, 1
      chloroanthracene, 2-chloroanthracene, and 9-chloroanthracene. We determined the
      effect of these compounds on GJIC and on the activation of extracellular receptor
      kinase (ERK 1 and 2), a MAPK, in F344 rat liver epithelial cells. Results showed
      that bay or bay-like regions, formed by either chlorine or a methyl group,
      reversibly inhibited GJIC at the same doses, time, and time of recovery, whereas
      the linear-planar isomers had no effect on GJIC. Similarly, the GJIC-inhibitory
      isomers also induced the phosphorylation of ERK 1 and ERK 2, while the non
      inhibitory isomers had no effect on the activation of these MAPKs. MAPK
      activation occurred 10-20 min after the inhibition of GJIC, which indicates that
      MAPK is not involved in the initial regulation of GJIC; instead altered GJIC may
      be affecting MAPK activation. The present study revealed that there are
      structural determinants of PAHs, which clearly affect epigenetic events known to
      be involved in the non-genetoxic steps of tumor promotion. These events are the
      release of a cell from growth suppression involving the reduction of GJIC,
      followed by the activation of intracellular mitogenic events.

PMID- 10416269
TI  - Development of a transgenic mouse model for carcinogenesis bioassays: evaluation
      of chemically induced skin tumors in Tg.AC mice.
AB  - Transgenic rodent models have emerged as potentially useful tools in the
      assessment of drug and chemical safety. The transgenic Tg.AC mouse carries an
      inducible v-Ha-ras oncogene that imparts the characteristic of genetically
      initiated skin to these animals. The induction of epidermal papillomas in the
      area of topically applied chemical agents, for duration of not more than 26
      weeks, acts as a reporter phenotype that defines the activity of the test
      article. We describe here the activity of six chemicals that have been previously
      characterized for activity in the standard 2-year bioassay conducted by the
      National Toxicology Program (NTP). Homozygous female Tg.AC mice were treated with
      benzene (BZ), benzethonium chloride (BZTC), o-benzyl-p-chlorophenol (BCP), 2
      chloroethanol (2-CE), lauric acid diethanolamine (LADA) and triethanolamine
      (TEA). BZ and LADA induced skin papillomas in a dose-dependent manner, while BCP
      induced papillomas only at the highest dose. BZTC, 2-CE, and TEA exhibited no
      activity. The correspondence of chemical activity in Tg.AC mice with that in the
      2-year bioassay was high. A comparison of responsiveness to BZ and LADA was made
      between hemizygous and homozygous female Tg.AC mice. Both genotypes appear to be
      equally sensitive to maximum doses of active compounds. The results reported here
      indicate that the Tg.AC transgenic mouse model can discriminate between
      carcinogens and noncarcinogens and that both mutagenic and nonmutagenic chemicals
      can be detected. These studies provide support for the adjunctive use of the
      Tg.AC transgenic mouse skin tumor model in drug and chemical safety assessment
      and for the prediction of the carcinogenic potential of chemicals.

PMID- 10416270
TI  - Evaluation of methylated DNA binding protein-1 in mouse liver.
AB  - DNA methylation (DNA-5-methylcytosine [MeC]) plays a key role in regulation of
      gene expression. Highly methylated genes tend to be silenced whereas
      hypomethylated genes have an increased potential for expression. One way in which
      methylation may lead to inhibition of transcription is by permitting the binding
      of methylated DNA-binding proteins, which then block access of transcription
      factors to DNA. A particular methylated DNA-binding protein, MDBP-1, has been
      identified in nuclear extracts prepared from various human and rat tissues, and
      binds in a sequence-specific manner to DNA containing methylated cytosines (P. C.
      Supakar et al., 1988, Nucleic Acids Res. 16, 8029-8044). In the current study, an
      electrophoretic mobility shift assay (EMSA) was employed to assess the presence
      of MDBP-1 in protein isolated from mouse liver and to examine characteristics of
      its binding to DNA. The ligand used in our EMSA was a 32P-end-labeled, double
      stranded, symmetrically methylated oligonucleotide containing the protein's
      binding site, 5'-CTAGATMGT-CAMGGMGAT-3' (M denotes 5-methyl-cytosine). Utilizing
      protein extracted from B6C3F1 mouse liver, we observed a complex that is competed
      by non-labeled, double-stranded, fully methylated ligand but not by an excess of
      a 26-mer, double-stranded oligonucleotide containing the binding site for AP-1.
      No complex was formed when a nonmethylated, double-stranded ligand, or our single
      stranded ligands (methylated or unmethylated) were used as EMSA ligands. Complex
      formation was observed utilizing double-stranded, hemimethylated ligands;
      however, the affinity of MDBP-1 for these was one-tenth the affinity of MDBP-1
      for fully methylated, double-stranded ligand. Additionally, protein isolated from
      C57BL/6 and C3H/He mouse liver was found to bind specifically to fully methylated
      ligand and hemimethylated ligands for MDBP-1, with similar characteristics as the
      binding of B6C3F1 mouse liver protein. These results indicate that MDBP-1 is
      present in mouse liver, and that the degree of methylation determines the
      strength of binding of MDBP-1 to DNA.

PMID- 10416271
TI  - Sensitivity of thyroid gland growth to thyroid stimulating hormone (TSH) in rats
      treated with antithyroid drugs.
AB  - Antithyroid drugs and phenobarbital (PB) have been shown to promote thyroid
      tumors in rats. It has been proposed that increased thyroid-stimulating hormone
      (TSH) mediates the thyroid tumor-promoting effect of antithyroid drugs and PB,
      and is increased because of decreased thyroxine (T4) concentration. However, PB
      is much less effective than antithyroid drugs at increasing TSH. It has been
      proposed that small increases in serum TSH produced by PB treatment is sufficient
      to promote thyroid tumors. However, the level to which TSH must be increased to
      stimulate the thyroid gland has not been reported. Therefore, we have examined
      the effect of increasing serum TSH concentration on thyroid growth by measuring
      thyroid gland weight and thyroid follicular cell proliferation. Serum TSH
      concentrations were increased by feeding rats various concentrations of
      propylthiouracil (PTU) or methimazole (MMI) for 21 days. Serum total T4, free T4,
      total T3 (triiodothyronine), free T3, and TSH concentrations were measured by
      radioimmunoassay. Thyroid follicular cell proliferation was measured by
      autoradiography and expressed as a labeling index (LI). PTU and MMI treatments
      reduced total and free T4 more than 95% by day 21, whereas total and free T3 were
      reduced 60%. TSH, thyroid follicular cell proliferation and thyroid weight were
      increased 560%, 1400%, and 200%, respectively, by day 21. TSH was significantly
      correlated with thyroid weight and LI. Moderate increases in serum TSH of between
      10 and 20 ng/ml increased the number of proliferating thyroid follicular cells,
      but had no effect on thyroid weight. These results support that small increases
      in serum TSH can be sufficient to stimulate thyroid follicular cell
      proliferation. Furthermore, thyroid follicular cell proliferation may be more
      useful than thyroid weight alone for assessing alterations in thyroid growth in
      rats treated with chemicals that produce only small to moderate increases in
      serum TSH.

PMID- 10416272
TI  - Quantitative relationships between the suppression of selected immunological
      parameters and the area under the corticosterone concentration vs. time curve in
      B6C3F1 mice subjected to exogenous corticosterone or to restraint stress.
AB  - The neuroendocrine response to stressors increases the concentration of several
      endogenous mediators, some of which are immunosuppressive. However, quantitative
      aspects of these effects have been overlooked. Although it should be possible to
      predict the degree of suppression of particular immunological functions by
      measuring the concentrations of stress-related mediators such as corticosterone,
      this cannot be done with data presently available. This study was designed to
      develop regression models to predict the relationship between the area under the
      corticosterone concentration vs. time curve (AUC) and two immunological
      parameters. Models were developed using mice treated with exogenous
      corticosterone and mice subjected to various periods of restraint stress. The
      latter treatment was included to determine if the effects of corticosterone were
      different from those of corticosterone in association with the other mediators
      induced in a restraint-stress response. Models relating corticosterone AUC to
      expression of MHC class II proteins on splenocytes were very similar, whether the
      corticosterone was exogenous or produced as part of a restraint-stress response.
      This was also true for splenic natural killer (NK) cell activity. However, MHC
      class II expression was more sensitive to the effects of corticosterone or
      restraint than was NK cell activity. The corticosterone and restraint models
      predicted the previously published effect of a chemical stressor (ethanol) on MHC
      class II expression, but neither model predicted the suppression of NK cell
      activity by ethanol. These results have mechanistic implications, which are
      discussed in the context of previous studies. The quantitative models described
      here should be useful in determining and predicting the stress-related portion of
      chemical-induced immunosuppression. In addition, these models provide
      quantitative data essential for a complete understanding of stress-induced
      immunosuppression.

PMID- 10416273
TI  - Arsenite alters heme synthesis in long-term cultures of adult rat hepatocytes.
AB  - Arsenite (As[III]) effects on the intermediate steps of heme biosynthesis were
      studied in adult rat hepatocytes seeded on a feeder layer of 3T3 cells (3T3
      hepatocytes) and maintained for 2 weeks with culture medium non-supplemented or
      supplemented with 150 microM 5-aminolevulinic acid (ALA). The activities of the
      intracellular enzymes porphobilinogen deaminase (PBG-D), uroporphyrinogen III
      synthase (UROIII-S), and uroporphyrinogen III decarboxylase (URO-D), and the
      intermediary uroporphyrins (URO), coproporphyrins (COPRO) and protoporphyrin IX
      (PROTO) were determined in these cultures. The 3T3-hepatocytes maintained the
      activities of PBG-D, UROIII-S and URO-D during 2 weeks and ALA addition to the
      culture medium increased PBG-D (2-3-fold) and UROIII-S (50%) activities and
      porphyrin production, which accumulated as PROTO. Exposure to 3.9 microM As(III)
      inhibited UROIII-S activity (down to 34%), and PBG-D and URO-D activities to a
      lower extent; these effects were magnified by ALA supplementation. As(III) also
      produced an intracellular accumulation and a decreased excretion of PROTO, and a
      31% reduction of the COPRO/URO ratio in the culture medium. Additionally, As(III)
      caused cytoplasmic vacuolization and lipid accumulation. Our results show that
      As(III) exposure selectively inhibits several intermediary enzymes of heme
      metabolism and affects the intra- and extracellular content of porphyrins and
      their ratio in the culture medium. They also confirm that 3T3-hepatocytes are a
      suitable in vitro model to study hepatic heme metabolism and its alterations by
      hepatotoxic chemicals.

PMID- 10416274
TI  - Quantitative polymerase chain reaction using an external control mRNA for
      determination of gene expression in a heterogeneous cell population.
AB  - Gene expression can be evaluated quantitatively by conventional RT-PCR or
      Northern blotting with the aid of a correction based on the expression of an
      internal control gene. However, this approach is not suitable for quantitating
      gene expression in a group of heterogeneous cell subsets, because the internal
      control gene expression may vary among the subsets. Therefore, we developed a new
      method for quantitative PCR using rat poly(A)+ RNA as an external control. We
      used this method to investigate cytokine gene expression in lymph node cells from
      mice during the induction of contact hypersensitivity. Expression of the murine
      glyceraldehydephosphate dehydrogenase (GAPDH) gene, a candidate internal control,
      was not constant in cells from trinitrochlorobenzene- and vehicle-applied
      animals, suggesting that GAPDH gene expression changes in heterogeneous lymph
      node-cell subsets during induction of contact hypersensitivity. Therefore, we
      decided to use rat GAPDH mRNA as an external control. Cytokine gene expression
      was measured by quantitative PCR and was corrected based on external rat GAPDH
      cDNA. The reliability of this quantitative PCR was superior to that of the
      conventional method with an internal control.

PMID- 10416275
TI  - Metallothionein induction attenuates the effects of glutathione depletors in rat
      hepatocytes.
AB  - Metallothionein (MT) is a protein involved in heavy metal homeostasis and
      detoxification. According to several studies, MT could be involved in the
      antioxidant defense system, in which glutathione (GSH) is an essential component.
      The aim of this study was to verify the implication of MT in the antioxidant
      defense system in isolated rat hepatocytes. For this purpose, hepatocyte cultures
      were exposed to treatments known to modify MT or GSH levels. Zinc (Zn) was used
      as an inducer of MT while diethyl maleate (DEM) and buthionine sulfoximine (BSO)
      were used as GSH depletors. GSH, MT, and antioxidant enzyme activities were
      measured under conditions of MT induction and GSH depletion. Induction of MT
      synthesis through an 18-hour exposure to Zn (20 microM), did not result in any
      significant change in GSH levels or in activities of the antioxidant enzymes,
      glutathione-peroxidase (GSH-Px), catalase, and superoxide dismutase (SOD). DEM
      caused GSH depletion in cells, whether they were exposed to Zn or not, that
      lasted one h; after that time, GSH rose back to basal levels. BSO also caused GSH
      depletion in cells exposed or unexposed to Zn, and no recovery in GSH levels was
      detectable during the entire period of exposure (12 h). However, GSH depletion
      induced by both DEM or BSO was attenuated in Zn-treated hepatocytes. Moreover,
      DEM and BSO exposures led to a depletion of MT levels in Zn-treated hepatocytes,
      indicating a link between GSH and MT metabolism. In cells unexposed to either Zn,
      DEM or BSO, there was an increase in GSH-Px and SOD activities after 6 and 12 h
      of incubation, respectively. Under the same conditions, catalase activity was
      inhibited after 6 h of incubation and returned to the activity found at t = 0
      after 12 h of incubation. DEM and BSO treatments had no significant effect on GSH
      Px or SOD activities although they led to inhibition of catalase activity. Taken
      together, our data indicate that MT induction, which creates a new pool of thiol
      groups in the cell cytosol, can attenuate GSH depletion induced by DEM or BSO. It
      appears that catalase is most sensitive to oxidative stress and that MT induction
      can antagonize the deleterious effects of such stress on the enzyme. This study
      supports the view that MT is part of the hepatocyte antioxidant-defense-system.

PMID- 10416276
TI  - Anticonvulsant-resistant seizures following pyridostigmine bromide (PB) and N,N
      diethyl-m-toluamide (DEET).
AB  - An acute toxic interaction has been described, in which sublethal doses of
      pyridostigmine bromide (PB) and the insect repellent N,N-diethyl-m-toluamide
      (DEET), when administered concomitantly, resulted in seizures and lethality. To
      investigate the possible relationships between seizures and lethality and the
      role of the cholinergic system in this interaction, PB (5 mg/kg), DEET (200
      mg/kg) or PB (3 mg/kg) + DEET (200 mg/kg) were administered i.p. to male ICR
      mice, alone or following i.p. pretreatment, with one of several anticonvulsant
      agents: diazepam, 10 mg/kg; fosphenytoin, 40 mg/kg; phenobarbital, 45 mg/kg; or
      dextrophan, 25 mg/kg), or the anticholinergic agents, atropine (5 mg/kg),
      atropine methyl nitrate (2.7 mg/kg), or mecamylamine (2.5 mg/kg). The
      anticonvulsants selected for this study act through different mechanisms to
      reduce seizures. None of the anticonvulsants was able to reduce the incidence of
      seizures following treatment with PB, DEET or PB + DEET. Only diazepam delayed
      the onset of seizures. Fosphenytoin or diazepam significantly prolonged the time
      to lethality following PB, but only fosphenytoin reduced the incidence of PB
      induced lethality. Diazepam or phenobarbital significantly prolonged the time to
      lethality following PB + DEET. Both atropine and atropine methyl nitrate
      protected against PB and PB + DEET-induced lethality and PB-induced seizures.
      Neither agent blocked seizures resulting from DEET or PB + DEET. Mecamylamine
      reduced seizures and lethality in PB-treated mice, but not in mice treated with
      DEET or PB + DEET. The results indicate that seizure activity is not a causative
      factor in the toxic interaction between PB and DEET. Furthermore, PB, DEET and PB
      + DEET induce seizures that are resistant to standard anticonvulsants, and each
      appears to operate through different mechanisms to produce seizures. Peripheral
      muscarinic receptors may play a specific role in lethality caused by PB + DEET.

PMID- 10416277
TI  - The importance of measured end-points in demonstrating the occurrence of
      interactions: a case study with methylchloroform and m-xylene.
AB  - Mixed exposures may result in significant changes in one biomarker of exposure
      without altering another biomarker, and this may have unknown significance in
      terms of exposure assessment and overall toxicity of the mixture. Results from a
      previous investigation showed that human exposure to methylchloroform (MC, 400
      ppm) and m-xylene (XYL, 200 ppm) during 4 h did not result in any significant
      effect on blood concentrations of these solvents, suggesting the absence of
      interaction between MC and XYL. Those results were adequately described by
      conducting a physiologically-based toxicokinetic (PBTK) modeling of the MC-XYL
      interaction in humans; however, the model suggested that urinary excretion of MC
      metabolites would be reduced as a result of combined exposure, whereas that of
      XYL metabolites would not be modified. An experimental verification of this model
      prediction was then undertaken with rats. In this study, Sprague-Dawley rats (n,
      5) were exposed during 4 h to MC (400 ppm) or XYL (200 ppm), alone or as a
      mixture. Results showed that combined exposure did not affect the blood
      concentration of MC whereas that of XYL was increased throughout the 2-h blood
      collection period following exposure. The excretion of MC metabolites during a
      period of 48 h following the onset of exposure, i.e., trichloroethanol (TCE: 
      71%) and trichloroacetic acid (TCA: -73%), were significantly reduced.
      Methylhippuric acid (MHA) was not affected by co-exposure to MC as expected from
      the PBTK model forecasts. These results exemplify the use of a priori PBPK
      modeling for designing interaction studies and choosing appropriate/sensitive end
      points for demonstrating the occurrence of potential interactions.

PMID- 10416278
TI  - Dose-response trend tests for tumorigenesis, adjusted for body weight.
AB  - Several studies have demonstrated a relationship between rodent body weight and
      tumor incidence for some tissue/organ sites. It is not uncommon for a chemical
      tested for carcinogenicity to also affect body weight. In such cases, comparisons
      of tumor incidence may be biased by body-weight differences across dose groups. A
      simple procedure was investigated for reducing this bias. This procedure divides
      the animals into a few groups based on body weight. Body weight at 12 months was
      used, before the appearance of a tumor was likely to affect body weight.
      Statistics for dose-response trend tests are calculated within body weight strata
      and pooled to obtain an overall dose-response trend test. This procedure is
      analogous to that currently used, of stratifying animals, based on their age at
      the time of removal from a study. Age stratification is used to account for
      differences in animal age across dose groups, which can affect comparisons of
      tumor incidence. Several examples were investigated where the high-dose group had
      reduced body weights and associated reductions in tumor incidence. When the data
      were analyzed by body-weight strata, some positive dose-response trends for tumor
      incidence were demonstrated. In one case, the weight-adjusted analysis indicated
      that a negative dose-response trend in tumor incidence was a real effect, in
      addition to a body weight reduction. These examples indicate that it is important
      to consider the effects of body weight changes as low as 10%, and perhaps below,
      that were caused by chemicals in 2-year bioassays for carcinogenesis. The simple
      procedure of analyzing tumor incidence within body-weight strata can reduce the
      bias introduced by weight differences across dose groups.

PMID- 10416279
TI  - Toxic characteristics of the synthetic lipid A derivative DT-5461 in rats and
      monkeys.
AB  - We compared lethal toxicity and potential for splenomegaly and disseminated
      intravascular coagulation (DIC) of the lipid A derivative DT-5461 with those of
      compound 506 (C506) and bacterial lipopolysaccharide (LPS). These agents were
      given intravenously, by either bolus intravenous injection (2 ml/min) or drip
      infusion (3 ml/4 h), into the tail vein of rats under various regimens. In naive
      rats, the lethal dose after bolus intravenous injection was clearly higher than
      that after drip infusion for C506 and LPS, but not for DT-5461. In partially
      hepatectomized or D-galactosamine-treated rats, a marked enhancement of the
      lethality was observed for all agents relative to that in naive rats.
      Splenomegaly was commonly seen in all surviving rats after treatment, and
      histopathological examination revealed lymphoid hyperplasia in the B-cell area of
      the white pulp zone and lympho-reticular cell proliferation of the red pulp zone.
      When administered intravenously by drip infusion to rats pretreated with 0.4 M
      lactic acid, both C506 and LPS provoked DIC. This was manifested by a decrease in
      platelet counts, prolongation of activated partial thromboplastin time (APTT),
      and an increase in fibrin-fibrinogen degradation products (FDP), with
      hepatocellular necrosis and glomercular fibrin thrombus formation. In contrast,
      DT-5461 showed no such toxic events with the same protocol. In14-day intravenous
      toxicity studies of DT-5461, rats were more susceptible to hepatocellular
      necrosis and splenomegaly than squirrel monkeys. These results demonstrate that
      DT-5461 is a promising compound, with antitumor activity dissociated from its
      toxic potential.

PMID- 10416280
TI  - Are we on the threshold of a new theory of disease? Toxicant-induced loss of
      tolerance and its relationship to addiction and abdiction.
AB  - 'Toxicant-induced loss of tolerance' (or TILT) describes a two-step disease
      process in which (1) certain chemical exposures, e.g., indoor air contaminants,
      chemical spills, or pesticide applications, cause certain susceptible persons to
      lose their prior natural tolerance for common chemicals, foods, and drugs
      (initiation); (2) subsequently, previously tolerated exposures trigger symptoms.
      Responses may manifest as addictive or abdictive (avoidant) behaviors. In some
      affected individuals, overlapping responses to common chemical, food, and drug
      exposures, as well as habituation to recurrent exposures, may hide (mask)
      responses to particular triggers. Accumulating evidence suggests that this
      disease process might underlie a broad array of medical illnesses including
      chronic fatigue, fibromyalgia, migraine headaches, depression, asthma, the
      unexplained illnesses of Gulf War veterans, multiple chemical sensitivity, and
      attention deficit disorder.

PMID- 10416281
TI  - Neural sensitization model for multiple chemical sensitivity: overview of theory
      and empirical evidence.
AB  - This paper summarizes theory and evidence for a neural sensitization model of
      hyperresponsivity to low-level chemical exposures in multiple chemical
      sensitivity (MCS). MCS is a chronic polysymptomatic condition in which patients
      report illness from low levels of many different, structurally unrelated
      environmental chemicals (chemical intolerance, CI). Neural sensitization is the
      progressive host amplification of a response over time from repeated,
      intermittent exposures to a stimulus. Drugs, chemicals, endogenous mediators, and
      exogenous stressors can all initiate sensitization and can exhibit cross
      sensitization between different classes of stimuli. The properties of
      sensitization overlap much of the clinical phenomenology of MCS. Animal studies
      have demonstrated sensitization to toluene, formaldehyde, and certain pesticides,
      as well as cross-sensitization, e.g., formaldehyde and cocaine. Controlled human
      studies in persons with self-reported CI have shown heightened sensitizability in
      the laboratory to nonspecific experimental factors and to specific chemical
      exposures. Useful outcome measures include spectral electroencephalography, blood
      pressure, heart rate, and plasma beta-endorphin. Findings implicate, in part,
      dopaminergic mesolimbic pathways and limbic structures. A convergence of evidence
      suggests that persons with MCS or with low-level CI may share some
      characteristics with individuals genetically vulnerable to substance abuse: (a)
      elevated family histories of alcohol or drug problems; (b) heightened capacity
      for sensitization of autonomic variables in the laboratory; (c) increased amounts
      of electroencephalographic alpha activity at rest and under challenge conditions
      over time. Sensitization is compatible with other models for MCS as well. The
      neural sensitization model provides a direction for further systematic human and
      animal research on the physiological bases of MCS and CI.

PMID- 10416283
TI  - Evolutionary game theory and multiple chemical sensitivity.
AB  - Newlin's [Newlin D.B. Evolutionary game theory of tolerance and sensitization in
      substance abuse. Paper presented to the Research Society on Alcoholism, Hilton
      Head, SC, 1998] evolutionary game theory of addictive behavior specifies how
      evolutionarily stable strategies for survival and reproduction may lead to
      addiction. The game theory of multiple chemical sensitivity (MCS) assumes that:
      (1) the MCS patient responds to low-level toxicants as stressors or as direct
      threats to their survival and reproductive fitness, (2) this activates the
      cortico-mesolimbic dopamine system, (3) this system is a survival motivation
      center--not a 'reward center', (4) the subject emits a counter-response that is
      in the same direction as the naive response to the chemicals, (5) previously
      neutral stimuli associated with chemicals also trigger conditioned responses that
      mimic those to the chemicals, (6) these counter-responses further activate the
      dopaminergic survival motivation system, and (7) this produces a positive
      feedback loop that leads to strong neural sensitization in these structures and
      in behavior controlled by this system, despite a small initial response.
      Psychologically, the MCS patient with a sensitized cortico-mesolimbic dopamine
      system is behaving as though his/her survival is directly threatened by these
      chemicals. Non-MCS subjects have counter-responses opposite in direction to those
      of the chemicals and show tolerance. An autoshaping/sign-tracking model of this
      game is discussed. This evolutionary game makes several specific, testable
      predictions about differences between MCS subjects, non-MCS controls, and
      substance abusers in laboratory experiments, and between sensitized and
      nonsensitized animals.

PMID- 10416282
TI  - EEG sensitization during chemical exposure in women with and without chemical
      sensitivity of unknown etiology.
AB  - This study tested the sensitization model proposed by Bell et al. [Bell I.R.,
      Miller C.S. and Schwartz G.E. An olfactory-limbic model of multiple chemical
      sensitivity syndrome: possible relationship to kindling and affective spectrum
      disorders. Biol. Psychiatry 1992: 32: 218-242] to study chemical sensitivity. The
      sensitization model indicates that a pharmacological stimulus or a traumatic
      event which elicits a strong response can sensitize limbic and/or mesolimbic
      pathways; and subsequent less intense trauma or stimuli, in the same or different
      modality, can elicit an amplified response. Three groups of subjects were tested:
      (1) women who reported chemical sensitivity and no sexual abuse (chemically
      sensitive, CS); (2) sexually abused (SA) women without chemical sensitivity; and
      (3) healthy women without chemical sensitivity or sexual abuse history (normal,
      N). All subjects were exposed to odorant and nonodorous control stimuli once a
      week for 3 weeks. Electroencephalographic activity was recorded while subjects
      sniffed the odorant and control stimuli. Results of the study revealed that both
      the CS and the SA group showed electroencephalogram (EEG) alpha sensitization
      across experimental sessions, while the N group showed little change over time.
      Additionally, EEG findings revealed that the CS group generated significantly
      greater alpha activity than the other two groups. Finally, while the groups were
      different on measures of psychological distress, these differences did not
      diminish the EEG findings. In summary, these findings suggest that intermittent
      exposure to chemicals elicits sensitization in CS and SA women without chemical
      sensitivity, supporting our expectations that chemical sensitivity is, in part, a
      manifestation of time-dependent sensitization (TDS). Additionally, these EEG
      findings indicate that CS women are unlike SA and healthy women in the amount of
      EEG alpha activity they generate. Finally, these findings indicate that
      psychological factors as assessed in this study do not explain
      electrophysiological differences between chemically and non-chemically-sensitive
      women.

PMID- 10416284
TI  - Multiple chemical sensitivity as a conditional response.
AB  - Pavlovian conditioning may contribute to some cases of multiple chemical
      sensitivity (MCS). On the basis of the conditioning analysis, environmental
      stimuli (especially olfactory cues) present at the time of a toxicant overdose
      become associated with the toxicant and elicit aversive conditional responses.
      Similar associations have been reported in patients receiving chemotherapy, and
      the literature on such 'pretreatment nausea' in cancer patients is relevant to
      understanding the role of conditioning in MCS. Evaluation of the contribution of
      conditioning to MCS has been complicated by confounding interpretations that
      emphasize conditional responses with interpretations which emphasize the
      psychiatric status of the patient. Appreciation of the contribution of Pavlovian
      conditioning to MCS will lead to a better understanding of this complex disorder.

PMID- 10416285
TI  - Mechanisms of allergy and chemical sensitivity.
AB  - Allergy and chemical sensitivity are closely related disorders in which
      environmental exposures produce inflammatory reactions. For allergy,
      environmental proteins bind to IgE antibody on mast cells leading to the release
      of inflammatory mediators. In chemical sensitivity, low molecular weight
      chemicals bind to chemoreceptors on sensory nerve C-fibers leading to the release
      of inflammatory mediators. Clinical manifestations are similar in the two
      conditions. The overlap between the two conditions has a basis in mechanism, so
      the similarity of clinical manifestations and high percentage of individuals with
      both conditions may have a biological basis. Chronic exposures can lead to
      adaptation phenomena. Depression has been associated with both allergy and
      chemical sensitivity. Both the allergic and chemical irritant responses may be
      subjected to conditioning so that the response is triggered by other stimuli.
      Evidence for conditioning is strongest for allergy. Both allergy and chemical
      sensitivity can be acquired in association with irritant exposures.

PMID- 10416286
TI  - Sensory irritation and multiple chemical sensitivity.
AB  - Many of the symptoms described in Sick Building Syndrome (SBS) and multiple
      chemical sensitivity (MCS) resemble the symptoms known to be elicited by airborne
      irritant chemicals. Irritation of the eye, nose, and throat is common to SBS,
      MCS, and sensory irritation (SI). Difficulty of breathing is often seen with SBS,
      MCS, and pulmonary irritation (PI). We therefore asked the question: can indoor
      air pollutants cause SI and/or PI? In laboratory testing in which mice breathed
      the dilute volatile emissions of air fresheners, fabric softeners, colognes, and
      mattresses for 1 h, we measured various combinations of SI and PI as well as
      airflow decreases (analogous to asthma attacks). Air samples taken from sites
      associated with repeated human complaints of poor air quality also caused SI, PI,
      and airflow limitation (AFL) in the mice. In previous publications, we have
      documented numerous behavior changes in mice (which we formally studied with a
      functional observational battery) after exposure to product emissions or
      complaint site air; neurological complaints are a prominent part of SBS and MCS.
      All together, these data suggest that many symptoms of SBS and MCS can be
      described as SI, PI, AFL, and neurotoxicity. All these problems can be caused by
      airborne irritant chemicals such as those emitted by common commercial products
      and found in polluted indoor air. With some chemical mixtures (e.g., emissions of
      some fabric softeners, disposable diapers, and vinyl mattress covers) but not
      others (e.g., emissions of a solid air freshener), the SI response became larger
      (2- to 4-fold) when we administered a series of two or three 1-h exposures over a
      24-h period. Since with each exposure the intensity of the stimulus was constant
      yet the magnitude of the response increased, we concluded that there was a change
      in the sensitivity of the mice to these chemicals. The response was not a
      generalized stress response because it occurred with only some mixtures of
      irritants and not others; it is a specific response to certain mixtures of
      airborne chemicals. This is one of the few times in MCS research that one can
      actually measure both the intensity of the stimulus and the magnitude of the
      response and thus be allowed to discuss sensitivity changes. The changing SI
      response of the mice might serve as a model of how people develop increasing
      sensitivity to environmental pollutants. Intensive study of this system should
      teach us much about how people respond to and change sensitivity to airborne
      irritant chemicals.

PMID- 10416287
TI  - Behavioral sensitization after repeated formaldehyde exposure in rats.
AB  - Multiple chemical sensitivity (MCS) is a phenomenon whereby individuals report
      increased sensitivity to chemicals in the environment, and attribute their
      sensitivities to prior exposure to the same or often structurally unrelated
      chemicals. A leading hypothesis suggests that MCS is akin to behavioral
      sensitization observed in rodents after repeated exposure to drugs of abuse or
      environmental stressors. Sensitization occurring within limbic circuitry of the
      central nervous system (CNS) may explain the multisymptom complaints in
      individuals with MCS. The present studies represent the continuing development of
      an animal model for MCS, the basis of which is the CNS sensitization hypothesis.
      Three behaviors were assessed in rats repeatedly exposed to formaldehyde (Form)
      inhalation. In the first series of experiments, rats were given high-dose Form
      exposure (11 parts per million [ppm]; 1 h/day x 7 days) or low-dose Form exposure
      (1 ppm; either 1 h/day x 7 days or 1 h/day x 5 days/week x 4 weeks). Within a few
      days after discontinuing daily Form, cocaine-induced locomotor activity was
      elevated after high-dose Form or 20 days of low-dose Form inhalation.
      Approximately 1 month later, cocaine-induced locomotor activity remained
      significantly elevated in the 20-day Form-exposed rats. The second experiment
      assessed whether prior exposure to Form (20 days, as above) would alter the
      ability to condition to an odor (orange oil) paired with footshock. The results
      suggested a tendency to increase the conditioned fear response to the odor but
      not the context of the footshock box, and a decreased tendency to extinguish the
      conditioned fear response to odor. The third experiment examined whether CNS
      sensitization to daily cocaine or stress would alter subsequent avoidance
      responding to odor (Form). Daily cocaine significantly elevated approach
      responses to Form, while daily stress pretreatment produced a trend in the
      opposite direction, producing greater avoidance of Form. Preliminary studies
      indicated that repeated daily Form inhalation (20 days, as above) produced a
      greater avoidance to subsequent Form presentation, suggesting that daily Form
      inhalation may serve as a stressor. The results support the hypothesis that
      repeated chemical exposure in rats may produce CNS plasticity manifest as greater
      sensitivity to dopaminergic drugs, enhanced fear conditioning to odor paired with
      an aversive event, and greater avoidance of odors. Some of these behavioral
      changes observed in rats may provide a link with symptoms in a subset of
      individuals with MCS.

PMID- 10416288
TI  - A rat model of neurobehavioral sensitization to toluene.
AB  - Some individuals report that, following either a single high-level or repeated
      lower-level exposures to chemicals (initiation), subsequent exposure to very low
      concentrations of chemicals (triggering) produces a variety of adverse effects,
      including disruption of cognitive processes. Our objective was to model this two
      step process in a laboratory animal. Two groups of 16 rats, eight male and eight
      female, received whole-body inhalation exposure to toluene, either at 80 ppm for
      6 h/day for 4 weeks (Repeat group) or to 1600 ppm for 6 h/day on one day only
      (Acute group). Two other groups (Trigger group and Clean group) of 16 were sham
      exposed. After 17 days without toluene exposure, the Acute, Repeat and Trigger
      groups began a series of daily toluene 'trigger' exposures (10 ppm for 1 h)
      followed immediately by testing on an operant repeated-acquisitions task
      requiring learning within and across sessions. The Clean group was sham-exposed
      prior to operant testing. Trigger or sham exposures and operant testing continued
      5 days/week for 17 sessions. Analysis of variance revealed a variety of
      statistically significant (P < 0.05) differences between treatment groups.
      Furthermore, the patterns of differences between groups differed (P < 0.05) for
      female and male rats. For example, male rats of the Trigger group made the most
      responses, and female rats of the Repeat group responded most slowly. The
      observation of important changes in the operant behavior of female and male rats
      previously exposed to toluene, at relatively low concentrations (80 or 1600 ppm)
      and then later re-exposed at very low concentrations (10 ppm), is consistent with
      the experiences of humans reporting cognitive difficulties following acute or
      chronic exposures to chemicals.

PMID- 10416289
TI  - The Environmental Exposure and Sensitivity Inventory (EESI): a standardized
      approach for measuring chemical intolerances for research and clinical
      applications.
AB  - The lack of a generally accepted case definition for multiple chemical
      sensitivity (MCS) and the absence of a standardized approach for measuring
      salient aspects of chemical sensitivity that would permit cross-comparison of
      findings by different investigators have hindered progress in this area. Based
      upon findings from an earlier study of 112 persons with self-reported chemical
      sensitivity who attributed their chemical sensitivity to a well-defined exposure
      event, we developed an instrument with self-rating scales to assess Symptom
      Severity, Chemical (Inhalant) Intolerances, Other Intolerances (e.g., foods,
      medications, alcohol), Life Impact, and Masking (a measure of ongoing chemical
      exposures). When administered to four patient groups and controls, the scales
      showed good reliability and validity overall (n = 421) and in each group. Used
      together, the scales provided sensitivity of 92% and specificity of 95% in
      differentiating chemically sensitive persons from controls. Our results support
      use of these scales individually or collectively for a variety of applications
      including the selection of chemically sensitive subjects and controls for
      research, assessment of chemical sensitivity in various study populations, cross
      comparison of groups studied by different investigators, pre- and post-assessment
      of therapeutic interventions, clinical evaluation of complex patients who report
      intolerances, and teaching medical residents and students how to evaluate
      patients for chemical sensitivity and MCS.

PMID- 10416290
TI  - A controlled comparison of symptoms and chemical intolerances reported by Gulf
      War veterans, implant recipients and persons with multiple chemical sensitivity.
AB  - Using the Environmental Exposure and Sensitivity Inventory (EESI), a standardized
      instrument for measuring chemical sensitivity, we obtained and compared ratings
      of symptoms, chemical (inhalant) intolerances, other intolerances (e.g., drugs,
      caffeine, alcohol, skin contactants), lifeimpact, and masking (ongoing exposures)
      in five populations: multiple chemical sensitivity (MCS) patients who did (n =
      96) or did not (n = 90) attribute onset of their illness to a specific exposure
      event, patients with implanted devices (n = 87), Gulf War veterans (n = 72), and
      controls (n = 76). For each patient group, mean scores on the first four scales
      were significantly greater than for controls. MCS patients reported avoiding more
      chemical exposures (were less masked) than the other groups. Across groups, for a
      given level of symptoms, as masking increased, mean scores on the Chemical
      Intolerance Scale decreased. In contrast, mean scores on the Other Intolerance
      Scale appeared to be less affected by masking. These findings suggest that some
      patients with antecedent chemical exposures, whether exogenous (chemical spill,
      pesticide application, indoor air contaminants) or endogenous (implant), develop
      new chemical, food, and drug intolerances. Reports of new caffeine, alcohol,
      medication, food, or other intolerances by patients may signal exposure-related
      illness. Masking may reduce individuals' awareness of chemical intolerances, and,
      to a lesser degree, other intolerances.

PMID- 10416291
TI  - Exacerbation of chemical sensitivity: a case study.
AB  - We report exacerbation of symptoms and chemical intolerances in three of four
      self-described chemically sensitive women following relocation to a newly
      constructed office building. Levels of total volatile organic compounds (TVOCs)
      in this building prior to occupancy were approximately 200 micrograms/m3 (toluene
      equivalent units) with a myriad of individual components present. By day 50 after
      occupancy, the concentration of TVOCs in the building dropped to approximately 50
      micrograms/m3. Nevertheless, three women reported significant worsening of their
      symptoms with spreading of their sensitivities to previously tolerated chemical
      exposures. One woman relocated to another building, while the other two managed
      their symptoms by reducing time spent in the building or by using a room air
      cleaner. By day 600 following occupancy, although TVOCs had increased
      significantly (perhaps due to cleaning agents), there were fewer individual VOCs
      present in the air, and some of the women were able to tolerate the air in the
      building. We conclude that complex mixtures of VOCs at very low levels tolerated
      by the majority of building occupants may pose problems for persons who report
      pre-existing chemical sensitivities. TVOC measurements may not correlate with
      symptoms in these individuals. Reasonable accommodations by an employer can
      reduce problem exposures, making it possible for some affected individuals to
      continue productive employment.

PMID- 10416292
TI  - Odor sensitivity and respiratory complaint profiles in a community-based sample
      with asthma, hay fever, and chemical odor intolerance.
AB  - This is a community-based study of odor sensitivity and respiratory complaints
      for persons reporting asthma (n = 14/141), hay fever (n = 72/140), and chemical
      odor intolerance (CI) (n = 41/181). CI, a symptom of multiple chemical
      sensitivity (MCS), was determined from self-ratings of feeling 'moderately' to
      'severely' ill using the Chemical Odor Intolerance Index (CII). Index odors
      included perfume, pesticide, drying paint, new carpet odor, and car exhaust. Six
      additional odors [natural gas, disinfectants, chlorinated water, room
      deodorizers, and environmental tobacco smoke (ETS)] were also assessed in the
      health and environment survey. Asthmatics reported feeling 'frequently' to
      'almost always' ill from the CII index odors of drying paint, new carpet odor,
      perfume, and cleaning agents compared to nonasthmatics. People with hay fever
      documented feeling 'frequently' to 'almost always' ill from pesticides, drying
      paint, and car exhaust compared to individuals without hay fever. The CI cited
      illness from air freshener, natural gas and chlorinated water, in addition to the
      index odors of perfume, paint, pesticides, new carpeting and auto exhaust. All
      three groups were significantly more likely to report feeling ill from ETS.
      People with asthma were significantly more likely to report lower lung
      complaints, such as wheeze and dyspnea. People with hay fever cited more chest
      tightness. The CI were significantly more likely to report upper and lower
      respiratory symptoms. Given this overlap in respiratory complaints, it could be
      that CI may serve to amplify these traditional immune-related disorders and/or
      suggest that having asthma or hay fever could make one more vulnerable to CI.

PMID- 10416293
TI  - Psychiatric illness in the first-degree relatives of persons reporting multiple
      chemical sensitivities.
AB  - The multiple chemical sensitivities (MCS) syndrome is characterized by
      unexplained physical and psychiatric complaints attributed by patients and some
      of their physicians to low-level chemical exposures. In this study, we
      interviewed 15 subjects with MCS and 21 controls about their first-degree
      relatives using the Family History-Research Diagnostic Criteria (FH-RDC).
      Subjects with MCS were more likely than controls to report their relatives to
      have major depression, alcoholism, panic disorder, obsessive-compulsive disorder,
      and antisocial personality disorder. They were also likely to have past suicide
      attempts, and to have received some form of psychiatric treatment
      (hospitalization, medication or electroconvulsive therapy, or counseling). Nearly
      30% of the relatives of subjects with MCS were reported to have MCS themselves.
      Possible reasons for the findings are discussed.

PMID- 10416294
TI  - Neurotoxicity in single photon emission computed tomography brain scans of
      patients reporting chemical sensitivities.
AB  - The subset of patients reporting chemical sensitivity with neurocognitive
      complaints usually exhibits specific abnormalities of brain metabolism consistent
      with neurotoxicity, on imaging with single photon emission computed tomography
      (SPECT). These recurrent neurotoxic patterns are characterized by a mismatch in
      tracer uptake between early- and late-phase imaging, multiple hot and cold foci
      throughout the cortex, temporal asymmetry and increased tracer uptake into the
      soft tissues and, sometimes, the basal ganglia. Previous studies confirm these
      neurotoxic findings in patients with neurotoxic chemical exposures and breast
      implants. Affective processes such as depression do not, alone, show this
      pattern. These abnormalities in SPECT images correlate with documented
      neurocognitive impairment. Controlled challenges to ambient chemicals can induce
      profound neurotoxic changes seen on SPECT imaging in chemically sensitive
      patients. Detoxification treatment techniques frequently produce significant
      improvement on brain SPECT brain imaging in these patients. Neurotoxicity appears
      to be characteristic in many cases of chemical sensitivity.

PMID- 10416295
TI  - Low-level chemical sensitivity: implications for research and social policy.
AB  - There is increasing evidence that human exposure to levels of chemicals once
      thought to be safe--or presenting insignificant risk--are, in fact, harmful. So
      called low-level exposures are now known to be associated with adverse biological
      effects including cancer, endocrine disruption, and chemical sensitivity. This
      requires that we change both (1) the way we design research linking chemicals and
      health, and (2) the solutions we devise to address chemically caused injury. The
      new and emerging science of low-level exposure to chemicals requires appropriate
      social policy responses which include regulation of toxic substances,
      notification of those exposed, and compensation and reasonable accommodation to
      those affected. Research and social policy need to be focused towards two
      distinct groups: (1) those individuals who could become chemically intolerant as
      a result of an initiating exposure, and (2) those individuals who have already
      become chemically intolerant and are now sensitive to chemicals at low levels.

PMID- 10416296
TI  - The development of judicial policy on the phenomenon of multiple chemical
      sensitivity in the post-Daubert era.

PMID- 10416297
TI  - Developing a pesticide policy for individuals with multiple chemical sensitivity:
      considerations for institutions.
AB  - Institutions are increasingly being asked to accommodate individuals with
      multiple chemical sensitivity (MCS). Most establishments have chosen to provide
      such accommodations on a case-by-case basis only. This paper investigates
      feasible actions that may be taken by institutions to reduce exposure of MCS
      individuals as well as the general institutional population to pesticides and
      other substances. Emphasis is placed on procedures that can be instituted on a
      regular basis and may be combined with case-by-case management for better
      resolution of problems.

PMID- 10416298
TI  - [Maternal-fetal mortality in advanced age].
AB  - In order to compare the maternal-fetal outcome in pregnant women of advanced age
      (bigger than 35 years old) with those smaller than 30 years. 268 pregnant women
      were studied that went for their control and attention of the childbirth,
      corresponding 134 patients of more than 35 years and 134 patients between 20-29
      years (control group). Cases were excluded if presented confounding variables
      (smoking, obesity, multiparity and maternal illnesses associated to the
      pregnancy). Data of maternal-fetal morbimortality were written down both groups
      and they were analyzed by means of X2 test or Fisher exact test for assessing
      differences between the groups, P < 0.05 was considered statistically
      significant, with a power of 80%, with a delta of 12%. The only two variables
      that had statistical significant were the number of cesarean sections 66 (49.2%)
      in the group of older women against 43 (32%) in the control group (P < 0.01) and
      normal vaginal deliveries (45 cases in the study group and 80 cases in the
      control group (P < 0.001). The rest of the analyzed variables none had difference
      statistically significant between both groups and they are described next:
      Forceps delivery was documented in 6 patients of the older group and 4 of the
      control group; 7 abortions were observed in a group and 17 in the other group of
      patients; there were not maternal deaths in both groups. The premature rupture of
      membranes was presented in 22 cases of the study group and in 24 cases of the
      control group; 8 congenital anomalies were presented in women's of advanced age
      children and 2 in mother's of the group control children; admission to the unit
      of therapy intensive neonatal happened in 17 products of the study group and in 9
      cases of the control group; there were 3 stillbirths in the women of advanced age
      and 1 stillbirth in the control group; 3 perinatal deaths were presented in the
      patients of advanced age and 2 cases in the control group, all these variables
      had a value of P greater than 0.05 (not significant). When controlling
      confounding variables that can influence in the increase of the maternal-fetal
      morbimortality, it was observed that the only two significant variables were
      smaller normal vaginal deliveries (P < 0.001) and higher number of cesarean
      sections (P < 0.01) in patients with advanced age, owing to most of them are
      subjected to cesarean section without evaluating the possibility to obtain the
      product by means of a childbirth, for what the indication of cesarean section
      should be revalued in advanced age multiparous pregnant and in case of not having
      factors of associated risk to attempt the birth for childbirth, reducing by this
      way the incidence of cesarean sections as well as the morbidity that this
      procedure may imply.

PMID- 10416299
TI  - [Physiopathologic bases for preeclampsia: a hypothesis].
AB  - Preeclampsia represents the main medical complication of pregnancy and one of the
      most important causes of maternal mortality around the world. At this time, the
      etiology of the illness is unidentified and there is not sure predictors for
      early identification. The objective of this article was to provide an integrative
      hypotheses that suggests the possibility of to relate an increment of placental
      lactogen, insulin resistance, hyperinsulinemia and risk of preeclampsia.

PMID- 10416301
TI  - [Brenner tumor. Report of a case and experience at the Spanish Hospital in
      Mexico].
AB  - Brenner tumor is a solid benign tumor of the ovary, with its origin in the
      parammesonephric celomic epithelium and represents about the 0.5 an the 0.79% of
      all ovarian tumors. We present a case of a woman in which we found a Brenner
      Tumor in the left ovary while we were performing an abdominal total hysterectomy.
      As a consequence we reviewed the experience in the Hospital Espanol de Mexico in
      the last 10 years. We concluded that we have the same frequency of presentation
      that in other parts of the world. None of our cases were malignant.

PMID- 10416300
TI  - [Maternal mortality from eclampsia. A 5-year experience].
AB  - Eclampsia is the most important cause of maternal mortality in our hospital. The
      main purpose of the present study was to define the main clinical, social and
      demographic profiles of the pregnant women at risk of fatality due to eclampsia.
      Of a total 71 maternal deaths that took place our hospital from January 1991 to
      December 1995, 37 cases were due to eclampsia, and they are the subject of the
      present analysis. RESULTS: The fatalities due to eclampsia represented 52.1% of
      the total mortality. The average age of these women were 26 years, 46% were
      primigravid and 20% were chronically hypertensive. Eclampsia was diagnosed at an
      average of 33 weeks gestation. The most important clinical signs were: severe
      headache, vomiting and convulsions. Systolic blood pressure on admission was 160
      mm Hg with an average of 110 mm Hg for the diastolic figure. Proteinuria greater
      that 3 g/L was present in 45% of the cases. Signs of hemolysis, a platelet count
      below 100,000 mm3 and liver involvement with increased levels of amino
      transferases. CONCLUSIONS: The pregnant women likely to die from eclampsia seems
      to be relatively older, multipara, with underlying chronic hypertension, with
      early onset of the clinical picture, and with multisystemic manifestations of the
      disease, mainly in the hematologic, hepatic and neurologic territories.

PMID- 10416302
TI  - [Clinical evaluation of patients submitted to open vs conventional gynecologic
      laparoscopy].
AB  - The objective was to comparate the clinical evolution and rates of complications
      for open and conventional gynecological laparoscopy. Were studied the cases of
      253 patients divided in two groups: Group 1 (n = 106) patients treated with open
      laparoscopy, and group 2 (n = 147) patients managed with conventional surgery.
      The major indication for performing laparoscopy was infertility management. There
      were not early or I ate complications of trocar insertion or operative
      laparoscopy in the group 1. However, in group 2 there were four complications (P
      < 0.05), two related with needle or trocar insertion. As conclusion, in the
      studied group open laparoscopy can to eliminate the risks of blind insufflation
      and trocar insertion observed in the classifical technique, is a safe and
      efficacious method to treat several gynecological pathologies.

PMID- 10416303
TI  - [The role of insulin-like growth factor in polycystic ovary syndrome].
AB  - The partnership the insulin-like growth factor (IGF) in women with polycystic
      ovary syndrome (PCOS) is characterized by mechanisms underlying alterations in
      the GH/IGF-1, axis. In the pathogenesis exist a synergism markedly enhanced
      between IGF-1 and insulin, and IGF-1 with LH to increase androgen production,
      causing a reduced IGFBPs and SHBG production, the resulting hyperandrogenism,
      within and outside the ovary, may inhibitor follicular maturation and the
      biosynthesis of estrogen. At the present, the data suggests up to date paracrine,
      autocrine as well as endocrine actions in the ovary in normal conditions and the
      lost of this homeostasis can be followed by neuro-endocrine.

PMID- 10416304
TI  - [Maternal and fetal morbidity in a group of women with gestational diabetes].
AB  - Normal pregnant women in the second and third trimester were screened to detect
      gestational diabetes. Using the protocol proposed by the World Health
      Organization, we identified 33 women whose two hr glucose levels was > 200 mg/dl.
      Only sixteen women had less than 34 weeks of pregnancy when were seen for the
      first time at the diabetes clinic, the other seventeen women had more than 34
      weeks when they presented to the diabetes clinic. The first group, was called the
      treated group and the second group was the non-treated group. The main clinical
      characteristics of these patients, treated vs non-treated, were (X +/- SD): age
      (years) 33.2 +/- 5.2 (20-40) vs 30.2 +/- 6.5 (20-39), p < 0.05; weeks of
      pregnancy at diagnosis: 27.9 +/- 4.1 (19-33) vs 36.1 +/- 2.3 (34-40), p < 0.05;
      weight (Kg): 79.9 +/- 13.1 (61.8-108) vs 87.4 +/- 16.8 (60.8-118), p = NS; length
      of pregnancy (weeks) 38 +/- 1.3 (36-40) vs 38.4 +/- 1.4 (35-40), p = NS; newborns
      weight (g): 3,654 +/- 650 (2,475-5,100) vs 3,221 +/- 529 (2,650-4,650), p = NS.
      There was an intrauterine death of a macrosomic fetus in the non-treated group.
      There were three macrosomic newborns in the treated group and one in the non
      treated group, p = NS. Also, there was a premature newborn of 1,975 g, whose
      pregnancy was interrupted for acute fetal distress. Delivery by cesarean section
      occurred in 29 women (87.8%), and it was mainly related to the diabetes
      diagnosis. The prevalence of macrosomia in the treated group supports the idea
      that treatment has to be established at least at 24 weeks of pregnancy, to reduce
      this rate. It is concluded that gestational diabetes is associated to an increase
      in maternal and fetal morbidity, requiring strict supervision to detect and treat
      fetal distress and a tight glucose control to decrease the macrosomia rate.

PMID- 10416305
TI  - [Evaluation of an educational course for pregnant adolescents].
AB  - The pregnancy among adolescent women in Mexico is close than half million by
      year, this problem could be attended through health education in the Mexican
      medical care system. Since 1995 the Instituto Nacional de Perinatologia has a
      free training program only for adolescents designed to improve the health care
      medical procedures and reduces some perinatals health risks. This paper shows the
      structural design, functioning strategies and results of its application. Through
      a pre codificated 48 item list, were analyzed transversally the clinical records
      of 234 adolescents engraved themselves to the course. Two groups were formed: the
      "A" group with the patients attended at least to three sessions (106) and the
      group "B" with the ones who did not (128). The data analysis was made by
      contrasting each item between the groups using the appropriate statistical tests.
      The group "A" had greater average in scholarship, the moreover socioeconomic
      characteristics and gynecoobstetric background did not show significant
      differences. Group "B" had a higher proportion of adolescent with aggregated
      pathology to the pregnancy. We too observed significant differences in the
      proportions of complications during the pregnancy evolution and in the postpartum
      period. The acceptance on the pregnancy by the adolescent, her family and by her
      couple also showed significant differences. The average weight of the newborns
      were greater statistically in the "A" group. The proportions of family planning
      methods acceptance was higher in the same group, who has too shorter intra
      hospitalary stay. This evaluation shows good fitness with the adolescents
      education expectatives and performance and favorable associations with some
      perinatals health risks.

PMID- 10416306
TI  - [Symptomatic diaphragmatic endometriosis. Laparoscopic treatment with laser CO2.
      Report of cases].
AB  - The endometriosis has been observed in 10% of the women in reproductive age and
      it is found in pelvis in most of the cases. However, occasionally it is located
      on nonpelvic organs and infrequently in diaphragmatic location. Two cases of
      diaphragmatic endometriosis with symptoms are presented and treated with CO2
      laser successful. There are a few reports of laparoscopic treatment of
      diaphragmatic endometriosis. The patients with clinical diagnosis of
      endometriosis and nonpelvic symptoms have the possibility of the disease in
      nonpelvic organs. The adequate treatment will be in benefit of the patient.

PMID- 10416307
TI  - Hand eczema in a nurse.

PMID- 10416308
TI  - Medical Claims Conciliation Panel annual report to the 1999 legislature.

PMID- 10416309
TI  - Natural rubber latex allergy, an epidemic in the health field.
AB  - The object of this paper is to educate health care providers of the markedly
      increased incidence of natural rubber latex (NRL) allergy to epidemic proportions
      during the past 10 to 12 years. A review of latex allergy problems in health care
      providers as well as patients is presented. Also reported is a questionnaire
      survey of institutions listed with the Health Care Association of Hawaii.

PMID- 10416310
TI  - Natural rubber latex. A short history of its production, use and sensitizing
      features in the development of latex allergy in adults and children.

PMID- 10416311
TI  - The legal aspects of the latex protein allergy epidemic.

PMID- 10416312
TI  - Plasma levels of E-selectin in normolipemic and hyperlipemic arteriopathic
      patients.
AB  - BACKGROUND: The authors studied the plasmatic levels of E-selectin in a group of
      normolipemic and hyperlipemic arteriopathic patients. METHODS: The series
      consisted of 73 subjects (53 male, 20 female, age 54 +/- 9) suffering from
      occlusive peripheral arteriopathy; 21 subjects with total cholesterol (TC) below
      200 mg/dl were considered as normolipemics (group A), 24 subjects with TC between
      200 and 240 mg/dl, mild hypercholesterolemics (group B), 18 with TC above 240
      mg/dl, severe hypercholesterolemics (group C); 10 subjects had high triglyceride
      values (above 200 mg/dl), (group D); 12 normal controls were also considered. For
      each subject the determination of the E-selectin E-plasma levels was performed
      with an immunoenzymatic method (kit ELISA Amersham). RESULTS: In group A a value
      of E-s (4.03 +/- 0.37 ng/ml) statistically lower (p < 0.05) compared to normal
      controls (5.71 +/- 0.61 ng/ml) was found; in group B the E-s value (3.81 +/- 0.31
      ng/ml) was slightly lower than that of group A; in group C the value of E-s was
      3.53 +/- 0.23 ng/ml, statistically lower compared normal controls (p < 0.01) and
      to group A (p < 0.05); in group D the E-s value (3.24 +/- 0.23 ng/ml) was sharply
      reduced compared to controls (p < 0.01) and to groups A-B-C (p < 0.05).
      CONCLUSIONS: The reduction or E-selectin, was proportional to the magnitude of
      total cholesterol and triglycerides; the chronicity of the vasculopathy and the
      dyslipidemia may be responsible for an impaired biosynthetic endothelial
      function.

PMID- 10416313
TI  - [Rheologic modifications induced by heparin therapy. Capillary blood viscosity,
      erythrocyte deformability, aggregation index].
AB  - BACKGROUND: The most important problem with which doctors have to deal every day
      in their practice, is occlusive vascular disease, at the basis of which there is
      commonly a process of thrombosis. For this reason, it is very important to define
      early the subjects at thrombosis risk and an appropriate therapeutic strategy.
      METHODS: We considered 13 inpatients at thrombosis risk, c/o sezione di Clinica
      Medica I, dipartimento di Medicina Interna e Terapia Medica, Universita di Pavia,
      IRCCS Policlinico S. Matteo, and 12 healthy volunteers, between March and June
      1998, evaluating age, sex, weight, diseases and ongoing therapy, hemocytological,
      hemocoagulational and hemorheological tests before and after heparinic therapy.
      RESULTS: General blood viscosity, measured by the rotational and double
      filtration method, presented no significant changes; on the contrary, capillary
      blood viscosity and erythrocyte deformability, measured by our new double
      filtration method, showed respectively an increase and a decrease. CONCLUSIONS:
      Calcium heparin is the most frequently used antithrombotic drug in thrombotic
      diseases and their prevention, but its action on the hemorheological profile is
      not clear. This study showed that it increases erythrocyte aggregation rate and
      decreases erythrocyte deformability, having a negative effect on the
      microcirculation.

PMID- 10416314
TI  - [Neurologic complication of carotid thrombendarterectomy].
AB  - BACKGROUND AND AIMS: Carotid endarterectomy (CEA) is often carried out to prevent
      cerebrovascular strokes. It is obviously important that neurological morbidity of
      the procedure is contained within acceptable limits (< 2%). METHODS: Between
      January 1991 and December 1997 a total of 239 CEA were performed in 216 patients
      (169 males and 47 females, mean age 66.6 +/- 14.2 years; range 43-81).
      Angioplasty was carried out using a precoagulated Dacron patch, except in cases
      in which the residual diameter of the internal carotid artery was greater than 5
      mm. A Javid shunt was used selectively if stump pressure < 50 mmHg. RESULTS: No
      major neurological complications were observed. A reversible focal neurological
      deficit was reported in 3 cases (1.2%). Neurological morbidity correlated to
      peripheral arterial occlusive disease appears to be correlated mainly with
      technical reasons or cerebral ischemia following clamping. CONCLUSIONS: The
      extensive use of angioplasty with patch and the selective use of a protective
      shunt improve the technical success rate of surgery, significantly helping to
      limit morbidity.

PMID- 10416315
TI  - [Ischemia-reperfusion of the colon following clamping of the abdominal aorta].
AB  - Aortic cross-clamping is the cornerstone of abdominal aortic aneurysm surgery.
      The transient ischemia of the inferior hemisoma, and mainly of the large bowel,
      is then a current condition, usually well tolerated. At the time of vascular
      clamps removal, the ischemia-reperfusion syndrome may take place, and evolution
      toward multiple organ failure is an actual risk. The large bowel has a crucial
      role in the sequence of events causing ischemia-reperfusion syndrome, even when
      intestinal ischemia is not evident during aneurysmectomy. In this paper, current
      concepts of ischemia-reperfusion syndrome are reviewed, and the role of the colon
      after abdominal aortic cross-clamping for aneurysmectomy is focused. Principles
      of prevention of MOF from ischemia-reperfusion syndrome are pointed out.

PMID- 10416317
TI  - Disability and burden of depressive disorders.

PMID- 10416316
TI  - Current indications for hormone replacement therapy.

PMID- 10416318
TI  - Survival after cardiopulmonary resuscitation in an urban Indian hospital.
AB  - BACKGROUND: Survival after cardiopulmonary resuscitation depends upon the quality
      of pre-hospital support, availability of resuscitation equipment and the
      competence of the resuscitator. There are few data on the prognosis of patients
      undergoing such resuscitation in India. METHODS: In a retrospective analysis of
      215 resuscitations done in a 125-bed community hospital between January 1995 and
      November 1997, return of spontaneous circulation and survival to discharge were
      evaluated. Multivariate methods were used to identify the predictors of
      successful outcome. RESULTS: Of all the patients, 14.4% were alive at discharge.
      Survival after a cardiorespiratory arrest in the hospital was 18.4%, which was
      significantly better than survival after pre-hospital events (5.9%; p = 0.027).
      Multivariate predictors of survival at discharge were resuscitation duration of
      less than 20 minutes [odds ratio (95% confidence limit): 32.6 (6.5-164.3)],
      presentation with ventricular tachycardia or fibrillation [odds ratio: 18.5 (4.4
      77.9)], in-hospital cardiorespiratory arrest [odds ratio: 5.2 (1.2-21.6)] and
      female sex [odds ratio: 3.2 (1.1-9.6)]. Bystander resuscitation, though rarely
      provided, increased survival at discharge (p = 0.026). CONCLUSIONS: With 5.5
      resuscitation attempts needed for one live discharge after in-hospital
      cardiorespiratory arrest and 17 attempts to save a life after pre-hospital
      events, our outcomes are comparable to those reported from developed nations. A
      return of pulse after shorter durations of cardiopulmonary resuscitation,
      ventricular fibrillation or tachycardia as the abnormal presenting rhythm, in
      hospital location of cardiorespiratory (CR) arrest and female sex were
      independent predictors of live discharge. Age and aetiology of CR arrest did not
      influence the outcome.

PMID- 10416319
TI  - Factors influencing response to lymphonodovenous shunt in filarial lymphoedema.
AB  - BACKGROUND: Although several studies have been published on lymphonodovenous
      shunt, there are no objective data either on the outcome of lymphoedema or on
      various parameters likely to influence the results. METHODS: A trial of
      lymphonodovenous shunt was carried out in 75 patients with unilateral filarial
      lymphoedema. The primary aim of the trial was to identify a cohort of responders
      as against non-responders and to correlate the outcome with various factors such
      as age, gender, duration and preoperative grade of lymphoedema, number of
      preoperative attacks of adenolymphangitis, operative impression of the lymph
      node, effect of venous reflex and type of nodovenous anastomoses. Change in
      oedema volume was measured objectively by water displacement method using the
      normal limb as a control. RESULTS: There was no operative mortality. Predominant
      postoperative complications included wound haematoma (8.5%), wound infection
      (13.6%) and transient lymphorrhoea (13.6%). In the immediate postoperative
      period, a reduction of 25%-50% in the oedema volume was recorded in 46.7% of
      cases and of more than 50% in 17.3% cases. The difference in response with
      respect to the type of lymphonodovenous shunt was not statistically significant,
      although the end-to-side type of shunt showed marginally better results. The
      response was significantly higher in patients with preoperative oedema volume
      more than 2 L. There was a significant reduction in postoperative attacks of
      adenolymphangitis, irrespective of the reduction in oedema volume. Of the 75
      patients, 22 showed regression of oedema volume to preoperative or higher levels
      in the postoperative phase. A majority (21/22) could be identified as non
      responders within 3 months of surgery. CONCLUSION: The best results of
      lymphonodovenous shunt were seen in patients with large-volume lymphoedema. The
      results are better when combined with early excisional surgery. Other factors did
      not significantly affect the outcome. Non-responders could be identified within 3
      months after surgery. Even in patients who did not respond well, a significant
      decrease in the frequency of adenolymphangitis attacks was observed. Higher
      initial oedema volume and history of higher frequency (25-50 per year) of
      adenolymphangitis attacks can be considered as indicators for good response to
      lymphonodovenous shunt.

PMID- 10416320
TI  - Surgical presentation of melioidosis in India.
AB  - BACKGROUND: Melioidosis, the disease caused by Burkholderia pseudomallei, is
      common in Southeast Asia. It has also been reported from India, where some
      investigators feel it is under-diagnosed and under-reported. We report our
      experience with melioidosis presenting as abscesses at unusual sites. METHODS:
      All consecutive patients with culture proven B. pseudomallei, who presented to a
      single surgical unit between 1995 and 1998, were evaluated. RESULTS: Three
      patients presented with splenic abscesses and one with a soft tissue abscess in
      the neck. One patient developed septicaemia. All patients responded favourably to
      ceftazidime and/or co-trimoxazole which was started as soon as the diagnosis was
      confirmed. CONCLUSION: Melioidosis is under-diagnosed in India, probably due to a
      low index of suspicion of this disease among clinicians. It should be considered
      as a possibility when abscesses are encountered at unusual sites. The pus must
      then be cultured to identify the causative agent.

PMID- 10416322
TI  - Diagnostic approach to choledocholithiasis.

PMID- 10416321
TI  - Epidemiology of visceral leishmaniasis in India.
AB  - Kala-azar has re-emerged from near eradication. The annual estimate for the
      incidence and prevalence of kala-azar cases worldwide is 0.5 million and 2.5
      million, respectively. Of these, 90% of the confirmed cases occur in India,
      Nepal, Bangladesh and Sudan. In India, it is a serious problem in Bihar, West
      Bengal and eastern Uttar Pradesh where there is under-reporting of kala-azar and
      post kala-azar dermal leishmaniasis in women and children 0-9 years of age.
      Untreated cases of kala-azar are associated with up to 90% mortality, which with
      treatment reduces to 15% and is 3.4% even in specialized hospitals. It is also
      associated with up to 20% subclinical infection. Spraying of DDT helped control
      kala-azar; however, there are reports of the vector Phlebotomus argentipes
      developing resistance. Also lymphadenopathy, a major presenting feature in India
      raises the possibility of a new vector or a variant of the disease. The
      widespread co-existence of malaria and kala-azar in Bihar may lead to a
      difficulty in diagnosis and inappropriate treatment. In addition, reports of the
      organism developing resistance to sodium antimony gluconate--the main drug for
      treatment--would make its eradication difficult. Clinical trials in India have
      reported encouraging results with amphotericin B (recommended as a third-line
      drug by the National Malaria Eradication Programme). Phase III Trials with a
      first-generation vaccine (killed Leishmania organism mixed with a low
      concentration of BCG as an adjuvant) have also yielded promising results.
      Preliminary studies using autoclaved Leishmania major mixed with BCG have been
      successful in preventing infection with Leishmania donovani. Until a safe and
      effective vaccine is developed, a combination of sandfly control, detection and
      treatment of patients and prevention of drug resistance is the best approach for
      controlling kala-azar.

PMID- 10416323
TI  - Should meta-analysis replace large randomized control trials?

PMID- 10416324
TI  - Approach to a patient with musculoskeletal complaints.

PMID- 10416325
TI  - Postgraduate training programmes in otolaryngology and head and neck surgery in
      India.

PMID- 10416326
TI  - Pilot sites for colorectal cancer screening get the green light.

PMID- 10416328
TI  - Who should pay for anti-obesity drugs?

PMID- 10416327
TI  - The politics of medical publishing.

PMID- 10416329
TI  - An unusual forum for a discussion on medical ethics.

PMID- 10416330
TI  - An iron fist in an iron glove.

PMID- 10416331
TI  - Ciprofloxacin-resistant Salmonella typhi.

PMID- 10416332
TI  - Nalidixic acid-resistant Salmonella typhi in Mumbai.

PMID- 10416333
TI  - Massive ovarian oedema.

PMID- 10416335
TI  - A methodology for applied medical research.

PMID- 10416334
TI  - Cancer survival estimation: the need to correct bias due to outcome-related
      follow up loss.

PMID- 10416336
TI  - Food poisoning due to organophosphorus compounds.

PMID- 10416337
TI  - [Childhood sexual abuse in the history of patients in high-frequency
      psychoanalytic long-term therapy--prevalence and diagnosis].
AB  - 276 treatment records of patients who were undergoing high-frequent, outpatient,
      individual, psychoanalytic therapy were analysed with respect to the prevalence
      and patterns of childhood sexual abuse in the history of these patients. 22.8% of
      all patients experienced narrowly defined sexual abuse during childhood (the end
      of the 17th year); additionally, 35.2% of all patients reported minor forms of
      sexually abusive experiences. The gender distribution, the age at onset of sexual
      abuse, and the relationship to the perpetrator were analysed. Looking at
      psychoanalytic diagnoses, a significant correlation between a history of
      childhood sexual abuse and a diagnosis of hysterical neurosis was found.

PMID- 10416338
TI  - [Quality of life, depression and coping behavior in patients awaiting heart
      transplant].
AB  - From a medical perspective, heart transplantation is now an established procedure
      for the treatment of patients with terminal heart failure. For the patient
      involved, it presents itself as a situation of great psychological distress,
      particularly during the waiting period. In the last few years, this situation has
      grown worse due to the decline in the number of donor organs and the resulting
      longer waiting period. The aim of this study was to systematically evaluate this
      phase of the transplantation procedure in a follow-up study. 52 patients could be
      assessed in follow-up. Although the patients had already differed from the
      healthy control group in the areas of depression, quality of life, and physical
      complaints (p < 0.001) at the beginning of the study, there was a significant
      increase of depression and a further decline in the reported quality of life in
      the course of the study. The patients presented themselves as having a low
      internal and a significantly increased external and fatalistic locus of control.
      The study stresses the necessity for supportive psychotherapeutic therapy in
      these patients.

PMID- 10416339
TI  - [Psychogenic impairment and current feelings in the elderly. Which options are
      offered by the biographical perspective?].
AB  - In the Eldermen study funded by the German Research Association (DFG), a
      consecutive sample of patients, aged > or = 60 (n = 120) and being treated for a
      variety of internal medical complaints in an acute geriatric hospital were
      examined with the help of comprehensive somatic diagnostics, standardised
      questionnaires, and a semi-structured biographical interview. The study
      investigates the relationship between burdensome and supportive biographical
      experiences and the extent of psychogenic impairment as well as aspects of
      feeling tone and self-concept in later life. For the degree of psychogenic
      impairment (Impairment Score. IS; Schepank 1995), subjectively experienced
      burdens and support were found to be more relevant than "objective" burdens. As
      expected, subjective burdens consistently experienced over several life phases,
      particularly in association with limited experienced support, were found to be
      associated with greater psychogenic impairment and a higher "case risk" in later
      life. However, the patients with the highest values for current life satisfaction
      as well as a more positive self-concept were not those patients who never
      experienced more burdens than support in their biographies, but rather those who
      experienced more burden than support in one life phase. The results are presented
      in relation to models of learning theory and object relation theory and discussed
      for their clinical relevance.

PMID- 10416341
TI  - [Can problem-based learning help medical students to assimilate knowledge?
      Evaluation of a first semester course in medical psychology].
AB  - Before the introduction of problem-based teaching and learning schemas, careful
      consideration must be given to the system devised for the evaluation of results.
      In the framework of a problem-based first-semester tutorial in medical
      psychology, certain interdisciplinary skills of prime importance to a doctor were
      tested to establish whether they were learnt more effectively by this approach
      than by traditional training methods. The experimental group was found to rank
      higher than controls in the following behavioural capacities: precise casework;
      differentiated approach to further treatment of patients; the ability to form
      hypotheses and to test them critically.

PMID- 10416340
TI  - [Mobile computer-assisted psychometric diagnosis. Economic advantages and results
      on test stability].
AB  - In psychotherapy, there is a rising need to evaluate the therapeutic process and
      outcome quality. However, the effort for documentation binds manpower and is a
      burden on economic resources. Hence, we studied the usability of a new by
      developed, mobile, computer-assisted basis assessment (ComBas 1.3) in comparison
      with paper-and-pencil versions with respect to its effects on data structure and
      cost reduction. More than 9000 standardised psychometric tests (personality
      inventory: Giessentest, complaint checklist: Giessener Beschwerdebogen, mood
      checklist: Berliner Stimmungsfragebogen) were applied with each method to 1400
      psychosomatic patients. It was found that usage of the mobile computer-assisted
      assessment reduced the time by 2/3 spent on documentation, because data
      organisation and accessibility for clinical, scientific, and educational needs
      were significantly improved. Moreover, no differences in stability coefficients
      and data distribution were seen between the two methods. In trait variables,
      there was also an equivalence in scale means, but in state variables, especially
      in complaint scales, we identified a tendency toward higher scale means in
      computer-assisted measurement. We cannot establish whether this is only a
      methodical effect or is additionally influenced by changes in samples during the
      evaluation period between 1989 and 1996. Hence, we concluded that comparison
      samples for state instruments should be adjusted to the applied test form and
      actualised for use in individual diagnostics.

PMID- 10416342
TI  - [Autopsy].

PMID- 10416343
TI  - [The stubbornness of Alphonse Laveran].

PMID- 10416344
TI  - [Recent epidemiologic trends in cancer of the esophagus].
AB  - In developed countries there is a decreasing incidence of oesophageal cancers in
      males. In France, a strong difference is still observed between northern and
      southern areas, incidence being twice in the former. Incidence is slightly
      increasing in females. For the past 20 years, the rate of adenocarcinoma of the
      lower third is growing, especially in North America. This trend is emerging in
      France, but remains at a lesser degree. Carcinomas of the lower oesophagus
      present clinical and epidemiological similarities with those of the cardia. This
      change could be explained by the increasing prevalence of gastro-oesophageal
      reflux. Alcohol and tobacco remain the main risk factors of squamous cell
      carcinoma. Aniseed aperitif, warm spirits and beer carry the highest risk. For
      tobacco, the risk is correlated to the duration of consumption and decreases
      after quitting.

PMID- 10416345
TI  - [Barrett's esophagus].
AB  - Barrett's oesophagus is a complication of oesophagogastric reflux. Diagnosis is
      made on the basis of endoscopy and histology showing glandular and intestinal
      metaplasia above the oeso-gastric junction. The most severe complication is
      adenocarcinoma. Endoscopic follow up is effective in individual patients. Other
      solutions would be either to protect the Barrett oesophagus from carcinogenic and
      cocarcinogenic agents contained in particular in the duodenal reflux fluid, or to
      ablate Barrett's mucosa by thermal or physicochemical processes, allowing
      subsequent regrowth of normal malpighian mucosa by suppression of the
      oesophagogastric reflux.

PMID- 10416346
TI  - [Diagnosis and evaluation of the extent of cancer of the esophagus].
AB  - Oesophageal cancer includes two distinct tumours: squamous cell cancer is related
      to alcohol and tobacco consumption; adenocarcinoma develops on a metaplastic
      columnar mucosa lining the oesophagus (Barrett's oesophagus). In Western
      countries the ratio of the 2 tumors is 6 to 4. Dysphagia is a late symptom in the
      evolution and corresponds in most cases to advanced cancer with poor prognosis.
      Treatment decision required evaluation of the performance status, search for
      associated tumors (mouth, pharynx and respiratory tract), and evaluation of the
      locoregional extension of the primary tumour. In the absence of dysphagia,
      detection of oesophageal cancer at an early stage is compatible with a curative
      option.

PMID- 10416347
TI  - [The natural history and complications of esophageal cancer].
AB  - Squamous cell carcinoma of the oesophagus has a poor prognosis, owing in part to
      the compromised status of the patients. Early oesophageal cancer is rarely
      diagnosed, even if its endoscopic aspects are well known. From the mucosa, the
      disease progresses step by step, and also via the submucosa. Furthermore,
      multiple locations are not uncommon. Bulky tumours progressively obstruct the
      oesophageal lumen while infiltrative tumours invade the oesophageal layers, and
      then the perioesophageal fat and the mediastinal organs. Involvement of
      mediastinal, cervical and abdominal lymph nodes occurs early. Distant metastases
      occur later. Complications are mainly due to the locoregional spread of the
      disease, leading to death.

PMID- 10416348
TI  - [Cancers associated with cancer of the esophagus].
AB  - Secondary neoplastic localisations observed in oesophageal epidermoid carcinoma
      are essentially in the upper oesophagogastric tract, in particular the
      hypopharynx, the oropharynx and the buccal cavity. The associated morbidity of
      the mucous membrane of the upper oesophagogastric tract and that of the
      oesophagus, with regard to the risk of developing epidermoid carcinoma, is linked
      to a common risk factor, simultaneous alcohol and tobacco intoxication. The high
      frequency of these secondary localisations, which can be synchronous or
      metachronous, suggests they should be routinely sought during pretreatment
      evaluation of oesophageal cancer as well as during mid- and long-term follow up.

PMID- 10416350
TI  - [Radio- and chemotherapy of cancer of the esophagus].
AB  - Surgical resection has been the mainstay of therapy for localised carcinoma of
      the oesophagus. However, the five-year survival rate after curative resection is
      only 20 to 30%, and other treatments have been tried to improve these results.
      Radiotherapy, chemotherapy and sequential or combined chemoradiotherapy have been
      used, either alone or in combination with surgery. Radiotherapy and chemotherapy
      do not improve survival and are restricted to very limited cases. Results of
      exclusive combined chemoradiotherapy are very similar to those of surgery, with
      five-year survival rate of 20%. The promising results of chemoradiotherapy
      followed by surgery need to be confirmed by further trials. Good survival rates
      obtained for responders to chemoradiotherapy require to find better means for
      identifying such patients before treatment.

PMID- 10416349
TI  - [Surgery of cancer of the esophagus].
AB  - Although the management of oesophageal cancers remains controversial, surgery
      provides the best chance of cure for patients with limited tumour, through
      complete resection of the lesion. Surgery can be proposed in 10 to 30% of the
      cases. Palliative surgery should be avoided. Despite some differences, squamous
      cell carcinoma and adenocarcinoma can be considered as closery similar in regard
      to surgery. Surgery is a locoregional treatment. Distant metastasis, even latent,
      are probably frequent at the time of diagnosis. Neoadjuvant or adjuvant treatment
      like chemotherapy with radiotherapy with concomittent radiotherapy, should be
      useful. The aim of follow-up is to diagnose second primary lesion at a curative
      state (upper digestive and respiratory tracts, bronchi).

PMID- 10416352
TI  - [2 histories].

PMID- 10416351
TI  - [Palliative and curative endoscopic treatment of cancer of the esophagus].
AB  - The most common indication for endoscopic treatment of oesophageal cancers is
      palliative, owing to their late diagnosis and high rate of inoperability. The aim
      is to maintain oesophageal permeability. Technical progress in tumoral reduction
      (ethanol necrosing injections, plain or argon electrocoagulation, laser), which
      can be combined to radiochemotherapy, has limited the use of other methods:
      dilatations have short-lived efficacy; inoperable oesotracheal fistula is the
      main indication for endoscopically inserted prosthesis. Curative endoscopy is
      indicated for localised and superficial tumours in patients who are judged unfit
      for surgery. Mucosectomy, photodynamic therapy, intracavitary brachytherapy or
      local injections of anticancer drugs can then be employed either alone or, more
      commonly, combined with one another and with general radiochemotherapy.

PMID- 10416353
TI  - [Procurement and transplantation of organs. Judicial and ethical aspects].

PMID- 10416354
TI  - [Fracture of the lower end of the radius in adults. Mechanisms, diagnosis,
      treatment].

PMID- 10416355
TI  - [Angina pectoris. Epidemiology, etiology, physiopathology, diagnosis, course,
      treatment].

PMID- 10416356
TI  - [Sarcoidosis. Diagnosis, course, treatment].

PMID- 10416358
TI  - [A lesson on the meeting of the medical residents].

PMID- 10416357
TI  - [Cranial injuries and management in emergency situations].

PMID- 10416359
TI  - [Inguinal, femoral and umbilical hernia. Physiopathology, diagnosis,
      complication, treatment].

PMID- 10416360
TI  - [Abutment tooth preparation for the perio-overdenture. A new technic for the
      preparation of the abutment tooth and the fashioning of the root cap for the
      perio-overdenture].

PMID- 10416361
TI  - [New pathways in periodontal plastic surgery. Aspects of the microsurgical
      operating technic].

PMID- 10416362
TI  - Evaluation of certain veterinary drug residues in food. Fiftieth report of the
      joint FAO/WHO Expert Committee on Food Additives.
AB  - This report presents the conclusions of a Joint FAO/WHO Expert Committee convened
      to evaluate the safety of residues of certain veterinary drugs in food and to
      recommend maximum levels for such residues. The first part of the report
      considers the neurotoxicity of anthelminthics belonging to the avermectin and
      milbemycin classes of compounds and the evaluation policy of the Committee in
      establishing Maximum Residue Levels (MRLs) for veterinary drugs in food. A
      summary follows of the Committee's evaluations of toxicological and residue data
      on a variety of veterinary drugs: five anthelminthic agents (eprinomectin,
      febantel, fenbendazole, oxfendazole and moxidectin), seven antimicrobial agents
      (gentamicin, procaine benzylpenicillin, sarafloxacin, spectinomycin,
      chlortetracycline, oxytetracycline and tetracycline), three antiprotozoal agents
      (diclazuril, imidocarb and nicarbazin), one glucocorticosteroid (dexamethasone),
      one production aid (recombinant bovine somatotropins) and one tranquilizing agent
      (azaperone). Annexed to the report are a summary of the Committee's
      recommendations on these drugs, including Acceptable Daily Intakes and MRLs, and
      further toxicological studies and other information required.

PMID- 10416363
TI  - The effect of experimental infectious mastitis on leukocyte subpopulations and
      cytokine production in non-lactating ewes.
AB  - The interactions between leukocytes and cytokines during the acute response to
      intramammary infections in the dry mammary gland of sheep were studied. Dry ewes
      were experimentally infected in one udder half with either Staphylococcus aureus
      or Escherichia coli, or infused with saline as control. Udder secretion samples,
      blood samples and udder tissue samples were collected before and 4, 8 and 24 h
      after infections/infusions. Total and differential leukocyte counts were
      calculated in both blood and mammary secretions, and flow cytometry was used to
      detect the presence of CD4+, CD8+, WC1+, IL-2R+, CD18+ or L-selectin +
      lymphocytes, CD18+ or L-selectin + neutrophils, and CD14+ leukocytes. Moreover,
      the concentrations of interleukin-1 beta (IL-1 beta), interleukin-8 (IL-8) and
      granulocyte-macrophage colony stimulating factor (GM-CSF) in udder secretions
      were measured using ELISA, and RT-PCR was used to detect the presence of
      corresponding cytokine mRNA in udder tissue biopsies. The results suggest an
      association between the concentrations of IL-1 beta, IL-8 and the intensity of
      neutrophil infiltration of the infected gland. Immunologically relevant changes
      in proportions of lymphocyte subpopulations might also occur in the acute phase
      of the inflammatory reaction of the udder. Greater cellular and cytokine
      responses to E. coli infection may have contributed to the milder clinical
      picture and more rapid resolution of infection than that seen for S. aureus.
      Enhancing the production of pro-inflammatory cytokines may improve defence
      against bacterial mastitis.

PMID- 10416364
TI  - RT-PCR amplification of various canine cytokines and so-called house-keeping
      genes in a species-specific macrophage cell line (DH82) and canine peripheral
      blood leukocytes.
AB  - Total ribonucleic acid (RNA) isolated from a continuous canine macrophage cell
      line (DH82) was used in reverse transcription polymerase chain reactions (RT-PCR)
      for the detection of transcripts of interleukin (IL)-8, -12, and tumour necrosis
      factor-alpha (TNF). Three different methods of RNA isolation (standard
      guanidinium-thiocyanate method with and without application of RNA matrix, and
      boiling) were used and compared in regard to RT-PCR results. The most suitable
      method was used to establish RT-PCR amplification of mRNA transcripts of IL-2, 
      10, and interferon-gamma (IFN) in RNA isolated from canine peripheral blood
      leukocytes. Integrity of RNA isolates was ensured by amplification of
      glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or beta-actin, IL-8, -12, and
      TNF were amplified from RNA isolated by various methods. Use of guanidinium
      thiocyanate with and without RNA matrix gave the most consistent results. Boiling
      as a mean of RNA isolation was quick and easy, but the RT-PCR results were
      extremely variable and multiple smaller bands were observed in the agarose gel in
      some preparations. IL-2, -10 and IFN transcripts were amplified from RNA isolated
      with guanidinium-thiocyanate from leukocytes stimulated with concanavalin A.
      DNase-treatment of RNA isolates was necessary to assure the destruction of
      genomic DNA and to avoid amplification of genomic sequences. This was especially
      a problem when using primers for GAPDH, beta-actin, IL-12, and TNF. Lack of DNase
      treatment may lead to false positive results. This may be especially a problem
      when amplification of so-called house-keeping genes is used as internal control
      for RNA integrity. These findings demonstrated that isolation of total RNA with
      guanidinium-thiocyanate followed by DNase-treatment gave reliable and consistent
      results for detection of cytokine transcripts by RT-PCR in a canine macrophage
      cell line and canine peripheral blood leukocytes.

PMID- 10416365
TI  - Health status of bulls used for natural breeding on farms in south west Scotland.
AB  - One hundred and nine breeding bulls were examined during the period November 1992
      to June 1993 on farms in south west Scotland for evidence of infectious diseases
      associated with breeding. Preputial washings were collected to screen for
      Campylobacter fetus venerialis, together with serial blood samples to assess
      their seroprevalence to Bovine Virus Diarrhoea virus (BVDv), Bovine Herpes Virus
      1 (BHV-1), Leptospira hardjo and Bovine Herpes Virus-4 (BHV-4). The possible
      impact of natural mating on the epidemiology of these diseases is described.
      Evidence of infections with Campylobacter fetus and BVH-4 were not found in this
      sample. The overall seroprevalence to BVDv was 78%, for BHV-1 49%, and L. hardjo
      27% at titres of > or = 1/400. This study shows that bulls may be responsible for
      the introduction and dissemination of these diseases when moved from farm to farm
      as part of normal cattle breeding in this area. Young unproven bulls may be
      particularly susceptible to endemic diseases associated with lowered reproductive
      performance.

PMID- 10416366
TI  - Interactions of Mycoplasma bovoculi with erythrocytes: role of p94 surface
      protein.
AB  - The attachment of two strains of Mycoplasma bovoculi to erythrocytes was measured
      using 35S-methionine-labelled organisms. Receptor sites of M. bovoculi involved
      in this attachment are trypsin-sensitive, since mild trypsin treatment of the
      intact organisms abolished this process completely. Pretreatment of erythrocytes
      with trypsin or increasing concentrations of neuraminidase resulted in no
      measurable effect. Monoclonal antibody MA25.5 directed against a M. bovoculi
      surface antigen of 94 kDa termed p94 blocked 40% of the attachment, while MA18.13
      directed against a 57 kDa protein band of M. bovoculi had no effect on the
      attachment process. Other properties of M. bovoculi were tested using six strains
      of the mycoplasma and erythrocytes from several animal species. None of the
      strains showed haemagglutinating or haemadsorbing activities.

PMID- 10416367
TI  - Isolation and identification of Vibrio metschnicovii from domestic ducks and
      geese.
AB  - Seven Vibrio-like field strains of German origin were isolated culturally from
      diseased domesticated ducks, muscovy ducks and geese, and were compared with
      reference strains NCTC 8443 (type strain) and NCTC 11170 of Vibrio metschnicovii
      using classical phenotypic and chemotaxonomic tests. Some V. cholerae strains
      were included in the chemotaxonomic tests for comparative purposes. On the basis
      of the classical phenotypic characteristics studied and the numerical analysis of
      the whole-cell fatty acid patterns, the Vibrio-like field strains were identified
      as Vibrio metschnicovii. The identification tables and the database of the
      computer software of two commercial micro-identification kits (API-20 NE, ID-32
      E) did not identify the field strains. Of the reference strains used, only NCTC
      8443 was correctly identified by the ID-32 E software.

PMID- 10416369
TI  - Comparison between a gamma-IFN assay and intradermal tuberculin test for the
      diagnosis of bovine tuberculosis in field trials in Brazil.
AB  - Bovine tuberculosis is a major problem in Brazil. The intradermal tuberculin test
      is the standard test for detection of bovine tuberculosis in Brazil but can lack
      both sensitivity and specificity. The purpose of this study was to compare a
      bovine gamma-IFN assay with the tuberculin test under field conditions in Brazil.
      A total of 1632 animals from 13 dairy farms were tested using the single cervical
      tuberculin test (SCTT). Among those animals, about 15% of each herd, 220 in
      total, represented a high-risk group and were selected to be tested using the
      gamma-IFN test. Of the 1632 animals tested, 207 presented significant reactions
      representing 12.7% of the cattle studied. In the selected group the number of
      animals positive by the gamma-IFN assay was 126/220 (57.3%) and the total number
      of reactive cows on SCTT was 106/220 (48.2%). The real number of infected cattle,
      following standards, was 120/220 (54.5%). From these results the relative
      sensitivity rate of gamma-IFN test was 100% including the false-positive results
      and 88.3% for the SCTT--a significant (P < 0.01) difference in favour of the
      gamma-IFN test of 11.7%. The gamma-IFN assay also identified some positive
      animals 60-120 days earlier than the SCTT. In conclusion, we believe that the
      gamma-IFN assay can be used alone or in combination with the SCTT, as a valuable
      tool for the control of bovine tuberculosis in the Brazilian national herd.

PMID- 10416368
TI  - Risk indicators for the seroprevalence of Mycoplasma hyopneumoniae, porcine
      influenza viruses and Aujeszky's disease virus in slaughter pigs from fattening
      pig herds.
AB  - Epidemiological aspects of Mycoplasma hyopneumoniae (Mh), influenza H1N1 and H3N2
      viruses, and Aujeszky's disease virus (ADV) were investigated in slaughter pigs
      from 50 fattening pig herds. Herd factors as potential risk indicators for
      respiratory disease were obtained by means of a questionnaire. At slaughter,
      blood samples were collected from each herd, and the proportion of seropositive
      pigs per herd was assessed for each of these pathogens. The median herd-level
      seroprevalence of the agents were: Mh 88%, H1N1 100%, H3N2 60% and ADV 90%. The
      percentage of herds in which all investigated fattening pigs were seronegative
      for these agents was: Mh 0%, H1N1 0%, H3N2 12% and ADV 18%. The percentage of
      herds in which all investigated fattening pigs were seropositive for these agents
      was: Mh 8%, H1N1 71%, H3N2 22% and ADV 40%. A positive association was found
      between influenza H1N1 and H3N2 viruses, and a negative association between
      influenza H3N2 virus and ADV. There were no risk indicators for the
      seroprevalence of Mh. Three risk indicators were associated with the
      seroprevalence of influenza H1N1 virus: a fully slatted floor, an increasing
      number of pigs in the municipality and dry feeding. Three risk indicators were
      found for the seroprevalence of influenza H3N2 virus: purchase of pigs from > or
      = two herds, an increasing number of pigs in the municipality and natural
      ventilation. The seroprevalence of ADV was influenced by two risk indicators: an
      increasing number of pig herds in the municipality and an increasing number of
      pigs per pen.

PMID- 10416370
TI  - Genome activation in alfamo- and ilarviruses.
AB  - Alfamo- and ilarviruses are characterized by the deficiency of their genomes
      (three messenger-sense RNAs) to start an infection cycle. The RNAs are in capsids
      built from a single species of protein of about 24 kD. A few dimers of this coat
      protein per RNA molecule are sufficient to activate the genome. Since the first
      description of genome activation [Bol JF, van Vloten-Doting L, Jaspars EMJ (1971)
      Virology 46: 73-85] three models have been proposed concerning its mechanism: the
      protection, the replicase and the messenger release hypotheses. The first two
      models make use of the fact that in these genera of RNA viruses the 3' termini of
      the RNAs bind the coat protein very strongly. The resulting structure would
      provide protection against 3'- to 5' exoribonucleases, or would permit correct
      initiation of minus-strand synthesis, respectively. However, naked inoculated
      RNAs of alfalfa mosaic virus appear to be quite stable in the cell, and in vitro
      the coat protein is inhibiting rather than stimulating initiation of minus-strand
      synthesis. The messenger release hypothesis states that the coat protein is
      needed for the release of viral messenger RNAs from membranous replication
      complexes throughout the whole viral replication cycle. This is supported by in
      vivo and in vitro observations, but as yet a detailed molecular mechanism is
      difficult to give.

PMID- 10416371
TI  - Identification of a novel HA conformational change inhibitor of human influenza
      virus.
AB  - Stachyflin is a novel compound having H1 and H2 subtype-specific anti-influenza A
      virus activity. Stachyflin has no inhibition on H3 subtype influenza A or
      influenza B viruses. The susceptibility of the reassortant viruses between H1 and
      H3 subtype influenza A viruses to Stachyflin indicated that its target was virus
      encoded hemagglutinin (HA). The results of the timing of Stachyflin addition
      against in vitro virus infection and virus-mediated hemolysis assay suggested
      that the drug inhibited the HA-mediated virus-cell fusion process. More directly,
      Stachyflin interfered with HA conformational change induced by low pH or heat
      treatment. The effect of Stachyflin could not be eliminated by washing of the
      Stachyflin-treated virus, which caused very specific virucidal effect. This is a
      remarkable property among small molecules which inhibit low-pH induced HA
      conformational change. From these findings, we concluded that the mechanism of
      Stachyflin action is to inhibit HA conformational change which is necessary for
      virus-cell membrane fusion. Stachyflin may be used as a tool for a study of
      molecular mechanism of low-pH induced HA conformational change, and offers
      potential as a pharmaceutical agent.

PMID- 10416372
TI  - Evidence for three groups of sequence variants of beet necrotic yellow vein virus
      RNA 5.
AB  - About half of Japanese isolates of beet necrotic yellow vein virus (BNYVV) were
      found to contain RNA 5 molecules, which were also detected in virus isolates from
      China and France. Sequence comparisons of RNA 5 (nucleotides 327 to 1171) in 25
      isolates showed that there are up to 8% sequence differences, and that RNA 5
      variants fall into three groups: group I contains most of the Japanese and
      Chinese isolates, group II two Japanese isolates, and group III four French
      isolates. The group I isolates fall into three small clusters. In the 26 kDa
      coding region of RNA 5, there was a maximum of 1.5% nucleotide sequence
      differences (6 amino acid changes) within the group and 8.4% nucleotide sequence
      differences (17 amino acid changes) between the groups. Comparisons of the coat
      protein gene of RNA 2 revealed that most of the Japanese and Chinese isolates
      belonged to the A type strain, but some isolates were of the B type. The French
      isolates (P type) were closely related to those of the A type. Mixed infections
      of the two types of virus and the two groups of RNA 5 were detected in a small
      area of Hokkaido. BNYVV might have been introduced into Japan and China by a
      similar route from at least two origins. These results, together with other
      evidence, suggest that the three groups of RNA 5 variants separated from an
      original population a long time ago and, thereafter, the group I population
      diverged further into three clusters, which may have been associated with the A
      type strain rather than the B type.

PMID- 10416373
TI  - Phylogenetic analysis of European encephalomyocarditis viruses: comparison of two
      genomic regions.
AB  - The phylogenetic relationships of encephalomyocarditis (EMC) viruses isolated
      from pigs and rodents in Europe were determined by comparison of nucleotide
      sequences from two different regions of the virus genome, the VP3/VP1 gene
      junction (part of the capsid-coding region) and part of the 3D polymerase-coding
      region. Thirty-five European EMC viruses could be divided into two genetic
      groups, one which contained viruses from Greece isolated between 1986 and 1997
      and from Belgium in 1991 and the other which contained viruses from Italy (1986
      1996), Cyprus (1994-1995), France (1995) and Belgium (1995-1996).

PMID- 10416374
TI  - Chaperonin 10 of Mycobacterium tuberculosis induces a protective immune response
      to foot-and-mouth disease virus.
AB  - Chaperonin 10 of M. tuberculosis conferred partial or total protection against
      generalized foot-and-mouth disease (FMD) in guinea-pigs challenged with O1
      Lausanne FMD virus. Chaperonin 10-immunized animals mounted an antibody response
      to the protein, one epitope of which was found in the C-terminal half. A similar
      recognition pattern was observed in FMD-convalescent guinea-pigs, swine and
      cattle. Anti-chaperonin 10 sera showed antiviral activity against FMDV-infected
      BHK-21 cells. There was strong evidence that early after infection these cells
      actively secrete their histones and that antisera to the chaperonin recognize
      them. The same antisera reacted with purified histones in immunoblotting. Most
      important, exogenously added histones abrogated the anti-viral activity of the
      antiserum and an anti-histone monoclonal antibody had strong antiviral activity
      against FMDV-infected BHK-21 cells. These results are consistent with previous
      reports on displacement of histones from the nuclear compartment and immune
      recognition of self-histones after viral infections. On the whole, they indicate
      that M. tuberculosis chaperonin 10 enables the immune system to react against
      early abnormalities of virus-infected cells; this is accomplished by antibody
      cross-reacting with histones released during virus infection.

PMID- 10416375
TI  - Characterization of an internal ribosome entry site within mRNA 5 of murine
      hepatitis virus.
AB  - The unique region of mRNA 5 of murine hepatitis virus contains two open reading
      frames, ORF 5a and ORF 5b. The downstream ORF 5b encodes the envelope (E)
      protein, an integral membrane protein of the virus. We have shown previously that
      the expression of ORF 5b is mediated by the internal entry of ribosomes. In the
      experiments reported here, we have used the in vitro translation of synthetic
      mRNAs to identify the region of mRNA 5 that mediates internal ribosome entry. Our
      results show that the 5' border of the MHV mRNA 5 IRES element is located between
      nucleotides 227 and 244 in ORF 5a, while the 3' border is located between
      nucleotides 140 and 172 in ORF 5b. The MHV mRNA 5 IRES element, therefore,
      contains not more than 280 nucleotides and encompasses the ORF 5b initiation
      codon. As evidenced by electrophoretic mobility shift assays, the IRES element of
      mRNA 5 interacts specifically with protein factors present in an L-cell lysate.

PMID- 10416376
TI  - Characterization of Spodoptera littoralis type B nucleopolyhedrovirus infection
      in selected insect cell lines.
AB  - We have examined Spodoptera littoralis type B nucleopolyhedrovirus (SpliNPV)
      infections in CLS79, Sf9, and Se1 cells derived from lepidopteran insects of the
      genus Spodoptera (Family: Noctuidae), Ld652Y cells from Lymantria dispar (Family:
      Lymantriidae), and Md210 cells from Malacosoma disstria (Family: Lasiocampidae).
      CLS79, Sf9, and Se1 cells were permissive for SpliNPV infection as these cell
      lines supported complete viral DNA replication, virus-specific transcription, and
      production of viable progeny. Neither Ld652Y nor Md210 cells supported production
      of viable SpliNPV progeny. Ld652Y cells supported limited viral DNA replication
      and displayed reduced and delayed transcription of viral-specific RNAs. Md210 did
      not support viral DNA replication and displayed dramatically reduced
      transcription of viral-specific RNAs. We used transient expression assays as an
      indirect measure of the translation of SpliNPV early gene products in Sf9,
      Ld652Y, and Md210 cells. While transactivation of viral promoter-mediated
      luciferase expression occurred in SpliNPV-infected Ld652Y cells, little to no
      transactivation activity was detected in SpliNPV-infected Md210 cells. Our data
      indicated that the block to productive SpliNPV infection in Ld652Y and Md210
      cells may be at the level of viral RNA transcription and further suggested that
      host factors play an important role in productive SpliNPV infection.

PMID- 10416377
TI  - Limitations to tobacco mosaic virus infection of turnip.
AB  - Turnip vein-clearing virus (TVCV) and tobacco mosaic virus (TMV) represent
      subgroups of tobamoviruses infecting cruciferous and solanaceous plants,
      respectively. To identify adaptations that may have been necessary in the
      evolution of the TVCV subgroup from a TMV-like ancestor, the infection of turnip
      plants by TMV and by chimeras between TMV and TVCV was explored. TMV accumulated
      at spatially limited sites on inoculated turnip leaves as determined by leaf
      skeleton hybridization. A plasmid DNA containing a complete TVCV cDNA, when
      transcribed in vitro, produced RNA that was infectious to tobacco and turnip
      plants. TVCV-TMV chimeric genomes with junctions within coding regions were not
      infectious to tobacco, though the movement protein (MP) chimera was infectious to
      tobacco with a TMV MP transgene. Reciprocal chimeras with junctions between genes
      were infectious to tobacco. TVCV with a TMV MP gene infected turnips. The other
      tested chimeras were not detected in non-inoculated leaves, but were found in the
      inoculated leaves. Thus, the TMV MP is not responsible for the limitation of TMV
      spread in turnips.

PMID- 10416378
TI  - Experimental vaccine activities of recombinant E1 and E2 glycoproteins and
      hypervariable region 1 peptides of hepatitis C virus in chimpanzees.
AB  - A chimpanzee was immunized with two recombinant envelope glycoproteins E1 and E2
      of hepatitis C virus (HCV), strain HCV-N2, and the hypervariable region 1 (HVR1)
      peptides of a different isolate, HCV-#6, then received an intravenous inoculation
      of 10 chimpanzee infectious doses of HCV-#6. With high humoral immune response
      against E1 and E2 but a low response against HVR1, the vaccinee became infected
      with the HCV. However, after increasing the titer of anti-HVR1 against HCV-#6,
      the vaccinee showed protection. Neutralization of HCV-#6 with the antiserum from
      this protected vaccinee was achieved by inoculation of this mixture into another
      chimpanzee. These results suggest that vaccination with a peptide-vaccine of
      homologous HVR1 is effective in the chimpanzee.

PMID- 10416379
TI  - Determination of 5'-leader sequences from radically disparate strains of porcine
      reproductive and respiratory syndrome virus reveals the presence of highly
      conserved sequence motifs.
AB  - We determined the untranslated 5'-leader sequence for three different isolates of
      porcine reproductive and respiratory syndrome virus (PRRSV): pathogenic European-
      and American-types, as well as an American-type vaccine strain. 5'-leader from
      European- and American-type PRRSV differed in length (220 and 190 nt,
      respectively), and exhibited only approximately 50% nucleotide homology.
      Nevertheless, highly conserved areas were identified in the leader of all 3 PRRSV
      isolates, which constitute candidate motifs for binding of protein(s) involved in
      viral replication. These comparative data provide a priori knowledge for
      mutational identification of virulence determinants in the 5' nontranslated part
      of the PRRSV genome.

PMID- 10416380
TI  - A different mode of entry by dengue-2 neutralisation escape mutant virus.
AB  - Entry processes were compared between dengue-2 (DEN-2) virus and a DEN-2
      neutralisation escape mutant virus in baby hamster kidney (BHK) cells. The mutant
      virus (mu6B2) was resistant to neutralisation by a monoclonal antibody, MAb 6B2.
      Infection of BHK cells by the wild-type DEN-2 virus resulted in direct
      penetration of the virions into the cytoplasm whereas the mutant virus entered
      cells by endocytosis. The continual presence of the monoclonal antibody might
      have asserted some pressure for the mutant to adopt a different mode of entry.

PMID- 10416381
TI  - Detection of bovine coronaviruses from adult cows with epizootic diarrhea and
      their antigenic and biological diversities.
AB  - Bovine coronavirus (BCV) was detected by reverse transcriptase-PCR, immune
      electron microscopy or virus isolation from adult cows at 6 out of 6 outbreaks of
      epizootic diarrhea in Japan. Six BCVs isolated in feces, intestinal content or
      tracheal exudate of the cows were analyzed for their antigenic properties by
      cross virus neutralization (VN) tests. The isolates were divided into two groups,
      one of which had closely related antigenicity with the reference Mebus and
      Kakegawa strains of BCV, and another which showed significant differences in VN
      antibody titers from the reference strains. Two isolates in the latter group,
      which were from the enteric and respiratory tracts of the same cows,
      respectively, were distinguished from each other by ELISA using monoclonal
      antibodies against the Kakegawa strain. The isolates showed various
      hemagglutination and receptor destroying enzyme titers against chicken or mouse
      erythrocytes.

PMID- 10416382
TI  - Variation in ORF3 of genogroup 2 Norwalk-like viruses.
AB  - The nucleotide sequences of the 3'-terminal open reading frame (ORF3) and 3'
      untranslated region (3'UTR) were determined for four Norwalk-like viruses (NLVs)
      belonging to genogroup 2. Three of the viruses, isolated in 1995 and 1996, were
      closely related to Mexico virus (92-93% nucleotide identity in ORF3). The fourth
      virus, isolated in 1984, was unique, showing only 49-58% nucleotide identity with
      other NLVs. The variation in sequence of the 3'-terminal ORF of NLVs was greater
      than that observed for other caliciviruses. This variation was partly due to
      repeated sequences and frameshifting. To investigate the properties of the ORF3
      encoded polypeptide, a signal sequence and N-linked glycosylation sites predicted
      for Camberwell virus were tested for function by in vitro translation in the
      presence of microsomes. Membrane insertion, cleavage of an N-terminal signal
      sequence, or glycosylation were not detected.

PMID- 10416383
TI  - The effect of cyclic AMP on expression of the major immediate-early genes and
      replication of human cytomegalovirus in human central nervous system cell lines.
AB  - The effect of dibutyryl cyclic AMP (dbcAMP) on interaction of human
      cytomegalovirus (HCMV) with human central nervous system cell lines was examined.
      Activation of the major immediate-early (IE) promoter (MIEP) of HCMV by dbcAMP
      was observed in human neuroblastoma IMR-32 cells, but not in glioma 118MGC and
      astrocytoma U373-MG cells. The 19 bp repeat element in the enhancer of the MIEP
      was most likely to be the cis-element that responded to dbcAMP in IMR-32 cells as
      we expected. In IMR-32 cells activation of the MIEP led to enhanced synthesis of
      the major IE proteins and infectious HCMV.

PMID- 10416384
TI  - Rotavirus strains bearing the VP4P[14] genotype recovered from South African
      children with diarrhoea.
AB  - Human rotavirus VP4P[14] strains were previously recovered in South Africa [18].
      The strains exhibited a long RNA pattern, VP6 subgroup II and VP7 serotype G1.
      Two of the VP8 genes were cloned and sequenced and demonstrated a high nucleotide
      homology with the prototype P[14] strains (PA169 and HAL1166).

PMID- 10416385
TI  - A monoclonal antibody that recognizes the predicted tick-borne encephalitis virus
      E protein fusion sequence blocks fusion.
AB  - The fusion motif of tick-borne encephalitis virus E protein has been predicted to
      be located within its conserved region (98-120). Results are presented to
      demonstrate that non-neutralizing monoclonal antibody which recognizes a
      synthetic peptide corresponding to residues 98-113 of the E protein sequence can
      block the fusion of the virus particles with artificial membranes.

PMID- 10416386
TI  - Treatment of lateral curvature by means of pressure correction. 1893.

PMID- 10416387
TI  - A concept of idiopathic scoliosis deformities as imperfect torsion(s).
AB  - Scoliosis is a complex three-dimensional deformity. With continued improvement in
      spinal implant design, the options for corrective load application have
      increased. Visualization of the scoliosis deformity as a torsion or torsions,
      similar to an elongated helical line, and integration of this visualization with
      current deformity classification have proven useful in developing instrumentation
      sequences addressing scoliosis as a three-dimensional deformity. These
      instrumentation sequences, which have been evolving since 1989, have been applied
      in more than 150 patients who show improved deformity correction without serious
      complications.

PMID- 10416388
TI  - S rod fixation to the sacrum in patients with neuromuscular spinal deformities.
AB  - A new form of pelvic fixation has been designed for use in patients with
      neuromuscular spinal deformities to overcome the problems imposed by the
      Galveston technique. One end of a Luque rod is prebent into an S shaped
      configuration and placed over the sacral ala supplying firm fixation across the
      lumbosacral junction without crossing the sacroiliac joint. It fixes firmly
      against the sacral ala by distracting against a hook or screw in the lumbar
      spine. A 12 year retrospective review of 67 patients with severe neuromuscular
      spinal deformities was accomplished. All surgeries were performed by one surgeon.
      All patients had good deformity correction with an average followup of 6 years
      and 2 months. Complications included: recurrence of pelvic obliquity (one
      patient), skin break-down over hardware (one patient), migration of hardware at
      sacrum (two patients), and rod breakage (five patients). The S rod is recommended
      for all patients with neuromuscular spinal deformities who require instrument
      fixation to the pelvis. Its ease of insertion and decreased operative time allow
      for a safe and dependable alternative fixation to the sacrum without crossing the
      sacroiliac joint.

PMID- 10416389
TI  - Short posterior fusion for patients with thoracolumbar idiopathic scoliosis.
AB  - Fifteen percent of all scolioses are idiopathic thoracolumbar and are
      characterized by significant imbalance in the frontal plane. A large curve of
      more than 40 degrees creates a trunk shift and under these circumstances an
      active correction is necessary. It is this imbalance that is the cause of
      increasing muscular fatigue. Arthritic changes may appear later which also are
      responsible for pain. The aim of a surgical procedure is to stop the progression
      of scoliosis, to obtain the reequilibrium of the spine in a frontal and a
      sagittal plane, and to correct the deformity. During the 1960s Dwyer6 developed
      his anterior instrumentation mainly for thoracolumbar and lumbar curves. In 1980
      Hall developed the concept of a short anterior fusion with overcorrection for
      patients with thoracolumbar curves. In the present study 10 patients are
      presented who were operated on for thoracolumbar adolescent idiopathic scoliosis
      using short posterior fusion instrumented by segmental convex transpedicle screw
      fixation and concave hook stabilization. With a mean followup of 49 months, the
      results show that frontal and sagittal balances are restored. In the present
      study all patients achieved frontal and sagittal balances at the last followup.
      The angular correction achieved by surgery always is more effective than what is
      visualized in radiographs of the patient in the bending position obtained before
      surgery. The correction of the major curve in the frontal plane improved from a
      mean angle of 47 degrees preoperatively to 14 degrees postoperatively and to 17
      degrees at the last followup. In all cases, mobile discs in the lower lumbar area
      are open. The posterior short fusion has the same power of correction as the
      anterior fusion with the advantage of an easier surgical approach and a better
      control of the lordosis. This paper will describe the operative indications, the
      choices of instrumented levels, and the medium term followup results.

PMID- 10416390
TI  - Anterior cruciate ligament reconstruction in patients who are prepubescent.
AB  - Between 1980 and 1996, 17 children who were prepubescent have had a combined
      intraarticular and extraarticular reconstruction of the anterior cruciate
      ligament using the iliotibial band that does not violate the physes. The average
      chronological age of the patients was 11 years (range, 2-14 years) and the
      average skeletal age of the patients was 10 years (range, 2-13 years). Eight of
      the 10 patients who had attained skeletal maturity were evaluated at an average
      of 66.5 months postoperatively (range, 25-168 months). All knees were stable
      subjectively by history and objectively by KT1000 testing. The average Lysholm
      score at assessment was 97.4. No child with a traumatic disruption had leg length
      discrepancy develop.

PMID- 10416391
TI  - Spinal deformity after selective dorsal rhizotomy in patients with cerebral
      palsy.
AB  - Selective dorsal rhizotomy is used widely as a means of treating spasticity
      associated with cerebral palsy. Little is known regarding the effect of the
      procedure on the development or progression of spinal deformity. The authors
      reviewed six patients with progressive deformity after rhizotomy. Prerhizotomy
      and postrhizotomy records of physical examinations and radiographs were reviewed
      retrospectively in an attempt to identify risk factors for development of and/or
      rapid progression of, spinal deformity. Detailed preoperative and postoperative
      evaluation of spinal alignment should be undertaken, particularly in those
      patients who may be at risk of rapidly progressive deformity.

PMID- 10416392
TI  - Extension to the sacrum of previous adolescent scoliosis fusions in adult life.
AB  - Numerous reports have indicated an increased risk for the development of
      precocious degenerative changes leading to pain in patients who had fusions done
      in adolescence for scoliosis, which extended into the lower lumbar spine. The
      anatomic situation may lead to instability, or spinal stenosis or both. This
      paper represents the evolving experience in reconstructive surgery for patients
      in whom a fusion was to be extended to the sacrum. Reconstructive surgery will
      require, if necessary, decompression posteriorly for spinal stenosis if present.
      Stabilization is acquired through an anterior and posterior approach with
      anterior and posterior instrumentation. The evolution of treatment modalities
      since 1976 shows a decreased pseudarthrosis rate from an initial 83% to 3% at
      present.

PMID- 10416393
TI  - Demineralized bone implants for nonunion fractures, bone cysts, and fibrous
      lesions.
AB  - Demineralized bone implants were used to treat eight patients with fracture
      nonunion, five patients with bone cysts, and eight patients with fibrous lesions.
      Five of the eight patients with nonunions had had previous unsuccessful attempts
      at reconstruction. After fixation and implantation with either human or bovine
      demineralized bone, all eight fractures healed. For those patients with nonunion
      fractures, mean followup time was 8 years, 5 months, and longest followup was 15
      years, 3 months. The cystic lesions in five patients included three typical
      aneurysmal bone cysts and two recurrent unicameral bone cysts. The aneurysmal
      bone cysts had excellent healing and bone remodeling. The two unicameral bone
      cysts were repacked more densely after 1 year and healed. For these patients with
      bone cysts, the mean followup time was 12 years, 5 months, and longest followup
      was 15 years, 1 month. The various fibrous lesions in seven of the eight patients
      were healed within 6 months, with only one requiring repacking. For these
      patients with fibrous bone lesions, the mean followup time was 9 years, 8 months,
      and longest followup was 14 years. A biopsy of the lesions in five patients was
      performed and in two cases showed osteoblasts and new bone around small particles
      of the implants. These results with long term followup show that allogeneic or
      xenogeneic demineralized bone implants offer a reasonable alternative for the
      treatment of typical nonunion fractures, bone cysts, and fibrous lesions of bone.

PMID- 10416394
TI  - Bilateral posterior pelvic resection osteotomies in patients with exstrophy of
      the bladder.
AB  - This paper describes a modification of bilateral posterior iliac osteotomies for
      bladder exstrophy, in which a strip of ilium is resected subperiosteally lateral
      to the sacroiliac joints, allowing easier anterior closure with less breakdown
      compared with traditional osteotomies. Thirty-one children underwent repair of
      bladder exstrophy between 1974 and 1994. Orthopaedic procedures included: closed
      reduction and cast application in the newborn period (four patients), classic
      bilateral posterior iliac osteotomies (12 patients), and bilateral posterior
      resection osteotomies (15 patients). Dehiscence occurred after one closed
      reduction, five classic osteotomies, and one resection osteotomy. Urinary
      continence was obtained in four patients who underwent closed reduction, nine
      patients who underwent classic posterior osteotomies, and nine patients who
      underwent posterior resection osteotomies.

PMID- 10416395
TI  - Simultaneous anterior and posterior hemivertebra excision.
AB  - The operative treatment of congenital scoliosis secondary to hemivertebra may
      involve in situ spinal epiphysiodesis, in situ fusion, or hemivertebra excision.
      The technique described in this paper, simultaneous anterior and posterior
      resection of the hemivertebra and correction of deformity with posterior
      instrumentation, has evolved from many different surgical methods used by the
      senior author in the past. This series of 11 patients describes the resection
      technique, degree of deformity correction, and complications encountered with
      this approach to a very difficult clinical problem. The preoperative mean age of
      the patients at the time of surgery was 18 months (range, 1 month-30 months), and
      preoperative curves averaged 47 degrees (range, 30 degrees-80 degrees). Immediate
      postoperative curves averaged 13 degrees (range, 1 degree-40 degrees), and at a
      mean of 28 months followup the curves averaged 14 degrees (range, 1 degree-47
      degrees). One patient experienced transient left leg weakness. There were no long
      term neurologic injuries and no other surgical complications.

PMID- 10416396
TI  - Lumbosacral fusion in children and adolescents using the modified sacral bar
      technique.
AB  - Between 1986 and 1995 10 patients who were 9 to 18 years of age underwent
      posterior spinal fusion and instrumentation to the pelvis for correction of
      spinal deformity using the modified sacral bar technique at the authors'
      institution. Etiologies of the spinal deformity included congenital scoliosis,
      cerebral palsy, myelomeningocele, neurofibromatosis, and postlaminectomy
      kyphosis. Indications for pelvic instrumentation were progressive scoliosis of
      the lower lumbar spine, pelvic obliquity greater than 15 degrees, and dysraphic
      posterior elements. Five of the patients had prior spinal surgery. Five patients
      had a prior or a planned pelvic osteotomy. Nine of the patients achieved
      lumbosacral fusion without an additional procedure. Major complications included
      loss of pelvic fixation in two patients, and a dural leak and a wound infection
      in another patient with myelomeningocele. Mean scoliotic curve correction was
      from 71.9 degrees to 34.5 degrees at final followup. Lumbar lordosis essentially
      was unchanged. Pelvic obliquity was corrected from a mean of 20.5 degrees
      preoperatively to a mean of 7.6 degrees at final followup. The modified sacral
      bar technique was selected for fusion to the sacrum because of planned or prior
      pelvic osteotomies, prior posterior spinal fusion and instrumentation, sacral
      dysraphism, or local anatomic anomalies. The modified sacral bar technique proved
      to be an effective technique in these patients.

PMID- 10416397
TI  - Periacetabular osteotomy without abductor dissection using direct anterior
      exposure.
AB  - The direct anterior exposure is a new abductor sparing surgical approach to
      perform periacetabular osteotomy, developed in an effort to eliminate the
      postoperative abductor morbidity associated with the classic Smith-Petersen
      approach. The direct anterior exposure also allows anterior arthrotomy of the hip
      joint, necessary to deal with intraarticular disease of the acetabular rim that
      is common in adult patients who require periacetabular osteotomy. The direct
      anterior exposure combines the medial portion of the classic Smith-Petersen
      iliofemoral exposure with or without the second window of the ilioinguinal
      exposure. An osteotomy of the anterior superior spine is done routinely to
      facilitate the approach by relaxing the attached sartorius and inguinal ligament
      origins. The authors' experience with the direct anterior exposure involves 195
      consecutive periacetabular osteotomies done since 1992, with 60 operations done
      using the full approach through two windows and 135 operations done using the
      limited approach through one window. There was no difference in functional or
      radiographic results, with both approaches allowing rapid functional recovery,
      excellent radiographic corrections, rapid bony healing, and minimal formation of
      heterotopic bone. No osteonecrosis or vascular injuries were seen. In nearly all
      patients, abductor function had returned to preoperative levels by 3 months after
      surgery, in distinct contrast to the authors' previous experience with the Smith
      Petersen approach. The authors consider the direct anterior exposure to be the
      surgical approach of choice for periacetabular osteotomy, with the more limited
      version proving satisfactory in all patients except the largest and most muscular
      patients. The full version is useful in large male patients.

PMID- 10416398
TI  - Spinal fusion in patients with congenital heart disease. Predictors of outcome.
AB  - The strong association between congenital heart disease and spinal deformity is
      well established, but data on the risks and outcome of spinal fusion surgery in
      patients with congenital heart disease are scarce. The purpose of this study was
      to identify predictors of perioperative risk and outcome in a large series of
      children and adolescents with congenital heart disease who underwent spinal
      fusion for scoliosis or kyphosis. In the authors' retrospective analysis of 74
      consecutive patients with congenital heart disease undergoing spinal fusion,
      there were two deaths (2.7%) and 18 significant complications (24.3%) in the
      perioperative period. Preoperative cyanosis (arterial oxygen saturation < 90% at
      rest) with uncorrected or incompletely corrected congenital heart disease was
      associated with both deaths. Complications occurred in nine of 18 (50%) patients
      with cyanosis and in 11 of 56 (20%) patients without cyanosis. As judged by
      multivariate analysis the best predictors of perioperative outcome were the
      overall physical status of the patient as represented by the American Society of
      Anesthesiologists' preoperative score and a higher rate of intraoperative blood
      loss. Seventeen of 43 patients (40%) with an American Society of
      Anesthesiologists score of 3 or higher experienced complications including two
      perioperative deaths. Successful spinal fusion and correction were achieved in
      97% of patients. Children and adolescents with congenital heart disease can
      undergo elective spinal fusion with risks that relate to overall cardiac status.
      Careful assessment of preoperative status by pediatric cardiologists and cardiac
      anesthesiologists familiar with surgical treatment of patients with congenital
      heart disease will assist the orthopaedic surgeon in providing the most realistic
      estimate of risk.

PMID- 10416400
TI  - Anterior only fusion for scoliosis in patients with myelomeningocele.
AB  - A series of patients with single major scoliosis curvatures attributable to spina
      bifida treated by anterior only spinal fusion was studied for 2 years to
      determine whether the infection rate could be decreased, adequate correction and
      pelvic balance could be provided, and posterior surgery could be avoided in these
      patients. Anterior surgery alone was performed for thoracolumbar scoliosis
      greater than 45 degrees if the compensatory thoracic curve was less than 40
      degrees and there was no significant junctional kyphosis. Fourteen patients were
      treated at a mean age of 11.9 years (range, 7-16 years), with a mean curve of 64
      degrees (range, 51 degrees-85 degrees), and motor levels distributed from T10-L4.
      Thirteen patients had prior neurosurgery for tether, syrinx, or Arnold-Chiari
      malformation. The spine was fused over a mean of seven vertebrae. A 3/16 inch
      Texas Scottish Rite Hospital rod was used most commonly (10 patients). Blood loss
      averaged 1100 cc. The mean curve correction was 57% at 40 months after surgery.
      Loss of correction occurred primarily by adding on outside the instrumented area.
      Mean pelvic obliquity was improved from 16 degrees to 9 degrees. There was one
      superficial infection. Results were good in five patients, fair in four, and poor
      in five. Failures were attributable to proximal decompensation in two patients
      who required revision surgery (two), neurologic deterioration in two, and screw
      pullout in one. Both patients with decompensation had syringomyelia. Both
      patients with neurologic deterioration had large curves (> 75 degrees). Both
      patients recovered after rod removal. Retrospectively, by eliminating patients
      with syrinx or with a curve greater than 75 degrees, all poor results would be
      eliminated. Anterior only fusion and instrumentation may have significant
      advantages, but only for selected patients with thoracolumbar curves less than 75
      degrees, compensatory curves less than 40 degrees, no increased kyphosis, and no
      syrinx. Quadriceps function should be monitored. On the basis of this preliminary
      experience, continued use of this approach using stricter selection seems
      warranted.

PMID- 10416399
TI  - Untreated acetabular dysplasia of the hip in the Navajo. A 34 year case series
      followup.
AB  - Patients born in the Many Farms District of the Navajo Indian Reservation from
      1955 to 1961 were studied. Five hundred forty-eight of the 628 infants born (87%)
      received clinical examinations and pelvic radiographs at some time during the
      first 4 years of their lives. Eighteen (3.3%) of the 548 infants examined had
      acetabular dysplasia. Because of traditional cultural beliefs, none of these
      children received medical treatment. Followup evaluations and radiographs were
      obtained in these 18 patients during early adolescence. In 10 of the original 18
      patients followup evaluations and radiographs were obtained at an average age of
      35 years. None of the dysplastic hips progressed to frank dislocation. The mean
      center edge angle improved from 7 degrees when the patients were 1 year of age,
      to 29 degrees when the patients were 12 years of age, to 30 degrees when the
      patients were 35 years of age. Despite overall improvement of hip measurements
      with maturity, eight hips in five of the 10 patients who were in their fourth
      decade of life and who were available for examination, had radiographic evidence
      of residual abnormalities. The hips in patients with subluxation during infancy
      were less likely to be normal as adults. The results of this 34-year followup
      study of untreated developmental hip dysplasia showed marked radiographic
      improvement in all patients during childhood; however, subtle abnormalities
      persisted in the radiographs of 40% of the hips.

PMID- 10416401
TI  - Occipitocervical fusions in children. Retrospective analysis and technical
      considerations.
AB  - This report presents a retrospective analysis of the authors' experience with
      occipitocervical fusions in children and adolescents during the last 2 decades. A
      description of an operative technique devised by the senior author (JEH), and a
      comparison of the results using this and other methods of fusion are given.
      Twenty-three patients underwent occipitocervical fusion. Fifteen of the patients
      were operated on using the authors' technique. To achieve stable fixation of the
      distal cervical vertebra a threaded Kirschner wire was passed transversely
      through the spinous process; occipital fixation was achieved by the traditional
      method of wiring corticocancellous bone graft to the skull through burr holes.
      The occipital wires then were wrapped around the Kirschner wire and the graft was
      cradled in the resulting nest. Halo immobilization was used in 10 patients for an
      average of 12.5 weeks (range, 6-24 weeks). Twenty-two patients achieved
      successful fusion at an average followup of 5.8 years (range, 1-14.33 years).
      Several complications, including transient quadriplegia in one patient,
      pseudarthrosis in two (one of which persists), hardware fixation failure in one,
      unintended distal extension of the fusion, pneumonia, wound infection, halo pin
      infection, skin breakdown under the halo vest, hydrocephalus, cerebrospinal fluid
      leak, and traumatic fusion fracture were encountered. Results using the technique
      described herein are comparable with or better than the results reported in the
      previous literature, and the results of the patients in this series in whom the
      technique was not used.

PMID- 10416402
TI  - Planning acetabular redirection osteotomies based on joint contact pressures.
AB  - Acetabular redirection osteotomy can be used to relieve pain, improve function,
      and extend the life of dysplastic hip joints. To understand better the factors
      that may determine the acetabular reorientation that minimizes pressures, joint
      contact pressures were calculated by computer assisted methods in 70 dysplastic
      and 12 normal hips (82 patients). Calculated pressures were consistent with
      pressures estimated and measured by other investigators. Contact areas were 26%
      smaller, and contact pressures were 23% higher, in the dysplastic hips compared
      with the normal hips. When the acetabula were reoriented to minimize contact
      pressures for an activity such as the midstance phase of gait, then contact
      pressures were elevated for dissimilar activities such as stair ascent. Contact
      pressures in the dysplastic hips were reduced when the acetabula were rotated in
      the frontal plane to increase lateral coverage or rotated in the sagittal plane
      to increase anterior coverage. In most of the dysplastic hips, contact pressures
      were reduced twice as much when the acetabulum was rotated in the frontal and the
      sagitta' planes. Computer assisted methods to quantify joint contact pressures
      can be used to assess potential candidates for reconstruction, plan acetabular
      redirection surgery, and possibly may improve the long term success of acetabular
      redirection osteotomy.

PMID- 10416403
TI  - Shoulder reconstruction in patients with chronic brachial plexus birth palsy. A
      case control study.
AB  - Patients with chronic brachial plexus birth palsy and persistent peripheral
      neurologic deficits frequently have problems related to their shoulder.
      Specifically, internal rotation and adduction contractures develop because of the
      loss of muscle balance about the glenohumeral joint. With time, progressive and
      predictable deformity of the glenohumeral joint occurs. The authors reviewed
      their results in treating patients with persistent functional deficits with
      either soft tissue procedures (tendon transfers and muscle releases) or
      rotational humeral osteotomies based on criteria incorporating patient age and
      degree of glenohumeral deformity. Patients in each group were evaluated
      prospectively and compared with each other. In all cases, patients in both groups
      experienced substantial improvements in global shoulder function. In the patients
      in the tendon transfer group, global Mallet scores improved from an average of
      9.5 to 15.6. Patients undergoing humeral osteotomies also had improvements in
      global Mallet score from an average of 9.5 to 15.1. This study confirms that both
      operations, when appropriately applied, will predictably improve shoulder
      function.

PMID- 10416404
TI  - Precoated femoral component in total hip arthroplasty. Results of 5- to 9-year
      followup.
AB  - One hundred nineteen consecutive primary hybrid total hip arthroplasties with a
      precoated femoral component were performed by one surgeon in 100 patients and
      followed up prospectively. Ninety-eight hips in 82 patients (mean age, 67 years)
      were evaluated clinically and radiographically at a mean of 6.5 years (range, 5-9
      years). The hips were evaluated clinically using the Harris hip score, and
      radiographs were evaluated for femoral cement grade, loosening, and osteolysis.
      Ninety-five hips remained in place at the most recent followup. Two femoral
      components were revised for definite loosening, and one well fixed femoral
      component was removed because of late hematogenous infection. Excluding the three
      hips that were revised, the clinical result was excellent or good in 79 hips
      (83%), fair in 12 hips (13%), and poor in four hips (4%). All other femoral
      components were well fixed. There were defects of the cement mantles (C1 and C2)
      in 90 hips. No femoral component had a stem and cement radiolucent line. Focal
      femoral osteolysis was seen in only two hips. One acetabular component was
      removed at 5 years because of late hematogenous infection. One acetabular
      component had asymptomatic migration. The remaining 96 acetabular components were
      well fixed. Focal acetabular osteolysis was present in four hips. The mean linear
      polyethylene wear rate was 0.06 (+/- 0.05) mm per year. In contrast to other
      reports of early failure and osteolysis, the use of a precoated femoral component
      in this study did not adversely affect the fixation of hybrid total hip
      arthroplasty, with definite failure of only 2% (two of 98) of the femoral
      components.

PMID- 10416405
TI  - Pseudosubluxation of the hip joint. A case report.
AB  - The case of a 32-year-old man who had a subluxation of his hip joint after open
      reduction and internal fixation for an acetabular fracture is presented. The
      subluxation resolved without surgical intervention. It is thought that the
      subluxation, herein termed pseudosubluxation, is similar to pseudosubluxation
      seen in the shoulder. The patient had sustained significant trauma to the
      abductor musculature and lateral hip region with a Morel-Lavelle lesion and a hip
      fracture coincident with his acetabular fracture. This entity has not been
      reported previously.

PMID- 10416406
TI  - Omnifit cementless total hip arthroplasty. A 10-year average followup.
AB  - Seventy-six hips in 67 patients were evaluated an average of 119 months (range,
      61-150 months) after total hip arthroplasty with porous coated Omnifit femoral
      and acetabular components. The patients were young (average age, 45 years), and
      most were male (67%). Two stems and one cup were revised for aseptic loosening,
      for aseptic revision rates of 2.6% on the femoral side and 1.3% on the acetabular
      side. Thigh pain was present in three cases, one of which was activity limiting.
      Twenty-five (35.7%) hips had evidence of osteolysis confined to proximal Gruen
      Zone 1 or 7 or to the acetabulum (22 proximal femoral, three both). There were no
      cases of intramedullary osteolysis in surviving stems. Thirteen (17.1%) hips have
      undergone reoperation for bone grafting of progressive proximal osteolysis
      without component revision, at an average 93 months after the total hip
      arthroplasty. At an average 40 months after reoperation, all stems remain well
      fixed, and there has been no recurrence of osteolysis of grafted femoral lesions.
      These results suggest that a circumferentially proximally porous coated femoral
      component in cementless total hip arthroplasty can provide stable fixation for as
      long as 12 years after implantation and caseal the canal from distal osteolysis.
      Serious concerns remain about the incidence of proximal femoral osteolysis.

PMID- 10416407
TI  - Total hip arthroplasty after failed intertrochanteric valgus osteotomy for
      advanced osteoarthrosis.
AB  - Thirty hips that had undergone conversion total hip arthroplasty because of
      failed intertrochanteric valgus osteotomy for advanced osteoarthrosis were
      analyzed clinically and radiographically for more than 2 years. The average
      followup after total hip arthroplasty was 7 years (range, 2-18 years). The
      average age of the patients at the time of valgus osteotomy was 42 years (range,
      30-63 years). The average age of the patients at the time of conversion total hip
      arthroplasty was 57 years (range, 43-76 years), and the average period between
      valgus osteotomy and conversion was 14 years (range, 3-24 years). Perioperative
      complications in conversion total hip arthroplasties were minimal, and
      intramedullary reaming was performed easily. Of the 30 conversion total hip
      arthroplasties, 12 cemented and 18 cementless components were used, respectively.
      Kaplan-Meier's survival analysis indicated that survivorship of cemented stems
      was significantly higher than that of conventional cementless stems. Cemented
      stems are preferable for conversion total hip arthroplasty after failed femoral
      valgus osteotomy.

PMID- 10416408
TI  - Laxity in posterior cruciate sparing and posterior stabilized total knee
      prostheses.
AB  - Two series of consecutive total knee replacements were compared retrospectively:
      118 HLS II posterior stabilized prostheses (Group 1) versus 138 HLS CP posterior
      cruciate ligament sparing prostheses (Group 2). Both implants were made by the
      same manufacturer. The prostheses had been inserted between 1989 and 1992. Mean
      followup was 4 years. The authors looked for evidence of laxity in the coronal
      and the sagittal planes, the correlation of laxity with other factors, and the
      effect of laxity on the objective and subjective outcome as measured with the
      Knee Society score. Group 2 had significantly more clinical and radiologic
      laxity. There was little difference between the two groups regarding the overall
      objective and subjective outcome; however, there was a significantly higher rate
      of excellent results in Group 1. Longer followup will be required to see whether
      the implants with laxity are at heightened risk for tibial component wear.

PMID- 10416409
TI  - Femoral anteversion and neck-shaft angle in children with cerebral palsy.
AB  - A database of femoral anteversion and neck-shaft angle was compiled of
      measurements made by the trigonometric fluoroscopic method of 147 patients (267
      hips) with cerebral palsy. The angles of femoral anteversion were similar at
      early ages between healthy children and children with cerebral palsy. However, as
      the age of the children increased, those with cerebral palsy showed little change
      in anteversion angle, whereas the healthy children had progressively decreasing
      angles of femoral anteversion as they approached adulthood. The neck-shaft angle
      was increased significantly in children with cerebral palsy compared with the
      angles of healthy children. Patients who were ambulatory were shown to have an
      increased angle of femoral anteversion and a decreased neck-shaft angle compared
      with nonambulatory patients. There was no significant difference in angles among
      the various distributions of involvement, including patients with diplegia,
      hemiplegia, and quadriplegia.

PMID- 10416410
TI  - Juxtaphyseal aneurysmal bone cysts.
AB  - Aneurysmal bone cysts are benign primary or secondary lesions that commonly arise
      in long bones and often before skeletal maturity. Little has been written about
      aneurysmal bone cysts that abut the physeal plate. The records of 15 patients
      with juxtaphyseal aneurysmal bone cysts were reviewed. Fourteen of the patients
      were referred with abnormal radiographs after evaluation for pain in the affected
      limb. One patient presented with abnormal radiographs after fracture about the
      aneurysmal bone cyst. None of the patients had evidence of growth plate
      disruption. The children's ages ranged from 2 to 14 years, with a mean of 9.8
      years. There were 10 boys and five girls. Lesion locations included: six in the
      proximal tibia, three in the distal fibula, two in the distal tibia, two in the
      proximal femur, one in the distal femur, and one in the distal radius. All of the
      lesions abutted the physeal plate and fell into one of the types in Campanacci's
      classification of juxtaphyseal aneurysmal bone cysts. Three lesions were
      classified as Type 1, eight were Type 2, and four were Type 3. This study
      included no cases of Type 4 or 5 lesions. Treatment of all lesions consisted of
      excision, curettage, and bone grafting with care taken to preserve the growth
      plate. Adjunctive cauterization was performed in two cases. There were no
      incidences of postoperative physeal plate arrest. Overgrowth of the fibula
      occurred in one patient. Three patients experienced recurrent lesions. One of the
      children underwent repeat curettage and bone grafting with no additional
      recurrence. In the other two children with recurrence, the lesion had grown away
      from the physeal plate while remaining static in size and asymptomatic. Based on
      this study, juxtaphyseal aneurysmal bone cysts may be treated satisfactorily with
      intralesional surgery and bone grafting with expectation of normal physeal
      growth.

PMID- 10416411
TI  - Elastofibroma dorsi. Study of two cases and magnetic resonance imaging findings.
AB  - Two cases of elastofibroma dorsi (one bilateral, one unilateral) in the
      periscapular and infrascapular region of two male patients are described.
      Magnetic resonance imaging revealed a tumorous mass of typical low signal
      intensity with interspersed areas of high signal intensity on T1 and T2 weighted
      spin echo sequences. In contrast to previous studies that reported mild
      enhancement within elastofibromas after administration of intravenous contrast
      agent, marked enhancement in one of two elastofibromas was found. This is
      considered to be atypical for benign lesions. After biopsy and histopathologic
      examination, an intended marginal resection was performed in both cases.
      Laboratory values, radiographs, and computed tomography may not be helpful in
      differentiating elastofibroma from malignant tumors. In addition to careful
      clinical investigation, magnetic resonance imaging is the method of choice
      leading to a presumptive diagnosis. Because marked enhancement on contrast agent
      images was observed, which is characteristic for malignant tumors, one should be
      aware that this feature does not exclude the presence of elastofibroma. Accurate
      diagnosis should be made preferably by biopsy and histopathologic evaluation
      before additional treatment is administered. Marginal resection is curative in
      patients with symptoms. Despite its low incidence, this pseudotumoral lesion
      should be known generally to differentiate it from malignant tumors and to avoid
      unnecessary wide or radical surgery.

PMID- 10416412
TI  - Synovial sarcoma of the foot and ankle.
AB  - Synovial sarcoma of the foot and ankle frequently is misdiagnosed, which leads to
      delays in treatment. The clinical records of 14 patients with synovial sarcoma of
      the foot and ankle were reviewed. Common findings at presentation were an
      enlarging mass with a variable incidence of pain, tenderness, and edema. The
      patients tended to be younger than patients with other soft tissue sarcomas (30
      years) and had a median duration of symptoms of 14 months. Of the 14 patients, 12
      underwent an attempted curative surgical procedure. Ten patients had partial foot
      amputations or below knee amputations, whereas two had an attempted limb salvage
      by wide resection. Of the 14 patients, one experienced regionally recurrent
      disease and eight had pulmonary metastasis developed. All patients who had
      metastasis develop died of their disease. Tumor size was not observed to be a
      prognostic variable in this group of patients. Patients with biphasic histologic
      features had a better outcome than did those with a monophasic subtype. Patients
      with a prolonged duration of symptoms before diagnosis had a better outcome,
      presumably because these tumors biologically were less aggressive. Wide resection
      can be considered in a select group of patients.

PMID- 10416413
TI  - Body mass and fracture risk. A study of 330 patients.
AB  - Low body mass is a major risk factor for low energy hip fractures among women.
      The purpose of this study was to ascertain whether normal body mass also protects
      against low energy wrist fractures. A retrospective analysis of body mass indices
      of 330 women who sustained hip or wrist fractures from falls was performed. Data
      were grouped by race and age. The mean body mass index for white patients with
      wrist fractures was 26.4, compared with a mean body mass index of 22.3 in white
      patients with hip fractures. For black patients, those with wrist fractures had a
      mean body mass index of 28.5, compared with a mean body mass index of 22.9 for
      those with hip fractures. Using data from The National Health and Nutrition
      Examination Surveys, the mean body mass index of patients with wrist fractures
      was seen to be equal to or greater than the national mean body mass index,
      whereas that of patients with hip fractures was substantially below average.
      Accordingly, normal body mass was protective against hip fractures but not
      against wrist fractures. Because adipose tissue more typically is distributed
      about the hip than the wrist, the protective mechanism of normal body mass
      against osteoporotic fractures may promote better preventative interventions
      against this disease.

PMID- 10416414
TI  - Critical size defect in the goat's os ilium. A model to evaluate bone grafts and
      substitutes.
AB  - Bone defects and their treatment are a well known problem in orthopaedic surgery.
      A critical size defect is a suitable model to study bone replacement materials.
      This study describes a critical size defect in the goal and the evaluation of
      three bone fillers (particulate autograft, particulate allograft, and a
      polyethylene oxide/polybutylene terephthalate copolymer) in this defect. The goat
      allows for implantation of large implants and has a metabolic rate more
      comparable with that of humans than small animals. The critical size defect,
      located in the goat's iliac wing, is easily reproducible and allows qualitative
      and quantitative evaluation of bone grafts and bone graft substitutes. After 3
      months of healing, the unfilled defects showed 13.5% bone in the defect, the
      autografted defects 36.3%, and the allografted 18.5%. The copolymer gave only
      1.5% bone in the defect; this is in contrast to previous reports. The described
      model allows for the evaluation of bone graft substitutes before introduction
      into clinical practice.

PMID- 10416415
TI  - The osseous response to corundum blasted implant surfaces in a canine hip model.
AB  - The purpose of this study was to examine the radiographic and histologic response
      to corundum blasted implant surfaces of varying roughness in a canine total hip
      arthroplasty model. Three types of tapered femoral implants were made from
      titanium alloy and were identical in every respect except surface finish. The
      entire surface of the femoral implant had a 2.9-, 4.2-, or 6.7-micron average
      surface roughness (Ra) from blasting with 60-, 24-, or 16-grit corundum
      particles, respectively. Twenty-two stems in 11 dogs were evaluated at 6 months.
      Twenty-one of the stems showed osseointegration, whereas in one stem a fibrous
      interface developed. Abundant new periimplant bone formation occurred,
      particularly within the intramedullary canal where trabeculae spanned implant to
      endosteal cortex gaps as large as 5 mm. Bone apposition with the 60-, 24-, and 16
      grit stems averaged 31.7%, 32%, and 27.9%, respectively; the differences were not
      statistically significant. However, the pattern of new bone formation was
      different in that the average length of each region of bone apposition for the 60
      and 24-grit surfaces was 50% greater than that for the coarser 16-grit surface.
      The observations of this study indicate that because of their highly
      osteoconductive nature, corundum blasted surfaces represent an important and
      valuable technology for the design of noncemented implants.

PMID- 10416416
TI  - Use of a polyglycolide lactide cement plug restrictor in total hip arthroplasty.
AB  - The use of a polyglycolide lactide cement plug restrictor in cemented femoral
      fixation during total hip arthroplasty was evaluated. Femoral cement
      pressurization was evaluated in vitro in a cadaveric model and the host response
      to polymer degradation was evaluated in vivo in a canine total hip arthroplasty
      model. Sixteen embalmed anatomic specimen femurs were prepared for cement femoral
      fixation. The intramedullary canal was plugged with either an ultrahigh molecular
      weight polyethylene cement plug restrictor or a polyglycolide lactide cement plug
      restrictor. Peak pressures in the proximal, mid, and distal portions of the
      cement mantle were recorded during cement insertion, cement pressurization, and
      implant insertion. There was no difference between the two plug groups in peak
      pressures throughout the cement mantle during cement insertion, pressurization,
      or implant insertion. Total hip arthroplasty using a cementless acetabular
      component and a cemented femoral stem was performed in 24 dogs. The femoral
      intramedullary canal was plugged with a polyethylene or a biodegradable cement
      plug restrictor. The dogs were sacrificed at 7 weeks, 10 months, or 15 months.
      Radiographically, no osteolytic lesions were seen around either plug type.
      Histomorphometrically, the polyglycolide lactide plugs appeared intact at 7 weeks
      and partially degraded by 10 and 15 months. In both plug groups, a mild
      fibrohistiocytic reaction with infiltration of fibrocytes, histocytes, and
      endothelial cells was seen. No osteolysis was observed. The results of the
      current study show that femoral cement pressurization can be attained in vitro
      using a biodegradable cement plug restrictor and that for as long as 15 months in
      the in vivo canine model there were no adverse reactions associated with use of
      these plugs compared with conventional ultrahigh molecular weight polyethylene
      plugs.

PMID- 10416417
TI  - A mechanical distal aiming device for distal locking in femoral nails.
AB  - Although the free hand technique remains the most popular method for distal
      interlocking screw insertion, proximally mounted radiation independent devices
      that compensate for implant deformation recently have been developed for the
      femur. However, the benefits of such systems have not been determined. This study
      prospectively compared the duration of the nailing procedure, the length of
      radiation time, and the accuracy of interlocking screw placement when using a
      radiation independent distal aiming system with those using the free hand
      technique. In 20 paired intact anatomic specimen femurs, one surgeon experienced
      only in the free hand technique performed statically locked intramedullary
      nailing using the two methods. For the aiming system and free hand technique,
      respectively, the total operation time was 19.1 +/- 8.4 minutes versus 20.9 +/-
      11.3 minutes, the distal locking time was 6.6 +/- 2.4 minutes versus 4.8 +/- 1.5
      minutes, the total fluoroscopy time was 23 +/- 17 seconds versus 69 +/- 34
      seconds, and the distal locking fluoroscopy time was 0 versus 37 +/- 15.5
      seconds. There were no failures in either group. Drill nail contact and distal
      screw damage were greater with the free hand technique. This study suggests that
      the main advantages of the aiming arm compared with the free hand technique
      include the elimination of radiation during distal interlocking and more precise
      screw placement with decreased insertion related hardware damage.

PMID- 10416419
TI  - Shoulder fusion combined with an elbow stabilizing orthosis.

PMID- 10416418
TI  - Pathologic femoral fracture in a 76-year-old woman.

PMID- 10416420
TI  - [Sympathetic nerve regulation: its role in cardiology. 65th Annual Session of the
      German Society for Cardiology--Heart-Circulation Research. Mannheim, 9 April
      1999].

PMID- 10416421
TI  - Caesarean section: a matter of choice?

PMID- 10416422
TI  - Inherited metabolic diseases: beyond newborn screening.

PMID- 10416423
TI  - The multiple endocrine neoplasia syndromes: genes and management.

PMID- 10416424
TI  - Angered patients and the medical profession.

PMID- 10416425
TI  - Cancer in the elderly: gathering the evidence.

PMID- 10416426
TI  - Women's role and satisfaction in the decision to have a caesarean section.
AB  - OBJECTIVE: To examine women's role in the decision to perform caesarean section
      (CS). DESIGN: Cross-sectional survey. Written questionnaires were completed seven
      weeks after giving birth by CS. SETTING: An obstetric tertiary referral hospital
      (Women's and Children's Hospital, Adelaide, South Australia), July to December
      1996. PARTICIPANTS: A consecutive sample of women who underwent CS over a six
      month period. To be eligible, women had to be at least 18 years old, able to
      complete a questionnaire in English and well enough to consent to study
      participation. MAIN OUTCOME MEASURES: Women's involvement in decision making,
      stated preference for CS, and satisfaction with obstetric care. RESULTS: 278
      women (76.4%) returned questionnaires: 171 women (61.5%; 95% confidence interval
      [CI], 55.8%-67.2%) reported being involved in the decision to have a CS. Factors
      influencing their decision were physical duress and partner's reaction during
      labour (emergency CS), considerations about recovery, planning for the event and
      pain (elective CS), and information from the doctor (both groups). Half the women
      "strongly agreed" that they were satisfied with the decision to have a CS, but
      40.9% only "agreed" and 4.7% were "not sure". About 20% reported they needed more
      information on other options, and only 28.8% "strongly agreed" that they had been
      given good information to prepare for the possibility of CS. 27.9% of women (95%
      CI, 22.5%-33.2%) "agreed" or "strongly agreed" that they had "insisted on a CS"
      and 21.3% (95% CI, 16.4%-26.2%) that they had told the staff they were "keen to
      have a CS". Given the option of a vaginal delivery, 37.8% of women (95% CI, 22.5%
      55.2%) with a breech presentation, and 34% of women (95% CI, 21.2%-48.8%) who had
      had a previous CS, chose a CS. CONCLUSIONS: It is of concern that over a third of
      women felt they had not been involved in the decision to have a CS; others were
      very positive about CS, but an appreciable proportion may not have received
      sufficient information. A broad-based strategy of providing more information to
      women and their partners could be one way of ensuring appropriate CS rates and
      should be tested in a randomised controlled trial.

PMID- 10416427
TI  - Hepatitis A outbreaks among illicit drug users and their contacts in Queensland,
      1997.
AB  - OBJECTIVE: To describe five outbreaks of hepatitis A virus (HAV) infection
      associated with illicit drug use during a statewide outbreak of HAV infection in
      Queensland. DESIGN: Risk factor prevalence survey. PATIENTS AND SETTING: All 875
      cases of HAV infection notified to Public Health Units in Queensland in the 12
      months to 30 November 1997. MAIN OUTCOME MEASURE: Type and prevalence of illicit
      drug use. RESULTS: Risk factor assessment was completed for 804 cases (91.9%). We
      identified five outbreaks of HAV infection linked to illicit drug use. These
      outbreaks accounted for 24.6% (215/875) of all notified cases and 39% (190/482)
      of notified cases in the 15-34 years age group. The main type of illicit drug use
      in four of the five outbreaks was injecting drug use (74%; 118/160), while in the
      other outbreak it was sharing of smoking implements for marijuana (38%; 21/55).
      CONCLUSION: Illicit drug use may be an under-recognised risk factor for HAV
      infection, particularly in young people. Faecal-oral transmission through poor
      personal hygiene, including sharing of implements for smoking marijuana, is the
      most probable route of transmission in these drug-linked outbreaks. The role of
      contaminated drug and needle-sharing remains to be clarified.

PMID- 10416428
TI  - Scintimammography: an adjunctive test for the detection of breast cancer.
AB  - OBJECTIVE: To describe the diagnostic utility of scintimammography in patients
      with a breast mass, including patients who have undergone previous breast surgery
      or radiotherapy. DESIGN: Descriptive outcome study. SETTING: A university
      teaching hospital and a private hospital breast clinic in New South Wales.
      SUBJECTS: 115 consecutively referred women investigated by x-ray mammography and
      scintimammography before surgical excision biopsy of a breast mass. MAIN OUTCOME
      MEASURES: Sensitivity and specificity of x-ray mammography and scintimammography
      in the detection of breast cancer overall, and in women who had or had not
      undergone previous breast surgery. RESULTS: 44 (38%) patients had undergone
      previous breast surgery or external beam radiotherapy, including nine with
      bilateral silicone breast implants. The overall (n = 115) sensitivity for the
      detection of breast cancer with scintimammography was 84%, compared with 66% for
      x-ray mammography (P = 0.004), and the respective specificities were 84% and 67%
      (P = 0.194). For patients who had a history of previous breast surgery, the
      respective sensitivities of the two tests were 83% and 50% (P = 0.006), compared
      with 85% and 73% (P = 0.087) for patients who had had no previous surgery.
      CONCLUSIONS: Scintimammography offers additional diagnostic advantage in the
      detection of breast cancer in patients who have had previous breast surgery or
      local radiotherapy.

PMID- 10416429
TI  - Maternal phenylketonuria: a continuing problem.
AB  - OBJECTIVES: To estimate the number of women of childbearing age in New South
      Wales whose children are at risk of the maternal phenylketonuria (PKU) syndrome
      (intellectual disability, microcephaly, congenital malformations). SETTING: New
      South Wales, 1996. DESIGN: Comparison of number of women with PKU aged 15-44
      years on the NSW PKU database (observed number) with expected number derived from
      population data. MAIN OUTCOME MEASURES: Observed and expected numbers of women
      with PKU (defined as blood phenylalanine levels > or = 400 mumol/L, and
      phenylalanine-restricted diet recommended) by age; number with no clinical
      contact with the PKU service in previous year; outcomes of pregnancies in women
      with PKU (January 1994 to July 1996). RESULTS: 110 women aged 15-44 years with
      PKU were listed on the database. The expected number was 145 (95% confidence
      interval, 122-171). The difference was greatest in the 30-44 years age group
      (born before comprehensive newborn screening), with only 55% of the expected
      number listed. Sixteen women who had been diagnosed with PKU at birth were not
      having regular follow-up, while 18 women had been diagnosed only after
      investigation of abnormalities in their children. Of 28 pregnancies managed by
      the NSW PKU service, 19 were considered unaffected by the maternal PKU syndrome
      and five affected (another three did not reach term; one outcome was unknown). Of
      46 unmanaged pregnancies, all were affected. CONCLUSION: There is an urgent need
      for better follow-up of women with PKU and for education of health professionals
      about the MPKU syndrome, its recognition, the risks of untreated pregnancy and
      the benefits of dietary treatment.

PMID- 10416430
TI  - Organophosphate poisoning versus brainstem stroke.
AB  - Two patients presented unconscious after deliberate organophosphate ingestion.
      Both were initially misdiagnosed as having brainstem stroke, and plans were made
      for withdrawing treatment within 24 hours. Once correctly diagnosed and
      appropriately treated, both recovered, illustrating the importance of considering
      a wide differential diagnosis before withdrawing support and of not relying on
      routine "drug screens" to detect organophosphates.

PMID- 10416431
TI  - Patients' complaints about medical practice.
AB  - OBJECTIVES: To survey complainants' experience and the outcome of lodging a
      complaint about medical treatment. DESIGN AND SETTING: Random sample survey. A 32
      item questionnaire was sent to 500 complainants by the New South Wales Health
      Care Complaints Commission (HCCC), and responses were returned reply-paid to the
      university. PARTICIPANTS: 290 people with complaints finalised by the HCCC
      between February 1996 and August 1997. OUTCOME MEASURES: Profile of complainants
      and doctor involved; type and place of incident; complainants' emotions at the
      time of the incident and at the conclusion of the complaints process; outcome of
      complaint, and satisfaction with outcome and intention to take further action.
      RESULTS: After excluding non-medical complaints, 290 of 314 questionnaires
      returned were analysed, giving a response rate of 63% (314/500): 64% of
      complaints were about clinical care, and the remainder related to rudeness or
      poor communication (22%), and unethical or improper behaviour (14%); 70% of
      complainants were women, and 44% of complaints were on behalf of another person;
      Complainants had a high socioeconomic status, and 60% were currently in paid
      employment; More than half the incidents occurred in doctors' consulting rooms;
      87% of the doctors involved were men, and over half were general practitioners.
      37% of complaints were dismissed; 21% of complainants did not know the outcome of
      their complaint, and 40% believed that the doctor had been disciplined. Most
      complainants were dissatisfied with the outcome; a quarter stated that they would
      sue, but 70% would do nothing further. All but two complainants would never
      consult the doctor involved again. CONCLUSIONS: Most of the respondents were not
      satisfied with either the process or the outcome. Typically they wanted stronger
      measures taken. Only a few wanted compensation; more wanted acknowledgement of
      harm done; and most wanted the doctor punished.

PMID- 10416432
TI  - Faking it: should cancer control agencies promote "fake" tanning lotions?

PMID- 10416433
TI  - Multiple endocrine neoplasia type 1: current concepts in diagnosis and
      management.

PMID- 10416434
TI  - Does the blood pressure need lowering?

PMID- 10416435
TI  - Confidentiality and the courts.

PMID- 10416436
TI  - Confidentiality and the courts.

PMID- 10416437
TI  - Confidentiality and the courts.

PMID- 10416438
TI  - Childhood eye injuries, 1983 to 1998.

PMID- 10416439
TI  - Antenatal screening and prenatal diagnosis of thalassaemia.

PMID- 10416440
TI  - Fragile X syndrome: do professionals know about it?

PMID- 10416441
TI  - Breast is still best.

PMID- 10416442
TI  - Forcing patterns of practice could be misguided.

PMID- 10416443
TI  - Microcytic anaemia due to iron malabsorption.

PMID- 10416444
TI  - The meaning of 'holistic'.

PMID- 10416445
TI  - Health promotion--are our health professionals well prepared?

PMID- 10416446
TI  - The placebo response--a powerful factor.

PMID- 10416447
TI  - Complaints against scientology doctors.

PMID- 10416448
TI  - From the horse's mouth: the regulations to the Medical Schemes Act--Part I.

PMID- 10416450
TI  - Developing a vision for SAMA. A discussion document by the Transformation and
      Constitutional Revisionary Task Team.

PMID- 10416449
TI  - Some lessons from my malpractice suit.

PMID- 10416451
TI  - The GP, the rep and the handouts.

PMID- 10416452
TI  - Thyroid scintigraphy in hyperthyroidism.

PMID- 10416453
TI  - Transient osteoporosis of the hip.

PMID- 10416454
TI  - Amniocentesis--too dangerous and too late?

PMID- 10416455
TI  - Spinal cord injuries in rugby players--more of the same.

PMID- 10416456
TI  - Rapid serological field tests for diagnosis of tuberculosis in South Africa-
      reasons for caution.

PMID- 10416458
TI  - An apparent reduction in the incidence and severity of spinal cord injuries in
      schoolboy rugby players in the western Cape since 1990.
AB  - OBJECTIVE: To determine the impact of the 1990 rugby law changes in South African
      schoolboy rugby on the number of schoolboys suffering paralysing spinal cord
      injuries in the subsequent eight rugby seasons (1990-1997) in the former Cape
      Province (now the Western Cape, but including Port Elizabeth and East London).
      METHODS: The study was a retrospective analysis of all patients with rugby
      related spinal cord injuries admitted to the Conradie and Libertas Spinal Units,
      Cape Town, between 1990 and 1997. Data were initially collected annually from
      patient files. From 1993 patients were interviewed in hospital and a standardised
      questionnaire was completed. Data were collated and analysed. RESULTS: There were
      67 spinal cord injuries in adult and schoolboy rugby players in the eight seasons
      studied. Fifty-four (80%) injuries were in adults and 13 (20%) in schoolboys,
      representing a 23% increase and a 46% reduction in the number of injured adults
      and schoolboys, respectively. Fifty-two per cent of those injuries for which the
      mechanism was recorded occurred in the tackle phase of the game; of these
      approximately equal numbers were due to vertex impact of the tackler's head with
      another object, or to illegal (high) tackles. Twenty-five per cent of injuries
      occurred in the ruck and maul and the remainder (23%) in the collapsed scrum. The
      only striking difference in the proportion of injuries occurring in the different
      phases of play was the absence of high-tackle injuries among schoolboys. The
      majority of injuries occurred at vertebral levels C4/5 (32%) and C5/6 (42%). Five
      players (8%) died, tetraplegia occurred in 48% and 35% recovered either fully or
      with minor residual disability. Playing position was recorded for half the
      injured players. Front-row forwards (props 33%, hookers 9%), locks (12%) wings
      and centres (21%) and loose forwards (15%), accounted for 90% of all injuries.
      CONCLUSIONS: Introduction of rugby law changes in South African schoolboy rugby
      in 1990 may have led to a 46% reduction in the number of spinal cord injuries in
      this group. In contrast, the number of these injuries in adult rugby players
      increased during the same time period due either to an increase in the number of
      adult players or to a real increase in the incidence of these injuries. More
      injured schoolboy than adult rugby players made total or near-complete recoveries
      from initially paralysing injuries (61% v. 28%). The reduced number of schoolboy
      injuries could not have resulted directly from the specific law changes
      introduced in 1990, which targeted scrum laws. Rather, the absence of illegal
      (high) tackle injuries among schoolboys appears to be the principal factor
      explaining fewer injuries in schoolboys, who suffered a higher proportion of
      injuries in the ruck and maul than did adult players. Accordingly we conclude
      that a further reduction in spinal cord injuries in adult and schoolboy rugby
      players in the Western Cape requires: (i) the elimination of injuries occurring
      in the ruck and maul, and to the tackler; (ii) the strict application of the high
      tackle rule in adult rugby; and (iii) a continuing, high level of vigilance.
      Concern must be expressed about the continuing number of paralysing spinal cord
      injuries in adult rugby players.

PMID- 10416457
TI  - General practitioners and national health insurance--results of a national
      survey.
AB  - OBJECTIVE: To determine the attitudes of South African general practitioners
      (GPs) to national health insurance (NHI), social health insurance (SHI) and other
      related health system reforms. DESIGN: A national survey using postal
      questionnaires and telephonic follow-up of non-responders. SETTING: GPs
      throughout South Africa. PARTICIPANTS: Four hundred and forty-three GPs were
      randomly selected from a national sampling frame of 6,781 GPs. MAIN OUTCOME
      MEASURES: Acceptance of NHI and GP preferences with regard to financing,
      provision, benefits, coverage and the role of GPs. MAIN RESULTS: A response rate
      of 82.1% was achieved. Sixty-two per cent of GPs approved of the introduction of
      some form of social or NHI in South Africa, while 24.1% disapproved. Approval
      rose to 81.6% if GPs were to maintain their independent status, e.g. own premises
      and working hours, to 75% if additional private top-up insurance was allowed, and
      to 79.9% if payment was by fee-for-service. Seventy per cent of GPs in the study
      stated that they had the capacity to treat more patients. The most important
      reason given for approving of NHI was to make health care more equitable and
      accessible to the majority of South Africans. A high proportion of GPs approved
      of increasing the level of interaction between GPs and district health
      authorities. CONCLUSIONS: Most GPs approved of some form of social or NHI system,
      provided that the system did not significantly threaten their professional
      autonomy or economic and financial situation.

PMID- 10416459
TI  - Physiological benefits of a prolonged moderate-intensity endurance training
      programme in patients with coronary artery disease.
AB  - OBJECTIVES: To assess the physiological changes that take place in patients with
      coronary artery disease after 6 and 18 months of moderate-intensity endurance
      training. DESIGN: Prospective non-randomised controlled study. SETTING:
      Johannesburg Cardiac Rehabilitation Centre, a community-based phase III cardiac
      rehabilitation programme. SUBJECTS: The 93 patients who completed 18 months of
      training form the experimental or 'complier' group, while the 18 patients who
      discontinued the programme form the comparison or 'dropout' group. OUTCOME
      MEASURES: Haemodynamic, electrocardiographic and metabolic measurements at rest
      and at submaximal and peak exercise levels on admission and after 6 and 18 months
      of endurance training. RESULTS: Among the compliers several significant changes
      took place. Resting heart rate and blood pressure decreased at 6 months (P <
      0.005). Submaximal heart rate, blood pressure, rate-pressure product and
      ventilation decreased at 6 months (P < 0.0001, P < 0.01, P < 0.001, P < 0.01
      respectively), and the rate-pressure product decreased further at 18 months (P <
      0.05). Ventilatory threshold increased at 6 months (P < 0.0001). Peak oxygen
      uptake, heart rate and ventilation increased at 6 months (P < 0.0001, P < 0.005
      and P < 0.0001, respectively), with no further changes at 18 months. Treadmill
      time increased at 6 months and again at 18 months (P < 0.0001). The only
      significant change in the dropout group was an increase in ST-segment depression
      on the exercise ECG from 0.2 to 0.6 mm (P < 0.05). CONCLUSION: The study confirms
      that cardiac rehabilitation is beneficial. Most changes occurred in the first 6
      months, the longer period of 18 months serving mostly as reinforcement of these
      and other lifestyle changes.

PMID- 10416460
TI  - Impact of the problem-based learning curriculum on the learning styles and
      strategies of medical students at the University of Transkei.
AB  - OBJECTIVES: This is a longitudinal cohort study of the learning styles and
      strategies of medical students in a problem-based, community-based curriculum as
      they progressed through the medical course. The purpose was to monitor and
      evaluate whether the programme was fulfilling the objective of producing self
      directed and lifelong learners. METHODS: The short version of the Lancaster
      Inventory of Learning Styles was administered to the students on admission and
      thereafter on a yearly basis through the first 4 years of the medical course.
      Data were fed onto a database and subsequently analysed using a commercially
      available statistical package. RESULTS: 140 students (falling to 106 by year 4)
      were interviewed and followed up through the study period. Of the students 75%
      were black and 25% were of Asian descent. On admission the students had high
      scores for individual achievement motivation, and for meaningful learning. They
      had moderate scores for reproducing learning, comprehension learning, operation
      learning and versatile learning. They had low scores for learning pathologies,
      especially globetrotting and improvidence. There was no sexual difference in
      learning styles. Asian students had significantly higher scores for meaningful
      learning and for versatile learning. The effect of the problem-based curriculum
      was to reduce the score for individual achievement, decrease the score for fear
      of examinations, increase the score for operation learning, increase the score
      for versatile learning, increase the score for syllabus boundness, and decrease
      the scores for learning pathologies, especially for improvidence and
      globetrotting. By year 4, there was similarity in the learning styles of black
      and Asian students. CONCLUSION: The problem-based curriculum had a positive
      effect on the learning styles of the students, especially the black students.

PMID- 10416461
TI  - Prevalence of infection with human herpesvirus 8/Kaposi's sarcoma herpesvirus in
      rural South Africa.
AB  - OBJECTIVE: To determine prevalence of infection with human herpesvirus 8 (HHV
      8)/Kaposi's sarcoma herpesvirus (KSHV) and to gain some insight into possible
      transmission dynamics of this novel virus in South Africa. METHODS: Stored,
      anonymous serum from 50 patients with a sexually transmitted disease (STD), 50
      adult medical ward patients (25 male, 25 female), and 36 paediatric ward patients
      in Hlabisa Hospital, KwaZulu-Natal, was screened by enzyme-linked immunosorbent
      assay (ELISA) for antibodies to the small capsid-related protein encoded by HHV
      8/KSHV orf65. Antibodies to the latency-associated nuclear antigen (LANA) were
      measured by immunofluorescence, and sera that were reactive in the ELISA but
      negative by immunofluorescence were re-tested by Western blot against the
      recombinant orf65 protein to exclude nonspecific reactivity. RESULTS: Overall, 47
      patients tested positive (34.6%), 76 tested negative (55.9%) and 13 (9.5%) had
      indeterminate results. Among those with a definite result, prevalence was similar
      among males (47.2%) and females (52.8%) and increased in later adulthood (< 18
      months 37.5%, 19-120 months 38.5%, 15-34 years 32.1%, 35-69 years 62.8%).
      Prevalence was highest among medical patients (58.1%); among those with an STD it
      was 31.1% (P = 0.01), and among children it was 22.8% (P = 0.001). When age
      adjusted, prevalence among medical patients (23.7%) was similar to that among
      patients with an STD. CONCLUSION: Prevalence of HHV-8/KSHV is high in this
      setting and transmission appears to be occurring in childhood as well as among
      adults. Larger population-based studies are required to detail the transmission
      dynamics of HHSV-8/KSHV.

PMID- 10416462
TI  - Tobacco consumption among Swaziland high-school students and their parents and
      teachers.

PMID- 10416463
TI  - Screening for small-for-gestational-age newborns using serial symphysis-fundal
      measurements.

PMID- 10416464
TI  - Panel set to create brucellosis vaccine for Yellowstone wildlife.

PMID- 10416465
TI  - The current and future market for veterinarians and veterinary medical services
      in the United States.

PMID- 10416466
TI  - Disagrees with comments on specialty designations.

PMID- 10416467
TI  - On the definition of feline interstitial cystitis.

PMID- 10416468
TI  - Is variable compensation always win-win?

PMID- 10416469
TI  - What is your diagnosis? Osteochondritis dissecans (OCD).

PMID- 10416471
TI  - Veterinary practice expenses and financial ratios.

PMID- 10416470
TI  - Theriogenology question of the month. Persistent estrus caused by functional
      granulosa cell tumor of the left ovary.

PMID- 10416472
TI  - Toxicosis in cats erroneously treated with 45 to 65% permethrin products.

PMID- 10416473
TI  - Sparganosis in feral hogs (Sus scrofa) from Florida.

PMID- 10416474
TI  - Effect of perioperative prophylactic antimicrobial treatment in dogs undergoing
      elective orthopedic surgery.
AB  - OBJECTIVE: To determine whether perioperative antimicrobial prophylaxis would
      reduce incidence of postoperative infection among dogs undergoing elective
      orthopedic procedures. DESIGN: Randomized, controlled, blinded, intention
      clinical trial. ANIMALS: Dogs of any breed, sex, or age undergoing elective
      orthopedic surgery at a veterinary teaching hospital. PROCEDURES: Dogs were
      randomly assigned to 1 of 3 groups: treatment with saline solution, treatment
      with potassium penicillin G, and treatment with cefazolin. Treatments were
      intended to be administered within 30 minutes prior to surgery; a second dose was
      administered if surgery lasted > 90 minutes. Dogs were monitored for 10 to 14
      days after surgery for evidence of infection. RESULTS: After the first 112 dogs
      were enrolled in the study, it was found that infection rate for control dogs
      (5/32 dogs) was significantly higher than the rate for dogs treated with
      antimicrobials (3/80 dogs). Therefore, no more dogs were enrolled in the study. A
      total of 126 dogs completed the study. Monte Carlo simulations indicated that
      compared with dogs that received antimicrobials prophylactically, dogs that
      received saline solution developed infections significantly more frequently.
      Difference in efficacy, however, was not observed between the 2 antimicrobial
      drugs used. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that
      perioperative antimicrobial prophylaxis decreased postoperative infection rate in
      dogs undergoing elective orthopedic surgery, compared with infection rate in
      control dogs. Cefazolin was not more efficacious than potassium penicillin G in
      these dogs.

PMID- 10416475
TI  - Percutaneous ultrasound-guided chemical parathyroid ablation for treatment of
      primary hyperparathyroidism in dogs.
AB  - OBJECTIVE: To evaluate the efficacy, feasibility, and safety of ultrasound-guided
      chemical ablation of parathyroid masses in dogs with primary hyperparathyroidism.
      DESIGN: Prospective clinical trial. ANIMALS: 8 dogs. PROCEDURE: In all dogs, a
      solitary parathyroid mass was evident ultrasonographically. Dogs were
      anesthetized with propofol, and a 27-gauge needle was directed into the
      parathyroid mass under ultrasound guidance. Ethanol (96%) was injected into the
      mass until there was evidence of diffusion of fluid throughout the mass. Serum
      total calcium, ionized calcium, phosphorus, and parathyroid hormone (PTH)
      concentrations were monitored daily for 5 to 7 days after the ablation procedure
      and again 1, 3, and 6 months after the procedure. Dogs were also monitored for
      adverse effects. Follow-up ultrasonography was performed 5 days and 1 month after
      the ablation procedure. RESULTS: One injection was required in 7 dogs, and 2
      injections were required in 1. Serum total and ionized calcium concentrations
      were within reference ranges within 24 hours after treatment in 7 dogs and within
      5 days in 1 dog. Serum PTH concentration decreased and serum phosphorus
      concentration increased within 24 hours after treatment in all 8 dogs. Transient
      hypocalcemia developed in 4 dogs during the first 5 days after treatment, but
      only 1 dog required treatment for hypocalcemic tetany. Hypercalcemia recurred in
      1 dog 1 month after the procedure and surgical removal of the parathyroid mass
      was required. Other adverse effects were not reported. CONCLUSIONS AND CLINICAL
      RELEVANCE: Ultrasound-guided chemical ablation of parathyroid masses is a safe
      and effective alternative to surgery for dogs with primary hyperparathyroidism.

PMID- 10416476
TI  - Severe neurologic sequelae in a dog after treatment of hypoadrenal crisis.
AB  - A 3-year-old mixed-breed dog was evaluated for lethargy, weakness, anorexia, and
      vomiting. The dog was dehydrated, hyponatremic, hypochloremic, and hypoglycemic.
      Results of an ACTH stimulation test indicated hypoadrenocorticism. Treatment to
      restore cardiovascular stability and serum electrolyte balance caused serum
      sodium concentration to increase by 32 mEq/L within 48 hours, and the dog
      developed severe neurologic signs that persisted for approximately 3 weeks.
      Magnetic resonance imaging revealed cerebrocortical lesions on day 6 and more
      severe lesions, including diffuse atrophy of the cerebral hemispheres, at 23
      weeks after initial evaluation; however, the dog recovered complete neurologic
      function. Serum sodium concentration should be monitored during treatment for
      hypoadrenal crisis to avoid rapid increases that can cause CNS damage.

PMID- 10416477
TI  - Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39
      cases (1990-1997).
AB  - OBJECTIVE: To compare outcome of surgical versus medical treatment of dogs with
      beta cell neoplasia. DESIGN: Retrospective study. ANIMALS: 39 dogs with clinical
      signs of hypoglycemia and serum glucose and insulin concentrations consistent
      with a diagnosis of beta cell neoplasia. PROCEDURE: Information on signalment;
      clinical history; physical examination findings; results of CBC, serum
      biochemical analyses, and urinalysis; serum glucose and insulin concentrations;
      results of thoracic radiography and abdominal ultrasonography; treatment and
      treatment complications; survival time; and cause of death were obtained from
      medical records. RESULTS: 26 dogs underwent exploratory celiotomy and partial
      pancreatectomy; 13 dogs were treated medically (i.e., dietary change and
      prednisone). Median survival time was significantly longer for dogs treated
      surgically than for dogs treated medically. Significant differences were not
      found in mean age, body weight, duration of clinical signs prior to diagnosis,
      serum glucose and insulin concentration, or results of other serum biochemical
      tests between dogs treated surgically and dogs treated medically; also, there was
      no significant correlation between any of these parameters and survival time for
      either group of dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that
      exploratory celiotomy and partial pancreatectomy are indicated once a tentative
      diagnosis of beta cell neoplasia is established in dogs.

PMID- 10416478
TI  - Comparison of two sampling tools for diagnosis of Tritrichomonas foetus in bulls
      and clinical interpretation of culture results.
AB  - OBJECTIVE: To compare sensitivity for diagnosing Tritrichomonas foetus infection
      in bulls using 2 sampling tools and to calculate negative predictive values for
      infection. DESIGN: Randomized clinical trial. ANIMALS: 30 Bos taurus bulls
      naturally or experimentally infected with T foetus. PROCEDURE: Preputial
      scrapings were obtained once/wk for 6 weeks using an artificial insemination
      pipette and a metal brush; which tool was used first for each bull was randomly
      determined. Samples were collected first from the left side of the prepuce and
      then from the right side and placed in commercially available transport media chi
      2 Values and confidence limits were adjusted for effect of clustering of results
      by bull. RESULTS: Significant differences in sensitivity of results were not
      found between samples collected using the brush or pipette. Using the pipette,
      sensitivity was estimated to be 91.6% (95% confidence interval, 84.3 to 95.7%);
      negative predictive values ranged from 41 to 99% for prevalence of infection of
      90 to 5%, respectively. Sensitivity was 88.8% for first sample obtained and 96.1%
      for second sample obtained. CONCLUSIONS AND CLINICAL RELEVANCE: Collection of
      preputial scrapings with an artificial insemination pipette or a metal brush and
      use of a commercially available culture system can provide a sensitive diagnostic
      test for T foetus infection in bulls. Calculated negative predictive values
      indicated that 1 or 2 tests would suffice in most clinical situations. For bulls
      from herds in which T foetus is endemic, 2 to 4 tests/bull may be required to
      ensure that each bull is not infected.

PMID- 10416479
TI  - Hepatic encephalopathy associated with paratuberculosis in a goat.
AB  - A 3-year-old pregnant Nubian goat that was examined because of weight loss,
      weakness, and change in attitude was determined to be infected with Mycobacterium
      paratuberculosis. Signs of depressed attitude, trembling, and ataxia were
      consistent with hepatic encephalopathy, which was confirmed by detection of
      hyperammonemia. These signs were consistent with histopathologic lesions in the
      liver and brain. Changes in energy balance and the hypoproteinemia that often
      develop in goats with paratuberculosis may lead to fat infiltration of the liver,
      hepatic insufficiency and, ultimately, hepatoencephalopathy.

PMID- 10416481
TI  - [Growth promoting antimicrobials].
AB  - The committee 'Growth promoting antimicrobials' of the Health Council of the
      Netherlands in 1998 advised immediate prohibition of all growth promoting
      antimicrobials related to human drugs and decrease of use of other growth
      promoting antimicrobials during the next three years in Europe. It is clear that
      frequent use of antibiotics is associated with development of resistance by
      selection in animals (and man), but it is not proven that this is an explanation
      of resistance in the human community. We know only little about the mechanisms
      and conditions of transfer of bacteria to man. Other questions raised are: what
      about the resulting possible increase of therapeutic application of antibiotics
      in animals, how to handle the increase of dung, nitrogen and phosphate in the
      environment and how farmers can survive with a decrease in income, sometimes by
      as much as 50%? Although many will feel sympathy for the report and its
      recommendations, implementing them will be difficult and possibly premature.

PMID- 10416480
TI  - [The role of allergy in interstitial cystitis].
AB  - In two women, aged 47 and 58 years, who suffered from longstanding urinary
      bladder complaints, various urologic treatments had been carried out, which
      however had had only a partial therapeutic effect. They also suffered from
      allergic rhinitis and multiple arthralgia. Allergologic investigations including
      nasal challenges with inhalant allergens and food ingestion challenges revealed
      the causative participation of the inhalant allergens and the food components in
      the urinary complaints. The all-round allergologic management, including dietary
      measures, avoidance of the relevant allergens and nasal as well as oral
      administration of disodium cromoglycate therapy, led to the almost complete
      disappearance of the urinary and other complaints. Interstitial cystitis is a
      regularly appearing urinary disorder, especially in female patients. In practice,
      the possible causative role of allergy and especially of food allergy is only
      rarely included in the differential diagnosis of this disorder.

PMID- 10416482
TI  - [Infections and bacterial resistance in the community].
AB  - The frequency of resistance to antibiotics among community acquired pathogens and
      the number of drugs to which they are resistant are increasing world wide.
      Antimicrobial resistance in the Netherlands is still low. Resistance to
      antimicrobial drugs is clearly linked to consumption of antibiotics within and
      outside of the hospital. Use of antibiotics in veterinary medicine may also
      contribute to the occurrence of antimicrobial resistance in human pathogens.
      Strategies to limit the spread of resistant strains should include encouraging
      the judicious use of antimicrobial agents. Guidelines for antibiotic therapy
      should be based on results derived from well designed surveillance studies.

PMID- 10416483
TI  - [Pharmacotherapy in bipolar disorder].
AB  - In the treatment of manic depressive disorders a distinction is made between
      acute treatment (combating the mania and the depression) and the maintenance
      treatment (prevention of subsequent episodes). In both forms of therapy the mood
      stabilizers are crucial: lithium carbonate, the anticonvulsants carbamazepine and
      valproic acid. The efficacy of lithium carbonate has been demonstrated in the
      acute treatment of mania and depression as well as in the maintenance treatment.
      Carbamazepine may be regarded as a good alternative, especially for the acute
      treatment of mania and for the maintenance treatment. Valproic acid so far has
      only be demonstrated to be efficacious in the acute treatment of mania.
      Monotherapy with a mood stabilizer is a first option, but its insufficient
      efficacy in many patients nevertheless necessitates a combined treatment, with
      two or even three mood stabilizers or with a mood stabilizer and other
      psychoactive agents. In the acute treatment of mania, antipsychotics are
      indicated in case of a severe or psychotic mania and benzodiazepines in severe
      disorders of sleep or restlessness. Antidepressants have a role as comedication
      in the acute treatment of the bipolar depression.

PMID- 10416484
TI  - [Roaming through the methodology. XIV. The premature ending of a randomized
      trial].
AB  - A randomized controlled trial that is stopped prematurely because of a striking
      benefit or a strong untoward effect is most probably suffering from a 'random
      high'. At premature stopping the conclusions will often either be too optimistic
      or too pessimistic. In the early phases of an investigation the intermediate
      results show wider fluctuations around the hypothetical 'truth' than in the later
      phases. Subjective arguments involved in the stopping of a trial may be
      eliminated by a so-called triple blind design: the data monitoring and safety
      committee receives the intermediate results but is not told which data are from
      the experimental group and which ones from the placebo group.

PMID- 10416485
TI  - [Differences in incidence of (violent) traumatic events in the national
      registration systems, population surveys and studies from family practice; a
      review of literature].
AB  - OBJECT: Comparison of (cumulative) incidences of traumatic events from population
      surveys and registration systems as well as from studies in general practice.
      DESIGN: Literature study. METHOD: Literature searches were done about the
      frequencies of accidents, sudden death, physical and sexual abuse listed in
      electronic databases and relevant catalogs covering 1986-1998, after which more
      references were searched via the references found, going back to 1984. RESULTS:
      There were large discrepancies between frequencies found in the several studies,
      such as national registration systems (n = 4), surveys in the open population (n
      = 10) and studies in general practice (n = 4). The incidence (per 1000 persons
      per year) of physical abuse were 66, 2.7 and 1-3 for surveys in the open
      population, police and general practitioners' registration systems respectively.
      For sexual abuse the figures were 21, 0.025 and 0.2-2.9 respectively. Different
      definitions and methods were used in the studies. CONCLUSION: General
      practitioners are aware of only a fraction of what their patients experience.

PMID- 10416486
TI  - [Increased frequency of icterus in parenterally fed patients after a change of
      lipid emulsion].
AB  - Parenteral nutrition is associated with liver enzyme abnormalities. Until 1993
      the incidence of icterus was low in both academic hospitals in Amsterdam, the
      Netherlands (Academic Medical Centre (AMC) and Academic Hospital of the Free
      University (AZVU)). In 1993 Intralipid in the nutrition was replaced by Endolipid
      in the home total parenteral nutrition programme (AMC) and by Lipofundin S in
      AZVU. Fifty per cent of the patients in the home programme developed severe
      fatigue, jaundice and thrombocytopenia. These signs and symptoms disappeared over
      months when parenteral nutrition without fat was given. After reintroduction of
      Intralipid these signs and symptoms never recurred. In AZVU the incidence of
      jaundice increased from 21% in 1992 to 79% in 1993 (p = 0.0002). After
      reintroduction of Intralipid in 1994 the incidence of jaundice decreased to 16%.
      CONCLUSION: Although the lipid emulsions are equivalent according to the product
      specification, the described observation suggests that Lipofundin S and Endolipid
      cause more icterus than Intralipid, possibly caused bij an impurity in the fat
      emulsion.

PMID- 10416487
TI  - [Variable manifestations of Hashimoto's encephalopathy].
AB  - Two women (aged 12 and 32 years) and a man aged 40 years presented with
      fluctuating confusional states, depressed level of consciousness, seizures and
      tremor or myoclonic activity; hallucinations occurred in two of them. Laboratory
      examinations showed antibodies to thyroid peroxidase in serum, elevated protein
      levels in CSF and normal cerebral MRI. The EEG findings were indicative of
      diffuse encephalopathy. Hashimoto's encephalopathy was diagnosed. One patient
      improved dramatically on prednisone therapy, the other two patients recovered
      spontaneously. Hashimoto's encephalopathy is a subacute, fluctuating
      encephalopathy with combinations of impaired level of consciousness, involuntary
      movements, and epileptic or psychiatric symptoms. It occurs in patients with
      antithyroid antibodies. It is important to consider this diagnosis, since some
      patients may benefit from treatment with corticosteroids.

PMID- 10416488
TI  - [European strategy for control of resistance to antibiotics].
AB  - The problem of international spread of bacterial resistance requires development
      of a strategy at worldwide or at least at European level. Clinically relevant
      monitoring systems for resistance and use of antibiotics have to be implemented
      to support the guidelines on prescription of antibiotics. Every hospital should
      establish an 'antibiotics team' controlling the prescription of antimicrobials
      and the observance of local formulary agreements. Veterinary use of growth
      promoting antimicrobials related to substances used in human medicine should be
      terminated. Future research should be aimed at resolving the problem of
      resistance to antimicrobials.

PMID- 10416489
TI  - [Clinical researchers and the pharmaceutic industry. The research contract is not
      an addendum].
AB  - The relation between a pharmaceutical company and a clinical investigator
      combines a certain form of entrepreneurship with scientific endeavour. Both
      parties are concerned with the content of the clinical study as well as with its
      business aspects. A good contract is essential for the project to succeed. In
      three cases based on actual experience the contract failed. In the first case,
      dosage miscalculation in the hospital pharmacy led to side effects in patients as
      a consequence of which the study was stopped. The pharmaceutical company sued the
      investigator. In the second case the investigator published data in a congress
      abstract, which prevented a patent by the company. In the third case scientific
      information was published by the company with the principal investigator
      featuring in the acknowledgement section of the article only. Investigators
      should have their own standard contract ready, and they should invest time and
      energy in understanding the contracts of the research they are carrying out.

PMID- 10416490
TI  - [Clinical researchers and the pharmaceutical industry].
AB  - The diminished financial support by the government of clinical investigation has
      led to clinical units that depend for their infrastructure largely on contract
      research for the pharmaceutical industry. This poses a threat to the independence
      of scientific research, to the freedom to publish scientific results and to the
      continuity of the research. Moreover, it is not easy for a researcher to retain a
      position of integrity and independence in the face of a jungle of conflicting
      interests and not to let personal interests prevail. The difficult relation
      between the physician and the pharmaceutical industry is the subject of a
      forthcoming short series of articles.

PMID- 10416491
TI  - [Genes and genetics in Hirschsprung's disease].
AB  - Hirschsprung's disease (HSCR) is a congenital disorder characterized by
      intestinal obstruction due to the absence of intramural ganglia along variable
      lengths of the colon. Occurrence among family members and recurrence risks among
      siblings are indications for involvement of genetic predispositions. Mutations
      have been discovered in five different susceptibility genes. One of the most
      important findings is the detection of specific mutations in the so-called RET
      gene, which can also be responsible for the multiple endocrine neoplasia type 2A
      (MEN2A) syndrome. HSCR patients with such specific mutations run an increased
      risk of developing MEN type 2A related tumours.

PMID- 10416492
TI  - [Prevention of cutaneous melanoma].
AB  - Cutaneous melanoma exhibited a rapidly increasing incidence during the 70 s and
      80 s. As a consequence primary and secondary prevention campaigns were developed,
      starting in Australia, where the incidence was by far the highest, but later also
      in the Netherlands. Mortality from melanoma in the Netherlands is stable at a
      rate of 2.4 per 100,000 person years since 1980. The melanoma incidence has
      stabilized since 1989 at a level of about 11 per 100,000. In the development of
      the melanoma it is not so much the accumulated exposure to sun that is of
      importance, as in squamous carcinoma, but rather incidental serious sunburn. It
      is especially exposure at an early age that increases the risk of melanoma as
      well as that of basal cell carcinoma. Primary prevention must be focussed on
      avoiding sunburn in young people. Secondary prevention can be realised by
      frequent controls of risk groups and a raised awareness for changing moles in the
      general population but also in physicians who see patients' skins for whatever
      reason.

PMID- 10416493
TI  - [Extrauterine pregnancy in Netherlands: patient characteristics, treatment, and
      pregnancy prognosis].
AB  - OBJECTIVE: To determine the probability of pregnancy after a finished
      extrauterine pregnancy (EUP) and the length of time in between. DESIGN:
      Prospective multicentric cohort study. METHOD: Of all patients with an EUP
      between May 1990 and October 1993, data were collected using a questionnaire from
      surgeons in five university hospitals and 30 general training and non-training
      hospitals. During the subsequent 3 years, the patients semi-annually reported on
      their pregnancy or wish to become pregnant using reply cards. RESULTS: A total of
      665 patients with an EUP were reported their mean age was 30.7 years (SD: 4.9).
      There were 341 patients who during the follow-up desired pregnancy, did not start
      an IVF procedure and supplied complete follow-up data 207 of them (61%) became
      pregnant after a median interval of 12 months. Age above 35, previous fertility
      problems, a Chlamydia antibody titre > or = 1:64 and adnexitis in the anamnesis
      were correlated with a longer interval until a subsequent pregnancy. The nature
      of the treatment (laparotomy versus laparoscopy, conservative versus radical and
      surgical versus pharmaceutical) did not affect the duration of the interval. If
      the contralateral tube was judged to be abnormal by the operator, pregnancy was
      still possible, but the occurrence of the pregnancy was delayed. CONCLUSION: The
      probability of pregnancy after an earlier EUP averages 61%; the interval until
      the next pregnancy, if any, depends mostly on factors that cannot be influenced
      at the time of the diagnosis of EUP.

PMID- 10416495
TI  - [Market effect on social security and occupational health services].
AB  - Between 1993 and 1998 a fundamental reform of the social security system and
      Occupational Health Services (OHSs) in the Netherlands was implemented in order
      to lower the relatively high sickness and disability rates. The principle of the
      government policy is to impose the financial consequences of incapacity for work
      as much as possible on those who cause it: employers and employees. The reform
      implies the creation of a market in both fields. Joining an OHS was made
      mandatory for all employers by ultimately the first of January 1998. Price and
      product competition between different suppliers of OHSs is promoted. This implies
      an explosive increase of the target population and the rise of commercial OHSs
      (which in 1997 provided for 570,000 employees). Other OHSs originated from
      industrial insurance boards (over 2 million) or from industrial health services
      (over 3 million). The change of system has increased the economic importance of
      sickness and health. The number of persons incapable for work has meanwhile
      grown, risk avoidance by enterprises being one of the causes. Owing to the
      enhanced interference of employers with absenteeism, the health care system is
      being asked for specific measures for employees and better contacts between
      industrial physicians and treating physicians.

PMID- 10416494
TI  - [The social security reform: wide-ranging effects on companies as well as
      occupational health services].
AB  - OBJECTIVE: To evaluate the reactions of companies and Occupational Health
      Services (OHSs) to the reform of the social security system by the government of
      the Netherlands; especially to inventory to what extent intended effects (more
      handicapped workers employed, more reintegration efforts) and unintended effects
      (exclusion handicapped workers, deteriorated quality OHSs) occurred. DESIGN:
      Inventory survey. METHOD: Data on number of OHSs and their sizes and staff
      compositions were collected in September 1997 through a questionnaire sent to all
      members of the National Association of OHSs (BOA). In addition, data on efforts
      of enterprises in the area of working circumstances in 1996 and in 1997 were
      derived from the published results of enquiries by telephone among a
      representative random sample of 4,000 enterprises. RESULTS: The number of
      employees in the care of the OHSs was twice as high in 1997 as in 1991. The
      number of OHS staff members had also doubled, but the proportion of physicians
      among the total staff had decreased. The number of employees per physician had
      increased by 34%. The nature of the contracts concluded with enterprises shows
      that the extension of the market has not led to more extensive OHS care, although
      it has brought about greater variation. Generally, large companies developed a
      policy to prevent disability and to employ more handicapped workers, while small
      and medium-size companies more often tried to exclude people that is at risk for
      disability or absenteeism. CONCLUSION: Intended effects occurred to a limited
      extent in larger companies and unintended effects mainly in small and medium-size
      companies.

PMID- 10416496
TI  - [Professional integrity among commercial occupational health services].
AB  - In the field of Occupational Health Services (OHSs) a fundamental change of the
      regime of supply of services was implemented in the Netherlands between 1993 and
      1998 by introducing market competition. This regime change is characterised as a
      shift from a suppliers' market where occupational physicians were able to
      determine the supply to a large extent, to a buyers' market where companies can
      choose from a large variety of services at different prices. The regime change
      does affect the position of the occupational physician drastically and many
      consider their professional integrity and independence threatened. To meet the
      demand for an independent judgement and advice in problems concerning the
      interaction between work and health, the professional group should organize
      itself more as a party in the market.

PMID- 10416497
TI  - [Physical diagnosis--signs of lumbosacral irritation].

PMID- 10416498
TI  - [Physical diagnosis--signs of lumbosacral irritation].

PMID- 10416499
TI  - [Physical diagnosis--lumbosacral irritation].

PMID- 10416500
TI  - [Therapeutic options for HIV-infection should lead to increased utilization of
      HIV tests].

PMID- 10416501
TI  - [Therapeutic options for HIV-infections should lead to increased utilization of
      HIV tests].

PMID- 10416502
TI  - [Selective intestinal decontamination prevents death in intensive care patients].

PMID- 10416503
TI  - [Behcet disease].

PMID- 10416504
TI  - [Mantoux test: quality of interpretation and tuberculin used].

PMID- 10416505
TI  - Increased risk of sensory neuropathy in workers with chloracne after exposure to
      2,3,7,8-polychlorinated dioxins and furans.
AB  - OBJECTIVE: The existence of a peripheral neuropathy after exposure to
      polychlorinated dioxins (PCDD) is still discussed, as studies concerning dioxin
      effects on the peripheral nervous system are rare and contradictory. MATERIAL AND
      METHODS: Clinical and neurophysiological examinations (motor conduction velocity
      of the peroneal nerve, sensory conduction velocities of the sural and ulnar
      nerves) were made in 156 dioxin exposed workers (42 with, 114 without cloracne)
      from one pesticide producing plant. Because of known risk factors for peripheral
      neuropathy, 7 workers with and 28 without cloracne were excluded from further
      analysis. RESULTS: Workers with chloracne had a significantly higher exposure
      against PCDD as documented by back calculated lipid levels. They complained
      significantly more often of sexual impotence (28.6% compared to 5.8% of workers
      without chloracne, P<0.001), had significantly more frequent clinical signs of a
      sensory neuropathy (= abnormal sensory findings plus deep tendon reflex
      abnormalities) restricted to the legs (17.1% compared to 1.2%, P<0.001), had
      significantly more frequent > or =2 neurophysiologic abnormalities (34.3%
      compared to 14.0%, P<0.025), and had significantly lower mean amplitudes of the
      motor compound muscle potential of the peroneal nerve. CONCLUSION: PCDD has a
      mild toxic effect on the peripheral nervous system manifesting as mild sensory
      neuropathy of the legs in a minority of the most severely exposed persons.

PMID- 10416506
TI  - Amino acids acting as transmitters in amyotrophic lateral sclerosis (ALS).
AB  - OBJECTIVES: In amyotrophic lateral sclerosis (ALS), a neurodegenerative disease
      of unknown origin, excitotoxic mechanisms are supposed to be involved. Divergent
      results are, however, presented either because of the heterogeneity of this
      disease, and/or different methodologies used to evaluate the excitotoxic amino
      acids content. The results of the most sensitive high performance liquid
      chromatography (HPLC) techniques with precolumn derivatization of fasting serum
      and CSF glutamate, aspartate, glycine and gamma-aminobutyric acid (GABA) in mild
      and severely progressing ALS cases are presented here. MATERIAL AND METHODS: We
      studied 25 ALS patients with different course of the disease and controls, which
      consisted of 10 cases with other motor neuron diseases and 20 healthy, age
      matched subjects. RESULTS: In the ALS patients with a mild course of the disease
      serum glutamate and aspartate content was either normal or slightly decreased, in
      all of these cases a rise in GABA and glycine was present. In the severely
      progressing ALS cases serum glutamate and aspartate was increased. The GABA
      content was either normal or increased, the glycine level appeared to be either
      normal or decreased. In CSF the amino acids changes in ALS were less pronounced
      as compared to serum. The most frequent finding was the increase in GABA
      concentration both in the mild and the severely progressing group. CSF glutamate
      in ALS patients with mild course of the disease was decreased, in the severely
      progressing cases the glutamate level appeared in a broad range from decreased to
      increased values. CSF aspartate was either normal or elevated, glycine values
      were present in a broad range from decreased to increased values. In the other
      tested motor neuron diseases no consistent changes in serum and CSF amino acids
      concentration was observed. CONCLUSIONS: The data from serum and CSF indicate
      that in ALS an imbalance between excitatory and inhibitory amino acids might be
      present in the brain, which may be induced in different ways in particular ALS
      patients. It may be an important factor for the mediation of neurons death.

PMID- 10416507
TI  - Vestibular evoked blood flow response in the basilar artery.
AB  - BACKGROUND AND PURPOSE: Monitoring of the basilar artery (BA) is difficult and
      has been sparsely performed. The aim of this study was to present physiological
      data of functional transcranial Doppler sonography (TCD) of the BA during caloric
      vestibular stimulation in healthy volunteers. METHODS: TCD of the BA was
      performed in 26 healthy volunteers (14 women, 12 men, age 25.1+/-3 years) during
      caloric vestibular stimulation. Vertigo was documented using
      electronystagmography (ENG) and a subjective vertigo scale ranging from 0 to 10
      points. Simultaneously, capnogpraphy was performed. RESULTS: All subjects
      experienced vertigo, nausea and oszillopsia during vestibular irrigation. The
      average subjective vertigo was for a period of 106 s (+/-65.4); the average
      subjective estimated degree of vertigo was 6.7 points (+/-1.5). In all subjects,
      ENG demonstrated horizontal nystagm to the left non-irrigated side. In 14
      subjects the subjective vertigo was rated by the individuals as extreme (point
      score > or =7) and in 12 subjects as low (point score <7). Mean flow velocity
      (MFV) in the BA increased significantly during vestibular irrigation, being more
      prominent in the initial irrigation and vertigo phase (5.8+/-5.9%, P<0.05) than
      in the second vertigo phase (2.2+/-8.8%, P<0.05). The calculated pulsatility
      index (PI), which indicates the condition of the small resistance vessels,
      decreased significantly (-4.9+/-8.1%; 4.3+/-8.9%, P<0.05) during both phases of
      vestibular activation. End tidal pCO2 did not change significantly (constant
      5.4+/-0.4 Vol%), but respiration frequency was significantly increased during
      vestibular stimulation (12.3+/-3.8 min(-1) to 16.4+/-5.3 min(-1) and 16.3+/-4.8
      min(-1), P<0.05) probably as a vegetative sign of vertigo. The observed MFV- and
      PI-changes were more prominent, although not quite significant, in the subgroup
      of subjects who experienced extreme subjective vertigo than in the subgroup who
      experienced low subjective vertigo. CONCLUSION: These observations indicate that
      MFV increase in the posterior circulation is due to activation of the
      vestibulocerebellum. In addition, it is possible that the previously elaborated
      MFV increase in the MCA might contribute to MFV increase in the BA via the
      posterior communicating artery. The difference in the 2 subgroups (extreme
      vertigo vs. low vertigo) may reflect the great variety of anatomical and
      physiological conditions of the peripheral vestibular organ, the brainstem
      anatomy and the corresponding blood supply. For clinical purposes this TCD-test
      may contribute to the investigation of the vasomotor reserve of the posterior
      circulation, e.g. in patients with vertebrobasilar ischemia, bilateral vestibular
      loss or local neurodegenerative disease.

PMID- 10416508
TI  - High numbers of perforin mRNA expressing CSF cells in multiple sclerosis patients
      with gadolinium-enhancing brain MRI lesions.
AB  - Enhanced expression of pro- and anti-inflammatory cytokines is a common finding
      in MS, but attempts to correlate cytokine expression with disease activity have
      produced conflicting results. In this paper, gadolinium-(Gd-)enhancing lesions on
      brain MRI were used as markers for active inflammation in patients with MS not
      treated with any immunomodulatory drugs. In parallel, in situ hybridization was
      used to detect blood and cerebrospinal fluid (CSF) mononuclear cells (MNC)
      expressing cytokine mRNA. An association was observed between numbers of perforin
      mRNA expressing CSF MNC and numbers of Gd-enhancing brain MRI lesions. Perforin
      mRNA expressing CSF MNC were not detected in any of the patients lacking active
      lesions on brain MRI. The expression of tumor necrosis factor-alpha, interleukin
      10 (IL-10) and IL-12 mRNA in CSF MNC did not differ between MS patients with and
      without active MRI lesions. Based on the present finding, a role for perforin in
      the disruption of the blood-brain barrier in MS can be hypothesized.

PMID- 10416509
TI  - Blinded, prospective, and serial evaluation by quantitative-EEG in interferon
      alpha-treated hepatitis-C.
AB  - OBJECTIVES: To estimate the effect of brain function due to IFN-alpha in chronic
      hepatitis C patients by the quantitative EEG. METHODS: 56 chronic hepatitis C
      patients were administered IFN-alpha intramuscularly at 9x10(6) IU daily for the
      first 4 weeks and then 3 times/week for the next 20 weeks. Serial EEGs were
      obtained in each subject before, at 2 and 4 weeks, and after completing the
      treatment. Resting EEG without artifacts was selected for quantitative EEG
      analysis, which was performed blindly. The frequency range was divided into delta
      to beta. The absolute and relative powers of each frequency band in each subject
      were calculated and the differences of these powers at different stages were
      analyzed statistically. RESULTS: The absolute powers of slow waves (delta, theta
      1, and theta 2) increased while alpha 2 and fast wave (beta) decreased
      significantly at all locations during IFN-alpha administration. The total power
      and alpha 1 values revealed no significant alterations. The relative power
      revealed the same alteration during treatment. These changes disappeared
      following the treatment. Such diffuse slowing in the EEG was revealed by the
      total change in the whole subjects. CONCLUSIONS: Diffuse slowing in the EEG was
      induced by IFN-alpha, was reversible, and was evident as the total change in the
      subjects. These findings suggested mild IFN-alpha-induced encephalopathy.

PMID- 10416510
TI  - Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism.
AB  - INTRODUCTION: We propose that the increase in TNF-alpha and IL-6 in the brain in
      idiopathic parkinsonism is in response to a peripheral immune/ inflammatory
      process, so ubiquitous as to be responsible for the resemblance between ageing
      and parkinsonism. METHODS: Circulating cytokine was measured in 78 subjects with
      idiopathic parkinsonism and 140 without, aged 30 to 90 years, all obeying
      inclusion/exclusion criteria. RESULTS: Serum TNF-alpha increased (P<0.0001) by
      1.37 (95% CI 0.75, 2.00)% x y(-1), IL-6 by 2.63 (1.75, 3.52) (P<0.0005). TNF
      alpha appeared elevated in parkinsonians whose postural and psychomotor responses
      were abnormal, being suppressed where they were normal: trends which contrasted
      with those in controls (P = 0.015 and 0.05, respectively). Parkinsonism appeared
      (P = 0.08) to have an effect on IL-6, equivalent to that of >10 years of ageing
      (28(-3, 69)%), but was not immediately related to between-subject differences in
      performance. CONCLUSION: Ageing and pathogenetic insult may be confounded, age
      being a progression, not a risk, factor.

PMID- 10416511
TI  - NMSP binding to dopamine and serotonin receptors in MPTP-induced parkinsonism:
      relation to dopa therapy.
AB  - We tested the hypothesis that N-methylspiperone binding to dopamine D2 receptors
      must be reduced when L-dopa therapy of parkinsonism augments the binding of
      dopamine to the receptors and improves the clinical state expressed by the Hoehn
      & Yahr stage. A patient with MPTP-induced parkinsonism underwent two positron
      emission tomographic studies of the D2-like dopamine receptors with N
      [11C]methylspiperone (NMSP). The first study took place 3 days after cessation of
      the L-dopa medication, the second 5 days after its resumption. Noticeable
      clinical deterioration occurred during both studies, consistent with significant
      dopamine receptor blockade by NMSP and elevated NMSP binding in both scans. The
      dopa treatment did not reduce the NMSP binding. On the contrary, the rate of
      binding of NMSP (k3) was increased on-dopa, compared to off-dopa. The increase
      was consistent with the slightly greater dopamine receptor density estimated
      after resumption of the dopa therapy. The NMSP binding to serotonin receptors
      suggested lower synaptic serotonin on-dopa than off-dopa. The results are
      consistent with negative correlation between the Hoehn & Yahr stage and the
      amount of dopamine bound to dopamine D2 receptors. Low synaptic serotonin may
      explain the depression seen in some patients on dopa for Parkinson's disease.

PMID- 10416512
TI  - Apolipoprotein E genotypes and cognitive functions in healthy elderly persons.
AB  - OBJECTIVES: We investigated whether apoE genotypes correlate with cognitive
      functions in clinically healthy persons. METHODS: In 1993 and 1995, we measured
      information processing speed, delayed free recall and semantic aspects of long
      term memory in 227 men and 105 women aged 65 and over, a randomly selected
      subsample of the prospective Basel Study. Cardiovascular risk factors and
      education were assessed. RESULTS: E2 were more prevalent in old-old (>75 years,
      23.5% vs. 15%) compared to E4 than in young-old (<75 years, 19.3% vs. 23.5%).
      Taking into account age and education, subjects with epsilon3/epsilon4 or
      epsilon4/epsilon4 alleles (E4) performed lowest in all 3 tests compared to those
      homozygous for epsilon3 (E3) or carriers of one or two epsilon2 alleles (E2)
      (reaction time P = 0.009, free recall P = 0.05, WAIS-R vocabulary P<0.05). In old
      old there was a significant difference between E2 and E4 for reaction time (P =
      0.02) and free recall (P<0.02) but not for vocabulary (P = 0.086). In all 3
      groups there were no significant changes after 2 years. The subgroup with the
      genotype epsilon2/epsilon4 performed consistently best in the cognitive tests.
      Cholesterol was significantly increased in the E4 and E3 group compared to the E2
      group. CONCLUSION: ApoE genotype correlates with cognitive performance. The
      increased prevalence of E2 in the old-old and the significantly lower plasma
      cholesterol levels suggest differential morbidity and mortality as important
      factors influencing the prevalence of cognitive disorders in late life.

PMID- 10416513
TI  - Increased apolipoprotein B serum concentration in Alzheimer's disease.
AB  - OBJECTIVE: To investigate the lipoprotein profile in a group of Alzheimer's
      disease (AD) patients. PATIENTS AND METHODS: Twenty-four patients with AD and 32
      elderly controls were evaluated. Fasting blood samples were obtained for
      determination of total VLDL, HDL and LDL cholesterol, lipoprotein (a),
      triglycerides, apolipoprotein A1 and apolipoprotein B. RESULTS: Significantly
      higher levels of apolipoprotein B were found in AD patients (P = 0.004), whereas
      the concentration of lipoprotein (a) and plasma lipids was not statistically
      different. Apo B levels were similar between AD patients with or without
      leukoaraiosis on CT scan. CONCLUSION: AD patients had high serum concentration of
      apolipoprotein B. This finding suggests that apolipoprotein E may not be the
      single factor in lipid metabolism to play a role in AD pathogenesis.

PMID- 10416514
TI  - First hospital-admission rate as an epidemiological indicator for patients with
      multiple sclerosis in Stockholm, 1984-1993.
AB  - OBJECTIVES: To evaluate the first hospital-admission patients with multiple
      sclerosis (MS) in the population. MATERIAL AND METHODS: By using the data from
      hospital discharge registry of MS diagnosis in Stockholm during 1984-1993, we
      calculated rates of first hospital-admission patients with MS in the population
      and evaluated the temporal trend of the rates during the study period. RESULTS:
      There were 719 first hospital-admission patients with MS corresponding to 1556
      admissions. The mean age at the first admission was nearly the same for male
      patients (44.3 years, SD: 12.9) and for female patients (44.6 years, SD: 13.7).
      The mean annual rate of first hospital-admission patients with MS was 4.46 per
      100,000 person-years. The sex rate ratio of first hospital-admission patients
      with MS between females and males was 2.19:1. CONCLUSION: The first hospital
      admission rate of MS could be used as an epidemiological indicator which is
      useful in planning of hospital service for MS patients.

PMID- 10416515
TI  - Vaccinations and steroids in MS: effects on disease progression and mood.
AB  - OBJECTIVE: To investigate the effects of vaccinations and steroids on disease
      progression and mood in patients with multiple sclerosis (MS). MATERIAL AND
      METHODS: Twenty-three patients with clinically definite MS were questioned with
      respect to vaccination history and the cumulative dose of steroids given during
      their life-time. EDSS scores and MRI scans of the brain were obtained and used to
      quantify clinical and MRI disease progression. Mood was assessed by using a self
      estimated adjective mood scale. RESULTS: The number of vaccinations showed no
      effect on disease progression or mood. High cumulative steroid doses were
      associated with rapid MRI disease progression and the number of supratentorial
      MRI lesions. The absence of band-like MRI lesions was correlated with rapid
      clinical and MRI disease progression. Self-estimated mood tended to be worse in
      patients with chronic-progressive MS compared to those with relapsing-remitting
      MS. CONCLUSION: Neither clinical nor MRI-documented disease progression nor mood
      are influenced by the total number of vaccinations whereas high cumulative
      steroid doses and the absence of band-like MRI lesions indicate rapidly
      progressive MS. Self-estimated mood tends to be worse in patients with chronic
      progressive MS compared to patients with relapsing-remitting MS.

PMID- 10416516
TI  - Impaired glucose tolerance, beta cell function and lipid metabolism in HIV
      patients under treatment with protease inhibitors.
AB  - OBJECTIVES: To evaluate metabolic abnormalities, beta-cell function, lipid
      profile and vascular risk factors in HIV patients on protease inhibitors (PI).
      DESIGN: Prospective cross-sectional study. METHODS: Thirty-eight HIV-1-infected
      patients receiving at least one PI were compared with 17 PI-naive HIV patients in
      an oral glucose tolerance test (OGTT). Serum glucose, insulin, proinsulin, and C
      peptide were determined. The fasting lipid pattern was analysed using
      electrophoresis and the assessment of apolipoproteins including lipoprotein (a).
      Fibrinogen, homocysteine, and anticardiolipin antibodies were also assessed.
      RESULTS: Twenty-seven (71%) of the PI-treated group had detectable
      hyperlipidaemia. Isolated hypertriglyceridaemia was present in 12 patients (44%),
      two (7%) of them had type V and 10 (37%) subjects had type IV hyperlipidaemia
      (Frederickson classification). Type IIb hyperlipidaemia defined as an increase of
      both very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) was
      found in 10 (36%) subjects, and five (18%) patients presented with isolated
      hypercholesterolaemia (type IIa). PI treatment was associated with significant
      higher fasting cholesterol, triglycerides, LDL and VLDL levels. Apolipoprotein B
      and E concentrations were significantly increased in patients receiving PI.
      Elevated concentrations of lipoprotein (a) (> 30 mg/dl) were detected in six
      (16%) of the hyperlipidaemic patients on PI. Eighteen (46%) patients on PI had
      impaired oral glucose tolerance and five (13%) had diabetes. Although four (24%)
      of the PI-naive patients were glucose intolerant, none had diabetes. Fasting
      concentrations and secretion response of insulin, proinsulin, and C-peptide to
      glucose ingestion was significantly increased in the PI-treated group suggesting
      a beta-cell dysfunction in addition to peripheral insulin resistance. Beta-cell
      abnormalities were associated with the abnormal lipid pattern and PI treatment.
      CONCLUSION: Combination drug regimens including PI are accompanied by impaired
      glucose tolerance, hyperproinsulinaemia as an indicator for beta-cell
      dysfunction, and lipid abnormalities proved to be significant risk factors for
      coronary heart disease. Moreover, PI may have an impact on the processing of
      proinsulin to insulin.

PMID- 10416517
TI  - Does tuberculosis accelerate the progression of HIV disease? Evidence from basic
      science and epidemiology.

PMID- 10416518
TI  - Unscheduled cyclin B expression and p34 cdc2 activation in T lymphocytes from HIV
      infected patients.
AB  - OBJECTIVE: To study the role of cell cycle regulation during HIV infection by
      investigating in vivo and in vitro cyclin B and p34 cdc kinase expression.
      METHODS: Cyclin B expression was analysed by Western blot in CD4 and CD8 cells
      from 25 HIV-infected patients and 24 uninfected individuals. In eight patients, a
      sequential analysis was performed after initiation of antiretroviral therapy
      (ART), and correlations with CD4 cell count and HIV viremia were studied.
      Sequential changes in cyclin B expression and p34 cdc kinase expression and
      activity were also studied in lymphocytes activated in vitro with
      phytohaemagglutinin (PHA). RESULTS: Lymphocytes from untreated HIV-infected
      patients demonstrate persistent in vivo overexpression of cyclin B in both CD4
      and CD8 cell subpopulations. When cells are stimulated to proliferate in vitro,
      biochemical events that characterize the entrance into the cell cycle [ornithine
      decarboxylase (ODC) activity, interleukin 2 production, interleukin 2 alpha-chain
      receptor (IL-2R, CD25) expression, total protein synthesis, total DNA synthesis]
      show similar timing and sequence in lymphocytes from HIV-infected and uninfected
      individuals. However, in peripheral blood lymphocytes (PBL) from HIV-infected
      patients, cyclin B and p34 cdc kinase show premature expression during the cell
      cycle. Both in vivo cyclin B overexpression and in vitro unscheduled cyclin B
      expression were almost completely reversed 2-4 weeks after initiation of
      effective ART. CONCLUSION: Increased and unscheduled expression of cyclin B and
      p34 cdc kinase is consistently observed in CD4 and CD8 cells from HIV-infected
      patients, both in vivo and after in vitro mitogenic stimulation. These
      alterations correlate with the level of viremia and may provide a link between
      the perturbation of lymphocyte proliferative homeostasis and the exaggerated
      propensity towards apoptosis.

PMID- 10416519
TI  - Variability and evolution of Kaposi's sarcoma-associated herpesvirus in Europe
      and Africa. International Collaborative Group.
AB  - OBJECTIVE: To study the evolution of Kaposi's sarcoma-associated herpesvirus
      (KSHV) or human herpesvirus type 8 in Europe and Africa. DESIGN AND METHODS: PCR
      and sequence analysis of the variable viral membrane glycoprotein gene K1 in 58
      tumour and peripheral blood samples from patients with AIDS-related Kaposi's
      sarcoma (KS), 'classic' (HIV-negative) KS, transplant KS, Multicentric
      Castleman's Disease, other lymphoproliferative disorders, and healthy KSHV
      infected individuals from the UK, Denmark, Sweden, Italy, Spain, Iceland, The
      Faroe Islands, Greece, The Gambia and Uganda. RESULTS: Three major groups of K1
      sequences were found: A, B and C, as defined previously. The K1 gene has evolved,
      both within and between these three groups, under positive selection. KSHV group
      B strains predominate in Africa and are more distant from groups A and C, found
      in Europe, than A and C are from each other. Within group C two subgroups, C' and
      C", can be identified. Subgroup C" is more closely related to group A in a region
      of the K1 protein and appears to be phylogenetically close to the branchpoint
      between A and C. Group A and C strains are currently found in both HIV-1-infected
      and -uninfected Europeans, and were already present in Europe before the start of
      the AIDS epidemic. We found some examples of closely related K1 sequences in
      Italy and Denmark, but in general KSHV strains in Europe did not cluster
      geographically. CONCLUSION: KSHV strains in East and West Africa are closely
      related but phylogenetically distant from those in Europe. The two major KSHV
      groups in Europe are more closely related, with some strains adopting an
      intermediate phylogenetic position. In Europe, KSHV strains may have been
      disseminated at least several decades ago. Variability in the K1 region is driven
      by selection and does not correlate with different KSHV-related pathologies or
      geographic regions where clinically more aggressive HIV-negative KS ('endemic'
      KS) is more common.

PMID- 10416521
TI  - Long-term evaluation of T-cell subsets and T-cell function after HAART in
      advanced stage HIV-1 disease.
AB  - OBJECTIVES: Evaluation of immunological reconstitution after 2 years of highly
      active antiretroviral therapy (HAART) in AIDS patients. DESIGN: Previous data
      showed the effectiveness of HAART but conflicting evidence of immune
      reconstitution has been found in severely immunocompromised patients. Therefore,
      T-cell subsets and functions were analysed during 24 months of HAART in 21 AIDS
      patients (mean baseline CD4 cell count, 20 x 10(6)/l). METHODS: Subjects were
      tested at baseline and after 4, 12 and 24 months of therapy for clinical symptoms
      and the following investigations were carried out: plasma HIV RNA, T-cell subsets
      and lymphoproliferative responses to mitogens (phytohaemagglutinin, anti-CD3),
      and recall antigens (Candida mannoprotein, tetanus toxoid and recombinant
      glycoprotein 160). RESULTS: Increase in body weight, improvement of Karnofsky's
      score and reduction of opportunistic infections were observed. All patients
      showed an initial increase in the CD4 memory subset, whereas naive CD4 cells
      consistently increased only after 1 year. The magnitude of immune recovery was
      stronger in patients showing a significant reduction in viral load. However seven
      out of 21 patients who did not reach a sustained suppression of viral load showed
      also an increase in T-cell subsets. The majority of patients recovered
      lymphoproliferative responses to mitogens, whereas only four subjects showed a
      functional response to Candida mannoprotein. No patients showed a response to HIV
      recombinant glycoprotein 160 or tetanus toxoid. CONCLUSIONS: The immune recovery
      observed is slower and not complete in severely immunocompromised patients. Our
      data suggest that HAART may be continued also in the absence of a significant HIV
      RNA decrease if alternative drugs are not available.

PMID- 10416520
TI  - HIV infection perturbs DNA content of lymphoid cells: partial correction after
      'suppression' of virus replication.
AB  - OBJECTIVE: To examine the DNA content of circulating lymphocytes obtained from
      HIV-1-infected persons and to explore the effects of antiretroviral therapy on
      these indices. DESIGN: Cross-sectional analysis and 48-week open label treatment
      trial (AIDS Clinical Trials Group Protocol 315) of zidovudine, lamivudine and
      ritonavir. METHODS: Peripheral blood lymphocytes were obtained from HIV-1
      infected patients and healthy controls and after 48 h of in vitro cultivation
      were stained with propidium iodide and analyzed for DNA content by flow
      cytometry. RESULTS: HIV-1-infected patients had more hypodiploid cells (19%),
      fewer G0-G1 phase cells (70%) and more S phase cells (10%) than did healthy
      controls (8%, 85% and 5% respectively; P = 0.002). Patients with sustained
      suppression of plasma HIV-1 RNA levels after antiretroviral therapy had only
      modest improvements in these indices. In contrast, patients who failed to
      suppress plasma HIV-1 RNA levels had decreases in G0-G1 cells to 54% (P = 0.032)
      and increases in S phase cells to 24% (P = 0.055). Plasma HIV-1 RNA levels and
      the percentage of S phase cells were correlated (r, 0.23; P = 0.047). In patients
      failing antiretroviral therapy, there was an inverse correlation between the
      percentage of G0-G1 cells and expression of the activation antigens CD38 and HLA
      DR on CD4 cells (r, -0.409; P = 0.016) and CD8 cells (r, -0.363; P = 0.035).
      CONCLUSIONS: Lymphocytes obtained from HIV-1-infected patients display
      perturbations in DNA content after brief cultivation in vitro reflective of
      immune activation in vivo. The marginal improvement in these indices after
      'successful' suppression of HIV-1 replication suggests that even low levels of
      HIV-1 replication are sufficient to induce immune activation and perturbations in
      DNA content.

PMID- 10416522
TI  - Short-term growth hormone administration at the time of opportunistic infections
      in HIV-positive patients.
AB  - OBJECTIVES: A 12-week course of recombinant human growth hormone is an effective
      but expensive therapy for established HIV-related wasting. Wasting in HIV disease
      is often episodic, coinciding with bouts of acute opportunistic infection. We
      hypothesized that a short course of growth hormone, targeted at the time of
      opportunistic infection, might improve protein metabolism thereby reducing lean
      tissue loss. METHODS: HIV-infected men with acute opportunistic infections, who
      received standard antimicrobial treatment for their infection as well as
      intensive nutritional counselling and oral energy supplements, were randomized to
      receive growth hormone or placebo for 14 days. Principal assessments were protein
      metabolism (measured by 13C-leucine infusion), body composition (measured by
      DEXA) and safety. RESULTS: There were no significant changes in outcome
      parameters in the placebo group (n = 11). In the growth hormone group (n = 9),
      protein catabolic rate decreased by 60% in the fasted state (P = 0.02 versus
      placebo), lean body mass increased by 2.2 kg (P = 0.03 versus baseline) and fat
      mass decreased by 0.7 kg (P = 0.002 versus baseline). There was no increase in
      adverse or serious adverse events in the growth hormone as compared with the
      placebo group. CONCLUSIONS: A two-week course of growth hormone at the time of
      acute opportunistic infection in HIV-infected patients improves protein
      metabolism and body composition during therapy and appears to be safe. This may
      represent a rational and economical approach to the use of growth hormone
      therapy.

PMID- 10416523
TI  - Loss of cytomegalovirus (CMV) viraemia following highly active antiretroviral
      therapy in the absence of specific anti-CMV therapy.
AB  - OBJECTIVE: To determine the effect of highly active antiretroviral therapy
      (HAART) on cytomegalovirus (CMV) viraemia and retinitis in patients at high risk
      of disease. DESIGN: Sixteen patients with CMV viraemia, but no evidence of end
      organ disease at the time of first receipt of HAART including a protease
      inhibitor, were studied. No patient had ever received specific anti-CMV therapy.
      METHODS: CMV load in blood was measured using quantitative competitive PCR at
      baseline and for a median follow-up of 21 months. Regular ophthalmological
      screening for retinitis was conducted throughout the study period. RESULTS: All
      16 patients became CMV negative by PCR following the commencement of HAART. CMV
      loads prior to treatment ranged from 2.0 x 10(3) to 4.1 x 10(6) copies/ml
      (median, 7.6 x 10(4) copies/ml). The median time to becoming PCR negative was
      13.5 weeks (range, 5-40 weeks). Fourteen patients remained CMV negative
      throughout follow-up. CMV viraemia recurred in two patients; these individuals
      were indistinguishable with respect to either baseline parameters or response to
      antiretroviral therapy. None of the 16 patients developed CMV retinitis.
      CONCLUSIONS: HAART including a protease inhibitor can result in the complete
      suppression of CMV viraemia, an effect not previously observed in HIV-infected
      patients in the absence of specific anti-CMV therapy. This response correlated
      with protection against CMV retinitis in a group of patients at high risk of
      development of disease. These results help to explain why the natural history of
      CMV disease has altered since the introduction of such therapeutic regimens.

PMID- 10416524
TI  - Efficacy of salvage therapy containing ritonavir and saquinavir after failure of
      single protease inhibitor-containing regimens.
AB  - OBJECTIVE: To assess the efficacy of salvage therapy containing ritonavir and
      saquinavir after failure of indinavir- or nelfinavir-containing regimens, and to
      determine correlates of success or failure. DESIGN: Retrospective chart review.
      SETTING. The Moore Clinic - the HIV clinic of Johns Hopkins Hospital. PATIENTS:
      Forty-one HIV-infected patients were identified through physician contacts,
      referrals from other providers, and review of a comprehensive clinical database.
      MAIN OUTCOME MEASURES: To determine response to salvage therapy, HIV-1 viral RNA
      (absolute and log10-transformed) was measured using the Roche Amplicor
      quantitative HIV-1 RNA assay after initiation of the salvage regimen. Potential
      correlates of response included: viral RNA at the time of switch; viral RNA at
      the time of switch as a percentage of baseline viral RNA; magnitude of decline in
      viral RNA; and the interval between virologic failure of single protease
      inhibitor therapy and switch to the salvage regimen. RESULTS: Thirteen (56.5%) of
      23 patients failing indinavir responded to salvage therapy (HIV RNA < 400
      copies/ml) with persistence throughout the follow-up period (median of 37 weeks;
      range 18-67 weeks). Mean absolute viral RNA at the time of switch was 20 238
      copies/ml (median, 9281) compared with 42 953 copies/ml (median, 24 650) for the
      10 non-responders. Mean log10 viral RNA at switch was 3.804 for responders versus
      4.405 for non-responders (P = 0.040). Among four responders who had failed
      nelfinavir, mean viral RNA was 9634 copies/ml and mean log10 viral RNA was 3.749
      at the time of switch. Two non-responders had a mean viral RNA of 21 551 and a
      mean log10 viral RNA of 4.037 at switch. CONCLUSIONS: In contrast with previous
      reports, salvage regimens containing ritonavir and/or saquinavir can be effective
      and durable following the failure of combination regimens containing either
      indinavir or nelfinavir. Salvage therapy may be more likely to succeed when it is
      initiated early in failure at low viral loads.

PMID- 10416525
TI  - Long-term evaluation of triple nucleoside therapy administered from primary HIV-1
      infection.
AB  - OBJECTIVE: To study the long-term effect of triple-drug therapy initiated at the
      time of primary HIV-1 Infection and to evaluate the persistance of replication
      competent virus in responding patients. METHODS: Prospective open-label pilot
      study. Patients received a combination of zidovudine, didanosine and lamivudine.
      Viral sequencing of the reverse transcriptase gene was performed before therapy
      and during follow-up. HIV-1 RNA and DNA as well as CD4 and CD8 T lymphocyte
      subsets were measured in blood and in lymph node biopsies during therapy.
      Isolated blood CD4 T cells were cultured in conditions that improved HIV
      isolation. Three patients received in vivo interleukin-2 and gamma-interferon in
      order to try to identify intracellular pools of replication-competent virus.
      SETTING: A tertiary care general hospital. PATIENTS: Fifteen patients observed
      within 28 days following the acute retroviral syndrome. RESULTS: After a mean
      follow-up of 27.5+/-2.9 months, plasma RNA remained < 20 copies/ml (four
      patients), fluctuated between 20 and 120 copies/ml (six patients) or rebounded
      (five patients). M184V and/or T215Y mutations were demonstrated in two of these
      last five patients. Proviral DNA in peripheral blood mononuclear cells (PBMC)
      decreased by an average of -1 log after 16+/-3 months, reaching undetectable
      levels in three patients. The culture of isolated CD4 T cells yielded virus in
      all but two patients. These last were characterized by a waning antibody
      reactivity on the Western blot, undetectable proviral DNA in PBMC and
      undetectable RNA in lymph nodes. Cytokine administration in vivo had no effect in
      one patient and unmasked plasma RNA in the other. Stopping therapy in the first
      patient led to a rebound in plasma RNA. CONCLUSION: Despite a lack of detectable
      plasma viral activity in some patients after 3 years of triple nucleoside therapy
      administered since the acute retroviral syndrome, replication-competent virus can
      still be demonstrated.

PMID- 10416526
TI  - The influence of nutritional and metabolic status on progression from
      asymptomatic HIV infection to AIDS-defining diagnosis.
AB  - BACKGROUND: Changes in body weight and lean tissue increase morbidity and
      mortality during AIDS; however there are few data on the effect of alterations in
      nutrition and metabolism on disease progression at earlier stages of HIV
      infection. OBJECTIVES: To assess whether change in weight, lean tissue or
      skeletal muscle affects progression to AIDS; to assess prospectively the effects
      of recognized alterations in nutrition and metabolism in asymptomatic HIV
      seropositive men on disease progression; and to examine prospectively changes in
      nutrition and metabolism at AIDS-defining diagnosis. METHODS: A group of 104
      asymptomatic HIV-seropositive men were recruited and prospectively examined at 3
      monthly intervals between April 1993 and September 1995. Nutritional status and
      metabolism were examined using indirect calorimetry, dual energy X-ray
      absorptiometry and urine excretion of simple sugars. Time-fixed and time
      dependent Cox's proportional hazard models were fitted to calculate risks of
      developing a first AIDS diagnosis, weight loss or death. RESULTS: During the
      study period, 31 subjects had a first AIDS diagnosis of whom 26 were fully
      assessed. Changes in nutrition and metabolism do not affect disease progression
      in asymptomatic HIV infection. However, subjects with a reduction in body weight
      and basal metabolic index tend to have a higher risk of progression to AIDS
      defining diagnosis, independent of CD4 count. There is a significant decrease in
      all body tissue compartments, a decrease in excretion of urinary sugars and
      significant increase in resting energy expenditure and fat oxidation associated
      with a first AIDS diagnosis. CONCLUSION: Change in metabolic and nutritional
      status at the asymptomatic stage of HIV infection does not influence disease
      progression significantly, although there is a trend suggesting weight loss has
      an independent effect on outcome. There is a cachectic response to AIDS-defining
      opportunistic infection or tumour.

PMID- 10416527
TI  - Indinavir-based treatment of HIV-1 infected patients: efficacy in the central
      nervous system.
AB  - OBJECTIVE: To study the pharmacokinetic properties and clinical efficacy of the
      HIV-1 protease inhibitor (PI) indinavir in the central nervous system (CNS).
      DESIGN: Twenty-five consecutive HIV-1 infected patients on combination therapy
      that included indinavir, had cerebrospinal fluid (CSF) and plasma samples taken
      on 32 different occasions, at different times after indinavir administration. CSF
      and viral load data obtained from these treated patients were compared with those
      from 36 untreated HIV-1 infected patients of similar immunological and
      demographic pre-treatment status. METHODS: Concentrations of indinavir were
      measured in CSF and plasma by high-pressure liquid chromatography with
      ultraviolet light detection and the data were used in pharmacokinetic modelling.
      RESULTS: The concentration of indinavir in plasma varied with time over a dose
      interval by about two orders of magnitude, whereas the concentration in CSF was
      relatively stable. The median concentration of indinavir in CSF was 210 nmol/l,
      which is above the 95% inhibitory concentration in vitro. Findings from the
      pharmacokinetic modelling indicate that indinavir is actively transported out of
      the CSF (P <0.001 compared with a passive transport-only model). In the PI
      treated group there was a reduction in viral load to below 50 copies/ml in most
      subjects and a normalization of the CSF cell content and IgG-index. CONCLUSIONS:
      This study has shown that one PI, indinavir, is present in the CSF at therapeutic
      concentrations, and is likely to contribute to the antiretroviral activities
      observed within the CNS.

PMID- 10416528
TI  - Spread of HIV infection in a rural area of Tanzania.
AB  - OBJECTIVE: To assess the spread of HIV into rural areas. METHODS: Since 1994 a
      demographic surveillance system (with 5-monthly rounds) and open adult cohort
      study have been established in a rural ward in Tanzania. Two sero-surveys of all
      resident adults aged 15-44 and 15-46 years were conducted in 1994 1995 and 1996
      1997 respectively. Qualitative data were collected on mobility, bars and
      commercial sex. RESULTS: Attendance of the two rounds of survey was 5820 (78%)
      and 6413 (80%) in 1994/1995 and 1996/1997 respectively. HIV prevalence increased
      from 5.8% to 6.6%. HIV incidence was 0.73 and 0.84 per 100 person years among men
      and women respectively. HIV incidence under the age of 20 years was low among
      both sexes. Striking differences in HIV prevalence and incidence were observed
      within the small geographic area studied: HIV prevalence in the trading center
      was twice that in the area surrounding the trading center (within 2 km) and three
      to four times that in the rural villages (within 8 km of the trading center).
      Aggregate level data showed significant differences between the trading center
      and nearby rural villages in terms of sexual behavior, commercial sex workers,
      mobility of the population, and alcohol use. CONCLUSION: This study documents the
      existence of very substantial HIV prevalence and incidence differences within a
      small geographic rural area. The rapid decrease in HIV prevalence within a small
      rural area emphasizes the importance of concentrating HIV prevention efforts on
      high transmission areas, such as trading centers, especially in resource-poor
      settings. Furthermore, this has considerable implications for monitoring the
      spread of HIV through sentinel sites, as such sites are typically located in high
      transmission areas.

PMID- 10416529
TI  - How soon after HIV seroconversion is antiretroviral therapy initiated? The UK
      Register of HIV Seroconverters Steering Committee.
AB  - OBJECTIVE: To estimate the time from HIV seroconversion to initiating
      antiretroviral therapy (ART) and whether this has changed over calendar time, and
      to estimate the CD4 cell count at which ART is initiated. DESIGN: Data from a
      cohort of HIV seroconverters in the UK were analysed with the initiation of ART
      as the outcome variable. METHOD: The association of the time from seroconversion
      to initiating ART with age, sex, exposure category, calendar time, CD4 cell count
      and acute infection at diagnosis was examined using Kaplan-Meier plots and Cox
      proportional hazards models. The CD4 level at which therapy was initiated was
      examined. Results Of 1308 seroconverters, 710 (54%) had started ART by 30
      September 1998. Median interval from seroconversion to initiating ART was
      estimated to be 59.5 months [95% confidence interval (CI), 54.7-63.6]. Compared
      with 1989-1994 (after adjusting for CD4 cell count), time to initiation of ART
      was significantly shorter in 1997-1998 with relative rates of initiating ART of
      1.02 (95% CI, 0.67-1.55), 1.07 (95% CI, 0.88-1.31) and 3.16 (95% CI, 2.56-3.90)
      pre-1989, 1995-1996, and 1997-1998, respectively. Median CD4 cell count at
      initiation of treatment was 73 (95% CI, 30-109), 136 (95% CI, 118-161), 110 (95%
      CI, 84-140) and 221 (95% CI, 200-250) x 10(6) cells/I for the periods pre-1989,
      1989-1994, 1995-1996 and 1997-1998, respectively. Of persons seroconverting in
      1997-1998, 19.5% initiated ART within 6 months of seroconversion compared with
      8.4% and 2.0% in 1995-1996 and 1989-1994, respectively. CONCLUSIONS: ART is being
      initiated closer to HIV seroconversion than in previous years. Whether the
      improvements in survival reported from recent observational studies result solely
      from increased efficacy of the regimens or also from the timing of their
      initiation is difficult to determine. No clinical trial has yet addressed the
      optimum timing of initiating ART in the era of potent therapies.

PMID- 10416530
TI  - Changes to AIDS dementia complex in the era of highly active antiretroviral
      therapy.
AB  - OBJECTIVES: To determine the protective efficacy of highly active antiretroviral
      therapy (HAART) against AIDS dementia complex (ADC) relative to other initial
      AIDS-defining illnesses (ADIs), Australian AIDS notification data over recent
      years were examined. METHODS: All initial ADIs in Australia over the period 1992
      1997 were included. Three initial ADI groups were established: ADC; other
      predominantly central nervous system (CNS) ADIs (toxoplasmosis and
      cryptococcosis); and non-CNS ADIs. For each ADI grouping, the proportion of total
      ADls, and median CD4 cell count in the pre-HAART era (1992-1995) were compared
      with the HAART era (1996 and 1997). RESULTS: Initial ADls peaked in Australia in
      1994 (n = 1049), with a gradual decline to 1996 (n = 722), and a marked decline
      in 1997 (n = 367). ADC constituted 4.4% of initial ADIs over the period 1992
      1995, but increased after the introduction of HAART to 6.0% in 1996 and 6.5% in
      1997 (P = 0.02). In contrast, the proportion of other CNS ADIs (1992-1995, 8.1%;
      1996, 6.0%; 1997, 8.2%; P = 0.41) was stable over the period 1992-1997. The
      median CD4 cell count at ADC diagnosis increased from 70/mm3 in 1992-1995 to
      120/mm3 in 1996 and 170/mm3 in 1997 (P = 0.04). Although the median CD4 cell
      count also increased significantly over this period for both other CNS ADIs (40
      60/mm3; P = 0.02), and non-CNS ADIs (60-70/mm3; P = 0.02), the increase was
      small. CONCLUSION: A proportional increase in ADC compared with other ADIs and a
      marked increase in the median CD4 cell count at ADC diagnosis have occurred since
      the introduction of HAART in Australia. These changes suggest that HAART has a
      lesser impact on ADC than on other ADIs, with the poor CNS penetration of many
      antiretroviral agents a possible explanation.

PMID- 10416532
TI  - Sexual behaviours, perception of risk of HIV infection, and factors associated
      with attending HIV post-test counselling in Ethiopia.
AB  - OBJECTIVES: To describe sexual behaviours, perception of risk of HIV infection,
      and factors associated with attending HIV post-test counselling (PTC) among
      Ethiopian adults. METHODS: Data on socio-demographic characteristics, knowledge
      of HIV infection, sexual history, medical examination, and HIV and syphilis
      serological status were compared, through uni- and multivariate analysis, in
      relation to attending PTC within 60 days of HIV testing. RESULTS: Between
      February 1997 and June 1998, 751 factory workers were enrolled in a cohort study
      of HIV infection progression. Despite reporting high-risk sexual behaviours,
      mainly for males (64% of males and 6% of females had more than five sexual
      partners in their lifetime, 16% of males and 2% of females reported having had
      recent casual partners), and knowing that HIV is commonly transmitted
      heterosexually in Ethiopia (97% of answers being correct, both genders combined),
      only 17% of males and 2% of females acknowledged having had activities which had
      put them at risk of HIV infection. HIV prevalence was 12%, and did not differ by
      gender. Of all study participants, 327 (43.5%) returned for PTC within 60 days of
      HIV testing. PTC attendance did not differ by age, gender, or HIV serological
      status. Factors independently associated with PTC attendance in males were: good
      knowledge of HIV infection, [odds ratio (OR) = 1.661, belief that medical follow
      up improves the course of HIV infection (OR = 2.02), history of genital symptoms
      (OR = 2.83), positive syphilis serology (OR = 2.62), recent weight loss (OR =
      1.89), and, with a negative association, being a manual worker (OR = 0.40), and
      history of recent casual sexual relationships (OR = 0.35). In women, belief that
      HIV/AIDS can be cured (OR = 3.16), never having been married (OR = 5.02), having
      five or less children (OR = 2.16), having been raped (OR = 3.42), and having used
      health facilities in the past year (OR = 1.73) were all positively and
      independently associated with PTC attendance. CONCLUSION: Study participants
      reported high-risk sexual behaviours, yet had a low perception of individual
      risk. Men attended for PTC because of their knowledge of HIV infection, their
      past sexual history or their current health status. Women attended for PTC
      because of their plans for the future, marriage and/or children, rather than
      their past sexual exposure. Only in cases of rape were they willing to learn of
      their HIV status.

PMID- 10416531
TI  - The changing pattern of admissions to a London hospital of patients with HIV:
      1988-1997. Royal Free Centre for HIV Medicine.
AB  - OBJECTIVE: To describe the changes over time in incidence of hospital admissions
      among patients with HIV, reasons for hospital admission, duration of stay,
      relationship with CD4 T-cell count and with antiretroviral treatment. METHODS:
      The incidence of hospital admissions during each calendar year from 1988 to 1997
      inclusive was calculated using a person-years analysis. In addition the
      proportion of patient follow-up spent in hospital and the impact of changing
      treatment regimens among all patients with HIV aged > or = 14 years and with at
      least one CD4 T-cell count seen at the Royal Free Hospital, London was also
      described. RESULTS: A total of 1806 patients were investigated with median follow
      up of 21.1 months. Among all patients, the proportion of follow-up time spent as
      an in-patient decreased from 3.9% in 1988 to 1.3% in 1997 (P = 0.0015; test for
      trend). Hospital admissions for any cause peaked during 1989 at 72.0 per 100
      patient years of follow-up (PYFU) and was 28.5 per 100 PYFU during 1997 (P <
      0.0001; test for trend). There was a statistically significant decline in the
      proportion of follow-up time spent as an in-patient among patients with CD4 T
      cell counts of < 50 x 10(6)/l from > 30% before 1990 to < 5% during 1997 (P =
      0.026; test for trend). Hospital admissions varied greatly according to treatment
      regimen; in 1996 and 1997 just 0.1% of follow-up time of patients on triple
      antiretroviral treatment regimens was spent as a hospital admission. CONCLUSIONS:
      Admissions to hospital began falling before the introduction of combination
      therapy and declined strikingly during 1996 and 1997 following the introduction
      of highly active antiretroviral therapy. These results have important
      implications for future allocation of resources and for patient management.

PMID- 10416533
TI  - Lactoferrin inhibits HIV-1 replication in vitro and exhibits synergy when
      combined with zidovudine.

PMID- 10416534
TI  - HIV-associated non-mycobacterial sepsis-bacteraemia, before and during the highly
      active antiretroviral therapy era.

PMID- 10416535
TI  - Identification of reverse transcriptase mutations associated with HIV-1 drug
      resistance mainly against non-nucleoside reverse transcriptase inhibitors in
      treatment-naive patients.

PMID- 10416537
TI  - Highly active antiretroviral therapy among drug users in Amsterdam: self
      perceived reasons for not receiving therapy.

PMID- 10416536
TI  - Clinical benefits of resistance assay for HIV-specific protease inhibitors: when
      to check and in whom?

PMID- 10416538
TI  - Cerebrospinal fluid and plasma HIV-1 RNA stability at 4 degrees C.

PMID- 10416539
TI  - Antiphospholipid antibodies are an epiphenomenon in HIV-infected patients.

PMID- 10416540
TI  - Immune activation and plasma viral load in HIV-infected African individuals.

PMID- 10416541
TI  - Ankle injuries: same joint, different sports.
AB  - Specific information on the incidence of ankle injury is not easy to establish,
      and studies use variable methodology and recording systems. There are problems in
      recording injury in many sports injury studies (23) as we often cannot calculate
      the relative risks without denominator data. Although we can estimate that ankle
      injuries make up about 10-15% of sports-related injury and that soccer and rugby
      are responsible for most sports-related injury in the United Kingdom, it is
      difficult to be more specific. Prevention and treatment strategies are also
      different, and taping and strapping is not widely practiced. Soccer has a
      particular injury pattern with some injuries particularly associated with the
      sport.

PMID- 10416542
TI  - Imaging of the foot and ankle in the injured athlete.
AB  - Currently the availability of magnetic resonance imaging has replaced much of the
      arthrotomography and CT scanning. The increased soft tissue contrast provided by
      MRI allows its use in assessing tendinous, ligamentous, cartilaginous, and in
      particular subtle bone marrow changes, which before its inception were never
      directly imaged. This article covers some of these dramatic changes and will
      provide the sports medicine clinician an update on current imaging techniques
      available to them with regard to foot and ankle injuries. Imaging of the foot and
      ankle has undergone a dramatic change over the last decade. The sports medicine
      clinician's understanding of these changes as well as the new imaging modalities
      available to them are of paramount importance in treating today's athlete.
      Modalities available in the 1970s and 1980s were usually limited to plain
      radiographs to be followed by bone scanning, arthrotomography, or CT scanning.

PMID- 10416543
TI  - Shoe inserts and orthotics for sport and physical activities.
AB  - The purposes of this paper were to discuss the perceived benefits of inserts and
      orthotics for sport activities and to propose a new concept for inserts and
      orthotics. There is evidence that inserts or orthotics reduce or prevent movement
      related injuries. However, there is limited knowledge about the specific
      functioning an orthotic or insert provides. The same orthotic or insert is often
      proposed for different problems. Changes in skeletal movement due to inserts or
      orthotics seem to be small and not systematic. Based on the results of a study
      using bone pins, one may question the idea that a major function of orthotics or
      inserts consists in aligning the skeleton. Impact cushioning with shoe inserts or
      orthotics is typically below 10%. Such small reductions might not be important
      for injury reduction. It has been suggested that changes in material properties
      might produce adjustments in the muscular response of the locomotor system. The
      foot has various sensors to detect input signals with subject specific
      thresholds. Subjects with similar sensitivity threshold levels seem to respond in
      their movement pattern in a similar way. Comfort is an important variable. From a
      biomechanical point of view, comfort may be related to fit, additional
      stabilizing muscle work, fatigue, and damping of soft tissue vibrations. Based on
      the presented evidence, the concept of minimizing muscle work is proposed when
      using orthotics or inserts. A force signal acts as an input variable on the shoe.
      The shoe sole acts as a first filter, the insert or orthotic as a second filter,
      the plantar surface of the foot as a third filter for the force input signal. The
      filtered information is transferred to the central nervous system that provides a
      subject specific dynamic response. The subject performs the movement for the task
      at hand. For a given movement task, the skeleton has a preferred path. If an
      intervention supports/counteracts the preferred movement path, muscle activity
      can/must be reduced/increased. Based on this concept, an optimal insert or
      orthotic would reduce muscle activity, feel comfortable, and should increase
      performance.

PMID- 10416544
TI  - Lateral ankle sprains: a comprehensive review: part 1: etiology, pathoanatomy,
      histopathogenesis, and diagnosis.
AB  - Ankle sprains are among the most common injuries sustained by athletes and seen
      by sports medicine physicians. Despite their prevalence in society, ankle sprains
      still remain a difficult diagnostic and therapeutic challenge in the athlete, as
      well as in society in general. The purpose of this section of our two-part study
      is to review scope of the problem, the anatomy and biomechanics of the lateral
      ankle ligaments, review the pathoanatomical correlates of lateral ankle sprains,
      the histopathogenesis of ligament healing, and define the mechanisms of injury to
      understand the basis of our diagnostic approach to the patient with this common
      acute and chronic injury. We extensively review the diagnostic evaluation
      including historical information and physical examination, as well as options for
      supplementary radiographic examination. We further discuss the differential
      diagnosis of the patient with recurrent instability symptoms. This will also
      serve as the foundation for part two of our study, which is to understand the
      rationale for our treatment approach for this common problem.

PMID- 10416545
TI  - Lateral ankle sprains: a comprehensive review part 2: treatment and
      rehabilitation with an emphasis on the athlete.
AB  - This is the second part of a two-part comprehensive review of lateral ankle
      sprains. In the first part of our review, we discussed the etiology, natural
      history, pathoanatomy, mechanism of injury, histopathogenesis of healing, and
      diagnostic approach to acute and chronic lateral ligamentous ankle injuries.
      Conservative intervention and treatment of grade I-III and chronic, recurrent
      sprains of the lateral ankle ligaments and appropriate rehabilitation guidelines
      are the topics of this article. We review the use and benefit of different
      modalities and external supports and outline our five-phase intervention program
      of rehabilitation based on the histopathogenesis of ligament healing. We discuss
      the expected timing of recovery of the acute injury as well as the management of
      chronic, recurrent ankle sprains. Treatment of acute ankle sprains depends on the
      severity of the injury. Conservative therapy has been found to be uniformly
      effective in treating grade I and II ankle sprains. Some controversy exists
      regarding the appropriate treatment of grade III injuries, particularly in high
      level athletes. Our belief is that the majority of these patients may also be
      treated well with conservative management. Other options for the management of
      grade III sprains will be briefly discussed at the end of this article.

PMID- 10416546
TI  - Forefoot problems in athletes.
AB  - Athletes who participate in high-impact sports involving running, jumping, or
      contact are at risk for forefoot injury. These injuries occur as a result of
      acute trauma or chronic overuse. Some athletes may be predisposed to injury
      because of preexisting foot deformity, such as cavus, hallux valgus, or Achilles
      contracture. This article reviews the common causes of forefoot pain in the
      athlete. The most common causes of forefoot pain in the athlete are metatarsal
      stress fracture, interdigital neuroma, sesamoid pathology, metatarsalgia, hallux
      rigidus, hallux valgus, and turf toe. The pathophysiology, clinical presentation,
      and treatment of these conditions are discussed.

PMID- 10416547
TI  - Biomechanics of the unstable ankle joint and clinical implications.
AB  - PURPOSE: The aim of this paper is to provide fundamental information about the
      biomechanics of the unstable ankle joint and to establish a rational for the
      daily clinic when dealing with patients in both, the acute and chronic unstable
      condition of the ankle joint complex. METHODS: The problem of the unstable ankle
      joint is worked up by analyses of the basic anatomy and biomechanics followed by
      an overview of its clinical manifestation including a differential diagnosis.
      RESULTS: The ankle joint and its surrounding ligaments represent a complex
      mechanical structure whose mechanical properties highly depend on ligament
      integrity. Recent in vitro studies have supported the hypothesis that, besides
      maintaining lateral ankle stability, the lateral ankle ligaments play a
      significant role in maintaining rotational ankle stability and in transferring
      movement between leg and foot. Instability of the ankle results from acute
      ligament injuries and may become chronic when complete ligament healing does not
      occur. Chronic instability syndrome may manifest with recurrent injuries with
      chronic lateral pain, tenderness, swelling, or induration with great difficulties
      in sports and daily activities. Symptomatic instability can be caused by
      mechanical instability with demonstrable instability, but it can be also present
      with no demonstrable instability. Impairment of ankle proprioception has been
      shown to be a major cause of symptomatic ankle instability. Other conditions may
      mimic ankle instability. CONCLUSIONS: The cause of chronic functional instability
      is often not mechanical instability but impairment of ankle proprioception. A
      history of insecurity, instability, and giving way is far more important in
      diagnosis than the physical and radiographic examination. If surgical treatment
      is advised, anatomical reconstruction of the ankle ligaments is mandatory for
      fear of altering the biomechanics.

PMID- 10416548
TI  - Foot and ankle problems in the young athlete.
AB  - In the U.S., greater than half of boys and one quarter of girls in the 8- to 16
      yr-old age range are engaged in some type of competitive, scholastic, organized
      sport during the school year. Children and adolescents are becoming more involved
      in sports at earlier ages and with higher levels of intensity. Foot and ankle
      problems, in particular, are the second most common musculoskeletal problem
      facing primary care physicians in children under 10 yr of age next to acute
      injury. This report focuses on foot and ankle problems, trauma, and overuse in
      the young athletic population. Guidelines are given for both conservative and
      surgical management. Specific problems addressed include pes planus, tarsal
      coalition, adolescent bunion, os trigonum, accessory navicular, physeal
      fractures, sprains, peroneal tendon subluxation, metatarsal fractures, sesamoid
      fractures, turf toe, stress fractures, tendonitis, osteochondritis dissecans,
      ankle impingement, bursitis, Haglund's deformity, sesamoiditis, plantar
      fasciitis, apophysitis, osteochondroses, cuboid syndrome, and reflex sympathetic
      dystrophy. An extensive review of the literature is performed and presented in
      combination with the extensive experience of a well-established sports medicine
      clinic at the Boston Children's Hospital.

PMID- 10416549
TI  - Peroneal tendon subluxation in athletes: new exam technique, case reports, and
      review.
AB  - Traumatic peroneal tendon subluxation is an uncommon cause of ankle pain. As a
      result, the diagnosis is often delayed. A new technique of examining the patient
      in the prone position, allowing for easier visualization of the subluxation or
      dislocation, is described. Three illustrative cases, including a rare case of
      midsubstance rupture of the peroneal retinaculum are presented along with a
      review the literature. An acute repair in athletes and in those patients who do
      not want to risk the chance of a 40-50% failure rate after 4-6 wk of casting is
      currently recommended. Surgical repair can be facilitated using Mitek suture
      anchors for acute, symptomatic chronic, and subacute injuries. Deepening of the
      groove is performed only in those patients that have no sulcus or a convexity of
      the groove.

PMID- 10416550
TI  - Os trigonum syndrome with flexor hallucis longus tenosynovitis in a professional
      football referee.
AB  - The presentation of posterior ankle pain in any patient poses a diagnostic
      dilemma. The os trigonum syndrome and flexor hallucis longus stenosing
      tenosynovitis have been reported to occur in professional and amateur ballet
      dancers. It is important to consider these diagnoses in a patient who is not a
      dancer, as is shown in the case presented here. The patient in this case is a
      professional referee who injured his ankle while working on artificial turf. The
      treatment for os trigonum syndrome and flexor hallucis longus tenosynovitis is
      initially conservative, but in refractory cases, surgical removal of the os and
      release of the flexor hallucis longus tendon can be successfully performed. This
      is the first reported case of os trigonum syndrome and flexor hallucis longus
      tenosynovitis presenting simultaneously in a patient who is not a dancer.

PMID- 10416551
TI  - Stress fracture of the proximal fibula in a young soccer player: a case report
      and a review of the literature.
AB  - A 14-yr-old soccer player complained of a history of leg pain with activity that
      had been present for several weeks. There was no history of direct trauma.
      Tenderness was found over the lateral aspect of the leg, and radiographs showed
      an area of calcification along the shaft of the proximal fibula. Because of the
      unusual location of the findings and to exclude a tumor, magnetic resonance
      imaging (MRI) was obtained which confirmed the diagnosis of a proximal fibular
      stress fracture. The patient returned to full sport participation with a period
      of relative rest, splinting, and strengthening and flexibility training. This
      case describes an injury that has not been reported in young athletes and only
      rarely described in active adults. The literature regarding this injury is
      reviewed, and two injury patterns of proximal fibular stress fractures are
      described.

PMID- 10416553
TI  - Head and face injuries in scholastic women's lacrosse with and without eyewear.
AB  - PURPOSE: The use of protective equipment has been absent or inconsistent in
      scholastic women's lacrosse leading to increasing concern for eye and head
      injury. There is a paucity of field data, however, on which to base strategic
      decisions on how best to prevent head injuries in young athletes. METHODS: This
      study examined the effects of protective eyewear on injury rates in scholastic
      women's lacrosse in a cohort of approximately 700 varsity and junior varsity
      players in central New York studied prospectively for 2 yr during a transition
      from sparse to almost complete eyewear use. RESULTS: The overall head/face injury
      rate was 0.71 injuries per 1000 exposures (games and practices) and was 16.5%
      lower in goggle wearers. In games alone, where more aggressive play and stick use
      prevails, the rate associated with protective eyewear use was markedly lower
      (51%). Considering specific regions, the rates for peri-orbit and forehead
      injuries among goggle users were substantially lower than for nonusers (6% and
      13%, respectively). Cheek and scalp injury rates tended to be higher among goggle
      wearers, but not statistically significantly so. Significant compensatory
      increases with goggle wear at other sites were not observed. Only a few injuries
      appeared to be mediated by the goggles themselves and potentially could have been
      more serious if the goggles had not been present. No direct eye (orbit) injuries
      were reported throughout the study period. CONCLUSION: On balance, then, the use
      of eyewear in women's lacrosse appears to be beneficial when users are compared
      with nonusers.

PMID- 10416552
TI  - Influence of high-intensity exercise training on the ventilatory response to
      exercise in patients with reduced ventricular function.
AB  - BACKGROUND: Exercise training increases exercise capacity in patients with
      reduced ventricular function in part through improved skeletal muscle metabolism,
      but the effect training might have on abnormal ventilatory and gas exchange
      responses to exercise has not been clearly defined. METHODS: Twenty-five male
      patients with reduced ventricular function after a myocardial infarction were
      randomized to either a 2-month high-intensity residential exercise training
      program or to a control group. Before and after the study period, upright
      exercise testing was performed with measurements of ventilatory gas exchange,
      lactate, arterial blood gases, cardiac output, and pulmonary artery and wedge
      pressures. RESULTS: In the exercise group, peak VO2 and VO2 at the lactate
      threshold increased 29 and 39%, respectively, whereas no increases were observed
      among controls. Maximal cardiac output increased only in the exercise group (1.7
      L x min(-1), P < 0.05), and no changes in rest or peak exercise pulmonary
      pressures were observed in either group. At baseline, modest inverse
      relationships were observed between pulmonary wedge pressure and peak VO2 both at
      rest (r = -0.56, P < 0.05) and peak exercise (r = -0.43, P < 0.05). Maximal
      VE/VCO2 was inversely related to maximal cardiac output (r = -0.72, P < 0.001).
      Training did not have a significant effect on these relationships. Training
      lowered VE/VO2, heart rate, and blood lactate levels at matched work rates
      throughout exercise and tended to lower maximal Vd/Vt. The slope of the
      relationship between VE and VCO2 was reduced after training in the exercise group
      (0.33 pre vs 0.27 post, P < 0.01), whereas control patients did not differ.
      CONCLUSIONS: Exercise training among patients with reduced left ventricular
      function results in a systematic improvement in the ventilatory response to
      exercise. Training increased maximal cardiac output, tended to lower Vd/Vt, and
      markedly improved the efficiency of ventilation. Peak VO2 and ventilatory
      responses to exercise were only modestly related to pulmonary vascular pressures,
      and training had no effect on the relationships between exercise capacity,
      ventilatory responses, and pulmonary pressures.

PMID- 10416554
TI  - Ventilatory responses to exercise in patients with asymptomatic left ventricular
      dysfunction.
AB  - PURPOSE: Based on reports that patients with severe left ventricular (LV)
      dysfunction have a greater ventilatory response to effort than healthy people, we
      evaluated the ventilatory responses to effort of patients with coronary artery
      disease and various degrees of LV impairment before and after 6 months of
      exercise training in a community-based cardiac rehabilitation program. METHODS:
      Out of 171 patients consecutively referred for cardiac rehabilitation, 102 were
      enrolled in the study. Fifteen patients were excluded because of lung disease and
      54 because of poor adherence to the exercise program. Patients were divided into
      three groups according to their ejection fraction (EF): Group 1 (G1) included 63
      patients with EF > or = 50%, Group 2 (G2) included 21 patients with EF > or = 35
      and < 50% and group 3 (G3) included 18 patients with EF < 35%. Peak oxygen
      uptake, minute ventilation (V(E)), and minute carbon dioxide production (VCO2)
      were measured before and after training in all participants. RESULTS: All groups
      showed a significant increase in peak oxygen uptake and treadmill time after
      training (G1: P = 0.0001 and P = 0.0001; G2: P = 0.0001 and P = 0.001; G3: P =
      0.01 and P = 0.01; respectively). Patients in G3 had a significantly higher
      V(E)/VCO2 ratio than patients in G2 and G1 at 9 min and peak exercise, before (9
      min: P = 0.046 and P = 0.025, peak: P = 0.024 and P = 0.002, respectively) and
      after training (9 min: P = 0.011 and P = 0.005, peak: P = 0.001 and P = 0.0001,
      respectively). The slope of the relation V(E) to VCO2 was significantly higher in
      G3 patients than in those in G2 and G1 (P = 0.0001, respectively) and was not
      reduced by exercise training in any group. CONCLUSIONS: Patients with severe LV
      dysfunction had a greater ventilatory response to exercise than those with
      moderately impaired or normal LV function. Exercise training increased the effort
      tolerance of all patients irrespective of their degree of LV dysfunction but
      failed to reduce the higher ventilatory responses to effort of patients with EF
      below 35%.

PMID- 10416557
TI  - Brain magnetic resonance imaging (MRI) and neurological changes after a single
      high altitude climb.
AB  - PURPOSE: Neurological impairment, mental dysfunction, and brain imaging changes
      caused by severe hypoxia have been described by several authors. However, the
      occurrence of transitory, long lasting, or permanent brain damage has been
      debated. Although climbing to 8000 m is reserved to a small number of climbers,
      there are hundreds of lowlanders spending relatively short holidays climbing
      peaks up to 6000 m in the Andes or in the Himalayas. They are usually not well
      acclimated and often suffer from acute mountain sickness (AMS). The aim of this
      study was to examine the effect of a single high altitude exposure on the changes
      in brain MRI and neuropsychological testing in climbers. METHODS: Brain MRI,
      medical history, and a battery of neuropsychological tests were obtained in eight
      male climbers between 31 and 48 yr of age a few days before and between 5 and 10
      d after returning to sea level following ascent to altitudes of over 6000 m
      without oxygen. RESULTS: The mean AMS symptom score recorded at 5500 m was three
      in all climbers, headache being the predominant symptom. CONCLUSION: We did not
      observe the changes in brain imaging and in neuropsychological testing observed
      by other authors. The residual central nervous system impairment following return
      from high altitude was not observed in our study, and the good results in
      neuropsychological testing were well correlated with the unchanged brain MRI
      imaging.

PMID- 10416556
TI  - Knee joint kinematics during the sidestep cutting maneuver: potential for injury
      in women.
AB  - PURPOSE: There is a paucity of data describing female lower limb biomechanics
      during "high risk" movements linked to noncontact ACL injury. This study
      compared, across gender, knee kinematics associated with sidestepping maneuvers
      to provide insight into why women display a significantly higher incidence of
      this injury than do men. METHODS: Thirty participants (16 men, 14 women) had
      bilateral knee joint kinematic data recorded while sidestepping. A custom
      software package (JTMOTION) quantified maximum, minimum, and range of motion
      during stance for each of the three clinical knee joint rotations
      (flexion/extension, adduction/abduction and external/internal rotation) over 20
      (leg x condition x trial (5)) trials. RESULTS: Gender differences possessed
      limited clinical significance with all maximum values well within safe ranges of
      knee motion. Women did, however, display increased intertrial variability for
      axial rotation patterns during cutting compared with men. This variability was
      thought to be unaffected by gender, with experience level found statistically (P
      < 0.01) to be the major determinant of knee kinematic variability during
      sidestepping. Hence, the level of exposure to sidestep cutting may have a large
      impact on the subsequent risk of ACL injury when when one performs these
      maneuvers. CONCLUSIONS: Gender differences in knee motions during cutting did not
      contribute to the increased risk of noncontact ACL injury in women compared with
      men. The reasons for this increased incidence, therefore, remain unclear. The
      potential relationship between gender and other parameters linked to ACL injury
      such as joint geometry, ligament morphology, and physical conditioning requires
      further investigation.

PMID- 10416555
TI  - Effects of short-term strenuous endurance exercise upon corpus luteum function.
AB  - PURPOSE: The present study tested whether short-term, abruptly initiated training
      can cause corpus luteum dysfunction when exercise is limited to either the
      follicular or luteal phase of the cycle. METHODS: Reproductive hormone excretion
      and menstrual characteristics were studied in sedentary women who exercised only
      during the follicular (N = 5) or the luteal (N = 4) phase. Six women served as
      controls, three of whom exercised at a low volume and three who remained
      sedentary. Weekly progressive increments in exercise volume continued until
      either ovulation (follicular group) or menses (luteal group) occurred. Physical
      activity and nutrient intake were closely monitored with the intent to maintain
      body weight. RESULTS: No luteal phase disturbances occurred in any of the control
      subjects, whereas 40% of follicular and 50% of luteal exercisers experienced
      luteal defects. The proportion of menstrual cycles disrupted was not different
      between luteal and follicular exercisers (50% vs 30%, respectively) but was
      significantly greater than the proportion of cycles disrupted in control subjects
      (P < 0.05). CONCLUSIONS: These results suggest that exposure to abrupt onset of
      training can alter luteal function, regardless of the menstrual cycle phase in
      which exercise occurs. This study also demonstrates that a relatively low volume
      of exercise suffices to induce mild disturbances in luteal function.

PMID- 10416558
TI  - Cardiopulmonary and CD4 cell changes in response to exercise training in early
      symptomatic HIV infection.
AB  - PURPOSE: The purposes of the present study were to assess the effects of a 12-wk
      laboratory based aerobic exercise program on cardiopulmonary function, CD4 cell
      count, and physician-assessed health status among symptomatic pre-AIDS HIV
      infected individuals (N = 28) and to assess the degree to which ill health was
      associated with exercise relapse. METHODS: Responses to graded exercise test,
      physician-assessed health status, and CD4 cell counts were determined at baseline
      and 12-wk follow-up for participants randomly assigned to exercise or control
      conditions, and reasons for exercise noncompliance were recorded. RESULTS:
      Approximately 61% of exercise-assigned participants complied (> 50% attendance)
      with the exercise program, and analyses of exercise relapse data indicated that
      obesity and smoking status, but not exercise-associated illness, differentiated
      compliant from noncompliant exercisers. Compliant exercisers significantly
      improved peak oxygen consumption (VO2peak; 12%), oxygen pulse (O2pulse; 13%),
      tidal volume (TV; 8%), ventilation (VE; 17%), and leg power (25%) to a greater
      degree than control participants and noncompliant exercisers (all P < 0.05).
      Although no group differences in health status were found, a significant
      interaction effect indicated that noncompliant exercisers' CD4 cells declined
      (18%) significantly, whereas compliant exercisers' cell counts significantly
      increased (13%; P < 0.05). CONCLUSION: We conclude that although aerobic exercise
      can improve cardiopulmonary functioning in symptomatic HIV-infected individuals
      with minimal health risks, attention to factors associated with exercise
      adherence is warranted.

PMID- 10416559
TI  - Smoking history is related to free-living daily physical activity in claudicants.
AB  - PURPOSE: To determine whether smoking history was related to free-living daily
      physical activity in peripheral arterial occlusive disease (PAOD) patients with
      intermittent claudication, and whether the effect of smoking history on physical
      activity level persisted after controlling for group differences in ambulatory
      function, peripheral circulation, and body composition. METHODS: Patients were
      separated into three groups: those who never smoked (N = 35), those who had a
      lower pack-year history of smoking (< or =40 pack-yr; N = 33), and those who had
      a higher pack-year history (>40 pack-yr; N = 30). Free-living daily physical
      activity was assessed by activity monitors (an accelerometer and a pedometer)
      worn on each hip over 2 consecutive weekdays. Patients also were characterized on
      ambulatory function, peripheral circulation, and body composition because of
      their relationship with physical activity. RESULTS: A progressive decline (P <
      0.001) in free-living daily physical activity with increasing smoking exposure
      was obtained from the accelerometer in the nonsmokers (482 +/- 36 kcal x d(-1);
      mean +/- SE), smokers with a lower pack-year history (361 +/- 37 kcal x d(-1)),
      and smokers with a higher pack-year history (227 +/- 23 kcal x d(-1)). A similar
      decline was found with the pedometer data (P < 0.001). After controlling for
      group differences in 6-min walk distance and in calf transcutaneous heating
      power, group differences in free-living daily physical activity were no longer
      significant. CONCLUSION: Progressive decrements in free-living daily physical
      activity with greater levels of smoking exposure in PAOD patients are primarily
      due to smoking-related impairments in ambulatory function and peripheral
      circulation.

PMID- 10416560
TI  - Exercise training-induced alterations in skeletal muscle antioxidant capacity: a
      brief review.
AB  - Cellular oxidants include a variety of reactive oxygen, nitrogen, and
      chlorinating species. It is well established that the increase in metabolic rate
      in skeletal muscle during contractile activity results in an increased production
      of oxidants. Failure to remove these oxidants during exercise can result in
      significant oxidative damage of cellular biomolecules. Fortunately, regular
      endurance exercise results in adaptations in the skeletal muscle antioxidant
      capacity, which protects myocytes against the deleterious effects of oxidants and
      prevents extensive cellular damage. This review discusses the effects of chronic
      exercise on the up-regulation of both antioxidant enzymes and the glutathione
      antioxidant defense system. Primary antioxidant enzymes superoxide dismutase,
      glutathione peroxidase, and catalase will be discussed as well as glutathione,
      which is an important nonenzymatic antioxidant. Growing evidence indicates that
      exercise training results in an elevation in the activities of both superoxide
      dismutase and glutathione peroxidase along with increased cellular concentrations
      of glutathione in skeletal muscles. It seems plausible that increased cellular
      concentrations of these antioxidants will reduce the risk of cellular injury,
      improve performance, and delay muscle fatigue.

PMID- 10416561
TI  - Effects of exercise and insulin on insulin signaling proteins in human skeletal
      muscle.
AB  - Insulin and exercise independently increase glucose metabolism in muscle.
      Moreover, exercise training or a prior bout of exercise increases insulin
      stimulated glucose uptake in resting skeletal muscle. The present study was
      undertaken to compare how physiological hyperinsulinemia and moderate intensity
      aerobic exercise affect the tyrosine phosphorylation state and activity of
      insulin signaling molecules in healthy, physically inactive volunteers. Subjects
      had biopsies of the vastus lateralis muscle before and immediately after 30 min
      of either hyperinsulinemia (euglycemic insulin clamp) or moderate-intensity
      exercise on a cycle ergometer (approximately 60% of VO2max). Insulin receptor and
      IRS-1 tyrosine phosphorylation, association of the p85 regulatory subunit of PI 3
      kinase with IRS-1, IRS-1 associated PI 3-kinase activity, and glycogen synthase
      activity were determined in muscle biopsy specimens taken from healthy subjects
      before and after insulin or exercise. Physiological hyperinsulinemia increased
      the rate of glucose disposal from 11.4 +/- 1.5 to 25.6 +/- 6.7 micromol x kg(-1)
      x min(-1) (P < 0.01), insulin receptor and IRS-1 tyrosine phosphorylation (173 +/
      19% and 159 +/- 35% of basal values, respectively, P < 0.05), association of the
      p85 regulatory subunit of PI 3-kinase with IRS-1 (159 +/- 10%, P < 0.05), and
      glycogen synthase fractional velocity (136 +/- 11%, P < 0.01). Exercise also
      increased glucose disposal, from 10.4 +/- 0.5 to 15.6 +/- 1.7 micromol x kg(-1) x
      min(-1) (P < 0.01) and glycogen synthase fractional velocity (253 +/- 35% of
      basal, P < 0.01). The exercise-induced increase in glycogen synthase was greater
      than that due to insulin (P < 0.05). In contrast to insulin, exercise decreased
      tyrosine phosphorylation of the insulin receptor to 72 +/- 10% of basal values (P
      < 0.05 vs basal and P < 0.05 vs insulin) and had no effect on IRS-1 tyrosine
      phosphorylation, or association of p85 with IRS-1. The exercise-induced decreased
      insulin receptor tyrosine phosphorylation could explain the well-known effect of
      exercise to enhance the sensitivity of muscle to insulin.

PMID- 10416562
TI  - Cardiovascular dynamics at the onset of exercise.
AB  - At the onset of exercise, the cardiovascular system adapts with a series of
      integrated responses to meet the metabolic demands of the exercising muscles. The
      importance of rapid increases in cardiac output and local muscle blood flow has
      been established by showing that small decreases in O2 supply at the onset of
      exercise cause delays in the increase in O2 utilization. With the development of
      techniques that can be applied to instantaneous measurement of the cardiovascular
      response, the mechanisms that regulate increased muscle perfusion have recently
      been investigated. In this introduction to the symposium, a model of the within
      muscle distribution of blood flow is considered as a function of the measured
      responses across an exercising skeletal muscle. This model demonstrates the
      necessity of considering the distribution of blood flow to the working fibers
      very early in exercise. The symposium provides insight into our current
      understanding of the factors involved in the regulation of skeletal muscle blood
      flow at the onset of exercise. Our ability to study the impact of cardiovascular
      disease on exercise performance has improved with the development of selective
      pharmacological agents to block or stimulate specific components of the
      cardiovascular response. These advances should provide the basis for future
      research.

PMID- 10416563
TI  - Control of skeletal muscle perfusion at the onset of dynamic exercise.
AB  - At the onset of exercise there is a rapid increase in skeletal muscle vascular
      conductance and blood flow. Several mechanisms involved in the regulation of
      muscle perfusion have been proposed to initiate this hyperemic response,
      including neural, metabolic, endothelial, myogenic, and muscle pump mechanisms.
      Investigators utilizing pharmacological blockade of cholinergic muscarinic
      receptors and sympathectomy have concluded that neither sympathetic cholinergic
      nor adrenergic neural mechanisms are involved in the initial hyperemia. Studies
      have also shown that the time course for vasoactive metabolite release,
      diffusion, accumulation, and action is too long to account for the rapid increase
      in vascular conductance at the initiation of exercise. Furthermore, there is
      little or no evidence to support an endothelium or myogenic mechanism as the
      initiating factor in the muscle hyperemia. Thus, the rise in muscle blood flow
      does not appear to be explained by known neural, metabolic, endothelial, or
      myogenic influences. However, the initial hyperemia is consistent with the
      mechanical effects of the muscle pump to increase the arteriovenous pressure
      gradient across muscle. Because skeletal muscle blood flow is regulated by
      multiple and redundant mechanisms, it is likely that neural, metabolic, and
      possibly endothelial factors become important modulators of mechanically induced
      exercise hyperemia following the first 5-10 s of exercise.

PMID- 10416564
TI  - Adaptation of blood flow during the rest to work transition in humans.
AB  - Beat-by-beat measurements show that limb blood flow rises rapidly and in a
      biphasic manner at the onset of rhythmic exercise in humans. In this review the
      time course of change in limb flow with the onset of exercise is described and
      the mechanisms that may or may not contribute to its regulation are discussed.
      The pumping action of contracting skeletal muscle appears to form an important
      regulator of increasing flow with the first contraction. However, evidence from
      human studies suggests that vasodilation begins with the first contraction.
      Whether this early dilation is regulated by neural recruitment of motor fibers
      and/or muscle contraction per se is discussed, but the mechanism(s) remains
      unclear. Finally, the contribution of endothelial-derived relaxation factors to
      the exponential increase in flow at the exercise onset is examined. Based on
      studies in humans with intra-arterial infusion of blocking drugs, neither
      acetylcholine, nitric oxide, nor prostaglandins appear to be essential for a
      normal dynamic flow response on going from rest to exercise. Overall, evidence
      from human studies supports the hypothesis that the rate of increase in blood
      flow during rhythmic voluntary exercise is closely coupled to motor unit
      recruitment with dilation beginning at the first contraction.

PMID- 10416565
TI  - Effects of muscle contraction on skeletal muscle blood flow: when is there a
      muscle pump?
AB  - PURPOSE: The purpose of this study was to determine the effects of rhythmic
      muscle contraction on the dynamics of venous outflow in rat skeletal muscle.
      METHODS: The effects of frequency and duration of tetanic contraction on venous
      blood flow (BF) were examined with transonic flow probes placed on the femoral
      artery and vein. RESULTS: Results reveal that instrumentation of the venous
      system with cannulas or flow probes alters vascular mechanics so that the muscle
      pump effect is masked. Measurements conducted without instrumentation of the
      venous vasculature in situ, as well as experiments with conscious exercising
      animals, indicate that the muscle pump enhances BF during exercise. Also, recent
      in vivo studies of humans indicate an important role for the muscle pump. In
      contrast, results reported herein and recent results from in situ experiments,
      which allow control of more parameters, indicate that there is no measurable
      muscle pump effect on BF during rhythmic muscle contraction. Review of the
      literature indicates that many in vitro/in situ experiments used instrumented
      veins that may have altered venous vascular mechanics and the interactions of
      muscle contraction and venous vascular mechanics, thus minimizing or abolishing
      the muscle pump effect. CONCLUSIONS: The muscle pump contributes to the initial
      increase in BF at exercise onset and to maintenance of BF during exercise.

PMID- 10416566
TI  - Muscle blood flow during exercise: the limits of reductionism.
AB  - This paper attempts to integrate some important concepts about the various
      mechanisms that are thought to cause blood flow to rise during rhythmic exercise.
      Mechanisms including the muscle pump, substances released by skeletal muscle,
      substances transported by blood, and factors released by nerves have been
      postulated to contribute to the rise in muscle blood flow during exercise.
      Additionally, the factors that initiate the dilation may not be those which
      sustain it. Although there is normally a close relationship between contractile
      activity, metabolic rate, and muscle blood flow, this relationship can be
      disrupted under a variety of circumstances and the active skeletal muscle
      overperfused. This delinking of flow and metabolism raises important questions
      about the nature of the vasodilating substances responsible for the rise in blood
      flow during exercise. We propose that understanding the mechanisms responsible
      for the "delinking" of flow and metabolism, along with a more synergistic view of
      current concepts, can provide new insight into the mechanisms which govern
      exercise hyperemia.

PMID- 10416567
TI  - Heart attacks and lower-limb function in master endurance athletes.
AB  - PURPOSE: Whether very vigorous physical activity bestows on the participant more
      health benefits or more adverse effects is unclear: we investigated whether men
      participating in competitive endurance sports in middle and old age are at
      increased risk of heart attacks as well as of lower-limb osteoarthritis and
      disability. METHODS: In our cohort study with an 11-yr follow-up, we studied 269
      male orienteering runners (mean age 48.6 yr at baseline; range 37-61), who in
      1984 were placed among the 60 best in their master orienteer age-class in
      Finland, and 188 male nonsmoking controls (mean age 50.4 yr; range 39-61)
      classified as healthy at 20 yr of age and without overt ischemic heart disease up
      until 1985. We followed mortality and studied the prevalence of questionnaire
      reported physician-diagnosed diseases and disabilities at the end of the follow
      up in late 1995. RESULTS: Two (0.7%) of the 269 runners and 10 (5.3%) of the 188
      controls had suffered myocardial infarctions during the follow-up, the age
      adjusted odds ratio (95% confidence interval) being 0.15 (0.03-0.67) in runners
      compared with controls (P = 0.0059). At follow-up, orienteering runners reported
      knee osteoarthritis and knee pain more often than did the controls, whereas the
      occurrence of hip osteoarthritis and hip pain did not differ. Disability due to
      hip or knee pain after the same everyday activities tended to be less in the
      runners. CONCLUSION: In top-level master endurance athletes having a long-term
      training background and participating in competitive endurance sports, the risk
      both of heart attack and of lower-limb disability is low.

PMID- 10416568
TI  - Localized muscle fatigue decreases the acuity of the movement sense in the human
      shoulder.
AB  - PURPOSE: The purpose of this study was to investigate alterations in the movement
      sense acuity during localized muscle fatigue in the human dominant shoulder.
      METHODS: Fourteen healthy volunteers (8 males and 6 females) with a mean age 23
      +/- 2 yr participated in the study. The subjects' ability to discriminate
      movement velocity relative to a reference velocity imposed over the dominant
      shoulder was tested following two experimental conditions: 1) Light exercise
      (LE), repetitive isokinetic horizontal flexion/extensions at the shoulder,
      ranging from 85 degrees to 20 degrees relative to the frontal plane, at 10% of
      maximal voluntary contraction (MVC) and 2) Hard exercise (HE), same movements as
      in LE, but performing MVC to fatigue. RESULTS: The results showed that subjects
      had a lower probability of distinguishing between different movement velocities
      following HE as compared with those during the LE condition (P < 0.001). When
      genders were compared, female subjects had a lower probability of distinguishing
      correctly than male subjects (P < 0.001). CONCLUSIONS: The acuity of the movement
      sense in the dominant shoulder is reduced in the presence of shoulder muscle
      fatigue. The possible influence of muscle fatigue via peripheral muscle receptors
      on movement sense is discussed.

PMID- 10416569
TI  - The prediction of speed and incline in outdoor running in humans using
      accelerometry.
AB  - PURPOSE: To explore whether triaxial accelerometric measurements can be utilized
      to accurately assess speed and incline of running in free-living conditions.
      METHODS: Body accelerations during running were recorded at the lower back and at
      the heel by a portable data logger in 20 human subjects, 10 men, and 10 women.
      After parameterizing body accelerations, two neural networks were designed to
      recognize each running pattern and calculate speed and incline. Each subject ran
      18 times on outdoor roads at various speeds and inclines; 12 runs were used to
      calibrate the neural networks whereas the 6 other runs were used to validate the
      model. RESULTS: A small difference between the estimated and the actual values
      was observed: the square root of the mean square error (RMSE) was 0.12 m x s(-1)
      for speed and 0.014 radiant (rad) (or 1.4% in absolute value) for incline.
      Multiple regression analysis allowed accurate prediction of speed (RMSE = 0.14 m
      x s(-1)) but not of incline (RMSE = 0.026 rad or 2.6% slope). CONCLUSION:
      Triaxial accelerometric measurements allows an accurate estimation of speed of
      running and incline of terrain (the latter with more uncertainty). This will
      permit the validation of the energetic results generated on the treadmill as
      applied to more physiological unconstrained running conditions.

PMID- 10416570
TI  - Physical and psychological predictors of exercise dosage in healthy adults.
AB  - PURPOSE: The purpose of this study was to examine the exercise dose-response
      issue in a sample of 121 regular exercisers categorized as relatively low,
      moderate, or high dosage physical activity participants. METHODS: Male and female
      students, faculty, and staff of a midwestern university, currently engaging in
      various exercise modalities at least two times per week, were assessed on a
      variety of factors hypothesized to impact one's degree of exercise involvement.
      RESULTS: ANOVA procedures indicated that low and high dosage groups differed
      significantly on the variables of age, exercise history, positive affect, and the
      locus of causality and stability attributional dimensions. Groups did not differ
      significantly in terms of body mass index, exercise efficacy, perceptions of
      either personal or external control over exercise behavior, or negative affective
      reactions to exercise behavior. CONCLUSIONS: Taken together, the findings of this
      study suggest that individuals who exercise at varying doses of physical activity
      may be differentiated by certain demographic, behavioral, physiological, and
      psychological variables.

PMID- 10416571
TI  - Muscle control in elite alpine skiing.
AB  - PURPOSE: The purpose of this study was to determine whether muscle control may be
      influenced by accelerative forces brought about by the downhill displacement of
      body mass in combination with the sharp turns during alpine skiing. METHODS:
      Sixteen elite skiers performed either super G (SG), giant slalom (GS), slalom
      (SL), or freestyle mogul (FM) skiing. Knee and hip joint angles and
      electromyographic (EMG) activity of the knee extensors were recorded. RESULTS:
      During the course of a turn, the minimum (deepest stance position) knee angle of
      the outside (main load-bearing) leg ranged from 60 degrees to 100 degrees, where
      the smallest angle was obtained in the FM event. Among the traditional alpine
      disciplines, smaller knee angles were obtained in the high-speed events (i.e.,
      knee angle: SG<GS<SL). Knee angular velocity of the outside leg ranged from 15
      degrees to 300 degrees x s(-1), with the slower movements in the high-speed
      disciplines (i.e., knee angular velocity: SG<GS<SL<FM). In all disciplines, EMG
      activity reached near-maximal levels during the course of a turn. In SG, GS, and
      SL, but not in FM skiing, a marked predominance of eccentric over concentric
      muscle actions was observed. The dominance of slow eccentric muscle actions has
      not been observed in other athletic activities. CONCLUSIONS: We believe these
      results have important implications for the design of specific training models.

PMID- 10416572
TI  - Anthropometry and bioelectrical impedance inconsistently predicts fatness in
      women with regional adiposity.
AB  - PURPOSE: This investigation examined the accuracy of several generalizable
      anthropometric (ANTHRO) and bioelectrical impedance (BIA) regression equations to
      estimate % body fat (%BF) in women with either upper body (UB) or lower body (LB)
      fat distribution patterns. METHODS: Thirty-six premenopausal women were
      individually matched for age (X = 38.6 +/- 6.6 yr), BMI (X = 25.5 +/- 4.2 kg x m(
      2)) and %BF (30.3 +/- 8.1%; hydrostatic, [UWW]) and placed by waist to hip ratio
      (WHR) into two distinct groups: LB (N = 18; WHR < or = 0.73) and UB (N = 18; WHR
      > or = 0.80). Equations tested were ANTHRO: Jackson et al. (JPW-7 and 3 site),
      1980; Durnin and Womersley (DW), 1974; Tran and Weltman (TW), 1989; and Vogel et
      al. (V), 1988; BIA: Lohman (L), 1992; Gray et al. (G), 1989; and VanLoan and
      Mayclin (VLM), 1987. Circumference and skinfold measures were made by a trained
      technician. BIA (Vallhalla, 1990B) measures were taken 4 h postprandially under
      controlled conditions of water intake and exercise. %BF by UWW (criterion) was
      not different between groups (UB = 30.8 +/- 8.2%; LB = 29.7 +/- 8%). RESULTS: In
      the UB group, three of five ANTHRO equations significantly overestimated %BF by
      approximately 6% (range = 3-8%) as compared with UWW. BIA overestimated %BF in UB
      by 5% using G and in both groups by about 6% using VLM, whereas L underestimated
      %BF in LB by about 4%. CONCLUSION: We conclude that ANTHRO and some BIA equations
      are accurate for predicting %BF in LB fat "shaped" women but are not appropriate
      for women with primarily abdominal fat patterning.

PMID- 10416573
TI  - Reliability of a new device to assess the oxygen consumption of human respiratory
      muscles.
AB  - PURPOSE: This study tests the reliability of a new device for assessing the
      oxygen consumption of the respiratory muscles (VO2 resp.). METHODS: Fourteen
      healthy male volunteers participated in the study. The device consists of an
      expandable external ventilatory dead space created with pieces of plastic tubing
      and a spirometer filled with 100% oxygen. It also incorporates a carbon dioxide
      absorber. Total VO2 (VO2 tot.) was recorded from the spirometric closed circuit
      and ventilation (V(E)), from the spirometer tracing. For each subject the test
      procedure was carried out in duplicate (T1 and T2) after an overnight fast. The
      dead space was increased at a constant rate of 260 mL every 90 s, and VO2 tot.
      and V(E) increased progressively. Because log VO2 tot. was linearly related to
      V(E), we calculated the slope value (log VO2-V(E)) and the Y-intercept (VE = 0)
      of the semilog regression representing, respectively, VO2 resp. and metabolic VO2
      (VO2 met.). RESULTS: When compared with values in the literature, these values
      did not differ from those recorded in subjects of a similar age group. The VO2
      resp. and VO2 met. calculated in T1 and T2 were not different (VO2 resp. = 0.0066
      +/- 0.0005 for T1 vs 0.0067 +/- 0.0005 log mL x min(-1)/L x min(-1) for T2 and
      VO2 met. = 269.3 +/- 28.6 for T1 vs 281.9 +/- 24.1 mL x min(-1) for T2). The
      coefficients of variation were: 25% at T1 and 23% at T2 for VO2 resp. and 34% at
      T1 and 29% at T2 for VO2 met. Moreover, significant correlations (r = 0.96, P <
      0.001 for VO2 resp., r = 0.95, P < 0.001 for VO2 met.), high coefficients of
      determination (r2 = 0.92 for VO2 resp., r2 = 0.90 for VO2 met.) and negligible
      SEE (0.0005 for VO2 resp., 0.2 mL x min(-1) for VO2 met.) were found between the
      two tests. When we plotted the mean values of VO2 resp. and VO2 met. measured at
      T1 and T2 against their respective differences, more than 95% of the slight
      differences ranged between the limits defined by mean value +/- 2 SD, reflecting
      the small discrepancy between duplicate measurements. CONCLUSION: The results
      confirm that the test performed with this device is useful and reliable for
      assessing the VO2 resp. in healthy subjects.

PMID- 10416574
TI  - Cause, prevalence, and response to occupational musculoskeletal injuries reported
      by physical therapists and physical therapist assistants.
AB  - BACKGROUND AND PURPOSE: Physical therapists (PTs) and physical therapist
      assistants (PTAs) are susceptible to occupational musculoskeletal injuries. The
      purpose of this study was to examine the reported causes and prevalence of
      occupational musculoskeletal injuries to PTs and PTAs during a 2-year period.
      SUBJECTS: A questionnaire was mailed to 500 PTs and 500 PTAs randomly selected
      from the American Physical Therapy Association 1996 active membership list. Six
      hundred sixty-seven questionnaires were returned, giving a response rate of 67%.
      METHOD: Based on a literature review and a pilot study, an occupational injury
      questionnaire was constructed and mailed. Self-reports of injuries were obtained.
      RESULTS: Thirty-two percent of the PTs and 35% of the PTAs reported sustaining a
      musculoskeletal injury. The highest prevalence of injury was to the low back (62%
      of injured PTs and 56% of injured PTAs). The PTs reported the upper back and the
      wrist and hand as having the second highest prevalence (23%). The PTAs reported
      the upper back as having the second highest prevalence (28%). The PTs and PTAs
      reported making changes in their work habits of improved body mechanics,
      increased use of other personnel, and frequent change of work position. The
      majority of PTs and PTAs reported they did not limit patient contact time or area
      of practice after sustaining an injury. CONCLUSION AND DISCUSSION: Although PTs
      and PTAs are recognized to be knowledgeable in prevention and treatment of
      musculoskeletal injuries, they are susceptible to sustaining occupational
      musculoskeletal injuries because of performing labor-intensive tasks.

PMID- 10416575
TI  - Behaviors that cause clinical instructors to question the clinical competence of
      physical therapist students.
AB  - BACKGROUND AND PURPOSE: Clinical instructors (CIs) observe behavior to determine
      whether students have the skills assumed necessary for safe and effective
      delivery of physical therapy services. Studies have examined assumptions about
      necessary skills, but few studies have identified the types of student behaviors
      that are "red flags" for CIs. This study examined the student behaviors that
      negatively affect students' clinical performance, which can alert CIs to
      inadequate performance. SUBJECTS: Twenty-eight female and 5 male CIs discussed
      the performance of 23 female and 17 male students who were anonymous. METHODS:
      Using questionnaires and semistructured interviews that were taped and
      transcribed, CIs described demographics and incidents of unsafe and ineffective
      physical therapy. After reading the transcripts, investigators identified and
      classified the behaviors into categories and checked their classification for
      reliability (kappa=.60-.75). RESULTS: Behaviors in 3 categories emerged as red
      flags for CIs: 1 cognitive category--inadequate knowledge and psychomotor skill
      (43% of 134 behaviors)--and 2 noncognitive categories--unprofessional behavior
      (29.1%) and poor communication (27.6%). The CIs noticed and valued noncognitive
      behaviors but addressed cognitive behaviors more often with students. Students
      who did not receive feedback about their performance were unlikely to change
      their behavior. The CIs used cognitive behaviors often as reasons to recommend
      negative outcomes. CONCLUSION AND DISCUSSION: Clinical instructors need to
      identify unacceptable cognitive and noncognitive behaviors as early as possible
      in clinical experiences. Evidence suggests that they should discuss their
      concerns with students and expect students to change.

PMID- 10416576
TI  - The relationship of lower-limb muscle force to walking ability in patients with
      amyotrophic lateral sclerosis.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to determine the level of
      muscle force associated with ability to walk in the community without assistance,
      in the community with assistance, or at home only in individuals with amyotrophic
      lateral sclerosis (ALS). SUBJECTS AND METHODS: Percentage of predicted maximal
      muscle force (%PMF) of lower-extremity muscles was determined, and walking
      ability was categorized in 118 patients with ALS during periodic visits to the
      Neuromuscular Research Unit. Data were derived from consecutive visits in which
      subjects demonstrated declines in walking ability. Means for %PMF of each muscle
      group and a limb average were calculated at each consecutive visit. RESULTS: The
      mean lower-extremity average %PMF was: (1) 54.01% (SD=12.76%) for subjects who
      walked independently in the community and 50.19% (SD=14.38%) during the next
      visit when these same subjects required assistance in the community
      (difference=3.82%, 95% confidence interval [CI]= 2.45-5.19);(2) 37.52%
      (SD=15.17%) during the last visit that subjects walked with assistance in the
      community and 32.18% (SD=13.83%) during the next visit when they walked only at
      home (difference=5.33%, 95% CI=3.61-7.06); and (3) 19.12% (SD=9.08%) during the
      visit when subjects were last able to ambulate at home versus 13.70% (SD=7.36%)
      when they became unable to walk (difference=5.42%, 95% CI=2.97-7.96). CONCLUSION
      AND DISCUSSION: The findings suggest there are required levels of lower-extremity
      muscle force for various categories of walking ability. Variations in forces
      within and between categories of walking ability, however, indicate the
      complexity of this relationship.

PMID- 10416577
TI  - Effect of positioning on recorded lung sound intensities in subjects without
      pulmonary dysfunction.
AB  - BACKGROUND AND PURPOSE: Physical therapists often use positioning to assist in
      the reexpansion of collapsed lung segments. An increase in lung sound intensity
      on auscultation is considered indicative of lung expansion. This study was
      designed to examine whether clinical interpretation of auscultatory findings is
      warranted. SUBJECTS: The subjects (5 male, 6 female) were young physical
      therapist students without pulmonary dysfunction (mean age=20.4 years, mean
      height=166.3 cm, mean weight=57.5 kg). Subjects with lung disease were excluded
      because pulmonary pathology is difficult to standardize. METHODS: Lung sounds
      electronically recorded over the posterior chest wall of subjects in sitting and
      side-lying positions were compared. Measures included peak intensity, frequency
      at maximum power, and median frequency. RESULTS: In the sitting position,
      inspiratory sounds recorded over the left posterior chest wall were louder than
      those recorded on the right side. In the side-lying positions, the sound
      intensity recorded from the dependent chest wall was louder than that recorded
      from the nondependent chest wall. In side-lying positions, the upper hemithorax
      is "nondependent," and the side in contact with the bed is "dependent." Sound
      intensities recorded over both posterior chest walls in the sitting position were
      louder than those recorded over the same lung area in the nondependent side-lying
      position. There was no difference in the sound intensity recorded between the
      sitting and dependent side-lying postures. CONCLUSION AND DISCUSSION: When
      comparative auscultation of the chest wall is used by physical therapists to
      assess the adequacy of pulmonary ventilation, patient posture and regional
      differences in breath sound intensity can influence clinical interpretation.

PMID- 10416578
TI  - Low-intensity laser therapy for benign fibrotic lumps in the breast following
      reduction mammaplasty.
AB  - BACKGROUND AND PURPOSE: Fibrotic masses in the breast secondary to fat necrosis
      or hematoma are a complication of breast reduction mammaplasty. The treatment
      commonly recommended for this condition is early surgical debridement of necrotic
      tissue from the entire area, which causes scarring. This case report describes
      the use of low-intensity laser therapy for fibrotic lumps following reduction
      mammaplasty. CASE DESCRIPTION: The patient was a 46-year-old woman who had breast
      reduction surgery 80 days prior to referral for physical therapy. At the time of
      referral, the largest mass was 8.0 cm in diameter. The patient reported pain and
      said she was distressed about the breast disfigurement. Laser irradiation was
      initiated at an energy density (ED) of 20 J/cm2 and a pulse repetition rate of
      5,000 pulses per second. The laser settings were adjusted during the 8-month
      treatment period. The final ED was 50 J/cm2. OUTCOMES: The mass was 33% of its
      original size after 3 treatments over the initial 11-day period. Pain relief was
      immediate. The rate of resolution decreased after the initial period. The patient
      had some tissue thickening at the time of discharge after 6 months of treatment.
      DISCUSSION: This case demonstrates the potential use of laser therapy as a
      treatment for benign breast lumps following mammaplasty.

PMID- 10416579
TI  - Knee instability.

PMID- 10416580
TI  - Bell palsy.

PMID- 10416581
TI  - Squamous cell carcinomas and increased apoptosis in skin with inhibited
      Rel/nuclear factor-kappaB signaling.
AB  - The Rel/nuclear factor-kappaB (Rel/NF-kappaB) transcription factors have been
      implicated previously in control of apoptosis, cell proliferation, and
      oncogenesis. Here we show that selective inhibition of Rel/NF-kappaB signaling in
      murine skin, by targeted overexpression of a super-repressor form of IkappaB
      alpha, results in an increased basal frequency of apoptotic cells and the
      spontaneous development of squamous cell carcinomas. Presence of hyperplasia and
      hair follicle degeneration demonstrate an important role for Rel/NF-kappaB
      signaling in normal epidermal development and homeostasis. Transgenic skin, in
      addition, showed an enhanced sensitivity to UV-induced apoptosis. These data
      suggest an involvement of the Rel/NF-kappaB signaling pathway in apoptosis and
      cancer development of the skin.

PMID- 10416582
TI  - Induction of intratumoral tumor necrosis factor (TNF) synthesis and hemorrhagic
      necrosis by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF knockout mice.
AB  - 5,6-Dimethylxanthenon-4-acetic acid (DMXAA) is a new antitumor drug currently
      undergoing clinical trial. Administration of DMXAA to mice with tumors leads to
      cessation of tumor blood flow and the onset of tumor hemorrhagic necrosis,
      accompanied by the production of the cytokine tumor necrosis factor (TNF).
      Previous studies have shown that DMXAA induces both tumor and host cells to
      synthesize TNF and that induced intratumoral TNF production correlates with the
      antitumor activity of DMXAA. To explore the hypothesis that TNF production by
      tumor cells contributed to the induction of hemorrhagic necrosis by DMXAA, TNF-/-
      (C57Bl/6 background) mice were used as recipients for the s.c. implantation of
      (TNF positive) colon 38 adenocarcinoma. Tumors removed 24 h after treatment with
      DMXAA (66 or 100 micromol/kg) were found to be hemorrhagic and necrotic. Cells
      expressing TNF mRNA in tumors removed 2 h after treatment with DMXAA (160
      micromol/kg) were found by in situ hybridization to be comparable in frequency
      and distribution with those in tumors from C57Bl/6 TNF-positive mice. However,
      the amount of TNF protein extracted from tumors from TNF knockout mice was lower
      than that from TNF-positive mice. Spleen and liver tissue from TNF knockout mice,
      in contrast to that from TNF-positive mice, produced no TNF mRNA. TNF protein was
      undetectable in liver and spleen tissue from TNF knockout mice, but was evident
      in tissue from TNF-positive mice. These results confirm that DMXAA has the novel
      ability of inducing tumors to synthesize TNF in situ.

PMID- 10416583
TI  - Liposomes complexed to plasmids encoding angiostatin and endostatin inhibit
      breast cancer in nude mice.
AB  - Gene therapy transfer of angiostatin and endostatin represents an alternative
      method of delivering angiogenic polypeptide inhibitors. We examined whether
      liposomes complexed to plasmids encoding angiostatin or endostatin inhibited
      angiogenesis and the growth of MDA-MB-435 tumors implanted in the mammary fat
      pads of nude mice. We determined that plasmids expressing angiostatin (PCI-Angio)
      or endostatin (PCI-Endo) effectively reduced angiogenesis using an in vivo
      Matrigel assay. We then investigated the efficacy of these plasmids in reducing
      the size of tumors implanted in the mammary fat pad of nude mice. Both PCI-Angio
      and PCI-Endo significantly reduced tumor size when injected intratumorally (P <
      0.05). Compared to the untreated control group, the mice treated with PCI-Angio
      and PCI-Endo exhibited a reduction in tumor size of 36% and 49%, respectively. In
      addition, we found that i.v. injections of liposomes complexed to PCI-Endo
      reduced tumor growth in the nude mice by nearly 40% when compared to either empty
      vector (PCI) or untreated controls (P < 0.05). These findings provide a basis for
      the further development of nonviral delivery of antiangiogenic genes.

PMID- 10416584
TI  - Association of matrilysin expression with recurrence and poor prognosis in human
      esophageal squamous cell carcinoma.
AB  - Matrix metalloproteinase-7 (matrilysin) has been implicated in tumor invasion and
      metastasis as well as tumor initiation and growth. In this study, we analyzed an
      association between immunohistochemically detected matrilysin expression at the
      invasive front in esophageal squamous cell carcinomas and clinicopathological
      characteristics and determined whether matrilysin predicts recurrence and/or
      survival Matrilysin expression at the invasive front was detected in 49% of 100
      carcinoma tissues and was associated with the depth of invasion (P < 0.0001),
      advanced tumor stage (P = 0.0159), recurrences (P = 0.0002), and recurrences
      within the first postoperative year (P = 0.002). Patients with matrilysin
      positive carcinoma had a significantly shorter disease-free and overall survival
      time than did those with a matrilysin-negative one (P < 0.0001). Matrilysin
      remained a significant predictive value for disease-free and overall survival in
      multivariate analysis, including conventional clinicopathological factors (P =
      0.0007 and 0.0004, respectively). Our results suggest that matrilysin may play a
      key role in the progression of esophageal carcinoma and that its detection may be
      useful for the prediction of recurrence and poor prognosis and, possibly, for
      selecting patients for anti-matrix metalloproteinase therapy.

PMID- 10416585
TI  - Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer
      patients.
AB  - Several epidemiological studies have indicated that female tobacco smokers may be
      at higher risk of lung cancer than males. In a study of lung cancer cases, we
      have found that female smokers had a significantly higher level of
      aromatic/hydrophobic DNA adducts in their nontumor lung tissue (15.39+/-9.47
      adducts/10(8) nucleotides, n = 29) than male smokers (12.08+/-8.14, a = 93; P =
      0.047). Females had significantly higher levels of adducts/pack-year (females
      0.95+/-0.82 adducts/pack-year and males 0.46+/-0.46; P = 0.0004) and
      adducts/cigaret/day (females 1.48+/-1.29 and males 0.89+/-0.74, P = 0.015). By
      quantitative reverse transcription-PCR, it was found that female smokers
      exhibited a significantly higher expression level of lung CYP1A1 (494+/-334
      CYP1A1 mRNA/10(6) glyceraldehyde-3-phophate dehydrogenase mRNA, n = 15) compared
      with males (210+/-208, n = 12; P = 0.016). Furthermore, for both sexes combined a
      significant correlation between CYP1A1 expression and DNA adduct level was found
      (r = 0.50, P = 0.009). In conclusion, the observed sex difference in
      aromatic/hydrophobic DNA adduct levels may at least in part be explained by
      different levels of CYP1A1 expression.

PMID- 10416586
TI  - Efficacy of the mobilization of peripheral blood stem cells by granulocyte colony
      stimulating factor in pediatric donors.
AB  - The advantages/disadvantages of the use of peripheral blood stem cells (PBSCs)
      for allogeneic transplantation still need to be clarified, particularly in
      children. We compared the kinetics, efficacy, and safety of PBSC mobilization by
      granulocyte colony-stimulating factor (G-CSF) and collection by apheresis between
      healthy pediatric and adult donors. A total of 19 pediatric (median age, 6 years)
      and 25 adult healthy donors (median age, 37 years) were given 10 micro/kg/day of
      G-CSF for 5 consecutive days for PBSC mobilization, which were harvested by
      apheresis on days 5 and/or 6. All of the donors tolerated the whole procedures.
      Serum trough levels of G-CSF determined by ELISA were significantly lower in the
      16 pediatric donors evaluated than in adults (n = 16) on days 3 and 4 (P < 0.05).
      Although the WBC counts on days 4 and 5 were significantly higher in adults than
      in children (P = 0.006 and 0.004, respectively), the numbers of circulating CD34+
      cells/unit of blood were identical. The number of blood CD34+ cells collected per
      unit of blood processed was identical in both donor populations. We propose that
      PBSCs could be effectively mobilized and collected in small children so that they
      could be donors for adult patients.

PMID- 10416587
TI  - Reversal of hypercalcemia with the vitamin D analogue EB1089 in a human model of
      squamous cancer.
AB  - EB1089, an analogue of 1,25 dihydroxyvitamin D with low calcemic activity is a
      potent inhibitor of parathyroid hormone-related peptide (PTHRP) production in
      vitro. The purpose of the present study was to determine whether EB1089 could
      reverse established hypercalcemia in BALB C nude mice implanted s.c. with a human
      epithelial cancer previously shown to produce high levels of PTHRP in vitro.
      Total plasma calcium was monitored before and after tumor development and
      increased steadily when the tumor reached > or =0.5 cm3. When total calcium was
      22.85 mmol/liter, animals were treated with a constant infusion of EB1089 or
      vehicle alone for a period of 2 weeks. A significant and sustained reduction of
      plasma calcium from 3.2+/-0.1 to 2.7+/-0.08 (P < 0.01) mmol/liter was observed
      during infusion with EB1089. In contrast, calcium levels in vehicle-treated
      animals continued to rise during the infusion period. Tumor growth velocity also
      slowed significantly after the administration of EB1089 as compared with vehicle
      treated animals. Plasma PTHRP levels measured at the end of the 2 weeks' infusion
      period were significantly lower in animals treated with EB1089 as compared with
      animals treated with vehicle alone (44+/-8 pg/ml versus 194+/-35 pg/ml, P <
      0.001). These results, therefore, demonstrate that EB1089 can reverse established
      hypercalcemia in a human model of squamous cancer.

PMID- 10416588
TI  - Antigen-presenting cells that phagocytose apoptotic tumor-derived cells are
      potent tumor vaccines.
AB  - We have reported recently that treatments combining injections of apoptotic
      bodies from tumor cells and interleukin 2 led to tumor regression and induced
      specific protection. In the present study, we show that tumor-bearing rats were
      cured with an 80% success rate by injection of antigen-presenting cells (APCs)
      that had phagocytosed apoptotic bodies derived from poorly immunogenic tumor
      cells, whereas phagocytic cells exposed to nonapoptotic tumor cell extracts were
      essentially without effect. In addition, curative vaccination using APCs that had
      phagocytosed apoptotic bodies generated a tumor-specific cytotoxic T-cell
      response and long-term protection from parental tumor challenge. Thus, systems
      using the processing and presentation of antigenic molecules by professional APCs
      after phagocytosis of apoptotic bodies appear to offer new possibilities for
      anticancer treatment.

PMID- 10416589
TI  - Induction of apoptosis and inhibition of tumorigenicity and tumor growth by
      adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression.
AB  - We studied the effects of fragile histidine triad (FHIT) gene overexpression
      mediated by an adenoviral vector, Ad-FHIT, on cell proliferation, apoptosis, and
      cell cycle kinetics in human cancer cells and on tumorigenicity and tumor growth
      in nude mice. Overexpression of the FHIT gene significantly inhibited cell growth
      in various Ad-FHIT-transduced human lung cancer cells and head and neck carcinoma
      cells with FHIT gene abnormalities, but not in normal human bronchial epithelial
      cells. Fewer than 20% of cells in all Ad-FHIT-transduced cells survived at 7 days
      after transduction. Overexpression of the FHIT gene induced cell apoptosis and
      altered cell cycle processes. The apoptotic cell population markedly increased,
      and cells accumulated in S phase after Ad-FHIT transduction. The tumorigenicity
      of human H1299 lung cancer cells transduced by Ad-FHIT, in comparison with that
      of the control transductants and untreated cells, was eliminated in vivo.
      Subcutaneous tumor growth in nude mice who received intratumoral injections of Ad
      FHIT, at a total dose of 3 x 10(10) plaque-forming units/tumor for H1299 tumors
      and 4 x 10(10)/tumor for A549 tumors, were suppressed by more than 85% and 90%,
      respectively, compared with that in nude mice who received injections of empty
      vector at the same dose or with PBS alone. Together, our results suggest that the
      FHIT gene, when delivered at high efficiency by a recombinant adenoviral vector,
      functions as a tumor suppressor gene both in vitro and in vivo.

PMID- 10416590
TI  - Biodistribution and vaccine efficiency of murine dendritic cells are dependent on
      the route of administration.
AB  - Dendritic cells (DCs) are professional antigen-presenting cells, well equipped to
      initiate an immune response. Currently, tumor antigen-derived peptide loaded DCs
      are used in clinical vaccination in cancer patients. However, the optimal dose
      and route of administration of a DC vaccine still remain to be determined. Using
      indium-111-labeled DCs, we investigated whether the route of administration does
      affect the biodistribution of DCs in lymphoid organs and whether it influences
      the outcome of DC vaccination in the B16 mouse melanoma tumor model. The results
      demonstrate that i.v. injected DCs mainly accumulate in the spleen, whereas s.c.
      injected DCs preferentially home to the T-cell areas of the draining lymph nodes.
      Using tyrosinase-related protein-2-derived peptide-loaded DC vaccination in a
      fully autologous B16 melanoma tumor model, we observed a delay in tumor growth,
      improved survival as well as increased antitumor cytotoxic T-cell reactivity
      after s.c. vaccination as compared to i.v. vaccination. These data demonstrate
      that optimal induction of antitumor reactivity against the autologous melanocyte
      differentiation antigen tyrosinase-related protein-2-derived peptide occurs after
      s.c. vaccination and correlates with the preferential accumulation of DCs in the
      T-cell areas of lymph nodes.

PMID- 10416592
TI  - Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and
      Burkitt's lymphoma is associated with 5' CpG island methylation.
AB  - The p73 gene is located on 1p36.2-3, a region that is frequently deleted in human
      cancer. Because p73 encodes for a protein that is both structurally and
      functionally homologous to the p53 protein, p73 has been postulated to be a
      candidate tumor suppressor gene. To date, however, mutations of p73 have not been
      found. To study methylation of the p73 5'CpG island, a human bacterial artificial
      chromosome clone containing exon 1 and the 5' region of p73 was isolated. There
      was no evidence for p73 exon 1 methylation in normal tissues. In contrast, p73
      was aberrantly methylated in approximately 30% of primary acute lymphoblastic
      leukemias (ALLs) and Burkitt's lymphomas. There was no evidence for methylation
      in any other types of hematological malignancies or solid tumors examined. In
      both leukemia cell lines and primary ALLs, methylation was associated with
      transcriptional loss of p73 by reverse transcription-PCR. We used single-strand
      conformational polymorphisms to screen for point mutations in a series of primary
      ALLs and found no mutations leading to a change in protein structure. Our results
      show that methylation of p73 is a frequent event in specific types of
      hematological malignancies and suggest that epigenetic silencing of p73 could
      have important consequences for cell-cycle regulation.

PMID- 10416591
TI  - Beta-catenin mutations are specific for colorectal carcinomas with microsatellite
      instability but occur in endometrial carcinomas irrespective of mutator pathway.
AB  - Some colorectal tumors with wild-type adenomatous polyposis coli gene have
      activating mutations in beta-catenin (encoded by CTNNB1) that result in decreased
      phosphorylation by GSK-3beta and increased signaling through the Tcf/Lef
      transcription factors. To investigate the relationship between CTNNB1 mutations
      and underlying pathways of genomic instability, we examined 80 colorectal cancers
      stratified by the presence or absence of microsatellite instability (MSI). CTNNB1
      mutations were identified in 13 (25%) of 53 cancers with high frequency MSI (MSI
      H), including 12 point mutations at exon 3 phosphorylation sites (codons 41 and
      45) and one deletion of the entire exon 3 degradation box. No CTNNB1 mutations
      were identified in 27 microsatellite stable or low frequency MSI (MSI-L)
      colorectal cancers (P < 0.01). In contrast, CTNNB1 mutations were identified in 3
      of 9 (33%) MSI-H and 10 of 20 (50%) MSS/MSI-L endometrial carcinomas, suggesting
      a more generalized involvement in these tumors. Only six (46%) of the endometrial
      carcinoma CTNNB1 mutations occurred at residues directly phosphorylated by GSK
      3beta, and only one of these was at either codon 41 or 45. All point mutations in
      MSI-H cancers were transitions, whereas 64% of those in MSS/MSI-L cancers were
      transversions (P < 0.01). The differences in the mutation profiles suggest that
      there may be molecular fingerprints of CTNNB1 mutations, determined by biological
      factors related to both tumor type and underlying pathways of genomic
      instability.

PMID- 10416593
TI  - Rapid isolation of chromosomal breakpoints from patients with t(4;11) acute
      lymphoblastic leukemia: implications for basic and clinical research.
AB  - Chromosomal translocations t(4;11)(q21;q23) are associated with a group of acute
      lymphoblastic leukemias with very poor prognosis. From the complete sequences of
      the breakpoint cluster regions of the human MLL and AF-4 translocation partner
      genes, a novel set of 66 oligonucleotides that facilitates the rapid
      identification of translocation breakpoints by PCR analysis of genomic DNA was
      designed. For each breakpoint, a pair of optimally snited primers can be
      assigned, which improves the monitoring of the disease during treatment.
      Comparison of the breakpoints with the corresponding parental sequences also
      contributes to our better understanding of the illegitimate recombination events
      leading to these translocations.

PMID- 10416594
TI  - The S387Y mutations of the transforming growth factor-beta receptor type I gene
      is uncommon in metastases of breast cancer and other common types of
      adenocarcinoma.
AB  - Recently, mutations of the transforming growth factor-beta receptor type I gene
      have been reported to occur at high frequency in breast cancer metastases, with
      all mutations being an identical C to A transversion at nucleotide 1160 of the
      gene (T. Chen et al, Cancer Res., 58: 4805-4810, 1998). This mutation would
      result in a serine to tyrosine substitution at codon 387 (S387Y) and would
      reportedly disrupt receptor function. Because this mutation reportedly occurred
      at high frequency in breast cancer metastases (42%) and much less frequently in
      primary breast cancer tumors (6%), this would seem to represent a pivotal genetic
      alteration in breast cancer progression. To further investigate the possible role
      of this specific genetic alteration in the progression of breast cancer and other
      forms of adenocarcinoma, we analyzed 20 breast cancer metastases, 15 lung
      adenocarcinoma metastases, and 13 colorectal cancer metastases for possible
      mutations at this site. Using both single-strand conformation polymorphism
      screening and sequencing, we found no mutations of this gene in any of our
      samples. Our results suggest the S387Y mutation of the transforming growth factor
      beta receptor type I gene is not common in these types of human cancers.

PMID- 10416595
TI  - Expression of B-myb in neuroblastoma tumors is a poor prognostic factor
      independent from MYCN amplification.
AB  - The transcription factors of the Myb family are expressed in several tissues and
      play an important role in cell proliferation, differentiation, and survival In
      this study, the expression of A-myb, B-myb, and c-myb was investigated in a group
      of 64 neuroblastomas at different dinical stages by a sensitive reverse
      transcription-PCR tchnique and correlated with patients' survival. All of the myb
      genes were frequently expressed in neuroblastoma tumors. Interestingly, the
      expression of B-myb, which was detected in 33 cases, was associated with an
      increased risk of death (P = 0.027 in a univariate analysis), whereas there was
      no correlation with A-myb and c-myb expression. In addition, in a multivariate
      Cox regression analysis that included myb gene expression, MYCN status, age at
      diagnosis, and tumor staging, MYCN amplification and B-myb expression were
      independently associated to an increased risk (P < 0.01 and P = 0.015,
      respectively). In overall survival curves obtained by stratifying the
      neuroblastoma cases on the basis of MYCN status and B-myb expression, the group
      of patients without MYCN amplification and positive for B-myb expression had
      worse survival probability than that without MYCN amplification and nonexpressing
      B-myb (P < 0.01). In summary, these findings provide the first demonstration that
      B-myb expression can be a useful prognostic marker in human neuroblastoma.
      Moreover, B-myb expression has a prognostic value complementary to MYCN
      amplification and can identify a group of high-risk patients that would not be
      predicted on the basis of the MYCN status only.

PMID- 10416596
TI  - Adenovirus-mediated delivery of antisense gene to urokinase-type plasminogen
      activator receptor suppresses glioma invasion and tumor growth.
AB  - The urokinase-type plasminogen activator (uPA) and uPA receptor (UPAR) play
      important roles in the proteolytic cascade involved in the invasiveness of
      gliomas and other invasive tumors. High-level expression of uPAR has been
      correlated with high-grade glioma cell lines and tumors We report here that down
      regulating uPAR levels by antisense strategy using an adenovirus construct (Ad
      uPAR) inhibited glioma invasion in Matrigel and spheroid in vitro models. sc.
      (U87-MG) and intracranial (SNB19) injections of Ad-uPAR-infected glioma cells did
      not produce tumors in nude mice. However, injection of the Ad-uPAR construct into
      previously established so U87-MG tumors in nude mice caused regression of those
      tumors. Our results support the therapeutic potential of targeting the uPA-uPAR
      system for the treatment of gliomas and other cancers.

PMID- 10416597
TI  - Blockage of the vascular endothelial growth factor stress response increases the
      antitumor effects of ionizing radiation.
AB  - The family of vascular endothelial growth factor (VEGF) proteins include potent
      and specific mitogens for vascular endothelial cells that function in the lation
      of angiogenesis Inhibition of VEGF-induced angiogenesis either by neutralizing
      antibodies or dominant-negative soluble receptor, blocks the growth of primary
      and metastatic experimental tumors Here we report that VEGF expression is induced
      in Lewis lung carcinomas (LLCs) both in vitro and vivo after exposure to ionizing
      radiation (IR) and in human tumor cell lines (Seg-1 esophageal adenocarcinoma,
      SQ20B squamous cell carcinoma, T98 and U87 glioblastomas, and U1 melanoma) in
      vitro. The biological significance of IR-induced VEGF production is supported by
      our finding that treatment of tumor-bearing mice (LLC, Seg-1, SQ20B, and U87)
      with a neutralizing antibody to VEGF-165 before irradiation is associated with a
      greater than additive antitumor effect. In vitro, the addition of VEGF decreases
      IR-induced killing of human umbilical vein endothelial cells, and the anti-VEGF
      treatment potentiates IR-induced lethality of human umbilical vein endothelial
      cells. Neither recombinant VEGF protein nor neutralizing antibody to VEGF affects
      the radiosensitivity of tumor cells These findings support a model in which
      induction of VEGF by IR contributes to the protection of tumor blood vessels from
      radiation-mediated cytotoxicity and thereby to tumor radioresistance.

PMID- 10416598
TI  - Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an
      early stage of tumorigenesis.
AB  - The transforming growth factor beta (TGF-beta) pathway is known to play an
      important role in both human and urine colon cancer. However, the staging, ligand
      specificity, and mechanism underlying the tumor suppressive activity of this
      pathway are unknown. We developed a mouse model for colon cancer that identifies
      an early role for TGF-beta1 in tumor suppression and implicates TGF-beta2 or TGF
      beta3 in the prevention of metastasis. Analysis of the development of colon
      cancer in TGF-beta1 knockout mice pinpoints the defect to the hyperplasty/adenoma
      transition and reveals that the mechanism involves an inability to maintain
      epithelial tissue organization and not a loss of growth control, increased
      inflammatory activity, or increased genetic instability. These mice provide a
      unique opportunity to investigate the specific role of TGF-beta1 at this critical
      transition in the development of colon cancer.

PMID- 10416599
TI  - Chemopreventive efficacy of sulindac sulfone against colon cancer depends on time
      of administration during carcinogenic process.
AB  - Epidemiological and model studies with laboratory animals have provided evidence
      that nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer.
      Sulindac, a nonsteroidal anti-inflammatory drug, has been shown to inhibit
      azoxymethane (AOM)-induced colon carcinogenesis in rats when administered
      continuously before, during, and after carcinogen treatment (initiation and
      postinitiation periods) or when given continuously beginning 14 weeks after
      carcinogen administration (promotion/ progression stage). The present study was
      designed to investigate the chemopreventive efficacy of sulindac sulfone
      (exisulind), the sulfone metabolite of sulindac, when administered during the
      promotion/progression stage of colon carcinogenesis in comparison to the effect
      during the initiation and postinitiation periods. We have also studied the
      modulating effect of exisulind on colonic tumor apoptosis. At 5 weeks of age,
      groups of male F344 rats were fed diets containing 0%, 0.06%, and 0.12%
      exisulind. At 7 weeks of age, groups of animals were injected s.c. with AOM (15
      mg/kg body weight, once weekly for 2 weeks). Animals intended for the
      promotion/progression study and receiving 0% exisulind were switched to an
      experimental diet containing 0.12% exisulind at 14 weeks after the second AOM
      treatment. All rats remained on their respective dietary regimens until the
      termination of the study, 50 weeks after the second AOM injection. Colon tumors
      were evaluated histopathologically for tumor type. Administration of 0.06% and
      0.12% exisulind during the initiation and postinitiation periods significantly
      inhibited the incidence and multiplicity of invasive and/or noninvasive
      adenocarcinomas of the colon. The inhibition of colon tumorigenesis by exisulind
      was associated with a significant retardation of body weight gain shortly after
      sulfone administration and increased apoptosis in the colon tumors. In contrast,
      administration of the higher dose (0.12%) of exisulind during the
      promotion/progression stage had only minimal effects on colon tumorigenesis and
      apoptosis in the colon tumors, suggesting that early administration, but not late
      administration, may be required for chemopreventive efficacy of this drug.

PMID- 10416600
TI  - Castration-induced apoptosis of androgen-dependent shionogi carcinoma is
      associated with increased expression of genes encoding insulin-like growth factor
      binding proteins.
AB  - Insulin-like growth factor (IGF)-I has well-characterized mitogenic and
      antiapoptotic effects that are essential for maintenance of the normal prostate
      and may be important during regression of the normal prostate and/or prostate
      tumors induced by androgen-targeting therapies for prostate cancer. IGF-I
      activity is modulated by IGF-binding proteins (IGFBPs). Here we examine IGFBP
      expression during regression of androgen-dependent Shionogi carcinoma tumors
      after castration. In this model, we observe a 90% reduction in Shionogi tumors by
      10 days postcastration. Northern blotting of RNA from tumors collected at various
      times after castration indicates a rapid induction of IGFBP-5 concomitant with
      apoptotic regression of tumors, as detected by Apoptag staining of tumor sections
      after castration. IGFBP-5 mRNA was not detectable in tumors from control animals,
      but levels increased 120-fold in tumors 3 days after castration. The mRNAs for
      IGFBP-3 and 4 were abundant in Shionogi tumors from intact mice and decreased to 
      33% and -20% of control, respectively. Castration had no significant effect on
      IGFBP-2 expression. Treatment with calcium channel blockers inhibited castration
      induced apoptosis and tumor regression and also significantly inhibited up
      regulation of IGFBP-5 after castration. These data provide strong evidence for a
      functional role of IGFBP-5 expression in mediating the apoptosis induced by
      androgen deprivation in androgen-dependent neoplasia.

PMID- 10416601
TI  - Systemic administration of a recombinant vaccinia virus expressing the cytosine
      deaminase gene and subsequent treatment with 5-fluorocytosine leads to tumor
      specific gene expression and prolongation of survival in mice.
AB  - Suicide gene therapy using the cytosine deaminase (CD) gene and 5-fluorocytosine
      (5-FC) has shown promising results for the treatment of colon carcinoma cells in
      vitro. Efficient viral infection and tumor-specific gene delivery is crucial for
      clinically measurable treatment effects. After proving efficient gene transfer in
      vitro, we demonstrate here that genes can be delivered to metastatic liver tumors
      in vivo in a highly selective manner using systemic delivery of a thymidine
      kinase-deleted (TK-) recombinant vaccinia virus (Western Reserve strain). When
      the vector was administered systemically in C57BL/6 mice or nude/athymic mice
      with established disseminated MC38 liver metastases, transgene expression in
      tumors was usually 1,000 to 10,000-fold higher compared with other organs (n =
      160; P < 0.0001). This tumor-specific gene transfer leads to significant tumor
      responses and subsequent survival benefits after the transfer of the CD gene to
      liver metastases and subsequent systemic treatment with the prodrug 5-FC (P <
      0.0001). We describe reporter gene and survival experiments both in
      immunocompetent and athymic nude mice, establishing a gene expression pattern
      over time and characterizing the treatment effects of the virus delivery/prodrug
      system. Cure rates of up to 30% in animals with established liver metastases show
      that suicide gene therapy using TK- vaccinia virus as a vector may be a promising
      system for the clinical application of tumor-directed gene therapy.

PMID- 10416602
TI  - Role of tumor necrosis factor alpha in hyperthermia-induced apoptosis of human
      leukemia cells.
AB  - We used the human myelomonoblastic leukemia cell line PLB-985 to study the
      effects of temperatures ranging from 37 degrees C to 43 degrees C for 1 h on the
      induction of apoptosis and cell cycle distribution in leukemia cells. The
      threshold temperature for the onset of apoptosis was 42 degrees C. Whereas
      hyperthermia exerted no effect on the expression of Bcl-2 and Bax, heat induced a
      >30-fold increase of tumor necrosis factor (TNF) alpha mRNA expression and a
      significant increase in TNF-alpha protein secretion. This endogenous production
      of TNF-alpha correlated directly with the temperature-induced apoptode effect.
      Blocking TNF-alpha expression via treatment with pyrrolidinedithiocarbamate or
      blocking TNF-alpha activity with neutralizing antibodies abrogated heat-provoked
      apoptosis. In addition, exposure of cell culture supernatant of heat-treated PLB
      985 cells to untreated cells induced an apoptotic effect. These data indicate a
      TNF-a-mediated self eradication of the leukemia cells after heat exposure.
      Inducing apoptosis with wild-type TNF-alpha or p55 and p75 protein muteins
      demonstrated that this effect was mediated by the p55 receptor. Interestingly,
      the autocrine suicidal loop found in immature leukemia cells was lost after
      granulocytic differentiation with 0.5% N,N-dimethylformamide. These data should
      be of critical importance for the understanding of the biological impact of fever
      as well as for developing therapeutic approaches to malignant diseases

PMID- 10416603
TI  - Highly augmented cytopathic effect of a fiber-mutant E1B-defective adenovirus for
      gene therapy of gliomas.
AB  - An E1B 55-kDa gene-defective adenovirus (Adv), ONYX-015, has been reported to be
      a highly useful replication-competent Adv that shows cytopathic effect for
      cancers with an abnormal p53 gene, without damaging normal tissues. In this
      study, we combined this Adv (Adv-E1AdB) with a fiber mutation, F/K20, which has a
      stretch of 20 lysine residues added at the COOH-terminus of the fiber and shows
      high transduction efficiency to gliomas. In U-373 MG glioma cells, the
      transduction efficiency of Adv-F/ K20 for lacZ was nine times higher than that of
      the Adv with wild-type fiber (Adv-F/wt) for lacZ. At a multiplicity of infection
      of 30, the replication efficiency of Adv-E1AdB-F/K20 was 11 times higher than
      that of Adv-E1AdB with wt fiber (Adv-E1AdB-F/wt). The ED50 value of AdvE1AdB
      F/K20 to U-373 MG cells, which is a measure of the in vitro cytopathic effect,
      was 32 times greater than that of Adv-E1AdB-F/wt. injection of Adv-E1AdB-F/K20
      suppressed the in vivo growth of tumors. The antitumoral effect of Adv-E1AdB
      F/K20 was remarkably stronger than that of Adv-E1AdB-F/wt. A greater quantity of
      replicated virus protein (hexon) by infection with Adv-E1AdB-F/K20 was
      demonstrated in vitro and in vivo, compared with that of Adv-E1AdB-F/wt. In
      conclusion, gene therapy using Adv-E1AdB-F/K20, which drastically augmented the
      antitumoral effect of Adv-E1AdB, will be a promising therapeutic approach for
      gliomas.

PMID- 10416604
TI  - Increased immunogenicity of tumor vaccines complexed with anti-Gal: studies in
      knockout mice for alpha1,3galactosyltransferase.
AB  - A major prerequisite for the success of tumor vaccines is their effective uptake
      by antigen-presenting cells (APCs) and transport of these APCs to the draining
      lymph nodes, where the processed and presented tumor-associated antigens activate
      tumor-specific naive T cells. We previously suggested that the immunogenicity of
      autologus tumor vaccines in humans may be augmented by engineering vaccinating
      tumor cell membranes to express alpha-galactosyl (alpha-gal) epitopes (i.e.,
      Galalpha1,3Galbeta1,4GlcNAc-R). Subsequent in situ binding of natural anti-Gal
      IgG molecules to these epitopes would result in the formation of immune complexes
      that target tumor vaccines for uptake by APCs, via the interaction of the Fc
      portion of anti-Gal with Fcgamma receptors on APCs. This hypothesis was tested in
      a unique experimental animal model of knockout mice for
      alpha1,3galactosyltransferase (alpha1,3GT) and the mouse melanoma B16-BL6
      (referred to here as BL6). Like humans, these mice lack alpha-gal epitopes and
      produce anti-GaL BL6 melanoma cels are highly tumorigenic, and like human tumor
      cells, they lack alpha-gal epitopes. Expression of alpha-gal epitopes on these
      melanoma cells was achieved by stable transfection with alpha,3GT cDNA. The
      transfected melanoma cells (termed BL6alphaGT) express approximately 2 x 10(6)
      alpha-gal epitopes per cell and readily form immune complexes with anti-Gal.
      Vaccination of the mice with 2 x 10(6) irradiated melanoma cells that express
      alpha-gal epitopes, followed by challenge with 0.5 x 10(6) live parental melanoma
      cells, resulted in protection for at least 2 months (i.e, no tumor growth) in one
      third of the mice, whereas all mice immunized with irradiated parental melanoma
      cells developed tumors 21-26 days post-challenge. The proportion of protected
      mice doubled when the mice were immunized twice with irradiated melanoma cells
      expressing alpha-gal epitopes and challenged with 0.2 x 10(6) live BL6 cells.
      Histological studies on the developing tumors in challenged mice that were
      immunized with melanoma cells expressing alpha-gal epitopes demonstrated
      extensive infiltration of T lymphocytes and macrophages, whereas no mononuclear
      cell infiltrates were observed in tumors of mice immunized with parental tumor
      cells. Overall, these studies imply that immunization of alpha1,3GT knockout mice
      with BL6 melanoma cells that express alpha-gal epitopes elicits, in a proportion
      of the population, protective immune response against the same tumor lacking such
      epitopes. These studies further suggest that similar immunization of cancer
      patients with autologous tumor vaccines that are engineered to express alpha-gal
      epitopes may increase the immune response to autologous tumor-associated antigens
      and, thus, may elicit immune-mediated destruction of metastatic cells expressing
      these antigens.

PMID- 10416605
TI  - Water soluble 20(S)-glycinate esters of 10,11-methylenedioxycamptothecins are
      highly active against human breast cancer xenografts.
AB  - Water-soluble 20(S)-glycinate esters of two highly potent 10,11-methylenedioxy
      analogues of camptothecin (CPT) have been synthesized and evaluated for their
      ability to eradicate human breast cancer tumor xenografts. The glycinate ester
      moiety increases the water solubility of the 10,11-methylenedioxy analogues 4-16
      fold. However, in contrast to CPT-11, a water-soluble CPT analogue that was
      recently approved for second line treatment of colorectal cancer, the 20(S)
      glycinate esters do not require carboxylesterase for conversion to their active
      forms. The glycinate esters are hydrolyzed to their parent, free 20(S)-hydroxyl
      active analogues in phosphate buffer (pH 7.5) and in mouse and human plasma. The
      glycinate esters are also 20-40-fold less potent than CPT-11 in inhibiting human
      acetylcholinesterase. In vivo, we examined 20(S)-glycinate-10,11
      methylenedioxycamptothecin, 20(S)-glycinate-7-chloromethyl-10,11
      methylenedioxycamptothecin, and CPT-11. We found that the two 10,11
      methylenedioxy analogues had antitumor activity against breast cancer xenografts
      that was comparable to that of CPT-11. Our results indicate that water-soluble
      20(S)-glycinate esters of highly potent CPT analogues provide compounds that
      maintain biological activity, do not require interactions with carboxylesterases,
      and do not inhibit human acetylcholinesterase.

PMID- 10416606
TI  - Enhanced apoptotic response to photodynamic therapy after bcl-2 transfection.
AB  - Apoptosis is a cellular death process involving the sequential activation of a
      series of caspases, endonucleases, and other enzymes. The initiation of apoptosis
      can be inhibited by overexpression of bcl-2 and certain other members of a
      related family of proteins. We examined the effects of bcl-2 overexpression on
      the apoptotic response to photodynamic therapy (PDT), using aluminum
      phthalocyanine as the photosensitizing agent. In this study, we compared the
      immortalized human breast epithelial cell line MCF10A with a subline (MCF10A/bcl
      2) transfected with the human bcl-2 gene. The latter was approximately 2-fold
      more sensitive to the phototoxic effects of PDT. At a 50 mJ/cm2 light dose,
      photodamage to MCF-10A/bcl-2 resulted in a greater loss of the mitochondrial
      membrane potential (delta(psi)m), enhanced release of mitochondrial cytochrome c,
      a more rapid and greater activation of caspase-3, and a greater apoptotic
      response. Western blot analysis revealed that the transfected cell line showed
      overexpression of both bcl-2 and bax, and that PDT caused selective destruction
      of bcl-2, leaving bax unaffected. The greater apoptotic response by the
      transfected line is, therefore, attributed to the higher bax:bcl-2 ratio after
      photodamage.

PMID- 10416607
TI  - Identification of sulfated oligosaccharide-based inhibitors of tumor growth and
      metastasis using novel in vitro assays for angiogenesis and heparanase activity.
AB  - Inhibitors of tumor angiogenesis and metastasis are rapidly emerging as important
      new drug candidates for cancer therapy. To facilitate the identification of such
      drugs, we recently developed novel and rapid in vitro assays for human
      angiogenesis and for the extracellular matrix-degrading enzyme heparanase, which
      has been implicated in tumor metastasis. In this study, sulfated
      oligosaccharides, which are structural mimics of heparan sulfate, were
      investigated as drug candidates because these compounds may interfere with
      heparan sulfate recognition by many angiogenic growth factors and may inhibit
      cleavage of heparan sulfate by heparanase. In the preliminary screening studies,
      it was found that inhibitory activity in both assay systems was critically
      dependent on chain length and degree of sulfation, highly sulfated linear
      oligosaccharides of five or more monosaccharides in length being the most active.
      However, two sulfated oligosaccharides stood out as potential antitumor drugs,
      phosphomannopentaose sulfate (PI-88) and maltohexaose sulfate, both of these
      compounds having the important property of simultaneously being potent inhibitors
      of in vitro angiogenesis and heparanase activity. Due to the ease of manufacture
      of the starting material, phosphomannopentaose, PI-88 was studied in more detail.
      PI-88 was shown to inhibit the primary tumor growth of the highly invasive rat
      mammary adenocarcinoma 13762 MAT by approximately 50%, inhibit metastasis to the
      draining popliteal lymph node by approximately 40%, and reduce the vascularity of
      tumors by approximately 30%, all of these effects being highly significant. Acute
      hematogenous metastasis assays also demonstrated that PI-88 was a potent (>90%)
      inhibitor of blood-borne metastasis. Thus, by the use of novel in vitro screening
      procedures, we have identified a promising antitumor agent.

PMID- 10416609
TI  - Direct amifostine effect on renal tubule cells in rats.
AB  - Clinical trials indicate that amifostine offers protection against cisplatin
      induced nephrotoxicity. It is unclear whether a direct pharmacological t on renal
      tubular cells is involved. We investigated the effect of amifostine pretreatment
      on the tubular apparatus and evaluated its nephroprotective potential. A total of
      32 rats were treated by i.p. administration of 0.9% saline solution (group 1), 5
      mg/kg cisplatin (group 2), 25 mg/kg amifostine (group 3), and 25 mg/kg amifostine
      followed by 5 mg/kg cisplatin (group 4) after 30 min. We recorded elevation of N
      acetyl-beta-D-glucosaminidase (NAG) in 24 h pooled urine as a specific marker for
      tubular lesions, renal leakage of magnesium as an unspecific nephrotoxicity
      marker, and survival over a 10-day observation period. A significant (P < 0.002)
      increase in urinary NAG after treatment was documented only in cisplatin-treated
      group 2 [day 2 (mean+/-SE), 93+/-2.1 units/gram creatinine; day 4, 70.6+/-16
      units/gram creatinine; normalization at day 8]. Treatment with amifostine before
      cisplatin administration resulted in a slight urinary NAG leakage (day 2, 2.8+/
      1.8 units/gram creatinine; day 4, 13.8+/-13 units/gram creatinine; normalization
      at day 6). No increase in urinary enzyme levels was seen in the other groups, and
      there were no significant differences in urinary magnesium between all groups.
      Four of eight rats in the cisplatin-treated group and one of eight rats in the
      amifostine plus cisplatin-treated group died.

PMID- 10416608
TI  - Human small cell lung cancer NYH cells selected for resistance to the
      bisdioxopiperazine topoisomerase II catalytic inhibitor ICRF-187 demonstrate a
      functional R162Q mutation in the Walker A consensus ATP binding domain of the
      alpha isoform.
AB  - Bisdioxopiperazine drugs such as ICRF-187 are catalytic inhibitors of DNA
      topoisomerase II, with at least two effects on the enzyme: namely, locking it in
      a closed-clamp form and inhibiting its ATPase activity. This is in contrast to
      topoisomerase II poisons as etoposide and amsacrine (m-AMSA), which act by
      stabilizing enzyme-DNA-drug complexes at a stage in which the DNA gate strand is
      cleaved and the protein is covalently attached to DNA. Human small cell lung
      cancer NYH cells selected for resistance to ICRF-187 (NYH/187) showed a 25%
      increase in topoisomerase IIalpha level and no change in expression of the beta
      isoform. Sequencing of the entire topoisomerase IIalpha cDNA from NYH/187 cells
      demonstrated a homozygous G-->A point mutation at nucleotide 485, leading to a
      R162Q conversion in the Walker A consensus ATP binding site (residues 161-165 in
      the alpha isoform), this being the first drug-selected mutation described at this
      site. Western blotting after incubation with ICRF-187 showed no depletion of the
      alpha isoform in NYH/187 cells in contrast to wild-type (wt) cells, whereas equal
      depletion of the beta isoform was observed in the two sublines. Alkaline elution
      assay demonstrated a lack of inhibition of etoposide-induced DNA single-stranded
      breaks in NYH/187 cells, whereas this inhibition was readily apparent in NYH
      cells. Site-directed mutagenesis in human topoisomerase IIalpha introduced into a
      yeast Saccharomyces cerevisiae strain with a temperature-conditional yeast TOP2
      mutant demonstrated that R162Q conferred resistance to the bisdioxopiperazines
      ICRF-187 and -193 but not to etoposide or m-AMSA. Both etoposide and m-AMSA
      induced more DNA cleavage with purified R162Q enzyme than with the wt. The R162Q
      enzyme has a 20-25% decreased catalytic capacity compared to the wt and was
      almost inactive at <0.25 mM ATP compared to the wt. Kinetoplast DNA decatenation
      by the R162Q enzyme at 1 mM ATP was not resistant to ICRF-187 compared to wt,
      whereas it was clearly less sensitive than wt to ICRF-187 at low ATP
      concentrations. This suggests that it is a shift in the equilibrium to an open
      clamp state in the enzyme's catalytic cycle caused by a decreased ATP binding by
      the mutated enzyme that is responsible for bisdioxopiperazine resistance.

PMID- 10416610
TI  - Combined immunodeficiency associated with increased apoptosis of lymphocytes and
      radiosensitivity fibroblasts.
AB  - Severe immunodeficiency characterized by lymphopenia was found in two siblings,
      one of whom was examined in detail. The calcium flux, pattern of tyrosine
      phosphorylation of proteins, and interleukin 2 (IL-2) production and
      proliferation in response to mitogens suggested that the peripheral blood T cells
      activated normally. The peripheral blood T cells were shown to have an activated
      phenotype with increased expression of CD45RO+ and CD95/Fas. Increased
      spontaneous apoptosis occurred in unstimulated lymphocyte cultures. The elevated
      apoptosis was not due to alterations in expression or to mutations in Bcl-2, Bcl
      X(L), or Flip, nor could the spontaneous apoptosis be prevented by blocking Fas,
      suggesting that it was independent of Fas signaling. This is the first inherited
      combined immunodeficiency associated with impaired lymphocyte survival.
      Fibroblasts derived from the patient showed appreciable radiosensitivity in
      clonal assays, but apoptosis was not elevated. Our results show that the
      fibroblasts represent a new radiosensitive phenotype not associated with cell
      cycle checkpoint defects, V(D)J recombination defects, or elevated chromosome
      breakage. We suggest that the affected gene plays a role in an undetermined
      damage response mechanism that results in elevated spontaneous apoptosis in
      lymphoid cells and radiosensitivity in fibroblasts.

PMID- 10416611
TI  - Two mechanisms for tumor evasion of preexisting cytotoxic T-cell responses:
      lessons from recurrent tumors.
AB  - Tumors evade host immunity at both the induction and effector phases Most studies
      have focused on tumor evasion at the induction phase, and, due in part to poor
      antitumor CTL responses to most tumors, the mechanism for evasion of CTL effector
      function is less clear. Here we have taken advantage of the strong CTL responses
      to a costimulator B7-1-transfected tumor to study the mechanism for tumor evasion
      of preexisting host immunity. We have investigated six independent recurrent
      tumors isolated from mice that were challenged with and had rejected B7-1
      transfected J558 (J558-B7) tumors. Because the mice had developed strong
      antitumor CTL responses, these recurrent tumors must have evaded preexisting
      antitumor CTLs. Indeed, whereas the parental J558-B7 cell line is efficiently
      lysed by the ex vivo tumor-infiltrating lymphocytes, all of the recurrent tumors
      are resistant to such lysis. Interestingly, the recurrent tumors can be divided
      into two groups. The group 1 tumors have vastly reduced levels of cell surface
      MHC class I with a concurrent reduction in the expression of multiple genes
      devoted to MHC class I antigen presentation. In contrast, the group 2 tumors have
      lost the expression of costimulatory molecule B7-1 while retaining cell surface
      MHC class I and expression of all antigen presentation genes studied. These
      results demonstrate that tumors can evade preexisting CTLs either by avoiding
      presentation of the tumor antigen or, surprisingly, by down-regulation of
      costimulatory molecules. The paradoxical requirements of both antigen and
      costimulatory molecules at the effector phase raised an interesting question on
      the nature of antitumor immunity.

PMID- 10416612
TI  - Expression of a dominant-negative mutant inhibitor-kappaBalpha of nuclear factor
      kappaB in human head and neck squamous cell carcinoma inhibits survival,
      proinflammatory cytokine expression, and tumor growth in vivo.
AB  - We demonstrated recently that constitutive expression of proinflammatory
      cytokines interleukin (IL)-1alpha, IL-6, IL-8, and granulocyte-macrophage colony
      stimulating factor in head and neck squamous cell carcinoma is correlated with
      activation of transcription factor nuclear factor (NF)-kappaB/Rel A (p50/p65),
      which binds the promoter region within each of the genes encoding this repertoire
      of cytokines. NF-kappaB can be activated after signal-dependent phosphorylation
      and degradation of inhibitor-kappaBalpha and has been reported to promote cell
      survival and growth. In the present study, we expressed a phosphorylation site
      mutant of inhibitor-kappaBalpha (IkappaBalphaM) in head and neck squamous cell
      carcinoma lines UM-SCC-9, -11B, and -38 to determine the effect of inhibition of
      NF-kappaB on cytokine expression, cell survival in vitro, and growth in vivo.
      After transfection with IKBalphaM, only a few UM-SCC-9 clones were obtained that
      stably expressed the mutant IkappaB, suggesting that expression of a mutant
      IkappaBalpha may affect survival of the transfected UM-SCC cell lines. After
      cotransfection of IkappaBalphaM with a Lac-Z reporter, we found that the number
      of surviving beta-galactosidase-positive cells in the three cell lines was
      reduced by 70-90% when compared with controls transfected with vector lacking the
      insert. In UM-SCC-9 cells that stably expressed IkappaBalphaM, inhibition of
      constitutive and tumor necrosis factor-a induced NF-kappaB activation, and
      production of all four cytokines was observed. Although UM-SCC-9 IkappaBalphaM
      transfected cells proliferated at the same rate as vector-transfected cells in
      vitro, a significant reduction in growth of tumor xenografts was observed in SCID
      mice in vivo. The decreased growth of UM-SCC-9 IkappaBalphaM-transfected tumor
      cells accompanied decreased immunohistochemical detection of the activated form
      of NF-kappaB in situ. These results provide evidence that NF-KB and IkappaBalpha
      play an important role in survival, constitutive and inducible expression of
      proinflammatory cytokines, and growth of squamous cell carcinoma. NF-kappaB could
      serve as a potential target for therapeutic intervention against cytokine and
      other immediate-early gene responses that contribute to the survival, growth, and
      pathogenesis of these cancers.

PMID- 10416613
TI  - Prognostic value of genomic alterations in invasive cervical squamous cell
      carcinoma of clinical stage IB detected by comparative genomic hybridization.
AB  - The clinical behavior of invasive cervical carcinoma of clinical stage IB varies
      considerably in tumors presenting without regional lymph node metastases. The
      early identification of patients at higher risk for poor outcome may prove useful
      because these patients would benefit from aggressive adjuvant treatments. In this
      study, comparative genomic hybridization was applied to evaluate whether genomic
      aberrations have prognostic significance in cervical carcinoma. Genomic
      alterations were evaluated in 62 cervical carcinomas of clinical stage IB. DNA
      sequence losses were most prevalent at chromosomes 4q (53%), 3p (52%), 13q (45%),
      4p (44%), Xq (44%), 5q (40%), 18q (37%), and 6q (35%). Several genomic
      alterations were associated with poor clinical outcome or metastasis. The total
      number of DNA aberrations/tumor (P < 0.02) and the number of DNA sequence
      losses/tumor (P < 0.04) were associated with disease-specific survival. 9p
      deletions were significantly more frequent in carcinomas with lymph node
      metastasis than in node-negative tumors (P < 0.03). Losses of chromosome 11p (P <
      0.0001) and 18q (P < 0.01) were associated with poor prognosis in cervical
      carcinomas without lymph node metastasis. These data suggest that inactivation of
      tumor suppressor genes on chromosomes 9p, 11p, and 18q may play a role in the
      progression of cervical carcinoma.

PMID- 10416614
TI  - A p21(Waf1/Cip1)carboxyl-terminal peptide exhibited cyclin-dependent kinase
      inhibitory activity and cytotoxicity when introduced into human cells.
AB  - In the present study, we report the cyclin-dependent kinase (Cdk)-inhibitory
      activity of a series of p21waf1/cip1 (p21) peptide fragments spanning the whole
      protein against the cyclin D1/Cdk4 and cyclin E/Cdk2 enzymes. The most potent p21
      peptide tested in our initial peptide series, designated W10, spanned amino acids
      139 to 164, a region of p21 that has been found independently to bind to
      proliferating cell nuclear antigen and also to inhibit Cdk activity. We go on to
      report the importance of putative beta-strand and 3(10)-helix motifs in the W10
      peptide for cyclin-dependent kinase-inhibitory activity. We also describe the
      cellular activity of W10 and derivatives that were chemically linked to an
      antennapedia peptide, the latter segment acting as a cell membrane carrier. We
      found that the W10AP peptide exhibited growth inhibition that resulted from
      necrosis in human lymphoma CA46 cells. Furthermore, regions in the W10 peptide
      responsible for Cdk-inhibition were also important for the degree of this
      cellular activity. These studies provide insights that may eventually, through
      further design, yield agents for the therapy of cancer.

PMID- 10416615
TI  - Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy
      reveals cancer predisposition.
AB  - Patients with the nucleotide excision repair (NER) disorder xeroderma pigmentosum
      (XP) are highly predisposed to develop sunlight-induced skin cancer, in
      remarkable contrast to photosensitive NER-deficient trichothiodystrophy (TTD)
      patients carrying mutations in the same XPD gene. XPD encodes a helicase subunit
      of the dually functional DNA repair/basal transcription complex TFIIH. The
      pleiotropic disease phenotype is hypothesized to be, in part, derived from a
      repair defect causing UV sensitivity and, in part, from a subtle, viable basal
      transcription deficiency accounting for the cutaneous, developmental, and the
      typical brittle hair features of TTD. To understand the relationship between
      deficient NER and tumor susceptibility, we used a mouse model for TTD that mimics
      an XPD point mutation of a TTD patient in the mouse germline. Like the
      fibroblasts from the patient, mouse cells exhibit a partial NER defect, evident
      from the reduced UV-induced DNA repair synthesis (residual repair capacity
      approximately 25%), limited recovery of RNA synthesis after UV exposure, and a
      relatively mild hypersensitivity to cell killing by UV or 7,12
      dimethylbenz[a]anthracene. In accordance with the cellular studies, TTD mice
      exhibit a modestly increased sensitivity to UV-induced inflammation and
      hyperplasia of the skin. In striking contrast to the human syndrome, TTD mice
      manifest a dear susceptibility to UV- and 7,12-dimethylbenz[a]anthracene-induced
      skin carcinogenesis, albeit not as pronounced as the totally NER-deficient XPA
      mice. These findings open up the possibility that TTD is associated with a so far
      unnoticed cancer predisposition and support the notion that a NER deficiency
      enhances cancer susceptibility. These findings have important implications for
      the etiology of the human disorder and for the impact of NER on carcinogenesis.

PMID- 10416616
TI  - The host environment promotes the constitutive activation of nuclear factor
      kappaB and proinflammatory cytokine expression during metastatic tumor
      progression of murine squamous cell carcinoma.
AB  - We reported previously that tumor cells isolated from metastases of the in vitro
      transformed squamous cell carcinoma line Pam 212 exhibit an elevation in
      constitutive production of proinflmmatory cytokines interleukin (IL)-1alpha, IL
      6, granulocyte-macrophage colony-stimulating factor, and KC (the murine homologue
      of chemokine Gro-alpha). The basis for constitutive expression of these cytokines
      after tumor progression in vivo is unknown. Regulation of the expression of these
      proinflammatory cytokines involves transcription factor nuclear factor kappaB (NF
      kappaB), which can be activated by cytokines such as tumor necrosis factor (TNF)
      alpha. In this study, we compared the constitutive and TNF-alpha-induced
      expression of proinflammatory cytokines in parental Pam 212 and metastatic LY-2
      and LY-8 cell lines and determined the relationship of cytokine expression to
      activation of NF-kappaB. We found that the metastatic cell lines exhibited an
      increase in constitutive and TNF-alpha-inducible expression of proinflammatory
      cytokines when compared with parental Pam 212 cells. The increased cytokine
      expression was associated with an increase in constitutive and TNF-alpha
      inducible activation of NF-kappaB as demonstrated by electrophoretic mobility
      shift assay and luciferase-reporter gene assay. Constitutive nuclear localization
      of NF-kappaB p65 was observed in LY-2 and LY-8 cells in culture and in tumor
      specimens but rarely in Pam 212 cells, consistent with the constitutive
      activation of NF-kappaB in tumor cels after selection in vivo. Induction of NF
      kappaB by TNF-alpha was inhibited by the addition of protease inhibitors calpain
      inhibitor I and N-tosyl-phechloromethyl ketone and antioxidant 1
      pyrrolidinecarbodithioic acid, whereas constitutive activation of NF-kappaB and
      cytokine KC mRNA expression was inhibited by N-tosyl-phechloromethyl ketone
      alone. Overexpression of a human Ikappa(B)alpha dominant suppresser in Pam 212
      cells inhibited TNF-alpha-induced NF-kappaB binding activity and KC expression.
      These data indicate that activation of NF-kappaB contributes to increased
      expression of proinflammatory cytokines during metastatic tumor progression of
      squamous cell carcinoma, and that distinct mechanisms may be involved in the
      regulation of constitutive and TNF-alpha-induced activation of NF-kappaB in
      squamous cell carcinoma.

PMID- 10416617
TI  - Inhibition of cyclin D1 expression in human pancreatic cancer cells is associated
      with increased chemosensitivity and decreased expression of multiple
      chemoresistance genes.
AB  - Cyclin D1 belongs to a family of protein kinases that have been implicated in
      cell cycle regulation. Inhibition of cyclin D1 expression has been recently shown
      (M. Kornmann, et al., J. Clin. Invest, 101: 344-352, 1998) to suppress pancreatic
      cancer cell growth and increase cytotoxic actions of cisplatinum. The aim of the
      present study was to determine whether inhibition of cyclin D1 expression also
      modulates the effects of other antineoplastic drugs and whether it is associated
      with alterations in the level of expression of drug resistance genes. The
      suppression of cyclin D1 expression after the stable transfection of a cyclin D1
      antisense construct in PANC-1 and COLO-357 human pancreatic cancer cells resulted
      in a significant increase in sensitivity to the fluoropyrimidines 5-fluorouracil
      and 5-fluoro-2'-deoxyuridine and to mitoxantrone. All of the antisense-expressing
      dones exhibited a decrease in thymidylate synthase and an increase in thymidine
      phosphorylase mRNA expression as determined by reverse transcription-PCR analysis
      and decreased levels of MDR-1 and MRP mRNA as determined by Northern blotting.
      These findings demonstrate that the inhibition of cyclin D1, in addition to
      suppressing the growth of pancreatic cancer cells, enhances their responsiveness
      to multiple chemotherapeutic agents and suggest that this effect may be due to
      the altered expression of several chemoresistance genes.

PMID- 10416618
TI  - Urothelium-specific expression of an oncogene in transgenic mice induced the
      formation of carcinoma in situ and invasive transitional cell carcinoma.
AB  - Although many genetic alterations are known to be associated with human
      transitional cell carcinoma (TCC) of the urinary bladder, relatively little is
      known about the roles of these molecular defects, singular or in combination, in
      bladder tumorigenesis. We have developed a transgenic mouse model of bladder
      tumorigenesis using a 3.6-kb promoter of uroplakin II gene to drive the
      urotheliums-specific expression of oncogenes. In this study, we demonstrate that
      transgenic mice bearing a low copy number of SV40T transgene developed bladder
      carcinoma in situ (CIS), whereas those bearing high copies developed CIS as well
      as invasive and metastatic TCCs. These results indicate that the SV40T
      inactivation of p53 and retinoblastoma gene products, defects frequently found in
      human bladder CIS and invasive TCCs, can cause the aggressive form of TCC. Our
      results also provide experimental proof that CIS is a precursor of invasive TCCs,
      thus supporting the concept of two distinct pathways of bladder tumorigenesis
      (papillary versus CIS/invasive TCC). This transgenic system can be used for the
      systematic dissection of the roles of individual or combinations of specific
      molecular events in bladder tumorigenesis.

PMID- 10416619
TI  - Overexpression of retinoic acid receptor beta in head and neck squamous cell
      carcinoma cells increases their sensitivity to retinoid-induced suppression of
      squamous differentiation by retinoids.
AB  - Nuclear retinoic acid receptor beta(RARbeta) expression is suppressed in many
      head and neck squamous cell carcinomas (HNSCCs), and an inverse relationship was
      found between squamous differentiation and RARbeta expression in such cells. To
      investigate the role of RARbeta in HNSCC growth and differentiation, we
      transfected a retroviral RARbeta2 expression vector (LNSbeta) into HNSCC SqCC/Y1
      cells, which do not express endogenous RARbeta but do express RARalpha, RARgamma,
      and retinoid X receptors. Transfected clones expressing RARbeta2 mRNA and protein
      exhibited enhanced sensitivity to the suppressive effects of all-trans-retinoic
      acid (ATRA) on squamous differentiation compared with cells transfected with the
      LNSX vector only; transglutaminase type I level was suppressed after a 3-day
      treatment with 10(-10) M ATRA in four of five LNSbeta clones, whereas it was not
      suppressed in LNSX cells even by 10(-6) M ATRA. Similarly, cytokeratin 1 mRNA
      level was more suppressed in ATRA-treated LNSbeta clones than it was in LNSX
      cells. This effect was independent of transrepression of activator protein-1.
      None of the LNSbeta-transfected clones showed an increased growth inhibition by
      ATRA, 9-cis-retinoic acid, or the synthetic retinoid 6-(5,6,7,8-tetrahydro
      5,5,8,8-tetramethyl-2-naphthalenyl)-2-naphthale necarboxylic acid. These findings
      suggest that, in SqCC/Y1 cells, RARbeta mediates suppression of squamous
      differentiation by ATRA without enhancing its growth-inhibitory effects.

PMID- 10416620
TI  - Differential reconstitution of mitochondrial respiratory chain activity and
      plasma redox state by cysteine and ornithine in a model of cancer cachexia.
AB  - The mechanism of wasting, as it occurs in malignant diseases and various
      etiologically unrelated conditions, is still poorly understood. We have,
      therefore, studied putative cause/effect relationships in a murine model of
      cancer cachexia, C57BL/6 mice bearing the fibrosarcoma MCA-105. The plasma of
      these mice showed decreased albumin and increased glutamate levels, which are
      typically found in practically all catabolic conditions. Skeletal muscles from
      tumor-bearing mice were found to have an abnormally low mitochondrial respiratory
      chain activity (mito.RCA) and significantly decreased glutathione (GSH) levels.
      The decrease in mito.RCA was correlated with an increase in the i.m. GSH
      disulfide/GSH ratio, the plasma cystine/thiol ratio, and the GSH disulfide/GSH
      ratio in the bile. This is indicative of a generalized shift in the redox state
      extending through different body fluids. Treatment of tumor-bearing mice with
      ornithine, a precursor of the radical scavenger spermine, reversed both the
      decrease in mito.RCA and the change in the redox state, whereas treatment with
      cysteine, a GSH precursor, normalized only the redox state. Treatment of normal
      mice with difluoromethyl-ornithine, a specific inhibitor of ornithine
      decarboxylase and spermine biosynthesis, inhibited the mito.RCA in the skeletal
      muscle tissue, thus illustrating the importance of the putrescine/spermine
      pathway in the maintenance of mito.RCA. Ornithine, cysteine, and N-acetyl
      cysteine (NAC) also reconstituted the abnormally low concentrations of the GSH
      precursor glutamate in the skeletal muscle tissue of tumor-bearing mice. Higher
      doses, however, enhanced tumor growth and increased the plasma glucose level in
      normal mice. In the latter, cysteine and NAC also decreased i.m. catalase and GSH
      peroxidase activities. Taken together, our studies on the effects of ornithine,
      cysteine, and NAC illuminate some of the mechanistic pathways involved in
      cachexia and suggest targets for therapeutic intervention.

PMID- 10416621
TI  - Head, neck, and facial injuries as markers of domestic violence in women.
AB  - PURPOSE: The diagnosis of domestic violence (DV) is difficult because of a lack
      of clearly defined signs and symptoms. The goal of this study was to confirm and
      refine the role of head, neck, and face (HNF) injuries as markers of DV. PATIENTS
      AND METHODS: A cross-sectional study design and a sample of female trauma
      patients treated in an inner-city hospital emergency room (Grady Memorial
      Hospital, Atlanta, GA) were used. The predictor study variable was injury
      location (HNF or other location). The outcome variable was traumatic origin (DV
      or other cause). A victim of DV was defined as a patient who gave a history of
      being injured by her spouse or sexual partner. Other data included age, nature of
      the injury (blunt or penetrating), and injury severity score (ISS). Descriptive,
      bivariate, and logistic regression statistical analyses were performed. RESULTS:
      The sample consisted of 100 injured women, with a mean age of 40+/-16.3 years and
      a mean ISS of 3.3+/-3.0. Thirty-four women were victims of DV. The mean age of
      the DV victims was 32.5+/-7.3 years, compared with a mean age of 43.9+/-18.2 year
      in the other-causes group (P = .001). The mean ISS for the DV victims was 3.4+/
      3.0, and the mean ISS for the other-causes group was 3.2+/-3.0 (P = .65). DV
      victims were 7.5 (2.5 < RR < 22.9) times more likely to have HNF injuries than
      other trauma patients (P < .001). Age was associated with cause and location of
      injury. After controlling for age, location remained statistically associated
      with cause (P = .0002). Sensitivity and specificity of HNF injuries and DV were
      91% and 59%, respectively. CONCLUSIONS: The data suggest that although HNF
      injuries and age were sensitive predictors of DV, they remain poor in their
      specificity as markers.

PMID- 10416622
TI  - Mandibular motion after closed and open treatment of unilateral mandibular
      condylar process fractures.
AB  - PURPOSE: This study compared mandibular and condylar mobility after open or
      closed treatment for fractures of the mandibular condylar process. PATIENTS AND
      METHODS: One hundred thirty-six patients (111 male, 25 female), 74 treated by
      closed and 62 by open methods, were included in this study. They underwent
      testing of mandibular and condyle mobility at 6 weeks, 6 months, and 1, 2, and 3
      years postsurgery. A jaw-tracking device was used to assess mandibular motion.
      Radiographs that were traced and digitized were used to assess condylar
      displacement and condylar mobility. Standard statistical methods were used to
      assess differences between groups. RESULTS: Patients treated by open reduction
      had significantly greater initial displacement of their condylar processes than
      did the group treated closed. Immediately after treatment and uprighting of the
      condyles in the open treatment group, patients treated closed had significantly
      more displacement. At 6 weeks, patients treated closed had some measures of
      mandibular mobility that were significantly greater than those in patients
      treated by open reduction. However, after the 6-week period there were minimal
      differences in mandibular mobility between groups. At 6 weeks, patients treated
      by open reduction had significantly greater vertical mobility of the condyle than
      patients treated closed despite less mouth opening. After the 6-week period,
      patients treated by open reduction continued to have greater condylar mobility on
      the fractured side than did patients treated by closed methods. No measures of
      postsurgical displacement correlated with mobility measures in patients treated
      by open reduction. However, several measures of mandibular displacement
      correlated with measures of mobility in patients treated closed, indicating that
      the more displaced the condylar process, the more limited the mobility of the
      mandible. CONCLUSIONS: Based on this study, patients treated for fractures of the
      mandibular condylar process by open reduction had somewhat greater condylar
      mobility than patients treated closed, even though the former group had more
      severely displaced fractures before surgery. Therefore, open reduction may
      produce functional benefits to patients with severely displaced condylar process
      fractures.

PMID- 10416623
TI  - Maxillofacial trauma in the elderly.
AB  - PURPOSE: This article gives a general description of the incidence, causes, and
      complexity of maxillofacial fractures in the elderly and discusses whether
      modification is required in assessment, surgical indications, and techniques in
      such cases. PATIENTS AND METHODS: A retrospective clinical and radiologic study
      evaluated 222 patients older than 60 years of age (mean age, 70.3) hospitalized
      with maxillofacial trauma over the period 1987 to 1996 in the Division of
      Maxillofacial Surgery, University of Turin. The patients were classified
      according to the following parameters: age, cause of injury, site of trauma,
      presence of associated fractures, pertinent medical history, type of treatment,
      length of hospitalization, and complications. The data were compared with those
      from a control group consisting of 178 adult patients younger than 60 years of
      age. RESULTS: The presence of a preexisting systemic pathologic condition was the
      most important factor in determining hospitalization time, which was greater than
      in the control group. In 89 patients (40.1%), no treatment was considered
      necessary, whereas 133 patients (59.9%) were treated by surgery. In 115 patients
      (86.5%), the fractures were treated by open reduction and internal fixation,
      whereas closed reduction was used in 18 patients (13.5%). There were
      complications with six patients (2.7%), and one died in the hospital.
      CONCLUSIONS: The findings of this study suggest that surgical intervention is
      less frequently indicated in facial trauma of the elderly because of physiologic,
      psychologic, and social changes brought on by the aging process. The principles
      of treatment, the results, and the complications do not differ greatly in this
      group when compared with the normal adult population.

PMID- 10416624
TI  - Efficacy of a mandibular manipulation technique in reducing the permanently
      displaced temporomandibular joint disc.
AB  - PURPOSE: The purpose of this study was to determine whether disc reduction
      occurred in patients with closed lock after mandibular manipulation (MM) and to
      analyze the factors that influenced the result. PATIENTS AND METHODS: Two hundred
      fifteen patients with closed lock received MM. Of these, 74 patients (79 joints)
      were assessed by means of magnetic resonance imaging (MRI) for disc reduction.
      The results of the MRI were compared with the findings from the clinical and
      radiographic examinations. RESULTS: According to the MRI assessment, only 18% (14
      of 79) of the joints had successful disc reduction. The unsuccessfully treated
      joints had severe joint pain, disc displacement, condylar bone change, and disc
      deformity. CONCLUSIONS: The results of this study suggest that successful
      reduction of the disc by MM is rare. They also suggest that MM is least effective
      in the advanced stages of internal derangement, when the disc becomes deformed.

PMID- 10416625
TI  - Temporomandibular joint reconstruction in children using costochondral grafts.
AB  - PURPOSE: The aim of this study was to evaluate the postoperative growth of the
      mandible after reconstruction of the condylar process using costochondral grafts
      in children. PATIENTS AND METHODS: Temporomandibular joint (TMJ) ankylosis was
      surgically treated and the joint reconstructed with a costochondral graft (CCG)
      in two boys and eight girls with a mean age of 7.4 years. Two children had
      bilateral ankylosis. Postoperative changes and craniofacial growth were monitored
      by lateral and posteroanterior (PA) cephalograms annually from 2 to 6 years (mean
      of 4 years). RESULTS: Postoperatively, in the eight children with unilateral TMJ
      reconstruction, the mandible (Co-Gn) grew an average of 14.7 mm in length on the
      affected side and 15.1 mm on the nonaffected side; ramus length (Co-Go) increased
      an average of 7.1 mm on the affected side and 7.3 mm on the nonaffected side.
      However, in five of the children the chin progressively deviated toward the
      nonaffected side after TMJ reconstruction. The CCGs tended to have a more
      vertically directed condylar growth pattern and a more laterally positioned
      condyle. In the two cases with bilateral TMJ reconstruction, the CCGs grew until
      there was a mandibular prognathism that required orthognathic surgery to set back
      the mandible. CONCLUSIONS: Using CCGs to reconstruct TMJ ankylosis in children
      provides a functional condyle with growth potential. However, there is a
      possibility of excessive growth of the graft, resulting in deviation of the chin
      and mandibular prognathism years later.

PMID- 10416626
TI  - Quantification of bone harvested from the iliac crest using a power-driven
      trephine.
AB  - PURPOSE: This study describes an alternate approach for harvesting cancellous
      bone from the anterior iliac crest and quantifies the amount of bone removed
      using a power-driven trephine without the need for an open procedure. The safety
      of this technique is also evaluated. MATERIALS AND METHODS: Twenty-five adult
      cadavers were used to determine the volume and weight of bone that could be
      harvested using a motorized trephine. A total of 50 anterior iliac crests were
      sampled. Core samples of cancellous bone were measured, weighed, and the volume
      calculated. The harvested sites were then dissected and evaluated for
      perforations. These data were compared with the measurement of the first 40
      consecutive cores trephined from patients requiring grafts. RESULTS: The bone
      harvested took the form of a compact core measuring, on average, 33.5 mm in
      length and 4.0 mm in diameter. The average weight of each core was 0.44 g, and
      the average volume was 0.42 cm3. Perforation to the medial aspect occurred in 4
      of 50 hips, and lateral perforations occurred in 7 of 50 hips. The greatest
      number of perforations occurred at depths greater than 30 mm and were found in
      the most atrophic cadavers. The 40 cores obtained from patients averaged 34.1 mm
      in length and 0.46 g in weight. The average volume per core was 0.45 cm3.
      CONCLUSIONS: The amount of trephinated autogenous cancellous bone procurable by
      means of a motor-driven trephine is suitable for cases of sinus lifting or to
      fill an alveolar cleft defect. Although the yield of cadaveric bone is slightly
      less than the amount obtainable from patients, it is a useful model to evaluate
      potential complications and estimate yields.

PMID- 10416627
TI  - Virtual arthroscopy of the visible human female temporomandibular joint.
AB  - PURPOSE: This study was designed to obtain views of the temporomandibular joint
      (TMJ) by means of computed arthroscopic simulation (virtual arthroscopy) using
      three-dimensional (3D) processing. MATERIAL AND METHODS: Volume renderings of the
      TMJ from very thin cryosection slices of the Visible Human Female were taken off
      the Internet. Analyze(AVW) software (Biomedical Imaging Resource, Mayo
      Foundation, Rochester, MN) on a Silicon Graphics 02 workstation (Mountain View,
      CA) was then used to obtain 3D images and allow the navigation "fly-through" of
      the simulated joint. RESULTS: Good virtual arthroscopic views of the upper and
      lower joint spaces of both TMJs were obtained by fly-through simulation from the
      lateral and endaural sides. It was possible to observe the presence of a partial
      defect in the articular disc and an osteophyte on the condyle. Virtual
      arthroscopy provided visualization of regions not accessible to real arthroscopy.
      CONCLUSION: These results indicate that virtual arthroscopy will be a new
      technique to investigate the TMJ of the patient with TMJ disorders in the near
      future.

PMID- 10416628
TI  - A sheep model for temporomandibular joint ankylosis.
AB  - PURPOSE: The purpose of this study was to develop an animal model for
      temporomandibular joint (TMJ) ankylosis. MATERIALS AND METHODS: Five sheep had
      removal of the temporal and condylar articular surface plus discectomy in the
      right TMJ; the left side was used as a control. One sheep was killed just after
      operation and four at 3 months. The joints were examined histologically, and a
      scoring system was developed to evaluate the extent of the ankylosis. The range
      of jaw movement was compared between preoperatively and 3 months. RESULTS: Two
      sheep lost 4% of their body weight by 3 months. The range of jaw movement,
      particularly to the left, decreased at 3 months (P < .001). The joint spaces were
      filled with fibrous tissue and cartilage-like tissue. Development of new bone
      from the damaged temporal and condylar surfaces was seen, but full bony fusion
      did not occur. The average histologic score of a zone was 4.9 on the degree-of
      ankylosis scale and 1.7 on the degree-of-calcification scale. There were
      statistically significant differences between the operated and control TMJs for
      both changes (P < .0001). CONCLUSION: Fibrous ankylosis occurs rapidly after
      removal of the TMJ articular surfaces and the disc. This model can be further
      developed to isolate relative factors in the development of ankylosis and in
      evaluation of different treatment methods.

PMID- 10416629
TI  - Effects of estrogen on the condylar cartilage of the rat mandible in organ
      culture.
AB  - PURPOSE: The effects of estrogen on bone have been well documented. However, very
      little is known about the regulatory role of estrogen on cartilage and, in
      particular, the secondary cartilage of the mandibular condyle. The aims of this
      study were to determine whether estrogen receptors are present in the condylar
      cartilage of the rat mandible and to assess the effect of varying 17beta
      estradiol (E2) concentrations on the proteoglycan content of this tissue.
      MATERIALS AND METHODS: Mandibular condyles of 16 female Sprague-Dawley rats were
      resected. Eighteen of these condyles were divided into three groups and the
      condylar cartilage was removed and placed in organ culture for 4 days with media
      containing different concentrations of estrogen: 10(-11) mol/L, 10(-8) mol/L, and
      10(-6) mol/L. The cartilage then was analyzed for proteoglycan content along with
      six specimens not passed through the organ culture. Six intact mandibular
      condyles also were resected and placed in organ culture with the same varying E2
      concentrations, and the condylar cartilage was analyzed for estrogen receptors
      along with two condyles not passed through the culture system. RESULTS: Estrogen
      receptors were evenly distributed within the chondroblastic and hypertrophic
      zones in the control group and the group with 10(-11) mol/L E2. With E2
      concentrations of 10(-8) mol/L and 10(-6) mol/L, there was a qualitative decrease
      in hypertrophic chondroblasts, thickness of the condylar cartilage, and a
      significant decrease in proteoglycan content. CONCLUSIONS: This study shows the
      presence of estrogen receptors in the secondary cartilage of the rat mandibular
      condyle. Estrogen has the potential to cause a decrease in extracellular matrix
      and thickness of this cartilage.

PMID- 10416630
TI  - Third molar management: a case for routine removal in adolescent and young adult
      orthodontic patients.
AB  - The role of the orthodontist is to treat patients to optimal function,
      aesthetics, and long-term stability. The controversy surrounding third molars has
      focused on the pathologic problems they may cause and the risk/benefits of their
      removal. Although malocclusion is not considered a disease, it is unreasonable to
      ignore the orthodontic issues related to third molars, especially in patients who
      make the investment to achieve an ideal occlusion. Part of a complete orthodontic
      treatment plan is a recommendation regarding third molars. The plan should
      include a rationale and recommendation for their removal based on the orthodontic
      treatment objectives.

PMID- 10416631
TI  - Third molar management: a case against routine removal in adolescent and young
      adult orthodontic patients.
AB  - In the nearly two decades since the National Institutes of Health conference,
      controversy and uncertainty have continued with respect to the diagnosis and
      treatment of impacted, nondiseased third molars in adolescents and young adults.
      Articles published over the past 10 years have studied the issue from the vantage
      point of risk management. Those who favor prophylactic removal justify this
      action on three premises: 1. All impacted third molars are potentially
      pathologic; therefore, prophylactic removal reduces or eliminates risk of future
      disease. 2. The presence of third molars can cause late crowding. 3. Removal
      during adolescence and young adulthood reduces risks of operative and
      postoperative complications compared with older patients. Those who favor
      conservative management offer three counter arguments: 1. Although impacted third
      molars do pose a risk of a pathologic condition, the risk is relatively small in
      comparison with the risks of operative and postoperative complications and the
      costs of unnecessary removal. 2. Although some investigators have shown a
      statistical association of third molars and late anterior crowding, the
      association is not strong enough to allow prediction of patients at risk. This is
      due principally to the high degree of individual variability, suggesting that
      many other factors interact in the development of postadolescent crowding. 3.
      Although studies have shown that morbidity is reduced when impacted, nondiseased
      third molars are removed during adolescence or young adulthood, the cost-risk
      benefit data do not justify routine removal. Proponents of prophylactic removal
      argue that the benefits outweigh the risks. Proponents of conservative management
      argue that the scientific evidence is inconclusive in support of prophylactic
      removal. Unfortunately, much of the clinical research has been flawed. This has
      led to contradictory interpretations that have not fully clarified the relative
      risks and benefits of early intervention. Untrustworthy data have served only to
      fuel the debate and controversy concerning proper protocols. However, careful
      analyses of the published research show that routine removal of impacted or
      unerupted, disease-free third molars cannot be justified. A case-by-case
      management protocol that requires monitoring development represents the consensus
      of most researchers in this field.

PMID- 10416632
TI  - Diagnosis and treatment of postoperative complications after skin resurfacing.
AB  - Chemical peel, dermabrasion, and laser skin resurfacing are alternative methods
      to achieve skin resurfacing for reconstructive or cosmetic applications. The
      potential postoperative complications are similar with all of these techniques.
      These postoperative complications and their therapy are reviewed.

PMID- 10416633
TI  - A rapidly progressive preauricular enlargement.

PMID- 10416634
TI  - Calcitonin treatment for central giant cell granulomas of the mandible: report of
      two cases.

PMID- 10416635
TI  - Trigeminocardiac reflex during temporomandibular joint arthroscopy: report of a
      case.

PMID- 10416636
TI  - Plasmacytoid myoepithelioma of the palate.

PMID- 10416637
TI  - Tongue metastasis from a malignant diffuse mesothelioma of the pleura: report of
      a case.

PMID- 10416638
TI  - Metastatic osteosarcoma to the mandibular gingiva: a case report.

PMID- 10416639
TI  - Bilateral central giant cell granulomas in a patient with neurofibromatosis:
      report of a case and review of the literature.

PMID- 10416640
TI  - Intraoral placement of the fixed mandibular implant.

PMID- 10416641
TI  - Monitoring of respiration using an amplified pretracheal stethoscope.

PMID- 10416642
TI  - Somebody struck a nerve!

PMID- 10416643
TI  - The problem of faculty retention.

PMID- 10416644
TI  - Are itinerant anesthesia services safe?

PMID- 10416645
TI  - Biochemical and genetic analysis of PHA synthases and other proteins required for
      PHA synthesis.
AB  - Polyhydroxyalkanoic acids (PHA) represent a complex class of storage polyesters
      that are synthesized by a wide range of different gram-positive and gram-negative
      bacteria as well as by some Archaea and that are deposited as insoluble
      cytoplasmic inclusions. PHA synthases, which are the key enzymes for PHA
      biosynthesis, have been characterized in much detail. At present 42 PHA synthase
      structural genes from 38 different bacteria have been cloned, and from 30 genes
      the nucleotide sequences were obtained. The strategies successfully employed to
      clone these genes and the current knowledge on the organization of the PHA
      synthase genes and other genes encoding proteins related to PHA metabolism will
      be compiled. In addition, the primary structures of the 30 PHA synthases were
      aligned and analyzed with respect to highly conserved amino acids and biochemical
      features. The direction, in which research should proceed, in order to increase
      our knowledge on biosynthesis of PHAs and to utilize this knowledge for the
      development of technically and economically feasible processes for the production
      of these polyesters will be outlined.

PMID- 10416646
TI  - Microbial inclusions with special reference to PHA inclusions and intracellular
      boundary envelopes.
AB  - Polyhydroxyalkanoates (PHAs), in the form of metabolic storage reserves, are
      assembled in intracellular cytoplasmic inclusions, often called granules. This
      review discusses both the structure and function of this assembly. In addition an
      overview of other microbial cellular inclusions is presented. This is not a
      compilation of all such structures but a description of those that are similar in
      many ways to either the structure or function of the PHA inclusions and are made
      up of monolayer envelopes and their storage compounds. Not unique, such
      inclusions provide many similar examples which, in turn, provide useful analogies
      to the PHA inclusions. A study of the PHA inclusions has been carried out in a
      comparative electron microscope examination and by protein analysis of a number
      of organisms and E. coli transformants.

PMID- 10416647
TI  - Recent advances in polyhydroxyalkanoate production by bacterial fermentation:
      mini-review.
AB  - Poly(3-hydroxybutyrate) [P(3HB)] and other polyhydroxyalkanoates (PHAs) have been
      drawing much attention as biodegradable substitutes for conventional
      nondegradable plastics. For the economical production of P(3HB), various
      bacterial strains, either wild-type or recombinant, and new fermentation
      strategies were developed for the production of P(3HB) with high concentration
      and productivity. To reduce the cost of carbon substrate, several processes for
      P(3HB) production from cheap carbon sources were also developed. P(3HB) can now
      be produced to a content of 80% of cell dry weight with the productivity greater
      than 4 g/l per h. Fermentation strategy was also developed for the efficient
      production of medium chain length PHA by high cell density culture. With all
      these advances, P(3HB) and PHAs can be produced by bacterial fermentation at a
      cost (ca. $2/kg) similar to that of other biodegradable polymers under
      development.

PMID- 10416648
TI  - Photosynthetic accumulation of poly-(hydroxybutyrate) by cyanobacteria--the
      metabolism and potential for CO2 recycling.
AB  - Regulatory mechanism in PHB [poly-(hydroxybutyrate)] accumulation by
      cyanobacteria, especially by a thermophilic isolate, Synechococcus MA19 was
      reviewed in comparison with a genetically engineered strain. The strain, MA19
      accumulates PHB under nitrogen starved and photoautotrophic conditions (MA19-N).
      Little PHB synthase activity was detected in crude extracts from the cells grown
      in nitrogen sufficient conditions (MA19 + N). The activity was detected
      exclusively in membrane fractions from MA19 + N. The change of the enzyme
      activity was insensitive to chloramphenicol, which suggests post-translational
      activation. In vitro, acetyl phosphate activated PHB synthase in membrane
      fractions from MA19 + N, and the extent of activation depended on the
      concentration of acetyl phosphate. Phosphotransacetylase which catalyzes the
      conversion of acetyl-CoA to acetyl phosphate was detected in crude extracts from
      MA19-N but not in those from MA19 + N. These results suggested that intracellular
      acetyl phosphate concentration could be controlled, depending on C-N balance and
      intracellular acetyl-CoA concentration. On the contrary, in genetically
      engineered cyanobacterium (transformant with PHB synthesizing genes from
      Ralstonia eutropha), it did not seem to be PHB synthase but acetyl-CoA flux that
      limits PHB synthesis. The closer association of PHB granules with thylakoid
      membranes in MA19 is suggested than that in the genetically-engineered
      cyanobacterium, which may reflect the difference of distribution of PHB synthase.
      Transposon-mutagenesis was used to acquire mutants of its altered PHB regulatory
      mechanism. PHA production by cyanobacteria was considered from the aspects of
      photobioreactors.

PMID- 10416649
TI  - Chain termination in polyhydroxyalkanoate synthesis: involvement of exogenous
      hydroxy-compounds as chain transfer agents.
AB  - We have identified a range of compounds which, when present during poly(3
      hydroxybutyrate) [P(3HB)] accumulation by Ralstonia eutropha (reclassified from
      Alcaligenes eutrophus), can act as chain transfer agents in the chain termination
      step of polymerization. End-group analysis by 31P NMR of polymer derivatized with
      2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane revealed that all these
      compounds were covalently linked to P(3HB) at the carboxyl terminus. All chain
      transfer agents possessed one or more hydroxyl groups, and glycerol was selected
      for further investigation. The number-average molecular mass (Mn) of P(3HB)
      produced by R. eutropha from glycerol was substantially lower than for polymer
      produced from glucose, and we identified two new end-group structures. These were
      attributed to a glycerol molecule bound to the P(3HB) chain via the primary or
      secondary hydroxyl groups. When a primary hydroxyl group of glycerol is involved
      in chain transfer, the end-group structure is in both [R] and [S] configurations,
      implying that chain transfer to glycerol is a random transesterification and that
      PHA synthase does not catalyse chain transfer. 3-Hydroxybutyric acid is the most
      probable chain transfer agent in vivo, with propagation and termination reactions
      involving transfer of the P(3HB) chain to enzyme-bound and free 3
      hydroxybutyrate, respectively. Only carboxyl end-groups were detected in P(3HB)
      extracted from exponentially growing bacteria. It is proposed that a compound
      other than 3-hydroxybutyryl-CoA acts as a primer in the initiation of polymer
      synthesis.

PMID- 10416650
TI  - Extracellular polymerization of 3-hydroxyalkanoate monomers with the polymerase
      of Alcaligenes eutrophus.
AB  - Previous investigations on the role of the polymerase in the synthesis of poly-3
      hydroxybutyrate (PHB) are reviewed, and the results from earlier in vitro studies
      on the activity and selectivity of the polymerase of Alcaligenes eutrophus are
      discussed. In the present study the effect of glycerol on stabilizing the
      polymerase after purification and on eliminating the lag phase in in vitro
      polymerization reactions of 3-hydroxybutyl CoA (HBCoA), and 3-hydroxyvaleryl CoA
      (HVCoA) are described. K(M) values were determined for the activity of the
      polymerase with both HBCoA and HVCoA, and the rates of propagation for both
      monomers were estimated. With a racemic mixture of HBCoA, the enzyme polymerized
      only the [R] monomer.

PMID- 10416651
TI  - Production of two phase polyhydroxyalkanoic acid granules in Ralstonia eutropha.
AB  - To synthesize layered granules consisting of selected phases of
      polyhydroxybutyrate (PHB) homopolymer and PH(B-co-V) copolymer, Ralstonia
      eutropha was grown on fructose and limited quantities (1 g/l) of valeric acid.
      Exhaustion of the valerate resulted in a carbon source shift and a shift in the
      composition of polyhydroxyalkanoate (PHA) being synthesized within the cell. The
      synthesis rates were 0.030 g PH(B-co-V)/l per h and 0.033 g PHB/l per h, giving a
      copolymer composition of 48% HV. The valerate was exhausted at approximately 12 h
      at a rate of 0.0894 g/l per h after which only PHB was produced through the
      remaining 12 h at 0.033 g PHB/l per h from the remaining fructose, which was
      utilized at a constant rate of 0.0861 g/l per h throughout all 24 h of the
      experiment. Differential scanning calorimetry (DSC) of isolated granules showed
      two glass transitions, confirming the presence of two distinct polymer phases
      within the layered granules. Transmission electron microscopic images stained
      with RuO4 revealed a heavily stained copolymer core within a lighter stained PHB
      shell, confirming the expected morphology of granule composition. Thus,
      biosynthesis can be exploited for the control of domain sizes in layered
      granules, potentially providing metabolic control over the physical properties of
      the resultant polymer.

PMID- 10416652
TI  - Biosynthesis of polyhydroxyalkanoates (PHA) by recombinant Ralstonia eutropha and
      effects of PHA synthase activity on in vivo PHA biosynthesis.
AB  - Recombinant strains of Ralstonia eutropha PHB 4, which harbored Aeromonas caviae
      polyhydroxyalkanoates (PHA) biosynthesis genes under the control of a promoter
      for R. eutropha phb operon, were examined for PHA production from various
      alkanoic acids. The recombinants produced poly(3-hydroxybutyrate-co-3
      hydroxyhexanoate) [P(3HB-co-3HHx)] from hexanoate and octanoate, and poly(3
      hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxypentano ate) [P(3HB-co-3HV-co
      3HHp)] from pentanoate and nonanoate. One of the recombinant strains, R. eutropha
      PHB 4/pJRDBB39d3 harboring ORF1 and PHA synthase gene of A. caviae (phaC(Ac))
      accumulated copolyesters with much more 3HHx or 3HHp fraction than the other
      recombinant strains. To investigate the relationship between PHA synthase
      activity and in vivo PHA biosynthesis in R. eutropha, the PHB- 4 strains
      harboring pJRDBB39d13 or pJRDEE32d13 were used, in which the heterologous
      expression of phaC(Ac) was controlled by promoters for R. eutropha phb operon and
      A. caviae pha operon, respectively. The PHA contents and PHA accumulation rates
      were similar between the two recombinant strains in spite of the quite different
      levels of PHA synthase activity, indicating that the polymerization step is not
      the rate-determining one in PHA biosynthesis by R. eutropha. The molecular
      weights of poly(3-hydroxybutyrate) produced by the recombinant strains were also
      independent of the levels of PHA synthase activity. It has been suggested that a
      chain-transfer agent is generated in R. eutopha cells to regulate the chain
      length of polymers.

PMID- 10416653
TI  - Improved production of poly(4-hydroxybutyrate) by Comamonas acidovorans and its
      freeze-fracture morphology.
AB  - Production of poly(4-hydroxybutyrate) [P(4HB)] by Comamonas acidovorans JCM10181
      was studied by introducing additional copies of its PHA synthase gene and the
      beta-ketothiolase gene. A multi-copy-number broad-host-range plasmid vector,
      pJRD215, was modified to contain the strong hybrid trc promoter in order to
      express these genes in the wild-type C. acidovorans. Increased copy-number of
      genes resulted in significant increase in the activities of corresponding
      enzymes, which could further be increased by inducing with isopropyl-beta-D
      thiogalactopyranoside (IPTG), indicating that the expression is under the
      transcriptional control of the trc promoter. P(4HB) biosynthesis in the
      recombinant C. acidovorans increased 2-fold to constitute more than 60 wt% of the
      dry cell weight. No significant decrease in the number-average molecular weights
      of P(4HB) in the recombinant strain was observed when compared with that of the
      wild-type. Freeze-fracture electron microscopy of intracellular P(4HB) granules
      revealed almost similar fracture morphology to the well-known mushroom-type
      deformation shown by polyhydroxyalkanoates with medium-chain-length monomers.

PMID- 10416654
TI  - Properties and biodegradability of ultra-high-molecular-weight poly[(R)
      hydroxybutyrate] produced by a recombinant Escherichia coli.
AB  - Ultra-high-molecular-weight poly[(R)-3-hydroxybutyrate] (P(3HB)) (Mw = 3-11 x
      10(6)) was produced from glucose by a recombinant Escherichia coli XL1-Blue
      (pSYL105) harboring Ralstonia eutropha H16 polyhydroxyalkanoate (PHA)
      biosynthesis genes. Morphology of ultra-high-molecular-weight P(3HB) granules in
      the recombinant cells was studied by transmission electron microscopy. The
      recombinant E. coli contained several P(3HB) granules within a cell. Freeze
      fracture morphology of ultra-high-molecular-weight P(3HB) granules showed the
      needle-type as that of P(3HB) granules in R. eutropha. Both the P(3HB) granules
      in wet cells and wet native granules isolated from the recombinant cells proved
      to be amorphous on the X-ray diffraction patterns. Mechanical properties of ultra
      high-molecular-weight P(3HB) films were markedly improved by stretching over
      400%, resulting from high crystallinity and highly oriented crystal regions.
      Biodegradability of the films of ultra-high-molecular-weight P(3HB) was tested
      with an extracellular polyhydroxybutyrate depolymerase from Alcaligenes faecalis
      T1. The rate of enzymatic erosion of P(3HB) films was not dependent of the
      molecular weight but was dependent of the crystallinity. In addition, it is
      demonstrated that all ultra-high-molecular-weight P(3HB) films were completely
      degraded at 25 degrees C in a natural river freshwater within 3 weeks.

PMID- 10416655
TI  - Production of poly(3-hydroxybutyrate) and its copolymer poly(3-hydroxybutyrate-co
      3-hydroxyvalerate) by Erwinia sp. USMI-20.
AB  - A locally isolated soil microorganism identified as Erwinia sp. USMI-20 has been
      found to produce poly(3-hydroxybutyrate), P(3HB), from either palm oil or glucose
      and its copolymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate), P(3HB-co-3HV),
      from a combination of palm oil and a second carbon source of either one of the
      following compounds: propionic acid, n-propanol, valeric acid and n-pentanol. It
      was found that Erwinia sp. USMI-20 could produce P(3HB) up to 69 wt.% polymer
      content with a dry cell weight of 4.4 g/l from an initial amount of 14.5 g/l of
      glucose followed by a feeding rate of glucose at 0.48 g/h glucose. On the other
      hand, the bacteria can achieve 46 wt.% of P(3HB) and a dry cell weight of 3.6 g/l
      from a batch fermentation in a 10-l fermentor from an initial concentration of
      4.6 g/l of palm oil. Further characterisation of the polymer production was also
      carried out by using different types of palm oil. Among the different palm oils
      that were used, crude palm oil was the best lipid source for P(3HB) production as
      compared to palm olein and palm kernel oil. In the production of the copolymer,
      P(3HB-co-3HV), the highest mole fraction of 3-HV units could be as high as 47
      mol% from a single feeding of valeric acid upon initial growth on palm oil.

PMID- 10416656
TI  - PHA production by activated sludge.
AB  - The production of polyhydroxyalkanoate by anaerobic-aerobic activated sludge was
      reviewed concentrating on the biochemical mechanisms and on the trials to
      increase polyhydroxyalkanoate (PHA) content in activated sludge. The anaerobic
      aerobic activated sludge system selects microorganisms with the capabilities to
      couple glycolysis, polyphosphate degradation, and PHA accumulation for anaerobic
      substrate uptake. Some of the PHA-related metabolisms observed there have not
      been seen in pure cultures so far. Such metabolisms are the formation of PHA
      containing 3-hydroxy-2-methylvalerate, and '3-hydroxyvalerate fermentation' in
      which glucose or glycogen is converted to 3-hydroxyvalerate-rich PHA while
      yielding energy. The PHA content of activated sludge can be increased up to 62%
      by applying a microaerophilic-aerobic activated sludge process. PHA production by
      activated sludge is worth investigation.

PMID- 10416657
TI  - PHA applications: addressing the price performance issue: I. Tissue engineering.
AB  - This paper describes the development of medical applications for
      polyhydroxyalkanoates (PHAs), a class of natural polymers with a wide range of
      thermoplastic properties. Methods are described for preparing PHAs with high
      purity, modifying these materials to change their surface and degradation
      properties, and methods for fabricating them into different forms, including
      tissue engineering scaffolds. Preliminary reports characterizing their in vivo
      behavior are given, as well as methods for using the natural polymers in tissue
      engineering applications.

PMID- 10416658
TI  - Development of environmentally friendly coatings and paints using medium-chain
      length poly(3-hydroxyalkanoates) as the polymer binder.
AB  - Unsaturated medium-chain-length poly(3-hydroxyalkanoates) (mcl-PHAs) produced by
      Pseudomonas putida from linseed oil fatty acids (LOFA) and tall oil fatty acids
      (TOFA), were used as the polymer binder in the formulation of high solid alkyd
      like paints. The relatively high concentration of unsaturated alkyl side chains
      incorporated into the PHA resins resulted in oxidative drying PHA paints having
      excellent coating properties. The homogeneously pigmented PHA coatings yielded
      high-gloss, smooth and strong films upon curing and showed an excellent
      flexibility, a good adhesion to different substrates, cohesive film properties
      and resistance to chipping.

PMID- 10416659
TI  - Hydrolysis of native poly(hydroxybutyrate) granules (PHB), crystalline PHB, and
      artificial amorphous PHB granules by intracellular and extracellular
      depolymerases.
AB  - Native poly(hydroxybutyrate) (PHB) granules, purified PHB and artificial
      amorphous PHB granules were examined as putative substrates for hydrolysis by the
      intracellular depolymerase system of Rhodospirillum rubrum and the extracellular
      depolymerase of Pseudomonas lemoignei. The R. rubrum depolymerizing system
      requires pretreatment of granules with a heat stable 'activator' fraction; the
      activator can be replaced by mild trypsin treatment. Artificial granules were
      prepared with a cationic detergent, cetyltrimethylammonium bromide (CTAB) and an
      anionic detergent, (sodium cholate). Cholate and CTAB PHB granules were
      hydrolyzed by both enzyme systems; however, some differences were noted. Cholate
      granules were hydrolyzed in the absence of the R. rubrum activator fraction.
      Activator was required for the hydrolysis of CTAB granules but could be replaced
      by heparin in the extracellular depolymerase system but not in the intracellular
      depolymerase system. A Triton X-114 extract of native PHB granules inhibited the
      hydrolysis of trypsin-activated granules by the intracellular depolymerase. The
      inhibition was reversed by the activator fraction. Detergent extracts of granules
      activated with the R. rubrum activator were unable to inhibit the hydrolysis of
      trypsin-activated granules. These data suggest that the activator acts to modify
      an inhibitor present on native granules.

PMID- 10416660
TI  - Extracellular degradation of medium chain length poly(beta-hydroxyalkanoates) by
      Comamonas sp.
AB  - The PHA-degrading isolate, strain P37C, was enriched from residential compost for
      its ability to hydrolyze the medium chain length PHA, poly(beta-hydroxyoctanoate)
      (PHO). It was subsequently found to grow on a wide range of PHAs, including both
      short chain length and medium chain length PHAs. The isolate was identified as
      belonging to the genus Comamonas. Strain P37C formed clear zones on poly(beta
      hydroxybutyrate) (PHB), (PHO) and poly(beta-hydroxyphenylvalerate) (PHPV) overlay
      plates. PHA clear zone tubes were prepared using seven different kinds of PHAs,
      ranging from PHB with four-carbon repeating units, to poly(beta-hydroxyoctanoate
      co-beta-hydroxyundecanoate) (PHOU) with 8- and 11-carbon repeating units. There
      was a direct correlation between PHA side chain length and rate of hydrolysis of
      the PHAs. A series of PHOUs containing varying percentages of unsaturated bonds
      were used to make a series of epoxidized PHOUs (PHOEs) with varying percentages
      of epoxy functions. Results of clear zone tube assays showed that these
      functionalized PHAs were all biodegradable by strain P37C, and there was no
      apparent correlation between rate of biodegradation and the proportion of
      functional groups in the PHAs. Biodegradability of these PHAs was verified using
      respirometry and enzyme assays. Cell-free supernatants containing activity toward
      PHAs were prepared, and strain P37C was shown to synthesize at least two distinct
      PHA depolymerases for the hydrolysis of SCL and MCL PHAs.

PMID- 10416661
TI  - Lipase-catalyzed ring-opening polymerization of lactones to polyesters and its
      mechanistic aspects.
AB  - Lipase catalysis induced a ring-opening polymerization of lactones with different
      ring-sizes. Small-size (four-membered) and medium-size lactones (six- and seven
      membered) as well as macrolides (12-, 13-, 16-, and 17-membered) were subjected
      to lipase-catalyzed polymerization. The polymerization behaviors depended
      primarily on the lipase origin and the monomer structure. The macrolides showing
      much lower anionic polymerizability were enzymatically polymerized faster than
      epsilon-caprolactone. The granular immobilized lipase derived from Candida
      antartica showed extremely efficient catalysis in the polymerization of epsilon
      caprolactone. Single-step terminal functionalization of the polyester was
      achieved by initiator and terminator methods. The enzymatic polymerizability of
      lactones was quantitatively evaluated by Michaelis-Menten kinetics.

PMID- 10416662
TI  - Ring-opening bulk polymerization of epsilon-caprolactone and trimethylene
      carbonate catalyzed by lipase Novozym 435.
AB  - The affects of lipase concentration on ring-opening bulk polymerizations of
      epsilon-caprolactone and trimethylene carbonate were studied by using Novozym 435
      (immobilized form of lipase B from Candida antarctica) as biocatalyst. The
      polymerization of epsilon-caprolactone was carried out in bulk at 70 degrees C.
      Three lipase concentrations of 9.77, 1.80 and 0.50 mg/mmol epsilon-CL were used
      in the experiment. The results showed that increasing the lipase concentration
      used in the polymerization system resulted in an increased rate of monomer
      consumption. For an enzyme concentration of 9.8 mg lipase per mmol monomer, an
      80% monomer conversion was achieved in a 4-h time period, while for the lower
      enzyme concentration of 1.8 mg lipase per mmol monomer, 48 h were needed to reach
      monomer conversion. Linear relationships between Mn and monomer conversions were
      observed in all three enzyme concentrations, suggesting that the product
      molecular weight may be controlled by the stoichiometry of the reactants for
      these systems. At the same monomer conversion level, however, Mn decreased with
      increasing enzyme concentration. After correcting for the amount of monomer
      consumed in initiation, the plot of ln[([M]o - [M]i)/([Mt] - [M]i)] versus
      reaction time was found to be linear, suggesting that the monomer consumption
      followed a first-order rate law and no chain termination occurred. For the TMC
      systems, the polymerization was carried out in bulk at 55 degrees C. Similar to
      the epsilon-CL systems, increasing the Novozym 435 concentration from 8.3 to 23.6
      mg/mmol TMC increased the rate of monomer conversion. Unlike the epsilon-CL
      systems, however, nonlinear relationships were obtained between Mn and monomer
      conversion, indicating that possible chain transfer and/or slow initiation had
      taken place in these systems. Consistent with the above result, nonlinear
      behavior was observed for the plot of ln[[M]o/[M]t] versus reaction time.

PMID- 10416663
TI  - Novel lipase-catalyzed ring-opening copolymerization of lactide and trimethylene
      carbonate forming poly(ester carbonate)s.
AB  - Poly(lactide-co-trimethylene carbonate)s were prepared by the lipase-catalyzed
      ring-opening copolymerization of lactide and trimethylene carbonate having
      carbonate content from 0 to 100%. Their thermal properties and enzymatic
      degradability were measured. The L,L-, D,D- and D,L-lactides were copolymerized
      with trimethylene carbonate by porcine pancreatic lipase to produce random
      copolymers having molecular weights of up to 21000. The glass transition
      temperature (Tg of the copolymer was dependent on the carbonate content and the
      Tg values linearly decreased from 35 degrees C (polylactide) to -8 degrees C
      [poly(trimethylene carbonate)]. Among the lipases tested, the porcine pancreatic
      lipase and proteinase K showed biodegradability towards poly(ester-carbonate)s.

PMID- 10416664
TI  - Structure and enzymatic degradation of poly(3-hydroxybutyrate) copolymer single
      crystals with an extracellular PHB depolymerase from Alcaligenes faecalis T1.
AB  - Lamellar single crystals of four random copolymers of (R)-3-hydroxybutyrate with
      different hydroxyalkanoates: poly(3-hydroxybutyrate-co-8 mol%-3-hydroxyvalerate)
      (P(3HB-co-8%-3HV)), poly(3-hydroxybutyrate-co-10 mol%-4-hydroxybutyrate) (P(3HB
      co-10%-4HB)), poly(3-hydroxybutyrate-co-8 mol%-3-hydroxyhexanoate) (P(3HB-co-8%
      3HH)) and poly(3-hydroxybutyrate-co-10 mol%-6-hydroxyhexanoate) (P(3HB-co-10%
      6HH)), were grown from dilute solutions of chloroform and ethanol. All single
      crystals have lath-shaped morphology and the second monomer units seem to be
      excluded from the P(3HB) crystal, on the basis of the electron diffraction
      diagrams. The enzymatic degradation of P(3HB-co-8%-3HH) and P(3HB-co-10%-6HH)
      single crystals was investigated with an extracellular PHB depolymerase from
      Alcaligenes faecalis T1. Adsorption of an extracellular PHB depolymerase,
      examined using an immuno-gold labelling technique, demonstrated a homogeneous
      distribution of enzyme molecules with a low concentration on the crystal
      surfaces. Enzymatic degradation of single crystals progressed from the edges and
      ends of crystals to yield narrow cracks along their long axes and the small
      crystal fragments. Lamellar thicknesses of single crystals and molecular weights
      of copolymer chains remained unchanged during the enzymatic hydrolysis. The above
      results support the hypothesis that the hydrophobic adsorption of the enzyme
      contributes to increase the mobility of molecular chains of single crystals and
      generate the disordered chain-packing regions. The active-site of PHB
      depolymerase takes place preferentially at the disordered chain-packing regions
      of crystal edges and ends with endo-exo enzymatic hydrolysis behaviour, termed
      processive degradation.

PMID- 10416665
TI  - Crystallization behavior and thermal properties of melt-crystallized poly[(R)-3
      hydroxybutyric acid-co-6-hydroxyhexanoic acid] films.
AB  - Melt-crystallized films of poly[(R)-3-hydroxybutyric acid-co-10mol% 6
      hydroxyhexanoic acid] (P[(R)-3HB-co-6HH]) were prepared by isothermal
      crystallization at various temperatures for 3 days, and subsequently stored at
      room temperature after the films formed well-developed and volume-filled
      spherulites. The lamellar morphologies and properties of melt-crystallized films
      were characterized by means of wide-angle X-ray diffraction, small-angle X-ray
      scattering, differential scanning calorimetry, transmission electron microscopy,
      and atomic force microscopy. The melting endotherm of P[(R)-3HB-co-6HH] films was
      composed of a broad peak starting around room temperature and of a sharper peak
      starting above the isothermal crystallization temperature. The stacking of flat
      on lamellae with lamellar periodicity of 8-10 nm was detected on the surface of
      P[(R)-3HB-co6HH] films after the primary crystallization at 110 degrees C. On
      storage at room temperature above the Tg (-5 degrees C) of copolyester, thin
      crystals of 1-4 nm thickness appeared on the surface of P[(R)-3HB-co-6HH] films
      crystallized at 110 degrees C. These results suggest that long sequences of (R)
      3HB units in a random copolyester form relatively thick P[(R)-3HB] crystalline
      lamellae during the primary crystallization process at a given crystallization
      temperature, while shorter sequences of (R)-3HB units, which are incapable of
      crystallizing at a given crystallization temperature, form relatively thin
      crystalline lamellae during the subsequent crystallization process at room
      temperature.

PMID- 10416666
TI  - Structural effects on enzymatic degradabilities for poly[(R)-3-hydroxybutyric
      acid] and its copolymers.
AB  - Poly[(R)-3-hydroxybutyric acid] and its copolymers were prepared by biosynthetic
      and chemosynthetic methods. The films of polyesters were prepared by both the
      solution-cast and melt-crystallized techniques. The enzymatic degradation of
      polyester films was carried out at 37 degrees C in an aqueous solution (pH 7.4)
      of PHB depolymerase from Alcaligenes faecalis. The rate of enzymatic erosion on
      the solution-cast films increased markedly with an increase in the fraction of
      second monomer units up to 10-20 mol% to reach a maximum value followed by a
      decrease in the erosion rate. Analysis of the water-soluble products liberated
      during the enzymatic degradation of polyester films showed the formation of a
      mixture of monomers and oligomers of (R)-3HB and hydroxyalkanoic acids units,
      suggesting that the active site of PHB depolymerase recognizes at least three
      monomeric units as substrate for the hydrolysis of ester bonds in a polymer
      chain. The rate of enzymatic erosion of melt-crystallized polyester films
      decreased with an increase in crystallinity. PHB depolymerase predominantly
      hydrolyzed the polymer chains in the amorphous phase and subsequently eroded
      crystalline phase. In addition, the enzymatic degradation of crystalline phase by
      PHB depolymerase progressed from the edges of crystalline lamellar stacks. The
      enzymatic erosion rate of crystalline phase in polyester films decreased with an
      increase in the lamellar thickness.

PMID- 10416667
TI  - Chemical composition distribution of bacterial copolyesters.
AB  - Poly(3-hydroxybutyrate) [P(3HB)] and its copolymers with hydroxyalkanoates are
      naturally occurring thermoplastic materials produced by bacteria. There are many
      potential uses for these copolyesters owing to their biodegradability and
      biocompatibility. The physical properties of the copolyesters vary depending on
      the chemical structure as well as the composition of the comonomers. Usually, we
      expect, copolymers to have a narrow chemical composition distribution (CCD).
      Several reports, however, have pointed out that some bacterial copolyesters have
      broad and/or multimodal CCD. Fractionation based on the chemical composition has
      also been reported for several bacterial copolyester samples. In this review, the
      literature concerning CCD and fractionation based on chemical composition is
      summarized. The width of CCD is approximated based on the data of diad sequence
      distribution. Generality of the complex CCD in bacterial copolyesters is also
      discussed.

PMID- 10416668
TI  - Lamellar thickening and cocrystallization of poly(hydroxyalkanoate)s on
      annealing.
AB  - Lamellar thickening behavior of microbial polyesters, poly(3-hydroxybutyrate)
      [P(3HB)], poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [P(3HB-co-3HV)] and poly(3
      hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] annealed at various
      temperatures was investigated to make sure of the occurrence of cocrystallization
      of both components. All the copolymers showed steep increases in melting points
      accompanied by partial melting as the annealing temperature increased up to just
      below the melting points. In contrast, long periods of P(3HB-co-7mol% 3HV)
      increased to twice, similar to those of P(3HB), with increasing annealing
      temperature up to just below the melting point, while long periods of P(3HB-co
      7mol% 4HB) and P(3HB-co-92mol% 3HV) only increased up to one and a half times.
      Lattice indices of unit cell of the former crystal were increased slightly, while
      those of the latter crystal remained unchanged. These results imply that the
      P(3HB) crystal can occlude the 3HV component to some extent, but hardly includes
      the 4HB component, and P(3HV) crystal also excludes the 3HB component.

PMID- 10416669
TI  - Determination of solubility parameters for poly(3-hydroxyalkanoates).
AB  - The three dimensional solubility parameters defined by Hansen are based on
      dispersion forces between structural units, interaction between polar groups and
      hydrogen bonding. For polar polymers such as poly(3-hydroxyalkanoates), P(3HA),
      this approach was used to obtain the three coordinates of a solubility parameter
      in terms of: a dispersion part, a polar part and a hydrogen bonding part. Thirty
      eight different solvents for poly(3-hydroxybutyrate), PHB, which are mentioned in
      the literature are examined by this method and the theoretical predictions are
      compared with the experimental reports. Another overall comparison between PHA
      polymers provides their Hansen and Hildebrand parameters for side chain lengths
      up to C13. In this series a linear progression in calculated solubility
      parameters with side chain length was found. An Appendix provides information and
      data on calculation of the solubility parameters. While the solubility
      information is limited and only covers homopolymers, it should help to highlight
      some of the contradictions regarding PHB solubility. This semi-empirical approach
      is only valid for amorphous polymers hence crystallinity effects, which are
      important with PHB, as well as molecular weight effects still require analysis.

PMID- 10416670
TI  - Detection, synthesis, structure, and function of oligo(3-hydroxyalkanoates):
      contributions by synthetic organic chemists.
AB  - Two types of the biological macromolecules poly(R-3-hydroxyalkanoates) have been
      identified: the high-molecular-weight microbial storage material (sPHA) and a
      short-chain variety, consisting of butyrate and valerate residues, complexed with
      other biomacromolecules such as calcium polyphosphate or proteins (cPHB/PHV).
      While sPHA has attracted, and still enjoys, a lot of attention from numerous
      scientists around the world, research on cPHB and the structurally and
      functionally related polymalate (PMA) is still in its infancy. In this article,
      we present a review on the chemical synthesis, structure, function and
      interactions of monodisperse cPHAs, the oligo(3-hydroxyalkanoates), with emphasis
      on the butyrates (OHB); we report hitherto unpublished results on the enzymatic
      degradation of cPHB and PMA, on a new analytical method for HB/HV detection in
      biological samples, and on OHB-mediated Ca2+ transport through phospholipid
      bilayers of artificial vesicles; finally, we discuss possible mechanisms of ion
      transport through cell membranes, as caused by cPHB. The speculative--and
      provocative--question is asked whether the structurally simple PHAs may have
      evolved as storage materials and amphiphilic macromolecules before poly-peptides,
      -saccharides, and -nucleic acids, in the history of life, or under prebiotic
      conditions.

PMID- 10416672
TI  - Novel synthesis of functionalized poly(3-hydroxybutanoic acid) and its
      copolymers.
AB  - Novel feasibility of fuctionalized poly(3-hydroxybutanoic acid), PHB, and its
      copolymers synthesis via ring-opening of beta-butyrolactone (ROP) mediated by
      activated anionic initiators or enzymes in vitro is presented. Using these new
      synthetic approaches, PHB with defined chemical structure of the end groups as
      well as block, graft and random copolymers have been obtained and characterized
      by IR, NMR, ESI-MS and GPC techniques. The relationship between the structure and
      properties of the novel polymeric materials prepared is discussed.

PMID- 10416671
TI  - Ring-opening polymerisation of beta-butyrolactone catalysed by distannoxane
      complexes: study of the mechanism.
AB  - The mechanism of the ring-opening polymerisation of beta-butyrolactones was
      studied. The ring-opening polymerisation of BL catatlysed by distannoxane
      complexes is of a living nature. The polymerisation of racemic BL gave a
      predominantly syndiotactic P(3HB). The temperature effect on syndiospecificity
      was used to determine the activation energy (deltaE = Esyndiotactic - Eisotactic)
      for syndiotactic versus isotactic diad placement. The deltaE value was obtained
      as -1.49 kcal/mol. The steric control leading to the observed syndiospecificity
      is due predominantly to diastereomeric interactions between the Sn-coordinated
      P(3HB) chain end. having a specific chain end stereochemistry, and the incoming
      BL enantiomeric monomers. The catalytic cycle derived from the mechanism of the
      polymerisation was proposed.

PMID- 10416673
TI  - Synthetic poly(beta-hydroxyalkanoates) with carboxylic acid or primary amine
      pendent groups and their complexes.
AB  - Degradable polyelectrolyte complexes were made by mixing a degradable carboxyl
      bearing polyacid, namely poly(beta-malic acid), with a degradable primary amine
      group-bearing polybase, namely poly(amino serinate), derived from serine. Both
      oppositely charged polyelectrolytes are functional polymers which belong to the
      family of poly(beta-hydroxy acid)-type aliphatic polyesters. Poly(amino serinate)
      polymers were synthesized by a new route starting from the N-carbobenzoxy
      derivative (N-Z) of DL- or L-serine. These derivatives were allowed to react with
      mesyl chloride to yield in one step corresponding N-protected derivatives of
      poly(N-Z-amino serinate) with molar masses in the 20000-40000 range after
      fractionation. Progressive deprotection of pendent primary amino groups was
      carried out using a HBr/acetic acid mixture and led to PAS with up to 95%
      deprotected amine repeat units for less than 15% decrease of the initial molar
      mass, as shown by N-reprotection with Z groups. Poly(beta-malic acid) and
      poly(amino serinate) were complexed by mixing aqueous solutions of the two
      polyelectrolytes: 1-1 neutral precipitates were formed regardless of the
      respective compositions, provided the molecular weights of both components were
      high enough. When allowed to age in aqueous media, the solid complexes went
      rapidly back into solution because of the hydrolytic degradation of at least one
      of the components. Whether the degradation of one component is affected by that
      of the other is still unknown.

PMID- 10416674
TI  - Synthesis and properties of malic acid-containing functional polymers.
AB  - Poly-L-lactides containing beta-alkyl alpha-malate-units were prepared by ring
      opening copolymerizations of L-lactide with 3-(s)-[(benzyloxycarbonyl)methyl]-
      (BMD) and 3-(s)-[(dodecyloxycarbonyl)methyl]-1,4-dioxane-2,5-diones (DMD). The
      solution-cast films of these copolymers were alkali-treated to form a carboxyl
      functionalized surface on which cell-binding Arg-Gly-Asp tripeptide (RGD) was
      immobilized with dicyclohexylcarbodiimide as coupling agent. For the copolymer of
      L-lactide and BMD the benzyl groups were removed by catalytic hydrogenolysis to
      obtain a fully carboxyl-functionalized copolymer (PLGM), and RGD was immobilized
      on the surface of its cast film. All the RGD-immobilized films thus prepared
      exhibited improved cell attachment compared with the original films. The cell
      attachment increased with increasing amount of immobilized RGD, which depended on
      the composition of the alpha-malate units in the copolymer. The RGD-immobilized
      PLGM films were degraded rapidly during the cell culture, while the RGD
      immobilized films of the beta-alkyl alpha-malate-containing polymers survived the
      cell culture with little degradation. The rate of hydrolysis increased with
      increasing content of alpha-malate units for both series, depending on the
      structure of the protecting groups of the beta-carboxyl. These results suggest
      that the RGD-immobilized polymers could be a new class of functional
      bioresorbable polymer having improved cell-attachment and adjustable hydrolysis
      rate.

PMID- 10416675
TI  - Polymers of malic acid and 3-alkylmalic acid as synthetic PHAs in the design of
      biocompatible hydrolyzable devices.
AB  - Poly(beta-malic acid) and poly(beta-3-alkylmalic acid) derivatives, as synthetic
      polyhydroxyalkanoates (PHAs), present several advantages as macromolecular
      materials for temporary biomedical applications. Indeed, such polymers, which can
      be synthesized through different chemical and biological routes, have cleavable
      ester bonds in their backbone for hydrolytic degradation, stereogenic centres in
      the monomers units for controlling the macromolecular structure. bioassimilable
      or non-toxic repeating units and lateral chemical functions which can be adapted
      to specific requirements. The strategy for building such complex architectures,
      with one or several specific pendant groups, is based on the anionic ring-opening
      polymerization or copolymerization of the large family of malolactonic and 3
      alkylmalolactonic acid esters. Because we are able to control the monomer
      synthesis and the polymerization step, we have been able to prepare different
      degradable materials for the biomedical field, such as: degradable associating
      networks made up by the association of random copolyesters containing a small
      percentage of hydrophobic moieties and beta-cyclodextrin copolymers; degradable
      macromolecular micelles constituted by degradable amphiphilic block copolymers of
      poly(beta-malic acid) as hydrophilic segments and poly(beta-alkylmalic acid alkyl
      esters) as hydrophobic blocks; and degradable nanoparticles made up by
      hydrophobic poly(beta-malic acid alkyl esters) derivatives. We have also prepared
      a terpolymer which exhibits growth factor-like properties in vivo. Finally,
      poly(beta-malic acid) has been used as an additive in the preparation of
      peritoneal dialysis bags.

PMID- 10416676
TI  - In vitro and in vivo degradation of lactic acid-based interference screws used in
      cruciate ligament reconstruction.
AB  - Nowadays, many degradable polymers are being used under the form of interference
      screws to fix the bone-tendon-bone autograft in anterior cruciate ligament
      reconstruction. However, little is known about the post-implantation fate of
      these screws, especially about the formation of crystalline residues which seems
      to be a critical factor for the success of surgery with temporary implants based
      on lactic and glycolic acid derived polymers (PLAGA). In an attempt to bring in
      some new insights, various high molecular weight stereoregular poly(lactide)s
      (PLAX with X = percentage of L-lactyl units) obtained by ring-opening
      polymerization of lactides in the presence of zinc-metal (PLA98-Zn), zinc lactate
      (PLA98-Znlac) or stannous octoate (PLA100-Sn), were processed by injection
      molding to make interference screws to be compared. In vivo data were collected
      from screws implanted in sheep knees with follow ups ranging from 6 months to 5
      years. Histology confirmed the heterogeneous degradation mechanism introduced
      nearly 10 years ago from in vitro investigations of homemade implants having
      simpler geometry. The effects of the initiator system (zinc- or tin derivatives)
      used to polymerize the lactide monomer on the properties of injection molded
      interference screws was also investigated in vitro in a phosphate buffer solution
      at 37 degrees C. Major differences in terms of hydrophilicity, hydrolysis rate
      and loss of mechanical properties were observed between PLA-Zinc and PLA-Tin.
      Discussion of the behavior of interference screws of different compositions was
      made on the basis of the present understanding of PLAGA morphology and
      degradation characteristics.

PMID- 10416677
TI  - New versatile, elastomeric, degradable polymeric materials for medicine.
AB  - The present investigation was focused on the cell compatibility of recently
      developed biodegradable polyesterurethane-foam (DegraPol-foam) to chondrocytes
      and osteoblasts. Both chondrocytes and osteoblasts, isolated from adult male
      rats, exhibited relatively high cell adhesion on DegraPol-foam. Scanning electron
      microscopy (SEM) showed that cells grew on the surface and into the open cell
      pores of the foam. Morphologically, cells found on the surface of the foam
      exhibited a flat cell appearance and built a confluent cell multilayer. In
      contrast, inside the foams cell showed rounded morphology building cell
      aggregates and cell islets. In addition, chondrocytes and osteoblasts
      proliferated on the DegraPol-foam and preserved their phenotype for up to 2
      weeks. During degradation of these polymers, small crystalline particles of short
      chain poly[(R)-3-hydroxybutyric acid] (Mn approximately 2300) (PHB-P) and lysine
      methyl ester are released. Therefore, lysine methyl ester and PHB-P, as possible
      degradation products of the polymer, are investigated here for their effects on
      macrophages and osteoblasts. Results obtained in the present study clearly
      indicate that macrophages and, to a lesser degree, osteoblasts have the ability
      to take up (phagocytose) PHB-P. At low concentrations, particles of PHB failed to
      induce cytotoxic effects or to activate macrophages. Osteoblasts showed only
      limited PHB-P phagocytosis and no signs of any cellular damage. At high
      concentrations of PHB-P, the cell viability of macrophages and to a lesser extent
      of osteoblasts was affected.

PMID- 10416678
TI  - PHA production, from bacteria to plants.
AB  - The genes encoding the polyhydroxyalkanoate (PHA) biosynthetic pathway in
      Ralstonia eutropha (3-ketothiolase, phaA or bktB; acetoacetyl-CoA reductase,
      phaB; and PHA synthase, phaC) were engineered for plant plastid targeting and
      expressed using leaf (e35S) or seed-specific (7s or lesquerella hydroxylase)
      promoters in Arabidopsis and Brassica. PHA yields in homozygous transformants
      were 12-13% of the dry mass in homozygous Arabidopsis plants and approximately 7%
      of the seed weight in seeds from heterozygous canola plants. When a threonine
      deaminase was expressed in addition to bktB, phaB and phaC, a copolyester of 3
      hydroxybutyrate and 3-hydroxyvalerate was produced in both Arabidopsis and
      Brassica.

PMID- 10416679
TI  - Changes in manganese superoxide dismutase expression after exposure of the retina
      to intense light.
AB  - Manganese superoxide dismutase (Mn-SOD) is a naturally-occurring scavenger of
      superoxide, one of several reactive oxygen intermediates. To determine if Mn-SOD
      expression is enhanced as a defensive mechanism against oxidative challenges,
      such as intense light exposure, rats were exposed to cyclic light (80 lux) for 2
      weeks, intense light (1,800 lux) for 24 h, and then again to cyclic light.
      Experimental and control (exposed to cyclic light only) eyes were enucleated 3 h,
      1, 3, 7, and 14 days after light challenge. Protein expression was examined
      immunohistochemically using rabbit antisera against rat Mn-SOD. There was no
      significant difference between the light-exposed and the control groups in the
      thickness of the outer nuclear layers. Both retinal pigment epithelial cells and
      photoreceptor inner segments in the normal retina were labeled for Mn-SOD. Mn-SOD
      labeling was lost 3 h and day 1 after light challenge. It was re-expressed in the
      retinal pigment epithelial cells 3, 7, and 14 days after the light challenge, and
      in the photoreceptor inner segments after day 14. These results suggest that the
      retina might have a protective potential against light damage, in which Mn-SOD
      may play an important role.

PMID- 10416680
TI  - Determination of fibrosis from cryostat sections using high performance liquid
      chromatography: skeletal muscle.
AB  - Analysis of hydroxyproline (collagen) and pyridinoline (collagen cross-links) in
      biopsies prepared for routine histological evaluation with OCT compound was
      performed. Frozen sections (250 microm-thick) were cut from cardiac muscle,
      diaphragm, liver, and soleus muscle from the rat. After removal of OCT compound
      by rinsing, the samples were dried, weighed and hydrolyzed in 6 N HCl. A portion
      of the hydrolysate was analyzed for hydroxyproline using high performance liquid
      chromatography with collagen type I as the standard. Collagen concentrations
      ranged from 6.6 microg/mg dry weight (liver) to 74.7 microg/mg dry weight
      (diaphragm). From the remainder of the hydrolyzate, pyridinoline cross-links of
      collagen were separated and analyzed similarly by high performance liquid
      chromatography. The concentration of pyridinoline ranged from 2.6 ng/mg dry
      weight (liver) to 35.6 ng/mg dry weight (diaphragm). These techniques were
      adequate to analyze both collagen and pyridinoline (i.e. collagen cross-links) in
      small biopsy samples (< 1 mg dry weight) routinely used in clinical pathology.
      The method proved useful in the quantitation of focal fibrosis in a partially
      denervated rat soleus. Denervation was confirmed using fast myosin
      immunohistochemistry which revealed large areas of small myofibres containing
      fast myosin. Collagen concentration increased by five-fold and collagen cross
      links by more than 7-fold consistent with fibrotic changes known to occur with
      denervation.

PMID- 10416681
TI  - Glycoconjugates of the rat ciliary body epithelium: a lectin histochemical and
      protein blotting study.
AB  - The present study sought to identify and partially characterize the
      glycoconjugates specific to the double-layered ciliary body epithelium of the rat
      eye by lectin histochemistry and lectin blottings. Hydrated paraffin sections of
      Carnoy-fixed Sprague-Dawley rat eyes were stained with a panel of 21 different
      biotinylated lectins, followed by streptavidin-peroxidase and the glucose oxidase
      diaminobenzidine-nickel staining procedure. The results of lectin histochemistry
      revealed that the inner epithelial layer was rich in GlcNAc(beta1,4)GlcNAc, alpha
      Gal, Gal(beta1,3)GalNAc, GalNAc(alpha1,3)GalNAc/Gal, GalNAc(alpha1,6)Gal,
      Fuc(alpha1,2)Gal(beta1,4)GlcNAc and Gal(beta1,4)GlcNAc(beta1,2)Man(alpha1,6)
      sugar residues as shown by its positive reactivities with S-WGA, PWA, DSA, GS-I
      B4, PNA, DBA, SBA, WFA, UEA-I, LTA and PHA-E. The reactivities of GS-I-B4, PNA,
      DBA and SBA were restricted to the inner layer at the tips of the ciliary
      processes. On the other hand, the outer epithelial layer was stained evenly by
      DSA and Jacalin, and partly by MAA, showing that this epithelial layer was rich
      in GlcNAc(beta1,4)GlcNAc, Gal(beta1,3)GalNAc and NeuAc(alpha2,3)Gal
      disaccharides. These lectin binding patterns of the ciliary body epithelium
      suggest a topographical and functional difference in this double cell-layered
      epithelium. Their possible roles in the secretion of aqueous humour and
      production of ciliary zonule are discussed. Some identified lectin markers
      specific to these two cell layers may be useful for further experimental studies.
      Glycoproteins extracted from the dissected ciliary body were separated by SDS
      PAGE electrophoresis and analyzed by protein blottings with 8 different lectins.
      The results showed that at least 10 major membrane-bound glycoproteins, with
      molecular weights ranging from 30 to 150 kD, rich in beta-GlcNAc, beta-Gal,
      alpha/beta-GalNAc and NeuAc(alpha2,6)Gal residues, were present in the microsomal
      fraction.

PMID- 10416682
TI  - Hemidesmosomal molecular changes in dermatitis herpetiformis; decreased
      expression of BP230 and plectin/HD1 in uninvolved skin.
AB  - Recent BP230-knockout experiments with subsequent blistering and recently
      identified plectin/HD1 mutations in epidermolysis bullosa simplex patients
      suggest that defective expression of BP230 and plectin/HD1 may predispose to
      blister formation in human skin. We have studied the expression of the epithelial
      adhesion complex as well as the basement membrane and anchoring fibril antigens
      in uninvolved dermatitis herpetiformis skin to find out if alterations can be
      detected in these structures predisposing to the blister formation typical of the
      disease. Ten uninvolved dermatitis herpetiformis skin specimens, which all showed
      clear granular deposits of IgA under the basement membrane in direct
      immunofluorescence and five normal skin specimens, were studied by indirect
      immunofluorescence technique. Six uninvolved dermatitis herpetiformis skin
      specimens showed distinctly decreased immunoreaction for BP230 and four
      uninvolved dermatitis herpetiformis skin specimens showed distinctly decreased
      immunoreaction for plectin/HD1. All five skin controls showed strong
      immunoreactions for BP230 and plectin/HD1. Other hemidesmosomal proteins
      including BP180 and integrin alpha6beta4, as well as basement membrane proteins
      laminin-5, laminin-1, nidogen and type IV collagen, and the anchoring fibril
      protein type VII collagen showed a normal strong expression. Our results suggest
      that alterations in BP230 and plectin/HD1 may contribute or predispose to blister
      formation in dermatitis herpetiformis skin.

PMID- 10416683
TI  - Changes in the metabolic and contractile characteristics of muscle in male cattle
      between 10 and 16 months of age.
AB  - Samples of semitendinosus muscle from 28 male cattle (18 Salers and 10 Limousins)
      were taken at 10 months (biopsy) and at 16 months of age (at slaughter). The
      animals had received the same diet and were slaughtered after the same duration
      of fattening. The activities of isocitrate dehydrogenase and lactate
      dehydrogenase were measured in the muscle samples. The five lactate dehydrogenase
      isoenzymes were separated by electrophoresis under non-denaturing conditions and
      assayed by densitometry. Fibres were identified by histochemistry by myofibrillar
      ATPase and succinate dehydrogenase activities as SO (slow oxidative), FOG (fast
      oxidative glycolytic) or FG (fast glycolytic), and by immunohistochemistry by
      their reaction to monoclonal antibodies specific to slow and fast myosin heavy
      chain reactions in I, IIC, IIA, IIAB and IIB type fibres. The isocitrate
      dehydrogenase activity was not modified between 10 and 16 months of age; the
      lactate dehydrogenase activity decreased and was correlated with an increase in
      the proportion of the H isozyme to the detriment of the proportion of the M form.
      This period was characterized by an increase in fibre size, increased expression
      of MHC IIa, resulting in more IIA fibres, less IIB fibres, and an increase in the
      percentage of type IIAB fibres, however the proportions of SO, FOG and FG, when
      analysed statistically, were not modified between 10 and 16 months of age.

PMID- 10416684
TI  - Life-long dietary restriction modulates the expression of collagens and collagen
      binding heat shock protein 47 in aged Fischer 344 rat kidney.
AB  - It has been shown that the expression of HSP47 and collagens is substantially
      increased in the sclerotic/fibrotic process in various organs, including kidney.
      However, the factors regulating the increased expression of HSP47 are not yet
      clear. In this study, we examined the effect of dietary restriction for the
      expression of collagens and collagen-binding HSP47 in the kidneys of 6- and 24
      month-old male Fischer 344 (F 344) rats fed ad libitum or 30% diet-restricted. No
      significant histological alteration was found in the kidneys of 6-month-old fed
      or diet-restricted rats. Kidneys obtained from 24-month-old freely fed rats
      showed glomerulosclerosis with marked tubulointerstitial damage including
      interstitial fibrosis, while in the kidneys of 24-month-old diet-restricted rats,
      renal damage was remarkably less than those noted in 24-month-old freely fed rat
      kidneys. Immunohistochemical analysis showed an increased accumulation of type I,
      type III and type IV collagens in areas of glomerulosclerosis and interstitial
      fibrosis in old rat kidneys. Dietary restriction significantly reduces renal
      accumulation of collagens in old age. Aging enhanced expression of HSP47 in 24
      month-old freely fed rat kidneys whereas dietary restriction suppressed its
      expression in 24-month-old diet-restricted rat kidneys. Also, phenotypic
      alterations of mesangial cells and interstitial cells (immunopositive for alpha
      smooth muscle actin), glomerular epithelial cells (immunopositive for desmin) and
      tubular epithelial cells (immunopositive for vimentin) were seen in 24-month-old
      freely fed rat kidneys and found to express HSP47. Dietary restriction
      significantly diminished phenotypically altered renal cells in 24-month-old rat
      kidneys. Our results suggest that increased expression of HSP47 is associated
      with age-related renal damage and that diet-restricted alteration of its
      expression is associated with the modulation of age-associated renal
      sclerosis/fibrosis.

PMID- 10416685
TI  - Expression of von Hippel-Lindau protein in normal and pathological human tissues.
AB  - To examine the localization of von Hippel-Lindau (VHL) protein in human tissues,
      we produced four novel monoclonal antibodies against human VHL protein. Western
      blot analysis revealed that two of these antibodies recognized the epitope in
      amino acid sequence 60-89 of the VHL protein and the others recognized sequences
      54-60 and 189-213. In a wild-type VHL gene-transfected cell line,
      immunocytochemistry and immunoelectron microscopy demonstrated the
      intracytoplasmic localization of VHL protein, particularly in mitotic cells. In
      normal human tissues, VHL protein was detected immunohistochemically in
      epithelial cells covering the body surface and the alimentary, respiratory, and
      genitourinary tracts; in secretory epithelial cells of exocrine and endocrine
      organs; in parenchymal cells of visceral organs; in cardiomyocytes; in neurons in
      nervous tissue; in lymphocytes in lymphoid tissue; and in macrophages. In
      pathological specimens, VHL protein was expressed in VHL-related tumor, as well
      as in endothelial cells, fibroblasts, and pericytes, all of which are involved in
      active angiogenesis. These findings suggest that these monoclonal antibodies can
      be useful for various immunological assays and that the VHL protein plays
      fundamental roles in physiological and pathological situations, especially in
      neovascularization.

PMID- 10416686
TI  - Obesity: a prognostic factor of severity in acute pancreatitis.
AB  - This study was conducted to assess the prognostic value of obesity in acute
      pancreatitis and to determine the role played by obesity-associated diseases in
      the course of the disease. We prospectively studied 49 patients with acute
      pancreatitis who were divided into three groups according to their body mass
      index (BMI). There were 22 patients in group I (BMI < or = 25 kg/m2, normal or
      low weight); 15 in group II (BMI >25 and < or = 29 kg/m2, overweight); and 12 in
      group III (BMI >29 kg/m2, obese). Other anthropometric parameters also were
      measured. The severity of pancreatitis was assessed according to the Atlanta
      classification system. Systemic complications were significantly more common
      among obese than nonobese patients (p < 0.05). Patients with severe pancreatitis
      had a higher body-fat percentage, measured by the subscapular skin-fold
      thickness, and a larger abdominal circumference than patients with mild
      pancreatitis. Although hypertensive or diabetic patients developed more systemic
      complications, the multivariate analysis demonstrated that the presence of these
      underlying diseases did not modify the prognostic role of obesity in acute
      pancreatitis. We conclude that obesity is a prognostic factor of outcome in acute
      pancreatitis. Obesity-associated diseases do not vary the prognostic value of
      obesity. It seems that truncal adiposity is the kind of obesity related to worse
      outcome of acute pancreatitis.

PMID- 10416687
TI  - Microcirculation in chronic alcoholic pancreatitis: a laser Doppler flow study.
AB  - Experimental chronic pancreatitis is associated with microcirculatory
      disturbances but can also be induced or aggravated by perfusion changes.
      Microcirculatory alterations in human chronic pancreatitis are poorly defined. In
      this clinical study we investigated pancreatic microcirculation in the normal
      human pancreas and in chronic pancreatitis by laser Doppler flowmetry. Laparotomy
      was performed on 13 patients with nonpancreatic disease and on nine patients with
      chronic alcoholic pancreatitis for pancreatic head resection. Blood flow was
      measured over the pancreatic head, the uncinate process, over the mesenteric
      vein, the pancreatic corpus, and over the pancreatic tail by laser Doppler
      flowmetry. Blood flow was highest in the head of a normal pancreas with a mean of
      436 +/- 34 perfusion units (PU), 399 +/- 43 PU in the uncinate process, 286 +/-
      30 PU in the pancreatic corpus, and 351 +/- 46 PU in the tail of the pancreas. In
      the normal pancreas, lowest blood flow was measured over the mesenteric vein (228
      +/- 23 PU). In chronic pancreatitis, blood flow in the pancreas was significantly
      decreased across the whole pancreas (p < 0.01). Furthermore flow-wave pattern was
      altered in chronic pancreatitis as compared with the normal pancreas. The normal
      human pancreas has a spatial variation in blood flow, correlating with the
      pancreatic arterial blood supply. In the chronically inflamed human pancreas,
      blood flow is significantly diminished, with a lower flow toward the pancreatic
      head.

PMID- 10416688
TI  - p53 overexpression in lymph node metastases predicts clinical outcome in ductal
      pancreatic cancer.
AB  - In this study, we evaluated the prognostic significance of both p53
      overexpression and proliferating activity in 133 primary ductal pancreatic
      carcinomas and in their regional synchronous lymph node metastases by
      immunohistochemistry, by using DO7 and MIB1 monoclonal antibodies, respectively.
      Tumor samples and lymph nodes were obtained from formalin-fixed, paraffin
      embedded archival material of patients operated on between 1976 and 1996.
      Patients had a well-documented clinical history and were given accurate follow
      up. p53 accumulation was observed in 77 (54%) of 133 primary tumors and in 22
      (44%) of 50 patients with nodal metastases. The p53 overexpression was directly
      related to proliferating activity (p = 0.01) in the primary tumors. A significant
      direct correlation was present between the p53 expression in the primary tumor
      and in nodal metastases (p = 0.01); the same occurred for proliferating activity
      by MIB1 (p = 0.002). The patients' overall survival was affected by the presence
      of nodal (p = 0.02) and distant (p = 0.0001) metastases. The p53 immunoreactivity
      in nodal metastases was associated with a statistically significant decrease in
      the postoperative survival period (p = 0.005). Multivariate analysis confirmed
      these results, and the only two parameters that maintained statistical
      significance were M1 status (p = 0.0006) and p53 overexpression in nodal
      metastases (p = 0.01).

PMID- 10416689
TI  - Salivary gland involvement in patients with chronic pancreatitis.
AB  - The salivary glands are structurally similar to the exocrine pancreas and may be
      involved in the course of diseases of autoimmune origin (sclerosing cholangitis,
      ulcerative rectocolitis, primary biliary cirrhosis). For a not-yet-quantified
      proportion of chronic pancreatitis (CP) cases, a possible autoimmune pathogenesis
      has been postulated. The aim of the study was to assess the frequency of salivary
      ductal system abnormalities in patients with CP. Fifty-one patients with CP
      consecutively admitted to our center were studied (44 men, seven women; mean age,
      48.2 +/- 10.8 years). The mean duration of disease was 11.7 years (range, 1-37
      years); 44 (86%) of 51 patients had pancreatic calcifications, 25 (49%) of 51
      diabetes, 25 (52%) of 48 steatorrhea, and 32 (63%) of 51 underwent pancreatic
      surgery. As a control group, we studied 10 patients of whom four with liver
      cirrhosis (three alcoholic and one posthepatitis; three men, one woman; mean age,
      57 +/- 12.5 years), and six with temporomandibular pain (five men and one woman;
      mean age, 42 +/- 10.3 years). The patients were given parotid sialography, the
      findings being read by two independent observers. In two CP patients, parotid
      sialography was unsuccessful. Fifteen (31 %) of 49 patients and none of the 10
      control patients exhibited abnormalities of the glandular ducts compatible with
      chronic inflammation of the salivary ducts (p = 0.039). None of the CP patients
      had salivary intraductal calcifications. Findings of parotid ductal abnormalities
      are frequent in the course of CP and may indicate a common pathogenetic
      mechanism, even of an immune type.

PMID- 10416690
TI  - Synthesis of steroids in pancreas: evidence of cytochrome P-450scc activity.
AB  - In pancreas, the activities of several sex steroid-transforming enzymes have been
      reported. Data have been obtained in perfused organs, total tissue homogenates,
      and subcellular organelles. These data, concurrent with the description of the
      presence of ligand-regulated steroid receptors, as well as the sexually dimorphic
      behavior of some pancreatic tumors, are clear evidence in support of the
      participation of steroid hormones in the pancreatic function. In this study, the
      steroidogenic ability of the pancreas was demonstrated by two different methods:
      (a) in tissue homogenates, by the identification of cytochrome P-450scc gene
      (CYP11A) transcripts after reverse transcription-polymerase chain reaction
      amplification (RT-PCR); and (b) in isolated mitochondria by the glutethimide
      dependent inhibition of cholesterol-pregnenolone biotransformation. The results
      obtained in a series of independent experiments showed that (a) the pancreatic
      tissue possessed transcriptional activity of the CYP11A gene, although to a
      lesser extent than the typical steroidogenic tissues, and (b) isolated
      mitochondria obtained from the pancreas were able consistently to synthesize
      pregnenolone; furthermore, the addition of the specific inhibitor
      aminoglutethimide (AMG) blocked its synthesis. On the whole, these findings are
      interpreted as clear evidences of the activity of the cytochrome P-450scc
      enzymatic complex (P450scc), responsible for the transformation of cholesterol
      into pregnenolone and considered the first and limiting step in steroid
      biosynthesis.

PMID- 10416691
TI  - Early changes of gene expression during cerulein supramaximal stimulation.
AB  - Administration of supramaximal doses of cerulein results in acute interstitial
      pancreatitis. To understand the pathogenesis of this disease, it would be of
      great importance to elucidate the changes during the early phase of the process.
      We report changes of gene expression in the pancreas during the first 6 h of
      cerulein supramaximal stimulation. The expression of genes, including the
      secretory enzyme amylase, the lysosomal enzyme cathepsin B, as well as the
      housekeeping genes beta-actin and glyceraldehyde-3-phosphate dehydrogenase
      (GAPD), was investigated in this study. The most prominent alteration in gene
      expression is beta-actin messenger RNA (mRNA), which increased continuously after
      cerulein infusion. Immunostaining for beta-actin was observed along the membrane
      of large cytoplasmic vacuoles in pancreatic acinar cells. The level of amylase
      mRNA decreased during the first 30 min of cerulein infusion, recovered to the
      control level at 1 h and increased twofold at 2 h. An obvious increase in
      cathepsin B mRNA was observed after 3 h of cerulein infusion and reached sixfold
      of the control at 6 h. A significant increase of GAPD mRNA level was observed at
      6 h of cerulein stimulation. In conclusion, this study provides direct evidence
      that the changes in gene expression, such as cathepsin B and amylase, after
      supramaximal cerulein stimulation, are regulated at the transcriptional level. It
      also suggests that beta-actin is involved in the formation of cytoplasmic
      vacuoles during supramaximal cerulein administration. Finally, this study
      indicates that beta-actin and GAPD may not be appropriate as RNA-loading controls
      for Northern blot analysis of pancreatic tissue.

PMID- 10416692
TI  - Properties of a recombinant human secretin receptor: a comparison with the rat
      and rabbit receptors.
AB  - A secretin receptor was cloned from a commercial human pancreatic complementary
      DNA (cDNA) bank. The amino acid sequence deduced from the nucleotide sequence
      differed slightly from the three different sequences previously published,
      suggesting a genetic polymorphism of the human receptor. The binding properties
      of the receptor were evaluated by testing natural secretin, related peptides, and
      synthetic analogs or fragments on membranes of Chinese hamster ovary (CHO) cells
      expressing the receptor after transfection. The second-messenger coupling was
      evaluated by adenylate cyclase measurement. The human secretin receptor was
      compared with the rat and the rabbit receptors. In the three animals species, rat
      and human secretin were equipotent; rabbit secretin was equipotent on human and
      rabbit secretin receptors and less potent on the rat receptor. Similar data were
      obtained for the [Arg16]-secretin analog. Deletion of histidine 1 and replacement
      of aspartate 3 reduced the affinity of the peptides for the three receptors;
      however, the reduction was more pronounced on rat than on human and rabbit
      secretin receptors. Finally, the low affinity of the rat and human receptors for
      vasoactive intestinal peptide (VIP) was identical; the rabbit receptor, however,
      had a 20-fold higher affinity. Thus the human secretin receptor shows properties
      of both rat and rabbit receptors. Evaluation of the properties of chimeric
      receptors will be useful to fit the ligand on the receptors.

PMID- 10416693
TI  - Effect of sumatriptan on external pancreatic secretion and its interaction with
      endogenous norepinephrine in the rat.
AB  - We reported previously that blocking norepinephrine reuptake by nisoxetine could
      modulate external pancreatic secretion in the rat. We report in this study the
      interaction of serotonin (5-HT) with endogenous catecholamines by using
      sumatriptan, an agonist of 5-HT1 receptors, in combination with nisoxetine.
      Urethane-anesthetized male Wistar rats were fitted with an acute pancreatic
      fistula. Nisoxetine (0.3 mg/kg, i.v.) and sumatriptan (0.1-1 mg/kg, s.c.) were
      administered alone or in combination. Pancreatic secretion was measured under
      stimulation by 2-deoxy-D-glucose (2DG; 75 mg/kg, i.v.), by vagal electrical
      stimulation (4 V, 2 ms, 10 Hz), or by acetylcholine (60-1,800 microg/kg.h). (i)
      2DG: Nisoxetine alone inhibited 2DG-induced pancreatic secretion (p < 0.01).
      Sumatriptan alone also produced a dose-related inhibition of 2DG-induced
      pancreatic secretion (p < 0.01). When sumatriptan and nisoxetine were combined,
      protein response to 2DG remained inhibited, whereas water and electrolyte
      secretion was restored. (ii) Vagal stimulation: Nisoxetine did not modify water
      and electrolyte output in response to vagal electrical stimulation (VES), whereas
      it inhibited protein response by 75%. Sumatriptan alone strongly inhibited
      pancreatic response to VES (p < 0.01). When nisoxetine and sumatriptan were
      combined, the protein response to VES remained inhibited, whereas water and
      electrolyte response to VES was restored. (iii) Acetylcholine: Nisoxetine and
      sumatriptan alone or combined did not modify pancreatic response to
      acetylcholine. These results indicate that noradrenergic and serotonergic agents
      can indirectly affect pancreatic secretion through a modulation of the vagal
      cholinergic pathway. Nisoxetine and sumatriptan interact negatively on
      hydroelectrolytic pancreatic secretion, whereas they inhibit the secretion of
      enzymes both alone and in combination.

PMID- 10416694
TI  - Systemic lymphocyte activation modulates the severity of diet-induced acute
      pancreatitis in mice.
AB  - To examine the role of lymphocyte activation in the development of local and
      systemic complications in acute pancreatitis, we compared disease severity of
      choline-deficient, 0.5% ethionine supplemented (CDE) diet-induced acute
      pancreatitis in T- and B-cell deficient SCID mice and immunocompetent C.B-17
      mice. Twenty-five female SCID and 17 female C.B-17 mice were fasted for 24 h and
      fed a CDE diet for 72 h. Twenty SCID and 12 C.B-17 mice were bled and their
      organs removed for histologic evaluation. Five control animals of both kinds were
      fed a regular diet for 6 days. Lung, kidney, and pancreas were examined
      microscopically, and pancreatic damage scored. Apoptosis was detected by DNA nick
      end labeling and confirmed by DNA laddering. Trypsinogen-activation peptide was
      measured by enzyme-linked immunosorbent assay (ELISA), and the catalytic activity
      of PLA2 was determined by a radiometric assay. Four-day mortality was 10% in SCID
      and 33% in C.B-17 mice, and 10-day mortality was 0 in SCID and 60% in C.B-17
      mice. SCID mice had mild pulmonary damage, whereas pulmonary injury was severe in
      C.B-17 mice. Pancreatic damage was severe in both groups. Even though in situ
      staining of apoptotic cells was found in all pancreatitis animals, apoptosis was
      confirmed by DNA laddering only in C.B-17 mice. In SCID mice, apoptotic cell
      staining positively correlated with necrosis (r = 0.91; p < 0.001). Plasma TAP
      and PLA2 catalytic activity did not differ significantly between the groups. In
      conclusion, the absence of T and B lymphocytes prevents severe pulmonary injury
      resulting from acute pancreatitis but does not influence pancreatic or renal
      damage. Our results suggest that systemic lymphocyte activation does not affect
      the initiating events that trigger pancreatic injury but modulates the systemic
      response, in particular, pulmonary injury caused by acute pancreatitis.

PMID- 10416695
TI  - The role of the pancreas in intestinal zinc secretion in metallothionein-null
      mice.
AB  - The distribution and excretion of endogenous Zn, including the role of the
      pancreas, were examined in fasted MT+/+ and MT-/- mice. At 3 and 6 h after
      receiving 65Zn tracer by subcutaneous injection, 65Zn levels were compared in
      tissues of MT+/+ and MT-/- mice. 65Zn levels were significantly higher in the
      liver and pancreas of the MT+/+ mice, whereas in the MT-/- mice, 65Zn levels were
      significantly higher in muscle, skin, and most of the gastrointestinal tract
      other than the stomach and upper small intestine. In MT-/- mice, 3% of the
      injected 65Zn was recovered in the luminal contents of the small intestine over 3
      6 h, compared with <1.5% in the MT+/+ mice. A loading dose of Zn (150 microg,
      s.c.) sufficient to raise the plasma Zn concentration by fourfold to fivefold in
      both MT+/+ and MT-/- mice resulted in similar increases in pancreatic Zn levels
      in each genotype, although more Zn appeared in the lower small intestine of MT-/-
      mice. Pancreatectomy decreased the level of 65Zn in the small intestine of MT-/-
      but not MT+/+ mice. Longer-term studies over 4 days demonstrated few differences
      in tissue 65Zn between MT+/+ and MT-/- mice, with the exception of the pancreas,
      where 65Zn retention after fasting in MT-/- mice was half that of MT+/+ mice. MT
      /- mice also had significantly lower Zn concentrations in the pancreas. Fecal
      excretion of 65Zn in MT-/- mice was greater than that of MT+/+ mice in the first
      24 h (24.7 vs. 18.2% of injected dose; p < 0.05). Besides metallothionein (MT),
      there were no significant differences in the molecular weight distribution of Zn
      binding ligands in the lumen of the small intestine between MT+/+ and MT-/- mice.
      Mice lacking MT I and II lose more endogenous Zn into the gut because of a
      relative failure of the pancreas to retain Zn. However, increased Zn secretion
      via the small intestinal mucosa may also contribute to intestinal Zn loss in MT-/
      mice.

PMID- 10416696
TI  - Supraphysiologic concentrations of cerulein induce apoptosis in the rat
      pancreatic acinar cell line AR4-2J.
AB  - Little is known as yet about the role of apoptosis in pancreatic damage. This
      study evaluated the effects of supraphysiologic concentrations of the
      cholecystokinin (CCK) analog, cerulein, which causes cell damage in vitro and
      acute pancreatitis in vivo, on cell proliferation and DNA fragmentation in the
      rat pancreatic acinar cell line AR4-2J. Cerulein inhibited the cell proliferation
      of AR4-2J time- and dose-dependently to approximately 60% of the control level at
      10(-6) M after 72 h. DNA fragmentation, as assessed by both electrophoresis and
      enzyme-linked immunosorbent assay (ELISA), occurred at cerulein concentrations >
      or = 10(-8) M. The maximal DNA fragmentation as measured by ELISA was reached
      after 24 h. Cerulein at concentrations > or = 10(-9) M induced wild-type p53.
      Glutathione (1 mM) diminished the effects of cerulein on both cell proliferation
      and DNA fragmentation, whereas spermine (100 microM), which partially attenuated
      DNA fragmentation, did not have an effect on cell proliferation. The CCK-A
      receptor antagonist loxiglumide completely abolished the effect of cerulein on
      DNA fragmentation. The serine-protease inhibitor FUT-175 (10 microM), the
      cysteine-protease inhibitor NCO-700 (5 mM), and ethylene glycol tetraacetic acid
      (EGTA; 500 microM) all had no effects on the changes in cell proliferation and
      DNA fragmentation induced by cerulein. The data suggest that supraphysiologic
      concentrations of cerulein rapidly induce apoptosis in AR4-2J cells and only
      later inhibit cell proliferation. These effects are mediated by CCK-A receptors.
      Cerulein-induced apoptosis may involve the induction of wild-type p53 or
      glutathione depletion or both.

PMID- 10416697
TI  - Optimization of culture conditions for the preservation of monkey pancreatic
      islets in culture.
AB  - Culturing of islets is essential for various purposes before transplantation. It
      is necessary to establish optimal culture conditions for each animal species for
      their preservation in culture. In this study, attempts were made to preserve the
      Indian bonnet monkey islets in culture. The islets were isolated from monkey
      pancreas by the collagenase digestion method. They were separated from acinar
      cells by dextran density-gradient centrifugation. They were preserved in a
      humidified atmosphere of 5% carbon dioxide and 95% air for 7 days. The culture
      medium used was RPMI-1640. Various optimal conditions such as volume of the
      culture medium used, number of islets in one culture dish, concentration of
      glucose in culture medium, and fetal calf serum percentage were tested for their
      better preservation in culture. After the culture period, they were tested for
      their insulin secretory capacity by exposing them to various secretagogues.
      Histologic appearance of the cultured islets also was examined. Both insulin
      secretory characteristics and histologic structure were found to be normal.

PMID- 10416698
TI  - Relationship between the histopathology of the endocrine-exocrine pancreas
      parenchyma and beta-cell function in the Chinese hamster CHIG/Han subline.
AB  - To investigate pancreatic histopathology in relation to islet function in type 2
      diabetes, pancreatic tissue was examined at disease onset and after death in the
      genetically diabetic Chinese hamster CHIG/Han subline. The pancreatic islets
      displayed vacuolation, intraislet fibrosis, variable stages of degranulation, and
      beta-cell necrosis, but no insulitis. These lesions were associated with changes
      in immunostaining of major islet peptides, impaired glucose-stimulated (10 mM)
      insulin secretion, reduced islet insulin content, and the severity of
      hyperglycemia. The exocrine pancreas was characterized by peri- and
      intrapancreatic fat and mononuclear cell infiltration. Biopsy of the pancreas had
      a marked effect on plasma glucose such that at 2 weeks after excision, in 9 and
      18% of the severely hyperglycemic hamsters, plasma glucose levels decreased to
      <7.2 and 15 mM, respectively, and 45% of the mildly hyperglycemic hamsters became
      transiently normoglycemic (<7.2 mM). The results showed that insulitis is not
      involved in beta-cell failure of diabetic CHIG/Han hamsters. Vacuolation of
      islets was the most prominent lesion associated with a functional islet
      abnormality and development of hyperglycemia. Attenuation of hyperglycemia after
      biopsy suggests that the pancreas, in type 2 diabetes, maintains the ability to
      respond to impairment with amelioration of the diabetic state.

PMID- 10416699
TI  - Expression of cholecystokinin in the pancreas during development.
AB  - We have reported that cholecystokinin-like immunoreactivity (CCK-LI) and its
      transcripts are expressed in rat pancreatic islets (Endocrinology 1998;139:389
      96). The purpose of this study was to elucidate the ontogeny of CCK during
      pancreatic development in the rat. Fetal rats from day 13 (E13) to 20 (E20) and
      postnatal (P) rats from day 1 to adulthood were used in this study.
      Immunohistochemical studies of rat pancreas were carried out with rabbit antisera
      against CCK-8 and gastrin-17. The absorption studies were performed by using CCK
      8 antiserum incubated with excess CCK-8 or gastrin-17. In situ hybridization was
      performed to demonstrate the CCK and gastrin transcripts in the pancreas. CCK and
      gastrin were first detected at E15, and they were distributed in the periphery of
      the islets in the fetal and neonatal pancreas. The mirror sections for CCK
      revealed positive cells with characteristics identical to those that stained
      positive for gastrin. The CCK-LI in early development was completely abolished by
      preabsorption with excess gastrin but not with CCK-8. These findings indicated
      that the CCK-LI in the fetal and neonatal pancreas was crossreacting gastrin
      rather than CCK-8. From weaning (P21) through adulthood, on the other hand, CCK
      LI was expressed diffusely in pancreatic islets, but there were no gastrin
      positive cells after weaning. In situ hybridization showed that CCK messenger RNA
      (mRNA) was present in rat pancreatic islets in adults but not in early
      development. Although CCK-positive cells were not detected in fetal and neonatal
      pancreatic islets, CCK was expressed in islets during and after weaning through
      adulthood, indicating that CCK in pancreatic islets might be developmentally
      regulated.

PMID- 10416700
TI  - Organized pancreatic necrosis: endoscopic, radiologic, and pathologic features of
      a distinct clinical entity.

PMID- 10416701
TI  - An update of the risk assessment for
      methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) with focus on rinse
      off products.
AB  - Methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) has been widely used
      during the last 20 years for the preservation of aqueous systems in cosmetics,
      toiletries and in various industrial applications. MCI/MI has a broad spectrum of
      activity against fungi and bacteria at very low concentrations. The allergic
      contact potential of MCI/MI has been known for many years. This paper provides a
      review of pre-clinical and clinical experimental studies as well as experience
      from dermatology clinics worldwide. This forms the basis for an update of the
      risk assessment for the use of MCI/MI in rinse-off products. The scientific data
      indicate that the actual sensitization rate observed with a contact allergen is
      extremely dependent on dose and type of exposure. This review of the data leads
      to the conclusion that, under normal use conditions, within the current
      permitted/ recommended use concentrations for MCI/MI of up to 15ppm, the risk of
      primary sensitization from the use of rinse-off products is negligible, and
      elicitation of allergic contact dermatitis in MCI/MI-sensitized individuals rare,
      after exposure to MCI/MI-preserved rinse-off products.

PMID- 10416702
TI  - Structure-activity relationships in the murine local lymph node assay for skin
      sensitization: alpha,beta-diketones.
AB  - The biological activity of skin-sensitizing chemicals is related to their ability
      to react, either directly or after metabolic activation, with appropriate skin
      proteins. For direct acting electrophilic compounds, this ability can be
      modelled, using the RAI (relative alkylation index) approach, by a combination of
      electrophilicity and hydrophobicity parameters. Several structure-activity
      relationships based on this approach have been reported, but most of them cover
      guinea pig sensitization test data on what chemists would classify as relatively
      soft electrophilic chemicals. In the present work, an electrophilicity parameter
      based on Taft substituent constants is derived for hard electrophiles having a
      reactive carbonyl group, and is used to calculate RAI values for the analysis of
      sensitization test data obtained in the murine local lymph node assay (LLNA) for
      a series of alpha, beta-diketones. The sensitization potential of these reactive
      hard electrophilic carbonyl compounds in the LLNA shows a good correlation with
      the RAI. Overall, the findings reaffirm our view that physical organic chemistry
      is the key to understanding why some chemicals sensitize more strongly than
      others, while some do not sensitize at all, and provide further evidence of the
      value of the LLNA for SAR studies.

PMID- 10416703
TI  - Unclassified endogenous eczema.
AB  - Patients with intractable eczema are often referred for patch testing to exclude
      contact dermatitis. If this is excluded, then a diagnosis of endogenous eczema is
      made. At our clinic, we find a sizeable proportion of these patients do not fit
      any of the known patterns of endogenous eczema. These patients are given the
      diagnosis of unclassified endogenous eczema and make up 8% of the patients seen
      at our Occupational and Contact Dermatitis Clinic. There is little information
      available on this group of patients, with no mention of this problem in the
      recent dermatological literature. Since March 1996, we have further investigated
      these patients, to develop some understanding of this category. 12 of 34 patients
      reviewed over this period had an elevated IgE level above 100 IU/ ml. Thus,
      despite no past history or family history of eczema, asthma or hayfever, at least
      1/3 of these patients are probably suffering from atypical, late onset atopic
      dermatitis. Patients were later contacted by telephone (average 2 years) to
      assess the natural history of this condition. In 20 of the 31 patients contacted,
      their eczema had either improved or resolved. We think that this important
      category of eczema needs to be recognized and further investigated.

PMID- 10416704
TI  - Acetone has anti-inflammatory effects on experimental contact reactions.
AB  - The effects of a topically applied corticosteroid and its acetone vehicle on
      experimental allergic, toxic and irritant reactions are presented. The
      corticosteroid budesonide in acetone or acetone alone was applied to reactions
      immediately after and at different time intervals within the 1st h after
      provocation. Classical naked eye observation was performed and the dermal
      cellular infiltrate was differentiated and counted using a previously well
      characterized method. "Treatment", whether with the steroid in acetone or acetone
      alone, had anti-inflammatory effects. For all reaction types, erythema and oedema
      diminished and a significant decrease in mononuclear cells was seen, when
      application occurred within the first 5 min after provocation. The effects were
      most marked for the toxic reaction to croton oil, the steroid and the vehicle
      being anti-inflammatory to the same extent. Application up to 60 min after
      provocation had anti-inflammatory effects for this reaction type. The mechanisms
      of acetone's anti-inflammatory effects are at present unclear. One possible
      explanation is that intercellular lipid organisation and, by extension, cellular
      membrane lipid organisation, are altered, influencing membrane receptor function.
      Possible anti-inflammatory effects of acetone should be considered in
      experimental and perhaps even clinical situations. Further investigation of the
      therapeutic possibilities of the finding seems warranted.

PMID- 10416705
TI  - Provocative use tests in CAPB-allergic subjects with CAPB-containing product.
AB  - Cocamidopropyl betaine (CAPB) has been identified as a cause of contact allergy
      in personal care products. Furthermore, it has been suggested that chemicals
      responsible are impurities, especially dimethylaminopropylamine (DMAPA). However,
      skin contact concentrations with these impurities, especially DMAPA, are very
      low. The aim of the study was to analyse whether subjects with previous positive
      patch tests to CAPB would react in provocative use tests of a product containing
      CAPB. 10 individuals with a clinical history of contact allergy to CAPB (by
      positive patch test and history) took part in a ROAT which used a CAPB-based
      shower gel at 25% (DMAPA concentration < 1 ppm). None of the subjects showed
      positive allergic reactions. 1 of the test subjects did experience a flare of
      atopic dermatitis at the treatment site. Later, all 10 subjects were patch tested
      to 3 different concentrations of CAPB and DMAPA (0.1%, 0.3%, 1%) to verify the
      threshold that was capable of inducing a positive test reaction. 5/10 showed
      clear + reactions to 1% CAPB (typically at D3), whilst a further 3 gave marginal
      and/or irritant reactions. Only 1 of the subjects showed an allergic reaction to
      DMAPA. Finally, in uncontrolled use testing with the shower gel, none of the test
      subjects reported any adverse skin reactions. Thus, the study confirmed that CAPB
      sensitive individuals can use a CAPB-based rinse-off product without the risk of
      experiencing an allergic reaction to CAPB.

PMID- 10416706
TI  - Long-lasting allergic patch test reactions: a study of patients with positive
      standard patch tests.
AB  - The purpose of this study was to determine the duration of patch test reactions
      and the frequency of long-lasting allergic patch test reactions (LLAPTR), and to
      identify the possible factors related to the development of the LLAPTR. For this
      purpose, a group of 263 patients positive to 1 or more allergens in the GIRDCA
      standard series was recruited. Readings were made for each patient 2 and 3 days
      after patch test application and continued every 2nd and 3rd day until the
      disappearance of all palpable erythema. The % of LLAPTR out of the total of
      reactions was high: 17.9%). Kathon CG was the hapten that caused LLAPTR most
      frequently, with 16 cases, a frequency of 76.1%), and a mean duration of the
      patch test reactions of 25.4 days. Risk factors investigated were age, sex,
      atopy, intensity of the patch test reaction and sensitivity to some allergens
      with the greatest number of positive patch tests. The relative importance of each
      risk factor was calculated by multivariate stepwise logistic regression analysis.
      It was found that a Kathon CG sensitivity was the most important risk factor for
      LLAPTR. 2nd was atopy, followed by strong patch test reaction. Rejected risk
      factors were sex, age and sensitivity to nickel sulfate, potassium dichromate,
      Disperse Blue 124, fragrance mix and p-phenylenediamine.

PMID- 10416707
TI  - Para-phenylenediamine-induced lichenoid eruptions.

PMID- 10416708
TI  - Allergic contact dermatitis due to Kathon CG in Hong Kong.

PMID- 10416709
TI  - Glove-related hand urticaria in the absence of Type I latex allergy.

PMID- 10416710
TI  - Occupational chemical burns caused by bromine.

PMID- 10416711
TI  - Allergic contact dermatitis from dithiocarbamate fungicides in a bricklayer.

PMID- 10416712
TI  - Contact dermatitis from levobunolol eyedrops.

PMID- 10416713
TI  - Patch testing with additional series of allergens.

PMID- 10416714
TI  - Allergic contact dermatitis from tropicamide ophthalmic solution.

PMID- 10416715
TI  - The trend of allergic contact dermatitis in the elderly population over a 15-year
      period.

PMID- 10416716
TI  - Occupational IgE-mediated contact urticaria from diphenylmethane-4,4-diisocyanate
      (MDI).

PMID- 10416717
TI  - Airborne allergic contact dermatitis from colophony in a car.

PMID- 10416718
TI  - Occupational airborne contact dermatitis from diphencyprone in a pharmacy
      employee.

PMID- 10416719
TI  - Contact allergy to budesonide in a breath-actuated inhaler.

PMID- 10416720
TI  - Contact dermatitis from benzoxonium chloride.

PMID- 10416721
TI  - Photoallergic contact dermatitis from Zovirax cream.

PMID- 10416722
TI  - Hairdresser's dermatitis caused by oak moss in permanent waving solution.

PMID- 10416723
TI  - Gold allergy and artificial sweat.

PMID- 10416724
TI  - The frequency of mercury intolerance in patients with chronic fatigue syndrome
      and healthy controls.

PMID- 10416725
TI  - Studying the effectiveness of neurocognitive remediation in schizophrenia.

PMID- 10416726
TI  - Interventions for neurocognitive deficits: editor's introduction.

PMID- 10416727
TI  - The effects of atypical antipsychotic drugs on neurocognitive impairment in
      schizophrenia: a review and meta-analysis.
AB  - Cognitive deficits are a fundamental feature of the psychopathology of
      schizophrenia. Yet the effect of treatment on this dimension of the illness has
      been unclear. Atypical antipsychotic medications have been reported to reduce the
      neurocognitive impairment associated with schizophrenia. However, studies of the
      pattern and degree of cognitive improvement with these compounds have been
      methodologically limited and have produced variable results, and few findings
      have been replicated. To clarify our understanding of the effects of atypical
      antipsychotic drugs on neurocognitive deficits in patients with schizophrenia, we
      have (1) reported on newly established standards for research design in studies
      of treatment effects on cognitive function in schizophrenia, (2) reviewed the
      literature on this topic and determined the extent to which 15 studies on the
      effect of atypical antipsychotics met these standards, (3) performed a meta
      analysis of the 15 studies, which suggested general cognitive enhancement with
      atypical antipsychotics, and (4) described the pharmacological profile of these
      agents and considered the pharmacological basis for their effects on
      neurocognition. Finally, we suggest directions for the development of new
      therapeutic strategies.

PMID- 10416728
TI  - Risperidone versus haloperidol on secondary memory: can newer medications aid
      learning?
AB  - The introduction of the new generation of antipsychotic medications for the
      treatment of schizophrenia has been accompanied by a growing interest in the
      neurocognitive effects of these drugs. The present study compared the effects of
      risperidone and haloperidol on secondary memory in a group of treatment-resistant
      schizophrenia patients. The study design included a baseline phase and two double
      blind phases in which patients were randomly assigned to medication under two
      different dose conditions (fixed dose and flexible dose). Secondary memory was
      assessed at baseline, fixed-dose, and flexible-dose phases, using the California
      Verbal Learning Test (CVLT). Six measures were selected, which formed three
      factors (general verbal learning ability, retention, and learning strategy).
      Risperidone-treated patients showed greater improvement than haloperidol-treated
      patients in general verbal learning ability, a finding characterized by
      significant treatment effects on CVLT measures of learning acquisition, recall
      consistency, and recognition memory. After controlling for benztropine status,
      differences on the measures of learning acquisition and recall consistency
      remained significant, and differences in recognition memory weakened slightly (p
      = 0.07). No significant treatment effects were noted on retention or learning
      strategy. These findings suggest that risperidone may exert a facilitating effect
      on the acquisition of new verbal information, an effect that does not appear to
      be due to the activation of semantic encoding strategies.

PMID- 10416730
TI  - Cognitive rehabilitation for schizophrenia: problems, prospects, and strategies.
AB  - Increasing awareness of the importance of neurocognitive impairments in
      schizophrenia has fostered considerable interest in the prospects for cognitive
      rehabilitation. Nevertheless, optimism has outpaced progress. We first review
      recent literature on the central assumptions that underlie cognitive
      rehabilitation, including the hypothesis that cognitive deficits play a central
      role in social disability and other problems schizophrenia patients experience in
      daily living, and that these impairments must be rectified if we are to achieve
      effective rehabilitation. We next discuss developments in knowledge about the
      neurobiology of schizophrenia that bear on the potential for cognitive
      rehabilitation and the selection of appropriate targets for intervention. Third,
      we propose a new research strategy for investigating cognitive functioning in
      schizophrenia and for examining the relationship of cognitive deficits to role
      functioning in the community: examining patients who have good vocational
      outcomes in order to identify strengths or compensatory factors that compensate
      for core deficits. We present new data that lend support to our proposed
      approach. We next discuss putative limits to cognitive rehabilitation based on
      data documenting cognitive deficits in healthy siblings and parents. Finally, we
      briefly describe an interim rehabilitation strategy that minimizes the load on
      cognitive processes rather than attempting to improve cognitive functioning.

PMID- 10416729
TI  - The effects of clozapine, risperidone, and olanzapine on cognitive function in
      schizophrenia.
AB  - Cognitive function is markedly impaired in most patients with schizophrenia.
      Antecedents of this impairment are evident in childhood. The cognitive disability
      is nearly fully developed at the first episode of psychosis in most patients. The
      contribution of cognitive impairment to outcome in schizophrenia, especially work
      function, has been established. Preliminary results indicate that cognitive
      function, along with disorganization symptoms, discriminate schizophrenia
      patients who are able to work full-time from those who are not. Typical
      neuroleptic drugs lack the ability to improve the various domains of cognitive
      function impaired in schizophrenia. Atypical antipsychotic drugs
      pharmacologically related to clozapine-quetiapine, olanzapine, risperidone,
      sertindole, and ziprasidone--share the ability to produce fewer extrapyramidal
      symptoms than typical neuroleptic drugs and more potent antagonism of serotonin2a
      relative to dopamine2 receptors. However, they have a number of different
      clinical effects. We have identified all the studies of clozapine, olanzapine,
      and risperidone that provide data on their effects on cognition in schizophrenia.
      Data for each drug are reviewed separately in order to identify differences among
      them in their effects on cognition. Twelve studies that report cognitive effects
      of clozapine are reviewed. These studies provide (1) strong evidence that
      clozapine improves attention and verbal fluency and (2) moderate evidence that
      clozapine improves some types of executive function. However, results of the
      effects of clozapine on working memory and secondary verbal and spatial memory
      were inconclusive. Risperidone has relatively consistent positive effects on
      working memory, executive functioning, and attention, whereas improvement in
      verbal learning and memory was inconsistent. Preliminary evidence presented here
      suggests that olanzapine improves verbal learning and memory, verbal fluency, and
      executive function, but not attention, working memory, or visual learning and
      memory. Thus, atypical antipsychotic drugs as a group appear to be superior to
      typical neuroleptics with regard to cognitive function. However, available data
      suggest that these drugs produce significant differences in specific cognitive
      functions. These differences may be valuable adjunctive guides for their use in
      clinical practice if cognitive improvements reach clinical significance. The
      effects of the atypical antipsychotic drugs on cholinergic and 5-HT2a-mediated
      neurotransmission as the possible basis for their ability to improve cognition
      are discussed. It is suggested that the development of drugs for schizophrenia
      should focus on improving the key cognitive deficits in schizophrenia: executive
      function, verbal fluency, working memory, verbal and visual learning and memory,
      and attention.

PMID- 10416731
TI  - Cognitive functioning in schizophrenia: implications for psychiatric
      rehabilitation.
AB  - Research in psychopathology and the cognitive neurosciences suggests new
      applications in psychiatric rehabilitation. Analysis of performance deficits on
      laboratory tasks can contribute to treatment planning, individual and family
      counseling, and staff consultation, much like it does in cases of brain injury
      and other types of central nervous system neuropathology. Recognition of the
      nature of cognitive impairments in schizophrenia can inform design of
      psychosocial techniques such as social and living skills training. Cognitive
      impairments are increasingly seen as potential targets for pharmacological and
      psychosocial treatment and rehabilitation. In this article, three key issues for
      application of cognitive technology in psychiatric rehabilitation of
      schizophrenia and related disorders are formulated as straightforward, clinically
      relevant questions: (1) What is the prognostic significance of cognitive
      impairment in acute psychosis? (2) Can cognitive functioning improve in the
      chronic, residual course? (3) How does cognitive improvement benefit other
      aspects of recovery and rehabilitation? These questions are addressed through
      review of previous findings and new multivariate analyses of cognitive
      functioning in the acute, post-acute, and chronic residual phases of
      schizophrenia.

PMID- 10416732
TI  - The effects of neurocognitive remediation on executive processing in patients
      with schizophrenia.
AB  - Approaches to cognitive remediation have differed across studies. Most of the
      larger studies have concentrated on group treatments designed without the benefit
      of recent laboratory-based studies. The current study describes a randomized
      trial of an intensive cognitive remediation program involving individual daily
      sessions of 1 hour for up to 3 months. It targets executive functioning deficits
      (cognitive flexibility, working memory, and planning) that are known to be
      problematic in people with schizophrenia. Procedural learning, as well as the
      principles of errorless learning, targeted reinforcement, and massed practice,
      was the basis of the intervention. The program was compared with an alternative
      therapy (intensive occupational therapy) to control for some of the effects of
      therapeutic contact. Some improvements in cognition followed both therapies. A
      differential effect in favor of cognitive remediation therapy was found for tests
      in the cognitive flexibility and the memory subgroups. There was a trend for
      those receiving atypical antipsychotic medication to benefit more from cognitive
      remediation for tests of cognitive flexibility. Although there were no consistent
      changes in symptoms or social functioning between groups, if improvement in
      cognitive flexibility tasks reached a threshold then there is some evidence that
      social functioning improved, even over the short duration of the trial. In
      addition, cognitive remediation differentially improved self-esteem. This study
      supports the view that cognitive remediation can reduce cognitive deficits and
      that this reduction may affect social outcome, at least in the short term.

PMID- 10416733
TI  - Should schizophrenia be treated as a neurocognitive disorder?
AB  - The search is on for meaningful psychopharmacological and cognitive/behavioral
      interventions for neurocognitive deficits in schizophrenia. Findings in this area
      are emerging rapidly, and in the absence of integrating frameworks, they are
      destined to emerge chaotically. Clear guidelines for testing neurocognitive
      interventions and interpreting results are critical at this early stage. In this
      article, we present three models of increasing complexity that attempt to
      elucidate the role of neurocognitive deficits in schizophrenia in relation to
      treatment and outcome. Through discussion of the models, we will consider
      methodological issues and interpretive challenges facing this line of
      investigation, including direct versus indirect neurocognitive effects of
      antipsychotic medications, selection of particular neurocognitive constructs for
      intervention, the importance of construct validity in interpreting
      cognitive/behavioral studies, and the expected durability of treatment effects.
      With a growing confidence that some neurocognitive deficits in schizophrenia can
      be modified, questions that seemed irrelevant only a few years ago are now
      fundamental. The field will need to reconsider what constitutes a successful
      intervention, what the relevant outcomes are, and how to define treatment
      efficacy.

PMID- 10416735
TI  - Outcome of schizophrenia in relation to brain abnormalities.
AB  - This article reviews the 21 studies that investigated possible relationships
      between structural brain abnormalities and outcome in schizophrenia. Fifteen
      studies used computer tomography to visualize brain morphology. In these studies,
      images were obtained of the ventricles but not of specific brain regions. The
      remaining six studies used magnetic resonance imaging, examining possible
      relationships between outcome, ventricular size, and specific brain regions. One
      out of two studies found relationships between brain structure and outcome. The
      data suggest that the extent of ventricular enlargement in patients with
      schizophrenia may be related to outcome. No clear relationship between outcome
      and changes in specific brain regions was found. Apart from considerations about
      the methodology of measuring different brain regions, the procedure used to
      measure outcome is important. Outcome, as it is assessed at various points during
      the course of illness, may be variable and seems to fluctuate during the first 10
      to 15 years of disease. Significantly, to date no studies relating outcome to
      brain structure have used patient samples with a duration of illness longer than
      15 years.

PMID- 10416734
TI  - Glucose-induced increase in memory performance in patients with schizophrenia.
AB  - Previous investigations have found that increasing circulating glucose
      availability can increase memory performance in rodents, healthy humans, and
      individuals with dementia of the Alzheimer's type. In this study, patients with
      schizophrenia, healthy control subjects, and controls with bipolar affective
      disorder were tested using double-blind treatment with either 50 g anhydrous
      dextrose plus 4 mg sodium saccharin (for "taste") or 23.7 mg saccharin alone,
      followed by cognitive testing on a complex battery. At this glucose dose, verbal
      memory performance on a paragraph recall task was increased during the glucose
      condition relative to the saccharin condition in the patients with schizophrenia;
      this effect was not detected in either the psychiatric or normal controls. The
      results provide preliminary support for the hypothesis that memory performance
      can be improved in patients with schizophrenia by increasing circulating glucose
      availability and suggest the importance of further evaluation of therapeutic
      manipulations of glucose availability.

PMID- 10416736
TI  - Cognitive asymmetry patterns in schizophrenia: active and withdrawn syndromes and
      sex differences as moderators.
AB  - Recognition memory for words and faces was examined in male and female
      schizophrenia patients for evidence of associations between putative left-right
      hemisphere asymmetry patterns and active (positive) versus withdrawn (negative)
      syndromes. Ninety-five normal controls and 104 schizophrenia patients with
      active, withdrawn, and mixed syndromes or in symptom remission were examined,
      including an unmedicated subgroup. Memory was poorer in patients than controls,
      while the remitted group had superior memory to psychotic patients. Active and
      withdrawn patients showed the hypothesized syndrome-dependent cognitive
      asymmetries: active (word > faces); withdrawn (faces > words), except active
      females who showed a word deficit. The results support selective lateralized
      temporoparietal impairment of either hemisphere in schizophrenia, with laterality
      related to active (face memory/right-sided impairment) and withdrawn (word
      memory/left-sided impairment) syndromes, except active syndrome females. These
      syndrome-related asymmetries moderated the sexually dimorphic asymmetries found
      in normal subjects. Consideration of individual differences both in sex and
      syndromes based on activity and withdrawal, and of left and right hemisphere
      memory modality, may assist in unraveling heterogeneity in schizophrenic
      cognition. The superior memory of recovered patients indicates that some memory
      impairment in schizophrenia is functional.

PMID- 10416737
TI  - Validity and usefulness of the Wisconsin Manual for Assessing Psychotic-like
      Experiences.
AB  - The Wisconsin Manual for Assessing Psychotic-like Experiences is an interview
      based assessment system for rating psychotic and psychotic-like symptoms on a
      continuum of deviancy from normal to grossly psychotic. The original manual
      contained six scales, assessing thought transmission, passivity experiences,
      thought withdrawal, auditory experiences, personally relevant aberrant beliefs,
      and visual experiences. A seventh scale assessing deviant olfactory experiences
      was subsequently added. The rating scales have good interrater reliability when
      used by trained raters. Cross-sectional studies indicated that the frequency and
      deviancy of psychotic-like experiences are elevated among college students who
      were identified, hypothetically, as psychosis prone by other criteria. Psychotic
      like experiences of moderate deviancy in college students successfully predicted
      the development of psychotic illness and poorer overall adjustment 10 years
      later. The manual is useful for identifying psychosis-prone individuals and is
      recommended for use in linkage and treatment outcome studies. The present article
      provides an interview schedule for collecting information required for rating
      psychotic-like experiences.

PMID- 10416738
TI  - Expressed emotion and relapse in young schizophrenia outpatients.
AB  - High familial expressed emotion (EE) reliably predicts 9-month relapse rates in
      schizophrenia patients. Difficulties interpreting the EE-relapse finding arise,
      however, because EE is usually assessed during a hospital admission, yet relapse
      following discharge is predicted. Researchers in Scotland assessed EE in
      relatives while the patients were out of hospital; using conservative relapse
      criteria, they failed to find higher subsequent 6- and 12-month relapse rates
      among patients living in high-EE homes (McCreadie and Phillips 1988). Our goal
      was to determine the ability of EE to predict relapse in a sample of 69
      schizophrenia outpatients using both conservative criteria (for 6-and 12-month
      rates) and standard relapse criteria (for 9- and 18-month rates). According to
      the conservative criteria, EE failed to predict 6- and 12-month relapse.
      According to the standard criteria, 9-month relapse rates were significantly
      greater among patients in high-EE households. In parental homes, relapse at both
      9 months and 18 months was best predicted by fathers' critical comments and
      mothers' emotional overinvolvement. Relapse was not associated with medication
      compliance and the amount of contact with high-EE relatives.

PMID- 10416739
TI  - Symptomatic overlap of cocaine intoxication and acute schizophrenia at emergency
      presentation.
AB  - Cocaine intoxication and acute abstinence alter brain dopaminergic functioning,
      resulting in behavioral changes closely mimicking the positive and negative
      symptoms of schizophrenia. In emergency room settings, recent cocaine abuse can
      be mistaken for schizophrenia and may cause inappropriate diagnosis and in some
      instances medical mismanagement. Schizophrenia patients presenting with recent
      cocaine abuse may also present with significant diagnostic and treatment
      dilemmas. This study attempts to distinguish between cocaine and schizophrenic
      psychosis by examining patients who present with both recent cocaine abuse and
      acute schizophrenia (CA+SZ), cocaine intoxication without schizophrenic illness
      (CA), and acute schizophrenia with no comorbid substance abuse (SZ) within the
      first 24 hours after arrival at the Bellevue psychiatric emergency service.
      Clinical assessment included the Brief Psychiatric Rating Scale, the Schedule for
      the Assessment of Positive Symptoms, and the Schedule for the Assessment of
      Negative Symptoms. Both cocaine abusing groups were required to have positive
      urine toxicology screens for inclusion in the study. Multivariate analysis of
      variance showed the CA+SZ patients present with a clinical profile that overlaps
      with CA patients on mood and negative symptom dimensions and overlaps with SZ
      patients on most positive symptoms. CA+SZ patients differed from both groups,
      however, by presenting with significantly more hallucinatory experiences than
      cocaine abusing or schizophrenia patient counterparts. Despite considerable
      overlap, each group of patients presented with a discernible cross-sectional
      symptom pattern.

PMID- 10416740
TI  - Antipsychotics: Past and Future: National Institute of Mental Health Division of
      Services and Intervention Research Workshop, July 14, 1998.
AB  - A workshop on "Antipsychotics: Past and Future" was convened by the National
      Institute of Mental Health (NIMH), Division of Services and Intervention Research
      (DSIR), on July 14, 1998, to review the results of recent antipsychotic drug
      research, discuss current standards of treatment, and identify areas needing
      further study. There has been a proliferation of new antipsychotic medications
      and a rapid increase in their clinical utilization. The new atypicals are
      beginning to supplant the older typical neuroleptic antipsychotics, and the
      scientific and ethical issues raised by this transition prompted the workshop.
      Given the apparent, albeit not fully defined, advantages of atypical drugs,
      particularly their safety profiles, the question is whether more comparisons with
      typical antipsychotics are warranted and whether clinical trial designs warrant
      (or would be justified in) the inclusion of typical drugs as standard active
      comparators. Workshop participants--including clinical researchers, patient
      advocates, bioethicists, and NIMH staff--discussed the conclusions drawn from
      current data, ethical issues for subjects in clinical trials, funding for ongoing
      studies using typical agents, and appropriate comparators for trials using
      atypical agents.

PMID- 10416741
TI  - First person account: talking through medication issues: one family's experience.

PMID- 10416742
TI  - Introductory comments on blood flow autoregulation in the optic nerve head and
      vascular risk factors in glaucoma.
AB  - It is widely suspected that tissue ischemia initiates or participates in optic
      disk damage in glaucoma. The details are not well delineated. Particularly
      puzzling is the clear separation of the clinical appearances of glaucoma and
      anterior ischemic optic neuropathy, which is also a presumed ischemic disease.
      When venous pressure at the exit point from the eye is elevated by intraocular
      pressure (IOP), the arteriovenous pressure difference is reduced. Nutrition is
      maintained only because of blood flow autoregulation. Intraocular pressure
      induced ischemia can result if autoregulation is impaired in an individual,
      either because of an innate deficiency or, perhaps, as a result of vasospastic
      disease. Autoregulation can also be impaired if another disease (e.g., an
      atheroma) has caused much of the autoregulatory capacity to be already utilized,
      so that little or none is left to respond to the additional challenge of IOP.
      Ischemia might also result from microvascular occlusion with platelet or clotting
      abnormalities, perhaps inducing glaucomatous optic neuropathy that is not
      dependent on IOP. A better understanding of the pathogenic mechanism (and how it
      may be different in various cases) is needed to predict more successfully an
      individual's risk of glaucomatous damage, to make decisions about the
      aggressiveness of treatment, and, one day, to direct therapy at the type of
      vascular abnormality present, in addition to or instead of lowering IOP.

PMID- 10416743
TI  - Nocturnal hypotension: role in glaucoma progression.
AB  - The role of systemic blood pressure in glaucomatous damage remains undefined,
      with systemic hypertension and hypotension being implicated in different studies.
      We have previously reported that the physiologic nocturnal blood pressure "dip"
      may be exaggerated in some glaucoma patients with progressive field loss. A 24
      hour ambulatory blood pressure recording was originally performed on 84 patients
      with glaucoma. The mean result across all our glaucoma patients were within the
      ranges reported in the literature for normal subjects. The normal-tension
      glaucoma and primary open-angle glaucoma groups did not differ significantly in
      blood pressure variables. Nocturnal blood pressure variables were lower in the
      patients with progressive field defects compared to those with stable visual
      fields. To determine long-term outcomes in these patients, we reevaluated the
      visual fields of the original 84 patients studied. In 70 patients with long-term
      visual field data (mean, 5.1 years), those who had shown greater nocturnal blood
      pressure dips were more likely to have shown field progression at some stage,
      despite good intraocular pressure control. Patients who had field progression
      showed significantly lower nocturnal blood pressure variables, with the dips of
      the systolic, diastolic, and mean arterial pressure significantly larger
      (systolic dip, P = 0.01). They also had a greater history of disk hemorrhages. A
      review of other 24-hour blood pressure studies in the literature shows that most
      are in agreement with these findings. The nocturnal reduction in blood pressure
      may, therefore, be an additional risk factor in glaucoma patients.

PMID- 10416744
TI  - Physiology of perfusion as it relates to the optic nerve head.
AB  - Blood flow in the optic nerve has been demonstrated to be autoregulated, and,
      thus, within certain limits, to be independent of the local perfusion pressure.
      As in the brain, a close coupling of neuronal activity and optic nerve head blood
      flow has been demonstrated. A number of regulatory systems and factors
      participate in the regulation of vascular tone in various organs, including the
      optic nerve. Metabolic and myogenic mechanisms keep local perfusion constant or
      adapted to the local metabolic needs. Such mechanisms seem to be involved in the
      regulation of optic nerve blood flow as well. In contrast, neuronal blood flow
      regulation is of minor importance in the optic nerve. Many of the regulatory
      modalities induce a response of vascular smooth muscle cells through stimulation
      of factors produced by the endothelial cell layer. Indeed, endothelial factors
      are of utmost importance in the regulation of optic nerve blood flow. The facts
      that there is a basal formation of nitric oxide, which leads to an active
      dilation of the ocular vasculature, and that endothelin-1 decreases blood flow to
      the anterior optic nerve in a dose-dependent manner suggest that alterations in
      these regulatory mechanisms might be relevant for optic nerve blood flow
      alterations as they relate to glaucomatous optic neuropathy. It is hoped that a
      detailed knowledge of blood flow regulation in the optic nerve might initiate new
      treatment modalities in optic neuropathies that are hemodynamic and vascular in
      nature.

PMID- 10416745
TI  - The role of age and cardiovascular disease in glaucomatous optic neuropathy.
AB  - The role of systemic cardiovascular disorders in glaucomatous optic neuropathy
      was studied experimentally in rhesus monkeys and clinically in humans. These
      studies suggest that, in the multifactorial phenomenon of glaucomatous optic
      neuropathy, among other risk factors, age, cardiovascular disease and nocturnal
      arterial hypotension may play an important role in the development and
      progression of glaucomatous optic neuropathy in many cases, independent of
      intraocular pressure. In glaucomatous optic neuropathy, age may be an indirect
      index of cardiovascular disease rather than an independent factor per se.
      Nocturnal arterial hypotension, particularly among hypertensive patients taking
      oral hypotensive medication, may be an important risk factor. Because 24-hour
      ambulatory blood pressure monitoring is becoming popular among ophthalmic
      researchers, multiple confounding factors in ambulatory blood pressure monitoring
      in patients with optic nerve head ischemic disorders that can produce misleading
      information are discussed.

PMID- 10416746
TI  - Vascular aspects in the pathophysiology of glaucomatous optic neuropathy.
AB  - Glaucoma remains a major eye illness with unknown etiology. Although elevated
      intraocular pressure is clearly a major risk factor, vascular deficits may
      contribute to initiation and progression of glaucoma. When intraocular pressure
      is acutely elevated in healthy individuals, the resistance index (derived from
      the peak systolic and end-diastolic velocities and an indirect index of vascular
      resistance distal to the site of measurement) in the central retinal and
      posterior ciliary arteries increases progressively. This result implies that
      mechanical and vascular factors may be coupled in such a way that perfusion of
      the retina and optic nerve head may be influenced by changes in the intraocular
      pressure. Further, at night, when ophthalmic artery flow velocities fall as
      arterial blood pressure falls in glaucoma patients, the risk of disease
      progression may be increased. The constancy of these same flow velocities in age
      matched healthy individuals points to a possible vascular autoregulatory defect
      in glaucoma. In addition, in normal-tension glaucoma, vasodilation (CO2
      inhalation) normalizes retrobulbar arterial flow velocities, hinting that some
      vascular deficits in glaucoma may be reversible. Finally, Ca2+ channel blockade
      improves contrast sensitivity in patients with normal-tension glaucoma, who also
      show increased retrobulbar vessel flow velocities, a result suggesting that
      visual function loss may be linked to ocular ischemia. Emerging evidence points
      to a role of ischemia in the pathogenesis of glaucoma, suggesting that treatments
      designed to improve ocular blood flow may benefit glaucoma patients.

PMID- 10416748
TI  - Modulation of Heidelberg Retinal Flowmeter parameter flow at the papilla of
      healthy subjects: effect of carbogen, oxygen, high intraocular pressure, and beta
      blockers.
AB  - The Heidelberg Retina Flowmeter (HRF) is intended to assess ocular blood flow by
      scanning laser doppler flowmetry. In the retina and possibly in the optic nerve
      head, carbogen increases blood flow, whereas pure oxygen or high intraocular
      pressure (IOP) decrease it. This study addresses whether at the papilla of
      healthy volunteers, the HRF parameter flow, is modulated by breathing 5% carbogen
      (5% carbon dioxide + 95% oxygen) for 7 minutes, breathing 100% oxygen for 7
      minutes, increasing IOP to 50 mm Hg with a suction cup, or decreasing IOP with a
      single topical ocular instillation of the beta-blockers 0.5% betaxolol (betoptic)
      or 0.5% timolol (timoptic). At the papilla (20 degrees x 5 degrees, 256 X 64
      pixels), values of HRF parameter, flow (50 X 50) pixels, increased after carbogen
      (N = 5, P < 0.05), but decreased after oxygen (N = 5, P < 0.05) or IOP increase
      (N = 5, P < 0.01). Although IOP values were significantly reduced by betaxolol (N
      = 9, P < 0.05) and timolol (N = 9, P < 0.01), HRF values were only significantly
      decreased (N = 9, P < 0.05) after timolol. In conclusion, at the papilla of
      healthy volunteers, a positive correlation exists between changes in values of
      the HRF-parameter, flow, and stimuli considered to modulate retinal and ONH blood
      flow. Furthermore, although of unkown clinical relevance, it appears that in
      contrast to betaxolol, values of the HRF parameter, flow, at the papilla of
      healthy volunteers are significantly decreased after a single instillation of
      timolol.

PMID- 10416747
TI  - Potential role of nitric oxide and endothelin in the pathogenesis of glaucoma.
AB  - Glaucoma is an optic nerve head neuropathy in which retinal ganglion cells are
      lost. A clear association exists between glaucoma and different risk factors,
      such as high intraocular pressure (IOP) or blood-flow dysregulation. Nitric oxide
      (NO) and endothelin, two recently identified cellular mediators, appear to be
      involved in the regulation of IOP as well as in the modulation of ocular blood
      flow. To some extent, NO is also involved in apoptosis, a mechanism of cell death
      that can lead to retinal ganglion cell loss in glaucoma. This article provides a
      short and simplified overview of the biochemistry of NO and endothelin and
      highlights the potential role of these two mediators in certain important aspects
      related to the pathogenesis of glaucoma.

PMID- 10416749
TI  - The Hettinger hand vibration test, vasospasm, and glaucoma.
AB  - Ocular vasospasm in response to local and/or systemic stimuli may contribute to
      ischemia of the optic nerve. The Hettinger hand vibration test was applied to
      patients with and without glaucoma to identify subgroups with a high systemic
      vasospastic tendency. A total of 580 subjects were tested (113 controls, 86
      glaucoma suspects, 270 with primary open-angle glaucoma, 71 with secondary open
      angle glaucoma, 30 with normal-tension glaucoma, and 10 with angle-closure
      glaucoma). The frequency distribution curve of Hettinger scores (HS) was bimodal,
      suggesting two distinct groups. Within each diagnostic group, a subpopulation
      with a high HS could be identified. Multivariate analysis demonstrated a
      significant association between the nonselective topical beta-blocker timolol and
      higher mean HS (P = 0.04) and a significantly higher proportion of subjects with
      HS of 1.5 or more (P = 0.01). Although subjects taking systemic beta1-selective
      blockers had significantly lower mean HS (P = 0.04), the proportion of patients
      with HS of 1.5 or more was not affected significantly by topical and systemic
      beta1-selective blocker use. Whereas topical nonselective beta-blockers may have
      an adverse effect on vasospastic tendency, systemic beta1-selective blockers may
      be partially protective against this effect.

PMID- 10416750
TI  - Visual field responses to a hand vibration stimulus.
AB  - Two short visual field tests were performed on 106 subjects approximately 5
      minutes apart with or without a hand vibration stimulus between the field tests.
      There were 31 eyes in the control group (10 without glaucoma, eight glaucoma
      suspects, 10 with primary open-angle glaucoma, and three with secondary open
      angle glaucoma). There were 75 eyes in the hand vibration group (16 without
      glaucoma, 20 glaucoma suspects, 25 with primary open-angle glaucoma, eight with
      secondary open-angle glaucoma, three with normal-tension glaucoma, and three with
      other forms of glaucoma). Average visual field sensitivities were significantly
      reduced in the arcuate zones after a hand vibration stimulus (-0.42 dB; SD, 1.26
      dB) when compared with sensitivities in the arcuate zones in subjects without the
      hand vibration stimulus (+0.38 dB; SD, 1.53 dB; P = 0.01). Multivariate analysis
      demonstrated a significant reduction in this response in the arcuate zone
      associated with use of betaxolol (P = 0.021) and timolol (P = 0.047). Betaxolol
      was associated with significantly smaller reductions in visual field
      sensitivities in the paracentral zone (P = 0.01). Reductions in visual field
      sensitivities that may be related to ocular vasospasm occurred after a hand
      vibration stimulus. This response may be able to be modified pharmacologically
      with topical beta-blockers, particularly betaxolol.

PMID- 10416751
TI  - Introductory comments on neuroprotection.

PMID- 10416752
TI  - A perspective of gene therapy in the glaucomas.
AB  - Gene therapy in the anterior and posterior segment tissues may have the potential
      to favorably influence aqueous hydrodynamics and retinal ganglion cell biology,
      thereby preventing, delaying, or minimizing glaucomatous damage to the optic
      nerve. We demonstrated the feasibility of using a herpes viral vector
      (ribonucleotide reductase defective HSV-1, hrR3) to deliver the lacZ reporter
      gene to living cat and rat eyes. Cats received injections into the anterior
      chamber and rats into the vitreous cavity. In cats, lacZ expression was
      detectable at 1 to 2 days in the anterior outer portion of the ciliary muscle and
      the lining of the intertrabecular spaces of the corneoscleral and uveal meshwork.
      Rat eyes showed lacZ expression in the retinal pigment epithelium and
      photoreceptor outer segments 2 days after injection.

PMID- 10416753
TI  - Direct and indirect approaches to neuroprotective therapy of glaucomatous optic
      neuropathy.
AB  - Retinal ganglion cell death is the final common pathway of virtually all diseases
      of the optic nerve, including glaucomatous optic neuropathy. In recent years it
      has been shown that retinal ganglion cells die after axonal injury via a
      programmed cell death process called apoptosis. The dynamics of retinal ganglion
      cell death reflect the timing and degree of the axonal injury, rather than its
      nature. For example, whether mediated by ischemia (corresponding to abnormalities
      of peripapillary circulation) or compression (e.g., changes in retrograde
      transport caused by increased intraocular pressure), the end result is a series
      of changes at the level of the axon, which subsequently affect the retinal
      ganglion cell body. Our studies on neuroprotection of retinal ganglion cells have
      focused on general mechanisms applicable to axonal injuries. By dissecting the
      pathways by which retinal ganglion cells die in these situations, strategies for
      protection may become manifest. We and others have found that production of
      certain reactive oxygen species is a necessary step for neuronal death after
      neurotrophin deprivation. In response, cells invoke compensatory mechanisms to
      maintain survival in the face of this attack. We have studied the transcriptional
      regulation of one candidate compensatory gene and discuss it as a model for gene
      based approaches to neuroprotective therapy for glaucomatous optic neuropathy. By
      approaching the problem of therapy from this point of view, it may become
      possible to prevent irreversible glaucomatous optic nerve changes by inducing
      endogenous cell-rescue mechanisms and, thus, with the retinal ganglion cells' own
      defense mechanisms, to prevent its death.

PMID- 10416754
TI  - Neuroprotection in relation to retinal ischemia and relevance to glaucoma.
AB  - Management of glaucoma is directed at the control of intraocular pressure (IOP),
      yet it is recognized now that increased IOP isjust an important risk factor in
      glaucoma. Therapy that prevents the death of ganglion cells is the main goal of
      treatment, but an understanding of the causes of ganglion cell death and
      precisely how it occurs remains speculative. Present information supports the
      working hypothesis that ganglion cell death may result from a particular form of
      ischemia. Support for this view comes from the fact that not all types of retinal
      ischemia lead to the pathologic findings seen in glaucomatous retinas or to
      cupping in the optic disk area. Moreover, in animal experiments in which ischemia
      is caused by elevated IOP, a retinal abnormality similar to that seen in true
      glaucoma is produced, whereas after occlusion of the carotid arteries a different
      pattern of damage is found. In ischemia, glutamate is released, and this
      initiates the death of neurons that contain ionotropic glutamate (NMDA)
      receptors. Elevated glutamate levels exist in the vitreous humor of patients with
      glaucoma, and NMDA receptors exist on ganglion cells and a subset of amacrine
      cells. Experimental studies have shown that a variety of agents can be used to
      prevent the death of retinal neurons (particularly ganglion cells) induced by
      ischemia. These agents are generally those that block NMDA receptors to prevent
      the action of the released glutamate or substances that interfere with the
      subsequent cycle of events that lead to cell death. The major causes of cell
      death after activation of NMDA receptors are the influx of calcium into cells and
      the generation of free radicals. Substances that prevent this cascade of events
      are, therefore, often found to act as neuroprotective agents. For a substance to
      have a role as a neuroprotective agent in glaucoma, it would ideally be delivered
      topically to the eye and used repeatedly. It is, therefore, of interest that
      betaxolol, a beta-blocker presently used to reduce IOP in humans, also has
      calcium channel-blocking functions. Moreover, experimental studies show that
      betaxolol is an efficient neuro protective agent against retinal ischemia in
      animals, when injected directly into the eye or intraperitoneally.

PMID- 10416755
TI  - Nitric oxide: a potential mediator of retinal ganglion cell damage in glaucoma.
AB  - In the glaucomatous optic nerve head, excessive nitric oxide (NO) may be
      responsible, at least in part, for degeneration of axons of retinal ganglion
      cells. We have demonstrated the apparent up-regulation and induction of certain
      isoforms of nitric oxide synthase (NOS), the enzyme that synthesizes NO, in
      astrocytes in the prelaminar and lamina cribrosa regions of optic nerve heads of
      patients with glaucoma. Evidence of NO toxicity, histochemical staining for
      nitrotyrosine, is present in these damaged optic nerve heads. In rats with
      experimentally induced, moderately elevated intraocular pressure, the isoforms of
      NOS were also identified.

PMID- 10416756
TI  - Why does the central nervous system not regenerate after injury?
AB  - Spinal cord injuries in humans and in other mammals are never followed by
      regrowth. In recent years, considerable progress has been made in analyzing
      mechanisms that promote and inhibit regeneration. The focus of this review is
      changes that occur in the transition period in development when the central
      nervous system (CNS) changes from being able to regenerate to the adult state of
      failure. In our experiments we have used the neonatal opossum (Monodelphis
      domestica), which corresponds to a 14-day embryonic rat or mouse. The CNS
      isolated from an opossum pup and maintained in culture shows dramatic
      regeneration. Fibers grow through and beyond lesions and reform synaptic
      connections with their targets. Similarly, anesthetized neonatal pups attached to
      the mother recover the ability to walk after complete spinal cord transection.
      Although the CNS isolated from a 9-day-old animal will regenerate in vitro, CNS
      from a 12-day-old will not. This is the stage at which glial cells in the CNS
      develop. Present research is devoted toward molecular screening to determine
      which growth-promoting molecules decrease during development, which inhibitory
      molecules increase, and which receptors on growing axons become altered. Despite
      progress in many laboratories, major hurdles must be overcome before patients can
      hope to be treated. Nevertheless, the picture today is not as discouraging as it
      was: one can think of strategies for research on spinal cord injury so as to
      promote regeneration and restore function.

PMID- 10416757
TI  - An experimental basis for implicating excitotoxicity in glaucomatous optic
      neuropathy.
AB  - Most therapy for glaucoma is directed at the management of the intraocular
      pressure (IOP). Conventional wisdom holds that excessive pressure within the eye
      leads to the ganglion cell loss/optic nerve damage seen in this disease. Both
      glutamate and elevated IOP can selectively damage the retinal ganglion cells in
      the mammalian eye. We have identified an elevated level of glutamate in the
      vitreous humor of glaucoma patients (27 microM as compared to 11 microM in the
      control population). This concentration of glutamate suffices--on its own--to
      kill retinal ganglion cells. It is plausible that the IOP may represent an
      initial insult that precipitates the production of excessive glutamate.
      Therefore, even if glutamate elevation is an epiphenomenon associated with the
      course of the disease, it may contribute to ganglion cell loss in humans.
      Lowering the IOP may slow down glutamate production, but if nothing is done to
      block the toxic effects of glutamate as well, visual loss may result despite
      excellent IOP control. If interventions can be found to retard the production or
      toxic effects of glutamate, it may be possible to slow glaucomatous visual loss.

PMID- 10416758
TI  - Apoptosis of retinal ganglion cells in glaucoma: an update of the molecular
      pathways involved in cell death.
AB  - Apoptosis is a genetically controlled form of cell death that ganglion cells
      undergo during normal development of the retina and in diseases affecting the
      optic nerve, such as glaucoma. This mechanism of cell death is controlled by
      specific genes and their products that are activated in the dying cell. To date,
      the mechanism of ganglion cell apoptosis is poorly understood, but research on
      cell death in other areas has provided a blueprint for the study of dying
      ganglion cells in animal models. Extensive research of the genetic pathways of
      apoptosis of neurons, in general, has yielded new information about the principal
      genes that are involved in this process. This review is meant to survey the major
      genetic players that are active in neuronal cell death and discuss their possible
      roles in retinal ganglion cells. One of the primary regulatory steps is the
      activation of the tumor-suppressor protein, p53. This protein functions as a
      transcription factor that can up-regulate the expression of the proapoptotic gene
      bax and down-regulate the expression of the antiapoptotic gene brl-2. Changes in
      the concentrations of these gene products can further stimulate apoptotic events,
      including changes in mitochondria that ultimately lead to the activation of a
      family of cysteine proteases called caspases that digest the dying cell from
      within. An understanding of the genetic pathways of apoptosis may lead to the
      design of new treatments that could prevent its activation or arrest the process
      when started.

PMID- 10416760
TI  - Introductory comments on potential differences between beta-blockers in the
      treatment of open-angle glaucoma.

PMID- 10416759
TI  - Retinal ganglion cell dysfunction induced by hypoxia and glutamate: potential
      neuroprotective effects of beta-blockers.
AB  - The objective of this study was to examine the effects of hypoxia, glutamate, and
      beta-blockers on the electrical activities of retinal ganglion cells. Single-unit
      extracellular and whole-cell voltage clamp recording techniques were used to
      record electrical activities from ganglion cells in the tiger salamander retina.
      This was performed under physiologic conditions, hypoxia, or elevated exogenous
      or endogenous glutamate levels. Light-evoked spike activities, glutamate-induced
      currents, and voltage-gated sodium and calcium currents were measured in the
      presence of the beta-1 selective antagonist betaxolol or the nonselective
      antagonist timolol. Hypoxia resulted in suppressing or blocking the OFF responses
      in the majority of ON-OFF ganglion cells tested, whereas the ON responses were
      only slightly affected. The presence of increased glutamate had similar findings
      and demonstrated an increase in the spontaneous firing rate of retinal ganglion
      cells. Betaxolol (2-50 microM) reduced the rate of spontaneous firing of retinal
      ganglion cells induced by glutamate. At 2 to 50 microM, betaxolol reversibly
      reduced the voltage-gated sodium currents and calcium currents in retinal
      ganglion cells. Timolol (up to 100 microM) did not demonstrate any detectable
      action on these currents. The physiologic responses of retinal ganglion cells to
      hypoxia or elevated glutamate levels in this animal model appear to be very
      similar. Although short-term exposure to hypoxia and glutamate used in this study
      exerts reversible actions on ganglion cells and does not induce permanent cell
      damage, such initial physiologic actions are likely to be precursors of permanent
      cell damage. Thus, hypoxia and elevated glutamate levels in the retina may
      represent a final pathway in diseases affecting retinal ganglion cells, such as
      glaucoma. Similar damage could result from different factors, such as decreased
      perfusion-induced ischemia or anomalous neuronal processing of glutamate.
      Betaxolol exerts its primary neuronal actions on retinal ganglion cells. It
      reversibly blocked voltage-gated calcium current and reduced the spontaneous
      firing rate by suppressing glutamate-gated currents and sodium currents in
      ganglion cells. These actions may protect ganglion cells from damage caused by
      ischemia or elevated glutamate levels.

PMID- 10416761
TI  - Color Doppler imaging of the retrobulbar circulation in glaucoma.
AB  - Color Doppler imaging is a noninvasive technique for investigating the
      retrobulbar circulation, showing specific retrobulbar vessels Ophthalmology
      Department, The Royal Victoria Hospital, Belfast, Northern Ireland and measuring
      blood velocity characteristics within these vessels. Color Doppler imaging is
      reproducible and has been used by many investigators to study blood velocity in
      the ophthalmic artery, the central retinal artery, and the short posterior
      ciliary arteries. The technique has shown statistically significant reductions in
      the flow velocities and increases in the resistance indices of these vessels in
      both primary open-angle glaucoma and normal tension glaucoma in comparison with
      normal control subjects. These changes correlate with disease severity and
      asymmetry and illustrate a compromised circulation in this region. Intraocular
      pressure and vasospasm have been shown to affect blood flow velocities in the
      same circulation. This article discusses studies that have elucidated these
      changes in various subpopulations of glaucoma subjects in an attempt to determine
      hemodynamic alterations between these disease types.

PMID- 10416762
TI  - In vitro studies of the effects of beta-adrenergic drugs on retinal and posterior
      ciliary microarteries.
AB  - The small-vessel myograph allows for precise measurements of physiopharmacologic
      responses of the ocular microarteries under controlled conditions. Studies using
      the myograph have shown that beta-adrenergic agonists are unable to induce
      significant relaxation in retinal and posterior ciliary microarteries, indicating
      that these microarteries have very few or no functional beta-adrenoceptors. Thus,
      beta-blockers would not be expected to have important adverse vasoconstrictory
      effects in the posterior part of the eye that are caused by their beta
      adrenoceptor binding capacities. On the contrary, some beta-blockers, such as
      propranolol (the standard beta-blocker in pharmacology) and betaxolol (a beta
      blocker used in ophthalmology), have vasorelaxant effects, probably a result of
      their Ca2+ channel-blocking activity. This activity shows no stereospecificity.
      Betaxolol could thus act as a vasodilator in glaucoma patients, on the condition
      that it penetrates in the posterior part of the eye after topical application. If
      so, it could also induce vasodilatation in circumstances of vascular endothelium
      injury, because this effect is endothelium-independent.

PMID- 10416763
TI  - Laser Doppler flowmetry of the optic nerve head in glaucoma.
AB  - The introduction of ocular laser Doppler flowmetry during the last decade has
      greatly improved our ability to noninvasively assess the hemodynamics of the
      optic nerve in patients with glaucoma. Studies with laser Doppler flowmetry have
      determined that blood flow in the optic nerve is diminished in eyes with primary
      open-angle glaucoma and that this decrease occurs in patterns consistent with
      glaucomatous damage. Lower systemic blood pressure is associated with lower blood
      flow, supporting numerous studies linking systemic hypotension to glaucomatous
      damage. This direct relationship between systemic blood pressure and optic nerve
      blood flow has significant implications in terms of the etiology of glaucomatous
      damage and the treatment of ocular and systemic diseases in the glaucoma patient.
      Further research is needed to determine whether the circulatory abnormalities of
      the optic nerve head are a cause or a result of glaucomatous damage.

PMID- 10416764
TI  - Objective perimetry in glaucoma: recent advances with multifocal stimuli.
AB  - The introduction of multifocal stimulus recording has enhanced our ability to
      examine the human visual field with electrophysiologic techniques. We have
      adapted the multifocal pattern visual evoked potential (PVEP) to detect visual
      field loss. In glaucoma patients we sought to determine the extent to which the
      PVEP amplitudes correlate with perimetric thresholds. Multifocal pseudorandomly
      alternated pattern stimuli, which were cortically scaled in size, were presented
      with use of the VERIS-Scientific system. Bipolar occipital straddle electrode
      positions were used. The visual field up to 25 degrees of eccentricity was
      investigated. Forty-three glaucoma patients with reproducible visual field
      defects were tested. The bipolar PVEP corresponded well with Humphrey visual
      field defects, showing loss of signal in the scotoma area. For Humphrey quadrant
      threshold totals and PVEP quadrant amplitudes, the correlation coefficient was
      strong (r = 0.49, P < 0.0001). The multifocal PVEP demonstrates good
      correspondence with the topography of the visual field. This technique represents
      the first practical application of the multifocal PVEP to objective detection of
      visual field defects in glaucoma.

PMID- 10416765
TI  - Periocular accumulation of timolol and betaxolol in glaucoma patients under long
      term therapy.
AB  - PURPOSE: To determine if betaxolol or timolol is present in measurable
      concentration in the Tenon capsule in patients under long-term topical therapy.
      METHODS: Small (1-cc) specimens of Tenon capsule were removed at the time of
      filtering surgery from 15 glaucoma patients under long-term preoperative topical
      therapy, nine of whom had been treated with timolol and six of whom had been
      receiving betaxolol. Methanol extracts of these tissue samples were analyzed
      quantitatively for the presence of either beta-adrenergic antagonist by high
      performance liquid chromatography. RESULTS: Drug was detected in every specimen.
      A mean total of 2.6 (range, 0.1-30.0) microg of betaxolol was detected per 1-cc
      specimen. CONCLUSION: Timolol and betaxolol penetrate the conjunctiva and
      accumulate in the Tenon capsule. In patients under long-term therapy, the
      periocular tissue can accumulate a greater quantity of beta-antagonist than is
      present in a daily dosage of applied eyedrops, manyfold higher than the maximal
      intraocular concentration.

PMID- 10416766
TI  - Systemic and ocular vascular roles of the antiglaucoma agents beta-adrenergic
      antagonists and Ca2+ entry blockers.
AB  - This review addresses whether the antiglaucoma agents beta-adrenergic antagonists
      and Ca2+ entry blockers cause vasoactive effects in the retinal and other ocular
      vasculatures, as they do in other tissues. The potent vasodilating effects of
      Ca2+ entry blockers on ocular vessels have recently been demonstrated in in vivo
      and in vitro studies, implying that the maintenance of ocular vascular tone
      relies almost exclusively on extracellular Ca2+. Ca2+ entry blockers may
      potentially play a role in relaxing the retinal, long posterior ciliary, and
      ophthalmociliary arteries to improve the ocular circulation in vascular diseases
      in which there is considerable vascular tone present. The beta-adrenergic
      antagonists are discussed with reference to their antihypertensive role, their
      effect on other vascular beds, and finally what is known of their effect in the
      ocular vasculature. The emerging evidence that particular selective beta
      adrenergic antagonists, such as betaxolol, are also potent Ca2+ channel entry
      blockers in other vascular beds is presented. Betaxolol has been shown to induce
      vasodilatation in the retinal and other ocular vascular beds, although studies
      have shown that beta1-adrenergic receptors are sparse in these vascular beds.
      This implies that an alternative mechanism must be responsible for betaxolol
      induced vasodilatation. Evidence is presented that betaxolol vasodilates via its
      potent Ca2+ channel entry blocking properties, and its potency and ability to
      vasodilate are compared with those of nimodipine and timolol, as well as with
      those of other Ca2+ channel entry blockers. Important areas for future research
      in this area are discussed.

PMID- 10416767
TI  - Optic disk appearances in primary open-angle glaucoma.
AB  - Primary open-angle glaucoma almost certainly develops in a multifactorial manner,
      with interplay between numerous risk factors affecting the disease. These risk
      factors, in addition to intraocular pressure, include a number of cardiovascular
      factors. Some of these factors may determine the appearance of the damaged
      glaucomatous optic nerve head. Patients with four specific optic disk appearances
      have been investigated, and differences have been identified in their demographic
      characteristics, prevalence of certain risk factors, the pattern of visual field
      damage, and circulatory abnormalities in their retrobulbar vessels. The findings
      provide evidence of the existence of subgroups of primary open-angle glaucoma
      with correlations between risk factor and type of optic disk. A reliable method
      by which the different disk appearances could be distinguished in an objective
      manner would be clinically valuable, and the scanning laser ophthalmoscope has
      shown potential promise to achieve this. The results of studies relating to
      various glaucomatous optic disk appearances are presented and discussed.

PMID- 10416768
TI  - Insulin therapy in cats.

PMID- 10416769
TI  - Echocardiographic measurements in the Irish wolfhound: reference values for the
      breed.
AB  - Out of 400 Irish wolfhounds cardiologically examined, echocardiographic
      measurements of 262 normal dogs were analyzed to obtain reference values for the
      breed. Based on regression analysis, several echocardiographic parameters showed
      significant linear correlation with body weight and with age, but coefficients of
      determination were low. Therefore, due to a high individual variability of
      echocardiographic measurements in adult Irish wolfhounds, the predictive value of
      body weight for echocardiographic measurements was clinically not relevant. Sex
      had no influence on echocardiographic values. For the estimation of myocardial
      function, end-systolic volume index (ESVI) (mean, 29.0 ml/m2 +/- standard
      deviation [SD], 5.9 ml/m2) was determined for the group of 262 normal dogs.

PMID- 10416770
TI  - Use of echocardiography in the diagnosis of dilated cardiomyopathy in Irish
      wolfhounds.
AB  - The purpose of this study was to compare the echocardiographic features of Irish
      wolfhounds with clinically inapparent dilated cardiomyopathy (DCM) (n = 33) to
      dogs with advanced DCM (n = 33) and to normal dogs (n = 262). Significant
      differences were detected between the three groups. In dogs with DCM, the most
      sensitive diagnostic measurements were: end-systolic volume index (ESVI), E-point
      to septal separation (EPSS), fractional shortening (FS), and left ventricular
      internal dimensions (LVIDd and LVIDs). Left atrial diameter was increased
      markedly in dogs with DCM and 83.3% of affected Irish wolfhounds had concurrent
      atrial fibrillation. Compared with early DCM, in advanced DCM there was a
      significant increase in end-diastolic right ventricular diameter, often combined
      with extensive pleural effusion, the leading sign of congestive heart failure in
      Irish wolfhounds.

PMID- 10416771
TI  - Pulsed Doppler assessment of left ventricular diastolic function in normal and
      cardiomyopathic cats.
AB  - Left ventricular (LV) diastolic function was evaluated in 16 cats with primary
      hypertrophic cardiomyopathy (HCM) using pulsed Doppler (PD) assessment of
      transmitral flow and isovolumic relaxation time. Data obtained was compared to
      data from 12 healthy, adult, research cats. Compared to normal cats, the HCM
      group showed significantly (p value less than 0.05) reduced early LV inflow
      velocities (mean +/- standard error [SE], peak velocity of 0.70+/-0.04 m/s versus
      0.54+/-0.04 m/s and integrated velocity of 0.48+/-0.08 m/s versus 0.37+/-0.03
      m/s); a reduced rate of deceleration of early inflow (mean+/-SE, -12.0+/-1.0 m/s2
      versus -5.1+/-1.1 m/s2); prolonged isovolumic relaxation time (mean +/- SE,
      45.7+/-3.3 ms versus 76.0+/-3.1 ms); and increased atrial systolic flow
      velocities (mean +/- SE, peak velocity of 0.29+/-0.04 m/s versus 0.48+/-0.04 m/s
      and integrated velocity of 0.21+/-0.03 m/s versus 0.34+/-0.03 m/s). The results
      suggest that PD provides a noninvasive method of identifying and quantifying
      functional diastolic impairment in cats with HCM.

PMID- 10416772
TI  - Hypertrophic cardiomyopathy in a litter of five mixed-breed cats.
AB  - A litter of five, 18-month-old, mixed-breed cats were determined to have
      hypertrophic cardiomyopathy (HCM). Although no overt clinical signs were present
      in any cat, systolic heart murmurs were present in each. Electrocardiograms were
      normal, while subjective interpretations of heart enlargement on radiographs were
      made on four cats. Echocardiographic analyses indicated abnormalities consistent
      with HCM. Overt clinical signs are absent two years following diagnosis.

PMID- 10416773
TI  - Hypercalcemia and calcium oxalate urolithiasis in cats: a report of five cases.
AB  - Five cats that presented for signs of lower urinary tract disease (i.e.,
      pollakiuria and hematuria) secondary to a calcium oxalate urolithiasis are
      presented. On evaluation, all five cats had elevations of both serum ionized as
      well as total serum calcium. The hypercalcemia resolved after discontinuation of
      urinary acidifying therapy or a dietary change, or both.

PMID- 10416774
TI  - Paraneoplastic polyneuropathy and subsequent recovery following tumor removal in
      a dog.
AB  - A 10-year-old, intact female Brittany spaniel was presented for evaluation of
      progressive tetraparesis. Physical examination and diagnostic testing revealed
      masses within the right mammary chain and left caudal lung lobe. Neuromuscular
      electrodiagnostic and histopathological findings were compatible with a
      peripheral polyneuropathy. Upon removal of the tumors, the dog's paresis
      disappeared. To the authors' knowledge, this is the first reported case in the
      veterinary literature of improvement following therapy of a suspected
      paraneoplastic neuropathy.

PMID- 10416775
TI  - Extensive venous thrombosis and hind-limb edema associated with adrenocortical
      carcinoma in a dog.
AB  - A 10-year-old, spayed female, mixed-breed dog was referred for evaluation of
      bilateral hindlimb edema and weakness. Abdominal ultrasonography showed increased
      echogenicity of the lumen of the caudal vena cava from the level of the urinary
      bladder to the level of the cranial pole of the right kidney. Bilateral saphenous
      venograms displayed numerous filling defects in the caudal vena cava, right
      external iliac vein, right femoral vein, and the right common iliac vein.
      Extensive venous thrombosis was diagnosed, and the animal was euthanized.
      Necropsy confirmed the presence of venous thrombosis and revealed a right
      adrenocortical carcinoma that had invaded the caudal vena cava.

PMID- 10416776
TI  - Treatment of aggressive testicular tumors in four dogs.
AB  - In this report, the authors describe four dogs referred for diagnosis and
      treatment of unusual and aggressive testicular tumors. For the vast majority of
      dogs with testicular tumors, orchiectomy is curative. All dogs in this report had
      surgical resection, and three of four dogs were treated with cisplatin
      chemotherapy. Cisplatin is widely recognized as the most active agent in
      testicular cancer in human medicine.

PMID- 10416777
TI  - Peripheral nerve sheath tumor of the diaphragm with osseous differentiation in a
      one-year-old dog.
AB  - A 12-month-old, spayed female German shepherd dog was referred to the Veterinary
      Teaching Hospital for repair of a diaphragmatic hernia. Abdominal exploration
      revealed an intact diaphragm, but thoracic exploration revealed a large mass
      originating from the diaphragm. Resection of the mass was incomplete and required
      reconstruction of the diaphragm. On histopathology, the mass was composed mainly
      of spindle-shaped cells with occasional areas of osseous and chondroid tissue.
      The tumor was diagnosed as a peripheral nerve sheath tumor (PNST) with chondro
      osseous differentiation. The dog was released four days after surgery; however,
      she began having difficulty breathing seven days after discharge, and the owners
      elected euthanasia. A necropsy was not performed. This is the first known report
      of a PNST originating in the diaphragm of a dog.

PMID- 10416778
TI  - Functional outcome in dogs after surgical treatment of caudal lumbar
      intervertebral disk herniation.
AB  - Caudal lumbar disk herniations (i.e., third lumbar [L3] to seventh lumbar [L7]
      intervertebral spaces) represent approximately 15% of surgically treated
      thoracolumbar disk herniations in dogs. A retrospective case-control study was
      conducted to determine the postoperative outcome of this subset of dogs in the
      authors' neurosurgical practice. Medical records (1985 through 1996) were
      reviewed for dogs with caudal lumbar disk herniation confirmed at surgery. Thirty
      six cases were identified. For each case, two dogs that underwent surgical
      treatment for upper motor neuron thoracolumbar disk herniation (tenth thoracic
      [T10] to L3 intervertebral spaces) were selected as controls. Probabilities of
      functional recovery for cases and controls were 81% and 85%, respectively (p
      value of 0.49). In dogs with caudal lumbar disk herniation, complete sensorimotor
      loss was the only significant predictor of functional recovery (p value of
      0.005). Disk herniations that occur at the thoracolumbar junction and those that
      occur in the caudal lumbar region should not be considered to be different in
      terms of surgical treatment and postoperative outcome. The lower motor neuron
      signs that often accompany caudal lumbar disk herniation reflect the site of
      spinal cord injury and do not necessarily predict a poor prognosis.

PMID- 10416779
TI  - Bone dysplasias in the labrador retriever: a radiographic study.
AB  - A radiographic study of the humeral head, elbow joint, hip joint, stifle joint,
      tarsal joint, and lumbosacral (LS) junction was performed in 1,018 Labrador
      retrievers in search for humeral head, femoral condyle, and tarsal
      osteochondroses; elbow and hip dysplasias; and transitional LS vertebrae. The
      ages of all dogs reported were one year or older. Elbow dysplasia was detected as
      the most common lesion (17.8%), with a higher prevalence in the male dog. Hip
      dysplasia was the second most common lesion (12.6%) and was found equally in the
      male and female. Elbows and hips were often affected in the same dog (4.2%).
      Transitional vertebral segments were found more frequently in the female (4.2%)
      than in the male (1.0%), and the condition was thought to be inherited.

PMID- 10416780
TI  - The effects of indwelling transurethral catheterization and tube cystostomy on
      urethral anastomoses in dogs.
AB  - The influence of urinary diversion procedures on urethral healing was studied in
      15 male dogs following transection and anastomosis of the intrapelvic portions of
      their urethras. Dogs were randomly assigned to one of three treatment groups and
      had urine diverted from the surgical site by indwelling transurethral catheter,
      cystostomy catheter, or a combination of transurethral catheter and cystostomy
      catheter. There were no statistically significant differences in urethral healing
      when considering the different diversion methods, based on clinical,
      radiographic, and urodynamic parameters evaluated.

PMID- 10416781
TI  - Determination of optimal time for mating by artificial insemination with chilled
      semen using luteinizing hormone surge as an indicator in beagles.
AB  - Artificial insemination (AI) was conducted using the second fraction of semen,
      which was collected from 15 male dogs, diluted to a total sperm count of
      100x10(6) for each insemination with egg-yolk Tris (eyT) citrate acid buffer and
      incubated at 4 degrees C for 48 hours. Luteinizing hormone (LH) surge was
      detected to determine the optimal time for mating using canine LH assay kits.
      Artificial insemination using 100x10(6) sperm was performed on the fourth and
      sixth days or the fifth and seventh days after the LH surge. The conception rates
      were 33% (4/12) and 89% (8/9), respectively; the whelping rates also showed
      similar results. Serum LH and follicle stimulating hormone (FSH) concentrations
      were measured in nine dogs, and the mean LH concentration (+/- standard
      deviation) at LH surge was 15.77+/-7.66 ng/ml. The time of the LH surge detected
      by the canine LH assay kit was very similar to that measured by radioimmunoassay
      (RIA).

PMID- 10416782
TI  - Fast-in situ hybridization and immunoenzymatic color pigment detection of mouse
      bone marrow micronucleus.
AB  - The development of a whole mouse genomic DNA probe coupled to color pigment
      painting detection methodology can accurately verify mouse micronuclei induced by
      chemicals or drugs leading to a lower probability of potential artifacts. Using
      color pigment painting detection of probes in conjunction with Wright's Giemsa
      counterstain instead of the current fluorescence detection technology ensures low
      cost, high resolution permanent documentation of slides for a particular test
      compound. The permanent color pigment-detected micronuclei and adjoining
      counterstain allows slides to be stored for future analysis without enhancing the
      signal or adding antifading agents that are associated with fluorescence
      detection. Combining innovative technology such as fast-in situ hybridization of
      DNA probes with immunoenzymatic color pigment detection provides rapid
      verification of true micronuclei (DNA containing) within 2-3 hr.

PMID- 10416783
TI  - Adult rodent double skeletal stain.
AB  - Rodent embryo double skeletal staining has long played a role in toxicological
      studies and is now an important part of selected genetic studies involving
      knockout or transgenic animals. However, phenotypic changes are sometimes not
      seen until animals reach adulthood. This study expands a previously developed
      embryonic staining method for use with adult mice.

PMID- 10416784
TI  - Screening of five specific cell cycle inhibitors using a T cell lymphoma cell
      line synchrony/release assay.
AB  - To obtain different cell populations at specific cell cycle stages, we used a
      cell culture synchronization protocol. Effects of five different cell cycle
      inhibitors acting throughout the cell cycle were examined by DNA flow cytometric
      analysis of a synchrony/release lymphoma cell line (CEM). The screening
      synchronized protocol showed that staurosporine, mimosine and aphidicolin are
      reversible G1 phase inhibitors that act at different times. Staurosporine acted
      in early G1, exhibited the strongest cytotoxic effect, and induced apoptosis.
      Mimosine and aphidicolin acted in late G1 and at the G1/S boundary, respectively.
      Hydroxyurea arrested CEM cells in early S phase, but later than the aphidicolin
      arrest point. Nocodazole synchronized CEM cells in M phase. All the inhibitors
      examined in this study can be used to synchronize cells at different phases of
      the cell cycle and were reversible with little toxicity except for staurosporine
      which is highly toxic. Because the regulatory mechanism of the cell cycle is
      disrupted by their effects on protein synthesis, however, these drugs must be
      used with caution.

PMID- 10416785
TI  - Electron microscopic autoradiography: an improved procedure using Aclar film and
      Grid-sticks.
AB  - A simple, time saving technique for electron microscopic autoradiography (EMARG)
      has been developed using both Aclar film and Grid-sticks. Rats were given 3 mg/kg
      [pyridine5-3H] nicorandil orally. After 15 min, animals were sacrificed, the
      hearts were removed, and myocardial samples for EMARG were prepared. Silver
      grains were detected clearly in myofibrils and in mitochondria, all showing well
      preserved ultrastructure. The use of Grid-sticks in the procedure improves
      handling of bulk samples.

PMID- 10416786
TI  - Photopolymerized 2-hydroxyethylmethacrylate as a mounting medium preserving
      immunocytochemical reaction and nuclear counterstain.
AB  - Immunocytochemical or cytoenzymological techniques often make use of coupling
      reactions between a substituted naphtol and a diazonium salt. A positive reaction
      results in an azo dye precipitate. Unfortunately, this precipitate is easily
      soluble in alcohols and organic solvents. Thus, usual mounting media are not
      usable and permanent preparations cannot be obtained. A stable mounting medium
      such as Apathy's syrup can be used, but nuclear counterstaining disappears in a
      few days. We tested the hydrophilic monomer 2-hydroxyethylmethacrylate,
      containing various photopolymerizing agents, as a permanent mounting medium. 2-2
      Dimethoxy 2-phenyl acetophenone proved to be the most useful photopolymerizer.
      The cytocentrifugation slides must be dried before mounting to avoid
      recrystallization artifacts. The azo dye precipitate and nuclear counterstaining
      can be preserved perfectly long-term. The cost of these media is very low.

PMID- 10416787
TI  - Detection of apoptotic cells in vitro: a practical standardized experimental
      protocol using human fibroblasts for initial laboratory studies.
AB  - This technical report presents a practical experimental protocol using human
      fibroblasts that is useful for initiating in situ methods for detection of
      apoptotic cells in vitro. The protocol details the growth of cells in
      multichamber wells, and includes a negative control, two positive controls, and
      untreated fibroblasts to be evaluated for apoptosis localization. Technical tips
      on handling of solutions, cell culture designs, and separation of slides by
      treatment are valuable steps for the laboratory beginning such studies. The
      methods proposed are both time and cost effective.

PMID- 10416789
TI  - Air drying method using nitrous oxide for chromosome counting in maize.
AB  - Nitrous oxide (N2O), colchicine, trifluralin, amiprophos-methyl, 8
      hydroxyquinoline, and temperature pretreatments (cold and cold-hot-cold) were
      compared for chromosome counting in maize (Zea mays L.). Pretreated root tips
      were prepared by enzymatic maceration and air drying, and the number of countable
      figures and mitotic indexes were recorded. N2O treatment at 10 atm for 3 hr
      produced the largest number of countable chromosome figures (266.5 per
      preparation) and an average of 44.2 nonoverlapped chromosome figures per
      preparation. Treatment with 0.04% 8-hydroxyquinoline for 3 hr exhibited a
      moderate number of countable chromosome figures (53.9 per preparation). The
      effects of colchicine, trifluralin, amiprophos-methyl and temperature
      pretreatments were limited.

PMID- 10416788
TI  - Corneal cell proteins and ocular surface pathology.
AB  - The cornea is a transparent and avascular tissue that functions as the major
      refractive structure for the eye. A wide variety of growth factors, chemokines,
      cytokines and their receptors are synthesized by corneal epithelial and stromal
      cells, and are found in tears. These molecules function in corneal wound healing
      and in inflammatory responses. Proteoglycans and glycoproteins are essential for
      normal corneal function, both at the air-epithelial interface and within the
      extracellular matrix. The ocular MUC mucins may play roles in forming the mucus
      layer of the tear film, in regulating tear film spread, and in inhibiting the
      adhesion of pathogens to the ocular surface. Lumican, keratocan and mimecan are
      the major keratan sulfate proteoglycans of the corneal stroma. They are
      essential, along with other proteoglycans and interfibrillar proteins, including
      collagens type VI and XII, for the maintenance of corneal transparency. Corneal
      epithelial cells interact with a specialized extracellular matrix structure, the
      basement membrane, composed of a specific subset of collagen type IV and laminin
      isoforms in addition to ubiquitous extracellular matrix molecules. Matrix
      metalloprotein-ases have been identified in normal corneal tissue and cells and
      may play a role in the development of ulcerative corneal diseases. Changes in
      extracellular matrix molecule localization and synthesis have been noted in other
      types of corneal diseases as well, including bullous keratopathy and keratoconus.

PMID- 10416790
TI  - Suprachoroidal hemorrhage.
AB  - Suprachoroidal hemorrhage is a feared complication of all types of intraocular
      surgery. Although rare, it is typically associated with severe visual disability,
      and this has prompted efforts to better understand the pathogenesis of this
      condition, to identify the patients at risk for this event, and to improve
      treatment of patients who develop this condition either intraoperatively or
      postoperatively. Controversy still exists regarding the best course of treatment
      for these patients. Although the introduction of perfluorocarbon liquids as a
      surgical adjunct during vitrectomy surgery may assist in the removal of
      suprachoroidal hemorrhage, the visual outcomes still remain disappointing.

PMID- 10416792
TI  - Vitrectomy in the management of diabetic retinopathy.
AB  - According to the Early Treatment Diabetic Retinopathy Study, at least 5% of eyes
      receiving optimal medical treatment will still have progressive retinopathy that
      requires laser treatment and pars plana vitrectomy. During the past decade,
      improvements in instrumentation and surgical techniques have allowed more
      difficult cases of diabetic retinopathy to be candidates for vitrectomy. However,
      although the thresholds for performing surgery within established indicated
      situations have been lowered, only a few additional indications have been
      established. Although vitrectomy improves the prognosis for a favorable visual
      outcome, preventive measures, such as improved control of glucose levels and
      timely application of panretinal photocoagulation, produce better results. The
      authors review the indications, techniques, and results of vitrectomy in the
      management of diabetic retinopathy.

PMID- 10416791
TI  - Blindness from bad bones.
AB  - Progressive visual loss is the most common neurologic finding in osteopetrosis.
      Several mechanisms may explain this phenomenon, including compression of the
      optic nerves caused by bony overgrowth of the optic canals and retinal
      degeneration. We report a child with osteopetrosis and progressive visual loss,
      even though patent optic canals were demonstrated by computed tomography and
      digital holography. This patient's visual loss was caused by increased
      intracranial pressure secondary, to obstruction of cerebral venous outflow at the
      jugular foramen. This case points to the importance of a full evaluation of the
      skull base foramina in the diagnostic workup of visual loss in patients with
      osteopetrosis.

PMID- 10416793
TI  - Retinoblastoma in transgenic mice: models of hereditary retinoblastoma.
AB  - Retinoblastoma, the most common intraocular malignancy ill childhood, has served
      as a paradigm for the study of genetic mechanisms of oncogenesis. The
      retinoblastoma susceptibility gene RB1 was the first tumor suppressor gene to be
      cloned, and genetic and molecular biologic studies of this tumor have greatly
      expanded the understanding of the mechanics of tumorigenesis. Human
      retinoblastoma has essentially no naturally occuring animal counterpart. The
      development of transgenic murine models of retinoblastoma have created an
      experimental tool for manipulation of a tumor gene system in vivo. These models
      have also enabled studies of new therapeutic modalities. This review outlines the
      development of the transgenic murine models of retinoblastoma, together with the
      genetic mechanisms of retinoblastoma origin. Current therapeutic innovations
      developed by means of the transgenic models are described.

PMID- 10416794
TI  - A new approach to an old problem.
AB  - A patient with progressive visual loss was found to have an optic nerve sheath
      meningioma. The patient was treated with stereotactic radiotherapy, a computer
      guided stereotactic technique that minimizes the risk of radiation-induced optic
      neuropathy. Six months after treatment, the patient was doing well and showed no
      signs of radiation-induced optic neuropathy.

PMID- 10416795
TI  - Max Linde, MD, a Luebeck ophthalmologist and patron of Edvard Munch.
AB  - Ophthalmologist Maximilian Linde (1862-1940) had a passion for contemporary art
      and owned one of the most important private collections in Europe. He first met
      little known Norwegian expressionist Edvard Munch in 1903, recognized special
      talent, and welcomed him into his family. With Linde's encouragement, patronage,
      and friendship, Munich became one of the most important artists of his time. Many
      of Munch's works were commissioned by Linde and many featured Linde and his
      family as subjects.

PMID- 10416796
TI  - Vision impairment and driving.
AB  - Driving is the primary mode of travel in many countries. It facilitates the
      performance of routine daily activities and is thus integral with the concept of
      quality of life. Vision is inarguably a fundamental component of safe driving.
      Drivers with certain eye conditions reduce their driving exposure and restrict
      their driving to the safest times, yet there is preliminary evidence that some
      eye conditions increase the risk of crashes. Visual acuity is only weakly related
      to crash involvement, whereas peripheral vision appears to play a more critical
      role. Color vision deficiency by itself is not a threat to safe driving. Based on
      the current literature, it is unclear whether other types of visual sensory
      impairment have a significant impact on driving safety and performance. Tests of
      visual attention and processing speed show great promise as methods of
      identifying high-risk drivers. There is a serious need for well-designed studies
      in key practical areas, such as the safety of low-vision drivers who use bioptic
      telescopes, the impact of monocular vision impairment on safety, and the
      effectiveness of vision rescreening policies after initial licensure. For
      ophthalmologists to guide patients about driving fitness, valid and reliable
      assessment tools must be developed and made widely available.

PMID- 10416797
TI  - Transscleral choroidal biopsy in the diagnosis of choroidal lymphoma.
AB  - A 57-year-old man with non-Hodgkin's B-cell lymphoma of the abdominal lymph nodes
      developed moderate cells in the anterior chamber and vitreous, choroidal
      infiltration, and total nonrhegmatogenous retinal detachment in both eyes while
      receiving chemotherapy. After a diagnostic vitrectomy in the left eye was
      nonrevealing, the patient was referred to the oncology service. Fine-needle
      aspiration biopsy of the choroidal infiltrate was not done because of poor
      visualization of the choroid through the turbid subretinal fluid. Transscleral
      choroidal biopsy was performed without complications and disclosed diffuse high
      grade B-cell lymphoma and no signs of endogenous infection. Transscleral
      choroidal biopsy is a useful technique in eyes with choroidal infiltration,
      especially when hazy media prohibit fine needle biopsy.

PMID- 10416798
TI  - Computerized detection of malignant tumors on digital mammograms.
AB  - This paper presents a tumor detection system for fully digital mammography. The
      processing scheme adopted in the proposed system focuses on the solution of two
      problems. One is how to detect tumors as suspicious regions with a very weak
      contrast to their background and another is how to extract features which
      characterize malignant tumors. For the first problem, a unique adaptive filter
      called the iris filter is proposed. It is very effective in enhancing
      approximately rounded opacities no matter what their contrasts might be. Clues
      for differentiation between malignant tumors and other tumors are believed to be
      mostly in their border areas. This paper proposes typical parameters which
      reflect boundary characteristics. To confirm the system performance for unknown
      samples, large scale experiments using 1212 CR images were performed. The results
      showed that the sensitivity of the proposed system was 90.5% and the average
      number of false positives per image was found to be only 1.3. These results show
      the effectiveness of the proposed system.

PMID- 10416800
TI  - Resampling of data between arbitrary grids using convolution interpolation.
AB  - For certain medical applications resampling of data is required. In magnetic
      resonance tomography (MRT) or computer tomography (CT), e.g., data may be sampled
      on nonrectilinear grids in the Fourier domain. For the image reconstruction a
      convolution-interpolation algorithm, often called gridding, can be applied for
      resampling of the data onto a rectilinear grid. Resampling of data from a
      rectilinear onto a nonrectilinear grid are needed, e.g., if projections of a
      given rectilinear data set are to be obtained. In this paper we introduce the
      application of the convolution interpolation for resampling of data from one
      arbitrary grid onto another. The basic algorithm can be split into two steps.
      First, the data are resampled from the arbitrary input grid onto a rectilinear
      grid and second, the rectilinear data is resampled onto the arbitrary output
      grid. Furthermore, we like to introduce a new technique to derive the sampling
      density function needed for the first step of our algorithm. For fast, sampling
      pattern-independent determination of the sampling density function the Voronoi
      diagram of the sample distribution is calculated. The volume of the Voronoi cell
      around each sample is used as a measure for the sampling density. It is shown
      that the introduced resampling technique allows fast resampling of data between
      arbitrary grids. Furthermore, it is shown that the suggested approach to derive
      the sampling density function is suitable even for arbitrary sampling patterns.
      Examples are given in which the proposed technique has been applied for the
      reconstruction of data acquired along spiral, radial, and arbitrary trajectories
      and for the fast calculation of projections of a given rectilinearly sampled
      image.

PMID- 10416799
TI  - A standardized blood sampling scheme in quantitative FDG-PET studies.
AB  - Quantitative estimation of brain glucose metabolism (rCMRGlc) with positron
      emission tomography and fluorodeoxyglucose involves arterial blood sampling to
      estimate the delivery of radioactivity to the brain. Usually, for an intravenous
      injection of 30 s duration, an accurate input curve requires a frequency of one
      sample every 5 s or less to determine the peak activity in arterial plasma during
      the first 2 min after injection. In this work, 13 standardized sampling times
      were shown to be sufficient to accurately define the input curve. This
      standardized input curve was subsequently fitted by a polynomial function for its
      rising part and by spectral analysis for its decreasing part. Using the measured,
      the standardized, and the fitted input curves, rCMRGlc was estimated in 32
      cerebral regions of interest in 20 normal volunteers. Comparison of rCMRGlc
      values obtained with the measured and the fitted input curves showed that both
      procedures gave consistent results, with a maximal relative error in mean rCMRGlc
      of 1% when using the autoradiographic method and 2% using kinetic analysis of
      dynamic data. This input-curve-fitting technique, which is not dependent on the
      peak time occurrence, allows an accurate determination of the input-curve shape
      from reduced sampling schemes.

PMID- 10416801
TI  - Simultaneous maximum a posteriori reconstruction of attenuation and activity
      distributions from emission sinograms.
AB  - In order to perform attenuation correction in emission tomography an attenuation
      map is required. We propose a new method to compute this map directly from the
      emission sinogram, eliminating the transmission scan from the acquisition
      protocol. The problem is formulated as an optimization task where the objective
      function is a combination of the likelihood and an a priori probability. The
      latter uses a Gibbs prior distribution to encourage local smoothness and a
      multimodal distribution for the attenuation coefficients. Since the attenuation
      process is different in positron emission tomography (PET) and single photon
      emission tomography (SPECT), a separate algorithm for each case is derived. The
      method has been tested on mathematical phantoms and on a few clinical studies.
      For PET, good agreement was found between the images obtained with transmission
      measurements and those produced by the new algorithm in an abdominal study. For
      SPECT, promising simulation results have been obtained for nonhomogeneous
      attenuation due to the presence of the lungs.

PMID- 10416802
TI  - Registration of stereo and temporal images of the retina.
AB  - The registration of retinal images is required to facilitate the study of the
      optic nerve head and the retina. The method we propose combines the use of mutual
      information as the similarity measure and simulated annealing as the search
      technique. It is robust toward large transformations between the images and
      significant changes in light intensity. By using a pyramid sampling approach
      combined with simulated reannealing we find that registration can be achieved to
      predetermined precision, subject to choice of interpolation and the constraint of
      time. The algorithm was tested on 49 pairs of stereo images and 48 pairs of
      temporal images with success.

PMID- 10416803
TI  - A multimodal registration algorithm of eye fundus images using vessels detection
      and Hough transform.
AB  - Image registration is a real challenge because physicians handle many images.
      Temporal registration is necessary in order to follow the various steps of a
      disease, whereas multimodal registration allows us to improve the identification
      of some lesions or to compare pieces of information gathered from different
      sources. This paper presents an algorithm for temporal and/or multimodal
      registration of retinal images based on point correspondence. As an example, the
      algorithm has been applied to the registration of fluorescein images (obtained
      after a fluorescein dye injection) with green images (green filter of a color
      image). The vascular tree is first detected in each type of images and
      bifurcation points are labeled with surrounding vessel orientations. An angle
      based invariant is then computed in order to give a probability for two points to
      match. Then a Bayesian Hough transform is used to sort the transformations with
      their respective likelihoods. A precise affine estimate is finally computed for
      most likely transformations. The best transformation is chosen for registration.

PMID- 10416804
TI  - Deformation analysis to detect and quantify active lesions in three-dimensional
      medical image sequences.
AB  - Evaluating precisely the temporal variations of lesion volumes is very important
      for at least three types of practical applications: pharmaceutical trials,
      decision making for drug treatment or surgery, and patient follow-up. In this
      paper we present a volumetric analysis technique, combining precise rigid
      registration of three-dimensional (3-D) (volumetric) medical images, nonrigid
      deformation computation, and flow-field analysis. Our analysis technique has two
      outcomes: the detection of evolving lesions and the quantitative measurement of
      volume variations. The originality of our approach is that no precise
      segmentation of the lesion is needed but the approximative designation of a
      region of interest (ROI) which can be automated. We distinguish between tissue
      transformation (image intensity changes without deformation) and expansion or
      contraction effects reflecting a change of mass within the tissue. A real lesion
      is generally the combination of both effects. The method is tested with
      synthesized volumetric image sequences and applied, in a first attempt to
      quantify in vivo a mass effect, to the analysis of a real patient case with
      multiple sclerosis (MS).

PMID- 10416805
TI  - A differential index assignment scheme for tree-structured vector quantization.
AB  - A differential index (DI) assignment scheme is proposed for the image encoding
      system in which a variable-length tree-structured vector quantizer (VLTSVQ) is
      adopted. Each source vector is quantized into a terminal node of VLTSVQ and each
      terminal node is represented as a unique binary vector. The proposed index
      assignment scheme utilizes the correlation between interblocks of the image to
      increase the compression ratio with the image quality maintained. Simulation
      results show that the proposed scheme achieves a much higher compression ratio
      than the conventional one does and that the amount of the bit rate reduction of
      the proposed scheme becomes large as the correlation of the image becomes large.
      The proposed encoding scheme can be effectively used to encode MR images whose
      pixel values are, in general, highly correlated with those of the neighbor
      pixels.

PMID- 10416806
TI  - Region tracking on level-sets methods.
AB  - Since the work by Osher and Sethian on level-sets algorithms for numerical shape
      evolutions, this technique has been used for a large number of applications in
      numerous fields. In medical imaging, this numerical technique has been
      successfully used, for example, in segmentation and cortex unfolding algorithms.
      The migration from a Lagrangian implementation to a Eulerian one via implicit
      representations or level-sets brought some of the main advantages of the
      technique, i.e., topology independence and stability. This migration means also
      that the evolution is parametrization free. Therefore, we do not know exactly how
      each part of the shape is deforming and the point-wise correspondence is lost. In
      this note we present a technique to numerically track regions on surfaces that
      are being deformed using the level-sets method. The basic idea is to represent
      the region of interest as the intersection of two implicit surfaces and then
      track its deformation from the deformation of these surfaces. This technique then
      solves one of the main shortcomings of the very useful level-sets approach.
      Applications include lesion localization in medical images, region tracking in
      functional MRI (fMRI) visualization, and geometric surface mapping.

PMID- 10416807
TI  - A new method for measuring red blood cell aggregation using pattern recognition
      techniques on backscattered ultrasound Doppler signals.
AB  - In order to study the important phenomenon of aggregation of red blood cell in
      vitro, an original ultrasound Doppler in vitro technique has been designed and
      developed in our laboratory. In the experiments held with this new technique,
      erythrocyte aggregation was examined by adding dextrans of different molecular
      weights and concentrations for a wide range of hematocrit values. Consequently, a
      large data base of backscattered ultrasound Doppler signals is created. In these
      signals, various pattern recognition methods have been applied, mainly
      morphological and statistical ones. It results from the employed analysis that
      the envelope, energy and area characteristics of the obtained backscattered
      signals are quite good indicators of the degree of RBCs aggregation. In this way,
      we have been able to: (a) Establish a quantitative relation between the presence
      of various dextrans and the degree of aggregation. (b) Determine the distribution
      of the size of the formed aggregates in the various experimental solutions. (c)
      Obtain a most accurate relation between ultrasound backscattering and actual size
      of the corresponding observed aggregates.

PMID- 10416808
TI  - Sodium fluorescein influence on the hemorheological profile of non-insulin
      dependent diabetes mellitus patients.
AB  - Sodium fluorescein angiography is a widely used technology in ophthalmology,
      which allows us to visualise the chorioretinal microcirculation. Previous reports
      showed a prolongation of the retinal circulation time along with erythrocyte
      hyperaggregation and a decrease of erythrocyte acetylcholinesterase activity and
      a possible interference with the erythrocyte's membrane fluidity. The aim of the
      present work is to investigate the influence of sodium fluorescein on the
      hemorheological profile of a group of 23 non-insulin dependent diabetes mellitus
      (NIDDM) patients undergoing routine retinal angiography. Thirty minutes after the
      endovenous administration of the fluorescein there was: (I) an increase of whole
      blood viscosity (p = 0.015), erythrocyte elongation index (EEI, p < 0.05), whole
      blood pH (p < 0.001), methemoglobin (p < 0.001) and carboxyhemoglobin (p < 0.001)
      concentrations; (II) no variation of plasma osmolality and erythrocyte
      aggregation index (EAI); (III) a decrease of the erythrocyte acetylcholinesterase
      activity, p < 001; (IV) no variation in membrane lipid fluidity, although 1,6
      diphenyl-1,3,5-hexatriene (DPH) correlated directly with the EEI, while 1,4
      trimethyl-phenyl-1,3,5-hexatriene (TMA-DPH) and EAI correlated inversely,
      suggesting that the decreasing EEI (lower erythrocyte deformablity) might be
      associated with an increased rigidity of the external polar region and
      fluidification of the hydrophobic region of the erythrocyte membrane, with an
      increasing EAI. In conclusion, the endovenous administration of sodium
      fluorescein in NIDDM patients during the retinal angiography procedure interferes
      with the erythrocyte membrane and possibly with the microcirculatory blood flow.

PMID- 10416809
TI  - Haemorheological profile in subjects with nonvalvular atrial fibrillation.
AB  - In a group of subjects (n = 35) with nonvalvular atrial fibrillation (AF)
      subdivided according to the presence (n = 16) or absence (n = 19) of left atrial
      spontaneous echocontrast (SEC), demonstrated using transthoracic and
      transesophageal echocardiography, we evaluated the principal haemorheological
      determinants: whole-blood viscosity, plasma and serum viscosity, haematocrit,
      whole-blood filtration (VBC) and mean erythrocyte aggregation (MEA). From the
      obtained data it was evident that in subjects with nonvalvular AF there was an
      impairment of the haemorheological profile that seemed more evident in AF
      subjects with SEC, although no significant haemorheological difference was
      present between AF subjects with and without SEC. These findings need to be
      underlined considering that this clinical condition is associated to a major
      thromboembolic risk.

PMID- 10416810
TI  - Thrombomodulin levels in asymptomatic familial hypercholesterolemia.
AB  - In order to ascertain whether young asymptomatic patients with heterozygous
      familial hypercholesterolemia (FH) but without clinical signs of atherosclerosis
      have increased plasma thrombomodulin (TM) levels expressing early endothelial
      damage, we determined TM in 23 heterozygous FH subjects (aged 28-44 years, x: 32
      +/- 6) and in a well matched control group (CG). In addition, carotid Doppler
      ultrasonography was done in all the patients and controls in order to assess the
      state of the vascular tree. Results show a tendency for FH subjects to have
      higher TM values than the CG (37.8 +/- 14.2 ng/ml vs. 30.1 +/- 11.2 ng/ml),
      although the differences are not statistically significant. When taken together
      the results of TM and carotid ultrasound, the sensitivity and specificity of the
      former were only 66% and 80%, respectively. The fact that only 66% of the FH
      patients with atherosclerotic injury had high TM values eliminates the
      possibility of using this as an early marker of atherosclerosis in FH
      individuals.

PMID- 10416811
TI  - Correlated random walk: a fractal approach to erythrocyte viscoelastic
      properties.
AB  - A numerical method is proposed to evaluate the fractal correlation coefficient on
      viscoelastic properties of mammalian erythrocyte membranes from the
      diffractometric data obtained with the erythrodeformeter [16]. The numerical
      method is formulated on the basis of the fractal approximation for ordinary
      Brownian motion (OBM) and fractionary Brownian motion (FBM) [10]. Photometric
      readings performed on the elliptical diffraction pattern, generated by the shear
      elongated cells and photometrically recorded curves of creep and recovery of
      cells, are used in the calculations of self-affine Brownian correlation
      coefficient, averaged over several millions of cells. The time dependence of the
      correlation coefficient from different hematological disorders and also from
      healthy donors was calculated, and significative differences were found between
      both results. Diffractometric data belonging to healthy donors behaves as white
      noise, while data series from different disease were found to be chaotic.

PMID- 10416812
TI  - Influence of aging and exercise-induced stress on human platelet function.
AB  - Ten healthy nonsmoking old men (age 52-70 years, OM) and ten healthy nonsmoking
      young men (age 20-30 years, YM) were submitted to an exercise test on a bicycle
      ergometer to examine the combined influence of aging and exercise-induced stress
      on platelet function. Data were analyzed by two-way ANOVA test to determine the
      statistical significance of differences between baseline, after exercise and
      after recovery values, and by Mann-Whitney test to compare differences between
      young and old groups. Our results show in OM at rest an increased platelet
      aggregability induced by the higher values of intraplatelet basal free calcium
      (143.3 +/- 4.8 vs. 121.5 +/- 6.0 nM, p < 0.05) and a statistically significant
      increase of plasma oxidative by-products evaluated as thiobarbituric acid
      reactive substances (TBA-RS: 5.9 +/- 0.7 vs. 1.5 +/- 0.1 micromol/l, p < 0.05).
      Further, significant modifications of calcium and TBA-RS levels were found in
      both groups because of exercise-induced stress. The positive relationships
      between calcium amount and plasma values of TBA-RS in OM before (r = 0.728, p =
      0.017) and after (r = 0.772, p = 0.009) physical test and in YM only at the end
      of exercise (r = 0.853, p = 0.002), underline that oxidative stress may modulate
      platelet function by influencing calcium homeostasis and platelet membrane
      permeability.

PMID- 10416813
TI  - Impairment of the erythrocyte membrane fluidity in survivors of acute myocardial
      infarction. A prospective study.
AB  - Erythrocytes have to constantly adapt themselves to the varying circulatory
      system shear stress forces and capillaries diameter. Membrane lipid and protein
      content have an important role in determining the erythrocyte shape and are main
      determinants of the membrane solid and fluid behaviour which enables the
      erythrocyte to respond to the outer environment modifications. Membrane fluidity
      is an inverse index of membrane microviscosity. The aim of the present work is to
      evaluate prospectively in three periods of time (discharge, after 6 months and
      one year later) in survivors of an acute myocardial infarction (AMI) the
      erythrocyte membrane fluidity (outer and inner bilayer) and establish a relation
      with the cardiovascular events or need of coronary revascularization during a two
      year clinical follow up. Sixty survivors of acute myocardial infarction were
      recruited during 1994-96 and were prospectively studied in three periods
      (discharge, 6 months and after one year), and were compared with a control group
      (n = 36). Membrane lipid fluidity was determined by means of fluorescence
      polarisation with two probes: 1,6-diphenyl-1,2,5-hexatriene (DPH) and 1,4
      trimethylamine 6-phenyl hexa-1,3,5-triene (TMA-DPH), for the characterisation of
      the hydrophobic and external polar region, respectively. The hydrophobic region
      was more rigidified (p < 0.01) in the erythrocytes from AMI patients, in relation
      to the control group. During the time of the study there was a progressive
      erythrocyte membrane rigidification (DPH p < 0.001; TMA-DPH p < 0.001). We found
      no relation between erythrocyte membrane fluidity and the coronary risk factors,
      cardiovascular events or the need of coronary revascularization during the
      clinical follow-up. In conclusion, after the myocardial infarction erythrocyte
      membrane of AMI survivors becomes more rigid with time, which could contribute to
      the decreased erythrocyte deformability and the increased blood viscosity
      previously described in this group of patients.

PMID- 10416814
TI  - Early hemorheologic aspects of overtraining in elite athletes.
AB  - A standardized questionnaire has been proposed by the French consensus group on
      overtraining of the Societe Francaise de Medecine du Sport (SFMS) and allows the
      calculation of a 'score' that may help to quantify the early clinical symptoms of
      the overtraining syndrome in sportsmen submitted to a heavy training program. We
      investigated a possible relationship between this score and blood rheology in 36
      male elite sportsmen (national level in football, volleyball and karate; age: 17
      33 yr) who underwent a standardized check-up including biological measurements
      and an exercise-test. The overtraining score ranged between 0 and 21 items and
      was correlated with blood viscosity (r = 0.413, p < 0.02). This correlation was
      explained by a correlation of this score with plasma viscosity (r = 0.512, p <
      0.01) and hematocrit (r = 0.387, p < 0.05). When subjects with a high score (>6)
      were compared to subjects with a lower score they appeared to have a higher blood
      viscosity at native (but not corrected) hematocrit (3.18 +/- 0.01 vs. 2.89 +/-
      0.05 mPa.s, p < 0.02), explained by higher values in both plasma viscosity (1.39
      +/- 0.02 vs. 1.31 +/- 0.02 mPa.s, p < 0.01) and hematocrit (42.8 +/- 0.45 vs.
      41.1 +/- 0.44, p < 0.05). By contrast, there was no difference in RBC
      deformability and aggregation. Overtrained subjects have also lower levels of
      zinc (0.72 +/- 0.024 vs. 0.84 +/- 0.023 mg/l, p < 0.01), ferritin (55.1 +/- 7.3
      vs. 92.3 +/- 9.4 ng/ml), and IGF-binding protein 3 (3.4 +/- 0.22 vs. 4.52 +/- 0.4
      ng/ml). Neither zinc nor ferritin status were likely to explain the rheologic
      alterations since disturbances in zinc or iron are rather associated with
      abnormalities in erythrocyte deformability or aggregability. Therefore, the early
      signs of overtraining in elite sportsmen are associated with a hemorheologic
      pattern that suggests some degree of reversal of the 'autohemodilution'
      associated with fitness in athletes.

PMID- 10416815
TI  - Hemorheology and vascular endothelial cells.
AB  - The vascular endothelium is a biologically active monolayer of cells provided an
      interface between blood and tissues. Vascular endothelial cells (ECs) have two
      functional states, which are allowed by their different properties: (i) vaso
      regulating properties: ECs releases vasomotor components, as endothelin (vaso
      constriction), prostacyclin and nitrite oxide (vaso dilatation); (ii)
      antithrombotic and hemostatic properties; and (iii) anti-adhesion properties. The
      endothelium is normally antithrombotic and anti-adhesive to ensure blood
      fluidity. During many cardio-vascular diseases, these properties may be reversed.
      Thus, the ECs have a determinant role in hemodynamic control through these
      various metabolic activities. Otherwise, many studies have demonstrated that
      local blood flow conditions have a crucial role on the EC properties
      (mechanotransduction concept). The knowledge of the properties of ECs and the
      control of the phenomena which define their functions is a key element in the
      cardiovascular diseases understanding.

PMID- 10416816
TI  - Effects of anti-M antiserum on surface charge of red cells.

PMID- 10416817
TI  - Opioid receptor upregulation in mu-opioid receptor deficient CXBK and outbred
      Swiss Webster mice.
AB  - Chronic in vivo treatment with opioid antagonists increases opioid receptor
      density and the potency of opioid agonists without altering receptor mRNA levels.
      To determine if basal receptor density affects opioid receptor upregulation, we
      examined the effect of chronic naltrexone treatment on mu-opioid receptor density
      and mRNA in two mice strains that differ in mu-opioid receptor density. CXBK mice
      (mu-opioid receptor deficient) and outbred Swiss Webster mice were implanted s.c.
      with a placebo or 15 mg naltrexone pellet for 8 days, the pellets removed and 24
      hr later opioid receptor density (mu, delta) and receptor mRNA level (mu)
      determined in whole brain; or morphine dose-response studies conducted. In
      placebo-treated CXBK mice, mu-opioid receptor density was approximately 40% less
      than in Swiss Webster mice, although mu-opioid receptor mRNA abundance was
      similar in both strains. In placebo-treated CXBK mice, morphine potency was
      approximately 6-fold less than Swiss Webster mice. Naltrexone treatment increased
      morphine potency (1.7-fold) and mu- (approximately 90%) and delta- (approximately
      20-40%) opioid receptor density in CXBK and Swiss Webster mouse brain similarly.
      Mu-opioid receptor mRNA was unchanged by naltrexone treatment in either strain.
      There was no difference in the basal or naltrexone-treated whole brain G(i
      alpha2) protein levels in CXBK or Swiss Webster mouse. These data indicate that a
      deficiency in mu-opioid receptors does not alter the regulation of opioid
      receptors by opioid antagonists in vivo, and suggest that adaptive responses to
      chronic opioid antagonist treatment are independent of opioid receptor density.

PMID- 10416819
TI  - Are there inositol 1,4,5-triphosphate (IP3) receptors in human sperm?
AB  - Calcium signaling plays important roles in mammalian fertilization, such as the
      calcium wave in egg and the acrosome reaction (AR) in sperm. The calcium wave is
      accompanied by a transient increase of cytosolic calcium, which is mediated by
      inositol 1,4,5-triphosphate (IP3) induced calcium release (IICR). During AR, it
      is commonly recognized that influx of extracellular calcium causes a dramatic
      increase of cytosolic calcium. Participation of IICR in the phenomena, however,
      remains unclear. To investigate whether IICR also participates in calcium
      mobilization during AR, the present study examined the existence of the IP3
      receptor family (IP3R type 1, 2 and 3) in human sperm and their changes during
      the reaction. Immunoblot analyses showed the existence of IP3R types 1 and 3 in
      human sperm, but IP3R type 2 was undetectable. The expression of IP3R type 1 was
      diminished after AR and was also detected in the vesiculated membrane fragment
      which was released by the fusion of the plasma membrane and the outer acrosomal
      membrane during AR. In contrast, the expression of IP3R type 3 on the blot was
      similar before and after the reaction. Immunohistochemical observations suggested
      that IP3R type 1 localized in the anterior portion of the sperm head and the
      expression was decreased after AR. IP3R type 3 was observed in the posterior
      portion of the sperm head, midpiece, and tail, and little change was found even
      after AR. The [3H]-IP3 binding assay suggested stoichiometric interactions
      between IP3 and IP3Rs of non-acrosome reacted and acrosome reacted human sperm.

PMID- 10416818
TI  - Endocrine and other responses to acute administration of cannabinoid compounds to
      non-stressed male calves.
AB  - There is an abundance of cannabinoid (CB) receptors for derivatives of cannabis
      plants in the brain and throughout the body, and several naturally occurring
      arachidonic acid derivatives can activate these receptors. The specific objective
      of this study was to activate these CB receptors in castrated male calves through
      administration of several CB agonists and to measure immediate changes in
      concentrations of several serum hormones, respiration rate, and sensitivity to
      pain. The rationale for the study was that exogenous activation of CB receptors
      might reveal whether the endogenous CB system (consisting of receptors and
      endogenous ligands) plays a role in the stress response of animals and
      specifically whether the activated CB system might be part of a coping mechanism
      to combat stress. Intravenous administration of three CB agonists (anandamide,
      methanandamide and WIN 55212-2) to nine castrated male calves under non-stress
      conditions provoked immediate increases of serum cortisol and respiration rate as
      well as rapidly caused hypoalgesia to cutaneous pain and thermal stimuli.
      Although anandamide and methanandamide did not affect serum prolactin,
      administration of another CB agonist (WIN 55212-2) did increase serum prolactin
      abruptly. None of the CB agonists affected serum growth hormone. In summary, many
      of the changes following administration of CB agonists were similar to a stress
      response in this species, but there were some agonist-specific differences,
      notably regarding prolactin secretion, as well as differences between calves and
      observations made in other species. Although CB receptors in calves may be
      activated by endogenous ligands during exposure to some stressors, the present
      results are also consistent with this CB system being part of a coping mechanism
      that helps animals deal with imposed stressors.

PMID- 10416820
TI  - Pharmacomechanical coupling in rat vas deferens: effects of agents that modulate
      intracellular release of calcium and protein kinase C activation.
AB  - The effects of agents that modulate intracellular release of calcium and protein
      kinase C (PKC) activation on noradrenaline (NA)-induced contractions of
      epididymal vas deferens in calcium-free/EGTA (1 mM) medium were investigated. NA
      (100 microM) or methoxamine (100 microM) evoked repeatable contractions.
      Clonidine (100-300 microM) was ineffective. The contractions to NA were reduced
      by procaine (1-10 mM) but not by thapsigargin (0.1-30 microM), ryanodine (1-30
      microM) or TMB-8 (1-30 microM). Contractions to cumulative additions of NA (1-100
      microM) were enhanced in the presence of cyclopiazonic acid (10 & 30 microM) but
      not ryanodine (10 & 30 microM). Sequential contractions to NA were not blocked by
      PKC inhibitors, calphostin C (1 microM) or Ro 31-8220 (1-30 microM) but were
      reduced by H-7 (1-30 microM), a broad spectrum protein kinase inhibitor. Although
      RT-PCR experiments detected mRNA for some Ca2+-dependent/DAG-activated and Ca2+
      independent/DAG-activated PKC isoforms in epididymal vas deferens, the PKC
      activators, phorbol 12, 13-dibutyrate (100 microM) or phorbol 12-myristate 13
      acetate (100 microM) failed to activate the tissues in calcium-free medium but
      enhanced subsequent contractions to NA. These results indicate a limited role for
      intracellular calcium stores and phorbol ester/DAG-sensitive PKC isoforms in NA
      induced contraction of epididymal rat vas deferens in calcium-free medium. The
      results suggest that pharmacomechanical coupling triggered by NA may involve the
      sensitization of contractile myofilaments to Ca2+ or a Ca2+-independent
      mechanism. The possible involvement of Ca2+-independent/DAG-insensitive PKC
      isoforms and agonist-dependent but PKC-independent sensitization pathway is
      discussed.

PMID- 10416821
TI  - Involvement of monoamine oxidase inhibition in neuroprotective and
      neurorestorative effects of Ginkgo biloba extract against MPTP-induced
      nigrostriatal dopaminergic toxicity in C57 mice.
AB  - The present study investigated the neuroprotective and neurorestorative effects
      of Ginkgo biloba extract (EGb 761) and its two components ginkgolides A (BN52020)
      and B (BN52021) in mice. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30
      mg/kg/d i.p. for six days) significantly reduced striatal dopamine (DA) levels in
      C57 mice measured by high performance liquid chromatography with electrochemical
      detection (HPLC-EC). When C57 mice were pretreated with EGb 761 (20, 50, 100
      mg/kg/d i.p.) for 7 days and then treated with the same extract 30 min before
      MPTP injection for 6 days, the neurotoxic effect of MPTP was antagonized in a
      dose-dependent fashion. Similar treatment with ginkgolides A and B (5, 10, 50
      mg/kg/d i.p.) showed no protective effect. When C57 mice were treated with EGb
      761 (50 mg/kg/d i.p.) after MPTP-lesion, the recovery of striatal dopamine (DA)
      levels was accelerated. However, similar treatment with ginkgolides A or B (10
      mg/kg/d i.p.) did not show any effect. EGb 761, but not ginkgolides A and B,
      nonselectively inhibited mouse brain MAO activity in vitro (IC50 = 36.45 +/- 1.56
      microg/ml) tested by an improved fluorimetric assay. The results demonstrate that
      EGb 761 administered before or after MPTP treatment effectively protects against
      MPTP-induced nigrostriatal dopaminergic neurotoxicity and that the inhibitory
      effect of EGb 761 on brain MAO may be involved in its neuroprotective effect.

PMID- 10416822
TI  - In vivo evaluation of the biodistribution of 11C-labeled PD153035 in rats without
      and with neuroblastoma implants.
AB  - The biodistribution of 11C-labeled 4-(3-bromoanilino)-6,7-dimethoxyquinazoline,
      an inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase, has
      been evaluated in vivo in rats using positron emission tomography (PET). Time
      activity data obtained after i.v. administration in one rat revealed that the
      radiotracer rapidly cleared from plasma with subsequent uptake in major organs of
      the body (brain, heart, liver, gastrointestinal tract and bladder). Uptake in
      proliferating tissue in rats with human neuroblastoma xenografts indicate that [O
      11C-methyl]PD153035 shows promise as a new agent for in vivo imaging of tumors
      with PET.

PMID- 10416823
TI  - ASP147 in the third transmembrane helix of the rat mu opioid receptor forms ion
      pairing with morphine and naltrexone.
AB  - We tested the hypotheses that the carboxylate side chain of Asp147 of the mu
      opioid receptor interacts with the protonated nitrogen of naltrexone and morphine
      and that this interaction is important for pharmacological properties of the two
      compounds. Mutation of Asp147 to Ala or Asn substantially reduced the affinity of
      naltrexone and the affinity, potency and efficacy of morphine, while the Glu
      mutant had similar properties as the wildtype, indicating the significant role of
      the carboxylate group of Asp147 in receptor binding and activation. This role
      could be due to its direct interaction with ligands or involvement in
      interhelical interactions. The unprotonated analogs of naltrexone and morphine,
      cyclopropylcarbonyl noroxymorphone (CPCNOM) and N-formylnormorphine (NFNM),
      respectively, were used to discriminate between these mechanisms. CPCNOM was much
      less potent as an antagonist and had substantially lower affinity for the mu
      receptor than naltrexone. Similarly, NFNM was unable to activate the mu receptor
      and had much lower affinity than morphine. These results indicate the importance
      of the protonated nitrogen. Notably, the D147A and D147N mutations did not
      appreciably affect the binding affinities of CPCNOM and NFNM. In addition, the
      D147E mutant had similar affinities for CPCNOM and NFNM as the D147A and D147N mu
      receptors. Thus, the carboxylate group of Asp147 is not important for binding of
      the two unprotonated compounds. These results indicate that the carboxylate group
      of Asp147 of the mu receptor interacts directly with the protonated nitrogen of
      naltrexone and morphine and this interaction is important for binding and
      receptor activation.

PMID- 10416825
TI  - Comparison of the relative activities of alpha-tocopherol and PMC on platelet
      aggregation and antioxidative activity.
AB  - In this study, PMC (2,2,5,7,8-pentamethyl-6-hydroxychromane), a potent
      antioxidant derived from alpha-tocopherol, dose-dependently inhibited agonist
      induced platelet aggregation in human platelet-rich plasma. PMC is over 5-10
      times more potent than alpha-tocopherol in inhibiting human platelet aggregation.
      Moreover, PMC (25-350 microM) dose-dependently reduced the relative fluorescence
      intensity of platelet membrane tagged with diphenylhexatriene (DPH). PMC is about
      6-times more potent than alpha-tocopherol on this effect. Furthermore,
      antioxidative activity of PMC was investigated using two in vitro models. PMC
      inhibited non-enzymatic iron-induced lipid peroxidation in rat brain homogenates
      with an IC50 value of 0.21+/-0.05 microM. It was more potent than alpha
      tocopherol or other classical antioxidants. PMC also scavenged the stable free
      radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). The concentration of PMC resulting
      in a decrease of 0.20 in the absorbance of DPPH was about 12.1+/-3.6 microM, was
      comparable in potency to alpha-tocopherol, butylated hydroxytoluence and Trolox.
      The antiplatelet activity of PMC may possibly be due initially to an increase in
      fluidity of the platelet membrane followed by inhibition of platelet aggregation.
      Our results indicate that PMC is a potentially effective antioxidant and
      antiaggregating agent, and could be helpful the design of compounds with more
      clinical effectiveness.

PMID- 10416824
TI  - Characterization of alpha1-adrenoceptor subtypes mediating noradrenaline-induced
      contraction of rat epididymal vas deferens in calcium-free medium.
AB  - The alpha1-adrenoceptor subtype mediating noradrenaline (NA)-induced contractions
      of rat epididymal vas deferens in Ca2+-free/EGTA (1 mM) medium was studied using
      competitive antagonists. The effects of chloroethylclonidine (CEC) was
      investigated in Ca2+-free and normal Krebs' medium and RT-PCR was used to
      identify alpha1-adrenoceptor specific mRNA in epididymal vas deferens. In Ca2+
      free medium, NA evoked sustained contractions but was less potent (pD2, 5.9) than
      in normal Krebs' medium (pD2, 7.3). The contractions in Ca2+-free medium were
      inhibited by prazosin (pA2, 9.3), 5-methylurapidil (pA2, 8.4), spiperone (pA2,
      7.6) and BMY 7378 (pK(B), 6.8) consistent with activation of alpha1A-subtype.
      Repeated pretreatment with CEC (100 microM) reduced the potency of NA and maximum
      contractions in normal and Ca2+-free media. CEC-sensitivity in normal Krebs'
      medium was enhanced by prior treatment with phenoxybenzamine. mRNA for alpha1a-
      and alpha1d- but not alpha1b-adrenoceptors were detected in epididymal vas
      deferens. These results suggest that NA contracts the tissue in Ca2+-free medium
      by the stimulation of alpha1A-adrenoceptors. Two factors affecting CEC
      sensitivity of NA-induced contractions in this tissue are discussed.

PMID- 10416826
TI  - The effect of therapeutic drugs and other pharmacologic agents on activity of
      porphobilinogen deaminase, the enzyme that is deficient in intermittent acute
      porphyria.
AB  - Drugs and toxins precipitate life-threatening acute attacks in patients with
      intermittent acute porphyria. These materials may act by directly inhibiting
      enzyme activity, thus further reducing porphobilinogen (PBG) deaminase activity
      below the ca. 50% level that results from the gene defect. To test this, we
      studied the effects of drugs that precipitate acute attacks (lead, phenobarbital,
      griseofulvin, phenytoin, sulfanilamide, sulfisoxazole, 17alpha-ethinyl estradiol,
      5beta-pregnan-3alpha-ol-20-one), drugs that are safe (lithium, magnesium,
      chlorpromazine, promethazine), and those with uncertain effects (ethyl alcohol,
      imipramine, diazepam, haloperidol) on activity of PBG deaminase in vitro and in
      vivo. In the in vitro studies, of PBG deaminase from human erythrocytes from
      normals and individuals with IAP, only lead (> or = .01 mM) inhibited enzyme
      activity. Chlorpromazine (> or = .01 mM), promethazine (> or = .01 mM) and
      imipramine (1 mM) seemed to increase enzyme activity. In most in vivo
      experiments, male rats were injected intraperitoneally with test material twice
      daily for 3 days and once on day four; and erythrocyte and hepatic PBG deaminase
      activity was assayed thereafter. Effects on enzyme activity were observed only
      with 17alpha-ethinyl estradiol (0.05 microg/kg/day; reduction of 11% in
      erythrocyte enzyme [NS], and of 20% in liver enzyme [P=.02]), and imipramine
      (12.5 mg/kg/day; reduction in erythrocyte enzyme activity of 13% [P<.001]). Rats
      given lead acetate in their drinking water (10 mg/ml) for the first 60 days of
      life, resulting in high blood and liver lead levels, had increased erythrocyte
      PBG deaminase (167% of control; P=.004). Thus, enzyme inhibition by lead in vitro
      was not reflected in a similar in vivo inhibition. The only inhibitory effects in
      vivo, with ethinyl estradiol and imipramine, appear to be mild and biologically
      inconsequential. We conclude that inhibition of PBG deaminase activity by
      materials that precipitate acute attacks is an unlikely mechanism by which these
      materials exert their harmful effects in patients with IAP.

PMID- 10416827
TI  - Glutamine: fructose-6-phosphate amidotransferase activity and gene expression are
      regulated in a tissue-specific fashion in pregnant rats.
AB  - We examined whether regulation of glutamine: fructose-6-phosphate
      amidotransferase (GFA), the rate-limiting enzyme of the hexosamine pathway, is
      tissue specific and if so whether such regulation occurs at the level of gene
      expression. We compared GFA activity and expression and levels of UDP-hexosamines
      and UDP-hexoses between insulin-sensitive (liver and muscle) tissues and a
      glucose-sensitive (placenta) tissue from 19 day pregnant streptozotocin diabetic
      and non-diabetic rats. In pregnant non-diabetic rats GFA activities averaged
      (1521+/-75 pmol/mg protein x min) in the placenta, 895+/-74 in the liver and 81+/
      11 in muscle (p<0.001 between each tissue). In the diabetic rats, GFA activities
      were approximately 50% decreased both in the liver (340+/-42 pmol/mg protein x
      min, p<0.05 vs control rats) and in skeletal muscle (46+/-3, p<0.05) compared to
      control rats. In the placenta, GFA activities were identical between diabetic
      (1519+/-112 pmol/mg protein x min) and non-diabetic (1521+/-75) animals. In the
      liver, the reduction in GFA activity could be attributed to a significant
      decrease in GFA mRNA concentrations, while GFA mRNA concentrations were similar
      in the placenta between diabetic and non-diabetic animals. UDP-N
      acetylglucosamine (UDP-GlcNAc), the end product of the hexosamine pathway, was
      significantly reduced in the liver and in skeletal muscle but similar in the
      placenta between diabetic and non-diabetic rats. In summary, GFA activity and
      expression and the concentration of UDP-GlcNAc are decreased in the liver but
      unaltered in the placenta, although GFA activity is almost 2-fold higher in this
      tissue than in the liver. These data provide the first evidence for tissue
      specific regulation of GFA and for its regulation at the level of gene
      expression.

PMID- 10416828
TI  - Brain region-specific studies of the excitatory behavioral effects of morphine-3
      glucuronide.
AB  - This study was designed to determine in rats whether morphine-3-glucuronide (M3G)
      produces its neuro-excitatory effects most potently in the ventral hippocampus
      (as has been reported previously for subanalgesic doses of opioid peptides).
      Guide cannulae were implanted into one of seven regions of the rat brain: lateral
      ventricle; ventral, CA1 and CA2-CA3 regions of the hippocampus; amygdala;
      striatum or cortex. After a 7 day recovery period, rats received intracerebral
      injections of (i) M3G (1.1 or 11 nmol) (ii) DADLE ([D-Ala2,D-Leu5]enkephalin),
      (45 nmol, positive controls) or (iii) vehicle (deionised water), and behavioral
      excitation was quantified over 80 min. High-dose M3G (11 nmol) evoked behavioral
      excitation in all brain regions but the onset, severity and duration of these
      effects varied considerably among brain regions. By contrast, low-dose M3G (1.1
      nmol) evoked excitatory behaviors only when administered into the ventral
      hippocampus and the amygdala, with the most potent effects being observed in the
      ventral hippocampus. Prior administration of the nonselective opioid antagonists,
      naloxone and beta-funaltrexamine into the ventral hippocampus, markedly
      attenuated low-dose M3G's excitatory effects but did not significantly alter
      levels of excitation evoked by high-dose M3G. Naloxone given 10 min after M3G
      (1.1 or 11 nmol) did not significantly attenuate behavioral excitation. Thus,
      M3G's excitatory behavioral effects occur most potently in the ventral
      hippocampus as reported previously for subanalgesic doses of opioid peptides, and
      appear to be mediated through at least two mechanisms, one possibly involving
      excitatory opioid receptors and the other, non-opioid receptors.

PMID- 10416829
TI  - Neuroprotective effect of L-lysine monohydrochloride on acute iterative anoxia in
      rats with quantitative analysis of electrocorticogram.
AB  - Lysine is one of the indispensible amino acids and L-lysine monohydrochloride
      (LMH) is widely available to public as a nonprescription oral supplement.
      Potential clinical usefulness of oral LMH supplements has been indicated in
      stroke, hypertension, and seizure induced by pentylenetetrazole (PTZ), etc. We
      compared the effects of LMH and flunarizine on the Electrocorticogram (EcoG) of
      rats intragastrically administered 1 hour before anoxia. LMH dose-dependently
      prolonged the time reaching the lowest ECoG average amplitude after anoxia and
      decreased the recovery time after recirculation in both 0.63 g/kg and 1.26 g/kg
      groups. There was significant difference between the LMH- and saline-pretreated
      groups but no significant difference between the 1.26 g/kg LMH- and 2.5 mg/kg
      flunarizine-pretreated groups. The difference was not significant in the 2.52
      g/kg group. The ECoG average amplitude did not reach isoelectric point and the
      lowest average amplitude was 10 percent of that of nomoxia in the 1.26 g/kg LMH
      pretreated group during 2-min anoxia. The average amplitude pretreated with LMH
      (0.63 and 1.26 g/kg) was lower than that of those pretreated with saline and
      flunarizine. The results tend to indicate that LMH can protect brain cells
      against anoxia by means of providing energy, reducing cerebral metabolic rate and
      inhibiting the effect of the excitable amino acids.

PMID- 10416830
TI  - Roles of capsaicin-sensitive sensory nerves, endogenous nitric oxide,
      sulfhydryls, and prostaglandins in gastroprotection by momordin Ic, an oleanolic
      acid oligoglycoside, on ethanol-induced gastric mucosal lesions in rats.
AB  - The roles of capsaicin-sensitive sensory nerves (CPSN), endogenous nitric oxide
      (NO), sulfhydryls (SHs), prostaglandins (PGs) in the gastroprotection by momordin
      Ic, an oleanolic acid oligoglycoside isolated from the fruit of Kochia scoparia
      (L.) SCHRAD., on ethanol-induced gastric mucosal lesions were investigated in
      rats. Momordin Ic (10 mg/kg, p.o.) potentially inhibited ethanol-induced gastric
      mucosal lesions. The effect of momordin Ic was markedly attenuated by the
      pretreatment with capsaicin (125 mg/kg in total, s.c., an ablater of CPSN), N(G)
      nitro-L-arginine methyl ester (L-NAME, 70 mg/kg, i.p., an inhibitor of NO
      synthase), N-ethylmaleimide (NEM, 10 mg/kg, s.c., a blocker of SHs), or
      indomethacin (10 mg/kg, s.c., an inhibitor of PGs biosynthesis). The attenuation
      of L-NAME was abolished by L-arginine (300 mg/kg, i.v., a substrate of NO
      synthase), but not by D-arginine (300 mg/kg, i.v., the enatiomer of L-arginine).
      The effect of the combination of capsaicin with indomethacin, NEM, or L-NAME was
      not more potent than that of capsaicin alone. The combination of indomethacin and
      NEM, indomethacin and L-NAME, or indomethacin and NEM and L-NAME increased the
      attenuation of each alone. These results suggest that CPSN play an important role
      in the gastroprotection by momordin Ic on ethanol-induced gastric mucosal
      lesions, and endogenous PGs, NO, and SHs interactively participate, in rats.

PMID- 10416831
TI  - Steroid regulation of progesterone synthesis in a stable porcine granulosa cell
      line: a role for progestins.
AB  - The objective of this investigation was to determine the effect of steroid
      hormones on the synthesis of progesterone in a stable porcine granulosa cell
      line, JC-410. We also examined the effect of steroid hormones on expression of
      the genes encoding the steroidogenic enzymes, cytochrome P450-cholesterol side
      chain cleavage (P450scc) and 3beta-hydroxy-5-ene steroid dehydrogenase (3beta
      HSD). We observed that 48 h exposure of the JC-410 cells to estradiol-17beta
      (estradiol), androstenedione, 5alpha-dihydrotestosterone, levonorgestrel, and 5
      cholesten-3beta, 25-diol (25-hydroxycholesterol) resulted in stimulation of
      progesterone synthesis. 25-Hydroxycholesterol augmented progesterone synthesis
      stimulated by estradiol, 5alpha-dihydrotestosterone, levonorgestrel and 8
      bromoadenosine 3':5'-cyclic monophosphate (8-Br-cAMP). This increase in
      progesterone synthesis was additive with estradiol, 5alpha-dihydrotestosterone
      and levonorgestrel, and synergistic with 8-Br-cAMP. Cholera toxin, progesterone,
      levonorgestrel and androstenedione increased P450scc mRNA levels, whereas
      estradiol had no effect. Cholera toxin, progesterone and levonorgestrel increased
      3beta-HSD mRNA levels, but estradiol and androstenedione had no effect. The
      results were interpreted to mean that estrogens, androgens and progestins
      regulate progesterone synthesis in the JC-410 cells. The effect of androgens
      appears to be mediated by stimulation of P450scc gene expression while progestins
      stimulate both P450scc and 3beta-HSD gene expression. Our results support the
      concept that progesterone is an autocrine regulator of its own synthesis in
      granulosa cells.

PMID- 10416832
TI  - Multiple domains of melatonin receptor are involved in the regulation of
      glucocorticoid receptor-induced gene expression.
AB  - Melatonin, the principal hormone of the pineal gland, elicits potent anti-stress,
      anti-aging and oncostatic properties and influences various immunological and
      endocrinological functions. We have previously described the effects of melatonin
      on glucocorticoid receptors and suggested its potential influence on gene
      transcription. In the present study, the mechanistic basis for melatonin effects
      on glucocorticoid receptor (GR)-dependent gene expression was examined.
      Activation of the melatonin transduction pathway affects type I glucocorticoid
      receptor expression and reduces its transcriptional activity. Coexpression of the
      intact melatonin and glucocorticoid receptors with MMTV promoter construct
      reduced the GR transcriptional activity. N- and C-terminus deletions of melatonin
      receptor revealed the existence of regulatory sites mediating this process. These
      data identify for first time one of the molecular targets of melatonin action and
      suggest that melatonin signaling may involve relatively direct signal
      transmission from the cell surface to the nucleus.

PMID- 10416833
TI  - Differences in steroid 5alpha-reductase iso-enzymes expression between normal and
      pathological human prostate tissue.
AB  - We studied the expression level and cell-specific expression patterns of 5alpha
      reductase (5alpha-R) types 1 and 2 iso-enzymes in human hyperplastic and
      malignant prostate tissue by semi-quantitative RT-PCR and in situ hybridisation
      analyses. In situ hybridisation established that 5alpha-R1 mRNA is preferentially
      expressed by epithelial cells and little expressed by stromal cells whereas
      5alpha-R2 mRNA is expressed by both epithelium and stroma. Semi-quantitative RT
      PCR has been performed on total RNA from different zones of normal prostate, BPH
      tissues and liver. We found that 5alpha-R1 and 5alpha-R2 mRNAs expression was
      near the same in all zones of normal prostate. In BPH tissue, 5alpha-R1 and
      5alpha-R2 mRNAs expression was slightly but significantly increased, when it was
      compared to the levels recorded for normal prostate. In cancer samples, 5alpha-R1
      mRNA expression was higher than in normal and hyperplastic prostate but the level
      of 5alpha-R2 mRNA was not statistically different from that observed in the
      different zones of normal prostate. In liver, 5alpha-R2 mRNA level was similar to
      that measured in BPH but 5alpha-R1 mRNA expression was ten times higher. The
      increase observed in 5alpha-R isoenzymes expression in BPH tissue could play an
      important role in the pathogenesis and/or maintenance of the disease.

PMID- 10416834
TI  - Osteoporosis influences the late period of fracture healing in a rat model
      prepared by ovariectomy and low calcium diet.
AB  - To elucidate the influence of osteoporosis on the fracture healing, we produced a
      rat osteoporosis model by ovariectomy and by maintaining a low calcium diet; and
      monitored the healing process radiographically, histologically, and
      biomechanically for 12 weeks. Radiologic, histologic and biomechanical findings
      of the fracture areas 6 weeks after making the fractures were almost identical in
      both the osteoporosis group and the control group. However, 12 weeks after making
      the fractures, newly generated bones in the osteoporosis group showed
      histological osteoporotic changes and their bone mineral density on the fracture
      site decreased. These findings show that estrogen-deficient and low calcium
      conditions greatly affect the bone in the later period of the healing process,
      but do not affect remarkably the early healing period. This is clinically
      important when we consider fracture treatments for patients with osteoporosis due
      to menopause.

PMID- 10416835
TI  - Regulation of thioredoxin mRNA in the rat uterus by gonadal steroids.
AB  - Estradiol has been shown to increase the level of thioredoxin mRNA in the uterus
      of the ovariectomized (ovx) rat. In this study the influence of progesterone,
      androgens, the anti-estrogen ICI 182780 and the anti-androgen Flutamid on
      thioredoxin expression, has been studied in the rat uterus. Thioredoxin mRNA
      concentrations were determined by solution hybridization. Ovx rats treated with
      progesterone alone showed no effect on thioredoxin expression. Combined treatment
      of ICI 182780 and estradiol attenuated the estradiol-induced increase in
      thioredoxin mRNA. When ovx rats were treated with a testosterone depot, the
      amount of thioredoxin mRNA was increased five-fold after 48 h and remained at
      that level during the rest of the 168 h monitored. A similar increase in
      thioredoxin mRNA could be seen after 5alpha-dihydrotestosterone treatment,
      indicating a true androgenic effect. In addition, the anti-androgen Flutamid
      attenuated the thioredoxin mRNA increase seen after 5alpha-dihydrotestosterone
      treatment alone. It is concluded that thioredoxin mRNA is regulated by growth
      promoting gonadal steroids in the rat uterus. The attenuation of the estrogen and
      androgen-induced increases of the thioredoxin mRNA with ICI 182780 and Flutamid,
      indicate that the effect is mediated via the estrogen receptor and androgen
      receptor respectively. None of these hormones affected the hepatic thioredoxin
      mRNA level in the same animals.

PMID- 10416836
TI  - Novel metabolites of the mammalian lignans enterolactone and enterodiol in human
      urine.
AB  - Enterolactone (ENL) and enterodiol (END) are found in high concentrations in
      human body fluids after ingestion of flaxseed and whole-grain products. Although
      much interest is presently focused on these mammalian lignans because of their
      putative beneficial health effects, little is known about their metabolic fate in
      humans. We have now identified nine novel metabolites of ENL and END in the urine
      of female and male humans ingesting flaxseed for five days. The chemical
      structures of six ENL metabolites and of three END metabolites were elucidated by
      GC/MS analysis and comparison with authentic reference compounds obtained by
      chemical synthesis. The six identified metabolites of ENL were the products of
      monohydroxylation at the para-position and at both ortho-positions of the parent
      hydroxy group of either aromatic ring. Likewise, the three END metabolites were
      formed through aromatic monohydroxylation at the para- and ortho-positions. The
      biological significance of these metabolites remains to be established.

PMID- 10416837
TI  - Cannulation in situ of equine umbilicus. Identification by gas chromatography
      mass spectrometry (GC-MS) of differences in steroid content between arterial and
      venous supplies to and from the placental surface.
AB  - Equine umbilicus was cannulated in utero and a series of cord plasma samples
      removed for analysis. After steroid extraction and derivatisation, gas
      chromatographic-mass spectrometric (GC-MS) analysis demonstrated large
      differences in steroid content between the plasma samples obtained from the
      umbilical artery and vein, the blood supplies leading to and from the placental
      surface, respectively. 3Beta-hydroxy-5,7-androstadien-17-one,
      dehydroepiandrosterone, pregnenolone, 3beta-hydroxy-5alpha-pregnan-20-one, 5
      pregnene-3beta,20beta-diol and 5beta-pregnane-3beta,20beta-diol were identified
      as major constituents in extracts from umbilical arterial plasma samples, mostly
      as unconjugated steroids. Together with 5alpha-pregnane-3,20-dione, these
      steroids were identified in extracts from umbilical venous plasma samples but at
      significantly reduced levels to those determined in arterial plasma samples.
      Oestradiol-17alpha, dihydroequilin-17alpha and dihydroequilenin-17alpha were
      identified in extracts (mostly sulphate-conjugated) from both umbilical arterial
      and venous plasma samples, much larger amounts being detected in the plasma
      sampled from, rather than to, the placental surface. Equilin, equilenin,
      oestrone, oestradiol-17beta, dihydroequilin-17beta and dihydroequilenin-17beta
      were not detected in the present studies. Isomers of 5(10)-oestrene-3,17beta-diol
      together with 5(10),7-oestradiene-3,17beta-diol and its possible oxidative
      artifact, 5(10),7,9-oestratriene-3,17beta-diol, were tentatively identified only
      in sulphate-conjugated extracts from umbilical venous plasma samples. No
      glucuronic acid-conjugated steroids could be detected. The implications of this
      work in the elucidation of the biosynthetic pathways leading to both the
      formation of oestrogens and C18 neutral steroids at the placental surface are
      discussed.

PMID- 10416838
TI  - Transformation of 3-hydroxy-steroids by Fusarium moniliforme 7alpha-hydroxylase.
AB  - Transformation of physiologically important 3-hydroxy-steroids by the DHEA
      induced 7alpha-hydroxylase of F. moniliforme was investigated. Whereas DHEA was
      almost totally 7alpha-hydroxylated, PREG, EPIA and ESTR were only partially
      converted into their 7alpha-hydroxylated derivatives because hydroxylation at
      other undetermined positions as well as reduction of ketone at C17 or C20 into
      hydroxyl also occurred. Cholesterol was not transformed by the enzyme. Kinetic
      parameters of the 7alpha-hydroxylation for these substrates were determined and
      confirmed that DHEA was the best substrate of the 7alpha-hydroxylase. Inhibition
      studies of DHEA 7alpha-hydroxylation by the other 3-hydroxy-steroids were also
      carried out and proved that DHEA, PREG, EPIA and ESTR shared the same active site
      of the enzyme. Induction effects of these steroids were compared, and DHEA
      appeared to be the best inducer of the 7alpha-hydroxylase of F. moniliforme.

PMID- 10416839
TI  - Two non-reactive ternary complexes of estrogenic 17beta-hydroxysteroid
      dehydrogenase: crystallization and preliminary structural analysis.
AB  - Human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD1, EC1.1.1.62) is
      an important enzyme that catalyses the last step of active estrogen formation.
      17Beta-HSD1 plays a key role in the proliferation of breast cancer cells. The
      three-dimensional structures of this enzyme and of the enzyme-estradiol complex
      have been solved (Zhu et al., 1993, J. Mol. Biol. 234:242; Ghosh et al., 1995,
      Structure 3:503; Azzi et al., 1996, Nature Struct. Biol. 3:665). The
      determination of the non-reactive ternary complex structure, which could mimic
      the transition state, constitutes a further critical step toward the rational
      design of inhibitors for this enzyme (Ghosh et al. 1995, Structure 3:503;
      Penning, 1996, Endocrine-Related Cancer, 3:41). To further study the transition
      state, two non-reactive ternary complexes, 17beta-HSD1-EM519-NADP+ and 17beta
      HSD1-EM553-NADP+ were crystallized using combined methods of soaking and co
      crystallization. Although they belong to the same C2 space group, they have
      different unit cells, with a = 155.59 A, b = 42.82 A, c = 121.15 A, beta = 128.5
      degrees for 17beta-HSD1-EM519-NADP+, and a = 124.01 A, b = 45.16 A, c = 61.40 A,
      beta = 99.2 degrees for 17beta-HSD1-EM553-NADP+, respectively. Our preliminary
      results revealed that the inhibitors interact differently with the enzyme than do
      the natural substrates.

PMID- 10416840
TI  - Tissue- and temporal-specific regulation of 11beta-hydroxysteroid dehydrogenase
      type 1 by glucocorticoids in vivo.
AB  - 11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyses the
      interconversion of active corticosterone and inert 11-dehydrocorticosterone.
      Short-term glucocorticoid excess upregulates 11beta-HSD-1 in liver and
      hippocampus leading to suggestions that 11beta-HSD-1 ameliorates the deleterious
      effects of glucocorticoid excess by its 11beta-dehydrogenase activity. However
      the predominant activity of 11beta-HSD-1 in vivo is 11beta-reduction, thus
      generating active glucocorticoid. We have re-examined the time-course of
      glucocorticoid regulation of 11beta-HSD-1 in the liver, hippocampus and kidney of
      adult male rats in vivo. Sham operation markedly reduced 11beta-HSD-1 mRNA
      expression in all tissues, and reduced 11beta-HSD bioactivity in liver and
      hippocampus when compared to untouched controls. Adrenalectomy reduced 11beta-HSD
      1 expression in all tissues in the short-term (7 days), followed by subsequent
      recovery of enzyme activity by 21 days in liver and hippocampus. Dexamethasone
      replacement of adrenalectomised rats attenuated the initial decrease in hepatic
      11beta-HSD-1 activity, but by 21 days dexamethasone reduced activity compared to
      control levels. Thus glucocorticoids regulate 11beta-HSD-1 in a complex tissue-
      and temporal-specific manner. This pattern of regulation suggests glucocorticoids
      repress 11beta-HSD-1 at least in the liver, a pattern of regulation more
      consistent with the evidence that 11beta-HSD-1 is an 11beta-reductase in vivo.
      Operational stress per se down-regulates 11beta-HSD-1 which has implications for
      interpretation and design of in vivo studies of 11beta-HSD-1.

PMID- 10416841
TI  - Biomechanical evaluation of assistive devices for transferring residents.
AB  - This is the first of two articles to report a biomechanical evaluation and
      psychophysical assessment of nine battery-powered lifts, a sliding board, a
      walking belt, and a baseline manual method for transferring nursing home
      residents from a bed to a chair. The objectives of the biomechanical evaluation
      were: (1) to investigate the effects of transfer method and resident weight on
      the biomechanical stress to nursing assistants performing the transferring task,
      and (2) to identify resident-transferring methods that could reduce the
      biomechanical stress to the nursing assistants. Nine nursing assistants served as
      test subjects; two elderly persons participated as residents. A four-camera
      motion analysis system, two force platforms, and a three-dimensional
      biomechanical model were used to measure biomechanical load. The results indicate
      that transfer method and resident weight affect a nursing assistant's low-back
      loading. The basket-sling and overhead lift devices significantly reduced the
      nursing assistants' back-compressive forces during the preparation phase of a
      resident transfer. In addition, the use of basket-sling, overhead, and stand-up
      lifts removed about two-thirds of the exposure to low-back stress (lifting
      activities per transfer) as compared to the baseline manual method. Thus, the use
      of these devices reduces biomechanical stress, and thereby will decrease the
      occurrence of resident-handling-related low-back injuries. Furthermore, lifting
      device maneuvering forces were found to be significantly different and a number
      of design/use problems were identified with various assistive devices. The second
      article will detail the psychophysical assessment of the same resident
      transferring methods.

PMID- 10416842
TI  - Subjective assessment of fork-lift truck seats under laboratory conditions.
AB  - A subjective assessment of fork-lift truck seats has been carried out to assess
      the range of preferred seat dimensions and the acceptability of different seat
      adjustments to fork-lift truck drivers. Twelve fork-lift truck seats fitted to a
      fixed bench were assessed by twelve fork-lift truck drivers. For each seat, each
      driver completed a questionnaire that covered the following areas: eleven seat
      dimensions, four seat adjustments and other features (arm rests, safety belts and
      safety wings). The drivers assessed the dimensions of a seat chosen at random,
      before moving to the adjacent seat in either a clockwise or anticlockwise
      direction. Before each assessment, they were asked to look forward and backward
      in the seat as though they were driving a fork-lift truck. In general,
      significant correlations were obtained between the subjective assessments and
      objective measurements of the seat dimensions. This enabled preferred seat
      dimension ranges to be defined. Fork-lift truck drivers ranked the forward
      backward and the backrest inclination adjustments as most important. The results
      showed that although the drivers had previous experience in the use of suspension
      seats, they did not understand the purpose of the weight adjustment. All
      adjustments should be easy to find, accessible, easy to move and they should
      enable a range of adjustments. In addition, clear and simple information on the
      seat is needed, especially for the weight adjustment. The most recently designed
      seats generally had dimensions within the preferred ranges compared with the
      older generation seats, mainly because they had more adjustments. However, the
      results show that adjustments on fork-lift truck seats could be improved further.
      Some tentative conclusions are made for the preferred fork-lift truck seat
      dimensions and adjustment ranges which are based on the evidence from this
      restricted sample of fork-lift truck drivers. They may be useful for seat and
      truck designers in the preparation of a standard on fork-lift truck seat
      dimensions.

PMID- 10416843
TI  - Manual handling risks and controls in a soft drinks distribution centre.
AB  - This paper describes an investigation into manual handling risks and controls
      within a soft drinks distribution centre, presented as a case study regarding
      compliance with the requirements of the Manual Handling Operations Regulations
      1992. Methods used included semi-structured interviews, document analysis,
      analysis of training, OWAS postural analysis and use of the NIOSH equation.
      Warehouse operators and delivery drivers were studied, and two methods of work
      compared involving pallets and cages. Significant differences were found between
      the two work methods with respect to harmful postures. Manual handling risks were
      found in both warehouse and delivery areas, some being classed as "excessive"
      using the NIOSH equation. As this company has a good safety record and considers
      itself proactive in the area of health and safety, the investigation raises
      concerns about how organisations have responded to the Manual Handling Operations
      Regulations.

PMID- 10416844
TI  - Lipoatrophia semicircularis and the relation with office work.
AB  - The relation between lipoatrophia semicircularis (LS--band-like circular
      depressions and isolated atrophy of the subcutaneous fatty tissue on the anterior
      thighs and sitting posture or pressure on the seat surface of office chairs was
      investigated in an office environment. A questionnaire was presented to 21
      subjects and electromyographic measurements, video analysis and pressure
      measurements were performed. Remarkable posture differences between the LS group
      and the group without LS were found: less use of the lumbar support of the chair,
      static sitting postures and a too high seat surface of the office chair were
      characteristics of the subjects with LS. These observations were confirmed by
      higher pressure measurements for the subjects with LS. In addition, highly
      significant pressure differences were found between different chairs.

PMID- 10416846
TI  - Marine vessel control using the tiller-motor system.
AB  - Operator performance on the tiller-motor system was investigated in a field
      survey and in a tracking simulator. Boat operators in Study 1 reported both
      control difficulties and discomfort, when using their tiller-motor system.
      Participants in Study 2 operated a tiller-motor simulator of a boat navigating a
      river over a 20 min period. Directional and speed control performance was found
      to be poor, particularly on the first trials and under emergency conditions.
      These results support the suggestion that the incompatible nature of the
      control/response relationship in tiller-motor systems can cause operator
      difficulties. The dimensions of the simulator were systematically varied and
      found to influence operator shoulder extension, and ratings of exertion and
      discomfort. Recommendations for tiller-motor system design and installation are
      offered.

PMID- 10416845
TI  - The validity of reported musculoskeletal problems. A study of questionnaire
      answers in relation to diagnosed disorders and perception of pain.
AB  - The objectives of the present study were to evaluate the validity of answers
      given in a questionnaire on musculoskeletal pain and conditions by means of a
      clinical assessment, and to get some understanding of the subject's perception of
      reported pain. This was performed by using measures of sensitivity and
      specificity comparing data from the questionnaire with the clinical diagnoses of
      conditions in the neck, shoulders and thoracic spine. Subjective perception of
      pain was obtained by the use of visual analogue scale (VAS) and pain drawings.
      For the combination of neck and shoulders, both sensitivity (95%) and specificity
      (88%) were high for current pain. The results of the study confirm the validity
      of the subjective reports of the respondents. A 'pain assessment instrument'
      including a questionnaire, VAS and pain drawings may be useful to reveal
      conditions in the neck and shoulders and thoracic spine, common sites of work
      related musculoskeletal disorders.

PMID- 10416847
TI  - Stress and strain of blue and white collar workers during work and leisure time:
      results of psychophysiological and behavioral monitoring.
AB  - This study of 29 blue and 57 white collar workers (mean age 50 and 51 yr)
      investigated behavior and the level of subjective stress and objective strain
      during work and leisure time. Physiological and psychological parameters as well
      as behavioral activities were assessed simultaneously using a special ambulatory
      monitoring device capable of storing 23 h records. Total strain was
      operationalized by heart rate (HR), physical strain by physical activity,
      emotional strain by non-metabolic HR, and mental strain by HR variability.
      Analysis of the physiological parameters for the working hours from 8 to 16 h
      revealed differences between the hours for physical activity, HR, and non
      metabolic HR but not for HR variability. Between 12 and 13 h, physical activity
      was somewhat lower and non-metabolic HR higher, presumedly caused by the lunch
      break. Physical activity and HR were higher for blue than white collar workers
      due to the different tasks of the workers. Self-reports of excitement and
      enjoyment during the working hours showed no main effects in the MANOVA.
      Comparison between total working time and leisure time revealed lower physical
      activity and HR but higher non-metabolic HR for leisure time. In the self
      reports, however, leisure time was rated less exciting and more pleasant than
      working time. There was no indication of higher emotional strain for one or the
      other group, but mental strain at work was somewhat higher for the blue collar
      workers. In a questionnaire, white collar workers reported having significantly
      more stress at work and outside work than blue collar workers. Analysis of the
      behavior during leisure time (physical activity, activity, social contacts)
      showed only minor differences between the groups.

PMID- 10416848
TI  - Prompting correct lifting posture using signs.
AB  - The use of a symbol to prompt the adoption of correct lifting posture was
      examined in three studies. Study 1 used an Appropriateness Test to evaluate nine
      symbols designed to encourage the adoption of correct lifting posture. Four
      symbols met the appropriateness criteria and were tested for comprehension in
      Study 2. Study 3 examined the effect of the best performing symbol from Study 2
      in a field setting which involved subjects lifting a small box. Results indicate
      significant increases in the adoption of the use of correct lifting posture when
      the symbol was present compared to a control condition. The study also identified
      the placement of a lifting criterion symbol onto packaging as a useful technique
      for communicating safety information.

PMID- 10416849
TI  - Ergonomic design in ancient Greece.
AB  - Although the science of ergonomics did not actually emerge until the 20th
      century, there is evidence to suggest that ergonomic principles were in fact
      known and adhered to 25 centuries ago. The study reported here is a first attempt
      to research the ergonomics concerns of ancient Greeks, on both a conceptual and a
      practical level. On the former we present a collection of literature references
      to the concepts of usability and human-centred design. On the latter, examples of
      ergonomic design from a variety of fields are analysed. The fields explored here
      include the design of everyday utensils, the sculpture and manipulation of marble
      as a building material and the design of theatres. Though hardly exhaustive,
      these examples serve to demonstrate that the ergonomics principles, in content if
      not in name, actually emerged a lot earlier than is traditionally thought.

PMID- 10416850
TI  - Accuracy of measurements for the revised NIOSH lifting equation. Applied
      Ergonomics 29(6) 433-438.

PMID- 10416852
TI  - Theory of health as expanding consciousness.

PMID- 10416851
TI  - A commentary on Newman's theory of health as expanding consciousness.

PMID- 10416853
TI  - Critical language and discourse study: their transformative relevance for
      critical nursing inquiry.
AB  - A pragmatic view of language and a critical study of discourse can advance
      nursing inquiry toward the study of racism, heterosexism, classism, and health.
      In critical language inquiry notions about humans, health and illness are seen as
      constructed in societal discourses. Critical language inquiry challenges nurse
      researchers to theorize not which research questions to ask, but how to ask
      research questions that broaden knowledge about the interconnections among
      language, discourse, health, and society. Critical discourse analysis, as a
      methodology, can be of significant utility in exploring the relationships among
      health, discourse, power, and society.

PMID- 10416854
TI  - Connecting and becoming culturally competent: a Lakota example.
AB  - Addressing how nurses become culturally competent is essential for knowledge
      development beyond why sociocultural understandings are important. This article
      reports participatory research conducted during intercultural immersion learning
      experiences of non-native nurses on an Indian reservation. Emphasizing
      collaborative relationships within unfamiliar social, political, and economic
      circumstances, and using Diekelmann's "concernful practices" as an organizing
      scheme, prompted participants to explicate practices that promote intercultural
      connecting. Suggesting integral shifts in value orientations with changes in
      cultural competence, the findings argue for attending to associations between
      those dynamics and potential for developing co-responsibility (with consumer
      groups) for advocating improved health and health care.

PMID- 10416855
TI  - Colonizing images and diagnostic labels: oppressive mechanisms for African
      American women's health.
AB  - The purpose of this article is to present colonizing images of African American
      women and describe how colonizing images and diagnostic labels function together
      to serve as oppressive mechanisms for African American women's health. The mammy,
      the matriarch, the welfare mother, the Jezebel, and the Black lady overachiever
      are representational images of African American women that contribute to how they
      are viewed and treated within the health care arena.

PMID- 10416856
TI  - The social construction of love and sexuality in a women's prison.
AB  - Incarcerated women have numerous physical, social, and emotional health care
      needs, including specific needs related to their expressions of sexuality while
      in prison. This report describes the results of a participatory action research
      study with incarcerated women utilizing critical hermeneutic data analysis
      techniques. While the public's view of sexuality between incarcerated women
      borders on the prurient and profane, this study suggests that women in prison
      continue to be sexual beings who come to "participate" in love and sex with one
      another based on their need for relationship and friendship. It is suggested that
      prison bureaucracies define women through a sexual lens, dually grounding their
      identities in the crimes they were sent to prison for and the perceived crimes of
      their sexuality. The need for nursing involvement and intervention with this
      marginalized and stigmatized population is discussed.

PMID- 10416857
TI  - Patients' images in nursing magazine advertisements.
AB  - Images of patients in advertisements can reflect and influence readers. Since
      studies have shown discrimination against women and minorities in health care,
      images of patients in nursing practice magazine advertisements (n=446) were
      assessed for their reflection of reality. More male than female images were
      found. Men were shown more frequently as critically ill or with cardiac disease
      than women. Most patients were Caucasian and under 65 years old. These findings,
      at variance with reality, may influence nursing care. Nursing magazine readers
      may perceive women as less critically ill and with less heart disease than men.
      The underrepresentation of minorities and the elderly negates their health care
      presence.

PMID- 10416858
TI  - Seeking the both/and of a nursing research proposal.
AB  - Much of contemporary nursing scholarship challenges us to critique the
      assumptions that underlie the processes of inquiry as well as the knowledge that
      we claim as our results. This article examines the layers of assumptions that
      circumscribe an ethnographic study of the relationships among health,
      environment, policy, and culture in one Hispanic community. The author seeks to
      analyze these assumptions as sources of meaning and interpretation by
      illuminating discourses contained within the text of the proposal. This discourse
      analysis provides perspectives from which to consider questions of knowledge,
      power, and relationships in nursing inquiry.

PMID- 10416859
TI  - Localization of the NO/cGMP-pathway in the cochlea of guinea pigs.
AB  - The presence of nitric oxide synthase (NOS) in substructures of the cochlea of
      guinea pigs is an issue of current focus. Moreover, information concerning the
      localization of cells effected by the NO/cGMP-pathway are rare. Paraffin sections
      of guinea pig cochlea were incubated with specific antibodies to the three known
      NOS isoforms, soluble guanylyl cyclase (sGC) and cyclic guanosine-monophosphate
      (cGMP), the second messenger system of NO. While detection of inducible iNOS
      failed in all cochlear structures, expression of endothelial eNOS was found in
      the spiral ligament, in the stria vascularis, in cells of the organ of Corti, in
      nerve fibers and in some perikaryia of the spiral ganglion. The cochlear nerve
      showed an accentuated affinity for immunostaining in distal, basal segments of
      the cochlea. Neuronal bNOS was found predominantly in the endosteum of the
      modiolus and cochlea and was less intensively present in all perikaryia of the
      spiral ganglion and in the spiral ligament. Supporting cells of the organ of
      Corti and cells in the limbus spiralis displayed only modest immunostaining,
      while bNOS was not found in outer and inner hair cells. NOS detection was
      accompanied by immunoreactivity to sGC and to cGMP. The presence of NOS and its
      second messenger system gives evidence for a possible involvement in
      neurotransmission, regulation of the cochlear amplifier and in homeostasis.

PMID- 10416860
TI  - Increase in glutamate-aspartate transporter (GLAST) mRNA during kanamycin-induced
      cochlear insult in rats.
AB  - Kanamycin (KM)-induced changes in expression of the gene for glutamate-aspartate
      transporter (GLAST) in the rat cochlea were analyzed by Northern blotting. With
      the administration of KM (600 mg/kg/day) once daily for 20 days, the expression
      of GLAST mRNA gradually increased and reached a peak on day 20. Although the
      expression of GLAST mRNA remained at a high level until 12 days after the
      completion of the KM treatment, it then fell to the normal level within 2 months.
      Such KM treatment resulted in loss of both inner and outer hair cells and a
      concomitant profound permanent threshold shift. The present findings suggest that
      during KM administration, high concentrations of extracellular glutamate released
      by collapsing hair cells induced GLAST mRNA expression. Increased GLAST mRNA
      might play an important role in the prevention of the secondary death of spiral
      ganglion neurons from glutamate neurotoxicity.

PMID- 10416861
TI  - Distribution and time course of hair cell regeneration in the pigeon utricle.
AB  - Vestibular and cochlear regeneration following ototoxic insult from
      aminoglycoside antibiotics has been well documented, particularly in birds. In
      the present study, intraotic application of a 2 mg streptomycin paste was used to
      achieve complete vestibular hair cell destruction in pigeons (Columba livia)
      while preserving regenerative ability. Scanning electron microscopy was used to
      quantify hair cell density longitudinally during regeneration in three different
      utricular macula locations, including the striola, central and peripheral
      regions. The utricular epithelium was void of stereocilia (indicating hair cell
      loss) at 4 days after intraotic treatment with streptomycin. At 2 weeks the
      stereocilia began to appear randomly and mostly in an immature form. However,
      when present most kinocilia were polarized toward the developing striola.
      Initially, regeneration occurred more rapidly in the central and peripheral
      regions of the utricle as compared to the striola. As regeneration proceeded from
      2 to 12 weeks, hair cell density in the striola region equaled the density noted
      in the central and peripheral regions. At 24 weeks, hair cell density of the
      central and peripheral regions was equal to normal values, however the striola
      region had a slightly greater hair cell density than that observed for normal
      animals.

PMID- 10416862
TI  - Does electrical stimulation of deaf cochleae prevent spiral ganglion
      degeneration?
AB  - Thirty-six drug deafened guinea pigs were studied to determine how electrical
      stimulation of the cochlea affects spiral ganglion cell (SGC) survival. Animals
      were divided into two groups, extracochlear and intracochlear stimulation, and
      each group was further divided into four stimulus subgroups: no stimulation
      (implanted controls), the inferior colliculus electrically evoked potential
      (ICEEP) threshold-2 dB, ICEEP threshold+2 dB, and ICEEP threshold+6 dB. Stimuli
      consisted of 200 micros/phase charge balanced biphasic current pulses presented
      at 100 pulses per second using monopolar stimulation. Animals were stimulated 5
      h/day, 5 days per week, for 8 weeks. The animals were then perfused and the
      cochleae serially sectioned at 4 microm saving every 8th section. We counted the
      number of intact SGCs, those containing a nucleus with chromatin, in each 20%
      segment of the cochlea and also measured SGC densities (number of neurons per mm2
      of Rosenthal's canal). The number of surviving spiral ganglion neurons was not
      significantly different (P > 0.05) between the implanted and the unimplanted ears
      in any of the experimental groups. However, the spiral ganglion neuron densities
      were significantly elevated in the electrically stimulated ears (P < 0.001) but
      not in the implanted but not chronically stimulated ears (P > 0.05). We measured
      the volume of Rosenthal's canal in one subgroup (ICEEP threshold+2 dB) and found
      a decrease in this volume in the stimulated ear compared to the unstimulated ear
      (P < 0.01). These findings support the hypothesis that chronic monopolar
      electrical intracochlear or extracochlear stimulation is not a neurotrophic
      factor, increasing spiral ganglion neuron survival, but instead causes a
      narrowing of Rosenthal's canal that accounts for the increased spiral ganglion
      neuronal densities seen in the stimulated cochleae.

PMID- 10416863
TI  - Measuring the cochlear blood flow and distortion-product otoacoustic emissions
      during reversible cochlear ischemia: a rabbit model.
AB  - Impairment to the cochlear blood flow likely induces many types of sensorineural
      hearing loss. Models using several small laboratory animals have been described
      in the literature that permit the simultaneous monitoring of the cochlear blood
      flow with laser-Doppler flowmetry and cochlear function using evoked responses.
      However, these models have not permitted a direct application of the resulting
      knowledge to the human condition, primarily due to differences in the
      translucence of the otic capsule between species. In the present study, to
      approximate conditions relevant to the human patient, the rabbit was utilized to
      develop a procedure in which laser-Doppler flowmetry could be used to measure the
      cochlear blood flow in an animal with an opaque otic capsule. At the same time,
      the cochlear function was monitored non-invasively using distortion-product
      otoacoustic emissions. In this manner, a laser-Doppler probe was positioned in
      the round window niche and the cochlear function measured using distortion
      product otoacoustic emissions during a systematic series of ischemic episodes.
      Cochlear ischemia was produced by deliberately compressing the eighth nerve
      complex at the porus of the internal acoustic meatus, for periods lasting from 1
      3 min, while cochlear blood flow and distortion-product otoacoustic emission
      measures were obtained simultaneously before, during and following the occlusion.
      Results demonstrated that the cochlear blood flow sharply decreased within 1 s
      after compression onset, whereas distortion-product otoacoustic emissions showed
      obstruction-induced changes after a delay of several seconds, provided that the
      blood flow decreased, at least 40%. Similarly, upon release of the compression,
      the cochlear blood flow began to recover within 1 s, whereas the recovery of the
      corresponding distortion-product otoacoustic emissions was slightly delayed.
      Although not apparent in the distortion-product otoacoustic emission recovery
      time course, the cochlear blood flow consistently overshot its initial baseline
      value during the recovery process. Thus, although cochlear ischemia produced
      changes in the distortion-product otoacoustic emission activity that generally
      followed the resulting alterations in the cochlear blood flow, the detailed
      relationship between the two measures was complex.

PMID- 10416864
TI  - Study of the gerbil utricular macula following treatment with gentamicin, by use
      of bromodeoxyuridine and calmodulin immunohistochemical labelling.
AB  - Effects of ototoxic drugs on the gerbil vestibular sensory epithelium were probed
      by use of immunocytochemical labelling with antibodies to both a mitogenic marker
      (bromodeoxyuridine) and a hair cell specific protein (calmodulin). Nine animals
      had gentamicin administered once daily for 5 days, as a transtympanic injection
      into the right middle ear. They additionally were given a daily intraperitoneal
      injection of bromodeoxyuridine, starting on the same day as the gentamicin
      injection and continuing until the day of sacrifice. Nine other animals, serving
      as controls for bromodeoxyuridine incorporation, received only the
      intraperitoneal injections of bromodeoxyuridine. The inner ears from three
      gerbils were obtained at 1, 2 or 4 weeks following the last gentamicin injection
      and utricles from the injected ears were processed for immunohistochemical
      analysis. In specimens where gentamicin was administered, we found evidence of
      bromodeoxyuridine incorporation in 17 cells (10 single cells and 7 pairs of
      cells) in a total of 216 sections taken from the central regions of the 9
      utricles. However, in control specimens, no bromodeoxyuridine labelling was found
      in any cells of the 216 sections examined. Of 10 single cells labelled with
      bromodeoxyuridine, two cells in the hair cell layer were labelled with antibodies
      against calmodulin. One had a faint labelling in the nucleus and the other in the
      stereocilia, but not in the cell bodies. Of 7 pairs of cells, two pairs with
      nuclei localized in the hair cell layer had faint labelling for calmodulin in the
      nuclei, but no labelling in any other part of the cell. The other 13 cells
      labelled with antibodies to bromodeoxyuridine were not labelled with antibodies
      to calmodulin. Our results suggest that the bromodeoxyuridine-labelled cells
      could not be positively identified as hair cells based on immunohistochemical
      labelling for calmodulin.

PMID- 10416865
TI  - The anatomy of the killer whale middle ear (Orcinus orca).
AB  - The paper first reviews our present understanding of the functional morphology of
      the odontocete (toothed whale) ear. The tympano-periotic complex forming the ear
      region consists of a ventral bowl-shaped tympanic bone in direct contact with the
      surrounding soft tissues and the incident sound, and a dorsal periotic bone
      containing the inner ear. Apparently sound brings the tympanic bone, and
      especially its thin tympanic plate, into vibration. The ossicles in the air
      filled middle ear cavity form a bridge from the tympanic plate to the periotic
      bone connecting the vibrating plate to the oval window and the inner ear. Our
      computer tomography (CT) sections and camera lucida drawings reveal two hitherto
      unknown features of the odontocete ear, both of them of potential relevance to
      sound reception and impedance matching. (1) It is well known that, in addition to
      the ossicular chain, two other bone structures connect the tympanic to the
      periotic bone. We show that the most delicate parts of these extra-ossicular
      connections consist of thin and folded bony sheets which apparently allow
      compliance in the tympano-periotic bone contacts and enable plate vibration in
      relation to the periotic bone. (2) The round head of the malleus, in combination
      with a fitting round depression on the periotic side, seems to form a joint. We
      propose that this (hypothetical) joint, together with the adjacent structures,
      forms a lever producing an amplification of the vibration velocity at the level
      of the oval window.

PMID- 10416866
TI  - Scaling of the cetacean middle ear.
AB  - Functionally interesting dimensions of the tympano-periotic complex were measured
      and compared in 18 odontocete and six mysticete species, ranging from small
      porpoises to the blue whale. We determined (i) the masses of the tympanic and
      periotic bones (T and P) and of the ossicles malleus, incus, and stapes (M, I and
      S), (ii) the volume occupied bythe tympanic bone (V), (iii) the areas of the
      tympanic plate and oval window (A1 and A2), (iv) the thickness of the tympanic
      plate (D), and (v) the densities of the ossicles (dM, dI, and dS). In most cases,
      roughly isometric scaling was found in both toothed and baleen whales. P is
      isometric to T, and the tympanic bone is structurally isometric in all species
      studied, although not within mysticetes as a group, shown by the isometric
      relations of V to T, of T(2/3) to A1, and of D to square root(A1). The
      essentially isometric scaling of the tympanic bone provides a basis for the
      functional models described by Hemila et al. (1999). The relation of S to M+I is
      also isometric, but the relation of M+I+S to T is negatively allometric, as is
      the relation of A2 to A1, both with slopes close to 2/3. The possible functional
      implication of this allometry is unknown. The mean ossicular density is 2.64
      g/cm3 for odontocetes, and 2.35 g/cm3 for mysticetes. The highly mineralized and
      convex tympanic plate provides cetaceans with a uniquely large and stiff sound
      collecting area.

PMID- 10416867
TI  - A model of the odontocete middle ear.
AB  - The high acoustic sensitivity of the bottlenose dolphin is physically defined and
      related to the anatomy of the middle ear. The paper presents a conceptual and
      parametric analysis of the demands imposed by this high sensitivity upon the
      middle ear mechanisms: the head and the middle ear structures must collect sound
      energy from a large area and concentrate it onto the oval window. Assuming that
      the specific input impedance of the mammalian cochlea is relatively constant, and
      smaller than the characteristic acoustic impedance of water, we find that the
      impedance matching task of the cetacean middle ear is very different from that of
      terrestrial mammals: instead of a large pressure amplification, cetaceans need
      amplification of particle velocity. Our mechanical four-bone model of the
      odontocete middle ear is based on the anatomy of the tympano-periotic complex and
      consists of four rigid bone units (tympanic bone, the malleus-incus complex,
      stapes, periotic bone) connected through elastic junctions. The velocity
      amplification is brought about by lever mechanisms and elastic couplings. The
      model produced velocity amplifications ranging from 7- to 23-fold when provided
      with middle ear parameters from the six odontocete species for which audiograms
      are available. The model reproduces the complete audiograms of these six species
      fairly well for frequencies up to about 100-120 kHz.

PMID- 10416868
TI  - Preservation of synapses on principal cells of the central nucleus of the
      inferior colliculus with aging in the CBA mouse.
AB  - The light and electron microscopic features of principal neurons of the central
      nucleus of the inferior colliculus were quantitated in the CBA mouse. Three age
      groups of mice were examined, including young (3 months), middle-aged (8 months)
      and old (25 months). No changes were noted in the size of the principal neurons
      over the age range examined. At the ultrastructural level, synapses on the somata
      of the principal neurons showed no change in the number or type of synapses, the
      length of synaptic apposition nor the size of synaptic terminal area. These
      results are in contrast with the moderately severe synapse loss which we
      previously reported in the C57BL/6 mouse strain, a strain which has a genetic
      deficit producing progressive sensorineural hearing loss starting in young
      adulthood (Kazee et al., 1995). In contrast, hearing is quite well-preserved
      across the lifespan in the CBA mouse strain, making this a useful animal to study
      the intrinsic effects of aging in the auditory system versus the effects of
      sensorineural hearing loss. The preservation of synapses on principal neurons in
      this strain suggests that synaptic loss is not an inevitable event in aging, but
      may be related to the preservation of peripheral auditory function and input to
      the neurons.

PMID- 10416869
TI  - Additive noise can enhance temporal coding in a computational model of analogue
      cochlear implant stimulation.
AB  - Conventional analogue multichannel cochlear implants are unlikely to convey
      formant information by the fine time structure of evoked discharges.
      Theoretically, however, the addition of noise to the channel outputs could
      enhance the representation of formants by time coding. In this study, the
      potential benefit of noise in analogue coding schemes was investigated using a
      computer model of cochlear implant stimulation. The cochlear nerve was modelled
      by the Frankenhauser-Huxley equations. For all five vowels investigated, the
      optimal addition of noise to the first channel of the simulated implant (200-671
      Hz) caused enhancement of the first formant representation (as seen in amplitude
      spectra of the simulated discharges). For vowels with a low-frequency second
      formant, clear enhancement of the second formant resulted from the optimal
      addition of noise to the third channel (1200-2116 Hz). On the basis of the
      present computational study, additive noise would be expected to enhance the
      coding of temporal information by the discharges of a single nerve fiber.

PMID- 10416870
TI  - Preferential and non-preferential transmission of formant information by an
      analogue cochlear implant using noise: the role of the nerve threshold.
AB  - Previous experiments have shown that, in principle, the addition of noise to any
      vowel coded by an analogue multichannel cochlear implant can enhance the
      representation of formant information by the temporal pattern of evoked nerve
      discharges. The optimal addition of noise to some vowel stimuli caused a largely
      uniform transmission of all input harmonics, including those related to a
      formant. But for other vowel stimuli, the optimal addition of noise caused
      preferential transmission of the harmonic closest to a formant compared with
      other input harmonics. Such preferential transmission may be useful to a cochlear
      implantee for formant estimation, but the basis of this transmission is unknown.
      In the present study, the nature of this preferential transmission was
      investigated with a set of parallel discriminators (or level-crossing detectors)
      to determine whether the inherent threshold of a nerve fiber was the main cause
      of the effect. An explicit threshold was found to account for some but not all of
      the previously observed preferential transmission. Furthermore, many
      discriminators were required to obtain preferential transmission. Therefore,
      preferential transmission of a formant-related harmonic may be best achieved by
      pre-processing a stimulus and using methods associated with stochastic resonance.

PMID- 10416871
TI  - Potassium channel ether a go-go mRNA expression in the spiral ligament of the
      rat.
AB  - Identification of the K+ transporters located in the lateral wall of the cochlea
      is essential for a better understanding of the mechanisms by which a positive
      endocochlear potential and a high K+ concentration are achieved in endolymph. In
      this study, we have determined the distribution of the K+ channel rat ether a go
      go (eag) mRNA in the cochlea. After reverse transcription of adult rat cochlear
      tissues, cDNA was amplified with primers specific to eag channel. The eag mRNA
      was localized in cochlear tissues by in situ hybridization using specific
      oligonucleotide probes tailed with digoxigenin conjugated UTP. Eag mRNA was
      detected in the organ of Corti but mainly in the fibrocytes of the spiral
      ligament but not in spiral prominence or in stria vascularis. The expression
      pattern of rat eag transcript in spiral ligament is complementary to the Na+,K+
      ATPase distribution in the cochlear lateral wall. The localization of eag mRNA
      suggests that eag potassium channel may be produced in the corresponding cells.
      Considering the importance of the K+ gradient in the cochlea, the result reported
      here suggests that eag channel may play a role in the control of K+ fluxes in the
      spiral ligament.

PMID- 10416872
TI  - Motoneuron axon distribution in the cat stapedius muscle.
AB  - Stapedius-motoneuron cell bodies in the brainstem are spatially organized
      according to their acoustic response laterality, as demonstrated by intracellular
      labeling of physiologically identified motoneurons [Vacher et al., 1989. J. Comp.
      Neurol. 289, 401-415]. To determine whether a similar functional spatial
      segregation is present in the muscle, we traced physiologically identified,
      labeled axons into the stapedius muscle. Ten labeled axons were visible in the
      facial nerve and five could be traced to endplates within the muscle. These five
      axons had 39 observed branches (others may have been missed). This indicates an
      average innervation ratio (> or = 7.8) which is much higher than that obtained
      from previous estimates of the numbers of stapedius motoneurons and muscle fibers
      in the cat. One well-labeled stapedius motor axon innervated only a single muscle
      fiber. In contrast, two labeled axons had over 10 endings and innervated muscle
      fibers spread over wide areas in the muscle. Two of the axons branched and
      coursed through two primary stapedius fascicles, indicating that the muscle zones
      innervated by different primary fascicles are not functionally segregated. In
      another series of experiments, retrograde tracers were deposited in individual
      primary nerve fascicles. In every case, labeled stapedius-motoneuron cell bodies
      were found in each of the physiologically identified stapedius-motoneuron regions
      in the brainstem. These observations suggest there is little, if any, functional
      spatial segregation based on separate muscle compartments in the stapedius
      muscle, despite there being functional spatial segregation in the stapedius
      motoneuron pool centrally.

PMID- 10416873
TI  - Peripherin immunoreactivity labels small diameter vestibular 'bouton' afferents
      in rodents.
AB  - Recent morphophysiological studies have described three different subpopulations
      of vestibular afferents. The purpose of this study was to determine whether
      peripherin, a 56-kDa type III intermediate filament protein present in small
      sensory neurons in dorsal root ganglion and spiral ganglion cells, would also
      label thin vestibular afferents. Peripherin immunohistochemistry was done on
      vestibular sensory organs (cristae ampullares, utriculi and sacculi) of
      chinchillas, rats, and mice. In these sensory organs, immunoreactivity was
      confined to the extrastriolar region of the utriculus and the peripheral region
      of the crista. The labelled terminals were all boutons, except for an occasional
      calyx. In vestibular ganglia, immunoreactivity was restricted to small vestibular
      ganglion cells with thin axons. The immunoreactive central axons of vestibular
      ganglion cells form narrow bundles as they pass through the caudal spinal
      trigeminal tract. As they exit this tract, several bundles coalesce to form a
      single, narrow bundle passing caudally through the ventral part of the lateral
      vestibular nucleus. Finally, we conclude that all labelled axons and terminals
      were vestibular afferents rather than efferents, as no immunoreactivity in the
      vestibular efferent nucleus of the brainstem was observed.

PMID- 10416875
TI  - Fatigue in cancer patients.
AB  - The interest in fatigue seems to be growing. A Medline search combining the key
      words fatigue and cancer yielded 248 entries compared with 72 entries 10 years
      previously. The studies published are mainly descriptive, augmenting the
      knowledge about the extent of fatigue associated with cancer, as well as during
      and after the various treatments used to fight it. New measurement instruments
      integrating the multidimensional concept of fatigue are being proposed. In 1998,
      the first study describing fatigue in children and adolescents with cancer was
      published. The knowledge of the causes of fatigue related to cancer remains
      extremely limited. In only a few studies are interventions and treatment
      possibilities for fatigue discussed. Hopefully, the refined knowledge about the
      characteristics of fatigue and its epidemiology will provide new etiologic
      understanding, resulting in effective treatment. This article provides a survey
      on the literature published in 1998.

PMID- 10416874
TI  - Boltzmann analysis of CM waveforms using virtual instrument software.
AB  - We describe a modification to our technique for the rapid analysis of low
      frequency cochlear microphonic (CM) waveforms in the basal turn of the guinea pig
      cochlea (Patuzzi and Moleirinho, 1998). The transfer curve relating instantaneous
      sound pressure in the ear canal to instantaneous receptor current through the
      outer hair cells (OHCs) is determined from the distorted microphonic waveform
      generated in the extracellular fluid near the hair cells, assuming a first-order
      Boltzmann activation curve. Previously, the analysis was done in real time using
      custom-built electronic circuitry. Here, the same task is performed numerically
      using virtual instrument software (National Instruments LabVIEW 4.1) running on a
      personal computer. The assumed theoretical function describing the CM waveform is
      Vcm = Voff + Vsat/[1 + exp[(Eo+Z.Po.sin(2pi f + phi(tot)))/kT]], where the six
      parameters are (i) a DC offset voltage (Voff); (ii) the frequency of the
      sinusoidal stimulus (f); (iii) the phase of the sinusoidal stimulus (phi(tot));
      (iv) the maximal amplitude of the distorted microphonic signal (Vsat); (v) the
      sensitivity of the transduction process (Z); and (vi) the operating point on the
      sigmoidal transfer curve (Eo). The software obtains the least-squares fit to the
      CM waveforms by continuously deriving the six parameters at a speed of about one
      determination per second. The independent fitting of the frequency and phase
      allows the data to be analysed off-line from data previously recorded to tape
      (i.e. the frequency and phase of the microphonic response need not be known
      accurately beforehand). We present here an outline of the software we have used,
      and give an example of the changes which can be monitored using the technique
      (transient asphyxia). The method's advantages and limitations have been discussed
      in our previous paper. The virtual instrument described here is available from
      the authors on request.

PMID- 10416876
TI  - Palliative management of dyspnea in advanced cancer.
AB  - Dyspnea is a common and devastating symptom of life-threatening disease.
      Approximately 90% of non-small cell lung cancer patients experience moderate to
      severe dyspnea by death. Currently, the pathology is ill-defined and measurement
      of this subjective symptom is imprecise. The treatment is directed at the
      underlying cause when appropriate. When specific therapies no longer exist,
      palliative interventions are necessary. This article outlines the current state
      of knowledge and standards of care for palliative interventions in dyspnea. These
      include nonpharmacologic interventions, oxygen supplementation, and medications.
      Further research is needed to clarify the role of each and to develop better
      pathophysiologic understanding.

PMID- 10416877
TI  - The syndrome of anorexia-cachexia.
AB  - Cancer anorexia/cachexia is a major clinical problem, especially in advanced
      cancer patients. Its pathogenesis is quite complex. Anorexia plays a central
      role, but cancer cachexia is more complex than pure chronic starvation. One of
      the key differences is the preferential mobilization of fat and the sparing of
      skeletal muscle in simple starvation compared with an equal mobilization of fat
      and skeletal muscle in cancer patients. An increase in basal energy expenditures
      seems to play a contributory role in many patients. Cytokines, essentially but
      not exclusively tumor necrosis factor alpha, play an essential role, and the
      syndrome can be compared with a low-grade chronic inflammatory state. As it is in
      most fields in medicine, prevention is more efficacious than treatment, and, to
      avoid the final and dramatic stages of cancer cachexia, adequate nutritional
      advice and support must be provided sufficiently early. Parenteral nutrition
      could facilitate the administration of complete doses of chemotherapy or
      radiotherapy, but no significant survival benefit or decrease in treatment
      induced toxicity have ever been demonstrated in prospective randomized trials.
      The gut should always be used if at all possible. Percutaneous endoscopic
      gastrostomy is used increasingly in patients who cannot eat but who have
      functionally intact gastrointestinal tracts, especially in patients with head and
      neck cancer. Eight randomized, double-blind, placebo-controlled studies have
      demonstrated that progestational drugs can somewhat stimulate appetite, food
      intake, and energy level; increase weight in many patients; and often decrease
      nausea and vomiting severity; however, pharmacologic treatment of cancer cachexia
      remains disappointing, and more trials with anticytokine drugs should be
      conducted.

PMID- 10416878
TI  - Research advances in oral mucositis.
AB  - Oral mucositis is a common toxicity of high-dose chemotherapy and upper mantle
      head and neck radiation. Published evidence from the past 14 months provides
      insight into the multiple possible mechanisms. In addition, the data highlight
      the clinical importance that this lesion exerts relative to infection risk,
      quality of life, and cost of care. Oral mucositis has emerged as a dose-limiting
      toxicity in selected cancer therapy models. Thus, it has direct impact on
      duration of disease remission, cure rates, and long-term survival. Because of its
      importance in the clinical setting, oral mucositis remains under extensive
      laboratory and clinical investigation. Advances in the 1980s relative to
      infection prevention and reduced duration of profound neutropenia via growth
      factors have elevated oral mucositis to a prominent toxicity of cancer therapy. A
      contemporary model for mucositis involving four principal phases was published in
      1998. Future research will likely add further insight into this model relative to
      the roles of mucosal immune dysregulation, colonizing microflora, and wound
      healing mechanisms. Basic and clinical studies directed to these several
      components may well lead to effective preventive strategies in the future, with
      positive impact on quality of life and survival of cancer patients.

PMID- 10416879
TI  - Genetics and the biologic basis of sarcomas.
AB  - Identification of genetic alterations has contributed greatly to the
      understanding of sarcoma biology. Additionally, detection of these abnormalities
      is providing new tools for the diagnosis of sarcomas. In this paper, three
      important new genetic findings from the past year are reviewed, including the
      t(12;15) translocation of congenital fibrosarcoma, mutation of the putative tumor
      suppressor gene hSNF5/INI1 in malignant rhabdoid tumor, and the association of c
      kit mutations with gastrointestinal stromal tumor. Highlighted are important
      studies concerning mechanisms of chromosomal translocation, functions of sarcoma
      specific fusion proteins, genetic abnormalities other than translocations,
      molecular diagnosis, and molecular profiling of gene expression. Particular
      emphasis is placed on information obtained with comparative genomic hybridization
      and microarray techniques, because these powerful technologies will facilitate
      the rapid acquisition of data that provide insight into the molecular genetic and
      biologic basis of sarcomas.

PMID- 10416880
TI  - The Ewing family of tumors and the search for the Achilles' heel.
AB  - The ideal cancer therapy would accomodate the specific biology of a tumor and be
      based upon understanding the mechanisms of malignancy. This vision has been the
      driving force in cancer research. However, the story of success in clinical
      cancer management is a story of empirie largely independent from progress in
      basic research. For the Ewing family of tumors (EFT) comprising Ewing's sarcoma
      and peripheral primitive neuroectodermal tumor, significant insights into the
      molecular basis have appeared recently. Some of last year's discoveries may have
      taken us closer to the identification of the Achilles' heel in this disease. The
      first clue has been obtained to the mechanism of chromosomal translocation, which
      constitutes a rate-limiting step in EFT pathogenesis. Also, researchers have
      progressed in understanding the control of EFT cell proliferation,
      differentiation, and death. A major role in these processes has been attributed
      to the EWS-ets gene rearrangement. Specific growth factor circuits appear to be
      involved in deregulated tumor cell growth. By analogy to heterologous cellular
      systems, it is possible to postulate an important functional role for CD99(MIC2)
      as it contributes to the malignant phenotype of EFT. In vitro, as well as the
      first in vivo, experimental evidence suggests that tumor cell expansion and
      spread can be counteracted by breaking these physiological pathways. Still, we
      are far from a tailored biological therapy of EFT. Before this goal may be
      achieved, we must seek further improvements and diversification of today's
      standard and intensified treatment regimens.

PMID- 10416881
TI  - Soft tissue sarcoma in adults.
AB  - Soft tissue sarcomas are a heterogeneous group of tumors, consisting of numerous
      histiotypes that all share a putative common mesenchymal origin. Although
      prognosis of these tumors is determined by clinical parameters (size, location,
      and resection margin status) and pathologic features (mitotic activity and
      necrosis), the histologic subtype has never been shown to be a consistent
      independent prognostic factor. Some relevant differences among these histiotypes
      are emerging, in specific biological parameters such as proliferation indices, in
      integrin expression profiles, and with regard to drug sensitivity. Several
      biological factors are considered to be prognostically important. Most attention
      is directed to regulators of cell-cycle progression. The significance of p53
      dysregulation is confirmed by the inhibition of cellular proliferation, both in
      in-vitro and in in-vivo sarcoma models, after reintroduction of wild type p53. A
      multidisciplinary approach is essential for the optimal treatment of soft tissue
      sarcomas. Multimodality treatment has led to a patient-tailored approach with
      limb-sparing resections integrated with external and/or interstitial irradiation.
      The value of chemotherapy both in the neoadjuvant and the adjuvant setting,
      although of critical value in other sarcomas such as Ewing's sarcoma and
      osteosarcoma, remains to be established for soft tissue sarcomas.

PMID- 10416883
TI  - Novel chemotherapeutic agents for gastrointestinal cancers.
AB  - Although 5-fluorouracil has been the most commonly prescribed chemotherapy agent
      in the treatment of patients with gastrointestinal malignancies, new agents
      discussed herein provide options for the treatment of patients with colorectal,
      gastric, and pancreas cancer. Irinotecan was recently approved for the treatment
      of patients with colorectal cancer refractory to 5-fluorouracil. It has also been
      evaluated in chemotherapy-naive patients both alone and in combination with 5
      fluorouracil plus leucovorin or with oxaliplatin. Evaluated primarily in patients
      with colorectal cancer, oxaliplatin, a novel platinum compound, is an active
      agent. In combination with 5-fluorouracil and leucovorin, oxaliplatin provides a
      higher response rate than 5-fluorouracil and leucovorin alone. Furthermore, when
      oxaliplatin was added to the same 5-fluorouracil-based regimen in which patients
      had disease progression, clinical activity was observed. Other agents discussed
      herein are raltitrexed and the oral fluorinated pyrimidines, including
      uracil:tegafur plus leucovorin, capecitabine, eniluracil plus oral 5
      fluorouracil, and S-1. Gemcitabine has been demonstrated to be more effective
      than 5-fluorouracil in the alleviation of disease-specific symptoms in patients
      with advanced pancreatic cancer. Gemcitabine also confers a modest survival
      advantage. Combinations of these novel compounds are evaluated in
      gastrointestinal malignancies in the advanced disease setting and in adjuvant
      therapy programs.

PMID- 10416884
TI  - Screening for colorectal cancer and other GI cancers.
AB  - Most of the major advances in the screening for gastrointestinal cancers this
      year were in the area of colorectal cancer screening. Currently, screening is
      recommended for the prevention of colorectal cancer in average and high-risk
      populations. For average risk populations, large randomized trials support the
      use of screening fecal occult blood testing, and case-control studies support the
      use of screening sigmoidoscopy. This year, several investigators have addressed
      issues related to the probability of identifying advanced lesions in the proximal
      colon following a positive screening flexible sigmoidoscopy. Similarly, two
      studies identified that villous histology in an index polyp was associated with
      an increased risk of recurrent colonic polyps. Additionally, two large trials
      provided new insight about the prevalence of mutations in the MLH1 or MSH2
      mismatch-repair genes among patients with colorectal cancer. Lastly, a case
      control study from Sweden provided the best evidence to date that surveillance
      colonoscopies for patients with long-standing ulcerative colitis may reduce
      cancer-related mortality. Although further work is needed, these studies have
      served to advance our knowledge of colorectal cancer screening substantially.

PMID- 10416886
TI  - Bibliography. Current world literature. Supportive care.

PMID- 10416887
TI  - Bibliography. Current world literature. Sarcomas.

PMID- 10416885
TI  - Developments in fluoropyrimidine therapy for gastrointestinal cancer.
AB  - The combination of 5-fluorouracil and leucovorin is the standard treatment in
      metastatic colorectal cancer and in Dukes' C colon cancer. There is, however, no
      agreement on the method for administration in metastatic colorectal cancer.
      Several new studies published in 1998 suggest that infusional 5-fluorouracil
      gives a higher response rate and better toxicity profile compared with a standard
      bolus 5-fluorouracil/leucovorin regimen. The median survival rate, however, is
      not different. Several new active drugs are being developed for advanced
      colorectal cancer. It has not yet been shown that these drugs as single agents
      are superior to an optimal 5-fluorouracil regimen. Combination trials of 5
      fluorouracil/leucovorin with oxaliplatin, CPT-11 and raltitrexed are ongoing, and
      it can be expected that several of these combinations will be more active than 5
      fluorouracil/leucovorin. The challenge for the future will be to show the most
      active combination and the best sequence of these combinations. The development
      of the orally administered fluoropyrimidines was rapid in 1998. Randomized
      studies comparing UFT, capecitabine, and eniluracil plus 5-fluorouracil with 5
      fluorouracil/leucovorin are ongoing.

PMID- 10416888
TI  - Bibliography. Current world literature. Gastrointestinal tract.

PMID- 10416889
TI  - Treatment methods for fractures of the mandibular angle.
AB  - Fractures of the mandibular angle are plagued with the highest rate of
      complication of all mandibular fractures. Over the past 10 years, various forms
      of treatment for these fractures were performed on an indigent inner city
      population. Treatment included: 1) closed reduction or intraoral open reduction
      and non-rigid fixation; 2) extraoral open reduction and internal fixation with an
      AO/ASIF reconstruction bone plate; 3) intraoral open reduction and internal
      fixation using a solitary lag screw; 4) intraoral open reduction and internal
      fixation using two 2.0 mm mini-dynamic compression plates; 5) intraoral open
      reduction and internal fixation using two 2.4 mm mandibular dynamic compression
      plates; 6) intraoral open reduction and internal fixation using two non
      compression miniplates; 7) intraoral open reduction and internal fixation using a
      single non-compression miniplate; and 8) intraoral open reduction and internal
      fixation using a single malleable non-compression miniplate. This paper reviews
      the results of those modes of treatment when used for the same patient population
      at one hospital. Results of treatment show that, in this patient population, the
      use of either an extraoral open reduction and internal fixation with the AO/ASIF
      reconstruction plate or intraoral open reduction and internal fixation, using a
      single miniplate, are associated with the fewest complications.

PMID- 10416890
TI  - Disc position and morphology in patients with nonreducing disc displacement
      treated by injection of sodium hyaluronate.
AB  - Disc position and morphology were examined in 21 patients (22 joints) with
      nonreducing disc displacement of the temporomandibular joint (TMJ) at more than
      12 months after undergoing injection of sodium hyaluronate into the superior
      joint space. The patients' clinical signs and symptoms improved during the follow
      up period. In all patients, the disc was displaced anteriorly on mouth closure
      and did not reduce into the normal position during mouth opening at follow-up,
      whereas a normal disc position was found in all the controls. In the patients,
      the disc deviated from the normal biconcave configuration found in all of the
      controls on the follow-up magnetic resonance imaging (MRI). Disc displacement
      apparently is persistent and continued disc deformity common in patients,
      although the clinical signs and symptoms improved.

PMID- 10416891
TI  - Zygomatico-coronoid ankylosis: a case report.
AB  - The clinical and radiographic diagnosis and treatment plan for a patient with a
      rare type of extracapsular ankylosis involving fusion of the zygoma and coronoid
      process are presented.

PMID- 10416892
TI  - Long-term results of endosteal implants used for restoration of oral function
      after oncologic surgery.
AB  - The aim of the present study was to analyse the long-term survival rate of
      endosteal implants used for restoration of oral function in patients having
      undergone oncologic surgery. Eighty-three consecutive patients, who had received
      a total of 409 endosteal implants ad modum Branemark, subsequent to resections of
      soft tissue and bone during ablation of oral malignancies, were enrolled into the
      study. A life-table analysis was used to determine the survival rate of the
      implants placed during a period of 13 years. Log rank tests and Cox regression
      analysis were employed to identify relevant effects of surgical parameters on
      implant survival. A total of 38 implant failures were encountered. Most of the
      losses (n = 19) occurred during the first year of functional loading. Subsequent
      failures were evenly distributed across the remaining follow-up period. The
      cumulative overall survival rate of implants was 56.5%. Previous radiation
      therapy, insertion into grafted bone or original jaw bone and the technique of
      grafting did not significantly affect the survival rates. In the Cox regression
      analysis, the timing of implant placement in the group of patients with bone
      grafts (primary vs. secondary placement) was significantly related to the
      survival rate (P = 0.0197), with a lower survival rate of 36.2% for primary
      insertion of implants and 67.1% for secondary placement.

PMID- 10416894
TI  - Low incidence of severe adverse effects after mandibular ridge reconstruction
      using hydroxylapatite.
AB  - The short and long term adverse effects after ridge reconstruction using
      hydroxylapatite (HA) are presented in this study. The HA was inserted using a
      modified tunnelling technique, followed by a lowering of the floor of the mouth
      and a vestibuloplasty using split thickness skin graft, 4-6 weeks later. The
      study comprised 637 patients followed for a period of 1 to 10 years (mean 6.0+/
      2.6 years). Major loss of HA was seen in 17 patients (2.7%). Donor site
      visibility (skin graft) appeared to improve greatly over the years from 29.2% to
      8.8% at the latest follow-up. Neurosurgery deficits also improved from 11.6%
      (paraesthesia and dysaesthesia) to 4.6%. Long term follow-up revealed a high
      percentage of patient satisfaction (97%), indicating that the low incidence of
      severe adverse effects of the procedure does play a significant role in the
      appreciation of the procedure and prosthetic care.

PMID- 10416893
TI  - Stability measurements of one-stage Branemark implants during healing in
      mandibles. A clinical resonance frequency analysis study.
AB  - Using a one-stage surgical protocol, 75 implants ad modum Branemark of three
      different designs were inserted in 15 edentulous mandibles of high bone density.
      All implants were followed with repeated stability measurements by means of
      resonance frequency analysis (RFA) from implant placement to connection of the
      fixed prostheses (3-4 months), in order to evaluate possible stability changes
      during healing. It was shown that the resonance frequency (RF) values slightly
      decreased for the majority of the implants during the study period independent of
      design. Consequently, the results of the present study indicated that the
      implants were as stable at time of placement as when measured at 3-4 months post
      surgery, i.e. when the prostheses were attached. The available data support the
      concept of direct loading of implants when inserted between the mental
      interforaminal regions. One implant failed during healing and the corresponding
      RF measurement disclosed, at six weeks post-surgery, a value being far below the
      one registered at implant placement. The lowered RF value indicated the failure
      several weeks before the mobility was clinically diagnosed. The presence or
      absence of a fixture/abutment junction did not exert any influence on the
      marginal bone level, as determined radiographically at the end of the short
      investigation period.

PMID- 10416895
TI  - The impact of extranodal spread of lymph node metastases in patients with oral
      cancer.
AB  - A retrospective study of 61 patients with histologically confirmed lymph node
      metastases was undertaken to evaluate the prognostic significance of extranodal
      spread (ENS) of metastases on the patterns of treatment failure and survival. ENS
      was present in 28 (46%) of the 61 patients and it was significantly associated
      with N stage. T stage, clinical stage, number of positive nodes, level of
      metastases, mode of treatment, and histological differentiation, however, did not
      influence the incidence of ENS. The 5-year disease-specific survival rate was
      57%. The values for patients with and without ENS were 40% and 72%, respectively,
      which were statistically significant. The univariate analysis showed that the
      presence of ENS was a significant predictor of patient survival (P = 0.008). The
      number and level of positive nodes and postoperative radiotherapy had no
      prognostic importance. ENS, however, was also associated with an increased risk
      of distant metastases.

PMID- 10416896
TI  - Platysma myocutaneous flap for intraoral reconstruction: an option in the
      compromised patient.
AB  - The platysma myocutaneous flap is an infrequently used flap in head and neck
      reconstruction. This flap should be considered for reconstruction of small and
      medium-sized defects of the oral cavity. We present two cases demonstrating the
      utility of this local flap in reconstruction. Advantages, contraindications and
      limitations of the platysma myocutaneous flap are discussed.

PMID- 10416897
TI  - The use of titanium mandibular reconstruction plates in patients with oral
      cancer.
AB  - A series of 21 patients, who were selected for primary mandibular stabilisation
      with titanium plates following excision of advanced malignant tumours, is
      reported. Success was defined as a plate that did not have to be removed due to
      fracture, exposure or infection. The overall success rate was 71%, with follow-up
      ranging from 7-53 months. The majority of plate losses were experienced when
      either anterior or large lateral defects which included the condyle were bridged
      and when patients were subjected to either pre- or postoperative radiotherapy.

PMID- 10416898
TI  - Tumors and tumor-like lesions of the oral cavity and related structures in
      Israeli children.
AB  - The present study comprises a total of 966 biopsies of the oral cavity and
      related structures obtained from children aged < or =15 years and examined at the
      Division of Oral Pathology of The Hebrew University. These cases represent 7.15%
      of the total number of biopsies (13508) during a fifteen-year period (1978-1992).
      Seven hundred and seventy six (776) biopsies (80.3%) represented inflammatory
      processes, cysts, pulp pathology and congenital malformations. The remaining 190
      biopsies (19.7%) comprised neoplastic and tumor-like lesions: 18 (9.5%) were
      benign odontogenic neoplasms, 77 (40.5%) were benign non-odontogenic neoplasms,
      18 (9.5%) were malignant tumors and the remaining 77 cases (40.5%) were tumor
      like lesions.

PMID- 10416899
TI  - Excision of cervical cystic lymphangioma using injection of hydrocolloid dental
      impression material. A technical case report.
AB  - A lymphangioma, arising in an adult patient, was completely removed after
      injection of hydrocolloid dental impression material. The postoperative course
      was uneventful, with no sign of foreign-body reaction. The agar impression
      material, which had excellent tractability during operation, may be used as a
      filling material, as long as preoperative examinations show that the tumor does
      not involve major vessels or nerves.

PMID- 10416900
TI  - A comparison between cutting torque and resonance frequency measurements of
      maxillary implants. A 20-month clinical study.
AB  - Oral implant treatment ad modum Branemark was undertaken in nine patients with
      edentulous maxillae. Cutting torque measurements and resonance frequency analyses
      (RFA) were conducted at implant placement and the corresponding values were
      subjected to correlation analyses. The implants were also evaluated with RFA at
      abutment connection and at one-year follow-up in order to identify possible
      changes in implant stability. A total of 61 implants were inserted, of which 49
      were of the Mk II self-tapping type. Two implants were lost during the study
      period. The cumulative torque was presented as a mean value for the
      upper/crestal, the middle and the lower/apical third of the implant site
      respectively, as well as an overall value for the whole site. The highest
      correlation (r = 0.84, P<0.05) was found when comparing the mean torque values of
      the upper/crestal portion with the resonance frequency values at implant
      placement. The Mk II implant sites were divided into three groups based on the
      values of the cutting torque, i.e. soft (group 1), medium (group 2) and dense
      bone (group 3). The mean value of each group was plotted against the
      corresponding mean value of resonance frequency measured at implant insertion.
      Statistical analysis showed significant differences in resonance frequency at
      implant insertion between groups 1 and 2 (P = 0.047) and between groups 1 and 3
      (P = 0.002). When repeating the resonance frequency analyses at second stage
      surgery and at one-year follow-up, no significant differences were detected
      between any of the groups. It was shown that the stability of implants placed in
      softer bone seemed to "catch up" over time with more dense bone sites.

PMID- 10416901
TI  - The effect of fibrin stabilizing factor (F.XIII) on healing of bone defects in
      normal and uncontrolled diabetic rats.
AB  - This study was undertaken to examine the effect of fibrin stabilizing factor
      (F.XIII) on healing of bone defects in normal and uncontrolled diabetic rats.
      Eighty rats were divided into two groups: group I (diabetic) and group II (non
      diabetic) (40 rats each). Diabetes was induced in group I using streptozotocin.
      Both groups were divided into two subgroups, control and experimental (20 rats
      each). Bone defect was created in the mandible. Rats in the experimental
      subgroups were injected with F.XIII, while those of the control groups were
      injected with saline (F.XIII solvent). Animals were killed at varying intervals
      and tissue sections stained with hematoxyline and eosin and Van-Gieson stains
      were examined. Differences in collagen deposition and bone formation were
      compared in both control and experimental groups. Collagen deposition was evident
      and appeared more oriented in diabetic rats treated with F.XIII, and signs of
      bone deposition started in the experimental group earlier than in the control
      group. On the other hand, F.XIII did not significantly affect healing in non
      diabetic rats. It is concluded from these results that F.XIII may enhance early
      stages of bone healing in uncontrolled diabetic rats.

PMID- 10416902
TI  - Validation of computer-assisted manufacture of titanium plates for cranioplasty.
AB  - We have constructed 300 titanium cranioplasty plates, over 150 cases using a
      computerised technique, the remainder by external impression. The clinical follow
      up of these cases over 8 years has shown consistently good results that justify
      our simple low-cost method of manufacturing these plates. Both techniques require
      the provision of a model on which to construct the plate. In the traditional
      technique, an approximate model is derived from the resected bone or a direct
      impression of the defect over the patient's scalp. Using the computerised
      technique, a more accurate model of the defect and the surrounding bone is milled
      in polyurethane foam from cross-sectional computerised tomographic (CT) scans.
      Sheet titanium is pressed to shape from a design outlined on a counterdie. The
      subsequent stages of the plate construction are then the same for both methods.
      This study describes the stages of the model manufacture, the validation of its
      accuracy and the plate construction that follows. Use of the computerised method
      has resulted in a reduction of errors, enabling the manufacture of a smaller
      plate than was possible previously. It has also enabled design changes through
      the achievement of greater accuracy in fit.

PMID- 10416903
TI  - Custom-made cast titanium implants produced with CAD/CAM for the reconstruction
      of cranium defects.

PMID- 10416904
TI  - Experience in teaching of cleft lip and palate surgery in Asia.

PMID- 10416905
TI  - Avoidance of tracheal intubation as a strategy to prevent ventilator-associated
      pneumonia.

PMID- 10416906
TI  - Why immunomodulatory therapies have not worked in sepsis.

PMID- 10416907
TI  - Does noninvasive ventilation reduce the ICU nosocomial infection risk? A
      prospective clinical survey.
AB  - OBJECTIVE: To observe the nosocomial infection (NI) distribution in ventilated
      patients of a single intensive care unit (ICU) according to the kind of control
      of the upper airways: noninvasive positive pressure ventilation (NPPV) versus
      endotracheal intubation (ETI). SETTING: ICU of a general hospital. DESIGN:
      Prospective clinical and epidemiologic survey. PATIENTS: In the period December
      1994-March 1997, 761 patients were included who needed mechanical ventilation for
      more than 48 h: 129 were ventilated by NPPV (NPPV group), 607 were intubated (ETI
      group) and 25 required intubation after a period of NPPV (NPPV-ETI group).
      MEASUREMENTS AND RESULTS: The data used were prospectively collected according to
      the NI epidemiologic surveillance protocol of "C. CLIN Sud Est, Rea Sud Est",
      France. NI included a ventilator-associated pneumonia (VAP), catheter-related
      infection, urinary tract infection and bacteremia. Occurrence of NI was estimated
      by the density of incidence. Covariate-adjusted NI and VAP risk factors were
      assessed by the Cox model. The incidence density of total NI was lower for NPPV
      than for ETI (14.2 versus 30.3 per 1000 patient-days, p < 0.01). The Cox model
      showed that the use of noninvasive ventilation, adjusted to the severity of
      illness (SAPS II), reduced not only the VAP risk (hazard ratio (HR) = 4.07) but
      also the NI risk (HR = 1.95). CONCLUSION: The use of NPPV reduces the risk of VAP
      and NI, compared to ETI, irrespective of the severity of the patient's illness.

PMID- 10416908
TI  - Gastric acidity and duodenogastric reflux during nasojejunal tube feeding in
      mechanically ventilated patients.
AB  - OBJECTIVE: In order to prevent gastric microbial overgrowth, which may complicate
      nasogastric feeding, administration of nutrients more distally into the gut has
      been advocated in intensive care patients, as it offers the advantage of keeping
      the stomach empty and acid. In this study, we assessed the impact of jejunal
      feeding upon gastic pH in a group of mechanically ventilated, critically ill
      patients, with special focus on duodenogastric reflux as a possible cause of
      gastric alkalinization during jejunal nutrition. DESIGN: Prospective experimental
      study. SETTING: Multidisciplinary intensive care unit of a university hospital.
      PATIENTS AND METHODS: Gastric pH was recorded by continuous pHmetry over a 4-h
      period of fasting followed by a 4-h period of nasojejunal feeding at 100 kcal/h
      in 21 mechanically ventilated, critically ill patients. To determine the
      contribution of duodenogastric reflux to modifications of gastric acidity, the
      diet was traced with [(111)In] DTPA (pentetic acid) in 11 of these 21 patients;
      gastric contents were aspirated every 30 min, then analysed for measurement of
      radioactivity, glucose, and bile acid concentration. MEASUREMENTS AND RESULTS:
      Median intragastric pH increased slightly from 1.59 (1.20-2.73; interquartile
      range) (fasting) to 2.33 (1.65-4.64) (feeding) (p = 0.013), and the length of
      time that the pH was 4 or above increased from 1 (0-24) to 9 (0-142) min (p =
      0.026). The variability of pH values and the number of acute alkalinization
      episodes did not change between the two phases. In 10 of 11 patients in which the
      diet was labeled with [(111)In] DTPA, reflux was documented at a given time of
      the feeding period. Bile acid concentrations in the stomach increased from 392
      (61-1076) (fasting) to 1446 (320-2770) micromol/l (feeding) (p = 0.010) and mean
      glucose concentration increased from 59 (28-95) to 164 (104-449) mg/dl (p =
      0.006). CONCLUSION: Duodenogastric reflux is common in mechanically ventilated
      critically ill patients with nasojejunal feeding tubes. It occurs both during
      fasting and during nasojejunal feeding. During nasojejunal feeding, moderate
      alkalinization of the gastric contents occurs as a result of bile and nutrient
      reflux.

PMID- 10416909
TI  - The prognostic significance of passing a daily screen of weaning parameters.
AB  - OBJECTIVE: While "weaning parameters" are commonly used to guide removal of
      mechanical ventilation devices, little information exists concerning their
      prognostic value. We evaluated whether passing weaning parameters was associated
      with survival. DESIGN: A prospectively followed cohort of mechanically ventilated
      patients. SETTING: Medical and coronary adult intensive care units of an 806-bed
      medical center. PATIENTS: 300 consecutively enrolled mechanically ventilated
      patients. MEASUREMENTS AND RESULTS: 216 patients who passed a daily screen of
      weaning parameters were more likely to be extubated successfully (87 vs 30%, p =
      0.0001), less likely to require ventilation for > 21 days (3 vs 30%, p = 0.0001),
      and had a higher survival to hospital discharge (74 vs 29%, p = 0.0001) than 84
      patients who never passed the screen. The overall accuracy of the daily screen
      for predicting successful extubation and in-hospital survival was 82 and 73%,
      respectively. Multivariate proportional hazards analysis of time until hospital
      death confirmed the beneficial effect of passing the daily screen (p = 0.01) and
      of duration of mechanical ventilation (p = 0.001) even after adjustment for
      differences in severity of illness, age, race, gender, diagnosis, and treatment
      assignment. While liberation from mechanical ventilation was predictive of
      survival at any time during the hospital stay (p = 0.001), the prognostic
      significance of the daily screen for hospital survival was related to how early
      after intubation it was passed. The difference in survival between patients who
      had passed and those who had not passed the daily screen was significant for 1
      1/2 weeks postintubation but progressively decreased over time. The average time
      to extubation after passing the daily screen increased from 3 days (range 0 to
      56), for those passing within 5 days of intubation, to 8 days (0 to 35), for
      those passing after 10 days of intubation (r = 0.26, p = 0.001). CONCLUSIONS:
      Passing a daily screen of weaning parameters is an independent predictor of
      successful extubation and survival, but its prognostic value decreases over time.
      Time spent on mechanical ventilation after passing the daily screen presents an
      important opportunity to optimize liberation from the ventilator.

PMID- 10416910
TI  - Alterations of soluble L- and P-selectins during cardiac arrest and CPR.
AB  - OBJECTIVE: To investigate the relationship between cytokines and the inflammatory
      responses in patients with out-of-hospital cardiac arrest, we examined the
      changes of cytokines as well as alterations in the markers of neutrophil
      activation, platelet and endothelial activation, and endothelial injury. DESIGN:
      Prospective, cohort study. SETTING: General intensive care unit of a tertiary
      care center. PATIENTS AND PARTICIPANTS: 26 out-of-hospital cardiac arrest
      patients were classified into two groups: those who achieved return of
      spontaneous circulation (ROSC) (n = 10) and those with no ROSC (n = 16). Eight
      normal healthy volunteers served as control subjects. MEASUREMENTS AND RESULTS:
      Serial levels of soluble L-selectin (sL-selectin), soluble P-selectin (sP
      selectin), neutrophil elastase, and soluble thrombomodulin were measured during
      and after cardiopulmonary resuscitation (CPR). Serial levels of tumor necrosis
      factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) were also measured. We
      could not find any elevations in either cytokine during the study period. In both
      groups, sP-selectin levels were significantly higher than those in control
      subjects from the time of arrival at the emergency department to 24 h after
      admission. sL-selectin levels in the two groups were markedly lower compared to
      those in control subjects at all sampling points. In patients with ROSC, cardiac
      arrest and CPR led to an increase in the levels of neutrophil elastase and
      soluble thrombomodulin that peaked 6 h or 24 h after arrival at the emergency
      department. No statistical differences in the levels of the two selectins,
      neutrophil elastase, and soluble thrombomodulin between the two groups were found
      during CPR. CONCLUSIONS: Out-of-hospital cardiac arrest and CPR induces platelet,
      neutrophil, and endothelial activation and is associated with endothelial injury.
      Inflammatory cytokines may not have an important role in human whole-body
      ischemia-reperfusion injury.

PMID- 10416911
TI  - Serum concentrations and clearances of folic acid and pyridoxal-5-phosphate
      during venovenous continuous renal replacement therapy.
AB  - OBJECTIVE: To determine to what extent hydrosoluble vitamins are removed by
      continuous renal replacement therapy (CRRT); to evaluate clearances, removal
      rates, and evolution of serum concentrations of folic acid and pyridoxal-5'
      phosphate (P-5'-P), the active moiety of vitamin B6 during CRRT. DESIGN: A
      prospective, non-interventional, descriptive study on vitamin losses induced by
      CRRT. SETTING: Medical and surgical intensive care units in a tertiary university
      affiliated hospital. PATIENTS: A total of ten critically ill patients in
      oligoanuric acute renal failure (five treated by continuous venovenous
      hemofiltration and five by continuous venovenous hemodiafiltration) with a mean
      effluent rate of 1801 +/- 468 ml/h. Nutritional support was not modified and
      additional vitamin supplements were not provided during study periods.
      MEASUREMENTS AND RESULTS: Concentrations of folic acid and P-5'-P were determined
      daily during CRRT. Samples for folic acid, P-5'-P, urea, and creatinine were
      taken simultaneously from the blood at the dialyzer inlet and from the effluent,
      at CRRT initiation, and daily thereafter over an average of 3.4 +/- 1.2 days.
      Samples were processed by immunochemiluminescence for folic acid and by
      radioenzymatic assay for P-5'-P determinations with normal ranges above 6.8
      nmol/l and from 11.5 to 179.3 nmol/l, respectively. Marked decreases in serum
      folic acid and P-5'-P concentrations were noticed over time with mean daily
      reductions of 12.6 and 13.7%. Serum folic acid concentrations decreased from 42.7
      to 16.0 nmol/l and serum P-5'-P decreased from 14.4 to 5.0 nmol/l in the blood
      coming in to the dialyzer over the study period. Clearances and removal rates
      were determined from the effluent side. During CRRT, mean (+/- SEM) folic acid
      and P-5'-P clearances were 20.5 +/- 6.3 ml/min (n = 34) and 13.2 +/- 10.6 ml/min
      (n = 22), whereas mean urea clearance was 27.1 +/- 5.1 ml/min (n = 26). Folic
      acid and P-5'-P removal rates were 27.0 +/- 34.2 and 3.4 +/- 2.0 nmol/h,
      corresponding to mean daily losses of nearly 650 and 80 nmol/day respectively.
      CONCLUSION: Significant losses of folic acid and P-5'-P (and most likely of other
      hydrosoluble vitamins) occur during CRRT. Considering that stores of most
      hydrosoluble vitamins are relatively low in critically ill patients,
      supplementation should be provided to patients treated similarly.

PMID- 10416912
TI  - The continuous measurement of cerebrospinal fluid gas tensions in critically ill
      neurosurgical patients: a prospective observational study.
AB  - OBJECTIVE: To determine the feasibility and usefulness of continuous
      cerebrospinal fluid pH and gas tension monitoring in critically ill neurosurgical
      patients. DESIGN: Prospective, observational study. SETTING: Neurosurgical
      intensive care unit in a teaching hospital. PATIENTS: Five critically ill
      neurosurgical patients (GCS < 8) requiring intensive care intracranial pressure
      monitoring and intermittent positive pressure ventilation. INTERVENTIONS:
      Placement of a Paratrend 7 sensor into the external ventricular drain.
      MEASUREMENTS AND MAIN RESULTS: The cerebrospinal fluid (CSF) pH, PCO2 and PO2
      were recorded at 1-min intervals. Intracranial pressure (ICP) and cerebral
      perfusion pressure (CPP) were recorded at 15-min intervals. The mean baseline CSF
      pH, O2 and PO2 values were 7.28 +/- 0.08 pH units, 44 +/- 6 torr and 43 +/- 27
      torr, respectively. The ranges of CSF pH, PCO2 and PO2 observed during the study
      were 6.3-7.8 pH units, 37-150 torr and 4-150 torr, respectively. A statistically
      significant correlation between ICP, CPP and CSF gas tensions occurred in patient
      3. Significant changes in CSF PO2 and pH were observed with augmentation of CPP
      and preceded clinical improvement in patient 4. There were no complications
      attributable to sensor placement. CSF gas tensions and pH values obtained from
      patients 3 and 4 suggest that these measurements may be an indicator of cerebral
      perfusion. CONCLUSIONS: Continuous CSF gas tension measurements in critically ill
      patients are possible and may be an indicator of adequacy of cerebral perfusion.
      The relative merits and limitations of the technique are discussed.

PMID- 10416913
TI  - Validation of "nine equivalents of nursing manpower use score" on an independent
      data sample.
AB  - OBJECTIVE: To compare the recently developed "nine equivalents of nursing
      manpower use score" (NEMS) with the simplified Therapeutic Intervention Scoring
      System (TISS-28). DESIGN: Prospective single centre study. SETTING: Adult 30-bed
      medical-surgical intensive care unit (ICU) in a tertiary care university
      hospital. PATIENTS: Data from all patients admitted in 1997 to the ICU were
      included in the study. METHODS AND RESULTS: NEMS and TISS-28 items were recorded
      prospectively for each nursing shift. There were three shifts per day. The
      Simplified Acute Physiology Score (SAPS) II was calculated for the first 24 h of
      ICU stay and each patient's basic demographic data were collected. The agreement
      between NEMS and TISS-28 was assessed by calculating the mean difference and the
      standard deviation of the differences between the two measures. Further,
      regression techniques and Pearson's correlation were used. Altogether, 2743
      patients with a total of 28,220 nursing shifts were included; 62% of the shifts
      were used for postoperative/trauma patients and 38% for medical patients. Mean
      NEMS was 26.0 +/- 8.1 and mean TISS-28 was 26.5 +/- 7.9. The scores differed by <
      or = 3 points in 49 % of all shifts. The bias was -0.5 +/- 5.3 (95% confidence
      interval -0.47 to -0.60) and the limits of agreement were -11.1 to +10.1. The
      relation between the two systems was NEMS = 4.7 +/- 0.8 x TISS-28 (r = 0.78, r2 =
      0.62, p < 0.001). Including postoperative/trauma patients only: NEMS = 1.9 +/-
      0.9 x TISS-28, for medical patients this equation was: NEMS = 6.0 + 0.8 x TISS
      28. First-day SAPS II explained 11% of the variability in first-shift NEMS and 5%
      of the variability in first-shift TISS-28. CONCLUSIONS: This study confirms a
      good agreement between TISS-28 and NEMS in a large, independent sample. However,
      as shown by the differences between medical and postoperative/trauma patients, a
      change in case mix may result in different regression equations. Further, wide
      limits of agreement indicate that there may be a rather large variability between
      the two measures at the individual level.

PMID- 10416914
TI  - GM-CSF increases in vitro the respiratory burst of human neutrophils after liver
      transplantation.
AB  - OBJECTIVE: Superoxide production by polymorphonuclear neutrophils (PMNs) under
      cyclosporin A (CsA) therapy following kidney transplantation is impaired. We
      investigated if the respiratory burst of PMNs is similarly depressed in patients
      undergoing CsA treatment following orthotopic liver transplantation (OLTx).
      Additionally, the in vitro influence of granulocyte-macrophage colony-stimulating
      factor (GM-CSF) on the superoxide anion production was examined during the
      respiratory burst. PATIENTS: 10 patients after OLTx and 10 healthy blood donors
      (control group). MEASUREMENTS AND RESULTS: PMNs were stimulated with bacteria
      (Escherichia coli) or a combination of tumour necrosis factor alpha (TNFalpha)
      and N-formyl-methionyl-leucyl-phenylalanine (FMLP). The respiratory burst was
      measured by oxidation of non-fluorescent dihydrorhodamine to the fluorescent
      rhodamine by means of flow cytometry. No differences in respiratory bursts from
      OLTx patients compared to those from healthy blood donors could be seen. Under
      TNFalpha/FMLP stimulation, the respiratory burst was significantly increased
      after in vitro incubation with GM-CSF (500 U ml(-1)) in patients following OLTx
      (from 58.2 to 74.5 %) as well as in the control group (from 47.4 to 61.9%).
      CONCLUSIONS: Our results demonstrate that superoxide production is not impaired
      under CsA treatment following OLTx. The respiratory burst of these patients' PMNs
      can even be augmented by GM-CSF in vitro.

PMID- 10416915
TI  - The use of the antioxidant tirilazad mesylate in human liver transplantation: is
      there a therapeutic benefit?
AB  - OBJECTIVES: To test the hypothesis whether in patients undergoing liver
      transplantation the antioxidant tirilazad mesylate can reduce hepatic ischaemia
      reperfusion injury and improve postoperative outcome. DESIGN: Prospective,
      randomised, placebo controlled trial. SETTING: University hospital. PATIENTS: 20
      patients were randomised to receive either tirilazad mesylate or placebo
      (saline). INTERVENTIONS: Patients in the tirilazad group (n = 10) received four
      intravenous infusions of tirilazad at 6-h intervals (men 3 mg/kg, women 3.75
      mg/kg) after the induction of anaesthesia. The other patients (n = 10) served as
      controls. MEASUREMENTS AND RESULTS: Plasma levels of malonaldehyde (MDA) were
      determined after the induction of anaesthesia prior to the infusion of tirilazad
      (baseline), during the anhepatic period, and 5 min and 24 h after reperfusion.
      Postoperatively, alanine aminotransferase, aspartate aminotransferase,
      prothrombin time, and serum cholinesterase were determined daily for 1 week.
      Compared to baseline, plasma MDA levels did not significantly change during the
      anhepatic period and after reperfusion and they did not differ between groups.
      Postoperative liver enzymes and prothrombin time did not differ between groups,
      but on the first (p = 0.03) and second (p = 0.01) postoperative day
      cholinesterase levels were significantly higher in tirilazad-treated patients
      than in control patients. For neither length of stay in the intensive care unit
      nor hospital stay were any differences observed between groups. CONCLUSIONS: In
      patients undergoing liver transplantation, tirilazad does not improve overall
      outcome. Whether the higher cholinesterase levels on the first 2 postoperative
      days in tirilazad treated patients indicates an earlier recovery of liver
      function remains to be tested.

PMID- 10416916
TI  - IV milrinone for cardiac output increase and maintenance: comparison in
      nonhyperdynamic SIRS/sepsis and congestive heart failure.
AB  - OBJECTIVE: To characterize the effect of the phosphodiesterase inhibitor (PDEI)
      milrinone in adult patients with a non-hyperdynamic condition during the course
      of the systemic inflammatory response syndrome (SIRS) or sepsis when compared
      with patients with congestive heart failure (CHF). PDEIs are potent inhibitors of
      cytokine production and expression. We hypothesized that there might be an
      outstanding beneficial effect of PDEIs in the setting of SIRS/sepsis. DESIGN:
      Prospective, open labeled, protocol-driven pilot study. PATIENTS: Nine patients
      with a nonhyperdynamic hemodynamic condition during SIRS/sepsis (group 1) and
      seven patients with CHF (group 2) requiring inotropic support. All patients were
      having heart disease. All patients had a combination of various catecholamines at
      the time of inclusion in the study and had received fluid resuscitation to an
      extent that left ventricular stroke work index (LVSWI) did not increase further.
      INTERVENTION: Milrinone infusion at a rate of 0.5 microg/kg per min in addition
      to preexisting catecholamine therapy. MEASUREMENTS AND RESULTS: Measurements of
      cardiac index (CI; thermodilution) and calculation of vascular resistance and
      LVSWI was done every 8 h for at least 40 h during milrinone infusion. CI and
      LVSWI significantly increased in both groups (p < 0.001 and p = 0.006,
      respectively). There were no significant differences between groups in these
      parameters (p > 0.11 and p > 0.13, respectively). The LVSWI increase occurred
      while there was a decrease in pulmonary capillary wedge pressure, suggesting a
      true and comparable improvement in cardiac function relatively independent of
      loading conditions. Preexisting catecholamines had to be increased in both groups
      (NS). Milrinone had to be discontinued in one patient due to hypotension.
      CONCLUSION: Milrinone administration is feasible in selected patients with a non
      hyperdynamic condition during SIRS/sepsis and with preexisting heart disease.
      Under the conditions of this study, milrinone was no better in terms of CI and
      LVSWI maintenance in septic cardiac dysfunction when compared with CHF. These
      results do not necessarily extend to other cohorts with no preexisting heart
      disease.

PMID- 10416917
TI  - Fluid therapy directly interferes with immunoassay for cardiac troponin I.
AB  - OBJECTIVE: To investigate interference in cardiac troponin I (cTNI) immunoassay
      induced by some widely used loading fluids. SETTING: A biochemistry unit of a
      university hospital. MEASUREMENTS AND RESULTS: Human serum with a cTNI
      concentration of 0.32 microg/l was diluted at 10, 20, 40, and 80% with saline
      serum (SS), Plasmion (P) (a modified fluid gelatin), hydroxyethyl starch (HES),
      and 20% human albumin (Alb). Serum with a cTNI concentration of 1.29 microg/l was
      diluted at 20, 40, 60, and 80%. Four samples with increasing cTNI concentrations
      (from 0 to 8.14 microg/l) were diluted at 80% with the four fluids. Differences
      (delta-C) between expected concentrations resulting from the dilutional effect
      and those measured with the Access cTNI immunoassay were expressed in microg/l.
      Statistical analysis was performed using a nonparametric test. No false
      positivity was observed. At a low cTNI concentration (0.32 microg/l),
      interference was observed with SS and HES at 40 and 80% dilution and with P and
      Alb at 80%. When cTNI was 1.29 microg/l, interference was observed with each
      fluid at a dilution of 20% and increased with the increase in dilution. The
      highest interference was observed with HES, the lowest with P. When the dilution
      was at 80% for increasing concentrations of cTNI, the higher the initial cTNI was
      the higher the interference appeared, mostly with SS and HES. CONCLUSIONS: SS, P,
      Alb, and HES interfere in this cTNI immunoassay. This interference is higher with
      SS and HES and is higher when the percentage of hemodilution or real cTNI
      concentration increases.

PMID- 10416918
TI  - Emphysematous pyelonephritis related to specific gas-forming Escherichia coli
      without diabetes mellitus.
AB  - A 60-year-old-man without a history of diabetes mellitus, or invasive
      manipulation or obstruction of the urinary tract was admitted for septic shock.
      Type I emphysematous pyelonephritis was clear in this case: gas within the renal
      parenchyma extending into the subcapsular region and the perirenal space was
      present on spiral computerised tomography (CT). Surgical nephrectomy was
      performed because biochemistry, urography and CT identified a damaged non
      functioning left kidney. The outcome was favourable. All urine, blood and
      nephrectomy specimen cultures were positive for a specific Escherichia coli which
      produced a high level of gas compared to a reference E. coli strain in the same
      standard medium, despite the absence of diabetes mellitus. Certain strains of
      bacteria are able to produce high levels of nitrogen, carbon dioxide and hydrogen
      and such fermentation in the absence of a high glucose serum level might explain
      the acute gas-producing bacterial renal infection.

PMID- 10416919
TI  - Immunonutrition in the critically ill.

PMID- 10416920
TI  - Sedation for the critically ill.

PMID- 10416921
TI  - The necessity of performing transesophageal echocardiography in patients with
      acute respiratory distress syndrome.

PMID- 10416922
TI  - Severe hypoxemia and pulmonary hypertension during orthotopic liver
      transplantation: a successful use of inhaled nitric oxide.

PMID- 10416923
TI  - Repeat percutaneous tracheostomy with the Ciaglia technique after translaryngeal
      tracheostomy.

PMID- 10416924
TI  - Acute reversible neurological and renal failure following acyclovir treatment.

PMID- 10416925
TI  - Survival after massive "ecstasy" (MDMA) ingestion.

PMID- 10416926
TI  - Neuromuscular disorders acquired in the ICU.

PMID- 10416927
TI  - Toward controlling myopia progression?

PMID- 10416928
TI  - Progression of myopia in Hong Kong Chinese schoolchildren is slowed by wearing
      progressive lenses.
AB  - PURPOSE: In Chinese societies, primary and secondary schoolchildren perform large
      amounts of reading and homework and thus spend long periods performing near work
      during their growth years. Progressive lenses, which can permit a focused retinal
      image at distance, intermediate, and near, without accommodation, may slow the
      development of myopia. This paper reports results of a 2-year longitudinal study
      to examine the effects of progressive lenses on myopia progression in myopic
      Chinese children; these children were aged between 9 and 12 years at the
      beginning of the study. METHODS: Prestudy vision screening tests and five
      examinations, which included noncycloplegic refraction, were conducted at half
      yearly intervals. Of those who completed the study, 32 children wore single
      vision (SV) lenses (the SV group) and 36 wore progressive lenses; of the latter,
      22 wore a +1.50 D addition (the P1 group) and 14 wore a +2.00 D addition (the P2
      group). Refractive error, corneal curvature, axial length, vitreous depth, and
      intraocular pressure were measured at every examination. Height was measured as
      an index of general growth. RESULTS: Progressive lenses significantly retarded
      the progression of the myopia in these children. Initially, the mean refractive
      error of the SV group was -3.67 D, of the P1 group was -3.73 D, and of the P2
      group was -3.67 D. The mean myopic progressions over the 2 years of the study
      were -1.23, -0.76, and -0.66 D for the SV, P1, and P2 groups, respectively.
      CONCLUSION: Progressive lenses reduce the progression of myopia. It may be that
      the interaction of the progressive lenses with the accommodation system is the
      cause of this reduction in myopia progression because the +2.00 D addition
      appeared more effective than the +1.50 D addition in slowing the progression.

PMID- 10416929
TI  - Distance, lighting, and parental beliefs: understanding near work in
      epidemiologic studies of myopia.
AB  - PURPOSE: To develop measures and indices of factors (distance of eye from object,
      posture, and lighting) that may modify a possible effect of near work activity on
      myopia. METHODS: The duration of near work, the distance of an object from eye,
      lighting conditions, and other sociodemographic characteristics were asked in an
      interview. Both distance and lighting information from the questionnaire were
      compared with more precise measurements. RESULTS: Diopter hours were quantified
      as the duration of near work multiplied by the reciprocal of the distance which
      the activity was performed. The intraclass correlation coefficient of the
      reliability of distance information for each type of near work activity ranged
      from 0.43 to 0.91. Home light meter readings were significantly higher for
      children who were reading under both room and reading light, and the distances
      from the questionnaire were comparable to the measured distances. CONCLUSIONS:
      Measures of posture, distance, and lighting factors have been developed to study
      the possible effect modifiers of the effects of near work on myopia.

PMID- 10416930
TI  - Effects of spectacle intervention on the progression of myopia in children.
AB  - The literature on myopigenesis suggests an active emmetropization mechanism
      regulated by optical defocus. The strongest evidence comes from compensatory
      ocular growth in response to lens-induced defocus in different species of
      animals. Based on these results, it has been suggested that, however useful,
      spectacle intervention for the optical correction of human myopia would lead to
      its exacerbation. The present study seeks to evaluate the progression of juvenile
      onset myopia in children differentiated by their lens wear patterns. Data from 43
      myopes from our longitudinal study of refraction were evaluated, with myopia
      defined as a spherical equivalent of at least -0.50 D. Refractions were obtained
      in the laboratory by noncycloplegic retinoscopy performed by one experienced
      optometrist at regular intervals. Information regarding the subjects'
      prescription lens-wearing history was obtained from the subjects and their eye
      care providers. Based on their wearing patterns, subjects were divided into four
      categories: (1) full-time wearers; (2) myopes who switched from distance to full
      time wear; (3) distance wearers; and (4) nonwearers. Exponential functions were
      fit to the individual refraction data. The age of onset of myopia, the mean
      myopia at onset of spectacle wear, and the refractive shift over a period of at
      least 3 years were derived from these fits. Results show that the 3-year
      refractive shifts are not significantly different among the four groups. A
      comparison of the extreme conditions, i.e., full-time vs. nonwear categories,
      also revealed no significant difference when the data were corrected for age
      effects despite the fact that the nonwearers exhibited an age-adjusted 3-year
      progression approximately one-half that of the full-time wearers. In summary, the
      present study failed to demonstrate any overall effects of spectacle intervention
      on the progression of human myopia. Further investigation using a larger sample
      is warranted.

PMID- 10416931
TI  - A 2-year longitudinal study of myopia progression and optical component changes
      among Hong Kong schoolchildren.
AB  - This study investigated refractive error and optical component changes in a group
      of 142 Hong Kong schoolchildren from age 6 to 17 years over a 2-year period
      between 1991 and 1993. Subjects were refracted subjectively and corneal
      curvatures and ocular dimensions were measured. At the end of the 2-year study,
      the mean spherical equivalent refraction (SER) was -1.86 D (SD 1.99 D) and 62% of
      the schoolchildren were myopic. The annual incidence of myopia was 11.8%.
      Children aged 10 years and under had a greater change in SER toward myopia than
      older children. The annual rate of myopia progression for the myopic children was
      -0.46 D (SD 0.40 D) and the rate of progression was greatest between age 6 and 10
      years old. Vitreous depth/axial length elongation was the main component
      contributing to the progression of myopia. Hong Kong schoolchildren develop
      myopia as early as 6 years old and myopia progresses at a greater rate compared
      with children of European extraction.

PMID- 10416932
TI  - Role of genetic factors in the etiology of juvenile-onset myopia based on a
      longitudinal study of refractive error.
AB  - In an attempt to determine the role of genetic factors in the development of
      myopia, we examined the relationship of infantile refractive error and parental
      history to juvenile-onset myopia and analyzed 43 pedigrees affected by juvenile
      onset myopia. Refraction data collected at regular intervals from a sample of
      juvenile subjects participating in a 24-year longitudinal study of refractive
      error were used. Results showed that children with two myopic parents were 6.42
      times as likely to become myopic as children with one or no myopic parents.
      Furthermore, children who had refractions in the lower half of the distribution
      at 6 to 12 months of age were 4.33 times as likely to develop myopia as children
      who had refractions in the upper half of the distribution at 6 to 12 months of
      age. The pedigree analysis indicated that 63% of individuals considered at risk
      for developing juvenile-onset myopia actually became myopic, with an equal number
      of affected males and females. These results suggest that juvenile-onset myopia
      of moderate amounts may be inherited as a complex trait involving both genetic
      and environmental factors.

PMID- 10416933
TI  - The effect of having myopic parents: an analysis of myopia in three generations.
AB  - PURPOSE: The etiology of myopia has been attributed to both genetic and
      environmental factors. The purpose of this paper is to attempt to distinguish
      between genetic and environmental factors in three generations of subjects from
      three locations. METHODS: Noncycloplegic autorefraction and distance visual
      acuity were measured in 3131 Chinese children 7 to 17 years old from Hong Kong,
      Tianjin, and Ban Chau. Data on the refractive status of the parents and
      grandparents were collected using questionnaires. Myopia was defined
      operationally as spherical equivalent refractive error (SER) of at least -1.00 D
      and uncorrected vision worse than logMAR 0.18 (6/9). RESULTS: The odds of having
      myopia for the grandparents', parents', and children's generations were 0.06,
      0.26, and 0.35, respectively. Having myopic parents increased the odds ratio for
      having myopia (odds ratio 1.85 for children's generation and 6.71 for parents'
      generation), showing a genetic influence. However, the odds of having myopia also
      increased in offspring of nonmyopic parents between generation 2 and 3,
      suggesting an environmental influence. Results of prevalence and odds ratios from
      the three locations also demonstrated an environmental effect on development of
      myopia. CONCLUSION: We propose that myopic development in Chinese follows a
      multifactorial and polygenic model in which the genetic input has remained
      constant while the environmental influence has increased over the last three
      generations.

PMID- 10416934
TI  - Relation between work and myopia in Singapore women.
AB  - BACKGROUND: Work and related activities may be connected to myopia development
      and progression. We investigated the relationship between working activities and
      the onset as well as worsening of myopia. METHODS: Information on the working
      status of the mothers of 374 children, the number of hours of close-up work
      activity, and whether the mother was short-sighted, was obtained by a face-to
      face interview. In addition, a subsample of 84 mothers was interviewed over the
      telephone and asked whether the myopia occurred in adulthood and, if so, the age
      of cessation of myopia. RESULTS: The adjusted odds ratio for myopia in working
      women was 1.9 [95% confidence interval (CI) 1.2 to 3.2] and the adjusted odds
      ratio for high myopia (> -6.0 D) was 1.6 (95% CI 0.8 to 3.0). Women who were
      working also had higher rates of adult-onset myopia, odds ratio 4.4 (95% CI 0.9
      to 21.2), and a later age of cessation of myopia than nonworking women.
      CONCLUSIONS: In our study, work was related to myopia in Singapore women. Work
      may be a surrogate for another risk factor, close-up work activities such as
      reading, writing, and computer use.

PMID- 10416935
TI  - Effects of muscarinic cholinergic receptor antagonists on postnatal eye growth of
      rhesus monkeys.
AB  - PURPOSE: To study a potential role for muscarinic receptors in the inhibition of
      deprivation-induced excessive axial elongation and myopia in a monkey model.
      METHODS: The right eyes of 20 newborn rhesus monkeys were occluded with a black
      contact lens. In seven monkeys each, either atropine or pirenzepine was topically
      applied daily to the occluded eyes. The nonoccluded fellow eyes and both the
      occluded and nonoccluded fellow eyes of another six monkeys were treated with
      vehicle solution. RESULTS: After 33 to 39 weeks, in 5 monkeys of the vehicle
      group, occluded eyes were longer and the myopic shift significantly greater than
      in the nonoccluded fellow eyes. In six atropine-treated monkeys, axial length and
      reduction of the initial hyperopia of occluded and nonoccluded fellow eyes were
      not different statistically. The myopic shift of the occluded eyes was
      significantly smaller than in the vehicle-treated occluded eyes. In the
      pirenzepine-treated group, axial length of the occluded eyes was similar to the
      nonoccluded eyes of controls and the occluded eyes of atropine-treated monkeys.
      There was a trend of pirenzepine to reduce the myopic shift of the occluded eye.
      No effect of atropine or pirenzepine was noted on muscarinic receptor density in
      retina, brain, or heart, but a small increase was observed in iris + ciliary
      body. CONCLUSIONS: The drug treatment results implicate muscarinic receptors in
      postnatal eye growth regulation. Because of interanimal differences our data do
      not indicate whether nonselective or selective muscarinic blockade is more
      effective in reducing deprivation-induced myopia.

PMID- 10416936
TI  - Mouse models for the analysis of myopia: an analysis of variation in eye size of
      adult mice.
AB  - PURPOSE: To assess the relative importance of genetic and environmental factors
      that modulate eye growth, eyes, lenses, and retinas of 507 mice belonging to 50
      strains were measured. METHODS: Mice of both sexes and a wide range of ages (27
      to 526 days) were perfused for electron microscopy and eyes, lenses, and retinas
      were dissected and measured. Our uniform fixation protocol was shown to cause a
      weight loss of 4 to 6%. Multiple linear regression methods were used to explore
      relations between eye and lens weight, retinal area, age, sex, body and brain
      weight, and retinal ganglion cell number. RESULTS: The eye and lens of mice
      continue to grow long after sexual maturity is reached at 40 to 60 days of age.
      The pace of growth matches the logarithm of age. Despite their smaller bodies,
      females have eyes as large as those of males. The correlation of eye weight to
      brain weight is remarkably low (r = 0.19), whereas that to retinal area is high
      (r = 0.86). Surprisingly, the correlation between lens weight and the size of the
      posterior segment (eye minus lens weight) is only 0.5 to 0.6, and ratios of these
      parameters are highly variable. Heritability of all traits is between 25 to 50%.
      CONCLUSIONS: The continued growth of eyes in adult mice provides an excellent
      system to test effects of genetic and molecular manipulations on the development
      and treatment of myopia. Heritability is sufficiently high to map genes that
      specifically modulate growth of different parts of the eye.

PMID- 10416937
TI  - Optical correction of induced axial myopia in the tree shrew: implications for
      emmetropization.
AB  - PURPOSE: To determine whether an active emmetropization mechanism is involved in
      the recovery from axial myopia through the use of a mammalian model of refractive
      development. Specifically, we sought to establish whether the emmetropization
      mechanism is visually guided by the level of clarity of the image falling on the
      retina, or if recovery is driven by a mechanism sensitive to abnormal eye shape.
      METHODS: Young tree shrews had axial myopia induced by monocular deprivation (MD)
      of pattern vision and then the myopic eye was either: (1) accurately corrected
      with a negative lens or (2) had a zero-powered lens placed in front of it. Their
      emmetropization response was monitored, both through the use of ocular refractive
      and biometric measures, as well as through the assessment of scleral dry weight
      and glycosaminoglycan synthesis, as indicators of scleral metabolism. RESULTS:
      Corrective lenses prevented recovery from induced myopia (-6.8 +/- 0.7 D after 5
      days MD vs. -6.6 +/- 0.6 D after 5 days of lens wear), whereas animals fitted
      with zero-powered lenses displayed near full recovery from the induced myopia (
      6.6 +/- 0.6 D vs. -1.7 +/- 0.3 D). Significant reductions in scleral dry weight (
      4.6 +/- 1.3%) and glycosaminoglycan synthesis (-28.6 +/- 7.3%) were found in the
      posterior sclera of animals wearing corrective lenses. Conversely, animals
      wearing zero-powered lenses displayed elevated levels of glycosaminoglycan
      synthesis (+62.3 +/- 11.1%) in conjunction with scleral dry weights that did not
      differ significantly between treated and fellow control eyes (-1.5 +/- 2.6%).
      CONCLUSIONS: Accurate correction of induced axial myopia prevents the refractive,
      biometric and scleral metabolic responses that are normally observed in tree
      shrew eyes recovering from induced myopia. These findings support the hypothesis
      that recovery is driven by an active emmetropization response dependent on the
      clarity of image falling on the retina and not by a mechanism that is sensitive
      to abnormal eye shape.

PMID- 10416938
TI  - Form deprivation myopia in adolescent monkeys.
AB  - BACKGROUND: Early in life, at ages corresponding to the rapid infantile phase of
      ocular growth in humans, visual feedback can modulate refractive development in
      monkeys and many other species. To determine if vision-dependent mechanisms can
      still influence refractive development in primates during the slow juvenile phase
      of ocular growth, the time period when myopia typically develops in human
      children, we examined the effects of form deprivation on adolescent monkeys.
      METHODS: Unilateral, form deprivation was produced in four rhesus monkeys by
      surgically fusing the eyelids of one eye. The onset of deprivation was between
      3.7 and 5 years of age, which corresponds to onset ages between approximately 15
      and 20 human years. The ocular effects of form deprivation were assessed by
      cycloplegic retinoscopy and A-scan ultrasonography. RESULTS: At the onset of form
      deprivation all four monkeys were isometropic and the axial dimensions in the two
      eyes were well matched. After 71 to 80 weeks of form deprivation, all of the
      deprived eyes had become relatively more myopic than their fellow non-treated
      eyes (mean anisometropia = -2.03 +/- 0.78 D) and they exhibited relative
      increases in vitreous chamber depth (mean = 0.55 +/- 0.31 mm) and axial length
      (mean = 0.49 +/- 0.35 mm). DISCUSSION: Our results demonstrate that vision
      dependent mechanisms can influence ocular growth and refractive development in
      "teenage" monkeys. These results raise the possibility that visual experience may
      be involved in the genesis of school-age myopia in children.

PMID- 10416939
TI  - Cognition, emotion and the brain: a different view.
AB  - This article contradicts the current paradigm of a brain which receives,
      processes, represents and stores information about objects and events. It
      considers the brain as an activating mechanism which is triggered by combinations
      and sequences of stimuli, modulates the intensities of neuronal arousals and
      relays them to particular combinations of organic effectors. Cognitive and
      affective events are created and expressed by the combinations and sequences of
      motor and autonomic effector arousals. The apperception of phenomena emerges by
      the integration of cognition, which is basically the expression of proprioceptive
      activities, with feelings, which are the expression of some autonomic system's
      activities. The cognitive and the affective abilities and expressions are
      distorted or abolished, if deprived of this integration. Thus, the article
      proposes an efferent attitude toward the 'psycho'-physiological process and a
      realistic attitude toward the brain's task.

PMID- 10416940
TI  - Important role of the kidney in human carbohydrate metabolism.
AB  - Recent studies using a combination of isotope and balance techniques have shown
      that, in the postabsorptive state, the human kidney contributes substantially to
      overall glucose production and consumption. The kidney may contribute as much as
      the liver to gluconeogenesis and play an important role in the counterregulation
      of hypoglycemia. Furthermore, increased renal glucose production may contribute
      to fasting hyperglycemia found in type I and type II diabetes mellitus. Finally,
      loss of renal tissue as a consumer of glucose could explain the insulin
      resistance of uremia. We hypothesize that the human kidney may play a more
      important role in human carbohydrate metabolism than previously appreciated.

PMID- 10416941
TI  - Carcinogenesis and the plasma membrane.
AB  - Presented is a two-stage hypothesis of carcinogenesis based on: (1) plasma
      membrane defects that produce abnormal electron and proton efflux; and (2)
      electrical uncoupling of cells through loss of intercellular communication. These
      changes can be induced by a wide variety of stimuli including chemical
      carcinogens, oncoviruses, inherited and/or acquired genetic defects, and
      epigenetic abnormalities. The resulting loss of electron/proton homeostasis leads
      to decreased transmembrane potential, electrical microenvironment alterations,
      decreased extracellular pH, and increased intracellular pH. This produces a
      positive feedback loop to enhance and sustain the proton/electron efflux and loss
      of intercellular communication. Low transmembrane potential is functionally
      related to rapid cell cycling, changes in membrane structure, and malignancy.
      Intracellular alkalinization affects a variety of pH-sensitive systems including
      glycolysis, DNA synthesis, DNA transcription and DNA repair, and promotes genetic
      instability, accounting for the accumulation of genetic defects seen in
      malignancy. The abnormal microenvironment results in the selective survival and
      proliferation of malignant cells at the expense of contiguous normal cell
      populations.

PMID- 10416942
TI  - Abortive apoptosis as an initiator of chromosomal translocations.
AB  - Apoptosis is a well-recognized regulator of a cell populations size and
      structure. Irreversible stages of apoptosis lead to activation of different
      enzymatic cascades, changes in cell morphology and DNA fragmentation. However,
      little is known about nuclear events which accompany the initial stages of
      apoptosis. These events are connected with introduction of limited amounts of
      double strand breaks into genomic DNA, some of which may be subsequently
      rejoined. We hypothesize here that the initial stages of apoptotic DNA
      fragmentation may be reversible and connected with the initiation of
      recombinational events and certain chromosomal translocations. The factors
      influencing apoptosis reversibility and cell survival after delivery of apoptotic
      stimuli may provide new insights into mechanisms of lymphocyte development and
      tumorigenesis.

PMID- 10416943
TI  - Neurodegeneration in ataxia-telangiectasia is caused by horror autotoxicus.
AB  - Ataxia-telangiectasia (A-T) is a pleiotropic, multi-system disorder with
      manifestations that include immune deficiency, sensitivity to ionizing radiation
      and neoplasms. Many of these manifestations are understood in principle since the
      identification in A-T patients of mutations in a gene encoding a protein kinase
      that plays a key role in signaling and repair of DNA damage. However, the cause
      of the neurodegeneration that afflicts patients with A-T for at least a decade
      before they succumb to overwhelming infections or malignancy remains mysterious.
      Based on our work in a mouse model of A-T and previous evidence of extra-neural
      autoimmune disorders in A-T, we postulate that the neurodegenerative process in A
      T is not due to a function for A-T mutated (ATM) essential for the postnatal
      brain, but to an autoimmune process (hence 'horror autotoxicus', Paul Ehrlich's
      term for autoimmune disorder). This hypothetical mechanism may be analogous to
      that in the so-called 'paraneoplastic' neurodegenerative syndromes in patients
      with various malignancies. Thus, alterations in the balance between cellular and
      humoral immunity in A-T probably result in autoantibodies to cerebral epitopes
      shared with cells of the immune system. This hypothesis has important
      implications for the understanding and development of effective palliative and
      even preventative strategies for A-T, and probably for other so far relentlessly
      progressive neurodegenerative disorders.

PMID- 10416944
TI  - Selective modification of sterol composition of hepatomas: new opportunities for
      chemotherapy.
AB  - The absence of feedback regulation of cholesterol biosynthesis in hepatomas
      suggests the possibility of substitution of cholesterol with its biosynthetic
      precursors (7-dehydrocholesterol or lanosterol) selectively in hepatomas without
      the accumulation of these precursors in liver and other normal tissues, by a
      combination of a high cholesterol diet and specific inhibitors of cholesterol
      biosynthesis (AY-9944 for accumulation of 7-dehydrocholesterol and ketoconazole
      for accumulation of lanosterol). We suggest: (1) using a selective accumulation
      of 7-dehydrocholesterol in hepatoma plasma membranes to increase the sensitivity
      of hepatoma cells to polyene antibiotics (amphotericin B, nystatin), because
      polyene antibiotics have higher affinity to 7-dehydrocholesterol compared to
      cholesterol; (2) using a selective accumulation of lanosterol in hepatoma cells
      to increase the sensitivity of hepatoma cells to different antitumor agents,
      because lanosterol is much less effective in supporting vital cell functions
      (including barrier properties of natural membranes) compared to cholesterol.

PMID- 10416945
TI  - Incinerator toxic emissions: a brief summary of human health effects with a note
      on regulatory control.
AB  - Toxic emissions from municipal solid waste (MSW) and hazardous waste incineration
      are discussed, with reference to recent reviews and to government standards and
      controls. Studies of known effects of aromatic hydrocarbons, other organics,
      dioxins, metals, and gases, on fish, soils, plants, and particularly humans are
      briefly reviewed. A summary of potential problems with existing and proposed
      incineration is developed, including: (1) lack of toxicity data on unidentified
      organic emissions; (2) unavoidability of hazardous metal emissions as particles
      and volatiles; (3) inefficient stack operation resulting in unknown amounts of
      increased emissions; (4) formation in the stack of highly toxic dioxins and
      furans, especially under inefficient conditions, and their build-up in the
      environment and in human tissue; (5) the lack of adequate disposal techniques for
      incinerator fly ash and wash-water; (6) the contribution of emitted gases such as
      NO2, SO2 and HCL to smog, acid rain, and the formation of ozone, and the
      deleterious effects of these on human respiratory systems; (7) the effects and
      build-up in human tissue of other emitted organics such as benzene, toluene,
      polychlorinated biphenyls (PCBs), alkanes, alcohols, and phenols; (8) lack of
      pollution-control and real-time efficiency-monitoring equipment in existing
      installations. The inability of regulatory bodies historically to ensure
      compliance with emission standards is discussed, and a concluding opinion is
      offered that it is inadvisable to engage in new incinerator construction with
      present knowledge and conditions.

PMID- 10416947
TI  - High-dose biotin, an inducer of glucokinase expression, may synergize with
      chromium picolinate to enable a definitive nutritional therapy for type II
      diabetes.
AB  - Glucokinase (GK), expressed in hepatocyte and pancreatic beta cells, has a
      central regulatory role in glucose metabolism. Efficient GK activity is required
      for normal glucose-stimulated insulin secretion, postprandial hepatic glucose
      uptake, and the appropriate suppression of hepatic glucose output and
      gluconeogenesis by elevated plasma glucose. Hepatic GK activity is subnormal in
      diabetes, and GK may also be decreased in the beta cells of type II diabetics. In
      supraphysiological concentrations, biotin promotes the transcription and
      translation of the GK gene in hepatocytes; this effect appears to be mediated by
      activation of soluble guanylate cyclase. More recent evidence indicates that
      biotin likewise increases GK activity in islet cells. On the other hand, high
      dose biotin suppresses hepatocyte transcription of phosphoenolpyruvate
      carboxykinase, the rate-limiting enzyme for gluconeogenesis. Administration of
      high-dose biotin has improved glycemic control in several diabetic animals
      models, and a recent Japanese clinical study concludes that biotin (3 mg t.i.d.
      orally) can substantially lower fasting glucose in type II diabetics, without
      side-effects. The recently demonstrated utility of chromium picolinate in type II
      diabetes appears to reflect improved peripheral insulin sensitivity--a parameter
      which is unlikely to be directly influenced by biotin. Thus, the joint
      administration of supranutritional doses of biotin and chromium picolinate is
      likely to combat insulin resistance, improve beta-cell function, enhance
      postprandial glucose uptake by both liver and skeletal muscle, and inhibit
      excessive hepatic glucose production. Conceivably, this safe, convenient,
      nutritional regimen will constitute a definitive therapy for many type II
      diabetics, and may likewise be useful in the prevention and management of
      gestational diabetes. Biotin should also aid glycemic control in type I patients.

PMID- 10416946
TI  - Can correction of sub-optimal coenzyme Q status improve beta-cell function in
      type II diabetics?
AB  - A stimulus to mitochondrial respiratory activity is a crucial component of the
      signal transduction mechanism whereby increased plasma glucose evokes insulin
      secretion by beta-cells. Efficient function of the glycerol-3-phosphate shuttle
      is important in this regard, and the rate-limiting enzyme in this shuttle--the
      mitochondrial glycerol-3-phosphate dehydrogenase (G3PD)--is underexpressed in the
      beta cells of human type II diabetics as well of rodents that are models for this
      disorder. Suboptimal tissue levels of coenzyme Q10 (CoQ) could be expected to
      further impair G3PD activity. Clinical reports from Japan suggest that
      supplemental CoQ may often improve beta-cell function and glycemic control in
      type II diabetics. Thus, it is proposed that correction of suboptimal CoQ status,
      by aiding the efficiency of G3PD and of respiratory chain function, will improve
      the glucose-stimulated insulin secretion of diabetic beta-cells.

PMID- 10416948
TI  - Pyruvate and hydroxycitrate/carnitine may synergize to promote reverse electron
      transport in hepatocyte mitochondria, effectively 'uncoupling' the oxidation of
      fatty acids.
AB  - In a recent pilot study, joint administration of pyruvate, hydroxycitrate (HCA),
      and carnitine to obese subjects was associated with a remarkable rate of body-fat
      loss and thermogenesis, strongly suggestive of uncoupled fatty-acid oxidation.
      Hepatocytes possess an uncoupling mechanism--reverse electron transport--that
      enables fasting ketogenesis to proceed independent of respiratory control.
      Electrons entering the respiratory chain at the coenzyme Q (CoQ) level via FAD
      dependent acyl coA dehydrogenase, can be driven 'up' the chain by the
      electrochemical proton gradient to reduce NAD+; if these electrons are then
      shuttled to the cytoplasm, returning to the respiratory chain at the CoQ level,
      the net result is heat generation at the expense of the proton gradient, enabling
      the uncoupled flow of electrons to oxygen. Pyruvate's bariatric utility may stem
      from its ability to catalyze the rapid transport of high-energy electrons from
      mitochondria to the cytoplasm, thus stimulating electron shuttle mechanisms. By
      enabling rapid mitochondrial uptake of fatty acids and thus disinhibiting
      hepatocyte ketogenesis, HCA/carnitine should initiate reverse electron transport:
      concurrent amplification of electron shuttle mechanisms by pyruvate can be
      expected to accelerate this reverse electron transport, thereby decreasing the
      electrochemical proton gradient. As a result, hepatocytes may be able to convert
      fatty acids to CO2 and heat with little net generation of ATP. These
      considerations suggest that it may be feasible to render hepatocytes functionally
      equivalent to activated brown fat, such that stored fat can be selectively
      oxidized in the absence of caloric restriction. Other measures which enhance the
      efficiency of hepatocyte electron shuttle mechanisms may increase the efficacy of
      this strategy.

PMID- 10416949
TI  - Toward a new definition of essential nutrients: is it now time for a third
      'vitamin' paradigm?
AB  - The concepts of vitamin 'deficiency' diseases and the recommended dietary
      allowances (RDAs) have not kept pace with the growing understanding of the
      cellular and molecular functions of vitamins and other micronutrients. As a
      consequence, many researchers and clinicians rely on outdated signs and symptoms
      in assessing nutritional deficiencies. A new paradigm, presented here, proposes
      that: (1) deficiencies can be identified on biochemical and molecular levels long
      before they become clinically visible; (2) the definition of essential
      micronutrients be broadened to include some carotenoids and flavonoids, as well
      as various human metabolites, such as coenzyme Q10, carnitine, and alpha-lipoic
      acid, which are also dietary constituents; (4) individual nutritional
      requirements are partly fixed by genetics but also dynamically influenced by
      variations in the body's biochemical milieu and external stresses; and (5) the
      distinction between nutritional and pharmacological doses of vitamins is
      meaningless, since high doses of micronutrients may be required to achieve normal
      metabolic processes in some people.

PMID- 10416951
TI  - Control and autoregulation of the blood circulation in the vertebrobasilar
      system.
AB  - The author establishes an analogy between the control mechanism and
      autoregulation of the cerebral blood flow and the protection of the vascular wall
      of the internal carotid artery constituted by the conjunction of the 'internal
      carotid-cavernous sinus' system with the 'vertebrobasilar-transverse-occipital
      dural sinus or basilar' 'sinus' system (an extension of the cavernous sinus) in
      the autoregulation and control of the encephalic circulation carried out through
      this latter vessel, together with the protection of its vascular walls. The
      author believes it to be very difficult to demonstrate in practice the
      functioning of these mechanisms, but he argues that the unusual anatomical
      features of the systems are indicative of their particular physiological roles.

PMID- 10416950
TI  - Diabetes and enterovirus autoimmunity in glacial Europe.
AB  - The incidence of insulin-dependent diabetes mellitus (IDDM), a chronic disease
      with a well-known genetic basis, is highest in Scandinavian and Sardinian
      populations. The high incidence of IDDM in Scandinavia and Sardinia, which were
      genetically isolated from the spread of agriculturists in Europe about 8000 years
      ago, suggests that an IDDM-susceptible genotype(s) may have been beneficial in
      Europe more than 8000 years ago. In glacial times, Europe had an extremely cold
      climate that was frequently interrupted by episodes of warming. When
      enteroviruses were locked in the ice and permafrost, glacial Europeans would have
      had little immunity to these viruses. Each time the climate warmed, enteroviruses
      would have spread through increased amounts of melt water. With a genetic ability
      to mount an autoimmune defense, the IDDM genotype(s) would have been beneficial
      in glacial Europe as a defense against all enteroviruses, including those that
      had co-evolved to mimic host tissue.

PMID- 10416952
TI  - The handshaking model of brain function: notes toward a theory.
AB  - John Hughlings Jackson described the system-level organization of the nervous
      system in terms of functional-control relations between neural centers. His model
      emphasized hierarchical organization along a rostral-caudal dimension, with
      applications primarily to cases of clinical disorders such as epilepsy and motor
      paralysis. This paper outlines a new systems-level model of brain function,
      updating Jackson's original idea to account for all three orientations of
      body/brain organization, and additional, non-hierarchical types of relations. The
      approach may provide a powerful tool for addressing many aspects of human brain
      and behavior, ranging from normal characteristics (such as individual differences
      and gender differences), to cases of frank neurological injury, to other
      conditions, such as hyperactivity and chronic pain, conventionally considered as
      'neurologically silent'.

PMID- 10416953
TI  - Wisdom of the body.
AB  - Modern medicine still fails to explain processes that operate in self-healing
      diseases. We may thus distinguish between two kinds of processes that operate in
      the body: explained and unexplained. The latter operate in self-healing diseases,
      and are either ignored by medicine or called placebos. Hippocrates regarded such
      processes as the healing force of nature and the task of the physician was to
      assist the healing force. The unexplained processes in physiology were defined by
      Starling and Cannon as Wisdom of the Body (WOB). This concept is applied here for
      a rational treatment of processes involved in health and in disease. WOB is an
      attribute of live organisms. It directs growing plants toward sunshine, guides
      amebas away from noxious agents, and determines the behavior of higher animals.
      It is essential for individual survival and was molded by natural selection.
      During evolution, WOB encountered all diseases, knows how to heal itself, and
      anticipates all diseases. The main task of the WOB is to maintain health, and
      improve its quality. It controls processes in the body so as to make them
      healthier. The WOB has its own language and should be considered when examining
      patients.

PMID- 10416954
TI  - Free radicals and reactive oxygen species in programmed cell death.
AB  - Oxidative stress, originating from reactive oxygen species and free radicals
      provides a constant challenge to eukaryotic cell survival. While implicated in a
      number of degenerative diseases, some associated with aging and with aging
      itself, the manner and extent to which oxidative stress contributes to the
      initiation or implementation of programmed-cell death is problematic. If
      oxidative stress is an important modulator of programmed-cell death, any ability
      intentionally to augment or inhibit it might ameliorate diseases in which the
      process is abnormally underactive or overactive.

PMID- 10416955
TI  - Interleukin-6 as a central mediator of cardiovascular risk associated with
      chronic inflammation, smoking, diabetes, and visceral obesity: down-regulation
      with essential fatty acids, ethanol and pentoxifylline.
AB  - Increased plasma levels of fibrinogen and C-reactive protein (CRP), as well as
      leukocytosis, are now established as risk factors for the thromboembolic
      complications of vascular disease. Chronic inflammation or infection associated
      with an acute-phase response--notably, periodontal disease and smoking-induced
      lung damage--are likewise known to increase cardiovascular risk. A common
      etiologic factor in these conditions may be interleukin-6 (IL-6), acting on
      hepatocytes to induce acute-phase reactants that increase blood viscosity and
      promote thrombus formation. Recent evidence that hypertrophied adipocytes release
      IL-6, and that hyperglycemia evokes IL-6 production by endothelium, may explain
      why plasma fibrinogen is increased in visceral obesity and poorly controlled
      diabetes. IL-6 is released by a range of tissues in response to stimulation by
      the monocyte-derived cytokines interleukin-1 and tumor necrosis factor; by
      suppressing production of these cytokines, fish oil, alpha-linolenic acid, and
      pentoxifylline can reduce IL-6 synthesis. Moderate ethanol consumption, as well
      as sex-hormone replacement, also appear to inhibit IL-6 production or activity.
      These practical protective measures may be of particular value to patients with
      pre-existing atheroma and elevated plasma levels of acute-phase reactants. Since
      IL-6 plays a crucial physiological role in osteoclast generation and activation,
      these measures may also aid preservation of bone density.

PMID- 10416956
TI  - Flavonoids and tannins: plant-based antioxidants with vitamin character.
AB  - Persistent activation of the neuroendocrine stress axis is the major cause of a
      continuous catabolic alteration of the metabolism. This often causes an oxidative
      stress situation with increased release of O2 and NO radicals and pro
      inflammatory cytokines. For the correction of these metabolic states, an adequate
      supply of plant-based antioxidants, especially flavonoids and tannins, is
      indicated. These are plant-based polyphenols which, like vitamins cannot be
      synthesized by the animal organism. Vitamin E in combination with vitamin C and
      beta-carotene are currently considered worldwide as the standard antioxidative
      therapy. However, it has recently been shown that, depending on the iron status
      of the recipient, pharmacological doses of these vitamins sometimes have
      beneficial, but often also no effect or harmful effects, so that, for a more
      reliable antoxidative action, adequate dietary supply of a mixture of flavonoids
      and tannins seems preferable.

PMID- 10416957
TI  - The p53 paradox in the pathogenesis of tumor progression.
AB  - Recent evidence suggests that the p53 molecule appears in two different forms:
      the mutant p53 that stimulates tumor progression, and wild type p53 that inhibits
      tumor progression. In addition, it has been established that tumor necrosis
      factor-alpha (TNF-alpha) can activate the expression of wild type p53 in concert
      with the nuclear transcription factor, NF-kappa B. Both TNF-alpha and NF-kappa B
      are also involved in the stimulation of the pathway that leads to the expression
      of major histocompatibility complex (MHC) class I molecules and, hence, antigen
      presentation to the T cells. In this paper we shall advance the hypothesis that:
      (i) TNF-alpha indirectly controls immune surveillance; and (ii) TNF-alpha
      controls DNA repair and tumor suppression through the regulation of wild type
      p53. Thus, it is hypothesized that elevated TNF-alpha is primarily responsible
      for promoting tumor progression.

PMID- 10416958
TI  - Short note: melatonin-dependent infertility.
AB  - Melatonin may be a key factor in the regulation of seasonal variation in gonadal
      activity. The circadian disturbances related to reproduction are probably
      subsequent to the seasonal change. Moreover, melatonin might also be considered
      essential for both spermatogenesis and folliculogenesis. Exposure to bright
      light, suppressing the concentration of melatonin in circulation, is hypothesized
      to be useful in treatment of both male and female infertility in couples with
      abnormal melatonin metabolism.

PMID- 10416959
TI  - On the biological treatment of autistic disorder.

PMID- 10416960
TI  - The neurophysiology of sleep and waking: intracerebral connections, functioning
      and ascending influences of the medulla oblongata.
AB  - This paper focuses on the successive historical papers related to medulla
      oblongata (M.O.) intracerebral connections, its activities and ascending
      influences regulating sleep waking behavior. The M.O. certainly influences the
      quantitative and qualitative processes of waking. However, its neurophysiological
      properties are often concealed by those of the upper-situated brain stem
      structures. The M.O., particularly the solitary tract nucleus, is involved in
      sleep-inducing processes. This nucleus seem to act as a deactivating system of
      the above situated reticular formation, but it also impacts directly on the
      thalamocortical slow wave and spindle-inducing processes. The M.O. is
      significantly involved in paradoxical sleep mechanisms. Indeed, the mesopontine
      executive centers are unable to induce paradoxical sleep without the M.O.
      Moreover, stimulation of the solitary tract nucleus afferents can induce
      paradoxical sleep, and the M.O. metabolic functioning is specifically disturbed
      by paradoxical sleep deprivation. Finally. there seems to be a paradoxical sleep
      Zeitgeber. Our current knowledge shows that this lowest brain stem level is
      crucial for sleep waking mechanisms. It will undoubtedly be further highlighted
      by future electrophysiologial and neurochemical studies.

PMID- 10416961
TI  - Group I metabotropic glutamate receptors: implications for brain diseases.
AB  - Glutamate is the major excitatory neurotransmitter in the brain and plays a
      unique role in a variety of central nervous system (CNS) functions. The discovery
      of the metabotropic receptors (mGluRs), a family of G-protein coupled receptors
      than can be activated by glutamate, has led to an impressive number of studies in
      recent years aimed at understanding their biochemical, physiological and
      pharmacological characteristics. The eight mGluRs now known are divided into
      three groups according to their sequence homology, signal transduction
      mechanisms, and agonist selectivity. Group I mGluRs include mGluR1 and mGluR5,
      which are linked to the activation of phospholipase C; Groups II and III include
      all others and are negatively coupled to adenylyl cyclases. The availability in
      recent years of agents selective for Group I mGluRs has made possible the study
      of the physiological roles of these receptors in the CNS. In addition to
      mediating glutamatergic neurotransmission, Group I mGluRs can modulate other
      neurotransmitter receptors, including GABA and the ionotropic glutamate
      receptors. Group I mGluRs are involved in many CNS functions and may participate
      in a variety of disorders such as pain, epilepsy, ischemia, and chronic
      neurodegenerative diseases. This class of receptor may provide important
      pharmacological therapeutic targets and elucidating its functions will be
      relevant to develop new treatments for neurological and psychiatric disorders in
      which glutamatergic neurotransmission is abnormally regulated. In this review
      anatomical, physiological and pharmacological results are presented with a
      special emphasis on the role of Group I mGluRs in functional and pathological
      processes.

PMID- 10416962
TI  - Maternal serum screening for Down syndrome in the first trimester: experience
      from Belarus.
AB  - We have carried out a large retrospective study of alpha-fetoprotein (AFP), free
      beta human chorionic gonadotrophin (hCG) and pregnancy-associated plasma protein
      (PAPP-A) in the first trimester of pregnancy. Unlike other studies all women had
      routine ultrasound dating, carried out during a nuchal translucency measurement
      project. A total of 13,477 serum samples were tested for AFP and 11,659 for free
      beta-hCG. A subset of 1564 samples from unaffected pregnancies were also tested
      for PAPP-A on a case-control basis. All three markers were also determined in 31
      samples from pregnancies with Down syndrome. Equations were derived to express
      results in multiples of the median using both gestational age and crown rump
      length and to adjust for maternal weight. Statistical modelling with Gaussian
      distribution parameters obtained in the study were used to predict the detection
      rate for a 5 per cent false-positive rate. The predicted rates were: 73.7 per
      cent for all three markers; 69.1 per cent for PAPP-A and free beta-hCG; 47.4 per
      cent for PAPP-A and AFP; 57.6 per cent for free beta-hCG and AFP. As these rates
      are similar to those in the second trimester, health planners may now want to
      consider a change in policy from second-trimester to first-trimester screening
      with biochemical markers.

PMID- 10416963
TI  - Appropriate biochemical parameters in first-trimester screening for Down
      syndrome.
AB  - Meta-analysis was used to calculate maternal serum marker distribution parameters
      for Down syndrome risk estimation in the first trimester. Data from 44 series
      were combined: relating to pregnancy associated plasma protein (PAPP)-A in 18,
      free beta human chorionic gonadotrophin (hCG) in 17, alpha-fetoprotein (AFP) in
      26 and unconjugated oestriol (uE3) in 9. All levels were expressed in multiples
      of the normal median (MOM) for gestational age. Individual PAPP-A levels were
      available for 439 first and second-trimester Down syndrome pregnancies. The
      median MOM value increased with gestation: 0.35 at 6-8 weeks (31 cases), 0.40 at
      9-11 weeks (197), 0.62 at 12-14 weeks (113) and 0.94 thereafter (98). A cubic
      regression equation was fitted so it could be estimated for each week of
      gestation. For the other markers the median value in Down syndrome was estimated
      from the weighted mean across all first-trimester series: 1.98 MOM for free beta
      hCG in 579 cases; 0.79 MOM for AFP in 243 and 0.74 MOM for uE3 in 226. Variance
      covariance matrices were calculated directly in unaffected pregnancies and from
      the difference between affected and unaffected pregnancies in Down syndrome.
      Based on these parameters we estimate that screening at 9-11 weeks with PAPP-A
      and free beta-hCG will yield a 64.6 per cent detection rate for a 5 per cent
      false-positive rate. Adding a third marker will increase detection to 66.6 per
      cent for AFP and 68.6 per cent for uE3; using all four markers it increases to
      70.1 per cent. Routine ultrasound nuchal translucency measurement in addition to
      serum testing will increase the rates to 86.4 per cent, 87.2 per cent, 87.9 per
      cent and 88.3 per cent, respectively.

PMID- 10416964
TI  - Maternal serum activin A and follistatin levels in pregnancies with Down
      syndrome.
AB  - Inhibin A is now an established second-trimester maternal serum marker of Down
      syndrome. Since activin A has a common beta-subunit to inhibin A we evaluated
      this substance and its binding protein, follistatin, as potential markers. We
      studied 30 affected and 199 unaffected pregnancies at 13-16 weeks' gestation.
      There was a statistically significant increase in activin A level among the cases
      with 8 (27 per cent) exceeding the 90th centile in the controls, and 6 (20 per
      cent) above the 95th centile. However, the extent of overlap was too great to be
      of value in screening. There was a small decrease in follistatin levels among
      cases but it did not reach statistical significance.

PMID- 10416965
TI  - SP1 in pregnancies with Down syndrome in the first trimester of pregnancy.
      International Prenatal Screening Research Group.
AB  - We conducted a study to determine the value of serum pregnancy-specific beta-1
      glycoprotein (Schwangerschafts protein 1, SP1) as an antenatal screening test for
      Down syndrome in the first trimester. Serum samples collected from women at 8 to
      14 weeks of pregnancy, immediately prior to having a chorionic villus sampling
      procedure on account of advanced maternal age, were retrieved from 96 women with
      Down syndrome pregnancies (cases) and from 480 women with unaffected pregnancies
      (controls). Cases and controls were ascertained at 21 obstetric centres in nine
      countries. Each case was matched with five controls for maternal age (same five
      year age groups), duration of storage of the serum sample (same calendar year)
      and gestational age (usually the same week of pregnancy). The levels of SP1 were
      lower in pregnancies associated with Down syndrome: the median level was 0.86
      multiples of the median level in the controls (95 per cent confidence interval
      0.76 to 0.97). This difference, though statistically significant, was not large
      enough for SP1 to be a useful marker in screening, at least from 10 weeks onwards
      where most of our data lie.

PMID- 10416967
TI  - High failure rate of umbilical vessel occlusion by ultrasound-guided injection of
      absolute alcohol or enbucrilate gel.
AB  - The success rate for injected umbilical vascular occlusion in the published
      literature exceeds 85 per cent. In this study we assessed the efficacy of two
      forms of injected sclerosants in achieving umbilical vessel occlusion. 12 cases
      of attempted ultrasound-guided occlusion over a 2 1/2 year period were reviewed.
      These were monochorionic (MC) twins (n=6), dichorionic twins (n=3) and singletons
      (n=3) undergoing fetocide for severe anomalies, or impending fetal demise.
      Absolute alcohol (n=6), enbucrilate gel (n=5) or both (n=1) were used in an
      attempt to achieve vascular occlusion. Complete vessel occlusion was achieved in
      only a third of cases (4/12), three with absolute alcohol and one with
      enbucrilate gel. In MC twins occlusion was successful in two of six cases. In
      contrast to previously published data, this large series, containing more cases
      than the total previously reported, shows considerably poorer success rates for
      injected umbilical vascular occlusion. Injection of currently available
      sclerosants can no longer be recommended for umbilical vascular occlusion in
      human fetuses.

PMID- 10416968
TI  - Haemolytic disease of the newborn caused by anti-c, anti-E and anti-Fya
      antibodies: report of five cases.
AB  - Fetal haemolytic disease caused by irregular antibodies is discussed on the basis
      of three cases with maternal anti-c alone, one with anti-E along with anti-c, and
      one with anti-Fya sensitization. All fetuses suffering from maternal c-allo
      immunization alone were treated with intra-uterine transfusions and the newborns
      received exchange transfusions. These interventions were also required in the
      case of simultaneous E and c-allo-immunization, and this was the most severe of
      the five cases. Delta OD450 results were consistent with the severity of the
      fetal condition in the c and/or E allo-immunization cases. Maternal anti-Fya
      sensitization caused only mild jaundice of the neonate, but the results of
      amniotic fluid analysis were quite misleading in that case. Antibody titres did
      not prove to have good prognostic values (though they were all above the critical
      level), and the direct antiglobulin test from cord blood was negative in three
      cases. Regular sonographic evaluations were performed and fetal blood samplings
      were a cornerstone of management.

PMID- 10416966
TI  - A comparison of different density gradients and antibodies for enrichment of
      fetal erythroblasts by MACS.
AB  - The enrichment of fetal cells, in particular fetal erythroblasts from the blood
      of pregnant women offers a promising non-invasive alternative for prenatal
      diagnosis. The purpose of this study was to compare the retrieval of
      erythroblasts by different density gradients and different antibodies against
      erythroid surface antigens, in both a model test system and in blood samples of
      pregnant women. We enriched erythroblasts from artificial mixtures of cord and
      adult blood (1:50) and from 16 ml of peripheral blood from pregnant women at a
      mean gestational age of 14+2 weeks. The yield of erythroblasts was calculated and
      compared using Wilcoxon's matched-pairs signed-rank test. In the artificial
      mixture most erythroblasts were retrieved using the heaviest density gradient
      (specific density of 1119) followed by antibody-labelled magnetic cell sorting
      (MACS). With anti-GPA the yield of erythroblasts from the artificial mixture was
      highest (9362.5 erythroblasts) compared with anti-CD36 (5164.3), anti-i (3455.2),
      anti-CD71 (3055.8) and HAE9 (2364.2). The difference between anti-GPA and anti
      CD71, HAE9 and anti-i was significant (p=0.0277). The enrichment of erythroblasts
      from peripheral blood of pregnant women showed similar results. The yield of
      erythroblasts using anti-GPA was the highest. These results enable us to simplify
      our enrichment protocols to a single density gradient of 1119 specific density
      followed by MACS, with anti-GPA.

PMID- 10416969
TI  - Maternal serum pregnancy-associated plasma protein A (PAPP-A) but not pregnancy
      specific beta1-glycoprotein (SP1) is a useful second-trimester marker for fetal
      trisomy 18.
AB  - The usefulness of early second-trimester serum determinations of pregnancy
      associated plasma protein A (PAPP-A) and pregnancy-specific beta1-glycoprotein
      (SP1) in suspected cases of fetal trisomy 18 was examined in a retrospective,
      cross-sectional study. Maternal serum PAPP-A and SP1 in 20 cases of fetal trisomy
      18 between 15 and 20 weeks of pregnancy, and in 40 controls matched for
      gestational age and storage time were determined and compared with hCG and free
      oestriol (uE3). In trisomy 18, the reduction in serum concentration was found to
      be more pronounced for PAPP-A than for hCG and free oestriol. While none of the
      40 control sera had a MoM below 0.2 for either PAPP-A, hCG or uE3, in the trisomy
      18 group (20 cases) 17 (85 per cent) of the PAPP-A but only 5 (25 per cent) of
      the hCG and 4 (20 per cent) of the uE3 results were below the 0.2 MoM threshold.
      SP1 did not distinguish between controls and trisomy 18. This chromosomal
      abnormality is too rare a condition to justify maternal serum PAPP-A
      determination in the second trimester as a routine procedure, but such a test can
      play a useful role whenever the risk of trisomy 18 is found to be only marginally
      increased after hCG and uE3 measurements.

PMID- 10416970
TI  - Molecular prenatal diagnosis of ataxia telangiectasia heterozygosity by direct
      mutational assays.
AB  - Ataxia telangiectasia (AT) is a severe autosomal recessive disease, rare but not
      infrequent in Italy. Owing to the seriousness of the disease, prenatal diagnosis
      has been attempted in the past by means of cytogenetic, biochemical, radio
      biological and indirect molecular analyses. We performed the first direct
      molecular prenatal diagnosis of AT on a chorionic villi sample from a 37-year-old
      woman at the 10th week of pregnancy. She had two previous children suffering AT
      and two induced abortions. At molecular analysis her affected children were
      compound heterozygotes for mutations 7792C-->T in exon 55 (from the mother) and
      8283delTC in exon 59 (from the father). The prenatal diagnosis was performed by
      two different operators in double-blind form. Mutation 7792C-->T was studied by
      restriction enzyme analysis using TaqI. Mutation 8283delTC was screened by
      heteroduplex analysis. The fetus was heterozygous for the mutation 7792C-->T
      (confirmed by sequencing). In order to verify the possible contamination by
      maternal DNA, polymorphic loci HLA-DRB1 and HLA-DQA1, together with
      microsatellite markers D6S259, D11S2000, D11S29, D11S1778 and D11S2179, were
      examined. All these loci were informative, showing that the fetus received only
      one allele from each parent. The heterozygosity for ATM mutation 7792C-->T was
      confirmed by molecular studies after the birth of a healthy male baby.

PMID- 10416971
TI  - Two years' prospective experience using fluorescence in situ hybridization on
      uncultured amniotic fluid cells for rapid prenatal diagnosis of common
      chromosomal aneuploidies.
AB  - A probe was generated from the YAC clone 831B9 that was suitable for the prenatal
      detection of trisomy 21 using fluorescence in situ hybridization (FISH). This
      probe was initially tested on a series of 650 unselected amniotic fluid samples
      prior to the karyotype being available. 630 were correctly identified as having
      two copies and 13 samples were correctly scored as having three copies of
      chromosome 21. Seven samples failed to produce a result. A trial was then
      initiated, reporting to clinicians the interphase FISH results before cytogenetic
      analysis had been performed. During the first 18 months of this trial 1504
      samples were tested: 1467 were correctly identified as disomic and 35 samples
      were correctly scored as trisomic for chromosome 21. Two samples failed to
      produce a result. A chromosome 18 specific probe (LI.84) was employed where there
      was a relevant clinical indication (181 samples) and 10 samples were correctly
      scored as having three copies of chromosome 18. Thus, this approach appears to be
      reliable and is popular with both clinicians and patients due to the speed of the
      result. However, it does not replace chromosomal analysis on cultured cells,
      which detected a range of abnormalities besides the trisomies and triploidies
      detected by FISH.

PMID- 10416972
TI  - Complex approach to prenatal diagnosis of cytochrome c oxidase deficiencies.
AB  - Different severe disorders of cytochrome c oxidase (COX) have been described in
      children, but only the defects with autosomal inheritance are suitable for
      prenatal diagnosis. To perform prenatal diagnosis of fatal infantile COX
      deficiency a complex approach has been used which combined determination of the
      genetic origin of the defect, and detailed analysis of the function, content and
      subunit composition of the enzyme in cultured fetal cells. The tissues and
      cultured fibroblasts of the patient with Leigh's syndrome showed a COX deficiency
      of systemic character. The decrease of COX activity to 5-11 per cent was
      accompanied by proportionally decreased content of the assembled COX enzyme. With
      the help of transmitochondrial cybrids derived from patient fibroblasts it was
      proven that the COX defect was of nuclear origin. In a successive pregnancy, the
      function of oxidative phosphorylation (OXPHOS) was analysed in cultured
      amniocytes by substrate-stimulated ATP production and COX activity was compared
      with the activity of citrate synthase. The amount and composition of OXPHOS
      complexes was estimated by two-dimensional (Blue Native/SDS) polyacrylamide gel
      electrophoresis and was verified immunochemically with specific antibodies. Three
      independent lines of evidence provided us with reliable data on the function of
      COX and OXPHOS in fetal cells which were sufficient to rule out the expected
      enzymatic defect within three weeks after amniocentesis.

PMID- 10416973
TI  - First-trimester diagnosis of infantile neuronal ceroid lipofuscinosis (INCL)
      using PPT enzyme assay and CLN1 mutation analysis.
AB  - Infantile neuronal ceroid lipofuscinosis (INCL) is a progressive
      neurodegenerative disorder in childhood which is caused by the deficiency of the
      lysosomal palmitoyl-protein thioesterase (PPT) encoded by the CLN1 gene. In a
      pregnancy at risk for INCL, chorionic villi (CV) were studied using a novel
      fluorometric PPT enzyme assay in combination with mutation-analysis of the CLN1
      gene. The PPT activity in chorionic villi was found to be deficient and
      homozygosity for the C451T mutation in CLN1 was found. The pregnancy was
      terminated and the PPT deficiency was confirmed in cultured CV cells as well as
      in the cultured fetal skin fibroblasts. This report shows the first early
      prenatal diagnosis of INCL performed by fluorometric enzyme analysis and mutation
      analysis of the CLN1 gene.

PMID- 10416974
TI  - Fetal cardiac abnormalities and their association with aneuploidy.

PMID- 10416975
TI  - The prenatal diagnosis of Pierre-Robin sequence.
AB  - The purpose of this study was to evaluate the spectrum of prenatal sonographic
      and chromosomal findings, associated anomalies and perinatal and neonatal
      outcomes in cases with Pierre-Robin sequence. All cases (20) with Pierre Robin
      sequence, who were born at China Medical College Hospital between 1990 and 1997,
      were included and analysed in this series. 12 pregnancies (60 per cent) were
      complicated by polyhydramnios and 9 (45 per cent) were combined with cleft
      palate. Four cases (20 per cent) with cardiac anomalies were also observed. Two
      fetuses (10 per cent) had abnormal karyotyping (one trisomy 21, one trisomy 18).
      All fetuses were delivered at or near term. Male deviation was observed in cases
      with isolated Pierre-Robin sequence or combined mild anomalies (male female
      ratio: 13:3). Two neonatal mortalities and three with mental retardation were
      observed. This investigation provides a basis for counselling patients with fetal
      micrognathia or neonatal Pierre-Robin sequence. The main prenatal sonographic
      findings of Pierre-Robin sequence are micrognathia, polyhydramnios and cleft
      palate. In cases of polyhydramnios, sonographic examination of the facial profile
      and palate are recommended. After the finding of polyhydramnios, micrognathia,
      and even cleft palate, clinicians should be aware of the possibility of neonatal
      Pierre-Robin sequence. Cardiac evaluation and karyotyping is also recommended.

PMID- 10416976
TI  - A case of recurrent congenital fetal anomalies associated with a familial
      subtelomeric translocation.
AB  - The potential of a new fluorescent in situ hybridization technique is discussed,
      which uses a complete set of telomeric probes to reveal cryptic chromosome
      rearrangements that remain undetected by standard cytogenetic analysis. We report
      the obstetric history of a patient who had a termination of pregnancy at 20 weeks
      for a fetus with multiple congenital anomalies but a normal male karyotype using
      conventional G-banding analysis on a mid-trimester placental biopsy. In a
      subsequent pregnancy, a diaphragmatic hernia and intra-uterine growth restriction
      were detected at 34 weeks' gestation and a fetal blood sample showed a normal
      female karotype. However, her child was born with dysmorphic features and
      additional severe abnormalities including microcephaly, anophthalmos and left
      fixed talipes. The child has shown marked developmental delay. In view of a
      strong family history of congenital abnormalities and recurrent miscarriage
      suggestive of a familial translocation, a fluorescent in situ hybridization
      technique using specific telomeric probes was performed on blood from the
      affected child and her parents. An unbalanced subtelomeric translocation was
      detected involving the long arms of chromosomes 2 and 7 in the child and a
      balanced translocation was detected in her father. Accurate genetic counselling
      and the opportunity for early prenatal diagnosis can now be offered to this
      family.

PMID- 10416977
TI  - Prenatal diagnosis of tuberous sclerosis with intracerebral signs at 14 weeks'
      gestation.
AB  - We report the ultrasound detection of cranial abnormalities at 14 weeks'
      gestation in a fetus subsequently confirmed as having tuberous sclerosis using
      DNA linkage analysis within the affected family. The presence of asymmetrical
      ventricular enlargement persisted antenatally. Magnetic resonance imaging at 26
      weeks indicated the possibility of poor gyral formation consistent with a
      neuronal migration disorder. Cardiac rhabdomyomata were not visualized on
      ultrasound scan until 30 weeks' gestation. Postnatal cranial ultrasound confirmed
      the significant neuropathology which was manifested by severe developmental delay
      and intractable fits in the child. The potential benefits of earlier diagnosis of
      tuberous sclerosis by cranial imaging are discussed, although in this patient the
      routine booking scan resulted in a path of prenatal diagnosis being undertaken
      which had originally been declined. A mechanism is proposed to explain the
      variable expression of tuberous sclerosis within this family based on altered
      TSC2 activity affecting neuronal migration.

PMID- 10416978
TI  - Trisomy 18 with total cranio-rachischisis and thoraco-abdominoschisis.
AB  - We describe a further case of trisomy 18 with total cranio-rachischisis and
      radial agenesis, and report the first case with thoraco-abdominoschisis. We
      review these rare findings in trisomy 18.

PMID- 10416979
TI  - Prenatal detection of a giant bilateral thoracic vascular lesion: prognostic
      evaluation and genetic aspects.
AB  - We describe a giant bilateral vascular mass in the skin of the chest diagnosed by
      ultrasound investigation in a fetus of 20 gestational weeks. Ultrasound and
      colour Doppler investigations detected no signs of early congestive heart failure
      but rapid and excessive enlargement of the vascular mass. Indications of
      increased fetal blood volume were found. The fetus had additional minor
      anomalies. Early in utero manifestation suggests a severe vascular malformation.

PMID- 10416981
TI  - Evolution of the centromeric alpha-satellite DNA sequences of human chromosome
      22.

PMID- 10416980
TI  - The association of increased fetal nuchal translucency and spinal muscular
      atrophy type I.
AB  - We report a fetus with spinal muscular atrophy type I, who presented with an
      increased nuchal translucency at 13 weeks' gestation. A review of the literature
      reveals additional cases of spinal muscular atrophy type I associated with
      increased nuchal translucency and suggests increased nuchal translucency may be
      an early finding in this disorder.

PMID- 10416982
TI  - Inconsistency of omphalocoele contents in three consecutive siblings with partial
      trisomy 3q and partial monosomy 11q.

PMID- 10416983
TI  - Current awareness in prenatal diagnosis.

PMID- 10416984
TI  - Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human
      malignant gliomas.
AB  - Malignant gliomas frequently show genetic aberrations of genes coding for cell
      cycle regulatory proteins involved in the control of G1/S phase transition. These
      include mutation and/or deletion of the retinoblastoma (RB1) gene, homozygous
      deletion of the CDKN2A and CDKN2B genes, as well as amplification and
      overexpression of the CDK4 and CDK6 genes. The D-type cyclins (cyclin D1, D2, and
      D3) promote cell cycle progression from G1 to S phase by binding to and
      activating the cyclin dependent kinases Cdk4 and Cdk6. Here, we have investigated
      a series of 110 primary malignant gliomas and 8 glioma cell lines for
      amplification and expression of the D-type cyclin genes CCND1 (11q13), CCND2
      (12p13), and CCND3 (6p21). We found the CCND1 gene amplified and overexpressed in
      one anaplastic astrocytoma of our tumor series. Two glioblastomas and one
      anaplastic astrocytoma showed CCND2 gene amplification, but lacked significant
      overexpression of CCND2 transcripts. Amplification and overexpression of the
      CCND3 gene was detected in the glioblastoma cell line CCF-STTG1, as well as in
      one primary glioblastoma and in the sarcomatous component of one gliosarcoma. Our
      data thus suggest that amplification and increased expression of CCND1 and CCND3
      contribute to the loss of cell cycle control in a small fraction of human
      malignant gliomas.

PMID- 10416985
TI  - Taylor's cortical dysplasia: a confocal and ultrastructural immunohistochemical
      study.
AB  - In the present report we describe the neuropathological characteristics of tissue
      surgically resected from three patients affected by intractable epilepsy
      secondary to cortical dysplasia. Common features, suggestive of a focal cortical
      dysplasia of Taylor, were observed in all specimens. Immunocytochemical
      procedures were performed using neuronal and glial markers and the sections were
      observed at light traditional and confocal microscopes. This part of the
      investigation pointed out: 1. cortical laminar disruption; 2. very large neurons
      displaying a pyramidal or round shape; 3. ballooned cells; 4. decrease of calcium
      binding proteins immunoreactivity; 5. abnormal nets of parvalbumin- and glutamic
      acid decarboxylase-positive puncta around giant neurons but not around ballooned
      cells. Ultrastructural investigation on the same material provided evidence of a
      high concentration of neurofilaments in giant neurons and of glial intermediate
      filaments in ballooned cells. In addition, immunolabeled GABAergic terminals
      clustered around giant neurons were not found to establish synapses on their cell
      bodies. The present data, derived from a limited sample of patients but showing
      very consistent features, suggest that in Taylor's type of cortical dysplasia a
      disturbance of migratory events could be paralleled by a disruption of cell
      differentiation and maturation and by an impairment of synaptogenesis. This
      latter mechanism seemed to affect especially the inhibitory elements, and could
      account for the hyperexcitability of this tissue and thus for the high
      epileptogenicity of Taylor's dysplasia.

PMID- 10416986
TI  - High frequency of TP53 mutations in juvenile pilocytic astrocytomas indicates
      role of TP53 in the development of these tumors.
AB  - In adults, the TP53 tumor suppressor gene is frequently mutated in astrocytic
      brain tumors which is supposed to represent an early event in their development.
      In juvenile pilocytic and low-grade astrocytomas, however, TP53 mutations have
      until now been reported as rare, which has led to the suggestion that these
      tumors may follow a different molecular pathogenesis with an involvement of genes
      other than TP53. Our analysis of 20 pilocytic and two low-grade astrocytomas of
      childhood, based on a comprehensive denaturing gradient gel electrophoresis
      (DGGE) mutation detection assay of the entire coding region, including all splice
      site junctions of TP53, showed mutations considered as causative in 7 of the 20
      (35%) pilocytic astrocytomas and in one of the two low-grade astrocytomas. Our
      finding is significantly different from the mutation frequency of 1.3% (2/155)
      previously reported for these tumor types. This may be attributed to the mutation
      detection system used, which also detects mutations occurring outside the
      evolutionary conserved region of TP53. Our results suggest that, contrary to the
      present notion, TP53 mutations may well play a role in the development of
      juvenile astrocytomas. Furthermore, no mutations were found in tumors of patients
      with progression of residual tumor after postoperative follow-up. This suggests
      that TP53 mutations may be associated with less aggressive forms of juvenile
      astrocytomas, analogous to the situation in adult astrocytomas.

PMID- 10416987
TI  - Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes
      in human glioma cell lines.
AB  - In this study we established the simultaneous status of TP53, p16, p14ARF and
      PTEN tumor suppressor genes in 34 randomly chosen human glioma cell lines. Nine
      cell lines (26.4%) harbored mutations or deletions in all four tumor suppressor
      genes and 22 cell lines (64%) had alterations in at least three.
      Mutations/deletions were found at the following frequencies: TP53 (76.5%), p14ARF
      (64.7%), p16 (64.7%), PTEN (73.5%). Thus, there was a high incidence of
      alterations in the cellular pathways involving the p53 transcription factor
      (94.1%), the retinoblastoma protein (64.7%) and the PTEN phosphatase (73.5%) and
      91% of cell lines carried mutations in two or more pathways. This provides the
      first clear genetic evidence that these tumor suppressors participate in
      biological pathways which are functioning separately/independently in glioma
      cells. The status of the gene alterations did not correlate with tumorigenicity
      in immunocompromized mice or any clinical parameters. Although the mutation rate
      was higher in glioma cell lines than that reported for glioma tissues, the
      alterations were molecularly representative of those found in adult de novo
      glioblastoma. This study highlights the importance of developing therapeutic
      approaches applicable to tumors with a broad range of genetic alterations and
      also provides an invaluable panel of glioma cell lines to make this possible.

PMID- 10416989
TI  - The neurobiology and neurogenetics of stem cells.

PMID- 10416988
TI  - Exacerbation of viral and autoimmune animal models for multiple sclerosis by
      bacterial DNA.
AB  - Theiler's murine encephalomyelitis virus (TMEV) infection and relapsing-remitting
      experimental allergic encephalomyelitis (R-EAE) have been used to investigate the
      viral and autoimmune etiology of multiple sclerosis (MS), a possible Th1-type
      mediated disease. DNA immunization is a novel vaccination strategy in which few
      harmful effects have been reported. Bacterial DNA and oligodeoxynucleotides,
      which contain CpG motifs, have been reported to enhance immunostimulation. Our
      objectives were two-fold: first, to ascertain whether plasmid DNA, pCMV, which is
      widely used as a vector in DNA immunization studies, could exert
      immunostimulation in vitro; and second, to test if pCMV injection could modulate
      animal models for MS in vivo. We demonstrated that this bacterially derived DNA
      could induce interleukin (IL)-12, interferon (IFN)gamma, (Th1-promoting
      cytokines), and IL-6 production as well as activate NK cells. Following pCMV
      injections, SJL/J mice were infected with TMEV or challenged with
      encephalitogenic myelin proteolipid protein (PLP) peptides. pCMV injection
      exacerbated TMEV-induced demyelinating disease in a dose-dependent manner.
      Exacerbation of the disease did not correlate with the number of TMEV-antigen
      positive cells but did with an increase in anti-TMEV antibody. pCMV injection
      also enhanced R-EAE with increased IFNgamma and IL-6 responses. These results
      caution the use of DNA vaccination in MS patients and other possible Th1-mediated
      diseases.

PMID- 10416990
TI  - Human neural stem cells: isolation, expansion and transplantation.
AB  - Neural stem cells, with the capacity to self renew and produce the major cell
      types of the brain, exist in the developing and adult rodent central nervous
      system (CNS). Their exact function and distribution is currently being assessed,
      but they represent an interesting cell population, which may be used to study
      factors important for the differentiation of neurons, astrocytes and
      oligodendrocytes. Recent evidence suggests that neural stem cells may also exist
      in both the developing and adult human CNS. These cells can be grown in vitro for
      long periods of time while retaining the potential to differentiate into nervous
      tissue. Significantly, many neurons can be produced from a limited number of
      starting cells, raising the possibility of cell replacement therapy for a wide
      range of neurological disorders. This review summarises this fascinating and
      growing field of neurobiology, with a particular focus on human tissues.

PMID- 10416991
TI  - Postnatal cerebral cortical multipotent progenitors: regulatory mechanisms and
      potential role in the development of novel neural regenerative strategies.
AB  - In the developing postnatal cerebral cortex, protracted generation of glia and
      neurons occurs and precise matching of local cell types is needed for the
      functional organization of regional microdomains characteristic of complex CNS
      tissues. Recent studies have suggested that multipotent progenitors play an
      important role in neural lineage elaboration during neurogenesis and gliogenesis
      after migration from paramedian generative zones. The presence of a separate
      reservoir of cerebral cortical multipotent cells under strict local environmental
      regulation would provide an appropriate mechanism for terminal developmental
      sculpting and for reconstitution of regional cellular pools after injury. We have
      isolated distinct pools of EGF- and bFGF-responsive multipotent progenitors from
      the postnatal mammalian cerebral cortex independent of the subventricular zone.
      These progenitor populations are under tight environmental regulation by specific
      hierarchies of cytokine subclasses that program the progressive elaboration of
      intermediate lineage-restricted progenitors and differentiated type I and II
      astrocytes, myelinating oligodendrocytes and neuronal subtypes that express
      specific neuromodulatory proteins. Neural lineage development from these cortical
      multipotent progenitors is a graded developmental process involving sequential
      induction of specific cytokine receptors, acquisition of factor responsiveness
      and complex lineage interdependence. The cortical multipotent progenitor pathways
      program the elaboration of neural lineage species with distinct cellular response
      properties when compared with analogous species derived from subventricular zone
      progenitors, indicating that the cortical multipotent cells contribute to the
      establishment of lineage diversity within the developing cortical cortex. In
      addition, the cortical multipotent cells generate dynamic intermediate progenitor
      pools that utilize temporally-coded environmental cues to alter neural fate
      decisions. These cumulative observations suggest that postnatal cerebral cortical
      multipotent cells represent a novel set of progenitor pathways necessary for
      normal mammalian cortical maturation, and may have important implications for our
      understanding of a wide variety of neuropathological conditions and for the
      development of more effective regenerative strategies to combat these pervasive
      neurological disorders.

PMID- 10416992
TI  - Building brains: neural chimeras in the study of nervous system development and
      repair.
AB  - The ability to isolate multipotential neuroepithelial precursor cells from the
      mammalian nervous system provides exciting perspectives for the in vitro analysis
      of early nervous system development and the generation of donor cells for neural
      repair. New models are needed to study the properties of these cells in vivo.
      Neural chimeras have revealed a remarkable degree of plasticity in the
      developmental potential of neuroepithelial precursor cells. Following
      transplantation into the cerebral ventricle of embryonic hosts, precursors
      derived from various brain regions and developmental stages participate in host
      brain development and undergo region-specific differentiation into neurons and
      glia. These findings indicate that in the developing nervous system, migration
      and differentiation of neural precursors cells are regulated to a large extent by
      extrinsic signals. Neural chimeras composed of genetically modified cells will
      permit the study of the molecular mechanisms underlying these guidance cues,
      which may eventually be exploited for cell replacement strategies in the adult
      brain. A key problem in neural transplantation is the availability of suitable
      donor tissue. Neural chimeras composed of embryonic stem (ES) cell-derived
      neurons and glia depict ES cells as a versatile and virtually unlimited donor
      source for neural repair. Generation of interspecies neural chimeras composed of
      human and rodent cells facilitates the translation of these advances into
      clinical strategies for human nervous system repair.

PMID- 10416993
TI  - Genetic regulatory elements introduced into neural stem and progenitor cell
      populations.
AB  - The genetic manipulation of neural cells has advantage in both basic biology and
      medicine. Its utility has provided a clearer understanding of how the survival,
      connectivity, and chemical phenotype of neurones is regulated during, and after,
      embryogenesis. Much of this achievement has come from the recent generation by
      genetic means of reproducible and representative supplies of precursor cells
      which can then be analyzed in a variety of paradigms. Furthermore, advances made
      in the clinical use of transplantation for neurodegenerative disease have created
      a demand for an abundant, efficacious and safe supply of neural cells for
      grafting. This review describes how genetic methods, in juxtaposition to
      epigenetic means, have been used advantageously to achieve this goal. In
      particular, we detail how gene transfer techniques have been developed to enable
      cell immortalization, manipulation of cell differentiation and commitment, and
      the controlled selection of cells for purification or safety purposes. In
      addition, it is now also possible to genetically modify antigen presentation on
      cell surfaces. Finally, there is detailed the transfer of therapeutic products to
      discrete parts of the central nervous system (CNS), using neural cells as elegant
      and sophisticated delivery vehicles. In conclusion, once the epigenetic and
      genetic controls over neural cell production, differentiation and death have been
      more fully determined, providing a mixture of hard-wired elements and more
      flexibly expressed characteristics becomes feasible. Optimization of the
      contributions and interactions of these two controlling systems should lead to
      improved cell supplies for neurotransplantation.

PMID- 10416994
TI  - Establishment and properties of neural stem cell clones: plasticity in vitro and
      in vivo.
AB  - The study of the basic physiology of the neural precursors generated during brain
      development is driven by two inextricably linked goals. First, such knowledge is
      instrumental to our understanding of how the high degree of cellular complexity
      of the mature central nervous system (CNS) is generated, and how to dissect the
      steps of proliferation, fate commitment, and differentiation that lead early
      pluripotent neural progenitors to give rise to mature CNS cells. Second, it is
      hoped that the isolation, propagation, and manipulation of brain precursors and,
      particularly, of multipotent neural stem cells (NSCs), will lead to therapeutic
      applications in neurological disorders. The debate is still open concerning the
      most appropriate definition of a stem cell and on how it is best identified,
      characterized, and manipulated. By adopting an operational definition of NSCs, we
      review some of the basic findings in this area and elaborate on their potential
      therapeutic applications. Further, we discuss recent evidence from our two groups
      that describe, based on that rigorous definition, the isolation and propagation
      of clones of NSCs from the human fetal brain and illustrate how they have begun
      to show promise for neural cell replacement and molecular support therapy in
      models of degenerative CNS diseases. The extensive propagation and engraftment
      potential of human CNS stem cells may, in the not-too-distant-future, be directed
      towards genuine clinical therapeutic ends, and may open novel and multifaceted
      strategies for redressing a variety of heretofore untreatable CNS dysfunctions.

PMID- 10416995
TI  - Case of the month: January 1999--Fetus with echogenic mass in third ventricle.
AB  - A 29-week gestational age newborn male infant was found to have an echogenic mass
      in the 3rd ventricle by prenatal ultrasound 2 weeks prior to delivery. At
      delivery he was poorly responsive and had hydrocephalus and ascites. A CT scan
      after birth showed cerebral infarction, amorphous tissue in the left hemisphere
      and numerous calcifications. Despite supportive treatment he died 4 days after
      birth. Postmortem examination of the brain revealed marked distortion of the
      architecture and a supratentorial undifferentiated neoplasm consistent with a
      PNET. The tumor showed extensive areas of hemorrhage and necrosis and involvement
      of lateral and third ventricles, brain parenchyma, and meninges.

PMID- 10416996
TI  - Case of the month: February 1999--54 year old man with severe muscle weakness.
AB  - A 54 year old man developed rhabdomyolysis one year after beginning treatment
      with a combination of lovastatin (an HMGCoA reductase inhibitor) and niacin.
      Muscle biopsy showed a severe necrotizing myopathy affecting both fibre types.
      Recovery occured gradually with cessation of medication. The spectrum of
      cholesterol lowering agent myopathy may include delayed cases of unusual
      severity.

PMID- 10416997
TI  - Case of the month: March 1999--A 26 year old HIV positive male with dura based
      masses.
AB  - A 26-year-old male with AIDS presented with a chief complaint of headaches and
      neck pain. An MRI revealed two enhancing extra-axial dura based masses, one in
      the area of the left sphenoid wing and one at the level of C2-3. In both cases,
      microscopic sections showed actin positive spindle cell neoplasms with long
      slender nuclei, consistent with leiomyomas. Both tumors were positive for Epstein
      Barr virus by in situ hybridization. This case report serves to emphasize the
      importance of considering soft tissue tumors such as leiomyoma in the
      differential diagnosis of mass lesions that occur in the central nervous system
      in AIDS and discusses the role of EBV in tumorigenesis.

PMID- 10416998
TI  - Comparison of short-term aerobic training and high aerobic power on tolerance to
      uncompensable heat stress.
AB  - This study investigated whether, in subjects of moderate aerobic fitness, short
      term aerobic training could replicate the improved physiological responses to
      exercise-heat stress observed in individuals with a high level of aerobic
      fitness. Males of moderate (MF; <50 ml x kg(-1) min(-1) VO2peak, n = 8) and high
      (HF; >55 ml x kg(-1) x min(-1) VO2peak, n = 8) aerobic fitness walked at 3.5 km x
      h(-1) in the heat (40 degrees C, 30% relative humidity) wearing nuclear,
      biological, and chemical protective clothing. Tests were conducted once on HF
      subjects and on MF subjects before (MF-Pre) and after (MF-Post) a 2-week program
      6 d x week(-1) of daily aerobic training (1 h treadmill exercise at 65% VO2peak
      for 12 d, 22 degrees C, 40% relative humidity). The training significantly
      increased VO2peak by 6.5%, while heart rate (fc) and rectal temperature (Tre)
      rise decreased during exercise in a thermoneutral environment. HF had lower body
      mass and body fat content than MF, and VO2peak remained lower in MF pre-or post
      training. In the heat, MF-Post had a decreased skin temperature (Tsk) and an
      increased sweat rate compared with MF-Pre, but no changes were observed in fc,
      Tre, or tolerance time (TT). No significant differences during the first 60 min
      in Tre and fc were observed between the MF-Post and the HF subjects, though the
      HF subjects exhibited a lower Tsk. The endpoint Tre, deltaTre, and TT remained
      significantly higher in HF than in either the MF-Pre or MF-Post subjects. It was
      concluded that, in preparation for exercise in an uncompensable heat stress
      environment, short-term aerobic training offers little, if any, benefit and is
      not an adequate substitute for a high level of aerobic fitness resulting from
      habitual exercise and training.

PMID- 10416999
TI  - Pulmonary and auditory function among experienced construction divers: a cross
      sectional study.
AB  - We studied pulmonary and auditory function in a cross-sectional study of 26
      experienced construction divers compared with 26 workshop workers matched for
      age, height, and smoking habits. The divers used air as breathing gas and
      performed open-sea bounce dives to a maximum of 50 m in sea water. The mean
      number of dives over a mean diving period of 20 yr (SD = 11) was 4746 (SD = 4743)
      (Range: 450-17000). Assessment of lung function included dynamic lung volume and
      flow and diffusion capacity (transfer factor) for carbon monoxide (TlCO). The
      auditory examination was performed measuring air conduction thresholds in a
      cabin. The results show a significantly higher mean forced vital capacity (FVC)
      of 6.01 L (SD = 0.88) in the divers compared with 5.67 L (SD = 0.84) (p = 0.045)
      in the controls, and an alveolar volume (VA) of 7.74 L (SD = 0.99) in the divers
      compared with 7.35 L (SD = 0.74) (p = 0.035) in the controls. There was a
      nonsignificant reduction in forced mid-expiratory flow rate (FEF25-75%) and a
      significant reduction in forced expiratory flow rate at 50% of FVC (FEF50%) among
      the divers of 4.69 L (SD = 1.41) compared with 5.76 L (SD = 2.03) among the
      controls of (p = 0.03). There were no differences in FEV1 and TlCO between the
      two groups. The divers showed reduced auditory function in their left ear
      compared with their right ear in the 3 kHz (p = 0.006) and 8 kHz (p = 0.022)
      area. No statistical difference was found in hearing thresholds of the divers
      compared with those of the controls. Our results indicate that exposure to diving
      may be associated with changes in pulmonary function and that the left ear may be
      more vulnerable than the right ear to hearing impairment in construction divers.

PMID- 10417000
TI  - Low-altitude overflights of fighters and the risk of hearing loss.
AB  - BACKGROUND AND OBJECTIVE: Much data are available on noise properties which cause
      hearing loss. There are not, however, reports on the effects of low-altitude
      overflight noise on the permanent threshold shift (PTS). METHODS: Low-altitude
      overflight noise generated by the Finnish Air Force's jet fighters and an
      advanced jet trainer was measured with flight distances varying from 50-310 m
      from the measurement point. The aircraft were always subsonic, velocities being
      usually 0.9 Mach or less. The measurements were undertaken because of two claims
      for the compensation of hearing loss caused by overflights of jet fighters on
      cross-country training missions. RESULTS: Peak noise levels (LCpeak) varied from
      109-150 dB depending on aircraft type and the use of afterburner. The 1-s single
      A-weighted exposure levels (ASEL) during these overflights were 95-135 dB which
      correspond to daily (8 h) exposure levels of 50-90 dB. CONCLUSIONS: According to
      these results and the principles of noise evaluation, there should be no risk of
      permanent hearing loss when the distance to an overflying jet fighter is more
      than 200 m. However, we have received two claims, and the audiometric analyses of
      two subjects who had suffered hearing loss in one ear in Finland during the 1990s
      may indicate that there is very likely a connection between the incidents and the
      hearing losses.

PMID- 10417001
TI  - Carbon dioxide accumulation, walking performance, and metabolic cost in the NASA
      launch and entry suit.
AB  - BACKGROUND: In the event of an emergency on landing, Space Shuttle crewmembers
      while wearing the Launch and Entry Suit (LES) must stand, move to the hatch, exit
      the spacecraft with the helmet visor closed breathing 100% O2, and walk or run
      unassisted to a distance of 380 m upwind from the vehicle. The purpose of this
      study was to characterize the inspired CO2 and metabolic requirements during a
      simulated unaided egress from the Space Shuttle in healthy subjects wearing the
      LES. METHODS: As a simulation of a Shuttle landing with an unaided egress, 12
      male subjects completed a 6-min seated pre-breathe with 100% O2 followed by a 2
      min stand and 5-min walking at 1.56 m x s(-1) (5.6 km x h(-1), 3.5 mph) with the
      helmet visor closed. During walks with four different G-suit pressures (0.0, 0.5,
      1.0, 1.5 psi; 3.4, 6.9, 10.3 kPa), inspired CO2 and walking time were measured.
      After a 10-min seated recovery, subjects repeated the 5-min walk with the same G
      suit pressure and the helmet visor open for the measurement of metabolic rate
      (VO2). RESULTS: When G-suit inflation levels were 1.0 or 1.5 psi, only one-third
      of our subjects were able to complete the 5-min visor-closed walk after a 6-min
      pre-breathe. Inspired CO2 levels measured at the mouth were routinely greater
      than 4% (30 mmHg) during walking. The metabolic cost at the 1.5 psi G-suit
      inflation was over 135% of the metabolic cost at 0.0 psi inflation. CONCLUSION:
      During unaided egress, G-suit inflation pressures of 1.0 and 1.5 psi resulted in
      elevated CO2 in the LES helmet and increased metabolic cost of walking, both of
      which may impact unaided egress performance. Neither the LES, the LES helmet, nor
      the G-suit were designed for ambulation. Data from this investigation suggests
      that adapting flight equipment for uses other than those for which it was
      originally designed can result in unforeseen problems.

PMID- 10417002
TI  - Does over-accomodation occur when using aircraft head-up displays?
AB  - BACKGROUND: Whether over-accommodation is caused by the use of head-up displays
      is still under debate. Most prior experimentation has involved cognitively
      demanding tasks, which are known to affect the accommodation response. The
      simulations have often been unrealistic and involved short working distances.
      HYPOTHESIS: Over-accommodation is caused not by the presence of a head-up display
      per se, but rather by the cognitive demand of the task. METHODS: The effect of
      increasing the task cognitive load and the use of forward looking infra-red
      imagery (FLIR) on the ocular accommodative response and task performance was
      assessed with a realistic head-up display assisted flying task. FLIR increases
      cognitive load due to its poor resolution and the need for interpretation of the
      images. RESULTS: Over-accommodation was found to be small in magnitude (0.17+/
      0.03D; range -0.02-0.45D) occurring only with cognitively demanding tasks and
      with forward looking infrared imagery. Response times to detect tanks in the
      outside world scene were slower with increased cognitive load and forward looking
      infra-red imagery, along with a reduced detection rate, decreased accuracy of
      tracking tanks in the outside world and poorer control of the head-up display
      pitch ladder. When discrimination was added to detection in an outside world
      task, decisions were delayed until they could be accurately made, rather than
      performance degraded. CONCLUSION: The use of a virtual head-up display in a
      simulated aircraft environment did not adversely affect ocular accommodation.
      However, increased cognitive demand or FLIR imagery caused significant inward
      shifts of accommodation.

PMID- 10417003
TI  - Different responses of cerebral vessels to -30 degrees head-down tilt in humans.
AB  - This study explored changes of the cerebral circulation and evaluated the
      responses to weightlessness in 12 volunteers (18-22 yr of age). The velocities,
      diameters and blood flow volume of the common carotid artery (CCA), internal
      carotid artery (ICA), vertebral artery (VA) and internal jugular vein (IJV) were
      measured with color Doppler echogram before and during simulated weightlessness. 
      30 degrees head-down tilt (HDT) for 45 min was used as a weightlessness
      simulation model. When the subjects' positions were changed from the supine to 
      30 degrees HDT, blood flow velocities along the CCA, ICA and IJV decreased
      significantly (p< 0.05), and their diameters were increased. The subjects were
      divided into two groups according to measured changes in flow volume of the ICA
      and IJV: group I with a net in-flow of cerebral blood flow (CBF) and group II
      with a net out-flow of CBF during HDT. Symptoms were recorded in the two groups
      during HDT (nasal congestion, sensation of head fullness, headache, and others)
      and graded on a four-point scale, from absent to serious. Results showed that
      group I had a higher symptoms score while group II had a lower symptoms score.
      Although this difference did not reach statistical significance, it suggests that
      cerebral blood flow changes may be partly responsible for the symptoms observed
      in subjects during HDT.

PMID- 10417004
TI  - Cancer incidence in Republic of Bulgaria aircrew, 1964-1994.
AB  - BACKGROUND: This study includes all cases of cancer among Republic of Bulgaria
      Air Force and civil aviation aircrew. Cancer incidence, Standardized Incidence
      Ratios (SIRs) and 95% confidential intervals were calculated for the pilots,
      using data about cancer incidence in the same age groups of the male population
      of the Republic of Bulgaria for the same period of time, taken from the National
      Cancer Register. RESULTS: The results show a considerable difference in the
      structure of cancer among males in Bulgaria, as compared to male pilots
      (r<0.0001). While cancer of the respiratory system has the greatest incidence
      among the civil population, cancer of the bladder has the greatest incidence
      among pilots, followed by testicular and skin cancer. For the period under
      consideration there is a lower risk of malignant diseases in pilots as compared
      to the rest of the population. There is a higher risk of testicular cancer only
      in civil aviation pilots. For Air Force aircrew there is a 10-fold higher risk of
      bladder cancer as compared to the rest of the population. CONCLUSION: We
      established an interdependence between age and cancer incidence, cancer incidence
      being higher among pilots in the age group from 20-40 yr. For the remaining age
      groups, cancer incidence among the civil population is approximately 2.5 times
      higher. Of the pilots with cancer, 73.53% returned to a flying career after an
      average of 7 mo treatment.

PMID- 10417005
TI  - Report of ejections in the Spanish Air Force, 1979-1995: an epidemiological and
      comparative study.
AB  - BACKGROUND: Ejection seats have saved many lives with more than 80% of pilots
      having survived an ejection. Nevertheless, ejection injuries are seen in all
      modern air forces. PURPOSE: An epidemiological study has been carried out on the
      48 ejections made by the Spanish Air Force (SpAF) from 1979-1995. METHODS: From
      data facilitated by the Flight Safety Section of the SpAF Staff, by the Flight
      Safety Section of Squadrons, and from personal reports of pilots who survived
      ejections a form was created. Relationships between data concerning aeronautical
      parameters, pilot data and injuries have been found, and a comparative study was
      made between these results and data shown by air forces of other countries.
      RESULTS: Of 48 pilots who ejected, 7 died, 25 had severe injuries, 11 had minor
      injuries and 5 had no injuries. The reason for the ejections included 35 cases of
      technical failure, and 13 cases of human error. Of 43 surviving pilots, 23 were
      injured only at the egress phase, 1 1 only at landing, and 9 cases at both
      moments. None of the five pilots who ejected outside the ejection envelope were
      able to adopt the correct position. However, of 43 pilots who ejected within the
      envelope, 19 were seated in good position. Of 13 pilots who maintained control of
      the airplane, 9 were able to adopt a correct position. Of 35 pilots who effected
      the ejection without control of the aircraft, 25 were not able to achieve a
      correct seated position. CONCLUSIONS: The pilot position in the ejection seat,
      plane control, ejection inside the envelope, the pilot's training in how to
      assume the necessary body position at both egress and landing phases are
      determining factors for successful ejections.

PMID- 10417006
TI  - Cerebral artery blood velocity in normal subjects during acute decreases in
      barometric pressure.
AB  - To investigate the effect of acute changes in barometric pressure on regional
      cerebral perfusion we studied the middle cerebral artery (MCA) blood velocity in
      five healthy male volunteers by means of a low-pressure chamber. The MCA blood
      velocity, arterial blood and respiratory gases were measured at the barometric
      pressures of 1, 0.8, 0.65, and 0.5 atmospheres. The observed blood velocity (Vo)
      showed no systematic changes. Decreases in barometric pressure induced hypoxia
      and hypocapnia. When normalizing the MCA blood velocity (Vn) to a standard P(CO2)
      (5.3 kPa), thereby correcting for the hypoxic induced hypocapnia, we obtained an
      inverse relationship between cerebral artery blood velocity and arterial blood
      oxygen content (CaO2). The oxygen supply to the brain, estimated as the product
      of Vo and CaO2, decreased with lowering of the barometric pressure. However, the
      product of Vn and CaO2 remained constant. This suggests the existence of a
      regulatory mechanism attempting to maintain a constant oxygen supply to the brain
      during acute changes in CaO2, if the hyperventilation induced decrease in PCO2
      can be omitted. In the artificial situation of a low pressure chamber, our
      findings are quite similar to those obtained at sea level. This indicates that
      the underlying mechanisms of control of cerebral blood flow do not change during
      acute exposure to altitude.

PMID- 10417007
TI  - Cerebral arterial gas embolism in air force ground maintenance crew--a report of
      two cases.
AB  - Two cases of cerebral arterial gas embolism (CAGE) occurred after a decompression
      incident involving five maintenance crew during a cabin leakage system test of a
      Hercules C-130 aircraft. During the incident, the cabin pressure increased to 8
      in Hg (203.2 mm Hg, 27 kPa) above atmospheric pressure causing intense pain in
      the ears of all the crew inside. The system was rapidly depressurized to ground
      level. After the incident, one of the crew reported chest discomfort and fatigue.
      The next morning, he developed a sensation of numbness in the left hand, with
      persistence of the earlier symptoms. A second crewmember, who only experienced
      earache and heaviness in the head after the incident, developed retrosternal
      chest discomfort, restlessness, fatigue and numbness in his left hand the next
      morning. Both were subsequently referred to a recompression facility 4 d after
      the incident. Examination by the Diving Medical Officer on duty recorded left
      sided hemianesthesia and Grade II middle ear barotrauma as the only abnormalities
      in both cases. Chest X-rays did not reveal any extra-alveolar gas. Diagnoses of
      Static Neurological Decompression Illness were made and both patients
      recompressed on a RN 62 table. The first case recovered fully after two
      treatments, and the second case after one treatment. Magnetic resonance imaging
      (MRI) of the brain and bubble contrast echocardiography performed on the first
      case 6 mo after the incident were reported to be normal. The second case was lost
      to follow-up. Decompression illness (DCI) generally occurs in occupational groups
      such as compressed air workers, divers, aviators, and astronauts. This is
      believed to be the first report of DCI occurring among aircraft's ground
      maintenance crew.

PMID- 10417008
TI  - Hyperhomocysteinaemia and upper extremity deep venous thrombosis: a case report.
AB  - A case is presented of a 24 yr old military aircrew applicant who developed a
      right axillary subclavian deep venous thrombosis following physical exertion.
      Investigations revealed damage to the right axillary subclavian venous system and
      limitation to flow. Coagulation studies also showed an elevated plasma
      homocysteine level. Hyperhomocysteinemia has recently been recognized as a risk
      factor for venous thromboembolic disease. Damage caused by the thrombosis, the
      hyperhomocysteinemia and environmental factors encountered in flight, may
      predispose him to recurrent episodes of thrombosis. This complex case involves
      aspects of hematology and the nature of coagulation which are only just being
      elucidated and as yet are poorly understood, and highlights some serious
      aeromedical implications for pilots afflicted with these conditions.

PMID- 10417009
TI  - Pharmaceutical use by U.S. astronauts on space shuttle missions.
AB  - We evaluated in-flight use of medications from astronaut debriefings after 79
      U.S. Space Shuttle missions. From the 219 records obtained (each representing one
      person-flight), 94% included some medication being taken during flight; of that
      number, 47% were for space motion sickness, 45% for sleep disturbances, and
      smaller percentages for headache, backache, and sinus congestion. Drugs were
      taken most often orally, followed in decreasing order of frequency by intranasal,
      intramuscular, and rectal routes. Drugs for space motion sickness were taken
      mostly during the first 2 d of flight, drugs for pain during the first 4 d, and
      drugs for sleeplessness and sinus congestion were taken consistently for 9 flight
      days. About 85% of all doses had no reported side effects, and most of the side
      effects that were reported happened during the first mission day. About 80% of
      the drug-dose events were perceived effective by the recipients; most of the
      reports of ineffectiveness occurred during the first mission day. Promethazine,
      the only drug given by three different routes (orally, intramuscularly, and
      rectally), was most effective and had minimal side effects when taken
      intramuscularly. This information, although useful, should be expanded to include
      objective measures of effectiveness so that therapeutic efficacy can be assessed
      during flight.

PMID- 10417010
TI  - Visual symptoms and G-LOC in the operational environment and during centrifuge
      training of Turkish jet pilots.
AB  - BACKGROUND: High-performance fighter aircraft produce high-sustained +Gz forces
      with rapid onset rates. Because of this G-producing capability, military jet
      pilots are subjected to physiological stress, which may lead to visual
      disturbances and G-induced loss of consciousness (G-LOC). Although visual
      disturbances are very common in jet flights, G-LOC is relatively rare but more
      dangerous. The frequency and causes of G-LOC need to be determined in the
      interest of flight safety. METHODS: Part I. A survey was conducted on Turkish jet
      pilots to reveal the incidence of symptoms due to +Gz acceleration. Anonymous
      questionnaires were given to F-16, F-4, and F-5 pilots. They consisted of
      inquiries about the occurrence of visual symptoms and/or G-LOC during +Gz
      acceleration in the operational environment. Part II. During the years 1992-1996,
      486 F-16, 801 F-4, and 256 F-5 fighter pilots underwent high "G" training at
      Turkish Aerospace Medical Center and they were assessed in terms of G-LOC rates.
      RESULTS: Part I. A total of 325 pilots who flew T-37 in undergraduate pilot
      training (UPT) answered the questionnaire. The pilots were divided into 3 groups
      according to the types of aircraft, which they fly now: 116 F-16, 182 F-4, and 27
      F-5 pilots. A total of 311 pilots (95.7%) reported having experienced greyouts
      and/or blackouts. With 25 pilots (7.7%) experiencing G-LOC, the G-LOC frequency
      according to the type of aircraft was: 5.2% (T-37) [in UPT]; 4.3% (F-16), 1.6% (F
      4), and 0% (F-5). Part II. In centrifuge training, the incidence of G-LOC in
      pilots of the various types of aircraft were: 12% (F-16), 6.4% (F-4), and 8.6% (F
      5). CONCLUSIONS: Centrifuge training reduces G-LOC rates of subsequent centrifuge
      training; and it is hoped might reduce the G-LOC rate in the operational
      environment. Almost all jet pilots reported having experienced +Gz related visual
      symptoms, but G-LOC seems to be a more common problem for pilots who fly rapid
      onset rate aircraft than pilots who fly high "G" capable but lower G onset rate
      aircraft.

PMID- 10417011
TI  - Soviet pilot-physician program.
AB  - The program for training pilot-physicians was started in 1952. It was the first
      and the only one in the history of the USSR/Russia. Young military physicians
      from different military forces and graduates of the Saratov Military Medical
      Faculty were invited to participate in the program. Selected military physicians
      were sent for 2 yr of flight training. Six graduates from Omsk School became
      bomber pilots, while eight graduates from Chuguev School were appointed
      instructor pilots. Special positions and regulations for pilot-physicians were
      not created. Some pilot-physicians continued their aviation career, and some
      returned to medicine. For a short time a limited number of pilot-physician
      positions existed in the research institute in Moscow. Two graduates from this
      program were appointed to these positions. One of the pilot-physicians became a
      cosmonaut; and at least six obtained scientific degrees in medicine and made
      significant contributions to the development of aerospace medicine.

PMID- 10417012
TI  - You're the flight surgeon. Irregular appearance and variegated color of a lesion.

PMID- 10417013
TI  - You're the flight surgeon. Occasional episodes of light-headedness, dizziness and
      nausea.

PMID- 10417014
TI  - Prevention of minor neck injuries in F-16 pilots.

PMID- 10417015
TI  - 1999 award winners of the Aerospace Medical Association.

PMID- 10417016
TI  - FAA aeromedical training programs for civil aviation pilots.

PMID- 10417017
TI  - Health and cost-benefits of chlamydia screening in young women.
AB  - BACKGROUND: The Health Plan Employer Data and Information Set (HEDIS) is a set of
      performance measures used to assess the quality of care delivered in managed care
      plans. New measures that address unevaluated areas of care are continuously being
      developed. Chlamydia screening among young women is one new measure that was
      recently adopted by the National Committee for Quality Assurance (NCQA) for
      inclusion in HEDIS. An essential criterion for new measures is that the clinical
      intervention is beneficial to health and cost-effective. GOAL: To assess the
      health benefits and cost-effectiveness of chlamydia screening among young women.
      STUDY DESIGN: A focused review of the literature was performed using Medline.
      Articles addressing the epidemiology of chlamydia infection, its health
      consequences, and the benefits, problems, and cost-effectiveness associated with
      chlamydia screening are reviewed. RESULTS: The literature reviewed shows
      scientific and cost-effectiveness data that support the adoption of the HEDIS
      measure for chlamydia screening among young women. CONCLUSION: The National
      Committee for Quality Assurance's recent adoption of the measure for chlamydia
      screening among young women into the formal HEDIS measurement set is justifiable
      from a health benefit standpoint and from a cost-effectiveness standpoint.

PMID- 10417018
TI  - Factors associated with hepatitis B vaccination among men having sexual relations
      with men in Montreal, Quebec, Canada. Omega Study Group.
AB  - OBJECTIVE: To determine factors associated with hepatitis B virus (HBV)
      vaccination status among HIV-uninfected men who have affective and sexual
      relations with men (MASM) in Montreal, Quebec, Canada. METHODS: The Omega Cohort
      is a study of the incidence and psychosocial determinants of HIV infection among
      MASM in Montreal. Participants complete a questionnaire and are HIV-tested every
      6 months. At baseline, we also performed testing for HBV markers and collected
      data on HBV vaccination history. RESULTS: Forty-six percent of 653 participants
      had received at least one dose of HBV vaccination, whereas 28% were completely
      vaccinated. Lack of vaccination was associated with injection drug use, having >
      or =20 regular lifetime partners, living outside Montreal, not having sex in
      bathhouses, and not having consulted a physician aware of the participant's
      sexual orientation. Among vaccinated MASM, incomplete vaccination was associated
      with having <20 lifetime casual partners, trading sex for drugs, having given
      goods for sex, having had unprotected anal sex with regular partners, and having
      no history of a previous sexually transmitted disease. CONCLUSION: A significant
      proportion of Montreal's MASM, some of whom are at risk of contracting HBV
      through sexual and parenteral transmission, have not been vaccinated for HBV. Men
      who have affective and sexual relations with men should be educated about the
      risk of HBV transmission and the seriousness of the disease.

PMID- 10417019
TI  - PCR-detected Chlamydia trachomatis infections from the uterine cervix of young
      women from the general population: prevalence and risk determinants.

PMID- 10417020
TI  - Correlates of herpes simplex virus seroprevalence among women attending a
      sexually transmitted disease clinic.
AB  - BACKGROUND: Infections by herpes simplex viruses type 1 (HSV-1) and type 2 (HSV
      2) are common in the United States. Herpes simplex virus type 2 is transmitted
      sexually, and the prevalence of antibodies to HSV-2 has increased in recent
      years. GOALS OF THIS STUDY: The objective of the present study was to estimate
      the seroprevalence of HSV-1 and HSV-2 antibodies among women attending a sexually
      transmitted disease (STD) clinic and to evaluate factors associated with HSV-1
      and HSV-2 seropositivity. STUDY DESIGN: The report describes a cross-sectional
      study conducted at an STD clinic. This study included 1,103 women between the
      ages of 18 and 35. Eighty-nine percent of the subjects were African Americans.
      The remaining subjects were white. RESULTS: The overall prevalence of HSV-1 and
      HSV-2 antibodies among study subjects was 72% and 64%, respectively. Both HSV-1
      and HSV-2 seropositivity were related directly to age and were higher among
      African Americans than whites. The prevalence of HSV-2 antibodies also increased
      with the number of lifetime sexual partners, an early age at first coitus, a
      history of syphilis, and the absence of HSV-1 antibodies. Drug use and recent use
      of barrier contraception were unrelated to either HSV-1 or HSV-2. COMMENT:
      Despite efforts by the public health community to prevent AIDS by promoting safe
      sexual practices, the prevalence of HSV-2 seropositivity has increased in recent
      years. Increased numbers of partners and an early age at first coitus are
      important correlates of HSV-2 infection. Public health interventions to prevent
      HSV-2 infection should target teenagers. Women of reproductive age attending STD
      clinics may also comprise an important target for interventions to prevent
      perinatal herpes.

PMID- 10417021
TI  - Investigation of a suspected outbreak of vaginal trichomoniasis among female
      inmates.
AB  - BACKGROUND AND OBJECTIVES: Female inmates have high rates of sexually transmitted
      diseases (STDs), and many incarcerated women and jail providers believe STDs are
      acquired within the jail. We investigated a suspected outbreak of trichomoniasis
      among female inmates and described the epidemiology of trichomonas infection.
      GOALS OF THIS STUDY: To determine the likelihood of within-jail acquisition of
      trichomoniasis. STUDY DESIGN: Retrospective chart review of gynecologic visits to
      the jail medical clinic and comparison of trichomoniasis surveillance data over a
      6-year time period. RESULTS: The minimum prevalence of trichomoniasis infection
      among 450 female inmates presenting to the medical clinic for gynecologic
      evaluation was 37%. Most infections were diagnosed early after incarceration, no
      woman developed a new infection after adequate treatment, and there was no
      clustering of cases by time or location. CONCLUSION: There was no evidence to
      support within-jail acquisition of trichomoniasis. The high rate of
      trichomoniasis and other STDs among incarcerated women warrant more comprehensive
      jail-based STD screening programs.

PMID- 10417022
TI  - Estimated incidence and prevalence of genital Chlamydia trachomatis infections in
      the United States, 1996.
AB  - BACKGROUND AND OBJECTIVE: Because genital Chlamydia trachomatis infections and
      their sequelae have a major impact on individuals and the health care system, it
      is important to periodically update estimates of chlamydia incidence and
      prevalence in the United States. STUDY DESIGN: Chlamydia incidence and prevalence
      were estimated using: (1) a method based on estimates of population-specific
      chlamydia prevalence, and (2) a method based on the chlamydia-to-gonorrhea case
      rate ratio. RESULTS: Using the prevalence-based method, point prevalence among
      persons 15 to 44 years of age was estimated to be 1.6 million chlamydial
      infections, and annual incidence, 2.4 million cases per year. Using a method
      based on the ratio of reported gonorrhea to chlamydia, incidence was estimated to
      be 2.8 million infections per year, and prevalence, 1.9 million. Adjustment for
      sensitivity of diagnostic tests yielded annual incidence estimates of 2.5 to 3.3
      million infections. CONCLUSIONS: Using two methods, we estimated the annual
      incidence of chlamydial infections in the United States among persons 15 to 44
      years of age to be approximately 3 million infections. Critical data needed for
      more precise estimates include: sensitivity of current diagnostics, better data
      on infections in males, the current extent of underdetection and underreporting,
      and better data on duration of infection in men and women.

PMID- 10417023
TI  - Invoking, monitoring, and relinquishing a public health power: the health hold
      order.
AB  - OBJECTIVE: To describe a quarter-century's use of a public health power (Health
      Hold Orders) as an adjunct to noncoercive sexually transmitted disease (STD)
      control efforts in a middle-American city. METHODS: Persons arrested for
      prostitution were involuntarily detained for up to 72 hours if they had not been
      tested for STD within 30 days of arrest. Such persons were mandatorily
      tested/treated for STD and voluntarily tested for HIV by health department
      providers in Colorado Springs from mid-1970 through 1994. RESULTS: Prostitutes
      viewed temporary detention as inconvenient, but not as inappropriate. Over the 25
      year interval, 4,965 examinations in prostitutes yielded 818 positive gonorrhea
      tests; the 1,564 tests performed under the health-hold order yielded 218 positive
      results. Positivity rates among prostitutes locally for reportable STD/HIV
      declined substantially during the period of observation, providing support for
      termination of the involuntary detention system. CONCLUSIONS: The involuntary
      detention system contributed to observed communitywide declines in STD/HIV
      prevalence. Our experience demonstrates the importance of surveillance and
      empiric validation in public health practice.

PMID- 10417024
TI  - The role of the police power in 21st century public health.
AB  - The police power is the right of the state to take coercive action against
      individuals for the benefit of society. The companion article by Potterat et al.,
      "Invoking, monitoring, and relinquishing a public health power: the health hold
      order," is a classic use of the police power in the control of a communicable
      disease, yet one that is increasingly controversial. Reaching an acceptable
      balance between the rights of society and those of individuals is the central
      issue facing public health in the next millennium, and the police power is at the
      center of this balance. This article reviews the constitutional basis of the
      police power, its historical use in public health, and the structural reasons why
      health departments preoccupied with personal health care cannot effectively use
      the police power to carry out public health enforcement.

PMID- 10417025
TI  - Association between auxotypes, serogroups, and antibiotic susceptibilities of
      Neisseria gonorrhoeae isolated from women in Mumbai (formerly Bombay), India.
AB  - OBJECTIVES: Gonococcal isolates were differentiated based on susceptibility
      pattern, penicillinase production (PPNG or non-PPNG), serogroup, auxotype,
      protein, and plasmid profile. The association between serogroup and auxotype and
      PPNG was determined. STUDY DESIGN: Women attending tertiary level health centers
      and the sexually transmitted disease (STD) clinic in Mumbai, India, were screened
      for Neisseria gonorrhoeae. Minimal inhibitory concentration testing was performed
      according to National Committee for Clinical Laboratory Standards (NCCLS)
      guidelines. Auxotypes, serogroups, protein profile, and plasmid content were also
      studied. RESULTS: Of the 33 isolates, 16 (48.5%) were resistant to penicillin,
      and 28 (84.8%) showed a chromosomally mediated resistance to tetracycline. Five
      (15.2%) isolates showed resistance to ciprofloxacin, whereas 12 (36.4%) showed a
      reduced susceptibility. Twenty-seven (81.8%) isolates belonged to the WI
      serogroup, and 15 (46.7%) were penicillinase producers (PPNG). Seventeen (51.5%)
      isolates were of the nonrequiring auxotype, whereas seven (21.2%) were proline
      requiring. Fifteen (55.6%) of the isolates belonged to the nonrequiring-WI
      auxotype/serogroup (A/S) class. Ten of the PPNG isolates possessed the 4.4 MDa
      plasmid, whereas four had the 3.2 MDa plasmid. Increases in the molecular weight
      of the major outer membrane protein were observed. CONCLUSION: A high prevalence
      of chromosomal resistance to penicillin and tetracycline was observed. The 4.4
      MDa plasmid was the most prevalent among the PPNG isolates. We observed
      ciprofloxacin resistance, which has not been reported in previous studies in
      India. The nonrequiring auxotype was the most prevalent, followed by the proline
      requiring auxotype. WI serogroup was the most commonly observed among the
      isolates studied. The nonrequiring/WI A/S class was the most prevalent among the
      PPNG.

PMID- 10417026
TI  - An interactive, computer-based program to educate patients about genital herpes.
AB  - BACKGROUND AND OBJECTIVES: Education and counseling constitute a substantial
      portion of management of patients with genital herpes. Innovative methods for
      education about genital herpes are needed. GOAL: To test the ability of an
      interactive, computer-based program to educate patients about genital herpes.
      STUDY DESIGN: Persons seeking care at five urban offices were asked to
      participate. A knowledge test about genital herpes was administered before and
      after participation. Participants' satisfaction was assessed with a
      questionnaire. RESULTS: Four hundred thirty-five participants enrolled, and 428
      completed the herpes knowledge test. Of six questions evaluated, a statistically
      significant increase in the proportion of correct answers was noted on five of
      six questions. Fifty-one percent of participants answered all the questions
      correctly after the program, compared with 39% before the program. Satisfaction
      with the program was very high. CONCLUSIONS: Innovative, computer-based programs
      can provide education and assist in the management of chronic sexually
      transmitted infections.

PMID- 10417027
TI  - Dementia with Lewy bodies: review and pharmacotherapeutic implications.
AB  - Alzheimer's disease accounts for 50-60% of dementia cases in older people.
      Dementia with Lewy bodies is now recognized as the second most common type of
      dementia. It is different from Alzheimer's disease and has important
      pharmacotherapeutic implications. Key features include early-onset, persistent,
      well-formed, visual hallucinations and motor features of parkinsonism.
      Pharmacologic management of neurobehavioral symptoms is complicated by an
      exaggerated response to neuroleptics, which causes excessive morbidity and
      mortality. Patients with dementia with Lewy bodies may be particularly responsive
      to cholinesterase inhibitors. When neurobehavioral symptoms are severe enough to
      require pharmacologic intervention, it is recommended that agents such as
      trazodone or cholinesterase inhibitors be considered first-line therapy. If these
      fail, neuroleptics may be prescribed with caution.

PMID- 10417028
TI  - Treatment of ACE inhibitor-induced cough.
AB  - Angiotensin-converting enzyme (ACE) inhibitors are widely administered to treat
      numerous medical conditions. Although they are generally well tolerated, they are
      associated with a dry cough that can lead to discontinuation of treatment. Data
      concerning the frequency, onset, and clinical effects vary among the agents. When
      discontinuing the ACE inhibitor is not an ideal option, pharmacologic treatment
      of the cough may be considered, such as cromolyn, baclofen, theophylline,
      sulindac, and local anesthetics.

PMID- 10417029
TI  - Atypical antipsychotics in older adults.
AB  - Psychotic symptoms are common in older adults and reflect a variety of
      psychiatric and medical conditions. Antipsychotic drugs form the core of the
      treatment of these symptoms; however, treatment of the elderly is complicated by
      a high frequency of comorbid medical illnesses, risk of side effects, and age
      related changes in pharmacodynamics and pharmacokinetics. The superior safety and
      efficacy of atypical antipsychotics makes them first-line agents for managing
      psychotic patients with schizophrenia. Their uses now extend to other conditions
      such as schizoaffective disorders, delusional disorder, and mood disorders with
      psychotic features. Although the drugs have been studied extensively in young
      subjects, well-designed, double-blind, placebo-controlled studies are relatively
      lacking in the elderly. Our knowledge of their safety, efficacy and dosage in
      older adults is based on a few studies with small samples or extrapolated from
      studies of younger patients. Several psychiatric and medical conditions that are
      associated with psychotic symptoms in older people are reviewed, as well as how
      these patients may benefit from treatment with these agents.

PMID- 10417030
TI  - Management of and counseling for psychotropic drug-induced sexual dysfunction.
AB  - Clinicians are increasingly faced with the need to identify, treat, and counsel
      patients regarding psychotropic drug-induced sexual dysfunction. Antipsychotic
      and antidepressant drugs have both rational mechanisms to explain their effects
      on sexual function and established literature documenting these effects. The
      agents have potential for causing decreased libido, delayed ejaculation, and
      anorgasmia. Management and counseling can be highly effective for patients taking
      these agents.

PMID- 10417031
TI  - The effect of amiodarone on the ventricular fibrillation threshold.
AB  - We evaluated the antifibrillatory effect of two different doses of amiodarone
      after cardiac arrest with a cardiopulmonary resuscitation (CPR) model in 19 pigs.
      Ventricular fibrillation was induced by pacing the right ventricle using a
      primary drive train at a cycle length of 270 msec for 8 beats. The minimum
      current strength necessary to induce sustained ventricular fibrillation was
      defined as the ventricular fibrillation threshold (VFT) measured in mA. Three VFT
      determinations were made at baseline, followed by 9 minutes of continuous CPR
      with two determinations of VFT, and three after stabilization. The pigs were
      placed into one of three groups: amiodarone 2 or 5 mg/kg, or placebo. The average
      poststabilization VFT in each group was compared with the average baseline VFT.
      Pigs receiving amiodarone 2 mg/kg had significantly higher VFT after
      stabilization than at baseline (22.88+/-12.76 to 27.10+/-10.18 mA, p=0.048), as
      did those receiving 5 mg/kg (17.03+/-7.01 to 28.08+/-11.58 mA, p=0.002). The
      deltaVFT was significantly greater with amiodarone 5 mg/kg than with vehicle
      (placebo), but not with 2 mg/kg. There were no changes in VFT in any group during
      CPR versus baseline. When active treatments were combined, the trend was toward
      better survival in the amiodarone groups (13/13) compared with the placebo group
      (4/6, p=0.076).

PMID- 10417032
TI  - Can we justify ipratropium therapy as initial management of acute exacerbations
      of COPD?
AB  - Although inhaled ipratropium is commonly accepted as the drug of choice for long
      term management of chronic bronchitis and emphysema, little evidence is available
      to promote its administration in conjunction with a beta2-agonist as part of
      initial management of exacerbations of chronic obstructive pulmonary disease
      (COPD) in the acute care setting. Reasons for its widespread acceptance for
      acutely ill patients may include its status as a first-line agent for long-term
      therapy, its relative safety, and attempts to provide optimal patient care. Since
      inhaled ipratropium is beneficial as immediate therapy for asthma in the
      emergency department, some practitioners attempted to extrapolate these findings
      to treatment of COPD. Review of available studies reveals wide variability in
      methodologies and results. Although some studies reported improvement in
      pulmonary function tests, no clinically significant differences in patient
      outcomes, including shorter hospitalization, were evident. In patients who fail
      traditional therapies, inhaled ipratropium is reasonable. Double-blind,
      randomized, placebo-controlled trials in patients receiving emergency department
      care and in hospitalized patients that reveal shorter length of stay or other
      improved outcomes, are necessary to establish routine addition of inhaled
      ipratropium to beta2-agonists in the initial management of acute COPD.

PMID- 10417033
TI  - Phenytoin and fosphenytoin: a model of cost and clinical outcomes.
AB  - We developed a pharmacoeconomic model to compare costs and clinical outcomes of
      administering phenytoin and fosphenytoin alone and in combination in hospitalized
      patients. Effectiveness data were obtained by distributing a questionnaire to 33
      registered nurses at three acute care hospitals who worked in critical care,
      neurology services, or emergency department. The questionnaire addressed methods
      of phenytoin and fosphenytoin administration, frequency of adverse reactions,
      methods of treating adverse reactions, and demographic information. The model
      estimated that if 50% of phenytoin loading doses were substituted with
      fosphenytoin, a reduction in adverse events resulted in an estimated increase of
      $36/patient cost to the hospital. If phenytoin maintenance dosages were
      substituted with fosphenytoin, the model predicted essentially no change in cost
      to the hospital. It appears that fosphenytoin reduces adverse events at a
      reasonable increase in total hospital costs.

PMID- 10417034
TI  - Low-dose diclofenac, naproxen, and ibuprofen cohort study.
AB  - The risk of a newly diagnosed episode of upper gastrointestinal bleeding, acute
      liver and renal failure, agranulocytosis, aplastic anemia, severe skin disorders,
      and anaphylaxis was examined within 30 days after the first prescription for a
      low dose of diclofenac, naproxen, or ibuprofen in a cohort in the United Kingdom.
      We identified 22,146 persons using diclofenac (< or = 75 mg), 46,919 using
      naproxen (< or = 750 mg), and 54,830 using ibuprofen (< or = 1200 mg). Age,
      gender, and comorbidity were similar in the three cohorts. Overall 64 potential
      cases were identified, and 20 were confirmed by medical record review. Incidence
      rates (95% CI) of upper gastrointestinal bleeding/10,000 people using diclofenac,
      naproxen, and ibuprofen were 1.8 (0.5-4.6), 2.3 (1.2-4.2), and 0.4 (0.04-1.3),
      respectively. There were three cases of hepatic injury, one with naproxen and two
      with ibuprofen. Although low, the incidence of gastrointestinal toxicity remains
      the main serious adverse event for all study drugs.

PMID- 10417035
TI  - Pharmaceutical care of patients with congestive heart failure: interventions and
      outcomes.
AB  - We evaluated a structured pharmaceutical care program for elderly patients (> 65
      yrs) with congestive heart failure (CHF) based on objective measures of disease
      control, quality of life, and use of health care facilities in a randomized,
      controlled, longitudinal, prospective clinical trial. The 42 patients in group A
      received education from a pharmacist on the disease and its treatment, and
      lifestyle changes that could help control symptoms. Patients also were encouraged
      to monitor their symptoms and comply with prescribed drug therapy. If necessary,
      dosage regimens were simplified in liaison with hospital physicians. The 41
      control patients (group B) received standard care. The following outcome measures
      were assessed in all patients at baseline (before the start of the trial) and at
      3, 6, 9, and 12 months: 2-minute walk test, blood pressure, body weight, pulse,
      forced vital capacity, quality of life [disease-specific (Minnesota Living with
      Heart Failure questionnaire) and generic (SF-36)], knowledge of symptoms and
      drugs, compliance with therapy, and use of health care facilities (hospital
      admissions, visits to emergency room, emergency calls). Patients in group A
      showed improved compliance with drug therapy, which in turn improved their
      exercise capacity compared with those in group B; education on management of
      symptoms, lifestyle changes, and dietary recommendations were also of benefit.
      Group A patients significantly improved knowledge of their drug therapy over the
      12-month study and had fewer hospital admissions compared with group B patients.
      They also had improved outcomes compared with group B, despite the small samples.
      An extension of this trial to other sites with pooling of results would provide
      additional evidence of the value of this structured program in elderly patients
      with CHF.

PMID- 10417036
TI  - Potentiation of warfarin by dong quai.
AB  - Dong quai is a Chinese herbal supplement touted for treatment of menstrual
      cramping, irregular menses, and menopausal symptoms. Phytochemical analyses found
      it to consist of natural coumarin derivatives, as well as constituents possessing
      antithrombotic, antiarrhythmic, phototoxic, and carcinogenic effects. A 46-year
      old African-American woman with atrial fibrillation stabilized on warfarin
      experienced a greater than 2-fold elevation in prothrombin time and international
      normalized ratio after taking dong quai concurrently for 4 weeks. No identifiable
      cause was ascertained for the increase except dong quai. The patient's
      coagulation values returned to acceptable levels 1 month after discontinuing the
      herb. One animal study suggests a pharmacodynamic interaction between the product
      and warfarin, but the true mechanism remains unknown. Practitioners should be
      aware of the possibility of such an interaction and should inform patients of
      potential hazards of taking the two together.

PMID- 10417037
TI  - Lamotrigine-induced blepharospasm.
AB  - Movement disorders such as tremor and ataxia occur commonly during therapy with
      antiepileptic drugs (AEDs). Dystonias, however, are rare. Blepharospasm, although
      reported with neuroleptic agents, has never been reported with AEDs. Our patient
      developed blepharospasm during therapy with lamotrigine.

PMID- 10417038
TI  - Acute myocardial infarction associated with anabolic steroids in a young HIV
      infected patient.
AB  - The use and abuse of anabolic-androgenic steroids have increased over the past
      decade and pose a medical and public health problem. In addition to their use by
      athletes to increase muscle mass and improve performance, people with wasting and
      malignant diseases are finding that the agents improve both their physical
      appearance and strength. Unfortunately, anabolic steroids are associated with a
      number of adverse effects, not the least of which is acute myocardial infarction,
      which occurred in a 39-year-old man with human immunodeficiency virus infection.
      It is important for clinicians to be aware of the association and to counsel
      patients carefully about this and other untoward effects that may occur with the
      agents.

PMID- 10417039
TI  - Generalized tetanus in a patient with a diabetic foot infection.
AB  - Tetanus is a preventable disease that continues to affect people in the United
      States due to poor immunization practices in our health care system. A 57-year
      old man with type 2 diabetes mellitus, hypertension, and end-stage renal disease
      with many hospital admissions came to the hospital emergency department because
      of a blackened great toe. He denied pain in the toe or knowledge of foot injury.
      The patient also complained of temporomandibular tenderness accompanied by
      inability to open his mouth completely. The man's problems progressed to
      generalized tetanus and required a long hospitalization. Clostridium tetani can
      flourish in the anaerobic environment of a diabetic foot infection. Practitioners
      should be aware of tetanus as a rare but potentially serious complication of
      diabetic foot infections.

PMID- 10417040
TI  - Sudden hearing loss associated with tacrolimus in a kidney-pancreas allograft
      recipient.
AB  - A 38-year-old woman with type 1 diabetes underwent kidney-pancreas
      transplantation. Her postoperative course was complicated due to recurrent acute
      graft rejections and pancreatitis. After initial immunosuppression with
      microemulsion cyclosporine, mycophenolate mofetil, and prednisone with muromonab
      CD3 induction, cyclosporine was switched to tacrolimus on day 44. The initial
      dosage was 5 mg twice/day, but it was gradually increased to 10 mg twice/day,
      aiming at 15-20 ng/ml. On day 17 of tacrolimus therapy the woman developed sudden
      hearing loss with tinnitus. The serum tacrolimus level was 28.3 ng/ml
      (therapeutic range 10-20 ng/ml) on day 20 of tacrolimus therapy, and peaked at
      34.9 ng/ml on day 28. Two audiograms performed on days 28 and 29 confirmed
      bilateral hearing loss of 80% for speech perception, characterized as mild to
      moderate sensorineural hearing loss with speech reception threshold of 35 dB
      (normal < 20 dB) in both ears. The tacrolimus dosage was gradually reduced to 6
      mg twice/day by day 36, with drug level 9.7 ng/ml, after which her hearing
      gradually recovered.

PMID- 10417041
TI  - Serotonin syndrome in a child associated with erythromycin and sertraline.
AB  - Serotonin syndrome is an uncommon, serious adverse reaction that is usually
      associated with the interaction of two or more serotonergic agents. A 12-year-old
      boy receiving sertraline developed the syndrome after erythromycin was added to
      his regimen. The proposed mechanism involves erythromycin inactivation of
      cytochrome P450 3A4 inhibition of sertraline metabolism, accumulation of the
      drug, and precipitation of the syndrome. It is important for clinicians to
      consider both pharmacokinetic and pharmacodynamic interactions to minimize the
      risk of the reaction.

PMID- 10417042
TI  - Prolonged opioid antagonism with naloxone in chronic renal failure.
AB  - Respiratory depression secondary to morphine intoxication occurred in an elderly
      patient with chronic renal failure (CRF). It was reversed with a continuous
      infusion of naloxone. Approximately 11 hours after the infusion was discontinued,
      the patient relapsed into respiratory depression consistent with opioid
      intoxication. He was rechallenged with a naloxone infusion with resolution of the
      opioid effects. This case suggests prolonged antagonism of opioid effects
      inconsistent with naloxone's reported pharmacologic effects. Serum naloxone
      concentrations measured after the end of the infusion suggest that the drug's
      pharmacokinetics were significantly altered. Further research is necessary to
      characterize pharmacokinetic changes that occur in CRF. In the absence of this
      information, similar patients should be closely monitored for relapse of
      respiratory depression after naloxone is discontinued.

PMID- 10417043
TI  - Potential interaction between azithromycin and warfarin.
AB  - Azithromycin is considered unlikely to interact with warfarin. Unlike other
      macrolide antibiotics, it is not hepatically metabolized and did not produce an
      interaction with warfarin in a single-dose study. A 71-year-old woman with a
      prosthetic heart valve, stabilized with warfarin, had international normalized
      ratios (INRs) maintained between 2.5 and 3.5. Six days after she received a
      prescription for a 5-day course of azithromycin, her INR was 15.16. Phytonadione
      10 mg was administered subcutaneously, and warfarin was held for 3 days until her
      INR fell to 2.10. She then was restabilized with warfarin. Until more information
      is known about the safety of warfarin and azithromycin, caution is advised when
      the agents are given together. Close monitoring of INR is recommended, and
      warfarin dosage adjustment may be necessary.

PMID- 10417044
TI  - Changing approaches to transplant conditioning for hematologic malignancy.

PMID- 10417045
TI  - Autologous bone marrow transplants to hematopoietic stem cell support with
      peripheral blood stem cells: a historical perspective.

PMID- 10417046
TI  - TNF-alpha gene therapy with myeloid progenitor cells lacks the toxicities of
      systemic TNF-alpha therapy.
AB  - We examined the antileukemic activity and the toxicity of HPC transduced with
      human tumor necrosis factor (TNF) cDNA. Both clonal (32Dcl3) and BM-derived
      primary hematopoietic progenitors (BM-Prog) expressing hTNF-alpha gene (32DTNF
      alpha and BMTNF-alpha cells, respectively) inhibited the development of leukemia
      in mice with a small dose of 32Dp210 cells, a myeloid leukemia cell line. Whether
      the trans-gene expressing 32DTNF-alpha cells produce toxicities commonly
      associated with systemic TNF-alpha therapy was determined by examining the effect
      of TNF-alpha-secreting progenitor cells on body weight, tissue histology, growth
      of HPC, and engraftment of BMT. Administration of a low or high dose of TNF-alpha
      secreting 32DTNF-alpha cells to mice failed to produce loss in body weight, a
      measure of TNF-alpha-related cachexia. There was also no evidence of tissue
      necrosis or mononuclear cell (MNC) infiltration in lung, liver, kidney, or
      intestine of mice injected with transduced progenitor cells. Furthermore, 32DTNF
      alpha cells showed no effect on the clonal growth of HPC in colony-forming assays
      or loss of cellularity in BM, spleen, or blood. Finally, TNF-alpha-secreting
      cells were found not to interfere with the engraftment of BM transplant and
      hematopoietic reconstitution thereafter. We conclude from these findings that
      unlike systemic administration of TNF-alpha, TNF-alpha gene therapy with
      transduced HPC is nontoxic and may have a role in eradicating residual leukemia
      after BMT.

PMID- 10417047
TI  - Enhancement of hematopoietic reconstitution with recombinant cytokines: effect of
      rhIL-6 in combination with rhGM-CSF and rhIL-3 on unmodified or T cell-depleted
      bone marrow.
AB  - We have investigated the response of unmanipulated and lymphocyte-depleted BM
      cells (BMC), pretreated with monoclonal rat antihuman lymphocyte (CD52) antibody
      (Campath-1G) used for prevention of GvHD, to incubation with rhIL-6 alone or in
      combination with rhGM-CSF, rhIL-3, or both. We investigated optimal conditions
      needed for incubation of human BMC under conditions that can be upscaled for
      clinical application prior to autologous (auto-BMT) and allogeneic blood or BM
      transplantation (allo-BMT). When used as a single agent, rhIL-6 showed no or a
      minimal effect in enhancing in vitro CFU-GM colony formation of human BMC. A
      potent additive effect was obtained when rhIL-6 was added to rhGM-CSF, rhIL-3, or
      a combination of both. Binding of the mAb Campath-1G, which is used for in vivo
      and in vitro depletion of immunocompetent lymphocytes to BMC, did not reduce the
      enhancing effect of a combination of rhGM-CSF and rhIL-3 on CFU-GM in the
      presence or absence of rhIL-6. Our present and previously published observations
      suggest that enhancement of hematopoiesis by rhIL-6 and other hematopoietic
      growth factors is T cell independent. Based on the present observations, pilot
      clinical studies to determine the potential benefit of in vitro activation of BMC
      prior to BMT with various cytokine combinations, including rhIL-6, seems
      justified. Our goal is to enhance hematopoietic reconstitution in vivo, focusing
      on possible enhancement of platelet reconstitution in vivo toward safer auto-BMT
      and more effective allo-BMT with better engraftment of T cell-depleted allografts
      while avoiding GvHD.

PMID- 10417048
TI  - The absolute number of circulating CD34+ cells as the best predictor of
      peripheral hematopoietic stem cell yield.
AB  - Many controversies still exist about the timing of leukapheresis procedures for
      PBSC transplantation. Thirty-nine patients were followed daily by monitoring the
      absolute PB WBC count and CD34+ cell enumeration prior to apheresis. These
      determinations were compared with the apheresis cell content (nucleated cells and
      CD34+ cells yield). There was a highly significant correlation between PB CD34+
      cells and apheresis CD34+ cell yield (r = 0.921, p < 0.001). A small but
      significant correlation was found between the PB WBC count and the apheresis
      nucleated cell content (r = 0.383, p < 0.001), but no correlation was found
      between PB WBC count and apheresis CD34+ cell yield (r = -0.065, p = 0.460). A
      target value of 20 x 10(6) CD34+ cells/L was determined to be the most reliable
      predictor to collect at least 1.0 x 10(6) CD34+ cells/kg in a single apheresis.
      Of the 39 patients, 20 could be followed after transplantation, and a good
      correlation was found for total number of CD34+ cells reinfused and platelet and
      neutrophil engraftment. No correlation was found for nucleated cells infused and
      engraftment. CD34+ cell determination is a better predictor than WBC count for
      timing leukapheresis and is thus recommended for monitoring the quality of the
      product.

PMID- 10417049
TI  - Interferon as maintenance therapy in refractory malignant lymphoma.
AB  - Patients with refractory malignant lymphoma (RML) have a poor prognosis when
      treated with conventional chemotherapy, as less than 20% remain alive and free of
      disease after 5 years. The use of myeloablative chemotherapy followed by BMT has
      improved the complete remission (CR) rate. Nevertheless, relapse rates remain
      unchanged, and only a few patients remain alive and free of disease for more than
      3 years. For this reason, we began a prospective randomized clinical trial to
      determine if IFN-alpha2B (5.0 MU three times a week for 1 year) can improve the
      prognosis in RML. Ninety-six patients with high or high-intermediate clinical
      risk RML and in CR after intensive chemotherapy were randomly assigned to receive
      or not to receive IFN as maintenance therapy. A median follow-up of 48.1 months,
      the time to treatment failure and survival were similar in both groups. Toxicity
      secondary to IFN administration was mild, and all patients received the planned
      doses of IFN. We conclude that IFN is not recommended at this dose and schedule
      as maintenance therapy in patients with RML who achieve CR. Different therapeutic
      approaches may be developed to improve outcomes for these patients.

PMID- 10417050
TI  - Comparison of T-cell-depleted BMT and PBPCT with respect to chimerism, graft
      rejection, and leukemic relapse.
AB  - Chimerism analysis by DNA-based methods is a valuable diagnostic tool for
      monitoring engraftment and leukemic relapse after allogeneic BMT or PBPC
      transplantation (PBPCT). We investigated the chimerism after T-cell-depleted BMT
      (n = 32) in comparison with T-cell-depleted PBPCT (n = 39). BM grafts were T-cell
      depleted using the Campath-IgM antibody plus complement. For T-cell depletion of
      the PBPC grafts, a selection of CD34+ cells with or without a subsequent CD2/3
      depletion was performed. In all patients, the T-cell dose of the transplant was <
      10(6)/kg body weight. Between day 13 and day 120 after transplantation, chimerism
      analysis was done by RFLP or amplified fragment length polymorphism (PCR-AFLP),
      with a detection limit of 1%-5% recipient cells. In the BMT group, 8 of 32 (25%)
      patients showed a mixed chimerism, but only one graft rejection and no leukemic
      relapse occurred after a median follow-up of 41 (3-84) months. All patients with
      PBPCT revealed a complete chimerism of their granulocytes, and 38 of 39 patients
      showed complete chimerism of their lymphocytes. Follow-up time in these patients
      is 7 (2-21) months, with no graft rejection and two leukemic relapses. G-CSF
      mobilized PBPC are superior to BM cells for full engraftment even after T-cell
      depleted transplantation. The more relevant factor for developing complete
      chimerism seems to be the quantity and possibly the quality of the stem cells
      rather than the residual T-cell load of the graft. However, a mixed chimerism of
      the lymphocytes early after transplantation does not predict a higher rate of
      graft rejection or leukemic relapse.

PMID- 10417051
TI  - The differentiating effect of retinoic acid and vincristine on acute myeloid
      leukemia.
AB  - We have shown previously that granulocytic maturation and differentiation
      occurred when HL-60 cells and leukemia cells from a patient with acute
      promyelocytic leukemia (APL) were exposed to all-trans retinoic acid (ATRA) after
      treatment with a noncytotoxic concentration of vincristine (VCR), suggesting that
      VCR might have synergistic action with ATRA in the treatment of APL. Leukemic
      cells obtained from 24 patients with AML were exposed to 20 nM VCR for 1 h,
      followed by 1 microM ATRA for 6 days. Changes in the expression of myeloid
      leukocyte antigens were observed using flow cytometry. Differentiation phenotype
      as determined by the decrease or increase in maturation cell marker was observed
      in three samples treated with VCR alone, four samples treated with RA alone, and
      two samples treated with the combination of VCR and RA. The results suggest that
      treatment using VCR and ATRA may be effective in the differentiation therapy of
      AML.

PMID- 10417052
TI  - Immunotherapy of malignant melanoma in a SCID mouse model using the highly
      cytotoxic natural killer cell line NK-92.
AB  - In this work, we evaluated the potential of the natural killer (NK) cell line NK
      92 and its IL-2-independent variants NK-92MI and CI, as immunotherapy for
      melanoma. In vitro, we found that NK-92 was much more cytotoxic to a number of
      human melanoma cell lines than lymphokine-activated killer (LAK) cells,
      particularly at low effector/target (E:T) ratios. In vivo treatment of mice
      challenged with MEWO melanoma cells with i.v. administered NK-92 and NK-92-MI
      resulted in a 1.5-2.5-fold increase in average length of survival. NK-92, MI, and
      CI were also effective against the WM1341 cell line, causing a 2-5-fold increase
      in survival when administered before the malignant cells. With s.c. injection,
      MEWO and WM1341 caused a primary tumor mass, secondary tumors, and metastatic
      cells. NK-92 cells reduced WM1341 primary tumor size by 40-90% and MEWO tumors by
      30-75%. Similar results were seen with NK-92MI and CI. These data show that NK-92
      cells are highly cytotoxic to human melanoma cells in vitro and in vivo and
      suggest that treatment with NK-92 cells may be a potentially effective
      immunotherapeutic modality in melanoma.

PMID- 10417053
TI  - Serum granulocyte colony-stimulating factor kinetics in children receiving
      intense chemotherapy with or without stem cell support.
AB  - In a previous study, we speculated that the early phase of hematopoietic recovery
      after PBSC transplantation (PBSCT) is rapid because of the increased production
      of endogenous cytokines by co-transfused monocytes and lymphocytes (Kawano Y, et
      al. Blood 81:856, 1993). To clarify this point, the serum level of G-CSF was
      measured using an ELISA, and various other cytokines, including GM-CSF,
      macrophage-CSF (M-CSF), SCF, IL-6, IFN-gamma, and soluble IL-2 receptor (IL-2R),
      were tested for comparison in children receiving conventional or high-dose
      chemotherapy and autologous transplantation with unmanipulated or purified PBSC.
      Serum G-CSF levels in patients receiving conventional chemotherapy (n = 21) or
      PBSCT without exogenous G-CSF treatment (n = 19) increased to 1245 +/- 2337 pg/ml
      and 2741 +/- 2331 pg/ml, respectively. Likewise, the peak level of G-CSF in
      patients who did not receive G-CSF was statistically equivalent to the trough
      level in those who did. There was no significant difference in the speed of
      hematopoietic recovery with or without G-CSF treatment in both the conventional
      chemotherapy and PBSCT cohorts. In addition, no meaningful change was observed in
      the kinetics of other tested factors in either conventional therapy or PBSCT
      settings, regardless of whether the patient did or did not receive G-CSF.
      Endogenously produced serum peak G-CSF levels after PBSCT with purified CD34+
      cells were identical to those after the same procedure with unmanipulated cells.
      These results confirm that children receiving intense chemotherapy followed by
      autologous PBSCT produce a high level of G-CSF during the cytopenic period that
      is not due to the infusion of a large amount of facilitating cells capable of
      producing G-CSF.

PMID- 10417054
TI  - Graft engineering of G-CSF-mobilized allogeneic leukapheresis products by
      counterflow centrifugal elutriation after CD34 column adsorption.
AB  - A major hindrance to the use of PBSC in allogeneic transplantation is the high
      rate of contamination with T lymphocytes, resulting in a considerable risk of
      GvHD. Natural killer (NK) cells are active against tumor cells but do not
      contribute to the development of GvHD. After adsorption of CD34+ cells of
      mobilized allogeneic leukapheresis products on a Ceprate column, we studied the
      separation of CD34 unadsorbed cells by counterflow centrifugal elutriation (CCE).
      Up to 1.0 x 10(10) cells were clearly separated into lymphocytes (fractions 110
      and 140 ml/min), monocytes, and polymorphonuclear cells (fraction rotor off).
      Characterized by flow cytometry, T cells were distributed nearly equal to
      fractions 110 and 140. NK cells were concentrated 3.4-fold in fraction 140 as
      compared with the unseparated cells. The ratio of NK cells/T cells was improved
      by 33%. These results indicate that CCE is an effective method to enrich NK cells
      and to reduce T cells in stem cell separation products. Therefore, it is an
      option for adoptive therapy of cancer patients after transplantations (e.g., CML
      in relapse).

PMID- 10417055
TI  - Comparative evaluation of procedures with a Baxter CS-3000 cell separator for
      collecting peripheral blood cells from children.
AB  - The safety and efficacy of apheresis using a newly developed procedure with a
      small volume separation container holder (SVSCH, Baxter) for the collection of
      PBSC from children with cancer were retrospectively compared with our historical
      experience with other procedures using different equipment and the CS-3000 plus
      cell separator. The procedures tested included the application of (a) specialized
      collection protocol 4 using the combination of an SVSCH and a small volume
      collection chamber (SVCC) (group A: 6 collections in 4 patients), (b) standard
      lymphocyte collection protocol 3 with GRANULO separation (G) and A-35 collection
      chambers (group B: 9 collections in 5 patients), and (c) modified collection
      procedure 1-120 with G and SVCC (group C: 7 collections in 3 patients). Although
      the retrospective nature of this study and the differences in the cohorts tested
      prevent a reliable analysis, the percent decrease in the peripheral platelet
      count after collection tended to be minimum in group A (11% +/- 5% versus 23% +/-
      4% [B] or 17% +/- 4% [C]). Moreover, the largest number of CD34+ cells was
      collected in group A (8.7 +/- 9.4 x 10(5)/100 ml processed blood) compared with
      groups B (5.5 +/- 7.5 x 10(5)/100 ml processed blood) and C (4.0 +/- 2.8 x
      10(5)/100 ml processed blood). These data suggest that a procedure incorporating
      SVSCH can be safely and effectively applied to small children and enables the
      selective collection of PBSC with less contamination by platelets, which is
      useful for subsequent cell processing.

PMID- 10417057
TI  - Long term hematopoietic damage after chemotherapy and cytokine.
AB  - Cancer chemotherapy causes severe damage to hematopoietic stem cells in both
      experimental animals and humans. While all levels of differentiation may be
      impacted, the most pivotal target of damage is the most primitive hematopoietic
      stem cell, PHSC. This cell not only suffers defective repopulating activity but
      also is quantitatively depleted. The causes of this damage are not clear. Severe
      possible explanations for this damage are discussed. They include: ineffective
      stromal support of stem cell function and reproduction; residual DNA damage
      preventing replication; accelerated cycling; and decreased responsiveness to
      normal physiologic growth stimuli. Efforts at chemoprotection, including
      manipulation of glutathione or aldehyde dehydrogenase levels, cytostatic
      peptides, immunomodulatory chemicals and cytokines are detailed. In particular,
      concern has been raised regarding potential deleterious consequences of combined
      chemotherapy-cytokine use, but substantiation of the cited data is warranted.

PMID- 10417056
TI  - Role of Kupffer cells in the ethanol-induced oxidative stress in the liver.
AB  - These studies test the hypothesis that acute and chronic alcohol intoxication
      stimulate the release of oxygen-derived radicals in the liver. Male Sprague
      Dawley rats received an intravenous bolus followed by continuous infusion of
      ethanol to maintain blood alcohol level at about 175 mg/dl for 0-18 hr. They were
      then allowed to recover from this "alcohol binge" and the release of free
      radicals during the recovery phase was monitored. In the chronic alcohol
      intoxication model, rats were fed with 40% ethanol in agar blocks for 16 weeks.
      Acute ethanol intoxication induced two phases of hepatic superoxide release. The
      first phase peaked during the first 3 hr of alcohol intoxication, while the
      second phase reached its maximum at 6 hr of recovery following a 12 hr binge. The
      recovery period was also associated with elevated serum transaminase activity.
      Kupffer cells were largely responsible for hepatic superoxide release during the
      first phase, while both Kupffer and hepatic sinusoidal endothelial cells
      contributed to the second phase of free radical formation. Acute ethanol
      intoxication did not induce endotoxemia. During chronic alcohol intoxication,
      increased levels of serum endotoxin, TNF, IL-1, and transaminase were observed
      and hepatic superoxide anion release was present. Superoxide release by isolated
      Kupffer cells, blood and hepatic PMNs of alcoholic rats was also significantly
      enhanced in the chronic alcoholic rats. These data indicate that acute alcohol
      intoxication may directly stimulate the release of reactive oxygen intermediates,
      whereas chronic alcohol may elicit free radical generation through enhanced
      endotoxin influx and cytokine release. These studies further demonstrate that
      free radicals produced by hepatic non-parenchymal cells are likely to play an
      important role in the pathogenesis of hepatic injury in susceptible individuals
      with alcohol-related liver disorders.

PMID- 10417058
TI  - The role of alcohol in the oxidant antioxidant balance in heart.
AB  - The myocardium, like other tissues, has enzyme and non-enzyme systems to
      neutralize free radicals. The enzymes superoxide dismutase, catalase and
      glutathione peroxidase and glutathione reductase as well as the non-enzyme
      antioxidants vitamin E and ascorbic acid are the main antioxidants. Oxidants are
      produced by the mitochondria under normal conditions and by other sources under
      pathologic conditions. The quantity of antioxidants present in the myocardium is
      matched to the production of oxygen free radicals that may be produced under
      basal physiological conditions. However, the myocardium can be exposed to
      increased levels of oxygen free radicals under conditions in which myocardial
      metabolism, i.e. mitochondrial oxidative phosphorylation, is accelerated to match
      the adenosine triphosphate utilized to support the increased work load on the
      heart or can be exposed to oxygen free radicals under pathologic conditions such
      as ischemia and reperfusion, inflammation, and cardiotoxic drugs such as anti
      cancer agents. Under such circumstances the normal heart has been shown to
      increase its antioxidant production and to be, with time, protected from further
      sources of oxygen free radicals. In particular, hearts previously exposed to a
      stimulus to produce greater antioxidant levels show less damage during ischemia
      reperfusion injury presumably because of neutralization of oxygen free radicals.
      This review will present several situations in which the myocardium increases its
      tolerance to ischemia reperfusion injury as a result of an initial oxidative
      stress.

PMID- 10417059
TI  - GEN GEN: the genomic genetic analysis of androgen-metabolic genes and prostate
      cancer as a paradigm for the dissection of complex phenotypes.
AB  - Prostate cancer will be diagnosed in about 179,300 men in the US in 1999 alone.
      Some 37,000 individuals die of this disease annually. Prostate cancer is
      characterized by a substantial racial/ethnic variation in risk: highest in
      African-American men, lowest in Asian men and intermediate in Caucasian and
      Latino men. We set out to investigate as our central hypothesis that genetic
      variants of genes involved in androgen metabolism by themselves and in
      combination significantly contribute to prostate cancer progression and its
      racial/ethnic variation. Specifically, we examined the hypothesis that DNA
      sequence (allelic) variations in the type II (or prostatic) steroid 5alpha
      reductase (SRD5A2) gene contribute substantially to the risk and progression of
      prostate cancer particularly across racial/ethnic lines. The "candidate gene",
      SRD5A2, was chosen because the reaction product [i.e. dihydrotestosterone (DHT)]
      of the enzyme encoded by this gene modulates directly cell division in the
      prostate. DHT binds to the androgen receptor (AR) and the DHT-AR complex leads to
      the transactivation of a variety of genes which ultimately modulates cell
      division in the prostate. Epidemiologic evidence suggests that variation in DHT
      levels play an important role in risk of prostate cancer. Thus, steroid 5alpha
      reductase activity encoded by SRD5A2 variant alleles may be important in
      regulating intraprostatic DHT steady state levels by controlling its
      biosynthesis. A second candidate gene, the type II 3beta-hydroxysteroid
      dehydrogenase (HSD3B2) gene, encodes the enzyme that initiates the metabolic
      inactivation of testosterone (T) to DHT. We have identified allelic variants in
      this gene as well. Here I review our strategy for identifying candidate genes for
      prostate cancer, a multifactorial disease. I summarize the significant findings,
      particularly of allelic variants in the HSD3B2 and SRD5A2 genes and discuss how
      they by themselves, in combination and through interactions with the environment
      may play a role in prostate cancer predisposition and its progression. Our
      approach, a multidisciplinary genomic genetic (GEN GEN) attack on the problem,
      may be useful in the analysis of other complex phenotypes as well.

PMID- 10417060
TI  - Mechanisms of alcohol-induced hepatotoxicity: studies in rats.
AB  - Alcohol treatment results in increases in the release of endotoxin from gut
      bacteria and membrane permeability of the gut to endotoxin, or both. Females are
      more sensitive to these changes. Elevated levels of endotoxin activate Kupffer
      cells to release substances such as eicosanoids, TNF-alpha and free radicals.
      Prostaglandins increase oxygen uptake and most likely are responsible for the
      hypermetabolic state in the liver. The increase in oxygen demand leads to hypoxia
      in the liver, and on reperfusion, alpha-hydroxyethyl free radicals are formed
      which lead to tissue damage in oxygen-poor pericentral regions of the liver
      lobule.

PMID- 10417061
TI  - Eradicating child poverty.

PMID- 10417062
TI  - How often should we go to the dentist?

PMID- 10417063
TI  - Functional foods: health boon or quackery?

PMID- 10417064
TI  - Moving the research agenda to where it matters.

PMID- 10417065
TI  - Children with HIV: the challenge for general practice.

PMID- 10417066
TI  - English teenager given heart transplant against her will.

PMID- 10417067
TI  - US Senate passes patients' bill of rights.

PMID- 10417068
TI  - More mentally ill people reported in US prisons.

PMID- 10417070
TI  - In brief 

PMID- 10417069
TI  - UK proposes new approach to personality disorders.

PMID- 10417071
TI  - US health maintenance organisations: better care from non-profit plans 

PMID- 10417072
TI  - Laparoscopic hernia surgery linked to increased complications 

PMID- 10417073
TI  - Power of attorney change in England and Wales.

PMID- 10417074
TI  - Leptospirosis in Philippine floods.

PMID- 10417075
TI  - NHS must pay nursing costs for dependent nursing home residents 

PMID- 10417076
TI  - UK considers logging adverse incidents 

PMID- 10417077
TI  - American Medical Association moves to regulate prescribing on the internet.

PMID- 10417078
TI  - Bristol trust admits liability in baby heart surgery case.

PMID- 10417079
TI  - European Commission's new president puts public health on the agenda.

PMID- 10417080
TI  - Unicef warns of polio risk in conflict regions.

PMID- 10417081
TI  - Incubators in Hungarian hospital lobbies allow babies to be abandoned more
      safely.

PMID- 10417082
TI  - Heterogeneity of coronary heart disease risk factors in Indian, Pakistani,
      Bangladeshi, and European origin populations: cross sectional study.
AB  - OBJECTIVE: To compare coronary risk factors and disease prevalence among Indians,
      Pakistanis, and Bangladeshis, and in all South Asians (these three groups
      together) with Europeans. DESIGN: Cross sectional survey. SETTING: Newcastle upon
      Tyne. PARTICIPANTS: 259 Indian, 305 Pakistani, 120 Bangladeshi, and 825 European
      men and women aged 25-74 years. MAIN OUTCOME MEASURES: Social and economic
      circumstances, lifestyle, self reported symptoms and diseases, blood pressure,
      electrocardiogram, and anthropometric, haematological, and biochemical
      measurements. RESULTS: There were differences in social and economic
      circumstances, lifestyles, anthropometric measures and disease both between
      Indians, Pakistanis, and Bangladeshis and between all South Asians and Europeans.
      Bangladeshis and Pakistanis were the poorest groups. For most risk factors, the
      Bangladeshis (particularly men) fared the worst: smoking was most common (57%) in
      that group, and Bangladeshis had the highest concentrations of triglycerides
      (2.04 mmol/l) and fasting blood glucose (6.6 mmol/l) and the lowest concentration
      of high density lipoprotein cholesterol (0.97 mmol/l). Blood pressure, however,
      was lowest in Bangladeshis. Bangladeshis were the shortest (men 164 cm tall v 170
      cm for Indians and 174 cm for Europeans). A higher proportion of Pakistani and
      Bangladeshi men had diabetes (22.4% and 26.6% respectively) than Indians (15.2%).
      Comparisons of all South Asians with Europeans hid some important differences,
      but South Asians were still disadvantaged in a wide range of risk factors.
      Findings in women were similar. CONCLUSION: Risk of coronary heart disease is not
      uniform among South Asians, and there are important differences between Indians,
      Pakistanis, and Bangladeshis for many coronary risk factors. The belief that,
      except for insulin resistance, South Asians have lower levels of coronary risk
      factors than Europeans is incorrect, and may have arisen from combining ethnic
      subgroups and examining a narrow range of factors.

PMID- 10417083
TI  - Influence of bacterial vaginosis on conception and miscarriage in the first
      trimester: cohort study.
AB  - OBJECTIVES: To assess whether bacterial vaginosis affects the rates of conception
      and miscarriage in the first trimester. DESIGN: Cohort study. SETTING: Assisted
      conception unit of a teaching hospital in Leeds. PARTICIPANTS: 867 consecutive
      women undergoing in vitro fertilisation. INTERVENTIONS: Screening for bacterial
      vaginosis with a Gram stained vaginal smear before egg collection. MAIN OUTCOME
      MEASURES: The presence of bacterial vaginosis or normal vaginal flora, and the
      rate of conception and miscarriage in the first trimester. RESULTS: 190 of 771
      (24.6%) women had bacterial vaginosis. No difference in conception rate was found
      between those women with bacterial vaginosis and those with normal vaginal flora:
      61 women (32.1%) and 146 of 493 women (29.6%) respectively (relative risk 1. 08,
      95% confidence interval 0.85 to 1.39; odds ratio 1.12, 0.77 to 1. 64). However,
      22 women (31.6%) with bacterial vaginosis who conceived had a significantly
      increased risk of miscarriage in the first trimester compared with 27 women
      (18.5%) with normal vaginal flora (crude relative risk 1.95, 1.11 to 3.42; crude
      odds ratio 2.49, 1.21 to 5.12). This increased risk remained significant after
      adjustment for factors known to increase the rate of miscarriage: increasing
      maternal age, smoking, history of three or more miscarriages, no previous live
      birth, and polycystic ovaries (adjusted relative risk 2.03, 1.09 to 3.78;
      adjusted odds ratio 2.67, 1.26 to 5.63). CONCLUSIONS: Bacterial vaginosis does
      not affect conception but is associated with an increased risk of miscarriage in
      the first trimester in women undergoing in vitro fertilisation, independent of
      other risk factors.

PMID- 10417084
TI  - Identifying appropriate tasks for the preregistration year: modified Delphi
      technique.
AB  - OBJECTIVES: To identify the tasks that should constitute the work of
      preregistration house officers to provide the basis for the development of a self
      evaluation instrument. DESIGN: Literature review and modified Delphi technique.
      SETTING: Northern Deanery within the Northern and Yorkshire office NHS executive.
      SUBJECTS: 67 educational supervisors of preregistration house officers. MAIN
      OUTCOME MEASURES: Percentage of agreement by educational supervisors to tasks
      identified from the literature. RESULTS: Over 61% of communication items, 70% of
      on call patient care items, 75% of routine patient care items, 45% of practical
      procedure items, and over 63% of self management items achieved over 95%
      agreement that they should be part of the house job of preregistration house
      officers. Poor agreement was found for the laboratory and clinical investigations
      that house officers could perform with or without supervision. CONCLUSIONS: The
      tasks of house officers were identified but issues in using this method and in
      devising a universally acceptable list of tasks for preregistration house
      officers were apparent.

PMID- 10417085
TI  - Changes in risk of hospital readmission among asthmatic children in Denmark, 1978
      93.

PMID- 10417087
TI  - "Now I can be remembered" 

PMID- 10417086
TI  - Outcome and use of health services four years after admission for acute
      myocardial infarction: case record follow up study.

PMID- 10417089
TI  - Email submissions from outside the united kingdom 

PMID- 10417088
TI  - General practice and the care of children with HIV infection: 6 month prospective
      interview study.
AB  - OBJECTIVES: To describe the use of primary care services by children infected
      with HIV and to explore the attitudes of their parents to the role of general
      practitioners in their children's care. DESIGN: A 6 month prospective study.
      Quantitative analysis of "contact diaries" kept by parents; qualitative analysis
      of face to face interviews with parents. PARTICIPANTS: Parents of children
      receiving care at a regional referral centre in London. RESULTS: Twenty four
      families (80% response rate) were recruited to the study. In 19 families the
      mother was black African. Half the children had been diagnosed with symptomatic
      HIV infection, half with AIDS. All the children were registered with a general
      practitioner who knew of the child's HIV infection. In five families there had
      initially been tensions in their relationship with their general practitioner but
      by the time of the study all but one family had established at least an
      "acceptable" relationship. Children with symptomatic HIV infection saw their
      general practitioner a mean of 7.5 times per patient year; for children with AIDS
      the figure was 5.8. Parents regarded the paediatric HIV team at the hospital as
      their primary source of medical care. Three factors constrained their use of
      general practice: their own anxieties about distinguishing "normal" symptoms from
      those related to HIV infection; their view that their general practitioner did
      not feel competent to treat HIV infected children; and their concerns about
      maintaining confidentiality in the surgery. CONCLUSIONS: Parents remain oriented
      towards the paediatric HIV team as their primary source of medical care and use
      general practice largely for routine prescriptions for their children. Any
      further development of the general practitioner's role will need to build on
      existing relationships with specialist providers and take account of parents'
      concerns.

PMID- 10417090
TI  - Fortnightly review: coeliac disease.

PMID- 10417091
TI  - Lesson of the week: contrast enhanced computed tomography in the early diagnosis
      of cerebral abscess.

PMID- 10417092
TI  - ABC of intensive care: outcome data and scoring systems.

PMID- 10417093
TI  - Fetal origins of adult disease-the hypothesis revisited.

PMID- 10417094
TI  - The private finance initiative: the politics of the private finance initiative
      and the new NHS.

PMID- 10417095
TI  - A view from the other side 

PMID- 10417096
TI  - Racism in psychiatry necessitates reappraisal of general procedures and
      Eurocentric theories.

PMID- 10417098
TI  - Recognition of depression and anxiety in primary care. General practitioners in
      study seemed to agree with commentary writer.

PMID- 10417097
TI  - Low vitamin D concentrations found in study of Asian children was not function of
      analytical method.

PMID- 10417099
TI  - Why heart disease mortality is low in France. Miscoding may explain Japan's low
      mortality from coronary heart disease.

PMID- 10417100
TI  - Pressures of acute obstetrics on consultants. Consultants are stretched to their
      limits.

PMID- 10417101
TI  - At least 35% more orthopaedic surgeons are needed to ensure consultant based
      service.

PMID- 10417102
TI  - Author defends meta-analysis that was criticised.

PMID- 10417103
TI  - Management of preterm labour. Nifedipine in management of preterm labour is safe.

PMID- 10417104
TI  - Many reports of RCTs give insufficient data for Cochrane reviewers.

PMID- 10417105
TI  - Electronic bibliographic tools for incorporating social science research into
      health care must be improved.

PMID- 10417106
TI  - Royal College of Surgeons of Edinburgh gives consultant fellows feedback on their
      training activity.

PMID- 10417107
TI  - Community study of infectious intestinal disease in England. Study underestimated
      morbidity due to specific pathogens.

PMID- 10417108
TI  - All parents should be given leaflet outlining full details of antenatal
      screening.

PMID- 10417109
TI  - Usefulness of contacting other experts when conducting literature searches.
      Secondary citation of work that was not published did not set good example.

PMID- 10417110
TI  - Clocks in delivery wards may not be sufficiently accurate to validate birth of
      "millennium babies".

PMID- 10417111
TI  - David fillmer alexander 

PMID- 10417112
TI  - Juniors start talks to avoid ballot on industrial action 

PMID- 10417113
TI  - Rural healthcare 

PMID- 10417115
TI  - Hamilton bailey: A Surgeon's life 

PMID- 10417114
TI  - The malthus factor 

PMID- 10417116
TI  - Detaining people with personality disorders 

PMID- 10417117
TI  - Netlines 

PMID- 10417118
TI  - Killing for profit: where is the outrage? 

PMID- 10417119
TI  - Old age psychiatry in swansea 

PMID- 10417120
TI  - Who needs Rubik's cube? 

PMID- 10417122
TI  - Coronary heart disease risk factors vary among south asian groups 

PMID- 10417121
TI  - Brain gum, CME, and keeping up to date 

PMID- 10417123
TI  - Bacterial vaginosis increases the risk of first trimester miscarriage 

PMID- 10417124
TI  - Preregistration house officers could benefit from a self evaluation instrument 

PMID- 10417125
TI  - GPs could take greater role in care of children with HIV 

PMID- 10417126
TI  - Management of asthma in danish children has improved 

PMID- 10417127
TI  - Host-pathogen interactions: redefining the basic concepts of virulence and
      pathogenicity.

PMID- 10417128
TI  - Anti-CD14 monoclonal antibodies inhibit the production of tumor necrosis factor
      alpha and interleukin-10 by human monocytes stimulated with killed and live
      Haemophilus influenzae or Streptococcus pneumoniae organisms.
AB  - In previous studies, we have shown that intact, heat-killed, gram-negative
      bacteria (GNB) and gram-positive bacteria (GPB) can stimulate the production of
      various proinflammatory and anti-inflammatory cytokines. The objective of the
      present study was to investigate whether the production of tumor necrosis factor
      alpha (TNF) and interleukin-10 (IL-10) by human monocytes stimulated by intact
      heat-killed or live Haemophilus influenzae or Streptococcus pneumoniae is
      mediated by CD14. Two anti-CD14 monoclonal antibodies (MAbs) were used to study
      the interaction between human monocytes and bacteria; lipopolysaccharide (LPS)
      was used to validate the effect of anti-CD14 MAb. MAb 18E12 decreased
      significantly TNF and IL-10 production upon stimulation with LPS or heat-killed
      bacteria and TNF production during stimulation by live bacteria. MAb My-4
      decreased production of TNF and IL-10 by monocytes stimulated with LPS, IL-10 but
      not TNF production upon stimulation with heat-killed H. influenzae, and
      production of neither TNF nor IL-10 upon stimulation with S. pneumoniae.
      Together, these results led to the conclusion that CD14 is involved in the
      recognition and stimulation of human monocytes by intact GNB and GPB.
      Consequentially, the option for adjunctive treatment of severe infections with
      anti-CD14 MAb is postulated.

PMID- 10417129
TI  - Immunostimulatory DNA as an adjuvant in vaccination against Leishmania major.
AB  - Oligodeoxynucleotides (ODN) which contain immunostimulatory CG motifs (CpG ODN)
      can promote T helper 1 (Th1) responses, an adjuvant activity that is desirable
      for vaccination against leishmaniasis. To test this, susceptible BALB/c mice were
      vaccinated with soluble leishmanial antigen (SLA) with or without CpG ODN as
      adjuvant and then challenged with Leishmania major metacyclic promastigotes. CpG
      ODN alone gave partial protection when injected up to 5 weeks prior to infection,
      and longer if the ODN was bound to alum. To demonstrate an antigen-specific
      adjuvant effect, a minimum of 6 weeks between vaccination and infection was
      required. Subcutaneous administration of SLA alone, SLA plus alum, or SLA plus
      non-CpG ODN resulted in exacerbated disease compared to unvaccinated mice. Mice
      receiving SLA plus CpG ODN showed a highly significant (P < 5 x 10(-5)) reduction
      in swelling compared to SLA-vaccinated mice and enhanced survival compared to
      unvaccinated mice. The modulation of the response to SLA by CpG ODN was
      maintained even when mice were infected 6 months after vaccination. CpG ODN was
      not an effective adjuvant for antibody production in response to SLA unless given
      together with alum, when it promoted production of immunoglobulin G2a, a Th1
      associated isotype. Our results suggest that with an appropriate antigen, CpG ODN
      would provide a stable, cost-effective adjuvant for use in vaccination against
      leishmaniasis.

PMID- 10417130
TI  - Identification of functional domains of Bordetella dermonecrotizing toxin.
AB  - Bordetella dermonecrotizing toxin (DNT) stimulates the assembly of actin stress
      fibers and focal adhesions by deamidating Gln63 of the small GTPase Rho. To
      clarify the functional and structural organization of DNT, we cloned and
      sequenced the DNT gene and examined the functions of various DNT mutants. Our
      analyses of the nucleotide and amino acid sequences revealed that the start codon
      of the DNT gene is a GTG triplet located 39 bp upstream of the reported putative
      initiation ATG codon; consequently, DNT contains an additional 13 amino acids at
      its N-terminal end. All of the N-terminally truncated mutants were found to
      modify Rho. The shortest fragment of DNT possessing the Rho modification activity
      consists of amino acids from Ile1176 to the C-terminal end. This fragment
      overlaps the region homologous to Escherichia coli cytotoxic necrotizing factors
      (CNFs), which show activity similar to that of DNT. The introduction of a
      mutation at Cys1305 located in the highly conserved region between CNFs and DNT
      eliminated the activity, indicating that this domain is the catalytic center of
      DNT. The N-terminal fragment (1 to 531) of DNT failed to modify Rho but reduced
      the DNT-induced polynucleation in MC3T3-E1 cells when simultaneously added with
      the holotoxin, suggesting competitive inhibition in the receptor-binding or
      internalizing step. Our finding that DNT consists of an N-terminal receptor
      binding and/or internalizing domain and a C-terminal catalytically active domain
      may facilitate analysis of the overall action of the toxin on the mammalian
      target cells.

PMID- 10417131
TI  - Vibrio cholerae intestinal population dynamics in the suckling mouse model of
      infection.
AB  - The suckling mouse has been used as a model to identify Vibrio cholerae
      intestinal colonization factors for over two decades, yet little is known about
      the location of recoverable organisms along the gastrointestinal (GI) tract
      following intragastric inoculation. In the present study, we determined the
      population dynamics of wild-type and avirulent mutant derivatives of both
      classical and El Tor biotype strains throughout the entire suckling mouse GI
      tract at various times after intragastric inoculation. Wild-type strains
      preferentially colonized the middle small bowel with a sharp demarcation between
      more proximal segments which had manyfold-fewer recoverable cells. Surprisingly,
      large and stable populations of viable cells were also recovered from the cecum
      and large bowel. Strains lacking toxin-coregulated pili (TCP(-)) were cleared
      from the small bowel; however, an El Tor TCP(-) strain colonized the cecum and
      large bowel almost as well as the wild-type strain. Strains lacking
      lipopolysaccharide O antigen (OA(-)) were efficiently cleared from the small
      bowel at early times but then showed net growth for the remainder of the
      infections. Moreover, large populations of the OA(-) strains were maintained in
      the large bowel. These results show that for the El Tor biotype neither TCP nor
      OA is required for colonization of the suckling mouse large bowel. Finally,
      similar percent recoveries of wild-type, TCP(-), and OA(-) strains from the small
      bowel at an early time after infection suggest that TCP and OA are not required
      for strains of either biotype to resist bactericidal mechanisms in the suckling
      mouse GI tract.

PMID- 10417132
TI  - Target cell range of Haemophilus ducreyi hemolysin and its involvement in
      invasion of human epithelial cells.
AB  - Haemophilus ducreyi, the causative agent of chancroid, produces a hemolysin,
      whose role in virulence is not well defined. To assess the possible role of
      hemolysin in pathogenesis, we evaluated its target cell range by using wild-type
      H. ducreyi 35000, nonhemolytic mutants with the hemolysin structural gene
      deleted, and isogenic strains expressing different amounts of hemolytic activity.
      The cytotoxicity of the various cell types was assessed by quantitating the
      release of lactate dehydrogenase into culture supernatants as a measure of cell
      lysis. In these experiments, human foreskin fibroblasts, human foreskin
      epithelial cells, and, to a lesser extent, HEp-2 cells were lysed by H. ducreyi
      hemolysin. Hemolysin also lysed human blood mononuclear cells and immune system
      cell lines including U937 macrophage-like cells, T lymphocytes, and B
      lymphocytes. In contrast, human polymorphonuclear leukocytes were not sensitive
      to hemolysin under the conditions tested. We also analyzed the effect of
      hemolysin on invasion of human epithelial cells and found that H. ducreyi strains
      expressing cloned hemolysin genes showed a 10-fold increase in invasion compared
      to the control strain. These data support the hypothesis that the H. ducreyi
      hemolysin is important in the pathogenesis of chancroid and may contribute to
      ulcer formation, invasion of epithelial cells, and evasion of the immune
      response.

PMID- 10417133
TI  - Pneumolysin, a protein toxin of Streptococcus pneumoniae, induces nitric oxide
      production from macrophages.
AB  - Nitric oxide (NO) production by inducible NO synthase (iNOS) during inflammation
      is an essential element of antimicrobial immunity but can also contribute to host
      induced tissue damage. Under conditions of bacterial sepsis, large amounts of NO
      are produced, causing hypotension, a critical pathological feature of septic
      shock. In sepsis caused by gram-positive organisms, the bacterial factors
      contributing to host NO production are poorly characterized. We show that a
      soluble toxin of Streptococcus pneumoniae, pneumolysin (Pln), is a key component
      initiating NO production from macrophages. In contrast to wild-type bacteria, a
      mutant of S. pneumoniae lacking Pln failed to elicit NO production from murine
      macrophages. Purified recombinant Pln induced NO production at low concentrations
      and independently of exogenous gamma interferon (IFN-gamma) priming of RAW 264.7
      macrophages. However, IFN-gamma was essential for Pln-induced NO production,
      since primary macrophages from mice lacking the IFN-gamma receptor or interferon
      regulatory factor 1, a transcription factor essential for iNOS expression, failed
      to produce NO when stimulated with Pln. In addition, Pln acts as an agonist of
      tumor necrosis factor alpha and interleukin 6 production in macrophages. The
      properties of Pln, previously identified as a pore-forming hemolysin, also
      include a role as a general inflammatory agonist.

PMID- 10417134
TI  - Loss of resistance to ingestion and phagocytic killing by O(-) and K(-) mutants
      of a uropathogenic Escherichia coli O75:K5 strain.
AB  - To determine the importance of the O75 O antigen and the K5 capsular antigen in
      resistance to phagocytosis and phagocytic killing, we used previously described
      O75(-) and K5(-) mutants from an O75(+) K5(+) wild-type uropathogenic Escherichia
      coli strain in phagocytosis assays with polymorphonuclear leukocytes (PMNs) and
      monocytes. At a 10-to-1 ratio of bacteria to phagocytes and in the presence of
      10% serum, the parental strain GR-12 was resistant to both PMNs and monocytes
      over a 2-h incubation period. The O75(-) and K5(-) mutants were similar in
      sensitivity to killing by both PMNs and monocytes, decreasing in viability by 80%
      in the first hour. Yet, a significant difference in killing between the O75(-)
      and K5(-) mutants was observed in the first 15 min of incubation. The K5(-)
      mutant decreased in numbers by almost 60%, while the O75(-) mutant increased in
      numbers similarly to GR-12 in the first 15 min. The difference in killing was
      found not to be due to the rate of opsonization. To further determine the
      mechanism of resistance, a fluorescence assay was used to differentiate attached
      and internalized bacteria. The K5 capsule hindered the association of both the
      wild-type strain and the O75(-) mutant in the initial incubation time with PMNs.
      In conclusion, both the K5 capsule and O75 O antigen play crucial roles in
      resistance to phagocytosis over time.

PMID- 10417135
TI  - Genetic basis for lipopolysaccharide O-antigen biosynthesis in bordetellae.
AB  - Bordetella bronchiseptica and Bordetella parapertussis express a surface
      polysaccharide, attached to a lipopolysaccharide, which has been called O
      antigen. This structure is absent from Bordetella pertussis. We report the
      identification of a large genetic locus in B. bronchiseptica and B. parapertussis
      that is required for O-antigen biosynthesis. The locus is replaced by an
      insertion sequence in B. pertussis, explaining the lack of O-antigen biosynthesis
      in this species. The DNA sequence of the B. bronchiseptica locus has been
      determined and the presence of 21 open reading frames has been revealed. We have
      ascribed putative functions to many of these open reading frames based on
      database searches. Mutations in the locus in B. bronchiseptica and B.
      parapertussis prevent O-antigen biosynthesis and provide tools for the study of
      the role of O antigen in infections caused by these bacteria.

PMID- 10417136
TI  - Role of phospholipase D in Pasteurella haemolytica leukotoxin-induced increase in
      phospholipase A(2) activity in bovine neutrophils.
AB  - The effects of Pasteurella haemolytica leukotoxin (LKT) on the activity of
      phospholipase D (PLD) and the regulatory interaction between PLD and
      phospholipase A(2) (PLA(2)) were investigated in assays using isolated bovine
      neutrophils labeled with tritiated phospholipid substrates of the two enzymes.
      Exposure of [(3)H]lysophosphatidylcholine-labeled neutrophils to LKT caused
      concentration- and time-dependent production of phosphatidic acid (PA), the
      product of PLD. LKT-induced generation of PA was dependent on extracellular
      calcium. Both production of PA and metabolism of [(3)H]-arachidonate ([(3)H]AA)
      labeled phospholipids by PLA(2) were inhibited when ethanol was used to promote
      the alternative PLD-mediated transphosphatidylation reaction, resulting in the
      production of phosphatidylethanol rather than PA. The role of PA in regulation of
      PLA(2) activity was then confirmed by means of an add-back experiment, whereby
      addition of PA in the presence of ethanol restored PLA(2)-mediated release of
      radioactivity from neutrophil membranes. Considering the involvement of
      chemotactic phospholipase products in the pathogenesis of pneumonic
      pasteurellosis, development and use of anti-inflammatory agents that inhibit LKT
      induced activation of PLD and PLA(2) may improve therapeutic management of the
      disease.

PMID- 10417137
TI  - Cytotoxic T-cell-mediated response against Yersinia pseudotuberculosis in HLA-B27
      transgenic rat.
AB  - Yersinia-induced reactive arthritis is highly associated with HLA-B27, the role
      of which in defense against the triggering bacteria remains unclear. The aim of
      this study was to examine the capacity of rats transgenic for HLA-B27 to mount a
      cytotoxic T-lymphocyte (CTL) response against Y. pseudotuberculosis and to
      determine the influence of the HLA-B27 transgene on this response. Rats
      transgenic for HLA-B*2705 and human beta(2)-microglobulin of the 21-4L line,
      which do not spontaneously develop disease, and nontransgenic syngeneic Lewis
      (LEW) rats were infected with Y. pseudotuberculosis. Lymph node cells were
      restimulated in vitro, and the presence of for Y. pseudotuberculosis-specific
      CTLs against infected targets was determined. Infection of 21-4L rats triggered a
      CD8(+) T cell-mediated cytotoxic response specific for Y. pseudotuberculosis.
      Analysis of this response demonstrated restriction by an endogenous major
      histocompatibility complex molecule. However, no restriction by HLA-B27 was
      detected. In addition, kinetics studies revealed a weaker anti-Yersinia CTL
      response in 21-4L rats than in nontransgenic LEW rats, and the level of
      cytotoxicity against 21-4L lymphoblast targets sensitized with Y.
      pseudotuberculosis was lower than that against nontransgenic LEW targets. We
      conclude that HLA-B27 transgenic rats mount a CTL response against Y.
      pseudotuberculosis that is not restricted by HLA-B27. Yet, HLA-B27 exerts a
      negative effect on the level of this response, which could contribute to impaired
      defense against Yersinia.

PMID- 10417138
TI  - Secretion of functional salivary peptide by Streptococcus gordonii which inhibits
      fimbria-mediated adhesion of Porphyromonas gingivalis.
AB  - Porphyromonas gingivalis, a putative periodontopathogen, can bind to human
      salivary components with its fimbriae. We have previously shown that fimbriae
      specifically bind to a peptide domain shared by a major salivary component, i.e.,
      proline-rich (glyco)proteins (PRPs). The synthetic domain peptide PRP-C (pPRP-C)
      significantly inhibits the fimbrial binding to PRPs. In this study, a recombinant
      strain of Streptococcus gordonii secreting pPRP-C was generated as a model of a
      possible approach to prevent the oral colonization by the pathogen. A duplicate
      DNA fragment (prpC) encoding pPRP-C was obtained by self-complementary annealing
      of synthetic oligonucleotides. prpC was connected downstream to a promoter and a
      gene encoding a signal peptide of Streptococcus downei glucosyltransferase I in
      frame. The linked fragments were inserted into the plasmid pMNK-4 derived from
      pVA838. The constructed plasmid was inserted to produce the transformant S.
      gordonii G9B, which then successfully secreted recombinant pPRP-C (r-pPRP-C) of
      the expected size. The concentrated bacterial culture supernatant containing r
      pPRP-C inhibited the binding of P. gingivalis cells and fimbriae to PRP1 in a
      dose-dependent manner up to 72 and 77%, respectively. The r-pPRP-C concentrate
      also inhibited the coaggregation of P. gingivalis with various streptococcal
      strains as effectively as synthetic pPRP-C in a dose-dependent manner.
      Collectively, pPRP-C was found to be able to prevent P. gingivalis adherence to
      salivary receptor protein and plaque-forming bacteria. These results suggest that
      this recombination approach with a nonperiodontopathic bacterium may be suitable
      for the therapeutic prevention of P. gingivalis adherence to the oral cavity.

PMID- 10417139
TI  - CTLA-4 blockade enhances the immune response induced by mycobacterial infection
      but does not lead to increased protection.
AB  - The murine immune response to a pulmonary mycobacterial infection is slow to
      develop, allowing bacterial numbers to increase in the lung for several weeks
      after infection. We sought to enhance the protective immune response induced
      during Mycobacterium bovis BCG infection by administering an antibody that blocks
      the interaction of CTLA-4 with its ligands, CD80 and CD86. We found that
      injection of anti-CTLA-4 monoclonal antibody (MAb) greatly enhanced and
      accelerated the immune response, as measured by increased cellularity of the
      draining mediastinal lymph nodes, and enhanced antigen-inducible proliferation
      and gamma interferon production by mediastinal lymphocytes in vitro. However,
      despite the apparently enhanced immune response in the mediastinal lymph node
      following treatment with anti-CTLA-4 MAb, there was no improvement in clearance
      of mycobacteria in the lungs, liver, or spleen. Examination of the primary site
      of infection, the lung, revealed that CTLA-4 blockade had no effect on the number
      or function of lymphocytes infiltrating the infected lung tissue. Taken together,
      these data suggest that in vivo CTLA-4 blockade enhances mycobacterial-infection
      induced lymphocyte expansion and effector cell cytokine production in the
      draining lymph node but does not alter the number or function of lymphocytes at
      the primary site of infection and therefore does not lead to enhanced clearance
      of the infection.

PMID- 10417140
TI  - Analysis of the immunological responses to transferrin and lactoferrin receptor
      proteins from Moraxella catarrhalis.
AB  - Moraxella catarrhalis expresses surface receptor proteins that specifically bind
      host transferrin (Tf) and lactoferrin (Lf) in the first step of the iron
      acquisition pathway. Acute- and convalescent-phase antisera from a series of
      patients with M. catarrhalis pulmonary infections were tested against Tf and Lf
      receptor proteins purified from the corresponding isolates. After the purified
      proteins had been separated by sodium dodecyl sulfate-polyacrylamide gel
      electrophoresis and Western blotting, we observed strong reactivity against Tf
      binding protein B (TbpB; also called OMP1) and Lf-binding protein B (LbpB) but
      little or no reactivity against Tf-binding protein A (TbpA) or Lf-binding protein
      A (LbpA), using the convalescent-phase antisera. Considerable antigenic
      heterogeneity was observed when TbpBs and LbpBs isolated from different strains
      were tested with the convalescent-phase antisera. Comparison to the reactivity
      against electroblotted total cellular proteins revealed that the immune response
      against LbpB and TbpB constitutes a significant portion of the total detectable
      immune response to M. catarrhalis proteins. Preparations of affinity-isolated
      TbpA and LbpA reacted with convalescent-phase antisera in a solid-phase binding
      assay, but blocking with soluble TbpB, soluble LbpB, or extracts from an LbpA(-)
      mutant demonstrated that this reactivity was attributed to contaminants in the
      TbpA and LbpA preparations. These studies demonstrate the immunogenicity of M.
      catarrhalis TbpB and LbpB in humans and support their potential as vaccine
      candidates.

PMID- 10417141
TI  - In vitro expansion of T-cell-receptor Valpha2.3(+) CD4(+) T lymphocytes in HLA
      DR17(3), DQ2(+) individuals upon stimulation with Mycobacterium tuberculosis.
AB  - The T-cell receptor (TCR) Valpha/beta gene product expression upon in vitro
      stimulation with mycobacteria was investigated to assess whether T-cell
      proliferation was associated with any specific TCR V gene usage. T-cell-enriched
      populations from peripheral blood of Mycobacterium bovis BCG-vaccinated healthy
      blood donors were stimulated in vitro with live or killed M. tuberculosis or with
      a soluble extract thereof. TCR Valpha/beta repertoire analysis of reactive CD4(+)
      and CD8(+) T cells revealed a selective HLA-DR17(3), DQ2-restricted expansion of
      Valpha2.3(+) CD4(+) T cells upon stimulation with live M. tuberculosis or its
      soluble extract. Third-complementarity-determining-region (CDR3) length analysis
      of the expanded Valpha2.3(+) T cells indicated an oligoclonal pattern with short
      CDR3 lengths in six of seven HLA-DR17(3), DQ2(+) individuals tested. In addition,
      Valpha/Vbeta repertoire analysis of T lymphocytes from a DR17(3), DQ2(+) donor
      before and after BCG vaccination revealed that positivity of skin test reactivity
      was associated with expansion of Valpha2.3(+) CD4(+) T lymphocytes with
      preferential use of a short CDR3 peak length after in vitro stimulation.
      Separation of M. tuberculosis soluble extract by fast protein liquid
      chromatography (FPLC) purification indicated that fractions corresponding to
      molecular masses of 60 to 70 and 15 to 25 kDa were particularly effective in
      eliciting Valpha2.3(+) CD4(+) T-cell expansion.

PMID- 10417142
TI  - Prior immunity to homologous and heterologous Salmonella serotypes suppresses
      local and systemic anti-fragment C antibody responses and protection from tetanus
      toxin in mice immunized with Salmonella strains expressing fragment C.
AB  - We have investigated the effect of preexisting immunity to homologous (Salmonella
      typhimurium) or heterologous (S. dublin) serotypes of Salmonella on the ability
      of an attenuated S. typhimurium aroA aroD vector (BRD509) to immunize mice
      against the heterologous antigen fragment C (FrgC). We studied two strains,
      BRD847 and BRD937, expressing FrgC carried on plasmids that differ only with
      respect to the promoter controlling FrgC expression, the nirB promoter in the
      case of BRD847 and the htrA promoter in the case of BRD937. Mice were
      preimmunized orally with S. typhimurium BRD509, S. dublin aroA aroD (BRD620), or
      saline. Forty-four days later, they were immunized orally with BRD847 or BRD937.
      Prior immunity to S. typhimurium severely depressed the serum immunoglobulin G
      (IgG) and IgA anti-FrgC response in both BRD847- and BRD937-immunized mice. Mice
      with existing immunity to S. dublin also had lower IgG anti-FrgC geometric mean
      titers (GMTs) than did mice preimmunized with saline, but this difference was
      significant only in the case of mice immunized with BRD937. However, in nonimmune
      mice or in mice preimmunized with S. typhimurium or S. dublin, the anti-FrgC IgG
      GMTs were always higher in mice in the BRD937 groups than in the equivalent
      BRD847 groups. This is reflected in the effect of prior immunity on the ability
      of oral immunization with BRD847 or BRD937 to protect mice from challenge with a
      lethal dose of tetanus toxin. All of the mice preimmunized with saline and then
      immunized with BRD847 or BRD937 survived challenge. Only 20% of the animals
      immunized with BRD847 and 60% of the mice in the BRD937 group survived tetanus
      toxin challenge if they were preimmunized with BRD509. Preexisting immunity to S.
      dublin did not affect the ability of BRD937 to immunize mice against tetanus, but
      it did reduce the efficiency of BRD847: only 60% percent of the mice survived
      challenge. The intestinal secretory IgA responses to FrgC were very similar in
      the BRD847 and BRD937 groups. Prior immunity did depress the IgA anti-FrgC titers
      but only significantly so in the mice preimmunized with BRD509. These results
      show that preexisting Salmonella immunity, particularly to homologous serotypes,
      can severely compromise the ability of live Salmonella vectors to deliver
      heterologous antigens to the mammalian immune system. However, the results also
      indicate that this may be overcome by the design of more powerful in vivo
      expression systems.

PMID- 10417143
TI  - Variable carbohydrate modifications to the catalytic chains of the RgpA and RgpB
      proteases of Porphyromonas gingivalis W50.
AB  - Proteases of Porphyromonas gingivalis are considered to be important virulence
      determinants of this periodontal bacterium. Several biochemical isoforms of
      arginine-specific proteases are derived from rgpA and rgpB. HRgpA is a
      heterodimer composed of the catalytic alpha chain noncovalently associated with a
      beta adhesin chain derived from the C terminus of the initial full-length
      translation product. The catalytic alpha chain is also present as a monomer
      (RgpA) either free in solution or associated with membranes. rgpB lacks the
      coding region for the adhesin domain present in rgpA and yields only monomeric
      forms (RgpB) which again may be soluble or membrane associated. In this study,
      the catalytic chains of this unusual group of enzymes are shown to be
      differentially modified by the posttranslational addition of carbohydrate. A
      monoclonal antibody (MAb 1B5) raised to the monomeric RgpA did not react with the
      corresponding recombinant RgpA alpha chain expressed in Escherichia coli but was
      immunoreactive with P. gingivalis lipopolysaccharide. MAb 1B5 also reacted with
      the membrane-associated forms of RgpA and RgpB but not with the heterodimeric
      HRgpA and the soluble form of RgpB. RgpA treated with denaturants was capable of
      binding to MAb 1B5 whereas treatment with periodate abolished this binding,
      suggesting the presence of carbohydrate residues within the epitope. Chemical
      deglycosylation abolished immunoreactivity with MAb 1B5 and caused a
      approximately 30% reduction in the size of the membrane-associated enzymes.
      Monosaccharide analysis of HRgpA and RgpA demonstrated 2.1 and 14.4%,
      respectively, carbohydrate by weight of protein. Furthermore, distinct
      differences were detected in their monosaccharide compositions, indicating that
      these protease isoforms are modified not only to different extents but also with
      different sugars. The variable nature of these additions may have a significant
      effect on the structure, stability, and immune recognition of these protease
      glycoproteins.

PMID- 10417144
TI  - Lipopolysaccharide-induced tumor necrosis factor alpha production by human
      monocytes involves the raf-1/MEK1-MEK2/ERK1-ERK2 pathway.
AB  - During gram-negative sepsis, human monocytes are triggered to produce large
      quantities of proinflammatory cytokines such as tumor necrosis factor alpha (TNF
      alpha) in response to endotoxin (lipopolysaccharide [LPS]). Several studies have
      identified signal transduction pathways that are activated by LPS, including
      activation of nuclear factor-kappaB (NF-kappaB) and activation of mitogen
      activated protein kinases (MAPKs), including ERK1 and ERK2, c-Jun N-terminal
      kinase, and p38. In this study, the relevance of ERK1 and ERK2 activation for LPS
      induced TNF-alpha production by primary human monocytes has been addressed with
      PD-098059, which specifically blocks activation of MAPK kinase (MEK) by Raf-1.
      TNF-alpha levels in the monocyte culture supernatant, induced by 10 ng of LPS/ml,
      were reduced by PD-098059 (50 microM). In addition, PD-098059 also reduced TNF
      alpha mRNA expression when cells were stimulated for 1 h with LPS. On the other
      hand, LPS-induced interleukin-10 (IL-10) levels in the monocyte supernatant were
      only slightly inhibited by PD-098059. Ro 09-2210, a recently identified MEK
      inhibitor, completely abrogated TNF-alpha levels at nanomolar concentrations. IL
      10 levels also were strongly reduced. To show the efficacy of PD-098059 and Ro 09
      2210, ERK1 and -2 activation was monitored by Western blotting with an antiserum
      that recognizes the phosphorylated (i.e., activated) forms of ERK1 and ERK2.
      Addition of LPS to human monocytes resulted in activation of both ERK1 and ERK2
      in a time- and concentration (50% effective concentration between 1 and 10 ng of
      LPS/ml)-dependent manner. Activation of ERK2 was blocked by PD-098059 (50
      microM), whereas ERK1 seemed to be less affected. Ro 09-2210 completely prevented
      LPS-induced ERK1 and ERK2 activation. LPS-induced p38 activation also was
      prevented by Ro 09-2210. These data further support the view that the ERK signal
      transduction pathway is causally involved in the synthesis of TNF-alpha by human
      monocytes stimulated with LPS.

PMID- 10417145
TI  - Genetic characterization of a Tn5-disrupted glycosyltransferase gene homolog in
      Brucella abortus and its effect on lipopolysaccharide composition and virulence.
AB  - We constructed a rough mutant of Brucella abortus 2308 by transposon (Tn5)
      mutagenesis. Neither whole cells nor extracted lipopolysaccharide (LPS) from this
      mutant, designated RA1, reacted with a Brucella O-side-chain-specific monoclonal
      antibody (MAb), Bru-38, indicating the absence of O-side-chain synthesis.
      Compositional analyses of LPS from strain RA1 showed reduced levels of
      quinovosamine and mannose relative to the levels in the parental, wild-type
      strain, 2308. We isolated DNA flanking the Tn5 insertion in strain RA1 by cloning
      a 25-kb XbaI genomic fragment into pGEM-3Z to create plasmid pJM6. Allelic
      exchange of genomic DNA in B. abortus 2308 mediated by electroporation of pJM6
      produced kanamycin-resistant clones that were not reactive with MAb Bru-38.
      Southern blot analysis of genomic DNA from these rough clones revealed Tn5 in a
      25-kb XbaI genomic fragment. A homology search with the deduced amino acid
      sequence of the open reading frame disrupted by Tn5 revealed limited homology
      with various glycosyltransferases. This B. abortus gene has been named wboA.
      Transformation of strain RA1 with a broad-host-range plasmid bearing the wild
      type B. abortus wboA gene resulted in the restoration of O-side-chain synthesis
      and the smooth phenotype. B. abortus RA1 was attenuated for survival in mice.
      However, strain RA1 persisted in mice spleens for a longer time than the B.
      abortus vaccine strain RB51, but as expected, neither strain induced antibodies
      specific for the O side chain.

PMID- 10417146
TI  - The cysteine-rich region of the Entamoeba histolytica adherence lectin (170
      kilodalton subunit) is sufficient for high-affinity Gal/GalNAc-specific binding
      in vitro.
AB  - Adherence of Entamoeba histolytica trophozoites to colonic mucin, epithelium, and
      other target cells is mediated by the amebic Gal/GalNAc lectin. We constructed in
      vitro expression vectors containing full-length (residues 1 to 1280), cysteine
      poor (1 to 353 and 1 to 480), and cysteine-rich (356 to 1143 and 480 to 900)
      fragments of the gene encoding the heavy subunit of the adherence lectin, hgl2.
      In vitro transcription followed by translation using a nuclease-treated rabbit
      reticulocyte lysate system was carried out. Immunoreactivity of in vitro
      translated Hgl2 was confirmed by immunoprecipitation with lectin-specific
      monoclonal antibodies (MAbs) 1G7 and 8A3, which recognize linear epitopes.
      Protein disulfide isomerase (PDI) refolding of Hgl2 enhanced immunoreactivity (P
      < 0.05) with the conformationally dependent MAb 3F4. Binding of PDI-refolded full
      length (P < 0.001) and cysteine-rich (P = 0.005) Hgl2 to CHO cells was galactose
      dependent and competitively inhibited by native hololectin (50% inhibitory
      concentration of 39.6 ng/ml). The cysteine-poor region (1 to 353) did not bind
      CHO cells. Both full-length (1 to 1280) and cysteine-rich (356 to 1143) Hgl2
      bound the glyconeoconjugate GalNAc(19)BSA in a GalNAc-specific manner. The
      smaller cysteine-rich fragment (480 to 900) also exhibited GalNAc-specific
      binding but to a lesser extent (P < 0.05) than residues 1 to 1280 and 356 to
      1143. Neither the cysteine-poor fragment (1 to 480), luciferase (protein
      control), nor control translation reactions (without hgl2 lectin mRNA) bound
      GalNAc(19)BSA. Binding to GalNAc(19)BSA was shown to be dependent on the
      concentration of GalNAc(19)BSA coated in each well or (35)S-lectin added (K(D) =
      0.85 +/- 0.37 pM). Binding was competitively inhibited by the terminal GalNAc
      containing glycoprotein asialofetuin (P < 0.005). Taken together, these data
      provide direct evidence that the cysteine-rich region of the Gal/GalNAc lectin
      heavy subunit contains one or more carbohydrate-binding domains.

PMID- 10417147
TI  - Antigenic variation of the class I outer membrane protein in hyperendemic
      Neisseria meningitidis strains in the netherlands.
AB  - Since 1980, the number of cases of meningococcal disease caused by serogroup B
      isolates with the P1.4 serosubtype has greatly increased in The Netherlands.
      Screening for this serosubtype in the strain collection of The Netherlands
      Reference Laboratory for Bacterial Meningitis revealed that a low number of P1.4
      strains had been present in the Dutch meningococcal population since 1965.
      Genotyping of P1.4 strains showed that one cluster of strains, the hyperendemic
      lineage III (D. A. Caugant et al., J. Infect. Dis. 162:867-874, 1990), is
      responsible for the increase since 1980. The diversity of the porA genes, which
      encode the P1 protein on which serosubtyping is based, was studied for
      genotypically different P1.4 strains and for lineage III strains expressing
      antigenically different P1 proteins. Sequence analysis showed that porA genes of
      genotypically distinct strains that express antigenically indistinguishable P1
      proteins are identical only in the epitope-encoding region, suggesting that this
      region has spread through the meningococcal population via horizontal gene
      transfer. Analysis of porA genes of lineage III strains showed that both
      horizontal gene transfer and partial deletion of the epitope-encoding region may
      contribute to the different antigenic properties for P1 of these strains. Phase
      variation of expression of the porA gene seems to account for most nonreacting
      strains. These results show that serosubtyping may underestimate the rise of a
      hyperendemic clone.

PMID- 10417148
TI  - Adhesion of Tritrichomonas foetus to bovine vaginal epithelial cells.
AB  - An in vitro culture system of bovine vaginal epithelial cells (BVECs) was
      developed to study the cytopathogenic effects of Tritrichomonas foetus and the
      role of lipophosphoglycan (LPG)-like cell surface glycoconjugates in adhesion of
      parasites to host cells. Exposure of BVEC monolayers to T. foetus resulted in
      extensive damage of monolayers. Host cell disruption was measured quantitatively
      by a trypan blue exclusion assay and by release of (3)H from [(3)H]thymidine
      labeled host cells. Results indicated contact-dependent cytotoxicity of host
      cells by T. foetus. The cytopathogenic effect was a function of T. foetus
      density. Metronidazole- or periodate-treated T. foetus showed no damage to BVEC
      monolayers. A related human trichomonad, Trichomonas vaginalis, showed no
      cytotoxic effects, indicating species-specific host-parasite interactions. A
      direct binding assay was developed and used to investigate the role of a major
      cell surface LPG-like molecule in host-parasite adhesion. The results of
      competition experiments showed that the binding to BVECs was displaceable, was
      saturable, and yielded a typical binding curve, suggesting that specific receptor
      ligand interactions mediate the attachment of T. foetus to BVECs. Progesterone
      treated BVECs showed enhanced parasite binding. T. foetus LPG inhibited the
      binding of T. foetus to BVECs; the LPG from T. vaginalis and a variety of other
      glycoconjugates did not. These data imply specificity of LPG on host-parasite
      adhesion. Periodate-treated parasites showed no adherence to host cells,
      indicating the involvement of carbohydrate containing molecules in the adhesion
      process.

PMID- 10417149
TI  - Predominance of CD4 Th1 and CD8 Tc1 cells revealed by characterization of the
      cellular immune response generated by immunization with a DNA vaccine containing
      a Trypanosoma cruzi gene.
AB  - Immunization with a plasmid DNA containing the gene encoding the catalytic domain
      of trans-sialidase (TS) elicits protective immune responses against experimental
      Trypanosoma cruzi infection. As several studies provided strong evidence that
      during infection CD4 Th1 and CD8 T cytotoxic type 1 (Tc1) cells are important
      factors in host resistance, the present study was designed to evaluate which T
      cell types were activated in DNA-vaccinated BALB/c mice. We found that bulk cells
      from DNA-immunized mice had CD4 and CD8 T cells that produced gamma interferon
      (IFN-gamma) but not interleukin-4 (IL-4) or IL-10. To characterize the TS
      specific T cells at the clonal level, we generated CD4 and CD8 clones. We
      obtained cytotoxic CD4 clones of the Th1 type that secreted large amounts of IFN
      gamma but not IL-4 or IL-10. Unexpectedly, we obtained other CD4 clones with a
      Th2 phenotype, secreting IL-4 and IL-10 but not IFN-gamma. All CD8 clones were
      cytotoxic and produced IFN-gamma. IL-4 and IL-10 were not secreted by these
      cells. Using synthetic peptides, we determined a CD8 epitope recognized by
      several clones as being represented by amino acids IYNVGQVSI. The antiparasitic
      activity of a CD4 Th1 and a CD8 Tc1 clone was assessed in vitro. CD4 or CD8 T
      cells significantly inhibited T. cruzi development in infected macrophages or
      fibroblasts, respectively. We concluded that DNA vaccine efficiently generates
      potentially protective CD4 Th1 and CD8 Tc1 cells specific for a T. cruzi antigen,
      therefore reinforcing the possibility of using this strategy for developing a
      preventive or therapeutic vaccine against Chagas' disease.

PMID- 10417150
TI  - Gamma interferon modulates CD95 (Fas) and CD95 ligand (Fas-L) expression and
      nitric oxide-induced apoptosis during the acute phase of Trypanosoma cruzi
      infection: a possible role in immune response control.
AB  - We have previously shown that splenocytes from mice acutely infected with
      Trypanosoma cruzi exhibit high levels of nitric oxide (NO)-mediated apoptosis. In
      the present study, we used the gamma interferon (IFN-gamma)-knockout (IFN-gamma(
      /-)) mice to investigate the role of IFN-gamma in modulating apoptosis induction
      and host protection during T. cruzi infection in mice. IFN-gamma(-/-) mice were
      highly susceptible to infection and exhibited significant reduction of NO
      production and apoptosis levels in splenocytes but normal lymphoproliferative
      response compared to the infected wild-type (WT) mice. Furthermore, IFN-gamma
      modulates an enhancement of Fas and Fas-L expression after infection, since the
      infected IFN-gamma(-/-) mice showed significantly lower levels of Fas and Fas-L
      expression. The addition of recombinant murine IFN-gamma to spleen cells cultures
      from infected IFN-gamma(-/-) mice increased apoptosis levels, Fas expression, and
      NO production. In the presence of IFN-gamma and absence of NO, although Fas
      expression was maintained, apoptosis levels were significantly reduced but still
      higher than those found in splenocytes from uninfected mice, suggesting that Fas
      Fas-L interaction could also play a role in apoptosis induction in T. cruzi
      infected mice. Moreover, in vivo, the treatment of infected WT mice with the
      inducible nitric oxide synthase inhibitor aminoguanidine also led to decreased NO
      and apoptosis levels but not Fas expression, suggesting that IFN-gamma modulates
      apoptosis induction by two independent and distinct mechanisms: induction of NO
      production and of Fas and Fas-L expression. We suggest that besides being of
      crucial importance in mediating resistance to experimental T. cruzi infection,
      IFN-gamma could participate in the immune response control through apoptosis
      modulation.

PMID- 10417151
TI  - Essential role of transcription factor nuclear factor-kappaB in regulation of
      interleukin-8 gene expression by nitrite reductase from Pseudomonas aeruginosa in
      respiratory epithelial cells.
AB  - Persistent infection with Pseudomonas aeruginosa increases interleukin-8 (IL-8)
      levels and causes dense neutrophil infiltrations in the airways of patients with
      chronic airway diseases. Recently, we have reported that nitrite reductase from
      P. aeruginosa induces the production of IL-8 in respiratory cells, including
      bronchial epithelial cells. To determine the molecular mechanism(s) of nitrite
      reductase-induced IL-8 expression in respiratory cells, A549 epithelial cells
      were transfected with plasmids containing serial deletions of the 5'-flanking
      region of the IL-8 gene and then exposed to nitrite reductase. Nitrite reductase
      significantly enhanced IL-8 gene promoter-driven reporter activity. This
      increased IL-8 gene expression was inhibited by mutating the nuclear factor
      kappaB (NF-kappaB) binding element. Nitrite reductase enhanced nuclear
      localization of the NF-kappaB binding complex. Furthermore, nitrite reductase
      induced the degradation of IkappaBalpha, the major cytoplasmic inhibitor of NF
      kappaB, and the expression of IkappaBalpha mRNA. These data support the critical
      role of the activation of NF-kappaB in nitrite reductase-induced IL-8 gene
      expression in airway epithelium.

PMID- 10417152
TI  - Molecular characterization of the hemin uptake locus (hmu) from Yersinia pestis
      and analysis of hmu mutants for hemin and hemoprotein utilization.
AB  - Sequence analysis of the hemin uptake locus (hmu) of Yersinia pestis revealed
      five genes, hmuRSTUV, required for use of hemin and hemoproteins as iron sources.
      The translated gene products have homologies with proteins of the hemin transport
      genes of several gram-negative bacteria. Promoters were identified upstream of
      hmuP'R (p1) and upstream of hmuS (p2); p1, which contains a Fur box, is regulated
      by iron and Fur, while p2 exhibits weak, but constitutive, activity. HmuR, which
      has homology with TonB-dependent outer membrane (OM) receptors, is localized to
      the OM of Y. pestis and is required for utilizing hemin and all hemoproteins
      under iron-depleted conditions. The proposed ABC transporter, HmuTUV, is
      necessary for use of hemin, hemin-albumin, and myoglobin, but not hemoglobin,
      hemoglobin-haptoglobin, or heme-hemopexin, as iron sources. In the absence of
      HmuTUV, HmuS, a cytoplasmic protein, is involved in use of hemoglobin and heme
      hemopexin. In mice, the 50% lethal doses of Y. pestis DeltahmuP'RSTUV mutants
      injected subcutaneously or retro-orbitally did not differ from that of the Hmu(+)
      parent strain. Thus, the hmu system is not essential for infection in mice via
      these routes. Growth studies showed that a DeltahmuP'RSTUV mutant could grow in
      iron-depleted medium containing high concentrations of hemoglobin, suggesting
      that an Hmu-independent, lower-affinity hemoglobin uptake system may exist.

PMID- 10417153
TI  - Multiple genes in the left half of the cag pathogenicity island of Helicobacter
      pylori are required for tyrosine kinase-dependent transcription of interleukin-8
      in gastric epithelial cells.
AB  - Helicobacter pylori strains that contain the cag pathogenicity island (PAI)
      elicit increased synthesis of gastric C-X-C chemokines, promote neutrophilic
      infiltration into the gastric epithelium, and stimulate the synthesis of
      interleukin-8 (IL-8) in cultured gastric epithelial cells. To investigate the
      effects of cag PAI genes on the transcription of the IL-8 gene, the Kato-3
      gastric epithelial cell line was stably transfected with plasmid DNA containing
      the IL-8 gene promoter fused to a luciferase reporter gene. The resulting
      reporter cell line, L5F11, was used to monitor the effects of infection in cell
      culture by H. pylori 26695 and isogenic derivatives with null mutations in genes
      in the cag PAI on transcription of the IL-8 gene. We found that null mutations in
      eight open reading frames, including homologs of the Agrobacterium virB9, virB10,
      and virB11 genes, in the left half of the cag PAI abrogated the induction of IL-8
      gene transcription. Further studies with the L5F11 cell line showed that IL-8
      gene transcription induced by H. pylori was blocked by the protein tyrosine
      kinase inhibitor herbimycin A but not by the protein kinase C inhibitor
      calphostin C or by the protein kinase G inhibitor KT5823. IL-8 gene transcription
      in L5F11 cells could also be induced by the cytokine tumor necrosis factor alpha
      (TNF-alpha) without exposure to H. pylori. This TNF-alpha-induced IL-8
      transcription was inhibited by the protein kinase A inhibitor H7, which had no
      significant effect on H. pylori-induced IL-8 transcription. These studies show
      that multiple genes in the left half of the cag PAI are essential for the
      transcription of the IL-8 gene in gastric epithelial cells and that this depends
      on protein tyrosine kinase activation.

PMID- 10417154
TI  - Characterization of a Haemophilus ducreyi mutant deficient in expression of
      cytolethal distending toxin.
AB  - Haemophilus ducreyi expresses a soluble cytolethal distending toxin (CDT) that
      kills HeLa, HEp-2, and other human epithelial cells in vitro. H. ducreyi CDT
      activity is encoded by a three-gene cluster (cdtABC), and antibody to the cdtC
      gene product can neutralize CDT activity in vitro (L. D. Cope, S. R. Lumbley, J.
      L. Latimer, J. Klesney-Tait, M. K. Stevens, L. S. Johnson, M. Purven, R. S.
      Munson, Jr., T. Lagergard, J. D. Radolf, and E. J. Hansen, Proc. Natl. Acad. Sci.
      USA 94:4056-4061, 1997). Culture supernatant fluid from a recombinant Escherichia
      coli strain containing the H. ducreyi cdtABC gene cluster readily killed both
      HeLa cells and HaCaT keratinocytes and had a modest inhibitory effect on the
      growth of human foreskin fibroblasts. Insertional inactivation of the cdtC gene
      in this recombinant E. coli strain eliminated the ability of this strain to kill
      HeLa cells and HaCaT keratinocytes. This mutated H. ducreyi cdtABC gene cluster
      was used to construct an isogenic H. ducreyi cdtC mutant. Monoclonal antibodies
      against the H. ducreyi CdtA, CdtB, and CdtC proteins were used to characterize
      protein expression by this cdtC mutant. Culture supernatant fluid from this H.
      ducreyi cdtC mutant did not detectably affect any of the human cells used in this
      study. The presence of the wild-type H. ducreyi cdtC gene in trans in this H.
      ducreyi mutant restored its ability to express a CDT that killed both HeLa cells
      and HaCaT keratinocytes. The isogenic H. ducreyi cdtC mutant was shown to be as
      virulent as its wild-type parent strain in the temperature-dependent rabbit model
      for experimental chancroid. Lack of expression of the H. ducreyi CdtC protein
      also did not affect the ability of this H. ducreyi mutant to survive in the skin
      of rabbits.

PMID- 10417155
TI  - Inactivation of the gbpA gene of Streptococcus mutans alters structural and
      functional aspects of plaque biofilm which are compensated by recombination of
      the gtfB and gtfC genes.
AB  - Inactivation of the gbpA gene of Streptococcus mutans increases virulence in a
      gnotobiotic rat model and also promotes in vivo accumulation of organisms in
      which gtfB and gtfC have recombined to reduce virulence (K. R. O. Hazlett, S. M.
      Michalek, and J. A. Banas, Infect. Immun. 66:2180-2185, 1998). These changes in
      virulence were hypothesized to result from changes in plaque structure. We have
      utilized an in vitro plaque model to test the hypothesis that the absence of GbpA
      alters S. mutans plaque structure and that the presence of gtfBC recombinant
      organisms within a gbpA background restores a wild-type (wt)-like plaque
      structure. When grown in the presence of sucrose within hydroxyapatite-coated
      wells, the wt S. mutans plaque consisted primarily of large aggregates which did
      not completely coat the hydroxyapatite surface, whereas the gbpA mutant plaque
      consisted of a uniform layer of smaller aggregates which almost entirely coated
      the hydroxyapatite. If 25% of the gbpA mutants used as inoculum were also gtfBC
      recombinants (gbpA/25%gtfBC), a wt-like plaque was formed. These changes in
      plaque structure correlated with differences in susceptibility to ampicillin;
      gbpA plaque organisms were more susceptible than organisms in either the wt or
      gbpA/25%gtfBC plaques. These data allow the conclusion that GbpA contributes to
      S. mutans plaque biofilm development. Since the changes in plaque structure
      detailed in this report correlate well with previously observed changes in
      virulence, it seems likely that S. mutans biofilm structure influences virulence.
      A potential model for this influence, which can account for the gtfBC
      recombination compensating gbpA inactivation, is that the ratio of glucan to
      glucan-binding protein is a critical factor in plaque development.

PMID- 10417156
TI  - Selective distribution of a high-affinity plasminogen-binding site among group A
      streptococci associated with impetigo.
AB  - Group A streptococci can be classified according to their tendency to cause
      either impetigo, pharyngitis, or both types of infection. Genotypic markers for
      tissue site preference lie within emm genes, which encode fibrillar surface
      proteins that play a key role in virulence. emm gene products (M and M-like
      proteins) display an extensive array of binding activities for tissue and plasma
      proteins of the human host. In a previous study, a high-affinity binding site for
      human plasmin(ogen) was mapped to the emm53 gene product. In this report, a
      structurally similar plasminogen-binding domain is found to be widely and
      selectively distributed among group A streptococci harboring the emm gene marker
      for the skin as the preferred tissue site for infection. The findings are highly
      suggestive of a central role for bacterial modulation of host plasmin(ogen)
      during localized infection at the epidermis.

PMID- 10417157
TI  - Cytoadherence of Babesia bovis-infected erythrocytes to bovine brain capillary
      endothelial cells provides an in vitro model for sequestration.
AB  - Babesia bovis, an intraerythrocytic parasite of cattle, is sequestered in the
      host microvasculature, a behavior associated with cerebral and vascular
      complications of this disease. Despite the importance of this behavior to disease
      etiology, the underlying mechanisms have not yet been investigated. To study the
      components involved in sequestration, B. bovis parasites that induce adhesion of
      the infected erythrocytes (IRBCs) to bovine brain capillary endothelial cells
      (BBEC) in vitro were isolated. Two clonal lines, CD7(A+I+) and CE11(A+I-), were
      derived from a cytoadherent, monoclonal antibody 4D9.1G1-reactive parasite
      population. This antibody recognizes a variant, surface-exposed epitope of the
      variant erythrocyte surface antigen 1 (VESA1) of B. bovis IRBCs. Both clonal
      lines were cytoadhesive to BBEC and two other bovine endothelial cell lines but
      not to COS7 cells, FBK-4 cells, C32 melanoma cells, or bovine brain pericytes. By
      transmission electron microscopy, IRBCs were observed to bind to BBEC via the
      knobby protrusions on the IRBC surface, indicating involvement of components
      associated with these structures. Inhibition of protein export in intact,
      trypsinized IRBCs ablated both erythrocyte surface reexpression of parasite
      protein and cytoadhesion. IRBCs allowed to recover surface antigen expression
      regained the ability to bind endothelial cells, demonstrating that parasite
      protein export is required for cytoadhesion. We propose the use of this assay as
      an in vitro model to study the components involved in B. bovis cytoadherence and
      sequestration.

PMID- 10417158
TI  - Plasmin-coated borrelia Burgdorferi degrades soluble and insoluble components of
      the mammalian extracellular matrix.
AB  - Borrelia burgdorferi, the spirochetal agent of Lyme disease, binds plasminogen in
      vitro. Exogenously provided urokinase-type plasminogen (PLG) activator (uPA)
      converts surface-bound PLG to enzymatically active plasmin. In this study, we
      investigated the capacity of a B. burgdorferi human isolate, once complexed with
      plasmin, to degrade purified extracellular matrix (ECM) components and an
      interstitial ECM. In a modified enzyme-linked immunosorbent assay using
      immobilized, soluble ECM components, plasmin-coated B. burgdorferi degraded
      fibronectin, laminin, and vitronectin but not collagen. Incubation of plasmin
      coated organisms with biosynthetically radiolabeled native ECM resulted in
      breakdown of insoluble glycoprotein, other noncollagenous proteins, and collagen,
      as measured by release of solubilized radioactivity. Radioactive release did not
      occur with untreated spirochetes or spirochetes treated with uPA or PLG alone.
      Kinetic and inhibition studies suggested that the breakdown of collagen was
      indirect and due to prior disruption of supportive ECM proteins. B. burgdorferi
      is an invasive bacterial pathogen that may benefit by use of the host's
      plasminogen activation system. The results of this study have identified
      mechanisms in which the spirochete can use this borrowed proteolytic activity to
      enhance invasiveness.

PMID- 10417159
TI  - Limited local and systemic antibody responses to Neisseria gonorrhoeae during
      uncomplicated genital infections.
AB  - Repeated infections with Neisseria gonorrhoeae are common among patients
      attending sexually transmitted disease clinics. We examined whether previous
      infections or site of infection altered the local and systemic antigonococcal
      antibody levels in males and females. Antibodies against N. gonorrhoeae MS11 and
      the patients' homologous infecting isolates were measured by enzyme-linked
      immunosorbent assay. In general, the local and systemic immune responses to
      gonococci were extremely modest. There was a slight increase in serum
      immunoglobulin G (IgG) against the MS11 strain and the homologous isolates in
      infected males. Levels of serum IgA1 antibodies against MS11 were slightly higher
      in infected than in uninfected females. A history of previous infections with N.
      gonorrhoeae did not alter the antibody levels in patients with a current
      infection, suggesting that immunological memory is not induced by uncomplicated
      gonococcal infections. Antibody responses to infected subjects' homologous
      isolates were observed in cervical mucus; IgA1 levels increased while IgG levels
      decreased. The decline in mucosal IgG against the homologous isolates was less
      common in subjects having both rectal and cervical infections; otherwise, no
      effect of rectal involvement was observed. The absence of substantially higher
      antibody levels to gonococci where there is infection at a site known to contain
      organized lymphoid tissue suggests that the low levels of responses to
      uncomplicated infections may not be due simply to an absence of inductive sites
      in the genital tract. We propose that in addition to its potential ability to
      avoid the effects of an immune response, N. gonorrhoeae does not elicit strong
      humoral immune responses during uncomplicated genital infections.

PMID- 10417160
TI  - Evidence of thymus-independent local and systemic antibody responses to
      Cryptosporidium parvum infection in nude mice.
AB  - Differences in susceptibility to persistent cryptosporidial infection between two
      strains of adult athymic nude mice prompted us to investigate the immune
      mechanism(s) that may control resistance to infection in these T-cell-deficient
      mice. We studied fecal oocyst shedding, serum and fecal parasite-specific
      antibody responses, and fecal immunoglobulin levels in athymic C57BL/6J nude and
      athymic BALB/cJ nude mice following oral inoculation with Cryptosporidium parvum
      oocysts at 8 to 9 weeks of age. C57BL/6J nude mice had significantly higher fecal
      parasite-specific immunoglobulin A (IgA) (days 27, 31, 35, and 42
      postinoculation) and IgM (days 10, 17, 24, 28, 31, 38, 42, and 48
      postinoculation) levels than BALB/cJ nude mice (P < 0.05) and significantly
      higher serum parasite-specific IgA levels at 63 days postinoculation (P < 0.03).
      Moreover, C57BL/6J nude mice shed significantly fewer C. parvum oocysts than
      BALB/cJ nude mice from days 52 to 63 postinoculation (P < 0.05). In contrast,
      BALB/cJ nude mice had higher levels of non-parasite-specific IgA (days 38 to 63
      postinoculation) and IgM (days 24, 35, 38, and 52 postinoculation) than C57BL/6J
      nude mice in feces (P < 0.05). These data suggest that parasite-specific fecal
      antibodies may be associated with resistance to C. parvum in C57BL/6J nude mice.

PMID- 10417161
TI  - Functional analysis of the Staphylococcus aureus collagen adhesin B domain.
AB  - The Staphylococcus aureus collagen adhesin (CNA) occurs in at least four forms
      that differ in the number (one, two, three, or four) of B domains. The B domains
      contain 187 amino acids and are located between the domains that anchor CNA to
      the cell envelope and the ligand-binding A domain. To determine whether a B
      domain is required for functional expression of CNA, we cloned the 2B cna gene
      from S. aureus strain Phillips and then eliminated both B domains by overlapping
      PCR. The absence of a B domain did not affect processing of the collagen adhesin
      to the cell surface or the ability to bind collagen. Based on our recent
      demonstration that the capsule can mask CNA on the surface of S. aureus cells (A.
      F. Gillaspy et al., Infect. Immun. 66:3170-3178, 1998), we also investigated the
      possibility that multiple B domains can extend the ligand-binding A domain
      outward from the cell surface and thereby overcome the inhibitory effect of the
      capsule. Specifically, we cloned the naturally occurring 4B CNA variant from S.
      aureus UAMS-639 and, by successive elimination of B domains, generated 1, 2, and
      3B variants that are isogenic with respect to the 4B clone. After introducing
      each variant into microencapsulated and heavily encapsulated strains of S. aureus
      and growing cells under conditions known to affect capsule production (e.g.,
      growth on Columbia agar), we correlated capsule production with exposure of CNA
      on the cell surface and the ability to bind collagen. Under no circumstance was
      the masking effect of the capsule reduced by the presence of multiple B domains.
      These results indicate that the B domains do not extend the ligand-binding A
      domain outward in a fashion that can overcome the inhibition of collagen binding
      associated with capsule production.

PMID- 10417162
TI  - A random survey of the Cryptosporidium parvum genome.
AB  - Cryptosporidium parvum is an obligate intracellular pathogen responsible for
      widespread infections in humans and animals. The inability to obtain purified
      samples of this organism's various developmental stages has limited the
      understanding of the biochemical mechanisms important for C. parvum development
      or host-parasite interaction. To identify C. parvum genes independent of their
      developmental expression, a random sequence analysis of the 10.4-megabase genome
      of C. parvum was undertaken. Total genomic DNA was sheared by nebulization, and
      fragments between 800 and 1,500 bp were gel purified and cloned into a plasmid
      vector. A total of 442 clones were randomly selected and subjected to automated
      sequencing by using one or two primers flanking the cloning site. In this way,
      654 genomic survey sequences (GSSs) were generated, corresponding to >320 kb of
      genomic sequence. These sequences were assembled into 408 contigs containing >250
      kb of unique sequence, representing approximately 2.5% of the C. parvum genome.
      Comparison of the GSSs with sequences in the public DNA and protein databases
      revealed that 107 contigs (26%) displayed similarity to previously identified
      proteins and rRNA and tRNA genes. These included putative genes involved in the
      glycolytic pathway, DNA, RNA, and protein metabolism, and signal transduction
      pathways. The repetitive sequence elements identified included a telomere-like
      sequence containing hexamer repeats, 57 microsatellite-like elements composed of
      dinucleotide or trinucleotide repeats, and a direct repeat sequence. This study
      demonstrates that large-scale genomic sequencing is an efficient approach to
      analyze the organizational characteristics and information content of the C.
      parvum genome.

PMID- 10417163
TI  - Thymic independence of adaptive immunity to the intracellular pathogen Shigella
      flexneri serotype 2a.
AB  - Shigella flexneri is a facultative intracellular pathogen. While immunity to
      several intracellular pathogens is mediated by T lymphocytes, it is unknown
      whether cellular immune responses are important to adaptive immunity to S.
      flexneri. We show that vaccination with S. flexneri serotype 2a confers
      protection to mice that lack T lymphocytes or gamma interferon (IFN-gamma),
      specific depletion of T lymphocytes does not alter the protection, and adoptive
      transfer of splenocytes from vaccinated mice does not confer protection to naive
      mice. In contrast, vaccination conferred no protection to mice that lack B
      lymphocytes and adoptive transfer of immune sera conferred partial protection to
      naive mice. These data demonstrate that in the mouse bronchopulmonary model,
      adaptive immunity to S. flexneri 2a is an antibody-mediated, B-lymphocyte
      dependent process and can be generated in the absence of T lymphocytes or IFN
      gamma.

PMID- 10417164
TI  - Early emergence of CD8(+) T cells primed for production of type 1 cytokines in
      the lungs of Mycobacterium tuberculosis-infected mice.
AB  - Several lines of evidence suggest that CD8 T cells are important in protection
      against tuberculosis. To understand the function of this cell population in the
      immune response against Mycobacterium tuberculosis, T cells from lungs of M.
      tuberculosis-infected mice were examined by flow cytometry. The kinetics of the
      appearance of CD8 T cells in lungs of infected mice closely paralleled that of
      CD4 T cells. Both CD4(+) and CD8(+) T cells displaying an activated phenotype
      were found in the lungs as early as 1 week postinfection. By 2 weeks, total cell
      numbers in the lungs had tripled and percentages of T cells were increased two-
      to threefold; the percentages of CD4(+) T cells were ca. twofold higher than
      those of CD8(+) T cells. Short-term stimulation with M. tuberculosis-infected
      antigen-presenting cells induced cytokine production by primed CD4(+) and CD8(+)
      T cells. Intracellular cytokine staining revealed that 30% +/- 5% of CD4(+) and
      23% +/- 4% of CD8(+) T cells were primed for production of gamma interferon (IFN
      gamma). However, a difference in in vivo IFN-gamma production by T cells was
      observed with approximately 12% of CD4(+) T cells and approximately 5% of CD8(+)
      T cells secreting cytokine in the lungs at any given time during infection. The
      data presented indicate that although early in infection the majority of IFN
      gamma is produced by CD4(+) T cells, cytokine-producing CD8(+) T cells are
      readily available when triggered by the appropriate stimuli.

PMID- 10417165
TI  - Decay-accelerating factor and cytoskeleton redistribution pattern in HeLa cells
      infected with recombinant Escherichia coli strains expressing Dr family of
      adhesins.
AB  - Escherichia coli strains expressing Dr fimbriae are able to enter epithelial
      cells by interacting with a complement-regulatory protein, decay-accelerating
      factor. This model of bacterial internalization, with a well-characterized
      bacterial ligand and host receptor, provides a unique opportunity to investigate
      the early stages of invasion. We used immunofluorescence staining techniques to
      examine the distribution of receptor and cytoskeletal proteins in HeLa cells
      infected with E. coli recombinant strains that expressed Dr family of adhesins:
      Dr, Dr-II, F1845, AFA-I, and AFA-III. A major rearrangement of decay-accelerating
      factor was found at the adherence sites of recombinant strains expressing Dr, Dr
      II, and F1845 adhesins. The changes in the distribution of receptor were
      significantly smaller on HeLa cells infected with E. coli bearing AFA-I or AFA
      III afimbrial adhesins. Receptor aggregation was associated with the
      redistribution of cytoskeleton-associated proteins such as actin, alpha-actinin,
      ezrin, and occasionally tropomyosin. Purified Dr fimbriae coated on polystyrene
      beads were capable of triggering clustering of receptor and accumulating actin at
      the adhesion sites of beads to HeLa cells. Using scanning and transmission
      electron microscopic techniques, we have shown that beads coated with Dr
      fimbriae, as opposed to beads coated with bovine serum albumin, were enwrapped by
      cellular microvilli and ultimately internalized into HeLa cells. This indicates
      that interaction of Dr fimbriae with decay-accelerating factor is associated with
      redistribution of receptor and is sufficient to promote bacterial
      internalization.

PMID- 10417166
TI  - Cloning, expression, and immunological evaluation of two putative secreted serine
      protease antigens of Mycobacterium tuberculosis.
AB  - Culture filtrate proteins (CFP) of Mycobacterium tuberculosis have been shown to
      contain immunogenic components that elicit at least partial protective immunity
      against Mycobacterium infection. To clone genes encoding some of the immunogenic
      proteins, we made a high-titer rabbit anti-CFP serum and used it to screen an M.
      tuberculosis genomic expression library in Escherichia coli. In this paper, we
      describe the molecular cloning of two new protein components of CFP and
      identified them as members of the serine protease gene family. Their open reading
      frames contain N-terminal hydrophobic secretory signals consistent with their
      detection in CFP. The predicted molecular masses of the mature, fully processed
      forms of both antigens are approximately 32 kDa, in agreement with their observed
      sizes on immunoblots of CFP probed with polyclonal rabbit antisera made to the
      recombinant proteins. Thus, these proteins have been designated MTB32A and
      MTB32B. Interestingly, and despite 66% amino acid sequence homology between the
      two proteins, polyclonal rabbit antisera made to each of the recombinant proteins
      were found to be specific for the respective immunizing antigens. The recombinant
      proteins were also evaluated in in vitro assays with donor peripheral blood
      mononuclear cells (PBMC) from healthy purified protein derivative (PPD)-positive
      individuals of diverse ethnic backgrounds. MTB32A but not MTB32B stimulated PBMC
      from healthy PPD-positive donors but not from PPD-negative donors to proliferate
      and secrete gamma interferon. MTB32A is encoded by a single-copy gene which is
      present in both virulent and avirulent strains of the M. tuberculosis complex and
      the BCG strain of Mycobacterium bovis but absent in the environmental
      mycobacterial species tested. In addition, nucleotide sequence comparison of
      mtb32a of the avirulent H37Ra strain and the virulent Erdman strain, as well as
      with the corresponding sequences (identified in the databases) of strain H37Rv
      and the clinical isolate CSU93, revealed 100% identity. MTB32A, therefore,
      represents a candidate for inclusion in subunit vaccine development. Finally, the
      possible role of MTB32 serine proteases as a virulence factor(s) during
      Mycobacterium spp. infection is discussed.

PMID- 10417167
TI  - Cloning, sequencing, and role in virulence of two phospholipases (A1 and C) from
      mesophilic Aeromonas sp. serogroup O:34.
AB  - Two different representative recombinant clones encoding Aeromonas hydrophila
      lipases were found upon screening on tributyrin (phospholipase A1) and egg yolk
      agar (lecithinase-phospholipase C) plates of a cosmid-based genomic library of
      Aeromonas hydrophila AH-3 (serogroup O34) introduced into Escherichia coli
      DH5alpha. Subcloning, nucleotide sequencing, and in vitro-coupled transcription
      translation experiments showed that the phospholipase A1 (pla) and C (plc) genes
      code for an 83-kDa putative lipoprotein and a 65-kDa protein, respectively.
      Defined insertion mutants of A. hydrophila AH-3 defective in either pla or plc
      genes were defective in phospholipase A1 and C activities, respectively.
      Lecithinase (phospholipase C) was shown to be cytotoxic but nonhemolytic or
      poorly hemolytic. A. hydrophila AH-3 plc mutants showed a more than 10-fold
      increase in their 50% lethal dose on fish and mice, and complementation of the
      plc single gene on these mutants abolished this effect, suggesting that Plc
      protein is a virulence factor in the mesophilic Aeromonas sp. serogroup O:34
      infection process.

PMID- 10417168
TI  - New exfoliative toxin produced by a plasmid-carrying strain of Staphylococcus
      hyicus.
AB  - A new serotype of Staphylococcus hyicus exfoliative toxin (SHET), serotype B, was
      isolated from the culture filtrate of a plasmid-carrying strain of S. hyicus. The
      new SHET was purified by precipitation with 70% saturated ammonium sulfate, gel
      filtration on a Sephadex G-75 column, column chromatography on DEAE-Cellulofine A
      500, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).
      The new SHET caused exfoliation of the epidermis as determined by the so-called
      Nikolsky sign when inoculated into 1-day-old chickens. The new SHET was
      serologically different from Staphylococcus aureus exfoliative toxins (ETs) (ETA,
      ETB, and ETC) and from the SHET from the plasmidless strain but showed the same
      molecular weight as the other serotypes of toxins on SDS-PAGE. It was
      thermolabile and lost its toxicity after being heated at 60 degrees C for 30 min.
      We propose that the new SHET be designated SHETB and that the SHET produced by
      the plasmidless strain be designated SHETA.

PMID- 10417170
TI  - A murine model for infection with Burkholderia cepacia with sustained persistence
      in the spleen.
AB  - Burkholderia cepacia is an opportunistic pathogen that causes severe systemic
      infections in patients with chronic granulomatous disease (CGD) or with cystic
      fibrosis (CF), but its mechanisms of virulence are poorly understood. We
      developed a murine model of systemic infection in wild-type (WT) and gamma
      interferon knockout (GKO) BALB/c mice to facilitate dissection of components of
      pathogenicity and host defense. Both WT and GKO mice were susceptible to chronic
      splenic infection with B. cepacia, but not with Pseudomonas aeruginosa. B.
      cepacia strains from patients with CGD persisted longer than those from CF
      patients. C57BL/6 mice were the most susceptible murine strain; bacteria
      persisted in the spleen for 2 months. DBA/2, BALB/c, and A/J strains of mice were
      relatively resistant to infection. Certain strains of B. cepacia complex can
      persist in the murine spleen after systemic infection; this may provide clues to
      its virulence in compromised hosts, such as those with CGD and CF.

PMID- 10417169
TI  - Characterization of an enterotoxigenic Escherichia coli strain from Africa
      expressing a putative colonization factor.
AB  - An enterotoxigenic Escherichia coli (ETEC) strain of serotype O114:H- that
      expressed both heat-labile and heat-stable enterotoxins and tested negative for
      colonization factors (CF) was isolated from a child with diarrhea in Egypt. This
      strain, WS0115A, induced hemagglutination of bovine erythrocytes and adhered to
      the enterocyte-like cell line Caco-2, suggesting that it may elaborate novel
      fimbriae. Surface-expressed antigen purified by differential ammonium sulfate
      precipitation and column chromatography yielded a single protein band with M(r)
      14,800 when resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis
      (16% polyacrylamide). A monoclonal antibody against this putative fimbrial
      antigen was generated and reacted with strain WS0115A and also with CS1-, CS17-,
      and CS19-positive strains in a dot blot assay. Reactivity was temperature
      dependent, with cells displaying reactivity when grown at 37 degrees C but not
      when grown at 22 degrees C. Immunoblot analysis of a fimbrial preparation from
      strain WS0115A showed that the monoclonal antibody reacted with a single protein
      band. Electron microscopy and immunoelectron microscopy revealed fimbria-like
      structures on the surface of strain WS0115A. These structures were rigid and
      measured 6.8 to 7.4 nm in diameter. Electrospray mass-spectrometric analysis
      showed that the mass of the purified fimbria was 14,965 Da. The N-terminal
      sequence of the fimbria established that it was a member of the CFA/I family,
      with sequence identity to the amino terminus of CS19, a new CF recently
      identified in India. Cumulatively, our results suggest that this fimbria is CS19.
      Screening of a collection of ETEC strains isolated from children with diarrhea in
      Egypt found that 4.2% of strains originally reported as CF negative were positive
      for this CF, suggesting that it is biologically relevant in the pathogenesis of
      ETEC.

PMID- 10417171
TI  - Trypanosoma cruzi infects human dendritic cells and prevents their maturation:
      inhibition of cytokines, HLA-DR, and costimulatory molecules.
AB  - Trypanosoma cruzi, a parasitic protozoan, is the etiological agent of Chagas'
      disease. Despite the many immune system disorders recognized in this infection
      and the crucial role played by dendritic cells (DC) in acquired immune responses,
      it was not known whether these cells could be infected by T. cruzi
      trypomastigotes and the consequences of such an infection on their immune
      functions. We now provide evidence that human monocyte-derived DC can be infected
      by T. cruzi and can support its intracellular multiplication. Interestingly, this
      infection has functional consequences on immature DC and on their maturation
      induced by lipopolysaccharide (LPS). First, after T. cruzi infection, the basal
      synthesis of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha)
      was impaired. Furthermore, the process of maturation of DC induced by LPS was
      drastically affected by T. cruzi infection. Indeed, secretion of cytokines such
      as IL-12, TNF-alpha, and IL-6, which are released normally at high levels by LPS
      activated DC, as well as the up-regulation of HLA-DR and CD40 molecules, was
      significantly reduced after this infection. The same effects could be induced by
      T. cruzi-conditioned medium, indicating that at least these inhibitory effects
      were mediated by soluble factors released by T. cruzi. Taken together, these
      results provide new insights into a novel efficient mechanism, directly involving
      the alteration of DC function, which might be used by T. cruzi to escape the host
      immune responses in Chagas' disease and thus might favor persistent infection.

PMID- 10417172
TI  - Early acidification of phagosomes containing Brucella suis is essential for
      intracellular survival in murine macrophages.
AB  - Brucella suis is a facultative intracellular pathogen of mammals, residing in
      macrophage vacuoles. In this work, we studied the phagosomal environment of these
      bacteria in order to better understand the mechanisms allowing survival and
      multiplication of B. suis. Intraphagosomal pH in murine J774 cells was determined
      by measuring the fluorescence intensity of opsonized, carboxyfluorescein
      rhodamine- and Oregon Green 488-rhodamine-labeled bacteria. Compartments
      containing live B. suis acidified to a pH of about 4.0 to 4.5 within 60 min.
      Acidification of B. suis-containing phagosomes in the early phase of infection
      was abolished by treatment of host cells with 100 nM bafilomycin A(1), a specific
      inhibitor of vacuolar proton-ATPases. This neutralization at 1 h postinfection
      resulted in a 2- to 34-fold reduction of opsonized and nonopsonized viable
      intracellular bacteria at 4 and 6 h postinfection, respectively. Ammonium
      chloride and monensin, other pH-neutralizing reagents, led to comparable loss of
      intracellular viability. Addition of ammonium chloride at 7 h after the beginning
      of infection, however, did not affect intracellular multiplication of B. suis, in
      contrast to treatment at 1 h postinfection, where bacteria were completely
      eradicated within 48 h. Thus, we conclude that phagosomes with B. suis acidify
      rapidly after infection, and that this early acidification is essential for
      replication of the bacteria within the macrophage.

PMID- 10417173
TI  - Interaction of Brucella abortus lipopolysaccharide with major histocompatibility
      complex class II molecules in B lymphocytes.
AB  - Lipopolysaccharide (LPS), a major amphiphilic molecule located at the outer
      membrane of gram-negative bacteria, is a potent antigen known to induce specific
      humoral immune responses in infected mammals. LPS has been described as a
      polyclonal activator of B lymphocytes, triggering the secretion of antibodies
      directed against distinct sugar epitopes of the LPS chain. But, how LPS is
      handled by B cells remains to be fully understood. This task appears to be
      essential for a better knowledge of the anti-LPS humoral immune response. In this
      study, we examine the internalization of LPS and its interaction with antigen
      presenting major histocompatibility complex (MHC) class II molecules in murine
      and human B-cell lines. By use of immunofluorescence, we observe that
      structurally different LPSs from Brucella and Shigella strains accumulate in an
      intracellular compartment enriched in MHC class II molecules. By use of
      immunoprecipitation, we illustrate that only Brucella abortus LPS associates with
      MHC class II molecules in a haplotype-independent manner. Taken together, these
      results raise the possibility that B. abortus LPS may play a role in T-cell
      activation.

PMID- 10417174
TI  - Activation of phosphotyrosine phosphatase activity attenuates mitogen-activated
      protein kinase signaling and inhibits c-FOS and nitric oxide synthase expression
      in macrophages infected with Leishmania donovani.
AB  - Intracellular protozoan parasites of the genus Leishmania antagonize host defense
      mechanisms by interfering with cell signaling in macrophages. In this report, the
      impact of Leishmania donovani on mitogen-activated protein (MAP) kinases and
      nitric oxide synthase (NOS) expression in the macrophage cell line RAW 264 was
      investigated. Overnight infection of cells with leishmania led to a significant
      decrease in phorbol-12-myristate-13-acetate (PMA)-stimulated MAP kinase activity
      and inhibited PMA-induced phosphorylation of the MAP kinase substrate and
      transcription factor Elk-1. Simultaneously, leishmania infection markedly
      attenuated the induction of c-FOS and inducible nitric oxide synthase (iNOS)
      expression in response to PMA and gamma interferon (IFN-gamma), respectively.
      These effects correlated with decreased phosphorylation of p44 and p42 MAP
      kinases on tyrosine residues. Consistent with the latter finding, lysates
      prepared from leishmania-infected cells contained an activity that
      dephosphorylated MAP kinase in vitro, suggesting the possibility of a phosphatase
      acting in vivo. Attenuation of both MAP kinase activity and c-FOS and iNOS
      expression was reversed by treatment of macrophages with sodium orthovanadate
      prior to infection. It was also found that the specific activity of the Src
      homology 2 domain containing tyrosine phosphatase (SHP-1) toward MAP kinase was
      markedly increased in leishmania-infected cells. These findings indicate that
      infection with L. donovani attenuates MAP kinase signaling and c-FOS and iNOS
      expression in macrophages by activating cellular phosphotyrosine phosphatases.
      This may represent a novel mechanism of macrophage deactivation during
      intracellular infection.

PMID- 10417175
TI  - Cell-mediated immune responses in four-year-old children after primary
      immunization with acellular pertussis vaccines.
AB  - Cell-mediated immune (CMI) responses to Bordetella pertussis antigens (pertussis
      toxin [PT], pertactin [PRN], and filamentous hemagglutinin [FHA]) were assessed
      in 48-month-old recipients of acellular pertussis [aP] vaccines (either from
      Chiron-Biocine [aP-CB] or from SmithKline Beecham [aP-SB]) and compared to CMI
      responses to the same antigens at 7 months of age, i.e., 1 month after completion
      of the primary immunization cycle. None of the children enrolled in this study
      received any booster of pertussis vaccines or was affected by pertussis during
      the whole follow-up period. Overall, around 75% of 4-year-old children showed a
      CMI-positive response to at least one B. pertussis antigen, independently of the
      type of aP vaccine received, and the proportion of CMI responders were at least
      equal at 48 and 7 months of age. However, longitudinal examination of individual
      responses showed that from 20 (against PT) to 37% (against FHA) of CMI responders
      after primary immunization became negative at 48 months of age. This loss was
      more than compensated for by conversion to positive CMI responses, ranging from
      36% against FHA to 69% against PRN, in other children who were CMI negative at 7
      months of age. In 60 to 80% of these CMI converters, a lack of decline or even
      marked elevation of antibody (Ab) titers against B. pertussis antigens also
      occurred between 20 and 48 months of age. In particular, the frequency of
      seropositivity to PRN and FHA (but not to PT) was roughly three times higher in
      CMI converters than in nonconverters. The acquisition of CMI response to B.
      pertussis antigens in 48-month-old children was not associated with a greater
      frequency of coughing episodes lasting >/=7 days and was characterized by a
      prevalent type 1 cytokine profile, with high gamma interferon and low or no
      production of interleukin-5, reminiscent of cytokine patterns following
      immunization with whole-cell pertussis vaccine or natural infection. Our data
      imply that vaccination-induced systemic CMI may wane by 4 years of age but may be
      acquired or naturally boosted by symptomless or minor clinical infection by B.
      pertussis. This might explain, at least in part, the persistence of protection
      against typical pertussis in aP vaccine recipients despite a substantial waning
      of both Ab and CMI responses induced by the primary immunization.

PMID- 10417176
TI  - The Treponema denticola major sheath protein is predominantly periplasmic and has
      only limited surface exposure.
AB  - The recent discovery that the Treponema pallidum genome encodes 12 orthologs of
      the Treponema denticola major sheath protein (Msp) prompted us to reexamine the
      cellular location and topology of the T. denticola polypeptide. Experiments
      initially were conducted to ascertain whether Msp forms an array on or within the
      T. denticola outer membrane. Transmission electron microscopy (EM) of negatively
      stained and ultrathin-sectioned organisms failed to identify a typical surface
      layer, whereas freeze-fracture EM revealed that the T. denticola outer membrane
      contains heterogeneous transmembrane proteins but no array. In contrast, a
      lattice-like structure was observed in vesicles released from mildly sonicated
      treponemes; combined EM and biochemical analyses demonstrated that this structure
      was the peptidoglycan sacculus. Immunoelectron microscopy (IEM) subsequently was
      performed to localize Msp in T. denticola. Examination of negatively stained
      whole mounts identified substantial amounts of Msp in sonicated organisms. IEM of
      ultrathin-sectioned, intact treponemes also demonstrated that the preponderance
      of antigen was unassociated with the outer membrane. Lastly, immunofluorescence
      analysis of treponemes embedded in agarose gel microdroplets revealed that only
      minor portions of Msp are surface exposed. Taken as a whole, our findings
      challenge the widely held belief that Msp forms an array within the T. denticola
      outer membrane and demonstrate, instead, that it is predominantly periplasmic
      with only limited surface exposure. These findings also have implications for our
      evolving understanding of the contribution(s) of Msp/Tpr orthologs to treponemal
      physiology and disease pathogenesis.

PMID- 10417177
TI  - Identification of a glycoprotein produced by enterotoxigenic Escherichia coli.
AB  - Enterotoxigenic Escherichia coli (ETEC) strain H10407 is capable of invading
      epithelial cell lines derived from the human ileocecum and colon in vitro. Two
      separate chromosomally encoded invasion loci (tia and tib) have been cloned from
      this strain. These loci direct nonadherent and noninvasive laboratory strains of
      E. coli to adhere to and invade cultured human intestinal epithelial cells. The
      tib locus directs the synthesis of TibA, a 104-kDa outer membrane protein that is
      directly correlated with the adherence and invasion phenotypes. TibA is
      synthesized as a 100-kDa precursor (preTibA) that must be modified for biological
      activity. Outer membranes of recombinant E. coli expressing TibA or preTibA were
      separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and
      blotted to nitrocellulose. The presence of glycoproteins was detected by
      oxidization of carbohydrates with periodate and labeling with hydrazide
      conjugated digoxigenin. Only TibA could be detected as a glycoprotein.
      Complementation experiments with tib deletion mutants of ETEC strain H10407
      demonstrate that the TibA glycoprotein is expressed in H10407, that the entire
      tib locus is required for TibA synthesis, and that TibA is the only glycoprotein
      produced by H10407. Protease treatment of intact H10407 cells removes the
      carbohydrates on TibA, suggesting that they are surface exposed. TibA shows
      homology with AIDA-I from diffuse-adhering E. coli and with pertactin precursor
      from Bordetella pertussis. Both pertactin and AIDA-I are members of the
      autotransporter family of outer membrane proteins and are afimbrial adhesins that
      play an important role in the virulence of these organisms. Analysis of the
      predicted TibA amino acid sequence indicates that TibA is also an
      autotransporter. Analysis of the tib locus DNA sequence revealed an open reading
      frame with similarity to RfaQ, a glycosyltransferase. The product of this tib
      locus open reading frame is proposed to be responsible for TibA modification.
      These results suggest that TibA glycoprotein acts as an adhesin that may
      participate in the disease process.

PMID- 10417178
TI  - Nine-year longitudinal study of antibodies to variant antigens on the surface of
      Plasmodium falciparum-infected erythrocytes.
AB  - PfEMP1 is an antigenically variable molecule which mediates the adhesion of
      parasitized erythrocytes to a variety of cell types and which is believed to
      constitute an important target for naturally acquired protective immune responses
      in malaria. For 9 years we have monitored individuals living in an area of low
      intensity, seasonal, and unstable malaria transmission in eastern Sudan, and we
      have used this database to study the acquisition, specificity, and duration of
      the antibody response to variant parasitized erythrocyte surface antigens. Both
      the levels and the spectrum of reactivity of these antibodies varied considerably
      among individuals, ranging from low levels of antibodies recognizing only few
      parasitized erythrocyte surface antigens to high levels of broad-specificity
      antibodies. In general, episodes of clinical malaria were associated with
      increases in the levels of parasitized erythrocyte surface-specific antibodies
      that subsided within months of the attack. This response was often, but not
      always, specific for the antigenic variants expressed by the parasite isolate
      causing disease. Our study provides evidence that Palciparum falciparum malaria
      is associated with a short-lived, variant-specific antibody response to PfEMP1
      like antigens exposed on the surface of parasitized erythrocytes. Furthermore,
      our data suggest that the antigenic repertoires of variant antigens expressed by
      different parasite isolates show considerable overlapping, at least under
      Sahelian conditions of low-intensity, seasonal, and unstable malaria
      transmission. Finally, we demonstrate the existence of persistent differences
      among individuals in the capacity to mount antibody responses to variant surface
      antigens.

PMID- 10417180
TI  - Purification and properties of proline-rich antimicrobial peptides from sheep and
      goat leukocytes.
AB  - We purified three proline-rich antimicrobial peptides from elastase-treated
      extracts of sheep and goat leukocytes and subjected two of them, OaBac5alpha and
      ChBac5, to detailed analysis. OaBac5alpha and ChBac5 were homologous to each
      other and to bovine Bac5. Both exhibited potent, broad-spectrum antimicrobial
      activity under low-concentration salt conditions. While the peptides remained
      active against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and
      Listeria monocytogenes in 100 mM NaCl, they lost activity against Staphylococcus
      aureus and Candida albicans under these conditions. ChBac5 was shown to bind
      lipopolysaccharide, a property that could enhance its ability to kill gram
      negative bacteria. Proline-rich Bac5 peptides are highly conserved in ruminants
      and may contribute significantly to their innate host defense mechanisms.

PMID- 10417179
TI  - Differential regulation of Salmonella typhimurium type III secreted proteins by
      pathogenicity island 1 (SPI-1)-encoded transcriptional activators InvF and hilA.
AB  - Salmonella enterica encodes a type III protein secretion system within a
      pathogenicity island (SPI-1) that is located at centisome 63 of its chromosome.
      This system is required for the ability of these bacteria to stimulate cellular
      responses that are essential for their pathogenicity. Expression of components
      and substrates of this system is subject to complex regulatory mechanisms. These
      mechanisms involve the function of HilA and InvF, two transcriptional regulatory
      proteins encoded within SPI-1. In this study, we examined the functional
      relationship between these two regulatory proteins. We found that strains
      carrying loss-of-function mutations in either hilA or invF differ in their
      ability to stimulate cellular responses. An S. typhimurium hilA mutant strain
      retained considerable signaling capacity that resulted in significant levels of
      internalization into host cells. In contrast, introduction of a nonpolar loss-of
      function mutation in invF rendered S. typhimurium significantly impaired in its
      ability to enter host cells. Consistent with these different phenotypes, we found
      that HilA and InvF control the expression of different genes. HilA regulates the
      expression of components of the type III secretion machinery, whereas InvF
      controls the expression of type III secreted proteins encoded outside of SPI-1.
      We also found that the expression of secreted proteins encoded within SPI-1 are
      under the control of both HilA and InvF. Our results therefore indicate that InvF
      and HilA differentially control the expression of components and substrates of
      the invasion-associated type III secretion system.

PMID- 10417181
TI  - Expression of Fas and Fas ligand on mouse renal tubular epithelial cells in the
      generalized shwartzman reaction and its relationship to apoptosis.
AB  - Previously we reported that the consecutive injection of lipopolysaccharide (LPS)
      into LPS-sensitized mice for the generalized Shwartzman reaction (GSR) appeared
      to induce the injury of renal tubular epithelial cells via apoptosis. The aim of
      this study was to characterize the mechanism of renal tubular epithelial cell
      injury in GSR. The expression of Fas and Fas ligand was immunohistochemically
      detected on renal tubular epithelial cells from GSR-induced mice, although
      neither Fas nor Fas ligand was found in cells from untreated control mice or in
      cells from mice receiving a single injection of LPS. GSR-induced renal tubular
      epithelial cell injury was produced in neither Fas-negative MRL-lpr/lpr mice nor
      Fas ligand-negative MRL-gld/gld mice. The administration of anti-gamma interferon
      antibody together with a preparative injection of LPS prevented the expression of
      Fas and Fas ligand and the apoptosis of renal tubular epithelial cells. A
      provocative injection of tumor necrosis factor alpha into LPS-sensitized mice
      augmented Fas and Fas ligand expression and the apoptosis of renal tubular
      epithelial cells. The administration of tumor necrosis factor alpha to
      interleukin-12-sensitized mice resulted in Fas and Fas ligand expression and the
      apoptosis. Sensitization with interleukin-12 together with anti-gamma interferon
      antibody did not cause the apoptosis of renal tubular epithelial cells. It was
      suggested that the Fas/Fas ligand system probably plays a critical role in the
      development of renal tubular epithelial cell injury through apoptotic cell death.

PMID- 10417182
TI  - Molecular and functional characteristics of a protective human monoclonal
      antibody to serotype 8 Streptococcus pneumoniae capsular polysaccharide.
AB  - The structural characteristics and biological activity of human antibodies that
      are reactive with the capsular polysaccharides of most serotypes of Streptococcus
      pneumoniae, including serotype 8, are unknown. This paper describes the
      generation, molecular structure, and protective efficacy of a human monoclonal
      antibody (MAb) reactive with the capsular polysaccharide of serotype 8
      Streptococcus pneumoniae. We generated the immunoglobulin M(kappa) [IgM(kappa)]
      MAb D11 by Epstein-Barr virus transformation of peripheral lymphocytes from a
      Pneumovax recipient. Nucleic acid sequence analysis revealed that MAb D11 uses V3
      15/V(H)3 and A20/V(kappa) gene segments with evidence of somatic mutation. In
      vitro studies revealed MAb D11-dependent complement deposition on the capsule of
      serotype 8 organisms via either the classical or the alternative complement
      pathway. In vivo, MAb D11 prolonged the survival of both normal and C4-deficient
      mice with lethal serotype 8 S. pneumoniae infection. Our findings demonstrate
      that a serotype-specific human IgM with certain structural and functional
      characteristics was protective in mice lacking a functional classical complement
      pathway and show that alternative complement pathway activation is an important
      determinant of pneumococcal protection.

PMID- 10417183
TI  - Intranasal immunization with pneumococcal polysaccharide conjugate vaccines
      protects mice against invasive pneumococcal infections.
AB  - Host defenses against Streptococcus pneumoniae depend largely on
      opsonophagocytosis mediated by antibodies and complement. Since pneumococcus is a
      respiratory pathogen, mucosal immune responses may play a significant role in the
      defense against pneumococcal infections. Thus, mucosal vaccination may be an
      alternative approach to current immunization strategies, but effective adjuvants
      are required. Protein antigens induce significant mucosal immunoglobulin A (IgA)
      and systemic IgG responses when administered intranasally (i. n.) with the
      glyceride-polysorbate based adjuvant RhinoVax (RV) both in experimental animals
      and humans. The immunogenicity and efficacy of pneumococcal polysaccharide
      conjugate vaccines (PNC) of serotypes 1 and 3 was studied in mice after i.n.
      immunization with RV. Antibodies were measured in serum (IgM, IgG, and IgA) and
      saliva (IgA) and compared to antibody titers induced by parenteral immunization.
      The PNCs induced significant systemic IgG and IgA antibodies after i.n.
      immunization only when given with RV and, for serotype 1, serum IgG titers were
      comparable to titers induced by subcutaneous immunization. In addition, i.n.
      immunization with PNC-1 in RV elicited detectable mucosal IgA. These results
      demonstrate that RV is a potent mucosal adjuvant for polysaccharides conjugated
      to proteins. A majority of the PNC-1-immunized mice were protected against both
      bacteremia and pneumonia after i.n. challenge with a lethal dose of serotype 1
      pneumococci, and protection correlated significantly with the serum IgG titers.
      Similarly, the survival of mice immunized i.n. with PNC-3 in RV was significantly
      prolonged. These results indicate that mucosal vaccination with PNC and adjuvants
      may be an alternative strategy for prevention against pneumococcal infections.

PMID- 10417185
TI  - Roles of CD4(+) T cells and gamma interferon in protective immunity against
      Babesia microti infection in mice.
AB  - Babesia microti produces a self-limiting infection in mice, and recovered mice
      are resistant to reinfection. In the present study, the role of T cells in
      protective immunity against challenge infection was examined. BALB/c mice which
      recovered from primary infection showed strong protective immunity against
      challenge infection. In contrast, nude mice which failed to control the primary
      infection and were cured with an antibabesial drug did not show protection
      against challenge infection. Treatment of immune mice with anti-CD4 monoclonal
      antibody (MAb) diminished the protective immunity against challenge infection,
      but treatment with anti-CD8 MAb had no effect on the protection. Transfer of
      CD4(+) T-cell-depleted spleen cells resulted in higher parasitemia than transfer
      of CD8(+) T-cell-depleted spleen cells. A high level of gamma interferon (IFN
      gamma), which was produced by CD4(+) T cells, was observed for the culture
      supernatant of spleen cells from immune mice, and treatment of immune mice with
      anti-IFN-gamma MAb partially reduced the protection. Moreover, no protection
      against challenge infection was found in IFN-gamma-deficient mice. On the other
      hand, treatment of immune mice with MAbs against interleukin-2 (IL-2), IL-4, or
      tumor necrosis factor alpha did not affect protective immunity. These results
      suggest essential requirements for CD4(+) T cells and IFN-gamma in protective
      immunity against challenge infection with B. microti.

PMID- 10417186
TI  - Myeloperoxidase exerts microbicidal activity against Mycobacterium tuberculosis.
AB  - We investigated the antimycobacterial role of myeloperoxidase (MPO), one of the
      most abundant granule proteins in human neutrophils. Our data indicate that
      purified MPO, in the presence of hydrogen peroxide, exerts a consistent killing
      activity against Mycobacterium tuberculosis H37Rv and against a clinical isolate.
      The activity is time and dose dependent and requires the presence of chloride
      ions in the assay medium.

PMID- 10417184
TI  - Comparative analysis of Legionella pneumophila and Legionella micdadei virulence
      traits.
AB  - While the majority of Legionnaire's disease has been attributed to Legionella
      pneumophila, Legionella micdadei can cause a similar infection in
      immunocompromised people. Consistent with its epidemiological profile, the growth
      of L. micdadei in cultured macrophages is less robust than that of L.
      pneumophila. To identify those features of the Legionella spp. which are
      correlated to efficient growth in macrophages, two approaches were taken. First,
      a phenotypic analysis compared four clinical isolates of L. micdadei to one well
      characterized strain of L. pneumophila. Seven traits previously correlated with
      the virulence of L. pneumophila were evaluated: infection and replication in
      cultured macrophages, evasion of phagosome-lysosome fusion, contact-dependent
      cytotoxicity, sodium sensitivity, osmotic resistance, and conjugal DNA transfer.
      By nearly every measure, L. micdadei appeared less virulent than L. pneumophila.
      The surprising exception was L. micdadei 31B, which evaded lysosomes and
      replicated in macrophages as efficiently as L. pneumophila, despite lacking both
      contact-dependent cytopathicity and regulated sodium sensitivity. Second, in an
      attempt to identify virulence factors genetically, an L. pneumophila genomic
      library was screened for clones which conferred robust intracellular growth on L.
      micdadei. No such loci were isolated, consistent with the multiple phenotypic
      differences observed for the two species. Apparently, L. pneumophila and L.
      micdadei use distinct strategies to colonize alveolar macrophages, causing
      Legionnaire's disease.

PMID- 10417187
TI  - Opacity-associated protein A contributes to the binding of Haemophilus influenzae
      to chang epithelial cells.
AB  - Opacity-associated protein A (OapA), which is responsible for the transparent
      colony phenotype of Haemophilus influenzae, has been implicated in the
      colonization of the nasopharynx in an infant rat model of carriage. In this
      report, we show that OapA mediates attachment to Chang epithelial cells examined
      by using genetically defined type b and nontypeable H. influenzae strains with or
      without OapA. We also showed that OapA was conserved among H. influenzae strains
      by comparing deduced amino acid sequences. Both recombinant OapA and polyclonal
      anti-OapA antiserum blocked the binding of H. influenzae to Chang epithelial
      cells, suggesting that the interaction of H. influenzae is specific to OapA.
      Moreover, the binding of recombinant OapA to epithelial cells further provided
      evidence that OapA can promote attachment of H. influenzae. Expression of oapA
      gene in a nonadherent Escherichia coli strain significantly increased the binding
      to Chang epithelial cells, and disruption of the oapA gene with kanamycin
      resistance cassette insertion resulted in a significant loss of binding. These
      findings demonstrate that OapA plays a role in H. influenzae binding to human
      conjunctival epithelial cells.

PMID- 10417188
TI  - Infection of primary human bronchial epithelial cells by Haemophilus influenzae:
      macropinocytosis as a mechanism of airway epithelial cell entry.
AB  - Nontypeable Haemophilus influenzae is an exclusive human pathogen which infects
      the respiratory epithelium. We have initiated studies to explore the interaction
      of the nontypeable H. influenzae strain 2019 with primary human airway epithelial
      cells by electron and confocal microscopy. Primary human airway cell cultures
      were established as monolayers on glass collagen-coated coverslips or on
      semipermeable membranes at an air-fluid interface. Scanning electron microscopy
      indicated that bacteria adhered to nonciliated cells in the population. The
      surface of infected cells showed evidence of cytoskeletal rearrangements
      manifested by microvilli and lamellipodia extending toward and engaging bacteria.
      Confocal microscopic analysis demonstrated that infection induced actin
      polymerization with an increase in cortical actin as well as evidence of actin
      strands around the bacteria. Transmission electron microscopic analysis showed
      lamellipodia and microvilli surrounding organisms, as well as organisms adherent
      to the cell surface. These studies also demonstrated the presence of bacteria
      within vacuoles inside of airway cells. Confocal microscopic studies with Texas
      red-labeled dextran (molecular weight, 70,000) indicated that H. influenzae cells
      were entering cells by the process of macropinocytosis. These studies indicate
      that nontypeable H. influenzae can initiate cytoskeletal rearrangement within
      human airway epithelium, resulting in internalization of the bacteria within
      nonciliated human airway epithelial cells by the process of macropinocytosis.

PMID- 10417189
TI  - Campylobacter jejuni 81-176 associates with microtubules and dynein during
      invasion of human intestinal cells.
AB  - Campylobacter jejuni uptake into cultured INT407 cells was analyzed kinetically
      over a wide range of starting multiplicities of infection (MOI; from 0.02 to
      20,000 bacteria/epithelial cell). The efficiency of internalization was the
      highest at MOI of 0.02 and decreased steadily at higher MOIs, presumably due to
      reported C. jejuni autoagglutination at higher densities. Total internalized
      Campylobacter CFU increased gradually from an MOI of 0.02 to a peak at an MOI of
      200 (reaching an average of two bacteria internalized per epithelial cell) and
      decreased at higher MOIs. The invasion process was apparently saturated within 2
      h at an MOI of 200, indicating stringent host cell limitations on this entry
      process. Furthermore, whereas control Salmonella typhi invaded all monolayer
      cells within 1 h, only two-thirds of monolayer cells were infected after 2 h with
      C. jejuni at MOIs of 200 to 2,000. The percentage of Campylobacter-infected host
      cells gradually increased to 85% after 7 h of infection, suggesting that C.
      jejuni entry may be host cell cycle dependent. Direct evidence of the involvement
      of microtubules in C. jejuni internalization, suggested previously by biochemical
      inhibitor studies, was obtained by time course immunofluorescence microscopic
      analyses. Bacteria initially bound to the tips of host cell membrane extensions
      containing microtubules, then aligned in parallel with microtubules during entry,
      colocalized specifically with microtubules and dynein but not with
      microfilaments, and moved over 4 h, presumably via microtubules to the
      perinuclear region of host cells. Orthovanadate, which inhibits dynein activity,
      specifically reduced C. jejuni 81-176 entry, suggesting that this molecular motor
      is involved in entry and endosome trafficking during this novel bacterial
      internalization process. Collectively, these data suggest that C. jejuni enters
      host cells in a targeted and tightly controlled process leading to uptake into an
      endosomal vacuole which apparently moves intracellularly along microtubules via
      the molecular motor, dynein, to the perinuclear region.

PMID- 10417190
TI  - Infection of mice lacking interleukin-7 (IL-7) reveals an unexpected role for IL
      7 in the development of the parasite Schistosoma mansoni.
AB  - A single intradermal administration of recombinant interleukin-7 (IL-7) has been
      shown to aggravate the course of murine schistosomiasis, to favor the development
      of Th2-associated antibodies specific for the parasite, and to alter migration
      kinetics and/or migratory route of the parasite within its vertebrate host. Here
      we show that after infection of IL-7-deficient mice with Schistosoma mansoni, the
      predominant parasite-specific humoral response follows a Th1 pattern, and the
      development of the parasite is greatly impaired. In IL-7-deficient mice,
      increased numbers of larvae reach the lungs and fewer larvae reach the liver,
      compared to control mice. In the absence of IL-7, female worms show an altered
      fecundity, leading to decreased numbers of eggs trapped in the tissues and to an
      amelioration of the pathology of the infected host. The most striking observation
      is the blockade of parasite growth in an IL-7-defective environment, leading to
      dwarf male and female worms. The results of this study have important
      implications for the role of IL-7 in the host-parasite relationship and show how
      parasites can disable or evade the host immune response.

PMID- 10417191
TI  - Plasma membrane expression of heat shock protein 60 in vivo in response to
      infection.
AB  - Heat shock protein 60 (hsp60) is constitutively expressed in the mitochondria of
      eukaryotic cells. However, it has been identified in other subcellular
      compartments in several disease states and in transformed cells, and it is an
      immunogenic molecule in various infectious and autoimmune diseases. To better
      understand the factors that influence expression of hsp60 in normal cells in
      vivo, we analyzed its cellular and subcellular distribution in mice infected with
      the intracellular bacterium Listeria monocytogenes. Western blotting of
      subcellular fractionated spleen cells showed that although endogenous hsp60 was
      restricted to the mitochondria in noninfected animals, it was associated with the
      plasma membrane as a result of infection. The low levels of plasma membrane
      associated hsp60 seen in the livers in noninfected animals subsequently increased
      during infection. Plasma membrane hsp60 expression did not correlate with
      bacterial growth, being most evident during or after bacterial clearance and
      persisting at 3 weeks postinfection. Using flow cytometry, we determined that Mac
      1(+), T-cell receptor gammadelta(+), and B220(+) cells represented the major
      Hsp60(+) populations in spleens of infected mice. By contrast, B220(+) cells were
      the predominant hsp60(+) population in livers of infected mice. Of the immune
      cells analyzed, the kinetic profile of the gammadelta T-cell response most
      closely matched that of hsp60 expression in both the spleen and liver.
      Collectively, these findings show that during infection hsp60 can be localized to
      the plasma membrane of viable cells, particularly antigen-presenting cells,
      providing a means by which hsp60-reactive lymphocytes seen in various infectious
      disease and autoimmune disorders may be generated and maintained.

PMID- 10417192
TI  - Dynamics of actin-based movement by Rickettsia rickettsii in vero cells.
AB  - Actin-based motility (ABM) is a virulence mechanism exploited by invasive
      bacterial pathogens in the genera Listeria, Shigella, and Rickettsia. Due to
      experimental constraints imposed by the lack of genetic tools and their obligate
      intracellular nature, little is known about rickettsial ABM relative to Listeria
      and Shigella ABM systems. In this study, we directly compared the dynamics and
      behavior of ABM of Rickettsia rickettsii and Listeria monocytogenes. A time-lapse
      video of moving intracellular bacteria was obtained by laser-scanning confocal
      microscopy of infected Vero cells synthesizing beta-actin coupled to green
      fluorescent protein (GFP). Analysis of time-lapse images demonstrated that R.
      rickettsii organisms move through the cell cytoplasm at an average rate of 4.8 +/
      0.6 micrometer/min (mean +/- standard deviation). This speed was 2.5 times
      slower than that of L. monocytogenes, which moved at an average rate of 12.0 +/-
      3.1 micrometers/min. Although rickettsiae moved more slowly, the actin filaments
      comprising the actin comet tail were significantly more stable, with an average
      half-life approximately three times that of L. monocytogenes (100.6 +/- 19.2 s
      versus 33.0 +/- 7.6 s, respectively). The actin tail associated with
      intracytoplasmic rickettsiae remained stationary in the cytoplasm as the organism
      moved forward. In contrast, actin tails of rickettsiae trapped within the nucleus
      displayed dramatic movements. The observed phenotypic differences between the ABM
      of Listeria and Rickettsia may indicate fundamental differences in the mechanisms
      of actin recruitment and polymerization.

PMID- 10417193
TI  - Citrobacter freundii invades and replicates in human brain microvascular
      endothelial cells.
AB  - Neonatal bacterial meningitis remains a disease with unacceptable rates of
      morbidity and mortality despite the availability of effective antimicrobial
      therapy. Citrobacter spp. cause neonatal meningitis but are unique in their
      frequent association with brain abscess formation. The pathogenesis of
      Citrobacter spp. causing meningitis and brain abscess is not well characterized;
      however, as with other meningitis-causing bacteria (e.g., Escherichia coli K1 and
      group B streptococci), penetration of the blood-brain barrier must occur. In an
      effort to understand the pathogenesis of Citrobacter spp. causing meningitis, we
      have used the in vitro blood-brain barrier model of human brain microvascular
      endothelial cells (HBMEC) to study the interaction between C. freundii and HBMEC.
      In this study, we show that C. freundii is capable of invading and trancytosing
      HBMEC in vitro. Invasion of HBMEC by C. freundii was determined to be dependent
      on microfilaments, microtubules, endosome acidification, and de novo protein
      synthesis. Immunofluorescence microscopy studies revealed that microtubules
      aggregated after HBMEC came in contact with C. freundii; furthermore, the
      microtubule aggregation was time dependent and seen with C. freundii but not with
      noninvasive E. coli HB101 and meningitic E. coli K1. Also in contrast to other
      meningitis-causing bacteria, C. freundii is able to replicate within HBMEC. This
      is the first demonstration of a meningitis-causing bacterium capable of
      intracellular replication within BMEC. The important determinants of the
      pathogenesis of C. freundii causing meningitis and brain abscess may relate to
      invasion of and intracellular replication in HBMEC.

PMID- 10417194
TI  - Heat-shocked monocytes are resistant to Staphylococcus aureus-induced apoptotic
      DNA fragmentation due to expression of HSP72.
AB  - Human peripheral blood monocytes became apoptotic following phagocytosis of
      Staphylococcus aureus. The consequences of heat stress for monocytes were studied
      with regard to the effect on S. aureus-induced apoptosis. Exposure of monocytes
      to 41.5 degrees C for 1 h resulted in HSP72 expression and had no influence on
      phagocytosis of bacteria; moreover, phagocytosis of S. aureus immediately or
      shortly after heat shock had no effect on the S. aureus-induced monocyte
      apoptosis, as evidenced by DNA fragmentation assay. In contrast, cells which
      recovered from heat shock for 18 to 24 h, although active as phagocytes, were
      resistant to the S. aureus-induced apoptosis. The observed protective effect was
      related to the induction of HSP72, since blocking of HSP72 synthesis by an
      antisense oligomer abolished the protective effect of heat shock on bacterium
      induced monocyte apoptosis.

PMID- 10417195
TI  - Attenuated host resistance against Mycobacterium bovis BCG infection in mice
      lacking osteopontin.
AB  - Expression of the cytokine osteopontin (OPN) is elevated in granulomas caused by
      Mycobacterium tuberculosis. We tested the hypothesis that OPN contributes to host
      protection in a mouse model of mycobacterial infection. When infected with
      Mycobacterium bovis BCG, mice lacking a functional OPN gene had more severe
      infections characterized by heavier bacterial loads and a delayed clearance of
      the bacteria. The OPN-null mice had greater granuloma burdens consistent with the
      elevated bacterial load. The ability of osteopontin to facilitate the clearance
      of mycobacteria was most pronounced early after infection and appeared to be
      independent of known mediators of resistance to infection by mycobacteria:
      antigen-specific T-cell immunity, gamma interferon production, and nitric oxide
      production. BCG grew more rapidly in macrophages derived from OPN-null mice than
      in those from wild-type mice, demonstrating that the null phenotype was due to an
      intrinsic macrophage defect. These results indicate that osteopontin augments the
      host response against a mycobacterial infection and that it acts independently
      from other antimycobacterial resistance mechanisms.

PMID- 10417196
TI  - Interleukin-1 and tumor necrosis factor activities partially account for
      calvarial bone resorption induced by local injection of lipopolysaccharide.
AB  - The present study was undertaken to test the hypothesis that tumor necrosis
      factor (TNF) and/or interleukin-1 (IL-1) activity mediates lipopolysaccharide
      (LPS)-induced bone resorption in vivo. To test this hypothesis, Escherichia coli
      LPS or Porphyromonas gingivalis LPS was injected into the subcutaneous tissues
      overlying mouse calvariae. Histological sections, prepared from the center of the
      lesion, were stained for tartrate-resistant acid phosphatase, and
      histomorphometric analysis was performed to quantify the osteoclast number and
      the area of bone resorption. In time course experiments using normal mice, a peak
      of bone resorption occurred 5 days after endotoxin stimulation. In dose-response
      experiments, IL-1 receptor type 1 deletion (IL-1R(-/-)), TNF double-receptor
      p55/p75 deletion (TNF p55(-/-)/p75(-/-)), combined TNF p55 and IL-1 receptor type
      1 deletion (TNF p55(-/-)/IL-1R(-/-)), and IL-1beta-converting enzyme-deficient
      (ICE(-/-)) mice and the respective wild-type mice were injected with 500, 100, or
      20 micrograms of P. gingivalis LPS and sacrificed 5 days after LPS injection. At
      the highest dose (500 micrograms), significant decreases in osteoclast number
      occurred in mutant mice compared to wild-type mice: (i) a 64% reduction for the
      TNF p55(-/-)/IL-1R(-/-) mice, (ii) a 57% reduction for the IL-1R(-/-) mice, (iii)
      a 41% reduction for the TNF p55(-/-)/p75(-/-) mice, and (iv) a 38% reduction for
      the ICE(-/-) mice. At the two lower doses, bone resorption was apparent but no
      significant differences between mutant and wild-type animals were observed. The
      present data indicate that at higher doses, LPS-induced bone resorption is
      substantially mediated by IL-1 and TNF receptor signaling. Furthermore, IL-1
      receptor signaling appears to be slightly more important than TNF receptor
      signaling. At lower LPS doses, other pathways leading to osteoclast activity that
      are independent of TNF and IL-1 are involved.

PMID- 10417197
TI  - Helicobacter pylori induces gastric epithelial cell apoptosis in association with
      increased Fas receptor expression.
AB  - The mechanisms involved in mediating the enhanced gastric epithelial cell
      apoptosis observed during infection with Helicobacter pylori in vivo are unknown.
      To determine whether H. pylori directly induces apoptosis of gastric epithelial
      cells in vitro and to define the role of the Fas-Fas ligand signal transduction
      cascade, human gastric epithelial cells were infected with H. pylori for up to 72
      h under microaerophilic conditions. As assessed by both transmission electron
      microscopy and fluorescence microscopy, incubation with a cagA-positive, cagE
      positive, VacA-positive clinical H. pylori isolate stimulated an increase in
      apoptosis compared to the apoptosis of untreated AGS cells (16.0% +/- 2.8% versus
      5.9% +/- 1. 4%, P < 0.05) after 72 h. In contrast, apoptosis was not detected
      following infection with cagA-negative, cagE-negative, VacA-negative clinical
      isolates or a Campylobacter jejuni strain. In addition to stimulating apoptosis,
      infection with H. pylori enhanced Fas receptor expression in AGS cells to a
      degree comparable to that of treatment with a positive control, gamma interferon
      (12.5 ng/ml) (148% +/- 24% and 167% +/- 24% of control, respectively). The
      enhanced Fas receptor expression was associated with increased sensitivity to Fas
      mediated cell death. Ligation of the Fas receptor with an agonistic monoclonal
      antibody resulted in an increase in apoptosis compared to the apoptosis of cells
      infected with the bacterium alone (38.5% +/- 7.1% versus 16.0% +/- 2.8%, P <
      0.05). Incubation with neutralizing anti-Fas antibody did not prevent apoptosis
      of H. pylori-infected cells. Taken together, these findings demonstrate that the
      gastric pathogen H. pylori stimulates apoptosis of gastric epithelial cells in
      vitro in association with the enhanced expression of the Fas receptor. These data
      indicate a role for Fas-mediated signaling in the programmed cell death that
      occurs in response to H. pylori infection.

PMID- 10417198
TI  - Protection against Mycobacterium avium by DNA vaccines expressing mycobacterial
      antigens as fusion proteins with green fluorescent protein.
AB  - Mycobacterium avium causes disseminated disease in humans with AIDS,
      paratuberculosis in ruminants, lymphadenopathy in swine, and tuberculosis in
      birds. We constructed DNA vaccines expressing mycobacterial antigens as fusion
      proteins with enhanced green fluorescent protein (EGFP). Plasmids p65K-EGFP, p85A
      EGFP, and p85B-EGFP expressed the M. avium 65-kDa antigen, the Mycobacterium
      bovis BCG 85A antigen, and the M. avium 85B antigen, respectively, as EGFP fusion
      proteins. We visualized protein expression directly in cultured murine
      fibroblasts and intact muscle. p65K-EGFP expressed fusion protein in a diffuse
      cytoplasmic pattern, and p85A-EGFP and p85B-EGFP produced a speckled pattern. We
      vaccinated C57BL/6 mice with three doses of plasmid DNA and then challenged them
      intraperitoneally with M. avium. Negative controls received saline, and positive
      controls received one dose of BCG vaccine. Mice in all groups developed
      disseminated infection with a high burden of organisms. Compared to negative
      controls, mice vaccinated with p85A-EGFP had an eightfold reduction in spleen M.
      avium CFU at 4 weeks after infection and a fourfold reduction at 8 weeks,
      reductions similar to those generated by BCG vaccine. Mice vaccinated with p65K
      EGFP had a fourfold CFU reduction at 4 weeks and no effect at 8 weeks. This is
      the first report of DNA vaccines expressing foreign antigens as fusion proteins
      with EGFP and the first report of successful DNA vaccination against M. avium.

PMID- 10417199
TI  - Detection of Als proteins on the cell wall of Candida albicans in murine tissues.
AB  - A murine model of disseminated candidiasis was utilized to determine whether
      Candida albicans Als proteins are produced in vivo. The kidneys, spleen, heart,
      liver, and lungs were collected from mice inoculated with one of three C.
      albicans strains (SC5314, B311, or WO-1). Immunohistochemical analysis of murine
      tissues by using a rabbit polyclonal anti-Als serum indicated that Als proteins
      were produced by each C. albicans cell in the tissues examined. Patterns of
      staining with the anti-Als serum were similar among the C. albicans strains
      tested. These data indicated that Als protein production was widespread in
      disseminated candidiasis and that, despite strain differences in ALS gene
      expression previously noted in vitro, Als protein production in vivo was similar
      among C. albicans strains. The extensive production of Als proteins in vivo and
      their presence on the C. albicans cell wall position these proteins well for a
      role in host-pathogen interaction.

PMID- 10417200
TI  - Differences in the concentrations of small, anionic, antimicrobial peptides in
      bronchoalveolar lavage fluid and in respiratory epithelia of patients with and
      without cystic fibrosis.
AB  - Affinity-purified rabbit polyclonal (PAB96-1) and mouse monoclonal (1G9-1C2)
      antibodies to synthetic H-DDDDDDD-OH, an antimicrobial anionic peptide (AP)
      originally isolated from ovine pulmonary surfactant, were prepared and used to
      assess the concentrations of AP-like molecules in human respiratory tract
      samples. In bronchoalveolar lavage fluids, concentrations of AP-like molecules
      measured by enzyme-linked immunosorbent assay were significantly lower in 13
      patients with cystic fibrosis (CF) (mean +/- standard deviation [SD], 0.78 +/-
      0.46 mM) than in 34 patients without CF (1. 30 +/- 0.66 mM) (P = 0.01). In
      pulmonary tissues of three patients without CF, very little antigen was stained
      in the apical cytoplasm of the bronchial and bronchiolar epithelium yet robust
      staining was seen in the alveolar epithelium. In pulmonary tissues of three
      patients with CF, robust staining of antigen was seen in the apical cytoplasm of
      the bronchial and bronchiolar epithelium yet no staining was seen in the alveolar
      epithelium. These results show that AP-like molecules are present in healthy
      human respiratory tract samples and differ in concentration and location of
      expression in patients with and without CF.

PMID- 10417201
TI  - The cloned locus of enterocyte effacement from enterohemorrhagic Escherichia coli
      O157:H7 is unable to confer the attaching and effacing phenotype upon E. coli K
      12.
AB  - The locus of enterocyte effacement (LEE) pathogenicity island of
      enterohemorrhagic Escherichia coli (EHEC) O157:H7 possesses the same genes in
      identical order and orientation as the LEE of enteropathogenic E. coli (EPEC)
      O127:H6 but is unable to form attaching and effacing (A/E) lesions or to secrete
      Esp proteins when it is cloned in an E. coli K-12 background. The A/E phenotype
      could not be restored by trans complementation with a variety of cloned EPEC LEE
      fragments, suggesting functional and/or regulatory differences between the LEE
      pathogenicity islands of EPEC O127:H6 and EHEC O157:H7.

PMID- 10417202
TI  - Fluorescent labels influence phagocytosis of Bordetella pertussis by human
      neutrophils.
AB  - To explore the role of neutrophil phagocytosis in host defense against Bordetella
      pertussis, bacteria were labeled extrinsically with fluorescein isothiocyanate
      (FITC) or genetically with green fluorescent protein (GFP) and incubated with
      adherent human neutrophils in the presence or absence of heat-inactivated human
      immune serum. In the absence of antibodies, FITC-labeled bacteria were located
      primarily on the surface of the neutrophils with few bacteria ingested. However,
      after opsonization, about seven times more bacteria were located intracellularly,
      indicating that antibodies promoted phagocytosis. In contrast, bacteria labeled
      intrinsically with GFP were not efficiently phagocytosed even in the presence of
      opsonizing antibodies, suggesting that FITC interfered with a bacterial defense.
      Because FITC covalently modifies proteins and could affect their function, we
      tested the effect of FITC on adenylate cyclase toxin activity, an important
      extracellular virulence factor. FITC-labeled bacteria had fivefold-less adenylate
      cyclase toxin activity than did unlabeled wild-type bacteria or GFP-expressing
      bacteria, suggesting that FITC compromised adenylate cyclase toxin activity.
      These data demonstrated that at least one extracellular virulence factor was
      affected by FITC labeling and that GFP is a more appropriate label for B.
      pertussis.

PMID- 10417204
TI  - Staphylococcus schleiferi subsp. schleiferi expresses a fibronectin-binding
      protein.
AB  - Staphylococcus schleiferi subsp. schleiferi is associated with a range of
      nosocomial infections, but the pathogenic mechanisms by which these occur are
      poorly understood. This study provides phenotypic and genotypic evidence for the
      expression of a cell wall-anchored fibronectin-binding protein by this species.

PMID- 10417203
TI  - Identification of genes encoding two-component lantibiotic production in
      Staphylococcus aureus C55 and other phage group II S. aureus strains and
      demonstration of an association with the exfoliative toxin B gene.
AB  - The production of exfoliative toxin B (ET-B), but not ET-A, was shown to be
      specifically associated with production of a highly conserved two-component
      lantibiotic peptide system in phage group II Staphylococcus aureus. Two
      previously studied but incompletely characterized S. aureus bacteriocins,
      staphylococcins C55 and BacR1, were found to be members of this lantibiotic
      system, and considerable homology was also found with the two-component
      Lactococcus lactis bacteriocin, lacticin 3147. sacalphaA and sacbetaA, the
      structural genes of the lantibiotics staphylococcins C55alpha and C55beta and two
      putative lantibiotic processing genes, sacM1 and sacT, were localized together
      with the ET-B structural gene to a single 32-kb plasmid in strain C55.
      Irreversible loss of both ET-B and two-component lantibiotic production occurs
      during laboratory passage of ET-B-positive S. aureus strains, particularly at
      elevated temperatures.

PMID- 10417205
TI  - Intranasal immunization of mice with influenza vaccine in combination with the
      adjuvant LT-R72 induces potent mucosal and serum immunity which is stronger than
      that with traditional intramuscular immunization.
AB  - Immunization of mice by the intranasal route with influenza virus hemagglutinin
      in combination with the mutant Escherichia coli heat-labile enterotoxin R72 (LT
      R72) induced significantly enhanced serum and mucosal antibodies, surpassing, in
      most cases, responses achieved by traditional intramuscular immunization using
      inactivated split influenza vaccine. Furthermore, intranasal immunization with LT
      R72 induced a potent serum immunoglobulin G2a response, indicating that this
      adjuvant has Th1 character.

PMID- 10417206
TI  - Avirulence of Candida albicans CaHK1 mutants in a murine model of hematogenously
      disseminated candidiasis.
AB  - Deletion of both alleles of the Candida albicans CaHK1 gene, which causes cells
      to flocculate when grown at pH 7.5, a pH comparable to that of mammalian blood,
      abolishes the ability of the yeast to establish a successful infection in a
      murine model of hematogenously disseminated candidiasis. Within 72 h all mice
      inoculated with the parental C. albicans strain had died. The mice infected with
      either the heterozygote or revertant strain, either of which harbors only one
      functional CaHK1 allele, also succumbed to the infection, although survivors were
      observed for up to 16 days postinfection. However, mice inoculated with the
      Deltacahk1 null strain survived for the course of the infection. These results
      indicate that CaHK1 is required for the virulence of C. albicans in a murine
      model of hematogenously disseminated candidiasis. In contrast, CaHK1 is not
      required for the virulence of C. albicans in a rat model of vaginal candidiasis.

PMID- 10417207
TI  - Infectivity of Plasmodium berghei sporozoites delivered by intravenous
      inoculation versus mosquito bite: implications for sporozoite vaccine trials.
AB  - Plasmodium berghei sporozoites delivered by mosquito bite were more infectious to
      outbred CD-1 mice than were sporozoites delivered by intravenous inoculation. The
      route of challenge also affected vaccine efficacy. In view of these findings and
      the fact that mosquito bites are the natural mode of sporozoite delivery,
      infectious mosquito bites should be considered the challenge protocol of choice
      for sporozoite vaccine efficacy trials.

PMID- 10417209
TI  - Elevated chemokine concentrations in sera of human immunodeficiency virus (HIV)
      seropositive and HIV-seronegative patients with tuberculosis: a possible role for
      mycobacterial lipoarabinomannan.
AB  - Levels of interleukin 8 (IL-8), gamma interferon-inducible protein 10 (IP-10),
      monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein
      1beta (MIP-1beta) were elevated in patients with tuberculosis. IP-10 and MCP-1
      levels were higher in human immunodeficiency virus (HIV)-seropositive patients
      than in HIV-seronegative patients with tuberculosis. Lipoarabinomannan induced IL
      8, MCP-1, and MIP-1beta in vitro, which was partly inhibited by anti-tumor
      necrosis factor antibody.

PMID- 10417208
TI  - Expression and immunogenicity of a mutant diphtheria toxin molecule, CRM(197),
      and its fragments in Salmonella typhi vaccine strain CVD 908-htrA.
AB  - Mutant diphtheria toxin molecule CRM(197) and fragments thereof were expressed in
      attenuated Salmonella typhi CVD 908-htrA, and the constructs were tested for
      their ability to induce serum antitoxin. Initially, expressed proteins were
      insoluble, and the constructs failed to induce neutralizing antitoxin. Soluble
      CRM(197) was expressed at low levels by utilizing the hemolysin A secretion
      system from Escherichia coli.

PMID- 10417210
TI  - Iron modulates phenotypic variation and phosphorylation of P270 in double
      stranded RNA virus-infected Trichomonas vaginalis.
AB  - Trichomonas vaginalis infected with a double-stranded RNA virus undergoes
      phenotypic variation on the basis of surface versus cytoplasmic expression of the
      immunogenic protein P270. Examination of batch cultures by flow cytofluorometry
      with monoclonal antibody (MAb) to P270 yields both fluorescent and nonfluorescent
      trichomonads. Greater numbers and intensity of fluorescent organisms with surface
      P270 reactive with MAb were evident in parasites grown in medium depleted of
      iron. Placement of iron-limited organisms in medium supplemented with iron gave
      increased numbers of nonfluorescent trichomonads. Purified subpopulations of
      trichomonads with and without surface P270 obtained by fluorescence-activated
      cell sorting reverted to nonfluorescent and fluorescent phenotypes when placed in
      high- and low-iron media, respectively. No similar regulation by iron of P270 was
      evident among virus-negative T. vaginalis isolates or virus-negative progeny
      trichomonads derived from virus-infected isolates. Equal amounts of P270 were
      detectable by MAb on immunoblots of total proteins from identical numbers of
      parasites grown in low- and high-iron media. Finally, P270 was found to be highly
      phosphorylated in high-iron parasites. Iron, therefore, plays a role in
      modulating surface localization of P270 in virus-harboring parasites.

PMID- 10417211
TI  - Effects of spatial variation of cells and nutrient and product concentrations
      coupled with product inhibition on cell growth in a polymer scaffold.
AB  - The effects of spatial variation of cells and nutrient and product concentration,
      in combination with product inhibition in cell growth kinetics on chondrocyte
      generation in a polymer scaffold, are analyzed. Experimental studies reported
      previously have demonstrated spatial dependence in the cultivation of
      chondrocytes. In the present study, the cell-polymer system is assumed to consist
      of two distinct phases. The cells, fluid, polymer matrix, and extracellular
      matrix comprise one phase, and the other phase consists of a fluid and polymer
      matrix. The only two species in the fluid considered to affect cell growth are
      the nutrient and product. The multiphase transport process of these two species
      in the cell-polymer system is described by the species continuity equations and
      corresponding boundary conditions for each individual phase. A volume-averaging
      approach is utilized for this system to derive averaged species continuity
      equations for the nutrient and product concentrations. The volume-averaging
      approach allows for a single species in a two-phase system to be represented by a
      single averaged continuity equation. Competitive product inhibition, saturation
      kinetics of substrate, and cell population control are assumed to affect the cell
      growth kinetics. A modified Contois growth kinetic model is used to represent the
      three factors that affect cell growth. A parameter analysis is performed and the
      results are compared qualitatively with experimental data found in the
      literature.

PMID- 10417212
TI  - Tolerance of Escherichia coli beta-galactosidase C-terminus to different-sized
      fusions.
AB  - The tolerance of the beta-galactosidase C-terminus to foreign protein fusions has
      been explored by using different-sized derivatives of the chimeric protein
      LACVP1. While the molecular mass of the partner domain shows a minor influence on
      protein toxicity for the producing E. coli cells, it dramatically affects the
      proteolytic susceptibility of the whole fusion. Surprisingly, the observed
      structural modulation of proteolysis is not an all-or-nothing process, but it
      exhibits a continuous effect concomitantly with the length of the fusion. The
      conformational effects caused by increasingly sized partners seem to
      progressively expose cryptic protease target sites, initiating a proteolytic
      cascade that dramatically reduces the yield of the recombinant protein.

PMID- 10417213
TI  - Use of molecularly imprinted polymers in a biotransformation process.
AB  - Molecularly imprinted polymers are highly stable and can be sterilised, making
      them ideal for use in biotransformation process. In this communication, we
      describe a novel application of molecularly imprinted polymers in an enzymatic
      reaction. The enzymatic condensation of Z-L-aspartic acid with L-phenylalanine
      methyl ester to give Z-L-Asp-L-Phe-OMe (Z-aspartame) was chosen as a model system
      to evaluate the applicability of using molecularly imprinted polymers to
      facilitate product formation. When the product-imprinted polymer is present, a
      considerable increase (40%) in product yield is obtained. Besides their use to
      enhance product yields, as demonstrated here, we suggest that imprinted polymers
      may also find use in the continuous removal of toxic compounds during biochemical
      reactions.

PMID- 10417214
TI  - Cellular growth in biofilms.
AB  - In this paper we develop a macroscopic evolutionary equation for the growth of
      the cellular phase starting from a microscopic description of mass transport and
      a simple structured model for product formation. The methods of continuum
      mechanics and volume averaging are used to develop the macroscopic representation
      by carefully considering the fluxes of chemical species that pertain to cell
      growth. The concept of structured models is extended to include the transport of
      reacting chemical species at the microscopic scale. The resulting macroscopic
      growth model is similar in form to previously published models for the transport
      of a single substrate and electron donor and for the production of cellular mass
      and exopolymer. The method of volume averaging indicates under what conditions
      the developed growth model is valid and provides an explicit connection between
      the relevant microscopic model parameters and their corresponding macroscopic
      counterparts.

PMID- 10417215
TI  - Modeling continuous bioleach reactors 
AB  - The results of recent research have shown that the bioleaching of sulfide
      minerals occurs via a two-step mechanism. In this mechanism, the sulfide mineral
      is chemically oxidized by the ferric-iron in the bioleaching liquor. The ferrous
      iron produced is subsequently oxidized to ferric-iron by the microorganism.
      Further research has shown that the rates of both the ferric leaching and ferrous
      iron oxidation are governed by the ferric/ferrous-iron ratio (i.e., the redox
      potential). During the steady-state operation of a bioleach reactor, the rate of
      iron turnover between the chemical ferric leaching of the mineral and the
      bacterial oxidation of the ferrous-iron will define the rate and the redox
      potential at which the system will operate. The balance between the two rates
      will in turn depend on the species used, the microbial concentration, the
      residence time employed, the nature of the sulfide mineral being leached, and its
      active surface area. The model described proposes that the residence time and
      microbial species present determine the microbial growth rate, which in turn
      determines the redox potential in the bioleach liquor. The redox potential of the
      solution, in turn, determines the degree of leaching of the mineral; that is,
      conversion in the bioleach reactor. Copyright 1999 John Wiley & Sons, Inc.

PMID- 10417216
TI  - Highly selective synthesis of 1,3-oleoyl-2-palmitoylglycerol by lipase catalysis.
AB  - 1,3-Oleoyl-2-palmitoylglycerol (OPO), an important structured triglyceride in
      infant nutrition, was synthesized by a two-step process in high yields and purity
      using sn1,3-regiospecific lipases. In the first step, tripalmitin (TP) was
      subjected to an alcoholysis reaction in an organic solvent catalyzed by sn1,3
      regiospecific lipases yielding the corresponding 2-monopalmitin (2-MP). The 2-MP
      was isolated in up to 85% yield and >95% purity by crystallization and esterified
      in the second step with oleic acid using the same lipases to form the structured
      triglyceride OPO in up to 78% yield containing 96% palmitic acid in the sn2
      position. Water activity, solvent, as well as carrier for lipase immobilization
      strongly influenced the yield and purity of products in both steps. The best
      results were achieved with lipases from Rhizomucor miehei and Rhizopus delemar
      immobilized on EP 100 and equilibrated to a water activity of 0.43. Special
      emphasis was given to develop this process in solvents that are allowed to be
      used in foodstuffs and to perform the second step in a solvent-free system.

PMID- 10417217
TI  - Fractionation of sugar beet pulp into pectin, cellulose, and arabinose by
      arabinases combined with ultrafiltration.
AB  - Incubation of beet pulp with two arabinases (alpha-L-arabinofuranosidase and endo
      arabinase), used singularly or in combination at different units of activity per
      gram of beet pulp, caused the hydrolysis of arabinan, which produced a
      hydrolyzate consisting mainly of arabinose. Pectin and a residue enriched with
      cellulose were subsequently separated from the incubation mixture. The best
      enzymatic hydrolysis results were obtained when 100 U/g of beet pulp of each
      enzyme worked synergistically with yields of 100% arabinose and 91.7% pectin.
      These yields were higher than those obtained with traditional chemical
      hydrolysis. The pectin fraction showed a low content of neutral sugar content and
      the cellulose residue contained only a small amount of pentoses. Semicontinuous
      hydrolysis with enzyme recycling in an ultrafiltration unit was also carried out
      to separate arabinose, pectin, and cellulose from beet pulp in 7 cycles of
      hydrolysis followed by ultrafiltration. The yields of separation were similar to
      those obtained in batch experiments, with an enzyme consumption reduced by 3.5
      times and some significant advantages over batch processes.

PMID- 10417218
TI  - Continuous ethanol fermentation of lactose by a recombinant flocculating
      Saccharomyces cerevisiae strain.
AB  - Alcohol fermentation of lactose was investigated using a recombinant flocculating
      Saccharomyces cerevisiae, expressing the LAC4 (coding for beta-galactosidase) and
      LAC12 (coding for lactose permease) genes of Kluyveromyces marxianus. Data on
      yeast fermentation and growth on a medium containing lactose as the sole carbon
      source are presented. In the range of studied lactose concentrations, total
      lactose consumption was observed with a conversion yield of ethanol close to the
      expected theoretical value. For the continuously operating bioreactor, an ethanol
      productivity of 11 g L(-1) h(-1) (corresponding to a feed lactose concentration
      of 50 g L(-1) and a dilution rate of 0.55 h(-1)) was obtained, which is 7 times
      larger than the continuous conventional systems. The system stability was
      confirmed by keeping it in operation for 6 months.

PMID- 10417219
TI  - An inverse correlation between stress resistance and stuck fermentations in wine
      yeasts. A molecular study.
AB  - During alcoholic fermentations yeast cells are subjected to several stress
      conditions and, therefore, yeasts have developed molecular mechanisms in order to
      resist this adverse situation. The mechanisms involved in stress response have
      been studied in Saccharomyces cerevisiae laboratory strains. However a better
      understanding of these mechanisms in wine yeasts could open the possibility to
      improve the fermentation process. In this work an analysis of the stress response
      in three wine yeasts has been carried out by studying the expression of several
      representative genes under several stress conditions which occur during
      fermentation. We propose a simplified method to study how these stress conditions
      affect the viability of yeast cells. Using this approach an inverse correlation
      between stress-resistance and stuck fermentations has been found. We also have
      preliminary data about the use of the HSP12 gene as a molecular marker for stress
      resistance in wine yeasts.

PMID- 10417220
TI  - H(2) photoproduction by batch culture of Anabaena variabilis ATCC 29413 and its
      mutant PK84 in a photobioreactor.
AB  - Hydrogen production by Anabaena variabilis ATCC 29413 and of its mutant PK84,
      grown in batch cultures, was studied in a photobioreactor. The highest volumetric
      H(2) production rates of native and mutant strains were found in cultures grown
      at gradually increased irradiation. The native strain evolved H(2) only under an
      argon atmosphere with the actual rate as high as the potential rate (measured in
      small vials under optimal conditions). In this case 61% of oxygenic
      photosynthesis was used for H(2) production. In contrast the mutant PK84 produced
      H(2) during growth under CO(2)-enriched air. Under these conditions at the
      maximum rate of H(2) production (10 mL h(-1) L(-1)), 13% of oxygenic
      photosynthesis was used for H(2) production and the actual H(2) production was
      only 33% of the potential. Under an atmosphere of 98% argon + 2% CO(2) actual
      H(2) production by mutant PK84 was 85% of the potential rate and 66% of oxygenic
      photosynthesis was used for H(2) production. Hydrogen production under argon +
      CO(2) by the mutant was strictly light-dependent with saturation at about 300
      microE m(-2) s(-1). However, the rate of photosynthesis was not saturated at this
      irradiation. At limiting light intensities (below 250 microE m(-2) s(-1)) 33-58%
      of photosynthesis was used for H(2) production. Hydrogen evolution by PK84 under
      air + 2% CO(2) was also stimulated by light; but was not saturated at 332 microE
      m(-2) s(-1) and did not cease completely in darkness. The rate of oxygen
      photoevolution was also not saturated. A mechanism for increasing cyanobacterial
      hydrogen production is proposed.

PMID- 10417221
TI  - Extension of logarithmic growth of Thiobacillus ferrooxidans by potential
      controlled electrochemical reduction of Fe(III).
AB  - In this study, we demonstrated that the period of logarithmic growth for
      Thiobacillus ferrooxidans could be extended when optimal conditions for cell
      growth were maintained using potential controlled electrochemical cultivation
      with sufficient aeration. The optimal pH and Fe(II) concentration for the
      electrolytic cultivation were determined to be 2.0 and 150 mM, respectively. When
      the potential was set to 0.0V vs Ag/AgCl, the Pt electrode reduced Fe(III) to
      Fe(II) with an efficiency of 95%. A porous glass microbubble generator was used
      to maintain adequate levels of dissolved oxygen, which was the electron acceptor
      for T. ferrooxidans when the cell density in the medium was high. Under these
      conditions, cells at an initial density of 10(7) cells/mL grew logarithmically
      for 4days until the cell density was 4 x 10(9) cells/mL. This corresponded to a
      period of logarithmic growth that was 3 times longer than was observed in batch
      cultures without electrolysis. In addition, the final cell density reached 10(10)
      cells/mL after 6 days of electrochemical cultivation, which was a 50-fold
      increase over conventional batch culture. Under conditions of increasing cell
      density, potentiostatic electrolysis made it possible to remove Fe(III), which
      causes product inhibition, at an increasing rate and to correspondingly increase
      the production rate of Fe(II), which is the electron donor for T. ferrooxidans.
      Thus, our cultivation system provides a sufficient supply of electron donor and
      acceptor for T. ferrooxidans, thereby elongating the period of logarithmic growth
      and producing very high cell densities.

PMID- 10417222
TI  - Response of Rhizopus oligosporus to temporal temperature profiles in a model
      solid-state fermentation system.
AB  - Membrane overcultures of Rhizopus oligosporus were shifted from 37 to 50 degrees
      C for 10 h and then returned to 37 degrees C, mimicking the temporal temperature
      profiles which typically occur in SSF due to heat transfer limitations. Analysis
      with a modified two-phase growth model suggests that the temperature upshift
      causes a 48% decrease in the number of actively extending hyphal tips, and that
      the first order death rate constant of tips increases from 0. 059 to 0.073 h(-1).
      The fungus did not immediately recover when the temperature was returned to 37
      degrees C. The model assumed that the specific growth rate constant microgram(g)
      was not affected by the increase of temperature, although contradictory data was
      obtained from radial growth rate experiments.

PMID- 10417223
TI  - Investigation of liquid-solid hydrodynamic boundary layers and oxygen
      requirements in hairy root cultures.
AB  - Rates of oxygen uptake, growth and alkaloid production by hairy roots in
      submerged culture were investigated using a recirculation reactor allowing
      operation at high liquid velocities for removal of hydrodynamic boundary layers.
      Measurements were performed at dissolved oxygen tensions of 31-450% air
      saturation. Critical oxygen concentrations for Atropa belladonna hairy roots were
      above air saturation, viz. 100-125% air saturation for oxygen uptake and 150% air
      saturation for growth, demonstrating that these roots cultivated in reactors with
      air sparging are oxygen-limited. The critical oxygen tension for oxygen uptake by
      Solanum aviculare hairy roots was 75% air saturation. Both the specific oxygen
      uptake rate and specific growth rate of A. belladonna hairy roots were dependent
      on the mass (g dry weight) of roots present; even in the absence of boundary
      layers, growth did not remain exponential over the entire culture period. Cryo
      scanning electron microscopy showed that hairy roots grown submerged in liquid
      medium were covered with thick layers of hydrated mucilage and root hairs,
      representing a significant additional barrier to oxygen transfer. Roots
      protruding out of the liquid medium showed no evidence of mucilage accumulation.
      The specific oxygen demand of A. belladonna root tips was 3.3-11.5 times higher
      than for the remainder of the roots, the ratio increasing as the dissolved oxygen
      tension was reduced. Specific growth rates, biomass yields from sugar, and
      atropine levels were maximum at around 150% air saturation, but decreased
      significantly with oxygen concentrations above ca. 200%.

PMID- 10417224
TI  - Cytogenetic analysis of chimeric antibody-producing CHO cells in the course of
      dihydrofolate reductase-mediated gene amplification and their stability in the
      absence of selective pressure.
AB  - Previously, the highest producing (HP) recombinant CHO subclones isolated at
      various methotrexate (MTX) levels showed different antibody production stability
      during long-term culture, although they were clonally derived from CS13
      transformant. In this study, genetic basis for their difference in antibody
      production stability was investigated using southern blot hybridization and
      fluorescence in situ hybridization (FISH) techniques. Southern analysis of HP
      subclones revealed that light-chain (LC) and heavy-chain (HC) cDNAs were located
      closely within 23 kb on an amplification unit, and the configuration of LC and HC
      cDNAs within this amplification unit was not disrupted during long-term culture
      in the absence of MTX. However, when LC and HC genes were localized on the
      metaphase chromosomes of HP subclones using FISH, the amplified sequences were
      present as an extended array on diverse marker chromosomes. HP subclones selected
      at higher MTX level had more kinds of marker chromosomes. CS13*-002 isolated at
      0.02 microM MTX had only one marker chromosome (m002), whereas CS13*-1.0 isolated
      at 1 microM MTX had five different ones (m10A, m10B, m10C, m10D, and m10E). Each
      marker chromosome showed different fate during long-term culture of HP subclones
      in the absence of MTX, resulting in different degrees of stability among the HP
      subclones. The m10A and m10B remained unchanged, whereas the others disappeared
      or evolved to variants with shortened amplified arrays. The cells containing
      stable marker chromosomes constituted dominant subpopulations in CS13*-1.0, and
      thereby CS13*-1.0 became most stable in regard to antibody production during long
      term culture. Furthermore, our dual-color FISH showed that the telomeric ends of
      amplified arrays on the stable marker chromosomes were always surrounded by
      (TTAGGG)(n) sequences, indicating that (TTAGGG)(n) sequences are closely related
      to the stability and evolution of amplified sequences. Taken together, our data
      show that the assessment of genotypic stability of amplified CHO cells is a
      prerequisite for understanding their production stability during long-term
      culture in the absence of selection pressure.

PMID- 10417225
TI  - Estimation of P-to-O ratio in Bacillus subtilis and its influence on maximum
      riboflavin yield.
AB  - Simultaneous growth and riboflavin overproduction were investigated using a
      previously developed stoichiometric model of Bacillus subtilis metabolism. A fit
      of model predictions to experimental data was used to obtain estimates of
      fundamental energetic parameters of B. subtilis. Although multiple solutions
      describe the experimental data, evidence for a P-to-O ratio of about 1(1/3) mole
      of ATP produced per atom of oxygen consumed in oxidative phosphorylation was
      provided by genomic analysis of electron transport components, because no
      homologue of the proton-translocating NADH dehydrogenase I was found in the B.
      subtilis genome database. These results allow us to devise a rational metabolic
      engineering strategy to improve riboflavin production. The potential influence of
      increased energy coupling in oxidative phosphorylation on riboflavin yield is
      discussed. Higher coupling is most significant under carbon-limiting conditions
      in slow-growing cells, that is, in fed-batch processes of industrial interest.

PMID- 10417226
TI  - Use of the abiotic proton balance for describing the pH-auxostat.
AB  - A new description of the pH-auxostat is obtained by using the abiotic proton
      balance in the mathematical model. The new model shows how the stoichiometry of
      metabolism affects the steady-state and stability characteristics of the pH
      auxostat. The model can also be used to determine the amount of ammonium salts to
      include in the medium, and can be applied to the pH-stat modal fed-batch reactor
      and the bistat.

PMID- 10417229
TI  - Oligomeric integrity--the structural key to thermal stability in bacterial
      alcohol dehydrogenases.
AB  - Principles of protein thermostability have been studied by comparing structures
      of thermostable proteins with mesophilic counterparts that have a high degree of
      sequence identity. Two tetrameric NADP(H)-dependent alcohol dehydrogenases, one
      from Clostridium beijerinckii (CBADH) and the other from Thermoanaerobacter
      brockii (TBADH), having exceptionally high (75%) sequence identity, differ by 30
      degrees in their melting temperatures. The crystal structures of CBADH and TBADH
      in their holo-enzyme form have been determined at a resolution of 2.05 and 2.5 A,
      respectively. Comparison of these two very similar structures (RMS difference in
      Calpha = 0.8 A) revealed several features that can account for the higher thermal
      stability of TBADH. These include additional ion pairs, "charged-neutral"
      hydrogen bonds, and prolines as well as improved stability of alpha-helices and
      tighter molecular packing. However, a deeper structural insight, based on the
      location of stabilizing elements, suggests that enhanced thermal stability of
      TBADH is due mainly to the strategic placement of structural determinants at
      positions that strengthen the interface between its subunits. This is also
      supported by mutational analysis of structural elements at critical locations.
      Thus, it is the reinforcement of the quaternary structure that is most likely to
      be a primary factor in preserving enzymatic activity of this oligomeric bacterial
      ADH at elevated temperatures.

PMID- 10417230
TI  - Rainbow trout (Oncorhynchus mykiss) urotensin-I: structural differences between
      urotensins-I and urocortins.
AB  - In bony fishes, both corticotropin-releasing factor (CRF) and urotensin-I play a
      role in the regulation of interrenal glucocorticoid release. The rainbow trout,
      Oncorhynchus mykiss, is a useful model for understanding the mechanisms of stress
      and the hypothalamo-pituitary-interrenal axis because of its phylogenetic
      position at the base of the euteleostei and its popularity as a food fish.
      Urotensin-I may act as a glucocorticoid releaser in a mechanism phylogenetically
      older than that of CRF. The structural and functional relationships of trout
      urotensin-I have been investigated. The transcript was cloned from a trout brain
      hypothalamic cDNA library. A single positive clone was isolated and sequenced. It
      possesses 3218 bases and has the longest 3' untranslated region of all urotensins
      I and CRF transcripts found to date. In comparison to the other fish orthologues,
      it has the closest sequence identity to the mammalian urocortins. The transcript
      appears to be differentially processed in brain and urophysis as determined by
      Northern blot analysis and the presence of polyadenylation signals in the 3'
      untranslated region. Synthetic trout urotensin-I activated both human CRF-R1 and 
      R2 receptor-transfected CHO cells with a potency similar to that of white sucker
      (Catostomus commersoni) urotensin-I. Both fish neuropeptides possessed an order
      of magnitude less potency than human urocortin in CRF-R2 transfected cells.

PMID- 10417231
TI  - 11-ketotestosterone induces male-type sexual behavior and gonadotropin secretion
      in gynogenetic crucian carp, Carassius auratus langsdorfii.
AB  - To determine if a gynogenetic teleost might have a sexually bipotential brain, we
      tested whether implantation of 11-ketotestosterone (KT) induces male-type sexual
      behavior and gonadotropin (GTH) secretion in adult gynogenetic crucian carp,
      "ginbuna," Carassius auratus langsdorfii. KT-implanted female ginbuna were tested
      for male spawning behavior by pairing them with a stimulus female in which sexual
      receptivity and attractivity were induced by prostaglandin F(2alpha) (PG)
      injection. When KT-implanted female ginbuna were paired with a PG-injected
      stimulus female ginbuna, all the KT-implanted fish tested showed male spawning
      behavior in response to the PG-injected females. KT-implanted fish also showed
      female spawning behavior when they were injected with PG. When the KT-implanted
      female ginbuna were exposed to waterborne 17alpha,20beta-dihydroxy-4-pregnen-3
      one (a female sex pheromone that stimulates male-typical GTH secretion in
      goldfish), all the KT-implanted fish showed an elevation of plasma GTH levels in
      response to the pheromone. These results demonstrate that gynogenetically evolved
      ginbuna, like goldfish, is sexually plastic and can be behaviorally and
      endocrinologically masculinized by androgen treatment without behavioral
      defeminization. These results support our hypothesis that adult teleosts retain a
      sexually bipotential brain regardless of reproductive strategy, i.e.,
      hermaphroditism, gonochorism, or gynogenesis.

PMID- 10417232
TI  - The effect of sex steroids on primary and secondary sex differentiation in the
      sexually dichromatic reedfrog (Hyperolius argus: Hyperolidae) from the Arabuko
      Sokoke Forest of Kenya.
AB  - The current study examined the role of steroids in primary and secondary sex
      differentiation in the African reedfrog (Hyperolius argus: Hyperolidae). This
      species is sexually dimorphic: males have a solid green dorsum and females are
      reddish-brown with large white spots. This study is the first to report the
      effects of sex steroids on the development of a sexually dichromatic species and
      the first to examine the role of sex steroids on development of the vocal sac.
      Both males and females metamorphosed solid green without spots. Approximately 2
      months after metamorphosis, control females transformed to the female-typical
      color pattern. Control males never developed this color pattern (remained green),
      but developed vocal sacs. To examine the role of sex steroid hormones on primary
      (gonadal differentiation) and secondary (vocal sac development and dorsal
      coloration) sex differentiation, testosterone (T) or estradiol-17beta (E(2)) were
      administered throughout larval development. At metamorphosis, 53% of the controls
      were males, based on gross gonadal morphology and histology of a subsample. Both
      doses of T produced 100% males. All E(2)-treated animals had ovarian cavities
      and/or follicles when examined histologically (at both doses) but 50% had
      testicular tissue in addition to these ovarian characteristics. Both doses of T
      induced vocal sac development and both doses of E(2) induced female coloration.
      Thus, both T and E(2) induced secondary sex characteristics (vocal sac
      development and dorsal color change, respectively) but E(2) produced
      hermaphroditic gonads, whereas T induced complete sex reversal.

PMID- 10417233
TI  - Induction of ovulation of mature oocytes by the maturation-inducing steroid
      17,20beta,21-trihydroxy-4-pregnen-3-one in the spotted seatrout.
AB  - Incubation of mature, hydrated, follicle-enclosed oocytes of the spotted
      seatrout, Cynoscion nebulosus, with the maturation-inducing steroid (MIS),
      17,20beta,21-trihydroxy-4-pregnen-3-one (20beta-S), for 9-12 h resulted in the
      appearance of ovulated oocytes in the culture media. The ovulation response was
      concentration-dependent and steroid-specific. The other teleost MIS, 17, 20beta
      dihydroxy-4-pregnen-3-one (17,20beta-P), was also a potent inducer of ovulation,
      whereas progesterone and 11-deoxycorticosterone did not stimulate ovulation above
      control levels and partially antagonized the action of 20beta-S. The agonist and
      antagonist activities of these steroids on ovulation are consistent with their
      relative binding affinities for the ovarian nuclear progestogen receptor
      previously characterized in this species. Both the RNA synthesis inhibitor
      actinomycin D and the protein synthesis inhibitor cycloheximide blocked MIS
      induced ovulation. This suggests that induction of ovulation by the MIS is
      through a genomic mechanism of action, and potentially involves the previously
      characterized nuclear progestogen receptor. Gonadotropin (hCG)-induced ovulation
      was blocked by addition of the steroid synthesis inhibitor cyanoketone, which was
      overcome by the addition of 20beta-S, but not pregnenolone. Thus, the most likely
      mechanism of gonadotropin-induced ovulation is an increase in the synthesis of
      the MIS. It is concluded that the processes of final oocyte maturation and
      ovulation are both regulated by the MIS. Whereas final oocyte maturation is
      mediated by the 20beta-S membrane receptor (P. Thomas and S. Das, 1997, Biol.
      Reprod. 57, 999-1007), ovulation is regulated by a genomic mechanism and is
      potentially mediated by the previously characterized nuclear progestogen
      receptor.

PMID- 10417234
TI  - Differences between rainbow trout and brown trout in the regulation of the
      pituitary-interrenal axis and physiological performance during confinement.
AB  - The responses of rainbow trout and brown trout to the same stressor were compared
      by measuring primary and secondary stress responses during and after a 5.5-h net
      confinement. Basal levels of adrenocorticotropic hormone (ACTH), alpha-melanocyte
      stimulating hormone (alpha-MSH), and glucose were higher in brown trout than in
      rainbow trout. While confinement induced transient increases in plasma ACTH and
      cortisol levels in both species, the magnitude of these responses, but not the
      time course, was greater in brown trout. Brown trout, but not rainbow trout,
      showed a reduction in plasma alpha-MSH levels after 5.5 h confinement before
      returning to control values, and the glucose levels in the brown trout were
      elevated throughout the confinement and recovery periods. Confinement also
      resulted in increased hematocrit values and reduced plasma sodium and chloride
      levels in both species. Rainbow trout appeared to recover faster from the
      confinement, as glucose and hematocrit values in the brown trout remained
      elevated and ionoregulatory disturbances persisted even after 46 h. During
      recovery effects on the immune system were more pronounced in brown trout than in
      rainbow trout. Circulating white blood cell numbers were reduced in both species
      following 23 h recovery, but remained low in the brown trout. Elevated
      alternative complement activity and oxygen radical production were found after 23
      h recovery, and reduced lysozyme activity was found after 46 h, in brown trout
      only. Results indicate that differences in the stress response of these closely
      related species, as illustrated by the intensity of the cortisol response,
      originate at the level of the pituitary and are also manifested through secondary
      stress responses.

PMID- 10417235
TI  - Egg yolk layers vary in the concentration of steroid hormones in two avian
      species.
AB  - Maternally derived steroid hormones are known to be present in the yolks of avian
      eggs; however, the physiological mechanisms involved in their deposition remain
      largely unexplored. Investigations of steroid production by avian follicles have
      demonstrated temporal differences in the concentrations of progesterone, 17beta
      estradiol, and testosterone during yolk formation. Because yolk is deposited
      peripherally in concentric spheres as the oocyte develops, differences in the
      production of follicular hormones during yolk formation should be manifested in
      differences in the localization of steroids within layers of the yolk. To
      investigate this hypothesis we analyzed steroid hormone concentrations in layers
      of individual eggs of the dark-eyed junco (Junco hyemalis) and the red-winged
      blackbird (Agelaius phoeniceus). We found that in the dark-eyed junco the
      concentration of progesterone is significantly greater at the periphery of the
      yolk, while the concentration of 17beta-estradiol is significantly greater near
      the center of the yolk. We also found in both the dark-eyed junco and the red
      winged blackbird that the concentration of testosterone remains constant from the
      interior to the intermediate layers of the yolk and then drops sharply between
      the intermediate and exterior layers. The patterns of hormone localization that
      we found agree with those predicted by studies of temporal changes in
      steroidogenesis in the maturing follicle of the chicken, thus suggesting that
      within-yolk variation in yolk steroid concentrations in the dark-eyed junco and
      the red-winged blackbird reflects temporal differences in the pattern of
      follicular steroidogenesis. Variation in the concentration of hormones among yolk
      layers presents a methodological concern for studies that involve the removal of
      yolk samples from viable eggs for subsequent hormonal analysis. This variation
      also has implications for the timing of embryonic exposure to steroid hormones.

PMID- 10417236
TI  - Effects of naloxone on neurohypophyseal peptide release by hypertonic stimulation
      in chicks.
AB  - The effects of opioid peptides on the osmotic release of neurohypophyseal
      hormones, arginine vasotocin (AVT) and mesotocin (MT), were determined in 2-day
      old chicks. Experiment 1 examined the effect of a variety of doses of naloxone,
      an opioid antagonist, on chicks administered isotonic or hypertonic solution.
      Plasma osmolality in chicks administered hypertonic solution was significantly
      higher than that in groups administered isotonic solution. None of the doses of
      naloxone affected plasma osmolality in response to isotonic and hypertonic
      solution. Plasma levels of AVT increased in hypertonic solution and this response
      was further enhanced by naloxone injection as the doses increased. The hypertonic
      solution alone did not affect plasma levels of MT, but additional treatment with
      naloxone slightly increased plasma levels of MT. Experiment 2 examined the effect
      of DAMGO ([d-Ala(2), N-Me-Phe(4),Gly-ol]-enkepha lin), a specific mu receptor
      agonist. Relatively high plasma osmolality caused by hypertonic solution was not
      affected by additional treatment with DAMGO. Plasma levels of AVT in response to
      hypertonic solution and to additional treatment with naloxone were reduced by
      higher doses of DAMGO. Experiment 3 examined the effect of naloxone on chicks
      administered different concentrations of NaCl. Administration of hypertonic
      solution resulted in an increase in plasma osmolality and plasma levels of AVT.
      Naloxone administration enhanced the increase in plasma AVT levels in response to
      hypertonic solution. Experiment 4 examined the effect of naloxone on different
      kinds of hypertonic solution, 0.15 M NaCl, 1.5 M NaCl, 2.55 M urea, and 1.95 M
      sucrose. The increases in plasma osmolality resulting from the administration of
      the urea and sucrose solutions were the same as those in the chicks injected with
      1.5 M NaCl. In sucrose-treated chicks, plasma levels of AVT increased in chicks
      administered naloxone but not in chicks injected with normal saline. In contrast,
      no significant changes in plasma levels of AVT were observed in urea treatment
      with or without naloxone. In Experiments 3 and 4, plasma levels of MT after
      administration of hypertonic solutions did not change. However, naloxone
      administration enhanced plasma levels of MT in osmotically stimulated chicks. The
      results of the present study suggest that opioid peptides attenuate the increase
      in plasma AVT and MT in hypertonic states.

PMID- 10417237
TI  - Relation of glucocorticosteroids and testosterone to the annual cycle of free
      living degus in semiarid central Chile.
AB  - We investigated seasonal patterns of plasma glucocorticosteroids (GCs) in both
      sexes and testosterone (T) in males in relation to the annual cycle in central
      Chile of a natural population of the degu (Octodon degus), a caviomorph rodent.
      We wanted to find out which GCs are present in degus, whether their seasonal
      variation suggests suppressive or synergistic interrelationships with T, and
      whether seasonal variation in GC levels indicates a relationship with energy
      mobilization and demands of reproduction. Degus mated in late autumn, and female
      body mass increased in pregnancy and remained high during lactation and
      throughout spring. Over the subsequent period of summer drought both sexes
      declined to a minimal body mass before the next mating season. Cortisol appears
      to be the principal GC in degus. In fact cortisol levels were so high that the
      extremely low levels of corticosterone measured were probably largely due to the
      cross-reactivity of our corticosterone antiserum with cortisol. Titers of
      cortisol in females exceeded 1000 ng/ml at lactation in the spring of 2 years;
      cortisol declined greatly following lactation and during the summer and reached
      its lowest mean level of about 500 ng/ml at mating. Males were more difficult to
      capture than females and thus our sampling was limited, but male cortisol levels
      were similar to those of females during the times of year when we measured them.
      Male T levels remained within a low range all year, but at mating, when mean T
      was highest (0.16 ng/ml) and when most males had detectable T, degus showed their
      lowest cortisol levels. The minimal cortisol level of males during mating
      represents a possible suppressive effect of T, as described in other mammals. At
      the time of their spring emergence, 60% of juvenile males had detectable T levels
      comparable to those of adults, suggesting important organizational effects of T
      at that time in their maturation. Peak cortisol titers in both sexes were
      associated with lactation in females, when energy mobilization, production, and
      body mass were at their greatest.

PMID- 10417238
TI  - Distribution and characterization of natriuretic peptide receptors in the kidney
      of the toad, Bufo marinus.
AB  - The location and characteristics of atrial natriuretic peptide binding sites in
      the kidney of the toad, Bufo marinus, were determined. Specific (125)I-rANP
      binding sites were observed on glomeruli and blood vessels, but little if any
      binding was observed over regions corresponding to the renal tubules. (125)I-rANP
      binding in tissue sections and/or isolated membranes was completely displaced in
      the presence of 1 microM rat ANP, frog ANP, and porcine C-type natriuretic
      peptide (membranes only); however, residual binding remained after incubation
      with 1 microM of the NPR-C ligand, C-ANF, indicating the presence of two distinct
      binding sites. Electrophoresis of kidney membranes cross-linked to (125)I-rANP
      identified specific bands at approximately 70 and 140 kDa which correspond to the
      monomeric mass of NPR-C and the guanylate cyclase receptors, respectively. In
      addition, rat ANP, frog ANP, and porcine CNP stimulated a significant increase in
      cGMP production rates in membrane preparations, while C-ANF had no stimulatory
      effect. Two partial cDNA clones generated using primers based on conserved
      regions of vertebrate natriuretic peptide receptors showed high homology to an
      NPR-C and the natriuretic peptide guanylate cyclase receptors (NPR-GC),
      respectively. This study provides evidence that the kidney of B. marinus contains
      both NPR-C and NPR-GC and that the glomerulus is potentially the principal site
      of ANP regulation in the kidneys.

PMID- 10417239
TI  - Characterization of teleost insulin receptor family members.
AB  - Insulin from mammals and fish has been used to determine insulin-binding
      affinities and receptor numbers with remarkable similarities between these two
      vertebrates, suggesting functional conservation. Yet, the nature and structure of
      teleost insulin receptors are not known. Therefore, the cloning and mRNA
      characterization of rainbow trout insulin receptors were undertaken. Three
      insulin receptor cDNAs were isolated by screening a cDNA library, confirmed as
      separate genes by genomic Southern hybridization, and designated as rainbow trout
      insulin receptor a (rtIR a), rainbow trout insulin receptor b (rtIR b), and
      rainbow trout insulin receptor c (rtIR c). A high degree of amino acid identity
      was observed between rainbow trout insulin receptors (rtIRs) and their human
      homolog, confirming the structural similarities between mammalian and fish
      insulin receptors. Reverse transcription-polymerase chain reaction from total RNA
      using either oligo(dT) or random hexamer primers resulted in a diminished ability
      to detect rtIR a and rtIR b mRNA when oligo(dT) was used, suggesting
      developmental and tissue-specific polyadenylation. The highest steady-state
      levels of rtIR mRNAs were consistently detected in juvenile and adult pyloric
      caeca (which also contained adipose and pancreatic tissue), while the lowest
      levels were consistently found in muscle. A high level of rtIR b and rtIR c mRNA
      was also found in ovary, while a high level of rtIR a was found in adult brain.
      Significant differences were also found between steady-state rtIR mRNA levels in
      corresponding juvenile and adult tissues. These results suggest a complex
      expression pattern of insulin receptor mRNAs in partial tetraploid fish.

PMID- 10417240
TI  - Characterization of teleost insulin receptor family members. II. Developmental
      expression of insulin-like growth factor type I receptor messenger RNAs in
      rainbow trout.
AB  - The insulin-like growth factor (IGF) system in teleosts consists of two ligands,
      IGF-I and IGF-II, multiple binding proteins, and high-affinity transmembrane
      receptors. There exists a large gap in our knowledge of the structure and
      expression of receptors mediating the biological effects of the IGFs in teleosts.
      For example, nucleotide sequence data other than those from the kinase domain,
      evidence of multiple genes, mRNA expression pattern and polyadenylation status in
      multiple tissues at different developmental stages, and quantitation of mRNA
      levels in multiple tissues are not known for any teleost. In the study described
      here, two rainbow trout IGF type I receptor cDNAs (rtIGFR Ia and rtIGFR Ib) were
      isolated by a 5' rapid amplification of cDNA ends method and confirmed as
      separate genes by genomic Southern blot hybridization. The predicted amino acid
      sequences are 85% identical to each other in the tyrosine kinase domain. Both
      cDNAs are more homologous to mammalian IGF type I receptors than to insulin
      receptors. Reverse transcription-polymerase chain reaction from total RNA using
      either oligo(dT) or random hexamers as primers resulted in a diminished ability
      to detect IGF receptor mRNAs when oligo(dT) was used, suggesting developmental
      and tissue-specific polyadenylation. The highest steady-state mRNA levels of
      rtIGFR Ia were found in juvenile gill and adult heart, while the highest levels
      of rtIGFR Ib were found in adult pyloric caeca, which also contained diffuse
      pancreatic and adipose tissue. The lowest steady-state mRNA levels of both rtIGFR
      Ia and rtIGFR Ib were found in juvenile heart, liver, muscle, and spleen, and
      adult liver. Significant differences in steady-state mRNA levels were also found
      between juveniles and adults. These results suggest a complex expression pattern
      of IGF type I receptor mRNAs in partial tetraploid fish.

PMID- 10417241
TI  - Sexually dimorphic development and binding characteristics of NMDA receptors in
      the brain of the platyfish.
AB  - This study investigated age- and gender-specific variations in properties of the
      glutamate N-methyl-d-aspartate receptor (NMDAR) in a freshwater teleost, the
      platyfish (Xiphophorus maculatus). Prior localization of the immunoreactive (ir)
      R1 subunit of the NMDAR protein (R1) in cells of the nucleus olfactoretinalis
      (NOR), a primary gonadotropin-releasing hormone (GnRH)-containing brain nucleus
      in the platyfish, suggests that NMDAR, as in mammals, is involved in modulation
      of the platyfish brain-pituitary-gonad (BPG) axis. The current study shows that
      the number of cells in the NOR displaying ir-R1 is significantly increased in
      pubescent and mature female platyfish when compared to immature and senescent
      animals. In males, there is no significant change in ir-R1 expression in the NOR
      at any time in their lifespan. The affinity of the noncompetitive antagonist
      ((3)H)MK-801 for the NMDAR is significantly increased in pubescent females while
      maximum binding of ((3)H)MK-801 to the receptor reaches a significant maximum in
      mature females. In males, both MK-801 affinity and maximum binding remain
      unchanged throughout development. This is the first report of gender differences
      in the association of NMDA receptors with neuroendocrine brain areas during
      development. It is also the first report to suggest NMDA receptor involvement in
      the development of the BPG axis in a nonmammalian vertebrate.

PMID- 10417242
TI  - Isolation and cDNA cloning of somatolactin in rabbitfish (Siganus guttatus).
AB  - We report the isolation and cDNA cloning of somatolactin (SL) from rabbitfish,
      Siganus guttatus. Rabbitfish SL was isolated from an alkaline extract of the
      pituitary glands by gel filtration chromatography on Sephadex G-100 and reversed
      phase high-performance liquid chromatography. SL was monitored by immunoblotting
      with flounder SL antiserum. The preparation (yield: 0.86 mg/g wet tissues)
      contained two immunoreactive bands of 24 and 28 kDa on SDS-PAGE. Overlapping
      partial cDNA clones corresponding to teleost SLs were amplified by PCR from
      single-strand cDNA from pituitary glands. Excluding the poly(A) tail, rabbitfish
      SL cDNA is 1605 bp long. It contains a 693-bp open reading frame encoding a
      signal peptide of 24 amino acids (aa) and a mature protein of 207 aa. Rabbitfish
      SL has two possible N-glycosylation sites at positions 11 and 121 and seven half
      Cys residues. The deduced amino acid sequence shows over 80% identity with those
      of advanced teleosts like sea bream, red drum, and flounder, 76% with the
      salmonids, 57% with the eel, and 46% with the goldfish SL.

PMID- 10417243
TI  - Estrogen regulates gonadotropin-releasing hormone in the nervus terminalis of
      Xenopus laevis.
AB  - The nervus terminalis or terminal nerve (TN) is a neuronal plexus found in the
      nasal cavity and rostral forebrain of most vertebrates. The hormone gonadotropin
      releasing hormone (GnRH) is found in a population of TN neurons as well as
      hypothalamic neurons which regulate pituitary secretion of the gonadotropins. The
      GnRH-containing neurons of the TN appear to represent a rostral continuation of
      the hypothalamic population since they both originate from the olfactory placode
      and are frequently anatomically continuous. Previous studies have shown that the
      hypothalamic GnRH neurons are regulated by circulating estrogen levels.
      Ovariectomy decreases while estrogen administration increases GnRH content in
      these neurons. It is not known whether the GnRH-containing TN neurons are also
      regulated in a similar manner. This study demonstrates that ovariectomy and
      estrogen readministration alters GnRH-immunoreactive (ir) levels in the TN of
      female Xenopus laevis in a manner similar to that seen in the hypothalamus. One
      week after ovariectomy, the density of TN GnRH-ir fibers in the olfactory bulb
      region (one site of TN termination) is significantly decreased. In contrast, a
      significant increase in GnRH-ir TN fiber density is observed following estrogen
      readministration to ovariectomized frogs. These findings demonstrate that
      estrogen regulates GnRH metabolism in neurons of the TN.

PMID- 10417244
TI  - Real-time fMRI paradigm control, physiology, and behavior combined with near real
      time statistical analysis.
AB  - This study presents an integrated approach to on-line fMRI data processing that
      combines real-time paradigm control and real-time MR image statistical analysis
      with nearly real-time integration of fMRI behavioral and physiological data. The
      real-time paradigms involve accurate timing control of multiple independent
      processing streams for stimulus presentation, physiological monitoring,
      behavioral response recording, and scanner synchronization. The real-time image
      analysis provides high resolution MR image reconstruction, head motion detection,
      translational motion correction, and t test statistical activation maps for
      either block design or single-trial based paradigms. The near real-time analysis
      allows physiological and behavioral data collected during a paradigm to be
      combined with the MR time series and provides extended data filtering and
      statistical processing within a few minutes after the end of the scan. This
      integrated approach improves fMRI reliability for both clinical and research
      studies.

PMID- 10417245
TI  - Detecting structural changes in whole brain based on nonlinear deformations
      application to schizophrenia research.
AB  - This paper describes a new method for detecting structural brain differences
      based on the analysis of deformation fields. Deformations are obtained by an
      intensity-based nonlinear registration routine that transforms one brain onto
      another one. We present a general multivariate statistical approach to analyze
      deformation fields in different subjects. This method was applied to the brains
      of 85 schizophrenic patients and 75 healthy volunteers to examine whether low
      frequency deformations are sufficiently sensitive to detect regional deviations
      in the brains of both groups. We observed significant changes caused by volume
      reduction in brains of schizophrenics bilaterally in the thalamus and in the
      superior temporal gyrus. On the left side, the superior frontal gyrus and
      precentral gyrus are found to be changed, while on the right side, the middle
      frontal gyrus was altered. In addition, there were significant changes in the
      occipital lobe (left lingual gyrus) and in the left cerebellum. Volume
      enlargement in brains of schizophrenics was observed in the right putamen and in
      the adjacent white matter of the thalamic region. Our data suggest a disturbance
      in the nodes of a prefrontal-thalamic-cerebellar circuitry. This provides further
      support for the model of "cognitive dysmetria," which postulates a disruption in
      these nodes. We have demonstrated the application of deformation-based
      morphometry by detecting structural changes in the whole brain. This technique is
      fully automatic, thus allowing for the inclusion of large samples, with no user
      bias or a priori-defined regions of interest.

PMID- 10417246
TI  - fMRI and EEG responses to periodic visual stimulation.
AB  - EEG/VEP and fMRI responses to periodic visual stimulation are reported. The
      purpose of these experiments was to look for similar patterns in the time series
      produced by each method to help understand the relationship between the two. The
      stimulation protocol was the same for both sets of experiments and consisted of
      five complete cycles of checkerboard pattern reversal at 1.87 Hz for 30 s
      followed by 30 s of a stationary checkerboard. The fMRI data was analyzed using
      standard methods, while the EEG was analyzed with a new measurement of activation
      the VEPEG. Both VEPEG and fMRI time series contain the fundamental frequency of
      the stimulus and quasi harmonic components-an unexplained double frequency
      commonly found in fMRI data. These results have prompted a reappraisal of the
      methods for analyzing fMRI data and have suggested a connection between our
      findings and much older published invasive electrophysiological measurements of
      blood flow and the partial pressures of oxygen and carbon dioxide. Overall our
      new analysis suggests that fMRI signals are strongly dependant on hydraulic blood
      flow effects. We distinguish three categories of fMRI signal corresponding to:
      focal activated regions of brain tissue; diffuse nonspecific regions of steal;
      and major cerebral vessels of arterial supply or venous drainage. Each category
      of signal has its own finger print in frequency, amplitude, and phase. Finally,
      we put forward the hypothesis that modulations in blood flow are not only the
      consequence but are also the cause of modulations in functional activity.

PMID- 10417247
TI  - Comparison of impaired subcortico-frontal metabolic networks in normal aging,
      subcortico-frontal dementia, and cortical frontal dementia.
AB  - Normal aging, progressive supranuclear palsy (PSP), and frontotemporal dementia
      (FTD) are characterized by different degrees of decline in frontal lobe
      functions. We used (18)FDG-PET and statistical parametric mapping (SPM96) to
      compare relative subcorticofrontal metabolic impairment at rest in 21 healthy
      elderly subjects (HES), 20 PSP patients, and 6 FTD patients. When HES were
      compared to 22 healthy young subjects, widespread decrease in metabolism was
      observed in bilateral medial prefrontal areas including anterior cingulate
      cortices, in dorsolateral prefrontal areas, in left lateral premotor area, in
      Broca's area, and in left insula. In PSP compared to the 43 healthy subjects
      (HS), we observed subcorticofrontal metabolic impairment including both motor and
      cognitive neural networks. Impairment of functional connections between midbrain
      tegmentum and cerebellar, temporal and pallidal regions was demonstrated in PSP
      as compared to HS. When comparing FTD to HS, glucose uptake was primarily reduced
      in dorsolateral and ventrolateral prefrontal cortices and in frontopolar and
      anterior cingulate regions. There was also bilateral anterior temporal, right
      inferior parietal, and bilateral striatal hypometabolism. Finally, FTD showed
      more severe striatofrontal metabolic impairment than PSP, while
      mesencephalothalamic involvement was only observed in PSP. Our data suggest that
      subcorticofrontal metabolic impairment is distributed in distinct
      subcorticocortical networks in normal aging, PSP, and FTD. Subcorticofrontal
      dementia in PSP is related to hypometabolism in discrete frontal areas, which are
      probably disconnected from certain subcortical structures. The concept of
      subcortical dementia is reinforced by our data, which show disrupted functional
      connections between mesencephalon and cerebellar cortex, inferior and medial
      temporal regions, and pallidum.

PMID- 10417248
TI  - Covariation of activity in habenula and dorsal raphe nuclei following tryptophan
      depletion.
AB  - Abnormal serotonergic function is implicated in the pathogenesis of affective
      disorders. We induced transient depressive relapses in volunteer patients by
      rapidly depleting plasma tryptophan, the precursor of serotonin (5-HT), and
      measured neural activity during different cognitive tasks using positron emission
      tomography (PET). Neural activity in several 5-HT-related brain areas, e.g.,
      dorsal raphe, habenula, septal region, amygdala, and orbitofrontal cortex,
      covaried significantly with plasma levels of tryptophan and ratings of depressed
      mood. Task-specific responses in left amygdala and left anterior cingulate were
      attenuated by tryptophan depletion. We used these PET data to test the hypothesis
      that projections from the habenula modulate dorsal raphe activity and that this
      modulation is enhanced in patients experiencing a profound mood change following
      serotonergic challenge. A strong linear correlation (r(2) > 0.5) between habenula
      and raphe activity was observed in subjects with postdepletion ratings >/=10 on a
      modified Hamilton depression scale, whereas subjects experiencing milder changes
      in mood had weaker habenula-raphe coupling (r(2) < 0.5). These data support a
      model of the serotonergic system in which the habenula projection to the raphe
      represents a convergent feedback pathway that controls the release of 5-HT
      throughout the brain. In our experiment we were able to engage this system in
      patients who were sensitive to tryptophan depletion.

PMID- 10417249
TI  - Visualization of magnetoencephalographic data using minimum current estimates.
AB  - The locations of active brain areas can be estimated from the magnetic field the
      neural current sources produce. In this work we study a visualization method of
      magnetoencephalographic data that is based on minimum[symbol: see text] (1)-norm
      estimates. The method can represent several local or distributed sources and does
      not need explicit a priori information. We evaluated the performance of the
      method using simulation studies. In a situation resembling typical
      magnetoencephalographic measurement, the mean estimated source strength exceeded
      baseline level up to 2 cm from the simulated point-like source. The method can
      also visualize several sources, activated simultaneously or in a sequence, which
      we demonstrated by analyzing magnetic responses associated with sensory
      stimulation and a picture naming task.

PMID- 10417250
TI  - Three distinct ventral occipitotemporal regions for reading and object naming.
AB  - This study investigates word and object processing during naming and viewing
      tasks and identifies three distinct regions in the left ventral occipitotemporal
      cortex. Irrespective of task, words and objects (relative to meaningless visual
      controls) activated the medial surface of the left anterior fusiform gyrus, a
      region that has previously been associated with semantic knowledge. A more
      lateral region was differentially active for naming words and objects relative to
      viewing the same stimuli and a more posterior region was differentially active
      for objects relative to words irrespective of task. In addition, we found that
      word processing resulted in greater activation than object processing on the
      dorsal surface of the left superior temporal gyrus and the left supramarginal
      gyrus. These regions appear to be important for converting orthography into
      phonology; their response to words irrespective of task is consistent with
      established psychological evidence that implicit phonological processing is
      stronger for words than objects.

PMID- 10417251
TI  - Transient neural activity in the medial superior frontal gyrus and precuneus time
      locked with attention shift between object features.
AB  - To investigate the contribution of the superior frontal gyrus and precuneus to
      the cognitive process of attention set shift, we examined the correlation between
      change in neural activity in these areas and the timing of attention set shift
      using event-related functional magnetic resonance imaging. Seven subjects
      underwent a card-sorting task in which they matched a test card to one of two
      target cards according to color or shape. The subjects had to determine the
      correct category based only on feedback and shift the sorting principle when the
      feedback changed from "correct" to "incorrect." Transient increase of neural
      activity time locked with attention shift phases was detected in the medial
      superior frontal gyrus (the rostral part of the supplementary motor area) and
      precuneus. During the control task, in which the feedback and the motor responses
      were preserved without any attention shift, this type of change in neural
      activity was not observed. Our findings indicate that increase in neural activity
      in these brain areas may be closely related to attention set shift between object
      features and suggest that these areas may play a role in the shifting of
      cognitive sets.

PMID- 10417252
TI  - Human cortical areas activated in relation to vergence eye movements-a PET study.
AB  - Human cortical areas activated in relation to vergence eye movements were
      determined using positron emission tomography. Binocular disparity-driven visual
      stimuli were presented using a head-mounted display. Eye movements were monitored
      continuously by an infrared limbus tracker. A combination of a bar and a cross
      was used as the target. In the vergence task, subjects were instructed to follow
      an approaching bar, while ignoring a stationary cross. Activation in relation to
      vergence eye movement was discriminated from activation in relation to motion
      vision by using the ignore-bar task as the control. In the ignore-bar task,
      subjects were instructed to fixate on a stationary cross, while ignoring an
      approaching bar. The fixation task was used as the basic control for both the
      vergence and the ignore-bar tasks. Areas of activation in relation to vergence
      eye movements were found in the bilateral temporooccipital junction, the left
      inferior parietal lobule, and the right fusiform gyrus by comparing regional
      cerebral flow between the vergence and ignore-bar tasks and by the conjunctive
      analyses of vergence-vs-ignore comparison with vergence-vs-fixation comparison.

PMID- 10417253
TI  - Selective visual and auditory attention toward utterances-a PET study.
AB  - The purpose of this study was to reveal functional areas of the brain modulating
      processing of selective auditory or visual attention toward utterances. Regional
      cerebral blood flow was measured in six normal volunteers using positron emission
      tomography during two selective attention tasks and a control condition. The
      auditory task activated the auditory, inferior parietal, prefrontal, and anterior
      cingulate cortices. The visual task activated the visual association, inferior
      parietal, and prefrontal cortices. Both conditions activated the same area in the
      superior temporal sulcus. During the visual task, deactivation was observed in
      the auditory cortex. These results indicate that there exists a modality
      dependent selective attention mechanism which activates or deactivates cortical
      areas in different ways.

PMID- 10417254
TI  - Time course of fMRI-activation in language and spatial networks during sentence
      comprehension.
AB  - Functional neuroimaging previously has been considered to provide inadequate
      temporal resolution to study changes of brain states as a function of cognitive
      computations; however, we have obtained evidence of differential amounts of brain
      activity related to high-level cognition (sentence processing) within 1.5 s of
      stimulus onset. The study used an event-related paradigm with high-speed
      echoplanar functional magnetic resonance imaging (fMRI) to trace the time course
      of the brain activation in the temporal and parietal regions as participants
      comprehended single sentences describing a spatial configuration. Within the
      first set of images, on average 1 s from when the participant begins to read a
      sentence, there was significant activation in a key cortical area involved in
      language comprehension (the left posterior temporal gyrus) and visuospatial
      processing (the left and right parietal regions). In all three areas, the amount
      of activation during sentence comprehension was higher for negative sentences
      than for their affirmative counterparts, which are linguistically less complex.
      The effect of negation indicates that the activation in these areas is modulated
      by the difficulty of the linguistic processing. These results suggest a
      relatively rapid coactivation in both linguistic and spatial cortical regions to
      support the integration of information from multiple processing streams.

PMID- 10417255
TI  - Anisotropy of water diffusion in corona radiata and cerebral peduncle in patients
      with hemiparesis.
AB  - Diffusion tensor imaging is a magnetic resonance method which provides
      quantitative measurements of the directionality (anisotropy) of diffusion.
      Anisotropy measurements can be used to obtain quantitative information about the
      microstructural integrity of white matter tracts. In intact tracts diffusion is
      restricted and directional because water molecules move predominantly
      longitudinally to tracts. The aim of this study was to measure the anisotropy of
      diffusion in patients with chronic hemiparesis. We measured in the corona radiata
      and the cerebral peduncle in 10 patients with a chronic hemiparesis and
      supratentorial lesions and 10 control subjects in regions of interest. In all
      patients anisotropy was reduced in the coronal radiata contralateral to the
      hemiparesis by more than 3 SD compared to control subjects. In three patients,
      each of which had a severe hemiparesis, anisotropy in the cerebral peduncle was
      reduced by more than 3 SD compared to normal control subjects. Our findings
      suggest that reduced anisotropy is associated with chronic hemiparesis.

PMID- 10417256
TI  - Chemokine and orphan receptors in HIV-2 and SIV tropism and pathogenesis.

PMID- 10417257
TI  - Global protein synthesis shutdown in Autographa californica nucleopolyhedrovirus
      infected Ld652Y cells is rescued by tRNA from uninfected cells.
AB  - Global protein synthesis arrest occurs in Autographa californica
      nucleopolyhedrovirus (AcNPV)-infected Ld652Y cells at late times postinfection
      (p.i.). A Lymantria dispar nucleopolyhedrovirus gene, hrf-1, precludes this
      protein synthesis arrest. We used in vitro translation assays to characterize the
      translation defect. Cell-free lysates prepared from uninfected Ld652Y cells,
      AcNPV-infected cells harvested at early times p.i., and cells infected with
      vAchrf-1, a recombinant AcNPV bearing hrf-1, all supported translation. Lysates
      prepared from AcNPV-infected Ld652Y cells at late times p.i. did not support
      translation, but activity was restored by adding small RNA species from mock-,
      vAchrf-1- (24 or 48 h p.i.), and AcNPV- (6 h p.i. ) infected cells. Small RNA
      species (24 and 48 h p.i.) from AcNPV-infected cells did not rescue translation.
      Assays of RNA species further fractionated by ion exchange chromatography
      demonstrated that tRNA rescued translation. Although specific defective tRNA
      species were not revealed by comparative two-dimensional gel analysis, analysis
      of (32)P-labeled tRNAs showed a reduction in de novo synthesis of small RNA
      isolated from AcNPV-infected cells compared with mock- and vAchrf-1-infected
      cells. This study suggests a mechanism of translation arrest involving defective
      or depleted tRNA species in AcNPV-infected Ld652Y cells.

PMID- 10417258
TI  - The genetic relationship between virulent and temperate Streptococcus
      thermophilus bacteriophages: whole genome comparison of cos-site phages Sfi19 and
      Sfi21.
AB  - The virulent cos-site Streptococcus thermophilus bacteriophage Sfi19 has a 37,392
      bp-long genome consisting of 44 open reading frames all encoded on the same DNA
      strand. The genome of the temperate cos-site S. thermophilus phage Sfi21 is 3.3
      kb longer (40,740 bp, 53 orfs). Both genomes are very similarly organized and
      differed mainly by gene deletion and DNA rearrangement events in the lysogeny
      module; gene replacement, duplication, and deletion events in the DNA replication
      module, and numerous point mutations. The level of point mutations varied from
      <1% (lysis and DNA replication modules) to >15% (DNA packaging and head
      morphogenesis modules). A dotplot analysis showed nearly a straight line over the
      left 25 kb of their genomes. Over the right genome half, a more variable dotplot
      pattern was observed. The entire lysogeny module from Sfi21 comprising 12 genes
      was replaced by 7 orfs in Sfi19, six showed similarity with genes from temperate
      pac-site S. thermophilus phages. None of the genes implicated in the
      establishment of the lysogenic state (integrase, superinfection immunity,
      repressor) or remnants of it were conserved in Sfi19, while a Cro-like repressor
      was detected. Downstream of the highly conserved DNA replication module 11 and 13
      orfs were found in Sfi19 and phiSfi21, respectively: Two orfs from Sfi21 were
      replaced by a different gene and a duplication of the phage origin of replication
      in Sfi19; a further orf was only found in Sfi21. All other orfs from this region,
      which included a second putative phage repressor, were closely related between
      both phages. Two noncoding regions of Sfi19 showed sequence similarity to pST1, a
      small cryptic plasmid of S. thermophilus.

PMID- 10417259
TI  - Comparative sequence analysis of the DNA packaging, head, and tail morphogenesis
      modules in the temperate cos-site Streptococcus thermophilus bacteriophage Sfi21.
AB  - The temperate Streptococcus thermophilus bacteriophage Sfi21 possesses 15
      nucleotide-long cohesive ends with a 3' overhang that reconstitutes a cos-site
      with twofold hyphenated rotational symmetry. Over the DNA packaging, head and
      tail morphogenesis modules, the Sfi21 sequence predicts a gene map that is
      strikingly similar to that of lambdoid coliphages in the absence of any sequence
      similarity. A nearly one to one gene correlation was found with the phage lambda
      genes Nu1 to H, except for gene B-to-E complex, where the Sfi21 map resembled
      that of coliphage HK97. The similarity between Sfi21 and HK97 was striking: both
      major head proteins showed an N-terminal coiled-coil structure, the mature major
      head proteins started at amino acid positions 105 and 104, respectively, and both
      major head genes were preceded by genes encoding a possible protease and portal
      protein. The purported Sfi21 protease is the first viral member of the ClpP
      protease family. The prediction of Sfi21 gene functions by reference to the gene
      map of intensively investigated coliphages was experimentally confirmed for the
      major head and tail gene. Phage Sfi21 shows nucleotide sequence similarity with
      Lactococcus phage BK5-T and a lactococcal prophage and amino acid sequence
      similarity with the Lactobacillus phage A2 and the Staphylococcus phage PVL. PVL
      is a missing link that connects the portal proteins from Sfi21 and HK97 with
      respect to sequence similarity. These observations and database searches, which
      demonstrate sequence similarity between proteins of phage from gram-positive
      bacteria, proteobacteria, and Archaea, constrain models of phage evolution.

PMID- 10417260
TI  - Gene 61.3 of bacteriophage T4 is the spackle gene.
AB  - The bacteriophage T4 e gene encodes lysozyme (e-lysozyme), which releases progeny
      phage after normal infection of Escherichia coli cells. A mutation in the spackle
      gene suppresses the defect in e-lysozyme (Emrich, 1968). The spackle gene was
      mapped between genes 41 and 61, but its precise location has not previously been
      determined. In the current study, we constructed an amber mutant of gene 61.3,
      amST14, by site-directed mutagenesis. The gene 61.3 mutant shares phenotypes with
      spackle mutants: The amST14 mutant forms large plaques with sharp edges and
      exhibits truncated lysis inhibition, and furthermore, the mutation can suppress
      the defect in e-lysozyme activity. In addition, cloned gene 61.3 can rescue (by
      homologous recombination) as well as complement the S12 mutation in the spackle
      gene. These results strongly suggest that gene 61.3 is the spackle gene. Indeed,
      the S12 mutant has one base deletion of five in a consecutive A tract in the gene
      61.3 coding region, substituting an unrelated 6-amino acid sequence for the 9 C
      terminal amino acids in the gene 61.3 protein. The gene 61.3 protein is predicted
      to localize in the periplasmic space after cleavage of a signal sequence.

PMID- 10417261
TI  - Antigenic epitopes of the hepatitis A virus polyprotein.
AB  - Forty-two antigenic domains were identified across the hepatitis A virus (HAV)
      polyprotein by using a set of 237 overlapping 20-mer synthetic peptides spanning
      the entire HAV polyprotein and a panel of serum samples from acutely HAV-infected
      patients. The term "antigenic domain" is used in this study to define a protein
      region spanned with consecutive overlapping immunoreactive peptides. Nineteen
      antigenic domains were found within the structural proteins, and 22 were found
      within the nonstructural proteins, with 1 domain spanning the junction of VP1 and
      P2A proteins. Five of these domains were considered immunodominant, as judged by
      both the breadth and the strength of their immunoreactivity. One domain is
      located within the VP2 protein at position 57-90 aa. A second domain, located at
      position 767-842 aa, contains the C-terminal part of the VP1 protein and the
      entire P2A protein. A third domain, located at position 1403-1456 aa, comprises
      the C-terminal part of the P2C protein and the N-terminal half of the P3A
      protein. The fourth domain, located at position 1500-1519 aa, includes almost the
      entire P3B, and the last domain, located at position 1719-1764 aa, contains the C
      terminal region of the P3C protein and the N-terminal region of the P3D protein.
      It is interesting to note that four of the five most immunoreactive domains are
      derived from small HAV proteins and/or encompass protein cleavage sites
      separating different HAV proteins. The HAV-specific immunoreactivity of each
      antigenically reactive peptide was confirmed by using seven HAV seroconversion
      panels. Collectively, these data demonstrate that HAV structural and
      nonstructural proteins contain antigenic epitopes that can be efficiently modeled
      with short synthetic peptides.

PMID- 10417262
TI  - Identification of a subgenomic mRNA encoding the capsid protein of mushroom
      bacilliform virus, a single-stranded RNA mycovirus.
AB  - Mushroom bacilliform virus is unique among mycoviruses of the higher fungi in
      having a genome of positive-sense single-stranded RNA. We have identified a
      subgenomic mRNA molecule encoding the viral capsid protein in mushroom
      bacilliform virus-infected mycelium of Agaricus bisporus. Transcription of
      subgenomic RNA commences at the sequence ACAAAA, 47 nucleotides upstream of the
      initiating AUG.

PMID- 10417263
TI  - Dissemination of SIV after rectal infection preferentially involves paracolic
      germinal centers.
AB  - Homosexual transmission remains a major mode of contamination in developed
      countries. Early virological and immunological events in lymphoid tissues are
      known to be important for the outcome of HIV infections. Little data are
      available, however, on viral dissemination during primary rectal infection. We
      therefore studied this aspect of rectal infection in rhesus macaques inoculated
      with the biological isolate SIVmac251. We show that infection is established
      initially in lymph nodes draining the rectum. Infected cells and virions are
      localized mainly in germinal centers at that stage. With increasing viral burden,
      infected cells are found throughout the lymph node parenchyma. In addition the
      difference in viral load between lymph nodes draining the rectum and other lymph
      nodes is attenuated or abolished. We discuss this pattern of viral dissemination
      with respect to the physiology of the mucosal immune system. The pattern and
      kinetics of viral dissemination after rectal infection have important
      implications for the development of efficient mucosal vaccines.

PMID- 10417264
TI  - Derivation and biological characterization of a molecular clone of SHIV(KU-2)
      that causes AIDS, neurological disease, and renal disease in rhesus macaques.
AB  - Previously, we described the derivation of a pathogenic strain of simian-human
      immunodeficiency virus (SHIV(KU-2)) consisting of the tat, rev, vpu, and env
      genes of HIV-1 (strain HXB2) in a genetic background of SIV(mac)239 that causes
      AIDS and productive infection of the CNS in rhesus macaques (Macca mulatta)
      (Raghavan et al., 1997, Brain Pathol. 7, 851-861). We report here on the
      characterization of a molecular clone of SHIV(KU-2), designated SHIV(KU-2MC4),
      that caused CD4(+) T cell loss as well as neurological and renal disease in
      macaques. DNA sequence analysis of selected SIV regions of SHIV(KU-2MC4) revealed
      10 nucleotide changes in the LTR, whereas Gag, Vif, Vpr, Vpx, and Nef had 1, 1,
      1, 2, and 13 predicted amino acid substitutions, respectively, compared to
      SIV(mac)239. DNA sequence analysis of HIV-1 derived regions of SHIV(KU-2MC4)
      revealed 2, 1, 2, and 18 predicted amino acid substitutions in the Tat, Rev, Vpu,
      and Env proteins, respectively, when compared to SHIV-4. Unlike the parental SHIV
      4, which is not tropic for macrophages, SHIV(KU-2MC4) replicated efficiently in
      macrophage cultures as determined by p27 assays. However, despite the numerous
      changes in the Env protein and newly acquired tropism for macrophages, SHIV(KU
      2MC4), like the parental SHIV-4, used CXCR4 exclusively as its coreceptor for
      entry into susceptible cells. Inoculation of SHIV(KU-2MC4) into two rhesus
      macaques resulted in severe infection in which the numbers of circulating CD4(+)
      T cells in the blood declined rapidly by 2 weeks postinoculation and virus
      producing cells in the peripheral blood mononuclear cells were identified
      throughout the course of infection. At the time of euthanasia (20 and 22 weeks),
      both macaques had lost a significant amount of weight and had no circulating
      CD4(+) T cells. In addition, one macaque developed intension tremors and
      uncoordinated movements. Virological examination of tissues at necropsy revealed
      active virus replication in both lymphoid and nonlymphoid tissues such as the
      lung and brain. Histological examination revealed that the induced
      immunodeficiency was associated with lymphoid depletion of the lymph nodes and
      spleen, opportunistic infections, lentiviral encephalitis, and severe
      glomerulosclerosis of the kidney. This molecular clone will serve as the basis
      for analyzing the molecular determinants through which SHIV(KU-2) causes severe
      CD4(+) T cell loss, neurological disease, and SHIV nephropathy in rhesus
      macaques.

PMID- 10417265
TI  - Expression of a chitinase gene and lysis of the host cell wall during Chlorella
      virus CVK2 infection.
AB  - A chitinase gene (vChti-1) encoded by the Chlorella virus CVK2 was cloned and
      characterized. The vChti-1 open reading frame consisted of 2508 bp corresponding
      to 836 amino acid residues. The predicted amino acid sequence contained two sets
      of a family 18 catalytic domain that is responsible for chitinase activity.
      Northern blot analysis revealed that the vChti-1 gene was expressed in virus
      infected Chlorella cells late in infection, when a single transcript of about 2.5
      kb appeared at 120 min postinfection. This result was confirmed by Western
      blotting with a specific anti-vChti-1 protein antibody; a protein of about 94 kDa
      was detected specifically beginning at 240 min postinfection and was present
      until cell lysis. The protein was not incorporated into viral particles but
      remained in the medium after cell lysis. The vChti-1 protein produced in virus
      infected cells showed chitinase activity on zymogram assays.

PMID- 10417266
TI  - Extensive sequence divergence and phylogenetic relationships between the
      fusogenic and nonfusogenic orthoreoviruses: a species proposal.
AB  - The orthoreoviruses can be divided into subgroups based on either their
      restricted host range or the unusual ability of certain members of this group of
      nonenveloped viruses to induce cell-cell fusion from within. Phylogenetic
      relationships cannot be inferred based on these biological properties because
      fusogenic reoviruses are present in both the avian and mammalian subgroups. To
      address this issue, the complete nucleotide sequences of the three S-class genome
      segments encoding the major sigma-class core, outer capsid, and nonstructural
      proteins of four fusogenic reoviruses were determined and used to establish the
      phylogeny of the orthoreoviruses. The viruses analysed included two strains of
      avian reovirus and the only known fusogenic mammalian reoviruses, Nelson Bay
      virus and baboon reovirus. Comparative sequence analysis of these fusogenic
      reoviruses and the prototypical nonfusogenic mammalian reoviruses indicated a
      highly diverged genus with both conserved and unique sequence-predicted
      structural motifs in the major sigma-class proteins. Phylogenetic analysis
      provided the basis for the first taxonomic subdivision of the orthoreoviruses
      into species classes based on inferred evolutionary relationships. It is proposed
      that the orthoreoviruses consist of at least four species that separate into
      three clades. The nonfusogenic mammalian reovirus species represent a single
      clade, and the fusogenic reoviruses separate into two distinct clades. The first
      clade of fusogenic reoviruses contains the avian reovirus- and Nelson Bay virus
      type species, with the second clade being occupied by the single baboon reovirus
      isolate that represents a fourth orthoreovirus species.

PMID- 10417267
TI  - Acidic pH enhancement of the fusion of Newcastle disease virus with cultured
      cells.
AB  - Fusion of the lentogenic strain "Clone 30" of Newcastle disease virus (NDV) with
      the cell line COS-7 has been studied. Fusion was monitored using the
      octadecylrhodamine B chloride dequenching assay [Hoekstra, D., de Boer, T.,
      Klappe, K. and Wilschut, J. (1984). Biochemistry 23, 5675-5681]. In the present
      work, fusion of NDV with COS-7 cells was found to occur in a time- and
      temperature-dependent fashion. Significant dequenching of the probe occurred at
      temperatures higher than 28 degrees C. A 20-fold excess of unlabeled virus
      inhibited fusion by about 53% compared with the control, whereas 62% inhibition
      of fusion was obtained after digestion of viral glycoproteins with trypsin. The
      data are discussed in terms of the nonfusion transfer of the probe. In addition,
      preincubation of cells with 50 mM ammonium chloride or 0.1% sodium azide
      prevented NDV from fusing with COS-7 cells by about 30% in comparison with the
      control. The cytopathic effect of NDV infection in cell culture in the presence
      of ammonium chloride was reduced compared with control. Moreover, viral
      preincubation at pH 5 yielded a mild inhibition of fusogenic activity. Our
      results suggest that NDV may use the endocytic pathway as a complementary way of
      entering cells by direct fusion with the plasma membrane.

PMID- 10417268
TI  - Restoration of a stem-loop structure required for potato virus X RNA accumulation
      indicates selection for a mismatch and a GNRA tetraloop.
AB  - The 5' region of potato virus X (PVX) RNA contains a stem-loop structure, stem
      loop 1 (SL1), that is required for efficient plus-strand RNA accumulation. To
      determine how changes to individual elements in SL1 are accommodated by the
      virus, we inoculated PVX transcripts containing modifications in the terminal
      tetraloop (TL), stem C (SC), and stem D (SD) regions onto Nicotiana benthamiana
      plants and analyzed progeny RNAs over a series of passages. Several progeny RNAs
      isolated from plants inoculated with the TL mutants containing changes to the
      first nucleotide of the GAAA motif or deletion of the entire TL sequence were
      found to contain multiple A insertions within the terminal loop region. The wild
      type TL motif, GAAA, was recovered for all TL mutants by the second passage,
      suggesting that the sequence and potential structure of this element are crucial
      for PVX infection. Revertant RNAs isolated from plants inoculated with mutants in
      SD and the central region of SC indicated that increased stem length is
      tolerated. Restoration of SD length to the 4 bp typical of the wild-type PVX RNA
      was accompanied by A insertion into loop C. Mutants with a conversion of the C55
      C78 mismatch to a G-C pair, relocation of this mismatch within the central region
      of SC, or deletion of C55-C78 were unable to infect protoplasts and plants. In
      contrast, the mutant with a conversion of the C55-C78 mismatch to an A-C
      mismatch, which exhibited low levels of PVX plus-strand RNA in protoplasts, was
      able to infect plants and quickly reverted to the wild-type C-C mismatch. These
      data indicate that important sequence and secondary structural elements within
      SL1 are required for efficient viral infection and that multiple A insertions
      within the TL and loop C regions, potentially by polymerase stuttering, accompany
      restoration of SL1 structure.

PMID- 10417269
TI  - The bare lymphocyte syndrome: molecular clues to the transcriptional regulation
      of major histocompatibility complex class II genes.

PMID- 10417270
TI  - Interleukin-2 signaling and inherited immunodeficiency.

PMID- 10417271
TI  - Unlinking tumor necrosis factor biology from the major histocompatibility
      complex: lessons from human genetics and animal models.

PMID- 10417272
TI  - Genes that regulate eosinophilic inflammation.

PMID- 10417273
TI  - Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by
      mutations in the procollagen I N-proteinase gene.
AB  - Ehlers-Danlos syndrome (EDS) type VIIC is a recessively inherited connective
      tissue disorder, characterized by extreme skin fragility, characteristic facies,
      joint laxity, droopy skin, umbilical hernia, and blue sclera. Like the animal
      model dermatosparaxis, EDS type VIIC results from the absence of activity of
      procollagen I N-proteinase (pNPI), the enzyme that excises the N-propeptide of
      type I and type II procollagens. The pNPI enzyme is a metalloproteinase
      containing properdin repeats and a cysteine-rich domain with similarities to the
      disintegrin domain of reprolysins. We used bovine cDNA to isolate human pNPI. The
      human enzyme exists in two forms: a long version similar to the bovine enzyme and
      a short version that contains the Zn++-binding catalytic site but lacks the
      entire C-terminal domain in which the properdin repeats are located. We have
      identified the mutations that cause EDS type VIIC in the six known affected human
      individuals and also in one strain of dermatosparactic calf. Five of the
      individuals with EDS type VIIC were homozygous for a C-->T transition that
      results in a premature termination codon, Q225X. Four of these five patients were
      homozygous at three downstream polymorphic sites. The sixth patient was
      homozygous for a different transition that results in a premature termination
      codon, W795X. In the dermatosparactic calf, the mutation is a 17-bp deletion that
      changes the reading frame of the message. These data provide direct evidence that
      EDS type VIIC and dermatosparaxis result from mutations in the pNPI gene.

PMID- 10417274
TI  - The molecular basis of malonyl-CoA decarboxylase deficiency.
AB  - We characterized a 2.1-kb human cDNA with a 1362-bp (454-amino acid) open reading
      frame showing 70.3% amino acid identity to goose malonyl-CoA decarboxylase (MCD).
      We have identified two different homozygous mutations in human MCD (hMCD) by
      using RT-PCR analysis of fibroblast RNA from two previously reported
      consanguineous Scottish patients with MCD deficiency. The first mutation is a
      442C-->G transversion resulting in a premature stop codon (S148X) in the N
      terminal half of the protein. The second is a 13-bp insertion in the mature RNA,
      causing a frameshift with predicted protein truncation. This insertion is the
      result of an intronic mutation generating a novel splice acceptor sequence (IVS4
      14A-->G). Both mutations were found to segregate appropriately within the
      families and were not found in 100 normal unrelated individuals. These mutations
      would be predicted to cause MCD deficiency, thus confirming this transcript as
      the hMCD ortholog. The peptide sequence of hMCD revealed a C-terminal peroxisomal
      targeting sequence (-SKL). This targeting signal appears to be functional in
      vivo, since the distribution of MCD enzymatic activity in rat liver homogenates
      as measured by means of subcellular fractionation-strongly suggests that MCD is
      localized to peroxisomes in addition to the mitochondrial localization reported
      elsewhere. These data strongly support this cDNA as encoding human MCD, an
      important regulator of fatty acid metabolism.

PMID- 10417275
TI  - Identification of a mutation cluster in mevalonate kinase deficiency, including a
      new mutation in a patient of Mennonite ancestry.
AB  - Mevalonate kinase (MKase) deficiency (MKD) is a rare autosomal recessive disorder
      in the pathway of cholesterol and nonsterol isoprenoid biosynthesis. Thus far,
      two disease-causing missense alleles have been identified, N301T and A334T. We
      report four additional mutations associated with MKD: L264F, T243I, L265P, and
      I268T, the last found in a patient of Mennonite ancestry. Electrophoretic
      analysis of bacterially expressed wild-type and mutant MKase indicated that I268T
      and T243I mutants produced normal or somewhat reduced amounts of MKase protein;
      conversely, L264F and L265P mutations resulted in considerably decreased, or
      absent, MKase protein. Immunoblot analysis of MKase from all patients suggested
      that the MKase polypeptide was grossly intact and produced in amounts comparable
      to control levels. Three mutations resulted in significantly diminished MKase
      enzyme activity (<2%), whereas the I268T allele yielded approximately 20%
      residual enzyme activity. Our results should allow more-accurate identification
      of carriers and indicate a mutation "cluster" within amino acids 240-270 of the
      mature MKase polypeptide.

PMID- 10417276
TI  - Redefinition of exon 7 in the COL1A1 gene of type I collagen by an intron 8
      splice-donor-site mutation in a form of osteogenesis imperfecta: influence of
      intron splice order on outcome of splice-site mutation.
AB  - Most splice-site mutations lead to a limited array of products, including exon
      skipping, use of cryptic splice-acceptor or -donor sites, and intron inclusion.
      At the intron 8 splice-donor site of the COL1A1 gene, we identified a G+1-->A
      transition that resulted in the production of several splice products from the
      mutant allele. These included one in which the upstream exon 7 was extended by 96
      nt, others in which either intron 8 or introns 7 and 8 were retained, one in
      which exon 8 was skipped, and one that used a cryptic donor site in exon 8. To
      determine the mechanism by which exon-7 redefinition might occur, we examined the
      order of intron removal in the region of the mutation by using intron/exon primer
      pairs to amplify regions of the precursor nuclear mRNA between exon 5 and exon
      10. Removal of introns 5, 6, and 9 was rapid. Removal of intron 8 usually
      preceded removal of intron 7 in the normal gene, although, in a small proportion
      of copies, the order was reversed. The proportion of abnormal products suggested
      that exon 7 redefinition, intron 7 plus intron 8 inclusion, and exon 8 skipping
      all represented products of the impaired rapid pathway, whereas the intron-8
      inclusion product resulted from use of the slow intron 7-first pathway. The very
      low-abundance cryptic exon 8 donor site product could have arisen from either
      pathway. These results suggest that there is commitment of the pre-mRNA to the
      two pathways, independent of the presence of the mutation, and that the order and
      rate of intron removal are important determinants of the outcome of splice-site
      mutations and may explain some unusual alterations.

PMID- 10417277
TI  - A loss-of-function model for cystogenesis in human autosomal dominant polycystic
      kidney disease type 2.
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is genetically
      heterogeneous, with at least three chromosomal loci (PKD1, PKD2, and PKD3) that
      account for the disease. Mutations in the PKD2 gene, on the long arm of
      chromosome 4, are expected to be responsible for approximately 15% of cases of
      ADPKD. Although ADPKD is a systemic disease, it shows a focal expression, because
      <1% of nephrons become cystic. A feasible explanation for the focal nature of
      events in PKD1, proposed on the basis of the two-hit theory, suggests that
      cystogenesis results from the inactivation of the normal copy of the PKD1 gene by
      a second somatic mutation. The aim of this study is to demonstrate that somatic
      mutations are present in renal cysts from a PKD2 kidney. We have studied 30 renal
      cysts from a patient with PKD2 in which the germline mutation was shown to be a
      deletion that encompassed most of the disease gene. Loss-of-heterozygosity (LOH)
      studies showed loss of the wild-type allele in 10% of cysts. Screening of six
      exons of the gene by SSCP detected eight different somatic mutations, all of them
      expected to produce truncated proteins. Overall, >/=37% of the cysts studied
      presented somatic mutations. No LOH for the PKD1 gene or locus D3S1478 were
      observed in those cysts, which demonstrates that somatic alterations are
      specific. We have identified second-hit mutations in human PKD2 cysts, which
      suggests that this mechanism could be a crucial event in the development of
      cystogenesis in human ADPKD-type 2.

PMID- 10417278
TI  - Molecular characterization of CTNS deletions in nephropathic cystinosis:
      development of a PCR-based detection assay.
AB  - Nephropathic cystinosis is an autosomal recessive disorder that is characterized
      by accumulation of intralysosomal cystine and is caused by a defect in the
      transport of cystine across the lysosomal membrane. Using a positional cloning
      strategy, we recently cloned the causative gene, CTNS, and identified pathogenic
      mutations, including deletions, that span the cystinosis locus. Two types of
      deletions were detected-one of 9.5-16 kb, which was seen in a single family, and
      one of approximately 65 kb, which is the most frequent mutation found in the
      homozygous state in nearly one-third of cystinotic individuals. We present here
      characterization of the deletion breakpoints and demonstrate that, although both
      deletions occur in regions of repetitive sequences, they are the result of
      nonhomologous recombination. This type of mechanism suggests that the
      approximately 65-kb deletion is not a recurrent mutation, and our results confirm
      that it is identical in all patients. Haplotype analysis shows that this large
      deletion is due to a founder effect that occurred in a white individual and that
      probably arose in the middle of the first millenium. We also describe a rapid PCR
      based assay that will accurately detect both homozygous and heterozygous
      deletions, and we use it to show that the approximately 65-kb deletion is present
      in either the homozygous or the heterozygous state in 76% of cystinotic patients
      of European origin.

PMID- 10417279
TI  - Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher
      Disease: duplications, the major cause of the disease, originate more frequently
      in male germ cells, but point mutations do not. The Clinical European Network on
      Brain Dysmyelinating Disease.
AB  - Pelizaeus-Merzbacher Disease (PMD) is an X-linked developmental defect of
      myelination affecting the central nervous system and segregating with the
      proteolipoprotein (PLP) locus. Investigating 82 strictly selected sporadic cases
      of PMD, we found PLP mutations in 77%; complete PLP-gene duplications were the
      most frequent abnormality (62%), whereas point mutations in coding or splice-site
      regions of the gene were involved less frequently (38%). We analyzed the maternal
      status of 56 cases to determine the origin of both types of PLP mutation, since
      this is relevant to genetic counseling. In the 22 point mutations, 68% of mothers
      were heterozygous for the mutation, a value identical to the two-thirds of
      carrier mothers that would be expected if there were an equal mutation rate in
      male and female germ cells. In sharp contrast, among the 34 duplicated cases, 91%
      of mothers were carriers, a value significantly (chi2=9. 20, P<.01) in favor of a
      male bias, with an estimation of the male/female mutation frequency (k) of 9.3.
      Moreover, we observed the occurrence of de novo mutations between parental and
      grandparental generations in 17 three-generation families, which allowed a direct
      estimation of the k value (k=11). Again, a significant male mutation imbalance
      was observed only for the duplications. The mechanism responsible for this strong
      male bias in the duplications may involve an unequal sister chromatid exchange,
      since two deletion events, responsible for mild clinical manifestations, have
      been reported in PLP-related diseases.

PMID- 10417281
TI  - A locus for isolated cleft palate, located on human chromosome 2q32.
AB  - We present evidence for the existence of a novel chromosome 2q32 locus involved
      in the pathogenesis of isolated cleft palate. We have studied two unrelated
      patients with strikingly similar clinical features, in whom there are apparently
      balanced, de novo cytogenetic rearrangements involving the same region of
      chromosome 2q. Both children have cleft palate, facial dysmorphism, and mild
      learning disability. Their karyotypes were originally reported as 46, XX,
      t(2;7)(q33;p21) and 46, XX, t(2;11)(q33;p14). However, our molecular cytogenetic
      analyses localize both translocation breakpoints to a small region between
      markers D2S311 and D2S116. This suggests that the true location of these
      breakpoints is 2q32 rather than 2q33. To obtain independent support for the
      existence of a cleft-palate locus in 2q32, we performed a detailed statistical
      analysis for all cases in the human cytogenetics database of nonmosaic, single,
      contiguous autosomal deletions associated with orofacial clefting. This revealed
      2q32 to be one of only three chromosomal regions in which haploinsufficiency is
      significantly associated with isolated cleft palate. In combination, our data
      provide strong evidence for the location at 2q32 of a gene that is critical to
      the development of the secondary palate. The close proximity of these two
      translocation breakpoints should also allow rapid progress toward the positional
      cloning of this cleft-palate gene.

PMID- 10417282
TI  - A genome scan for familial combined hyperlipidemia reveals evidence of linkage
      with a locus on chromosome 11.
AB  - Familial combined hyperlipidemia (FCHL) is a common familial lipid disorder
      characterized by a variable pattern of elevated levels of plasma cholesterol
      and/or triglycerides. It is present in 10%-20% of patients with premature
      coronary heart disease. The genetic etiology of the disease, including the number
      of genes involved and the magnitude of their effects, is unknown. Using a subset
      of 35 Dutch families ascertained for FCHL, we screened the genome, with a panel
      of 399 genetic markers, for chromosomal regions linked to genes contributing to
      FCHL. The results were analyzed by use of parametric-linkage methods in a two
      stage study design. Four loci, on chromosomes 2p, 11p, 16q, and 19q, exhibited
      suggestive evidence for linkage with FCHL (LOD scores of 1.3-2.6). Markers within
      each of these regions were then examined in the original sample and in additional
      Dutch families with FCHL. The locus on chromosome 2 failed to show evidence for
      linkage, and the loci on chromosome 16q and 19q yielded only equivocal or
      suggestive evidence for linkage. However, one locus, near marker D11S1324 on the
      short arm of human chromosome 11, continued to show evidence for linkage with
      FCHL, in the second stage of this design. This region does not contain any strong
      candidate genes. These results provide evidence for a candidate chromosomal
      region for FCHL and support the concept that FCHL is complex and heterogeneous.

PMID- 10417280
TI  - Chromosome breakage in the Prader-Willi and Angelman syndromes involves
      recombination between large, transcribed repeats at proximal and distal
      breakpoints.
AB  - Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct
      neurobehavioral disorders that most often arise from a 4-Mb deletion of
      chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively. At
      a de novo frequency of approximately.67-1/10,000 births, these deletions
      represent a common structural chromosome change in the human genome. To elucidate
      the mechanism underlying these events, we characterized the regions that contain
      two proximal breakpoint clusters and a distal cluster. Novel DNA sequences
      potentially associated with the breakpoints were positionally cloned from YACs
      within or near these regions. Analyses of rodent-human somatic-cell hybrids, YAC
      contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated
      sequences (the END repeats) at or near the breakpoints. The END-repeat units are
      derived from large genomic duplications of a novel gene (HERC2), many copies of
      which are transcriptionally active in germline tissues. One of five PWS/AS
      patients analyzed to date has an identifiable, rearranged HERC2 transcript
      derived from the deletion event. We postulate that the END repeats flanking 15q11
      q13 mediate homologous recombination resulting in deletion. Furthermore, we
      propose that active transcription of these repeats in male and female germ cells
      may facilitate the homologous recombination process.

PMID- 10417283
TI  - The gene for hypotrichosis of Marie Unna maps between D8S258 and D8S298:
      exclusion of the hr gene by cDNA and genomic sequencing.
AB  - Hypotrichosis of Marie Unna (MU) is an autosomal dominant hair-loss disorder with
      onset in childhood. A genomewide search for the gene was performed in a large
      Dutch family using 400 fluorescent microsatellite markers. Linkage was detected
      with marker D8S258, and analysis of this family and a further British kindred
      with additional markers in the region gave a combined maximum two-point LOD score
      of 13.42, with D8S560. Informative recombinants placed the MU gene in a 2.4-cM
      interval between markers D8S258 and D8S298. Recently, recessive mutations in the
      hr gene were reported in families with congenital atrichia, and this gene was
      previously mapped close to the MU interval. By radiation-hybrid mapping, we
      placed the hr gene close to D8S298 but were unable to exclude it from the MU
      interval. This, with the existence of the semidominant murine hr allele, prompted
      us to perform mutation analysis for this gene. Full-length sequencing of hr cDNA
      obtained from an affected individual showed no mutations. Similarly, screening of
      all exons of the hr gene amplified from the genomic DNA of an affected individual
      revealed no mutations. Analysis of expressed sequences and positional cloning of
      the MU locus is underway.

PMID- 10417284
TI  - Autosomal dominant cerebellar ataxia type III: linkage in a large British family
      to a 7.6-cM region on chromosome 15q14-21.3.
AB  - Autosomal dominant cerebellar ataxia type III (ADCA III) is a relatively benign,
      late-onset, slowly progressive neurological disorder characterized by an
      uncomplicated cerebellar syndrome. Three loci have been identified: a moderately
      expanded CAG trinucleotide repeat in the SCA 6 gene, the SCA 5 locus on
      chromosome 11, and a third locus on chromosome 22 (SCA 10). We have identified
      two British families in which affected individuals do not have the SCA 6
      expansion and in which the disease is not linked to SCA 5 or SCA 10. Both
      families exhibit the typical phenotype of ADCA III. Using a genomewide searching
      strategy in one of these families, we have linked the disease phenotype to marker
      D15S1039. Construction of haplotypes has defined a 7.6-cM interval between the
      flanking markers D15S146 and D15S1016, thereby assigning another ADCA III locus
      to the proximal long-arm of chromosome 15 (SCA 11). We excluded linkage of the
      disease phenotype to this region in the second family. These results indicate the
      presence of two additional ADCA III loci and more clearly define the genetic
      heterogeneity of ADCA III.

PMID- 10417285
TI  - A gene for lymphedema-distichiasis maps to 16q24.3.
AB  - Lymphedema-distichiasis (LD) is a dominantly inherited syndrome with onset of
      lymphedema at or just after puberty. Most affected individuals have distichiasis
      fine hairs arising inappropriately from the eyelid meibomian glands-which is
      evident from birth. A study of three families with LD has shown linkage to
      chromosome 16q24.3, and subsequent analysis of the region for recombinant genes
      places the locus between D16S422 and D16S3074, a distance of approximately 16 cM.
      Possible candidate genes in this interval include the N-proteinase for type 3
      collagen, PCOLN3; the metalloprotease PRSM1; and the cell matrix-adhesion
      regulator, CMAR.

PMID- 10417286
TI  - Linkage analysis in a large Brazilian family with van der Woude syndrome suggests
      the existence of a susceptibility locus for cleft palate at 17p11.2-11.1.
AB  - van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized
      by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate
      (CP), bifid uvula, and hypodontia (H). The expression of VWS, which has
      incomplete penetrance, is highly variable. Both the occurrence of CL/P and CP
      within the same genealogy and a recurrence risk <40% for CP among descendants
      with VWS have suggested that the development of clefts in this syndrome is
      influenced by modifying genes at other loci. To test this hypothesis, we have
      conducted linkage analysis in a large Brazilian kindred with VWS, considering as
      affected the individuals with CP, regardless of whether it is associated with
      other clinical signs of VWS. Our results suggest that a gene at 17p11.2-11.1,
      together with the VWS gene at 1p32-41, enhances the probability of CP in an
      individual carrying the two at-risk genes. If this hypothesis is confirmed in
      other VWS pedigrees, it will represent one of the first examples of a gene,
      mapped through linkage analysis, which modifies the expression of a major gene.
      It will also have important implications for genetic counseling, particularly for
      more accurately predicting recurrence risks of clefts among the offspring of
      patients with VWS.

PMID- 10417287
TI  - Localization of a gene for familial patella aplasia-hypoplasia (PTLAH) to
      chromosome 17q21-22.
AB  - Patella aplasia-hypoplasia (PTLAH) is a rare genetic defect characterized by
      congenital absence or marked reduction of the patella. PTLAH can occur either as
      an isolated defect or in association with other malformations, and it
      characteristically occurs in the nail-patella syndrome and in some chromosome
      imbalances. We report the first evidence of linkage for isolated PTLAH in an
      extended Venezuelan family. After exclusion of the candidate chromosome regions
      where disorders associated with PTLAH have been mapped, a genomewide scan was
      performed that supported mapping of the disease locus within a region of 12 cM on
      chromosome 17q22. Two marker loci (D17S787 and D17S1604) typed from this region
      gave maximum LOD scores >3. Accordingly, multipoint analysis gave a maximum LOD
      score of 3.39, with a most likely location for the disease gene between D17S787
      and D17S1604. Sequencing of the noggin gene, a candidate mapping between these
      markers, failed to reveal any mutation in affected subjects.

PMID- 10417288
TI  - Multiplex-FISH for pre- and postnatal diagnostic applications.
AB  - For >3 decades, Giemsa banding of metaphase chromosomes has been the standard
      karyotypic analysis for pre- and postnatal diagnostic applications. However,
      marker chromosomes or structural abnormalities are often encountered that cannot
      be deciphered by G-banding alone. Here we describe the use of multiplex-FISH (M
      FISH), which allows the visualization of the 22 human autosomes and the 2 sex
      chromosomes, in 24 different colors. By M-FISH, the euchromatin in marker
      chromosomes could be readily identified. In cases of structural abnormalities, M
      FISH identified translocations and insertions or demonstrated that the rearranged
      chromosome did not contain DNA material from another chromosome. In these cases,
      deleted or duplicated regions were discerned either by chromosome-specific
      multicolor bar codes or by comparative genomic hybridization. In addition, M-FISH
      was able to identify cryptic abnormalities in patients with a normal G-karyotype.
      In summary, M-FISH is a reliable tool for diagnostic applications, and results
      can be obtained in </=24 h. When M-FISH is combined with G-banding analysis,
      maximum cytogenetic information is provided.

PMID- 10417289
TI  - Evaluation of parental mitochondrial inheritance in neonates born after
      intracytoplasmic sperm injection.
AB  - Intracytoplasmic sperm injection (ICSI) is now used when severe male-factor
      infertility has been documented. Since defective mitochondrial functions may
      result in male hypofertility, it is of prime importance to evaluate the risk of
      paternal transmission of an mtDNA defect to neonates. DNA samples from the blood
      of 21 infertile couples and their 27 neonates born after ICSI were studied. The
      highly polymorphic mtDNA D-loop region was analyzed by four PCR-based approaches.
      With denaturing gradient gel electrophoresis (DGGE), which allows 2% of a minor
      mtDNA species to be detected, the 27 newborns had a DGGE pattern identical to
      that of their mother but different from that of their father. Heteroplasmy
      documented in several parents and children supported an exclusive maternal
      inheritance of mtDNA. The parental origin of the children's mtDNA molecules also
      was studied by more-sensitive assays: restriction-endonuclease analysis (REA) of
      alpha[32P]-radiolabeled PCR products; paternal-specific PCR assay; and depletion
      of maternal mtDNA, followed by REA. We did not detect paternal mtDNA in nine
      neonates, with a sensitivity level of 0.01% in five children, 0.1% in two
      children, and 1% in two children. The estimated ratio of sperm-to-oocyte mtDNA
      molecules in humans is 0.1%-1.5%. Thus, we conclude that, in these families, the
      ICSI procedure performed with mature spermatozoa did not alter the uniparental
      pattern of inheritance of mtDNA.

PMID- 10417290
TI  - Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at
      nucleotide 8993.
AB  - Mitochondrial genetics is complicated by heteroplasmy, or mutant load, which may
      be from 1%-99%, and thus may produce a gene dosage-type effect. Limited data are
      available for genotype/phenotype correlations in disorders caused by mtDNA
      mutations; therefore, prenatal diagnosis for mtDNA mutations has been hindered by
      an inability to predict accurately the clinical severity expected from a mutant
      load measured in fetal tissue. After reviewing 44 published and 12 unpublished
      pedigrees, we considered the possibility of prenatal diagnosis for two common
      mtDNA mutations at nucleotide 8993. We related the severity of symptoms to the
      mutant load and predicted the clinical outcome of a given mutant load. We also
      used the available data to generate empirical recurrence risks for genetic
      counseling, which may be used in conjunction with prenatal diagnosis.

PMID- 10417291
TI  - A major quantitative-trait locus for mole density is linked to the familial
      melanoma gene CDKN2A: a maximum-likelihood combined linkage and association
      analysis in twins and their sibs.
AB  - Important risk factors for melanoma are densely clustered melanocytic nevi
      (common moles) and mutations in the p16 (CDKN2A) gene. Nevi may be subclassified
      as raised or flat. In our sample, raised nevi were 27% of the total, and the two
      kinds had a correlation of.33. Correlations for total-nevus count (TNC) in 153 MZ
      and 199 DZ twin pairs were.94 and.60, respectively, which are compatible with a
      very-high degree of genetic determination. We hypothesized that some of the
      genetic variance might be due to variation in the p16 gene. Analysis of linkage
      to a highly polymorphic marker (D9S942), located close to p16, detected
      quantitative-trait-loci (QTL) effects accounting for 27% of variance in TNC,
      rising to 33% if flat but not raised moles were considered. Total heritability
      was higher for raised (.69) than for flat (.42) moles, but QTL linkage was 0 for
      raised moles, whereas it accounted for 80% of the heritability of flat moles;
      additionally, family environment accounted for only 15% of variance in raised
      versus 46% in flat moles. These findings suggest that raised and flat nevi have
      very different etiologies. Longer alleles at D9S942 were associated with higher
      flat-mole counts, and a novel modification to a within-sibship association test
      showed that this association is genuine and not due to population stratification,
      although it accounts for only 1% of total variance. Since germline mutations in
      the exons of CDKN2A are rare, it is likely that variants in the noncoding regions
      of this gene, or in another gene nearby, are responsible for this major
      determinant of moliness and, hence, of melanoma risk.

PMID- 10417292
TI  - A genomic screen of autism: evidence for a multilocus etiology.
AB  - We have conducted a genome screen of autism, by linkage analysis in an initial
      set of 90 multiplex sibships, with parents, containing 97 independent affected
      sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing
      50 ASPs. In total, 519 markers were genotyped, including 362 for the initial
      screen, and an additional 157 were genotyped in the follow-up. As a control, we
      also included in the analysis unaffected sibs, which provided 51 discordant sib
      pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial
      phase of the work, we observed increased identity by descent (IBD) in the ASPs
      (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing
      in the ASPs could not be attributed to the effect of a small number of loci but,
      rather, was due to the modest increase in the entire distribution of IBD. These
      results are most compatible with a model specifying a large number of loci
      (perhaps >/=15) and are less compatible with models specifying </=10 loci. The
      largest LOD score obtained in the initial scan was for a marker on chromosome 1p;
      this region also showed positive sharing in the replication family set, giving a
      maximum multipoint LOD score of 2.15 for both sets combined. Thus, there may
      exist a gene of moderate effect in this region. We had only modestly positive or
      negative linkage evidence in candidate regions identified in other studies. Our
      results suggest that positional cloning of susceptibility loci by linkage
      analysis may be a formidable task and that other approaches may be necessary.

PMID- 10417293
TI  - Mitochondrial genetic analyses suggest selection against maternal lineages in
      bipolar affective disorder.
AB  - Previous reports of preferential transmission of bipolar affective disorder (BP)
      from the maternal versus the paternal lines in families suggested that this
      disorder may be caused by mitochondrial DNA mutations. We have sequenced the
      mitochondrial genome in 25 BP patients with family histories of psychiatric
      disorder that suggest matrilineal inheritance. No polymorphism identified more
      than once in this sequencing showed any significant association with BP in
      association studies using 94 cases and 94 controls. To determine whether our BP
      sample showed evidence of selection against the maternal lineage, we determined
      genetic distances between all possible pairwise comparisons within the BP and
      control groups, based on multilocus mitochondrial polymorphism haplotypes. These
      analyses revealed fewer closely related haplotypes in the BP group than in the
      matched control group, suggesting selection against maternal lineages in this
      disease. Such selection is compatible with recurrent mitochondrial mutations,
      which are associated with slightly decreased fitness. Although such mismatch
      distribution comparisons have been used previously for analyses of population
      histories, this is, as far as we are aware, the first report of this method being
      used to study disease.

PMID- 10417294
TI  - mtDNA history of the Cayapa Amerinds of Ecuador: detection of additional founding
      lineages for the Native American populations.
AB  - mtDNA variation in the Cayapa, an Ecuadorian Amerindian tribe belonging to the
      Chibcha-Paezan linguistic branch, was analyzed by use of hypervariable control
      regions I and II along with two linked regions undergoing insertion/deletion
      mutations. Three major maternal lineage clusters fit into the A, B, and C
      founding groups first described by Schurr and colleagues in 1990, whereas a
      fourth lineage, apparently unique to the Cayapa, has ambiguous affinity to known
      clusters. The time of divergence from a common maternal ancestor of the four
      lineage groups is of sufficient age that it indicates an origin in Asia and
      supports the hypothesis that the degree of variability carried by the Asian
      ancestral populations into the New World was rather high. Spatial autocorrelation
      analysis points out (a) statistically significant nonrandom distributions of the
      founding lineages in the Americas, because of north-south population movements
      that have occurred since the first Asian migrants spread through Beringia into
      the Americas, and (b) an unusual pattern associated with the D lineage cluster.
      The values of haplotype and nucleotide diversity that are displayed by the Cayapa
      appear to differ from those observed in other Chibchan populations but match
      those calculated for South American groups belonging to various linguistic
      stocks. These data, together with the results of phylogenetic analysis performed
      with the Amerinds of Central and South America, highlight the difficulty in the
      identification of clear coevolutionary patterns between linguistic and genetic
      relationships in particular human populations.

PMID- 10417296
TI  - Point and interval estimates of marker location in radiation hybrid mapping.
AB  - Radiation hybrid (RH) mapping is a powerful method for ordering loci on
      chromosomes and for estimating the distances between them. RH mapping is
      currently used to construct both framework maps, in which all markers are ordered
      with high confidence (e.g., 1,000:1 relative maximum likelihood), and
      comprehensive maps, which include markers with less-confident placement. To deal
      with uncertainty in the order and location of markers, marker positions may be
      estimated conditional on the most likely marker order, plausible intervals for
      nonframework markers may be indicated on a framework map, or bins of markers may
      be constructed. We propose a statistical method for estimating marker position
      that combines information from all plausible marker orders, gives a measure of
      uncertainty in location for each marker, and provides an alternative to the
      current practice of binning. Assuming that the prior distribution for the
      retention probabilities is uniform and that the marker loci are distributed
      independently and uniformly on an interval of specified length, we calculate the
      posterior distribution of marker position for each marker. The median or mean of
      this distribution provides a point estimate of marker location. An interval
      estimate of marker location may be constructed either by using the 100(alpha/2)
      and 100(1-alpha)/2 percentiles of the distribution to form a 100(1-alpha) %
      posterior credible interval or by calculating the shortest 100(1-alpha) %
      posterior credible interval. These point and interval estimates take into account
      ordering uncertainty and do not depend on the assumption of a particular marker
      order. We evaluate the performance of the estimates on the basis of results from
      simulated data and illustrate the method with two examples.

PMID- 10417295
TI  - Testing the robustness of the likelihood-ratio test in a variance-component
      quantitative-trait loci-mapping procedure.
AB  - Detection of linkage to genes for quantitative traits remains a challenging task.
      Recently, variance components (VC) techniques have emerged as among the more
      powerful of available methods. As often implemented, such techniques require
      assumptions about the phenotypic distribution. Usually, multivariate normality is
      assumed. However, several factors may lead to markedly nonnormal phenotypic data,
      including (a) the presence of a major gene (not necessarily linked to the markers
      under study), (b) some types of gene x environment interaction, (c) use of a
      dichotomous phenotype (i.e., affected vs. unaffected), (d) nonnormality of the
      population within-genotype (residual) distribution, and (e) selective (extreme)
      sampling. Using simulation, we have investigated, for sib-pair studies, the
      robustness of the likelihood-ratio test for a VC quantitative-trait locus
      detection procedure to violations of normality that are due to these factors.
      Results showed (a) that some types of nonnormality, such as leptokurtosis,
      produced type I error rates in excess of the nominal, or alpha, levels whereas
      others did not; and (b) that the degree of type I error-rate inflation appears to
      be directly related to the residual sibling correlation. Potential solutions to
      this problem are discussed. Investigators contemplating use of this VC procedure
      are encouraged to provide evidence that their trait data are normally
      distributed, to employ a procedure that allows for nonnormal data, or to consider
      implementation of permutation tests.

PMID- 10417297
TI  - Genetic analysis of families with Parkinson disease that carry the Ala53Thr
      mutation in the gene encoding alpha-synuclein.

PMID- 10417298
TI  - Mutation of the XNP/ATR-X gene in a family with severe mental retardation,
      spastic paraplegia and skewed pattern of X inactivation: demonstration that the
      mutation is involved in the inactivation bias.

PMID- 10417299
TI  - A 22q11.2 deletion that excludes UFD1L and CDC45L in a patient with conotruncal
      and craniofacial defects.

PMID- 10417300
TI  - De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2
      mutation.

PMID- 10417301
TI  - X chromosome-inactivation patterns confirm the late timing of monoamniotic-MZ
      twinning.

PMID- 10417302
TI  - Refinement of the locus for autosomal recessive Retinitis pigmentosa (RP25)
      linked to chromosome 6q in a family of Pakistani origin.

PMID- 10417303
TI  - Evidence for a BRCA1 founder mutation in families of West African ancestry.

PMID- 10417304
TI  - Power comparisons of the transmission/disequilibrium test and sib
      transmission/disequilibrium-test statistics.

PMID- 10417307
TI  - Effect of CWG methylation on expression of plant genes.
AB  - The presence of two DNA methyltransferases in Pisum raises the possibility that
      they serve different functions. In vitro methylation of CWG sequences in the
      strong cauliflower mosaic virus 35S promoter had no effect on reporter gene
      expression. In contrast, in vitro methylation of CWG sequences in the relatively
      weak, CG-deficient Phaseolus vulgaris rbcS2 promoter inhibited transcription.
      Expression of both constructs was strongly inhibited by extensive CG methylation.
      A search of published plant promoter sequences revealed that the CG content of
      promoters is very variable, with some promoters having typical CG islands. In
      contrast, the distribution of CWG sequences is more even with little evidence for
      CWG islands.

PMID- 10417308
TI  - Functional divergence between the half-sites of the DNA-binding sequence for the
      yeast transcriptional regulator Rap1p.
AB  - The yeast transcriptional regulator Rap1p binds to the DNA consensus sequence
      ACACCCAYACAYYY. We have previously shown that DNA-binding sites in which all four
      Y (Y=T or C) positions were Ts (UASrpg sequences) synergized more efficiently to
      activate transcription than sequences in which all Ys were Cs (telomere
      sequences) [F.-Z. Idrissi, J. Fernandez-Larrea and B. Pina (1998) J. Mol. Biol.
      284, 925-935]. Here we provide evidence that the DNA consensus sequence for Rap1p
      behaves as a combination of two ACAYYY half-sites with different functionality,
      the presence of Ts in the second half-site being the determinant for the
      transcriptional behaviour of the UASrpg sequences. DNA structure in the different
      complexes with Rap1p varied from being relatively uniform to appear rather
      distorted, this also being dependent on the presence of Ts in the second half
      site. These distortions did not cause sharp bends or kinks in the DNA molecule.
      Computer analysis suggests that high-affinity binding of Rap1p to UASrpg
      sequences requires a rearrangement of the C-terminal Myb domain of the protein.
      We propose that the structural alterations in Rap1p-DNA complexes, both in the
      DNA and in the protein, affect the transcription potential of the complex in an
      allosteric manner. We also propose that the dimeric nature of the Rap1 DNA
      binding domain is a key structural feature that explains the disparate functions
      of its DNA-binding sites in vivo.

PMID- 10417309
TI  - Sequencing and functional expression of the malonyl-CoA-sensitive carnitine
      palmitoyltransferase from Drosophila melanogaster.
AB  - Using expressed sequence tag data, we obtained a cDNA for a carnitine
      palmitoyltransferase I (CPT I)-like molecule from Drosophila melanogaster. The
      cDNA encodes a 782-residue protein that shows 49% and 48% sequence identity with
      the rat liver and skeletal-muscle isoforms of CPT I respectively. The sequence
      has two predicted membrane-spanning regions, suggesting that it adopts the same
      topology as its mammalian counterparts. The sequence contains all the residues
      that have been shown to be characteristic of carnitine acetyltransferases.
      Expression in the yeast Pichia pastoris confirmed that the cDNA does encode a CPT
      enzyme. The activity was found to be associated with a mitochondria-enriched
      fraction. Kinetic analysis revealed a K(m) for carnitine of 406 microM and a K(m)
      for palmitoyl-CoA of 105 microM. The CPT activity was very sensitive to
      inhibition by malonyl-CoA, with an IC(50) of 0.74 microM when the activity was
      assayed with 35 microM palmitoyl-CoA and 1% (w/v) albumin at pH 7.0. A histidine
      residue at position 140 in rat liver CPT I has been indicated to be important for
      inhibition by malonyl-CoA. The equivalent residue (position 136) in Drosophila
      CPT I is arginine, implying that any basic residue might be compatible with such
      sensitivity. Evidence is presented that, unlike in mammals, Drosophila has only a
      single CPT I gene. Sequences suggesting the existence of a splice variant in the
      5' untranslated region were found; this was consistent with the existence of two
      promoters for the CPT I gene.

PMID- 10417310
TI  - Factors involved in the duodenal expression of the human calbindin-D9k gene.
AB  - Calbindin-D9k is expressed in the cytoplasm of intestinal cells, where it is
      critical for dietary calcium absorption. Two striking aspects of the expression
      of this gene are its vitamin-D dependency and regional differences in expression,
      with high levels only in duodenum. We report studies of the human calbindin-D9k
      promoter. Differences between the reported sequences of the human calbindin-D9k
      promoter were first clarified before undertaking a functional analysis of this
      sequence. Studies of the rat gene have indicated that several transcription
      factors, including the caudal-related homeobox factor (CDX-2), hepatic nuclear
      factor-4 and CCAAT-enhancer-binding protein alpha (C/EBPalpha), could interact
      with elements in the promoter. Although these elements are conserved in the human
      gene, we show here that their intestinal distribution makes them unlikely to be
      critical positive factors. The calbindin-D9k gene contains multiple potential
      binding sites for homeobox transcription factors; one of these, known as IPF-1 or
      PDX-1, co-localizes in the intestine with calbindin-D9k. We show in gel-shift
      assays that the sequence within a putative vitamin-D-response element in the
      human calbindin-D9k promoter can bind expressed IPF-1/PDX-1 protein, although we
      cannot confirm binding of the vitamin-D-receptor protein. CDX-2 binds to the
      region around the TATA box, as in the rat gene, and may act as a negative factor
      in the distal intestine. Transfection studies in Caco-2 and MCF-7 cells with
      heterologous reporter vectors containing up to 1303 bp of the gene showed that
      this functioned as a weak promoter and indicated the presence of suppressor
      sequences, but did not show vitamin-D responsiveness. This indicates that other
      elements are also needed for the control of human calbindin-D9k expression.

PMID- 10417312
TI  - Differential DNA binding by the androgen and glucocorticoid receptors involves
      the second Zn-finger and a C-terminal extension of the DNA-binding domains.
AB  - The androgen and glucocorticoid hormones evoke specific in vivo responses by
      activating different sets of responsive genes. Although the consensus sequences
      of the glucocorticoid and androgen response elements are very similar, this in
      vivo specificity can in some cases be explained by differences in DNA recognition
      between both receptors. This has clearly been demonstrated for the androgen
      response element PB-ARE-2 described in the promoter of the rat probasin gene.
      Swapping of different fragments between the androgen- and glucocorticoid-receptor
      DNA-binding domains demonstrates that (i) the first Zn-finger module is not
      involved in this sequence selectivity and (ii) that residues in the second Zn
      finger as well as a C-terminal extension of the DNA-binding domain from the
      androgen receptor are required. For specific and high-affinity binding to
      response elements, the DNA-binding domains of the androgen and glucocorticoid
      receptors need a different C-terminal extension. The glucocorticoid receptor
      requires 12 C-terminal amino acids for high affinity DNA binding, while the
      androgen receptor only involves four residues. However, for specific recognition
      of the PB-ARE-2, the androgen receptor also requires 12 C-terminal residues. Our
      data demonstrate that the mechanism by which the androgen receptor binds
      selectively to the PB-ARE-2 is different from that used by the glucocorticoid
      receptor to bind a consensus response element. We would like to suggest that the
      androgen receptor recognizes response elements as a direct repeat rather than the
      classical inverted repeat.

PMID- 10417313
TI  - Functional co-operation between the subunits in heterodimeric platelet-derived
      growth factor receptor complexes.
AB  - To determine the importance of the phosphorylation capacity of receptor kinase as
      well as the ability to serve as docking sites for SH2-domain-containing signal
      transduction molecules, we established pig aortic endothelial cell lines stably
      expressing kinase-active platelet-derived growth factor (PDGF) alpha-receptors
      together with kinase-inactive beta-receptors, and vice versa. After stimulation
      with PDGF-AB, heterodimeric receptor complexes were formed in which the kinase
      inactive receptor was phosphorylated by the kinase-active receptor, although less
      efficiently than in heterodimers of wild-type receptors. The kinase-active
      receptor was only minimally phosphorylated. Thus the phosphorylation within the
      receptor dimer occurred in trans between the components. Analyses of the
      abilities of heterodimeric receptor complexes of one kinase-active and one kinase
      inactive receptor to mediate mitogenicity, chemotaxis and activation of mitogen
      activated protein kinase revealed less efficient effects than those of
      heterodimers of wild-type receptors. Importantly, however, the fact that
      signalling capacities were retained illustrates a functional co-operation between
      the two receptor molecules in the dimer, where one receptor provides a functional
      kinase and the other acts as a substrate and provides docking sites for
      downstream signalling molecules.

PMID- 10417314
TI  - Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus
      laevis oocytes.
AB  - Observations on lactate transport in brain cells and cardiac myocytes indicate
      the presence of a high-affinity monocarboxylate transporter. The rat
      monocarboxylate transporter isoform MCT2 was analysed by expression in Xenopus
      laevis oocytes and the results were compared with the known characteristics of
      lactate transport in heart and brain. Monocarboxylate transport via MCT2 was
      driven by the H(+) gradient over the plasma membrane. Uptake of lactate strongly
      increased with decreasing pH, showing half-maximal stimulation at pH 7.2. A wide
      variety of monocarboxylates and ketone bodies, including lactate, pyruvate, beta
      hydroxybutyrate, acetoacetate, 2-oxoisovalerate and 2-oxoisohexanoate, were
      substrates of MCT2. All substrates had a high affinity for MCT2. For lactate a
      K(m) value of 0.74+/-0.07 mM was determined at pH 7.0. For the other substrates,
      K(i) values between 100 microM and 1 mM were measured for inhibition of lactate
      transport, which is about one-tenth of the corresponding values for the
      ubiquitously expressed monocarboxylate transporter isoform MCT1. Monocarboxylate
      transport via MCT2 could be inhibited by alpha-cyano-4-hydroxycinnamate, anion
      channel inhibitors and flavonoids. It is suggested that cells which express MCT2
      preferentially use lactate and ketone bodies as energy sources.

PMID- 10417311
TI  - Structure and organization of the human antimicrobial peptide LL-37 in
      phospholipid membranes: relevance to the molecular basis for its non-cell
      selective activity.
AB  - The antimicrobial peptide LL-37 belongs to the cathelicidin family and is the
      first amphipathic alpha-helical peptide isolated from human. LL-37 is considered
      to play an important role in the first line of defence against local infection
      and systemic invasion of pathogens at sites of inflammation and wounds.
      Understanding its mode of action may assist in the development of antimicrobial
      agents mimicking those of the human immune system. In vitro studies revealed that
      LL-37 is cytotoxic to both bacterial and normal eukaryotic cells. To gain insight
      into the mechanism of its non-cell-selective cytotoxicity, we synthesized and
      structurally and functionally characterized LL-37, its N-terminal truncated form
      FF-33, and their fluorescent derivatives (which retained structure and activity).
      The results showed several differences, between LL-37 and other native
      antimicrobial peptides, that may shed light on its in vivo activities. Most
      interestingly, LL-37 exists in equilibrium between monomers and oligomers in
      solution at very low concentrations. Also, it is significantly resistant to
      proteolytic degradation in solution, and when bound to both zwitterionic
      (mimicking mammalian membranes) and negatively charged membranes (mimicking
      bacterial membranes). The results also showed a role for the N-terminus in
      proteolytic resistance and haemolytic activity, but not in antimicrobial
      activity. The LL-37 mode of action with negatively charged membranes suggests a
      detergent-like effect via a 'carpet-like' mechanism. However, the ability of LL
      37 to oligomerize in zwitterionic membranes might suggest the formation of a
      transmembrane pore in normal eukaryotic cells. To examine this possibility we
      used polarized attenuated total reflectance Fourier-transform infrared
      spectroscopy and found that the peptide is predominantly alpha-helical and
      oriented nearly parallel with the surface of zwitterionic-lipid membranes. This
      result does not support the channel-forming hypothesis, but rather it supports
      the detergent-like effect.

PMID- 10417316
TI  - Influence of substrates on in vitro dephosphorylation of glycogen phosphorylase a
      by protein phosphatase-1.
AB  - The kinetic theory of the substrate reaction during modification of enzyme
      activity has been applied to a study of the dephosphorylation of phosphorylase a
      by protein phosphatase-1 (ppase-1). On the basis of the kinetic equation of the
      substrate reaction in the presence of ppase-1, all the inactivation rate
      constants for the free enzyme and the enzyme-substrate(s) complexes have been
      determined. Binding of the allosteric substrate, glucose 1-phosphate, to one
      subunit of phosphorylase a protects completely against ppase-1 action on either
      the same subunit or the adjacent subunit, whereas binding of the non-allosteric
      substrate, glycogen, to one subunit protects this subunit partially, but has no
      effect on the modification on the neighbouring subunit. Analysis of the data
      suggests that the allosteric behaviour of phosphorylase a can be interpreted in
      terms of a modified concerted model. The present method also provides a novel
      approach for studying dephosphorylation reactions. Since the experimental
      conditions used resemble more closely the in vivo situation where the substrate
      is constantly being turned over while the enzyme is being modified, this new
      method would be particularly useful when the regulatory mechanism of the
      reversible phosphorylation reaction toward certain enzymes is being assessed.

PMID- 10417315
TI  - Adenylosuccinate synthase from Saccharomyces cerevisiae: homologous
      overexpression, purification and characterization of the recombinant protein.
AB  - Adenylosuccinate synthase (EC 6.3.4.4) catalyses the first committed step in the
      synthesis of adenosine. We have overexpressed the cloned gene of Saccharomyces
      cerevisiae (ADE12) in S. cerevisiae. The recombinant enzyme exhibits similar
      kinetic behaviour to that of the native enzyme purified from S. cerevisiae. This
      ter-reactant dimeric enzyme shows Michaelis-Menten kinetics only with IMP. l
      Aspartate and GTP display a weak negative co-operativity (Hill coefficient 0. 8
      0.9). This negative co-operativity has not yet been reported for adenylosuccinate
      synthases from other organisms. Another unusual feature of the enzyme from S.
      cerevisiae is its negligible inhibition by adenine nucleotides and its pronounced
      inhibition by Cl(-) ions.

PMID- 10417317
TI  - The cartilage-specific (V+C)- fibronectin isoform exists primarily in homodimeric
      and monomeric configurations.
AB  - Fibronectin is an extracellular-matrix glycoprotein encoded by a single gene, but
      with significant protein heterogeneity introduced through alternative RNA
      splicing and post-translational modifications. The (V+C)(-) splice variant, in
      which nucleotides encoding protein segments III-15 and I-10 are deleted along
      with the entire variable region, is unique in that expression is restricted to
      cartilaginous tissues. All known fibronectin splice variants retain the two C
      terminal cysteine residues essential for dimerization, but cellular and/or
      structural constraints appear to influence homo- and heterodimerization patterns.
      Dimerization patterns of the (V+C)(-) isoform were studied under native
      conditions within canine articular cartilage and experimentally in COS-7, NIH-3T3
      and CHO-K1 cell cultures. In all systems, (V+C)(-) fibronectin secretion was
      predominantly in a homodimeric configuration. Lower levels of (V+C)(-) monomers
      were also present. Heterodimers of (V+C)(-) with V(+),C(+) (V120) isoforms were
      not detected. Heterodimers of (V+C)(-) with V(-),C(+) (V0) subunits were detected
      only at low levels. Functional properties may differ significantly among
      monomers, homodimers and heterodimers. The unique dimerization pattern of (V+C)(
      ) fibronectin is consistent with this isoform having specialized functional
      properties in situ that are important for either the structural organization and
      biomechanical properties of cartilage matrix or regulation of a chondrocytic
      phenotype.

PMID- 10417318
TI  - Secretagogue-dependent phosphorylation of phogrin, an insulin granule membrane
      protein tyrosine phosphatase homologue.
AB  - Phogrin, a 60/64 kDa integral membrane protein localized to dense-core secretory
      granules of neuroendocrine cells, was found to be reversibly phosphorylated in
      intact pancreatic beta-cells. Phosphorylation occurred in response to a variety
      of secretory stimuli, including glucose and depolarizing concentrations of K(+).
      In MIN6 cells, the glucose dose-response and time course of phogrin
      phosphorylation paralleled that of insulin secretion. Like secretion, glucose- or
      K(+)-stimulated phosphorylation required the presence of Ca(2+). The calmodulin
      antagonist W-7 and the Ca(2+)/calmodulin-dependent kinase II inhibitor KN-93 dose
      dependently inhibited both phosphorylation and secretion, while the 'inactive'
      analogue KN-92 was effective only at significantly higher concentrations.
      Phosphorylation of phogrin was also stimulated in cells exposed to forskolin, an
      effect presumably mediated by protein kinase A (cAMP-dependent protein kinase).
      Under these conditions, phogrin phosphorylation could be dissociated from the
      secretory response. In MIN6 cells, as in pancreatic islets, cAMP potentiates
      rather than initiates insulin release. Thus our observations are consistent with
      a role for phogrin phosphorylation in the signal-transduction pathway at a site
      proximal to the exocytic event itself, possibly regulating secretory-granule
      mobilization and recruitment to the exocytic site.

PMID- 10417319
TI  - Role of lipid packing in the activity of phospholipase C-delta1 as determined by
      hydrostatic pressure measurements.
AB  - Previous studies with phospholipid monolayers revealed a large decrease in the
      activity of phosphoinositide-specific phospholipase C-delta(1) (PLC-delta(1))
      which catalyses the hydrolysis of PtdIns(4, 5)P(2) as lateral pressure is applied
      to the membrane. If stress on the membrane is the sole inhibitor of PLC-delta(1)
      activity, the enzyme must penetrate the membrane surface to engage its substrate.
      To test the effect on PLC-delta(1) activity of lipid packing in the absence of a
      directional stress, we examined the effects of increasing hydrostatic pressure on
      enzymic activity. We find that, in contrast with monolayer studies, increasing
      lipid packing by hydrostatic pressure does not affect membrane binding and
      increases enzymic activity by 90% in going from atmospheric pressure to 10(8) Pa
      (approx. 1000 atm). The increase in activity could be accounted for mainly by
      electrostriction of water around the multiply-charged product. Our results show
      that when there is no net stress on the monolayer, lipid packing does not alter
      PLC-delta(1) activity, possibly because penetration of the enzyme into the
      membrane surface is shallow. We suggest that, in biological membranes, the
      activity of this and possibly other interfacial proteins is independent of
      headgroup packing.

PMID- 10417320
TI  - Stimulation of glycosylphosphatidylinositol biosynthesis in mammalian cell-free
      systems by GTP hydrolysis: evidence for the involvement of membrane fusion.
AB  - The second step in glycosylphosphatidylinositol (GPI) biosynthesis, the
      deacetylation of GlcNAc-phosphatidylinositol (GlcNAc-PI), has been shown to be
      stimulated by GTP hydrolysis [Stevens (1993) J. Biol. Chem. 268, 9718-9724]. We
      have now developed a system to study this regulation that uses microsomes from
      cells defective in the first step in GPI biosynthesis (class A, C and H lymphoma
      mutants) and the second reaction in the pathway (G9PLAP.85). With this mixed
      microsome system, the deacetylation of GlcNAc-PI was almost completely dependent
      on GTP hydrolysis. Because GlcNAc-PI synthesized by the G9PLAP.85 microsomes
      cannot readily move to the first-step-mutant microsomes to be deacetylated, this
      result indicated that the role of GTP was to facilitate the 'apparent' transfer
      of this substrate between membrane vesicles. The microsomes could be stably
      preactivated by pretreatment with GTP before GPI biosynthesis was initiated,
      indicating that fusion was the most likely mechanism for this regulation. GlcNAc
      PI deacetylation could also be stably preactivated in EL4 microsomes, suggesting
      that fusion also occurred in wild-type membranes. Some differential localization
      of the GlcNAc-PI synthetic and deacetylation activities with the endoplasmic
      reticulum was found. Therefore fusion seems to stimulate GPI biosynthesis in
      mammalian microsomes by bringing together the first two enzymes in the pathway in
      the same membrane vesicle.

PMID- 10417321
TI  - Comparative inhibition by hard and soft metal ions of steroid-binding capacity of
      renal mineralocorticoid receptor cross-linked to the 90-kDa heat-shock protein
      heterocomplex.
AB  - We analysed the inhibitory effects in vitro and in vivo of several metal ions on
      aldosterone binding to the rat kidney mineralocorticoid receptor with the purpose
      of assessing possible toxic effects of those ions on sodium retention, as well as
      to obtain information on receptor structural requirements for ligand binding. For
      the assays in vitro, the inhibitory effects of 20 metal ions were analysed on
      steroid-binding capacity for renal receptor cross-linked to 90-kDa heat-shock
      protein (hsp90) by pretreatment with dimethyl pimelimidate. Cross-linking
      prevented the artifactual dissociation of hsp90 (and, consequently, the loss of
      steroid binding) from the mineralocorticoid receptor due to the presence of high
      concentrations of salt in the incubation medium. Cross-linked heterocomplex
      showed no difference in ligand specificity and affinity with respect to native
      receptor, but increased stability upon thermal- or ionic-strength-induced
      destabilization was observed. Treatments in vitro with metal ions in the range
      10(-8)-10(-1) M resulted in a differential inhibitory effect for each particular
      ion on aldosterone binding. Using the negative logarithm of metal concentration
      for 50% inhibition, the ions could be correlated with their Klopman hardness
      constants. The analysis of this relationship led us to postulate three types of
      reaction: with thiol, imidazole and carboxyl groups. The essential role played by
      these residues in steroid binding was confirmed by chemical modification of
      cysteines with dithionitrobenzoic acid, histidines with diethyl pyrocarbonate and
      acidic amino acids with Woodward's reagent (N-ethyl-5-phenylisoxazolium-3'
      sulphonate). Importantly, the toxic effects of some metal ions were also observed
      by treatments in vivo of adrenalectomized rats on both steroid-binding capacity
      and aldosterone-dependent sodium-retaining properties. We suggest that those
      amino acid residues are involved in the activation process of the
      mineralocorticoid receptor upon steroid binding. Thus toxic effects observed with
      these metal ions may be a consequence of modifications of those essential groups.
      Our results support the notion that toxicity of metals on renal mineralocorticoid
      function may be predicted according to their chemical hardness.

PMID- 10417322
TI  - Roles of calreticulin and calnexin during mucin synthesis in LS180 and HT29/A1
      human colonic adenocarcinoma cells.
AB  - Molecular chaperones are presumed to associate with large secretory mucin
      glycoproteins during their synthesis in the endoplasmic reticulum (ER), but have
      not been identified to date. We decided to look for possible involvement of the
      chaperones calreticulin (CRT) and calnexin (CLN) during synthesis of two similar
      gastrointestinal mucins, MUC2 and MUC5AC. Pulse-chase labelling of MUC2 and
      MUC5AC with [(35)S]methionine/cysteine ([(35)S]Promix) was performed using LS180
      and HT29/A1 colonic carcinoma cell lines and was followed by immunoprecipitation
      with anti-mucin and anti-chaperone antibodies. The precipitated labelled mucin
      precursors were analysed by SDS/PAGE and autoradiography. Using antibodies
      specific for each mucin, newly synthesized monomeric precursors of both MUC2 and
      MUC5AC were detected after a 15 min pulse and then disappeared as oligomers were
      formed during a 2 h chase period. Only homo-oligomers of MUC2 and MUC5AC were
      present in the cells. Using anti-CRT, the MUC2 monomeric precursor and oligomer
      were co-precipitated from both cell lines after a 15 min pulse and the oligomer
      less strongly after a 0.5 h chase, but there was little co-precipitation after a
      2 h chase. At this time, MUC2 immunoprecipitated by anti-MUC2 was completely
      oligomerized and was endo-beta-N-acetylglucosaminidase-resistant, indicating that
      the mucin had reached the Golgi region. MUC2 co-precipitated with CRT at zero
      time and 0.5 h was endo-beta-N-acetylglucosaminidase-sensitive; therefore CRT
      must have associated with MUC2 in the ER. Treatment with tunicamycin (TUN)
      diminished the binding of MUC2 to CRT, suggesting a requirement for initial N
      glycan addition during this process. Using anti-CLN, only a weak co-precipitation
      of MUC2, compared with that seen with anti-CRT, was detected in LS180 cells. In
      contrast with the findings for MUC2, there was no co-precipitation of MUC5AC with
      CRT or CLN from either cell line at the various time points. In conclusion, CRT
      and CLN appear to be involved in MUC2 synthesis at the stage of folding and
      oligomerization in the ER. Since no interaction of the chaperones with MUC5AC was
      detected at a similar stage of synthesis, these two structurally similar
      secretory mucins seem to have different chaperone requirements in the ER.

PMID- 10417324
TI  - Oligomeric self-association of basic fibroblast growth factor in the absence of
      heparin-like glycosaminoglycans.
AB  - Basic fibroblast growth factor (FGF-2) represents a class of heparin-binding
      growth factors that are stored in the extracellular matrix attached to heparin
      like glycosaminoglycans (HLGAGs). It has been proposed that cell surface HLGAGs
      have a central role in the biological activity of FGF-2, presumably by inducing
      dimers or oligomers of FGF-2 and leading to the dimerization or oligomerization
      of FGF receptor and hence signal transduction. We have previously proposed that
      FGF-2 possesses a natural tendency to self-associate to form FGF-2 dimers and
      oligomers; HLGAGs would enhance FGF-2 self-association. Here, through a
      combination of spectroscopic, chemical cross-linking and spectrometric
      techniques, we provide direct evidence for the self-association of FGF-2 in the
      absence of HLGAGs, defying the notion that HLGAGs induce FGF-2 oligomerization.
      Further, the addition of HLGAGs seems to enhance significantly the FGF-2
      oligomerization process without affecting the relative percentages of FGF-2
      dimers, trimers or oligomers. FGF-2 self-association is consistent with FGF-2's
      possessing biological activity both in the presence and in the absence of HLGAGs;
      this leads us to propose that FGF-2 self-association enables FGF-2 to signal both
      in the presence and in the absence of HLGAGs.

PMID- 10417323
TI  - Analysis of DNase-I-hypersensitive sites at the 3' end of the cystic fibrosis
      transmembrane conductance regulator gene (CFTR).
AB  - The cystic fibrosis transmembrane conductance regulator gene (CFTR) exhibits a
      complex pattern of expression that shows temporal and spatial regulation,
      although the control mechanisms are not fully known. We have mapped DNase-I
      hypersensitive sites (DHSs) flanking the CFTR gene with the aim of identifying
      potential regulatory elements. We previously characterized DHSs at -79.5 and 
      20.9 kb with respect to the CFTR translational start site and a regulatory
      element in the first intron of the gene at 185+10 kb. We have now mapped five
      DHSs lying 3' to the CFTR gene at 4574+5.4, +6.8, +7.0, +7.4 and +15.6 kb that
      show some degree of tissue specificity. The DHSs are seen in chromatin extracted
      from human primary epithelial cells and cell lines; the presence of the +15.6 kb
      site is tissue-specific in transgenic mice carrying a human CFTR yeast artificial
      chromosome. Further analysis of the 4574+15.6 kb DHS implicates the involvement
      of CCAAT-enhancer-binding protein (C/EBP), cAMP-response-element-binding protein
      (CREB)/activating transcription factor (ATF) and activator protein 1 (AP-1)
      family transcription factors at this regulatory element.

PMID- 10417325
TI  - Two moles of O2 consumption and one mole of H2O2 formation during cholesterol
      peroxidation with cholesterol oxidase from Pseudomonas sp. strain ST-200.
AB  - Cholesterol oxidase from Pseudomonas sp. strain ST-200 oxidized cholesterol and
      cholestanol to 6beta-hydroperoxycholest-4-en-3-one and 5alpha-cholestan-3-one
      respectively. The former was converted spontaneously to several oxysteroids such
      as 6-hydroxycholest-4-en-3-one and cholest-4-ene-3,6-dione, with the consumption
      of 2 mol of O(2) and the formation of 1 mol of H(2)O(2) for each mole of
      cholesterol oxidized. An oxidized form of the cholesterol oxidase dehydrogenates
      cholesterol, probably to the 5-en-3-one derivative. A reduced form of the enzyme,
      yielded from the cholesterol dehydrogenation reaction, dioxygenated cholest-5-en
      3-one to 6beta-hydroperoxycholest-4-en-3-one.

PMID- 10417326
TI  - Active isoprenoid pathway in the intra-erythrocytic stages of Plasmodium
      falciparum: presence of dolichols of 11 and 12 isoprene units.
AB  - N-glycosylation of proteins is required for the intra-erythrocytic schizogony of
      Plasmodium falciparum. In eukaryotic cells, this process involves the transfer of
      oligosaccharides from a dolichyl pyrophosphate derivative to asparagine residues.
      We have identified dolichol, dolichyl phosphate and dolichyl pyrophosphate
      species of 11 and 12 isoprenoid residues by metabolic labelling with
      [(3)H]farnesyl pyrophosphate, [(3)H]geranylgeranyl pyrophosphate and
      [(14)C]acetate in the different intra-erythrocytic stages of P. falciparum. This
      is the first demonstration of short-chain dolichols in the phylum Apicomplexa.
      The results demonstrate the presence of an active isoprenoid pathway in the intra
      erythrocytic stages of P. falciparum. Parasites treated with mevastatin, a 3
      hydroxy-3-methylglutaryl-CoA reductase inhibitor, show depressed biosynthesis of
      dolichol, dolichyl phosphate and isoprenoid pyrophosphate. This effect is
      observed in all intra-erythrocytic stages of the parasite life cycle, but is most
      pronounced in the ring stage. N-linked glycosylation of proteins was inhibited in
      the ring and young-trophozoite stages after mevastatin treatment of parasite
      cultures. Therefore the isoprenoid pathway may represent a different approach to
      the development of new anti-malarial drugs.

PMID- 10417327
TI  - Apolipoprotein B mRNA and lipoprotein secretion are increased in McArdle RH-7777
      cells by expression of betaine-homocysteine S-methyltransferase.
AB  - The cDNA encoding rat betaine-homocysteine S-methyltransferase (BHMT) was
      isolated through production of monoclonal antibodies against protein fractions
      enriched with apolipoprotein B (apo B)-mRNA-editing complexes. BHMT mRNA was
      expressed predominantly in liver, and also in kidney, but not in small intestine.
      In stable McArdle RH-7777 (McA) cell lines expressing differing levels of BHMT,
      the editing efficiency of apo B mRNA was unchanged. Evaluation of apo B-mRNA
      expression revealed that steady-state levels were increased significantly and in
      parallel with BHMT protein expression. The highest levels of BHMT mRNA and BHMT
      enzyme activity expressed in stably transfected McA cells were comparable with
      those found in rat hepatocytes. In contrast to the changes in apo B-mRNA
      abundance, levels of other apolipoprotein-encoding mRNAs and several liver
      specific and ubiquitously expressed mRNAs were unchanged by BHMT expression. In
      the cell line expressing the highest level of BHMT, apo B-containing lipoprotein
      secretion was increased, indicating utilization of increased endogenous message.
      Results suggest that apo B-mRNA abundance in McA cells is related to the
      expression of BHMT, an enzyme important in homocysteine metabolism.

PMID- 10417328
TI  - Specific inhibition of skeletal alpha-actin gene transcription by applied
      mechanical forces through integrins and actin.
AB  - Skeletal alpha-actin (skA), a prominent fetal actin isoform that is re-expressed
      by adult cardiac myocytes after chronic overload in vivo, provides a model for
      studying cytoskeletal gene regulation by mechanical forces in vitro. We have
      determined the mechanisms by which perpendicular applied forces acting through
      integrins and the actin cytoskeleton regulate the expression of skA. Rat-2
      fibroblasts were transiently transfected with plasmids containing 5'-regulatory
      regions of the skA gene fused to luciferase coding sequences. A constant,
      perpendicular force (0.2 pN/micrometer(2)) was applied by using a collagen
      magnetic bead model; a 25% deformation was obtained on the dorsal cell surface.
      In this system, force is applied through focal adhesion integrins and strongly
      induces actin assembly [Glogauer, Arora, Yao, Sokholov, Ferrier and McCulloch
      (1997) J. Cell Sci. 110, 11-21]. skA promoter activity was inhibited by 68% in
      cells subjected to 4 h of applied force, whereas Rous sarcoma virus promoter
      activity was unaffected. In cells transiently transfected with a skA expression
      vector there was also a parallel 40% decrease in skA protein levels by force, as
      shown by Western blotting. In L8 cells, constitutive skA expression was decreased
      by more than 50%. Analyses of specific motifs in the skA promoter revealed that
      transcriptional enhancer factor 1 and Yin and Yang 1 sites, but not serum
      response factor and Sp1 sites, mediated inhibitory responses to force. In cells
      treated with cycloheximide the force-induced inhibition was abrogated, indicating
      a dependence on new protein synthesis. Inhibition of actin filament assembly with
      either cytochalasin D or Ca(2+)-depleted medium blocked the inhibitory effect
      induced by the applied force, suggesting that actin filaments are required for
      the regulation of skA promoter activity. Western blot analysis showed that p38
      kinase, but not Jun N-terminal kinase or extracellular signal-regulated protein
      kinase 1/2, was activated by force; indeed, the p38 kinase inhibitor SB203580
      relieved the force-induced inhibition of skA. We conclude that the force-induced
      inhibition of skA promoter activity requires an intact actin cytoskeleton and can
      be mapped to two different response elements. This inhibition might be mediated
      through the p38 kinase.

PMID- 10417329
TI  - Protein and gene structure of a blue laccase from Pleurotus ostreatus1.
AB  - A new laccase isoenzyme (POXA1b, where POX is phenol oxidase), produced by
      Pleurotus ostreatus in cultures supplemented with copper sulphate, has been
      purified and fully characterized. The main characteristics of this protein
      (molecular mass in native and denaturing conditions, pI and catalytic properties)
      are almost identical to the previously studied laccase POXA1w. However, POXA1b
      contains four copper atoms per molecule instead of one copper, two zinc and one
      iron atom per molecule of POXA1w. Furthermore, POXA1b shows an unusually high
      stability at alkaline pH. The gene and cDNA coding for POXA1b have been cloned
      and sequenced. The gene coding sequence contains 1599 bp, interrupted by 15
      introns. Comparison of the structure of the poxa1b gene with the two previously
      studied P. ostreatus laccase genes (pox1 and poxc) suggests that these genes
      belong to two different subfamilies. The amino acid sequence of POXA1b deduced
      from the cDNA sequence has been almost completely verified by means of matrix
      assisted laser desorption ionization MS. It has been demonstrated that three out
      of six putative glycosylation sites are post-translationally modified and the
      structure of the bound glycosidic moieties has been determined, whereas two other
      putative glycosylation sites are unmodified.

PMID- 10417330
TI  - APS, an adapter protein with a PH and SH2 domain, is a substrate for the insulin
      receptor kinase.
AB  - APS (adapter protein with a PH and SH2 domain) is the newest member of a family
      of tyrosine kinase adapter proteins including SH2-B and Lnk. We previously
      identified SH2-B as an insulin-receptor-binding protein and substrate [Kotani,
      Wilden and Pillay (1998) Biochem J. 335, 103-109]. Here we show that APS
      interacts with the insulin receptor kinase activation loop through its SH2 domain
      and insulin stimulates the tyrosine-phosphorylation of APS. Furthermore, the
      phosphorylation of activation-loop tyrosine residues 1158 and 1162 are required
      for this interaction.

PMID- 10417331
TI  - The final step of pantothenate biosynthesis in higher plants: cloning and
      characterization of pantothenate synthetase from Lotus japonicus and Oryza
      sativum (rice).
AB  - We have isolated a Lotus japonicus cDNA for pantothenate (vitamin B(5))
      synthetase (PS) by functional complementation of an Escherichia coli panC mutant
      (AT1371). A rice (Oryza sativum) expressed sequence tag, identified by sequence
      similarity to PS, was also able to complement the E. coli auxotroph, as was an
      open reading frame from Saccharomyces cerevisiae (baker's yeast). The Lotus and
      rice cDNAs encode proteins of approx. 34 kDa, which are 65% similar at the amino
      acid level and do not appear to encode N-terminal extensions by comparison with
      PS sequences from other organisms. Furthermore, analysis of genomic sequence
      flanking the coding sequence for PS in Lotus suggests the original cDNA is full
      length. The Lotus and rice PSs are therefore likely to be cytosolic. Southern
      analysis of Lotus genomic DNA indicates that there is a single gene for PS.
      Recombinant PS from Lotus, overexpressed in E. coli AT1371, is a dimer. The
      enzyme requires d-pantoate, beta-alanine and ATP for activity and has a higher
      affinity for pantoate (K(m) 45 microM) than for beta-alanine (K(m) 990 microM).
      Uncompetitive substrate inhibition becomes significant at pantoate concentrations
      above 1 mM. The enzyme displays optimal activity at about 0.5 mM pantoate (k(cat)
      0.63 s(-1)) and at pH 7.8. Neither oxopantoate nor pantoyl-lactone can replace
      pantoate as substrate. Antibodies raised against recombinant PS detected a band
      of 34 kDa in Western blots of Lotus proteins from both roots and leaves. The
      implications of these findings for pantothenate biosynthesis in plants are
      discussed.

PMID- 10417332
TI  - Characterization of a human MHC class III region gene product with S-thioesterase
      activity.
AB  - Palmitoylated proteins contain a 16-carbon saturated fatty acyl group that is
      post-translationally attached by a labile thioester bond. These modified proteins
      are mainly membrane-bound; the lability of the thioester bond allows the process
      to be reversible, a unique property of this modification. We report here that the
      gene for G14, located in the class III region of the human MHC, encodes a
      polypeptide with significant sequence similarity to mammalian palmitoyl protein
      thioesterase (PPT1), an enzyme that removes palmitate from palmitoylated
      proteins. The gene for G14, also known as PPT2, is transcribed as at least five
      different transcripts, which are expressed in different cell lines of the immune
      system. Immunoprecipitation of these mammalian cells, with an anti-G14 antiserum,
      showed a specific band of approx. 42 kDa in cell extracts and supernatants.
      Expression of the G14 cDNA in the baculovirus system revealed that it encoded a
      secreted glycosylated polypeptide with S-thioesterase activity. The enzymic
      activity of the recombinant G14 protein was further characterized in quantitative
      spectrophotometric assays, which revealed that it had the highest S-thioesterase
      activity for the acyl groups palmitic and myristic acid followed by other long
      chain acyl substrates. The S-thioesterase activity of the G14 protein was found
      to be considerably higher in supernatants than in cell extracts, which was
      consistent with the protein's being secreted. The G14 polypeptide contains, in
      addition to an N-terminal lipase domain, a C-terminal domain common to the
      cytokine receptor superfamily, which might determine the substrate specificity
      and/or the protein target of the G14 protein.

PMID- 10417333
TI  - Extracellular signal-regulated protein kinase (ERK)-dependent and ERK-independent
      pathways target STAT3 on serine-727 in human neutrophils stimulated by
      chemotactic factors and cytokines.
AB  - STAT3 (signal transducer and activator of transcription 3) is a latent
      transcription factor that is activated by tyrosine phosphorylation (Tyr-705) in
      cells stimulated with cytokines or growth factors. Recent studies suggest that
      one or more cytoplasmic serine kinases also phosphorylate STAT3 and are necessary
      for maximal gene activation. Here we demonstrate, with a site-specific antibody,
      that STAT3 is phosphorylated on Ser-727 in human neutrophils stimulated with
      chemotactic factors (N-formyl-methionyl-leucyl-phenylalanine and complement C5a),
      cytokines [granulocyte/macrophage colony-stimulating factor (GM-CSF) and
      granulocyte colony-stimulating factor (G-CSF)], or a protein kinase C activator
      (PMA). (2-Amino-3'-methoxyphenyl)oxanaphthalen-4-one (PD 98059), an inhibitor of
      extracellular signal-regulated protein kinase (ERK) activation, blocked the
      serine phosphorylation of STAT3 induced by chemotactic factors or PMA. The drug
      was less effective on cytokines: it virtually abolished the response to GM-CSF
      that occurred 5 min after stimulation but only partly decreased those at 15-30
      min and did not appreciably alter responses to G-CSF regardless of incubation
      time. 1-(5-Isoquinolinylsulphonyl)-2-methylpiperazine dihydrochloride (H7), an
      inhibitor of a putative STAT3 serine kinase, and 4-(4-fluorophenyl)-2-(4
      methylsulphinylphenyl)-5-(4-pyridyl) 1H-imidazole (SB 203580), an inhibitor of
      p38 mitogen-activated protein (MAP) kinase, did not dampen any of these serine
      phosphorylation responses. We propose that neutrophils use both ERK-dependent and
      ERK-independent pathways to phosphorylate Ser-727 on STAT3. The former pathway is
      recruited by all ERK-activating stimuli, whereas the latter pathway uses an
      undefined serine kinase and is recruited selectively by cytokines.

PMID- 10417334
TI  - Regulation of cerebellar Ins(1,4,5)P3 receptor by interaction between
      Ins(1,4,5)P3 and Ca2+.
AB  - We have characterized in detail the Ca(2+)-dependent inhibition of
      [(3)H]Ins(1,4,5)P(3) ([(3)H]InsP(3)) binding to sheep cerebellar microsomes, over
      a short duration (3 s), with the use of a perfusion protocol. This procedure
      prevented artifacts previously identified in studies of this Ca(2+) effect. In a
      cytosol-like medium at pH 7.1 and 20 degrees C, a maximal inhibition of approx.
      50% was measured. Both inhibition and its reversal were complete within 3 s.
      Ca(2+) decreased the affinity of the receptor for InsP(3) by approx. 50% (K(d)
      146+/-24 nM at pCa 9 and 321+/-56 nM at pCa 5.3), without changing the total
      number of binding sites. Conversely, increasing the [(3)H]InsP(3) concentration
      from 30 to 400 nM tripled the IC(50) for Ca(2+) and decreased the maximal
      inhibition by 63%. This is similar to a partial competitive inhibition between
      InsP(3) binding and inhibitory Ca(2+) binding and is consistent with InsP(3) and
      Ca(2+) converting InsP(3) receptor into two different states with different
      affinities for these ligands. Mn(2+) and Sr(2+) also inhibited [(3)H]InsP(3)
      binding but were respectively only 1/10 and 1/200 as effective as Ca(2+). No
      inhibition was observed with Ba(2+). This selectivity is the same as that
      previously reported for the inhibitory Ca(2+) site of InsP(3)-induced Ca(2+)
      flux, suggesting that the same site is used by Ca(2+) to convert cerebellar
      InsP(3) receptor to a low-affinity state and to inhibit its channel activity. Our
      results also suggest a mechanism by which InsP(3) counteracts this Ca(2+)
      dependent inhibition.

PMID- 10417335
TI  - The purified and reconstituted ornithine/citrulline carrier from rat liver
      mitochondria catalyses a second transport mode: ornithine+/H+ exchange.
AB  - The mechanism of unidirectional transport of ornithine (i.e. in the absence of a
      counter-metabolite) has been investigated in proteoliposomes reconstituted with
      the ornithine carrier purified from rat liver mitochondria. The efflux of
      [(3)H]ornithine from proteoliposomes was stimulated by the addition of H(+) (but
      not of other cations) to the incubation medium. On keeping the pH in the
      compartment containing ornithine constant at 8.0, the flux of ornithine into or
      out of the proteoliposomes increased on decreasing the pH in the opposite
      compartment from 8.0 to 6.0. Ornithine influx was also stimulated when a higher
      H(+) concentration was generated inside the vesicles relative to the outside by
      the K(+)/H(+) exchanger nigericin in the presence of an outwardly directed K(+)
      gradient. A valinomycin-induced electrogenic flux of K(+) did not affect
      ornithine transport in the absence of a counter-metabolite. Furthermore, changes
      in fluorescence of the pH indicator pyranine, included inside the
      proteoliposomes, showed that the flux of ornithine is accompanied by
      translocation of H(+) in the opposite direction. It is concluded that the
      mitochondrial ornithine carrier catalyses an electroneutral exchange of
      ornithine(+) for H(+), in addition to the well-known 1:1 exchange of metabolites.
      Lysine(+), but not citrulline, can also be exchanged for H(+) by the ornithine
      carrier. The ornithine(+)/H(+) transport mode of the exchanger is an essential
      step in the catabolism of excess arginine.

PMID- 10417336
TI  - Identification and characterization of an intracellular protein complex that
      binds fibroblast growth factor-2 in bovine brain.
AB  - The fibroblast growth factor (FGF) family is composed of polypeptides with
      sequence identity which signal through transmembrane tyrosine kinase receptors.
      We report here the purification from bovine brain microsomes of an FGF-2-binding
      complex composed of three proteins of apparent molecular masses 150 kDa, 79 kDa
      and 46 kDa. Only the 150 kDa and 79 kDa proteins bound FGF-2 in cross-linking and
      ligand-blotting experiments. Binding of FGF-2 to p79 is enhanced in the presence
      of calcium. Peptide sequences allowed the identification of p150 and the cloning
      of the cDNAs encoding p79 and p46. The deduced amino acid sequence of p79 reveals
      high similarity to those of gastrin-binding protein and mitochondrial enoyl-CoA
      hydratase/hydroxyacyl-CoA dehydrogenase. p46 is similar to mitochondrial ketoacyl
      CoA thiolase. Stable transfection of FR3T3 rat fibroblast cells with p79 cDNA
      analysed by electron microscopy following immunolabelling of ultra-thin
      cryosections revealed a localization of p79 in the secretory pathway, mainly in
      the endoplasmic reticulum and the Golgi region, where it is specifically
      associated with the molecular chaperone calnexin. In vivo a protein similar to
      the Golgi protein MG-160 forms a complex with FGF-2 and p79.

PMID- 10417338
TI  - Cloning of a galactose-binding lectin from the venom of Trimeresurus stejnegeri.
AB  - A galactose-binding lectin isolated from the venom of Trimeresurus stejnegeri is
      a homodimer C-type lectin. The cloned cDNA encoding the monomer of Trimeresurus
      stejnegeri lectin (TSL) was sequenced and found to contain a 5'-end non-coding
      region, a sequence which encodes 135 amino acids, including a typical 23 amino
      acid signal peptide followed by the mature protein sequence, a 3'-end non-coding
      region, a polyadenylation signal, and a poly(A) region. To completely
      characterize the deduced amino acid sequence, on-line HPLC-MS and tandem MS were
      used to analyse the intact monomer and its proteolytic peptides. A modified
      peptide fragment was also putatively identified by HPLC-MS analysis. The deduced
      amino acid sequence was found to contain a carbohydrate-recognition domain
      homologous with those of some known C-type animal lectins. Thus TSL belongs to
      group VII of the C-type animal lectins as classified by Drickamer [(1993) Prog.
      Nucleic Acid Res. Mol. Biol. 45, 207-232]. At present, a number of C-type lectins
      have been purified from snake venom, but most of them have been characterized
      only at the protein level. To our knowledge, this is the first known cDNA
      sequence of a true C-type lectin from snake venom.

PMID- 10417337
TI  - An unusual case of 'uncompetitive activation' by ascorbic acid: purification and
      kinetic properties of a myrosinase from Raphanus sativus seedlings.
AB  - Myrosinase (thioglucoside glucohydrolase; EC 3.2.3.1) is a plant enzyme that
      hydrolyses glucosinolates, principally to isothiocyanates. Myrosinase was
      purified to homogeneity in good yield from 8-day-old seedlings of Raphanus
      sativus (daikon) using a four-step procedure involving chromatographies on anion
      exchange, hydrophobic Phenyl-Sepharose, gel filtration and concanavalin A
      Sepharose. In order to stabilize the enzyme and to avoid excessive peak
      broadening during chromatography, 30% (v/v) glycerol was added to dialysis and
      chromatography buffers. The purified enzyme was eluted as a single peak from a
      gel-filtration sizing column with an apparent molecular mass of 120 kDa. The
      enzyme was resolved into two subunits with molecular masses of 61 and 62 kDa by
      SDS/PAGE. Ascorbic acid activated the purified enzyme more than 100-fold. The
      V(max) and K(m) values for the hydrolysis of allyl glucosinolate (sinigrin) were
      2.06 micromol/min per mg of protein and 23 microM in the absence of ascorbate and
      280 micromol/min per mg of protein and 250 microM in the presence of 500 microM
      ascorbate, respectively. As the ascorbate concentration was increased from 50 to
      500 microM, the V(max) and K(m) values increased in parallel, and thus the
      V(max)/K(m) ratio remained constant. Similarly, raising the concentrations of
      sinigrin increased the concentration of ascorbic acid required for half-maximal
      activation (K(a)). At a sinigrin concentration of 250 microM, the K(a) for
      ascorbic acid was 55 microM. Sulphate, a reaction product, was a competitive
      inhibitor of activity, having a K(i) of 60 mM with respect to sinigrin and of 27
      mM with respect to ascorbate. Thus activation of myrosinase from R. sativus by
      ascorbic acid exemplifies an unusual and possibly unique example of linear
      'uncompetitive activation' (i.e. a proportionate increase in V(max) and K(m)) of
      an enzyme. The enzyme also had beta-glucosidase activity and hydrolysed p
      nitrophenyl-beta-d-glucopyranoside.

PMID- 10417339
TI  - Fibrinogen up-regulates the expression of monocyte chemoattractant protein 1 in
      human saphenous vein endothelial cells.
AB  - High concentrations of fibrinogen in plasma have been associated with an
      increased risk of saphenous vein graft pathology. We have investigated the
      ability of fibrinogen to up-regulate the expression of monocyte chemoattractant
      protein 1 (MCP-1) in cultured human saphenous vein endothelial cells (HSVEC)
      isolated from saphenous vein. Increasing concentrations of fibrinogen (0-4
      microM) stimulated a 20-fold increase in MCP-1 secretion within 4 h. Incubation
      of HSVEC with 2 microM fibrinogen for 4 h also caused a 2-fold increase in the
      MCP-1-to-glyceraldehyde-3-phosphate dehydrogenase mRNA ratio. The fibrinogen
      mediated MCP-1 secretion fell to basal levels after preincubation of HSVEC with
      the complex of fibrinogen fragments D and E but remained unchanged after
      preincubation of HSVEC with either fibrinogen fragment E, s-ICAM-1 or the
      pentapeptide GRGDV. In contrast, fibrinogen fragment D acted as a potent
      inhibitor of fibrinogen-mediated MCP-1 secretion. Labelled fibrinogen fragment D
      bound to HSVEC with a K(d) of 6.5 microM. These findings indicate that
      fibrinogen, at physiological concentrations, uses an epitope on the fibrinogen D
      domain to bind to a receptor on HSVEC to up-regulate MCP-1 expression and
      secretion. This receptor seems to be distinct from intercellular adhesion
      molecule 1 and the integrins previously recognized as fibrinogen receptors.

PMID- 10417341
TI  - Spectral characterization and chemical modification of FMN-containing ascorbyl
      free-radical reductase from Pleurotus ostreatus.
AB  - Ascorbyl free-radical reductase was purified 1143-fold with an overall yield of
      9.9% from the cytosolic fraction of Pleurotus ostreatus. The native enzyme had a
      molecular mass of 127 kDa and SDS/PAGE revealed that the enzyme consists of two
      subunits, each with a molecular mass of 62 kDa. The enzyme utilized only NADH as
      an electron donor. The enzyme was highly specific for ascorbyl free radical as an
      electron acceptor and capable of catalysing the reduction of ferricyanide and 2,6
      dichloroindophenol as artificial electron acceptors. The apparent K(m) values of
      the enzyme towards NADH and ascorbyl free radical were 35+/-0.22 and 2.1+/-0.03
      microM, respectively. The catalytic mechanism of this enzyme is of Ping Pong
      type. The enzyme contained FMN as a prosthetic group and showed the
      characteristic absorption spectrum ascribed to the charge-transfer interaction of
      thiolate anion with FMN. The enzyme contained eight cysteine residues per monomer
      and was inactivated more rapidly by mercurials than by thiol-alkylating reagents.
      Kinetic analysis of the inactivation process revealed that the enzyme had 1 mol
      of thiol group/mol of subunit in the active site with a pK(a) of 6.9. The
      modification of the thiol group of the enzyme caused the loss of charge-transfer
      absorbance centred at 540 nm and blocked the electron-transfer process from NADH
      to FMN. The modification of lysine, arginine and histidine residues led to the
      loss of its activity. Unlike the active enzyme, the fluorescence quenching of
      NADH was not observed in the lysine-modified enzyme, which implies that lysine
      residues can participate in the interaction with NADH.

PMID- 10417340
TI  - Measurement of perimitochondrial Ca2+ concentration in bovine adrenal glomerulosa
      cells with aequorin targeted to the outer mitochondrial membrane.
AB  - Microdomains of high cytosolic free Ca(2+) concentration in the proximity of
      mitochondria might have an important role in the stimulation of steroidogenesis
      in bovine adrenal glomerulosa cells. In the present study we have investigated
      local changes of free Ca(2+) concentration near the outer mitochondrial membrane
      ([Ca(2+)](om)) under stimulation with angiotensin II (Ang II) and K(+).
      Glomerulosa cells in primary culture were transfected with a recombinant cDNA
      encoding the N-terminal region of the human translocase protein 20 of the outer
      mitochondrial membrane, in frame with the Ca(2+)-sensitive photoprotein aequorin.
      This chimaeric aequorin (TomAeq) was associated with mitochondria-enriched
      subcellular fractions of transfected COS-7 cells and was susceptible to
      proteinase K, showing that it was targeted to the outer mitochondrial membrane,
      facing the cytosolic space. In bovine adrenal glomerulosa cells transfected with
      TomAeq cDNA, Ang II induced a transient [Ca(2+)](om) peak reaching 1.42+/-0.28
      microM, which decreased immediately to the basal resting value. The peak response
      to Ang II was strikingly lower than the peak response of mitochondrial free
      Ca(2+) concentration, which increased to 5.4+/-1.2 microM. The smaller response
      of [Ca(2+)](om) to Ang II compared with the elevated matrix response did not
      result from buffering effects of the organelle, from altered mechanisms of
      intramitochondrial Ca(2+) transport or from differences in the affinity of the
      chimaeric aequorins for Ca(2+). This approach has allowed us to follow
      perimitochondrial Ca(2+) homeostasis in bovine glomerulosa cells under
      stimulation with Ca(2+)-mobilizing agonists and to reveal a strong gradient of
      Ca(2+) concentration between the mitochondrial matrix and the immediate
      environment of the organelle.

PMID- 10417342
TI  - Autocrine regulation of growth stimulation in human epithelial ovarian carcinoma
      by serine-proteinase-catalysed release of the urinary-type-plasminogen-activator
      N-terminal fragment.
AB  - Ovarian carcinomas secrete single-chain urinary-type plasminogen activator
      (scuPA) and expression of uPA is up-regulated relative to normal ovarian
      epithelium, leading to an enhanced proteolytic capacity which may facilitate
      invasion. Furthermore, the uPA receptor (uPAR) is present on ovarian carcinoma
      cells and is occupied in tumour tissues. In the present study, incubation of
      scuPA with serum-free conditioned medium from ovarian carcinoma cells resulted in
      release of a 14 kDa polypeptide. N-terminal sequence analysis identified this
      fragment as the uPA N-terminal fragment (NTF), which contains a growth-factor and
      a kringle domain. NTF generation was abolished by serine-proteinase inhibitors,
      but not inhibitors of matrix metalloproteinases, and was not enhanced by the
      addition of plasminogen or plasmin. To determine whether ovarian carcinoma-cell
      growth is altered by uPA, the effect of exogenous scuPA or NTF on proliferation
      was analysed. Both NTF and scuPA induced a dose-dependent increase in
      proliferation, with maximal stimulation obtained at 10-20 nM. Furthermore,
      blocking the interaction of endogenous uPA with uPAR using anti-NTF antibodies
      significantly inhibited proliferation. Together these data indicate that, in
      addition to enhancing the invasive activity of ovarian carcinoma cells via
      increased pericellular proteolysis, uPA also acts as a mitogen for ovarian
      carcinoma cells, suggesting a biochemical mechanism whereby uPA may contribute to
      ovarian carcinoma progression by modulating both cell invasion and proliferation.

PMID- 10417343
TI  - Transcripts encoding the sperm surface protein tMDC II are non-functional in the
      human.
AB  - Five members of the MDC (metalloproteinase-like,disintegrin-like cysteine-rich
      domain) family of proteins (fertilin alpha, fertilin beta, tMDC I, tMDC II and
      tMDC III) are expressed on the surface of macaque (Macaca fascicularis) sperm,
      where they have been proposed to play a role in sperm-egg binding via an
      interaction between their disintegrin-like domain and one or more integrins on
      the egg plasma membrane. Of these, two (fertilin alpha and tMDC I) have recently
      been shown to be non-functional in the human. Here we report the existence of
      multiple isoforms of human tMDC II transcripts in the human, all of which are
      also non-functional owing to the presence of deletions and in-frame termination
      codons, when compared with the macaque orthologue, a finding which is further
      supported by the lack of immunoreactivity on Western blots of human testis and
      sperm extracts probed with a macaque anti-tMDC II polyclonal antiserum. These
      results are discussed in the context of our proposed model for multiple proteins
      implicated in sperm-egg interactions.

PMID- 10417344
TI  - Cytological evidence that the C-terminus of carnitine palmitoyltransferase I is
      on the cytosolic face of the mitochondrial outer membrane.
AB  - Carnitine palmitoyltransferase I (CPT I) is a key enzyme in the regulation of
      beta-oxidation. The topology of this enzyme has been difficult to elucidate by
      biochemical methods. We studied the topology of a fusion protein of muscle-type
      CPT I (M-CPT I) and green fluorescent protein (GFP) by microscopical means. To
      validate the use of the fusion protein, designated CPT I-GFP, we checked whether
      the main characteristics of native CPT I were retained. CPT I-GFP was expressed
      in HeLa cells after stable transfection. Confocal laser scanning microscopy in
      living cells revealed an extranuclear punctate distribution of CPT I-GFP, which
      coincided with a mitochondrial fluorescent marker. Immunogold electron microscopy
      localized CPT I-GFP almost exclusively to the mitochondrial periphery and showed
      that the C-terminus of CPT I must be on the cytosolic face of the mitochondrial
      outer membrane. Western analysis showed a protein that was 6 kDa smaller than
      predicted, which is consistent with previous results for the native M-CPT I.
      Mitochondria from CPT I-GFP-expressing cells showed an increased CPT activity
      that was inhibited by malonyl-CoA and was lost on solubilization with Triton X
      100. We conclude that CPT I-GFP adopts the same topology as native CPT I and that
      its C-terminus is located on the cytosolic face of the mitochondrial outer
      membrane. The evidence supports a recently proposed model for the domain
      structure of CPT I based on biochemical evidence.

PMID- 10417345
TI  - Solution structure of a defensin-like peptide from platypus venom.
AB  - Three defensin-like peptides (DLPs) were isolated from platypus venom and
      sequenced. One of these peptides, DLP-1, was synthesized chemically and its three
      dimensional structure was determined using NMR spectroscopy. The main structural
      elements of this 42-residue peptide were an anti-parallel beta-sheet comprising
      residues 15-18 and 37-40 and a small 3(10) helix spanning residues 10-12. The
      overall three-dimensional fold is similar to that of beta-defensin-12, and
      similar to the sodium-channel neurotoxin ShI (Stichodactyla helianthus neurotoxin
      I). However, the side chains known to be functionally important in beta-defensin
      12 and ShI are not conserved in DLP-1, suggesting that it has a different
      biological function. Consistent with this contention, we showed that DLP-1
      possesses no anti-microbial properties and has no observable activity on rat
      dorsal-root-ganglion sodium-channel currents.

PMID- 10417348
TI  - Enhanced purinoceptor-mediated Ca2+ signalling in L-fibroblasts overexpressing
      type 1 inositol 1,4,5-trisphosphate receptors.
AB  - Mouse L-fibroblast cells stably transfected with either type 1 Ins(1, 4,5)P(3)
      receptor (InsP(3)R) cDNA (L15) or the vector control (Lvec) have been used to
      investigate the functional consequences of increased InsP(3)R density on receptor
      mediated Ca(2+) signalling. L15 cells express approx. 8-fold higher levels of the
      type 1 InsP(3)R compared with Lvec cells, which endogenously express essentially
      only the type 1 InsP(3)R protein. Stimulation of Lvec and L15 cells with UTP or
      ATP increased cytosolic Ca(2+) concentration to a greater extent in L15 cells at
      all agonist concentrations. UTP and ATP were equipotent, suggestive of the
      presence of endogenous cell-surface metabotropic P2Y(2)-purinoceptors. In both
      cell clones the purinoceptors were coupled via pertussis-toxin-insensitive G
      protein(s) to phospholipase C activation, resulting in similar concentration
      dependent accumulations of InsP(3). Single-cell microfluorimetry revealed that
      overexpression of InsP(3)Rs reduced the threshold for purinoceptor-mediated
      Ca(2+) signalling. L-fibroblasts also exhibited temporally complex sinusoidal
      cytosolic Ca(2+) oscillations in response to submaximal agonist concentrations,
      with significant increases in oscillatory frequencies exhibited by cells
      overexpressing InsP(3)Rs. Sustainable oscillatory responses were dependent on
      Ca(2+) entry and, at higher agonist concentrations, cytosolic Ca(2+) oscillations
      were superseded by biphasic peak-and-plateau Ca(2+) responses. Overexpression of
      InsP(3)Rs in L15 cells resulted in a 4-fold reduction in the threshold for this
      change in the temporal pattern of Ca(2+) mobilization. These data provide the
      first direct evidence demonstrating that altering the expression of the type 1
      InsP(3)R significantly affects receptor-mediated InsP(3)-induced Ca(2+)
      mobilization.

PMID- 10417346
TI  - Co-expression of metabotropic glutamate receptor type 1alpha with homer-1a/Vesl
      1S increases the cell surface expression of the receptor.
AB  - Homer-1a is a 30 kDa protein that forms part of a family of conserved Homer
      related proteins that interact with the C-termini of the metabotropic glutamate
      receptors mGluR1alpha and mGluR5a. Analysis of HEK-293 cells by PCR showed that
      they contained mRNA coding for members of the Homer family with the predominant
      form being Homer-1b, which is consistent with the immunochemical analysis of
      these cells. Homer-1a could not be detected by immunochemical analysis. To
      examine the function of Homer-1a, HEK-293 cells were transfected with cDNA
      encoding mGluR1alpha or Homer-1a or co-transfected with both cDNAs. When cells
      were co-transfected with the cDNAs for both proteins, immunofluorescent staining
      and biotinylation of cell surface molecules revealed a significant increase in
      the amount of receptor present at the cell surface in contrast to cells
      transfected with mGluR1alpha cDNA alone. This finding was consistent with a
      concomitant increase in the production of inositol phosphates after treatment of
      the doubly transfected cells with agonist. Intracellular immunostaining for both
      proteins revealed that they were co-localized and underwent a redistribution into
      a large vesicular compartment when they were co-expressed.

PMID- 10417347
TI  - Aldolase A Ins(1,4,5)P3-binding domains as determined by site-directed
      mutagenesis.
AB  - We substituted neutral amino acids for some positively charged residues (R42,
      K107, K146, R148 and K229) that line the active site of aldolase A in an effort
      to determine binding sites for inositol 1, 4,5-trisphosphate. In addition, D33
      (involved in carbon-carbon bond cleavage) was mutated. K229A and D33S aldolases
      showed almost no catalytic activity, but Ins(1,4,5)P(3) binding was similar to
      that determined with the use of wild-type aldolase A. R42A, K107A, K146R and
      R148A had markedly decreased affinities for Ins(1,4,5)P(3) binding, increased
      EC(50) values for Fru(1,6)P(2)-evoked release of bound Ins(1,4,5)P(3) and
      increased K(i) values for Ins(1,4, 5)P(3)-evoked inhibition of aldolase activity.
      K146Q (positive charge removal) had essentially no catalytic activity and could
      not bind Ins(1,4,5)P(3). Computer-simulated docking of Ins(1,4,5)P(3) in the
      aldolase A structure was consistent with electrostatic binding of Ins(1,4,5)P(3)
      to K107, K146, R148, R42, R303 and backbone nitrogens, as has been reported for
      Fru(1,6)P(2) binding. Results indicate that Ins(1,4,5)P(3) binding occurs at the
      active site and is not dependent on having a catalytically active enzyme; they
      also suggest that there is competition between Ins(1,4,5)P(3) and Fru(1, 6)P(2)
      for binding. Although Ins(1,4,5)P(3) binding to aldolase involved electrostatic
      interactions, the aldolase A Ins(1,4, 5)P(3)-binding domain did not show other
      similarities to pleckstrin homology domains or phosphotyrosine-binding domains
      known to bind Ins(1,4,5)P(3) in other proteins.

PMID- 10417349
TI  - Molecular and functional analysis of mouse decay accelerating factor (CD55).
AB  - Molecular cloning of mouse decay accelerating factor (DAF; CD55) predicted two
      forms of the molecule, one transmembrane (TM) and the other
      glycosylphosphatidylinositol (GPI)-anchored; these are encoded by separate genes
      termed Daf-GPI and Daf-TM. In the present study several additional isoforms of
      mouse DAF, generated by alternative splicing from these genes, are described.
      Northern-blot analysis of RNA and reverse transcriptase-PCR from various tissues
      indicated that spleen and testis expressed high levels of DAF, which comprised
      several species. These species were cloned and sequence analysis revealed various
      novel forms in addition to those previously reported. Two novel forms were
      derived from the Daf-TM gene but the transmembrane sequence defined previously
      was replaced by a unique GPI-anchor addition sequence; one clone also had part of
      the serine/threonine/proline (STP) region deleted. A third clone, encoding a
      transmembrane protein, was also derived from this gene but the entire STP region
      was deleted. A fourth clone, derived from the Daf-GPI gene, contained a novel C
      terminal sequence, suggestive of a secreted form of the protein. Two DAF cDNAs
      (TM and GPI-anchored) were stably expressed in Chinese hamster ovary cells. When
      these cells were attacked with mouse or rat complement and analysed for C3b
      deposition, DAF-transfected cells had greatly reduced C3b deposition compared
      with controls. Transfection with DAF also conferred protection from complement in
      a cell-lysis assay, and a soluble, recombinant form of mouse DAF inhibited
      complement in a haemolytic assay.

PMID- 10417350
TI  - Multiple forms of p55PIK, a regulatory subunit of phosphoinositide 3-kinase, are
      generated by alternative initiation of translation.
AB  - A cDNA encoding p55PIK, one of the regulatory subunits of phosphoinositide
      (phosphatidylinositol) 3-kinase, was cloned from a cDNA library derived from the
      mouse mammary epithelial cell line C57MG. The cDNA coding for full-length p55PIK
      was transiently expressed in COS-7 cells. Western blot analysis of p55PIK
      expression using a specific antibody against p55PIK revealed that multiple
      protein products with different molecular masses were detected in COS-7 cell
      extracts. Experiments presented here demonstrate that multiple forms of p55PIK
      detected in COS-7 cells were produced by alternative initiation of translation.
      We also show that at least two in-frame start codons (AUG#2 and AUG#5) in p55PIK
      mRNA are used in COS-7 cells for the initiation of translation of p55PIK into
      proteins of 54 kDa and 50 kDa respectively. p55PIK mRNA was also alternatively
      translated into two proteins in PC cells, a mouse teratoma cell line, indicating
      that the alternative initiation of translation of p55PIK is not restricted to COS
      7 cells. Results from immunoprecipitation and Western blot analysis showed that
      two forms (54 kDa and 50 kDa protein species) of p55PIK were detected in C57MG
      cells. Interestingly, when C57MG cells were treated with insulin, only p55PIK,
      but not p50PIK, bound to insulin receptor substrate-1 protein, providing evidence
      that different forms of p55PIKs may have specific distinct roles in signal
      transduction pathways.

PMID- 10417351
TI  - Phosphorylation and activation of phosphodiesterase type 3B (PDE3B) in adipocytes
      in response to serine/threonine phosphatase inhibitors: deactivation of PDE3B in
      vitro by protein phosphatase type 2A.
AB  - Phosphodiesterase type 3B (PDE3B) has been shown to be activated and
      phosphorylated in response to insulin and hormones that increase cAMP. In order
      to study serine/threonine protein phosphatases involved in the regulation of rat
      adipocyte PDE3B, we investigated the phosphorylation and activation of PDE3B in
      vivo in response to phosphatase inhibitors and the dephosphorylation and
      deactivation of PDE3B in vitro by phosphatases purified from rat adipocyte
      homogenates. Okadaic acid and calyculin A induced dose- and time-dependent
      activation of PDE3B. Maximal effects were obtained after 30 min using 1 microM
      okadaic acid (1.8-fold activation) and 300 nM calyculin A (4-fold activation),
      respectively. Tautomycin and cyclosporin A did not induce activation of PDE3B.
      Incubation of adipocytes with 300 nM calyculin A inhibited protein phosphatase
      (PP) 1 and PP2A completely. Okadaic acid (1 microM) reduced PP2A activity by
      approx. 50% but did not affect PP1 activity, and 1 microM tautomycin reduced PP1
      activity by approx. 60% but PP2A activity by only 11%. This indicates an
      important role for PP2A in the regulation of PDE3B. Furthermore, rat adipocyte
      PDE3B phosphatase activity co-purified with PP2A but not with PP1 during MonoQ
      chromatography. As compared with insulin, okadaic acid and calyculin A induced
      phosphorylation of PDE3B by 2.8- and 14-fold respectively, whereas tautomycin and
      cyclosporin A had no effect. Both calyculin A and okadaic acid induced
      phosphorylation on serine 302, the site known to be phosphorylated on PDE3B in
      response to insulin and isoproterenol (isoprenaline), as well as on sites not
      identified previously. In summary, PP2A seems to be involved in the regulation of
      PDE3B in vivo and can act as a PDE3B phosphatase in vitro. In comparison with
      insulin, calyculin A induced a dramatic activation of PDE3B and both calyculin A
      and okadaic acid induced phosphorylation on additional sites, which could have a
      role in signalling pathways not yet identified.

PMID- 10417352
TI  - Novel cell lines for the analysis of preprotachykinin A gene expression identify
      a repressor domain 3' of the major transcriptional start site.
AB  - Until now, no clonal cells have been identified that support the expression of a
      marker gene expressed from the rat preprotachykinin A (rPPT) promoter. We have
      analysed recently available cell lines that are candidates for supporting
      reporter gene expression directed by the rPPT promoter. These are the neuronal
      derived cell line NF2C and the pancreatic cell lines RINm5F and a derivative RIN
      1027-B2. The NF2C line was derived from the brain homogenate of a transgenic
      animal in which a temperature-sensitive simian virus 40 large T antigen was
      expressed from a neurofilament promoter. All three lines are able to support
      expression of a reporter gene directed by a fragment of the 5' rPPT promoter.
      Analysis of reporter gene expression supported by various fragments of the rPPT
      promoter demonstrated that although -865 to +92 bp supported expression, the
      addition of fragments between +92 and +447 bp led to repression of expression.
      Subsequent analysis of reporter gene constructs microinjected into primary
      cultures of dorsal root ganglion neurons (DRG) confirmed the existence of this
      repressor domain. This repression could be relieved totally in both RIN cell
      lines and partly in NF2C cells by mutating residues between +373 and +396 bp.
      This indicates that these cell lines support PPT promoter activity similar to
      that observed in DRG and determines a novel repressor domain within the promoter.

PMID- 10417353
TI  - Characterization of homogeneous recombinant rat ovarian 20alpha-hydroxysteroid
      dehydrogenase: fluorescent properties and inhibition profile.
AB  - In rat ovary, 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), a member of the
      aldo-keto reductase (AKR) superfamily, converts progesterone into the inactive
      progestin 20alpha-hydroxyprogesterone and has been implicated in the termination
      of pregnancy. Here we report a convenient overexpression system that permits the
      purification of milligram quantities of homogeneous recombinant 20alpha-HSD with
      wild-type enzyme activity. The availability of this enzyme has permitted detailed
      kinetic, inhibition and fluorescence analyses. The enzyme exhibited narrow
      steroid specificity, catalysing reactions only at C-20; it reduced progesterone
      and 17alpha-hydroxyprogesterone and oxidized 20alpha-hydroxypregnanes. It also
      turned over common AKR substrates, such as 9, 10-phenanthrenequinone and 4
      nitrobenzaldehyde. The intrinsic fluorescence spectrum of 20alpha-HSD was
      characterized and was quenched on the binding of NADP(H), yielding a KNADPd of
      0.36 microM and a KNADPHd of 0.64 microM. NADP(H) binding generated an energy
      transfer band that could not be quenched by steroids. Inhibition studies
      conducted with non-steroidal and steroidal anti-inflammatory drugs and synthetic
      oestrogens indicated that even though rat ovarian 20alpha-HSD and rat liver
      3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) share more than 67% amino acid
      identity, their inhibition profiles are markedly different. Unlike 3alpha-HSD,
      most of these compounds did not inhibit 20alpha-HSD. Only meclofenamic acid and
      hexoestrol were potent competitive inhibitors for 20alpha-HSD, yielding K(i)
      values of 18.9 and 14.3 microM respectively. These studies suggest that selective
      non-steroidal AKR inhibitors could be developed for 20alpha-HSD that might be
      useful in maintaining pregnancy and that specific inhibitors might be developed
      from either N-phenylanthranilates or biphenols.

PMID- 10417354
TI  - NIEHS announces first transition to independent positions (TIP) awards 

PMID- 10417355
TI  - Comparative hazards of chrysotile asbestos and its substitutes: A European
      perspective.
AB  - Although the use of amphibole asbestos (crocidolite and amosite) has been banned
      in most European countries because of its known effects on the lung and pleura,
      chrysotile asbestos remains in use in a number of widely used products, notably
      asbestos cement and friction linings in vehicle brakes and clutches. A ban on
      chrysotile throughout the European Union for these remaining applications is
      currently under consideration, but this requires confidence in the safety of
      substitute materials. The main substitutes for the residual uses of chrysotile
      are p-aramid, polyvinyl alcohol (PVA), and cellulose fibers, and it is these
      materials that are evaluated here. Because it critically affects both exposure
      concentrations and deposition in the lung, diameter is a key determinant of the
      intrinsic hazard of a fiber; the propensity of a material to release fibers into
      the air is also important. It is generally accepted that to be pathogenic to the
      lung or pleura, fibers must be long, thin, and durable; fiber chemistry may also
      be significant. These basic principles are used in a pragmatic way to form a
      judgement on the relative safety of the substitute materials, taking into account
      what is known about their hazardous properties and also the potential for
      uncontrolled exposures during a lifetime of use (including disposal). We conclude
      that chrysotile asbestos is intrinsically more hazardous than p-aramid, PVA, or
      cellulose fibers and that its continued use in asbestos-cement products and
      friction materials is not justifiable in the face of available technically
      adequate substitutes.

PMID- 10417356
TI  - Mortality and air pollution: associations persist with continued advances in
      research methodology.

PMID- 10417357
TI  - Relationship between ozone and respiratory health in college students: A 10-year
      study.

PMID- 10417358
TI  - Emergency planning and the acute toxic potency of inhaled ammonia.
AB  - Ammonia is present in agriculture and commerce in many if not most communities.
      This report evaluates the toxic potency of ammonia, based on three types of data:
      anecdotal data, in some cases predating World War 1, reconstructions of
      contemporary industrial accidents, and animal bioassays. Standards and guidelines
      for human exposure have been driven largely by the anecdotal data, suggesting
      that ammonia at 5,000-10,000 parts per million, volume/volume (ppm-v), might be
      lethal within 5-10 min. However, contemporary accident reconstructions suggest
      that ammonia lethality requires higher concentrations. For example, 33,737 ppm-v
      was a 5-min zero-mortality value in a major ammonia release in 1973 in South
      Africa. Comparisons of secondary reports of ammonia lethality with original
      sources revealed discrepancies in contemporary sources, apparently resulting from
      failure to examine old documents or accurately translate foreign documents. The
      present investigation revealed that contemporary accident reconstructions yield
      ammonia lethality levels comparable to those in dozens of reports of animal
      bioassays, after adjustment of concentrations to human equivalent concentrations
      via U.S. Environmental Protection Agency (EPA) procedures. Ammonia levels
      potentially causing irreversible injury or impairing the ability of exposed
      people to escape from further exposure or from coincident perils similarly have
      been biased downwardly in contemporary sources. The EPA has identified ammonia as
      one of 366 extremely hazardous substances subject to community right-to-know
      provisions of the Superfund Act and emergency planning provisions of the Clean
      Air Act. The Clean Air Act defines emergency planning zones (EPZs) around
      industrial facilities exceeding a threshold quantity of ammonia on-site. This
      study suggests that EPZ areas around ammonia facilities can be reduced, thereby
      also reducing emergency planning costs, which will vary roughly with the EPZ
      radius squared.

PMID- 10417359
TI  - A case-crossover analysis of air pollution and mortality in Philadelphia.
AB  - This study reassessed Schwartz and Dockery's analysis of daily mortality from
      nonexternal causes among residents of Philadelphia, Pennsylvania, over 8 years,
      from 1973 to 1980 [American Review of Respiratory Disease 145:600-604 (1992)]. A
      Poisson regression analysis using the same model found that a 100-microg/m(3)
      increment in the 48-hr mean concentration of total suspended particulates (TSP)
      was associated with increased all-cause mortality [rate ratio = 1.069; 95%
      confidence interval (CI), 1.043-1.096) after adjustment for quadratic trend,
      season, year, previous day's mean temperature, dew point, winter temperature, and
      indicators of hot (temperature > 80 degrees F) and humid days (dew point > 66
      degrees F). Critics suggested that time-varying factors such as season and day of
      week were not sufficiently controlled in this analysis and subsequent studies in
      other locations. We used a conditional logistic regression analysis with a case
      crossover design to reanalyze the data, with air pollution in the prior and
      subsequent weeks to the day of death serving as referent periods. The case
      crossover approach controls for season and day of week by design rather than
      modeling. We found that a 100-microg/m(3) increment in the 48-hr mean level of
      TSP was associated with increased all-cause mortality [odds ratio (OR) = 1.056;
      CI, 1.027-1.086) after adjustment for the same weather variables as above.
      Similar associations were observed for deaths in individuals over 65 years of age
      (OR = 1.074; CI, 1. 037-1.111) and for deaths due to cardiovascular disease (OR =
      1.063; CI, 1.021-1.107). The current case-crossover analysis confirms the general
      conclusion of the previous Poisson regression analysis of an association of TSP
      with daily mortality in Philadelphia, Pennsylvania.

PMID- 10417360
TI  - Reanalysis of the effects of air pollution on daily mortality in Seoul, Korea: A
      case-crossover design.
AB  - We used the case-crossover design to identify any increase in mortality in Seoul,
      Korea, when there were higher levels of ambient air pollution on case-days than
      would be expected solely as a result of chance. This empirical study showed that
      either unidirectional retrospective (selecting only control days prior to death)
      or prospective (selecting only control days after death) control sampling could
      cause risk estimates to be confounded by seasonal waves as well as time trends in
      air pollution levels. In bidirectional control sampling in which exposures at
      death were compared with exposures both before and after death, the estimated
      mortality was resistant to confounding by time patterns of air pollution. Using a
      bidirectional control sampling approach, the results from a conditional logistic
      regression model controlling for weather conditions showed that the nonaccidental
      mortality associated with a 50-ppb increment over a 3-day moving average of SO(2)
      concentrations, including the concurrent day and preceding 2 days, was 1.023 [95%
      confidence interval (CI), 1.016-1.084]. The relative risk of death was 1.023 (CI,
      0.999-1.048) per 50 ppb for 1-hr maximum O(3) and 1.010 (CI, 0.988-1.032) per 100
      microg/m(3 )or total suspended particulates. In conclusion, the findings of this
      study were 2-fold: given the consistency of the observed association between
      SO(2) and daily mortality across different analysis methods, the association
      reported here indicates that air pollution is a probable contributor to premature
      death; and bidirectional control sampling is needed in a case-crossover design
      applied to air pollution epidemiologic studies to control confounding by seasonal
      patterns of air pollution as well as time trends.

PMID- 10417361
TI  - Daily mortality and air pollution in Santa Clara County, California: 1989-1996.
AB  - Since the last revision of the national particulate standards, there has been a
      profusion of epidemiologic research showing associations between particulates and
      health effects--mortality in particular. Supported by this research, the U.S.
      Environmental Protection Agency promulgated a national standard for particulate
      matter [less than/equal to] 2.5 microm in aerodynamic diameter (PM(2.5)).
      Nevertheless, the San Francisco Bay Area of California may meet this new
      standard. This study investigates the relationship between daily mortality and
      air pollution in Santa Clara County (a Bay Area county) using techniques similar
      to those utilized in earlier epidemiologic studies. Statistically significant
      associations persist in the early 1990s, when the Bay Area met national air
      pollution standards for every criteria pollutant. Of the various pollutants, the
      strongest associations occur with particulates, especially ammonium nitrate and
      PM(2.5). The continuing presence of associations between mortality and air
      pollutants calls into question the adequacy of national standards for protecting
      public health.

PMID- 10417362
TI  - Flame retardant exposure: polybrominated diphenyl ethers in blood from Swedish
      workers.
AB  - Polybrominated diphenyl ethers (PBDEs) are used as additives in polymers and
      textiles to prohibit the development of fires. Because of the production and use
      of PBDEs, their lipophilic characteristics, and persistence, these compounds have
      become ubiquitous environmental contaminants. The aim of the present study was to
      determine potential exposures of PBDEs to clerks working full-time at computer
      screens and personnel at an electronics-dismantling plant, with hospital cleaners
      as a control group. Five PBDE congeners--2,2',4,4'-tetraBDE; 2,2',4,4',5,5'
      hexaBDE; 2,2',4,4',5, 6'-hexaBDE; 2,2',3,4,4',5',6-heptaBDE; and decaBDE--were
      quantified in blood serum from all three categories of workers. Subjects working
      at the dismantling plant showed significantly higher levels of all PBDE congeners
      in their serum as compared to the control group. Decabromodiphenyl ether is
      present in concentrations of 5 pmol/g lipid weight (lw) in the personnel
      dismantling electronics; these concentrations are comparable to the
      concentrations of 2,2',4, 4'-tetraBDE. The latter compound was the dominating
      PBDE congener in the clerks and cleaners. The major compound in personnel at the
      dismantling plant was 2,2',3,4,4',5',6-heptaBDE. Concentrations of this PBDE
      congener are almost twice as high as for 2,2',4, 4'-tetraBDE in these workers and
      seventy times the level of this heptaBDE in cleaners. The total median PBDE
      concentrations in the serum from workers at the electronics-dismantling plant,
      clerks, and cleaners were 37, 7.3, and 5.4 pmol/g lw, respectively. The results
      show that decabromodiphenyl ether is bioavailable and that occupational exposure
      to PBDEs occurs at the electronics-dismantling plant.

PMID- 10417363
TI  - Radiation and mortality of workers at Oak Ridge National Laboratory: positive
      associations for doses received at older ages.
AB  - We examined associations between low-level exposure to ionizing radiation and
      mortality among 14,095 workers hired at the Oak Ridge National Laboratory between
      1943 and 1972. Workers at the facility were individually monitored for external
      exposure to ionizing radiation and have been followed through 1990 to ascertain
      cause of death information. Positive associations were observed between low-level
      exposure to external ionizing radiation and mortality. These associations were
      larger for doses received after 45 years of age, larger under longer lag
      assumptions, and primarily due to cancer causes of death. All cancer mortality
      was estimated to increase 4.98% [standard error (SE) = 1.5] per 10-mSv cumulative
      dose received after age 45 under a 10-year lag, and 7.31% (SE = 2.2) per 10-mSv
      cumulative dose received after age 45 under a 20-year lag. Associations between
      radiation dose and lung cancer were of similar magnitude to associations between
      radiation dose and all cancers except lung cancer. Nonmalignant respiratory
      disease exhibited a positive association with cumulative radiation dose received
      after age 45, whereas ischemic heart disease exhibited no association with
      radiation dose. These findings suggest increases in cancer mortality associated
      with low-level external exposure to ionizing radiation and potentially greater
      sensitivity to the carcinogenic effects of ionizing radiation with older ages at
      exposure.

PMID- 10417365
TI  - Excretion of arsenic in urine as a function of exposure to arsenic in drinking
      water.
AB  - Urinary arsenic (As) concentrations were evaluated as a biomarker of exposure in
      a U.S. population chronically exposed to inorganic As (InAs) in their drinking
      water. Ninety-six individuals who consumed drinking water with As concentrations
      of 8-620 microg/L provided first morning urine voids for up to 5 consecutive
      days. The study population was 56% male, and 44% was younger than 18 years of
      age. On one day of the study period, all voided urines were collected over a 24
      hr period. Arsenic intake from drinking water was estimated from daily food
      diaries. Comparison between the concentration of As in individual urine voids
      with that in the 24-hr urine collection indicated that the concentration of As in
      urine was stable throughout the day. Comparison of the concentration of As in
      each first morning urine void over the 5-day study period indicated that there
      was little day-to-day variation in the concentration of As in urine. The
      concentration of As in drinking water was a better predictor of the concentration
      of As in urine than was the estimated intake of As from drinking water. The
      concentration of As in urine did not vary by gender. An age-dependent difference
      in the concentration of As in urine may be attributed to the higher As dosage
      rate per unit body weight in children than in adults. These findings suggest that
      the analysis of a small number of urine samples may be adequate to estimate an
      individual's exposure to InAs from drinking water and that the determination of
      the concentration of InAs in a drinking water supply may be a useful surrogate
      for estimating exposure to this metalloid.

PMID- 10417364
TI  - Effects of weight loss and exercise on the distribution of lead and essential
      trace elements in rats with prior lead exposure.
AB  - We studied the effects of weight loss and non-weight-bearing exercise (swimming)
      on blood and organ lead and essential metal concentrations in rats with prior
      lead exposure. Nine-week-old female Sprague-Dawley rats (n = 37) received lead
      acetate in their drinking water for 2 weeks, followed by a 4-day latency period
      without lead exposure. Rats were then randomly assigned to one of six treatment
      groups: weight maintenance with ad libitum feeding, moderate weight loss with 20%
      food restriction, and substantial weight loss with 40% food restriction, either
      with or without swimming. Blood lead concentrations were measured weekly. The
      rats were euthanized after a 4-week period of food restriction, and the brain,
      liver, kidneys, quadriceps muscle, lumbar spinal column bones, and femur were
      harvested for analysis for lead, calcium, copper, iron, magnesium, and zinc using
      atomic absorption spectrophotometry. Both swimming and nonswimming rats fed
      restricted diets had consistently higher blood lead concentrations than the ad
      libitum controls. Rats in the substantial weight loss group had higher organ lead
      concentrations than rats in the weight maintenance group. Rats in the moderate
      weight loss group had intermediate values. There were no significant differences
      in blood and organ lead concentrations between the swimming and nonswimming
      groups. Organ iron concentrations increased with weight loss, but those of the
      other metals studied did not. Weight loss also increased hematocrits and
      decreased bone density of the nonswimming rats. The response of lead stores to
      weight loss was similar to that of iron stores because both were conserved during
      food restriction in contrast to decreased stores of the other metals studied. It
      is possible that weight loss, especially rapid weight loss, could result in lead
      toxicity in people with a history of prior excessive lead exposure.

PMID- 10417366
TI  - The adverse effect of low levels of ambient air pollutants on lung function
      growth in preadolescent children.
AB  - The main purpose of our study was to assess the effect of low concentrations of
      ambient air pollution on lung function growth in preadolescent children. We
      accounted for height velocity over the follow-up period and also for other
      possible confounders such as baseline anthropometric and physiologic
      characteristics of children. In addition to outdoor air pollution, we considered
      the possible effects of social class and exposure to indoor pollutants such as
      gas stove fumes or environmental tobacco smoke. The cohort prospective study was
      carried out in 1,001 preadolescent children from two areas of Krakow, Poland,
      that differed in ambient air pollutants. In the city center (higher pollution
      area), the mean annual level [+/- standard deviation (SD)] of suspended
      particulate matter was 52.6 +/- 53.98 microg/m(3) and that of SO(2) was 43.87 +/-
      32.69 microg/m(3); the corresponding values in the control area were 33.23 +/-
      35.99 microg/m(3) and 31.77 +/- 21.93 microg/m(3). Mean lung function growth rate
      adjusted to height velocity and lung function level at the study entry was
      significantly lower in boys and girls living in the more polluted areas. Also,
      the proportion of children with the slower lung function growth (SLFG) was higher
      in the children from the more polluted area of the city. The analysis completed
      in the group of children after the exclusion of asthmatic subjects and those with
      asthmalike symptoms confirmed that, in boys, odds ratios (ORs) for SLFG [forced
      vital capacity (FVC)] and air pollution after adjustment to baseline FVC, height,
      and growth rate was significant [OR = 2.15; 95% confidence interval (CI), 1.25-3.
      69)]. The analysis also confirmed that for SLFG(FEV(1)) the OR was 1. 90 (CI,
      1.12-3.25). The corresponding OR values in girls were insignificant (OR = 1.50;
      CI, 0.84-2.68 and OR = 1.39; CI, 0.78-2. 44). The association between ambient
      pollutants and poorer gain of pulmonary volumes in children living in more
      polluted areas suggests that air pollution in the residence area may be a part of
      the causal chain of reactions leading to retardation in pulmonary function growth
      during the preadolescent years.

PMID- 10417367
TI  - Long-term residence in areas of high ozone: associations with respiratory health
      in a nationwide sample of nonsmoking young adults [dsee comments].
AB  - Few studies have examined the respiratory effects of multiyear ozone exposures in
      human populations. We examined associations between current respiratory health
      status and long-term ozone exposure histories in 520 Yale College (New Haven, CT)
      students who never smoked. Questionnaires addressed current respiratory symptoms,
      respiratory disease history, residential history, and other factors. The symptoms
      of cough, phlegm, wheeze apart from colds, and a composite respiratory symptom
      index (RSI) were selected as outcome measures. Forced vital capacity (FVC),
      forced expiratory volume in 1 sec (FEV(1)), forced expiratory flow rate between
      25 and 75% of FVC (FEF(25-75)), and forced expiratory flow rate at 75% of FVC
      (FEF(75)) were obtained by forced expiration into spirometers. Ozone exposure was
      treated as a dichotomous variable, where subjects were assigned to the high
      exposure group if they lived for 4 or more years in a U.S. county with 10-year
      average summer-season daily 1-hr maximum ozone levels [greater/equal to] 80 ppb.
      Lung function and respiratory symptoms were analyzed by multiple linear and
      logistic regression on ozone exposure, controlling for covariates. Lung function
      was lower in the group with high ozone exposures: differences were statistically
      significant for FEV(1) [-3.1%; 95% confidence interval (CI), -0.2 to -5.9%] and
      FEF(25-75) (-8.1%; CI, -2.3 to -13.9%), and nearly so for FEF(75) (-6.7%; CI, 1.4
      to -14.8). Gender-specific analyses revealed stronger associations for males than
      for females. The symptoms of chronic phlegm, wheeze apart from colds, and RSI
      were increased in the ozone-exposed group, with odds ratios of 1.79 (CI, 0.83
      3.82), 1.97 (CI, 1.06-3.66), and 2.00 (CI, 1.15-3.46), respectively. We conclude
      that living for 4 or more years in regions of the country with high levels of
      ozone and related copollutants is associated with diminished lung function and
      more frequent reports of respiratory symptoms.

PMID- 10417368
TI  - Application of DNA arrays to toxicology.
AB  - DNA array technology makes it possible to rapidly genotype individuals or
      quantify the expression of thousands of genes on a single filter or glass slide,
      and holds enormous potential in toxicologic applications. This potential led to a
      U.S. Environmental Protection Agency-sponsored workshop titled "Application of
      Microarrays to Toxicology" on 7-8 January 1999 in Research Triangle Park, North
      Carolina. In addition to providing state-of-the-art information on the
      application of DNA or gene microarrays, the workshop catalyzed the formation of
      several collaborations, committees, and user's groups throughout the Research
      Triangle Park area and beyond. Potential application of microarrays to
      toxicologic research and risk assessment include genome-wide expression analyses
      to identify gene-expression networks and toxicant-specific signatures that can be
      used to define mode of action, for exposure assessment, and for environmental
      monitoring. Arrays may also prove useful for monitoring genetic variability and
      its relationship to toxicant susceptibility in human populations.

PMID- 10417369
TI  - Arsenic-related Bowen's disease, palmar keratosis, and skin cancer.
AB  - Chronic arsenical intoxication can still be found in environmental and industrial
      settings. Symptoms of chronic arsenic intoxication include general pigmentation
      or focal "raindrop" pigmentation of the skin and the appearance of hyperkeratosis
      of the palms of the hands and soles of the feet. In addition to arsenic-related
      skin diseases including keratosis, Bowen's disease, basal-cell-carcinoma, and
      squamous-cell carcinoma, there is also an increased risk of some internal
      malignancies. Arsenic-related diseases are common in areas of the world where the
      drinking water has a high arsenic content. In this paper, we describe a 35-year
      old male patient who had arsenic-related keratosis, squamous-cell carcinoma in
      the palmar area of his left hand, and Bowen's disease on his left thigh. The
      patient worked in a borax mine for 15 years, so he was exposed to arsenic in
      drinking water, airborne arsenic in his workplace, and had direct contact. The
      patient was treated for 11 months for arsenic-related keratosis until an axillary
      lymph node metastasis occurred; the lesion was excised and diagnosed to be
      malignant. Bowen's disease was detected when the patient was being treated for
      cancer. No other malignancy was found. The patient is still receiving regular
      follow-up care.

PMID- 10417370
TI  - What is a tumor promoter?

PMID- 10417371
TI  - Comments on "PM(2.5) mortality in long-term prospective cohort studies: cause
      effect or statistical association?".

PMID- 10417372
TI  - The path to DNA repair.

PMID- 10417373
TI  - Talking trash: the economic and environmental issues of landfills.
AB  - The U.S. per-capita figure for garbage production has topped four pounds per
      person per day, and that amount is rising at roughly 5% per year. In the past,
      municipal solid waste was sent to the nearest local landfill or incinerator. But
      in 1988, the U.S. Environmental Protection Agency instituted the first federal
      standards for landfills, designed to make them safer. Over 10,000 small municipal
      landfills have since been consolidated into an estimated 3,500 newer, safer
      landfills, some of which are "megafills" that can handle up to 10,000 tons of
      waste a day. The new landfills are outfitted to prevent air and water pollution
      and limit the spread of disease by scavengers. Although the new landfills provide
      better controls against air and water pollution as well as an alternate source of
      municipal income, they are not entirely problem-free. Some experts believe the
      new landfill technology has not been properly tested and will therefore not
      provide protection in the long run. Others feel that poorer, less well-informed
      communities are targeted as sites for new landfills. In addition, many people
      that live near megafills, which may draw garbarge from several states, are
      unhappy about the noise, truck traffic, odors, and pests caused by the
      facilities.

PMID- 10417375
TI  - Plasma jet takes off.
AB  - Thanks to a series of joint research projects by Los Alamos National Laboratory,
      Beta Squared of Allen, Texas, and the University of California at Los Angeles,
      there is now a more environmentally sound method for cleaning semiconductor chips
      that may also be effective in cleaning up chemical, bacterial, and nuclear
      contaminants. The Atmospheric Pressure Plasma Jet uses a type of ionized gas
      called plasma to clean up contaminants by binding to them and lifting them away.
      In contrast to the corrosive acids and chemical solvents traditionally used to
      clean semiconductor chips, the jet oxidizes contaminants, producing only benign
      gaseous by-products such as oxygen and carbon dioxide. The new technology is also
      easy to transport, cleans thoroughly and quickly, and presents no hazards to its
      operators.

PMID- 10417374
TI  - Trading trash: why the U.S. won't sign on to the Basel convention.
AB  - Environmentalists worry that hazardous wastes produced in industrialized nations
      are being dumped in cash-starved developing countries--the countries with the
      least political or economic clout to resist and the fewest resources for managing
      these toxic imports. Imported waste can pose a serious threat to the health of
      human populations and ecosystems if not managed appropriately. In 1989, the
      international community initiated efforts to reduce the flow of hazardous wastes
      from industrialized countries to developing countries by drafting a treaty known
      as the Basel Convention on the Control of Transboundary Wastes and their
      Disposal. The convention's mission is to strictly regulate the international
      transfer of hazardous wastes and to ensure that wastes are managed and disposed
      of in an environmentally sound manner. Although the United States supports the
      convention in theory, it remains the only industrialized country within the
      Organization for Economic Cooperation and Development yet to ratify it. However,
      legislation drafted by the Clinton administration that is soon to go before the
      106th Congress could make the United States a party to the convention.

PMID- 10417376
TI  - Mycobacterium avium interaction with macrophages and intestinal epithelial cells.
AB  - Mycobacterium avium is an environmental microorganism that is adapted to live
      both in the environment (mainly in water and soil) and in bird, fish and mammal
      hosts. In humans, M. avium infection is seen in patients with some sort of
      immunosuppression, such as patients with chronic lung disease, and Acquired
      Immunodeficiency Syndrome. More recently, other populations were shown to be at
      risk to develop M. avium disease. For the majority of time, humans acquire M.
      avium through the intestinal tract where the bacterium comes in contact with and
      translocates the intestinal mucosa. M. avium possesses a unique manner to
      interact with the intestinal mucosa, and, following invasion, can enter and
      survive within macrophages and monocytes. Although in vitro entry seems to be
      dependent on binding to the complement receptor, this finding has not been
      observed in vivo where the bacterium appears to enter macrophages by alternative
      mechanisms. The bacterium appears to trigger little inflammatory response, and is
      able to adapt itself to different environments in the host.

PMID- 10417377
TI  - Deficient cellular immunity--finding and fixing the defects.
AB  - The critical role of cellular immunity in resistance to infectious diseases is
      glaringly revealed by life-threatening infections if T cell function is disrupted
      by an inherited or acquired immunodeficiency. Although treatment has historically
      focused on infectious complications, understanding of the cellular and molecular
      basis of immunodeficiency and technologies useful for enhancing cellular immunity
      have both been rapidly evolving. A new era of molecular and cellular therapy is
      emerging as approaches to correct abnormal genes, the loss of T cell
      subpopulations, and aberrant T cell homeostasis make the transition from bench to
      bedside.

PMID- 10417379
TI  - Radar and optical observations of asteroid 1998 KY26 
AB  - Observations of near-Earth asteroid 1998 KY26 shortly after its discovery reveal
      a slightly elongated spheroid with a diameter of about 30 meters, a composition
      analogous to carbonaceous chondritic meteorites, and a rotation period of 10.7
      minutes, which is an order of magnitude shorter than that measured for any other
      solar system object. The rotation is too rapid for 1998 KY26 to consist of
      multiple components bound together just by their mutual gravitational attraction.
      This monolithic object probably is a fragment derived from cratering or
      collisional destruction of a much larger asteroid.

PMID- 10417380
TI  - Estimating the mass of asteroid 433 eros during the NEAR spacecraft flyby 
AB  - The Near Earth Asteroid Rendezvous (NEAR) spacecraft flew within 3830 kilometers
      of asteroid 433 Eros on 23 December 1998. The gravitational perturbation on NEAR
      was evident in the spacecraft tracking data. Ground-based Doppler and range
      tracking of the spacecraft as well as spacecraft images of the asteroid's center
      of figure and surface features were used to determine the mass and rotation pole
      of Eros. The mass of Eros is (7.2 +/- 1.8) x 10(18) grams and, coupled with a
      volume estimate provided by the NEAR imaging team, this mass suggests a bulk
      density of 2.5 +/- 0.8 grams per cubic centimeter. The rotation pole position is
      15.6 (+/-3.7) degrees in right ascension and 16.4 (+/-1.8) degrees in
      declination, which is consistent with ground-based and NEAR imaging team
      observations.

PMID- 10417378
TI  - Light-dependent sequestration of TIMELESS by CRYPTOCHROME.
AB  - Most organisms have circadian clocks consisting of negative feedback loops of
      gene regulation that facilitate adaptation to cycles of light and darkness. In
      this study, CRYPTOCHROME (CRY), a protein involved in circadian photoperception
      in Drosophila, is shown to block the function of PERIOD/TIMELESS (PER/TIM)
      heterodimeric complexes in a light-dependent fashion. TIM degradation does not
      occur under these conditions; thus, TIM degradation is uncoupled from abrogation
      of its function by light. CRY and TIM are part of the same complex and directly
      interact in yeast in a light-dependent fashion. PER/TIM and CRY influence the
      subcellular distribution of these protein complexes, which reside primarily in
      the nucleus after the perception of a light signal. Thus, CRY acts as a circadian
      photoreceptor by directly interacting with core components of the circadian
      clock.

PMID- 10417382
TI  - Pacemaking the ice ages by frequency modulation of Earth's orbital eccentricity 
AB  - Evidence from power spectra of deep-sea oxygen isotope time series suggests that
      the climate system of Earth responds nonlinearly to astronomical forcing by
      frequency modulating eccentricity-related variations in insolation. With the help
      of a simple model, it is shown that frequency modulation of the approximate
      100,000-year eccentricity cycles by the 413,000-year component accounts for the
      variable duration of the ice ages, the multiple-peak character of the time series
      spectra, and the notorious absence of significant spectral amplitude at the
      413,000-year period. The observed spectra are consistent with the classic
      Milankovitch theories of insolation, so that climate forcing by 100,000-year
      variations in orbital inclination that cause periodic dust accretion appear
      unnecessary.

PMID- 10417383
TI  - The role of sub-milankovitch climatic forcing in the initiation of the northern
      hemisphere glaciation 
AB  - Mechanisms responsible for the initiation of major glaciation in the Northern
      Hemisphere at about 2.75 million years ago are poorly understood. A laminated
      terrestrial sequence from Pula maar, Hungary, containing about 320,000 years in
      annual layers between 3.05 and 2. 60 million years ago, provides a detailed
      record of rates of climatic change across this dramatic transition. An analysis
      of the record implies that climatic variations at sub-Milankovitch frequencies
      (less than or equal to 15,000 years) were an important driving force during this
      transitional interval and that, as the threshold was approached, these increased
      in frequency and amplitude, possibly providing the final trigger for the
      amplification of Northern Hemisphere ice sheets.

PMID- 10417381
TI  - Imaging of asteroid 433 eros during NEAR's flyby reconnaissance 
AB  - During the 23 December 1998 flyby of asteroid 433 Eros, the Near-Earth Asteroid
      Rendezvous (NEAR) spacecraft obtained 222 images of Eros, as well as supporting
      spectral observations. The images cover slightly more than two-thirds of Eros
      (best resolution is approximately 400 meters per pixel) and reveal an elongated,
      cratered body with a linear feature extending for at least 20 kilometers. Our
      observations show that Eros has dimensions of 33 x 13 x 13 kilometers. The
      volume, combined with the mass determined by the NEAR radio science experiment,
      leads to a density of 2.5 +/- 0.8 grams per cubic centimeter. This relatively
      high density, and the presence of an extensive linear feature, suggest that Eros
      may be a structurally coherent body.

PMID- 10417384
TI  - Superradiant rayleigh scattering from a bose-einstein condensate 
AB  - Rayleigh scattering off a Bose-Einstein condensate was studied. Exposing an
      elongated condensate to a single off-resonant laser beam resulted in the
      observation of highly directional scattering of light and atoms. This collective
      light scattering is caused by the coherent center-of-mass motion of the atoms in
      the condensate. A directional beam of recoiling atoms was built up by matter wave
      amplification.

PMID- 10417385
TI  - The U.S. Carbon budget: contributions from land-Use change 
AB  - The rates at which lands in the United States were cleared for agriculture,
      abandoned, harvested for wood, and burned were reconstructed from historical data
      for the period 1700-1990 and used in a terrestrial carbon model to calculate
      annual changes in the amount of carbon stored in terrestrial ecosystems,
      including wood products. Changes in land use released 27 +/- 6 petagrams of
      carbon to the atmosphere before 1945 and accumulated 2 +/- 2 petagrams of carbon
      after 1945, largely as a result of fire suppression and forest growth on
      abandoned farmlands. During the 1980s, the net flux of carbon attributable to
      land management offset 10 to 30 percent of U.S. fossil fuel emissions.

PMID- 10417386
TI  - An adhesin of the yeast pathogen Candida glabrata mediating adherence to human
      epithelial cells.
AB  - Candida glabrata is an important fungal pathogen of humans that is responsible
      for about 15 percent of mucosal and systemic candidiasis. Candida glabrata
      adhered avidly to human epithelial cells in culture. By means of a genetic
      approach and a strategy allowing parallel screening of mutants, it was possible
      to clone a lectin from a Candida species. Deletion of this adhesin reduced
      adherence of C. glabrata to human epithelial cells by 95 percent. The adhesin,
      encoded by the EPA1 gene, is likely a glucan-cross-linked cell-wall protein and
      binds to host-cell carbohydrate, specifically recognizing asialo-lactosyl
      containing carbohydrates.

PMID- 10417387
TI  - Transcriptional activation of APETALA1 by LEAFY.
AB  - Plants produce new appendages reiteratively from groups of stem cells called
      shoot apical meristems. LEAFY (LFY) and APETALA1 (AP1) are pivotal for the switch
      to the reproductive phase, where instead of leaves the shoot apical meristem
      produces flowers. Use of steroid-inducible activation of LFY demonstrated that
      early expression of AP1 is a result of transcriptional induction by LFY. This AP1
      induction is independent of protein synthesis and occurs specifically in the
      tissues and at the developmental stage in which floral fate is assumed. Later
      expression of AP1 appears to be only indirectly affected by LFY.

PMID- 10417388
TI  - Activation of a floral homeotic gene in Arabidopsis.
AB  - The patterned expression of floral homeotic genes in Arabidopsis depends on the
      earlier action of meristem-identity genes such as LEAFY, which encodes a
      transcription factor that determines whether a meristem will generate flowers
      instead of leaves and shoots. The LEAFY protein, which is expressed throughout
      the flower, participates in the activation of homeotic genes, which are expressed
      in specific regions of the flower. Analysis of a LEAFY-responsive enhancer in the
      homeotic gene AGAMOUS indicates that direct interaction of LEAFY with this
      enhancer is required for its activity in plants. Thus, LEAFY is a direct upstream
      regulator of floral homeotic genes.

PMID- 10417389
TI  - Role of bacterial intimin in colonic hyperplasia and inflammation.
AB  - Enteropathogenic Escherichia coli (EPEC) cells adhere to gut epithelial cells
      through intimin alpha: the ligand for a bacterially derived epithelial
      transmembrane protein called the translocated intimin receptor. Citrobacter
      rodentium colonizes the mouse colon in a similar fashion and uses a different
      intimin: intimin beta. Intimin alpha was found to costimulate submitogenic
      signals through the T cell receptor. Dead intimin beta+ C. rodentium, intimin
      alpha-transfected C. rodentium or E. coli strain K12, and EPEC induced mucosal
      hyperplasia identical to that caused by C. rodentium live infection, as well as a
      massive T helper cell-type 1 immune response in the colonic mucosa. Mutation of
      cysteine-937 of intimin to alanine reduced costimulatory activity in vitro and
      prevented immunopathology in vivo. The mucosal changes elicited by C. rodentium
      were interferon-gamma-dependent. Immunopathology induced by intimin enables the
      bacteria to promote conditions that are favorable for increased microbial
      colonization.

PMID- 10417391
TI  - Neuronal protection in stroke by an sLex-glycosylated complement inhibitory
      protein.
AB  - Glycoprotein adhesion receptors such as selectins contribute to tissue injury in
      stroke. Ischemic neurons strongly expressed C1q, which may target them for
      complement-mediated attack or C1qRp-mediated clearance. A hybrid molecule was
      used to simultaneously inhibit both complement activation and selectin-mediated
      adhesion. The extracellular domain of soluble complement receptor-1 (sCR1) was
      sialyl Lewis x glycosylated (sCR1sLex) to inhibit complement activation and
      endothelial-platelet-leukocyte interactions. sCR1 and sCR1sLex colocalized to
      ischemic cerebral microvessels and C1q-expressing neurons, inhibited neutrophil
      and platelet accumulation, and reduced cerebral infarct volumes. Additional
      benefit was conferred by sialyl Lewis x glycosylation of the unmodified parent
      sCR1 molecule.

PMID- 10417390
TI  - Genetic selection of peptide inhibitors of biological pathways.
AB  - Genetic selections were used to find peptides that inhibit biological pathways in
      budding yeast. The peptides were presented inside cells as peptamers, surface
      loops on a highly expressed and biologically inert carrier protein, a
      catalytically inactive derivative of staphylococcal nuclease. Peptamers that
      inhibited the pheromone signaling pathway, transcriptional silencing, and the
      spindle checkpoint were isolated. Putative targets for the inhibitors were
      identified by a combination of two-hybrid analysis and genetic dissection of the
      target pathways. This analysis identified Ydr517w as a component of the spindle
      checkpoint and reinforced earlier indications that Ste50 has both positive and
      negative roles in pheromone signaling. Analysis of transcript arrays showed that
      the peptamers were highly specific in their effects, which suggests that they may
      be useful reagents in organisms that lack sophisticated genetics as well as for
      identifying components of existing biological pathways that are potential targets
      for drug discovery.

PMID- 10417392
TI  - Correlational structure of spontaneous neuronal activity in the developing
      lateral geniculate nucleus in vivo.
AB  - The properties of spontaneous activity in the developing visual pathway beyond
      the retina are unknown. Multielectrode recordings in the lateral geniculate
      nucleus (LGN) of awake behaving ferrets, before eye opening, revealed patterns of
      spontaneous activity that reflect a reshaping of retinal drive within higher
      visual stages. Significant binocular correlations were present only when cortico
      thalamic feedback was intact. In the absence of retinal drive, cortico-thalamic
      feedback was required to sustain correlated LGN bursting. Activity originating
      from the contralateral eye drove thalamic activity far more strongly than that
      originating from the ipsilateral eye. Thus, in vivo patterns of LGN spontaneous
      activity emerge from interactions between retina, thalamus, and cortex.

PMID- 10417393
TI  - Altered expression of cell cycle proteins and prolonged duration of cardiac
      myocyte hyperplasia in p27KIP1 knockout mice.
AB  - -The precise role of cell cycle-dependent molecules in controlling the switch
      from cardiac myocyte hyperplasia to hypertrophy remains to be determined. We
      report that loss of p27(KIP1) in the mouse results in a significant increase in
      heart size and in the total number of cardiac myocytes. In comparison to
      p27(KIP1)+/+ myocytes, the percentage of neonatal p27(KIP1)-/- myocytes in S
      phase was increased significantly, concomitant with a significant decrease in the
      percentage of G(0)/G(1) cells. The expressions of proliferating cell nuclear
      antigen, G(1)/S and G(2)/M phase-acting cyclins, and cyclin-dependent kinases
      (CDKs) were upregulated significantly in ventricular tissue obtained from early
      neonatal p27(KIP1)-/- mice, concomitant with a substantial decrease in the
      expressions of G(1) phase-acting cyclins and CDKs. Furthermore, mRNA expressions
      of the embryonic genes atrial natriuretic factor and alpha-skeletal actin were
      detectable at significant levels in neonatal and adult p27(KIP1)-/- mouse hearts
      but were undetectable in p27(KIP1)+/+ hearts. In addition, loss of p27(KIP1) was
      not compensated for by the upregulation of other CDK inhibitors. Thus, the loss
      of p27(KIP1) results in prolonged proliferation of the mouse cardiac myocyte and
      perturbation of myocyte hypertrophy.

PMID- 10417394
TI  - E2F-1 overexpression in cardiomyocytes induces downregulation of p21CIP1 and
      p27KIP1 and release of active cyclin-dependent kinases in the presence of insulin
      like growth factor I.
AB  - The heart is a postmitotic organ unable to regenerate after injury. The
      mechanisms controlling cell cycle arrest in cardiomyocytes are still unknown.
      Adenoviral delivery of E2F-1 to primary rat cardiomyocytes resulted in an
      increase in the expression of key cell cycle activators and apoptosis in >90% of
      the cells. However, insulin-like growth factor I (IGF-I) rescued cardiomyocytes
      from E2F-1-induced apoptosis. Furthermore, overexpression of E2F-1 in the
      presence of IGF-I induced the specific downregulation of total p21(CIP1) and
      p27(KIP1) protein levels and their dissociation from cyclin-dependent kinases
      (cdks). In contrast, p16(INK4) and p57(KIP2) protein levels and their association
      with cdks remained unaltered. The dissociation of p21(CIP1) and p27(KIP1) from
      their cdk complexes correlated well with the activation of cdk2, cdk4, and cdk6
      and the release from cell cycle arrest. Under these circumstances, the number of
      cardiomyocytes in S phase rose from 1.2% to 23%. These results indicate that IGF
      I renders cardiomyocytes permissive for cell cycle reentry. Finally, the specific
      downregulation of p21(CIP1) and p27(KIP1) further suggests their key role in the
      maintenance of cell cycle arrest in cardiomyocytes.

PMID- 10417395
TI  - Mechanical stretch and angiotensin II differentially upregulate the renin
      angiotensin system in cardiac myocytes In vitro.
AB  - Pressure overload in vivo results in left ventricular hypertrophy and activation
      of the renin-angiotensin system in the heart. Mechanical stretch of neonatal rat
      cardiac myocytes in vitro causes secretion of angiotensin II (Ang II), which in
      turn plays a pivotal role in mechanical stretch-induced hypertrophy. Although in
      vivo data suggest that the stimulus of hemodynamic overload serves as an
      important modulator of cardiac renin-angiotensin system (RAS) activity, it is not
      clear whether observed upregulation of RAS genes is a direct effect of
      hemodynamic stress or is secondary to neurohumoral effects in response to
      hemodynamic overload. Moreover, it is unclear whether activation of the local RAS
      in response to hemodynamic overload predominantly occurs in cardiac myocytes or
      fibroblasts or both. In the present study, we examined the effect of mechanical
      stretch on expression of angiotensinogen, renin, angiotensin-converting enzyme
      (ACE), and Ang II receptor (AT(1A), AT(1B), and AT(2)) genes in neonatal rat
      cardiac myocytes and cardiac fibroblasts in vitro. The level of expression of
      angiotensinogen, renin, ACE, and AT(1A) genes was low in unstretched cardiac
      myocytes, but stretch upregulated expression of these genes at 8 to 24 hours.
      Stimulation of cardiac myocytes with Ang II also upregulated expression of
      angiotensinogen, renin, and ACE genes, whereas it downregulated AT(1A) and did
      not affect AT(1B) gene expression. Although losartan, a specific AT(1)
      antagonist, completely inhibited Ang II-induced upregulation of angiotensinogen,
      renin, and ACE genes, as well as stretch-induced upregulation of AT(1A)
      expression, it did not block upregulation of angiotensinogen, renin, and ACE
      genes by stretch. Western blot analyses showed increased expression of
      angiotensinogen and renin protein at 16 to 24 hours of stretch. The ACE-like
      activity was also significantly elevated at 24 hours after stretch. Radioligand
      binding assays revealed that stretch significantly upregulated the AT(1) density
      on cardiac myocytes. Interestingly, stretch of cardiac fibroblasts did not result
      in any discernible increases in the expression of RAS genes. Our results indicate
      that mechanical stretch in vitro upregulates both mRNA and protein expression of
      RAS components specifically in cardiac myocytes. Furthermore, components of the
      cardiac RAS are independently and differentially regulated by mechanical stretch
      and Ang II in neonatal rat cardiac myocytes.

PMID- 10417396
TI  - Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic
      phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro.
AB  - Oxidative stress has been implicated in the pathophysiology of myocardial
      failure. We tested the hypothesis that inhibition of endogenous antioxidant
      enzymes can regulate the phenotype of cardiac myocytes. Neonatal rat ventricular
      myocytes in vitro were exposed to diethyldithiocarbamic acid (DDC), an inhibitor
      of cytosolic (Cu, Zn) and extracellular superoxide dismutase (SOD). DDC inhibited
      SOD activity and increased intracellular superoxide in a concentration-dependent
      manner. A low concentration (1 micromol/L) of DDC stimulated myocyte growth, as
      demonstrated by increases in protein synthesis, cellular protein, prepro-atrial
      natriuretic peptide, and c-fos mRNAs and decreased sarcoplasmic reticulum
      Ca(2+)ATPase mRNA. These actions were all inhibited by the superoxide scavenger
      Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid). Higher concentrations of DDC
      (100 micromol/L) stimulated myocyte apoptosis, as evidenced by DNA laddering,
      characteristic nuclear morphology, in situ terminal deoxynucleotidyl transferase
      mediated nick end-labeling (TUNEL), and increased bax mRNA expression. DDC
      stimulated apoptosis was inhibited by the SOD/catalase mimetic EUK-8. The growth
      and apoptotic effects of DDC were mimicked by superoxide generation with xanthine
      plus xanthine oxidase. Thus, increased intracellular superoxide resulting from
      inhibition of SOD causes activation of a growth program and apoptosis in cardiac
      myocytes. These findings support a role for oxidative stress in the pathogenesis
      of myocardial remodeling and failure.

PMID- 10417399
TI  - Reentry and fibrillation in the mouse heart. A challenge to the critical mass
      hypothesis.
AB  - The idea that fibrillation is only possible in hearts exceeding a critical size
      was introduced by W. Garrey >80 years ago and has since been generally accepted.
      In ventricular tissue, this critical size was originally estimated to be 400
      mm(2). Recent estimates suggest that the critical size required for sustained
      reentry is approximately 100 to 200 mm(2), whereas 6 times this area is required
      for ventricular fibrillation. According to these estimates, fibrillation is not
      possible in the mouse heart, where the ventricular surface area is approximately
      100 mm(2). To test whether sustained ventricular fibrillation could be induced in
      such an area, we used a high-speed video imaging system and a voltage-sensitive
      dye to quantify electrical activity on the epicardial surface of the Langendorff
      perfused adult mouse heart. In 6 hearts, measurements during ventricular pacing
      at a basic cycle length (BCL) of 120 ms yielded maximum and minimum conduction
      velocities (CV(max) and CV(min)) of 0.63+/-0.04 and 0.38+/-0.02 mm/ms,
      respectively. At a BCL of 80 ms, CV(max) and CV(min) changed to 0.55+/-0.03 and
      0. 34+/-0.02 mm/ms. Action potential durations (APDs), measured at 70%
      repolarization at those pacing frequencies were found to be 44.5+/-2. 9 and
      40.4+/-2.6 ms, respectively. The wavelengths (CVxAPD) were calculated to be
      28.6+/-3.4 mm in the CV(max) direction and 16.8+/-1. 5 mm in the CV(min)
      direction at BCL 120 ms. Wavelengths were significantly reduced (P<0.05) at BCL
      80 ms (CV(max), 22.2+/-1.8 mm; CV(min), 13.7+/-0.9 mm). In 5 hearts, stationary
      vortex-like reentry organized by single rotors (4 of 5 hearts) or by pairs of
      rotors (1 of 5 hearts) was induced by burst pacing. In the ECG, the activity
      manifested as sustained monomorphic tachycardia. Detailed analysis showed that
      the local CVs were reduced in the vicinity of the rotor center, which allowed the
      reentry to take place within a smaller area than was calculated from wavelength
      measurements during pacing. In 4 of 7 hearts, burst pacing resulted in a
      polymorphic ECG pattern indistinguishable from ventricular fibrillation. These
      data challenge the critical mass hypothesis by demonstrating that ventricular
      tissue with an area as small as 100 mm(2) is capable of undergoing sustained
      fibrillatory activity.

PMID- 10417398
TI  - Glucocorticoid regulation of cardiac K+ currents and L-type Ca2+ current in
      neonatal mice.
AB  - Previous studies have reported that dexamethasone (Dex) prolongs cardiac action
      potential repolarization in mice and rats. However, the cellular mechanisms of
      this effect have not been addressed. Because action potential duration is
      influenced by a complex interplay of both inward and outward currents, this study
      evaluated the role of K+ currents and the L-type Ca2+ current in response to
      chronic in vivo Dex treatment. Accordingly, neonatal mice were randomly allocated
      to treatment with Dex (1 mg/kg per day) or placebo (saline) given subcutaneously
      for 5 days. At 14 to 15 days of age, the L-type Ca2+ current and K+ currents were
      recorded in ventricular myocytes using whole-cell patch-clamp techniques. The
      density of peak outward K+ currents was significantly decreased in the chronic
      Dex-treated group, but the current measured at the end of a 1-second
      depolarization pulse was similar in both groups. We further measured the
      magnitudes of the fast-inactivating (I(to)) and the slowly inactivating (I(slow))
      currents that contribute to the peak outward K+ currents. I(to) was reduced from
      17.5+/-3.0 pA/pF (control) to 10.6+/-2.5 pA/pF (Dex) at +50 mV (P<0.05), but
      I(slow) was not significantly different. These data suggest that downregulation
      of I(to) is responsible for the reduced peak outward current. Time courses of the
      onset and offset of in vivo Dex effects were also assessed. A period of 3 days of
      treatment was required to observe the Dex effect on peak outward K(+) currents,
      whereas a 7-day period after discontinuation of Dex was required to recover the
      baseline current density. Acute in vitro treatment with Dex (1 micromol/L) had no
      effect on K+ current densities. In addition, chronic Dex treatment significantly
      increased the density of the L-type Ca2+ current (I(Ca-L)) from -7.2+/-0.5 pA/pF
      of control to -8.9+/-0.6 pA/pF of Dex at +10 mV, P<0.05. In conclusion, chronic
      in vivo Dex treatment decreases I(to) and increases I(Ca-L) in neonatal mouse
      ventricular myocytes, both of which contribute to the prolongation of cardiac
      action potential repolarization induced by glucocorticoids.

PMID- 10417397
TI  - Spatiotemporal development and distribution of intercellular junctions in adult
      rat cardiomyocytes in culture.
AB  - The mode of development of the intercalated disk (ID) is largely unknown, and the
      hypothesis was tested that the assembly of cell adhesion junctions may precede
      the formation of gap junctions (GJ) in developing ID in adult rat cardiomyocyte
      (ARC) in long-term culture. Immunostaining for connexin 43 (Cx43) and for cell
      adhesion junction proteins (N-cadherin, catenins, and desmoplakin) in single- and
      double-label techniques was analyzed and quantified by confocal and electron
      microscopy. All proteins investigated disappeared 48 hours after ARC isolation
      and reappeared parallel to redifferentiation of ARC. The newly formed ID,
      observed after 5 days, showed the presence of N-cadherin, catenins, and
      desmoplakin, low levels of Cx43, and absence of ultrastructurally discernible gap
      junctions. A progressive incorporation of Cx43 within ID was observed after 6
      days, when cell adhesion junction proteins were already organized as zipper-like
      structures. Quantitative confocal analysis revealed a progressive augmentation of
      the fluorescence intensity of Cx43, associated with an increase in both the
      number and size of GJ, resulting in a substantial increase in the percentage of
      total GJ length per reassembled ID from 1.67% (day 6) to 15.58% (day 12). In the
      present study, we show that (1) the formation of the ID can be followed in ARC in
      culture and (2) the assembly of the adhering type of junction is the prerequisite
      for subsequent GJ formation within the ID. These findings may have clinical
      relevance in elaborating strategies for using myocardial grafts and for the
      potential restoration of GJ communication in cardiac diseases.

PMID- 10417400
TI  - BTEB2, a Kruppel-like transcription factor, regulates expression of the
      SMemb/Nonmuscle myosin heavy chain B (SMemb/NMHC-B) gene.
AB  - We have recently characterized the promoter region of the rabbit embryonic smooth
      muscle myosin heavy chain (SMemb/NMHC-B) gene and identified the 15-bp sequence,
      designated SE1, located at -105 from the transcriptional start site as an
      important regulatory element for its transcriptional activity in a smooth muscle
      cell (SMC) line. In this study, we attempted to isolate cDNA clones encoding for
      the transcription factors that control the expression of the SMemb gene through
      binding to this cis-regulatory element. We screened a lambdagt11 cDNA library
      prepared from C2/2 cells, a rabbit-derived SMC line, by using a radiolabeled
      concatenated oligonucleotide containing SE1 as a probe. Sequence analysis
      revealed that one of the cDNA clones corresponds to the rabbit homologue of basic
      transcriptional element binding protein-2 (BTEB2), which has previously been
      identified as one of the Kruppel-like transcription factor. Gel mobility shift
      assays and antibody supershift analyses with nuclear extracts from C2/2 cells
      indicate that BTEB2 is a major component of nuclear factor:SE1 complexes.
      Furthermore, a glutathione S-transferase-BTEB2 fusion protein binds to the SE1 in
      a sequence-specific manner. In support of the functionality of BTEB2 binding,
      basal promoter activity and BTEB2-induced transcriptional activation were
      markedly attenuated by the disruption of the SE1. In adult rabbit tissues, BTEB2
      mRNA was most highly expressed in intestine, urinary bladder, and uterus. BTEB2
      mRNA levels were downregulated in rabbit aorta during normal development.
      Moreover, immunohistochemical analysis indicated a marked induction of BTEB2
      protein in the neointimal SMC after balloon injury in rat aorta. These results
      suggest that BTEB2 mediates the transcriptional regulation of the SMemb/NMHC-B
      gene and possibly plays a role in regulating gene expression during phenotypic
      modulation of vascular SMC.

PMID- 10417401
TI  - Bradycardia-induced coronary angiogenesis is dependent on vascular endothelial
      growth factor.
AB  - A marked coronary angiogenesis is known to occur with chronic bradycardia. We
      tested the hypothesis that vascular endothelial growth factor (VEGF), an
      endothelial cell mitogen and a major regulator of angiogenesis, is upregulated in
      response to low heart rate and consequential increased stroke volume. Bradycardia
      was induced in rats by administering the bradycardic drug alinidine (3 mg/kg body
      weight) twice daily. Heart rate decreased by 32% for 20 to 40 minutes after
      injection and was chronically reduced by 10%, 14%, and 18.5% after 1, 2, and 3
      weeks of treatment, respectively. Arterial pressure and cardiac output were
      unchanged. Left ventricular capillary length density (mm/mm(3)) increased
      gradually with alinidine administration; a 15% increase after 2 weeks and a 40%
      increase after 3 weeks of alinidine treatment were documented. Left ventricular
      weight, body weight, and their ratio were not significantly altered by alinidine
      treatment. After 1 week of treatment, before an increase in capillary length
      density, VEGF mRNA increased >2-fold and then declined to control levels after 3
      weeks of treatment. VEGF protein was higher in alinidine-treated rats than in
      controls after 2 weeks and increased further after 3 weeks of treatment.
      Injection of VEGF-neutralizing antibodies over a 2-week period completely blocked
      alinidine-stimulated angiogenesis. In contrast, bFGF mRNA was not altered by
      alinidine treatment. These data suggest that VEGF plays a key role in the
      angiogenic response that occurs with chronic bradycardia. The mechanism
      underlying this VEGF-associated angiogenesis may be an increase in stretch due to
      enhanced diastolic filling.

PMID- 10417402
TI  - Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule
      1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed
      to lesion formation.
AB  - The recruitment of mononuclear leukocytes and formation of intimal macrophage
      rich lesions at specific sites of the arterial tree are key events in
      atherogenesis. Inducible endothelial cell adhesion molecules may participate in
      this process. In aortas of normal chow-fed wild-type mice and rabbits, vascular
      cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1),
      but not E-selectin, were expressed by endothelial cells in regions predisposed to
      atherosclerotic lesion formation. En face confocal microscopy of the mouse
      ascending aorta and proximal arch demonstrated that VCAM-1 expression was
      increased on the endothelial cell surface in lesion-prone areas. ICAM-1
      expression extended into areas protected from lesion formation.
      Hypercholesterolemia induced atherosclerotic lesion formation in rabbits, LDL
      receptor and apolipoprotein E knockout mice, and Northern blot analysis
      demonstrated increased steady-state mRNA levels of VCAM-1 and ICAM-1, but not of
      E-selectin. Immunohistochemical staining revealed that VCAM-1 and ICAM-1 were
      expressed predominantly by endothelium in early lesions and by intimal cells in
      more advanced lesions. In early and advanced lesions, staining was most intense
      in endothelial cells at and adjacent to lesion borders. ICAM-1 staining extended
      into the uninvolved aorta. These expression patterns were highly reproducible in
      both species. The only difference was that VCAM-1 expression in endothelium over
      the central portions of lesions was found frequently in rabbits and rarely in
      mice. The expression of VCAM-1 by arterial endothelium in normal animals may
      represent a pathogenic mechanism or a phenotypic marker of predisposition to
      atherogenesis.

PMID- 10417403
TI  - Very low density lipoprotein-mediated signal transduction and plasminogen
      activator inhibitor type 1 in cultured HepG2 cells.
AB  - In normal subjects and in patients with cardiovascular disease, plasma
      triglycerides are positively correlated with plasminogen activator inhibitor type
      1 (PAI-1) levels. Moreover, in vitro studies indicate that VLDLs induce PAI-1
      synthesis in cultured cells, ie, endothelial and HepG2 cells. However, the
      signaling pathways involved in the effect of VLDL on PAI-1 synthesis have not yet
      been investigated. We report that VLDLs induce a signaling cascade that leads to
      an enhanced secretion of PAI-1 by HepG2 cells. In myo-[(3)H]inositol-labeled
      HepG2 cells, VLDL (100 microg/mL) caused a time-dependent increase in
      [(3)H]inositol phosphates, the temporal sequence being tris>bis>monophosphate.
      VLDL brought about a time-dependent stimulation of membrane-associated protein
      kinase C (PKC) activity and arachidonate release. Finally, VLDL stimulated
      mitogen-activated protein (MAP) kinase, and this effect was reduced by 1-(5
      isoquinolinylsulfonyl)-2-methylpiperazine (H7), which suggests that PKC plays a
      pivotal role in MAP kinase phosphorylation. VLDL-induced PAI-1 secretion was
      completely prevented by U73122, a specific inhibitor of phosphatidylinositol
      specific phospholipase C, by H7 or by PKC downregulation, and by mepacrine (all
      P<0.01 versus VLDL-treated cells). 3,4,5-Trimethoxybenzoic acid 8-(diethylamino)
      octyl ester, which prevents Ca2+ release from intracellular stores, inhibited
      VLDL-induced PAI-1 secretion by 60% (P<0.05), and the MAP kinase/extracellular
      signal-regulated kinase kinase (MEK) inhibitor PD98059 completely suppressed both
      basal and VLDL-induced PAI-1 secretion. These data demonstrate that VLDL-induced
      PAI-1 biosynthesis results from a principal signaling pathway involving PKC
      mediated MAP kinase activation.

PMID- 10417404
TI  - Crystallization and preliminary crystallographic study of HIP/PAP, a human C
      lectin overexpressed in primary liver cancers.
AB  - Human HIP/PAP is an adhesion protein expressed in normal pancreatic and Paneth
      cells and overexpressed in hepatocellular carcinoma. HIP/PAP was crystallized
      using the Hampton Research Crystal Screen and SAmBA software to define the
      optimal crystallization protocol. The crystals belong to the orthorhombic space
      group P2(1)2(1)2(1), with unit-cell parameters a = 30.73, b = 49.35, c = 92.15 A
      and one molecule in the asymmetric unit. Flash-frozen crystals diffract to 1. 78
      A resolution using synchrotron radiation. A molecular-replacement solution was
      obtained using the human Reg/lithostathine structure and the AMoRe software.

PMID- 10417405
TI  - Structures of the complexes of peanut lectin with methyl-beta-galactose and N
      acetyllactosamine and a comparative study of carbohydrate binding in Gal/GalNAc
      specific legume lectins.
AB  - The crystal structures of complexes of peanut lectin with methyl-beta-galactose
      and N-acetyllactosamine have been determined at 2.8 and 2.7 A, respectively.
      These, and the complexes involving lactose and the T-antigenic disaccharide
      reported previously, permit a detailed characterization of peanut-lectin
      carbohydrate association and the role of water molecules therein. The water
      molecules in the combining site are substantially conserved in the four
      complexes. The role of interacting sugar hydroxyl groups, when absent, are often
      mimicked by ordered water molecules not only at the primary combining site, but
      also at the site of the second sugar ring. The similarity of peanut-lectin-sugar
      interactions with those in other galactose/N-acetylgalactosamine-specific lectins
      also extend to a substantial degree to water bridges. The comparative study
      provides a structural explanation for the exclusive specificity of peanut lectin
      for galactose at the monosaccharide level, compared with that of the other
      lectins for galactose as well as N-acetylgalactosamine. The complexes also
      provide a qualitative structural rationale for differences in the strengths of
      binding of peanut lectin to different sugars.

PMID- 10417406
TI  - Structure of orthorhombic crystals of beef liver catalase.
AB  - The growth mechanisms and physical properties of the orthorhombic crystal form of
      beef liver catalase were investigated using in situ atomic force microscopy
      (AFM). It was observed that the crystals grow in the <001> direction by an
      unusual progression of sequential two-dimensional nuclei of half unit-cell layers
      corresponding to the 'bottoms' and 'tops' of unit cells. These were easily
      discriminated by their alternating asymmetric shapes and their strong growth-rate
      anisotropy. This pattern has not previously been observed with other
      macromolecular crystals. Orthorhombic beef liver catalase crystals exhibit an
      extremely high defect density and incorporate great numbers of misoriented
      microcrystals, revealed intact by etching experiments, which may explain their
      marginal diffraction properties. To facilitate interpretation of AFM results in
      terms of intermolecular interactions, the structure of the orthorhombic crystals,
      having an entire tetramer of the enzyme as the asymmetric unit, was solved by
      molecular replacement using a model derived from a trigonal crystal form. It was
      subsequently refined by conventional techniques. Although the packing of
      molecules in the two unit cells was substantially different, with very few
      exceptions no significant differences in the molecular structures were observed.
      In addition, no statistically significant deviation from ideal 222 molecular
      symmetry appeared within the tetramer. The packing of molecules in the crystal
      revealed by X-ray analysis explained in a satisfying way the process of crystal
      growth revealed by AFM.

PMID- 10417407
TI  - Crystallographic analysis of potent and selective factor Xa inhibitors complexed
      to bovine trypsin.
AB  - Factor Xa is a serine protease which activates thrombin (factor IIa) and plays a
      key regulatory role in the blood-coagulation cascade. Factor Xa is, therefore, an
      important target for the design of anti-thrombotics. Both factor Xa and thrombin
      share sequence and structural homology with trypsin. As part of a factor Xa
      inhibitor-design program, a number of factor Xa inhibitors were
      crystallographically studied complexed to bovine trypsin. The structures of one
      diaryl benzimidazole, one diaryl carbazole and three diaryloxypyridines are
      described. All five compounds bind to trypsin in an extended conformation, with
      an amidinoaryl group in the S1 pocket and a second basic/hydrophobic moiety bound
      in the S4 pocket. These binding modes all bear a resemblance to the reported
      binding mode of DX-9065a in bovine trypsin and human factor Xa.

PMID- 10417408
TI  - Disorder and twin refinement of RNA heptamer double helices.
AB  - An RNA helix with seven base pairs which was derived from the acceptor stem of
      Escherichia coli tRNA(Ala), rGGGGCUA.rUAGCUCC (ALA(wt)), as well as a variant,
      rGGGGCUA.rUAGCCCC (ALA(C70)), in which the single G.U wobble base pair of ALA(wt)
      was replaced by G.C, crystallize in space group C2. Both non-isomorphic crystal
      forms display a complex packing pattern, which can be described alternatively as
      disorder or pseudo-merohedral twinning. The structure of ALA(wt) was determined
      by SIRAS phasing using an isomorphous iodine derivative, rGGGGCi(5)UA.rUAGCUCC
      (ALA(I)). All three RNA structures were subsequently subjected to twin refinement
      in space group P1, using anisotropic thermal displacement parameters at
      resolutions of 1.16, 1.23 and 1.4 A for ALA(wt), ALA(I) and ALA(C70),
      respectively. Alternatively, the structure of ALA(wt) was refined in space group
      C2 assuming twofold disorder of the molecular orientation. The refined structures
      are of reasonable quality according to all available indicators. There are no
      systematic differences between the molecular models resulting from twin
      refinement and disorder refinement.

PMID- 10417409
TI  - A database analysis of potential glycosylating Asn-X-Ser/Thr consensus sequences.
AB  - An analysis of the frequency of occurrence of various residues at position X was
      carried out on the consensus glycosylating sequence Asn-X-Ser/Thr using the PDB
      three-dimensional database. 488 non-homologous proteins bearing 696 Asn-X-Ser/Thr
      (X not equal Pro) sequences were analysed. More than 65% of Asn residues, when
      they occur as part of the consensus sequence, lie on the surface of the protein,
      implying a potentiality for glycosylation. A deviation parameter (DP) was
      calculated as a measure of preferential (positive) or non-preferential (negative)
      selection. At the X position in the consensus-sequence segment, the amino acids
      Gly, Asn and Phe have statistically significant positive DP values. The high
      value of DP for Asn is a consequence of the preferential occurrence of
      homodoublets, while for Phe it may be a consequence of the stacking interaction
      of the aromatic ring with the glycan. Gly at the X position in the consensus
      glycosylating sequence may be functionally significant owing to its preference
      and its high percentage of occurrence in proteins. The Ramachandran (Phi,Psi)
      angles around Gly in the consensus sequence show clustering in the region which
      is disallowed for non-glycyl residues. In this region, a hydrogen bond between
      the side chain of Asn and the peptide backbone/side chain of Ser/Thr is possible,
      reflecting a positional as well as a conformational role in the consensus
      glycosylating sequence. For the 44 confirmed N-glycosylating sequences, an in
      depth analysis of the (Psi(N), Phi(X), Psi(X), Phi(S/T)) dihedral angles, which
      position the side chains of Asn and Ser/Thr, shows that these can be grouped into
      nine conformational states. In most cases, a direct or water-mediated hydrogen
      bond between OD1 of Asn and OG of Ser/Thr is possible, reflecting the possible
      importance of this hydrogen bonding in the glycosylation process.

PMID- 10417410
TI  - Packing of aromatic rings against tryptophan residues in proteins.
AB  - The geometry of the interaction of the aromatic side chains of phenylalanine
      (Phe), tyrosine (Tyr), tryptophan (Trp) and histidine (His) with the indole ring
      of Trp has been analyzed using the structures in the Protein Data Bank in order
      to understand the dependence of the packing behaviour on the size and chemical
      nature of the aromatic rings. The Phe ring prefers to interact either
      perpendicularly, with its edge pointing towards the Trp face, or in an offset
      stacked arrangement. The edge-to-face motif is typical of a Trp-Trp pair. While
      parallel stacking is the dominant feature of Trp-His interaction, Tyr packs in a
      more uniform manner around Trp with a higher than expected occurrence at the edge
      and a few cases of possible OH-pi interaction.

PMID- 10417411
TI  - Derivative manipulation in the structure solution of the integral membrane LH2
      complex.
AB  - The structure of the peripheral light-harvesting complex from Rhodopseudomonas
      acidophila strain 10050 was determined by multiple isomorphous replacement
      methods. The derivatization of the crystals was augmented by the addition of a
      backsoaking stage. The soak/backsoaked data comparison had greater isomorphism
      and showed simpler Patterson maps than the standard native/soak comparison.
      Amplitudes from the derivatized then backsoaked crystals and from the derivatized
      crystals were compared in order to extract a subset of heavy-atom sites. Using
      this information, the full array of sites were found from a derivative/native
      comparison, eventually leading to excellent electron-density maps.

PMID- 10417412
TI  - The geometry of metal-ligand interactions relevant to proteins.
AB  - Geometrical data which could be of relevance in the structure determination,
      structure refinement, assessment or understanding of metalloproteins have been
      extracted from the Cambridge Structural Database (CSD). The CSD contains
      crystallographic data from 'small-molecule' structures determined by X-ray or
      neutron diffraction to an accuracy much better than that of most current protein
      structure determinations. The structures selected have a crystallographic R
      factor </= 0.065 and contain Ca, Mg, Mn, Fe, Cu or Zn interacting with ligands
      which are analogues of the amino-acid side chains commonly found in proteins;
      they include carboxylate groups, alcohols, phenolates, thiolates, imidazole
      groups and also water molecules. For each pair, the mean metal-donor-atom
      distance, the sample standard deviation and the range of observed values are
      tabulated, using approximately 4500 observations in all. Where practicable,
      subsets with different coordination numbers and/or oxidation states are given.
      Also included are inter-bond angles at the ligand donor atom, the orientation of
      carboxylate and imidazole groups with respect to the metal-donor-atom bond and
      some other aspects of ligand geometry. Thus, for example, target distances and
      their standard deviations could be easily looked up for the validation of a
      metalloprotein structure or for use in restrained refinement with low-resolution
      data.

PMID- 10417413
TI  - Protein crystallization with a combination of hard and soft precipitants.
AB  - Much effort and progress have been made in understanding the nucleation and
      crystallization of globular proteins, and many techniques have been developed to
      crystallize proteins in the past decades. The advantages of the use of combined
      precipitants in protein crystallization have been much appreciated.
      Unfortunately, there is still no theory or empirical guide on how to combine so
      many precipitants and how to use combined precipitants, although many proteins
      have been crystallized successfully using combined precipitants. This report
      gives a proposal about how to use conventional precipitants to obtain protein
      crystals, based on a novel idea of hard and soft precipitant combinations.

PMID- 10417414
TI  - Two-wavelength MAD phasing: in search of the optimal choice of wavelengths.
AB  - The multiwavelength anomalous dispersion (MAD) method is increasingly being used
      to determine protein crystal structures. In theory, data collection at two
      wavelengths is sufficient for the determination of MAD phases, but three or even
      more wavelengths are used most often. In this paper, the results of the phasing
      procedure using only two wavelengths for proteins containing different types of
      anomalous scatterers are analyzed. In these cases, it is shown that this approach
      leads to interpretable maps, similar in quality to those obtained with data
      collected at three wavelengths, provided that the wavelengths are chosen so as to
      give a large contrast in the real part of the anomalous scattering factor f. The
      consequences for a rational MAD data-collection strategy are discussed.

PMID- 10417415
TI  - Crystallization and preliminary X-ray analysis of human rhinovirus serotype 2
      (HRV2).
AB  - Human rhinoviruses, the major cause of mild recurrent infections of the upper
      respiratory tract, are small icosahedral particles. Over 100 different serotypes
      have been identified. The majority (91 serotypes) use intercellular adhesion
      molecule 1 as the cell-attachment site; ten serotypes (the minor group) bind to
      members of the low-density lipoprotein receptor. Three different crystal forms of
      the minor-group human rhinovirus serotype 2 (HRV2) were obtained by the hanging
      drop vapour-diffusion technique using ammonium sulfate and sodium/potassium
      phosphate as precipitants. Monoclinic crystals, space group P2(1), diffracted at
      least to 2.8 A resolution, and two complete virus particles were located in the
      crystal asymmetric unit. A second type of crystals had a compact cubic like
      morphology and diffracted beyond 2.5 A resolution. These crystals belong to a
      primitive orthorhombic space group, with unit-cell parameters a = 309.3, b =
      353.5, c = 759.6 A, and contain one virus particle in the asymmetric unit. A
      third type of crystals, with a prismatic shape and belonging to space group I222,
      was also obtained under similar crystallization conditions. These latter
      crystals, with unit-cell parameters a = 308.7, b = 352.2, c = 380.5 A, diffracted
      to high resolution (beyond 1.8 A) and contained 15 protomers per asymmetric unit;
      this requires that three perpendicular crystal twofold axes coincide with three
      of the viral particle's dyad axes.

PMID- 10417416
TI  - Crystallization and preliminary X-ray diffraction studies of mammalian purple
      acid phosphatase.
AB  - The oxidized form of purple acid phosphatase from pig allantoic fluid has been
      crystallized in the presence of phosphate using the hanging-drop technique. The
      crystals belong to the space group P2(1)2(1)2(1) and have unit-cell parameters a
      = 66.8, b = 70.3, c = 78.7 A. Diffraction data collected from a cryocooled
      crystal using a conventional X-ray source extend to 1.55 A resolution. A
      knowledge of the three-dimensional structure of mammalian purple acid phosphatase
      will aid in understanding the substrate specificity of the enzyme and will be
      important in the rational design of inhibitors, with potential in the treatment
      of bone diseases.

PMID- 10417417
TI  - Crystallization and preliminary diffraction data analysis of both single and
      pseudo-merohedrally twinned crystals of rubredoxin oxygen oxidoreductase from
      Desulfovibrio gigas.
AB  - Crystals of rubredoxin oxygen oxidoreductase have been obtained and
      characterized. They belong to space group P2(1)2(1)2, with unit-cell dimensions a
      = 88.24 (15), b = 101.25 (7), c = 90.80 (3) A. The homodimer (86 kDa) in the
      asymmetric unit is related by a non-crystallographic twofold rotation axis
      parallel to the ab 'diagonal' direction, as shown by the self-rotation maximum in
      the section with chi = 180 degrees. This pseudo-crystallographic symmetry element
      was also found to be the twinning axis of pseudo-merohedrally twinned crystals,
      leading to apparent pseudo-tetragonal P42(1)2 crystal symmetry.

PMID- 10417418
TI  - Crystallization and preliminary diffraction data of a platelet-aggregation
      inhibitor from the venom of Agkistrodon piscivorus piscivorus (North American
      water moccasin).
AB  - Applaggin (Agkistrodon piscivorus piscivorus platelet-aggregation inhibitor) is a
      potent inhibitor of blood platelet aggregation derived from the venom of the
      North American water moccasin. The protein consists of 71 amino acids, is rich in
      cysteines, contains the sequence-recognition site of adhesion proteins at
      positions 50-52 (Arg-Gly-Asp) and shares high sequence homology with other snake
      venom disintegrins such as echistatin, kistrin and trigramin. Single crystals of
      applaggin have been grown and X-ray diffraction data have been collected to a
      resolution of 3.2 A. The crystals belong to space group P4(1)2(1)2 (or its
      enantiomorph), with unit-cell dimensions a = b = 63.35, c = 74.18 A and two
      molecules per asymmetric unit. Molecular replacement using models constructed
      from the NMR structures of echistatin and kistrin has not been successful in
      producing a trial structure for applaggin.

PMID- 10417419
TI  - Crystallization and preliminary crystallographic investigations of rhodanese from
      Azotobacter vinelandii.
AB  - The rhdA gene identified in Azotobacter vinelandii codes for a protein, RhdA,
      which displays rhodanese (thiosulfate-cyanide sulfurtransferase) activity. RhdA
      was overexpressed and purified to homogeneity. The protein crystallized in the
      orthorhombic space group P2(1)2(1)2 with unit-cell parameters a = 44.4, b =
      150.8, c = 53.8 A; on a synchrotron source the diffraction patterns could be
      collected to a resolution limit of 1.8 A. Evaluation of the crystal density
      indicates that the crystal lattice accommodates one molecule per asymmetric unit
      and that the solvent content is 59% of the total volume.

PMID- 10417420
TI  - Crystallization and preliminary crystallographic analysis of the Escherichia coli
      tyrosine aminotransferase.
AB  - Tyrosine aminotransferase catalyzes transamination for both dicarboxylic and
      aromatic amino-acid substrates. The substrate-free Escherichia coli tyrosine
      aminotransferase (eTAT) bound with the cofactor pyridoxal 5'-phosphate (PLP) was
      crystallized in the trigonal space group P3(2). A low-resolution crystal
      structure of eTAT was determined by molecular-replacement methods. The overall
      folding of eTAT resembles that of the aspartate aminotransferases, with the two
      identical subunits forming a dimer in which each monomer binds a PLP molecule via
      a covalent bond linked to the epsilon-NH(2) group of Lys258. Comparison of the
      structure of eTAT with those of the open, half-open or closed form of chicken or
      E. coli aspartate aminotransferases shows the eTAT structure to be in the open
      conformation.

PMID- 10417421
TI  - Crystallization and initial X-ray analysis of rabbit mature sterol carrier
      protein 2.
AB  - Sterol carrier protein 2 (SCP2) is a basic intracellular protein which
      facilitates the in vitro intermembrane transfer of cholesterol, phospholipids and
      glycolipids. SCP2 was expressed in Escherichia coli, purified to apparent
      electrophoretic homogeneity and crystallized. Single crystals were obtained by
      hanging-drop vapour diffusion using ammonium sulfate as precipitant. These
      crystals belong to space group P4(1)2(1)2 or its enantiomorph, with unit-cell
      parameters a = b = 57.5, c = 86.5 A, and have one molecule in the
      crystallographic asymmetric unit. Intensity data to 1.8 A resolution were
      collected from native SCP2 crystals using synchrotron radiation, were processed
      and scaled with an R(linear) = 4.9%.

PMID- 10417422
TI  - Crystallization and preliminary X-ray characterization of VanA from Enterococcus
      faecium BM4147: towards the molecular basis of bacterial resistance to the
      glycopeptide antibiotic vancomycin.
AB  - A recombinant form of Enterococcus facieum BM4147 D-alanine-D-lactate ligase
      (VanA) has been prepared and crystallized. VanA was found to crystallize only in
      the presence of a phosphinate inhibitor analogue of D-alanine-D-alanine. The
      crystals grow in 40-45% ammonium sulfate, 0.1 M 3-(N-morpholino)-propanesulfonic
      acid pH 6.0 and reach dimensions of 0.4 x 0.2 x 0.1 mm. The crystals diffract to
      at least 2.5 A and are in the centred orthorhombic space group C222(1), with unit
      cell dimensions a = 123.2, b = 225.4, c = 72.4 A.

PMID- 10417423
TI  - Crystallization and X-ray crystallographic analysis of m-calpain, a Ca2+
      dependent protease.
AB  - The absolute requirement of Ca(2+) for proteolytic activity is a feature unique
      to the calpains, a family of heterodimeric cysteine proteases. Conditions are
      described which give rise to diffraction-quality crystals of m-calpain in two
      crystal forms, P1 and P2(1). Data have been collected from native crystals of m
      calpain in both P1 and P2(1) forms, to 2.6 and 2.15 A, respectively.
      Selenomethionine-containing crystals have been grown in both forms, and anomalous
      data from the P2(1) selenomethionine enzyme provided the location of 17 of the 19
      Se atoms in the protein.

PMID- 10417424
TI  - [PTEN: a tumor suppressor with original properties].
AB  - A large effort has been made to understand the intracellular function of a novel
      tumor-suppressor gene, PTEN, recently identified in the 10q23 chromosome region
      that is often altered in human tumors. PTEN is a multifunctional protein endowed
      with a phosphatase activity capable of dephosphorylating not only proteins, at
      tyrosine, serine or threonine residues, but also phospholipids of the
      phosphatidylinositol pathway. Its protein phosphatase activity allows it to
      inhibit the Ras/Mek/Erk cascade, as well as FAK, the focal adhesion kinase, and
      thus to affect the interactions of cells with intracellular matrix which are
      important in the mechanism of invasion. Its lipid phosphatase activity blocks the
      PI3K/Akt pathway, provokes an arrest in G1 of the cell cycle and an increased
      sensitivity to apoptosis. PTEN therefore acts simultaneously on the morphology
      and the proliferation of tumoral cells and has thus been attributed a major role
      in tumor suppression.

PMID- 10417425
TI  - [Clinical research in oncology: which stakes for the next decade?].

PMID- 10417426
TI  - [Epidemiology of non-Hodgkin's lymphoma: recent data].
AB  - Non-Hodgkin's lymphoma consists of a group of disorders which is increasing for
      the last decades. In the USA, since the early 1970s, the incidence rate has
      increased by almost 60% and ranges from 3 to 4% per year, which is faster than
      for the majority of cancers. Important advances in our knowledge of
      histopathology together with new diagnostic tools, as well as the improvement of
      the registered data and ageing of the population, only partially explain this
      increase. Two viruses have been identified as possible etiologic agents for non
      Hodgkin's lymphoma: the Epstein-Barr virus and HTLV-I. More recently, HHV8 and
      the hepatitis C virus have been incriminated in the occurrence of non-Hodgkin's
      lymphomas. Congenital and acquired immunodeficiencies (due to immunosuppressive
      therapy and viral disease such as Aids) might also represent predisposing
      factors. However, the epidemic HIV infection is the most strongly correlated with
      the increasing incidence of non-Hodgkin's lymphoma in the United States. Finally,
      epidemiologic studies indicate that environmental factors may play an important
      role in the etiology of non-Hodgkin's lymphoma, specially toxic chemicals used in
      farming.

PMID- 10417427
TI  - [Nonsurgical treatment of hepatocellular carcinoma].
AB  - Hepatocellular carcinoma is responsible in France for approximately 5,500 deaths
      per year. Incidence rates are growing and the general status of patients is
      improving mainly because of earlier diagnosis and improvement in the treatment of
      complications of liver cirrhosis. In most of the cases the severity of the
      underlying liver disease is the prominent prognostic factor. Its treatment
      remains a difficult challenge for oncologists. Unfortunately surgery is usually
      contraindicated. Most trials of systemic chemotherapy are disappointing with poor
      response rates and severe side effects; new drugs and direct delivery in the
      hepatic artery appear to be of interest. Results with interferon are interesting
      but requires more studies. The lack of efficacy of antiandrogenic and
      antiestrogenic treatments were recently demonstrated; a recent randomized study
      showing the interest of somatostatin requires confirmation. Reports on
      radiotherapy are anecdotals. A lot of studies using liver directed therapies were
      conducted worldwide. Percutaneous ethanol injections (PEI) are well tolerated and
      are highly effective in small solitary tumors (> 70% of complete necrosis) but
      less in larger tumors; recurrences are frequent. No randomized trial have been
      performed concerning PEI but survival rates seem similar to those of surgery. A
      randomized controlled trial recently demonstrates that injection of acetic acid
      is more effective than injection of ethanol. Chemoembolization was extensively
      studied because of the demonstration of objective responses but all trials failed
      to demonstrate an improvement in survival. Intraarterial injection of radioactive
      Lipiodol achieves the same response rate and the same survival than
      chemoembolization but is significantly best tolerated. This treatment is superior
      to best supportive cares in patients with portal vein thrombosis. In conclusion,
      despite the fact that this disease is very frequent we have currently too many
      treatment options and are lacking of simple rules. The best treatment remains
      prevention, and the efficacy of hepatitis B vaccination was recently demonstrated
      in Taiwan.

PMID- 10417429
TI  - [Standards, options and recommendations (SOR) for clinical care of squamous cell
      carcinoma of the oropharynx. Groupe de travail SOR].
AB  - CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in
      1993, is a collaboration between the Federation of the French Cancer Centres
      (FNCLCC), the 20 French Cancer Centres and specialists from French Public
      Universities, General Hospitals and Private Clinics. The main objective is the
      development of clinical practice guidelines to improve the quality of health care
      and outcome for cancer patients. The methodology is based on literature
      systematic review and critical appraisal by a multidisciplinary group of experts,
      with feedback from specialists in cancer care delivery. OBJECTIVES: To develop
      clinical practice guidelines according to the definitions of Standards, Options
      and Recommendations for the management of squamous carcinoma of the oropharynx.
      METHODS: Data have been identified by literature search using Medline (1991-1998)
      and the expert groups personal reference lists. Once the guidelines were defined,
      the document was submitted for review to national and international independent
      reviewers and to the medical committees of the 20 French Cancer Centres. RESULTS:
      The main recommendations for squamous cell carcinoma of the oropharynx management
      are that: 1) diagnosis and initial assessment should be based on appropriate
      clinical and radiological findings; 2) the therapeutic strategy is based on
      surgery, radiotherapy, bradytherapy and chemotherapy; 3) in limited tumours, the
      recommended strategy involved the use of one of these modality; 4) a
      multimodality approach is recommended for the treatment of extended resectable
      tumours. Following results of recent meta-analyses, use of neo-adjuvant
      chemotherapy is not recommended. The same studies have shown that association of
      chemotherapy and radiotherapy either in sequence or in combination significantly
      improve survival of extended curable tumours. These associations are recommended
      within the framework of clinical trials; 5) follow-up of squamous carcinoma of
      the oropharynx should involve physical examination of the upper aerodigestive
      tract and the lymph nodes areas every three months during the first year, every
      six months during the second year and then every year. An annual chest x-ray is
      recommended. Other investigations should be performed as indicated by symptoms
      and clinical manifestations.

PMID- 10417428
TI  - [Herceptin, a monoclonal humanized antibody anti-HER2: a major therapeutic
      progress in breast cancers overexpressing this oncogene?].
AB  - HER2 is overexpressed in about 25% to 30% of breast cancers and associated with
      poor prognosis, resistance to hormonotherapy and lack of sensitivity to CMF-based
      adjuvant chemotherapy. Herceptin (trastuzumab), a humanized monoclonal antibody,
      administered as a single agent, produces objective responses in phase II trials
      in patients with metastatic breast cancers overexpressing HER2. It has shown a
      substantial benefit in a phase III trial which compares a standard first line
      chemotherapy (doxorubicin and cyclophosphamide or taxol alone) to the same
      chemotherapy with Herceptin in metastatic breast cancer. The Herceptin arm had
      significantly higher response rate (+ 53%), an improvement in the median duration
      of response (+ 57%) as well as in time to progression (+ 65%) compared to
      chemotherapy alone.

PMID- 10417430
TI  - [Cervical cancer screening for high risk women: is it possible? Results of a
      cervical cancer screening program in three suburban districts of Lyon].
AB  - Between november 1993 and october 1996, a cervical screening program was proposed
      for women 25-65-year-old who tend to have little or no medical supervision, in
      three suburban districts of Lyon. The data and results of the two last Pap-smears
      have been collected together with details of gynecological follow-up. Both
      general practitioners and gynaecologists were actively involved. A total of 3,792
      women (12.3% of the target) were registered, with a larger proportion of women
      over 60 (17.7%). According to the "Consensus of Lille", only 403 women (34.4%)
      had adequate screening (over 50 y: 25.8%, 35-49 y: 39.4%, 25-35 y: 36.5%) and
      2,489 women had inappropriate gynaecological follow-up: no smear for 185 women
      (4.9%) and inadequate schedule of follow-up visits for 476 others (12.5%).
      Missing data (date or results of Pap smear) were noted for 1,828 patients
      (48.2%). The screening procedure for women over 50 years was carried out mainly
      by general practitioner. Of 3,127 registered smears, 62 positive results were
      found (2.1%). Of these women, 9 were lost to follow-up and 4 did not have
      appropriate tests. Others results were: 27 negative further investigations, 9
      CIN1, 7 CIN2, 3 CIN3, 1 in situ carcinoma and 2 invasive carcinoma. Despite low
      participation, this pilot study indicates that a procedure can be established to
      integrate high risk women in cervical cancer screening programme. Active
      participation of general practitioners is essential.

PMID- 10417431
TI  - [Identification of sentinel lymph node in breast cancer: experience from the
      Institut Curie].
AB  - Sentinel lymph node (SN) biopsy is a recently developed, minimally invasive
      technique for staging the axilla in breast cancer. This new procedure of
      selective lymphadenectomy has been the subject of several studies, but there is
      not currently a consensus of opinion to define which is the best method of
      identification. At the Institut Curie since 1996, we have been using the Patent
      blue dye. The current series present the result of 122 patients with T1, T2, N0
      or N1a breast cancer consecutively operated between december 1997 and august
      1998. Sentinel nodes were identified in 107 out of 122 (87.7%) and accurately
      predicted axillary nodal status in 104 out of 107 (97.1%) cases. Three out of 35
      node positive patients would have been missed with sentinel node biopsy alone,
      for a false negative rate of 8.5%. In all 3 cases, one lymph node presented with
      a micrometastases. In 15 cases out of 35 with metastatic axillary nodes, the only
      positive node was the SN (43%). The encouraging results of this study shows that
      it is possible to identify, in a large number of cases, the sentinel node by
      means of Patent blue dye only. This article detailed the technique used and
      reviews the literature concerning other methods of identification.

PMID- 10417432
TI  - [Advanced breast cancer: an evaluation of the cost of recurrence].
AB  - In the context of a medicoeconomic study of the adjuvant treatment of breast
      cancer, we evaluated the cost of the recurrence. This cost was assessed from the
      medical records of 146 patients having presented either distant metastases, or a
      local recurrence followed or not by metastases between 1983 and 1990. We checked
      according to published data that the frequency of the metastatic risk is
      negligible if beyond 5 years after the local recurrence. Costs are expressed in
      1995 French Francs (FF), with the French Social Security point of view. From the
      medical records, we calculated the mean cost of each type of recurrence using
      medical costs (visits, drugs and treatments, assessments, tests, hospital care,
      outpatient services.) and non medical costs (patient transportation). The costs
      are 175,168 FF (standard deviation or SD: 127,972) for metastatic recurrence, and
      respectively 287,582 FF (SD: 142,280) and 115,705 FF (SD: 78,677) for local
      recurrence followed or not by metastases. There is a significant difference
      between these figures (p < 0.001). The hospitalization costs are around 66% of
      the total cost of each type of recurrences and they are significantly higher (p <
      0.005) when metastatic disease occurs after a local recurrence. The mean cost of
      isolated local recurrence added to metastatic recurrence, 290,873 FF, is not
      different from that of local recurrence followed by metastases, 287,582 FF (p =
      0.15). These results will be integrated in a model in order to evaluate the long
      term economic consequences of an adjuvant strategy in the treatment of breast
      cancer and presented in other publications.

PMID- 10417433
TI  - Fetal alcohol syndrome (FAS) in dermatology: an overview and an evaluation.
AB  - Certain skin disorders are affected by alcohol abuse. Maternal alcohol abuse
      during pregnancy also gives rise to a typical malformation pattern in the child
      with a varying degree of severity (grade I-III). The diagnosis of fetal alcohol
      syndrome (FAS) is based on the detailed history of the maternal alcohol
      consumption in combination with the clinical, morphological, intellectual and
      psychosocial development of the child. The behavior of the child is also of
      diagnostic value. The grade of severity of the FAS can be determined during the
      first three years of life on the basis of a scoring system. In addition to
      medical care and surgical treatment of associated disorders, early support for
      the mental development of the child is of immense importance. Furthermore, the
      medical, social and psychological care of the mother must be considered. In the
      field of dermatology, knowledge about the pathomechanism of FAS is also important
      for its prevention in unborn children. Women of childbearing age presenting with
      dermatological signs of possible alcohol abuse, should alert the dermatologist to
      the possible risk to the child of FAS. Familiarity with FAS and the ability to
      recognise its clinical features are important for the adequate treatment and
      support of the affected child and for the mother suffering from alcohol disease,
      in cooperation with other treating doctors.

PMID- 10417434
TI  - Macrolide immunosuppressants.
AB  - Macrolide immunosuppressants are a new class of compounds sharing a macrolide
      like structure and potent immunosuppressive activity in vitro and in vivo.
      Tacrolimus, the best known substance of this group, is registered in many
      countries for the prevention of transplant rejection. Numerous new substances of
      this group are in the pipelines of the pharmaceutical industries. Macrolide
      immunosuppressants are also effective in dermatological disorders. Due to their
      chemical structure these compounds can be used for topical treatment. Clinical
      studies have already shown highly effective topical therapy of atopic dermatitis
      with tacrolimus and the ascomycin derivative SDZ ASM 981, another macrolide
      immunosuppressant. In this article the pharmacological aspects of macrolide
      immunosuppressants, their supposed mechanisms of action, pre-clinical and
      clinical experience are reviewed.

PMID- 10417435
TI  - Effectiveness of a new therapeutic regimen with albendazole in cutaneous larva
      migrans.
AB  - Twenty-four (13 males and 11 females) adult Caucasian patients affected by
      cutaneous larva migrans, characterized by extensive and/or multiple lesions, were
      treated with oral albendazole according to a new therapeutic regimen (400 mg/day
      for 7 days). No other topical or systemic drug was used nor any physical
      treatment. All patients were cured at the end of the therapy. No recurrence was
      observed. No side effect was either complained of or observed, nor was any
      laboratory abnormality recorded. On the basis of this study, albendazole is
      effective in cutaneous larva migrans characterized by extensive and/or multiple
      lesions. This new therapeutic regimen avoids no response and recurrence, which
      are not uncommonly observed following shorter (e.g.: 1-5 days) therapies with
      albendazole. The longer duration of the therapy is not accompanied by the
      appearance of more severe and/or new side effects or laboratory abnormalities.

PMID- 10417436
TI  - Rothmund-Thomson syndrome with herpes encephalitis.
AB  - A 4-year-old Japanese boy with Rothmund-Thomson syndrome suffered from severe
      herpes encephalitis at 5 months of age. The serum level of immunoglobulin G was
      low and the responsiveness of peripheral blood mononuclear cells to bacterial
      superantigens was poor. It was suggested that these immunological abnormalities,
      possibly associated with Rothmund-Thomson syndrome, led to severe infection with
      herpes simplex virus in our patient.

PMID- 10417437
TI  - Expression of basic fibroblast growth factor and its receptor by fibroblast,
      macrophages and mast cells in hypertrophic scar.
AB  - Basic fibroblast growth factor (bFGF) is a potent mitogenic and chemotactic
      factor for endothelial cells and fibroblasts. To investigate the pathological
      role of bFGF in hypertrophic scar, we performed an immunohistochemical study on
      bFGF and bFGF receptor (bFGF-R) in hypertrophic scar (HS) including keloid, in
      comparison with normal scar (non-HS) and normal skin. To identify bFGF and bFGF-R
      positive cells, double immunostaining with antibody to mast cell (MC, tryptase)
      or tissue macrophage (CD68) was carried out. The expression of bFGF and bFGF-R in
      cultured fibroblasts from scars was also examined. In HS, many positive cells for
      bFGF or bFGF-R were observed between collagen bundles in addition to the positive
      area in normal skin. Although most of the positive cells for bFGF or bFGF-R were
      fibroblasts, the positive rates of bFGF in macrophages was also increased (p <
      0.005). The positive rate of bFGF in MCs and the positive rates of bFGF-R in
      macrophages and MCs were not changed. No obvious difference was observed between
      non-HS and normal skin in the expression of bFGF and bFGF-R. Cultured fibroblasts
      from HS showed a strong nuclear staining of bFGF, but not from non-HS and normal
      skin. bFGF-R was equally expressed with a diffuse cytoplasmic pattern by
      fibroblasts from all sources. bFGF may play an important role in the pathological
      fibrotic process of HS in which fibroblasts are persistently activated. Cellular
      source of the abnormal bFGF in HS may be both fibroblasts themselves and
      macrophages.

PMID- 10417438
TI  - Expression of the hair stem cell-specific keratin 15 in pilar tumors of the skin.
AB  - Keratin 15 (K15) was recently shown to be a specific marker of stem cells of the
      hair-follicle bulge. We studied the reactivity of an antibody to the CD8 antigen
      (C8/144B), recognizing K15, on 66 cutaneous tumors with known or alleged pilar
      differentiation, in order to assess its usefulness in the diagnosis of this group
      of tumors. 2/2 basal cell nevi, 5/8 trichoepitheliomas and 1/3 trichofolliculomas
      showed substantial reactivity. Much weaker reactivity was observed in cases of
      trichilemmal tumors (trichilemmomas and trichilemmal cysts); by contrast, all
      cases of pilomatricomas, basal cell carcinomas and epidermoid cysts were
      completely unreactive. These results are in keeping with the admitted
      differentiation of the tumors studied, and suggest further that basal cell
      carcinomas do not differentiate towards hair bulge cells. From a practical point
      of view, immunostaining for K15 seems to be an additional useful adjunct for the
      differential diagnosis between basal cell carcinoma and trichoepithelioma.

PMID- 10417439
TI  - An ultrastructural and immunohistochemical study of pigmented dermatofibrosarcoma
      protuberans (Bednar tumor).
AB  - A case of Bednar tumor on the right shoulder of a 47-year-old Japanese woman is
      reported. Histological examination showed plump, spindle cells arranged in a
      storiform pattern in central areas of the tumor and a diffuse infiltration of the
      dermal stroma, which was frequently extended into the subcutis at the periphery
      of the tumor. The tumor contained a fairly identified population of dendritic
      pigmented cells. Ultrastructurally, most cells had folded nuclei, were spindle
      shaped and had long, slender cytoplasmic projections. Dendritic pigmented cells,
      which were dispersed among neoplastic cells, contained premelanosomes and mature
      melanosomes. Immunohistochemically, tumor cells exhibited positive reactions for
      vimentin and CD 34 and failed to show a positive reaction for neuron specific
      enolase, HMB-45 or S-100 protein. Factor X IIIa was only expressed on tumor cells
      around melanin-containing cells, which reacted positively with antibodies to S
      100 protein and vimentin. These results indicate that the phenotype of tumor
      cells around melanin-containing cells differs from other tumor cells and that
      this difference may be caused by the relationship of tumor cells and melanin
      containing cells.

PMID- 10417440
TI  - Two recent cases of tertiary syphilis.
AB  - Tertiary syphilis is now a rare disease in Europe, mainly as a result of
      occasional antibiotherapy for concomitant infections. However early syphilis is
      rising in USA and Germany, and it is necessary to maintain an high level of
      knowledge and suspicion to achieve a diagnosis in the tertiary stage of the
      disease. In this report two patients with benign tertiary syphilis are described.
      The first one is a 55-year-old female with erythemato-violaceous annular scaling
      plaques on the right buttock and scapula and on both thighs, which had a negative
      and then a low VDRL titer. The second case is a 33-year-old mentally handicapped
      female with erythematous plaques, with psoriasiform scaling in the trunk and well
      defined crusted ulcers on the face, which also had negative VDRL. Biopsy of the
      skin lesions revealed plasmocytic infiltrate with endothelial swelling without
      granulomas and with negative silver stains in both patients. The investigation
      for cardiovascular and neurological involvement was negative in both patients.
      Diagnosis of tertiary syphilis can be difficult as clinical pictures can be
      misleading, similar to other granulomatous diseases, and serological titers can
      be low or negative. We recall the necessity of ruling out neurological and
      cardiac involvement in this stage of syphilis. These cases are reported as a
      reminder of the possibility of syphilis, so that new cases are not misdiagnosed
      and mistreated as other diseases.

PMID- 10417441
TI  - Hair removal in 40 hirsute women with an intense laser-like light source.
AB  - Until recently, previously applied methods to remove hair have ultimately proven
      ineffective or resulted in the formation of scars and small wounds. Different
      methods for removing hair in a more or less permanent way have been used:
      electrolysis, thermolysis and the blend method. In this study we describe the
      removal of hair without side-effects by means of non-laser incoherent emitted
      light, produced by the ILS flashlamp. In a multicenter study we treated 40 women
      with a median age of 38.6 years with hirsute hair growth of different hair
      colours on the upper lip and chin. In general 76.7% of the hair was removed
      within 6 treatments, with an average fluence of 38.7 J/cm2 and a mean wavelength
      of 585 nm per patient. A correlation was found between the percentage reduction
      of hairs and the number of treatments and between hair removal and needle
      epilation before treatment. Furthermore, a correlation was seen between hair
      reduction and wavelengths of 570 nm and 550 nm. No association was found between
      hair removal and clinical data of the patients, nor between hair reduction and
      technical data of the device. This study presents a new alternative for hair
      removal.

PMID- 10417442
TI  - Heterogeneity of atopic dermatitis defined by the immune response to inhalant and
      food allergens.
AB  - Although atopic dermatitis (AD) is a common disease, its etiopathogenesis is not
      well known. The diagnosis of AD is based solely on the clinical criteria proposed
      by Hanifin and Rajka. In order to understand the immunological mechanisms
      involved in the pathogenesis of AD, we have classified the patients affected by
      this disease in four groups according to the results of skin prick-tests,
      specific IgE and patch-tests. This classification is intended to separate and
      compare the patients affected by AD according to the involvement of immunological
      type I and/or type IV mechanisms. Our results show that, although all the
      patients studied are clinically affected by AD, there are four different groups
      of patients who present an apparently diverse immunopathological mechanism. There
      is a group that seems to have an IgE mediated mechanism, another group that
      suggests a cell mediated mechanism, another group which seems to involve both
      mechanisms, and yet another group that apparently does not show any of the above
      mentioned mechanisms. In the present article we hypothesize and argue that the
      imbalance of the immune system is a consequence of the still unknown
      etiopathogenetic mechanism of AD, but perhaps not the cause of AD.

PMID- 10417443
TI  - Peristomal subepidermal autoimmune blistering disease.
AB  - Peristomal subepidermal autoimmune blistering disease has rarely been reported in
      the literature [1-3]. We report a new case of this entity. In the three reported
      cases, the diagnosis of bullous pemphigoid was retained. In our case, clinical
      and immunological patterns rather favour a cicatricial pemphigoid.

PMID- 10417444
TI  - Papillary cystadenoma: a rare tumor of the minor salivary glands.
AB  - Papillary cystadenoma of the minor salivary glands is a rare benign neoplasm that
      clinically resembles mucous cysts. Characteristic histological features are
      diagnostic. However, salivary gland histology is particularly difficult to
      interpret. Primarily, as further clinical and histological differential diagnoses
      have to take into account the well-differentiated cystic mucoepidermoid carcinoma
      and the papillary cystic type of acinic cell carcinoma, both malignant neoplasms
      of the salivary glands. We report on a 39 year old female with a bluish cystic
      lesion at the buccal mucosa, which occurred 14 years after the excision of a
      similar appearing, histologically proven mucous retention cyst at the same
      location. The histology of this tumor, however, revealed a papillary cystadenoma.
      Although rare, benign and malignant salivary gland neoplasms occur in minor
      salivary glands, and are clinically indistinguishable from mucous retention
      cysts. The dermatologist should be familiar with these differential diagnoses,
      since different therapeutic consequences result from an early diagnosis obtained
      by excision and histological examination of oral cystic tumors.

PMID- 10417445
TI  - Recurrent proximal white subungual onychomycosis associated with a defect of the
      polymorphonuclear chemotaxis.
AB  - Proximal white subungual onychomycosis (PWSO) is a rare form of nail infection
      that occurs almost exclusively in immunocompromised patients. Initially, in
      several reports, PWSO was described in ARC and AIDS patients. Later this pattern
      of onychomycosis was observed in patients with renal transplants, who received
      immunosuppressive therapy, and recently in a woman with active systemic lupus
      erythematosus (SLE) treated with systemic steroid therapy. We report a case of
      recurrent PWSO in a woman affected by a defect of polymorphonuclear chemotaxis.
      The association between PWSO and a defect of neutrophil chemotaxis, not yet
      described in the literature, suggests a point of discussion about the role of
      polymorphonuclear leucocyte functions in the defense mechanisms of the host
      affected by dermatophytosis. In this report the close association between PWSO
      and an immunocompromised condition is once again described. For this reason the
      authors emphasize the importance of investigating the common and uncommon causes
      of immunodeficiency in all patients affected by PWSO.

PMID- 10417447
TI  - Laboratory assistant's occupational allergic airborne contact dermatitis from
      nickel presenting as rosacea.
AB  - A male laboratory assistant working in a metallurgical laboratory with airborne
      exposure to nickel dust developed highly pruritic, rosacea-like symptoms. The
      symptoms cleared within eight days without treatment when the patient was off
      work. Patch testing confirmed nickel allergy. Based on the patient's work and
      clinical history it was evident that occupational exposure to airborne nickel
      induced the highly abnormal rosacea-like symptoms, not previously reported from
      nickel.

PMID- 10417446
TI  - Demonstration of antibody to 230 kDa bullous pemphigoid antigen in lichen planus
      like keratosis.
AB  - We describe a 67-year-old man with lichen planus-like keratosis associated with
      anti-230 kDa bullous pemphigoid antigen (BPAG1) autoantibody. The patient had
      noticed solitary dark brown macule more than 6 years previously on his left
      chest. Histological findings showed hypergranulosis, irregular acanthosis,
      liquefaction degeneration of basal cells, band-like infiltration of lymphocytes
      at the subepidermal portion, and a cleft at the basement membrane zone (BMZ),
      resulting in the formation of subepidermal blisters. Direct immunofluorescence
      findings of perilesional skin showed a linear deposition of IgG at BMZ. On
      indirect immunofluorescent study using normal human skin, circulating IgG
      autoantibody to BMZ was present in the patient's serum at a titer of 1:80. The
      antigen located on the epidermal site of normal skin split by 1M NaCl was reacted
      with the patient's serum. Immunoblot analysis using epidermal extracts
      demonstrated the presence of IgG antibody directed to BPAG1 in the patient's
      serum. These observations suggest that the presence of an antibody to BPAG1 could
      be caused by the damage of basal cells following lichen planus-like keratosis.

PMID- 10417448
TI  - Syphilitic aneurysm of the abdominal aorta.
AB  - A case of syphilitic aneurysm of the abdominal aorta is described. This unusual
      finding may be misdiagnosed as "inflammatory" abdominal aortic aneurysm, another
      condition associated with an intense periaortic inflammatory reaction. The
      authors discuss the differential diagnostic problems and the surgical technique
      advisable in these cases.

PMID- 10417449
TI  - Photoprotection and prevention of melanoma.
AB  - This article summarizes the current position on primary prevention of melanoma,
      including what is the evidence relating sunlight exposure to the development of
      melanoma, what forms of photoprotection there are and what are their relative
      values. There have been increasing incidence and mortality rates due to melanoma
      in most countries where they are being recorded. The initial approach in many
      countries has been to develop some form of early detection program in an attempt
      to diagnose and treat at a curable stage the melanomas that are occurring now.
      Primary prevention of melanoma is the more long term approach to the problem
      which many countries are now considering and a number are actively pursuing.
      Recent concern about stratospheric ozone depletion has contributed to the desire
      for the primary prevention approach. There are epidemiological data associating
      the risk of melanoma with increased exposure to sunlight in people with fair
      skin. They show that it is sunlight exposure in childhood and in doses sufficient
      to cause sunburn remembered many years later, that is particularly associated
      with risk of melanoma in adulthood. The exact spectrum of radiation in sunlight
      which is responsible for these tumours is not known, although the ultraviolet
      range is believed to be most important, particularly UVB but probably also UVA.
      The approach to photoprotection is a reduction in the overall exposure to
      sunlight, not just a single component of it. The natural protection of shade,
      clothing and hats is promoted as the best protection. Sunscreens have assumed a
      major component of primary prevention programs based on their convenience of use
      and also on their widespread promotion by those people who have a commercial
      interest in them. These products protect predominantly in the UVB range for which
      there is a sun protection factor (SPF) grading, as well as having some activity
      in the UVA range (for which there is not yet a satisfactory grading method).

PMID- 10417450
TI  - Apoptosis and the skin.
AB  - In multicellular organisms, homeostasis is maintained by a balance between cell
      proliferation and cell death. Two common forms of cell death, called apoptosis
      and necrosis, have been described. Apoptosis, which is often equated with
      programmed cell death, is a physiological form of cell death that is responsible
      for the deletion of cells. Apoptosis is morphologically and biochemically
      characterized by cell shrinkage, dense chromatin condensation, cellular budding,
      fragmentation, rapid phagocytosis by nearby cells, and DNA fragmentation into
      units of approximately 200 base pairs. Apoptosis can be triggered by a wide
      variety of stimuli such as cytokines, hormones, drugs, and viruses, and their
      signal transduction tightly regulated by genes such as Bcl-2. Effector caspases
      are finally activated, resulting in apoptotic cell death. In the skin, there is
      considerable evidence that apoptosis plays an important role in the pathogenesis
      of a wide variety of skin diseases. In lichenoid tissue reactions, the Civatte
      body or colloid body is a form of apoptotic keratinocytes which is mediated by T
      lymphocytes via Fas-FasL interaction or through the perforin-granzyme B pathway.
      In several skin tumors, Bcl-2 or FasL expression is involved in the proliferation
      or regression of the tumors, or in the escape from immune attack by T cells.
      Moreover, apoptosis is also responsible for the homeostasis of skin, such as the
      keratinocyte differentiation and hair cycle. In this review, we describe the
      basic concept of apoptosis and its relevance to skin diseases.

PMID- 10417452
TI  - Randomised double-blind comparison of morphine vs. a morphine-alfentanil
      combination for patient-controlled analgesia.
AB  - In a randomised, double-blind study, we compared a combination of morphine and
      alfentanil with morphine alone for patient-controlled analgesia (PCA) after
      Caesarean section under spinal anaesthesia. After surgery, patients were randomly
      allocated to receive PCA with a bolus dose of either morphine 0.75 mg plus
      alfentanil 0.125 mg (Group MA, n = 40) or morphine 1.5 mg alone (Group M, n = 37)
      with a lockout interval of 8 min and no hourly dose limit. Clinical assessments
      were made in the first 24 h, after which patients completed a written
      questionnaire. There were no differences between groups in PCA usage or visual
      analogue scale pain scores measured at 2, 4, 6 and 24 h. There was a low
      incidence of side-effects in both groups. In the questionnaire, patients in Group
      MA scored higher compared with Group M when asked to grade speed of onset and
      effectiveness of analgesia after a PCA bolus; there were no differences in
      grading for duration of analgesia or overall patient satisfaction. Addition of
      alfentanil to morphine may have advantages for PCA.

PMID- 10417451
TI  - The obstructed airway in head and neck surgery.

PMID- 10417453
TI  - A survey of epidural analgesia for labour in the United Kingdom.
AB  - A postal survey of obstetric units throughout the UK was conducted to obtain
      information about the provision of epidural analgesia for labour. Ninety per cent
      of units offered a 24-h epidural service and the average epidural rate was 24%.
      The most commonly administered epidural test dose was 3 ml of bupivacaine 0.5%
      and bupivacaine 0. 25% was most often used as the initial epidural top-up.
      Continuous infusions of low-dose bupivacaine and opioid mixtures were the most
      popular method of maintenance epidural analgesia. Twenty-four per cent of units
      offered combined spinal-epidural analgesia in addition to standard epidural
      analgesia. Midwives played a prominent role in the administration of epidural
      bolus top-ups and also in the assessment and maintenance of continuous epidural
      infusions.

PMID- 10417454
TI  - Thoracic epidural infusions for post-thoracotomy pain: a comparison of fentanyl
      bupivacaine mixtures vs. fentanyl alone.
AB  - A randomised double-blind clinical trial was conducted on 106 patients scheduled
      for pulmonary resection. Patients received an epidural infusion containing 0.1%,
      0.2% bupivacaine or saline in combination with fentanyl 10 microgram.ml -1.
      Adequacy of analgesia was assessed at rest and during movement over 24 h.
      Analgesic efficacy was assessed using visual analogue scores and an
      observer/verbal ranking scale. Pain scores were higher in the fentanyl-only group
      at the 2 h assessment (p < 0.05). Otherwise, there were no between-group
      differences in pain scores or in the total amounts of epidural solution used. All
      patients received continuous haemodynamic monitoring. There were no between-group
      differences in the number of episodes of hypotension or in the number of
      interventions for hypotension. However, the use of intra-operative vasopressor
      and the incidence of temporary neurological complications was higher in the 0.2%
      bupivacaine group (p < 0.05). We conclude that, in the early postoperative
      period, the addition of bupivacaine 0.1% improves fentanyl epidural analgesia in
      patients undergoing lung resection and is not associated with the disadvantages
      seen with the addition of bupivacaine 0.2%.

PMID- 10417455
TI  - Vascular trauma associated with routine spinal anaesthesia.
AB  - Samples of cerebrospinal fluid obtained from 130 patients undergoing spinal
      anaesthesia were examined microscopically. Subarachnoid puncture was performed
      using either a 25G Whitacre or 25G Quincke spinal needle. Two samples were
      collected from each patient and the red blood cell count of the second sample
      collected was taken as a measure of the vascular trauma associated with the
      procedure. Red blood cells were seen in 50 (38%) of these samples, of which 18
      (14%) contained > 100 red blood cells.mm-3. Paraesthesia was felt by 11 (8.5%)
      patients and the occurrence of paraesthesia was associated with significantly
      raised red blood cell counts (p < 0.0001). There was also a correlation between
      the number of needle passes made at lumbar puncture and the red blood cell count
      in the sample (p < 0. 0001). Neither spinal needle type nor antiplatelet drug
      therapy influenced red blood cell counts (p = 0.66 and 0.37, respectively). These
      findings suggest that routine spinal anaesthesia is often complicated by minor
      degrees of vascular trauma, especially when paraesthesiae or technical difficulty
      occur at subarachnoid puncture.

PMID- 10417456
TI  - Dosage of neostigmine for reversal of rocuronium block from two levels of
      spontaneous recovery.
AB  - Spontaneous recovery, and recovery following neostigmine 20, 35 or 50
      microgram.kg-1 administered at 10 or 25% of recovery of the first twitch of the
      train-of-four, was assessed in 80 patients after rocuronium administration under
      continued isoflurane anaesthesia. In an additional 40 patients, isoflurane
      administration was discontinued and neostigmine 35 or 50 microgram.kg-1 was given
      at 10 or 25% recovery. The administration of neostigmine reduced the recovery
      times significantly. A neostigmine dose of 20 microgram.kg-1 resulted in slower
      recovery compared with the higher doses, particularly when reversal was attempted
      at a first twitch height of 10%. Higher doses of neostigmine given at a first
      twitch height of 25% resulted in rapid reversal of block [mean (SD) times of 7.0
      (4.8) and 6.4 (1.9) min with the 35 and 50 microgram.kg-1 doses, respectively,
      for attaining a train-of-four ratio of 0.8]. Discontinuing isoflurane did not
      alter recovery times. The incidence of emetic symptoms did not differ between
      groups, including one group that received atropine instead of glycopyrronium in
      combination with neostigmine. We conclude that rocuronium block can be
      antagonised safely using a neostigmine dose of 35 microgram.kg-1, although
      recovery may be slightly slower if administered at a first twitch of 10% of
      control.

PMID- 10417457
TI  - The use of cricoid pressure with the intubating laryngeal mask.
AB  - Unexpected difficulty with tracheal intubation contributes to anaesthetic
      morbidity and mortality. The intubating laryngeal mask is effective in
      facilitating blind intubation. We have evaluated the effect of cricoid pressure
      on the ability to insert an intubating laryngeal mask, and to pass a tracheal
      tube through it. Insertion and intubation through the mask were attempted in 50
      patients, Mallampati grade 1-3, randomly allocated to cricoid and noncricoid
      pressure groups. Tracheal intubation was successful in 21 (84%) of the noncricoid
      group and 13 (52%) of the cricoid group (p = 0.03). Cricoid pressure may have to
      be released to allow correct placement and intubation through the intubating
      laryngeal mask.

PMID- 10417458
TI  - Portable ultrasonic scanning of the anterior neck before percutaneous
      dilatational tracheostomy.
AB  - We used portable ultrasound scans to identify relevant anatomical structures in
      the necks of 30 patients before percutaneous tracheostomy. We identified the
      tracheal midline, thyroid isthmus and blood vessels and located a safe level for
      needle insertion. Anterior jugular veins were seen in 15 patients; eight were
      near the midline and were considered vulnerable. Three veins were more than 4 mm
      in diameter and these larger vessels were electively ligated. Four patients had
      arteries which were considered vulnerable to damage. All patients underwent
      successful percutaneous tracheostomy. Portable ultrasound provides a simple
      method of screening for vulnerable blood vessels in the neck and for locating the
      midline before percutaneous tracheostomy. This method is particularly suitable
      for patients with landmarks that are difficult to visualise or palpate. Based on
      the ultrasonic findings we can make an informed decision about referral for
      surgical tracheostomy.

PMID- 10417459
TI  - An in vitro evaluation of flow from multihole epidural catheters during
      continuous infusion with four different infusion pumps.
AB  - We have observed in vitro the distribution of flow from 10 identical multihole
      epidural catheters during continuous infusion with four different infusion pumps.
      The pumps chosen were the B Braun Perfusor Secura FT syringe driver and three
      volumetric infusion pumps utilising different pumping mechanisms (Dekra 3000 BL,
      Graseby 500 and CADD-Prizm). These pumps infused 0.9% saline through each
      catheter at 5 ml.h-1, 15 ml.h-1, 50 ml.h-1 and 99 ml.h-1 for 3 min. The number of
      holes through which flow occurred and the catheter hole where flow predominated
      during each test were recorded. The pressure waveform generated during each
      infusion was displayed and the peak pressure recorded. In 38 of the 160 tests
      (24%) the largest proportion of flow was seen at the hole closest to the catheter
      tip. The CADD pump generated multihole flow during significantly more tests (p <
      0.0001) than the other pumps and produced significantly higher driving pressures
      (p < 0.001) at all infusion rates compared with the Graseby and Perfusor pumps.
      The CADD was the only pump to produce flow from all three holes of the catheter
      at 5 ml.h-1.

PMID- 10417460
TI  - Anterior mediastinal masses: an anaesthetic challenge.
AB  - A patient with a large anterior mediastinal mass with minimal respiratory
      symptoms presented for a diagnostic biopsy of the mass. A pre-operative thoracic
      computed tomographic scan demonstrated narrowing of the distal trachea, and right
      and left main stem bronchi. An awake intubation was done. Thiopentone and muscle
      relaxant were given and surgery commenced. High airway pressure developed and
      ventilation became difficult, although oxygenation remained satisfactory
      throughout. Anaesthetic implications are discussed. We recommend that patients
      with more than 50% obstruction of the airway at the level of the lower trachea
      and main bronchi have their femoral vessels cannulated in readiness for
      cardiopulmonary bypass.

PMID- 10417461
TI  - Life-threatening airway obstruction caused by a retropharyngeal haematoma.
AB  - We present the case of a 68-year-old woman who had a large cervicomediastinal
      haematoma that caused life-threatening airway obstruction. Retropharyngeal
      haematoma may occur in any age group and following a variety of causes.
      Retropharyngeal haematomas must be considered as a cause of airway obstruction
      following common injuries such as blunt cervical trauma or internal jugular vein
      cannulation. A high index of suspicion and early lateral neck X-ray is essential
      for safe management of this rare but potentially life-threatening injury.

PMID- 10417462
TI  - Cerebral perfusion monitored using transcranial Doppler during acute anaphylaxis.
AB  - We present a case of severe acute anaphylaxis that occurred during preparation of
      a patient for carotid endarterectomy. Intra-arterial blood pressure and
      transcranial Doppler monitoring had been established before the anaphylactic
      reaction began and therefore the changes in arterial blood pressure and middle
      cerebral artery blood-flow velocity could be observed as they happened. This made
      it possible to assess directly the effectiveness of our management, which
      followed the resuscitation guidelines issued by the Association of Anaesthetists.
      In particular, this was a rare opportunity to confirm whether the recommended
      management is effective in restoring cerebral blood flow, and not just blood
      pressure, in a 'real life' situation, as most resuscitation information is based
      on laboratory-based animal studies. Evidence is presented which suggests that the
      administration of adrenaline in this setting is associated with increases in
      cerebral blood flow that are independent of arterial blood pressure.

PMID- 10417463
TI  - The cuffed oropharyngeal airway vs. the laryngeal mask airway: a randomised cross
      over study of oropharyngeal leak pressure and fibreoptic view in paralysed
      patients.
AB  - We conducted a randomised cross-over study of 20 patients to test the hypothesis
      that oropharyngeal leak pressure and the fibreoptic view differ between the
      cuffed oropharyngeal airway and laryngeal mask airway in paralysed patients. We
      also tested the design premise that inflation of the cuffed oropharyngeal airway
      cuff elevates the epiglottis from the posterior pharyngeal wall. Both airways
      were inserted into each patient in random order. Oropharyngeal leak pressure and
      fibreoptic view were documented at zero volume and after each additional 10 ml up
      to the maximum recommended volume for each device. The laryngeal mask had a
      higher maximum (23 vs. 16 cmH2O, p = 0.03), minimum (9 vs. 2 cmH2O, p < 0.02) and
      overall (17 vs. 9 cmH2O, p < 0.001) oropharyngeal leak pressure compared with the
      cuffed oropharyngeal airway. The glottic inlet was visible more frequently with
      the laryngeal mask (96 vs. 39%, p < 0.0001). There was no elevation of the
      epiglottis from the posterior pharyngeal wall with the cuffed oropharyngeal
      airway. We conclude that the laryngeal mask forms a more effective seal and
      provides a better fibreoptic view of the glottic inlet than the cuffed
      oropharyngeal airway in paralysed patients. Inflation of the cuffed oropharyngeal
      airway cuff does not cause elevation of the epiglottis.

PMID- 10417464
TI  - The use of mini-dose suxamethonium to facilitate the insertion of a laryngeal
      mask airway.
AB  - The use of mini-dose suxamethonium to facilitate the insertion of a laryngeal
      mask airway was investigated. Sixty patients were assigned randomly in a double
      blind manner to receive 0.9% sodium chloride or suxamethonium 0.1 mg.kg-1
      intravenously, following intravenous induction with propofol 2.5 mg.kg-1. The
      laryngeal mask was inserted after the first attempt in 87% of patients. Mini-dose
      suxamethonium improved the correct positioning of the laryngeal mask during the
      first attempt (93 vs. 67%, p < 0.02), decreased the incidence of swallowing (p <
      0.001), gagging (p < 0.001) and head or limb movement (p < 0.05). Laryngeal mask
      insertion was graded as easy in 93% of patients who had mini-dose suxamethonium,
      compared with 60% in the placebo group (p < 0.01). The duration of apnoea between
      the two groups was not significantly different (0.54 vs. 0.61 min, p = 0. 46).
      The total dose of propofol needed to insert the laryngeal mask was lower in the
      suxamethonium group (2.57 vs. 3.25 mg.kg-1, p < 0. 01) and was associated with
      less hypotension (p < 0.05). Fasciculation (17%) and mild myalgia (23%) were
      common despite the small dose of suxamethonium used. In conclusion, mini-dose
      suxamethonium facilitates laryngeal mask insertion. Myalgia is common and the
      technique is not recommended for patients who are prone to suxamethonium myalgia.

PMID- 10417465
TI  - Accumulation of carbon dioxide under ophthalmic drapes during eye surgery: a
      comparison of three different drapes.
AB  - Carbon dioxide accumulation under ophthalmic drapes is caused by their impaired
      permeability to exhaled carbon dioxide in spontaneously breathing patients. Three
      different ophthalmic drapes were examined under clinical conditions. Sixty
      unpremedicated patients of each gender, aged over 60 years and with an ASA status
      of I-III undergoing cataract surgery under retrobulbar anaesthesia were included
      in the study. Patients with known pulmonary diseases were excluded. The patients
      were divided into three groups of 20 patients each. In all groups, oxygen was
      insufflated under the drapes at a constant flow of 21.min-1. Carbon dioxide
      concentration in the inspired air, transcutaneous carbon dioxide pressures,
      respiratory rate and oxygen saturation by pulse oximetry were measured.
      Accumulation of carbon dioxide under the drapes, increase of partial pressure of
      transcutaneous carbon dioxide and hyperventilation were observed in all three
      groups. An oxygen supply of 21.min-1 prevented hypoxaemia but not hypercapnia.
      Therefore, producers of ophthalmic drapes are encouraged to look for further ways
      to increase the carbon dioxide permeability of their drapes with the aim of
      reducing carbon dioxide accumulation and hyperventilation in spontaneously
      breathing patients undergoing eye surgery.

PMID- 10417466
TI  - Nefopam and clonidine in the prevention of postanaesthetic shivering.
AB  - Postanaesthetic shivering affects up to 70% of patients after general
      anaesthesia, and may be very distressing. Various drugs have been used to treat
      or prevent postanaesthetic shivering, but the ideal one has not yet been found.
      Sixty patients undergoing elective abdominal or orthopaedic surgery under general
      anaesthesia were included in a randomised, double-blind study. Patients received
      clonidine (3 microgram.kg-1), nefopam (0.15 mg.kg-1) or saline 0.9% as a placebo
      at the end of surgery, prior to extubation. Nefopam and clonidine significantly
      reduced the incidence and severity of shivering in comparison with the placebo.
      The recovery time, between the end of anaesthesia and extubation, was
      significantly longer in the clonidine-treated patients [13.6 (5.2) min] than in
      either the nefopam [9.6 (2.8) min] or the placebo [10.0 (5.4) min] groups. Mean
      arterial blood pressure and heart rate were significantly lower in the clonidine
      group compared with both other groups. Our results suggest that nefopam and
      clonidine are effective in the prevention of postanaesthetic shivering. However,
      following clonidine administration the recovery time was prolonged and
      hypotension was significantly greater than after nefopam.

PMID- 10417468
TI  - Death in the dental chair.

PMID- 10417467
TI  - A comparison of the antibacterial activity of levobupivacaine vs. bupivacaine: an
      in vitro study with bacteria implicated in epidural infection.
AB  - The purpose of the study was to compare the antibacterial activity of bupivacaine
      with levobupivacaine against a range of bacteria implicated in epidural infection
      to determine whether any differences existed between the two drugs.
      Concentrations of 0.125%, 0.25% and 0.5% bupivacaine and levobupivacaine were
      inoculated with suspensions of either Staphylococcus epidermidis, Staphylococcus
      aureus or Enterococcus faecalis. After incubation, the mixtures were plated onto
      blood agar and colony counts were recorded after a further period of incubation.
      The minimum bactericidal concentration of local anaesthetic against the three
      bacteria studied was found to be 0.25% for bupivacaine and 0.5% for
      levobupivacaine showing racemic bupivacaine to have a more potent antibacterial
      action than levobupivacaine. This finding suggests that the dextrobupivacaine
      isomer of racemic bupivacaine has a more potent antibacterial action than the
      levobupivacaine isomer.

PMID- 10417470
TI  - An unexpected complication of the intubating laryngeal mask.

PMID- 10417472
TI  - Management of anaesthesia for Jehovah's witnesses.

PMID- 10417473
TI  - Rigid bronchoscopy during percutaneous tracheostomy.

PMID- 10417474
TI  - Unilateral lung hyperinflation following tracheal tube change.

PMID- 10417475
TI  - Cannon oximetry.

PMID- 10417476
TI  - A safe, simple and effective technique for securing nasojejunal tubes in the
      intensive care unit.

PMID- 10417477
TI  - Homogenous mixing of propofol emulsion into an infusion solution.

PMID- 10417478
TI  - An unusual case of hysterical postoperative coma.

PMID- 10417479
TI  - Poor anaesthetist hygienic practices - a problem across all grades of
      anaesthetist.

PMID- 10417480
TI  - Prolonged bleeding from epidural catheterisation reconsidered.

PMID- 10417481
TI  - Multiple choice examinations.

PMID- 10417482
TI  - 'Peanuts and palacos'.

PMID- 10417484
TI  - Drug-induced hyponatraemia in elderly patients.

PMID- 10417485
TI  - Antibiotic resistance: a current perspective.

PMID- 10417486
TI  - LDL particle size: an important drug target?

PMID- 10417488
TI  - Spontaneous reporting--of what? Clinical concerns about drugs.

PMID- 10417487
TI  - Drug interactions, renal impairment and hypoglycaemia in a patient with Type II
      diabetes.

PMID- 10417489
TI  - Paroxetine in human milk.
AB  - AIMS: The primary aims of the study were to estimate the exposure of infants to
      paroxetine via breast milk and to determine the maternal milk:plasma ratio (M/P)
      of paroxetine. Secondary aims were to compare single point and area under the
      curve (AUC) estimates of M/P, to assess variability of M/P in fore and hind milk,
      and to compare the observed M/P with that predicted by a model. METHODS: Two
      studies were performed. In one study, six nursing mothers who were being treated
      with paroxetine were studied over a 24 h dose interval at steady-state. The total
      amount of paroxetine in the milk was measured, which represented the 'dose' to
      the infant. The M/PAUC was calculated and compared with a predicted value. In the
      second study, four nursing mothers who were being treated with paroxetine, were
      studied at steady-state, around a normal infant feeding time. A single plasma
      sample and a prefeed milk sample were taken approximately 3 h after the morning
      dose of paroxetine, and a postfeed milk sample taken around 1 h later. The dose
      received by the infant was estimated from the average milk concentrations of the
      pre and postfeed samples using standard assumptions, and M/P calculated directly.
      Plasma concentrations of paroxetine were measured in 8 of the 10 infants in the
      two studies. RESULTS: The mean dose of paroxetine received by the infants in the
      first study was 1.13% (range 0.5-1.7) of the weight adjusted maternal dose. The
      mean M/PAUC was 0.39 (range 0.32-0.51). The predicted M/P was 0.22. The mean dose
      of paroxetine received by the infants in the second study was 1.25% (range 0.38
      2.24) of the weight adjusted maternal dose. The mean M/P was 0.96 (range 0.31
      3.33) and did not differ between fore and hind milk. The drug was not detected in
      the plasma of seven of the infants studied and was detected but not quantifiable
      (<4 microg l-1 ) in one infant. No adverse effects were observed in any of the
      infants. CONCLUSIONS: Measured M/P and estimated infant dose were similar in the
      two studies, although the range was wider for the single point study. Paroxetine
      can be considered 'safe' during breast feeding because the dose transferred to
      the infant is well below the recommended safety limit of 10% of the weight
      adjusted maternal dose, concentrations in the infants were generally
      undetectable, and no adverse effects were reported.

PMID- 10417490
TI  - Effect of activated charcoal alone or given after gastric lavage in reducing the
      absorption of diazepam, ibuprofen and citalopram.
AB  - AIMS: The efficacy of activated charcoal alone, and gastric lavage followed by
      charcoal in reducing the absorption of diazepam, ibuprofen and citalopram was
      studied in healthy volunteers. METHODS: In a randomized cross-over study with
      three phases, nine healthy volunteers were administered single oral doses of 5 mg
      diazepam, 400 mg ibuprofen and 20 mg citalopram, taken simultaneously after an
      overnight fast. Thirty minutes later, the subjects were assigned to one of the
      following treatments: 200 ml water (control), 25 g activated charcoal as a
      suspension in 200 ml water or gastric lavage followed by 25 g charcoal in
      suspension given through the lavage tube. Plasma concentrations of diazepam,
      ibuprofen and citalopram were determined up to 10 h. RESULTS: The AUC(0,10 h) of
      diazepam was reduced by 27% (P<0.05) by both charcoal alone and charcoal combined
      with lavage. The increase in plasma diazepam concentration from 0.5 h onwards was
      prevented by both interventions (P</=0.05), whereas the Cmax of diazepam was not
      significantly affected by either treatment. The AUC(0, 10 h) of ibuprofen was
      reduced by 49% (P<0.05) after the combination treatment and by 30% (P<0.05) after
      charcoal alone, but there was no significant difference between these two
      treatments. Both charcoal alone and the combination treatment were equally
      effective in preventing the increase in plasma ibuprofen from 0.5 h onwards
      (P<0.01). The Cmax of ibuprofen was reduced by 45% (P<0.05) and by 21% (P=NS),
      respectively. The AUC(0,10 h) of citalopram was reduced by 51% (P<0.05) after
      both charcoal alone and charcoal combined with lavage, and the Cmax by 52%
      (P<0.05) and 54% (P<0.05), respectively. The increase in plasma citalopram
      concentration from 0.5 h onwards was reduced by about 50% (P<0.01) by both
      interventions. CONCLUSIONS: Activated charcoal alone and charcoal combined with
      lavage showed similar efficacy in preventing the absorption of diazepam,
      ibuprofen and citalopram. These results suggest that gastric lavage needs not be
      routinely performed before administration of charcoal.

PMID- 10417491
TI  - Plasma concentrations of disodium cromoglycate after various inhalation methods
      in healthy subjects.
AB  - AIMS: To compare the plasma concentrations of disodium cromoglycate (DSCG)
      following various inhalation procedures in healthy volunteers. METHODS: Nine
      healthy subjects inhaled 2 mg of aerosol, 20 mg of nebuliser solution only, 20 mg
      of nebuliser solution mixed with isotonic saline, or 20 mg of nebuliser solution
      mixed with saline and procaterol, a beta2-adenoceptor agonist, on separate
      occasions 2-3 weeks apart. Plasma concentrations of DSCG were determined by high
      performance liquid chromatography (h.p.l.c.). RESULTS: The peak plasma
      concentrations of DSCG were 1.5+/-0.7 (range 0.4-2.4) ng ml-1 in the aerosol
      group, 8.8+/-6.2 (range 5.3-19.9) ng ml-1 in the nebuliser solution only group,
      17.2+/-16.3 (range 5.0-38.6) ng ml-1 in the nebuliser solution plus isotonic
      saline group, and 24.5+/-11. 9 (range 10.2-44.9) ng ml-1 in the nebuliser
      solution plus saline and procaterol group. Thus subjects who used the nebuliser
      had markedly higher plasma concentrations of DSCG than subjects who used the
      aerosol inhaler. CONCLUSIONS: These findings may have important implications for
      the evaluation of inhalation treatment with DSCG for bronchial asthma.

PMID- 10417492
TI  - Comparison of (S)-mephenytoin and proguanil oxidation in vitro: contribution of
      several CYP isoforms.
AB  - AIMS: To compare the oxidative metabolism of (S)-mephenytoin and proguanil in
      vitro and to determine the involvement of various cytochrome P450 isoforms.
      METHODS: The kinetics of the formation of 4'-hydroxymephenytoin and cycloguanil
      in human liver microsomes from 10 liver samples were determined, and inhibition
      of formation was studied using specific chemical inhibitors and monoclonal
      antibodies directed towards specific CYP450 isoforms. Expressed CYP450 enzymes
      were used to characterize further CYP isoform contribution in vitro. Livers were
      genotyped for CYP2C19 using PCR amplification of genomic DNA followed by
      restriction endonuclease digestion. RESULTS: All livers were wildtype with
      respect to CYP2C19, except HLS#5 whose genotype was CYP2C19*1/CYP2C19*2. The Km,
      Vmax and CLint values for the formation of 4'-hydroxymephenytoin from (S)
      mephenytoin and the formation of cycloguanil from proguanil ranged from 50.8 to
      51.6 and 43-380 microm, 1.0-13.9 and 0.5-2.5 nmol mg-1 h-1, and 20.2-273.8 and
      2.7-38.9 microl h-1 mg-1, respectively. There was a significant association
      between the Vmax values of cycloguanil and 4'-hydroxymephenytoin formation
      (rs=0.95, P=0.0004). Cycloguanil formation was inhibited significantly by
      omeprazole (CYP2C19/3A), troleandomycin (CYP3A), diethyldithiocarbamate
      (CYP2E1/3A), furafylline (CYP1A2), and (S)-mephenytoin. 4'-Hydroxymephenytoin
      formation was inhibited significantly by omeprazole, diethyldithiocarbamate,
      proguanil, furafylline, diazepam, troleandomycin, and sulphaphenazole (CYP2C9).
      Human CYP2E1 and CYP3A4 monoclonal antibodies did not inhibit the formation of
      cycloguanil or 4'-hydroxymephenytoin, and cycloguanil was formed by expressed
      CYP3A4 and CYP2C19 supersomes. However, only expressed CYP2C19 and CYP2C19
      supersomes formed 4'-hydroxymephenytoin. CONCLUSIONS: The oxidative metabolism of
      (S)-mephenytoin and proguanil in vitro is catalysed by CYPs 2C19 and 1A2, with
      the significant association between Vmax values suggesting that the predominant
      enzymes involved in both reactions are similar. However the degree of selectively
      of both drugs for CYP isoforms needs further investigation, particularly the
      involvement of CYP3A4 in the metabolism of proguanil. We assert that proguanil
      may not be a suitable alternative to (S)-mephenytoin as a probe drug for the
      CYP2C19 genetic polymorphism.

PMID- 10417493
TI  - Induction of zidovudine glucuronidation and amination pathways by rifampicin in
      HIV-infected patients.
AB  - AIMS: The objective of the study was to determine the effect of multiple doses of
      rifampicin on the steady-state pharmacokinetics of zidovudine and its 5'
      glucuronosyl (GZDV) and 3'-amino (AMT) metabolites. METHODS: Eight asymptomatic
      HIV-infected patients (seven male, one female) participated in this three-period
      longitudinal study. Each patient received zidovudine (200 mg every 8 h) for 14
      days (period 1), followed by rifampicin (600 mg every 24 h) with zidovudine for
      14 days (period 2), and then zidovudine alone for a further 14 days (period 3).
      Blood and urine samples were collected over 6 h on the last day of each period
      for measurements of zidovudine and GZDV by h.p.l.c.-u.v. and AMT by h.p.l.c.-m.s
      m.s. RESULTS: Compared with zidovudine-alone values in period 1, 14 days of
      coadministration with rifampicin significantly increased zidovudine oral
      clearance (89%) and formation clearances to GZDV (100%) and AMT (82%).
      Correspondingly, there were decreases in maximum plasma concentration (43%), AUC
      (47%) and urine recovery (37%) of zidovudine. GZDV/zidovudine and AMT/zidovudine
      AUC ratios increased by 99% and 36%, respectively, despite a significant 29%
      decrease in AMT AUC. After stopping rifampicin for 14 days, values of these
      pharmacokinetic parameters returned to within 26% of baseline. Over the three
      periods AMT plasma levels were <18 ng ml-1 (n=6) and <40 ng ml-1 (n=2), and molar
      AMT/zidovudine AUC ratios ranged from 1.7% to 4.5%. CONCLUSIONS: Rifampicin
      induced zidovudine glucuronidation and amination pathways resulting in decreased
      plasma and urine exposures to zidovudine. AMT plasma exposure decreased because
      induction was more pronounced for the major GZDV metabolite. The magnitude of the
      residual inductive effect was minimal at 14 days after stopping rifampicin.

PMID- 10417495
TI  - The effects of moclobemide on the pharmacokinetics of the 5-HT1B/1D agonist
      rizatriptan in healthy volunteers.
AB  - AIMS: The new 5-HT1B/1D agonist rizatriptan (MK-0462) has recently been
      registered for the treatment of migraine. Its primary route of metabolism is via
      monoamine oxidase-A (MAO-A). Antidepressants such as the MAO-A inhibitor
      moclobemide may be used in patients with chronic headache syndromes. Hence, this
      study aimed to investigate the interactions between rizatriptan and moclobemide.
      METHODS: In a double-blind, randomized, placebo-controlled, two-period cross-over
      study 12 healthy, young volunteers (six males, six females) were treated with
      moclobemide (150 mg twice daily) or placebo for 4 days. On the fourth day, a
      single dose of rizatriptan (10 mg) was administered, and subsequently blood and
      urine samples were collected for assay of rizatripan and N-monodesmethyl
      rizatriptan. Plasma concentrates of 3,4-dihydroxyphenylglycol (DHPG), a marker of
      MAO-A inhibition, were also assessed. Supine and standing blood pressure were
      measured regularly. RESULTS: Both treatments were well tolerated. During
      moclobemide, the increase in supine diastolic blood pressure following
      rizatriptan administration was augmented. Inhibition of MAO by moclobemide was
      inferred from a persistent decrease in DHPG level (43% on average). When
      rizatriptan was coadministered with moclobemide, the area under the plasma drug
      concentration-time profiles for rizatriptan and its N-monodesmethyl metabolite
      increased 2.2-fold (90% CI, 1.93-2.47) and 5.3-fold (90% CI, 4.81-5.91),
      respectively, when compared with placebo. Peak plasma drug concentrations for
      rizatriptan and its n-monodesmethyl metabolite increased 1.4-fold (90% CI, 1.11
      1.80) and 2.6-fold (90% CI, 2.23-3.14), respectively, and half-lives of both were
      prolonged. CONCLUSIONS: Moclobemide inhibited the metabolism of rizatriptan and
      its active N-monodesmethyl metabolite through inhibition of MAO-A. Thus,
      moclobemide may considerably potentiate rizatriptan action. Concurrent
      administration of moclobemide and rizatriptan is not recommended.

PMID- 10417494
TI  - The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of
      (R/S)-verapamil in humans.
AB  - AIMS: The purpose of this human intestinal perfusion study was to investigate the
      effect of ketoconazole on the jejunal permeability and first-pass metabolism of
      (R)- and (S)-verapamil in humans. METHODS: A regional single-pass perfusion of
      the jejunum was performed using a Loc-I-Gut(R) perfusion tube in six healthy
      volunteers. Each perfusion lasted for 200 min and was divided into two periods of
      100 min each. The inlet concentration of (R/S)-verapamil was 120 mg l-1 in both
      periods, and ketoconazole was added at 40 mg l-1 in period 2. (R/S)-verapamil was
      also administered as a short intravenous infusion of 5 mg, over a period of 10
      min. The appearance ratios of the CYP3A formed metabolites (R)- and (S)
      norverapamil were also estimated in the outlet jejunal perfusate. RESULTS: The
      effective jejunal permeability (Peff) of both (R)- and (S)-verapamil was
      unaffected by the addition of ketoconazole in period 2 suggesting that
      ketoconazole had no effect on the P-glycoprotein mediated efflux. However, the
      appearance ratio of both (R)- and (S)-norverapamil in the outlet jejunal
      perfusate decreased in the presence of ketoconazole. The rate of absorption into
      plasma of (R)- and (S)-verapamil increased despite the low dose of ketoconazole
      added, indicating an inhibition of the gut wall metabolism of (R/S)-verapamil by
      ketoconazole. CONCLUSIONS: Ketoconazole did not affect the jejunal Peff of (R/S)
      verapamil, but it did increase the overall transport into the systemic
      circulation (bioavailability), probably by inhibition of the gut wall metabolism
      of verapamil. This might be due to ketoconazole being less potent as an inhibitor
      of P-glycoprotein than of CYP3A4 in vivo in humans.

PMID- 10417498
TI  - Inhibition of vasoconstriction by the thromboxane A2 antagonist GR32191B in the
      human radial artery.
AB  - AIMS: The newly revived coronary bypass graft, the radial artery (RA), is more
      spastic than the internal mammary artery. Thromboxane A2 is a potent
      vasoconstrictor for arterial grafts. This study was therefore designed to
      determine whether the specific thromboxane A2 (TP) receptor antagonist, GR32191B,
      is effective in inhibition of prostanoid or nonprostanoid receptors in the RA.
      METHODS: The effect of GR32191B was studied in human RA segments, taken from
      coronary bypass patients, in organ chambers. Two effects of GR32191B were tested:
      (1) the relaxation induced by GR32191B in the RA precontracted with the TP
      receptor agonists U46619 and PGF2alpha or nonprostanoid vasoconstrictors
      (noradrenaline [NA], angiotensin II [AII], and K+ ) and (2) the inhibitory effect
      of GR32191B on TP receptor agonists and nonprostanoid vasoconstrictors. RESULTS:
      In U46619 (10 nm, n=7) and PGF2alpha (1 microm, n=7) precontracted RA, GR32191B
      induced 100% relaxation (10-100 microm ) but not after precontraction with
      nonprostanoid stimuli (5.8% for K+, 25 mm, n=6, 24.4% for NA, 3 microm, n=8, and
      53.2% for AII, 3 nm, n=5) (P<0.001). Treatment with GR32191B (30 nm )
      significantly depressed the contraction with U46619 (from 160.1+/-11.0% to
      116.8+/-13.1%, P<0. 05) or PGF2alpha (from 91.3+/-12.3% to 42.2+/-9.2%, P<0.01).
      The contraction was further abolished by 3 microm GR32191B. However, GR32191B at
      3 microm did not significantly inhibit the contraction induced by either NA, AII,
      or K+. CONCLUSIONS: GR32191B is a highly potent and specific TP receptor
      antagonist for the human RA. It may be particularly useful in inhibiting TXA2
      mediated vasoconstriction and therefore in reducing the complications related to
      vasospasm in this graft.

PMID- 10417496
TI  - Platelet glycoprotein IIb/IIIa blockade with tirofiban: effect on aggregation
      caused by P256, an antibody to human IIb/IIIa receptors.
AB  - AIMS: P256 is a divalent antibody which aggregates human platelets by interaction
      with glycoprotein (GP) IIb/IIIa receptors. We investigated the effect of
      tirofiban, an antagonist of the GP IIb/IIIa receptor, on P256-mediated platelet
      aggregation. METHODS: Responses to agonists were measured turbidometrically at 37
      degrees C in stirred citrated platelet-rich plasma from venous blood samples from
      healthy human volunteers. Inhibitory effects were determined by comparison with
      aggregation to the same concentration of agonist in a vehicle treated sample.
      RESULTS: Tirofiban inhibited a near maximally effective dose of P256 (10-7 mol l
      1 ) with an IC50 of 9. 3x10-8 mol l-1. Tirofiban (10-7 mol l-1 ) inhibited
      responses to arachidonic acid, U46619 and P256 similarly, whereas aspirin (1.
      1x10-4 mol l-1 ) inhibited arachidonic acid more effectively than P256 (P<0.007
      by anova ). CONCLUSIONS: Tirofiban potently and selectively inhibits P256
      stimulated aggregation of human platelets.

PMID- 10417497
TI  - A double-blind, placebo-controlled investigation of the effects of fexofenadine,
      loratadine and promethazine on cognitive and psychomotor function.
AB  - AIMS: To assess whether fexofenadine in a range of doses from 80 to 180 mg has
      any disruptive effects on aspects of psychomotor and cognitive function in
      comparison with placebo, loratadine and promethazine, an antihistamine known to
      produce psychomotor and cognitive impairment. METHODS: Twenty-four healthy
      volunteers received fexofenadine 80 mg, 120 mg and 180 mg, loratadine 10 mg,
      promethazine 30 mg (as a positive internal control) and placebo in a six-way
      crossover, double-blind study. Following each dose, subjects were required to
      perform a series of tests of cognitive function and psychomotor performance at
      1.5, 3, 6, 9, 12 and 24 h post dose. The test battery included critical flicker
      fusion (CFF), choice reaction time (CRT) and assessment of subjective sedation
      (LARS). Overall levels of activity were monitored by means of wrist mounted
      actigraphs throughout each of the 24 h experimental periods. RESULTS:
      Fexofenadine at all doses tested was not statistically different from placebo in
      any of the tests used and loratadine did not cause any significant impairment of
      cognitive function. Significant impairments were found following promethazine.
      Promethazine caused a significant reduction in CFF threshold and this effect was
      evident up to 12 h post dose (P<0.05). There was a significant increase in
      recognition reaction time at 3 and 6 h post promethazine administration, and the
      drug caused a significant (P<0. 002) increase in the percentage of 'sleep-like'
      activity from actigraph records during the daytime. CONCLUSIONS: Fexofenadine at
      doses up to 180 mg appears free from disruptive effects on aspects of psychomotor
      and cognitive function in a study where the psychometric assessments have been
      shown to be sensitive to impairment, as evidenced by the effects of the verum
      control promethazine 30 mg.

PMID- 10417499
TI  - Histamine response and local cooling in the human skin: involvement of H1- and H2
      receptors.
AB  - AIMS: Histamine may contribute locally to cutaneous blood flow control under
      normal and pathologic conditions. The objective of this study was to observe the
      influence of skin temperature on histamine vasodilation, and the roles of H1-and
      H2-receptors using novel noninvasive methods. METHODS: Eleven healthy subjects
      received, double-blind, single doses of the H1-receptor antagonist cetirizine (10
      mg), cetirizine (10 mg) plus the H2-receptor antagonist cimetidine (400 mg), or
      placebo on separate occasions. Histamine was dosed cumulatively by iontophoresis
      to the forearm skin at 34 degrees C and 14 degrees C. Laser-Doppler flux (LDF)
      was measured at the same sites using customised probeholder/iontophoretic
      chambers with Peltier cooling elements. Finger mean arterial pressure (MAP) was
      measured and cutaneous vascular conductance calculated as LDF/MAP. RESULTS:
      Histamine vasodilation was reduced in cold skin. Cetirizine shifted the histamine
      dose-response at both temperatures: statistically significantly at 14 degrees C
      only. Combined H1- and H2-receptor antagonism shifted the response significantly
      at both temperatures. CONCLUSIONS: H1- and H2-receptors mediate histamine-induced
      skin vasodilation. The sensitivity of these receptors, particularly the H1-
      receptor, is attenuated at low skin temperature. Whether the reduced effect in
      cold skin represents specific receptor or postreceptor desensitization, or
      nonspecific attenuation of cutaneous vasodilation remains to be elucidated.

PMID- 10417500
TI  - Relaxant effects of antidepressants on human isolated mesenteric arteries.
AB  - AIMS: The therapeutic action of tricyclic agents may be accompanied by unwanted
      effects on the cardiovascular system. The evidence for the effects on vascular
      and nonvascular smooth muscle comes from animal studies. Whether these studies
      can be extrapolated to human vessels remains to be determined. Therefore, the
      present study was designed to investigate the influence of amitriptyline,
      nortriptyline and sertraline on the contractile responses of human isolated
      mesenteric arteries to electrical field stimulation, noradrenaline and potassium
      chloride. METHODS: Arterial segments (lumen diameter 0.8-1.2 mm) were obtained
      from portions of the human omentum during the course of 41 abdominal operations
      (22 men and 19 women), and rings 3 mm long were mounted in organ baths for
      isometric recording of tension. In some artery rings the endothelium was removed
      mechanically. RESULTS: In precontracted artery rings amitriptyline, nortriptyline
      and sertraline (3x10(-7)-10(-4) m ) produced concentration-dependent relaxation
      that was independent of the presence or absence of vascular endothelium.
      Incubation with indomethacin (3x10(-6) m ) reduced the pD2 values thus indicating
      the participation of dilating prostanoid substances in this response.
      Amitriptyline and nortriptyline inhibited both the neurogenic-and noradrenaline
      induced contractions. In contrast, only the highest concentration of sertraline
      reduced the adrenergic responses. Amitriptyline, nortriptyline and sertraline
      inhibited contractions elicited by KCl and produced rightward shifts of the
      concentration-response curve to CaCl2 following incubation in calcium-free
      solution. CONCLUSIONS: These results indicate that amitriptyline and
      nortriptyline could act as adrenoceptor antagonists and direct inhibitors of
      smooth muscle contraction of human mesenteric arteries, whereas sertraline might
      principally exert its action only as direct inhibitor of smooth muscle
      contraction. This relaxant mechanism involves an interference with the entry of
      calcium.

PMID- 10417501
TI  - Cohort study on calcium channel blockers, other cardiovascular agents, and the
      prevalence of depression.
AB  - AIMS: Some reports have suggested that calcium channel blockers may be associated
      with an increased incidence of depression or suicide. There is a paucity of
      evidence from large scale studies. The aim of this study was to assess rates of
      depression with calcium channel antagonists using data from prescription event
      monitoring studies. METHODS: Observational studies on large cohorts of patients
      using lisinopril, enalapril (ACE inhibitors), nicardipine (type 2 calcium channel
      blocker) and diltiazem (type 3 calcium channel blocker) were conducted, using
      prescription-event monitoring. Rates of depression in the different drugs and
      rate ratios (95% CI) were computed. RESULTS: The crude overall rates of
      depression during treatment were 1.89, 1.92 and 1.62 per 1000 patient months for
      the ACE inhibitors, diltiazem and nicardipine, respectively. Using the ACE
      inhibitors as the reference group, the rate ratios for depression were 1.07 (0.
      82-1.40) and 0.86 (0.69-1.08) for diltiazem and nicardipine, respectively.
      CONCLUSIONS: This study does not support the hypothesis that calcium channel
      blockers are associated with depression, when considering patients treated in
      general practice in the UK.

PMID- 10417502
TI  - Risk of malformations and other outcomes in children exposed to fluconazole in
      utero.
AB  - AIM: Fluconazole is an active drug systematically used in the oral treatment of
      vaginal candidiasis and other fungal diseases. We examined the risk of
      malformations and other birth outcomes following pregnancy related exposures.
      METHOD: From 1 January 1991 to 31 December 1996 we identified 165 women who had
      taken fluconazole just before or during pregnancy in the Pregnancy Outcome
      Section of the North Jutland Pharmacoepidemiological Prescription Database,
      Denmark, which is linked to the Danish Medical Birth Registry. We compared their
      birth outcomes (malformation, low birth weight and preterm delivery) with the
      outcomes among 13 327 women who did not receive any prescriptions during their
      pregnancies. RESULTS: The prevalence of malformation was 3.3% (four cases) among
      the 121 women, who had used fluconazole in the first trimester, and 5.2% (697
      cases) in offspring to controls (odds ratio: 0.65, 95% confidence limits: 0.24
      1.77). Furthermore, we did not find any significantly elevated risk of preterm
      delivery (odds ratio: 1.17, 95% confidence limits: 0.63-2.17) and low birth
      weight (odds ratio: 1.19, 95% confidence limits: 0.37-3.79). CONCLUSION: The
      study showed no increased risk of congenital malformations, low birth weight or
      preterm birth in offspring to women who had used single dose fluconazole before
      conception or during pregnancy.

PMID- 10417503
TI  - Drug and Therapeutics (D & T) committees in Dutch hospitals: a nation-wide survey
      of structure, activities, and drug selection procedures.
AB  - AIMS: To determine structure, activities and drug selection processes used by
      Dutch hospital drug and therapeutics (D & T) committees. METHODS: A pretested
      structured survey questionnaire based on the Australian process and impact
      indicators, previous research, and consultation of professionals was developed.
      Subsequently, D & T committees that met predefined selection criteria were asked
      to participate. RESULTS: The overall response rate was 70% (38/54). D & T
      committees varied considerably in size and representation of clinical expertise.
      Although responsibilities were theoretically alike, actual responsibilities were
      frequently passed on to other authorities, such as pharmacy staff. Few committees
      used detailed guidelines or decision supportive matrices to establish
      transparency in drug selection. With respect to drug selection, the value scores
      on the information resources used, the factors involved, and the selection
      criteria used varied. Hospital pharmacists were likely to be most involved and to
      have the greatest impact. A consensus was most difficult to achieve for drugs
      used in cardiology, oncology, and psychiatry. Interference of industrial
      marketing strategies on drug selection was recognized and identified.
      CONCLUSIONS: Our results indicate that Dutch hospital D & T committees differ
      with respect to their clinical expertise and their activities, a situation
      comparable with that observed in other countries. Furthermore, the lack of
      transparency in drug selection was considerable. These findings clarify the
      differences previously found between Dutch hospital drug formularies.

PMID- 10417504
TI  - Withdrawal of peripheral vasodilators in primary care.
AB  - AIMS: To investigate the use of peripheral vasodilators in selected practices in
      primary care and to observe the effect of withdrawing therapy in a sample of
      patients. METHODS: Patients receiving repeat prescriptions for peripheral
      vasodilators, identified from two practices in Grampian, were interviewed prior
      to and following withdrawal of therapy. RESULTS: Of the 35 patients, review of
      the continued need for therapy was documented in the medical notes of only one
      patient. Treatment was successfully withdrawn from 17 patients, generating
      considerable savings. CONCLUSIONS: Review of peripheral vasodilators merits
      further attention in larger numbers of patients.

PMID- 10417505
TI  - The pharmacokinetics of lamivudine in healthy Chinese subjects.
AB  - AIMS: The purpose of this study was to investigate the pharmacokinetics of daily
      oral doses of lamivudine administered to healthy Chinese subjects for 1 week.
      METHODS: Twenty-four subjects were enrolled, 12 males and 12 females, all between
      the ages of 18 and 40 years. After an overnight fast, all subjects received a
      single oral dose of 100 mg lamivudine. Blood was obtained before lamivudine
      administration and at regular intervals to 24 h post dose. Subsequent doses were
      given once daily for a total of 7 days. On the last day another full
      pharmacokinetic profile was obtained to 24 h postdose. Timed urine collections
      were performed for all subjects on day 1 only. Pharmacokinetic parameters were
      calculated by using standard non compartmental techniques. RESULTS: Lamivudine
      was well absorbed in all subjects (tmax 1 h). On day 1 and day 7 the overall
      geometric mean Cmax was 1304 and 1385 ng ml-1, and AUC(0,24h) was 4357 and 4353
      ng ml-1 h, respectively. On average 78% of the lamivudine dose was recovered in
      urine as parent compound. Pharmacokinetic parameters were very similar between
      male and female subjects, between day 1 and day 7 and in comparison with data
      obtained in many other pharmacokinetic studies. CONCLUSIONS: This study
      demonstrated that the pharmacokinetics of lamivudine are essentially identical
      between Chinese and Caucasian subjects, and between males and females. It
      confirms 100 mg lamivudine is an appropriate dose for use in Chinese patients,
      providing adequate exposure for optimal antiviral effect.

PMID- 10417506
TI  - Serum concentrations of tramadol enantiomers during patient-controlled analgesia.
AB  - AIMS: Tramadol, a centrally acting analgesic, is used as a racemate containing
      50% of a (+)- and 50% of a (-)-enantiomer. This paper presents the
      pharmacokinetic results of postoperative patient-controlled analgesia using (+)
      tramadol, (-)-tramadol or the racemate. METHODS: Ninety-eight patients recovering
      from major gynaecological surgery were treated in a randomised, double-blind
      study with (+)-tramadol, (-)-tramadol or the racemate. Following an i.v. bolus up
      to a maximum of 200 mg, patient-controlled analgesia with demand doses of 20 mg
      was made available for 24 h. Prior to each demand, the serum concentrations of
      the enantiomers of tramadol and its metabolite M1 were measured in 92 patients.
      RESULTS: The mean concentrations of tramadol during the postsurgery phase were
      470+/-323 ng ml-1, 590+/-410 ng ml-1 and 771+/-451 ng ml-1 in the (+)-, racemate-
      and (-)-group, respectively ((+) vs (-), P<0.05); the mean concentrations of the
      metabolite M1 were 57+/-18 ng ml-1, 84+/-34 ng ml-1 and 96+/-41 ng ml-1 in the
      (+)-, racemate- and (-)-group, respectively ((+) vs (-) and (+) vs racemate,
      P<0.05). The mean concentrations of (+)-tramadol and (+)-M1 were lower in the
      racemate- than in the (+)-group (P<0.05), those of (-)-tramadol and (-)-M1 were
      lower in the racemate than in the (-)-group (P<0.05). In the racemate group, the
      mean serum concentrations of (+)-tramadol were higher than those of (-)-tramadol
      (P<0.05), whereas the mean serum concentrations of (-)-M1 were higher than those
      of (+)-M1 (P<0. 05). CONCLUSIONS: The therapeutic serum concentration of tramadol
      and M1 showed a great variability. The lowest mean concentrations were measured
      in the (+)-group and the highest in (-)-group. This is in agreement with the
      clinical finding that (+)-tramadol is a more potent analgesic than (-)-tramadol.

PMID- 10417507
TI  - Flow ratios to express results obtained with the human in vivo 'perfused forearm
      technique'.
AB  - AIMS: To determine the accuracy of forearm blood flow (FBF) ratio (flow in
      infused arm/flow in control arm) to detect unilateral increases in forearm blood
      flow. METHODS: In nine healthy male volunteers, we measured the effect of
      infusion of saline into the brachial artery at a rate of 2 ml/100 ml forearm min
      1 on FBF ratio during control, mental arithmetic (MAR) and lower body negative
      pressure (LBNP) at -40 mmHg. RESULTS: Saline infusion increased FBF ratio from
      baseline by 115.9+/-17.4, 82.0+/-19.0 and 159.6+/-53.3% for control, MAR and
      LBNP, respectively (P<0.05 for MAR vs control). CONCLUSIONS: FBF ratio may
      underestimate unilateral increases in forearm blood flow during simultaneous
      mental arousal.

PMID- 10417508
TI  - The treatment of eczema with Chinese herbs: a systematic review of randomized
      clinical trials.
AB  - AIMS: Chinese herbal treatments are being promoted as a treatment for eczema. The
      aim of this study was to systematically review the evidence for or against this
      notion. METHODS: Extensive literature searches were carried out to identify all
      randomised clinical trials on the subject. Data were extracted from these in a
      predefined standardized fashion. RESULTS: Only two randomized clinical trials
      were located. Both imply that a complex mixture of Chinese herbs is more
      effective than placebo in treating eczema. Yet several caveats exist, most
      importantly the lack of independent replication. Adverse effects have also been
      reported. CONCLUSIONS: At present it is unclear whether Chinese herbal treatments
      of eczema do more good than harm.

PMID- 10417509
TI  - Itchy folliculitis and human immunodeficiency virus infection:
      clinicopathological and immunological features, pathogenesis and treatment.
AB  - The predominant itchy folliculitis associated with human immunodeficiency virus
      (HIV) infection appears to be an eosinophilic folliculitis (EF). This is
      characterized by lytic degeneration of sebaceous glands and an inflammatory
      infiltrate in which eosinophils and CD8+ T lymphocytes predominate. All patients
      have low CD4 counts and present late on in their HIV disease. Lesional
      distribution is mainly truncal, with a significant proportion also having facial
      involvement. Our prospective survey has shown that it is impossible to
      differentiate clinically between infective folliculitis and EF, and we recommend
      therefore that all cases are biopsied. We review the clinicopathological and
      immunological aspects of HIV-associated itchy folliculitis, in particular HIV
      associated EF as well as current theories on pathogenesis and treatment. We
      suggest that HIV-associated EF is an autoimmune disease with the sebocyte or some
      constituent of sebum acting as the autoantigen.

PMID- 10417510
TI  - Expression of the neuronal isoform of nitric oxide synthase (nNOS) and its
      inhibitor, protein inhibitor of nNOS, in pigment cell lesions of the skin.
AB  - Nitric oxide (NO) is involved in many physiological processes. In cancer, low
      levels of NO are thought to enhance tumour progression and metastasis. NO is
      generated from arginine by NO synthase (NOS); the Ca2+-dependent neuronal isoform
      or nNOS (expressed by neurones and inhibited by the protein inhibitor of nNOS,
      PIN), is also expressed by cultured normal melanocytes and by all malignant
      melanoma (MM) cell lines. We studied the expression of nNOS and PIN in paraffin
      sections of 177 and 58 pigment cell lesions, respectively, using
      immunohistochemistry; the activity of the necessary cofactor NADPH was studied in
      26 frozen cases. Normal melanocytes in situ lacked nNOS and PIN expression, but
      were NADPH +. Almost half of common acquired benign naevi expressed nNOS;
      however, halo naevi and congenital naevi expressed nNOS very frequently.
      Dysplastic naevi and MM showed variable nNOS immunoreactivity in 72% and 83% of
      cases, respectively. Early (Clark I and Clark II) MM displayed nNOS staining most
      frequently, and all MM with an invasive radial growth phase expressed nNOS in the
      papillary dermis. In contrast, only 67% of metastatic MM were nNOS +. PIN was
      coexpressed with nNOS in 40 of 58 lesions. NADPH activity was present in all nNOS
      + naevi, but in two malignant cases, NADPH activity was not accompanied by nNOS
      expression. We conclude that nNOS expression is induced de novo in benign and
      malignant pigment cell lesions which have all the requirements (NADPH, PIN)
      necessary for the production and modulation of NO. We postulate that the frequent
      expression of nNOS in the junctional part of dysplastic naevi may be responsible
      for their particular histological features. NO generated by the neoplastic dermal
      cells in the invasive radial growth phase may contribute to the increased number
      of blood vessels in the papillary dermis.

PMID- 10417511
TI  - The depigmenting effect of alpha-tocopheryl ferulate on human melanoma cells.
AB  - Oral vitamin E (alpha-tocopherol, alpha-T) supplementation has been reported to
      improve facial hyperpigmentation. alpha-Tocopheryl ferulate (alpha-TF) is a
      compound of alpha-T and ferulic acid connected by an ester bond; ferulic acid is
      also an antioxidant, and could scavenge free radicals induced by ultraviolet (UV)
      radiation, and thus maintain the long-lasting antioxidative effect of alpha-T.
      Our aim was to see whether alpha-TF might be useful as a whitening agent and an
      antioxidant to improve and prevent facial hyperpigmentation following UV
      exposure. In this study, the inhibitory effect of alpha-TF on melanogenesis was
      examined biochemically using human melanoma cells in culture. The results show
      that alpha-TF, solubilized in ethanol or in 0.5% lecithin, inhibited melanization
      significantly, as did alpha-T at a concentration of 100 microg/mL, without
      inhibiting cell growth. This phenotypic change was associated with inhibition of
      tyrosinase and 5, 6-dihydroxyindole-2-carboxylic acid polymerase activities, and
      the degree of inhibition was dose dependent. No significant effect on DOPAchrome
      tautomerase activity was observed. alpha-TF did not directly inhibit tyrosinase
      activity of the large granule fraction extracted from human melanoma cells, and
      Western blotting revealed that there were no changes in protein content or in
      molecular size of tyrosinase, tyrosinase-related protein (TRP)-1 or TRP-2.
      Therefore, the inhibition of tyrosinase activity by alpha-TF might be due to
      effects at the post-translational level, and possibly by a secondary molecule
      activated by alpha-TF. These results suggest that alpha-TF is a candidate for an
      efficient whitening agent which suppresses melanogenesis and inhibits biological
      reactions induced by reactive oxygen species.

PMID- 10417512
TI  - Amplification of MelanA messenger RNA in addition to tyrosinase increases
      sensitivity of melanoma cell detection in peripheral blood and is associated with
      the clinical stage and prognosis of malignant melanoma.
AB  - An improved protocol for reverse transcription-polymerase chain reaction (RT
      PCR), amplifying tyrosinase and MelanA/MART-1 mRNA from peripheral blood, was
      used to test 340 blood samples from 225 patients with malignant melanoma for the
      presence of circulating tumour cells. Positive results for tyrosinase or MelanA
      were obtained in 19% of patients in stage I (n = 74), 31% in stage II (n = 45),
      29% in stage III (n = 48) and 52% in stage IV (n = 58). Amplification of MelanA
      in addition to tyrosinase resulted in a 30% enhanced sensitivity of melanoma cell
      detection compared with amplification of tyrosinase alone. The sensitivity was
      further enhanced by analysis of at least two blood samples per patient and
      performing at least two PCR analyses per sample. During a median follow-up of 4
      months, patients with a positive PCR showed a 2. 4-fold increased risk for
      relapse compared with PCR-negative patients. These data indicate that the
      detection of circulating melanoma cells in peripheral blood using our optimized
      protocol for RT-PCR correlated with the clinical stage of disease and is
      therefore likely to be a prognostic marker for recurrence. MelanA is a sensitive
      additional marker to tyrosinase in detecting micrometastases using RT-PCR.

PMID- 10417513
TI  - Increased sensitivity for the detection of malignant melanoma cells in peripheral
      blood using an improved protocol for reverse transcription-polymerase chain
      reaction.
AB  - Conflicting results have been obtained by various research groups using
      tyrosinase reverse transcription-polymerase chain reaction (RT-PCR) for detecting
      micrometastases in the blood of melanoma patients, with positive results ranging
      from 0 to 100% in disseminated melanoma. Methodological differences in the
      processing of blood samples may in part account for these discrepancies. The aim
      of this study was to standardize and optimize the experimental conditions for RT
      PCR detection of melanoma cells in peripheral blood. We analysed the effect of
      different parameters of sample processing on the sensitivity of the tyrosinase RT
      PCR using peripheral blood spiked with defined numbers of SKMEL28 melanoma cells.
      Purification of the mononuclear cell fraction using a Ficoll gradient with a
      density of 1.077 g/mL prior to RNA isolation gave the highest sensitivity, with
      the detection of two SKMEL28 cells in 5 mL of blood. In addition, the RNA
      isolation method and the kind of RT enzyme used had a significant impact on the
      sensitivity and reproducibility of tyrosinase detection, whereas variations in
      the PCR conditions had only a minor influence. Furthermore, we showed that
      amplification of MelanA in addition to tyrosinase resulted in an approximately
      10% enhanced sensitivity of melanoma cell detection, whereas gp100/pMel17 and
      MUC18 gene products were also detected in blood from non-melanoma patients.
      MelanA could serve as a sensitive marker in addition to tyrosinase for detecting
      micrometastases.

PMID- 10417514
TI  - Evidence for the cofactor role of human T-cell lymphotropic virus type 1 in
      mycosis fungoides and Sezary syndrome.
AB  - The aetiology of mycosis fungoides (MF) and Sezary syndrome (SS) is unknown. A
      pathogenic role for the human T-cell lymphotropic virus type 1 (HTLV-1) has been
      suggested but remains controversial. We used an animal model to test the
      possibility that peripheral blood mononuclear cells (PBMC) obtained from MF
      patients harbour the HTLV-1 virus which may be infective. The polymerase chain
      reaction (PCR) was used to detect HTLV-1 proviral DNA sequences in PBMC of 27 MF
      patients and one SS patient of non-Iranian origin. Positive results were found in
      six of the patients. Twelve of the 28 patients tested by Western blot showed HTLV
      1 antibodies. Twenty-eight immunosuppressed inbred Fisher F344 rats were
      inoculated intravenously with cultures of PBMC obtained from the 28 patients.
      Eight of these 28 rats showed antibodies to HTLV-1 while the proviral genome was
      demonstrated in the blood of only two of the rats. PBMC from two MF patients, in
      spite of showing negative results for the proviral genome by PCR, still induced
      HTLV-1 antibody formation in the F344 rat model. None of 10 control rats
      inoculated with normal donor PBMC showed antibodies to HTLV-1, nor the proviral
      genome. The present study suggests that HTLV-1 plays a cofactor role in MF/SS
      patients.

PMID- 10417516
TI  - The steady-state turnover of murine epidermal Langerhans cells.
AB  - We have investigated the steady-state turnover of murine epidermal Langerhans
      cells (LCs) using an X-irradiation model, 3H-thymidine autoradiography and
      cultured epidermal sheet explants, and by assessing the LC population in normal
      mice. The LC density after whole-body irradiation without any cutaneous shielding
      was not significantly different from that in skin shielded during whole-body
      irradiation (P > 0.05), indicating that the additional irradiation to the skin
      did not contribute to a decrease in LC density. In both instances, the LC number
      gradually decreased in a linear fashion. The results indicate that epidermal LCs
      continuously leave the epidermis and are continually replaced by circulating
      precursor cells from the bone marrow at a steady rate. Autoradiographic studies
      after a pulse injection of 3H-thymidine showed a labelling index of 0.013%,
      indicating that local mitosis is not an important contributor to the maintenance
      of the epidermal LC population. Although local X-irradiation resulted in
      temporary reduction of LC density, epidermal sheet explant culture obtained
      immediately after local X-irradiation showed no difference in LC density as
      compared with control unirradiated skin, indicating that the decrease in LC
      density was not due to significant LC destruction. From these data, we calculated
      that the half-life of murine LCs in the epidermis is approximately 9 days.

PMID- 10417515
TI  - Increased expression of tenascin C by keloids in vivo and in vitro.
AB  - Tenascin C, undulin, collagen XIV and fibronectin are extracellular matrix
      glycoproteins with a partial DNA sequence homology. During embryogenesis,
      tenascin C is abundant in mesenchymal tissues but its distribution in human adult
      tissue is severely restricted. The levels of tenascin C expression are enhanced
      with skin inflammation, wound healing and hyperproliferative skin diseases and
      return to normal in normal scar tissue after wound contraction is completed.
      Undulin/collagen XIV is associated with collagen fibrils and fibronectin is
      present throughout the dermis in adult skin but it is produced by keloidal
      fibroblasts in an increased amount. In this study we investigated by
      immunohistochemistry the expression of the three extracellular matrix proteins in
      keloids and normal skin as well as in keloidal and normal fibroblasts in vitro.
      In keloids, increased tenascin C expression was observed especially in the
      reticular dermis associated with collagen fibrils sharply demarcating the limit
      of the lesion. In normal tissue, tenascin C was only expressed beneath the basal
      lamina and dermal-epidermal junction. Corresponding to the in vivo findings,
      tenascin C expression was increased in keloidal fibroblasts compared with normal
      fibroblasts in vitro (P < 0.003), whereas undulin/collagen XIV and fibronectin
      expression in keloids and keloidal fibroblasts was similar to that in normal
      tissue and normal fibroblasts, respectively. Therefore, tenascin C is a marker
      associated with keloids and we suggest that keloidal fibroblasts, once
      stimulated, continue to produce tenascin C independently from circulating
      factors.

PMID- 10417518
TI  - A prospective study of 200 women with dermatoses of pregnancy correlating
      clinical findings with hormonal and immunopathological profiles.
AB  - In 1994 we set up a specialist clinic for pregnancy dermatoses, both to improve
      the management of pregnant women with skin problems and to enhance our general
      understanding of the pregnancy dermatoses. This clinic has provided a large
      database of 200 women which has formed the basis for a prospective study over a 2
      year period. In each case the dermatological diagnosis was clearly defined on
      clinical criteria, with additional help from histopathology and direct
      immunofluorescence of the skin where appropriate. We have included a number of
      patients who presented with relatively trivial diagnoses, as this reflects the
      referral patterns of our midwives, general practitioners and obstetricians within
      our hospital and local population. Our results show that all patients with
      specific dermatoses of pregnancy conformed well to the classification established
      by Holmes and Black in 1983. The role of the sex hormones [oestradiol, human
      chorionic gonadotrophin (hCG) and cortisol] in polymorphic eruption (PEP) and
      prurigo of pregnancy was studied in 125 cases and compared with 138 normal
      healthy pregnant controls. For pruritic folliculitis (PF), serum androgens were
      measured to establish if these were elevated. Nearly all patients were followed
      up postpartum, with respect to both maternal and fetal prognosis (some were
      unfortunately lost to follow-up). Many patients were primiparous (47%) and
      presented in their third trimester (49%). This study shows a surprisingly high
      prevalence of eczema during pregnancy. It is possible that earlier cases in the
      literature termed prurigo of pregnancy may in fact have been eczema, thus
      explaining the low incidence of prurigo in this study. Hormonal analysis showed a
      significant reduction in serum cortisol levels in patients with PEP compared with
      normal pregnant controls (P = 0.03), although hCG and oestradiol showed no
      differences. Serum androgens were not significantly elevated in patients with PF
      compared with controls. Birthweight (analysed by the individualized birthweight
      ratio) was significantly reduced in both the PF and pemphigoid gestationis
      groups. In the PEP and PF groups there was a male/female infant ratio of 2 : 1,
      not noted in previous studies. In all cases studied there were no adverse effects
      either on maternal or fetal outcome as a result of the pregnancy dermatosis. This
      study indicates that all patients fulfilled the criteria of the previous
      classification of the specific dermatoses of pregnancy, although we also now
      highlight the frequency of eczema in pregnancy and speculate as to possible
      causes. There were no cases of papular dermatitis of pregnancy. We feel that the
      specialist clinic is an important service which has improved the management of
      these women and identified areas for further research.

PMID- 10417517
TI  - A comparison of the expression of known basement membrane components with the
      linear IgA disease antigens using the novel substrate cylindroma.
AB  - Linear IgA disease (LAD) is characterized by IgA basement membrane zone
      autoantibodies. Immunofluorescence, immunoblotting and immunoelectron microscopy
      studies have established the complexity and heterogeneity of the target antigens.
      We have studied the expression of the LAD antigens by cylindroma, a benign
      epithelial tumour that secretes abundant basement membrane, using 57 LAD sera
      categorized by indirect immunofluorescence on intact and salt-split skin. The
      expression of known components of hemidesmosomes, the anchoring filaments,
      extracellular matrix and the anchoring fibrils could be differentiated and were
      compared with the expression of the LAD antigens. The results showed that the LAD
      sera bound to the cylindroma tumour in two distinctive patterns. Thirty-three
      sera were positive on cylindroma. Twenty-seven sera bound to the basement
      membrane around the tumour clusters and the islets within the clusters in a thin
      linear band that was occasionally discontinuous. This was similar to the pattern
      observed with antibodies to the hemidesmosome components, the alpha6beta4
      integrin and the bullous pemphigoid antigens BP230 and BP180. This pattern was
      observed with sera that bound to the epidermal (11) and the dermal (3) aspects of
      split skin or were negative (11), and with one serum which bound only to intact
      skin. Seven sera, all binding to the dermal aspect of split skin, bound the
      tumour cluster basement membrane in a thick band that was identical in appearance
      to that seen with antibodies to collagen VII; however, binding to the islets was
      either identical to collagen VII or similar but differentiated with double
      staining. Some sera were negative on cylindroma. Using fluorescence overlay
      antigen mapping we demonstrated colocalization of some epidermal-associated LAD
      target antigens with known hemidesmosome proteins, and colocalization of some
      dermal-associated LAD target antigens with anchoring fibril components. The
      results using cylindroma as substrate suggest that LAD autoantibodies may react
      with three or more target antigens. We propose from the results of this study
      that the autoantibodies in LAD target multiple antigens associated with
      hemidesmosomes and anchoring fibrils.

PMID- 10417519
TI  - The characteristics of nocturnal scratching in adults with atopic dermatitis.
AB  - Patients with atopic dermatitis (AD) are known to suffer from nocturnal itch, and
      the resultant scratching may worsen the skin lesions. We observed nocturnal
      scratching for 112 nights in 35 adult patients with AD, using an infrared video
      camera system. To quantify the amount of scratching, we counted scratching bouts
      lasting more than 5 s and calculated the duration of all the scratching bouts
      (total scratching time, TST). The percentage of TST in the total recording time
      (TST%) was used as an index of nocturnal scratching. Mean +/- SD TST% was 14.3 +/
      13.9 for patients with severe AD, 6.2 +/- 3.7 for those with moderate AD and 0.7
      +/- 0.4 for those with mild AD. The higher TST% in the severely affected group
      was attributed mainly to a longer duration rather than a higher frequency of
      bouts. Patients scratched more in the first third of the night than in the later
      two-thirds. Both the group of patients whose disease distribution pattern was
      generalized and those who showed a head-neck-shoulder type distribution scratched
      their heads, faces and necks for longer than other parts of the body. Repeated
      measurement performed on individual subjects resulted in a similar TST% when
      there was little change in skin lesions. TST% reduced by 15 +/- 21% when the
      patients showed marked improvement. The measurement of nocturnal scratching helps
      to evaluate the severity of itch in AD. In addition, the infrared video
      successfully detected the location and nature of nocturnal scratching in AD.

PMID- 10417520
TI  - Capsaicin treatment induces histamine release and perfusion changes in psoriatic
      skin.
AB  - To determine whether neurogenic factors may be of importance in the regulation of
      histamine release and blood flow in psoriatic plaque, the effect of capsaicin was
      studied in 22 psoriatic patients with active, untreated psoriatic lesions. In
      each of 12 patients, one microdialysis fibre was placed in non-lesional skin and
      one was placed in lesional skin at depths of 0.7 and 0.9 mm, respectively.
      Dialysates were collected for the analysis of histamine in the resting state and
      after 60 min of repetitive epicutaneous application of 1% capsaicin above the
      microdialysis catheter. In 10 patients, topical capsaicin and placebo were
      applied for 24 h to lesional/lesion-free skin. Skin blood flow and perfusion
      (evaluated using the 133xenon clearance technique and scanning laser Doppler,
      respectively) were measured before the application of capsaicin and after
      removal. After 60 min of capsaicin treatment, both the perfusion and interstitial
      concentration of histamine, as well as the net release of histamine, were
      significantly increased in affected (from 38 +/- 6 to 45 +/- 6 nmol/L, mean +/-
      SEM) and unaffected (from 15 +/- 2 to 19 +/- 2 nmol/L) skin. Compared with
      placebo, 24 h of treatment with capsaicin caused a 15% decrease in perfusion in
      lesional skin. The results are compatible with the hypothesis that capsaicin
      sensitive nerves may induce histamine release in non-lesional and lesional skin
      and that afferent unmyelinated nerve fibres may contribute to the high blood flow
      in psoriatic plaques.

PMID- 10417521
TI  - A high prevalence of cytomegalovirus antigenaemia in patients with moderate to
      severe chronic plaque psoriasis: an association with systemic tumour necrosis
      factor alpha overexpression.
AB  - Microbiological aspects are considered to be of pathophysiological importance in
      psoriasis, but there has so far been no information regarding cytomegalovirus
      (CMV) infection. This is of interest due to the high prevalence of latent
      infection in the general population, the frequent reactivation in inflammatory
      diseases, and the immunomodulating capacity of CMV. To detect active infection we
      analysed CMV antigen expression of peripheral blood mononuclear cells (PBMC) from
      psoriatic patients (n = 30) in comparison with healthy volunteers (n = 65). Using
      three monoclonal antibodies and immunocytological staining (alkaline phosphatase
      antialkaline phosphatase technique), we frequently found CMV antigenaemia in
      psoriasis (43%) compared with healthy laboratory staff (12%, P < 0. 01) and blood
      donors (6%, P < 0.001). Clearance of CMV antigenaemia was observed with
      antipsoriatic treatment. CMV antigenaemia was symptomless, and was associated
      with seropositivity for anti-CMV IgG but not IgM antibodies, indicating
      subclinical activation of latent infection. Serological investigations in 85
      psoriatic patients gave no evidence for a higher prevalence of latent CMV
      infection. In psoriatic lesions, CMV DNA was only rarely detected by polymerase
      chain reaction. As it has been shown that tumour necrosis factor (TNF)-alpha can
      induce CMV reactivation, we determined TNF-alpha plasma concentrations and mRNA
      expression in PBMC from psoriatic patients. Elevated TNF-alpha levels were found
      and correlated with the frequency of CMV antigen-expressing PBMC, suggesting a
      critical role of TNF-alpha in CMV activation. We speculate that active,
      subclinical CMV infection may be of pathophysiological importance in psoriasis.

PMID- 10417522
TI  - Tacrolimus ointment improves psoriasis in a microplaque assay.
AB  - Tacrolimus (FK506) is an effective and well tolerated immunosuppressant used to
      prevent allograft rejection. We describe the evaluation of two tacrolimus
      ointment formulations for treatment of chronic plaque-type psoriasis. This was a
      microplaque assay with randomized, double-blind design. Sixteen patients (15 men,
      one woman, all white and 28-69 years old) with chronic plaque-type psoriasis
      participated. Six different ointments were applied to discrete microplaques, 17
      mm in diameter, on a descaled psoriasis lesion: these were tacrolimus ointment
      with diisopropyl adipate as penetration enhancer, tacrolimus ointment without
      diisopropyl adipate, 0.1% betamethasone 17alpha-valerate ointment, 0.005%
      calcipotriol ointment and, as controls, the ointment bases for tacrolimus and
      betamethasone. Ointments were reapplied and the area was sealed every 2-3 days
      during the 14-day treatment period. After 7 and 14 days, erythema and
      infiltration were graded on a scale of 0-4, and superficial blood flow was
      measured with a laser Doppler flowmeter. Epidermal thickness was measured
      histologically at the end of treatment. Compared with the vehicle controls, sites
      treated with tacrolimus ointment (with or without penetration enhancer) showed a
      significant reduction in erythema and infiltration (P < 0. 001), a significant
      reduction in superficial blood flow (P < 0.01) and a significant decrease in
      epidermal thickness (P < or = 0.001). Results for betamethasone and calcipotriol,
      when compared with the vehicle controls, were similar. These results suggest
      that, under conditions of descaling and occlusion, tacrolimus ointment is
      effective in the treatment of psoriasis.

PMID- 10417523
TI  - PUVA and cancer risk: the Swedish follow-up study.
AB  - There is concern about the long-term carcinogenic effects of psoralen and
      ultraviolet A radiation (PUVA) for treatment of skin disorders. Many authors have
      found an increased risk for cutaneous squamous cell carcinoma (SCC). Except in
      anecdotal reports, malignant melanoma had not been observed in patients treated
      with PUVA until recently. In the U.S.A., a 16-centre prospective study of 1380
      patients showed for the first time that there might also be an increased risk for
      malignant melanoma in patients treated with high cumulative dosages of PUVA. We
      have therefore followed up the Swedish PUVA cohort until 1994. This cohort had
      previously been followed up until 1985. Information from 4799 Swedish patients
      (2343 men, 2456 women) who had received PUVA between 1974 and 1985 was linked to
      the compulsory Swedish Cancer Registry in order to identify individuals with
      cancer. The average follow-up period was 15.9 years for men and 16.2 for women.
      We did not find any increased risk for malignant melanoma in our total cohort of
      4799 patients treated with PUVA or in a subcohort comprising 1867 patients
      followed for 15-21 years. For cutaneous SCC there was an increase in the risk:
      the relative risk was 5.6 (95% confidence interval, CI 4. 4-7.1) for men and 3.6
      (95% CI 2.1-5.8) for women. Significant (P < 0.05) increases were also found in
      the incidence of respiratory cancer in men and women and of kidney cancer in
      women. In conclusion, we did not find any increased risk for malignant melanoma
      in our patients treated with high doses of PUVA and followed up for a long time.
      We confirm previous reports of an increase in the incidence of cutaneous SCC in
      patients treated with PUVA, and recommend that patients should be carefully
      selected for PUVA and rigorously followed up.

PMID- 10417524
TI  - Polymorphisms of HLA-DM genes in Japanese patients with psoriasis vulgaris.
AB  - We analysed the polymorphisms of HLA-DM genes in 85 unrelated Japanese patients
      with psoriasis vulgaris and 52 healthy controls using the polymerase chain
      reaction-restriction fragment length polymorphism method. The frequency of
      DMA*0101 was decreased (79% vs. 89%, P < 0.05) and that of DMA*0102 was increased
      (20% vs. 11%, P < 0.05) in the patients. However, neither of these remained
      significant after P-values were corrected for the number of comparisons made (Pc
      > 0.05). As we reported previously, HLA-C molecules are assumed to play a more
      important part than HLA-DM genes in the development of psoriasis vulgaris.

PMID- 10417525
TI  - An immunohistochemical study of abnormal keratinocyte differentiation in
      molluscum contagiosum.
AB  - To investigate abnormalities in the keratinization process in lesional epidermis
      of molluscum contagiosum, production of filaggrin, loricrin, Ted-H-1 antigen,
      involucrin, cystatin A and CD95 ligand (CD95L) was investigated using specific
      antibodies. Anti-filaggrin monoclonal antibody (MoAb) did not react with
      keratohyalin granules (KHG), but with the substance around virus particles in the
      stratum corneum. KHG reacted with anti-loricrin polyclonal antibody (PoAb) and
      anti-Ted-H-1 MoAb. Anti-involucrin PoAb and anti-cystatin A PoAb reacted with
      materials in the cytoplasm of the middle stratum spinosum to the stratum
      granulosum. CD95L was expressed in the cell membrane region of the living cell
      layers in lesional epidermis. These observations suggest that the keratinization
      process may be altered in molluscum contagiosum.

PMID- 10417526
TI  - Pacinian collagenoma.
AB  - An unusual histological variant of collagenoma is described. A 36-year-old woman
      presented with a lump in the left hypothenar eminence. Histological examination
      revealed a well-delineated lesion composed of paucicellular collagen fibres
      arranged in concentric lamellations giving rise to an onion skin appearance. The
      overlying epidermis was thin and the lateral borders were demarcated by an
      epidermal collarette. Inflammation and xanthoma cells were absent and occasional
      capillaries were present. The lesion was positive for collagen stains, reticulin
      and CD34. This lesion represents an uncommon histological form of collagenoma or
      fibroma. It can be distinguished from histological look-alikes on the basis of
      the characteristic morphology and immunophenotype.

PMID- 10417527
TI  - Lichenoid tissue reaction in porphyria cutanea tarda.
AB  - We report a patient presenting with lichenoid plaques on exposed skin who had the
      metabolic features of porphyria cutanea tarda (PCT). Histology of lesional skin
      demonstrated a lichenoid inflammatory cell infiltrate in the upper dermis, while
      direct immunofluorescence revealed immunoreactive colloid bodies. Monochromator
      irradiation testing demonstrated photosensitivity in the visible spectrum
      consistent with porphyria. Solar-simulated irradiation induced a papular reaction
      with lichenoid histological changes. We propose that this atypical presentation
      of PCT may reflect a lichenoid tissue response to a porphyrin-mediated
      photochemical reaction.

PMID- 10417528
TI  - Paraneoplastic cicatricial pemphigoid.
AB  - We report a 39-year-old woman with antiepiligrin cicatricial pemphigoid (CP) in
      association with non-small cell carcinoma of the lung. At presentation, mucosal
      lesions showed minimal response to combined systemic immunosuppressive agents.
      Following the diagnosis of non-small cell lung carcinoma and subsequent treatment
      with gemcitabine (a second-line chemotherapeutic agent), a significant reduction
      in both tumour mass and mucosal blistering was observed. Metastatic disease was
      subsequently associated with recurrent oral erosions. We believe this patient
      represents the first reported case of paraneoplastic CP.

PMID- 10417529
TI  - Pigmented squamous cell carcinoma of the scrotum associated with a lentigo.
AB  - Only 13 cases of pigmented squamous cell carcinoma (SCC) have been reported in
      the English language literature, with most frequent development in the oral
      cavity and conjunctiva. However, no case of pigmented SCC of the scrotum has been
      reported. We report here a case of pigmented SCC that arose primarily in the
      scrotum of a 70-year-old man. Light microscopically, this tumour exhibited the
      typical features of a pigmented SCC, including not only keratinization and
      intercellular bridges but also colonization by plump dendritic melanocytes with
      marked pigmentation. These features were clearly confirmed by
      immunohistochemistry, including strong positivity of tumour cells for high
      molecular-weight cytokeratin and of colonizing melanocytes for HMB-45. The tumour
      was associated with a lentiginous lesion and partly involved it. Melanocytes
      entrapped from the lentigo might therefore have been activated during enlargement
      of this tumour, resulting in melanocyte colonization. Fourteen cases of pigmented
      SCC, including ours, are clinicopathologically reviewed.

PMID- 10417531
TI  - Human herpesvirus type 8 and epstein-barr virus-associated cutaneous lymphoma
      taking anaplastic large cell morphology in a man with HIV infection.
AB  - Human herpesvirus type 8 (HHV-8, Kaposi's sarcoma-associated herpesvirus)
      positive lymphoma taking anaplastic large cell morphology in the skin is
      described in a 46-year-old man with AIDS. Multiple erythematous nodules appeared
      on the trunk and extremities during the treatment of AIDS. Histological
      examination of cutaneous nodules showed dense infiltration of CD30 + atypical
      lymphoid cells in the deep dermis. Immunoglobulin JH gene rearrangement was
      detected in these lymphoma cells. Both Epstein-Barr virus-encoded small RNA and
      HHV-8 mRNA (T1.1/nut-1) were detected in these lymphoma cells by in situ
      hybridization. Remarkable retention of the pericardial fluid was observed at the
      same time that cutaneous lesions grew, and lymphoma cells in the pericardial
      fluid showed the same phenotype as the cutaneous lymphoma. Chemotherapy with
      cyclophosphamide, doxorubicin, vincristine and prednisone effectively reduced
      both the cutaneous nodules and pericardial fluid. However, the patient died 4
      months after diagnosis because of cytomegalovirus infection. As far as we know,
      this is the first report of an HHV-8-positive cutaneous lymphoma taking
      anaplastic large cell morphology. This case suggests the association of AIDS
      related anaplastic large cell lymphoma with HHV-8.

PMID- 10417530
TI  - Follicular mycosis fungoides.
AB  - We describe a patient with follicular mycosis fungoides (MF), a rare
      folliculotropic variant of cutaneous T-cell lymphoma (CTCL). Follicular
      involvement in CTCL usually presents clinically as alopecia mucinosa associated
      histologically with follicular mucinosis. Follicular MF differs from alopecia
      mucinosa/follicular mucinosis associated with MF with regard to its clinical
      presentation, histology and, presumably, prognosis. Our patient presented with
      the characteristic findings of follicular MF, i.e. infiltrated plaques showing
      numerous enlarged, comedo-like follicular infundibula; histology was dominated by
      exclusive folliculotropism of atypical lymphocytes sometimes forming follicular
      Pautrier's microabscesses, and by lack of epidermotropism and follicular
      mucinosis. Despite photochemotherapy and treatment with oral retinoids and
      interferon alpha, the patient's follicular MF rapidly developed into a
      progressive CTCL with large tumorous lesions, but responded to electron beam
      therapy. The course of our patient's disease confirms the notion that follicular
      MF may be associated with a worse prognosis than classical MF. However, electron
      beam irradiation induced remission of follicular MF that was maintained by a
      combination therapy consisting of extracorporeal photopheresis and interferon
      alfa.

PMID- 10417532
TI  - Paget's disease of the vulva associated with local adenocarcinoma and previous
      breast adenocarcinoma: report of two cases.
AB  - We report two women in whom vulval Paget's disease occurred in association with
      local adenocarcinoma and previous breast adenocarcinoma. The first patient
      presented at the age of 83 years with moist erythematous changes over the
      perineum and an indurated area near the anus. Biopsy of the indurated area showed
      Paget's cells throughout the epidermis and, below, adenocarcinoma infiltrating
      the dermis. Ten years previously, she had undergone a left mastectomy for
      infiltrating ductal carcinoma of the breast. The second patient was diagnosed as
      having Paget's disease at the age of 74 years. A vulval biopsy showed Paget's
      cells in the epidermis but, in addition, there were changes suggestive of
      adenocarcinoma of the sweat glands. Her symptoms of vulval itching had started at
      the age of 45 years and had led to a simple vulvectomy at the age of 57 years.
      Retrospective review of this vulvectomy specimen showed Paget's disease. She had
      also previously been treated for infiltrating ductal adenocarcinoma of the breast
      and adenocarcinoma of the rectum. The management of Paget's disease is difficult
      because of its high recurrence rate and, as illustrated by our two cases,
      treatment is difficult if the patients are elderly and in poor general health.

PMID- 10417533
TI  - Chronic radiodermatitis following repeated percutaneous transluminal coronary
      angioplasty.
AB  - We review three patients who developed chronic radiodermatitis subsequent to
      undergoing multiple percutaneous transluminal coronary angioplasties (PTCAs). All
      patients had had chronic ischaemic heart disease (IHD) and had undergone lengthy
      PTCA on several occasions. The skin eruption was characterized by an atrophic
      rectangular plaque on the left upper back, presenting as mottled hyper- and
      hypopigmentation with reticulate telangiectasia. Histologically, the eruption
      demonstrated epidermal atrophy, hyalinized and irregularly stained collagen, and
      telangiectasia of superficial vessels in the dermis. Although the risk of
      radiation injury in most patients undergoing cardiac catheterization is low, this
      danger should not be ignored. In particular, patients with long-standing IHD and
      numerous repeated catheterizations to only one or two occluded coronary arteries
      should be considered at high risk.

PMID- 10417534
TI  - Interleukin 5-inducing activity in the blister fluid of eosinophilic pustular
      dermatosis.

PMID- 10417535
TI  - Bullous pemphigoid associated with chronic B-cell lymphatic leukaemia: the anti
      230-kDa autoantibody is not synthesized by leukaemic cells.

PMID- 10417536
TI  - Bullous pemphigoid preceded by recurrent oral lesions: identification of
      autoantibodies against BP180 by immunoblot using epidermal extracts and BP180
      fusion proteins.

PMID- 10417537
TI  - Absence of a link between human herpesvirus 8 and pemphigus.

PMID- 10417539
TI  - Does plantar epidermoid cyst with human papillomavirus infection originate from
      the eccrine dermal duct?

PMID- 10417538
TI  - Parvovirus B19 infection associated with acute hepatitis and a purpuric exanthem.

PMID- 10417541
TI  - Vesiculobullous mycosis fungoides.

PMID- 10417540
TI  - Porokeratosis in patients with hepatitis C virus infection: does hepatitis C
      virus infection provide a link between porokeratosis and immunosuppression?

PMID- 10417542
TI  - Angiosarcoma of the head and neck associated with xeroderma pigmentosum variant.

PMID- 10417543
TI  - Eccrine angiomatous hamartoma with verrucous features.

PMID- 10417544
TI  - Sweet's syndrome associated with oral squamous cell carcinoma and exhibiting the
      Koebner phenomenon.

PMID- 10417545
TI  - Nodular prurigo occurring in the same distribution as sciatic pain from a
      prolapsed intervertebral disc.

PMID- 10417546
TI  - Leg ulcers in patients treated with hydroxyurea for myeloproliferative disorders:
      what is the trigger?

PMID- 10417547
TI  - Abnormal liver function tests induced by dapsone in a patient with dermatitis
      herpetiformis and primary sclerosing cholangitis.

PMID- 10417548
TI  - Severe erythrodermic reactions to the proton pump inhibitors omeprazole and
      lansoprazole.

PMID- 10417549
TI  - Successful treatment of severe refractory atopic dermatitis with mycophenolate
      mofetil.

PMID- 10417550
TI  - Pruritic folliculitis of pregnancy treated with narrowband (TL-01) ultraviolet B
      phototherapy.

PMID- 10417551
TI  - Anaphylactic reaction after a mouse bite in a 9-year-old girl.

PMID- 10417552
TI  - The sportsman's groin.

PMID- 10417553
TI  - Clinical dilemma: The missing mammographic abnormality.

PMID- 10417554
TI  - Modern management of pulmonary embolism.
AB  - BACKGROUND: Pulmonary embolism is a significant cause of morbidity and death
      after operation. The introduction of new technologies in the diagnosis, and
      thrombolysis in the treatment, of pulmonary embolism has led to a need to
      reappraise the management of this condition. METHODS: This review encompasses a
      comprehensive discussion of diagnostic modalities and therapeutic strategies used
      in the current management of pulmonary embolism. Relevant papers on the diagnosis
      and treatment of pulmonary embolism were identified from a Medline search for the
      period 1967-1998. Additional papers were derived from the reference lists of
      retrieved articles. Articles presenting prospectively gathered data have been
      referenced preferentially. RESULTS AND CONCLUSION: Algorithms for the diagnosis
      and treatment of pulmonary embolism are presented.

PMID- 10417556
TI  - DIGEST: professor seiki matsuno and Dr michiaki unno, chief editors of surgery
      today (The japanese journal of surgery), have selected from the october-december
      1998 issues of the journal for this quarter's digest. A digest of BJS for the
      same period written by Mr colin johnson, european editor, appears in the japanese
      journal 

PMID- 10417555
TI  - Preoperative alcoholism and postoperative morbidity.
AB  - BACKGROUND: Preoperative risk assessment has become part of daily clinical
      practice, but preoperative alcohol abuse has not received much attention.
      METHODS: A Medline search was carried out to identify original papers published
      from 1967 to 1998. Relevant articles on postoperative morbidity in alcohol
      abusers were used to evaluate the evidence. RESULTS: Prospective and
      retrospective studies demonstrate a twofold to threefold increase in
      postoperative morbidity in alcohol abusers, the most frequent complications being
      infections, bleeding and cardiopulmonary insufficiency. Wound complications
      account for about half of the morbidity. The pathogenic mechanisms include
      preoperative immune incompetence, subclinical cardiac insufficiency and
      haemostatic imbalance. In addition, surgical trauma and/or postoperative
      abstinence result in an exaggerated stress response, which may further contribute
      to postoperative morbidity. CONCLUSION: Alcohol consumption should be included in
      the preoperative assessment of likely postoperative outcome. Reduction of
      postoperative morbidity in alcohol abusers may include preoperative alcohol
      abstinence to improve organ function, or perioperative alcohol administration to
      avoid the abstinence response.

PMID- 10417557
TI  - Live kidney donor assessment in the UK and Ireland.
AB  - BACKGROUND: The criteria and methods for assessing live kidney donors are not
      clear. This study was undertaken to establish whether there is a consensus
      regarding the organization and methods of assessment of living kidney donors by
      renal transplant centres in the UK and the Republic of Ireland. METHODS: All
      transplant centres in the UK and Ireland involved in living donor kidney
      transplantation were contacted by telephone survey followed by postal
      questionnaire. RESULTS: Considerable variation was observed in the organization
      of living kidney donor evaluation and the methods of assessment used. The upper
      and lower age limits considered acceptable for kidney donation were variable,
      with six of 29 centres setting no lower age limit and 11 setting no upper age
      limit. Four centres do not currently offer living donor kidney transplantation.
      Of the 29 centres involved with living donor transplantation ten had no protocol
      for donor assessment. A dedicated transplant coordinator/nurse practitioner was
      employed by 20 centres and ten routinely used an independent medical assessor to
      evaluate living related donors. The frequency and duration of donor follow-up
      after kidney donation also varied widely, with 18 centres providing life-time,
      seven limited and three no follow-up after initial postoperative assessment.
      CONCLUSION: The wide variation in organizational structure and method of
      assessment of living kidney donors in the UK and Ireland supports the need for
      establishment of guidelines for this practice.

PMID- 10417558
TI  - Saphenoperitoneal shunts for patients with intractable ascites associated with
      chronic liver disease.
AB  - BACKGROUND: Ascites is a common complication in patients with chronic liver
      disease. Some patients are resistant to diuretics and need therapeutic
      paracentesis on a regular basis. This is inconvenient in the long term and also
      has resource implications. Alternatively, these patients may be treated by
      peritoneovenous shunts, which require insertion of a foreign body into a central
      vein and are prone to occlusion. A new technique for peritoneovenous shunting
      without the use of foreign material is described. METHODS: Eight patients with
      chronic liver disease and diuretic-resistant ascites underwent this procedure.
      During operation, the long saphenous vein was divided at the mid-thigh level and
      inverted towards the inguinal canal, where it was anastomosed directly to the
      peritoneum at the internal inguinal ring using non-absorbable suture material.
      RESULTS: Seven patients had successful shunt formation; the remaining patient had
      to have the shunt removed because of ascitic leakage. In those who underwent
      successful shunt formation, the need for paracentesis and the dose of diuretic
      was significantly reduced over a median follow-up of 8 months. Hospital stay in
      the month after discharge was significantly less than that in the month before
      operation. Three patients died during follow-up from causes unrelated to the
      operation. One patient underwent successful liver transplantation. CONCLUSION:
      This study suggests that saphenoperitoneal shunting is potentially a safe and
      effective therapy for patients with diuretic-resistant ascites. It retains the
      benefits of peritoneovenous shunting without the adverse effects of insertion of
      foreign material.

PMID- 10417559
TI  - Rescue of liver grafts from hepatic artery occlusion in living-related liver
      transplantation.
AB  - BACKGROUND: Hepatic artery thrombosis after liver transplantation remains a
      significant cause of graft loss and death. Retransplantation is a difficult
      option after living-related liver transplantation in Japan. METHODS: Twenty-seven
      patients underwent living-related liver transplantation with left-sided liver
      grafts donated from their relatives. The hepatic artery was anastomosed end to
      end under a surgical microscope. Anticoagulant therapy was maintained for 2 weeks
      after operation. Routine post-transplant Doppler ultrasonography together with
      serum blood tests were performed twice a day during the first 2 weeks. RESULTS:
      Three patients developed hepatic artery occlusion, which was identified by
      routine Doppler ultrasonography before the serum transaminase values increased on
      days 7, 7 and 3 after surgery respectively. In two of the three patients, no
      apparent arterial thrombosis was recognized and vasospasm was therefore
      considered to be the cause of the occlusion. Arterial patency was restored by
      urgent revascularization with reanastomosis in all patients, but one patient with
      a functional graft died from a cerebral haemorrhage on day 47. CONCLUSION: Early
      diagnosis of hepatic artery occlusion by routine Doppler ultrasonography and
      revascularization of the graft is an indispensable strategy for preventing graft
      loss after living-related liver transplantation.

PMID- 10417560
TI  - Role of tissue factor expression on tumour cell invasion and growth of
      experimental pancreatic adenocarcinoma.
AB  - BACKGROUND: Tissue factor (TF), the physiological procoagulant, is expressed in
      pancreatic tissue as a result of malignant transformation. The aim of this
      investigation was to assess its role in pancreatic tumour cell invasion and
      primary tumour growth. METHODS: The full-length TF gene (1360 base pairs) was
      cloned into the plasmid DNA vector pcDNA3 in sense and antisense orientations,
      and these vectors were used to transfect the MIA PaCa-2 human pancreatic
      adenocarcinoma cell line. TF gene expression was characterized by Northern blot
      analysis, total cellular antigenic content by enzyme-linked immunosorbent assay
      and cell surface procoagulant activity by enzymatic assay. Invasion of tumour
      cells in vitro was determined by a standard Matrigel assay, and primary tumour
      growth was measured in immunodeficient mice. RESULTS: Overexpression of the TF
      gene, confirmed by an increased signal on Northern blotting, was associated with
      increases in both total antigenic content for TF (P = 0.001) and cell surface
      procoagulant activity (P = 0.008) in sense cells compared with wild-type cells.
      Likewise, both in vitro tumour cell invasion (P = 0.001) and primary tumour
      growth (P = 0.007) were increased in sense transfectants. CONCLUSION: Expression
      of TF enhances in vitro invasion and primary tumour growth of MIA PaCa-2 cells,
      suggesting that this procoagulant molecule might have a role in pancreatic tumour
      biology. Presented in part to the 83rd meeting of the Surgical Research Society,
      Oxford, UK, January 1996 and awarded the David Patey Prize, and in part to the
      1997 Annual Meeting of the Association of Surgeons of Great Britain and Ireland,
      Bournemouth, UK, April 1997.

PMID- 10417561
TI  - Value of splenic preservation during distal pancreatectomy for chronic
      pancreatitis.
AB  - BACKGROUND: Pain relief after distal pancreatectomy for chronic pancreatitis is
      reportedly satisfactory in 50-80 per cent of patients. This study attempted to
      determine clinical and radiological features that might select patients likely to
      benefit from distal pancreatectomy, and whether splenic preservation influenced
      the outcome. METHODS: Thirty-eight patients with chronic pancreatitis, who
      underwent distal pancreatectomy between 1982 and 1998, were reviewed
      retrospectively. The outcome of surgery was correlated with the aetiology of
      pancreatitis and radiological appearance on endoscopic retrograde
      cholangiopancreatography and computed tomography. RESULTS: Good results were
      achieved in 23 of 36 patients for whom follow-up (median 48 months) was
      available, including all 11 with obstructive pancreatitis. The spleen was
      preserved in 22 patients. Twelve patients became diabetic after surgery: three of
      20 in whom the spleen was preserved and nine of 16 who underwent splenectomy.
      CONCLUSION: Non-alcoholic patients with a normal pancreas proximal to a dominant
      ductal stricture had a consistently good outcome from surgery. Spleen-preserving
      distal pancreatectomy, although technically demanding, can be performed safely
      with results equivalent to those of distal pancreatectomy with splenectomy or
      autotransplantation. Splenic preservation, apart from preventing postsplenectomy
      sepsis, might also delay the onset of diabetes.

PMID- 10417562
TI  - Human pancreatic carcinoma cells are sensitive to photodynamic therapy in vitro
      and in vivo.
AB  - BACKGROUND: The aim of this study was to assess the efficiency of photodynamic
      therapy (PDT) on human pancreatic cancer cells in vitro and in an animal model.
      METHODS: Human pancreatic tumour cell lines were submitted to PDT with
      pheophorbide a (Ph a), a chlorophyll derivative, in culture and after grafting
      into athymic mice. Ph a was tested in culture (10-10-10-5 mol/l) with a 5-J/cm2
      energy treatment and on tumour-bearing Nude mice (30 mg/kg intraperitoneally)
      with a 100-J/cm2 PDT session. The effect of PDT was assessed in vitro using
      proliferative, apoptotic and clonogenic tests and in vivo on tumour growth and on
      the induction of tumour necrosis. RESULTS: PDT inhibited tumour cell growth in
      culture by affecting DNA integrity. This tumour cell photodamage started at low
      concentration (10-7 mol/l) as corroborated by clonogenic and tumour growth tests.
      A strong necrosis was achieved in vivo with a single PDT session. CONCLUSION: PDT
      destroyed human pancreatic carcinoma after low photosensitizer supply and weak
      energy application. It exerted this tumoricidal effect via apoptosis induction
      with a gentle protocol, and apoptosis and/or necrosis with a stronger protocol.

PMID- 10417563
TI  - Deep venous thrombosis in peripheral vascular disease.
AB  - BACKGROUND: This prospective study aimed to determine the prevalence of lower
      limb deep venous thrombosis in patients with peripheral vascular disease (PVD).
      METHODS: Some 136 patients admitted for arteriography, angioplasty or arterial
      reconstruction with limiting claudication (n = 72), ischaemic rest pain (n = 26)
      or gangrene (n = 38) and 40 control subjects admitted for general surgical
      procedures but without evidence of PVD were screened with colour duplex
      ultrasonography for the presence of venous thrombosis in the lower limb deep
      veins before any surgical or radiological procedures were undertaken. Patient
      age, the ankle : brachial pressure index (ABPI) and the presence of other risk
      factors for venous thromboembolism were also recorded. RESULTS: Venous thrombosis
      was found in 27 of 136 patients with PVD and two of 40 control patients (P =
      0.03). Logistic regression analysis demonstrated that decreasing ABPI
      independently contributed to an increased risk of deep venous thrombosis.
      CONCLUSION: There was a high prevalence of venous thrombosis among patients with
      PVD which was related to the severity of the ischaemia. Presented to the South
      West Vascular Surgeons Meeting in Newport, UK, March 1998

PMID- 10417564
TI  - Use of colour duplex imaging to diagnose and guide angioplasty of lower limb
      arterial lesions.
AB  - BACKGROUND: The purpose of this study was to investigate whether colour duplex
      imaging alone could safely and effectively be used to diagnose lower limb
      arterial lesions and guide subsequent percutaneous transluminal angioplasty
      (PTA). METHODS: Patients with discrete lower limb arterial lesions, preferably
      stenoses, which could be visualized clearly by colour duplex imaging were
      selected for duplex-guided PTA. Duplex-guided PTA was performed in an operating
      theatre using conventional balloon catheters. RESULTS: Duplex imaging was used to
      diagnose and guide PTA of 55 arterial lesions in 50 legs of 45 patients. There
      were 53 stenoses and two occlusions. The median (range) ankle : brachial pressure
      index was 0. 86 (0.52-1.10) before dilatation and 1.00 (0.83-1.40) immediately
      after dilatation (P = 0.0001). There were no complications during or after any of
      the procedures and 46 of the 47 symptomatic legs were markedly improved at a
      median follow-up of 23 days. Radiographic imaging was not required for any of the
      procedures. CONCLUSION: It is possible to diagnose and angioplasty lower limb
      arterial lesions using colour duplex imaging alone.

PMID- 10417565
TI  - Protective effect of preconditioning and adenosine pretreatment in experimental
      skeletal muscle reperfusion injury.
AB  - BACKGROUND: Prolonged ischaemia followed by reperfusion (I/R) of skeletal muscle
      results in significant tissue injury. Ischaemic preconditioning (IPC), achieved
      by repeated brief periods of I/R before prolonged ischaemia or adenosine
      pretreatment, can prevent I/R injury in cardiac muscle. The aim of this study was
      to ascertain in a rodent model if damage to skeletal muscle due to global
      hindlimb tourniquet-induced I/R could be similarly attenuated. METHODS:
      Anaesthetized rats were randomized (n = 6-10 per group) to five groups: sham
      operated controls; I/R (4 h of ischaemia, 2 h of reperfusion); IPC (three cycles
      of 10 min of ischaemia/10 min of reperfusion) alone; IPC immediately preceding
      I/R; or adenosine 1000 microg/kg immediately before I/R. At the end of
      reperfusion, biopsies were taken from the left gastrocnemius muscle for
      measurement of myeloperoxidase (MPO) and reduced glutathione (GSH). Before
      ischaemia and at the end of reperfusion, blood samples were taken for measurement
      of nitric oxide metabolites, tumour necrosis factor (TNF) alpha and macrophage
      inflammatory protein (MIP) 2. RESULTS: IPC before I/R resulted in lower levels of
      MPO (P < 0.001) and TNF-alpha (P = 0.004), and higher levels of GSH (P < 0.001)
      and nitric oxide metabolites (P = 0.002) than I/R alone. Adenosine had effects
      comparable to IPC pretreatment (P < 0.001 for MPO, P = 0.002 for GSH, P = 0.02
      for nitric oxide metabolites and P = 0.001 for TNF-alpha). There was no
      difference in the blood pressure or the MIP-2 concentration among the groups.
      CONCLUSION: IPC or pretreatment with adenosine ameliorates the I/R injury of
      skeletal muscle.

PMID- 10417566
TI  - Smoking may be associated with complications in diverticular disease.
AB  - BACKGROUND: The vast majority of people with diverticula remain asymptomatic or
      develop minor symptoms while a small group develop serious complications that are
      associated with significant morbidity and mortality rates. The aim was to
      identify any risk factors predisposing to complications. METHODS: Eighty patients
      with diverticular disease were studied. Patients in group 1 (n = 45) with
      complications requiring hospitalization or surgery were compared with those in
      group 2 (n = 35) with asymptomatic diverticula or minor symptoms. Logistic
      regression analysis was performed. RESULTS: No differences in epidemiological
      factors, concurrent and past medical and surgical conditions or chronic
      medication were detected between the two groups. Generalized disease was not
      associated with more complications than sigmoid disease. However, smoking seemed
      to be an independent factor predisposing to complications; the proportion of
      smokers in group 1 was significantly greater (24 of 45) than that in group 2 (ten
      of 35) (odds ratio 2.9, P = 0.028). CONCLUSION: In patients with diverticular
      disease, smoking is associated with an increased risk of complications.

PMID- 10417567
TI  - Smoking and alcohol abuse are major risk factors for anastomotic leakage in
      colorectal surgery.
AB  - BACKGROUND: Several studies have examined the association between anastomotic
      leakage and intraoperative risk factors in colorectal surgery, but only a few
      have taken patients' lifestyle into account. The aim of this study was to assess
      the association between anastomotic leakage and lifestyle factors such as smoking
      habits and alcohol consumption. METHODS: Between January 1993 and October 1996,
      333 unselected consecutive patients in one surgical department underwent colonic
      or rectal resection with anastomosis. The association between clinical
      anastomotic leakage and 24 variables related to patient history, diagnosis and
      surgery was assessed retrospectively and analysed by logistic regression.
      RESULTS: The rate of clinical anastomotic leakage was 15.9 per cent (53 of 333
      patients). Multiple regression analysis showed that smokers, compared with non
      smokers, had an increased risk of anastomotic leakage (relative risk (RR) 3.18
      (95 per cent confidence interval (c. i.) 1.44-7.00)), as did alcohol abusers
      compared with abstainers (RR 7.18 (95 per cent c.i. 1.20-43.01)). In the
      analysis, well known risk factors for anastomotic leakage such as site of
      anastomosis, age and stage of training of the surgeon were taken into account.
      CONCLUSION: Smoking and alcohol abuse are important predictive factors for
      anastomotic leakage after colonic and rectal resection.

PMID- 10417568
TI  - Clinical assessment of positron emission tomography for the diagnosis of local
      recurrence in colorectal cancer.
AB  - BACKGROUND: The clinical value of positron emission tomography (PET) for the
      diagnosis of local pelvic recurrence of colorectal cancer was evaluated. METHODS:
      Computed tomography (CT) and magnetic resonance imaging (MRI) of the pelvis were
      performed at regular intervals in 23 patients who had undergone resection for
      colorectal cancer. The 23 patients had a total of 25 lesions. PET images of the
      25 lesions and of six primary lesions in patients with rectal cancer were
      obtained. A differential absorption ratio (DAR) was calculated in order to
      examine the accumulation of [18F]2-fluoro-2-deoxy-D-glucose (18FDG) on PET
      images. Histological diagnoses of the pelvic masses were obtained by CT-guided
      needle biopsy. RESULTS: On CT or MRI, a pelvic mass with a spicular shape (n = 1)
      was non-recurrent, whereas a nodular or lumpy shape indicated a locally recurrent
      lesion (n = 10). Masses with a nodulospicular shape (n = 12) did not correlate
      with the histological features. On PET, 15 of 16 histologically proven local
      recurrences were imaged positively. By setting a DAR of 2.8 as a cut-off value,
      local recurrences could be diagnosed with 100 per cent accuracy. CONCLUSION: PET
      is a clinically useful tool for the detection of local recurrence of colorectal
      cancer, particularly for distinguishing between recurrence and granulation
      tissues in the pelvic cavity.

PMID- 10417569
TI  - Laparoscopically assisted colorectal surgery in the elderly.
AB  - INTRODUCTION: Open colorectal surgery in elderly patients is associated with
      increased morbidity and mortality rates compared with those in younger age
      groups. It also requires more intensive postoperative support, longer
      hospitalization, and in many cases leads to prolonged rehabilitation or
      institutionalization. Because of its less invasive nature, laparoscopically
      assisted colorectal surgery may lead to a reduced period of convalescence.
      However, the safety of advanced laparoscopic surgical techniques in the elderly
      has not been established, so this prospective comparative study was undertaken.
      METHODS: All patients aged 80 years or more who were undergoing an elective
      laparoscopic or open colorectal procedure between 1 January 1992 and 30 June 1997
      were assessed prospectively. Patients having simple stoma formation were
      excluded. Perioperative care, operative results and subsequent function were
      analysed. RESULTS: There were 42 patients in the laparoscopic group and 35 in the
      open group, with a median age of 84 years in each group. Five patients undergoing
      laparoscopic surgery required conversion to an open procedure. No complications
      related to laparoscopy occurred. Three patients died after operation in the
      laparoscopic group and four in the open group, with morbidity in seven and 15
      patients respectively. Median hospital stay was 9 (range 4-21) days for patients
      having the laparoscopic operation, and 17 (range 7-28) days in the open cases. At
      4 weeks after operation 30 of the 35 independent patients surviving the operation
      in the laparoscopic group and 16 of 28 in the open group were back to
      preoperative activity levels. CONCLUSION: In this series laparoscopically
      assisted colorectal surgery was safe and was associated with a low incidence of
      complications, short hospitalization and a rapid return to preoperative activity
      levels when compared with open colorectal resections in this age group.

PMID- 10417570
TI  - Staging of rectosigmoid neoplasia with colonoscopic endoluminal ultrasonography.
AB  - BACKGROUND: The accurate staging of colorectal neoplasia may aid the
      stratification of patients for adjuvant treatment. At present the mural extent of
      neoplasia proximal to the mid rectum is difficult to determine. Prediction of
      mural invasion could help identify patients suitable for radical resection,
      minimal access surgery or endoscopic treatment. Colonoscopic endoluminal
      ultrasonography (EUS) was used in a prospective study to determine the stage of
      rectosigmoid neoplasia in 121 patients. METHODS: Mural tumour (T) stage was
      designated by EUS as uT0/1-uT4 in 121 patients. Nodal (N) staging was performed
      in 39 cases. EUS staging was compared with histological stage (pT and pN) in 93
      patients who underwent resection. RESULTS: Mural staging of disease using
      colonoscopic EUS showed good correlation with histo-pathological stage (kappa =
      0.85 (95 per cent confidence interval 0.76-0.95)). Overall pT and pN stage
      accuracy of EUS was 92 and 65 per cent respectively. CONCLUSION: EUS accurately
      assessed tumour stage although node staging remained suboptimal. Colonoscopic EUS
      may aid the selection of treatment in patients with rectosigmoid neoplasia.

PMID- 10417571
TI  - DNA aneuploidy as a marker of premalignancy in surveillance of patients with
      ulcerative colitis.
AB  - BACKGROUND: Patients with ulcerative colitis have an increased risk of developing
      colorectal cancer. Specific and sensitive markers for premalignancy are needed.
      The present study evaluates the status of DNA aneuploidy (abnormal stemlines) as
      such a marker. METHODS: A prospective surveillance programme was conducted for
      all patients with ulcerative colitis from a defined area. Regular colonoscopy
      with mucosal sampling for histological evaluation and flow cytometric DNA
      analysis was performed. Some 147 patients were studied from 1984 to 1997.
      RESULTS: DNA aneuploidy was found in 20 patients. All but one had total colitis.
      The time from onset of disease to aneuploidy ranged from 5 to 31 years. Fourteen
      of the patients developed morphological alterations. In the same interval 127
      patients, of whom 75 had total colitis, did not develop aneuploidy. Among
      patients with morphological alterations and aneuploidy, aneuploidy preceded these
      alterations in four patients and was present at the same examination in three; in
      seven patients the morphological alterations preceded the aneuploidy. Aneuploidy
      was diagnosed before the appearance of a dysplasia- associated lesion or mass in
      four of five cases. CONCLUSION: Flow cytometric DNA analysis has definite value
      as a complement to histological examinations in cancer surveillance of patients
      with ulcerative colitis. Aneuploidy indicates a high risk for developing severe
      premalignant changes. However, there is no evidence to support the use of DNA
      aneuploidy as a sole indication for prophylactic surgery against cancer.

PMID- 10417572
TI  - Peroperative time-motion analysis of diagnostic laparoscopy with laparoscopic
      ultrasonography.
AB  - BACKGROUND: Advanced technology is being introduced rapidly into laparoscopic
      procedures, frequently without an accurate evaluation of its functioning. In this
      study, standardized time-motion analysis was applied to evaluate the peroperative
      surgical process and the technical equipment used in 18 cases of diagnostic
      laparoscopy with laparoscopic ultrasonography (DLLU). METHODS: The image through
      the laparoscope, the ultrasonograph and an overview of the operating theatre were
      recorded simultaneously. The time for each phase, efficient actions (e.g.
      identifying lesions by inspection, making an ultrasonogram or taking a biopsy)
      and limiting factors (e.g. technical problems, time spent waiting) were
      determined, and a current standard was defined. RESULTS: Of the actions
      performed, 52 per cent were qualified as efficient, 17 per cent were classified
      as time spent waiting for personnel, instruments were positioned in 13 per cent,
      and unnecessary instrument exchanges were involved in 10 per cent. The evaluation
      led to a significant reduction in delay times and resulted in design criteria for
      improved biopsy instruments. The current standard was calculated from the mean
      time and number of actions determined for each phase. CONCLUSION: This time
      motion study provided detailed insight into the peroperative process of DLLU,
      leading to improvements in the surgical process and instruments used. The defined
      current standard will enable evaluation of the learning curve and new
      technologies.

PMID- 10417573
TI  - Prospective study of symptoms and gastro-oesophageal reflux 10 years after
      posterior partial fundoplication.
AB  - BACKGROUND: This was a prospective study of symptoms, and short-term and long
      term reflux competence after partial fundoplication. METHODS: Some 101 patients
      were operated consecutively with posterior partial (270 degrees ) fundoplication.
      Indications for surgery were reflux disease without erosive oesophagitis in 25
      patients, moderate oesophagitis in 43, severe oesophagitis in 25 and
      paraoesophageal hernia in eight. Symptom score, manometry and pH tests were
      performed before operation, 6 months after operation and after 6-14 years.
      RESULTS: All patients (n = 101) were free from heartburn and regurgitation at
      early follow-up. There was evidence of clinical recurrence at late follow-up (n =
      87) in two of 22 patients without oesophagitis before operation, two of 39 with
      moderate oesophagitis before operation and three of 19 patients with severe
      oesophagitis before operation; 92 per cent had good reflux control at late follow
      up. CONCLUSION: Posterior partial fundoplication shows excellent reflux control
      at early follow-up. Ten years later fewer than 10 per cent of patients have
      recurrence, which is more common in patients who had severe oesophagitis before
      operation.

PMID- 10417574
TI  - Experimental study of the influence of intestinal flora on the healing of
      intestinal anastomoses.
AB  - BACKGROUND: The beneficial effects of the normal intestinal flora on wound
      healing in the skin have already been confirmed, and this study attempted to
      elucidate the influence of the intestinal flora on the healing process in
      intestinal anastomoses. METHODS: Five groups of rats were studied: germ-free,
      conventional, monocontaminated with Lactobacillus acidophilus La5 or Escherichia
      coli X7 and ex-germ-free (conventionalized). All animals underwent ileal and
      colonic resections followed by anastomoses. Seven days later they were killed and
      the bursting pressure and hydroxyproline concentration of the anastomoses were
      measured. The microbiological status of the animals was confirmed weekly.
      RESULTS: No bacteria were detected in the germ-free rats and no other bacteria
      were found in the monocontaminated animals. Conventional rats had a significantly
      higher anastomotic bursting pressure both in the ileum compared with rats
      monocontaminated with L. acidophilus, and in the colon compared with germ-free
      rats. The ex-germ-free rats also showed a significantly higher bursting pressure
      than germ-free animals and rats monocontaminated with either L. acidophilus or E.
      coli in the ileum and colon. CONCLUSION: The presence of the intestinal flora
      enhanced the healing of intestinal anastomoses. The data suggest that this effect
      depends on differences in the types of bacteria in the intestine.

PMID- 10417575
TI  - Outcome of primary radiocephalic fistula for haemodialysis.

PMID- 10417576
TI  - Scientific surgery 

PMID- 10417577
TI  - Effect of botulinum toxin type A on movement-associated rhytides following CO2
      laser resurfacing.
AB  - BACKGROUND: Many patients who undergo CO2 laser resurfacing for correction of
      rhytides experience recurrence of movement-associated wrinkles within 6 to 12
      months following the laser procedure. OBJECTIVE: The purpose of this study was to
      evaluate the effect of botulinum toxin type A (Botox) injections on movement
      associated rhytides following cutaneous laser resurfacing. METHODS: Forty
      patients who had received full face CO2 laser resurfacing for the treatment of
      facial rhytides were randomized to receive Botox injections to the glabella,
      forehead or lateral canthal regions or to receive no additional treatment
      (control group). Clinical and photographic assessments were performed at baseline
      and at 3, 6 and 9 months. RESULTS: Enhanced and more prolonged correction of
      forehead, glabellar and/or lateral canthal rhytides was observed in patients
      treated with Botox injections postoperatively compared to non-Botox treated
      control patients. CONCLUSION: The use of botulinum toxin type A following
      cutaneous CO2 laser resurfacing results in prolonged correction of movement
      associated rhytides. It is advised that patients receive information regarding
      the benefits of maintenance therapy with botulinum toxin as part of their routine
      preoperative education.

PMID- 10417578
TI  - Treatment of upper lip wrinkles: a comparison of 950 microsec dwell time carbon
      dioxide laser with unoccluded Baker's phenol chemical peel.
AB  - BACKGROUND: The high energy, pulsed, or computer-scanned continuous wave carbon
      dioxide laser (CO2 laser) has gained popularity as a wrinkle treatment because of
      its minimal thermal injury and precise control of tissue vaporization depth.
      Chemical peels such as phenol have also been effective in treating facial
      wrinkles. This is, to our knowledge, the first study comparing the use of CO2
      laser to phenol for treatment of wrinkles on the upper lip. OBJECTIVE: To compare
      the effectiveness and side effect profile of the 950 microsec dwell time CO2
      laser to that of unoccluded Baker's phenol chemical peel in the treatment of
      upper lip wrinkles. METHODS: Twenty female subjects with moderate to severe upper
      lip wrinkles were randomly treated with Baker's phenol on one side of the upper
      lip and the 950 microsec dwell time CO2 laser on the other side. RESULTS: The
      average upper lip laser-treated wrinkle score (0 = none to 5 = severe) decreased
      from 4.30+/-0.20 before treatment to 1.11+/-0.28 at 6 months after treatment. The
      average upper lip phenol-treated wrinkle score decreased from 4.20+/-0.20 to
      0.47+/-0.12. The degree in which the wrinkle score improved after phenol
      treatment compared with that after laser treatment was statistically significant
      (p<0.03). CONCLUSION: Treatment of upper lip wrinkles with Baker's phenol
      resulted in greater improvement than treatment with the 950 microsec dwell time
      CO2 laser.

PMID- 10417579
TI  - Pilot study evaluating topical onion extract as treatment for postsurgical scars.
AB  - BACKGROUND: Post surgical scars can be erythematous, raised, pruritic and
      painful. Numerous modalities are available to improve the appearance and
      symptomatology of these scars. A topical onion gel extract is the newest in the
      armamentarium of scar treatments. The active ingredient in this gel is allium
      cepa. Published studies evaluating the usefulness of this gel in the treatment of
      scars are not available. OBJECTIVE: To evaluate the effectiveness of topical
      onion gel extract in improving the appearance and symptomatology of postsurgical
      scars and to compare the results of its use to those of a topical emollient
      ointment. METHODS: Seventeen patients with surgical scars resulting from Mohs
      surgery were assigned to 1 of 2 groups on the day of suture removal. Each group
      applied a designated topical product 3 times a day for 1 month. Photographic
      documentation and questionnaires using a visual analog scale were completed for
      each scar enrolled in the study. RESULTS: Using the Fischer's exact test, no
      statistically significant difference between pre- and posttreatment evaluations
      of scar erythema and pruritus in patients using topical onion extract gel was
      found. A statistically significant reduction in scar erythema was found in
      patients using a petrolatum based ointment. CONCLUSIONS: Scar hydration is an
      important factor in wound healing and can be achieved with topical petrolatum
      based ointment. Topical onion gel extract was ineffective in improving scar
      erythema and pruritus in our patients.

PMID- 10417580
TI  - Glycolic acid versus Jessner's solution: which is better for facial acne
      patients? A randomized prospective clinical trial of split-face model therapy.
AB  - BACKGROUND: Many clinicians perform glycolic acid peels for facial acne patients,
      but there has not been a well-controlled study to compare this new therapy with
      other conventional modalities. OBJECTIVE: To compare the effectiveness of
      treatment and side effects in the treatment of facial acne by two agents, 70%
      glycolic acid and Jessner's solution. METHODS: Twenty-six patients with facial
      acne were treated simultaneously with 70% glycolic acid and Jessner's solution
      biweekly on each side of the face. The treatment sides were randomized and the
      evaluation of treatment was done biweekly by a blinded evaluator who did not know
      the randomization code. Dr. Cunliffe's acne grading system was used for objective
      comparison. All patients were also asked about the improvement of facial acne and
      about the side effects experienced. Finally, the patients answered the preference
      test between the 2 peeling methods. RESULTS: Acne grading of both treatments
      improved after 3 treatment sessions. However, there were no significant
      differences in treatment effects between the 2 methods. As far as side effects
      were concerned, sites treated with Jessner's solution showed a significantly
      increased degree of exfoliation compared to glycolic acid (p < 0.01). CONCLUSION:
      Glycolic acid is less widely used than Jessner's solution due to its inconvenient
      application technique. But considering the equal treatment effect and lesser
      degree of exfoliation in glycolic acid, we would recommend the use of glycolic
      acid over Jessner's solution for acne patients.

PMID- 10417581
TI  - Q-switched ruby laser treatment of a congenital melanocytic nevus.
AB  - BACKGROUND: The treatment of medium-sized (1.5-20 cm diameter) congenital
      melanocytic nevi (CMN) has been the concern of dermatologists for decades.
      Although many techniques have been described and utilized, no single treatment
      has emerged as applicable under all circumstances. METHODS: The Q-switched ruby
      laser (QSRL) at 694 nm, a wavelength well absorbed by melanin relative to other
      optically absorbing structures in skin, causes highly selective destruction of
      pigment-laden cells. In addition, the 20-nanosecond pulse duration produced by
      this laser approximates the thermal relaxation time for melanosomes, thereby
      confining the energy to the targeted cells. RESULTS: In the present report,
      treatment using the QSRL resulted in complete clinical removal of a biopsy
      documented medium-sized compound CMN with no recurrence after 5 years. In
      contrast to other therapeutic modalities, complications such has hypertrophic
      scarring, dyspigmentation, or atrophy were not observed.

PMID- 10417582
TI  - Variations of the pursestring suture in skin cancer reconstruction.
AB  - BACKGROUND: The pursestring suture (PSS) utilizes a circumferentially placed
      intradermal suture to decrease the size of a defect. Its primary application in
      dermatologic surgery has been to allow placement of a smaller full-thickness skin
      graft and to enhance secondary intention wound healing. OBJECTIVE: To present our
      experience with 3 variations of the PSS. METHODS: The oval defects resulting
      after surgical excision of cutaneous malignancies were managed with 3 variations
      of the traditional pursestring technique. These variations included (1) complete
      closure of the PSS-reduced defect by the placement of traditional interrupted
      sutures; (2) PSS with the Burow's triangle graft; (3) use of a PSS only part way
      around an oval defect to avoid distortion of a nearby free margin. RESULTS: In
      the 7 years of performing these variations of the PSS technique, we have
      consistently achieved favorable results. CONCLUSION: We report 3 simple-to-use
      variations of the PSS technique that have been extremely useful in the management
      of cutaneous malignancies.

PMID- 10417583
TI  - Treatment of melasma using kojic acid in a gel containing hydroquinone and
      glycolic acid.
AB  - BACKGROUND: Melasma is difficult to clear. Many agents have been used, such as
      hydroquinone, and glycolic acid and glycolic acid peels, kojic acid, a tyrosinase
      inhibitor in the fungus Aspergilline oryzae. OBJECTIVE: To see if the addition of
      2% kojic acid in a gel containing 10% glycolic acid and 2% hydroquinone will
      improve melasma further. METHODS: Forty Chinese women with epidermal melasma were
      treated with 2% kojic acid in a gel containing 10% glycolic acid and 2%
      hydroquinone on one half of the face. The other half was treated with the same
      application but without kojic acid. The side receiving the kojic acid was
      randomized. Determination of efficacy was based on clinical evaluation,
      photographs and self-assessment questionnaires at 4 weekly intervals until the
      end of the study at 12 weeks. The non-parametric Wilcoxon's rank sum test was
      used for statistical analysis. RESULTS: All patients showed improvement in
      melasma on both sides of the face. The side receiving the kojic acid did better.
      More than half of the melasma cleared in 24/40 (60%) patients receiving kojic
      acid compared to 19/40 (47.5%) patients receiving the gel without kojic acid. In
      2 patients, there was complete clearance of melasma, and this was on the side
      where kojic acid was used. Side effects include redness, stinging, and
      exfoliation. These were seen on both sides of the face, and they settled by the
      third week. CONCLUSION: The addition of kojic acid to a gel containing 10%
      glycolic acid and 2% hydroquinone further improves melasma.

PMID- 10417584
TI  - Combined CO2/erbium:YAG laser resurfacing of peri-oral rhytides and side-by-side
      comparison with carbon dioxide laser alone.
AB  - BACKGROUND: Laser resurfacing of facial rhytids has become a popular treatment
      option for many patients with wrinkles, photoaging, and acne scarring. Laser
      wavelength options and optimization of techniques continue to evolve in an
      attempt to shorten the healing phase associated with laser skin resurfacing.
      OBJECTIVE: To prospectively study the clinical effects of pulsed carbon dioxide
      (CO2) laser resurfacing of facial rhytids used alone, compared with a combination
      of CO2 and the pulsed Erbium:YAG (Er:YAG) laser. METHODS: Forty treatment sites
      on 20 patients were randomized and evaluated following treatment of the upper lip
      region with a combination of CO2 laser resurfacing alone or with the same CO2
      laser treatment followed by 3 passes with the Er:YAG laser. Patient diaries were
      maintained to assess erythema, crusting, pain, itching, swelling, pigmentary
      changes, and the day of first make-up application. Blinded objective grading of
      improvement was independently assessed by 4 blinded observers at time intervals
      3, 6, and 10 days, and 1, 2, and 4 months. Chromometer measurements of erythema
      were also analyzed and percentage moisture recorded. RESULTS: Subjectively, all
      patients reported, on average, 10 days of redness and 2.4 days of pain, with no
      significant difference noted between the two procedures. On average, patients
      were able to apply make-up 5.5 days postoperatively, regardless of which
      procedure used. However, the combined CO2/Er:YAG laser treatment patients
      experienced reduced duration of crusting, compared to the patients treated with
      CO2 alone. The duration of crusting was reduced on average from 7.4 to 6.5 days,
      and also the duration of itching was reduced in patients receiving combined
      treatment from 5.5 to 4.8 days. Chromometer measurements noted no significant
      difference between techniques in the rate of resolution of erythema. Blinded
      objective grading revealed that crusting was reduced on average from 7.2 to 6.0
      days, and swelling was reduced from 6.3 to 6.0 days in patients receiving the
      combined procedure. No cases of permanent hyperpigmentation, hypopigmentation, or
      scarring occurred in any patients. CONCLUSION: The addition of the Er:YAG laser
      following CO2 laser resurfacing reduces the duration of crusting, swelling, and
      itching postoperatively. Medium to deep (Grade III) facial rhytids were improved
      by 70% with both procedures with no significant difference noted between
      techniques.

PMID- 10417585
TI  - Distribution of human hair in follicular units. A mathematical model for
      estimating the donor size in follicular unit transplantation.
AB  - BACKGROUND: Human hair emerges from the scalp in groupings known as follicular
      units. In follicular unit transplantation, the follicular unit is the exclusive
      element to be moved in the transplant. OBJECTIVE: To study the distribution of
      follicular units in the human occipital (donor) scalp. METHODS: Using digital
      photography, we counted in 50 patients the hair density, follicular unit density,
      and the proportion of 1-, 2-, and 3-hair units per square centimeter. We measured
      the median distance between the follicular units. All the data obtained was
      statistically analyzed. RESULTS: In the occipital (donor) scalp the number of
      follicular units per square centimeter ranges between 65 and 85, and the hair
      density ranges between 124 and 200. The proportions of the different hair
      groupings change according to the patient's hair density. We have developed a
      mathematical model that can predict the number and the most probable distribution
      of 1, 2, and 3 hair groupings, based on the patient's hair density. The distance
      between follicular units ranges from 1.0 mm to 1.4 mm. CONCLUSION: Hair
      transplant surgeons can now predict the total number of follicular units to be
      obtained from any given donor strip. In addition, the proportion of 1-, 2-, and 3
      hair follicular units can also be anticipated. Some variance is to be expected
      due to the lack of uniform density in the donor area.

PMID- 10417586
TI  - Split skin grafts in the treatment of pyoderma gangrenosum. A report of four
      cases.
AB  - BACKGROUND: Pyoderma gangrenosum (PG) is an uncommon necrotising, non-infective
      ulceration of the skin. The management of PG is aimed at limiting tissue
      destruction, promoting the healing of the wound, and providing an acceptable
      cosmetic result. However, skin grafting is normally avoided because of the
      potential risk of pathergy-the localization of skin damaged by trauma. REPORT: We
      describe the use of split skin grafts in the management of ulcerative pyoderma
      gangrenosum in 4 patients. RESULTS: Our cases demonstrate that split skin grafts
      are a useful treatment modality in patients with ulcerative PG, producing a good
      cosmetic result. One case illustrates the importance of ensuring the disease is
      quiescent prior to grafting, to avoid pathergy. The other cases emphasise the
      need for prolonged immunosuppressive therapy to minimise the chance of
      reactivation of the disease process. CONCLUSION: Our preliminary experience of 4
      cases of ulcerative PG indicates that split skin grafts have a role to play in
      its management. The ultimate cosmetic result is considered to be superior to
      allowing the wound to heal by secondary intention. To limit the risk of pathergy
      developing, our experience suggests a role for prolonged courses of
      immunosuppressive therapy. The most effective dose and duration of
      immunosuppressive therapy in patients with PG treated with split skin grafts
      remains to be determined. A controlled study would be of benefit to compare it
      with other current treatment options.

PMID- 10417587
TI  - Use of a lyophilized bovine collagen matrix in postoperative wound healing.
AB  - BACKGROUND: Immediate reconstruction is the preferred approach to the management
      of defects following Mohs micrographic surgery. In a minority of patients,
      however, reconstruction is contraindicated, and a long-term biological dressing
      that stimulates wound healing and minimizes wound care is desirable. OBJECTIVE:
      We wanted to assess the utility of a lyophilized, type I bovine collagen matrix
      (SkinTemp) in wound care and wound healing following Mohs micrographic surgery.
      METHODS: Fifteen patients were treated with a bovine collagen matrix following
      Mohs micrographic surgery. Study wounds were evaluated for time to complete
      granulation, time to complete epithelialization, and adverse reactions including
      infection and allergy. The time to complete healing (granulation and
      epithelialization) for this group was compared to 15 size- and site-matched
      surgical defects. RESULTS: The use of bovine collagen matrix provided more rapid
      wound healing than traditional second intention healing at all anatomic sites
      studied. The time to complete healing averaged 6.1 weeks with bovine collagen
      matrix versus 9.4 weeks for the control group. Use of bovine collagen matrix
      required an average of 3.0 dressing changes weekly compared to 7.0 changes weekly
      in the control group. There were no wound infections or allergic reactions to it.
      CONCLUSIONS: A Type I bovine collagen matrix provided a safe, readily available
      alternative to traditional methods of second intention healing. It minimized
      wound care while reducing the time for complete healing. A larger study should be
      performed to confirm the results of this pilot study.

PMID- 10417588
TI  - Mohs micrographic surgery for fungal soft tissue infections.
AB  - BACKGROUND: Invasive fungal infections of the integument are relatively rare. In
      the immunocompromised patient, however, they may show an extremely aggressive
      biological behavior despite high dosed topical or systemic antifungal therapy. As
      the fungal tissue invasion usually reaches well beyond the area of clinical
      necrosis or other visible changes, standard surgical excision often proves to be
      inadequate, resulting in the need for repeated relatively wide excisions with the
      resulting substantial loss of initially healthy tissues. OBJECTIVE: To present
      the use of Mohs surgery as a safe and effective treatment modality for invasive
      fungal infections in a patient with a zygomycetes infection of his scalp.
      RESULTS: The micrographic excision of the highly aggressive fungal infection, the
      acute postoperative course, and the delayed reconstruction with a split-thickness
      skin graft were all well tolerated without complications. CONCLUSION: Mohs
      micrographic excision deserves serious consideration in the treatment of
      aggressive localized fungal infections.

PMID- 10417589
TI  - The effects of topical vitamin E on the cosmetic appearance of scars.
AB  - BACKGROUND: Vitamin E is a generic term for a group of tocol and tocotrienol
      derivatives. Since the discovery that vitamin E is the major lipid soluble
      antioxidant in skin, this substance has been tried for the treatment of almost
      every type of skin lesion imaginable. Anecdotal reports claim that vitamin E
      speeds wound healing and improves the cosmetic outcome of burns and other wounds.
      Many lay people use vitamin E on a regular basis to improve the outcome of scars
      and several physicians recommend topical vitamin E after skin surgery or
      resurfacing. OBJECTIVE: We attempted to determine whether topically applied
      vitamin E has any effect on the cosmetic appearance of scars as suggested by
      multiple anectodal reports. METHODS: Fifteen patients who had undergone skin
      cancer removal surgery were enrolled in the study. All wounds were primarily
      closed in 2 layers. After the surgery, the patients were given two ointments each
      labeled A or B. A was Aquaphor, a regular emollient, and the B was Aquaphor mixed
      with vitamin E. The scars were randomly divided into parts A and B. Patients were
      asked to put the A ointment on part A and the B ointment on part B twice daily
      for 4 weeks. The study was double blinded. The physicians and the patients
      independently evaluated the scars for cosmetic appearance on Weeks 1, 4, and 12.
      The criteria was simply to recognize which side of the scar looked better if
      there was any difference. The patients' and the physicians' opinions were
      recorded. A third blinded investigator was shown photographs of the outcomes and
      their opinion was also noted. RESULTS: The results of this study show that
      topically applied vitamin E does not help in improving the cosmetic appearance of
      scars and leads to a high incidence of contact dermatitis. CONCLUSIONS: This
      study shows that there is no benefit to the cosmetic outcome of scars by applying
      vitamin E after skin surgery and that the application of topical vitamin E may
      actually be detrimental to the cosmetic appearance of a scar. In 90% of the cases
      in this study, topical vitamin E either had no effect on, or actually worsened,
      the cosmetic appearance of scars. Of the patients studied, 33% developed a
      contact dermatitis to the vitamin E. Therefore we conclude that use of topical
      vitamin E on surgical wounds should be discouraged.

PMID- 10417590
TI  - Treatment of spider veins using a 10 millisecond pulse-duration frequency-doubled
      neodymium YAG laser.
AB  - BACKGROUND: The pulsed dye laser has been the standard for treating vascular
      lesions. Although quite effective for treating facial vessels and port-wine
      stains, spider veins of the lower extremities are more difficult to treat. Recent
      studies have shown that lasers with longer pulse durations are more effective at
      treating spider veins. A new long-pulse frequency-doubled Neodymium:YAG laser has
      been developed with a 10-ms pulse duration and sufficient energy to enable
      treatment with a 3- or 4-mm diameter treatment beam. OBJECTIVE: To determine the
      effectiveness of the long pulse Neodymium:YAG laser for treating spider veins of
      the lower extremities. METHODS: Spider veins less than 0.75 mm in diameter on the
      legs of 15 female volunteers were treated in 1 or 2 areas. Treatments were
      administered through a water-cooled chill tip using the frequency-doubled
      Neodymium:YAG laser with a 10-ms pulse duration. A dose of 16 J/cm2 was
      administered, completing 3 passes over each visible vein during each session, for
      a total of 2 sessions administered 6 weeks apart. Photographs of treatment areas
      were digitally analyzed for degree of vessel clearance. RESULTS: Computer-based
      image analysis revealed clearing of over 75% of veins following 2 treatments with
      16 J/cm2. Side effects were minimal, and the treatments were well tolerated.
      CONCLUSIONS: The 532 nm, 10 ms pulse duration, frequency-doubled Neodymium:YAG
      laser is safe and effective for treating spider veins of the lower extremities
      less than 0.75 mm in diameter, in patients with Fitzpatrick skin Types I-III.

PMID- 10417591
TI  - Acute massive pulmonary embolism following high ligation combined with
      compression sclerotherapy for varicose veins report of a case.
AB  - A case of acute pulmonary embolism following high ligation and compression
      sclerotherapy for varicose veins is reported. A 54-year-old women developed
      superficial varicosities and stasis pigmentation on her left leg 1 year prior to
      her first visit to hospital. No deep vein thrombosis was detected by ascending
      phlebography performed 3 months prior to operation. High ligation combined with
      compression sclerotherapy was performed for the varicose veins. One day after
      treatment, the patient complained of chest pain and discomfort, and then
      collapsed. Perfusion scintigraphy revealed multiple embolisms in the bilateral
      lungs. The patient recovered after aggressive anticoagulant and thrombolytic
      therapy. Although pulmonary embolism is a rare complication of sclerotherapy, it
      is potentially one of the most serious.

PMID- 10417592
TI  - Use of the cotton-tipped applicator in lower eyelid surgery.

PMID- 10417593
TI  - The role of lasers and light sources in the treatment of leg veins.
AB  - Telangiectasia of the legs occurs in 29% to 41% of women in the United States.
      The variation in size, flow, depth, and type preclude the possibility of a single
      effective treatment modality. When a systematic approach is used where feeder
      vessels are first surgically removed and sclerotherapy proceeds from largest to
      smallest vessels, 80-90% of vessels respond to a single sclerotherapy treatment.
      Because of the relatively modest results demonstrated with lasers and light
      sources and the high rate of success and the relatively low cost of ambulatory
      phlebectomy, compression sclerotherapy and superficial sclerotherapy, we
      generally recommend using lasers and light sources only for vessels that remain
      after this treatment approach. Lasers and light sources should be considered
      prior to sclerotherapy in patients who are fearful of needles, who do not
      tolerate sclerotherapy, who fail to respond to sclerotherapy, or who are prone to
      telangiectatic matting. Carefully monitored, controlled studies are essential to
      better define the role of the available laser and light sources in the treatment
      of leg veins.

PMID- 10417594
TI  - Inappropriate training for unqualified professionals.

PMID- 10417595
TI  - Treatment of leg veins.

PMID- 10417596
TI  - Delays in protease inhibitor use in clinical practice.
AB  - OBJECTIVE: To determine the clinical factors associated with delayed protease
      inhibitor initiation. DESIGN: Chart review and telephone survey. SETTING: General
      medicine practice at an academic medical center in Boston, Mass. PATIENTS: One
      hundred ninety patients living with HIV and a viral load of more than 10,000
      copies/ml. MEASUREMENTS AND MAIN RESULTS: The main outcome measurement was time
      to first protease inhibitor prescription after first elevated HIV viral load
      (>10,000 copies/ml). In this cohort, 190 patients had an elevated viral load
      (median age 39; 87% male; 12% history of injection drug use; 63% AIDS; 53% with
      depression; 17% history of pneumocystis pneumonia; 54% CD4 <200). In Cox
      proportional hazards modeling, significant univariate correlates for delayed
      protease inhibitor initiation were higher CD4 cell count (hazard ratio [HR] 2. 38
      for CD4 200-500 compared with <200, 95% confidence interval [CI] 1.59, 3.57; and
      HR 8.33 for CD4> 500; 95% CI 2.63, 25.0), higher viral load (HR 0.43 for each 10
      fold increase; 95% CI 0.31, 0.59), injection drug use (HR 2.08; 95% CI 1.05,
      4.17), AIDS (HR 0.24; 95% CI 0.15, 0.36), and history of pneumocystis pneumonia
      (HR 0.32; 95% CI 0.21, 0.49). In multivariate models adjusted for secular trends
      in protease inhibitor use, factors significantly associated with delay of
      protease inhibitor initiation (p <.05) were higher CD4 cell count (for CD4 200
      500, HR 2.63; 95% CI 1.61, 4.17; for CD4> 500, HR 11.11; 95% CI 3.57, 33.33),
      higher viral load (HR 0.66 for each 10-fold increase; 95% CI 0.45, 0.98), history
      of pneumocystis pneumonia (HR 0.57; 95% CI 0.37, 0.90), history of depression (HR
      1. 49; 95% CI 1.03, 2.13), and history of injection drug use (HR 2.70; 95% CI
      1.35, 5.56). CONCLUSIONS: HIV-infected patients with higher CD4 cell counts or a
      history of depression or history of injection drug use have significant and
      lengthy delays of protease inhibitor therapy. Although some delays may be
      clinically appropriate, enhancement of provider and patient education might prove
      beneficial. Further research should examine reasons for delays in protease
      inhibitor initiation and their appropriateness.

PMID- 10417597
TI  - Smoking status as a vital sign.
AB  - OBJECTIVE: We conducted this study to determine if a smoking status stamp would
      prompt physicians to increase the number of times they ask, advise, assist, and
      arrange follow-up for African-American patients about smoking-related issues.
      DESIGN: An intervention study with a posttest assessment (after the physician
      visit) conducted over four 1-month blocks. The control period was the first 2
      weeks of each month, while the following 2 weeks served as the intervention
      period. SETTING: An adult walk-in clinic in a large inner-city hospital.
      PARTICIPANTS: We consecutively enrolled into the study 2,595 African-American
      patients (1,229 intervention and 1, 366 control subjects) seen by a housestaff
      physician. INTERVENTIONS: A smoking status stamp placed on clinic charts during
      the intervention period. MAIN RESULTS: Forty-five housestaff rotated through the
      clinic in 1-month blocks. In univariate analyses, patients were significantly
      more likely to be asked by their physicians if they smoke cigarettes during the
      intervention compared with the control period, 78.4% versus 45.6% (odds ratio
      [OR] 4.28; 95% confidence interval [CI] 3.58, 5.10). Patients were also more
      likely to be told by their physician to quit, 39.9% versus 26.9% (OR 1.81; 95% CI
      1.36, 2.40), and have follow-up arranged, 12.3% versus 6.2% (OR 2.16; 95% CI
      1.30, 3.38). CONCLUSIONS: The stamp had a significant effect on increasing rates
      of asking about cigarette smoking, telling patients to quit, and arranging follow
      up for smoking cessation. However, the stamp did not improve the low rate at
      which physicians offered patients specific advice on how to quit or in setting a
      quit date.

PMID- 10417598
TI  - Are Latinos less satisfied with communication by health care providers?
AB  - OBJECTIVE: To examine associations of patient ratings of communication by health
      care providers with patient language (English vs Spanish) and ethnicity (Latino
      vs white). METHODS: A random sample of patients receiving medical care from a
      physician group association concentrated on the West Coast was studied. A total
      of 7,093 English and Spanish language questionnaires were returned for an overall
      response rate of 59%. Five questions asking patients to rate communication by
      their health care providers were examined in this study. All five questions were
      administered with a 7-point response scale. MAIN RESULTS: We estimated the
      associations of satisfaction ratings with language (English vs Spanish) and
      ethnicity (white vs Latino) using ordinal logistic models, controlling for age
      and gender. Latinos responding in Spanish (Latino/Spanish) were significantly
      more dissatisfied compared with Latinos responding in English (Latino/English)
      and non-Latino whites responding in English (white) when asked about: (1) the
      medical staff listened to what they say (29% vs 17% vs 13% rated this "very
      poor," "poor," or "fair"; p <.01); (2) answers to their questions (27% vs 16% vs
      12%; p <.01); (3) explanations about prescribed medications (22% vs 19% vs 14%; p
      <.01); (4) explanations about medical procedures and test results (36% vs 21% vs
      17%; p <.01); and (5) reassurance and support from their doctors and the office
      staff (37% vs 23% vs 18%; p <.01). CONCLUSION: This study documents that
      Latino/Spanish respondents are significantly more dissatisfied with provider
      communication than Latino/English and white respondents. These results suggest
      Spanish-speaking Latinos may be at increased risk of lower quality of care and
      poor health outcomes. Efforts to improve the quality of communication with
      Spanish-speaking Latino patients in outpatient health care settings are needed.

PMID- 10417599
TI  - Clinical examination for the detection of protective sensation in the feet of
      diabetic patients. International Cooperative Group for Clinical Examination
      Research.
AB  - OBJECTIVE: We compared the reproducibility and accuracy of conventional clinical
      examination of the diabetic foot to monofilament examination. We also sought to
      simplify the monofilament examination by reducing it to fewer touch points.
      METHODS: In a cross-sectional study at 10 centers in the United States, Canada,
      and Switzerland, general internists and residents performed a structured history
      and physical examination for neuropathy on the feet of diabetic patients.
      Independent examination by two observers included monofilament sensation,
      pinprick, vibration, position sense, and ankle reflexes. MAIN RESULTS: A total of
      304 patients were examined by at least one practitioner, and 200 received
      duplicate examinations. Monofilament examination and ankle reflexes had the best
      reproducibility, with moderate agreement (kappa = 0.59); pinprick, position, and
      vibration sense had fair agreement (kappa = 0.28-0.36). No component of the
      history or physical examination, singly or in aggregate, was both sensitive and
      specific for identifying a patient with an abnormal monofilament examination. A
      simplified monofilament examination using only 4 sites per foot (total 8 sites)
      detected 90% of patients with an abnormal 16-site monofilament evaluation.
      CONCLUSIONS: Conventional clinical examination had low reproducibility and
      correlated poorly with monofilament examination for the identification of the at
      risk patient. The Semmes-Weinstein monofilament examination, a reproducible,
      valid, and generalizable test of foot sensation, is recommended as the screening
      procedure of choice for examining diabetic feet.

PMID- 10417600
TI  - Screening for undetected mental disorders in high utilizers of primary care
      services.
AB  - OBJECTIVE: To define the prevalence and detection rates of mental disorders among
      high utilizers as compared with typical utilizers, and to examine the effect of
      case-mix adjustment on these parameters. DESIGN: Cross-sectional study. SETTING:
      General internal medicine outpatient clinic associated with an urban, academic
      medical center. PATIENTS: From patients attending a general medicine clinic, 304
      were selected randomly in three utilization groups, defined by number of clinic
      visits: (1) high utilizers; (2) case-mix adjusted high utilizers; and (3) typical
      utilizers (control patients). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:
      The presence of any mental disorder was ascertained by the PRIME-MD screening
      instrument. Chart review on all patients was performed to ascertain mental
      disorders detected by primary care physicians. The prevalence of mood disorders
      was markedly higher in high utilizers (29%) than in adjusted high utilizers (15%)
      or controls (10%) (p <.001). Anxiety disorders were slightly, but not
      statistically, more prevalent in the group adjusted for case mix (16%) than in
      other high utilizers (12%) or controls (9%). Alcoholism was significantly more
      prevalent in controls (12%) than in adjusted (6%) or other high utilizers (3%) (p
      <.03). The discrepancy in detection rates between PRIME-MD and chart review for
      any mental disorder was less for high utilizers (37% vs 31%) as compared with
      adjusted high utilizers (31% vs 11%) or controls (24% vs 8%). CONCLUSIONS: Mood
      disorders are associated with a high overall burden of illness, while anxiety
      disorders are more predominant among outliers after case-mix adjustment.
      Detection rates differ substantially by utilization pattern. Screening efforts
      can be more appropriately targeted with knowledge of these patterns.

PMID- 10417602
TI  - Practice guidelines and late-life depression assessment in long-term care.
AB  - To determine how well nursing home physicians believe they can detect and treat
      depression, we conducted a national survey, eliciting a 63% response rate. More
      than 75% of respondents believed they detected and treated depression well.
      Excellent depression training (vs "good," "fair," "poor/none") was associated
      with better self-reported recognition (odds ratio [OR] 14.25; 95% confidence
      interval [CI] 1.81, 111.93) and treatment skills (OR 6.72; 95% CI 1. 91, 23.64).
      Screening tool use predicted greater self-assessed detection (OR 1.89; 95% CI
      0.92, 3.87) and treatment competency (OR 2.00; 95% CI 1.14, 3.50). Practice
      guideline awareness was associated with greater self-reported treatment
      competency (OR 2.47; 95% CI 1.56, 3.91).

PMID- 10417601
TI  - Patient preferences for colon cancer screening.
AB  - OBJECTIVE: To measure patient preferences for four different screening
      strategies: annual fecal occult blood testing (FOBT) alone; flexible
      sigmoidoscopy (FSIG) every 5 years alone; both annual FOBT and FSIG every 5
      years; or no screening. DESIGN: Survey. SETTING: University internal medicine
      clinic. PATIENTS: Convenience sample of 146 adults (aged 50-75 years) with no
      previous history of colon cancer. INTERVENTION: Three-part educational program on
      colon cancer screening administered verbally by trained research assistants.
      MEASUREMENTS AND MAIN RESULTS: Patient preferences for screening were measured at
      three points: after descriptive information about colon cancer and screening
      options (testing procedure information); after information about test performance
      but with no out-of-pocket costs (test performance information); and finally with
      hypothetical out-of-pocket costs (cost information). After only descriptive test
      information, the most popular strategies were FOBT alone (45%) or both tests
      (38%). Fewer patients preferred FSIG alone (13%). After information about test
      performance, more subjects preferred both tests (47%), and fewer subjects
      preferred FOBT alone (36%) (p =.12). With hypothetical out-of-pocket costs, the
      proportion preferring FOBT alone increased to 53%, while those preferring both
      tests decreased to 31% (p <.001). Less than 5% of patients preferred no
      screening. CONCLUSIONS: Patient preferences for colon cancer screening were
      modestly sensitive to information about test performance and strongly sensitive
      to out-of-pocket costs. The heterogeneity of patients' preferences for how to be
      screened supports informed shared decision making as a possible means of
      improving colon cancer screening.

PMID- 10417604
TI  - A vision for JGIM 

PMID- 10417603
TI  - A medicolegal curriculum for internal medicine residents.
AB  - Many residents lack knowledge about medicolegal issues. To assess the ability of
      64 primary care residents to learn legal medicine, we studied the impact of a
      medicolegal curriculum in a randomized, controlled study. We measured residents'
      medicolegal knowledge using a novel test, the Legal Medicine Evaluation (LME). We
      found that the mean LME score of residents exposed to the curriculum increased
      15.5 points (on a 100-point scale) to 65.9 ( p <.01), while the mean LME score of
      control residents increased only 3.5 points, to 53.5 ( p =. 05). Clearly,
      residents can learn basic medicolegal principles. Thus, observed deficiencies in
      medicolegal knowledge most likely arise from inadequate medicolegal instruction.

PMID- 10417606
TI  - Medical education curricula. Where's the beef?

PMID- 10417605
TI  - When should we delay highly active antiretroviral therapy?

PMID- 10417608
TI  - I Am a large white toad 

PMID- 10417607
TI  - Survival analysis for cardiac risk stratification.

PMID- 10417610
TI  - In this issue 

PMID- 10417609
TI  - Running home 

PMID- 10417611
TI  - CD11b+ cells and ultraviolet-B-resistant CD1a+ cells in skin of patients with
      polymorphous light eruption.
AB  - After ultraviolet exposure Langerhans cells (epidermal CD1a+ cells) disappear
      from the healthy skin, and CD11b+ macrophage-like cells, which are reported to
      produce interleukin-10, appear in a matter of days. These phenomena are related
      to the ultraviolet-induced local suppression of contact hypersensitivity
      reactions. A defect in this suppression might allow inadvertent immune reactions
      to develop after ultraviolet (over)exposure; i.e., it could cause ultraviolet-B
      induced polymorphous light eruption. In order to test this we first exposed
      buttock skin of eight healthy volunteers to six minimal erythema doses from
      Philips TL12 lamps, and indeed observed a dramatic disappearance of CD1a+ cells
      48 and 72 h later, at which time the number of CD11b+ cells increased in the
      dermis, and some occurred in the epidermis. The epidermis thickened and showed
      large defects, filled by CD11b+ cells, just below the stratum corneum. In 10
      patients with polymorphous light eruption (five with a normal minimal erythema
      dose and five with a low minimal erythema dose) CD1a+ cells were present in the
      epidermis as well as in the dermis before exposure. Strikingly, these cells were
      still present in considerable number at 48 and 72 h after exposure to six minimal
      erythema doses. CD11b+ cells already present in the dermis before ultraviolet
      exposure, increased after ultraviolet exposure, and subsequently also invaded the
      epidermis. Despite the six minimal erythema doses, there were no apparent defects
      in the epidermis of the polymorphous light eruption patients. This deviant early
      response to ultraviolet radiation is likely to be of direct relevance to the
      polymorphous light eruption and is perhaps useful as a diagnostic criterion.

PMID- 10417612
TI  - Mitigation of delayed-type hypersensitivity reactions by a CD44 variant isoform
      v3-specific antibody: blockade of leukocyte egress.
AB  - In allergic alterations of human skin the majority of infiltrated leukocytes
      express CD44v3, but no other CD44 variant isoform. Vessel endothelium, too, is
      brightly stained with a CD44v3-specific antibody. Being concerned about
      therapeutic intervention, it became of importance to define whether expression of
      CD44v3 on the endothelial cells or on the leukocytes or on both is of functional
      importance. As expression of CD44v3 in the mouse on activated endothelium and on
      subpopulations of activated CD4+ cells, B cells and monocytes was similar to the
      expression in the human, we answered the question in a mouse delayed-type
      hypersensitivity model. The effect of anti-CD44v3 was compared with the effect of
      anti-CD44s and anti-CD44v10, both known to suppress delayed-type hypersensitivity
      reactions. Anti-CD44v3 mitigated the delayed-type hypersensitivity reaction in
      dinitrofluorobenzene sensitized and challenged mice comparable with anti-CD44s
      and anti-CD44v10. The seemingly similar effects of CD44 isoform-specific
      antibodies, however, resulted from a distinct modulation of response. Anti-CD44s
      mainly suppressed T cell activation and interleukin-2 as well as interferon-gamma
      expression. Anti-CD44v10 inhibited the activation of monocytes in the draining
      lymph nodes and in the infiltrate, which led to a strong reduction in the
      proinflammatory cytokines tumor necrosis factor-alpha and interleukin-12 and in
      edema formation. Anti-CD44v3 had only a weak effect on cytokine expression by
      isolated subpopulations of leukocytes, but suppressed cytokine production by
      helper T cells when cocultured with antigen-presenting cells, i.e., blocked an
      interaction between antigen-presenting cells and helper T cells. The dominating
      effect of anti-CD44v3, however, relied on a blockade of leukocyte extravasation.
      As leukocytes transferred into dinitrofluorobenzene sensitized, anti-CD44v3
      treated and lethally irradiated mice did not infiltrate the sensitized skin, anti
      CD44v3 most likely prevented leukocyte extravasation by blocking CD44v3 on
      endothelial cells.

PMID- 10417613
TI  - Pemphigus vulgaris and pemphigus foliaceus antibodies are pathogenic in
      plasminogen activator knockout mice.
AB  - Previous studies have suggested that urokinase plasminogen activator is required
      for blister formation in pemphigus vulgaris and pemphigus foliaceus. Other
      studies, however, have shown that downregulation of plasminogen activator does
      not inhibit blisters induced by pemphigus immunoglobulin G. To eliminate the
      possibility that small amounts of urokinase plasminogen activator might be
      sufficient for blister formation, we passively transferred pemphigus
      immunoglobulin G to urokinase plasminogen activator knockout neonatal mice.
      Pemphigus foliaceus and pemphigus vulgaris immunoglobulin G caused gross blisters
      and acantholysis in the superficial and suprabasal epidermis, respectively, to
      the same degree in knockout and control mice, demonstrating that urokinase
      plasminogen activator is not absolutely required for antibody-induced blisters.
      Some studies have shown elevated tissue-type plasminogen activator in pemphigus
      lesions. Tissue-type plasminogen activator, however, is not necessary for blister
      formation, because pemphigus foliaceus and pemphigus vulgaris immunoglobulin G
      caused blisters to the same degree in tissue-type plasminogen activator knockout
      and control mice. To rule out that one plasminogen activator might compensate for
      the other in the knockout mice, we bred urokinase plasminogen activator, tissue
      type plasminogen activator double knockouts. After passive transfer of pemphigus
      foliaceus and pemphigus vulgaris immunoglobulin G these mice blistered to the
      same degree as the single knockout and control mice, and histology indicated
      blisters at the expected level of the epidermis. These data definitively
      demonstrate that plasminogen activator is not necessary for pemphigus
      immunoglobulin G to induce acantholysis in the neonatal mouse model of pemphigus.

PMID- 10417615
TI  - Protein C inhibitor is expressed in keratinocytes of human skin.
AB  - Protein C inhibitor is a member of the serpin family that inhibits a variety of
      serine proteases. Protein C inhibitor is present in numerous body fluids and is
      produced in the liver and by various epithelial cells. To determine if this
      epithelial serpin is present in skin, immunohistochemical studies were performed
      that showed strong staining for protein C inhibitor antigen in the epidermis.
      Protein C inhibitor mRNA was detected in the keratinocyte cell line HaCaT and the
      epidermoid carcinoma cell line A431 using reverse transcription-polymerase chain
      reaction suggesting that also in normal skin protein C inhibitor is derived from
      keratinocytes. Conditioned media from these cell lines were analyzed on
      immunoblots, which revealed a protein C inhibitor-antigen band that comigrated
      with protein C inhibitor derived from the hepatoma cell line HepG2. Using an
      enzyme-linked immunosorbent assay specific for total protein C inhibitor antigen
      the accumulation of protein C inhibitor in the cell culture supernatants of HaCaT
      keratinocytes was found to be 0.3 ng per h per 1 million cells. This is similar
      to the amount of plasminogen activator inhibitor-1 produced by these cells, which
      also produce tissue plasminogen activator and urokinase. Fluorescence-activated
      cell sorter analysis revealed similar expression of intracellular protein C
      inhibitor antigen in proliferating and confluent HaCaT cells. These findings
      demonstrate that protein C inhibitor antigen is present in the normal epidermis
      and that protein C inhibitor is constitutively expressed by keratinocytes in
      culture. Therefore, protein C inhibitor may provide protease inhibitory activity
      not only to internal, but also to the external surface of the body. Additionally,
      protein C inhibitor could contribute to the regulation of retinoid supply in the
      epidermis, as we have shown recently that retinoic acid binds specifically to
      protein C inhibitor.

PMID- 10417614
TI  - The role of oxidative DNA damage in human arsenic carcinogenesis: detection of 8
      hydroxy-2'-deoxyguanosine in arsenic-related Bowen's disease.
AB  - Arsenic is widely distributed in nature in the form of either metalloids or
      chemical compounds, which cause a variety of pathologic conditions including
      cutaneous and visceral malignancies. Recently, reactive oxygen species have been
      hypothesized to be one of the causes of arsenic-induced carcinogenesis. 8-Hydroxy
      2'-deoxyguanosine is one of the major reactive oxygen species-induced DNA base
      modified products that is widely accepted as a sensitive marker of oxidative DNA
      damage. We studied the presence of 8-hydroxy-2'-deoxyguanosine by
      immunohistochemistry using N45.1 monoclonal antibody in 28 cases of arsenic
      related skin neoplasms and arsenic keratosis as well as in 11 cases of arsenic
      unrelated Bowen's diseases. The frequency of 8-hydroxy-2'-deoxyguanosine positive
      cases was significantly higher in arsenic-related skin neoplasms (22 of 28; 78%)
      than in arsenic-unrelated Bowen's disease (one of 11; 9%) (p < 0.001 by chi2
      test). 8-Hydroxy-2'-deoxyguanosine was also detected in normal tissue adjacent to
      the arsenic-related Bowen's disease lesions. Furthermore, arsenic was detected by
      neutron activation analysis in the deparaffined skin tumor samples of arsenic
      related disease (four of five; 80%), whereas arsenic was not detected in control
      samples. Our results strongly suggest the involvement of reactive oxygen species
      in arsenic-induced human skin cancer. Key word: neutron activation analysis.

PMID- 10417616
TI  - Pretreatment of human keratinocyte sheets with laminin 5 improves their grafting
      efficiency.
AB  - Laminin 5 is essential in epithelial attachment to stromal tissues, suggesting
      that it might improve keratinocyte attachment in a variety of clinical
      situations. In this study, we examined the effect of exogenous laminin 5 upon the
      efficiency of transplantation of keratinocyte sheets in animal models.
      Keratinocyte sheets were prepared according to the method of Rheinwald & Green
      (1975). Purified laminin 5 was added to the sheets of group 1 (1.0 microg per
      cm2), Dulbecco's modified Eagle's medium alone was added to group 2. The sheets
      were grafted to the panniculus carnosus of nude mice (BALB/C nu/nu) (n = 12) and
      nude rats (Fisher 344) (n = 15). The take rate was assessed by measurement of the
      area of surviving epithelium at 7 d postgrafting. Laminin 5 bound the
      keratinocyte sheets of group 1. At 7 d postgrafting, the area of
      epithelialization of group 1 was significantly larger than that of group 2.
      Immunohistochemistry staining showed that collagen IV, laminin 5, and collagen
      VII stained more strongly at the dermal-epidermal junction in group 1 than in
      group 2. Integrin chains alpha6 and beta4 were similar in both groups. Electron
      microscopy at day 3 after grafting, showed the lamina densa of group 1 to be more
      continuous than in group 2. Pretreatment of cultured human keratinocyte sheets
      with laminin 5 improved the extent of epithelial coverage and increased the rate
      of neobasement membrane formation. The results suggest that laminin 5 promotes
      epithelial attachment by increasing the rate of basement membrane assembly.

PMID- 10417617
TI  - Enhanced expression of eotaxin and CCR3 in atopic dermatitis.
AB  - Chemokines are thought to play an important part in the development of
      inflammation in atopic dermatitis. Eotaxin, a CC chemokine, is a potent
      chemoattractant and activator of human eosinophils, basophils and Th2 lymphocytes
      which acts via the chemokine receptor CCR3. We studied the expression of eotaxin
      and CCR3, as well as MCP-3, MIP-1alpha and interleukin-8, in atopic dermatitis
      and normal skin by immunohistochemistry and nested reverse transcriptase
      polymerase chain reaction. Skin biopsy specimens were obtained from nonlesional
      and lesional skin of patients with atopic dermatitis and of nonatopic controls.
      Immunoreactivity and transcripts of eotaxin and CCR3 were significantly increased
      in lesional skin from atopic dermatitis, but not in nonatopic controls. In
      nonlesional atopic dermatitis samples CCR3 expression was also significantly
      increased at the mRNA and protein level, whereas eotaxin was increased at the
      mRNA level only. No significant difference in the expression of MCP-3, MIP
      1alpha, and interleukin-8 was observed between skin samples from atopic
      dermatitis and nonatopic controls. The enhanced local production of eotaxin may
      lead to the recruitment of eosinophils and T lymphocytes, which both express CCR3
      and contribute to the initiation and maintenance of inflammation.

PMID- 10417618
TI  - Cellular fibronectin is induced in ultraviolet-exposed human skin and induces IL
      10 production by monocytes/macrophages.
AB  - CD11b+ monocytic/macrophagic cells that infiltrate human skin after in vivo
      ultraviolet exposure potently produce interleukin-10. We hypothesized that
      binding of monocyte beta1 integrins to ultraviolet-induced extracellular matrix
      ligands, such as fibronectin, after entry of blood monocytes into the dermis, is
      involved in the modulation of immunoregulatory monocytic cytokines.
      Immunostaining of human skin and reverse transcriptase-polymerase chain reaction
      studies revealed that the embryonic isoform of cellular fibronectin, in which the
      extra domain A (EDA) segment is spliced in (EDA+ cellular fibronectin), and
      confers enhanced binding to beta1 integrins, is newly induced and is associated
      with infiltrating CD11b+ cells post in vivo ultraviolet exposure. We then tested
      the effect of fibronectin on resting purified peripheral monocytes in vitro. We
      found that monocyte interleukin-10, but not interleukin-12, was significantly
      induced in a concentration-dependent manner by in vitro binding to cellular
      fibronectin (n = 6), but not plasma fibronectin. Tumor necrosis factor-alpha was
      also induced in a concentration-dependent manner, but to a lesser extent.
      Monoclonal antibodies to beta1 integrins beta-subunit (CD29) also strongly
      induced tumor necrosis factor-alpha and interleukin-10 production, but not
      interleukin-12. Neutralization of tumor necrosis factor-alpha reduced by 54% the
      interleukin-10 production that was induced by monocytes binding to cellular
      fibronectin, indicating that interleukin-10 induction is at least in part
      dependent upon concomitant autocrine tumor necrosis factor-alpha release. In
      conclusion, ultraviolet skin injury results in increased production and
      deposition of EDA+ cellular fibronectin in the papillary dermis, which may be one
      of the key signals capable of inducing interleukin-10 but not interleukin-12 in
      monocytes that infiltrate micromilieu of human skin after ultraviolet exposure.

PMID- 10417619
TI  - Immune complexes from vasculitis patients bind to endothelial Fc receptors
      independent of the allelic polymorphism of FcgammaRIIa.
AB  - Cutaneous leukocytoclastic vasculitis is characterized by the deposition of
      circulating immune complexes, neutrophil extravasation, and vessel destruction,
      but mechanisms of circulating immune complexes capture within postcapillary
      venules are unknown. We demonstrate that circulating immune complexes from sera
      of vasculitis patients bind to cultured endothelium in an Fc gamma receptor IIa
      dependent fashion. In lesional skin, endothelial cells bind immunoglobulin G2 >
      immunoglobulin G3 and immunoglobulin G4, but not immunoglobulin G1, even before
      obvious neutrophil transmigration and vessel damage. As the human Fc gamma
      receptor IIa proteins exist in two allotypes (one with a histidine at position
      131, which binds immunoglobulin G1, 2, 3 and the other with an arginine at
      position 131, which binds immunoglobulin G1, and 3, but is unable to bind
      immunoglobulin G2), we expected an altered prevalence of histidine 131 forms in
      vasculitis patients. Sequence analysis, however, revealed an equal distribution
      of allotypes in patients and controls. In conclusion, circulating immune complex
      binding to endothelial Fc gamma receptor IIa is among the initial steps in the
      development of vasculitis. Although immunoglobulin G2 is the predominant subtype
      precipitated at endothelial surfaces, it is not required for fixing circulating
      immune complexes to endothelium, because patients homozygote for Fc gamma
      receptor IIa-arginine 131 equally develop leukocytoclastic vasculitis as those
      bearing the Fc gamma receptor IIa-histidine 131 allele. As immunoglobulin G1 is
      virtually absent in leukocytoclastic vasculitis lesions and immunoglobulin G4
      does not bind to both Fc gamma receptor IIa alleles, these complexes, in addition
      to immunoglobulin G2, should contain immunoglobulin G3 in order to fix to
      vascular Fc gamma receptor IIa, at least in persons homozygous for Fc gamma
      receptor IIa-arginine 131. KEYWORDS: CD32/immunoglobulin G
      subtypes/leukocytoclastic vasculitis/microvessels.

PMID- 10417620
TI  - Successful treatment of alopecia areata-like hair loss with the contact
      sensitizer squaric acid dibutylester (SADBE) in C3H/HeJ mice.
AB  - A type of hair loss closely resembling human alopecia areata has been described
      in C3H/HeJ mice. In order to test the assumed analogy with human alopecia areata,
      we investigated the efficacy of treatment with the contact allergen squaric acid
      dibutylester. In 12 C3H/HeJ mice with alopecia areata an allergic contact
      dermatitis was induced and elicited weekly on one side of the back by topical
      applications of squaric acid dibutylester. Overt hair regrowth was observed only
      on the treated side of the back in nine of 12 mice. Histopathologic examination
      revealed a change in the distribution of the inflammatory infiltrate from a dense
      perifollicular lymphocytic infiltrate around the mid and lower regions of hair
      follicles in untreated skin to a uniform presence in the upper dermis in treated
      skin. Immunohistomorphometric studies revealed that treatment with squaric acid
      dibutylester increased the CD4+/CD8+ ratio from approximately 1:2 in untreated
      alopecia areata to 1:1 in treated alopecia areata. Additional immunohistochemical
      investigations showed an aberrant expression of major histocompatibility complex
      class I, major histocompatibility complex class II and intercellular adhesion
      molecule 1 on keratinocytes of the mid and lower parts of hair follicles in
      untreated alopecia areata. In successfully treated skin ectopic major
      histocompatibility complex class I and II expression was clearly reduced, whereas
      intercellular adhesion molecule 1 expression showed only minor changes. In
      conclusion, alopecia areata-like hair loss in C3H/HeJ mice responded to treatment
      with the contact sensitizer squaric acid dibutylester analogous to human alopecia
      areata. Moreover, successful treatment changes the aberrant expression of major
      histocompatibility complex class I and II in a way similar to that observed in
      human alopecia areata. These observations support the concept that alopecia
      areata-like hair loss in C3H/HeJ mice can be utilized as an appropriate model for
      the study of human alopecia areata.

PMID- 10417621
TI  - UVB increases urokinase-type plasminogen activator receptor (uPAR) expression.
AB  - Keratinocytes synthesize and secrete urokinase-type plasminogen activator, which
      binds to its specific receptor on keratinocytes. When bound to urokinase-type
      plasminogen activator receptor, urokinase-type plasminogen activator
      proteolytically converts surface bound plasminogen to plasmin, which in turn
      cleaves many extracellular components leading to pericellular proteolysis. The
      activation of the urokinase system has been observed during re-epithelialization
      of skin wounds and in lesions of the autoimmune blistering skin disease
      pemphigus. As pemphigus is photoinducible, we investigated the effect of
      ultraviolet B on urokinase-type plasminogen activator and urokinase-type
      plasminogen activator receptor expression in the epidermal keratinocyte cell line
      A431. Ultraviolet B increased cellular and secreted urokinase-type plasminogen
      activator protein (enzyme-linked immunosorbent assay) and urokinase-type
      plasminogen activator receptor cell surface expression (flow cytometry) 24 h
      postirradiation. Northern blot analysis indicated that ultraviolet B increased
      urokinase-type plasminogen activator receptor mRNA. Compared with a more rapid
      mRNA induction by epidermal growth factor (maximal after 4 h) the ultraviolet B
      response was maximal after 24 h and prolonged up to 36 h. The mRNA induction was
      not dependent on protein synthesis as judged by cycloheximide incubation.
      Ultraviolet B did not influence urokinase-type plasminogen activator receptor
      mRNA stability (actinomycin D incubation). A transiently transfected
      chloramphenicol acetyltransferase-reporter construct containing a -398/+51
      urokinase-type plasminogen activator receptor promoter fragment was activated
      when cells were exposed to ultraviolet B. This induction was almost completely
      abolished by mutating a -182/-176 AP-1 binding sequence. Ultraviolet B increased
      the binding capacity at this AP-1 motif in electrophoretic mobility shift assays.
      These data identify a distinct transcriptional mechanism by which ultraviolet B
      induces urokinase-type plasminogen activator receptor. The epidermal induction of
      components of the proteolytic urokinase system by ultraviolet B may help explain
      the photoinducibility of pemphigus lesions.

PMID- 10417622
TI  - Hypoxia potentiates ultraviolet A-induced riboflavin cytotoxicity.
AB  - Flavins are thought to be important chromophores for chronic photo-induced skin
      injury, but the mechanism is not well known. We have reported that the primary
      cytotoxicity remaining in ultraviolet A-irradiated riboflavin solution is
      attributable to hydrogen peroxide. Because the dermis is more hypoxic than the
      atmosphere, we investigated the cytotoxicity of riboflavin solution during and
      after ultraviolet A irradiation under hypoxia. Riboflavin solution showed
      stronger cytotoxicity during irradiation under hypoxia than under air. Riboflavin
      solution that had been irradiated under hypoxia at lower ultraviolet A doses
      showed stronger cytotoxicity and contained more hydrogen peroxide than solution
      irradiated under air at the same doses. At higher ultraviolet A doses, however,
      the cytotoxicity and hydrogen peroxide quantity were similar in riboflavin
      solutions irradiated under different oxygen conditions. The effect of a singlet
      oxygen quencher, sodium azide, on the induction of cytotoxicity and production of
      hydrogen peroxide by ultraviolet A irradiation of riboflavin solution was
      examined. The presence of sodium azide in the solution during ultraviolet A
      irradiation suppressed the cytotoxicity and hydrogen peroxide production to
      similar levels at various ultraviolet A doses regardless of oxygen conditions. At
      the maximum suppression by sodium azide, hydrogen peroxide production decreased
      to 10% of the unsuppressed production. About 40% of the oxygen molecules of
      hydrogen peroxide produced was thought to be derived from oxygen dissolved in the
      riboflavin solution.

PMID- 10417623
TI  - Rolipram inhibits staphylococcal enterotoxin B-mediated induction of the human
      skin-homing receptor on T lymphocytes.
AB  - The cutaneous lymphocyte-associated antigen defines T lymphocytes with cutaneous
      tropism under inflammatory conditions. Bacterial infections participate in
      cutaneous inflammations, such as atopic dermatitis or psoriasis. Bacterial
      superantigens, such as staphylococcal enterotoxin B, can activate peripheral
      blood mononuclear cells to induce effector T cells bearing the T cell skin homing
      receptor cutaneous lymphocyte-associated antigen via enhancement of interleukin
      12 production. We have identified and characterized the anti-inflammatory effects
      of different phosphodiesterase inhibitors on this system. Our data indicate that
      the selective type 4 phosphodiesterase inhibitor rolipram inhibits the
      Staphylococcal enterotoxin B-mediated generation of cutaneous lymphocyte
      associated antigen positive CD3+ cells from peripheral blood mononuclear cells by
      reducing interleukin-12 production in a concentration-dependent manner.
      Conversely, type 3 phosphodiesterase or type 5 phosphodiesterase selective
      inhibitors were not effective. The rolipram inhibitory effect was on interleukin
      12 production, as exogenously added interleukin-12 could revert rolipram
      suppression. These results suggest that selective type 4 phosphodiesterase
      inhibition may have beneficial effects on T cell mediated skin inflammatory
      processes characterized by the presence of bacterial infections, that are thought
      to exacerbate ongoing skin inflammation.

PMID- 10417624
TI  - Haplotype analysis of families with erythropoietic protoporphyria and novel
      mutations of the ferrochelatase gene.
AB  - Ferrochelatase, the enzyme that catalyzes the terminal step in the heme
      biosynthetic pathway, is the site of the defect in the human inherited disease
      erythropoietic protoporphyria. Molecular genetic studies have shown that the
      majority of erythropoietic protoporphyria cases are transmitted in dominant
      fashion and that mutations underlying erythropoietic protoporphyria are
      heterogeneous. We performed haplotype analysis of American families that shared
      recurrent ferrochelatase gene mutations yet had forbearers from several European
      countries. This was to gain insight into whether these mutations represent
      mutational hotspots at the ferrochelatase gene, or propagation of ancestral
      alleles bearing the mutations. Two recurrent mutations were found to occur on
      distinctive chromosome 18 haplotypes, consistent with being hotspot mutations. On
      the other hand, we found three sets of two unrelated families that shared the
      same haplotypes bearing these mutations, which could reflect geographic
      dispersion of ancestral mutant alleles. In addition, we report novel mutations
      associated with erythropoietic protoporphyria: g(+ 1)-->t transversion of the
      exon 4 donor site, g(+ 1)-->a transition of the exon 6 donor site, and t(+ 2)-->a
      substitution at the exon 9 donor site; these mutations are predicted to cause
      splicing defects of the associated exons. We also identified a g(+ 5)-->a
      transition of the exon 1 donor site in four unrelated families with
      erythropoietic protoporphyria, and a G(- 1)-->A substitution at the exon 9 donor
      site in an additional family. The probability that these sequence changes are
      normal polymorphisms was virtually excluded (p < 0.0001) by their absence in 120
      ferrochelatase alleles from 30 normal subjects and 30 individuals with manifested
      erythropoietic protoporphyria with or without a known mutation.

PMID- 10417625
TI  - Increased formation of thromboxane in vivo in humans with mastocytosis.
AB  - Clinical manifestations of mastocytosis are mediated, at least in part, by
      release of the mast cell mediators histamine and prostaglandin D2. It has been
      previously reported that in addition to prostaglandin D2, mast cells produce
      other eicosanoids, including thromboxane. Nonetheless, little information exists
      regarding the formation of other prostanoids in vivo. The most accurate method to
      examine the systemic production of eicosanoids in vivo is the quantitation of
      urinary metabolites. We previously developed a highly accurate assay employing
      mass spectrometry to measure a major urinary metabolite of thromboxane, 11
      dehydro-thromboxane B2, in humans. We utilized this assay to quantitate
      thromboxane production in 17 patients with histologically proven mastocytosis. We
      report that thromboxane formation was significantly increased (>2 SD above the
      mean) in at least one urine sample from 65% of patients studied. Of these, 91% of
      patients with documented systemic involvement had elevated thromboxane
      generation. In addition, endogenous formation of thromboxane was highly
      correlated with the urinary excretion of the major urinary metabolite of
      prostaglandin D2 (r = 0.98) and Ntau-methylhistamine (r = 0.91), suggesting that
      the cellular source of increased thromboxane in vivo could be the mastocyte.
      Enhanced thromboxane formation in patients with this disorder is unlikely to be
      of platelet origin as other markers of platelet activation, platelet factor 4 and
      beta-thromboglobulin, were not increased in three patients with marked
      overproduction of thromboxane. Furthermore, the recovery of 11-dehydro
      thromboxane B2 excretion in two patients after the administration of aspirin
      occurred significantly more rapidly than the recovery of platelet thromboxane
      generation. These studies, therefore, report that thromboxane production is
      significantly increased in the majority of patients with mastocytosis that we
      examined and provide the basis to elucidate the role of this eicosanoid in
      disorders of mast cell activation.

PMID- 10417626
TI  - Effect of the lactic acid bacterium Streptococcus thermophilus on ceramide levels
      in human keratinocytes in vitro and stratum corneum in vivo.
AB  - The effects of Streptococcus thermophilus on ceramide levels either in vitro on
      cultured human keratinocytes or in vivo on stratum corneum, have been
      investigated. In vitro, Streptococcus thermophilus enhanced the levels of
      ceramides in keratinocytes in a time-dependent way. The presence of high levels
      of neutral, glutathione-sensitive, sphingomyelinase in Streptococcus thermophilus
      could be responsible for the observed ceramide increase. The application of a
      base cream containing sonicated Streptococcus thermophilus in the forearm skin of
      17 healthy volunteers for 7 d also led to a significant and relevant increase of
      skin ceramide amounts, which could be due to the sphingomyelin hydrolysis through
      bacterial neutral sphingomyelinase. Indeed, similar results were obtained with a
      base cream containing purified bacterial neutral sphingomyelinase. In addition,
      the inhibition of bacterial neutral sphingomyelinase activity through glutathione
      blocked the skin ceramide increase observed after the treatment. The topical
      application of a sonicated Streptococcus thermophilus preparation, leading to
      increased stratum corneum ceramide levels, could thus result in the improvement
      of lipid barrier and a more effective resistance against xerosis.

PMID- 10417627
TI  - Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus
      foliaceus Italian patients.
AB  - Pemphigus refers to a group of autoimmune blistering skin diseases, mainly
      identified as pemphigus vulgaris and pemphigus foliaceus, both characterized by
      the presence of autoantibodies against keratinocyte adhesion molecules, leading
      to loss of cell-cell adhesion with consequent blister formation. Pemphigus
      vulgaris is reported to be associated with human leukocyte antigen DR4 and/or DR6
      whereas no data are available on pemphigus foliaceus, except for the endemic
      Brazilian form (fogo selvagem), which is reported to be associated with DR1 and
      DR4. We here report human leukocyte antigen molecular typing on a total of 87
      patients, 61 with pemphigus vulgaris and 26 with pemphigus foliaceus, versus 128
      healthy matched controls. Generic typing showed an increase of DRB1*04 and
      DRB1*14 and a decrease of DRB1*07 in both pemphigus vulgaris and pemphigus
      foliaceus patients. Molecular subtyping of DR4+ and DR14+ subjects showed a
      highly significant association between the DRB1*1401 and both pemphigus vulgaris
      (p < 0.0001) and pemphigus foliaceus patients (p < 0.0001) together with a
      significant increase of the linked DQB1*0503 (pemphigus vulgaris p < 0.0001;
      pemphigus foliaceus p < 0.0001). Moreover, whereas the association between
      DRB1*0402 and pemphigus vulgaris (p < 0.0001) has been confirmed, no significant
      association between a specific allele of the DR4 group and pemphigus foliaceus,
      has been found. Therefore, at least in Italian patients, pemphigus vulgaris and
      pemphigus foliaceus share DRB1*1401 and DQB1*0503, as susceptible human leukocyte
      antigen alleles, whereas DRB1*0402 is only found associated with pemphigus
      vulgaris. The observation that both diseases, pemphigus vulgaris and pemphigus
      foliaceus, carry the same susceptible human leukocyte antigen alleles has been
      interpreted as a common genetic background predisposing to pemphigus as, like in
      other autoimmune disorders, it is not sufficient to explain the onset of the
      disease on the basis of the sole aforementioned alleles. Other linked genes
      and/or environmental factors should play a facilitating role in the outbreak of
      pemphigus, either pemphigus vulgaris or pemphigus foliaceus.

PMID- 10417628
TI  - FGF expression allows nevus cells to survive in three-dimensional collagen gel
      under conditions that induce apoptosis in normal human melanocytes.
AB  - Melanocytes, the pigment forming cells of the skin, form an almost
      nonproliferating cell population located to the lowermost part of the epidermis.
      Normally melanocytes are not found higher in the epidermis or in the dermis. Nevi
      consist of melanocytes with altered growth characteristics and localization. The
      common pigmented nevus, a benign skin lesion, develops when melanocytes
      proliferate in the dermo-epidermal junction or in the dermis. Here we report
      growth characteristics of in vitro cultured normal human melanocytes and dermal
      nevus-derived melanocytes. As previously reported, nevus cells have a moderate to
      high FGF-2 expression level. Here we demonstrate that dermal nevus cells are able
      to survive in three-dimensional type 1 collagen culture, while normal human
      melanocytes rapidly undergo apoptosis. Melanocytes also, however, survive in
      collagen cultures in the presence of exogenous FGF-2. The survival of nevus cells
      in collagen is suppressed by protamine, an inhibitor of FGF-mediated cell
      stimulation. The in vivo growth environment of dermal nevus cells consists
      largely of type I and type III collagens. The results suggest that FGF-2
      expression by nevus cells allows them to adapt to grow in the dermis. FGF-2
      obviously has importance as a melanocyte survival factor and probably also in the
      development of malignant melanoma.

PMID- 10417629
TI  - Autoantibodies in lichen planus pemphigoides react with a novel epitope within
      the C-terminal NC16A domain of BP180.
AB  - Lichen planus pemphigoides is an autoimmune subepidermal blistering disease. The
      finding of immunoglobulin G antibodies directed against the basement membrane
      zone differentiates it from bullous lichen planus. The aim of this study was to
      identify the target antigen of lichen planus pemphigoides autoantibodies. Sera
      from lichen planus pemphigoides patients (n = 4) stained the epidermal side of
      NaCl-split human skin in a pattern indistinguishable from that produced by
      bullous pemphigoid sera. In bullous pemphigoid, the autoimmune response is
      directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein.
      We previously demonstrated that bullous pemphigoid sera predominantly react with
      a set of four epitopes (MCW-0 through MCW-3) clustered within a 45 amino acid
      stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By
      immunoblotting and enzyme-linked immunosorbent assay, lichen planus pemphigoides
      sera were also strongly reactive with recombinant bullous pemphigoid 180 NC16A.
      The lichen planus pemphigoides epitopes were further mapped using a series of
      overlapping recombinant segments of the NC16A domain. All lichen planus
      pemphigoides sera reacted with amino acids 46-59 of domain NC16A, a protein
      segment that was previously shown to be unreactive with bullous pemphigoid sera.
      Two lichen planus pemphigoides sera, in addition, reacted with the immunodominant
      antigenic region associated with bullous pemphigoid. In conclusion, there are now
      five bullous diseases that are associated with an autoimmune response to BP180:
      bullous pemphigoid; pemphigoid/herpes gestationis; cicatricial pemphigoid; linear
      immunoglobulin A disease; and lichen planus pemphigoides. In addition, we have
      identified a novel epitope within the BP180 NC16A domain, designated MCW-4, that
      appears to be uniquely recognized by sera from patients with lichen planus
      pemphigoides.

PMID- 10417630
TI  - High prevalence of a variety of epidermodysplasia verruciformis-associated human
      papillomaviruses in psoriatic skin of patients treated or not treated with PUVA.
AB  - Epidermodysplasia verruciformis-associated human papillomaviruses and in
      particular human papillomavirus type 5 were recently shown to be highly prevalent
      in psoriatic skin. We have analyzed lesional skin from 54 psoriasis patients for
      infections with genital-specific and epidermodysplasia verruciformis-specific
      human papillomaviruses to define the spectrum of involved human papillomavirus
      types and to test if it is influenced by psoralen ultraviolet A therapy. Using
      polymerase chain reaction analysis we could detect human papillomavirus sequences
      in skin lesions of 83% of the tested patients. In contrast, human papillomavirus
      DNA was only demonstrated in 19% of skin samples from 42 dermatologically
      healthy, immunocompetent individuals. Sequence analysis of the polymerase chain
      reaction amplimers revealed 14 human papillomavirus types, all belonging to the
      epidermodysplasia verruciformis or epidermodysplasia verruciformis-related
      papillomaviruses. Only in one case we identified sequences related to those of
      genital viruses, which, however, represented a putatively new human
      papillomavirus type. The most prevalent human papillomavirus type in our patient
      series was human papillomavirus type 36, found in 62% of the patients positive
      for human papillomavirus-DNA, followed by human papillomavirus type 5 (38%) and
      human papillomavirus type 38 (24%). Multiple infections with two to five
      different human papillomavirus types could be detected in skin samples of 63% of
      the analyzed patients. The overall human papillomavirus detection rate did not
      differ significantly between patients which have been subjected to psoralen
      ultraviolet A photochemotherapy or solely treated with topical preparations (77
      vs 89%). Human papillomavirus type 5, however, could be detected significantly
      more frequent in lesions of psoralen ultraviolet A-treated patients (p < 0.001).
      Our data strongly argue for infections with epidermodysplasia verruciformis
      specific papillomaviruses being an almost consistent feature of the lesional
      psoriatic skin and substantiate the importance of further studies to elucidate a
      possible involvement of human papillomaviruses in psoriasis pathology.

PMID- 10417631
TI  - Control of cutaneous blood vessels in psoriatic plaques.
AB  - The aim of this study was to compare local blood flow in psoriatic plaques before
      and after provocations known to alter cutaneous vascular resistance, in order to
      determine whether plaque hyperemia is caused by a failure of normal vascular
      control mechanisms. Cutaneous blood flow was recorded using a laser Doppler
      flowmeter over plaque skin (plaque site) and clinically normal skin (nonplaque
      site) on the opposite arm, at least 5 cm away from the nearest plaque. It is
      important to note that most of the laser Doppler signal comes from the
      subpapillary plexus of the skin and only a small portion (2%-10%) is produced by
      capillary blood flow. In the psoriatic plaques the basal flux was between nine
      and 13 times greater than nonplaque skin. The biologic zero (a signal independent
      of perfusion, which also persists after complete proximal arterial occlusion) was
      also significantly greater at plaque sites compared with nonplaque sites.
      Sympathetic and local vasoconstriction in psoriatic skin was shown to be intact
      and responses to vasodilator tests were likewise intact, i.e., there was no
      failure of response to normal vascular control mechanisms, albeit some
      quantitative differences. Tests of vasodilatation indicated that, although basal
      flux is high in plaque compared with nonplaque skin, arterioles supplying plaque
      skin can dilate further, i.e., lesional arterioles are not normally maximally
      dilated but have a basal constrictor tone. Interestingly, the red cell flux at
      maximum dilatation in nonplaque skin is less than even the basal flux in plaque
      skin. This means that in plaque skin either there are more arterioles than in
      nonplaque skin, or there is chronic, structural widening of the existing
      arterioles in plaque skin.

PMID- 10417632
TI  - Antibodies to tissue transglutaminase as serologic markers in patients with
      dermatitis herpetiformis.
AB  - Dermatitis herpetiformis is a gluten-sensitive disease with a symmetrically
      distributed blistering over extensor surfaces. The association with celiac
      disease is further supported by the high rate of immunoglobulin A autoantibodies
      to endomysium in patients with dermatitis herpetiformis, which are highly
      specific and sensitive indicators of celiac disease. Therefore, we determined
      immunoglobulin A antibodies to tissue transglutaminase, the recently discovered
      endomysial autoantigen in celiac disease, in patients with dermatitis
      herpetiformis and controls. Sera of 61 patients with dermatitis herpetiformis, as
      characterized by granular immunoglobulin A deposits in the subepidermal basement
      membrane and known endomysial antibody titers (determined by indirect
      immunofluorescence) as well as 84 control sera of patients with dermal or
      intestinal diseases unrelated to dermatitis herpetiformis, were analyzed for
      circulating immunoglobulin A antibodies to tissue transglutaminase by enzyme
      linked immunosorbent assay. Immunoglobulin A anti-tissue transglutaminase titers
      in patients with dermatitis herpetiformis were significantly elevated above the
      controls. Furthermore, the immunoglobulin A anti-tTG titers showed a positive
      correlation with semiquantitative endomysial antibody data. Compared with
      endomysial antibodies, determination of immunoglobulin A anti-tissue
      transglutaminase reached a specificity and sensitivity of 97.6% and 89.1%.
      Patients with dermatitis herpetiformis have elevated immunoglobulin A
      autoantibodies to tissue transglutaminase, confirming its pathogenic relation
      with celiac disease and further supporting the usefulness of this novel assay for
      screening and therapy control.

PMID- 10417633
TI  - Cutaneous delayed-type hypersensitivity response is inhibited in transgenic mice
      with keratinocyte-specific CD44 expression defect.

PMID- 10417634
TI  - SCF-KIT pathway in human epidermal melanocyte homeostasis.

PMID- 10417636
TI  - Hot off the bench-late breaking abstracts society for investigative dermatology
      annual meeting may 5-9, 1999 

PMID- 10417635
TI  - IgG1 and IgG3 are the major immunoglobulin subclasses targeting epitopes within
      the NC16A domain of BP180 in pemphigoid gestationis.

PMID- 10417637
TI  - Displacement of cellular proteins by functional analogues from plasmids or
      viruses could explain puzzling phylogenies of many DNA informational proteins.
AB  - Comparative genomics has revealed many examples in which the same function is
      performed by unrelated or distantly related proteins in different cellular
      lineages. In some cases, this has been explained by the replacement of the
      original gene by a paralogue or non-homologue, a phenomenon known as non
      orthologous gene displacement. Such gene displacement probably occurred early on
      in the history of proteins involved in DNA replication, repair, recombination and
      transcription (DNA informational proteins), i.e. just after the divergence of
      archaea, bacteria and eukarya from the last universal cellular ancestor (LUCA).
      This would explain why many DNA informational proteins are not orthologues
      between the three domains of life. However, in many cases, the origin of the
      displacing genes is obscure, as they do not even have detectable homologues in
      another domain. I suggest here that the original cellular DNA informational
      proteins have often been replaced by proteins of viral or plasmid origin. As
      viral and plasmid-encoded proteins are usually very divergent from their cellular
      counterparts, this would explain the puzzling phylogenies and distribution of
      many DNA informational proteins between the three domains of life.

PMID- 10417638
TI  - Characterization of a single-strand origin, ssoU, required for broad host range
      replication of rolling-circle plasmids.
AB  - Single-stranded DNA (ssDNA) promoters are the key components of the single-strand
      origins (ssos) of replication of rolling-circle (RC) replicating plasmids. The
      recognition of this origin by the host RNA polymerase and the synthesis of a
      short primer RNA are critical for initiation of lagging-strand synthesis. This
      step is thought to be a limiting factor for the establishment of RC plasmids in a
      broad range of bacteria, because most of the ssos described are fully active only
      in their natural hosts. A special type of sso, the ssoU, is unique in the sense
      that it can be efficiently recognized in a number of different Gram-positive
      hosts. We have experimentally deduced the folded structure and characterized the
      ssDNA promoter present within the ssoU using P1 nuclease digestion and DNase I
      protection assays with the Bacillus subtilis and Staphylococcus aureus RNA
      polymerases. We have also identified the RNA products synthesized from this ssDNA
      promoter and mapped the initiation points of lagging-strand synthesis in vivo
      from ssoU-containing plasmids. Through gel mobility shift experiments, we have
      found that ssDNA containing the ssoU sequence can efficiently interact with the
      RNA polymerase from two different Gram-positive bacteria, S. aureus and B.
      subtilis. We have also realigned the narrow and broad host range sso sequences of
      RC plasmids, and found that they contain significant homology. Our data support
      the notion that the strength of the RNA polymerase-ssoU interaction may be the
      critical factor that confers the ability on the ssoU to be fully functional in a
      broad range of bacteria.

PMID- 10417640
TI  - Host-dependent requirement for specific DnaA boxes for plasmid RK2 replication.
AB  - The replication origin of the broad-host-range plasmid RK2, oriV, contains four
      DnaA boxes, which bind the DnaA protein isolated from Escherichia coli. Using a
      transformation assay, mutational analysis of these boxes showed a differential
      requirement for replication in different Gram-negative bacteria. DnaA boxes 3 and
      4 were required in E. coli and Pseudomonas putidabut not as strictly in
      Azotobacter vinelandii and not at all in P. aeruginosa. In vitro replication
      results using an extract prepared from E. coli demonstrated that the activity of
      origin derivatives containing mutations in boxes 3 or 4 or a deletion of all four
      DnaA boxes could be restored by the addition of increasing amounts of purified
      DnaA protein. High levels of DnaA protein in the presence of the TrfA protein
      also resulted in the stimulation of open complex formation and DnaB helicase
      loading on oriV, even in the absence of the four DnaA boxes. These observations
      at least raise the possibility that an alternative mechanism of initiation of
      oriV is being used in the absence of the four DnaA boxes and that this mechanism
      may be similar to that used in P. aeruginosa, which does not require these four
      DnaA boxes for replication.

PMID- 10417639
TI  - Mode of action of AraR, the key regulator of L-arabinose metabolism in Bacillus
      subtilis.
AB  - The AraR protein is a negative regulator involved in L-arabinose-inducible
      expression of the Bacillus subtilis araABDLMNPQ-abfA metabolic operon and of the
      araE/araR genes that are organized as a divergent transcriptional unit. The two
      ara gene clusters are found at different positions in the bacterial chromosome.
      AraR was overproduced in Escherichia coli and purified to more than 95%
      homogeneity. AraR binds specifically to DNA fragments carrying the promoter
      region of the ara genes. DNase I protection assays showed that AraR binds to two
      sequences within the promoters of the araABDLMNPQ-abfA operon and the araE gene,
      and to one sequence in the araR promoter. The AraR target sequences are
      palindromic and share high identity, defining a 16 bp AraR consensus operator
      sequence showing half-symmetry, ATTTGTAC. Binding of AraR to DNA was inhibited by
      L-arabinose but not by other sugars. The two operator sites within the
      araABDLMNPQ-abfA operon and araE promoters are located on the same side of the
      DNA helix, and a pattern of enhanced and diminished DNase I cleavage was observed
      between them, but not in the araR promoter. Quantitative DNase I footprinting in
      DNA templates containing one, two or three AraR binding sites showed that the
      repressor binds cooperatively to the two operator sites within the metabolic
      operon and araE promoters but not to the site located in the araR promoter. These
      results are consistent with two modes for AraR transcriptional repression that
      might correlate with different physiological requirements: a high level of
      repression is achieved by DNA bending requiring two in-phase operator sequences
      (metabolic operon and araE transport gene), whereas binding to a single operator,
      which autoregulates araR expression, is 10-fold less effective.

PMID- 10417641
TI  - The type IV bundle-forming pilus of enteropathogenic Escherichia coli undergoes
      dramatic alterations in structure associated with bacterial adherence,
      aggregation and dispersal.
AB  - BFP, a plasmid-encoded type IV bundle-forming pilus produced by enteropathogenic
      Escherichia coli (EPEC), has recently been shown to be associated with the
      aggregation of bacteria and dispersal of bacteria from bacterial microcolonies.
      In standard 3 h HEp-2 cell assays, EPEC adhere in localized microcolonies; after
      6 h, bacterial microcolonies are no longer present, indicating that bacterial
      aggregation and dispersal occurs in vitro during EPEC adhesion to cultured
      epithelial cells. To examine the role of BFP in EPEC aggregation and dispersal,
      we examined HEp-2 cell adhesion of strain E2348/69 and defined E2348/69 mutants
      by immunofluorescence and immunoelectron microscopy. BFP was expressed initially
      as approximately 40 nm diameter pilus bundles that promoted bacteria-bacteria
      interaction and microcolony formation. BFP subsequently underwent a striking
      alteration in structural organization with the formation of much longer and
      thicker ( approximately 100 nm diameter) pilus bundles, which frequently
      aggregated laterally to form even thicker bundles often arranged in a loose three
      dimensional network; EPEC dispersal from bacterial microcolonies was associated
      with this transformation of BFP from thin to thick bundles. Bacterial dispersal
      and transformation of BFP from thin to thick bundles did not occur with a bfpF
      mutant of strain E2348/69. It is concluded that BFP promotes both the formation
      and the dispersal of EPEC microcolonies, that the dispersal phase requires BfpF
      and that dispersal is associated with dramatic alterations in the structure of
      BFP bundles.

PMID- 10417642
TI  - The smcL gene of Listeria ivanovii encodes a sphingomyelinase C that mediates
      bacterial escape from the phagocytic vacuole.
AB  - The ruminant pathogen Listeria ivanovii differs from Listeria monocytogenes in
      that it causes strong, bizonal haemolysis and a characteristic shovel-shaped co
      operative haemolytic ('CAMP-like') reaction with Rhodococcus equi. We cloned the
      gene responsible for the differential haemolytic properties of L. ivanovii, smcL.
      It encodes a sphingomyelinase C (SMase) highly similar (> 50% identity) to the
      SMases from Staphylococcus aureus (beta-toxin), Bacillus cereus and Leptospira
      interrogans. smcL was transcribed monocistronically and was expressed
      independently of PrfA. Low-stringency Southern blots demonstrated that, within
      the genus Listeria, smcL was present only in L. ivanovii. We constructed an smcL
      knock-out mutant. Its phenotype on blood agar was identical to that of L.
      monocytogenes (i.e. weak haemolysis and no shovel-shaped CAMP-like reaction with
      R. equi ). This mutant was less virulent for mice, and its intracellular
      proliferation was impaired in the bovine epithelial-like cell line MDBK. The role
      of SmcL in intracellular survival was investigated using an L. monocytogenes
      mutant lacking the membrane-damaging determinants hly, plcA and plcB, being thus
      unable to grow intracellularly. Complementation of this mutant with smcL on a
      plasmid was sufficient to promote bacterial intracellular proliferation in MDBK
      cells. Transmission electron microscopy showed that SmcL mediates the disruption
      of the phagocytic vacuole and the release of bacteria into the cytosol.
      Therefore, L. ivanovii possesses a third phospholipase with membrane-damaging
      activity that, together with PlcA and PlcB, may act in concert with the pore
      forming toxin Hly to mediate efficient escape from the vacuolar compartment. The
      5' end of smcL is contiguous with the internalin locus i-inlFE, which is also
      specific to L. ivanovii and is required for full virulence in mice. Thus, smcL
      forms part of a novel virulence gene cluster in Listeria that is species
      specific.

PMID- 10417643
TI  - Helicobacter pylori cadA encodes an essential Cd(II)-Zn(II)-Co(II) resistance
      factor influencing urease activity.
AB  - Inactivation of Helicobacter pylori cadA, encoding a putative transition metal
      ATPase, was only possible in one of four natural competent H. pylori strains,
      designated 69A. All tested cadA mutants showed increased growth sensitivity to
      Cd(II) and Zn(II). In addition, some of them showed both reduced 63Ni
      accumulation during growth and no or impaired urease activity, which was not due
      to lack of urease enzyme subunits. Gene complementation experiments with plasmid
      (pY178)-derived H. pylori cadA failed to correct the deficiencies, whereas
      resistance to Cd(II) and Zn(II) was restored. Moreover, pY178 conferred increased
      Co(II) resistance to both the cadA mutants and the wild-type strain 69A.
      Heterologous expression of H. pylori cadA in an Escherichia coli zntA mutant
      resulted in an elevated resistance to Cd(II) and Zn(II). Expression of cadA in E.
      coli SE5000 harbouring H. pylori nixA, which encodes a divalent cation importer
      along with the H. pylori urease gene cluster, led to about a threefold increase
      in urease activity compared with E. coli control cells lacking the H. pylori cadA
      gene. These results suggest that H. pylori CadA is an essential resistance pump
      with ion specificity towards Cd(II), Zn(II) and Co(II). They also point to a
      possible role of H. pylori CadA in high-level activity of H. pylori urease, an
      enzyme sensitive to a variety of metal ions.

PMID- 10417644
TI  - The active site of the rolling circle replication protein Rep75 is involved in
      site-specific nuclease, ligase and nucleotidyl transferase activities.
AB  - The plasmid pGT5 from the hyperthermophilic archaeon Pyrococcus abyssi replicates
      via a rolling circle mechanism. The protein Rep75, encoded by this plasmid,
      exhibits a nicking-closing (NC) activity in vitro on single-stranded
      oligonucleotides containing the pGT5 double-stranded origin sequence. In
      addition, Rep75 catalyses a site-specific nucleotidyl terminal transferase (NTT)
      activity, e.g. it can transfer one AMP or dAMP (from ATP or dATP) to the 3'-OH of
      an oligonucleotide corresponding to the left part of the nicking site. The Rep75
      sequence contains a motif similar to the active-site motifs of Rep proteins from
      the PhiX174/pC194 superfamily. We show here that the tyrosine present in this
      motif is indeed essential for DNA cleavage by Rep75, but is dispensable for its
      NTT activity. However, a nearby arginine, which is not required for DNA cleavage,
      is involved in both NTT and closing, indicating that the same active site is
      involved in the NC and NTT activities of Rep75. For both NTT and NC, the G
      residue in 3' of the nicking site is essential, whereas the A residue in 5' is
      dispensable for NC, despite its conservation in RC plasmids of the PhiX174/pC194
      superfamily. The NTT and closing activities have an optimal temperature lower
      than the nicking activity. These data indicate that the three reactions catalysed
      by Rep75 can be uncoupled, although they share part of their mechanisms. Finally,
      we show that NC is inhibited by ATP or dATP at concentrations that promote NTT.
      We propose a model in which the NTT activity of Rep75 plays a role in the
      regulation of pGT5 replication in vivo.

PMID- 10417645
TI  - Interactions of HasA, a bacterial haemophore, with haemoglobin and with its outer
      membrane receptor HasR.
AB  - The major mechanism by which bacteria acquire free or haemoglobin-bound haem
      involves direct binding of haem to specific outer membrane receptors. Serratia
      marcescens and Pseudomonas aeruginosa have an alternative system, which involves
      an extracellular haemophore, HasA, that captures free or haemoglobin-bound haem
      and shuttles it to a specific cell surface outer membrane receptor, HasR. Both
      haem-free (apoprotein) and haem-loaded (holoprotein) HasA bind to HasR, evidence
      for direct protein-protein interactions between HasA and HasR. HasA binding to
      HasR takes place in a tonB mutant. TonB is thus required for a step subsequent to
      HasA binding.

PMID- 10417647
TI  - Molecular function of the dual-start motif in the lambda S holin.
AB  - The lambda S gene represents the prototype of holin genes with a dual-start
      motif, which leads to the synthesis of two polypeptides, S105 and S107. They
      differ at their N-terminus by only two amino acids, Met-1 and Lys-2, at the
      beginning of the longer product. Despite the minor difference, the two proteins
      have opposing functions in lysis, with protein S107 being an inhibitor and
      protein S105 being an effector of 'hole formation' in the inner membrane. Here,
      we have studied the molecular mechanism underlying the 'lysis clock' contributed
      by the dual-start motif. We have used protein fusions in which the secretory
      signal sequence of the M13 procoat protein VIII has been abutted to the N
      terminal Met residues of S105 and S107 respectively. S-dependent 'hole formation'
      required removal of the signal sequence in both fusion proteins, as both the VIII
      S105 and the VIII-S107 fusion proteins were non-functional when leader peptidase
      cleavage was inhibited. These results strongly supported the hypothesis that
      functional assembly of S proteins requires translocation of their N-terminus to
      the periplasm. Using signal sequence cleavage as a measure of translocation, we
      observed that the translocation kinetics of the N-terminus of the S107 moiety was
      reduced about threefold when compared with the N-terminus of the S105 moiety.
      Moreover, depolarization of the membrane resulted in an immediate cleavage of the
      signal sequence and 'hole formation' exerted by the S107 moiety of the VIII-S107
      fusion protein. A model is presented in which S107 with a reversed topology of
      its N-terminus interacts with S105 and poisons 'hole formation'. Upon
      depolarization of the membrane, translocation of the N-terminus of S107 to the
      periplasm results in the functional assembly of S proteins, i.e. 'hole
      formation'.

PMID- 10417648
TI  - PDZ domains determine the native oligomeric structure of the DegP (HtrA)
      protease.
AB  - DegP (HtrA) is a periplasmic heat shock serine protease of Escherichia coli that
      degrades misfolded proteins at high temperatures. Biochemical and biophysical
      experiments have indicated that the purified DegP exists as a hexamer. To examine
      whether the PDZ domains of DegP were required for oligomerization, we constructed
      a DegP variant lacking both PDZ domains. This truncated variant, DegPDelta,
      exhibited no proteolytic activity but exerted a dominant-negative effect on
      growth at high temperatures by interfering with the functional assembly of
      oligomeric DegP. Thus, the PDZ domains contain information necessary for proper
      assembly of the functional hexameric structure of DegP.

PMID- 10417646
TI  - Entamoeba histolytica : a novel cysteine protease and an adhesin form the 112 kDa
      surface protein.
AB  - Here, we present evidence that a cysteine protease (EhCP112) and a protein with
      an adherence domain (EhADH112) form the Entamoeba histolytica 112 kDa adhesin.
      Immunoelectron microscopy and immunofluorescence assays using monoclonal
      antibodies (mAbAdh) revealed that, during phagocytosis, the adhesin is
      translocated from the plasma membrane to phagocytic vacuoles. mAbAdh inhibited
      54% adherence, 41% phagocytosis, and 35% and 62% destruction of MDCK cell
      monolayers by live trophozoites and their extracts respectively. We cloned a 3587
      bp DNA fragment (Eh112 ) with two open reading frames (ORFs) separated by a 188
      bp non-coding region. The ORF at the 5' end (Ehcp112 ) encodes a protein with a
      cysteine protease active site, a transmembranal segment and an RGD motif. The
      second ORF (Ehadh112 ) encodes a protein recognized by mAbAdh with three putative
      transmembranal segments and four glycosylation sites. Northern blot, primer
      extension and Southern blot experiments revealed that Ehcp112 and Ehadh112 are
      two adjacent genes in DNA. Ehcp112 and Ehadh112 genes were expressed in bacteria.
      The recombinant peptides presented protease activity and inhibited adherence and
      phagocytosis, respectively, and both were recognized by mAbAdh. The EhCP112 and
      EhADH112 peptides could be joined by covalent or strong electrostatic forces,
      which are not broken during phagocytosis.

PMID- 10417649
TI  - Na+ translocation by the NADH:ubiquinone oxidoreductase (complex I) from
      Klebsiella pneumoniae.
AB  - Complex I is the site for electrons entering the respiratory chain and therefore
      of prime importance for the conservation of cell energy. It is generally accepted
      that the complex I-catalysed oxidation of NADH by ubiquinone is coupled
      specifically to proton translocation across the membrane. In variance to this
      view, we show here that complex I of Klebsiella pneumoniae operates as a primary
      Na+ pump. Membranes from Klebsiella pneumoniae catalysed Na+-stimulated electron
      transfer from NADH or deaminoNADH to ubiquinone-1 (0.1-0.2 micromol min-1 mg-1).
      Upon NADH or deaminoNADH oxidation, Na+ ions were transported into the lumen of
      inverted membrane vesicles. Rate and extent of Na+ transport were significantly
      enhanced by the uncoupler carbonylcyanide-m-chlorophenylhydrazone (CCCP) to
      values of approximately 0.2 micromol min-1 mg-1 protein. This characterizes the
      responsible enzyme as a primary Na+ pump. The uptake of sodium ions was severely
      inhibited by the complex I-specific inhibitor rotenone with deaminoNADH or NADH
      as substrate. N-terminal amino acid sequence analyses of the partially purified
      Na+-stimulated NADH:ubiquinone oxidoreductase from K. pneumoniae revealed that
      two polypeptides were highly similar to the NuoF and NuoG subunits from the H+
      translocating NADH:ubiquinone oxidoreductases from enterobacteria.

PMID- 10417650
TI  - Structural and transcriptional analysis of the pyrABCN, pyrD and pyrF genes in
      Aspergillus nidulans and the evolutionary origin of fungal dihydroorotases.
AB  - The six biochemical steps of the de novo pyrimidine biosynthesis pathway are
      conserved in all known organisms. However, in animals and fungi, unlike
      prokaryotes, at least the first two activities are grouped on a multifunctional
      enzyme. Here, we report cloning, mapping and transcriptional characterization of
      some pyrimidine biosynthesis genes in the filamentous fungus Aspergillus
      nidulans. The first two steps of the pathway are performed by a multifunctional
      enzyme comprising the activities of carbamoyl phosphate synthetase (CPSase) and
      aspartate transcarbamylase (ATCase). This polypeptide is encoded by a 7 kbp
      cluster gene, pyrABCN, which has a high degree of nucleotide identity with the
      Ura2 gene in Saccharomyces cerevisiae. The enzyme of the third step,
      dihydroorotase (DHOase), is encoded by a separate locus, pyrD. However, the
      pyrABCN gene apparently contains an evolutionary remnant of a DHOase-encoding
      sequence, similarly to the Ura2 gene of Saccharomyces cerevisiae. The pyrABCN
      gene is transcribed as a single 7 kb mRNA species. The level of transcripts of
      pyrABCN, pyrD and, to a lesser degree, pyrF genes responds to the presence of
      exogenous pyrimidines and to the conditions of pyrimidine starvation.
      Derepression of pyrABCN and pyrD under pyrimidine starvation is noticeably
      enhanced in pyrE mutants that accumulate dihydroorotic acid. The pyrABCN gene
      maps to the distal portion of the right arm of the chromosome VIII, whereas the
      pyrD gene, in contrast to early genetic data, is closely linked to the brlA gene
      and located to the right of it. Our data on mitotic recombination should help to
      verify the genetic map of the chromosome VIII. Comparison of amino acid sequences
      of active dihydroorotases with related enzymes and with their non-functional
      homologues in yeast and Aspergillus indicates that the active dihydroorotases
      from fungi are more similar to ureases and enzymes of the pyrimidine degradation
      pathway. The 'silent' dihydroorotase domains of the multifunctional enzymes from
      fungi and active DHOase domains of the multifunctional enzymes in higher
      eukaryotes are more closely related to bacterial dehydroorotases.

PMID- 10417651
TI  - Multiple insertions of fimbrial operons correlate with the evolution of
      Salmonella serovars responsible for human disease.
AB  - On centisome 7, Salmonella spp. contain a large region not present in the
      corresponding region of Escherichia coli. This region is flanked by sequences
      with significant homology to the E. coli tRNA gene aspV and the hypothetical E.
      coli open reading frame yafV. The locus consists of a mosaic of differentially
      acquired inserts forming a dynamic cs7 region of horizontally transferred
      inserts. Salmonella enterica subspecies I, responsible for most Salmonella
      infections in warm-blooded animals, carries a fimbrial gene cluster (saf) in this
      region as well as a regulatory gene (sinR). These genes are flanked by inverted
      repeats and are inserted in another laterally transferred region present in most
      members of Salmonella spp. encoding a putative invasin (pagN ). S. enterica
      subspecies I serovar Typhi, the Salmonella serovar that causes the most severe
      form of human salmonellosis, contains an additional insert of at least 8 kb in
      the sinR-pagN intergenic region harbouring a novel fimbrial operon (tcf ) similar
      to the coo operon encoding the CS1 fimbrial adhesin expressed by human-specific
      enterotoxigenic E. coli. It is suggested that the multiple insertions of fimbrial
      genes that have occurred in the cs7 region have contributed to phylogenetic
      diversity and host adaptation of Salmonella spp.

PMID- 10417652
TI  - An RGS protein regulates the pheromone response in the fission yeast
      Schizosaccharomyces pombe.
AB  - The rate and extent of a cell's response to an extracellular stimulus is
      influenced by regulators that act on the intracellular signalling machinery.
      Although not directly involved in propagating the intracellular signal,
      regulators control the activity of the proteins that transmit the signals. To
      understand this aspect of cell signalling, we have studied the pheromone response
      pathway in the fission yeast Schizosaccharomyces pombe, a relatively simple
      signalling system in a genetically tractable organism. We demonstrate this
      approach by investigating the role of Rgs1, a member of the Regulator of G
      protein Signalling (RGS) family of proteins. The rgs1 gene was identified through
      the Sz. pombe genome sequencing project (accession number Q09777) and recognized
      as having similarity to RGS proteins [Tesmer et al. (1997) Cell 89: 251-261], but
      this is the first report concerning the activity of the protein. Strains lacking
      rgs1 (Deltargs1) are hypersensitive to pheromone stimulation and unable to
      conjugate with a mating partner. Inhibition of mating occurs at a relative late
      stage in the process as Deltargs1 strains exhibit pheromone-dependent
      transcription and form shmoos. Expression of SST2 (an RGS protein that regulates
      pheromone signalling in the budding yeast Saccharomyces cerevisiae) overcomes the
      hypersensitivity of the Deltargs1 strains but fails to rescue their mating
      defect.

PMID- 10417653
TI  - The opcA and (psi)opcB regions in Neisseria: genes, pseudogenes, deletions,
      insertion elements and DNA islands.
AB  - Previous data have indicated that the opc gene encoding an immunogenic invasin is
      specific to Neisseria meningitidis (Nm) and is lacking in Neisseria gonorrhoeae
      (Ng). The data presented here show that Nm and Ng both contain two paralogous opc
      like genes, opcA, corresponding to the former opc gene, and (psi)opcB, a
      pseudogene. The predicted OpcA and OpcB proteins possess transmembrane regions
      with conserved non-polar faces but differ extensively in four of the five surface
      exposed loops. Gonococcal OpcA was expressed weakly under in vitro conditions,
      and it is unknown whether these bacteria can express this protein at high levels.
      Analysis of the sequences flanking opcA and (psi)opcB revealed a framework of
      conserved housekeeping genes interspersed with DNA islands. These regions also
      contained several pseudogenes, deletions and IS elements, attesting to
      considerable genome plasticity. Both opcA and (psi)opcB are located on DNA
      islands that have probably been imported from unrelated bacteria. A third island
      encodes the dcmD/dcrD R/M genes in Ng versus a small open reading frame in most
      strains of Nm. Rare strains of Nm were identified in which the R/M island has
      been imported. DNA islands in Nm and Ng seem to have been acquired by
      recombination via conserved flanking housekeeping genes rather than by insertion
      of mobile genetic elements.

PMID- 10417654
TI  - Induction of the mtrCDE-encoded efflux pump system of Neisseria gonorrhoeae
      requires MtrA, an AraC-like protein.
AB  - The mtr (multiple transferable resistance) gene complex in Neisseria gonorrhoeae
      encodes an energy-dependent efflux pump composed of the MtrC-MtrD-MtrE cell
      envelope proteins that serves to export structurally diverse antimicrobial,
      hydrophobic agents (HAs). Many of these agents have membrane-acting detergent
      activity. Using Triton X-100 (TX-100) as a representative HA, we found that the
      mtrCDE efflux pump operon could be induced to higher levels of expression when an
      HA-sensitive strain was exposed to sublethal concentrations of this non-ionic
      detergent and the structurally related spermicide, nonoxynol-9. This induction
      was at the level of mtrCDE gene transcription and was independent of the MtrR
      repressor, which normally decreases mtrCDE gene expression. However, the enhanced
      resistance of gonococci to TX-100 was dependent on the expression of a previously
      undescribed gonococcal protein that belonged to the AraC/XylS family of
      transcriptional activators. We have termed this protein MtrA to signify its
      likely role in the activation of mtrCDE gene expression. Taken together with
      previous studies dealing with the genetic control of mtrCDE gene expression, we
      propose that gonococci can modulate their resistance to HAs through both positive
      and negative transcriptional control processes. The action of these regulatory
      processes is probably of importance in determining the survival capacity of
      gonococci at mucosal surfaces that contain detergent-like HAs.

PMID- 10417656
TI  - A regulatory system hitherto found only in gram-positive bacteria in a gram
      negative bacterium that grows only in co-culture with a Bacillus strain.

PMID- 10417655
TI  - The channel-forming toxin aerolysin neutralizes human immunodeficiency virus type
      1.
AB  - Aerolysin is a channel-forming toxin secreted by Aeromonas spp. that binds to
      glycosyl phosphatidylinositol (GPI)-anchored proteins, such as Thy-1, on
      sensitive target cells. Receptor binding is followed first by oligomerization of
      the toxin and then by insertion of the oligomers into the membrane to form stable
      channels that disrupt the permeability barrier. Human immunodeficiency virus type
      1 (HIV-1) produced from T cells is known to incorporate Thy-1 and other GPI
      anchored proteins into its membrane. Here, we show that aerolysin is capable of
      neutralizing HIV-1 in a dose-dependent manner and that neutralization depends
      upon the presence of these proteins in the viral envelope. Pretreatment with
      phosphatidylinositol-specific phospholipase C to remove GPI-anchored proteins
      greatly reduced HIV-1 sensitivity to the toxin, and virus originating from a
      mutant cell line that lacks GPI-anchored proteins was not neutralized. Aerolysin
      variants with single amino acid changes that prevent oligomerization or insertion
      of the toxin were unable to inactivate the virus, implying that channel formation
      is necessary for neutralization to occur. These findings represent the first
      evidence that a pathogenic human virus can be neutralized by a bacterial toxin.

PMID- 10417657
TI  - Possible origin of the Legionella pneumophila virulence genes and their relation
      to Coxiella burnetii.

PMID- 10417658
TI  - Is FatP a long-chain fatty acid transporter?

PMID- 10417659
TI  - REVIEW: tau protein pathology in Alzheimer's disease and related disorders.
AB  - Abundant neurofibrillary lesions made of hyperphosphorylated microtubule
      associated protein tau constitute one of the defining neuropathological features
      of Alzheimer's disease. However, tau containing filamentous inclusions in
      neurones and/or glial cells also define a number of other neurodegenerative
      disorders clinically characterized by dementia and/or motor syndromes. All these
      disorders, therefore, are grouped under the generic term of tauopathies. In the
      first part of this review we outline the morphological and biochemical features
      of some major tauopathies, e. g. Alzheimer's disease, argyrophilic grain disease,
      Pick's disease, progressive supranuclear palsy and corticobasal degeneration. The
      impact of the recent finding of tau gene mutations in familial frontotemporal
      dementia and parkinsonism linked to chromosome 17 on other tauopathies is
      discussed in the second part. The review closes with a look towards a new
      understanding of neurodegenerative disorders characterized by filamentous nerve
      cell inclusions. The recent identification of the major protein component of
      their respective inclusions led to a surprising convergence of seemingly
      unrelated disorders. The new findings now allow us to classify neurodegenerative
      disorders with filamentous nerve cell inclusions into four main categories: (i)
      the tauopathies; (ii) the alpha-synucleinopathies; (iii) the polyglutamine
      disorders; and (iv) the iquitin disorders'. Within the proposed classification
      scheme, tauopathies constitute the most frequent type of disorder.

PMID- 10417660
TI  - Immunohistochemical expression of trk receptor proteins in focal cortical
      dysplasia with intractable epilepsy.
AB  - Focal cortical dysplasia (FCD), which is often associated with intractable
      epilepsy, is a form of abnormal structure of the cerebral cortex caused by a
      disorder of normal neocortical development. In such cerebral lesions obtained
      from four patients (two male, two female; average age 32.3 years at operation),
      the immunohistochemical expression of Trk receptors, which interact with
      neurotrophins and result in both growth and maturational changes in neuronal
      cells, was investigated in relation to the possible histogenesis of these
      lesions. In all cases, a derangement of the cortical laminar structure,
      dysplastic cytomegalic neurones, and large round balloon cells were the
      characteristic histological features. Immunohistochemically, the TrkA expression
      was localized in large dysplastic cytomegalic neurones, and TrkB expression was
      observed in large dysplastic and relatively small neuronal cells within the
      affected cortex. Although the exact roles of neurotrophins and their receptors in
      the pathogenesis of FCD remain uncertain, its development might be governed by
      such neurotrophic influences, and thus possibly prevent the death of abnormal
      neuronal cells. In addition, Trk receptors in FCDs may also play a role in
      establishing in the intrinsic epileptogenicity of FCDs.

PMID- 10417661
TI  - Inflammatory response and retinal ganglion cell degeneration following
      intraocular injection of ME7.
AB  - Scrapie is a prion disease which occurs naturally in sheep and which can be
      transmitted experimentally to rodents. After intracerebral injection of ME7 into
      mouse, an atypical inflammatory response, characterized by T-lymphocytes and
      activated microglia is present early in the course of the disease. In the present
      work, we have investigated the relationship between this inflammatory response,
      astrocytosis and neuronal loss along the visual pathway after intraocular
      injection (intraocular) of ME7 in C57BL/6J mice. We have demonstrated that
      microglia activation and T-lymphocyte recruitment accompanies the spread of prion
      pathology along the visual pathway and in the early stages of the disease is
      restricted to the subcortical visual pathway. Inflammation was also present in
      non-visual areas in association with PrPsc deposition at late stages of the
      disease, possibily indicating that diffusion of the scrapie agent also
      contributes to the spread of the disease. After intraocular injection of the
      prion agent, the disease is believed to be transported into the brain via axons
      of retinal ganglion cells (RGCs). Despite the high levels of infectivity reported
      to be present in the retina early in the disease after intraocular injection of
      ME7, retinal pathology has not been extensively investigated. We have studied the
      RGCs response in whole mount retinas after intraocular injection of ME7. We have
      shown that RGCs degenerate after intraocular injection of ME7 whereas amacrine
      cells, retinal interneurones, are more resistant. Our results suggest that two
      distinct population of neurones, exposed in vivo at the same time to the same
      agent scrapie strain, show different susceptibility to the toxic effects of
      PrPsc.

PMID- 10417662
TI  - Tenascin-R and C in multiple sclerosis lesions: relevance to extracellular matrix
      remodelling.
AB  - In the present study the distribution of the inhibitory extracellular molecules
      tenascin-R (TN-R) and tenascin- C (TN-C) was examined by immunocytochemistry
      during evolution of the multiple sclerosis (MS) lesion, in which astrogliosis is
      a prominent feature. Sections were cut from five control cases and from 22 blocks
      containing lesions representing different pathological stages in 18 cases of
      secondary progressive MS. Widespread expression of TN-R was found in the normal
      human central nervous system (CNS), while that of TN-C was in general restricted
      to white matter. In acute MS plaques however, there was a similar striking loss
      of both TN-R and TN-C up to the edge of the lesion, where the macrophage density
      is greatest, extending into the apparently normal white matter. In subacute
      lesions a TN-C and/or TN-R-immunopositive reactive astrocyte subpopulation was
      prominent, reflecting synthesis of extracellular matrix molecules. Both tenascins
      were expressed throughout chronic MS plaques at levels similar to those seen in
      adjacent white matter. The loss of TN-R and TN-C in acute plaques is indicative
      of enzyme-mediated breakdown of the matrix which may be a marker of blood-brain
      barrier breakdown and leucocyte extravasation. Subsequent production of tenascins
      by reactive astrocytes may result in glial scar formation impeding remyelination
      and axonal repair in MS lesions.

PMID- 10417664
TI  - The expression of myelin protein mRNAs during remyelination of lysolecithin
      induced demyelination.
AB  - To gain insights into the mechanisms of myelin repair in the CNS and to establish
      the extent to which this process resembles myelination in development we have
      examined the patterns of expression of transcripts of the major myelin proteins,
      myelin basic protein (MBP) and proteolipid protein (PLP) during remyelination of
      lysolecithin-induced demyelination in the adult rat spinal cord. Injection of 1
      microliter 1% lysolecithin into the dorsal funiculus caused a dramatic decrease
      in levels of MBP exon 1 and MBP exon 2-containing transcripts and PLP/DM20
      transcripts. Between 10 and 21 days post-lesion induction there was a gradual
      increase in levels of expression of all transcripts, which had returned to levels
      associated with normally myelinated spinal cord white matter at 21 days. These
      increases in levels of expression corresponded to the appearance of remyelinated
      axons, detected on toluidine blue-stained resin sections. Foci of high levels of
      expression occurred in regions of the lesion in which new myelin sheath formation
      was occurring, although the level of expression throughout the lesion never
      exceeded levels associated with myelin sheath maintenance in normal white matter
      due to the asynchronous pattern of remyelination. The changes in levels of
      expression of MBP exon 2 closely followed those of MBP exon 1. Our results
      indicate that (i) myelin protein gene expression associated with myelinogenesis
      during remyelination follows a similar pattern to that of myelinogenesis during
      development and that (ii) in rat models of demyelination changes of expression of
      MBP exon 1 and exon 2-containing transcripts are of equal value, an observation
      relevant to quantifying the effects of putative remyelination-enhancing
      strategies using the lysolecithin model.

PMID- 10417663
TI  - Insulin-like growth factors and binding proteins in multiple sclerosis plaques.
AB  - Insulin-like growth factors (IGFs) play an important role in development and
      myelination in the central nervous system (CNS) as well as in the proliferation
      and differentiation of cells of the immune system. To assess the influence of
      this growth factor family on demyelination and repair in multiple sclerosis (MS),
      the expression of IGF-I, IGF-II, insulin, IGF binding proteins (IGFBP) 1-3 and
      IGF-I receptor (IGF-IR) in CNS tissue from MS and normal control cases was
      studied by immunocytochemistry. In active MS lesions, the expression of IGF-I,
      insulin and IGFBP1 was detected in hypertrophic astrocytes while that of IGF-II
      and IGFBP2 and 3 was confined to foamy macrophages within lesions and activated
      microglia in adjacent white matter. IGF-IR, the major IGF receptor, was
      immunolocalized in macrophages and an astrocyte subpopulation in plaques.
      Oligodendrocytes in normal-appearing white matter expressed only IGFBP1, not IGFs
      or IGF-IR. As the remyelinating capacity of oligodendrocytes could be impaired
      owing to the absence of IGF-IR, the prevailing role of IGFs in inflammatory
      demyelination may be to promote phagocytosis of myelin and astrogliosis.

PMID- 10417665
TI  - Cell death mechanisms in the olfactory bulb of rats infected intranasally with
      Semliki forest virus.
AB  - Semliki Forest virus (SFV) infection of mice is used as a model to study
      pathogenic processes occurring in viral encephalitis. It has previously been
      shown that avirulent strains of SFV differ from virulent strains in showing
      restricted multiplication in neurones and in producing localized rather than
      widespread lesions in the central nervous system (CNS). Restricted neuronal
      damage is age-dependent and does not occur in neonatal animals. In this study,
      cell death mechanisms occurring in the CNS of adult rats infected intranasally
      (i.n.) with a virulent (SFV4) and an avirulent (A7) strain of SFV have been
      investigated. Although i.n. infection of rats was less efficient than that of
      mice, SFV4 reached a higher titre in the CNS of infected animals than A7.
      Neuronal destruction and leucocytic infiltration occurred throughout the
      forebrain of SFV4-infected rats. A7-infected rats remained clinically normal
      although degenerate neurons and inflammatory changes were present primarily in
      the olfactory system. Following infection with either A7-SFV or SFV4, TUNEL
      positive nuclei were seen in areas of leucocytic infiltration and among the
      poorly differentiated cells of the rostral migratory stream. Migrating cells had
      condensed nuclear chromatin, compacted cytoplasm and intact cellular membranes,
      characteristic of apoptosis, and were sparsely immunolabelled for viral antigen.
      In SFV4-infected rats, large numbers of contiguous neurones in forebrain areas
      exhibited cytoplasmic eosinophilia and karyolysis and were surrounded by
      phagocytic cells. Such neurones contained dense intracytoplasmic deposits of
      viral antigen and showed weak cytoplasmic TUNEL staining; electron microscopy
      showed membrane disruption, organelle disintegration, irregular chromatin
      condensation and cytoplasmic aggregation of virus particles. Bcl-2 staining was
      similar in infected and control rats and was most intense in randomly distributed
      Purkinje cells in the cerebellum; neurons in the olfactory bulbs were unstained.
      These findings indicate that during SFV encephalitis, infiltrating leucocytes and
      neural precursor cells undergo apoptosis whilst productively infected neurons
      undergo necrosis.

PMID- 10417667
TI  - Serological responses of Gambian children to immunization with the malaria
      vaccine SPf66.
AB  - Antibody responses to the malaria vaccine SPf66 and to its constituent peptides
      were measured over a period of 2 years in Gambian children who had been immunized
      with SPf66 or with a control vaccine (inactivated polio vaccine). Three hundred
      and six of 308 children (99%) who had received three doses of SPf66 vaccine had
      antibodies to SPf66 at a level above that found in European controls who had not
      been exposed to malaria. Responses to the constituent peptides derived from 35.1,
      55.1 and 83.1-kDa proteins were found in 88%, 97% and 97% of children,
      respectively; 26% had an antibody response to the NANP repeat peptide of
      circumsporozoite protein which is also included in the SPf66 vaccine. A response
      to SPf66 was found in 22% of children who had received the control vaccine.
      Antibody responses to NANP, 35.1, 55.1 and 83.1-kDa peptide were found in 3%,
      33%, 49% and 33% of these children. Overall, no significant correlation was found
      between the level of anti-SPf66 antibody at the beginning of the malaria
      transmission season following vaccination and the subsequent risk of malaria.
      However, further analysis showed that among the control children who had acquired
      antibodies to SPf66 as a result of natural exposure to malaria, those with high
      levels of anti-SPf66 were less at risk of malaria, perhaps reflecting their
      greater previous exposure and thus immunity. In contrast, among children who had
      received three doses of SPf66, those with high antibody levels were at greater
      risk of have malaria during the subsequent malaria transmission season.

PMID- 10417666
TI  - Calcium homeostasis and ultrastructural studies in a patient with limb girdle
      muscular dystrophy type 2C.
AB  - There is increasing evidence that gamma-sarcoglycan is absent and other
      sarcoglycans are reduced in patients with the limb-girdle muscular dystrophy type
      2C (LGMD2C) form of severe childhood autosomal recessive muscular dystrophy. In
      the present investigation, we combined microspectrofluorimetry and electron
      microscopy techniques to investigate the physiological function and the
      ultrastructure of control and LGMD2C myotubes. Results obtained from Ca2+
      measurements showed that the resting level of the cytosolic free calcium ([Ca2+
      ]i ) in control myotubes was 73+/-3.4 nmol/l (mean+/-se, n=35) and in LGMD2C
      myotubes was 69+/-4 nmol/l (n=44). Carbachol (CCh, 10 micromol/l ) induced a
      335+/-10 nmol/l (n=8) rise in [Ca2+ ]i in control myotubes and 531.9+/-32 nmol/l
      (n=23) in LGMD2C myotubes. Similarly, elevations of [Ca2+ ]i by 35 mmol/l K+ were
      324+/-32 nmol/l (n=8) in control myotubes and 442.8+/-24 nmol/l (n=22) in LGMD2C
      myotubes. Caffeine (10 mmol/l) activated similar [Ca2+]i peaks in control and
      LGMD2C myotubes but induced a biphasic response in LGMD2C in four out of 12
      myotubes and only a monophasic response in control myotubes. The ultrastructural
      results showed that the plasma membrane was abnormally indented and convoluted in
      both the LGMD2C biopsy and the LGMD2C cultured myotubes. It is suggested that the
      reduction in components of the dystrophin-glycoprotein complex results in the
      instability and an increase in the surface area of the plasma membrane, which may
      result in a higher population of Ca2+ channels in the LGMD2C myotubes.

PMID- 10417668
TI  - Egg-hatching inhibition in mice immunized with recombinant Schistosoma bovis 28
      kDa glutathione S-transferase.
AB  - The capacity of a recombinant glutathione S-transferase from Schistosoma bovis
      (rSb 28GST) to protect BALB/c mice against homologous and heterologous infections
      with, respectively, S. bovis or Schistosoma mansoni has been studied. Two
      injections of the rSb 28GST and an intravenous boost resulted in a marked
      specific IgG response on the day of experimental challenge with S. bovis or S.
      mansoni cercariae. Immunization of BALB/c mice led to a reduction in egg
      maturation and egg viability after infection with S. bovis or S. mansoni. Adult
      worm recoveries after an S. bovis challenge infection and tissue egg densities
      (intestine and liver) in S. mansoni challenge infection were also reduced in the
      immunized groups, but these differences were not statistically significant. No
      association between in vitro inhibition of GST enzymatic activity induced by
      immunized mouse sera and worm burden reduction was recorded. The analysis of the
      immune response, on the day of perfusion, showed the production of immunoglobulin
      (Ig)G1, IgG2a and IgG2b specific antibodies and the production of interleukin
      (IL)-4 and IL-5 by spleen cells after rSb 28GST stimulation. These data suggest
      that rSb 28GST immunization induces a moderate effect upon egg maturation and egg
      hatching, suggesting the involvement of similar mechanisms of action and common,
      but not exclusive, targets during S. bovis and S. mansoni infections. As a
      consequence, immunization with rSb 28GST may prove useful in affecting the
      pathology and transmission of African schistosomes.

PMID- 10417669
TI  - Salivary gland extract from Ixodes ricinus ticks inhibits production of
      interferon-gamma by the upregulation of interleukin-10.
AB  - Tick saliva has been shown to modulate host immunity by a so far unknown
      mechanism. We have demonstrated an inverted effect of salivary gland extract
      (SGE), derived from partially fed Ixodes ricinus females, on the production of
      two cytokines, interferon (IFN)-gamma and interleukin (IL)-10, in vitro. While
      SGE markedly suppressed the elaboration of IFN-gamma by mouse splenocytes
      stimulated with lipopolysaccharide (LPS), the production of IL-10 was increased
      in comparison with SGE-untreated cultures. The suppressive effect of SGE could be
      abolished by the addition of an IL-10 neutralizing monoclonal antibody to
      splenocyte cultures. Similar results were obtained when live Borrelia afzelii
      spirochetes, which are transmitted in Europe by I. ricinus ticks, were used for
      the cytokine induction. These results suggest that tick saliva can upregulate the
      IL-10 production at the tick feeding site, which consecutively inhibits the
      elaboration of pro-inflammatory cytokines, for example IFN-gamma. This
      immunosuppression may facilitate the establishment of tick-transmitted pathogens
      in the host.

PMID- 10417670
TI  - Humoral responses in mice following vaccination with DNA encoding glutathione S
      transferase of Fasciola hepatica: effects of mode of vaccination and the cellular
      compartment of antigen expression.
AB  - The humoral responses in mice following vaccination with DNA constructs encoding
      Fasciola hepatica glutathione S-transferase (GST) have been evaluated. GST47 cDNA
      was subcloned into two DNA vaccine vectors, VR1012 and VR1020, which direct
      expression to the cytoplasmic and extracellular compartments, respectively.
      Expression was confirmed by transfection into COS 7 cells. Groups of mice were
      vaccinated with these constructs, by either intramuscular injection with the
      VR1012-or VR1020-based constructs, or intradermal vaccination (with a gene gun)
      with the VR1020-based construct. Vaccination with the construct designed for
      secretion resulted in an increased humoral response compared to vaccination with
      the nonsecretory construct. The level of the total humoral response after
      vaccination with the secretion construct was not dependent on the route of
      vaccination. However, the isotype profile of the response differed between the
      groups; intramuscular vaccination with the construct directing cytoplasmic
      expression yielded an immuoglobulin (Ig)G2a dominant (Th1-type) response,
      intradermal vaccination with the secretory construct a IgG1/IgE dominant (Th2
      type) response, and intramuscular vaccination with the secretory construct a
      mixed isotype response. These results demonstrate that the immunogenicity of a
      DNA vaccine based on Fasciola GST, as well as the isotype of the response against
      GST, is determined by the mode of vaccine administration.

PMID- 10417671
TI  - TNF-alpha, nitric oxide and IFN-gamma are all critical for development of
      necrosis in the small intestine and early mortality in genetically susceptible
      mice infected perorally with Toxoplasma gondii.
AB  - We previously reported that genetic susceptibility of mice to peroral infection
      with T. gondii is associated with CD4+ T cell-dependent, interferon (IFN)-gamma
      mediated necrosis of their small intestine. We examined the role of tumour
      necrosis factor (TNF)-alpha and nitric oxide (NO), in addition to IFN-gamma. At 7
      days after infection, a marked increase in CD4+ T cells was observed in lamina
      propria mononuclear cells (LPC) of the small intestine as compared with normal
      mice, and significantly greater amounts of mRNA for IFN-gamma, TNF-alpha, and
      inducible NO synthase (iNOS) were detected in LPC of the small intestine of
      infected than uninfected animals. Treatment of infected mice with anti-TNF-alpha
      monoclonal antibody (mAb) or the iNOS inhibitor, aminoguanidine, prevented
      necrosis and prolonged time to death. Infected iNOS-targeted mutant mice did not
      develop the disease whereas infected, control mice did. Treatment with anti-TNF
      alpha mAb did not affect the expression of IFN-gamma in the LPC but inhibited
      expression of iNOS in the infected mice, indicating the role of TNF-alpha in the
      induction of iNOS. These results suggest that NO induced by a combination of IFN
      gamma and TNF-alpha through activation of iNOS is a critical mediator of
      intestinal pathology and contributes to early mortality in genetically
      susceptible mice.

PMID- 10417672
TI  - Genetic immunization of mice with DNA encoding the 23 kDa transmembrane surface
      protein of Schistosoma japonicum (Sj23) induces antigen-specific immunoglobulin G
      antibodies.
AB  - The 23 kDa transmembrane surface protein of schistosomes is of recognized
      interest in studies of immune responsiveness in schistosomiasis. To examine the
      immunogenicity of the 23 kDa antigen of Schistosoma japonicum, Sj23, when
      delivered by genetic immunization, mice were immunized using a DNA construct
      containing the Sj23 cDNA under the control of a CMV promotor. Serological
      analysis of peripheral blood from immunized mice demonstrated that this construct
      was able to induce the production of antigen-specific IgG antibodies that
      recognized a schistosome antigen of 23 kDa in Western blots. Despite inducing
      antigen-specific antibodies, the Sj23 DNA vaccine was unable to confer protection
      in immunized mice subjected to challenge with S.japonicum cercariae. Appropriate
      engineering of the unique structure of the Sj23 kDa transmembrane protein of
      schistosomes may provide a novel vehicle for expressing foreign epitopes from
      other infectious agents or, possibly, cancer antigens, anchored to the surface of
      transfected cells.

PMID- 10417673
TI  - The relationship between circulating and intestinal Heligmosomoides polygyrus
      specific IgG1 and IgA and resistance to primary infection.
AB  - Specific serum and intestinal immunoglobulin (Ig)G1 and IgA responses to
      Heligmosomoides polygyrus were measured in a panel of seven inbred mouse strains
      which exhibit 'rapid' (<6 weeks (SWRxSJL)F1), 'fast' (<8 weeks, SJL and SWR),
      'intermediate' (10-20 weeks, NIH and BALB/c) or 'slow' (>25 weeks, C57BL/10 and
      CBA) resolution of primary infections. Mice with 'rapid', 'fast' or
      'intermediate' response phenotypes produced greater serum and intestinal antibody
      responses than those with 'slow' phenotypes. The F1 hybrids ((SWRxSJL)F1) of two
      'fast' responder strains showed the earliest antibody response with maximum
      titres evident within 6 weeks of infection. There was a negative correlation
      between the serum IgG1 responses and worm burdens in individual mice within a
      number of mouse strains, and also between serum IgG1 and IgA responses and worm
      burdens in the 'rapid' ((SWRxSJL)F1) responder strain. The presence of IgG1 in
      the gut was found to be due to local secretion rather than plasma leakage. Using
      Western immunoblotting, serum IgG1 from 'rapid' and 'fast' responder but not
      'slow' responder mice was found to react with low molecular weight antigens (16
      18 kDa) in adult worm excretory/secretory products.

PMID- 10417674
TI  - Antibodies to a merozoite surface protein promote multiple invasion of red blood
      cells by malaria parasites.
AB  - The 40-50 kDa merozoite surface antigen (MSA2) is a candidate molecule for use in
      a malaria vaccine. The gene for MSA2 from the 3D7 isolate of Plasmodium
      falciparum was amplified by polymerase chain reaction and cloned into the
      bacterial expression vector pGEX-3X to obtain a fusion protein of MSA2 with
      Schistosoma japonicum glutathione S-transferase. The recombinant fusion protein
      was used to immunize rabbits. After four injections, the sera had Western
      blotting and immunofluorescence titres of 10(-6). Immune sera, and immunoglobulin
      (Ig)G, F(ab)'2, F(ab) prepared from the immune sera, were assessed for their
      effects on the growth of 3D7 parasites in vitro by microscopy and a [3H]
      hypoxanthine incorporation assay. The antibodies did not significantly inhibit
      red blood cell invasion and parasite growth when added to cultures as 10% v/v
      serum or as immunoglobulin preparations at concentrations up to 200 microg ml(
      1). However, in the presence of IgG or F(ab)'2, but not F(ab), antibodies to
      MSA2, the proportions of red blood cells invaded by more than one merozoite
      increased significantly. Multiple invasion is attributed to merozoites cross
      linked by bivalent antibodies, attaching to and subsequently invading the same
      red cell. These observations have a bearing on the evasion of host immune
      responses by the parasite and the use of full-length recombinant MSA2 protein in
      a malaria vaccine.

PMID- 10417675
TI  - Experimental investigations on the B and T cell immune response in primary
      alveolar echinococcosis.
AB  - Susceptibility/resistance of the intermediate host to alveolar echinococcosis
      (AE) seems to be based on hitherto unknown immunological mechanisms, possibly
      involving the activation of different CD4+ T cell immune responses (Th1/Th2).
      Mice of two strains previously characterized as 'susceptible' (C57BL/6 J) and
      'resistant' (C57BL/10 J) to secondary AE were orally infected with eggs of
      Echinococcus multilocularis and the course of infection was analysed by
      macroscopical, pathohistological and immunohistochemical examinations of the
      lymphocytes and cytokines participating in the periparasitic granulomas and by
      serological examinations of cytokines and E. multilocularis-specific antibodies.
      Although differences in the extent of parasitic growth were seen between the two
      groups, the composition of the granulomas was quite similar with CD4+ cells being
      the dominant lymphocyte subpopulation, succeeded by B cells and CD8+ cells.
      Interferon (IFN)-gamma-, interleukin (IL)-2- and IL-4-expressing cells could not
      be detected in the lesions of the early phase of the infection, possibly
      indicating the host's immunosuppression, but were present at the end. IL-10 was
      the most prominent cytokine throughout the course of the disease. Serological
      analyses of the cytokine concentrations revealed small amounts at the beginning
      and high levels at the end of the infection. The pattern of cytokine response was
      similar for IL-4 in both strains, but different for IL-2 and IL-10 in the late
      phase, when the C57BL/10 J strain developed higher levels than the C57BL/6 J
      strain. Correspondingly only small amounts of immunoglobulin (Ig)M, IgG1, IgG2a
      and IgG3 could be detected at the beginning of disease, followed by higher levels
      at the end. The courses of antibody titres were similar in both groups except
      IgG3, which was more pronounced in the C57BL/10 J strain. Parasite-specific IgG2b
      could neither be detected in the C57BL/6 J nor in the C57BL/10 J strain by the
      test system used. The results of the study suggest both subsets of CD4+ T cells
      (Th1 and Th2) being involved in murine primary alveolar echinococcosis. A strict
      differentiation of mice in susceptible and resistant animals based on the
      activation of different CD4+ T cell immune responses (Th1 'resistant' and Th2
      'susceptible') should be avoided.

PMID- 10417676
TI  - Leishmania major infection in interleukin-4 and interferon-gamma depleted mice.
AB  - The outcome of experimental Leishmania major infection in mice is closely
      correlated with the type of CD4+ helper T cell (Th) response. Whereas a Th1
      response is host protective, a Th2 response leads to a disseminated, fatal course
      of disease. Previous studies in this murine model have shown, that the two
      prominent Th1 and Th2 cytokines, interferon (IFN)-gamma and interleukin (IL)-4,
      themselves play a major role in the determination of the resulting Th response.
      Treatment of susceptible mouse strains (BALB/c) with anti-IL-4 induces a Th1
      response, allowing the animals to cure the infection. Treatment of resistant
      strains (e.g. C3H/HeN) with anti-IFN-gamma induces a Th2 response with
      dissemination of the disease. In this report, we investigated the course of
      infection and Th response in susceptible and resistant mice treated with anti-IL
      4 and anti-IFN-gamma simultaneously. Both mouse strains showed an initial
      exacerbation of the disease and an overall reduced cytokine response early after
      infection. Later during infection both strains had a strong Th1 response that was
      resulting in cure of disease in C3H/HeN mice. BALB/c mice however, could not
      control the spread of infection despite the strong Th1 response.

PMID- 10417677
TI  - Cytokine and chemokine secretion by human peripheral blood cells in response to
      viable Echinococcus multilocularis metacestode vesicles.
AB  - In human alveolar echinococcosis, asexually proliferating metacestodes of
      Echinococcus multilocularis progressively infiltrate host tissues and cause
      serious pathology to the affected organs. This study employed an in vitro culture
      of E. multilocularis and examined the production of cytokines and chemokines by
      peripheral blood cells from echinococcosis patients in response to viable
      proliferating E. multilocularis metacestode vesicles (Em-vesicles). A significant
      interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production
      was elicited in echinococcosis patients when their cells were cocultured with
      viable Em-vesicles and autologous immune sera. Furthermore, in echinococcosis
      patients, substantial amounts of cytokines were detected; and the levels of IL-12
      and IL-13 found in patients correlated with the actual state of clinical disease.
      These observations suggest that viable E. multilocularis vesicles will induce
      significant cellular production of cytokines and chemokines in patients, and that
      such immune mediators may activate and enhance antibody-dependent cellular
      effector mechanism against proliferating metacestodes of E. multilocularis.

PMID- 10417678
TI  - Argyrophilic grains in late-onset Creutzfeldt-Jakob diseased brain.
AB  - Braak's argyrophilic grains (ArG) are spindle-shaped structures originally
      described in patients with dementia. Herein, a unique case of sporadic
      Creutzfeldt-Jakob disease (CJD) accompanied by numerous ArG is presented. The
      pathological picture was typical of CJD based on the findings of routine
      hematoxylin-eosin staining. The highest density of ArG was observed throughout
      the parahippocampal gyrus and the temporal gyri; however, the sector CA1 of the
      hippocampus showed less ArG. An immunohistochemical analysis for prion protein
      (PrP) revealed diffuse fine neuropil staining in the cerebral cortex, while the
      ArG themselves did not demonstrate any immunoreaction for PrP. No correlation was
      observed between the densities of ArG and either the presence of senile plaques,
      neurofibrillary tangles or neuropil threads in the present case. To our
      knowledge, this is the first report of CJD demonstrating numerous ArG.

PMID- 10417679
TI  - Villous tumor of the colon and rectum with special reference to roles of p53 and
      bcl-2 in adenoma-carcinoma sequence.
AB  - Villous tumors are rare and their histological diagnosis from biopsy specimens is
      often difficult. To ascertain its tumor progression, including the genetic
      events, would be useful for clinical treatment. Clinicopathological features and
      the expression of p53 and bcl-2 proteins were investigated in 50 villous tumors
      from 49 patients. The patients' ages ranged widely from 32 to 84 years (average,
      61 years). Females were more frequently affected than males (male:female ratio,
      20:29). Thirty-six (72%) of the villous tumors were present within the sigmoid
      colon and rectum. Histologically, 17 (34%) of these contained carcinomas in
      villous adenomas (CIVA), while 24 (73%) of 33 villous adenomas (VA) contained
      high-grade dysplasia. Most of the CIVA revealed well-differentiated
      adenocarcinoma, often with focal or diffuse mucin pools. Three lesions of
      invasive carcinomas were composed of extremely well-differentiated components.
      The average size of the CIVA (79 mm) was significantly larger than that of the VA
      (51 mm). Overexpression of p53 protein was recognized in 12% of VA, in 24% of
      mucosal components of CIVA and in 18% of invasive components of CIVA.
      Overexpression of bcl-2 was recognized in 57% of VA, 33% of mucosal components of
      CIVA, and 7% of invasive components of CIVA. Several characteristic features were
      recognized in villous tumors, which comprised: (i) a high frequency of
      coexistence of carcinoma; (ii) multiple foci of carcinomas arising in adenomatous
      tumors; (iii) a lower histological grade of carcinomas, often with mucin pools;
      (iv) the existence of extremely well-differentiated adenocarcinomas; and (v) less
      frequent expression of p53 protein in the carcinomatous components. According to
      these findings, the pathway of tumor progression in the villous tumors is
      possibly different from that of sporadic colorectal carcinomas. Because of the
      peculiarity of villous tumors, careful clinical management is required.

PMID- 10417680
TI  - Preservation of pathological tissue specimens by freeze-drying for
      immunohistochemical staining and various molecular biological analyses.
AB  - Conditions of preserving DNA, RNA and protein in pathological specimens are of
      great importance as degradation of such macromolecules would critically affect
      results of molecular biological analysis. The feasibility of freeze-drying as a
      means of preserving pathological tissue samples for molecular analysis has
      previously been shown. In the present study, further tests on long-term storage
      conditions and analyses of freeze-dried samples by polymerase chain reaction
      (PCR), reverse transcriptase (RT)-PCR, western blotting and immunohistochemistry
      are reported. Rat chromosomal DNA of freeze-dried samples stored for 4 years
      showed slight degradation while RNA degradation was more prominently seen at an
      earlier stage of storage. However, these 4 year DNA and RNA samples were still
      able to serve as a template for some PCR and RT-PCR analyses, respectively.
      Overexpression of c-erbB-2 and p53 protein was demonstrated by western blotting
      and immunohistochemical staining using freeze-dried human breast cancer tissues.
      Although macromolecules in freeze-dried samples degrade to some extent during the
      preservation period, they should still be of value for certain molecular
      biological analyses and morphological examination; hence, providing more
      convenient and inexpensive ways of pathological tissue storage.

PMID- 10417681
TI  - Degenerative processes of elastic fibers in sun-protected and sun-exposed skin:
      immunoelectron microscopic observation of elastin, fibrillin-1, amyloid P
      component, lysozyme and alpha1-antitrypsin.
AB  - Degenerative processes of elastic fibers in sun-protected and sun-exposed skin
      were analyzed by light and electron microscopic (post-embedding)
      immunocytochemistry using antisera to elastin, fibrillin-1, amyloid P component,
      lysozyme and alpha1-antitrypsin. To assess the effect of aging and sun exposure,
      biopsy specimens of sun-protected skin (back) and severely and moderately sun
      exposed skin (face and forearms) were obtained from a young age group (1-27
      years), an adult group (31-56 years) and an old aged group (61-100 years).
      Elastin and fibrillin-1 were the essential components of elastic fibers; elastin
      being localized in the electron-lucent matrix and fibrillin-1 in the dense
      microfibrillar strands. Aging and sun exposure provoked degenerative condensed
      spots, which represented widened dense microfibrillar strands, in the matrix of
      altered elastic fibers in the reticular dermis. Amyloid P component was first
      deposited on the peripheral microfibrils, and then in the intermediate density
      zone of the spots. Lysozyme was observed in both the electron-dense core and in
      the intermediate density zone of the spots. Deposition of lysozyme correlated
      with basophilic degeneration of the elastic fibers. In the severely photodamaged
      facial skin of the aged, which showed solar elastosis in the upper reticular
      dermis, fibrillin-1 immunoreactivity was lost from the thickened and vacuolated
      elastic fibers that lacked condensed spots, and amyloid P component, lysozyme and
      alpha1-antitrypsin were diffusely deposited in the elastin-positive matrix. It
      seemed that amyloid P component deposition on the elastic fibers was closely
      associated with aging, while immunoreactive lysozyme was related to sun exposure.
      Vertically oriented, thin, elastic (oxytalan) fibers in the papillary dermis
      tended to decrease with age, with frequent deposition of amyloid P component but
      no lysozyme. In the facial skin of the aged, dermal papillae disappeared, with
      the formation of degenerative elastic globules beneath the dermal-epidermal
      junction. The present study demonstrated an intimate relationship between
      ultrastructural alterations and deposition of exogenous substances on the
      degenerative elastic fibers in sun-exposed and/or aged skin.

PMID- 10417683
TI  - Why couldn't an accurate diagnosis be made? An analysis of 1044 consecutive
      autopsy cases.
AB  - The protocols of 1044 consecutive patients autopsied between 1983 and 1997 at
      Sumitomo Hospital (Osaka, Japan) were retrospectively analyzed and the findings
      were compared with clinical diagnoses. In 73 cases, the clinical diagnosis
      apparently differed from the autopsy findings, and in six cases the origin of a
      malignant neoplasm remained unsolved even at autopsy. Of the 73 discrepant cases,
      24 were a result of clinician misjudgment and a neglect to conduct further
      examinations. Missed diagnosis due to an erroneous pathological report, technical
      error of endoscopy, and misleading results obtained by new non-invasive
      technologies accounted for seven, nine, and 11 cases, respectively. Twenty-two
      cases were missed because the clinician could not carry out precise examination.
      It is concluded that advances in diagnostic technology and medical knowledge have
      not reduced the value of an autopsy.

PMID- 10417682
TI  - Distribution of sialic acid-dependent carbohydrate epitope in thyroid tumors:
      immunoreactivity of FB21 in paraffin-embedded tissue sections.
AB  - The reactivity of monoclonal antibody FB21, which recognizes a sialic acid
      dependent carbohydrate epitope, was tested with 94 non-neoplastic and neoplastic
      thyroid tissue specimens using immunohistochemical methods on formalin-fixed,
      paraffin-embedded tissue sections. These specimens included 11 cases of
      adenomatous goiter, three cases of Basedow's disease, 30 cases of follicular
      adenoma, 20 cases of papillary carcinoma, 15 cases of follicular carcinoma, six
      cases of medullary carcinoma, and nine cases of anaplastic carcinoma. FB21
      reacted with 14 of 15 cases of follicular carcinoma that showed a microfollicular
      or trabecular pattern, and with nine of 20 cases of papillary carcinoma. A
      positive reaction was found on the cell surface membranes or apical parts of
      neoplastic follicles. FB21 also reacted with five of 30 cases of follicular
      adenoma. These cases showed a follicular pattern and positive staining pattern
      similar to that in follicular carcinoma. Adenomatous goiters, Basedow's disease,
      medullary carcinomas, and anaplastic carcinomas were negative for FB21
      reactivity. Although the different reactivities of FB21 with papillary carcinoma
      and follicular carcinoma remain to be investigated, the high frequency of
      reactivity with FB21 suggests that it may be useful as a complement to
      morphological diagnosis in follicular carcinoma.

PMID- 10417684
TI  - K-ras gene point mutation in neogenetic lesions of subpleural fibrotic lesions:
      either an early genetic event in lung cancer development or a non-specific
      genetic change during the inflammatory reparative process.
AB  - In the present study, K-ras mutation was investigated in 156 neogenetic epithelia
      that appeared in the lesion of subpleural fibrosis in order to elucidate the
      close relationship of lung cancer development with pulmonary interstitial
      pneumonia. The neogenetic epithelia were histologically subclassified into six
      types: (i) ciliated bronchial epithelium (CBE); (ii) squamous metaplastic
      epithelium (SME); (iii) cuboidal immature epithelium (CIE); (iv) stratified
      immature epithelium (SIE); (v) mucus cell epithelium (MCE); and (vi) intestinal
      metaplastic epithelium (IME). K-ras mutation was detected in 9.6% of neogenetic
      epithelia overall; 21% of CIE, 12% of SIE, 16% of SME, but not in other types of
      neogenetic epithelia. Immunohistochemically, CIE and SIE frequently expressed
      surfactant apoprotein and SME was characteristic to carcinoembryonic antigen
      expression. According to Ki-67 immunostain, CIE, SIE and SME are likely to grow
      faster than other histological types of epithelia. K-ras mutation was seen
      exclusively in codon 12 with predominant G to A and G to C substitutions without
      any G to T transversions, results which are somewhat different to previous
      studies in lung cancers. The present study clearly demonstrated that K-ras
      mutation appeared in certain histological types of neogenetic epithelia, but
      raised the question of whether K-ras mutation in neogenetic epithelia during the
      inflammatory reparative process might be an early genetic event in lung
      carcinogenesis.

PMID- 10417685
TI  - Spiradenocylindromas of the skin: tumors with morphological features of
      spiradenoma and cylindroma in the same lesion: report of 12 cases.
AB  - Twelve cases of spiradenocylindromas, which revealed features of both spiradenoma
      and cylindroma in the same tumor mass, are presented. Nine female patients had
      multiple neoplasms occurring mostly on the scalp, and two female and one male
      patient had a solitary cutaneous lesion. Three of the female patients with
      multiple cutaneous tumors had a familial history of similar cutaneous neoplasms.
      In one of the patient's family, the multiple cutaneous tumors were known to occur
      in multiple family members in four consecutive generations. One patient with
      multiple cutaneous lesions was known to have associated multiple kidney cysts as
      confirmed by computed tomography. Histologically, spiradenocylindromas are
      composed of intermixed areas that are either of typical spiradenoma in appearance
      or of typical cylindroma appearance. Apocrine and trichoepitheliomatous
      differentiation seen in two cases in the present series points to spiradenomas,
      as well as cylindromas, having complex hair follicle (folliculo-sebaceous
      apocrine) rather than eccrine differentiation. The presence of lymphoid tissue
      was a histological feature in the present series, which was prominent in all the
      spiradenomatous parts of the tumors and which was scanty or practically absent in
      all the cylindromatous parts. The selective presence of lymphocytes in
      spiradenoma and an absence in cylindroma suggest that spiradenomas have the
      unique property of attracting lymphocytes. The malignant tumors arising in three
      patients in the present series had the morphology of a poorly differentiated
      epithelioid neoplasm. Three patients died of the disease and the other patients
      were either free of disease or alive with disease 1-30 years on follow up.

PMID- 10417686
TI  - Immunohistochemical analysis of pericryptal fibroblast sheath and proliferating
      epithelial cells in human colorectal adenomas and carcinomas with adenoma
      components.
AB  - In order to examine stromal-epithelial interaction during the oncogenic
      progression of large bowel tumors, the association between pericryptal fibroblast
      sheath (PCFS) and expression of Ki-67 antigen was evaluated in 87 cases of
      colorectal adenoma and 95 cases of carcinoma with an adenoma component (CWA). For
      the immunohistochemistry, anti-alpha-smooth muscle actin antibody (alpha-SMA) and
      anti-Ki-67 antigen antibody (MIB-1) were used. In adenomas and adenoma components
      of CWA, the quantity of neoplastic glands with PCFS was reduced relative to the
      progression of histological atypia. Pericryptal fibroblast sheath was virtually
      absent from invasive carcinoma areas of CWA. Increased expression of Ki-67
      correlated with the degree of histological atypia of adenomas. A significant
      reverse correlation was also seen between Ki-67 expression and PCFS-positive
      glands in adenoma components of CWA. These findings suggest that the prevalence
      of PCFS and Ki-67 expression are important indicators of colorectal neoplasia
      progression. The significant reduction of PCFS in colorectal epithelial neoplasms
      reflects progression in the adenoma-carcinoma sequence.

PMID- 10417687
TI  - Proliferative activity and tumor angiogenesis is closely correlated to stromal
      cellularity of fibroadenoma: proposal fibroadenoma, cellular variant.
AB  - Fibroadenoma (FA) is the most common benign tumor of the breast in adult women.
      Some FA have a highly cellular stroma, making it difficult to differentiate from
      phyllodes tumors (PT). Forty-three FA were grouped into: (i) 27 conventional type
      (FACT) median stromal cellularity (SC) of highest cellular area (HCA), < or = 125
      cells/1 high-power field (HPF); and (ii) 16 cellular variant (FACV) median SC of
      HCA, > 125 cells/1 HPF. These were studied for the proliferative activity of
      their stromal cells. Expression of c-fos, p53, basic fibroblast growth factor
      (bFGF), fibroblast growth factor receptor (FGFR), and vascular endothelial growth
      factor (VEGF) in the stromal cells were examined in the FA and 12 PT to determine
      whether it is possible to separate FACV from FACT. The proliferative activity of
      stromal cells was evaluated by the labeling index (LI) of proliferating cell
      nuclear antigen (PCNA). Conventional type fibroadenoma stromal cells had the
      lowest frequency of c-fos, p53, bFGF, FGFR and VEGF protein expression; PT
      stromal cells had the highest frequency of expression; and FACV stromal cells had
      an intermediate frequency of expression. Multivariate analysis demonstrated that
      bFGF and FGFR expression are significantly correlated with SC of FA. Separation
      of FACV from FACT by SC seems appropriate in revealing the phenotypic and
      biological differences of FA. The SC of FA seems to be regulated by bFGF and FGFR
      expression.

PMID- 10417688
TI  - Thyroid papillary carcinoma arising in ectopic thyroid tissue within a branchial
      cleft cyst.
AB  - A case of papillary carcinoma arising in ectopic thyroid tissue within a
      branchial cleft cyst is described. A 46-year-old woman presented with a 2.0 x 2.0
      cm mass in her left lateral neck. The excised mass showed a cystic lesion with a
      thyroid papillary carcinoma. Following a lateral cervical cystectomy, subsequent
      thyroid gland and lymph nodes dissections were performed. Pathological
      examination showed an adenomatous goiter and no primary carcinoma in the thyroid
      gland, as well as metastatic papillary carcinoma in the lymph nodes. Two cases of
      thyroid papillary carcinoma arising in ectopic thyroid tissue within a branchial
      cyst have been reported previously, but no lymph node metastases were recognized.
      The first case of papillary carcinoma arising in ectopic thyroid tissue within a
      branchial cleft cyst, and accompanied by lymph node metastasis is presented.

PMID- 10417689
TI  - Right intraventricular metastasis of squamous cell carcinoma of the uterine
      cervix: an autopsy case and literature review.
AB  - An autopsy case of squamous cell carcinoma of the uterine cervix, which developed
      cardiac intracavitary metastasis in a 28-year-old Filipina, is reported. At
      autopsy, the right ventricle contained a soft, red-purple, cauliflower-like mass.
      Histologically, this mass was made up of sheets of malignant squamous cells
      similar to the primary uterine foci. The metastases were extensive and associated
      with multiple organ involvement. Although this case was stage Ib at operation,
      vascular invasion at the primary site was characteristic, and the intracavitary
      tumor of the right ventricle developed without myocardial involvement. The
      carcinoma of the primary site extended along the inferior vena cava and settled
      as an intracardiac obstructive mass. A literature review (including the present
      case) disclosed only 14 uterine cervical carcinomas with right intracavitary
      metastasis. The mean age of these patients was 46 years of age (range, 28-77
      years). The clinical stage was Ib in two cases, IIa in one case, IIb in six
      cases, and IIIb in two cases. The prognosis of these cases was poor; 13 of the
      patients died at an average of 19.1 months after diagnosis.

PMID- 10417690
TI  - Sarcomatoid carcinoma of the pancreas: a case report with immunohistochemical
      study.
AB  - Sarcomatoid carcinoma of the pancreas is an uncommon neoplasm. The
      immunohistochemical characteristics of this unique type of pancreatic tumor were
      studied. Histologically, there was diffuse proliferation of atypical spindle
      cells that had hyperchromatic, short, spindle-shaped nuclei and pale cytoplasm. A
      few tiny foci of small tubular structures were seen in connection with the
      atypical spindle-shaped cells. Immunohistochemical examination showed that the
      spindle cells were positive for epithelial cell markers (cytokeratin AE3,
      cytokeratin AE1, epithelial membrane antigen) and DF3 (MUC1 apomucin-related
      antigen (ARA)), and were negative for markers such as vimentin, desmin, neuron
      specific enolase, and myoglobin. DF3 antigen is known to be expressed in invasive
      ductal carcinoma of the pancreas and liver, as well as of the breast. Other MUC1
      ARA (MY.1E12, MUC1 glycoprotein, HMFG-1, HMFG-2) and anti-CA19-9 were also
      detected in the present case. Thus, this tumor was diagnosed as anaplastic
      carcinoma (sarcomatoid carcinoma).

PMID- 10417692
TI  - Combined small and transitional cell carcinoma of the urinary bladder with CA19-9
      production.
AB  - It is well known that extrapulmonary small cell carcinoma, which exhibits
      morphological features similar to those observed in the lung, occurs in various
      organs. Clinically, most cases manifest aggressive biological behavior. A case of
      small cell carcinoma of the urinary bladder producing a high level of serum
      carbohydrate antigen (CA) 19-9, in which expression was confirmed in cancer cells
      of small as well as transitional cell carcinoma in the same tumor mass by
      immunostaining is reported. This paper documents combined small and transitional
      cell carcinoma of the urinary bladder with CA19-9 production, although it has
      already been reported that adenocarcinoma or transitional cell carcinoma in
      various organs frequently expresses CA19-9. Observations suggest that the
      histogenesis of some cases of combined small and transitional cell carcinoma in
      the urinary bladder may be the same, as both can produce CA19-9.

PMID- 10417691
TI  - Prostatic signet-ring cell carcinoma: case report and literature review.
AB  - Signet-ring cell carcinoma (SRCC) of the prostate is a very rare neoplasm and
      there have been only 38 cases reported to date. Here the 39th case of prostatic
      SRCC containing a small amount of neutral mucin, prostatic specific antigen (PSA)
      and prostatic specific acid phosphatase (PSAP) in the signet-ring cells is
      reported. It was also found that some intracytoplasmic lumina were derived from
      the shallow or deep invagination of luminal membranes of cancer cells that formed
      the neoplastic glands. Using immunohistochemistry, a combination of monoclonal
      antibodies against cytokeratins 7 and 20 as well as PSA and PSAP may be useful in
      differentiating prostatic primary SRCC from metastatic SRCC originating in the
      gastrointestinal tract.

PMID- 10417694
TI  - A case of large cell calcifying Sertoli cell tumor in a child with a history of
      nasal myxoid tumor in infancy.
AB  - A case of an 8-year-old Japanese boy with a testicular large cell calcifying
      Sertoli cell tumor (LCCSCT) is presented. This report appears to be the first
      Japanese case of LCCSCT. The patient presented with left testicular swelling and
      gynecomastia. His family history was not contributory; however, his past history
      was remarkable for a benign myxoid tumor in the nasal cavity, which was removed
      at the age of 2 months. After removal of the testicular tumor, the gynecomastia
      disappeared gradually and no recurrence or metastasis developed during a 15 month
      follow-up period. Although the tumor was initially interpreted as a Leydig cell
      tumor, a review of the slides after the patient's past history of nasal myxoid
      tumor was revealed led us to the diagnosis of LCCSCT. An accurate diagnosis of
      LCCSCT is crucial because this tumor is occasionally associated with Carney
      complex, which can comprise various pathological conditions, including cardiac
      myxoma, that may be life-threatening. Myxoma of Carney complex has been described
      to occur in the heart, skin, oral cavity and breast in a wide age range, but
      there have been no reports referring to nasal myxoid tumor associated with Carney
      complex.

PMID- 10417693
TI  - Primary amebic meningoencephalitis due to Naegleria fowleri: an autopsy case in
      Japan.
AB  - Free-living amebas represented by Naegleria fowleri, Acanthamoeba and Balamutia
      have been known to cause fatal meningoencephalitis since Fowler and Carter (1965)
      reported the first four human cases. An autopsy case of a 25-year-old female with
      primary amebic meningoencephalitis (PAM) due to Naegleria fowleri is described.
      Headache, lethargy and coma developed in this patient, and her condition
      progressed to death 8 days after the onset of clinical symptoms. Cerebral spinal
      fluid examination confirmed clusters of amebas, which were grown in culture and
      identified as Naegleria fowleri. At autopsy, lesions were seen in the central
      nervous system (CNS) and the ethmoid sinus. The CNS had severe, suppurative
      meningoencephalitis with amebic trophozoites mingled with macrophages. This case
      is the first report of PAM due to Naegleria fowleri in Japan.

PMID- 10417695
TI  - Apoptosis in abortive hair follicular components in the organoid nevus.
AB  - A previously undescribed fact that a small number of apoptotic bodies are present
      in about 62% of abortive hair follicles of the organoid nevus is discovered. The
      immaturity and frequency of apoptosis in the hair follicles seemed to be closely
      related to the hairless condition of the organoid nevus.

PMID- 10417696
TI  - Application of tyramide signal amplification system to immunohistochemistry: a
      potent method to localize antigens that are not detectable by ordinary method.
AB  - Tyramide signal amplification-avidin-biotin complex (TSA-ABC) method is a
      powerful technique used to detect antigens that are not detectable by ordinary
      immunohistochemistry. It is worth trying in cases where localization of antigens
      by the conventional method has failed and antibodies are precious.

PMID- 10417698
TI  - Targeted disruption of the plastid RNA polymerase genes rpoA, B and C1: molecular
      biology, biochemistry and ultrastructure.
AB  - The plastid encoded RNA polymerase subunit genes rpoA, B and C1 of tobacco were
      disrupted individually by PEG-mediated plastid transformation. The resulting off
      white mutant phenotype is identical for inactivation of the different genes. The
      mutants pass through a normal ontogenetic cycle including flower formation and
      production of fertile seeds. Their plastids reveal a poorly developed internal
      membrane system consisting of large vesicles and, occasionally, flattened
      membranes, reminiscent of stacked thylakoids. The rpo- material is capable of
      synthesising pigments and lipids, similar in composition but at lower amounts
      than the wild-type. Western analysis demonstrates that plastids contain nuclear
      coded stroma and thylakoid polypeptides including terminally processed lumenal
      components of the Sec but not of the DeltapH thylakoid translocation machineries.
      Components using the latter route accumulate as intermediates. In striking
      contrast, polypeptides involved in photosynthesis encoded by plastid genes could
      not be detected by Western analysis, although transcription of plastid genes,
      including the rrn operon, by the plastid RNA polymerase of nuclear origin is
      found as expected. Remarkably, ultrastructural, sedimentation and Northern
      analyses as well as pulse experiments suggest that rpo- plastids contain
      functional ribosomes. The detection of the plastid-encoded ribosomal protein Rpl2
      is consistent with these results. The findings demonstrate that the consequences
      of rpo gene disruption, and implicitly the integration of the two plastid
      polymerase types into the entire cellular context, are considerably more complex
      than presently assumed.

PMID- 10417697
TI  - Molecular cloning and functional expression of codeinone reductase: the
      penultimate enzyme in morphine biosynthesis in the opium poppy Papaver
      somniferum.
AB  - The narcotic analgesic morphine is the major alkaloid of the opium poppy Papaver
      somniferum. Its biosynthetic precursor codeine is currently the most widely used
      and effective antitussive agent. Along the morphine biosynthetic pathway in opium
      poppy, codeinone reductase catalyzes the NADPH-dependent reduction of codeinone
      to codeine. In this study, we have isolated and characterized four cDNAs encoding
      codeinone reductase isoforms and have functionally expressed them in Escherichia
      coli. Heterologously expressed codeinone reductase-calmodulin-binding peptide
      fusion protein was purified from E. coli using calmodulin affinity column
      chromatography in a yield of 10 mg enzyme l-1. These four isoforms demonstrated
      very similar physical properties and substrate specificity. As least six alleles
      appear to be present in the poppy genome. A comparison of the translations of the
      nucleotide sequences indicate that the codeinone reductase isoforms are 53%
      identical to 6'-deoxychalcone synthase from soybean suggesting an evolutionary
      although not a functional link between enzymes of phenylpropanoid and alkaloid
      biosynthesis. By sequence comparison, both codeinone reductase and 6'-deoxy-
      chalcone synthase belong to the aldo/keto reductase family, a group of
      structurally and functionally related NADPH-dependent oxidoreductases, and
      thereby possibly arise from primary metabolism.

PMID- 10417699
TI  - Temperature sensing by plants: the primary characteristics of signal perception
      and calcium response.
AB  - Cold elicits an immediate rise in the cytosolic free calcium concentration
      ([Ca2+]c) of plant cells. We have studied the concerted action of the three
      underlying mechanisms, namely sensing, sensitisation and desensitisation, which
      become important when plants in the field are subjected to changes in
      temperature. We applied different regimes of temperature changes with well
      defined cooling rates to intact roots of Arabidopsis thaliana expressing the
      calcium-indicator, aequorin. Our results indicate that temperature sensing is
      mainly dependent on the cooling rate, dT/dt, whereas the absolute temperature T
      is of less importance. Arabidopsis roots were found to be sensitive to cooling
      rates of less than dT/dt = 0.01 degrees C/s. However, at cooling rates below
      0.003 degrees C/s (i.e. cooling 10 degrees C in 1 h) there is no detectable
      [Ca2+]c response at all. At low temperature, the sensitivity of the plant cold
      detection system is increased. This in turn produces greater cooling-induced
      [Ca2+]c elevations. Prolonged or repeated cold treatment attenuates the [Ca2+]c
      responses to subsequent episodes of cooling.

PMID- 10417700
TI  - Regulation of phytochrome B signaling by phytochrome A and FHY1 in Arabidopsis
      thaliana.
AB  - Phytochrome A (phyA) and phytochrome B (phyB) share the control of many processes
      but little is known about mutual signaling regulation. Here, we report on the
      interactions between phyA and phyB in the control of the activity of an Lhcb1*2
      gene fused to a reporter, hypocotyl growth and cotyledon unfolding in etiolated
      Arabidopsis thaliana. The very-low fluence responses (VLFR) induced by pulsed far
      red light and the high-irradiance responses (HIR) observed under continuous far
      red light were absent in the phyA and phyA phyB mutants, normal in the phyB
      mutant, and reduced in the fhy1 mutant that is defective in phyA signaling. VLFR
      were also impaired in Columbia compared to Landsberg erecta. The low-fluence
      responses (LFR) induced by red-light pulses and reversed by subsequent far-red
      light pulses were small in the wild type, absent in phyB and phyA phyB mutants
      but strong in the phyA and fhy1 mutants. This indicates a negative effect of phyA
      and FHY1 on phyB-mediated responses. However, a pre-treatment with continuous far
      red light enhanced the LFR induced by a subsequent red-light pulse. This
      enhancement was absent in phyA, phyB, or phyA phyB and partial in fhy1. The
      levels of phyB were not affected by the phyA or fhy1 mutations or by far-red
      light pre-treatments. We conclude that phyA acting in the VLFR mode (i.e. under
      light pulses) is antagonistic to phyB signaling whereas phyA acting in the HIR
      mode (i.e. under continuous far-red light) operates synergistically with phyB
      signaling, and that both types of interaction require FHY1.

PMID- 10417702
TI  - Phosphorylation of pea chloroplast acetyl-CoA carboxylase.
AB  - We have examined whether chloroplast acetyl-CoA carboxylase is a phosphoprotein.
      Pea (Pisum sativum) chloroplasts were incubated in the presence of [gamma-33P]
      ATP and radiolabeled proteins were examined after immunoprecipitation with
      antibodies against all four known subunits of heteromeric chloroplast acetyl-CoA
      carboxylase. The beta-subunit of the carboxyltransferase was found to be labeled
      by 33P. Phosphoamino acid analysis of the immunoprecipitated beta-subunit of the
      carboxyltransferase indicates that it is phosphorylated on serine residues.
      Incorporation of 33P into carboxyltransferase beta-subunit decreased in
      chloroplasts transferred to dark conditions after labeling in the light.
      Dephosphorylation of pea chloroplast extracts by an alkaline phosphatase-agarose
      conjugate reduced in vitro acetyl-CoA carboxylase activity by 67%. Furthermore,
      while acetyl-CoA carboxylase activity and its carboxyltransferase half-reaction
      were reduced in dephosphorylated extracts, the biotin carboxylase half-reaction
      was not inhibited. The evidence presented here points to the carboxyltransferase
      beta-subunit of chloroplast acetyl-CoA carboxylase as a candidate for regulation
      by protein phosphorylation/dephosphorylation.

PMID- 10417701
TI  - Molecular and functional regulation of two NO3- uptake systems by N- and C-status
      of Arabidopsis plants.
AB  - Root NO3- uptake and expression of two root NO3- transporter genes (Nrt2;1 and
      Nrt1) were investigated in response to changes in the N- or C-status of
      hydroponically grown Arabidopsis thaliana plants. Expression of Nrt2;1 is up
      regulated by NO3 - starvation in wild-type plants and by N-limitation in a
      nitrate reductase (NR) deficient mutant transferred to NO3- as sole N source.
      These observations show that expression of Nrt2;1 is under feedback repression by
      N-metabolites resulting from NO3- reduction. Expression of Nrt1 is not subject to
      such a repression. However, Nrt1 is over-expressed in the NR mutant even under N
      sufficient conditions (growth on NH4NO3 medium), suggesting that expression of
      this gene is affected by the presence of active NR, but not by N-status of the
      plant. Root 15NO3- influx is markedly increased in the NR mutant as compared to
      the wild-type. Nevertheless, both genotypes have similar net 15NO3- uptake rates
      due to a much larger 14NO3- efflux in the mutant than in the wild-type.
      Expressions of Nrt2;1 and Nrt1 are diurnally regulated in photosynthetically
      active A. thaliana plants. Both increase during the light period and decrease in
      the first hours of the dark period. Sucrose supply prevents the inhibition of
      Nrt2;1 and Nrt1 expressions in the dark. In all conditions investigated, Nrt2;1
      expression is strongly correlated with root 15NO3- influx at 0.2 mM external
      concentration. In contrast, changes in the Nrt1 mRNA level are not always
      associated with similar changes in the activities of high- or low-affinity NO3-
      transport systems.

PMID- 10417703
TI  - Structural and functional analysis of the six regulatory particle triple-A ATPase
      subunits from the Arabidopsis 26S proteasome.
AB  - The 26S proteasome is a multi-subunit ATP-dependent protease responsible for
      degrading most short-lived intracellular proteins targeted for breakdown by
      ubiquitin conjugation. The complex is composed of two relatively stable
      subparticles, the 20S proteasome, a hollow cylindrical structure which contains
      the proteolytic active sites in its lumen, and the 19S regulatory particle (RP)
      which binds to either end of the cylinder and provides the ATP-dependence and the
      specificity for ubiquitinated proteins. Among the approximately 18 subunits of
      the RP from yeast and animals are a set of six proteins, designated RPT1-6 for
      regulatory particle triple-A ATPase, that form a distinct family within the AAA
      superfamily. Presumably, these subunits use ATP hydrolysis to help assemble the
      26S holocomplex, recognize and unfold appropriate substrates, and/or translocate
      the substrates to the 20S complex for degradation. Here, we describe the RPT gene
      family from Arabidopsis thaliana. From a collection of cDNAs and genomic
      sequences, a family of genes encoding all six of the RPT subunits was identified
      with significant amino acid sequence similarity to their yeast and animal
      counterparts. Five of the six RPT sub- units are encoded by two genes; the
      exception being RPT3 which is encoded by a single gene. mRNA for each of the six
      proteins is present in all tissue types examined. Five of the subunits (RPT1 and
      3-6) complemented yeast mutants missing their respective orthologs, indicating
      that the yeast and Arabidopsis proteins are functionally equivalent. Taken
      together, these results demonstrate that the RP, like the 20S proteasome, is
      functionally and structurally conserved among eukaryotes and indicate that the
      plant RPT subunits, like their yeast counterparts, have non-redundant functions.

PMID- 10417704
TI  - Arabidopsis thaliana proteins related to the yeast SIP and SNF4 interact with
      AKINalpha1, an SNF1-like protein kinase.
AB  - AKINalpha1, a Ser/Thr kinase from Arabidopsis thaliana belongs to the highly
      conserved SNF1 family of protein kinases in eukaryotes. Recent data suggest that
      the plant SNF1-related kinases (SnRK1 family) are key enzymes implicated in the
      regulation of carbohydrate and lipid metabolism. In Saccharomyces cerevisiae and
      mammals, the SNF1 and AMPKalpha protein kinases interact with two other families
      of proteins, namely SNF4/AMPKgamma and SIP1/SIP2/GAL83/AMPKbeta, to form active
      heterotrimeric complexes. In this paper, we describe the characterisation of
      three novel cDNAs. AKINbeta1 and AKINbeta2 encode proteins similar to SIP1, SIP2
      and GAL83 and AKINgamma codes for a protein showing similarity with SNF4. Using
      the two-hybrid system, specific interactions have been shown between A. thaliana
      AKINbeta1/beta2, AKINgamma and AKINgamma as well as between the A. thaliana and
      S. cerevisiae subunits. Interestingly, AKINbeta1, AKINbeta2 and AKINgamma mRNAs
      accumulate differentially in A. thaliana tissues and are modulated during
      development and under different growth conditions. These data suggest the
      presence in higher plants of a conserved heterotrimeric complex. Moreover, the
      differential transcription of different non-catalytic subunits can constitute a
      first level of regulation of the SNF1-like complex in plants.

PMID- 10417705
TI  - Cryptochrome 1 controls tomato development in response to blue light.
AB  - Cryptochrome genes (CRY) are a novel class of plant genes encoding proteins that
      bear a strong resemblance to photolyases, a rare class of flavoproteins that
      absorb light in the blue (B) and UV-A regions of the spectrum and utilise it for
      photorepair of UV-damaged DNA. In Arabidopsis, both CRY1 and CRY2 are implicated
      in numerous blue light-dependent responses, including inhibition of hypocotyl
      elongation, leaf and cotyledon expansion, pigment biosynthesis, stem growth and
      internode elongation, control of flowering time and phototropism. No information
      about the in vivo function of CRY genes is available in other plant species. The
      tomato CRY1 gene (TCRY1) encodes a protein of 679 amino acids, which shows 78%
      identity and 88% similarity to Arabidopsis CRY1. In order to verify the in vivo
      function of TCRY1, we constructed antisense tomato plants using the C-terminal
      portion of the gene. Partial repression of both mRNA and protein levels was
      observed in one of the transformants. The progeny from this transformant showed
      an elongated hypocotyl under blue but not under red light. This character co
      segregated with the transgene and was dependent on transgene dosage. An
      additional, partially elongated phenotype was observed in adult plants grown in
      the greenhouse under dim light and short days with no artificial illumination.
      This phenotype was suppressed by artificial illumination of both short and long
      photoperiods. The synthesis of anthocyanins under blue light was reduced in
      antisense seedlings. In contrast, carotenoid and chlorophyll levels and second
      positive phototropic curvature were essentially unaltered.

PMID- 10417706
TI  - Increased steady state mRNA levels of the STM and KNAT1 homeobox genes in
      cytokinin overproducing Arabidopsis thaliana indicate a role for cytokinins in
      the shoot apical meristem.
AB  - This study investigates the consequences of endogenously enhanced biosynthesis of
      the plant hormone cytokinin in Arabidopsis thaliana (L.) Heynh. Transcriptional
      control of the bacterial ipt gene by the Drosophila melanogaster hsp70 promoter
      enabled temperature-dependent increased cytokinin production in transgenic
      plants. Heat-treated plants accumulated higher levels of unbound and bound zeatin
      type cyto-kinins, the latter being preferentially N-conjugated glucosides.
      Cytokinin overproduction significantly increased the biomass of seedlings. Ipt
      transgenics had higher steady state mRNA levels of the shoot meristem specifying
      homeobox genes KNAT1 and STM, similar to the cytokinin-overproducing shoot
      meristem mutant amp1 (hpt, cop2, pt) This finding, together with previously
      described phenotypic similarities between transgenic cytokinin-overproducing
      plants and plants overexpressing the KNAT1 or KN1 genes, suggests that these
      factors act on the same pathway. We hypothesize that cytokinins act upstream of
      KNAT1 and STM. The influence of cytokinins on homeobox genes provides a link
      between the hormone and the developmental genes and indicates a role for
      cytokinins in the shoot apical meristem.

PMID- 10417708
TI  - A bacterial haloalkane dehalogenase gene as a negative selectable marker in
      Arabidopsis.
AB  - The dhlA gene of Xanthobacter autotrophicus GJ10 encodes a dehalogenase which
      hydrolyzes dihalo- alkanes, such as 1, 2-dichloroethane (DCE), to a halogenated
      alcohol and an inorganic halide (Janssen et al. 1994, Annu. Rev. Microbiol. 48,
      163-191). In Xanthobacter, these alcohols are further catabolized by alcohol and
      aldehyde dehydrogenase activities, and by the product of the dhlB gene to a
      second halide and a hydroxyacid. The intermediate halogenated alcohols and, in
      particular, the aldehydes are more toxic than the haloalkane substrates or the
      pathway products. We show here that plants, including Arabidopsis, tobacco, oil
      seed rape and rice, do not express detectable haloalkane dehalogenase activities,
      and that wild-type Arabidopsis grows in the presence of DCE. In contrast, DCE
      applied as a volatile can be used to select on plates or in soil transgenic
      Arabidopsis which express dhlA. The dhlA marker therefore provides haloalkane
      dehalogenase reporter activity and substrate dependent negative selection in
      transgenic plants.

PMID- 10417707
TI  - The Nicotiana tabacum plasma membrane aquaporin NtAQP1 is mercury-insensitive and
      permeable for glycerol.
AB  - A new aquaporin from Nicotiana tabacum (cv. Samsun) was characterized. It shares
      sequence homology to the Arabidopsis thaliana PIP1 protein family. By two-phase
      partitioning and immunoblot analysis, plasma membrane localization could be
      demonstrated. The corresponding mRNA is highly abundant in roots and flowers,
      while it is rarely expressed in leaves and stems. Functional expression in
      Xenopus oocytes revealed that NtAQP1 can mediate glycerol transport in addition
      to water flow. However, NtAQP1 is impermeable for Na+, K+ and Cl- ions. The water
      permeability and selectivity could not be modulated by addition of mercurials or
      the activity of cAMP-dependent protein kinases.

PMID- 10417710
TI  - Ethylene-regulated gene expression in tomato fruit: characterization of novel
      ethylene-responsive and ripening-related genes isolated by differential display
AB  - Differential display was used to isolate early ethylene-regulated genes from late
      immature green tomato fruit in order to obtain a broader understanding of the
      molecular basis by which ethylene coordinates the ripening process. Nineteen
      novel ethylene-responsive (ER) cDNA clones were isolated that fell into three
      classes: (i) ethylene up-regulated (ii) ethylene down-regulated, and (iii)
      transiently induced. Expression analysis revealed that ethylene-dependent changes
      in mRNA accumulation occurred rapidly (15 min) for most of the ER clones. The
      predicted proteins encoded by the ER genes are putatively involved in processes
      as diverse as primary metabolism, hormone signalling and stress responses.
      Although a number of the isolated ER clones correspond to genes already
      documented in other species, their responsiveness to ethylene is described here
      for the first time. Among the ER clones sharing high homology with regulatory
      genes, ER43, a putative GTP-binding protein, and ER50, a CTR1-like clone, are
      potentially involved in signal transduction. ER24 is homologous to the multi
      protein bridging factor MBF1 involved in transcriptional activation, and finally,
      two clones are homologous to genes involved in post-transcriptional regulation:
      ER49, a putative translational elongation factor, and ER68, a mRNA helicase-like
      gene. Six ER clones correspond to as yet unidentified genes. The expression
      studies indicated that all the ER genes are ripening-regulated, and, depending on
      the clone, show changes in transcript accumulation either at the breaker,
      turning, or red stage. Analysis of transcript accumulation in different organs
      indicated a strong bias towards expression in the fruit for many of the clones.
      The potential roles for some of the ER clones in propagating the ethylene
      response and regulating fruit ripening are discussed.

PMID- 10417709
TI  - Aquaporin Nt-TIPa can account for the high permeability of tobacco cell vacuolar
      membrane to small neutral solutes.
AB  - Members of the major intrinsic protein (MIP) family, described in plants as water
      selective channels (aquaporins), can also transport small neutral solutes in
      other organisms. In the present work, we characterize the permeability of plant
      vacuolar membrane (tonoplast; TP) and plasma membrane (PM) to non-electrolytes
      and evaluate the contribution of MIP homologues to such transport. PM and TP
      vesicles were purified from tobacco suspension cells by free-flow
      electrophoresis, and membrane permeabilities for a wide range of neutral solutes
      including urea, polyols of different molecular size, and amino acids were
      investigated by stopped-flow spectrofluorimetry. For all solutes tested, TP
      vesicles were found to be more permeable than their PM counterparts, with for
      instance urea permeabilities from influx experiments of 74.9 +/- 9.6 x 10(-6) and
      1.0 +/- 0.3 x 10(-6) cm sec-1, respectively. Glycerol and urea transport in TP
      vesicles exhibited features of a facilitated diffusion process. This and the high
      channel-mediated permeability of the same TP vesicles to water suggested a common
      role for MIP proteins in water and solute transport. A cDNA encoding a novel
      tonoplast intrinsic protein (TIP) homologue named Nicotiana tabacum TIPa (Nt
      TIPa) was isolated from tobacco cells. Immunodetection of Nt-TIPa in purified
      membrane fractions confirmed that the protein is localized in the TP. Functional
      expression of Nt-TIPa in Xenopus oocytes showed this protein to be permeable to
      water and solutes such as urea and glycerol. These features could account for the
      transport selectivity profile determined in purified TP vesicles. These results
      support the idea that plant aquaporins have a dual function in water and solute
      transport. Because Nt-TIPa diverges in sequence from solute permeable aquaporins
      characterized in other organisms, its identification also provides a novel tool
      for investigating the molecular determinants of aquaporin transport selectivity.

PMID- 10417711
TI  - Transfer of rps14 from the mitochondrion to the nucleus in maize implied
      integration within a gene encoding the iron-sulphur subunit of succinate
      dehydrogenase and expression by alternative splicing.
AB  - The maize mitochondrial genome does not contain a gene coding for ribosomal
      protein S14. In this paper we show that the functional rps14 gene was
      translocated to the nucleus and acquired the signals conferring expression and
      product targeting to the mitochondrion in a way not previously described.
      Transferred rps14 was found integrated between both exons of a gene encoding the
      iron-sulphur subunit of the respiratory complex II (sdh2). Sdh2 exon 1 and rps14
      were separated by a typical plant nuclear intron that was spliced to give a
      mature poly(A)+ mRNA of 1.4 kb. This processed mRNA encoded a chimeric SDH2
      (truncated)-RPS14 polypeptide, and we show that this chimeric polypeptide is
      targeted into isolated plant mitochondria, where it is proteolytically processed
      in a complex way. An alternative splicing event utilizing the same 5' splice site
      and a different downstream 3' splice site generated a second mature poly(A)+ mRNA
      of 1.3 kb that contained both sdh2 exons. This sdh2 transcript encoded an SDH2
      polypeptide highly conserved compared with its homologues in other organisms, and
      it contained the three cysteine-rich clusters that made up the three non-heme
      iron-sulphur centres responsible for electron transport. To our knowledge, these
      results constitute the first evidence of alternative splicing playing a role in
      the expression and targeting of two mitochondrial proteins with different
      functions from the same gene.

PMID- 10417713
TI  - RNA maturation of the rice SPK gene may involve trans-splicing.
AB  - A gene encoding a calcium-dependent seed-specific protein kinase (SPK) is
      abundantly expressed in developing rice seeds (Kawasaki, T et al. Gene (1993)
      129, 183-189). Rice genomic clones encoding SPK were isolated using the entire
      cDNA fragment as a probe. Physical mapping of these genomic clones indicated that
      the genomic region corresponding to the entire cDNA was divided into two
      different regions, SPK-A and SPK-B, located on different rice chromosomes. The
      results of RACE-PCR analyses showed that the respective transcripts from SPK-A
      and SPK-B contained additional sequences which were not found in the SPK cDNA,
      and that these sequences were removed like introns during maturation of the SPK
      mRNA. These results suggest that two different RNAs were independently
      transcribed from SPK-A and SPK-B and joined, possibly by trans-splicing.

PMID- 10417714
TI  - Footprinting in vivo reveals changing profiles of multiple factor interactions
      with the beta-phaseolin promoter during embryogenesis
AB  - Whereas in vitro techniques are essentially limited to the analysis of
      interactions with a single or limited number of cis-elements, in vivo
      footprinting techniques can be used to assess the total profile of factor
      interactions with a promoter. By probing with dimethylsulphate and using
      sensitive ligation-mediated PCR analytical techniques, the in vivo status of the
      phas promoter was determined in transcriptionally active (embryo) and inactive
      (leaf) tissues. Changes in factor occupancy were detected during embryogenesis,
      and the greatest complexity seen (at mid-maturation) was in accordance with the
      many potential binding sites predicted on the basis of sequence comparison.
      Evidence was obtained that several cis-elements not previously shown to be used
      for factor binding in plant promoters are occupied. The great complexity of
      footprints may represent the need for multiple factor interaction to achieve high
      levels of transcription. Alternatively, it is possible that the differential
      levels of expression in individual regions of the embryo evident from
      histochemical analysis of the GUS reporter result from the interaction of
      relatively few factors, with the overall footprinting pattern representing a
      summation of patterns from various tissues.

PMID- 10417712
TI  - Identification of three kinds of mutually related composite elements conferring S
      phase-specific transcriptional activation.
AB  - Conservation of the Oct motif (CGCGGATC) is a remarkable feature of plant histone
      gene promoters. Many of the Oct motifs are paired with a distinct motif, Hex, TCA
      or CCAAT-box, constituting the type I element (CCACGTCANCGATCCGCG), type II
      element (TCACGCGGATC) and type III element (GATCCGCG-N14-ACCAATCA). To clarify
      the roles of these Oct-containing composite elements (OCEs) in cell cycle
      dependent and tissue-specific expression, we performed gain-of-function
      experiments with transgenic tobacco cell lines and plants harboring a derivative
      of the 35S core promoter/beta-glucuronidase fusion gene in which three or four
      copies of an OCE had been placed upstream. Although their activities were
      slightly different, results showed that each of the three types of OCEs could
      confer the ability to direct S phase-specific expression on a heterologous
      promoter. In transgenic plants, the type I and III elements exhibited a similar
      activity, directing expression in meristematic tissues, whereas the activity of
      the type II element appeared to be restricted to young cotyledons and maturating
      guard cells. Mutational analyses demonstrated that the co-operation of Oct with
      another module (Hex, TCA or CCAAT-box) was absolutely required for both temporal
      and spatial regulation. Thus, OCEs play a pivotal role in regulation of the
      expression of plant histone genes.

PMID- 10417715
TI  - Low-pH-mediated elevations in cytosolic calcium are inhibited by aluminium: a
      potential mechanism for aluminium toxicity.
AB  - Aluminium, the most abundant metal in the earth's crust, is highly toxic to most
      plant species. One of the prevailing dogmas is that aluminium exerts this effect
      by disrupting cellular calcium homeostasis. However, recent research gives
      strongly conflicting results: aluminium was shown to provoke either an increase
      or a decrease in cytosolic free calcium concentration ([Ca2+]c). To solve this
      question, we have adopted a novel approach: [Ca2+]c measurements in intact plant
      roots as opposed to isolated cells, and the correlative measurements of
      intracellular and external pH. The results obtained show that plant roots respond
      to low external pH by a sustained elevation in [Ca2+]c. In the presence of
      aluminium, this pH-mediated elevation in [Ca2+]c does not occur, therefore any
      potential calcium-mediated protection against low pH is likely to be irreversibly
      inhibited. The severity of the inhibitory effect of aluminium on [Ca2+]c depends
      on the concentration of external calcium, thus perhaps explaining why the effects
      of aluminium toxicity are ameliorated in calcium-rich soils. It seems possible
      that a primary toxic effect of aluminium might be to impair calcium-mediated
      plant defence responses against low pH.

PMID- 10417716
TI  - The distinctive roles of five different ARC genes in the chloroplast division
      process in Arabidopsis.
AB  - ARC (accumulation and replication of chloroplasts) genes control different
      aspects of the chloroplast division process in higher plants. In order to
      establish the hierarchy of the ARC genes in the chloroplast division process and
      to provide evidence for their specific roles, double mutants were constructed
      between arc11, arc6, arc5, arc3 and arc1 in all combinations and phenotypically
      analysed. arc11 is a new nuclear recessive mutant with 29 chloroplasts compared
      with 120 in wild type. All the phenotypes of the double mutants are unambiguous.
      ARC1 down-regulates proplastid division but is on a separate pathway from ARC3,
      ARC5, ARC6 and ARC11. ARC6 initiates both proplastid and chloroplast division.
      ARC3 controls the rate of chloroplast expansion and ARC11 the central positioning
      of the final division plane in chloroplast division. ARC5 facilitates separation
      of the two daughter chloroplasts. ARC5 maps to chromosome 3 and ARC11 and ARC6
      map approximately 60 cM apart on chromosome 5.

PMID- 10417717
TI  - Transcriptional activation by Arabidopsis GT-1 may be through interaction with
      TFIIA-TBP-TATA complex.
AB  - GT-1 belongs to the class of trihelix DNA-binding proteins and binds to a
      promoter sequence found in many different genes. Data presented in this report
      show that GT-1 contains a trans-activation function in yeast and in plant cells.
      However, in tobacco BY-2 protoplasts, this activity functions only when an
      internal region containing the DNA-binding domain is deleted. Gel-shift and co
      immunoprecipitation assays have revealed that GT-1 can interact with and
      stabilize the TFIIA-TBP-TATA complex. These results suggest that GT-1 may
      activate transcription through direct inter- action with the transcriptional pre
      initiation complex.

PMID- 10417718
TI  - Double mutation in eleusine indica alpha-tubulin increases the resistance of
      transgenic maize calli to dinitroaniline and phosphorothioamidate herbicides
AB  - The repeated use of dinitroaniline herbicides on the cotton and soybean fields of
      the southern United States has resulted in the appearance of resistant biotypes
      of one of the world's worst weeds, Eleusine indica. Two biotypes have been
      characterized, a highly resistant (R) biotype and an intermediate resistant (I)
      biotype. In both cases the resistance has been attributed to a mutation in alpha
      tubulin, a component of the alpha/beta tubulin dimer that is the major
      constituent of microtubules. We show here that the I-biotype mutation, like the R
      biotype mutation shown in earlier work, can confer dinitroaniline resistance on
      transgenic maize calli. The level of resistance obtained is the same as that for
      E. indica I- or R-biotype seedlings. The combined I- and R-biotype mutations
      increase the herbicide tolerance of transgenic maize calli by a value close to
      the summation of the maximum herbicide tolerances of calli harbouring the single
      mutations. These data, taken together with the position of the two different
      mutations within the atomic structure of the alpha/beta tubulin dimer, imply that
      each mutation is likely to exert its effect by a different mechanism. These
      mechanisms may involve increasing the stability of microtubules against the
      depolymerizing effects of the herbicide or changing the conformation of the
      alpha/beta dimer so that herbicide binding is less effective, or a combination of
      both possibilities.

PMID- 10417719
TI  - Short communication: the cell cycle dependent phosphorylation of histone H3 is
      correlated with the condensation of plant mitotic chromosomes
AB  - Mitotically dividing cells of Secale cereale, Hordeum vulgare and Vicia faba were
      studied by indirect immunofluorescence using an antibody recognizing
      phosphorylated histone H3. The study revealed the following features: (i) the H3
      phosphorylation starts at prophase and ends at telophase in the pericentromeric
      chromatin, is associated with the condensation of mitotic chromosomes and is
      independent of the distribution of late replicating heterochromatin. (ii)
      Compared with other chromosome regions, the pericentromeric chromatin is histone
      H3 hyperphos- phorylated. (iii) The study of a semi-dicentric chromo- some
      revealed that only at intact centromeres is the chromatin hyperphosphorylated at
      H3.

PMID- 10417720
TI  - The late pollen-specific actins in angiosperms.
AB  - The actin gene family of Arabidopsis has eight functional genes that are grouped
      into two ancient classes, vegetative and reproductive, and into five subclasses
      based on their phylogeny and mRNA expression patterns. Progress in deciphering
      the functional significance of this diversity is hindered by the lack of tools
      that can distinguish the highly conserved subclasses of actin proteins at the
      biochemical and cellular level. In order to address the functional diversity of
      actin isovariants, we have used Arabidopsis recombinant actins as immunogens and
      produced several new anti-actin monoclonal antibodies. One of them, MAb45a,
      specifically recognizes two closely related reproductive subclasses of actins. On
      immunoblots, MAb45a reacts strongly with actins expressed in mature pollen but
      not with actins in other Arabidopsis tissues. Moreover, immunocytochemical
      studies show that this antibody can distinguish actin filaments in pollen tubes
      from those in most vegetative tissues. Peptide competition analyses demonstrate
      that asparagine at position 79 (Asn79) within an otherwise conserved sequence is
      essential for MAb45a specificity. Actins with the Asn79 epitope are also
      expressed in the mature pollen from diverse angiosperms and Ephedra but not from
      lower gymnosperms, suggesting that this epitope arose in an ancestor common to
      angiosperms and advanced gymnosperms more than 220 million years ago. During late
      pollen development in angio- sperms there is a switch in expression of actins
      from vegetative to predominantly reproductive subclasses, perhaps to fulfil the
      unique functions of pollen in fertilization.

PMID- 10417721
TI  - The dormancy-related peroxiredoxin anti-oxidant, PER1, is localized to the
      nucleus of barley embryo and aleurone cells.
AB  - Protection against desiccation-induced injury, including damage by reactive
      oxygen species (ROS), is a necessary component of the genetic programmes active
      during late seed development. Likewise, protection against ROS respiration by
      products is required during seed imbibition and germination. Late embryogenesis
      abundant (LEA) proteins are proposed to protect seed tissues against desiccation
      induced damage. Specifically, the atypical Lea gene Per1 in barley (Hordeum
      vulgare L.) has been proposed to play a protective role in embryo and aleurone
      cells against free-radical damage during late seed development and early
      imbibition. PER1 represents a subgroup of the peroxiredoxin family of thiol
      requiring anti-oxidants with one conserved cysteine residue (1-Cys), and displays
      in vitro anti-oxidant activity. In this work, we use antiserum generated against
      PER1 to study protein accumulation patterns as well as localization at the
      tissue, cellular and subcellular level. While previous studies have shown the
      Per1 transcript to be dormancy-related, we show here that the protein level is
      maintained in imbibed dormant seeds, but not in non-dormant seeds. Our data
      identify the location of this seed-specific peroxiredoxin as the nucleus of
      immature embryos and aleurone layers. Highest levels of protein are detected in
      nucleoli. In contrast, in mature imbibed dormant seeds, cytosolic levels are
      comparable to that of the nucleus. A putative nuclear localization signal (NLS)
      of bipartite nature was identified in the C-terminal end of the PER1 sequence.
      Protective roles for PER1 in seeds are discussed.

PMID- 10417722
TI  - Three 4-coumarate:coenzyme A ligases in Arabidopsis thaliana represent two
      evolutionarily divergent classes in angiosperms.
AB  - The enzyme 4-coumarate:CoA ligase (4CL) plays a key role in channelling carbon
      flow into diverse branch pathways of phenylpropanoid metabolism which serve
      important functions in plant growth and adaptation to environmental
      perturbations. Here we report on the cloning of the 4CL gene family from
      Arabidopsis thaliana and demonstrate that its three members, At4CL1, At4CL2 and
      At4CL3, encode isozymes with distinct substrate preference and specificities.
      Expression studies revealed a differential behaviour of the three genes in
      various plant organs and upon external stimuli such as wounding and UV
      irradiation or upon challenge with the fungus, Peronospora parasitica.
      Phylogenetic comparisons indicate that, in angiosperms, 4CL can be classified
      into two major clusters, class I and class II, with the At4CL1 and At4CL2
      isoforms belonging to class I and At4CL3 to class II. Based on their enzymatic
      properties, expression characteristics and evolutionary relationships, At4CL3 is
      likely to participate in the biosynthetic pathway leading to flavonoids whereas
      At4CL1 and At4CL2 are probably involved in lignin formation and in the production
      of additional phenolic compounds other than flavonoids.

PMID- 10417724
TI  - Expression analysis of two gene subfamilies encoding the plasma membrane H+
      ATPase in Nicotiana plumbaginifolia reveals the major transport functions of this
      enzyme.
AB  - The plasma membrane H+-ATPase couples ATP hydrolysis to proton transport, thereby
      establishing the driving force for solute transport across the plasma membrane.
      In Nicotiana plumbaginifolia, this enzyme is encoded by at least nine pma (plasma
      membrane H+-ATPase) genes. Four of these are classified into two gene
      subfamilies, pma1-2-3 and pma4, which are the most highly expressed in plant
      species. We have isolated genomic clones for pma2 and pma4. Mapping of their
      transcript 5' end revealed the presence of a long leader that contained small
      open reading frames, regulatory features typical of other pma genes. The gusA
      reporter gene was then used to determine the expression of pma2, pma3 and pma4 in
      N. tabacum. These data, together with those obtained previously for pma1, led to
      the following conclusions. (i) The four pma-gusA genes were all expressed in
      root, stem, leaf and flower organs, but each in a cell-type specific manner.
      Expression in these organs was confirmed at the protein level, using subfamily
      specific antibodies. (ii) pma4-gusA was expressed in many cell types and notably
      in root hair and epidermis, in companion cells, and in guard cells, indicating
      that in N. plumbaginifolia the same H+-ATPase isoform might be involved in
      mineral nutrition, phloem loading and control of stomata aperture. (iii) The
      second gene subfamily is composed, in N. plumbaginifolia, of a single gene (pma4)
      with a wide expression pattern and, in Arabidopsis thaliana, of three genes
      (aha1, aha2, aha3), at least two of them having a more restrictive expression
      pattern. (iv) Some cell types expressed pma2 and pma4 at the same time, which
      encode H+-ATPases with different enzymatic properties.

PMID- 10417723
TI  - Oxygen deprivation stimulates Ca2+-mediated phosphorylation of mRNA cap-binding
      protein eIF4E in maize roots.
AB  - Flooding of maize seedlings causes O2 deprivation that leads to a global
      reduction in protein synthesis and selective translation of cytoplasmic mRNAs.
      Since selective translation in animal cells can involve the cap-binding protein
      eIF4E, we characterized the distinct mRNA cap-binding proteins eIF4E and eIFiso4E
      of maize. These proteins have 45% deduced amino acid sequence identity and are
      highly conserved at residues of eIF4E that function in intermolecular
      interactions in animals. Maize eIF4E is a phosphoprotein. O2 deprivation resulted
      in a decrease in the isoelectric point of eIF4E, consistent with additional
      phosphorylation. Modification of eIF4E was mimicked by treatment with caffeine
      under aerobic conditions and blocked by treatment with ruthenium red under O2
      deprivation, implicating Ca2+ as a second messenger in eIF4E modification. In
      contrast, no isoelectric variants of eIFiso4E were detected. The possible role of
      cytosolic Ca2+ and pH in regulation of mRNA cap-binding protein activity under O2
      deprivation is discussed.

PMID- 10417725
TI  - Vacuolar processing enzyme is up-regulated in the lytic vacuoles of vegetative
      tissues during senescence and under various stressed conditions.
AB  - Vacuolar processing enzyme (VPE) has been shown to be responsible for maturation
      of various seed proteins in protein-storage vacuoles. Arabidopsis has three VPE
      homologues; betaVPE is specific to seeds and alphaVPE and gammaVPE are specific
      to vegetative organs. To investigate the activity of the vegetative VPE, we
      expressed the gammaVPE in a pep4 strain of the yeast Saccharomyces cerevisiae and
      found that gammaVPE has the ability to cleave the peptide bond at the carbonyl
      side of asparagine residues. An immunocytochemical analysis revealed the specific
      localization of the gammaVPE in the lytic vacuoles of Arabidopsis leaves that had
      been treated with wounding. These findings indicate that gammaVPE functions in
      the lytic vacuoles as the betaVPE does in the protein-storage vacuoles. The
      betaVPE promoter was found to direct the expression of the beta-glucuronidase
      reporter gene in seeds and the root tip of transgenic Arabidopsis plants. On the
      other hand, both the alphaVPE and gammaVPE promoters directed the expression in
      senescent tissues, but not in young intact tissues. The mRNA levels of both
      alphaVPE and gammaVPE were increased in the primary leaves during senescence in
      parallel with the increase of the mRNA level of a senescence-associated gene
      (SAG2). Treatment with wounding, ethylene and salicylic acid up-regulated the
      expression of alphaVPE and gammaVPE, while jasmonate slightly up-regulated the
      expression of gammaVPE. These gene expression patterns of the VPEs were
      associated with the accumulation of vacuolar proteins that are known to respond
      to these treatments. Taken together, the results suggest that vegetative VPE
      might regulate the activation of some functional proteins in the lytic vacuoles.

PMID- 10417726
TI  - The Pib gene for rice blast resistance belongs to the nucleotide binding and
      leucine-rich repeat class of plant disease resistance genes.
AB  - Rice blast, caused by the fungal pathogen Magnaporthe grisea, is one of the most
      serious diseases of rice. Here we describe the isolation and characterization of
      Pib, one of the rice blast resistance genes. The Pib gene was isolated by a map
      based cloning strategy. The deduced amino acid sequence of the Pib gene product
      contains a nucleotide binding site (NBS) and leucine-rich repeats (LRRs); thus,
      Pib is a member of the NBS-LRR class of plant disease resistance genes.
      Interestingly, a duplication of the kinase 1a, 2 and 3a motifs of the NBS region
      was found in the N-terminal half of the Pib protein. In addition, eight cysteine
      residues are clustered in the middle of the LRRs, a feature which has not been
      reported for other R genes. Pib gene expression was induced upon altered
      environmental conditions, such as altered temperatures and darkness.

PMID- 10417727
TI  - Gibberellin 2-oxidation and the SLN gene of Pisum sativum.
AB  - Two cDNAs encoding gibberellin 2-oxidases were isolated from maturing pea seeds.
      The first, PsGA2ox1, was isolated by activity screening of a Lambda-ZAP cDNA
      library excised into phagemid form and expressed in Escherichia coli. The second,
      PsGA2ox2, was obtained initially as a PCR product using degenerate primers
      designed according to conserved regions of plant 2-oxoglutarate-dependent
      dioxygenases. E. coli heterologous expression products of PsGA2ox1 and PsGA2ox2
      converted GA1 to GA8, as shown by HPLC-radiocounting, and gas chromatography-MS.
      PsGA2ox1 converted GA20 to GA29, but GA20 was a poor substrate for the PsGA2ox2
      expression product. Furthermore, PsGA2ox1 converted GA29 to GA29-catabolite at a
      low level of efficiency while PsGA2ox2 did not catalyse this step. A cDNA of
      PsGA2ox1 isolated from plants of genotype sln contained a single base deletion
      which was predicted to produce a truncated protein and gibberellin 2-oxidase
      activity could not be demonstrated from this cDNA. A 10 bp size difference
      between the introns of the SLN and sln PsGA2ox1 genes was used to show co
      segregation between the SLN and sln phenotypes and the size of the PCR products.
      PsGA2ox1 transcripts were more abundant in cotyledons than in shoots, while the
      reverse was the case for PsGA2ox2. The expression patterns of the genes, together
      with the effects of the sln mutation, indicate that PsGA2ox1 plays a major role
      in GA20 deactivation in both shoots and maturing seeds, while the PsGA2ox2 gene
      might be important for GA1 deactivation in the shoot.

PMID- 10417728
TI  - Short communication: emission of nitrous oxide (N2O) from transgenic tobacco
      expressing antisense NiR mRNA 
AB  - The emission of N2 and N2O from intact transgenic tobacco (clone 271) expressing
      antisense nitrite reductase (NiR) mRNA, and wild-type plants grown aseptically,
      on NO3-, NO2- or NH4+ -containing medium was investigated. 15N contents of gas
      sampled from gas-sealed pots, in which the plants were grown on 15N-containing
      medium, were analyzed by gas chromato- graphy and mass spectrometry (GC-MS). No
      emission of N2 was detected in either of the gas samples from plant clone 271 or
      the wild-type grown on NO3--containing medium. N2O emission from clone 271 grown
      on NO3--containing medium was detected, but not from the wild-type plants. The
      N2O emission rate of clone 271 was 106 ng N2O mg-1 incorporated N week-1 and the
      N2O emission was inhibited by tungstate (a nitrate reductase inhibitor). No
      emission of N2O was found from clone 271 or wild-type plants grown on medium
      containing NH4+. Emission of N2O also was detected from clone 271 grown on NO2-
      containing medium and its emission rate increased with increasing NO2- levels in
      plants. We speculate that NO3- is reduced to NO2- and that a part of NO2- is
      metabolized to N2O in clone 271.

PMID- 10417729
TI  - Cymbidium hybrida dihydroflavonol 4-reductase does not efficiently reduce
      dihydrokaempferol to produce orange pelargonidin-type anthocyanins.
AB  - Some angiosperms are limited to a range of possible flower colors. This
      limitation can be due to the lack of an anthocyanin biosynthetic gene or to the
      substrate specificity of a key anthocyanin biosynthetic enzyme, dihydroflavonol 4
      reductase (DFR). Cymbidium hybrida orchid flowers primarily produce cyanidin-type
      (pink to red) anthocyanins and lack the pelargonidin-type (orange to brick-red)
      anthocyanins. To investigate the underlying molecular mechanism of this flower
      color range, we cloned a Cymbidium DFR gene and transformed it into a DFR-
      petunia line. We found that the Cymbidium DFR did not efficiently reduce
      dihydrokaempferol (DHK), which is an essential step for pelargonidin production.
      Phylogenetic analysis of a number of DFR sequences indicate that the inability to
      catalyze DHK reduction has occurred at least twice during angiosperm evolution.
      Our results indicate that developing a pelargonidin-type orange flower color in
      Cymbidium may require the transformation of a DFR gene that can efficiently
      catalyze DHK reduction.

PMID- 10417730
TI  - Technical advance: transcriptional activator TGV mediates dexamethasone-inducible
      and tetracycline-inactivatable gene expression 
AB  - A chemically regulated gene expression system that can be switched on with
      dexamethasone and switched off with tetracycline was constructed. It is based on
      a transcriptional activator (TGV) that consists of the Tn10 encoded Tet
      repressor, the rat glucocorticoid receptor hormone binding domain and the
      transcriptional activation domain of Herpes simplex virion protein VP16. When
      stably expressed in transgenic tobacco plants, it mediates dexamethasone
      inducible transcription from a synthetic promoter (PTop10) consisting of seven
      tet operators upstream of a TATA-box. Tetracycline interferes with induction by
      negatively regulating the DNA-binding activity of the TetR moiety of TGV. The
      boundaries of the expression window of the TGV-driven PTop10 reach from
      undetectable levels of the reporter enzyme beta-glucuronidase in the absence of
      dexa- methasone to induced levels reaching 15-20% of the Cauliflower Mosaic Virus
      35S promoter (PCaMV35S). By modifying the sequence of PTop10, we generated a new
      target promoter (PTax) that is stably expressed over several generations and that
      can be activated to levels comparable to PCaMV35S, while yielding only slightly
      elevated background activities.

PMID- 10417732
TI  - Thematic review series VII: genetic variability in response to infection
      introduction 

PMID- 10417731
TI  - Ecdysone agonist inducible transcription in transgenic tobacco plants.
AB  - A novel chemical-induced gene regulatory system for plants consisting of two
      molecular components is described. The first, or regulatory, cassette comprises a
      chimeric receptor composed of the hinge and ligand binding domains of the
      Heliothis virescens ecdysone receptor and the transactivation domain of the
      Herpes simplex VP16 protein fused to the DNA binding domain and transactivation
      of a mammalian glucocorticoid receptor. The second component, a reporter
      cassette, contains six copies of the glucocorticoid response element (GRE) fused
      to the minimal 35SCaMV promoter and beta-glucuronidase. The system uses a
      commercially available non-steroidal ecdysone agonist, RH5992 (tebufenozide), as
      an inducer. Activation of gene expression is shown in both tobacco transient
      protoplasts and transgenic plants. The response is ligand dependent and is
      modulated by the change in minimal promoter context. The system is capable of
      inducing transgene activity up to 420-fold corresponding to 150% of the activity
      observed with positive controls (35SCaMV:GUS).

PMID- 10417733
TI  - The immunogenetics of resistance to malaria.
AB  - The genetic basis of susceptibility to malaria has been studied extensively using
      a variety of approaches. The protective role of several erythrocytic variants is
      now well established. More recently, there has been growing evidence that genes
      determining a variety of immune responses influence susceptibility to malaria.
      Some of these genes may specifically affect susceptibility to particular strains
      of malaria parasite. The recent adoption of genetic linkage approaches
      supplements the established strategy of assessing candidate gene polymorphisms in
      case-control studies. Immunogenetic associations with severe malaria have already
      suggested new approaches for intervention, and the highly polygenic nature of
      susceptibility to this disease suggests that the identification and analysis of
      new susceptibility and resistance loci should be worthwhile.

PMID- 10417734
TI  - Thalassemia and malaria: new insights into an old problem.
AB  - The hemoglobinopathies are probably the world's most common genetic diseases: The
      World Health Organization has estimated that at least 5% of the population are
      carriers for one or other of the most serious forms, the alpha- and beta
      thalassemias and the structural variant hemoglobins S, C, and E, which are found
      at polymorphic frequencies in many countries. All these hemoglobinopathies are
      believed to provide protection against malaria, and it is thought that, in
      malarial regions of the world, natural selection has been responsible for
      elevating and maintaining their gene frequencies, an idea first proposed 50 years
      ago by J.B.S. Haldane. Epidemiological studies undertaken in the 1950s on
      hemoglobin S in Africa provided support for the "malaria hypothesis," but until
      recently it has proved extremely difficult to verify it for the thalassemias. The
      application of molecular methods has, however, provided new opportunities to
      address this old question. Population and molecular genetic analysis of
      thalassemia variants, and microepidemiological studies of the relationship
      between alpha-thalassemia and malaria in the southwest Pacific, have provided
      unequivocal evidence for protection. Surprisingly, some of this protection
      appears to derive from enhanced susceptibility in very young thalassemic children
      to both Plasmodium falciparum and, especially, P. vivax, and this early exposure
      appears to provide the basis for better protection in later life.

PMID- 10417735
TI  - The Nramp1 protein and its role in resistance to infection and macrophage
      function.
AB  - Susceptibility to infectious diseases is under genetic control in humans. Animal
      models provide an ideal tool to study the genetic component of susceptibility and
      to identify candidate genes that can then be tested for association or linkage
      studies in human populations from endemic areas of disease. The Nramp1 gene was
      isolated by positional cloning the host resistance locus Bcg/Ity/Lsh, and
      mutations at this locus impair the resistance of mice to infections with
      intracellular parasites, such as Salmonella, Leishmania, and Mycobacterium.
      Allelic variants at the human Nramp1 homologue have recently been found to be
      associated with susceptibility to tuberculosis and leprosy in humans. The Nramp1
      protein is an integral membrane protein expressed exclusively in the lysosomal
      compartment of monocytes and macrophages. After phagocytosis, Nramp1 is targeted
      to the membrane of the microbe-containing phagosome, where it may modify the
      intraphagosomal milieu to affect microbial replication. Although the biochemical
      mechanism of action of Nramp1 at that site remains unknown, Nramp homologues have
      been identified in many other animal species and actually define a protein family
      conserved from bacteria to humans. Some of these homologues have been shown to be
      divalent cation transporters. Recently, a second member of the mammalian Nramp
      family, Nramp2, was discovered and shown to be mutated in animal models of iron
      deficiency. The Nramp2 protein was subsequently shown to be the major transferrin
      independent iron uptake system of the intestine. Together, these results suggest
      that Nramp1 may control intracellular microbial replication by actively removing
      iron or other divalent cations from the phagosomal space.

PMID- 10417736
TI  - Inherited variability of tumor necrosis factor production and susceptibility to
      infectious disease.
AB  - Tumor necrosis factor (TNF) is a critical mediator of host defense against
      infection but may cause severe pathology when produced in excess. Individuals
      vary in the amount of TNF produced when their peripheral blood mononuclear cells
      are stimulated in vitro, and family studies indicate that much of this
      variability is genetically determined. Since the TNF response to infection is
      partly regulated at the transcriptional level, TNF promoter polymorphisms have
      been the subject of intense interest as potential determinants of disease
      susceptibility. A single nucleotide polymorphism at nucleotide -308 relative to
      the transcriptional start site has been associated with susceptibility to severe
      malaria, leishmaniasis, scarring trachoma, and lepromatous leprosy. Some
      experimental data indicate that this polymorphism acts to upregulate TNF
      transcription, but this remains controversial. Detailed analysis of multiple
      genetic markers at this locus and more sophisticated investigations of TNF
      transcriptional regulation, in different cell types and with a wide range of
      stimuli, are required to understand the molecular basis of these disease
      associations.

PMID- 10417738
TI  - Understanding the genetic basis of susceptibility to mycobacterial infection.
AB  - Genetic factors have long been suspected of determining susceptibility and
      resistance to mycobacterial infection. The recent identification of families with
      a unique susceptibility to mycobacterial infection, and the identification of
      mutations in the genes for either the interferon-gamma (IFN-gamma) receptor or
      the interleukin (IL)-12 receptor as the cause of the defect, has provided an
      important clue to the pathways critical for resistance to mycobacterial infection
      in humans. Although the genetically determined absence of key cytokines or their
      receptors results in susceptibility to lethal mycobacterial infections in early
      childhood, it is likely that more subtle mutations that result in only partial
      dysfunction of macrophage upregulation pathways may play a role in susceptibility
      to tuberculosis (TB) and leprosy in the general population.

PMID- 10417737
TI  - Genetic determinants of HIV-1 infection and its manifestations.
AB  - The human immunodeficiency virus type 1 (HIV-1), which has become pandemic within
      a single generation, has encountered an immune system in which genetically
      encoded elements have evolved gradually under different environmental pressures
      in diverse populations. Important heritable differences in genes that alter
      susceptibility to HIV-1 infection or the rate of deterioration of immunity, or
      both, have been discovered in cohorts carefully defined for intensity of exposure
      to the virus, viral subtype characteristics, and onset and course of infection.
      For the highly polymorphic human leukocyte antigen (HLA) antigen processing and
      presenting system, the principle that small contributions of multiple interactive
      HLA marker combinations (primarily in the class I pathway) significantly modulate
      the course of HIV-1 infection has now been confirmed in several independently
      evaluated groups of patients. Variants of HLA genes probably also play some role
      in the acquisition of infection by the various routes of transmission. Genes for
      an elaborate set of circulating chemokine molecules and their cell-surface
      receptors clearly regulate cell attachment and penetration of HIV. Certain
      allelic forms of one, the CCR5 gene, alter susceptibility to infection and the
      rate of progression of disease; in the homozygous state, a deleted form (Delta32
      CCR5) strongly protects against infection, and in infected heterozygotes, it
      slows the disease process somewhat. Mutants in genes of other chemokine system
      components further differentiate the response to infection, and frequencies of
      these forms vary between and within races. Work relating additional genetic
      markers to HIV infection or disease is at earlier stages. Dissecting the effects
      of multiple variants in complex gene systems will clearly require organized
      comprehensive approaches in considerably larger populations than have typically
      been assembled.

PMID- 10417739
TI  - The potential influence of insulin and plasminogen activator inhibitor type 1 on
      the formation of vulnerable atherosclerotic plaques associated with type 2
      diabetes.
AB  - Insulin-resistant states, including type 2 diabetes mellitus, are associated with
      increased concentrations of plasminogen activator inhibitor type 1 (PAI-1) in
      blood and in extracted coronary atheroma, as well as with an increased incidence
      of acute coronary syndromes, known to be precipitated by the rupture of
      vulnerable atherosclerotic plaques. However, plaque rupture is potentiated by
      proteolysis. Accordingly, the parallel relationship between augmentation of
      concentrations of an inhibitor of proteolysis and plaque vulnerability appears to
      be paradoxical. The following resolution is proposed. Reduced cellularity of
      plaques may result when high concentrations of PAI-1 in early atheroma inhibit
      the migration of vascular smooth muscle cells into the neointima. Such migrating
      cells subsequently proliferate. If their total number is reduced, the composition
      of plaques may be altered throughout development with the reduction of vascular
      smooth muscle cell content and consequent additional changes. In aggregate, such
      changes may render mature, complex plaques vulnerable to rupture mediated by
      proteolysis responsible for the degradation of thin fibrous caps on relatively
      acellular, lipid-laden plaques.

PMID- 10417740
TI  - Novel mechanisms of calcium handling by the osteoclast: A review-hypothesis.
AB  - The osteoclast is a cell that is unique in its ability to resorb bone and, in
      doing so, becomes exposed to unusually high millimolar Ca2+ concentrations. It is
      generally accepted that, during resorption, osteoclasts can "sense" changes in
      their ambient Ca2+ concentration. This triggers a sharp cytosolic Ca2+ increase
      through both Ca2+ release and Ca2+ influx. The change in cytosolic Ca2+ is
      transduced finally into inhibition of bone resorption. It has been shown that a
      type 2 ryanodine receptor isoform, expressed uniquely in the plasma membrane,
      functions as a Ca2+ influx channel and possibly as a Ca2+ sensor. Ryanodine
      receptors are ordinarily Ca2+ release channels that have a microsomal membrane
      location in a wide variety of eukaryotic cells, including the osteoclasts.
      However, only recently has it become obvious that ryanodine receptors are also
      expressed in osteoclast nuclear membranes, at which site they probably gate
      nucleoplasmic Ca2+ influx. Nucleoplasmic Ca2+ in turn regulates key nuclear
      processes, including gene expression and apoptosis. Here, we review the potential
      mechanisms underlying the recognition, movement, and effects of Ca2+ in the
      osteoclast. We will also speculate on the general biological significance of the
      unique processes used by the osteoclast to handle high Ca2+ loads during bone
      resorption.

PMID- 10417741
TI  - Enterococci: new aspects of an old organism.
AB  - Enterococci are a long-known cause of bacterial endocarditis and a more recently
      recognized cause of nosocomial infection and superinfection. While much is known
      about the many antibiotic resistances of enterococci, less is known about the
      organism itself and how it causes disease. This article presents a brief overview
      of enterococci and its possible virulence factors and summarizes the authors'
      efforts to understand the features of this organism that may contribute to its
      disease potential.

PMID- 10417742
TI  - Inosine monophosphate dehydrogenase: A molecular switch integrating pleiotropic
      GTP-dependent beta-cell functions.
AB  - Studies of pancreatic islet function in the pathogenesis of type 2 diabetes
      mellitus have tended to focus on the short-term control of insulin secretion.
      However, the long-term control of beta-cell mass is also relevant to diabetes,
      since this parameter is reduced substantially even in non-insulin-dependent
      diabetes in humans. In animal models of type 2 diabetes, the normal balance
      between beta-cell proliferation and programmed cell death is perturbed. We take
      the perspective in this overview that inosine monophosphate dehydrogenase (IMPDH;
      EC 1.1.1. 205) may represent a previously neglected molecular integrator or
      sensor that exerts both functional (secretory) and anatomical (proliferative)
      effects within beta-cells. These properties reflect the fact that IMPDH is a rate
      limiting enzyme in the new synthesis of the purine guanosine triphosphate (GTP),
      which modulates both exocytotic insulin secretion and DNA synthesis, as well as a
      number of other critical cellular functions within the beta-cell. Alterations in
      the expression or activity of IMPDH may be central to beta-cell replication, cell
      cycle progression, differentiation, and maintenance of adequate islet mass,
      effects that are probably mediated both by GTP directly, and indirectly via low
      molecular mass GTPases. If GTP becomes depleted, a hierarchy of beta-cell
      functions becomes progressively paralyzed, until eventually the effete cell is
      removed via apoptosis.

PMID- 10417745
TI  - Abner McGehee harvey 1911-1998 

PMID- 10417743
TI  - Characterization of a multicopy family of genes encoding a surface-expressed
      serine endoprotease in rat Pneumocystis carinii.
AB  - A unique family of genes encoding serine endoproteases related to the
      Saccharomyces cerevisiae serine endoprotease kexin was identified in Pneumocystis
      carinii. Unlike previously described serine endoprotease genes that are single
      copies, multiple copies of the P. carinii serine endoprotease are distributed
      throughout the genome. The proteins predicted by these variant genes demonstrate
      sequence variability, but they retain the conserved active sites associated with
      endoprotease activity. The serine endoprotease was localized to the organism
      surface by immunohistochemical and immunofluorescence studies and to the electron
      lucent layer of the cyst wall by immunoelectron microscopy. The findings of
      multiple copies of the serine endoprotease gene in the P. carinii genome, and its
      localization to the cell surface, suggest that this protease plays an important
      role in the biology of P. carinii and that antigenic variation of the surface
      expressed serine endoprotease may be a strategy for immune evasion. P. carinii
      serine endoprotease provides a novel target for chemotherapeutic and immune-based
      approaches to the treatment of P. carinii pneumonia.

PMID- 10417744
TI  - Angiotensin II induces alpha3(IV) collagen expression in cultured murine proximal
      tubular cells.
AB  - Angiotensin II (ANG II) induces cellular hypertrophy of cultured proximal tubular
      cells from various species. This hypertrophic response is associated with an
      increase in synthesis of basement membrane-associated collagen type IV. Previous
      investigations by our group have shown that ANG II stimulates mRNA and protein
      expression of the "classic" alpha1 and alpha2(IV) chains in cultured murine
      proximal tubular cells (murine cortical tubules [MCT cells]). Since it is clearer
      today that kidney basement membranes also contain heterotrimers of novel type IV
      collagens, the aim of the present study was to evaluate whether ANG II may
      influence the expression of alpha3 and alpha5(IV) collagen chains in MCT cells. A
      single dose of 10-8-10-6 M ANG II stimulated mRNA expression of alpha3(IV), but
      not of alpha5(IV), in MCT cells cultured in serum-free media. This response was
      mediated through AT1-receptors because losartan, but not an AT2-receptor
      antagonist, abolished the ANG II-induced expression of alpha3(IV) transcripts.
      Transient transfection of MCT cells with transforming growth factor-beta1 (TGF
      beta1) antisense phosphorothioate-modified oligonucleotides partly abolished the
      ANG II-induced alpha3(IV) mRNA expression. Furthermore, Western blots of cellular
      lysates incubated with polyclonal antibodies generated against the recombinant
      collagen chains revealed that ANG II stimulated alpha3(IV) but not alpha5(IV)
      protein expression. This stimulation was partly prevented by co-incubation with a
      neutralizing anti-TGF-beta1-3 antibody. In summary, our data indicate that ANG II
      stimulates expression of the alpha3(IV) collagen chain in cultured MCT cells, due
      in part to TGF-beta1 activation.

PMID- 10417747
TI  - Editorial: ten years later 

PMID- 10417746
TI  - Sidney C. Werner 1909-1994 

PMID- 10417748
TI  - Perspective article: transforming growth factor-beta: crossroad of glucocorticoid
      and bleomycin regulation of collagen synthesis in lung fibroblasts.
AB  - Fibrosis is a consequence of injury which is characterized by accumulation of
      excess collagen and other extracellular matrix components, resulting in the
      destruction of normal tissue architecture and function. Transforming growth
      factor-beta, a potent wound healing agent, has also been shown to be an agent
      that can produce fibrosis because it is a potent stimulator of collagen
      synthesis. Both glucocorticoids and bleomycin have recently been shown to affect
      collagen synthesis in opposite directions, by utilizing a common pathway of
      involving transforming growth factor-beta activator protein binding to the
      transforming growth factor-beta element. This article presents a mechanistic
      overview of collagen synthesis regulation by glucocorticoids and bleomycin
      through the transforming growth factor-beta pathway.

PMID- 10417749
TI  - Becaplermin gel in the treatment of pressure ulcers: a phase II randomized,
      double-blind, placebo-controlled study.
AB  - Pressure ulcers are associated with significant rates of morbidity and mortality,
      particularly in the geriatric and spinal cord-injured populations. Newer
      pharmacologically active therapies include the use of topically applied
      recombinant human platelet-derived growth factor-BB (becaplermin), the active
      ingredient in REGRANEX) (becaplermin) Gel 0.01%, which has been approved in the
      United States for treatment of lower extremity diabetic neuropathic ulcers that
      extend into the subcutaneous tissue or beyond and have an adequate blood supply.
      In this study, the efficacy of becaplermin gel in the treatment of chronic full
      thickness pressure ulcers was compared with that of placebo gel. A total of 124
      adults (>/= 18 years of age) with pressure ulcers were assigned randomly to
      receive topical treatment with becaplermin gel 100 microg/g (n = 31) or 300
      microg/g (n = 32) once daily alternated with placebo gel every 12 hours,
      becaplermin gel 100 microg/g twice daily (n = 30), or placebo (sodium
      carboxymethylcellulose) gel (n = 31) twice daily until complete healing was
      achieved or for 16 weeks. All treatment groups received a standardized regimen of
      good wound care throughout the study period. Study endpoints were the incidence
      of complete healing, the incidence of >/= 90% healing, and the relative ulcer
      volume at endpoint (endpoint/baseline). Once-daily treatment of chronic pressure
      ulcers with becaplermin gel 100 microg/g or 300 microg/g significantly increased
      the incidences of complete and >/= 90% healing and significantly reduced the
      median relative ulcer volume at endpoint compared with that of placebo gel (p <
      0.025 for all comparisons). Becaplermin gel 300 microg/g did not result in a
      significantly greater incidence of healing than that observed with 100 microg/g.
      Treatment with becaplermin gel was generally well tolerated and the incidence of
      adverse events was similar among treatment groups. In conclusion, once-daily
      application of becaplermin gel is efficacious in the treatment of chronic full
      thickness pressure ulcers.

PMID- 10417750
TI  - Recombinant adenoviral mediated gene transfer in ischemic impaired wound healing.
AB  - Chronic nonhealing wounds represent a large clinical problem resulting in severe
      disabilities and large healthcare expenditures. Despite the scope of this
      problem, effective new therapies are lacking. The deficiency of growth factors in
      chronic wounds has brought attention to the topical application of growth
      factors, but initial clinical trials have resulted in only modest improvements in
      healing despite large, repetitive doses. The modest improvement in healing
      observed in these trials show that growth factors can improve chronic wound
      healing, but a better means of growth factor delivery is needed. We hypothesized
      that gene therapy using a recombinant adenoviral vector could be used to induce
      transgene production directly by cells in the wound. An adenovirus containing the
      beta-galactosidase reporter transgene (Ad-LacZ) was used in the ischemic rabbit
      ear model to test this hypothesis. Ad-LacZ resulted in efficient transgene
      delivery to cells participating in the wound healing response, with expression up
      to 2 weeks. However, wound reepithelialization was impaired in Ad-LacZ treated
      wounds compared to vehicle control wounds. Adenoviral mediated gene transfer is a
      promising efficient means of growth factor delivery to chronic wounds. However,
      selection of the proper transgene with appropriate biologic activity in wound
      healing may be essential to overcome the potential adverse effects of adenoviral
      infection.

PMID- 10417751
TI  - Temporal expression of urokinase plasminogen activator, plasminogen activator
      inhibitor and gelatinase-B in chronic wound fluid switches from a chronic to
      acute wound profile with progression to healing.
AB  - The plasminogen activator/plasmin system is known to initiate a proteolytic
      cascade resulting in the activation of matrix metalloproteinases in vitro leading
      to the degradation of extracellular matrix. To investigate whether or not this
      cascade is present during delayed wound healing and contributes to the
      pathophysiological basis of impaired healing we examined the temporal expression
      of urokinase plasminogen activator, plasminogen activator inhibitor-1 and
      gelatinase-B in fluid collected from chronic venous leg ulcers compared to acute
      surgical mastectomy wounds. Using a chromogenic substrate assay, levels of active
      urokinase plasminogen activator in chronic wounds were found to be about five
      fold higher compared to sera and two fold higher compared to mastectomy wounds.
      Levels of active plasminogen activator inhibitor-1 in chronic wounds were four
      times higher than those found in sera and two times higher than those found in
      mastectomy wound fluid. Using a fibrin overlay system and reverse zymography, we
      found that when the wound was not healing, the expression of urokinase
      plasminogen activator in chronic wound fluid was initially detected in the active
      forms (50 and 33 kDa), but that as the wound healed and decreased in size, was
      detected as an inhibitor- bound urokinase plasminogen activator-plasminogen
      activator inhibitor-1 complex ( congruent with 80-116 kDa). When the expression
      of active urokinase plasminogen activator was highest, no plasminogen activator
      inhibitor-1 was detectable. In contrast, urokinase plasminogen activator was
      always detected in the inhibitor bound form as a urokinase plasminogen activator
      plasminogen activator inhibitor-1 complex in blood- and plasma-derived serum and
      mastectomy wound fluid. Plasminogen activator inhibitor-1 was detected in blood
      derived serum and mastectomy wound fluid but not in plasma derived serum.
      Expression of matrix metalloproteinase-9 in chronic wound fluids, analyzed by
      gelatin zymography, showed that when urokinase plasminogen activator was detected
      in the active forms, matrix metalloproteinase-9 was overexpressed by
      approximately twice that found in mastectomy wounds and approximately 30 times
      that detected in blood-derived sera. When urokinase plasminogen activator
      appeared almost entirely as an enzyme- inhibitor complex, the level of expression
      of matrix metalloproteinase-9 was similar to that seen in mastectomy wound fluid.
      We conclude that the switch in urokinase plasminogen activator expression from an
      active to inhibitor bound form correlates with the decrease seen in matrix
      metalloproteinase-9 expression suggesting the presence of a proteolytic cascade
      initiated by the plasminogen activator/plasmin system during wound healing
      leading to the activation of matrix metalloproteinase-9. In addition, expression
      of urokinase plasminogen activator and matrix metalloproteinase-9 appear to be
      useful biomarkers to determine clinical wound healing status.

PMID- 10417752
TI  - Gelatinase activity in keloids and hypertrophic scars.
AB  - Keloids and hypertrophic scars are characterized by excessive deposition of
      collagen, which may result from insufficient protein degradation. Little is known
      about the levels of two gelatinases, matrix metalloproteinase-2 (72 kD type IV
      collagenase) and matrix metalloproteinase-9 (matrix metalloproteinase-9; 92 kD
      type IV collagenase) in these abnormal scars. The purpose of this study was to
      determine levels of these proteinases in tissue from hypertrophic scars, keloids,
      and donor skin. Ten hypertrophic scar samples, 9 keloid samples, and 10 donor
      skin samples were frozen, pulverized, homogenized, clarified by centrifugation,
      and analyzed for matrix metalloproteinases by quantitative zymography. Identity
      of matrix metalloproteinases was determined using a conditioned media reference
      standard, molecular weight ladders, and Western blotting. Levels of matrix
      metalloproteinase-9 activity were very low or undetectable in all samples.
      However, matrix metalloproteinase-2 activity was significantly elevated in
      keloids and hypertrophic scars vs. donor samples: 2.6 and 3.9-fold increases for
      latent matrix metalloproteinase-2, 7.8 and 6.9-fold increases for active matrix
      metalloproteinase-2, respectively. We conclude that little matrix
      metalloproteinase-9 activity (the gelatinase involved in early tissue repair) is
      present in keloids and hypertrophic scars, while matrix metalloproteinase-2
      activity (the gelatinase involved in prolonged tissue remodeling) is present in
      donor skin and is significantly increased in hypertrophic scars and keloids.

PMID- 10417753
TI  - In vivo characterization of keratinocyte growth factor-2 as a potential wound
      healing agent.
AB  - Human keratinocyte growth factor-2 exerts a proliferative effect on epithelial
      cells and mediates keratinocyte migration. It has also been shown to increase
      both deposition of granulation tissue and collagen and maturation of collagen.
      Because these properties should affect the healing trajectory of wounds, this
      study set out to investigate the effects of keratinocyte growth factor-2 on the
      healing of three different types of wounds. Human meshed skin grafts explanted to
      athymic "nude" rats, surgical incisions in Sprague-Dawley rats, and acute
      excisional rat wounds inoculated with Escherichia coli were used. Two
      concentrations of recombinant human keratinocyte growth factor-2 were compared to
      a vehicle control and keratinocyte growth factor-1. Keratinocyte growth factor-2
      significantly accelerated the rate of epithelialization in the meshed skin graft
      model and effected a modestly more rapid gain in breaking strength of surgical
      incisions than keratinocyte growth factor-1 or the vehicle control treatment.
      Neither keratinocyte growth factors accelerated wound closure by contraction of
      the excisional wounds. Based on these data, keratinocyte growth factor-2 may be
      useful in accelerating healing in wounds healing mainly by the process of
      epithelialization such as venous stasis ulcers, partial thickness burn wounds,
      and skin graft donor sites. It might also accelerate the gain in incisional wound
      strength in acute surgical or traumatic wounds.

PMID- 10417754
TI  - Collagen fiber orientation as quantified by small angle light scattering in
      wounds treated with transforming growth factor-beta2 and its neutalizing
      antibody.
AB  - The purpose of this study was determine quantitative differences in collagen
      fiber orientation in a wound healing model in the presence of transforming growth
      factor-beta2 and anti-transforming growth factor-beta2,3 antibody. Full-thickness
      wounds were made in the paravertebral area of two young pigs. Wounds were treated
      once, topically, with either transforming growth factor-beta2 or anti
      transforming growth factor-beta2 antibody, or with methylcellulose gel. Control
      wounds were left untreated. Tissue biopsies were obtained from each wound on days
      7, 14 and 46 post wounding. Tissue sections were stained with hematoxylin and
      eosin, and collagen fiber preferred orientation was quantified using small angle
      light scattering. Our results indicated that wounds treated with transforming
      growth factor-beta2 and anti-transforming growth factor-beta2,3 antibody had a
      significantly higher degree of orientation of collagen fibers than normal
      unwounded skin on days 7, 14 and 46 (p < 0.001). Transforming growth factor-beta2
      treated wounds had a higher degree of orientation of collagen fibers than
      control wounds on days 7 and 14 (p < 0.001), and control wounds displayed a
      higher degree of orientation than wounds treated with anti-transforming growth
      factor-beta2,3 and normal unwounded skin at all time points (p < 0.001). These
      results suggest that differences in the dermal collagen degree of orientation
      correlate with scarring, and show that small angle light scattering can be used
      quantitatively to assess differences in the collagen fiber architecture of dermal
      wounds.

PMID- 10417755
TI  - Evaluation of clinically applicable exsanguination treatments to alleviate venous
      congestion in an animal skin flap model.
AB  - This study compares the effectiveness of alleviating venous congestion with
      mechanically-made outlets or leech therapy in promoting skin flap survival. Free
      flaps of abdominal skin (3 x 6 cm) were raised on Sprague-Dawley rats and
      subjected to ischemic events, simulating venous congestion. Animals received 1)
      no treatment; 2) two treatments involving two 18-gauge needle-puncture outlets;
      or 3) two sessions of leech therapy. Flap perfusion was monitored with a scanning
      laser Doppler flowmeter. Photographic images of flaps at 7 days were assessed for
      areas of normal tissue (n = 15), and laser Doppler flowmeter data consisted of
      control (n = 6), outlet (n = 6), and leech (n = 7). Both the needle-puncture
      outlet (40.0% +/- 9.24%) and leech treated (34.6% +/- 7.34%) groups had a
      significantly greater surviving skin area than untreated control flaps (8.0% +/-
      5.0%), with 2 of 15 flaps receiving mechanical outlets exhibiting > 90% surviving
      area. After 7 days, laser Doppler flowmeter data showed greater mean perfusion in
      the outlet (71.7% +/- 16.8%) and leech (92.6% +/- 17.2%) treated groups, compared
      to controls (15.2% +/- 10.2%). There was a significant increase in perfusion in
      the outlet (13.3% +/- 6.2%) and leech (9.1% +/- 1.1%) treated groups from the end
      of secondary ischemia to day 7 (p < 0.05) compared to controls. The results
      suggest that two spatially separated outlets are as effective as one leech in
      increasing the area of surviving skin in venous congested flaps.

PMID- 10417756
TI  - beta-catenin mutation and expression analysis in ovarian cancer: exon 3 mutations
      and nuclear translocation in 16% of endometrioid tumours.
AB  - The molecular mechanisms involved in the generation of epithelial ovarian cancers
      are poorly understood, but evidence suggests that the different histological
      subtypes may arise from independent tumorigenic events. beta-Catenin is emerging
      as an important oncogene in the transformation of a number of epithelial cancers,
      and mutations have been reported in a small study of endometrioid ovarian
      adenocarcinomas. Mutations in the NH(2)-regulatory domain of beta-catenin
      stabilise the cytoplasmic levels of this protein, which promotes up-regulation of
      the beta-catenin-T-cell factor-lymphoid enhancer factor transcriptional complex.
      We report here beta-catenin (CTNNB1) exon 3 mutation analysis in 149 epithelial
      ovarian carcinomas. This revealed 10/63 (16%) endometrioid ovarian tumours with
      activating mutations of the beta-catenin gene. All mutations were missense
      changes within the GSK3beta consensus site, affecting serine residues at codons
      33 and 37 and glycine at codon 34. Immuno-histochemical analysis identified
      cytoplasmic stabilisation and nuclear translocation in those endometrioid tumours
      with mutations. This phenotypic change was also identified in 3 other
      endometrioid tumours that did not have somatic mutations within exon 3 of CTNNB1.
      Stabilisation of the free, monomeric pool of beta-catenin and the probable
      resulting constitutive activation of its Tcf-associated transcriptional complex
      appears to be a specific oncogenic event in endometrioid ovarian adenocarcinoma.

PMID- 10417757
TI  - HLA-A alleles of patients with pyothorax-associated lymphoma: anti-Epstein-Barr
      virus (EBV) host immune responses during the development of EBV latent antigen
      positive lymphomas.
AB  - Pyothorax-associated lymphoma (PAL) is an Epstein-Barr virus (EBV) latent antigen
      positive lymphoma resembling EBV-transformed lymphoblastoid cell lines (LCLs) and
      develops in non-immunocompromised patients. Thus, deficient anti-viral-antigen
      immune responses might be involved in the development of PAL. As MHC class I
      restricted cytotoxic T lymphocytes (CTLs) are the major constituent of anti-viral
      immune responses, the HLA allele type and its expression may affect the
      development of PAL. Flow-cytometric analyses of PAL cell lines and LCLs using the
      W6/32 monoclonal antibody revealed that expression of HLA class I varied among
      cell lines. Although one PAL cell line, OPL-2, exhibited low expression, an LCL
      and another PAL cell line, OPL-1, strongly expressed HLA class I. Among the EBV
      latent infection genes, EBV nuclear antigens 2, 3, 4 and 6 and latent membrane
      proteins can induce efficient CTL responses in combination with HLA-A2 or -A11.
      HLA-A alleles of PAL patients were determined using low-resolution PCR-based
      typing with HLA-A locus sequence-specific primer combinations. The antigen
      frequencies of HLA-A2 and -A11 in PAL patients were not significantly different
      from those in the normal Japanese population. Although HLA class I antigen should
      be expressed during the course of lymphomagenesis, no HLA-A alleles influenced
      the development of overt PALs.

PMID- 10417758
TI  - RER(+) phenotype in prostate intra-epithelial neoplasia associated with human
      prostate-carcinoma development.
AB  - The mutator (RER(+)) phenotype has been shown to be a mutational mechanism for
      tumour-suppressor-gene inactivation in colorectal cancer. A group of 60 prostate
      carcinoma patients was studied to determine the frequency, intratumour
      distribution and timing of mutator phenotype in this cancer. Ten microsatellite
      loci were analyzed in 172 carcinoma foci (CF) and in 57 associated non-cancerous
      prostate tissues, including 31 areas of prostate intra-epithelial neoplasia (PIN)
      and 26 non-dysplastic areas with glandular hyperplasia (HP). We detected lesions
      with the RER(+) phenotype in 42% (25/60) of the prostate tumours. Clonal foci
      with RER(+) phenotype were detected at similar frequencies in pre-cancereous PIN
      (16%, 5/31) as in associated carcinoma foci (22%, 37/172), but were detected in
      only one of the 26 non-dysplastic prostate tissues studied (4%). Thus, clonal
      RER(+) foci were significantly more frequent in CF than in HP (p < 0.05). MI
      itself was significantly more frequent in CF (53%, p < 0.0001) and in PIN (35%, p
      < 0.05) than in HP (12%). Furthermore, 5 PIN harboured microsatellite mutations
      also detected in the associated cancer. Our overall results therefore strongly
      suggest that the mutator phenotype may occur as an early event in prostate
      tumorigenesis.

PMID- 10417759
TI  - Novel mutation in the ATP-binding site of the MET oncogene tyrosine kinase in a
      HPRCC family.
AB  - Germline mutations in the tyrosine-kinase domain of the MET proto-oncogene were
      found in patients suffering from the hereditary predisposition to develop
      multiple papillary renal-cell carcinomas (hereditary PRCC, HPRCC). PRCCs are
      often multiple and bilateral even in patients without a family history. We
      analyzed the germline of patients carrying multiple or single papillary tumors
      with and without family history. One patient had a familial cancer and carried a
      novel (V1110I) germline MET mutation, located in MET gene exon 16. This mis-sense
      mutation was found in affected members of this patient's family. Interestingly,
      the V1110I mutation is located in the ATP-binding site of the MET kinase and is
      homologous to the V157I mutation that triggers the sarcomagenic potential of the
      v-erbB oncogene. The V1110I mutated MET receptor is an active kinase and
      transforms NIH-3T3 fibroblasts in the in vitro assays. Patients without
      familiality did not show germline mutations in the MET kinase domain, showing
      that multiple and bilateral papillary kidney tumors develop in the absence of
      these mutations. In conclusion, we describe a new mutation in the MET oncogene
      kinase domain, associated to HPRCC, affecting an amino-acid residue critical for
      kinase activation in different oncogenes.

PMID- 10417760
TI  - Microsatellite instability in medullary breast carcinomas.
AB  - Microsatellite instability (MSI) has been reported to occur in a wide variety of
      sporadic tumours, such as colorectal and gastric cancers. MSI positivity has been
      associated with a particular clinico-pathologic profile, including the presence
      of abundant lymphoid infiltration, poor differentiation and a relatively good
      outcome for the patients. Since medullary breast carcinomas (MBCs) share these
      clinico-pathologic features with the MSI-positive tumours described above, we
      evaluated MSI in this particular histologic type of breast cancer. DNA of 24 MBC
      cases was extracted from formalin-fixed, paraffin-embedded tissue. The presence
      of MSI was analysed using BAT-26. We also searched mutations in 2 target genes:
      TGF-beta RII and BAX. Five cases of the series were also analysed for 1 (CA)
      dinucleotide tandem repeat sequence (D1S158), 8 tetranucleotide repeat sequences
      (D3S1358, D5S818, D7S820, D8S1179, D13S317, D21S11, FGA and VWA) and 1
      pentanucleotide repeat (dAAAAT), localized in intron 1 of p53 gene. We found 2
      carcinomas (8.3%) with BAT-26 instability. None of the cases had mutations in the
      "target genes", TGF-beta RII and BAX, including the 2 cases with BAT-26
      instability. No MSI was observed using the panel of tetra- and pentanucleotide
      markers. Loss of heterozygosity was found in some loci. No significant difference
      in mean MIB-1 index according to RER status was observed. The low frequency of
      MSI in MBC is similar to that of other histologic types of breast cancer.
      Although MBCs share some clinico-pathologic features with colorectal and gastric
      carcinomas, which exhibit a high frequency of MSI, the underlying genetic events
      leading to this breast tumour are different from those leading to tumours of the
      digestive tract.

PMID- 10417761
TI  - Prostaglandin-H-synthase isozyme expression in normal and neoplastic human skin.
AB  - Expression of prostaglandin-H-synthase (PGHS) isozymes was analyzed in 50
      biopsies of normal human skin and of pre-malignant and malignant skin lesions, by
      means of quantitative RT-PCR, immunoprecipitation and Western blotting, as well
      as immunohistochemistry. Normal skin constitutively expressed PGHS-1 in all cell
      layers of the epidermis, in endothelial cells of small blood vessels and in sweat
      gland epithelium. PGHS-2 expression was very low and restricted to a few
      keratinocytes of the interfollicular and follicular epidermis. Steady-state
      concentrations of PGHS-1 and PGHS-2 mRNA were similar in normal skin and in basal
      cell carcinomas, but PGHS-1 mRNA was reduced and PGHS-2 mRNA was elevated in
      actinic keratoses, squamous-cell carcinomas and keratoacanthomas. PGHS-1 protein
      was detected in all tumor biopsies, being occasionally increased in basal-cell
      carcinomas. High amounts of PGHS-2 protein were found in actinic keratoses,
      squamous-cell carcinomas and keratoacanthomas, but not in basal-cell carcinomas.
      Four malignant melanomas included in this study contained PGHS-1 but no PGHS-2
      protein. Immunohistochemical analysis of the biopsies identified keratinocytes,
      in addition to cells of inflammatory infiltrates and of dendritic morphology, as
      the major PGHS-expressing cell types. PGHS-2-specific signals were spread
      throughout the epidermal part of actinic keratoses and squamous-cell carcinomas.
      These data suggest that constitutive up-regulation of PGHS-2 expression is a
      consistent pre-malignant event in squamous-cell cancer development in man, as it
      is in animal models of skin carcinogenesis. Thus, pre-cancerous lesions such as
      actinic keratoses present a likely target for chemoprevention of skin cancer by
      selective PGHS-2 inhibitors.

PMID- 10417762
TI  - Independent and joint effects of tobacco smoking and alcohol drinking on the risk
      of esophageal cancer in men and women.
AB  - To estimate the independent and joint effects of tobacco smoking and alcohol
      drinking, we analyzed data from a series of 5 hospital-based case-control studies
      of squamous-cell carcinoma of the esophagus conducted in high-risk areas in South
      America. A total of 830 case subjects and 1779 control subjects were included in
      the pooled analysis. All exposure characteristics of amount, duration, cessation
      and type of alcohol and tobacco consumed were strongly related to esophageal
      cancer risk in both sexes. Women had the same exposure profile as men, but the
      magnitudes of the associations were lower than were those among men. Black
      tobacco smoking was associated with a 2-fold increased risk as compared with the
      smoking of blond or mixed tobacco. Quitting either of the 2 habits significantly
      reduced esophageal-cancer risk. Alcohol and tobacco alone were strongly related
      to the risk of esophageal cancer, even in the absence of the other exposure. A
      history of simultaneous exposure to cigarette smoking and alcohol drinking had a
      strong multiplicative effect on risk. Concomitant exposure to heavy alcohol
      drinking and black-tobacco smoking identified the group with the highest risk for
      developing esophageal cancer (odds ratio = 107). A synergistic interaction was
      found between the 2 habits, particularly in women and in moderately exposed men.
      Moderate cigarette smoking without drinking and moderate alcohol drinking without
      smoking had a negligible effect on esophageal-cancer risk. However, simultaneous
      exposure to the same moderate amounts increased the risk 12- to 19-fold in men
      and in women respectively. The overall public-health implications of these
      findings are obvious for a tumor that depends on preventive strategies for its
      control.

PMID- 10417763
TI  - Attenuation by d-limonene of sodium chloride-enhanced gastric carcinogenesis
      induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.
AB  - The effects of prolonged administration of d-limonene, a monocyclic monoterpene,
      on sodium chloride-enhanced induction of gastric carcinogenesis by N-methyl-N'
      nitro-N-nitrosoguanidine, the labeling and apoptotic indices, and ornithine
      decarboxylase (ODC) activity of gastric cancers were investigated in Wistar rats.
      After 25 weeks of carcinogen treatment, rats were given chow pellets containing
      10% sodium chloride and 1% limonene ad libitum. In week 52, the incidence of
      gastric cancers, the labeling index and ODC activity were significantly higher
      and the apoptotic index was significantly lower in rats given sodium chlolide
      than in untreated control rats. However, in rats given both sodium chloride and d
      limonene, the incidence of gastric cancers, the labeling index and ODC activity
      were significantly lower and the apoptotic index was significantly higher than in
      rats given sodium chloride alone. Our findings suggest that limonene attenuates
      the gastric carcinogenesis enhanced by sodium chloride via increased apoptosis
      and decreased ODC activity in gastric cancers.

PMID- 10417765
TI  - Malignant rhabdoid-tumor cell line showing neural and smooth-muscle-cell
      phenotypes.
AB  - Malignant rhabdoid tumor (MRT) is a rare and extremely aggressive malignant tumor
      in childhood. In this study, an MRT cell line, designated KP-MRT-NS, was
      established from the ascitic fluid taken from an 11-month-old girl, whose tumor
      had originated from the left kidney. Ultrastructural findings demonstrated the
      typical aggregation of whorls of intermediate filaments. Chromosome constitution
      was described as 46, XX, add (10)(q26)[17]/46, idem, dis (1;2)(q22;q31)[3] based
      on ISCN (1995) and a del (22)(q11.2) was not found in this cell line. The origin
      of MRT is controversial, various cellular origins having been proposed because of
      the phenotypic diversity of MRT. Therefore, in this study, to clarify the origin
      of MRT, the expressions of cytoplasmic proteins including smooth-muscle-specific
      proteins (alpha-smooth-muscle actin, basic calponin, smooth-muscle-myosin-heavy
      chain isoforms of SM1 and SM2) in the primary-MRT tissue and cell line were
      analyzed. In the primary-tumor tissue, the expressions of neurofilament, vimentin
      and alpha-smooth-muscle actin were demonstrated by indirect immunofluorescence.
      In the KP-MRT-NS cell line, the expression of neurofilament, alpha-smooth-muscle
      actin, basic calponin and smooth-muscle-myosin heavy chain of SM1 and SM2
      isoforms was revealed by immunofluorescence, Western blot and/or reverse
      transcriptase-polymerase chain reaction (RT-PCR). MyoD1 mRNA, determined as a
      skeletal-muscle-cell lineage marker, was not expressed in the primary-tumor
      tissue or in the KP-MRT-NS cell line. According to our findings, the MRT cells
      are of both neural and smooth-muscle cell phenotypes, and support the neural
      crest origin of MRT.

PMID- 10417764
TI  - Mass-spectrometric evaluation of HLA-A*0201-associated peptides identifies
      dominant naturally processed forms of CTL epitopes from MART-1 and gp100.
AB  - Melanoma-reactive human cytotoxic T lymphocytes (CTLs) mediate tumor regression
      in vivo through specific recognition of MHC-associated peptide epitopes, many of
      which are encoded by the melanocytic tissue differentiation proteins gp100/Pme117
      and MART-1/Melan-A. Vaccines using these peptides may induce protective or
      therapeutic immunity against melanoma. Rational design of such approaches is
      aided by a clear understanding of the identity of these antigenic peptides;
      however, most CTL epitopes described to date were identified indirectly.
      Especially where these peptides may be used in human clinical trials for the
      treatment or prevention of cancer, there is substantial need for direct
      evaluation of HLA-A*0201-associated peptides from MART-1 and gp100 that are
      naturally processed and presented. To that end, we have isolated peptides
      directly from HLA-A*0201 molecules of human melanoma cells and have determined
      that naturally processed epitopes for HLA-A*0201-restricted, melanoma-reactive
      CTLs include the nonamers MART-1(27-35) (AAGIGILTV), gp100(154-162) (KTWGQYWQV),
      gp100(209-217) (ITDQVPFSV) and gp100(280-288) (YLEPGPVTA) and the decamer
      gp100(476-485) (VLYRYGSFSV). Among these, the one that appears to be most
      abundant at the cell surface is gp100(154-162) (KTWGQYWQV). The others are among
      the less abundant peptides. HLA-A*0201-restricted CTLs from one melanoma patient
      who has survived metastatic disease recognized MART-1(27-35) (AAGIGILTV),
      gp100(280-288) (YLEPGPVTA) and gp100(154-162) (KTWGQYWQV) and were cross-reactive
      on longer peptides that contained these nonamer sequences. These peptides,
      identified by both an indirect genetic approach and by a direct peptide approach,
      can be used for tumor vaccine strategies with confidence that they are identical
      to the naturally processed peptide epitopes presented at the surface of melanoma
      cells in association with HLA-A*0201 molecules.

PMID- 10417766
TI  - Alteration of jun proto-oncogene status by plasmid transfection affects growth of
      human ovarian cancer cells.
AB  - The AP-1 transcription factor (the Jun and Fos proteins) is suspected of playing
      an important role in the biology of human cancer. Human epithelial ovarian tumors
      and cancer cell lines express the c-jun and jun-B proto-oncogenes at a high
      level, in contrast with the jun-D gene. We have investigated here the functional
      relevance of these observations for the growth of ovarian cancer cells. Transient
      constitutive expression of a dominant negative c-jun mutant (TAM67) in human
      AZ224, SKOV3 and OVCAR3 ovarian cancer cells inhibited the outgrowth of selection
      marker-resistant colonies by at least 75% as opposed to a control plasmid.
      Transfection of jun-B did not affect these cell lines, while jun-D transfection
      had a cell line-specific effect. In comparison, transfection of the tumor
      suppressor gene p53 had a less important inhibitory effect on OVCAR3 cells and no
      effect on SKOV3 and AZ224 cells when compared to TAM67. Regulated TAM67
      expression in AZ224 cells, from plasmids containing the mouse metallothionein or
      the MMTV promoter, suppressed cancer cell growth in vitro and in nude mice
      without evidence of increased cell death. Our observations support a role for the
      c-jun proto-oncogene as a positive mediator of human ovarian cancer cell growth
      and make it a potential therapeutic target.

PMID- 10417767
TI  - Inhibition of human malignant glioma growth in vivo by human recombinant
      plasminogen kringles 1-3.
AB  - Human malignant gliomas are highly vascularized and aggressive tumors.
      Angiogenesis inhibitors have been shown to induce regression of a variety of
      primary and metastatic tumors in vivo. However, their usefulness in treating
      brain tumors is not well understood. Angiostatin, a multiple kringle (1-4 of 5)
      containing fragment of plasminogen, is one of the highly effective natural
      cryptic angiogenesis inhibitors. In our study, the therapeutic efficacy of non
      glycosylated and small molecular size recombinant kringles 1-3 (rPK1-3) was
      examined in the treatment of brain tumors generated by stereotactic intracerebral
      implantation of U-87 human glioma cells in nude mice. Mice bearing tumors 7 days
      post-implant were treated daily with rPK1-3 (100 mg/kg) s.c. for 21 days. Treated
      animals showed suppressed brain tumor growth by greater than 71.2% along with a 3
      fold increase of apoptotic index and suppressed vascularization by 78.9%, without
      any observable signs of toxicity. Analysis of bFGF and VEGF expression in the
      tumors of treated animals using immuno-histochemical methods showed near complete
      absence of growth factors. Our results indicate that the non-glycosylated, small
      molecular size rPK1-3 is an efficient tumoristatic agent for the treatment of
      intracranial human glioma xenografts in mice and might provide new strategies for
      the treatment of brain tumors.

PMID- 10417769
TI  - Identification by differential display of a protein phosphatase-2A regulatory
      subunit preferentially expressed in malignant melanoma cells.
AB  - We described the occurrence of 4 transcripts differentially displayed between
      syngeneic murine B16F10 (metastatic melanoma) and Melan-a (immortalised
      melanocytes) cell lines. We now report that one such transcript, which is B16F10
      specific, represents a protein phosphatase-2A B' regulatory subunit. No
      expression of this transcript was detected in the weakly metastatic B16F1 by
      Northern blotting. Moreover, the transcript was not expressed by spontaneously
      immortalised, non-tumorigenic, melanocytes (Melan-Ab and Melan-a2), nor was it
      expressed by ras-transformed, tumourigenic melanocytes (Melan-Ab-LTR-ras).
      Cloning of the 5'-end region of this transcript (termed band 8A) from B16F10
      cells revealed an intracisternal A-particle insertion, including the long
      terminal repeat region, which could account for the observed high expression in
      B16F10 cells. Single cell clones of B16F10 manifested an experimental metastasis
      capacity, which correlated with band 8A expression with the lowest expressors
      being least metastatic. The human homologue of the B' regulatory subunit,
      B56gamma, is expressed preferentially at the mRNA level in human melanoma cell
      lines compared with normal epidermal melanocytes. In situ hybridisation studies
      on human clinical samples detected high expression of this gene in a number of
      malignant melanomas. Our results imply strongly that this protein phosphatase-2A
      regulatory subunit may have a role in melanoma tumour progression.

PMID- 10417768
TI  - CD3X anti-nitrophenyl bispecific diabodies: universal immunotherapeutic tools for
      retargeting T cells to tumors.
AB  - We developed a universal recombinant bispecific molecule (BiMol) that is capable
      of redirecting cytotoxic T cells to tumor cells via tagged anti-tumor ligands
      such as antibody fragments or cytokines. A recombinant bispecific diabody with
      binding specificities for the CD3 molecule on T cells as well as for the hapten
      nitrophenyl (NIP) was produced. This bispecific molecule is capable of
      redirecting cytotoxic T cells to kill a series of malignant cells, including B
      cell lymphoma, Hodgkin's lymphoma, and colon carcinoma via NIP-conjugated ligands
      to tumor-associated antigens. Cytotoxic activity of the diabody was found to be
      comparable to tetradoma-derived bispecific antibodies with similar specificities.
      Our findings demonstrate that universal CD3xanti-NIP diabodies could be used for
      T cell based cellular immunotherapy in a variety of human malignancies.
      Additionally, these bispecific molecules allow fast and economic testing of tumor
      associated antigens on malignant cells for their potential use as
      immunotherapeutic target structures if corresponding hapten-conjugated antibodies
      or ligands are available.

PMID- 10417770
TI  - Induction of effective antitumor immunity in a mouse brain tumor model using B7-1
      (CD80) and intercellular adhesive molecule 1 (ICAM-1; CD54) transfection and
      recombinant interleukin 12.
AB  - Although tumor-specific T lymphocytes recognize tumor-associated antigens (TAA)
      present on their cell surface via major histocompatibility complex (MHC)
      molecules, T cells require other activating signals. These are provided by
      costimulatory molecules, including B7-1 (CD80), B7-2 (CD86) and intercellular
      adhesive molecule 1 (ICAM-1; CD54). Transfecting mouse tumor cell lines with the
      B7 gene can lead to primary tumor rejection and the establishment of protective
      immunity. However, some studies have shown that the B7 effect upon T-cell
      dependent tumor immunity is limited. Therefore, we examined the antitumor effects
      of recombinant interleukin 12 (IL-12) and genetically engineered glioma cells
      expressing B7-1 or both B7-1 and ICAM-1. Vaccination of mice with B7-1-expressing
      tumor cells substantially inhibited the growth of subcutaneously inoculated
      gliomas but not those located in the brain. Vaccination with B7-1-expressing
      tumor cells and systemic recombinant IL-12 (rIL-12) was more effective than
      either B7-1-expressing tumor cells or rIL-12 alone. Our murine brain tumor model
      also showed that vaccination with tumor cells expressing both B7-1 and ICAM-1
      combined with rIL-12 prolonged survival. We have demonstrated the therapeutic
      potential of vaccination with rIL-12 and tumor cells expressing both B7-1 and
      ICAM-1 in the control of glioma growth.

PMID- 10417772
TI  - Heterogenous susceptibility to CD95-induced apoptosis in melanoma cells
      correlates with bcl-2 and bcl-x expression and is sensitive to modulation by
      interferon-gamma.
AB  - The expression and functionality of the Fas receptor (CD95/APO-1) play an
      important role for the maintenance of tissue homeostasis. Various types of tumor
      cells have been shown to escape immune recognition by constitutive resistance to
      CD95-mediated apoptosis. Furthermore, several apoptosis-related proteins have
      been reported to influence CD95 sensitivity. We tested an unselected panel of 11
      melanoma cell lines for sensitivity to CD95 and the corresponding expression of
      CD95, CD95L, bcl-2, bcl-x, bcl-xS, bax and FLIP proteins. Despite detection of
      CD95 cell-surface expression in 9 out of the 11 cell lines tested, only 3
      melanoma cell lines were sensitive to anti-CD95-MAb-induced cell death. Apoptosis
      related proteins CD95L, bcl-2, bcl-x, bcl-xS and bax were found to be
      heterogenously expressed in different melanoma cell lines tested. The
      susceptibility of melanoma cells to anti-CD95-MAb-mediated apoptosis was
      associated with low protein expression of both bcl-2 and bcl-x. The level of CD95
      cell-surface expression in melanoma cells was no indicator for CD95 sensitivity.
      Furthermore, FLIP protein was detectable in 7 out of the 11 cell lines, but
      showed no correlation to CD95 sensitivity. Certain cytokines have been described
      as modulating the susceptibility of tumor cells to CD95-induced cell death. Since
      IFN-alpha was proved to be clinically efficient in melanoma therapy, we tested
      whether interferons have the ability to induce sensitivity to CD95 in primarily
      resistant melanoma cell lines. Here we show that IFN-gamma, but not IFN-alpha, is
      able to increase the susceptibility of sensitive cell lines and to induce CD95
      sensitivity in resistant melanoma cell lines, accompanied by up-regulation of the
      protein expression level of CD95 and/or bcl-xS.

PMID- 10417771
TI  - Soluble MUC1 secreted by human epithelial cancer cells mediates immune
      suppression by blocking T-cell activation.
AB  - Solid tumors may secrete factors that mediate immune suppression in patients. We
      investigated the effect of supernatants from 25 human tumor cell lines on T
      lymphocytes from healthy donors. A profound inhibition of proliferation, cytokine
      secretion and cytotoxic activity was seen when T-cells were cultured in
      concentrated tumor supernatants from 6 cell lines fractionated into high (>100
      kDa) m.w. molecules. Interestingly, the inhibitory effects were reversed when the
      tumor supernatant was removed. Cell cycle studies of inhibited T-cells showed
      most of them were growth arrested in the G(0)/G(1) phase similar to naive T
      cells. In addition, these T-cells did not express IL2-receptors and expression of
      CD54 (ICAM-1) and CD58 (LFA-3) resembled that of resting T-cells. Protein gel
      electrophoresis of the tumor supernatants and western blot analysis demonstrated
      the presence of soluble MUC1 in the inhibitory tumor supernatants but not in
      control supernatant. Most importantly, depletion of soluble MUC1 by
      immunoprecipitation from the tumor supernatants neutralized the inhibitory
      effects on T-lymphocytes. Therefore, our results show that MUC1 shed by cultured
      epithelial tumor cells mediates inhibition of T-cell proliferation and function
      by inducing cell growth arrest.

PMID- 10417774
TI  - Gelatinase B (MMP-9), but not its inhibitor (TIMP-1), dictates the growth rate of
      experimental thymic lymphoma.
AB  - Dysregulation of metalloproteinase production at tumor sites contributes to the
      modification of local stromal tissue necessary for tumor development. Gelatinase
      B (matrix metalloproteinase-9, MMP-9) is one of the key enzymes that have been
      associated with the progression of several tumors. Paradoxically, MMP-9
      expression by tumor cells, most notably by lymphoma cells, is concomitant with
      the expression of its physiological inhibitor, TIMP-1. Not only are both genes
      often co-expressed in the most aggressive forms of lymphomas but also both are up
      regulated upon contact with stromal cells. Since TIMP-1 is known to regulate
      growth in several cell types and some aggressive lymphoma cells express TIMP-1
      constitutively without MMP-9, it is unclear whether the over-expression of MMP-9
      is counterbalanced by TIMP-1 and whether TIMP-1 expression alone could favor the
      development of lymphoma. To gain further insight into the respective roles of MMP
      9 and TIMP-1 in lymphoma, we generated lymphoma cell lines expressing
      constitutively high levels of MMP-9 or TIMP-1 and compared these cells for the
      ability to form thymic lymphoma in vivo. Moreover, we generated lymphoma cell
      lines expressing constitutively high levels of both MMP-9 and TIMP-1 to reproduce
      the net physiological balance resulting from the expression of both genes
      simultaneously and to determine which gene overrides the other. Our results show
      that mice injected with lymphoma cells expressing MMP-9 constitutively developed
      thymic lymphoma more rapidly than those injected with control lymphoma cells.
      Over-expression of TIMP-1 alone did not significantly influence tumor progression
      of lymphoma nor did it delay the capacity of MMP-9 to accelerate the development
      of thymic lymphoma.

PMID- 10417773
TI  - Antiangiogenic radioimmunotherapy of human solid tumors in SCID mice using (125)I
      labeled anti-endoglin monoclonal antibodies.
AB  - Endoglin (CD105), which is a component of the TGF-beta receptor complex, is
      highly expressed at the surface of proliferating human endothelial cells such as
      those of tumor vessels. In the present study, we tested the antitumor efficacy of
      (125)I-labeled anti-endoglin monoclonal antibodies (MAbs), SN6f and SN6j, against
      s. c. tumors of MCF-7 human breast cancer cells in SCID mice by i.v.
      administration. SN6f and SN6j cross-react weakly with mouse endothelial cells,
      but show no significant reactivity with MCF-7 tumor cells. These MAbs are
      effectively internalized into the cells after binding to the cell surface antigen
      of endothelial cells. Four groups of SCID mice (n = 10 or 9 in each group)
      inoculated s.c. with 8 x 10(6) MCF-7 cells were treated with (125)I-SN6f (10
      microCi), (125)I-SN6j (10 microCi), a (125)I-labeled isotype-matched control IgG
      (10 microCi) or PBS. The systemic therapy was performed in 2 series, i.e., on
      days 3, 5, 7 and days 58, 60, 62. Both (125)I-SN6f and (125)I-SN6j showed
      significant growth suppression of the tumors, whereas the (125)I-labeled control
      IgG did not show any significant antitumor efficacy. No significant toxicity or
      weight loss was observed in mice treated with either (125)I-SN6f or (125)I-SN6j.
      After 100 days of observation, autopsies revealed no significant organ damage.
      Our results show the possible usefulness of antiangiogenic radioimmunotherapy
      using (125)I-labeled anti-endoglin MAbs.

PMID- 10417775
TI  - Involvement of fibronectin in the regulation of urokinase production and binding
      in murine mammary tumor cells.
AB  - Tumor invasion and metastasis development is a multistep process involving
      adhesion molecules as well as tumor proteases. It has been reported that tumor
      cells lacking fibronectin (FN) expression and engineered to re-express FN showed
      a marked reduction in metastatic ability. Besides its effects on cell adhesion
      and migration, FN could be modulating other cellular events associated with the
      metastatic cascade. To test this hypothesis, we analyzed the production of
      urokinase-type plasminogen activator (uPA), and its receptor (uPAR), 2 molecules
      involved in the invasive phenotype, in cells over-expressing RGD wild-type FN
      (FNwt clones) or RGD-mutated FN (FN RGD-minus clones). Secreted uPA activity and
      antigen were significantly up-regulated in FN-expressing clones, although RGD
      minus cells secreted approximately 50% less uPA than the FNwt ones.
      Interestingly, while control and FN RGD-minus clones were able to readily bind
      uPA to their surface, FNwt clones exhibited impaired uPA binding. Furthermore,
      treatment of the parental cell line as well as the control and FN-expressing
      clones with exogenous purified FN or RGD peptides induced up-regulation of uPA
      production and the reduction of uPA membrane binding, which was associated with
      lower expression of uPAR. This modulation by FN was found to be dependent on RGD
      sequence and beta1 integrin. These results strongly suggest a novel activity for
      the multifunctional glycoprotein FN regarding the regulation of uPA production as
      well as the capacity of tumor cells to bind uPA.

PMID- 10417776
TI  - Enhanced activity of cyclin A-associated kinase in immortalized human
      fibroblasts.
AB  - Deregulation of cell cycle regulatory mechanisms leads to disruption of normal
      control of cell growth and may be associated with neoplastic transformation. To
      determine whether immortalized human cells have alterations in their cell cycle
      regulatory mechanisms, we analyzed cell cycle regulatory proteins in 2
      immortalized human fibroblast cell lines, KMST-6 and OUMS-24/P6X, established by
      repeated irradiation with (60)Co gamma rays alone or mutant p53 gene transfection
      plus X-ray irradiation, respectively. Both the immortalized cell lines had
      markedly enhanced activity of cyclin A-associated kinase as compared with their
      normal counterparts. The high activity of cyclin A-associated kinase was well
      correlated with the increased expression of cyclin A mRNA and its protein. In
      addition, the immortalized cell lines showed significantly reduced amounts of
      p21(Cip1/Waf1/Sdi1), a potent inhibitor of cyclin dependent kinases. Furthermore,
      among the pRb family of proteins, p107 and p130, were hyperphosphorylated in both
      the immortalized cell lines, suggesting possible participation in upregulation of
      cyclin A associated kinase activity. These changes represent some important
      characteristics of immortalized cells.

PMID- 10417777
TI  - Effect of a chimeric anti-ganglioside GM2 antibody on ganglioside GM2-expressing
      human solid tumors in vivo.
AB  - Ganglioside GM2 is expressed on the surface of neuroblastoma and glioblastoma
      cells, and may also be detected on lung cancer cells. We reported previously that
      anti-ganglioside GM2 antibody exhibited strong in vitro anti-tumor activity
      against adriamycin-resistant cancer cells, which overexpressed ganglioside GM2.
      In the present study, we examined the in vivo anti-tumor effect of the chimeric
      anti-ganglioside GM2 antibody, KM966, against human lung and breast carcinoma
      cells, SBC-3 and MCF-7, and respective adriamycin-resistant clones, SBC-3/ADM and
      AdrR MCF-7 in BALB/c nu/nu mice. Ratios of tumor volume (T/C) between KM966
      treated group and control group were 0.01 for SBC-3, 0.00 for SBC-3/ADM, 0.85 for
      MCF-7 and 0.34 for AdrR MCF-7 cells, respectively. Nude mice, which were
      pretreated with anti-asialo GM1 antibody to remove natural killer cells, were
      transplanted with 4 x 10(7) of SBC-3 and SBC-3/ADM subcutaneously. Seven days
      later, when tumors had grown to a diameter of over 8 mm, mice began to receive
      intravenous treatment of 120 microgram/mouse KM966 daily. Fourteen daily
      treatments induced regression to less than 4-mm diameter in 4/5 SBC-3 tumors and
      5/5 of SBC-3/ADM tumors. All SBC-3/ADM tumors disappeared completely, suggesting
      that KM966 exerts a strong in vivo anti-tumor effect on ganglioside GM2
      expressing cancer cells. In KM966-treated mice, the surface of the tumor cells
      stained positive with anti-human IgG. In addition, numerous leukocytes had
      infiltrated into the tumor mass. Antibody-dependent cell-mediated cytotoxicity
      (ADCC) of KM966 against tumor cells was examined in vitro by (51)Cr-release assay
      and revealed that KM966 induces ADCC activity against ganglioside GM2-expressing
      tumors. Our results suggest that immunotherapy using KM966 may be useful for the
      treatment of ganglioside GM2-expressing solid tumors.

PMID- 10417778
TI  - Induction of inflammatory angiogenesis by monocyte chemoattractant protein-1.
AB  - Almost any growth of tumors is to some extent associated with an inflammatory
      reaction which may be anti-tumorigenic by acting directly on tumor cells or
      protumorigenic cells presumably by inducing tumor-associated angiogenesis. In
      this study, we have analyzed the angiogenesis-inducing capacity of monocyte
      chemoattractant protein-1 (MCP-1), a key regulatory molecule of monocyte
      trafficking to sites of inflammation. MCP-1 was found to be potently angiogenic
      when implanted into rabbit cornea, exerting potency similar to the specific
      angiogenic vascular endothelial growth factor (VEGF)-A(121). MCP-1-induced
      angiogenesis in the cornea is associated with prominent recruitment of
      macrophages, whereas VEGF-A(121)-induced corneal angiogenesis is devoid of
      inflammatory cell recruitment. Based on these findings, we studied MCP-1
      expression and macrophage recruitment in human invasive ductal mammary carcinomas
      in comparison with the physiological angiogenic processes in bovine ovarian
      corpus luteum. Macrophage recruitment was always associated with MCP-1
      expression. High macrophage counts in mammary tumors corresponded with poor
      prognosis. In contrast, physiological ovarian angiogenesis was associated with
      only minimal inflammatory recruitment of macrophages. Our data show that MCP-1 is
      an indirect inflammation-associated inducer of angiogenesis and demonstrate
      distinct qualitative differences between tumor angiogenesis in human mammary
      tumors and physiological angiogenesis in the ovary.

PMID- 10417779
TI  - Expression of human BRCA1 and BRCA2 proteins in lung from a fetus at 19 weeks'
      gestation.

PMID- 10417780
TI  - Neurotrophic factors and neuromuscular disease: I. General comments, the
      neurotrophin family, and neuropoietic cytokines.
AB  - Neurotrophic factors are growth factors or cytokines that are inducible
      polypeptides and permit intercellular communication. An explosion of information
      about neurotrophic factors is setting the stage for significant advances in
      neural disease therapy in the next century. The effects of these trophic factors
      are overlapping and pleiotropic, acting on many cell types and tissues to control
      proliferation and differentiation of developing neurons and to exert a variety of
      functions on mature neurons. Studies of receptors unique to several neurotrophic
      factor families have revealed exquisite mechanisms of signal transduction.
      Preclinical trials in neuromuscular disease were promising, but results from
      initial clinical trials have been disappointing; new and better designed clinical
      trials are under way. Laboratory investigators also are exploring techniques to
      deliver factors directly to the central nervous system by means of viral vectors
      or to exert neurotrophic signals on the nervous system using novel small
      molecules that stimulate neurotrophic factor or neuroimmunophilin receptors.
      Combination therapies, refined delivery techniques, and treatment timing may be
      the key for successful treatment with neurotrophic factors. In this two-part
      review, we discuss the neurobiology of neurotrophic factors, the characteristics
      of the major neurotrophic factors, and their therapeutic potential in
      neuromuscular disease.

PMID- 10417781
TI  - Neurotrophic factors and neuro-muscular disease: II. GDNF, other neurotrophic
      factors, and future directions.
AB  - This is the second of two reviews in which we discuss the essential aspects of
      neurotrophic factor neurobiology, the characteristics of each neurotrophic
      factor, and their clinical relevance to neuromuscular diseases. The previous
      paper reviewed the neurotrophin family and neuropoietic cytokines. In the present
      article, we focus on the GDNF family and other neurotrophic factors and then
      consider future approaches that may be utilized in neurotrophic factor treatment.

PMID- 10417782
TI  - Age-related changes in fastest and slowest conducting axons of thenar motor
      units.
AB  - Single thenar motor unit F waves (FMUPs) were collected from 23 healthy
      volunteers (age range 21-91 years, mean 46 +/- 20 SD). In each subject, 10
      distinct FMUPs were recorded, using surface stimulating and recording electrodes,
      and the conduction velocity (CV) of each motor unit was calculated. The
      distribution of CVs (overall range 42-66 m/s; individual FMUP CV dispersion range
      6-27% of the maximal FMUP CV) was close to those previously reported whatever the
      technique used. With age, a progressive CV reduction was observed, and maximal
      FMUP CV was significantly correlated with age (r = -0.58, P < 0.01), whereas no
      statistically significant correlation was found between minimal FMUP CV and age
      (r = -0.27, ns). Individual FMUP CV dispersion presented a statistically
      significant decrease with age (r = -0.46, P < 0.05). Furthermore, thenar motor
      unit number (MUNE), estimated by the adapted multiple point stimulation method,
      decreased progressively with age and was statistically correlated with maximal
      FMUP CV (r = 0.59, P < 0.01), whereas there was no correlation with minimal FMUP
      CV (r = 0.34, ns). Thus, we propose that motor unit loss is progressive with age
      throughout life, affecting particularly the largest and fastest conducting motor
      units. Preferential involvement of these fibers could be responsible for the age
      related changes in motor nerve CV.

PMID- 10417783
TI  - Anti-MAG IgM penetration into myelinated fibers correlates with the extent of
      myelin widening.
AB  - The purpose of this study was to evaluate the relationship between immunoglobulin
      M (IgM) antibodies penetration into myelinated peripheral nerve fibers and the
      widening of the peripheral myelin sheaths in anti-myelin-associated glycoprotein
      (anti-MAG) demyelinating IgM monoclonal polyneuropathy. Demyelinating
      polyneuropathy with monoclonal IgM is often associated with anti-MAG
      autoantibodies, which are thought to initiate the disease with IgM deposits
      usually present on the myelin sheaths. We analyzed nerve biopsies from 12
      patients with an anti-MAG demyelinating neuropathy by confocal and electron
      microscopy. The total number of nerve fibers and the proportion of IgM-associated
      fibers were quantified after immunohistochemical staining. The affinities of IgM
      were examined by analyzing the binding pattern of serum IgM on normal peripheral
      nerve sections. Ultrastructural examinations of the biopsies showed a good
      correlation between in situ widened myelin sheaths and the IgM penetration level
      into myelinated fibers. The terminal complement complex appears not be involved
      in the penetration of IgM into the myelinated fibers. Our findings suggest a
      causative role of the IgM anti-MAG antibodies in the ultrastructural
      modifications of the myelin sheaths. The basement membrane and myelin components
      appear to be the major targets of the IgM monoclonal antibodies. However, the
      pathogenic mechanism whereby IgM antibodies reach their targets and induce nerve
      damage are still unclear.

PMID- 10417784
TI  - Superimposed single impulse and pulse train electrical stimulation: A
      quantitative assessment during submaximal isometric knee extension in young,
      healthy men.
AB  - Superimposed electrical stimulation techniques can be used to detect central
      activation failure (CAF), defined as incomplete central nervous system
      recruitment, suboptimal activation of motor units, or both. The purpose of this
      study was to evaluate superimposed electrical stimulation techniques to be used
      to detect CAF during isometric knee extension. We performed three sets of
      experiments and compared the torque increments from transcutaneous electrical
      stimulation with: (i) single impulses of different amplitudes (100 V, 150 V, and
      200 V) and a pulse train of 100 Hz (100 V, 100 ms); (ii) pulse trains (100 Hz,
      100 V) of different lengths (100 ms, 200 ms, and 300 ms); and (iii) pulse trains
      (100 Hz, 100 ms) of different amplitudes (50 V, 100 V, 150 V, and 200 V).
      Stimulation was evaluated at submaximal (80% of MVC) isometric knee extension in
      24 healthy young men using a Biodex isokinetic dynamometer. Electrodes were
      placed over the rectus femoris muscle and all stimulation impulses were
      monophasic, rectangular waves of 0.2-ms duration. Pulse train stimulation at 100
      V always elicited a torque increment, whereas single impulse stimulation, even at
      200 V, only caused a torque increment in about half of the trials. For each
      subject, the pulse train generated a significantly larger torque increment than
      for any of the three single impulses. There was no significant difference in
      torque increment between the three pulse trains of different lengths. Pulse
      trains at 150 V and 200 V generated significantly larger torque increments than
      at 50 V and 100 V. High-frequency maximal train stimulation may thus improve the
      detection of CAF during isometric knee extension. Detection of CAF may be
      important in the clinical assessment of muscle weakness, investigating the
      mechanisms underlying muscle weakness, and evaluating potential therapeutic
      strategies.

PMID- 10417785
TI  - In vivo microdialysis-A technique for analysis of chemical activators of muscle
      pain.
AB  - The accurate measurement of the chemical activators of pain in skeletal muscle
      has proved to be a major challenge. This study examined the applicability of
      microdialysis to the measurement of pain-producing substances in skeletal muscle
      using a defined model of ischemia and reperfusion in the rat. Microdialysis
      probes were placed into muscle of anesthetized rats. Ischemia was induced for 4
      h, followed by reperfusion for 1 h. Perfusates were analyzed for hypoxanthine,
      potassium, prostaglandin (PG) E(2) and histamine. A 20-fold increase in perfusate
      hypoxanthine concentration was seen prior to reperfusion (70.1 +/- 27.1 microM
      for ischemic versus 3.7 +/- 1.9 microM for control; P < 0.05). An initial
      increase in PGE(2) concentration was seen during ischemia (7.4 +/- 2.0 nM versus
      3.4 +/- 1.4 nM; P < 0.05) and immediately post-reperfusion (17.9 +/- 5.2 nM
      versus 4.0 +/- 1.1 nM; P < 0.05). Potassium concentration was significantly
      increased following occlusion and reperfusion. This indicates the applicability
      of microdialysis to the measurement of pain-producing substances in muscle during
      ischemia and reperfusion. Further use will provide novel information on muscle
      pain both in defined model systems and in clinical situations in humans.

PMID- 10417786
TI  - Comparison of motor conduction abnormalities in lumbosacral radiculopathy and
      axonal polyneuropathy.
AB  - We compared the frequencies and types of motor conduction abnormalities found in
      peroneal and tibial nerves of patients with either L5/S1 radiculopathies (n = 47)
      or axonal polyneuropathies (n = 49). In axonal neuropathies, compound muscle
      action potentials (CMAPs) were more likely to be either unobtainable or, if
      present, of low amplitude, prolonged in distal latency or both. F responses were
      more often absent, impersistent, or prolonged in minimal latency. In contrast,
      CMAPs in lumbosacral radiculopathies were more likely to be normal in both
      amplitude and distal latency. The most frequent F-response abnormality in
      radiculopathies was a prolonged maximum-minimum latency range rather than
      abnormalities of minimal latency or persistence. Logistic regression analysis
      demonstrated that different patterns of motor conduction abnormalities result
      from lumbosacral radiculopathy and distal axonopathies. The model was able to
      correctly classify disease state in 76% of subjects with a sensitivity of 74% and
      specificity of 80%.

PMID- 10417787
TI  - Tracheostomy in Guillain-Barre syndrome.
AB  - Specific treatment has been shown to shorten the duration of mechanical
      ventilation in Guillain-Barre syndrome (GBS) and could obviate the need for
      tracheostomy in a significant proportion of patients. However, the factors
      predictive of prolonged ventilation are undetermined, and the timing and use of
      tracheostomy in patients with GBS have not been systematically studied. The
      medical records of 60 patients ventilated for GBS were reviewed. Only 13 patients
      (22%) could be weaned within 3 weeks. Patients ventilated longer were
      significantly older (P = 0.04), and 21% had underlying pulmonary disease. Median
      duration of ventilation in patients treated with plasma exchange (n = 31) was not
      shortened. Fifty-two patients (87%) received a tracheostomy at a median of 9 days
      after intubation. In this series, where patients with comorbidity were included,
      tracheostomy was still necessary in the majority of ventilated patients. This
      procedure can be anticipated in elderly patients and in the presence of
      preexisting pulmonary disease.

PMID- 10417788
TI  - Multielectrode surface EMG for noninvasive estimation of motor unit size.
AB  - To noninvasively estimate the motor unit size, we present a novel surface
      electromyographic (EMG) measurement system consisting of a surface multielectrode
      with four-pin electrodes and a pair of surface-disk electrodes. Surface motor
      unit action potentials (MUAPs) were recorded with the multielectrode, in the so
      called multielectrode surface EMG (MSEMG), which was spatially filtered to
      localize the sensing area and reduce the noise. In addition, a modified
      decomposition algorithm, considering the geometrical configuration of the
      multielectrode, was designed to identify the individual MUAPs in the measured
      MSEMG. The identified MUAP was subsequently used as the triggering source for the
      EMG signals recorded by the surface-disk electrodes. From a pool of 34 subjects
      with neuromuscular diseases and 14 normal subjects, the median amplitudes of
      surface-disk EMG after spike-triggered averaging, called MSEMG-MUAP, correlated
      well (r = 0.82, P < 0.0001) with those of macro EMG. Moreover, the MSEMG-MUAP
      recording during a ramp force contraction exhibited the common size principle
      phenomenon during motor unit recruitment. The results of this study demonstrate
      that the MSEMG-MUAP measurement is a feasible approach for estimating the motor
      unit size from the skin surface.

PMID- 10417789
TI  - Anti-GQ1b IgG antibody is associated with ataxia as well as ophthalmoplegia.
AB  - Close association between the increase in anti-GQ1b immunoglobulin G (IgG)
      antibody and ophthalmoplegia in Miller Fisher syndrome (MFS) and Guillain-Barre
      syndrome (GBS) has been reported. We investigated whether anti-GQ1b IgG antibody
      also is associated with ataxia, another of the MFS triad. Of 149 patients who had
      anti-GQ1b IgG antibody without profound weakness, 144 showed ophthalmoplegia (120
      showed both ophthalmoplegia and ataxia; 24, ophthalmoplegia without ataxia). In
      contrast, five showed ataxia without ophthalmoplegia. Some large neurons of the
      dorsal root ganglia were immunostained with anti-GQ1b monoclonal antibody. Anti
      GQ1b IgG antibody may thus be associated with ataxia as well as ophthalmoplegia.
      Ataxia may be due to its binding to a subset of primary sensory neurons.

PMID- 10417790
TI  - Clinical utility of reflex studies in assessing cervical radiculopathy.
AB  - We prospectively studied the diagnostic utility of upper limb segmental reflexes
      in patients with suspected cervical radiculopathy (CR). Fifty-three patients (29
      men and 24 women), referred for electrodiagnostic testing, were positive for at
      least one of four clinical criteria for CR: abnormal (1) history, (2) motor
      (myotomal) examination, (3) sensory (dermatomal) examination, and (4) changes in
      deep tendon reflexes (DTR). All underwent electrodiagnostic assessment, needle
      electrode examination (NEE), specialized segmental reflexes (heteronymous and
      Hoffman's reflexes [H reflexes]), and neuroimaging. The clinical diagnosis was
      supported in all 32 patients who entered the study with two or more clinical
      signs for CR. Abnormal NEE was found in 90% of subjects with three clinical
      signs, 59% with two signs, and only 10% of those with one sign. H reflexes
      demonstrated a sensitivity of 72% and specificity of 85% for detection of CR and
      were particularly helpful when forming conclusions in the 21 subjects with only
      one clinical sign for CR. Specialized segmental H-reflex studies of the upper
      limb were as sensitive and specific as neuroimaging (magnetic resonance imaging).

PMID- 10417791
TI  - Caveolin-3 and sarcoglycans in the vacuolar myopathies and centronuclear
      myopathy.
AB  - Expression of dystrophin, beta-spectrin, merosin, and alpha- and beta
      sarcoglycans on the vacuolar membranes in some types of vacuolar myopathies has
      previously been reported. We studied expression of caveolin-3; alpha-, beta-,
      gamma-, and delta-sarcoglycans; dystrophin; and merosin on the vacuolar membranes
      in various vacuolar myopathies. Caveolin-3 and dystrophin were expressed on the
      vacuolar membranes in lysosomal glycogen storage disease with normal acid
      maltase, hypokalemic myopathy, and centronuclear myopathy. Sarcoglycans and
      merosin were expressed only on the vacuolar membrane in lysosomal glycogen
      storage disease with normal acid maltase. Immunostain of caveolin-3 and
      sarcoglycans is therefore useful for differential diagnosis of vacuolar
      myopathies.

PMID- 10417792
TI  - Changes in the compound action current amplitudes in relation to the conduction
      velocity and functional recovery in the reconstructed peripheral nerve.
AB  - The average axon diameter in the proximal segment of a transected and
      reconstructed peripheral nerve will decrease shortly after the transection and
      increase again when the regenerating axons make contact with their targets. The
      magnetically recorded nerve compound action current (NCAC) amplitude and the
      conduction velocity (CV) are directly related to the axon diameters. In this
      experiment, the peroneal nerve was unilaterally transected and reconstructed in
      42 rabbits. After 3, 4.5, 6, 8, 12, 20, and 36 weeks of regeneration time, hind
      leg motor function recovery, NCAC amplitude, and CV(1st peak) were studied. Our
      results demonstrate a significant decrease in signal amplitude and CV in the
      first 8 weeks after reconstruction. These decreases are related (P < 0.05). After
      8 weeks of regeneration time, motor function and the CV of the recorded signals
      start to recover, but the signal amplitudes do not. Based on the correlation of
      the CV and signal amplitude with axon diameter, they would both be expected to
      increase with recovering function. As an explanation for this lack of increase of
      signal amplitude, we suggest that, at the same time as some axons reach their
      target organs and start to mature, a number of the axons which have not reached a
      proper target organ will lose their signal-conducting capability. This will cause
      a decrease in compound signal amplitude, which cancels out the expected increase
      in NCAC amplitude, due to axonal maturation.

PMID- 10417793
TI  - Quadriceps muscle strength, contractile properties, and motor unit firing rates
      in young and old men.
AB  - Changes with age in the voluntary static and dynamic strength of the quadriceps
      muscle group have been well characterized, and the importance of the muscle group
      for locomotion and independent living have been highlighted in both normal human
      aging and in clinical studies. Surprisingly few studies of this muscle group have
      described age-related changes in voluntary activation ability using twitch
      interpolation and changes in stimulated contractile properties, and none have
      assessed the influence of old age on motor unit firing rates. We compared in 13
      young (mean age 26 years) and 12 old (mean age 80 years) men the voluntary
      isometric strength, stimulated contractile properties, and average steady state
      motor unit firing rates in the quadriceps muscle. Maximum voluntary contraction
      (MVC) force and twitch tension were approximately 50% lower in the old men, but
      contractile speed was only approximately 10% slower than in the young men. There
      was no difference in the ability of either group to activate the quadriceps to a
      high degree (94-96%). At all isometric force levels tested (10%, 25%, 50%, 75%,
      and 100% MVC), there were no differences in mean motor unit firing rates. In both
      groups, the range of firing rates was similar and not large ( approximately 8 Hz
      at 10% MVC and 26 Hz at MVC). Thus, the substantial age-related weakness in this
      muscle does not seem to be related to changes in neural drive.

PMID- 10417795
TI  - Influence of handling procedures on rat plasma creatine kinase activity.
AB  - Ten-week-old Sprague-Dawley rats were held behind the front legs before and
      during anesthetic injection of sodium pentobarbital (group 1, 12 rats), or lifted
      by the base of the tail before and during injection (group 2, 12 rats). Creatine
      kinase (CK) values were higher (P = 0.004) in group 1 (median 564 IU/L) than in
      group 2 (median 272 IU/L). Handling rats by holding them behind the front legs
      may reduce the usefulness of CK activity as a measure of muscular disorders.

PMID- 10417794
TI  - Practice parameter: The care of the patient with amyotrophic lateral sclerosis
      (An evidence-based review).

PMID- 10417796
TI  - Desmin phosphorylation abnormalities in cytoplasmic body and desmin-related
      myopathies.
AB  - Cytoplasmic body myopathy (CBM) and desmin-related myopathy (DRM) are both
      characterized by an abnormal accumulation of desmin. To determine whether these
      abnormalities involve similar or different forms of desmin, we performed desmin
      two-dimensional electrophoresis: our results showed an increase in the two acidic
      isoforms in CBM muscles as compared with an increase in the number of acidic
      isovariants in DRM samples. A process of hyperphosphorylation involved in these
      acidic forms was confirmed by alkaline phosphatase application onto the muscle
      samples in both pathological conditions.

PMID- 10417797
TI  - Muscle fiber conduction velocity at different states of isotonic contraction.
AB  - Conduction velocity (CV), relative twitch force (RTF) and contraction time (CT)
      of single muscle fibers (SF) and small muscle fiber bundles (FB) were measured at
      different states of isotonic contraction with double impulse stimuli at varying
      interstimulus intervals (ISI) from 0 to 1000 ms in the biceps brachii muscle in
      vivo. During an isotonic contraction, muscle fibers conducted the action
      potential on average 0.18 m/s faster along the muscle fiber membrane than did
      relaxed muscle fibers. This difference was statistically significant (P < 0.001).
      There was a significant positive correlation between the degree of isotonic
      contraction and fiber bundle conduction velocity (FBCV) with a first peak at the
      maximum RTF at an ISI of 9 ms and a second peak at the maximum CT at an ISI of
      100 ms.

PMID- 10417798
TI  - Postoperative lateral femoral cutaneous neuropathy.
AB  - Lateral femoral cutaneous (LFC) neuropathy was diagnosed in a woman who developed
      pain and paresthesias in the right thigh 6 days after abdominal hysterectomy by a
      suprapubic approach. After surgery, the patient slept in the fetal position to
      control the postoperative suprapubic pain. The LFC neuropathy improved with
      therapy including avoidance of hip flexion during sleep. Prolonged postoperative
      hip flexion to relieve the abdominal incisional pain provides an explanation for
      LFC neuropathy after abdominal surgery when the onset of symptoms is delayed.

PMID- 10417799
TI  - Proximal Martin-Gruber anastomosis mimicking ulnar neuropathy at the elbow.
AB  - We present a case of Martin-Gruber anastomosis (MGA) mimicking conduction block
      between the above- and below-elbow sites of ulnar nerve stimulation. We review
      the anatomical and electrophysiological literature on this subject and discuss
      its clinical implications. The potential for a MGA to occur very proximally in
      the forearm and thus mimic ulnar neuropathy at the elbow is underrecognized. We
      recommend that a check for MGA be performed on all patients with an apparent
      conduction block at the elbow, and suggest that 3 cm distal to the medial
      epicondyle may be an optimal below-elbow ulnar nerve stimulation site.

PMID- 10417800
TI  - A new mutation in the regulatory domain of the myophosphorylase gene affecting
      protein dimer contact.
AB  - We have identified a novel missense mutation in the myophosphorylase gene in a
      Spanish patient with McArdle's disease. The patient was homozygous for a T-to-C
      transition at codon 115 (L115P) in exon 3, which changed an encoded leucine (CUG)
      to a proline (CCG). This is the first mutation to be described in exon 3 and in a
      protein domain related to dimer contact. These data further emphasize the
      importance of private mutations in McArdle's disease, some of which are
      associated with specific ethnic groups.

PMID- 10417801
TI  - Asymmetrical polyneuropathy with a stepwise progressive course and well
      demarcated areas of demyelination.
AB  - A female patient was 12 years old when she presented with hemiatrophy and muscle
      weakness on the right side of her body. Then a stepwise worsening occurred, and
      at 19 years of age sensory symptoms were also noticed, as well as a mild
      involvement of the left part of her body. The cerebrospinal fluid (CSF) protein
      level was elevated without cells. The main electrophysiological abnormality was a
      marked temporal dispersion of the compound muscle action potentials (CMAPs).
      Motor nerve conduction velocities were moderately reduced. A superficial peroneal
      nerve biopsy revealed well-demarcated areas of demyelination with prominent
      Schwann cell hyperplasia. Neither deletion nor duplication of the PMP22 gene nor
      mutation of the P0 or connexin 32 genes was found by molecular genetic
      investigations. Immunotherapy was administered, and over the next 6 years the
      symptomatology fluctuated. This unusual disorder seems to be a variant of chronic
      acquired demyelinating polyneuropathy and may be immunologically mediated.

PMID- 10417802
TI  - Adult-onset nemaline myopathy: Another cause of dropped head.
AB  - A 59-year-old man with severe neck extensor weakness had findings diagnostic of
      nemaline myopathy on muscle biopsy. Review of the literature shows that dropped
      head occurs in nearly half of the patients with adult-onset nemaline myopathy.
      Other leading causes of dropped head syndrome are amyotrophic lateral sclerosis,
      myasthenia gravis, and isolated neck extensor myopathy.

PMID- 10417803
TI  - Intraoperative monitoring reduces complications and is therefore useful.

PMID- 10417804
TI  - Intraoperative monitoring is of limited use in routine practice.

PMID- 10417805
TI  - Electro-oculographic findings in an unusual case of paramyotonia congenita.

PMID- 10417806
TI  - Electromyography and magnetic resonance imaging in the evaluation of
      radiculopathy.

PMID- 10417810
TI  - Non-myelin-forming perisynaptic schwann cells express protein zero and myelin
      associated glycoprotein.
AB  - Perisynaptic Schwann cells (PSCs) envelop axonal terminals and are
      physiologically distinct from the nearby myelinating Schwann cells (MSCs), which
      surround the same innervating motor axons. PSCs have special functions at the
      neuromuscular synapse, where they detect and can modulate neurotransmitter
      release. Although PSCs are similar to non-myelinating Schwann cells in that they
      do not form multiple myelin wrappings around nerve terminals, they do wrap around
      single nerve terminals. These differences, as well as others, lead us to question
      whether PSCs are truly of Schwann cell origin. We thus characterized the
      expression of molecules, classically associated with myelin and Schwann cells, in
      PSCs at the frog neuromuscular junction. We wondered whether PSCs express the
      Schwann cell marker protein zero (P(0)) and whether their lack of myelination was
      related to an absence of myelin-associated glycoprotein (MAG), a protein found in
      myelinating cells that is considered important in myelination. Instead, we found
      that PSCs express both P(0) and MAG, and other myelinating glial markers such as
      galactocerebroside and 2',3'-cyclic nucleotide 3'-phosphodiesterase. In
      denervated preparations, P(0) and MAG expression persisted, including at newly
      formed PSC extensions. Because PSCs do not myelinate, it is clear that expression
      of these proteins alone is not sufficient for myelin formation. It is possible
      that factors present at synapses may prevent myelination, while P(0) and MAG may
      mediate adhesion between nerve terminals and the surrounding PSCs. The results
      indicate that PSCs are of Schwann cell origin.

PMID- 10417811
TI  - Cytosolic phospholipase A2 is induced in reactive glia following different forms
      of neurodegeneration.
AB  - Many recent studies have emphasized the deleterious role of inflammation in CNS
      injury. Increases in free fatty acids, eicosanoids, and products of lipid
      peroxidation are known to occur in various conditions of acute and chronic CNS
      injury, including cerebral ischemia, traumatic brain injury, and Alzheimer's
      disease. Although an inflammatory response can be induced by many different
      means, phospholipases, such as cytosolic phospholipase A(2) (cPLA(2)), may play
      an important role in the production of inflammatory mediators and in the
      production of other potential second messengers. cPLA(2) hydrolyzes membrane
      phospholipids and its activity liberates free fatty acids leading directly to the
      production of eicosanoids. We investigated the cellular localization of cytosolic
      phospholipase A(2) in the CNS following: (1) focal and global cerebral ischemia,
      (2) facial nerve axotomy, (3) human cases of Alzheimer's disease, (4) transgenic
      mice overexpressing mutant superoxide dismutase, a mouse model of amyotrophic
      lateral sclerosis, and (5) transgenic mice overexpressing mutant amyloid
      precursor protein, which exhibits age-related amyloid deposition characteristic
      of Alzheimer's disease. We show that in every condition evaluated, cytosolic
      phospholipase A(2) is present in reactive glial cells within the precise region
      of neuron loss. In conditions where neurons did not degenerate or are protected
      from death, cytosolic phospholipase A(2) is not observed. Both astrocytes and
      microglial cells are immunoreactive for cytosolic phospholipase A(2) following
      injury, with astrocytes being the most consistent cell type expressing cytosolic
      phospholipase A(2). The presence of cytosolic phospholipase A(2) does not merely
      overlap with reactive astroglia, as reactive astrocytes were observed that did
      not exhibit cytosolic phospholipase A(2) immunoreactivity. In most conditions
      evaluated, inflammatory processes have been postulated to play a pivotal role and
      may even participate in neuronal cell death. These results suggest that cytosolic
      phospholipase A(2) may prove an attractive therapeutic target for
      neurodegeneration.

PMID- 10417812
TI  - Glutamate transporter EAAC1 is expressed in neurons and glial cells in the rat
      nervous system.
AB  - Oligonucleotide and cRNA probes were used for non-radioactive in situ
      hybridization, carried out to identify the cell types in the nervous system of
      rat expressing the glutamate transporter EAAC1 mRNA. The results were compared
      with immunocytochemical data obtained using an antibody against a synthetic EAAC1
      peptide. The present data confirm that EAAC1 is expressed in neurons of the CNS.
      Additionally, our findings indicate the localization of EAAC1 mRNA and protein in
      peripheral neurons (spinal ganglia) and in glial cells, i.e., oligodendrocytes in
      various white matter regions of the CNS, ependymal cells, and epithelial cells of
      the plexus choroideus of the four ventricles, as well as in satellite cells of
      spinal ganglia. Immunolabeling revealed a preferentially cytoplasmic staining of
      neurons and glial cells. The cytoplasmic staining was frequently granular,
      suggesting a localization of EAAC1 protein in vesicle membranes. A membrane
      localization of EAAC1 was also indicated by Western blotting, which showed
      immunoreactivity only in the 100,000 x g pellet of brain homogenate. We conclude
      that the glutamate transporter EAAC1 is not restricted to neurons but may also
      play an important role in glial cells, particularly in oligodendrocytes.

PMID- 10417813
TI  - HIV-1 Nef alters the expression of betaII and epsilon isoforms of protein kinase
      C and the activation of the long terminal repeat promoter in human astrocytoma
      cells.
AB  - In the human immunodeficiency virus type 1 (HIV-1)-infected brain, the virus does
      not replicate in astrocytes, but a synthesis of viral regulatory proteins occurs
      in these cells, leading to accumulation of Nef. As an approach to understand the
      effects of Nef on astrocyte functional activity, we analyzed whether
      intracellular Nef interferes with the expression and activation of the enzyme
      protein kinase C (PKC), which is an important regulator of astroglial functions
      and HIV-1 replication. Astrocytoma clones (U251 MG) not expressing Nef (Neo), or
      expressing wild-type Nef (Bru) or nonmyristoylated Nef (TH) were used to monitor
      the expression and activation of 10 PKC isoforms. The same clones were used to
      evaluate the effect of Nef on the viral long terminal repeat (LTR) promoter after
      activation of PKC with the phorbol ester 12-myristate 13-acetate (PMA). PKC
      intracellular distribution and activation were evaluated by Western blot analysis
      of cytosolic and membrane fractions of control and Nef-expressing clones. PMA
      induced LTR activation was analyzed in clones transfected with a plasmid encoding
      for the CAT reporter gene controlled by the LTR promoter, by using an enzyme
      linked immunosorbent assay to measure CAT expression. Nef selectively
      downregulated the expression and activation of betaII and epsilon PKC isoforms in
      astrocytoma cells. Such downregulation correlated with an inhibition of LTR
      activation after PMA stimulation. The myristoylation of Nef and its membrane
      localization were essential for these effects. These results suggest that Nef may
      alter astrocytic functions by interfering with PKC expression and activation and
      contribute to the restriction of HIV-1 replication in astrocytes.

PMID- 10417814
TI  - Glutathione levels in primary glial cultures: monochlorobimane provides evidence
      of cell type-specific distribution.
AB  - Because glutathione (GSH) levels in glia play an important role in cellular
      defense against oxidative and nitrosative stress, the present study was designed
      to study GSH levels in the primary glial cell cultures. Here we used fluorescence
      microscopy and spectroscopy with monochlorobimane for measurement of
      intracellular glutathione content. Monochlorobimane showed high specificity for
      GSH with very little binding to protein sulphydryls as ascertained from the low
      fluorescence intensity of the protein fraction of the cells as well as from the
      low fluorescence of the GSH-depleted cells. The formation of the monochlorobimane
      glutathione conjugate was observed to be enzymatically catalyzed as seen from its
      higher rate of formation in the presence of cell homogenate. A monochlorobimane
      concentration of 60 microM was used for conjugation of cellular GSH; at higher
      mBCl concentrations there was no appreciable increase in fluorescence. Therefore,
      cultures were treated with 60 microM mBCl for an incubation time of 20 min
      (beyond this time, export of the bimane-glutathione adduct was significantly
      large) and examined by fluorescence microscopy. This adduct could be fixed with a
      mixture of paraformaldehyde and glutaraldehyde, and excellent fixation was
      observed with 4% paraformaldehyde and 0.2% glutaraldehyde. Analysis of the
      fluorescence images revealed differences in fluorescence intensity between astro-
      and microglial cells, which were identified by glial fibrilliary acidic protein
      and OX42 staining, respectively. Microglial cells isolated from primary glial
      cultures were found to have higher GSH content than astrocytes. Biochemical
      determination of GSH levels in microglia isolated from primary glial cultures
      corroborated this fact. From our findings it seems that owing to the greater
      intracellular concentration of reactive oxygen and nitrogen species to which
      microglia are subjected, especially under conditions of inflammation, this cell
      type is fortified with higher GSH levels as a means to combat oxidative and
      nitrosative stress.

PMID- 10417815
TI  - Expression of the murine complement regulatory protein crry by glial cells and
      neurons.
AB  - The expression of the murine complement regulatory protein, Crry, in the CNS
      remains largely unexplored. In this study, we examined murine astrocytes and
      microglia purified from neonatal brain and sections of adult murine brain for the
      expression of Crry. Using RT-PCR, immunohistochemistry, in situ hybridization,
      flow cytometry, and Western blot analysis, we demonstrated that astrocytes and
      microglia express Crry protein and RNA. Crry expression is greater on microglia
      than astrocytes and, as determined by Western blot analysis, each cell type
      expresses a Crry protein of different molecular weight. Interestingly, neuronal
      expression of Crry was seen only at the RNA level. These data demonstrate Crry
      expression by astrocytes, microglia, and neurons in the murine CNS and suggest
      that Crry may play an important role in protecting the CNS against complement
      mediated damage.

PMID- 10417816
TI  - Potassium buffering by Muller cells isolated from the center and periphery of the
      frog retina.
AB  - Muller (radial glial) cells span the retina from the outer to the inner limiting
      membranes. They are the only glial cells found in the amphibian retina. The
      thickness of the frog (Rana pipiens) retina decreases by a factor of about four
      from the center to the periphery. Thus, Muller cells were isolated, by enzymatic
      dissociation, with stalk lengths from 20 to 140 microm. Their ability to transfer
      K(+) via the stalk between soma and endfoot was studied. Membrane currents were
      recorded using the whole-cell voltage-clamp technique with the pipette sealed to
      either the endfoot or the soma. Inward (I(KIN)) or outward (I(KO)) currents were
      elicited by rapid increases (3 to 10 mM) or decreases (3 to 1 mM) of the
      extracellular K(+) concentration ([K(+)](o)) either by local application (close
      or distant to the recording pipette) or around the entire cell (whole cell
      perfusion). For the long central cells, the ratio I(KIN)/I(KO) was 4.6 +/- 0.6 SE
      (n = 9) at the endfoot and 1.7 +/- 0.1 SE (n = 8) at the soma. In cells from the
      retinal periphery, the ratio I(KIN)/I(KO) was higher, 7.0 +/- 0.27 (n = 8) at the
      endfoot and 3.2 +/- 0.1 (n = 10) at the soma. The results suggest that there is
      less inward rectification in the somatic than in the endfoot membrane. As
      expected from previous studies, the sensitivity of the cells to K(+) was higher
      at the endfoot than at the soma. The amplitude of I(KIN) at the endfoot compared
      to the soma was about 8-fold for the long central cells but only about 1.5-fold
      for the short peripheral cells. Currents spread readily from endfoot to soma in
      the peripheral cells. In the long central Muller cells the soma and endfoot
      appeared electrotonically isolated. The "functional length constant", lambda, of
      cell stalk processes was about 70 microm. The relative decrement of large inward
      currents was stronger than that of smaller outward currents; this difference
      ("artificial rectification") is explained by a simple model, where larger
      currents (inward) are attenuated more than smaller (outward) currents. The data
      support the hypothesis that in the retinal periphery, Muller cells provide
      extensive spatial K(+) buffering from both plexiform layers into the vitreous
      body. In the central retina, however, such currents are limited within a short
      (interlaminar) range.

PMID- 10417817
TI  - Cultured glial cells express the SNAP-25 analogue SNAP-23.
AB  - Astrocytes release glutamate and aspartate in response to elevated intracellular
      calcium levels, and it has been proposed that this occurs by a vesicular release
      mechanism, in which SNARE proteins are implicated. Although syntaxin,
      synaptobrevin, and cellubrevin have been shown to be expressed by cultured
      astrocytes, SNAP-25 has not been detected. By using immunocytochemical,
      immunoblotting, and polymerase chain reaction techniques, the present study
      demonstrates that SNAP-23, an analogue of SNAP-25, is expressed by astrocytes
      both in culture and in rat cerebellum. These findings provide additional evidence
      that astrocytes release excitatory amino acids by a vesicular mechanism involving
      SNARE proteins. SNAP-23 and also syntaxin 1 and cellubrevin were found to be
      expressed in glial precursor cells, oligodendrocytes, and microglia. These data
      suggest that the t-SNAREs SNAP-23 and syntaxin 1 and the v-SNARE cellubrevin
      participate in general membrane insertion mechanisms involved in diverse glial
      cell functions such as secretion, phagocytosis, and myelinogenesis.

PMID- 10417818
TI  - Creatine kinase transcript accumulation: effect of nerve during muscle
      development.
AB  - To determine the role of the nerve in regulating the accumulation of cytoplasmic
      creatine kinase (CK) mRNAs in hindleg muscles of the developing mouse, the
      lumbosacral spinal cords of 14-day gestation mice (E14) were laser ablated, and
      the accumulation of muscle CK (MCK) and brain CK (BCK) mRNAs was evaluated just
      prior to birth with in situ hybridization. Numbers of molecules of each of these
      transcripts/ng total RNA in the soleus and extensor digitorum longus (EDL)
      muscles were determined with competitive PCR and compared to transcripts found in
      innervated crural muscles. Data suggest that: 1) the level of BCK mRNA
      accumulation in innervated hindlimb muscles peaks at E16.5 and remains at fetal
      levels until the second month postnatal, when it falls to the level found in the
      adult. Given that MCK transcripts meet or exceed adult levels by day 28
      postnatal, the "down-regulation" of the BCK gene and the "up-regulation" of the
      MCK gene are not tightly coupled; 2) the developmental switch from BCK to MCK, as
      the dominant cytoplasmic CK mRNA, occurs in innervated and aneural leg muscles
      between E14 and E16.5, indicating this switch is not nerve dependent; 3) the
      absence of innervation has no effect on BCK mRNA accumulation. MCK transcripts/ng
      total RNA continue to increase in aneural muscle throughout the late fetal
      period, but from E16.5-E19.5 the MCK transcript levels in aneural muscles become
      progressively lower than in age-matched innervated muscles. Thus, the
      accumulation of the muscle specific cytoplasmic CK, but not BCK, transcripts is
      affected by the absence of innervation during the fetal period. Dev Dyn
      1999;215:285-296.

PMID- 10417819
TI  - Differential developmentally regulated expression of gelsolin family members in
      the mouse.
AB  - The gelsolin family of actin-modulating proteins contains seven mammalian members
      of which three have similar domain structure and function: gelsolin, capG, and
      adseverin. Previous studies have provided some information on the expression of
      these proteins, but no comprehensive analysis of expression during development
      has been performed. By in situ hybridization to murine embryo sections, we show
      that gelsolin expression is widespread but focal from e12.5 onward, with the
      exception of brain and mucosal epithelium. In contrast, CapG expression is high
      in mucosal epithelium, inner renal medulla, and adrenal cortex, and seen at much
      lower levels more broadly. Adseverin expression is even more restricted, being
      seen at sites of endochondral bone formation during development only, and in
      developing and adult outer renal medulla and intestine. In parallel analyses the
      three genes demonstrated patterns of expression that were complementary and non
      overlapping in nearly all organs. The observations suggest new functions for
      these proteins in organ systems and tissues where their expression was not
      previously recognized. They further suggest that the proteins have distinct
      tissue-specific functions in modulating the actin cytoskeleton during cellular
      motile activities, and that such functions have diverged since the genes arose
      ancestrally by gene duplication. Dev Dyn 1999;215:297-307.

PMID- 10417820
TI  - Conservation of gene expression during embryonic lens formation and cornea-lens
      transdifferentiation in Xenopus laevis.
AB  - Few molecular comparisons have been made between the processes of embryogenesis
      and regeneration or transdifferentiation that lead to the formation of the same
      structures. In the amphibian, Xenopus laevis, the cornea can undergo
      transdifferentiation to form a lens when the original lens is removed during
      tadpole larval stages. Unlike the process of embryonic lens induction, cornea
      lens transdifferentiation is elicited via a single inductive interaction
      involving factors produced by the neural retina. In this study, we compared the
      expression of a number of genes known to be activated during various phases of
      embryonic lens formation, during the process of cornea-lens transdifferentiation.
      mRNA expression was monitored via in situ hybridization using digoxigenin-labeled
      riboprobes of pax-6, Xotx2, xSOX3, XProx1, and gamma6-cry. We found that all of
      the genes studied are expressed during both embryogenesis and cornea-lens
      transdifferentiation, though in some cases their relative temporal sequences are
      not maintained. The reiterated expression of these genes suggests that a large
      suite of genes activated during embryonic lens formation are also involved in
      cornea-lens transdifferentiation. Ultimately functional tests will be required to
      determine whether they actually play similar roles in these processes. It is
      significant that the single inductive event responsible for initiating cornea
      lens transdifferentiation triggers the expression of genes activated during both
      the early and late phases of embryonic lens induction. These findings have
      significant implications in terms of our current understanding of the "multistep"
      process of lens induction. Dev Dyn 1999;215:308-318.

PMID- 10417822
TI  - Dynamics of placodal lineage development revealed by targeted transgene
      expression.
AB  - Examination of the expression pattern of the winged-helix transcription factor BF
      1 outside of the neural tube in mouse embryos suggests that BF-1 is restricted to
      a population of cells that gives rise to the ectodermal placodes and their
      derivatives. Within the sensory cranial nerve ganglia, the expression of BF-1
      distinguishes cells that arise from the placodes from those derived from the
      neural crest. Expression of a lacZ transgene targeted to the BF-1 locus was used
      to follow the placodal lineage during mouse development. Analysis of placodal
      development in mice with a targeted deletion of BF-1 reveals that, although BF-1
      is required for proliferation of the cells arising from the nasal placode, it is
      not required for the proliferation, survival, or both, of placode-derived cells
      in the sensory cranial nerve ganglia. Dev Dyn 1999;215:332-343.

PMID- 10417821
TI  - 1.3 kilobases of the lung type I cell T1alpha gene promoter mimics endogenous
      gene expression patterns during development but lacks sequences to enhance
      expression in perinatal and adult lung.
AB  - The T1alpha gene is one of few markers for the type I cell phenotype in the adult
      mammalian lung. Type I cells form a large, thin epithelial layer that facilitates
      gas exchange and transport of fluids between the air spaces and capillaries. The
      T1alpha gene has a complex pattern of developmental expression in lung and brain;
      in vitro studies indicate that expression is regulated in part by thyroid
      transcription factor 1, forkhead proteins, and Sp1/Sp3 proteins. To explore the
      mechanisms that confine T1alpha expression in intact adult animals to alveolar
      type I and choroid plexus epithelial cells, we generated mice bearing a 1.3-kb
      T1alpha promoter-chloramphenicol acetyltransferase (CAT) gene. In situ
      hybridization and RNase protection assays show that the 1.3-kb promoter confers a
      pattern of CAT expression that largely matches the endogenous T1alpha in embryos
      and mid-term fetuses in lung and central nervous system. However, the 1.3-kb
      promoter lacks elements important for perinatal up-regulation of T1alpha in the
      lung and maintenance of that expression in the adult lung and brain. The final
      adult pattern of T1alpha expression may be directed by elements outside the 1.3
      kb fragment, perhaps those 5' to the 1.3-kb fragment as we show herein, or in 3'
      and intronic regions. Dev Dyn 1999;215:319-331.

PMID- 10417823
TI  - Expression of Melk, a new protein kinase, during early mouse development.
AB  - A new gene named maternal embryonic leucine zipper kinase, Melk, has been
      recently identified (Heyer et al. [1997] Mol. Reprod. Dev. 47:148-156). As a
      basis for further study of the function of the gene, we have examined the
      expression of Melk across a wide range of embryonic stages, from the ovulated egg
      and 2-cell embryo through the gastrulation and early organogenesis stages, by in
      situ hybridization and immunohistochemistry. Melk is expressed in a spatially and
      temporally specific pattern during mammalian embryogenesis. The strongest
      expression was detected during maturation of oocytes and preimplantation
      development. Given its expression pattern, Melk may play an important role during
      preimplantation embryonic development. Dev Dyn 1999;215:344-351.

PMID- 10417824
TI  - Zebrafish stat3 is expressed in restricted tissues during embryogenesis and stat1
      rescues cytokine signaling in a STAT1-deficient human cell line.
AB  - Transcription factors of the STAT family are required for cellular responses to
      multiple signaling molecules. After ligand binding-induced activation of cognate
      receptors, STAT proteins are phosphorylated, hetero- or homodimerize, and
      translocate to the nucleus. Subsequent STAT binding to specific DNA elements in
      the promoters of signal-responsive genes alters the transcriptional activity of
      these loci. STAT function has been implicated in the transduction of signals for
      growth, reproduction, viral defense, and immune regulation. We have isolated and
      characterized two STAT homologs from the zebrafish Danio rerio. The stat3 gene is
      expressed in a tissue-restricted manner during embryogenesis, and larval
      development with highest levels of transcript are detected in the anterior
      hypoblast, eyes, cranial sensory ganglia, gut, pharyngeal arches, cranial motor
      nuclei, and lateral line system. In contrast, the stat1 gene is not expressed
      during early development. The stat3 gene maps to a chromosomal position syntenic
      with the mouse and human STAT3 homologs, whereas the stat1 gene does not. Despite
      a higher rate of evolutionary change in stat1 relative to stat3, the stat1
      protein rescues interferon-signaling functions in a STAT1-deficient human cell
      line, indicating that cytokine-signaling mechanisms are likely to be conserved
      between fish and tetrapods. Dev Dyn 1999;215:352-370.

PMID- 10417826
TI  - Development and in vitro testing of a miniature robotic system for computer
      assisted colonoscopy.
AB  - In this article we present a new concept for computer-assisted colonoscopy based
      on a miniature robot capable of propelling itself semiautonomously along the
      colon. The miniature robot is designed to perform the same functions as current
      colonoscopy systems-i.e., visualization and tissue sampling for biopsy-and
      exploits an innovative inchworm-like locomotion principle based on adhering to
      the colon wall by vacuum suction. The miniature robot is connected by a thin and
      flexible umbilical cable to an external control unit; this unit provides
      pneumatic actuation signals in the appropriate sequence to the miniature robot,
      and information on the robot's functioning to the endoscopist, who can either
      teleoperate or directly supervise its operation. A prototype colonoscopy system
      using this robot has been fabricated and tested in vitro, with promising results.
      The proposed concept has strong potential for further development, since
      miniaturization and functional integration of instrumentation and tools, together
      with computer assistance, not only make colonoscopy more acceptable, but can also
      open up a wide range of new applications in endoluminal diagnosis, therapy, and
      surgery.

PMID- 10417825
TI  - Focal adhesion kinase, paxillin, and bcl-2: analysis of expression,
      phosphorylation, and association during morphogenesis.
AB  - Cell adhesive mechanisms which determine tissue architecture during morphogenesis
      are tightly regulated and have an impact on apoptosis, cell migration,
      proliferation, and differentiation. Bcl-2 is a death repressor that protects
      cells from apoptosis initiated by a variety of stimuli including loss of cell
      adhesion. Utilizing the kidney as a model of an organ that undergoes three
      dimensional development we demonstrate that bcl-2 directly associates with
      paxillin. Focal adhesion kinase (FAK)(p125) and paxillin(p68) were highly
      expressed and tyrosine phosphorylated during development but declined to low
      levels following renal maturation (postnatal day 20) in normal mice. The decline
      in the expression of p125 FAK and p68 paxillin occurred together with an increase
      in specific cleavage products of lower molecular weights. Mice deficient in bcl-2
      are born with renal hypoplasia and succumb to renal failure as a result of renal
      multicystic disease. In kidneys from postnatal day 20 bcl-2 -/- mice, tyrosine
      phosphorylation of p125 FAK and p68 paxillin was not down-regulated. However, the
      level of expression was similar to that of normal mice. These results demonstrate
      that the developmentally regulated expression and phosphorylation of FAK and
      paxillin, in the presence of bcl-2, is necessary for normal morphogenesis. The
      interaction of paxillin with bcl-2 during nephrogenesis may provide an
      alternative to integrin(s) signaling through paxillin/FAK thus bypassing the need
      for adhesion-mediated survival during three dimensional morphogenesis. Dev Dyn
      1999;215:371-382.

PMID- 10417827
TI  - Evaluation of a telerobotic system to assist surgeons in microsurgery.
AB  - A tool was developed that assists surgeons in manipulating surgical instruments
      more precisely than is possible manually. The tool is a telemanipulator that
      scales down the surgeon's hand motion and filters tremor in the motion. The
      signals measured from the surgeon's hand are transformed and used to drive a six
      degrees-of-freedom robot to position the surgical instrument mounted on its tip.
      A pilot study comparing the performance of the telemanipulator system against
      manual instrument positioning was conducted at the University of Southern
      California School of Medicine. The results show that a telerobotic tool can
      improve the performance of a microsurgeon by increasing the precision with which
      he can position surgical instruments, but this is achieved at the cost of
      increased time in performing the task. We believe that this technology will
      extend the capabilities of microsurgeons and allow more surgeons to perform
      highly skilled procedures currently performed only by the best surgeons. It will
      also enable performance of new surgical procedures that are beyond the
      capabilities of even the most skilled surgeons.

PMID- 10417828
TI  - Comparison of three methods of estimating confidence intervals for stereotactic
      error.
AB  - When planning a stereotactic procedure, it is clinically valuable to know the
      spatial confidence intervals of a particular stereotactic technique. To do this,
      the aggregate error distribution of the stereotactic technique must first be
      estimated. In a frame-based stereotactic procedure, there is an imaging step and
      a treatment delivery step. If error is introduced independently at these steps,
      then the error of a stereotactic procedure may be computed from the error
      distributions of the component steps. Three computational methods of doing this
      were compared: parametric, convolution, and Monte Carlo. To test these methods,
      the error distributions of an imaging technique, a delivery technique, and the
      corresponding stereotactic imaging-plus-delivery system were measured empirically
      using a phantom, computed tomography, and the CRW stereotactic system. The three
      methods gave concordant estimates of mean aggregate error (respectively 2.71 +/-
      1.52, 2.45 +/- 2.30, 2.51 +/- 2.34, and 2.47 +/- 2.31 mm for the empiric,
      convolution, Monte Carlo, and parametric methods). However, the estimates of the
      confidence intervals differed between the parametric and the nonparametric
      methods. In particular, the parametric method gave significantly higher estimates
      of the 99% spatial confidence interval (6.40 mm versus 5.41 mm and 5.38 mm for
      the convolution and Monte Carlo methods). Knowledge of the confidence intervals
      allows a neurosurgeon to determine a priori whether a particular stereotactic
      technique is likely to satisfy a clinically defined error budget, and thereby
      achieve clinical success.

PMID- 10417829
TI  - Intraoperative navigation for breast cancer surgery using 3D ultrasound images.
AB  - The aim of this work was to develop an intraoperative image-guidance system for
      breast cancer surgery using three-dimensional (3D) ultrasound imaging. Using a 10
      MHz annular array mechanical sector probe, ultrasound images were obtained from
      nine volunteer patients with breast cancer immediately before removal of the
      tumor in the operating room. A 3D tumor image was reconstructed using a
      workstation, then superimposed on the video image of the breast based on
      geometrical data. These data were obtained simultaneously by an optical 3D
      position sensor. The 3D images of the tumors were validated by the pathological
      data obtained after the surgery. In eight cases, the superimposed images were
      successfully obtained in approximately 15-20 min following scanning of the tumor.
      Scattered lesions around the main tumor were also visualized in the reconstructed
      tumor images, but artifacts of the ductal lesion caused by noise could not be
      eliminated in some cases. This system should be very effective in helping the
      surgeon to recognize the extent of a tumor within the breast itself and to
      determine the margin of surgical resection for breast conservation surgery.

PMID- 10417831
TI  - Editorial comment 

PMID- 10417830
TI  - Clinical evaluation of multimodality registration in frameless stereotaxy.
AB  - Computer-assisted frameless neurosurgery bases its accuracy and reliability on
      registration. The aim of this prospective study was to compare the clinical
      accuracy of different registration techniques used for computer-assisted
      frameless neurosurgery. Ninety-eight registrations in 44 patients were used to
      compare the clinical accuracy of self-adhesive marker (MR) and facial landmark
      (FR) registrations used alone or in conjunction with surface-fit registration
      (MR/SR and FR/SR, respectively) for cranial neurosurgery. The computer estimated
      error (CEE) of each registration was compared to the real error (RE). This was
      obtained by holding the frameless pointer at the center of three different
      markers and measuring the distance from the real-time representation on the
      computer three-planar images to the center of the marker on the screen. The most
      accurate registration was obtained using MR; the RE of MR was 1.6 +/- 0.1 mm
      compared to 3.4 +/- 0.4 mm for FR. Although the smallest CEE error was obtained
      using MR/SR, this was not sustained by the RE. Furthermore, the RE of FR/SR was
      significantly larger than the CEE (Student t test, p <.001). This study
      corroborates previous results showing that, in the clinical setting, self
      adhesive marker registration is more accurate than facial landmark registration.
      Furthermore, although surface-fit registration can be used in conjunction with
      self-adhesive marker registration, this does not improve the degree of real
      accuracy for cranial registration.

PMID- 10417832
TI  - Strategy, technology, and techniques of surgical treatment of supratentorial
      intracerebral hematomas.
AB  - The present study targets the problem of the surgical approach to treatment of
      intracranial hematomas. We examined a total of 242 patients with clinically
      evident spontaneous nontraumatic intracerebral hematomas. The majority of
      patients (79%) were treated in the acute phase of stroke. The patients underwent
      one of the following treatments: (a) In 731 patients, the hematomas were removed
      following craniotomy and cortiectomy performed under direct visualization, with a
      mortality rate of 42.5%; (b) in 64 patients, the hematomas were evacuated
      stereotactically, with a mortality rate of 21.9%; (c) in four patients, only
      ventricular drainage was used; and (d) 101 patients were treated with routine
      nonsurgical methods (comprising the pharmaceutical or conservative group), with a
      mortality rate of 49.5%. The overall mortality rate was 40%. In 43 patients, a
      special balloon was implanted into the hematoma cavity after evacuation to
      prevent recurrent bleeding. Although the first part of this work is now finished,
      further study of the dynamics of hemorrhage and additional results are needed
      prior to making a decision on how to divide patient management into the two
      categories of surgical and nonsurgical treatment.

PMID- 10417833
TI  - Relapses in idiopathic inflammatory myopathies.

PMID- 10417835
TI  - Defect in the wiring of reinforced laryngeal mask leading to airway obstruction.

PMID- 10417837
TI  - An unusual site for a PA catheter.

PMID- 10417838
TI  - Oral feeding after caesarean section.

PMID- 10417839
TI  - It's all in the colour.

PMID- 10417840
TI  - Intolerance of isotretinoin in a patient with anhidrotic ectodermal dysplasia.

PMID- 10417841
TI  - Combination treatment of psoriasis with photochemotherapy and tazarotene gel, a
      receptor-selective topical retinoid.

PMID- 10417842
TI  - Renovascular hypertension. Clinical and diagnostic clues.
AB  - Renovascular hypertension (RVH), although relatively rare, is the most frequent
      among the secondary forms of arterial hypertension; in addition interventional
      radiology has remarkably increased, because of its relative invasiveness, the
      possibilities of treating and in many cases curing RVH bypassing the traditional
      surgical approach. For these reasons in recent years a number of screening tests
      has been developed and added to renal angiography and to the measurement of
      plasma renin which, still now, represent the reference methods among the
      morphological and the functional tests respectively. These new and promising
      techniques include the magnetic resonance angiography, the spiral computed
      tomography, the renal scintigraphy and the ultrasound scanning of renal arteries
      with the associated measurement of velocimetric indices. In selected populations
      all these methods have been shown to possess an high specificity and sensitivity
      but if applied to a general population of hypertensive patients their positive
      predictive values are going to be necessarily low because of the low prevalence
      of the disease. Accordingly, it is mandatory for the physician, before sending
      patients to these investigations, to preselect those who, on the basis of a
      thorough clinical examination are more likely to harbour a renal artery stenosis.

PMID- 10417843
TI  - Interventional radiology in the treatment of renal artery stenosis.
AB  - Percutaneous transluminal renal angioplasty (PTRA) alone or in combination with
      stent implantation, is increasingly used as an alternative technique to surgical
      revascularization for treatment of renal artery stenosis (RAS) wich may cause
      hypertension or jeopardize renal function. Herein we report the results obtained
      with 305 PTRAs performed in 242 hypertensive patients, 144 of whom had
      atherosclerotic RAS, 69 fibromuscolar dysplasia, 15 Ras in transplanted kidneys,
      6 restenosis in surgically revascularized kidneys, 4 Takayasu arteritis and 4
      neurofibromatosis. Stents were implanted in 68 cases, mostly in atherosclerotic
      stenoses. The technical success was achieved in 261 arteries (85.6%), with 33
      failures (10.8%) and 11 (3.6%) procedures not completed for anatomical reasons.
      PTRA related complications were observed in 23 cases (7.5%), but no fatalities
      occurred. An overall benefit on blood pressure control was observed in 41% of
      patients with atherosclerotic RAS and in 68% of those with fibromuscolar
      dysplasia. It appears that independently from the ethiology PTRA is technically
      effective in correcting RAS; yet the position of PTRA with respect to that of
      medical or surgical treatment needs to be better delineated through randomized,
      controlled studies aimed at comparing the clinical efficacies of these different
      approaches.

PMID- 10417844
TI  - Interventional radiology in the treatment of urological vascular complications.
AB  - Urological vascular complications (UVC) are largely secondary to percutaneous
      procedures that are nowadays extensevely used by the urologists and the
      nephrologists. The major frequency of UVC is observed after the renal biopsy, in
      a percentage varying from 7 to 17% in different series; UVC are less frequent
      after a nephrostomic procedure (near 1-3%). UVC consist of artero-venous fistulas
      (AVF) and pseudoaneurysms (PA), that generally cause haemorrhage, particularly
      macroscopic hematuria. In the vast majority of cases hematuria resolves
      spontaneously or with conservative therapy but, in the 4 to 9% of patients
      persists and requires an adequate therapy, often in emergency. Interventional
      radiology permits an effective and timely treatment of the lesions, using the
      techniques of transcatheter embolization that are greatly improved in the last 20
      years and that present rate of technical success greater than 80%. Moreover
      radiological embolization shows a low incidence of complications and lower
      hospitalization cost with respect to surgical treatment. Herein we describe the
      different techniques of embolization, the indications and the results as appears
      from the literature and the personal experience. The latter is based on a series
      of 31 procedures performed in 26 patients, with a rate of technical and clinical
      success of 93.5%.

PMID- 10417845
TI  - Ultrasound-fluoroscopy guided access to the intrarenal excretory system.
AB  - The access to the collecting system can be performed under fluoroscopy
      computerized tomography, ultrasonographic, mixed ultrasonographic and
      fluoroscopic guidance. In this paper the creation of a percutaneous
      transparenchymal ultrasound-fluoroscopy guided access to the intrarenal
      collecting system completely performed by urologist for different purposes is
      presented. In five years 297 patients underwent 330 percutaneous kidney accesses
      to perform derivative nephrostomies (217 pts), percutaneous nephrolithotomies (37
      pts), antegrade ureteral manoeuvres (34 pts), antegrade endopyelotomies (7 pts),
      transitional cell carcinoma of the upper tract resection (2 pts). 11 patients out
      of these had a percutaneous kidney access in a transplanted kidney. The
      percutaneous access was successful in 98% of the attemps. A posterior calyx of
      the lower group (74%), of the medium group (25%) or of the upper group (1%) was
      accessed. In 73 accesses the mean target calyx diameter was 12.8 mm (range 5-45
      mm), the mean operative time 5.4 minutes and the mean fluoroscopy time 5.1
      seconds. In 84.5% of the patients the access was performed under local anesthesia
      when a dilation of the tract was not required. Gross haematuria was observed in
      3.9% of the accesses and an arterial lesion treated by embolization in 0.9% of
      the accesses. Blood transfusion was required in 0.3% of the patients. The
      ultrasound-fluoroscopy guided access is at least as precise as the fluoroscopy
      guided one moreover it makes the procedure less invasive and it makes more
      precise the surgical planning.

PMID- 10417846
TI  - Interventional radiology in the treatment of uretero-pelvic-junction.
AB  - Numerous authors have reported successful results with both antegrade or
      retrograde endopyelotomy. Both procedures have proved to be efficient in primary
      as in secondary obstructions. Some additional etiological factors, such as
      crossing vessels high-grade hidronephrosis and poorly functioning kidney, may
      decrease the success rate of these minimally invasive techniques. The development
      of a cutting balloon catheter used under fluoroscopic control simplified the
      retrograde technique. This technique proved to be easier to perform than
      antegrade or retrograde endoscopic incision and did not require specialized
      instrumentation. In our experience 6 patients from 30 to 65 years old (average
      age 52) with an ureteropelvic-junction obstruction secondary to open surgery
      underwent endopyelotomy with the cutting balloon device. At the three month
      followup 4 patients had renographic patent ureteropelvic junction and no
      modifications were seen at one year follow up The retrograde endopyelotomy under
      fluoroscopic control seems to offer a rapid and effective treatment of UPJO. It
      is indicated for all primary and secondary UPJO obstruction apart forpatients
      with a concomitant renal stone or with high-insertion ureteropelvic junction.

PMID- 10417847
TI  - Permanent stenting in the treatment of ureteral strictures.
AB  - Permanent metallic stents have found wide application for use in the vascular and
      biliary systems and currently devices are also available for use in the urinary
      tract. Permanent stenting of the ureter has proven to be an useful option in the
      management of obstruction caused by external compression due to malignancy
      whereas the efficacy of permanent stenting in the treatment of benign ureteral
      strictures is still controversial. We treated three patients with benign ureteral
      strictures by implantation of a self-expanding endoluminal stent that resulted in
      ureteral patency persisting up to 24 months.

PMID- 10417848
TI  - Management of bladder outlet obstruction by insertion of stents in the
      radiological suite.
AB  - Intraurethral mechanical support using prosthetic devices known as stents has
      become an increasingly used therapeutic approach in bladder outlet obstructions.
      This article is an overview on the stents used in the obliterated prostate and
      urethra which can be inserted in a radiological suite. The insertion of each
      currently available stent under fluoroscopy, transabdominal and transrectal
      sonography is described.

PMID- 10417849
TI  - Scleroembolization techniques in the treatment of varicocele.
AB  - Varicocele is a common finding in adolescents and adult men. Its association with
      male infertility has been well documented: varicoceles are reported to be present
      in 20% to 40% of infertile men. It has been demonstrated that varicocele
      correction leads to an improvement in the quality of semen in most cases.
      Percutaneous sclerotization is an established method for treatment of varicocele
      performed on an outpatient basis. In our report we intend to review our
      experience in venographic study and transcatheter sclerotherapy based on 560
      cases of infertile patients with varicocele. Our study confirms that percutaneous
      therapy of varicocele may lead to improved spermatogenesis in the majority of
      patients.

PMID- 10417850
TI  - Arterial embolization in the treatment of post-traumatic priapism.
AB  - Priapism is a prolonged penile erection not associated with sexual arousal. Two
      types of priapism have been described: the more common one is the "veno
      occlusive" priapism and can be frequently observed as the consequence of an
      intracavernosal injection of vaso-active drugs for the treatment of erectile
      dysfunction. The less common type of priapism is known as "high flow" priapism
      and usually follows perineal or direct penile trauma. The clinical presentation
      in case of high flow priapism is quite typical: hystory of recent penile or
      perineal trauma followed, by the onset of a painless, incomplete and constant
      erection of the penis. A color-flow Doppler sonogram should be performed as first
      diagnostic step: this examination allows to identify the presence of patent
      cavernous arteries and prominent venous drainage with focal area of high flow
      turbulence along the pathway of one or both the cavernous arteries. An arterial
      blood sample taken from the corpora will confirm the diagnosis. At first,
      conservative therapeutical attempts can be suggested, with mechanical external
      compression of the perineum, the use of ice packs, corporeal aspiration and
      irrigation with saline. Besides, intracorporeal administration of alpha-agonists
      and methylene blue should be performed. Unfortunately, these conservative
      measures often result unsuccessful, and more invasive approaches must be
      considered. The radiological superselective transcatheter embolization of the
      proximal artery supplying arterial-lacunar fistula should be the present
      treatment of choice in these cases of high-flow priapism refractory to
      conservative and medical treatments. The first successful management of high flow
      priapism by selective arterial embolization was reported by Wear and coworkers in
      1977. Autologous clots and gelatine sponge have been extensively used and become
      very popular as the embolic agent. More recently, platinum microcoils have been
      proposed with the aim to achieve more precise and selective embolization. In our
      single-case-experience on the treatment of high flow priapism by arterial
      embolization, we used the recently introduced tungsten microcoils. At the time of
      the follow-up, 2 months later, patient reported satisfactory intercourse with an
      approximately 75% of penile rigidity. By comparison with microsurgical ligature
      of the damaged vessel, selective embolization is, at least theoretically, a less
      invasive procedure, particularly with reference to the trauma caused to the
      erectile tissue. High-flow priapism is a fairly rare urological pathology which
      does not require immediate and emergency treatment (as is the case, instead, with
      venous-occlusive priapism), since the risk of post-ischaemic fibrosis is excluded
      thanks to the fact that oxygen is supplied to the cavernous tissue. Once the
      diagnosis has been established with certainty, therefore, the specialist has the
      necessary time at disposal to arrange for the most appropriate therapeutic steps.
      When, as is frequently the case, conservative measures prove ineffective, the
      current treatment of choice for cases of fistula of the cavernous artery would
      appear to be superselective embolization of the artery, provided same can be
      performed at specialized centres and by experienced personnel.

PMID- 10417851
TI  - [Urologic importance of interventional radiology techniques].
AB  - In radiology several therapeutical methods were developed and introduced into
      clinical routine in the last 10 to 15 years. In part these techniques are in
      competition with established surgical procedures although their main advantage is
      significantly less invasion. For the urologist diagnostic radiological procedures
      like selective blood sampling from renal or suprarenal vessels for hormone
      determination or CT-guided biopsy of retroperitoneal tumors are of special
      interest as well as procedures with therapeutic aims such as placement of
      drainage-tubes, percutaneous therapy of varicoceles and arterial endovascular
      interventions for hemorrhage or vascular wall stenosis. The role of these
      interventional techniques relevant for urology is described and critically
      discussed.

PMID- 10417852
TI  - [Temporary retrograde and anterograde ureteral catheterization].
AB  - This article examines the technical modalities or ureteral catheterization. The
      authors also discuss unconventional modalities which, if used without prejudice,
      can sometimes constitute brilliant and economic solutions to complex problems
      which are often impossible to resolve otherwise. After a summary of the history
      of ureteral catheterization, the authors present the main indications for
      temporary ureteral catheterization: radiographic and fluoroscopic examination of
      the ureter; separate cytological harvesting; separate bacteriological harvesting;
      confirmation of the side of unilateral haematuria; preliminary temporary
      dilatation of the ureter to prepare it for ureteroscopy; temporary drainage of
      the excretory tract after endourological investigation. The authors also present
      particular situations may be observed temporary catheterization, or even
      permanent stenting, for example in the case of procedures in children, pregnant
      women and renal transplant recipients.

PMID- 10417853
TI  - Single dose recombinant human erythropoietin reduces transforming growth factor
      beta in patients on chronic haemodialysis.
AB  - Short-term effects of recombinant human erythropoietin on serum levels of
      transforming growth factor beta-1, interleukin 1-alpha, interleukin 3, interferon
      gamma, and tumour necrosis factor alpha in patients with chronic renal failure on
      chronic haemodialysis were investigated. Recombinant human erythropoietin was
      applied subcutaneously in a dose of 75 IU/kg on 19 patients. Serum levels of
      transforming growth factor beta-1, interleukin 1-alpha, interleukin 3, interferon
      gamma, tumour necrosis factor alpha and erythropoietin, red blood cell
      parameters: red blood cell count, haemoglobin, haematocrit, and erythrocyte
      indices were determined before and after recombinant human erythropoietin single
      application. Transforming growth factor beta-1 serum levels were decreased after
      recombinant human erythropoietin (22.70 +/- 1.51 ng/ml versus 18.77 +/- 1.70
      ng/ml (p < 0.01). None of the other investigated parameters was influenced
      significantly by recombinant human erythropoietin. Recombinant human
      erythropoietin in patients with chronic renal failure on chronic haemodialysis
      may influence anaemia not only through its stimulating effect on erythropoiesis,
      but also by direct oxygen-independent decrease of at least one of the negative
      regulators of erythropoiesis--the transforming growth factor beta.

PMID- 10417854
TI  - Early steps in insulin action.
AB  - The biological effects of insulin are initiated by the binding of insulin to the
      insulin receptor. Insulin binds to the extracellular domain of the insulin
      receptor and induces conformational changes in the receptor, leading to
      autophosphorylation of the receptor on intracellular tyrosine residues. These
      phosphorylated tyrosine residues act as binding sites for proteins which
      subsequently may be phosphorylated by the insulin receptor. As a result, yet
      other proteins can be recruited to form larger complexes and, in the case of
      enzymes, changes in their activity may take place. By a combination of these
      processes, the activated insulin receptor initiates cascades of biochemical
      events which are regulated mainly by specific phosphorylation or
      dephosphorylation reactions. Intermediates which are involved in the normal
      insulin signalling pathway are subjects of expanding research.

PMID- 10417855
TI  - Blood ammonia and ventilation at maximal exercise.
AB  - This study, intended to evaluate the role of ammonia (NH3) as a ventilatory
      stimulus, was conducted in three groups of subjects: 14 sedentary individuals, 12
      triathletes, 5 patients with a glycolytic deficiency (Mc Ardle disease). All
      subjects performed maximal exercise tests on a cycle ergometer. Ventilation
      measured at maximal oxygen consumption (VE 100%) was correlated with lactatemia
      (lactate 100%) and ammonemia (NH3 100%) in the sedentary group, but only with
      ammonemia in triathletes, although NH3 100% and lactate 100% were correlated in
      both groups, which suggests that correlation between VE 100% and NH3 100% is not
      a false correlation. In patients with Mc Ardle disease, unable to produce lactate
      during exercise, VE 100% was correlated with NH3 100%. NH3 may act indirectly by
      increasing the production of lactate in cereberal tissue. Another hypothesis
      rests on the fact that the catabolism of ammonia leads to an increase in
      intracerebral glutamate which may act as a ventilatory stimulus.

PMID- 10417856
TI  - Effects of bilateral electrolytic lesions of the medial nucleus accumbens on
      exploration and spatial learning.
AB  - Rats with electrolytic lesions of the medial part of the nucleus accumbens,
      comprising the shell region, were compared to sham-operated rats in tests of
      exploration in a T-maze, in a hole-board, and in an elevated (+)-maze and in a
      test of water maze spatial learning. Rats with medial nucleus accumbens lesions
      had higher choice latencies than sham-operated controls during the beginning of
      the spontaneous alternation test. A higher number of hole pokes was found in the
      lesioned group, but only during the beginning of the second day of testing. In
      the elevated (+)-maze, lesioned rats had a higher number of closed and total arm
      entries and spent more time in the center region. The lesioned group did not
      differ from the control group for the number of alternations in the T-maze, for
      horizontal and vertical motor activity in the hole-board, and for acquisition or
      reversal of spatial learning in the Morris water maze. These results indicate
      that lesions of the medial nucleus accumbens slowed down decision time during
      spontaneous alternation testing and increased exploration in a time and test
      specific manner without altering acquisition of a reference memory task.

PMID- 10417857
TI  - Thyroid hormone regulation of MHC isoform composition and myofibrillar ATPase
      activity in rat skeletal muscles.
AB  - Myosin heavy chain (MHC) isoform composition and Ca2+ Mg2+ dependent ATPase
      activity were determined in myofibrils prepared from skeletal muscles (diaphragm,
      soleus, plantaris and tibialis anterior) of euthyroid (C), hypothyroid (Tx) and
      hyperthyroid (T3) rats. Direct comparison between T3 and Tx gave an indication of
      the maximal effect of thyroid hormones. Significant differences in MHC-1 and MHC
      2B proportions and in ATPase activity were found in all muscles. The difference
      in MHC-2A/X proportion was significant only in soleus, diaphragm and plantaris.
      When T3 and C were compared, significant variations in MHC isoform composition
      were found only in plantaris and diaphragm. The comparison between Tx and C
      showed significant differences in MHC isoform distribution and in ATPase activity
      in most muscles. The differences in ATPase activity among muscles and among
      thyroid states were consistent with those in MHC isoform distribution. From the
      correlations between ATPase activity and MHC isoform distribution the enzymatic
      activities of individual MHC isoforms were calculated. The results indicate that
      MHC isoform distribution is controlled by thyroid state in all skeletal muscles
      and that changes in MHC isoforms distribution are accompanied by proportional
      changes in ATPase activity.

PMID- 10417858
TI  - Glass ring-wall sealing to prevent leakage from electrode culture chambers: a
      technical note.
AB  - Entellan is a good sealing substance for culture chamber walls and does not
      interfere with the growth of the cultured DRG cells. If the Entellan becomes
      brittle the glass ring can easily be loosened by placing the chamber with the
      sealed ring for 24 hrs in xylene. Repeated rinsing with xylene and subsequently
      with hydrated steps of ethanol (100%-70%-30%) allows the ring-wall and chamber
      floor with its electrodes to be reused.

PMID- 10417859
TI  - Effects of halothane on mechanical response of skeletal muscle from malignant
      hyperthermia susceptible patients.
AB  - The purpose of this investigation was to compare the effects of halothane on
      malignant hyperthermia (MH) and normal isolated muscle bundle performance during
      isometric contraction and relaxation phases. Mechanical parameters were measured:
      peak tension (PT), time to peak tension (TPT) and positive peak of isometric
      tension derivative (+dP/dtmax) characterized the contraction phase. Half
      relaxation time (RT1/2) and negative peak of isometric tension derivative (
      dP/dtmax) characterized the relaxation phase. The ratio R = (+dP/dtmax)/(
      dP/dtmax) was used to study the coupling between contraction and relaxation under
      isometric condition. In normal muscle, halothane increased PT by nearly 40%
      without altering TPT. The +dP/dtmax value increased concomitantly with the 
      dP/dtmax values, thus no changes in R was observed. In MH muscle, PT was first
      potentiated (0.5-1.0 vol% halothane) and then depressed (2.0-3.0 vol% halothane).
      TPT and +dP/dtmax were not altered whereas RT1/2 increased progressively with
      concomitant decrease in -dP/dtmax, thus R increased by nearly 40%. The amplitude
      of MH muscle contracture with stepwise concentrations of halothane was correlated
      with the increase of RT1/2 and R, and the decrease of -dP/dtmax. These results
      suggest that halothane alters the relaxation phase more than the contraction
      phase in MH human skeletal muscle compared to normal muscle.

PMID- 10417861
TI  - Influence of molecular lipophilicity on the diffusion of arylpropionate non
      steroidal anti-inflammatory drugs into the cerebrospinal fluid.
AB  - The diffusion of seven arylpropionic acid non-steroidal anti-inflammatory drugs
      (NSAIDs) into the cerebrospinal fluid (CSF) has been investigated in male Wistar
      rats by means of quantitative structure-activity relationship (QSAR) study. After
      intraperitoneal administration of each drug (5 mg/kg), blood and CSF samples were
      collected at different times (0.5, 1, 3, and 6 h). The fraction bound to plasma
      proteins (fb) was determined using ultracentrifugation. The total (CT) and free
      (CF) plasma concentrations and the concentrations in CSF (CCSF) were measured by
      a reversed-phase high performance liquid chromatographic (RP-HPLC) method. The
      areas under the curve of the free plasma (AUCF) and CSF (AUCCSF) concentrations
      were calculated according to the trapezoidal rule. The overall drug transit into
      CSF was estimated by the ratio RAUC (AUCCSF: AUCF). The lipophilicity of the
      compounds was expressed as their polycratic capacity factors (log k'w) measured
      in a RP-HPLC system. The RAUC ranged from 0.24 to 6.58 and fb from 91.4 to 99.8%.
      The compounds with an intermediate lipophilicity value (3 < logk'w < 3.6) easily
      entered the CSF (RAUC > 1). A parabolic relationship was found between log k'w
      and log RAUC, emphasizing the role of molecular lipophilicity in the diffusion
      into CSF. Considering the fb value of each drug in regard to this non-linear
      relationship, it can be hypothesized that the diffusion rate of NSAIDs into the
      CSF depends primarily on the lipophilicity.

PMID- 10417860
TI  - The effect of the new oral hypoglycemic agent A-4166 on glucose turnover in the
      high fat diet-induced and/or in the hereditary insulin resistance of rats.
AB  - A-4166, a phenylalanine derivative, is a hypoglycemic agent, which has been shown
      to improve blood glucose levels mainly due to the rapid and short term
      stimulation of insulin release. Nevertheless, a possible extrapancreatic action
      of A-4166 has not yet been investigated. Therefore, insulin action (euglycemic
      hyperinsulinemic 6.4 mU.kg-1.min-1 clamp plus 3H-2-deoxyglucose tracer
      administration) was studied after 3 weeks on either standard (BD) or high fat
      (HF) diet in normal control (C) or in hereditary insulin resistant (hHTg) rats
      which were given a single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after
      clamp commencement. HF feeding reduced the glucose infusion rate (GIR) required
      to maintain euglycemia to about 50% of C (p < 0.001). In hHTg rats, HF did not
      further pronounce the pre-existing decrease of GIR of hHTg animals fed BD. A-4166
      changed GIR neither in C, nor in the hHTg group. The estimated glucose disposal
      (Rd) (C-BD: 32.3 +/- 1.9 vs C-HF: 25.5 +/- 1.9 mg.kg-1.min-1, p < 0.001) and
      glucose metabolic index (Rg') in skeletal muscles (Q. femoris: C-BD: 25.6 +/- 1.5
      vs C-HF: 12.3 +/- 1.1 mmol.100 g-1.min-1, p < 0.001) were reduced by HF in
      control rats but were not restored by a concomitant bolus of A-4166.
      Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166 brought back
      their Rd (hHTg-HF: 23.5 +/- 1.3 vs hHTg-HF plus A-4166: 31.0 +/- 3.5 p < 0.03)
      and Rg' (Soleus muscle: hHTg-HF: 29.2 +/- 3.2 vs hHTg-HF plus A-4166: 41.3 +/-
      4.0) to values of the control group on BD. In summary, a) a single bolus
      administration of A-4166 to the control or to the insulin resistant hHTg rats,
      fed either the BD or HF diets, did not abolish the reduction of GIR required to
      maintain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166
      caused a significant increase of the estimated plasma glucose disposal (Rd) and
      skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF diet; c) we
      suggest that A-4166 may have an extrapancreatic action but this needs to be
      proven using a long-term administration plan of A-4166.

PMID- 10417862
TI  - Binding profiles of a series of 2-arylpropionic acid esters on cloned human
      muscarinic receptor subtypes (m1-m5) and their relationship to nootropic
      activity.
AB  - The muscarinic binding profile of a series of 2-arylpropionic acid esters on
      cloned human muscarinic receptor subtypes (m1-m5) was determined to investigate
      whether there is a correlation between pharmacological activity and muscarinic
      receptor subtype selectivity. Among the tested compounds, 1, 7 and 9 showed the
      highest affinity for the m2 and m4 receptors. Compounds 1, 7 and 9 show good
      affinity for m4 receptors (pKi = 7.87; 7.73 and 7.10, respectively) and are able
      to discriminate 10-60 fold between m4/m1, m4/m3, and m4/m5 subtypes. Conversely,
      these compounds are able only to weakly discriminate between m4/m2. Compounds 1
      (50-300 micrograms kg-1 i.p.) and 7 (1-10 micrograms kg-1 i.p.), injected 20 min
      before the training session, are able to prevent the amnesia induced by
      dicyclomine (2 mg kg-1 i.p.) in the mouse passive-avoidance test. Compounds 1 and
      7, at the highest antiamnesic doses, do not modify motor coordination and
      spontaneous motility as evaluated by the rota-rod test and Animex apparatus
      experiments.

PMID- 10417863
TI  - Long-term intraspinal infusions of opioids with a new implantable medication
      pump.
AB  - Experiences with long-term intraspinal infusion of opioid drugs using the new
      implantable medication pump VIP 30 in patients with chronic non-malignant pain
      are reported. During a 19-month period 10 patients with chronic pain--mainly
      mixed nociceptive-neuropathic pain--underwent implantation of the medication pump
      for long-term treatment. The mean follow-up period was 9.5 months. Pain relief
      was classified as very good in 22.2%, good in 44.4%, moderate in 22.2% and poor
      in 11.1%. In 88.9% of the cases the patients stated they would undergo the same
      procedure again. Technical problems (catheter dislocation) developed in 1/10
      patients could be surgically corrected. One pump including catheter was explanted
      because of an infected seroma within the pocket area. Long-term intrathecal
      application of opioids with the VIP 30 pumps is an effective and safe treatment
      in patients with chronic non-malignant pain.

PMID- 10417864
TI  - Effect of amlodipine on blood pressure responses in local and whole-body cooling
      in normotensive men.
AB  - The objective of this study was to determine the ability of amlodipine (CAS 88150
      42-9, Norvasc) to affect the cold-induced rise of blood pressure and heart rate
      in normotensive men. Fourteen normotensive men underwent a one-hand cold pressor
      test (+10 degrees C, 5 min) and a whole-body cold air exposure test (+5 degrees
      C, 45 min) in a crossover study with and without amlodipine at a seven-day
      interval. Amlodipine decreased the levels of initial systolic and diastolic blood
      pressure before both tests, but it had no influence on heart rate. During the
      cold pressor test, amlodipine lowered the peak diastolic pressure from 96 +/- 10
      mmHg (mean +/- SD) to 92 +/- 10 mmHg (p = 0.024). The rise of diastolic blood
      pressure was 13 +/- 7 mmHg with amlodipine and 16 +/- 8 mmHg without amlodipine
      (p = 0.138). During the whole-body cold air exposure test, amlodipine decreased
      the systolic pressure from 135 +/- 2 mmHg to 133 +/- 3 mmHg (p = 0.008) and the
      diastolic pressure from 88 +/- 2 mmHg to 86 +/- 1 mmHg (p = 0.005). However, the
      cold-induced rise of blood pressure in whole-body cooling was not affected by
      amlodipine, because it also decreased the initial values. Amlodipine did not
      affect the initial or cold-induced changes of heart rate in these tests. In
      conclusion, in normotensive men amlodipine lowers the peak of diastolic blood
      pressure in a cold pressor test. In whole-body cold air exposure, amlodipine
      slightly decreases the levels of both systolic and diastolic pressures, but has
      no effect on the cold-induced rise of blood pressure. Amlodipine does not prevent
      the cold-induced physiological responses of blood pressure or heart rate.

PMID- 10417865
TI  - Study on the effectiveness of toborinone (OPC-18790) in the treatment of heart
      failure in patients following cardiac surgery.
AB  - Toborinone ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-qui
      nolinone, CAS 128667-95-8, OPC-18790), a novel cardiotonic agent with an
      inhibitory action on phosphodiesterase, is known to have a potent positive
      inotropic action with no positive chronotropic effect. The effectiveness of this
      drug in the treatment of heart failure occurring immediately after extracorporeal
      circulation (ECC) in cardiac surgery was investigated. The study was conducted in
      12 patients with valvular heart disease showing a cardiac index (CI) of below 2.8
      l/min/m2 and/or pulmonary capillary wedge pressure (PCWP) or pulmonary arterial
      diastolic pressure (PAD) of above 8 mmHg immediately after extracorporeal
      circulation. In group A (n = 6), toborinone was infused at a rate of 40
      micrograms/kg/min for the first 5 min and then at 10 micrograms/kg/min for 85
      min. In group B (n = 6), the drug was infused at a rate of 10 micrograms/kg/min
      for the entire 90 min. CI, mean systemic arterial pressure (mSAP), mean pulmonary
      artery pressure (mPAP), CVP, PCWP, and heart rate were measured at 5, 15, 30, 60,
      and 90 min after the start of infusion. The infusion volume required to maintain
      a constant PCWP was also estimated. In group A, CI increased rapidly and
      significantly from the baseline of 2.48 +/- 0.23 l/min/m2 to 3.57 +/- 1.07
      l/min/m2 at 5 min after the start of infusion, and at that time mSAP was slightly
      decreased. In group B, CI increased gradually from the baseline of 2.53 +/- 0.18
      l/min/m2 to 3.08 +/- 0.34 l/min/m2 at 15 min after the start of infusion, but
      almost no change was seen in mSAP. During the first 30 min, group A required a
      significantly larger infusion volume (983 +/- 395 ml) than group B (475 +/- 184
      ml). From 30 to 90 min after the start of infusion, CI remained increased to
      similar levels in both groups and mSAP levels were also similar. There were no
      significant differences between the two groups in any other parameter. Continuous
      infusion of toborinone appears to be effective for treating heart failure
      occurring immediately after ECC in cardiac surgery. Initial loading at a rate of
      40 micrograms/kg/min rapidly increased CI but was accompanied by mild
      hypotension. Constant infusion at 10 micrograms/kg/min brought about a more
      gradual effect that was similar to that of loading at 40 micrograms/kg/min, but
      without inducing hypotension. Thus, infusion at 10 micrograms/kg/min is
      considered preferable in order to avoid a larger-than-necessary infusion volume.

PMID- 10417866
TI  - Pharmacokinetics, metabolism and bioavailability of the new anti-allergic drug BM
      113. Part I: Pharmacokinetics and tissular distribution in Sprague-Dawley rats.
AB  - A new anti-allergic drug, BM 113 (1-(benzhydryloxyethyl)piperidino-4
      ethylacetate, CAS 115313-90-1; BM 113 maleate: CAS 115313-91-2) with a
      piperidinic structure, showing antihistaminic properties was studied in male and
      female Sprague-Dawley rats after i.v. or p.o. administrations of 0.750 mg/kg 3H
      BM 113. This product presented a rapid faecal elimination after i.v. and oral
      administration. The total recovery of the dose was obtained after 144 h. Biliary
      elimination was very fast: 54% of the intravenous dose were biliarily eliminated
      within 2 h, essentially as a conjugated form. For both i.v. and p.o. routes, the
      blood kinetics were biexponential. Intravenous administration led to elimination
      half-lives of 1.36 h and 0.75 h for the first phase and 38.6 h and 56.5 h for the
      second one for males and females, respectively. After oral administration,
      rebounds corresponding to the presence of enterohepatic cycle or metabolites were
      observed. Thus, the determination of half-lives was not possible. Slight but
      significant differences of some pharmacokinetic parameters were observed between
      genders. The results obtained during the protein binding study corresponded to
      the BM 113 metabolite known as BM 212. The free fraction corresponded to 55.5%.
      Tissular concentrations showed a rapid distribution of 3H-BM 113 followed by a
      slow elimination. In most of the tissues, the decrease was biexponential. The
      organs containing most of the radioactivity were those of the intestinal tract
      and the liver. Other tissues presented concentrations close to those of plasma.
      Lipidic tissues, showing low BM 113 concentrations, presented a slower
      elimination, probably related to the high lipophilicity of molecule.

PMID- 10417867
TI  - In vitro topical delivery of non-steroidal anti-inflammatory drugs through human
      skin.
AB  - The objective of the present study was to evaluate in vitro the percutaneous
      absorption, across human skin, of 5 non-steroidal anti-inflammatory drugs
      (NSAIDs) formulated as gels: ketoprofen (CAS 22071-15-4), epolamine diclofenac
      (CAS 15307-86-5), piroxicam (CAS 36322-90-4) and niflumic acid (CAS 4394-00-7) or
      as emulgel: diclofenac sodium (CAS 15307-79-6) and to compare the different
      formulations as drug delivery systems. Because the concentrations of the NSAIDs
      in the different excipients were not identical, the comparison of their
      diffusional properties was expressed in term of release efficiency (or diffusion
      efficacy). The results obtained show that, across human skin under standardized
      experimental conditions, ketoprofen and piroxicam have the best rank order
      followed by niflumic acid, diclofenac sodium and epolamine diclofenac.

PMID- 10417868
TI  - Nonsteroidal anti-inflammatory activity of 1,2,4-triazolyl-heterocarboxylic
      derivatives.
AB  - A series of 1,2,4-triazolyl-thiophene and 1,2,4-triazolyl-pyrazole carboxylic
      acid derivatives was tested for acute toxicity and nonsteroidal anti-inflammatory
      activity. Some of these compounds showed potent analgesic activity and
      interesting nonsteroidal anti-inflammatory properties in different acute and
      chronic inflammation models.

PMID- 10417869
TI  - Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine
      H2-receptor antagonistic activity.
AB  - Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor
      antagonist with gastroprotective activity. The aim of this study was to
      investigate the property of the gastro-protective activity of lafutidine by
      examining the effect on ammonia-induced change in transmucosal potential
      difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent
      induced cell damage. Intragastrical application of lafutidine accelerated the
      recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia
      solution and the accelerating effect was abolished by chemical deafferentation,
      but not with indometacin, a cyclooxygenase inhibitor. The application of
      capsaicin, as a reference compound, significantly promoted the recovery of the
      ammonia-induced PD reduction and this effect was not altered with indometacin.
      Lafutidine given intragastrically caused a sustained increase in GMBF in a dose
      dependent fashion, which was also completely inhibited in the deafferentated
      rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin
      E2, lafutidine did not protect isolated gastric superficial epithelial cells from
      ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of
      lafutidine is induced by promoting the restitution of the damaged mucosa after a
      noxious agent, not by directly protecting the epithelial cells and this effect
      may be caused through the mechanism of capsaicin-sensitive afferent nerves.

PMID- 10417870
TI  - Pharmacokinetics of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist.
      2nd communication: Absorption and excretion in rabbits, dogs and monkeys after a
      single administration of 14C-NS-49.
AB  - The absorption and excretion of NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'
      fluoromethanesulfonanilide hydrochloride, CAS 137431-04-0), a phenethylamine
      class alpha 1A-adrenoceptor agonist, were studied in male rabbits, dogs, and
      monkeys after intravenous or oral administration of 14C-NS-49. After single oral
      administration of 14C-NS-49 (1 mg/kg) to rabbits and dogs, the plasma
      concentrations of radioactivity and NS-49 reached maximums at about 2 h, then
      decreased triexponentially. In monkeys, both maximums were reached 3 h after
      administration, and both concentrations decreased biexponentially. Most of the
      plasma radioactivity was due to unchanged NS-49 in the rabbits and dogs,
      indicating poor metabolism of this drug. In the monkeys, however, the percentage
      of unchanged NS-49 in the plasma radioactivity was low, about 20%, during a 24-h
      period after oral administration. After intravenous and oral administrations of
      14C-NS-49, radioactivity was primarily excreted in the urine in all the species
      tested. The absorption rates found by comparing the urinary excretions of
      radioactivity after both routes of administration were 71% for rabbits, 92% for
      dogs, and 95% for monkeys. The percentages of NS-49 in the radioactivity excreted
      in the urine after intravenous and oral administrations, respectively, were 77%
      and 68% for rabbits, 96% and 96% for dogs, and 57% and 29% for monkeys. The
      systemic availability calculated from the unchanged drug excreted in the urine
      was similar to the absorption rates for rabbits and dogs. This indicates that
      first-pass metabolism of this drug is very limited in both species. The systemic
      availability for monkeys, however, was about half the absorption rate due to the
      first-pass effect. Renal clearance accounted for most of the total clearance for
      rabbits and dogs, but only about half that for monkeys.

PMID- 10417871
TI  - In vitro antibacterial activity of thiamphenicol glycinate acetylcysteinate
      against respiratory pathogens.
AB  - After 30 years of therapeutic use, thiamphenicol glycinate acetylcysteinate (CAS
      20192-91-0) is still widely employed in the treatment of upper and lower
      respiratory tract infections. This is due to its particular characteristic to
      exert at pulmonary level, either the antibacterial activity of thiamphenicol (CAS
      15318-45-3) and the mucolytic activity of N-acetylcysteine (CAS 616-91-1). The
      aim of this study was to evaluate the present pattern of susceptibility of
      several clinical isolates to thiamphenicol and the interference of N
      acetylcysteine on this parameter. The studies have been performed in vitro.
      Equimolar concentrations of N-acetylcysteine and even higher concentrations did
      not interfere with the antibacterial activity of thiamphenicol against
      Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae. The
      spectrum of activity of thiamphenicol was similar to that observed in the past
      and was superior to that of erythromycin and amoxicillin. The activity of
      thiamphenicol was greater than that of erythromycin against H. influenzae and
      streptococci and equivalent versus Branhamella catarrhalis. In comparison with
      amoxicillin the activity of thiamphenicol was higher against H. influenzae and B.
      catarrhalis and slightly lower against streptococci. The results demonstrate that
      thiamphenicol maintains its therapeutic value confirming the importance of
      thiamphenicol glycinate acetylcysteinate in the treatment of respiratory tract
      infections.

PMID- 10417872
TI  - Antibacterial and antifungal activities of complexes of ruthenium (II).
AB  - Twenty ruthenium (II) complexes (1-5) were evaluated for their in vitro
      antibacterial and antifungal activity against Enterococcus faecalis (ATCC 29212),
      Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Pseudomonas
      aeruginosa (ATCC 27853), Candida albicans and Candida tropicalis. Compounds 1d,
      1e, 1h, 1i and 1j showed more pronounced antimicrobial activity against Gram
      positive bacteria and fungi as compared to the nitrogen donor ruthenium
      complexes; hydrophobic substituents were significantly more effective. None of
      the compounds 1-5 exhibited antimicrobial activity against the Gram-negative
      strains Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 27853)
      with the concentrations ranging between 12.5 and 800 micrograms/ml.

PMID- 10417873
TI  - Effects of D-methionine-containing solution on tumor cell growth in vitro.
AB  - The effects of a nutrition therapy with D-methionine (Met)-containing solution
      were investigated in cell cultures of the AH109A cell line. The growth of AH109A
      hepatoma cells in culture media with D-Met-supplemented medium, L-Met
      supplemented medium (control) and Met-free medium was compared. The D-Met
      supplemented medium inhibited the cell growth to an extent similar to that
      manifested in the Met-free medium. The total free amino acid concentrations in
      the control medium decreased by approximately 40% on day 6 post-culture. However,
      the free amino acid concentrations in D-Met-supplemented and Met-free media did
      not change. Furthermore, alanine, which was not added to RPMI-1640, was detected
      in the control medium on day 6 post-culture. These results suggest the
      possibility of application of D-Met-containing solution to cancer patients
      receiving total parenteral nutrition.

PMID- 10417874
TI  - Ajoene in the topical short-term treatment of tinea cruris and tinea corporis in
      humans. Randomized comparative study with terbinafine.
AB  - Ajoene (CAS 92284-99-6), an organic trisulphur originally isolated from garlic,
      has an antimycotic activity which has been widely demonstrated both in vitro and
      in vivo. The objective of this work was to compare the safety and effectiveness
      of ajoene (0.6%, gel) with terbinafine (CAS 91161-71-6) (1%, cream) for the
      treatment of tinea corporis and tinea cruris. The patients selected were 60
      soldiers with clinical and mycological diagnosis of either dermatophytosis. They
      were distributed at random in two treatment groups, one treated with ajoene at
      0.6% and the other with terbinafine at 1%. All patients were evaluated clinically
      and mycologically 30 and 60 days after completion of the treatment, which was
      considered effective when clinical signs and symptoms had disappeared and the
      mycological cultures were negative. Thirty days after treatment, the percent
      healing rate was 77 and 75 for the groups treated with ajoene and terbinafine,
      respectively. Sixty days after treatment, the healing rate 73% and 71% for the
      groups treated with ajoene and terbinafine, respectively. These results and those
      obtained in previous studies confirm that ajoene is a new agent for the topic
      treatment of superficial mycoses, and for the first time show the therapeutic
      usefulness of an inhibitor of phospholipids biosynthesis in eukaryotes.

PMID- 10417875
TI  - Maternal cytoplasmic factors for generation of unique cleavage patterns in animal
      embryos.

PMID- 10417876
TI  - Multiple endo-1,4-beta-D-glucanase (cellulase) genes in Arabidopsis.
AB  - The plant cell wall is modified in coordination with almost all plant
      developmental processes. Modifications in the cell wall are thought to be
      mediated by cell wall hydrolases, including those encoded by a large family of
      genes specifying endo-1,4-beta-D-glucanases (EC 3.2.1.4), which participate in
      the breakdown of beta-1,4 glucosidic linkages. The enzymes expected to modify
      cellulose, commonly referred to as cellulases, are encoded by members of this
      gene family. In Arabidopsis the endo-1,4-beta-D-glucanase (EGase) gene family is
      extensive (more than 12 members) and encompasses structurally different classes
      of genes encoding proteins with contrasting enzyme functions. Within the family
      there are enzymes located at the plasma membrane that are presumed to act at the
      innermost layers of the cell wall, and enzymes that are secreted and are presumed
      to act at any stratum within the cell wall, including the outermost layer. Both
      structural gene groups are members of the glycosyl hydrolase gene Family 9.
      Evidence suggests that EGases anchored in the plasma membrane play a role in cell
      wall biosynthetic processes, presumably by editing cellulose synthesis or during
      the assembly of the cellulose-hemicellulose network. Those EGases that are
      extracellular play specific roles in cell wall catabolic processes and their
      activity ranges from partial and localized to massive and catastrophic. This
      range in activity is linked to processes such as cell growth and cell death,
      respectively. For all Arabidopsis EGases nothing is known about their true in
      vivo substrate, mode of action, or to what extent they can act on cellulose or
      other beta-1,4 glucans. The study of the EGase gene family is in its infancy, and
      because of the possible agronomic implications this group of genes deserves
      continued attention.

PMID- 10417877
TI  - The anterior margin of the mammalian gastrula: comparative and phylogenetic
      aspects of its role in axis formation and head induction.
AB  - Recent findings on morphology and gene expression in several mammalian embryos
      suggest that there is a new landmark and possibly a center with organizer
      activity in the anterior margin of the embryo at the onset of gastrulation. This
      review compiles morphological variations and similarities found among mammals
      during gastrulation stages and, at the same time, stresses the common aspects, at
      the morphological and the molecular level, of setting up the body plan with
      regard to axis formation and head induction. Both morphological and functional
      aspects are then used to draw comparisons with equivalent developmental stages in
      lower vertebrate species, such as birds, amphibia, and bony fish. Finally, a
      suggestion is made as to how gastrulation may have evolved in the vertebrate
      phylum.

PMID- 10417878
TI  - The other side of the embryo: an appreciation of the non-D quadrants in leech
      embryos.

PMID- 10417879
TI  - Sperm nuclear activation during fertilization.
AB  - The delivery of the paternal genome to the egg is a primary goal of
      fertilization. In preparation for this step, the nucleus of the developing
      spermatozoon undergoes extensive morphological and biochemical transformations
      during spermatogenesis to yield a tightly compacted sperm nucleus. These
      modifications are essentially reversed during fertilization. As a result, the
      incorporated sperm nucleus undergoes many steps in the egg cytoplasm as it
      develops into a male pronucleus. The sperm nucleus (1) loses its nuclear
      envelope, (2) undergoes nucleoprotein remodeling, (3) decondenses and increases
      in size, (4) becomes more spherical, (5) acquires a new nuclear envelope, and (6)
      becomes functionally competent to synthesize DNA and RNA. These changes are
      coordinate with meiotic processing of the maternal chromatin, and often result in
      behaviors asynchronous with the maternal chromatin. For example, in eggs
      fertilized during meiosis, the sperm nucleus decondenses while the maternal
      chromatin remains condensed. A model is presented that suggests some reasons why
      this puzzling behavior exists. Defects in any of the processes attending male
      pronuclear development often result in infertility. New assisted reproductive
      technologies have been developed that ensure delivery of the sperm nucleus to the
      egg cytoplasm so that a healthy embryo is produced. An emerging challenge is to
      further characterize the molecular mechanisms that control sperm nuclear
      transformations and link these to causes of human infertility. Further
      understanding of this basic process promises to revolutionize our understanding
      of the mystery of the beginning of new life.

PMID- 10417880
TI  - Fibroblast growth factor signaling regulates growth and morphogenesis at multiple
      steps during brain development.
AB  - The fibroblast growth factor (FGF) family comprises several members with distinct
      patterns of expression in the developing central nervous system. FGFs regulate
      the early specification and the subsequent growth of central nervous system
      regions. These different actions require the coordinated activation of distinct
      sets of target genes by FGFs at the appropriate stage of development. The role of
      FGF2 in the growth and morphogenesis of the cerebral cortex is reviewed in
      detail. The cellular and molecular mechanisms that underlie the action of FGF2 on
      cortical development are discussed.

PMID- 10417881
TI  - [Microbubbles for the kidney].

PMID- 10417882
TI  - [Imaging in battered child syndrome].

PMID- 10417883
TI  - [Intracranial manifestations of battered child syndrome].

PMID- 10417884
TI  - [Osteoarticular manifestations of battered child syndrome].

PMID- 10417885
TI  - [Bone scintigraphy and battered child syndrome].

PMID- 10417886
TI  - [Abdominal visceral lesions in battered child syndrome].

PMID- 10417887
TI  - [The radiologic report in battered child syndrome].

PMID- 10417888
TI  - [Interventional radiology and the medical applications of information systems:
      what consequences for the radiology department?].
AB  - The French health care system reform has introduced some changes in the
      distribution of hospital budgets according to the distribution of admitted
      patients in diagnosis related groups (DRGs). This new model of budget allocation
      does not take into account the more technical nature of some medical procedures
      and services and does not promote the implementation of new technologies. Using
      four simulated clinical cases, we studied the length of stay in different DRGs
      and the number of associated points (points d'indice synthetique d'activite,
      ISA). The addition of the interventional radiologic procedures did not modify the
      DRG (which remained unchanged from the initial DRG). In order to achieve
      recognition of the specific nature of interventional radiology procedures, a
      database should be created and an economical evaluation conducted.

PMID- 10417889
TI  - [The value of orbital ultrasonography in ethmoid sinusitis in children].
AB  - PURPOSE: To assess the value of orbital sonography (US) compared to CT in the
      management of children with ethmoid sinusitis. MATERIAL AND METHODS: A total of
      13 consecutive patients admitted for non-complicated ethmoid sinusitis (absence
      of visual or neurological symptoms) were prospectively evaluated at US and CT.
      RESULTS: Three patients had no evidence of postseptal involvement at US. Ten
      patients had variable degree of postseptal involvement at US: hypoechoic area or
      fluid collection in the extraconal fat along the medial orbital wall. Results
      were confirmed at CT in all patients. CONCLUSION: US is useful to confirm the
      presence of postseptal involvement in patients with ethmoid sinusitis. Contrary
      to CT, findings at US remain non-specific as to the nature of involvement.
      Nonetheless, US is helpful for patient management.

PMID- 10417890
TI  - [Acute cholecystitis using computed tomography: usefulness of the trabeculation
      of the peri-cholecystic adipose tissue].
AB  - PURPOSE: To evaluate the significance of pericholecystic fat stranding on CT, and
      to compare it to other CT findings in patients with acute cholecystitis.
      MATERIALS AND METHODS: The CT examinations of 14 patients with proven acute
      cholecystitis were retrospectively reviewed and evaluated for the presence of
      findings consistent with this diagnosis. RESULTS: The most common CT finding was
      stranding of the pericholecystic fat (13 patients), followed by gallbladder
      distension (11 patients). Pericholecystic or perihepatic fluid was present in 6
      patients in association with severe acute cholecystitis (6 patients) and biliary
      peritonitis (2 patients). CONCLUSION: Stranding of the pericholecystic fat was
      the most common CT findings in patients with acute cholecystitis, followed by
      gallbladder distension.

PMID- 10417891
TI  - [An MRI study of the normal pelvis in the immediate postpartum period].
AB  - PURPOSE: To describe the MR findings of the pelvis in the early post-partum
      period, after vaginal delivery or cesarean section. MATERIALS AND METHODS:
      Fifteen asymptomatic patients were imaged using a 1.5 Tesla MR unit between 1 and
      7 days following delivery. Eight patients had a vaginal delivery, and seven
      patients had a cesarean section. RESULTS: The following items were evaluated:
      uterus size, architecture, and contents; uterine and abdominal wall scars;
      parametrium; peritoneal cavity; ovarian veins. CONCLUSION: MRI provided a good
      evaluation of the pelvic changes related to pregnancy and delivery. Knowledge of
      the normal findings should improve diagnosis of early post-partum complications.

PMID- 10417892
TI  - [Post-traumatic aneurysmal dissection of the extracranial internal carotid
      artery; helical computed tomographic and angiographic aspects: a case].
AB  - A 20-year-old man presented with mild intracranial bleeding, a Horner's syndrome,
      and left neck swelling following head injury. Following noncontrast CT of the
      brain, a contrast-enhanced helical CT was performed through the neck that showed
      a hematoma in the poststyloid space (carotid sheath) with irregular diameter of
      the ICA. Selective digital subtraction angiography confirmed the presence of left
      cervical ICA dissection with pseudoaneurysm formation. The aneurysm was resected
      and an end-to-end anastomosis was done using an inverted saphenous graft.
      Histology confirmed a diagnosis of traumatic ICA dissection with pseudoaneurysm
      formation and there was no evidence of pre-existing pathology. Helical CT is a
      simple, widely available, and relatively non-invasive imaging technique that
      correlates well with angiography. It should be considered in the evaluation of
      patients with suspected cervical ICA dissection.

PMID- 10417893
TI  - [Trans-ethmoid encephaloceles].
AB  - We report two cases of ethmoidal cephaloceles. Ethmoidal cephaloceles are very
      rare and most commonly present with recurrent episodes of meningitis or sometimes
      as a nasal mass. Diagnosis is made at MR and CT. Such imaging studies should be
      obtained in patients with recurrent meningitis or patients with polypoid nasal
      lesions prior to biopsy.

PMID- 10417894
TI  - [Intrathyroid parathyroid adenoma].
AB  - Parathyroid adenomas are embedded within thyroid tissue in about 2-5% of cases.
      Intrathyroid parathyroid adenomas are easily detected at US. As such, US should
      be performed prior to surgical intervention.

PMID- 10417895
TI  - [Congenital mesothelial cyst of the diaphragm: imaging aspects. Apropos of 2
      cases in adults and review of the literature].
AB  - The authors report 2 cases of congenital mesothelial cyst of the diaphragm
      diagnosed in adults. The differential diagnosis will be discussed and the
      literature reviewed.

PMID- 10417896
TI  - [What is it? Pseudotumoral calcinosis].

PMID- 10417897
TI  - [Antoine Beclere (1856-1939). In memory of Antoinette Beclere, the admirable
      guardian of her father's works].

PMID- 10417898
TI  - [Proper technics in imaging the pelvis. Paris, October 1998. Post-menopausal
      metrorrhagia].

PMID- 10417899
TI  - [The spring session of SIGU. Montpellier, 18 April 1998. Imaging in
      endometriosis].

PMID- 10417900
TI  - [Elements of the evaluation of the functional nature of ovarian cysts].

PMID- 10417901
TI  - [The role of imaging in the diagnosis and staging of cancer of the prostate].

PMID- 10417902
TI  - [Radio-anatomy of the knee].
AB  - The authors review the radiologic anatomy of the knee joint with particular
      points of interest such as the cruciate ligaments, the menisci, and the articular
      cartilage. All imaging modalities are shown with special attention regarding MR
      imaging.

PMID- 10417903
TI  - [Pain in the internal knee compartment].
AB  - The anatomical classification of the traumatic or non traumatic lesion gives a
      mnemotechnical list which assists in the etiological search for pain of the inner
      aspect of the knee: skin, sub cutaneous tissue, medial lateral ligament,
      meniscus, cartilage, sub chondral bone, cruciate ligaments. Each mean of imaging
      detect specific lesions according to its technical capabilities: standard X Ray
      film, arthrography, CT scanner, MRI, bone scintigraphy, and echography. In
      practice, strategy is adapted to the clinical presentation, traumatic or non
      traumatic. In emergency situations, one is looking for bone, ligamentous, and
      meniscus lesions. Without acute traumatism, one can discover ligamentous tear
      sequellae (Pelligrini Stieda's ossifications), transient osteoporosis
      (algodystrophy), degenerative lesions (arthrosis) of the inner compartment.
      Always remember "close to the knee", it is necessary to check for more serious
      infectious or tumoral pathology. If standard plain films remain the first means
      of examination, and are still useful, MRI is becoming increasingly necessary for
      a complete anatomical evaluation.

PMID- 10417904
TI  - [Radio-anatomy markers and applications of current imaging of the ankle and back
      of the foot].
AB  - The only aim of this work is to emphasize some anatomic and pathologic
      particularities of the constitutional elements of the ankle and the hind-foot,
      and their application in the actual imaging of this region. The characteristics
      of talus, calcaneus, navicular bone, talo-crural, sub-talar, medio-tarsal and
      tarso-metatarsal joints, calcaneus tendon, plantar aponevrosis, medial and
      lateral tendon of the ankle are successively detailed.

PMID- 10417905
TI  - [Imaging of the ankle and back of the foot in athletes].
AB  - Imaging of the ankle and the hind-foot in sportmen includes plain radiographies
      that are often insufficient. When necessary, imaging modalities such as
      sonography, CT (arthroCT and tenoCT), and MR imaging are of valuable interest for
      trauma medical doctors and surgeons. The role of those modalities is emphasized
      lesion by lesion.

PMID- 10417906
TI  - [Imaging of cartilage. Current status and prospects].
AB  - This work describes the composition, organisation, metabolism, biomechanical and
      physiologic properties of normal cartilage. The initial involution process, of
      biochemical nature, preceding by far the morphological changes is described as
      well as the degenerative, inflammatory and traumatic pathogenesis. The modern
      cartilage imaging techniques are described with emphasis on MRI.

PMID- 10417908
TI  - [Common and difficult].

PMID- 10417907
TI  - [Para-articular and intraosseous synovial cysts and articular mucoid cysts].
AB  - The authors review the mechanism and imaging findings of intraarticular,
      juxtaarticular, and intraosseous ganglion cysts. They specially emphasize
      particular features according to the most frequent locations.

PMID- 10417909
TI  - [Persistence of the pupillary membrane. Apropos of 3 cases].
AB  - Persistent pupillary membrane has in most cases no functional consequence.
      Nevertheless, a thick membrane involving visual axis sometimes requires surgical
      removal. We describe three cases of this surgery with pathologic examination and
      functional results.

PMID- 10417910
TI  - [Blepharitis due to Demodex: myth or reality?].
AB  - PURPOSE: Demodex folliculorum has been incriminated in the development of
      blepharitis although much controversy persists. Certain authors suggest that
      Demodex is a direct pathogen in chronic palpebral conditions while others
      consider the saprophyte to be innocuous to skin. METHODS: We conducted a
      prospective study of eyelashes in 100 persons, searching for Demodex folliculorum
      and chronic blepharitis. Microscopy in immersion oil after storage in a moist
      chamber was performed. RESULTS: The incidence of Demodex folliculorum was very
      high in patients with blepharitis compared with normal controls. Incidence
      increased with age. Harmless cuffs around the base of the eyelashes was found in
      4% with Demodex irradior. CONCLUSION: Demodex should be considered as the cause
      of chronic blepharitis. Anti-Demodex treatment is indicated when the parasite is
      found.

PMID- 10417911
TI  - [Vitreous hemorrhage and pre-retinal hemorrhage "without obvious point of origin"
      in diabetic patients. Apropos of 5 cases].
AB  - Five diabetic patients with nonproliferative retinopathy or controlled
      retinopathy after photocoagulation developed intravitreous or preretinal
      hemorrhages of unknown origin. Intravitreous hemorrhage of unknown origin is
      characterized by the absence of angiographic hyperfluorescence suggestive of
      neovascularization. Examination of the retinal periphery with a three mirror lens
      reveals the absence of tears and an normally appearing arteriovenous network with
      no sign of bleeding. The clinical cases reported here demonstrated: 1) the
      significance of posterior vitreous detachment in the genesis of hemorrhage, 2)
      the difficulty encountered in assessing the seriousness of the hemorrhage and
      providing optimal treatment, 3) the importance of initiating treatment early.

PMID- 10417912
TI  - [Fronto-naso-ethmoido-sphenoido-maxillo-orbital mucocele with ophthalmologic
      presentation].
AB  - PURPOSE: We present a case of a large mucocele pressing the orbit forward and
      compared our findings with those reported by others. CASE REPORT: A 23-year-old
      woman was examined for an inflammatory tumor of the internal canthus. She had a
      6/10 vision loss of the left eye, diplopia, and non-axial exophthalmos. CT scan
      and magnetic resonance imaging evidenced a huge sinus mucocele behind the orbit.
      Surgery using the paralateronasal approach was performed. Pathology confirmed the
      diagnosis of mucocele. DISCUSSION: Ophthalmic complications of mucoceles result
      from tumor growth leading to compressive optic neuropathy or even compression of
      the chiasma. A sinus mucocele should be suspected upon indirect clinical signs
      and lead to neuroradiological explorations. Magnetic resonance imaging reveals
      iso- or high signals on T1-weighted sequences and high signal on T2-weighted
      sequences. MRI evidences intracranial or orbital extension. CT scan reveal the
      degree of bone erosion. Prognosis is favorable after surgical treatment. It is
      important to correctly diagnose mucocele on the basis of clinical and
      neuroradiological findings in order to propose early surgery and prevent
      permanent visual loss by compressive optic neuropathy.

PMID- 10417913
TI  - [A retrospective study of 1,500 personal cases of ptosis].
AB  - PURPOSE: Whether congenital or acquired, unilateral or bilateral, ptosis is due
      to deficiency of levator muscle of the upper eyelid and comprises one of the most
      prevalent defects of palpebral pathology. PATIENTS AND METHODS: We
      retrospectively reviewed 1,500 personal cases of ptosis, 890 of them had
      undergone surgical procedures over the period 1986-1997. We recorded: etiologic
      factors, the frequency of different forms of ptosis, the associated anomalies,
      operative techniques and postoperative results. RESULTS AND DISCUSSION: Simple
      congenital ptosis was the most frequent form. Levator muscle resection was the
      most largely used operative technique. Minor hypocorrection was often accepted
      and poor results were found in 22% of the operated cases.

PMID- 10417914
TI  - [Deep sclerectomy in congenital glaucoma. Preliminary results].
AB  - PURPOSE: Trabeculectomy is an efficient procedure for congenital glaucoma, but
      can lead to postoperative complications. These complications seem to be less
      frequent with deep sclerectomy. The aim of this study is to evaluate results of
      this surgical technique for congenital glaucoma. MATERIALS AND METHODS: Twelve
      eyes from eight patients (age 2 to 84 months) with congenital glaucoma underwent
      sclerectomy and were followed-up for 10 months postoperatively. Success criteria
      was intraocular pressure inferior to 16 mm Hg under general anaesthesia. RESULTS:
      No per or immediate postoperative complication was observed. For nine eyes (75%),
      intraocular pressure was controlled at final examination. For three eyes,
      postoperative intraocular pressure was elevated and one of them underwent re
      operation. CONCLUSIONS: Success rate of sclerectomy for congenital glaucoma is
      equivalent to trabeculectomy. Absence of anterior chamber opening diminishes
      postoperative complications risk. Further study with longer follow-up is
      currently under evaluation.

PMID- 10417915
TI  - [Dermoid cysts. Epidemiology, clinical and anatomo-pathologic aspects,
      therapeutic management].
AB  - We retrospectively analyzed a series of 17 tumors suggestive of dermoid cysts
      operated on from January 1, 1991, through November 30, 1997. Mean patient age was
      3.68 years. The periorbital localization predominated. Two cases of intraorbital
      localizations required lateral and medial orbitotomy. Surgical treatment was
      given in all other cases. We observed no complication nor recurrence.

PMID- 10417916
TI  - [Mediterranean spotted fever. Apropos of a case].
AB  - We report the case of a patient who presented an engigmatic chorioretinopathy.
      The rickettsial etiology was confirmed late. This case recalls the general
      ophthalmological features of Mediterranean spotted fever. The serology pattern
      and different clinical arguments led to diagnosis.

PMID- 10417917
TI  - [Inflammatory pseudotumor of the lacrimal gland. Apropos of 2 cases].
AB  - BACKGROUND: Inflammatory pseudotumors of the orbit are relatively common
      accounting for 12 to 15% of all orbital diseases. Lacrimal gland location is
      exceptional. CASE REPORTS: We report 2 patients aged 30 and 25 years who
      underwent surgery for an isodense tumor of the lacrimal gland.
      Immunohistochemistry revealed an inflammatory pseudotumoral process. Both
      patients are recurrence-free 2 years follow-up. DISCUSSION: Inflammatory
      pseudotumors of the orbit, particularly those located in the lacrimal gland still
      raise unresolved questions concerning the pathogenesis, diagnosis and treatment.
      CONCLUSION: Lacrimal gland localizations of inflammatory pseudotumors must be
      recognized due to difficulties in diagnosis and therapeutic management.

PMID- 10417918
TI  - [Exophthalmos and blindness disclosing an ethmoidal-maxillary malignant non
      Hodgkin's T-cell lymphoma. Apropos of a case].
AB  - BACKGROUND: We report a case of non-Hodgkin's malignant lymphoma of the
      cervicofacial region revealed by unilateral exophthalmos and blindness, an
      unusual mode of expression. CASE REPORT: A 40-year-old man with a 4-month history
      of diabetes mellitus had suffered from exophthalmos and blindness of the right
      eye for 20 years. Physical examination showed a homolateral hemifacial
      tumefaction and ophthalmoplegia. The right ocular fundus showed papillar edema
      and non-proliferative diabetic retinopathy. The left eye was normal. The
      otolaryngology explorations revealed a voluminous tumor in the anterior nasal
      cavity and in the cavum. Two biopsies were performed. Histology reported non
      Hodgkin's T-cell lymphoma. Orbitocerebral and cervicofacial computed tomography
      visualized the aggressive ethmoidomaxillary extension with intraorbital and
      intracranial involvement. Chemotherapy (CHOP) combined with radiotherapy led to
      tumor regression and involution of the exophthalmos. Diagnostic difficulties,
      management and prognosis are discussed.

PMID- 10417919
TI  - [An example of dominant inheritance in the transmission of chronic open-angle
      glaucoma. Apropos of an Algerian family].
AB  - BACKGROUND: The hereditary nature of chronic open-angle glaucoma (COAG) is
      recognized in 20 to 25% of the cases. Disease prevalence among relatives of
      patients with glaucoma is higher than in the general population. Several
      inheritance modes may co-exist. METHOD: Forty-seven members of a family living in
      eastern Algeria were studied. Three generations were examined. RESULTS: There
      were 15 cases of COAG (8 men and 7 women) in this family, i.e. 32% of the
      members. Affected members were aged from 23 to 80 years. DISCUSSION: An
      epidemiologic, clinical and genetic analysis of this family provided information
      concerning the transmission modes of COAG. CONCLUSION: It is highly likely that
      in this family, COAG was transmitted by autosomal dominant inheritance with
      strong penetrance. Genetic analysis excluded locus GLC1A mutation, confirming the
      heterogeneous nature of COAG inheritance.

PMID- 10417920
TI  - [Inclusion conjunctivitis in adults].

PMID- 10417921
TI  - [Conjunctival adnexal lymphoid tissue lymphoma, a suspect in chronic
      conjunctivitis].

PMID- 10417922
TI  - [Conjunctivitis and ocular parasitic diseases].

PMID- 10417923
TI  - [Is the functional prognosis of congenital glaucoma so unfavorable?].

PMID- 10417924
TI  - [Orbital lymphoma and AIDS. Apropos of a case].
AB  - We report the case of a 33-year-old HIV-seropositive male who had a large cell
      Epstein-Barr virus-associated non-Hodgkin's orbital lymphoma. A thorough medical
      examination enabled us to find on thoracic CT-scan a mediastinal lymph node
      involvement as large as 18 cm in diameter. The regression of the tumor was
      dramatic under chemotherapy with complete disappearance of the tumor and no
      recurrence was found after more than 21 months follow-up. We discuss the
      differential diagnosis with orbital infection.

PMID- 10417925
TI  - [Black hidrocystoma of the free margin of the eyelid].
AB  - A clinico-pathologic case of a black hidrocystoma of the left eyelid margin is
      reported in a 45-year-old female patient. Clinically, a black nodule was
      disclosed after eversion of the superior left lid. A surgical full thickness
      eyelid focal resection was performed to remove the cyst. Histopathology found a
      cyst covered with an epithelium with a double layer of cells and filled with a
      brownish granular content, typical of a black hidrocystoma.

PMID- 10417926
TI  - [Diabetic retinopathy and pregnancy].

PMID- 10417928
TI  - Should UK emergency physicians undertake diagnostic ultrasound examinations?
AB  - From the published evidence there is no doubt that emergency physicians in
      America can undertake focused ultrasound examinations and that, by extrapolation,
      this would also be the case for UK emergency physicians. If this skill is to
      become part of the diagnostic armamentarium of the emergency physician, however,
      it needs to be demonstrated to be cost effective compared with the alternatives
      already available to the hospital. Trials to test for this benefit should adopt a
      hospital and not an emergency department perspective if the results are to
      influence health policy and specialty training.

PMID- 10417927
TI  - Emergency medical treatment of anaphylactic reactions. Project Team of the
      Resuscitation Council (UK)

PMID- 10417929
TI  - Current and future role of ultrasound in the emergency department.

PMID- 10417930
TI  - Effect of closed circuit television on urban violence.
AB  - OBJECTIVE: To evaluate the effect of city and town centre closed circuit
      television (CCTV) surveillance on violence in terms of accident and emergency
      (A&E) department and police assault data. METHODS: A&E department and local
      police assault data in three centres in Wales (Cardiff, Swansea, and Rhyl) two
      years before and two years after the installation of CCTV were studied. British
      Crime Survey and police crime statistics were used as control data. RESULTS: A&E
      records of 24,442 assault patients and 3228 violent offences recorded by the
      police were studied. Data from two A&E departments (Swansea (+3%) and Rhyl
      (+45%)) showed increases in recorded assaults after CCTV installation but a
      decrease (12%) in the largest centre, Cardiff. There was an overall reduction in
      town/city centre violence from the A&E department perspective of 1% in the two
      years after CCTV installation. In contrast, police data demonstrated changes in
      the opposite direction (-44%, -24%, and +20% respectively) contributing to an
      overall decrease of 9%. British Crime Survey and police statistics for England
      and Wales demonstrated no overall change and a 16% increase respectively.
      CONCLUSIONS: City centre CCTV installation had no obvious influence on levels of
      assaults recorded in A&E departments. There was a negative relationship between
      police and A&E recording in all three centres. A&E departments are important and
      unique sources of information about community violence.

PMID- 10417933
TI  - Oral contraceptives and oral antibiotics: interactions and advice in an accident
      and emergency setting.
AB  - OBJECTIVE: (1) To determine what advice, if any, would be given by accident and
      emergency (A&E) doctors to women who were taking the combined oral contraceptive
      pill (OCP) if they had been issued with broad spectrum antibiotics and (2) after
      an audit programme had been instigated, whether appropriate advice was given to
      such women. METHODS: A questionnaire was circulated to 12 doctors working in the
      Exeter A&E department to assess their level of knowledge in prescribing
      antibiotics to women taking the OCP. Notes of women aged 15-50 who had been
      prescribed broad spectrum antibiotics were examined to see if a contraceptive
      history had been taken. If the patient was found to be taking the combined OCP it
      was noted whether documented advice had been given about using an additional form
      of contraception. Six months later after two education sessions had been held,
      prescriptions and notes were examined. A patient education leaflet was produced
      to be given to these women, indicating what additional precautions should be
      taken after having been prescribed antibiotics. SETTING: The A&E department of a
      busy district general hospital. SUBJECTS: Women aged 15-50 who had been issued
      with broad spectrum antibiotics. RESULTS: The level of knowledge in regard to
      contraceptive advice given to women taking the OCP among doctors working in an
      A&E department was poor. However, after educational sessions and the production
      of a patient information leaflet, there was an improvement in women receiving
      correct advice. CONCLUSIONS: The clinical significance of drug interactions
      between oral contraceptives and antibiotics indicates the importance of asking a
      full contraceptive drug history of any woman of childbearing age and documenting
      this in the notes. Regular audit of this topic is needed to keep it at the front
      of doctors' minds.

PMID- 10417932
TI  - Who gives pain relief to children?
AB  - OBJECTIVE: To compare pre-hospital parental administration of pain relief for
      children with that of the accident and emergency (A&E) department staff and to
      ascertain the reason why pre-hospital analgesia is not being given.
      DESIGN/METHODS: An anonymous prospective questionnaire was given to
      parents/guardians of children < 17 years. The children were all self referred
      with head injuries or limb problems including burns. The first part asked for
      details of pain relief before attendance in the A&E department. The second part
      of the questionnaire contained a section for the examining doctor and triage
      nurse to fill in. The duration of the survey was 28 days. RESULTS: Altogether 203
      of 276 (74%) of children did not receive pain relief before attendance at the A&E
      department. Reasons for parents not giving pain relief included 57/203 (28%) who
      thought that giving painkillers would be harmful; 43/203 (21%) who did not give
      painkillers because the accident did not happen at home; and 15/203 (7%) who
      thought analgesia was the responsibility of the hospital. Eighty eight of the 276
      (32%) did not have any painkillers, suitable for children, at home. A&E staff
      administered pain relief in 189/276 (68%). CONCLUSIONS: Parents often do not give
      their children pain relief before attending the A&E department. Parents think
      that giving painkillers may be harmful and often do not have simple analgesics at
      home. Some parents do not perceive that their child is in pain. Parents require
      education about appropriate pre-hospital pain relief for their children.

PMID- 10417931
TI  - Prospective survey to verify the Ottawa ankle rules.
AB  - OBJECTIVE: To determine if the Ottawa ankle rules are valid in the setting of an
      urban teaching hospital in the UK. DESIGN: A prospective survey. SETTING:
      Accident and emergency department, Western Infirmary, Glasgow from 1 April 1995
      to 31 August 1995. SUBJECTS: 800 patients with an acute ankle injury. RESULTS:
      800 patients were used for analysis of which 584 (73%) were radiographed; 70
      (12%) had fractures, 63 (10.8%) of which were significant. Four of these patients
      with fractures fulfilled none of the Ottawa ankle rules criteria for plain
      radiography. CONCLUSION: Application of the Ottawa ankle rules to this group of
      patients would have produced a sensitivity of 93.6%. Although useful, decision
      rules should be used with care and not replace clinical judgment and experience.

PMID- 10417934
TI  - Antibiotics, the pill, and pregnancy.
AB  - OBJECTIVES: To establish if advice concerning risks of pregnancy when taking oral
      contraceptive pill and antibiotics is being offered. METHOD: A retrospective
      audit of notes of 100 female patients aged 15-39 who were prescribed antibiotics.
      RESULTS: Documentation of use of contraception was noted in 3% of patients.
      Advice concerning risks and further precautions was noted in this 3% but not in
      any other records. CONCLUSION: The audit identified a gap in documentation and/or
      clinical practice in advising women of childbearing age of the risk of conceiving
      when using oral contraceptive pill and antibiotics. Recommendations are given as
      to how this may be addressed.

PMID- 10417935
TI  - Questionnaire survey of interpreter use in accident and emergency departments in
      the UK.
AB  - OBJECTIVE: To determine the support for a national telephone interpreter service
      from accident and emergency (A&E) departments across the UK, and the factors that
      may influence that support. To determine the nature of interpreter needs for
      these departments. METHODS: Postal questionnaire survey of 255 A&E departments in
      the UK. RESULTS: A total of 197 replies were received, a response rate of 77.3%.
      Altogether 186 respondents answered the question on support for a national
      telephone interpreter service and 124 (66.7%) would support one. Those
      departments in favour were no more likely to have required an interpreter in the
      last seven days (chi 2 = 0.16, df = 1, p = 0.69), be in the inner city (Fisher's
      exact test, two sided probability, p = 1), have predominantly local population
      needs compared with tourist needs (chi 2 = 0.65, df = 1, p = 0.42), or be current
      users of a telephone interpreter service (chi 2 = 0.01, df = 1, p = 0.93).
      Seventy-nine of 180 (42.9%) departments had used some form of interpreter in the
      seven days preceding completion of the survey. Seventy-six of 86 (88.4%) of those
      departments using face to face interpreters had experienced difficulty obtaining
      an interpreter out of hours. Nationally, the following proportion of all A&E
      departments listed the named language as occurring among the three most common
      languages requiring interpretation: French 0.46 (95% confidence interval 0.42 to
      0.50), Urdu 0.30 (0.26 to 0.34), and German 0.24 (0.21 to 0.27). CONCLUSIONS:
      There is widespread need and support for a national telephone interpreter service
      that would match the requirements of 24 hour emergency health care provision.

PMID- 10417937
TI  - Needle aspiration or chest drain for spontaneous pneumothorax.

PMID- 10417936
TI  - Electrocardiographic diagnosis of acute myocardial infarction in the presence of
      left bundle branch block.

PMID- 10417938
TI  - Oral or intravenous steroids in acute severe asthma.

PMID- 10417939
TI  - The role of therapeutic needle aspiration in radial head fractures.

PMID- 10417940
TI  - The role of diagnostic needle aspiration in olecranon bursitis.

PMID- 10417941
TI  - Dealing with the police.

PMID- 10417942
TI  - Massive pulmonary embolus in a 14 year old boy.
AB  - Pulmonary embolus in children is rare. A case of massive pulmonary embolus, after
      surgery, in a child of 14 years is described. Accident and emergency doctors
      should be aware that pulmonary embolus can occur in children and exercise a high
      index of suspicion for the diagnosis in those patients with risk factors for the
      condition who present acutely with typical symptoms such as dyspnoea, chest pain,
      haemoptysis, or collapse.

PMID- 10417943
TI  - Right heart thrombus: the importance of early intervention.
AB  - A case report of mobile, right heart thrombus in the accident and emergency (A&E)
      department is presented. Though frequently associated with major pulmonary
      embolism, recognition is usually at postmortem examination. Detection of the
      presence of mobile thrombus in the right heart by early echocardiogram and prompt
      treatment may be life saving. Surgical or medical treatment options are dependent
      on local facilities. Early specialist involvement with a contingency plan in A&E
      departments are advised.

PMID- 10417944
TI  - Serotonin syndrome caused by overdose with paroxetine and moclobemide.
AB  - Well known clinical syndromes can be produced by overdose with more commonly
      ingested substances such as opiates or tricyclic antidepressants. A case of a
      much more unusual syndrome presenting to the accident and emergency department
      resulting from overdose with a combination of tablets is reported. The clinical
      presentation of serotonin syndrome and its management are described. This
      resulted from acute ingestion of paroxetine, a selective serotonin reuptake
      inhibitor, and moclobemide, a monoamine oxidase inhibitor.

PMID- 10417945
TI  - A case of acute renal failure and compartment syndrome after an alcoholic binge.
AB  - A 25 year old man presented with anuria and bilateral leg pain two days after an
      alcoholic binge. He subsequently developed rhabdomyolysis causing acute renal
      failure, with compartment syndrome of both lower legs. This required urgent
      dialysis and fasciotomy respectively within six hours of admission. He remained
      dialysis dependent for three weeks and only after four months was he able to
      weight bear on both legs. Alcohol is a leading cause of rhabdomyolysis. Early
      recognition and prompt treatment is essential to prevent serious complications.

PMID- 10417946
TI  - Aortic rupture as a result of low velocity crush.
AB  - A case of aortic disruption in a 35 year old lorry driver is described. This
      occurred as a result of a low velocity crushing force. Clinicians should be aware
      that this mechanism of injury may result in aortic disruption as well as the more
      commonly mentioned severe deceleration force.

PMID- 10417948
TI  - Massive hiatal hernia.

PMID- 10417947
TI  - An unusual case of patella dislocation.

PMID- 10417949
TI  - Retroperitoneal abscess presenting with a buttock swelling and anaemia.

PMID- 10417950
TI  - Persistent "haematoma".

PMID- 10417951
TI  - Accident and emergency medicine--the next 25 years.

PMID- 10417952
TI  - The PEP transducer.

PMID- 10417953
TI  - Protocols for deep vein thrombosis.

PMID- 10417954
TI  - Empirical thrombolysis in catastrophic pulmonary embolism.

PMID- 10417955
TI  - Activated charcoal preparations.

PMID- 10417956
TI  - Dietary calcium and mineral/vitamin supplementation: a controversial problem.
AB  - There is a consensus that adequate calcium intake during bone development, and
      possibly in adulthood and senescence, helps to prevent bone resorption and
      osteoporosis. The uptake of dietary calcium should be sufficient to maintain both
      normal serum calcium concentrations and parathyroid hormone levels in the low
      normal range throughout the day, otherwise, increased bone resorption occurs.
      Calcium intake varies with race and with environmental and dietary conditions.
      Estimating the appropriate amount of calcium to be added to dietary sources for
      an optimal supplementation regimen is therefore difficult. Few intervention
      studies have evaluated the dose-effect relationship for calcium supplementation
      conclusively. The mechanisms regulating fractional calcium absorption as a
      function of intake suggest that very high daily doses are probably useless. They
      may be unsafe in the long term because of the risks of hypercalciuria and kidney
      stones, and of an imbalance in the ratio of calcium to magnesium. Concomitant
      supplementation with limited amounts of magnesium may reduce this risk and
      improve mineralization. Dietary intake is 500-600 mg/day in most studies, making
      400 mg/day an appropriate supplementary dose for most premenopausal women (RDA
      1000 mg/day). After the menopause and during lactation (RDA 1200-1500 mg/day),
      800 mg/day is probably appropriate, particularly if low doses of vitamin D are
      taken concomitantly.

PMID- 10417958
TI  - Reduction of hamster egg abnormalities in repeatedly induced ovulation by using
      the minimum effective dose of human chorionic gonadotrophin.
AB  - The minimum dose of human chorionic gonadotrophin needed to induce ovulation was
      determined in hamsters, in which the luteinizing hormone surge was blocked by
      administration of phenobarbitone. Doses of 1.0, 2.5, 5.0 and 10.0 IU human
      chorionic gonadotrophin were injected subcutaneously, and 5.0 IU was found to be
      the minimum dose needed to induce ovulation in all of a group of seven hamsters.
      When this minimum dose was used to induce ovulation repeatedly, one, two or three
      times, in groups of seven hamsters the percentages of abnormal eggs seen were
      5.3%, 5.6% and 6.4%, respectively. These results indicate that the marked
      increases in the proportions of abnormal eggs produced when ovulation is
      repeatedly induced, which have been observed in previous studies, can be
      prevented by using the minimum effective dose of human chorionic gonadotrophin.

PMID- 10417957
TI  - Is there a relationship between smoking and asthma in adults?
AB  - A case-control study was carried out to investigate the possibility of a
      relationship between smoking and asthma in adults. The study group of 141
      asthmatic adults and 423 age- and sex-matched non-asthmatic controls were
      selected from 4341 men and women aged 18 years and over, who were registered with
      a family practice. Both groups were interviewed by telephone about past and
      present smoking habits. Current smokers constituted 22% of the asthmatic group
      and 15% of the controls (not significantly different). The prevalence of those
      who had given up smoking (quitters) was significantly higher in asthmatics than
      in controls (8.5% versus 3.6%). Asthma began at younger ages in smokers than in
      quitters and non-smokers. In smokers, the duration of smoking was associated with
      the duration of asthma. No other significant differences in or associations
      between smoking habits and asthma were found. No major relationship between
      smoking and asthma was demonstrated.

PMID- 10417959
TI  - Effects of streptococcal preparation OK-432 on cytokine induction in spleen and
      tumour tissues of mice bearing MH-134 tumour cells.
AB  - Streptococcal preparation OK-432 is a bacterial immunopotentiator extensively
      used in Japan for adjuvant cancer therapy. Using C3H/He mice bearing MH-134
      tumour cells, cytokine inductions of tumour necrosis factor-alpha, interleukin 1
      beta, interleukin 6 and interferon-gamma were determined in spleen and tumour
      tissues by reverse transcriptase-polymerase chain reaction analysis. No
      significant induction of cytokine mRNA was observed after subcutaneous
      administration of OK-432 (OK-432, s.c.) or after intratumoural injection of IFN
      gamma (IFN-gamma, i.t.), compared with controls, either in spleen or tumour
      tissues. In contrast, subcutaneous administration of OK-432 followed by
      intratumoural OK-432 injection (OK-432, s.c. + i.t.) was found to induce some
      cytokine mRNAs significantly. The mRNA levels of tumour necrosis factor alpha and
      interferon-gamma in spleen tissue and those of interleukin 1 beta and interferon
      gamma in tumour tissues were significantly elevated in mice with OK-432, s.c. +
      i.t. treatment compared with controls. These results suggest that treatment with
      OK-432, s.c. + i.t. effectively induced splenic antitumour immunity as well as
      local immunity against tumour cells.

PMID- 10417960
TI  - Association between hyperhomocysteinaemia and hypertension in Sri Lankans.
AB  - This study examined the relationship between homocysteine and its metabolites,
      and hypertension in a cohort of Sri Lankan patients with essential hypertension.
      Serum homocysteine, cysteine, cysteinylglycine and glutathione were measured in
      86 patients with a diagnosis of essential hypertension and compared with those of
      an age- and sex-matched control group. Patients with hypertension had
      significantly higher mean serum concentrations of homocysteine, cysteine and
      cysteinylglycine. The odds ratio for hypertension for those with a mean serum
      homocysteine concentration above 18 mumol/l was 2.8. Hyperhomocysteinaemia is a
      risk factor for hypertension in Sri Lankans and can lead to a threefold increase
      in risk.

PMID- 10417961
TI  - Pyogenic infectious spondylitis in a patient with diabetes: case report.
AB  - A case of pyogenic infectious spondylitis associated with diabetes was reported.
      The patient experienced focal back pain 2 weeks after amputation of her left foot
      due to diabetic gangrene. Magnetic resonance imaging of the lumbar spine revealed
      decreased T1-weighted signals of Th11 and Th12 vertebral bodies and prevertebral
      masses, and these lesions were also detected as high signal intensities in T2
      weighted magnetic resonance imaging. The images were consistent with a diagnosis
      of pyogenic infectious spondylitis and the patient responded to treatment with
      broad-spectrum antibiotics. Percutaneous drainage of the abscesses was also
      needed. Early magnetic resonance imaging examination was particularly helpful in
      the accurate diagnosis and treatment of this rare disorder.

PMID- 10417962
TI  - A rare case of pituitary hyperplasia with suprasellar extension due to primary
      myxoedema: case report.
AB  - The development of pituitary tumours as a consequence of primary target organ
      failure is rare. We report here a rare case of pituitary hyperplasia with
      suprasellar extension due to primary myxoedema. This case presentation suggested
      the importance of detailed endocrine investigation and repeated magnetic
      resonance imaging for the differential diagnosis of pituitary enlargement to
      avoid unnecessary surgery.

PMID- 10417964
TI  - Maturity-onset diabetes of the young (MODY): a new challenge for pediatric
      diabetologists.
AB  - The differential diagnosis of hyperglycemia in childhood and adolescence has to
      take into consideration early-onset non-insulin-dependent diabetes, defined as
      maturity onset diabetes of the young (MODY). To date, mutations in genes of five
      proteins have been shown to cause MODY: glucokinase (MODY2), hepatic nuclear
      factor-1 alpha (HNF-1 alpha) (MODY3), hepatic nuclear factor-4 alpha (HNF-4
      alpha) (MODY1), insulin promoter factor 1 (IPF-1) (MODY4) and hepatic nuclear
      factor-1 beta (HNF-1 beta) (MODY5), but other MODY genes still await elucidation.
      Clinical and metabolic heterogeneity of these subtypes of type 2 diabetes need to
      be defined, as deficiency of each factor has its own phenotype. Pediatric
      diabetologists should be aware of the increasing importance of MODY as a possible
      cause of hyperglycemia in children and adolescents. This will allow for the early
      diagnosis of these metabolic conditions and for the appropriate follow-up and
      treatment.

PMID- 10417963
TI  - Targeted gene mutations define the roles of insulin and IGF-I receptors in mouse
      embryonic development.
AB  - Insulin-like growth factors (IGFs) and their receptors regulate embryonic and
      post-natal growth. Genetic evidence derived from targeted mouse mutants indicates
      that both the insulin receptor (IR) and IGF-I receptors (IGF-IRs) are required
      for mouse embryonic growth. However, the roles of IRs and IGF-IRs are
      functionally distinct, with IGF-IRs mediating both IGF-I and IGF-II actions, and
      IRs mediating IGF-II, rather than insulin, action. The combined interactions of
      IGF-IRs and IRs with IGF-I and IGF-II account for the entirety of the growth
      effects of these two ligands, and provide the molecular basis for IGFs-mediated
      intrauterine growth and differentiation. Genetic ablation experiments of insulin
      receptor substrate-1 (IRS-1) and -2 (IRS-2), two important molecules in the IR
      and IGF-IR signaling pathways, are also beginning to shed light onto the
      mechanisms accounting for the specificity of IR and IGF-IR signaling. IRS-1
      deficient mice are growth retarded, while IRS-2-deficient mice develop diabetes,
      indicating that the two molecules play a more specific role than previously
      recognized in IGF-IR and IR signaling.

PMID- 10417966
TI  - Body mass index is different in normal Chinese and Caucasian infants.
AB  - Body mass index (BMI) is one of the anthropometric measurements for assessing
      nutritional status, body composition and adiposity in children. Racial
      differences in BMI between black and white children and adolescents have been
      shown in several studies. The aim of this study was to determine whether an
      ethnic difference in BMI exists between Chinese and Caucasian children in the
      first two years of life. The BMI of Chinese and Caucasian infants was compared so
      as to assess the usefulness of the National Center for Health Statistics (NCHS)
      growth reference data in the assessment of nutritional status of Chinese
      children. Mean weight, length and BMI were compared between six cohorts of
      Chinese children and five cohorts of Caucasian children together with the NCHS
      growth reference data. The changes in the mean BMI curves during the first two
      years of life in the two ethnic groups were entirely different but the different
      cohorts in the same ethnic groups displayed a similar pattern of change with age.
      The difference in change in BMI in the Chinese cohorts was related to the
      difference in change in their mean weight as compared to the NCHS weight-for-age
      reference data. In contrast, the change in mean length of the well-nourished Hong
      Kong Chinese children in the present study followed the mean NCHS height-for-age
      values. The results of this study suggest that linear growth would be better for
      the assessment of health and nutrition in infancy and early childhood. If BMI and
      weight-for-height standards were to be used then an ethnic group-specific and
      population based reference data set should be used.

PMID- 10417965
TI  - Insulin-like growth factor-I treatment in two children with growth hormone gene
      deletions.
AB  - Two unrelated Brazilian patients had homozygous 6.7 kb deletions in the GH-1 gene
      (girl and boy, 1.8 and 3.3 yr, heights -7.9 and -6.0 SDS, respectively).
      Desensitization using small amounts of exogenous GH (0.033 IU/kg body
      weight/week, divided into daily s.c. injections) was attempted, but anti-GH
      antibodies appeared. Replacement with usual doses of hGH induced only transient
      increase in growth. IGF-I therapy with increasing doses resulted in catch-up
      growth without side-effects. Growth velocity was 7.5 cm/yr in the first year and
      8.4 cm/yr in the next 6 months in patient 1, and 6.7 cm/yr in the first year, 5.9
      cm/yr in the second year and 7.9 cm/yr in the third year of IGF-I treatment in
      patient 2, when the daily dose of 240 micrograms/kg was divided into three
      injections. IGFBP-3 levels were low (0.55 and 0.40 mg/I) and did not increase
      after IGF-I treatment, suggesting that this GH effect is not mediated by IGF-I,
      and injected IGF-I had a rapid disappearance rate. We conclude that IGF-I
      promotes growth by endocrine mechanisms and constitutes an effective treatment
      for patients with GH insensitivity secondary to GH antibodies.

PMID- 10417967
TI  - Bone mineral density and metabolism in children treated with L-thyroxine.
AB  - It has been suggested that long term treatment with L-thyroxine could reduced
      bone mineral density (BMD). The purpose of this study was to determine whether
      BMD is decreased by L-thyroxine treatment in children. Dual energy X-ray
      absorptiometry (DEXA) was used to assess lumbar spine (L2-4) and femur neck BMD
      in 40 children aged 9-15 years, taking L-thyroxine (100 micrograms/m2/day) for a
      mean period of 1.45 +/- 0.60 years for colloid diffuse goiter. Patients were
      matched with controls for age, sex, weight, height and pubertal stage. BMD at
      both the femur neck and lumbar spine was not significantly different from that of
      the control group. No correlation was found between BMD values and TSH levels
      which is the index of tissue hyperthyroidism. BMD was also not correlated with
      duration of the therapy. Osteocalcin, alkaline phosphatase, calcitonin and
      parathormone levels were measured to asses bone turnover; none of them were
      significantly different from those of controls and they did not change during
      follow up. In conclusion we suggest that long-term L-thyroxine therapy in
      children has no adverse effect on BMD.

PMID- 10417968
TI  - Bone age progression during five years of substitutive therapy for the induction
      of puberty in thalassemic girls--effects on height and sitting height.
AB  - It is known that in thalassemic patients there is a disproportion between lower
      and upper segments whose causes have not yet been identified. We evaluated
      whether the administration of estrogens to induce puberty in hypogonadic
      thalassemic girls caused an inappropriate acceleration of bone maturation and
      whether this had a negative influence on final and sitting height. MATERIALS AND
      METHODS: Twelve thalassemic patients with spontaneous puberty (Group A) and seven
      patients with hypogonadism (Group B) were studied. The mutations of the beta gene
      were identified by DNA analysis. We took into account four observations, ranging
      from the onset of spontaneous puberty in group A or the start of substitutive
      therapy in group B, to 5 years later. At each observation we considered:
      chronological age (CA), bone age (BA), height (Ht) expressed in cm and as
      standard deviation score (HtSDS) calculated with respect to CA (HtSDSCA) and BA
      (HtSDSBA), growth spurt, sitting height, expressed as SDS (SH-SDS), and height
      gain (HG). The delta BA and delta CA were calculated between the first and the
      final observation values to evaluate the bone age acceleration (delta BA/delta
      CA). RESULTS: No acceleration of BA was noted. delta BA/delta CA was 0.98 +/- 0.1
      in group A and 0.89 +/- 0.1 in group B (p > 0.05). All patients in group B had
      the most severe form (beta degree/beta degree) of thalassemia. During the final
      observation, SH-SDS was -1.43 +/- 1.2 and -2.9 +/- 0.6 in group A and B
      respectively (p < 0.002), while no difference between the two groups for HtSDSCA
      and HtSDSBA was observed. HG was greater in group A than in group B (17.7 +/- 5.4
      cm vs 10.8 +/- 5.2 cm) (p < 0.002), such as the spurt 8.6 +/- 1.4 cm (group A)
      and 6.1 +/- 2.6 cm (group B) (p < 0.05). CONCLUSIONS: Girls with hypogonadism did
      not show an inappropriate acceleration of BA, as they reached near final height
      similar to girls with spontaneous puberty. The auxological parameters showed a
      more severe body disproportion with the prevalence of the lower segment in the
      hypogonadic girls. This could be explained by a higher degree of bone marrow
      hyperplasia related to the most severe form of thalassemia and a higher blood
      consumption. As a consequence, damage at the vertebral level might determine an
      inability of the bone tissue to respond to estrogens. We suggest beginning
      estrogen therapy earlier in order to obtain better truncal growth.

PMID- 10417969
TI  - Long-term treatment with GHRH [1-44] amide in prepubertal children with classical
      growth hormone deficiency.
AB  - A cohort of 20 GH deficient prepubertal patients were treated with GHRH [1-44] 10
      micrograms/kg or 20 micrograms/kg twice daily for up to four years (5 patients).
      GHRH treatment resulted in sustained improvement in height velocity. The mean
      prepubertal height velocity was 3.57 +/- 1.05 cm/yr pretreatment; 8.49 +/- 1.45
      cm/yr at year 1; 6.86 +/- 1.45 cm/yr at year 2; 6.22 +/- 0.74 cm/yr at year 3;
      and 6.16 +/- 0.97 cm/yr at year 4. IGF-I levels increased and remained within
      normal range. The difference between the children's and the parents' Ht SD scores
      significantly diminished from a pretreatment difference of -2.43 to -0.48 after
      four years of treatment. No adverse effects were noted during treatment. We
      conclude that twice-daily GHRH [1-44] treatment in a small group of prepubertal
      GH deficient children resulted in sustained improvement in height and growth
      velocity, and achieved height SDS approaching closely those of their parents.

PMID- 10417971
TI  - Urinary free cortisol (UFC) values in newborns under stress.
AB  - Children with adrenocortical insufficiency are commonly instructed to increase
      three to five times baseline glucocorticoid replacement dose during periods of
      stress such as surgery or febrile illness. The present study was undertaken to
      determine whether these recommendations reflect the actual change in urinary free
      cortisol (UFC) output during stress in neonates and to test the effect of stress
      on the diurnal variation of cortisol in this age group. DESIGN AND PATIENTS:
      Twenty-four hour urinary free cortisol (UFC) excretion was determined in 75
      neonates during the first 2 days of life. Thirty were healthy and 45 were
      neonates with respiratory distress. In 60 babies the 24-h UFC was collected in 6
      h fractions for the determination of diurnal variation of urinary cortisol.
      RESULTS: The mean change in UFC was 4.5 times higher in the sick babies than in
      the controls. A distinct diurnal variation of UFC was noted in both healthy and
      sick babies. CONCLUSIONS: In contrast with previous publications a distinct
      diurnal pattern was noted in the majority of neonates.

PMID- 10417970
TI  - Factors at onset predictive of lasting remission in pediatric patients with
      Graves' disease followed for at least three years.
AB  - Seventeen pediatric patients (mean age at diagnosis 10 yr and 9 mo +/- 2 yr and 9
      mo) with Graves' disease treated with 0.3-0.7 mg/kg/day methimazole and followed
      for at least three years, during which drug suspension was attempted on
      attainment of good clinical and metabolic compensation, were retrospectively
      studied to look for factors predictive of lasting remission present at onset.
      Lasting remission was defined as a clinical and laboratory picture of
      euthyroidism lasting at least one year in the absence of treatment at the end of
      the follow-up. A distinction was drawn between patients who reached remission
      after one or two courses (groups 1 and 2) and those who never attained a lasting
      remission (group 3). TRAb (TBIAb) levels at onset were the only factor
      significantly correlated with the response to treatment. Age at diagnosis, goiter
      size and fT3 and fT4 concentrations were not significantly correlated with the
      clinical picture. The series was too small to allow any assessment of the real
      importance of these factors, though a generally better response was displayed by
      children over 11 years old, without appreciable or with very small goiter and
      moderately increased thyroid hormone levels at onset (fT3 < 25 pg/ml in 10/10 in
      groups 1 and 2 and 2/7 in group 3 patients; fT4 < 40 pg/ml in 7/10 in groups 1
      and 2 and 3/7 in group 3 patients). It was also found that better results were
      obtained when the initial drug course was protracted for at least two years.

PMID- 10417972
TI  - Parenteral nutrition-associated cholestasis in preterm neonates: evaluation of
      ursodeoxycholic acid treatment.
AB  - BACKGROUND/OBJECTIVE: Parenteral nutrition is an integral part of the care of
      premature infants. Cholestatic liver disease is a frequent complication of
      prolonged parenteral nutrition, especially in premature infants. It has been
      suggested that ursodeoxycholic acid may alter the course of parenteral nutrition
      associated cholestasis in children and adults. We attempted to determine the
      efficacy of ursodeoxycholic acid in premature infants with parenteral nutrition
      associated cholestasis. METHODS: Retrospective chart review of all infants
      receiving ursodeoxycholic acid for parenteral nutrition-associated cholestasis in
      a 40 bed neonatal intensive care unit. Efficacy of ursodeoxycholic acid was
      evaluated by response of bilirubin, alanine aminotransferase, aspartate
      aminotransferase, and alkaline phosphatase over a treatment period of at least 1
      month. RESULTS: Six infants with parenteral nutrition-associated cholestasis who
      had received ursodeoxycholic acid for one month were identified. Doses of
      ursodeoxycholic acid ranged from 15-30 mg/kg/day. Cholestasis appeared at a mean
      age of 47 +/- 17 (mean +/- SD) days after a mean of 42 +/- 15 days of parenteral
      nutrition. Transaminase levels decreased in three, and either increased or did
      not change in the other three infants. Bilirubin levels decreased in all infants.
      Alkaline phosphatase showed a non significant trend to decreased levels.
      Consistent improvement in all infants was noted only after 10 days of full
      enteral nutrition. No toxicity was found during ursodeoxycholic acid treatment.
      CONCLUSIONS: Ursodeoxycholic acid treatment in premature infants appears to be
      safe, and leads to an early sustained decrease in bilirubin levels by two weeks
      of therapy. The response of transaminase levels was not sustained in our small
      cohort.

PMID- 10417973
TI  - Bisphosphonates in children with osteogenesis imperfecta may improve bone
      mineralization but not bone strength. Report of two patients.

PMID- 10417974
TI  - Precocious puberty in a patient with indicanuria.
AB  - A 7-5/12 year-old girl, who was followed-up after diagnosis of indicanuria,
      presented with symptoms of bilateral breast enlargement. Her breast development
      was at Tanner stage II. No pubic or axillary hair was observed. Pelvic
      ultrasonography revealed multiple follicles on both ovaries. Basic
      endocrinological evaluation and cranial magnetic resonance imaging (MRI) were
      normal. The diagnosis of precocious puberty was established with respect to the
      pubertal response to GnRH stimulation test. Although precocious puberty has been
      reported associated with some metabolic diseases, this is the first description
      in a patient with indicanuria. The question of whether precocious puberty in our
      patient with indicanuria is a coincidence or whether it is related to metabolic
      changes activating the hypothalamo-pituitary-gonadal axis remains open.

PMID- 10417975
TI  - Robinow syndrome with growth hormone deficiency: treatment with growth hormone.
AB  - We describe a 5 years and nine months old boy who presented with facial features,
      vertebral anomalies and dwarfism consistent with Robinow syndrome. Investigations
      revealed growth hormone (GH) deficiency to be the cause of his dwarfism. We
      reviewed data on four other patients with Robinow syndrome from the Genentech
      National Cooperative Growth Study (NCGS). Results of GH testing on three out of
      four were available and showed GH deficiency. Recombinant human GH therapy in our
      patient and the three patients from the NCGS resulted in a significant increase
      in the growth rate per year. The cause of dwarfism in children with Robinow
      syndrome has hitherto not been studied. We propose its association with GH
      deficiency and that treatment with rhGH can result in a significant increase in
      the growth rate of these children.

PMID- 10417976
TI  - Ectopic ACTH syndrome due to thymic carcinoid tumor in a girl.
AB  - An 8 year-old girl had a cushingoid appearance for six months. Hormone study
      showed extremely high serum levels of cortisol (> 60 micrograms/dl) and
      adrenocorticotropic hormone (930 pg/ml). Initial chest X-ray showed nothing
      unusual, but a technetium-99mm MIBI scan showed an accumulation lesion in the
      left upper chest cavity. Chest magnetic resonance imaging demonstrated that the
      mass was in the superior anterior mediastinum. She had complete removal of the
      tumor with partial thymectomy. The pathology revealed a thymic carcinoid tumor.
      Carcinoid tumors of the thymus are extremely rare in children and they usually
      present with Cushing's syndrome. To our knowledge, this is the youngest patient
      who has ever been reported with this disease.

PMID- 10417977
TI  - Pheochromocytoma and clear-cell renal carcinoma in a child with von Hippel-Lindau
      disease: a patient report.
AB  - A 6 year-old boy with von Hippel-Lindau (VHL) disease presented with hypertension
      due to bilateral pheochromocytomas. At age 13 he developed a renal carcinoma and
      bilateral paragangliomas. His mother had retinal angiomas, bilateral
      pheochromocytomas and a cerebellar hemangioblastoma. This unusual presentation
      illustrates the complexity and difficulties associated with the management of VHL
      disease.

PMID- 10417978
TI  - Puberty and urinary iodine excretion.

PMID- 10417979
TI  - Detergent-insoluble glycosphingolipid/cholesterol-rich membrane domains, lipid
      rafts and caveolae (review).
AB  - Within the cell membrane glycosphingolipids and cholesterol cluster together in
      distinct domains or lipid rafts, along with glycosyl-phosphatidylinositol (GPI)
      anchored proteins in the outer leaflet and acylated proteins in the inner leaflet
      of the bilayer. These lipid rafts are characterized by insolubility in detergents
      such as Triton X-100 at 4 degrees C. Studies on model membrane systems have shown
      that the clustering of glycosphingolipids and GPI-anchored proteins in lipid
      rafts is an intrinsic property of the acyl chains of these membrane components,
      and that detergent extraction does not artefactually induce clustering.
      Cholesterol is not required for clustering in model membranes but does enhance
      this process. Single particle tracking, chemical cross-linking, fluorescence
      resonance energy transfer and immunofluorescence microscopy have been used to
      directly visualize lipid rafts in membranes. The sizes of the rafts observed in
      these studies range from 70-370 nm, and depletion of cellular cholesterol levels
      disrupts the rafts. Caveolae, flask-shaped invaginations of the plasma membrane,
      that contain the coat protein caveolin, are also enriched in cholesterol and
      glycosphingolipids. Although caveolae are also insoluble in Triton X-100, more
      selective isolation procedures indicate that caveolae do not equate with
      detergent-insoluble lipid rafts. Numerous proteins involved in cell signalling
      have been identified in caveolae, suggesting that these structures may function
      as signal transduction centres. Depletion of membrane cholesterol with
      cholesterol binding drugs or by blocking cellular cholesterol biosynthesis
      disrupts the formation and function of both lipid rafts and caveolae, indicating
      that these membrane domains are involved in a range of biological processes.

PMID- 10417980
TI  - Interactions of the monomeric and dimeric flavones apigenin and amentoflavone
      with the plasma membrane of L929 cells; a fluorescence study.
AB  - Flavonoids are ubiquitous polyphenolic compounds, found in vascular plants, which
      are endowed with a large variety of biological effects. Some of these effects
      have been assumed to result from interactions with the cell plasma membrane. In
      order to investigate the nature of these interactions a fluorescence study was
      performed with two flavonoids, currently used in one of the laboratories:
      apigenin and its homologous dimer amentoflavone. After preliminary assays with
      DPH in several types of phospholipid liposomes, the effects of these flavonoids
      on the membrane of mouse L929 fibroblasts were compared, using the non-permeant
      probe TMA-DPH. Amentoflavone, unlike apigenin, induced a static quenching effect,
      which denoted an important, but reversible, association of the molecule with the
      plasma membrane. In addition, amentoflavone treatment induced a dose-dependent
      increase in TMA-DPH fluorescence anisotropy, which could be interpreted as an
      increase in membrane lipidic order. For apigenin, the effect was much less
      important. Moreover, exploiting the capacity of TMA-DPH to label endocytic
      compartments, it was shown that, after association with the membrane,
      amentoflavone is not internalized into the cell. Possible correlations of these
      membrane effects with other biological properties are discussed.

PMID- 10417981
TI  - On the mechanism of bilitranslocase transport inactivation by
      phenylmethylsulphonyl fluoride.
AB  - Bilitranslocase is a plasma membrane carrier involved in the uptake of bilirubin
      and other organic anions from the blood into the liver cell. In the membrane, the
      carrier occurs as two interchangeable metastable forms, with high and low
      affinity for the substrates, respectively. The latter form can be specifically
      produced by either cysteine- or arginine modification. In liver plasma membrane
      vesicles, the serine-specific reagent phenylmethylsulphonyl fluoride is a partial
      inhibitor of bilitranslocase-mediated BSP transport rate. In this work,
      phenylmethyl-sulphonyl fluoride is shown to reduce the carrier maximal transport
      rate, without affecting its affinity for that substrate. In addition, it is found
      that the chemical modification caused by this reagent neither influences the
      equilibrium between the high- and the low-affinity forms nor prevents their free
      interconversion. From the effects of combined derivatizations of cysteine(s),
      arginine(s) and serine(s), it is concluded that the functionally relevant
      aminoacid residues lie in a close spatial arrangement. Also, in this study, the
      PMSF-modified serine(s) is shown to be involved in bilirubin binding by
      bilitranslocase.

PMID- 10417982
TI  - Flexible programs for the prediction of average amphipathicity of multiply
      aligned homologous proteins: application to integral membrane transport proteins.
AB  - Simple flexible programs (TREEMOMENT and PILEUPMOMENT) are described for
      depicting the average amphipathicity (hydrophobic moment) along multiply aligned
      sequences of a family of evolutionarily related proteins. The programs are
      applicable to any number of aligned sequences and can be set for any desired
      angle corresponding to a residue repeat unit in a protein secondary structural
      element such as 100 degrees per residue for an alpha-helix or 180 degrees per
      residue for a beta-strand. These programs can be used to identify amphipathic
      regions common to the members of a protein family. The use of these programs is
      exemplified by showing that some families of integral membrane transport proteins
      (i.e. permeases of the bacterial phosphotransferase system (PTS) and the anion
      exchangers of animals) exhibit strikingly amphipathic alpha-helical structures
      immediately preceding the first hydrophobic transmembrane segment of their
      membrane-embedded domain(s). Other families, such as the major facilitator
      superfamily of uniporters, symporters and antiporters, do not exhibit this
      structural feature. The amphipathic structures in PTS permeases have been
      implicated in membrane insertion during biogenesis.

PMID- 10417983
TI  - The effect of Mg2+, nucleotides and ATPase inhibitors on the uptake of [3H]-cGMP
      to inside-out vesicles from human erythrocytes.
AB  - An ATP-dependent transport system is responsible for the cellular extrusion of
      cGMP. The objective of the present study was to determine the effect of Mg2+, ATP
      and other nucleotides (2'-dATP, GTP and ADP), exogenous ATPase modulators (such
      as metavanadate, ouabain, EGTA, NEM, bafilomycin A1 and oligomycin A) on the cGMP
      transport. The uptake of [3H]-cGMP (1 microM) at 37 degrees C was studied in
      inside-out vesicles from human erythrocytes. Magnesium caused a maximal
      activation between 5 and 10 mM and the optimal ATP concentration was 1.25 mM with
      K50-values of 0.3-0.5 mM. Among other nucleotides tested, 2'-dATP (K50 of 0.7 mM)
      was nearly as effective as ATP, whereas cGMP accumulated slowly in the presence
      of GTP. ADP and metavanadate (P-type ATPase inhibitor) showed to be competitive
      inhibitors with Ki values of 0.15 mM and 10 microns, respectively. NEM (a
      sulphydryl agent) reduced the ATP-dependent uptake in a concentration-dependent
      manner with a Ki value of 10 microM. Ouabain (Na+/K(+)-ATPase inhibitor) had no
      effect. Bafilomycin A1 (V-type ATPase inhibitor) and oligomycin (F-type ATPase
      inhibitor) were the most potent inhibitors with Ki values of 0.7 and 1.8 microM,
      respectively. The present study suggests that the cellular cGMP extrusion is
      energized by an ATPase with a unique inhibitor profile, which clearly
      differentiates it from the other major classes of membrane-bound ATPases.

PMID- 10417985
TI  - The lamprey (Lampetra fluviatilis) erythrocyte; morphology, ultrastructure, major
      plasma membrane proteins and phospholipids, and cytoskeletal organization.
AB  - The aim of this study was to characterize the erythrocyte of the lamprey
      (Lampetra fluviatilis), a primitive vertebrate. The lamprey erythrocyte
      predominantly has a non-axisymmetric stomatocytelike shape. It has a nucleus and
      a haemoglobin-filled cytosol with a few organelles and vesicular structures.
      Surprisingly, there is no marginal band of microtubules. Sodium dodecylsulphate
      polyacrylamide gel electrophoresis followed by Coomassie blue staining of
      isolated plasma membranes revealed a single band at the level of the human
      spectrin doublet. Major bands also occurred at approximately 175 kDa and
      comigrating with human erythrocyte actin (approximately 45 kDa). The presence of
      spectrin, actin and vimentin was shown by immunoblotting. Band 3 protein, the
      anion exchanger in higher vertebrates, seemed to be highly deficient or lacking,
      as was also the case with ankyrin. Confocal laser scanning microscopy combined
      with immunocytochemical methods showed spectrin, actin and vimentin mainly to be
      localized around the nucleus, from where actin- and vimentin-strands extended out
      into the cytoplasm. Actin also seemed to be present at the plasma membrane.
      Phospholipid analyses of plasma membrane preparations showed the presence of the
      same four major phospholipid groups as in the human erythrocyte, although with
      higher and lower amounts of phosphatidylcholine and sphingomyelin, respectively.
      The low fluorescein isothiocyanate conjugated annexin V binding, as monitored by
      flow cytometry, indicated that phosphatidylserine is mainly confined to the inner
      membrane leaflet in the lamprey erythrocyte plasma membrane.

PMID- 10417984
TI  - Tagetone modulates the coupling of flunitrazepam and GABA binding sites at GABAA
      receptor from chick brain membranes.
AB  - The effects of tagetone on flunitrazepam (FNTZ) binding to synaptosomal membranes
      from chick brains in the presence and absence of allosteric modulations induced
      by gamma-aminobutyric acid (GABA) were investigated. Tagetone, at 50
      micrograms/ml (final concentration), decreased the binding affinity of [3H]FNTZ
      to synaptosomal membranes form chick brain (Kd = 3.34 +/- 0.36 nM without
      tagetone and Kd,t = 5.86 +/- 0.86 nM with tagetone; p < 0.05, two tailed
      Student's t-test) without affecting maximal binding (Bmax = 488 +/- 24 fmoles/mg
      protein, and Bmax,t = 500 +/- 25 fmoles/mg protein in the absence and in the
      presence of tagetone respectively). The potency of GABA to stimulate [3H]FNTZ
      binding increased in the presence of tagetone (EC50 values were 2.78 and 1.12
      microM with and without tagetone respectively). GABA was able to decrease
      merocyanine delta A570-610 values in a concentration dependent manner; half
      maximal effect was attained at a GABA concentration of 34 +/- 13 microM.
      Tagetone, at a concentration of 50 micrograms/ml and in the presence of GABA 30
      microM or 60 microM, enhanced the ability of GABA alone on decreasing delta A570
      610. Tagetone alone did not change delta A570-610 values. FNTZ, a well known GABA
      modulator, could also potentiate the effect of GABA. Theoretical calculations
      indicate that the effects on merocyanine delta A570-610 value are mainly exerted
      at the membrane potential level (delta psi m). The present results strongly
      suggest that tagetone affected the function of GABAA receptor in a complex way:
      on the one hand it impaired FNTZ binding: on the other hand tagetone improved
      both the coupling between FNTZ and GABA binding sites and it enhanced GABA
      induced chloride permeability. Changes in the geometrical and electrostatic
      properties of the self-organized membrane structure may account for these effects
      of tagetone.

PMID- 10417986
TI  - Isolation and characterization of highly purified mitochondrial outer membranes
      of the yeast Saccharomyces cerevisiae (method).
AB  - Mitochondrial outer membrane vesicles (OMV) from the yeast Saccharomyces
      cerevisiae were prepared by osmotic swelling and mechanical disruption of
      mitochondria that had been isolated at pH 6.0 and purified by density gradient
      centrifugation. The OMV were obtained in a yield of 1% (protein/protein) with
      respect to the mitochondria. The OMV were shown to be essentially free of
      mitochondrial inner membrane protein markers, while contamination with
      endoplasmic reticulum was around 5% (protein-based). The very low
      phosphatidylserine synthase activity present in the OMV preparation indicated
      that contamination with mitochondria-associated membranes (MAM) was negligible.
      The resistance of the outer membrane protein Tom40 to digestion by trypsin
      demonstrated the sealed nature and right-side out orientation of the OMV.
      Analysis of the phospholipid composition revealed that the contents of
      phosphatidylcholine and phosphatidylinositol are higher and the content of
      phosphatidylethanolamine is lower in the mitochondrial outer membrane as compared
      to whole mitochondria. Cardiolipin is largely depleted in the OMV.

PMID- 10417987
TI  - [The anatomic lobulation of the prostate, a controversial description].
AB  - Vesalius, in 1543, described, for the first time, the prostate as an unique
      organ. But, in the 19th century, two schools confronted; for Cruveilhier and
      Testut, the prostate was made of several lobes, when Cloquet and Sappey thought
      it as a unique zone. Albarran, in 1902, described the sub-uretral glands.
      Thereafter, Cuneo, in 1911 and Franks, in 1954, described two zones, one,
      internal, formed by the Albarran's glands, and the other, external, concerning
      the whole prostatic gland. On the contrary, Lowsley, in 1912, and Gil Vernet, in
      1953, described several lobes, 5 for Lowsley, 3 for Gil Vernet. Recently, in
      1968, and 1978, McNeal had made the proof that the prostate is histologically and
      anatomically heterogeneous, with three zones, transitional, central and
      peripheral ones.

PMID- 10417988
TI  - [The myocutaneous flap of the nasal transverse muscle].
AB  - The reconstruction of the nasal tip give difficulties. The nasal myocutaneous
      flap seems a good solution. We have studied twenty fresh corpses after injection
      of coloured latex and barium. This flap and its vascular pedicle were constant.
      We describe the technique. We used this flap on thirteen patients. The
      indications are the cutaneous lesions of the middle of the nasal tip or the
      nostrils. The results are excellent because this flap respects the anatomical
      unit of the nose. The morphological and esthetical results are excellent.

PMID- 10417989
TI  - [Superficial veins of the leg].
AB  - This clinical work studies the normal pattern of the saphenous veins, their main
      variations with a short embryological reference. Some pathological cases are
      described; the perforator veins are very important; the role of the valves at the
      groin is emphasized.

PMID- 10417990
TI  - [Arterial vascularization of the amygdaloid nucleus in man and in sheep].
AB  - These present studies, performed on human adult brains and on sheep with
      injection method, have shown that the amygdaloid nucleus has its special,
      separate and rich arterial system. The main source of its vascularization both in
      the human and sheep brains are 1-3 branches of the proximate segment of the
      middle cerebral artery. The supplementary source is formed by the deep
      ramifications of the superficial arterioles of the middle cerebral artery as well
      approximately by the small branches of the anterior choroidal artery. Each of
      these arterioles distributes and supplies only the amygdaloid nucleus and does
      not form precapillary anastomoses.

PMID- 10417992
TI  - [A novel approach to the biomechanical study of the talocrural joint in man using
      MRI. Contribution of dynamic images].
AB  - A cineradiographic study of the talocrural joint allows a new biomechanical
      approach of the ankle: MRI with axial and coronal slides were realized: for
      volume reconstruction in passive movement; scanner was used for axial slides in
      active movement. There is evidently neither distosis of the bimalleolar grip in
      dorso- and plantar flexion, nor movement of the lateral malleolus of the fibula,
      in opposition to the classical description. An anatomical rotation is discussed.

PMID- 10417991
TI  - [Divergent asymmetries of the temporo-parietal cortical areas: anatomo-functional
      correlations and evolutionary and developmental implications].
AB  - Human brains present a clear asymmetry of the postero-lateral cortical area, so
      called "planum temporale" (Geschwind and Levitsky). This asymmetry is on favour
      of the left brain. A similar asymmetry is observed on the parietal operculum. MRI
      studies of 37 healthy volunteers have shown a clear difference between
      individuals. Mixing the index of temporal and parietal asymmetry, the authors
      consider four types: the most frequent pattern concerns 90% of right handed. For
      the others, 10% there are left handed as right handed. On conclusion, planum as
      many asymmetry and opercular asymmetry can be divergent, and both canan to
      determines handedness.

PMID- 10417993
TI  - [Venous vascularization of the heart in the African. Tributary veins of the
      coronary sinus].
AB  - This anatomic study realized on 40 African adults hearts, studies the veins
      related to the coronary sinus. By using injection of the coronary arteries and
      corrosion of the myocardium, this study discovers certain particularities of the
      small coronary vein and of the posterior descending interventricular vein in
      Africans.

PMID- 10417994
TI  - [Sinus node vascularization in the black African].
AB  - The aim of this study is to identify in 43 adults African hearts the different
      arteries of the sinus node. The method used is the injection corrosion technic of
      the coronary vessels. This study conclude that the right coronary system is the
      principal way of irrigation of sinus node in Africans (46.6% of cases).

PMID- 10417996
TI  - [The canons of morphotypes in adults. Anatomic atlas and database].
AB  - Orthopedic surgery for subjects of small stature, (between 130 cm and 160 cm),
      after the end of the normal growth cycle, requires a definition of the
      individual's morphotype, according to the standard canons. There exists a
      "classic canon", from Mediterranean culture, which divides the human body, from
      the waist, into two unequal parts (in the longitudinal dimension), which can vary
      from excessive shortness to excessive height. These proportions are strongly
      hereditary. In the transversal sense, there exists also measurements which can
      widely vary. These, are also strongly hereditary. Thus, defining five
      measurements: Stature. Height from the waist to the ground. Height from the waist
      to the top-head. Width of the shoulders. Width of the pelvis. From these five
      measurements, in the longitudinal and transversal dimensions, we obtain the well
      defined outlines of the subject's morphotype as well as, all other variations of
      this morphotype. Because there are separate variations of the transversal and
      longitudinal canons. A canon is specific to a group or a population. There are an
      infinite number of canons on this earth. Before starting limb lengthening
      surgery, it's necessary to define the morphotype (canon) of the subject. The
      harmony or dysharmony of his body proportions. As well as determine, at which
      point of lengthening, will the patient realise a true benefit for this difficult
      surgery.

PMID- 10417995
TI  - [The pericardium: a heterogeneous tissue. Anatomic and morphometric
      considerations].
AB  - BACKGROUND AND AIMS OF THE STUDY: Short-term glutaraldehyde fixed autologous
      pericardium is widely used in cardiac valve repair or in autologous pericardial
      bioprosthesis construction. The thinner the tissue, the better the fixation. The
      aim of this study was to determine thickness and useful surface area of
      pericardium in relation to harvesting site using a digital thickness counter
      (0.01 mm precision). Parietal pericardium fragments were obtained from the
      pericardial sac of six fresh cadavers (group I). In the other groups, pericardial
      strips (80 x 30 mm) were obtained from patients undergoing surgery: group II
      patients (n = 5 females) and group III (n = 10 males) were non-cardiomegalic
      (cardiothoracic ratio (CTR) < 0.5)), while group IV patients (n = 5) were all
      cardiomegalic (CTR > 0.5). Results were reported on a coloric scale according to
      measurement position. In group I, mean surface area was 93 +/- 18 cm2, and
      thickness gradually increased from 0.1 to 0.6 mm, maximally on the diaphragm,
      along the left heart side. In other groups, a gradual increase in thickness was
      identified towards the diaphragmatic zone. Significant differences in tissue
      thickness appear as a result of cardiomegaly, but are not related to the sex of
      the patients. Pericardium taken from the right anterior aspect of the pericardial
      sac in patients without cardiomegaly is the most appropriate tissue for valve
      reconstructive surgery, due to its thin nature and hence better fixation
      properties.

PMID- 10417997
TI  - [Vascularization of the trochanter fragment after digastric trochanterotomy in
      man].
AB  - We examined the human vascular anatomy to the greater trochanter after digastric
      trochanterotomy, using some injection techniques and practiced the
      trochanterotomy (digastric, classic). We found 3 major sources of blood supply to
      the greater trochanter: the proximal soft tissues, including the gluteus medius
      and minimus, were mainly vascularized from the internal iliac artery system, and
      the distal soft tissues, including the vastus lateralis, were vascularized from
      the branches of the lateral circumflex femoral artery (LCFA). A third possible
      source of blood circulation came from the LCFA, but this branch was only found in
      12 to 15 samples. Many vascular structures from the LCFA were concentrated in the
      anterior half of the vastus lateralis muscle which were deeply imbedded and ran
      upward to the trochanteric insertion of the vastus lateralis muscle. The distance
      from the superior tip of the greater trochanter to the point at which the first
      branch of the descending branch of the LCFA enters into the vastus lateralis
      muscles was from 65 mm. to 125 mm. The descending branch was found consistently
      in all 20 samples. Our results proved that with digastric trochanterotomy, we can
      preserve all three sources of vascularization whereas with classic
      trochanterotomy the supply from the transverse and descending branches of the
      LCFA are lost.

PMID- 10417998
TI  - [Partial arthrodeses of the wrist: experimental studies].
AB  - The partial arthrodeses of the wrist joint are well known as a method of
      treatment of several articular pathologies. Although there exists controversies
      about the final range of motions. In the goal to compare the state of the
      ligaments to the final range of motions we realised some of the most popular
      intracarpal arthrodeses in an anatomical laboratory. For our study we used 10
      fresh cadaver specimens with the mean age of 88 years (84-95). The arthrodeses
      were realised with Kirschner wires. Biggest range of motion (more than 70%) was
      obtained after scapho-lunatum, scapho-capitatum and luno-triquetrum arthrodeses,
      while after luno-capitatum, scapho-luno-capitatum and triquetro-hamato-luno
      caitatum it was the poorest--less than 50% of the initial state. We found a
      correlation between the state of the ligaments and the final results--in
      specimens with tears of the ligaments the results were closer to the perfect-ones
      from the clinical series. In our opinion the measurement of radial and ulnar
      deviation in clinical practice is not exact and should not be considered in the
      elaboration of scientific databases.

PMID- 10418000
TI  - [Pectineal ligament of Cooper. Micromorphometric study].
AB  - The pectineal ligament is used in surgery as a support element in the treatment
      of groin hernias and female urinary stress incontinence. The question is to
      determine the anatomical characters that account for its strength. Three
      complementary approaches have been considered: an anatomical dissection study
      established the origin of the different fibers the ligament is composed of; a
      morphometric study determined the areas where the ligament is the thickest; and
      microscopic anatomy clearly showed the arrangement of the fibers. The pectineal
      ligament continues the near-by fibers fibrous elements, notably thanks to its
      ends. The latter are significantly thicker. At microscopic level, the regular
      layout of the pectineal ligament fibers accounts for its resistance.

PMID- 10417999
TI  - [Radio-anatomic study of the ophthalmic artery].
AB  - It is possible to have a good definition of structures with modern neuro-imaging.
      Ophthalmic artery is a neat vessel with lot of branches and sinous pathway, which
      are difficult to have in the same frame. A good knowledge of the classical
      anatomy is necessary to interpret correctly the pictures obtained with neuro
      imaging. The aim of this study is to compare classical dissections (dissections
      after latex injection, corrosion with Altufix P.10, radiography after Minimum
      injections) with radio-anatomical images (computed scanns, angiographies, MRI).
      We have also studied origin, pathway, collateral branches of ophthalmic artery.

PMID- 10418001
TI  - [Anatomic study and review of the literature on the Martin Gruber anastomosis].
AB  - We dissected 72 upper limbs of fresh cadavers and found 17 cases of the Martin
      Gruber anastomosis. The incidence was 23.6%. They can be classified into 5 types.
      Type I (n = 5, 29.4%): Communication between the anterior interosseous and the
      ulnar nerves. Type II (n = 3, 17.6%): Communication between the median and the
      ulnar nerves. Type III (n = 3, 17.6%): Communication between the muscular
      branches of the flexor digitorum profundus muscle (FDP). Type IV (n = 3, 17.6%):
      Communication between the anterior interosseous and the ulnar nerves, the
      muscular branches of the flexor digitorum profundus muscle (FDP) originated from
      the connection. Type V (n = 3, 17.6%): The anastomotic branch originated from the
      median nerve and joined the ulnar at two different points as well as connecting
      with the ulnar branch of the FDP. Through histologic examination, we found the
      number and size of nerve fascicles which every connection contained to be very
      different. In one case of type II only one single nerve fascicle was found. We
      propose the hypothesis that the different amounts of nerve fascicles innervate
      different amounts of intrinsic hand musculature. The communication which
      contained one single nerve fascicle only innervate the first dorsal interosseous
      muscle (FDI).

PMID- 10418002
TI  - [The lumbar vein at L2 and the reno-azygo-lumbar arch: anatomic and radiologic
      studies].
AB  - The lumbar vein at L2 was described by C. Gillot and B. Singer (1974). On the
      right side, after drawing off the 12th intercostal vein, it forms the lateral
      root of the azygos vein. Its way is as a frame, transverse going along the body
      of the 2nd lumbar vertebra, then upward along the spine after having integrated
      the veins of the L2-L3 intervertebral foramen. In its typical form, the vein is
      at L2 but it can be at L1 or L3. It takes the name of lateral root of the azygos
      vein only after receiving the 12th intercostal vein. Because of its diameter (5
      mm), it forms a cavo-caval anastomosis via the azygos vein. The renal azygo
      lumbar arch of Lejars is the equivalent on the left side of the right vein at L2.
      This arch contributes to the formation of the lateral root of the hemi-azygos
      vein. The right vein at L2 and the reno-azygo-lumbar arch were studied by
      dissections and by radiologic protocols. The radiologic studies (CT, MRI, 3D
      reconstructions) were carried out after injections of gelatin-gadolinium-minimum
      and altufix-minimum mixtures. The results showed the numerous variations of
      origin of the azygos system. The use of multiple and complementary technics are
      very helpful to describe these variations.

PMID- 10418003
TI  - [Intravenous polyclonal immunoglobulins (IVIG): what use in transplantation?].
AB  - Intravenous human polyclonal immunoglobulins G (IVIg) were initially used as
      substitutive therapy for primary and secondary immunodeficiencies then for
      various autoimmune diseases. More recently they were proposed in organ transplant
      recipients as they induce a decrease of the anti-HLA antibodies titer in HLA
      immunized patients. Few retrospective and prospective trials have been performed
      yet, though they clearly show a beneficial effect of IVIg on kidney graft
      survival. This paper reviews the different potential mechanisms of action of IVIg
      their use and potential efficacy in organ transplant recipients.

PMID- 10418004
TI  - [Kidney transplantation and travel in the tropics].
AB  - About 1600 kidney transplants are performed each year in France. The quality of
      life of grafted patients has therefore improved, to the extent that such patients
      are now envisaging professional or other activity and stays in tropical or sub
      tropical regions. However, this is not without some degree of risk or difficulty.
      Anti-malarial drugs may interfere with other medication, particularly ciclosporin
      in kidney grafted patients. Moreover, other vaccinations such as anti-amaril
      immunization are recommended or even required by certain countries. Yet the
      immunodepression induced by this in grafted patients is a contraindication for
      such vaccination. For the other types of immunization, the risk/benefit ratio is
      not always obvious.

PMID- 10418005
TI  - [Risk factors of chronic rejection in kidney transplantation, results of a single
      center study].
AB  - Chronic rejection remains the single most important cause of renal allograft loss
      after the first year post-transplant. We performed a matched case control study
      within our cohort of 471 renal allograft recipients, comparing 66 patients with
      histologically proven chronic rejection with 66 controls. Analysis of
      immunological (transfusion, sensitisation, HLA matching, number of
      transplantation, number of acute rejections (AR), immunosuppression) and non
      immunological (donors and recipients age and sex, CMV disease, post-transplant
      acute tubular necrosis, cold ischemia) factors which could predict the occurrence
      of chronic rejection (CR) was performed, using Wilcoxon rank test, Mac Nemar test
      and Cox model. Univariate analysis showed that potential risk factors for CR are:
      donor age > 45 years (p = 0.05), recipient age < 40 years (p = 0.008), CMV
      disease (p = 0.03), number of acute rejection episodes (p = 0.009),
      retransplantation (p = 0.002). Multivariate analysis showed that only the
      following factors significantly increased the risk of CR: AR episodes (p = 0.01)
      with an odds-ratio at 3.5 (95% CI = 1.3-3.9) for the second acute rejection
      episode and at 6.5 (95% CI = 1.5-29.4) for the third acute rejection episode,
      donor age > 45 years (p = 0.03) with an odds-ratio at 3.5 (95% CI = 1.1-10.6).
      Our data suggest that better matching at donor recipient age and more potent
      immunosuppressive protocols resulting in no acute rejection may improve the long
      term graft survival. They also show that the use of old donors (> 45 years), as a
      response to organ shortage is detrimental for long term renal function.

PMID- 10418006
TI  - [Prevalence of HIV infection in dialysis patients: results of a national
      multicenter study].
AB  - In order to determine the prevalence of HIV infection in french patients with end
      stage renal disease (ESRD) on maintenance dialysis therapy, questionnaire forms
      were mailed out in february 1997 to the heads of the 260 dialysis facilities. We
      documented number of patients on maintenance dialysis therapy (hemo and
      peritoneal dialysis) and for HIV infected dialysis patients: age, gender, cause
      and duration of ESRD, known duration of HIV infection, risk factors for HIV
      infection, HBV and/or HCV infection, presence of clinical acquired
      immunodeficiency syndrome (AIDS), total CD4 count and treatment with
      antiretroviral agents. Questionnaire forms were returned from 98% of the dialysis
      facilities. As of february 1997 some 22,707 patients with ESRD were treated by
      renal replacement therapy, 19,947 by hemodialysis (HD) and 2760 by peritoneal
      dialysis (PD). 82 patients with ESRD and HIV infection were reported
      corresponding to 0.36% prevalence rate of all patients undergoing dialysis at the
      time specified. The 82 study subjects with ESRD and HIV infection received
      hemodialysis (79 patients) or peritoneal dialysis (3 patients) in 42 facilities.
      Forty seven patients were treated in Paris and suburbs and 9 in our own center.
      All 82 patients comprised 63% men and 47% women which included patients coming
      from Africa (37%), Caribbean and Oceania (28%), Europe (35%) of a mean age of
      41.8 years. Modes of transmission were homobisexuals 15%, heterosexuals 31%,
      intravenous drug abusers 17%, blood transfusion 17% and unknown 20%. The mean
      duration of HIV infection was 96 months (range 12-168 months) and the mean
      duration of ESRD was 58 months (range 1-235 months). HIV associated nephropathy
      was established in 31%. AIDS was diagnosed in 25 patients. Seventy one percent of
      the patients were receiving an antiretroviral drug (tritherapy in 25% of cases).
      In conclusion HIV prevalence rate among French dialysis patients is low and
      focused in Paris and oversea. Sexual transmission is the most important HIV
      contamination but blood transfusion transmission remains greater than in general
      HIV population. Survival has improved compared with the survival rate reported in
      the 1980s.

PMID- 10418007
TI  - [Long-term consequences of co-infection by hepatitis G virus in hepatitis c virus
      infected kidney transplant patients].
AB  - The objectives of this retrospective study were to determine the prevalence of
      hepatitis G virus (HGV) infection in hepatitis C virus positive (HCV+ve) renal
      transplant (RT) patients and to evaluate the impact of HGV both on liver function
      tests, liver histology tests and renal parameters such as the prevalence of acute
      rejection and renal function. Seventy-one HCV+ve renal transplant patients with a
      functioning graft for whom a post renal transplant liver biopsy was available,
      were included. Serum HGV RNA was assessed by reverse transcription polymerase
      chain reaction before, at the time of, and after renal transplantation. A total
      of 21 (30%) of the HCV+ve RT patients had a positive HGV RNA (Group 1); seventeen
      of these patients (81%) were already HGV RNA+ve when the most recent renal
      transplantation was performed. The other 4 patients became HGV RNA+ve following
      renal transplantation. The mean duration of HGV infection was at least 119 +/- 64
      months (18-240). Patients in group 1 did not statistically differ from the 50 HGV
      RNA-ve/HCV+ve RT patients (Group 2) according to sex ratio; time on dialysis;
      number of blood transfusions; HLA matching; the duration of HCV infection;
      duration and type of immunosuppression or levels of liver enzymes i.e. aspartate
      aminotransferase, alanine aminotransferase and gamma glutamyl transpeptidase;
      serum HCV RNA concentration; or frequency of genotype 1b. However, Group 1
      patients were statistically younger (41 +/- 10 y compared to 47 +/- 10 y; p =
      0.016) than Group 2 patients. Liver histology showed a significantly lower degree
      of fibrosis in Group 1 (0.4 +/- 0.5) than in Group 2 (1 +/- 1.2; p = 0.02); two
      patients from Group 2 but none of Group 1 had overt cirrhosis. Conversely, the
      extent of hepatic inflammation and hepatocellular necrosis was not statistically
      different between the two groups. The number of patients who experienced at least
      one acute rejection episode was significantly higher in Group 1 (76.2%) than in
      Group 2 (46%; p = 0.02), although the difference was no longer significant in the
      multivariate analysis. In conclusion, this study shows that: i) HGV infection was
      often present when the patients seroconverted for HCV; ii) HGV RNA+ve/HCV+ve RT
      patients experience acute rejection more frequently than HGV RNA-ve/HCV+ve RT
      patients; iii) HGV infection seems to have no detrimental effect upon liver
      enzymes or liver histology in HCV+ve RT patients.

PMID- 10418008
TI  - [Natural science and introduction to physical chemistry in nephrology].
AB  - Osmosis, as described in 1825 by H.J. Dutrochet, played a role in the role in the
      beginning of physical chemistry and of the evaluation of renal functions. In
      1871, the osmotic pressure, not so well understood by scientists, was again
      suggested by de Vries who described the "plasmolysis", a phenomenon corresponding
      to cell retraction when incubated in high molecular concentration solutions.
      Although the results were not well interpretated, this phenomenon was related to
      the osmotic pressure. Van't Hoff studied the mechanisms phenomena and compared it
      to the gas volume/pressure relationship. Dreser measured in urine the cryoscopic
      delta that had just discovered by Raoult in animal and man, after a water load (
      0.20 degree C) or a water restriction (-2.50 degrees C) and calculated
      approximately the amount of energy required to eliminate water at various
      different concentrations of solutes. Koranyi used the same methods in disease
      states. The loss of difference between the maximal and minimal delta indicates a
      functional renal insufficiency. This was the term first proposed by Koranyi
      outlining the role of the kidney in the regulation of the milieu interieur and
      more specifically in the regulation of water and solute concentration.
      Hyposthenuria, best named isosthenuria, in the range of osmotic pressure usually
      indicates terminal renal failure. Koranyi named this test funktionelle
      Nierendiagnostik, a start for the physiological investigations of renal
      functions.

PMID- 10418009
TI  - [Klebsiella oxytoca septicemia following platelet transfusion].
AB  - Two fractions of a three-day-old apheresis platelet collection from a known
      habitual donor were transfused to two children with thrombocytopenia and
      bleeding. Both patients developed evidence of severe infection during the
      transfusion. One died despite intensive care and antimicrobial therapy. The
      other, whose transfusion was cut short, recovered. A Klebsiella oxytoca strain
      was recovered from the two transfusion bags, from a third unused bag, and from
      blood samples from the patient who died. Genotyping results established that all
      these isolates were identical. Tests for K. oxytoca were negative on the batches
      of blood donation material, the bottle of antiseptic used, and throat and stool
      specimens from the donor and phlebotomists. The most likely hypothesis is that
      the donor developed transient asymptomatic bacteremia during the 136-minute-long
      collection procedure and that the organism subsequently grew in the platelet
      collections, which were kept at 20-24 degrees C with agitation for three days
      before being used.

PMID- 10418010
TI  - [Infection after total hip replacement by Staphylococcus caprae. Case report and
      review of the literature].
AB  - We report a case of Staphylococcus caprae bone and joint infection, that
      illustrate difficulties to diagnose coagulase-negative staphylococci (CNS)
      orthopedic surgery infections, specially following implantation of prostheses.
      Four of 5 strains successivelly isolated from deep and/or peri-operative
      specimens during late infection after total hip replacement (THR) have been
      identified, using commercial systems and conventionnal tests, as S. caprae.
      Identity of biochemical profile, antibiotype and pulsotype of the 4 isolates
      confirmed the pathogenicity of this animal CNS, rarely described as a human
      pathogen. Analysis of the 24 S. caprae human cases previously described evidence
      a relation ship between this bacteria and bone and joint infections, with
      implantation of prosthetic material as supplementary risk factor. S. caprae,
      whose major identification criteria are resumed, may have previously been
      misidentified as some similar CNS; this bacteria is probably part of our normal
      flora but may be recognized as an opportunistic pathogen, responsible for both
      nosocomial and community acquired infections.

PMID- 10418011
TI  - ["Second look" at cytotoxin B of Clostridium difficile in the course of diarrhea
      associated with antibiotic therapy].
AB  - Clostridium difficile is a sporulated obligate anaerobe responsible for most
      cases of antibiotic-associated colitis, for 15 to 25% of cases of antibiotic
      related diarrhea, and for a substantial proportion of nosocomial infections. The
      most important laboratory test for the diagnosis of C. difficile infection is
      examination of the stool for C. difficile toxins A and/or B. Detection of
      cytotoxin B using the direct cytotoxicity assay (D-CA) is the gold standard test.
      Whether routine isolation of the organism from stool is warranted remains
      controversial. OBJECTIVES: To evaluate second-look CA done on C. difficile
      culture-positive filtrates from stool samples negative by the D-CA. METHODS: 300
      consecutive stool samples sent to the Alfred Fournier Institute from April
      through October 1998 for a CA were routinely cultured on modified Cefoxitin
      Cycloserine Fructose Agar medium (CCFA). All CA-negative samples that grew C.
      difficile were examined by second-look CA. RESULTS: 245 stool specimens (81.7%)
      were negative by both CA and culture. The remaining 55 specimens all yielded C.
      difficile by culture; 32 (58.2%) had a positive D-CA and nine (16.4%) a negative
      D-CA with a positive second-look CA done on culture filtrates. CONCLUSION: Our
      data suggest that stool specimens sent for a direct CA should be routinely
      cultured to provide material for a second-look CA on culture-positive filtrates
      if the first CA prove negative. Culturing also allows to study antimicrobial drug
      resistance phenotypes and epidemiological markers.

PMID- 10418012
TI  - [Severe community-acquired bacterial pneumonia from Streptococcus pneumonia in
      HIV-infected patients: epidemiology and prognostic features of mortality].
AB  - In HIV-infected patients, community-acquired pneumonia due to Streptococcus
      pneumoniae is more common, more often associated with bacteremia, and more likely
      to recur. The epidemiology of this condition is discussed based on a literature
      review. Factors predictive of mortality in severe cases managed in intensive care
      units are analyzed.

PMID- 10418013
TI  - [Determination of the nosocomial origin of vancomycin-resistance strains of
      Enterococcus isolated from stool of patients in a hematology department].
AB  - Patients severely neutropenic, when hospitalized, occasionally receive selective
      digestive decontamination, and the risk of vancomycin-resistant strain selection
      is a drawback since glycopeptide resistance is often associated with betalactam
      and aminoglycosid resistance. Bacterial translocation can lead to multiresistant
      bacterial sepsis. Eighteen Enterococcus faecium strains were collected from
      patients hospitalized in the leukemia unit of the Universitary Hospital of Lille
      (CHRU, Pr Bauters) between October 1992 and July 1997 and were studied.
      Nosocomial acquisition or endogenous origin were investigated to choose well
      adapted prevention. All the vancomycin-resistant strains were shown by Polymerase
      Chain Reaction having the van A gene. The clonality of these strains was
      investigated by Pulsed-Field-Gel-Electrophoresis after Sma I restriction.
      Pulsotype analysis showed variable homology (52%-100%). Our results do not show
      evidence of patient-to-patient E. faecium transmission and suggest vancomycin
      resistant strains were independently selected by antibiotic therapy from
      individual fecal flora. Except when epidemic events or happen, this strain
      isolation is more related to antibiotic prescription than misuse of isolation
      techniques.

PMID- 10418014
TI  - Emergence of multidrug-resistant Enterobacter cloacae: nosocomial outbreak or
      change of microbial ecology?
AB  - Frequent selection of mutants resistant to extended and broad spectrum
      cephalosporins in Enterobacter cloacae is observed in hospital. As we noticed an
      unusual number of isolates of these strains and to answer the question arose
      whether these Enterobacter had a common source, we retrospectivally studied 56
      strains collected in 11 wards of the hospital. Using PFGE with Spe 1 restriction
      analysis we identified a prevalent clone (11 patients) dispatched in 8 wards. We
      also obviously proved cross-contamination patients to patients with other clones.
      PFGE allow us to point out that clonal Enterobacter cloacae has taken place in
      our hospital, even if there is no real outbreak. A reinforcement of basic
      hygienic measures and a control of antibiotics prescription seemed very important
      to jugulate the sudden increase of multiresistant Enterobacter cloacae
      prevalence.

PMID- 10418015
TI  - [Investigation of an epidemic of an extended spectrum beta-lactamase producing
      Escherichia coli in a geriatrics department].
AB  - An outbreak of extended-spectrum beta-lactamase-producing (ESBL) Escherichia coli
      urinary tract infection occurred on one floor of a department of the G.
      Clemenceau hospital. There were nine cases from March to August 1994, all of
      which resolved under antimicrobial therapy. Two further cases occurred, leading
      to a program of routine rectal swab cultures in all patients on the floor
      involved (first floor). ESBL E. coli carriage was found in six patients. Follow
      up rectal swabs were obtained until September 1995 from all patients on the floor
      who were infected or colonized with ESBL E. coli between March and October 1994.
      Between March and June 1995, routine rectal swabs were also obtained from the
      patients on the other two floors of the department. Seven other carriers were
      detected and also underwent follow-up rectal swabs until September 1995.
      Ribotyping of the strains done at the national enteric molecular typing center
      (Pasteur Institute, Paris) demonstrated four patterns (CM1, CM2, CM3, and CM4).
      The strains from the first six carriers all shared the CM1 pattern, whereas among
      the seven carriers detected later, four (second and third floors) had a CM1
      strain and the remaining three (first floor) each had a strain of the three other
      ribotypes (CM2, CM3, and CM4). ESBL E. coli can be carried in the digestive tract
      for several months. During the outbreak, the same strain was found in all the
      patients, whereas a variety of strains were found after the outbreak in patiens
      without clinical symptoms due to ESBL E. coli. Routine rectal swab cultures are
      useful for evaluating the extent of outbreaks. However, the only effective
      outbreak control measures are compliance with strict hygiene procedures
      (signalization, technical and geographic isolation) and appropriate antimicrobial
      therapy. These measures were effective at the G. Clemenceau Hospital since there
      have been no further cases of ESBL E. coli since they were implemented. The
      rectal swab program has therefore been stopped, whereas strict universal hygienic
      precautions are still adhered to faithfully.

PMID- 10418016
TI  - [Inquiry into the incidence of nosocomial infections and evaluation of the
      transmission of methicillin-resistant Staphylococcus aureus in an orthopedic
      surgical unit].
AB  - Nosocomial infections are an important cause of morbidity and mortality.
      Methicillin resistant Staphylococcus aureus (MRSA) is often the severe causal
      agent in this kind of infections. In order to evaluate risk factors for
      nosocomial infections and nasal MRSA carriage, an incidence study was carried out
      on patients hospitalized in an orthopaedic surgery department in Boucicaut
      Hospital (Paris). This study was carried out over a five month period. Data of
      all the patients who stayed more than two days in the unit were collected in
      medical and nursing records. Nasal swab specimens were taken at the admission of
      each patient included in order to screen nasal MRSA carriers. Statistical
      analysis were performed using Epi Info software version 6.0. A total of 451
      patients were included in the study. Nosocomial infections incidence rate was
      11.5%. Risk factor significantly associated with nosocomial infection was high
      wound containation classes III and IV (Altemeier). Incidence rate of MRSA
      carriage was 3.1%. A previous hospitalization in a general hospital 6 months
      before an admission at Boucicaut Hospital was the only risk factor identified.
      According to this, these patients, when they are admitted, are proposed to be
      preventely isolated awaiting their microbiological results.

PMID- 10418017
TI  - [Outbreak of methicillin-resistant Staphylococcus aureus in general hospital
      intensive care unit].
AB  - Mantes' hospital polyvalent intensive care unit (ICU) experienced an outbreak
      episode caused by methicillin resistant Staphylococcus aureus (MRSA). Suspicion
      of physicians was strengthened by observing the weekly reading of multiresistant
      germs and the significative increase of MRSA carriers incidence rate, compared
      with the number of admission in the ICU: 5.5% to 11.3%. This outbreak was
      surprising: it happened immediately after the installation in a new hospital and
      the reinforcement of nosocomial infection surveillance (systematic screening of
      every patient admitted to the I.U.C., his isolation if he presents risk factors
      to multiresistant germs, increasing of handwashing stations). The overlapping
      period of hospitalisation concerning the 13 patients being reported as SARM
      carrier, having the same antibiogram, and the epidemic curve suggested a cross
      contamination. The index case was a MRSA carrier the day of her admission and
      have had a recent hospitalisation in a high risk unit. MRSA has always been
      isolated in nasal swab. Six patients among the thirteen carriers developed an
      infection and have been treated by vancomycin: two systemic infections and four
      pulmonary infections. The mortality rate was 33% and only one of them seemed to
      be directly due to MRSA. Area samples were all negative. The clinical staff have
      been screened with nasal swab. We identified only one nasal MRSA carrier. The
      pulsed-field gel electrophoresis study showed that 9/11 which have been analysed
      were identical. This outbreak brought about staff, more sensibilisation to the
      nosocomial infection and updating of plain hygien rules leaded to its stop five
      months later.

PMID- 10418018
TI  - [Is the a connection between prolonged carriage and clonal hospital-to-hospital
      clonal spread of multiresistant Pseudomonas aeruginosa of the O12 serotype? Are
      the specific habits of the hospitals involved the cause?].
AB  - Results obtained using our expert computer program (SIR, 12A, Montpellier,
      France) over the last seven years (1991-1998) suggest that the increased
      incidence of superficial pus infection or colonization with O12 Pseudomonas
      aeruginosa, together with the significantly longer carriage duration for this
      organism as compared to non O12. P. aeruginosa, may contribute to the current
      endemic clonal spread of O12 P. aeruginosa in a general hospital in Rodez,
      France, and in neighboring extended-care facilities. This ecological observation
      may reflect poor compliance with basic hygiene procedures in the Rodez hospital
      and in neighboring hospitals. The O12 P. aeruginosa clone in the Rodez hospital
      is indistinguishable from the one that has disseminated throughout Europe,
      suggesting that the ecological observation and hypothesis described herein may
      deserve to be investigated in other institutions that are also the site of
      endemic clonal O12 P. aeruginosa dissemination.

PMID- 10418019
TI  - [In vitro demonstration of a true post-beta-lactamases inhibitor effect (PLIE) of
      clavulanic acid on Klebsiella pneumoniae and Haemophilus influenzae].
AB  - In vivo, serum concentrations of beta-lactamase inhibitors measured during the
      last part of the dosing interval are below the levels associated with in vitro
      activity. Nevertheless, beta-lactam plus beta-lactamase inhibitor combinations
      remain active in vivo throughout the dosing interval. One of the many reasons for
      this contradiction may be the PLIE. The PLIE can be evaluated only in the light
      of the postantibiotic effect (PAE). Also, accurate determination of the PLIE
      requires a careful investigation of all bacterial regrowth delays (BRDs) inherent
      to the technical procedures used. The purpose of the study reported herein was to
      determine the true in vitro PLIE of clavulanic acid (CA) against two beta
      lactamase-producing strains, a Klebsiella pneumoniae strain (amoxicillin [AMX]
      MIC > 256 mg/L; CA MIC = 64 mg/L; and AMX + CA MIX = 4 mg/L) and a Haemophilus
      influenzae strain (AMX MIC = 32 mg/L; CA > 32 mg/L; AMX-CA = 1 mg/L). For each
      strain, a stationary phase inoculum of 10(7) was preexposed for 2 h to either CA
      alone or CA + AMX in various concentrations. Dilution to 10(-2) or 10(-3) was
      performed to eliminate the CA and/or AMX after the preexposition phase. Hourly
      bacterial counts were done between 0 and 8 h and after 24 h. Control cultures
      exposed to AMX after dilution showed a growth delay possibly ascribable to the
      time needed for bacteria to produce a large enough amount of beta-lactamases.
      Control experiments were done to unequivocally differentiate PLIE from PAE and
      BRD. The true PLIE values thus obtained ranged from 0 to 4.5 h for K. pneumoniae
      and from 0 to 15 h for H. influenzae. For both strains, a PLIE was demonstrated
      after exposure to CA alone.

PMID- 10418020
TI  - [The Pneumococcus Observatory of the Central Region, from June 1, 1997 to May 31,
      1998].
AB  - 714 pneumococcus were listed from 14 laboratories between the 1 June 1997 and the
      31 May 1998. Data capture was done on Epi info software and concerned age, file
      number, consultation/hospitalization, sample type, susceptibility to oxacilline
      (5 micrograms), the results of the E-test for penicillin G, amoxicillin,
      cefotaxime and the results of the routine disk diffusion susceptibility method.
      Strains with reduced susceptibility to penicillin G (PRSP) were collected by the
      coordinating center to perform MICs by the reference method of agar dilution and
      serotyping. Over 714 strains, 45.7% of the samples originated from lungs,
      followed by 22% for blood samples, 14% for ear pus and 2.3% for CSF. 34% of the
      patients were female. 36.7% were children under 16 (57.8% PRSP) and 63.3% were
      adults (41% PRSP). 338 strains (47.3%) were determined as PRSP and 293 of them
      were studied by the coordinating center. 81 of the 293 PRSP (27.7%) were
      resistant et 212 (72.3%) were intermediate to penicillin G. 81% of the PRSP
      studied had a CMI value for penicillin G within +/- 1 log2 dilution. 20 strains
      of PRSP were resistant for amoxicillin (6.8% of the PRSP) and two (0.7% of the
      PRSP) for cefotaxime. 289 serotyping were done, most met serotypes were 23 (25%),
      14 (23%). The least met was 15 (2.4%). These results let assess the epidemiology
      of pneumococcus in our region.

PMID- 10418021
TI  - Epidemiological study of Staphylococcus aureus resistant to methicillin
      responsible for nosocomial infections in nine French hospitals.
AB  - A number of European studies found that nosocomial infections were caused by a
      limited number of methicillin-resistant Staphylococcus aureus (MRSA) strains. A
      study was undertaken to determine the number of MRSA clones responsible for
      nosocomial infections in France. Strains responsible for nosocomial infections
      meeting CDC criteria were collected one week every month from June to October
      1997 in nine French hospitals. Strains that were positive by the oxacillin
      resistance screening test were studied for the IS 431, femA, and mecA genes.
      Strain type was identified using pulsed-field gel electrophoresis of fragments
      produced by Smal digestion. Susceptibility to antimicrobials was evaluated based
      on inhibition zone diameters and minimal inhibitory concentrations determined
      using the agar dilution method. The 83 strains studied were distributed across
      four pulsotypes. Eleven resistance phenotypes were identified by ascending
      hierarchical classification based on inhibition zone diameters. MRSAs responsible
      for nosocomial infections belong to a limited number of clones that express
      variable levels of resistance to antimicrobials.

PMID- 10418022
TI  - [Nasopharyngeal carriage of resistance pneumococci in day-care centers in the
      Alps-Maritimes region].
AB  - To provide ongoing information on regional trends of antibiotic resistance
      prevalence to pneumococci, a cross selectional survey was conducted on a large
      representative sample of children attending day-care centers. Children were
      analyzed in spring (n = 378) and autumn (n = 379) for nasopharyngeal carriage.
      Streptococcus pneumoniae was detected in 149 children (39.4%) in Spring and 204
      (59.8%) in Autumn. Half of these isolated strains showed penicillin insensitivity
      or resistance. A high proportion of children (43.6% in spring and 47.5% in
      autumn) had been treated with antibiotics during the 3 months prior to sample
      collection; 21.6% of isolated strains were serotype 6B, 20.1% type 23F, 18.9%
      type 19A and 19F, 11.5% type 14. Reduced susceptibility was frequently noted in
      serotype 23F, 14 and 19F, representing 93%, 94% and 46% of identified serotypes,
      respectively. Acquisition of a strain of PRP was correlated with prescription of
      antibiotics during the previous three months (p < 0.05). This type of survey on
      children in day-care centers can contribute to the understanding of regional
      variations in antibiotic resistance and provide information for epidemiological
      surveillance.

PMID- 10418023
TI  - [Continuous versus intermittent cefepime infusion in critical care. Preliminary
      results].
AB  - The bactericidal activity of beta-lactams is time-dependent, and the time spent
      above the MIC (T > MIC) is the best predictor of efficacy. A prospective,
      randomized, open-label study was conducted in intensive care unit (ICU) patients
      with gram-negative rod infections to compare the efficacy of cefepime given as a
      continuous versus an intermittent infusion. Of the 18 patients included to date,
      14 had severe pneumonia and four bacteremia. All patients received amikacin, 15
      mg/kg/d, and cefepime, 4 g/d. Patients were randomized to cefepime administration
      as a continuous infusion (Group 1, n = 9) or as an intermittent infusion (Group
      2, n = 9, 2 g every 12 h). No significant differences were found between the two
      groups for age, sex, initial infection, IGS II score (46 vs 48, NS) or the MIC of
      the gram-negative organism. Mechanical ventilation and hospital stay durations,
      recovery rates, and pharmacokinetic parameters (24-h AUIC, 12-h AUIC, T > MIC,
      and T > 5 x MIC) were compared in the two groups using the chi-square and Mann
      Whitney tests. P values < 0.05 were considered statistically significant. There
      were no significant differences for mechanical ventilation duration, recovery
      rate, hospital stay duration (34 vs 36 days, NS), 24-h AUIC (624 vs 473, NS), or
      the 12-h AUIC (235 vs 238, NS). There were two interesting findings: T > MIC was
      significantly (P < 0.05) higher in Group 1 (23.84 +/- 0.2) than in Group 2 (20.7
      +/- 3), and T > 5 x MIC was also significantly (P < 0.01) higher in Group 1
      (23.61 +/- 0.6) than in Group 2 (16.6 +/- 6). Although clinical outcomes were
      similar in the two groups, it is reasonable to assume that the longer time spent
      with a cefepime level above the MIC in the continuous infusion group was
      associated with a more stable bactericidal effect.

PMID- 10418024
TI  - [Pharmacokinetics of fusidic acid in patients with seriously infected burns].
AB  - The pharmacokinetics of fusidic acid (FA) were studied in 10 infected severe
      burns patients (35 +/- 5 yrs, 81 +/- 17 kg) i.e. 43 +/- 10% in 3rd degree.
      Treatment was given at the dose of 500 mg/8 hours (2-hour infusion). The kinetics
      of FA were evaluated on D1 (1st infusion) and at steady state on D4 (10th
      infusion), each sequence involving 9 whole blood samples. Samples were assayed by
      high-performance liquid chromatography. Data were analysed by a non-compartmental
      method. Mean duration of treatment, considered effective in all cases, was 5.9 +/
      2.1 days. The systemic safety of FA was felt to be good. Kinetic analysis
      revealed the existence of significant differences between D1 and D4 concerning
      the parameters Cmax, Cmin, AUC, Cl and Vss. These events are attributable to the
      non-linear nature of the human kinetics of FA. Accumulation ratios R1 and R2 did
      not differ i.e. 1.51 +/- 0.25 and R2 = 2.44 +/- 0.68. Kinetic modelling based
      upon the experimental tracing obtained on D1 revealed good coincidence of the
      predictive tracing in relation to data determined on D4. The dosage algorithm of
      500 mg/8 hours was microbiologically satisfactory with Cmin measured on D1 and at
      steady state constantly greater than the MIC of the main organisms concerned (<
      to 2 micrograms/ml). Reduction in the parameters Cmax and AUC in comparison with
      a group of healthy subjects ultimately led to shortening of the mean T1/2 of FA.
      In the absence of impaired liver function, this is attributable to the known
      increase in hepatic clearances in burns patients and, to a certain extent, to the
      existence of translesional extra-hepatic clearance, which could contribute to the
      success of treatment.

PMID- 10418025
TI  - [Evaluation of allergic-type reactions to antibiotics and rapid immunotherapy].
AB  - Adverse effects of medications, most notably antimicrobials, are becoming
      increasingly common and raise difficult challenges in the area of clinical
      pattern definition (wide variety of symptoms, polypharmacy in many cases),
      diagnosis, and methodology (need for a rapid diagnosis, frequent obscurity of
      causative mechanisms, and less than ideal reliability of laboratory techniques).
      Sixty patients were treated by rush immunotherapy to one or more antimicrobials.
      The pretreatment evaluation included oriented history taking, skin tests, blood
      cell counts, IgE assays, and cell activation tests (basophils and lymphocytes).
      The results of this study confirm the usefulness of skin tests (intradermal,
      prick, or patch tests), which provided etiological orientation in 54 of the 60
      cases. They also provide additional evidence of the lack of reliability of
      currently available in vitro tests (only 29 of the 60 tests were positive).

PMID- 10418027
TI  - [Evaluation of Hemofast MRSA for identification of Staphylococcus aureus and
      detection of methicillin-resistance staphylococci, directly in blood culture
      broths].
AB  - The newly developed Hemofast MRSA system for Staphylococcus aureus identification
      and methicillin-resistant staphylococci (MRS) detection in blood culture broths
      was evaluated in 106 Bactec broths containing grapelike clusters of Gram-positive
      cocci. All 26 S. aureus positive broths were correctly identified by Hemofast
      MRSA within two hours, and 81% were identified within one hour. Sensitivity and
      specificity were both 100%. Accuracy of MRS detection was 100%, i.e., no
      discrepancies versus the agar diffusion method were found. When the 28 broths
      containing coagulase negative staphylococci (CNS) were tested using an inoculum
      ten fold larger than for S. aureus testing, a number of discrepancy were
      recorded. For 49 other broths containing CNS, accuracy was 98.5% when the test
      was interpreted based on the growth rate of the strain, according to the
      manufacturer's instructions. One broth containing S. epidermidis strain
      susceptible yielded a false result with Hemofast MRSA, indicating that it
      probably contained a contaminant. The other discrepancies occurred with specimens
      containing mixed populations with CNS or a Micrococcus strain. Most (85%) results
      were available within 4 hrs 30 min, irrespective of the S. aureus or CNS strains.
      Avoiding the isolation step on agar, Hemofast MRSA saves 24 to 48 hours, thus
      allowing earlier antistaphylococcal treatment.

PMID- 10418026
TI  - [Value of a rapid screening technique for vaginal carriage of group B
      Streptococcus during hig-risk pregnancies].
AB  - Vaginal colonization by Group B streptococci (GBS) during pregnancy is associated
      with lige-threatening neonatal infections acquired during passage through the
      birth canal. Factors associated with an increased risk of GBS transmission to the
      neonate include prematurity, premature spontaneous rupture of the membranes
      before 37 weeks of gestational age, prolonged (> 12 h) rupture of the membranes
      at full term, fever in the mother, multiple pregnancy, and a history of GBS
      infection. A study was conducted to evaluate the performance characteristics of a
      rapid GBS screening test comparatively with conventional microbiological
      cultures. The 113 high-risk women admitted for delivery to the obstetrics
      department of the Charleville-Mezieres Hospital from January to May 1998 were
      included in the study. Vaginal specimens were examined by both the Strep B OIA
      test (International Microbio) and by conventional culturing. Comparison of the
      results of these two methods showed that sensitivity and specificity of the Strep
      B OIA test were satisfactory. The Strep B OIA test is a rapid test suitable for
      use in emergency situations. A positive result should lead to intrapartum
      prophylactic antimicrobial therapy.

PMID- 10418029
TI  - [Retrospective study of the value of the RIBA-3 test in 68 patients with
      discordant serologies with regard to hepatitis C obtained with third generation
      ELISA tests. Is there still a value in RIBA-3?].
AB  - The aim of the present study is to evaluate the ability of RIBA-3 to resolve
      cases with controversial ELISA results, since modifications have been introduced
      by the manufacturer in July 1997 to analyse immunoblot patterns. Sera from 68
      patients are studied: 49 controversial cases Ortho/Murex, 17 Ortho/Abbott and 2
      cases tested by the three ELISA kits. Indeterminate patterns by ELISA assays
      remain unresolved in 65% of the samples. RIBA analysis performed in patients with
      controversial results Ortho/Murex seems to reveal a lack in sensitivity of the
      Murex kit, but does not show differences in the specificity between these two
      immunoassays. The RIBA patterns among the samples with Ortho/Abbott controversial
      results do not demonstrate any discrepancy in the sensitivity of these ELISA
      tests but it appears that Ortho could be less specific. Our data need to be
      further confirmed by the analysis of more samples. At last, when the ELISA result
      is included in the grayzone, the RIBA pattern is generally indeterminate and it
      is negative in other cases. Finally, the controversial ELISA results, that are
      mainly found in patients with severe immunosuppression, remain indeterminate
      depending on the RIBA test. Moreover, the immunoblot is less sensitive and more
      expensive than any other HCV ELISA test, so there is no convenience to use it for
      confirmation of a preliminary positive or indeterminate screening.

PMID- 10418028
TI  - [Comparison of different techniques for the detection of heterogeneous resistance
      to methicillin in Staphylococcus aureus].
AB  - The methods for detection of methicillin resistant S. aureus (MRSA) can fail to
      detect resistance because phenotypic expression is often heterogeneous (40% of
      strains). Seventy four strains of S. aureus [4 methicillin susceptible strains,
      10 homogeneous MRSA (Ro) and 60 heterogeneous MRSA (Rh)] were isolated from
      different french hospitals in Paris. These strains were tested by different
      methods: oxacillin screen plate with 6 micrograms/ml oxacillin and 4% NaCl, agar
      diffusion method with 5 micrograms oxacillin disk tested either at 30 degrees C
      on Mueller-Hinton medium or at 37 degrees C on Mueller-Hinton plus 5% NaCl, BBL
      Crystal MRSA ID system tested with two inocula (0.5 and 1 McFarland equivalent
      bacterial suspension) at 37 degrees C for 4 h and 5 h. Dot-blot hybridization was
      performed under stringent condition with the mecA probe. The accuracy of the
      different methods for the detection of methicillin resistance is equivalent,
      except for the BBL crystal system with a 0.5 McFarland inoculum wich detects the
      resistance with an accuracy of 86% for Ro strains and 69% for Rh strains. In
      other respects, there was a close correlation with the detection of the
      phenotypic resistance and the presence of mecA gene. So this study demonstrates
      that these various methods can be used for the detection of methicillin resistant
      S. aureus. For a rapid detection (below 5 h) the BBL crystal system with a 1
      McFarland inoculum can be used; the agar diffusion method remains a good method
      provided some conditions (inoculum, incubation temperature, addition of salt,
      incubation period); the oxicillin screnn plate is a very attractive method for it
      is easy and reliable.

PMID- 10418030
TI  - [Utilization of Bichrolatex albicans test for the rapid identification of Candida
      albicans in blood culture bottles in fungemia: preliminary results from a
      multicenter study].
AB  - In patients with fungemia, reliable and rapid identification of the causative
      organism has a large impact on treatment decisions. The Bichrolatex albicans test
      (Fumouze, Levallois-Perret, France) allows rapid identification of Candida
      albicans in colonies. Its usefulness for identifying C. albicans in liquid blood
      culture media was evaluated using a previously published protocol. Ninety-seven
      blood culture bottles from 86 fungemia episodes in 13 study centers were studied.
      C. albicans contributed 52% of the fungemia episodes, whereas C. glabata and C.
      tropicalis contributed 15% and 11.5%, respectively. The 48 bottles containing a
      yeast other than C. albicans were all negative by the Bichrolatex albicans test.
      Of the remaining 48 bottles, which were positive for C. albicans, 33 produced
      marked to moderate agglutination and 15 were negative. In one case of mixed
      fungemia (C. albicans plus C. glabata), weak agglutination was seen. Sensitivity
      of the test was 69%, negative predictive value was 76%, specificity was 100%, and
      positive predictive value was 100%. Because of its limited sensitivity, the
      Bichrolatex albicans test cannot be recommended as a confirmation test for C.
      albicans fungemia. In contrast, the specificity and positive predictive value of
      the test are excellent.

PMID- 10418031
TI  - [Susceptibility of Clostridium difficile to metronidazole using the E-test:
      effect of the culture medium].
AB  - The treatment of intestinal Clostridium difficile infections rests on
      administration of either a glycopeptide or metronidazole. Given the current
      shifts in resistance patterns of anaerobes to antimicrobials, a study of the
      susceptibility of C. difficile to metronidazole was timely. The objective of this
      study was to evaluate the influence of the culture medium on the Minimal
      Inhibitory Concentration (MIC) of metronidazole as determined using the E-test.
      Thirty-one strains were grown on three different media supplemented with 5% horse
      blood, namely Columbia agar, Wilkens Chalgren agar, and Brucella agar. Results
      were compared to those obtained using the reference agar dilution method (ADM).
      As recommended by the French Society for Microbiology, susceptibility was defined
      as an MIC < or = 4 mg/L. When used on strains susceptible by the ADM, the E-test
      yielded lower values than the ADM with all three media. Furthermore, findings
      suggest that E-test results obtained with strains whose MIC is in the 4 to 8 mg/L
      range by the ADM should be interpreted with caution and, in some cases, tested
      using the ADM.

PMID- 10418032
TI  - [Selection of virulent mutants of Streptococcus pneumoniae. Utilization of a
      murine model of septicemia].
AB  - Genetic construction of virulence deficient mutant is a strategy to analyse
      virulence genes of Streptococcus pneumoniae and was used to virulence factors as
      capsule, pneumolysin, autolysin and PspA. We perform a model allowing the in vivo
      positive selection of virulent S. pneumoniae mutants. Mice which are the most
      susceptible animals to pneumococcal infection, offer the best model for screening
      virulent S. pneumoniae. Indeed, after intraperitoneal injection of bacterial mix
      which was composed to a lot of avirulent bacteria (6 log10 CFU per mouse) (V1015
      strain, DL50 = 7.05) and few virulent pneumococci (1 to 2 log10 CFU per mouse)
      (P4241 strain, DL50 < 1), mice cleared all avirulent bacteria but not virulent
      pneumococci. Thus, mice dead in 3 to 4 days with septicaemia and positive
      hemoculture contained only virulent strain. This model was validated by in vivo
      selection of a virulent mutant (V1042, DL50 = 4.1) which was obtained after
      transformation of avirulent strain V1015 with the genomic fragment of virulent
      strain P4241. Our model of screening was the only one allowing detection of
      virulent S. pneumoniae mutants. This new genetic strategy which consisted in gene
      addition and used mouse as selection agent, could be used to discover new
      virulence genes required to in vivo bacterial development.

PMID- 10418034
TI  - [A case report of post-rubella myelitis in an adult].
AB  - Neurological complications following rubella are only rarely encountered. We
      report a case of isolated myelitis. A 44-year-old healthy female suffered from an
      erythematous macular rash which rapidly cleared. However, the following days,
      dysuria initiated hospitalization. On admission, she was febrile but alert and in
      normal mental status. General physical examination was quite unremarkable. Four
      days later, she suffered from acute urinary retention, fecal retention and
      vaginal hypoesthesia. Routine laboratory data, chest skull and spinal column X
      rays were unremarkable. The sterile cerebrospinal fluid contained 30
      lymphocytes/mm3, 0.48 g/ml of protein but normal amount of glucose. Rubella
      antibody titers showed a significant elevation and specific IgM were detected by
      immunocapture. Improvement was rapid and recovery was uneventful except a mild
      vaginal hypoesthesia that persisted 5 weeks later. Diffuse myelitis occurring
      shortly after rubella vaccination have also been described. The
      immunopathological mechanisms by which involvement of the nervous system occurs
      is far from clear. Little is known about the pathogenesis of post-vaccination
      myelitis and although the mecanism of sensitization and the specific neural
      antigens are not known, post-infectious and post-vaccinal myelitis are thought to
      share a common pathogenic basis.

PMID- 10418033
TI  - [Prenatal diagnosis of viral infections. A two year study in Strasbourg].
AB  - We report here the results of a 2-year study on the prenatal diagnosis of viral
      infections in Strasbourg. This screening was carried out by virus isolation, by
      PCR assay, or by detection of IgM fetal antibody for 98 pregnant women at risk of
      transmitting one of the viruses that causes fetal disease such as parvovirus B19
      (B19), Herpesviruses [cytomegalovirus (CMV), varicella-zoster virus, herpes
      simplex virus] and rubella virus. A viral etiology was proven in 7 out 98 cases:
      PCR applied to B19 DNA detection was positive in 5 amniotic fluids (AF), 2 fetal
      serums and one ascitic liquid. The diagnosis of 2 cases of CMV infection was
      obtained by both PCR and virus isolation in AF from twins fetuses. The detection
      of specific IgM in maternal serum or fetal serum is useful to achieve the
      diagnosis but serological tests on other samples have no efficiency. No virus was
      found in any other specimen, but the genome of Toxoplasma gondii was detected by
      PCR in 1 of 17 AF samples analyzed at the Institut de Parasitologie. These
      findings show that PCR assay is a sensitive method for the positive diagnosis of
      intrauterine infection and promises to careful follow-up of the pregnancy.

PMID- 10418035
TI  - [PCR SSCP study of an echovirus 30 meningitis outbreak].
AB  - Between April and October 1997, 21 children of 4 days to 13 years old were
      admitted to the Pedatric Unit of Aulnay Sous Bois's Hospital for viral
      meningitidis. The number of white blood cells in the cerebrospinal fluid (CSF)
      was between 1 and 612 cells/mm3, with, on an average, 56% of segmented cells, 34%
      lymphocytes and 34% monocytes. Proteins and glucose of CSF were standard. One CSF
      was normal. Viral meningitidis was confirmed by viral culture of CSF onto MRC5.
      Enterovirus were identified by direct immunofluorescence (Monoclonal Mouse Anti
      Enterovirus, Dako). Serotyping (Enterovirus antisera, Eurobio, Trousses 4)
      identified an echovirus 30 in all cases. A highly conserved 154 bp sequence at
      the 5'non-coding region was studied by reverse transcription-polymerase chain
      reaction (RT-PCR) followed by single-strand conformation polymorphism (SSCP)
      (GenPhor, Pharmacia) analysis. Two dominant SSCP patterns were observed: the
      first contained 4/21 strains and the other 10/21 strains. The SSCP patterns of
      the 7 other strains were different. These results show that 2 echovirus 30
      dominant clones were responsible of viral meningitidis admitted to the Pediatric
      Unit of Aulnay Sous Bois's hospital, between april and october 1997. The PCR-SSCP
      of the 5'non-coding region of echovirus 30 is a convenient, simple, reproducible
      epidemiologic method and it's easily applicable in a general hospital.

PMID- 10418036
TI  - [Imported dengue: study of 44 cases observed from 1994 to 1997 in 9 university
      hospital centers. Infectio-Sud-France group].
AB  - Imported dengue is increasingly observed in non endemic countries. We report a
      retrospective study of 44 cases of dengue fever diagnosed in nine french
      university hospitals between 1994 and 1997. The patients were aged between 13 and
      67 years. Most of them were tourists and had been traveling for a few weeks, in
      French West Indies and French Guyana (18), South-East Asia (10), India (7) or
      Polynesia (4). Only, two contracted the disease in Africa. The onset of symptoms
      preceded the return or followed it within 7 days. The most frequent clinical
      presentation was a febrile and painful syndrome. Cutaneous manifestations (rash
      or macular exanthem) were observed in 59% of cases, digestive symptoms in 50%,
      pharyngitis and/or cough in 25%, microadenopathy in 20%, moderate mucous
      haemorrhagic manifestations in 16% and neuropsychiatric manifestations in 14%.
      The common biological abnormalities were thrombocytopenia (84%), leukopenia
      (59%), and elevated transminases (57%). The diagnosis, orientated by negativity
      of malaria smears, the knowledge of an epidemic in the visited country, or
      occurrence of similar cases in the entourage, were argued by serological results:
      presence of anti-DEN IgM in 25 cases, serological conversion (anti- DEN IgG) in 7
      cases or very high seropositivity (anti-DEN IgG > 1/1280) in 12 cases. No virus
      isolation was obtained.

PMID- 10418038
TI  - [Polymorphism of protease genes in patients infected with HIV-1 and response to
      therapy including a protease inhibitor].
AB  - Protease inhibitors (PIs) are recently introduced drugs that have improved the
      survival of HIV-infected patients when given in combination with two reverse
      transcriptase inhibitors. The HIV-1 protease gene is naturally highly
      polymorphic. Selection pressure due to IP use can result in major or minor
      resistance-associated mutations (RAMs). This study investigated whether presence
      before IP therapy of minor RAMs on the protease gene predicts the virological
      response. Of the 58 PI-naive patients included in the study, 12 had received two
      nucleoside reverse transcriptor inhibitors, 14 had received indinavir, 16
      ritonavir, and 28 saquinavir-SGC. Viral load was measured on D0 (prior to PI
      initiation) and at M3 and M6 (Roche Monitor 1.5 with 200 and 20 copies/ml as the
      thresholds). The protease gene was fully sequenced on D0 using the ABI 377
      automatic sequencer after RNA amplification by nested RT-PCR. None of the viral
      strains exhibited major mutations, but 57 of 58 (98%) had at least one minor
      mutation (median number of substitutions, 4), 60% had 1 to 4 substitutions, and
      40% had 5 to 9 substitutions. Substitutions seen with a prevalence > 20% were
      located at codons 15, 35, 37, 41, 63, and 77. Numbers of substitutions at M3 and
      M6 were not correlated with viral load or the nature of the PI used, and neither
      were they significantly different between patients with more or fewer than 20
      copies/ml. These data suggest that the protease genotype at PI initiation does
      not predict the efficacy of a regimen including a PI and is of no assistance in
      deciding whether or not to include a PI in a triple combination regimen.

PMID- 10418039
TI  - [IFN-tau, a new interferon type I with antiretroviral activity].
AB  - Type I interferon (IFN) such as IFN-alpha have demonstrated relative efficiency
      in HIV-infected patients with Kaposi's sarcoma. Nevertheless, their clinical uses
      have been restricted by several major side effects. IFN-tau is a non-cytotoxic
      type I IFN. In the present manuscript, we described its in vitro effects towards
      HIV replication and its mode of action. IFN-tau is a potent antiviral molecule
      that interferes with an early step of HIV biological cycle. Moreover, it induces
      IL-6 synthesis by macrophages, and this cytokine favorises its antiviral
      efficacy, probably by amplifying the induction of 2', 5'OAS and RNase L.
      Altogether, these results confirm the interest of IFN-tau as adjuvant therapy in
      HIV infection, and more particularly in HIV/HCV-infected patients.

PMID- 10418037
TI  - [Seroprevalence of hepatitis B and C viruses in a psychiatric institution].
AB  - Many patients admitted to psychiatric institutions have a history of risk factors
      for contamination with the hepatitis B and C viruses (HBV and HCV). Immunization
      policies for psychiatric institution patients are not widely know. A study
      conducted in a 600-bed psychiatric institution in Paris, France, to evaluate the
      proportion of potentially contaminating patients at admission, as well as
      immunization use in HBV-negative patients. Serologic markers for the HBV and HCV
      were looked for prospectively in all patients admitted over a two-month period.
      Immunization use was evaluated in the patients who had a first serologic test in
      1995 or 1996 and follow-up tests until the end of 1997. The prospective part of
      the study demonstrated preadmission exposure to the HBV in 23.0 +/- 6.0% of
      patients. This proportion was larger in men (26.0%) than in women (14.8%),
      although the difference was not statistically significant (P = 0.10). Four
      patients (2.0%) tested positive for the HbS Ag. Among the HBV-negative patients,
      13.0% received the vaccine; all had protective antibody levels. These patients
      were younger and more likely to be first-time admissions (18.4% vs 3.6%, P <
      0.01). HCV seroprevalence was 6.0%. Serologic tests for the HBV were requested
      for 327 patients between January 1995 and december 1996. Among the patients who
      were seronegative at admission and received follow-up at the study hospital, only
      13.8% were immunized at this hospital. Of the HCV-positive subjects, 63.3% were
      also HBV-positive. None of the HCV-positive HBV-negative subjects received
      immunization subsequently. Six to eight per cent of patients admitted to the
      study hospital are potentially contaminating for the HBV or HCV. The level of
      hepatitis B vaccine use is too low, particularly in high-risk patients. These
      data indicate a need for policies aimed at effectively preventing HBV and HCV
      transmission (information, education, immunization campaigns), both during the
      psychiatric institution stay and after discharge.

PMID- 10418040
TI  - Interpretation of high levels of HIV-1 RNA in the cerebrospinal fluid (CSF) using
      amplicor HIV-1 monitor test.
AB  - A retrospective study of 19 cerebrospinal fluid (CSF) specimens from 14 HIV
      positive subjects with subacute encephalopathy, neuropathy, or unexplained
      peripheral myelopathy was done comparatively with plasma specimens collected on
      the same day and tested in the same run as the corresponding CSF specimen. A
      single patient had a high HIV RNA level in CSF as compared to plasma (CSF/plasma
      ratio > 10), which seemed correlated with the clinical course. Further studies
      are needed to confirm that a high CSF/plasma HIV RNA ratio is associated with
      greater symptom severity.

PMID- 10418041
TI  - [Experience with nevirapine taken once daily in 93 HIV-infected patients].
AB  - Due to its long half-life (25-30 hours) the once daily administration of
      nevirapine would appear logical but we do not have data regarding the
      tolerability and efficacy of this schedule. We have therefore tried to evaluate
      this schedule in 93 HIV-infected patients beginning a treatment containing
      nevirapine. The tolerability of once daily nevirapine was similar to the usual
      schedule with 15% of mucocutaneous allergy. The immunologic and virologic
      efficacy of once daily nevirapine was confirmed with a mean RNA HIV decrease of
      1.4 log, 1.3 log, 1.1 log and 1.3 log at M1, M3, M6 and M9 respectively. The best
      results were observed in naive patients. Residual plasma concentration of
      nevirapine was performed in 35 patients with a mean value of 3.8 mg/l.

PMID- 10418042
TI  - [AIDS with inaugural Pneumocystis pneumonia pneumonia. Impact of triple
      antiretroviral therapy].
AB  - To evaluate the impact of the advent of triple combination therapy for AIDS on
      the nature of the first AIDS-definiting event, a retrospective study was
      conducted in the infectious diseases department of the Croix-Rousse Teaching
      Hospital in Lyon, France. The 280 patients entered in the AIDS registry of the
      department between January 1, 1994, and August 31, 1998, were studied. In 1994
      and 1995, 33.05% of registry entries were for a first AIDS-defining event. After
      the introduction of triple combination therapy during the second half of 1996,
      this proportion increased significantly from 30.1% for the period between January
      1, 1994, and June 30, 1996, to 56.7% for the period from July 1, 1996 to August
      31, 1998 (P = 0.00003). The proportion of Pneumocystis carinii pneumonia (PCP)
      occurring as the first AIDS-defining event also rose significantly between these
      two periods, from 47.5% to 82.1% (P = 0.002). These data indicate that triple
      combination therapy may be associated with an increase in the proportion of first
      AIDS-defining events, most notably of inaugural PCP. National data support this
      possibility. It would be of interest to conduct early screening campaigns for
      AIDS in order to allow early effective therapy.

PMID- 10418043
TI  - [Secondary prophylaxis for herpes zoster wi oral acyclovir in HIV patients].
AB  - We studied 39 AIDS patients from 1989 to 1996, with previous history of herpes
      zoster. Twelve of them received acyclovir (ACV) secondary prophylaxis. There were
      31 males and 8 females, mean age 33.9 years (19-60) during first herpes zoster.
      Transmission was sexual in 71.8%. Among these 39 patients, 78 herpes zoster
      episodes occurred. Median CD4 lymphocytes was 18/mm3 (0-232) among the 12
      patients with ACV prophylaxis. Mean posology of ACV was 2,400 mg (1,600-4,000)
      per day, during mean 10 months (median 4 months). ACV prophylaxis was used
      because of high frequence of herpes zoster (more than 4) (4 cases), neurologic
      complications in 4 cases (1 myelitis, 1 myeloradiculitis, 1 vascularitis and 1
      meningo-encephalitis), disseminated herpes zoster in 4 cases and one hyperalgic
      zoster. Ten from these 12 patients occurred no zoster recurrence. Among patients
      without prophylaxis, zoster recurrences were more frequent at 12 months (68%
      versus 22% among patients with prophylaxis). This prophylaxis seems to be
      interesting, particularly in deep immunocompromised patients (CD4 < 50/mm3) with
      serious herpes zoster or frequent recurrences (more than 4). However, since
      protease inhibitors treatments, zoster incidence is decreasing in HIV+ patients.
      This prophylaxis will probably be less usefull than before.

PMID- 10418044
TI  - [A new outbreak of trichinosis: 117 cases in the Midi-Pyrenees region.
      Epidemiology, clinical features and management].
AB  - Trichinellosis is an uncommon condition that is nevertheless a continuing problem
      as shown by two recent outbreaks in our region. The clinical features are
      reviewed briefly. The physical and laboratory test findings in the 117 patients
      affected during the first outbreak (February 1998) are reported, as well as the
      methods used to treat these patients.

PMID- 10418046
TI  - [Epidemiology of fungemia in a university hospital; therapeutic incidence].
AB  - Twenty-two candidemia happened in our hospital from January 1997 to may 1998. We
      studied the clinical evolution of the patients and the sensitivity of the yeasts
      to antifungal therapy (Fungitest and E-Test method). We found 11 Candida albicans
      (CA), 10 Candida non albicans (CNA) (3 C. glabrata, 2 C. parapsilosis, 4 C.
      tropicalis, 1 C. krusei) and 1 Saccharomyces cerevisiae. The mean age of the
      patients was 56.4 years. There were 13 men and 9 women. We found one group of 8
      (36.4%) oncohematological patients, one group of 8 (36.4%) patients with
      abdominal surgery, one group of 3 (13.6%) children and one group of 3 adults
      (13.6%) who spent more than 10 days in an intensive care unit. Ten times, these
      candidemia were associated with bacteriemia, 4 times with several bacteria. Three
      patients died because of the candidemia, 2 times with CNA and one time with CA.
      There wasn't any resistance to amphotericin B or ketoconazole. All the CA and 3
      CNA (30%) remained sensitive to the four antifungal drugs we used (amphotericin
      B, ketoconazole, fluconazole, itraconazole). The 3 C. glabrata and the C. krusei
      were resistant or limit to fluconazole. Since the generalization of the use of
      fluconazole, the epidemiology is marked by the emergence of new strains of CA
      with high level of resistance to azols, and of CNA. In our hospital, the CA
      remain preponderant and only the CNA are resistant to fluconazole making
      difficult the choice of empiric treatment for serious fungemia.

PMID- 10418045
TI  - [Disseminated infestation of Enterocytozooon bieneusi a an HIV-infected patient].
AB  - An HIV-positive patient developed disseminated Enterocytozoon bieneusi infection.
      The parasite was identified in stool, duodenal biopsy, nasal discharge, and
      sputum specimens using transmission electron microscopy. Albendazole therapy
      failed to improve the symptoms or eradicate the parasite. The patient survived
      for nine months after the diagnosis of E. bieneusi infection.

PMID- 10418047
TI  - [Can one use probabilistic protocols for antibiotic therapy in intensive care
      units?].
AB  - Due to a large spectrum, empiric antibiotics treatments participate to the
      increase in bacterial resistance. In order to improve its indications, the
      implementation of therapeutic guidelines in an ICU was studied. Empiric therapy
      was administered in 30% of the 178 patients receiving antimicrobial agents. Large
      spectrum drugs were prescribed in 26% of empiric treatments. The mean duration of
      empiric antibiotics administration was 3.2 days. It was concluded that it was
      possible to use guidelines of empiric antibiotic in an intensive care unit.

PMID- 10418048
TI  - [Lower respiratory infections: when to treat at home? When to hospitalize? ECRIR
      Group].

PMID- 10418049
TI  - [Prescription and use of antibiotics in ambulatory care. Drug Agency].
AB  - OBJECTIVE: This study was conducted to describe changes in prescription practices
      outside the hospital, to evaluate the adaptation of such prescriptions to current
      scientific knowledge, and to compare medical practices in France with those in
      other European countries. METHODS: Data were collected from several sources:
      analysis of the literature, surveys conducted in the Loiret department and in the
      Rhone-Alps region, ten-year healt surveys (INSEE), data from the Sentinel
      network, sales statements from pharmaceutical firms, the Permanent Survey of
      Medical Prescription (EPPM) of the Medical Information and Statistics (IMS) firm.
      Comparisons between France, the United Kingdom and Germany were conducted by the
      French Medicine Agency's Pharmaco-economic Studies and Information Department
      using data furnished by the IMS firm and by pharmaceutical firms. RESULTS: In
      France, antibiotic sales increased by a mean annual rate of 2.1%, expressed in
      antibiotic units, and 2.6%, expressed in turnover (manufacturer price) between
      1991 and 1996. The majority of these antibiotics were prescribed for respiratory
      and ENT infections with a presumed viral etiology such as rhino-pharyngitis and
      acute bronchitis. The results of the different surveys were in agreement showing
      that antibiotic prescriptions are made in approximately 40% of all consultations
      for rhino-pharyngitis and in 80% of those for acute bronchitis. Antibiotics were
      prescribed in more than 90% of cases of pharyngitis whatever the age of the
      patient. The situation was different for acute middle ear infections as the
      number of consultations has remained relatively unchanged over the last 10 years
      while antibiotic prescriptions have strongly increased, reaching 80% of the
      consultations. The number of consultations for pharyngitis and acute rhino
      pharyngitis appears to be greater in France than in the United Kingdom and in
      Germany. Likewise, the proportion of patients using antibiotics after consulting
      for presumed viral conditions would be higher in France with different antibiotic
      classes being used. CONCLUSIONS: There is a gap between official guidelines
      (product description documents, therapeutic information documents, good practice
      guidelines, consensus conferences) and the state of current practices. Excessive
      and poorly-adapted antibiotic prescription favors the disturbing phenomenon of
      resistance which is all the more alarming because the emergence of resistant
      strains is difficult to predict and concerns bacteria causing the most common
      infections. To improve medical practices and achieve a persistent reduction in
      the use of antibiotics for viral infections, validated recommendations should be
      distributed to physicians. An effort should be made to prescribe the most
      appropriate active substance at optimal dose and treatment duration to limit the
      development of bacterial resistance. In addition, patients and the general public
      should be informed of the absence of any beneficial effect and the individual and
      collective risks involved in using antibiotics for viral infections in order to
      help them better understand and comply to their physician's prescription.

PMID- 10418050
TI  - [Paraneoplastic Cushing's syndrome and small cell bronchial carcinoma].
AB  - Approximately 30% of small-cell bronchogenic cancers are associated with
      hypersecretion of ACTH. However, in most cases, there is no clinical expression.
      When a paraneoplastic Cushing syndrome occurs, it is an independent factor of
      poor prognosis. Management is extremely complex. Treatment must be based on high
      dose inhibitors prior to chemotherapy. Opportunistic infections, often fungal
      infections, are the main complications, even outside periods of aplasia, and
      cause significantly earlier mortality.

PMID- 10418052
TI  - [Inhaled corticosteroid therapy in mild and moderate persistent asthma.
      Acceptability of a new inhalation system: the jet].
AB  - The objectives of this study were to assess the acceptability and efficacy of Jet
      (a metered dose inhaler with a 100 ml chamber giving 250 micrograms
      beclomethasone dipropionate per puff) in patients with mild to moderate asthma
      using a dose-for-dose schedule in substitution for their standard metered dose
      inhaler with or without an inhalation chamber. An open trial was conducted over 5
      weeks in 356 asthma patients treated with inhaled corticosteroids at a mean 914
      +/- 198 micrograms/24 h dose. beta 2-agonists were used by all patients, either
      systematically (prescription) or as needed. Prior to the study, 27% of the
      patients used a standard metered dose inhaler with a large-volume inhalation
      chamber and 73% used a standard metered dose inhaler alone. The rate of
      nocturnal, early morning, and diurnal symptoms and cough decreased by 31.4, 33.4,
      46.9, and 37.0% respectively and the variability of peak expiratory flow rate
      fell from 2 +/- 0.08% to 0.9 +/- 0.02% in the group using the metered dose
      inhaler with the chamber and from 1.3 +/- 0.04 to 0.5 +/- 0.01% in the group
      using the standard metered dose inhaler. The investigators determined that
      treatment efficacy was good or excellent in 94.8%. These findings should be
      confirmed by studies comparing Jet directly with other inhalation chamber systems
      or with standard metered dose inhalers. For 97.5% of the patients, it was easy to
      learn to use Jet and 88.2% of the patients felt no discomfort when using Jet;
      64.8% of the patients stated they experienced clinical improvement. At the end of
      the trial, 77.9% of the patients (76.3% of those who used the inhalation chamber
      during the study and 78.4% of those who used the metered dose inhaler alone)
      stated they preferred Jet over their prior system.

PMID- 10418051
TI  - [Community-acquired pneumonia caused by Staphylococcus aureus in non-HIV infected
      adult patients].
AB  - Staphylococcus aureus is the sixth frequent cause of community-acquired
      pneumonia. We report 19 cases of staphylococcal pneumonia in 3 women and 16 men,
      mean age 55 years. Predisposing factors were: age > 65 years, alcoholism, chronic
      bronchopulmonary disease, immunodepression, renal failure, diabetes. The portal
      was usually the respiratory tract. Symptom onset was progressive. Thirteen
      patients had signs of severe disease. Radiology showed localized excavated
      infiltrations in 8 cases, with a pleural reaction in 9. Bacteriological diagnosis
      was made on fibroscopic brushings on pleural fluid. Blood cultures were positive
      in 6 of 16 cases. Meti-S S. aureus was found in 17/19 cases. Outcome was
      favorable in 15 patients. These often severe infections require early antibiotic
      therapy using beta lactams active against S. aureus, combined when necessary with
      another antibiotic.

PMID- 10418053
TI  - [A retrospective study of 53 cases of resectable primary bronchopulmonary cancers
      associated with Pierre Marie syndrome].
AB  - The prognosis of primary lung cancer associated with hypertrophic osteopulmonary
      arthropathy is not well known. Between July 1973 adn August 1995, we cared for 53
      consecutive patients with resectable non-small-cell lung cancer associated with
      osteoplumonary arthropathy. There were 51 men and 2 women, mean age 56 years. In
      83% of the cases the lung cancer was revealed by hypertrophic osteopulmonary
      arthropathy. The tumor generally involved the right lung (n = 38) and the upper
      lobe (n = 35). There was no peripheral or central predominance. Complete tumoral
      resection was performed in 47 patients, incomplete resection in 4 and exploratory
      thoracotomy in 2. The main histologies were adenocarcinoma (50%) and squamous
      cell carcinoma (40%). Among the 51 resected tumors, 27 were grade I, 5 grade II,
      17 grade III and 2 grave IV. Overall 5-year survival was 39%, reaching 51% for
      grade I, 40% for grade II, 27% for grade III and 0% for grade IV. The pulmonary
      manifestations of hypertrophic osteopulmonary arthropathy regressed within the
      first postoperative hours in all the patients whose tumor was resected and in 1
      of the 2 patients who underwent exploratory thoracotomy. AT follow-up, the
      hypertropic pulmonary arthropathy had disappeared in all resected patients except
      1 with a grade I tumor. Tumor recurrence was proven in 18 resected patients, 5 of
      whom also had recurrent osteopulmonary arthropathy. Our results suggest that
      primary lung cancer associated with hypertrophic pulmonary arthropathy has
      characteristic features and that prognosis is comparable with primary lung cancer
      alone.

PMID- 10418055
TI  - [Reexpansion pulmonary edema].
AB  - Reexpansion pulmonary edema is an uncommon complication which sometimes occurs
      after evacuation of a large amount of air or fluid from the pleural space. We
      report two cases that illustrate the diversity of the clinical expression, severe
      in one case and latent in the other. The pathophysiology of reexpansion pulmonary
      edema remains obscure. Increased pulmonary capillary permeability, favored by
      previous atelectatic parenchyma and rapid reexpansion appears to be the main
      cause. Treatment is basically preventive. Curative treatment is based on adequate
      oxygenation and circulation. Lower aspiration pressure and oxygenation were
      sufficient in our patients. Severe clinical prognosis has been reported in the
      literature with a 15 to 20% mortality despite use of mechanical ventilation in
      particularly serious situations.

PMID- 10418054
TI  - [Cyclophosphamide-induced interstitial pneumopathy. Course data of
      bronchoalveolar lavage apropos of a case and review of the literature].
AB  - A patient treated with cyclophosphamide for breast cancer developed functional
      and clinicoradiological signs of sub-acute diffuse interstitial pneumopathy.
      Bronchoalveolar lavage revealed lymphocyte alveolitis. Differential diagnoses
      were excluded and the course was favorable after cyclophosphamide withdrawal. The
      bronchoalveolar lavage results obtained initially and at follow-up and two
      previous lavages reported in the literature demonstrate the importance of this
      examination in the diagnosis of drug-induced pneumopathy.

PMID- 10418056
TI  - Current aspects of the pathogenesis and therapy of Wegener's granulomatosis.

PMID- 10418057
TI  - Young age at onset, renal involvement, and arterial hypertension are of adverse
      prognostic significance in juvenile systemic lupus erythematosus.
AB  - OBJECTIVE: To look for associations between mortality, clinical or laboratory
      data, and age at disease onset in systemic lupus erythematosus patients aged 16
      years or younger at disease onset. PATIENTS AND METHODS: The medical records of
      patients seen at the Clinics Hospital, State University of Campinas, Sao Paulo,
      Brazil, between 1979 and 1995 were reviewed retrospectively. All 59 included
      patients (48F/11M) fulfilled four or more American College of Rheumatology
      criteria for systemic lupus erythematosus. Patients with discold, drug-induced or
      neonatal lupus, or other systemic connective tissue diseases were excluded.
      Patients were studied individually then classified in three groups based on age
      at disease onset, as follows: Group I, < or = 9 years of age; Group II, 10-14
      years of age; and Group III, 15-16 years of age. Clinical and laboratory
      abnormalities and mortality were compared in the three groups. RESULTS: The most
      frequent clinical manifestations were joint symptoms (91.5%), renal involvement
      (71.1%), malar rash (61%), alopecia (61%), fever (59.3%) and photosensitivity
      (52.5%). Laboratory findings included antinuclear antibody in 94.9% of cases. LE
      cells in 71.1%, low serum complement in 65.3%, anti-DNA in 63.4%, hematuria in
      62.7%, and proteinuria in 61%. The mortality rate was 23.7% (9F/5M) overall,
      18.7% in females, and 45.4% in males (P = 0.07). The cause of death was infection
      in eight patients (57.1% of decedents), central nervous system disease in five
      (35.7%), and renal insufficiency in one (7.2%). Disease onset before 15 years of
      age (P = 0.026), renal involvement (P = 0.03), and arterial hypertension (P =
      0.002) were predictive of mortality. Mortality was not influenced by gender or
      race.

PMID- 10418058
TI  - Ro60 ribonucleoprotein inhibits transcription by T3 RNA polymerase in vitro.
AB  - BACKGROUND: Ro60 ribonucleoprotein is a conserved molecule belonging to the
      family of Ro ribonucleoproteins and targeted by autoantibodies produced in
      patients with systemic lupus erythematosus or Sjogren's syndrome. Ro60 plays a
      role in postranscription events, as well as in the nucleocytoplasmic shuttling of
      RNA polymerase III transcripts. OBJECTIVE: To evaluate the in vitro effects of
      Ro60 on T3 RNA polymerase transcription. METHODS: Ro60 ribonucleoprotein was
      affinity-purified from human spleen extracts using 4B-Sepharose linked to anti
      Ro60 monoclonal antibodies. Purified Ro60 was incorporated into the T3 RNA
      polymerase transcription reaction system using pTRI-beta-Actin-human DNA as a
      template. RESULTS: Ro60 inhibited initiation of the transcription process in a
      dose-dependent manner; neither elongation nor termination was affected by Ro.
      CONCLUSION: In vitro, Ro60 appears to inhibit the transcription of a T3 RNA
      polymerase-dependent template.

PMID- 10418060
TI  - Sporadic ulcerative-mutilating acropathy of the foot. Features and therapeutic
      indications.
AB  - Ulcerative-mutilating acropathy occurs as an inherited (Thevenard's disease) and
      a sporadic (Bureau-Barriere syndrome) variant. We report a retrospective study in
      nine patients with the sporadic variant. All nine had painless foot ulcers with
      trophic disorders and severe skeletal alterations. Electrodiagnostic testing
      showed polyneuropathy with sensory disorders in seven patients. Motor conduction
      velocity was normal. Radiological changes were confined to the lower limbs. The
      clinical course and treatment of sporadic ulcerative-mutilating acropathy are
      presented.

PMID- 10418059
TI  - Anti-NuMA antibodies: an uncommon specificity in scleroderma sera.
AB  - BACKGROUND: Serum antibodies in scleroderma patients are generally directed
      against the nucleolus and centromeres. A small proportion of patients have serum
      antibodies to the centrioles and mitotic apparatus. OBJECTIVE: To determine the
      prevalence of serum autoantibodies against the mitotic apparatus in scleroderma
      patients. MATERIAL AND METHODS: Sera from 113 patients with various forms of
      scleroderma were tested for antinuclear antibodies by indirect immunofluorescence
      on HEp-2 cells. The specificity of the antibodies was determined by Western blot.
      RESULTS: Only two scleroderma sera recognized the mitotic apparatus. Western blot
      results showed that in both cases the target was an about 235 kDa protein
      corresponding to the NuMA determinant. Affinity-purified anti-NuMa antibodies
      were used to perform immunolocalization in synchronized HEp-2 cells using
      scanning laser confocal microscopy. The anti-NuMA autoantibodies recognized the
      mitotic asters but neither the centrioles nor the microtubules. CONCLUSION: Our
      data suggest that anti-NuMA autoantibodies may be devoid of clinical significance
      in scleroderma. However, they remain useful as probes in cell biology studies.

PMID- 10418062
TI  - Pain in Parkinson's disease patients.

PMID- 10418063
TI  - Mechanisms of action of bisphosphonates.

PMID- 10418061
TI  - Osteonecrosis-like syndrome of the medial tibial plateau can be due to a stress
      fracture. MR findings in 13 patients.
AB  - OBJECTIVE: To demonstrate the contribution of magnetic resonance imaging to the
      elucidation of mechanisms involved in "osteonecrosis-like syndrome of the medial
      tibial plateau". PATIENTS AND METHODS: A magnetic resonance study with sagittal
      and coronal sections was done in 13 patients (age range, 57-95 years) two weeks
      to four months into a painful syndrome meeting the definition of "osteonecrosis
      like syndrome of the medial tibial plateau". Gadolinium injection was used in
      nine patients. Clinical symptoms resolved within a few weeks in all 13 cases.
      RESULTS: T1-weighted images without gadolinium showed diffuse low signal from the
      epiphysis (n = 12) containing an area of even lower signal seen either as a
      crescent-shaped subchondral image (n = 3/12) or as a linear image (n = 9/12). On
      postgadolinium images, the low signal was abolished except for a line of low
      signal parallel to the subchondral bone. T2-weighted images demonstrated diffuse
      high signal from the medial tibial plateau with persistence of the line of low
      signal (n = 8/12). CONCLUSION: Magnetic resonance imaging allows to analyze the
      anatomic lesion responsible for "osteonecrosis-like syndrome of the medial tibial
      plateau". Our magnetic resonance findings were similar to those seen in stress
      fractures at other sites.

PMID- 10418065
TI  - Rigid spine syndrome. Two case-reports.
AB  - Rigid spine syndrome is characterized by massive spinal rigidity, usually most
      marked in the cervical region. Stiffness of the peripheral joints is sometimes
      present. We report two cases. Patient 1 was a 12-year-old boy diagnosed at three
      years of age with Duchenne's muscular dystrophy because of delayed onset of
      walking. Contracture of the Achilles tendons, flexion contracture of the elbows,
      and loss of motion of the cervical spine were the main findings during the
      current evaluation. Radiographs of the affected joints were normal. An
      electrocardiogram showed an incomplete left bundle branch block. Muscle enzyme
      activities were moderately elevated. A myopathic pattern was seen on the
      electromyogram. A muscle biopsy showed muscle fiber atrophy with peri- and
      endomysial fibrosis. Patient 2 was a 39-year-old man with a five-year history of
      isolated rigidity of the cervical spine thought to be due to a
      spondylarthropathy. Extension was the only movement possible at the cervical
      spine. The peripheral joints showed no motion range limitation. Findings were
      normal from radiographs of the spine and sacroiliac joints, an erythrocyte
      sedimentation rate determination, an electromyogram, and muscle enzyme activity
      assays. A muscle biopsy showed muscle fiber atrophy with peri- and endomysial
      fibrosis. DISCUSSION: Rigid spine syndrome is rare in rheumatological practice
      and can simulate a number of other muscle and joint diseases. Peri- and
      endomysial fibrosis may be strongly suggestive, although nonpathognomonic.
      Involvement of the heart governs the prognosis.

PMID- 10418064
TI  - Pneumococcal polyarticular septic arthritis in a patient with rheumatoid
      arthritis.
AB  - Rheumatoid arthritis is the most commonly reported host-related risk factor for
      septic arthritis. This risk is highest in severe, seropositive, long-standing
      (mean, 10 years) rheumatoid arthritis responsible for extraarticular symptoms and
      treated with systemic glucocorticoids. The clinical presentation of the joint
      infection is often atypical, leading to diagnostic wanderings. In 25% of cases,
      the infection is polyarticular, with 3.5 involved joints on average.
      Staphylococcus aureus is the most common causative organism. Streptococcus
      pneumoniae causes 5% of all cases of septic arthritis and is more often
      responsible for polyarticular infections than other organisms. Polyarticular
      septic arthritis carries a poor prognosis, with a mortality rate of 50% in
      rheumatoid arthritis patients. Despite its low incidence, polyarticular septic
      arthritis should be routinely considered in the differential diagnosis of
      rheumatoid flares. We report a case of pneumococcal septic arthritis involving
      five joints in a patient with known rheumatoid arthritis. Three other cases with
      involvement of more than four joints have been published.

PMID- 10418066
TI  - Lipoma arborescens of the knee.
AB  - Lipoma arborescens is a rare intraarticular lesion characterized by diffuse
      replacement of the subsynovial tissue by mature fat cells, producing villous
      transformation of the synovium. The etiology of this benign condition is unknown.
      The most typical site of involvement is the knee, most notably at the
      suprapatellar pouch, although other joints can be affected. Symptoms consist of
      gradual joint swelling, variable pain, motion range restriction, and intermittent
      joint effusions or bleeding. We report a case of lipoma arborescens and discuss
      the clinical features, diagnosis, and treatment of this disorder based on a
      literature review. Although it is rare, lipoma arborescens should be included in
      the differential diagnosis of patients with chronic joint swelling or
      hemarthrosis.

PMID- 10418068
TI  - Vascular purpura and cryoglobulinemia after influenza vaccination. Case-report
      and literature review.

PMID- 10418067
TI  - Multiple rheumatoid bursitis with migrating chylous cysts. Report of a case in a
      European woman and review of the literature.
AB  - We report a case of recurrent multiple bursitis (19 episodes at nine sites)
      requiring seven surgical procedures in a European women with a 38-year history of
      severe, nodular, destructive seropositive rheumatoid arthritis unresponsive to
      second-line drugs. The episodes of bursitis were not correlated with activity of
      the joint disease. Some cysts migrated over a considerable distance. At least two
      cysts contained chylous fluid. The histologic study of one cyst demonstrated a
      cholesterol crystal granuloma. Potential relationships linking cholesterol
      crystals, chylous cysts, and migrating multiple bursitis are discussed. The
      relevant literature is reviewed.

PMID- 10418069
TI  - Scurvy can mimick cutaneous vasculitis. Three case reports.

PMID- 10418070
TI  - The number needed to be treated as a valuable parameter in interpreting clinical
      trial findings.

PMID- 10418072
TI  - Time in human endurance models. From empirical models to physiological models.
AB  - This article traces the study of interrelationships between power output, work
      done, velocity maintained or distance covered and the endurance time taken to
      achieve that objective. During the first half of the twentieth century,
      scientists examined world running records for distances from < 100 m to > 1000
      km. Such examinations were empirical in nature, involving mainly graphical and
      crude curve-fitting techniques. These and later studies developed the use of
      distance/time or power/time models and attempted to use the parameters of these
      models to characterise the endurance capabilities of athletes. More recently,
      physiologists have proposed theoretical models based on the bioenergetic
      characteristics of humans (i.e. maximal power, maximal aerobic and anaerobic
      capacity and the control dynamics of the system). These models have become
      increasingly complex but they do not provide sound physiological and mathematical
      descriptions of the human bioenergetic system and its observed performance
      ability. Finally, we are able to propose new parameters that can be integrated
      into the modelling of the power/time relationship to explain the variability in
      endurance time limit at the same relative exercise power (e.g. 100% maximal
      oxygen uptake).

PMID- 10418071
TI  - Leucine supplementation and intensive training.
AB  - Leucine, isoleucine and valine, the branched-chain amino acids (BCAA), make up
      about one-third of muscle protein. Of these, leucine has been the most thoroughly
      investigated because its oxidation rate is higher than that of isoleucine or
      valine. Leucine also stimulates protein synthesis in muscle and is closely
      associated with the release of gluconeogenic precursors, such as alanine, from
      muscle. Significant decreases in plasma or serum levels of leucine occur
      following aerobic (11 to 33%), anaerobic lactic (5 to 8%) and strength exercise
      (30%) sessions. In skeletal muscle, there is a decrease in leucine level and a
      reduction in glycogen stores during exhaustive aerobic exercise. Basal fasting
      serum leucine levels decrease by 20% during 5 weeks of speed and strength
      training in power-trained athletes on a daily protein intake of 1.26 g/kg
      bodyweight. The leucine content of protein is assumed to vary between 5 and 10%.
      There are suggestions that the current recommended dietary intake of leucine be
      increased from 14 mg/kg bodyweight/day to a minimum of 45 mg/kg bodyweight/day
      for sedentary individuals, and more for those participating in intensive training
      in order to optimise rates of whole body protein synthesis. Consumption of BCAA
      (30 to 35% leucine) before or during endurance exercise may prevent or decrease
      the net rate of protein degradation, may improve both mental and physical
      performance and may have a sparing effect on muscle glycogen degradation and
      depletion of muscle glycogen stores. However, leucine supplementation (200 mg/kg
      bodyweight) 50 minutes before anaerobic running exercise had no effect on
      performance. During 5 weeks of strength and speed training, leucine
      supplementation of 50 mg/kg bodyweight/day, supplementary to a daily protein
      intake of 1.26 g/kg bodyweight/day, appeared to prevent the decrease in the serum
      leucine levels in power-trained athletes. According to 1 study, dietary
      supplementation of the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB)
      3 g/day to humans undertaking intensive resistance training exercise resulted in
      an increased deposition of fat-free mass and an accompanying increase in
      strength. Muscle proteolysis was also decreased with HMB, accompanied by lower
      plasma levels of enzymes indicating muscle damage and an average 50% decrease in
      plasma essential amino acid levels. Furthermore, BCAA supplementation (76%
      leucine) in combination with moderate energy restriction has been shown to induce
      significant and preferential losses of visceral adipose tissue and to allow
      maintenance of a high level of performance. Caution must be paid when
      interpreting the limited number of studies in this area since, in many studies,
      leucine has been supplemented as part of a mixture of BCAA. Consequently, further
      research into the effects of leucine supplementation alone is needed.

PMID- 10418073
TI  - Exercise and the treatment of type 2 diabetes mellitus. An update.
AB  - Exercise has long been considered a cornerstone in the treatment regimen for
      patients with type 2 (non-insulin-dependent) diabetes mellitus. Aerobic endurance
      exercise has traditionally been advocated as the most suitable exercise mode.
      Several exercise studies have evaluated the effect of exercise on insulin
      sensitivity and glycaemic control in patients with type 2 diabetes mellitus.
      However, the results obtained have been highly heterogeneous regarding the effect
      of exercise on insulin sensitivity and glycaemic control. Only in certain
      subgroups (e.g. patients with type 2 diabetes mellitus under 55 years of age,
      those with diabetes treated through diet and those who have diabetes with fairly
      good metabolic control), does exercise seem to be beneficial with regard to
      improvement in glycaemic control. There has been little research into the effects
      of resistance training on glucose metabolism in patients with type 2 diabetes
      mellitus compared with the amount of research involving aerobic endurance
      exercise. The incidence of type 2 diabetes mellitus increases with increasing
      age, partly because of the decline in muscle mass associated with aging. This
      corresponds with a decline in metabolic function, supporting the usefulness of
      resistance training. Available studies support the usefulness of resistance
      training in the treatment of type 2 diabetes mellitus. Therefore, based on the
      published studies reviewed, this author proposes that an optimal exercise
      programme for individuals with type 2 diabetes mellitus should include components
      that improve cardiorespiratory fitness, muscular strength and endurance, i.e. a
      combination of aerobic endurance training and circuit-type resistance training.
      Programmes combining various modes of exercise positively influence patient
      compliance with the exercise programme. The vast majority of patients with type 2
      diabetes mellitus can undertake an individualised exercise programme without
      significantly increased risks of complications.

PMID- 10418075
TI  - Strength training: single versus multiple sets.

PMID- 10418076
TI  - Early retirement in the United States.
AB  - Despite improvements in health and longevity, many workers in the United States
      retire young. By age 62, only 44 percent of men and 24 percent of women are still
      working full-time. The combination of younger retirement and increasing longevity
      means that Americans are spending more years in retirement than at any time in
      history. The widespread availability of post-retirement benefits is an important
      aspect of this national trend. Eligibility for employer-provided retirement
      benefits can begin as young as age 50 and occurs quite frequently at age 55.
      Eligibility for Social Security benefits begins at age 62. Eligibility for
      Medicare begins at age 65. As the population ages, the implementation of cost
      saving reforms in retirement programs has become an increasing policy concern. To
      sustain the major public entitlement programs, proposals have been made to raise
      the age of eligibility for Social Security and Medicare, or to reduce benefit
      levels, or to target benefits to those most in need. Other cost-saving changes
      have been considered, and in many cases implemented, in employer-provided
      retirement benefits. These policy changes will have implications for the
      retirement decisions of working Americans in the future. This report, drawing on
      research sponsored by the National Institute on Aging, reviews the trend in the
      United States toward earlier retirement as well as some recent research findings
      on how retirement decisions relate to public and private retirement policies.
      With the changing age demographics of the population, the implementation of cost
      saving reforms to retirement policies and other changes in the economic
      circumstances of individuals as they age, the work and retirement decisions of
      older workers will continue to evolve over the coming decades.

PMID- 10418077
TI  - The costs of body mass index levels in an employed population.
AB  - We studied 3,066 First Chicago NBD employees by using health risk appraisals and
      personnel data to determine the direct and indirect costs (in 1996 dollars)
      associated with varying levels of body mass index (BMI). The BMI is the most
      widely used measure of weight adjusted by height. We found that as BMI increases,
      so do the number of sick days, medical claims and health care costs and that the
      mean annual health care costs for the BMI "at risk" population (men with a BMI of
      > or = 27.8 kg/m2, women > or = 27.3 kg/m2) was $2,274 versus $1,499 for the "not
      at risk" group. Major differences in health care costs were observed for
      employees 45 years old and older, particularly among the women in this age group.
      Analysis was completed for those employees with and without a risk for BMI. A "J
      shaped" curve between medical claims costs and BMI exists, with the low point
      occurring at about 25 to 27 kg/m2. We conclude that indirect and direct costs to
      an employer increase with increasing BMI. Employers may benefit from helping
      employees achieve a healthier weight. The initial target population should be
      those who are at highest risk of complications from obesity.

PMID- 10418074
TI  - Histopathology of common tendinopathies. Update and implications for clinical
      management.
AB  - Tendon disorders are a major problem for participants in competitive and
      recreational sports. To try to determine whether the histopathology underlying
      these conditions explains why they often prove recalcitrant to treatment, we
      reviewed studies of the histopathology of sports-related, symptomatic Achilles,
      patellar, extensor carpi radialis brevis and rotator cuff tendons. The literature
      indicates that healthy tendons appear glistening white to the naked eye and
      microscopy reveals a hierarchical arrangement of tightly packed, parallel bundles
      of collagen fibres that have a characteristic reflectivity under polarised light.
      Stainable ground substance (extracellular matrix) is absent and vasculature is
      inconspicuous. Tenocytes are generally inconspicuous and fibroblasts and
      myofibroblasts absent. In stark contrast, symptomatic tendons in athletes appear
      grey and amorphous to the naked eye and microscopy reveals discontinuous and
      disorganised collagen fibres that lack reflectivity under polarised light. This
      is associated with an increase in the amount of mucoid ground substance, which is
      confirmed with Alcian blue stain. At sites of maximal mucoid change, tenocytes,
      when present, are plump and chondroid in appearance (exaggerated
      fibrocartilaginous metaplasia). These changes are accompanied by the increasingly
      conspicuous presence of cells within the tendon tissue, most of which have a
      fibroblastic or myofibroblastic appearance (smooth muscle actin is demonstrated
      using an avidin biotin technique). Maximal cellular proliferation is accompanied
      by prominent capillary proliferation and a tendency for discontinuity of collagen
      fibres in this area. Often, there is an abrupt discontinuity of both vascular and
      myofibroblastic proliferation immediately adjacent to the area of greatest
      abnormality. The most significant feature is the absence of inflammatory cells.
      These observations confirm that the histopathological findings in athletes with
      overuse tendinopathies are consistent with those in tendinosis--a degenerative
      condition of unknown aetiology. This may have implications for the prognosis and
      timing of a return to sport after experiencing tendon symptoms. As the common
      overuse tendon conditions are rarely, if ever, caused by 'tendinitis', we suggest
      the term 'tendinopathy' be used to describe the common overuse tendon conditions.
      We conclude that effective treatment of athletes with tendinopathies must target
      the most common underlying histopathology, tendinosis, a noninflammatory
      condition.

PMID- 10418078
TI  - The college crowd: United States, 1998.
AB  - Educational attainment in the United States has been steadily improving. Almost
      one-fourth of U.S. adults age 25 or more has received a bachelor's degree or
      better--26.5 percent of men and 22.4 percent of women. Because of shifting
      demographic trends, enrollment of traditional college-age students was somewhat
      sluggish earlier in the 1990s but is now starting to increase once again. In 1998
      an estimated 14.6 million students were enrolled in college-level classes across
      the United States. The proportion of the college population comprised of students
      35 years of age or more has more than doubled since 1972, rising from 8.6 percent
      to just over 18 percent. College education costs generally continue to increase
      faster than inflation. To meet these costs many students work and are stretching
      out the time required to earn their degrees. Only about 40 percent of all
      students receive their bachelor's degree within four years of graduation from
      high school. The number of college graduates is exceeding the number of college
      level jobs being created and from a purely economic viewpoint may warrant some
      students to consider alternative career paths and training.

PMID- 10418079
TI  - U.S. cancer incidence, mortality and survival: 1973-1996.
AB  - Earlier predictions of morbidity and mortality improvements for the four leading
      sites of cancer are beginning to occur. After decades of increases, incidence and
      mortality rates for all cancers combined have declined since 1992. Between 1990
      and 1996 the age-adjusted death rates for all cancers had dropped 3.7 percent to
      166.9 per 100,000 and incidence rates had decreased 2.8 percent to 388.6. The
      overall decreases were greater among men than women; male mortality rates dropped
      6.2 percent and incidence dropped 5.2 percent for men versus 1.8 and 1.9 percent,
      respectively, for women. Lung cancer incidence among men continued its more than
      10-year decline in age-adjusted rates and mortality rates dropped for a fifth
      consecutive year to 68.2 per 100,000 population. Among women, lung cancer
      incidence rates began to plateau in the mid-1990s similar to the pattern
      experienced by men a decade earlier. The rates of prostate cancer have begun to
      decrease but remain 65 to 75 percent higher among black men than white. Mortality
      rates dropped 9.5 percent among white men but only 2.0 percent among blacks since
      1990. By 1996 even breast cancer death rates were declining ahead of the
      predicted decrease by the end of the century. Mortality rates for all women
      combined was 24.3 per 100,000 population, 24.0 for white women and 30.8 for
      blacks, 11.3, 12.1 and 2.5 percent, respectively lower than in 1990. The
      previously noted decreases in colorectal cancer mortality and incidence continue
      with age-adjusted rates dropping to 16.8 and 42.7 per 100,000 population,
      respectively, in 1996.

PMID- 10418080
TI  - [Nutrition of horses: digestion, energy and protein evaluation and nutritional
      standards].
AB  - The diet of horses should cover the energy and nutrient requirements of these
      animals. The desired composition of the ration depends on its digestion in the
      equine gastrointestinal tract. Nutritional problems or diseases caused by
      incorrect composition of the ration or by incorrect feeding should be prevented.
      The digestion of carbohydrates, fats, and proteins in the different parts of the
      gastrointestinal tract is described. In addition, the recently introduced net
      energy and digestible protein evaluation systems for feeds, and the energy and
      protein requirements of horses are presented.

PMID- 10418081
TI  - [Nutrition of horses: ration calculation and assessment].
AB  - In various situations it is desirable to evaluate the diet of horses. Such
      situations occur when nutrition is considered as the cause of disease or symptoms
      or and when a diet or diet change raises concern about whether the animal is
      receiving sufficient nutrients. Ration evaluation consists of translating feed
      ingredients into nutrients supplied and comparing this with nutrient
      requirements. The basics of ration evaluation are illustrated by means of four
      examples of horse diets.

PMID- 10418082
TI  - [Moxidectin poisoning in a foal?].
AB  - A 2 day old foal was presented with central nervous depression (coma) after
      moxidectin overdose. Moxidectin belongs to the milbemycin anthelmintics which
      elicit their working mechanism through a GABA (gamma-aminobutyric acid)
      stimulatory mode of action. The foal developed profound hypothermia, bradycardia
      and hypoventilation. Absence of urine voiding and mild abdominal distension
      suggested a ruptured bladder, which was confirmed by transabdominal ultrasound
      and clinical-pathologic parameters. Repeat auscultation of the ventral lung parts
      and the occurrence of gastric reflux were suggestive of an aspiration pneumonia.
      The foal underwent surgical bladder repair, however, did succumb due to mixed
      acidosis and early signs of sepsis postoperatively. The findings in this foal are
      suggestive for moxidectin overdosing. The GABAergic working mechanism of
      moxidectin does explain the development of profound central nervous depression
      and its sequels hypothermia, bradycardia, hypoventilation and paralytic ileus.
      Dyssynergia was unexpected, however, has to be related to a central nervous
      problem, rather than a peripheral nervous problem.

PMID- 10418083
TI  - [Beijerinck Virology Medal 1998 for Albert D. M. E. Osterhaus].

PMID- 10418084
TI  - A historian is a prophet in reverse.

PMID- 10418085
TI  - Phimosis in antiquity.
AB  - The medical term phimosis has been in use since antiquity, but in contrast to the
      imprecise definition of the term that is characteristic of nineteenth-century and
      some controversial modern medical writing. Greek and Roman medical writers imbued
      it with a clinically precise definition. Using the tools of the history of
      medicine, an analysis of the medical writings of antiquity reveals that phimosis
      was defined exclusively as a rare, inflammatory or cicatricial stricture of the
      preputial orifice consequent to a true pathological condition rather than a
      disease process in itself. Putative associations between phimosis and diseases
      such as urinary tract infections or cancer were not made in antiquity and are
      reflections of modern, geographically isolated social anxieties. The modern
      European scientific conceptualisation of phimosis, however, represents a return
      to the precise terminology and conservative therapeutic approach characteristic
      of Greek and Roman medicine.

PMID- 10418086
TI  - Urodynamics in the anatomical work of Leonardo da Vinci (1452-1519).
AB  - Leonardo da Vinci (1452-1519) incorporates the symbiosis of art and medicine and
      can be addressed as the founder of medical illustration in the time of the
      Renaissance. His anatomy studies were not published in his time, which explains
      why Leonardo's outstanding knowledge of anatomy, physiology, and medicine had no
      impact on his scientific contemporaries and is therefore primarily of
      retrospective importance in the history of medicine. The collection of anatomical
      illustrations remained unknown until their rediscovery in the eighteenth century
      and their wide publication at the beginning of our century. This article
      systematically reviews Leonardo's genitourinary drawings with regard to
      urodynamic aspects of the upper and lower urinary tract, highlighting topics such
      as vesicoureteral reflux and urinary sphincter mechanisms.

PMID- 10418087
TI  - Some historical aspects of urinals and urine receptacles.
AB  - In the history of mankind the first receptacles for urine were made and employed
      for diagnostic purposes and developed over centuries to a sophisticated matula.
      In ancient Greek and Roman history, chamber pots existed and urine was collected
      to bleach sheets, but it was only in the late medieval and renaissance times that
      a real urine receptacle or urinal for daily use was developed. We give a short
      description of the materials used, including clay, pewter, copper, and silver,
      but more sophisticated receptacles made of china, such as the bourdaloue, and of
      glass, such as the Kuttrolf, were also developed for use during long church
      ceremonies. Less known are the wooden "pipes" from Turkestan, used to keep babies
      dry. In the long history of mankind, urinals sometimes became very original
      objects.

PMID- 10418088
TI  - Varicocele--a historical perspective.
AB  - Varicocele is an essential part of andrological urology. Due to its frequency and
      to the problems connected with it, varicocele became a subject of interest at an
      early stage in the history of medicine. Questions arose as to how the changes and
      the consequences resulting from this condition should be treated. Even today,
      some questions regarding the etiopathology and therapy of varicocele remain
      unanswered.

PMID- 10418090
TI  - The surgeon and his intention: Gustav Simon (1824-1876), his first planned
      nephrectomy and further contributions to urology.
AB  - One of the historic landmarks in urology is the first planned nephrectomy
      performed in 1869 by Gustav Simon of Heidelberg (1824-1877). In the history of
      medicine the reflections and considerations of the specialized surgeon reveal
      distinguished analyses of the "case" and, thus, the beginning of a modern
      scientific discussion of a patient's quality of life. Available primary and
      secondary sources were screened to present a differentiated aspect of this
      milestone in the history of urology. The analysis of the first German indicated
      nephrectomy shows the introduction of scientifically orientated thinking in
      urology, especially in Germany during the middle of the nineteenth century, and
      parallels the rise of urology and general surgery.

PMID- 10418089
TI  - Victor Ivanchich (1812-1892) and Josef Weiger (1810-1863): early cooperation of a
      urologist and an anesthesiologist.
AB  - Today the cooperation of the highly developed specialities anesthesiology and
      urology is daily practice in every hospital and does not need further explanation
      in medical reports. The history of medicine tells us that the situation was
      different during the pioneer days of surgery in the last century. Although the
      statement that the patient underwent surgery while under general anesthesia was
      mostly included in the reports of operations at that time, the need for a
      specially trained doctor to perform anesthesia was hardly recognized. Most
      surgeons delegated this task to young colleagues or even to persons who had not
      been medically trained. The urologic surgeon Victor Ivanchich may have been an
      exception in including his special anesthesiologist Josef Weiger in several of
      his publications on lithotrity.

PMID- 10418091
TI  - Albert Adamkiewicz (1850-1921)--his artery and its significance for the
      retroperitoneal surgeon.
AB  - The artery of Adamkiewicz is an important retroperitoneal vessel that is chiefly
      responsible for vascularization of the lumbar enlargement of the lower spinal
      cord. The significance of this artery, named after Albert Adamkiewicz, a talented
      Polish pathologist known for his pioneering work on spinal anatomy and
      physiology, has not been widely recognized. It is a useful landmark among the
      numerous blood vessels that nourish the spine. Injury to the artery of
      Adamkiewicz can result in devastating ischemia of the lower spinal cord.

PMID- 10418092
TI  - Patent medicines for the treatment of genitourinary diseases.
AB  - The present article addresses the nineteenth-century advertising of patent
      medicines in America, sold to "cure" diseases of the kidney and bladder, the
      "loss of manhood", and "debilitating conditions of the generative system." Most
      of the proprietary remedies made extravagant claims of effectiveness concerning a
      wide variety of ailments, and some claimed to cure every disease. Examples of
      promotional excesses demonstrate how the public was persuaded to buy a
      kaleidoscope of largely useless and occasionally harmful patent nostrums. The
      ephemera considered became a part of the history of medicine related to urology.

PMID- 10418094
TI  - Werner Forssmann: surgeon, urologist, and Nobel Prize winner.

PMID- 10418093
TI  - The development of urological endoscopy in America.
AB  - This article deals with the history of medicine in American urology, where
      endoscopy is a very important subject. The development of endoscopy in America
      unrolled in three phases: the acquisition of European techniques and instruments,
      realization of the ideas of American researchers, and original creations that
      forwarded endoscopy considerably. European instruments were acquired in the
      nineteenth century, culminating in the instruments developed by Max Nitze. When
      Wappler started the production of endoscopes in 1905, they were the basis for the
      development of numerous modifications and innovations such as electrosurgery,
      developed by Beer in 1910, with the Resonator created by Wappler; the
      resectoscope, invented by Stern and McCarthy in 1931; "cold light" using glass
      fibers for illumination, described by ACMI in 1960; the flexible fiber
      ureterorenoscope, described by Marshall in 1960; and fluorescence cystoscopy,
      introduced by I. M. Bush and W. F. Whitmore in 1964.

PMID- 10418095
TI  - William P. Didusch (1895-1981): an illustrator of urology.

PMID- 10418096
TI  - Comparative investigations of airborne culturable microorganisms in selected
      waste treatment facilities and in neighbouring residential areas.
AB  - The evaluation of airborne microorganisms in waste treatment facilities is
      complicated by different measuring systems, a lack of measuring standards and
      large variations between individual counts. In the present study, different
      sectors of the waste management industry were compared by determining median
      values of airborne culturable microorganisms from numerous parallel counts over a
      prolonged time period. The samples were taken during the warm season using the
      six-stage Andersen volumetric sampler in a large composting plant and its
      immediate vicinity, in an agricultural composting plant, a waste disposal site,
      and a sorting facility for recyclable materials. Control samples were taken at a
      site not influenced by the waste management industry in an open and largely
      uninhabited area. The highest median values for culturable bacteria (37 degrees
      C) found were 1.1 x 10(5) CFU/m3, for moulds (25 degrees C) 1.4 x 10(5) CFU/m3,
      and for A. fumigatus (37 degrees C) 1.7 x 10(4) CFU/m3 in the sorting cabins of
      the sorting facility (p < 0.001). The highest median values for thermophilic
      bacteria (actinomycetes and bacillaceae, 50 degrees C) were 7.3 x 10(3) CFU/m3 in
      the large composting facility. In all other facilities as well as in the
      neighbouring residential areas of all facilities investigated, all median values
      were significantly lower and corresponded to the naturally occurring levels:
      approx. 10(2) CFU/m3 for bacteria, approx. 10(3) CFU/m3 for moulds and approx.
      10(1) CFU/m3 for A. fumigatus and thermophilic bacteria. Only in the neighbouring
      residential area of the large composting plant, the median values for
      thermophilic bacteria were approx. 10(2) CFU/m3, but an additional impact from
      farms cannot be excluded in this case. These results show permanent increased
      loads of the investigated microorganisms inside large composting facilities and
      especially in the sorting cabins for recyclable materials. The increasing number
      of reports on potential health hazards in these areas require adequate measures
      on the part of occupational medicine in order to limit the health risk to a
      minimum. The most important task is the automatization of the sorting process for
      recyclable materials.

PMID- 10418097
TI  - Occurrence, removal and seasonal variation of thermophilic campylobacters and
      Arcobacter in sewage sludge.
AB  - The presence of thermophilic campylobacters and Arcobacter was investigated in
      four types of sewage sludge taken from the treatment plant in Bologna (Italy):
      primary, activated, thickened and anaerobically digested sludge. Campylobacter
      jejuni and Campylobacter coli were more numerous during the March-September
      period and were found only in primary sludge (22.7%) with mean counts of 278
      MPN/g dry matter and 1403 MPN/g dry matter respectively. Arcobacter butzleri were
      found in all types of sludge with frequencies of 80% in activated and thickened
      sludges and 41% in digested sludges. They were more numerous in the spring/summer
      period with peaks in April, May, June and September. They were less sensitive to
      anerobic digestion than fecal bacteria, probably due to their microaerophilic
      growth properties. However, since they are found in anaerobically digested
      sludges at mean values of 7649 MPN/g dry matter the land application of digested
      sludges may cause high risks infection.

PMID- 10418098
TI  - Enterovirus genome detection in wastewater: multi centric evaluation of a
      commercial kit.
AB  - A multi-centric study was carried out in three laboratories, to evaluate the
      efficiency of a standardized kit for the detection of enterovirus genome in
      wastewater. Twenty one samples of 20 liters of wastewater were analyzed before
      and after concentration through glass wool. Each sample was analyzed with the
      Amplicor kit as well as with techniques developed independently in each
      laboratory. The results show that the Amplicor kit is well suited to the
      detection of enterovirus genome in treated wastewater. The results may be
      compared to those obtained with semi-nested RT-PCR techniques used in each
      laboratory. However, the Amplicor kit technique is more simple and has the
      advantage of providing a standardized technique useful for comparative studies.
      During this work it was observed that the sensitivity of the detection of
      infectious viruses and virus genome was improved when concentrated samples were
      used for analysis.

PMID- 10418100
TI  - Comparison of membrane filtration methods for the recovery of legionellae from
      naturally contaminated domestic drinking water supplies.
AB  - We compared four methods for the cultural recovery of legionellae from naturally
      contaminated water samples: (A) inoculating 1 and 0.1 ml directly on the
      selective solid growth medium, (B) filtration through cellulose nitrate membrane
      filters and inoculating the resuspended residue corresponding to 100 and 10 ml of
      the original sample on the medium, (C) filtration through polycarbonate filters
      and inoculating the resuspended residue corresponding to 100 and 10 ml of the
      original sample, and (D) filtration of 100 and 10 ml through cellulose nitrate
      filters and incubating the filter directly on the medium. Of the water samples
      tested in parallel, 103 samples tested positive for legionellae in at least two
      of these methods. The mean number of CFU/ml recovered by methods A, B, C, and D
      werte 5.45, 1.85, 1.70, and 2.26, respectively. The differences between the
      methods proved to be highly significant except for methods B and C (p = 0.112),
      the results of which correlated closely with each other (r = +0.96). In
      comparison with method A the recovery rates of methods B, C, and D were found to
      be 60, 57, and 69%, respectively. We recommend the use of method A for the
      recovery of legionellae at concentrations of > or = 1 CFU/ml. If legionellae
      below this concentration are to be detected we recommend method D as the easiest
      and most sensitive technique.

PMID- 10418099
TI  - Resistance of enterococci to heat and chemical agents.
AB  - Within the framework of the standardisation efforts on disinfectant testing on
      the European level the test germ Enterococcus hirae ATCC 10541 has been included
      for some time in the test requirements whereas the test strain Enterococcus
      faecium, which has frequently been used up to now, has been largely ignored. We
      compared the thermal and the chemical resistance of both test germ species. In
      the quantitative suspension test with active ingredients from the group of
      aldehydes, phenols, quaternaries and oxidizing agents with the exception of
      peracetic acid, no significant differences were determined between the two
      strains. In the case of the studies on thermal resistance at 65 degrees C and 68
      degrees C, Enterococcus faecium ATCC 6057, by contrast, proved to be far more
      resistant than Enterococcus hirae ATCC 10541. According to these results,
      priority should be given to Enterococcus faecium over Enterococcus hirae as the
      test germ for chemical and also chemothermal disinfection.

PMID- 10418101
TI  - Chlorate as an inorganic disinfection by product in swimming pools.
AB  - Chlorate and chlorite concentrations were determined in water samples taken from
      33 swimming pools. In the pools under investigation, disinfection of the water is
      carried out either by gaseous chlorine (n = 14) or hypochlorite solution in
      conjunction with flocculation and sand filtration. A number of the pools also use
      ozone treatment to augment the disinfection process. Chlorite was not detectable
      in any of the samples (detection limit 1 mg/l). High concentrations of chlorate
      were detected in samples from a number of the pools; in one case as high as 40
      mg/l. Higher chlorate concentrations were found to be associated with those pools
      using hypochlorite solution as a disinfecting agent. In contrast, relatively low
      chlorate concentrations were found in pools treated with gaseous chlorine. In
      order to elucidate any relationship between the chlorate content of pool water
      and that of the respective hypochlorite stock solution, chlorate and bromate
      concentrations were determined in the hypochlorite stock solutions of nine pools.
      Bromate concentration in the stock solutions were not found to exceed 1.2 g/l,
      chlorate was measured in concentrations of up to 44.5 g/l. The additional use of
      ozone as part of the water purification process appears to have no significant
      influence on chlorate concentration. Chlorate has no bactericidal properties and
      does not interfere with the measurement of certain parameters relevant to hygiene
      in swimming pools such as free and combined chlorine, pH or redox potential. At
      present, the effects of high chlorate concentrations in swimming pool water are
      unclear. Our initial investigations indicate that chlorate has no cytotoxic
      (Neutral-Red assay) or irritating properties (HET-CAM assay). However, both
      chlorate and chlorite are known to interfere with the haematopoetic system. In
      Germany, the MCL for chlorite in drinking water is 0.2 mg/l. It is therefore
      strongly recommended that measures should be taken to reduce chlorate
      concentrations in swimming pool water.

PMID- 10418102
TI  - Calmodulin, gametes and fertilisation.
AB  - The role of calmodulin in fertilisation events was examined in a zona-free mouse
      system by using a selective calmodulin inhibitor, calmidazolium (1 microM). The
      effects of this antagonist were studied either on the ooplasmic calcium
      oscillations induced by fertilisation by using the Ca2+ indicator, fluo-3/AM, or
      on pronucleus formation 4 h later by using the nucleic acid stain, Syto-15. When
      the calmidazolium treatment was applied to one or the other gamete before
      insemination, the fertilisation process was affected only when spermatozoa were
      treated: most of the oocytes were partially fertilised as demonstrated by the
      profile of Ca2+ oscillations and the presence of polar bodies with no typical
      male and female pronuclei. When the treatment was applied during insemination,
      more than half the oocytes were unfertilised and only a few were partially
      fertilised. These results demonstrate that: (1) the calmodulin-dependent events
      taking place in spermatozoa before insemination appear essential at least for
      regular Ca2+ oscillations and for pronucleus formation; (2) the inhibition of
      calmodulin by calmidazolium applied to metaphase II oocytes before insemination
      has no major impact on their fertilising ability; and (3) at the time of gamete
      fusion calmodulin, either from the oocyte or from the spermatozoon, is essential
      for fertilisation to occur.

PMID- 10418103
TI  - Functional interactions between sulphated polysaccharides and proacrosin:
      implications in sperm binding and digestion of zona pellucida.
AB  - Acrosin is a serine protease located within mammalian acrosome as inactive
      proacrosin. Sulphated polymers bind to proacrosin and acrosin, to a domain
      different from the active site. Upon binding, these polymers induce proacrosin
      activation and some of them, such as fucoidan, inhibit sperm binding to the zona
      pellucida. In this work we have studied the interaction of solubilised zona
      pellucida glycoproteins (ZPGs), heparin and ARIS (Acrosome Reaction Inducing
      Substance of Starfish) with boar and human acrosin. We have found that ARIS,
      solubilised ZPGs and fucoidan, but not heparin, inhibit the binding of the
      monoclonal antibody against human acrosin C5F10 to boar or human proacrosin.
      These results suggest that fucoidan, solubilised ZPGs and ARIS bind to a related
      domain on the proacrosin surface. Moreover, ARIS was able to induce human
      proacrosin activation. On the other hand, neither ARIS nor heparin from porcine
      intestinal mucosa or bovine lung induced hamster sperm acrosome reaction or sperm
      motility. Recent data showed that acrosin is involved in dispersal of the
      acrosomal matrix after acrosome reaction. Thus, the control of the ZPG glycan
      chains over proacrosin activation may regulate both sperm penetration rate and
      limited proteolysis of zona pellucida proteins.

PMID- 10418105
TI  - Role of actin filaments in the hatching process of mouse blastocyst.
AB  - Hatching has been suggested to occur as a result of protease-mediated lysis and
      the blastocoele tension. However, even if rupturing is initiated at multiple
      sites, interestingly only a single site is used for escape. This implies that
      there are several mechanisms involved in hatching. In this study, the involvement
      of actin filaments in mouse embryo hatching was examined. We treated mouse
      embryos with cytochalasin B for 12 h or 24 h at the morula, middle blastocyst,
      expanded blastocyst, lobe-formed blastocyst and hatching blastocyst stages, and
      measured the amount and distribution of actin filaments using a confocal
      microscope. At morula, middle blastocyst, lobe-formed blastocyst and hatching
      blastocyst stages embryonic development was completely arrested by cytochalasin
      B. However, when transferred to cytochalasin-B-free medium, the embryos resumed
      development and escaped the zona pellucida. In the expanded blastocysts
      development was almost completely inhibited by cytochalasin B, but rupturing
      occurred in some embryos. However, development stopped completely at the ruptured
      stage. Distribution of actin filaments was prominent at rupturing and hatching
      sites regardless of cytochalasin B treatment. The amount of actin filaments was
      prominent at hatching embryos compared with other developmental stages of
      embryos. These actin filaments were distributed intensively between the
      trophectodermal cells, and formed locomotion patterns. Taken together, these
      results suggest that not only tension and lytic enzymes are required to rupture,
      but the activity of actin filaments may have a crucial role in the process of
      hatching.

PMID- 10418104
TI  - Identification and characterisation of Xenopus moesin, a Src substrate in Xenopus
      laevis oocytes.
AB  - The cortical actin cytoskeleton, consisting of actin filaments and actin binding
      proteins, immediately underlies the inner surface of the plasma membrane and is
      important both structurally and in relaying signals from the surface to the
      interior of the cell. Signal transduction processes, initiated in the cortex,
      modulate numerous cellular changes ranging from modifications of the local
      cytoskeleton structure, the position in the cell cycle, to cell behaviour. To
      examine the molecular mechanisms and events associated with cortical changes. We
      have investigated targets of the protein tyrosine kinase, Src, which is
      associated with the cortical cytoskeleton, in Xenopus laevis oocytes. When a mRNA
      encoding an activated form of Src tyrosine kinase (d-Src) is injected into
      oocytes several changes are observed: proteins are phosphorylated, the rate at
      which progesterone matures an oocyte to an egg is accelerated, and the cortex at
      the site of injection appears to contract. Previous studies have implicated actin
      filaments in the Src-stimulated cortical rearrangements. In this study we
      identify two actin binding proteins-cortactin and moesin--as Src substrates in
      Xenopus oocytes that are Src substrates. We cloned and characterised the cDNA
      encoding one of those, Xenopus moesin, a member of the ezrin/radixin/moesin (ERM)
      family of actin binding proteins. In addition, we have determined that moesin is
      recruited to the cortex at the site of Src mRNA injection.

PMID- 10418106
TI  - Analysis of aneuploidy for chromosomes 13, 21, X and Y by multicolour
      fluorescence in situ hybridisation (FISH) in a 47,XYY male.
AB  - The frequency of aneuploid sperm was assessed by fluorescence in situ
      hybridisation (FISH) in a 47,XYY male previously studied by sperm karyotyping. A
      total of 20,021 sperm were studied: 10,017 by two-colour FISH for chromosomes 13
      and 21 and 10,002 by three-colour FISH for the sex chromosomes using chromosome 1
      as an autosomal control for diploidy and lack of hybridisation. Results were
      compared with more than 500,000 sperm from 18 normal men. The frequencies of X
      bearing (49.4%) and Y-bearing sperm (49.8%) were not significantly different from
      50% as shown in our sperm karyotyping study. There was no significant increase in
      the frequency of diploid sperm compared with control donors. There was a
      significant increase in the frequency of disomy for chromosome 13 (p < 0.0001)
      and XY disomy (p = 0.0008) compared with control donors. However, since the
      frequency of disomy was 0.40% for chromosome 13 and 0.55% for XY disomy, it is
      not surprising that these increases were not discovered previously in our
      analysis of 75 sperm karyotypes. Our results suggest that the extra Y chromosome
      is eliminated during spermatogenesis in the majority of cells but that there may
      be a small but significant increase in the frequency of aneuploid sperm in these
      men.

PMID- 10418108
TI  - Proteolytic activity of rabbit perivitelline spermatozoa.
AB  - Acrosin, an acrosomal serine protease, has been associated with binding of
      spermatozoa and their penetration through the zona pellucida. This study was
      aimed at determining whether the remaining proacrosin/acrosin system on rabbit
      perivitelline spermatozoa still has proteolytic activity and whether this
      activity is involved in further penetration of unfertilised rabbit eggs. Eight
      hundred and sixty-five rabbit perivitelline spermatozoa were evaluated by the
      gelatin-substrate film technique for the detection of acrosin on individual
      spermatozoan. Fifteen per cent of the studied spermatozoa showed small digestion
      halos on the gelatin film. The proteolytic activity of rabbit perivitelline
      spermatozoa was inhibited in the presence of 1 mg/ml of soybean trypsin inhibitor
      (SBTI) or with 20 micrograms/ml of a mixture of the monoclonal anti
      proacrosin/acrosin antibody. In vitro fertilisation occurred in 21.8% of rabbit
      oocytes co-incubated with perivitelline spermatozoa and was completely inhibited
      when oocytes were incubated with 600 micrograms/ml of a mixture of three anti
      acrosin monoclonal antibodies (ACRO-A8C10, ACRO-C2B10 and ACRO-C5F10).
      Inseminations in the presence of anti-cholera monoclonal antibody (irrelevant to
      spermatozoa) resulted in 17.6% fertilisation. These results support the idea that
      the residual proacrosin/acrosin system in perivitelline spermatozoa might be
      involved in spermatozoal binding and/or second penetration through the zona
      pellucida.

PMID- 10418107
TI  - Protein phosphorylation in bovine oocytes following fertilisation and
      parthenogenetic activation in vitro.
AB  - This study examined the event of protein phosphorylation in bovine oocytes in
      response to sperm penetration and parthenogenetic activation. In vitro matured
      oocytes were labelled with [32P]orthophosphate at 3 h intervals from 3 h to 18 h
      or from 0 h to 12 h following in vitro fertilisation and parthenogenetic
      activation, respectively. The level of protein dephosphorylation, at
      approximately 43 kDa, was similar in fertilised and parthenogenetically activated
      bovine oocytes. However, the level of protein phosphorylation at 40 kDa, 23 kDa
      and 18 kDa was different between these two samples. There were no such changes of
      protein phosphorylation and dephosphorylation in the control oocytes. Further, by
      two-dimensional gel electrophoresis there is a difference in the level of protein
      phosphorylation at 18 kDa between the fertilised and activated oocytes. These
      results suggest that this protein phosphorylation may be related to the formation
      of the male pronucleus in bovine oocytes.

PMID- 10418109
TI  - Fate of genetically marked mitochondrial DNA from spermatocytes microinjected
      into mouse zygotes.
AB  - Cytoplasts from single spermatocytes of NZB/BinJ mice were separated from the
      nuclei and individually microinjected into B6D2F1 (C57BL/6 x DNBA/2J) hybrid
      embryos at the pronuclear stage (20 h after hCG injection). Of 363 zygotes
      injected, 311 (86%) survived and developed. From these experiments, we
      transferred 222 embryos into 20 pseudopregnant recipients. Eighteen (90%) became
      pregnant and 82 pups were born (37% of transfers). Mitochondrial DNA (mt DNA)
      from the NZB/BinJ strain lacks a RsaI restriction site and can thus be
      distinguished from the host embryo following PCR amplification. We were unable to
      detect the transferred mtDNA in blastocysts on day 4-5 after injection. Nor could
      we detect NZB/BinJ mtDNA in placentae, nor in tissues from mice born to host
      mothers following the transfer of blastocysts that developed from injected
      zygotes. Rejection of paternal mitochondria by the embryo normally occurs at the
      4- to 8-cell stage in mice and is apparently dependent on mutual recognition
      between the mitochondria and the nuclear genome. We conclude that this mechanism
      has probably already developed by the time the germ cells have become committed
      to meiosis.

PMID- 10418110
TI  - The role of structural integrity of the fertilising spermatozoon in early human
      embryogenesis.
AB  - While the fertilising spermatozoon supplies the active centre directing the human
      zygote's first mitotic division, the relative contributions of the sperm head and
      tail (as well as the importance of the sperm's general structural integrity) to
      subsequent developmental processes remain incompletely studied. The sperm nucleus
      contains paternal chromatin necessary for restoration of a diploid genome, but
      the functional role of the sperm tail (either attached or dissected) in early
      human embryonic growth is not known. In this investigation using oocytes donated
      by in vitro fertilisation patients, human oocytes were injected with isolated
      sperm heads (n = 73), isolated sperm flagella (n = 11) or both (dissected sperm
      heads + free sperm tails, n = 26). The formation of bipronucleate zygotes was
      recorded for each method. Among oocytes surviving injection with isolated sperm
      heads, 44 of 66 (67%) formed two pronuclei. Of oocytes receiving only sperm
      tails, 2 of 11 (18%) displayed two pronuclei, but a single polar body was evident
      in both cases. When dissected spermatozoa parts (head + tail) were jointly
      injected, 12 of 26 (46%) developed two pronuclei. From embryos resulting from
      each of these three fertilisation regimes, blastomere biopsies were obtained and
      subjected to multiprobe fluorescent in situ hybridisation (FISH) analysis to
      detect mosaicism or aneuploidy arising from these experimental treatments. Only
      embryos with growth sufficient to permit sampling of at least two blastomeres
      were evaluated, and FISH analysis was successful in 25 of 29 (86%) embryos
      tested. Of 12 embryos derived from injection of an isolated sperm head, only one
      was normal diploid; the remaining 11 were mosaic. Both embryos resulting from
      injection of an unattached sperm tail were mosaic. Of 11 embryos generated from
      oocyte injection with sperm head + tail segments, 10 (91%) were mosaic and only
      one was normal diploid. Results from this study show that injection of isolated
      sperm segments can permit oocyte activation and bipronuclear formation. However,
      a high rate of mosaicism in human embryos originating from disrupted sperm or
      sperm components suggests that more than a 'sum of parts' is needed for later
      development. The structural integrity of the intact fertilising spermatozoon
      appears to contribute to normal human early embryogenesis.

PMID- 10418111
TI  - DNA replication in the 1-cell mouse embryo: stimulatory effect of histone
      acetylation.
AB  - Temporal and spatial distribution of the sites of DNA replication were examined
      in 1-cell mouse embryos. Embryos were labelled with bromodeoxyuridine (BrdU) at
      hourly intervals after fertilisation, and the incorporation of BrdU was examined
      by laser-scanning confocal microscopy following immunostaining with an anti-BrdU
      antibody. DNA replication first started uniformly in both the male and female
      pronuclei in the intranuclear region and then was observed in the peripheral
      regions of nucleus and nucleolus. These changes, however, occurred asynchronously
      in that the female pronucleus required a longer time to complete replication in
      the intranuclear region but not in the peripheral regions. Inhibiting
      transcription with alpha-amanitin had no effect on the temporal and spatial
      patterns of DNA replication. Treatment of the embryos with trapoxin, a specific
      inhibitor of histone deacetylase, accelerated the completion of replication in
      the peripheral regions but not in the intranuclear region. These results suggest
      that DNA replication is temporally and spatially regulated in the 1-cell embryos
      and that acetylation of histones, but not transcription, is involved in the
      regulation of DNA replication.

PMID- 10418112
TI  - Inactivation of p34cdc2 kinase by the accumulation of its phosphorylated forms in
      porcine oocytes matured and aged in vitro.
AB  - Culturing of matured porcine oocytes in vitro results in the enhancement of their
      cytoplasmic ability for oocyte activation (so-called ageing), although they are
      arrested at metaphase II. The enhanced ability for oocyte activation is related
      to decreased activity of the maturation promoting factor (MPF). In the present
      study we clarified the molecular mechanism of MPF inactivation during ageing,
      especially the changes in the phosphorylation status of p34cdc2, a catalytic
      subunit of MPF, compared with that in fertilised oocytes. The MPF activity
      decreased gradually when maturation culture was prolonged from 36 to 72 h,
      confirming the decreasing MPF activity in aged oocytes. The activity of 48 h
      matured oocytes also decreased after in vitro fertilisation. Immunoblotting of
      p34cdc2 with anti-PSTAIRE antibody revealed that the culturing of matured oocytes
      induces a gradual increase in pre-MPF, which is a p34cdc2 and cyclin B complex
      inactivated by phosphorylation at the inhibitory phosphorylation site of p34cdc2.
      In contrast, pre-MPF decreased after fertilisation, indicating the degradation of
      cyclin B. These results suggest that the molecular mechanisms of inactivation of
      MPF are different between oocyte activation and ageing, and that the mechanism
      during ageing might be based on the inhibitory phosphorylation of p34cdc2,
      whereas that of oocyte activation is based on the degradation of cyclin B.

PMID- 10418113
TI  - Mitogen-activated protein kinase in human eggs.
AB  - Mitogen-activated protein (MAP) kinase in human eggs has been investigated by
      using immunoblotting with both anti-Active MAPK and anti-ERK2 antibodies. The
      results showed that the main form of MAP kinase was p42ERK2. It was in a
      dephosphorylated form in oocytes at the germinal vesicle stage, but fully
      phosphorylated in unfertilised mature eggs. MAP kinase phosphorylation was
      significantly decreased when pronuclei were formed after intracytoplasmic sperm
      injection. Neither MAP kinase expression nor activity was detected in
      morphologically degenerated eggs. Although MAP kinase still existed in early
      embryos arrested at the 8-cell or morula stages, little, if any, activity could
      be detected. These data suggest that MAP kinase may play an important role in the
      cell cycle regulation of human eggs, as in other mammalian species.

PMID- 10418114
TI  - Severe vs. nonsevere firesetters revisited.
AB  - The study reported here compares a group of 75 severe firesetters with a group of
      105 nonfiresetters and minor firesetters along 32 variables that have been
      positively correlated with juvenile firesetting behavior. A chisquare analysis of
      the data revealed that the frequencies observed in the 75 "severe" cases differ
      significantly from those in the "nonsevere" group. A prediction equation was
      derived from the 14 most salient variables. This equation can be used to
      differentiate severe/high-risk from minor/low-risk firesetters 95% of the time.

PMID- 10418115
TI  - School-based peer sexual harassment.
AB  - Peer sexual harassment in schools is an often overlooked problem that contributes
      to a hostile school environment: one major study found that 85% of girls and 76%
      of boys reported experiencing some form of sexual harassment in school. This
      article describes the extent and impact of peer sexual harassment in schools and
      the responses of the victims, school personnel, and perpetrators to peer sexual
      harassment. It discusses and analyzes the evolution of peer sexual harassment
      lawsuits and the recent U.S. Supreme Court decision concerning such actions. It
      concludes steps that social workers and other school personnel should take to
      prevent or alleviate such problems.

PMID- 10418116
TI  - Caregiver substance abuse among maltreated children placed in out-of-home care.
AB  - Child protective services (CPS) case records of 639 children placed in out-of
      home care due to maltreatment were reviewed, and substance abuse by the child's
      caregiver prior to the child's placement was evaluated systematically. Based on
      several different sources of information, 79% of the caregivers were found to
      meet the criteria for caregiver substance abuse (CSA). Children with and without
      evidence of CSA differed on age, ethnicity, family composition, and type of
      maltreatment. The importance of operational specificity in defining CSA and
      implications for policy and service delivery are discussed.

PMID- 10418117
TI  - Responding to children's disclosure of familial abuse: what survivors tell us.
AB  - This study is based on the reports of 384 adults who were abused physically,
      sexually, and/or emotionally in childhood by family members. It describes the
      survivors' attempts, as children, to get help by disclosing the abuse to someone
      who might intervene; those who did not disclose explain their reasons. The
      results indicate that disclosure usually did not bring an end to the abuse, and
      that little action was taken to control the perpetrator, even after disclosure
      took place. The responses received by the children to their disclosure are linked
      to their levels of self-esteem and family functioning as adults.

PMID- 10418118
TI  - Social work intervention with Bedouin-Arab children in the context of blood
      vengeance.
AB  - Blood vengeance is a culturally specific phenomenon that can place Bedouin-Arab
      children at high risk of neglect. This case study examines the psychological and
      social implications of vengeance on children, the children's coping strategies,
      and the role of social work. The social work function includes
      nonauthoritarianism, strategies for forming a positive helping alliance, and
      various forms of culturally sensitive assessment and intervention. The study
      therefore yields insight into bridging the emic-etic gap in conceptualizing and
      responding to child neglect in a non-Western society.

PMID- 10418119
TI  - Behaviorally impaired children in out-of-home care.
AB  - This study was undertaken to determine the nature of the out-of-home care
      placement experience for 131 behaviorally impaired children entering care over
      the course of a year in Nebraska. Variables analyzed included behavioral
      impairment, age at entry, age at termination, gender, race/ethnicity, family
      violence, geographical area before and at termination, closeness to home of most
      recent placement, and length of time in care. Multiple regression analysis showed
      that behavioral impairment was the strongest predictor of length of time in care,
      accounting for 2.4% of the variability.

PMID- 10418121
TI  - Increased levels of DNA topoisomerases in cultured CHO cells treated with the
      antitumour drug 5-azacytidine.
AB  - Cultured Chinese hamster ovary (CHO) cells were treated with the cytidine
      analogue 5-azacytidine (5-azaC) which, in good agreement with results previously
      described from studies carried out in other primary or established mammalian cell
      lines, resulted in extensive chromosome decondensation and a shift in the time of
      replication of normally late-replicating heterochromatin to earlier replication.
      DNA topoisomerases (mainly topo I) have been involved in transcription, and the
      hypomethylating effect of 5-azaC reportedly results in the expression of silenced
      genes. Whether such an increase in transcription is paralleled by increased
      levels of both topo I and topo II, as well as by an enhancement in the
      topoisomerase activities, has been investigated in this work. The results seem to
      suggest that both the relative amount of topoisomerases and their activities are
      enhanced after a protracted treatment with the cytidine analogue over those
      observed in untreated controls. These observations could be significant for
      antitumour therapy.

PMID- 10418120
TI  - Effect of aflatoxin G1 on germination, growth and metabolic activities of some
      crop plants.
AB  - The effect of different concentrations of aflatoxin G1 on growth and germination
      of Zea mays and Vicia faba seeds, as well as on some biochemical parameters viz
      chlorophyll, carotenoid, protein and lipid content of seedlings, were studied.
      Inhibition of seed germination and seedling growth of maize and broad bean
      increased with increases in toxin concentration. A reduction in carbohydrates in
      the shoot systems of maize and broad bean was accompanied by a corresponding
      reduction in chlorophyll content. The total proteins and total lipids of V. faba
      were significantly greater at a 10 micrograms/ml concentration of aflatoxin G1,
      whereas in Z. mays significant inhibition (p < 0.05) was observed. At 5.0
      micrograms/ml aflatoxin G1 lipids and proteins were reduced in both plants but
      the effect was less obvious at lower concentrations.

PMID- 10418122
TI  - Two-carbon bridge substituted cocaines: enantioselective synthesis, attribution
      of the absolute configuration and biological activity of novel 6- and 7
      methoxylated cocaines.
AB  - In an effort to learn more about the general structure-activity relationships of
      cocaine with the aim to elucidate those structural features that might confer
      antagonistic properties to such analogues, we describe herein our synthetic
      efforts to prepare two-carbon bridge functionalized (methoxylated and
      hydroxylated) analogues. Our approach makes use of a modification of the
      classical Willstatter synthesis of cocaine: Mannich type cyclization of
      acetonedicarboxylic acid monomethyl ester with methylamine hydrochloride and 2
      methoxysuccindialdehyde in a citrate buffer solution afforded the 6- and 7
      substituted 2-carbomethoxy-3-tropinones 3a,b and 4a,b in approximate yields of
      64%. Reduction of the (+/-)-tropinone derivatives was performed with sodium
      amalgam in a sulfuric acid solution to afford a mixture of (+/-)-methoxyecgonine
      and (+/-)-methoxypseudoecgonine derivatives 5, 11 and 6, 7, 12, 13. Benzoylation
      of these alcohols yielded the desired cocaine and pseudococaine-like compounds 8,
      14 and 9, 10, 15, 16. Additionally, we show that enzymatic hydrolysis of these
      cocaine analogues using pig liver esterase (PLE) affords a practical means for
      achieving their chemical resolution. The enantiomers of the methoxycocaine
      analogues were also prepared starting from chiral (+)- and (-)-6
      methoxytropinone. All new analogues were examined for their ability to displace
      [3H]mazindol binding and to inhibit high-affinity uptake of [3H]dopamine into
      striatal nerve ending (synaptosomes). It appeared evident that methoxylation of
      the cocaine two-carbon bridge provides compounds of particular interest: the Ki
      for the binding of the methoxypseudococaines is about two to four times smaller
      than the Ki for inhibition of dopamine uptake, thus enabling these compounds
      capable of countering the effects of cocaine to some extent.

PMID- 10418123
TI  - Ergoline derivatives: receptor affinity and selectivity.
AB  - Ergot comprises a group of indole alkaloids which are predominantly found in
      various species of the ascomycete Claviceps. In pharmacopoeias, the sclerotia of
      Claviceps purpurea (Fr.) Tulasne parasitizing on rye, Secale cereale L., are
      designed as ergot or Secale cornutum. Now, the term ergot is used in a broader
      sense to describe the sclerotia of various Claviceps species growing on different
      host plants or their saprophytic mycelia. Due to their many fascinating features,
      there is a continuing and extensive interest in these secondary metabolites.
      Thus, the chemistry of ergot alkaloids and derivatives has presented many
      challenges to organic chemists. The ergot alkaloids and derivatives have
      attracted great interest for their broad spectrum of pharmacological action that
      includes central, neurohumoral and peripheral effects. These are mainly responses
      mediated by noradrenaline, serotonin, or dopamine receptors. No other group of
      natural products exhibits such a wide spectrum of biological action. For this
      reason, ergot has been termed a veritable treasure house of pharmacological
      constituents'. Moreover, ergot alkaloids have been an important stimulus in the
      development of new drugs by providing structural prototypes of molecules with
      pronounced pharmacological activities. This concise review, moving from the
      experience of our group in Pharmacia & Upjohn, will briefly mention the most
      representative ergoline derivatives featured in the literature. Our work in this
      field originated compounds with quite different pharmacological activities. In
      fact, by continuous modification of the same main template structure, the
      ergoline skeleton, it ultimately led to the development of new dopaminergic
      agents and to the identification of new series of serotonergic agents.

PMID- 10418124
TI  - Heterocyclic NO prodrugs.
AB  - An overview of the different heterocyclic NO-releasing compounds is given.
      Mesoionic heterocycles like sydnone imines are one example. This class is
      discussed on the synthesis and the mechanism of NO formation from Molsidomine and
      its first metabolite SIN-1. Furthermore, 1,2,3,4 oxatriazolium olates and
      imidates are presented in an example of the synthesis of GEA-3175. Heterocyclic N
      oxides are another group of compounds capable of NO release under certain
      conditions. This class is discussed in the example of furoxane carboxamides like
      CAS-1609, and some SAR-data show the great impact of intramolecular hydrogen
      bridges on their in vitro activity. Each class of compounds requires different
      cofactors for NO release: sydnone imines need oxidants like oxygen, furoxanes are
      converted to NO via reaction with thioles.

PMID- 10418125
TI  - In vitro hepatic microsomal metabolism of N-benzyl-N-methylaniline.
AB  - In the present study, the in vitro microsomal metabolism of a tertiary aniline, N
      benzyl-N-methylaniline (NBNMA) was studied to determine whether this compound
      produces an amide derivative (benzoyl) together with N-dealkylation and C- and N
      oxidation products as metabolites. The preparations of the corresponding
      potential metabolites were undertaken and were separated using TLC and HPLC.
      Incubations were performed using rat microsomal preparations fortified with
      NADPH. The substrate and its potential metabolites were extracted into
      dichloromethane in the presence of NaCl and examined by TLC and HPLC-UV. The
      results indicated that NBNMA did not produce the corresponding amide (benzoyl
      derivative) or N-oxide metabolite but was dealkylated to the corresponding
      secondary amine. Two p-hydroxylated phenolic metabolites were also observed.
      These findings support the concept that nitrones are essential intermediate
      metabolites for the formation of amides from secondary aromatic amines (chemical
      rearrangement to amide via an oxaziridine intermediate). The carbinolamine
      produced from NBNMA does not seem stable enough to allow further oxidation to the
      amide and therefore this intermediate is broken down to the dealkylation
      products. N-Dealkylations and p-hydroxylations are major metabolic reactions
      following in vitro hepatic microsomal metabolism of the benzylic tertiary
      aniline, NBNMA.

PMID- 10418127
TI  - Penetration of beta-lactamase inhibitors into the periplasm of gram-negative
      bacteria.
AB  - The effectiveness of a beta-lactamase inhibitor/beta-lactam combination against
      Gram-negative pathogens depends on many interplaying factors, one of which is the
      penetration of the inhibitor across the outer membrane. In this work we have
      measured the relative penetrations of clavulanic acid, sulbactam, tazobactam and
      BRL 42715 into two strains of Escherichia coli producing TEM-1 beta-lactamase,
      two strains of Klebsiella pneumoniae producing either TEM-1 or K-1, and two
      strains of Enterobacter cloacae each producing a Class C beta-lactamase. It was
      shown that clavulanic acid penetrated the outer membranes of all these strains
      more readily than the other beta-lactamase inhibitors. For the strains of E. coli
      and K. pneumoniae clavulanic acid penetrated approximately 6 to 19 times more
      effectively than tazobactam, 2 to 9 times more effectively than sulbactam and 4
      to 25 times more effectively than BRL 42715. The superior penetration of
      clavulanic acid observed in this study is likely to contribute to the efficacy of
      clavulanic acid/beta-lactam combinations in combating beta-lactam resistant
      bacterial pathogens.

PMID- 10418126
TI  - Investigation of steroid receptor function in the budding yeast Saccharomyces
      cerevisiae.
AB  - Steroid hormones are small lipophilic molecules that control a wide range of
      responses in both the developing and adult organism. The actions of these
      molecules are mediated by soluble receptor proteins that function as hormone
      activated transcription factors. The first steroid receptors were expressed in
      the yeast Saccharomyces cerevisiae over 10 years ago, and to date virtually all
      the classical steroid receptors, together with a number of non-steroid members of
      the nuclear receptor superfamily, have been expressed in yeast. The ability to
      reconstitute steroid receptor signalling in yeast cells by co-expression of the
      receptor protein and a reporter gene driven by the appropriate hormone response
      element has presented researchers with a powerful model system for investigating
      receptor action. In this review, the use of yeast-based steroid receptor
      transactivation assays to investigate the roles of molecular chaperones, the
      mechanisms of DNA binding and gene activation, and the functional properties of
      hormone mimics will be discussed.

PMID- 10418128
TI  - Effects of pressure stress on the fission yeast Schizosaccharomyces pombe cold
      sensitive mutant nda3.
AB  - To investigate the influence of pressure stress on the cell cycle of
      Schizosaccharomyces pombe, we used a cold-sensitive nda3-KM311 mutant which
      arrests cell division at a step similar to the mitotic prophase, proposed by
      Hiraoka and colleagues (Cell 39 (1984) 349-358), under the restrictive
      temperature, 20 degrees C. The nda3-KM311 cells were first aerobically grown at
      30 degrees C, transferred to 20 degrees C for 4 h and shifted to a permissive
      temperature of 36 degrees C for 15 min. The cells were treated with 100-200 MPa
      pressure and studied by electron and fluorescence microscopy. At 100 MPa, the
      nuclear membrane was damaged and the matrix of mitochondria had an electron-dense
      area. At 150 MPa, the nuclear membrane was broken over broad areas; numerous
      small vacuoles had fused into large pieces. Actin patches were concentrated in
      the central region and actin rings were seen in the 20 degrees C-grown cells.
      Even at 100 MPa, specific actin distribution was lost. Although at 100 MPa, long
      and fine actin cables were seen all over the cells, large actin patches and the
      actin rings remained in the center of the cell. They changed into thick and short
      cables at 150 MPa and above 200 MPa they decomposed but the actin ring was
      visible even with faint fluorescence. Immunoelectron microscopic observation
      confirmed this phenomenon.

PMID- 10418129
TI  - Transcription of cspA, the gene for the major cold-shock protein of Escherichia
      coli, is negatively regulated at 37 degrees C by the 5'-untranslated region of
      its mRNA.
AB  - The gene for CspA, the major cold-shock protein in Escherichia coli, is tightly
      regulated at both optimal and low temperatures. While CspA is drastically induced
      after temperature downshift, it is hardly detectable at 37 degrees C. Here we
      demonstrate that the deletion of parts of the 5'-untranslated region (5'-UTR) of
      the cspA mRNA results in constitutive expression of CspA at 37 degrees C. By
      analyzing the amounts and the stabilities of the mRNAs produced from the deletion
      constructs, we rule out the possibility that the CspA production is due to the
      stabilization of the mutant mRNAs. We propose that significant premature
      termination or pausing occurs during the transcription of the unusually long 5'
      UTR of the cspA mRNA at 37 degrees C, which represents a new mechanism that
      contributes to the tight repression of CspA production at higher temperature.

PMID- 10418130
TI  - Studies of the subtilin leader peptide as a translocation signal in Escherichia
      coli K12.
AB  - Subtilin is an antimicrobial peptide of the lantibiotic family that is produced
      by Gram-positive Bacillus subtilis, and its biosynthesis involves expression of
      presubtilin which consists of a leader segment and a mature segment. The leader
      segment is unlike a typical sec-type general secretion signal, and its ability to
      mediate translocation through a non-sec pathway has been previously studied by
      fusing the subtilin leader to an alkaline phosphatase reporter and expressing it
      in B. subtilis 168 [Izaguirre, G. and Hansen, J. N. (1997) Appl. Environ.
      Microbiol. 63, 3965-3971]. In this work, we have expressed the same subtilin
      leader-AP fusion in Gram-negative Escherichia coli, and found that the AP
      polypeptide is translocated into the periplasmic compartment and assembles into
      an enzymatically active form. The subtilin leader segment was not cleaved from
      this enzymatically active AP, which remained associated with the membrane.
      Conversion of the cells to spheroplasts followed by treatment with proteinase K
      showed that about 50% of the bound AP was sufficiently exposed on the surface of
      the spheroplasts to be inactivated by proteolytic cleavage.

PMID- 10418131
TI  - Identification of the promoter region of the Xanthomonas campestris pv. citri
      recA gene responsible for induction by DNA-damaging agents.
AB  - The abundance of the RecA protein and of recA transcripts was markedly increased
      on exposure of Xanthomonas campestris pathovar citri to various DNA-damaging
      agents, including mitomycin C. The promoter sequence responsible for mediating
      the sensitivity of recA expression to DNA damage was investigated by subcloning a
      426-bp restriction fragment of the 5' untranslated and coding region of the gene
      into a promoterless vector containing the luxAB genes of Vibrio fischeri.
      Xanthomonas campestris pv. citri cells transformed with this vector responded to
      DNA-damaging agents with a marked increase in luciferase activity. Deletion of
      nucleotides from the 5' end of the recA fragment inserted into the reporter
      plasmid revealed that the 58 bp upstream of the transcription initiation site are
      sufficient to mediate induction of recA expression by mitomycin C.

PMID- 10418132
TI  - Hemolysin of Aeromonas sobria stimulates production of cyclic AMP by cultured
      cells.
AB  - Hemolysin of Aeromonas sobria possesses both cytotoxic activity against mammalian
      cells and enterotoxic activity. Histopathological examination revealed that
      hemolysin causes diarrhea without damaging the intestinal epithelial cells. And
      the fluid accumulated in the mouse intestinal loop by the action of the hemolysin
      is watery. These observations indicated that the enterotoxic activity of
      hemolysin is not dependent on its cytotoxic activity. To clarify the mechanism of
      the enterotoxic action of hemolysin, we examined cyclic nucleotide levels in
      cultured cells exposed to this toxin. These results showed that hemolysin
      stimulates the production of cyclic AMP in cultured cells and the cyclic AMPs
      thus produced emerge in the milieu of cells.

PMID- 10418133
TI  - Determination of the genome size of Ehrlichia spp., using pulsed field gel
      electrophoresis.
AB  - Ehrlichiae are obligatory intracellular, Gram-negative bacteria which belong to
      the alpha subclass of the phylum Proteobacteria and are responsible for
      infectious diseases of humans. Little is known about genetics and genomic
      organization of Ehrlichia spp. The genome sizes of four representatives of the
      genus Ehrlichia were determined for the first time by pulsed field gel
      electrophoresis. The sizes for E. sennetsu, E. risticii, E. chaffeensis (strain
      Arkansas and strain 91HE17), and the HGE agent were 878.5 kb, 880.3 kb, 1225.8
      kb, 1262.3 kb and 1494 kb respectively.

PMID- 10418134
TI  - The respiratory burst-inhibiting acid phosphatase AcpA is not essential for the
      intramacrophage growth or virulence of Francisella novicida.
AB  - Acid phosphatases capable of inhibiting the respiratory burst of neutrophils have
      been identified in certain intracellular pathogens. Here we evaluate the role of
      AcpA, a respiratory burst-inhibiting acid phosphatase of Francisella, in the
      virulence and intracellular growth of this organism. An F. novicida acpA null
      mutant was created and found to exhibit wild-type growth kinetics in both cell
      line and inflammatory mouse macrophages. The acpA mutant also shows wild-type
      replication in the spleens of experimentally infected mice. These data suggest
      that AcpA is not essential for the intracellular growth or virulence of F.
      novicida.

PMID- 10418135
TI  - Identification of lactoferrin-binding proteins in bovine mastitis-causing
      Streptococcus uberis.
AB  - All strains of Streptococcus uberis evaluated bound to lactoferrin (Lf) in milk
      as detected by polyacrylamide gel electrophoresis and Western blotting. A biotin
      avidin-based microplate binding assay and ELISA also revealed that these
      bacterial strains bound to purified Lf. Binding of bacteria of Lf was not
      inhibited by mannose and galactose, indicating that glycosidic domains of the Lf
      molecule were not involved in binding. Lf binding was also unaffected by bovine
      transferrin. Western blot analysis demonstrated that there were at least two
      bacterial proteins involved in Lf-binding. Lf binding by S. uberis could enable
      this bacterium to acquire iron necessary for its growth.

PMID- 10418136
TI  - Plasmid-encoded tetracycline resistance in Salmonella enterica subsp. enterica
      serovars choleraesuis and typhimurium: identification of complete and truncated
      Tn1721 elements.
AB  - During routine screening of Salmonella enterica subsp., S. enterica isolates of
      animal origin for plasmid-encoded tetracycline resistance, two tetracycline
      resistance plasmids, the 50 kbp plasmid pGFT3 of Salmonella choleraesuis and the
      9.5 kbp plasmid pGFT4 of Salmonella typhimurium var. Copenhagen DT002, were
      detected. The respective tetracycline resistance genes (tet) were identified by
      hybridization and PCR analysis to belong to hybridization class A. Conjugation
      experiments identified plasmid pGFT3 as a conjugative plasmid. Molecular analysis
      of the tet(A) gene area and the flanking regions identified a complete Tn1721
      like transposon on plasmid pGFT3 and a truncated Tn1721-like element on plasmid
      pGFT4. The complete Tn1721-like element was integrated into a transposase reading
      frame of a truncated Tn3 transposon also located on plasmid pGFT3. The truncated
      Tn1721-like element of plasmid pGFT4 lacked the entire transposase part. This
      Tn1721-relic was integrated in an unknown reading frame which on amino acid level
      showed homology to the Rop protein of Escherichia coli. A model for the deletion
      of the transposase part was developed on the basis of the sequences present at
      the termini of the truncated Tn1721-like element.

PMID- 10418137
TI  - The cytoplasmic helical linker domain of receptor histidine kinase and methyl
      accepting proteins is common to many prokaryotic signalling proteins.
AB  - Mutations in the cytoplasmic linker regions of receptor histidine kinase and
      chemoreceptor proteins have been shown previously to significantly impair
      receptor functions. Here we demonstrate significant sequence similarities between
      these regions in numerous histidine kinases, methyl-accepting proteins, adenylyl
      cyclases and other prokaryotic signalling proteins. It is suggested that these
      'HAMP domains' possess roles of regulating the phosphorylation or methylation of
      homodimeric receptors by transmitting the conformational changes in periplasmic
      ligand-binding domains to cytoplasmic signalling kinase and methyl-acceptor
      domains.

PMID- 10418138
TI  - The actin-based motility of intracellular Listeria monocytogenes is not
      controlled by small GTP-binding proteins of the Rho- and Ras-subfamilies.
AB  - In this study, we analyzed whether the actin-based motility of intracellular
      Listeria monocytogenes is controlled by the small GTP-binding proteins of the Rho
      and Ras-subfamilies. These signalling proteins are key regulatory elements in
      the control of actin dynamics and their activity is essential for the maintenance
      of most cellular microfilament structures. We used the Clostridium difficile
      toxins TcdB-10463 and TcdB-1470 to specifically inactivate these GTP-binding
      proteins. Treatment of eukaryotic cells with either of these toxins led to a
      dramatic breakdown of the normal actin cytoskeleton, but did not abrogate the
      invasion of epithelial cells by L. monocytogenes and had no effect on the actin
      based motility of this bacterial parasite. Our data indicate that intracellular
      Listeria reorganize the actin cytoskeleton in a way that circumvents the control
      mechanisms mediated by the members of the Rho- and Ras-subfamilies that can be
      inactivated by the TcdB-10463 and TcdB-1470 toxins.

PMID- 10418139
TI  - Organization of the genes involved in the ribulose monophosphate pathway in an
      obligate methylotrophic bacterium, Methylomonas aminofaciens 77a.
AB  - The 4.4-kb PstI fragment harboring the gene encoding 3-hexulose-6-phosphate
      synthase, rmpA, which was previously cloned from the chromosome of an obligate
      methylotroph, Methylomonas aminofaciens 77a, was investigated in detail. In
      addition to the rmpA gene, the fragment contained three open reading frames
      encoding transaldolase (rmpD), IS10-R (rmpI), and 6-phospho-3-hexuloisomerase
      (PHI) (rmpB). The rmpB gene product was overproduced in Escherichia coli cells,
      purified to homogeneity, and then enzymatically identified as PHI. The gene
      organization of the ribulose monophosphate pathway enzymes together with a
      transposon, IS10-R, is discussed from both evolutionary and regulatory aspects.

PMID- 10418140
TI  - Dissimilatory Fe(III) reduction by Clostridium beijerinckii isolated from
      freshwater sediment using Fe(III) maltol enrichment.
AB  - A microorganism which reduces Fe(III) during the fermentation of glucose was
      isolated from freshwater sediment. The Fe(III) was supplied to enrichment
      cultures as a soluble complex with the bidentate ligand maltol (3-hydroxy-2
      methyl-4-pyrone). Advantages that were afforded by the use of Fe(III)(maltol)3
      over previously published methods included negation of the requirement for assays
      of Fe(II) formation. Because Fe(III)(maltol)3 has a characteristic deep red
      colour, Fe(III) reduction could be quantified spectrophotometrically by
      monitoring the disappearance of the complex in liquid cultures. Furthermore,
      Fe(III) reduction on agar plates containing the complex was apparent by zones of
      decolourisation around the bacterial colonies. 16S rRNA gene sequencing indicated
      the isolate to be a strain of Clostridium beijerinckii. Growth experiments were
      performed on the isolate in batch cultures with varying concentrations of Fe(III)
      citrate and 50 mM glucose. Increasing the level of Fe(III) citrate present was
      found to alter the fermentation balance, with less acidic products being formed.
      The presence of Fe(III) led to increases in the growth rate and growth yield,
      which were both approximately doubled when the supply of the cation reached 25
      mM. A NAD(P)H-dependent Fe(III) reductase activity was localised to the bacterial
      membrane and found not to be sensitive to respiratory inhibitors. Taken together,
      these data suggest that dissimilatory Fe(III) reduction by the isolate provides a
      means of utilising the cation as an electron sink, thus facilitating pyridine
      nucleotide to be recycled during fermentative metabolism.

PMID- 10418141
TI  - Thermostable alpha-galactosidase from Bacillus stearothermophilus NUB3621:
      cloning, sequencing and characterization.
AB  - An alpha-galactosidase gene from the thermophilic bacterium Bacillus
      stearothermophilus NUB3621 was cloned, sequenced, expressed in Escherichia coli
      and the recombinant protein was purified. The Bacillus enzyme, designated AgaN,
      is similar to alpha-galactosidases of family 36 in the classification of glycosyl
      hydrolases. The enzyme was estimated to be a tetramer with a molecular mass of
      subunits 80.3 kDa. The purified AgaN is thermostable and has a temperature
      optimum of activity at 75 degrees C and a half-life of inactivation of 19 h at 70
      degrees C. AgaN displays high affinity for oligomeric substrates such as
      melibiose and raffinose and is able to hydrolyze raffinose in the presence of 60%
      sucrose with high efficiency.

PMID- 10418142
TI  - Role of the amino-terminal region of the DnaA protein in opening of the duplex
      DNA at the oriC region.
AB  - We report in this paper that the amino acid residues Ile-26 and Leu-40 of the
      DnaA protein are essential for the DNA replication activity in vitro. Lines of
      evidence to support this conclusion are as follows. Variants of the DnaA protein
      containing either an Ile-26-Ser or Leu-40-Ser replacement were unable to support
      oriC DNA replication in vitro. Though the mutant DnaA proteins retained the
      capability to bind oriC DNA, they were unable to open the duplex DNA at oriC.
      Based on these and other results, we conclude that the N-terminal region of the
      DnaA protein is involved in the oligomerization of this protein, an essential
      step for the duplex opening activity at oriC.

PMID- 10418143
TI  - Identification of the genes encoding enzymes involved in the early biosynthetic
      pathway of pteridines in Synechocystis sp. PCC 6803.
AB  - The biosynthetic pathway for the pteridine moiety of cyanopterine, as well as
      tetrahydrobiopterine, has been investigated in Synechocystis sp. PCC 6803. Open
      reading frames slr0426, slr1626, slr0078 and sll0330 of the organism putatively
      encoding GTP cyclohydrolase I, dihydroneopterine aldolase, 6
      pyruvoyltetrahydropterine synthase and sepiapterine reductase, respectively, have
      been cloned into T7-based vectors for expression in Escherichia coli. The
      recombinant proteins have been purified to homogeneity and demonstrated to
      possess expected genuine activities except that of sll0330. Our result is the
      first direct evidence for the functional assignment of the open reading frames in
      Synechocystis sp. PCC 6803. Furthermore, the 6-pyruvoyltetrahydropterine synthase
      gene is demonstrated for the first time in prokaryotes. Based on the result,
      biosynthesis of cyanopterine is discussed.

PMID- 10418144
TI  - Biochemical diversity of Mycoplasma fermentans strains.
AB  - In this study, the metabolism of a diverse range of Mycoplasma fermentans strains
      was investigated. It was shown that the ability to utilise glucose, fructose and
      N-acetylglucosamine differentiated strains, and that the patterns and kinetics of
      substrate utilisation were correlated with the site of isolation, i.e. joint
      fluid, respiratory tract, urinary tract or cell culture. Interestingly, isolates
      from the urogenital tract of AIDS patients used fructose in preference to
      glucose. There was also some correlation of fructose and N-acetylglucosamine
      utilisation of isolates with M. fermentans sub-groups, identified in an
      independent study, and based on the distribution of insertion sequence-like
      elements in the M. fermentans genome.

PMID- 10418145
TI  - Co-expression of 3-ketoacyl-ACP reductase and polyhydroxyalkanoate synthase genes
      induces PHA production in Escherichia coli HB101 strain.
AB  - The Escherichia coli 3-ketoacyl-ACP reductase gene (fabGEc) was cloned using a
      PCR technique to investigate the metabolic link between fatty acid metabolism and
      polyhydroxyalkanoate (PHA) production. Three plasmids respectively harboring
      fabGEc and the poly-3-hydroxyalkanoate synthesis genes phaCAc and phaC1Ps from
      Aeromonas caviae and Pseudomonas sp. 61-3 respectively were constructed and
      introduced into E. coli HB101 strain. On a two-stage cultivation using
      dodecanoate as the sole carbon source, recombinant E. coli HB101 strains
      harboring fabGEc and phaC genes accumulated PHA copolymers (about 8 wt% of dry
      cell weight) consisting of several (R)-3-hydroxyalkanoate units of C4, C6, C8,
      and C10. It has been suggested that overexpression of the fabGEc gene leads to
      the supply of (R)-3-hydroxyacyl-CoA for PHA synthesis via fatty acid degradation.

PMID- 10418146
TI  - A conspicuous adaptability to antibiotics in the Escherichia coli mutator strain,
      dnaQ49.
AB  - By repeating the cycle of mutagenesis and selection, the Escherichia coli dnaQ49
      mutator acquired high level resistance to ampicillin (30,000 micrograms ml-1),
      streptomycin (26,000 micrograms ml-1) and ofloxacin (3000 micrograms ml-1). Under
      the strong pressure of ofloxacin, dnaQ49 also followed the history of mutations
      in the gyrase and topoisomerase i.v. genes previously observed in clinical
      isolates of quinolone-resistant E. coli. The results of these in vitro
      experiments suggest that naturally existing mutators may participate in the rapid
      acquisition of resistance to various antibiotics in patients. A possible
      mechanism for the occurrence of this adaptability is discussed with special
      reference to the property of mutagenesis accompanying DNA replication.

PMID- 10418147
TI  - Microbial remediation of NTO in aqueous industrial wastes.
AB  - The bioremediation of aqueous wastes containing 5-nitro-1,2,4-triazol-3-one (NTO)
      was investigated. The microorganism used is a Bacillus licheniformis strain,
      isolated from the contaminated solutions by enrichment techniques. The
      biodegradation was carried out in the waste (15 g l-1 NTO) and proceeded through
      the nitroreduction of NTO, followed by the ring cleavage of the formed primary
      amine 5-amino-1,2,4-triazol-3-one (ATO). Both steps were optimized and according
      to the optimal conditions, the nitroreduction of NTO is total in 24 h, while the
      degradation of ATO requires 2 weeks of incubation. The end products of the
      biodegradation were carbon dioxide (40%), urea and a polar compound, assumed to
      be hydroxyurea. A mechanism of ATO ring cleavage was postulated in the light of
      experimental data, and led us to propose an overall degradation sequence for NTO.

PMID- 10418148
TI  - Development of a yeast-based assay system for monitoring microsatellite
      instability.
AB  - Simple sequence repeats (microsatellites) are found in all eukaryotic genomes.
      Instabilities within these sequences have been associated with several human
      disorders including Huntington's chorea and myotonic dystrophy. Further studies
      have identified links between microsatellite instability, faulty mismatch repair
      and certain human cancers, in particular a form of hereditary colorectal cancer.
      The assay system described here consists of a congenic set of yeast strains
      mutated in DNA replication and mismatch repair genes and assay plasmids with
      which it is possible to measure differences in microsatellite stability in the
      range of 5-850-fold. The development of this technology will allow monitoring of
      environmental and dietary influences on the genomic stability in the context of
      human disease.

PMID- 10418149
TI  - Effects of pre-protein overexpression on SecB synthesis in Escherichia coli.
AB  - Protein translocation through the cytoplasmic membrane of Escherichia coli
      involves cytosolic chaperones. The export-dedicated chaperone SecB mediates
      targeting of a subset of pre-proteins. In this report, synthesis of SecB in
      response to plasmid-mediated overexpression of pre-proteins was studied.
      Overexpression of SecB-dependent pre-proteins stimulated synthesis of SecB under
      conditions where the cellular export capacity was saturated or uncomplexed SecB
      was trapped. On the contrary, overexpression of SecB-independent pre-beta
      lactamase reduced the promoter activity of secB. The results suggest that
      uncomplexed SecB can be sequestered by synthesis of SecB-dependent pre-proteins.
      Furthermore, these data demonstrate the distinct action of the SecB- and signal
      recognition particle-dependent protein targeting pathways.

PMID- 10418150
TI  - Characterization of IS1541-like elements in Yersinia enterocolitica and Yersinia
      pseudotuberculosis.
AB  - We characterized Yersinia enterocolitica and Yersinia pseudotuberculosis
      insertion sequences related to insertion sequence 1541, recently identified in
      Yersinia pestis. For each of the two species, two insertion sequence copies were
      cloned and sequenced. Genetic elements from Y. pseudotuberculosis were almost
      identical to insertion sequence 1541, whereas these from Y. enterocolitica were
      less related. Phylogenetic analysis of the putative transposases encoded by
      insertion sequences from the three pathogenic members of the genus Yersinia
      showed that they clustered with those encoded by Escherichia coli and Salmonella
      enterica elements belonging to the insertion sequence 200/insertion sequence 605
      group. Insertion sequences originating from Y. pestis and Y. pseudotuberculosis
      constitute a monophyletic lineage distinct from that of Y. enterocolitica.

PMID- 10418152
TI  - Degradation of Candida albicans Can1 permease expressed in Saccharomyces
      cerevisiae.
AB  - The Candida albicans amino-acid Can1 permease expressed in Saccharomyces
      cerevisiae is degraded in the vacuole after internalisation by endocytosis. The
      CaCan1 inactivation and degradation is slow and not inducible by ammonium ions or
      'stress' conditions. Using Saccharomyces cerevisiae mutants defective in
      ubiquitin-protein ligase and ubiquitin-protein hydrolase we have shown that the
      degradation of heterologous CaCan1 permease is ubiquitin dependent.

PMID- 10418151
TI  - PCR amplification of the spliced leader gene for the diagnosis of trypanosomatid
      parasites of plants and insects in methanol-fixed smears.
AB  - A PCR-based method was adapted for the amplification of DNA from methanol-fixed
      smears of insects and plants parasitized by trypanosomatids. The PCR target was
      the multicopy spliced leader (SL) gene. Amplicons were hybridized with an
      oligonucleotide probe (SL3') specific for Phytomonas. The method has the
      advantage of dispensing with the cultivation of parasites, many of which are very
      fastidious or non-cultivable. The technique was applied to archival glass slides
      and to newly collected material. It proved to specific for Phytomonas spp.,
      enabling their detection in plants and insects. Sequence comparison of the
      amplicons obtained revealed the existence of different strains/species of
      Phytomonas circulating among diseased palsms and fruit.

PMID- 10418153
TI  - Peripheral encoding of behaviorally relevant acoustic signals in a vocal fish:
      single tones.
AB  - The midshipman fish, Porichthys notatus, generates acoustic signals for
      intraspecific communication. Nesting males produce long-duration "hums" which
      attract gravid females and can be effectively mimicked by pure tones. In this
      study we examine the encoding of tonal signals by the midshipman peripheral
      auditory system. Single-unit recordings were made from afferents innervating the
      sacculus while presenting sounds via an underwater loudspeaker. Units were
      characterized by iso-intensity spike rate and vector strength of synchronization
      curves, as well as by peristimulus time histograms. Additionally, response
      intensity curves and responses to long-duration (up to 10 s) stimuli were
      obtained. As has been seen in other teleosts, afferents had highly variable
      activity profiles. Excitatory frequencies ranged from 60 to over 300 Hz with most
      units responding best around 70 or 140 Hz. Thresholds at 90 Hz ranged from 95 to
      145 dB re 1 microPa. Strong synchronization provided a robust temporal code of
      frequency, comparable to that described for goldfish. Spike rate showed varying
      degrees of adaptation but high rates were generally maintained even for 10-s
      stimuli. The midshipman peripheral auditory system is well suited to encoding
      conspecific communication signals, but nonetheless shares many response patterns
      with the auditory system of other teleosts.

PMID- 10418154
TI  - Noise improves transfer of near-threshold, phase-locked activity of the cochlear
      nerve: evidence for stochastic resonance?
AB  - Stochastic resonance can be described as improved detection of weak periodic
      stimuli by a dynamic nonlinear system, resulting from the simultaneous
      presentation of a restricted dynamic range of low-intensity noise. This property
      has been reported in simple physical and biological activities. The present study
      describes data consistent with the interpretation that stochastic resonance can
      be observed in the response of cochlear neurons. These experiments utilized low
      levels (-5 to 25 dB SPL) of stimuli and noise (5 to 30 dB SPL). Stimuli consisted
      of simultaneously presented 8 kHz (F1) and 8.8 kHz (F2) tone bursts, which
      generated an 800 Hz F2-F1 cochlear nerve envelope ensemble response in the
      gerbil. The mean response threshold was approximately -3 dB SPL. Simultaneous
      presentation of a low-intensity wideband noise increased the amplitude of this
      response. This was observed with tonal stimuli having intensities of 0-5 dB SPL;
      responses to stimulus levels > 10 dB were attenuated by noise. Response amplitude
      was increased by noise levels of 10-15 dB; the amplitude was unaffected by lower
      levels of noise, and decreased in the presence of higher noise levels. These
      properties are compatible with those of stochastic resonance.

PMID- 10418155
TI  - Electric organ discharges of the gymnotiform fishes: III. Brachyhypopomus.
AB  - We measured and mapped the electric fields produced by three species of
      neotropical electric fish of the genus Brachyhypopomus (Gymnotiformes, Rham
      phichthyoidea, Hypopomidae), formerly Hypopomus. These species produce biphasic
      pulsed discharges from myogenic electric organs. Spatio-temporal false-color maps
      of the electric organ discharges measured on the skin show that the electric
      field is not a simple dipole in Brachyhypopomus. Instead, the dipole center moves
      rostro-caudally during the 1st phase (P1) of the electric organ discharge, and is
      stationary during the 2nd phase (P2). Except at the head and tip of tail,
      electric field lines rotate in the lateral and dorso-ventral planes. Rostrocaudal
      differences in field amplitude, field lines, and spatial stability suggest that
      different parts of the electric organ have undergone selection for different
      functions; the rostral portions seem specialized for electrosensory processing,
      whereas the caudal portions show adaptations for d.c. signal balancing and mate
      attraction as well. Computer animations of the electric field images described in
      this paper are available on web sites http:/(/) www.bbb.caltech.edu/ElectricFish
      or http:/(/)www.fiu.edu/-stoddard/electric fish.html.

PMID- 10418156
TI  - Preferences for and against stimuli paired with food.
AB  - Pigeons were presented with a concurrent-chains schedule in which terminal-link
      entries were assigned to two response keys on a percentage basis. The terminal
      links were fixed delays that sometimes ended with food and sometimes did not. In
      most conditions, 80% of the terminal links were assigned to one key, but a
      smaller percentage of the terminal links ended with food for this key, so the
      number of food reinforcers delivered by the two alternatives was equal. When the
      same terminal-link stimuli (orange houselights) were used for both alternatives,
      the pigeons showed a preference for whichever alternative delivered more frequent
      terminal links. When different terminal-link stimuli (green vs. red houselights)
      were used for the two alternatives, the pigeons showed a preference for whichever
      alternative delivered fewer terminal links when terminal-link durations were
      long, and no systematic preferences when terminal-link durations were short. This
      pattern of results was consistent with the predictions of Grace's (1994)
      contextual choice model. Preference for the alternative that delivered more
      frequent terminal links was usually stronger in the first few sessions of a
      condition than at the end of a condition, suggesting that the conditioned
      reinforcing effect of the additional terminal-link presentation was, in part,
      transitory.

PMID- 10418157
TI  - A discrimination analysis of training-structure effects on stimulus equivalence
      outcomes.
AB  - Experiments designed to establish stimulus equivalence classes frequently produce
      differential outcomes that may be attributable to training structure, defined as
      the order and arrangement of baseline conditional discrimination training trials.
      Several possible explanations for these differences have been suggested. Here we
      develop a hypothesis based on an analysis of the simple simultaneous and
      successive discriminations embedded in conditional discrimination training and
      testing within each of the training structures that are typically used in
      stimulus equivalence experiments. Our analysis shows that only the comparison-as
      node (many-to-one) structure presents all the simple discriminations in training
      that are subsequently required for consistently positive outcomes on all tests
      for the properties of equivalence. The sample-as-node (one-to-many) training
      structure does not present all the simple discriminations required for positive
      outcomes on either the symmetry or combined transitivity and symmetry
      (equivalence) tests. The linear-series training structure presents all the simple
      discriminations required for consistently positive outcomes on tests for
      symmetry, but not for symmetry and transitivity combined (equivalence) or
      transitivity alone. Further, the difference in the number of simple
      discriminations presented in comparison-as-node training versus the other
      training structures is larger when the intended class size is greater than three
      or the number of classes is larger than two. We discuss the relevance of this
      analysis to interpretations of stimulus equivalence research, as well as some
      methodological and theoretical implications.

PMID- 10418159
TI  - Optimal detection of flash intensity differences using rod photocurrent
      observations.
AB  - The rod photocurrent contains two noise components that may limit the
      detectability of flash intensity increments. The limits imposed by the low- and
      high-frequency noise components were assessed by computing the performance of an
      optimal detector of increments in flash intensity. The limits imposed by these
      noise components depend on the interval of observation of the photocurrent
      signal. When the entire photocurrent signal, lasting 3 or more seconds, is
      observed, the low-frequency component of the photocurrent noise (attributed to
      the quantal noise of the incoming light, as well as random isomerizations of
      enzymes within the phototransduction cascade) is the most significant limitation
      on detectability. When only the first 380 ms or less is observed, the high
      frequency component of the noise (due to the thermal isomerizations of the cGMP
      gated channel) presents a significant limit on the detectability of flashes.

PMID- 10418158
TI  - Network stability from activity-dependent regulation of neuronal conductances.
AB  - Activity-dependent plasticity appears to play an important role in the
      modification of neurons and neural circuits that occurs during development and
      learning. Plasticity is also essential for the maintenance of stable patterns of
      activity in the face of variable environmental and internal conditions. Previous
      theoretical and experimental results suggest that neurons stabilize their
      activity by altering the number or characteristics of ion channels to regulate
      their intrinsic electrical properties. We present both experimental and modeling
      evidence to show that activity-dependent regulation of conductances, operating at
      the level of individual neurons, can also stabilize network activity. These
      results indicate that the stomatogastric ganglion of the crab can generate a
      characteristic rhythmic pattern of activity in two fundamentally different modes
      of operation. In one mode, the rhythm is strictly conditional on the presence of
      neuromodulatory afferents from adjacent ganglia. In the other, it is independent
      of neuromodulatory input but relies on newly developed intrinsic properties of
      the component neurons.

PMID- 10418161
TI  - The continuum of operating modes for a passive model neuron.
AB  - Whether cortical neurons act as coincidence detectors or temporal integrators has
      implications for the way in which the cortex encodes information--by average
      firing rate or by precise timing of action potentials. In this study, we examine
      temporal coding by a simple passive-membrane model neuron responding to a full
      spectrum of multisynaptic input patterns, from highly coincident to temporally
      dispersed. The temporal precision of the model's action potentials varies
      continuously along the spectrum, depends very little on the number of synaptic
      inputs, and is shown to be tightly correlated with the mean slope of the membrane
      potential preceding the output spikes. These results are shown to be largely
      independent of the size of postsynaptic potentials, of random background synaptic
      activity, and of shape of the correlated multisynaptic input pattern. An
      experimental test involving membrane potential slope is suggested to help
      determine the basic operating mode of an observed cortical neuron.

PMID- 10418160
TI  - On the role of biophysical properties of cortical neurons in binding and
      segmentation of visual scenes.
AB  - Neuroscience is progressing vigorously, and knowledge at different levels of
      description is rapidly accumulating. To establish relationships between results
      found at these different levels is one of the central challenges. In this
      simulation study, we demonstrate how microscopic cellular properties, taking the
      example of the action of modulatory substances onto the membrane leakage current,
      can provide the basis for the perceptual functions reflected in the macroscopic
      behavior of a cortical network. In the first part, the action of the modulatory
      system on cortical dynamics is investigated. First, it is demonstrated that the
      inclusion of these biophysical properties in a model of the primary visual cortex
      leads to the dynamic formation of synchronously active neuronal assemblies
      reflecting a context-dependent binding and segmentation of image components.
      Second, it is shown that the differential regulation of the leakage current can
      be used to bias the interactions of multiple cortical modules. This allows the
      flexible use of different feature domains for scene segmentation. Third, we
      demonstrate how, within the proposed architecture, the mapping of a moving
      stimulus onto the spatial dimension of the network results in an increased speed
      of synchronization. In the second part, we demonstrate how the differential
      regulation of neuromodulatory activity can be achieved in a self-consistent
      system. Three different mechanisms are described and investigated. This study
      thus demonstrates how a modulatory system, affecting the biophysical properties
      of single cells, can be used to achieve context-dependent processing at the
      system level.

PMID- 10418162
TI  - On the approximation rate of hierarchical mixtures-of-experts for generalized
      linear models.
AB  - We investigate a class of hierarchical mixtures-of-experts (HME) models where
      generalized linear models with nonlinear mean functions of the form psi (alpha +
      xT beta) are mixed. Here psi (.) is the inverse link function. It is shown that
      mixtures of such mean functions can approximate a class of smooth functions of
      the form psi (h(x)), where h(.) epsilon W2;K infinity (a Sobolev class over [0,
      1]s), as the number of experts m in the network increases. An upper bound of the
      approximation rate is given as O(m-2/s) in Lp norm. This rate can be achieved
      within the family of HME structures with no more than s-layers, where s is the
      dimension of the predictor x.

PMID- 10418163
TI  - Low expression of the ClC-2 chloride channel during postnatal development: a
      mechanism for the paradoxical depolarizing action of GABA and glycine in the
      hippocampus.
AB  - In early postnatal development, during the period of synapse formation, gamma
      aminobutyric acid (GABA) and glycine, the main inhibitory transmitters in the
      adult brain, paradoxically excite and depolarize neuronal membranes by an outward
      flux of chloride. The mechanisms of chloride homeostasis are not fully
      understood. It is known that in adult neurons intracellular chloride accumulation
      is prevented by a particular type of chloride channel, the ClC-2. This channel
      strongly rectifies in the inward direction at potentials negative to ECl thus
      ensuring chloride efflux. We have tested the hypothesis that in the developing
      hippocampus, a differential expression or regulation of ClC-2 channels may
      contribute to the depolarizing action of GABA and glycine. We have cloned a
      truncated form of ClC-2 (ClC-2nh) from the neonatal hippocampus which lacks the
      157 bp corresponding to exon 2. In situ hybridization experiments show that ClC
      2nh is the predominant form of ClC-2 mRNA in the neonatal brain. ClC-2nh mRNA is
      unable to encode a full-length protein due to a frameshift, consequently it does
      not induce any currents upon injection into Xenopus oocytes. Low expression of
      the full-length ClC-2 channel, could alter chloride homeostasis, lead to
      accumulation of [Cl-]i and thereby contribute to the depolarizing action of GABA
      and glycine during early development.

PMID- 10418165
TI  - Field test of a paradigm: hysteresis of heart rate in thermoregulation by a free
      ranging lizard (Pogona barbata).
AB  - The discovery that changes in heart rate and blood flow allow some reptiles to
      heat faster than they cool has become a central paradigm in our understanding of
      reptilian thermoregulation. However, this hysteresis in heart rate has been
      demonstrated only in simplistic laboratory heating and cooling trials, leaving
      its functional significance in free-ranging animals unproven. To test the
      validity of this paradigm, we measured heart rate and body temperature (Tb) in
      undisturbed, free-ranging bearded dragons (Pogona barbata), the species in which
      this phenomenon was first described. Our field data confirmed the paradigm and we
      found that heart rate during heating usually exceeded heart rate during cooling
      at any Tb. Importantly, however, we discovered that heart rate was proportionally
      faster in cool lizards whose Tb was still well below the 'preferred Tb range'
      compared to lizards whose Tb was already close to it. Similarly, heart rate
      during cooling was proportionally slower the warmer the lizard and the greater
      its cooling potential compared to lizards whose Tb was already near minimum
      operative temperature. Further, we predicted that, if heart rate hysteresis has
      functional significance, a 'reverse hysteresis' pattern should be observable when
      lizards risked overheating. This was indeed the case and, during heating on those
      occasions when Tb reached very high levels (> 40 degrees C), heart rate was
      significantly lower than heart rate during the immediately following cooling
      phase. These results demonstrate that physiological control of thermoregulation
      in reptiles is more complex than has been previously recognized.

PMID- 10418164
TI  - Heritable variation in resistance to gastro-intestinal nematodes in an unmanaged
      mammal population.
AB  - The impact of parasites on natural populations has received considerable
      attention from evolutionary biologists in recent years. Central to a number of
      theoretical developments during this period is the assumption of additive genetic
      variation in resistance to parasites. However, very few studies have estimated
      the heritability of parasite resistance under field conditions, and those that
      have are mainly restricted to birds and their ectoparasites. In this paper, to
      our knowledge, we show for the first time in a free-ranging mammal population,
      Soay sheep (Ovis aries) living on the islands of St Kilda, that there is
      significant heritable variation in resistance to gastrointestinal nematodes. This
      result is consistent with earlier studies on this population which have indicated
      locus-specific associations with parasite resistance. We discuss our results in
      the context of current studies examining heritable resistance to parasites in
      domestic sheep and the possible mechanisms of selective maintenance of genetic
      variation for resistance to gastrointestinal nematodes in the St Kilda Soay sheep
      population.

PMID- 10418166
TI  - Trace element content of commercial shampoos: impact on trace element levels in
      hair.
AB  - Popular shampoos were screened for their contents in trace elements, using ICP-MS
      detection in a semi-quantitative mode. Hair samples from volunteers were analyzed
      before and after hair washing with selected shampoos to demonstrate the effect of
      the contamination and the impact on occupational medicine. While some shampoos
      showed high levels of certain elements, the degree of contamination on the hair
      was found to be negligible. Only one shampoo tested, formulated with selenium
      sulfide, was found to seriously contaminate the hair.

PMID- 10418167
TI  - Multi-elemental analysis of jet engine lubricating oils and hydraulic fluids and
      their implication in aircraft air quality incidents.
AB  - The flight crews of aircraft often report symptoms including dizziness, nausea,
      disorientation, blurred vision and tingling in legs and arms. Many of these
      incidents have been traced to contamination of cabin air with lubricating oil, as
      well as hydraulic fluid, constituents. Considering that these air contaminants
      are often subjected to temperatures in excess of 500 degrees C, a large number of
      different exposures can be expected. Although the reported symptoms are most
      consistent with exposures to volatile organic compounds, carbon monoxide, and the
      organophosphate constituents in these oils and fluids, the involvement of these
      agents has not been clearly demonstrated. Possible exposure to toxic elements,
      such as lead, mercury, thallium and others, have not been ruled out. In order to
      assess the potential of exposure to toxic elements a multi-elemental analysis was
      done on two hydraulic fluids and three lubricating oils which have been
      implicated in a number of air quality incidents. A secondary objective was to
      establish if the multi-elemental concentrations of the fluids tested are
      different enough to allow such an analysis to be used as a possible method of
      identifying the source of exposure that might have been present during aircraft
      air quality incidents. No significant concentrations of toxic elements were
      identified in any of the oils or hydraulic fluids. The elemental compositions of
      the samples were different enough to be used for identification purposes and the
      measurement of only three elements was able to achieve this. Whether these
      findings have an application, in aircraft air quality incident investigations,
      needs to be established with further studies.

PMID- 10418168
TI  - A study of fibrous aerosols in the home environment in Sosnowiec, Poland.
AB  - This work constitutes the first report on the concentration of airborne
      respirable fibers, and their length distribution in different groups of homes in
      Sosnowiec, Poland. The measurements have been made by using the MIE Laser Fiber
      Monitor FM-7400. Mean concentration level of the respirable fibers, longer than 5
      microns, ranged from 350 m-3 through 910 m-3 up to 1020 m-3 in the homes located
      in suburban areas, near the busy streets, and in the buildings covered with
      asbestos-cement sheets, respectively. These results indicate the outdoor asbestos
      containing materials as the main sources of airborne fibers inside the Sosnowiec
      dwellings.

PMID- 10418169
TI  - Strontium-90 concentration measurements in human bones and teeth in Greece.
AB  - Strontium-90 concentration was measured in human bones and teeth collected in
      Greece during the period 1992-1996. One hundred and five bone samples, mainly
      cancellous bone, and 108 samples, taken from a total of 896 individual teeth were
      processed. Samples were classified according to the age and sex of the donors.
      Samples were chemically pre-treated according to a specially devised method to
      enable extraction of 90Y, at equilibrium with 90Sr in the original sample.
      Subsequently, 90Y beta activity was measured with a gas proportional counter.
      Radiostrontium concentration in bone samples showed small variations with respect
      to age or sex, with an average value of 30 mBq 90Sr/g Ca. However, 90Sr
      concentration measurements in teeth demonstrated a pronounced structure, which
      clearly reflects contamination from the 1960s atmospheric nuclear weapons tests
      and the more recent Chernobyl accident. This difference is attributed to the
      different histological structure of skeletal bones and teeth, the later
      consisting mainly of compact bone. An age-dependent model for radiostrontium
      concentration in human bones and teeth is developed which is able to successfully
      reproduce the experimental data. Through a fitting process, the model also
      yielded calcium turnover rates for compact bone, as a function of age, as well as
      an estimate of radiostrontium contamination of foodstuffs in Greece for the past
      four decades. The results obtained in this study indicate that radiostrontium
      environmental contamination which resulted from the atmospheric nuclear weapons
      tests in the 1960s, exceed by far that caused by the Chernobyl accident.

PMID- 10418171
TI  - Sustainable supplies of water for coal washeries in India.
AB  - The effluents from coal washeries cause serious pollution problems to surface
      waters. Models have been developed to evaluate the dispersion of pollutants in
      the river. For the removal of suspended solids from the coal washery effluents
      the aid of a synthetic flocculant was found to be very effective in terms of
      settling rate, retention time and cost. For sustainable water supplies to the
      coal washeries the methodology developed was found to be very effective and may
      also be applicable to other washeries.

PMID- 10418170
TI  - Trace element levels in whole blood samples from residents of the city Badajoz,
      Spain.
AB  - Copper, lead, cadmium, and zinc were determined by anodic stripping voltammetry
      after sample digestion and potentiometric stripping analysis was used for Pb and
      Cd determination in original samples. Selenium was determined by cathodic
      stripping voltammetry or hydride generation AAS. Element levels found in the
      whole blood sample in a group of 82 people are for Cd: 0.98 +/- 0.94 ng/ml; for
      Pb: 46.7 +/- 28.6 ng/ml; for Cu: 1.07 +/- 0.12 micrograms/ml; for Zn: 6.95 +/-
      1.08 micrograms/ml, and for Se: 116 +/- 25 ng/ml. Analytical data have been
      correlated to age, sex, smokers or non-smokers, drinking and food habits.

PMID- 10418173
TI  - Immunohistochemical analysis of nm23-H1 protein in bladder cancer.
AB  - BACKGROUND: The nm23 gene was first identified from murine K-1735 melanoma cell
      lines and possesses metastasis-suppressor activity. However, conflicting results
      concerning the metastasis-suppressor activity of nm23-H1 gene product have been
      reported in human solid tumors. The significance of nm23-H1 protein in bladder
      cancer remains to be determined. Therefore, we examined nm23-H1 protein
      expression immunohistochemically in bladder cancer. METHODS: Formalin-fixed,
      paraffin-embedded tissue specimens were obtained from 39 patients with primary
      bladder cancer who had undergone radical cystectomy between 1987 and 1994. The
      specimens were examined immunohistochemically using a monoclonal antibody to nm23
      H1, and the results of immunostaining were compared with clinicopathologic
      factors and patient survival. RESULTS: Positive nm23-H1 protein expression was
      confined primarily to the cytoplasm of bladder cancer cells. A higher frequency
      of nm23-H1 positive expression was seen in higher stage tumors. There was a
      positive trend for the expression of nm23-H1 protein with the progression of the
      tumor (p < 0.025). No relationship was found between nm23-H1 protein expression
      and patients' clinicopathologic factors including age, tumor size, tumor
      morphology and tumor grade. Furthermore, nm23-H1 protein expression was not
      correlated with patient survival. CONCLUSIONS: These results suggest that in
      bladder cancer nm23-H1 protein expression may play an important role in tumor
      progression rather than in metastasis suppression.

PMID- 10418172
TI  - Influence of polymorphism at p53, CYP1A1 and GSTM1 loci on p53 mutation and
      association of p53 mutation with prognosis in lung cancer.
AB  - BACKGROUND: We previously found that the majority (9/11) of p53 tumor suppressor
      gene mutations in 60 lung cancer patients in Taiwan were small intragenic
      deletions and nonsense mutations. To gain insights into the possible etiologic
      factors involved in these mutations and the prognostic significance of p53 gene
      mutations in lung cancer in Taiwan, we investigated the influence of polymorphism
      at p53, cytochrome p450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1)
      loci on p53 gene mutation, and the association of p53 gene mutation with
      prognosis in these lung cancer patients. METHODS: The polymorphism of these genes
      was determined by polymerase chain reaction followed by restriction enzyme
      digestion. The Pearson chi 2 test was used to compare allelic distributions
      between lung cancer patients and controls. The log-rank test was used to assess
      the significance of the survival differences between patients with and without
      p53 mutations. RESULTS: There was no significant difference with respect to the
      genotype distribution of p53, CYP1A1 and GSTM1 polymorphisms between patients
      with and without p53 mutations, although a tendency toward increasing frequency
      of the wild-type homozygote genotype of p53 polymorphism was noted in lung cancer
      patients containing p53 mutations. We further analyzed the association of p53
      mutation with prognoses in lung cancer patients for whom postoperative survival
      data were available. The estimated median survival times for patients with and
      without p53 mutation were 25 and 28 months, respectively. There was no
      significant correlation between p53 mutation and survival. CONCLUSIONS: Our data
      suggest that p53 gene mutation may not be associated with polymorphisms of p53,
      CYP1A1 and GSTM1 genes, and it may have no significant effect on the prognosis of
      lung cancer patients in Taiwan.

PMID- 10418175
TI  - Interleukin-8 and alcoholic liver disease.
AB  - Interleukin-8 (IL-8), a cytokine produced by a host of cells including monocytes,
      macrophages, Kupffer cells and hepatocytes, can activate neutrophils. Peripheral
      neutrophilia and liver neutrophil infiltration are frequently noted in patients
      with alcoholic liver disease (ALD). Serum IL-8 levels are markedly elevated in
      patients with alcoholic hepatitis compared with those in patients with alcoholic
      cirrhosis, alcoholic fatty liver and non-alcoholic liver disease. The levels are
      also elevated in patients who die of hepatic failure and correlate with
      biochemical and histologic parameters and severity of liver injury. Patients with
      high serum IL-8 had a higher mortality rate than those with lower levels. In
      liver tissue from patients with ALD, local IL-8 levels also correlated with the
      degree of neutrophil infiltration. Serum IL-8 levels decreased gradually with
      abstinence from alcohol. Ethanol can increase plasma endotoxin, a potent inducer
      of tumor necrosis factor (TNF)-alpha and IL-1. Subsequently, TNF-alpha and IL-1,
      together with endotoxin, stimulate circulating and local IL-8 in ALD. Activated
      IL-8 then mediates neutrophil infiltration, a pivotal process in the pathogenesis
      of ALD. IL-8 levels might reflect the stage and severity of ALD and might serve
      as a predictor of survival in patients with alcoholic hepatitis. The development
      of agents with an anti-IL-8 effect is promising for the therapy of ALD.

PMID- 10418174
TI  - Leiomyosarcoma of the gastric cardia and fundus.
AB  - BACKGROUND: Gastric leiomyosarcoma is rare among gastric malignancies, and only
      20% of the cases are located in the gastric cardia or fundus. It has clinical
      manifestations different from tumors in other sites of the stomach. We reviewed
      cases of leiomyosarcoma of the gastric cardia or fundus to evaluate their
      clinicopathologic characters and patient survival. METHODS: From May, 1981, to
      June, 1998, a total of 15 patients who underwent curative resection of
      leiomyosarcoma of the gastric cardia or fundus were retrospectively identified
      and studied. All the clinical and pathologic data were reviewed and recorded.
      RESULTS: There were 11 men and four women. Their mean age was 59.1 years (range,
      37-73 years). Tarry stools and epigastric fullness and pain were the most common
      symptoms, followed by body weight loss. All 15 patients had submucosal tumors in
      the gastric cardia or fundus, as shown by endoscopy, barium contrast radiography
      and computerized tomography. The incidence of esophageal involvement by the
      tumors was quite low. The mean tumor size was 10 cm, ranging from 4 cm to 20 cm.
      Locoregional organs were involved in nine patients. The median and mean survivals
      were 17.8 months and 31.7 months, respectively (range, 10.1-80.1 months) after
      curative resection. The three-year and five-year survival rates were 53% and 22%,
      respectively. CONCLUSIONS: The definitive preoperative diagnosis of the tumor is
      difficult before surgery, even though imaging studies show positive findings.
      Surgical resection with an adequate safe margin of normal tissue is the treatment
      of choice. Tumor size, serosal invasion with locoregional organ involvement and
      high tumor grade were the prognostic factors in the study.

PMID- 10418176
TI  - Psychosocial risk factors of teenage pregnancy in eastern Taiwan.
AB  - BACKGROUND: Teenage pregnancy is a growing worldwide problem, associated with
      adolescents' social and health problems and poor perinatal outcome. This study
      was conducted to investigate psychosocial factors predisposing to the high
      teenage pregnancy rate in Hualien, eastern Taiwan. METHODS: A regional hospital
      based study was conducted with a retrospective analysis of hospital records and
      questionnaires to collect personal and family data regarding the perinatal
      outcome of 100 pregnant teenagers and 100 pregnant adults, who had normal
      deliveries at the Buddhist Tzu-Chi General Hospital between 1994 and 1995.
      RESULTS: A significantly higher percentage of teenage mothers were of aboriginal
      origin than adult mothers (63% vs 25%; p < 0.05) and lived in rural areas (80% vs
      19%; p < 0.05). There was also a higher incidence of late antenatal care (31% vs
      11%; p < 0.05) drinking (36% vs 9%; p < 0.05) and a greater history of smoking
      (34% vs 7%; p < 0.05) among teenage mothers. About 86% of teenage mothers did not
      use any contraception. The preterm birth rate was not significantly higher in the
      adult group, but teenage mothers tended to have significantly lower birth weight
      infants (19% vs 9%; p < 0.05) and a decreased incidence of cesarean section (19%
      vs 33%; p < 0.05). About 20% of the teenage mothers had their first coitus before
      the age of 13, while none of the adult mothers had sexual coitus before the age
      of 13. CONCLUSIONS: In this hospital-based study, teenage mothers tended to be of
      aboriginal origin, lived in rural areas, had early sexual exposure without
      contraception, had drinking and smoking habits, were late seeking antenatal care
      and gave birth to low birth weight infants.

PMID- 10418178
TI  - Prevalence of Proteus species in urinary tract infections in a regional hospital
      in Trinidad.
AB  - BACKGROUND: Proteus bacteria are a well-known cause of urinary tract infections
      (UTIs). The prevalence of UTIs is high among catheterized patients and those
      undergoing manipulation of the urinary tract. This study assessed the prevalence
      of UTIs due to Proteus species, the predisposing factors, complications and
      extent of antimicrobial resistance at a regional teaching hospital. METHODS:
      Urine samples in sterile containers from inpatients and outpatients were
      inoculated onto cysteine lactose electrolyte deficient agar and sheep blood agar
      plates with calibrated (0.001 ml) platinum loops and incubated aerobically at 35
      degrees C to 37 degrees C for 18 to 24 hours. A colony count of 10(5) bacteria/ml
      or more was the criterion for significant bacteriuria. Proteus spp were
      identified and classified into four groups. Susceptibility testing was performed
      via the Kirby-Bauer disc diffusion technique on Mueller-Hinton agar using
      ampicillin (10 micrograms), tetracycline (30 micrograms), nalidixic acid (30
      micrograms), gentamicin (10 micrograms), nitrofurantoin (30 micrograms), co
      trimoxazole (30 micrograms) and cefuroxime (30 micrograms). RESULTS: Of 1,397
      urine specimens from hospital and community patients, 414 had one or more species
      of bacteria isolated, of which 74 (17.9%) were Proteus spp. Hospital-acquired
      UTIs accounted for more than two-thirds (51/74, 68.9%) of Proteus spp isolates,
      while community-acquired UTIs accounted for approximately one-third (23/74,
      31.1%) of all Proteus isolates. The prevalence of Proteus UTIs in males was 34 of
      184 (18.5%) and was slightly higher than in females (40/230, 17.4%). P mirabilis
      was the most frequently isolated Proteus sp (55/74, 74.3%), followed by P
      vulgaris (9/74. 12.2%), Morganella morganii, (7/74, 9.5%) and Providencia
      rettgeri (3/74, 4.0%). Forty-nine of 55 (89%) P mirabilis isolates were biotype
      2. Catheterization was the most common predisposing factor in 32.4% of hospital
      acquired Proteus UTIs. More than 92% of Proteus isolates were sensitive to
      gentamicin and nalidixic acid, whereas, ampicillin (35%) and tetracycline (18%)
      were the least effective drugs. CONCLUSIONS: Proteus was isolated from about 18%
      of patients with significant bacteriuria. Most isolates occurred in hospitalized
      patients with indwelling urinary catheters and in patients with benign prostatic
      hypertrophy, diabetes and prostatectomy. Proper catheter care may improve
      infection control and reduce the morbidity of UTIs associated with Proteus spp.

PMID- 10418177
TI  - Normative data of quantitative thermal and vibratory thresholds in normal
      subjects in Taiwan: gender and age effect.
AB  - BACKGROUND: Quantitative sensory testing has gained popularity as a tool in the
      diagnosis of peripheral neuropathies. This study aims to establish normative data
      of quantitative thermal and vibratory thresholds in normal subjects in Taiwan. In
      addition, we also examined the effect of age and gender differences on these
      thresholds. METHODS: The study included 100 healthy subjects (50 males and 50
      females) who were admitted for regular physical examination. The quantitative
      testing of thermal, cold and vibratory sensations were performed having recourse
      to a Thermotest instrument applied on the right hand and foot of these subjects.
      Measurements included perception thresholds of warm (WT), cold (CT), heat pain,
      cold pain and vibration as well as a visual analog pain scale. RESULTS: Age was
      comparable between the sexes, but the male subjects were taller than the female
      subjects. A higher WT and CT in the hand, but not in the foot, were found in the
      male subjects in comparison with the female subjects. Heat pain threshold and
      cold pain threshold of both sites did not significantly differ between genders.
      Moreover, the groups did not differ in vibration threshold and visual analog pain
      scale. Young subjects (age < 30 years) showed a higher CT in the foot than the
      older subjects (age > 50 years). None of the above parameters were different
      between these two age groups. Overall, the age or height bore no significant
      relation to the difference between WT and CT (DDWT-CT). CONCLUSIONS: The female
      subjects were found to be more sensitive to warm and cold stimulation in the hand
      than their counterparts. These results have provided valuable normative data on
      sensory perceptive thresholds in Taiwanese, which are useful as a tool in the
      diagnosis of peripheral neuropathy.

PMID- 10418179
TI  - Alterations of gingival morphology in nifedipine-fed rats.
AB  - BACKGROUND: Gingival enlargement induced by nifedipine (NIF), a calcium
      antagonist, has been reported in human and animal studies. However, three
      dimensional morphologic measurements of gingivae have never been used to describe
      this type of enlargement. We previously established an animal model of
      cyclosporin-induced gingival enlargement. The present study used morphologic
      measurements to examine whether or not NIF-induced gingival enlargement occurs in
      the animal model. METHODS: Eighty male Sprague-Dawley rats were divided into four
      groups. Rats in each group received daily NIF, at a dosage of 0, 10, 30 or 50
      mg/kg body weight, by gastric feeding for nine weeks. Gingival dimensions
      (including buccolingual and mesiodistal widths, and vertical height) were
      assessed from stone models obtained from the mandibular incisor regions every
      three weeks. RESULTS: Over the course of the nine-week experiments, significant
      dimensional changes of the gingivae were observed according to two main factors:
      1) the dose or, 2) the treatment duration. Gingival dimensions (including
      buccolingual and mesiodistal widths, and vertical height) significantly increased
      with the duration of NIF treatment. Dimensional alterations of gingivae were
      noted among the different dosage groups, but significant differences were mainly
      observed in those groups compared to the 50 mg/kg group. CONCLUSIONS: The finding
      of increased gingival morphology in NIF-treated rats in this study shows that
      gingival enlargement can be induced by NIF in rats.

PMID- 10418180
TI  - Human recombinant DNA-derived antihemophilic factor (factor VIII) in the
      treatment of hemophilia A.
AB  - BACKGROUND: Plasma-derived factor VIII concentrates used in the treatment of
      hemophilia A have the potential danger of transfusion-associated viral disease.
      The safety and efficacy of a recombinant factor VIII preparation for the
      treatment of this disorder were evaluated in this study. METHODS: We compared the
      pharmacokinetics of plasma-derived and recombinant factor VIII in 12 previously
      treated subjects with severe hemophilia A. RESULTS: The recovery and elimination
      half-lives of the recombinant factor VIII were equal to those of plasma-derived
      factor VIII. It was well tolerated via parenteral therapy, and only two mild
      adverse reactions (5%) were reported. No evidence of new viral infection was
      noted during the study period with the recombinant factor VIII. CONCLUSIONS: The
      biologic activity of the recombinant factor VIII is comparable with that of
      plasma factor VIII concentrate. It is safe and efficacious for the treatment of
      hemophilia A.

PMID- 10418181
TI  - Clinical response and patient acceptance of a prefilled, disposable insulin pen
      injector for insulin-treated diabetes.
AB  - BACKGROUND: The aim of this study was to evaluate the clinical response and
      patient acceptance of a prefilled, disposable insulin pen injector (Novolet, Novo
      Nordisk, Bagsvaerd, Denmark) for treating insulin-dependent diabetic patients.
      METHODS: After a run-in period of six weeks, 19 patients participated in an open,
      randomized, controlled, crossover study with two 12-week periods using insulin
      pens or conventional syringes. Clinical responses were assessed every 12 weeks,
      including glycosylated hemoglobin (HbA1c), seven-point blood glucose profiles and
      hypoglycemic reactions. At the end of the trial, patients completed
      questionnaires about their acceptance of the insulin delivery device. RESULTS:
      Neither of the regimens rendered significant changes in HbA1c, blood glucose
      profiles or hypoglycemic episodes. Most of the study subjects reported that the
      prefilled, disposable devices were convenient and easy to use, and many of them
      wished to continue using the device for insulin delivery. CONCLUSIONS: The
      clinical response was the same for both treatment regimens, but most subjects
      preferred the prefilled disposable pen injector for insulin delivery because it
      was more convenient for daily use.

PMID- 10418182
TI  - Development of a coronary artery aneurysm three months after stent implantation:
      a case report.
AB  - Coronary artery stents have been used widely to prevent acute closure as a
      bailout procedure, or to decrease restenosis after balloon angioplasty. Stent use
      has increased substantially in recent years due to the ease and simplicity with
      which stents provide a predictable angiographic result. However, few data exist
      on the long-term safety of stents. This case report describes a 63-year-old male
      patient who developed intimal dissection after balloon angioplasty and who
      underwent coronary stent placement of a sheathed stent (half Palmaz-Schatz stent,
      3.5 mm in diameter and 7 mm in length) as a bailout procedure. Postdilatation
      with a 3.5-mm balloon was performed at the maximum pressure of 14 atmospheres
      with a satisfactory angiographic result. However, an aneurysmal dilatation at the
      stent site was noted three months later. High-pressure stent use without
      immediately visible vascular dissection by angiography may not be effective for
      prevention of coronary aneurysm development in a case such as this. Aneurysmal
      dilatation may be a late complication in cases of coronary artery stent
      placement.

PMID- 10418183
TI  - Acute febrile neutrophilic dermatosis (Sweet's syndrome) in hairy cell leukemia:
      a case report.
AB  - Sweet's syndrome is a cutaneous reactive process that is usually associated with
      fever, but rarely occurs in patients with hairy cell leukemia (HCL). We report
      the case of a patient with HCL who developed typical Sweet's syndrome five months
      after the diagnosis of HCL. Skin eruptions and constitutional symptoms subsided
      rapidly after short-term systemic adrenocorticosteroid treatment without
      recurrence, until the patient died from disease exacerbation and uncontrolled
      infection. According to his manifestations, chemical allergens, microorganisms or
      HCL progression were unlikely to have been the precipitating factors for
      development of Sweet's syndrome. Because immunologic disorders and opportunistic
      infection are not uncommon in patients with HCL, a skin biopsy should be taken as
      early as possible when cutaneous lesions and fever develop in order to establish
      a correct diagnosis. Hence, unnecessary and prolonged use of antibiotics is
      avoided and prompt relief of the symptoms by appropriate management can be
      achieved.

PMID- 10418184
TI  - Salmonella infection in total hip replacement--report of successful
      reimplantation and review of the literature.
AB  - A case of Salmonella enteritidis group C infection following total hip
      replacement was treated by resectional arthroplasty and appropriate antibiotics.
      Total hip replacement with reimplantation of an antibiotic-impregnated cemented
      hip prosthesis was performed five months later. The postoperative course was
      smooth and hip function was good, without any sign of infection recurrence
      throughout 10 years of follow-up. The treatment protocol and clinical results are
      discussed along with a review of the literature.

PMID- 10418185
TI  - [Facial nerve identification in the translabyrinthine approach: an alternative
      method].
AB  - Since the abrupt drop in the mortality rate as a result of the introduction of
      microsurgical dissection techniques in the treatment of acoustic neuromas,
      surgeons have concentrated their efforts on preserving hearing and facial nerve
      function. In the translabyrinthine approach, identification of the facial nerve
      at the fundus of the internal auditory canal is an important step for subsequent
      dissection. However, the identification techniques available to date carry with
      them some potential risk of facial nerve injury when performed by inexperienced
      surgeons. In addition, they are time-consuming procedures. The authors present an
      alternative method for identification of the facial nerve at the fundus of the
      internal auditory canal during the translabyrinthine approach. The superior
      ampullary nerve is interrupted at the superior cribrosa area where it is not in
      intimate relationship with the facial nerve. Medial reflection of the superior
      ampullary nerve and the superior vestibular nerve facilitates identification of
      the facial nerve and preparation of a vestibulo-facial dissection plane.

PMID- 10418186
TI  - [Protective effect of allopurinol in the exposure to noise pulses].
AB  - Free oxygen radicals cause particularly severe tissues and organ damage. They
      appear to play an important role in the cochlea, mediating noise-exposure damage.
      In the present study 16 guinea pigs were implanted with permanent electrodes to
      record cochlear action potential. Eight animals were exposed to a 2-3 kHz, 125 dB
      SPL noise pulse, at a rate of 4 stimulations per second for 1.8 hours. Prior to
      noise exposure four out of eight animals were treated with a known dose of
      allopurinol. The remaining eight animals were used as controls. Endolymphatic
      malondialdehyde concentration was used as indicator of the lipid peroxidization
      processes exerted by the free radicals. No significant difference was found
      between the variations in hearing threshold and malondialdehyde concentration in
      the animals treated with allopurinol and then exposed to noise vs. the control
      group. The electophysiological and biochemical results have, therefore,
      demonstrated that preventative administration of allopurinol can provide valid
      protection vs. noise impulse damage.

PMID- 10418187
TI  - [Treatment approaches to benign paroxysmal positional vertigo. Clinical features
      in 228 cases of posterior and lateral canalolithiasis].
AB  - After having discussed the etiopathogenesis, epidemiology and physiopathology of
      Benign Paroxysmal Positional Vertigo (BPPV), the authors present their case study
      covering audiovestibology out-patients treated in the last two years: 228 cases
      of canalotithiasis-derived BPPV, both posterior (186 cases) and lateral (42
      cases). These patients were diagnosed and treated between July 1996 and July 1998
      and account for 15% of the 1550 patients complaining of balance and postural
      disorders seen during that period. Analysis of the results shows BPPV
      epidemiological data that are practically the same those reported in the
      literature: greater incidence in females, predominance of posterior
      canalolithiasis and optimal use of the canalith repositioning techniques. The
      authors reconfirm the effectiveness of the Semont maneuver and its variations in
      the treatment of those forms involving the posterior semicircular canal (97%
      healing). As regards BPPV due to lateral canalolithiasis. The authors feel the
      vestibular "barbecue" rehabilitation techniques suggested by Lempert--i.e. a 270
      degrees rotation starting from the decubitus position on the pathological side,
      rather than Baloh's traditional 360 degrees rotation--is most suitable for the
      treatment of BPPV stemming from lateral canalolithiasis. The Lempert technique
      provided satisfactory results (76% healing) and a reduction in the number of
      failures (24%).

PMID- 10418188
TI  - [A new mini-invasive technique for the treatment of sleep breathing disorders:
      preliminary results of a clinical experience].
AB  - The REPOSE system is a new, mini-invasive technique with which the base of the
      tongue is suspended to treat sleep breathing disorders (SBD) induced by
      hypertrophy of the base of the tongue. The surgical technique calls for the intra
      oral insertion of a small titanium screw in the anterior portion of the mandible.
      Two polypropylene threads are attached to the screw and these are passed through
      the base of the tongue and then tied at the point where it is inserted in the
      floor of the mouth, thus effectively suspending the base of the tongue. 10
      patients with SBD due to hypertrophy of the base of the tongue underwent this
      procedure. Only one major complication was found: an infection requiring
      sectioning of the suspension thread. For an average 7 to 30 days all patients
      showed signs of odinophagia, bilateral otalgia, dysphagia and dislalia. In all
      patients snoring either disappeared altogether or was significantly reduced.
      Statistical analysis of the pre- and post-operative polysonnograph data showed a
      significant reduction in the apnea index (AI), the respiratory distress index
      (RDI) (p = 0.009) as well as a significant improvement in the degree of oxygen
      saturation (SaO2) (p = 0.008). The results were independent from the body mass
      since the patients did not lose weight during the follow-up period.

PMID- 10418189
TI  - [Ileocolic free autograft in advanced cervical oncology].
AB  - In head and neck oncology, cancer of the hypopharynx and esophagus still proves
      difficult to interpret because all treatments give poor results. In order to
      improve the quality of life for these patients as quickly as possible, one-step
      reconstructive methods such as the gastric pull-up and free autografts of
      revascularized intestinal segments are increasingly being used. This work
      presents a method for a free autograft of the ileocolic segment. After cervical
      pharyngolaryngoesophagectomy, this method provides a continent aerodigestive
      carrefour, protected by the ileocolic valve. Three patients successfully
      underwent this procedure. Deglutition and phonation were recovered quite quickly:
      between 18 and 38 days. On the basis of the results and after further, more in
      depth experience--including adequate follow-up and post-radiotherapy
      coloesophageal electromanometry to determine the presence and type of motor
      propulsion exerted by the distal esophagus--the authors conclude that this method
      is one of the most interesting options available for the surgical reconstruction
      of pharyngoesophageal circular defects.

PMID- 10418191
TI  - Sperm viability in ram semen diluted and stored in three different extenders.
AB  - Semen was collected with an artificial vagina from 4 one-year-old rams, in order
      to study the changes in sperm motility and membrane integrity of spermatozoa
      split-diluted and stored at 5 degrees C during 7 days in sodium citrate, Tris,
      and milk-based extenders, respectively. Sperm motility was assessed subjectively
      and sperm membrane integrity was determined using the fluorescent probes Calcein
      AM and Ethidium homodimer. Representative samples were studied using scanning
      electron microscopy (SEM). The average incidence of sperm motility decreased over
      time in all the extenders (p < 0.001). The incidence of spermatozoa showing
      progressive motility and intact plasma membrane was significantly higher in semen
      diluted with sodium citrate than in the other 2 extenders following 4 days of
      dilution until the end of the study. Evaluation with SEM confirmed the findings
      obtained with the supra vital fluorescent dyes. The results of the present study
      indicated that there were no differences between sodium citrate-, Tris- or milk
      based extenders when ovine liquid semen was stored at 5 degrees C during a short
      period (2 days). However, when semen was stored for longer time, spermatozoa in
      the sodium citrate-based extender sustained its viability better.

PMID- 10418190
TI  - [Intrapetrous carotid artery aneurysm].
AB  - Intratemporal carotid artery aneurysms are rare lesions, with only 54 cases
      reported in the literature. Their most common symptoms are pulsatile tinnitus,
      hearing loss and signs of Eustachian tube obstruction. In case of aneurysm
      rupture, bleeding may be so profuse as to require emergency legation of the
      common carotid in the neck. Arteriography is the diagnostic gold standard for
      this disorder. Successful treatment usually involves selective aneurysm
      embolization or carotid closure with detachable balloons. The authors report a
      new case of intratemporal carotid artery aneurysm previously treated with
      selective embolization. To avoid the risk of aneurysm recanalization and/or
      infection through the external auditory canal, middle ear obliteration and blind
      sac closure of the external canal were performed in this case.

PMID- 10418192
TI  - Comparison between a live, attenuated anticoccidial vaccine and an anticoccidial
      ionophore, on performance of broilers raised with or without a growth promoter,
      in an initially Eimeria-free environment.
AB  - An experiment was carried out to study the effects of vaccination with Paracox, a
      live, attenuated vaccine against avian coccidiosis, on broilers isolated from
      extraneous Eimeria parasites. The study involved 3200 broiler chickens raised in
      floor pens similar to commercial conditions, but in an initially Eimeria-free
      environment. Forty percent of the chickens were vaccinated at 3 days of age and
      given either a basal unmedicated feed or a feed supplemented with the feed
      antibiotic virginiamycin. Unvaccinated birds were given either the basal feed or
      feed supplemented either with virginiamycin or the anticoccidial ionophore
      narasin. At slaughter at 36 days of age vaccinated birds had a lower live weight
      than non-vaccinated birds. The difference was 4.6% in unmedicated, and 6.0% in
      virginiamycin medicated chickens. Feed conversion ratio at slaughter was 2.5%
      higher for unmedicated vaccinated birds, and 1.3% higher for virginiamycin
      medicated vaccinated birds, compared to respective non-vaccinated groups. There
      was no significant difference in overall performance of unvaccinated birds given
      narasin as compared to virginiamycin. At 10 days post vaccination vaccinated
      birds had a higher number of Clostridium perfringens in the caeca, but there was
      no difference thereafter. Throughout the experiment, caecal clostridial counts
      were considerably higher in vaccinated unmedicated birds than in unvaccinated
      birds given narasin. The number of oocysts shed in the vaccinated groups was very
      low, but during a subsequent challenge with E. maxima and E. tenella the birds'
      immunity was found to be satisfactory.

PMID- 10418193
TI  - The influence of supplements of selenite, selenate and selenium yeast on the
      selenium status of dairy heifers.
AB  - The aim of the study was to define possible differences between selenite,
      selenate and selenium yeast on various aspects of selenium status in growing
      cattle. Twenty-four Swedish Red and White dairy heifers were fed no supplementary
      selenium for 6 months. The basic diet contained 0.026 mg selenium/kg feed dry
      matter (DM). After the depletion period the animals were divided into 4 groups;
      group I-III received 2 mg additional selenium daily as sodium selenite, sodium
      selenate, and a selenium yeast product, respectively. Group IV, the control
      group, received no additional selenium. The total dietary selenium content for
      groups I-III during the supplementation period was 0.25 mg/kg DM. After the
      depletion period the mean concentration of selenium in blood (640 nmol/l) and
      plasma (299 nmol/l) and the activity of GSH-Px in erythrocytes (610 mukat/l) were
      marginal, but after 3 months of supplementation they were adequate in all 3
      groups. The concentration of selenium in blood and plasma was significantly
      higher in group III than in groups I and II, but there was no significant
      difference between groups I and II. The activity of GSH-Px in erythrocytes did
      not differ between any of the supplemented groups. The animals in the control
      group had significantly lower concentrations of selenium in blood and plasma and
      lower activities of GSH-Px in erythrocytes than those in the supplemented groups.
      The activity of GSH-Px in platelets was also increased by the increased selenium
      intake. There was no difference in the concentration of triiodothyronine (T3)
      between any of the groups, but the concentration of thyroxine (T4) was
      significantly higher in the unsupplemented control group.

PMID- 10418194
TI  - Acute phase response in dairy cows with experimentally induced Escherichia coli
      mastitis.
AB  - Six Finnish Ayrshire cows were challenged intramammarily with 1500 CFU of
      Escherichia coli (E. coli) into single udder quarters, and the challenge was
      repeated into contralateral quarters 3 weeks later. All cows received flunixine
      meglumine once, and 3 of them were also treated with enrofloxacin. At the 2nd
      challenge, treatments were changed vice versa. The development of mastitis was
      followed by monitoring of systemic and local clinical signs, and with serial milk
      and serum samples. Intramammary challenge with E. coli produced clinical mastitis
      in all cows, the severity of the disease varying greatly between the animals. No
      significant changes between the 2 treatment regimens or sequent challenges were
      found for any of the clinical parameters. The response of each cow followed the
      same pattern after both challenges; three of the cows became mildly and the other
      3 either moderately or severely affected. Two severely affected cows had to be
      euthanized because of severe mastitis. Serum haptoglobin and amyloid-A
      concentrations peaked 2-3 days after bacterial challenge. Serum haptoglobin did
      not correlate with the severity of the disease. Serum amyloid-A rose gradually in
      the severely affected cows, and significant differences were found between
      severely versus moderately or mildly affected cows at day 4. Serum tumor necrosis
      factor alpha concentrations increased only in the severely affected cows. Serum
      cortisol response was prolonged in the severely diseased animals, and was
      significantly lower after the second challenge. Serum nitrite/nitrate
      concentration increased in the severely affected cows. This indicated excess
      nitric oxide production during acute E. coli mastitis. Strongly decreased milk
      production, and high bacterial growth in the infected quarters were best
      predictors for the outcome from acute E. coli mastitis.

PMID- 10418195
TI  - Relation of milk production loss to milk somatic cell count.
AB  - Milk production loss was studied in relation to increased somatic cell count
      (SCC). Available data were weekly test-day milk yields and SCC (in 1,000
      cells/ml), and mastitis incidences. In total, 18,131 records from 274 cows were
      used. Production loss was determined for test-day kg milk, kg protein, and kg
      energy-corrected milk. Least-squares analysis of variance was used to estimate
      the direct effect of Log10(SCC) on production. The recorded measures of
      production were first corrected for fixed effects, with adjustment factors
      estimated from a healthy data-set. The average daily milk yield was 19.7 kg/day
      in first lactation and 22.0 in later lactations. The geometric mean of SCC was
      63.1 in first lactation and 107.2 in later lactations. The incidence of clinical
      mastitis treated by a veterinarian was 19.8% of the lactations-at-risk. Linear
      relationships were found between the production parameters and Log10(SCC).
      Quadratic and cubic effects were evaluated, but were found to contribute little
      to the overall fit of the models. The individual milk yield loss was 1.29 kg/day
      for each unit increase in Log10(SCC) for cows in first lactation. Milk yield
      decreased by 2.04 kg/day per unit Log10(SCC) for older cows. Corresponding values
      for protein yield were 0.042 and 0.067 kg/day for first and later lactations,
      respectively.

PMID- 10418196
TI  - Influence of restricted suckling and level of feed supplementation on postpartum
      reproductive performance of zebu and crossbred cattle in the semi-arid tropics.
AB  - This study was carried out in central Tanzania on a group of 45 Zebu and 37
      crossbred cows which were 4 to 10 years old. At calving time, the animals were
      allocated to one of the 4 treatment groups. In addition to free access to grazing
      for all cows in the study, in group H:AR (n = 18), cows were fed a high level of
      concentrate supplementation (4kg/day) and calves were artificially reared; in
      group H:RS (n = 24), cows were fed a high level of concentrate supplementation
      (4kg/day) and calves were only allowed restricted suckling up until the weaning
      age of 6 months. In group L:AR (n = 23) cows were fed a low level of concentrate
      supplementation (2kg/day) and calves were artificially reared; and in group L:RS
      (n = 17) cows were fed a low level of concentrate supplementation (2kg/day) and
      calves were only allowed restricted suckling up until the weaning age of 6
      months. Milk progesterone was used as a means of determining the postpartum
      resumption interval (PRI) and the interval from parturition to conception (PCI).
      The overall PRI was 47.4 +/- 0.4 days and was significantly affected by breed but
      not by calving season, with crossbred cows exhibiting a shorter PRI than Zebu
      cows. The effect of the treatments was significant, with cows in the group H:AR
      displaying a significantly shorter PRI than those in the other groups, while cows
      in group L:RS showed a significantly longer PRI than those in the other groups.
      The overall PCI was 149.5 +/- 3.7 days, and was not significantly affected by
      breed or calving season. The effect of the treatments was significant, with cows
      in the group H:AR having a significantly shorter PCI than cows in the other
      groups, while cows in group L:RS showed a significantly longer PCI than those in
      the other groups. Crossbred cows had higher live weights at calving (299.4 kg)
      than Zebu cows (272.6 kg), while all cows gained weight during the first 3 months
      after calving. The treatments had a significant effect on weight gain, with cows
      in the group H:AR gaining significantly more weight than those in the other
      groups. Cows which had high live weights at calving exhibited significantly
      shorter PRI and PCI than the lighter cows. Animals which had gained more than 5
      kg during the first month after calving, or which had gained more than 8 kg
      during the first 3 months after calving, showed significantly shorter PRI and PCI
      than cows which had gained less weight. The results show that the calf rearing
      system and the level of feed supplementation interact with each other and can
      influence the postpartum anoestrous period in Zebu and Zebu crossbred cattle.
      Increasing the level of nutrition in restricted suckling cows tended to improve
      the postpartum anoestrous period, but the positive effects of supplementation
      could not completely compensate for the negative effects of suckling.

PMID- 10418197
TI  - Serum antibodies to bovine coronavirus in Swedish sheep.
AB  - Altogether 218 sheep sera from 40 flocks in different parts of Sweden were
      screened for antibodies to bovine coronavirus (BCV). Nineteen per cent of the
      sera were positive and there was a significantly higher frequency (p < 0.05) of
      at least one positive sample in flocks with more than 100 adult sheep than in
      smaller flocks. There was also a significantly higher frequency (p < 0.001) of
      positive samples from sheep older than 4 years than from younger ones. Only a
      weak relationship between BCV positivity (2 or more positive samples, p < 0.05)
      and cattle contact was demonstrated in this study. Possible transmission routes
      and other factors that could have affected the result are discussed. In light of
      our finding that all 5 sheep experimentally exposed to BCV through contact with
      infectious cow faeces seroconverted, we conclude that the antibodies found in
      Swedish sheep are probably the result of BCV infections directly or indirectly
      transmitted from cattle.

PMID- 10418198
TI  - Implantation of temperature loggers in 100 Danish dairy calves: surgical
      procedure and follow-up.
AB  - One hundred Danish dairy calves had temperature loggers implanted subcutaneously
      on the neck. Post-operatively, the calves were given a single antibiotic
      treatment, and tissue reactions were assessed on 6 post-operative visits. After
      approximately 5 months, the loggers were removed and material submitted for
      histologic examination. This paper presents 1) the surgical procedure, 2) the
      prevalence of tissue reaction at the post-operative visits, 3) the degree of
      implant recovery, 4) the results of histopathologic examinations, 5) an
      evaluation of age at implantation or veterinary practitioner as risk factors for
      tissue reaction and missing implant recovery 5 months after implantation, and 6)
      evaluation of tissue reaction as a risk factor for lack of recovery 5 months
      after implantation. The implant was rejected on 7 calves (7%). Additionally, 5
      calves (5%) had the temperature logger removed because of presence of an abcess.
      No migration of the temperature loggers were observed. The results of a repeated
      measures analysis and the histopathological findings indicate that contamination
      during the surgery resulted in inflammation and abcess formation. It is
      recommended that in the presence of an abcess, the temperature logger should be
      removed.

PMID- 10418199
TI  - A case of trisomy 22 in a live hereford calf.
AB  - A case of the rare genetic trisomy 22 in a live calf is described. The calf had
      low blood thyroxine level and low growth rate. It had several defects including
      brachygnathia superior, strabismus convergence, aortal cusp insufficiency and
      hypertrophy of clitoris. Chromosome analysis was performed on cultured blood
      lymphocytes and fibroblast cells. In all counted metaphases 61 chromosomes were
      present. The extra chromosome was identified as a chromosome 22 by R-banding. The
      defects of the calf have similarities with cases of partial trisomy 3p25-pter in
      human. This section of the human chromosome 3 corresponds to sections of cattle
      chromosome 22.

PMID- 10418200
TI  - Pregnancy status of reindeer calves (Rangifer tarandus tarandus) on two occasions
      during the winter season.

PMID- 10418201
TI  - Reproductivity of nine Trichinella isolates in guinea pigs and mice.

PMID- 10418202
TI  - Lyme disease and the Lyme disease vaccines.
AB  - Both OspA vaccines, with or without adjuvant, are effective and safe. People must
      receive repeated doses of the vaccine, however, to receive effective protection.
      If the vaccines are to be part of a Lyme disease prevention strategy, doctors and
      patients must pay attention to booster shot timing. Maximum public health benefit
      can be achieved only if the Lyme disease vaccines are integrated into broad
      individual and community-based efforts to prevent Lyme disease and other tick
      borne diseases. Only people at significant risk of contracting Lyme disease
      should consider vaccination, and vaccination should merely complement--not
      replace--personal precautions for avoiding tick bites.

PMID- 10418203
TI  - Multimodal approach of cranial ultrasound in children.
AB  - The potential uses of cranial ultrasound have been overlooked for years because
      of the advent of fascinating neuroimaging studies such as computed tomography
      (CT) and magnetic resonance imaging (MRI) study. In this article, the authors
      introduce the developments and refinement in modern pediatric neurosonology. In
      the past, only neonates with widely open fontanels seemed to be good candidates
      for cranial ultrasound study. Actually, any tiny skull defect can be used as an
      acoustic window. And the thin skulls of children do not hinder the ability of
      ultrasound to obtain acceptable image transcranially. Today, many CT and MRI
      studies can be replaced with the advanced cranial ultrasound if clinicians or
      neurologists recognize the advantages. Cranial ultrasound can provide Doppler
      hemodynamic studies which CT and MRI can not. Only ultrasound can provide
      convenient, real-time intraoperative guidance and continuous bedside monitoring
      in patients who need neurological intensive care. Cranial ultrasound also plays
      an important role in follow-up studies because it is convenient, economical, and
      safe, especially in children. To obtain all the benefits from an ultrasound
      study, one has to realize the "multimodal" applications of it, including the
      applications of all acoustic windows, multifrequency transducers, and hemodynamic
      study with the aid of power Doppler and contrast agents. With a multimodal
      approach, physicians can achieve the utmost from the powerful modern cranial
      ultrasound in pediatric patients.

PMID- 10418204
TI  - Urine free beta-human chorionic gonadotropin levels between 14 and 21 weeks of
      gestation in Taiwanese pregnancies.
AB  - BACKGROUND: The purpose of this study was to determine the reference range of
      maternal urine free beta-human chorionic gonadotropin (beta -hCG) concentrations
      between 14 and 21 weeks of gestation. METHODS: We measured the concentrations of
      urine free beta -hCG from 268 healthy singleton Taiwanese pregnancies between 14
      and 21 weeks of gestation. Results were corrected for creatinine (Cr)
      concentration and converted to the multiple of the median (MOM) level for the
      appropriate gestation. Gestational ages of all cases were determined using
      ultrasound dating. RESULTS: The median levels of urine free beta -hCG and free
      beta-hCG/Cr had a downward trend in association with the increasing gestation
      age. The median, 5th, 10th, 90th and 95th centiles of free beta- hCG/Cr MOM
      values were 1.02, 0.20, 0.25, 2.32 and 3.38 MOM, respectively. Urine free beta-
      hCG/Cr MOM values showed a log Gaussian distribution with the mean and standard
      deviation (SD) distribution of -0.0657 and 0.3792, respectively. CONCLUSION: To
      allow for differences in free beta -hCG/Cr median values at various ages of
      gestation, establishment of the reference range is essential for further
      development of maternal urine screening for Down syndrome.

PMID- 10418205
TI  - Indocyanine green clearance test in non-cirrhotic hepatitis patients: a
      comparison and analysis between conventional blood sampling method and Finger
      Piece Monitoring method.
AB  - BACKGROUND: The indocyanine green (ICG) Finger Piece Monitor system is a non
      invasive method for measuring blood ICG concentrations for the evaluation of
      hepatic function. This study was conducted to determine its clinical usefulness
      in non-cirrhotic patients. METHODS: Traditional liver function tests, alpha
      fetoprotein, prothrombin time, and ICG clearance tests, by both blood sampling
      method and Finger Piece Monitoring method were performed simultaneously on 56 non
      cirrhotic hepatitis patients. The plasma clearance rate (K) and 15-minute
      retention ratio (R15) of ICG were analyzed and compared with traditional liver
      function test results. RESULTS: The clearance rate using the Finger Piece
      Monitoring method was slightly lower than that of the blood sampling method (9.16
      +/- 5.00%/min vs. 11.24 +/- 3.56%/min) with good correlation (r = 0.721, p =
      0.0003). The 15-minute retention ratio using the Finger Piece Monitoring method
      showed better correlation with blood sampling method (32.83 +/- 23.99% vs. 28.49
      +/- 23.74%, r = 0.944, p = 0.0002). Analysis between traditional laboratory tests
      and fR15 revealed a higher fR15 value in patients with bilirubin-total-T > or = 3
      mg/dl (49.71 +/- 26.22% vs. 22.23 +/- 13.48%), alpha-fetoprotein > or = 100 ng/ml
      (61.96 +/- 15.84% vs. 28.52 +/- 21.74%), and PT prolongation > or = 3 sec (71.46
      +/- 16.80% vs. 29.03 +/- 21.06%). CONCLUSION: There is a good correlation between
      the conventional blood sampling method and the ICG Finger Piece Monitoring system
      method. The ICG Finger Monitoring system provides an alternative for traditional
      laboratory tests for the evaluation of hepatic dysfunction in hepatitis patients.

PMID- 10418206
TI  - Anal manometric findings before and after hemorrhoidectomy: a preliminary report.
AB  - BACKGROUND: A difference of opinion exists as to whether patients with
      symptomatic hemorrhoids, patients after hemorrhoidectomy, and patients with no
      hemorrhoids have different anal physiologies. METHODS: Twenty-four patients with
      symptomatic hemorrhoids undergoing hemorrhoidectomy were investigated using
      anorectal manometry. There were 12 male and 12 female patients with a mean age of
      42 years (range: 23 to 72 years). The anorectal manometry was performed one day
      before the operation and 8 to 12 weeks after the operation. Another normal group,
      comprised of 138 volunteers, was included and matched for age and gender.
      RESULTS: The anorectal inhibitory reflex was present in all the normal group
      (NG), symptomatic hemorrhoid (SH), and post-hemorrhoidectomy (PH) patients. No
      major incontinence was noted clinically. The mean resting pressure (MRP) in the
      SH group (mean: 84.5 +/- 28.7 cmH2O, range: 26 to 166 cmH2O) was significantly
      greater than in the NG (mean: 74.4 +/- 14.9 cmH2O, range: 61 to 116 cmH2O) and
      the PH groups (mean: 63.7 +/- 23.6 cmH2O, range: 20 to 116 cmH2O) (p = 0.032 and
      0.005, respectively). After hemorrhoidectomy, the MRP was significantly decreased
      compared to the normal group (p = 0.018). The other manometric data showed no
      statistical change in these three groups. CONCLUSION: The results indicate that
      persons with SH have a higher MRP than normal. Overactivity of the internal
      sphincter muscle may be a cause rather than a result of symptomatic hemorrhoids.
      Compared with the SH and normal groups, the MRP was significantly decreased to
      prevent recurrent symptomatic hemorrhoids in the PH group. Though the MRP was
      significantly decreased, no major incontinence was noted after hemorrhoidectomy,
      and this might be due to the increase in rectal compliance and mean squeeze
      pressure.

PMID- 10418207
TI  - Prognostic factors and strategy of treatment in Fournier's gangrene: a 12-year
      retrospective study.
AB  - BACKGROUND: Fournier's gangrene (FG) is a fulminant and fatal infection of the
      genitalia. However, the clinical course is unpredictable. This study
      retrospectively analyzed the possible prognostic factors of FG. METHODS: Data
      obtained from 57 patients treated for FG from January 1985 through December 1996
      were retrospectively analyzed. Possible prognostic factors including age,
      diagnostic delay, hospital stay, underlying diseases, clinical symptoms, origins,
      extents, bacteriologic findings, diverting colostomy and mortality rate were all
      considered in the analysis. RESULTS: Patients with extensive or localized FG had
      mortality rates of 31.3% and 16.0%, respectively (p = 0.227). The mortality rates
      of patients with FG of anorectal, urogenital and non-specific origin were 30.3%,
      0% and 40.0%, respectively (p = 0.712). The mortality rates of patients with FG
      of anorectal origin who received primary or secondary diverting colostomy were
      16.7% and 40.0%, respectively. However, the mortality rate of patients with FG of
      anorectal origin who did not undergo diversion was 29.4%. The mortality rate of
      patients with FG presenting with septic shock at emergency was 53.8% as compared
      with 0% in those without septic shock (p < 0.001). CONCLUSION: Fournier's
      gangrene is a rapidly progressive and life threatening infection of the
      genitalia. Age, underlying diseases, origin, extent and fecal diversion can not
      be regarded as prognostic factors of FG. Early primary diverting colostomy may
      reduce the mortality rate in those with severe infection of anorectal origin.
      Presence of septic shock in those with FG is the most important and the only
      factor related to death.

PMID- 10418208
TI  - Timing of shoulder exercise after modified radical mastectomy: a prospective
      study.
AB  - BACKGROUND: There are several factors those contribute to the amount of axillary
      drainage after modified radical mastectomy. The drains should be removed as early
      as possible. Whether the active shoulder movement of the lesion side increases
      the amount of axillary drainage needs to be studied prospectively. METHODS: From
      1994 through 1995, 344 consecutive patients were randomly divided into three
      groups. One hundred sixteen patients in the early group performed upper arm
      exercises including pendulum, wall climbing and pulley exercises beginning the
      third post-operative day. One hundred fifteen patients in the later group
      patients did the same exercises beginning the sixth post-operative day and 113
      patients in the delayed group did the same exercises after all the drains were
      removed. RESULTS: There were no significant differences in patient
      characteristics, including age, body weight, operation methods and the pathology
      in the three groups. The amount of axilla fossa drainage was significantly less
      in the patients in the delayed group than in the early and later group (485 ml,
      568 ml, 559 ml, respectively, p = 0.032). However, there were no differences in
      the amount of chest wall site drainage or the number of aspiration of seroma
      among the three groups. The drains were removed on the average of seventh and
      ninth post-operative day in the delayed and early group patients, respectively (p
      = 0.124). Although the range of motion (ROM) of the shoulders in the delayed
      group patients was slightly limited during the first month after operation, ROM
      returned at 3 months and no difference was found 6 months after operation.
      CONCLUSION: Upper arm exercise can start after the drains in the axilla are
      removed. The delay does not limit the shoulder function at 6 months after
      modified radical mastectomy.

PMID- 10418209
TI  - Comparison of clinical efficacy and adverse effects between extended-release
      felodipine and slow-release diltiazem in patients with isolated systolic
      hypertension.
AB  - BACKGROUND: Isolated systolic hypertension (ISH) is a risk factor for
      cardiovascular disease. Extended-release felodipine (felodipine ER) has been
      shown to be effective in the treatment of ISH in Caucasians. However, its
      pharmacological properties are different from another calcium blocker, diltiazem.
      Also, the effectiveness, tolerability, and adverse reactions of these two
      antihypertensive agents for ISH have not been thoroughly assessed in Chinese.
      METHODS: Sitting blood pressures (BP), heart rate, body weight, adverse
      reactions, and serum biochemistry were assessed in 70 patients with isolated
      systolic hypertension (34 treated with felodipine ER and 36 slow-release
      diltiazem [diltiazem SR] for 10 weeks). Each patient was given 5 mg of felodipine
      ER or 90 mg of diltiazem SR once daily and was doubled to twice daily if
      necessary. RESULTS: Five patients on felodipine ER and four on diltiazem SR
      withdrew because of intolerable side effects. By ten weeks, 67.6% of the patients
      responded to a daily dose of 5-10 mg of felodipine ER and 58.3% to a daily dose
      of 90-180 mg of diltiazem SR. At the end of treatment, felodipine ER lowered the
      mean BP from 187/83 mmHg at baseline to 149/74 mmHg, whereas diltiazem SR
      decreased the BP from 185/84 mmHg to 158/78 mmHg (not significant between the two
      groups). The heart rate did not change significantly in either group. Overall,
      these two groups of patients had the same rate of adverse reactions (50.0% vs.
      50.0%) with similar profiles of the adverse effects. CONCLUSION: Equivalent doses
      of felodipine ER and diltiazem SR are effective first-line monotherapeutic agents
      for the treatment of ISH.

PMID- 10418210
TI  - Management of aggressive benign and malignant bone tumors of the shoulder region.
AB  - BACKGROUND: The shoulder girdle is one of the most common sites of aggressive
      malignant and benign bone tumors. Curative resections and sparing of the limb are
      possible. However, reconstruction methods remain a challenge and the functional
      results vary. METHODS: Fourteen patients with aggressive benign or malignant bone
      tumors about the shoulder girdle who were treated with surgical resection with
      possible need for reconstructions were retrospectively analyzed. There were 8 men
      and 6 women. Their ages ranged from 15 to 70 years; the mean age at operation was
      36 years. Ten patients had malignant bone tumors and four had extensive giant
      cell tumors. A variety of reconstructive procedures were performed after
      resection of the tumors. The choice of procedure depended on the type of
      resection and the needs of the patients. Supplementary chemotherapy or
      radiotherapy was undertaken after surgical procedures in 9 patients. RESULTS: The
      length of follow up ranged from 16 months to 10 years. The functional results
      were described and graded quantitatively according to the functional rating
      system of the Musculoskeletal Tumor Society. Overall, 6 patients achieved
      excellent and good shoulder functions at follow-up examination, while 8 acquired
      fair or poor functional results. Four patients died from lung metastasis, while
      10 survived and are disease free. Resection of the glenoid cavity and the
      proximal part of the humerus with loss of the abductor mechanism resulted in poor
      function of the shoulder. CONCLUSION: The choice of treatment options depended
      upon the staging of tumors, the extent of resection, the needs of individual
      patients, the preservation and reconstruction of rotator cuff, the experience of
      surgeons, and the facilities at the hospital. The functional results were related
      to the area of involvement and the type of resection. The preservation of the
      abductor mechanism provided good functional results.

PMID- 10418211
TI  - Cleft of the lip and palate in twins.
AB  - BACKGROUND: Cleft lip and palate is one of the most common congenital anomalies
      in Taiwan. Its etiology remains unknown for the majority of the patients. The
      study of twins is a classic method for evaluating the relative roles of genetic
      and environmental factors in the formation of the anomaly. METHODS: In this
      study, 37 pairs of twins and one set of triplets with cleft lip and palate were
      evaluated. Clinical data were collected for zygosity determination and analysis
      of etiologic factors. The concordance rate and heritability index were assessed.
      RESULTS: The results showed that the concordance rate was 26% for all twins and
      57% among the monozygotic pairs, which is higher than those rates for the
      Caucasian population. The heritability index was 53%, higher than the other
      reports as well. The influence of the environment could not be ruled out.
      CONCLUSION: The results confirm a strong genetic role in the etiology of clefts
      in our patients. Environmental factors were acting as well. The findings in this
      study support the multifactorial threshold model in the development of cleft lip
      and palate.

PMID- 10418213
TI  - Surgical treatment of morbid obesity with vertical banded gastroplasty: a
      comparison between TA90-4.8 and TA90-B.
AB  - BACKGROUND: In this study, we wanted to determine the results of vertical banded
      gastroplasty for morbid obesity and compare the results of using the TA90-4.8
      with using the TA90-B instrument. METHODS: Patients with body weight over 100% of
      or 45 kg above their ideal body weight, body mass index (BMI) over 40 kg/m2, or
      BMI over 35 kg/m2 with osteoarthritis, venous stasis, sleep apnoea, or frequent
      abortion were selected for surgical intervention. They were purposely divided
      into two groups. Vertical banded gastroplasty was performed in group A with two
      applications of TA90-4.8 (N = 26) and in group B with one application of TA90-B
      (N = 24). The outlet of the gastric pouch was 10 to 12 mm and reinforced with a
      1.5 cm strip of Marlex to give a circumference of 5.5 cm. The follow-up body
      weight, BMI, and percentage of weight in excess of the ideal weight were compared
      between the two groups. The results were classified as excellent (0 to 25% excess
      weight), fair (26 to 50% excess weight), good (51 to 75% excess weight), poor (76
      to 100% excess weight), and worse (> 100% excess weight). A failure was defined
      as a body weight of greater than 76% excess weight and a repeated operation being
      needed regardless of the ultimate outcome. RESULTS: There were no differences
      between the two groups regarding age, gender, preoperative body weight, BMI, and
      excess weight. The operative time was longer for group A (175 +/- 39 min) than
      for of group B (140 +/- 23 min) (p < 0.0001). In the follow-up period, the
      postoperative body weight, BMI, and excess weight showed no differences between
      the two groups. Four patients in group A had poor results, three due to staple
      disruption and one due to sweet-eating. One patient in group B had stenosis of
      the stomach pouch and needed another operation to release the stenosis. Thus,
      five failures (10%) were found in this study. CONCLUSION: Vertical banded
      gastroplasty is an effective modality for treating morbid obesity. Two
      applications of TA90-4.8 are not recommended because they result in frequent
      staple disruption.

PMID- 10418212
TI  - Proton chemical shift imaging of the hippocampus in patients with complex partial
      seizures.
AB  - BACKGROUND: Cerebral metabolites can be evaluated non-invasively using in vivo
      proton magnetic resonance spectroscopy (MRS). Decreased N-acetylaspartate (NAA)
      and increased choline-containing compounds (Cho) and creatine-phosphocreatine
      (Cr) have been found in the hippocampus of patients with complex partial seizures
      (CPS). METHODS: We prospectively studied hippocampal proton MRS of 10 patients
      with CPS and 12 control subjects by using the chemical shift imaging (CSI)
      technique. The spectral data were analyzed in terms of the ratio between the
      integral peak area of NAA and that of (Cho + Cr). RESULTS: Compared with the
      control group, patients with CPS showed a significantly lower NAA/(Cho + Cr)
      ratio, both in the anterior and posterior hippocampus (p value = 0.001 and 0.002,
      respectively). Metabolic abnormalities of the hippocampus were detected using
      proton CSI in all the patients with normal MRI results (4 patients) and those
      with normal EEG results (3 patients). Lateralizations using proton CSI were
      obtained in all the 10 patients in this study, including concordant
      lateralization in the 6 patients with MRI-detectable abnormalities. CONCLUSION:
      The hippocampal abnormalities in patients with CPS can be detected early using
      proton CSI than using MRI or surface EEG. Lateralization of the seizure focus
      using proton CSI is possible, but further correlation with the surgical outcome
      in a larger study group is necessary.

PMID- 10418214
TI  - Ischemic bowel disease in chronic dialysis patients.
AB  - BACKGROUND: Ischemic bowel disease, especially acute mesenteric ischemia, carries
      high morbidity and mortality rates. Any delay in diagnosis or treatment
      aggravates the patient's outcome. Owing to the scarcity of reports concerning
      ischemic bowel disease in chronic dialysis patients, we investigated the ischemic
      bowel disease in chronic dialysis patients. METHODS: From January 1986 through
      April 1997, medical records of 2416 chronic dialysis patients at our hospital
      were reviewed. Among them, 5 patients with surgically documented ischemic bowel
      disease were enrolled. The clinical manifestations, laboratory findings,
      operative findings, pathologic test results and prognoses of these patients are
      reported. RESULTS: Abdominal pain, abdominal distension and bloody stool were
      major initial presentations. The mean age of the patients was 62.4 years at the
      time of diagnosis of ischemia. All patients had hypertension, 3 patients had
      hyperlipidemia, three patients had diabetes mellitus and three patients had
      history of shunt occlusion. Four patients had leukocytosis. Image studies
      revealed dilatation of bowel loops in four patients. Peritonitis made exploratory
      laparotomy necessary. The findings during operation showed turbid ascites and
      variable degrees of bowel ischemia or gangrene. The methods of surgical
      intervention depended on the severity of the disease. Only one patient died due
      to extensive ischemic bowel involvement and subsequent sepsis. CONCLUSION: It is
      mandatory to have an index suggestive of ischemic bowel disease in chronic
      dialysis patients with unexplained abdominal pain or discomfort. Early diagnosis
      and aggressive surgical intervention is the cure modality for patients with acute
      ischemic bowel disease.

PMID- 10418215
TI  - Radiation therapy in primary central nervous system lymphoma.
AB  - BACKGROUND: Treatment of primary central nervous system lymphoma (PCNSL) in
      Chinese individuals has rarely been reported. Therefore, this article presents
      our experience in managing PCNSL with radiotherapy. METHODS: A thorough review
      was made of the medical records of 13 patients diagnosed with PCNSL at Kaohsiung
      Chang Gung Memorial Hospital from 1988 through 1997. The clinical
      characteristics, treatment modalities, and results were analyzed as well.
      RESULTS: Thirteen patients diagnosed with PCNSL were identified, of which 10
      cases originated in the brain whereas three were of spinal origin. Seven of the
      patients were man and six were women, with a mean age of 54.9 +/- 13.1 years
      (range 29 to 74 years). Diffuse large cell lymphoma (11 cases) was the most
      common histology. Limb weakness (11 cases) and headache (7 cases) were the most
      common complaints at presentation. Nine patients received radiation therapy alone
      and four patients received radiation therapy plus chemotherapy after surgical
      resection or biopsy. Follow-up computed tomography (CT) scans 3 to 4 months after
      the completion of radiotherapy revealed that nine patients (69%) had a complete
      response and four (31%) had a partial response. Local recurrence occurred in five
      patients (56%) treated with radiation therapy alone and in one patient (25%)
      treated with combined modalities. The overall actuarial survival rate was 54% at
      2 years and 27% at 5 years. CONCLUSION: Results in this study indicate that the
      initial response to radiotherapy is satisfactory. However, a local relapse
      frequently occurs. Future considerations should focus on new modes of treatment,
      such as three-dimensional conformal radiation therapy for dose escalation or a
      combination of chemotherapy and radiotherapy.

PMID- 10418216
TI  - Pseudomyxoma peritonei with high serum CA19-9: report of three cases.
AB  - Pseudomyxoma peritonei (PMP) is an unusual form of intraabdominal neoplasm that
      produces a large amount of extracellular mucin. It is often associated with
      mucinous tumors of gastrointestinal tract or ovary. Herein, we report 3 patients
      with pseudomyxoma peritonei with high serum carbohydrate antigen 19-9 (CA19-9)
      levels. The first patient, who had a CA19-9 level of 1132 U/ml, had well
      differentiated rectal cancer and died of chemotherapy complications, pneumonia
      and septic shock; one month after admission. The other 2 cases with CA19-9 levels
      of 2520 U/ml and 679 U/ml had tumors of unknown origins and had survived more
      than 1 year and 3 months after treatment, respectively. Usually, elevated serum
      CA19-9 levels are found in patients with pancreatic, biliary, colorectal, gastric
      or liver cancers. However, many studies have shown high serum CA19-9 levels are
      associated with mucinous carcinoma. Immunochemical studies also showed positive
      staining of CA19-9 in mucinous tumors. PMP is composed of large amounts of mucin,
      therefore, we suggest that serum and ascites CA19-9 levels should be routinely
      checked in patients with PMP.

PMID- 10418217
TI  - Advanced bilateral retinoblastoma treated conservatively with lens sparing
      external beam radiation therapy: report of three cases.
AB  - From 1995 through 1998, 3 children with bilateral advanced retinoblastoma were
      treated primarily with external beam radiation therapy; 6 eyes were irradiated
      with a lens sparing technique, doses varied from 5500 to 5700 cGy, and follow-up
      period ranged from 14 to 36 months. Recurrent tumors were found in 3 eyes, and a
      new growing tumor in one eye. Three eyes underwent enucleation eventually; one
      eye refused enucleation and finally developed optic nerve extension. The overall
      ocular cure rate was 2/6 (33.3%). One eye sustained visual acuity of 20/30, the
      other eye retained some peripheral vision; both eyes were blind in one patient.
      There were no deaths, metastasis, or secondary malignant tumors in our study.
      Advanced bilateral retinoblastoma with simultaneous radiation therapy instead of
      bilateral enucleation does not increase the risk of death, and more children will
      enjoy the benefits of retaining some vision in the affected eye through the use
      of this conservative therapeutic regimen.

PMID- 10418218
TI  - Congenital hepatic arterioportal fistula complicated with gastrointestinal
      bleeding treated with transcatheter embolization: case report.
AB  - Congenital hepatic arterioportal fistula (HAVF) is extremely rare in children. We
      present a patient with congenital hepaticoportal arteriovenous fistula
      complicated with gastrointestinal bleeding treated using transcatheter arterial
      embolization. Our patient was the youngest (2 days old) case ever reported with
      congenital HAVF and the first one to receive arterial embolization for HAVF
      during childhood. The 3-year-old girl was suggested of having congenital HAVF
      using Doppler ultrasonography. However, her family refused further investigation,
      and she was lost to follow-up. Three years later, she was sent to our hospital
      due to melaena. Repeated ultrasonography revealed dilated intrahepatic portal
      vein with arterial flow demonstrated using Doppler imaging. No esophageal varices
      or gastric or duodenal ulcer was seen during endoscopy. Angiography showed a HAVF
      and transcatheter embolization was done simultaneously. Follow-up at one and two
      weeks post-embolization revealed no more shunt flow within the portal vein,
      though cystic like dilatation of the portal vein persisted, and no thrombosis was
      observed. This case emphasizes that transcatheter arterial embolization can be
      easily and successfully used for treating childhood congenital HAVF. Abnormal
      dilatation of the portal vein in children needs doppler evaluation and possibly
      angiography.

PMID- 10418219
TI  - Hepatocellular carcinoma presenting with acquired porphyria: a case report and
      review of the literature.
AB  - Hepatocellular carcinoma (HCC) with acquired porphyria is a very rare condition.
      It is characterized variably by hyperpigmentation, skin fragility and
      photodistributed subepidermal vesicles. The serum, urine and/or stool porphyrin
      levels, usually markedly elevated, can change according to the clinical course.
      We report here a case of hepatocellular carcinoma presenting with a
      paraneoplastic syndrome of acquired porphyria. A 73-year-old Chinese woman had
      the characteristic facial pigmentation of cutaneous porphyria and histologically
      proven hepatocellular carcinoma. Her serum zinc protoporphyrin was elevated and
      her urine tested positive for coproporphyrin. Her protoporphyrin and alpha
      fetoprotein levels dropped after transarterial chemoembolization treatment.
      Acquired porphyria in hepatocellular carcinoma occurs exclusively in older
      persons with huge hepatocellular carcinoma and/or cirrhosis. Before diagnosis, it
      must be carefully differentiated from inherent porphyrias with HCC, and
      porphyrias induced by drugs or heavy metal intoxication must be ruled out.

PMID- 10418221
TI  - Bilateral coronoid process hyperplasia with limitation on mouth opening: case
      report.
AB  - Coronoid process hyperplasia with limitation of mouth opening is rare. The
      pathology is often ignored, but it can be easily detected using dental panoramic
      view of x-ray films. Definition of the coronoid process hyperplasia can be made
      by measuring the height of coronoid process and the ratio of coronoid/condyle
      height on lateral cephalometric x-ray film. Etiology of the coronoid process
      hyperplasia can be congenital or acquired. Differentiation of the diagnosis may
      be difficult. The congenital type occurs at early age with clinical
      manifestations. Proposed hypotheses for the formation of coronoid process
      hyperplasia include increased activity within the temporalis muscle from
      conditions such as functional stress, compression, and tension. For patients with
      coronoid process hyperplasia and restriction on mouth opening, conservative
      treatment should first be attempted. Surgical treatment is considered if
      conservative treatment fails. Coronoidectomy with early mobilization and
      aggressive physiotherapy corrects the problem. We present a patient with coronoid
      process hyperplasia with limitation of mouth opening who was successfully
      treated.

PMID- 10418220
TI  - Thoracoscopic retrieval of foreign body after penetrating chest injury: report of
      two cases.
AB  - Video-assisted thoracic surgery has proved to be valuable in many settings in
      thoracic surgery. The use of video-assisted thoracic surgery in trauma has
      recently rapidly increased. It is useful in acute or delayed management of
      patients with blunt and penetrating chest trauma. It is safe for removal of
      clotted hemothorax, treatment of thoracic empyema, treatment of persistent
      pneumothorax, treatment of chylothorax, and for diagnosis of diaphragmatic
      injury. We report two cases using thoracoscopy to remove intrathoracic metal
      fragments and avert the need for thoracotomy. In the first patient, a metal
      fragment injury was sustained via a penetrating wound from the supraclavicular
      notch to the right upper lung. The metal fragment was retrieved and the lung was
      repaired thoracoscopically using conventional suturing techniques. A second
      patient sustained a broken pin injury to the left upper mediastinum via a low
      neck wound. The pin was successfully removed under videothoracoscopy. Both
      patients recovered uneventfully and had shortened hospital stays. We feel that
      thoracoscopy offers a therapeutic as well as diagnostic benefit in stable
      patients with penetrating chest trauma.

PMID- 10418223
TI  - Descending mesocolon defect herniation: case report.
AB  - Internal hernia, herniation of the internal organs through defects in the
      intraabdominal cavity, is rare. Due to the rarity of this pathology and lack of
      the specific symptoms and signs, early diagnosis and treatment are always
      stressful to the clinician and misdiagnoses may occur in the emergency room. The
      prognosis of a patient with uncomplicated internal hernia is excellent. We report
      a 21-year-old Chinese man with internal herniation through a defect of mesocolon,
      presented as an impalpable abdominal mass which was shown only on imaging
      studies. In addition to the typical whirlpool pattern, a huge solid mass between
      the pancreatic tail and stomach was found under computed tomography (CT) scan.
      The major symptoms were intermittent epigastralgia and abdominal fullness that
      had bothered him for years. Physical examination results showed only mild
      epigastric tenderness. Computed tomography scans and exploratory laparotomy of
      the abdomen played vital roles during diagnosis. The herniated organ was a
      portion of jejunum with partial small intestinal obstruction.

PMID- 10418222
TI  - Branchio-oculo-facial syndrome: case report.
AB  - Branchio-oculo-facial (BOF) syndrome is a rare dominant autosomal disorder. Less
      than 50 cases have been reported up to now. We present a Chinese boy with BOF
      syndrome who has characteristic features of bilateral postauricular cervical
      branchial cysts, bilateral complete cleft of primary palate, bilateral lacrimal
      duct obstruction and bilateral low set ears with posterior rotation. His
      intelligence and growth were normal at the age of 7 years. This is the first case
      reported in Taiwan. The overlap between BOR syndrome and BOF syndrome include
      external ear abnormalities with hearing loss, lacrimal duct obstruction,
      branchial cleft remnants, and renal or ureteral defects. The relationship between
      these two syndromes is still unclear. Contiguous gene deletion phenomenon,
      different mutations in the same gene, or distinct entities all have been
      proposed. The literature was reviewed and discussed, especially the reports about
      the gene EYA1 (eyes absent-like 1), which is responsible for branchio-oto-renal
      syndrome. If we can detect mutations of EYA1 gene in BOF patients, this could be
      the key for solving the above debate.

PMID- 10418224
TI  - Dissecting aortic aneurysm complicated with acute disseminated intravascular
      coagulation: case report.
AB  - Acute disseminated intravascular coagulation (DIC) is a rare complication of
      aortic aneurysm with or without dissection. We describe an 88-year-old man who
      presented with severe hemorrhagic diathesis and a pulsating abdominal mass. An
      abdominal computed tomography (CT) scan revealed a dissecting abdominal aortic
      aneurysm with thrombus formation, and his coagulation profile showed the features
      of acute DIC. After he had received blood component therapy, including fresh
      frozen plasma and cryoprecipitate concentrates, and intravenous heparin infusion
      (10,000 U/day), the bleeding diathesis and coagulopathy improved. An
      aneurysmectomy was performed smoothly without excessive bleeding. Coagulation
      parameters returned to normal after surgery. Dissecting aortic aneurysm should be
      considered as a possible etiology of acute disseminated intravascular
      coagulation, even it occurs in rare situations. Surgical intervention is still
      the main strategy to normalize coagulopathy. Bleeding diathesis must be corrected
      before surgery in order to prevent massive intraoperative bleeding.

PMID- 10418225
TI  - Gastric adenocarcinoma with tonsil and submaxillary gland metastases: case
      report.
AB  - Local invasion, hematogenous and lymphatic metastases are the major modes of
      spreading gastric cancer. The most common sites of metastases in patients with
      gastric cancer are liver, peritoneum, omentum, lungs and mesentery. Of the two
      pathological types of gastric cancer, intestinal-type gastric cancer showed
      preferential metastasis to the liver, whereas the diffuse-type showed a
      preference for peritoneal involvement and lymph node metastasis. However,
      metastases of gastric cancer to the head and neck regions are not common. The
      hematogenous route appears to account for a great majority of metastases to the
      head and neck regions. Malignant neoplasm metastases to major salivary glands or
      tonsils are not common. Several patients with cancers from the infraclavicular
      area have been reported with parotid gland or tonsil metastases. However,
      metastasis of gastric adenocarcinoma to the tonsils or submandibular glands is
      rare. We present a patient with recurrent gastric adenocarcinoma with both tonsil
      and submandibular gland metastases which is even rarer.

PMID- 10418226
TI  - Florid osseous dysplasia: case report.
AB  - Florid osseous dysplasia (FOD) is a benign, non-neoplastic lesion characterized
      by multiple sclerosing masses only within the jawbones. It is most prevalent in
      middle-aged black women but uncommon in Orientals. Most cases are asymptomatic
      and should be left untreated. However, the jawbone involved in FOD is very
      susceptible to infection, including osteomyelitis developed from periodontitis,
      pulpopathosis, bone biopsy, wearing removable partial dentures, root canal
      therapy, tooth extraction, inappropriate dental treatment, etc. If secondary
      osteomyelitis develops, antibiotic and conservative dental therapy treatment is
      recommended for removing the sources of the odontogenic infection. Surgical
      removal of inflamed masses is indicated if the inflammatory signs and symptoms
      are persistent after antibiotic and conservative dental therapy. Here we report a
      rare FOD case in which an osteomyelitis resulting from generalized periodontitis
      and bone biopsy was triggered. The patient was accepted for surgery and follow-up
      in our department. The current literature of this disease is reviewed as well,
      focusing especially on the clinical manifestations, radiographic features,
      differential diagnosis, and treatment.

PMID- 10418227
TI  - Prosthetic reconstruction in the cleft lip and palate patient with an
      extracoronal resilient attachment retained removable partial overdenture: case
      report.
AB  - There are still some difficulties in prosthetic reconstruction of cleft lip and
      palate patients with conventional prostheses or implant retained prostheses. The
      most common difficulties are insufficient alveolar bone quality and quantity,
      inadequate soft tissue, and abutment teeth. The patient we report on was a 23
      year-old man with a clinical diagnosis of right incomplete cleft lip and palate
      combined with midface dysplasia. The maxillary six anterior teeth were
      reconstructed. The maxillary right central incisor and canine were used as
      abutments for an extracoronal resilient attachment (ERA) retained removable
      partial overdenture. The STERN ERA SYSTEM is a hinged resilient attachment with
      an ideal stress breaking characteristic, a good retentive function, and easy
      chairside replacement. The 2-year follow-up examination revealed an adequate
      esthetic appearance with good retention and stability of the prosthesis. A
      removable partial overdenture using the teeth adjacent to the cleft area as
      abutments with an adequate attachment design is an alternative method for
      prosthetic reconstruction of cleft lip and palate deformity.

PMID- 10418228
TI  - [Sub-retinal fluid interleukin-10 (Il-10) and interleukin-13 (Il-13)
      concentration in patients with retinal detachment].
AB  - PURPOSE: To evaluate the presence of IL-10 and IL-13 in subretinal fluid of
      patients with rhegmatogenous retinal detachment. MATERIAL AND METHOD: The studies
      comprised 14 patients on with retinal detachment operated. The presence of
      cytokines was evaluated using immunoenzymatic assay. RESULTS: IL-10 and IL-13
      were found in all subretinal fluid samples. Our results suggest that the presence
      of IL-10 and IL-13 has the influence on suppression of inflammatory agent release
      and activity during retinal detachment.

PMID- 10418229
TI  - [Content of certain sugars and polyols in cataractous nucleus in non-diabetics
      and diabetic patients with type II diabetes].
AB  - PURPOSE: Sugars and polyols content assessment in cataractous nucleus in
      diabetics and non-diabetics. MATERIAL AND METHODS: Cataractous nucleus was
      obtained during extracapsular cataract extraction derived from 52 diabetic and 58
      non-diabetic patients. The content of glucose, fructose, sorbitol and mioinositol
      in examined material was determined using iquid gas chromatography. RESULTS:
      Average contents of sorbitol, glucose and fructose in cataractous nucleus
      diabetic patients (ZSC) are significantly higher than in non-diabetics (ZS). No
      changes were observed in mioinositol content in both studied groups. CONCLUSION:
      The role of the polyol pathway in the development of diabetic cataract is
      considerable.

PMID- 10418230
TI  - [Evaluation of the use of intravitreal air in retinal detachment surgery].
AB  - PURPOSE: To analyse the effects and complications after the use of intravitreal
      air in retinal surgery. MATERIAL AND METHODS: 185 patients (89 female, 96 male,
      aged from 12 to 81 years) with retinal detachment treated in the Department of
      Ophthalmology in Bydgoszcz in the period from 1992 to 1997, in whom intravitreal
      air was used. Patients with breaks lying above the 5 and 7 o'clock meridians were
      included in the treatment with intravitreal air. Follow-up period was from 6
      months to 5 years. RESULTS: In 94% of cases the treatment was successful. In 2.7%
      the transient rise of intraocular pressure was noted. CONCLUSION: The use of
      intravitreal air in retinal surgery is an effective, safe, easy to perform, cheap
      and commonly available method used in retinal detachment surgery.

PMID- 10418231
TI  - [Results of retinal detachment surgery in aphakic and pseudo-aphakic eyes].
AB  - PURPOSE: The authors present results of conventional treatment of a patient with
      the retinal detachment in the aphakic and pseudophakic eyes. MATERIAL AND
      METHODS: The group consisted of 34 persons: 10 women and 24 men, aged from 40-79
      years. Earlier the intracapsular (in 24 eyeballs) and extracapsular (in 3
      eyeballs), lens extraction had been performed. The intraocular lens was inserted
      into 7 eyes. The following surgical technics were performed: cerclage in 16 eyes,
      screlar invagination in 5 eyes, scleral invagination with an extrascleral implant
      in 7 eyes, the extrascleral implant alone in 6 eyes. RESULTS: Total retinal
      reattachment was attained in 85% in aphakic eyes and 100% in pseudophakic eyes.

PMID- 10418232
TI  - [Diode laser trans-scleral cyclo-photo-coagulation].
AB  - The purpose of this study is to present the results of treatment of refractory
      glaucoma with diode laser transscleral cyclophotocoagulation (DLCT). 88 patients
      (from 10 to 91 years old) were treated with diode laser. The follow up was 6
      months. Mean intraocular pressure (IOP) before treatment was 38.2 mm Hg, 1 week
      after treatment--23.8 mm Hg, 1 month after treatment--21.3 mm Hg, after 6 months-
      19.0 mm Hg. We repeated treatment in 5 patients (5.6%). In 2 patients we observed
      hypotony--about 2 mm Hg. Diode laser cycloablation is a relatively safe and
      effective method in treatment of advanced refractory glaucoma.

PMID- 10418233
TI  - [Color Doppler ultrasonography in diagnosis of post-traumatic optic neuropathy].
AB  - PURPOSE: To evaluate the parameters of blood flow in orbital arteries of patients
      with traumatic optic neuropathy. MATERIAL AND METHODS: Colour Doppler imaging of
      the ophthalmic artery, central retinal artery and posterior ciliary arteries was
      carried out in 13 patients with traumatic injury of the optic nerve. The peak
      systolic, end-diastolic flow velocities and resistance index were measured.
      RESULTS: In 4 patients, whose vision was intact immediately after the injury and
      later deteriorated, the parameters of blood flow in the central retinal artery
      (CRA) were normal. Also in 3 patients with loss of vision to 1/50-3/50 after the
      injury the parameters of blood flow in the CRA were in the normal limit. In 3
      other patients, who had only light perception after injury, there was decreased
      peak systolic blood flow and only trace or no flow was demonstrated in the CRA
      during the diastolic phase. In the remaining 3 patients, who displayed no light
      perception after the injury, no flow was observed in the CRA with Colour Doppler
      method. CONCLUSION: Colour Doppler ultrasonography is a useful supplementary
      method in diagnostics of traumatic optic neuropathy. The Colour Doppler findings
      seem to correlate well with clinical pathologies of the optic nerve after its
      traumatic injury.

PMID- 10418234
TI  - [The evaluation of contrast sensitivity in children and adolescents with insulin
      dependent diabetes mellitus].
AB  - PURPOSE: The evaluation of contrast sensitivity in children and adolescents with
      type I diabetes mellitus with and without retinopathy, taking into account
      metabolic control. MATERIAL AND METHODS: We examined 100 young patients (71
      without retinopathy and 29 with background retinopathy on fluorescein
      angiography) and 60 control non-diabetic subjects matched for age and sex,
      without visual or systemic symptoms. Contrast sensitivity was measured in spatial
      frequency of 3, 6, 12 and 18 cycles/degree (c/d). RESULTS: Contrast sensitivity
      was significantly lower (p < 0.001) in four spatial frequencies in all diabetic
      patients and in IDDM patients without retinopathy than in control group. Patients
      with IDDM and retinopathy had abnormal contrast sensitivity at spatial frequency
      18 c/d when compared with patients without retinopathy. There was no correlation
      between contrast sensitivity and HbA1c values. CONCLUSIONS: Contrast sensitivity
      measurement in children and adolescents with type I diabetes is useful in the
      evaluation of the nature of early abnormalities in retinal function of diabetics.

PMID- 10418235
TI  - [The assessment of lateral orbitotomy by Kronlein-Reese-Berke in surgical
      treatment of primary non-malignant orbital tumors].
AB  - AIM: The assessment of lateral orbitotomy by Kronlein-Reese-Berke was made to
      evaluate the possibility of radical removal of primary orbital tumors, function
      of visual system and cosmetic effect after lateral orbitotomy. MATERIAL AND
      METHODS: The authors analysed a group of 14 patients treated for primary non
      malignant orbital tumors. They were treated in I ENT Clinic of Silesian Medical
      Academy in Katowice surgically by Kronlein-Reese-Berke lateral orbitotomy. A
      control examination (after 3 years) performed in all 14 patients did not show
      recurrence of tumor, the motility of the eye ball and visual function was normal,
      cosmetic effect was good. CONCLUSIONS: We suggest that in the cases of primary
      non-malignant tumors localised in the lateral part of the orbita, orbitotomy by
      Kronlein-Reese-Berke is the optimal surgical approach.

PMID- 10418236
TI  - [Therapeutic contact lenses in infant corneal ulcerations].
AB  - PURPOSE: We present our own results of treatment in corneal ulcerations with
      therapeutic contact lenses in 4 infants aged between 3 days to 5 weeks. MATERIAL
      AND METHODS: Four patients (5 eyes) with deep corneal ulcerations of various
      origin were treated with soft contact lenses at the Clinic of Pediatric
      Ophthalmology in Katowice. All eyes received one type of the therapeutic lens.
      Contact lenses were worn between 8 and 21 days. After application of contact
      lenses pharmacological therapy was used individually for each patient, according
      to the result of microbiological tests. RESULTS: All patients were successfully
      cured. A scar of cornea was observed only in one infant because the contact lens
      had been used too late. Four infants had no corneal haze after the treatment.
      CONCLUSION: The best results were obtained using the contact lenses early, during
      the first days of treatment. Contact lenses caused decreasing of pain and reduced
      application of medicines. They were a good protection for injured cornea.

PMID- 10418237
TI  - [The diagnosis of psychogenic visual problems in children and young adults with
      application of visual evoked responses (VER)].
AB  - PURPOSE: To present diagnostical and therapeutical problems connected with
      children and adolescents suspected of aggravation or simulation of visual
      problems. MATERIAL: 5 patients between 10 and 13 years old with visual
      disturbances sent to ophthalmologist with suspicion of neuritis retrobulbaris or
      tumor cerebri. METHODS: Complexive diagnostical investigations (including visual
      field tests, color vision tests, visual evoked potentials) with complete
      ophthalmological examinations of visual organ and psychological evaluation of
      patients. RESULTS: The normal results of ophthalmological examinations and of all
      diagnostical investigations including visual evoked potentials. Psychological
      evaluation of patients showed psychological troubles of the young ones.
      CONCLUSIONS: The normal results of visual evoked potentials confirm the diagnosis
      of psychogenic visual disturbances and allow to save children before other
      medical invasive investigations. Such patients with psychogenic visual
      disturbances and their families usually need a special kind of psychogenic
      therapy.

PMID- 10418238
TI  - [Morning glory syndrome: a case report].
AB  - The case of morning glory syndrome in two years old patient is presented.

PMID- 10418239
TI  - [The intermediate uveitis with systemic symptoms: a case report].
AB  - The case of 26-year old male patient with typical clinical intermediate uveitis
      (vitritis, periphlebitis) with accompanying leucopenia, bradycardia and
      demyelination focal areas in brain of unknown etiology is presented. The
      asymptomatic periphlebitis was also found in the eyes of his twin brothers (30
      years old) and sister (20 years old).

PMID- 10418240
TI  - [Scleritis resembling choroidal melanoma: a case report].
AB  - The clinical manifestations of the disease, its course and response to the
      therapy were typical of the inflammatory state in the eye. However, magnetic
      resonance imaging suggested the presence of an intraocular tumour.
      Immunoscintigraphic studies using technetium-labelled antimelanoma antibodies
      initially and 9 months later yielded positive results with the increasing
      antibody titer. Fine-needle aspiration biopsy did not reveal the presence of
      neoplastic cells. The eyeball was removed due to a chronic inflammatory process
      and loss of vision. Histopathological examination demonstrated a tumour-like
      lesion with the signs of inflammatory infiltration without mitotic activity.

PMID- 10418241
TI  - [The role of apoptosis in physiology and pathology of the retina].
AB  - Apoptosis is a genetically regulated form of cell death. Specific morphological
      and biochemical changes characterize apoptosis, including nuclear chromatin
      condensation, cytoplasmatic condensation, membrane blebbing and, on the molecular
      level, internucleosomal fragmentation of nuclear DNA. Cell death by apoptosis is
      essential for normal development and tissue homeostasis, and it is involved also
      in a variety of pathologic processes. Apoptosis is the final common pathway of
      photoreceptor cell death in retinal dystrophies and degeneration, retinal
      detachment, vitreoretinal proliferation, retinoblastoma and retinal injury. The
      authors present a brief literature review concerning studies on the role of
      apoptosis in pathogenesis on retinal diseases.

PMID- 10418242
TI  - [The possibilities of using the newest experimental results in the progressive
      myopia treatment].
AB  - Most recent experimental results concerning the pathomechanism of myopia are
      discussed. Anatomical, physiological, and biochemical changes taking place in the
      eye with experimental myopia are described. Special attention is focused on the
      following substances inhibiting the progress of experimental myopia: apomorphine,
      reserpine, 6-hydroxydopamine, atropine, pirenzepine, chlorpyrifos, alpha-amino-3
      hydroxy-5-methyl-4-isoxazole propionic acid, kainic acid, naloxane,
      formoguanamine, gentamicin, sodium iodate, central and peripheral antagonist of
      vasoactive intestinal polypeptide, basic fibroblast growth factor. The
      possibilities of the above-mentioned pharmacological agents in the progressive
      myopia treatment are indicated.

PMID- 10418244
TI  - [It's time physicians start to weigh and measure! Large waist-measurements are
      independent risk factors].

PMID- 10418243
TI  - [Annoyances of summer--current data on stings and bites].

PMID- 10418246
TI  - [The ethics committee at the Karolinska Institute comments on shortages of a
      study on spinal surgery].

PMID- 10418245
TI  - [Few reports according to Lex Maria. What is the responsibility of the National
      Board of Health and Welfare?].

PMID- 10418247
TI  - [Increasing incidence of hospital infections unless measures are taken].

PMID- 10418248
TI  - [Asymmetric skull in healthy infants sleeping in supine position is rare].

PMID- 10418249
TI  - [Arsenic, leukemia and old horses].

PMID- 10418250
TI  - [Aortic compression in atonic bleeding after parturition].

PMID- 10418251
TI  - [A high degree of accuracy is possible in the diagnosis of appendicitis.
      Laboratory tests, ultrasonography and computerized tomography are of great
      value].
AB  - Although acute appendicitis is often difficult to diagnose and negative
      laparotomy rates of 25 per cent are common, several options are currently
      available for the preoperative work-up. Careful history taking and physical
      examination are essential, together with analysis of inflammatory variables (C
      reactive protein and white cell count). After admission, additional help is
      available in the form of ultrasonography and computerised tomography (CT),
      ultrasonography apparently being best in slender and normal weight patients (body
      mass indices < 25) and CT in overweight patients. The article reports how,
      without using invasive laparoscopy, a negative laparotomy rate of 7.2 per cent
      (11% in women and 4% in men) was obtained in 1998 at a hospital serving a
      population of 330,000.

PMID- 10418252
TI  - [A case report. Stump appendicitis two months after laparoscopic appendectomy].

PMID- 10418253
TI  - [Risk of food-borne infections is both reduced and increased. Expertise is
      greater, but so is the risk of exposure].
AB  - Food-borne disease is increasingly reported, and the spectrum of microorganisms
      involved is broad. Diarrhoeal disease is common, and official statistics
      represent only a minority of cases. Factors associated with an increasing risk of
      infection include industrialization and globalization of food production,
      international travel, and the import of exotic foodstuffs. The risk is diminished
      by good animal husbandry, hygienic handling and transportation of foodstuffs, and
      technical procedures such as heat and radiation treatment. Our expertise is
      expanding, but food-handling skills in the general public seem to be
      deteriorating. However, the impression of increasing risk may to some extent be
      attributable to intensified publicity in the media, and on the whole our food has
      probably become safer.

PMID- 10418254
TI  - [Health care safety should be focused on prevention. Lessons to be learned from
      aviation, nuclear power plants and offshore industries].
AB  - In many respects the approach to questions of safety adopted in the aviation,
      nuclear energy and offshore oil industries is highly relevant to safety in the
      health care sector, even where legislation is concerned. Characteristic features
      are the emphasis on risk-factor identification, and such demands as risk
      analysis, knowledge checks, and the limitation of working hours. In addition,
      there is a need of disaster inquiries in cases of serious incidents, and of an
      organisation specifically responsible for safety issues. Regarding the
      development of an incident report system for use in health care, the importance
      of which increases with the risks involved, a commendable model is the risk
      report system adopted by civil aviation authorities in the USA, where those
      submitting reports are guaranteed immunity.

PMID- 10418255
TI  - [Warfarin can have a negative effect on bone formation].

PMID- 10418256
TI  - [A pioneer in medicine: Ruth Svensson--parasitologist, missionary-physician,
      psychiatrist].

PMID- 10418258
TI  - [A person who suffers of obesity is obese!].

PMID- 10418257
TI  - [Hybrid-terms are not necessarily wrong but should be used carefully].

PMID- 10418259
TI  - [Goat milk and sheep milk saved Chopin during the cold winter in Mallorca].

PMID- 10418260
TI  - The importance of randomized clinical trials and evidence-based medicine: a
      clinician's perspective.
AB  - Clinical evaluation of therapies for patient care has evolved during the
      twentieth century from a variety of scientific methods. As a result of medical,
      political, and economic changes that occurred in the 1990s, randomized clinical
      trials and evidence-based methods are presently in the forefront of the
      physician's thinking in the decision-making process for therapeutic
      interventions. A new standard of patient care has emerged during this process.
      This report provides clinician's viewpoint of the importance and interpretation
      of evidence-based methods and suggests a strategy when such evidence does not
      exist.

PMID- 10418261
TI  - [Mitral valve surgery in elderly patients].
AB  - The increase in life expectancy results in a larger number of elderly patients
      with mitral valve pathology requiring surgical correction. Generally speaking,
      the indications for surgery are identical to those which apply to other age
      groups, but the greater incidence of mortality and, especially, of morbility make
      a degree of selectivity advisable. More than with any group, it is important to
      consider the risk: benefit ratio. However, in the majority of cases, it is
      possible to optimise the clinical condition of the patients with a significant
      decrease in risk. One of the most controversial aspects is that of the advantages
      or disadvantages of mitral valvuloplasty vs. prosthetic replacement. Although the
      eventual lower durability of the valvuloplasty might be considered a
      contraindication, because of the risk of reintervention at a later age, I believe
      that valvuloplasty is also preferable in elderly patients. This is confirmed by
      the well known fact that mitral valvuloplasty for myxomatous mitral
      regurgitation, prevailing in this age group, has the most durable results among
      all types of pathology. In the last 10 years, 433 patients above 70 years of age
      (11.6% of the total) were subjected to valvular surgery in Coimbra. Valvuloplasty
      was possible in more than 90% of the cases of mitral valve surgery. The mortality
      was only 2.6%, but significantly higher than that observed in younger patients
      (0.8%). In conclusion, mitral valve surgery in elderly patients is feasible with
      acceptable mortality and morbidity, but pre-operative optimization of the
      patients is essential.

PMID- 10418262
TI  - [Implantation of mechanical prosthetic valves in the pediatric age group. Review
      of the last ten years].
AB  - Our aim is to evaluate the outcome of 13 patients, under the age of 18, who
      underwent 15 valve replacements with mechanical prostheses, from January 1985
      through December 1995, in our Hospital. The mean age was 11.7 +/- 5.0 years (from
      eight months to 18 years); six patients were male. The follow-up was five months
      to 9.5 years. All of them were initially in NYHA classes III or IV, under medical
      therapy. Indication for valve replacement was rheumatic valve disease in five and
      congenital in eight. The mitral valve was replaced in eight patients, the aortic
      in three and both valves in two patients. Two patients (15%) died in the early
      post operative period. After the procedure there was a remarkable hemodynamic
      improvement of the remaining patients; the echocardiographic evaluation showed
      good left ventricular function in all patients and a reduction in systolic
      pressure of the pulmonary artery and dimensions of the right chambers of the
      heart. Two patients had perivalvular leaks. Nine patients were NYHA functional
      class I, one in class II and one in class III. All patients received warfarin
      anticoagulation and antibiotic prophylaxis for infective endocarditis. There was
      no incidence of anticoagulant related haemorrhage or thromboembolic or infectious
      events. One patient (7.6%) underwent valve replacement as the first procedure;
      the others underwent valvuloplasty before replacement of the valve. Although
      valve replacement in this population should only take place when conventional
      forms of therapy fail, in our group we observed low mortality and morbidity
      rates.

PMID- 10418263
TI  - [Case report of tuberous sclerosis and congenital heart disease].
AB  - The cardiac manifestation usually associated with Tuberous Sclerosis is
      rhabdomyoma. The authors present a clinical case of Tuberous Sclerosis with the
      particular coexistence of congenital heart disease (mitral anomaly and pulmonary
      stenosis) and a single intracardiac rhabdomyoma that appeared at the age of four
      years.

PMID- 10418264
TI  - [Radiation therapy and cardiac pacemakers].
AB  - The number of patients with cardiac pacemakers submitted annually to radiation
      therapy is increasing. Radiation therapy causes interference in the normal
      functioning processes, directly by chemical changes in the structure of the
      device and also by electromagnetic disturbances generated in the process of
      treatment. The changes in the technology used in the manufacture of cardiac
      pacemakers after the 70's, with the introduction of complementary metal-oxide
      semi-conductors (CMOS) in the circuits, drastically increased the chance of
      dangerous interference in the normal function of cardiac pacemakers occurring
      when in contact with an ionizing radiation source. The authors briefly describe
      the mechanisms underlying the radio-induced damage usually observed. A review of
      the literature on this issue is made and solutions are pointed out to perform
      safe radiation therapy and minimize the risk of device malfunction.

PMID- 10418265
TI  - [Homocysteinemia and vascular disease--a new risk factor is born].
AB  - In recent years there has been growing evidence that high levels of plasmatic
      homocysteine constitute an independent risk factor for early cardiovascular
      disease. In this article we review the main theories of atherosclerosis which
      take into account the proteins, namely homocysteine, homocysteine metabolism, the
      cause that may be responsible for high levels of homocysteinemia, the
      pathophysiologic mechanisms of vascular lesion induced by hyperhomocysteinemia,
      the clinical evidence that homocysteinemia constitutes a vascular risk factor and
      finally, the evidence that it is possible to control homocysteinemia with
      supplementation of co-factors of homocysteine metabolism, namely vitamin B6, B12
      or folic acid.

PMID- 10418266
TI  - [Echocardiography and new diagnostic criteria for infective endocarditis].
AB  - A review of made of clinical and echocardiographic features of infective
      endocarditis, emphasizing the contribution to new diagnostic criteria made by
      Duke University and analysing different studies about their sensitivity and
      specificity and their advantages over the classic von Reyn criteria. A short
      historical overview is also made and the importance of echocardiography,
      particularly the transesophageal approach, for the diagnosis of infective
      endocarditis and its complications is discussed, bearing in mind the new
      diagnostic criteria.

PMID- 10418267
TI  - [Transesophageal echocardiography in the operating room].
AB  - The need to optimize cardiac surgery performance combined with the capability
      that intraoperative transesophageal echocardiography (ETE) has to evaluate the
      surgical results in real time, without invading the operative field and with an
      image quality as good as epicardial echo, have led to the increasing use of this
      tool in the surgical setting. After describing the historical evolution and
      defining the leading indications to perform intraoperative echocardiography, the
      author reports his experience with intraoperative TEE. The echocardiographic
      evaluation of the surgically repaired mitral valve deserves particular attention
      as it represents the leading reason to perform intraoperative TEE in his
      experience. Between January 91 and January 98, 116 intraoperative TEE were
      performed, most of them (65%) in patients submitted to valvular surgery,
      particularly for the evaluation of reparative mitral valve surgery results (34%).
      The results of conservative surgery was considered satisfactory in 33 patients
      (82%) ad unsatisfactory in six (15%). These patients have had a second run of
      cardiopulmonary by-pass and a mitral prosthesis was implanted in all of them.
      Looking ahead, the author concludes with the importance that three-dimensional
      and myocardial contrast echocardiography will have on broadening the indications
      to perform intraoperative TEE.

PMID- 10418269
TI  - [Apical hypertrophic cardiomyopathy with mid-ventricular obstruction, sustained
      ventricular tachycardia and apical necrosis].

PMID- 10418270
TI  - Traditional healers and sexually transmitted diseases.

PMID- 10418271
TI  - Management of burns--Eusol.

PMID- 10418272
TI  - Pneumococcal disease in sub-Saharan Africa: could currently available vaccines
      avert a crisis?

PMID- 10418273
TI  - Management of burns.

PMID- 10418274
TI  - Enhancing participation of women of child-bearing age in a literacy for health
      project in southeastern Nigeria.
AB  - This paper summarizes the approach of a 'literacy for health project' in
      southeastern Nigeria to recruit and maintain participants. Literacy for health
      projects enhance and develop the educational abilities of women while at the same
      time acting as a vehicle to combat the problems associated with maternal and
      child health. We describe ways to foster and enhance the participation of women
      of child-bearing age in a literacy for health project operated in Igbo-speaking
      southeastern Nigeria. Findings reveal that of four literacy centres,
      participation rates ranged from 50.35% to 61.1%. We maintain that efforts
      designed to impart the transference of literacy and numeracy skills to such women
      in southeastern Nigeria must: (a) address the farming needs, practices and
      operations of the target community prior to programme implementation; (b)
      consider the inclusion of counsellors in addition to traditional village health
      workers and/or literacy instructors; (c) determine the impact of using other
      sites based on community activities; as opposed to traditional locations such as
      schools and churches; (d) use incentives to motivate participants; and (e) extend
      the current level of participation beyond focus groups to planning beyond
      curriculum development.

PMID- 10418275
TI  - Ectopic pregnancy in Korle Bu Teaching Hospital, Ghana: a three-year review.
AB  - A retrospective study of ectopic pregnancies seen in Korle Bu Teaching Hospital
      from January 1991 to December 1993 was conducted. The incidence was 39.5/1000
      deliveries; patients with ectopic were not of lower parity than those with normal
      pregnancies. The incidence of historical predisposing factors was 11.08%,
      although findings at operation indicated a much higher incidence of previous
      pelvic inflammatory disease (PID). Dizziness/fainting and abdominal distension
      were more frequent than has been reported elsewhere. This was due to a very high
      incidence of ruptured ectopic pregnancies (98.1%) with mean volume of
      haemoperitoneum of 1.37 l. 16.3% of patients were misdiagnosed initially. The
      second commonest site of tubal pregnancy, after the ampullary region, was
      cornual. The case fatality rate was 27.9/1000, with more than half of the deaths
      occurring before or soon after arrival in hospital. In order to reduce the
      incidence of ruptured ectopic pregnancies we suggest, among other measures, that
      appropriate diagnostic facilities be provided.

PMID- 10418276
TI  - Growth monitoring: family participation: effective community development.
AB  - Growth monitoring was introduced into most developing countries in the 1970s with
      the aim of combating under nutrition in infancy and childhood. Ten years later
      analysis showed weight charts were not completed satisfactorily and not used in
      decision making. Although growth monitoring is now seldom mentioned in nutrition
      studies, the authors of this study are convinced of its value. With new
      technology using the direct recording scales (DRS), illiterate or semi-literate
      mothers are able to complete the growth curve on the weight chart and acquire
      understanding about the process and its significance for their infant. This study
      investigates the understanding of the growth curve by the rest of the family. The
      mother, their daughters and significantly, the grandmothers were shown to have
      comprehended the meaning of the growth curve. In families where mothers weighed
      their infant using the DRS, a smaller proportion were found to be suffering from
      periods of growth failure compared with families where the infant was weighed by
      community health workers with a dial scale. There are obvious gains if
      technologies are moved from the clinic into the family and the community. The
      weighing and charting of children by DRS may be a further step in the fight to
      overcome undernutrition in developing countries.

PMID- 10418277
TI  - Dengue haemorrhagic fever in adults: a prospective study of 110 cases.
AB  - One hundred and ten adult patients hospitalized with dengue haemorrhagic fever
      (DHF) during the recent outbreak in North India were prospectively studied. Of
      these, 48 (43.6%) were grade I, 40 (36.4%) grade II, 10 (9.1%) grade III and 12
      (10.9%) grade IV DHF. Dengue shock syndrome (DSS) was seen in 22 (20%) patients.
      Fever, headache, myalgias and arthralgias were the common symptoms seen in 100%,
      80.9%, 76.2% and 52.3% patients, respectively. Spontaneous bleeding was seen in
      62 patients (56.4%) with mucocutaneous bleeding being the most common (46
      patients). Gastrointestinal bleeding was seen in 38 (34.5%) patients. In as many
      as 40 patients, the haemorrhagic manifestations occurred after the fever had come
      down. Fifty-five patients (50%) required platelet transfusions. Twelve patients
      died, giving a mortality rate of 10.9% in the present study. Prompt recognition
      and supportive treatment can be lifesaving.

PMID- 10418278
TI  - The 'handy tablets delivery device'.

PMID- 10418279
TI  - Poncet's disease in a north Indian hospital.
AB  - Although the entity of tuberculous rheumatism or Poncet's disease has sometimes
      been the subject of debate, it has been reported infrequently in the English
      literature. We discuss here seven patients (5 women, 2 men; age 18-48 years) who
      presented primarily with polyarthritis and fever and developed pulmonary, pleural
      or nodal tuberculosis later in the course of disease. Rheumatoid arthritis,
      collagen vascular diseases and other common causes of polyarthritis were ruled
      out by appropriate investigations. Polyarthritis resolved in all the patients
      after the institution of antitubercular treatment and did not recur, thus
      providing a therapeutic confirmation of the clinical diagnosis.

PMID- 10418280
TI  - Traditional healers as a source of information and advice for people with
      sexually transmitted diseases in rural Zambia.

PMID- 10418281
TI  - Cancer awareness among a Nigerian population.
AB  - We conducted a population survey with the objective of identifying the level of
      cancer awareness. In Nigeria many patients present late for medical care. We
      analysed data from 460 literate Nigerians. Three hundred and sixty (78.3%) had
      heard about cancer. 34.1% identified particular risk age categories, while 62.2%
      said that cancer could occur at any time. Awareness of warning signs and sites of
      cancer location was very poor and only 33% recognized that a breast lump was a
      warning sign. Knowledge of methods of early detection was also very low and only
      50% said that cancer is curable when detected early. This investigative survey
      highlighted a considerable ignorance and lack of awareness of cancer among the
      Nigerian population.

PMID- 10418282
TI  - Skin grafting in difficult situations.

PMID- 10418284
TI  - Management of open tibial fractures.

PMID- 10418283
TI  - The differential diagnosis and management of breast lumps in the tropics.
AB  - Breast cancer is less common in the Tropics than in the West, but presents a
      formidable challenge due to late presentation. Public education is vital if the
      outcome is to be improved. There are many benign pathologies which present
      similarly to cancer--this underlines the need for proper diagnosis, as mastectomy
      is often not necessary. It is important to remember that non-peurperal breast
      abscesses may be the first sign of HIV infection.

PMID- 10418285
TI  - Fluid and electrolyte balance for adults (without a biochemical laboratory).

PMID- 10418286
TI  - A case of dystocia in conjoined twins.

PMID- 10418287
TI  - Prevalence of sexually transmitted disease in tuberculosis patients in Malawi.

PMID- 10418288
TI  - Where there is no anaesthetist.

PMID- 10418289
TI  - Child labour.

PMID- 10418290
TI  - AIDS treatment in Africa.

PMID- 10418291
TI  - Methods of oxygen delivery in children: which is best?

PMID- 10418293
TI  - Community involvement in the monitoring and evaluation of their children's
      progress.

PMID- 10418292
TI  - Management of burns: skin cover.

PMID- 10418294
TI  - Neonatal care during a residents' strike.
AB  - Medical officers from a primary health centre and rural hospital were posted at
      our neonatal care unit during the residents' strike that lasted 69 days. They
      were trained in labour room care and in special care of high-risk babies. Four
      weeks later they were to be first-on-call. During the pre-strike, strike and post
      strike period, there was no significant difference in the number of high-risk
      deliveries and admissions and deaths at the special care unit (SCU). The low-tech
      neonatal care that we followed, can be practised at the first referral centre in
      rural areas of developing countries by the team led by a medical officer.

PMID- 10418295
TI  - Active prophylactic management of respiratory obstruction after standard
      thyroidectomy for giant goitre in the middle belt region of Nigeria.
AB  - Respiratory obstruction is a lethal complication of thyroidectomy for giant
      goitre. Prophylactic tracheal splintage by retaining the endotracheal tube in
      situ for 24 h post-operatively and its meticulous management in the intensive
      care unit (ICU) is a safe and rewarding practice. Over a 7-year period, 33
      patients, all women who had standard thyroidectomy for giant goitre were managed
      accordingly. There was no incidence of post-operative respiratory distress, nor
      mortality in the series. The average duration of stay in ICU was 2 days for all
      patients and the average hospital stay was 6 days for 27 of the 33 patients
      (81.8%). We suggest that judicious post-thyroidectomy management of giant goitre
      patients in ICU with endotracheal tube in situ for 24 h improves their survival
      chances.

PMID- 10418296
TI  - Bangladesh national drug policy: an example for the Third World?
AB  - The need and the lack of resources of the Third World poor urgently demands the
      elimination of 'luxury' drugs. The innocent victims can only be safe if these do
      not find their way on to the market. A National Drug Policy based on the ED
      Concept is essential for the developing countries and BNDP may provide a helpful
      model.

PMID- 10418297
TI  - Flaws in the out-patient flow at a semi-rural hospital in northern Namibia.
AB  - The aim of this study was to determine the quantity and quality of our service in
      the out-patient department (OPD). During 2 weeks in November and December 1996
      all out-patients were followed throughout their stay. Service times, waiting
      times, time on arrival, time on departure and completeness of the service were
      recorded. All in all, 4999 patients, who had 17,436 contacts with healthcare
      providers were recorded. Approximately 500 out-patients were seen daily with
      48.43% follow-ups and 15.24% referrals. Two-thirds (74.79%) of all patients
      arrived before 1100 h. Between 200 and 300 patients were present in the OPD at
      any time between 0900 h and 1600 h. Twelve per cent (621 patients) left the
      hospital with an incomplete service. Of the 1511 patients screened by the nurses
      only 20 (1.32%) were treated by them. The way the work was organized was
      inefficient and client unfriendly. Inefficient, because available expertise was
      not utilized. Client unfriendly, because this leads to situations where patients
      were denied the service to which they were entitled.

PMID- 10418298
TI  - Community-based teaching of tropical diseases: an experience with filariasis.
AB  - The Department of Community Health Christian Medical College, Vellore, India,
      developed a module in 1981 to teach filariasis to medical undergraduates, using a
      community-based approach aimed at providing a comprehensive picture of this
      disease. Students learn in four phases during the 5 1/2 years they spent in
      medical school. Student assessment is done during and at the end of each phase.
      Student feedback of the programme has been very positive. This paper describes
      the salient features of the module and suggests it could be adopted by other
      institutions to teach tropical diseases of public health importance that are
      relevant to that particular region or country.

PMID- 10418299
TI  - The importance of psychosocial paediatrics in the developing world.

PMID- 10418300
TI  - HIV and syphilis serostatus of antenatals in traditional Maasai pasturalist
      communities in Kajiado District, Kenya: 1989-1992.
AB  - Although much research has been carried out on high risk populations, little is
      known about HIV prevalence in traditional rural communities who limit contact
      with other tribes, non-traditional tribesman and Europeans. This study considers
      traditional Maasai living near a high HIV transmission area. A time series
      analysis assessed the trend of HIV-1 and syphilis prevalences in the study area.
      Data consist of antenatal blood specimens (n = 2082 women) collected during 1989
      1992. An estimated 100% of pregnant women residing in the study areas are
      included in the study. Standardized HIV-1 prevalences among women for 1989-1992
      ranged between 0.95% and 2.23%. A chi 2 test for trends was not significant,
      analysis of age-specific prevalences revealed no significant result. Standardized
      syphilis prevalence varied from 1.89% to 12.82% during the 3 years. Prevalence
      declined in 1990, but increased significantly thereafter. A steep 1992 increase
      in syphilis was not associated with an increase in HIV. Chi square test for
      trends for age-specific syphilis was not significant. In 2082 samples only one
      woman was positive for both HIV and syphilis. In 4 years no increase in HIV
      prevalence was detected among traditional Maasai woman living near a high
      transmission area. No significant variation across ages was detected. However,
      syphilis increased sharply in one time period, 1992. Despite the low HIV
      prevalence among Maasai, the higher prevalence of syphilis suggests that the HIV
      epidemic is at an early phase and may increase soon. It may also suggest that HIV
      does not yet have a high prevalence at markets where Maasai sell their herds, but
      is concentrated at truck stops.

PMID- 10418301
TI  - Oropharyngeal delivery of oxygen to children.
AB  - Oropharyngeal oxygen was administered to 13 patients with rapid breathing and
      hypoxaemia, six of whom were newborns. Feeding tube, No. 8F, was used in newborns
      for delivery of oxygen and No. 1 OF for others. Oxygen flow rate, 0.5 litre/min
      for four newborns and 1 litre/min, for the rest, was adequate to maintain oxygen
      saturations 90% and above. There were no instances of tube blockage or
      displacement.

PMID- 10418303
TI  - Banning the anti-personnel mine: a treaty too far?

PMID- 10418302
TI  - Enucleation for ritual practices.
AB  - Five cases of enucleation performed on seeing eyes are presented, highlighting
      the dangers this procedure poses to the patient. It also presents the problems
      this can pose to the development of ophthalmology.

PMID- 10418305
TI  - Maxillofacial injuries due to assault in Maiduguri, Nigeria.

PMID- 10418304
TI  - Snake bites in rural area of Maharashtra State, India.

PMID- 10418306
TI  - Neisseria meningitidis nasopharynx colonization of diseased patients on
      presentation and on discharge.
AB  - Fifty-one meningococcal disease patients were randomly selected and a paired
      throat swab was taken before and after specific therapy. Neisseria meningitidis
      nasopharyngeal carriage after intravenous antibiotic therapy were found in only
      two cases (4%; 95% confidence interval (CI) 0.5-13). All close contacts of the
      cases received chemoprophylaxis and throat swabs taken 10 days later were
      negative.

PMID- 10418307
TI  - Choledocholithiasis mimicking Ascaris lumbricoides: problem in ultrasound
      differential diagnosis.

PMID- 10418308
TI  - Orbital teratoma.

PMID- 10418309
TI  - Problems of suprapubic prostatectomy.

PMID- 10418310
TI  - A low-cost spacer device.

PMID- 10418311
TI  - Safety of mineral oil in urological procedures.

PMID- 10418312
TI  - Hypoglycaemic shock: normal or abnormal response to injury?

PMID- 10418313
TI  - HIV infection in Dharam, Nepal.

PMID- 10418314
TI  - Skin meshing.

PMID- 10418315
TI  - Buerger's disease: the role of omental transfer.

PMID- 10418316
TI  - Bronchiectasis: frequent misdiagnosis in sub-Saharan Africa.

PMID- 10418317
TI  - An indicator of the participation of children in manual labour.

PMID- 10418318
TI  - Waist-to-hip ratio as cardiovascular risk factor in Asian Indians: what role is
      played by age and sex?

PMID- 10418319
TI  - HIV in leprosy patients.

PMID- 10418320
TI  - The Gap effect for spatially oriented responses.
AB  - The gap effect refers to the finding that a temporal gap between fixation point
      offset and target onset typically results in shorter saccadic latencies than if
      the fixation point remains on. Recently, this gap effect was found for aimed hand
      movements as well as saccadic eye movements, but not for simple keypress
      responses. In order to examine the hypothesis that the hand gap effect occurs for
      different types of spatially oriented movements, two experiments were conducted.
      In the first experiment, subjects produced spatially oriented responses to a
      peripheral target and the target location was known in advance of the targets
      presentation. This spatially oriented detection task yielded gap effects for both
      eye and hand responses. In the second experiment, the duration of the temporal
      gap was varied between 0-400 ms. The duration of the temporal gap had similar
      effects on the magnitudes of both the eye and hand gap effects, suggesting that a
      common mechanism may underlie the gap effect for saccadic and manual pointing
      movements. Overall, the results of the present experiments confirm the finding of
      a gap effect for spatially oriented hand movements and suggest that this effect
      may be related to the functioning of the superior colliculus.

PMID- 10418321
TI  - Synthetic stimuli attenuate the effect of attention on the dichotic right-ear
      advantage.
AB  - This study assessed attentional effects on the right-ear advantage (REA) for a
      dichoticlistening task that used synthetic-speech syllables. Presenting subjects
      with monaural tone cues at various intervals prior to dichotic pairs of natural
      speech syllables, T. A. Mondor and M. P. Bryden 1991 (The influence of attention
      on the dichotic REA. Neuropsychologia, 29, 1179-1190) found a reduced REA with
      longer intervals. This suggested that tone cues at longer intervals helped
      overcome a right-ear attentional bias. Despite sufficient statistical power, in
      the present study no reduction in the REA was found with longer intervals between
      tones and synthetic-speech syllables. As synthetic-speech stimuli tend to fuse
      better into the percept of a single stimulus than do natural-speech stimuli,
      attentional effects on the REA may be reduced with dichotic stimuli that fuse.

PMID- 10418322
TI  - Pectins and xyloglucans exhibit antimutagenic activities against nitroaromatic
      compounds.
AB  - Because a high daily consumption of polysaccharides-containing food is assessed
      to decrease the risk of cancer of the gastrointestinal system, different types of
      carbohydrates were investigated for their antimutagenic activity against
      different standard mutagens. Within the screening pronounced antimutagenic
      effects were found for xyloglucan and different pectins and pectin-like
      rhamnogalacturonans against 1-nitropyrene induced mutagenicity. Inhibition rates
      were dose-dependent and varied between 20 and 50%. Concerning the mode of action
      a direct interaction of the polymers with the cells is claimed, protecting the
      organisms from the mutagenic attack.

PMID- 10418324
TI  - Flavonoids from Cleome droserifolia suppress NO production in activated
      macrophages in vitro.
AB  - The effect of an Egyptian medicinal plant, Cleome droserifolia (Forssk.) Del. on
      nitric oxide (NO) production in bacillus Calmette-Guerin-induced mouse peritoneal
      macrophages activated by lipopolysaccharide was investigated in vitro. The
      methanol extract of C. droserifolia reduced the NO production, and two flavonoids
      were isolated as the active components. The new one was determined to be 5,4'
      dihydroxy-6,7,8,3',5'-pentamethoxyflavone (1) and the other was identified as
      5,4'-dihydroxy-6,7,8,3'-tetramethoxyflavone (8-methoxycirsilineol; 2). Compound 1
      concentration-dependently suppressed the NO production and was effective at a non
      toxic concentration (12.5 micrograms/ml). The suppressive activity of 2 was
      weaker than that of 1.

PMID- 10418323
TI  - Scopoletin: an inducible nitric oxide synthesis inhibitory active constituent
      from Artemisia feddei.
AB  - Bioassay-guided fractionation of an H2O extract of Artemisia feddei has furnished
      an inducible nitric oxide synthase (iNOS) inhibitory coumarin, scopoletin (1) and
      one of the inactive sesquiterpenes, achillin (2). Compound 1 showed inhibition of
      nitric oxide (NO) synthesis in a dose-dependent manner in murine macrophage-like
      RAW 264.7 cells stimulated with interferon-gamma (IFN-gamma) plus
      lipopolysaccharide (LPS). The inhibition of NO synthesis of 1 was due to
      suppression of iNOS mRNA and iNOS protein, as determined by Northern and Western
      blotting, respectively.

PMID- 10418325
TI  - Sophoricoside analogs as the IL-5 inhibitors from Sophora japonica.
AB  - Fruits of Sophora japonica L. (Leguminosae) exhibited an inhibitory effect in the
      IL-5 bioassay of mIL-5-dependent Y16 proliferation. The isoflavonoids of
      sophoricoside, genistein, orobol, and genistin were isolated as the IL-5
      inhibitors from fresh fruits of the plant by activity-guided fractionation. Among
      the IL-5 inhibitors, sophoricoside exhibited the highest inhibitory effect with
      89% inhibition at 12.5 microM, 82% at 6.3 microM, 72% at 3.1 microM, 59% at 1.6
      microM, and 24% at 0.8 microM where the 50% inhibition (IC50) was shown at the
      concentration of 1.5 microM. Oxyphenylbutazone as the positive control exhibited
      the IC50 value at the concentration of 31.7 microM. In the order of IC50 values
      the inhibitory potency in the IL-5 bioassay was sophoricoside > orobol (9.8
      microM) approximately equal to genistin (10.6 microM) > genistein (51.9 microM).
      The position of O-glycosylation and number of hydroxy groups in the isoflavonoids
      seem to play an important role in the inhibitory effect in the IL-5 bioassay.

PMID- 10418326
TI  - Evaluation of the anti-plasmodial activity of bisbenzylisoquinoline alkaloids
      from Abuta grandifolia.
AB  - Three alkaloids were isolated from the bark of the traditional medicinal plant
      Abuta grandifolia (Mart.) Sandw. (Menispermaceae) and tested for in vitro anti
      plasmodial activity. Two of them were identified as the Type VIII
      bisbenzylisoquinoline alkaloids, krukovine (1) and limacine (2), while the least
      abundant compound (3) could only be characterised to Type I of the same class.
      Krukovine exhibited potent anti-plasmodial activity with IC50 values of 0.44
      microgram/ml and 0.022 microgram/ml against K1 (chloroquine-resistant) and T9-96
      (chloroquine-sensitive) Plasmodium falciparum, respectively. Both limacine and
      compound 3 exhibited moderate anti-plasmodial activity against K1 with IC50
      values of 1.35 micrograms/ml and 1.58 micrograms/ml, respectively. Limacine gave
      an IC50 value of 0.24 microgram/ml against T9-96. Krukovine and limacine showed
      greater activity against T9-96 than against K1, exhibiting similar activity
      profiles to that of chloroquine diphosphate (0.187 microgram/ml and 0.013
      microgram/ml against K1 and T9-96, respectively). This indicates that krukovine
      and limacine may be affected by the mechanism of chloroquine resistance present
      in K1 P. falciparum.

PMID- 10418327
TI  - In vivo metabolism of aloemannan.
AB  - The metabolism of fluoresceinyl isothiocyanate labeled aloemannan (FITC-AM) was
      examined by p.o. and i.v. administration in mice at a dose of 120 mg/kg. Analysis
      of FITC-AM in urine and feces showed that FITC-AM (MW 500 KD) was metabolized
      into smaller molecules that mainly accumulated in the kidneys. AM was catabolized
      by the human intestinal microflora to catabolites 1 and 2 with molecular weights
      of 30 and 10 KD, respectively. Hydrolysis of AM showed hexosamine peaks on HPAE.
      The findings suggest that the immunomodulation of AM may come from not only
      neutral polysaccharides but also contaminated hexosamine in AM.

PMID- 10418328
TI  - Prevention by a silymarin/phospholipid compound of ethanol-induced social
      learning deficits in rats.
AB  - We explored the possibility that silymarin (SY), a fraction from Silybum
      marianum, might protect against the effects of in utero exposure to ethanol upon
      subsequent social memory function. Three groups of 8 pregnant female Sprague
      Dawley rats each were provided with a liquid diet containing 35% ethanol derived
      calories (EDC). One experimental group received a daily subcutaneous injection of
      400 mg/kg SY, the second, a 400 mg/kg oral dose of SY, a third group was
      maintained on the 35% EDC diet. A fourth group served as the pair-fed control
      group. The liquid diet regimen was maintained throughout pregnancy. Rats pups
      were fostered by dams in a fifth group that had been maintained on rat chow. At
      90 days the pups were tested for social memory. Social recognition scores
      recorded for the ethanol pups were significantly poorer than those observed in
      both SY/ethanol groups and the chow group.

PMID- 10418329
TI  - A comparative study on commercial, botanical gardens and wild samples of the
      roots of Platycodon grandiflorum by HPLC analysis.
AB  - Thirteen commercial samples of Platycodi radix of Platycodon grandiflorum, were
      collected from China (5 kinds), Korea (5 kinds), and Japan (3 kinds) along with 8
      kinds of botanically cultivated Platycodi radix, 3 kinds of wild Platycodi radix
      collected from different places in Japan. HPLC analysis showed that the
      commercial botanical and wild samples of P. radix all contained platycodins and a
      total of twelve peaks were identified by co-HPLC anlaysis with authentic samples
      isolated earlier from this laboratory. The peak purity and identify were checked
      with a PDA. The contents of the major saponins, platycodins A, C, D were
      determined and the peak-area ratios of platycodins A, C, D were shown to be
      correlated with their sources of origin. The commercial samples from China and
      Korea each gave a distinct HPLC pattern with peak-area ratio of platycodins A, C,
      D at 1:2:3 and 2:4:1, respectively. HPLC analysis showed that those on the
      Japanese market were either imported from China or Korea based upon their HPLC
      patterns while the Japanese botanical garden or wild type samples gave a higher
      total saponin content with the peak-area ratio of platycodins A, C, D at 1:2:1.

PMID- 10418331
TI  - Antiviral activities against HSV-1, HCMV, and HIV-1 of rhamnan sulfate from
      Monostroma latissimum.
AB  - Rhamnan sulfate (RS), a natural sulfated polysaccharide isolated from Monostroma
      latissimum, showed potent inhibitory effects on the virus replication of herpes
      simplex virus type 1 (HSV-1), human cytomegalovirus (HCMV), and human
      immunodeficiency virus type 1 (HIV-1) in vitro. The antiviral action of RS was
      not only due to the inhibition of virus adsorption, but also might involve the
      later steps of viral replication in host cells on the basis of the results of
      time-of-addition experiments. Furthermore, RS and 3'-azido-3'-deoxythymidine
      (AZT) were synergistic in their anti-HIV-1 activities. These data indicate that
      RS is a potent antiviral substance against HSV-1, HCMV, and HIV-1.

PMID- 10418330
TI  - alpha-Glucosidase inhibitors from Commelina communis.
AB  - A methanolic extract of Commelina communis showed potent inhibitory activity
      against alpha-glucosidase. One pyrrolidine alkaloid, 2,5-dihydroxymethyl-3,4
      dihydroxypyrrolidine (DMDP, 1) and four piperidine alkaloids, 1
      deoxymannojirimycin (2), 1-deoxynojirimycin (3), alpha-homonojirimycin (4) and 7
      O-beta-D-glucopyranosyl alpha-homonojirimycin (5) were isolated by bioassay
      directed fractionation and separation. These compounds have been identified for
      the first time from Commelina communis, supporting the pharmacological basis of
      this plant that has been used as a traditional herbal medicine for the treatment
      of diabetes.

PMID- 10418332
TI  - Azaanthraquinone: an antimicrobial alkaloid from Mitracarpus scaber.
AB  - An ethanolic extract of the aerial parts of Mitracarpus scaber demonstrated good
      antimicrobial activity. Bioassay directed fractionation of this extract led to
      the isolation of benz[g]isoquinoline-5,10-dione (1) as an active component.
      Compound 1 showed significant in vitro inhibitory activity against the AIDS
      related pathogens.

PMID- 10418334
TI  - Antimicrobial activity and stability of tingenone derivatives.
AB  - Quinone-methide triterpenes of the tingenone series were evaluated for their
      antimicrobial activity. These compounds were effective against Bacillus cereus,
      B. subtilis, Sarcina lutea, Staphylococcus aureus, Microsporum gypseum and a Gram
      negative bacterium, Klebsiella pneumoniae. Under acidic conditions, the quinone
      methide part of these compounds rearranged into the divinyl-phenolic system, and
      the antimicrobial activity was thus lost.

PMID- 10418333
TI  - Antimalarial activity and cytotoxicity of (-)-roemrefidine isolated from the stem
      bark of Sparattanthelium amazonum.
AB  - (-)-Roemrefidine, an aporphine alkaloid isolated from Sparattanthelium amazonum
      Martius (Hernandiaceae) a vine from Bolivia, has been found to be active against
      both resistant and sensitive strains of Plasmodium falciparum in vitro and
      against P. berghei in mice. The compound demonstrated no cytotoxic activity
      against three cell lines (KB, HEp-2 and HeLa).

PMID- 10418336
TI  - A new phenolic fatty acid ester with lipoxygenase inhibitory activity from
      Jacaranda filicifolia.
AB  - The dichloromethane extract of the stem of jacaranda filicifolia Don. showed
      inhibitory activity in vitro against soybean 5-lipoxygenase. Systematic
      fractionation to isolate the compounds responsible resulted in the isolation of
      three active compounds, 2 alpha, 3 alpha-dihydroxyurs-12-en-28-oic acid, beta
      sitosterol, and one of which was new which was characterised as 2-(4
      hydroxyphenyl)ethyl 1-dodecyloctadecanoate. This type of compound has not
      previously been reported to inhibit lipoxygenase.

PMID- 10418335
TI  - Inhibitory effects of higenamine on dopamine content in PC12 cells.
AB  - The inhibitory effects of (+/-)-higenamine, a benzylisoquinoline alkaloid, on
      dopamine biosynthesis in PC12 cells were investigated. Higenamine decreased the
      intracellular dopamine content dose-dependently and showed 55.2% inhibition of
      dopamine content in PC12 cells at a concentration of 20 microM with 24 h
      incubation. The IC50 value of higenamine was 18.2 microM. Dopamine content was
      lowered and reached minimal level at 12-24 h after exposure to higenamine. In
      this condition, tyrosine hydroxylase, the rate-limiting enzyme of catecholamine
      biosynthesis, was also inhibited by the treatment of higenamine in PC12 cells
      (21.9% inhibition at 20 microM). Higenamine at 20 microM lowered the
      intracellular Ca2+ concentration by 33.1% inhibition relative to control in PC12
      cells. These results suggest that the inhibition of tyrosine hydroxylase activity
      by higenamine might partially contribute to the decrease in dopamine content in
      PC12 cells.

PMID- 10418337
TI  - Inhibitory effect of luteolin 4'-O-glucoside from Kummerowia striata and other
      flavonoids on interleukin-5 bioactivity.
AB  - Interleukin (IL)-5 is a chemotactic factor of eosinophils, and promotes the
      growth and survival of eosinophils, which plays an important role in the
      eosinophilia-associated allergic inflammation. In this study, luteolin 4'-O
      glucopyranoside was identified as the IL-5 inhibitor from Kummerowia striata
      Thunb. (Leguminosae) by activity-guided fractionation followed by structural
      analysis compared with reported spectral data. The flavone compound exhibited
      dose-dependent inhibitory effect on IL-5 bioactivity with 95% inhibition at 30
      microM, 79% at 15 microM, 60% at 7.5 microM, 54% at 3.8 microM and 29% at 1.9
      microM, where 50% of inhibition (IC50) value was shown at the concentration of
      3.7 microM. Furthermore, the inhibitory effect on IL-5 bioactivity by other
      flavonoid compounds available was estimated. In view of the IC50 values, the
      inhibitory potency on IL-5 bioactivity was in order of luteolin 4'-O
      glucopyranoside > cosmosiin (14.2 microM) approximately equal to apigenin (16.4
      microM) approximately equal to luteolin (18.7 microM) > quercimeritrin (27.3
      microM) approximately equal to kaempferol (30.0 microM).

PMID- 10418338
TI  - (-)-Epiafzelechin: cyclooxygenase-1 inhibitor and anti-inflammatory agent from
      aerial parts of Celastrus orbiculatus.
AB  - An inhibitor of cyclooxygenase (COX)-1 activity of prostaglandin H2 synthase was
      isolated from aerial parts of Celastrus orbiculatus Thunb. (Celastraceae), an
      oriental folk medicine for rheumatoid arthritis by activity-guided column
      chromatographic methods. The COX inhibitor was identified as (-)-epiafzelechin, a
      member of flavan-3-ols by the structural analysis with HR-EI-mass, 1H-NMR and 13C
      NMR spectral data. The compound exhibited a dose-dependent inhibition on the COX
      activity with an IC50 value of 15 microM. (-)-Epiafzelechin exhibited about 3
      fold weaker inhibitory potency on the enzyme activity than indomethacin as a
      positive control. (-)-Epiafzelechin exhibited significant anti-inflammatory
      activity on carrageenin-induced mouse paw edema when the compound (100 mg/kg) was
      orally administrated at 1 h before carrageenin treatment.

PMID- 10418339
TI  - Tracheal relaxant activity of cissaglaberrimine and trilobinine, two aporphinic
      alkaloids from Cissampelos glaberrima.
AB  - In the present work we studied the relaxant effect of two aporphinic alkaloids
      isolated from the roots barks of Cissampelos glaberrima St. Hil.
      (Menispermaceae), (+)-cissaglaberrimine (CGE; a tertiary alkaloid) and (+)
      trilobinine (TBE; a quaternary alkaloid). In guinea-pig tracheal preparations,
      CGE and TBE reduced the spontaneous tone and inhibited the contractions induced
      by carbachol and histamine. TBE was 6 times more potent than CGE in reducing the
      spontaneous tone and it was also 1.5 times more potent in antagonising the
      effects of carbachol and histamine. The inhibitory effect of CGE in contractions
      induced by histamine was not attenuated in the presence of timolol (10 microM).
      However, in the same experimental conditions, timolol almost completely abolished
      the inhibitory effect of TBE. These results showed that the relaxations induced
      by TBE were dependent on the activation of beta 2-adrenoceptors, while the
      mechanism involved in relaxations induced by CGE remains to be determined.

PMID- 10418340
TI  - Inhibition of rat adjuvant-induced arthritis by ginkgetin, a biflavone from
      ginkgo biloba leaves.
AB  - Ginkgetin, a biflavone isolated from Ginkgo biloba leaves, was previously
      reported as an inhibitor of group II phospholipase A2. In this study, ginkgetin
      was evaluated for in vivo antiarthritic and analgesic activities. Ginkgetin (10
      20 mg/kg/day) strongly reduced arthritic inflammation in an animal model of rat
      adjuvant-induced arthritis (86% inhibition at 16 days at a dose of 20 mg/kg/day)
      via intraperitoneal injection, while prednisolone (5 mg/kg/day) showed 79%
      reduction. Histological examination of the knee joints confirmed our findings.
      When analgesic activity was measured, ginkgetin showed a dose-dependent
      inhibition in an animal model of acetic acid-induced writhing. ED50 values for
      ginkgetin and indomethacin were 8.9 and 3.8 mg/kg, respectively. All these
      results indicate that ginkgetin may be a potential antiarthritic agent having
      analgesic activity.

PMID- 10418341
TI  - Biological activity of the essential oil of Myrcianthes sp. nov. "black fruit"
      from Monteverde, Costa Rica.
AB  - The leaf essential oil of an undescribed species of Myrcianthes has been obtained
      from Monteverde, Costa Rica. The essential oil exhibits in vitro cytotoxic
      activity against Hep-G2 and SK-Mel-28 human tumor cell lines. A GC/MS analysis
      shows the essential oil to be composed of 2-heptanol, alpha-pinene, beta-pinene,
      limonene, cineole, and alpha-terpineol, alpha-Pinene, beta-pinene, and limonene
      account for the cytotoxic activity of the leaf essential oil of Myrcianthes sp.
      nov. "black fruit".

PMID- 10418342
TI  - Antigiardial isoflavones from Machaerium aristulatum.

PMID- 10418343
TI  - AAOHN Advisory: Antitrust considerations for professionals.

PMID- 10418344
TI  - Health risks of health care workers: health risks appraisal results from the
      newly independent country of Georgia.
AB  - Health promotion and disease prevention activities should be carried out by all
      health care professionals. These activities are especially important in the Newly
      Independent States (NIS) of the former Soviet Union where resources are not
      available to meet all health care needs. Little is known about actual health
      risks among health care professionals in the NIS. Such self knowledge is
      important to link professional's prevention activities to risk factors for
      disease. To determine the prevalence of selected health risks of health
      professionals in Tbilisi, the capital of the NIS Georgia, a survey was conducted
      in 1996 with a convenience sample of 107 physicians and nurses. Participants
      completed the Healthier People Health Risk Appraisal (HPHRA), then researchers
      measured each subject's height, weight, blood pressure, and total cholesterol.
      Compared to the U.S. norms used in the HPHRA program analysis, measured group
      results for the Georgians were in the very high risk category for lack of
      seatbelt usage and stressful lifestyle, in the high risk category for lack of
      exercise, and in the moderately high risk category for blood pressure and
      smoking. The measured weight and reported alcohol consumption for Georgians was
      comparable to the U.S. national averages and total cholesterol values were below
      U.S. average levels.

PMID- 10418345
TI  - Intuition comes of age: workplace applications of intuitive skill for
      occupational and environmental health nurses.
AB  - 1. Intuition is an internal experience. It is a way of knowing something directly
      without an intervening analytic thought. It functions more subjectively than
      objectively. 2. The subjective nature of intuition makes it challenging to use in
      the business world yet the value it adds makes it worth the effort. Intuition
      adds value when making judgment calls, managing unforeseeables, when creativity
      and innovation are necessary. Intuition is the skill of responding appropriately,
      in the moment, to specific situations. Intuition "opens the doors" to new
      possibilities which can then be applied and evaluated analytically. 3. Intuition
      can be enhanced in the workplace by becoming familiar with some of the ways it is
      experienced, and facilitate co-workers to express their intuitions more openly.
      Another way to enhance intuition at work is to ask questions which collect non
      analytic data. 4. Making intuitive thinking a regular part of team meetings will
      improve the productivity of the team and encourage individual use of intuitive
      skill. Individual intuitive skill can be increased with paying regular attention
      to physical responses, images, feelings, and synchronicities.

PMID- 10418346
TI  - Ambient noise levels in mobile audiometric testing facilities: compliance with
      industry standards.
AB  - Excessive ambient noise levels in audiometric test booths may elevate and
      therefore invalidate hearing thresholds of employees included in a hearing
      conservation program. This study was conducted to determine if a sample of mobile
      test vans and trailers operating in the Midwest met the 1983 Occupational Safety
      and Health Administration (OSHA) maximum permissible ambient noise levels
      (MPANLs), the MPANLs in the American National Standards Institute (ANSI) S3.1
      1991, and the suggested National Hearing Conservation Association (NHCA) values.
      Ambient noise levels were measured in 13 audiometric test booths contained in 12
      different industrial mobile test vans and trailers operating in the Midwest.
      Results indicated that all 13 (100%) of the industrial mobile test vans and
      trailers evaluated complied with 1983 OSHA permissible levels and the NHCA 1996
      recommended levels. With regard to the 1991 ANSI MPANLs, 5 (38%) of the 13 booths
      were in compliance at all frequencies. Those that failed did so at 125, 250, and
      500 Hz. It appears that the NHCA levels need to be used for all hearing
      conservation programs with respect to compliance for noise levels in mobile
      audiometric test booths.

PMID- 10418347
TI  - Integrating occupational health protection and health promotion: theory and
      program application.
AB  - 1. The worksite offers an excellent setting to focus on both health protection
      and health promotion. Collaboration between health professionals concerned with
      health protection and health promotion would achieve common goals of risk
      reduction related to job risks and life risks. 2. Workers who experience "double
      jeopardy" because they are exposed to job risks and life risks would benefit
      most. 3. Benefits of integration include lower health risks, joint responsibility
      to promote health and safety shared between management and workers, and cost
      effectiveness. 4. The social ecological model is useful in developing an
      integrated program as it is multidimensional, interdisciplinary, and includes the
      dynamic interplay between the environment and personal factors impacting the
      health outcome.

PMID- 10418348
TI  - Orthopedic massage: a model for alternative treatment of cumulative trauma
      disorders.
AB  - 1. Complementary and alternative treatments are being used with increasing
      frequency to treat many cumulative trauma disorders. 2. Orthopedic massage is a
      system composed of a wide variety of massage treatment methods. 3. Orthopedic
      massage is an effective method for treating many cumulative trauma disorders.

PMID- 10418349
TI  - Epidemiology and prevention.

PMID- 10418350
TI  - 1998-1999 National Directory of Certified Nephrology Nurses.

PMID- 10418351
TI  - Research priorities for nephrology nursing: American Nephrology Nurses'
      Association's Delphi Study.
AB  - The purpose of this study was to identify and prioritize research topics of
      importance for nephrology nursing and the American Nephrology Nurses' Association
      (ANNA). This was an explorative survey design using the Delphi technique.
      Nephrology nurses who are members of ANNA participated in the study. In Round 1
      participants included 90 members of the Advanced Practice Special Interest Group.
      Round 2 participants were 537 nephrology nurses who attended the 28th ANNA
      National Symposium. Participants in Round 3 were 491 ANNA members who had at
      least a master's degree in nursing or another field. A three-round Delphi
      technique was used to solicit, identify, and prioritize problems for nephrology
      nursing research. In Round 1, 90 nurses identified problems in response to an
      open-ended question. These responses were analyzed and categorized into a 21-item
      research survey that was used for subsequent rounds. Round 2 participants rated
      each research question/topic on the survey on a 1 to 5 scale for level of
      importance. In addition, they were asked to identify the top-ranked research
      priorities from the 21 questions. In Round 3, the participants were asked to do
      the same as in Round 2. In addition, they indicated whether the research priority
      was primarily a nursing responsibility or a collaborative effort with other
      health care personnel. Based on 3 rounds of the Delphi study and analysis of both
      level of importance and rated-research priority, the five areas that were
      identified as research priorities are (a) nursing interventions to prevent
      vascular access infections, (b) nursing interventions to maintain vascular access
      patency, (c) educational needs of patients and families, (d) levels of nursing
      competence and the effect on patient outcomes, and (e) validation of nursing
      interventions to achieve patient outcomes. These research priorities provide
      direction for nephrology nursing research and the ANNA. This Delphi study
      represents a significant step for ANNA in its commitment to research.

PMID- 10418353
TI  - Renal transplant recipients' and their physicians' expectations regarding return
      to work posttransplant

PMID- 10418352
TI  - Renal transplant recipients' and their physicians' expectations regarding return
      to work posttransplant.
AB  - The purpose of the study was to explore the return to work (RTW) expectations of
      adult renal transplant recipients and their transplant physicians. The design was
      a prospective survey. Data was collected from 25 adult end stage renal disease
      (ESRD) patients who were admitted to a large Midwestern transplant center for
      renal transplantation and the surgeons who performed their transplant operations.
      Self-administered questionnaires were completed pretransplant by the recipients
      and surgeons, and at 6 weeks posttransplant by the recipients. Recipients who
      were employed pretransplant and were more likely to expect to RTW posttransplant,
      did so at higher rates than recipients who were not employed pretransplant and
      had physicians who did not expect them to RTW. The results illustrate that
      posttransplant RTW expectations of both renal transplant recipients and their
      physicians, when assessed pretransplant, are often congruent and are indicative
      of recipient posttransplant vocational rehabilitation.

PMID- 10418354
TI  - Predictors of QoL in renal transplant recipients: bridging the gap between
      research and clinical practice. Posttransplant Quality of Life Intervention Study
      Group.
AB  - Previous research in quality of life (QoL) in renal transplant recipients has
      identified three factors predictive of improved QoL: reduction in adverse events,
      facilitation of employment, and enhancement of social support. After a decade of
      QoL outcome research, the researchers have proposed a multidisciplinary approach
      to posttransplant care by developing a clinical pathway using the three
      predictive factors. Putting into practice the research outcome, this pathway
      systematically addresses and evaluates each of the study arms and the impact on
      QoL. A clinical team has been instrumental in developing a model of practice that
      incorporates the research outcomes.

PMID- 10418355
TI  - The role of Viagra in the treatment of male impotence in ESRD.

PMID- 10418357
TI  - Time management networking session.

PMID- 10418356
TI  - CQI in anemia management: using the fishbone approach to improve outcomes. Case
      study of the anemic patient.
AB  - Anemia management outcomes can be improved through a concentrated effort by
      nephrology nurses and other members of the nephrology team. This article focuses
      on the use of a Fishbone CQI diagram that can help clinicians identify and manage
      specific etiologies that effect erythropoiesis.

PMID- 10418358
TI  - As a registered nurse are you truly a patient advocate?

PMID- 10418359
TI  - A journey through mental illness.

PMID- 10418360
TI  - Trauma nursing: an advanced practice case study.
AB  - Trauma is the leading cause of death in people less than 40 years of age. Blunt
      or penetrating trauma injuries may be a result of gunshot wounds, stabbings, head
      injuries,burns, falls or motor vehicle collisions. Unlike other patients entering
      the health care system, trauma victims have no time for hospital preparation. The
      physiologic and psychosocial complications resulting directly from the traumatic
      incident provide response patterns not typical of other patients. Further to this
      unpredictability, the trauma patient usually sustains multiple system injuries,
      making it difficult to design critical pathways in care plans. The complexity is
      heightened by the patient's unique perception of the traumatic event, which can
      be even more important than the physical injury in determining the ultimate
      impact of the trauma.

PMID- 10418361
TI  - Booking clients for addiction treatment: what works best?
AB  - Considerable effort has been devoted to trying to improve the nature and quality
      of drug abuse treatment over the past 30 years. While there is evidence that
      certain treatment modalities are more effective than others, there is little
      evidence that inpatient treatment is more effective than outpatient, that
      treatment of a long duration is more effective than that of a short duration or
      that intense treatment is more effective than less intense treatment. Attempts to
      match drug abusers to an optimal treatment type have largely been unsuccessful.

PMID- 10418362
TI  - Isolated and invisible gay, lesbian and bisexual youth.
AB  - A 14-year-old boy confides that he feels he does not fit in with the other boys
      and does not understand why. Would you consider that he might be questioning his
      sexual orientation? Would you be able to explore these feelings without bias? Do
      you have an understanding of the developmental process for gays and lesbians? Can
      you dispel myths and give accurate information?

PMID- 10418363
TI  - The Calgary Conjoint Nursing Program. Part II: Successful political action.
AB  - When three calgary institutions decided to develop a collaborative nursing
      program to prepare for the transition to baccalaureate nursing education by the
      year 2000, the planners found that they had to overcome a broad range of
      political and institutional hurdles. Faculty from Mount Royal College, Foothills
      Hospital School of Nursing and the University of Calgary spent six years
      developing the curriculum and planning for the implementation of the Calgary
      Conjoint Nursing Program (CCNP). (See The Calgary Conjoint Nursing Program, Part
      I: Spirit of Collaboration, in the March 1999 issue of this journal.)

PMID- 10418364
TI  - [New immigrant women and health].
AB  - The Canadian health care system serves an increasingly ethnically diverse
      clientele, especially in major urban centres. Sustained inflows of immigrants
      demand that social and health care services partially revise their mission to
      help these newcomers maintain their health following arrival in Canada, since
      their health generally tends to deteriorate over time. This poses a special
      challenge for women who have immigrated recently, because their health is often
      jeopardized by vulnerability linked to their socioeconomic status. Responding in
      a culturally appropriate way to each person's needs entails a choice of health
      promotion and disease prevention strategies. While this choice is based on
      specific definitions of the concepts, it also must reflect immigrant women's
      perceptions of what constitutes promotion, prevention and health. The purpose of
      this study was to develop a profile of their perceptions and use of preventive
      social and health care services. Our respondents reported that health is the
      absence of psychological and physical problems and that health promotion is
      associated primarily with a good diet, physical exercise, control of stress, and
      continuing to lead an active life (work, education). They believe that disease
      prevention lies primarily in overcoming financial problems and gaining access to
      a healthy diet and medical care. These views are similar to North American
      concepts. Research could confirm the similarities and differences between
      immigrant women and host populations. Nursing interventions would support
      culturally appropriate comprehensive action that addresses the individual,
      family, community and social aspects.

PMID- 10418365
TI  - The cyber-savvy advantage.
AB  - Your patient asks for information on pain-control studies. Your sister wants
      advice on combining acupuncture with traditional medicine. And your friend
      queries you about mesothelioma--his father's newly diagnosed illness. How can you
      provide up-to-date information on these and other health-related questions
      without turning to outdated textbooks and back issues of your favorite journals?

PMID- 10418367
TI  - Performing CPR and holding hands. Interview by Barbara Sibbald.
AB  - A while back, ER nurse Janet MacDonald was caring for an elderly woman who had
      suffered a small stroke. The woman was scheduled for a CT scan the next morning,
      but when MacDonald told her she'd have to go home she became very upset and said
      she was scared. Very scared. "It was like a slap in the face," says MacDonald,
      who realized she wasn't caring for the patient's needs, just the hospital's. The
      nurse in charge agreed the woman needed to stay and they found a place for her.

PMID- 10418366
TI  - My clinical practicum in Belize.

PMID- 10418368
TI  - The future of nursing.
AB  - The White paper, "The New NHS, Modern-Dependable" has marked a turning point for
      the National Health Service and Nursing, replacing the internal market with
      integrated care, and sets out a vision of health service that meets the full
      range of patients' needs in all care settings. Assuring quality is an
      underpinning theme of the White paper, with nursing having a vital role in
      driving this agenda forward. Quality encompasses the environment of care, the
      professionalism, skill and compassion of staff, the effectiveness of treatments
      and respect and dignity of patients. This is an exciting time for nursing with
      many challenges, as the recognition and value for nursing grows. The profession
      has the ability to rise to these challenges and make a real difference to
      people's health and well being.

PMID- 10418369
TI  - Future developments in renal care, the patient's perspective.
AB  - This paper explores from a patients perspective, how collaboration between staff
      and patients enhances the quality of care for patients with ends stage renal
      disease. The role of patient associations and professional associations are
      discussed.

PMID- 10418370
TI  - Informing the UK's South Asian communities on organ donation and transplantation.
AB  - There is a growing demand for human organs for transplantation, particularly of
      the kidney among the UK's South Asian population which, due to problems with
      histocompatibility can only be met with a significant increase in the number of
      Asian donors. Specific attempts have only recently been made to attract donors
      from South Asian communities using 'ethnically-targeted mass media'. A recent
      pilot study sought to evaluate the effectiveness of these initiatives in
      providing information with regards to organ donation for the South Asian
      population. The findings show that detailed information related to
      transplantation activity had been learned only through the experience of people
      undergoing transplants within the community and has been transmitted through
      various informal networks rather than through the resources provided by the
      Department of Health. This paper provides an overview of who the South Asians are
      and how these community networks were established.

PMID- 10418372
TI  - Management of anaemia in renal failure.
AB  - The management of renal anaemia has been transformed over the last decade by the
      advent of recombinant human erythropoietin (EPO) therapy. In relation to the use
      of erythropoietin, three major topics have emerged which have stimulated the most
      discussion and controversy. This article explores these three areas: the use of
      EPO in pre-dialysis patients, iron management in patients receiving EPO therapy,
      and target haemoglobin.

PMID- 10418371
TI  - The evolution of kidney transplantation in Spain. Role of the nurse.
AB  - This paper provides an overview of the role of the nurse in kidney
      transplantation with a particular emphasis on Spanish units. The evolution of the
      care of kidney transplant patients has tended towards a holistic approach, with
      the nurse being responsible for the integral care of the patient during the
      entire hospitalisation period. Nursing care covers the full range of functions,
      including education, outpatient clinic, continuous care, evaluation of care, and
      preparation for discharge. At the present time, the Spanish patient with serious
      kidney disease has a better chances of receiving an organ than in any of the
      countries in our geographical setting, thanks to the excellent health care
      professionals working in the setting of the Spanish health care system, and to
      the support of the entire Spanish society in favour of donation and
      transplantation. Clearly, personal and collective attitudes are not improvised,
      and the infrastructure required for this type of treatment is not a question of
      chance.

PMID- 10418373
TI  - Clinical outcomes for patients with diabetic nephropathy.
AB  - Diabetic nephropathy is the chief cause of morbidity and premature mortality in
      patients with diabetes with clinically significant renal disease being present in
      30-50% of type 1 and 10% of type 2 diabetics after 10-20 years of the disease.
      End stage renal failure is commonly associated with other complications of
      diabetes, such as severe retinopathy and vasculopathy of the coronary, cerebral
      and peripheral arteries. Diabetic patients represent 35% in USA and about 20% in
      Europe of all new end stage renal disease patients. This paper reviews the
      current practices to prevent complications and discusses clinical issues and
      outcomes associated with the different renal replacement therapies.

PMID- 10418374
TI  - Why do renal nurses focus on issues of compliance when working in the
      rehabilitative HD setting?
AB  - Renal nurses are aware that a process of rehabilitation and adaptation must be
      facilitated for ESRF patients to acquire adjustments in health behaviours and
      lifestyle. These philosophies advocate the use of holistic nursing approaches,
      however, it has been observed that renal nurses frequently adopt a compliance
      approach for their client group, an approach which impedes rather than enhances
      the rehabilitative process. The author researched the question of why renal
      nurses focus on issues of compliance when working in the rehabilitative HD
      setting using modified grounded theory principles. Tentative findings suggest
      renal nurses are cogniscent of rehabilitation/adaptive philosophies, but are
      constrained in their use by stressful working environments and limited resources.
      Recommendations to enhance practice and suggestions for further study are made.

PMID- 10418375
TI  - Outcome measurements in dialysis: the consensus and the conflicts.
AB  - There are several published sources of guidelines and studies measuring dialysis
      parameters. The practical aspects of measuring and improving these parameters in
      a typical clinical setting are discussed in this paper and the paper concludes
      with recommendations for actions that can be taken at the current time.

PMID- 10418376
TI  - Pre-dialysis serum albumin is a poor indicator of nutritional status in stable
      chronic haemodialysis patients.
AB  - The correlation between pre-dialysis serum albumin and mortality has been linked
      with malnutrition. We measured pre and post-dialysis albumin in 86 stable
      haemodialysis patients and compared them with anthropometric measurements and
      body mass index (BMI). On the basis of pre-dialysis albumin 13% of patients would
      be classified as high risk, whilst on the basis of post-dialysis albumin only 12%
      would be classified as high risk. Change in albumin could be predicted by fluid
      removal during haemodialysis. Pre-dialysis albumin correlated weakly with mid
      upper arm circumference (MUAC). Post dialysis albumin correlated with MUAC and
      triceps skin fold thickness (TSF). There was a weak negative correlation between
      age and post-dialysis albumin. TSF strongly correlated with MUAC and BMI. Pre
      dialysis albumin appears to be a poor predictor of nutritional status and does
      not correlate well with other nutritional parameters. The excess risk of death
      associated with a low pre-dialysis albumin may be related to fluid overload
      rather than malnutrition.

PMID- 10418378
TI  - Rediscovering home haemodialysis. Returning choice to patients.
AB  - Increased demand for haemodialysis and the stresses on existing units have led to
      a crisis in renal replacement therapy around the world. Allied to this is a
      realisation that dialysis needs to be viewed increasingly as a long-term option
      for patients. New approaches to treating people with dialysis need to be
      developed to reflect this. By adopting a modern approach, home haemodialysis can
      be a viable, indeed an optimal, treatment for many patients.

PMID- 10418377
TI  - Blood recirculation in malfunctioning catheters for haemodialysis.
AB  - Venous catheters are increasingly used for chronic haemodialysis, with dual lumen
      catheters being the most commonly used as blood recirculation (REC%) is
      relatively low. The aim of this study was therefore to evaluate blood
      recirculation in dual lumen catheters, both well-functioning and malfunctioning,
      with reversed lumens. In our study, blood recirculation in well-functioning
      catheters with standard lumens is similar to that found in previous studies.
      However, when lumens are reversed, blood recirculation increases significantly
      (6.7 +/- 4 vs 19 +/- 11%, p < 0.001). REC% in malfunctioning catheters (10.8 +/-
      2%) was higher than normal function (p < 0.05) but lower than reversed flow in
      normal catheters (p < 0.01). Therefore, inadvertent reversal of lumens in a well
      functioning catheter increases REC% in a significant manner, thus worsening
      haemodialysis efficiency. We conclude that, in inflow failure catheters, lumens
      can be reversed because REC% is acceptable. However, inadvertent reversal of
      lumens in a well-functioning catheter increases REC% to a level which may
      compromise the adequacy of haemodialysis.

PMID- 10418379
TI  - Ultrafiltration controller failing: a case report. Problem investigation and
      solution.

PMID- 10418380
TI  - Health-related hardiness with different ethnic populations.
AB  - There has been successive strong support for the validity of the Health-Related
      Hardiness Scale (HRHS) in chronic illness and health-related research over time.
      The article summarizes health-related hardiness research completed with adults
      that has relevance for ethnic populations, describes progress with translation of
      the HRHS, and discusses recommendations for future work, such as international
      programs using hardiness interventions, continued progress on the translation of
      the HRHS, and improved retrieval and dissemination of results from HRHS research
      internationally. The HRHS has been used in more than 250 studies that focused on
      either health promotion or adaptation to health problems. The instrument has been
      translated into seven languages, with the most extensive work being reported with
      the Spanish version.

PMID- 10418381
TI  - Psychological hardiness: state of the science.
AB  - Over the past 20 years there has been increasing interest in the concept,
      psychological hardiness. Hardiness is defined as a constellation of attitudes,
      beliefs, and behavioral tendencies that consist of three components: commitment,
      control, and challenge. The article presents a review and assessment of more than
      50 journal publications on hardiness that have appeared since 1987. A
      presentation of the conceptualization of hardiness and the state of the science
      of hardiness is presented. Limitations in the current science of hardiness are
      delineated. These limitations include the identification of: factors related to
      conceptualization and instrumentation, the types of hardiness studies lacking in
      the current literature, and the types of subjects rarely used in hardiness
      research.

PMID- 10418382
TI  - The concept of hardiness: persistent problems, persistent appeal.
AB  - Despite increased critical debate, the concept of hardiness continues to be a
      popular focus of research, and little has changed in how hardiness is defined,
      measured, and applied. The article argues that the concept of hardiness remains
      inherently problematic. In particular, hardiness is plagued by definitional
      problems, problems of construct validity, measurement problems, and class,
      gender, and age bias. The persistent appeal of the hardiness construct lies
      partially in researchers' desire to discover why some people are able to
      withstand the health-damaging effects of stress. More important, the article
      argues that hardiness is appealing because it continues to be easier to focus on
      individual problems and solutions rather than look for and try to change the
      social factors that affect health status and well-being.

PMID- 10418383
TI  - A conceptual model of feminine hardiness.
AB  - Comprehensive literature reviews of hardiness consistently reveal empirical
      ambiguities and conceptual limitations. The article describes a grounded theory
      study focused on the conceptual nature of hardiness. In a group of 13 women with
      breast cancer, two major characteristics of hardiness emerged: a strong sense of
      purpose and the ability to endure. These characteristics are described in terms
      of their internal dimensions, manifestations, and outcomes. The findings are
      compared with the original conceptualization of hardiness, specifically its
      attributes of commitment, control, and challenge. The similarities and
      differences expand, extend, and modify the original definition of hardiness.

PMID- 10418385
TI  - Verification of the Health-Related Hardiness Scale: cross-cultural analysis.
AB  - The article describes data collected using Pollock's Health-Related Hardiness
      Scale (HRHS) in two cultural groups of nurses. The purposes of the study were to
      verify the workability of the HRHS cross-culturally and to compare the effects of
      health hardiness in nurses in the United States and Taiwan. A total of 163
      American and 615 Taiwanese nurses participated and answered a self-administered
      questionnaire by using Pollock's 34-item HRHS. Psychometric analyses identified
      two factors of hardiness that are different from Pollock's factors. Pollock's
      findings were verified, and the HRHS is valid for measuring hardiness constructs
      as exemplified by the strong factor loading obtained from this study, which
      ranged from 0.43 to 0.68 for American nurses and 0.47 to 0.68 for Taiwanese
      nurses.

PMID- 10418384
TI  - The Health-Related Hardiness Scale: Spanish language equivalence and translation.
AB  - The article describes the development and initial evaluation of a Spanish
      language version of the Health-Related Hardiness Scale (HRHS) and reports on the
      Spanish language HRHS (SHRHS). The second study back-translated the SHRHS, which
      demonstrated a strong correlation with the first translation obtained by Boytell,
      Velasco-Whetsell, and Coffin, further supporting the accuracy and reliability of
      the SHRHS.

PMID- 10418386
TI  - Hardiness, social support, and health status: are there differences in older
      African-American and Anglo-American adults?
AB  - The article reports a study examining the relationships among hardiness, social
      support, and health status in older African-American and Anglo-American adults (n
      = 110). The theoretical framework of the study was based on the
      interrelationships of the personal resources of hardiness, social support, health
      status, and sociodemographic factors, including race. Pearson's correlation
      coefficients and t tests were performed to examine the relationships among the
      variables. Hardiness correlated significantly with greater social support, better
      perceived health status, increasing age, and lower income. Social support
      correlated significantly with better perceived health status, increasing age, and
      higher income. Perceived health status correlated significantly with lower age.
      Older Anglo-American adults had significantly higher scores on hardiness, whereas
      older African-American adults had significantly higher scores on social support.
      Implications for holistic nursing practice are discussed.

PMID- 10418387
TI  - Determinants of health-related hardiness among urban older African-American women
      with chronic illnesses.
AB  - A systematic probability sample of 100 community-living older African-American
      women with chronic illnesses was evaluated during clinic visits to an urban
      safety-net hospital to explore health and demographic factors predictive of
      health-related hardiness (HRH). Questionnaires on HRH, function, self-assessed
      health, morbidity, health behavior, and selected demographics were used for
      collection of data. Multiple linear regression analyses ascertained that years of
      education and function explained 20% of the variance in HRH. Findings raise
      issues regarding validity of HRH prediction models and the cultural
      appropriateness of current methods of assessing HRH in older African-American
      women.

PMID- 10418388
TI  - Relationship of hardiness and sense of coherence to post-liver transplant return
      to work.
AB  - The article reports a retrospective survey designed to determine the relationship
      of hardiness and sense of coherence to post-liver transplant return to work
      (RTW). Instruments used included Pollock's Health-Related Hardiness Scale and
      Antonovsky's Sense of Coherence Questionnaire. Study results were based on 230
      adult liver transplant recipients responding to a mailed questionnaire. After
      transplantation, 63% of the participants were working. Participants with higher
      levels of hardiness and higher sense of coherence scores demonstrated higher RTW
      rates. Using logistic regression, a model comprising hardiness and sense of
      coherence correctly classified 90% of the participants who returned to work.

PMID- 10418390
TI  - Solidifying home care through professional development.

PMID- 10418389
TI  - Cancer: a personal perspective.

PMID- 10418391
TI  - Home health services affected by a variety of federal initiatives.

PMID- 10418392
TI  - Balancing an ethics of conviction and an ethics of responsibility.
AB  - Ethics is one means that societies use to deal with certain kinds of problems,
      specifically those that can cause harm. One approach to these problems is the
      creation of laws designed to prevent or limit harm in specified situations. Thus
      ethics and politics, although not equivalent, are closely related. Because both
      arenas are concerned with a multiplicity of relationships defining complex
      situations, it is not surprising that, in our desire to address a social harm,
      some relationships are emphasized but others are de-emphasized or overlooked
      completely. When this oversight occurs, harm may be the likely result for some
      group or groups even if others benefit. Nurturing our ability to see and
      appreciate the full range of situations and relationships can contribute to
      better ethical responses and better laws.

PMID- 10418393
TI  - Dual disorders: clients suffering from psychiatric disorders and alcohol or drug
      abuse disorders.
AB  - If home care providers are to be diligent in assessing the total well-being of
      their clients, they need to assess for dual disorders (DDs), a co-occurrence
      (comorbidity) of psychiatric disorders and alcohol or other drug disorders
      (AODDs). Table 1 lists acronyms for different types of DDs. Home care clients who
      suffer from depression and other mental health problems are not uncommon, nor are
      clients who suffer from AODDs. What health professionals often do not realize,
      however, is that clients may be suffering from both. Failure to effectively treat
      clients' DDs will negatively affect their recovery. Their DD may be causing or
      contributing to their physical problems and affecting their judgment, motivation,
      and insight into their problems.

PMID- 10418394
TI  - Personal perception of chronic illness.
AB  - Nurses caring for patients in the home must see them as a complex collection of
      many parts that require a holistic approach. With the plethora of therapies
      blending the relationship between mind and body, patients are seeking to be
      treated as a whole person rather than a physical illness. A diagnosis of cancer
      or other serious illness affects the physical, psychologic, spiritual, and
      economic aspects of the person's life, and patients with these diagnoses know the
      illness and its treatment will decrease many of their normal activities and limit
      their effectiveness. Because of this disruption, chronic illness causes stress
      and anxiety in both patient and the family. Therefore nurses must be ready to
      assess, intervene, and monitor the ongoing progress of both patient and family.

PMID- 10418395
TI  - Technology + teamwork = success.
AB  - "Pain is an incredibly complicated pathophysiologic process, as well as a highly
      individualized experience," says Dr. K.A. Erdmann, a pain management specialist
      with American Pain Management (APM), a high technology medical consulting firm.
      "In fact, it is by far the most subjective, difficult, and expensive symptom to
      treat. The pain impulse can be generated anywhere along the peripheral nerve, up
      the tracts in the spinal cord, and even into the brain itself."

PMID- 10418396
TI  - The risk of occupational exposure and infection with infectious diseases: Part 3.
AB  - This article is the third of a series devoted to the epidemiology of selected
      infectious diseases known to be transmitted in health care settings. Part 1 (Home
      Care Provider 1998;3:251-2) consisted of a brief review of general preventive
      measures associated with standard and transmission-based precautions. Part 2
      (Home Care Provider 1998;3:304-5) included a discussion of specific viral
      illnesses associated with blood-borne transmission. This article will address
      cytomegalovirus (CMV) and herpes infections along with influenza and meningitis.

PMID- 10418397
TI  - Home chemotherapy: basic concepts.
AB  - The diagnosis of cancer imposes a devastating sense of loss of control over a
      patient's life. Home chemotherapy allows patients to become active participants
      in administering their own therapy, providing an opportunity to regain some of
      that control. The purpose of this article is to provide an overview of some basic
      concepts of chemotherapy that relate to home therapy regardless of the specific
      therapeutic agent prescribed.

PMID- 10418398
TI  - The value of strength training for older adults.
AB  - Health in older adults can best be measured in terms of functional status.
      Skeletal muscle strength has been reported to be a determinant of functional
      status in older individuals. Two major contributors to the decline in muscle
      function as a person ages are disuse and physical inactivity. Declining muscle
      function through a loss of muscular strength may decrease functional independence
      and mobility and increase the risk for falls and injuries, physical frailty, and
      disability. Older individuals lacking an appropriate amount of muscular strength
      may not be able to perform various activities of daily living, which are
      important indicators of independence.

PMID- 10418399
TI  - Making the transition from hospital to home: caring for the newly diagnosed child
      with cancer.
AB  - Current trends in the management of health care show increasing pressure for
      earlier discharge of children, and their families may or may not be ready to
      continue the child's care at home. This article provides information that helps
      the home care provider bridge the transition from hospital care to home care.
      Care frequently is coordinated by a hospital-based clinical nurse specialist who
      provides psychosocial support, reinforces teaching, minimizes risks for
      complications, and performs home infusion therapy, such as antibiotics,
      chemotherapy, analgesics, total parenteral nutrition, and biologic therapy.

PMID- 10418400
TI  - A place to care: the homebound elderly.
AB  - As America's elderly population continues to age, accessing adequate primary
      health care becomes more difficult. A survey of 22 homebound elderly people
      examined their acceptance of the expanded role functions of nurse practitioners
      to meet primary care needs in their homes. Chi-square analyses correlated
      participants' answers to demographic information. Only the variables of income
      and religion indicated statistical significance (P < .05) when correlated with
      expanded functions. Protestants, elders with no religious affiliation, and those
      with incomes below $20,000 indicated they would allow nurse practitioners to
      perform more expanded role functions than Catholics and those with higher incomes
      would. Generalizability is limited because of the small sample size, indicating a
      need for additional research with larger samples and more diverse populations.

PMID- 10418401
TI  - Supporting the home care client receiving chemotherapy.
AB  - Chemotherapy has been one of the four major cancer treatment modes for several
      decades; the other three are surgery, radiation, and immunotherapy. This article
      presents breast cancer as a model for understanding chemotherapy because, given
      its prevalence in American populations, the home care provider is highly likely
      to encounter clients with this diagnosis. Detailed explanations of the categories
      and pharmacodynamics of cytotoxic drugs are beyond the scope of this article. As
      always, caregivers should study specific drugs when individual clients are taking
      them. However, because most cancer patients receive a combination of
      chemotherapeutic agents and many agents are indicated for a variety of primary
      tumors, similarities exist in the toxicities clients experience and the
      appropriate management strategies.

PMID- 10418402
TI  - How the Joint Commission evaluates care provided to cancer patients.

PMID- 10418403
TI  - Do Medicare HMOs and Medicare FFS differ in their use of the Medicare hospice
      benefit?
AB  - This study compares use of the hospice benefit in Medicare fee-for-service (FFS)
      and Medicare risk-health maintenance organization (HMO) options in South Florida
      in 1992. A higher percentage of deaths occurred in hospice in the HMO option than
      in the FFS option. Compared to individuals in the FFS option, HMO-enrolled
      hospice users had longer lengths of hospice stay, lower 7-day mortality and
      higher 180-day (6 month) survival. These differences are consistent with the
      physician's financial incentives associated with the two programs.

PMID- 10418404
TI  - Hospice care for injection drug using AIDS patients.
AB  - Injection drug use now accounts for the majority of new AIDS cases. Treatment for
      these patients is both more complex and more costly than for other AIDS patients
      as the factors associated with drug use are obstacles to treatment. Using data
      from a national survey of hospices, the findings from this study indicated that
      resources, hospice size, years in operation, and the Medicaid waiver were
      associated with hospice involvement with these patients. Staff training and
      supports are important factors in adequately dealing with the issues that these
      patients present.

PMID- 10418405
TI  - Balancing the focus: art and music therapy for pain control and symptom
      management in hospice care.
AB  - Pain and symptom management are a major part of hospice care. Literature and
      direct experience suggest that pain can be resistant if psychological, emotional,
      or spiritual issues are not addressed. This article explains how art and music
      therapies can work in conjunction with traditional medical treatment of pain
      control in the hospice setting. The process of pain modulation through the use of
      art and music interventions is diagrammed and described. Brief clinical examples
      demonstrate the use of art and music therapies for pain reduction with a variety
      of hospice patients. Information regarding appropriate education and training
      necessary for art and music therapists to practice in their field is presented.

PMID- 10418406
TI  - Literary resources for bereavement.
AB  - The bereavement process can be aided by multiple resources. Hospice counselors
      and related therapeutic professionals turn most easily to their own disciplines
      and training. In this article, complementary or ancillary resources from
      literature have been offered. If healing includes the "storying" and "restorying"
      of lives, then literature can enrich and facilitate the mourning process.
      Suggestions of resources and some of their connections to hospice care have been
      offered.

PMID- 10418407
TI  - Analysis of Texas & New Mexico Hospice Organization's new Code of Ethics.
AB  - Unique among professional codes of ethics is the Texas & New Mexico Hospice
      Organization's Code of Ethics. Where other codes concentrate only on principles
      based ethics, this new code identifies five models of bioethics currently used in
      resolving ethical dilemmas. This report's primary purpose analyzes the code's
      four precepts in the context of (1) principles-based ethics, (2) casuistic-based
      ethics, (3) covenant-based ethics, (4) evidence-based ethics and narrative-based
      ethics. The second purpose is to present the practicality of these often esoteric
      concepts in the day-to-day work of palliative care providers. Indications are
      that this code of ethics, because of its broad scope, is more useful than other
      principles-based-only codes.

PMID- 10418408
TI  - Professional development.

PMID- 10418409
TI  - Establishing and maintaining competency.
AB  - The recruitment and hiring processes are crucial to quality assurance and cost
      containment in home healthcare. Competency-based orientation programs designed to
      provide outcome-focused orientation for the intravenous nurse who is new to
      homecare will benefit both the new employee and the homecare agency. Development
      of such a program is discussed, and consideration is given to program design,
      program evaluation, and ongoing employee education. Sample employee and program
      assessment tools are provided.

PMID- 10418410
TI  - Marketing your expertise.
AB  - Marketing an existing or new venture is a vital part of business. For the nurse
      entrepreneur, marketing involves applying previously learned skills to new
      situations. The methods used to market a service may mean the difference between
      success and failure. Unfortunately many entrepreneurs think that because they
      have a great idea, clients will beat a path to their door. Marketing requires
      planning, creativity, time, and money. It is an ongoing process that must be
      evaluated regularly. When marketing achieves results, clients commit to using the
      entrepreneur's services and profits are realized. Basic marketing concepts are
      considered, and strategies for developing a workable marketing plan are
      presented.

PMID- 10418411
TI  - Creating a professional presentation. A template of success.
AB  - Successful individuals speak and write effectively. Effective speakers know their
      subject, convey a message, and understand their audience. Guidelines to enhance
      speaking skills, identify adult learner/learning style strategies, and use
      audiovisual aids more successfully in presentations are presented. The
      professional career benefits of presentations are discussed.

PMID- 10418412
TI  - Developing an interactive intravenous education and training program.
AB  - Intravenous therapy knowledge, skills, and attitudes of nurses within a
      healthcare organization vary greatly. Primary nursing education programs,
      responsibility for i.v. therapy in previous jobs, patient populations, types of
      therapies provided, and clinical setting are just a few of the factors
      contributing to these variations. However, administrators usually expect all
      nurses to function in all areas of clinical practice. The gap between actual and
      expected knowledge and skills can be extremely wide, especially in i.v. therapy.
      Interactive multimedia i.v. education products provide a way to narrow that gap
      in a quick and cost-effective manner when appropriate planning processes are used
      to incorporate them into an educational program.

PMID- 10418413
TI  - The nurse as rhetorician. Writing the clinically based article for professional
      publication.
AB  - Effective communication skills are a critical component of quality nursing care.
      Nurses are modern-day rhetoricians who must rely on their powers of observation,
      interpretation, and persuasion as they provide care for patients and interact
      with family members and medical professionals. Clinicians have an obligation to
      use their rhetorical skills to communicate their knowledge to the wider medical
      community by publishing in nursing journals. Advice is provided to those
      intravenous nurse specialists who are interested in writing a clinically based
      article for a professional publication, such as the Journal of Intravenous
      Nursing.

PMID- 10418414
TI  - On the consequences of loss.

PMID- 10418415
TI  - Review of the clinical pharmacology and use of the benzodiazepines.
AB  - Benzodiazepines are commonly used in the perioperative period for the anxiolytic
      and amnestic effects they provide. The purpose of this article is to provide an
      understanding of the clinical pharmacology and mechanism of action for these
      agents, as well as the knowledge needed for the safe administration of
      benzodiazepines. The benzodiazepines most commonly used in the perioperative
      period are presented along with important facts and information regarding their
      use. The effected organ systems and drug interactions are also presented.
      Discussion of the benzodiazepine reversal agent, flumazenil, is included,
      followed by a discussion of nursing interventions.

PMID- 10418416
TI  - Is the postanesthesia care unit becoming an intensive care unit?
AB  - The increasing number of critically ill patients requiring prolonged lengths of
      stay in the surgical intensive care unit has led hospitals to examine ways of
      using the PACU as a short-term area for critically ill patients. This article
      identifies common problems associated with this situation, and offers
      suggestions/guidelines to facilitate a smooth transition and ensure competent
      care of these patients. This article will not focus on financial issues related
      to patient charges. The criteria established in this article are based on
      personal experience.

PMID- 10418417
TI  - Quantitative research versus quality assurance, quality improvement, total
      quality management, and continuous quality improvement.
AB  - The purpose of this report is to provide a review of the scientific method used
      in the quantitative research studies for consumers, evaluators, and applied nurse
      researchers. The fundamental characteristics of the problem-solving/ performance
      improvement processes of quality assurance, quality improvement, total quality
      management, and continuous quality improvement are described. Research is
      compared with these processes, and is followed by a discussion about the
      publication of quantitative research findings.

PMID- 10418418
TI  - Anesthetic implications of illicit drug use.
AB  - Individuals who abuse illicit drugs have an increased incidence of traumatic
      injury, medical illness, and drug overdose. Subsequently, many of these drug
      abusers will require perianesthesia care. The health care professionals
      responsible for their care must have an understanding of the prevalence, the
      pharmacology, and medical complications of illicit drug use, including the
      potential interactions with anesthetic agents.

PMID- 10418419
TI  - Hunting for sacred cows.
AB  - "Sacred cows" are behavioral patterns that we continue to use even though they
      may no longer be effective. Their continued use tramples creativity, reduces
      innovative thought, limits the ability to respond quickly to change, and
      ultimately becomes costly to individuals and organizations. In less turbulent
      times, sacred cows were a source of irritation that managers worked around. There
      is no longer time available for managers to "work around" sacred cows. They must
      be rounded up and dealt with. It is only by confronting their own sacred cows
      that nurse managers will find the energy to maintain a caring environment for
      patients' families and staff.

PMID- 10418420
TI  - Reducing the pain of venipuncture.
AB  - Patient satisfaction with nursing care is the strongest predictor of overall
      satisfaction. Reducing discomfort of routine procedures, such as venipuncture for
      an intravenous insertion, can contribute to perceived satisfaction. This article
      reviews three common pharmacological interventions that can be used by
      perianesthesia nurses to reduce the pain of venipuncture.

PMID- 10418421
TI  - Notes from the American Society of Anesthesiologists annual meeting.

PMID- 10418422
TI  - The power of suggestion.

PMID- 10418423
TI  - Novice or expert in school nursing: how do we know?

PMID- 10418424
TI  - Courage revisited.

PMID- 10418425
TI  - Cardiovascular risk prevalence among diverse school-age children: implications
      for schools.
AB  - Cardiovascular risk reduction programs in school-aged populations must be based
      on accurate assessments of risk. This cross-sectional, descriptive study presents
      the prevalence of cardiovascular risk with respect to blood pressure, obesity,
      and fitness in 4th, 5th, and 6th grade children. School nursing research
      assistants conducted 358 interviews and clinical risk assessments with children
      and their parents. A total of 180 children (53%) were found to have one or more
      cardiovascular risk factors. Our findings of a high level of risk illustrate the
      need for school nurses to take a leadership role to reduce risk and foster "heart
      healthy" school environments.

PMID- 10418426
TI  - National survey to identify the nursing interventions used in school settings.
AB  - A national survey of members of the National Association of School Nurses was
      conducted to identify interventions from the Nursing Interventions Classification
      (NIC) that are used by school nurses. Usable responses were returned from 522
      school nurses. The findings were that 163 interventions were used, on the
      average, from every day to once a year, and all but three interventions were used
      by one or more respondents. Certain interventions were significantly associated
      with special education or grade level of children served by nurses. It is
      concluded that the NIC is a useful tool to standardize documentation for school
      nursing.

PMID- 10418427
TI  - Hearing conservation: an industry-school partnership.
AB  - An informal observation of hearing test results of employees in hearing
      conservation programs noted hearing losses among younger workers. As part of a
      community service project for the Arizona Valle del Sol Association of
      Occupational Health Nurses, a pilot hearing conservation program was implemented
      in two junior high schools in Mesa, Arizona. Occupational health nurses conducted
      sound level measurements in band rooms and industrial technology (shop) classes.
      Members of the professional association then taught classes of seventh, eighth,
      and ninth graders about the effects of noise on hearing; how to protect their
      hearing and use hearing protection; and how to keep their ears clean. Pre- and
      post-tests were distributed. Sound levels ranged from about 80 to 110 decibels in
      band rooms and 95-110 decibels in shop rooms. The post-tests revealed increases
      in knowledge regarding the effects of noise on hearing, ways to determine if
      noise is damaging to hearing, and safe measures to clean ears. Students also
      indicated a willingness to wear hearing protection when exposed to noise. The
      success of this pilot program supports the expansion of a partnership between
      industry and schools with the goal of hearing conservation.

PMID- 10418428
TI  - Crisis preparedness.
AB  - There were many lessons learned from the incident and the subsequent critique.
      Picture a similar incident in your school building. Are you prepared? Does your
      plan have the essential elements to allow you to deal effectively with multiple
      injuries? While it is true you cannot plan for every contingency, you can develop
      a triage plan and evaluate your environment as to how it would serve in a similar
      situation. Make preparations now while you have the time, instead of during an
      emergency.

PMID- 10418429
TI  - A student emergency: helping school staff cope.
AB  - A serious illness, injury, or other medical emergency in a student while in
      school can be upsetting to school staff not accustomed to such situations. A
      healthcare emergency in a special health needs child in one school district
      prompted a nurse and a building principal to develop a protocol which would
      enable school staff to effectively assist the nurse in the event of a student
      emergency. The plan involved training school personnel to assist the nurse and
      the administrator in tasks such as answering and monitoring telephones, serving
      as a runner, controlling unnecessary traffic into the nurse's office, and passing
      clean supplies to the nurse.

PMID- 10418430
TI  - Criteria for software evaluation: legal issues.
AB  - The maintenance of electronic health records in the school setting requires
      knowledge of the legal standards of both electronic records and health records.
      School nurses are responsible for the selection of software and hardware that
      meet federal and state legal standards. Software capabilities that enhance the
      legal value of the student health record are: overwrite protection, multi-user
      passwords, multi-level access, auditability, rejection, automatic back-up, and
      the ability to enter and process dates for the year 2000.

PMID- 10418431
TI  - School nursing role and competence.
AB  - How will school nurses attain, maintain and advance their professional competence
      in an evolving school nursing and school health environment? This article is
      designed to assist school nurses to understand competence and nursing
      competencies and related issues affecting their role. The Southern Regional
      Education Board/Council on Collegiate Education for Nursing (SREB/CCEN) is
      exploring a linkage of undergraduate nursing curriculum to school nursing
      competencies. In addition, a method now used to evaluate school nurse competence
      in one school district is included.

PMID- 10418432
TI  - Implications for nursing of the Human Genome Project.
AB  - Information obtained from the Human Genome Project, initiated in 1990 and
      targeted for completion in 2005, will influence both health care and nursing
      practice. It will substantially revise our understanding of disease
      susceptibility and causation. Additional genetic tests will be developed and gene
      therapies explored. The project has implications for both nursing research and
      nursing practice. This article reviews the establishment of the Human Genome
      Project, reports on current progress of the project, and identifies some
      implications of the project for health care generally and nursing specifically.

PMID- 10418433
TI  - Nipple feeding preterm infants: an individualized, developmentally supportive
      approach.
AB  - Many NICU infants present with complex issues that affect the transition to full
      nipple feeding. At a time when length of stay is critical, this transition can be
      facilitated by an individualized, developmentally supportive approach. The
      approach described in this article involves (1) observing the infant for
      behavioral cues of stability or stress during nippling, as reflected in change in
      color, state of alertness, breathing, and swallowing; (2) individualizing
      intervention to help the infant regain and maintain coordination; and (3)
      facilitating parents' competence and confidence in feeding their infant.
      Contingent interventions are used to promote physiologic homeostasis and self
      regulation.

PMID- 10418435
TI  - Complete congenital heart block: a review and case study.
AB  - Complete congenital heart block (CCHB) is a rare disease of the newborn that
      carries significant morbidity and mortality. It generally occurs as a result of
      the presence of maternal autoantibodies that are transferred to the fetus and
      affect the fetal heart, or it may be associated with a congenital structural
      abnormality of the heart. Infants with CCHB are at risk for diminished cardiac
      output and the subsequent development of congestive heart failure. Many infants
      require the placement of a cardiac pacemaker. It is essential that the nurse
      caring for these infants have a good understanding of the disease process and be
      familiar with the unique problems that these infants and their families may
      encounter.

PMID- 10418434
TI  - A survey of skin care practices for premature low birth weight infants.
AB  - PURPOSE: To provide baseline information about current skin care practices in
      premature low birth weight infants (< 1,000 gm birth weight) in typical NICUs
      within the U.S. DESIGN: Descriptive survey. SAMPLE: 104 hospitals with at least
      2,500 deliveries per year and at least 20 Level III NICU beds. MAIN OUTCOME
      VARIABLES: Environmental conditions, bathing practices and products, adhesive
      products used to secure IVs and endotracheal tubes, skin protectants used with
      diaper rash, treatment systems for fragile preterm skin, and treatment systems
      for denuded skin. RESULTS: Most units surveyed based their premature low birth
      weight skin care protocols on a combination of gestational age and birth weight
      criteria. One-quarter of the units had no skin care protocols at all. Among the
      units, there was considerable practice variation with respect to common nursing
      procedures such as bathing, adhesive application, and wound care.

PMID- 10418436
TI  - Spironolactone.
AB  - The greater survival rate of premature neonates has increased the use of various
      drugs, including diuretics, which may be used for a variety of clinical
      indications in neonates. Rational use of specific diuretics, including
      recognition of the potential complications, depends on adequate knowledge and
      clinical assessment by NICU nurses.

PMID- 10418437
TI  - Open the door, turn on the light.

PMID- 10418438
TI  - The C*O*S*T of pediatric health care: a Third World perspective.

PMID- 10418439
TI  - Early identification of hearing-impaired infants.

PMID- 10418441
TI  - The future of nephrology nursing: 2000 and beyond.
AB  - These collective initiatives will lead to additional community wide efforts as we
      move into the next century, for it is through these efforts that we will continue
      to enhance the care our patients receive. APNs, continued professional
      development and recruitment of health care professionals into nephrology will be
      pivotal to meet the evolving needs of this patient population. Nursing will play
      an increasingly integral role in influencing the health care arena as all
      disciplines must work together in our changing environment.

PMID- 10418440
TI  - Hindmilk feedings.

PMID- 10418443
TI  - Programs in technician training. Listed by state.

PMID- 10418442
TI  - Seeing dialysis technicians as nephrology practitioners in the 21st century.

PMID- 10418444
TI  - Technician training in Canada: dialysis on-line.

PMID- 10418445
TI  - The role of nephrology nurses and technicians in the implementation of NKF-DOQI.

PMID- 10418446
TI  - Life Options Patient Opinion Study identifies keys to a long life for dialysis
      patients.
AB  - Results of a recent survey of 31 people on dialysis show that, initially, most of
      them had no real expectation of living a long life when they started treatment.
      How and why have their perceptions changed? What can providers and other patients
      learn from this Life Options Patient Opinion Study? For people on dialysis,
      rehabilitation means living long and living well, despite the challenges of
      kidney disease. The first step to successful renal rehabilitation is ensuring
      that the clinical prerequisites of anemia control, adequate dialysis, a well
      functioning vascular access, and proper nutrition are in place. In addition,
      research indicates that people on dialysis are more likely to experience positive
      outcomes and better quality of life when they are informed about their disease
      and its treatments; have solid support systems; exercise regularly and remain
      active and productive, and engage in self-care. It is the combination of good
      clinical care plus rehabilitation management that can help dialysis patients
      return to active and fulfilling lives. In 1993 the Life Options Rehabilitation
      Advisory Council (LORAC) developed a comprehensive approach to renal
      rehabilitation, based on the "5E's:" Encouragement, Education, Exercise,
      Employment, and Evaluation. Since then, the 5E's have served as the basis for
      numerous activities of the Life Options Rehabilitation Program. The Patient
      Opinion Study examined the patient experience as a way to begin identifying the
      keys to a long life on dialysis.

PMID- 10418447
TI  - Refocusing nephrology social work: NKF/CNSW launch program to target treatment
      outcomes.

PMID- 10418448
TI  - Managed care is not the "cure-all" for improving quality and controlling costs in
      ESRD.

PMID- 10418449
TI  - Scope of practice, the pre-ESRD patient, the principal physician, physician
      extenders. The specialist's role in the 21st century.

PMID- 10418450
TI  - A lesson in mediation.

PMID- 10418452
TI  - How will managed care impact nursing practice?

PMID- 10418451
TI  - Is there increasing evidence to change the management of renal bone disease?

PMID- 10418453
TI  - Looking for a good story....

PMID- 10418454
TI  - The road to oz.

PMID- 10418456
TI  - The financial report: how it can aid case managers.

PMID- 10418455
TI  - Patterns of health resource utilization, costs, and intensity of need for primary
      care clients receiving public health nursing case management.
AB  - Case management has been promoted as a managed care strategy that improves
      quality of care and contains costs. Health resource utilization patterns and
      associated costs were examined for a generalized primary care population
      receiving a public health nursing model of case management intervention during a
      30-week period. Subjects were referred by providers practicing in an academic
      health science center and included two client subsamples: chronically ill adults
      and younger families requiring health maintenance. Health resource utilization
      patterns and associated costs were examined in relation to intensity of need for
      care levels as determined by the Community Health Intensity Rating Scale. Results
      of this pilot study suggest that during public health nursing case management
      intervention, health resource utilization patterns changed from the
      preintervention period. Total health resource utilization costs were correlated
      with care needs related to health management behavior of the chronically ill.

PMID- 10418457
TI  - Outcomes for high-risk neonates in a managed care clinical system.
AB  - The purpose of this study was to compare a conventional system and a managed care
      clinical system for the care of high-risk neonates. The variables selected for
      the comparison of these two systems included neurobehavioral organization as
      evidenced by feeding behaviors, length of stay, severity of illness,
      readmissions, and cost of care. The sample consisted of 260 neonates (111 in the
      conventional system, 149 in the managed care system). In addition, two neonatal
      diagnosis-related groups were selected: 386 (extreme immaturity) and 387
      (prematurity with major problems). Findings showed that the managed care clinical
      system enhanced neurobehavioral organization specifically in the feeding
      behaviors by reducing the number of days needed to master oral feedings. Although
      there was an increase in complications, costs were controlled.

PMID- 10418458
TI  - Patient pathways as a tool for empowering patients.

PMID- 10418459
TI  - Case management information systems: how to put the pieces together now and
      beyond year 2000.
AB  - Healthcare organizations must establish the goals and objectives of their case
      management processes before functional and system requirements can be defined. A
      gap analysis will identify existing systems that can be used to support case
      management as well as areas in need of systems support. The gap analysis will
      also identify short-term tactical projects and long-term strategic initiatives
      supporting the automation of case management. The projects resulting from the gap
      analysis must be incorporated into the organization's business and information
      systems plan and budget to ensure appropriate funding and prioritization.

PMID- 10418460
TI  - Ethical dilemmas in artificial nutrition and hydration: initiation vs.
      withholding.

PMID- 10418461
TI  - Rehabilitation considerations for the client with chronic, nonmalignant pain.
AB  - Chronic, nonmalignant pain is a significant stressor for one in five Americans.
      It robs society of productive work days and families of the stability generated
      through positive personal interaction, a steady, adequate source of income, and
      confidence in the ability to handle the future. On a personal level, there is
      increased stress, which generates increased attention to physical symptoms, a
      loss of self-esteem, and feelings of helplessness, powerlessness, and
      hopelessness. These psychological issues can spiral out of control, wreaking
      havoc not only in the client, but also in family dynamics and roles. Case
      managers are in an ideal position to help blunt the toll of this pain by active
      listening and focusing on interventions that help the client take an active role
      in his or her care and maintain as much independence as possible.

PMID- 10418462
TI  - NHS Direct: so far, so good.

PMID- 10418463
TI  - Consultants--medical and nursing.

PMID- 10418464
TI  - Give and take.

PMID- 10418466
TI  - Wounded healers.

PMID- 10418465
TI  - Tackling racism.

PMID- 10418467
TI  - Five become one.

PMID- 10418468
TI  - Worth their weight in gold.

PMID- 10418469
TI  - Racism? Not here!

PMID- 10418470
TI  - Performance rating.

PMID- 10418471
TI  - Don't walk away.

PMID- 10418472
TI  - Clinical governance.

PMID- 10418473
TI  - Moving branches.
AB  - Clinical experience is identified in this comparative study as the most
      influential factor in student transfer between the Project 2000 specialist
      branches. Expecting prospective students to have exposure to branch-specific
      client groups prior to starting their pre-registration education and improving
      flexibility of transfer between the branches could help to reduce student wastage
      from the profession as a whole.

PMID- 10418474
TI  - Is the Scope of Practice endangered by lack of vision?
AB  - When The Scope of Professional Practice was published in 1992 it was hailed as
      one of the UKCC's most influential documents, with the potential to revolutionize
      nursing by extending the boundaries of practice. Is the Scope being implemented
      as originally visualised--or it is going to fail because of a lack of vision and
      imagination?

PMID- 10418476
TI  - Casting: Part One.
AB  - In this, the first of two continuing professional development articles on
      casting, Margaret Prior and Susan Miles consider important aspects of the nursing
      care of patients and their casts at the time of application and as their care
      continues, with emphasis on the health and safety aspects.

PMID- 10418475
TI  - The dangers of smoking.
AB  - In the USA, some individuals are taking the giants of the tobacco industry to
      court and winning. Last month, Patricia Henley, 53, a lifelong smoker suffering
      from inoperable lung cancer won $51 million dollars (31.7 m Pounds) from Philip
      Morris, makers of Marlboro. This article explores recent research into the damage
      caused by smoking--of which lung cancer is only one part.

PMID- 10418477
TI  - Preparing your CV.

PMID- 10418478
TI  - Opportunities in mental health education.

PMID- 10418479
TI  - Calculating drug dosage.

PMID- 10418480
TI  - Cardiopulmonary resuscitation.

PMID- 10418481
TI  - Seeing clearly through the fog.

PMID- 10418483
TI  - Violent treatment.

PMID- 10418482
TI  - Recruitment--the next step.

PMID- 10418485
TI  - Heart of nursing.

PMID- 10418484
TI  - NICE and easy. National Institute for Clinical Excellence.

PMID- 10418486
TI  - Legacy of war.

PMID- 10418487
TI  - Get glammed up.

PMID- 10418488
TI  - A grown-up approach.

PMID- 10418489
TI  - Millennium fireworks.

PMID- 10418490
TI  - It is time institutional racism, chaotic inner city mental health services and
      child cruelty were all brought out into the open.

PMID- 10418491
TI  - The ICN on women's health. International Council of Nurses.
AB  - This report, one of a series issued to mark the centennial year of the
      International Council of Nurses, highlights some of the critical steps on the way
      towards the recognition of women's health rights.

PMID- 10418492
TI  - A survey of therapeutic touch practitioners.
AB  - Therapeutic touch is the name of a specific nursing technique that was devised by
      Dr Dolores Krieger, an American nurse, in the early 1970s. This article provides
      a brief overview of therapeutic touch, and describes the responses received to a
      survey exploring the views and experiences of its practitioners in Britain.

PMID- 10418493
TI  - Von Willebrand disorder.
AB  - Von Willebrand disorder (VWD) is a disorder of blood coagulation. It has
      similarities with haemophilia but with some important differences which are
      described in this article. Ideally, treatment should be in specialist centres. By
      knowing the prevalence and clinical manifestations of VWD, nurses working outside
      these specialist areas may help many more people to be correctly diagnosed.

PMID- 10418494
TI  - Changing attitudes through persuasive communication.
AB  - Nurses are uniquely placed to provide effective health education with the aim of
      promoting attitude and behavioural change. This article explores the literature
      relating to attitude formation, attitude change and the nature of persuasive
      communication, and identifies specific strategies that will be useful to all
      nurses.

PMID- 10418495
TI  - Dysphagia in acute strokes.
AB  - Nurses are well placed to perform a key role in detecting and managing dysphagia
      in acute stroke patients. This article describes the anatomy and physiology
      involved in swallowing and provides a guide to assessing and feeding patients who
      have difficulty swallowing.

PMID- 10418496
TI  - Family-friendly policies.

PMID- 10418497
TI  - Nursing in primary care groups.

PMID- 10418498
TI  - Documenting discharges and transfers in long-term care.

PMID- 10418499
TI  - Managing discomfort with a walking epidural.

PMID- 10418500
TI  - Understanding signal-averaged ECGs.

PMID- 10418502
TI  - Myths & facts ... about head lice.

PMID- 10418501
TI  - After the stick.

PMID- 10418503
TI  - Psychiatric complications of corticosteroids.

PMID- 10418504
TI  - Using a closed-wound drainage system.

PMID- 10418505
TI  - Actionstat: compartment syndrome.

PMID- 10418506
TI  - Alzheimer's disease: your role in the caregiving equation.

PMID- 10418507
TI  - New drugs 99, Part III.

PMID- 10418508
TI  - Cardiovascular emergency!

PMID- 10418509
TI  - The miracle patient.

PMID- 10418510
TI  - Reflections on death and dying.

PMID- 10418511
TI  - Deaccessing an implanted port.

PMID- 10418512
TI  - What you should expect from your attorney....

PMID- 10418513
TI  - . . . and what your attorney expects from you.

PMID- 10418514
TI  - Defending against sexual assault charges.

PMID- 10418516
TI  - Travel nurse web sites.

PMID- 10418515
TI  - Should you hit the road?

PMID- 10418518
TI  - Catch your flight, not a cold.

PMID- 10418517
TI  - Learning English/Spanish phrases.

PMID- 10418519
TI  - Going to bat for you.

PMID- 10418521
TI  - Nurse the patient...

PMID- 10418520
TI  - A taste of Italy.

PMID- 10418522
TI  - Information on the net often needs checking.

PMID- 10418523
TI  - Ethics in action. An 85-year-old man with mild dementia often threatens the
      safety of other patients when he gets out of bed.

PMID- 10418524
TI  - The newest critical care drugs.

PMID- 10418525
TI  - Tailoring care for obese patients.

PMID- 10418526
TI  - Brain attack! A call to action.

PMID- 10418527
TI  - The great multistate licensure debate.

PMID- 10418528
TI  - Evolutions. Capnography.

PMID- 10418529
TI  - Revolutions. Continuous spirometry.

PMID- 10418530
TI  - An effective way to manage breakthrough pain.

PMID- 10418531
TI  - Medical mysteries.

PMID- 10418532
TI  - Carvedilol.

PMID- 10418533
TI  - Reminders for health maintenance visits.

PMID- 10418534
TI  - The "prescription-to-OTC switch" movement. Its effects on antifungal vaginitis
      preparations.
AB  - More than 600 over-the-counter (OTC) products have ingredients or dosages that
      were previously available by prescription only. The criteria for switching drugs
      include a low potential for misuse or abuse, safety and efficacy, and the ability
      for effective use by the average person. In addition, the conditions the drugs
      treat should be benign and self-limited. In 1990, the first topical imidazole for
      candidal vaginitis was approved by the Food and Drug Administration for over-the
      counter use. Suggested benefits of this switch were increased patient autonomy
      and reduced costs. Risks include potential for misdiagnoses, resulting in
      inappropriate use, unnecessary use, or delay in treatment, which could lead to
      increased cost and morbidity. Despite the wide use of these products, there is
      little evidence examining the outcome of the switch. Limited available data
      suggest that the switch of the antifungal preparations reduces costs with little
      objective evidence of harm resulting from the switch.

PMID- 10418536
TI  - Athletes' view of the preparticipation physical examination. Attitudes toward
      certain health screening questions.
AB  - OBJECTIVES: To determine the value student-athletes place on the preparticipation
      physical examination (PPE) in ensuring safe participation and to determine
      whether these athletes would accept a station-based PPE that emphasizes health
      related issues. DESIGN: Survey. SETTING: Athletic departments of 2 small
      southeastern colleges. PARTICIPANTS: Population of student-athletes enrolled in
      these colleges. MAIN OUTCOME MEASURES: Athletes' views on the necessity of the
      PPE to ensure safe participation in athletics, willingness to pay a fee for the
      currently free examination, appropriateness of the PPE as a setting for
      counseling by physicians regarding age-specific health screening issues, and PPE
      as the only routine health maintenance contact with a physician during the year.
      RESULTS: A majority of athletes (66%) believed they could safely participate in
      athletics and avoid severe injuries or death and minor injuries without
      undergoing a PPE. Most athletes believed the PPE prevents or helps to prevent
      both major (89%) and minor (76%) injuries. Male and female respondents would not
      be uncomfortable with a physician or other health care provider asking questions
      regarding health-related issues. However, many athletes (especially women)
      believed that the PPE is not a place for specific questions (questions related to
      sexual activity and health, eating disorders, smoking, and personal and family
      use of alcohol). CONCLUSIONS: Most student-athletes do not see a value of the PPE
      in regard to safe athletic participation; most athletes believe that the PPE
      prevents or helps to prevent injuries when there is no clear evidence to support
      this assumption; and athletes are receptive to most preventive health screening,
      but do not feel comfortable with certain issues being raised (i.e., gynecologic
      health, eating disorders, and alcohol and nicotine use). With specific
      modifications aimed toward the needs and comfort level of the student-athlete,
      the PPE may provide an opportunity to present health-related education and
      counseling by means of unique and innovative materials to a group of adolescents
      and young adults.

PMID- 10418535
TI  - Domestic violence and primary care. Attitudes, practices, and beliefs.
AB  - OBJECTIVE: To assess the attitudes and beliefs of the primary care provider team
      (physicians, physician assistants, nurses, and medical assistants) toward the
      identification and management of abused patients and perpetrators of domestic
      violence (DV). DESIGN: Survey of the health care team using a confidential
      questionnaire. SETTING AND SUBJECTS: Five primary care clinics with 240 providers
      at a large urban health maintenance organization. RESULTS: The response rate was
      86% (206 respondents). Fifty percent of clinicians and 70% of nurses/assistants
      believed that the prevalence of DV in their practice was 1% or loss; 1 in 10
      clinicians and nearly half of nurses/assistants had never identified an abused
      person; 45% of clinicians never or seldom asked about DV when examining injured
      patients; and all participants were much less confident in asking about DV than
      about smoking or consuming alcohol. Twenty-five percent believed the abused
      person's personality led to the violence; 28% believed they did not have
      strategies to help abused persons; and 20% were concerned for their personal
      safety in discussing DV. Only 10% believed they had management information, but
      77% had not attended any educational programs on DV in the past year.
      CONCLUSIONS: This study provides important information about current knowledge,
      attitudes, and beliefs of health care providers toward the diagnosis and
      management of DV. This information should prove useful to all who attempt to
      design clinical strategies and educational programs to address this issue.

PMID- 10418537
TI  - Characteristics of women US family physicians.
AB  - CONTEXT: There have been no national studies comparing women family physicians
      (FPs) with other physicians; determining FP characteristics is useful in
      workforce and health systems planning and may also be of inherent interest to FPs
      and others. DESIGN AND PARTICIPANTS: A comparison of the FP (n = 347) and other
      (n = 4154) respondents to the Women Physicians' Health Study. MAIN OUTCOME
      MEASURES: Personal and clinical practices. RESULTS: Women FPs are more likely to
      be US-born and self-defined as politically liberal than were other women
      physicians. Those graduating from medical school in the 1950s through 1970s were
      less and those graduating in the 1980s were far more likely to be board certified
      than were other women physicians. Although their personal and household incomes
      were significantly lower, their professional satisfaction was similar to those of
      other women specialists, and they reported a lesser frequency of severe work
      stress. Personal health-related habits and health status of women FPs were
      similar to those of other women physicians. For all 14 counseling practices
      examined, the amount of counseling they reported performing, the clinical
      relevance they ascribed to those practices, their self-confidence in performing
      the practices, and the amount of training they received was as high as or higher
      than that of other women primary care practitioners and usually exceeded those of
      non-primary care physicians outcomes at the P < .001 level. CONCLUSIONS: Although
      women FPs resemble other women physicians in some respects, they are more
      liberal, are professionally well-satisfied, and are relatively avid
      preventionists.

PMID- 10418538
TI  - Long-term outcomes of initial antidepressant drug choice in a "real world"
      randomized trial.
AB  - OBJECTIVE: To compare the long-term clinical, quality-of-life, and economic
      outcomes after an initial prescription for fluoxetine, imipramine hydrochloride,
      or desipramine hydrochloride. DESIGN: Randomized, controlled trial. SETTING:
      Primary care clinics of a staff-model health maintenance organization in the
      Seattle, Wash, area. PATIENTS: Four hundred seventy-one adults beginning
      antidepressant drug treatment for depression. INTERVENTION: Random assignment of
      initial medication (desipramine, fluoxetine, or imipramine), with treatment
      (dosing, medication changes or discontinuation, and follow-up visits) managed by
      a primary care physician. MEASUREMENTS: Interviews at baseline and at 6, 9, 12,
      18, and 24 months examined medication use, clinical outcomes (Hamilton Depression
      Rating Scale and depression subscale of the Hopkins Symptom Checklist), and
      quality of life (Medical Outcomes Study SF-36 Health Survey). Medical costs were
      assessed using the health maintenance organization's accounting data. RESULTS:
      Patients assigned to fluoxetine therapy were significantly more likely to
      continue taking the initial antidepressant but no more likely to continue any
      antidepressant therapy. The fluoxetine group did not differ significantly from
      either tricyclic drug group on any measure of depression severity or quality of
      life. For 24 months, antidepressant drug costs were approximately $250 higher for
      patients assigned to fluoxetine therapy, but total medical costs were essentially
      identical. CONCLUSIONS: Initial selection of fluoxetine or a tricyclic
      antidepressant drug should lead to similar clinical outcomes, functional
      outcomes, and overall costs. Differences in antidepressant prescription costs are
      blunted by the large minority of tricyclic-treated patients who switch to use of
      more expensive medications. Restrictions on first-line use of fluoxetine in
      primary care will probably not reduce overall treatment costs.

PMID- 10418539
TI  - TCAs vs SSRIs. Same bang for whose buck?

PMID- 10418540
TI  - Luteal phase sertraline treatment for premenstrual dysphoric disorder. Results of
      a double-blind, placebo-controlled, crossover study.
AB  - OBJECTIVE: To test the efficacy of late-luteal phase dosing of sertraline
      hydrochloride in women with moderate-to-severe premenstrual dysphoric disorder.
      This highly prevalent disorder often causes significant psychosocial impairment.
      DESIGN: Double-blind, crossover trial of each 2-menstrual cycle of baseline,
      sertraline treatment, and placebo. Randomization to sertraline treatment vs
      placebo occurred after a 2-cycle, drug-free period. SETTING: A large outpatient
      multispecialty clinic in central Texas. PATIENTS: Fifty-seven women aged 19 to 49
      years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth
      Edition, diagnosis of premenstrual dysphoric disorder. INTERVENTIONS: Late-luteal
      phase treatment with sertraline hydrochloride in daily doses of 50 mg (cycle 1)
      followed by 100 mg (cycle 2) vs placebo. MAIN OUTCOME MEASURES: The 22-item
      calendar of premenstrual experiences was completed daily and constituted the
      primary outcome measure, consisting of a total score and behavioral and physical
      factor scores. RESULTS: A repeated-measures analysis of variance for crossover
      designs found a significant beneficial effect from sertraline treatment in
      improving the calendar of premenstrual experiences total (P < .01), behavioral
      factor (P < .01), and physical factor (P < .04) scores. Most women improved when
      taking sertraline, 50 mg, although a dose increase to 100 mg yielded further
      improvement in approximately 25% of women. Use of sertraline was extremely well
      tolerated; the only adverse event reported by 10% or more of women was insomnia
      in 8 (14%) of them. CONCLUSIONS: Luteal phase treatment with sertraline was a
      safe and effective treatment for moderate-to-severe premenstrual dysphoric
      disorder. Further controlled studies are needed to confirm the results of this
      preliminary study.

PMID- 10418541
TI  - A randomized controlled trial of shared decision making for prostate cancer
      screening.
AB  - OBJECTIVE: To evaluate a patient-educational approach to shared decision making
      for prostate cancer screening. DESIGN: Randomized controlled trial with preoffice
      visit assessment and 2-week follow-up. SETTING: University-based family practice
      center. PATIENTS: Men aged 45 through 70 years with no history of prostate cancer
      or treatment for prostate disease (N = 160). Two patients were unavailable for
      follow-up. INTERVENTION: Twenty-minute educational videotape on advantages and
      disadvantages of prostate-specific antigen (PSA) screening for prostate cancer.
      MAIN OUTCOME MEASURES: A measure of patients' core knowledge of prostate cancer
      developed for this study, reported preferences for PSA testing, and ratings of
      the videotape. RESULTS: Patients' core knowledge at baseline was poor. At 2-week
      follow-up, subjects undergoing videotape intervention showed a 78% improvement in
      the number of knowledge questions answered correctly (P = .001), and knowledge
      increased about mortality due to early-stage prostate cancer, PSA screening
      performance, treatment-related complications, and disadvantages of screening. No
      overall change was observed for control subjects. At follow-up, 48 (62%) of 78
      intervention patients planned to have the PSA test compared with 64 (80%) of 80
      control patients (18.5% absolute reduction; 95% confidence interval, 4.6%-32.4%;
      P = .009). Intervention subjects rated favorably the amount of information
      provided and the clarity, balance, and length of the videotape and would
      recommend the videotape to others. CONCLUSIONS: Patient education regarding the
      potential benefits and harms of early detection of prostate cancer can lead to
      more informed decision making. Incorporating the PSA videotape into the periodic
      health examination for asymptomatic men aged 50 years and older is recommended.

PMID- 10418542
TI  - Ethical theories and clinical practice. One family physician's approach.
AB  - Many physicians find clinical ethics unhelpful in managing real-life patient care
      conflicts. In part, this is because different ethical theories often analyze
      situations in different ways. I review several clinical ethics methods that I
      have found useful in different patient care situations and discuss how this
      eclectic approach to ethical problems is consistent with primary care in general.

PMID- 10418543
TI  - Clinical ethics. What's law got to do with it?

PMID- 10418544
TI  - Alzheimer disease. Report of the Council on Scientific Affairs.
AB  - Alzheimer disease (AD) takes a heavy economic, social, physical, and
      psychological toll on patients, families, and society. Because of the increasing
      life expectancy in the United States, AD is expected to afflict approximately 14
      million people within the next few decades. There is currently no cure, only
      interventions that can temporarily ameliorate the profound cognitive losses and
      behavioral manifestations of the disorder. Community services are fragmented and
      underutilized. Physicians, in their traditional role as gatekeepers, can
      encourage more families to use supportive services. This article reviews the
      guidelines on the diagnosis and treatment of AD of the Agency for Health Care
      Policy and Research, the American Academy of Neurology, the Veterans Health
      Administration, and the American Psychiatric Association. Although these
      guidelines contain valuable information, they do not adequately address the role
      of the family physician and the need for continuity of care. Recommendations
      regarding AD from the Council on Scientific Affairs, which were adopted as
      American Medical Association policy in December 1997, are included in this
      article.

PMID- 10418545
TI  - Health care plan decisions regarding preventive services.
AB  - BACKGROUND: Medical decisions previously made by physicians and patients are
      increasingly influenced by health plans. It is important to understand how these
      decisions are made and who makes them. OBJECTIVES: To determine protocols used by
      health plans for recommending preventive services and to identify methods used to
      develop these protocols. METHODS: An interviewer conducted semistructured
      telephone interviews with medical directors from 6 major types of health plans
      regarding coverage of certain procedural preventive services. Each medical
      director was asked: (1) Is this procedure paid for by the health plan? (2) What
      is the frequency recommended for this procedure? (3) What age groups do you
      recommend for this procedure? (4) Do you encourage patients to receive this
      procedure, and if so, how? (5) Who developed these preventive services
      recommendations? (6) How were these recommendations developed? RESULTS: Ten
      interviews were completed representing 6 chosen types of health plans. While the
      different plans varied little regarding the preventive services recommended,
      there was variation in efforts to promote recommended services to members. There
      were also differences among the plans in the decision-making process for
      developing preventive services recommendations. CONCLUSIONS: Managed care
      organizations promote certain preventive services to members. All health plans
      had at least 1 preventive medicine task force charged with making coverage
      decisions about preventive services. However, more could be done to rationalize
      development of preventive services recommendations, primarily, implementation of
      evidence-based guidelines.

PMID- 10418546
TI  - Unusual ECG after syncope in an elderly woman.

PMID- 10418547
TI  - A smoker with paroxysmal dyspnea.
AB  - A 40-year-old woman who had experienced recurring episodes of dyspnea for 28
      years presented to the emergency department with increasing shortness of breath,
      wheezing, and dry cough of three days' duration. She had been seen at another
      hospital shortly after symptoms began but left against medical advice. She did
      not have fever, chills, or other symptoms of upper respiratory infection.

PMID- 10418548
TI  - New strategies for smoking cessation.

PMID- 10418549
TI  - The enteric nervous system: a second brain.
AB  - Once dismissed as a simple collection of relay ganglia, the enteric nervous
      system is now recognized as a complex, integrative brain in its own right.
      Although we still are unable to relate complex behaviors such as gut motility and
      secretion to the activity of individual neurons, work in that area is proceeding
      briskly--and will lead to rapid advances in the management of functional bowel
      disease.

PMID- 10418550
TI  - Recurrent fainting, dysesthesia, and impotence.

PMID- 10418551
TI  - Thrombotic thrombocytopenic purpura today.
AB  - Thrombotic thrombocytopenic purpura (TTP) usually responds to plasma exchange and
      plasma infusion. However, until recently, it was not clear how the treatment
      works. New understanding of the pathophysiology of TTP has clarified that issue
      and suggested new therapies that may eliminate plasma infusion and its risks.

PMID- 10418552
TI  - Case in point. Lung hernia.

PMID- 10418553
TI  - Reducing the risk of malpractice claims.
AB  - Many physicians will be sued for malpractice at some time during their careers.
      Risk of litigation can be reduced by adopting practices that include keeping
      thorough medical records, educating office personnel, and fostering good patient
      physician relationships. The last is important because patients who view their
      physicians as caring tend not to sue even if an adverse outcome occurs.

PMID- 10418554
TI  - Case of the month: triple carcinomas in Cronkhite-Canada syndrome.

PMID- 10418555
TI  - No advantage of reoperation for positive resection margins in node positive
      gastric cancer patients?

PMID- 10418557
TI  - Resection-line involvement in gastric cancer patients undergoing curative
      resections: implications for clinical management.
AB  - BACKGROUND: Resection-line involvement has been suggested as an important
      prognostic factor for gastric cancer. METHODS: The relationship between resection
      line involvement and outcome was examined in patients undergoing potentially
      curative resection for gastric cancer. RESULTS: Tumor positive resection-lines
      were seen in 22 of the 259 evaluable patients (8.4%). Resection-line involvement
      was associated with tumor location (P = 0.01) and tumor differentiation (P =
      0.02). Positive margins were associated with worse survival. However, if both
      groups of patients are stratified according to lymph node metastases, resection
      line involvement determined a shorter survival only in patients with N0 stage
      disease. CONCLUSIONS: Our data suggest, in the case of positive margins, that re
      laparatomy should be considered only for patients with N0 stage disease, while
      patients with metastatic lymph nodes should be watched closely without the need
      for a more aggressive surgical approach.

PMID- 10418556
TI  - A dose-finding study of lenograstim (glycosylated rHuG-CSF) for peripheral blood
      stem cell mobilization during postoperative adjuvant chemotherapy in patients
      with breast cancer. Lenograstim/Breast Cancer Study Group.
AB  - BACKGROUND: The optimum dose of granulocyte colony-stimulating factor (G-CSF) for
      peripheral blood stem cell (PBSC) mobilization after disease-oriented,
      conventional-dose chemotherapy remains unknown. METHODS: A multicenter dose
      finding study of glycosylated G-CSF (lenograstim) for the mobilization of PBSCs
      following adjuvant CAF chemotherapy (cyclophosphamide, doxorubicin and 5
      fluorouracil) was performed in 38 patients with postoperative breast cancer. Each
      10, ten and eight patients were sequentially allocated to one of the three dose
      groups (2, 5 and 10 micrograms/kg, respectively) of lenograstim. Lenograstim was
      administered subcutaneously (s.c.) daily from day 8 to the day of the last
      apheresis and CD34+ cells and colony-forming units-granulocyte macrophage (CFU
      GMs) in peripheral blood were measured serially. Additionally, 10 patients who
      received adjuvant CAF chemotherapy alone also participated in the study, as a
      control. RESULTS: Lenograstim was well tolerated up to 10 micrograms/kg, except
      for one patient given 10 micrograms/kg who developed transient grade 3 hepatic
      enzyme elevation. The peak levels of CD34+ cells and CFU-GMs in peripheral blood
      showed dose-response relationships. The median peak CD34+ cells for the 0, 2, 5
      and 10 micrograms/kg dose groups were 5.4, 34.3, 55.0 and 127.6 cells/microliter,
      respectively, and those of CFU-GMs for the 0, 2, 5 and 10 micrograms/kg dose
      groups were 0.01, 0.33, 1.32 and 3.30 CFU-GMs/microliter, respectively.
      CONCLUSIONS: Considering the previous reports suggesting that a pre-apheresis
      number of 40-50 CD34+ cells/microliter in peripheral blood is highly predictive
      for achievement of more than 2.5 x 10(6) CD34+ cells/kg in a standard apheresis
      procedure of 10 litres, the optimum dose of lenograstim for PBSC mobilization
      following CAF chemotherapy in patients with postoperative breast cancer is 5
      micrograms/kg/day s.c.

PMID- 10418558
TI  - Clinical significance of magnetic resonance cholangiopancreatography for the
      diagnosis of cystic tumor of the pancreas compared with endoscopic retrograde
      cholangiopancreatography and computed tomography.
AB  - BACKGROUND: Cystic tumor of the pancreas has been investigated by a variety of
      imaging techniques. Magnetic resonance cholangiopancreatography (MRCP) is being
      widely used as a non-invasive diagnostic modality for investigation of the
      biliary tree and pancreatic duct system. The purpose of this study was to compare
      MRCP images with those of endoscopic retrograde cholangiopancreatography (ERCP)
      and computed tomography (CT) in order to clarify the diagnostic efficacy of MRCP
      for cystic tumor of the pancreas. METHODS: We retrospectively studied 15 patients
      with cystic tumor of the pancreas that had been surgically resected and
      histopathologically confirmed. There were five cases of intraductal papillary
      adenocarcinoma, five of intraductal papillary adenoma, two of serous cyst
      adenoma, two of retention cyst associated with invasive ductal adenocarcinoma and
      one of solid cystic tumor. RESULTS: In all cases MRCP correctly identified the
      main pancreatic duct (MPD) and showed the entire cystic tumor and the
      communication between the tumor and the MPD. On the other hand, the detection
      rate by ERCP of the cystic tumor and the communication between the cystic tumor
      and the MPD was only 60%. Although the detection rates by CT for the septum and
      solid components inside the cystic tumor were 100 and 90.0%, respectively, those
      of MRCP for each were 58.3 and 20.0%. CONCLUSION: MRCP is capable of providing
      diagnostic information superior to ERCP for the diagnosis of cystic tumor of the
      pancreas. Although MRCP may provide complementary information about the whole
      lesion of interest, the characteristic internal features of cystic tumor of the
      pancrease should be carefully diagnosed in combination with CT.

PMID- 10418559
TI  - A dose-finding study of nedaplatin and cyclophosphamide for patients with
      gynecological malignancies.
AB  - BACKGROUND: Nedaplatin is a new analogue of cisplatin with similar efficacy but
      less renal toxicity. We investigated the appropriate dose of nedaplatin in
      combination with cyclophosphamide for patients with gynecological malignancies.
      METHODS: Nine patients (five with ovarian cancer and four with uterine cervical
      cancer) were studied. Three patients received 60 mg/m2 of nedaplatin combined
      with 500 mg/m2 of cyclophosphamide every 4 weeks. Another three patients were
      each administered 80 or 100 mg/m2 of nedaplatin with the same dose of
      cyclophosphamide. A total of 27 courses was given. RESULTS: No patient needed
      dose reduction due to myelosuppression and no severe adverse events were
      observed. CONCLUSIONS: Treatment with 100 mg/m2 of nedaplatin and 500 mg/m2 of
      cyclophosphamide is feasible for patients with gynecological malignancies.
      However, phase II studies are needed to clarify the efficacy of this combination
      chemotherapy.

PMID- 10418560
TI  - Comparative study of assays for prostate-specific antigen molecular forms.
AB  - BACKGROUND: The detection of prostate-specific antigen (PSA) molecular forms such
      as free PSA and PSA-ACT and the use of PSA molecular ratios, especially the
      percentage of free to total PSA, have been reported to improve the diagnostic
      accuracy of prostate cancer in the patients with slightly elevated serum PSA
      values. However, the correlation among the values of serum free PSA or PSA-ACT
      obtained in various assays remains unclear. METHODS: Serum free PSA and PSA-ACT
      values were detected with the following assays: Hybritech, DPC, EIKEN, Abbott,
      Roche and Can-Ag for free PSA and Dainippon, Chugai, EIKEN and Bayer for PSA-ACT.
      The data obtained with each assay were compared with Hybritech (free PSA) and
      Dainippon (PSA-ACT) as standards. RESULTS: The free PSA data obtained with the
      Hybritech, EIKEN, Abbott and Can-Ag kits were similar. The values obtained with
      the DPC and Roche kits showed a linear regression of y = ax + b with those
      obtained with the Hybritech, with a b value of zero and an a value of 1.20 and
      1.57, respectively. The serum PSA-ACT values detected with the Dainippon and
      Chugai kits were identical. The equation for converting the data obtained with
      the EIKEN kits to the Dainippon value was 0.7636 x (EIKEN) + 0.1381. CONCLUSIONS:
      Serum free PSA and PSA-ACT values obtained with various assays were not
      necessarily the same. Some kits for the assay of free PSA and PSA-ACT gave the
      same serum values. The free PSA values obtained with the other kits could be
      converted using appropriate equations. The gamma-Sm values showed wide variations
      and were not considered suitable as a measurement of free PSA.

PMID- 10418561
TI  - Malignant Brenner tumors of the ovary and tumor markers: case reports.
AB  - We investigated the tumor marker for malignant Brenner tumors, which had not been
      established because of the rarity and variable histological criteria.
      Representative areas of two cases of malignant Brenner tumor were investigated by
      means of the peroxidase-antiperoxidase method using monoclonal antibody to CA125
      and CA72-4 antigen and the streptavidin-biotin immunoperoxidase complex method
      using monoclonal antibody to SCC antigen. Based on clinical course and
      immunohistochemical studies, serum CA125 and CA72-4 for Case 1 and SCC and CA72-4
      for Case 2 were appropriate tumor markers for the establishment of the extent of
      tumor burden before treatment and to monitor the response to therapy. The
      discrepancy of the tumor markers of the two present cases is considered to be a
      reflection of the difference in the malignant component of these cases. However,
      serum CA72-4 was an appropriate tumor marker for both malignant Brenner tumors.

PMID- 10418562
TI  - Two cases of metastatic bladder cancers showing diffuse thickening of the bladder
      wall.
AB  - Metastatic bladder cancer showing diffuse thickening of the bladder wall is very
      rare. We report two cases of metastatic bladder cancer arising from a stomach
      cancer and acute lymphocytic leukemia. Hydronephrosis and diffuse thickening of
      the bladder wall were revealed by ultrasonography and computed tomography.
      Transurethral biopsy and percutaneous whole wall needle biopsy of the bladder
      were useful for diagnosis. The possibility of metastasis or recurrence of prior
      and other malignancies should therefore be considered when the clinical features
      described here are encountered.

PMID- 10418563
TI  - Knowledge of ethical lapses and other experiences on clinical licensure
      examinations.
AB  - While clinical licensure examinations claim to protect the public from
      incompetent practitioners, serious problems related to issues of validity,
      reliability, and ethics have been reported. The ethical lapses are difficult to
      document, and reports of problems have been strictly anecdotal. This study's
      primary purpose was to verify those anecdotal reports by mailing a twenty-one
      item survey to a national random sample of one thousand general dentists who
      graduated from a United States-accredited dental school between 1980 and 1994.
      For those who responded (42.9 percent) results show that 23.9 percent did not
      arrange for follow-up care for the patient even though it was indicated. Eight
      percent reported knowledge of instances where a lesion was intentionally created;
      19.3 percent knew of premature treatment provided for purposes of the
      examination; 13.7 percent knew of a colleague who coerced a patient into
      accepting treatment; 32.5 percent reported knowledge of unnecessary radiographs.
      About half of all respondents agreed that the examination was not an accurate
      assessment of ability, and a similar proportion doubted that human patients were
      necessary. A more reliable and valid assessment strategy that does not jeopardize
      patient care is needed.

PMID- 10418564
TI  - Use of discriminant and regression analyses to modify a clinical certification
      board examination.
AB  - The National Dental Examining Board of Canada (NDEB) conducts mandatory, high
      stakes, pass/fail, certification examinations for dental licensure. One of these
      examinations was a seven-part, simulated clinical examination in which candidates
      were required to perform procedures on typodonts. These requirements were two
      intracoronal and two extracoronal preparations, an amalgam restoration, a
      provisional crown, and a diagnostic wax-up. Feedback from candidates and
      examiners indicated that one or more of the requirements may not have been
      contributing effectively to the overall evaluation of candidates. The NDEB's
      Clinical Examination Committee therefore requested that an in-depth statistical
      analysis be performed to identify potential areas of concern and to provide a
      basis for modifying the examinations. The results of two examination sessions
      with a total of 168 candidates were subjected to both a discriminant and a
      logistic regression analysis. Every candidate had results for each of the seven
      requirements, and no candidate participated in both sessions of the examination.
      The discriminant analysis revealed that six of the seven requirements could be
      used to reliably assign examinees according to their true pass/fail
      classifications. Stepwise discriminant analysis resulted in a 98.81 percent
      classification success rate with a corresponding 2.50 percent false-positive
      classification error rate. The logistic regression analysis showed that five
      components correctly predicted 99.40 percent with a 1.25 percent false-positive
      rate. The Clinical Examination Committee concluded that one requirement
      (diagnostic wax-up) should be eliminated and that a second requirement (PFM
      preparation) be significantly modified and reevaluated. This study demonstrates
      the usefulness of statistical methods in the analysis and modification of a
      clinical certification board examination.

PMID- 10418565
TI  - Exposures to blood and body fluids among dental school-based dental health care
      workers.
AB  - A survey of United States dental schools was conducted to determine the annual
      incidence of reported percutaneous and mucosal exposures to blood and other body
      fluids among dental school-based dental health care workers (DHCW). A response
      rate of 51.9 percent provided information on 10,433 DHCW and 1.6 million student
      clinic and 169,836 school-based faculty practice patient visits. This response
      represents approximately half of all DHCW and student clinic visits in U.S.
      dental schools in AY 1996/1997. A total of 652 exposures were reported, of which
      629 occurred in student clinics. Dental schools averaged twenty-three reported
      exposures per year, and the overall annual reported exposure rate in student
      clinics was 4.0/10,000 patient visits and 1.3/10,000 in faculty practice. Dental
      students accounted for 62.5 percent of all reported exposures, a rate of
      106.3/1000 students per year. The exposure rate for dental students was
      significantly greater that any other category of DHCW. Expressed in terms of
      person years, an exposure rate of 0.17 was comparable to that reported for dental
      schools but considerably less than found in other dental care settings. A second
      survey directed to individual DHCW drew responses from only 8.3 percent of the
      10,433 DHCW. Among these respondents, 31 percent of those acknowledging an
      exposure reported it. A judgment that the injury was not serious, the time
      necessary to report an exposure, and a belief that the patient was healthy were
      the primary reasons for not reporting. The results of this study provide dental
      schools with benchmarks for comparing their reported exposure experience and
      assessing programs intended to prevent and manage exposures.

PMID- 10418566
TI  - Outcomes assessment in dental hygiene programs.
AB  - In 1996, the American Dental Association's Commission on Dental Accreditation
      instituted a revised accreditation standard for dental hygiene educational
      programs entitled Standard 12-Outcomes Assessment. As a result of this standard,
      all dental hygiene programs were required to assess the attainment of goals
      through a formal outcomes assessment process. This study examined and analyzed
      the implementation process used by dental hygiene programs. Twenty-two dental
      hygiene program directors were interviewed to collect information regarding their
      experiences. The directors indicated that their programs routinely and
      effectively assess student outcomes and use the acquired information to make
      needed program improvements and to demonstrate accountability to groups having a
      vested interest in the program. Several factors, such as the policy itself, as
      well as gaining faculty and administrative support, were viewed as important to
      implementation. Time constraints were identified as a major barrier. Outcomes
      assessment data have also been used by dental hygiene programs as leverage for
      funding requests that resulted in significant program enhancement.

PMID- 10418567
TI  - Dental hygiene program directors' perceptions of graduate dental hygiene
      education and future faculty needs.

PMID- 10418569
TI  - Creating your own medical Web site. It's not as hard as you might think.

PMID- 10418568
TI  - Dissolution of a good partnership?

PMID- 10418570
TI  - When to discontinue ACE inhibitors for nephropathy.

PMID- 10418571
TI  - Ongoing debate over 'complete' physicals.

PMID- 10418572
TI  - Echocardiography for mitral valve prolapse?

PMID- 10418573
TI  - Parkinson's disease--the shaking palsy. Underlying factors, diagnostic
      considerations, and clinical course.
AB  - Parkinson's disease is a progressive neurologic disorder without cure. About 1%
      of the US population over 50 years of age is afflicted. Loss of dopaminergic
      neurons originating in the substantia nigra is the typical pathologic feature. It
      is theorized that both genetic and environmental factors have a role in the
      etiology of the disease. The classic tetrad of parkinsonian signs includes
      tremor, rigidity, bradykinesia, and disturbances in posture and gait. Initial
      signs and symptoms can be subtle and nonspecific. As the disease progresses,
      vocal, neurologic, autonomic, and psychiatric complications may develop.
      Mortality rates have not changed in 30 years despite new therapy. Differentiating
      true Parkinson's disease from other causes of parkinsonism can be challenging but
      is crucial to outcome.

PMID- 10418574
TI  - Advising patients about international travel. What they can do to protect their
      health and safety.
AB  - As international travel becomes increasingly common, primary care physicians are
      often asked for advice about travel-related health issues. Having a basic
      knowledge of both health and safety issues is essential. Pregnant women and
      patients with chronic medical conditions need to be aware of factors that can
      compromise their health during airline flights. All travelers need to know about
      required and recommended immunizations; prevention and treatment of jet lag,
      motion sickness, altitude sickness, food-borne illness, traveler's diarrhea, and
      sunburn; protection from insects and swimming hazards; how to obtain medical care
      in foreign countries; and how to protect themselves in the event of a crime or
      medical emergency.

PMID- 10418575
TI  - Taking the itch out of poison ivy. Are you prescribing the right medication?

PMID- 10418576
TI  - Preventing diabetic foot complications. Tight glucose control and patient
      education are the keys.
AB  - Foot disease is a common complication of diabetes that can have tragic
      consequences. Tight glucose control can reduce microvascular diabetic
      complications, including peripheral sensory neuropathy and thus development of
      foot ulcers. Patient education is essential for risk-factor reduction and early
      recognition of foot complications. Awareness and training of healthcare providers
      in diagnosing and treating diabetic foot disease are paramount and may begin with
      such simple measures as adding a wall poster or chart reminder to conduct foot
      examinations in all diabetic patients at every office visit.

PMID- 10418577
TI  - Antimicrobial therapy for diabetic foot infections. A practical approach.
AB  - Infection of the diabetic foot is a common problem in clinical practice and is
      associated with significant morbidity. Optimal management requires a
      multidisciplinary approach. Aggressive surgical debridement and wound management,
      carefully chosen antimicrobial therapy, and modification of host factors (i.e.,
      hyperglycemia, concomitant arterial insufficiency) are all equally important for
      a successful outcome. Empirical antibiotic selection should be followed by
      culture-guided definitive therapy.

PMID- 10418578
TI  - Local wound care in diabetic foot complications. Aggressive risk management and
      ulcer treatment to avoid amputation.
AB  - Techniques to prevent and treat lower extremity amputation in patients with
      diabetes vary from simple foot inspection to complicated vascular and
      reconstructive surgery. Early identification of risk factors, careful and regular
      evaluation, and aggressive treatment in a multidisciplinary team approach prevent
      amputation in most cases of diabetic foot ulcer. Suitable treatment of these
      ulcers consists of minimizing pressure, resolving infection, correcting ischemia,
      and maintaining a warm, moist, clean environment to enhance wound healing.
      Success in these efforts not only preserves quality of life for diabetic patients
      but also saves money for the healthcare system.

PMID- 10418579
TI  - Routine anesthesia for circumcision. Two effective techniques.
AB  - Circumcision of male newborns is one of the most common procedures performed in
      the United States. Use of local anesthesia reduces the pain and distress
      associated with neonatal circumcision. Dr Mattson describes two techniques that
      provide effective anesthesia with minimal risks for newborns undergoing
      circumcision.

PMID- 10418580
TI  - Bronchiectasis: the 'other' obstructive lung disease.
AB  - Bronchiectasis belongs to the family of chronic obstructive lung diseases, even
      though it is much less common than asthma, chronic bronchitis, or emphysema.
      Clinical features of these entities overlap significantly. The triad of chronic
      cough, sputum production, and hemoptysis always should bring bronchiectasis to
      mind as a possible cause. Chronic airway inflammation leads to bronchial dilation
      and destruction, resulting in recurrent sputum overproduction and pneumonitis.
      Once the diagnosis is confirmed, any potential predisposing conditions should be
      aggressively sought. The relapsing nature of bronchiectasis can be controlled
      with antibiotics, chest physiotherapy, inhaled bronchodilators, proper hydration,
      and good nutrition. In rare circumstances, surgical resection or bilateral lung
      transplantation may be the only option available for improving quality of life.
      Prognosis is generally good but varies with the underlying syndrome.

PMID- 10418581
TI  - Recurrent appendicitis. Uncommon, but it does occur.

PMID- 10418582
TI  - What's causing this occipital headache? Cerebral dural venous sinus thrombosis.

PMID- 10418583
TI  - Tips for a safe trip.

PMID- 10418584
TI  - Using quality-of-life instruments to assess surgical outcomes.

PMID- 10418585
TI  - A prospective randomized study of the systemic immune response after laparoscopic
      and conventional Nissen fundoplication.
AB  - BACKGROUND: Laparoscopic techniques are thought to reduce the postoperative
      immunologic and metabolic changes of conventional operations. Until now, the only
      clinical data available were obtained from patients operated on for symptomatic
      gallstones; moreover, few studies were randomized. This randomized prospective
      study compares the systemic immune response after laparoscopic and conventional
      Nissen fundoplication. METHODS: Seventeen patients scheduled for Nissen
      fundoplication were randomly assigned to undergo either a laparoscopic or a
      conventional procedure. Postoperative inflammatory response was assessed by
      measuring the white blood cell count, C-reactive protein, and soluble tumor
      necrosis factor receptors p55 and p75. Postoperative immune function was assessed
      by measuring monocyte HLA-DR expression and the stress response was assessed by
      measuring plasma cortisol concentrations. RESULTS: Laparoscopic surgery resulted
      in significantly lower plasma CRP levels 1 day after surgery. Both approaches
      resulted in a significant decrease in HLA-DR expression within 2 hours after
      surgery. After the laparoscopic approach, postoperative expression was restored
      to preoperative values within 1 day after surgery. However, after conventional
      surgery HLA-DR expression remained suppressed and did not return to preoperative
      values until the fourth postoperative day. No significant differences between the
      2 procedures were observed in white cell blood count, sTNFr-p55 and p75, nor in
      postoperative cortisol levels. CONCLUSIONS: Although both laparoscopic and
      conventional Nissen fundoplication result in an activation of the systemic immune
      response, this study suggests that this response could be less after the
      laparoscopic approach. The differences found may reflect a lower risk for
      postoperative infective complications.

PMID- 10418586
TI  - Liver transplantation with monosegments.
AB  - BACKGROUND: Shortage of size-matched pediatric donors led to the development of
      surgical techniques to reduce or split livers and thus increase the potential
      pool of donors. Despite this, neonatal transplantation remains a problem because
      of the small size of the recipients. Further reduction of the left lateral
      segment is possible to provide a single segment graft (segment III). We report
      our experience of transplanting 6 babies using this technique. METHODS: Of 310
      children transplanted in our center between October 1989 and March 1998, 6
      patients, 2 male and 4 female, median age 37.5 days (range 5 to 92 days), median
      weight 3.45 kg (range 2.45 to 5.46 kg) were transplanted with a monosegment. The
      cause of liver failure was neonatal hemochromatosis in 4, retransplantation for
      hepatic artery thrombosis in 1, and hepatitis B in one. The donor liver was
      reduced or split to a left lateral segment. Segment II was then resected and
      discarded before transplantation. RESULTS: Overall, graft and patient survival is
      83.3%. Five patients are alive with good graft function at a mean follow-up of
      30.4 months (range 8 to 82 months). One child who was transplanted for hepatic
      artery thrombosis died from sepsis and multiorgan failure 48 hrs after
      transplant. None of the survivors had vascular or biliary complications.
      CONCLUSIONS: Monosegment liver transplantation with segment III appears to be a
      satisfactory option for treating small babies with liver failure.

PMID- 10418587
TI  - Value of stimulated serum thyroglobulin levels for detecting persistent or
      recurrent differentiated thyroid cancer in high- and low-risk patients.
AB  - BACKGROUND: Serum thyroglobulin determination has been reported to be a sensitive
      indicator of persistent or recurrent differentiated thyroid cancer of follicular
      cell origin (DTC) after total thyroidectomy. The purpose of this investigation
      was to determine the accuracy of serum thyroglobulin levels in predicting
      persistent or recurrent DTC in euthyroid and hypothyroid patients. METHODS: One
      hundred ninety consecutive patients with DTC of follicular cell origin who had 4
      or more thyroglobulin levels measured after total thyroidectomy were
      retrospectively evaluated. One hundred fifteen patients had serum thyroglobulin
      levels measured when hypothyroid for radioiodine scanning or ablation. Serum
      thyroglobulin levels were determined by commercial assays. One hundred twenty-two
      patients less than 45 years old were considered at low risk, whereas 68 patients
      more than or equal to 45 years old were considered at high risk on the basis of
      TNM classification. The mean follow-up period was 62 months. RESULTS: After
      thyroidectomy with or without central or modified radical neck dissection 120
      patients had normal thyroglobulin levels (< or = 3 ng/mL) while receiving thyroid
      hormone. One hundred thirteen of the 120 patients (94%) with normal serum
      thyroglobulin levels had no evidence of recurrent tumor, whereas 6% (7 patients)
      had persistent or recurrent disease. Among 76 patients with persistent (28
      patients) or recurrent (48 patients) disease, 70 had a serum thyroglobulin level
      > 3 ng/mL while receiving thyroid hormone. Overall, 14 of 115 patients, including
      2 of 61 (3%) in the high-risk group and 12 of 54 (22%) in the low-risk group,
      only had elevated serum thyroglobulin levels when hypothyroid with high serum
      thyroid-stimulating hormone (TSH) levels documenting persistent or recurrent
      disease. In 1 patient the serum thyroglobulin level (240 ng/mL) was falsely
      elevated probably as a result of interfering antibodies because no tumor was
      identified surgically or pathologically, and the thyroglobulin concentration was
      < 3 ng/mL when analyzed in 3 other laboratories. CONCLUSION: Serum thyroglobulin
      testing is sensitive (91%) and specific (99%) for identifying patients with
      persistent or recurrent differentiated thyroid cancer. Serum thyroglobulin levels
      are most precise when patients are hypothyroid (high TSH) and may be unreliable
      in patients with antithyroglobulin antibodies. We recommend TSH-stimulated
      thyroglobulin testing for all patients after total thyroidectomy for
      differentiated thyroid cancer of follicular cell origin regardless of patient age
      or risk group.

PMID- 10418588
TI  - Carotid endarterectomy without angiography: can clinical evaluation and duplex
      ultrasonographic scanning alone replace traditional arteriography for carotid
      surgery workup? A prospective study.
AB  - BACKGROUND: The aim of this study was to determine whether clinical evaluation
      and duplex ultrasonography (DUS) alone can replace contrast cerebral
      arteriography (CA) for the detection of patients suitable for surgery at our
      institution. METHODS: During an 18-month period, 100 patients underwent DUS and
      CA during evaluation for carotid endarterectomy (CEA). All patients were studied
      prospectively; in each case an initial decision for or against CEA on the basis
      of DUS evaluation of the internal carotid arteries (ICAs) was subsequently
      compared with the surgeon's final management plan after CA. Of the 200 ICAs
      evaluated, 113 were considered for CEA but 14 were excluded from the study
      because the patient could not be evaluated before and after CA. This left 99 ICAs
      (86 patients) available for comparative analysis. RESULTS: The outcome of the 2
      diagnostic modalities was perfectly consistent in 95.3% of the ICAs (kappa =
      0.969). The clinical management decision was altered by the CA findings in only 2
      cases (2%). Of the 99 ICAs considered suitable, 97 underwent CEA. No
      arteriographic complications occurred among the 100 patients undergoing CA. The
      perioperative stroke risk and mortality rates were 0%. CONCLUSIONS: Ninety-eight
      percent of the ICAs considered for surgery would have received appropriate
      clinical treatment on the strength of the patients' neurologic history and the
      outcome of DUS alone. Our results indicate that DUS is sufficient to establish
      the need for surgery in symptomatic and asymptomatic patients being considered
      for CEA and can replace CA in most clinical circumstances.

PMID- 10418589
TI  - Incidence, prognosis, and etiology of end-stage liver disease in patients
      receiving home total parenteral nutrition.
AB  - BACKGROUND: Elevations in liver function tests have been reported in patients
      receiving total parenteral nutrition (TPN). The clinical aspects of end-stage
      liver disease (ESLD) associated with the prolonged use of home TPN have not been
      fully clarified. In previous series patients with duodenocolostomies appeared to
      be at higher risk than persons with some jejunum or ileum remaining in situ.
      METHODS: The records of 42 patients treated with home TPN for more than 1 year
      were examined. This constituted 283 person-years of home TPN. Patients with
      duodenocolostomies were examined as a separate group on the basis of the
      literature experience. RESULTS: Six of 42 patients who received chronic home TPN
      had ESLD with 100% subsequent mortality, at an average of 10.8 +/- 7.1 months
      after the initial bilirubin elevation. Thirteen of 42 patients had superior
      mesenteric artery or vein thrombosis (SMT) leading to duodenocolostomy. In 8 of
      these 13 patients with SMT and underlying inflammatory or malignant disorder, 2
      had ESLD. The remaining 5 SMT patients who had only minimal liver enzyme
      elevation over 13.6 +/- 6.7 (range 3 to 19) years of home TPN were significantly
      younger (36 +/- 7 years vs 64 +/- 13 years) and did not have underlying
      inflammation either by clinical diagnosis or as reflected in the high normal
      serum albumin level (> or = 4.0 g/dL). Despite their extreme short bowel syndrome
      and long exposure to home TPN, ESLD did not develop. CONCLUSIONS: Approximately
      15% of patients who receive prolonged TPN have ESLD with a high rate of morbidity
      and mortality. The combination of chronic inflammation and the short bowel
      syndrome appears to be necessary for the development of ESLD with prolonged home
      TPN.

PMID- 10418590
TI  - Effects of laparoscopy on intraperitoneal tumor growth and distant metastases in
      an animal model.
AB  - BACKGROUND AND AIMS: Laparoscopic surgery for colorectal cancer is currently
      being evaluated in humans. The aim of this study was to examine the effect of
      laparoscopy on intraperitoneal tumor growth and distant metastases in an animal
      model. We also examined the effect of combining laparotomy with laparoscopy and
      on infusing the peritoneal cavity with normal saline solution (NaCl), water, and
      sodium hypochlorite after laparoscopy on intraperitoneal tumor growth. MATERIAL
      AND METHODS: Female Fischer rats were given MtLn3 adenocarcinoma cells by
      intraperitoneal injection to produce intraperitoneal tumor growth and by tail
      vein injection to produce lung metastases. A pneumoperitoneum was then induced to
      a pressure of 8 mm Hg with carbon dioxide (CO2), helium, or room air. After this,
      animals were allowed to either recover or underwent laparotomy or infusion of
      NaCl, water, or sodium hypochlorite before recovery, depending on the experiment.
      At 21 days all animals were killed and intraperitoneal tumor growth was assessed
      by counting the number of peritoneal and serosal nodules and by weighing the
      omental pad of tumor. Lung metastases were assessed by counting the number of
      metastases after fixation. RESULTS: Laparoscopy caused a marked intraperitoneal
      dissemination of tumor with a median of 17 (10 to 20) peritoneal and serosal
      nodules for CO2, 19.5 (12.5 to 25) for helium, and 15.0 (9.5 to 17.7) for room
      air compared with 0 (0 to 1) for controls (P < .0001). The weight of omental
      tumor was also significantly increased (P < .02) in the CO2, helium, and room air
      groups. Infusion with NaCl, water, or sodium hypochlorite had no effect on tumor
      dissemination after laparoscopy. The combination of laparoscopy and laparotomy
      caused a significant reduction (P < .05) in the number of peritoneal nodules but
      had no significant effect on omental tumor growth. Laparoscopy also had no effect
      on the number of pulmonary metastases induced compared with controls.
      CONCLUSIONS: This study shows that laparoscopy promotes intraperitoneal
      dissemination of tumor. This effect is independent of the insufflating gas used
      and is not affected by use of a cytotoxic agent. The use of gasless laparoscopy
      should be encouraged by those undertaking curative laparoscopic surgery for
      colorectal cancer.

PMID- 10418591
TI  - Impact of experimental peritonitis on bone marrow cell function.
AB  - BACKGROUND: The effects of abdominal sepsis on the regulation of cell turnover in
      bone marrow and on the function of hematopoietic stem cells were investigated.
      METHODS: In a new mouse model of abdominal sepsis (colon ascendens stent
      peritonitis [CASP]) the proliferation, apoptosis, and colony-forming capacity of
      bone marrow cells were determined. RESULTS: Both experimental peritonitis and
      sham surgery increased proliferation of bone marrow cells significantly (P <
      .01). Incubation with granulocyte-macrophage colony-stimulating factor but not
      granulocyte colony-stimulating factor further augmented proliferation of bone
      marrow cells from septic mice. In contrast to cell proliferation, bone marrow
      cell apoptosis was significantly (P < .001) increased in response to CASP but not
      to sham surgery. CASP surgery and treatment of normal bone marrow cells with
      lipopolysaccharide, tumor necrosis factor-alpha, interleukin 1 beta, and
      interferon gamma increased the number of apoptotic cells to a similar extent.
      Stem cell assays revealed that during the late phase of peritonitis the colony
      formation by granulocytic-monocytic precursors was increased, whereas mature
      erythroid colony-forming cells were suppressed. Incubation of normal bone marrow
      cells with lipopolysaccharide and cytokines showed similar effects. CONCLUSIONS:
      These results reveal differential effects of experimental peritonitis on various
      hematopoietic lineages and suggest a potential role of inflammatory mediators for
      the dysregulation of bone marrow cell function during abdominal sepsis.

PMID- 10418592
TI  - Carbon dye as an adjunct to isosulfan blue dye for sentinel lymph node
      dissection.
AB  - BACKGROUND: The success of intraoperative lymphatic mapping depends on accurate
      identification of the sentinel node. We hypothesized that a carbon particle
      suspension would allow histopathologic confirmation of the sentinel lymph node
      through deposition of carbon within that node. METHODS: An animal model was used
      to compare the lymphatic mapping accuracy of carbon dye with that of isosulfan
      blue dye, the standard agent for intraoperative visualization of the sentinel
      lymph node. Twenty-two rats underwent lymphatic mapping in each distal lower
      extremity with various combinations of carbon dye and isosulfan blue dye. All
      stained (blue or black) nodes in the inguinal drainage basin were removed for
      pathologic analysis, including carbon particle analysis. A meticulous search
      identified all nonstained (nonsentinel) nodes in the same basin. These
      nonsentinel nodes were examined for carbon particles by light microscopy. Dermal
      diffusion of mapping agents at the injection site was also recorded. Animals were
      then observed for 28 days to assess the toxicity of mapping agents. RESULTS:
      Although isosulfan blue dye and full-strength carbon dye each stained all
      sentinel nodes, the latter obscured histologic detail. The combination of 2.5%
      carbon dye, 7.5% saline solution, and 90% isosulfan blue dye also stained all
      sentinel nodes; carbon particles were seen on light microscopy in all 13 stained
      nodes and did not interfere with histologic evaluation. No unstained node
      contained carbon particles, although the number of nonsentinel nodes was small.
      Carbon dye exhibited significantly less intradermal diffusion than isosulfan blue
      dye, but the carbon left a permanent mark on the skin. No toxicity or side effect
      associated with the use of carbon dye was observed. CONCLUSION: Carbon dye allows
      histopathologic confirmation of sentinel lymph nodes identified by isosulfan blue
      dye.

PMID- 10418594
TI  - The incidence and nature of surgical adverse events in Colorado and Utah in 1992.
AB  - BACKGROUND: Despite more than three decades of research on iatrogenesis, surgical
      adverse events have not been subjected to detailed study to identify their
      characteristics. This information could be invaluable, however, for guiding
      quality assurance and research efforts aimed at reducing the occurrence of
      surgical adverse events. Thus we conducted a retrospective chart review of 15,000
      randomly selected admissions to Colorado and Utah hospitals during 1992 to
      identify and analyze these events. METHODS: We selected a representative sample
      of hospitals from Utah and Colorado and then randomly sampled 15,000
      nonpsychiatric discharges from 1992. With use of a 2-stage record-review process
      modeled on previous adverse event studies, we estimated the incidence, morbidity,
      and preventability of surgical adverse events that caused death, disability at
      the time of discharge, or prolonged hospital stay. We characterized their
      distribution by type of injury and by physician specialty and determined
      incidence rates by procedure. RESULTS: Adverse events were no more likely in
      surgical care than in nonsurgical care. Nonetheless, 66% of all adverse events
      were surgical, and the annual incidence among hospitalized patients who underwent
      an operation or child delivery was 3.0% (confidence interval 2.7% to 3.4%). Among
      surgical adverse events 54% (confidence interval 48.9% to 58.9%) were
      preventable. We identified 12 common operations with significantly elevated
      adverse event incidence rates that ranged from 4.4% for hysterectomy (confidence
      interval 2.9% to 6.8%) to 18.9% for abdominal aortic aneurysm repair (confidence
      interval 8.3% to 37.5%). Eight operations also carried a significantly higher
      risk of a preventable adverse event: lower extremity bypass graft (11.0%),
      abdominal aortic aneurysm repair (8.1%), colon resection (5.9%), coronary artery
      bypass graft/cardiac valve surgery (4.7%), transurethral resection of the
      prostate or of a bladder tumor (3.9%), cholecystectomy (3.0%), hysterectomy
      (2.8%), and appendectomy (1.5%). Among all surgical adverse events, 5.6%
      (confidence interval 3.7% to 8.3%) resulted in death, accounting for 12.2%
      (confidence interval 6.9% to 21.4%) of all hospital deaths in Utah and Colorado.
      Technique-related complications, wound infections, and postoperative bleeding
      produced nearly half of all surgical adverse events. CONCLUSION: These findings
      provide direction for research to identify the causes of surgical adverse events
      and for targeted quality improvement efforts.

PMID- 10418595
TI  - Quality in surgery: from outcomes to process--and back again.

PMID- 10418593
TI  - Inhibiting early activation of tissue nuclear factor-kappa B and nuclear factor
      interleukin 6 with (1-->3)-beta-D-glucan increases long-term survival in
      polymicrobial sepsis.
AB  - BACKGROUND: Recent data implicate the activation of nuclear factor-kappa B (NF
      kappa B) and nuclear factor interleukin 6 (NF-IL6) as important steps in the
      pathophysiologic mechanisms of adult respiratory distress syndrome and systemic
      inflammatory response syndrome. METHODS: This study evaluated the effect of
      immunomodulating polysaccharides on transcription factor activation, cytokine
      expression, and mortality in a murine cecal ligation and puncture (CLP) model.
      ICR/HSD mice were treated with glucan (50 mg/kg) 1 hour before or 15 minutes
      after CLP. Liver and lung tissue were harvested at 3 hours and mortality trends
      were observed for 20 days. RESULTS: CLP increased liver and lung NF-kappa B and
      NF-IL6 nuclear binding activity as well as tumor necrosis factor-alpha and
      interleukin 6 messenger RNA levels at 3 hours. Pretreatment or posttreatment with
      glucans inhibited tissue NF-kappa B and NF-IL6 nuclear binding activity and
      tissue cytokine messenger RNA levels. Prophylaxis with glucan phosphate or
      scleroglucan increased (P < .001) long-term survival (20% CLP vs 65% glucan
      phosphate, 75% scleroglucan). Posttreatment with glucan phosphate also increased
      (P < .05) long-term survival (20% vs 65%). CONCLUSIONS: Pretreatment or
      posttreatment with biologic response modifiers decreased tissue transcription
      factor nuclear binding activity and cytokine message in liver and lung of septic
      mice. Inhibiting early transcription factor activation and cytokine message
      expression correlates with improved outcome in polymicrobial sepsis as denoted by
      increased long-term survival.

PMID- 10418596
TI  - Beyond the Trendelenburg position: Friedrich Trendelenburg's life and surgical
      contributions.
AB  - Friedrich Trendelenburg (1844-1924) was a giant figure in the formative years of
      modern surgical practice. His name lives on in the Trendelenburg position, a
      pelvis-up, head-down position that is of great use in surgical practice. That
      position, however, was certainly well known before Trendelenburg and the linkage
      of his name was by no means the greatest of Trendelenburg's achievements.
      Trendelenburg was a world class surgeon, innovator, and educator who made novel
      advances that spanned the entire range of surgical practice.

PMID- 10418597
TI  - The advent of antibiotics: episodes from the early days of the "miracle drugs".

PMID- 10418598
TI  - Pyoderma gangrenosum: an idiopathic case and recurrence after surgery.

PMID- 10418599
TI  - Gastroduodenal boari flap for bile duct replacement.

PMID- 10418600
TI  - Teratoma in the region of adrenal gland: a unique entity masquerading as
      lipomatous adrenal tumor.
AB  - BACKGROUND: The aim of this study was to establish the clinical and pathologic
      aspects of 3 atypical lipomatous lesions in the region of the adrenal gland.
      METHODS: Three young Chinese patients (ages 18, 18, and 37 years) were seen for
      nonspecific back pain. Radiologic examination revealed a lipomatous lesion in the
      region of the adrenal gland, and hormonal assessment was normal. Calcification
      was noted in 2 of the 3 lesions. Adrenalectomy was performed because of the size
      (diameter 7.5, 10, 11 cm) of the tumors with suspected local symptoms. RESULTS:
      On gross examination 2 tumors were cystic and 1 was solid. In all 3 patients the
      diagnosis was mature teratomas. The tumors were composed of mature tissues
      arising from more than 1 germinal layer. There was no evidence of immature
      elements or malignancy. Adipose tissue was the predominant component in the
      tumors. There was no evidence of recurrent diseases in all these patients during
      follow-up. CONCLUSIONS: To our knowledge, this is the first report of teratomas
      occurring in the adrenal region. Teratoma should clinically and radiologically be
      included in the differential diagnoses of lipomatous adrenal lesions. Excision of
      the teratoma is advocated.

PMID- 10418602
TI  - "Spontaneous" perforation of the common bile duct.

PMID- 10418601
TI  - Tumoral calcinosis regression after subtotal parathyroidectomy: a case
      presentation and review of the literature.

PMID- 10418603
TI  - "Spontaneous" perforation of the common bile duct.

PMID- 10418604
TI  - [The ophthalmologist, man of culture].

PMID- 10418605
TI  - [The role of the sympathetic system in ocular pathology].
AB  - Neurovegetative system consist of preganglionar fibre from neural tube and
      postganglionar from neural crest. We examined 13 patients with Fuchs' syndrome.
      The first sign was heterochromia, followed by keratic precipitates, pathological
      cataract and finally secondary glaucoma. The cause of Fuchs' syndrome was the
      damage of superior cervical ganglion. We studied 4 cases of Claude Bernard
      Horner's syndrome through damages of preganglionar sympathetic system, in 3 cases
      because of laterocervical neoplasia and in the last case through brachial plexus
      damages.

PMID- 10418606
TI  - [Glaucomatous optic neuropathy. Its etiopathogenetic aspects; the therapeutic
      consequences].
AB  - In recent years, glaucoma is considered a progressive, primitive, intrinsic
      neuropathy, associated with a disease of the corneoscleral trabeculum. After a
      short recall of the anatomy and microvascular physiology of the optic nerve, we
      mention the main etiopathogenic hypothesis, insisting upon the significance of
      the optic nerve blood flow abnormalities. We discuss then the possible existence
      of an autoregulation system of blood flow at the level of the optic nerve and the
      main factors which may be involved in the optic nerve perfusion. In the end, we
      present some therapeutical consequences, outlining the future expectations.

PMID- 10418607
TI  - [The eye and kidney diseases].
AB  - The study points out the main conditions in which the ocular lesions are
      associated with the renal ones. These conditions are grouped as follows: 1.
      Ocular complications of the renal disorders, hemodialysis and renal
      transplantation. 2. General disorders with simultaneous ocular and renal lesions.
      3. Oculo-renal syndromes.

PMID- 10418608
TI  - [Corneal ulcerative lesions in type-I immediate hypersensitivity].
AB  - The vernal keratoconjunctivitis (KCV) is included within the category of the
      hypersensitiveness diseases, the immunopathological mechanism which causes the
      disease being represented by a type-I hypersensibility reaction. The mechanism
      which determines the appearance of the corneal lesions isn't entirely cleared up,
      but there are however some pathogenic links which have been already deciphered.
      The type I hypersensibility reaction is taking place within two stages: stage I
      the stage of the sensitizing contact and stage II the stage of the unleashing
      contact. During the first stage, the Langerhans cells take over and process the
      allergen, exhibiting on their surface only the antigenic part. The Langerhans
      cells interact with the T helper native cells (Tho), cells from which there will
      result the predominantly differentiated Th2 subtype. The Thz cells will activate,
      by means of the interleukines, the B cells (which produce the IgE), the mast
      cells and the eosinophilic cells. During the second stage, the allergen is coming
      into contact with the IgE specific antibodies, which are fastened on the mast
      cells membrane, generating the opening of their granules. The result of this
      evolution is represented by the unleash of vasoactive mediators, own enzymes,
      chemical mediators (among which there is also the eosinophilic chemotactic factor
      ECFA). The latter contributes to the infiltration of the epithelial and of the
      subepithelial tissue with eosinophilic cells. The major basic protein (PBM), one
      of the proteins released from the eosinophilic cells' big granules, plays a major
      pathogenic role in the production of the corneal ulcer, by means of its direct
      cytotoxic effect and also by means of inhibiting the migration of the epithelial
      corneal cells. The role of the mast cells and also the role of the neutrophile
      cells within the framework of the pathogenesis of the ulcer is disputable,
      because some specific enzymes tryptase, respectively elastase--have been found
      within the debris of the corneal ulcer. The allergic keratoconjunctivitis (KCA)
      represents the ocular manifestation of the systemic hypersensitiveness. In the
      beginning the immunopathogenic mechanism which causes the lesions is represented
      by a type-I hypersensibility reaction, but during its evolution, the
      characteristic histopathological changes (chronic granulomas, perivascularitis,
      subendothelial fibrosis) are suggesting a complex immunoregulatory disfunction.

PMID- 10418609
TI  - [Paranystagmic ocular dyskinesias].
AB  - In the paper there are described and systematised semeiologically the
      paranystagmic eye dyskinesias. Their neuro-ophthalmological significance and
      their diagnostic value are discussed. Although there is a large semiological
      diversity, they signify the sufferance of the cerebellum or the brainstem or of
      both.

PMID- 10418610
TI  - [The use of viscoelastic compounds in cataract surgery].
AB  - The viscoelastic substances are very useful generally in cataract surgery, but
      absolutely useful in phacoemulsification. In present is used for viscoelastic
      compounds two terms that assemble the rheologic and physics-chemical properties:
      is said about the viscoelastic substance that is cohesive and dispersive
      (respective cohesivity or dispersivity property). Thus both types of viscoelastic
      substances--cohesive and dispersive--is used, sequentially, in one system. This
      double technique provides a fluid, heterogeneous work environment, which differ
      from the other techniques that use only one viscoelastic substance and provide a
      fluid, homogeneous work environment.

PMID- 10418611
TI  - [The polymerase reaction--PCR--a new diagnostic method in herpetic keratitis].
AB  - In the short history of molecular biology the emergence of a new technique--PCR
      (polymerase chain reaction)--has transformed the way we approach fundamental and
      clinical ophthalmologic problems. Its principle consists in the capacity of
      amplification of specific segments of DNA. In this paper we summarize the way in
      which PCR can identify herpetic DNA in cornea. The method is precise, the sample
      need not be chemical pure and the result is obtained in a few hours.

PMID- 10418612
TI  - [The functional results in primary surgical cataract associated with diabetes
      mellitus].
AB  - The purpose of this study is to display the influence of diabetes on the course
      of the operation, postoperative complications and functional results in operated
      primary cataract. MATERIAL AND METHODS: We performed a study on 42 eyes with
      cataract and diabetes operated in the University Eye Hospital from Cluj-Napoca
      during 1992-1996. RESULTS: From the 42 cases, 32 had diabetes non-insulin
      dependent. Background diabetic retinopathy was present in only 16 cases (38%). In
      33 cases it was performed EEC + PC - IOL. Postoperative, in 38 cases it was
      striate keratitis, in 21 eyes pigmentary migration and in 3 cases uveitis. As
      late postoperative complications we had 5 secondary cataract and 1 retinal
      detachment. Functional results were in majority cases between 0.1-0.3.
      CONCLUSIONS: Diabetes do not influence the course of planned extracapsular
      extraction with PC-IOL, which is the best choice for the patients with cataract
      and diabetes. Functional results depends on the presence of diabetic retinopathy.

PMID- 10418613
TI  - [The extension of retinoblastoma into neighboring structures].
AB  - Fourteen cases with retinoblastoma has been histologic studied. In eleven cases
      of them has been observed the invasion in the neighbour structures following the
      tumoral mass development: four cases in the vitreous, one case in the vitreous
      and the choroid, sclera and the optic nerve, one case in the vitreous choroid and
      optic nerve, two cases in the optic nerve. The tumoral invasion in the neighbour
      structures was observed only at the undifferentiated retinoblastoma.

PMID- 10418614
TI  - [Antitumor radiotherapy in ophthalmology].
AB  - The paper presents the sources, the radiations and the clinical methods, as well
      as the technique used for the treatment of the neoplastic ocular diseases. At the
      same time, it is underlined the significance of the radiotherapy as the only
      efficient therapeutically mean for a certain ocular tumoral disease.

PMID- 10418615
TI  - [Controversies connected with the therapeutic approach in palpebral
      epitheliomas].
AB  - OBJECTIVE: We try to clarify some controversies related to the palpebral
      epitheliomas, controversies related to the therapeutical applied attitude
      (surgery, radiotherapy or the association of the two therapeutical methods), to
      the indications and contraindications of their application. MATERIAL AND METHOD:
      It is a review study of the Military Hospital and Oncologic Institute Cluj-Napoca
      casuistry between 1984-1994, which comprises 244 patients with palpebral
      epitheliomas, histologically confirmed. This casuistry was followed taking into
      consideration the age, sex, histological type, anatomo clinical presentation, TNM
      clinical stage, the localisation of the tumor, the type of the applied treatment,
      complications, healing and the therapeutical failures. RESULTS: The efficiency of
      the applied therapeutical methods was considered related to their obtained
      results to the therapeutical failures. The rate of healing at 5 years was 90.57%
      for the whole group. CONCLUSIONS: 1. The two methods of treatment seems to be
      equally sensible concerning the therapeutical efficiency in stages I and II. 2.
      In the advanced stages (III and IV) our option is for mixing the two methods. An
      optimum treatment for each patient is possible only if there is a close
      cooperation between the ophthalmologist-surgeon, plastic surgeon and the
      radiation oncologist.

PMID- 10418616
TI  - [Carcinomas of the inner canthus--combined treatment].
AB  - It is described a therapeutical protocol which combines surgery and radiotherapy
      in a "particular" way for carcinomas of the medial palpebral canthus. This
      consist of a surgical excision of tumors without covering the denuded area after
      2-3 weeks of external radiotherapy--Chaoul type.

PMID- 10418617
TI  - [The anterior segment ischemia syndrome].
AB  - Starting from a clinical case, the paper presents a rare complication of the
      strabismus and retinal detachment surgery: the anterior segment ischemia
      syndrome. In this context, we discuss the clinical and pathogenetic circumstances
      of apparition, underlining the great importance of primary prophylaxis.

PMID- 10418618
TI  - [Anterior ischemic optic neuropathy after systemic hypotension and anemia].
AB  - There are shown two cases of anterior ischemic optic neuropathy produced by
      arterial hypotension and anemia, due to a gastric bleeding and a hemodialysis
      treatment. Arterial hypotension can obliterate the optic nerve arteries, because
      of a weak haemodynamic balance previously affected, modifying the perfusion
      pressure at this level. The acute or chronic haemorrhages can produce anterior
      ischemic optic neuropathy in patients with vascular risk factors, by means of
      arterial hypotension and secondary anemia. Hemodialysis can produce anterior
      ischemic optic neuropathy through secondary arterial hypotension. It is necessary
      an emergency therapy to reuse arterial blood pressure and rearrange the
      hemodynamic balance.

PMID- 10418619
TI  - [Glial hamartoma of the papilla].
AB  - There are shown two cases of glial hamartoma of the optic nerve head. In both
      cases the retinal vessels are tortuous around the optic nerve disc, and the
      choroid shows a brown colour, like a choroidal naevus. Histologically this kind
      of tumors of the optic nerve head are astrocytomas and they are met specially
      under the age of twenty. The glial hamartoma of the optic nerve head is a rare
      disease.

PMID- 10418621
TI  - [Ergo-ophthalmologic problems of electronic display devices].
AB  - The paper approaches the problem of activity in front of a display. The authors
      show the compounds of an electronic device, theirs effects on visual acuity of
      the worker and the condition that are needed for visual comfort. Ergo
      ophthalmologically it is important to examine periodically all the employers that
      use displays.

PMID- 10418622
TI  - [The mechanism of cataract formation in persons with beta-thalassemia].
AB  - We examined 63 patients with beta-thalassemia whose ages range from 7 to 57
      years. Lens opacities were presented in 14 patients--22%. The period these
      persons had transfusions and were submitted to iron chelating drug--deferoxamine
      and the concentration of there serum ferritin in the last seven years were noted.
      Comparing persons with identical ages and transfusion periods we found that
      patients who were submitted to less chelation therapy patients which started
      these therapy later and patients with higher values of mean ferritin or with
      significant picks were in danger to developed cataract. Patients younger of 10
      years old didn't developed cataract despite high values of ferritin. All patients
      after 30 did have lens opacities.

PMID- 10418623
TI  - [CMV retinitis--"the lightning that announces a storm"].
AB  - After a theoretic presentation, the authors show the results of a study on 11
      patients with cytomegalovirus retinitis. We observed the slowing of the evolution
      of the retinal lesions. Of 11 patients, 8 comes the first time to the physician
      for ocular symptoms. The CMV retinitis may predict the presence of HIV infection.

PMID- 10418624
TI  - [Oculomotor disorders due to general causes].
AB  - The paper presents the clinical course and the problems appeared in making
      positive and etiological diagnosis for three cases of oculomotor disorders with
      diplopia, in adult patients. These are two cases of thyroid ophthalmopathy and
      one of myasthenia gravis. Atypical evolution in one case of thyroid
      ophthalmopathy and in that one with myasthenia gravis, made difficult the
      diagnosis and requested complex investigations.

PMID- 10418625
TI  - [Genetic studies in retinoblastoma].
AB  - For a fifteen year period it has been hospitalized in Ophthalmologic Clinic from
      Craiova nineteen cases with retinoblastoma, seventeenth of them have been
      sporadic forms and two hereditary forms. It was found chromosomal changes at the
      two hereditary forms, consisting by a deletion of the long arm of chromosome 13.

PMID- 10418626
TI  - [Vascular risk factors in glaucoma].
AB  - The study realised in the Eye Clinic of the Central Military Hospital during
      February 1995-November 1997 analyses the impact of the vascular risk factors on
      the evolution of the primary glaucoma. The group consists in 533 patients which
      primary open angle glaucoma, from which 90.6% patients with primary open angle
      glaucoma and 9.3% with normal tension glaucoma. The assessment of the patients in
      order to identify the vascular risk factors it was performed on the basis of
      anamnestic questionnaire, following: degenerative vasculopathies, spastic
      vasculopathies, arterial hypotension and coronary insufficiency. 70.5% of the
      patients presented minimum one vascular risk factor. In the case of the patients
      with primary open angle glaucoma, we found a high frequency of the degenerative
      vasculopathies. In the patients with normal tension glaucoma the most frequent
      factor were: arterial hypotension and spastic vasculopathies. The coronary
      insufficiency had equal distribution in the primary open angle glaucoma and
      normal tension glaucoma. The parameters of the disease were affected faster in
      the patients with vascular risk factors. The outcomes of the study allow to
      estimate that the screening of the vascular risk factors has a distinct
      importance in the evolution and accurate treatment of glaucoma.

PMID- 10418627
TI  - [The results of multimodal treatment in retinoblastoma].
AB  - The paper is a retrospective study about complex treatment (surgery, chemotherapy
      and radiotherapy) in a group of 25 patients with retinoblastoma. The best results
      were in patients with early diagnosis, who came soon after surgery for
      chemotherapy and radiotherapy. Non presentation for chemotherapy and radiotherapy
      was the main cause of therapeutical fail.

PMID- 10418628
TI  - [The evolution of corneal astigmatism after cataract surgery].
AB  - The study is a prospective one based on the observations of 186 eyes. The
      preexisting astigmatism was measured and the patients were divided in two main
      groups based on this astigmatism: by-the-rule and against-the-rule astigmatism. I
      evaluated the effects on the corneal astigmatism of different types of cataracts
      surgical procedures. The measurements sustain the results published in the
      specialty literature. By-the-rule astigmatism increases post-operatively and
      decreases in time, passing in an against-the-rule astigmatism. Against-the-rule
      astigmatism passes into an by-the-rule one and in the final he regains his
      previous type.

PMID- 10418629
TI  - [The efficacy of Charleux's peripheral iridectomy].
AB  - The simplicity of Charleux's technique for peripheral iridectomy is underlined.
      In a lot of 15 eyes with acute angle closure glaucoma, the i.o.p. after surgery
      was under 21 mm Hg when the attack lasted less than 48 hours. In a second group
      of 20 eyes with occludable angle/congener eyes suffered attacks/peripheral
      iridectomy with Charleux's technique prevented acute angle closure/56 months of
      postoperative observation.

PMID- 10418630
TI  - [The tomographic diagnosis of Basedow's orbitopathy].
AB  - The inflammatory and infectious circumstances involving the orbit are known as
      'orbitopathies' Considering the progress of immunology and imagistical
      investigations, it has been proposed a new classification of these entities. This
      classification divides the orbithopathies in specific and nonspecific. This paper
      brings up the case of a 65 year old female patient, showing unilateral proptosis
      with progressive evolution for about one year. The local examination and
      paraclinical investigations (computerised tomography and thyroid gland
      scintigram) sustained the diagnosis of Basedow disease. The ophthalmopathy in
      Basedow disease is a specific orbital involvement. Considering it's high rate of
      occurrence among the exophthalmic eyes (10%) it rests a severe disease, with a
      not yet fully understood physiopathology and a controversial treatment. The
      basedowian ophthalmopathy is, as well, an autoimmune disease, which requires the
      presence of T lymphocytes at the level of the orbital tissue. The computerised
      tomography gives us a direct visualisation of the enlarged muscles in
      hyperthyroidism (the muscles can increase 8 times their normal size), that is why
      we have to recommend it every time we are facing a patient with proptosis,
      especially unilateral.

PMID- 10418631
TI  - [Cystic iris tumors].
AB  - The paper approaches a rare ophthalmological pathology, cystic iris tumors. The
      authors show two clinical cases treated in the Clinic of Ophthalmology,
      Timisoara. In both cases the clinical and paraclinical diagnosis was confirmed by
      postoperator anatomopathological examination.

PMID- 10418632
TI  - [Exophthalmos in giant cerebral arteriovenous vascular malformations].
AB  - We present the most important ophthalmologic signs related to the
      angiocinematographic aspects in two patients presenting giant arteriovenous
      malformations in the frontal part of the brain. In both cases the first clinical
      sign of the disease was unilateral proptosis associated with scleroconjunctival
      arteriovenous malformation. In the presented cases we could not establish any
      relationship between the intensity of the proptosis, the scleroconjunctival
      vascular malformation and the size of the intracranial arteriovenous
      malformation. We point on the importance of the proptosis associated with
      scleoconjunctival vascular malformation representing the first signs in
      intracranial arteriovenous malformations.

PMID- 10418634
TI  - [Mandibulofacial dysostosis].
AB  - Also known as Treacher-Collins or Franceschetti-Zwahlen-Klein syndrome, the
      mandibulofacial dysostosis is characterized by bilateral involvement of facial
      structures, including malar and mandibular hypoplasia, underdeveloped zygomatic
      bone, antimongoloid slant and external and middle ear anomalies. The syndrome is
      inherited as an autosomal dominant trait with incomplete penetrance and variable
      expressivity. The authors report the case of a 19-years-old patient with
      characteristic cranio-facial malformations.

PMID- 10418633
TI  - [A case of an incomplete Urrets-Zavalia syndrome as a result of operated
      keratoconus].
AB  - The article presents a case of incomplete Urrets-Zavalia syndrome after perforant
      corneal transplant for advanced keratoconus, as well as some considerations about
      the technique of perforant keratoplasty and the pre/postoperative cares.

PMID- 10418635
TI  - [Retinopathy of prematurity].
AB  - The paper presents theoretical aspects about the pathogenesis, diagnosis and
      treatment of the retinopathy of prematurity.

PMID- 10418636
TI  - [All that the anesthesiologist should be for you in 1998].
AB  - An original question. Following a recent questionnaire of the Ministry of Public
      Health we are often stressed, tried, we work to hard. We arrive before the
      surgeons, remain the defender of patient during the OR stay. Outside of the OR we
      are fighters against "Pain". We do protect the organism of the patient against
      the consequences of the surgical aggression. The physiology in a totality and the
      maintenance of the vital function of the patient is our major concern. The
      Anaesthetist reanimator will focus on the essential. The author also discusses
      the "qualification" and activities of a Emergency room or Intensive Care
      specialty. This evolution will limit our activity. The value of team work is
      stressed the anaesthesist focus on the essential, the patient, his life ... He is
      a "Doctor"

PMID- 10418637
TI  - Our national training and postgraduate programs. What do we need for 2010?

PMID- 10418638
TI  - Views on the future anesthesia working environment.

PMID- 10418639
TI  - Quality of care in anaesthetic practice: how should it be measured?

PMID- 10418640
TI  - The best way to defend our profession, intra murally and beyond.

PMID- 10418641
TI  - Anaesthesia for day care surgery, patient selection, evaluation, preoperative
      preparation and selection of drugs.
AB  - Paediatric patients are a challenge to the anaesthetist because of their specific
      differences in behaviour, physiology, pharmacology, congenital anomalies and
      pathology. The number of day care paediatric patients show a steady increase. It
      is important that anticipated anaesthetic problems are solved or prevented by a
      good preoperative evaluation and preparation. Adequate psychological preparation
      and parental presence on induction and recovery have been shown to be a very
      good, if not the best premedication especially for toddlers. Relaxation of fluid
      restriction has led to more cooperation of the paediatric patient. Provided
      physicians, anaesthetists, surgeons and nurses share the same positive view on
      day care surgery, the facility will be greatly appreciated by both children and
      their parents.

PMID- 10418642
TI  - Why and how we will monitor the state of anesthesia in 2010?

PMID- 10418643
TI  - Miss-'n-mix and mimics.

PMID- 10418644
TI  - The analgesic effect of preoperative administration of propacetamol, tenoxicam or
      a mixture of both in arthroscopic, outpatient knee surgery.
AB  - A prospective, randomized, double-blind, placebo-controlled, comparative study
      was undertaken to assess the efficacy of the preemptive use of propacetamol,
      tenoxicam or the combination of both in arthroscopic, outpatient surgery of the
      knee. One hundred patients aged 18 to 65 years, ASA 1-2, scheduled for
      arthroscopy were randomized to receive propacetamol 30 mg/kg i.v. (repeated after
      6 hours), tenoxicam 0.5 mg/kg i.v. (max. 40 mg), the combination of both or
      placebo one hour prior to a standard anesthetic. There were no differences with
      regard to total dose opioid consumption, sedation scores and side effects in the
      four groups.

PMID- 10418645
TI  - Slow EEG-power spectra correlate with haemodynamic changes during laryngoscopy
      and intubation following induction with fentanyl or sufentanil.
AB  - We studied nociception-associated arousal following laryngoscopy and intubation
      in patients scheduled for elective open heart surgery, using EEG power spectra
      and hemodynamics. Either fentanyl (7 micrograms/kg; n = 30) or sufentanil (1
      microgram/kg; n = 30) were given in a randomized fashion to induce anesthesia in
      heavily premedicated patients, followed by pancuronium bromide (100
      micrograms/kg). EEG-power spectra (delta, theta, alpha, beta) as well as mean
      arterial blood pressure (MAP) and heart rate (HF) were measured at the following
      end-points: before the induction of anesthesia (control), 1 and 10 minutes after
      laryngoscopy and intubation (L & I). Linear regression analysis was computed to
      determine which of the EEG power spectra was most sensitive to detect
      insufficient blockade of nociceptive-related arousal when correlated with
      haemodynamics. In the fentanyl group the change in HF closely correlated with the
      decrease of power in the slow delta- and theta-domain (r2 = 0.98 and r2 = 0.89
      respectively) of the EEG. The change in MAP also closely correlated with a
      decrease in the slow delta- and theta-domain (r2 = 0.97 and r2 = 0.99
      respectively). There was little correlation in regard to spectral edge frequency
      (SEF) and HF and MAP changes (r2 = 0.36 and r2 = 0.12 respectively). In the
      sufentanil group the change in HF correlated closely with an increase of power in
      the fast alpha and a decrease in the slow theta-domain (r2 = 0.91 and r2 = 0.98
      respectively) of the EEG. The changes in MAP closely correlated with an increase
      in the fast alpha-band a decrease in the slow theta-domain (r2 = 0.98 and r2 =
      0.73 respectively). Also there was little correlation of SEF with HF and MAP
      changes (r2 = 0.09 and r2 = 0.02 respectively). Among the EEG-spectra, reduction
      of power in the slow delta- and theta-bands are the most sensitive parameters to
      determine insufficient antinociception of opioids commonly used for the induction
      in cardiac anesthesia. Increase of power in the alpha-band seems to be closely
      correlated with cortical reactivation and reduction of hypnosis, while a
      reduction of power especially in the deltabut more so in the theta-band of the
      EEG reflects nociception related arousal.

PMID- 10418646
TI  - The impact of nitrous oxide on postoperative nausea and vomiting after desflurane
      anesthesia for breast surgery.
AB  - A recent meta-analysis showed that omitting N2O significantly reduced
      postoperative vomiting (POV) compared with a N2O regime. Our study was designed
      to evaluate the effect of the combination of desflurane with N2O versus
      desflurane alone on postoperative nausea and vomiting (PONV) in a subgroup of
      female patients and PONV was considered as the primary endpoint. After approval
      of the local Ethics Committee and informed consent 60 female in-patients (ASA I &
      II), aged 18-65 y, scheduled for breast surgery with a duration of 1-3 h were
      included. Obese patients or patients with a history of PONV and motion sickness
      were excluded. No prophylactic anti-emetic therapy was allowed during the study.
      Patients received a standardized anesthetic technique consisting of propofol for
      induction, vecuronium and fentanyl for intubation, followed by desflurane with or
      without N2O (randomisation list) and fentanyl supplements if required for
      maintenance of anesthesia. At the end of anesthesia PONV was recorded during 24 h
      in different periods. There were no significant differences between the groups
      with respect to demographic data and duration of anesthesia. In addition, there
      were no significant differences in the amount of intraoperative fentanyl or
      postoperative narcotics. The incidence of PONV was significantly higher in the
      group of patients receiving desflurane in N2O-O2 mixture compared with the group
      receiving desflurane in AIR-O2 mixture. The combination of desflurane with N2O in
      female patients undergoing breast surgery is associated with a significantly
      higher incidence of PONV and a higher need of antiemetic drugs, when compared to
      a N2O free regime.

PMID- 10418647
TI  - Assessment of the postoperative residual curarisation using the train of four
      stimulation with acceleromyography.
AB  - The aim of this study was to measure the incidence of patients with train of four
      ratio < 0.9 in the immediate postoperative period using acceleromyography. At
      arrival in recovery room, 257 patients were enrolled. Train of four ratio was
      assessed at the adductor pollicis using TOF-GUARD INMT apparatus. Patients were
      divided in two groups according to TOF ratio < (group 1) or > (group 2) to 0.9.
      Demographic variables, dose (mg), dose/weight ratio (mg.kg-1) of atracurium and
      surgery duration (min) were registered. There was no difference in demographic
      variables, duration of surgery (100.90 +/- 67.38/94.83 +/- 62.42 min), number of
      incidence reversal of neuromuscular block. Patients in group 1 (n = 72) received
      a higher dose (54.58 +/- 38.03/41.43 +/- 19.47 mg) of atracurium compared to
      group 2 (n = 176). Thirty percent of patients presented a train of four ratio <
      0.7 and 13% < 0.9. TOF-GUARD INMT was easy to use.

PMID- 10418648
TI  - Use of Anaesthesia Simulator: initial impressions of its use in two Belgian
      University Centers.
AB  - 459 trainees in Anesthesia and Intensive Care Medicine, accompanied by fully
      certified specialists from several Belgian University Hospital Centers, spend at
      least a 3 hour session at the Anaesthesia Simulator. Each session comprises three
      segments: the briefing, the simulation session and the debriefing. The use of
      simulations allows significant individualization of the learning experience. The
      simulator helps to develop the capacity to understand, explain a phenomenon and
      to resolve problems. Another important aspect of the use of the simulator
      involves the trainee's "right to make mistakes". This allows to widen the
      spectrum of executional situations, and decreases the number of dangerous
      situations. Two University Centers (ULg and UCL) have each organized simulator
      sessions despite some differences in their approaches. The simulator is a
      teaching tool worthy of an obligatory role in the most up-to-date training
      possible of modern anesthesiologist. This is all the more important given that
      the current practice of anesthesiology is so complex that any error could cost a
      human life.

PMID- 10418649
TI  - Lower limb exsanguination and embolism.
AB  - We report a case of fatal pulmonary embolism during lower limb exsanguination in
      orthopaedic surgery. A 76-year-old woman underwent an open fixation of an
      external femoral condyle fracture one day after injury. Subarachnoidal
      anaesthesia was performed and Esmarch compression bandages were applied in
      preparation for tourniquet ischaemia. At this time, the patient lost
      consciousness, became apneic and collapsed. Resuscitation procedures were
      instituted and transoesophageal echocardiography revealed pulmonary embolism. In
      spite of haemodynamic support and thrombolytic therapy, the patient died.
      Postmortem examination revealed multiple thromboemboli of recent origin in the
      right heart cavities, in the pulmonary arteries and in the popliteal and tibial
      veins of the injured leg. Preventive, diagnostic and therapeutic options of this
      catastrophic event and indications of pulmonary embolectomy are discussed.

PMID- 10418650
TI  - Treatment for postdural puncture headache associated with late postpartum
      eclampsia.
AB  - Postdural puncture headache (PDPH) is the most common complication of accidental
      or deliberate dural puncture. It also occurs after epidural or spinal analgesia
      for labor and delivery. Treatment may be conservative with analgesics and/or
      caffeine. Definitive treatment can be accomplished with an epidural blood patch
      (EBP). We present a case of postpartum convulsions which were temporally related
      to a caffeine infusion and an EBP.

PMID- 10418651
TI  - Music therapy.
AB  - Nurses have used music as an intervention for many years. A sizeable number of
      investigations to determine the efficacy of music in managing pain, in decreasing
      anxiety and aggressive behaviors, and in improving performance and well-being
      have been conducted by nurses and other health professionals. Nursing and non
      nursing research reports published between the years 1980-1997 were reviewed.
      Great variation existed in the type of musical selection used, the dose of the
      intervention (number of sessions and length exposure), the populations studied,
      and the methodologies used. Overall, music was found to be effective in producing
      positive outcomes.

PMID- 10418652
TI  - Sleep promotion in adults.
AB  - Insomnia is among the most frequent health complaints brought to the attention of
      primary care providers. The prevalence estimates are highest in women, older
      adults, and patients with medical or psychiatric disorders. Clinical researchers
      have studied many barriers to sleep as well as some sleep promotion interventions
      for the ill and aging adult. Environmental, personal, and person-environment
      rhythm factors have been identified as correlates of poor sleep. All
      interventions studied by nurse researchers are non-pharmacological and have been
      classified as interventions that (a) create an environment more conductive to
      sleep, (b) relax the sleeper, or (c) entrain the circadian sleep-wake rhythm.
      This chapter summarizes results of published research on correlates of poor sleep
      and interventions to promote sleep. The chapter includes the relevant studies
      conducted by researchers in related disciplines as well as nurses' research. The
      arcs software package was used to facilitate summarization of intervention
      studies. It was concluded that correlates of poor sleep are well described, but
      theories of sleep promotion are not well explicated. Also, the research base for
      sleep promotion interventions for use with clinical populations other than those
      with chronic insomnia is sparse. Gaps in knowledge are identified and conceptual
      and methodological issues are discussed as the basis for future directions in
      sleep promotion research.

PMID- 10418653
TI  - Guided imagery interventions for symptom management.
AB  - For the past several decades, papers in the nursing literature have advocated the
      use of cognitive interventions in clinical practice. Increasing consumer use of
      complementary therapies, a cost-driven health care system, and the need for
      evidence-based practice all lend urgency to the validation of the efficacy of
      these interventions. This review focuses specifically on guided imagery
      intervention studies identified in the nursing, medical and psychological
      literature published between 1966 and 1998. Included were 46 studies of the use
      of guided imagery for management of psychological and physiological symptoms.
      There is preliminary evidence for the effectiveness of guided imagery in the
      management of stress, anxiety and depression, and for the reduction of blood
      pressure, pain and the side effects of chemotherapy. Overall, results of this
      review demonstrated a need for systematic, well-designed studies, which explore
      several unanswered questions regarding the use of guided imagery. These include
      the effects of different imagery language, symptoms for which guided imagery is
      effective, appropriate and sensitive outcome measures, method of delivery of the
      intervention and optimum dose and duration of the intervention, and individual
      factors that influence its effectiveness.

PMID- 10418654
TI  - Patient-centered communication.
AB  - The term patient-centered communication (PCC) has been used to describe a group
      of communication strategies and behaviors that promote mutuality, shared
      understandings, and shared decision making in health care encounters. There is
      evidence to suggest that advanced practice nurse and patients use these
      strategies to co-produce highly individualized clinical discourse. Although the
      communication behaviors associated with PCC have been studied separately, their
      impact as an integrated communications strategy has not been studied. Suggestions
      for developing PCC as a mid-range theory of health care communication
      encompassing other more specific communication concepts are offered.

PMID- 10418655
TI  - Acute pain.
AB  - The review of acute pain describes the problem of unresolved pain and its effects
      on the neural, autonomic, and immune systems. Conceptualizations and mechanisms
      of pain are reviewed as well as theories of pain management. Descriptive studies
      of patient and nurse factors that inhibit effective pain management are
      discussed, followed by studies of pharmacological and nonpharmacological
      interventions. Critical analysis reveals that most studies were atheoretical, and
      therefore, this proliferation of information lacked conceptual coherence and
      organization. Furthermore, the nature and extent of barriers to pain management
      were described, but few intervention studies have been devised, as yet, to modify
      the knowledge, beliefs, and attitudes of nurses and patients that are barriers to
      pain management. Although some of the complementary therapies have sufficient
      research support to be used in clinical pain management, the physiological
      mechanisms and outcomes need to be studied. It is critical at this time to design
      studies of interventions to improve assessment, decision making, attentive care,
      and patient teaching.

PMID- 10418656
TI  - The chronobiology, chronopharmacology, and chronotherapeutics of pain.
AB  - Data for this review of chronobiology, chronopharmacology, chronotherapeutics and
      pain were derived from electronic searches of the medical literature (Medline)
      utilizing both Silver Platter and OVID search engines. Further information was
      obtained from personal conversations with members of the International Society
      for Chronobiology involved in chronopharmacology and pain research and reviews of
      non-Medline-referenced materials and journals such as Chronobiologia and the
      Annual Review of Chronopharmacology. A variety of data from proceedings were
      available, but was not utilized because of their nonreferred status and the
      relative unavailability of such sources; however, peer-reviewed, published
      proceedings have been included in this review. A total of 62 studies were
      identified as relevant to this review of biological rhythms and pain; of these,
      only 6 were conducted by nurses. Studies were broadly categorized by purpose as
      experimental chronobiology in humans (9), experimental chronobiology in animals
      (12), clinical chronobiology (25), chronopharmacology in animals (6),
      chronopharmacology in humans (6), and chronotherapeutic interventions (4). All
      statistically significant findings were reported at the p < 0.05 level.

PMID- 10418657
TI  - Chronic low back pain: early interventions.
AB  - Low back pain is a common and costly social problem. Many of the long term
      outcomes of chronic low back pain (CLBP), such as those related to occupational
      and social function or patient and family coping, are sensitive to nursing
      intervention. To identify potentially productive areas for nursing intervention
      research, studies from 1990 to 1998 were reviewed that investigated (a) potential
      early indicators that acute or subchronic low back pain would result in chronic
      pain and disability, (b) patient perspectives on adaptation to chronic pain, and
      (c) the value of interventions undertaken during the acute and subchronic phases
      of back pain to modify long-term outcomes. Sixteen quantitative studies were
      identified that prospectively investigated the natural history and outcomes of
      low back pain. Six qualitative studies that investigated the perspectives of
      patients with back pain were also identified. Ten randomized clinical trials were
      identified that investigated interventions undertaken during the acute or
      subchronic stages of back pain. Clinical interventions that included advice to re
      engage in activity, support to develop personalized goals, reinforcement for
      healthy gains and appropriate functional activities, and physical conditioning
      exercises tended to be successful in returning patients to work or limiting their
      self-reported disability and pain. Interventions that promoted communication at
      the work-site or modified the patient's job were also successful in promoting a
      faster return to work. Nonetheless, this is a nascent area of research in need of
      improvements related to the selection of appropriate subjects and controls, the
      timing and duration of interventions, and the reliability with which
      interventions are implemented. Furthermore, patients with back pain are most
      likely to benefit when nursing theories about chronic pain are linked to clinical
      intervention research.

PMID- 10418658
TI  - Wandering in dementia.
AB  - In this paper, published research studies addressing the phenomenon of wandering
      in dementia are reviewed. Empirical findings of 108 studies are categorized and
      summarized to reveal dimensions of wandering behavior, significance of wandering
      as a clinical phenomenon, correlates of wandering, and tested intervention
      strategies. Implications for improving methodological rigor of future studies are
      offered and gaps in the current knowledge base are identified.

PMID- 10418659
TI  - Cognitive interventions among older adults.
AB  - This chapter reviews psychoeducational and/or psychosocial interventions designed
      to improve cognitive function in adults without cognitive impairment. Included
      are sections on (a) meta-analyses and other reviews; (b) cognitive aging and
      cognitive improvement; (c) memory training; (d) depression and memory
      improvement; (e) self-efficacy and aging memory; (f) maintenance of gains and
      subject retention; (g) comprehensive memory improvement program; and (h) future
      research. Several aspects of memory training now known to influence outcomes,
      i.e., memory performance, need to be considered in future studies. First, follow
      up instruction (booster sessions) facilitates the use of these newly learned
      memory strategies in elders' everyday lives. Second, elders' memory self-efficacy
      (beliefs and confidence) impacts performance. Third, the inclusion of subjective
      measures in memory training is recommended. Fourth, greater emphasis needs to be
      placed on the modification of participants' attitudes toward aging-related memory
      loss. Fifth, designs must emphasize the long-term outcomes of the memory
      training. Sixth, establishing a relationship between a memory intervention and
      functional ability (IADLs) is the next step in assisting older adults to remain
      independent. If early failure in cognitive ability can be improved through
      intervention, perhaps early decline in functional independence and the need for
      formal services, e.g., nursing home placement, can be delayed.

PMID- 10418660
TI  - Primary health care.
AB  - Primary Health Care (PHC) has been promulgated for over two decades as a global
      strategy for ensuring basic health care for all people. PHC is characterized by
      equity, accessibility, availability of resources, social participation,
      intersectoral community action, and cultural sensitivity. While PHC can be
      discussed as philosophy or a process, it is critical that PHC be understood as a
      community focus in health care that differs from a primary care focus on
      individuals. Capturing PHC components in community-based interventions in order
      to advance the development of a rigorous research base requires a shift in
      thinking about what constitutes acceptable methods and evidence for evaluating
      changes in health care. To this end, the authors of this review discuss
      perspectives and available research that inform practice within multidisciplinary
      teams, highlight the importance of social discourse, and review participatory
      evaluation issues for achieving a working relationship with communities.
      Particular attention is focused on education for nurses' roles in PHC activities
      within implementation models fostering community mobilization and development. An
      action plan is suggested as a means for situating discrete research activity
      within a PHC framework.

PMID- 10418661
TI  - Uncertainty in chronic illness.
AB  - In this chapter, the research on uncertainty in chronic illness is reviewed and
      critiqued. Two theoretical perspectives of uncertainty that can be applied across
      the range of chronic illness are presented. Research on the causes and
      consequences of uncertainty in chronic illness are considered and critiqued. The
      review addresses research on adults and on parents of chronically ill children.
      Conclusions include the areas requiring further investigation.

PMID- 10418662
TI  - Nursing research in Italy.
AB  - Nursing in Italy is achieving a higher academic status as a result of decades of
      efforts in scientific knowledge development. Beginning in the 1980s, Italian
      nurses, supported by researchers from allied disciplines, have begun to design
      and implement research at the local, regional, and national level. This study is
      the first effort ever made to identify the main characteristics of Italian
      nursing research published in Italian journals. The review covers 14 years (1983
      1997). Overall, 240 studies from 11 journals, research reports from books, and
      several conference proceedings have been considered. Inclusion criteria were
      based on quality of research design, considering components such as sampling,
      sample size, and method of data analysis. Each article was analyzed according to
      an interpretive scheme focusing on method of analysis, scientific merit, and
      authorship. Of the 240 studies reviewed, journal articles selected from ten
      Italian journals accounted for 175 (73%), or the majority, of reviewed sources.
      Sixty-five (26%) research reports complete the remaining number. The major areas
      of research identified include nursing practice (43%), nursing education (6%),
      nursing administration and professional issues (34%), and knowledge and
      perceptions in society and nursing (17%). The majority of the research studies
      utilized survey models (47%), including several retrospective and longitudinal
      studies, followed by exploratory or descriptive (36%) and quasi-experimental
      (17%) designs. Many reports failed to identify the method of sampling used in the
      research design. However, of those that did, convenience samples were most often
      used. Random sampling was rarely reported. The majority of studies employed only
      descriptive statistics (i.e., frequency distribution, central tendency,
      variability, contingency tables, and correlation). Only few studies made use of
      advanced statistics for testing hypotheses (parametric and non-parametric tests)
      among which only a low percentage cited reliability testing. In 42% of the
      studies, the authors were represented by a group of nurses. Nurses and physicians
      worked together to author another 30% of the studies. The remaining studies were
      authored by either individual nurses (24%) or nurses and nonmedical professionals
      (4%). Much of the reviewed research has been carried out by nurses who have
      little or no research training.

PMID- 10418663
TI  - [Occupation-specific mode of self injury within the scope of a fictitious
      assault].
AB  - In typical cases self-inflicted injuries in fictitious offences show a
      characteristic pattern of findings with multiple, uniform, and mostly superficial
      skin lesions. If the actors possess special experiences, knowledge or instruments
      -particularly in the field of medicine--the injuries inflicted by themselves may
      have an appearance whose autoaggressive origin is less obvious. The case of a 43
      year-old nurse is reported who was admitted for surgical treatment with two cuts
      in the abdomen extending into the subcutis; she pretended to have been attacked
      by 2 masked men who stabbed her for xenophobic motives. In reality she had
      inflicted the cuts upon herself after applying a local anaesthetic. The necessary
      equipment (Scandicain, disposable syringes, stitch cutter) was taken from her
      place of work. Self-inflicted injuries specific to medical professions, as well
      as fictitious offences with atypical cut- and stab-wounds and the insinuated
      motives of the alleged offenders are discussed.

PMID- 10418664
TI  - [Sudden death after release from police detention].
AB  - 3 fatalities shortly after discharge from police custody are reported. Case 1: A
      55-year old alcoholic was discharged from police custody after taking a blood
      sample under violent conditions and found dead in his flat 2 days later. Cause of
      death: arrhythmia due to acute coronary insufficiency or alcoholic
      cardiomyopathy. Case 2: A 27-year-old alcoholic was met highly intoxicated twice
      in the course of one day, was put in the family's care and was found dead the
      next morning. Cause of death: alcohol/drug intoxication with agonal aspiration.
      Case 3: A 32-year-old man known to be prone to seizures and to become aggressive
      under the influence of alcohol was left by the police in medical care confined to
      a litter in a "hog-tied" fashion with the help of 3 belts. Cause of death:
      cerebral hypoxia after respiratory and cardiac arrest of unknown reason. A causal
      relationship with positional restraint is discussed. The cases reported underline
      the duty of the police to examine prior to discharge from custody with the
      appropriate lot of care whether the person held in custody has recovered from the
      helpless state due to disease, injury or intoxication or if medical treatment is
      required.

PMID- 10418665
TI  - [Self-inflicted stab wound for simulating self-defense?].
AB  - During a violent conflict, a young man was shot dead in front of a bar. The
      offender stated that he had acted in self defence after having been attacked with
      a knife. Taking into account the testimonies, the medical findings (f. ex.
      sonotomogram of the left femur) as well as the crime scene regarding the position
      of the body, it could not be excluded from the forensic point of view that a
      knife attack of the later victim had taken place. Nevertheless, the court
      convicted the man who had shot for murder and gave a life prison sentence.

PMID- 10418666
TI  - [Forensic aspects of spatially and temporally related multiple corpses].
AB  - The authors analysed 171 cases of two or more corpses, found in a spatial and
      temporal coherence. The investigation revealed cases of manifold-homicides,
      homicides with suicide of the perpetrator, manifold-suicides, affects of cryptic,
      non human dangers from the outside, joint exposition to potential dangerous
      situations and casual deaths of two people at one place due to natural, internal
      diseases. The necessity of an autopsy in each case is pointed out.

PMID- 10418667
TI  - [Inhalation heat shock].
AB  - Using the example of a recent case, we examine the possibilities of trace
      analysis and fire protection techniques in the investigation of fire deaths. The
      effective cooperation between forensic pathologists and fire inspectors is
      presented and we discuss the mathematical-physical uses of fire simulation
      calculations. We review the trace analysis results and discuss the variety of
      technical possibilities of modern engineering techniques for fire protection.

PMID- 10418668
TI  - [Fatal accidental mixed poisoning of 3 men at the same time].
AB  - The case history presented reports on three 30- to 40-years-old men, who were
      found dead in a party like situation in the living room. The toxicological
      investigation proved alcohol and THC as well as therapeutic Flunitrazepam- and
      Pentobarbital levels and toxic 7- Amino-Flunitrazepam concentrations. The
      background of this surprising scene led up to the conclusion of an accidental
      death caused by a mixed intoxication.

PMID- 10418669
TI  - [Healed fractures of the larynx and lingual bone in forensic autopsy].
AB  - Laryngohyoid fractures are a frequently investigated matter, especially in the
      forensic literature. On the other hand, there are only very few (old) forensic
      reports of such fractures in survived cases. However, healed fractures are not
      seldom found in forensic autopsies: In a personal series of 1160 forensic
      autopsies (adult persons) a careful dissection of the laryngohyoid complex was
      done by 1 investigator. Only a macroscopic examination of the cartilages was
      carried out; radiographs and histological slices were not regularly made.
      Therefore only a part of existing old fractures is detectable; for example,
      healed fissures are not visible with this simple method. Furthermore, asymmetries
      of the thyroid laminae cannot be declared as posttraumatic without additional
      examination, because this condition is described as possible anatomic anomaly.
      From that, the injury frequencies presented here only mark the lower threshold of
      the existence of such findings. Healed fractures of the upper thyroid horns and
      the major hyoid horns can be easily detected even in a routine examination, if
      healing resulted in a fixed dislocation or apposition of bone surrounding the
      former fracture site. In the present series, this was the predominant
      localization of old fractures: the upper thyroid horns (43 cases), followed by
      the hyoid cornua (12 cases), a combination of both sites (5) and cricoid
      fractures (5). Of the total 65 healed fractures (5.6%), 35 were found in the
      group of 290 chronic alcoholics (12.1%) and only 3.4% in non-alcoholics. In the
      subgroup of middle-aged alcoholics, the fracture rate increased up to 19%.
      However, this group did not present a higher rate of fresh laryngohyoid injuries
      (not related to strangulation) than the other cases. The old fractures probably
      resulted from minor "daily" injuries (like falls), which are common, especially
      in chronic alcoholics. The frequency of such findings should be in mind if an
      apparently fresh fracture, found in an actual autopsy, should be related to the
      cause of death: there is a real chance, that this fracture occurred prior, and
      without causal connection to the factors resulting in death. Therefore a
      histological examination of the age of this finding is necessary. Cricoid
      fractures are quite uncommon, except in serious external neck trauma. In 1 of our
      5 cases, this fracture was caused by repeated cruelty, finally resulting in
      death.

PMID- 10418670
TI  - [Mass spectrometry in the study of bioclasters of amino acids and peptides].
AB  - The study of homo- and heterocluster quasimolecular ions of 20 L-amino acids (A)
      and five dipeptides by the TOF-PDMS method indicated that the intensity of
      quasimolecular ions of the corresponding homo-([An + H]+ and [Bm + H]+, where A
      and B are biomolecules (A, dipeptides), n and m = 1 .... 5) and heteroclusters
      ([An.Bm + H]+, n and m = 1 .... 5) depends mainly on the hydrophobicity of the
      constituents of the A cluster. The most intensive peaks of homo- and
      heterocluster ions were obtained for hydrophobic amino acids: L-Ile, L-Leu, L
      Val, and L-Phe, and for dipeptides containing these amino acids. The assumption
      is made that the stereochemical parameters of heterocluster quasimolecular ions
      in the TOF-PDMS method are determined by the physicochemical mechanisms involved
      in the processes of ionization/desorption of biomolecules and do not reflect
      directly biologically significant interactions of biomolecules in vivo.

PMID- 10418671
TI  - [Interaction of Ag+ ions with ribonucleotides of canonical bases].
AB  - The interaction of Ag+ ions with ribonucleotides of canonical bases in aqueous
      solution was studied by differential UV spectroscopy. Atoms coordinating silver
      ions (N7, O6 of guanosine 5'-monophosphate, N3, O2 of cytidine 5'-monophosphate,
      N7, N1, N3 of adenosine 5'-monophosphate and N3 of uridine 5'-monophosphate) and
      the binding constants characterizing the formation of appropriate complexes were
      determined. The differences in the relative affinity of Ag+ ions for the atoms of
      nucleotide bases correlate with the potential on them.

PMID- 10418672
TI  - [Periodicity in contacts of RNA-polymerase with promotors].
AB  - Periodicities in the position of E.coli RNA polymerase promoter contacts on
      several promoters (lacUV5, T7 A3, tetR, lambda cin, lambda c17, RNA1, and trp
      S.t.) were found by means of Fourier analysis. The comparison of the Fourier
      spectrum of core RNA polymerase contacts on the lacUV5 promoter and that of
      holoenzyme revealed a more prominent 7-periodicity in the Fourier spectrum of
      holoenzyme contacts. 6-, 7-, and 8-periodicities were found in the primary
      structure of the majority of E.coli promoters. It is shown that RNA polymerase
      recognizes specific periodic patterns in the promoter structure.

PMID- 10418673
TI  - [Effect of weak combined low frequency constant and alternative magnetic fields
      on intrinsic fluorescence of proteins in aqueous solutions].
AB  - It was shown that weak combined static (42 microT) and low-frequency variable (40
      nT; 3-5 Hz) magnetic fields change the intensity of intrinsic fluorescence of
      some proteins (cytochrome c, bovine serum albumin, horseradish peroxidase,
      alkaline phosphatase). The effect can be interpreted as a change in the
      conformational state of the protein in water environment by the action of weak
      magnetic fields. The dynamics of the process, the concentration dependence, the
      binding of proteins to the fluorescence probe 1,8-ANS after treatment with
      magnetic fields, the frequency dependence of these reactions, and the dependence
      of the effect on the presence of the static constituent of the magnetic field
      were studied. It was shown that the changes in the intrinsic fluorescence of some
      enzymes (horseradish peroxidase, alkaline phosphatase) are related to changes in
      their functional activity. It was found that the effect is partially transferred
      via a solvent (water, 0.01 M NaCl) preliminarily treated with magnetic field. In
      the solvent, changes in its intrinsic fluorescence by the action of weak magnetic
      fields were also registered.

PMID- 10418674
TI  - [Regulation of catalytic properties of enzymes in "inverse micelles"].
AB  - A triple system (inverse micellae) that simulates the membrane environment of the
      enzyme was studied. Inverse micellae were obtained using anionic (aerosol OT),
      synthetic (Brij 56), and natural (lecithin) surfactants. It was found that upon
      inclusion of an enzyme into inverse micellae, its activity can be regulated by
      changing the structure and nature of the surfactant matrix. It was shown that
      enzyme activity in micellar environment is much higher than in water solution.
      Moreover, the enzyme solubilized in inverse micellae (acid phosphatase) shows a
      superactivity. It was found that surfactants specifically interact with
      solubilized enzyme, and the activity of the enzyme is inversely proportional to
      surfactant concentration. The mechanisms of viscotropic regulation of enzyme
      activity are discussed.

PMID- 10418675
TI  - [Oxidative destruction of estradiol after treatment with hydrogen peroxide
      catalyzed by horseradish peroxidase and methemoglobin].
AB  - It is shown that estradiol in the presence of horse radish peroxidase interacts
      with hydrogen peroxide, which is evidenced by an increase in its optical density
      at 280 nm. The photometering of samples containing estradiol and horse radish
      peroxidase upon their titration with hydrogen peroxide indicated that the
      increase in optical density stops after introducing hydrogen peroxide equimolar
      in concentration to estradiol. The stoichiometric ratio of estradiol consumed
      during oxidative destruction to hydrogen peroxide was 1:1. In the presence of
      ascorbate, the oxidative destruction of estradiol by the action of hydrogen
      peroxide, catalyzed by horse radish peroxidase, was observed only after a latent
      period and showed the same regularities as in the absence of ascorbate. It was
      found by calorimetry that, during the latent period, estradiol catalyzes the
      degradation of hydrogen peroxide and ascorbate without undergoing oxidative
      destruction. The substrates of the peroxidase reaction benzidine, 1-naphthol, and
      phenol interact with hydrogen peroxide in the presence of ascorbate and horse
      radish peroxidase in a similar way. Presumably, upon interaction with hydrogen
      peroxide in the presence of horse radish peroxidase, estradiol, like other
      substrates of this reaction, undergoes oxidative destruction by the mechanism of
      peroxidase reaction. It is shown that oxidative destruction of estradiol by the
      action of hydrogen peroxide can also be catalyzed by methemoglobin by the same
      mechanism. These data are important for understanding the role of estradiol in
      the organism and the pathways of its metabolic conversions.

PMID- 10418676
TI  - [Fluorescent energy transfer study of lysozyme complexes with liposomes].
AB  - The method of radiationless energy transfer was used to study the structure of
      lysozyme complexes with liposomes composed of phosphatidylcholine and
      diphosphatidylglycerol (4:3, mol:mol). 4-(n-Dimethylaminostyryl)-1
      methylpyridinium n-toluenesulfonate, 4-(n-dimethylaminostyryl)-1-hexylpyridinium
      n-toluenesulfonate, 4-(n-dimethylaminostyryl)-1-dodecylpyridinium n
      toluenesulfonate, and 3-metoxybenzanthrone were used as donors, and nile blue and
      rhodamine 6G, as acceptors. An increase in the surface area of model membranes
      upon binging of the protein to lipid bilayer was found.

PMID- 10418677
TI  - [Effect of oxidized low density lipoproteins on the structure of platelet
      membrane. Use of electron paramagnetic resonance].
AB  - The effect of low-density lipoproteins on the structure of platelet plasma
      membrane was studied by electron paramagnetic resonance spectroscopy. Low-density
      lipoproteins were incubated with platelet rich plasma at a volume ratio 1:1.
      Plasma incubated with buffer served as a control. After incubation, the fluidity
      of platelet plasma membrane was determined by electron spin resonance probes 5
      doxylstearate and 16-doxylstearate, which were immobilized in membranes of cells
      subjected to triple precipitation. Significant differences in the order parameter
      S, which characterizes the spectrum of the 5-doxylstearate probe, for samples
      incubated with the buffer and oxidized low-density lipoproteins were found. The
      dependence of the parameter on incubation time and the extend of oxidation of low
      density lipoproteins were obtained. No significant differences in rotational
      correlation time of 16-doxylstearate between platelets incubated with and without
      oxidized low-density lipoproteins was observed within the limits of experimental
      error; however, the changes in the half-width of the low-field component may be
      considered reliable. The interaction of oxidized low-density lipoproteins with
      platelets leads to an increase in plasma membrane fluidity, thereby mediating the
      activating action on platelets.

PMID- 10418679
TI  - [Dna comets as markers of cells death].
AB  - Unstimulated human peripheral blood lymphocytes gradually underwent death during
      incubation in vitro. According to morphological criteria, the type of death was
      identified as apoptosis. After immobilization in agarose, lysis, and
      electrophoresis, these lymphocytes formed DNA comets, which differed in DNA
      content, tail length, tail moment, and the fraction of DNA migrating in the comet
      tail. We classified the comets in 3 groups in accordance with the values of these
      parameters. There was a good correlation between the fraction of apoptotic cells
      (morphological data) and the fraction of "apoptotic" DNA comets. The results
      showed that DNA comets may be adequate markers of cell death (including
      apoptosis). The use of DNA comets as markers of spontaneous death made it
      possible to reveal an increased level of apoptosis in vitro lymphocytes from
      patients with systemic lupus erythematosus.

PMID- 10418680
TI  - [A device for sample pretreatment during flow cytometry].
AB  - A device for the preliminary treatment of samples immediately prior to flow
      cytofluorimetric analysis is described. The device is intended for several
      procedures: (a) mixing of batched sample volumes with the reagent and efficient
      stirring of the mixture; (b) disintegration of cell aggregates; and (c)
      disruption of cell membranes to release the cell contents (chromosomes,
      micronuclei, nuclei etc.). The pretreatment is useful for studying the kinetic
      parameters of fast cellular processes in the flow, a more correct analysis of the
      cell cycle and the study of karyotypes of single mitotic cells. The device was
      called a magnetic microstirrer.

PMID- 10418678
TI  - [Effect of thermoreverse polymer matrix and collagen on the growth of human
      fibroblasts].
AB  - The effect of a support composed of polymers based on poly-N-isopropyl acrylamide
      and poly-t-butyl acrylamide and collagen on human fibroblasts was studied. As the
      temperature was decreased to 4 degrees C, the polymeric support is converted to a
      diluted state and cells spontaneously detached from it. The presence of collagen
      in the support prevented the detachment of cells and increased cell growth. It
      was shown by microcalorimetry, that in a copolymer-collagen mixture, a
      microstratification takes place.

PMID- 10418681
TI  - [Quantity and quality of animal immunocompetent cells in relation with variations
      in solar activity].
AB  - It is shown that the number and quality (synthetic activity) of immunocompetent
      cells in animal peripheral blood correlate with the parameters of solar activity
      (number of spots on the Sun and solar fluctuations).

PMID- 10418682
TI  - [Similarity of the effects of first-generation antiarrhythmia agents and
      decreased extracellular concentration of sodium ions on action potentials of
      atrial myocytes].
AB  - In rabbit right atria beating in a spontaneous sinus rhythm, myocytes of two
      types were studied, which differ by the initial form of action potentials. First
      class antiarrhythmics and a gradual decrease in extracellular Na+ concentration
      induced qualitatively similar and unidirectional changes in the form of action
      potentials of myocytes. In some myocytes of the "conducting system" type, a slow
      diastolic depolarization was observed after repolarization, and the form of their
      action potentials became similar to that of the pacemaker cells. An enhancement
      of the action caused short-time arrhythmias.

PMID- 10418683
TI  - [Experimental-theoretical study of the force-interval relationship in the
      developing chicken myocardium].
AB  - The force-interval relationship was studied on myocardium preparations from chick
      embryos and hatched chickens. It is shown that the force-interval relationships
      of myocardium change during ontogenesis. A negative staircase (a decrease in the
      isometric force with increasing stimulation rate) in the chick embryo myocardium
      and a positive steady-state relationship in hatched stage myocardium were
      revealed. Changes in the force after switching from one stimulation frequency to
      another, the effects of poststimulation potentiation, as well as responses to the
      introduction of pauses and extrasystols at a constant stimulation rate were
      recorded. All the effects observed in the transient processes in preparations
      from hatched stage myocardium were more pronounced than in embryo myocardium. Our
      previous mathematical model of calcium recirculation in cardiomyocytes was
      adapted for simulating the main features of force-interval relationships in
      embryonal and relatively developed myocardium. The main source of regulatory
      calcium in the model of hatched stage myocardium is sarcoplasmic reticulum. In
      the model of embryo myocardium, it was postulated, based on data available in
      literature, that the main regulator of contractile response of the muscle is
      calcium that enters cardiomyocytes from extracellular medium. To describe force
      interval relationships, by this model, the decreasing dependence of the entry of
      extracellular calcium on the intervals between stimuli was introduced.

PMID- 10418685
TI  - [Distribution of neural memory, loading factor, its regulation and optimization].
AB  - Recording and retrieving functions of the neural memory are simulated as a
      control of local conformational processes in neural synaptic fields. The
      localization of conformational changes is related to the afferent temporal
      spatial pulse pattern flow, the microstructure of connections and a plurality of
      temporal delays in synaptic fields and afferent pathways. The loci of
      conformations are described by sets of afferent addresses named address domains.
      Being superimposed on each other, address domains form a multilayer covering of
      the address space of the neuron or the ensemble. The superposition factor
      determines the dissemination of the conformational process, and the fuzzing of
      memory, and its accuracy and reliability. The engram is formed as detects in the
      packing of the address space and hence can be retrieved in inverse form. The
      accuracy of the retrieved information depends on the threshold level of
      conformational transitions, the distribution of conformational changes in
      synaptic fields of the neuronal population, and the memory loading factor. The
      latter is represented in the model by a slow potential. It reflects total
      conformational changes and displaces the membrane potential to monostable
      conformational regimes, by governing the exit from the recording regime, the
      potentiation of the neurone, and the readiness to reproduction. A relative
      amplitude of the slow potential and the coefficient of postconformational
      modification of ionic conductivity, which provides maximum reliability, accuracy,
      and capacity of memory, are calculated.

PMID- 10418684
TI  - [Mathematical model of histamine bronchospasm].
AB  - A mathematical model of changes in histamine concentration in the wall of human
      bronchiole was constructed. The parameters of the model adequately characterize
      the state of patients with bronchial asthma.

PMID- 10418686
TI  - [Activity of the autoimmune process during systemic rheumatic diseases and
      distribution of constant brain potential].
AB  - The data obtained upon examination of patients with systemic rheumatic diseases
      were analyzed by the methods of multiple regression and step-by-step discriminant
      analysis. Is was shown that the activity of autoimmune process correlates with
      the parameters of distribution of constant potential level in the brain of each
      patient, irrespective of diagnosis. The scatter of potential values was the most
      important predictor of activity. An increase in the activity of the autoimmune
      process correlated with a decrease in the scatter of potential values at
      recording points; the cerebral cortex became equipotential.

PMID- 10418687
TI  - [Constant brain potentials as neurophysiological markers of autoimmune process].
AB  - Neuroimmune interactions in systemic rheumatic diseases were studied. The state
      of the central nervous system was assessed from the parameters of constant brain
      potentials, and the state of the immune system, from a complex of
      immunobiochemical parameters. The highest multiple correlation coefficients were
      revealed between the immunobiochemical parameters and the parameters of the
      constant brain potential, which characterize linear and standard deviations of
      potentials in temporal zones from potentials at other points of recording. The
      results are discussed in terms of structural and functional integration of the
      immune and nervous systems.

PMID- 10418688
TI  - [Two-step exposure of biological objects to infrared laser and microwave
      radiation].
AB  - The effect of two-step exposure of bacterial objects to infrared laser and
      microwave pulse radiations was studied. The effect is determined by the time
      interval between two excitation steps and pulse duration. It was shown that the
      biologically active dose of microwave radiation is much lower than that of
      infrared laser radiation; however, laser radiation induces a stronger cellular
      response. It was found that microwaves enhance the efficiency of infrared laser
      radiation.

PMID- 10418690
TI  - Increased volume and glial density in primate prefrontal cortex associated with
      chronic antipsychotic drug exposure.
AB  - BACKGROUND: Long term medication with antipsychotic drugs is known to produce
      changes in neurotransmitter levels and receptor sensitivity in the cortex;
      however, the anatomic consequences of chronic antipsychotic exposure are not well
      established. METHODS: Accordingly, rhesus monkeys were given daily oral doses of
      typical or atypical antipsychotic drugs (TAP or AAP) or a placebo for 6 months.
      After treatment, a stereologic method was used to assess neuronal and glial
      density and cortical thickness in prefrontal area 46. RESULTS: Neuronal density
      in drug-treated monkeys and controls did not differ in any cortical layer. Glial
      density was elevated in monkeys that received antipsychotic medications: as much
      as 33% in layers that receive dense excitatory afferents (layers I in TAP monkeys
      and IV in AAP monkeys). In addition, layer V was wider in all drug-treated
      monkeys. CONCLUSIONS: Our findings indicate that glial proliferation and
      hypertrophy of the cerebral cortex is a common response to antipsychotic drugs.
      We hypothesize that these responses play a regulatory role in adjusting
      neurotransmitter levels or metabolic processes. Finally, the negative results
      with respect to neuronal density indicate that the elevated neuronal density
      found in the schizophrenic cortex is unlikely to be a medication effect.

PMID- 10418689
TI  - Global variation of a 40-bp VNTR in the 3'-untranslated region of the dopamine
      transporter gene (SLC6A3).
AB  - BACKGROUND: The dopamine transporter (DAT) is the primary mechanism for dopamine
      clearance from the synapse in midbrain dopaminergic neurons, and the target of
      psychostimulant and neurotoxic drugs such as cocaine, amphetamine, and MPTP.
      Consequently, the gene for DAT (SLC6A3) has been the focus of many population
      based case-control association studies using a 40-bp VNTR in the 3'-untranslated
      region. Results have differed depending on the population studied, suggesting
      allele frequency effects are involved. For this reason, a global survey of allele
      frequencies for this VNTR polymorphism was performed. METHODS: Individuals (n =
      1528) from 30 populations around the world were typed for this VNTR using PCR and
      agarose gel electrophoresis. RESULTS: As with previous studies, the ten-repeat
      allele is most common, except for a Middle Eastern population in which the nine
      repeat allele is most frequent. Frequencies of the nine- and ten-repeat alleles
      vary widely even among European populations. CONCLUSIONS: Many previous
      association studies have used "white" or "black" U.S. populations. However, many
      different ethnic groups have contributed to these populations. The large
      variation in allele frequencies observed in this study emphasizes the inadequacy
      of most past studies using the case-control design and the importance of matching
      patient and control populations in future association studies.

PMID- 10418691
TI  - Clinical and neurobiological correlates of DXS1047 genotype in Alzheimer's
      disease.
AB  - BACKGROUND: The goal of the current study was to explore the clinical,
      neuropathological, and neurochemical correlates of the DXS1047 202 bp allele in a
      group of 50 autopsy-confirmed cases of Alzheimer's disease (AD) who lacked other
      concomitant brain diseases. We previously published the results of a genome
      survey for novel risk loci for typical-onset (> or = 60 years) AD conducted at 10
      cM resolution (Zubenko et al 1998a, b). This survey detected associations of
      alleles at six microsatellite loci with AD, including the 202 bp allele of the
      DXS1047 locus that resides within Xq25 on the human cytogenetic map. METHODS:
      Clinical assessments were performed as part of a longitudinal study of AD and
      related disorders. Autopsies were performed using standardized methods and the
      resulting diagnoses were made according to established criteria. Genotyping,
      morphometry, and neurochemical analyses were performed using postmortem brain
      tissue. RESULTS: Patients with AD who carried the DXS1047 202 bp allele
      manifested cortical norepinephrine levels that ranged from 2.1 to 3.6 times the
      corresponding values for noncarriers (p = .002), controlling for the potential
      effects of gender, age at symptomatic onset or death, and postmortem interval. In
      contrast, carriers tended to have lower cortical levels of dopamine (p = .10).
      CONCLUSIONS: These findings support the results of our previous genome survey and
      suggest that the DXS1047 locus, or a locus in close proximity, modulates
      biological variables relevant to the pathophysiology of AD. In addition to
      providing insights into the clinical biology of AD, the characterization of
      biologically meaningful subtypes, including genotypic subtypes associated with
      particular neurobiological derangements, may be important to the advancement of
      experimental therapeutics in AD.

PMID- 10418692
TI  - Estrogen replacement therapy and cognitive decline in memory-impaired post
      menopausal women.
AB  - BACKGROUND: Estrogen replacement therapy (ERT) may delay dementia-related
      cognitive decline in post-menopausal women, but few studies have longitudinally
      examined this relationship and none has controlled for baseline functioning or
      concurrent medication. METHODS: We report the results of a 1-year retrospective
      longitudinal study examining cognitive functioning in female estrogen and
      nonestrogen users (n = 3128) who presented to the state of California memory
      disorder clinics in a naturalistic multisite study of senile dementia,
      Alzheimer's type (SDAT), and other cognitive impairments. RESULTS: At baseline,
      estrogen users had significantly lower rates of SDAT diagnoses (possible and
      probable) than nonestrogen users, and significantly higher rates of the lesser
      diagnoses of "cognitive impairment" and "no dementia." ERT was significantly
      associated with higher cognitive functioning at baseline and at 1 year follow-up
      (n = 358). Nonestrogen users deteriorated significantly from baseline to follow
      up; estrogen users did not. Results were similar in groups matched on baseline
      Blessed-Roth Dementia Rating Scale (BRDRS) ratings (n = 32) and in a variety of
      subpopulations. CONCLUSIONS: These findings are consistent with estrogen acting
      as a protective factor against cognitive deterioration in post-menopausal women
      with SDAT and other cognitive impairments, and may suggest an increased effect in
      earlier stages of cognitive impairment.

PMID- 10418694
TI  - Frequency of long allele in serotonin transporter gene is increased in depressed
      suicide victims.
AB  - BACKGROUND: There is evidence indicating that serotonin uptake and density of 5
      HT2A receptors are altered in brain regions of depressed suicide victims and in
      platelets of depressed suicidal subjects. The present investigation tested the
      hypothesis that these changes in the serotonergic system in depressed suicide
      victims are trait rather than state markers and associated with a polymorphism in
      respective candidate genes. METHODS: Two polymorphic variants (102T/C
      polymorphism and His452Tyr functional polymorphism) of the 5-HT2A receptor gene
      and a functional polymorphism in the 5' regulatory region of the 5-HT transporter
      gene, have been determined in genomic DNA obtained from postmortem brain samples
      of 24 depressed suicide victims and 31 control subjects of the same ethnic
      background. In a subset of subjects, density (Bmax) of 5-HT uptake sites (labeled
      with 3H-paroxetine) and of 5-HT2A receptors (labeled with 3H-ketanserin) was also
      determined in prefrontal cortex samples. RESULTS: The major finding of this study
      was a significantly higher frequency of the 5-HT transporter gene long (L) allele
      (chi 2 = 3.9, df = 1; p = .048) in depressed suicides. No significant differences
      between suicides and controls were observed for the 102T/C polymorphism and
      His452Tyr polymorphism of 5-HT2A receptor gene. The density of 3H-paroxetine
      binding sites tended to be higher in subjects expressing the short (S) allele of
      5-HT transporter gene. Furthermore, there was a significant difference in
      serotonin transporter binding sites between the genotype S/S and combined
      genotypes S/L and L/L. CONCLUSIONS: Our finding provides the first evidence
      suggesting that a functional polymorphism in the regulatory region of serotonin
      transporter gene may be associated with suicide in depressed subjects.

PMID- 10418693
TI  - Physostigmine challenge before and after chronic cholinergic blockade in elderly
      volunteers.
AB  - BACKGROUND: As a test of possible muscarinic up-regulation, the cortisol response
      to intravenous (i.v.) physostigmine (an anticholinesterase) was measured in 9
      elderly volunteers before and after chronic cholinergic blockade with the
      muscarinic cholinergic antagonist scopolamine. METHODS: Each of the 9 elderly
      control subjects was given two physostigmine (0.5 mg i.v.) infusions separated by
      21 doses of nightly scopolamine (1.2 mg p.o.). No scopolamine was administered
      the night before infusions, and glycopyrrolate (0.2 mg i.v.) was administered
      prior to physostigmine, to block its peripheral effects. Vital signs were
      monitored and blood samples were collected at six time points surrounding the
      physostigmine infusion (-10, +10, +20, +30, +50, and +70 min). Behavioral
      measures and cognitive tests were administered prior to and 30 min after the
      physostigmine. RESULTS: The cortisol response to physostigmine was greater after
      the second (post-chronic scopolamine) infusion study compared to the first (p <
      .05) as measured by an area under the curve analysis of all time points. When
      individual time points were compared, the mean cortisol response was
      significantly increased after the second physostigmine infusion at the +50- and
      +70-min time points (p < .05). There were no significant changes in behavioral
      rating scales, cognitive tests, or vital signs between the two physostigmine
      infusion study days. CONCLUSIONS: This study demonstrates increased hypothalamic
      pituitary-adrenocortical axis responsivity to a central nervous system
      cholinergic stimulus after chronic muscarinic blockade in 9 elderly control
      subjects. It also gives further evidence to support previous suggestions of
      muscarinic plasticity, specifically postsynaptic up-regulation, in the aging
      brain following exposure to chronic anticholinergic treatment.

PMID- 10418695
TI  - Patterns of axis I comorbidity in early-onset versus late-onset major depressive
      disorder.
AB  - BACKGROUND: This study of a large clinical sample of depressed patients examined
      whether childhood onset as compared with adult onset Major Depressive Disorder
      (MDD) would confer a greater risk for Axis I comorbidity and whether childhood
      onset MDD would also differ from adult onset MDD in the pattern of comorbid
      disorders. METHODS: We examined lifetime co-occurrence of Axis I disorders among
      381 adult outpatients with MDD by Structured Clinical Interview for DSM-III-R
      Patient Edition (SCID-P). Subjects were divided into childhood onset (n = 47),
      adolescent onset (n = 101) and adult onset (n = 233) MDD groups. RESULTS: We
      found that the two early-onset groups exhibited significantly increased rates of
      Axis I comorbidity. The childhood onset group accounted for a disproportionately
      high percentage of depressed adults with two or more comorbid Axis I disorders.
      Social and simple phobias and alcohol abuse/dependence were significantly more
      prevalent among individuals with childhood onset MDD than among individuals with
      adult onset MDD. Alcohol abuse/dependence, but not anxiety disorders, was
      significantly more prevalent among adolescent onset than adult onset MDD groups.
      Panic, generalized anxiety, obsessive-compulsive and somatoform disorders were
      equally distributed across MDD onset groups. Comorbid disorders were much more
      likely to have followed onset of MDD among individuals with childhood compared
      with adult onset, except for social phobia which more frequently preceded the
      depression. The relative ordering among the comorbid conditions with respect to
      whether they followed or preceded MDD did not vary notably across the three age
      of onset groups. CONCLUSIONS: We conclude that early-onset MDD is associated with
      an increased density of Axis I comorbidity that seems to be limited to specific
      disorders.

PMID- 10418697
TI  - Biogenic amine activity in response to fluoxetine and desipramine in
      differentially reared rhesus monkeys.
AB  - BACKGROUND: It has been hypothesized that adverse early experience may be a
      mechanism by which children become vulnerable to later psychopathology via
      alteration of neurochemical or hormonal systems associated with such disorders.
      Such effects may in turn affect later responses to pharmacologic agents that act
      on these systems. METHODS: In this study, 18 mother-reared (MR) and 18 peer
      reared (PR) rhesus monkeys experienced six 1-week separations from cagemates
      interspersed with 1-week reunions, while housed in like-reared groups of 3.
      Within rearing groups, equal numbers of animals received either fluoxetine (2
      mg/kg), desipramine (5 mg/kg) or placebo delivered daily beginning 4 weeks before
      the first separation. Levels of norepinephrine (NE), the NE metabolite MHPG, the
      dopamine metabolites DOPAC and HVA, and the serotonin metabolite 5HIAA were
      measured in CSF samples collected approximately every 2 to 3 weeks during these
      procedures. RESULTS: Following treatment, DMI increased NE and decreased MHPG in
      the DMI-treated groups, while 5HIAA was decreased in the fluoxetine-treated
      groups following treatment. The increase in NE was followed by a sharp decline
      over the course of treatment, which was accompanied by an increase in MHPG. The
      rearing groups did not show a differential response to the drug treatments, and
      the separation manipulation itself had few effects. The mother-reared group
      showed higher levels of NE and DOPAC over all samples and higher levels of HVA in
      most samples. CONCLUSIONS: These rearing effects on biogenic amine activity were
      observed even in the presence of pharmacologic treatments that effectively
      altered the activity of these systems, and are consistent with previous findings
      from the same subject. The higher NE values observed in mother-reared infants
      over separations and reunions may have been due to higher basal levels of NE than
      peer-reared monkeys or to greater responsiveness to the stress of repeated social
      disruption or both. These findings agree with other primate studies showing that
      rearing differences persist beyond the infancy period and add to growing evidence
      of the important influence of the early social environment on neurobiologic
      development in primates.

PMID- 10418696
TI  - Tryptophan-depletion challenge in depressed patients treated with desipramine or
      fluoxetine: implications for the role of serotonin in the mechanism of
      antidepressant action.
AB  - BACKGROUND: Brain serotonin (5-HT) content is dependent on plasma levels of the
      essential amino acid, tryptophan (TRP). We have previously reported that rapid
      TRP depletion more frequently reversed the antidepressant response to monoamine
      oxidase inhibitors and 5-HT reuptake inhibitors than to desipramine (DMI). This
      study further investigates the relationship of relapse during TRP depletion to
      antidepressant type in nonrefractory, depressed patients randomly assigned to
      treatment with either DMI or fluoxetine (FLU). METHODS: Fifty-five drug-free
      depressed (DSM-III-R) patients were randomly assigned to antidepressant treatment
      with either DMI or FLU. All patients were either treatment naive (n = 34) or had
      previously received successful antidepressant treatment (n = 21). During the
      treatment phase, 35 patients had therapeutic responses by predetermined criteria
      (DMI 18/25; FLU 17/23) and 30 of these (15 DMI responders and 15 FLU responders)
      went on to TRP depletion testing. Patients received two 2-day test sessions
      involving administration of similar amino acid drinks. One session led to rapid
      TRP depletion and the other did not. Behavioral ratings [Hamilton Depression
      Scale (HDRS)] and plasma for TRP levels were obtained prior to, during, and after
      testing. Relapse was defined as a 50% increase in HDRS with total < or = 17.
      RESULTS: Total and free TRP decreased 70% to 80% 5 hours after the TRP-free
      drink. While 8/15 FLU responders relapsed, only 1/15 of the DMI responders
      relapsed. No patient experienced significant depressive symptoms during control
      testing. CONCLUSIONS: Rapid depletion of plasma TRP transiently reverses the
      antidepressant response in many patients on FLU but not DMI. Depressive relapse
      during TRP depletion appears to be more related to antidepressant type than to
      patient variables since patients were randomly assigned to the two treatments.
      Antidepressant response to FLU appears to be more dependent on 5-HT availability
      than that of DMI, suggesting that antidepressants mediate their therapeutic
      effects through different mechanisms.

PMID- 10418698
TI  - The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and
      mood in healthy male subjects.
AB  - BACKGROUND: Efforts to model putative serotonergic deficits associated with
      affective disorders have frequently involved acute tryptophan depletion (ATD) as
      a manipulation strategy aimed at lowering brain serotonin synthesis. In an
      attempt to widen the scope of the measurement probes used in these
      investigations, the central actions of ATD and a subsequent dose of fenfluramine
      were examined via utilization of quantitative electroencephalography (EEG) and
      mood ratings. METHODS: Electroencephalograms (EEG) and subjective mood ratings
      were assessed in 28 healthy men before and after double-blind ingestion of a
      tryptophan-depleting (T-) amino acid mixture, or a nutritionally balanced (B)
      amino acid mixture containing tryptophan, and again after a single-blind oral
      dose of D,L-fenfluramine hydrochloride (60 mg). RESULTS: Compared to the B
      mixture, the T- mixture reduced total plasma tryptophan by more than 75% 5 hours
      after ingestion. Tryptophan depletion was associated with a modest lowering of
      mood and a slowing of EEG as indicated by increases in delta amplitude.
      Fenfluramine caused no change in mood but increased fast wave (beta) activity in
      anterior recordings when administered after the T-, but not after the B mixture.
      CONCLUSIONS: Quantitative EEG measurements may be a promising method for studying
      the central mechanisms underlying serotonin-mediated changes in mood and
      behavior.

PMID- 10418699
TI  - Prophylactic treatment of seasonal affective disorder (SAD) by using light
      visors: bright white or infrared light?
AB  - BACKGROUND: Thirty-eight patients with SAD participated in a light visor study
      addressing two questions. 1. Can the development of a depressive episode be
      prevented by daily exposure to bright light started before symptom onset in early
      fall and continued throughout the winter? 2. Does the light have to be visible in
      order to have beneficial effects? METHODS: Three groups participated in the
      study: I (n = 14) received bright white light (2500 lux); II, (n = 15) received
      infrared light (0.18 lux); III (n = 9, control group) did not receive any light
      treatment at all. RESULTS: Infrared light is just as effective as bright white
      light. Both are more effective than the control condition. CONCLUSIONS: Light
      visors can be effectively used to prevent the development of SAD. The fact that
      exposure to infrared light was as effective as exposure to bright white light
      questions the specific role of visible light in the treatment of SAD.

PMID- 10418700
TI  - Elevated basal and thapsigargin-stimulated intracellular calcium of platelets and
      lymphocytes from bipolar affective disorder patients measured by a fluorometric
      microassay.
AB  - BACKGROUND: A number of investigators have reported finding elevated basal and
      stimulated intracellular calcium levels in the platelets or lymphocytes of
      bipolar disorder patients. METHODS: Intracellular calcium was measured by a micro
      fura-2 fluorometric method in the platelets and lymphocytes of 30 affective
      disorder patients and 14 control subjects. RESULTS: We observed significantly
      elevated basal calcium concentrations in bipolar patient platelets and
      lymphocytes compared to control subjects. Bipolar patient platelet calcium
      responses to thrombin, serotonin, and thapsigargin were also significantly
      greater than control subjects. The peak calcium levels of lymphocytes of bipolar
      patients were greater than control subjects only when stimulated by thapsigargin.
      There were significant differences between bipolar and unipolar patients in basal
      and thapsigargin-stimulated calcium measures but not between bipolar I and
      bipolar II patients. Unmedicated versus medicated calcium measures were not
      significantly different. We also found little correlation between calcium
      measures and the severity of mood rating. CONCLUSIONS: Using this method, we were
      able to confirm and extend the work of others, indicating altered intracellular
      calcium homeostasis in the blood cells of bipolar disorder patients. In addition,
      our data suggest that storage operated calcium channels may be the source of the
      elevated intracellular calcium in platelets and lymphocytes of bipolar patients.

PMID- 10418701
TI  - Consequences of deterministic and random dynamics for the course of affective
      disorders.
AB  - BACKGROUND: Uni- and bipolar affective disorders tend to be recurrent and
      progressive. Illness patterns can evolve from isolated episodes to more rapid,
      rhythmic, and "chaotic" mood patterns. Nonlinear deterministic dynamics are
      currently proposed to explain this progression. However, most natural systems are
      nonlinear and noisy, and cooperative behavior of possible clinical relevance can
      result. METHODS: The latter issue has been studied with a mathematical model for
      progression of disease patterns in affective disorders. RESULTS: Deterministic
      dynamics can reproduce a progression from stable, to periodic, to chaotic
      patterns. Noise increases the spectrum of dynamic behaviors, enhances the
      responsiveness to weak activations, and facilitates the occurrence of aperiodic
      patterns. CONCLUSIONS: Noise might amplify subclinical vulnerabilities into
      disease onset and could induce transitions to rapid-changing dysrhythmic mood
      patterns. We suggest that noise-mediated cooperative behavior, including
      stochastic resonance, should be considered in appropriate models for affective
      illness.

PMID- 10418702
TI  - P300 decrements in teenagers with conduct problems: implications for substance
      abuse risk and brain development.
AB  - BACKGROUND: The purpose of this study was to evaluate the effects of conduct
      disorder problems, family history, gender, and age on P300
      electroencephalographic potentials in teenagers. METHODS: The 257 subjects, aged
      15 to 20 years, were assigned to one of twelve groups defined by the crossing of
      three between-subjects factors: 1) gender; 2) ranking below vs above the median
      number of conduct disorder problems for their gender; and 3) no family history of
      alcohol or drug dependence vs familial alcohol dependence vs familial heroin or
      cocaine dependence. RESULTS: P300 amplitude was smaller among subjects reporting
      a greater number of conduct problems prior to age 15 vs those reporting fewer
      problems of this type. No family history effects were detected. Another set of
      analyses examined the effects of age on conduct problem-related decrements in
      P300. Smaller P300 amplitudes within the posterior scalp region were associated
      with a greater number of conduct problems among subjects younger than 16.5 years.
      Among subjects greater than this median age, the effects of these behaviors were
      only apparent over the frontal scalp. CONCLUSIONS: It is concluded that P300
      decrements previously attributed to familial alcohol/substance dependence might
      be the result of a coincident increase in the prevalence of conduct disorder
      problems. The analysis of age interactions suggests that P300 amplitude
      decrements observed at posterior scalp sites among subjects with more conduct
      problems disappear at approximately 16 to 17 years of age. After that age,
      decrements in frontal brain function may begin to emerge in the subset of conduct
      problem subjects who are at risk for developing adult antisocial personality
      disorder.

PMID- 10418703
TI  - Laboratory and psychometric measurements of impulsivity among violent and
      nonviolent female parolees.
AB  - BACKGROUND: Female parolees participated in a study to determine the relationship
      between behavioral and psychometric measures of impulsivity and their previous
      criminal history. METHODS: Subjects were assigned to a violent (n = 10) or
      nonviolent group (n = 20) based upon their criminal history. Subjects were given
      two response options defined as: 1) an impulsive choice--small monetary reward (5
      cents) after a short fixed delay of 5 sec, and 2) a self-control choice--a larger
      monetary reward (15 cents) after a variable longer delay initially set at 15 sec.
      The measure of impulsivity in this behavioral choice procedure was the number of
      trials on which the subject selected the impulsive option. This definition of
      impulsivity is based upon an extensive experimental literature in nonhumans and
      humans related to delay of gratification, that is, the ability to tolerate long
      delays imposed between the initiation of behavior and the presentation of a
      reinforcer. RESULTS: Our results indicated that the violent female subjects
      selected the impulsive option significantly more often than the nonviolent female
      parolees. CONCLUSIONS: The correlation between impulsive and aggressive responses
      among the female parolees was nonsignificant and negative, in contrast to a
      significant positive correlation previously reported among male parolees.

PMID- 10418704
TI  - Visual P3a in male subjects at high risk for alcoholism.
AB  - BACKGROUND: Voltage of the P300 component of event-related potentials (ERPs) has
      been proposed as a phenotypic marker of risk for alcoholism. P3a elicited by
      intrusive events is important in the context of deficits in inhibition found
      during psychophysiological and behavioral evaluations in children of alcoholics.
      METHODS: ERPs were recorded from a group of adult children of alcoholics (n = 26)
      and controls (n = 23) with a three-stimulus visual oddball paradigm. The task
      required a difficult perceptual discrimination between a frequent (.80) vertical
      line and an infrequent (.10) 2 degrees tilted line (target). An easily
      discriminable nontarget infrequent horizontal line also occurred (.10). Subjects
      were required to press a button to the target. P3a was compared using mixed-model
      ANCOVAs at 31 sites organized in 5 scalp regions. Current source density (CSD)
      maps were also analyzed. RESULTS: High-risk (HR) subjects manifested reduced P3a
      amplitudes compared to controls at frontal, central, parietal, and temporal
      electrodes. CSD analyses supported these findings with group differences found
      for all the scalp regions. CONCLUSIONS: The results are discussed in relation to
      previous HR studies. P3a reductions may be related to deficits in neuronal
      inhibition during stimulus processing. These results suggest that P3a amplitude
      may be important as a marker for vulnerability to alcoholism.

PMID- 10418705
TI  - Leptin, neuropeptide Y, and peptide YY in long-term recovered eating disorder
      patients.
AB  - BACKGROUND: Disturbances of leptin, neuropeptide Y (NPY), and peptide YY (PYY)
      have been found in women who are ill with anorexia or bulimia nervosa. It is not
      certain whether peptide disturbances are cause or consequence of eating
      disorders. METHODS: Plasma leptin and cerebrospinal fluid leptin, NPY, and PYY
      concentrations were measured in women who were recovered from anorexia or bulimia
      nervosa to determine whether alterations persisted after recovery. RESULTS: NPY,
      PYY, and leptin concentrations were similar across all diagnostic groups.
      CONCLUSIONS: Alterations in NPY, PYY, and serum leptin concentrations are
      probably secondary to pathological eating behaviors. Alterations of these
      peptides are unlikely to be trait-related disturbances that contribute to the
      etiology of eating disorders.

PMID- 10418706
TI  - In the frontline of palliative medicine and psychosocial oncology.

PMID- 10418707
TI  - Radiation inhibition of arterial restenosis -- a new frontier.

PMID- 10418708
TI  - Epstein-Barr virus distribution in Hodgkin's disease in an unselected Swedish
      population.
AB  - All patients with Hodgkin's disease (HD) (n = 117) identified in the
      Uppsala/Orebro region of Sweden between 1985 and 1988 were examined for the
      presence of Epstein-Barr virus (EBV) in the Hodgkin and Reed-Sternberg (HRS)
      cells. EBV was detected with LMP-1 immunostaining and in situ hybridization for
      EBERs. Overall, 32 (27%) tumours were EBV-positive but there were significant
      differences in EBV-positivity between histopathological subgroups (p = 0.03). In
      MC, 8/21 (38%) were positive, in NS 20/67 (23%), LD 3/3, LP 1/5, and in
      unclassified 0/1. Patients with EBV-positive tumours were significantly older,
      mean 52 vs. 42 years (p = 0.02), and were likely to have significantly more B
      symptoms or advanced stage disease. Patients with EBV-positive tumours tended to
      have a poorer survival rate (p = 0.11). The proportion of EBV-positive tumours,
      and especially the proportion of EBV-positive MC, was lower than previously
      reported. This could be explained by selection of patients from previous studies,
      or by differences in EBV-positivity in different geographical or ethnic
      populations of HD.

PMID- 10418709
TI  - A 252Cf-based instrument for in vivo body protein monitoring in cancer patients.
AB  - A hospital-based facility for in vivo prompt gamma neutron activation analysis of
      nitrogen for body protein determination is described. The patient is laid on a
      movable couch and is scanned with a vertically collimated neutron beam from a
      252Cf neutron source (the amount of Cf varying from 120 to 40 microg due to the
      physical decay) positioned below the patient. Four large NaI(Tl) detectors are
      used to measure the 10.8 MeV gamma-rays from nitrogen. To check the long-term
      stability of the system, a solid phantom simulating the geometry of the adult
      human trunk, having similar elemental composition as tissue, was constructed.
      Repeated phantom measurements over 6 months gave a reproducibility in nitrogen
      determination of 2.9% (1 SD). Duplicate patient measurements carried out within a
      week showed a reproducibility of 5% (1 SD). A calibration method for absolute
      protein measurements in patients is presented. Patients are normally measured for
      40 min; giving a mean whole-body equivalent dose of 0.25 mSv. Results from
      measurements on 13 cancer patients are presented.

PMID- 10418710
TI  - Hereditary cancer.
AB  - Cancer cases are often clustered in certain families and pedigree analysis
      indicates that at least 5% of cancer patients have a genetic predisposition to
      the disease. During the past decade the basic mechanisms for hereditary cancer
      have been outlined and a large number of the genes involved have been identified.
      This rapid development has changed the clinical management of cancer families,
      which now includes surveillance programs directed to early diagnosis of tumors as
      well as predictive mutation testing to identify gene carriers. This review
      outlines the molecular basis for hereditary cancer that has become the basis for
      genetic counseling of cancer families. The organization of clinics for cancer
      families in Sweden and the clinical implications of surveillance programs and
      gene testing for cancer predisposition are discussed.

PMID- 10418711
TI  - Spontaneous apoptosis as a predictor of radiotherapy in patients with stage IIB
      squamous cell carcinoma of the uterine cervix.
AB  - The purpose of this study was to investigate the correlation between the
      spontaneous apoptotic index (SAI) determined from pretreatment biopsy specimens
      with the various clinical outcomes of patients with FIGO stage IIB squamous cell
      carcinoma of the uterine cervix in a retrospective analysis. Forty-eight patients
      treated with curative radiotherapy between 1989 and 1993 were evaluated.
      Pretreatment biopsy specimens of those patients were scored for apoptosis,
      mitosis, and proliferating cell nuclear antigen (PCNA) immunohistochemical
      staining. The range of the SAI was 0.2-4.7% (median 1.1%). Patients whose tumours
      had a SAI above the median had better local control (p = 0.0062) and overall
      survival (p = 0.0053) than those with a lower SAI. Furthermore, the SAI was
      marginally significant on local control by a multivariate Cox regression analysis
      (p = 0.0571). There was no correlation between the SAI and proliferation (mitosis
      and PCNA).

PMID- 10418712
TI  - Malignant ovarian germ cell tumours -- a survival and prognostic analysis.
AB  - The medical records and histopathology of all ovarian germ cell tumours (OGCT) in
      a tertiary centre between 1980 and 1996 were reviewed. Response, overall survival
      (OS), relapse-free survival (RFS) and prognostic factors were analysed. Sixty
      seven patients with OGCT were identified and treated, including 33 dysgerminomas,
      18 immature teratomas, 10 endodermal sinus tumours, and 6 mixed tumours. Fifty
      three patients (79%) received conservative surgery, 24 (36%) had residual disease
      post-primary surgery, and 43 (64%) had chemotherapy. Complete response was
      achieved in 62 patients (93%), 4 out of 5 patients who relapsed were successfully
      salvaged; OS and RFS at 5 years were 89% and 76%, respectively. Advancing stage
      of disease was the only significant adverse prognostic factor (p = 0.0001 for OS,
      and 0.0003 for RFS at 5 years). Out of 44 women with the potential to conceive
      following treatment, there were 16 successful pregnancies. None of the children
      born subsequent to the chemotherapy were reported to have any congenital
      abnormalities. The review indicates a high cure rate in OGCT with combined
      surgery and chemotherapy and that conservative surgery and preservation of
      fertility are feasible.

PMID- 10418714
TI  - Equity in health and health care reforms.
AB  - In planning healthcare reforms increasing attention has been focused on the issue
      of equity. Inequities in the provision of healthcare exist even in relatively
      egalitarian societies. Poverty is still one of the major contributors to ill
      health and there are many powerful influences in society that continue to thwart
      the goal of a maximally equitable system for the provision of healthcare. The
      principles of equity in a healthcare system have been well articulated in recent
      years. It is incumbent on healthcare professionals who understand the issues to
      join the efforts towards a more humane and equitable healthcare system in their
      societies.

PMID- 10418713
TI  - Prognostic significance of pretherapeutic and therapeutic factors in patients
      with advanced cancer of the uterine cervix treated with radical radiotherapy
      alone.
AB  - The prognostic importance of various pretherapeutic and therapeutic factors was
      analysed in a group of 413 cervical cancer patients with stage IIB (183 pts) and
      IIIB (230 pts) treated with radical radiotherapy, which consisted of external
      irradiation and intracavitary brachytherapy. Univariate analysis of
      pretherapeutic factors revealed the prognostic significance of patient age,
      history of abortion, stage, haemoglobin and hematocrit levels. Five-year overall
      survival rate in stage IIB patients was 51%, in stage IIIB 40% and the respective
      rates for local control at each stage were 61%, and 46%. Univariate analysis of
      therapeutic factors showed that survival and local control rates increased with
      the dose, but a significant difference was found only in the case of a
      paracentral (point A) dose. In a multivariate analysis only patient age,
      abortions, and clinical stage appeared to have a significant and independent
      impact on survival. Linear regression analysis results indicated that
      prolongation of treatment time between 33 and 108 days caused a loss of local
      control of 0.36% per day.

PMID- 10418715
TI  - Post-traumatic stress symptoms in patients undergoing autologous stem cell
      transplantation.
AB  - The aim of this explorative study was prospectively to evaluate the presence of
      post-traumatic stress symptoms (PTSS) in patients with hematological malignant
      disorders undergoing autologous stem cell transplantation (ASCT). The findings
      were related to sense of coherence and quality of life aspects. Twenty patients
      were evaluated with four standardized instruments before undergoing ASCT and then
      at two follow-ups. The patients participating in the study reported PTSS levels
      high enough to merit attention. Although PTSS declined over time, the levels were
      still high compared with other studied populations of cancer patients. Intrusive
      and avoidant symptoms correlated significantly to anxiety and depression but not
      to sense of coherence and physical dimensions. The high levels of PTSS and their
      relation to emotional distress emphasize the importance of psychosocial care for
      this group of patients.

PMID- 10418716
TI  - Health-related quality of life in patients with endocrine tumours of the
      gastrointestinal tract.
AB  - Health-related quality of life (HRQOL) (EORTC QLQ-C30) and levels of anxiety and
      depression (HADS) were investigated in patients with endocrine tumours of the
      gastrointestinal tract treated with interferon and/or a somatostatin analogue. In
      addition, patient perceptions of the importance of and satisfaction with some
      HRQOL aspects were studied. QOL was perceived as quite good, but more than half
      of the patients reported diarrhoea. The levels of anxiety and depression were
      low. Patients perceived physical HRQOL aspects as most important for a good QOL
      and stated the highest satisfaction with some social aspects. Patients who
      reported high levels of anxiety or depression were less satisfied with several
      HRQOL aspects, had more health problems, and a lower level of functioning on
      several of the EORTC QLQ-C30 scales and single items. Neither demographic nor
      medical background variables seemed to have an influence on the results. The
      relatively high QOL could be explained by the fact that most patients had had
      their treatment for a long period and thus had time to adjust to the situation.

PMID- 10418717
TI  - Specialist palliative care within the acute hospital setting.
AB  - The hospital-based specialist palliative care service is the latest extension of
      the hospice movement in the UK, bringing the message of specialist palliative
      care back into the hospital setting. There are now over 200 palliative care
      services within the acute setting, including 76 specialist palliative care teams.
      The composition, advantages and disadvantages of such teams are described, and
      the challenge and importance of evaluating these services are discussed.

PMID- 10418718
TI  - Prognostic value of lymphoma-specific S-phase fraction compared with that of
      other cell proliferation markers.
AB  - The proliferation-associated antigens Ki67 (immunohistochemistry) and
      proliferative cell nuclear antigen (PCNA) (immunohistochemistry and
      immunoblotting) were analysed together with DNA synthesis (3H-thymidine
      incorporation) and cell-cycle distribution (tumour-specific S-phase fraction
      determined by flow cytometry) in lymph node suspensions from 63 patients with
      newly diagnosed B-Cell non-Hodgkin's lymphomas. Details of clinical parameters,
      treatment and patient outcome were available for all patients, and
      retrospectively analysed. Of the proliferation-associated parameters, only high S
      phase fraction (p < 0.00001) and high PCNA expression by immunoblotting (p =
      0.012) were predictive of a poor prognosis. Of the conventional parameters, high
      grade malignancy, high International Prognostic Index (IPI) score, bulky disease
      and presence of B symptoms predicted a patient for poor survival. High S-phase
      fraction was predictive of a short survival for the low-grade lymphomas analysed
      separately (p < 0.00001), as well as for patients treated with an Adriamycin- and
      a non-Adriamycin-containing regimen (p < 0.005 for both groups). In a
      multivariate analysis, S-phase fraction (p = 0.00006), IPI score (p = 0.015) and
      B symptoms (p = 0.017) had independent prognostic values, but not histological
      grade.

PMID- 10418719
TI  - Prognostic significance of marker half-life during chemotherapy in non
      seminomatous germ cell testicular tumors.
AB  - Decrease in serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG)
      levels is considered as a response during chemotherapy of non-seminomatous germ
      cell testicular tumors, but data on the prognostic significance of marker half
      life remains inconclusive. Serum marker half-life was evaluated in 34 patients
      with elevated markers, receiving chemotherapy (CT). Marker half-life was
      calculated from the natural logarithm of the sequential AFP or HCG
      concentrations. The correlation between event-free (EFS) and overall survival
      (OS) with unfavorable half-lives of AFP and HCG was evaluated. Median actual half
      life (AHL) AFP was 3.9 days (range, 1.4-21.5) and median AHL HCG was 4.4 days
      (range, 1.4-21.0); 82% of the patients had a satisfactory initial decline in AFP,
      and 71% had a satisfactory initial decline in HCG. There was a significant
      difference in EFS and OS between the two groups of patients with an AFP half-life
      < 7 days and > 7 days. HCG half-life did not adversely affect EFS and OS. The
      correlation of better EFS and OS with appropriate AFP marker half-life during
      chemotherapy could provide a dynamic method, which could complement the standard
      baseline prognostic factors, for the prediction of prognosis.

PMID- 10418720
TI  - Late medical sequelae after therapy for supradiaphragmatic Hodgkin's disease.
AB  - A total of 221 consecutive early stage Hodgkin's disease (HD) patients were given
      mantle field irradiation only or in combination with chemotherapy in 1971-1991.
      In 1994 these patients responded to a mailed self-report questionnaire covering
      items on late medical symptoms. Of 200 patients (91%) who reported that their
      thyroid function had been tested, 110 patients (55% of those tested) had thyroid
      hypofunction at follow-up in 1994. Ninety-five patients (86% of patients with
      biochemical hypothyreosis) had started hormonal substitution. In 1993 and 1994,
      101 of these patients who had received mantle field irradiation in 1980-1988 were
      called in for interview, clinical examination and thyroid function tests.
      Eighteen patients (18%) had started hormonal substitution treatment earlier, but
      58 (70%) of the other 83 patients were found to have biochemical hypothyreosis.
      Of the 221 patients who completed the questionnaire, 66 patients (30%) reported
      dyspnoea on exertion for more than 3 years after treatment, 8 patients (4%)
      reported a history of myocardial infarction, 6 patients (3%) reported pericardial
      disease and 25 patients (11%) heart valve disease. Increased expenses incurred
      for dental care were reported by 106 patients (48%), increasing to 55% when
      Waldeyer's ring had been irradiated. The consequences of late sequelae after
      mantle field irradiation for future treatment are discussed.

PMID- 10418721
TI  - Long-term follow-up of neoadjuvant cisplatin and 5-fluorouracil chemotherapy in
      bulky squamous cell carcinoma of the cervix.
AB  - Fifteen patients with bulky (designated as > 3 cm largest diameter) FIGO stage Ib
      or IIa squamous cervical cancer were treated with cisplatin (100 mg/m2 on day 1)
      and 5-fluorouracil (1000 mg/m2 continuously on days 1-5) administered
      intravenously at 21-day intervals for a total of two or three courses before
      planned radical hysterectomy. A complete clinical response was noted in four
      patients and a partial response in ten patients, which represents a 93% overall
      response rate. One patient had stable disease (two courses of chemotherapy), and
      none had progressive disease. Median tumor volume was 78.5 cm3 and 2.5 cm3 at
      diagnosis and after neoadjuvant chemotherapy, respectively (p < 0.001). This
      indicates that chemotherapy resulted in a 97% median reduction of tumor volume.
      Median overall and disease-free survival was not reached, and the actuarial five
      year survival rate was 73% and 67%, respectively. There was no grade 4 toxicity.
      Myelosuppression was acceptable; however, two patients experienced significant
      ototoxicity, and in two patients serum creatinine increased. All patients with
      major toxicity received two cycles of chemotherapy only. The improved local
      control and survival in our series are in accordance with other results reported,
      but need to be confirmed in a randomized prospective trial.

PMID- 10418722
TI  - Immunolocalization of androgen receptor in canine prostatic hyperplasia--effect
      of antiandrogen.
AB  - The effect of a synthetic steroidal anti-androgen, chlormadinone acetate (CMA),
      on spontaneous benign prostatic hyperplasia (BPH) in the dog was investigated.
      Old male beagle dogs (5 to 8 years old) were divided into the following
      experimental groups: group 1 consisting of BPH controls, and group 2 which
      received CMA of 0.3 mg/kg/day orally for 6 months. In group 1, glandular
      hyperplasia of the prostate was clearly observed. The glandular epithelial cells
      showed uniformly intense nuclear immunostaining for androgen receptor (AR). In
      contrast, CMA produced marked atrophy of the glandular epithelium. The
      interacinar fibromuscular stroma was prominent. Furthermore, nuclear
      immunostaining for AR in both epithelial and stroma cells was remarkably
      decreased. These results indicate that the uptake of testosterone and/or its
      androgenic effect on the prostate may be suppressed by CMA. The decreased AR
      immunostaining may be explained by the decrease in the number of AR and/or
      antibody binding sites for AR.

PMID- 10418723
TI  - Effects of barium on delayed rectifier potassium current in bullfrog sympathetic
      neurons pretreated with wortmannin.
AB  - The effect of barium (1 mM) on a delayed rectifier-type potassium current was
      examined in bullfrog sympathetic neurons. An M-type potassium current was
      eliminated by pretreatment of the cells with a microbial product, wortmannin (10
      microM). An A-type potassium current was continuously inactivated by setting a
      holding potential at -65 mV. In treated cells (n = 10), the delayed rectifier at
      0 mV averaged 2200 +/- 107 pA in the presence of barium (1 mM) as compared to
      2308 +/- 110 pA in the controls, and 2085 +/- 103 pA after washing out the
      barium. It is concluded that the delayed rectifier is insensitive to barium
      blockage in amphibian autonomic neurons.

PMID- 10418724
TI  - Regulation of intracranial pressure in the rat with chronic moderate hypercapnia.
AB  - STUDY OBJECTIVES: In this animal study we investigated whether CO2-induced
      intracranial hypertension was sustained in chronic hypercapnia. DESIGN: We kept
      five rats in a 10% CO2-air mixture (PaCO2 73.4 +/- 6.2 Torr, mean +/- 1SD) for 22
      weeks, and then measured the rats' intracranial pressure while breathing the 10%
      CO2- air mixture or the room air. RESULTS: The intracranial pressures recorded
      during chronic hypercapnia in systole and diastole were 7.0 +/- 1.9 and 5.4 +/-
      1.6 mm Hg, respectively. When the rats were acutely exposed to the room air
      (PaCO2, 51.9 +/- 10.2 Torr), the intracranial pressures in systole and diastole
      were 6.1 +/- 1.4 and 5.0 +/- 0.8 mm Hg, respectively, were not significantly
      different from those during hypercapnia (P>0.05, paired t-test). CONCLUSIONS: The
      intracranial pressure in rats with chronic moderate hypercapnia was not
      significantly different from normocapnic rats, and this change was associated
      with a blunting of intracranial pressure autoregulation.

PMID- 10418725
TI  - EMG potentials elicited by forehead taps in the sternocleidomastoid muscles and
      lower leg muscles--a study on patients with vestibular lesions.
AB  - The aim of the present study was to determine whether a tap on the forehead
      evokes a vestibulospinal reflex in the sternocleidomastoid muscles and the lower
      leg muscles in patients with vestibular lesions. Although first positive-negative
      short-latency EMG potentials with a mean positive potential peak of about 12.6 ms
      and a mean negative potential peak of about 17.3 ms were found in the bilateral
      sternocleidomastoid muscles in normal subjects, they were lacking in patients
      with vestibular lesions. The first negative short-latency EMG potentials had a
      mean latency of 48.3 +/- 3.1 ms (onset) to 98.3 +/- 6.3 ms (end) in both
      gastrocnemius muscles in normal subjects, but they were delayed in patients with
      vestibular lesions.

PMID- 10418726
TI  - Evaluation of vertical semicircular canal function by the caloric test--a study
      on patients with benign paroxysmal positional vertigo.
AB  - The morbidity of benign paroxysmal positional vertigo (BPPV) was investigated
      from the functional standpoint by analyzing nystagmus elicited by the caloric
      test. As a result of an investigation of the three (horizontal, vertical and
      torsional) components of the nystagmus elicited by the caloric stimulus (cold
      water), the vertical nystagmus differed in direction between the left and the
      right ear in 3 out of the 4 BPPV cases. The vertical nystagmus elicited by the
      caloric stimulus reflected the functions of the anterior and posterior
      semicircular canals, and investigation of the difference in function between the
      anterior and posterior semicircular canal from the direction of the vertical
      nystagmus appeared to be feasible.

PMID- 10418727
TI  - Per capita gross national product and summarized odds ratio for epidemiologic
      studies on the relationship between passive smoking and lung cancer.
AB  - The summarized odds ratios of epidemiologic studies on the relationship between
      exposure to environmental tobacco smoke (ETS) and lung cancer by country were
      recalculated, using the odds ratio values in a 1992 report entitled, "Respiratory
      Health Effects of Passive Smoking: Lung Cancer and Other Disorders" by the US
      Environmental Protection Agency. The relationship between the summarized odds
      ratio and per capita gross national product (GNP) in 1964 was studied by the
      country. The graphic relationship between the summarized odds ratio (ordinate)
      and GNP (abscissa) showed an upward convex curve. The summarized odds ratios of a
      developing country (China) and developed countries (USA, Western Europe) in 1964
      indicated a very weak association, while those of other countries (Greece, Hong
      Kong, and Japan) were slightly greater than unity (1.0). This means that ETS in
      the developing and developed countries in 1964 hardly affected lung cancer,
      whereas that in the other areas affected lung cancer somewhat. Socioeconomic
      status in developed countries is far better than that in developing countries,
      and factors related to socioeconomic status may affect the summarized odds ratio.
      It is recognized that cancer is diagnosed clinically some years after cancer risk
      factors appear. If the socioeconomic status involves some risk factors which
      affect lung cancer, the relationship between the summarized odds ratio and the
      GNP may be significant. Therefore, we can forecast that the summarized odds ratio
      of Japan will decrease to close to unity and that that of China will increase in
      the future because of economic growth, making it possible for the Chinese
      Government to adopt a policy to reduce the influence of ETS on health.

PMID- 10418728
TI  - Factors influencing physiological FDG uptake in the intestine.
AB  - The intestine is a well-known site of physiological 18F-fluorodeoxyglucose (FDG)
      accumulation in positron emission tomography (PET). To identify factors
      influencing physiological FDG uptake in the intestine, the intensity of FDG
      uptake was evaluated in a total of 1,068 healthy adults. Non-attenuation
      corrected whole-body PET images were obtained for all subjects and visually
      evaluated. Subjects were then classified into two groups according to the
      intensity of intestinal FDG uptake. Sex, age, presence or absence of
      constipation, and serum glucose, hemoglobin A1c, and free fatty acid levels were
      compared between the two groups. High intestinal FDG uptake was observed at an
      overall rate of 11.0%. Sex (female), age, and bowel condition (constipation) were
      found to affect intestinal FDG uptake. The factors we identified lead to further
      questions regarding the relationship between intestinal motility and glucose
      uptake that warrant further study.

PMID- 10418729
TI  - Ultrastructural study in canine prostatic hyperplasia--effect of antiandrogen.
AB  - Ultrastructural changes in canine prostates after treatment with chlormadinone
      acetate (CMA) were investigated. Old male beagle dogs (5-8 years old ) were
      divided into two experimental groups; group 1 consisted of benign prostatic
      hyperplasia (BPH) controls, and group 2 received 0.3 mg/kg/day CMA orally for 6
      months. In group 1 animals, the most striking ultrastructural changes were
      detected in the rough endoplasmic reticulum (rER) and Golgi complexes. The
      secretory granules were lined up along the apical plasma membrane, and exocytosis
      was frequently seen. In group 2 animals, the cytoplasm was electron-lucent and
      contained relatively few, poorly developed organelles. The rER was sparse and
      consisted of a few scattered, short profiles studded with ribosomes. The Golgi
      complexes were inconspicuous. The secretory granules were markedly decreased in
      both number and size. Furthermore, mitochondrial degeneration such as swollen or
      disappeared mitochondrial cristae or decreased electron density of the matrix
      were frequently seen in the smooth muscle cells. Based on our data, atrophy after
      treatment with CMA may be due to shrinkage of both glandular and stromal
      compartments in the prostate tissue.

PMID- 10418730
TI  - Induction of apoptosis in purified animal and plant nuclei by Xenopus egg
      extracts.
AB  - We have developed a cell-free system that can trigger the nuclei purified from
      mouse liver and suspension-cultured carrot cells to undergo apoptosis as defined
      by the formation of apoptotic bodies and nucleosomal DNA fragments. The effects
      of different divalent cations and cycloheximide on DNA cleavage in this system
      were assessed. The fact that nuclei of plant cells can be induced to undergo
      apoptosis in a cell-free animal system suggests that animals and plants share a
      common signal transduction pathway triggering in the initiation stage of
      apoptosis.

PMID- 10418731
TI  - Spatial and temporal regulation of collagenases-3, -4, and stromelysin -3
      implicates distinct functions in apoptosis and tissue remodeling during frog
      metamorphosis.
AB  - Matrix metalloproteinases (MMPs) are a family of extracellular proteases capable
      of degrading various proteinaceous components of the extracellular matrix (ECM).
      They have been implicated to play important roles in a number of developmental
      and pathological processes, such as tumor metastasis and inflammation. Relatively
      few studies have been carried out to investigate the function of MMPs during
      postembryonic organ-development. Using Xenopus laevis development as a model
      system, we demonstrate here that three MMPs, stromelysin-3 (ST3), collagenases-3
      (Col3), and Col4, have distinct spatial and temporal expression profiles during
      metamorphosis as the tadpole transforms into a frog. In situ hybridizations
      reveal a tight, but distinct, association of individual MMPs with tissue
      remodeling in the tail and intestine during metamorphosis. In particular, ST3
      expression is strongly correlated with apoptosis in both organs as demonstrated
      by analyses of serial sections with in situ hybridization for ST3 mRNA and TUNEL
      (terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick end
      labeling) for apoptosis, respectively. On the other hand, Col3 and Col4 are
      present in regions where extensive connective tissue remodeling take place. These
      results indicate that ST3 is likely to play a role in ECM-remodeling that
      facilitate apoptotic tissue remodeling or resorption while Col3 and Col4 appear
      to participate in connective tissue degradation during development.

PMID- 10418732
TI  - Myeloid cell-lineage and premylocytic-stage-specific- expression of themouse
      myeloperoxidase gene is controlled at initiation as well as elongation levels of
      transcription.
AB  - The myeloperoxidase (MPO) is an important microbicidal protein present at high
      concentration in the primary granule of mature granulocyte and its expression is
      regulated in both myeloidcell-lineage and premyelocytic-stage-specific manners. A
      better understanding of the underlying control mechanisms should provide insights
      into the temporal and co-ordinate regulation of the gene expression during
      granulopoiesis. We have identified its promoter by mapping the start(s) of
      transcription using various molecular approaches together with demonstrating the
      promoter function of the relevant DNA segment in a transient transfection
      reporter assay. Besides the major start of transcription mapped at G residue, 11
      nucleotide upstream of the 3' end of exon 0, the usage of that is specific to the
      MPO expressing cell lines, we have shown that irrespective of the MPO-expression
      status of the hematopoietic cells, transcription occurs broadly within a two kb
      region upstream of the 5' proximity of the gene, and is largely terminated in
      intron 2. These data support a model of the premyelocytic-stage-specific MPO
      expression, the control of which is operated at initiation as well as elongation
      levels of transcription.

PMID- 10418733
TI  - Heat shock induction of a 65 kDa ATP-binding proteinase in rat C6 glioma cells.
AB  - The 45, 55, 65 and 100 kDa ATP-binding proteinases (ATP-BPases) of the heat
      shocked (44 degrees C for 30 min, recovery for 12 h) rat C6 glioma cells were
      purified by DEAE-ionexchange and ATP-affinity chromatography. Their molecular
      masses, isoelectric points (pI), pH-optima and other properties were analyzed by
      native proteinase gels. It was shown that the 65 kDa ATP-BPase is specifically
      induced by heat shock and not detectable in control cells. Its N-terminal 1-9
      amino acid sequence was determined by Edman degradation, but no homologies to
      other proteins in the protein data bases were found. 30 and 31 kDa proteinases
      can be cleaved from the 45, 55 and 65 kDa proteinases to which they are linked. A
      possible relationship of the heat-induced 65 kDa ATP-BPase with the ATP-dependent
      proteinases (ATP-DPases) in prokaryotes and eukaryotes is discussed.

PMID- 10418734
TI  - Comparative investigation on spindle behavior and MPF activity changes during
      oocyte maturation between gynogenetic and amphimictic crucian carp.
AB  - The spindle behavior and MPF activity changes in the progression of oocyte
      maturation were investigated and compared with cytological observation and kinase
      assay between gynogenetic silver crucian carp and amphimictic colored crucian
      carp. MPF activity was measured by using histone H1 as phosphorylation substrate.
      There were two similar oscillatory MPF kinase activity changes during oocyte
      maturation in two kinds of fishes with different reproductive modes, but there
      existed some subtle difference between them. The subtle difference was that the
      first peak of MPF kinase activity was kept to a longer-lasting time in the
      gynogenetic silver crucian carp than in the amphimictic colored crucian carp. It
      was suggested that the difference may be related to the spindle behavior changes,
      such as tripolar spindle formation and spindle rearrangement in the gynogenetic
      crucian carp.

PMID- 10418736
TI  - Metrological support of the Institute for Reference Materials and Measurements
      (IRMM) to clinical chemistry.

PMID- 10418735
TI  - Suppression of angiotensin II stimulated responses in aortic vascular smooth
      muscle cells of experimental cirrhotic rats.
AB  - Functional responses to angiotensin II (AT-II) were determined in aortic vascular
      smooth muscle cells (VSMCs) from experimental cirrhotic rats. Our data showed
      that AT-II-stimulated extracellular acidification rate (ECAR), which was measured
      by Cytosensor microphysiometry, was significantly reduced in the aortic VSMCs
      from the cirrhotic rats as compared to those from the control animals. The
      ability of AT-II to promote formation of inositol phosphates, the second
      messenger produced by the activation of Gq-coupled receptors, was also
      considerably suppressed in the cirrhotic VSMCs. Furthermore, the maximal p42/44
      MAPK phosphorylation stimulated by AT-II was significantly reduced in the
      cirrhotic VSMCs in contrast to that in the normal VSMCs. Taken together, our data
      clearly demonstrated that the functional responses to AT-II was severely
      suppressed in aortic VSMCs in cirrhosis, indicating the impairment of general Gq
      coupled receptor signaling and subsequent biological function in the cirrhotic
      VSMCs.

PMID- 10418737
TI  - Web applications for total quality management.
AB  - Total quality management involves the consideration of many quality subjects as
      part of the management, such as quality processes, quality education, quality
      assurance, quality planning, quality results and quality document management. But
      crucial quality elements are also communication, data management and information
      sharing. Web applications and other associated computer communication
      applications such as E-mail and newsgroups, for example, offer to the laboratory
      environment the best tools to achieve proper communication and data
      management/sharing. These applications, enabling the set-up of Internet and
      Intranet sites, are used to share the information in the form of simple text
      pages or of completely interactive pages, which could comprise audio and video
      files, web page formulae and web data management applications. These applications
      are being associated to several applications and also being integrated into the
      laboratory information system (LIS).

PMID- 10418738
TI  - Inflammation, the acute phase response and atherosclerosis.
AB  - There is increasing evidence that atherosclerosis is a chronic inflammatory
      disorder resulting from a combination of processes, and that acute exacerbations
      of this inflammation are associated with the acute coronary syndromes such as
      myocardial infarction and unstable angina. Measurement of the serum level of
      acute phase proteins, such as C-reactive protein and serum amyloid A protein, has
      been used to predict the risk of acute events in patients with atherosclerosis.
      Prospective studies have shown that higher serum acute phase protein levels,
      often within the reference range, are associated with increased risk of
      myocardial infarction (MI), stroke or peripheral vascular disease and predict
      risk of infarction and death among high-risk patients. These observations have
      important implications for the assessment of patients and for treatment.

PMID- 10418739
TI  - Characterization of two distinct mechanisms for induction of apoptosis in human
      vascular endothelial cells.
AB  - Tissue homeostasis is fundamentally influenced by the functional integrity and
      state of endothelial cells. Survival and death of endothelial cells are
      encountered in cardiovascular disease and may, moreover, affect and determine the
      development of atherosclerosis and restenosis following intracoronary
      therapeutical interventions. Apoptosis was studied in cultured human umbilical
      vein endothelial cells (HUVEC) to investigate the regulation of endothelial cell
      death following serum/growth factor depletion as well as incubation with
      actinomycin-D. Apoptosis was verified by DNA fragmentation and quantified by
      fluorescence activated cell sorting (FACS) analysis after TdT-mediated
      deoxyuridine-triphosphate nick end-labeling (TUNEL). An ELISA was used for
      detecting intracytoplasmatic nucleosomes. Untreated HUVEC showed 16+/-6% TUNEL
      positive cells after 24 hours as analyzed by FACS. Serum/growth factor depletion
      increased apoptosis by 79+/-7%, while 50 ng/ml of the pro-apoptotic drug
      actinomycin-D induced comparable effects (72+/-11%). Apoptosis by serum/ growth
      factor depletion could be blocked completely by the anti-apoptotic agent
      cycloheximide (2 microg/ml), but was ineffective in blocking actinomycin-D
      induced apoptosis. Pyrrolidine dithiocarbamate (PDTC) also acted as an anti
      apoptotic agent by blocking apoptosis induced by actinomycin-D, but had no effect
      on apoptosis induced by factor depletion. Thus, two independent mechanisms for
      regulation of apoptosis are suggested to be present in human vascular endothelial
      cells.

PMID- 10418740
TI  - Lipid peroxidation and antioxidant defenses in cystic fibrosis patients.
AB  - Lipid peroxidation biomarkers and antioxidant status were measured in 76 cystic
      fibrosis (CF) patients and compared to 40 control subjects. Univariate and
      multivariate statistics were performed in this study. Results showed that
      indicators of lipid peroxidation were higher in CF patients than in controls;
      thiobarbituric acid reactants and autoantibodies against oxidized low-density
      lipoproteins were significantly increased in CF patients. Red blood cells and
      whole blood glutathione peroxidase activities were lower in CF patients than in
      controls. No difference in red blood cell superoxide dismutase activity was
      observed. Measured concentration of glutathione peroxidase in plasma showed a
      higher mean value of this protein in CF patients than in controls. Retinol, alpha
      tocopherol and beta-carotene concentrations were all reduced in CF patients as
      compared to controls; this was particularly pronounced for beta-carotene. The
      decreased alpha-tocopherol concentration was associated with higher percent
      hemolysis in CF patients. The results of this study indicate that both lipid
      peroxidation biomarkers and antioxidant status were disturbed in CF patients,
      despite medical assistance. Measures of oxidative stress parameters, such as
      thiobarbituric acid reactants, glutathione peroxidase, and beta-carotene
      concentrations can be considered as significant indicators to discriminate CF
      patients and control subjects.

PMID- 10418741
TI  - Autoantibodies against oxidised low-density lipoprotein in patients with
      obstructive sleep apnoea.
AB  - Autoantibodies against oxidised low-density lipoprotein (OxLDL-Abs) have been
      proposed to be an indicator of endothelial dysfunction and a novel tool for
      finding individuals with a high cardiovascular risk. In a cross-sectional study,
      OxLDL-Abs were measured in 297 patients with obstructive sleep apnoea (OSA) and
      54 controls using an enzyme-linked immunosorbent assay. The autoantibodies were
      increased in patients with OSA when compared to controls (age, body mass index
      (BMI) and gender adjusted, p = 0.001). However, within the OSA patients, OxLDL
      Abs were not related to smoking, hypertension or BMI, and there was a weak
      negative correlation (r = -0.16, P = 0.007) between age and levels of OxLDL-Abs.
      In conclusion, at present the measurement OxLDL-Abs still remains a method for
      basic research and is not applicable for screening of at-risk patients with OSA.

PMID- 10418742
TI  - Inter-alpha-inhibitor (IalphaI) concentration in pig plasma is independent of
      acute phase protein response.
AB  - Human inter-alpha-inhibitor (IalphaI) has been shown to exert a beneficial
      therapeutic effect in a porcine model of endotoxin shock. It is therefore useful
      to have a better understanding of IalphaI metabolism during severe inflammatory
      syndromes. Experimental bacterial pneumonia was induced in pigs. The acute phase
      response was highlighted by an increase in pig major acute phase protein (pig
      MAP) and haptoglobin concentrations in plasma collected daily over 4 days. In the
      same samples, the IalphaI levels remained unchanged. Moreover, crossed
      immunoelectrophoretic and immunoblot analyses did not show any qualitative
      modification of IalphaI throughout the experiment. IalphaI has been reported to
      be a negative acute phase protein in both humans and rats. Here we demonstrated
      that IalphaI behavior clearly differs in humans and pigs and is definitively
      species specific.

PMID- 10418743
TI  - Advances in reverse transcription polymerase chain reaction analysis of cellular
      mRNA levels of transforming growth factor-beta1 by capillary electrophoresis with
      laser-induced fluorescence detection.
AB  - The prosclerotic transforming growth factor beta1 (TGF-beta1) is a key factor in
      the induction and maintenance of fibrosis in different organs. To assess relative
      changes in TGF-beta1 mRNA levels, the comparative kinetic reverse transcription
      polymerase chain reaction strategy was used. In this method, cellular mRNA levels
      of the target and a house-keeping gene are reverse transcribed, amplified by the
      polymerase chain reaction (PCR) and the kinetics of PCR amplification are
      compared. Since the current determination of the PCR products, using
      electrophoretic separation in polyacrylamide gel, staining and scanning of the
      gel, is time-consuming (> or = 5 hours) and inaccurate, we have developed a
      method using capillary gel electrophoresis (CGE) in combination with laser
      induced fluorescence (LIF) detection for quantification of PCR-products. Using
      the CGE-LIF method, a minute aliquot of the PCR reaction mixture is separated and
      quantified within 10 min. Comparison of the values with those obtained by
      polyacrylamide gel electrophoresis demonstrates the improved sensitivity (> 1000
      fold) and accuracy of the proposed method. The CGE-LIF procedure offers a
      convenient way of automated, comparative analysis of low levels of mRNA via
      reverse transcription PCR in low cell numbers or small amounts of tissue samples.

PMID- 10418744
TI  - Determination of ascorbic acid in plasma and urine by high performance liquid
      chromatography with ultraviolet detection.
AB  - A reliable simple reversed-phase liquid chromatographic method for the routine
      determination of ascorbic acid in plasma and urine with ultraviolet detection is
      described. This method enables the complete separation of the ascorbic acid peak
      from others with a recovery of above 95% within 8 minutes. The method can be used
      for analysing multiple samples within a day. In addition, the storage conditions
      and stability of ascorbic acid in plasma and urine were investigated. Samples of
      plasma and urine can be stored on ice in darkness for at least 60 min without
      reduction of ascorbic acid concentration. Prepared samples can be stored in
      darkness at 4 degrees C for at least 120 min and in liquid nitrogen for 42 days.

PMID- 10418745
TI  - A new liquid homogeneous assay for the determination of HDL-cholesterol. A
      comparison to precipitation with phosphotungstic acid/MgCl2 and a lyophilized
      homogeneous assay.
AB  - We evaluated a new ready to use liquid assay for the homogeneous determination of
      HDL-cholesterol (HDL-C; Merck, Darmstadt, Germany) in comparison to
      phosphotungstic acid precipitation and a homogeneous assay, based on sulfated
      alpha-cyclodextrin and polyethylene glycol-modified enzymes (Roche
      Diagnostics/Boehringer Mannheim, Germany). The new liquid homogeneous HDL-C assay
      had inter-assay coefficients' of variation of less than 2.1%. The method is
      linear up to at least 3.11 mmol/I HDL-C, but even at 4.40 mmol/I the deviation
      from the expected value is less than 5%. Spinking experiments with low density
      lipoproteins and very low density lipoproteins proved that the new assay was
      specific for high density lipoproteins up to cholesterol associated with low
      density lipoproteins (LDL-C) and very low density lipoproteins (VLDL)
      triglyceride concentrations of 18.13 and 22.60 mmol/l, respectively. Free fatty
      acids above 2mmol/l did not interfere. Icteric samples with bilirubin
      concentrations between 170 and 400 micromol/l did not show any systematic
      deviation compared to the precipitation procedure. In addition, serum hemoglobin
      concentrations up to 7.0 mmol/l and ascorbic acid up to 3000 micromol/l did not
      interfere with the HDL-C assay. An intermethod comparison including 120 samples
      revealed good agreement of the liquid HDL-C assay and the precipitation procedure
      (y = 0.943x + 0.074 mmol/l; r = 0.992). The new homogeneous HDL-C assay is thus
      precise, comparable and robust. Due to its ease of handling this assay will
      significantly facilitate attempts to include the differentiation between HDL-C
      and LDL-C in the routine screening for cardiovascular risk factors and in the
      monitoring of lipid lowering therapy.

PMID- 10418746
TI  - On the standardization of total prostate-specific antigen: an exercise with two
      reference preparations.
AB  - In this study, 112 serum samples were analyzed for total prostate-specific
      antigen with three well-established assays i.e. Tandem R and Tandem E (both from
      Hybritech Inc., San Diego, USA) and Prostatus Free/Total from Wallac Oy, Turku,
      Finland. Thirty-two samples were collected from prostate cancer patients, 32 from
      patients with benign prostate hyperplasia and 48 from men participating in a
      screening study for prostate cancer. The aim of the study was to compare the
      results before and after recalculation with the data obtained with two reference
      preparations for total prostate-specific antigen: Stanford 90:10 PSA Calibrator
      and Certified Reference Material 613 Prostate-Specific Antigen. Comparing the
      actual results revealed almost perfect correlations between Tandem R and Tandem E
      and between both Tandem assays and Prostatus. We observed statistically
      significant differences in accuracy between Tandem R and Tandem E: y(Tandem E)=
      1.05 x(Tandem R)+0.07 and between Tandem E and Prostatus: y(Prostatus)= 0.94
      x(Tandem E)+0.02 In both comparisons prostate-specific antigen values ranged from
      0-40 microg/l. Recalculation with both reference preparations did not solve these
      discrepancies. One exception was the combination Tandem R and Tandem E. The
      application of either reference preparation solved the differences in accuracy
      here. In conclusion, even after recalibration, assays for total prostate-specific
      antigen are still not completely interchangeable.

PMID- 10418747
TI  - Analytical quality specifications for serum lactate dehydrogenase isoenzyme 1
      based on clinical goals.
AB  - The aim of the study was to deduce analytical quality specifications for the
      determination of catalytic concentration of serum lactate dehydrogenase isoenzyme
      1 (S-LD-1) according to clinical goals (the clinical utility model). We defined
      clinical goals for false positive and false negative S-LD-1 measurements in the
      monitoring of patients with testicular germ cell tumors (TGCT), clinical stage I,
      on a surveillance only program. The absolute S-LD-1 catalytic concentrations were
      routinely corrected for contamination from preanalytical hemolysis. A reference
      group of 37 men had a near In-Gaussian distribution for the absolute S-LD-1
      catalytic concentration. The geometric mean was 76 U/l and an S-LD-1 >128 U/l
      (99.72 percentile, the decision limit) indicated a high risk of a relapse of
      TGCT. We have previously shown that an S-LD-1 >160 U/l (treatment limit) was
      associated with a suboptimal outcome from the treatment of metastatic TGCT. The
      maximum allowable analytical positive bias was 5 U/l, and the maximum allowable
      analytical negative bias was -32 U/l. The maximum allowable analytical
      coefficient of variation, CV(A), was 11% (approximately 14 U/l) at a bias = -5
      U/l. For S-LD-1 measurements not corrected for hemolysis, the decision limit was
      145 U/l, the maximum allowable negative bias -19 U/l, and CV(A) 8%(approximately
      12 U/l). A routine correction for hemolysis had a large impact on the analytical
      quality specifications.

PMID- 10418748
TI  - Physiological HEPES buffer proposed as a calibrator for pH measurement in human
      blood.
AB  - N-(2-hydroxyethyl)-piperazine-N'-2-ethanesulfonic acid, known as HEPES buffer,
      with pK in the physiological range was studied for use as an alternative to
      conventional phosphate buffer for the calibration of pH in modern clinical
      analyzers. In different series of aqueous equimolar HEPES buffer, pH was measured
      at 37 degrees C with a capillary glass electrode standardized previously using
      phosphate, and variations due to changes in total HEPES buffer concentration
      (0.025 to 0.320 mol/l), and NaCl (0 to 0.250 mol/l) were monitored. For 0.05
      equimolar HEPES buffer without NaCl, the pH of 7.362+/-0.003 (n = 15) obtained
      coincided well with the reference pH (7.364) from the National Institute of
      Standards and Technology (NIST). In particular, in the preferred 0.05 equimolar
      HEPES buffer/0.110 mol/l NaCl, which is isotonic to human plasma (0.160 mol/l),
      and termed physiological HEPES buffer (PHB), the pH of 7.346+/-0.003 (n = 84) can
      be related to the calculated corresponding reference pH from NIST without liquid
      junction (7.374), and is also compatible with the pH measured in normal arterial
      blood, pH = 7.403+/-0.003 (n = 20). Hence, in the two-point calibration of
      clinical analyzers, PHB, which is defined operationally with respect to the glass
      electrode and to phosphate buffer, may be useful as a calibrator in the range of
      buffer adjustment control to meet the correct values for pH when measuring in
      blood. Whereas Na-HEPES salt is hygroscopic and does not meet the declared purity
      grade (> 99%), pure HEPES acid is non-hygroscopic and conforms to the
      manufacturer's purity grade (> or = 99%). Therefore, for easy preparation of PHB,
      HEPES acid is the preferred starting material.

PMID- 10418749
TI  - Towards common reference intervals in clinical chemistry. An attempt at
      harmonization between three hospital laboratories in Skane, Sweden.
AB  - The population sample of the Kristianstad survey, a reference intervals survey in
      the county of Kristianstad, was used to establish new reference intervals in
      clinical chemistry at the laboratories of the Central Hospital in Kristianstad,
      the University Hospital in Lund and the University Hospital in Malmo. Three
      hundred and fifty nine subjects, male and female, aged 20-80+ years, were invited
      to participate in the study, with a participation rate of 70%. Up to 70 analyses
      were performed on each subject, general clinical chemistry parameters in all
      three laboratories, specialized analyses where available. Separate a priori
      exclusion criteria were defined for each test. In addition, the test pattern of
      each individual was evaluated for signs of preclinical disease. Twelve cases of
      preclinical disease were discovered and clinically confirmed. Details on all test
      methods are presented along with information concerning instruments used,
      calibration procedures, methods of calculation and obtained reference intervals.
      Although the methods were in general calibrated against acknowledged reference
      materials, in some instances differences were found that made common reference
      intervals across all laboratories impossible. Problems relating to the practical
      use of international recommendations and the establishment of reliable reference
      intervals are discussed.

PMID- 10418750
TI  - Evaluation of an automated immunoassay method for cytokine measurement using the
      Immulite Immunoassay system.
AB  - Cytokines are key mediators in cell regulation and communication. The
      concentration of these proteins can rapidly and importantly increase during
      severe clinical situations. However, current techniques are not adapted to stat
      measurement, thus making their clinical use limited. In this context, the
      commercialization of five new kits for cytokine measurement interleukin ((IL)-1,
      IL-6, IL-8, tumor necrosis factor (TNF)-alpha and IL-2R) on an automated
      immunoanalyzer, the Immulite, seems to be a new approach for the determination of
      these markers. We report here the evaluation of the performance of these tests.
      The technique is based on a solid phase (bead) two site chemiluminescent enzyme
      immunometric assay. The analysis is performed within 60 to 90 minutes and the
      calibration is stable for 15 days. The values of the between-run imprecision
      study were similar to those from the within-run study with coefficients of
      variation (CV) ranging from 2% (low values of IL-8) to 11.5% for intermediate
      concentrations of IL-6 (500 pg/ml). CVs were usually around 5%. The accuracy was
      determined by a linearity study using standards (except for IL-2R) provided by
      the National Institute for Biological Standards and Control (NIBSC). Slopes
      obtained during this study were close to 1 (r2 = 0.99), except for IL-6, for
      which the slope was 1.55. TNF-alpha values were close to those expected. IL-1
      results were about 20% higher. IL-6 values were over estimated above 100 pg/ml
      and under estimated below this value. IL-8 study seemed to be impaired by the
      poor stability of this molecule in the NIBSC preparation. Correlation study with
      standard laboratory techniques gave variable results: for IL-1 (n = 43) the slope
      was 0.77 (study carried out using cell culture media), for IL-6 (n = 54) the
      slope was 0.78, for IL-8 (n = 37) the slope was 1.64, for TNF-alpha (n = 40) the
      slope was 0.33 and the slope for IL-2R (n = 51) was 5.1. For the last cytokine,
      the unit in Immulite assay was different from the one used in our comparison
      technique. Cross-calibration results were consistent with these data and show
      that the bias is probably linked to a calibration problem. The study demonstrated
      excellent practicality of the system, and good stability of the calibration curve
      (15 days). However, the sample volume required (350 microl for the IL-6 and the
      TNF-alpha) could constitute a limitation for pediatric measurements.

PMID- 10418751
TI  - Surveillance of resistance against antimicrobial agents.

PMID- 10418752
TI  - Perspectives for the treatment of hepatitis B virus infections.
AB  - Primarily resulting as a spin-off of the search for effective anti-HSV or anti
      HIV agents, several compounds have been identified as effective and promising
      candidate anti-HBV drugs, i.e. famciclovir (penciclovir), BMS-200475, lamivudine
      (3TC), (-)FTC, L(-)Fd4C, L-FMAU, DAPD (DXG), bis(POM)-PMEA and bis(POC)-PMPA.
      They all inhibit HBV replication in Hep G2 2.2.15 at concentrations that are well
      below the cytotoxicity threshold. All these nucleoside analogues require three
      phosphorylation steps to be active, in their triphosphate form, as inhibitors of
      the HBV DNA polymerase, except for PMEA (adefovir) and PMPA (tenofovir), which
      need only two phosphorylation steps, to PMEApp and PMPApp, respectively, to
      interact as chain terminators with the HBV DNA polymerase reaction. Several of
      these compounds (for example, famciclovir, lamivudine and adefovir) have proven
      to be efficacious in the duck and/or woodchuck hepatitis models, and,
      accordingly, famciclovir, lamivudine and adefovir have also proven to be
      effective (i.e. in reducing HBV DNA levels) in patients with chronic HBV
      infection. Yet, famciclovir and lamivudine may lead to the emergence of
      resistance mutations (i.e. L528M and M552V/I) in the HBV DNA polymerase upon long
      term treatment. These penciclovir- and lamivudine-resistant HBV mutants still
      retain susceptibility to adefovir, which, in turn, has so far not been found to
      engender resistance mutations in HBV. As has become obvious from the experience
      with the treatment of HIV infections, future HBV chemotherapy may reside in
      combination drug therapy so as to achieve the highest possible virus reduction,
      thereby minimizing the likelihood of drug resistance development.

PMID- 10418753
TI  - New criteria for selecting the proper antimicrobial chemotherapy for severe
      sepsis and septic shock.
AB  - The mortality rate resulting from severe bacterial sepsis, particularly that
      associated with shock, still approaches 50% in spite of appropriate antimicrobial
      therapy and optimum supportive care. Bacterial endotoxins that are part of the
      cell wall are one of the cofactors in the pathogenesis of sepsis and septic shock
      and are often induced by antimicrobial chemotherapy even if it is administered
      rationally. Not all antimicrobial agents are equally capable of inducing septic
      shock; this is dependant on their mechanism of action rather than on the
      causative pathogen species. The quantity of endotoxin released depends on the
      drug dose and whether filaments or spheroplast formation predominates. Some
      antibiotics such as carbapenems, ceftriaxone, cefepime, glycopeptides,
      aminoglycosides and quinolones do not have the propensity to provoke septic shock
      because their rapid bactericidal activity induces mainly spheroplast or fragile
      spheroplast-like bacterial forms.

PMID- 10418754
TI  - Comparative efficacies of levofloxacin and ciprofloxacin against Streptococcus
      pneumoniae in a mouse model of experimental septicaemia.
AB  - The in vivo efficacies of levofloxacin and ciprofloxacin were compared against
      three clinical isolates of Streptococcus pneumoniae, using a mouse protection
      model. Two strains (SP 22 and SP 28) were penicillin-sensitive while one strain
      (SP 46) was penicillin-resistant. Each strain had identical susceptibility to
      both drugs. Using mice with renal impairment induced by uranyl nitrate injection,
      the elimination half-life of each antibiotic was prolonged to approximate human
      pharmacokinetic profiles of the drugs. The dosing regimen of each drug that
      yielded serum levels in mice which mimic human therapeutic concentrations of the
      drugs, were designed. One hour after intraperitoneal inoculation with minimum
      lethal dose of each strain, either levofloxacin at a dosing regimen of 10.6 mg/kg
      every 8 h or ciprofloxacin at 9.5 mg/kg every 8 h was subcutaneously administered
      for a total of six or 15 doses. In treatment, monitored daily for 5-8 days,
      levofloxacin resulted in higher survival compared with ciprofloxacin for the
      three strains. For example, percent survival following levofloxacin treatment
      recorded at day 4 postinfection with SP 22, SP 28 and SP 46 were 41, 90 and 30%,
      respectively, while the corresponding values after ciprofloxacin treatment were
      27, 75 and 16%, respectively. However, statistical analysis did not reveal a
      significant difference (p > 0.05). The lack of significant difference observed in
      the efficacies of both drugs reflected the comparability of their 24-h AUC/MIC
      ratios. It is suggested that, with some strains of S. pneumoniae, the efficacy of
      levofloxacin may be equivalent to that of ciprofloxacin in the treatment of
      systemic pneumococcal infections caused by susceptible strains of the organism.

PMID- 10418755
TI  - A multi-centre study of nosocomial methicillin-resistant Staphylococcus aureus in
      Greece. Greek MRSA Study Group.
AB  - All 105 non-replicate consecutive Staphylococcus aureus strains isolated in 1997
      from seven Greek hospitals, were found to be susceptible to vancomycin,
      teicoplanin and chloramphenicol, but only five (8%) were susceptible to all 16
      antibiotics tested. Forty-three (41%) isolates were methicillin-resistant, 58%
      homogeneously (homMRSA) and 42% heterogeneously (hetMRSA). Resistance of homMRSA
      strains to other antibiotics was generally high (88-100%), although only one
      strain was resistant to netilmicin. Resistance in hetMRSA (6-39%) or in MSSA (5
      11%) was significantly lower. Consequently, the majority (76%) of homMRSA were
      multi-drug resistant, while the dominant phenotype of hetMRSA and MSSA was
      resistance to penicillin (50% and 76%, respectively). Comparison of these strains
      with isolates from 1994 showed higher resistance rates to erythromycin among
      MSSA, to erythromycin and amikacin among hetMRSA and to rifampicin among homMRSA
      strains.

PMID- 10418756
TI  - A randomised, multicentre study of ceftriaxone versus standard therapy in the
      treatment of lower respiratory tract infections.
AB  - In this study the efficacy and cost-effectiveness of i.v. ceftriaxone 1 g once
      daily (CTX) was compared with standard i.v. antibiotic treatment (STD) for lower
      respiratory tract infections (LRTI). STD was given according to the guidelines of
      the American Thoracic Society and consisted of either cefuroxime 1500 mg three
      times daily (q8h), amoxicillin/clavulanic acid 1200 mg q8h or ceftriaxone 2 g
      once daily; each with or without a macrolide. After a minimum of 5 days i.v.
      therapy, patients could be switched to oral therapy. One hundred patients were
      enrolled in the study; 52 patients received CTX and 48 STD. Groups were
      comparable with respect to demographic and baseline characteristics. Seventy
      patients had a confirmed diagnosis of pneumonia. Twenty-nine patients had a
      severe type I exacerbation of chronic bronchitis. In one patient the diagnosis of
      LRTI could not be confirmed. In approximately 50% of the patients a
      microbiological diagnosis could be made. The most important isolated pathogens
      from sputum and blood were (positive blood cultures in brackets): Streptococcus
      pneumoniae 14 (9) and Haemophilus influenzae 16. Mean duration of i.v. therapy
      was 7.4 days in both groups. Average duration of hospitalisation was 15.0 days
      for CTX patients and 15.9 days for STD patients. Overall cure and improvement
      rate at the end of treatment was 47 (90%) for patients receiving ceftriaxone 1 g
      compared to 37 (77%) for patients receiving standard therapy. Pathogens were
      eradicated or presumed to be eradicated in 84% of the CTX patients and in 76% of
      the STD patients. Mean total costs per treatment were lower for CTX than for STD
      treatment: NLG 169 versus 458. These results show, that i.v. ceftriaxone 1 g once
      daily is as effective as standard therapy in the treatment of LRTI and that its
      use reduces treatment costs, in view of the multiple daily dosing regimens of
      most standard therapies.

PMID- 10418757
TI  - Selection of resistant variants of respiratory pathogens by quinolones.
AB  - Quinolones are widely used in the treatment of respiratory tract infections.
      However, some disquiet has been expressed over using quinolones for community
      acquired pneumonia since their activity is generally rather poor against
      Streptococcus pneumoniae. In addition, it is known that resistant variants emerge
      at a fairly high frequency during exposure of Enterobacteriaceae to quinolones;
      if this also occurred during quinolone treatment of community-acquired pneumonia
      it could lead to an increased risk of clinical failure. We therefore determined
      the selection rate of quinolone-resistant variants for six strains of S.
      pneumoniae, Haemophilus influenzae and Moraxella catarrhalis with nalidixic acid
      (except for S. pneumoniae), ciprofloxacin, ofloxacin and levofloxacin. We were
      only able to select resistant variants at low frequency from two of the six
      strains of S. pneumoniae with ciprofloxacin: no resistant variants were selected
      by either ofloxacin or levofloxacin. Variants of H. influenzae and M. catarrhalis
      with decreased susceptibility to quinolones were produced both with more strains
      and with a greater frequency; however, these variants still remained susceptible
      according to the NCCLS guidelines. Our study suggests that resistant variants of
      S. pneumoniae are relatively unlikely to occur in individuals treated with
      fluoroquinolones especially if they are given quinolones with enhanced anti-gram
      positive activity compared to ciprofloxacin.

PMID- 10418758
TI  - Efficacy of trovafloxacin in an in vitro pharmacodynamic simulation of an
      intraabdominal infection.
AB  - An in vitro model simulating trovafloxacin concentrations in human serum after
      standard doses was used to investigate the activity of this drug with time
      against Bacteroides fragilis, Escherichia coli, Enterococcus faecalis and
      Staphylococcus aureus. Antibiotic concentrations used for each incubation period
      were: 4.24 mg/l (0-1 h), 3.69 mg/l (1-3 h), 3.25 mg/l (3-6 h), 2.38 mg/l (6-8 h),
      1.35 mg/l (8-24 h). A 99.9% initial inoculum reduction (> 3 log10 cfu/ml) was
      defined as bactericidal activity. Bactericidal activity against these organisms
      was obtained with trovafloxacin after the first hour of incubation, and similar
      activity was obtained against B. fragilis, E. faecalis and S. aureus after 3 h,
      when they were tested individually. When the strains were tested as mixed
      culture, there was bactericidal activity against E. coli after 1 h incubation and
      after 3 h for S. aureus. This activity was observed against B. fragilis and E.
      faecalis after 6 h incubation in the mixed culture assays and after 3 h when
      organisms were tested individually. Regrowth was not observed over a 24 h period.
      These data show that trovafloxacin might be effective in intraabdominal
      infections caused by mixed aerobic and anaerobic microorganisms.

PMID- 10418759
TI  - In vitro activities of the oxazolidinone compounds linezolid (PNU-100766) and
      eperzolid (PNU-100592) against middle ear isolates of Streptococcus pneumoniae.
AB  - Two hundred and sixteen isolates of Streptococcus pneumoniae recovered between
      1994 and 1996 from the middle ears of children with acute otitis media were
      tested for their susceptibility to penicillin, erythromycin, clindamycin and the
      oxazolidinones, linezolid (PNU-100766) and eperezolid (PNU-100592). There were
      116 isolates from the Children's Hospital of Pittsburgh and 100 isolates from a
      national collection. Eighty percent of the local strains were susceptible to
      penicillin (MIC < 0.1 mg/l); 20% of the local strains and all of the national
      strains had reduced susceptibility to penicillin. All strains of S. pneumoniae
      tested had an MIC < 2.0 mg/l for both oxazolidinones. A regional difference was
      noted in the frequency of resistance to erythromycin with local isolates being
      more susceptible than isolates from the national collection. This difference was
      most pronounced among the high-level penicillin-resistant strains of S.
      pneumoniae.

PMID- 10418760
TI  - Formula to help select rational antimicrobial therapy (FRAT): its application to
      community- and hospital-acquired urinary tract infections.
AB  - The selection of antimicrobial agents is guided by the use of formularies which
      often constrain prescribing options. There are several factors which influence
      the inclusion of specific agents. Two of the most important factors are microbial
      etiology of a disease and the incidence of antibiotic resistance. Various
      surveillance programs have highlighted the regional differences in antimicrobial
      susceptibility/resistance among various pathogens. This simple formula enables
      individual physicians, pharmacy and therapeutic committees and managed care
      formulary managers to harness local etiology and susceptibility information. In
      this paper the formula is applied to community- and hospital-acquired urinary
      tract infections.

PMID- 10418761
TI  - Multiple dose pharmacokinetics of artemether in Chinese patients with
      uncomplicated falciparum malaria.
AB  - Multiple dose pharmacokinetics of artemether and dihydroartemisinin were
      investigated in chinese patients treated for malaria. They received over 2 days
      either 4 x 80 mg artemether orally (n = 48) or 4 x 80-480 mg co-artemether (n =
      40), a combination of artemether and lumefantrine (benflumetol). Lag time = 0.48
      h (mean), Cmax after first dose = 157 ng/ml, t(max) = 1.73 h and elimination half
      life = 1.16 h. The lag and absorption times were 0.5 h longer for co-artemether
      compared with artemether. Dihydroartemisinin paralleled artemether
      pharmacokinetics. Artemether Cmax after the last dose was one-third of the Cmax
      after the first dose while, inversely, dihydroartemisinin Cmax increased over
      time. We suggest that auto-induction of gut mucosa enzymes and/or liver enzymes
      causes a time-dependent increase in first-pass metabolisation of artemether.

PMID- 10418763
TI  - The WHO model list of essential drugs.

PMID- 10418762
TI  - The comparative efficacy and tolerability of CGP 56697 (artemether +
      lumefantrine) versus halofantrine in the treatment of uncomplicated falciparum
      malaria in travellers returning from the Tropics to The Netherlands and France.
AB  - CGP 56697 (Riamet) is a new oral anti-malarial drug composed of artemether and
      lumefantrine (benflumetol) which combines the fast, short-acting artemether for
      rapid parasite clearance with the prolonged action of lumefantrine for intended
      radical cure. In this double-blind, comparative trial, the efficacy and
      tolerability of CGP 56697, given as a course of 4 x 4 tablets over 48 h, was
      compared to halofantrine, given as 3 x 2 tablets over 12 h with a second course 1
      week later. Patients (mostly non-immune) with acute, uncomplicated Plasmodium
      falciparum infection were randomly assigned to either CGP 56697 (n = 51) or
      halofantrine (n = 52). CGP 56697 proved superior with respect to parasite
      clearance time (median 32 vs. 48 h, P < 0.001) and parasite reduction at 24 h
      (median 99.7 vs. 89.6%, P < 0.001) with a non-significant difference in
      resolution of fever (median 24 vs. 32 h, P = 0.835). However, a 28-day cure rate
      of 82% was observed for CGP 56697 and 100% for halofantrine. Significant QTc
      prolongations (> 30 ms) were seen 6-12 h after halofantrine intake but not after
      CGP 56697 intake. CGP 56697 is an effective, well-tolerated treatment for
      uncomplicated falciparum malaria but for this dosing regimen the recrudescence
      rate is unacceptablyhigh (18%). For travellers contracting malaria abroad, we
      propose a six-dose regimen of CGP 56697 over 3 days.

PMID- 10418764
TI  - Activity of grepafloxacin and other fluoroquinones and newer macrolides against
      recent clinical isolates of Chlamydia pneumoniae.
AB  - Chlamydia pneumoniae is a frequent cause of community-acquired respiratory tract
      infection including pneumonia and bronchitis. Quinolones have attracted interest
      as potential therapy for community-acquired respiratory tract infections because
      they are active against a wide range of pathogens including C. pneumoniae and
      Mycoplasma pneumoniae. The in vitro susceptibilities of C. pneumoniae were
      determined for grepafloxacin, levofloxacin, moxifloxacin, trovafloxacin,
      clarithromycin and azithromycin. Isolates of C. pneumoniae tested included two
      reference strains, TW-183 and CM-1, and 12 recent clinical isolates from adults
      with community-acquired pneumonia. Susceptibility testing was performed in HEp-2
      cells grown in 96-well microtiter plates. The MIC was the lowest antibiotic
      concentration at which no inclusions were seen. The MBC was the lowest
      concentration which resulted in no inclusions after passage in antibiotic-free
      medium. Grepafloxacin was the most active quinolone tested with an MIC50 of 0.125
      mg/l, MIC90 and MBC90 of 0.5 mg/l. Grepafloxacin may have a role in the treatment
      of C. pneumoniae infections, but prospective clinical studies utilizing culture
      are lacking.

PMID- 10418765
TI  - In vitro activities of five new antimicrobial agents against Brucella melitensis.

PMID- 10418767
TI  - The association between the perception of threat in a dating situation and sexual
      victimization.
AB  - The purpose of the present investigation was to assess the relation between
      threat perception in a dating situation and sexual victimization. During an
      initial session, participants in the experimental condition (n = 116) viewed a
      video that depicts a heterosexual couple interacting on a date and reflects risk
      factors for sexual assault. Participants in the control condition (n = 108)
      viewed a video that does not contain such risk factors. Participants in each
      condition also responded to survey instruments assessing demographic variables,
      history of child sexual abuse, history of adolescent sexual assault, and
      perception of threat cues in the stimulus videos. A subset of participants (n =
      66) returned for a 5-month follow-up session and was assessed for experience of
      sexual assault during the follow-up period. Results fail to support an
      association between threat perception and sexual victimization history or an
      association between threat perception and sexual victimization during the follow
      up period.

PMID- 10418766
TI  - A comparison of gang and individual rape incidents.
AB  - This study examined differences between gang and individual offender rape
      incidents reported to the Chicago police. Analyses showed that victims and
      offenders in gang rape incidents were younger, more likely to be unemployed, but
      not different in marital status or race than victims and offenders in individual
      rapes (e.g., single offender, single victim crimes). Gang rapes were
      characterized by more alcohol and drug involvement, fewer weapons, more night
      attacks, less victim resistance, and more severe sexual assault outcomes compared
      with individual rapes. Regression analyses revealed distinct correlates of
      physical injury outcomes for gang and individual rape incidents. Implications for
      treatment and prevention of these types of assaults are discussed.

PMID- 10418768
TI  - Sexual coercion history, calloused sexual beliefs and judgments of sexual
      coercion in a date rape analogue.
AB  - This study compared men with and without a history of coercive sexual behavior on
      their judgments of how far a man should go in using coercion in an audiotaped
      date rape simulation. Calloused sexual beliefs (CSB) and a "token resistance"
      manipulation were expected to differentially interact with coercion history.
      Results showed no effect for "token resistance." Calloused sexual beliefs
      interacted with coercion group, such that sexually coercive men high in CSB took
      significantly longer to stop the date rape interaction than coercive men low in
      CSB, who did not differ from noncoercive men. These findings support a model of
      sexual coercion in which a cognitive set consisting of rape-supportive beliefs
      may serve as a disinhibitor of behavior.

PMID- 10418769
TI  - An examination of social cognitive theory with differences among sexually
      aggressive, physically aggressive and nonaggressive children in state care.
AB  - Three groups of boys in Washington State care (37 sexually aggressive, 17
      physically aggressive, and 15 nonaggressive) are compared on measures of behavior
      and cognition. Bandura's Social Cognition theory is offered as a possible
      explanation for sexual aggression by children. Two theory-based hypothesis are
      tested. First, are sexually aggressive children cognitively deficient when
      compared to the other groups? Second, do the sexually aggressive children have
      cognitive distortions about their behavior and about sex? Similarities were found
      in the aggressive and sexually aggressive groups on several measures. Physically
      aggressive boys were found to have some sexual behavior problems. Sexually
      aggressive boys were also found to be physically aggressive. Physically
      aggressive boys were found to have the least severe and least frequent
      victimization history. No support was found for the first hypothesis, while some
      evidence of cognitive distortions regarding both social behavior and sex was
      found in the sexually aggressive children. Discussion and some implications for
      research and practice are offered.

PMID- 10418770
TI  - Violent substance abusers in domestic violence treatment.
AB  - Although substance abuse is frequently encountered in men receiving services in
      violence treatment settings, systematic study of these 'dual-problem' men has
      lagged. This study had two main objectives: (1) the characterization of
      psychoactive substance abuse disorders in a naturalistic sample of men in
      domestic violence treatment; and (2) clarification of the role of substance abuse
      on the sociodemographic, personality, psychosocial, and abuse characteristics of
      dual-problem men. Fifty-three adult men who were attending domestic violence
      treatment were recruited. They were administered the Addiction Severity Index,
      the Conflicts Tactics Scale, Structured Clinical Diagnostic Interview, the 16PF
      and the Symptoms Checklist-90. Partners, when available, were asked to provide
      corroboration. Sixty-three percent of the men had a current diagnosis of
      psychoactive substance abuse or dependence, while 92.5% had a lifetime diagnosis.
      Of the former, the majority was diagnosed as multiply dependent on alcohol and
      other drugs. As the severity of the substance abuse increased, so too did the
      dangerousness and frequency of abusive behaviors. Moreover, dual-problem men
      reported more hostility, apprehension, frustration and suspiciousness and past
      arrests than did their violence-only cohorts as well as a history of multiple
      (unsuccessful) treatments for substance abuse. These findings suggest that the
      trend toward multiple drug complaints seen in other clinical milieus is also
      being confronted in conjugal violence settings. In addition to the greater
      therapeutic challenge such dual-problem men present, these findings speak to the
      need to investigate integrated treatment approaches to improve the outlook of men
      grappling with both conjugal violence and multiple substance abuse problems.

PMID- 10418771
TI  - Capture-recapture analysis of batterer reassaults: an epidemiological innovation
      for batterer program evaluation.
AB  - Capture-recapture analysis is an analytical tool being used in epidemiological
      research to estimate incidence rates for missing cases and unreliable reporting.
      Its contribution to batterer program evaluations is examined through a capture
      recapture analysis of a multisite evaluation of batterer programs (n = 853).
      Capture-recapture analysis is applied to various subsamples of the multisite
      study and to different outcomes (i.e., any reassault, "severe" reassault) to
      explore the utility of capture-recapture. Finally, the capture-recapture
      estimates are compared to only the women's reports and to adjusted women's
      reports (women's reports supplemented with arrest records and men's reports),
      which are the basis of existing batterer program evaluation. The capture
      recapture reassault estimate for the 15-month follow-up is equal to the adjusted
      women's reports (39%), but is 7% greater than the women reports. The subsample
      estimates for the individual sites appear to vary as a result of unreliable or
      unavailable arrest records.

PMID- 10418772
TI  - What happens when health practitioners report domestic violence injuries to the
      police? A study of the law enforcement response to injury reports.
AB  - This study was undertaken to learn whether law enforcement agencies in California
      ("agencies") have standard policies and procedures in place for responding to
      reports of domestic violence injuries from health practitioners ("HP reports"),
      and to describe the variation in policies and procedures across agencies. Using a
      structured interviewing tool with closed- and open-ended questions, a survey was
      taken of domestic violence experts from 39 agencies throughout California. Forty
      one agencies were asked to participate in the study. Interviews were completed
      with 39. Almost all agencies reported that they have standard procedures in place
      for responding to HP reports when the reports are made by telephone. Agencies
      handle written HP reports differently than telephone HP reports. HP reports
      constitute a very small proportion of agencies' overall domestic violence
      caseloads. Emergency departments are the usual source of HP reports. Although the
      law requires both an immediate telephone report and a written report, fewer than
      one quarter of sampled agencies always received both types of HP reports. Most
      agencies use standard response protocols when reports of domestic violence
      incidents are made by telephone, whether the reporting party is a health
      practitioner or someone else. Written HP reports do not fit into the agencies'
      usual response protocol for domestic violence situations. Because agencies'
      protocols are best suited to situations requiring prompt dispatch of an
      investigating officer, only reports made by telephone have the opportunity to
      promote an effective law enforcement response.

PMID- 10418773
TI  - A nitric oxide synthesis inhibitor administered into the medial preoptic area
      increases seminal emissions in an ex copula reflex test.
AB  - Nitric oxide synthesis inhibitors, when administered systemically or into the
      ventricles of the brain, affect several indices of male sexual behavior. Some of
      the systemic effects are assumed to be due to local vasoconstriction at the
      penis. Others are suggested to be mediated within the brain. In these
      experiments, the nitric oxide synthesis inhibitor L-NMMA, and its less active
      enantiomer, D-NMMA, were microinjected into the medial preoptic area of male
      rats. In an ex copula test of genital reflexes, L-NMMA increased the number of
      seminal emissions, while D-NMMA had no effect. These results are consistent with
      the hypothesis that nitric oxide is a tonic inhibitor of sympathetic nervous
      system tone, possibly in part through an influence on dopamine synthesis or
      release.

PMID- 10418774
TI  - Intravenous cocaine precipitates panic-like flight responses and lasting
      hyperdefensiveness in laboratory rats.
AB  - There is an emerging body of clinical evidence that cocaine use in humans can
      result in serious fear or panic-related emotional disturbances. The present study
      evaluated the effects of intravenous cocaine administration upon defensive
      responses of rats to a threatening conspecific in a test situation, an oval
      runaway, permitting the display of the full range of the rat defensive
      repertoire. A battery of tests was employed to evaluate avoidance/escape, flight,
      freezing, defensive upright and defensive attack behaviors. In the first
      experiment male Long-Evans rats implanted with a chronic indwelling jugular
      catheter were placed in the runway and tested immediately after administration of
      either 0, 1, or 4 mg/kg of cocaine hydrochloride. The 4-mg/kg dose produced a
      dramatic flight response, the direction of which depended upon the direction of
      the approaching threat source. The same dose produced increased defensive upright
      postures during forced contact with the stimulus animal. Experiment 2 examined
      the time course for cocaine-induced hyperdefensiveness. Rats were administered
      either saline or 4 mg/kg cocaine intravenously and were tested following a delay
      of either 0, 5, 15, or 30 min following infusion. Cocaine-treated rats again
      displayed high levels of flight, which declined with increased time between
      infusion and testing. However, increased defensiveness persisted even at the 30
      min delay for several defensive measures including avoidance, freezing, and
      defensive upright posture. Thus, following an initial period of rapid flight with
      intravenous cocaine administration, there was a lasting hyperdefensiveness in
      cocaine-treated rats. The present results suggest that cocaine may exert its
      panic-producing effects by acting upon neurobehavioral systems subserving
      defensive behavior, and that understanding of these systems is critical for
      understanding the neurobiology of panic disorder.

PMID- 10418775
TI  - Paradoxical effects of serotonin and opioids in pemoline-induced self-injurious
      behavior.
AB  - Self-injurious behavior (SIB) is a symptom of various psychiatric disorders with
      differing etiologies. Although no generally effective pharmacological treatment
      of SIB is available, subsets of individuals exhibiting SIB have been found to
      respond to opioid antagonists and selective serotonin reuptake inhibitors
      (SSRIs). The present study evaluated the efficacy of these two treatments in the
      pemoline-induced model of self-biting behavior (SBB) in rats. Using a factorial
      design, adult rats receiving daily pemoline at 100 mg/kg or the peanut oil
      vehicle were pretreated with either distilled water vehicle (1 cc/kg), naltrexone
      (1 mg/kg), or paroxetine (1 mg/kg). Each day, animals were rated on the severity
      of SBB and also periodically behavioral changes were evaluated using various
      other outcome measures. Paroxetine significantly increased the severity of SBB
      induced by pemoline, while naltrexone only marginally increased the SBB. These
      results were not expected and suggest that further studies into the role of
      serotonin agonists and antagonists are needed in evaluating this model.

PMID- 10418776
TI  - Pharmacological evaluation of ricinine, a central nervous system stimulant
      isolated from Ricinus communis.
AB  - The extract of the pericarp of castor bean (Ricinus communis) showed some typical
      central nervous system stimulant effects when administered to mice. The animals
      became exophthalmic, presented tremors and clonic seizures and died a few minutes
      after receiving larger doses of the extract. At lower doses the extract improved
      memory consolidation and showed some neuroleptic-like properties, such as a
      decrease in exploratory behavior and catalepsy. The memory-improving effect and
      the seizure-eliciting properties of the extract were also observed with the
      administration of ricinine, a neutral alkaloid isolated from the extract.
      However, the neuroleptic-like properties of the extract were not observed with
      ricinine. As the therapeutic index of ricinine is of the order of 200, the
      compound may be considered as a promising cognition-enhancing drug that may be
      used for the treatment of human amnesias.

PMID- 10418777
TI  - Reduction of fat and protein intakes but not carbohydrate intake following acute
      and chronic fluoxetine in female rats.
AB  - Fluoxetine hydrochloride, a selective serotonin reuptake inhibitor, leads to
      reductions in food intake and body weight and is under investigation as a
      possible treatment for obesity. Additionally, it has been suggested that
      fluoxetine administration could lead to a selective suppression in carbohydrate
      consumption. Because women more often than men seek weight reduction treatment,
      the present study examined the acute and chronic effects of fluoxetine on food
      intake, macronutrient selection, body weight, estrous cycle, and motor activity
      in female rats. Female Long-Evans rats were provided with separate sources of
      protein, fat and carbohydrate, and nutrient intakes were recorded following
      single (5.0, 10.0, and 20.0 mg/kg, IP) and chronic daily (10 mg/kg for 28 days)
      injections of fluoxetine. Acute and chronic administration of fluoxetine
      significantly reduced total caloric intake when compared to vehicle treatment.
      Moreover, fluoxetine significantly suppressed fat and protein intakes, but not
      carbohydrate intake following both acute and chronic drug administration. Animals
      chronically treated with fluoxetine gained significantly less weight than animals
      treated with vehicle. Chronic fluoxetine treatment did not significantly alter
      estrous cycle. However, in both fluoxetine- and vehicle-treated animals, total
      caloric intake, and carbohydrate and protein intakes were reduced and fat intake
      was increased when estrogen levels were high. Fluoxetine significantly reduced
      motor activity up to 4 h postinjection, and increased motor activity 24 h
      postinjection.

PMID- 10418778
TI  - The effects of atypical antipsychotics and phencyclidine (PCP) on rotorod
      performance.
AB  - A series of six experiments were conducted to determine the effects of
      haloperidol, clozapine, olanzapine, and phencyclidine (PCP) on rotorod
      performance. Rodents were trained to walk on a rotorod to avoid a mild shock to a
      criterion of 20 rpm for 3 min. None of the vehicles of any of these drugs
      disrupted rotorod performance. Haloperidol disrupted rotorod performance at doses
      of 0.03, 0.1, and 0.3 mg/kg, and olanzapine disrupted rotorod performance at
      doses of 3.0 and 10.0 mg/kg. Clozapine produced a much milder disruption across
      all three doses (3.0, 10.0, and 30.0 mg/kg). PCP produced a consistent and severe
      disruption of rotorod performance at doses of 4.0 and 6.0 mg/kg, but not at a
      dose of 2.0 mg/kg. Twenty-four hours postinjection there were no residual PCP
      effects on rotorod performance. Coadministration of either haloperidol or
      olanzapine with PCP did not reverse PCP-induced disruption in rotorod
      performance, while clozapine produced a partial reversal at only one dose. These
      findings indicate that olanzapine functions similarly to classic antipsychotics
      with respect to their effects on locomotion and balance.

PMID- 10418779
TI  - Involvement of dopamine receptors on locomotor stimulation and sensitization
      elicited by the interaction of ethanol and mazindol in mice.
AB  - We have previously observed that the combination of ethanol (EtOH) and the
      anorectic drug mazindol (MZ) produces more marked effects on behavior than either
      substance alone. In the present study we examined whether the repeated
      administration of the drug combination could induce sensitization to its motor
      activating effects in mice and, if so, whether this response could be affected by
      dopamine (DA) receptors antagonists. Male Swiss albino mice were treated daily
      for 7 days with combined EtOH+MZ (1.2 g/kg, 5.0 mg/kg IP), EtOH (1.2 g/kg IP), MZ
      (5.0 mg/kg IP), or control solution coadministered with the D1 dopamine
      antagonist SCH-23390 (0.025 or 0.05 mg/kg IP), the mixed dopamine antagonist
      haloperidol (0.05 or 0.075 mg/kg IP), or vehicle. After the injections on days 1,
      7, and 10, mice were assessed in activity cages at different time intervals.
      Repeated administration of MZ resulted in an enhancement of its locomotor
      activating effects, behavioral sensitization. Further, the combined EtOH+MZ
      treatment also resulted in sensitization to its locomotor effects. Moreover, the
      development of MZ and EtOH+MZ sensitization was attenuated by both SCH-23390 and
      haloperidol. These data demonstrate that following repeated MZ or EtOH+MZ
      exposure mice show locomotor sensitization through DA receptor stimulation. Also,
      these findings suggest that a major determinant of combined anorectic-alcohol
      misuse may be the increased stimulating effects produced by such combination.

PMID- 10418780
TI  - Pyridostigmine bromide alters locomotion and thigmotaxis of rats: gender effects.
AB  - Male rats and female rats in the proestrous and metestrous stages of estrus were
      tested to determine the effects of pyridostigmine bromide on locomotion rate and
      thigmotactic response using doses of 3.0, 10.0, and 30.0 mg/kg. Thirty minutes
      after administration of the pyridostigmine bromide the rats were videorecorded
      for 2 h in a 1 m2 open-field arena. The rats' activities were analyzed for the
      drug's effect on speed throughout the 2 h and during six 20-min segments. Also,
      the times that the rats were observed moving through the central 50% of the arena
      were determined. Locomotion rates decreased significantly, and thigmotaxses
      increased significantly in all groups of rats as a dose response to
      pyridostigmine bromide. Habituation occurred over 2 h for both responses,
      primarily during the first 40 min. Female rats were more affected than males, but
      metestrous and proestrous females did not differ significantly in their
      responses. At the 30 mg/kg the effect was persistent throughout the test period.
      Proestrous females dosed at 30 mg/kg had much higher pyridostigmine bromide serum
      levels than metestrous females and males.

PMID- 10418781
TI  - Inhibition by ginsenosides Rb1 and Rg1 of cocaine-induced hyperactivity,
      conditioned place preference, and postsynaptic dopamine receptor supersensitivity
      in mice.
AB  - A single or repeated administration of cocaine (15 mg/kg) in mice produced
      hyperactivity and conditioned place preference (CPP). Ginsenoside Rb1 (Rb1) and
      ginsenoside Rg1 (Rg1), prior to and during the cocaine treatment in mice,
      inhibited cocaine-induced hyperactivity and CPP. The development of enhanced
      postsynaptic dopamine (DA) receptor sensitivity in mice displaying a cocaine
      induced CPP was evidenced by the enhanced response in ambulatory activity to the
      DA agonist, apomorphine (2 mg/kg). Rb1 and Rg1 inhibited the development of
      postsynaptic DA receptor supersensitivity. However, Rb1 and Rg1 did not show any
      antidopaminergic activity at the postsynaptic DA receptors, because the
      apomorphine-induced climbing behavior was not inhibited by Rb1 and Rg1.
      Therefore, it is presumed that Rb1 and Rg1 modulate DA activity induced by
      cocaine at the presynaptic DA receptors, and this modulation results in the
      inhibition of postsynaptic dopaminergic activation. These results suggest that
      the cocaine-induced CPP may be associated with enhanced DA receptor sensitivity.
      The inhibition by Rb1 and Rg1 of cocaine-induced hyperactivity and CPP may be
      closely related with the inhibition of dopaminergic activation induced by cocaine
      at the presynaptic DA receptors.

PMID- 10418782
TI  - A further study on asymmetric cross-sensitization between MK-801 and
      phencyclidine-induced ambulatory activity.
AB  - Our previous study found that MK-801-sensitized rats showed cross-sensitization
      to the locomotor stimulant effects of phencyclidine, but phencyclidine sensitized
      rats did not show cross-sensitizaton to MK-801. This study was designed to
      determine whether the asymmetric cross-sensitization was due to injection
      environment conditioning or possibly reduced phencyclidine-like effects following
      further repeated injections of phencyclidine. Adult female Sprague-Dawley rats
      were used in this study, and their activity was assessed with an automated
      photoelectric system. Results confirmed the early finding that four daily
      injections of phencyclidine (3.2 mg/kg) or MK-801 (0.32 mg/kg) produced locomotor
      sensitization, and that the two drugs showed asymmetric cross-sensitization.
      Moreover, injection-environment conditioning was ruled out as a possible cause
      for cross-sensitization from MK-801 to phencyclidine, and possibly reduced
      phencyclidine-like effects following further repeated injections was also ruled
      out as a cause for the failure of cross-sensitization from phencyclidine to MK
      801. These additional results further confirm our previous finding, and indicate
      that there are significant differences in the neural mechanisms underlying
      phencyclidine- and MK-801-induced sensitization.

PMID- 10418783
TI  - Behavioral sensitization to apomorphine in adult rats exposed to cocaine during
      the preweaning period: a preliminary study.
AB  - Sixty-day-old rats treated with cocaine (50 mg/kg SC) during postnatal days (PND)
      11-20 received daily injections of apomorphine (2.0 mg/kg SC) for 10 consecutive
      days to examine the development of sensitization to a direct dopamine agonist.
      Behavior was monitored on days 1, 5, and 10, using a photobeam system, and on day
      10 using the videotape assessments as well. Locomotor sensitization to
      apomorphine developed in the preweaning vehicle-treated males only. Neither the
      cocaine-treated males nor any females exhibited locomotor sensitization to
      repeated apomorphine injections at 2 mg/kg. There were no other treatment-related
      effects except for grooming, which showed an interaction between treatment and
      gender. Overall, every behavior analyzed showed significant apomorphine effects,
      except rearing. Margin time (wall hugging), grooming, and quiet were
      significantly decreased by apomorphine, while locomotion and the duration of
      sniffing were increased. In summary, these data indicate that with respect to
      locomotor activity, the development of sensitization to apomorphine at 2.0 mg/kg
      is prevented by preweaning cocaine administration in males. These data further
      suggest that developmental cocaine exposure produces long-term alterations in DA
      D1 receptor-mediated responses in male rats.

PMID- 10418785
TI  - Feeding and reward interactions from chronic paroxetine treatment.
AB  - The self-stimulation paradigm was used to evaluate threshold changes following
      acute and chronic administration of the selective serotonergic reuptake inhibitor
      paroxetine; stimulation sites were located in medial forebrain bundle structures.
      Rats received daily systemic injections of one of three doses of paroxetine (2.5,
      5, or 7.5 mg/kg), either with or without stimulation, while the last group
      received the same number of vehicle injections with stimulation. Frequency
      thresholds were collected over a period of 6 h on day 1 (acute phase); no marked
      difference in the values were observed over this time span. Thereafter, the
      animals were tested every third day (chronic phase), for a total of 11 sessions
      or roughly 31 days. Commencing around day 10 of the drug treatment, the higher
      dose of paroxetine produced a significant and persistent facilitation in self
      stimulation thresholds, mimicking the delay in clinical response in humans that
      is well documented. We also monitored on a daily basis the animals' weights and
      food intake. A large difference in the percent efficiency of food utilization,
      measured by calculating the ratio of weight change to food intake, was observed
      between the animals receiving stimulation and those that were not, exclusive to
      the higher dose of paroxetine. The percent efficiency of food utilization
      remained low in the animals only receiving the drug treatment, whereas they
      returned to baseline levels and above in subjects receiving both paroxetine and
      stimulation. Two findings emerge from these data: 1) the paradigm appears to
      model the human response to this class of antidepressants, and 2) rewarding
      stimulation seems to counteract the drug-induced weight loss.

PMID- 10418784
TI  - Lead-induced decrements in waiting behavior: involvement of D2-like dopamine
      receptors.
AB  - Some behavioral changes produced by chronic postweaning lead (Pb) exposure have
      been linked to mesolimbic dopamine (DA) system alterations. This study sought to
      determine the role of DA systems in Pb-induced changes in a fixed ratio (FR)
      waiting-for-reward paradigm. Rats exposed chronically from weaning to 0, 50, or
      150 ppm Pb acetate drinking solutions earned free reinforcers for waiting after
      completion of an FR, with increasing time between successive free reinforcers.
      Responses during the waiting period reset the FR requirement. Once performance
      stabilized, the effects of acute IP administration of the D1 agonist SKF82958,
      the D2 agonist quinpirole, the D1 antagonist SCH23390, and the D2 antagonist
      eticlopride were determined. Pb itself increased FR response rates and decreased
      mean waiting time, a pattern of behavior that increased the number of earned
      reinforcers, but doubled the number of responses/reinforcer. None of the DA
      compounds mimicked Pb effects when administered to controls. Only DA agonists
      altered waiting behavior and responses per reinforcer. Quinpirole, in particular,
      appeared to reverse Pb effects on the FR wait baseline by increasing waiting time
      and decreasing FR resets to control levels. These findings point to a particular
      role for D2 DA function in Pb's detrimental effects on waiting.

PMID- 10418786
TI  - Reduced progesterone metabolites are not critical for plus-maze performance of
      lactating female rats.
AB  - Lactation has been associated with anxiolysis in several tests of anxiety. These
      observations, considered together with observations that progesterone and its
      5alpha-reduced metabolites are anxiolytic in cycling, nonlactating females,
      raised the question of whether the changes in anxiety-related behaviors that
      accompany lactation are driven by reduced progesterone metabolites. Lactating
      female rats were tested on the plus-maze on postpartum days 2 or 7, and
      demonstrated enhanced open-arm performance relative to cycling, nonlactating
      females. Hormonal analysis indicated that while serum levels of both progesterone
      and its 3alpha,5alpha-reduced metabolite were increased in lactating females, the
      turnover of progesterone to the metabolite was markedly reduced during lactation.
      Furthermore, treatment with a 5alpha-reductase inhibitor for 3 days prior to
      testing potentiated the open-arm performance in lactating females, implying that
      enhanced open-arm performance was not mediated by the reduction of progesterone
      or other steroids. Additionally, analysis of GABA(A) receptor function indicated
      that parturition and lactation did not alter the sensitivity of the receptor to
      GABA or to modulation by reduced steroids. The mechanisms driving enhanced plus
      maze behavior in lactating females appear to differ from mechanisms identified in
      nonlactating females.

PMID- 10418788
TI  - Ibogaine enhances the expression of locomotor sensitization in rats chronically
      treated with cocaine.
AB  - Pretreatment (19 h) with the putative antiaddictive agent, ibogaine, has been
      shown previously to potentiate cocaine-induced locomotion in rats. The present
      study demonstrates that the magnitude of this effect of ibogaine is dependent on
      the previous cocaine history of the animal, on the time following ibogaine
      treatment, and on the number of ibogaine treatments. Compared to rats with no
      previous cocaine experience, ibogaine pretreatment (40 mg/kg, IP, 19 h earlier)
      markedly enhanced the expression of locomotor sensitization in response to a
      cocaine challenge injection (7.5 mg/kg) in rats that were chronically treated
      with cocaine (15 mg/ kg, IP, daily for 5 days). Tolerance to cocaine-induced
      locomotor sensitization appeared to occur in vehicle-pretreated chronic cocaine
      controls. Following a second series of identical treatments (beginning 3-4 days
      after the initial treatment series), locomotor responding to the cocaine
      challenge was further enhanced by a second ibogaine injection in chronically
      cocaine-treated animals. Twenty-four hours later, when animals were challenged
      again with cocaine in the absence of any further ibogaine pretreatment, the
      effect of ibogaine had dissipated. Consistent with previous studies from this
      laboratory, these data demonstrate that ibogaine can enhance sensitivity to the
      psychomotor stimulant effect of cocaine. The results of the present study further
      indicate that the extent of this effect depends on the animal's history of
      exposure to both ibogaine and cocaine.

PMID- 10418787
TI  - Cocaine-induced oscillation is conditionable.
AB  - We have recently shown that under some circumstances, sensitization produced by a
      stimulant such as cocaine (COC) can give way, with successive drug
      administrations, to alternating attenuations and reinstatements of the effect, an
      outcome that we have termed oscillation. Because sensitization to COC can be
      conditioned, we inquired whether COC-induced oscillation also was conditionable.
      The end point used was shock-induced hypoalgesia (paw withdrawal from a hot
      plate), as we have previously shown that oscillation follows initial
      sensitization of this measure with one to five pretreatments of 12 mg/kg (IP) of
      COC spaced at 1-week intervals, with the last COC injection occurring 30 min
      prior to the footshock. Experiment 1 indicated that a conditioned stimulus (CS)-
      a distinctive environment--which repeatedly had been paired with COC, would
      substitute for the last COC injection in sustaining the oscillatory effect.
      Experiment 2 showed that a previously established CS successfully substituted for
      all COC injections in first inducing sensitization that was then followed by
      oscillation. These findings strongly suggest that COC-induced oscillation shares
      with COC-induced sensitization, the property that both can be conditioned.

PMID- 10418789
TI  - The effects of phenytoin on instrumental appetitive-to-aversive transfer in rats.
AB  - Antiepileptic medications are the primary treatment for seizure conditions. Over
      the past several years, it has become clear that the medications themselves may
      contribute to the negative cognitive side effects that people with epilepsy often
      report. In the experiments reported here, the effects of phenytoin treatment have
      been evaluated in rats performing an instrumental appetitive-to-aversive transfer
      task. We find that rats treated with phenytoin fail to acquire the avoidance
      response when transferred from an appetitive to an aversive context. This deficit
      is not due to any sensory or motor slowing resulting from the drug, nor is it a
      deficit that is specific to learning in an aversive context. Rather, we suggest
      that the deficits shown by phenytoin-treated rats in the appetitive-to-aversive
      transfer reflect a fundamental inability in altering the associations that were
      formed during the initial appetitive training.

PMID- 10418790
TI  - Genetic determinants of severity of acute withdrawal from diazepam in mice:
      commonality with ethanol and pentobarbital.
AB  - Potentially life-threatening seizures can occur following withdrawal from
      benzodiazepines, ethanol, or barbiturates. In animals, withdrawal severity has
      been shown to be partially genetically determined for each drug class.
      Susceptibility to these drugs is partially determined by common genetic factors,
      but the evidence is conflicting. We tested the hypothesis that acute
      benzodiazepine withdrawal convulsions are influenced by at least some genes that
      also affect withdrawal from ethanol and pentobarbital. Results in inbred mouse
      strains demonstrate that strain susceptibility is genetically correlated with
      susceptibility to ethanol and pentobarbital. The proportion of variance accounted
      for by genetic factors common to diazepam and ethanol was estimated at 69%.
      Results contrast with previous data obtained in mice that were serially tested
      for withdrawal severity from ethanol, pentobarbital, and then diazepam, because
      serial testing of mice significantly affected the previous results for some
      strains. Diazepam withdrawal severity was also genetically correlated with
      pentobarbital withdrawal. Together, these results suggest that some genes
      influence severity of withdrawal from several types of depressant drugs.

PMID- 10418791
TI  - Nalorphine's ability to substitute for morphine in a drug discrimination
      procedure is a function of training dose.
AB  - Rats trained to discriminate the mu agonists fentanyl or morphine from their
      respective vehicles generalize to the partial mu agonist nalorphine incompletely
      and inconsistently. Any number of factors may influence the generalization
      patterns obtained, one of which being the specific dose of the full opioid
      agonist used during training, a factor reported to influence generalization with
      other partial opioid agonists. To assess if training dose influences stimulus
      generalization to nalorphine and to support its role in the aforementioned
      variability across studies, in the present experiments rats were trained to
      discriminate either a low (5.6 mg/kg) or a high (10 mg/kg) dose of morphine from
      distilled water within the taste aversion baseline of drug discrimination
      learning. Subjects were then given a range of doses of morphine, nalorphine,
      methadone, or naloxone to assess the degree of substitution (if any) of these
      compounds for the training dose of morphine. For all subjects, morphine fully
      substituted for itself, and the opioid antagonist naloxone failed to substitute
      for the morphine cue. Rats generalized the morphine cue to nalorphine in subjects
      trained at the lower dose but not in subjects trained at the higher dose. Rats
      generalized the morphine cue to methadone in the latter group (the high dose
      group), indicating that the failure to generalize to nalorphine in this group was
      not a general inability of an opioid agonist to substitute for morphine. Naloxone
      blocked morphine stimulus control in all subjects and nalorphine control in the
      low-dose group for which nalorphine substituted for morphine, suggesting that
      morphine control (and the nalorphine substitution) was based on opioid activity.
      These results indicate that the substitution patterns of nalorphine in morphine
      trained subjects are a function in part of the dose of morphine used in training
      and support the position that nalorphine is a partial opioid agonist with
      intermediate efficacy.

PMID- 10418792
TI  - Review of evidence for a novel model of cocaine-induced cardiovascular toxicity.
AB  - Cocaine is known to produce life-threatening cardiovascular complications in some
      but not all individuals. This review considers the premise that an appropriate
      animal model for cocaine-induced cardiotoxicity should be characterized by
      varying sensitivity in the population to the deleterious effects of cocaine. We
      have studied such a model in which physiological, biochemical, and pathological
      sensitivity to cocaine varies in rats. Our studies have identified a subset of
      rats that respond to cocaine with a decrease in cardiac output and a substantial
      increase in systemic vascular resistance (named vascular responders). In
      contrast, another group, designated mixed responders, is characterized by a
      smaller increase in systemic vascular resistance and a small increase in cardiac
      output. We reported that vascular responders are more likely to develop
      hypertension and cardiomyopathies with repeated cocaine administration. Under
      chloralose anesthesia, vascular responders have more profound pressor responses
      to cocaine and an initial brief spike in renal sympathetic nerve activity not
      usually noted in mixed responders. Vascular responders have higher resting and
      cocaine-induced dopamine turnover in the striatum. In addition, vascular
      responders have higher alpha-adrenergic vasoconstrictor tone, whereas mixed
      responders have higher adrenergic cardiac tone. The difference in cardiac output
      and systemic vascular resistance responses to cocaine in these two subsets of the
      population can be prevented by L-type calcium channel, muscarinic, or alpha
      adrenergic blockade. Similar hemodynamic response variability is noted with other
      psychoactive agents and with acute stress, suggesting that the response patterns
      are not unique to cocaine. We propose that individual hemodynamic response
      variability is dependent on differences in CNS responsiveness and correlated with
      the incidence of cardiovascular disease.

PMID- 10418793
TI  - Oral versus transdermal selegiline: antidepressant-like activity in rats.
AB  - These studies compared the dose-response effects of oral vs. transdermal
      selegiline on antidepressant-like activity and brain monoamine oxidase (MAO)
      activities in rats. Rats received selegiline by gavage (0-100 mg/kg) or via
      transdermal patches (0-4.8 cm2, 0-8.7 mg/kg) daily for 7 days; antidepressant
      like activity was determined using the forced-swim test. Following behavioral
      testing, cerebral cortices were assayed for MAO-A and MAO-B activities. Doses of
      selegiline that selectively inhibited MAO-B (3 and 10 mg/kg/day by gavage and 0.4
      mg/kg/day via patch) did not alter either immobility or latency time. However,
      the oral administration of 30 or 100 mg/kg/day or the transdermal administration
      of 8.7 mg/kg/day, doses that led to greater than 70% inhibition of MAO-A,
      decreased immobility time significantly. The IC50s for inhibition of MAO-A
      following oral and transdermal administration for 7 days were 19.8 and 1.1 mg/kg,
      respectively. Results indicate that both oral and transdermal selegiline have
      antidepressant-like activity as assessed by the forced-swim test, and that
      transdermal administration, which bypasses first-pass metabolism, allows for
      using lower doses than oral administration.

PMID- 10418794
TI  - The acute effects of monoamine reuptake inhibitors on the stimulus effects of
      hallucinogens.
AB  - In a previous study it was observed that fluoxetine potentiates the stimulus
      effects of lysergic acid diethylamide (LSD). In the present investigation,
      stimulus control was established in groups of rats using as training drugs the
      hallucinogens lysergic acid diethylamide (LSD); 0.1 mg/kg), (-)-2,5-dimethoxy-4
      methylamphetamine [(-)-DOM; 0.56 mg/kg], ibogaine (10 mg/kg), and 5-methoxy-N,N
      dimethyltryptamine (5-MeO-DMT; 3 mg/kg). A two-lever, fixed-ratio 10, positively
      reinforced task with saline controls was employed. The hypotheses tested were
      that (a) monoamine uptake inhibitors other than fluoxetine potentiate the
      discriminative effects of LSD, and (b) hallucinogens other than LSD are
      potentiated by acute pretreatment with monoamine uptake inhibitors. The effects
      of a range of doses of each of the training drugs were determined both alone and
      following pretreatment with the monoamine reuptake inhibitors fluoxetine,
      fluvoxamine, and venlafaxine. In LSD-trained subjects, all three reuptake
      inhibitors caused a significant increase in LSD-appropriate responding. Similar
      results were observed in rats trained with (-)-DOM and with ibogaine. In 5-MeO
      DMT-trained subjects, only fluoxetine resulted in an enhancement of drug
      appropriate responding. The reuptake inhibitors given alone elicited varying
      degrees of responses appropriate for the respective training drugs. For
      fluoxetine in rats trained with LSD and ibogaine, for venlafaxine in LSD trained,
      and for fluvoxamine in (-)-DOM trained, the degree of responding met our
      criterion for intermediate responding, i.e., significantly different from both
      training conditions. Subsequent experiments in (-)-DOM-trained subjects examined
      a range of doses of each of the reuptake inhibitors in combination with a fixed
      dose of (-)-DOM (0.1 mg/kg), which alone yielded about 50% (-)-DOM-appropriate
      responding. With the exception of the point obtained with the highest dose of
      venlafaxine, all data were compatible with additivity of effects rather than true
      potentiation. In summary, the present data extend our previous observation of the
      augmentation of the stimulus effects of LSD by fluoxetine to include other
      hallucinogens. The mechanisms by which these interactions arise and possible
      differential effects of acute and chronic treatment remain to be established.

PMID- 10418795
TI  - Opioid receptor blockade promotes weight loss and improves the display of sexual
      behaviors in obese Zucker female rats.
AB  - Obese Zucker female rats are hyperphagic, overweight, infertile, and
      hyporesponsive to the inductive effects of ovarian steroid hormones on sexual
      behaviors. It has been postulated that endogenous opioid activity may contribute
      to their obesity and reproductive dysfunction. To test this hypothesis,
      ovariectomized, adult obese Zucker rats were treated with the opioid receptor
      antagonist, naltrexone, or saline prior to measurement of steroid-induced sexual
      behaviors, food intake, and body weight. In estradiol benzoate (EB)-treated rats,
      naltrexone injection increased the display of sexual receptivity (lordosis
      quotient, LQ: saline, 11+/-10%; 5 mg/kg naltrexone, 54+/-15%, p < 0.05) and also
      elicited proceptivity (PRO), which was never observed after saline injection. In
      EB plus progesterone-treated animals, naltrexone administration enhanced both
      sexual receptivity and proceptivity (LQ: saline, 17+/-10%; 5 mg/kg naltrexone,
      96+/-3%; p < 0.05; PRO: saline, 3.0+/-2.4 bouts/min; 5 mg/kg naltrexone, 45.3+/
      12 bouts/min; p < 0.01). Naltrexone injection also decreased 24-h food intake
      (saline, 24.2+/-0.7 g; 5 mg/kg naltrexone, 17.6+/-1.2 g; p < 0.05) and weight
      change (saline, +7.3+/-0.8 g; 5 mg/kg naltrexone, -4.5+/-1.4 g, p < 0.01).
      Morphine treatment blocked these effects of naltrexone on sexual behaviors, food
      intake, and body weight. These data suggest that endogenous opioids contribute to
      hyperphagia, obesity, and behavioral hyporesponsiveness to ovarian steroid
      hormones in obese Zucker rats.

PMID- 10418796
TI  - Differences between activation thresholds for platelet P-selectin glycoprotein
      IIb-IIIa expression and their clinical implications.
AB  - Increased platelet reactivity is a descriptor of the risk of cardiovascular
      events in healthy men and in patients with overt coronary artery disease. We
      sought to determine if differential thresholds exist for activation of platelets
      with respect to alpha-granule degranulation and fibrinogen binding in healthy
      volunteers and in patients with acute coronary syndromes. We also sought to
      characterize the effect of aspirin on activation. Platelet activation was
      assessed with flow cytometry in whole blood anticoagulated with corn trypsin
      inhibitor and incubated with fluorescein isothiocyanate conjugated fibrinogen (to
      define activation of glycoprotein IIb-IIIa), a phycoerythrin conjugated antibody
      to P-selectin (a marker of alpha-granule degranulation), and selected
      concentrations of adenosine diphosphate (ADP) or thrombin receptor agonist
      peptide. ADP-induced fibrinogen binding was found to be a low threshold
      activation event (40% of platelets bound fibrinogen in response to 0.2 microM
      ADP). Alpha-granule degranulation was a higher threshold event (33% of platelets
      expressed P-selectin in response to 1.0 microM ADP). Intra- and interindividual
      variability were most apparent with low concentrations of agonist (0.2 microM
      ADP). Patients with acute coronary syndromes (on aspirin) had significantly
      increased P-selectin expression in response to ADP compared with healthy subjects
      (on aspirin), but no difference in ADP-induced fibrinogen binding was observed.
      Daily ingestion of 325 mg of aspirin had no effect on either P-selectin
      expression or fibrinogen binding in healthy subjects. Analysis of platelet
      reactivity with flow cytometry characterizes activation with respect to specific
      components of the process and should facilitate development and optimal titration
      of antiplatelet therapy.

PMID- 10418797
TI  - Inhibition of platelet aggregation by abciximab but not by aspirin can be
      detected by a new point-of-care test, the hemostatus.
AB  - We have investigated the type of platelet defect that can be detected with the
      Hemostatus test performed with the Hepcon/HMS instrument (Medtronic) designed to
      investigate platelet function during and after surgery. This assay is based on
      the comparison of the activated clotting time of whole blood measured in
      cartridges containing kaolin or kaolin and platelet-activating factor in
      different concentrations. Addition of platelet-activating factor shortened the
      blood activated clotting time when the platelet counts were normal. However, when
      platelet counts were below 70000/microL, the activated clotting time was
      prolonged in all channels including those without platelet-activating factor
      showing the influence of platelets in the formation of the clot under the
      conditions tested. Inhibition of platelet aggregation with c7E3 (abciximab,
      ReoPro) also induced a much-prolonged activated clotting time, and a similar
      finding was seen with blood from a patient with Glanzmann's thrombasthenia
      confirming the need for platelet aggregation and/or the glycoprotein (GP) IIb
      IIIa complex. In contrast, the interaction of GP Ib with von Willebrand Factor
      was not of major importance, since inhibition of this interaction with the anti
      GP Ib murine monoclonal antibody, ALMA-12, did not modify the activated clotting
      time. Furthermore, the activated clotting time measured for patients with an
      acquired defect in von Willebrand Factor activity were unchanged. Finally,
      inhibition of thromboxane A2 formation by aspirin did not influence the results
      of this test. Globally, the Hemostatus test was able to detect major
      abnormalities of GP IIb-IIIa function in the presence or absence of platelet
      activating factor.

PMID- 10418798
TI  - The effect of short-term cold exposure on risk factors for cardiovascular
      disease.
AB  - The aim of this study was to see if a short-term period of exposure to cold in
      young healthy subjects causes changes in hematological factors known to be
      associated with the promotion of thrombogenesis. Over a period of 48 hours,
      changes in the distribution of erythrocytes, granulocytes, and blood platelets,
      as well as several coagulation, inflammatory, and fibrinolytic parameters, were
      monitored in 11 young healthy male subjects following a short period (1 hour) of
      cold exposure (CE) (ambient temperature, 11 degrees C) or exposure to
      thermoneutral conditions (ambient temperature, 26 degrees C) in winter
      (November). The major findings were: (1) a CE-induced hemoconcentration as
      indicated by an increase in erythrocyte count (3.2% increase); (2) after
      appropriate adjustments for changes in hemoconcentration, a cold-induced
      mobilization of granulocytes (14.5% increase) and a cold-induced decrease in
      lymphocytes (7% decrease); (3) thromboxane B2 release following endotoxin
      stimulation of whole blood was increased by 27.4% in the CE experiments; (4)
      diurnal rhythms were observed in granulocytes, blood platelets, middle plate
      volume, tissue plasminogen activator, and plasma activator inhibitor; and (5) CE
      caused no significant changes in lipopolysaccharide-induced tissue factor, nor in
      the blood coagulation factor VII or cytokines, interleukin-6, and tumor necrosis
      factor. It is concluded that short-term cold exposure in young healthy subjects
      initiates a mild inflammatory reaction and a tendency for an increased state of
      hypercoagulability.

PMID- 10418799
TI  - The gene expression of coagulation factor VIII in mammalian cell lines.
AB  - Both the full-length and B domain-deleted cDNA of factor VIII were constructed in
      plasmid pcDNA3, respectively, and successfully expressed in Cos-7 cells. The
      yield of recombinant factor VIII-deltaB (0.4 U/mL/10(6) cells/day) was
      approximately four times higher than that of the recombinant factor VIII. In
      addition, it was indicated that the gene expression of factor VIII is specific
      for cells from different tissues. The highest expression level was found in the
      hepatocellular carcinoma line SMMC-7721, followed by kidney, ovary, and lung cell
      lines. To compare the efficiency of gene expression of recombinant factor VIII,
      the factor VIII-deltaB gene was further reconstructed in different forms in the
      expression plasmid pCMV-dhfr for transient gene expression in Chinese hamster
      ovary cells. The redundant 5'- and 3'-untranslated sequences of factor VIII
      deltaB were deleted. The cDNA encoding the heavy and light chains of factor VIII
      were constructed, respectively. Among them the high yield of the recombinant
      factor VIII was found in the coexpression of the heavy and light chain cDNA
      fragments of factor VIII. The deletion of the redundant 5'-untranslated sequence
      of factor VIII-deltaB was also beneficial for gene expression. As expected, the
      gene coexpression of factor VIII-deltaB and von Willibrand Factor cloned by the
      long-polymerase chain reaction method was also helpful for enhancing the
      expression level of recombinant factor VIII. A monoclonal antibody raised against
      factor VIII was prepared and used for the specific assay of recombinant factor
      VIII by the competitive ELISA method, the assay results were consistent with
      those determined by the one-stage bioassay.

PMID- 10418800
TI  - Thrombin inhibitors suppress the thrombin-thrombomodulin-mediated generation of
      activated protein C.
AB  - In the treatment of unstable coronary artery disease, direct thrombin inhibitors
      have shown no or only limited benefit as compared with heparin, despite
      theoretical advantages. One explanation may be that the direct thrombin
      inhibitors to a greater extent than heparin have an inhibiting effect on the
      generation and activity of activated protein C. In the present study, this
      hypothesis was tested in an in vitro, "purified" system, where human protein C
      underwent activation to activated protein C by the thrombin-thrombomodulin
      complex. Direct thrombin inhibitors, inogatran and hirudin, unfractionated
      heparin+antithrombin, or dalteparin+antithrombin, were added to the system before
      activation to evaluate their inhibitory effect on the generation of activated
      protein C. At inhibitor concentrations well below the achieved plasma levels in
      major clinical trials, the thrombin-thrombomodulin-mediated activation of protein
      C was inhibited by all the studied inhibitors in a dose-dependent manner, but,
      contrary to our hypothesis, to a greater extent by unfractionated
      heparin+antithrombin and dalteparin+antithrombin than by the direct thrombin
      inhibitors, hirudin and inogatran. Despite difficulties to draw conclusions for
      the in vivo situation, the in vitro inhibition, by all studied inhibitors, of the
      generation of activated protein C, found in this study may be a possible
      explanation for ongoing cardiovascular events despite adequate treatment with
      thrombin inhibitors, in patients with unstable coronary artery disease. This
      inhibition of the generation of activated protein C may also contribute to the
      rebound in cardiovascular events after withdrawal of effective antithrombotic
      treatment.

PMID- 10418801
TI  - Familial occurrence of primary antiphospholipid syndrome.

PMID- 10418802
TI  - Good correlation between clinical bleeding tendencies and bleeding pattern from
      the bleeding time incision.

PMID- 10418803
TI  - Platelet contribution to blood coagulation in patients with markedly reduced
      platelet aggregation.

PMID- 10418804
TI  - Bronchoscopy-related infections and pseudoinfections--New York, 1996 and 1998.
AB  - Bronchoscopy is a useful diagnostic technique that can be performed safely by
      trained specialists when the bronchoscopes in both inpatient and ambulatory-care
      settings are reprocessed properly to prevent transmission of infection. The New
      York State Department of Health received reports of three clusters of culture
      positive bronchoscopy specimens obtained in 1996 and 1998 from patients at local
      health-care facilities. This report summarizes the results of investigations of
      these clusters, which indicated involvement of Mycobacterium tuberculosis, M.
      intracellulare, or imipenem-resistant Pseudomonas aeruginosa. Between patient
      uses, bronchoscopes had been cleaned, visually inspected, leak tested, and
      processed by STERIS System 1 processors (STERIS, Mentor, Ohio).

PMID- 10418805
TI  - Rubella outbreak--Westchester County, New York, 1997-1998.
AB  - Since licensure of rubella vaccines in 1969, the incidence of rubella and
      congenital rubella syndrome (CRS) in the United States has decreased
      substantially. Rubella infection during the first trimester of pregnancy can
      result in miscarriage, stillbirth, or infants with a pattern of birth defects
      (i.e., CRS). One of the national health objectives for 2000 is to eliminate
      indigenous rubella and CRS (objective 20.1). During 1997-1998, 524 cases of
      rubella were reported in the United States (CDC, unpublished data, 1999). This
      report describes a rubella outbreak in Westchester County, New York, demonstrates
      the importance of accurately defining and vaccinating at-risk populations to
      prevent transmission, and underscores how collaboration with community-based
      organizations can facilitate the development and implementation of control
      measures.

PMID- 10418806
TI  - Thimerosal in vaccines: a joint statement of the American Academy of Pediatrics
      and the Public Health Service.
AB  - The Food and Drug Administration (FDA) Modernization Act of 1997 called for FDA
      to review and assess the risk of all mercury-containing food and drugs. In line
      with this review, U.S. vaccine manufacturers responded to a December 1998 and
      April 1999 FDA request to provide more detailed information about the thimerosal
      content of their preparations that include this compound as a preservative.
      Thimerosal has been used as an additive to biologics and vaccines since the 1930s
      because it is very effective in killing bacteria used in several vaccines and in
      preventing bacterial contamination, particularly in opened multidose containers.
      Some but not all of the vaccines recommended routinely for children in the United
      States contain thimerosal.

PMID- 10418807
TI  - Aggressive behavior in patients with attention-deficit/hyperactivity disorder,
      conduct disorder, and pervasive developmental disorders.
AB  - Aggressive behaviors are frequently observed in patients with attention
      deficit/hyperactivity disorder, conduct disorder, and pervasive developmental
      disorders. Several theories have been postulated to explain the etiology of
      aggression in these disorders, but no one theory can account for all the
      different types of aggressive behaviors observed. Numerous uncontrolled studies
      with small sample sizes have produced mixed results of pharmacologic agents now
      being used to treat aggression. This article discusses the phenomenology,
      etiology, assessment, and pharmacologic treatment of aggressive behavior in
      patients who have attention-deficit/hyperactivity disorder, conduct disorder, and
      pervasive developmental disorders.

PMID- 10418808
TI  - Recognition and treatment of DSM-IV intermittent explosive disorder.
AB  - Although models of impulsive aggression are often associated with psychiatric
      disorders, some individuals demonstrate violent outbursts of rage that are
      variously referred to in the field as rage attacks, anger attacks, episodic
      dyscontrol, and intermittent explosive disorder. According to DSM-IV,
      intermittent explosive disorder is characterized by discrete episodes of failure
      to resist aggressive impulses resulting in serious assaults or destruction of
      property. Virtually no research has been done on intermittent explosive disorder
      as defined by DSM-IV criteria, and this article discusses the phenomenology,
      comorbidity, and treatment response of 27 individuals who met the DSM-IV criteria
      for the disorder. The association of the explosive episodes in these subjects
      with maniclike affective symptoms, the high rate of lifetime comorbid bipolar
      disorder, and the favorable response of explosive episodes to mood-stabilizing
      drugs suggest that intermittent explosive disorder may be linked to bipolar
      disorder.

PMID- 10418809
TI  - Phenomenology and treatment of agitation.
AB  - Agitation is a troublesome, common symptom in major depression that can be
      difficult to manage. It is sometimes a side effect of antidepressant treatment
      and may occasionally represent a mixed bipolar episode. If agitation fails to
      respond to an antidepressant alone, treatment may be augmented with a
      benzodiazepine, a neuroleptic, or lithium. Preliminary evidence indicates that
      divalproex, which has been found useful for bipolar disorder and for agitation
      associated with Alzheimer's disease, may also be effective for agitated
      depression. A controlled trial is now underway.

PMID- 10418810
TI  - Anger attacks in patients with depression.
AB  - Anger attacks are sudden intense spells of anger that resemble panic attacks but
      lack the predominant affects of fear and anxiety associated with panic attacks.
      They typically occur in situations in which an individual feels emotionally
      trapped and experiences outbursts of anger that are later described by the
      patient as being uncharacteristic and inappropriate to the situation at hand.
      Anger attacks consist of both behavioral and autonomic features, and various
      criteria and an Anger Attacks Questionnaire have been designed to identify the
      presence of these attacks. The prevalence of anger attacks in depressed patients
      is approximately 30% to 40%, and the attacks have disappeared in 53% to 71% of
      depressed patients treated with fluoxetine, sertraline, or imipramine. This
      article discusses the development of the concept of anger attacks, the presence
      of anger attacks in depression and other psychiatric disorders, and the current
      treatment of anger attacks.

PMID- 10418811
TI  - Treatment of aggression in patients with bipolar disorder.
AB  - Bipolar disorder is generally viewed as a disturbance of mood. However, prominent
      aspects of behavior that occur during depressive and manic states of bipolar
      disorder, including psychosis, aggression, and anxiety, are not specific to mood
      syndromes and occur across many psychiatric states. Severe hyperarousal--beyond
      that usually associated with classic manic or depressive episodes--could result
      in a variety of behavioral or symptomatic disturbances including aggression,
      impulsivity, and anxiety. Since aggression is a well-recognized aspect of mood
      syndromes, the management of aggression is likely to be an important component of
      managing bipolar disorder.

PMID- 10418812
TI  - Primate models to understand human aggression.
AB  - Although primate studies have yielded models of aggressive behaviors that
      clinicians encounter in their clinical practice, further studies need to be
      performed to establish insights into the biological mechanisms that underlie
      these behaviors. Nonetheless, studies of aggression in rhesus monkeys point to 2
      chief categories of aggression--defensive and offensive--and suggest differing
      underlying neural mechanisms for these types of behaviors. Defensive aggression
      is fear motivated and related to extreme asymmetric right frontal activity in the
      brain and high plasma cortisol concentrations. On the other hand, offensive
      and/or impulsive aggression is associated with low serotonergic activity in the
      central nervous system, high levels of testosterone, and lower levels of
      cortisol. Moreover, all forms of aggression in rhesus monkeys appear to be
      modulated by environmental factors, and marked disruptions to the mother-infant
      relationship likely confer increased risk.

PMID- 10418813
TI  - Managing anger and aggression in patients with posttraumatic stress disorder.
AB  - Posttraumatic stress disorder was categorized as a clinical entity in 1980 in
      response to assertions by trauma survivors (particularly Vietnam veterans) and
      their clinicians that existing diagnostic categories failed to adequately
      describe their symptoms. The diagnostic features of the current DSM-IV diagnosis
      have been expanded, and the concept of the disorder is still evolving.
      Posttraumatic stress disorder rarely occurs in "pure" form, and individuals
      suffering from the disorder commonly meet criteria for Axis I and Axis II
      disorders. Research is now emerging that supports the prevalence of aggression in
      posttraumatic stress disorder. Treatment approaches vary, but pharmacotherapy
      aimed at targeting individual symptoms or clusters can promote mood
      stabilization. This article discusses the evolving concept of posttraumatic
      stress disorder as a clinical entity, the association of anger and aggression
      with the disorder, and the psychopharmacologic approaches to treatment.

PMID- 10418814
TI  - Managing aggressive behavior in patients with obsessive-compulsive disorder and
      borderline personality disorder.
AB  - Obsessive-compulsive disorder (OCD) is one of the most common psychiatric
      disorders, occurring in 2% to 3% of the U.S. population. Borderline personality
      disorder is found in 2% of the U.S. population. These disorders denote the
      endpoints on a spectrum of compulsive and impulsive disorders. One endpoint marks
      compulsive or risk-aversive behaviors characterized by overestimation of the
      probability of future harm, highlighted by OCD. The other endpoint designates
      impulsive action characterized by the lack of complete consideration of the
      negative results of such behavior, such as borderline and antisocial personality
      disorders. This article examines studies testing the efficacy of different
      medications in treating compulsive and impulsive disorders. Mood stabilizers such
      as divalproex, selective serotonin reuptake inhibitors, monoamine oxidase
      inhibitors, and neuroleptics have documented efficacy in treating aggression and
      affective instability in impulsive patients.

PMID- 10418815
TI  - Evaluation and management of aggressive behavior in the elderly demented patient.
AB  - Aggression is common in elderly patients with dementia and often leads to
      placement of these patients in long-term care facilities. Unfortunately,
      identification and evaluation of aggression is sometimes hindered by disagreement
      as to how aggression is distinguished from agitation. Aggression in elderly
      patients with dementia is best understood as a product of the interaction of
      neurobiological, cognitive, and environmental factors. Such a complex etiology
      calls for an approach to treatment that considers pharmacologic therapy as well
      as environmental manipulation; however, further research is needed to clarify the
      causes of aggression in elderly patients with dementia and thus allow the
      refinement of approaches to treatment.

PMID- 10418816
TI  - Brain imaging correlates.
AB  - Because aggressive behavior occurs in so many psychiatric disorders, it is
      important to have an understanding of the aggression complex of symptoms, which
      occurs in posttraumatic stress disorder, bipolar disorder, depression, dementia,
      schizophrenia, attention-deficit/hyperactivity disorder, and the obsessive
      compulsive spectrum of disorders. The effective treatment of aggression symptoms
      would benefit from the identification of the neuroanatomical circuitry implicated
      in aggression, and a number of studies in humans and animals using magnetic
      resonance imaging (MRI) and computed tomography provide evidence that helps
      identify this circuitry. However, future research still must address several
      questions.

PMID- 10418817
TI  - Identification of antigens on porcine pulmonary microvascular endothelial cells
      recognized by human xenoreactive natural antibodies.
AB  - Transplantation of organs between species is prevented in part by humoral immune
      responses triggered by xenoreactive natural antibodies. Although the immune
      barrier to xenotransplantation of the lung is thought to be qualitatively and
      quantitatively different than the immune barrier to xenotransplantation of the
      kidney or heart, the antibody-antigen reactions responsible for rejection of
      pulmonary xenografts have not been characterized. To begin to address this issue
      for porcine lungs transplanted into humans, we analyzed the porcine pulmonary
      endothelial antigens recognized by human xenoreactive natural antibodies. Human
      and baboon natural antibodies recognized glycoprotein and glycolipid antigens
      isolated from the membranes of porcine pulmonary microvascular endothelial cells.
      The antigens included the integrin chains alpha1, alpha2, alpha3, alpha5,
      alpha(v), beta1, beta 3, the von Willebrand Factor, and fibronectin. These
      glycoproteins seemed to be recognized by the same antibodies that bind to porcine
      kidney or cardiac xenografts. Natural antibodies also recognized at least four
      glycolipids containing from one to five sugar residues, although at a lower level
      per unit number of cells than glycoprotein antigens. The epitope recognized by
      natural antibodies was predominantly Gal alpha1-3Gal, a structure expressed by
      lower mammals but not by humans and baboons. The antigens recognized by human
      antibodies in the porcine lung may provide insight into the pathogenesis of the
      rejection reaction. Moreover, the similarity of porcine lung antigens to porcine
      kidney and heart antigens suggests that differences in the rejection reactions
      between these organs reflects the distinct responses of the organs to humoral
      immunity.

PMID- 10418819
TI  - Changes in the morphology and the distribution of rat intestinal eosinophils
      during infection with the nematode Nippostrongylus brasiliensis.
AB  - Increases in the numbers of eosinophil leukocytes present in the lamina propria
      of intestines infected with nematodes is a well described phenomenon, yet the
      role of these leukocytes and their actions in this situation are not yet fully
      understood. Morphologic changes in these cells occur with the course of the
      infection, as do alterations in their location within the gut; these findings may
      give important clues to the function of this prominent cell. We observed changes
      in intestinal eosinophils in the August rat during infection with the nematode
      Nippostrongylus brasiliensis and found, together with the well known increases in
      number infiltrating the lamina propria at Day 20 (three times the levels in
      normal animals), a distinct change in the morphology of individual cells which
      included increase of the cell's overall size and changes in shape, as well as a
      dissemination of cytoplasmic granules in relationship to the cell's nucleus. No
      ultrastructural evidence of extracellular degranulation or intact eosinophil
      cytoplasmic granules outside the bounds of cell cytoplasmic membranes was seen.
      This finding is important considering the light microscopic appearance of
      individual eosinophil granules apparently distributed extracellularly, and lying
      in the connective tissue of the lamina propria, a common histopathologic
      observation in eosinophilic conditions. Eosinophils within the lamina propria
      changed their location as the infection progressed, tending to move to line up
      along the subepithelial zones. In addition, eosinophils were observed both at the
      light and electron microscopic levels to be passing through the basement membrane
      and into the epithelial layer. This latter phenomenon was confirmed using
      confocal optical slicing where eosinophils were commonly observed on the luminal
      side of the nuclei of the gut epithelium. These observations strongly suggest
      that morphologic alterations occur in eosinophils in the lamina propria and these
      changes may be associated with functional alterations in these cells akin to the
      putative phenomenon of "activation." Our findings indicate that eosinophils have
      the capacity to enlarge and extend their cytoplasmic processes between various
      components of the lamina propria and move toward the basement membrane during an
      active infection, as well as into, and possibly through, the intestinal
      epithelium. These findings emphasize the need for careful consideration of the
      changing morphologic status of eosinophils when investigating biologic changes
      associated with the activation of these cells in tissue inflammatory responses.

PMID- 10418818
TI  - Detection of M. tuberculosis DNA in sarcoidosis: correlation with T-cell
      response.
AB  - The pathogenetic role of Mycobacterium tuberculosis (M. tuberculosis) in
      tuberculosis is well defined, whereas its role in sarcoidosis is controversial.
      In sarcoidosis, activation of T-helper cells is observed, which is comparable to
      tuberculosis. The aim of this study was first to investigate whether M.
      tuberculosis DNA could be retrospectively detected in samples of patients with
      clinically verified sarcoidosis by polymerase chain reaction (PCR) and second, to
      analyze the relationship between M. tuberculosis DNA positive samples and T-cell
      response in sarcoidosis patients. Formalin fixed paraffin-embedded lung tissues
      or cell sediments of bronchoalveolar lavage, respectively, from 65 patients with
      sarcoidosis and lung tissues from 40 tuberculosis patients were investigated by
      means of different PCR assays in comparison to control samples. The primers used
      were derived from insertion sequence IS 986/6110 specific for the M. tuberculosis
      complex (123 bp PCR) and from the gene encoding the 38 kDa protein antigen b (419
      bp PCR). The 123 bp assay yielded a specificity of 97% and a sensitivity of 95%.
      In contrast, the 419 bp PCR method showed a lower sensitivity of only 8% likely
      because of possible DNA degradation during fixation and embedding procedures of
      the tissue and the fact that this PCR uses a single copy element as target. We
      amplified the M. tuberculosis complex specific 123 bp fragment in 64% of samples
      from sarcoidosis patients. The specificity of PCR products in these cases was
      confirmed by DNA sequencing. Interestingly in the M. tuberculosis positive
      sarcoidoses, we found increased serum levels of soluble interleukin-2 receptor in
      correlation to the sarcoidosis stages (p < 0.05). In conclusion, the
      determination of M. tuberculosis by PCR alone does not permit a differentiation
      between sarcoidosis and tuberculosis. However these results support the
      contention that M. tuberculosis may play a pathogenetic role at least in the part
      of sarcoidosis patients with elevated interleukin-2 receptor values.

PMID- 10418820
TI  - Acetaldehyde prevents nuclear factor-kappa B activation and hepatic inflammation
      in ethanol-fed rats.
AB  - Acetaldehyde has been proposed as one of the mediators of liver injury in
      alcoholic liver disease. We investigated whether increased acetaldehyde levels
      affected the development of alcoholic liver injury. Male Wistar rats were fed a
      liquid diet containing fish oil and ethanol by intragastric infusion. Sustained
      elevations of acetaldehyde were achieved by daily treatment with two inhibitors
      of aldehyde dehydrogenase (ALDH): disulfiram and benzcoprine. Pathologic changes,
      plasma and liver acetaldehyde, nuclear factor-kappa B (NF-kappaB) and I kappa B
      alpha (I kappaB alpha) protein, tumor necrosis factor-alpha (TNF-alpha) and
      cyclooxygenase 2 (COX-2) mRNA were evaluated. Treatment with the ALDH inhibitors
      led to increased acetaldehyde in liver and plasma but prevented necrosis and
      inflammation. Steatosis was not affected. Both inhibitors decreased activation of
      NF-kappaB and down-regulated TNF-alpha and COX-2 expression. Decreased activation
      of NF-kappaB was accompanied by I kappaB alpha preservation. Acetaldehyde
      probably inhibits NF-kappaB activation through I kappaB alpha preservation. Down
      regulation of TNF-alpha and COX-2 occur secondary to inhibition of NF-kappaB and
      account for the absence of necrosis and inflammation in the ALDH inhibitor
      treated groups.

PMID- 10418821
TI  - Salicylate attenuates gentamicin-induced ototoxicity.
AB  - Aminoglycosides, primarily gentamicin, are the most commonly used antibiotics
      worldwide despite their toxicity to the kidney and the inner ear. A preventive
      therapy against these side effects should combine safety and efficacy with low
      cost because aminoglycoside-induced deafness is most prevalent in developing
      countries. We have previously shown that aminoglycosides catalyze the formation
      of free radicals in an iron-dependent reaction and have delineated the structure
      of an iron-gentamicin complex. Here we demonstrate that 2-hydroxybenzoate
      (salicylate), which can act as an iron chelator and antioxidant, effectively
      protects against gentamicin-induced hearing loss in guinea pigs. Co-therapy with
      salicylate reduced a profound gentamicin-induced auditory threshold shift of more
      than 60 dB to less than 20 dB. Morphological assessment of the inner ear
      confirmed protection of auditory sensory cells. Salicylate altered neither serum
      levels of gentamicin nor its antibacterial efficacy. Because the required
      salicylate levels correspond to anti-inflammatory levels in humans, this
      treatment holds promise for clinical application.

PMID- 10418822
TI  - Monocyte expression of adhesion molecules in HIV-infected patients: variations
      according to disease stage and possible pathogenic role.
AB  - We used flow cytometry to study the expression of adhesion molecules at the cell
      surface and actin polymerization of whole-blood monocytes in 35 HIV-infected
      patients at different stages of the disease. Monocytes were activated in vivo, as
      demonstrated by increased expression of the adhesion molecule CD11b/CD18, reduced
      L-selectin antigen expression, and increased actin polymerization. These
      abnormalities were present in asymptomatic patients with CD4+ cell counts greater
      than 500/microl and did not increase with disease progression or viral load.
      Sialyl-Lewis x and CD31 expression at the monocyte surface was normal in
      asymptomatic and symptomatic non-AIDS patients. In contrast expression of both
      molecules was strongly reduced in patients with AIDS. This change, despite normal
      maximal CD11b/CD18 expression and normal maximal actin polymerization, could
      contribute to the increased susceptibility to bacterial infections in AIDS. In
      contrast enhanced monocyte activation may promote their transendothelial
      migration in non-AIDS patients, possibly explaining the macrophage infiltration
      that can occur early in the disease.

PMID- 10418823
TI  - Cyno-EBV (EBV-related herpesvirus from cynomolgus macaques) induces rabbit
      malignant lymphomas and their tumor cell lines frequently show specific
      chromosomal abnormalities.
AB  - Malignant lymphoma (ML) induction in rabbits by Epstein-Barr virus (EBV)-related
      herpesvirus of cynomolgus (Cyno-EBV) is reported. Twenty-seven of 30 (90%)
      rabbits inoculated intravenously with Cyno-EBV-producing simian (cynomolgus)
      lymphocyte cell line (Ts-B6) cells developed ML between 45 and 115 days after
      inoculation. The peroral inoculation of Ts-B6 cells induced ML in only 2 of 10
      (20%) rabbits (75 to 85 days). Five of 6 (83%) rabbits injected with cell-free
      pellets from Ts-B6 cultures also developed ML (27 to 122 days). Antibody response
      to the viral capsid antigen of EBV was also detected in sera from rabbits
      inoculated with Ts-B6. ML of the large cell or mixed type infiltrated diffusely
      in many organs, frequently involving the spleen, liver, kidneys, heart, and less
      frequently the lungs, lymph nodes, brain, eyes, gastrointestinal tract, thymus,
      and bone marrow. A chromosomal analysis of five lymphoma cell lines established
      from tumor-bearing rabbits revealed the rabbit karyotype. Three of these cell
      lines showed the chromosomal abnormalities with 12q- or t (7p+:12q-). EBV-encoded
      small RNA-1 and EBV-associated nuclear antigen 1 were expressed in Ts-B6 cells,
      the tumor tissues, and all rabbit cell lines by in situ hybridization and by
      immunofluorescence tests, respectively. EBV DNA was also detected in Ts-B6 cells
      and rabbit lymphoma cell lines by polymerase chain reaction and Southern blot
      analysis. The Southern blots of EBV termini revealed oligoclonal bands in the
      Cyno-EBV-induced rabbit lymphomas. No lymphoma was induced by the inoculation of
      B95-8 (EBV-producing cells) or peripheral leukocytes from normal cynomolgus
      (controls). These data suggest that the high rate of lymphoma induction in
      rabbits may be caused not by human EBV (B95-8) but by Cyno-EBV from Ts-B6 cells.
      A sequence analysis of the IR1 (BamHIW) region of Cyno-EBV revealed that this
      region is quite similar to that of herpesvirus Macaca fascicularis 1, which is a
      causative agent for a monkey model of AIDS-related lymphomas. The present rabbit
      model of lymphoma with specific chromosomal abnormalities is very useful to
      clarify the role of EBV in human EBV-associated lymphoma and provides a means for
      studying prophylactic and therapeutic regimens.

PMID- 10418824
TI  - Intracellular glutathione redox status modulates MCP-1 expression in pulmonary
      granulomatous vasculitis.
AB  - A wide spectrum of human lung diseases is characterized by the presence of
      granulomas. Although understanding of the pathways leading to their development
      remains incomplete, data from in vitro studies suggest that neutrophils,
      monocytes, and their secreted products (eg, hydrogen peroxide, H2O2) influence
      the pathogenesis of pulmonary granulomatous disease through the regulation of
      local chemokine and cytokine production. Using a well-characterized rat model of
      glucan-induced pulmonary granulomatous vasculitis, we sought to determine the
      role of intracellular glutathione (GSH) redox status in the expression of
      monocyte chemoattractant protein-1 (MCP-1). Previous studies have revealed that
      vascular wall MCP-1 expression is obligatory for granuloma development and that
      both neutrophils and hydrogen peroxide are required for MCP-1 induction. Because
      in vitro expression of MCP-1 is in part mediated by the redox-sensitive
      transcription factors nuclear factor-kappa B (NF-kappaB) and activator protein-1
      (AP-1), we studied their activation as a function of varying intracellular GSH
      redox status in the pathogenesis of glucan-induced pulmonary granulomatosis.
      Infusion of particulate yeast cell wall glucan into rats resulted in a rapid
      decrease in intracellular GSH concentrations which was accompanied by the
      activation of NF-kappaB and AP-1. The pattern of AP-1 and NF-kappaB activation in
      turn correlated temporally with the expression of MCP-1. Administration of L
      buthionine-S, R-sulfoximine, a specific inhibitor of gamma-glutamyl cysteine
      synthetase, resulted in a significant reduction in intracellular GSH pools. GSH
      depletion resulted in a more than 100% increase in pulmonary MCP-1 concentrations
      and increased cytosolic to nuclear translocation of NF-kappaB while having no
      effect on AP-1 levels. These observations suggest that in the pathogenesis of
      pulmonary granulomatous disease, intracellular glutathione redox status modulates
      the expression of MCP-1 through redox-sensitive transcription factors.

PMID- 10418825
TI  - Follicular dendritic cell dysfunction and disorganization of lymphoid structures
      in MRL/lpr mice.
AB  - The follicular dendritic cell (FDC) in secondary lymphoid organs plays a key role
      in the function of the germinal center (GC) of the lymphoid follicle (LF) for
      regulation of the humoral immune response. MRL MpJ-lpr/lpr (MRL/lpr) mice, which
      have an abnormal humoral immune response, are a model for autoimmune disease. The
      present study was undertaken to investigate FDC dysfunction and LF
      disorganization in the spleen and lymph nodes of MRL/lpr mice. In 12-week-old
      MRL/lpr mice, antigen (Ag) trapping of FDC and half-life of trapped Ag on FDC was
      reduced. Although immunohistochemistry revealed well-developed FDC networks
      positive for complement receptors and having in vitro immune complex trapping in
      cryostat sections, Ag-trapping was not detected in 16-week-old MRL/lpr mice.
      Moreover a marked decrease in the number of GC and that of GC cell of residual GC
      in the MRL/lpr mice was observed by 12 weeks of age. Also reduced expression of
      intercellular adhesion molecule-1, FcgammaRII/III, and FDC-specific Ag (FDC-M1)
      on FDC was detected in 16-week-old MRL/lpr mice. The accumulation of double
      negative (CD4-CD8-) T cells, which is a characteristic feature of MRL/lpr mice,
      was observed around LF; however they did not infiltrate the LF and FDC network.
      In conclusion the loss of Ag-trapping on FDC and simultaneous disorganization of
      the lymphoid structure may be related closely to the immunologic abnormality
      observed in MRL/lpr mice.

PMID- 10418826
TI  - Volume-weighted mean nuclear volume as a prognostic factor in renal cell
      carcinoma.
AB  - Volume-weighted mean nuclear volume (MNV) has been reported to have important
      prognostic value in many cancers. We investigated the prognostic value of MNV in
      patients with renal cell carcinoma (RCC). A retrospective study of the 155
      patients with RCC treated by radical nephrectomy between 1976 and 1996 was
      conducted. MNV was evaluated in the surgical specimens using a stereologic
      technique. Univariate analyses by the log-rank test and then a multivariate
      analysis by the Cox proportional hazards model were performed to analyze the
      prognostic value of histopathologic parameters such as Robson stage, tumor-node
      metastasis (TNM) classification, tumor grade, and MNV. There were significant
      correlations between MNV and Robson stage, TNM classification and tumor grade.
      Robson stage, TNM classification, tumor grade, and MNV were correlated
      significantly with disease-specific survival of RCC patients. There was no
      significant difference in disease-specific survival between patients with Grade 1
      and Grade 2 tumors (94.8% of all patients), but MNV could predict the clinical
      outcome of these groups. MNV also was correlated significantly with disease
      specific survival at all tumor stages. Multivariate analysis showed pT
      classification, M classification, tumor grade, and MNV to be independently
      associated with survival. These studies strongly suggest that MNV may provide new
      and useful information to accurately predict the prognosis of patients with RCC.

PMID- 10418827
TI  - Tumor cells are the source of osteopontin and bone sialoprotein expression in
      human breast cancer.
AB  - Bone sialoprotein (BSP) and osteopontin (OPN) are secreted glycoproteins with a
      conserved Arg-Gly-Asp (RGD) integrin-binding motif and are expressed
      predominantly in bone. The RGD tripeptide is commonly present in extracellular
      attachment proteins and has been shown to mediate the attachment of osteosarcoma
      cells and osteoclasts. To determine the origin and incidence of BSP and OPN mRNA
      expression in primary tumor, a cohort of archival, primary invasive breast
      carcinoma specimens was analyzed. BSP transcripts were detected in 65% and OPN
      transcripts in 77% of breast cancers examined. In general, BSP and OPN
      transcripts were detected in both invasive and in situ carcinoma components. The
      transcripts were not detected in surrounding stromal cells or in peritumoral
      macrophages. Despite its abundance in carcinomas, BSP expression was not detected
      in a panel of 11 human breast cancer cell lines (MCF-7, T47D, SK-Br-3, MDA-MB
      453, MDA-MB-231, MDA-MB-436, BT549, MCF-7ADR, Hs578T, MDA-MB-435, and LCC15-MB)
      and OPN expression was detected only in two of these (MDA-MB-435 and LCC15-MB).
      To examine the possibility that expression of these genes was down-regulated in
      cell culture, several cell lines were grown as nude mouse xenografts in vivo;
      however, these tumors also failed to express BSP. OPN expression was identified
      in all cell lines grown as nude mouse xenografts. Our data suggest that in human
      primary breast tumors, the origin of BSP and OPN mRNA is predominantly the breast
      cancer cells and that expression of these transcripts is influenced by the tumor
      environment.

PMID- 10418828
TI  - Human renal cell carcinoma xenografts in SCID mice: tumorigenicity correlates
      with a poor clinical prognosis.
AB  - To establish human renal cell carcinoma (RCC) xenografts for preclinical studies,
      55 renal tumors (33 primary and 22 metastatic lesions) were transplanted
      subcutaneously into severe combined immunodeficient mice. Twenty of 49 evaluable
      tumors (40.8%) grew with a median latency period of 89 days (36 to 209 days) from
      the day of engraftment. Tumor growth was stabilized after the fifth passage with
      a median time between passages of 38 days (19 to 80 days). Tumorigenicity was
      correlated with the metastatic phenotype of the tumor (54% success rate, p =
      0.007) and with reduced survival of patients. Despite a possible evolution of
      histological features and tumor grading, established RCC xenografts were
      comparable to parental tumors, as assessed by karyotype and DNA-ploidy analyses.
      Molecular cytogenetic analysis also revealed specific genetic alterations
      characterizing distinct RCC types that were constant in parental and
      corresponding xenografts. In addition, this xenograft model has permitted the
      selection of minor tumor subclones with a proliferative advantage and minimal
      overexpressed chromosomal regions. We conclude that severe combined
      immunodeficient mice are useful recipients for the establishment of long-term RCC
      xenografts that can be used as valuable tools to evaluate the activity of new
      therapeutic approaches and to study biological parameters determining in vivo
      aggressiveness of human RCC.

PMID- 10418830
TI  - Correlation between tumor vascularity, vascular endothelial growth factor
      production by tumor cells, serum vascular endothelial growth factor levels, and
      serum angiogenic activity in patients with breast carcinoma.
AB  - Angiogenesis is an important prognostic factor in invasive breast carcinoma. We
      analyzed sera and tumor samples from 36 patients with primary breast carcinomas
      to determine the relationship between tumor vascularity, vascular endothelial
      growth factor (VEGF) production by tumor cells, levels of circulating VEGF
      (measured by ELISA assay), and levels of endothelial growth factors analyzed by a
      functional test of human umbilical vein endothelial cells (HUVEC) proliferation.
      Tumor vascularity was correlated directly with VEGF production by the tumor,
      indicating that VEGF production is a relevant factor in determining angiogenesis
      in primary tumor. No correlation was found either between the number of vessels
      in the tumor or the production of VEGF by tumor cells and the levels of serum
      angiogenic factors including VEGF. On the contrary, the two serum tests
      correlated together because a high serum level of VEGF is more frequent in cases
      with the presence of HUVEC-stimulating growth factors. These data indicate that
      the principal source of factors stimulating angiogenesis in the primary tumor is
      the tumor itself. This is an important issue in the context of anti-angiogenic
      therapeutic approaches, which should be planned to interfere with tumor
      production of angiogenic factors rather than with circulating angiogenic factors.
      In conclusion, whereas the vessel count and VEGF production by tumor cells are
      parameters that give direct information on tumor angiogenesis, long-term follow
      up is necessary to determine the clinical significance of the determination of
      serum HUVEC-stimulating factors in the progression of breast carcinoma.

PMID- 10418829
TI  - Potential roles of metalloprotease mediated ectodomain cleavage in signaling by
      the endothelial receptor tyrosine kinase Tie-1.
AB  - The orphan receptor tyrosine kinase Tie-1 is expressed predominantly in
      endothelial cells. Expression of this receptor is increased in physiologic
      angiogenesis and pathologic situations including tumor growth and arteriovenous
      malformations. Tie-1 is essential for vascular development where it acts in later
      stages of angiogenesis to suppress endothelial activation and stabilize the newly
      formed vessel. Stimulation of protein kinase C in endothelial cells results in
      endoproteolytic cleavage of Tie-1, releasing the extracellular ligand-binding
      domain of the receptor. We show that this is mediated by a metalloprotease.
      Immunoprecipitation and immunoblotting of lysates prepared from human placentas
      confirm that Tie-1 truncation occurs in vivo. We propose cleavage of this
      receptor may be a mechanism for inducing vessel destabilization by preventing
      ligand-activated signaling through Tie-1. Using an antibody that recognizes the
      carboxy terminus of the intracellular domain, we show that the Tie-1 endodomain
      formed on cleavage persists as a cell-associated fragment for several hours.
      Subcellular fractionation reveals this tyrosine kinase containing receptor
      fragment to be localized in the membrane fraction of the cell.
      Immunoprecipitation with antibodies recognizing phosphotyrosine demonstrates that
      cleavage of Tie-1 stimulates association of newly generated endodomain with
      cellular phosphoproteins. Furthermore, there was a marked induction of tyrosine
      phosphorylation of several proteins after PMA-induced endodomain generation.
      These data indicate that ectodomain cleavage may be a mechanism for down
      regulating ligand-induced signaling through Tie-1 while activating an alternative
      ligand-independent signaling pathway in endothelial cells. Ectodomain cleavage
      occurs in some other receptor tyrosine kinases. We suggest that rather than
      solely being a means of down-regulating receptor activity, ectodomain cleavage
      may be a novel way for a receptor to switch between two alternative signaling
      pathways.

PMID- 10418831
TI  - Correlation of methylation of the hMLH1 promoter with lack of expression of hMLH1
      in sporadic gastric carcinomas with replication error.
AB  - Recent studies have demonstrated that the majority of sporadic colorectal
      carcinomas with replication error (RER) do not harbor mutations of the hMLH1 and
      hMSH2 genes that account for about 70% of hereditary nonpolyposis colon cancer.
      Despite the absence of mutations of the hMLH1 gene, the majority of RER-positive
      sporadic colorectal carcinomas lack hMLH1 protein expression, which have been
      reported to be related to hypermethylation of the promoter region of hMLH1 gene.
      High frequency of microsatellite instability (MSI) has been observed in about 15%
      of sporadic gastric carcinomas. The relationship of tumor MSI, methylation of
      promoter regions of hMLH1 or hMSH2, and expression of corresponding gene products
      has not been studied in gastric carcinomas as thoroughly as in colorectal
      carcinomas. We explored the relationship between methylation of hMLH1 or hMSH2
      promoter regions and its protein expression in both RER-positive and RER-negative
      gastric carcinomas. Of 93 cases, 20 cases comprised the RER+ group (MSI-H tumors)
      and the remainder comprised the RER- group (7 cases, MSI-L; 66 cases, MSS). By
      immunohistochemistry absence of hMLH1 protein expression was limited entirely to
      the RER+ group (20 of 20, 100%). All 93 cases showed hMSH2 protein expression.
      Nineteen (95%) of 20 RER+ tumors harbored hypermethylation of the hMLH1 promoter
      region whereas only four cases (5.5%) of the 73 RER- tumors did. Hypermethylation
      of the hMSH2 promoter region was not observed in either the RER+ group or the RER
      group. These results suggest that hypermethylation of the hMLH1 promoter region
      may be the principal mechanism of gene inactivation in sporadic gastric
      carcinomas with a high frequency of MSI.

PMID- 10418832
TI  - Real-time hTERT quantification: a promising telomerase-associated tumor marker.

PMID- 10418833
TI  - The "Aunt Minnie" ability--revisited.

PMID- 10418834
TI  - Substance abuse, violence, and outcome after traumatic spinal cord injury.
AB  - Alcohol and drug use have been shown to contribute to the onset of traumatic
      spinal cord injury and to be a marker for later onset substance abuse issues.
      Admission toxicology (drug and alcohol) screens were collected from 87
      consecutive rehabilitation medicine patients with a diagnosis of acute traumatic
      spinal cord injury. Forty-six patients (53%) presented with positive screens (44%
      alcohol only, 30% drug only, 26% both). Seventy-five percent of those with
      positive alcohol screens met state criteria for alcohol intoxication (blood
      alcohol level, > or =0.08 mg/dl). Compared with individuals with negative
      screens, those with positive screens were significantly (P < 0.05) younger and
      unmarried. Compared with nonviolence-related spinal cord injury, patients with
      violence-related spinal cord injury (gunshot wound and assault) were
      significantly (P < 0.01) more likely to have positive admission toxicology
      screens (76% v 41%), drug screens (62% v 14%), and intoxication screens (72% v
      34%). Rehabilitation outcome comparisons between those with positive and negative
      screens revealed similar length of stay, admission and discharge Functional
      Independence Measure (FIM) scores, FIM change scores, and FIM efficiency scores.
      This study has important implications with regard to substance abuse issues and
      their impact on traumatic spinal cord injury outcome, which may assist in better
      targeting prevention.

PMID- 10418835
TI  - Lateral femoral cutaneous nerve conduction v somatosensory evoked potentials for
      electrodiagnosis of meralgia paresthetica.
AB  - The aim of this study is to compare sensory nerve conduction with somatosensory
      evoked potentials of the lateral femoral cutaneous nerve to determine which is
      the most reliable electrodiagnostic method to assess meralgia paresthetica.
      Thirty patients with unilateral clinically defined meralgia paresthetica and 30
      controls were studied with both methods. The main outcome measures were sensory
      action potential side-to-side amplitude ratio, somatosensory evoked potentials
      side-to-side latency difference, and side-to-side amplitude ratio. Sensory nerve
      conduction was abnormal in all patients: only four participants had abnormal
      somatosensory evoked potentials with double derivation (Fz/Cz and Ci/Cc)
      recording, and eight participants had abnormal findings with Fz/Cz derivation.
      Overall, this study demonstrates that sensory nerve conduction is the more
      reliable method for meralgia paresthetica electrodiagnosis. In fact, only very
      serious nerve damage regularly induces abnormal somatosensory evoked potentials,
      which is not recommended for routine electrodiagnostic study of meralgia
      paresthetica.

PMID- 10418836
TI  - Vitamin K deficiency and osteopenia in disuse-affected limbs of vitamin D
      deficient elderly stroke patients.
AB  - Bone mineral density is reduced in stroke patients on the hemiplegic and
      contralateral sides, reflecting a degree of paralysis and vitamin D deficiency.
      Because the deficiency of vitamin K, a factor essential for site-specific
      carboxylation of bone Gla protein, is also associated with reduced bone mineral
      density, an additional contribution of vitamin K to bone changes was assessed in
      168 elderly patients with long-standing post-stroke hemiplegia and
      hypovitaminosis D. Sera were analyzed to relate vitamin K1 concentrations to bone
      related biochemical indexes and bone mineral density measured by
      radiodensitometry of the second metacarpal. Bone mineral density was lower on
      both sides in patients than in the 56 controls (P < 0.02). Serum vitamin K1
      concentrations, which correlated positively with bone Gla protein concentrations
      (P < 0.0001), were lower in patients (0.48 +/- 0.47 nmol/L) than controls (1.33
      +/- 0.49; P < 0.0001). Serum bone Gla protein and 25-hydroxyvitamin D
      concentrations were lower in patients than controls (P < 0.0001), whereas ionized
      Ca concentrations were higher in patients (1.277 +/- 0.041 mmol/L) than controls
      (1.210 +/- 0.049; P < 0.0001), correlating with the Barthel index. Multivariate
      linear regression identified vitamin K1, bone Gla protein, 25-hydroxyvitamin D,
      ionized calcium, and the Barthel index as independent bone mineral density
      determinants on the hemiplegic side and 25-hydroxyvitamin D, calcium, and the
      Barthel index on the intact side. Immobilization and vitamin K deficiency had
      stronger osteopenic effects on the hemiplegic side than contralaterally.

PMID- 10418837
TI  - Using the measure of processes of care with parents of children hospitalized for
      head injury.
AB  - Despite recommendations that rehabilitation programs adopt family/patient
      satisfaction as an outcome measure, few studies have addressed satisfaction with
      services for children with head injury. This report describes our use of the
      Measure of Processes of Care (MPOC) to document the perceptions of care of
      parents whose children were hospitalized with a head injury and to compare
      parental perceptions of care with those of the service providers (n = 16). The
      MPOC is a self-administered questionnaire consisting of 56 items, each of which
      is included in one of five care-giving scales: (1) enabling and partnership; (2)
      providing general information; (3) providing specific information about the
      child; (4) coordinated and comprehensive care; (5) respectful and supportive
      care. The MPOC was mailed to parents of children with a head injury who were
      consecutively admitted to a pediatric trauma center during a 5-mo period. The
      results, based on the responses of 73 parents (response rate, 59.3%), revealed
      that the needs of these parents are being met to varying degrees. Mean scores for
      the five scales ranged from 4.6 to 6.4 and from 5.9 to 6.6 for parents and
      providers, respectively. Significant differences between the groups were found
      for two scales: providing general and specific information. Because of the low
      percentage of valid responses for three of the five scales, the MPOC appears to
      be an inappropriate tool for use with parents of children with mild head injury
      (89%) in the acute care setting. The MPOC, however, is applicable for parents of
      children who are more severely injured (e.g., average hospital stay, 9 days) and
      is informative for rehabilitation service providers.

PMID- 10418838
TI  - Quality of life and exercise tolerance in chronic obstructive pulmonary disease:
      effects of a short and intensive inpatient rehabilitation program.
AB  - The quality of life and the exercise endurance of patients with chronic
      obstructive pulmonary disease are impaired. The aim of our study was to determine
      the impact of a 3-wk intensive inpatient rehabilitation program on the quality of
      life of patients with chronic obstructive pulmonary disease and to examine the
      correlation between quality-of-life measures and physiologic measures throughout
      rehabilitation. Thirty-two patients with chronic obstructive pulmonary disease
      (20 men, 12 women) were evaluated by spirometry and maximal exercise testing for
      exercise endurance and by the French version of the Nottingham Health Profile for
      quality of life. Rehabilitation components were individualized exercise at
      ventilatory threshold (4 hr/day), health education, and physical therapy and
      relaxation for 3 wk. Our results showed an improvement in the quality of life
      (especially in physical mobility, energy, and social isolation) and exercise
      endurance (increase of 14% of maximal power and symptom-limited oxygen uptake).
      In contrast, no significant correlations were found between the quality of life
      and physiologic parameters (gas exchange, cardiovascular and lung function
      parameters) throughout rehabilitation. Changes in the quality of life seem to be
      independent of the physiologic results during the course of a short and intensive
      inpatient rehabilitation program. Quality of life should, therefore, be more
      systematically evaluated to determine the psychosocial benefits, which, although
      subjective, are important for encouraging patients' compliance with
      rehabilitation programs.

PMID- 10418839
TI  - Performance of static standing balance in children with spastic diplegic cerebral
      palsy under altered sensory environments.
AB  - Seven children with spastic diplegic cerebral palsy and 14 age- and gender
      matched nondisabled children participated in the present study for an
      investigation and comparison of their static standing balance under altered
      sensory environments. The type of visual input (full, occluded, or sway
      referenced vision) and the type of somatosensory input (fixed or compliant foot
      support) were varied factorially to give six sensory environments. Each
      participant was tested barefooted for 30 s under all six conditions. A force
      platform collected the ground reaction force, from which standing balance was
      calculated as the sway area of the center of pressure. The results showed that
      when somatosensory information was reliable (fixed foot support), there was no
      significant difference in stance stability between the children with spastic
      diplegic cerebral palsy and their matched controls, and both types of children
      were equally affected by the type of visual input. However, when somatosensory
      information was unreliable (compliant foot support), the difference in stance
      stability between the children with spastic diplegic cerebral palsy and their
      matched controls was significantly greater when the visual input was deprived
      (occluded) or unreliable (sway referenced) than when it was reliable. These
      results suggest that the children with spastic diplegic cerebral palsy may have
      difficulties in resolving intersensory conflicts for maintenance of standing
      balance, or the demands of motor control in sensory conflict conditions outweigh
      the motor ability of children with spastic diplegic cerebral palsy.

PMID- 10418840
TI  - Mechanisms of action of phenol block and botulinus toxin Type A in relieving
      spasticity: electrophysiologic investigation and follow-up.
AB  - This preliminary study was designed to investigate the effects of botulinus toxin
      Type A and phenol treatments on electrophysiologic tests evaluating spinal
      afferent and efferent motor pathways involved in spasticity. The questions posed
      were whether different types of mechanisms act on reducing spasticity with these
      different treatment modalities and whether the tests are correlated with clinical
      recovery. Twenty patients with lower limb spasticity secondary to stroke were
      randomly assigned to receive 400 mouse units of botulinus toxin Type A injected
      into the calf muscles or to receive a tibial nerve blockade with 3 ml of 5%
      phenol. The amplitudes of the Achilles tendon response, M response, H reflex
      response, and maximum H:M ratio and Achilles tendon response to H response ratio
      were recorded from the soleus muscle at baseline and at Weeks 2, 4, and 12. The
      most obvious change was a reduction in the amplitude of the tendon response in
      the group that received botulinus toxin Type A, and it was a reduction in the M
      response amplitude in the group that received phenol. The decrease in the tendon
      response amplitude and tendon response to H ratio in the group that received
      botulinus toxin Type A and the decrease in the M response amplitude in the phenol
      group were found to be well correlated with clinical recovery as assessed by the
      Ashworth scale. The findings suggested that botulinus toxin Type A injection
      decreases spasticity primarily by affecting the fusimotor system and muscle
      spindle, and the involvement of the alpha-motor fibers within the tibial nerve is
      the most likely factor contributing to the reduction of spasticity after phenol
      blockade. The therapeutic effectiveness of these agents could be assessed and
      followed up by the changes in electrophysiologic responses matching their
      mechanisms of action. The findings should be supported by further
      electrophysiologic techniques.

PMID- 10418841
TI  - Increased norepinephrine levels during catheterization in patients with spinal
      cord injury.
AB  - The hypothesis for this study was that catecholamine levels increase during
      urinary catheterization in human patients with spinal cord injury. Catecholamine
      levels, blood pressure, and pulse were measured prospectively in 40 subjects at
      baseline and during urinary catheterization. Results showed a significant
      increase in norepinephrine levels from baseline 245 +/- 240 pg (standard
      deviation (SD)) to 314 +/- 311 pg (SD) during catheterization (P = 0.018,
      Wilcoxon's). Results also showed a nonsignificant increase in epinephrine levels
      from baseline (56 +/- 70 pg, SD) to catheterization (84 +/- 125 pg, SD; P = 0.35,
      Wilcoxon's). Systolic blood pressure increased from 114 to 124 mm Hg (P = 0.004,
      paired t test). Diastolic blood pressure increased from 75 to 78 mm Hg (P = 0.11,
      paired t test). There was no significant change in diastolic blood pressure or
      pulse (P = 0.11 and P = 0.29, respectively, paired t test). In conclusion,
      norepinephrine levels increased during catheterization in patients with spinal
      cord injury. Knowledge of catecholamine levels in this process may assist in
      determining both pathophysiology and potential pharmacologic treatment options in
      future studies.

PMID- 10418842
TI  - Spastic paretic stiff-legged gait: biomechanics of the unaffected limb.
AB  - A concern for individuals with hemiparesis affecting their gait, which heretofore
      has never been studied, is the possibility that various compensations occurring
      in the unaffected limb may strain or fatigue the muscles or ligaments and/or
      predispose to joint injury in that limb. We studied the biomechanics of the
      unaffected limb during walking in 20 subjects with hemiparesis who had stiff
      legged gait as a result of stroke. An optoelectronic motion analysis and force
      platform system was used to estimate torques in all three planes about the hip,
      knee, and ankle. Sagittal plane joint motion and power about the unaffected hip,
      knee, and ankle were also studied. Data were compared with control walking data
      collected from 20 able-bodied controls. On average, peak torques and powers were
      all either reduced or the same compared with controls, even though in some
      instances values were >2 standard deviations (SD) above the control means. Our
      findings suggest that on average the probability of excessive muscular-tendon
      effort and the risk for biomechanical injury in the unaffected limb are minimal
      compared with able-bodied, walking controls. However, given individual
      variability, we recommend routine clinical gait analysis for all people with
      stiff-legged gait to eliminate excessive values in certain biomechanical
      parameters, which could, if not addressed, predispose to muscle-tendon strain or
      joint or ligamentous injury.

PMID- 10418843
TI  - Adrenal and pituitary hormone patterns after spinal cord injury.
AB  - Current evidence indicates that the neuroendocrine system is the highest
      regulator of immune/inflammatory reactions. We hypothesized that immune
      alterations, which were related to the level of injury, found in a cohort of
      spinal cord-injured subjects may be influenced by altered hormonal patterns
      postinjury. Therefore, we investigated aspects of both pituitary and adrenal
      function in the same cohort of spinal cord-injured subjects. We found significant
      elevations in both cortisol and dehydroepiandrosterone sulfate in chronic spinal
      cord-injured survivors compared with their able-bodied age- and gender-matched
      controls. Levels of dehydroepiandrosterone, adrenocorticotropin, and prolactin
      were not different in spinal cord-injured subjects overall compared with their
      controls. Both dehydroepiandrosterone sulfate and dehydroepiandrosterone were
      higher in tetraplegics compared with their controls, but we found no such
      differences in paraplegics compared with their controls. When the two groups of
      spinal cord-injured subjects were compared with each other, we also found
      differences between these two subject groups in dehydroepiandrosterone sulfate
      and dehydroepiandrosterone (higher in the tetraplegics compared with
      paraplegics). We found no differences between either group of spinal cord-injured
      subjects and their controls for adrenocorticotropin, prolactin, or cortisol.
      These data suggest that some hormonal differences between subjects and their
      controls may be further related to the level of injury (specifically
      dehydroepiandrosterone and dehydroepiandrosterone). Finally, we investigated
      correlations within subjects for the above hormones. Dehydroepiandrosterone
      sulfate and prolactin were highly correlated (the higher the
      dehydroepiandrosterone sulfate, the higher the prolactin) but only in the
      tetraplegic subjects.

PMID- 10418844
TI  - Comparison of speech-evoked v tone-evoked P300 response: implications for
      predicting outcomes in patients with traumatic brain injury.
AB  - The P300 response is a cognitive event-related potential recorded over the scalp.
      The tone-evoked P300 response has been used to predict outcomes of patients with
      brain injury. However, it may lead to false predictions because some normal
      people have a very small tone-evoked P300 response. It is hypothesized that
      speech may generate a more robust P300 response than tones. A voice-generator
      prototype was designed for this study. The rare speech signal was the word
      "mommy" in a female voice. The common signal was a 1000-Hz tone. Twenty-two
      normal adults (11 males, 11 females; age range, 18-60 yr) were tested for both
      speech-evoked and tone-evoked P300 responses. Speech-evoked P300 responses had
      significantly larger amplitudes (mean, 12.1 microV) than the tone-evoked
      responses (mean, 5.9 microV; P < 0.0001). Six subjects with brain injury were
      also tested using the same protocol: two subjects with severe brain injury showed
      no response to either stimulus. Both died within 1 wk after the testing. Although
      two subjects with moderate brain injury could not complete the testing because of
      agitated behavior, two other subjects with mild traumatic brain injury showed a
      larger speech-evoked than tone-evoked P300 response. The speech-evoked P300
      response may be promising in predicting outcomes of patients with brain injury.

PMID- 10418845
TI  - Uncommon causes of anterior knee pain: a case report of infrapatellar contracture
      syndrome.
AB  - The uncommon causes of anterior knee pain should always be considered in the
      differential diagnosis of a painful knee when treatment of common origins become
      ineffective. A case is presented in which the revised diagnosis of infrapatellar
      contracture syndrome was made after noting delayed progress in the rehabilitation
      of an active female patient with a presumed anterior horn medial meniscus tear
      and a contracted patellar tendon. The patient improved after the treatment
      program was augmented with closed manipulation under arthroscopy and
      infrapatellar injection of both corticosteroids and a local anesthetic.
      Infrapatellar contraction syndrome and other uncommon sources of anterior knee
      pain, including arthrofibrosis, Hoffa's syndrome, tibial collateral ligament
      bursitis, saphenous nerve palsy, isolated ganglions of the anterior cruciate
      ligament, slipped capital femoral epiphysis, and knee tumors, are subsequently
      discussed. Delayed functional advancement in a rehabilitation program requires
      full reassessment of the patient's diagnosis and treatment plan. Alternative
      diagnoses of knee pain are not always of common origins. Ample knowledge of
      uncommon causes of anterior knee pain is necessary to form a full differential
      diagnosis in patients with challenging presentations.

PMID- 10418846
TI  - Salon sink radiculopathy: a case series.
AB  - Cervical radiculopathy can be diagnosed on physical examination with the Spurling
      test, which narrows neural foramina via neck extension along with coupled
      rotation and side-bending. In the presence of cervical radiculopathy, this test
      can reproduce radicular symptoms by transmitting compressive forces to affected
      nerve roots as they traverse the neural foramina. Treatment of cervical
      radiculopathy includes patient education to avoid obvious postures that
      exacerbate radicular symptoms and to assume positions that centralize discomfort.
      A potentially harmful position to which many patients are unwittingly subjected
      at least several times per year occurs when their hair is being shampooed in a
      salon sink before a haircut. This posture causes neck extension and is combined
      with rotation and side-bending as the patient's head is being manipulated during
      the shampooing. When the stylist then also applies a mild compressive force while
      shampooing the patient's hair, hyperextension of the neck is produced. We present
      two patients with cervical radiculopathy that was significantly exacerbated after
      the patient's hair had been shampooed in a salon sink; subsequently, these
      patients required oral administration of steroids. These cases illustrate that
      patients with suspected or known cervical radiculopathy should be forewarned to
      avoid this otherwise seemingly innocuous activity.

PMID- 10418847
TI  - Uniform Data System for Medical Rehabilitation: report of first admissions to
      subacute rehabilitation for 1995, 1996 and 1997.

PMID- 10418848
TI  - Vision rehabilitation for physiatry residents: a model curriculum.

PMID- 10418850
TI  - Implications of insulin resistance: concerns beyond glucose. Proceedings of a
      symposium. Colorado Springs, Colorado, USA. August 1998.

PMID- 10418849
TI  - Neural network applications in physical medicine and rehabilitation.
AB  - The purpose of this article is to provide an overview of neural networks and
      their applications in physical medicine and rehabilitation. Conventional
      statistical models may present certain limitations that can be overcome by neural
      networks. We show what neural networks are, how they "learn" regularities from
      the data, and how they can classify previously unseen cases. We present
      advantages and disadvantages of using neural networks and compare them with
      regression models. We explain how neural networks can be used as statistical
      tools for making inferences using the example of a prognostic model that predicts
      ambulation after spinal cord injury.

PMID- 10418851
TI  - Cellular mechanisms of insulin resistance in humans.
AB  - Carbon nuclear magnetic resonance (13C NMR) spectroscopy and phosphorus (31p) NMR
      spectroscopy have been used to help define the contribution of insulin-stimulated
      muscle glycogen synthesis to whole-body insulin-stimulated glucose metabolism in
      normal individuals and the extent to which this process is defective in patients
      with type 2 (non-insulin-dependent) diabetes. Assessments of the response to
      hyperglycemic-hyperinsulinemic clamping have shown that abnormalities of muscle
      glycogen synthesis, apparently mediated by a defect in GLUT-4 transport and/or
      hexokinase activity, play a major role in causing insulin resistance in type 2
      diabetes. Studies of the mechanisms by which free fatty acids (FFA) cause insulin
      resistance in humans indicate that increased FFA levels inhibit glucose
      transport, which may be a consequence of decreased insulin receptor substrate
      (IRS-1)-associated phosphatidylinositol 3-kinase activity. 13C NMR spectroscopy
      studies have documented that liver glycogen concentrations are reduced and the
      rate of hepatic gluconeogenesis is increased in subjects with type 2 diabetes;
      thus, the higher rate of glucose production in type 2 diabetes can be attributed
      entirely to increased rates of hepatic gluconeogenesis. These cellular mechanisms
      of insulin resistance can be addressed through combination therapy with agents
      that reverse the principal pathophysiologic defects of type 2 diabetes. The
      biguanide metformin appears to lower glucose by suppressing hepatic glucose
      production, whereas the thiazolidinedione troglitazone appears to increase
      glucose clearance by peripheral tissues. The two agents together have been shown
      to provide better glucose control than either drug alone, without stimulating
      insulin secretion.

PMID- 10418852
TI  - Epidemiology of insulin resistance and its relation to coronary artery disease.
AB  - The relation of insulin resistance to cardiovascular risk, particularly for
      coronary artery disease (CAD), has been well established in many prospective
      studies. The clustering of insulin resistance and/or hyperinsulinemia,
      hypertriglyceridemia, hypertension, and low HDL is now considered a feature of
      the insulin resistance syndrome. However, the association is complex and the
      pathways by which elevated insulin adversely affects both CAD risk factors and
      the risk of developing CAD have yet to be elucidated. Postprandial lipemia may be
      a mechanistic link between insulin resistance and CAD. Hyperinsulinemia appears
      to be a weak, but positive, independent cardiovascular risk factor. The strongest
      relations are seen in middle-aged rather than older persons and at higher
      elevations of plasma insulin levels. Individuals with type 2 diabetes have a risk
      of myocardial infarction (MI) equivalent to that of nondiabetic persons who have
      had a previous MI. Given the relatively weak association between duration of
      diabetes and severity of hyperglycemia and cardiovascular disease, common
      antecedents may underlie both CAD and type 2 diabetes.

PMID- 10418853
TI  - Atherosclerotic plaque rupture: emerging insights and opportunities.
AB  - Reduction in acute,coronary events requires interventions that affect the
      mechanisms leading to formation of atherosclerotic lesions, as well as the
      molecular events that precipitate acute myocardial infarction. Data from clinical
      trials indicate that it is the vulnerability of atherosclerotic plaque to
      rupture, rather than the degree of atherosclerosis, that is the primary
      determinant of thrombosis-mediated acute coronary events. The characteristics of
      a plaque that is vulnerable to rupture include a thin fibrous cap separating the
      circulation from procoagulants in the plaque's lipid core; increased numbers of
      inflammatory cells (e.g., macrophages and T cells); and a relative paucity of
      vascular smooth muscle cells (VSMC). Plaque stability reflects various dynamic
      factors: interaction of inflammatory cells, VSMC production of the extracellular
      matrix that is the bulwark of the fibrous cap, inhibition of this process by
      certain cytokines, and increased degradation of the matrix by matrix
      metalloproteinases. There is growing interest in the concept that intervention in
      the inflammatory processes of atherogenesis might reduce lesion formation and/or
      progression. There has also been substantial progress in understanding the
      transcriptional regulation of proteins that are critically involved in
      atherogenesis. Recently, peroxisomal proliferator-activated receptors (PPARs)
      have been identified as a potential link between insulin resistance and
      atherosclerosis. This concept is supported by the discovery through drug
      screening of thiazolidinediones (troglitazone, rosiglitazone), compounds that are
      not only ligands for PPARgamma, a nuclear receptor involved in adipogenesis, but
      also are antidiabetic agents.

PMID- 10418854
TI  - Insulin signaling in the arterial wall.
AB  - Insulin has several direct vascular actions that contribute to either vascular
      protection or injury, depending on the cell type. Vascular protective effects of
      insulin include stimulation of endothelial cell production of the vasodilator
      nitric oxide (NO). This, in turn, inhibits formation of lesions dependent on
      migration and proliferation of vascular smooth muscle cells (VSMCs), attenuates
      binding of inflammatory cells to the vascular wall, and inhibits thrombosis by
      reducing platelet adhesion and aggregation. However, insulin also promotes a host
      of deleterious vascular effects by stimulating the actions of various growth
      factors acting through the mitogen-activated protein kinase (MAPK) signaling
      pathway. MAPK may mediate the effects of insulin and angiotensin II on VSMC
      production of plasminogen activator inhibitor-1, which attenuates fibrinolysis.
      Thus, 1 of the 2 major pathways of insulin action is the phosphatidylinositol 3
      kinase pathway, which is important for glucose transport in skeletal muscle, as
      well as endothelial NO production and insulin-induced vasodilation. The second
      insulin-activated pathway is the MAPK pathway, which promotes VSMC growth factors
      and migration induced by insulin, thrombin, angiotensin II, and platelet-derived
      growth factor. The thiazolidinediones, which act as ligands for peroxisomal
      proliferator-activated receptor gamma, may inhibit VSMC growth and migration
      through inhibition of a variety of transcription factors involved in the MAPK
      pathway.

PMID- 10418855
TI  - Vascular reactivity.
AB  - Endothelial dysfunction appears to be an integral aspect of the insulin
      resistance syndrome, independently of hyperglycemia. The ability of insulin to
      cause endothelium-derived nitric oxide (NO)-dependent vasodilation amplifies its
      overall effect of stimulating skeletal muscle glucose uptake and modulating
      vascular tone. The dose-dependent physiologic increase in skeletal muscle blood
      flow in response to insulin, which is highly associated with the rate of glucose
      metabolism, is impaired in insulin-resistant states. Insulin appears to mediate
      vasodilation by direct stimulation of release of NO from endothelium. Studies of
      the response to the endothelium-dependent vasodilator methacholine chloride in
      lean and obese nondiabetic subjects and obese subjects with type 2 diabetes
      mellitus indicate that there may be marked endothelial dysfunction very early in
      insulin resistance. The potent vasoprotective effects of NO mitigate various
      atherogenic processes, including vascular smooth muscle cell proliferation,
      platelet adhesion and thrombogenesis, lipid peroxidation, and monocyte adhesion
      to endothelial cells. The interaction between insulin and NO may contribute to
      the prominent outcomes of insulin resistance syndrome (viz., hypertension,
      thrombosis, and atherosclerosis).

PMID- 10418856
TI  - Insulin resistance and lipid metabolism.
AB  - The 3 major components of the dyslipidemia of insulin resistance are increased
      triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol, and
      changes in the composition of low-density lipoprotein (LDL) cholesterol.
      Hyperinsulinemia and the central obesity that typically accompanies insulin
      resistance are thought to lead to overproduction of very low-density lipoprotein
      (VLDL) cholesterol. The result is more triglyceride-rich particles, fewer HDL
      particles, and more small, dense LDL. Postprandial triglyceride levels and
      measures of postprandial remnants also may contribute to increased coronary
      artery disease (CAD) risk in individuals with insulin resistance. Deficiency of
      lipoprotein lipase, an insulin-sensitive enzyme, might explain the abnormal
      levels of remnant particles in insulin resistance. The potential benefits of
      successful treatment of dyslipidemia are illustrated by clinical trials in
      patients with the dyslipidemia characteristic of insulin resistance (i.e., normal
      or only moderately elevated LDL, elevated VLDL, and low HDL). Both weight loss
      and exercise can improve insulin resistance and associated dyslipidemia. In
      patients with type 2 diabetes mellitus, certain antidiabetic therapies can also
      improve the lipid profile by improving insulin resistance.

PMID- 10418857
TI  - Insulin resistance and systemic hypertension.
AB  - There is a complex relation among insulin sensitivity, hypertension, and
      endothelial function. Although there are few prospective data on the relation
      between insulin levels and the development of hypertension, there is some
      evidence that insulin resistance precedes the onset of established hypertension
      in high-risk patients. Because insulin is a vasodilator, it would need to
      activate a variety of other potential physiologic mechanisms to play a causal
      role in the pathogenesis of hypertension. There are changes in the arterial wall
      in patients with hyperinsulinemia, and characteristic decreases in elasticity of
      the arterial wall have been noted in hypertensive patients with insulin
      resistance. Hyperglycemia, hyperinsulinemia, and hypertriglyceridemia appear to
      jointly contribute to increased arterial stiffness. There are, however, ethnic
      and racial disparities in the association of insulin, insulin sensitivity, and
      blood pressure, as this relation is not strongly observed in the black population
      in the United States and elsewhere. This may reflect complex relations among
      obesity, diabetes, and hypertension, which are more common in patients with
      African ancestry, although recent evidence supports the probability that the
      differences are genetically determined. Whatever the precise mechanisms, clinical
      investigations demonstrate the benefit of early interventions to improve insulin
      sensitivity and control hypertension, as well as to reduce hypercholesterolemia.
      In particular, enhanced insulin sensitivity may improve hypertension and its
      subsequent damage to vessel walls.

PMID- 10418858
TI  - Insulin resistance and thrombosis: a cardiologist's view.
AB  - Atherogenesis in the vasculature is accelerated by changes in the dynamic
      equilibrium between endogenous tissue plasminogen activator and plasminogen
      activator inhibitor-1 (PAI-1). Increased expression of PAI-1, decreased
      expression of tissue plasminogen activator, or both can lead to decreased
      fibrinolytic activity and predispose to thrombosis. Increased concentrations of
      insulin (and proinsulin) in the plasma increase plasma PAI-1, although the
      mechanisms of this effect are not known. In addition, it has been observed that
      basal fibrinolytic activity is decreased in patients with type 2 diabetes; this
      may accelerate atherosclerosis by exposing vascular luminal wall surfaces to
      persistent and recurrent thrombi. Abnormalities in the vessel wall appear to
      contribute to the increased risk. There is also evidence that PAI-1 content is
      increased in atherosclerotic lesions of patients with type 2 diabetes, suggesting
      that interventions to reduce insulin resistance and improve glycemic control may
      improve the fibrinolytic response. Clinical studies in patients with polycystic
      ovary syndrome (characterized by insulin resistance, hyperinsulinemia, ovarian
      androgen overproduction, and impaired fibrinolytic capacity) demonstrated that
      treatment with troglitazone, an insulin-sensitizing agent, can markedly reduce
      blood levels of PAI-1. There is also clinical evidence that these agents may
      contribute to regression of intimal medial thickness in patients with type 2
      diabetes, providing further indication that antidiabetic interventions may help
      inhibit the progression of early atherosclerotic lesions.

PMID- 10418859
TI  - Science fiction becomes a reality: the use of bone morphogenetic protein in
      orthopedics.

PMID- 10418860
TI  - Clinical evaluation of rhBMP-2/ACS in orthopedic trauma: a progress report.
AB  - Recombinant human bone morphogenetic protein-2 (rhBMP-2) is an osteoinductive
      protein that plays a pivotal role in bone growth and regeneration. Studies
      conducted in many mammalian species and, most recently, human clinical studies,
      have provided definitive evidence of the ability of rhBMP-2 to induce bone. The
      findings of these studies provide a rationale for investigating whether rhBMP-2
      therapy will be clinically useful in orthopedic practice. Consequently, we have
      initiated a clinical research program to evaluate the safety and efficacy of
      rhBMP-2 therapy in open tibial fractures. A prospective observational study
      (involving no rhBMP-2 treatment) was conducted to define an appropriate patient
      population for rhBMP-2 clinical trials and has provided critical information
      related to the design and execution of future studies. The rhBMP-2 clinical
      trials include a small pilot feasibility study and several larger studies. Data
      from the pilot feasibility study have demonstrated that implantation of rhBMP-2
      (combined with an absorbable collagen sponge) is surgically feasible and safe.
      Larger, multicenter clinical studies are now ongoing in the United States and
      abroad.

PMID- 10418861
TI  - Preclinical and clinical evaluation of osteogenic protein-1 (BMP-7) in bony
      sites.
AB  - Osteogenic proteins (OPs), also referred to as bone morphogenetic proteins
      (BMPs), are a family of bone-matrix polypeptides isolated from a variety of
      mammalian species. Implantation of osteogenic proteins induces a sequence of
      cellular events that leads to the formation of new bone. In preclinical studies,
      the implantation of recombinantly produced human osteogenic protein-1 (OP-1, also
      referred to as BMP-7) into surgically created, critical-size diaphyseal segmental
      defects resulted in the regeneration of new bone that was fully functional
      biologically and biomechanically. Injection of an OP-1 solution into a fresh
      fracture model accelerated the bone repair process compared with control fracture
      healing. This was the result of greater and earlier new bone formation. Further
      study has demonstrated that OP-1 can be used as a bone graft substitute to
      promote spinal fusion, aid in the incorporation of metal implants, and improve
      the performance of autograft and allograft bone. Clinical study of OP-1 implanted
      in conjunction with a bovine bone-derived type 1 collagen carrier for the
      treatment of tibial nonunion fractures has shown healing characteristics similar
      to that obtained with autogenous iliac crest bone graft. Advantages of OP-1
      included no donor site complications, less blood loss, and a shorter operative
      time.

PMID- 10418862
TI  - Treatment of ipsilateral femoral neck and shaft fractures with the Russell-Taylor
      reconstructive nail.
AB  - Twenty-seven ipsilateral femoral neck and shaft fractures were treated with the
      Russell-Taylor reconstructive nail. Follow-up ranged from 6-48 months (average:
      23.6 months). Femoral neck fractures healed within an average of 3.7 months and
      femoral shaft fractures healed within an average of 4.8 months. Complications
      included one case of avascular necrosis of the femoral head, a varus healing of
      one femoral neck fracture, and a rotational malalignment of the femoral shaft in
      another case. There were no cases of hardware failure. The Russell-Taylor
      reconstructive nail allows concomitant hip and shaft fractures to be fixed with a
      single implant.

PMID- 10418863
TI  - The prevalence of cervical spondylolisthesis.
AB  - This study assessed the prevalence of cervical spondylolisthesis in patients
      undergoing radiographic studies for reasons unrelated to their cervical spine.
      Scout lateral cervical spine radiographs of 174 patients who had barium swallows
      were reviewed for the degree and level of cervical spondylolisthesis. Nine
      patients were found to have >2 mm of anterior subluxation of the cervical spine
      for a prevalence of 5.2%. Two patients had involvement at the C2-C3 level, one
      patient at C3-C4, four patients at C4-C5, one patient at C5-C6, and one patient
      at C7-T1. Subluxation ranged from 2 to 4 mm. Posterior subluxation
      (retrolisthesis) was not found in any patient. None of the nine patients with
      spondylolisthesis had complaints of neck pain or upper extremity symptoms, and
      none had a history of rheumatoid arthritis or cervical trauma.

PMID- 10418864
TI  - Colles' fracture: management by percutaneous crossed-pin fixation versus plaster
      of Paris cast immobilization.
AB  - Colles' fracture is the most common fracture seen in orthopedic practice, but no
      consensus has been reached on an effective method to maintain the initial
      reduction achieved. This prospective, randomized study of 50 patients evaluates
      the efficacy of maintaining reduction and consequent functional end results of
      two treatment methods, ie, percutaneous crossed-pin fixation followed by plaster
      of Paris cast immobilization with the wrist in functional position versus
      conventional plaster of Paris cast immobilization. The anatomical and functional
      end results were significantly better with percutaneous crossed-pin fixation at
      final follow-up.

PMID- 10418865
TI  - Mutilating injuries to the hand: early amputation or repair and reconstruction.

PMID- 10418866
TI  - Bone morphogenetic proteins in orthopedics: from basic science to clinical
      practice.

PMID- 10418867
TI  - A new technique for determining proper mechanical axis alignment during total
      knee arthroplasty: progress toward computer-assisted TKA.
AB  - Successful total knee arthroplasty (TKA) relies on proper positioning of
      prosthetic components to restore the mechanical axis of the lower extremity. This
      report presents and analyzes a new noninvasive method using the Optotrack
      (Northern Digital Inc, Ontario, Canada) to accurately determine the center of the
      femoral head. This method, together with direct digitization of the bony
      landmarks of the knee and ankle intraoperatively, permits placement of the lower
      extremity in proper alignment intraoperatively. It also permits the surgeon to
      follow all the angles of movement or rotation and all displacements that occur at
      each step of the operative procedure. knee intraoperatively via a customized
      Windows-based program. In addition to presenting our first case, which,
      importantly, represents the first computer-assisted TKA in a patient, we report
      on the accuracy and reproducibility of the technique for locating the center of
      the femoral head obtained during an extensive series of cadaver studies. Location
      of the femoral head, a major aspect of effecting neutral mechanical axis
      alignment, appears to be possible to within 2-4 mm, which corresponds to an
      angular accuracy of better than 1 degree. This method requires no computed
      tomography scans or other preliminary marker placement. The only basic
      requirement other than the instrumentation described is a freely mobile hip,
      which is generally present in TKA patients.

PMID- 10418868
TI  - Symptomatic carpal boss.

PMID- 10418869
TI  - Intraosseous ganglion of the glenoid.

PMID- 10418870
TI  - Radiologic case study. Infantile cortical hyperostosis (Caffey's disease).

PMID- 10418871
TI  - A PCR based method for the identification of equine influenza virus from clinical
      samples.
AB  - In this paper we describe the development of a nested RT-PCR assay for the rapid
      diagnosis and characterisation of influenza virus directly from clinical
      specimens. Viral RNA is extracted from nasal swabs by the guanidine thiocyanate
      extraction method, and subsequently reverse transcribed. The complementary DNA is
      then used as template in a nested PCR reaction. Primers designed for use in this
      assay are specific for three templates; (1) the nucleoprotein (NP) gene, (2) the
      haemagglutinin gene of the H7N7 equine influenza virus (A1), and (3) the
      haemagglutinin gene of the H3N8 equine influenza virus (A2). We show that the
      assays are specific for the target genes chosen, and display sensitivity similar
      to virus isolation. The NP assay detects a variety of different influenza
      subtypes, whereas A1 and A2 assays are specific for influenza subtypes H7N7 and
      H3N8, respectively. Sequencing of amplicons obtained in the A2 assay yields
      information on antigenic regions of the haemagglutinin molecule, and use of this
      procedure in the routine surveillance of equine influenza will enable tentative
      characterisation of circulating viruses despite difficulties in isolating field
      strains of the H3N8 subtype. The A1 assay will be useful in ascertaining whether
      viruses of the H7N7 subtype still circulate amongst horses, or whether these are
      extinct.

PMID- 10418872
TI  - Nucleotide sequence of UK and Australian isolates of feline calicivirus (FCV) and
      phylogenetic analysis of FCVs.
AB  - We have determined the first complete genome sequence and capsid gene sequences
      of feline calicivirus (FCV) isolates from the UK and Australia. These were
      compared with other previously published sequences. The viruses used in the
      comparisons were isolated between 1957 and 1995 from various geographical
      locations and obtained from cats showing a range of clinical signs. Despite these
      diverse origins, comparisons between all strains showed a similar degree of
      sequence variation within both ORF1 (non-structural polyprotein) and ORF2 (major
      capsid protein) (amino acid distances of 7.7-13.0% and 8.8-18.6%, respectively).
      In contrast, ORF3 (putative minor structural protein) sequences indicated a more
      heterogenous distribution of FCV relatedness (amino acid distances of 1.9-17.9%).
      Phylogenetic analysis suggested that, unlike some other caliciviruses, FCV
      isolates within the current data set fall into one diverse genogroup. Within this
      group, there was an overall lack of geographic or temporal clustering which may
      be related to the epidemiology of FCV infection in cats. Analysis of regions of
      variability in the genome has shown that, as well as the previously identified
      variable regions in ORF2, similar domains exist within ORFs 1 and 3 also,
      although to a lesser extent. In ORF1, these variable domains largely fall between
      the putative non-structural protein functional domains.

PMID- 10418873
TI  - Purification and characterization of protease produced by Staphylococcus aureus
      isolated from a diseased chicken.
AB  - A protease produced by Staphylococcus aureus, isolated from a chicken suffering
      from dermatitis, was purified by successive precipitation with ammonium sulfate,
      ion-exchange chromatography on Q-Sepharose FF, Sp-Sepharose FF and Mono-Q
      columns. By Mono-Q column chromatography, two proteases (protease 1 and 2) were
      obtained. The molecular weights of protease 1 and 2 were estimated at 23.1 and
      22.7 kDa, respectively, by SDS-polyacrylamide gel electrophoresis. Their
      isoelectric points were 5.85 and 5.55, respectively, and they possessed antigenic
      similarity when examined by the immunoblotting. The N-terminal amino acid
      sequences of both the proteases were identical (RAQYVNQLKNFKIRETQ). The
      activities of both the proteases were strongly increased by reducing agents such
      as L-cysteine and sodium thioglycolate. Their activity was inhibited by thiol
      protease inhibitors, but was not inhibited by metalloprotease or serine protease
      inhibitors. From the results, it seems likely that these proteases, produced by
      S. aureus from diseased chickens, might belong to the thiol protease group.

PMID- 10418874
TI  - Isolation of Verocytotoxin-producing Escherichia coli O157:H7 from cattle at
      slaughter in Italy.
AB  - Cattle arriving for slaughter at a large abattoir in northern Italy between April
      1997 and January 1998 were examined for intestinal carriage of Verocytotoxin
      producing Escherichia coli (VTEC) O157 using an immunomagnetic separation
      technique. Sixty sorbitol non-fermenting VTEC O157 strains were isolated from 59
      (13.1%) of the 450 cattle examined. In particular, VTEC O157 was found in 37
      (16.6%) of 223 feedlot cattle and in 22 (16.1%) of 137 dairy cull cows, but not
      in the 90 veal calves sampled. The isolation rate was higher during warm weather
      (17.5%), falling to an average of 2.9% during the winter months. VT-negative,
      O157 latex-agglutinating E. coli strains were isolated from 23 (5.1%) of the 450
      animals. PCR analysis showed that all 60 VTEC O157 strains carried the VT2 gene
      and that 25 strains also carried the VT1 gene. In addition, four of the VT
      negative, O157 latex-agglutinating E. coli strains carried the VT2 gene. Atypical
      biochemical features were observed in some VTEC O157: two strains (3.3%) showed
      beta-glucuronidase activity, and seven (11.7%) produced urease.

PMID- 10418875
TI  - Molecular fingerprinting of Riemerella anatipestifer by repetitive sequence PCR.
AB  - Riemerella anatipestifer is a gram-negative rod-shaped bacterium associated with
      epizootic infections in poultry. A total of 35 R. anatipestifer isolates
      including the type strain ATCC11845T, reference and field strains for 18
      different serotypes were characterized by repetitive sequence based-PCR (rep-PCR)
      with outwardly-directed primers based on the repetitive extragenic palindromic
      (REP) consensus sequence. This technique was applied by using either extracted
      genomic DNA or preparation of whole bacterial cells harvested directly from plate
      cultures. Rep-PCR discriminated the R. anatipestifer isolates into 19
      electrophoretic types. DNA fingerprints obtained from rep-PCR of extracted
      genomic DNA or from preparations of whole cells yielded comparable patterns.
      Substantial variation was seen among the rep-PCR fingerprints of different
      serotypes. Moreover, different polymorphisms of the rep-PCR fingerprints were
      evident among epidemiologically unrelated isolates of the same serotype. These
      results suggest the presence of repetitive extragenic palindromic-like elements
      within the genome of R. anatipestifer that can be used in some isolates to
      discriminate between different strains belonging to the same serotype. Rep-PCR
      may serve as a useful molecular tool for subtyping R. anatipestifer isolates for
      epidemiologic investigations. The whole cell procedure offers the advantage of
      ease of performance requiring only small quantities of cells.

PMID- 10418876
TI  - Characterization of bovine coronavirus isolates/from eight different states in
      the USA.
AB  - Bovine coronavirus isolates from eight different states of the USA were compared
      for their antigenic properties and susceptibility to hygromycin B. Antigenic
      differences were observed among the isolates in a one-way hemagglutination
      inhibition (HI) test using a polyclonal antiserum against the Mebus bovine
      coronavirus isolate. Differences were observed on isoelectric focusing among
      viral proteins with isoelectric points between 4.45-4.65. Most of the BCV
      isolates were susceptible to hygromycin B (0.5 mM) whereas a few hygromycin B
      resistant isolates were also found.

PMID- 10418877
TI  - Characterization of flagellin from Clostridium chauvoei.
AB  - Differential centrifugation and cesium chloride-equilibrium centrifugation were
      used to purify the flagella from the strain Okinawa of the formalin-fixed
      Clostridium chauvoei. SDS-PAGE profile of purified flagella showed that a major
      protein band with a molecular mass of 46 kDa, corresponding to the flagellin
      monomer, and at least two minor protein bands with molecular masses of
      approximately 73 and 100 kDa were found. The amino acid composition of C.
      chauvoei flagellin was similar to the flagellin of Salmonella typhimurium and
      Bacillus subtilis. In addition, C. chauvoei flagellin monomer shared limited
      sequence homology with the N-terminal amino acid sequence reported for other
      bacterial flagellins. N-terminal sequences of two minor bands corresponded to the
      flagellin monomer, indicating that higher molecular mass bands were polymeric
      forms of the flagellin monomer.

PMID- 10418878
TI  - Culture and adolescent development.

PMID- 10418879
TI  - Youth action strategies in violence prevention.
AB  - PURPOSE: To describe a school-based youth-driven violence prevention project. The
      objectives were to provide opportunities for students to plan health-related
      activities, develop their awareness of the importance of violence prevention, and
      identify ways to cope with and influence their environment with respect to this
      issue. METHODS: This project was initiated in three Canadian high schools with
      noon-hour discussions and a television talk show as the selected activities.
      Three hundred forty-eight students' perceptions of violence and the effectiveness
      of the noon-hour discussions were evaluated by use of a questionnaire. Feedback
      on the talk show was obtained from viewers' calls. Data were analyzed using
      descriptive statistics. Chi-square and Student's t-test were calculated to
      compare boys and girls on variables measuring their perception of violence, as
      well as to compare those who attended the noon-hour sessions and those who did
      not. RESULTS: The majority of students (86.4%) believed that the noon-hour
      discussions increased their awareness of violence prevention and that the
      information provided was useful (83.6%). Nearly two-thirds (63.8%) of the
      students reported that attending the discussions changed their understanding of
      violence. The numerous calls received from viewers suggest that the talk show was
      effective in increasing public awareness. CONCLUSIONS: Youth-led health promotion
      activities provide excellent opportunities for youth to become involved and
      empowered. While adolescents need guidance to initiate activities, their
      creativity and energy must be acknowledged. The success of the noon-hour
      discussions and talk show demonstrates the importance of exploring and developing
      novel community participation strategies with youth.

PMID- 10418880
TI  - How do vocational and relationship stressors and identity formation affect
      adolescent mental health?
AB  - PURPOSE: This article examines the effects of stressors in both the vocational
      and relationship career of youngsters in the formation of their identity; the
      effects of identity formation on adolescent mental health; the influence of
      career stressors on mental health, directly or via identity, and differences in
      these effects on boys and girls. METHODS: Data were used from the Dutch national
      panel study, Utrecht Study of Adolescent Development, a study of developmental
      processes as they occur in the life course of young people during the 1990s.
      Using LISREL, we tested hypotheses on two waves of a sample of 1222 respondents
      between 15 and 24 years of age in Wave 1 (1991). RESULTS: The correlation between
      relationship stressors and relationship identity can be neglected, while
      vocational stressors lead to a less achieved vocational identity, particularly in
      boys. Occupational and relationship identity have similar effects on mental
      health (i.e., the more achieved the identity, the better the person's mental
      health). Vocational and especially relationship stressors lead to poorer mental
      health, but did not affect the mental health of boys and girls differently. The
      same goes for the influence of relationship and vocational identity formation on
      mental health. CONCLUSIONS: Career stressors, especially stressors in the
      relationship domain, appear to have significant long-term effects on adolescent
      mental health. Vocational and relationship identity formation are also
      significant predictors for adolescent mental health.

PMID- 10418881
TI  - Violence of French adolescents toward their parents: characteristics and
      contexts.
AB  - PURPOSE: To determine the social, familial, and psychiatric characteristics of
      children who batter their parent(s); and to report clinical vignettes of this
      phenomenon and contexts which precipitate such violence. METHODS: In this
      retrospective study, we analyzed the medical records of the 645 children
      hospitalized in a child and adolescent psychiatry department between 1987 and
      1996. RESULTS: The principle findings were that: (a) 3.4% of the patients
      demonstrate parent battering; (b) the average age of parent batterers is 14 years
      old, and they are predominately male; and (c) their mothers are more often the
      victims than their fathers, and there is a high frequency of psychiatric
      disorders among parents. Seven clinical vignettes have been presented to
      represent different family contexts of the 22 cases of domestic violence in this
      study. CONCLUSIONS: Further studies are needed to deepen our knowledge of
      violence perpetrated by adolescents toward their parents. A better knowledge of
      etiological mechanisms involved would permit more preventative action for
      families at risk.

PMID- 10418882
TI  - The correlates of depressed mood in adolescents in Hong Kong.
AB  - PURPOSE: Most studies of depressed mood and its correlates in adolescents have
      been conducted in Western countries. This study examined the relationship between
      a broad range of stressors and depressed mood in a community sample of Hong Kong
      adolescents. METHODS: Secondary school students (n = 996) completed the Chinese
      Beck Depression Inventory (C-BDI), provided demographic information, and
      indicated their perceptions of family and peer relationships, school function and
      pressures, and subjective health, and some measures salient to the Hong Kong
      environment: triad gang pressure, religiosity, and intent to emigrate. The
      correlation between C-BDI and these variables was assessed in bivariate and
      multivariate analyses. RESULTS: Hong Kong adolescents reported higher levels of
      depressive symptoms than a comparison group of Western teenagers. Girls showed
      more symptoms than boys. All stressors correlated in bivariate analyses with C
      BDI, indicating similar influences on depressed mood in Western and Hong Kong
      teenagers. In multivariate analyses, the stressors contributed cumulatively to
      the C-BDI score. Perceptions of a lack of parental understanding and peer
      acceptance appeared as the strongest variables in predicting depressed mood.
      CONCLUSIONS: Depressed mood is highly prevalent among Hong Kong teenagers.
      Stressors play a cumulative role in their relationship to mood. Our findings
      point to the importance of broad screening of this vulnerable population.

PMID- 10418883
TI  - Attitudes and practices of Israeli physicians toward adolescent health care: a
      national survey.
AB  - PURPOSE: To assess practices and attitudes of Israeli physicians with regard to
      adolescent health. METHODS: Questionnaires were sent to a sample of 1050 Israeli
      physicians specializing in pediatrics (P) family practice (FP), and internal
      medicine (IM). They were requested to report their experience, perceived skills,
      and desire for further training regarding 16 adolescent health items grouped
      under four topics: medical, sexuality, risk behavior, and psychosocial problems.
      A scoring system was applied to assess their report. Attitudes toward
      confidentiality in the same topics were also surveyed. RESULTS: Questionnaires
      were received from 306 (29%) physicians, of whom 42% were P, 35% were FP, and 29%
      were IM. The majority (96%) of respondents included adolescents in their
      practice, and adolescents comprised 33%, 17%, and 11% of the registered patient
      population of the P, FP, and IM, respectively. The mean scores for practice,
      perceived skills, and desire for further training were generally low. Analysis of
      variance revealed significant differences among the three physicians groups in
      all surveyed topics, resulting from the low scores of the IM group. A diversity
      regarding confidentiality was noted, in that younger FP were most willing to keep
      health issues confidential. CONCLUSIONS: Physicians in Israel have limited
      experience and perceive themselves to be underskilled in dealing with adolescent
      health issues. Training programs in adolescent health need to be developed to
      meet the needs of physicians in Israel.

PMID- 10418884
TI  - Primary dysmenorrhea in young Western Australian women: prevalence, impact, and
      knowledge of treatment.
AB  - PURPOSE: To explore the prevalence of dysmenorrhea among senior high school girls
      in Perth, Western Australia, its impact on school, sporting, and social
      activities, students' management strategies, and their knowledge of available
      treatment. METHODS: A total of 388 female students in Grades 11 and 12 at three
      metropolitan secondary schools completed an anonymous questionnaire administered
      during class time. The following definition of dysmenorrhoea was used: any type
      of pain or discomfort associated with menstrual periods including cramps, nausea,
      and headaches. RESULTS: The reported prevalence of dysmenorrhea among these girls
      was 80%; 53% of those girls with dysmenorrhea reported that it limited their
      activities. In particular, 37% said that dysmenorrhea affected their school
      activities. The most common medication used by those reporting dysmenorrhea was
      simple analgesics (53%), followed by nonsteroidal anti-inflammatory drugs
      (NSAIDs), used by 42%. More than a quarter of respondents (27%) were unaware that
      NSAIDs were a possible treatment option for dysmenorrhea. CONCLUSION: The
      prevalence and impact of dysmenorrhea on Grade 11 and 12 girls is high, and they
      lack knowledge of and experience with effective treatment. Health education
      measures are needed in this area to prevent unnecessary suffering and
      interruption to school routine.

PMID- 10418885
TI  - Hepatitis infection among adolescents resident in Melbourne Juvenile Justice
      Centre: risk factors and challenges.
AB  - OBJECTIVE: To describe patterns of infection with, and risks for, hepatitis A, B
      and C viruses (HAV, HBV, and HCV) in male adolescents detained in the Melbourne
      Juvenile Justice Centre (MJJC). METHODS: A cross-sectional serosurvey for HAV,
      HBV, and HCV among 90 male adolescents aged 15-18 years who were resident in MJJC
      for more than 1 week in 1996. RESULTS: Nine percent had been exposed to HAV, 8%
      were positive or equivocal for exposure to HBV, and 21% were antibody positive
      for HCV. All those with hepatitis markers except one positive for HAV had been
      injection heroin users for more than 1 year. Of those who were not HBcAb
      positive, only 28% were immune to HBV. For most respondents, sexual and drug
      using risks began in the early teens and were associated with leaving school
      prematurely. CONCLUSIONS: Respondents were vulnerable to exposure to blood-borne
      viruses from an early age, posing a challenge for health education programs. An
      opportunity exists for harm minimization and prevention of spread of blood-borne
      viruses within the first year of injection drug use in this population.

PMID- 10418887
TI  - Dieting behavior among 11-15-year-old girls in Merseyside and the Northwest of
      England.
AB  - PURPOSE: To examine the general dieting behavior and characteristics of
      adolescent girls in the United Kingdom, and in particular, the Northwest of
      England. METHODS: A total of 569 girls, ages 11-15 years, from six schools in the
      Merseyside and Lancashire area, representing a cross-section of social status,
      completed a nonstandardized questionnaire concerning general dieting behavior.
      Data were analyzed using SPSS (p < .05 was considered significant). RESULTS: The
      incidence of dieting was 35.3%. The earliest reported age of starting to diet was
      8 years. Significantly more girls from the independent schools (45.2%) had
      started to diet by the age of 10 years, compared to girls from the comprehensive
      schools (24%) (p = .03). Of those who had dieted, 30.3% had dieted up to two
      times during the previous 12 months, 17.4% had dieted up to four times, and 6%
      had dieted for most of the time. Most girls (33%) dieted for 2-4 weeks at a time,
      and 66% thought that dieting was good for their health. Only 52% said their
      parents did not approve of them dieting. Most girls (42.1%) dieted because they
      felt they were too fat. CONCLUSION: This study has shown that many young girls
      are engaging in potentially harmful dieting practices from a very early age, and
      are of the opinion that dieting is a healthy activity. This would suggest that
      many misconceptions are held with regard to nutritional advice and education, and
      that such information should be reviewed and changed accordingly.

PMID- 10418886
TI  - Use of Western-based HIV risk-reduction interventions targeting adolescents in an
      African setting.
AB  - PURPOSE: To evaluate an intervention (based on one which had previously been
      successful in reducing adolescent human immunodeficiency virus (HIV) risk
      behaviors in the United States) among adolescents residing in Namibia, a country
      located in sub-Saharan Africa. METHODS: A randomized trial of a 14-session face
      to-face intervention emphasizing abstinence and safer sex was conducted among 515
      youth (median age 17 years; median grade 11) attending 10 secondary schools
      located in two districts in Namibia. Knowledge, attitudes, intentions, and HIV
      risk behaviors were assessed at baseline and in the immediate postintervention
      period. RESULTS: Knowledge increased significantly among intervention compared to
      control youth (88% vs. 82%; correct responses, p < .0001). At postintervention
      follow-up, more intervention than control youth believed that they could be
      intimate without having sex, could have a girlfriend or boyfriend for a long time
      without having sex, could explain the process of impregnation, knew how to use a
      condom, and could ask for condoms in a clinic. Fewer intervention than control
      youth believed that if a girl refused to have sex with her boyfriend it was
      permissible for him to strike her, and that condoms took away a boy's pleasure.
      More intervention than control youth anticipated using a condom when they did
      have sex, and fewer expected to drink alcohol. Finally, after intervention, there
      was a trend for increased condom use. There were significant gender-related
      differences at baseline, although intervention impact was generally equivalent.
      CONCLUSIONS: These findings provide support for the judicious adaptation of
      successful Western HIV prevention programs in other cultural settings. A single
      intervention approach appears to be effective in short-term follow-up with both
      genders.

PMID- 10418888
TI  - Coronary heart disease risk factors in male adolescents, with particular
      reference to smoking and blood lipids.
AB  - PURPOSE: To examine coronary heart disease (CHD) risk factors, particularly blood
      lipids and smoking, in adolescent boys in the Sydney Metropolitan area, and to
      investigate possible differences between boys from English-speaking (ESB) and non
      English-speaking backgrounds (NESBs). METHODS: Male volunteers aged 15-18 years
      were recruited from the senior years of four secondary schools in different
      geographical areas of Sydney. Body mass index (BMI), waist-hip ratio (WHR), blood
      lipids, and percent body fat were measured. Behavioral variables were estimated
      by questionnaire. RESULTS: A total of 110 boys were recruited; 74% were from an
      ESB. Mean WHR (0.836 +/- 0.045), waist circumference (80.6 +/- 9.4 cm), and
      percent body fat (21.0 +/- 6.3) were similar across age groups. Atherogenicity of
      the lipid profile, as measured by the ratio of total cholesterol to high-density
      lipoprotein cholesterol (TC:HDL-C), was lower in boys aged 15 years than in any
      other age group (p < .05). TC:HDL-C was strongly associated with BMI (r = .57; p
      < .0001) and WHR (r = .35; p < .01). Smokers had higher BMI, were less active and
      had lower HDL-C (p < .001) and higher TC:HDL-C (p < .0001) than nonsmokers.
      Smoking, even of short duration, and quite moderate consumption of cigarettes
      (6/day) were associated with a deterioration of the lipid profile. Boys from
      NESBs had a higher degree of risk in all of the factors examined. CONCLUSIONS:
      Regular smoking of short duration has an appreciable impact on lipid and
      lipoprotein concentrations in this sample of Australian adolescent boys. Boys
      from an NESB appear to be at greater risk of developing CHD in later life.

PMID- 10418889
TI  - Trauma-related hospitalizations among urban adolescents in New Zealand:
      priorities for prevention.
AB  - PURPOSE: To: (a) determine the magnitude, characteristics, and in-patient costs
      of injury among hospitalized urban adolescents in New Zealand (NZ); (b) identify
      regional priorities for injury prevention and investigative research; and (c)
      compare the study findings with published data from other industrialized
      countries. METHODS: The 1989-1993 files of the NZ Hospital Discharge Database
      were accessed to identify and analyze trauma-related admissions of adolescents
      residing in NZ's largest metropolitan region. RESULTS: The estimated 9569
      hospitalizations for injury accounted for one-fourth of all adolescent admissions
      in the region, a mean annual hospitalization rate of 1292/100,000 population and
      a minimum annual cost of NZ $5.8 million for in-patient care. Males and
      indigenous Maori youth had comparatively higher rates of hospitalizations for
      most major causes of injury. Falls, pedal cyclist injury, cuts, and piercing
      injuries were leading causes of hospitalization for trauma in early adolescence.
      Admission rates for motorcylist and other motor vehicle occupant trauma and self
      inflicted injury increased substantially among older adolescents. Sport and
      recreational activities comprised at least one-sixth of injury admissions.
      CONCLUSIONS: The overall rates of injury resulting in hospitalization among
      Auckland adolescents were comparable to those reported from Australia and France,
      but higher than those from the United States, Canada, and Israel. By identifying
      priority issues and high-risk groups, this study provides a foundation for
      regional injury control initiatives. It also demonstrates the utility and
      limitations of E-coded hospital discharge registries in defining the burden of
      serious nonfatal trauma.

PMID- 10418891
TI  - Multiple sclerosis and hepatitis B vaccine?

PMID- 10418890
TI  - Alternative methods in the investigation of adolescents' sexual life.
AB  - PURPOSE: To describe two methodological approaches to surveying adolescents'
      sexual life which were combined within a national survey. METHODS: The
      questionnaire was designed during a 5-day workshop. Ten adolescents played the
      roles of imaginary adolescents involved in different situations related to sexual
      life. The information obtained through the analysis of these role-plays was used
      to establish the sequence of the questions, their content, and wording. The
      questionnaire was computerized so that it could be completed by the adolescents
      using laptop computers. Its arborescent structure, leading each respondent from
      one module to another, made possible the adjustment of the questions to each
      respondent's stage of development and type of sexual experience. RESULTS: A total
      of 4283 teenagers (2075 girls and 2208 boys, and 4 refusals) 16-20 years were
      included. Only 7.6% did not fill in the whole questionnaire. By the age of 18
      years, more than 50% of boys and girls were sexually active. Half of sexually
      active teenagers have discussed contraception issue before engaging in their
      first intercourse, but much fewer (14-35%) have discussed issues related to HIV
      transmission. During their first sexual intercourse, the majority of the
      respondents used a condom (girls, 63%; boys, 58%) or condom plus oral
      contraception (girls, 11%; boys, 17%). CONCLUSION: Youth participation and role
      play decrease the conceptual biases often associated with professionals'
      perceptions and bring tools enabling a better exploration of circumstances and
      negotiations surrounding the sexual encounter. The computerized questionnaire
      increases confidentiality, attractiveness, easy data collection, and, above all,
      adjustment of the questions to the respondent's level of experience. These
      methods could be more systematically used in surveys targeting sensitive issues
      related to adolescents' health.

PMID- 10418892
TI  - Typhoid fever vaccines.

PMID- 10418893
TI  - Xenogeneic and allogeneic anti-MHC immune responses induced by plasmid DNA
      immunization.
AB  - Major histocompatibility complex (MHC) proteins are known to be incorporated into
      the human immunodeficiency virus (HIV-1) envelope as the virion buds from the
      host cell surface. Studies using simian immunodeficiency virus (SIV) infection of
      macaques have demonstrated that immunization with uninfected human cells or
      purified HLA proteins can provide protection from challenge with live SIV when it
      is grown in human cells expressing the same MHC alleles. Thus the induction of
      anti-MHC immune responses represents an important option to consider with respect
      to vaccine design for SIV and HIV. Here we examine plasmid DNA immunization
      strategies as an alternative to cellular or protein immunogens for the induction
      of xenogeneic and allogeneic immune responses in C57BL/6 mice and in an HLA
      transgenic mouse model system, respectively. We compared the immunogenicity of
      HLA-A2- and HLA-B27-expressing splenocytes with the corresponding plasmid DNA
      immunogens. Results from the transgenic mouse experiments indicate that plasmid
      DNA immunization with both class I and class II MHC-encoding vectors can elicit
      antibody responses recognizing conformationally intact MHC molecules. Our data
      also show that immunization with class I MHC-encoding DNA immunogens can elicit
      cytotoxic T-lymphocyte responses, demonstrating the potential to mobilize both
      antibody and cell-mediated anti-MHC immune responses in the context of this
      approach to HIV-1 vaccine design.

PMID- 10418894
TI  - Incremental effectiveness of pneumococcal vaccine on simultaneously administered
      influenza vaccine in preventing pneumonia and pneumococcal pneumonia among
      persons aged 65 years or older.
AB  - The effectiveness of simultaneously administered influenza and pneumococcal
      vaccines vs. influenza vaccine alone in preventing pneumonia, pneumococcal
      pneumonia and pneumococcal bacteraemia among the elderly was studied. The
      vaccines were offered to all persons aged 65 years or older (N=43,500) living in
      35 administrative districts in Northern Finland. A total of 26,925 persons (62%)
      decided to participate. Allocation to the vaccination groups took place by year
      of birth (odd/even). The total follow-up of those vaccinated consisted of 38,037
      person years. The incremental effectiveness of the pneumococcal vaccine was -20
      (95% CI -50- + 10%) for pneumonia, -20 (95% CI -90- + 20%) for pneumococcal
      pneumonia and + 60% (95% CI -40- +90%) for pneumococcal bacteraemia. Thus the
      pneumococcal polysaccharide vaccine did not offer any additional protection from
      pneumonia among elderly people in Finland although it reduced the incidence of
      bacteraemia.

PMID- 10418895
TI  - Use of polymerase chain reaction (PCR) for the detection of vaccine contamination
      by infectious laryngotracheitis virus.
AB  - Quality control of biologicals for veterinary use includes certification of
      freedom from extraneous agents. Contamination of vaccines may originate from
      various materials used for production and during manufacturing process.
      Requirements for avian virus vaccines to demonstrate freedom of adventitious
      agents are stated in the European Pharmacopoeia and include monitoring for
      infectious laryngotracheitis virus (ILTV). ILTV is an avian herpesvirus belonging
      to the alphaherpesvirus subfamily causing acute respiratory disease. To date the
      methods to detect ILTV contaminating biologicals consist of demonstration of
      antibody induction in chicken after immunization or virus cultivation in
      embryonated eggs. These methods are time consuming and laborious. Therefore, a
      specific, simple and sensitive in vitro polymerase chain reaction (PCR) for the
      detection of ILTV contamination in avian virus vaccines was developed. Primers
      were designed to amplify part of the p32 gene. Four different ILTV vaccine
      strains could be unequivocally detected. The identity of the amplified fragment
      was confirmed by restriction endonuclease analysis.

PMID- 10418896
TI  - Immunity to poliomyelitis, diphtheria and tetanus in pediatric patients before
      and after renal or liver transplantation.
AB  - Few studies have considered the safety, efficacy and appropriateness of
      vaccinations in pediatric patients before and after solid organ transplantation.
      The aim of this study was to evaluate the immune status after primary vaccination
      to diphtheria, tetanus and poliomyelitis in pediatric patients before and after
      hepatic transplantation and to poliomyelitis in pediatric patients before and
      after renal transplantation. All the patients had received a complete primary
      immunization schedule for diphtheria and tetanus and poliomyelitis. Immunity to
      the three polioviruses was evaluated in 56 patients with renal transplant, 27 on
      chronic dialysis and 33 controls and in 39 patients with hepatic transplant, 25
      with chronic hepatic failure and their 36 controls. Immunity to diphtheria and
      tetanus was evaluated in 52 liver transplant patients, 29 children with chronic
      hepatic failure and 54 healthy children. Renal transplant patients were less
      protected and had lower antibody geometric mean titers than healthy controls for
      polioviruses 1 and 2. Whereas, protection in the children liver transplant
      patients was similar to that in their controls. Patients with chronic hepatic
      failure had higher antibody geometric mean titers to diphtheria and polioviruses
      1 and 3 than their control group. Immunosuppression after transplantation has a
      negative influence on the immune status after primary vaccination in children
      with renal transplant. Whereas children with chronic hepatic failure have higher
      antibodies than a normal population. When possible, it could be advisable to
      individualize immunization schedules in patients at high risk.

PMID- 10418897
TI  - Influenza virus subtype cross-reactivities of haemagglutination inhibiting and
      virus neutralising serum antibodies induced by infection or vaccination with an
      ISCOM-based vaccine.
AB  - In order to study the levels of cross-reactivity of the influenza virus-specific
      antibody response upon infection or vaccination, usually hemagglutination
      inhibition assays are performed. In the present study post-infection ferret sera
      and serum samples obtained from cynomolgus macaques which were vaccinated with an
      ISCOM preparation based on the influenza virus strain A/Netherlands/18/94 (H3N2)
      were analyzed for cross-reactivity in the hemagglutination inhibition assay and
      in virus neutralization assays. It was shown that the cross-reactivity of the
      antibodies induced upon vaccination or infection with influenza virus proved to
      be more limited in the virus neutralization assay than in the hemagglutination
      assay. The strong antibody response induced by vaccination with the
      A/Netherlands/18/94-ISCOM preparation was shown to be cross-reactive with recent
      influenza virus strains, which were isolated since 1992, but not with older
      strains.

PMID- 10418898
TI  - The adjuvant combination monophosphoryl lipid A and QS21 switches T cell
      responses induced with a soluble recombinant HIV protein from Th2 to Th1.
AB  - The induction of protective immunity with recombinant vaccines is dependent on
      the identification of adjuvant or delivery systems that can augment immune
      responses, especially cellular immune responses, to soluble protein antigen. In
      this study we demonstrate that an adjuvant formulation comprising QS21, a
      purified form of saponin and 3D-monophosphoryl lipid A (MPL), a nontoxic
      derivative of lipopolysaccharide (LPS), enhances cellular and humoral immune
      responses to a recombinant HIV protein. Analysis of cytokine secretion by antigen
      specific T-cells from the spleen demonstrated that QS21 augmented Th1 and Th2
      responses, whereas addition of 3D-MPL resulted in preferential induction of type
      1 T-cells. Furthermore, analysis of the subclass of the IgG antibody in the serum
      in mice immunized with gp120 with the combined adjuvant formulation confirmed the
      selective activation of Th1 cells in vivo. 3D-MPL was found to enhance B7-1
      expression and IL-12 production by macrophages, which are known to be involved in
      the LPS-induced enhancement of Th1 responses. Thus 3D-MPL appears to act as an
      adjuvant, without the toxicity associated with LPS, by controlled and selective
      potentiating effects on antigen presentation and T-cell activation.

PMID- 10418899
TI  - T-cell and antibody response characterisation of a new recombinant pre-S1, pre-S2
      and SHBs antigen-containing hepatitis B vaccine; demonstration of superior anti
      SHBs antibody induction in responder mice.
AB  - The incidence of non-responders to hepatitis B (HB) virus SHBs antigen (Ag)
      vaccines has prompted the development of pre-S containing vaccines. The aim of
      this study was to characterise the murine immune response to a novel recombinant
      particle (Hepagene) (Medeva plc) containing pre-S1, pre-S2 and SHBsAg components.
      Hepagene induced potent in vitro spleen T-cell proliferative responses in both
      BALB/c (maximum stimulation index (SI) = 38) and SWR/J (maximum SI = 43) strains
      of mouse, following immunisation. High concentrations of interferon-gamma and low
      concentrations of interleukin-10 were detected in the media of spleen cells
      stimulated with Hepagene. The anti-Hepagene antibody response was higher in SWR/J
      mice and alhydrogel adjuvant significantly improved the titres. Anti-pre-S1
      antibody was detected in both strains of mouse, whereas antipre-S2 antibody was
      only detected in SWR/J mice. IgG subclass analysis of the anti-Hepagene response
      revealed a Th2-type response in BALB/c mice and a mixed Th1/Th2 response in SWR/J
      mice. Hepagene induced higher anti-SHBs antibody responses than Engerix-B (11097
      and 1276 IU/ml, respectively) in BALB/c mice. Hepagene therefore, stimulates
      strong cellular and humoral immune responses in murine models. The high anti-SHBs
      antibody response suggests that Hepagene is an improved hepatitis B virus
      vaccine.

PMID- 10418900
TI  - Vaccination for control of Salmonella in poultry.
AB  - Salmonella spp. are facultative intracellular pathogens causing localised or
      systemic infections, in addition to a chronic asymptomatic carrier state. They
      are of worldwide economic and public health significance. In poultry, which
      represent important sources of cheap protein throughout the world, fowl typhoid
      and pullorum disease continue to cause economic losses in those parts of the
      world where the poultry industries are continuing to intensify and where open
      sided housing is common. A number of serotypes that cause human gastro-enteritis
      are also increasing. The costs or impracticality of improvements in hygiene and
      management together with the increasing problems of antibiotic resistance suggest
      that vaccination in poultry will become more attractive as an adjunct to existing
      control measures. However, our understandings of the immunology of Salmonella
      infections in poultry is rudimentary and much poorer than that of equivalent
      infections in mice and live vaccine development for poultry has therefore been
      largely empirical. In addition to the killed Salmonella vaccines which have been
      used over the past few years with variable efficacy, a number of live vaccines
      have become available and some new vaccines will appear on the market over the
      next few years. These new vaccines should fulfil the criteria of efficacy, safety
      and compatibility with existing systems for monitoring infection before they are
      released on to a mass market. In this review we attempt to summarise the current
      understanding of Salmonella immunology in poultry together with the progress that
      has been made in poultry vaccine development.

PMID- 10418901
TI  - Derivation of attenuated porcine epidemic diarrhea virus (PEDV) as vaccine
      candidate.
AB  - The field isolate of porcine epidemic diarrhea virus (PEDV) was serially passaged
      in Vero cells. The cell passaged PEDV, designated KPEDV-9, was tested for its
      pathogenicity in the neonatal pigs, immunogenicity and safety in the pregnant
      sows. The result indicated that KPEDV-9 at the 93rd passage revealed reduced
      pathogenicity in the neonatal pigs. Pregnant sows inoculated with the attenuated
      virus showed increased immune responses by ELISA. In addition, delivered piglets
      were protected from challenge of wild type PEDV. The safety test in pregnant sows
      indicated that all inoculated animals farrowed the average numbers of litters of
      piglets. The results of this study supported that the attenuated virus derived
      from serial passage could be applied as vaccine for protecting suckling piglets
      against PEDV infection.

PMID- 10418902
TI  - Vaccination of Swiss Albino mice against experimental visceral leishmaniasis with
      the FML antigen of Leishmania donovani.
AB  - The FML antigen of Leishmania donovani in combination with saponin, aluminum
      hydroxide (Al(OH)3) and Freund's incomplete adjuvant (FIA) was used in vaccines
      tested in an outbred murine model of visceral leishmaniasis, either through
      intraperitoneal or subcutaneous routes. The humoral response was significantly
      higher in the groups treated with FML + saponin or FML + Al(OH)3 than in
      controls, both before and after the infection. Animals immunized by the i.p.
      route developed higher antibody titres. A significant and specific reduction of
      parasitic load in relation to saline (85%, p < 0.01) and saponin (p < 0.025)
      controls, was seen in animals treated with FML + saponin by the i.p.
      Coincidentally with this reduction, an increase in antibodies of the IgG2a
      subtype was detected only in animals treated with FML + saponin i.p. A reduction
      of 88% in parasitic load was achieved by the combination of FML + Al(OH)3 (s.c.),
      but the Al(OH)3 treatment itself accounted for 68% of this protection. In our
      conditions, vaccination with FML + saponin i.p. was superior to other treatments
      and had no toxic effect due to saponin.

PMID- 10418903
TI  - Comparison of the quality of protection elicited by toxoid and peptide liposomal
      vaccine formulations against ricin as assessed by markers of inflammation.
AB  - Ricin is a very toxic substance which inhibits protein synthesis and produces
      severe tissue damage and inflammation. It is very potent when inhaled as an
      aerosol and protection has been examined in a series of studies using vaccine
      candidates including a formaldehyde inactivated ricin toxoid and the A chain of
      ricin, a polypeptide equivalent to half of the toxin molecule. Initially,
      subcutaneous injections of both compounds were found to protect against inhaled
      ricin but not without some subsequent adverse signs. Intra-pulmonary vaccination
      using liposomal formulations of these compounds was investigated with a view to
      improving lung condition following challenge. Using the humoral and local
      pulmonary immune responses as indices of vaccine performance, no significant
      difference between toxoid or peptide vaccines was found. In the third and current
      study, the quality of lung protection by vaccines was assessed using markers of
      inflammation. Thus, the profiles of inflammatory cell and protein influx into the
      lung were determined following intratracheal (i.t.) challenge with ricin of rats
      treated with liposomal vaccine formulations. Results showed that liposomal ricin
      toxoid offered a better quality of protection with a significantly lower influx
      of polymorphonuclear leucocytes (neutrophils) and little pulmonary oedema
      compared with the A chain/liposome formulation. Further, there was no significant
      difference between the quality of protection offered by the A chain when
      administered subcutaneously or locally into the lung by i.t. instillation.
      Liposomal ricin toxoid is a good candidate vaccine and optimised pulmonary
      delivery by inhalation should be further examined.

PMID- 10418904
TI  - Antibody responses in humans to an inactivated hantavirus vaccine (Hantavax).
AB  - Hantaviruses cause haemorrhagic fever with renal syndrome (HFRS) and result in
      severe human morbidity and mortality. Safe and effective vaccines are needed
      urgently in order to reduce the incidence of human illness. Hitherto studies of
      hantavirus vaccine efficiency have been limited to individuals at low risk of
      infection. In this study the immune response to an inactivated hantavirus vaccine
      was measured in 64 human volunteers at high risk of infection by virtue of
      residence and occupation. 30 d after vaccination, 79% of subjects developed a
      significant hantavirus antibody titre as measured by immunofluorescence (IFA) and
      62% by enzyme linked immunosorbent assay (ELISA). Seroconversion rates increased
      to 97% one month after the booster dose. Neutralising antibody titres paralleled
      this trend with 13% of vaccine recipients producing neutralising antibody one
      month after the first dose and 75% of vaccine recipients responding one month
      after boosting. Antibody titres had declined by one year, however, with only 37%
      and 43% of sera positive by IFA and ELISA, respectively. Re-vaccination at this
      time produced a vigorous anamnestic response with 94% and 100% of vaccine
      recipients yielding positive antibody titres. Only 50% of the sampled population,
      however, produced neutralising antibodies following the booster dose one year
      later. The vaccine was well tolerated and there were no apparent differences in
      the responses of males and females. However, further improvement of this vaccine
      is necessary in order to induce a more longlasting humoral immune response.

PMID- 10418905
TI  - Vaccination with different HSV-1 glycoproteins induces different patterns of
      ocular cytokine responses following HSV-1 challenge of vaccinated mice.
AB  - We previously reported that vaccination of BALB/c mice with different baculovirus
      expressed HSV-1 glycoproteins induced varying degrees of protection against HSV-1
      ocular challenge, ranging from complete protection to no protection, to
      exacerbation of eye disease. To correlate specific local immune responses with
      protection and exacerbation of corneal scarring, we examined immune cell
      infiltrates in the cornea after ocular HSV-1 challenge of vaccinated mice. Mice
      were vaccinated with gD, which completely protects against corneal scarring, gG,
      which produces no protection against corneal scarring, or gK, which exacerbates
      corneal scarring. Cryostat sections of cornea were taken at different times after
      challenge and examined for infiltrating cells containing IL-2, IL-4, IFN-gamma,
      IL-6, or TNF-alpha. No corneal infiltrates were seen before challenge or 1 day
      after ocular challenge in any groups. By days 3-7, many cells containing IL-4 and
      IFN-gamma, but few cells containing IL-2, had infiltrated into the corneas of gG
      or mock vaccinated mice. At the same times, many cells containing IL-2, but few
      cells containing IL-4 or IFN-gamma, were seen in the corneas of gD vaccinated
      mice. In contrast, the corneas of mice vaccinated with gK contained large amounts
      of IL-2, IFN-gamma, and IL-4. Our results suggest that: (1) corneas from gD
      vaccinated mice had no corneal disease and developed a response highly biased
      toward IL-2 responses; (2) corneas from gG or mock vaccinated eyes had
      significant corneal disease and developed a mostly IL-4 and IFN-gamma cytokine
      response; and (3) corneas from gK vaccinated mice had exacerbated corneal disease
      and developed strong IL-2, IL-4 and IFN-gamma cytokine responses.

PMID- 10418907
TI  - The effect of reconstitution of an Haemophilus influenzae type b-tentanus toxoid
      conjugate (PRP-T) vaccine on the immune responses to a diphtheria-tetanus-whole
      cell pertussis (DTwP) vaccine: a five-year follow-up.
AB  - Controversial results have been obtained from previous studies on the combined
      administration of Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T)
      and diphtheria-tetanus-whole-cell pertussis (DTwP) combination vaccines, with
      regard to possible reciprocal interference between the constituent antigens. To
      document the priming effect and possible long-term immunogenic interference of
      PRP-T and DTwP combination vaccines, a randomized, double-blind, controlled study
      was conducted in Belgium. A total of 168 healthy infants received, at 3, 4 and 5
      months of age, DTwP vaccine mixed just prior to injection either with PRP-T
      vaccine (group A, DTwP//PRP-T, N = 85) or with placebo (group B, DTwP//Placebo, N
      = 83). At the age of 14 months, children of both groups were randomized to
      receive either a dose of DTwP//PRP-T vaccine (subgroups A1 and B1) or a dose of
      Hib polysaccharide (PRP) vaccine (subgroups A2 and B2). Those children in
      subgroups A1 and B1 had an additional serum sample taken at the age of 5 years
      (at the time of a DT booster). The immune response to Hib polysaccharide at the
      age of 4, 5 and 6 months confirmed the excellent immunogenicity profile of PRP-T
      in infants. In addition, the vigorous anamnestic response (i.e. a 20-fold
      increase of GMT) to a booster dose of the plain capsular polysaccharide (PRP)
      reflected the efficient Hib-priming induced by the combined DTwP//PRP-T vaccine.
      Reconstitution of PRP-T with DTwP did not affect the immune response to
      diphtheria toxoid or pertussis agglutinins. Nevertheless, at almost any time
      point during the five-year follow-up, the tetanus antitoxin GMT values were
      significantly lower in the DTwP//PRP-T group (A and A1) than in the DTwP//Placebo
      group (B and B1). Despite the suppressive effect on GMT values, intergroup
      differences in rates of seroprotection were never significant, except after doses
      2 and 3 for which there were lower percentages of children in group A with
      antitoxin titers > 0.05 IU/mL and > 1.0 IU/mL. In the group primed with the
      combined DTwP//PRP-T vaccine, (1) a DT booster dose at the age of 5 years
      provoked a 150-fold increase in tetanus antitoxin GMT, (2) a high tetanus
      antitoxin GMT value was attained (GMT = 19.3 IU/mL) and (3) all children in this
      group had tetanus antitoxin titers > 1.0 IU/mL, so it may be concluded that all
      these children will still be protected against tetanus until at least the age of
      the next recommended booster dose (i.e. the age of 15 years). No differences in
      the occurrence of adverse events were observed between the groups who received
      the DTwP//PRP-T vaccine or the DTwP//Placebo vaccine, both vaccines being
      associated with events customarily attributable to DTwP (data not shown). Our
      results indicate (1) that the combination vaccine, DTwP//PRP-T, represents a safe
      and effective alternative for the existing uncombined vaccines and (2) that the
      long-term effect of interference between the components of future combination
      vaccines should be studied with subsequent booster doses, followed by the
      evaluation of persistence of antibodies over several years.

PMID- 10418908
TI  - Stability of aluminium-containing adjuvants to autoclaving.
AB  - Aluminium phosphate adjuvant remained amorphous when autoclaved for 30 or 60 min
      at 121 degrees C. However, deprotonation and dehydration reactions occurred as
      evidenced by a decrease in the pH. The protein adsorption capacity, rate of acid
      neutralization at pH 2.5 and point of zero charge also decreased indicating that
      the deprotonation/dehydration reactions resulted in a decreased surface area.
      Autoclaving aluminium hydroxide adjuvant increased the degree of crystallinity as
      measured by the width at half height of the major band in the X-ray
      diffractogram. The pH decreased during autoclaving suggesting that the same
      deprotonation/dehydration reactions which reduced the surface area of aluminium
      phosphate adjuvant were responsible for the increased degree of crystallinity.
      These reactions also resulted in a reduced surface area as both the protein
      adsorption capacity and viscosity decreased following autoclaving.

PMID- 10418906
TI  - Randomised trial of intradermal Mycobacterium vaccae or intradermal hepatitis B
      immunisation in children with HIV infection.
AB  - This study assessed the safety of inactivated Mycobacterium vaccae as a candidate
      vaccine to prevent disseminated mycobacterial disease in children with HIV
      infection. 35 children ages 1-8 with CD4 counts > or =300/mm3 in New Hampshire,
      Boston and Chicago were randomised in a 2:1 schedule to receive a 3-dose series
      of intradermal M. vaccae vaccine (MV) or hepatitis B vaccine (HBV) at 2-month
      intervals. Immunisation was safe and well tolerated; 2-day median vaccine site in
      duration was 5 mm in MV recipients and 0 mm in HBV recipients (p < 0.001). There
      were no significantly different changes in viral load or CD4 count between the
      two vaccine groups. No PPD skin test conversions occurred after immunisation. MV
      is safe and well tolerated and deserves further evaluation as a vaccine to
      prevent mycobacterial disease in HIV-infected children.

PMID- 10418909
TI  - Immunization with heat-killed Toxoplasma gondii stimulates an early IFN-gamma
      response and induces protection against virulent murine malaria.
AB  - In this study, we describe protection of BALB/c mice by immunization with heat
      killed T. gondii tachyzoites against infection with Plasmodium yoelii 17XL which
      causes cerebral malaria and death in mice by day 7-8 post infection. Immunization
      resulted significant reduction in parasitemia at the peak period of infection.
      Protection induced by heat-killed T. gondii was associated with marked increase
      in NK cell number and IFN-gamma mRNA expression early in the infection. The level
      of IFN-gamma or TNF-alpha was found to diminish in T. gondii-treated mice as the
      infection progressed to the late stage. This declined response of IFN-gamma or
      TNF-alpha was associated with marked increase in the expression of IL-10, a
      counterregulatory cytokine. Pretreatment of mice with live T. gondii induced poor
      level of protection as compared with that of heat-killed parasites. Mice that
      received P. yoelii infection alone, had an elevated IFN-gamma response in the
      late stage of infection. Development of cerebral malaria in untreated mice was
      accompanied by an augmented production of TNF-alpha and nitric oxide (NO), the
      proinflammatory mediators. These findings suggest that nonspecific immunization
      with T. gondii leads to restoration of an early IFN-gamma response in P. yoelii
      infected mice and in the establishment of an immunoregulatory mechanism that
      effectively antagonizes the disease-promoting effects of proinflammatory
      cytokines in the late phase of infection.

PMID- 10418910
TI  - Immunogenicity and reactogenicity in UK infants of a novel meningococcal vesicle
      vaccine containing multiple class 1 (PorA) outer membrane proteins.
AB  - The development of effective vaccines against serogroup B meningococci is of
      great public health importance. We assessed a novel genetically engineered
      vaccine containing six meningococcal class 1 (PorA) outer membrane proteins
      representing 80% of prevalent strains in the UK. 103 infants were given the
      meningococcal vaccine at ages 2, 3 and 4 months with routine infant
      immunisations, with a fourth dose at 12-18 months. The vaccine was well
      tolerated. Three doses evoked good immune responses to two of six meningococcal
      strains expressing PorA proteins contained in the vaccine. Following a fourth
      dose, larger bactericidal responses to all six strains were observed, suggesting
      that the initial course had primed memory lymphocytes and revaccination
      stimulated a booster response. This hexavalent PorA meningococcal vaccine was
      safe and evoked encouraging immune responses in infants. Vaccines of this type
      warrant further development and evaluation.

PMID- 10418911
TI  - Reactogenicity and immunogenicity of reduced antigen content diphtheria-tetanus
      acellular pertussis vaccines as a booster in 4-7-year-old children primed with
      diphtheria-tetanus-whole cell pertussis vaccine before 2 years of age.
AB  - BACKGROUND: The recent introduction of acellular pertussis vaccines (Pa) offers
      the possibility of booster doses in older children and adults. This can be
      conveniently accomplished by combining acellular pertussis antigens with
      diphtheria and tetanus toxoids. However the optimal dosage for the booster
      injection has not yet been determined. OBJECTIVE: To compare the reactogenicity
      and immunogenicity of diphtheria-tetanus-acellular pertussis vaccines (DTPa) with
      lower antigen contents to a licensed DTPa vaccine when given at 4-7 years of age
      as a booster to DTPw-primed children. METHODS: Two hundred and twenty-six
      children primed with four doses of DTPw before 2 years of age were enrolled and
      allocated to three groups to receive one dose of either DTPa (Infanrix,
      SmithKline Beecham, Biologicals), a reduced antigen formulation of this vaccine
      (dtpa, SmithKline Beecham Biologicals), or an experimental low dose formulation
      (dtpa-exp; d and t, Michigan Biologic Products Institute). Reactogenicity was
      assessed using diary cards for 15 days. Immunogenicity was determined as antibody
      responses against the vaccine components in pre- and 1 month postvaccination
      sera. RESULTS: Of the 225 children who completed the study, 60.0-66.7% reported
      symptoms, with no significant differences in rates between groups. Local,
      systemic and unsolicited symptoms occurred with similar frequencies in all three
      groups, the vast majority (> 90%) being considered as mild or moderate. No
      serious adverse events related to vaccination were reported. After vaccination,
      all subjects displayed seroprotective concentrations against diphtheria and
      tetanus, and 98.7-100% had antibodies against the three pertussis component
      antigens. The group receiving the reduced dose of the licensed vaccine showed
      antibody concentrations comparable to those of the full dose group. However, the
      group receiving the experimental low dose formulation had statistically
      significantly lower antibody concentrations against both diphtheria and tetanus
      toxoids compared with the two other groups, as well as significantly lower anti
      FHA antibody concentrations. CONCLUSIONS: Reducing the antigen content of dtpa
      had no deleterious effect on the immunogenicity of the vaccine when given as a
      fifth dose at 4-7 years of age in DTPw-primed children. The reactogenicity
      profile of both the reduced antigen dtpa vaccines and DTPa were acceptable, the
      vast majority of local and systemic reactions being considered as mild to
      moderate, with no vaccine-related serious adverse events reported. The use of
      lower antigen content dtpa vaccine as a booster in children aged 4-7 is safe and
      immunogenic.

PMID- 10418912
TI  - Protection of turkeys against Chlamydia psittaci challenge by gene gun-based DNA
      immunizations.
AB  - Particle-mediated (Helios Gene Gun) transfer to the turkey epidermis of plasmid
      DNA expressing the major outer membrane protein (MOMP) of an avian Chlamydia
      psittaci strain was evaluated for its ability to raise an immune response and
      protection against challenge with the homologous strain. In turkeys, the delivery
      of pcDNA1/MOMP coated onto 0.6 microm gold beads was the most efficient compared
      to immunisations using 1.0 or 1.6 microm gold beads. The delivery of as little as
      1 microg pcDNA1/MOMP coated onto 0.6 microm gold beads was efficient.
      Immunisation with 1.0 microm gold beads required twice more (2 microg) DNA to
      achieve comparable results. The use of 2 microg DNA coated onto 1.6 microm gold
      beads had no effects. The gene gun delivery both primed T-helper and B-cell
      memory although recombinant MOMP-expressing cells did not induce high-titre
      antibody responses. The significance of gene gun-based DNA immunisation as a
      means of preventing severe clinical signs, lesions and chlamydia excretion in a
      turkey model of Chlamydia psittaci infection was demonstrated.

PMID- 10418913
TI  - Bacterial expression of the major antigenic regions of porcine rotavirus VP7
      induces a neutralizing immune response in mice.
AB  - The outer capsid protein of rotavirus, VP7, is a major neutralization antigen. A
      chimeric protein comprising Escherichia coli (E. coli) outer membrane protein A
      (OmpA) and part of porcine rotavirus VP7 containing all three antigenic regions
      (217 amino acids) was expressed in Salmonella and E. coli as an outer-membrane
      associated protein. Mice immunized intraperitoneally or orally, respectively,
      with live E. coli or Salmonella cells expressing this chimeric protein produced
      antibodies against native VP7 as determined by enzyme-linked immunosorbent assays
      and neutralization tests. This indicates that the VP7 fragment from a porcine
      rotavirus which is antigenically similar to human rotavirus serotype 3, when
      expressed in bacteria as a chimeric protein, can form a structure resembling its
      native form at least in some of the major neutralization domains. These results
      indicate that the use of a live bacterial vector expressing rotavirus VP7 may
      represent a strategy for the development of vaccines against rotavirus-induced
      diarrhoea in infants.

PMID- 10418914
TI  - A prime-boost regime that combines Montanide ISA720 and Alhydrogel to induce
      antibodies against the HIV-1 derived multiepitope polypeptide TAB9.
AB  - A phase I clinical trial with the HIV-1-derived multi-epitope polypeptide (MEP)
      TAB9 in the oil adjuvant Montanide ISA720 (M-ISA720) was recently performed.
      Although severe local reactions were reported after the second and third
      injections of this vaccine candidate, the first inoculation was well tolerated.
      In this article we evaluated a prime-boost regime consisting of one inoculation
      of TAB9 in M-ISA720 followed by a booster with the same antigen in aluminum
      hydroxide. This combination of adjuvants elicited similar antibody levels in
      rabbits than the traditional two-dose schedule with M-ISA720. A control group
      injected three times with TAB9 in aluminum hydroxide developed markedly lower
      antibody titers. These results showed that although oil adjuvants are better than
      alum for priming the immune system for antibody production against TAB9, both
      kinds of adjuvants can be equally effective in booster immunizations. Therefore,
      by using the more reactogenic oil adjuvant only for priming, we should be able to
      eliminate the undesirable reactions characteristic of these compounds while
      achieving equivalent levels of specific antibodies.

PMID- 10418917
TI  - Do we need 3 doses of hepatitis B vaccine?
AB  - The hepatitis B virus (HBV) vaccine may provide protection through the clonal
      expansion of specific memory cells without necessarily having to produce high
      serum antibody levels. We develop a mathematical model which distinguishes
      between the accumulation of sensitive memory B and T-helper cells prior to a
      booster and the high circulating antibody levels present in an individual after a
      booster. We suggest this immune memory accumulates primarily in an antigen
      independent fashion. These phenomena suggest individuals may be immune to
      infection six months after the priming vaccine dose(s) regardless of whether they
      receive a booster or not. This hypothesis is supported by immunogenicity data and
      by two independent vaccine efficacy trials comparing 0, 1 month schedules with 0,
      1 and 6 month schedules.

PMID- 10418915
TI  - Intranasal murine model of Bordetella pertussis infection: II. Sequence variation
      and protection induced by a tricomponent acellular vaccine.
AB  - When pertussis toxin S1 subunit and pertactin structural genes in Bordetella
      pertussis clinical isolates from France and Germany were sequenced, 3 previously
      described S1 subunit types (S1 A, B and E), and 4 pertactin types (PRN A, B, C,
      A*) were found. PRN A*, present in the WHO reference strain 18323, was not
      described previously. In a respiratory mouse model, a tricomponent acellular
      pertussis vaccine (Infanrix) was highly effective in promoting lung clearance of
      all isolates expressing different S1 subunit and pertactin suggesting that use of
      acellular vaccine will not increase the risks of pertussis infection by these B.
      pertussis variants.

PMID- 10418916
TI  - Long-term efficacy of plasma-derived hepatitis B vaccine: a 15-year follow-up
      study among Chinese children.
AB  - To determine necessity and timing of booster of hepatitis B vaccine, we need to
      observe the duration of its protection. We report the results of a 15-year follow
      up of a cohort of 649 children who participated a randomized, double blind,
      placebo-controlled trial on a plasma-derived hepatitis B vaccine in 1982. During
      the 15 years after vaccination, more vaccinated children had anti-HBs of 10 S/N
      ratios or over, compared with the controls, at all nine observations. At 15 years
      50.0% (26/52) of the participants studied in the vaccinated group and 33.3% of
      the tested controls (18/54) retained anti-HBs levels of S/N ratios> or =10 (P <
      0.09). However, since 5 years after vaccination, median S/N ratios of anti-HBs
      among the vaccinated children with detectable anti-HBs were lower than those of
      the controls except that detected at 15 years. 16.7% (9/54) of the tested
      children in the control group were HBsAg positive at 15 years after vaccination,
      in comparison with 1.9% (1/52) of the tested children in the vaccinated (P <
      0.02). 28 chronic HBsAg carriers were identified in the control cohort over the
      15 years, whereas only 1 case was noted in the vaccinated group (8.2% vs. 0.3%, P
      < 0.00001), corresponding to an efficacy of 96%.

PMID- 10418918
TI  - Efficacy of live adjuvanted mesogenic Newcastle disease vaccine in chickens.
AB  - 120 white leghorn chickens primed with a lentogenic Newcastle disease (ND) live
      vaccine at 7 days of age were divided into three equal groups of 8 weeks of age
      and vaccinated with a live mesogenic ND vaccine (NDV). One group received only
      Newcastle disease mesogenic vaccine (RDVK) in normal saline, the second group
      received RDVK with groundnut oil as adjuvant and the third group received RDVK
      with liquid paraffin as adjuvant. Sera were collected at different time points
      for the assessment of antibody level against ND virus (NDV) by the
      haemagglutination inhibition (HI) test. The commonly used non-adjuvanted RDVK
      could not evince 100% protective HI titre beyond 11 weeks of age but in both the
      adjuvanted groups 100% protective HI titre was evident up to 20 weeks of age. On
      challenge at 20 weeks of age both the adjuvanted groups withstood challenge but
      in the non-adjuvanted group 80% of chickens withstood the challenge. A
      significant difference in immune response between the adjuvanted and non
      adjuvanted groups was seen but not between both the adjuvanted groups. The
      advantage of vegetable oil (groundnut oil) as an adjuvant for live mesogenic ND
      vaccine has been discussed.

PMID- 10418919
TI  - The infant rat model adapted to evaluate human sera for protective immunity to
      group B meningococci.
AB  - The infant rat infection model previously developed to evaluate protective
      ability of passively administered murine antibodies to group B meningococcal
      (MenB) surface antigens was adapted for human sera. Several challenge doses were
      tested, aiming at sensitive detection of protection with little interassay
      variability. Doses of 10(5) and 10(6) colony forming units of strain IH5341
      (MenB:15:P1.7,16) injected intraperitoneally gave consistently high levels of
      bacteremia and meningitis developed in 6 h in 50-100% of the pups. A monoclonal
      antibody mAb735 to the MenB capsule, injected 1-2 h before bacterial challenge,
      gave full protection at a dose of 2 microg/pup. Sera from adult volunteers
      immunized with a MenB outer membrane vesicle vaccine reproducibly reduced
      bacterial counts in the blood and cerebrospinal fluid, whereas a normal human
      serum, lacking bactericidal and opsonophagocidal activity, was unprotective.

PMID- 10418920
TI  - Iscom and iscom-matrix enhance by intranasal route the IgA responses to OVA and
      rCTB in local and remote mucosal secretions.
AB  - Iscoms, with rCTB incorporated via the GM1 receptor, enhanced in mice the mucosal
      immunogenicity of rCTB as antigen after intranasal (i.n.) administration both by
      inducing IgA response in the remote intestinal tract mucosa and by a 100-fold
      increase of the specific IgA locally in the lungs. Iscom-matrix as a separate
      entity mixed with rCTB enhanced the rCTB-IgA response similarly. While OVA in
      iscoms induced high mucosal IgA responses, iscom-matrix co-administered with OVA
      induced low or no mucosal IgA response to OVA. A synergism between iscoms and
      rCTB could only be seen as an adjuvant targeting effect enhancing the IgA
      response to OVA in the remote genital tract mucosa. In serum, the
      immunomodulatory effect of iscoms after i.n. administration was seen as an
      enhanced serum IgG2a response.

PMID- 10418921
TI  - Immunogenicity of various presentation forms of PorA outer membrane protein of
      Neisseria meningitidis in mice.
AB  - In this study we compare different vaccine formulations containing meningococcal
      PorA outer membrane protein; purified PorA, outer membrane vesicles (OMV) and
      immune-stimulating complexes (iscom). Bactericidal antibodies could be generated
      by the OMV and iscom formulation but not with purified PorA using either A1PO4 or
      Quil-A as adjuvant. OMV and iscom formulations revealed similar immunogenicity
      when tested in a dose response manner, with respect to bactericidal as well as
      OMV-binding antibodies. The anti-OMV IgG subclass response induced by PorA in OMV
      formulation was found in all subclasses IgG1, IgG2a, IgG2b, IgG3. OMP-iscoms
      induced very high IgG1 anti-OMV antibodies but almost no IgG3 response. Also, OMP
      iscoms appeared to be a potent inducer of antibodies directed against linear
      peptides corresponding to surface exposed loops of PorA. In addition, iscoms as
      well as purified PorA with Quil-A as adjuvant (but not with A1PO4) induced high
      levels of antibodies against purified PorA. In summary, in addition to the OMV
      formulation, only iscoms containing PorA are able to generate an anamnestic and
      bactericidal antibody response.

PMID- 10418922
TI  - Vaccination with Rev and Tat against AIDS.

PMID- 10418924
TI  - Dose dependency of antibody response in infants and children to pneumococcal
      polysaccharides conjugated to tetanus toxoid.
AB  - Three injections of tetravalent pneumococcal polysaccharide-tetanus toxoid
      conjugate vaccine (PncT) were given to infants at 2, 4 and 6 months of age
      simultaneously with diphtheria-tetanus-pertussis and Haemophilus influenzae type
      b-tetanus toxoid conjugate vaccines. Three doses (1, 3 or 10 microg) of
      polysaccharides were used. Children were boosted with unconjugated polysaccharide
      vaccine at 14 months of age. No dose dependency was seen after primary
      immunization. However, booster response to three vaccine serotypes was highest in
      the group primed with the lowest dose of conjugate vaccine. As the magnitude of
      the response to booster may be related to the number of polysaccharide-specific
      memory B cells, we hypothesize that the 10 microg dose of the tetravalent
      conjugate vaccine is too high for optimal induction of immunologic memory.

PMID- 10418923
TI  - Safety and immunogenicity of live attenuated human-bovine (UK) reassortant
      rotavirus vaccines with VP7-specificity for serotypes 1, 2, 3 or 4 in adults,
      children and infants.
AB  - Live rotavirus vaccine candidates representing VP7 serotypes 1, 2, 3 or 4 derived
      by reassortment between bovine UK rotavirus and human rotavirus strains D, DS-1,
      P or ST3 were evaluated for safety and immunogenicity in adults, children and
      infants. Infection was defined by evidence of rotavirus shed in stools or a 4
      fold or greater increase in serum rotavirus-specific IgA or IgG ELISA or plaque
      reduction neutralization antibody. A single oral dose (10(5.3) or 10(5.8) pfu) of
      reassortant virus was well tolerated and infected most infants: 10/20 (50%) by D
      x UK; 9/11 (82%) by DS-1 x UK; 8/10 (80%) by P x UK and 13/14 (93%) by ST3 x UK.
      All 14 infants given two doses of D x UK were infected. These findings
      demonstrating satisfactory levels of attenuation, safety, infectivity and
      immunogenicity of each reassortant in infants warrant additional studies of a
      candidate vaccine containing these four strains.

PMID- 10418925
TI  - Influence of antigenic forms and adjuvants on the IgG subclass antibody response
      to Aujeszky's disease virus in mice.
AB  - The influence of antigenic forms of Aujeszky's disease virus (ADV) and adjuvant
      types on the production of IgG subclass antibodies in mice was investigated.
      Particulate antigen, inactivated ADV, alone induced IgG1 and lower IgG2a antibody
      production, while the antigen adsorbed onto aluminum phosphate gel (alum)
      enhanced IgG1 antibody production but suppressed IgG2a antibody production as
      well as solubilized ADV antigen adsorbed onto alum. QS21 saponin purified from
      Quillaja saponaria promoted the production of IgG1 and IgG2a antibodies in a
      large extent against the both particulate and soluble antigens, while this
      saponin has strong hemolytic activity. Lablaboside F saponin isolated from
      Dolichos lablab without hemolytic activity, also induced the production of large
      IgG1 and little IgG2a antibody against both antigens. Oil-based adjuvant, ISA70
      of water-in-oil type and ISA25 of oil-in-water type, increased IgG1 and IgG2a
      antibodies against the both soluble and particulate antigens, whereas a
      combination of ISA25 and soluble antigen reduced IgG2a antibody response. These
      results indicate that IgG1 antibody production was not suppressed by a
      combination of antigenic form and adjuvant type, however, IgG2a antibody
      production was influenced.

PMID- 10418926
TI  - Induction of humoral and cellular responses in cynomolgus monkeys immunised with
      mannan-human MUC1 conjugates.
AB  - Mice immunised with oxidised mannan conjugated to the human mucin 1 (MUC1),
      produce MHC Class 1 restricted CD8+ cytotoxic T-cells which eradicate MUC1 +
      tumours, indicating potential for the immunotherapy of MUC1 + cancers in humans.
      We now describe preclinical studies performed in cynomolgus monkeys immunised
      with human or murine MUC1 conjugated to oxidised mannan, where immune responses
      and toxicity were examined. High titred antibodies specific for MUC1 were
      produced, MUC1 specific CD4+ and CD8+ T-cell proliferative responses and specific
      cytotoxic precursor cells (CTLp) were found, but not MUC1 specific cytotoxic T
      cells (CTL). There was no toxicity and monkeys can be immunised against human
      MUC1 with mannan-MUC1 conjugates, but a humoral response (Th2 type) predominates.
      The results contrast with those obtained in mice when a CTL response (Th1 type)
      predominates.

PMID- 10418927
TI  - Primary biliary cirrhosis. Overview.

PMID- 10418928
TI  - Immunopathology of primary biliary cirrhosis.
AB  - A major advance in the study of primary biliary cirrhosis was identification of
      the major B-cell auto-antigen as the mitochondrial enzyme pyruvate dehydrogenase
      dihydrolipoamide acetyltransferase (PDC-E2). Subsequent studies revealed that PDC
      E2 also contained epitopes recognized by patients' T cells. Furthermore, aberrant
      expression of MHC class II, intercellular adhesion molecules, lymphocyte co
      stimulatory molecules and B-cell epitopes of PDC-E2 was observed on patients'
      biliary epithelium, supporting the concept that biliary epithelial cells are the
      target of a focused autoimmune reaction. Changes in distribution of auto-antigen
      on biliary epithelium and the presence of auto-antibody in patient's serum have
      both been shown to occur very early in the natural history of primary biliary
      cirrhosis, suggesting an intimate role for these molecules in immunopathogenetic
      mechanisms.

PMID- 10418929
TI  - Anti-mitochondrial antibodies and other immunological tests in primary biliary
      cirrhosis.
AB  - Primary biliary cirrhosis (PBC) has been classified as an autoimmune disease. It
      is characterized by a multitude of immune-mediated symptoms and phenomena.
      Humoral autoimmunity directed against mitochondrial auto-antigens or structures
      cross-reactive with these proteins represents the basis of one of the most
      specific tests in any autoimmune disease: the detection of auto-antibodies
      against pyruvate dehydrogenase. The molecular cloning and expression of antigens
      of the ketoacid dehydrogenase complex has led to the establishment of highly
      specific and reliable testing systems for anti-mitochondrial antibodies (AMA).
      The characterization of specific antinuclear auto-antibodies has contributed to
      the diagnosis of AMA-negative PBC and is an important marker in overlap syndromes
      of PBC and other autoimmune liver diseases.

PMID- 10418930
TI  - Genetic susceptibility to primary biliary cirrhosis.
AB  - Family studies suggest that genetic factors play a role in determining
      susceptibility to primary biliary cirrhosis (PBC). A number of polymorphic genes
      with small and additive effects may thus encode factors predisposing to this
      'polygenic' disease. All the published data on genetic predisposition to PBC have
      been obtained from association studies, based on comparison of the frequency of
      an allele in unrelated affected and unaffected individuals from a population;
      however, many studies have examined only small datasets. There is evidence from
      several different populations to support a role for the major histocompatibility
      complex (MHC) class II antigen, HLA DR8, in increased risk of PBC. Other
      'candidate' genes, selected on the basis of postulated mechanisms of breakdown of
      self-tolerance, are now beginning to be tested in association studies, including
      cytokines and immunomodulatory molecules. These studies and other approaches to
      identifying genes that confer susceptibility to an autoimmune disorder,
      exemplified by PBC, are discussed.

PMID- 10418931
TI  - Evidence-based therapy of primary biliary cirrhosis.
AB  - Primary biliary cirrhosis (PBC) is a disease which predominantly affects middle
      aged women and is characterized by destruction of the interlobular bile ducts by
      chronic, often granulomatous, inflammation. This causes ductopenia and consequent
      cholestasis. Progressive fibrosis leads to cirrhosis and eventual liver failure.
      The frequent association of other autoimmune diseases and direct laboratory
      evidence of disturbed immune function suggest that PBC is an immune-mediated
      liver disease. Hence many clinical trials of therapy have employed
      immunosuppressive drugs. Another approach to therapy has been to reduce the
      degree of liver damage secondary to the cholestasis by altering the intra-hepatic
      bile acid milieu. These very different approaches to treatment of PBC are
      reviewed.

PMID- 10418932
TI  - Prevention and treatment of osteoporosis in primary biliary cirrhosis.
AB  - Osteoporosis is not a feature unique to primary biliary cirrhosis (PBC) but is
      also found in other categories of liver disease. The principles developed for
      monitoring and treating postmenopausal osteoporosis can also be followed for
      patients with PBC. Monitoring of dietary intake of calcium and vitamin D serum
      levels is essential, and the threshold for initiating supplementation should be
      low. Bisphosphonates can be considered the most rational choice when specific
      therapy is required.

PMID- 10418933
TI  - The pathogenesis and treatment of pruritus and fatigue in patients with PBC.
AB  - The pathogenesis of the pruritus that complicates cholestasis in patients with
      primary biliary cirrhosis (PBC) is uncertain. The limited and inconsistent
      efficacy of conventional empiric therapies, such as anion exchange resins and
      rifampicin, has led to inconclusive trials of invasive experimental therapies,
      such as plasmapheresis, charcoal haemoperfusion and partial external diversion of
      bile. However, some double-blind, placebo-controlled trials that used a
      subjective primary efficacy end-point (the perception of pruritus) have suggested
      that certain drugs that affect the metabolism of many compounds, for example
      rifampicin, may be efficacious. The potential mechanisms by which such drugs may
      mediate a beneficial effect have not been determined. There is a paucity of data
      to indicate whether peripheral events, such as the accumulation of bile acids in
      interstitial fluid of the skin, initiate the neural events which mediate this
      form of pruritus. Recent findings suggest that central events in the brain,
      specifically an increase in neurotransmission/ neuromodulation mediated by
      endogenous opioid agonists (increased opioidergic tone), may be implicated. This
      hypothesis is supported by three lines of evidence. (1) Opioid receptor ligands
      with agonist properties (e.g. morphine) mediate pruritus. (2) Endogenous opioid
      mediated neurotransmission/neuromodulation in the central nervous system (CNS) is
      increased in cholestasis. (3) Controlled trials have shown that opiate
      antagonists induce ameliorations of the behavioural consequence of the pruritus
      of cholestasis (scratching activity). In such trials, measurements of scratching
      activity independent of limb movements constituted an objective quantitative
      primary efficacy end-point. Potent opiate antagonists, that are bioavailable when
      given by mouth, such as nalmefene and naltrexone, may have a place in the long
      term management of pruritus in patients with PBC. Evidence that increased
      serotoninergic neurotransmission also contributes to the pruritus is at present
      less strong than that implicating an involvement of the opioid system, and
      further investigation is needed to determine whether specific serotonin receptor
      subtype ligands have a place in the treatment of pruritus in patients with PBC.
      There is some evidence which suggests that increased serotoninergic
      neurotransmission in the CNS contributes to fatigue of central origin, but
      whether there is a causal relationship between altered serotoninergic
      neurotransmission and the profound fatigue that occurs in many patients with PBC
      is currently uncertain.

PMID- 10418935
TI  - Clinical relevance of recurrence of primary biliary cirrhosis after liver
      transplantation.
AB  - Review of the literature shows that recurrence of primary biliary cirrhosis
      occurs in about 10% of patients in the first few years after liver
      transplantation. The cumulative risk is expected to increase in time. The rate of
      recurrent disease may be affected by the immunosuppression used. Weaning from
      immunosuppression may initiate recurrence. Disease progression is slow and no
      reason for graft loss.

PMID- 10418934
TI  - Recurrence of primary biliary cirrhosis after transplantation. The pathologist's
      view.
AB  - There is now good evidence that primary biliary cirrhosis can recur after
      transplantation. The diagnosis rests on the liver histology which may be
      difficult to interpret in the setting of a grafted liver where specific markers
      are lacking. The triggering factor(s), rate of recurrence and the precise role of
      immunosuppression remain to be determined.

PMID- 10418936
TI  - Hepatitis C virus infection risk factors in patients admitted in hospital
      emergency departments in Picardy. Value of oriented screening based on
      recommendations of the 'Direction Generale de la Sante'.
AB  - OBJECTIVE AND DESIGN: Oriented hepatitis C virus (HCV) screening on the basis of
      transfusion, previous or current parenteral drug addiction, invasive procedures,
      and in family members of patients with hepatitis C, was recommended in France by
      the 'Direction Generale de la Sante' (DGS). The aim of this study was to estimate
      the frequency of these risk factors in patients admitted in hospital emergency
      departments in Picardy. METHODS: Between 1 June and 31 July 1996, physicians of
      the emergency units of seven hospitals in Picardy were asked to question admitted
      patients about risk factors mentioned in the DGS recommendations, and to suggest
      a screening test when at least one of these risk factors was present. RESULTS:
      Among 1648 patients, 68.7% had at least one of these risk factors. Screening was
      accepted by 723 patients, 58.7% of those with at least one risk factor, and more
      than 70% of those with history of transfusion and/or drug addiction. It was
      immediately performed in 451, and 2.4% had anti-HCV antibodies. The prevalence of
      anti-HCV antibodies was 1.5% in patients without history of transfusion or drug
      addiction and 7.9% in those with at least one of these two risk factors.
      CONCLUSION: Oriented screening based on transfusion or drug addiction history
      seems to have better efficiency than the screening policy recommended by the DGS.
      Poor reliability of answers about medical history was observed probably because
      of stress related to emergency circumstances. A screening test proposed to
      patients with these major risk factors by their usual physician would be probably
      more efficient.

PMID- 10418937
TI  - Interferon retreatment in chronic hepatitis C: which patients to choose, and what
      schedule to use.
AB  - OBJECTIVE; To evaluate the results of a large cohort of non-responder or
      relapsing responder patients with chronic hepatitis C retreated with various
      schedules of interferon (IFN). METHODS: Our study included 276 patients (158 non
      responders and 118 relapsing responders) who underwent IFN retreatments. Among
      the non-responder group, 158 patients underwent further courses of IFN. In
      particular, 108 patients underwent one course of IFN retreatment, 40 patients
      underwent two courses, eight patients underwent three courses, and two patients
      underwent four courses. Regarding the relapsing responder group, the 118 patients
      were retreated with the same dosage for varying periods. In particular, 50
      patients were treated for 6 months, 43 patients for 12 months, and 25 for 24
      months. Patients in the subgroups of IFN retreatment were homogeneous as far as
      age and gender distribution, as well as virological and histological
      characteristics, are concerned. Qualitative and quantitative HCV-RNA was
      evaluated at baseline, at the end of treatment and at the last check-up of follow
      up. HCV genotype was determined on baseline serum samples. Alanine transaminase
      (ALT) levels were tested monthly. RESULTS: Long-term biochemical (normal ALT
      levels) and virological (HCV-RNA negative) response was obtained in 2.6% of non
      responder retreated patients, and in 33.9% of relapsing responder retreated
      patients. Evaluation of response on the basis of the duration of treatment showed
      that 48%, 19% and 16% of relapsing responder patients retreated for 24, 12 and 6
      months, respectively, obtained long-term biochemical and virological response.
      CONCLUSION: Non-responder patient retreatment is inefficient especially in
      cirrhotic and/or genotype 1 b patients. IFN retreatment is warranted in relapsing
      responder patients. In particular, 24-month therapy induces significant long-term
      biochemical and virological response.

PMID- 10418938
TI  - Colorectal cancer screening in Italy: feasibility and cost-effectiveness in a
      model area.
AB  - OBJECTIVE: To evaluate the feasibility and cost-effectiveness of screening
      programmes for colorectal cancer in Italy. DESIGN; We compared five types of
      programmes: annual faecal occult blood testing, sigmoidoscopy (every 5 years),
      faecal occult blood testing plus sigmoidoscopy (every 1 and 5 years), colonoscopy
      (every 10 years) (all in the age group 55-69 years, last examination at 70 years)
      and 'filter' colonoscopy. The latter had to be performed in persons at 50 years
      of age and repeated every 10 years until the age of 70. Costs for the tests and
      colon cancer care were paid by the Regional Health Office to the hospitals
      performing the procedures/treatments. SETTING: Data were applied to a small model
      area in northern Italy (Gemona, 80,000 inhabitants) with well-known demographic
      (age distribution) and epidemiological (colon cancer incidence) features.
      RESULTS: All-inclusive 10-year costs per screenee and per death prevented (in US
      dollars) were: 965 and 77,200 for faecal occult blood testing; 436 and 15,500 for
      sigmoidoscopy; 1521 and 35,000 for sigmoidoscopy plus faecal occult blood
      testing; 510 and 15,100 for colonoscopy; 510 and 14,000 for 'filter' colonoscopy.
      With 'filter' colonoscopy the programme required 870 colonoscopies per year,
      while with colonoscopy 13,700 colonoscopies were needed at time zero.
      CONCLUSIONS: In Italy, screening programmes based on sigmoidoscopy/colonoscopy
      are more cost effective than those based on faecal occult blood testing. 'Filter'
      colonoscopy at age 50 appears superior to the other types of endoscopy-based
      screening programmes because it utilizes, at any point in time, a much smaller
      fraction of available resources.

PMID- 10418939
TI  - Molecular forms of gastrin in the circulation of patients with achlorhydria.
AB  - BACKGROUND/AIM: To study circulating gastrin profile, both fasting and
      postprandially, in patients with achlorhydria due to auto-immune atrophic
      gastritis, comparing these with normal healthy controls. METHODS: Circulating
      gastrins were measured using three region-specific radio-immunoassays: amidated
      gastrins (R98), N-terminal G34 (R526) and N-terminal G17 (GP168). Samples were
      analysed further using gel chromatography. RESULTS: Fasting gastrin
      concentrations were elevated in achlorhydria as measured using all three
      antisera: median 714 pmol/l (range 107-5176) in achlorhydria versus 12 pmol/l (2
      33) in controls (R98), 343 pmol/l (45-4316) versus 10 pmol/l (5-41) (R526), and
      720 pmol/l (14-6000) versus 2 pmol/l (1-10) (GP168). In patients, 47% of gastrin
      was amidated (95% in controls) and 30% was processed N-terminally only to G71 (4%
      in controls). Gastrin rose significantly postprandially: 1643 pmol/l (269-7142)
      in patients versus 24 pmol/l (5-142) in controls (R98), 432 pmol/l (113-4756)
      versus 15 pmol/l (7-45) (R526) and 2189 pmol/l (304-7150) versus 15 pmol/l (7-45)
      (GP168). Only 25% was amidated in the patient group (93.5% in controls) and 21%
      remained as component I (4% in controls). CONCLUSIONS: This abnormal gastrin
      profile associated with hypergastrinaemia secondary to achlorhydria is consistent
      with saturation of the enzymes involved in the processing of the pro-hormone, in
      particular amidation of the C-terminus.

PMID- 10418940
TI  - Primary cutaneous B-cell lymphoma: an association of chronic hepatitis C
      infection.
AB  - Primary cutaneous B-cell lymphoma is a low-grade malignancy, distinct from other
      lymphomas in terms of biological activity and response to treatment. We describe
      a 77-year-old woman with a five-year history of chronic hepatitis C infection who
      developed a lower-limb lesion over a period of 3 months which was diagnosed as a
      high-grade cutaneous B-cell lymphoma. Despite a lack of definitive evidence
      implicating hepatitis C virus (HCV) in the aetiology of lymphomas, there is
      considerable research which establishes a strong association between these two
      diseases. On the basis of published research and the demonstration of HCV RNA in
      the lymphomatous tissue, we consider this to be a rare case of primary cutaneous
      lymphoma in association with hepatitis C.

PMID- 10418942
TI  - Sporadic carcinoid of the stomach: a highly proliferative disease with a probable
      role for p53 protein dysregulation.
AB  - We describe here one case of sporadic carcinoid of the stomach, occurring in a 65
      year-old man. It is a rare, recently recognized entity, with only few cases
      reported in the literature. We were able to detect strong MIB-1 and p53
      expression in this tumour, with 86 and 80% of tumoral cells positive,
      respectively. These data suggest that gastric sporadic carcinoids are a highly
      proliferative entity probably induced by dysregulation of p53 function.

PMID- 10418941
TI  - Ticlopidine-induced prolonged cholestasis: a case report.
AB  - We report a case of ticlopidine-induced prolonged cholestasis in a 60-year-old
      man with no previous hepatobiliary disease who presented with sudden right upper
      abdominal pain, jaundice and pruritus three months after starting ticlopidine
      therapy. Other drugs taken by the patient were not considered probable causes.
      The diagnostic evaluation showed no biliary obstruction and other possible causes
      of intra-hepatic cholestasis were excluded. The liver biopsy showed a cholestatic
      hepatitis with bile duct damage. The disease ran a severe and protracted course,
      but symptoms and jaundice eventually subsided five months after drug withdrawal.
      More than a year later, relevant abnormalities of liver function tests consistent
      with anicteric cholestasis still persist, fulfilling criteria for a minor form of
      drug-induced prolonged cholestasis. This syndrome has been reported infrequently
      in relation to several drugs, mainly chlorpromazine, and only once with
      ticlopidine.

PMID- 10418943
TI  - Intestinal obstruction and gastrointestinal bleeding due to systemic amyloidosis
      in a woman with occult plasma cell dyscrasia.
AB  - A 60-year-old woman presented to our hospital with repeated vomiting. Upper
      gastrointestinal endoscopy revealed a 1 cm diameter ulcer with clean base on the
      roof of the gastric antrum. Histological examination of gastric biopsies revealed
      abundant amorphous eosinophilic deposits in the submucosa. Congo red stain for
      amyloid was positive. A barium follow-through study revealed a mass in the
      jejunum causing incomplete obstruction. Urine for Bence Jones protein was
      negative. Serum protein electrophoresis did not reveal any abnormal band and
      serum immunoelectrophoresis did not detect any monoclonal immunoglobulin. Bone
      marrow examination, however, revealed an increased proportion of plasma cells.
      Subsequent immunohistochemical staining demonstrated monoclonal lambda light
      chains in the marrow plasma cells, thereby confirming a plasma cell dyscrasia.
      Amyloidosis involving the gastrointestinal tract can produce a wide variety of
      non-specific symptoms and signs. A high index of suspicion is necessary to arrive
      at an early diagnosis. Management consists of supportive therapy for the
      gastrointestinal tract as well as treatment of the underlying condition.

PMID- 10418944
TI  - Antiproliferative and cytotoxic effects of prenylated flavonoids from hops
      (Humulus lupulus) in human cancer cell lines.
AB  - Six flavonoids [xanthohumol (XN), 2',4',6',4-tetrahydroxy-3'-prenylchalcone (TP);
      2',4',6',4-tetrahydroxy-3'-geranylchalcone (TG); dehydrocycloxanthohumol (DX);
      dehydrocycloxanthohumol hydrate (DH); and isoxanthohumol (IX)] from hops (Humulus
      lupulus) were tested for their antiproliferative activity in human breast cancer
      (MCF-7), colon cancer (HT-29) and ovarian cancer (A-2780) cells in vitro. XN, DX
      and IX caused a dose-dependent (0.1 to 100 microM) decrease in growth of all
      cancer cells. After a 2-day treatment, the concentrations at which the growth of
      MCF-7 cells was inhibited by 50% (IC50) were 13.3, 15.7 and 15.3 microM for XN,
      DX and IX, respectively. After a 4-day treatment, the IC50 for XN, DX and IX were
      3.47, 6.87 and 4.69 microM, respectively. HT-29 cells were more resistant than
      MCF-7 cells to these flavonoids. In A-2780 cells, XN was highly antiproliferative
      with IC50 values of 0.52 and 5.2 microM after 2 and 4 days of exposure,
      respectively. At 100 microM, all the hop flavonoids were cytotoxic in the three
      cell lines. Growth inhibition of XN- and IX-treated MCF-7 cells was confirmed by
      cell counting. XN and IX inhibited DNA synthesis in MCF-7 cells. As
      antiproliferative agents, XN (chalcone) and IX (flavanone isomer of XN) may have
      potential chemopreventive activity against breast and ovarian cancer in humans.

PMID- 10418945
TI  - Dietary omega-3 fatty acids as potential inhibitors of carcinogenesis: effect on
      DNA adduct formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in
      mice and rats.
AB  - The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is
      carcinogenic in the CDF1 mouse, causing lymphomas (spleen and lymph nodes) and in
      the F344 rat, causing mammary tumours in the female and colon tumours in the
      male. Dietary fish oil, a rich source of omega-3 fatty acids, exhibits
      chemopreventive properties in several rodent tumour models. The potential
      chemopreventive properties of dietary omega-3 fatty acid ethyl ester concentrate
      (O3C) were tested by evaluating its effects on the formation and removal of PhIP
      DNA adducts. In the first experiment, a powdered AIN-76A diet containing 4.0%
      (w/w) O3C inhibited PhIP-DNA adduct formation in various organs of the CDF1
      mouse, but not in those of the F344 rat. In a subsequent, second experiment,
      groups of male CDF1 mice were maintained for 43 days on AIN-76A diets containing
      the following percentages (w/w) of corn oil ethyl esters and O3C: 7.0 and 0, 5.5
      and 1.5, 4.0 and 3.0, and 1.0 and 6.0, respectively. All animals received 0.04%
      (w/w) PhIP in the diet during weeks 3 and 4. Using 32P-postlabelling assays, PhIP
      DNA adducts were analysed in various organs and white blood cells (WBC) on days
      1, 8 and 15 after removal of PhIP from the diet. In the liver, O3C-containing
      diets inhibited adduct formation at all three time points (40.3-60.0%, 53.4-75.7%
      and 43.3-64.3% on days 1, 8 and 15, respectively). In the spleen, inhibition was
      evident only on days 8 (35.4-38.8%) and 15 (38.4-56.5%). O3C diets inhibited
      adduct formation in the stomach, small intestine and caecum at all three time
      points (except in the stomach and caecum on day 15) amounting to 18.5-31.5%
      decreases in the stomach, 40.0-60.3% decreases in the small intestine and 24.4
      31.4% decreases in the caecum. The extent of inhibition was not related to O3C
      concentration. In the colon and WBC, adduct levels were independent of the type
      of diet. In all organs, adduct levels decreased significantly over time, with day
      15 levels being 6.3-31.6% of those on day 1. Rate of adduct removal was
      independent of the type of diet. It is concluded that dietary O3C inhibits PhIP
      DNA adduct formation in a target organ (spleen) as well as in non-target organs
      (liver and gastrointestinal tract) of the CDF1 mouse, but that the rate of adduct
      removal is independent of the O3C content of the diet.

PMID- 10418946
TI  - Exposure to N-nitroso compounds in a population of high liver cancer regions in
      Thailand: volatile nitrosamine (VNA) levels in Thai food.
AB  - The recent case-control studies in Thailand indicate that a high incidence of
      liver cancer in Thailand has not been associated with common risk factors such as
      hepatitis B infection, aflatoxin intake and alcohol consumption. While the
      infestation by the liver fluke Opisthorchis viverrini (OV) accounted for the high
      risk in north-east Thailand, there was no such exposure in the other regions of
      the country where the incidence of liver cancer is also high. Case-control
      studies suggest that exposure to exogenous and possibly endogenous nitrosamines
      in food or tobacco in betel nut and cigarettes may play a role in the development
      of hepatocellular carcinoma (HCC), while OV infestation and chemical interaction
      of nitrosamines may also be aetiological factors in the development of
      cholangiocarcinoma (CCA). Over 1800 samples of fresh and preserved food were
      systematically collected and tested between 1988 and 1996. All the food items
      identified by anthropological studies to be consumed frequently in four major
      regions of Thailand were analysed for volatile nitrosamines using gas
      chromatography combined with a thermal energy analyser. Relatively high levels of
      N-nitrosodimethylamine (NDMA), N-nitrosopiperidine (NPIP) and N
      nitrosopyrrolidine (NPYR) were detected in fermented fish ("Plasalid"). NDMA was
      also detected at levels ranging from trace amounts to 66.5 microg/kg in several
      salted and dried fish ("Larb-pla" and "Pla-siu"). NDMA and NPYR were frequently
      detected in several vegetables, particularly fermented beans ("Tau-chiau") at
      levels ranging between 1 and 95.1 microg/kg and 0-146 microg/kg, respectively.
      The possible role of nitrosamines in Thai food in the aetiology of liver cancer
      (HCC, CCA) is discussed.

PMID- 10418947
TI  - Metabolic fates in humans of linamarin in cassava flour ingested as stiff
      porridge.
AB  - Insufficiently processed products from cassava roots may contain residual amounts
      of cyanogenic glucosides, mainly linamarin. The fate of orally ingested linamarin
      was studied following a meal of cassava porridge prepared from cassava flour from
      southern Tanzania with 82 mg cyanide equivalents (3035 micromol) of linamarin per
      kg dry weight. Following ingestion of amounts of porridge containing 243-571
      micromol linamarin by 15 healthy adults a mean (range) of 21% (1-47%) of the
      linamarin ingested was excreted in the urine within 24 hours and a mean of 1% in
      the next 24 hours. Serum thiocyanate, the main cyanide metabolite, increased in
      all subjects from a mean (+/-SD) of 34+/-26 to 78+/-28 micromol/litre (P <
      0.001). In a second group of seven subjects we found that the ingestion of
      porridge with a mean (range) of 431 micromol (203-669%) of linamarin resulted in
      a mean linamarin excretion of 127 micromol/litre and an excess thiocyanate
      excretion of 118 micromol/litre and that 216 micromol was unaccounted for. We
      conclude that less than one-half of orally ingested linamarin is converted to
      cyanide and hence thiocyanate, about one-quarter is excreted unchanged and
      another quarter is metabolized into an as yet unknown compound.

PMID- 10418948
TI  - Prevention of N-nitrosodiethylamine-induced lung tumorigenesis by ellagic acid
      and quercetin in mice.
AB  - The polyphenolic antioxidants, consumed as an integral part of vegetables, fruits
      and beverages, are suggested as possessing anticarcinogenic properties. In the
      present study we have looked into the anticarcinogenic potential of plant
      polyphenols ellagic acid (EA) and quercetin against N-nitrosodiethylamine-induced
      lung tumorigenesis in mice. Ellagic acid was able to significantly reduce tumour
      incidence to 20% from the control value of 72.2%. Similarly, tumour burden was
      also decreased, although not significantly, from 3.15 to 2.5. Quercetin (QR)
      caused the tumour incidence to decrease from 76.4% to 44.4% when fed until the
      third dose of carcinogen. Both of the polyphenols suppressed the tumour incidence
      mainly by acting at the initiation phase of the carcinogenesis, since continuing
      the feeding of polyphenols until the termination of the experiment did not cause
      any apparent change in tumour incidence or tumour burden. Besides this, ellagic
      acid was found to be a better chemopreventor than quercetin. In order to search
      for their mechanism of action, the effect of feeding of these compounds on
      reduced glutathione (GSH), an important endogenous antioxidant, and on lipid
      peroxidation was investigated. Both ellagic acid and QR caused a significant
      increase in GSH and decrease in NADPH- and ascorbate-dependent lipid
      peroxidation. Ellagic acid was found to be more effective in decreasing the lipid
      peroxidation and increasing the GSH. This may be one of the reasons for its
      observed better anticarcinogenic property as compared to quercetin.

PMID- 10418950
TI  - Paeonol promotion of DNA adduct formation and arylamines N-acetyltransferase
      activity in human colon tumour cells.
AB  - Paeonol was used to determine any effects on the N-acetyltransferase (NAT)
      activity in human colon tumour cells as measured by HPLC exhibited for the
      amounts of N-acetyl-2-aminofluorene (AAF) and N-acetyl-p-aminobenzoic acid (N-Ac
      PABA) and remaining 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). The NAT
      activity in the human colon tumour intact cells and cytosols was promoted by
      paeonol in a dose-dependent manner, that is, the higher the concentrations of
      paeonol, the higher the promotion of NAT activity. The apparent Vmax values from
      NAT of human colon tumour cells were also promoted by paeonol in cytosols and in
      intact cells. The data also demonstrated that co-treatment with paeonol in the
      media an increase in AF-DNA adduct formation was seen in the human colon tumour
      cells. This report is the first demonstration to show paeonol did promote human
      colon tumour cell NAT activity and AF-DNA adduct formation.

PMID- 10418949
TI  - Effects of berberine on arylamine N-acetyltransferase activity in human bladder
      tumour cells.
AB  - Berberine was used to determine inhibition of arylamine N-acetyltransferase (NAT)
      activity in human bladder tumour cells. The NAT activity was measured by HPLC
      assaying for the amounts of N-acetyl-2-aminofluorene (AAF) and N-acetyl-p
      aminobenzoic acid (N-Ac-PABA) and remaining 2-aminofluorene (AF) and p
      aminobenzoic acid (PABA). Two assay systems were performed, one with cellular
      cytosols, the other with intact bladder tumour cell suspensions. The NAT activity
      in human bladder tumour cells was inhibited by berberine in a dose-dependent
      manner, that is, the higher the concentration of berberine, the higher the
      inhibition of NAT activity. The values of apparent Km and Vmax calculated from
      cytosol NAT and intact cells were also decreased by berberine. This report is the
      first demonstration to show berberine did affect human bladder tumour cell NAT
      activity.

PMID- 10418951
TI  - Toxicity of lactide in dogs after 2 and 13 weeks of daily oral dosing.
AB  - Two-week and 13-week studies were conducted to determine the toxicity of lactide
      when the compound is administered orally in gelatin capsules to beagle dogs. In
      the 2-week study, daily doses of 0, 10, 100, 400, 1000 and 2500 mg/kg body
      weight/day were administered to dogs of both sexes for 14 consecutive days. All
      dogs survived to the end of the study. Clinical signs consistent with irritation
      of the alimentary tract occurred in dogs in the 1000 and 2500 mg/kg dose groups.
      Reductions in body weight gain and in absolute and relative thymus weights were
      observed in the same two dose groups, and reductions in absolute and relative
      spleen weights were seen in the 2500 mg/kg dose group. These changes were
      considered to be secondary to the stress resulting from irritation of the
      gastrointestinal tract. Gross and microscopic lesions were indicative of
      irritation, and included dark foci and haemorrhage of the stomach lining, and
      erosion and ulceration of the stomach and the oesophagus. Also noted in all high
      dose dogs was renal tubular regeneration, which may represent repair of previous
      necrosis of the tubular epithelium. In the 13-week study, no deaths occurred when
      dogs were given daily oral doses of 0, 4, 20 or 100 mg/kg body weight/day. No
      clinical signs of toxicity were observed, and the compound had no effect on body
      weights, food consumption, or any of the clinical chemistry, haematology or
      urinalysis parameters assessed. Gross and microscopic findings considered to be
      potentially related to lactide administration were minimal, and included a
      stomach focus in one dog of each sex in the 100 mg/kg group. The stomach focus in
      the 100 mg/kg female dog was manifested microscopically as a stomach ulcer. Based
      on these results, the primary toxic effect of lactide was considered to be
      irritation of the gastrointestinal tract, and the no-observed-adverse-effect
      level (NOAEL) after subchronic oral dosing in dogs was considered to be 100
      mg/kg/day.

PMID- 10418952
TI  - Effects of intermittent vomitoxin exposure on body weight, immunoglobulin levels
      and haematuria in the B6C3F1 mouse.
AB  - Continuous dietary exposure of female B6C3F1 mice to the trichothecene vomitoxin
      (VT) results in reduced body weight gain, elevated production of serum
      immunoglobulin A (IgA), kidney mesangial IgA deposition and glomerulonephritis.
      To assess whether intermittent consumption of dietary VT, as might occur during
      natural animal and human exposures, has similar effects to those for continuous
      consumption, a comparison was made between two schedules of dietary exposure.
      Female B6C3F1 mice were fed for 13 weeks with either a semipurified AIN-76A diet
      containing 20 ppm VT continuously or with 20 ppm VT intermittently (every other
      week). The effect these diets had on body weight gain, serum immunoglobulin (Ig)
      profile, mesangial Ig deposition and haematuria were assessed and compared with
      each other as well as with mice fed a control diet. Reduced body weight gains in
      the treatment groups were seen as early as 2 weeks. After week 4, the mean body
      weight of the intermittent group appeared higher than the continuous group during
      the weeks when it was fed a control diet, but dropped to continuous group levels
      during the weeks they were fed VT. Serum IgA levels in the intermittent group
      remained at control levels and were significantly lower than the continuous group
      during the course of the study. In contrast, serum IgG and serum immunoglobulin M
      (IgM) levels for the intermittent and continuous groups were significantly
      decreased compared with control. Mesangial IgA deposition was significantly lower
      in the intermittent group compared with the continuous group, and had levels
      comparable to mice on the control diet. Haematuria was significantly greater in
      both treatment groups compared with control at weeks 5 and 13 when the
      intermittent group was fed VT containing diet, but haematuria in the intermittent
      group dissipated at week 10 when it was fed control diet. The results presented
      here suggest that the type of dietary exposure regimen is critical in determining
      the extent of toxic effects induced by VT. Thus, when animal models are used for
      assessing the toxic effects of mycotoxins, it may be useful to consider the
      effects of intermittent and sporadic exposure.

PMID- 10418953
TI  - Depression of glutathione content, elevation of CYP2E1-dependent activation, and
      the principal determinant of the fasting-mediated enhancement of 1,3-dichloro-2
      propanol hepatotoxicity in the rat.
AB  - The influence of fasting (18 hours) on the hepatotoxicity of 1,3-dichloro-2
      propanol (1,3-DCP) and on various hepatic parameters has been assessed in the
      rat. Fasting produced an enhancement of the hepatotoxicity which was associated
      with alterations in a variety of hepatic parameters when measured relative to
      protein content, most notably glutathione (GSH) levels (decrease) and CYP2E1
      mediated enzyme activity (increase), two parameters previously identified as
      being important determinants to the toxicity. Fasting also decreased the liver
      weight normalized to body weight. When this was taken into account, total liver
      CYP2E1-mediated enzyme activity was not significantly altered whereas the total
      liver GSH level was markedly reduced following fasting. These results imply that
      the reduction in hepatic GSH is the principal determinant of the enhanced
      susceptibility to 1,3-DCP hepatotoxicity following fasting.

PMID- 10418954
TI  - European Commission--Directorate General DG XXIV Consumer Policy and Consumer
      Health Protection. Notes of Guidance for testing of cosmetic ingredients for
      their safety evaluation (Second Revision). Adopted: 20 December 1996. Revised: 16
      January 1997. The Scientific Committee on Cosmetology of the European Commission.

PMID- 10418955
TI  - A tiered approach to threshold of regulation.
AB  - This paper presents methods for extending the principle of a single "threshold of
      regulation" to a range of dietary concentrations between 0.5 and 15 parts per
      billion by using structure-activity relationships, genotoxicity, and short-term
      toxicity data. The database used to develop the FDA's threshold of regulation was
      examined to determine whether structural parameters or the result of certain
      short-term toxicity tests could be used to define a subset of less potent
      substances that supports higher threshold levels. In addition, results of
      reproductive toxicity tests for 3306 compounds and other multidose toxicity tests
      for 2542 compounds were compared with the database of carcinogenic potencies to
      establish that carcinogenic endpoints are the most conservative toxicity endpoint
      for establishing thresholds of regulation.

PMID- 10418956
TI  - Toxicity of oxidized fats II: tissue levels of lipid peroxides in rats fed a
      thermally oxidized corn oil diet.
AB  - Male Wistar albino rats were fed for 21 days on a diet in which fat (12%) was
      included either as fresh corn oil, malonaldehyde content = 0.11+/-0.05 micro
      microg/g (control) or thermally oxidized corn oil, malonaldehyde content = 0.20+/
      0.03 microg/g (experimental) and the tissue levels of lipid peroxides in six
      organs-namely, liver, kidney, brain, heart, lungs and testes-were determined. Of
      the organs studied, significantly (P < 0.1) higher concentrations of lipid
      peroxides were observed only in the liver and kidney of the experimental rats. In
      the course of the feeding, the experimental rats showed significantly (P < 0.1)
      lower gains in body weights as well as higher relative liver weights than the
      control rats.

PMID- 10418957
TI  - Certain pesticide-induced carbohydrate metabolic disorders in the serum of
      freshwater fish Clarias batrachus (Linn.).
AB  - A freshwater edible catfish, Clarias batrachus (Linn.), was exposed to sublethal
      concentrations of two different groups of pesticides-carbaryl, a carbamate and
      phorate, an organophosphorus (OP) pesticide-for 24, 72, 120 and 168 hours. The
      alterations and the disorders of carbohydrate metabolism were studied in the
      serum. Serum glucose, alkaline phosphatase and bilirubin levels increased with
      both the pesticides throughout the exposure period. The results indicate that the
      carbohydrate metabolism was adversely affected by both the pesticides, as
      evidenced in the serum of the fish.

PMID- 10418958
TI  - Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk
      assessment.
AB  - The metabolism, toxicity and results of tests for carcinogenicity have been
      reviewed with respect to the safety for humans of coumarin present in foodstuffs
      and from fragrance use in cosmetic products. Coumarin is a natural product which
      exhibits marked species differences in both metabolism and toxicity. The majority
      of tests for mutagenic and genotoxic potential suggest that coumarin is not a
      genotoxic agent. The target organs for toxicity and carcinogenicity in the rat
      and mouse are primarily the liver and lung. Moreover, the dose-response
      relationships for coumarin-induced toxicity and carcinogenicity are non-linear,
      with tumour formation only being observed at high doses which are associated with
      hepatic and pulmonary toxicity. Other species, including the Syrian hamster, are
      seemingly resistant to coumarin-induced toxicity. There are marked differences in
      coumarin metabolism between susceptible rodent species and other species
      including humans. It appears that the 7-hydroxylation pathway of coumarin
      metabolism, the major pathway in most human subjects but only a minor pathway in
      the rat and mouse, is a detoxification pathway. In contrast, the major route of
      coumarin metabolism in the rat and mouse is by a 3,4-epoxidation pathway
      resulting in the formation of toxic metabolites. The maximum daily human exposure
      to coumarin from dietary sources for a 60-kg consumer has been estimated to be
      0.02 mg/kg/day. From fragrance use in cosmetic products, coumarin exposure has
      been estimated to be 0.04 mg/kg/day. The total daily human exposure from dietary
      sources together with fragrance use in cosmetic products is thus 0.06 mg/kg/day.
      No adverse effects of coumarin have been reported in susceptible species in
      response to doses which are more than 100 times the maximum human daily intake.
      The mechanism of coumarin-induced tumour formation in rodents is associated with
      metabolism-mediated, toxicity and it is concluded that exposure to coumarin from
      food and/or cosmetic products poses no health risk to humans.

PMID- 10418959
TI  - A toxicological assessment of curdlan.
AB  - Curdlan was approved for use by the FDA in December 1996 as a formulation aid,
      processing aid, stabilizer and thickener or texturizer for use in food. It has
      been evaluated for safety by a series of animal studies and in vitro tests
      including acute, subchronic and chronic toxicity studies and reproduction and
      carcinogenicity studies. In addition, nutritional studies in rodents and
      tolerance and metabolic studies in man have been carried out. The only effects
      seen in these studies were reductions in weight gain at the higher dietary
      concentrations due to the replacement of part of the diet by curdlan, which is
      calorifically inert. No evidence of any toxicity or carcinogenicity nor of any
      effects on reproduction was seen, although there was an effect on body weights of
      the pups with the 15% diet, which was shown in additional studies to be due to
      the reduced food availability in the animals at this dose level. There was no
      evidence of effects on the nutritional status of the animals nor on the
      absorption of minerals. This reviews the available toxicological data on curdlan.

PMID- 10418960
TI  - Partial inhibition of the P-glycoprotein-mediated transport of anthracyclines in
      viable resistant K562 cells after irradiation in the presence of a verapamil
      analogue.
AB  - P-glycoprotein (P-gp) is a membranous ATPase responsible for the multidrug
      resistance phenotype. The effect on P-gp-mediated transport of anthracyclines of
      cell irradiation in the presence of 2,2-diphenyl-5-[N-1-(o
      azidophenyl)ethylamino]valeronitrile (VP*), a photoactivable analogue of
      verapamil was studied in viable K562/ADR cells. The derivatives were daunorubicin
      (DNR), idarubicin (IDA), 8-(S)-fluoro-idarubicin (F-IDA), 2'-bromo-4'
      epidaunorubicin (Br-DNR) and pirarubicin (PIRA). It was observed that the
      irradiation in the presence of the verapamil analogue was unable to completely
      inhibit the P-gp-mediated efflux of anthracyclines and we estimated that P-gp
      retained 10-20% of its ability to pump these toxins. The ability of verapamil,
      DNR, IDA, F-IDA, Br-DNR and PIRA to inhibit the effect of VP* was studied. For
      this purpose, cells were irradiated in the presence of VP* and various
      concentrations of either verapamil or of one of the anthracyclines and then the P
      gp functionality was checked by its ability to pump pirarubicin. It was observed
      that (i) the effect observed, when cells were irradiated in the presence of VP*,
      was completely blocked by the presence of verapamil; (ii) that anthracyclines are
      able to partially inhibit the VP* effect. This inhibition occurs at low
      concentration of anthracycline and depends on the nature of the derivative used.
      With those used in that study, after the photoirradiation of K562 ADR cells in
      the presence of VP* and anthracycline, P-gp has retained 50 +/- 5% of its
      functionality. The anthracycline concentration required for this inhibition is
      rather low, the total drug concentration yielding 50% of the effect ranged from
      0.5 (Br-DNR) to 4 microM (F-IDA). The corresponding cytosolic concentrations are
      highly correlated with the values of Km determined previously.

PMID- 10418961
TI  - Effect of nonenzymatic glycation of albumin and superoxide dismutase by
      glucuronic acid and suprofen acyl glucuronide on their functions in vitro.
AB  - Acyl glucuronides bind irreversibly to plasma proteins, and one mechanism
      proposed for this covalent binding is similar to that for glycation of protein by
      reducing sugars. Because glycation of protein by glucose and other reducing
      sugars can alter protein function, this lead to the hypothesis that the glycation
      of proteins by acyl glucuronides may cause similar effects. When human serum
      albumin (HSA) was incubated with 0.5 M glucose for 5 days, the unbound fractions
      of diazepam and warfarin were increased by 41 and 35%, respectively, less than
      that caused by glucuronic acid which increased the unbound fractions by 90% for
      diazepam and 420% for warfarin. When HSA was incubated with suprofen glucuronide
      (SG) at a much lower concentration of 0.005 M for only 24 h, the effects on the
      unbound fractions of diazepam and warfarin to HSA were altered dramatically with
      increases of 340 and 230%, respectively. After incubation of superoxide dismutase
      (SOD) with 0.5 or 1 M reducing sugars for 14 days, the enzyme activity decreased
      to 82 and 61% of initial levels at day 14, respectively, whereas glucuronic acid
      almost completely inactivated the enzyme activity over the same period. Even at a
      very low concentration (0.005 M) of SG, SOD activity was reduced significantly to
      11% of initial levels by day 14, which was comparable to the effect by 0.5 and
      1.0 M concentrations of glucuronic acid. Sodium dodecyl sulfate polyacrylamide
      gel electrophoresis and matrix associated laser desorption/ionization time of
      flight mass spectrometry indicated that several equivalents of reducing sugars or
      SG became attached to albumin after incubation. These results suggest that acyl
      glucuronides may affect the function of proteins by the formation of glycated
      protein in vivo and may be associated with the toxicity of xenobiotics
      metabolized to labile acyl glucuronides.

PMID- 10418962
TI  - Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its
      derivatives demethoxycurcumin and bisdemethoxycurcumin.
AB  - Curcumin, a naturally occurring phytochemical responsible for the colour of
      turmeric shows a wide range of pharmacological properties including antioxidant,
      anti-inflammatory and anti-cancer effects. We have earlier shown that curcumin in
      the presence of Cu(II) causes strand cleavage in DNA through generation of
      reactive oxygen species, particularly the hydroxyl radical. Thus, curcumin shows
      both antioxidant as well as pro-oxidant effects. In order to understand the
      chemical basis of various biological properties of curcumin, we have studied the
      structure-activity relationship between curcumin and its two naturally occurring
      derivatives namely demethoxycurcumin (dmC) and bisdemethoxycurcumin (bdmC).
      Curcumin was found to be the most effective in the DNA cleavage reaction and a
      reducer of Cu(II) followed by dmC and bdmC. The rate of formation of hydroxyl
      radicals by the three curcuminoids also showed a similar pattern. The relative
      antioxidant activity was examined by studying the effect of these curcuminoids on
      cleavage of plasmid DNA by Fe(II)-EDTA system (hydroxyl radicals) and the
      generation of singlet oxygen by riboflavin. The results indicate that curcumin is
      considerably more active both as an antioxidant as well as an oxidative DNA
      cleaving agent. The DNA cleavage activity is the consequence of binding of Cu(II)
      to various sites on the curcumin molecule. Based on the present results, we
      propose three binding sites for Cu(II). Two of the sites are provided by the
      phenolic and methoxy groups on the two benzene rings and the third site is due to
      the presence of 1,3-diketone system between the rings. Furthermore, both the
      antioxidant as well as pro-oxidant effects of curcuminoids are determined by the
      same structural moieties.

PMID- 10418963
TI  - Kinetics of redox interaction between substituted quinones and ascorbate under
      aerobic conditions.
AB  - One-electron reduction of quinones (Q) by ascorbate (AscH ); (1) AscH + Q --> Q*-
      + Asc*- + H+, followed by the oxidation of semiquinone (Q*-) by molecular oxygen;
      (2) Q*- + O2 --> Q + O2*-, results in the catalytic oxidation of ascorbate (with
      Q as a catalyst) and formation of active forms of oxygen. Along with enzymatic
      redox cycling of Q. this process may be related to Q cytotoxicity and underlie an
      antitumor activity of some Qs. In this work, the kinetics of oxygen consumption
      accompanied the interaction of ascorbate with 55 Qs including substituted 1,4-
      and 1,2-benzoquinones, naphthoquinones and other quinoid compounds were studied
      in 50 mM sodium phosphate buffer, pH 7.40, at 37 degrees C by using the Clark
      electrode technique. The capability of Q to catalyze ascorbate oxidation was
      characterized by the effective value of kEFF calculated from the initial rate of
      oxygen consumption (R(OX)) by the equation R(OX) = kEFF[Q][AscH-] as well as by a
      temporary change in R(OX). The correlation of kEFF with one-electron reduction
      potential, E(Q/Q*-), showed a sigma-like plot, the same for different kinds of
      Qs. Only the Qs which reduction potential E(Q/Q*-) ranged from nearly -250 to +
      50 mV displayed a pronounced catalytic activity, kEFF increased with shifting
      E(Q/Q*-) to positive values. The following linear correlation between kEFF (in M
      (-1) s(-1)) and E(Q/Q*-) (in mV) might be suggested for these Qs: lg(kEFF)= 3.91
      + 0.0143E(Q/Q*-). In contrast, Qs with E(Q/Q*-) < - 250 mV and E(Q/Q*-) > + 50 mV
      showed no measurable catalytic activity. The Qs studied displayed a wide variety
      in the kinetic regularities of oxygen consumption. When E(Q/Q*-) was more
      negative than - 100 mV, Q displayed a simple ('standard') kinetic behavior--R(OX)
      was proportional to [AscH-][Q] independently of concentration of individual
      reagents, [AscH-] and [Q]; R(OX) did not decrease with time if [AscH-] was held
      constant: Q recycling was almost reversible. Meanwhile, Qs with E(Q/Q*-) > - 100
      mV demonstrated a dramatic deviation from the 'standard' behavior that was
      manifested by the fast decrease in R(OX) with time and non-linear dependence of
      even starting values of R(OX) on [Q] and [AscH-]. These deviations were caused
      basically by the participation of Q*- in side reactions different from (2). The
      above findings were confirmed by kinetic computer simulations. Some biological
      implications of Q-AscH- interaction were discussed.

PMID- 10418964
TI  - Expression and distribution of cytochrome P450 2E1 in B6C3F1 mouse liver and
      testes.
AB  - Cytochrome P450 2E1 (CYP2E1) is believed to have a significant role in the
      bioactivation of 1,3-butadiene (BD) to DNA reactive epoxide metabolites that
      induce somatic and germ cell genotoxicity in mice. To assess the potential role
      of in situ bioactivation of BD by mouse testes for inducing germ cell
      genotoxicity, the presence of CYP2E1 in testes has been demonstrated by reverse
      transcriptase-polymerase chain reaction (RT-PCR), immunoprecipitation-Western
      blotting methods (IP-Western) and immunohistochemistry of tissue sections.
      Detection of CYP2E1 in the testes was limited to interstitial cells. In liver a
      known site of BD bioactivation and a positive control tissue used for these
      studies, a discrete, zonal staining pattern of liver CYP2E1 expression detected
      by immunohistochemical staining was shown. These results suggest that in situ
      bioactivation of BD in testes by CYP2E1 may contribute to BD-induced germ cell
      genotoxicity.

PMID- 10418966
TI  - Overview: hepatocytes and cryopreservation--a personal historical perspective.
AB  - Hepatocytes represent an important tool for the investigation of species
      differences in drug metabolism and toxicity. Data obtained with hepatocytes from
      multiple animal species, including man, allow better prediction of the effects of
      xenobiotics in man. Cryopreservation of hepatocytes extends the use of this
      important experimental system by enhancing the convenience of its use. Also, it
      allows the researchers to perform experiments not plausible with freshly isolated
      hepatocytes, such as the direct comparison of xenobiotic toxicity and metabolism
      in hepatocytes from multiple human donors in a single experiment.

PMID- 10418965
TI  - 2-(Allylthio)pyrazine inhibition of aflatoxin B1-induced hepatocarcinogenesis in
      rats.
AB  - 2-(Allylthio)pyrazine (2-AP), a synthetic pyrazine derivative with an allylsulfur
      moiety, has hepatoprotective effects against toxicants. Effect of 2-AP on hepatic
      tumorigenesis in association with glutathione S-transferase (GST) induction was
      examined in rats exposed to aflatoxin B1 (AFB1). Both AFB1-DNA adduct formation
      in the liver and urinary elimination of 8,9-dihydro-8-(N7-guanyl)-9-hydroxy
      aflatoxin B1 (AFB1-N7-guanine) adduct were also determined. Male Sprague Dawley
      rats were treated with 2-AP at the daily oral doses of 10, 25 and 50 mg/kg for 16
      consecutive days, during which four repeated doses of AFB1 (1.0 mg/kg) were given
      to the animals. Rats were then subjected to two-thirds of hepatectomy, followed
      by administration of phenobarbital (PB). Focal areas of hepatocellular alteration
      were identified after 44 days and preneoplastic foci expressing the placental
      form of glutathione S-transferase P (GST-P) were quantified by immunostaining of
      liver sections. 2-AP reduced the volume of liver occupied by GST-P foci by 65
      96%. Under these experimental conditions, 2-AP treatment resulted in significant
      elevations in GST activity in the liver. Levels of radiolabeled AFB1 covalently
      bound to hepatic DNA, RNA and proteins were significantly reduced in rats treated
      with 2-AP for 5 days. 2-AP pretreatment also caused a 45% reduction in the
      urinary elimination of AFB1-N7-guanine adduct over the 24-h postdosing period.
      The present findings demonstrated that 2-AP exhibited protective effects against
      AFB1-induced hepatocarcinogenesis in rats with a marked decrease in the level of
      AFB1-DNA adduct. Reduction of hepatic DNA adducts might result from elevations of
      activity of GST, which catalyzes detoxification of the carcinogen.

PMID- 10418967
TI  - Survival and function of isolated hepatocytes after cryopreservation.
AB  - Cryopreservation in liquid nitrogen is presently the only way for long-term
      storage of isolated hepatocytes. Freeze-thaw conditions are not well defined yet;
      the most critical parameters appear to be the choice of the cryoprotectant,
      composition of the freezing medium, and cooling and thawing rates. Comparable
      results have been obtained with hepatocytes from various species, including man.
      Cryopreservation usually results in low cell recovery and early alterations of
      functional activities. However, both phase I and phase II xenobiotic metabolism
      is still active after thawing, at least during a short period. Moreover, survival
      and function of cryopreserved hepatocytes can be improved when these cells have a
      high energy status, are cryopreserved after immobilization in a gel, separated
      from dead cells on a Percoll gradient or placed in more favorable culture
      conditions (e.g. in coculture with liver non parenchymal cells). Additional
      studies are needed to improve freeze-thaw protocols and to better characterize
      liver parenchymal cells after storage, including evaluation of their
      responsiveness to specific inducers.

PMID- 10418968
TI  - Cryopreserved human hepatocytes: characterization of drug-metabolizing enzyme
      activities and applications in higher throughput screening assays for
      hepatotoxicity, metabolic stability, and drug-drug interaction potential.
AB  - Cryopreserved human hepatocytes were extensively characterized in our laboratory.
      The post-thaw viability, measured via dye exclusion, ranged from 55 to 83%, for
      hepatocytes cryopreserved from 17 donors. Post-thaw viability and yield (viable
      cells per vial) were found to be stable up to the longest storage duration
      evaluated of 120 days. Drug-metabolizing enzyme activities of the cryopreserved
      hepatocytes (mean of ten donors) as percentages of the freshly isolated cells
      were: 97%, for cytochrome P450 isoform (CYP) 1A2, 78% for CYP2A6, 96% for CYP2C9.
      86% for CYP2Cl9, 90% for CYP2D6, 164% for CYP3A4, 76% for UDP-glucuronidase, and
      88% for umbelliferone sulfotransferase. Known species-differences in 7
      ethoxycoumarin (7-EC) metabolism were reproduced by cryopreserved hepatocytes
      from human, rat, rabbit, dog, and monkey, illustrating the utility of
      cryopreserved hepatocytes from multiple animal species in the evaluation of
      species-differences in drug metabolism. Higher throughput screening (HTS) assays
      were developed using cryopreserved human hepatocytes for hepatotoxicity,
      metabolic stability, and inhibitory drug-drug interactions. Dose-dependent
      cytotoxicity, measured using MTT metabolism as an endpoint, was observed for the
      known hepatotoxic chemicals tamoxifen, clozapine, cadmium chloride, diclofenac,
      amiodarone, tranylcypromine, precocene II, but not for 2-thiouracil. Cell density
      and time-dependent metabolism of 7-EC and dextromethorphan were observed in the
      HTS assay for metabolic stability. Known CYP isoform-specific inhibitors were
      evaluated in the HTS assay for inhibitory drug-drug interactions. Furafylline,
      sulfaphenazole, quinidine, and ketoconazole were found to be specific inhibitors
      of CYP1A2, CYP2C9, CYP2D6, and CYP3A4, respectively. Tranylcypromine and
      diethyldithiocarbamate were found to be less specific, with inhibitory effects
      towards several CYP isoforms, including CYP2A6, CYP2C9, CYP2C19, and CYP2E1.
      These results suggest that cryopreserved human hepatocytes represent a useful
      experimental tool for the evaluation of drug metabolism, toxicity, and inhibitory
      drug-drug interaction potential.

PMID- 10418970
TI  - Induction of cytochrome-P450 in cryopreserved rat and human hepatocytes.
AB  - Our laboratory has been routinely using suspended and cultured human hepatocytes
      for predicting drug metabolism and enzyme induction by drug candidates to aid
      drug discovery. Increasing limitation and irregular availability of human tissue
      has indicated the need for maximizing the use of this valuable resource.
      Cryopreservation of surplus hepatocytes after isolation would greatly increase
      the potential of this model. However, cryopreservation of hepatocytes by various
      methods has resulted in cells with poor metabolic activity and unacceptably low
      survival rates in culture. Recently, Zaleski et al. (Biochem. Pharmacol. 46
      (1993) 111-116) reported that cryopreserved rat hepatocytes retained metabolic
      capacity similar to fresh hepatocytes when the cells were preincubated for 30 min
      at 37 degrees C in Krebs Ringer bicarbonate buffer prior to freezing. To further
      explore this methodology, both the functional capacity of the cells in culture as
      well as their ability to retain CYP inducibility were investigated with thawed
      cryopreserved hepatocytes. Although human hepatocytes were used in this study the
      initial work focused on rat hepatocytes as a cell model. Our results showed that
      while the preincubation step did not appear to effect the initial viability of
      cryopreserved hepatocytes, survival of the cells in culture was greatly enhanced.
      Plating efficiencies for nonpreincubated cryopreserved hepatocytes were decreased
      to approximately 15% of fresh cells after 48 h in culture. In contrast, cells
      that had been preincubated prior to freezing had an excellent plating efficiency
      (approximately 60%) and responded to classical CYP inducers dexamethasone, beta
      naphthoflavone and phenobarbital in a manner indistinguishable from that of fresh
      hepatocytes. Experiments with human hepatocytes have also demonstrated similar
      results. This is the first time to our knowledge that cryopreserved hepatocytes
      from both rat and human have been shown to reproducibly respond to CYP inducers
      in culture.

PMID- 10418969
TI  - Comparative effects of rifabutin and rifampicin on cytochromes P450 and UDP
      glucuronosyl-transferases expression in fresh and cryopreserved human
      hepatocytes.
AB  - The aim of this study was to evaluate rifabutin (RBT) and rifampicin (RIF)
      capabilities in inducing various xenobiotic metabolizing enzymes such as
      cytochromes P450 (CYPs) and UDP-glucuronosyl-transferases (UGTs) in cultured
      fresh and cryopreserved human hepatocytes. Enzyme induction was assessed through
      the use of several diagnostic markers, i.e. testosterone, midazolam (MDZ),
      diazepam (DZP) and 7-ethoxyresorufin for CYP-dependent enzyme reactions; and AZT
      for UGT-dependent enzyme reactions. RBT concentrations (0.118, 0.708 microM) were
      selected according to previously published pharmacokinetic data in patients. The
      known CYP3A4 inducer in humans, RIF, was used as a positive control. At the
      concentrations used, no sign of cytotoxicity was evidenced. Both compounds were
      able to dose-dependently induce the overall metabolism of testosterone
      (approximately 2-fold for RBT, 4-fold for RIF) and the formation of the 6beta
      hydroxylated-derivative (up to approximately 4-fold over control for RBT and
      approximately 10-fold for RIF), which is CYP3A4 dependent. The other hydroxylated
      metabolites (16alpha-OH and 2alpha-OH) were also enhanced. The metabolism of MDZ,
      which is specifically metabolized by CYP3A4 in humans, was also investigated
      following drug's exposure to hepatocytes. DZP one, which is governed by various
      CYPs, including CYP3A, was also investigated. RBT was shown to increase the
      biotransformation of both benzodiazepines (approximately 1.9-fold over control).
      Moreover, the effects of both drugs on ethoxyresorufin O-deethylase activity
      (EROD), which is representative of CYPIA1/2 isoforms, were tested. Results showed
      only a moderate induction of this marker (approximately 2-fold over control) when
      compared to the high effect observed after hepatocyte exposure to 3
      methylcholantene (approximately 14-fold over control). Finally, the action of RBT
      and RIF on UGTs expression was investigated by using AZT as diagnostic substrate:
      glucuronides formation was not significantly affected by the two rifamycin
      derivatives. On the whole, exposure of fresh or cryopreserved human hepatocytes
      to RBT dose-dependently affected the levels of drug metabolizing enzymes in a
      dose-dependent manner. However, as already demonstrated by in vivo
      pharmacokinetic studies, its inducing properties towards CYPs, CYP3A in
      particular, are less pronounced than RIF.

PMID- 10418971
TI  - Maintenance of steroid metabolism and hormone responsiveness in cryopreserved
      dog, monkey and human hepatocytes.
AB  - The efficient and effective use of hepatocytes from larger species and rare human
      material requires a reliable storage method for cells not needed on the day of
      preparation. Cryopreservation would seem to be the only viable alternative. In
      this study the suitability of a published cryopreservation technique on dog,
      monkey and human hepatocytes has been examined and the cells were tested for
      functionality directly after thawing and subsequent to culture using steroid
      metabolism and hormone responsiveness of glycogen phosphorylase a. Monkey and
      human hepatocytes appear to survive the freezing and thawing process better than
      dog cells-the latter losing the ability to respond to adrenergic stimuli and
      their ability to maintain steroid metabolism in culture. Although monkey and
      human cells do preserve their steroid metabolising capacity after freeze/thawing,
      there is not the significant increase in enzyme activity seen during culturing
      freshly isolated cells. It would appear, therefore, that some damage has occurred
      to the cells during the freeze/thaw process. As previously noted, Williams'
      medium E is superior to Ham's F-10 in maintaining enzyme activities in culture.
      It is suggested that cryopreservation is the way forward for the development of
      stockpiles of viable hepatocytes for biomedical and toxicological research and
      development but that further modifications to the process are still necessary to
      optimise the maintenance of liver-specific functions in the thawed cells.

PMID- 10418972
TI  - A multi-laboratory evaluation of cryopreserved monkey hepatocyte functions for
      use in pharmaco-toxicology.
AB  - Ethical, economic and technical reasons hinder regular supply of freshly isolated
      hepatocytes from higher mammals such as monkey for preclinical evaluation of
      drugs. Hence, we aimed at developing optimal and reproducible protocols to
      cryopreserve and thaw parenchymal liver cells from this major toxicological
      species. Before the routine use of these protocols, we validated them through a
      multi-laboratory study. Dissociation of the whole animal liver resulted in
      obtaining 1-5 billion parenchymal cells with a viability of about 86%. An
      appropriate fraction (around 20%) of the freshly isolated cells was immediately
      set in primary culture and various hepato-specific tests were performed to
      examine their metabolic, biochemical and toxicological functions as well as their
      ultrastructural characteristics. The major part of the hepatocytes was frozen and
      their functionality checked using the same parameters after thawing. The
      characterization of fresh and thawed monkey hepatocytes demonstrated the
      maintenance of various hepato-specific functions. Indeed, cryopreserved
      hepatocytes were able to survive and to function in culture as well as their
      fresh counterparts. The ability for synthesis (proteins, ATP, GSH) and
      conjugation and secretion of biliary acids was preserved after deep freeze
      storage. A better stability of drug metabolizing activities than in rodent
      hepatocytes was observed in monkey. After thawing, Phase I and Phase II
      activities (cytochrome P450, ethoxycoumarin-O-deethylase, aldrin epoxidase,
      epoxide hydrolase, glutathione transferase, glutathione reductase and glutathione
      peroxidase) were well preserved. The metabolic patterns of several drugs were
      qualitatively and quantitatively similar before and after cryopreservation.
      Lastly, cytotoxicity tests suggested that the freezing/thawing steps did not
      change cell sensitivity to toxic compounds.

PMID- 10418973
TI  - Cryopreserved porcine hepatocyte cultures.
AB  - Cryopreservation of freshly isolated hepatocytes is regarded the standard
      technique for long term storage of liver cells. Frankly, we were not successful
      in reproducing viability rates of about 70% of that which have been reported by
      most authors as results of various freezing protocols for hepatocyte suspensions.
      In fact, we saw mostly devastating results. We assume that intracellular ice
      crystal formation as well as osmotic changes during freezing and thawing of liver
      cells cause hazardous effects, especially on membranes of cells after enzymatic
      isolation, and, thus, generally result in a severe loss in number and impaired
      specific hepatocyte functions in subsequent culture. We tried to improve results
      by freezing cell cultures instead. We allowed hepatocytes to regain a more stable
      condition prior to storage and placed them in tissue flasks in a uniform
      configuration, rather than to pack cell suspensions in vials or bags under rather
      indefinable conditions. Porcine hepatocytes (viability 92+/-2%) were isolated
      from slaughterhouse organs and cultured in a double gel (sandwich) configuration.
      At day 3, cultures were rate controlled frozen (RCF) and stored in a cell bank
      for three hours (Group A) or 14 days at -80 degrees C (Group B), respectively.
      Non-frozen cells (NF) and cultures subjected to a linear freezing rate of -10
      degrees C/min (LFR, Group C) with 3 h of storage served as controls from
      identical cell batches. Upon thawing, at day 2 of subsequent culture,
      fluorescence microscopy studies revealed a survival rate of 75+/-10% (mean+/
      S.D.) in the RCF groups. Time of storage (3 h, 14 d) did not influence results.
      Survival in Group C was 10+/-5%. Cell integrity was measured by LDH-release,
      which indicated a larger damage of cells in the LFR group, and thereby resembled
      the morphological findings. Functional parameters, such as albumin synthesis and
      CYT P 450-activity were comparable to non-frozen liver cells at 48 h after
      thawing in the RCF groups (A + B), and showed significantly higher levels in
      these groups as compared to the LFR Group (C). We recommend to freeze hepatocytes
      in culture in a rate controlled fashion rather than cell suspensions. This way a
      cell bank of cryopreserved hepatocyte cultures for batch controlled
      investigations can be easily obtained. This could ameliorate the availability of
      rare (human) cell material and might also improve the quality of data generated
      from in vitro experiments in hepatology or pharmacology/toxicology with liver
      cells from identical sources. It remains to be seen whether this technique might
      also be of value in hybrid bioartificial liver devices to make these systems
      become readily available upon clinical demand.

PMID- 10418974
TI  - Present status of the application of cryopreserved hepatocytes in the evaluation
      of xenobiotics: consensus of an international expert panel.
AB  - Successful cryopreservation of freshly isolated hepatocytes would significantly
      decrease the need for freshly-procured livers for the preparation of hepatocytes
      for experimentation. Hepatocytes can be prepared, cryopreserved, and used for
      experimentation as needed at different times after isolation. Cryopreservation is
      especially important for research with human hepatocytes because of the limited
      availability of fresh human livers. Based on the cumulative experience of this
      international expert panel, a consensus was reached on the various aspects of
      hepatocyte cryopreservation, including cryopreservation and thawingprocedures and
      applications of the cryopreserved hepatocytes. Key to successful cryopreservation
      includes slow addition of cryopreservants, controlled-rate freezing with
      adjustment for the heat of crystallization, storage at -150 degrees C, and rapid
      thawing. There is a general consensus that cryopreserved hepatocytes are useful
      for short-term xenobiotic metabolism and cytotoxicity evaluation.

PMID- 10418975
TI  - Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple
      functions.
AB  - Nuclear receptors are ligand-inducible transcription factors which mediate the
      physiological effects of steroid, thyroid and retinoid hormones. By regulating
      the assembly of a transcriptional preinitiation complex at the promoter of target
      genes, they enhance the expression of these genes in response to hormone. Recent
      evidence suggests that nuclear receptors act in part by recruiting multiple
      coregulator proteins which may have specific functions during transcriptional
      initiation. Liganded receptors recruit members of the SRC family, a group of
      structurally and functionally related transcriptional coactivators. Receptors
      also interact with the transcriptional cointegrators p300 and CBP, which are
      proposed to integrate diverse afferent signals at hormone-regulated promoters.
      p300/CBP and members of the SRC coactivator family have intrinsic histone
      acetyltransferase activity which is believed to disrupt the nucleosomal structure
      at these promoters. Other nuclear receptor coactivators include a member of the
      SWI/SNF complex, BRG-1, which couples ATP hydrolysis to chromatin remodelling,
      and the E3 ubiquitin-protein ligases E6-AP and RPF-1. Finally, nuclear receptor
      coactivators appear to be organized into preformed subcomplexes, an arrangement
      that may facilitate their efficient assembly into diverse higher order
      configurations.

PMID- 10418976
TI  - Steroidogenic factor 1 (SF-1) is essential for endocrine development and
      function.
AB  - Steroidogenic factor 1 (SF-1), an orphan nuclear receptor, initially was isolated
      as a key regulator of the tissue-specific expression of the cytochrome P450
      steroid hydroxylases. Thereafter, analyses of sites of SF-1 expression during
      mouse embryological development hinted at considerably expanded roles for SF-1,
      roles that were strikingly confirmed through the analyses of SF-1 knockout mice.
      These SF-1 knockout mice exhibited adrenal and gonadal agenesis, associated with
      male-to-female sex reversal of their internal and external genitalia and death
      from adrenocortical insufficiency. These findings showed unequivocally that SF-1
      is essential for the embryonic survival of the primary steroidogenic organs. SF-1
      knockout mice also had impaired pituitary expression of gonadotropins and
      agenesis of the ventromedial hypothalamic nucleus (VMH), establishing that SF-1
      regulates reproductive function at all three levels of the hypothalamic-pituitary
      gonadal axis. This article reviews the experiments that have defined these
      essential roles of SF-1 in endocrine development and highlights important areas
      for future studies.

PMID- 10418977
TI  - Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment.
AB  - The diagnostic term congenital adrenal hyperplasia (CAH) applies to a family of
      inherited disorders of steroidogenesis caused by an abnormality in one of the
      five enzymatic steps necessary in the conversion of cholesterol to cortisol. The
      enzyme defects are translated as autosomal recessive traits, with the enzyme
      deficient in more than 90% of CAH cases being 21-hydroxylase. In the classical
      forms of CAH (simple virilizing and salt wasting), owing to 21-hydroxylase
      deficiency (21-OHD), androgen excess causes external genital ambiguity in newborn
      females and progressive postnatal virilization in males and females. Non
      classical 21-OHD (NC21OHD) refers to the condition in which partial deficiencies
      of 21-hydroxylation produce less extreme hyperandrogenemia and milder symptoms.
      Females do not demonstrate genital ambiguity at birth. The gene for adrenal 21
      hydroxylase, CYP21, is located on chromosome 6p in the area of HLA genes.
      Specific mutations may be correlated with a given degree of enzymatic compromise
      and the clinical form of 21-OHD. NC21OHD patients are predicted to have mild
      mutations on both alleles or one severe and one mild mutation of the 21-OH locus
      (compound heterozygote). In most cases the mutation groups represent one
      diagnosis (e.g., Del/Del with SW CAH), however we have found several non
      correlations of genotype to phenotype. Non-classical and classical patients were
      found within the same mutation group. Phenotypic variability within each mutation
      group has important implications for prenatal diagnosis and treatment. Prenatal
      treatment of 21-OHD with dexamethasone has been utilized for a decade. An
      algorithm has been developed for prenatal diagnosis and treatment, which, when
      followed closely, has been safe for both the mother and the fetus, and has been
      effective in preventing ambiguous genitalia in the affected female newborn. This
      is an instance of an inborn metabolic error successfully treated prenatally.
      Since 1986, prenatal diagnosis and treatment of congenital adrenal hyperplasia
      due to 21-hydroxylase deficiency (21-OHD) has been carried out in 403 pregnancies
      in The New York Hospital Cornell Medical Center. In 280, diagnoses were made by
      amniocentesis, while 123 were diagnosed using chorionic villus sampling. Of the
      403 pregnancies evaluated, 84 babies were affected with classical 21-OHD. Of
      these, 52 were females, 36 of whom were treated prenatally with dexamethasone.
      Dexamethasone administered at or before 10 weeks of gestation (23 affected female
      fetuses) was effective in reducing virilization. Thirteen cases had affected
      female sibs (Prader stages 1-4); 6 of these fetuses were born with entirely
      normal female genitalia, while 6 were significantly less virilized (Prader stages
      1-2) than their sibs, and one was Prader stage 3. Eight newborns had male sibs: 4
      were born with normal genitalia, 3 were Prader stages 1-2, and 3 were born Prader
      stages 3-4. No significant or enduring side effects were noted in either the
      mothers or the fetuses, indicating that dexamethasone treatment is safe.
      Prenatally treated newborns did not differ in weight, length, or head
      circumference from untreated, unaffected newborns. Based on our experience,
      proper prenatal diagnosis and treatment of 21-OHD is effective in significantly
      reducing or eliminating virilization in the newborn female. This spares the
      affected female the consequences of genital ambiguity of genital surgery, sex
      misassignment, and gender confusion.

PMID- 10418978
TI  - The endocrinology of the menopause.
AB  - Menopause is defined as the permanent cessation of menstruation resulting from
      the loss of ovarian follicular activity. Ovarian primordial follicle numbers
      decrease with increasing age up to about age 38 following which there is a much
      steeper decline in the last 12 or so years of reproductive life. At the time of
      the menopause itself, few follicles remain within the ovary. The recent
      availability of assays specific for the dimeric inhibins A and B has permitted
      clarification of the endocrine events leading up to and occurring around the time
      of final menses. Those women who show clear elevations in serum FSH above age 40,
      while continuing to cycle regularly have significantly lower inhibin B levels
      than those whose FSH levels remain in the range seen earlier in reproductive
      life. Early in the menopause transition, when cycle irregularity is first
      observed, the initial event is a decline in circulating inhibin B levels in the
      early follicular phase. In the late perimenopause, levels of estradiol and
      inhibin A also fall, inhibin B levels remain low and FSH is markedly elevated.
      The variability of hormone levels in women in their 40s, even in those who are
      continuing to cycle regularly makes FSH and estradiol unreliable markers of
      menopausal status. Serum androgen levels appear to fall with age rather than
      having any clear cut relationship to the menopause transition or menopause. The
      endocrine changes which occur during the menopausal transition and early
      postmenopausal period have clinical consequences in terms of symptoms and changes
      in bone mass.

PMID- 10418979
TI  - An estrogen receptor basis for raloxifene action in bone.
AB  - Although controversy remains regarding direct effects of estrogen on bone, in
      vivo data clearly show that estrogens suppress bone turnover, resulting in
      decreased bone resorption and formation activity. Selective estrogen receptor
      modulators (SERMs), such as raloxifene, produce effects on bone which are very
      similar to those of estrogen. In vitro, both raloxifene and estrogen inhibit
      mammalian osteoclast differentiation and bone resorption activity, but only in
      the presence of IL-6. Data from a number of ovariectomized rat model
      manipulations (i.e. hypophysectomy, low calcium diet and drug combinations)
      demonstrate a strong parallel between the antiosteopenic effects of raloxifene
      and estrogen. A characteristic action of estrogens on the skeleton is inhibition
      of longitudinal bone growth, an effect which is not observed with other
      resorption inhibitors, including calcitonin and bisphosphonates. Consistent with
      an estrogen-like mechanism on bone, raloxifene inhibits longitudinal bone growth
      in growing rats. In addition to the overall similarity of the bone activity
      profile in animals, estrogen and raloxifene also produce similar effects on
      various signaling pathways relative to the antiosteopenic effect of these two
      agents. For example, IL-6, a cytokine involved in high turnover bone resorption
      following estrogen deficiency in rats, is suppressed by both raloxifene and
      estrogen. Raloxifene and estrogen also produce a similar activation of TGF-beta3
      (a cytokine associated with inhibition of osteoclast differentiation and
      activity) in ovariectomized rats. Like 17beta-estradiol, raloxifene binds with
      high affinity to both estrogen receptor-alpha (ER alpha) and estrogen receptor
      beta (ER beta). Crystal structure analyses have shown that 17beta-estradiol and
      raloxifene bind to ER alpha with small, but important, differences in three
      dimensional structure. These subtle differences in the conformation of the
      ligand:receptor complex are likely the basis for the key pharmacological
      differences between estrogens and the various SERMs (i.e. raloxifene vs
      tamoxifen). Raloxifene also produces estrogen-like effects on serum cholesterol
      metabolism and the vasculature. Thus, while raloxifene exhibits a complete
      estrogen antagonist in mammary tissue and the uterus, it produces beneficial
      effects on the cardiovascular system and prevents bone loss via an estrogen
      receptor mediated mechanism.

PMID- 10418980
TI  - Tamoxifen resistant breast cancer: coregulators determine the direction of
      transcription by antagonist-occupied steroid receptors.
AB  - Pharmacological antagonists of steroid receptor action had been thought to exert
      their effects by a passive mechanism driven principally by the ability of the
      antagonist to compete with agonist for the ligand binding site. However, recent
      analyses of antagonist-occupied receptor function suggest a more complex picture.
      Antagonists can be subdivided into two groups, type I, or pure antagonists, and
      type II, or mixed antagonists that can have variable transcriptional activity
      based upon differential dimerization and DNA binding properties. This led us to
      propose that receptor antagonism may not simply be a passive competition for the
      ligand binding site, but may, in some cases, involve active recruitment of
      corepressor or coactivator proteins to produce a mixed transcriptional phenotype.
      We used a yeast two-hybrid screen to identify proteins that interact specifically
      with antagonist-occupied receptors. Two proteins have been characterized: L7/SPA,
      a ribosome-associated protein that is localized in both the cytoplasm and
      nucleus, but with no known extranucleolar nuclear function; and hN-CoR, the human
      homolog of the mouse thyroid receptor corepressor mN-CoR. In in vivo
      transcription assays we show that L7/SPA enhances the partial agonist activity of
      type II mixed antagonists, and that N-CoR and the related corepressor, SMRT,
      suppresses it. The coregulators do not affect agonists or pure antagonists.
      Moreover, the net agonist activity seen with mixed antagonists is a function of
      the ratio of coactivator to corepressor. Based upon these results, we proposed
      that in breast tumors the inappropriate agonist activity seen with therapeutic
      antagonists such as tamoxifen is responsible for the hormone-resistant state. To
      confirm this, we are quantitating coactivator/corepressor ratios in breast tumor
      cells lines and clinical breast cancers. Results should provide new insights into
      the mechanisms underlying the progression of breast cancer to hormone resistance,
      and may suggest strategies for delaying or reversing this process.

PMID- 10418982
TI  - Steroid metabolising enzymes in the determination of brain gender.
AB  - The neurotrophic effects of oestrogen formed in the brain are important in brain
      sexual differentiation of the central nervous system and behaviour. Aromatase,
      converting testosterone to oestradiol-17beta, is a key enzyme involved in brain
      development. In primary cell cultures of foetal hypothalamus, we have found that
      male neurones consistently have higher aromatase activity than in the female.
      Using a specific antibody to the mouse aromatase, immunoreactivity was localized
      in the neural soma and neurites in hypothalamic cultures. Additionally more male
      foetal hypothalamus neurones express aromatase than in the female. Testosterone
      increases aromatase activity in parallel with a greater number of aromatase
      immunoreactive neurones. Testosterone also increases soma size, neurite length,
      and branching of cultured hypothalamic neurones. The neuronal aromatase activity
      appears to be sensitive to the inductive effects of androgen only during the
      later stages of foetal development. Endogenous inhibitors of the aromatase are
      also likely to have a regulatory role. This work suggests that regulation of a
      network of aromatase neurones, sensitive to the hormonal environment of the
      hypothalamus, may determine when oestrogens are available for neurotrophic
      effects underlying brain differentiation.

PMID- 10418981
TI  - EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the
      mammary gland and endometrium.
AB  - Breast cancer is the most frequent cancer in women while it is the second cause
      of cancer death. Estrogens are well recognized to play the predominant role in
      breast cancer development and growth and much efforts have been devoted to the
      blockade of estrogen formation and action. The most widely used therapy of breast
      cancer which has shown benefits at all stages of the disease is the use of the
      antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and
      antagonist activity and major efforts have been devoted to the development of
      compounds having pure antiestrogenic activity in the mammary gland and
      endometrium. Such a compound would avoid the problem of stimulation of the
      endometrium and the risk of endometrial carcinoma. We have thus synthesized an
      orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM
      800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is
      the compound having the highest affinity for the estrogen receptor, including
      estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen,
      raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent
      inhibitory activity on both ER alpha and ER beta compared to any of the other
      antiestrogens tested. An important aspect of EM-652 is that it inhibits both the
      AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of
      hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen
      receptors. AF1 activity is constitutive, ligand-independent and is responsible
      for mediation of the activity of growth factors and of the ras oncogene and MAP
      kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER alpha
      and ER beta and blocks SRC-1-stimulated activity of the two receptors. EM-652 was
      also found to block the recruitment of SRC-1 at AF1 of ER beta, this ligand
      independent activation of AF1 being closely related to phosphorylation of the
      steroid receptors by protein kinase. Most importantly, the antiestrogen
      hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity
      while the pure antiestrogen EM-652 completely abolishes this effect, thus
      strengthening the need to use pure antiestrogens in breast cancer therapy in
      order to control all known aspects of ER-regulated gene expression. In fact, the
      absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of
      tamoxifen observed up to 5 years become negative at longer time intervals and why
      resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown
      to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary
      carcinoma in the rat, a well-recognized model of human breast cancer. It is of
      interest that the addition of dehydroepiandrosterone, a precursor of androgens,
      to EM-800, led to complete inhibition of tumor development in this model. Not
      only the development, but also the growth of established DMBA-induced mammary
      carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also
      observed when medroxyprogesterone was added to treatment with EM-800. Uterine
      size was reduced to castration levels in the groups of animals treated with EM
      800. An almost complete disappearance of estrogen receptors was observed in the
      uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most
      potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7
      and T-47D cells in vitro when compared with ICI 182780, ICI 164384,
      hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no
      stimulatory effect on the basal levels of cell proliferation in the absence of E2
      while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal
      growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of
      the percentage of cycling cancer cells. (ABSTRACT TRUNCATED)

PMID- 10418983
TI  - Progesterone as a neurosteroid: synthesis and actions in rat glial cells.
AB  - The central nervous system (CNS) and the peripheral nervous system (PNS) are
      targets for steroid hormones where they regulate important neuronal functions.
      Some steroid hormones are synthesized within the nervous system, either de novo
      from cholesterol, or by the metabolism of precursors originating from the
      circulation, and they were termed 'neurosteroids'. The sex steroid progesterone
      can also be considered as a neurosteroid since its synthesis was demonstrated in
      rat glial cell cultures of the CNS (oligodendrocytes and astrocytes) and of the
      PNS (Schwann cells). Both types of glial cells express steroid hormone receptors,
      ER, GR and PR. As in target tissue, e.g. the uterus, PR is estrogen-inducible in
      brain glial cell cultures. In the PNS, similar PR-induction could not be seen in
      pure Schwann cells derived from sciatic nerves. However, a significant PR
      induction by estradiol was demonstrated in Schwann cells cocultured with dorsal
      root ganglia (DRG), and we will present evidence that neuronal signal(s) are
      required for this estrogen-mediated PR-induction. Progesterone has multiple
      effects on glial cells, it influences growth, differentiation and increases the
      expression of myelin-specific proteins in oligodendrocytes, and potentiates the
      formation of new myelin sheaths by Schwann cells in vivo. Progesterone and
      progesterone analogues also promotes myelination of DRG-Neurites in tissue
      culture, strongly suggesting a role for this neurosteroid in myelinating
      processes in the CNS and in the PNS.

PMID- 10418984
TI  - Prenatal stress and glucocorticoid effects on the developing gender-related
      brain.
AB  - Hormonal and neurotransmitter environment of nondifferentiated cells in the
      developing brain determines many of gender-specific behavioural and
      neuroendocrine functions. Early postnatal and long-term effects of maternal
      stress or prenatal glucocorticoid on sex-related peculiarities of the brain
      morphology, biogenic monoamine turnover, testosterone metabolism, hypothalamic
      noradrenaline (NA) and adrenocortical responses to an acute stress were studied
      in Wistar rat offsprings. Maternal stress (1 h immobilization daily for
      gestational days 15-21) prevented development of sexual dimorphism in neuronal
      cell nuclei volumes in suprachiazmatic nucleus (SCN) in 10 day old pups. That was
      associated with a disappearance of male female differences in NA and 5
      hydroxytryptamine turnover in the preoptic area (POA) and dopamine (DA) turnover
      in the mediobasal hypothalamus (MBH) by decreasing them in male pups.
      Hydrocortisone acetate (5 mg daily during the last week of pregnancy) produced
      changes in NA turnover in the POA of males and females which were quite similar
      to those after maternal stress. Changes in aromatase and 5alpha-reductase
      activities in the POA of male pups were quite opposite as affected by maternal
      stress or prenatal glucocorticoid. Sexual differences in 5alpha-reductase
      activity in the MBH appeared due to its increase in prenatally stressed male
      pups. In contrast to adult males, in adult females maternal stress did not
      restrict hypothalamic NA and blood plasma corticosterone response to acute stress
      (1 h immobilization). Our findings on morphology and functions of gender-related
      developing brain areas stand in correlation with modifying effects of maternal
      stress and prenatal glucocorticoid on behavior and neuroendocrine regulations.

PMID- 10418985
TI  - Androgen-activating enzymes in the central nervous system.
AB  - In the rat brain, several steroids can be converted by specific enzymes to either
      more potent compounds or to derivatives showing new biological effects. One of
      the most studied enzyme is the 5alpha-reductase (5alpha-R), which acts on 3keto
      delta4 steroids. In males, testosterone is the main substrate and gives rise to
      the most potent natural androgen dihydrotestosterone. In females, progesterone is
      reduced to dihydroprogesterone, a precursor of allopregnanolone, a natural
      anxiolytic/anesthetic steroid. Other substrates are some gluco- and minero
      corticoids. Two isoforms of the 5alpha-R, with limited degree of homology, have
      been cloned: 5alpha-R type 1 and type 2. The 5alpha-R type 1 possesses low
      affinity for the various substrates and is widely distributed in the body, with
      the highest levels in the liver; in the brain, this isoform is expressed
      throughout life and does not appear to be controlled by androgens. 5Alpha-R type
      1 in the rat brain is mainly concentrated in myelin membranes, where it might be
      involved in the catabolism of potentially neurotoxic steroids. The 5alpha-R type
      2 shows high affinity for the various substrates, a peculiar pH optimum at acidic
      values and is localized in androgen-dependent structures. In the rat brain, the
      type 2 isoform is expressed at high levels only in the perinatal period and is
      controlled by androgens, at least in males. In adulthood, the type 2 gene appears
      to be specifically expressed in localised brain regions, like the hypothalamus
      and the hippocampus. The 5alpha-R type 2 is present in the GT1 cells, a model of
      LHRH-secreting neurons. These cells also contain the androgen receptor, which is
      probably involved in the central negative feedback effect exerted by androgens on
      the hypothalamic-pituitary-gonadal axis. The physiological significance of these
      and additional data will be discussed.

PMID- 10418986
TI  - In vitro studies on the role of the peripheral-type benzodiazepine receptor in
      steroidogenesis.
AB  - In vitro studies using isolated cells, mitochondria and submitochondrial
      fractions demonstrated that in steroid synthesizing cells, the peripheral-type
      benzodiazepine receptor (PBR) is an outer mitochondrial membrane protein,
      preferentially located in the outer/inner membrane contact sites, involved in the
      regulation of cholesterol transport from the outer to the inner mitochondrial
      membrane, the rate-determining step in steroid biosynthesis. Mitochondrial PBR
      ligand binding characteristics and topography are sensitive to hormone treatment
      suggesting a role of PBR in the regulation of hormone-mediated steroidogenesis.
      Targeted disruption of the PBR gene in Leydig cells in vitro resulted in the
      arrest of cholesterol transport into mitochondria and steroid formation;
      transfection of the mutant cells with a PBR cDNA rescued steroidogenesis
      demonstrating an obligatory role for PBR in cholesterol transport. Molecular
      modeling of PBR suggested that it might function as a channel for cholesterol.
      This hypothesis was tested in a bacterial system devoid of PBR and cholesterol.
      Cholesterol uptake and transport by these cells was induced upon PBR expression.
      Amino acid deletion followed by site-directed mutagenesis studies and expression
      of mutant PBRs demonstrated the presence in the cytoplasmic carboxy-terminus of
      the receptor of a cholesterol recognition/interaction amino acid consensus
      sequence. This amino acid sequence may help for recruiting the cholesterol coming
      from intracellular sites to the mitochondria.

PMID- 10418987
TI  - Molecular pathology and mechanism of action of the steroidogenic acute regulatory
      protein, StAR.
AB  - The first and rate-limiting step in the synthesis of all steroid hormones is the
      conversion of cholesterol to pregnenolone by the mitochondrial enzyme, P450scc.
      Tropic hormones such ACTH and gonadotropins induce steroidogenesis via cAMP by
      elaborating intracellular cAMP which stimulates P450scc activity in two distinct
      ways. Chronic stimulation (h to days) occurs through the induction of P450scc
      gene transcription leading to increased P450scc protein and consequent increased
      steroidogenic capacity. Acute regulation, over minutes, occurs through the
      phosphorylation of preexisting StAR and the rapid synthesis of new StAR protein.
      StAR, the steroidogenic acute regulatory protein, increases the flow of
      cholesterol into mitochondria, thus regulating substrate availability to whatever
      amount of P450scc is available. In the absence of StAR, up to 14% of maximal StAR
      induced level of steroidogenesis persists as StAR-independent steroidogenesis.
      Congenital lipoid adrenal hyperplasia, an autosomal recessive disorder in which
      conversion of cholesterol to pregnenolone is severely impaired, results in female
      genitalia in 46,XY genetic males, variable onset of a severe salt-losing crisis
      in the first months of life, but normal feminization and cyclical vaginal
      bleeding in 46,XX females. Lipoid CAH was once thought to be due to P450scc
      mutations, but in fact homozygous P450scc mutations cannot exist in human beings
      as they would prohibit placental progesterone production, causing spontaneous
      abortion of the affected fetus. Lipoid CAH is caused by StAR mutations, which
      result in tropic hormone-induced intracellular accumulation of cholesterol in the
      adrenals and gonads. Our two-hit model, which considers the persistence of StAR
      independent steroidogenesis and the differences in the fetal and postnatal ages
      at which the testis, adrenal zona glomerulosa, adrenal zona fasciculata and ovary
      are stimulated, predicts and explains all of the various clinical manifestations
      of lipoid CAH. Structure function studies of StAR show that the critical domains
      for biological activity reside in the protein's carboxy-terminus. When the N
      terminal mitochondrial targeting sequences are deleted and the resulting N-62
      StAR remains in the cytoplasm, it retains the ability to stimulate
      steroidogenesis both in intact cells or when added to isolated mitochondria in
      vitro. These observations suggest that StAR acts on the outer mitochondrial
      membrane to promote sterol translocation to P450scc, and that the importation of
      StAR into mitochondria terminates its action. Data from circular dichroism and
      Fourier-transform infrared spectroscopy show that the mutant StAR proteins in
      lipoid CAH are misfolded, suggesting disrupted interaction with another protein.
      Preliminary data suggest that StAR facilitates cholesterol desorption from
      membranes, stimulating transfer from the outer mitochondrial (donor) membrane to
      the inner mitochondrial (acceptor) membrane.

PMID- 10418988
TI  - Effects of disruption of the mitochondrial electrochemical gradient on
      steroidogenesis and the Steroidogenic Acute Regulatory (StAR) protein.
AB  - The steroidogenic acute regulatory (StAR) protein, which mediates cholesterol
      delivery to the inner mitochondrial membrane and the P450scc enzyme, has been
      shown to require a mitochondrial electrochemical gradient for its activity in
      vitro. To characterize the role of this gradient in cholesterol transfer,
      investigations were conducted in whole cells, utilizing the protonophore carbonyl
      cyanide m-chlorophenylhydrazone (m-CCCP) and the potassium ionophore valinomycin.
      These reagents, respectively, dissipate the mitochondrial electrochemical
      gradient and inner mitochondrial membrane potential. Both MA-10 Leydig tumor cell
      steroidogenesis and mitochondrial import of StAR were inhibited by m-CCCP or
      valinomycin at concentrations which had only minimal effects on P450scc activity.
      m-CCCP also inhibited import and processing of both StAR and the truncated StAR
      mutants, N-19 and C-28, in transfected COS-1 cells. Steroidogenesis induced by
      StAR and N-47, an active N-terminally truncated StAR mutant, was reduced in
      transfected COS-1 cells when treated with m-CCCP. This study shows that StAR
      action requires a membrane potential, which may reflect a functional requirement
      for import of StAR into the mitochondria, or more likely, an unidentified factor
      which is sensitive to ionophore treatment. Furthermore, the ability of N-47 to
      stimulate steroidogenesis in nonsteroidogenic HepG2 liver tumor cells, suggests
      that the mechanism by which StAR acts may be common to many cell types.

PMID- 10418989
TI  - Suppression of gene expression by tethering KRAB domain to promoter of ER target
      genes.
AB  - Estrogens play an important role in the development and progression of breast
      cancer. Although estrogen antagonist treatment often results in the arrest or
      remission of breast cancer growth, most breast cancers recur and become resistant
      to estrogen ablative therapy. The molecular mechanisms underlying these actions
      remain largely undefined. It is hypothesized that tumor cells of an advanced
      stage may develop compensatory pathways to stimulate the expression of estrogen
      receptor (ER) target genes or downstream events, independent of estrogen action.
      In this study, we developed a chimeric repressor to turn off ER target genes with
      the aim of directly investigating the role of ER target genes in tumor
      progression. The chimeric repressor contains the ER DNA-binding domain that
      recognizes estrogen response elements (EREs), a Krupple-associated box (KRAB)
      repressor domain which silences target genes when tethered to their promoter
      regions and a truncated progesterone ligand-binding domain which responds only to
      the exogenous synthetic ligand, RU486. The ability of the chimeric repressor to
      block ER mediated transcription was assessed in transient transfection assays. ER
      induced reporter activity was inhibited by the repressor in a dose-dependent
      manner, with the maximum effect of more than 80% reduction. The inhibitory
      activity of the chimeric repressor was tightly under the control of RU486.
      Effective suppression by the repressor on the natural promoter of ER target gene,
      complement factor 3 (C3), was also observed. The inhibitory activity was specific
      to ER, since the repressor has no effect on other nuclear receptor systems
      tested. Furthermore, the repressor could inhibit the 4-hydroxy-tamoxifen (4OH-T)
      induced ER activity. Taken together, our results demonstrate that the inducible
      repressor we have designed could specifically inhibit ER target gene expression
      in response to an exogenous synthetic ligand. This repressor will provide a
      useful tool to study the role of ER target genes in breast cancer progression and
      it may be potentially useful for gene therapy of breast cancer.

PMID- 10418990
TI  - A comparison of transcriptional activation by ER alpha and ER beta.
AB  - We have compared the ability of ER alpha and ER beta to stimulate transcription
      from a number of reporter genes in different cell lines and demonstrate that the
      activity of AF1 in ER beta is negligible compared with that of ER alpha on ERE
      based reporters. The activity of AF2 in ER alpha and ER beta is similar and this
      is likely to reflect their similar ability to bind coactivators. As a
      consequence, when transcription from a gene depends on both AF1 and AF2 the
      activity of ER alpha greatly exceeds that of ER beta but when AF1 is not required
      ER alpha and ER beta have similar transcriptional activities.

PMID- 10418991
TI  - The therapeutic use of androgens in women.
AB  - Androgens have significant and varied actions in women and there is now
      acknowledgment that women may experience symptoms secondary to androgen
      deficiency. There is also substantial evidence that prudent androgen replacement
      can be effective in relieving both the physical and psychological symptoms of
      androgen insufficiency, and is indicated for clinically affected women.
      Testosterone replacement for women is now available in a variety of formulations.
      It appears to be safe, with the caveat that doses are restricted to the
      'therapeutic' window for androgen replacement in women, such that the beneficial
      effects on wellbeing and quality of life are achieved without incurring
      undesirable virilizing side effects. The predominant symptom of women with
      androgen deficiency is loss of sexual desire. This is not limited to women
      experiencing a surgical menopause but may also be a feature of women who have
      either undergone premature or natural menopause. There is increasing interest in
      other uses of androgen replacement in women that include premenopausal iatrogenic
      androgen deficiency states, glucocorticosteroid-induced bone loss, management of
      wasting syndromes and possibly premenopausal bone loss, premenopausal loss of
      libido and the treatment of the premenstrual syndrome.

PMID- 10418992
TI  - Progestins in the menopause.
AB  - While the benefits of progestin use in hormone replacement therapy (HRT) are well
      recognised as far as endometrial protection is concerned, their risks and
      drawbacks have generated controversial articles. The data related to the
      progestin effect on breast tissue has been interpreted differently from country
      to country. However it has been admitted that, according to the type of progestin
      used, the dose and duration of its application, a predominant antiproliferative
      effect is observed in the human breast cells. As far as breast cancer risk is
      concerned, most epidemiological studies do not suggest any difference between the
      estrogens given alone or combined to progestins in HRT. When the cardiovascular
      risk factors are considered, some molecules with a higher androgenic potency than
      others, attenuate the beneficial effects of estrogens on the lipid profile and
      the vasomotion as well. On the other hand, other progestins devoid of androgenic
      properties do not exert these deleterious effects. The epidemiological data does
      not suggest any negative effect of the progestins administered together with
      estrogens on cardiovascular morbidity or mortality. However, recent results
      suggest that in women with established coronary heart disease (CHD), HRT may not
      protect against further heart attacks, when the progestin selected possesses
      androgenic properties. Complying with the classic contra indications of HRT and
      selecting molecules devoid of estrogenic, androgenic, or glucocorticoid effect
      should allow a larger use of the progestins without any major drawback.

PMID- 10418993
TI  - Interactions in the transcriptional regulation exerted by Stat5 and by members of
      the steroid hormone receptor family.
AB  - The pathways which connect extracellular signals with the regulation of the
      activity of transcription factors are being investigated in molecular detail.
      Extensive progress has been made in the description of the mode of action of
      steroid hormones and of cytokines. Steroid hormones associate intracellularly
      with latent receptor molecules, cause the dissociation of masking proteins, the
      dimerization of receptors, and their binding to specific hormone response
      elements in the promoters of target genes. Cytokines also activate latent
      transcription factors (Stats--signal transducers and activators of
      transcription), but act through an enzymatic mechanism. Tyrosine kinases
      associated with the transmembrane cytokine receptors phosphorylate Stat
      molecules. The phosphorylated monomers dimerize and assume specific DNA binding
      ability. Both classes of transcription factors bind to different response
      elements and regulate different target genes and both signals, cytokines and
      steroid hormones, can affect growth differentiation and homeostasis of different
      cell types. Here, we describe that Stat5, a molecule activated by several
      essential cytokines, functionally interacts with members of the steroid receptor
      family. We find that glucocorticoid receptor, mineralocorticoid receptor and
      progesterone receptor synergize with Stat5 in the induction of the transcription
      from the beta-casein gene promoter. The estrogen receptor diminishes Stat5
      mediated induction and the androgen receptor has no effect. Conversely, Stat5
      negatively interferes with glucocorticoid receptor, mineralocorticoid receptor
      and progesterone receptor induced transcription from the MMTV LTR and the
      estrogen receptor induced transcription from an ERE-containing promoter.

PMID- 10418994
TI  - Aromatase and its inhibitors.
AB  - Inhibitors of aromatase (estrogen synthetase) have been developed as treatment
      for postmenopausal breast cancer. Both steroidal substrate analogs, type I
      inhibitors, which inactivate the enzyme and non-steroidal competitive reversible,
      type II inhibitors, are now available. 4-hydroxyandrostenedione (4-OHA), the
      first selective aromatase inhibitor, has been shown to reduce serum estrogen
      concentrations and cause complete and partial responses in approximately 25% of
      patients with hormone responsive disease who have relapsed from previous
      endocrine treatment. Letrozole (CGS 20, 269) and anastrozole (ZN 1033) have been
      recently approved for treatment. Both suppress serum estrogen levels to the limit
      of assay detection. Letrozole has been shown to be significantly superior to
      megace in overall response rates and time to treatment failure, whereas
      anastrozole was found to improve survival in comparison to megace. Both were
      better tolerated than the latter. The potential of aromatase within the breast as
      a significant source of estrogen mediating tumor proliferation and which might
      determine the outcome of inhibitor treatment was explored. Using
      immunocytochemistry and in situ hybridization, aromatase and mRNAarom was
      detected mainly in the epithelial cells of the terminal ductal lobular units
      (TDLU) of the normal breast and also in breast tumor epithelial cells as well as
      some stromal cells. Increase in proliferation, measured by increased thymidine
      incorporation into DNA and by PCNA immunostaining in response to testosterone was
      observed in histocultures of breast cancer samples. This effect could be
      inhibited by 4-OHA and implies that intratumoral aromatase has functional
      significance. An intratumoral aromatase model in the ovariectomized nude mouse
      was developed which simulated the hormone responsive postmenopausal breast cancer
      patient. This model also allows evaluation of the efficacy of aromatase
      inhibitors and antiestrogens in tumors of estrogen receptor positive, human
      breast carcinoma cells transfected with the human aromatase gene. Thus, the cells
      synthesized estrogen which stimulated tumor formation. Both aromatase inhibitors
      and antiestrogens were effective in suppressing tumor growth in this model.
      However, letrozole was more effective than tamoxifen. When the aromatase
      inhibitors were combined with tamoxifen, tumor growth was suppressed to about the
      same extent as with the aromatase inhibitors alone. Thus, there was no additive
      or synergistic effects of combining tamoxifen with aromatase inhibitors. This
      suggests that sequential treatment with these agents is likely to be more
      beneficial to the patient in terms of longer response to treatment.

PMID- 10418995
TI  - Molecular determinants of steroid recognition and catalysis in aldo-keto
      reductases. Lessons from 3alpha-hydroxysteroid dehydrogenase.
AB  - Hydroxysteroid Dehydrogenases (HSDs) regulate the occupancy of steroid hormone
      receptors by converting active steroid hormones into their cognate inactive
      metabolites. HSDs belong to either the Short-chain Dehydrogenase/Reductases
      (SDRs) or the Aldo-Keto Reductases (AKRs). The AKRs include virtually all
      mammalian 3alpha-HSDs, Type 5 17beta-HSD, ovarian 20alpha-HSDs as well as the
      steroid 5beta-reductases. Selective inhibitors of 3alpha-HSD isoforms could
      control occupancy of the androgen and GABA(A) receptors, while broader based AKR
      inhibitors targeting 3alpha-HSD, 20alpha-HSD and prostaglandin F2alpha synthase
      could maintain pregnancy. We have determined three X-ray crystal structures of
      rat liver 3alpha-HSD, a representative AKR. These structures are of the apoenzyme
      (E), the binary-complex (E.NADP-), and the ternary complex
      (E.NADP+.testosterone). These structures are being used with site-directed
      mutagenesis to define the molecular determinants of steroid recognition and
      catalysis as a first step in rational inhibitor design. A conserved catalytic
      tetrad (Tyr55, Lys84, His117 and Asp50) participates in a 'proton-relay' in which
      Tyr55 acts as general acid/base catalyst. Its bifunctionality relies on
      contributions from His117 and Lys84 which alter the pKb and pKa, respectively of
      this residue. Point mutation of the tetrad results in different enzymatic
      activities. H117E mutants display 5beta-reductase activity while Y55F and Y55S
      mutants retain quinone reductase activity. Our results suggest that different
      transition states are involved in these reaction mechanisms. The ternary complex
      structure shows that the mature steroid binding pocket is comprised of ten
      residues recruited from five loops, and that there is significant movement of a C
      terminal loop on binding ligand. Mutagenesis of pocket tryptophans shows that
      steroid substrates and classes of nonsteroidal inhibitors exhibit different
      binding modes which may reflect ligand-induced loop movement. Exploitation of
      these findings using steroidal and nonsteroidal mechanism based inactivators may
      lead to selective and broad based AKR inhibitors.

PMID- 10418997
TI  - Current status of androgen suppression and radiotherapy for patients with
      prostate cancer.
AB  - Analogous to the impact of anti-estrogen therapy in breast cancer, anti-androgen
      therapy may have a greater impact on the castrate male with non-metastatic
      disease. The use of castration or a LHRH drug alone, does not appear to
      adequately suppress intra-prostatic DHT (Dihydrotestosterone) levels. Normal
      prostate elements appear to be more efficient than metastatic elements at
      converting DHT precursors to active DHT. Thus, blocking this step may be more
      critical for clinically localized disease. Laverdiere et al. reported a 2 year
      positive (+) biopsy rate of 65% with XRT alone compared to 28% when 3 months of
      NHT preceded radiotherapy, but 5% if NHT was continued for a total of 10.5 months
      of combined androgen blockade (CAB). Bolla et al. incorporated one month of NHT
      prior to XRT followed by 3 years of an LHRH drug. An improvement in local
      control, disease free survival and overall survival of nearly 20% was noted at 5
      years. Thus far, these important studies demonstrate that a survival benefit may
      require long term adjuvant hormonal therapy. There is a need for further studies
      to define the optimal timing and duration of CAB and the role of XRT. Long term
      data recently provided by the Radiation Therapy Oncology Group (RTOG) may provide
      insights into criteria for defining which patients are likely to benefit the most
      from long term CAB.

PMID- 10418996
TI  - Recent advances in the development of steroid sulphatase inhibitors.
AB  - Inhibition of steroid sulphatase is now an important target for the development
      of new drugs for the treatment of women with endocrine-dependent breast tumours.
      The first potent sulphatase inhibitor identified, oestrone-3-O-sulphamate (EMATE)
      proved. unexpectedly, to be oestrogenic. A number of strategies have therefore
      been adopted to design and synthesize a non-oestrogenic inhibitor. For this, a
      number of modifications have been made to the A and D rings of the oestrone
      nucleus. 2 Methoxyoestrone-3-O-sulphamate, while having similar in vitro and in
      vivo sulphatase inhibitory potency to that of EMATE, was devoid of oestrogenic
      activity when tested at 2 mg/kg in an ovariectomised rat uterine weight gain
      assay. 17-Deoxyoestrone-3-O-sulphamate was also a potent steroid sulphatase
      inhibitor and while it was devoid of oestrogenic activity when tested at 0.1
      mg/kg, did stimulate uterine growth at 1.0 mg/kg. As an alternative approach to
      the use of steroid-based inhibitors a number of single ring, bicyclic non-fused
      ring, and two fused ring sulphamate analogues were designed, synthesized and
      tested for their ability to inhibit steroid sulphatase activity. In general,
      although the single ring and bicyclic non-fused ring sulphamate analogues could
      inhibit sulphatase activity, they were considerably less potent than EMATE. The
      mono- and bis-sulphamate derivatives of 5,7-dihydroxyisoflavone were relatively
      potent, inhibiting in vivo steroid sulphatase activity by 62 and 81% respectively
      at a single oral dose of 10 mg/kg. A study of the structure-activity relationship
      of a series of coumarin-based sulphamates has led to the development of a number
      of potent non-steroidal inhibitors, one of which has a similar potency to that of
      EMATE. The identification of potent steroid- and non-steroid-based sulphatase
      inhibitors will enable the therapeutic value of this therapy to be examined in
      the near future.

PMID- 10418998
TI  - In vivo function of VDR in gene expression-VDR knock-out mice.
AB  - Vitamin D exerts many biological actions through nuclear vitamin D receptor (VDR)
      mediated gene expression. The transactivation function of VDR is activated by
      binding 1alpha,25-dihydroxyvitamin D3[1alpha,25(OH)2D3], an active form of
      vitamin D. Conversion from 25(OH)D3 is finely regulated in kidney by 25(OH)D3
      1alpha-hydroxylase[25(OH)D 1alpha-hydroxylase], keeping serum levels of
      1alpha,25(OH)2D3 constant. Deficiency of vitamin D and mutations in the genes
      like VDR (type II genetic rickets) are known to cause rickets like lowered serum
      calcium, alopecia and impaired bone formation. However, the molecular basis of
      vitamin D VDR system in the vitamin D action in intact animals remained to be
      established. In addition, the 1alpha-hydroxylase gene from any species had not
      yet been cloned, irrespective of its biological significance and putative link to
      the type I genetic rickets. We generated VDR-deficient mice (VDR KO mice). VDR KO
      mice grew up normally until weaning, but after weaning they developed abnormality
      like the type II rickets patients. These results demonstrated indispensability of
      vitamin D-VDR system in mineral and bone metabolism only in post-weaning life.
      Using a newly developed cloning system, we cloned the cDNA encoding a novel P450
      enzyme, mouse and human 1alpha-hydroxylase. The study in VDR KO mice demonstrated
      the function of liganded VDR in the negative feed-back regulation of
      1alpha,25(OH)2D3 production. Finally, from the analysis of type I rickets
      patients, we found missense genetic mutations in 1alpha-hydroxylase, leading to
      the conclusion that this gene is responsible for the type I rickets.

PMID- 10418999
TI  - Mutagenesis of the glucocorticoid receptor in mice.
AB  - The glucocorticoid receptor is an ubiquitously expressed transcription factor
      involved in the regulation of many different physiological processes. Activated
      by glucocorticoids the receptor regulates transcription positively or negatively
      either by direct binding to DNA or by protein protein interactions. In order to
      define the role of the receptor during development and in physiology several
      mutations have been generated in the mouse. Mice with a disrupted glucocorticoid
      receptor gene die shortly after birth due to respiratory failure indicating an
      important role of the receptor in lung function. Transcription of genes encoding
      gluconeogenic enzymes in the liver is decreased, proliferation of erythroid
      progenitors is impaired and the HPA axis is strongly upregulated. To analyze
      molecular mechanisms of glucocorticoid receptor action in vivo a point mutation
      has been introduced into the mouse genome which allows to separate DNA-binding
      dependent from DNA-binding-independent actions of the receptor. Mice homozygous
      for the point mutation survive indicating that DNA-binding of the receptor is not
      required for survival. Induction of glucoconegenic enzymes and proliferation of
      erythroid progenitors however is impaired. Interestingly, repression of
      corticotropin releasing factor (CRF) synthesis is maintained, whereas
      proopiomelanocortin (POMC) expression is upregulated. Since mice with a disrupted
      glucocorticoid receptor gene die shortly after birth attempts using the Cre/loxP
      recombination system are made to bypass early lethality and to study the function
      of the receptor in defined cell types of adult animals.

PMID- 10419000
TI  - Heritability and the risk of developing androgen excess.
AB  - Androgen excess is one of the most common reproductive endocrinologic
      abnormalities of women. Excluding specific etiologies such as androgen-secreting
      neoplasms and non-classic adrenal hyperplasia, the majority of androgen excess is
      functional in nature. It is clear that studies concerned with the heritability of
      this disorder greatly depend on how it is defined. Patients with the PolyCystic
      Ovary Syndrome (PCOS) are clearly included. However, we argue that ovulatory
      women with hirsutism and hyperandrogenemia should also be considered as affected
      which, together with PCOS, comprise the population of women we define as having
      Functional Androgen Excess (FAE). Our data, and that of others, suggests that
      FAE/PCOS is a familial disorder, with a single autosomal dominant gene effect and
      a variable phenotype. Inheritance appears to be equally probable from the
      maternal as from the paternal side of the family. Nonetheless, our data also
      suggests that the affection rate among mothers is less than expected, which may
      be due to decreased fertility of affected mothers, or to our inability to detect
      the disorder in older, menopausal or hormonally treated individuals. Finally, it
      appears that a woman's risk for developing PCOS is approximately 40% if her
      sister is affected. While considering FAE/PCOS to be a dominant genetic disorder
      with a high degree of expressivity, its highly variable phenotype suggests that
      besides a single genetic mutation other factors must be contributing to the
      development and expression of the disorder. These factors may include
      environmental influences (such as fat and carbohydrate consumption) exercise
      level, peripubertal stress and/or hormonal exposure; and additional genetic
      defects, such as those that regulate insulin secretion or determine body type.

PMID- 10419001
TI  - Polycystic ovary syndrome: evidence for a primary disorder of ovarian
      steroidogenesis.
AB  - Polycystic ovary syndrome (PCOS) is a very common endocrinopathy of uncertain
      aetiology in which the most consistent biochemical abnormality is hypersecretion
      of androgens. In this review, evidence is presented to support the view that a
      primary abnormality of ovarian androgen biosynthesis provides the basis for the
      syndrome. PCOS is a familiar disorder and we demonstrate, in molecular genetic
      studies, that CYP11a, the gene coding for P450 side chain cleavage, is a key
      susceptibility locus for development of hyperandrogenism.

PMID- 10419002
TI  - Effects of hyperinsulinemia on vascular blood flows in experimental obesity.
AB  - Human obesity, which is very common in Polycystic Ovaries Syndrome and in "X
      Syndrome", constitutes an insulin-resistance state in which multiple clinical,
      biochemical and hemodynamic alterations coexist. Insulin resistance in the obese
      has been recently associated with an endothelial dysfunction. To investigate the
      possibility that clinical and metabolic derangements related to insulin
      resistance could induce changes in vascular blood flows, we have studied the
      levels of mesenteric (MBF), renal (RBF) and femoral (FBF) blood flows in Beagle
      dogs kept for 2 years on a normal (control group) or high fat diet (obese group).
      This experimental model exhibits many of the abnormalities with the human
      syndrome. In addition, we have tested the effects of chronic treatment with
      captopril (capto group) in monotherapy or in association with pravastatin
      (prava+capto group) on the hemodynamic changes associated with this diet. After
      the two year follow-up, Transonic flow probes were placed around the three
      arteries to measure basal blood flows and their response to a hyperinsulinemic
      normoglycemic test in anesthetized animals. During this test the degree of
      insulin sensitivity was estimated. In association with higher body weight, blood
      pressure, insulin resistance, and fasting levels of insulin and total
      cholesterol, the obese group exhibited decreased basal levels of FBF and a
      greater femoral vasoconstriction during hyperinsulinism (P < 0.05 vs control).
      Combined therapy with captopril and pravastatin ameliorated the reduction in
      basal FBF and hyperinsulinism-induced vasoconstriction (P < 0.05), in addition to
      the beneficial effects on insulin sensitivity, and clinical and metabolic
      parameters. Synergistic beneficial effects of both drugs on lipid and
      carbohydrate profiles may account for this positive outcome, by attenuating the
      atherogenic process associated with this model.

PMID- 10419004
TI  - Estrone sulfatase versus estrone sulfotransferase in human breast cancer:
      potential clinical applications.
AB  - Estrone sulfate (E1S) is concentrated in high levels in human breast cancer
      tissue. The values are particularly high in postmenopausal women and many times
      those circulating in the plasma. Also, the tissular concentration of this
      conjugate are significantly higher in tumoural tissue than in the area of the
      breast considered as normal. The enzyme which hydrolyzes E1S: sulfatase, as well
      as the enzyme which biosynthesises this conjugate: sulfotransferase, are present
      in significant concentrations in breast cancer tissue. Consequently, E1S is a
      balance between the activities of the two enzymes. As breast cancer tissue has
      all the enzymes necessary for the synthesis of estradiol (E2), and the formation
      of E2 from E1S 'via sulfatase' is the main pathway, it was very attractive to
      explore inhibitory agents of this enzyme. It was observed that different
      substances including antiestrogens (4-hydroxytamoxifen, ICI 164,384) and various
      progestins (promegestone, nomegestrol acetate, medrogestone) as well as Org OD14
      (tibolone) can block the sulfatase activity. In addition, it was demonstrated
      that different progestins (medrogestone, nomegestrol acetate, TX-525) and org
      OD14 can stimulate the sulfotransferase activity for the formation of the
      biologically inactive E1S. It is concluded that the inhibition of sulfatase and
      the stimulation of sulfotransferase activity can open interesting possibilities
      to explore these effects in patients with breast cancer.

PMID- 10419003
TI  - Alterations in gonadal steroidogenesis in individuals expressing a common genetic
      variant of luteinizing hormone.
AB  - Some pathologies of the pituitary-gonadal function have recently been found to be
      due to mutations of the gonadotropin or gonadotropin receptor genes. Although
      these conditions are extremely rare, they are very informative, by elucidating
      some less well characterized facets of normal gonadotropin function and the
      molecular pathogenesis of disturbances in sexual differentiation and fertility.
      In contrast, there is a common polymorphism in the Luteinizing Hormone (LH) beta
      subunit gene, where two point mutations cause two alterations in the amino acid
      sequence (Trp8 --> Arg and Ile15 --> Thr) and introduce an extra glycosylation
      signal to Asn13. The carriers of this variant gene are largely healthy, but
      certain mild differences in their gonadal function have been found, as reflected
      by alterations in gonadal steroidogenesis, pubertal development and
      predisposition to diseases such as infertility, polycystic ovarian syndrome, and
      breast and prostatic cancer. The purpose of this chapter is to review the current
      knowledge of the occurrence, special functional features and clinical correlates
      of this LH variant.

PMID- 10419005
TI  - Intratumoral levels of estrogens in breast cancer.
AB  - Breast cancer tissue is an endocrine organ and particularly the estrogen
      biosynthetic properties of this tissue have been well studied. The concentration
      of estradiol in breast cancer tissue from postmenopausal patients is considerably
      higher than that in the circulation and appears to depend largely on local
      production. Androgenic precursor steroids are abundantly present, but estrogen
      storage pools like fatty acid derivatives appear to be less important than
      initially thought. New, potent and highly specific aromatase inhibitors
      effectively inhibit peripheral conversion of androgens to estrogens (Cancer Res.
      53: 4563, 1993) as well as intratumour aromatase, median aromatase activity being
      89% lower in the tissue from patients pretreated with aromatase inhibitor 7 days
      prior to surgery (P < 0.001). Also the intratissue concentrations of estrogens
      were decreased (64% and 80% reduction, respectively for estrone and estradiol; P
      = 0.001 and <0.05; Cancer Res. 57: 2109, 1997). These results illustrate that
      intratissue estrogen biosynthesis is effectively inhibited by the new generation
      of aromatase inhibitors. The pathophysiological consequences of this finding are
      currently under study.

PMID- 10419006
TI  - Estrogen, alcohol and breast cancer risk.
AB  - Estrogen replacement has been used for many years to reverse the hypoestrogenic
      symptoms of menopause and prevent osteoporosis. Studies have found that estrogen
      replacement also decreases cardiovascular risk. In addition, social use of
      alcohol has been found to decrease cardiovascular risk. Therefore, both estrogen
      replacement therapy and alcohol use have been proposed to have cardiovascular
      benefits, and are often used in combination. Epidemiologic evidence indicates
      that estrogen replacement therapy after menopause increases breast cancer risk.
      Regular alcohol consumption is also associated with increase in risk. However,
      interactions between the two are poorly understood. In addition, if alcohol
      alters circulating estrogen levels in estrogen users, this may have implications
      in terms of altering the risks:benefit ratio of estrogen replacement in an
      undesirable direction. For example, there are data suggesting that the use of
      both alcohol and estrogen may increase breast cancer risk more than the use of
      either one alone. Data support both acute and chronic effects of alcohol in
      raising circulating estrogen levels in premenopausal women on no hormonal
      medications. In postmenopausal women studies focusing on acute effects of alcohol
      on estrogen metabolism indicate that alcohol has a much more pronounced effect in
      women using estrogen replacement than in those who do not. Studies evaluating
      chronic effects of alcohol ingestion on circulating estrogens in postmenopausal
      women are needed.

PMID- 10419007
TI  - Mechanisms of androgen receptor activation and function.
AB  - Androgens play a crucial role in several stages of male development and in the
      maintenance of the male phenotype. Androgens act in their target cells via an
      interaction with the androgen receptor, resulting in direct regulation of gene
      expression. The androgen receptor is a phosphoprotein and modulation of the
      phosphorylation status of the receptor influences ligand-binding and consequently
      transcription activation of androgen responsive genes. Androgen binding induces a
      conformational change in the ligand-binding domain, accompanied by additional
      receptor phosphorylation. Subsequently the liganded androgen receptor interacts
      with specific androgen response elements in the regulatory regions of androgen
      target genes, resulting in stimulation of gene expression. Anti-androgens induce
      a different conformational change of the ligand-binding domain, which does not or
      only partially result in stimulation of transactivation. Interestingly, different
      anti-androgens can induce different inactive conformations of the androgen
      receptor ligand-binding domain. Recent evidence strongly supports a ligand
      dependent functional interaction between the ligand-binding domain and the NH2
      terminal transactivating domain of the androgen receptor. Two regions in the NH2
      terminal domain are involved in this interaction, whereas in the ligand-binding
      domain the AF-2 AD core region is involved.

PMID- 10419008
TI  - Molecular defects of the androgen receptor.
AB  - Defects of the androgen receptor cause a wide spectrum of abnormalities of
      phenotypic male development, ranging from individuals with mild defects of
      virilization to those with complete female phenotypes. In parallel with this
      phenotypic spectrum, a large number of different mutations have been identified
      that alter the synthesis or functional activity of the receptor protein. In many
      instances, the genetic mutations identified lead to an absence of the intact,
      full-length receptor protein. Such defects (splicing defects, termination codons,
      partial or complete gene deletions) invariably result in the phenotype of
      complete androgen insensitivity (complete testicular feminization). By contrast,
      single amino acid substitutions in the androgen receptor protein can result in
      the entire phenotypic spectrum of androgen resistant phenotypes and provide far
      more information on the functional organization of the receptor protein. Amino
      acid substitutions in different segments of the AR open-reading frame disturb AR
      function by distinct mechanisms. Substitutions in the DNA binding domain of the
      receptor appear to comprise a relatively homogeneous group. These substitutions
      impair the capacity of the receptor to bind to specific DNA sequence elements and
      to modulate the function of responsive genes. Amino acid substitutions in the
      hormone-binding domain of the receptor have a more varied effect on receptor
      function. In some instances, the resulting defect is obvious and causes an
      inability of the receptor to bind hormone. In other instances, the effect is
      subtler, and may result in the production of a receptor protein that displays
      qualitative abnormalities of hormone binding or from which hormone dissociates
      more rapidly. Often it is not possible to correlate the type of binding defect
      with the phenotype that is observed. Instead, it is necessary to measure the
      capacity of the receptor that is synthesized in functional assays in order to
      discern any type of correlation with phenotype. Finally, two types of androgen
      receptor mutation do not fit such a categorization. The first of these--the
      glutamine repeat expansion that is observed in spinal and bulbar muscular atrophy
      -leads to a reduction of receptor function that can be measured in heterologous
      cells or in fibroblasts established from such patients. The expression of ARs
      containing such expanded repeats in men is associated with a degeneration of
      motor neurons in the spinal cords of affected patients. Likewise, the alterations
      of androgen receptor structure that have been detected in advanced forms of
      prostate cancer also behave as gain-of-function mutations. In this latter type of
      mutation, the exquisite specificity of the normal androgen receptor is relaxed
      and the mutant receptors can be activated by a variety of steroidal and non
      steroidal ligands.

PMID- 10419009
TI  - Human Ad4BP/SF-1 and its related nuclear receptor.
AB  - Ad4BP (or SF-1) is an essential transcriptional factor for steroidogenesis as
      well as for the development of the reproductive axis. We elucidated the structure
      of the human Ad4BP gene. The spliced variants of Ad4BP gene, ELP1 and ELP2 in
      mice, are unlikely to be present in humans since the analysis of the human gene
      revealed an in frame stop codon, 36-bp before the first ATG of Ad4BP. The
      promoter sequence of human Ad4BP, upstream of non-coding exon 1 was highly
      conserved, and E-box was also found to be essential for the transcription of
      human Ad4BP gene. During the process of the human Ad4BP gene cloning, we happened
      to obtain an Ad4BP-related gene, FTZ-F1beta which also belongs to the nuclear
      receptor family. We revealed cDNA structures of rat FTZ-F1beta, and found that
      rat has at least two types of FTZ-F1beta isoforms, which differ only by 21 amino
      acids length in the A/B domain. The tissue distributions of FTZ-F1beta in rat
      examined by RT-PCR, was found to be abundant in liver, pancreas, and
      gastrointestinal tracts. These results suggest that the physiological
      significance of FTZ-F1beta is different from that of Ad4BP.

PMID- 10419010
TI  - Cell-type specificity of human CYP11A1 TATA box.
AB  - Expression of the CYP11A1 (SCC) genes, which encode the enzyme important for the
      first step of steroid biosynthesis, occurs in the adrenal gland and gonads, and
      is stimulated by cAMP. Transfection of serial deletions of the SCC promoter,
      which drives reporter gene expression, showed that a minimal promoter containing
      only the TATA box could direct cAMP-dependent transcription. Transcription factor
      SF1, which binds to a site next to the TATA box, can stimulate basal
      transcription but not cAMP response, either in adrenal cell lines or in COS-1 co
      transfected with the SF1 expression plasmid. These data lead to the conclusion
      that the minimal promoter containing only the TATA box can drive cell type
      specific, cAMP-dependent transcription. Additional experiments replacing the TATA
      sequence of SCC with other TATA sequences suggested that the TATA sequence itself
      is important for this cAMP-dependent transcription.

PMID- 10419011
TI  - Cyclic AMP-independent effects of ACTH on glomerulosa cells of the rat adrenal
      cortex.
AB  - The aim of the present paper is to point out the complexity of ACTH action in
      glomerulosa cells of the adrenal cortex. We demonstrate that the increase in cAMP
      production induced by ACTH is the result of a balance between activation of
      adenylyl cyclase and direct modulation of a PDE2 phosphodiestease activity, an
      effect mediated by inhibition of cGMP content. Moreover, Ca2+ is essential for
      cAMP production and aldosterone secretion, but its exact primary action is not
      clearly determined. We recently described that ACTH activated a chloride channel,
      via the Ras protein, which can be involved in steroidogenesis. ACTH also
      increases tyrosine phosphorylation of several proteins. These data, together with
      those of phospholipase C activation, indicate that ACTH action in the adrenal is
      complex, and most certainly not limited to cAMP production, in particular for the
      low concentrations of the hormone. Some years ago, cAMP was considered to be the
      unique second messenger of ACTH action; now it becomes more and more evident that
      ACTH triggers complex signaling pathways using several second messengers in a
      closely interacting way. The most predominant point is that these signals are
      observed for low concentrations of ACTH.

PMID- 10419012
TI  - Developmental effects of estrogenic chemicals are predicted by an in vitro assay
      incorporating modification of cell uptake by serum.
AB  - Many estrogenic chemicals found in the environment (xenoestrogens) show a lower
      affinity for plasma estrogen binding proteins relative to the natural estrogens
      such as estradiol. These binding proteins, which include alphafetoprotein in rats
      and mice, sex hormone binding globulin in humans, and albumin in all species,
      regulate estrogen uptake into tissues. Therefore, the in vivo estrogenic potency
      relative to estradiol of xenoestrogens that show lower binding to these serum
      proteins will thus be underestimated in assays that compare the potency of
      xenoestrogens to estradiol and do not take serum binding into account. We have
      examined the effects of the binding components in serum on the uptake of a number
      of xenoestrogens into intact MCF-7 human breast cancer cells. Since most
      estrogenic chemicals are not available in radiolabeled form, their uptake is
      determined by competition with [3H]estradiol for binding to estrogen receptors
      (ER) in an 18-h assay. Serum modified access (SMA) of cell uptake of
      xenoestrogens is calculated as the RBA in serum-free-medium divided by the RBA in
      serum, and the bioactive free fraction of xenoestrogen in serum is then also
      calculated. We predicted the concentration of two xenoestrogens, bisphenol A and
      octylphenol, required to alter development of the prostate in male mouse fetuses.
      Whereas octylphenol was predicted to be a more potent estrogen than bisphenol A
      when tested in serum-free medium, our assay predicted that bisphenol A would be
      over 500-times more potent than octylphenol in fetal mice. The finding that
      administration of bisphenol A at a physiologically relevant dose predicted from
      our in vitro assay to pregnant mice from gestation day 11 to 17 increased adult
      prostate weight in male offspring relative to controls (similar to the effect of
      estradiol), while the same doses of octylphenol did not alter prostate
      development, provided support for our hypothesis.

PMID- 10419013
TI  - The role of chloride ions in the regulation of steroidogenesis in rat Leydig
      cells and adrenal cells.
AB  - The role of chloride ions in the regulation of steroidogenesis in rat Leydig
      cells and adrenal cells has been investigated. It was found that the chloride
      channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS)
      inhibited LH but not dibutyryl cAMP (dbcAMP)-stimulated steroidogenesis in the
      Leydig cells. This was found to be via an inhibition of cAMP production, because
      both LH- and forskolin-stimulated cAMP productions were inhibited by DIDS. The
      exclusion of chloride ions enhanced steroidogenesis during incubation of Leydig
      cells and adrenal cells with dbcAMP. The adrenal cells were found to be more
      sensitive to dbcAMP than Leydig cells and the enhancing effects of chloride
      removal were higher. In the presence of chloride ions, near maximum
      steroidogenesis was achieved with approximately 60 microM and 1 mM dbcAMP in the
      adrenal and Leydig cells, respectively. In the absence of chloride ions the
      concentrations required decreased approximately 50-fold and 10-fold,
      respectively. It is concluded that although LH may regulate DIDS sensitive
      chloride channels, the enhanced stimulation of cAMP-mediated steroidogenesis by
      chloride exclusion is not mediated via these channels. We propose a model based
      on the present and previous studies [1] with Leydig tumour (MA10) cells i.e. that
      intracellular chloride ion depletion enhances the action of cAMP on protein
      synthesis which results in increased synthesis of the Steroidogenic Acute
      Regulator (StAR) protein and consequently increased steroidogenesis.

PMID- 10419014
TI  - Cyclic-AMP-dependent protein kinase (PKA) in testicular cells. Cell specific
      expression, differential regulation and targeting of subunits of PKA.
AB  - LH and FSH regulate via cyclic adenosine 3'5' cyclic monophosphate (cAMP) and
      cAMP-dependent protein kinase (PKA), steroid biosynthesis is Leydig and Sertoli
      cells, respectively. Cyclic AMP also regulates a number of different cellular
      processes such as cell growth and differentiation, ion channel conductivity,
      synaptic release of neurotransmitters, and gene transcription. The principle
      intracellular target for cAMP in mammalian cells is the PKA. The fact that this
      broad specificity protein kinase mediates a number of discrete physiological
      responses following cAMP engagement, has raised the question of how specificity
      is maintained in the cAMP/PKA system. Here we describe features of this signaling
      pathway that may contribute to explain how differential effects of cAMP may be
      contributed to features of the PKA signaling pathway.

PMID- 10419015
TI  - Autocrine regulation of Leydig cell differentiated functions by insulin-like
      growth factor I and transforming growth factor beta.
AB  - The expression and the maintenance of specific differentiated function of Leydig
      cells are regulated not only by gonadotropin but by locally produced factors,
      which may act as autocrine regulators. Many factors, in particular growth
      factors, have been postulated to have such a type of effect on testicular cells,
      but very few fulfilled the three criteria required to establish a
      paracrine/autocrine role: (a) presence of receptors and biological action on
      local cells; (b) local secretion regulated by physiological signals; and (c)
      blockade of the factor or its receptors must modify the function of local cells.
      In the present work we demonstrate that two factors, insulin-like growth factor 1
      (IGF-I) and transforming growth factor beta1 (TGFbeta1) fulfilled the three
      criteria: (a) IGF-I stimulates the transcription of the genes encoding Leydig
      cell differentiated function, leading to an enhanced steroidogenic responsiveness
      to LH/hCG; (b) Leydig cells (LC) express and secrete IGF-I and this secretion is
      enhanced by hCG; and (c) incubation of LC with IgG anti-IGF-I, but not with IgG
      control, markedly reduced the steroidogenic responsiveness to LH/hCG. In contrast
      to IGF-I, TGFbeta is a potent inhibitor of LC differentiated function. Moreover,
      LC express TGFbeta1 mRNA and secrete this peptide. To prove that the locally
      produced TGFbeta has an autocrine role, LC were transfected with 10 microM of an
      antisense oligonucleotide (AON) complementary to the translation initiation
      region of TGFbeta1 mRNA. Transfection with AON but not with sense deoxynucleotide
      induces a complete disappearance of TGFbeta immunoreactivity in LC and an
      enhanced hCG-induced testosterone production by LC. This increased steroidogenic
      responsiveness was associated with a significant enhancement of both LH/hCG
      receptor mRNA and P450c17 mRNA. Taken together, the above results show that both
      factors play an autocrine role, although opposite, on Leydig cell function.

PMID- 10419016
TI  - Implication of ENaC in salt-sensitive hypertension.
AB  - Arterial blood pressure is critically dependent on sodium balance. The kidney is
      the key player in maintaining sodium homeostasis. Aldosterone-dependent
      epithelial sodium transport in the distal nephron is mediated by the highly
      selective, amiloride-sensitive epithelial sodium channel (ENaC). Direct evidence
      that dysfunction of ENaC participates in blood pressure regulation has come from
      the molecular analysis of two human genetic diseases, Liddle's syndrome and
      pseudohypoaldosteronism type 1 (PHA-1). Both, increased sodium reabsorption
      despite low aldosterone levels in Liddle's patients and decreased sodium
      reabsorption despite high aldosterone levels in PHA-1 patients, demonstrated that
      ENaC is an effector for aldosterone action. Gene-targeting and classical
      transgenic technology enable the generation of mouse models for these diseases
      and the analysis of the involvement of the epithelial sodium channel (ENaC) in
      the progress of these diseases. A first mouse model using alphaENaC transgenic
      knockout mice [alphaENaC(-/-)Tg] mimicked several clinical features of PHA-1,
      like salt-wasting, metabolic acidosis, high aldosterone levels, growth
      retardation and increased early mortality. Such mouse models will be necessary in
      testing the involvement of genetic and/or environmental factors like salt-intake
      in hypertension.

PMID- 10419017
TI  - The type I and type II 11beta-hydroxysteroid dehydrogenase enzymes.
AB  - Local tissue concentrations of glucocorticoids are modulated by the enzyme 11beta
      hydroxysteroid dehydrogenase which interconverts cortisol and the inactive
      glucocorticoid cortisone in man, and corticosterone and 11-dehydrocorticosterone
      in rodents. The type I isoform (11beta-HSD1) is a bidirectional enzyme but acts
      predominantly as a oxidoreductase to form the active glucocorticoids cortisol or
      corticosterone, while the type II enzyme (11beta-HSD2) acts unidirectionally
      producing inactive 11-keto metabolites. There are no known clinical conditions
      associated with 11beta-HSD1 deficiency, but gene deletion experiments in the
      mouse indicate that this enzyme is important both for the maintenance of normal
      serum glucocorticoid levels, and in the activation of key hepatic gluconeogenic
      enzymes. Other important sites of action include omental fat, the ovary, brain
      and vasculature. Congenital defects in the 11beta-HSD2 enzyme have been shown to
      account for the syndrome of apparent mineralocorticoid excess (AME), a low renin
      severe form of hypertension resulting from the overstimulation of the non
      selective mineralocorticoid receptor by cortisol in the distal tubule of the
      kidney. Inactivation of the 11beta-HSD2 gene in mice results in a phenotype with
      similar features to AME. In addition, these mice show high neonatal mortality
      associated with marked colonic distention, and remarkable hypertrophy and
      hyperplasia of the distal tubule epithelia. 11Beta-HSD2 also plays an important
      role in decreasing the exposure of the fetus to the high levels of maternal
      glucocorticoids. Recent work suggests a role for 11beta-HSD2 in non
      mineralocorticoid target tissues where it would modulate glucocorticoid access to
      the glucocorticoid receptor, in invasive breast cancer and as a mechanism
      providing ligand for the putative 11-dehydrocorticosterone receptor. While
      previous homologies between members of the SCAD superfamily have been of the
      order of 20-30% phylogenetic analysis of a new branch of retinol dehydrogenases
      indicates identities of > 60% and overlapping substrate specificities. The
      availability of crystal structures of family members has allowed the mapping of
      conserved 11beta-HSD domains A-D to a cleft in the protein structure (cofactor
      binding domain), two parallel beta-sheets, and an alpha-helix (active site),
      respectively.

PMID- 10419018
TI  - Cortisol as a mineralocorticoid in human disease.
AB  - The type 2 isozyme of 11beta-hydroxysteroid dehydrogenase inactivates cortisol to
      cortisone and enables aldosterone to bind to the MR. Congenital deficiency of the
      enzyme results in cortisol-mediated mineralocorticoid excess and arises because
      of inactivating mutations in the HSD11B2 gene. Inhibition of the enzyme following
      licorice or carbenoxolone ingestion results in a similar, though milder phenotype
      and the enzyme is overwhelmed in ectopic ACTH syndrome. Loss of 11beta-HSD2
      expression may be important in sodium balance and blood pressure control in some
      patients with renal disease. Finally, while some studies demonstrate impaired
      11beta-HSD activity in broader populations of patients with hypertension, further
      studies are required to clarify the role of 11beta-HSD2 in 'essential'
      hypertension.

PMID- 10419019
TI  - Aldosterone synthase (CYP11B2) polymorphisms and cardiovascular function.
AB  - In addition to regulating renal sodium resorption and, thus, intravascular
      volume, aldosterone may have direct effects on the cardiovascular system. We
      previously identified a polymorphism (-344C/T) in the promoter of the aldosterone
      synthase (CYP11B2) gene that affects binding of the SF-1 transcription factor and
      thus might influence gene expression. We found that, whereas this polymorphism
      has inconsistent associations with levels of aldosterone secretion and blood
      pressure, the -344C allele is strongly associated with increased left ventricular
      size and decreased baroreflex sensitivity in healthy individuals. These
      physiological parameters are cardiovascular risk factors. Indeed, preliminary
      studies suggest that the -344C allele is also associated with increased risk of
      myocardial infarction in high risk dyslipidemic males.

PMID- 10419020
TI  - Characterization of UDP-glucuronosyltransferases active on steroid hormones.
AB  - In recent years, the enzymes which are involved in the formation of DHT in
      steroid target tissues have been well investigated, however, enzymes responsible
      for the catabolism and elimination of steroids in these tissues, in particular
      the uridine diphospho-glucuronosyltransferase (UGT) family of enzymes, have
      received much less attention. We have recently demonstrated that human and monkey
      are unique in having high plasma levels of C19 steroid glucuronides. These
      circulating conjugates have been proposed to reflect the peripheral conversion of
      adrenal and gonadal C19 steroids to potent androgens, especially DHT. In humans,
      the presence of steroid UGT activities is found in the liver and several
      extrahepatic tissues including the prostate, mammary gland and ovary. In
      addition, UGT activities were observed in breast and prostate tumor cell lines
      such as MCF-7 and LNCaP, respectively. In agreement with the presence of steroid
      conjugating enzymes in extrahepatic tissues, UGT cDNA clones, which encode
      steroid conjugating proteins, have been isolated from libraries constructed from
      human and monkey prostate mRNA. The presence of UGT transcripts and proteins in
      extrahepatic tissues in both species, as determined by Northern blot,
      ribonuclease protection, specific RT-PCR, in situ hybridization, Western blot and
      immunocytochemistry analysis, indicate the relevance of steroid glucuronidation
      in tissues other than the liver. Knowing that both the human prostate and the
      human prostate cancer LNCaP cell line express steroid metabolizing proteins,
      including UGT enzymes, regulation of UGT mRNA and protein levels, as well as
      promoter activity was studied in these cells. The results demonstrate a
      differential regulation between the two highly related isoforms UGT2B15 and
      UGT2B17, where only the expression of UGT2B17 was affected following treatments
      of LNCaP cells with androgens, growth factors or cytokines. Steroid conjugation
      by UGT enzymes is potentially involved in hormone inactivation in steroid target
      tissues, thus modifications in UGT expression levels may influence hormonal
      responses.

PMID- 10419021
TI  - 3D-structure of human estrogenic 17beta-HSD1: binding with various steroids.
AB  - Human estrogenic dehydrogenase (17beta-HSD1) catalyses the last step in the
      biosynthesis of the active estrogens that stimulate the proliferation of breast
      cancer cells. While the primary substrate for the enzyme is estrone, the enzyme
      has some activity for the non-estrogenic substrates. To better understand the
      structure function relationships of 17beta-HSD1 and to provide a better ground
      for the design of inhibitors, we have determined the crystal structures of 17beta
      HSD1 in complex with different steroids. The structure of the complex of
      estradiol with the enzyme determined previously (Azzi et al., Nature Structural
      Biology 3, 665-668) showed that the narrow active site was highly complementary
      to the substrate. The substrate specificity is due to a combination of hydrogen
      bonding and hydrophobic interactions between the steroid and the enzyme binding
      pocket. We have now determined structures of 17beta-HSD1 in complex with
      dihydrotestosterone and 20alpha-OH-progesterone. In the case of the C19 androgen,
      several residues within the enzyme active site make some small adjustments to
      accommodate the increased bulk of the substrate. In addition, the C19 steroids
      bind in a slightly different position from estradiol with shifts in positions of
      up to 1.4 A. The altered binding position avoids unfavorable steric interactions
      between Leu 149 and the C19 methyl group (Han et al., unpublished). The known
      kinetic parameters for these substrates can be rationalized in light of the
      structures presented. These results give evidence for the structural basis of
      steroid recognition by 17beta-HSD1 and throw light on the design of new
      inhibitors for this pivotal steroid enzyme.

PMID- 10419022
TI  - Two 17beta-hydroxysteroid dehydrogenases (17HSDs) of estradiol biosynthesis:
      17HSD type 1 and type 7.
AB  - Two 17beta-hydroxysteroid dehydrogenases (17HSDs), type 1 and type 7, are enzymes
      of estradiol biosynthesis, in addition to which rodent type 1 enzymes are also
      able to catalyze androgens. Both of the 17HSDs are abundantly expressed in
      ovaries, the type 1 enzyme in granulosa cells and type 7 in luteinized cells. The
      expression of 17HSD7, which has also been described as a prolactin receptor
      associated protein (PRAP), is particularly up-regulated in corpus luteum during
      the second half of rodent pregnancy. A moderate or slight signal for mouse
      17HSD7/PRAP mRNA has also been demonstrated in samples of placenta and mammary
      gland, for example. Human, but not rodent, 17HSD1 is expressed in placenta,
      breast epithelium and endometrium in addition to ovaries. A cell-specific
      enhancer, silencer and promoter in the hHSD17B1 gene participate in the
      regulation of type 1 enzyme expression. The enhancer consists of several
      subunits, including a retinoic acid response element, the silencer has a binding
      motif for GATA factors, and the proximal promoter contains adjacent and competing
      AP-2 and Sp binding sites.

PMID- 10419023
TI  - Characterization of the HSD17B4 gene: D-specific multifunctional protein 2/17beta
      hydroxysteroid dehydrogenase IV.
AB  - The HSD17B4 gene codes for a 80 kDa multifunctional enzyme containing three
      distinct functional domains and is localized in peroxisomes. The N-terminal part
      exhibits 3-hydroxyacyl-CoA dehydrogenase and 17beta-hydroxysteroid dehydrogenase
      activity whereas the central part shows enoyl-CoA hydratase activity. The carboxy
      terminal part of the protein has sterol-carrier-protein activity. The protein is
      widely expressed, however in several tissues like brain, uterus and lung its
      expression is limited to specific cells like Purkinje cells or luminal
      epithelium. The HSD17B4 gene consist of 24 exons and 23 introns with classical
      intron-exon junctions spanning more than 100 kbp. The importance of the HSD17B4
      protein is stressed by the identification of patients with severe clinical
      abnormalities due to mutations in the HSD17B4 gene. We have now checked the
      consequences of one frequent mutation, G16 S, which results in inactivation of
      the enzyme due to loss of interaction with NAD+.

PMID- 10419024
TI  - Do intracrine mechanisms regulate aromatase expression?

PMID- 10419025
TI  - Glucocorticoids, oxysterols, and cAMP with glucocorticoids each cause apoptosis
      of CEM cells and suppress c-myc.
AB  - In clones of the CEM human acute lymphoblastic leukemic cell line,
      glucocorticoids, oxysterols and activators of the cAMP pathway acting
      synergistically with glucocorticoids, each can cause apoptotic cell death.
      Morphologically and kinetically, these deaths resemble one another. The kinetics
      are striking: in each case, after addition of the lethal compound(s), an interval
      of approximately 24 h follows, during which cell growth continues unabated.
      During this "prodromal" period, removal of the apoptotic agent leaves the cells
      fully viable. We hypothesize that a sequence of biochemical events occurs during
      the prodrome which eventually results in the triggering of the full apoptotic
      response as evidenced by the activation of caspases and DNA fragmentation. At
      some point, the process is irreversible and proceeds relatively rapidly to cell
      death. Suppression of c-Myc seems a universal early event evoked by each of these
      lethal compounds or combinations, and we conclude that the negative regulation of
      this proto-oncogene is an important aspect of the critical pre-apoptotic events
      in these cells.

PMID- 10419026
TI  - Proapoptotic effects of antiestrogens, progestins and androgen in breast cancer
      cells.
AB  - The promoting action of E2 in breast cancer cells has been, until now, mainly
      linked to its action on prolifieration. Because of the importance of an increase
      in apoptosis in breast cancer prevention, we have studied the possible effects of
      various antiestrogens, progestins and an androgen on its occurrence in three
      hormone-dependent breast cancer cell lines. The antiestrogens were, a
      triphenylethylene derivative, 4 hydroxytamoxifen (4OHTAM) and two steroidal
      antiestrogens, IC1182780 and RU58668. The progestins were Org2058, a pregnane
      derivative, tibolone (OrgOD14), a normethyltestosterone derivative and OrgOM38
      (the delta4 isomer of OrgOD14) and the androgen dihydrotestosterone (DHT).
      Apoptosis was studied in MCF-7, ZR75-1 and T47-D cells using morphological
      approaches and flow cytometry. The antiestrogens, the progestins and DHT were
      proapoptotic but to different potencies according to the cell line studied.
      Indeed, the 'pure' steroidal antiestrogens were more efficient than 4OHTam in
      increasing apoptosis. We have also studied the level of expression of some of the
      proteins involved in the regulation of apoptosis. Bcl-2 and bcxL, two
      antiapoptotic members of the bcl-2 family proteins, were inhibited by the
      progestins and the antiestrogens. In contrast, the proapoptotic proteins, bax and
      bak seemed to be constitutively expressed. Thus, since the ratio of proapoptotic
      and antiapoptotic proteins determines apoptosis or cell survival, the hormone
      effects are operating by modulating the antiapoptotic regulators of the balance.
      These data demonstrate that antiestrogens, progestins, and androgens can promote
      apoptosis in breast cancer cells, an effect which could be of importance in the
      therapeutic prevention of breast cancer.

PMID- 10419027
TI  - Sex hormone-binding globulin, its membrane receptor, and breast cancer: a new
      approach to the modulation of estradiol action in neoplastic cells.
AB  - The role of human Sex Hormone-Binding Globulin (SHBG), the plasma carrier of sex
      steroids, and its membrane receptor, SHBG-R, in estrogen-dependent breast cancer
      has been investigated in our laboratory in the past few years. SHBG-R is
      expressed in MCF-10 A cells (not neoplastic mammary cells), MCF-7 cells (breast
      cancer, ER positive) and in tissue samples from patients affected with ER
      positive breast cancer, but not in estrogen-insensitive MDA-MB 231 cells. The
      SHBG/SHBG-R interaction, followed by the binding of estradiol to the complex
      protein/receptor, causes a significant increase of the intracellular levels of
      cAMP, but does not modify the amount of estradiol entering MCF-7 cells. The
      estradiol-induced proliferation of MCF-7 cells is inhibited by SHBG, through SHBG
      R, cAMP and PKA. Similarly, the proliferation rate of tissue samples positive for
      SHBG-R was significantly lower than the proliferation rate of negative samples.
      SHBG and SHBG-R could thus trigger a 'biologic' anti-estrogenic pathway. In order
      to get a more detailed knowledge of this system, we first examined the frequence
      of the reported mutated form of SHBG in 255 breast cancer patients. The mutated
      SHBG is characterized by a point mutation (Asp 327 --> Asn) causing an additional
      N-glycosylation site, which does not affect the binding of steroids to SHBG. The
      frequence of the mutation was significantly higher (24.5%) in estrogen-dependent
      breast cancers than in healthy control subjects (11.6%). This observation
      confirms the close relationship between SHBG and estrogen-dependent breast cancer
      and suggests that the mutation could modify SHBG activity at cell site. Lastly,
      the possibility of using SHBG to modulate the estradiol action in breast cancer
      was further studied by transfecting MCF-7 cells with an expression vector
      carrying the SHBG cDNA (study in collaboration with G.L. Hammond). Transfected
      cells are able to produce significant amount of SHBG in their medium, but their
      SHBG-R is reduced to undetectable levels. The SHBG produced by transfected MCF-7
      cells is, however, able to inhibit estradiol-induced proliferation of MCF-7 cells
      expressing a functional receptor. Thus, the local production of SHBG obtained
      with transfection could be a useful tool to control cell growth in estrogen
      dependent breast cancer.

PMID- 10419028
TI  - Sex hormone-binding globulin mediates steroid hormone signal transduction at the
      plasma membrane.
AB  - Sex hormone-binding globulin is a plasma glycoprotein that binds certain
      estrogens and androgens with high affinity. Over the past several years it has
      been shown that, in addition to functioning as a regulator of the free
      concentration of a number of steroid hormones, SHBG plays a central role in
      permitting certain steroid hormones to act without entering the cell. The system
      is complex. SHBG interacts with a specific, high affinity receptor (R(SHBG)) on
      cell membranes that appears to transduce its signal via a G protein. The SHBG
      R(SHBG) complex causes the activation of adenylyl cyclase and the generation of
      cAMP within a matter of minutes after exposure to an appropriate steroid. Only
      steroids that bind to SHBG can activate SHBG-R(SHBG), but not all steroids that
      bind have this function, e.g. are agonists. All steroids that bind to SHBG but do
      not activate adenylyl cyclase are antagonists. The signals generated by the
      steroid-SHBG-R(SHBG) complex generate messages that have effects on the
      transcriptional activity of classic, intracellular receptors for steroid
      hormones. These and other downstream effects of this system are reviewed.

PMID- 10419030
TI  - Surgical exposure in translabyrinthine approaches--an anatomical study.
AB  - OBJECTIVE: Translabyrinthine approach (TLA) is a procedure of choice for the
      removal of vestibular schwannomas in cases of profound hearing loss. There is a
      lack of anatomic studies reviewing the surgical anatomy of the cerebellopontine
      angle (CPA) as seen in the classical and enlarged TLAs. METHODS: Seven formalin
      preserved cadavers were dissected. Structures, visualized in the CPA through the
      TLA, were scored according to the degree of their exposure (1, structure not
      seen; 2, partial exposure; 3, full exposure). RESULTS: The acousticofacial
      bundle, anterior inferior cerebellar artery and flocculus had the highest scores
      in both types of surgery. However. the fifth, ninth, and tenth cranial nerves,
      prepontine cistern, pons, superior cerebellar artery, and posterior inferior
      cerebellar artery had higher scores, i.e. better exposure, in the enlarged TLA
      than in the classical TLA. CONCLUSION: These findings suggest that the enlarged
      TLA be preferred in cases of larger tumors extending to either jugular foramen or
      middle fossa whereas the indications of the classical TLA should be limited to
      vestibular neurectomy and removal of smaller tumors.

PMID- 10419029
TI  - Correlation between rCBF and speech perception in cochlear implant users.
AB  - OBJECTIVE: Although cochlear implants (CIs) have provided the opportunity for
      bilaterally deaf individuals to recover their hearing abilities, the speech
      perception performances of the CI users varies considerably. To elucidate the
      cortical mechanisms of processing speech signals coded by CIs, we evaluated the
      correlation between the brain activity during speech activation and speech
      perception in CI users by PET. METHODS: Fourteen postlingually deaf CI users were
      examined. CI used in the patients was a 22-channel system and its speech-coding
      strategy was the Nucleus spectral peak (SPEAK) strategy. To evaluate the speech
      perception performances, we examined vowel perception, consonant perception and
      speech tracking performances in the Japanese language. Regional cerebral blood
      flow (rCBF) was measured during no sound stimulation and speech sound
      stimulation. PET data of the silent condition was subtracted from that of speech
      stimulation to determine changes in rCBF. In the search for changes in rCBF in
      the areas for auditory processing, three regions of interest (ROI) were selected;
      primary auditory area, auditory association area and Broca's area. The
      correlation between the rCBF changes in the ROIs and the speech perception
      performances was analyzed using Pearson's correlation coefficient. RESULTS: The
      patient's speech perception performances ranged widely. Although there were no
      significant correlations between the speech perception and the rCBF increases in
      the primary auditory area and Broca's area, there were positive correlations in
      the auditory association area. In the left auditory association area, the
      correlation coefficient of the vowel perception performance was 0.546 (P <0.05)
      and that of the speech-tracking test was 0.657 (P < 0.05). Regarding the
      consonant perception performance, the correlation coefficient was 0.743 (P <
      0.01). There was a positive correlation only between the consonant perception
      performance and the rCBF increase (R = 0.576, P < 0.05) in the right auditory
      association area. These correlations are stronger in the left hemisphere than in
      the right hemisphere. CONCLUSIONS: It is suggested that the improvement of the
      auditory processing of speech in CI users with SPEAK strategy is accompanied by
      the recruitment of more neurons in the auditory association areas. The adult
      auditory cortices may still have plasticity or

PMID- 10419031
TI  - Equivalent dipoles for middle latency auditory evoked potentials using the dipole
      tracing method.
AB  - During the last decade, new dipole localization techniques have prompted the
      search for the neuronal generators of evoked potentials. In this study we have
      reported the equivalent dipoles for the middle latency auditory evoked potentials
      (MAEPs) by the mean of these localization using the dipole tracing method. MAEPs
      that were recorded from 19 normal human subjects attending to random binaural
      clicks were analyzed using the dipole tracing method. Equivalent dipoles (EDs)
      were found, using both the single-dipole model and the two-dipole model, for
      components occurring from 0 to 60 ms after stimulus onset. The dipole analysis
      accounted for the real head geometry based on three-dimensional digitization of
      measured head shape, and the results were experimentally correlated to those of
      magnetic resonance imaging to increase the accuracy of ED localization. For
      components in the first 15 ms latency (P0 and Na), neither model provided EDs
      with reproducible high dipolality. Na was particularly difficult to analyze, as
      this component was often contaminated by myogenic potentials. The results
      provided by the two-dipole model for the Pa component (20-30 ms) showed three
      variations: in three subjects, one ED was located in each supratemporal cortex;
      in another three, one ED was located in the right temporal cortex and the other
      in the midbrain; and in the remaining thirteen subjects, both EDs were in the
      midbrain. The single-dipole model and the two-dipole model both found EDs in the
      midbrain for Nb. Further study is necessary to determine the cause or causes of
      the variety in our results. And it is also necessary to try the study using
      unilateral ear stimulation with/without contralateral masking noise for
      understanding the mechanism of the binaural interaction.

PMID- 10419032
TI  - Fate of cartilage material used in middle ear surgery light and electron
      microscopy study.
AB  - OBJECTIVE: To evaluate the fate of autograft and homograft cartilage used in the
      middle ear. METHOD: Animal experimental study was carried out on 20 healthy
      guinea pigs by implanting small pieces of auto- and homograft costal cartilage in
      the middle ears for different periods of time (1, 3 and 6 months). The grafts
      were removed and examined by light and electron microscopy. Cartilage autografts,
      obtained from seven human cases at revision tympanoplasty, were also examined by
      light and electron microscopy. RESULTS: In the animal experimental study the
      chondrocytes were degenerated while the matrix was preserved in both auto- and
      homograft specimens. The homografts were as good as the autografts as in both
      cases the cartilage matrix was preserved. In the human specimens obtained after
      10-15 months of implantation (six cases), the matrix was preserved, the lacunae
      were empty and the chondrocytes were degenerated. The specimen removed after 31/2
      years (one case) showed viable chondrocytes of big size with defined cell
      organelles. CONCLUSION: This work provides evidence for the beneficial role of
      cartilage in middle ear surgery as the matrix retained its structure. There is
      also a possibility for the chondrocytes to remain viable for a long time after
      implantation. It seems also that homograft cartilage is a good option during
      tympanoplasty and is comparable to autografts. In the animal study the homografts
      were as good as the autografts as in both cases cartilage matrix was preserved.

PMID- 10419033
TI  - Effects of galvanic stimulation of the mastoid process on the gastric motility
      induced by caloric stimulation.
AB  - The effects of galvanic stimulation to the mastoid portion on the
      vestibuloautonomic symptoms induced by caloric stimulation, such as nausea,
      vomiting, and vertigo, were evaluated in this study. Gastric motility was
      measured by electrogastrography (EGG) in 20 healthy volunteers (11 male and nine
      female) aged 20-30 (average: 25.4) years. Electrical stimulation of the mastoid
      process with 1.0-3.0 mA, 1.0 ms, 100 Hz was applied using a bipolar-biaural
      method during caloric stimulation of the external auditory canal. The dominant
      frequency and power of EGG were determined using running spectral frequency
      analysis and the time-course of EGG was evaluated in a pseudo three dimensional
      graphic. Frequency of EGG was classified into normogastria with 3 cpm,
      bradygastria with lower than 3 cpm, and tachygastria with higher than 3 cpm. At
      quiescent period, normogastria was 78.7 +/- 3.7%, bradygastria 5.0 +/- 1.1%, and
      tachygastria 16.4 +/- 3.7%. Caloric stimulation with warm water in the unilateral
      ear and cold water in the contralateral ear elicited vestibuloautonomic symptoms,
      with accompanied decreases in normogastria (57.7 +/-4.6%, P < 0.01) and increases
      in tachygastria (34.8 +/- 4.8%, P < 0.01). Cathodal stimulation to the mastoid
      process ipsilateral to cold water irrigation during caloric stimulation restored
      normal pattern of gastric motility: normogastria in 77.1 + 5.3% and tachygastria
      in 19.3 +/- 4.7%, and relieved vestibuloautonomic symptoms. Cathodal stimulation
      to the inhibited vestibular system ameliorates the vestibular symptoms induced by
      caloric stimulation.

PMID- 10419034
TI  - Critical evaluation of deafness.
AB  - OBJECTIVE: The purpose of this study is to investigate the clinical aspects of
      profound hearing loss (PHL) and their significance for defining deafness.
      METHODS: The audiological data were reviewed from 3660 patients who were
      evaluated in the Otolaryngology Clinic at Louisiana State University in
      Shreveport, LA, over a 5-year period. The medical charts from the patients were
      also reviewed for the information of medical diagnosis, surgical records and
      radiological findings. RESULTS: There were 34 patients identified with bilateral
      PHL or deaf, 177 patients with unilateral PHL and 123 patients with borderline
      PHL. Congenital hearing loss and unknown-cause hearing loss in this series were
      predominant with 267 cases (79.9%). A surgical management was indicated in 39
      cases (11.7%) including middle ear infection, ossicular chain abnormalities and
      auditory nerve/brainstem tumors. CONCLUSION: This study suggests that
      audiometrically PHL should be thoroughly evaluated to detect reversible or
      remediable conditions by surgical and medical approaches. The diagnosis of
      deafness should be confirmed by an integration of the audiological data and
      medical documents including surgical and radiological findings. Aural
      rehabilitation program should be designed for deaf patients with varied etiology
      and degree of residual peripheral hearing sensitivity following medical
      clearance.

PMID- 10419035
TI  - Epidemiological research into nasopharyngeal carcinoma in the Chubu region of
      Japan.
AB  - Although patient death due to nasopharyngeal carcinoma (NPC) is increasing, few
      epidemiological analyses of NPC in Japan have been conducted since Sawaki's
      report in 1979. To determine the current incidence of NPC in Japan we examined
      NPC case in the Chubu area from 1986 to 1995. The leaders and reporting
      representatives of all otorhinolaryngological groups in the area were asked for
      their support of this epidemiological research. A total of 607 cases (445 male
      and 162 female NPC patients) were analyzed epidemiologically, histologically,
      serologically and clinically in this study. The incidence of NPC gradually
      increased with age. The mean age of the patients was 54.1 years. The age
      standardized annual incidence in the Chubu region was 0.28 per 10(5) persons per
      year. The incidence in prefectures bordering Japan Sea (0.36) was significantly
      higher than that of prefectures facing the Pacific Ocean (0.21, P<0.05). On the
      basis of World Health Organization (WHO) histological criteria, 12%) of the cases
      were classified as WHO I, 54% as WHO II and 34% as WHO III. As for tumor origin,
      in 58% of the cases it originated posterosuperiorly, in 32% laterally and in 1%
      inferiorly. Tumor staging showed 4% to belong to stage I, 9% to stage II, 15% to
      stage III and 72% to stage IV. The positive rates of serum titers of the
      antibodies to Epstein Barr virus

PMID- 10419036
TI  - Malondialdehyde levels and superoxide dismutase activity in experimental
      maxillary sinusitis.
AB  - OBJECTIVE: Acute maxillary sinusitis is one of the most common diseases in human.
      Reactive oxygen metabolites (ROMs) produced also physiologically in the body, are
      normally neutralised by antioxidative enzymes such as superoxide dismutase (SOD).
      Infection is one of the causes of increased ROMs production. The most important
      mechanism of tissue damage produced by ROMs is the peroxidation of lipids found
      in cell membranes and it may be estimated by malondialdehyde (MDA) levels. The
      purpose of this study, is to investigate tissue damage caused by ROMs in
      maxillary sinusitis in 24 rabbits. METHODS: Experimental sinusitis was induced by
      blocking the right nose and inoculating Staphylococcus aureus into the right
      maxillary sinuses. Left maxillary sinuses were the control group. Animals were
      divided into three groups and killed at 3, 5 and 7 days. Mucosas of each
      maxillary sinus were examined histopathologically and MDA levels were determined.
      Blood samples were obtained preoperatively (control blood) and on killing days
      (experimental blood). Serum MDA levels and erythrocyte SOD activities were
      determined. RESULTS: All the infected sinuses displayed signs of the
      inflammation. MDA levels and SOD activities in the experimental blood samples
      were significantly higher than those of the control group (P < 0.05). Mucosal MDA
      levels in the experimental group were significantly higher than the controls (P <
      0.01). CONCLUSIONS: In maxillary sinusitis caused by S. aureus an increased ROMs
      production was observed and it may contribute to tissue damage of sinusitis.

PMID- 10419037
TI  - Histamine H1 receptor and reactivity of the nasal mucosa in sensitized guinea
      pigs.
AB  - OBJECTIVE: Nasal Hypersensitivity to histamine is higher in allergic patients
      than that in normal control, suggesting that affinity and/or density of H1
      receptors in nasal mucosa may be increased in patients with allergic rhinitis.
      The purpose in this study is to examine the correlation between the
      hyperresponsiveness and number of histamine H1 receptors in guinea pig nasal
      mucosa. METHODS: Guinea pigs were sensitized by DNP-Ascaris antigen. To block
      histamine H1 receptors, ketotifen was used and the number of receptors was
      counted by receptor binding assay technique. These data were compared with nasal
      airway volume (VOL) assessed by acoustic rhinometry of the same animals to know
      whether the number of H1 receptors is correlated to the nasal responsiveness to
      the antigen, or not. Eighty animals were divided into five groups which are
      composed of nonsensitized and sensitized group pretreated with saline, 0.1, 1.0
      and 10 mg/kg of ketotifen, respectively. RESULTS: The number of H1 receptors
      (Bmax) was significantly increased in sensitized group compared with that in
      control. It decreased dose dependently by pretreatment of ketotifen. The percent
      change of VOL showed - 31.1 +/- 4.1% at 10 min and - 42.9 +/- 4.1% at 30 min
      after antigen challenge in sensitized animals. This was dose dependently
      inhibited by ketotifen. There was a highly inverse correlation between VOL and
      Bmax (r = -0.708, P< 0.0001). CONCLUSION: These results suggest that
      sensitization increases the number of histamine H1 receptor, and that increased
      number of H1 receptor in nasal mucosa in sensitized guinea pigs may be one of the
      causes of nasal hyperresponsiveness to antigen.

PMID- 10419038
TI  - Immediate tonsillectomy for peritonsillar abscess.
AB  - OBJECTIVE: Peritonsillar abscess (PTA) is one of the most common infectious
      diseases of the head and neck region requiring surgical intervention to relieve
      symptoms such as severe throat pain, fever, dysphagia, and trismus. However, the
      appropriate management of PTA is still controversial. In Europe and the US,
      immediate tonsillectomy under general anesthesia has been accepted as the
      treatment for PTA. But in Japan, immediate tonsillectomy has been regarded as
      contraindicated for PTA because of difficulties encountered in the operation
      during the acute stage, as well as possible postoperative complications. METHODS:
      A total of 103 cases of PTA treated at our clinic during the past 16 years were
      reviewed; immediate tonsillectomies had been performed in 99 of them. Surgical
      findings, postoperative course, and bacteriological examination were surveyed.
      RESULTS: The results showed that immediate tonsillectomy under general anesthesia
      was carried out safely without complications. Dramatic relief of the symptoms was
      obtained within a few days following each operation. A high incidence of
      anaerobes was observed by bacteriological examination, suggesting that sufficient
      drainage is required to treat this disease. CONCLUSION: We conclude that
      immediate tonsillectomy should be performed for peritonsillar abscess.

PMID- 10419039
TI  - Immunoreactivity in granular cell tumours of the larynx.
AB  - OBJECTIVE: To elucidate histogenesis and behaviour of laryngeal granular cell
      tumours (GCT) and to determine the role of p53 protein expression in these
      lesions. METHODS: The clinical, pathological and immunohistochemical findings of
      three cases of laryngeal GCTs are described. RESULTS: All tumours were surgically
      excised and appeared histologically benign. Pseudoepitheliomatous hyperplasia,
      mitosis and nuclear pleomorphism were not found in any of the three cases. All
      lesions were negative for keratin 8, desmin and actin. Only one case stained for
      collagen IV. Positive staining was found for S-100 protein and CD68 in all
      tumours. Ki-67 and Bcl-2 staining was confined to occasional cells. p53
      reactivity was seen in all tumours; positivity ranged from 35 to 42%. The three
      patients have remained free of disease without complications up to 10 years after
      treatment. CONCLUSION: Immunohistochemical findings support benign behaviour and
      a Schwann cell origin for laryngeal GCT. The expression of p53 by granular cells
      is unclear but appears to be unrelated to behaviour.

PMID- 10419040
TI  - New classification of stage IV squamous cell carcinoma of the oropharynx.
AB  - OBJECTIVE: The recent progress in reconstructive surgery for the treatment of
      head and neck carcinomas has made it possible to radically resect cancers.
      However. the choice of treatment for oropharyngeal carcinoma is rather difficult.
      Radical treatment sometimes results in severe complications, suggesting that some
      modes of treatment might reduce the quality of life. The 5-year survival rate of
      patients with stage IV oropharyngeal carcinoma is still very poor. It is
      necessary to re-classify stage IV squamous cell carcinoma of the oropharynx in
      relation to the prognosis. Foote et al. (Base of tongue carcinoma: patterns of
      failure and predictors of recurrence after surgery alone. Head Neck 1993:15:300
      307) demonstrated the two subgroups of stage IV oropharyngeal squamous cell
      carcinoma, as favorable stage IV and unfavorable stage IV. In this study, we have
      re-examined the validity of these subsets and we have demonstrated the new
      subsets of stage IV squamous cell carcinoma of the oropharynx. METHODS: We have
      examined 221 cases of oropharyngeal squamous cell carcinoma at the Cancer
      Institute Hospital in Tokyo between 1971 and 1994. A total of 107 cases of stage
      IV were included. We analyzed these cases retrospectively. RESULTS: Based on the
      subsets demonstrated by Foote et al., there were no significant differences
      between the two groups in our cases, suggesting that these subsets were not
      useful for the choice of the treatment. In order to make a new classification in
      view of better choice of treatment, either radical treatment or palliative
      therapy, these cases were divided into two new groups of stage IV. one group with
      relatively good results (T1-3 N2 M0 and T4 NO-1 M0; new favorable stage IV), and
      the other with very poor results (any-T any-N M1 and any-T N3 M0 and T4 N2 M0;
      new unfavorable stage IV). Patients with the new favorable stage IV have a 5-year
      survival rate of 30.4%, and those with the new unfavorable stage IV had a
      survival rate of 0%. CONCLUSION: These new subsets of stage IV can be directly
      related to the prognosis, and are therefore useful in the choice of treatment.

PMID- 10419041
TI  - Histopathological analysis of apoptosis, and expression of p53, bcl-2, bax, and
      Ki-67 in laryngeal squamous cell carcinomas and dysplasia.
AB  - The growth of neoplasia is determined by the proliferation and loss of cells. The
      purpose of this study is to determine the frequency of apoptosis in laryngeal
      carcinomas and to examine its relationship to the pathological parameters,
      including ki-67 expression, and to expression of p53, bcl-2, and bax protein. The
      materials are 67 cases of laryngeal squamous cell carcinomas (SCCs) and 22 cases
      of squamous dysplasia using biopsy and surgery specimens. Apoptotic cells were
      determined by the modified TUNEL method. Expressions of p53, bcl-2, and bax, i.e.
      apoptosis-related genes, and ki-67, a proliferation marker, were
      immunohistochemically examined. The relationships between apoptosis and the
      clinicopathological findings were studied. The stage of the carcinoma was not
      related to the apoptotic index. The expression of p53 was frequently detectable
      in the advanced carcinomas with T3, T4 and N-positive. The apoptotic index was
      not significantly related to recurrence, metastasis or histological
      differentiation. Apoptosis occurred frequently in the cornified areas of well
      differentiated SCCs. The expressions of ki-67 observed in the poorly
      differentiated SCCs was significantly higher than that observed in the well
      differentiated SCCs (P< 0.01). The apoptotic index increased after irradiation in
      the carcinoma. No relationship was found between apoptotic index, ki-67 index,
      and expression of p53, bcl-2 and bax. The apoptotic index obtained form the SCCs
      was significantly higher than that obtained form squamous dysplasias (P < 0.05).
      Various apoptosis-related findings including p53 expression were observed in the
      advanced type of laryngeal SCCs, and apoptosis of the carcinoma was suggested to
      be controlled by complicated factors including bcl-2.

PMID- 10419042
TI  - Differential diagnosis of cervical lymph nodes in head and neck cancer by
      ultrasonography.
AB  - OBJECTIVE: Determination of whether an enlarged cervical lymph node is metastatic
      or not is clinically important in head and neck oncology. Differential diagnosis
      of the lymph node, however, is still a diagnostic problem. The purpose of this
      study is to clarify the ultrasonographic findings of the metastatic lymph nodes
      of head and neck squamous cell carcinoma and to establish the criteria. METHODS:
      We investigated 36 metastatic lymph nodes in head and neck squamous cell
      carcinoma and 24 non-metastatic nodes in benign disease with a 10-MHz transducer.
      We examined the size, shape, and internal echo (echo level, punctate bright
      echogenic spots, hilus echogenic line, cystic pattern) of these nodes. Based on
      this investigation, we evaluated 70 lymph nodes from 25 other patients by
      ultrasonography. RESULTS: The short axis diameter and shape of metastatic nodes
      were larger and rounder than those of non-metastatic ones. Of the metastatic
      nodes, 69% showed hypoechoic and 31% isoechoic levels, and 78% exhibited punctate
      bright echogenic spots. Of the non-metastatic nodes, 92% showed hypoechoic and 8%
      isoechoic levels, and none of them showed the spots. The hilus echogenic line was
      not present in any metastatic node, but it was seen in 58% of non-metastatic
      ones. Of the metastatic nodes, 19% exhibited a cystic pattern; none of the non
      metastatic nodes showed the pattern. According to our criteria based on these
      results, the accuracy rate was 98.6% (69/70). The sensitivity and specificity
      were 97.2% (35/36) and 100% (34/34), respectively. The false positive rate and
      the false negative rate were 0% (0/70) and 1.4% (1/70), respectively. CONCLUSION:
      Internal echo findings and shape of lymph nodes can be an important diagnostic
      tool, and our ultrasonographical criteria of the lymph nodes are very useful for
      the differential diagnosis of the cervical lymph nodes.

PMID- 10419043
TI  - Primary non-Hodgkin's lymphoma of brachial plexus.
AB  - We report the case of a 65-year-old man with non-Hodgkin's lymphoma (NHL) not
      only in the brachial plexus but also in the central nervous system and parotid
      gland. He was referred to our hospital for evaluation of a right parotid mass. He
      also presented with bilateral facial palsy and paralysis of the left superior
      limb. Computed tomography scan and magnetic resonance imaging revealed mass
      lesions in the right parapharyngeal space, the deep lobe of the right parotid
      gland. and the left brachial plexus. A gallium-67 citrate scan demonstrated
      abnormal uptake in the left brachial plexus. These symptoms and lesions improved
      during steroid therapy. However, the symptoms worsened again after steroid
      therapy was discontinued. We performed a right parotidectomy to confirm the
      diagnosis. Histopathological study revealed NHL. He was treated with combination
      chemotherapy, and most of the lesions and symptoms, except bilateral facial
      palsy, improved. Despite follow-up treatment, a brain metastasis occured, and he
      died 16 months after the onset of symptoms.

PMID- 10419044
TI  - A case of bilateral eosinophilic granuloma in the temporal bone.
AB  - We present a case of bilateral eosinophilic granuloma in the temporal bone in a
      47-year-old woman, who visited our hospital with a headache and a feeling of
      occlusion in her left ear. Her left tympanic membrane was slightly turbid and
      pure tone audiometry revealed mild left sensorineural deafness. CT disclosed a
      shadow of soft tissue in the left mastoid antrum and mastoid cells, which was
      indicative of marked destruction of the bone. Because MRI findings led us to
      suspect otitis media cholesteatoma, a mastoidectomy was performed. The mastoid
      antrum and mastoid cells were filled with easily bleeding granulation, and there
      was a wide range of bone deficit in the posterior cranial fossa.
      Histopathologically, the granulation tissue was an eosinophilic granuloma. Her
      postoperative clinical progress was good and she was discharged. However 2 months
      after discharge, she had a feeling of occlusion in the right ear and CT revealed
      a shadow in the right mastoid antrum and cells. Therefore, right tympanoplasty
      was performed and the same findings as in the left ear were obtained. A
      histopathological diagnosis of eosinophilic granuloma was made again. To date,
      there has been no recurrence.

PMID- 10419045
TI  - A case of multiple symmetrical lipomatosis (Madelung's disease).
AB  - Multiple symmetrical lipomatosis (Madelung's disease) is a rare disease with
      multiple symmetrical unencapsulated fatty accumulation diffusely involving the
      neck, the shoulders and the upper extremities (Kohan et al. Otolaryngol. Head
      Neck Surg. 1993;108:156-159). We describe a 48-year-old Japanese man with a
      history of alcoholism and liver cirrhosis who reported gradually enlarging masses
      in his cervical region for 4 years. MRI revealed large masses suggesting lipomas
      in the neck. The patient underwent a two-stage lipectomy. This patient is the
      13th case reported in Japan since 1978, though over 200 cases have been reported
      since 1846 in Europe, most of them from the Mediterranean (Kitano et al. ORL
      1994;56:177 180; Kaku et al. Endocrinol. Diabetol. 1997;4:103-106).

PMID- 10419046
TI  - Squamous cell carcinoma arising in a Warthin's tumor.
AB  - Warthin's tumor is a well-defined salivary gland neoplasm consisting of
      epithelial and lymphoid components. However, malignant transformation is
      extremely rare. Such a patient who developed squamous cell carcinoma within a
      Warthin's tumor of the parotid gland is described and possible pathogenesis is
      discussed.

PMID- 10419047
TI  - The evaluation of adenoviral p53-mediated bystander effect in gene therapy of
      cancer.
AB  - Because many tumors have mutated p53, one potential strategy proposed for cancer
      gene therapy is the introduction of the wild-type p53 gene into tumor cells. One
      puzzling aspect of this approach is that currently available gene transfer
      protocols result in a small percentage of tumor cells being transduced in vivo,
      thus implicating a "bystander effect" to achieve therapeutic efficacy. Because
      bystander effects in the context of p53-mediated gene therapy have not been well
      characterized, we evaluated the role of in vitro and in vivo bystander effects of
      adenovirally delivered p53 (AdWTp53). Using human tumor cell lines that did not
      express p53 protein but were infectible with adenovirus and showed sensitivity to
      p53-mediated apoptosis, we were unable to demonstrate an AdWTp53-mediated in
      vitro bystander effect, despite seeing strong bystander effects when cells were
      infected with an adenovirus containing the suicide gene herpes simplex virus
      thymidine kinase and treated with ganciclovir. In contrast, in vivo flank mixing
      studies using one of these cell lines showed a weak but significant p53-mediated
      bystander effect (a 40% inhibition of tumor growth). This bystander effect
      translated into a small survival advantage in an established intraperitoneal
      tumor model when tumor burden was low at the time of viral instillation. The
      survival advantage was lost, however, when tumor burden was increased. This study
      indicates that treatment of human tumors using AdWTp53 may be possible; however,
      because of the weak bystander effect in vivo, effective treatment will likely
      require a large percentage of tumor cells to be transduced.

PMID- 10419048
TI  - Regression of orthotopic brain tumors by cytokine-assisted tumor vaccines primed
      in the brain.
AB  - This study investigated the therapeutic effects of a rat glioma cell line, C6,
      that was engineered to secrete mouse GM-CSF (mGM-CSF) on intracerebral (i.c.)
      brain tumors. Significant antitumor immunity was induced in rats when the live or
      irradiated mGM-CSF-secreting tumor vaccine was implanted i.c. The antitumor
      activity was effective on small tumors and, to a lesser extent, on large tumors
      or tumors existing in vivo for a longer duration. Immunohistochemical analysis
      revealed cellular infiltrates (granulocytes, macrophages, and CD4+ and CD8+ T
      cells) at both the vaccine site and the tumor site, indicating that immune
      responses were similarly activated when tumor vaccine was inoculated in the
      brain, as at the subcutis. Additional studies demonstrated that the therapeutic
      effects of tumor vaccines on the large tumors or the long-existing tumors were
      enhanced by strategies such as increasing the dosage of tumor vaccines, using
      combined vaccines consisting of mGM-CSF and human interleukin-2, or combining
      tumor vaccine with herpes simplex virus thymidine kinase/ganciclovir treatment.
      All of the modified strategies yielded synergistic therapeutic effects on the
      large tumor burdens. The data presented herein suggest that cytokine gene therapy
      is highly promising for the treatment of i.c. gliomas.

PMID- 10419049
TI  - Tumor-suppressive activity of CD66a in prostate cancer.
AB  - CD66a (human homolog of rat cell-cell adhesion molecule, also known as biliary
      glycoprotein) is a cell surface protein of the immunoglobulin family. CD66a has
      been shown to mediate homotypic cell adhesion. Aside from this, no other
      functions of this molecule have been demonstrated. We have observed previously
      that CD66a protein expression is lost in most prostate tumors, suggesting that
      the down-regulation of CD66a is associated with the abnormal growth of prostate
      cells. CD66a is homologous (65% identity) to rat cell-cell adhesion molecule,
      which has been shown to have tumor-suppressive activity. This homology suggests
      the possibility that CD66a might also be a tumor suppressor. In this report, we
      show that restoring CD66a expression in DU145 human prostate cancer cells by
      adenovirus (Ad)-mediated gene transfer dramatically altered the malignant
      phenotype of these cells, as evidenced by their reduced ability to form tumors in
      a xenograft animal model. This result suggests that loss of CD66a protein plays
      an important role in the development of prostate cancer, and that restoring CD66a
      expression might provide an effective treatment for prostate cancer. We further
      explored the possibility of using Ad vectors to deliver CD66a as a potential
      therapeutic agent for prostate cancer. Direct injection of Ad-CD66a, an Ad vector
      carrying the CD66a gene, into DU145 tumors in mice significantly suppressed the
      growth of these tumors. This antitumor activity of CD66a was found to be dose
      dependent. These results suggest that CD66a has tumor-suppressive activity and
      that Ad-CD66a is a potential therapeutic agent for prostate cancer treatment.

PMID- 10419050
TI  - Phase I trial of interferon-gamma (IFN-gamma) retroviral vector administered
      intratumorally to patients with metastatic melanoma.
AB  - BACKGROUND: Interferon-gamma (IFN-gamma) gene/retroviral vector cell vaccinations
      have generated protective responses from unmodified tumor cell challenges as well
      as a regression of established tumors in animal models. The purpose of this trial
      was to determine the feasibility and safety of a direct intratumoral injection of
      IFN-gamma retroviral vector in advanced melanoma patients. METHODS: This was a
      phase I study, in which 13 patients received a single daily injection of a
      retroviral vector with the IFN-gamma gene for 5 consecutive days (1.5 x 10(8)
      colony-forming units total dose); patients subsequently underwent resection of
      the injected lesion to confirm DNA transduction in situ. RESULTS: No toxicity
      related to the injected vector was observed. Replication competent retrovirus was
      not observed in any prepared samples (n = 65). IFN-gamma expression was confirmed
      in 3 of 10 harvested tumor samples; one was equivocal, and DNA transduction was
      unable to be confirmed by enzyme-linked immunospot assay in six samples.
      CONCLUSIONS: An injection of IFN-gamma gene/retroviral vector is well tolerated.
      DNA transduction was demonstrated in human subjects, confirming the feasibility
      of the direct injection approach for the gene therapy of solid tumors. Further
      trials to determine optimal schedule and potential efficacy are indicated.

PMID- 10419051
TI  - Interleukin-12 cDNA skin transfection potentiates human papillomavirus E6 DNA
      vaccine-induced antitumor immune response.
AB  - Human papillomaviruses are associated with >90% of all cases of uterine cervical
      tumors. The E6 and E7 oncoproteins of human papillomavirus are potentially ideal
      targets of immune therapy for cervical cancer, because their expression is
      necessary for cellular transformation. Although both E6 and E7 proteins contain
      numerous predicted cytotoxic T lymphocyte (CTL) epitopes that are capable of
      binding to human leukocyte antigens, the majority of earlier in vivo tumor
      rejection studies have focused on E7. We show here that gene gun-mediated skin
      transfection of plasmid vector encoding the nontransforming, amino-terminal half
      of E6 resulted in the induction of E6-specific CTL activity and tumor rejection
      in a murine model. The use of recombinant murine interleukin-12 (rmIL-12) as a
      vaccine adjuvant has been shown to result in both an enhancement and suppression
      of immune responses, depending upon the doses of rmIL-12 and the experimental
      systems used. We demonstrate here that local expression of transgenic mIL-12 at
      the E6 DNA vaccination site potentiated E6-specific CTL responses and increased
      vaccine-induced antitumor therapeutic efficacy. Our results indicate that
      transfection of the mIL-12 gene at the vaccination site may represent an
      attractive adjuvant for cancer gene immunotherapy.

PMID- 10419052
TI  - Human long-term culture initiating cells are sensitive to benzylguanine and 1,3
      bis(2-chloroethyl)-1-nitrosourea and protected after mutant (G156A) methylguanine
      methyltransferase gene transfer.
AB  - Human hematopoietic progenitors express low levels of O6-alkylguanine-DNA
      alkyltransferase and are sensitive to 1,3-bis(2-chloroethyl)-1-nitrosourea
      (BCNU), particularly following O6-benzylguanine (BG)-mediated O6-alkylguanine-DNA
      alkyltransferase inhibition. Expression of the BG-resistant mutant (G156A)
      methylguanine methyltransferase (deltaMGMT) gene in hematopoietic cells confers
      resistance to BG and BCNU. Because BCNU targets both early and late human
      hematopoietic cells and results in prolonged and cumulative myelosuppression, we
      attempted to protect early hematopoietic progenitors (long-term culture
      initiating cells (LTC-ICs)) by retroviral-mediated transfer of the deltaMGMTgene.
      A total of 33-56% of LTC-ICs were transduced with MFG-deltaMGMT retrovirus as
      determined by evidence of provirus in secondary colony-forming units at 5 weeks
      of culture under conditions optimal for the survival and proliferation of early
      hematopoietic progenitors. The addition of flt-3 ligand to cultures increased the
      transduction rate of LTC-ICs. Furthermore, 17.8 +/- 8.1% of deltaMGMT-transduced
      LTC-ICs survived doses of BG and BCNU; these doses allowed the survival of only 0
      1% of untransduced LTC-ICs. This finding compares favorably with the 8-12% of
      CD34+ cell-derived colony-forming units that we previously showed became
      resistant to BG and BCNU after deltaMGMTgene transfer. Thus, deltaMGMT
      transduction of human early hematopoietic progenitor LTC-ICs confers resistance
      to BG and BCNU and may allow transduced LTC-ICs selective survival and enrichment
      over untransduced cells in patients undergoing BG and BCNU chemotherapy.

PMID- 10419054
TI  - Different efficacy of in vivo herpes simplex virus thymidine kinase gene
      transduction and ganciclovir treatment on the inhibition of tumor growth of
      murine and human melanoma cells and rat glioblastoma cells.
AB  - Initial studies have demonstrated the therapeutic efficacy for cancer treatment
      of in vivo transfer of the herpes simplex virus thymidine kinase gene followed by
      ganciclovir (GCV) treatment. However, recent studies have questioned the validity
      of this approach. Using retroviral vector-producing cells (VPC) as a source for
      in vivo gene transfer, we evaluated the efficacy of in vivo transduction of
      malignant cells using three different tumor cell models: B16 murine and IIB-MEL
      LES human melanomas and a C6 rat glioblastoma. In vitro studies showed a
      bystander effect only in C6 cells. In vivo studies showed an inhibition of tumor
      growth in the two melanoma models when tumor cells were coinjected with VPC
      producing retroviral vectors carrying the herpes simplex virus thymidine kinase
      gene, followed by GCV treatment; however, 100% of mice developed tumors in both
      models. Under similar experimental conditions, 70% (7 of 10) of syngeneic rats
      completely rejected stereotactically transferred C6 tumor cells; most of them (5
      of 10) showed a prolonged survival. Treating established C6 tumors with VPC
      producing retroviral vectors carrying the herpes simplex virus thymidine kinase
      gene and GCV led to the cure of 33% (4 of 12) of the animals. Rats that rejected
      tumor growth developed an antitumor immune memory, leading to a rejection of a
      stereotactic contralateral challenge with parental cells. The immune infiltrate,
      which showed the presence of T lymphocytes, macrophages, and polymorphonuclear
      cells at the site of the first injection and mainly T lymphocytes and macrophages
      at the site of tumor challenge, strengthened the importance of the immune system
      in achieving complete tumor rejection.

PMID- 10419053
TI  - DNA vaccination against the ovarian carcinoma-associated antigen folate receptor
      alpha (FRalpha) induces cytotoxic T lymphocyte and antibody responses in mice.
AB  - Human folate receptor alpha (FRalpha) is a folate-binding protein that is
      selectively overexpressed in ovarian carcinoma and has been regarded as a
      suitable target antigen for immunotherapy purposes. To study the possible use of
      this antigen in DNA vaccination, FRalpha cDNA was ligated into the VR1012 (Vical)
      expression vector under the transcriptional control of the cytomegalovirus
      promoter. A total of 100 microg of purified plasmid DNA was injected
      intramuscularly in BALB/c mice three times at 14-day intervals. At 10 days after
      the second injection, the sera of the animals (100%) displayed significant
      antibody titers (by indirect immunofluorescence and fluorescence-activated cell
      sorter analysis) against syngeneic C26 cells transduced with FRalpha, but not
      against unmodified C26 cells. Immunoglobulin G2a was the predominant isotype. In
      addition, specific cytotoxic T lymphocyte activity against FRalpha-transduced C26
      cells could be detected in splenocytes from all immunized animals. Coinjection of
      a plasmid containing interleukin-2 cDNA increased both antibody titers and
      cytotoxic T lymphocyte activity. Challenge by subcutaneous injection with FRalpha
      transduced C26 cells (performed 10 days after the third injection) showed a
      statistically significant delay in tumor growth. Vaccination with the FRalpha and
      interleukin-2 cDNA mixture, which was performed after an intravenous injection of
      FRalpha-transduced cells, enhanced the mean survival time and reduced the number
      of lung metastases, thus suggesting that such vaccination is effective even
      against preexisting tumor cells.

PMID- 10419055
TI  - Biodistribution of an adenoviral vector carrying the luciferase reporter gene
      following intravesical or intravenous administration to a mouse.
AB  - The biodistribution and resulting pattern of transgene expression were determined
      following intravesical administration of an adenoviral vector carrying the
      luciferase reporter gene (AdLuc). Female BALB/c mice were subjected to
      intravesical instillation of 1 x 10(9) or 5 x 10(9) plaque-forming units of
      AdLuc. After sacrifice, transgene expression was detected in tissues using
      luciferase assays; vector DNA was detected by vector-specific polymerase chain
      reaction. These experiments showed very little vector dissemination outside of
      the bladder by this route of administration. High-level expression of the vector
      transgene in the bladder was found to diminish by severalfold after 3 days. In a
      supporting study, vector dissemination and resulting transgene expression were
      determined following tail vein injection of 5 x 10(9) plaque-forming units of
      AdLuc. Vector was distributed to and expressed in every organ analyzed, with the
      highest concentration and level of expression observed in the liver.

PMID- 10419056
TI  - Construction and characterization of a recombinant adenoviral vector expressing
      human interleukin-12.
AB  - Interleukin-12 (IL-12) is a 70-kDa heterodimeric cytokine composed of a 35-kDa
      subunit (p35) and a 40-kDa subunit (p40). We have demonstrated previously that
      intratumoral delivery of a recombinant adenoviral vector expressing the mouse IL
      12 gene significantly prolongs the survival time of mice with metastatic colon
      carcinoma in the liver. We now report the molecular cloning of cDNA for both
      subunits of human IL-12 (hIL-12) in a recombinant adenoviral vector in which the
      p40 and p35 subunits are linked and coexpressed using the encephalomyocarditis
      virus internal ribosome entry site. The recombinant adenoviral vector was used to
      transduce human tumor cell lines, and the presence of hIL-12 in the conditioned
      media was illustrated by enzyme-linked immunosorbent assay. The biological
      activity of hIL-12 in the conditioned media was also demonstrated in vitro
      through its ability to induce interferon-gamma production from peripheral blood
      mononuclear cells (PBMCs), to stimulate PBMC proliferation, and to enhance
      natural killer activity from normal human PBMCs to lyse natural killer-sensitive
      K562 target cells. The results of these studies support the application of this
      recombinant adenoviral vector construct as an efficient gene delivery vehicle in
      phase I/II clinical studies of hIL-12 gene therapy for cancer.

PMID- 10419057
TI  - Inhibitory effect on the establishment of hepatic metastasis by transduction of
      the tissue plasminogen activator gene to murine colon cancer.
AB  - Hepatic metastasis is a major factor in limiting the prognosis of patients with
      colon carcinoma. Recent investigations indicate a correlation between plasminogen
      activator profiles and hepatic metastasis. We examined the effectiveness of
      tissue plasminogen activator (tPA) gene therapy using a hepatic metastasis model
      of murine colon carcinoma. Murine colon carcinoma Colon 26 cells transduced with
      an MFGtPA retroviral vector (Colon 26/tPA) or an MFGLacZ retroviral vector (Colon
      26/LacZ) were injected into the liver via the superior mesenteric vein of BALB/c
      mice, whose survival rates were checked daily. The mean survival rate of mice
      with hepatic metastasis induced by Colon 26/LacZ was 23.1 days, whereas that of
      mice with Colon 26/tPA was >100 days. The in vitro proliferation of Colon 26/tPA
      was comparable with that of Colon 26/LacZ, and antitumor immunity to wild-type
      Colon 26 cells was not induced after an intrahepatic injection of Colon 26/tPA.
      We suggest that transduction of the tPA gene to murine colon cancer is useful
      against the establishment of hepatic metastasis.

PMID- 10419058
TI  - Uric acid as a cardiovascular risk factor in arterial hypertension.
AB  - BACKGROUND: Increased serum urate concentrations is a frequent finding in
      patients with hypertension. Since hyperuricaemia is associated with obesity,
      renal disease, hyperlipidaemia, and atherosclerosis the question as to whether
      serum urate is a cardiovascular risk factor per se has remained elusive. In
      considering the relationship between uric acid and hypertension three aspects
      should be answered: (a) the significance of hyperuricaemia; (b) the
      pathophysiological mechanism of the association; and (c) whether hyperuricaemia
      is deleterious. SIGNIFICANCE OF HYPERURICAEMIA: Several arguments favour the
      concept that increased serum urate in hypertensive patients most likely reflects
      renal vascular involvement. PATHOPHYSIOLOGICAL MECHANISM: Hyperuricaemia is
      accompanied by a relatively diminished uric acid excretion rate in hypertensive
      patients. Selective insulin resistance and hyperinsulinism estimulates the
      tubular sodium-hydrogen exchanger and facilitates the active reabsorption of
      urate. IS HYPERURICAEMIA DELETERIOUS?: In addition to the renal (urolithiasis)
      and articular disturbances that hyperuricaemia may cause, vascular damage due to
      arterial hypertension may limit the availability of oxygen for ATP synthesis.
      Tissue hypoxia determines increased adenine nucleotide degradation which ends in
      uric acid overproduction. The formation of uric acid is accompanied by an
      enhanced synthesis of reactive oxygen species which play a significant role in
      tissue damage. The hypothesis that hyperuricaemia indicates hypertensive vascular
      damage is plausible and if unequivocally demonstrated may contribute to delineate
      evidence-based therapeutic strategies for hypertensive-hyperuricaemic patients.

PMID- 10419059
TI  - Non-peptide angiotensin type 1 receptor antagonists in the treatment of
      hypertension.
AB  - Angiotensin II (Ang II) acts at the cellular level on two receptor subtypes: the
      AT1 receptor which can be blocked by losartan and its analogues (the 'sartan
      family'), and the AT2 receptor that does not react with the above antagonists but
      which can be blocked by different compounds, such as PD123319. AT1 receptor
      blockade has proven to be a highly effective means of interference with the renin
      angiotensin system (RAS) and hence of reducing high blood pressure. As a result
      of the terminal blockade of the RAS cascade, circulating Ang II levels tend to
      rise two- to threefold. The free access of such enhanced levels to uninhibited
      AT2 receptors may be clinically relevant, as argued in the present review. The
      most extensive experimental and clinical experience with AT1 receptor blockade so
      far has been obtained with the pioneer drug losartan, although major
      contributions have also been made on candesartan cilexetil, irbesartan and
      valsartan. All of these four drugs have been instrumental in substantial clinical
      trials, serving as sources of information in the clinically oriented part of this
      review. AT1 receptor blocking drugs generally provide a relatively gradual
      decrease in blood pressure, which is comparable to that obtained with
      conventional anti-hypertensive drugs. Clinical trials reveal an astounding lack
      of drug-related adverse effects, scoring even better than placebo in terms of
      frequencies and sometimes patterns. The trough/peak ratio on single dosages seems
      to have been mastered, particularly with the second generation of AT1 receptor
      blockers, as is evident from 24 h ambulatory blood pressure monitoring.
      Combination with low-dose thiazide regimens is well established. Intermediate
      endpoints (micro-albuminuria and left ventricular hypertrophy) appear to be
      controllable. Morbid cardiovascular sequelae are currently under study in
      comparison with beta- and calcium channel blockade.

PMID- 10419060
TI  - The relationship between birth weight and blood pressure amplifies from childhood
      to adulthood.
AB  - OBJECTIVE: To investigate relationships between birth characteristics and blood
      pressure at age 20 years and to assess whether effects of birth weight on blood
      pressure are amplified from childhood to adulthood. DESIGN: A longitudinal study
      of 584 men and women from Adelaide, Australia, examined previously at 8 years and
      followed up at age 20 years. RESULTS: Birth weight was negatively associated with
      systolic pressure at age 20 years in men (regression coefficient 2.6 mmHg per kg;
      95% confidence interval 0.7, 4.4) and women (regression coefficient 4.6 mmHg per
      kg; 95% confidence interval 2.9, 6.4), after adjustment for current weight There
      was an interaction with current size (P = 0.05 for men and P = 0.09 for women),
      such that effects were enhanced among individuals with relatively high weight or
      weight for height. Shortness at birth, thinness at birth, and low birth weight
      relative to placental weight were also associated with elevated systolic pressure
      at age 20 years. Effects of birth weight on blood pressure were stronger at age
      20 than at age 8 years (P < 0.01 for men and P = 0.03 for women). This was not
      due simply to increased variability of blood pressure in adulthood. There were
      greater rises in blood pressure with age among individuals of relatively low
      birth weight. CONCLUSIONS: These findings are further evidence that poor fetal
      growth is associated with elevated blood pressure in later life. The results
      support the hypothesis that the relationship is amplified with increasing age.

PMID- 10419061
TI  - Characteristics of blood pressure measured at home in the morning and in the
      evening: the Ohasama study.
AB  - OBJECTIVE: To determine the qualitative and quantitative differences of blood
      pressure measured at home (home measurement) in the morning versus the evening.
      METHODS: Of 3744 participants, aged 20 years or older in the Ohasama population,
      more than 14 home measurements in the morning and in the evening, respectively,
      were obtained in each of 1207 individuals (881 untreated, 56.1 +/- 11.4 years and
      326 treated, 66.0 +/- 9.2 years). A casual/screening measurement was also
      obtained in these individuals. RESULTS: The home measurements in the morning were
      significantly higher than those in the evening. The bivariate linear regression
      analysis demonstrated that the difference between diastolic home measurement in
      the morning and that in the evening increased with an increase in diastolic home
      measurements. The multiple step-wise linear regression analysis, however,
      demonstrated that male sex, the use of antihypertensive medication, and SD of
      home measurements in individuals (blood pressure variability), but not level of
      home measurements, were positively associated with the difference between home
      measurement in the morning and that in the evening. The SD of home measurement in
      the evening in individuals was significantly larger than that in the morning, and
      the SD in treated individuals was significantly larger than that in untreated
      individuals. The correlations between casual and home measurements were moderate
      in untreated individuals (r = 0.509-0.567) but poor in treated subjects (r= 0.223
      0.384). The correlations between home systolic measurements in the morning and in
      the evening were very close in both treated and untreated subjects (r = 0.814
      0.902). The correlations between the SD of home measurements in the morning and
      in the evening were moderate in both treated and untreated individuals (r = 0.585
      0.657). CONCLUSIONS: Qualitative and quantitative differences in home blood
      pressure measurement, due to the differential time of measurement, should be
      taken into consideration in clinical use of home blood pressure measurements.

PMID- 10419062
TI  - Dissection of silencer elements in first intron controlling the human renin gene.
AB  - OBJECTIVE: A silencer within the renin first intron (intron A) was identified
      using Calu-6 cells, a pulmonary carcinoma cell line which produced renin. In the
      present study, a dissection of the first intron was performed to determine
      precisely the cis-regulatory elements involved in the silencer transcriptional
      effects. MATERIALS AND METHODS: Intron A was completely sequenced to characterize
      potential binding sites for known transcription factors. Partial portions of
      intron A were subcloned upstream the 892 bp of the renin promoter and transfected
      in different models of renin-producing cells: primary culture of human chorionic
      cells, human Calu-6 cells and mouse As4.1 cells. RESULTS: There is significant
      DNA homology (67%) between the 3' and 5' ends of the human and rat renin first
      intron. Several transcription factor binding sites identified in human first
      intron, but not in rat intron, do not contribute to the reported silencer
      activity. Transfections of renin/ luciferase constructs containing partial
      portions of first intron inserted upstream of the 892 bp in both renin-producing
      cells do not allow the precise characterization of cis-elements involved in the
      silencer effect. CONCLUSIONS: The silencer located renin intron A is cell
      specific. The integrity of the human first intron seems necessary for its
      repressor activity on renin proximal promoter in renin-producing cells.

PMID- 10419063
TI  - Angiotensin II stimulates DNA and protein synthesis in vascular smooth muscle
      cells from human arteries: role of extracellular signal-regulated kinases.
AB  - OBJECTIVE: This study investigates the growth effects and associated signaling
      pathways of angiotensin II (Ang II) in human vascular smooth muscle cells.
      METHODS: Cultured vascular smooth muscle cells derived from resistance arteries
      (< 300 microm diameter) from subcutaneous gluteal biopsies of healthy subjects (n
      = 6) and human aortic vascular smooth muscle cells were used. Cells were studied
      between passages 3 and 6. Both 3H-thymidine and 3H-leucine incorporation were
      measured as indices of vascular smooth muscle cell hyperplasia (DNA synthesis)
      and cell hypertrophy (protein synthesis), respectively. Growth effects of Ang II
      (10(-12) - 10(-6) mol/l), in the absence and presence of 10(-5) mol/l losartan
      (AT1 antagonist) and PD123319 (AT2 antagonist), were determined. Ang II-induced
      effects were compared to those of endothelin-1. To determine whether
      extracellular signal-regulated kinase (ERK)-dependent pathways play a role in Ang
      II-mediated growth, cells were pretreated with the selective ERK kinase (MEK)
      inhibitor, PD98059 (10(-5) mol/l). ERK activation was determined by Western blot
      in the absence and presence of PD98059. RESULTS: Ang II dose-dependently
      increased 3H-thymidine incorporation in cells from aorta (Emax = 276 +/- 10.4% of
      control) and resistance arteries (Emax = 284 +/- 5.1% of control). Ang II also
      stimulated 3H-leucine incorporation in cells from aorta (Emax = 162 +/- 11.6 of
      control) and resistance arteries (Emax 175 +/- 10% of control). Unlike Ang II,
      endothelin-1 failed to significantly alter cellular growth, except at high
      concentrations (> 10(-7) mol/l), where it had a weak stimulatory effect Losartan,
      but not PD123319, blocked Ang II-stimulated growth responses. Ang II
      significantly increased phosphorylation of ERK-1 and ERK-2, with maximum
      responses obtained at 5 min. PD98059 inhibited Ang II-stimulated ERK activity and
      abrogated agonist-induced DNA and protein synthesis. Losartan, but not PD123319
      inhibited Ang II-induced phosphorylation of ERK-1 and ERK-2. CONCLUSIONS: Ang II
      stimulates both hyperplasia and hypertrophy in vascular smooth muscle cells from
      human arteries. These growth effects are mediated via Ang II receptors of the AT1
      subtype that are linked to ERK-dependent signaling pathways.

PMID- 10419064
TI  - Effects of chronic oral treatment with imidapril and TCV-116 on the
      responsiveness to angiotensin II in ventrolateral medulla of SHR.
AB  - OBJECTIVE: To examine whether chronic oral treatment with an angiotensin
      converting enzyme inhibitor imidapril and an angiotensin II type 1 receptor
      antagonist TCV-116 would alter the response to angiotensin II in the rostral
      ventrolateral medulla. METHODS: Twelve-week-old spontaneously hypertensive rats
      (SHR) were treated with imidapril (20 mg/kg per day, n = 7), TCV-116 (5 mg/kg per
      day, n = 8) or vehicle (n = 8) for 4 weeks. Wistar- Kyoto rats (WKY) (n = 8)
      served as normotensive controls. At 16 weeks of age, angiotensin II (100 pmol)
      was microinjected into the rostral ventrolateral medulla of anaesthetized rats.
      RESULTS: Blood pressure decreased significantly in the rats treated with either
      imidapril or TCV-116. Pressor responses to angiotensin II microinjected into the
      rostral ventrolateral medulla were comparable in the untreated SHR, the imidapril
      treated SHR and WKY (12 +/- 2, 15 +/- 4 and 10 +/- 1 mmHg, respectively), but
      were abolished in SHR treated with TCV-116 (0 +/- 2 mmHg, P< 0.01). Angiotensin
      converting enzyme activity in the brain stem was significantly lower in SHR
      treated with imidapril (0.70 +/- 0.06 nmol/mg per h), but significantly higher in
      SHR treated with TCV-116 (1.62 +/- 0.04 nmol/mg per h) than in the untreated SHR
      (1.37 +/- 0.05 nmol/mg per h). CONCLUSIONS: Chronic oral treatment with imidapril
      and TCV-116 may have divergent influences on the renin-angiotensin system within
      the brain stem. TCV-116, but not imidapril, abolishes the pressor effect of
      angiotensin II in the rostral ventrolateral medulla.

PMID- 10419065
TI  - High salt intake potentiates the renal vascular and glomerular damage caused by
      low doses of angiotensin II in uni-nephrectomized rats.
AB  - OBJECTIVE: We recently reported that the renin-angiotensin system plays an
      important role in the progression of vascular and kidney injuries, even in Dahl
      salt-sensitive rats with volume-dependent hypertension. In this study, we
      investigated whether a high-salt diet increases susceptibility to kidney injury
      induced by angiotensin II in normotensive, uni-nephrectomized Sprague-Dawley
      rats, which mimics the condition of salt-volume repletion and blunted renin
      angiotensin system. METHODS: The rats were fed either a low-salt (0.3% NaCl) or a
      high-salt (4% NaCl) diet and divided into five groups: two control groups with a
      low-salt or a high-salt diet without angiotensin II infusion (saline infusion),
      and three angiotensin II groups (angiotensin II infusion, 10 or 50 ng/kg per min
      with high-salt diet, 50 ng/kg per min with low-salt diet, subcutaneously). The
      rats were kept on these regimes for 8 weeks. The blood pressure was measured
      every week. Functional and morphological alterations in the kidney were assessed
      at the end of the experiment RESULTS: There were no differences in the arterial
      blood pressures of the five experimental groups. However, angiotensin II infusion
      increased the weights of the heart and aortic walls in a dose-dependent manner in
      the high-salt groups. There was also a dose-dependent increase in proteinuria, N
      acetyl-beta-D-glucosaminidase activity (NAG) excretion, and additional glomerular
      and arterial injuries in the kidney, associated with angiotensin II infusion in
      the high-salt groups. In the rats given a higher dose of angiotensin II, the high
      salt diet significantly increased the weights of the heart and aortic walls and
      exacerbated the renal function and morphological injuries, compared to the low
      salt group. High-salt diet alone increased the kidney and heart weights. However,
      it did not significantly influence the results of the morphological and
      functional study. On the other hand, angiotensin II infusion on a low-salt diet
      showed a trend towards glomerular damage; however, the effects were small and not
      significant. Similarly, there were few effects of angiotensin II infusion on
      morphology and functional study on a low-salt diet CONCLUSION: These data clearly
      show that a high-salt intake increases susceptibility of the kidney to injuries
      induced by low doses of angiotensin II in normotensive, uni-nephrectomized rats.

PMID- 10419066
TI  - Regulation of adrenal angiotensin receptor subtypes: a possible mechanism for
      sympathectomy-induced adrenal hypertrophy.
AB  - OBJECTIVE: Previous studies indicate that the adrenal gland plays a compensatory
      role in the maintenance of blood pressure in chemically sympathectomized rats.
      However, the mechanisms responsible for compensatory adrenal responses are poorly
      understood. This study examined the regulation of adrenal growth and type 1 A, 1
      B, and type 2 angiotensin II (Ang II) receptor (AT1A, AT1B and AT2) expression in
      the adrenal gland induced by sympathectomy. METHODS: Five-week-old male Sprague
      Dawley rats were treated with either guanethidine (50 mg/kg per day,
      intraperitoneally) or vehicle for 5 weeks. Norepinephrine and epinephrine levels
      in the atrium of the heart were measured by high-pressure liquid chromatography.
      Plasma renin activity was determined by radioimmunoassay. Adrenal AT1 and AT2
      receptor density was determined by radioligand binding assay. Adrenal AT1A, AT1B
      and AT2 mRNA levels were determined by Northern blot analysis. RESULTS:
      Norepinephrine and epinephrine levels in the atrium of the heart were decreased
      86% (P < 0.0001) and 58% (P < 0.05) by guanethidine treatment, respectively.
      Plasma renin activity was decreased 71% (P< 0.001) in guanethidine-treated rats
      compared with vehicle. In contrast, the ratio of adrenal to body weight was
      increased 38% in guanethidine-treated rats compared with vehicle (P< 0.001).
      Adrenal AT1 and AT2 receptor density was increased by guanethidine treatment (P<
      0.05). Adrenal mRNA levels for AT2 (P< 0.001) and AT1A (P< 0.01), but not AT1B
      (P>0.05), were increased in guanethidine-treated rats compared with vehicle (P<
      0.01). There were positive correlations between adrenal weight and AT2 (r = 0.9,
      P< 0.001) and AT1A (r = 0.6, P< 0.05) but not AT1B (r = - 0.01, P > 0.05)
      expression. CONCLUSIONS: Impairment of the sympathetic nervous system with
      guanethidine withdraws the normal stimulation of this system on the circulating
      renin-angiotensin system, but upregulates the expression of adrenal Ang II
      receptors. Increased expression of adrenal AT2 and AT1A receptors may play an
      important role in adaptive adrenal hypertrophy and hormonal responses to
      sympathectomy.

PMID- 10419067
TI  - Influence of smoking on baroreceptor function: 24 h measurements.
AB  - OBJECTIVE: Recent studies showed that smoking four cigarettes per hour impairs
      baroreflex sensitivity in humans. In this study, baroreceptor function was
      qualified more precisely by 24 h measurements using the new portable Portapres
      system, allowing a continuous non-invasive registration of blood pressure curves.
      METHODS: Twenty-four smoking individuals (12 male/12 female) who smoked more than
      10 cigarettes per day for more than 6 years were investigated. Thirty non-smokers
      (15 male/15 female) served as controls. Data were evaluated separately for the
      08:00-22:00 h and 22:00-08:00 h periods. RESULTS: Within one 24 h period, smokers
      showed a higher blood pressure [female: mean arterial blood pressure (MAP) 85.5
      mmHg; male: MAP 93 mmHg] compared to non-smokers (female: MAP 80 mmHg; male: MAP
      90 mmHg). During daytime (08:00-22:00 h), this difference reached a level of
      statistical significance (P< 0.05) in female subjects. Heart rate was
      significantly higher in smokers (female: 86 bpm; male: 80 bpm) compared to non
      smokers (female: 77 bpm; male: 70 bpm) during the 24 h observation period. The
      number of sequences (seq) in smokers surpassed the number of sequences in non
      smokers by about 53 seq/day, which corresponds to a significant difference of
      4.5%. At night the sympathetic -systolic blood pressure/-pulse interval (-SBP/
      PI) sequences of the smoking group predominated over the -SBP/-PI sequences in
      the non-smoking group. On the other hand, the parasympathetic +SBP/+PI sequences
      were significantly less in smokers between 22:00 and 08:00 h. The regressions
      (i.e. D pulse interval/D SBP [ms/mmHg]), which represent the baroreceptor
      sensitivity, were clearly smaller in smokers. CONCLUSIONS: The present study
      provides evidence that chronic tobacco (nicotine) abuse causes pathological
      alterations of autonomic nervous blood pressure regulation which can be measured
      under normal living conditions and may be described as sympathovagal dysbalance
      and decreased baroreceptor sensitivity. Taken together with processes such as
      elevated catecholamine blood levels, these alterations may explain the higher
      risk of cardiovascular diseases.

PMID- 10419068
TI  - Significance of sympathetic nervous system in sodium-induced nocturnal
      hypertension.
AB  - OBJECTIVE: The purpose of this study was to investigate the effects of salt
      loading on circadian patterns of blood pressure (BP) and sympathetic nervous
      activity. SUBJECTS AND METHODS: Seventy-six patients with essential hypertension
      were hospitalized and placed on a low-salt diet (2 g/day) for 7 days followed by
      a high-salt diet (20-23 g/day) for another 7 days. On the last day of each salt
      diet, 24 h ambulatory BP, plasma noradrenaline concentrations, urinary
      noradrenaline excretion, plasma renin activity (PRA) and plasma aldosterone
      concentration (PAC) were measured. Patients whose average mean BP was increased
      by more than 10% by salt loading were assigned to the salt-sensitive (SS) group
      (n = 44); the remaining patients, whose mean BP was increased by less than 10%,
      were assigned to the non-salt-sensitive (NSS) group (n = 32). RESULTS: Salt
      loading converted the circadian pattern of BP from dippers, whose mean BP during
      the night-time was decreased by more than 10% from the daytime BP, to non-dippers
      in the SS group but not in the NSS group. A nocturnal decrease in plasma
      noradrenaline concentration was unaffected after salt loading in the NSS group
      but dampened in the SS group. The night-time/daytime ratio of urinary
      noradrenaline excretion, which was increased after salt loading in the SS group
      only, was greater in the SS group than in the NSS group under the high-salt diet.
      The salt-induced suppression rate of PRA and PAC was similar between the SS and
      NSS groups. CONCLUSION: BP fails to fall during the night under the high-salt
      diet in patients with the SS type of essential hypertension. This may be related
      to the lack of nocturnal decrease in sympathetic nervous activity.

PMID- 10419069
TI  - Basal sympathetic nerve activity is enhanced with augmentation of baroreceptor
      reflex in Wistar fatty rats: a model of obesity-induced NIDDM.
AB  - AIM: Wistar fatty rats (WFR) develop mild hypertension associated with obesity,
      hyperglycaemia and hyperinsulinaemia, and are thus assumed to be a good model of
      insulin resistance-related hypertension. We determined whether the activity of
      the sympathetic nervous system and its baroreflex-mediated regulation are
      involved in the development of hypertension in this strain. METHODS: Renal
      sympathetic nerve activity (RSNA) was recorded in pre-hypertensive WFR (n = 8,
      age 12 weeks) and Wistar lean rats (WLR) (n = 8) during changes in arterial
      pressure by phenylephrine and nitroprusside infusion in the conscious state.
      Baroreflex control of RSNA and heart rate were examined by logistic function
      analysis. RESULTS: The mean arterial pressure (MAP) of WFR was similar to that of
      WLR (108 +/- 4 versus 101 +/- 2 mmHg, not significant). Basal RSNA was elevated
      in WFR compared with WLR (86 +/- 2 versus 51 +/- 2% maximum, P< 0.01). Baroreflex
      control of RSNA was shifted to higher pressure levels (mid-range, 119 +/- 4
      versus 99 +/- 4 mmHg, P < 0.05) in WFR compared with WLR, in spite of similar
      MAP. However, baroreflex sensitivity concerning RSNA was greater in WFR than WLR
      (3.07 +/- 0.15 versus 1.63 +/- 0.12% maximum/mmHg, P < 0.01). Baroreflex control
      of heart rate was also shifted to higher pressure levels (mid-range 129 +/- 4
      versus 100 +/- 5 mmHg, P < 0.01) and its sensitivity was increased in WFR
      compared with WLR (4.62 +/- 0.51 versus 3.16 +/- 0.10 bpm/mmHg, P< 0.05).
      CONCLUSION: These results suggest that baroreflex is not impaired in spite of
      elevation of blood pressure and that the raised sympathetic nerve activity may
      contribute to the development of hypertension in WFR.

PMID- 10419070
TI  - Lacidipine reduces high blood pressure and the target organ damage induced by
      high fructose diet in rats.
AB  - OBJECTIVE: Normotensive rats fed a high fructose diet (HFD) develop
      hypertriglyceridemia, hyperinsulinemia and hypertension. The glomerular changes
      observed in the kidneys of these animals are similar to those observed in
      diabetic rats. The aim of this study was to evaluate whether lacidipine could be
      effective not only in preventing, but also in inducing the regression of
      hypertension, and renal and cardiac damage in rats fed HFD. METHODS: Thirty male
      Wistar-Kyoto (WKY) rats received HFD for 1 month; thereafter, five rats were
      sacrificed (Group 1) and the other 25 rats were divided into three groups: Group
      2 (five rats) received HFD plus placebo, Group 3 (10 rats) HFD plus lacidipine 3
      mg/kg per day, and Group 4 (10 rats) HFD plus hydralazine 10 mg/kg per day. At
      the end of the second month all animals were sacrificed. Kidneys and hearts were
      immediately removed. Renal deposits of collagen I, collagen IV, fibronectin and
      cardiac deposits of collagen III were assessed by means of immunohistochemistry.
      RESULTS: In the rats receiving HFD plus placebo, blood pressure was increased
      after the first and the second month of diet. This increase was reversed by
      lacidipine and hydralazine but, although both drugs normalized blood pressure,
      only lacidipine was effective in reducing renal and cardiac damage. CONCLUSIONS:
      These data suggest that lacidipine is effective in reversing hypertension and
      reducing target organ damage induced by HFD. Moreover, this protective effect on
      target organs appears to be not simply a consequence of blood pressure reduction,
      but seems to be connected to the type of hypotensive drug administered.

PMID- 10419071
TI  - Effect of the calcium channel blocker nitrendipine in normotensive and
      spontaneously hypertensive, diabetic rats on kidney morphology and urinary
      albumin excretion.
AB  - OBJECTIVE: To investigate the effect of nitrendipine on the development of renal
      changes in experimental diabetes. DESIGN: Streptozotocin (STZ)-induced diabetic
      normotensive Wistar rats (WIS) and spontaneously hypertensive rats (SHR) were
      randomly allocated to nitrendipine treatment (250 mg/kg fodder) or placebo
      treatment for 6 months. METHODS: Blood pressure was assessed by the tail-cuff
      method, urinary albumin excretion (UAE) was determined, and glomerular basement
      membrane (GBM) thickness, mesangial volume, and mean glomerular volume (MGV) were
      estimated by morphometric measurements. RESULTS: In diabetic WIS, nitrendipine
      significantly reduced UAE after 2 months of treatment (P< 0.05), while no effect
      was was seen after 4-6 months. In diabetic SHR, no effect on UAE was seen at any
      time. Nitrendipine was unable to inhibit the renal and glomerular enlargement in
      diabetic WIS and SHR. Diabetes plus hypertension was associated with significant
      increase in GBM thickness, while diabetes or hypertension alone showed no
      significant increase in GBM. Nitrendipine treatment was unable to prevent
      increased GBM in diabetic SHR. CONCLUSION: Nitrendipine inhibits an early
      increase in UAE in normotensive, diabetic rats, but fails to sustain this effect
      in long-term diabetes. No effect of nitrendipine was observed in SHR.

PMID- 10419072
TI  - Interaction between lifetime captopril treatment and NaCI-sensitive hypertension
      in spontaneously hypertensive rats and Wistar-Kyoto rats.
AB  - DESIGN: Previous studies that were based on daytime arterial pressure recordings
      indicate that lifetime treatment with captopril exacerbates the hypertensive
      response to a high NaCl diet in spontaneously hypertensive rats (SHR) but has no
      such effect in normotensive Wistar-Kyoto (WKY) rats. The present study used 24-h
      recording methods to examine the hypothesis that during the normal waking hours
      of rats (night-time) the hypertensive response to a high NaCl diet is exacerbated
      in SHR and induced in WKY rats treated with lifetime captopril. METHODS: SHR and
      WKY rats were (1) untreated, (2), lifetime captopril treated or (3) lifetime
      captopril treated but removed from the treatment 2 weeks prior to exposure to a
      high (8%) NaCl diet RESULTS: Compared to untreated SHR, in SHR that were
      continuously treated with captopril, the high NaCl diet caused a more rapid and
      greater rise in arterial pressure. Discontinuation of the captopril treatment did
      not significantly diminish this NaCl-sensitivity. In untreated WKY rats, the high
      NaCl diet did not alter mean arterial pressure, but in the lifetime captopril
      treated WKY rats the high NaCl diet induced a rapid rise in arterial pressure. In
      WKY rats, discontinuation of the lifetime captopril treatment did not diminish
      this NaCl-induced rise in arterial pressure, even though baseline mean arterial
      pressure in this group is similar to that in untreated WKY rats. CONCLUSIONS:
      Lifetime captopril treatment accelerates the hypertensive response to a high NaCl
      diet in SHR, and it induces a similar response in WKY rats. In both strains, the
      lifetime captopril treatment causes a change in the response that is not
      dependent on concurrent administration of the drug. This finding further suggests
      that lifetime captopril treatment causes a long-term resetting of cardiovascular
      response mechanisms.

PMID- 10419073
TI  - Left ventricular geometry and function in patients with essential hypertension
      and microalbuminuria.
AB  - BACKGROUND: Microalbuminuria has recently emerged as a strong, independent
      predictor of cardiovascular mortality in patients with essential hypertension,
      yet the pathophysiological mechanisms underlying this association remain to be
      elucidated. OBJECTIVE: To study the relationship between microalbuminuria and
      left ventricular geometry and function and extra-cardiac vascular changes in a
      group of 211 untreated hypertensive patients. METHODS: Albuminuria was evaluated
      as albumin-to-creatinine ratio in three non-consecutive first morning urine
      samples. Left ventricular mass index and function were assessed by M-B mode
      echocardiography and carotid wall thickness by high-resolution ultrasound scan.
      RESULTS: The prevalences of microalbuminuria and left ventricular hypertrophy
      were 14 and 47% respectively. Patients in the top quartile of albuminuria showed
      a higher left ventricular mass index (57 +/- 1.8, 55 +/- 2, 47 +/- 1.4 and 48 +/-
      1.6 g/m2.7, respectively; P< 0.0001) as well as a higher prevalence of left
      ventricular hypertrophy (72, 65, 26 and 25%, respectively; P< 0.001) and
      especially concentric hypertrophy (56, 47, 17 and 21%, respectively; P< 0.0001)
      in the four quartiles of albuminuria. Microalbuminuric patients showed depressed
      left ventricular performance as indicated by a reduced midwall fractional
      shortening (15.7 +/- 0.3, 15.9 +/- 0.3, 16.7 +/- 0.4 and 16.8 +/- 0.3%,
      respectively; P< 0.02). Furthermore patients in the top quartile of albuminuria
      showed increased carotid wall thickness as compared to normoalbuminuric patients
      (0.78 +/- 0.03, 0.7 +/- 0.04, 0.65 +/- 0.03 and 0.6 +/- 0.03 mm, respectively; P
      < 0.001). CONCLUSIONS: Hypertensive patients with microalbuminuria show a higher
      prevalence of unfavourable left ventricular geometric patterns, depressed left
      ventricular function and early signs of extra-cardiac vascular damage. These
      findings strengthen the role of microalbuminuria as an indicator of subclinical
      cardiovascular disease and may account for the worse outcome that is usually
      associated with increased urinary albumin excretion in essential hypertension.

PMID- 10419074
TI  - Left ventricular chamber and wall mechanics in the presence of concentric
      geometry.
AB  - BACKGROUND: To test the hypothesis that in the presence of left ventricular
      concentric geometry the definition of 'normal' ejection fraction should be
      reconsidered, and normality should rather be considered to have a higher than
      usual lower limit METHODS: M-mode echocardiographic endocardial shortening (eS)
      was studied in 148 hypertensive patients with left ventricular concentric
      geometry (relative wall thickness > or = 0.42), 78 with normal (54 +/- 10 years,
      27 women) and 70 with depressed midwall shortening (mS) (53 +/- 10 years, 26
      women), based on normal distribution of stress-corrected mS, and compared to a
      reference adult population of 297 age-matched normal subjects (54 +/- 8 years,
      121 women) with eS > or = 28%. RESULTS: Patients with low mS exhibited higher
      heart rates and body mass indices than control individuals (both P < 0.01); blood
      pressure, left ventricular mass, relative wall thickness and peripheral
      resistance were higher than in patients with normal mS, whereas cardiac index was
      reduced (all P< 0.01). Adjustment for body mass index and race attenuated but did
      not eliminate the differences between the two groups of patients (0.05 < P <
      0.0001). In contrast, eS was higher than normal in patients with normal midwall
      shortening, whereas was 'normal' in patients with low left ventricular midwall
      function. More than 80% of patients in the lowest quartile of apparently normal
      eS exhibited clear-cut low left ventricular midwall function. CONCLUSIONS:
      'Normal' left ventricular chamber function in the presence of concentric geometry
      is associated with depressed midwall performance, more severe left ventricular
      hypertrophy, lower cardiac output and higher peripheral resistance. 'Normal' eS
      is the hallmark of normal myocardial function when left ventricular geometry is
      normal, but should be considered as a marker of systolic dysfunction when
      associated with concentric left ventricular geometry. Normal limits for eS should
      be therefore reset to upper values.

PMID- 10419075
TI  - Impact of arterial elastance as a measure of vascular load on left ventricular
      geometry in hypertension.
AB  - OBJECTIVE: Effective arterial elastance (Ea), integrating the pulsatile component
      of left ventricular (LV) afterload, is an estimate of aortic input impedance. We
      evaluated relationships of Ea with left ventricular anatomy and function in
      essential hypertension. DESIGN: A cross-sectional analysis in 81 normotensive and
      174 untreated hypertensive individuals enrolled in a referral hypertension
      centre. METHODS: Using echocardiography we determined left ventricular mass index
      (LVMI), relative wall thickness (RWT), stroke volume (SV), endocardial (FSe) and
      midwall (FSm) fractional shortening and total peripheral resistance (TPR).
      Carotid pressure waveforms were obtained by arterial tonometry, and end-systolic
      pressure (Pes) was measured at the dicrotic notch. Ea index (EaI) was calculated
      as Pes/(SV index); LV elastance (Ees) was estimated as Pes/LV end-systolic
      volume, and ventriculo-arterial coupling was evaluated by the Ea/Ees ratio.
      RESULTS: EaI was higher in hypertensives than in normotensives (3.02 +/- 0.63
      versus 2.40 +/- 0.52 mmHg/l per m2; P< 0.0001). Using the 95% upper confidence
      limit in normotensives, hypertensives were divided in two groups with normal or
      elevated EaI. The 38 hypertensives with elevated EaI had higher RWT (0.41 +/-
      0.06 versus 0.37 +/- 0.05), lower LVMI (87.5 +/- 18.5 versus 96.8 +/- 19.3 g/m2),
      higher TPR (2247 +/- 408 versus 1658 +/- 371 dynes/cm s(-5)) and lower FSe and
      FSm (35 +/- 5 versus 39 +/- 5 and 16 +/- 2 versus 18 +/- 2%; all P< 0.05) than
      patients with normal EaI. Ea/Ees ratio was increased and cardiac output was
      reduced in hypertensives with elevated EaI. CONCLUSIONS: High values of EaI
      identify a minority of hypertensive patients characterized by elevated TPR, left
      ventricular concentric remodelling, depressed left ventricular systolic function
      and impaired ventriculo-arterial coupling.

PMID- 10419076
TI  - A prospective study of hypertension and the incidence of kidney stones in men.
AB  - OBJECTIVE: To examine whether hypertension predicts the incidence of kidney stone
      disease. DESIGN: Prospective cohort study (the Olivetti Prospective Heart Study).
      SETTING: The Olivetti factory in Southern Italy. SUBJECTS: Five hundred and three
      male workers, aged 21 - 68 years, with no evidence of kidney stone disease at
      baseline. Follow-up 8 years. MAIN OUTCOME MEASURES: Anthropometry, blood
      pressure, biochemistry and history of kidney stone disease were evaluated at the
      baseline examination in 1987. Occurrence of kidney stone disease was evaluated
      again in 1994-1995. Hypertension was defined as systolic blood pressure > or =
      160 or diastolic blood pressure, > or = 95 mmHg or both, or being on drug therapy
      for hypertension. Occurrence of kidney stone disease was defined as radiological
      or echographic evidence of calculi or documented passage of one or more stones.
      RESULTS: At baseline, 114/503 men (22.7%) had hypertension and 32 were on drug
      treatment. After 8 years, 52 (10.3%) incident cases of kidney stone disease were
      detected. The majority (n = 45) had a documented passage of one or more stones.
      The incidence of kidney stone disease was higher in hypertensive than in
      normotensive men (19/114 (16.7%) versus 33/389 (8.5%); P = 0.011). Hypertensive
      men had a greater risk of developing kidney stones than normotensive ones (RR
      1.96; 95% confidence interval 1.16-3.32). The risk was unaffected by the
      exclusion of treated hypertensives (2.01; 1.13-3.59) and after adjustment for age
      (1.89; 1.12-3.18), body weight (1.78; 1.05-3.00) or height (2.00; 1.19-3.38).
      CONCLUSIONS: Hypertension in middle-aged men is a significant predictor of kidney
      stone disease rather than a consequence of renal damage caused by the kidney
      stones.

PMID- 10419077
TI  - Ambulatory 24-h blood pressure assessment of the felodipine-metoprolol
      combination versus amlodipine in mild to moderate hypertension. Lorraine General
      Physician Investigators Group.
AB  - OBJECTIVE: To measure the time effect profiles of a once daily administered
      combination tablet felodipine-metoprolol 5/50 mg (Logimax, Astra) and amlodipine
      5 mg (Norvasc, Pfizer) on blood pressure and heart rate using 24-h ambulatory
      blood pressure monitoring. DESIGN: Randomized multicentre parallel-group study
      with a single-blind placebo run-in period of 4 weeks duration and a 6-week double
      blind active treatment period. PATIENTS AND METHODS: Out of 245 randomized
      outpatients (90 men, 155 women) with uncomplicated mild-to-moderate primary
      hypertension and mean sitting diastolic blood pressure (DBP) 95-115 mmHg
      inclusive, 212 (102 on felodipine-metoprolol, 110 on amlodipine) were eligible
      for analysis. 24-h ambulatory blood pressure monitoring was performed at the end
      of the placebo run-in (baseline) and after 6 weeks active treatment
      (posttreatment). RESULTS: Both felodipine-metoprolol and amlodipine induced
      smooth and consistent reduction in DBP and systolic blood pressure throughout the
      24-h period, hence not altering the diurnal rhythm. However, felodipine
      metoprolol reduced all average blood pressures (24-h, day- and night-time) more
      than amlodipine (for 24-h average blood pressure 14.4/9.5 mmHg and 8.9/5.5 mmHg,
      respectively). Medians of individual diastolic trough-to-peak (T/P) ratios were
      similar for felodipine-metoprolol and amlodipine (54 and 50%, respectively),
      while for the systolic T/P ratios, the corresponding values were 74 and 35%,
      repectively; no significant difference between treatments was seen. As
      distinguished from amlodipine, both heart rate and rate pressure product were
      markedly decreased on felodipine-metoprolol throughout the 24-h period and even
      during the early morning hours. In general, both treatments were well tolerated.
      CONCLUSIONS: Both felodipine-metoprolol and amlodipine achieved optimal control
      of blood pressure during the inter-dosing interval in line with their
      pharmokinetic profiles. The vasodilatory adverse events were slightly more
      reported with felodipine-metoprolol combination, but due to more pronounced
      lowering of the average blood pressures and the potent additional effect on heart
      rate and rate pressure product, the efficacy/tolerability balance seems to be
      equal to or better than that obtained with monotherapy such as amlodipine.

PMID- 10419078
TI  - Effect of eprosartan and losartan on uric acid metabolism in patients with
      essential hypertension.
AB  - OBJECTIVE: The influence of angiotensin II AT-1 receptor antagonists on uric acid
      metabolism, and the potential differences among them with regard to this effect,
      remains to be precisely established. This study was designed to compare the
      effects of losartan and eprosartan on uric acid metabolism in patients with mild
      to moderate essential hypertension. DESIGN: Randomized, double-blind, parallel
      group study in hypertensive patients. SETTING: Outpatient clinic. PATIENTS:
      Following a 2- to 3-week single-blind placebo run-in period, 60 patients with
      sitting diastolic blood pressure > or = 95 and < or = 114 mmHg were randomized.
      Fifty-eight patients completed the study. INTERVENTIONS: Patients were randomized
      to receive losartan 50 mg or eprosartan 600 mg once daily for 4 weeks. MAIN
      OUTCOME MEASURES: The primary endpoint was the change in the ratio of urinary
      uric acid/creatinine in the period 0-4 h of a 24 h urine collection after 4 weeks
      of treatment. Secondary endpoints included 24 h urinary uric acid excretion, as
      well as serum urate and anti-hypertensive efficacy. RESULTS: Mean urinary uric
      acid/creatinine changes from baseline were 0.14 (day 1) and 0.11 (week 4) for
      losartan and -0.04 for eprosartan (at both day 1 and week 4; P < 0.01 between
      groups at both time-points). The mean increase in 24 h urinary uric acid
      excretion with losartan was 0.7 mmol/24 h (25% increase from baseline) at both
      day 1 and week 4. No significant difference was observed in the change of serum
      urate levels versus baseline between both treatment groups after 4 weeks (- 23.4
      and - 19.5 micromol/l for losartan and eprosartan, respectively). Patients with
      hyperuricaemia in both treatment groups showed similar modifications of uric acid
      metabolism compared with non-hyperuricaemic subjects. Blood pressure control
      (sitting diastolic blood pressure < 90 mmHg or < 100 mmHg with a decrease of at
      least 10 mmHg from baseline) was achieved in 22 patients (73%) with eprosartan
      and in 16 (53%) with losartan. CONCLUSIONS: Losartan increased uric acid
      excretion in hypertensive patients, whilst eprosartan did not Neither AT-1
      receptor antagonist substantially modified serum urate concentrations.

PMID- 10419079
TI  - Compliance with aspirin or placebo in the Hypertension Optimal Treatment (HOT)
      study.
AB  - OBJECTIVE: The Hypertension Optimal Treatment (HOT) study is a large, prospective
      trial aimed at defining the level of diastolic blood pressure required during
      anti-hypertensive therapy in order to achieve maximal protection against
      cardiovascular complications. A further aim is to assess the effects on morbidity
      and mortality of a 75 mg daily dose of aspirin compared with placebo. SUBJECTS
      AND METHODS: Compliance with double-blind administration of aspirin or placebo
      added to anti-hypertensive treatment was evaluated for 1 year in a subset (n =
      530) of the study population (n = 18 790) by placing the medication in a
      container closed with an electronic cap that records precisely the time of each
      opening. RESULTS: The 1-year compliance rate (percentage of days with one opening
      per day) could be assessed in 501 patients. It averaged 78.3 +/- 25% in aspirin
      treated patients (n = 236, mean +/- SD), compared with 78.5 +/- 25% in patients
      having received placebo (n = 265), and was not influenced by age, sex or country
      (Germany, Italy, Switzerland, UK). The compliance rate was also similar
      irrespective of whether the patients had reached their target blood pressure, but
      was significantly better during the first than the second 6-month monitoring
      period (84.1 +/- 22% versus 72.3 +/- 32%, n = 501). CONCLUSIONS: The high rate of
      compliance with aspirin or placebo observed in the HOT study suggests that the
      patients were highly motivated and may account for the unusually good blood
      pressure control achieved in this trial during long-term anti-hypertensive
      treatment.

PMID- 10419080
TI  - Essentiality of fatty acids.
AB  - All fatty acids have important functions, but the term "essential" is applied
      only to those polyunsaturated fatty acids (PUFA) that are necessary for good
      health and cannot be completely synthesized in the body. The need for arachidonic
      acid, which is utilized for eicosanoid synthesis and is a constituent of membrane
      phospholipids involved in signal transduction, is the main reason why the n-6
      class of PUFA are essential. Physiological data indicate that n-3 PUFA also are
      essential. Although eicosapentaenoic acid also is a substrate for eicosanoid
      synthesis, docosahexaenoic acid (DHA) is more likely to be the essential n-3
      constituent because it is necessary for optimal visual acuity and neural
      development. DHA is present in large amounts in the ethanolamine and serine
      phospholipids, suggesting that its function involves membrane structure. Because
      the metabolism of n-6 PUFA is geared primarily to produce arachidonic acid, only
      small amounts of 22-carbon n-6 PUFA are ordinarily formed. Thus, the essentiality
      of n-3 PUFA may be due to their ability to supply enough 22-carbon PUFA for
      optimal membrane function rather than to a unique biochemical property of DHA.

PMID- 10419081
TI  - Sphingolipid metabolism in the regulation of bioactive molecules.

PMID- 10419082
TI  - Lipids in vascular function.
AB  - Physiological and pathological vascular responses depend on the action of
      numerous intercellular mediators, ranging from hormones to gases like nitric
      oxide, proteins, and lipids. The last group consists not only of the different
      types of lipoproteins, but also includes a broad array of other lipophilic
      signaling molecules such as fatty acids, eicosanoids, phospholipids and their
      derivatives, sphingolipids and isoprenoids. Due to space limitations, it is
      impossible to discuss all the vascular effects of lipophilic mediators or
      compounds. Therefore, we will focus on one of the most important lipid-mediated
      diseases, atherosclerosis. Lipoproteins and especially their native or oxidized
      lipid compounds affect vascular function in many different ways, and these
      effects do not only modulate atherogenesis but are of paramount physiological and
      pathophysiological importance in other diseases, such as inflammation, tumor
      metastasis, or normal wound healing.

PMID- 10419083
TI  - Dietary fatty acids and coronary heart disease.
AB  - The effects of dietary fats have been established in epidemiological and
      intervention studies and through relationship to risk factors for development of
      coronary heart disease (CHD). During a period where the impressive effects of
      hydroxymethylglutaryl-CoA reductase inhibitors on the mortality of CHD dominate
      the medical journals, it is important to realize the major effects of dietary
      fatty acids on a series of events included in the multifactorial disorder of CHD.

PMID- 10419084
TI  - Antioxidant and other activities of phenolics in olives/olive oil, typical
      components of the Mediterranean diet.

PMID- 10419086
TI  - Administration of docosahexaenoic acid influences behavior and plasma
      catecholamine levels at times of psychological stress.
AB  - The purpose of the present research was to clarify the effect of docosahexaenoic
      acid (DHA) intake on behavior and plasma catecholamines (CA). In Study 1, 42
      students took either DHA-rich oil capsules containing 1.5-1.8 g DHA/d or control
      oil capsules containing 97% soybean oil plus 3% of another fish oil for 3 mon in
      a double-blind fashion. They took a psychological test (PF Study) at the start
      and end of the study. This study started at the end of summer vacation and ended
      just before the final exams. In the control group, external aggression
      (aggression against others) in PF Study was significantly increased at the end of
      the study as compared with that measured at the start (+8.9%), whereas it was not
      significantly changed in the DHA group (-1.0%). In a similar double-blind study
      (Study 2), we measured external aggression under nonstressful conditions.
      External aggression slightly decreased in the control group, whereas there were
      no significant changes in the DHA group. In Study 3 with 14 students, plasma CA
      were measured at the start and end of capsule administration period of 2 mon.
      Subjects were under continuous stress of the final exams that lasted throughout
      the whole study period. The ratio of plasma epinephrine to norepinephrine
      concentrations was significantly increased in the DHA group (78%), whereas it
      stayed at the same level in the control group. In Study 4, mice were fed either
      DHA-deficient diet or -sufficient diet for 4 wk, and their rearing frequency (an
      anxiety index) was measured. In the DHA-sufficient group, the rearing frequency
      was significantly less than in the other group. These effects of DHA intake may
      be applied to people in an attempt to ameliorate stress-related diseases.

PMID- 10419085
TI  - Fatty acids, antioxidants, and coronary heart disease from an epidemiological
      perspective.
AB  - Oxidized low density lipoproteins (LDL) play a major role in the development of
      atherosclerosis. Saturated fatty acids, especially fatty acids with 12-16 carbon
      atoms, are the most important determinants of the LDL cholesterol level. The LDL
      lipoprotein fraction can be oxidized by, e.g., smoking. Oxidative damage of LDL
      lipoproteins can be prevented by nutritive, e.g., vitamin E, and nonnutritive
      antioxidants, e.g., flavonoids. It can therefore be hypothesized that fatty acids
      and antioxidants are important determinants of coronary heart disease (CHD).
      There is a large body of evidence from prospective studies that LDL cholesterol
      lowering is associated with a lower CHD risk. The evidence for a protective
      effect of antioxidants on CHD risk is much weaker and is most promising for
      vitamin E and flavonoids. The Seven Countries Study showed that at the population
      level saturated fat, cigarette smoking, and flavonoids are important determinants
      of long-term CHD mortality. These results suggest that a diet low in saturated
      fat and rich in antioxidants in combination with no smoking is associated with
      low CHD risk.

PMID- 10419087
TI  - Evidence for the unique function of docosahexaenoic acid during the evolution of
      the modern hominid brain.
AB  - The African savanna ecosystem of the large mammals and primates was associated
      with a dramatic decline in relative brain capacity associated with little
      docosahexaenoic acid (DHA), which is required for brain structures and growth.
      The biochemistry implies that the expansion of the human brain required a
      plentiful source of preformed DHA. The richest source of DHA is the marine food
      chain, while the savanna environment offers very little of it. Consequently Homo
      sapiens could not have evolved on the savannas. Recent fossil evidence indicates
      that the lacustrine and marine food chain was being extensively exploited at the
      time cerebral expansion took place and suggests the alternative that the
      transition from the archaic to modern humans took place at the land/water
      interface. Contemporary data on tropical lakeshore dwellers reaffirm the above
      view with nutritional support for the vascular system, the development of which
      would have been a prerequisite for cerebral expansion. Both arachidonic acid and
      DHA would have been freely available from such habitats providing the double
      stimulus of preformed acyl components for the developing blood vessels and brain.
      The n-3 docosapentaenoic acid precursor (n-3 DPA) was the major n-3-metabolite in
      the savanna mammals. Despite this abundance, neither it nor the corresponding n-6
      DPA was used for the photoreceptor nor the synapse. A substantial difference
      between DHA and other fatty acids is required to explain this high specificity.
      Studies on fluidity and other mechanical features of cell membranes did not
      reveal a difference of such magnitude between even alpha-linolenic acid and DHA
      sufficient to explain the exclusive use of DHA. We suggest that the evolution of
      the large human brain depended on a rich source of DHA from the land/water
      interface. We review a number of proposals for the possible influence of DHA on
      physical properties of the brain that are essential for its function.

PMID- 10419089
TI  - Changes in membrane microdomains and caveolae constituents in multidrug-resistant
      cancer cells.
AB  - Cancer chemotherapy often fails because of the development of tumors which are
      resistant to most commonly used cytotoxic drugs. This phenomenon, multidrug
      resistance (MDR), is usually mediated by overexpression of P-glycoprotein (P-gp),
      an ATPase that pumps out the drugs used in chemotherapy, thereby preventing their
      accumulation in cancer cells and greatly reducing their cytotoxic efficacy. A
      large body of work indicates that MDR is associated also with marked changes in
      membrane lipid composition. Most notably, elevated levels of cholesterol,
      glycosphingolipids (e.g., glucosylceramide), and sphingomyelin have been
      reported. These lipids are enriched in caveolae and in membrane microdomains
      termed detergent-insoluble glycosphingolipid-enriched complexes (DIGs). Recently
      we demonstrated that in multidrug-resistant tumor cells there is a dramatic
      increase in the number of caveolae and in the level of caveolin-1, an essential
      structural constituent of caveolae. Another constituent of membrane microdomains,
      phospholipase D, is also elevated in MDR cells. These findings may be related to
      the fact that a significant fraction of cellular P-gp is associated with caveolin
      rich membrane domains. The possible role of DIGs and caveolae in the acquisition
      and/or maintenance of the multidrug resistant phenotype is discussed.

PMID- 10419091
TI  - Targeting of cytosolic phospholipase A2 to plasma membrane inhibits its
      activation by G-protein coupled receptors.

PMID- 10419088
TI  - New developments in phospholipase A2.
AB  - Some of the most recent data concerning various phospholipases A2, with special
      emphasis on secretory, cytosolic, and calcium-independent phospholipases A2 are
      summarized. Besides their contribution to the production of proinflammatory lipid
      mediators, the involvement of these enzymes in key cell responses such as
      apoptosis or tumor cell metastatic potential is also discussed, taking advantage
      of transgenic models based on gene invalidation by homologous recombination. The
      possible role of secretory and cytosolic platelet-activating factor acetyl
      hydrolases is also briefly mentioned. Finally, the ectopic expression in
      epididymis of an intestinal phospholipase B opens some novel issues as to the
      possible function of phospholipases in reproduction.

PMID- 10419090
TI  - Activation of mitogen-activated protein kinase and cytosolic phospholipase A2 by
      hydrogen peroxide in fibroblasts.

PMID- 10419093
TI  - Hormonal regulation of phosphatidylcholine metabolism and transport.

PMID- 10419092
TI  - Inhibition of Ca2+-independent phospholipase A2 affects arachidonate-, not
      docosahexaenoate-, phospholipid remodeling in U(III) cells.

PMID- 10419094
TI  - Abnormalities in sarcolemmal phospholipase D and phospholipase C isoenzymes and
      in their interactions in post-infarcted failing hearts.

PMID- 10419095
TI  - Role of sphingosine in induced apoptosis.

PMID- 10419096
TI  - Sphingosine kinase: assay conditions, tissue distribution in rat, and subcellular
      localization in rat kidney and liver.

PMID- 10419097
TI  - Alpha2-adrenergic receptor-mediated release of lysophosphatidic acid by
      adipocytes: a paracrine signal for preadipocyte growth.

PMID- 10419098
TI  - Phosphatidic acid-dependent activation of adenosine-3',5'-cyclic-monophosphate
      phosphodiesterase is necessary for Arg-vasopressin induction of myogenesis.

PMID- 10419099
TI  - Regulation of cAMP-phosphodiesterases by phosphatidic acid binding.

PMID- 10419100
TI  - Tumor necrosis factor-alpha and ceramides in insulin resistance.
AB  - The present studies tested the hypothesis that some effects of tumor necrosis
      factor-alpha (TNF-alpha) are mediated by activation of sphingomyelinases and the
      production of ceramides. Differentiated 3T3-L1 adipocytes were incubated with
      short-chain ceramide analogs, (C2- and C6-ceramides: N-acetyl- and N-hexanoyl
      sphingosines, respectively), and this treatment increased 2-deoxyglucose uptake
      in the absence of insulin progressively from 2-24 h. This effect was inhibited by
      blocking the activations of mitogen-activated protein kinase,
      phosphatidylinositol 3-kinase (PI 3-kinase), and ribosomal S6 kinase which
      mediated an increase in GLUT1 concentrations. Long-term increases in PI 3-kinase
      activity associated with insulin receptor substrate-1 (IRS-1) increased the
      proportion of GLUT1 and GLUT4 in plasma membranes. These events explain the
      increases in noninsulin-dependent glucose uptake and incorporation of this
      glucose into the fatty acid and glycerol moieties of triacylglycerol. The
      mechanisms by which TNF-alpha and ceramides increase PI 3-kinase activity were
      investigated further by using rat2 fibroblasts. Incubation for 20 min with TNF
      alpha, bacterial sphingomyelinase, or C2-ceramides increased PI 3-kinase activity
      by about fivefold, and this effect depended upon a stimulation of tyrosine kinase
      activity and an increase in Ras-GTP. This demonstrates the existence of a novel
      signaling pathway for TNF-alpha that could contribute to the effects of this
      cytokine in stimulating basal glucose uptake. By contrast, treating the 3T3-L1
      adipocytes for 2-24 h with C2-ceramide diminished insulin-stimulated glucose
      uptake by decreasing the insulin-induced translocation of GLUT1 and GLUT4 to
      plasma membranes. This inhibition was observed when there was no increase in
      basal glucose uptake, and it occurred downstream of PI 3-kinase. Our work
      provides further mechanisms whereby TNF-alpha and ceramides produce insulin
      resistance and decrease the effectiveness of insulin in stimulating glucose
      disposal from the blood. Conversely, TNF-alpha and ceramides increase the ability
      of adipocytes to take up glucose and store triacylglycerol in the absence of
      insulin.

PMID- 10419101
TI  - Magnetic resonance imaging-based balance analysis of linoleate utilization during
      weight loss in obese humans.

PMID- 10419102
TI  - Diabetes puts myocardial n-3 fatty acid status at risk in the absence of
      supplementation in the rat.

PMID- 10419103
TI  - Neuroprotective effect of fish oil in diabetic neuropathy.

PMID- 10419104
TI  - Hyperglycemia inhibits liver fatty acid oxidation and increases triacylglycerol
      secretion in humans.

PMID- 10419105
TI  - Effects of 3-thia fatty acids on beta-oxidation and carnitine
      palmitoyltransferase-I activity in cultured hepatocytes.

PMID- 10419106
TI  - Polyunsaturated fatty acids and breast cancer.

PMID- 10419107
TI  - Altered lipid metabolism associated with the progression of premalignant lesions
      in rat liver.

PMID- 10419108
TI  - Reversal of tumor cell drug resistance by essential fatty acids.

PMID- 10419109
TI  - Protection from chemotherapy-induced alopecia by docosahexaenoic acid.

PMID- 10419110
TI  - Proliferation and types of killing of leukemia cell lines by very long chain
      polyunsaturated fatty acids.

PMID- 10419111
TI  - Cytotoxic drug efficacy correlates with adipose tissue docosahexaenoic acid level
      in locally advanced breast carcinoma.

PMID- 10419112
TI  - Effects of eicosapentaenoic and docosahexaenoic acids dietary supplementation on
      cell proliferation and apoptosis in rat colonic mucosa.

PMID- 10419114
TI  - Essentiality of docosahexaenoic acid in retina photoreceptor cell development.

PMID- 10419113
TI  - Fatty acid composition in serum phospholipids and risk of breast cancer: a
      prospective cohort study in Northern Sweden.

PMID- 10419115
TI  - A role for cerebral and retinal endothelial cells in the supply of
      docosahexaenoic acid to the brain and the retina?

PMID- 10419116
TI  - Effects of dietary oils and cholesterol supplement on fluidity and enzyme
      activities of liver microsomes in the rat.

PMID- 10419118
TI  - Postprandial hypertriglyceridemia induced by saturated vs. monounsaturated fatty
      acids is related to reduced hepatic lipoprotein receptors binding in NZW rabbits.

PMID- 10419117
TI  - The effect of palmitic acid on lipoprotein cholesterol levels and endogenous
      cholesterol synthesis in hyperlipidemic subjects.
AB  - The present study assesses the effect of high vs. low palmitic acid intakes on
      plasma lipoprotein cholesterol levels and on rates for endogenous synthesis of
      cholesterol in healthy and hyperlipidemic subjects. Four diets were formulated to
      provide combinations of 16:0 at two levels of 18:2n-6. Subjects received each
      diet treatment for 21 d, followed by washout periods of 21 d. On day 21 of each
      diet treatment, a fasting blood sample was drawn for lipoprotein determination
      and to provide a measure of the background level of deuterium. A priming dose of
      deuterium was consumed and a second blood sample obtained 24 h after the first
      sample. Isotope ratio mass spectrometry was used to determine the incorporation
      of deuterium into the newly synthesized cholesterol molecule, and fractional
      synthetic rates were calculated. Serum total cholesterol and low density
      lipoprotein-cholesterol was not significantly affected by the high level of 16:0
      when diets also contained a high level of 18:2n-6. There was no effect of dietary
      16:0 on high density liproprotein-cholesterol at either the high or low levels of
      intake. The results indicate that 16:0 has no effect on serum lipoprotein
      profiles in the presence of recommended intakes for 18:2n-6.

PMID- 10419119
TI  - Effects of age and dietary n-3 fatty acids on the metabolism of [13C]-alpha
      linolenic acid.

PMID- 10419120
TI  - Carbon recycling from linoleate during severe dietary linoleate deficiency.

PMID- 10419121
TI  - A chronic ethanol-feeding study in rhesus monkeys.
AB  - This study describes the effect of chronic ethanol-feeding in rhesus monkeys.
      Animals which were maintained on a diet containing 18:2n-6 and 18:3n-3 as 1.4 and
      0.08% of the calories, respectively, and consumed alcohol (mean 2.6 g kg(-1) d(
      1)) had decreased amounts of 20:4n-6 and 22:6n-3 in their livers and plasma
      lipids compared with controls. Alcohol consumption did not appear to effect the
      absorption of 2H(5)-18:2n-6 and 18:3n-3 esters into the blood following an oral
      dose. There was an increase in 2H5 enrichment in plasma 20:4n-6 and 22:6n-3,
      indicating that alcohol may have increased production of these fatty acids. There
      was a greater concentration of 4-hydroxynonenal in the plasma of alcohol-exposed
      monkeys compared to controls.

PMID- 10419122
TI  - The metabolism of essential fatty acids in rat liver is influenced more by
      dietary fat than dietary ethanol.

PMID- 10419123
TI  - Effects of n-3 and n-6 polyunsaturated fatty acids on 3-hydroxy-3-methylglutaryl
      CoA reductase in liver and mammary glands of low density lipoprotein-receptor
      knockout mice.

PMID- 10419125
TI  - Dietary fat influences the production of Th1- but not Th2-derived cytokines.

PMID- 10419124
TI  - Dietary fatty acids and the immune system.

PMID- 10419126
TI  - Very low dietary intake of n-3 fatty acids affects the immune function of healthy
      elderly people.

PMID- 10419127
TI  - The effect of dietary fat on cytokine production by murine macrophages in
      different activation states.

PMID- 10419128
TI  - Phospholipid modulation of monocyte oxidative activity measured by luminol
      enhanced chemiluminescence.

PMID- 10419129
TI  - Novel, selective delta6 or delta5 fatty acid desaturase inhibitors as
      antiinflammatory agents in mice.

PMID- 10419130
TI  - In vitro interactions of gamma-linolenic acid and arachidonic acid with
      ceftazidime on multiresistant Pseudomonas aeruginosa.

PMID- 10419132
TI  - The growing family of peroxisomal thiolases.

PMID- 10419131
TI  - Regulation of the biosynthesis of 22:5n-6 and 22:6n-3: a complex intracellular
      process.
AB  - Both 22:4n-6 and 22:5n-3 are synthesized from n-6 and n-3 fatty acid precursors
      in the endoplasmic reticulum. The synthesis of both 22:5n-6 and 22:6n-3 requires
      that 22:4n-6 and 22:5n-3 are metabolized, respectively, to 24:5n-6 and 24:6n-3 in
      the endoplasmic reticulum. These two 24-carbon acids must then move to
      peroxisomes for partial degradation followed by the movement of 22:5n-6 and 22:6n
      3 back to the endoplasmic reticulum for use as substrates in membrane lipid
      biosynthesis. Clearly an understanding of the control of intracellular fatty acid
      movement as well as of the reactions carried out by microsomes, peroxisomes, and
      mitochondria are all required in order to understand not only what regulates the
      biosynthesis of 22:5n-6 and 22:6n-3 but also why most tissue lipids selectively
      accumulate 22:6n-3.

PMID- 10419133
TI  - Alpha-oxidation of 3-methyl-branched fatty acids: a revised pathway confined to
      peroxisomes.

PMID- 10419134
TI  - Adipose peroxisome proliferator-activated receptor gamma mRNA expression in
      insulin-resistant obese patients: relationship with adipocyte membrane
      phospholipids.

PMID- 10419135
TI  - Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase and carnitine
      palmitoyltransferase II are potential control sites of hepatic ketogenesis under
      conditions of peroxisome proliferation.

PMID- 10419136
TI  - Suspicion of latent delta5-desaturase and peroxisomal beta-oxidation deficiency
      in elderly women over 75 years of age.

PMID- 10419137
TI  - The mitochondrion is the principal target for nutritional and pharmacological
      control of plasma triglyceride.

PMID- 10419139
TI  - Expression of the extracellular fatty acid-binding protein during muscle fiber
      formation in vivo and in vitro.

PMID- 10419141
TI  - Albumin interferes with the uptake metabolism of arachidonic acid by human
      leukocytes.

PMID- 10419140
TI  - Molecular modeling and experimental confirmation of selective mobilization of
      polyunsaturates from triacylglycerols.

PMID- 10419138
TI  - Cellular fatty acid transport in heart and skeletal muscle as facilitated by
      proteins.
AB  - Despite the importance of long-chain fatty acids (FA) as fuels for heart and
      skeletal muscles, the mechanism of their cellular uptake has not yet been
      clarified. There is dispute as to whether FA are taken up by the muscle cells via
      passive diffusion and/or carrier-mediated transport. Kinetic studies of FA uptake
      by cardiac myocytes and the use of membrane protein-modifying agents have
      suggested the bulk of FA uptake is due to a protein component. Three membrane
      associated FA-binding proteins were proposed to play a role in FA uptake, a 40
      kDa plasma membrane FA-binding protein (FABPpm), an 88-kDa FA translocase
      (FAT/CD36), and a 60-kDa FA transport protein (FATP). In cardiac and skeletal
      myocytes the intracellular carrier for FA is cytoplasmic heart-type FA-binding
      protein (H-FABP), which likely transports FA from the sarcolemma to their
      intracellular sites of metabolism. A scenario is discussed in which FABPpm,
      FAT/CD36, and H-FABP, probably assisted by an albumin-binding protein, cooperate
      in the translocation of FA across the sarcolemma.

PMID- 10419142
TI  - Elongation and trafficking of arachidonate in lipids of vascular smooth muscle
      cells.

PMID- 10419143
TI  - The effect of n-3 fatty acids on leukotriene formation from neutrophils in
      patients on hemodialysis.

PMID- 10419144
TI  - n-3 fatty acids in the prevention of cardiac arrhythmias.
AB  - In animals and probably in humans n-3 polyunsaturated fatty acids (PUFA) are
      antiarrhythmic. A report follows on the recent studies of the antiarrhythmic
      actions of PUFA. The PUFA stabilize the electrical activity of isolated cardiac
      myocytes by inhibiting sarcolemmal ion channels, so that a stronger electrical
      stimulus is required to elicit an action potential and the relative refractory
      period is markedly prolonged. This appears at present to be the probable major
      antiarrhythmic mechanism of PUFA.

PMID- 10419145
TI  - The inhibition of endothelial activation by unsaturated fatty acids.
AB  - Dietary long-chain fatty acids (FA) may influence pathological processes
      involving endothelial activation and leukocyte-endothelial interactions, such as
      inflammation and atherosclerosis. We previously showed that the n-3 FA
      docosahexaenoate (22:6n-3, DHA) inhibits cytokine-stimulated expression of
      endothelial-leukocyte adhesion molecules and soluble cytokines in the range of
      nutritionally achievable plasma concentrations. More recently we assessed
      structural determinants of VCAM-1 inhibition by FA. Cultured endothelial cells
      were incubated first with various saturated, monounsaturated, n-6 or n-3
      polyunsaturated FA alone and then together with interleukin-1 or tumor necrosis
      factor. Saturated FA did not inhibit cytokine-induced endothelial activation,
      while a progressive increase in inhibitory activity was observed, for the same
      chain length, with the increase in double bonds accompanying the transition from
      monounsaturates to n-6 and, further, to n-3 FA. Comparison of various FA
      indicated no role of the double-bond position or configuration; the greater
      number of double bonds could explain the greater inhibitory activity of n-3 vs. n
      6 FA. In order to ascertain mechanisms for these effects, we demonstrated
      inhibition of nuclear factor-kappaB (NF-kappaB) activation by DHA in parallel
      with a reduction in hydrogen peroxide (a critical mediator of NF-kappaB
      activation) released by endothelial cells either extracellularly or
      intracellularly. This suggests that a property related to fatty acid
      peroxidability (the presence of multiple double bonds) is related to inhibitory
      properties of hydrogen peroxide release and, consequently, of endothelial
      activation.

PMID- 10419146
TI  - Dietary fish oil promotes positive inotropy and efficiency of digitalis.

PMID- 10419147
TI  - n-3 fatty acids and the risk of sudden cardiac death assessed by 24-hour heart
      rate variability.

PMID- 10419149
TI  - The 3-thia fatty acid, a novel bioactive compound, which changes the plasma
      profile from atherogenic to cardioprotective.

PMID- 10419148
TI  - Stearic acid-rich diets do not increase thrombotic risk factors in healthy males.

PMID- 10419150
TI  - Dietary n-3 polyunsaturated fatty acids and oxidants increase rat mammary tumor
      sensitivity to epirubicin without change in cardiac toxicity.

PMID- 10419151
TI  - Roles of lipid-activated receptors in the adipogenic action of fatty acids.

PMID- 10419152
TI  - Dietary polyunsaturated fatty acids and hepatic gene expression.
AB  - Dietary polyunsaturated fatty acids (PUFA) have profound effects on hepatic gene
      transcription leading to significant changes in lipid metabolism. PUFA rapidly
      suppress transcription of genes encoding specific lipogenic and glycolytic
      enzymes and induce genes encoding specific peroxisomal and cytochrome P450 (CYP)
      enzymes. Using the peroxisome proliferator-activated receptor alpha (PPAR alpha)
      null mouse, we showed that dietary PUFA induction of acyl CoA oxidase (AOX) and
      CYP4A2 require PPAR alpha. However, PPAR alpha is not required for the PUFA
      mediated suppression of fatty acid synthase (FAS), S14, or L-pyruvate kinase (L
      PK). Studies in primary rat hepatocytes and cultured 3T3-L1 adipocytes showed
      that metabolites of 20:4n-6, like prostaglandin E2 (PGE2), suppress mRNA encoding
      FAS, S14, and L-PK through a Gi/Go-coupled signal transduction cascade. In
      contrast to adipocytes, 20:4n-6-mediated suppression of lipogenic gene expression
      in hepatic parenchymal cells does not require cyclooxygenase. Transfection
      analysis of S14CAT fusion genes in primary hepatocytes shows that peroxisome
      proliferator-activated PPAR alpha acts on the thyroid hormone response elements (
      2.8/-2.5 kb). In contrast, both PGE2 and 20:4n-6 regulate factors that act on the
      proximal promoter (-150/-80 bp) region, respectively. In conclusion, PUFA affects
      hepatic gene transcription through at least three distinct mechanisms: (i) a PPAR
      dependent pathway, (ii) a prostanoid pathway, and (iii) a PPAR and prostanoid
      independent pathway. PUFA regulation of hepatic lipid metabolism involves an
      integration of these multiple pathways.

PMID- 10419153
TI  - The double bond in unsaturated fatty acids is the necessary and sufficient
      requirement for the inhibition of expression of endothelial leukocyte adhesion
      molecules through interference with nuclear factor-kappaB activation.

PMID- 10419154
TI  - Reduction of scavenger receptor expression and function by dietary fish oil is
      accompanied by a reduction in scavenger receptor mRNA.

PMID- 10419155
TI  - The effect of eicosapentanoic acid on matrix metalloproteinase gene expression.

PMID- 10419157
TI  - Effects of fish oil and n-3 fatty acids on the regulation of delta9-fatty acid
      desaturase mRNA and -activity in rat liver.

PMID- 10419158
TI  - Fatty acid synthase gene expression in rat mammary carcinoma.

PMID- 10419156
TI  - Opposite regulation of prostaglandin H synthase isoforms by eicosapentaenoic and
      docosahexaenoic acids.

PMID- 10419159
TI  - Effects of maternal docosahexaenoic acid supplementation on visual function and
      growth of breast-fed term infants.

PMID- 10419160
TI  - The postpartum docosahexaenoic acid status of lactating and nonlactating mothers.

PMID- 10419161
TI  - The female docosahexaenoic acid status related to the number of completed
      pregnancies.

PMID- 10419162
TI  - Effects of third trimester consumption of eggs high in docosahexaenoic acid on
      docosahexaenoic acid status and pregnancy.

PMID- 10419163
TI  - Essential fatty acid status in malnourished children.

PMID- 10419164
TI  - A hypothesis to explain the reduced blood levels of docosahexaenoic acid in
      inherited retinal degenerations caused by mutations in genes encoding retina
      specific proteins.
AB  - Some humans and animals with inherited retinal degenerations (RD) have lower
      blood levels of docosahexaenoic acid (22:6n-3) than controls. As a result of
      recent studies, clearly the low blood 22:6n-3 phenotype is found in multiple RD
      phenotypes and no mutation thus far identified in humans or animals is involved
      in lipid metabolism. Therefore, it seems reasonable to suggest that the primary
      defect is not in 22:6n-3 metabolism, but rather in some common convergent pathway
      that ultimately leads to the reduction of blood and tissue 22:6n-3 levels. One
      possibility is that the different mutations produce a metabolic stress that
      provokes structural and biochemical adaptive changes in photoreceptor cells and
      their rod outer segments. If the stress is oxidant, the retina could downregulate
      22:6n-3 and upregulate antioxidant defenses. How such a stress could lead to
      changes in blood levels of 22:6n-3 is not obvious. However, the consistent
      finding of the 22:6n-3 phenotype in many different retinal degeneration genotypes
      suggests that some form of communication exists between the retina and other
      tissues that serves to reduce blood levels of 22:6n-3.

PMID- 10419166
TI  - Low serum docosahexaenoic acid is a significant risk factor for Alzheimer's
      dementia.

PMID- 10419165
TI  - Rats with low levels of brain docosahexaenoic acid show impaired performance in
      olfactory-based and spatial learning tasks.
AB  - Studies were carried out to determine if decreased levels of central nervous
      system docosahexaenoic acid (DHA), a result of consuming an n-3-deficient diet,
      had an effect on learning- and memory-related behaviors in adult male rats.
      Females were reared on an n-3-deficient or n-3-adequate diet beginning at 21 d of
      life. Their male pups, the F2 generation, were weaned to the diet of the dam and
      tested at 9-12 wk of age. An olfactory-based discrimination and Morris water maze
      task were used to assess performance. Whole brain was collected after the
      behavioral experiments and central nervous system fatty acid content was analyzed
      in olfactory bulb total lipid extracts. F2 generation male rats consuming the n-3
      deficient diet had an 82% decrease in DHA compared to rats consuming the n-3
      adequate diet. The n-3-deficient animals made significantly more total errors in
      a 7-problem, 2-odor discrimination task compared to the n-3-adequate group.
      Furthermore, the escape latency in the Morris water maze task was significantly
      longer for the n-3-deficient rats compared to the n-3-adequate rats. These
      results indicate that rats with decreased DHA levels in the central nervous
      system perform poorer in these tasks compared to rats with higher DHA levels and
      suggest the presence of learning deficits in these animals.

PMID- 10419167
TI  - Ethyl docosahexaenoic acid administration during intrauterine life enhances
      prostanoid production and reduces free radicals generation in the fetal rat
      brain.

PMID- 10419168
TI  - The role of docosahexaenoic acid (22:6n-3) in neuronal signaling.

PMID- 10419169
TI  - n-3 polyunsaturated fatty acid deficiency and dopamine metabolism in the rat
      frontal cortex.

PMID- 10419171
TI  - Interactions between lipid metabolism and schizophrenia: the biochemical changes
      which may have made us human.

PMID- 10419170
TI  - Amount and type of unsaturated aldehydes in chicken plasma and tissues depend
      more on dietary lipids than on vitamin E status.

PMID- 10419174
TI  - Triglyceride as a risk factor, epidemiology.

PMID- 10419172
TI  - n-3 fatty acids and human lipoprotein metabolism: an update.

PMID- 10419175
TI  - Triglyceride-lowering effect of n-3 long chain polyunsaturated fatty acid:
      eicosapentaenoic acid vs. docosahexaenoic acid.

PMID- 10419176
TI  - Fish oil in hypertriglyceridemia: safety and recommendations.

PMID- 10419173
TI  - Long-chain n-3 polyunsaturated fatty acids and triacylglycerol metabolism in the
      postprandial state.
AB  - Elevated plasma triacylglycerol (TG; triglyceride) concentrations, especially in
      the postprandial state, have been associated with an increased risk of coronary
      heart disease (CHD). Postprandial lipemia represents a complex series of
      reactions which occur following the ingestion of a meal containing fat and is
      associated with a number of adverse metabolic events including the production of
      atherogenic chylomicron remnants, the formation of the highly atherogenic small
      dense low density lipoprotein particles, a reduction in the concentration of the
      cardioprotective high density lipoprotein fraction and the activation of
      coagulation factor VII. Fish oils are a rich source of the long-chain n-3
      polyunsaturated fatty acids (PUFA), eicosapentaenoic acid and docosahexaenoic
      acid. Long chain n-3 PUFA are effective hypotriglyceridemic agents, lowering both
      fasting and postprandial TG concentrations. There is a large body of evidence
      which shows that n-3 PUFA reduces plasma TG concentrations through reduced
      endogenous very low density lipoprotein production. This in turn may account for
      the reduced postprandial lipemic response following n-3 PUFA supplementation.
      However, this does not preclude a contribution of enhanced chylomicron clearance,
      which may be mediated through altered chylomicron size, structure or chemical
      composition, or altered lipoprotein lipase metabolism in terms of enzyme
      concentration, activity, or affinity for chylomicrons. However the precise
      biochemical nature of this effect remains to be established. The reduction of
      postprandial plasma TG concentrations by n-3 PUFA may partly explain why n-3 PUFA
      intake is inversely related to CHD mortality.

PMID- 10419177
TI  - Regulation of cellular 15-lipoxygenase activity on pretranslational,
      translational, and posttranslational levels.
AB  - In mammalian cells, enzymatic lipid peroxidation catalyzed by 12/15-lipoxygenases
      is regulated by pretranslational, translational, and posttranslational processes.
      In rabbits, rats, and mice induction of experimental anemia leads to a systemic
      up-regulation of 12/15-lipoxygenases expression. In addition, interleukins-4 and 
      13 were identified as strong up-regulators of this enzyme in human and murine
      monocyte/macrophages and in the lung carcinoma cell line A549, and the
      interleukin-4(13) cell surface receptor as well as the signal transducer and
      activator of transcription 6 (STATG) appears to be involved in the signal
      transduction cascade. On the level of translation, 15-lipoxygenase synthesis is
      blocked by the binding of regulatory proteins to a characteristic guanine
      cytosine-rich repetitive element in the 3'-untranslated region of the rabbit 15
      lipoxygenase mRNA, and the formation of such 15-lipoxygenase mRNA/protein
      complexes was identified as molecular reason for the translational inactivity of
      the 15-lipoxygenase mRNA in immature red blood cells. However, proteolytic
      breakdown of the regulatory proteins which were recently identified as hnRNP K
      and hnRNP E1 overcomes translational inhibition during later stages of
      reticulocyte maturation. For maximal intracellular activity, 12/15-lipoxygenases
      require a rise in cytosolic calcium concentration inducing a translocation of the
      enzyme from the cytosol to cellular membranes as well as small amounts of
      preformed hydroperoxides which act as essential activators of the enzymes. 12/15
      Lipoxygenases undergo irreversible suicide inactivation during fatty acid
      oxygenation, and this process may be considered an element of down-regulation of
      enzyme activity. Suicide inactivation and proteolytic breakdown may contribute to
      the disappearance of functional 12/15-lipoxygenase at later stages of
      erythropoiesis.

PMID- 10419178
TI  - Fatty acid ethyl esters: nonoxidative ethanol metabolites with emerging
      biological and clinical significance.

PMID- 10419179
TI  - The effects of cigarette smoking on the metabolism of essential fatty acids.

PMID- 10419180
TI  - Impairment of antioxidant defense mechanisms in elderly women without increase in
      oxidative stress markers: "a weak equilibrium".

PMID- 10419182
TI  - Vitamin E inhibition of O2*- production in the promonocyte cell line THP-1 is
      essentially due to RRR-delta-tocopherol.

PMID- 10419181
TI  - A high linoleic acid diet increases oxidative stress in vivo and affects nitric
      oxide metabolism in humans.

PMID- 10419183
TI  - Stimulation of platelet aggregation in response to arachidonic acid hydroperoxide
      via phospholipase activation.

PMID- 10419184
TI  - New products from the agri-food industry: the return of n-3 fatty acids into the
      food supply.
AB  - The meat from animals and fish in the wild, chicken eggs produced under complete
      natural conditions, and wild plants contain higher amounts of n-3 fatty acids
      compared to domesticated or cultivated ones. The composition of meats, fish, and
      eggs is dependent on animal feed. Fish-meal, flax, and n-3 from algae in animal
      feeds increase the n-3 fatty acid content of egg yolks and lead to the
      availability of n-3 fatty acid-enriched eggs in the marketplace. Research is
      ongoing for the production of n-3 fatty acid-enriched products from poultry,
      beef, lamb, pork, milk, bakery products, etc. In the case of n-3 fatty acid
      enriched eggs, the egg under complete natural conditions (Greek or Ampelistra
      egg) can serve as a guide for proper composition. Otherwise, the amount of n-3
      fatty acids is determined by the organoleptic properties of the products. It is
      essential in the process of returning the n-3 fatty acids into the food supply
      that the balance of n-6/n-3 fatty acids in the diet that existed during evolution
      is maintained. Clinical investigations confirm the importance of n-3 fatty acids
      for normal function during growth and development and in the modulation of
      chronic diseases. The availability of n-3 fatty acid-enriched products should
      lead to improvements in the food supply. Pregnant and lactating women and infants
      should benefit since their diet is deficient in n-3 fatty acids, especially for
      the vegetarians among them. Studies with n-3-enriched eggs lower cholesterol
      levels, platelet aggregation, and blood pressure. Since cardiovascular disease,
      hypertension, and autoimmune, allergic, and neurological disorders appear to
      respond to n-3 fatty acid supplementation, a diet balanced in n-3 and n-6 fatty
      acids consistent with the diet during human evolution should decrease or delay
      their manifestation.

PMID- 10419186
TI  - Equal antithrombotic and triglyceride-lowering effectiveness of eicosapentaenoic
      acid-rich and docosahexaenoic acid-rich fish oil supplements.

PMID- 10419185
TI  - n-3 fatty acids and coronary heart disease--the urgent need of clinical trials.

PMID- 10419187
TI  - Comparison of n-3 polyunsaturated fatty acids from vegetable oils, meat, and fish
      in raising platelet eicosapentaenoic acid levels in humans.

PMID- 10419189
TI  - Docosahexaenoic acid-enriched foods: production and effects on blood lipids.

PMID- 10419188
TI  - Intake of small amounts of n-3 fatty acids decreases platelet lipid peroxidation
      in elderly people.

PMID- 10419190
TI  - Free radical-scavenging actions of olive oil phenolics.

PMID- 10419191
TI  - Green tea extract does not affect urinary markers of lipid peroxidation or
      thromboxane or nitric oxide synthesis during a high-linoleic acid diet in healthy
      females.

PMID- 10419192
TI  - Metabolism of anandamide and 2-arachidonoylglycerol: an historical overview and
      some recent developments.
AB  - Anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol are the two
      endogenous agonists of cannabinoid receptors discovered to date. Like other
      eicosanoids, and unlike classical neuromodulators, these two compounds are
      synthesized by neurons on demand, i.e., their biosynthesis, rather than release,
      is stimulated by Ca2+ influx and cell membrane depolarization. Both
      endocannabinoids can be produced from membrane phosphoglycerides through the
      action of phospholipases, although de novo pathways have also been suggested.
      Once released by cells, the action of both anandamide and 2-arachidonoylglycerol
      is terminated--after their diffusion through the cell membrane--by the hydrolysis
      of the amide or ester bonds to yield arachidonic acid, which is then immediately
      reincorporated into phospholipids. One enzyme, fatty acid amide hydrolase,
      catalyzes the hydrolysis of both endocannabinoids in nervous and nonnervous
      cells. This enzyme also recognizes N-palmitoylethanolamine, an antiinflammatory
      congener of anandamide, with a catalytic efficiency that depends on the cell type
      under study. However, the existence of different isozymes with different affinity
      for anandamide and N-palmitoylethanolamine has not been investigated. Moreover,
      little work has been performed on the regulation of anandamide formation and
      breakdown, and several open questions remain as to the possible biosynthetic and
      degradative mechanisms of cannabimimetic 2-arachidonoylglycerol in nucleated
      blood cells such as macrophages. Finally, the co-existence of both
      endocannabinoids in invertebrates has not been fully established. Here we briefly
      review the state of the art, and present new data from our laboratory, on these
      four largely unexplored aspects of endocannabinoid metabolism.

PMID- 10419193
TI  - Formation of N-acyl-phosphatidylethanolamine and N-acylethanolamine (including
      anandamide) during glutamate-induced neurotoxicity.
AB  - N-Acyl-phosphatidylethanolamine (NAPE) is present in very small amounts in
      mammalian tissues (less than 0.1% of total phospholipids). However, NAPE as well
      as its degradation product, N-acylethanolamine (NAE), can be formed in certain
      neuronal tissues in response to increased [Ca2+]i. A high [Ca2+]i will activate
      the NAPE-forming N-acyltransferase using the sn-1 acyl group of a donor
      phospholipid as substrate in the transfer reaction. This membrane-bound enzyme
      seems to have no substrate specificity with respect to transfer of acyl groups;
      thus the fatty acids in the N-acyl group of NAPE are mainly 16:0 and 18:1,
      corresponding to the fatty acids in the sn-1 acyl group of the donor
      phospholipids. The NAPE-hydrolyzing phospholipase D also seems not to be acyl
      group specific. In mouse neocortical neurons in primary culture, formation of
      NAPE and NAE is stimulated by glutamate via activation of the N-methyl-D
      aspartate-receptor. Both NAPE and, to a lesser extent, NAE accumulate in a linear
      fashion for many hours while at the same time the neurons are dying. Likewise, in
      neurons prelabeled with 14C-arachidonic acid, 14C-arachidonic acid-labeled NAPE,
      and anandamide (= N-arachidonoylethanolamine) are accumulating. The formation of
      NAPE and NAE may represent a cytoprotective response in relation to various forms
      of neurotoxicity.

PMID- 10419194
TI  - The pool of fatty acids covalently bound to platelet proteins by thioester
      linkages can be altered by exogenously supplied fatty acids.
AB  - The goals of this investigation were, first, to develop a chemical strategy to
      identify and quantitate the mass of fatty acid which is covalently bound to
      proteins by thioester linkage in unactivated platelets, and, second, to determine
      whether exogeneously added fatty acids can alter the fatty acid composition of
      thioester bound fatty acids. Studies with radiolabeled fatty acids cannot
      identify and quantitate the actual fatty acids bound to proteins because they
      permit analysis of only the radiolabeled fatty acids added and their metabolites.
      Therefore, in the absence of metabolic labeling by radiolabeled fatty acids, we
      isolated the thioester-linked fatty acids from platelet proteins using
      hydroxylamine at neutral pH to form fatty acid hydroxamates. The hydroxamates
      were subsequently converted to fatty acid methyl esters by acid methanolysis for
      quantitation by gas chromatography-mass spectrometry. Using platelet specimens
      from 14 subjects, 74% of the fatty acid recovered from the unactivated platelet
      proteins as thioester linked was palmitate. Importantly, however, 22% was stearic
      acid, and oleate was 4% of the total thioester bound fatty acid. There was
      minimal variability (2.6-fold at maximum) between the subjects in the amount of
      the thioester-linked palmitate and thioester-linked stearate. However, there was
      substantial variability (>100-fold at maximum) between subjects in the amount of
      thioester-linked oleate. We also demonstrated that incubation of platelets with
      exogenous fatty acids can alter the profile of fatty acids bound to platelet
      proteins by thioester linkages. Incubation of platelets with 100 microM palmitate
      for 3 h increased the amount of thioester-linked palmitate by up to 26%, and
      incubation of platelets with 100 microM stearate increased the amount of
      thioester-linked stearate up to 30%. In support of the observation that
      radiolabeled fatty acids other than palmitate were shown to be capable of binding
      to platelet proteins by thioester linkage, our results indicate that the fatty
      acids actually bound to unactivated platelet proteins include a significant
      amount of stearate, and variable amounts of oleate, as well as palmitate. In
      addition, the data show that palmitate and stearate can be increased, as a
      percentage of total protein-bound fatty acid, by incubation with exogenous
      palmitate and stearate, respectively.

PMID- 10419195
TI  - The influence of a novel antioxidant fatty acid on the development of stenosis
      after balloon injury.

PMID- 10419196
TI  - Effects of beta-oxa and beta-thia polyunsaturated fatty acids on agonist-induced
      increase in endothelial cell adhesion molecules.

PMID- 10419197
TI  - Possible mechanisms for the putative antiatherogenic and antitumorigenic effects
      of conjugated polyenoic fatty acids.

PMID- 10419198
TI  - Docosahexaenoic acid supplementation improves the moderately severe dementia from
      thrombotic cerebrovascular diseases.

PMID- 10419200
TI  - Factors associated with fecal shedding of verotoxin-producing Escherichia coli
      O157 on dairy farms.
AB  - Fecal samples were collected from 4,361 dairy cows on 91 dairy operations between
      26 February and 8 July 1996. Fecal samples were cultured for Escherichia coli
      O157, and positive isolates were probed for verotoxin-producing genes. A total of
      52 (1.2%) fecal samples on 22 (24.2%) operations were positive for verotoxin
      producing E. coli O157. Herds in which samples were collected on or after 1 May
      1996 were significantly more likely to test positive than herds sampled before
      that date (odds ratio = 7.7). Herds maintained on farms on which alleyways were
      flushed with water to remove manure were 8.0 times more likely to have samples
      test positive for verotoxin-producing E. coli O157 than were herds maintained on
      farms cleaned by use of other methods of manure removal.

PMID- 10419199
TI  - Dietary 18:3n-3 and 22:6n-3 as sources of 22:6n-3 accretion in neonatal baboon
      brain and associated organs.
AB  - The bioequivalence of dietary linolenic acid (LNA) and docosahexaenoic acid (DHA)
      for brain DHA accretion was measured in neonatal baboons at 4-6 wk of age using
      stable isotope tracers. Neonates consumed a conventional U.S. term-infant formula
      devoid of long chain polyunsaturates and with an n-6/n-3 ratio of about 10:1. At
      4 wk of age, neonates were dosed with either 13C LNA or 13C DHA. At 6 wk of age,
      neonate brain, retina, and other organs were harvested for fatty acid and
      isotopic analyses. The relative accretion of labeled DHA was 7-fold greater as a
      percentage of dose for the DHA-dosed animals compared to the LNA-dosed animals.
      The baboon is an omnivore that regularly consumes meat and insects; its plasma
      lipid profile responds similarly to humans in response to changes in feeding and
      living habits. These observations suggest that the baboon is a suitable model for
      human unsaturated fatty acid studies.

PMID- 10419201
TI  - Development of a medium for differentiation between Escherichia coli and
      Escherichia coli O157:H7.
AB  - A new medium (Escherichia coli O157:H7 medium: EOH) was developed for
      differentiation between E. coli and E. coli O157:H7. The EOH medium was compared
      with sorbitol MacConkey agar (SMAC), which is the most popular medium to
      enumerate E. coli O157:H7. Several combinations of 35 dyes were evaluated to
      develop the new medium. Indigo carmine (0.03) g/liter) and phenol red (0.036
      g/liter) were found as the best combination for differentiation between E. coli
      O157:H7 and E. coli and added to the basal agar medium (SMAC medium excluding
      neutral red and crystal violet) for EOH medium. On the dark blue EOH medium, E.
      coli produced a yellow color with clear zone, whereas E. coli O157:H7 produced a
      red color without clear zone. For differentiation between E. coli and E. coli
      O157:H7, EOH has much better potential than SMAC. Furthermore. the red color
      produced by normal E. coli in SMAC may mask the light gray color produced by E.
      coli O157: H7, whereas the yellow color with clear zone did not mask the red
      color without clear zone in the EOH medium. The recovery numbers of E. coli
      O157:H7 from inoculated ground beef, pork, and turkey were not significantly
      different between SMAC and EOH media (P > 0.05). The recovery rates of heat- and
      cold-injured E. coli O157:H7 also were not significantly different (P > 0.05).

PMID- 10419202
TI  - Comparison of chemical treatments to eliminate enterohemorrhagic Escherichia coli
      O157:H7 on alfalfa seeds.
AB  - The focus of this study was to determine the efficacy of various chemicals in
      eliminating 2.04 to 3.23 log10 CFU/g of Escherichia coli O157:H7 from alfalfa
      seeds and to determine the survivability of the pathogen on seeds stored for
      prolonged periods at three temperatures. Significant (P < or = 0.05) reductions
      in populations of E. coli O157:H7 on inoculated seeds were observed after
      treatments with 500 and 1,000 ppm of active chlorine (as Ca[OCl]2) for 3 but not
      10 min and with > or =2,000 ppm of Ca(OCl)2 regardless of pretreatment with a
      surfactant. Treatment with 20,000 ppm of active chlorine failed to kill 2.68
      log10 CFU/g of seeds. Acidified NaClO2 (500 ppm) was effective in reducing
      populations of the pathogen by >2 logs per g. Acidified ClO2 significantly
      reduced populations of E. coli O157:H7 on seeds at concentrations > or =100 ppm,
      and 500 ppm of ClO2 reduced the pathogen from 2.7 log10 CFU/g to <0.5 CFU/g.
      Chlorine (as NaOCl) was not effective at concentrations < or =1,000 ppm;
      significant reduction was achieved only after treatment with 2,000 ppm for 3 or
      10 min. Notable reduction in populations was observed after treatment with 30 or
      70% C2H3OH, but there was a dramatic decrease in germination percentage.
      Treatment with 0.2% H2O2 significantly reduced populations, and the organism was
      not detected by direct plating after treatment with > or =1% H2O2. Significant
      reduction in population of E. coli O157:H7 occurred after treatment with 1%
      trisodium phosphate, 40 ppm of Tsunami and Vortexx, and 1% Vegi-Clean. A
      significant decrease in the number of E. coli O157:H7 on dry seeds was observed
      within 1 week of storage at 25 and 37 degrees C, but not at 5 degrees C. Between
      1 and 38 weeks, populations on seeds stored at 5 degrees C remained relatively
      constant. The pathogen was recovered from alfalfa seeds initially containing 3.04
      log 10 CFU/g after storage at 25 or 37 degrees C for 38 weeks but not 54 weeks.

PMID- 10419203
TI  - Microbiological quality of retail imported unprepared whole lettuces: a PHLS Food
      Working Group Study. Public Health Laboratory Service.
AB  - A study of imported unprepared whole lettuces sampled from supermarkets,
      greengrocers, shops, and market stalls found that all were of acceptable
      microbiological quality. Twenty-seven out of 151 (18%) imported lettuce samples
      had Enterobacteriaceae levels of 10(4) CFU/g or more. However, these bacteria
      that constitute part of the natural microflora of unprepared vegetables may also
      be derived from the soil and/or by poor handling. The pathogens, Salmonella spp.,
      Shigella spp., Campylobacter spp., Escherichia coli O157:H7, Vibrio cholerae,
      Listeria monocytogenes, and also Escherichia coli, an indicator of fecal
      contamination, were not detected in any imported lettuces, indicating that
      hygiene, harvesting, and production practices were good. Imported lettuces with
      Enterobacteriaceae levels of 10(4) CFU/g or more varied with type of retail
      premises and the temperature at which the lettuces were displayed. Samples from
      greengrocers, shops, and market stalls were more likely to contain
      Enterobacteriaceae at levels in excess of 10(4) CFU/g than those from
      supermarkets.

PMID- 10419204
TI  - Evaluation of TaqMan PCR assay for detecting Salmonella in raw meat and shrimp.
AB  - We evaluated the TaqMan Salmonella amplification/detection kit from PE Applied
      Biosystems, which uses a polymerase chain reaction (PCR) assay for rapid
      detection of Salmonella in food samples. This system uses the 5' nuclease
      activity of Taq DNA polymerase, which digests an internal fluorogenic probe to
      monitor the amplification of the target gene. The system's sensitivity and
      specificity were evaluated using 42 serotypes of 68 Salmonella strains isolated
      from fecal samples from patients in Tokyo, Japan, and 39 non-Salmonella strains
      in 22 genera. There were no false-negative or false-positive results. This PCR
      assay can detect 3 CFU per PCR tube of Salmonella in pure culture (120 CFU/ml of
      TSB culture). PCR signals were attenuated with artificially contaminated shrimp,
      but a similar detection limit was obtained. TaqMan's performance was tested with
      100 meat and chicken samples purchased from stores in Tokyo. Overall, two of the
      DNA extraction protocols (the Chelex and EnviroAmp methods) worked equally well,
      with some exceptions. Of the 100 samples analyzed, 10 were positive for
      Salmonella with both conventional culture methods and the kit and 89 were
      negative with both. One sample was negative by the culture method but positive by
      the kit assay. These results indicate that TaqMan is a reliable and rapid method
      for Salmonella analysis in the food industry. With this system, food samples can
      be analyzed for Salmonella in less than 20 h.

PMID- 10419206
TI  - Influence of soft rot bacteria on growth of Listeria monocytogenes on potato
      tuber slices.
AB  - Growth of Listeria monocytogenes on potato tuber slices and its interaction with
      four representative species of soft rot bacteria (Pseudomonas fluorescens, P.
      viridiflava, Erwinia carotovora subsp. carotovora, and Xanthomonas campestris)
      were investigated. When potato tuber slices were inoculated with one of two L.
      monocytogenes strains (Scott A and ATCC 15313), an increase in numbers of 3 to 4
      logs per gram of tissue was observed with samples that were stored at 20 degrees
      C for 6 days. However, an increase of about 2 logs was observed with samples that
      were stored at 8 degrees C for 12 days. When potato slices were simultaneously
      inoculated with L. monocytogenes and one of the four soft rot bacteria, the
      growth of L. monocytogenes was inhibited in the presence of P. fluorescens or P.
      viridiflava but was not significantly affected in the presence of E. carotovora
      or X. campestris. The antagonism of the two pseudomonads to L. monocytogenes was
      also observed in potato tuber extract and in culture media. Formation of
      inhibition zones was observed only in iron-deficient media but not in the medium
      supplemented with FeCl3. In addition, production of fluorescent siderophore
      (pyoverdin) by these two pseudomonads was demonstrated. L. monocytogenes was
      unable to colonize macerated plant tissue induced by soft-rotting bacteria 2 days
      before inoculation of the pathogen. These results indicate that growth of L.
      monocytogenes on potato tuber slices is differentially affected by soft rot
      bacteria and that antagonism of fluorescent pseudomonads to L. monocytogenes is
      possibly caused by the production of iron-chelating siderophore by these
      pseudomonads.

PMID- 10419205
TI  - Growth control of Listeria monocytogenes on cold-smoked salmon using a
      competitive lactic acid bacteria flora.
AB  - A Lactobacillus sake strain LKE5 and four strains of Carnobacterium piscicola
      were evaluated as biopreservation cultures to control the growth of Listeria
      monocytogenes on vacuum-packed, cold-smoked salmon stored at 5 degrees C. All
      five strains were antilisterial as live cultures in an agar diffusion assay. Cell
      free supernatants of two strains of C. piscicola and L. sake LKE5 were also
      antilisterial because of the production of bacteriocins. The presence of high
      cell numbers of strains of C. piscicola had no influence on the sensory quality
      of cold-smoked salmon stored at 5 degrees C, but L. sake LKE5 caused strong
      sulfurous off-flavors and was rejected as a culture for biopreservation of cold
      smoked salmon. A bacteriocin-producing strain of C. piscicola (A9b) initially
      caused a 7-day lag phase of L. monocytogenes, followed by a reduction in numbers
      of L. monocytogenes from 10(3) CFU/ml to below 10 CFU/ml after 32 days of
      incubation, coinciding with the detection of antilisterial compounds. The
      presence of a nonbacteriocin-producing strain of C. piscicola (A10a) prevented
      the growth of L. monocytogenes during the 32-day incubation. The growth of L.
      monocytogenes was strongly repressed on cold-smoked salmon in the presence of C.
      piscicola A9b and A 10a, respectively. The initial cell numbers of L.
      monocytogenes that were found on Oxford plates incubated at 25 degrees C reached
      low maximum cell counts of 10(4) and 2 x 10(3) after 14 and 20 days of storage in
      mixed culture with C. piscicola A9b and A10a.

PMID- 10419207
TI  - Growth and toxin production by Clostridium botulinum in English-style crumpets
      packaged under modified atmospheres.
AB  - To determine the safety of a high moisture bakery product, packaged under
      modified atmospheres, challenge studies were done on English-style crumpets
      (water activity [a(w)] 0.990, pH 6.5) inoculated postbaking with Clostridium
      botulinum types A and proteolytic B spores (5 X 10(2) spores/g). Products were
      packaged either in air, in air with an Ageless FX200 oxygen absorbent, or in a
      CO2/N2 (60:40) gas mixture, stored at ambient temperature (25 degrees C), and
      monitored for toxicity daily. All inoculated crumpets were toxic within 4 to 6
      days and were organoleptically acceptable at the time of toxigenesis. Counts of
      C. botulinum increased to approximately 10(5) CFU/g at the time of toxicity. To
      determine the effect of baking on product safety, subsequent challenge studies
      were done on crumpets inoculated with 5 x 10(2) spores/g (baked weight basis)
      prior to baking. All crumpets were toxic after only 6 days, irrespective of
      packaging conditions, and toxigenesis again preceded spoilage. Temperature
      profile studies showed that the maximum internal temperature reached during
      baking was 97 degrees C, and the total baking process was equivalent to 0.03 min
      at 121 degrees C. The actual time to toxin production in both studies (4 to 6
      days) correlated well with the predicted time (3.4 days) using the U.S.
      Department of Agriculture Pathogen Modeling Program (version 5.1) for proteolytic
      strains of C. botulinum. These studies confirm that high moisture bakery
      products, if contaminated with C. botulinum spores either pre- or postbaking,
      could pose a public health hazard, if packaged in air (in a high gas barrier
      package where O2 was depleted and CO2 was generated during storage) or under
      modified atmosphere packaging conditions and stored at ambient temperature.

PMID- 10419208
TI  - Modeling the aerobic growth and decline of Staphylococcus aureus as affected by
      pH and potassium sorbate concentration.
AB  - The effects of pH (5.0, 5.2, 5.4, 5.6, and 5,8) and concentration of potassium
      sorbate (10.0 and 16.6 mM) at two water activity values (0.90 and 0.92) on the
      aerobic growth and decline of Staphylococcus aureus ATCC 6538P, 196-E, and FDA
      C243 were studied using brain-heart infusion broth. The inoculum was
      approximately 4 to 5 log CFU/ml, and the incubation temperature was 30 degrees C.
      Samples were periodically enumerated on tryptic soy agar. The Gompertz model was
      used to obtain microbial growth parameters, specific growth rate was obtained as
      a derived parameter, and the inhibition index was calculated. A linear model was
      fitted in cases of bacteriostatic or bactericidal action of the treatment. The
      ATCC 6538P strain showed the highest resistance in the range of tested
      conditions. Microbial behavior was modeled considering the main controlling
      factors, and a response surface methodology was used to determine the effects of
      undissociated acid concentration and pH. These results can be used to establish
      treatment conditions for microorganism growth or inhibition.

PMID- 10419209
TI  - The storage life of packed shredded Iceberg lettuce dipped in glycine betaine
      solutions.
AB  - The effects of glycine betaine dip, packaging method, and storage time on the
      sensory quality of shredded Iceberg lettuce were first modeled using a
      statistical experimental design, followed by a second storage test verifying the
      effect of the glycine betaine treatment. Shredded lettuce was dipped in 0 to 100
      mg/liter active chlorine solution and then in 0 to 1.0 mol/liter glycine betaine
      solution, packed in 25 microm oriented polypropylene film, 250 g per package, and
      stored at 5 degrees C for 8 days. Models with good predictability were created
      suggesting that the glycine betaine dip helped retain sensory quality, especially
      appearance (P < 0.05). The models also suggested that washing periods over 60 s
      were not needed and that the microperforation of packages should not exceed 0.31
      mm2 per package. The modeled positive effect on sensory quality was verified in
      the second storage test (P < 0.05). The optimum glycine betaine concentration was
      0.2 mol/liter. Chlorination of the first dip particularly retained appearance of
      packed lettuce.

PMID- 10419210
TI  - Different responses of planktonic and attached Bacillus subtilis and Pseudomonas
      fluorescens to sanitizer treatment.
AB  - Three commercial sanitizers containing iodophor (I), peracetic acid/ hydrogen
      peroxide (PAH), or chlorhexidine gluconate (CG) were evaluated in vitro against
      planktonic and sessile Bacillus subtilis or Pseudomonas fluorescens cells grown
      in Standard One Nutrient Broth. Sessile cells were attached to stainless steel or
      polyurethane test surfaces. Planktonic and attached cells of both bacteria were
      enumerated by plate counts after sanitizer treatment for 1, 3, or 5 min. Sessile
      cells were dislodged from test surfaces by shaking them with beads. Cell
      morphologies were monitored by scanning electron microscopy (SEM). Attached B.
      subtilis and P. fluorescens cells on both surface types were less susceptible to
      all three sanitizers than their planktonic counterparts. PAH, I, and CG were
      equally effective against planktonic P. fluorescens cells, which were reduced by
      99.999% after 1, 3, and 5 min exposure. PAH was the only sanitizer effective
      against attached P. fluorescens cells on both surface types; it reduced counts by
      < or = 99.9% after 1, 3, and 5 min exposure. PAH was also the most effective
      sanitizer against planktonic B. subtilis cells, reducing counts by 99.9% after 1,
      3, and 5 min. Sessile B. subtilis cells on both surface types were the least
      susceptible to all sanitizers; counts were reduced by only 99.5% or less after
      exposure to PAH for 5 min. SEM revealed that planktonic and attached cells of
      both bacteria exhibited symptoms of surface roughness, indentations, and shape
      distortions after treatment with any of the sanitizers.

PMID- 10419211
TI  - Microbiological status of Australian sheep meat.
AB  - Two studies were undertaken to determine the microbiological status of sheep
      carcass meat and frozen, bulk-packed sheep meat produced in Australia. Samples
      were collected from 470 sheep carcasses and 415 cartons of frozen sheep trimmings
      over a period of approximately 12 months. Samples were collected from plants
      processing sheep carcasses for domestic or export markets. On carcasses, where
      bacterial counts were obtained, the mean of the log10 aerobic plate count (APC)
      was 3.92/cm2, the geometric mean of the most probable number (MPN) per square
      centimeter of Escherichia coli (biotype I) was 23, and the geometric mean of the
      coliform count was 38 MPN per cm2. A high percentage (75%) of samples was
      positive for E. coli (biotype I), 81% were positive for coliforms, 5.74% were
      positive for Salmonella spp., and 1.29% were positive for Campylobacter.
      Bacterial counts were higher on carcasses chilled over a weekend than on
      carcasses chilled for 24 h. The total number of bacteria on carcasses processed
      for domestic markets was similar to that on carcasses processed for export
      markets. E. coli O157 was not isolated from any of the 465 samples tested. Of the
      frozen export samples that tested positive, the mean of the log10 APC was 3.47/g,
      the geometric mean of the E. coli (biotype I) count was 9 MPN per g, and the
      geometric mean of the coliform count was 19 MPN per g. Of the frozen export
      samples tested, 48% were positive for E. coli (biotype I), 58% were positive for
      coliforms, and 6.5% were positive for Salmonella spp. E. coli O157 was recovered
      from 1 of 343 frozen sheep meat samples tested (0.29%). Bacterial counts were
      higher on samples of domestic product than on samples of export product. Results
      from both surveys are compared with data from similar studies conducted in other
      countries.

PMID- 10419212
TI  - Swab-based enzyme immunoassay system for detection of meat residues on food
      contact surfaces as a hygiene monitoring tool.
AB  - An enzyme immunoassay system based on the use of a macroporous swab as a solid
      phase for the capture and subsequent immunoenzymatic detection of immunoglobulin
      G (IgG) from meat residues on food contact surfaces was developed as a hygiene
      monitoring tool. Moistened polyester swabs coated with anti-bovine or anti
      chicken IgG were rubbed on the test surface, and the captured IgG was
      subsequently detected directly on the swabs by brief sequential reactions with
      anti-bovine or anti-chicken IgG-peroxidase conjugate and chromogenic peroxidase
      substrate.

PMID- 10419213
TI  - Potential for disruption of central nervous system tissue in beef cattle by
      different types of captive bolt stunners.
AB  - The application of pneumatic-powered air injection stunners (PPAISs), pneumatic
      powered stunners (PPSs), and cartridge-fired stunners (CFSs) in commercial beef
      slaughter plants was evaluated to determine the extent of dissemination of
      central nervous system tissue. Fifteen beef slaughter plants in the western and
      central United States were visited to observe stunning methods and the condition
      of the hearts at postmortem inspection. As inspectors performed the normal
      opening of the hearts, the research observer evaluated the contents of the heart
      for the presence of clots and/or visible tissue segments in the right ventricle.
      In eight plants where PPAISs were used, 33% of hearts examined (n = 1,050)
      contained large clots in the right ventricles. In the four plants where CFSs were
      used, 1% of the hearts (n = 480) contained detectable clots. In three plants
      where the newly modified PPSs were used, 12% of the hearts (n = 450) contained
      detectable clots. Large segments of spinal cord were detected, collected,
      photographed, and confirmed histologically from two hearts in a plant that used a
      PPAIS. Most of the material was found in a single right ventricle and was
      composed of 10 to 13 cm segments of spinal cord.

PMID- 10419215
TI  - Biogenic amines and sensory changes associated with the microbial flora of
      Mediterranean gilt-head sea bream (Sparus aurata) stored aerobically at 0, 8, and
      15 degrees C.
AB  - Changes in the concentrations of tyramine, agmatine, putrescine, cadaverine,
      spermidine, tryptamine, spermine, histamine, and trimethylamine were studied in
      parallel with the development of the microbial population during the storage of
      Mediterranean gilt-head sea bream (Sparus aurata) at three temperatures (0, 8, 15
      degrees C). Changes in sensory scores were also recorded. Pseudomonads and H2S
      producing bacteria were the dominant microorganisms. Enterobacteriaceae and
      lactic acid bacteria were also present in the fish microflora. Among the biogenic
      amines, putrescine and cadaverine were detected when pseudomonads exceeded 10(6)
      to 10(7) CFU/g. Histamine was produced only in samples stored at 15 degrees C.
      Tyramine, tryptamine, agmatine, and trimethylamine were absent regardless of the
      storage temperature.

PMID- 10419214
TI  - An enzyme-linked immunosorbent assay for glial fibrillary acidic protein as an
      indicator of the presence of brain or spinal cord in meat.
AB  - The current methods to detect central nervous system (CNS) tissue in blood,
      lungs, or meat are cumbersome, time consuming, and costly. The objective of this
      study was to use glial fibrillary acidic protein (GFAP), which is restricted to
      the CNS, in an enzyme-linked immunosorbent assay (ELISA) for the detection of CNS
      tissue in blood and muscle from beef cattle. Bovine brain, cerebral cortex,
      spinal cord, sciatic nerve, diaphragm, blood clots, and other skeletal muscle
      were obtained from three animals at slaughter. The limit for detection of GFAP
      was approximately 1.0 ng and the standard curve was linear up to 40 ng. Tissue
      samples gave responses parallel to the GFAP standard, suggesting that standard
      and unknown samples were immunoreactively identical. No GFAP was detected in
      skeletal muscle (ground beef, shoulder clod, and diaphragm) and blood clots.
      Trace amounts (13.5 to 51 ng/mg) were present in sciatic nerve. In contrast, high
      levels of GFAP (55 to 220 microg/ mg) were present in spinal cord, cerebral
      cortex (17 microg/mg), and whole brain (9 to 55 microg/mg). In a storage study
      using two animals in two separate studies, immunoreactive GFAP was detectable for
      up to 8 days at 4 degrees C in all tissues containing neural elements. Thus,
      mixtures of muscle with spinal cord or brain retained almost 80% of their
      immunoreactivity after 8 days at 4 degrees C, while brain and spinal cord alone
      retained approximately 50% and 25%, respectively, of their initial activities. In
      a repeat experiment, 80 to 100% of the initial activity was retained in these
      tissues after 8 days at 4 degrees C. The results of the current study demonstrate
      that the GFAP ELISA provides a valid and repeatable method to detect CNS tissue
      contamination in meat.

PMID- 10419216
TI  - Survival of Anisakis simplex in microwave-processed arrowtooth flounder
      (Atheresthes stomias).
AB  - The purpose of this study was to define the relationship between survival and
      temperature of nematodes of the species Anisakis simplex in microwave-processed
      arrowtooth flounder (Atheresthes stomias). Ten fillets (each 126 to 467 g, 0.5 to
      1.75 cm thick), with an average of five larvae of Anisakis simplex per fillet,
      were processed to target temperatures on high (100%) power using a commercial 700
      W microwave oven. Fillets were neither covered nor rotated and had a temperature
      probe inserted to two-thirds depth into the thickest portion. After the fillet
      was digested using a 1% pepsin solution, the viability of nematodes was
      determined by viewing them under a dissecting microscope. Survival rates were 31%
      at 140 degrees F (60 degrees C), 11% at 150 degrees F (65 degrees C), 2% at 160
      degrees F (71 degrees C), 3% at 165 degrees F (74 degrees C), and 0% at 170
      degrees F (77 degrees C). Microwave processing of standardized fillet
      "sandwiches," 14 cm long, 4.5 cm wide, and approximately 1.75 cm high, each of
      which was preinoculated with 10 live nematodes, resulted in no survival at either
      160 degrees F or 170 degrees F. Using ultraviolet light to detect both viable and
      nonviable nematodes in fillet sandwiches as an alternative method to pepsin
      digestion resulted in survival rates of 1% at 140 degrees F (60 degrees C), 3% at
      145 degrees F (63 degrees C), and 0% at 150 degrees F (65 degrees C). Smaller
      fillet sandwiches, which most likely had fewer cold spots during microwave
      processing, required 150 degrees F (65 degrees C), whereas larger whole fillets
      required 170 degrees F (77 degrees C) to kill larvae of Anisakis simplex. The
      parasites were most likely inactivated by a thermal mechanism of microwave
      treatment. Damage to the nematodes was often evident from ruptured cuticles that
      were no longer resistant to digestive enzymes. The high hydrostatic pressure and
      low chloride content of the pseudocoelomic fluid probably contributed greatly to
      the damage incurred by the larvae.

PMID- 10419217
TI  - Heat resistance of Bacillus cereus spores: effects of milk constituents and
      stabilizing additives.
AB  - Heat resistance of Bacillus cereus spores (ATCC 7004, 4342, and 9818) heated in
      different types of milk (skim, whole, and concentrated skim milk), skim milk
      containing stabilizing additives (sodium citrate, monopotassium phosphate, or
      disodium phosphate, 0.1%), and cream was investigated. Thermal resistance
      experiments were performed at temperatures within the range of 92 to 115 degrees
      C under continuous monitoring of pH. For strain 4342 no significant differences
      (P < 0.05) in D values were detected in any case. For strains 7004 and 9818
      higher D values of about 20% were obtained in whole and concentrated skim milk
      than those calculated in skim milk. From all stabilizing additives tested, only
      sodium citrate and sodium phosphate increased the heat resistance for strain
      9818. However, when the menstruum pH was measured at the treatment temperature,
      different pH values were found between the heating media. The differences in heat
      resistance observed could be due to a pH effect rather than to the difference in
      the substrates in which spores were heated. In contrast, when cream (fat content
      20%) was used, lower D values were obtained, especially for strains 7004 and
      9818. z values were not significantly modified by the milk composition, with an
      average z value of 7.95+/-0.20 degrees C for strain 7004, 7.88+/-0.10 degrees C
      for strain 4342, and 9.13+/-0.16 degrees C for strain 9818.

PMID- 10419218
TI  - Inhibition of aflatoxin-producing fungi by Welsh onion extracts.
AB  - Welsh onion ethanol extracts were tested for their inhibitory activity against
      the growth and aflatoxin production of Aspergillus flavus and A. parasiticus. The
      survival of spores of A. flavus and A. parasiticus depended on both the extract
      concentration and the exposure time of the spores to the Welsh onion extracts.
      The mycelial growth of two tested fungi cultured on yeast extract-sucrose broth
      was completely inhibited in the presence of the Welsh onion ethanol extract at a
      concentration of 10 mg/ml during 30 days of incubation at 25 degrees C. The
      extracts added to the cultures also inhibited aflatoxin production at a
      concentration of 10 mg/ml or permitted only a small amount of aflatoxin
      production with extract concentration of 5 mg/ml after 2 weeks of incubation.
      Welsh onion ethanol extracts showed more pronounced inhibitory effects against
      the two tested aflatoxin-producing fungi than did the same added levels of the
      preservatives sorbate and propionate at pH values near 6.5.

PMID- 10419219
TI  - Centralized packaging of retail meat cuts: a review.
AB  - Centralized packaging of retail meat cuts is growing more popular because of its
      economies and potential to maintain quality, enhance safety, and extend the shelf
      life of fresh meat. Requirements for optimizing shelf life of centrally prepared
      retail cuts for periods up to 15 weeks are slightly different from those needed
      to extend the shelf life of fresh, chilled meat. Chilled meat primarily
      deteriorate at the cut or uncut muscle surface. In long-term storage, primal cuts
      are placed in an atmosphere saturated with carbon dioxide and containing very low
      residual oxygen. These cuts are held at -1.5+/-0.5 degrees C. When the meat is
      removed, it is fabricated into retail or food service cuts. New fresh surfaces
      are created in the process, revitalizing the meat's appearance. After being
      prepared for retail display, the meat normally has four more days of shelf life.
      Depending on the meat species, shelf life is usually limited by development of
      undesirable organoleptic changes, usually defects in color, which are independent
      of microbial presence. The microbes consist of a lactic acid bacterial population
      that maximizes under storage conditions at about 10(8) CFU/cm2 well before shelf
      life ends. Circumstances are different with centralized distribution of retail
      ready fresh meat. The wholesale storage period following initial packaging of the
      retail cuts is about 20 to 30 days. Prepared products must withstand retail
      display for up to 2 days without further manipulation of package contents. Retail
      packages are simply moved from their storage container (usually a unit or
      overwrap containing a modified atmosphere) to retail display, where desirable
      meat color develops upon exposure to air. Three gas atmospheres have some
      potential to satisfy storage needs for centralized distribution of retail-ready
      packages: 100% CO2, 100% N2, or 70% N2 + 30% CO2. Shelf life is limited by
      undesirable changes in surfaces exposed at initial packaging, caused by growth of
      psychrotrophic bacteria. If 100% CO2 is used, these are all lactic acid bacteria
      (LAB). Therefore, initial bacterial numbers on the meat and storage temperature
      become critical to success. The most attractive storage option is 100% CO2 used
      at - 1.5 +/-0.5 degrees C. This review presents the reason for that
      recommendation, along with basic concepts of meat chemistry, a discussion of
      modified atmosphere packaging, meat microbiology, and current results with
      simulated centralized packaging of retail-ready meats.

PMID- 10419220
TI  - The relationship between psychosocial well-being and alcohol and drug use
      following substance misuse treatment.
AB  - The relationship between psychosocial status and alcohol and drug use at 12-month
      follow-up was evaluated for clients of two addictions treatment programs (90
      treated for alcohol; 51 for drugs or drugs and alcohol). Psychosocial status at
      follow-up was mostly unrelated to alcohol use among clients who were not using
      drugs prior to treatment. Among drug users, returning to both alcohol and drug
      use was strongly associated with poorer psychosocial status, with partial
      correlational analyses indicating that (a) drug use was the main factor
      associated with poorer status and (b) poorer status was likely a consequence
      rather than a precursor of drug use. The implications of these findings are
      discussed.

PMID- 10419221
TI  - Effects of a culturally congruent intervention on cognitive factors related to
      drug-use recovery.
AB  - This paper describes a culturally congruent intervention to promote recovery from
      illegal drug use among African Americans and reports initial outcomes. The
      intervention was based on the transtheoretical stages-of-change model and on
      techniques of focused dyadic counseling and motivational interviewing. Subjects
      were randomly assigned to the culturally congruent intervention or to a control
      condition. Each condition featured a single counseling session during which drug
      related and other needs were assessed and appropriate referrals offered. Posttest
      data indicated that subjects in the culturally congruent condition were more
      involved in the counseling session, more willing to self-disclose, more motivated
      to seek help for drug-use-associated problems, and higher on preparation for
      change.

PMID- 10419222
TI  - Tobacco smoking and other suspected antecedents of nonmedical psychostimulant use
      in the United States, 1995.
AB  - This study investigates the extent to which tobacco smoking is associated with
      the nonmedical use of psychostimulants and the temporal order of the age of first
      use for tobacco and psychostimulants within a nationally representative sample of
      United States household residents. At the same time, alcohol use and other
      suspected determinants of psychostimulant use are investigated and held constant,
      using multiple regression models. Data were taken from public use files of the
      1995 National Household Survey on Drug Abuse. Conditional logistic regression
      analyses were performed to derive estimated relative odds of using stimulants for
      tobacco smokers versus nonsmokers, holding constant other potentially distorting
      influences. This study provides recent evidence on tobacco smoking as one of the
      potentially malleable risk factors for the nonmedical use of stimulant drugs.

PMID- 10419223
TI  - Visiting public drinking places: an explorative study into the functions of pub
      going for late adolescents.
AB  - Alcohol consumption by adolescents is a well-established risk factor with a
      variety of negative consequences such as violence, aggression, and traffic
      accidents. Only limited attention, however, has been paid to the context in which
      most of young people' s alcohol consumption takes place. The potential importance
      of visiting public drinking places is rarely explained from a developmental
      perspective. This study addresses this issue by focusing on the relation between
      pub-going and indicators of social integration, maturing out, and psychosocial
      well-being in a 17 to 18-year-old population. Adolescents who went to pubs and
      discos had more friends, more often had a best same-sex friend, spent more time
      with their friends, had more satisfying contacts with friends, and experienced
      feelings of loneliness less often. They were also more likely to be involved in a
      romantic relationship, to have a job, and to place less emphasis on educational
      aspirations. No differences were found on levels of stress and self-esteem
      between visitors and nonvisitors. The consequences of these outcomes for further
      research and prevention policies are discussed.

PMID- 10419224
TI  - Illegal drug-using trends among students in a Spanish university in the last
      decade (1984-1994).
AB  - A sample of 2,086 university students in Valladolid (Spain) were surveyed in 1994
      to assess their current use of illicit drugs. That information was used as a
      baseline to show the trends in the last decade in order to compare two other
      studies carried out on a similar target population in 1984 and 1990. Of those
      surveyed, 28.3% had taken some illicit drug within their lifetime, 16.7% in the
      previous year, and 7.2% in the previous month. Cannabis was the most common
      illicit drug used in the three levels among these students. 14.2 is the average
      starting age at which inhalants are used and 19.3 for opiates. 49.8% were opposed
      to any drug legalization. More than a quarter of the students (28.7%) could be
      considered as a mental disorder case-finding as measured by Golberg's General
      Health Questionnaire (GHQ), which was much more relevant among illicit drug users
      than among nonusers. A decrease in illegal drug use frequency among university
      students has been observed in the last 10 years.

PMID- 10419225
TI  - Program quality effects on patient outcomes during methadone maintenance: a study
      of 17 clinics.
AB  - This study was designed to replicate Ball and Ross's benchmark research, which
      was the first to identify a set of program quality factors for methadone
      maintenance programs and relate them to patient outcomes. Ball and Ross's
      treatment domain variables were measured in a new and larger sample of methadone
      clinics, and eight candidate program quality factors were derived. Both studies
      found that program factors defined by more frequent counseling contacts, higher
      director involvement with treatment, and more director experience were associated
      with lower drug use by patients during treatment. Several patient and counselor
      characteristics also were associated with drug-use outcomes.

PMID- 10419226
TI  - Foetal nutrition, foetal growth restriction and health later in life.
AB  - Retarded intrauterine growth has been linked to increased risk of perinatal
      mortality and morbidity, sudden infant death and poorer health later in life. The
      independent variables used in these studies are mainly neonatal size parameters,
      such as weight, ponderal index and ratios of head and abdominal measures. These
      are, in terms of foetal development and growth, crude parameters. This paper
      discusses the concepts of growth retardation used in most clinical and
      epidemiological studies. It is again emphasized that small for gestational age
      (SGA) and intrauterine growth retardation (IUGR) are different concepts. SGA is a
      size parameter that may or may not reflect restricted foetal growth and is
      therefore of limited value. Even IUGR, defined as retarded foetal growth rate,
      may be a too crude a criterion to select foetuses with short- and long-term
      health risks. Other biophysical measurements, such as foetal blood flow patterns
      and biochemical parameters, may be helpful in a better selection of these
      foetuses and infants. Furthermore, different causes of IUGR, e.g. poor maternal
      nutrition versus insufficient placental function, may not have the same effects
      on the foetus. The discrepancies in the results of studies on the relationship
      between IUGR or foetal malnutrition and short- and long-term health risks may be
      explained by the crudeness of the independent variables used. In the future,
      research on the biology of the developing human foetus should be more focused in
      the studies of the relationship between the intrauterine environment and
      nutrition and risk of poor health later in life.

PMID- 10419227
TI  - Optimality of the birth population reduces learning and behaviour disorders and
      sudden infant death after the first month.
AB  - The weight distribution pattern of all births can be divided into a "skewing to
      the left" to lower weights and high neonatal mortality, a "skewing to the right"
      to higher weights (>3500g) and minimum neonatal and postneonatal mortality, and a
      "symmetrical distribution" with mortality in between. This study was initiated
      with the hypothesis that a deficit in newborns of more than 3500 g would
      adversely affect postneonatal death. Higher and rising postneonatal mortality
      solely attributable to sudden infant death of unknown cause (sudden infant death
      syndrome; SIDS) was observed in the Nordic countries with a lower proportion of
      heavy newborns. Minor environmental intervention almost eliminated excess
      mortality from this cause, supporting raised susceptibility with a depressed
      birthweight in postneonatal SIDS. This contrasts with classical neonatal low
      birthweight SIDS, which is stable despite numerous attempts at reduction,
      supporting a multi-factorial aetiology: low maternal age, low education, low
      socioeconomic status, maternal smoking, infection, etc. The postneonatal SIDS
      epidemic associated with a deficit in heavy newborns is thought to be a result of
      changing behaviour in pregnancy: moderate iatrogenic dietary restriction and
      young women favouring a low-calorie, low-fat diet, especially in the third
      trimester when the foetus is most vulnerable, which delays myelination and
      somatic growth and renders the infant susceptible to minor morbidity and
      irregularity. The timing of death and neuropathological findings suggestive of
      repeated hypoxic episodes in more than 80% of cases of SIDS prior to death
      support this theory. The similar weight distribution patterns in SIDS and all
      births in Denmark, the UK and the USA suggest a substantial proportion of the
      neonates in these countries could be growth-retarded and at risk of hypoxic
      episodes in infancy. A few cases, particularly males (sex-ratio = 1.7), suffer
      SIDS, the majority survive. Many, mostly males, present minor CNS signs and
      learning and behaviour problems. The male predominance accords with males more
      than 500 g higher optimal birthweight than females and susceptibility to a
      depressed weight at birth. In order to prevent postneonatal dying, SIDS and
      reduce learning/behaviour disorders it is necessary to raise the proportion of
      heavy newborns by promoting foetal growth rate equal to the maternal intrinsic
      rate by eating to one's appetite a balanced diet, favouring a diet high in marine
      fat, especially in third trimester, in order to ensure maturation of the CNS and
      prolong gestation, thereby increasing birthweight. Although the increased
      survival of some very low birthweight neonates confounds the issue, a division
      between SIDS in neonatal and postneonatal death is recommended in order to assess
      the proportion of "avoidable infant death" as opposed to persistent classical
      neonatal SIDS.

PMID- 10419228
TI  - Development of perception in action in healthy and at-risk children.
AB  - Devising effective assessment techniques and therapy for movement disorders in
      young children requires in-depth measures of the child's perceptuo-motor
      functioning. It is argued that the field of movement disorders can benefit from
      an ecological approach to perception and action, where perception subserves
      action and action influences perception. Three notions central to the ecological
      approach are described and illustrated with our recent research on infant and
      child perceptual and motor behaviour.

PMID- 10419229
TI  - Literacy and nutrition: a grass roots experience from Bangladesh.

PMID- 10419230
TI  - A community-based health intervention programme in pastoral and agricultural
      Pokot communities in Western Kenya.
AB  - Multiple micronutrient deficiencies in the perinatal phase are associated with
      poor child growth and functional impairment. For the pastoral child there is
      additional risk due to lifestyle and isolation from healthcare. Successful
      improvement in the child-rearing practices and maternal vitamin A and iron status
      requires community-based interventions that are sustainable. It is therefore
      recommended that for pastoral communities participatory techniques that identify
      and mobilize community resources should be used in the implementation of
      intervention programes.

PMID- 10419231
TI  - Babies, brains and culture: optimizing neurodevelopment on the savanna.
AB  - Cross-cultural child development research has demonstrated the influence of
      infant experience as well as constitutional, neurodevelopmental influences in
      infant outcomes. African infant precocity found in a number of studies is
      examined in the light of developmental models and in the context of the enriched
      child-rearing environment of pre-industrial societies. Examples are drawn from
      fieldwork in East Africa that demonstrate the different contributions of
      pregnancy, nutrition, early learning and cultural factors on developmental
      outcomes. The multiple enhancing infant rearing and nutritional factors are
      postulated to optimize the rate of neuro-development thereby contributing to
      psychomotor precocity.

PMID- 10419232
TI  - Child health and environmental pollution in the Aral Sea region in Kazakhstan.
AB  - Environmental pollutants, which may occur in breast milk and in various food
      products and drinking water, and which are also transferred to the foetus,
      constitute a severe threat to the health of infants and children. Among such
      compounds, various organochlorines, such as pesticides for the control of
      parasites (DDTs, HCHs), and products of industry and agriculture, such as dioxins
      and dioxin-like compounds (PCBs), are much discussed, in addition to organic
      mercury and heavy metals, such as lead and cadmium. The consequences of acute
      exposure to PCB have been documented in Japan following the ingestion of rice oil
      contaminated by PCBs. In Sweden birthweight has been found to be reduced and the
      perinatal mortality rate higher than expected in regions with high consumption of
      fatty fish from the Baltic Sea. In addition, from studies around Lake Michigan,
      it has been shown that children who have been exposed to PCBs in utero have
      retarded cognitive development. In the Aral Sea basin in Central Asia people have
      been subjected to long-term exposure to various pesticides, which have been
      distributed over the cotton fields in huge quantities. Organochlorines are
      resistant to breakdown in nature, thus they enter the food chain, eventually
      entering the human diet, and they may also be inhaled from dust. Such compounds
      accumulate in the foetus by placental transport and continue to do so postnatally
      if the infants are breastfed, as they may be present in high concentrations in
      human milk. The health of children living in the Aral Sea region is reported to
      be poor, with high morbidity and mortality and a high rate of chronic diseases
      and retarded mental and physical development. However, in addition to being
      subjected to environmental pollution, these children also suffer from health
      hazards related to poverty. Through epidemiological studies it may be possible to
      obtain information about to what extent exposure to environmental pollution from
      organochlorines contributes to the poor health of people living in the Aral Sea
      region.

PMID- 10419233
TI  - Behavioural effects in female rats of postnatal exposure to sub-toxic doses of
      polychlorinated biphenyl congener 153.
AB  - Polychlorinated biphenyls (PCBs) are widespread environmental contaminants that
      are also present in human tissues and breast milk. Behavioural disturbances have
      been reported in both children and animals exposed perinatally to PCBs. The
      present study assessed the behavioural consequences in female rats of postnatal
      exposure to the di-ortho-substituted 2,2',4,4',5,5'-hexachlorobiphenyl (IUPAC no.
      153), which is one of the PCB congeners most frequently detected in human milk.
      The different groups of mothers were dosed via gavage with 5 mg/kg bodyweight of
      PCB 153 in corn oil or 5 ml/kg bodyweight corn oil vehicle every second day from
      day 3 to day 13 after delivery. The exposure did not affect the bodyweight of the
      dams nor the physical development of the pups. Operant behavioural testing of the
      female offspring by two different schedules of reinforcement was performed.
      First, the animals were tested by a multiple schedule with two components: fixed
      interval (FI) and extinction (EXT), which has proved sensitive in revealing
      changes in activity level. There were no statistically significant differences in
      frequency or interresponse times of lever pressing between the PCB-exposed female
      rats and the controls. These results were in contrast to a previous, analogous
      study where PCB 153 produced an increased frequency of lever presses during the
      FI in male rats, indicating a sex-specific behavioural effect of PCB 153. The
      female offspring was also tested by a conjunctive schedule with two components:
      variable interval (VI) and differential reinforcement of low rate (DRL). This
      schedule revealed slower acquisition of time discrimination in the PCB 153
      exposed females as compared with the controls. The VI-DRL results showed that PCB
      153 may also produce long-lasting behavioural effects in female rats following
      postnatal exposure through the mother's milk.

PMID- 10419234
TI  - The Adolescence Scale (AS-ICSM): a tool for the retrospective assessment of
      puberty milestones.
AB  - Neurodevelopmental theories of psychosis, and schizophrenia in particular, have
      led to renewed interest in the relationships between brain maturation, adult
      personality and timing of puberty. Here we present a brief Adolescence Scale (AS
      ICSM) for the retrospective assessment of puberty milestones. The recommended
      version comprises one item for females, three for males and one common to both.
      An original version of five items was administered to 318 young adults. We found
      good internal consistencies of Cronbach's alpha = 0.87 for females and 0.83 for
      males, having excluded an item assessing timing of growth spurt. These findings
      show that the AS-ICSM is a reliable and economic tool for research into the
      concomitants of early and late puberty.

PMID- 10419235
TI  - Cytokine determinations and rapid diagnosis of early onset neonatal septicaemia.

PMID- 10419236
TI  - Congenital toxoplasmosis, later relapses and treatment.

PMID- 10419237
TI  - Short children: height is not the only problem.

PMID- 10419238
TI  - Nocturnal enuresis.

PMID- 10419239
TI  - Interferon-alpha in viral and bacterial gastroenteritis: a comparison with C
      reactive protein and interleukin-6.
AB  - The aim of the study was to identify serum markers able to differentiate
      bacterial and viral origin in acute diarrhoea. Interferon-alpha (INF-alpha), C
      reactive protein (CRP) and interleukin-6 were determined on admission in the sera
      of 119 children aged between 1 mo and 14 y who were hospitalized for rotavirus (n
      = 60) or bacterial diarrhoea (Salmonella spp. 39 cases, Shigella spp. 15 cases,
      Campylobacter jejuni 5 cases). CRP concentration was >10 mg/l in 48.3% of
      children with viral gastroenteritis and 86.4% of children with bacterial
      gastroenteritis. IL6 concentration was >100 pg/ml in 11.7% and 26.3% of cases,
      respectively. INF-alpha was detected in 79.1% of children with rotavirus (sens
      79%) and in 3.5% (spec 93%) with bacterial gastroenteritis. However the INF-alpha
      assay takes 48 h and pathogens are often identified from stools before interferon
      results are available. We found that serum markers are not discriminating enough
      to differentiate between viral and bacterial gastroenteritis in emergency cases.

PMID- 10419240
TI  - Oral bedtime cornstarch supplementation reduces the risk for nocturnal
      hypoglycaemia in young children with type 1 diabetes.
AB  - The effect of oral cornstarch supplementation was evaluated in 14 pre-school
      children with type 1 diabetes in a randomized, double-blind, placebo-controlled
      trial. The children received cornstarch (0.3 g/kg) or placebo at bedtime on five
      occasions each, and their blood glucose concentrations were measured at bedtime,
      at 02.00 h and in the morning. The mean nocturnal blood glucose concentration (at
      02.00 h) was 2.2 mmol/L higher and the number of blood glucose concentrations
      below 5 mmol/L were reduced by 64% when cornstarch had been ingested at bedtime.
      We conclude that cornstarch may be used in pre-school children with type 1
      diabetes to reduce the risk for nocturnal hypoglycaemia.

PMID- 10419241
TI  - Upper gastrointestinal disease, Helicobacter pylori and recurrent abdominal pain.
AB  - Over a 5-y period, 396 children complaining of recurrent abdominal pain (RAP)
      underwent upper gastrointestinal endoscopy in order to identify any underlying
      organic pathology and determine the prevalence of Helicobacter pylori (H. pylori)
      infection. Histologically confirmed mucosal inflammation was found in 338 out of
      396 children (85.4%); in 113 of 396 patients (28.5%), H. pylori was identified on
      the gastric mucosa. Significant discriminating factors between H. pylori positive
      and negative children with RAP included age (mean age for positive 11 y vs. 8.1 y
      for negative, p < 0.01) and gender (male gender predominance in the H. pylori
      positive, p < 0.001). No significant difference was found between H. pylori
      positive and negative groups regarding incidence and character of the presenting
      symptoms. All H. pylori positive children (100%) had abnormal histology compared
      with 225 out of 283 negative ones (79.5%). Histologically confirmed gastritis was
      the most prominent finding in H. pylori positive children compared with H. pylori
      negative (98.2% vs. 19%, p < 0.001). Conversely, oesophagitis was more common in
      H. pylori negative children (47.7% vs. 27.4%, p < 0.001). The incidence of peptic
      ulcer was higher in H. pylori infected patients than in the H. pylori negative
      group (5.3% vs. 1%, p < 0.05). Our data suggest that gastrointestinal pathology
      is more common than previously thought in children with RAP, while H. pylori
      infection is a relatively important factor in the etiology of upper
      gastrointestinal inflammation in RAP syndrome.

PMID- 10419242
TI  - Height, health and growth hormone.
AB  - The principal objective of this paper is to provide health practitioners with
      information on the positive aspects of shorter stature for use in counseling
      short children with poor self-images. Another objective is to provide information
      on the physical capabilities, health potential and psychosocial characteristics
      of shorter stature as a baseline for deciding whether a healthy short child
      should receive growth hormone therapy. The information presented here was
      obtained from review of publications covering medical and nutritional research,
      gerontological studies, athletic performance and environmental, biological and
      engineering aspects of the human body. It was found that the popular belief in
      the superiority of tall stature is based primarily on social bias rather than on
      a scientific foundation. Studies indicating that taller people are healthier or
      more productive than shorter ones have ignored a wide range of evidence that
      shorter people are highly creative, productive, long-lived, athletic and better
      for the environment. The authors urge medical and scientific professionals to
      consider the many advantages of shorter stature in terms of health, social and
      environmental benefits.

PMID- 10419243
TI  - Reduced spontaneous growth hormone secretion in patients with Turner's syndrome.
AB  - We evaluated growth hormone (GH) secretion in 81 patients with Turner's syndrome
      (TS) (mean age 10.7+/-3.6 y) with respect to karyotype, auxological
      characteristics and growth response to GH treatment (1 IU/kg/wk). None of the
      patients had spontaneous puberty or had started replacement therapy with
      estrogens. Thirty-nine patients (48%) had monosomia 45X, 29 (36%) structural
      abnormalities of the X chromosome and 13 (16%) X mosaicism. Before the start of
      GH therapy, each patient underwent an evaluation of mean nocturnal GH
      concentration (MGHC) and 75 patients also underwent 2 pharmacological tests. MGHC
      of the TS patients did not differ from that of 29 prepubertal GH-deficient girls
      (GH peaks < 8 microg/l after pharmacological tests) and both groups were lower (p
      < 0.0001 and p < 0.0005, respectively) than MGHCs of 27 short normal girls (GH
      peak > 8 microg/l). MGHC of the patients with TS was negatively correlated (p <
      0.001) with bodyweight excess (BWE) at multiple regression analysis. MGHC of the
      TS patients with BWE < 20% was significantly higher (p < 0.02) than that of the
      TS patients with BWE > 20%, but again did not differ from that of the GH
      deficient patients and was lower (p < 0.001) than that of the short normal girls.
      MGHC did not significantly differ between the 3 groups subdivided according to
      karyotype. Forty-four percent of the TS patients showed GH responses to
      pharmacological tests < 8 microg/l. Height velocity SDS at first and second year
      of therapy was not influenced by MGHC levels, chronological or bone age, target
      height or BWE. In conclusion, spontaneous secretion in our patients with TS was
      lower than that of the short normal prepubertal girls and did not differ from
      that of GH-deficient subjects, even if we excluded overweight patients. The level
      of GH secretion was unable to predict GH response to treatment.

PMID- 10419244
TI  - Role of parvovirus B19 infection in childhood idiopathic thrombocytopenic
      purpura.
AB  - Although parvovirus B19 exhibits a strong tissue-tropism for erythroid progenitor
      cells leading to anaemia, several case reports indicate that parvovirus B19
      infection may also cause the development of thrombocytopenia. Despite recent
      studies, the frequency and clinical relevance of this association have remained
      questionable. Consequently, and in view of the paucity of evidence regarding a
      viral aetiology for idiopathic thrombocytopenic purpura (ITP), we examined the
      role of parvovirus B19 in 47 children with newly diagnosed ITP. Specific viral
      DNA indicating a current or recent parvovirus B19 infection was demonstrated in 6
      of 47 patients (13%) employing the polymerase chain reaction technique. Our study
      suggests that children with ITP and associated parvovirus B19 infection are
      characterized by acute onset of profound thrombocytopenia. Among the parvovirus
      B19 positive children, duration of disease was brief in three children treated
      with immunoglobulin but chronic in the remaining three patients given high-dose
      steroids. Prospective studies are needed to confirm these initial observations.
      This virus should be considered as a possible aetiologic agent in some children
      with ITP.

PMID- 10419245
TI  - Parents' fear regarding fever and febrile seizures.
AB  - In order to improve the effectiveness of information, we studied parents'
      perceptions and knowledge about fever and febrile seizures. A questionnaire study
      was carried out among the parents whose children (n = 230) participated in a
      randomized controlled trial of ibuprofen to prevent recurrent febrile seizures.
      Of the 230 parents, 181 (79%) responded to the questionnaire. Of all parents, 45%
      were afraid or very afraid of fever, which was strongly associated with being
      afraid of recurrent febrile seizures. Parents of children with a non-West
      European background were more afraid. The consequences of parental fear included
      frequent temperature measurements (25% measured five times per day or more),
      sleeping in the same room (24%) and 13% remained awake at night. Witnessing a
      febrile seizure is a frightening experience for parents; a majority thought that
      febrile seizures were harmful, because they look dangerous. Forty-seven percent
      thought that their child was dying during the initial febrile seizure. On the
      other hand, reassuring information may be helpful: 21% mentioned it as their
      reason to consider febrile seizures not harmful. We conclude that parental fear
      of fever and febrile seizures is a major problem with several negative
      consequences for daily family life. Adequate provision of information may reduce
      parental fear. We suggest that information about fever and febrile seizures
      should be provided to all parents, preferably during their contact with the
      providers of preventive healthcare. The parents of children with a non-West
      European origin need extra attention.

PMID- 10419246
TI  - Pain in paediatric oncology: interviews with children, adolescents and their
      parents.
AB  - Pain diagnostics and treatment are crucial components in the care of children
      with cancer. This study evaluated the extent and causes of pain, the use of
      methods for monitoring pain intensity, principles of pain management and adverse
      effects of pain treatment. In addition, care, support and information given to
      children and parents were evaluated. Structured interviews were conducted with 55
      children with malignant disease and their parents. Pain was a common symptom and
      a major problem during different phases of cancer treatment and pain evaluation
      was unsystematic. Pain due to treatment and procedures was a greater problem than
      pain due to the malignant disease itself, and two thirds of the pain experienced
      by these children seemed to have iatrogenic origin. Younger children and children
      with short disease duration were more concerned about procedural pain. Parents
      and children thought that more efficient pain treatment was often possible.
      Parents claimed to judge their child's pain better than professionals, and
      children and parents wanted more information on different aspects of pain and
      pain treatment. Pain identification and treatment can be substantially improved
      through increased use of methods for pain evaluation and through giving enhanced
      information to families about pain and pain treatment.

PMID- 10419248
TI  - Assisted mechanical ventilation using combined elastic and resistive unloading in
      cats with severe respiratory failure: effects on gas exchange and phrenic nerve
      activity.
AB  - This study tests the efficacy of respiratory mechanical unloading as a mode of
      assisted mechanical ventilation in cats with an intact breathing-control system
      but severe pulmonary parenchymal injury. Twelve anaesthetized, intubated cats
      received multiple saline lung lavages so that their total respiratory system
      compliance decreased from 56.1+/-10.4 to 26.8+/-6.8 ml/kPa (p < 0.001) and their
      PaO2 fell to 12.38+/-4.71 kPa when 100% O2 was used as inspired gas. They were
      then exposed to three consecutive 15-min periods of CPAP of 0.5 kPa, respiratory
      unloading and again CPAP of 0.5 kPa. Unloading was applied with end-expiratory
      pressure of 0.5 kPa, elastic assistance of 0.03 kPa/ml and resistance
      compensation of 2.0 kPa/l/s. Arterial blood gases for the CPAP baselines did not
      differ significantly before and after unloading: pH 7.14+/-0.04 vs. 7.16+/-0.06;
      PaCO2 8.99+/-2.07 vs. 8.33+/-2.01 kPa; PaO2 12.4+/-4.7 vs. 13.3+/-7.6 kPa. Nor
      did the baselines differ in terms of tidal volume, respiratory rate and phrenic
      nerve activity. Unloading increased tidal volume substantially by about 50% and
      increased respiratory rate slightly, while inspiratory time remained unchanged.
      PaCO2 fell to 6.63+/-1.57 kPa and pH rose to 7.25+/-0.06. Phrenic nerve activity
      was significantly down-regulated in terms of total number of impulses and mean
      impulse frequency in the phrenic nerve burst. These results suggest that combined
      elastic and resistive unloading may be an effective means of assisted mechanical
      ventilation in severe respiratory failure of pulmonary parenchymal origin.

PMID- 10419247
TI  - Clinical symptoms and social factors in a cohort of children spontaneously
      clearing Helicobacter pylori infection.
AB  - In a cohort study of 305 Swedish children, repeated blood samples and structured
      questionnaires were obtained from 6 mo to 11 y of age. Of the 40 children
      seropositive for Helicobacter pylori in one or more samples, 32 (80%) had cleared
      the infection by 11 y of age. No association was found between H. pylori
      seropositivity at any time and reported antibiotic consumption, size of home and
      family, type of day-care, history of atopic disease, length of breastfeeding or
      peptic ulcer disease in the family. Girls reported more (p = 0.002) unspecified
      abdominal pain during childhood than boys, but the difference in H. pylori
      infection rate (15/150, 10% for boys and 25/144, 17% for girls) was not
      significantly different (p = 0.09). Unspecified abdominal pain during childhood
      was reported more often (OR adjusted for gender = 2.2, 95% CI = 1.0-4.4, p =
      0.04) for the children seropositive at some point (17/39, 44%) than for the
      seronegative children (54/217, 25%). RAP at 11 y of age was more often reported
      by the 9/36 (25%) children seropositive at some time in life than by the 23/172
      (13%) seronegatives, but the difference was not statistically significant (OR
      adjusted for gender = 2.0, 95% CI = 0.8-4.6, p = 0.1). The study shows that H.
      pylori seropositivity was associated with a parental report of unspecified
      abdominal pain during childhood. Also, a history of unspecified abdominal pain
      was more common (OR = 51.6, 95% CI = 15.6-220, p < 0.001) in children reporting
      RAP at 11 y of age.

PMID- 10419250
TI  - Evaluation of interleukin-6, tumour necrosis factor-alpha and interleukin-1beta
      for early diagnosis of neonatal sepsis.
AB  - The objective of this study was to assess the contribution of interleukin-6 (IL
      6), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) to
      an early diagnosis of early-onset neonatal sepsis. A cohort of 117 newborn
      infants delivered during a 1-y period had IL-6, TNF-alpha and IL-1beta, blood and
      cerebrospinal fluid (CSF) cultures, leucocyte and platelet count collected on the
      initial evaluation of possible early-onset sepsis. They were divided into four
      groups: I, positive blood and/or CSF cultures; II, probably infected with
      clinical sepsis but negative cultures; III, same as group II but mother received
      antibiotic antepartum; and IV, newborn infants that did not receive any
      antibiotic therapy. There were no differences among the four groups with respect
      to mean gestational ages and birthweights, median Apgar scores, type of delivery,
      or number of newborn infants with leucocyte count <5000 mm(-3) or >25000 mm(-3),
      platelet count <100000 mm(-3), immature/total neutrophil ratio >0.2, absolute
      neutrophil count <1000mm(-3) and median IL-1beta levels. Median IL-6 and TNF
      alpha levels were significantly higher in groups with patients with a diagnosis
      of clinical sepsis than in controls. The optimal cut-off point was 32 pg ml(-1)
      for IL-6 and 12 pg ml(-1) for TNF-alpha. The combination of both provided a
      sensitivity of 98.5%. In conclusion, the combination of IL-6 and TNF-alpha is a
      highly sensitive marker of sepsis in the immediate postnatal period.

PMID- 10419249
TI  - Clinically symptomatic central venous catheter-related deep venous thrombosis in
      newborns.
AB  - The objective of this study was to evaluate the incidence of clinically
      symptomatic central venous catheter (CVC)-related deep venous thrombosis (DVT) in
      newborns and small infants and to try to identify clinical and genetic risk
      factors for catheter-related DVT among children with thrombotic complications.
      CVC was inserted in 44 consecutive infants (age range 0-90 d) during the period
      January 1990 to December 1995 in the neonatal intensive care unit (NICU) of
      Kuopio University Hospital in Kuopio. The symptoms of DVT were: syndrome of
      superior vena cava in 2, swelling at the CVC puncture site in 6 and repeated CVC
      obstructions in 2. The formation of DVT was verified by venography. Children with
      DVT (n = 10) had 26 (10-365, in total 623) catheter days compared with 9 d (1
      155, in total 591) in patients without DVT (n = 26) (p < 0.005). The median
      (range) number of days from catheter insertion to diagnosis of DVT was 19 (7
      210). CVC had to be removed from 11 (25%) children due to various complications.
      There was no DVT-related mortality. A positive family history with thromboembolic
      episodes at a young age was found in 3 of 10 families with a child suffering CVC
      related DVT. The levels of coagulation inhibitors were evaluated at the age of 9
      69 mo in all 10 (23%) children with CVC-related DVT. We detected no deficiencies
      in protein S, protein C or antithrombin III. One child was heterozygous for the
      point mutation (R506Q) in the factor V gene known to cause activated protein C
      resistance (APCR). We conclude that newborns with CVC are at great risk of DVT
      and that the aetiology of DVT can rarely be identified via measurements of
      coagulation inhibitors.

PMID- 10419251
TI  - Clinical and molecular biological analysis of a nosocomial outbreak of vancomycin
      resistant enterococci in a neonatal intensive care unit.
AB  - Vancomycin-resistant enterococci (VRE) have emerged as important nosocomial
      pathogens since 1988. We report here an outbreak of VRE between April 1997 and
      May 1997 in our neonatal intensive care unit (NICU). All isolates from four
      patients were identified as Enterococcus faecium positive and were resistant to
      vancomycin and teicoplanin. All of the patients with VRE were isolated for at
      least 5 d after admission to the unit and the positive cultures lasted between 13
      and 31 d. There were no cases of sepsis or mortality in the patients with VRE.
      Two cases had previously received vancomycin therapy. All isolates were shown to
      have the vanA gene and had the same band pattern on repetitive PCR. After the
      four episodes, all equipment used to care for the patients were decontaminated
      and the staff engaged in therapy used disposable gloves and gowns. There were no
      more episodes. However, the NICU is no longer a safety area with regards to
      vancomycin-resistant enterococcal infection.

PMID- 10419252
TI  - Incidence, ultrasonic patterns and resolution of nephrocalcinosis in very low
      birthweight infants.
AB  - This longitudinal study was undertaken in order to elucidate the incidence and
      natural course of nephrocalcinosis in preterm infants and to evaluate whether the
      ultrasonic classification for nephrocalcinosis used here is suitable for
      predicting subsequent resolution of the condition. A total of 129 very low
      birthweight infants were screened for nephrocalcinosis by renal ultrasonography
      at 2 wk, 6 wk and 3 mo. The pyramidal changes were classified as peripheral,
      scattered or extensive. Follow-up renal ultrasonography was performed on the
      infants with nephrocalcinosis at 6, 12, 18 and 24 mo, and thereafter annually up
      to 6 y of age, or until ultrasonic resolution. The overall incidence of
      nephrocalcinosis was 20% (26/129). Nephrocalcinotic changes were peripheral in 14
      out of the 26 infants (54%), scattered in 7 (27%) and extensive in 5 (19%).
      Ultrasonic resolution had taken place in all the cases with peripheral
      nephrocalcinosis by 12 mo, but 3 of the 7 infants with the scattered pattern and
      3 of the 4 with the extensive pattern (1 died) were still affected at 24 mo. In
      two cases with extensive nephrocalcinosis the condition still persisted at 5-6 y
      of age. We conclude that about 20% of very low birthweight infants develop
      nephrocalcinosis during the first 3 mo of life. In about half of the affected
      infants renal changes are restricted and transient, but more extensive forms may
      last several years. The classification of nephrocalcinosis used here is
      appropriate for predicting later ultrasonic resolution.

PMID- 10419253
TI  - Late neurological sequelae of non-hemolytic hyperbilirubinemia of healthy term
      neonates.
AB  - Records of the only children's hospital equipped to perform exchange transfusions
      in West Berlin were used to identify all 29 non-hemolytic healthy term newborns
      with total serum bilirubin between 20 and 30 mg/dL, 16 of whom were available for
      follow-up neurological examination according to Touwen. Compared to 18 case
      controls with bilirubin <12 mg/dL, jaundiced children scored significantly worse
      only on the choreiform dyskinesia scale.

PMID- 10419254
TI  - Phenylketonuria: diet for life or not?
AB  - In order to evaluate the argument whether or not a restricted phenylalanine diet
      should be maintained for life in patients with phenylketonuria (PKU), 16 patients
      with early treated PKU but off diet since their 11th birthday were investigated.
      The evaluation included a detailed neurological examination, IQ,
      neurophysiological testing and MRI of the brain. Even if IQ and
      electrophysiological studies were normal or unchanged if compared to results
      before diet discontinuation, all patients revealed abnormal neurological signs.
      We conclude that the diet should be continued during adult life, but somewhat
      higher phenylalanine levels (<10mg/dl;<600 micromol/l) than at younger ages
      should be allowed.

PMID- 10419255
TI  - Three children with congenital toxoplasmosis: early report from a Swedish
      prospective screening study.
AB  - The aim of this prospective study was to define the incidence of congenital
      toxoplasmosis in Sweden. Blood eluates collected on filter papers, Guthrie cards,
      from 40978 newborn babies were analysed for specific immunoglobulin M (IgM) and
      IgG antitoxoplasma antibodies. This is a preliminary report of three children
      with congenital toxoplasmosis, defined by the occurrence of antitoxoplasma
      specific IgM antibodies. Two children were asymptomatic at birth. They were both
      normally developed at the age of 12 and 15 months, respectively. The third child
      had unidentified but uncomplicated symptoms of infection in the neonatal period.
      As a result of the screening congenital toxoplasmosis was confirmed and treatment
      instituted. Microphthalmus and peripheral chorioretinitis were detected in one
      eye. In spite of the chemotherapeutic treatment he developed hydrocephalus
      needing neurosurgical intervention at the age of 3 months. His development at 14
      months was normal. The incidence in Sweden of congenital toxoplasmosis detected
      by specific IgM antitoxoplasma antibodies in blood from filter papers is less
      than 1:10000.

PMID- 10419256
TI  - Fatal biphasic brainstem and spinal leptomeningitis with Cryptococcus neoformans
      in a non-immunocompromised child.
AB  - Cryptococcal meningitis is one of the most common life-threatening, invasive
      fungal infections of the central nervous system in patients with defective T
      lymphocyte function. It is, however, unusual in children. We report on a non
      immunocompromised 10-y-old boy without evidence of immunological abnormality who
      developed headache, vomiting, disturbances of consciousness and areflexia.
      Magnetic resonance imaging of the brain and the spinal cord revealed enlargement
      of the ventricles and high signal lesions in the leptomeninges at the level of
      the cerebral peduncles and the cervical and thoracic cord. Cerebrospinal fluid
      analysis was positive for Cryptococcus neoformans. He was treated with
      amphotericin B and was symptom-free within 1 wk. Despite an extended course of
      therapy his symptoms suddenly relapsed and he succumbed to the medical
      complications of cardiac and respiratory failure. Central nervous system
      appearances at postmortem were those of cryptococcal leptomeningitis.

PMID- 10419257
TI  - Partial trisomy 13q22-->qter and monosomy 18q21-->qter as a result of familial
      translocation.
AB  - We report on a patient with a partial trisomy of chromosome 13q22-->qter and
      partial monosomy of chromosome 18q21-->qter showing distinct malformations. The
      phenotype of this unbalanced karyotype has not been previously described. The
      proband had a craniofacial dysmorphism, neck pterygium, closed fists with
      overlapping fingers, cutaneous appendix of the left fist, equinovarus and
      postaxial hexadactyly of the feet, atrial septum defect, unilateral
      cryptorchidism and hypertrophic pyloric stenosis. Using fluorescence in situ
      hybridization (FISH) the father's karyotype 46,XY.ish t(13;18)(13pter-
      >13q22::18q21-->18qter; 18pter-->18q21::13q22-->13qter) and the child's 46,XY.ish
      der(18)(18pter-->18q21::13q22-->13qter)pat were established. The mother's
      karyotype was normal. A risk of unbalanced offspring in carriers of a balanced
      reciprocal translocation depends on the length and genetic constitution of the
      exchanged segments. Risk figures should come only from empirical data. A
      phenotypically normal child with a balanced or normal karyotype could be born in
      the case of alternate segregation. Amniocentesis should therefore be recommended
      in any further pregnancy.

PMID- 10419258
TI  - Nocturnal enuresis: a suggestion for a European treatment strategy.
AB  - The objective of this study was to review the published literature on aetiology
      and treatment of nocturnal enuresis, with the aim of providing a treatment
      strategy which is easy for the patient and their family to follow. Results from
      European studies conducted over the last 15 y were included in this review. It
      can be concluded from the results of these studies that enuresis is the cause and
      not the result of a psychiatric disorder. However, there is still considerable
      variation in success rates, from 28 to 90%. It is of vital importance that a
      caring approach from the doctor and a positive family and patient attitude are
      present for successful treatment. The first choice of treatment should be the one
      most acceptable to the family, e.g. alarm, desmopressin and combination
      treatment.

PMID- 10419260
TI  - Rapid detection of Escherichia coli O157:H7 in ground beef using a fiber-optic
      biosensor.
AB  - A portable fiber-optic biosensor was used to detect Escherichia coli O157:H7 in
      seeded ground beef samples. The principle of the system is a sandwich immunoassay
      using cyanine 5 dye-labeled polyclonal anti-E. coli O157:H7 antibodies for
      generation of a specific fluorescent signal. Signal acquisition is effected by
      launching light from a 635-nm diode laser into a dual tapered 600-microm silica
      fiber. Fluorescent molecules within approximately 100 nm of the fiber surface are
      excited by the evanescent field, and a portion of the emission recouples into the
      fiber. A photodiode allows for quantitation of the collected emission light at
      wavelengths of 670 to 710 nm. Biotin-avidin interactions are used to attach
      polyclonal antibodies specific for E. coli O157:H7 to the final 7.5 cm of the
      fiber probe. The biosensor was able to detect E. coli O157:H7 to 3 to 30 CFU/ml
      in seeded ground beef samples. The reaction was highly specific. Signals with
      Listeria monocytogenes, Salmonella Typhimurium, or E. coli nonO157:H7 were 2 to
      3% of those observed with a similar concentration of E. coli O157:H7. Assays were
      conducted at or near real-time with results obtained within 20 min of sampling.

PMID- 10419259
TI  - Hunger behaviour contributes to early nutritional homeostasis.

PMID- 10419261
TI  - Rapid detection of Salmonella in chicken washes by immunomagnetic separation and
      flow cytometry.
AB  - Use of flow cytometry to rapidly detect Salmonella in chicken carcass washes was
      investigated. A direct immunomagnetic separation method was used to prepare
      samples and was found to be an effective method for separating target cells from
      debris in chicken carcass washes. When flow cytometry was combined with
      immunomagnetic separation, the average lowest detectable level of Salmonella
      detected was 2.3 x 10(4) CFU/ml. Fifty of 100 wash samples from six groups were
      inoculated with 2 x 10(-1) CFU of Salmonella Typhimurium per milliliter. After 18
      h of enrichment at 37 degrees C, all samples were tested for Salmonella using
      flow cytometry and conventional culture methods. An identification correlation of
      96% was found between flow cytometry and xylose-lysine-tergitol agar plating.
      Quantitative analysis established a significant linear relationship between the
      enumeration results of flow cytometry and xylose-lysine-tergitol agar plate
      counts (R2 = 0.796). Time required for flow cytometry, including sample
      processing and flow cytometric analysis, was less than 1 h.

PMID- 10419262
TI  - Use of selective media to recover Salmonella and Vibrio cholerae after growth in
      reconditioned pork-processing wastewater.
AB  - Selective plating media are used for the enumeration and isolation of bacterial
      pathogens from food and water samples. This study compared the quantitative
      recovery of Salmonella spp. and Vibrio cholerae grown in nutrient-limited, filter
      sterilized, reconditioned wastewater over the temperature range of 4 to 45
      degrees C using nonselective and pathogen-specific selective media. Viable
      Salmonella were enumerated on tryptic soy agar (TSA) and XLT-4, and viable V.
      cholerae were enumerated on TSA and thiosulfate-citrate-bile-sucrose agar. There
      was a statistically significant (P < 0.05) higher recovery of both pathogens over
      the growth temperature range on TSA compared to the selective media. Trehalose, a
      stress-induced metabolite of Salmonella, was isolated from the cells grown in the
      reconditioned wastewater, whereas, the V. cholerae exhibited a change in cellular
      morphology from rod to coccoid shape. These results suggest that growth in
      nutrient-limited water injured or stressed the individual pathogens. Care should
      be used in choosing the procedure and plating medium for quantitative recovery of
      pathogens from such a nutrient-limiting environment.

PMID- 10419263
TI  - Recovery and survival of Escherichia coli O157:H7 in reconditioned pork
      processing wastewater.
AB  - The pathogen Escherichia coli O157:H7 has been recovered from various water
      sources and food samples. The growth potential of this bacterium in nutrient
      limited, reconditioned wastewater from a pork-processing plant was determined
      over a temperature range of 4 to 46 degrees C. Even though the biological oxygen
      demand of the wastewater was <2 mg/liter, results of bioassays for assimilable
      organic carbon and the coliform growth response of the water suggested that
      sufficient nutrients were present to support limited bacterial growth. A three
      strain mixture of E. coli O157:H7 grew over the temperature range of 10.2 to 29.4
      degrees C. Bioassays appear to be a good indicator of the ability of this
      wastewater to support growth of this pathogen. Statistically higher levels of
      bacterial growth (P < 0.05) were detected on a nonselective medium (tryptic soy
      agar) than on a selective medium (sorbitol-MacConkey agar), suggesting that
      stress or injury of the bacterium occurs when the organism is exposed to the
      nutrient-limited conditions of the wastewater. These results indicate that E.
      coli O157:H7 can survive and grow in this particular nutrient-limited wastewater,
      suggesting a potential hazard if this water becomes contaminated with this
      pathogen.

PMID- 10419264
TI  - Incidence of Salmonella, Campylobacter jejuni, Campylobacter coli, and Listeria
      monocytogenes in poultry carcasses and different types of poultry products for
      sale on the Belgian retail market.
AB  - From January 1997 to May 1998, 772 samples of poultry carcasses and poultry
      products for sale on the retail market in Belgium were analyzed for the presence
      of Salmonella spp., Salmonella Enteritidis, Campylobacter jejuni, C. coli, and
      Listeria monocytogenes per 100 cm2 or 25 g. Poultry samples were contaminated
      with Salmonella (36.5%), C. jejuni and C. coli (28.5%), and L. monocytogenes
      (38.2%). In about 12.3% of the poultry samples, the L. monocytogenes
      contamination level exceeded 1 CFU per g or cm2. Significant differences in
      pathogen contamination rates of poultry products were noticed between the poultry
      products originating from Belgian, French, and U.K. abattoirs. Poultry products
      derived from broiler chickens running free in pine woods until slaughtering age
      (12 to 13 weeks) had a significantly (P < 0.05) lower contamination rate of
      Salmonella than poultry products from enclosed broilers slaughtered at the age of
      6 to 8 weeks. A significantly (P < 0.05) lower pathogen contamination rate was
      noted for Salmonella, C. jejuni, and C. coli for poultry cuts without skin
      compared to poultry cuts with skin on. An increase in pathogen contamination rate
      was noticed during cutting and further processing. To diminish C. jejuni, C.
      coli, Salmonella, and L. monocytogenes contamination rates, hygienic rules of
      slaughter and meat processing must be rigorously observed. At the moment, zero
      tolerance for these pathogens is not feasible, and there is a need to establish
      criteria allowing these pathogens to be present at reasonable levels in the
      examined poultry samples.

PMID- 10419265
TI  - Characterization of the risk to human health of pathogenic Escherichia coli
      isolates from chicken carcasses.
AB  - The purpose of this study was to evaluate the risk for human health associated
      with pathogenic Escherichia coli isolated from airsacculitis and cellulitis in
      chickens, by comparing the genotypic and phenotypic profiles of avian E. coli
      isolates and E. coli strains isolated from sick humans during the same period and
      in the same geographical area as the avian isolates. A total of 96 isolates and
      46 isolates from lesions of cellulitis and airsacculitis, respectively, were
      obtained. Isolates from the backs of some of the affected and healthy birds and
      91 intestinal and extraintestinal isolates from humans with diarrhea, urinary
      tract infections, or septicemia were examined. The frequency of antimicrobial
      resistance was in general higher in the avian than in the human isolates. VT1-VT2
      Eae and VT2-Eae, pathotypes associated with hemolytic and uremic syndrome and
      bloody diarrhea in humans, were the most frequently encountered pathotypes in
      human intestinal isolates but were not recovered from the avian isolates. Aero
      Pap-TSH and Aero-TSH were the most frequently encountered pathotypes in avian
      isolates but were rarely observed in human isolates. No avian isolate was of
      serogroup O157, whereas many human isolates belonged to this O group. O78 and O2
      were the most frequently observed O groups in avian isolates but were rarely
      found in human isolates. Only two avian isolates demonstrated possible
      relatedness to human isolates based on pulsed-field gel electrophoresis profiles,
      but they belonged to different pathotypes. Our results suggest that avian
      isolates recovered from cellulitis and air sacullitis possess very few of the
      attributes required to cause diseases in humans. It is also concluded that
      isolates from cellulitis and airsacculitis do not represent a greater hazard than
      isolates from the back of healthy birds.

PMID- 10419266
TI  - Antibacterial effect of lactoferricin B on Escherichia coli O157:H7 in ground
      beef.
AB  - The antibacterial activity of lactoferricin B on enterohemorrhagic Escherichia
      coli O157:H7 in 1% peptone medium and ground beef was studied at 4 and 10 degrees
      C. In 1% peptone medium, 50 and 100 microg of lactoferricin B per ml reduced E.
      coli O157:H7 populations by approximately 0.7 and 2.0 log CFU/ml, respectively.
      Studies comparing the antibacterial effect of lactoferricin B on E. coli O157:H7
      in 1% peptone at pH 5.5 and 7.2 did not reveal any significant difference (P >
      0.5) at the two pH values. Lactoferricin B (100 microg/g) reduced E. coli O157:H7
      population in ground beef by about 0.8 log CFU/g (P < 0.05). No significant
      difference (P > 0.5) was observed in the total plate count between treatment and
      control ground beef samples stored at 4 and 10 degrees C. The antibacterial
      effect of lactoferricin B on E. coli O157:H7 observed in this study is not of
      sufficient magnitude to merit its use in ground beef for controlling the
      pathogen.

PMID- 10419267
TI  - Antagonistic effect of Enterococcus faecium J96 against human and poultry
      pathogenic Salmonella spp.
AB  - Production of antagonistic compounds was studied in a strain of Enterococcus
      faecium isolated from the intestinal tract of a free-ranging chicken. Production
      of lactic acid and a bacteriocin was observed in cultures of this bacterium,
      alone and in mixed culture fermentations with pathogenic Salmonella serotypes
      (i.e., Gallinarum, Pullorum, Enteritidis, and Typhimurium). Growth inhibition of
      these avian and human pathogens was observed after 4 h of incubation at 37
      degrees C in CAm broth, a medium developed according to the nutrients present in
      chicken food. The antibacterial action was due to the combined effect of lactic
      acid and bacteriocin. Accumulation of these metabolites caused both a
      bacteriostatic and a bactericidal action against the gram-negative bacteria
      assayed.

PMID- 10419268
TI  - Enhancing microbiological safety of fresh orange juice by fruit immersion in hot
      water and chemical sanitizers.
AB  - Trials were conducted with hot water and chemicals to sanitize Valencia oranges
      contaminated by natural microflora or inoculated with Escherichia coli. Microbial
      loads and sensory quality of fresh juice extracted from surface-heated fruit were
      also evaluated. E. coli on fruit surfaces was reduced by either hot water or
      chemical treatments. An estimated 5-log reduction of E. coli was attained by
      immersing inoculated fruit in hot water at 80 degrees C for 1 min or 70 degrees C
      for 2 min. Immersing inoculated fruit in various chemical solutions at about 30
      degrees C for 8 min only reduced E. coli by about 1.8- to 3.1-log cycles on
      nonstem-scar surfaces of the fruit. In general, both hot water and chemical
      treatments were less effective at removing microflora from the stem-scar area.
      Rapid hot-water immersions at 80 degrees C for 1 min and 70 degrees C for 2 min
      reduced both fruit-surface and initial juice microbial loads without altering
      original sensory quality of fresh juice.

PMID- 10419269
TI  - Inactivation of Listeria monocytogenes/Pseudomonas biofilms by peracid
      sanitizers.
AB  - The ability of peracetic acid and peroctanoic acid sanitizers to inactivate mixed
      culture biofilms of a Pseudomonas sp. and Listeria monocytogenes on stainless
      steel was investigated. Types of biofilms tested included a 4-h attachment of the
      mixed-cell suspension and a 48-h biofilm of mixed culture formed in skim milk or
      tryptic soy broth. Biofilm-containing coupons were immersed in solutions of
      hypochlorite, peracetic acid, and peroctanoic acid either with or without organic
      challenge. Organic challenge consisted of either coating the biofilms with milk
      that were then allowed to dry, or adding milk to the sanitizing solution to
      achieve a 5% concentration. Surviving cells were enumerated by pouring
      differential agar directly on the treated surfaces. The peracid sanitizers were
      more effective than chlorine for inactivating biofilm in the presence of organic
      challenge. The 48-h mixed-culture biofilm grown in milk was reduced to less than
      3 CFU/cm2 by 160 ppm of peracid sanitizer after 1 min of exposure. Peroctanoic
      acid was more effective than peracetic acid against biofilm cells under
      conditions of organic challenge. Pseudomonas and L. monocytogenes were
      inactivated to similar levels by the sanitizer treatments, even though
      Pseudomonas predominated in the initial biofilm population.

PMID- 10419270
TI  - Psychrotrophic clostridia causing spoilage in cooked meat and poultry products.
AB  - Certain types of commercially produced noncured turkey breast and roast beef are
      precooked in situ, stored at 4 degrees C or below, and typically given use by
      dates of greater than 50 days. While of rare, sporadic occurrence, an unpleasant
      spoilage characterized by strong H2S odor and gas production has been observed in
      these products. This spoilage is due to the growth of psychrotrophic anaerobic
      sporeformers. Isolates from roast beef resemble Clostridium laramie while
      isolates from uncured turkey have been designated C. ctm for cooked turkey meat.
      The turkey breast isolates were characterized by temperature growth ranges,
      carbohydrate fermentations, and other biochemical reactions. Growth of all
      isolates was inhibited in broth media by 3.0% NaCl, 100 ppm nitrite, 2.0% sodium
      lactate, or 0.2% sodium diacetate. Inoculated studies were performed with three
      isolates in cooked turkey product. All three isolates grew and spoiled product at
      10 and 3.3 degrees C, and one isolate grew at 0.5 and -3 degrees C. Some
      differences in growth were observed with the lactate and diacetate treatments in
      turkey meat among the three isolates. One isolate appeared to utilize the
      lactate, two were inhibited. Overall, 0.1% diacetate consistently delayed growth,
      although to different degrees, for all isolates.

PMID- 10419271
TI  - Spray-drying of bacteriocin-producing lactic acid bacteria.
AB  - Cell survival, cellular damage, and antagonistic activity were investigated after
      spray-drying of four bacteriocin-producing strains of lactic acid bacteria:
      Lactococcus lactis subsp. lactis 140, isolated from natural whey culture and
      producing a narrow-inhibitory spectrum bacteriocin); L. lactis subsp. lactis G35,
      isolated from pizza dough and producing nisin; Lactobacillus curvatus 32Y and
      Lactobacillus sp. 8Z, isolated from dry sausages. Trials were performed with
      bacteria suspended in skimmed milk or directly grown in whey. Three air
      temperatures at the inlet of the drier (160, 180, and 200 degrees C) and three
      flow rates (10, 13, and 17 ml/min) were assayed. Cell viability and bacteriocin
      activity of the dried materials were determined immediately after the process and
      after 5, 15, 30, and 60 days of storage at 4 degrees C. There was no significant
      difference between the two feeding suspensions in cell survival, always
      decreasing with the increase of inlet-air temperature. No loss of bacteriocin
      activity was detected in reconstituted powders, nor was any loss of ability to
      produce bacteriocin found after drying. Investigations of sensitivity to NaCl
      revealed only temporary damage to dried bacteria. During storage for 2 months at
      4 degrees C, all samples, but mainly the lactococcal strains, displayed a gradual
      decrease in cell survival. Bacteriocin activity remained at the same level,
      allowing powders to be considered as effective biopreservatives.

PMID- 10419272
TI  - Use of hazard analysis critical control point and alternative treatments in the
      production of apple cider.
AB  - The purpose of this study was to evaluate the practices of Maryland cider
      producers and determine whether implementing hazard analysis critical control
      point (HACCP) would reduce the microbial contamination of cider. Cider producers
      (n = 11) were surveyed to determine existing manufacturing practices and
      sanitation. A training program was then conducted to inform operators of safety
      issues, including contamination with Escherichia coli O157:H7, and teach HACCP
      concepts and principles, sanitation procedures, and good manufacturing practice
      (GMP). Although all operators used a control strategy from one of the model HACCP
      plans provided, only one developed a written HACCP plan. None developed specific
      GMP, sanitation standard operating procedures, or sanitation monitoring records.
      Six operators changed or added production controls, including the exclusion of
      windfall apples, sanitizing apples chemically and by hot dip, and cider treatment
      with UV light or pasteurization. Facility inspections indicated improved
      sanitation and hazard control but identified ongoing problems. Microbiological
      evaluation of bottled cider before and after training, in-line apples, pomace,
      cider, and inoculated apples was conducted. E. coli O157:H7, Salmonella, or
      Staphylococcus aureus were not found in samples of in-line apple, pomace, and
      cider, or bottled cider. Generic E. coli was not isolated on in-coming apples but
      was found in 4 of 32 (13%) in-line samples and 3 of 17 (18%) bottled fresh cider
      samples, suggesting that E. coli was introduced during in-plant processing. To
      produce pathogen-free cider, operators must strictly conform to GMP and
      sanitation procedures in addition to HACCP controls. Controls aimed at preventing
      or eliminating pathogens on source apples are critical but alone may not be
      sufficient for product safety.

PMID- 10419273
TI  - Food hygiene and hazard analysis critical control point in the United Kingdom
      food industry: practices, perceptions, and attitudes.
AB  - A mail survey was designed and distributed to 1,650 managers of food businesses
      across the manufacturing, retail, and catering sectors of the United Kingdom food
      industry. Respondents were asked about the food hygiene practices of their
      business, their use of systems such as hazard analysis critical control point
      (HACCP), and their attitudes toward a range of food hygiene-related issues.
      Complete responses were received from 254 businesses, a response rate of 15.3%.
      The results showed that 69% of manufacturers were using HACCP systems,
      significantly more than the 13% and 15% in the retail and catering sectors,
      respectively (P < 0.05); 53% of manufacturing, 59% of retail, and 48% of catering
      managers thought that their business represented a low risk to food safety. Among
      businesses using HACCP, specific training in the system was significantly related
      to the likelihood that businesses had adopted all seven of the HACCP principles
      (P < 0.05). Business size was a significant factor in the use of HACCP in both
      the manufacturing and retail sectors. Higher levels of food hygiene
      qualifications among business managers, business status, and higher perceptions
      among managers of the risk to food safety of the business were also significantly
      related to HACCP use in all sectors (P < 0.05). The results from this survey have
      implications for the future development of HACCP, particularly within the UK
      retail and catering sectors. Risk communication and training are highlighted as
      areas of concern for marketing HACCP within these industry sectors.

PMID- 10419274
TI  - Inactivation of Escherichia coli O157:H7 and Escherichia coli 8739 in apple juice
      by pulsed electric fields.
AB  - The effect of high voltage pulsed electric field (PEF) treatment on Escherichia
      coli O157:H7 and generic E. coli 8739 in apple juice was investigated. Fresh
      apple juice samples inoculated with E. coli O157:H7 and E. coli 8739 were treated
      by PEF with selected parameters including electric field strength, treatment
      time, and treatment temperature. Samples were exposed to bipolar pulses with
      electric field strengths of 30, 26, 22, and 18 kV/cm and total treatment times of
      172, 144, 115, and 86 micros. A 5-log reduction in both cultures was determined
      by a standard nonselective medium spread plate laboratory procedure. Treatment
      temperature was kept below 35 degrees C. Results showed no difference in the
      sensitivities of E. coli O157:H7 and E. coli 8739 against PEF treatment. PEF is a
      promising technology for the inactivation of E. coli O157:H7 and E. coli 8739 in
      apple juice.

PMID- 10419275
TI  - Antimicrobial resistance of gram-negative enteric bacteria from pigs in a
      nonantimicrobial-exposed herd before and after transportation.
AB  - Loading pigs onto trucks and transporting them for 30 min resulted in a
      significant increase in proportion of antimicrobial resistance of gram-negative
      enteric bacteria in fecal material. Similarly, the mean number of antimicrobial
      agents in the resistance patterns of these bacteria increased during loading and
      transportation. However, the increases were of a transient nature, as resistance
      values were similar to those of a nontransported control group 1 day after the
      pigs had been transported.

PMID- 10419277
TI  - Fate of Escherichia coli O157:H7 and Salmonella Enteritidis on currency.
AB  - The fate of foodborne pathogens Escherichia coli O157:H7 and Salmonella
      Enteritidis on coin surfaces was determined at room temperature (25 degrees C). A
      five-strain mixture of E. coli O157:H7 or Salmonella Enteritidis of approximately
      5 x 10(4) CFU was applied to the surfaces of sterile U.S. coins (pennies,
      nickels, dimes, and quarters) and to the surfaces of two control substrata
      (Teflon and glass coverslips). During storage at room temperature, E. coli
      O157:H7 survived for 7, 9, and 11 days on the surfaces of pennies, nickels, and
      dimes and quarters, respectively. However, the pathogen died off within 4 to 7
      days on both the Teflon and glass surfaces. Salmonella Enteritidis survived for
      1, 2, 4, and 9 days on the surfaces of pennies, nickels, quarters, and dimes,
      respectively. Unlike E. coli O157:H7, survival of Salmonella Enteritidis was
      greatest on both Teflon and glass coverslips, with more than 100 cells per
      substratum detected at the 17th day of storage. Results indicate that coins could
      serve as potential vehicles for transmitting both E. coli O157:H7 and Salmonella
      Enteritidis.

PMID- 10419276
TI  - Bacterial contamination in the environment of food factories processing ready-to
      eat fresh vegetables.
AB  - A total of 196 samples were collected from equipment for trimming, washing,
      slicing, soaking, dehydrating, blending, and packaging and from the floor and air
      of operation rooms before and after operation in two food factories processing
      ready-to-eat fresh vegetables located in the suburbs of Tokyo. Heavy
      contamination determined by an aerobic plate count of >5.0 log CFU/cm2 or ml was
      observed after operation in most of the samples examined, as were samples taken
      before operation on the interior surfaces of equipment for washing, slicing,
      dehydrating, and blending, the surfaces of blades for slicing, and the floor
      surfaces of operation rooms. From these environmental samples, the coliform group
      was detected before operation. Although 67 strains of 70 coliforms isolated were
      nonfecal, three Escherichia coli strains were detected in the surface of the
      operation room floors and the gloves of employees. Bacillus cereus was isolated
      from 9 of 86 and 17 of 85 samples examined before and after operation with the
      number of 2.0 to 3.0 log CFU/cm2 or ml. Listeria spp. were not detected in the
      environment of the food factories.

PMID- 10419278
TI  - Starter culture activity in refrigerated fermented soymilk.
AB  - The refrigerated shelf life of soymilk fermented with single cultures of
      Lactobacillus fermentum, L. casei, Streptococcus salivarius subsp. thermophilus,
      and Bifidobacterium longum was evaluated. During storage at 4 degrees C for 28
      days, the stability of the microflora differed markedly among the starter
      cultures. After 28 days, the average numbers of S. salivarius subsp. thermophilus
      decreased by two log cycles to 6.0 x 10(7) CFU/ml, whereas those of L. casei
      increased gradually by more than two log cycles to 4.6 x 10(9) CFU/ml. Numbers of
      B. longum and L. fermentum remained moderately high (8.7 x 10(8) CFU/ml and 3.7 x
      10(8) CFU/ml, respectively) even after 28 days of storage. S. salivarius subsp.
      thermophilus and L. casei continued to metabolize sucrose during the storage
      period, but the pattern of consumption was different among the strains. The other
      starter cultures did not seem to have significant activity (P > 0.05) on the
      residual sugars. In most cases, L(+)-lactate predominated.

PMID- 10419279
TI  - Fumonisin production by Fusarium species isolated from cereals and feeds in
      Spain.
AB  - The ability of Fusarium species to produce fumonisins was studied with 145
      isolates of the following species: F. moniliforme (119 isolates), F. subglutinans
      (12 isolates), F. proliferatum (9 isolates), F. avenaceum (1 isolate), F.
      oxysporum (1 isolate), and F. semitectum (3 isolates). All isolates were cultured
      on autoclaved corn kernels. The production of fumonisins was determined by a high
      performance liquid chromatography-o-phthaldialdehyde-fluorescence method.
      Fumonisin production was restricted to isolates of F. moniliforme (94.1%) and F.
      proliferatum (100%), in the section Liseola, including all strains isolated from
      wheat, barley, peas, and soybean. One strain of F. proliferatum isolated from
      maize produced 30,949 microg/g of fumonisin B1 and 16,966 microg/g of fumonisin
      B2.

PMID- 10419281
TI  - Foodborne infections during pregnancy.
AB  - The consequences of foodborne illness can be particularly devastating during
      pregnancy because both the woman and her fetus are at risk. Escalated production
      of progesterone during pregnancy leads to down-regulation of cellular (cell
      mediated) immune functions. Many foodborne pathogens (and other pathogens) are
      intracellular pathogens, and infections caused by these pathogens are controlled
      by cell-mediated immunity. The pregnancy-induced decrease in cell-mediated immune
      functions leads to increased susceptibility of the pregnant woman to certain
      infections. Hepatitis E virus, Coxiella burnetii, Listeria monocytogenes, and
      Toxoplasma gondii are intracellular pathogens that have a predilection for the
      maternal-fetal unit and may induce serious disease in the mother and/or fetus. In
      the United States, T. gondii and L. monocytogenes are the most important
      foodborne pathogens in pregnancy, and these organisms can induce death or grave
      disease in the fetus and newborn. The pregnant woman, in order to protect herself
      and her fetus from the consequences of foodborne illness, must practice a high
      standard of food hygiene and personal cleanliness.

PMID- 10419280
TI  - Fumonisin production on irradiated corn kernels: effect of inoculum size.
AB  - Production of fumonisins B1, B2, and B3 by Fusarium moniliforme was evaluated on
      irradiated corn kernels inoculated with different spore concentrations (10,
      10(2), 10(3), 10(5), and 10(6)), a water activity of 0.97, and a temperature of
      25 degrees C. There was a direct relationship between the level of toxin produced
      and inoculum size. The highest levels of total fumonisin produced after 35 days
      of incubation were 5,028 and 9,063 ng/g at 10(5) and 10(6) spores per ml,
      respectively. The pattern of fumonisin production (FB1 > FB2 > FB3) in cultures
      growing from different inocula was not affected during the 35 days of incubation.
      The ratio between FB2 and FB1 varied from 0.15 to 0.42, whereas the ratio between
      FB3 and FB1 varied from 0.34 to 0.87.

PMID- 10419283
TI  - Non-quassinoid constituents from the twigs and thorns of Castela polyandra.
AB  - The structures of two new constituents, a beta-glycoside (1) and a steroid (2),
      isolated from the twigs and thorns of Castela polyandra, were established by a
      combination of spectroscopic and single-crystal X-ray analysis.

PMID- 10419282
TI  - Biologically active anthracenones from roots of Karwinskia parvifolia.
AB  - Tullidinol, a neurotoxin isolated from fruits and roots of several Karwinskia
      species, was resolved for the first time into two stereoisomers. This was
      achieved by means of preparative HPLC from roots of Karwinskia parvifolia.
      Structural assignments were made on the basis of spectroscopic data, including
      long range correlations as well as geometry optimization by means of semi
      empirical methods.

PMID- 10419284
TI  - Development of validated stereoselective methods for methadone determination in
      clinical samples.
AB  - A stereoselective analysis of methadone (Mtd) in whole blood and serum was
      developed using liquid chromatography on a protein based chiral stationary phase.
      Liquid-liquid extraction (LLE) and solid phase extraction methods were applied
      before chromatographic analysis. The extraction procedure, as well as the choice
      of the biological matrix, showed significant differences in the extraction yield
      and in the precision of the assays. Serum was selected for this assay and LLE was
      chosen as the preparation step because of its simplicity and rapidity. The total
      procedure was validated and applied to clinical samples. Samples taken from 45
      heroin-addicted patients were analyzed. A correlation was found between the dose
      administered and Mtd concentration (total and R-form), but interindividual
      variability of the total normalized Mtd was seen (concentration varied from 90 to
      530 ng/ml). Furthermore, two populations were apparently observed with a mean Mtd
      concentration of 200 and 475 ng/ml, respectively. Stereoselective analyses showed
      that more than 50% of the patients presented a nonracemic ratio, and particularly
      about 25% showed a preferential metabolism of the active R-Mtd enantiomer.
      Therefore, the stereoselective determination of Mtd is necessary to improve the
      quality of the treatment of heroin addiction.

PMID- 10419285
TI  - Enatioseparation and anti-rhinovirus activity of 3-benzylchroman-4-ones.
AB  - In a series of homo-isoflavonoids, chloro-substituted rac-3-benzylchroman-4-ones
      (3 d-f) showed an antiviral in vitro activity against selected picornaviruses. In
      order to study the anti-rhinovirus activity of each stereoisomer, racemic
      mixtures of 3 d and 3 e were successfully resolved by high-performance liquid
      chromatography, using a Whelk-O 1 column as chiral stationary phase. The CD
      spectra confirm that the two eluates of each compound are enantiomers but do not
      allow the assignment of their absolute configurations. The antiviral activity of
      the isomers and their racemates was tested in vitro against human rhinovirus
      serotype 1B and 14 infection, by means of the plaque reduction assay. All
      homoisoflavonoids tested exhibited an inhibitory effect on rhinovirus replication
      with an activity depending on virus serotype and compound. The two enantiomers of
      each compound and the corresponding racemate were equipotent, clearly showing
      that the configuration of the chiral center in position 3 does not influence the
      activity against both rhinovirus serotypes.

PMID- 10419286
TI  - SCAR 99. PACS: Performance Improvement in Radiology. Proceedings of the 16th
      Symposium for Computer Applications in Radiology. Houston, Texas, USA. May 6-9,
      1999.

PMID- 10419287
TI  - Risk of malignancy associated with cyclosporin use in psoriasis.

PMID- 10419288
TI  - Familial anetoderma.

PMID- 10419289
TI  - Bullous pemphigoid as an initial presentation of renal oncocytoma.

PMID- 10419290
TI  - Increase production of lactonizing lipase (LipL) from Pseudomonas sp. strain 109
      by lipids and detergents.
AB  - LipL of Pseudomonas sp. strain 109 is a unique lipase capable of catalyzing
      macrocyclic lactone synthesis using omega-hydroxyfatty acid esters as substrates.
      Several fatty acid esters were tested as inducers of LipL production. The
      addition of either soybean oil or a non-ionic detergent (Noigen HC) resulted in a
      44 to 45-fold increase in extracellular LipL, and the presence of both resulted
      in a further 56-fold increase. Among the triglycerides tested, triolein was the
      most effective, with a 50-fold increase in LipL production. A Northern blot
      hybridization analysis found that the lipL transcript increased in the presence
      of soybean oil or Noigen HC, indicating that the production of LipL is regulated
      at the transcriptional level.

PMID- 10419291
TI  - Inhibition of the acid lipase activity by apolipoprotein A-I in the presence of
      lysosomal proteases.
AB  - It was found that the inhibition of the lysosomal acid lipase activity by rat
      apolipoprotein A-I (apo A-I) was increased with the degradation of apo A-I by the
      lysosomal proteases. We demonstrated that apo A-I could effectively inhibit the
      acid lipase activity even in the presence of the lysosomal proteases using the
      hepatic lysosomal fraction.

PMID- 10419292
TI  - Use of organic solvents and small molecules for locating binding sites on
      proteins in solutions.
AB  - Application of a modified ePHOGSY and other NMR experiments to an H2O-DMSO
      solution of the protein FKBP12 identified the presence of one molecule of DMSO
      bound in the substrate binding site. It occupies the same spatial region occupied
      by the pipecolidine moiety of the immunosuppressive drugs FK506 and Rapamycin
      complexed to the protein. The binding constant K(D) for ths DMSO molecule was
      only 275 mM. A substructure search of small molecules similar to DMSO resulted in
      the identification of molecules with improved binding affinity. This work
      represents a clear example of the powerful interplay of molecular modelling and
      NMR.

PMID- 10419293
TI  - Why heart disease mortality is low in France. Commentary: alcohol and other
      dietary factors may be important.

PMID- 10419294
TI  - Why heart disease mortality is low in France. Commentary: intrauterine nutrition
      may be important.

PMID- 10419295
TI  - Why heart disease mortality is low in France. Commentary: heterogeneity of
      populations should be taken into account.

PMID- 10419296
TI  - Left ventricular dysfunction among elderly patients in general practice. ...as
      are echocardiograms.

PMID- 10419297
TI  - Left ventricular dysfunction among elderly patients in general practice. Evidence
      based medicine is not yet possible in these patients.

PMID- 10419298
TI  - Clinical trials in primary care. Paying doctors for clinical trials is unethical.

PMID- 10419299
TI  - Migraine and stroke in young women. Prospective study is needed to determine what
      clinical practice in migraine should be.

PMID- 10419300
TI  - Vaccines and their real or perceived adverse effects. Studies of adverse effects
      of vaccination have duty to present full picture.

PMID- 10419301
TI  - Neurogenetic determinism and the new euphenics. Child and adolescent
      psychiatrists use methylphenidate because it makes children better.

PMID- 10419302
TI  - Radiosurgery for brain tumours. Not all practitioners of this technique can have
      succumbed to marketing.

PMID- 10419303
TI  - Presumed consent. We know that our daughter lives on.

PMID- 10419304
TI  - Airline passenger dies after being sedated. ...or to potentiating effects on
      diazepam.

PMID- 10419305
TI  - Assessments forgotten.

PMID- 10419306
TI  - Service start-ups. Get physical.

PMID- 10419308
TI  - Diversity. Still now Rainbow Coalition.

PMID- 10419307
TI  - Y2K ready. Supply grab?

PMID- 10419309
TI  - Covering up. For small players, a big leap.

PMID- 10419310
TI  - Digital debut. Newbie.net.

PMID- 10419311
TI  - Do Y2K glitches deserve liability caps?

PMID- 10419312
TI  - Fragile future: a rural hospital weighs its options.

PMID- 10419313
TI  - Courtesy counts. Bucks start here.

PMID- 10419315
TI  - Web sightings. Koop's coup.

PMID- 10419314
TI  - Emergency surgery. Service: the cutting edge.

PMID- 10419316
TI  - Venture capital. The Net--or nyet.

PMID- 10419317
TI  - Help on wheels. Porta pulse.

PMID- 10419318
TI  - Faith healing? Soul care.

PMID- 10419319
TI  - Construction. Built to bend.

PMID- 10419320
TI  - Doctors & HMOs. From balking to brokering.

PMID- 10419321
TI  - Should Medicare add drugs to its list of benefits?

PMID- 10419322
TI  - Forget the pound of cure ... when it comes to prevention, supply doesn't generate
      demand.

PMID- 10419324
TI  - The Blues buyer. Anthem eats up.

PMID- 10419323
TI  - Right practice, wrong time?

PMID- 10419325
TI  - Surrogate births. Born, but not free.

PMID- 10419326
TI  - Proceedings of the 22nd International Symposium on Chromatography. Part I. Rome,
      Italy, 13-18 September 1998.

PMID- 10419328
TI  - Accident and emergency medicine or emergency medicine?

PMID- 10419327
TI  - Accident and emergency medicine or emergency medicine.

PMID- 10419329
TI  - Use of the Cochrane Library by emergency physicians.

PMID- 10419330
TI  - Journal clubs.

PMID- 10419331
TI  - Pseudomyxoma peritonei.

PMID- 10419333
TI  - Anomalous pancreaticobiliary junction without congenital choledochal cyst.

PMID- 10419332
TI  - Quality of life in patients with benign anorectal disorders.

PMID- 10419334
TI  - Abscisic acid.

PMID- 10419335
TI  - Visual attention: spotlight on the primary visual cortex.
AB  - Visual search tasks appear to involve spatially selective attention to the
      target, but evidence for attentional modulation in the visual area with the most
      precise retinotopic organization V1 has been elusive. Recent imaging studies show
      that spatial attention can indeed enhance visual responses in human V1.

PMID- 10419336
TI  - New quinolones in clinical practice.

PMID- 10419337
TI  - III International Symposium on Heat Shock Proteins: Expression, Immunity and
      Women's Health. New York, New York, USA. April 10-11, 1999. Proceedings and
      abstracts.

PMID- 10419338
TI  - Ecology and industrial microbiology techniques. Web alert.

PMID- 10419339
TI  - Anguish from Belgrade.

PMID- 10419340
TI  - The 'heart failure nurse' to help us close the gap between what we can and what
      we do achieve.

PMID- 10419341
TI  - Measuring the occurrence of myocardial infarction.

PMID- 10419342
TI  - Quality of life after coronary angioplasty or bypass surgery.

PMID- 10419343
TI  - The gap between reliable evidence and adoption of therapies.

PMID- 10419344
TI  - Myocardial infarction, urgent angioplasty and intra-arterial balloon
      counterpulsation.

PMID- 10419345
TI  - Significance of bladder biopsies in Ta,T1 bladder tumors: a report from the EORTC
      Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder
      Committee.
AB  - OBJECTIVES: We investigated to what extent biopsies of normal-appearing
      urothelium taken from patients with Ta,T1 bladder cancer showed malignant
      disease: carcinoma in situ, or papillary tumor. We also investigated biopsies
      underlying the papillary tumor, adjacent to the tumor, and from suspicious
      appearing mucosa. METHODS: In EORTC protocol 30863 (low-risk tumors), 393
      patients underwent a biopsy of normal-appearing urothelium. In protocol 30911
      (intermediate- and high-risk tumors), multiple biopsies were taken from normal-
      appearing urothelium in 602 patients. RESULTS: No abnormalities were found in the
      random biopsies of 376 (95.6%) patients with low-risk tumors and in 532 (88.4%)
      patients with intermediate- and high-risk tumors. Six (1.5%) patients with low
      risk tumors and at least 21 (3.5%) patients with higher-risk tumors showed
      carcinoma in situ in their random biopsies. None of the patients in the low-risk
      group and 1 (0.2%) patient in higher-risk group had an invasive tumor (T2).
      CONCLUSIONS: This analysis indicates that biopsies of normal-appearing urothelium
      in Ta,T1 bladder cancer patients show no abnormalities in about 90% of the
      patients. Performing such biopsies does not contribute to the staging or to the
      choice of adjuvant therapy after transurethral resection.

PMID- 10419346
TI  - Gastrostomy placement and mortality among hospitalized Medicare beneficiaries.

PMID- 10419347
TI  - Large paraesophageal varices on endosonography predict recurrence of esophageal
      varices and rebleeding.

PMID- 10419348
TI  - Common bile duct stones become smaller after endoscopic biliary stenting.

PMID- 10419350
TI  - Functional expression of the multidrug resistance-associated protein in the yeast
      Saccharomyces cerevisiae.

PMID- 10419351
TI  - Management of postoperative pain in animals used in research.

PMID- 10419352
TI  - Endocrinology and art.

PMID- 10419349
TI  - Phenotypic analysis of local cellular responses in calves infected with bovine
      respiratory syncytial virus.
AB  - Changes in lymphocyte subsets in the trachea, pulmonary tissue, bronchoalveolar
      lavage (BAL), peripheral blood and bronchial lymph node (BLN) of gnotobiotic
      calves infected with bovine respiratory syncytial virus (BRSV) were analysed by
      flow cytometry. Following BRSV infection, virus titres in the nasopharynx reached
      a peak between days 5 and 7 and infection was resolving from day 10. Although
      calves did not develop signs of clinical respiratory disease, there was evidence
      of gross pneumonia and histological changes typical of BRSV bronchiolitis, which
      were most extensive from day 710 of infection. Following BRSV infection there was
      a recruitment of CD8+ T cells into the trachea and lung, which peaked on day 10
      after infection. Thus, there were approximately equal numbers of CD8+ and CD4+ T
      cells in the lung and trachea of uninfected calves, whereas by day 10 of
      infection, CD8+ cells outnumbered CD4+ cells by 3:1 in the lungs and 6:1 in the
      trachea of the infected calves. Although the increase in CD4+ T cells into the
      lungs was less marked than that of CD8+ T cells, changes in expression of CD45R,
      CD45RO, L-selectin and interleukin-2 receptors all suggested that CD4+ T cells
      were activated during BRSV infection. Changes in gamma delta T cells were not
      observed in BRSV-infected calves. There was a marked increase in B cells in the
      BLN after infection and BLN CD4+ T cells changed from the majority expressing L
      selectin and CD45R in uninfected calves to a predominance of L-selectin- CD45R-
      CD45RO+ phenotype, 10 days after infection. In conclusion, CD8+ T cells
      constitute the major lymphocyte subpopulation in the respiratory tract of calves
      recovering from BRSV infection.

PMID- 10419353
TI  - An evidence-based review of decompressive surgery in acute spinal cord injury:
      rationale, indications, and timing based on experimental and clinical studies.
AB  - OBJECT: The authors conducted an evidence-based review of the literature to
      evaluate critically the rationale and indications for and the timing of
      decompressive surgery for the treatment of acute, nonpenetrating spinal cord
      injury (SCI). METHODS: The experimental and clinical literature concerning the
      role of, and the biological rationale for, surgical decompression for acute SCI
      was reviewed. Clinical studies of nonoperative management of SCI were also
      examined for comparative purposes. Evidence from clinical trials was categorized
      as Class I (well-conducted randomized prospective trials), Class II (well
      designed comparative clinical studies), or Class II (retrospective studies).
      Examination of studies in which animal models of SCI were used consistently
      demonstrated a beneficial effect of early decompressive surgery, although it is
      difficult to apply these data directly to the clinical setting. The clinical
      studies provided suggestive (Class III and limited Class II) evidence that
      decompressive procedures improve neurological recovery after SCI. However, no
      clear consensus can be inferred from the literature as to the optimum timing for
      decompressive surgery. Many authors have advocated delayed treatment to avoid
      medical complications, although good evidence from recent Class II trials
      indicates that early decompressive surgery can be performed safely without
      causing added morbidity or mortality. CONCLUSIONS: There is biological evidence
      from experimental studies in animals that early decompressive surgery may improve
      neurological recovery after SCI, although the relevant interventional timing in
      humans remains unclear. To date, the role of surgical decompression in patients
      with SCI is only supported by Class III and limited Class II evidence.
      Accordingly, decompressive surgery for SCI can only be considered a practice
      option. Furthermore, analysis of the literature does not allow definite
      conclusions to be drawn regarding appropriate timing of intervention. Hence,
      there is a need to conduct well-designed experimental and clinical studies of the
      timing and neurological results of decompressive surgery for the treatment of
      acute SCI.

PMID- 10419354
TI  - Posterior approach for cervical intramedullary arteriovenous malformation with
      diffuse-type nidus. Report of three cases.
AB  - The treatment of spinal intramedullary arteriovenous malformations (AVMs) with a
      diffuse-type nidus that contains a neural element poses different challenges
      compared with a glomus-type nidus. The surgical elimination of such lesions
      involves the risk of spinal cord ischemia that results from coagulation of the
      feeding artery that, at the same time, supplies cord parenchyma. However, based
      on evaluation of the risks involved in performing embolization, together with the
      frequent occurrence of reperfusion, which necessitates frequent reembolization,
      the authors consider surgery to be a one-stage solution to a disease that
      otherwise has a very poor prognosis. Magnetic resonance (MR) imaging revealed
      diffuse-type intramedullary AVMs in the cervical spinal cords of three patients
      who subsequently underwent surgery via the posterior approach. The AVM was
      supplied by the anterior spinal artery in one case and by both the anterior and
      posterior spinal arteries in the other two cases. In all three cases, a posterior
      median myelotomy was performed up to the vicinity of the anterior median fissure
      that divided the spinal cord together with the nidus, and the feeding artery was
      coagulated and severed at its origin from the anterior spinal artery. In the two
      cases in which the posterior spinal artery fed the AVM, the feeding artery was
      coagulated on the dorsal surface of the spinal cord. Neurological outcome
      improved in one patient and deteriorated slightly to mildly in the other two
      patients. Postoperative angiography demonstrated complete disappearance of the
      AVM in all cases. Because of the extremely poor prognosis of patients with spinal
      intramedullary AVMs, this surgical technique for the treatment of diffuse-type
      AVMs provides acceptable operative outcome. Surgical intervention should be
      considered when managing a patient with a diffuse-type intramedullary AVM in the
      cervical spinal cord.

PMID- 10419355
TI  - Plexiform neurofibroma of the cauda equina. Case report.
AB  - Plexiform neurofibroma of the cauda equina has been reported only twice
      previously. The authors report the first pediatric patient in whom such a tumor
      has been found. A 4-year-old boy presented with low-back pain that radiated
      bilaterally into the L-4 and L-5 dermatomes. A dermal sinus noted at the
      midthoracic level was surrounded by a hemangiomatous lesion. Magnetic resonance
      imaging confirmed the presence of the dermal sinus and revealed a well-defined
      lumbosacral mass that showed heterogeneous intensity with irregular enhancement.
      Intraoperatively, a solid mass, which engulfed the entire cauda equina, could not
      be dissected from the roots. The dermal sinus tract, however, was excised from
      the thoracic spine. The patient underwent radiotherapy to control the tumor and
      relieve his pain. Plexiform neurofibromas of the cauda equina are characterized
      by an insidious and progressive clinical course. The tumor mass may engulf all
      the roots of the cauda equina. No plexiform neurofibroma of the cauda equina has
      been reported to be associated with neurofibromatosis Type 1. The authors assume
      that the thoracic-level dermal sinus observed in this child was an incidental
      finding.

PMID- 10419356
TI  - Multiple extradural arachnoid cysts as a cause of spinal cord compression in a
      child. Case report.
AB  - Symptomatic arachnoid cysts of the spine are uncommon in children and have only
      rarely been reported to occur extradurally. The authors report a case of multiple
      extradural spinal arachnoid cysts in a 9-year-old child who presented with signs
      of spinal cord compression. The extent of the disease, which affected the
      thoracic, lumbar, and sacral spine, and the number of independent cysts make this
      case unique and suggest an underlying defect in the dura of the spinal canal that
      is predisposed to the formation of cysts. The investigations of choice, surgical
      planning, and surgical technique are considered. The literature is reviewed and
      mechanisms of cyst formation discussed.

PMID- 10419357
TI  - Current use and timing of spinal surgery for management of acute spinal surgery
      for management of acute spinal cord injury in North America: results of a
      retrospective multicenter study.
AB  - OBJECT: A multicenter retrospective study was performed in 36 North American
      centers to examine the use and timing of surgery in patients who have sustained
      acute spinal cord injury (SCI). The study was performed to obtain information
      required for the planning of a randomized controlled trial in which early and
      late decompressive surgery are compared. METHODS: The records of all patients
      aged 16 to 75 years with acute SCI admitted to 36 centers within 24 hours of
      injury over a 9-month period in 1994 and 1995 were examined to obtain data on
      admission variables, methods of diagnosis, use of traction, and surgical
      variables including type and timing of surgery. A total of 585 patients with
      acute SCI or cauda equina injury were admitted to participating centers, although
      approximately half were ultimately excluded because they did not meet inclusion
      criteria. Common causes for exclusion were late admission, age, gunshot wound,
      and absence of signs of compression on imaging studies. Thus, only approximately
      50% of patients with acute SCI would be eligible for inclusion in a study of
      acute decompressive surgery. Although all patients underwent computerized
      tomography (CT) scanning, only 54% underwent magnetic resonance imaging, and CT
      myelography was performed in only 6%. Complete neurological injuries (American
      Spinal Injury Association Grade A) were present in 57.8%. Traction was applied in
      only 47% of patients who sustained cervical injury, in whom decompressive
      traction was successful in only 42% of cases. Neurological deterioration occurred
      in 8.1% of cases after traction. Surgery was performed in 65.4% of patients. The
      timing of surgery varied widely: less than 24 hours postinjury in 23.5%, between
      25 and 48 hours postinjury in 15.8%, between 48 and 96 hours in 19%, and more
      than 5 days postinjury in 41.7% of patients. CONCLUSIONS: These data indicate
      that although surgery is commonly performed in patients with acute SCI, one third
      of cases are managed nonoperatively, and there is very little agreement on the
      optimum timing of surgical treatment. The results of this study confirm the need
      for a randomized controlled trial to assess the optimum timing of decompressive
      surgery in SCI.

PMID- 10419358
TI  - Anomaly of the axis causing cervical myelopathy. Case report.
AB  - Although the craniovertebral junction is one of the most common sites at which
      anomalies develop, spina bifida occulta of the axis (C-2) associated with
      cervical myelopathy is extremely rare. The authors present the case of a 46-year
      old man who developed progressive tetraparesis caused by a cervical canal
      stenosis at the level of the axis. The spinal cord was compressed by an
      invaginated bifid lamina of the axis. The patient made a remarkable recovery
      after undergoing decompressive laminectomy of C-3 and removal of the bifid
      posterior arch of the axis.

PMID- 10419359
TI  - Anterior sacral meningocele associated with a rectal fistula. Case report and
      review of the literature.
AB  - The authors report a case of anterior sacral meningocele associated with a rectal
      fistula in a patient who had presented 20 years earlier with bacterial
      meningitis. To their knowledge, this is the first case in which a rectal fistula
      developed due to an anterior sacral meningocele. The clinical presentation,
      diagnosis, and treatment of this uncommon lesion is discussed.

PMID- 10419360
TI  - Magnetic resonance imaging-monitored conservative management of traumatic spinal
      epidural hematomas. Report of four cases.
AB  - Spinal epidural hematomas (SEHs) are uncommon complications of traumatic injury
      to the spine. Emergency surgical evacuation is the standard treatment. Although
      it is recognized in the literature, the possibility of nonsurgical treatment of
      traumatic SEH is far from being codified. The authors report excellent outcomes
      in four conservatively managed patients who had sustained a severe spine injury
      with fracture of the lumbar vertebral body and in whom traumatic SEHs were
      diagnosed by magnetic resonance imaging. Although in the authors' experience a
      good spontaneous outcome in this subgroup of minimally symptomatic patients
      harboring moderate-sized SEHs has been achieved, further studies are necessary to
      understand the real spectrum of nonsurgical treatment of such lesions.

PMID- 10419361
TI  - Percutaneous treatment of gas-containing lumbar disc herniation. Report of two
      cases.
AB  - A limited number of cases have been reported in which gas-containing lumbar disc
      herniation caused compression of nerve roots. The authors describe two patients
      in whom computerized tomography scanning revealed a large intraspinal gas
      collection that appeared to be causing nerve root compression and that was
      successfully evacuated by percutaneous needle aspiration.

PMID- 10419362
TI  - Tumoral calcinosis of the lumbar spine. Case illustration.

PMID- 10419363
TI  - Cervical corpectomy.

PMID- 10419364
TI  - Outcome of 51 cases of unilateral locked cervical facets: interspinous braided
      cable for lateral mass plate fusion compared with interspinous wire and facet
      wiring with iliac crest.
AB  - OBJECT: To increase knowledge about unilateral facet dislocation, including
      presentation, radiological findings, management, and outcome, the authors
      reviewed the cases of 51 consecutive patients with unilateral locked facets of
      the cervical spine who underwent treatment over an 11-year period. With the
      development of internal fixation devices, the authors compared the procedure of
      using interspinous wire and facet wiring of iliac crest to fix unilateral locked
      facets with that in which interspinous braided cable and lateral mass plates were
      used. METHODS: Thirty-seven patients (73%) presented with radiculopathy, eight
      (16%) with neck pain only, and six (12%) with spinal cord injuries (SCIs). Plain
      x-ray films demonstrated subluxation in only 44 (86%) of 51 cases. All patients
      underwent cervical computerized tomography (CT) scanning, and in all patients
      with SCI, a magnetic resonance (MR) image was obtained. Fracture in addition to
      facet locking was seen on 24 (47%) of 51 CT scans. Disc disruption with cord
      compression was seen in five cases (10%). Based on CT and/or MR imaging findings,
      a closed reduction procedure was believed to be contraindicated in 11 cases
      (22%). Of the remaining 40 patients, 13 (33%) underwent closed reduction
      procedures. Two patients who underwent a closed reduction procedure were placed
      in a halo brace but experienced resubluxation. Thus, all cases were surgically
      treated. Forty-six patients underwent posterior reduction and/or internal
      fixation alone (in 24 cases spinous process fixation with facet wiring was
      connected to struts of iliac crest, and in 22 cases interspinous braided cable
      for lateral mass plating was used). Initial surgery, regardless of technique, was
      successful in 45 (98%) of 46 cases. One patient experienced a resubluxation and
      underwent reoperation in which anterior cervical fusion and plating were
      performed. Four of six patients with SCI underwent an emergency combined anterior
      posterior decompressive procedure in which internal fixation was performed, and
      the patients experienced immediate neurological improvement. Overall there were
      no cases of neurological worsening or death, and there were three cases of wound
      infection. At 1 year postsurgery, all deficits had improved. Of 37 cases of
      radiculopathy, three patients (8%) experienced persistent 4/5 weakness, and the
      remaining patients were normal, including four patients in whom diagnosis was
      delayed. The six patients with SCI all improved significantly by 1 year.
      Persistent neck pain was seen in nine cases (18%). Although the lateral mass
      plates and interspinous cable are stronger, easier to place, and significantly
      lessened the amount of resultant kyphosis (p < 0.02), the results of chi-square
      analysis demonstrated only a slight trend for improved clinical outcome compared
      with the use of wire and iliac crest (p = 0.1). CONCLUSIONS: Cervical CT and MR
      imaging provide information that aids in the diagnosis and management of patients
      with unilateral locked facets of the cervical spine. The authors' experience
      strongly suggests that a reduction procedure in which internal fixation and bone
      fusion are performed will be the most successful treatment for this injury.

PMID- 10419365
TI  - A new type of microelectrode for obtaining unitary recordings in the human spinal
      cord.
AB  - OBJECT: In this paper the authors report on the conception and adjustment of a
      microelectrode used to obtain unitary recordings in the human spinal cord.
      METHOD: To overcome the difficulties related to intraoperative pulsations of the
      spinal cord, the authors opted to use a floating microelectrode. Because the
      recordings are obtained most often from spontaneous activities, it is difficult,
      with a single microelectrode, to separate spikes from electrical artifacts that
      are related to the switching of devices. Consequently, the authors designed a
      dual microelectrode made of two tungsten-in-glass-attached microelectrodes
      separated by 300 microm. Because the two electrodes cannot obtain recordings in
      the same neuron, it is possible to distinguish unambiguously spikes (recorded on
      one tip) from electrical artifacts (recorded simultaneously on the two tips). The
      dual microelectrode is 2 cm long, with a 20-microm tip length, and 800 to 1200
      Ohms impedance. This microelectrode can be implanted "free hand," in the dorsal
      horn, by using a microsurgical forceps under a surgical microscope. The data
      analysis is performed off-line with spike sorter hardware. In the dorsal horns in
      17 patients who were selected to undergo a dorsal root entry zone (DREZ)
      rhizotomy to treat various pathological conditions, unitary recordings were
      obtained using this double microelectrode. The authors recorded 57 neurons in
      good conditions of stability and isolation. CONCLUSIONS: The microelectrode
      described in this paper was successfully used to obtain recordings in neurons in
      more than 85% of the patients. This simplified, floating double microelectrode
      can therefore be considered for use in microsurgical DREZ rhizotomy to obtain
      unitary recordings in the human spinal dorsal horn.

PMID- 10419367
TI  - Artificial lamina-assisted laminoplasty performed in seven cases.
AB  - OBJECT: The authors attempted to simplify the operative approach to severe
      multilevel cervical spondylotic myelopathy. Seven patients with progressive and
      severe myelopathy underwent modified double-door laminoplasty during a 5-month
      period. METHODS: The double-door laminoplasty procedure was modified by using two
      artificial titanium laminae obtained by simple surgical 0.5-mm Ti-mesh (rather
      than by bone graft or ceramic spacers). Preoperatively, gait disturbance was
      present in all patients with long-tract signs on neurological examination. In all
      cases the sagittal diameter of the cervical spinal canal was somewhat reduced (<
      10 mm) by congenital stenosis, and further severe compression of the spinal cord
      resulted from osteophytic bars and calcified ligamenta flava at different levels.
      No abnormal alignment, pathological movements, or instability was present.
      Computerized tomography (CT) studies demonstrated severe multilevel cervical
      compression, and T2-weighted magnetic resonance (MR) imaging demonstrated
      pathological areas of hyperintensity within the spinal cord in all cases. In the
      initial follow-up study (range 8-12 months), the patients who underwent this
      procedure experienced marked improvement of gait disturbance without any
      significant incidence of morbidity or complications. Postoperative CT and MR
      imaging studies demonstrated complete spinal cord decompression and restoration
      of the patency of the subarachnoid spaces. CONCLUSIONS: The proposed procedure
      has the advantage of achieving both an immediate stabilization of the open
      laminae by means of a bridgelike mechanism and protection from the possible
      compression of the dural sac by paravertebral muscles.

PMID- 10419366
TI  - Surgical treatment for patients with cervical flexion myelopathy.
AB  - OBJECT: Cervical flexion myelopathy is a rare condition that mainly affects
      adolescent boys. In recent years, avoidance of neck flexion has been advocated as
      the treatment for cervical flexion myelopathy, and treatment with a cervical
      collar and surgery in which fusion of the cervical spine is performed have been
      found to be effective. However, previously reported series contained only a
      limited number of patients. The authors report their experience with treating 10
      male patients in whom surgery was performed to correct cervical flexion
      myelopathy, and they evaluate the patients' surgical outcome. METHODS: The
      authors performed anterior decompressive surgery and fusion in the cervical spine
      by using a long bone graft after resection of one or two vertebrae in seven
      patients. The other three patients underwent posterior fusion of four or five
      laminae. After surgery, symptom progression was stopped in all patients, muscle
      strength improved in seven, and sensory disturbance was alleviated in another
      two. However, the muscular atrophy in the upper extremities, which was evident in
      nine patients preoperatively, improved in only two. CONCLUSIONS: Because some
      neurological improvement was seen in nine of 10 patients, it is believed that
      surgical fusion of the cervical spine is an effective treatment for patients with
      cervical flexion myelopathy.

PMID- 10419368
TI  - Significance of a persistent positive straight leg raising test after lumbar disc
      surgery.
AB  - OBJECT: Results of the straight leg raising (SLR) test provide the clinician with
      valuable information regarding possible causes of a patient's pain. In a previous
      study the results have also demonstrated a correlation between the outcome of the
      test and the severity of pain, as well as the prognostic value of the test;
      patients for whom the SLR test is persistently positive postoperatively appear to
      have a poorer short-term outcome. In a prospective study of 200 consecutive
      patients who underwent surgery for disc herniation, the authors evaluated the
      frequency of repeated surgery and outcome of surgery in patients with a
      persistent postoperative positive SLR test. METHODS: The preoperative
      radiological evaluation included myelography, computerized tomography scanning,
      and/or magnetic resonance imaging. Preoperatively as well as 4, 12, and 24 months
      postoperatively, each patient was interviewed and examined using a standard
      protocol in which common symptoms and signs were described. The result of the SLR
      test was also classified into one of four categories: positive 0 to 30 degrees ;
      positive 30 to 60 degrees, positive greater than 60 degrees, or negative, and the
      surgical results were evaluated using a four-grade scale. Preoperatively, the SLR
      test was positive in 86% of patients. At 4 months postoperatively, 22% still had
      a positive SLR test. For the patients whose SLR test was positive 4 months
      postoperatively, the long-term outcome at all three follow-up examinations was
      inferior; this difference was statistically significant. CONCLUSIONS: During the
      2-year period, the reoperation rate was 18% (eight of 44) in patients with a
      positive postoperative SLR test compared with 4.5% (seven of 156) in patients
      whose postoperative SLR test was negative. A postoperative positive SLR test thus
      correlates to an unfavorable surgical outcome.

PMID- 10419369
TI  - Magnetic resonance imaging evaluation of the cervical spine in the comatose or
      obtunded trauma patient.
AB  - OBJECT: Confirmation of cervical spine stability is difficult to obtain in the
      comatose or obtunded trauma patient. Concurrent therapies such as endotracheal
      intubation and the application of rigid cervical collars diminish the utility of
      plain radiographs. Bony as well as supportive soft-tissue structures must be
      evaluated before the cervical spine can be determined to be uninjured. Although
      major injuries to extradural soft-tissue structures in the awake trauma patient
      are frequently excluded by physical examination, when the patient is obtunded the
      physical examination may be unreliable. Therefore, an enhanced diagnostic method
      for the evaluation of soft-tissue injury is desirable. The authors conducted a
      study in which magnetic resonance (MR) imaging was used as such a method to
      assess posttraumatic spinal stability in the comatose or obtunded patient.
      METHODS: Early, limited (sagittal T1- and T2-weighted) MR imaging was performed
      posttruama in 121 patients to assess soft-tissue injury. In all patients the
      mechanism of injury potentially could be associated with cervical spine
      instability, and each patient was endotracheally intubated because of head injury
      or severe multisystem injuries. All patients underwent imaging studies within 48
      hours of injury and were either treated or cleared and spinal precautions were
      discontinued. Patients were excluded from this study if they had an obvious
      cervical spine injury identified on the initial radiographic studies or if they
      were determined to be too medically unstable to undergo MR imaging within the
      acute period (<48 hours postinjury). Thirty-one (25.6%) of the 121 patients were
      found to have sustained significant injury to the paravertebral ligamentous
      structures, the disc interspace, or the bony cervical spine. These injuries were
      undetected by plain radiography. The other 90 patients (74.4%) were determined
      within 48 hours not to have sustained a soft-tissue injury. Eight patients (6.6%)
      ultimately underwent surgery to treat the cervical spine injury, and MR imaging
      was the first test that identified the injury in each of these patients. There
      were no complications related to imaging procedures. CONCLUSIONS: Sagittal T1-
      and T2-weighted MR imaging appears to be a safe, reliable method for evaluating
      the cervical spine for nonapparent injury in comatose or obtunded trauma
      patients. In the early postinjury period, nursing and medical care are thereby
      facilitated for patients in whom occult injury to the spine is ruled out and for
      whom those attendant precautions are unnecessary.

PMID- 10419370
TI  - Visceral and vascular complications resulting from anterior lumbar interbody
      fusion.
AB  - OBJECT: The literature on abdominal and general surgery-related complications
      following anterior lumbar interbody fusion (ALIF) is scant. In this retrospective
      review of 60 patients in whom ALIF was performed at their institutions between
      1996 and 1998, the authors detail the associated complications and their
      correlation with perioperative factors. The causes, strategies for their
      avoidance, and the clinical course of these complications are also discussed.
      METHODS: The study group was composed of 31 men and 29 women whose mean age was
      42 years (range 29-71 years). The preoperative diagnosis was discogenic back pain
      in 33 patients (55%); failed back syndrome in 11 (18.3%); pseudarthrosis in five
      (8.3%); postlaminectomy syndrome in four (6.6%); spondylolisthesis in three (5%);
      burst fracture in two (3.3%); and malignancy in two (3.3%). A retroperitoneal
      approach to the spine was used in 57 of the 60 patients. One interspace was
      exposed in 28 patients (46.6%), two in 28 (46.6%), and three in four (6.6%).
      Discectomy and interbody fusion in which the authors placed titanium cages or
      bone dowels was performed in 56 patients and corpectomy with instrumentation in
      four. Seven (11.6%) of 60 patients had undergone previous abdominal surgery and
      29 (48.3%) had undergone previous spinal surgery. The follow-up period averaged
      12+/-4 months (mean+/-standard deviation). Twenty-four general surgery-related
      complications occurred in 23 patients (38.3%), including sympathetic dysfunction
      in six; vascular injury in four; somatic neural injury in three; sexual
      dysfunction in three; prolonged ileus in three; wound incompetence in two; and
      deep venous thrombosis, acute pancreatitis, and bowel injury in one patient each.
      There were no deaths. The incidence of complications was not associated with
      underlying diagnosis (p>0.1), age (p>0.5), previous abdominal or spinal surgery
      (p>0.1), or the number of levels exposed (p>0.1). CONCLUSIONS: This report
      provides a detailed analysis of the general surgery-related complications
      following ALIF. Although many of these complications have been recognized in the
      literature, the significance of sympathetic dysfunction appears to have been
      underestimated. The high incidence of complications in this series likely
      reflects the strict criteria. Many of these complications were minor and resolved
      over time without long-term sequelae.

PMID- 10419371
TI  - Nontraumatic acute spinal subdural hematoma: report of five cases and review of
      the literature.
AB  - Acute subdural spinal hematoma occurs rarely; however, when it does occur, it may
      have disastrous consequences. The authors assessed the outcome of surgery for
      this lesion in relation to causative factors and diagnostic imaging (computerized
      tomography [CT], CT myelography), as well as eventual preservation of the
      subarachnoid space. The authors reviewed 106 cases of nontraumatic acute subdural
      spinal hematoma (101 published cases and five of their own) in terms of cause,
      diagnosis, treatment, and long-term outcome. Fifty-one patients (49%) were men
      and 55 (51%) were women. In 70% of patients the spinal segment involved was in
      the lumbar or thoracolumbar spine. In 57 cases (54%) there was a defect in the
      hemostatic mechanism. Spinal puncture was performed in 50 patients (47%). Late
      surgical treatment was performed in 59 cases (56%): outcome was good in 25 cases
      (42%) (in 20 of these patients preoperative neurological evaluation had shown
      mild deficits or paraparesis, and three patients had presented with subarachnoid
      hemorrhage [SAH]). The outcome was poor in 34 cases (58%; 23 patients with
      paraplegia and 11 with SAH). The formation of nontraumatic acute spinal subdural
      hematomas may result from coagulation abnormalities and iatrogenic causes such as
      spinal puncture. Their effect on the spinal cord and/or nerve roots may be
      limited to a mere compressive mechanism when the subarachnoid space is preserved
      and the hematoma is confined between the dura and the arachnoid. It seems likely
      that the theory regarding the opening of the dural compartment, verified at the
      cerebral level, is applicable to the spinal level too. Early surgical treatment
      is always indicated when the patient's neurological status progressively
      deteriorates. The best results can be obtained in patients who do not experience
      SAH. In a few selected patients in whom neurological impairment is minimal,
      conservative treatment is possible.

PMID- 10419372
TI  - Combined chest wall resection with vertebrectomy and spinal reconstruction for
      the treatment of Pancoast tumors.
AB  - OBJECT: Traditionally, superior sulcus tumors of the lung that involve the chest
      wall and spinal column have been considered to be unresectable, and historically,
      patients harboring these tumors have been treated with local radiation therapy
      with, at best, modest results. The value of gross-total resection remains unclear
      in this patient population; however, with the recent advances in surgical
      technique and spinal instrumentation, procedures involving more radical removal
      of such tumors are now possible. At The University of Texas M. D. Anderson Cancer
      Center, the authors have developed a new technique for resecting superior sulcus
      tumors that invade the chest wall and spinal column. They present a technical
      description of this procedure and results in nine patients in whom stage IIIb
      superior sulcus tumors extensively invaded the vertebral column. METHODS: These
      patients underwent gross-total tumor resection via a combined approach that
      included posterolateral thoracotomy, apical lobectomy, chest wall resection,
      laminectomy, vertebrectomy, anterior spinal column reconstruction with
      methylmethacrylate, and placement of spinal instrumentation. There were six men
      and three women, with a mean age of 55 years (range 36-72 years). Histological
      examination revealed squamous cell carcinoma (three patients), adenocarcinoma
      (four patients), and large cell carcinoma (two patients). The mean postoperative
      follow-up period was 16 months. All patients are currently ambulatory or remained
      ambulatory until they died. Pain related to tumor invasion improved in four
      patients and remained unchanged in five. In three patients instrumentation failed
      and required revision. There was one case of cerebrospinal fluid leakage that was
      treated with lumbar drainage and one case of wound breakdown that required
      revision. Two patients experienced local tumor recurrence, and one patient
      developed a second primary lung tumor. CONCLUSIONS: The authors conclude that in
      selected patients, combined radical resection of superior sulcus tumors of the
      lung that involve the chest wall and spinal column may represent an acceptable
      treatment modality that can offer a potential cure while preserving neurological
      function and providing pain control.

PMID- 10419373
TI  - Occipitocervicothoracic fixation for spinal instability in patients with
      neoplastic processes.
AB  - OBJECT: Occipitocervicothoracic (OCT) fixation and fusion is an infrequently
      performed procedure to treat patients with severe spinal instability. Only three
      cases have been reported in the literature. The authors have retrospectively
      reviewed their experience with performing OCT fixation in patients with
      neoplastic processes, paying particular attention to method, pain relief, and
      neurological status. METHODS: From July 1994 through July 1998, 13 of 552
      patients who underwent a total of 722 spinal operations at the M. D. Anderson
      Cancer Center have required OCT fixation for spinal instability caused by
      neoplastic processes (12 of 13 patients) or rheumatoid arthritis (one of 13
      patients). Fixation was achieved by attaching two intraoperatively contoured
      titanium rods to the occiput via burr holes and Luque wires or cables; to the
      cervical spinous processes with Wisconsin wires; and to the thoracic spine with a
      combination of transverse process and pedicle hooks. Crosslinks were used to
      attain additional stability. In all patients but one arthrodesis was performed
      using allograft. At a follow-up duration of 1 to 45 months (mean 14 months), six
      of the 12 patients with neoplasms remained alive, whereas the other six patients
      had died of malignant primary disease. There were no deaths related to the
      surgical procedure. Postoperatively, one patient experienced respiratory
      insufficiency, and two patients required revision of rotational or free
      myocutaneous flaps. All patients who presented with spine-based pain experienced
      a reduction in pain, as measured by a visual analog scale for pain. All patients
      who were neurologically intact preoperatively remained so; seven of seven
      patients with neurological impairment improved; and six of seven patients
      improved one Frankel grade. There were no occurrences of instrumentation failure
      or hardware-related complications. In one patient a revision of the
      instrumentation was required 13.5 months following the initial surgery for
      progression of malignant fibrous histiosarcoma. CONCLUSIONS: In selected
      patients, OCT fixation is an effective means of attaining stabilization that can
      provide pain relief and neurological preservation or improvement.

PMID- 10419374
TI  - Endoscopic thoracic sympathectomy.
AB  - OBJECT: Thoracic sympathectomy has evolved as a treatment option for patients
      with hyperhidrosis and pain disorders. In the past, surgical procedures were
      highly invasive and caused significant morbidity, but the minimally invasive
      thoracoscopic procedure provides detailed visualization of the sympathetic
      ganglia and is associated with minimal postoperative morbidity. METHODS: The
      authors performed 112 thoracoscopic sympathectomy procedures in 65 patients, and
      the outcomes were equivalent to those previously established for open surgical
      techniques; however, the rate of surgery-related morbidity, length of hospital
      stay, and time until return to normal activity were substantially reduced.
      Complications and recurrence of symptoms were comparable with those demonstrated
      in previous reports. Overall patient satisfaction and willingness to undergo a
      repeated operative procedure ranged from 66 to 99%. Postoperatively, higher
      satisfaction rates were observed in patients with hyperhidrosis whereas in those
      with pain syndromes, satisfaction rates were lower. CONCLUSIONS: Minimally
      invasive thoracoscopic sympathectomy procedures are useful in treating
      sympathetically mediated disorders, and the results indicate that the procedure
      is associated with reduced morbidity and similar outcome when compared with
      results obtained after open surgery. Hyperhidrosis is well treated, but patients
      with pain syndromes have significantly poorer outcomes.

PMID- 10419375
TI  - Apoptosis following spinal cord injury in rats and preventative effect of N
      methyl-D-aspartate receptor antagonist.
AB  - OBJECT: The aims of this study were to clarify the histological and histochemical
      changes associated with cell death in the spinal cord after acute traumatic
      injury and to examine the role of excitatory amino acid release mediated by N
      methyl-D-aspartate (NMDA) receptors. METHODS: Following laminectomy, the spinal
      cord in 70 rats was injured at the T-9 level by applying extradural static weight
      compression, in which a cylindrical compressor was used to induce complete and
      irreversible transverse spinal cord injury (SCI) with paralysis of the lower
      extremities. The injured rats were killed between 30 minutes and 14 days after
      injury, and the injured cord was removed en bloc. Rats that received NMDA
      receptor antagonist (MK-801) were killed at the same time points as those that
      received saline. The specimens were stained with hematoxylin and eosin, Nissl,
      and Kluver-Barrera Luxol fast blue and subjected to in situ nick-end labeling, a
      specific in situ method used to allow visualization of apoptosis. Thirty minutes
      post-SCI, a large hematoma was observed at the compressed segment. Six hours
      after injury, large numbers of dead cells that were not stained by in situ nick
      end labeling were observed. Between 12 hours and 14 days postinjury, nuclei
      stained by using the in situ nick-end labeling technique were observed not only
      at the injury site but also in adjoining segments that had not undergone
      mechanical compression, suggesting that the delayed cell death was due to
      apoptosis. The number of cells stained by in situ nick-end labeling was maximum
      at 3 days postinjury. The results of electron microscopic examination were also
      consistent with apoptosis. In the MK-801-treated rats, the number of cells
      stained by in situ nick-end labeling was smaller than in nontreated rats at both
      24 hours and 7 days after injury. CONCLUSIONS: These findings suggest that NMDA
      receptor activation promotes delayed neuronal and glial cell death due to
      apoptosis.

PMID- 10419376
TI  - [Angiotensin II receptor antagonists as the agents to treat cerebrovascular
      disease].
AB  - Recently, several antagonists of angiotensin II receptors (AII-A) have been
      developed and are now used as antihypertensive agents. The regional cerebral
      blood flow appears to show typical changes during the course of cerebral ischemia
      and AII-A may have a favorable effect on the flow in some situations. Moreover,
      activation of the renin-angiotensin system plays an important role in the
      development of cerebrovascular lesions in chronic hypertension. Because several
      enzymes appear to produce angiotensin II in the absence of classical renin
      angiotensin system, it is possible that angiotensin II is produced in some blood
      vessels even after inhibition of the activity of ACE. Thus, AII-A may be more
      effective to treat cerebrovascular lesions during hypertension than ACE
      inhibitors.

PMID- 10419377
TI  - Clinical-Pathologic Conference in Thoracic Surgery: T1 N1 stage IIA
      adenocarcinoma.

PMID- 10419378
TI  - The mimimally invasive direct coronary artery by-pass procedure: what is its
      future role?

PMID- 10419379
TI  - Arch-first technique through left antero-axillary thoracotomy or bilateral
      anterior thoracotomy.

PMID- 10419380
TI  - Dengue in the State of Rio de Janeiro, Brazil, 1986-1998.
AB  - This paper presents epidemiological, laboratory, and clinical data on 12 years of
      dengue virus activity in the State of Rio de Janeiro from the time the disease
      was first confirmed virologically in April 1986 through April 1998. DEN-1 and DEN
      2 viruses are the serotypes circulating in the state and were responsible for the
      epidemics reported during the last 12 years. The results published here show both
      the impact of dengue virus infections on the population and laboratory advances
      that have improved dengue diagnosis.

PMID- 10419381
TI  - Wild birds as hosts of Amblyomma cajennense (Fabricius, 1787) (Acari: Ixodidae).
AB  - We evaluated the prevalence, mean intensity and relative density of ticks in 467
      wild birds of 67 species (12 families) from forest and cerrado habitats at two
      protected areas of Minas Gerais, between March and September 1997. Ticks
      collected (n=177) were identified as larvae and nymphs of Amblyomma cajennense
      and four other species of Amblyomma. We report for the first time 28 bird species
      as hosts of the immature stages of A. cajennense, demonstrating the lack of host
      specificity of the larvae and nymphs. A. cajennense had 15% prevalence on birds,
      with a mean infestation intensity of 0.37 ticks per host sampled, and 2.5 ticks
      per infested bird. Prevalence varied in relation to host species, diet and
      between birds from forests at two successional stages. There were no differences
      in relation to host forest dependence, participation in mixed flocks of birds,
      and nest type constructed. A. cajennense is a species of medical and veterinary
      importance, occurring on domestic animals but is known little of its occurrence
      on wildlife.

PMID- 10419382
TI  - Sabethes (Peytonulus) luxodens, a new species of Sabethini (Diptera: Culicidae)
      from Ecuador.
AB  - The adult male, larva and pupa of Sabethes (Peytonulus) luxodens, a new species
      from Ecuador, are described. The species is distinguished from Sabethes aurescens
      (Lutz), which it closely resembles in all life stages.

PMID- 10419383
TI  - A mitochondrial DNA phylogeny indicates close relationships between populations
      of Lutzomyia whitmani (Diptera: Psychodidae, Phlebotominae) from the rain-forest
      regions of Amazonia and northeast Brazil.
AB  - Phylogenetic analysis of all 31 described mitochondrial (cytochrome b) haplotypes
      of Lutzomyia whitmani demonstrated that new material from the State of Rondonia,
      in southwest Amazonia, forms a clade within a lineage found only in the rain
      forest regions of Brazil. This rain-forest lineage also contains two other clades
      of haplotypes, one from eastern Amazonia and one from the Atlantic forest zone of
      northeast Brazil (including the type locality of the species in Ilheus, State of
      Bahia). These findings do not favour recognizing two allopatric cryptic species
      of L. whitmani, one associated with the silvatic transmission of Leishmania shawi
      in southeast Amazonia and the other with the peridomestic transmission of Le.
      braziliensis in northeast Brazil. Instead, they suggest that there is (or has
      been in the recent past) a continuum of inter-breeding populations of L. whitmani
      in the rain-forest regions of Brazil.

PMID- 10419385
TI  - EC 99. 7th European Meeting on Complement in Human Disease. Helsinki, Finland,
      June 17-20, 1999. Proceedings and abstracts.

PMID- 10419384
TI  - [Triatoma bassolsae sp. n. from Mexico, with a key to species of phyllosoma
      complex (Hemiptera, Reduviidae)].
AB  - According to the descriptions of five closely related species of the genus
      Triatoma Laporte, 1832: T. phyllosoma (Burmeister, 1835), T. pallidipennis (Stal,
      1872), T. picturata Usinger, 1939, T. longipennis Usinger, 1939 and T. mazzottii
      Usinger, 1941 and further published studies, these species could be included in a
      "specific complex" named as the species formerly described. All these species are
      typical from Mexico and another species was found in the same country, in the
      State of Puebla: Triatoma bassolsae sp. n. This species was morphologically
      compared with the other five of the "phyllosoma" complex, including the external
      male genitalia. The most important characters used to separate T. bassolsae from
      T. phyllosoma (which is the most similar to the other species) are the
      morphometric relationships on the head, with a longer anteocular region and a
      significant longer second rostral segment, a long and conspicuous pilosity in
      different areas of the body and specially on the head, and the characters of the
      anterolateral, lateral and discal tubercles of the pronotum, very long and sharp
      in the new species. The male genitalia has several differences between T.
      bassolsae and T. phyllosoma specially significant on the surface of the endosome
      process and on the branches of the phallosome support, separated at the apex in
      the new species. Types and paratypes are incorporated in the respective
      institutions in Mexico DF and Rio de Janeiro.

PMID- 10419386
TI  - Race, sex, and physicians' referrals for cardiac catheterization.

PMID- 10419387
TI  - Race, sex, and physicians' referrals for cardiac catheterization.

PMID- 10419388
TI  - Racial differences in the outcome of left ventricular dysfunction.

PMID- 10419389
TI  - Racial differences in the outcome of left ventricular dysfunction.

PMID- 10419390
TI  - Racial differences in the outcome of left ventricular dysfunction.

PMID- 10419391
TI  - Myocardial bridging in children with hypertrophic cardiomyopathy.

PMID- 10419392
TI  - Oligoarthritis mediated by tumor-specific T lymphocytes in renal-cell carcinoma.

PMID- 10419393
TI  - Treatment of severe combined immunodeficiency.

PMID- 10419394
TI  - Metronidazole-resistant vaginal trichomoniasis--an emerging problem.

PMID- 10419395
TI  - Vaccination against hepatitis A.

PMID- 10419396
TI  - The prevention of ventilator-associated pneumonia.

PMID- 10419397
TI  - Nutrition-Gene Interactions in Human Populations: The Amerindian Case.
      Proceedings of the 2nd Nestle Conference on Nutrition. Mexico City, Mexico,
      January 29-30, 1998.

PMID- 10419398
TI  - Thyroid function and adverse outcome--What is the message?

PMID- 10419399
TI  - Chronic fatigue syndrome?

PMID- 10419400
TI  - Chronic fatigue syndrome?

PMID- 10419401
TI  - Danger of artificial nails.

PMID- 10419402
TI  - Plastic hair balls--A real hazard!

PMID- 10419403
TI  - Varicella vaccine.

PMID- 10419404
TI  - [Genetic variability in the pathogenesis of HIV infection].

PMID- 10419405
TI  - Pinker and the brain.

PMID- 10419406
TI  - For the sake of knowing...

PMID- 10419407
TI  - Going to extremes. Archaea: bridging the gap between bacteria and eukarya (A
      Keystone Symposia), Taos, NM, USA, 9-14 January 1999.

PMID- 10419408
TI  - Computer science and meta-evolution. Evolution as computation, the Center for
      Discrete Mathematics and Theoretical Computer Science (DIMACS), Princeton,
      University, Princeton, NJ, USA, 11-12 January 1999.

PMID- 10419409
TI  - Intravesical treatment of bladder cancer: current problems and needs.
AB  - Especially in patients with superficial bladder cancer being at risk of tumor
      progression, therapeutic or adjuvant treatment concepts are required. Based upon
      experimental trials and clinical case reports, intravesical immunotherapy has
      been developed and further refined in many prospective studies through the last
      25 years. Supported by the results of several phase III trials, today
      instillation therapy with Bacille bilie de Calmette-Guerin (BCG) is accepted as
      standard therapeutic intervention in carcinoma in situ of the bladder and for
      prophylaxis of tumor recurrence in superficial, bladder cancer. Current protocols
      are aiming at the determination of the optimal dosage and regimen and the
      investigation of the impact of BCG therapy on tumor progression. Furthermore,
      there is significant clinical need to identify factors predicting the outcome of
      BCG therapy in a given patient. Based upon the promising results of BCG therapy,
      several cytokines have been investigated, specifically in order to decrease the
      side effects of BCG. However, despite of some efficacy and lower side effects,
      other forms of immunotherapy, e.g., interferon, interleukin 2, or keyhole limpet
      hemocyanin, must still be regarded as experimental and need further
      investigation.

PMID- 10419410
TI  - [Proceedings of the 41st Kasseler Symposium. Postoperative pain treatment-
      definition and perspectives. Baunatal, 12-13 June 1998].

PMID- 10419412
TI  - Proceedings of the American Chemical Society Symposium on Impact of Processing on
      Food Safety. San Francisco, California, USA. April 14-18, 1997.

PMID- 10419413
TI  - Assessment of Childhood and Adolescent Obesity. Results from an International
      Obesity Task Force workshop. Dublin, June 16, 1997.

PMID- 10419411
TI  - Plagiarism or forgetfulness?

PMID- 10419414
TI  - Introduction: the use of body mass index to assess obesity in children.
AB  - The International Obesity Task Force (IOTF) was established in 1994 to address
      the increase in the worldwide prevalence of obesity. The goals of the IOTF are to
      1) raise awareness in the population and among governments that obesity is a
      serious medical condition, 2) develop policy recommendations for a coherent and
      effective global approach to the management and prevention of obesity, and 3)
      implement appropriate strategies to manage and prevent obesity on a population
      basis worldwide. To assess the global prevalence of obesity in children and
      adolescents, the IOTF convened a workshop on childhood obesity to determine the
      most appropriate measurement to assess obesity in populations of and adolescents
      around the world. At the workshop, a variety of issues related to this problem
      were considered--including the best measure of fatness, the effect of application
      of a variety of existing standards on the prevalence of obesity in the same
      population, and the role of factors such as visceral adiposity and natural
      history in the definition of obesity. This article and those that follow
      represent the information presented at the workshop. The workshop concluded that
      the body mass index (BMI; in kg/m2) offered a reasonable measure with which to
      assess fatness in children and adolescents and that the standards used to
      identify overweight and obesity in children and adolescents should agree with the
      standards used to identify grade 1 and grade 2 overweight (BMI of 25 and 30,
      respectively) in adults.

PMID- 10419415
TI  - Defining obesity in childhood: current practice.

PMID- 10419416
TI  - Validity of the body mass index as an indicator of the risk and presence of
      overweight in adolescents.

PMID- 10419418
TI  - Tracking of body mass index in children in relation to overweight in adulthood.

PMID- 10419417
TI  - Fatness and body mass index from birth to young adulthood in a rural Guatemalan
      population.

PMID- 10419419
TI  - Relation between visceral fat and disease risk in children and adolescents.

PMID- 10419420
TI  - Comparison of weight and height relations in boys from 4 countries.

PMID- 10419421
TI  - Curve smoothing and transformations in the development of growth curves.

PMID- 10419422
TI  - The European Childhood Obesity Group (ECOG) project: the European collaborative
      study on the prevalence of obesity in children.

PMID- 10419423
TI  - A new international growth reference for young children.

PMID- 10419424
TI  - Workshop on childhood obesity: summary of the discussion.

PMID- 10419425
TI  - Medical management of aldosterone-producing adenomas.
AB  - BACKGROUND: No data are available on the long-term medical management of
      aldosterone-producing adenomas. OBJECTIVE: To demonstrate the efficacy of medical
      management of aldosterone-producing adenomas in terms of blood pressure and serum
      potassium concentration and to discuss morbidity associated with medical
      management. DESIGN: Retrospective cohort study. SETTING: Large tertiary care
      referral center. PATIENTS: 24 patients with documented aldosterone-producing
      adenomas who were treated medically for at least 5 years. MEASUREMENTS:
      Aldosterone excretion rate, plasma renin activity, and size and location of
      adenomas (by computed tomography). Blood pressure and serum electrolytes were
      measured at the time of diagnosis and last follow-up. RESULTS: From the time of
      diagnosis to the time of last follow-up, systolic blood pressure decreased from
      175 mm Hg to 129 mm Hg (95% CI for difference, 37.1 to 53.8 mm Hg) and diastolic
      blood pressure decreased from 106 mm Hg to 79 mm Hg (CI for difference, 20.8 to
      33.9 mm Hg). Serum potassium concentration increased from 3.0 mmol/L to 4.3
      mmol/L (CI for difference, 1.1 to 1.5 mmol/L). CONCLUSIONS: Medical management of
      aldosterone-producing adenomas is a viable option for controlling blood pressure
      and serum potassium concentration.

PMID- 10419426
TI  - Older persons' preferences for site of terminal care.
AB  - BACKGROUND: Little is known about patients' preferences for site of terminal
      care. OBJECTIVE: To describe older persons' preferences for home or hospital as
      the site of terminal care and to explore potential reasons for their preferences.
      DESIGN: Cross-sectional quantitative and qualitative interviews. SETTING:
      Participants' homes. PATIENTS: Community-dwelling persons 65 years of age or
      older who were recently hospitalized with congestive heart failure, chronic
      obstructive pulmonary disease, or pneumonia and were not selected according to
      life expectancy; 246 patients participated in quantitative interviews and 29
      participated in qualitative interviews. MEASUREMENTS: Preference for site of
      terminal care and the reasons for that preference. RESULTS: In quantitative
      interviews, 118 patients (48%) preferred terminal care in the hospital, 106 (43%)
      preferred home, and 22 (9%) did not know. One third changed their preference when
      asked about their preference in the event of a nonterminal illness. Reasons for
      preference identified during qualitative interviews included the desire to be
      with family members and concerns about burden to family members and their ability
      to provide necessary care. Concern about long-term care needs resulted in
      preference for a nursing home when choice was not constrained to home and
      hospital. CONCLUSIONS: Preference for home as the site of care for terminal
      illness exceeds existing practice. However, the current debate about home versus
      hospital as the ideal site for end-of-life care may ignore an important issue to
      older persons--namely, the care of disabilities that precede death.

PMID- 10419428
TI  - Empirical derivation of an electronic clinically useful problem statement system.
AB  - Problem lists are tools to improve patient management. In the medical record,
      they connect diagnoses to therapy, prognosis, and psychosocial issues. Computer
      based problem lists enhance paper-based approaches by enabling cost-containment
      and quality assurance applications, but they require clinically expressive
      controlled vocabularies. Because existing controlled vocabularies do not
      represent problem statements at a clinically useful level, we derived a new
      canonical problem statement vocabulary through semi-automated analysis and
      distillation of provider-entered problem lists collected over 6 years from 74,696
      patients. We combined automated and manual methods to condense 891,770 problem
      statements entered by 1961 care providers at Grady Memorial Hospital in Atlanta,
      Georgia, to 15,534 Canonical Clinical Problem Statement System (CCPSS) terms. The
      nature and frequency of problem statements were characterized, interrelations
      among them were enumerated, and a database capturing the epidemiology of problems
      was created. The authors identified 23,503 problem relations (co-occurrences,
      sign-symptom complexes, and differential diagnoses) and 22,690 modifier words
      that further categorized "canonical" problems. To assess completeness, CCPSS
      content was compared with that of the 1997 Unified Medical Language System
      Metathesaurus (containing terms from 44 clinical vocabularies). Unified Medical
      Language System terms expressed 25% of individual CCPSS terms exactly (71% of
      problems by frequency), 27% partially, and 48% poorly or not at all. Clinicians
      judged that CCPSS terms completely captured their clinical intent for 84% of 686
      randomly selected free-text problem statements. The CCPSS represents clinical
      concepts at a level exceeding that of previous approaches. A similar national
      approach could create a standardized, useful, shared resource for clinical
      practice.

PMID- 10419427
TI  - Whipple endocarditis without overt gastrointestinal disease: report of four
      cases.
AB  - BACKGROUND: Cardiac manifestations of Whipple disease are rarely diagnosed before
      death. OBJECTIVE: To describe four patients with endocarditis caused by
      Tropheryma whippelii who did not have overt gastrointestinal disease. DESIGN:
      Case series. SETTING: Five hospitals in eastern Switzerland. PATIENTS: Three men
      and one woman undergoing replacement of insufficient heart valves. MEASUREMENTS:
      Histologic characteristics of heart valves and intestinal biopsy; broad-range and
      specific polymerase chain reaction for T. whippelii. RESULTS: Tropheryma
      whippelii was found in the heart valves (three aortic valves and one mitral
      valve) of four patients with culture-negative endocarditis necessitating valve
      replacement. All patients had arthralgia for different lengths of time. Only one
      patient had mild gastrointestinal symptoms. Histologic characteristics of
      intestinal mucosa were normal in all patients, and polymerase chain reaction on
      intestinal biopsy was positive for T. whippelii in only one patient, who did not
      have diarrhea. In all patients, arthralgia resolved promptly after institution of
      antibiotic therapy. Disease did not recur in any patient after prolonged
      antibiotic therapy with cotrimoxazole. CONCLUSION: In patients with culture
      negative endocarditis, the absence of clinical, microscopic, or microbiological
      evidence of gastrointestinal disease did not rule out T. whippelii.

PMID- 10419429
TI  - Surveillance for endometrial cancer in women receiving tamoxifen.
AB  - Recent studies showing a protective effect of tamoxifen in women at high risk for
      breast cancer have expanded the indications of the drug. While acting as an
      estrogen antagonist in the breast, tamoxifen can have estrogenic effects on the
      endometrium; consensus opinion is that tamoxifen increases the risk for
      endometrial cancer. Because an increasing number of women are taking tamoxifen, a
      strategy for gynecologic surveillance is needed. Studies examining the relation
      between risk for endometrial cancer and tamoxifen use have conflicting results.
      However, because of an overall interpretation that tamoxifen use slightly
      increases risk for endometrial cancer, some researchers advocate routine
      ultrasonography and endometrial biopsy for screening asymptomatic women receiving
      tamoxifen. This paper reviews the literature on endometrial cancer in women
      taking tamoxifen and the usefulness of various screening methods in this setting.
      Risk factors and screening criteria for endometrial cancer in the general
      population are discussed, and a strategy for surveillance of women taking
      tamoxifen is proposed. Patients should be screened for signs or symptoms of
      endometrial abnormality before taking tamoxifen. This evaluation, which should
      include a careful history, pelvic examination, and Papanicolaou smear, should be
      repeated annually while the patient is receiving tamoxifen. Although transvaginal
      ultrasonography is not recommended for routine screening, it is indicated if an
      adequate pelvic examination cannot be performed or if additional risk factors are
      present. The likelihood of abnormality is greater for patients who have abnormal
      bleeding, discharge, abnormal glandular cells on Papanicolaou smear, or an
      endometrial measurement on ultrasonography of more than 8 mm; these findings
      should prompt an aggressive evaluation of the endometrium.

PMID- 10419430
TI  - Optimizing care for persons with HIV infection. Society of General Internal
      Medicine AIDS Task Force.
AB  - Treatment advances and outcomes data have raised new concerns about how to
      optimize care for patients with HIV infection. This paper reviews evidence on 1)
      the relation between experience and type of training and patient outcomes, 2) the
      relation between the components of primary care and patient outcomes, and 3)
      primary care physicians' basic HIV knowledge and skills in screening and
      prevention. Several studies indicate that greater experience in HIV care leads to
      improved patient outcomes. The relation between outcomes and type of training
      (subspecialist or generalist) is less clear, and studies have not distinguished
      between type of training and experience. Less experienced physicians may be able
      to provide high-quality care if appropriate consultation from expert physicians
      is available. Components of primary care, including accessibility, continuity,
      coordination, and comprehensiveness, are associated with better patient outcomes.
      Optimal care of HIV infection requires a combination of disease-specific
      expertise and primary care skills and organization. Criteria for expertise in HIV
      management should focus on actual patient care experience and HIV expertise
      rather than on subspecialty training per se. The management of HIV has become
      sufficiently complex that primary care physicians cannot be routinely expected to
      have extensive specialized knowledge in this area. However, many primary care
      physicians have weaknesses in the basic HIV-related skills that are needed in
      most settings, such as HIV test counseling and recognition of important HIV
      related symptom complexes. Primary care physicians need to strengthen these basic
      HIV-related medical skills.

PMID- 10419432
TI  - Reduction of medical verbiage: fewer words, more meaning.

PMID- 10419431
TI  - Afebrile blood culture-negative endocarditis.

PMID- 10419433
TI  - If the fates allow.

PMID- 10419434
TI  - Arthritis and I.

PMID- 10419435
TI  - Risk factors for infective endocarditis.

PMID- 10419436
TI  - Risk factors for infective endocarditis.

PMID- 10419437
TI  - Risk factors for infective endocarditis.

PMID- 10419439
TI  - Vitamin C increases nitric oxide availability in coronary atherosclerosis.

PMID- 10419438
TI  - Cholesterol lowering in older patients.

PMID- 10419440
TI  - Graves disease after bone marrow transplantation.

PMID- 10419441
TI  - Celiac disease during interferon treatment.

PMID- 10419442
TI  - Iron in multivitamin supplements.

PMID- 10419443
TI  - Life, death, and AIDS.

PMID- 10419444
TI  - Nutrition and policy. 4: Dietary supplements.

PMID- 10419445
TI  - Highly active antiretroviral therapy in a large urban clinic: risk factors for
      virologic failure and adverse drug reactions.
AB  - BACKGROUND: In clinical trials, highly active antiretroviral therapy (HAART)
      reduces plasma HIV-1 RNA levels to less than 500 copies/mL in 60% to 90% of
      patients with HIV-1 infection. The performance of such therapy outside of the
      clinical trial setting is unclear. OBJECTIVE: To determine factors associated
      with failure to suppress HIV-1 RNA levels and adverse drug reactions in a cohort
      of patients in whom protease inhibitor-containing therapy was begun in a large
      urban clinic. DESIGN: Retrospective cohort study. SETTING: Johns Hopkins HIV
      Clinic in Baltimore, Maryland. PATIENTS: 273 protease inhibitor-naive patients
      began taking a protease inhibitor regimen containing at least one other
      antiretroviral drug to which the patients had not previously been exposed.
      MEASUREMENTS: Demographic variables, plasma HIV-1 RNA levels, CD4+ lymphocyte
      counts, and adverse drug reactions. RESULTS: Levels of HIV-1 RNA were
      undetectable in 42% of the cohort at 1 to 90 days, in 44% at 3 to 7 months, and
      in 37% at 7 to 14 months. Factors associated with failure to suppress viral load
      at two or more time points included higher rates of missed clinic appointments,
      nonwhite ethnicity, age 40 years or younger, injection drug use, lower baseline
      CD4+ lymphocyte count, and higher baseline viral load. In a multivariate model,
      only higher rates of missed clinic appointments were independently associated
      with viral suppression at 1 year. Ritonavir was associated with adverse drug
      reactions about twice as frequently as indinavir or nelfinavir, and women
      experienced significantly more adverse effects than men. CONCLUSIONS: Unselected
      patients in whom HAART is started in a clinic setting achieve viral suppression
      substantially less frequently than do patients in controlled clinical trials.
      Missed clinic visits were the most important risk factor for failure to suppress
      HIV-1 RNA levels. Studies are needed to identify interventions that maximize the
      performance of HAART in inner-city clinics.

PMID- 10419446
TI  - Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. An
      uncontrolled trial.
AB  - BACKGROUND: Gastric lymphoma of mucosa-associated lymphoid tissue (MALT) is
      related to Helicobacter pylori infection and may depend on this infection for
      growth. OBJECTIVE: To determine the response of gastric MALT lymphoma to
      antibiotic treatment. DESIGN: Prospective, uncontrolled treatment trial. SETTING:
      University hospital referral center and three collaborating university and
      community hospitals. PATIENTS: 34 patients with stage I or stage II N1 gastric
      MALT lymphoma. INTERVENTION: Two of three oral antibiotic regimens--1)
      amoxicillin, 750 mg three times daily, and clarithromycin, 500 mg three times
      daily; 2)tetracycline, 500 mg four times daily, and clarithromycin, 500 mg three
      times daily; or 3) tetracycline, 500 mg four times daily, and metronidazole, 500
      mg three times daily--were administered sequentially (usually in the order
      written) for 21 days at baseline and at 8 weeks, along with a proton-pump
      inhibitor (lansoprazole or omeprazole) and bismuth subsalicylate. MEASUREMENTS:
      Complete remission was defined as the absence of histopathologic evidence of
      lymphoma on endoscopic biopsy. Partial remission was defined as a reduction in
      endoscopic tumor stage or 50% reduction in the size of large tumors. RESULTS: 34
      patients were followed for a mean (+/-SD) of 41 +/- 16 months (range, 18 to 70
      months) after antibiotic treatment. Of 28 H. pylori-positive patients, 14 (50%
      [95% CI, 31% to 69%]) achieved complete remission, 8 (29%) achieved partial
      remission (treatment eventually failed in 4 of the 8), and 10 (36% [CI, 19% to
      56%]) did not respond to treatment. Treatment failed in all 6 (100% [CI, 54% to
      100%]) H. pylori-negative patients. Patients with endoscopic appearance of
      gastritis (stage I T1 disease) were most likely to achieve complete remission
      within 18 months. Tumors in the distal stomach were associated with more
      favorable response than tumors in the proximal stomach. CONCLUSIONS: A subset of
      H. pylori-positive gastric MALT lymphomas, including infiltrative tumors, may
      respond to antibiotics. The likelihood of early complete remission seems to be
      greatest for superficial and distal tumors.

PMID- 10419447
TI  - Mechanical ventilation in a cohort of elderly patients admitted to an intensive
      care unit.
AB  - BACKGROUND: It has been argued that life support for the elderly should be
      limited to conserve resources. As this population increases, so will the
      importance of evaluating appropriate use of mechanical ventilation in this group.
      OBJECTIVE: To determine whether age has an independent effect on the outcomes of
      patients treated with mechanical ventilation after admission to an intensive care
      unit (ICU). DESIGN: Prospective cohort study. SETTING: University-based tertiary
      care medical center. PATIENTS: 63 patients 75 years of age or older and 237
      patients younger than 75 years of age enrolled from medical and coronary ICUs.
      MEASUREMENTS: In-hospital mortality rate, duration of mechanical ventilation,
      lengths of stay in the ICU and in the hospital, and cost of care. RESULTS: Median
      duration of mechanical ventilation was 4.2 days (interquartile range, 2.1 to 9.3
      days) for patients 75 years of age or older and 6.4 days (interquartile range,
      3.4 to 11.4 days) for patients younger than 75 years of age (P = 0.14). When the
      length of time required to "pass" a daily screening test of weaning variables was
      used as an indicator of recovery from respiratory failure, elderly patients
      passed earlier than younger patients (risk ratio, 1.58 [95% CI, 1.13 to 2.22]; P
      = 0.03). The cost of ICU care was lower for older ($12,822 [CI, $9821 to $26,313]
      than for younger ($19,316 [CI, $9699 to $39,950]) patients (P = 0.03). Median
      hospital costs tended to be lower in the older group ($21,292 compared with
      $29,049; P = 0.17). After adjustment for ethnicity, sex, and severity of illness
      in a multivariate logistic regression analysis, patient age of 75 years or older
      was predictive of 1 less day on the ventilator (CI, -2.8 to 1.2 days). Lengths of
      stay in the ICU (beta-coefficient, -0.5 days [CI, -3.0 to 2.7 days]) and in the
      hospital (beta-coefficient, 0.3 days [CI, -3.7 to 5.5 days]) did not differ for
      persons 75 years of age or older after these adjustments (P > 0.1). Intensive
      care unit and hospital costs, however, were lower for elderly persons (P = 0.02).
      The in-hospital mortality rate was 38.1% among elderly patients and 38.8% among
      younger patients (P > 0.2); Cox proportional hazards analysis confirmed that
      survival did not differ between the two groups (relative risk for older patients,
      0.82 [CI, 0.52 to 1.29]). CONCLUSIONS: After adjustment for severity of illness,
      elderly patients spent similar time on mechanical ventilation and in the ICU and
      hospital but had a lower cost of care than younger patients. These outcomes are
      not explained by differences in mortality rate and suggest that mechanical
      ventilation should not be restricted in elderly patients with respiratory failure
      on the basis of chronologic age.

PMID- 10419448
TI  - Matrix metalloproteinases.

PMID- 10419449
TI  - E1A sensitizes cells to tumor necrosis factor-induced apoptosis through
      inhibition of IkappaB kinases and nuclear factor kappaB activities.
AB  - The adenovirus E1A protein has been implicated in increasing cellular
      susceptibility to apoptosis induced by tumor necrosis factor (TNF); however, its
      mechanism of action is still unknown. Since activation of nuclear factor kappaB
      (NF-kappaB) has been shown to play an anti-apoptotic role in TNF-induced
      apoptosis, we examined apoptotic susceptibility and NF-kappaB activation induced
      by TNF in the E1A transfectants and their parental cells. Here, we reported that
      E1A inhibited activation of NF-kappaB and rendered cells more sensitive to TNF
      induced apoptosis. We further showed that this inhibition was through suppression
      of IkappaB kinase (IKK) activity and IkappaB phosphorylation. Moreover, deletion
      of the p300 and Rb binding domains of E1A abolished its function in blocking IKK
      activity and IkappaB phosphorylation, suggesting that these domains are essential
      for the E1A function in down-regulating IKK activity and NF-kappaB signaling.
      However, the role of E1A in inhibiting IKK activity might be indirect.
      Nevertheless, our results suggest that inhibition of IKK activity by E1A is an
      important mechanism for the E1A-mediated sensitization of TNF-induced apoptosis.

PMID- 10419450
TI  - LEKTI, a novel 15-domain type of human serine proteinase inhibitor.
AB  - Proteinase inhibitors are important negative regulators of proteinase action in
      vivo. We have succeeded in isolating two previously unknown polypeptides (HF6478
      and HF7665) from human blood filtrate that are parts of a larger precursor
      protein containing two typical Kazal-type serine proteinase inhibitor motifs. The
      entire precursor protein, as deduced from the nucleotide sequence of the cloned
      cDNA, exhibits 15 potential inhibitory domains, including the Kazal-type domains,
      HF6478, HF7665, and 11 additional similar domains. An inhibitory effect of HF7665
      on trypsin activity is demonstrated. Because all of the 13 HF6478- and HF7665
      related domains share partial homology to the typical Kazal-type domain but lack
      one of the three conserved disulfide bonds, they may represent a novel type of
      serine proteinase inhibitor. The gene encoding the multidomain proteinase
      inhibitor, which we have termed LEKTI, was localized on human chromosome 5q31-32.
      As shown by reverse transcriptase-polymerase chain reaction and Northern blot
      analysis, it is expressed in the thymus, vaginal epithelium, Bartholin's glands,
      oral mucosa, tonsils, and the parathyroid glands. From these results, we assume
      that LEKTI may play a role in anti-inflammatory and/or antimicrobial protection
      of mucous epithelia.

PMID- 10419451
TI  - Cardiac-specific overexpression of the alpha(1) subunit of the L-type voltage
      dependent Ca(2+) channel in transgenic mice. Loss of isoproterenol-induced
      contraction.
AB  - The L-type voltage-dependent calcium channel (L-VDCC) regulates calcium influx in
      cardiac myocytes. Activation of the beta-adrenergic receptor (betaAR) pathway
      causes phosphorylation of the L-VDCC and that in turn increases Ca(2+) influx.
      Targeted expression of the L-VDCC alpha(1) subunit in transgenic (Tg) mouse
      ventricles resulted in marked blunting of the betaAR pathway. Inotropic and
      lusitropic responses to isoproterenol and forskolin in Tg hearts were
      significantly reduced. Likewise, Ca(2+) current augmentation induced by iso-
      proterenol and forskolin was markedly depressed in Tg cardiomyocytes. Despite no
      change in betaAR number, isoproterenol-stimulated adenylyl cyclase activity was
      absent in Tg membranes and NaF and forskolin responses were reduced. We postulate
      an important pathway for regulation of the betaAR by Ca(2+) channels.

PMID- 10419452
TI  - Modulation of rap activity by direct interaction of Galpha(o) with Rap1 GTPase
      activating protein.
AB  - We used the yeast two-hybrid system to identify proteins that interact directly
      with Galpha(o). Mutant-activated Galpha(o) was used as the bait to screen a cDNA
      library from chick dorsal root ganglion neurons. We found that Galpha(o)
      interacted with several proteins including Gz-GTPase-activating protein (Gz-GAP),
      a new RGS protein (RGS-17), a novel protein of unknown function (IP6), and
      Rap1GAP. This study focuses on Rap1GAP, which selectively interacts with
      Galpha(o) and Galpha(i) but not with Galpha(s) or Galpha(q). Rap1GAP interacts
      more avidly with the unactivated Galpha(o) as compared with the mutant (Q205L)
      activated Galpha(o). When expressed in HEK-293 cells, unactivated Galpha(o) co
      immunoprecipitates with the Rap1GAP. Expression of chick Rap1GAP in PC-12 cells
      inhibited activation of Rap1 by forskolin. When unactivated Galpha(o) was
      expressed, the amount of activated Rap1 was greatly increased. This effect was
      not observed with the Q205L-Galpha(o). Expression of unactivated Galpha(o)
      stimulated MAP-kinase (MAPK1/2) activity in a Rap1GAP-dependent manner. These
      results identify a novel function of Galpha(o), which in its resting state can
      sequester Rap1GAP thereby regulating Rap1 activity and consequently gating signal
      flow from Rap1 to MAPK1/2. Thus, activation of G(o) could modulate the Rap1
      effects on a variety of cellular functions.

PMID- 10419453
TI  - Requirement for anticoagulant heparan sulfate in the fibroblast growth factor
      receptor complex.
AB  - A divalent cation-dependent association between heparin or heparan sulfate and
      the ectodomain of the fibroblast growth factor (FGF) receptor kinase (FGFR)
      restricts FGF-independent trans-phosphorylation between self-associated FGFR and
      determines specificity for and mediates binding of activating FGF. Here we show
      that only the fraction of commercial heparin or rat liver heparan sulfate which
      binds to immobilized antithrombin formed an FGF-binding binary complex with the
      ectodomain of the FGFR kinase. Conversely, only the fraction of heparin that
      binds to immobilized FGFR inhibited Factor Xa in the presence of antithrombin.
      Only the antithrombin-bound fraction of heparin competed with (3)H-heparin bound
      to FGFR in absence of FGF, whereas both antithrombin-bound and unretained
      fractions competed with radiolabeled heparin bound independently to FGF-1 and FGF
      2. The antithrombin-bound fraction of heparin was required to support the heparin
      dependent stimulation of DNA synthesis of endothelial cells by FGF-1. The
      requirement for divalent cations and the antithrombin-binding motif distinguish
      the role of heparan sulfate as an integral subunit of the FGFR complex from the
      wider range of effects of heparan sulfates and homologues on FGF signaling
      through FGFR-independent interactions with FGF.

PMID- 10419454
TI  - Pleckstrin 2, a widely expressed paralog of pleckstrin involved in actin
      rearrangement.
AB  - We have identified a cDNA for pleckstrin 2 that is 39% identical and 65%
      homologous to the original pleckstrin. Like the original pleckstrin 1, this
      protein contains a pleckstrin homology (PH) domain at each end of the molecule as
      well as a DEP (Dishevelled, Egl-10, and pleckstrin) domain in the intervening
      sequence. A Northern blot probed with the full-length cDNA reveals that this
      homolog is ubiquitously expressed and is most abundant in the thymus, large
      bowel, small bowel, stomach, and prostate. Unlike pleckstrin 1, this newly
      discovered protein does not contain obvious sites of PKC phosphorylation, and in
      transfected Cos-7 cells, it is a poor substrate for phosphorylation, even after
      PMA stimulation. Cells expressing pleckstrin 2 undergo a dramatic shape change
      associated with actin rearrangement, including a loss of central F-actin and a
      redistribution of actin toward the cell cortex. Overexpression of pleckstrin 2
      causes large lamellipodia and peripheral ruffle formation. A variant of
      pleckstrin 2 lacking both PH domains still had some membrane binding but did not
      efficiently induce lamellipodia, suggesting that the PH domains of pleckstrin 2
      contribute to lamellipodia formation. This work describes a novel, widely
      expressed, membrane-associating protein and suggests that pleckstrin 2 may help
      orchestrate cytoskeletal arrangement.

PMID- 10419455
TI  - T cell activation stimulates the association of enzymatically active tyrosine
      phosphorylated ZAP-70 with the Crk adapter proteins.
AB  - Engagement of the T cell antigen receptor initiates signal transduction involving
      tyrosine phosphorylation of multiple effector molecules and the formation of
      multimolecular complexes at the receptor site. Adapter proteins that possess SH2
      and SH3 protein-protein interaction domains are implicated in the assembly of
      cell activation-induced signaling complexes. We found that Crk adapter proteins
      undergo activation-induced interaction with the zeta-chain associated protein
      (ZAP-70) tyrosine kinase in the human T cell line, Jurkat. Incubation of various
      glutathione S-transferase fusion proteins with a lysate of activated Jurkat cells
      resulted in selective association of ZAP-70 with Crk, but not Grb2 or Nck,
      adapter proteins. In addition, tyrosine-phosphorylated ZAP-70 co
      immunoprecipitated with Crk from a lysate of activated Jurkat cells, and ZAP-70
      association with GST-Crk was observed in a lysate of activated human peripheral
      blood T cells. Association between the two molecules was mediated by direct
      physical interaction and involved the Crk-SH2 domain and phosphotyrosyl
      containing sequences on ZAP-70. The association required intact Lck, considered
      to be an upstream regulator of ZAP-70, because it could not take place in
      activated JCaM1 cells, which express normal levels of ZAP-70 but are devoid of
      Lck. Finally, glutathione S-transferase-Crk fusion proteins were found to
      interact predominantly with membrane-residing tyrosine-phosphorylated ZAP-70 that
      exhibited autophosphorylation activity as well as phosphorylation of an exogenous
      substrate, CFB3. These findings suggest that Crk adapter proteins play a role in
      the early activation events of T lymphocytes, apparently, by direct interaction
      with, and regulation of, the membrane-residing ZAP-70 protein tyrosine kinase.

PMID- 10419456
TI  - Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen
      independent prostate cancer lines.
AB  - We measured the insulin-stimulated amount of Akt1, Akt2, and Akt3 enzymatic
      activities in four breast cancer cell lines and three prostate cancer cell lines.
      In the estrogen receptor-deficient breast cancer cells and the androgen
      insensitive prostate cells, the amount of Akt3 enzymatic activity was
      approximately 20-60-fold higher than in the cells that were estrogen- or androgen
      responsive. In contrast, the levels of Akt1 and -2 were not increased in these
      cells. The increase in Akt3 enzyme activity correlated with an increase in both
      Akt3 mRNA and protein. In a prostate cancer cell line lacking the tumor
      suppressor PTEN (a lipid and protein phosphatase), the basal enzymatic activity
      of Akt3 was constitutively elevated and represented the major active Akt in these
      cells. Finally, reverse transcription-PCR was used to examine the Akt3 expression
      in 27 primary breast carcinomas. The expression levels of Akt3 were significantly
      higher in the estrogen receptor-negative tumors in comparison to the estrogen
      receptor-positive tumors. To see if the increase in Akt3 could be due to
      chromosomal abnormalities, the Akt3 gene was assigned to human chromosome 1q44 by
      fluorescence in situ hybridization and radiation hybrid cell panel analyses.
      These results indicate that Akt3 may contribute to the more aggressive clinical
      phenotype of the estrogen receptor-negative breast cancers and androgen
      insensitive prostate carcinomas.

PMID- 10419457
TI  - Role of sphingosine 1-phosphate in the mitogenesis induced by oxidized low
      density lipoprotein in smooth muscle cells via activation of sphingomyelinase,
      ceramidase, and sphingosine kinase.
AB  - Oxidized LDL (oxLDL) have been implicated in diverse biological events leading to
      the development of atherosclerotic lesions. We previously demonstrated that the
      proliferation of cultured vascular smooth muscle cells (SMC) induced by oxLDL is
      preceded by an increase in neutral sphingomyelinase activity, sphingomyelin
      turnover to ceramide, and stimulation of mitogen-activated protein kinases (Auge,
      N., Escargueil-Blanc, I., Lajoie-Mazenc, I., Suc, I., Andrieu-Abadie, N.,
      Pieraggi, M. T., Chatelut, M., Thiers, J. C., Jaffrezou, J. P., Laurent, G.,
      Levade, T., Negre-Salvayre, A., and Salvayre, R. (1998) J. Biol. Chem. 273, 12893
      12900). Since ceramide can be converted to other bioactive metabolites, such as
      the well established mitogen sphingosine 1-phosphate (S1P), we investigated
      whether additional ceramide metabolites are involved in the oxLDL-induced SMC
      proliferation. We report here that incubation of SMC with oxLDL increased the
      activities of both acidic and alkaline ceramidases as well as sphingosine kinase,
      and elevated cellular sphingosine and S1P. Furthermore, the mitogenic effect of
      oxLDL was inhibited by D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol and N,N
      dimethylsphingosine which are inhibitors of ceramidase and sphingosine kinase,
      respectively. These findings suggest that S1P is a key mediator of the mitogenic
      effect of oxLDL. In agreement with this conclusion, exogenous addition of
      sphingosine stimulated the proliferation of cultured SMC, and this effect was
      abrogated by dimethylsphingosine but not by fumonisin B1, an inhibitor of the
      acylation of sphingosine to ceramide. Exogenous S1P also promoted SMC
      proliferation. Altogether, these results strongly suggest that the mitogenic
      effect of oxLDL in SMC involves the combined activation of sphingomyelinase(s),
      ceramidase(s), and sphingosine kinase, resulting in the turnover of sphingomyelin
      to a number of sphingolipid metabolites, of which at least S1P is critical for
      mitogenesis.

PMID- 10419458
TI  - Competitive inhibition of human immunodeficiency virus type-1 protease by the Gag
      Pol transframe protein.
AB  - The human immunodeficiency virus type-1 (HIV-1) transframe protein p6* is located
      between the structural and enzymatic domains of the Gag-Pol polyprotein, flanked
      by the nucleocapsid (NC) and the protease (PR) domain at its amino and carboxyl
      termini, respectively. Here, we report that recombinant highly purified HIV-1 p6*
      specifically inhibits mature HIV-1 PR activity. Kinetic analyses and cross
      linking experiments revealed a competitive mechanism for PR inhibition by p6*. We
      further demonstrate that the four carboxyl-terminal residues of p6* are essential
      but not sufficient for p6*-mediated inhibition of PR activity. Based on these
      results, we suggest a role of the transframe protein p6* in regulating HIV-1 PR
      activity during viral replication.

PMID- 10419459
TI  - The gene expression of the amiloride-sensitive epithelial sodium channel alpha
      subunit is regulated by antagonistic effects between glucocorticoid hormone and
      ras pathways in salivary epithelial cells.
AB  - The functional expression of the amiloride-sensitive epithelial sodium channel
      (ENaC) in select epithelia is critical for maintaining electrolyte and fluid
      homeostasis. Although ENaC activity is strictly dependent upon its alpha-subunit
      expression, little is known about the molecular mechanisms by which cells
      modulate alpha-ENaC gene expression. Previously, we have shown that salivary
      alpha-ENaC expression is transcriptionally repressed by the activation of
      Raf/extracellular signal-regulated protein kinase pathway. Here, this work
      further investigates the molecular mechanism(s) by which alpha-ENaC expression is
      regulated in salivary epithelial Pa-4 cells. A region located between -1.5 and 
      1.0 kilobase pairs of the alpha-ENaC 5'-flanking region is demonstrated to be
      indispensable for the maximal and Ras-repressible reporter expression. Deletional
      analyses using heterologous promoter constructs reveal that a DNA sequence
      between -1355 and -1269 base pairs functions as an enhancer conferring the high
      level of expression on reporter constructs, and this induction effect is
      inhibited by Ras pathway activation. Mutational analyses indicate that full
      induction and Ras-mediated repression require a glucocorticoid response element
      (GRE) located between -1323 and -1309 base pairs. The identified alpha-ENaC GRE
      encompassing sequence (-1334/-1306) is sufficient to confer glucocorticoid
      receptor/dexamethasone-dependent and Ras-repressible expression on both
      heterologous and homologous promoters. This report demon- strates for the first
      time that the cross-talk between glucocorticoid receptor and Ras/extracellular
      signal-regulated protein kinase signaling pathways results in an antagonistic
      effect at the transcriptional level to modulate alpha-ENaC expression through the
      identified GRE. In summary, this study presents a mechanism by which alpha-ENaC
      expression is regulated in salivary epithelial cells.

PMID- 10419460
TI  - Tissue plasminogen activator binds to human vascular smooth muscle cells by a
      novel mechanism. Evidence for a reciprocal linkage between inhibition of
      catalytic activity and cellular binding.
AB  - Human vascular smooth muscle cells (VSMC) bind tissue plasminogen activator (tPA)
      specifically, saturably, and with relatively high affinity (K(d) 25 nM), and this
      binding potentiates the activation of cell-associated plasminogen (Ellis, V., and
      Whawell, S. A. (1997) Blood 90, 2312-2322). We have observed that this binding
      can be efficiently competed by DFP-inactivated tPA and S478A-tPA but not by tPA
      inactivated with H-D-Phe-Pro-Arg-chloromethyl ketone (PPACK). VSMC-bound tPA also
      exhibited a markedly reduced inhibition by PPACK, displaying biphasic kinetics
      with second-order rate constants of 7. 5 x 10(3) M(-1) s(-1) and 0.48 x 10(3) M(
      1) s(-1), compared with 7. 2 x 10(3) M(-1) s(-1) in the solution phase. By
      contrast, tPA binding to fibrin was competed equally well by all forms of tPA,
      and its inhibition was unaltered. These effects were shown to extend to the
      physiological tPA inhibitor, plasminogen activator inhibitor 1. tPA.plasminogen
      activator inhibitor 1 complex did not compete tPA binding to VSMC, and the
      inhibition of bound tPA was reduced by 30-fold. The behavior of the various forms
      of tPA bound to VSMC correlated with conformational changes in tPA detected by CD
      spectroscopy. These data suggest that tPA binds to its specific high affinity
      site on VSMC by a novel mechanism involving the serine protease domain of tPA and
      distinct from its binding to fibrin. Furthermore, reciprocally linked
      conformational changes in tPA appear to have functionally significant effects on
      both the interaction of tPA with its VSMC binding site and the susceptibility of
      bound tPA to inhibition.

PMID- 10419461
TI  - Identification by chimera formation and site-selected mutagenesis of a key amino
      acid residue involved in determining stereospecificity of guinea pig 3
      hydroxysteroid sulfotransferase isoforms.
AB  - The 3-hydroxysteroid sulfotransferases that have been isolated and cloned from
      humans and rodents appear to have broad substrate specificities. In the guinea
      pig, however, two 3-hydroxysteroid sulfotransferases have been isolated that
      function according to an innate stereospecificity: the alpha-isoform acts on
      steroids with a 3-hydroxyl group oriented in the alpha position, whereas the beta
      isoform acts on steroids where the 3-hydroxyl group is in a beta orientation. To
      examine the structural basis for this remarkable stereoselectivity, chimeras of
      the two enzymes, which are 87% identical, were constructed. A chimera consisting
      of the NH(2)-terminal 91 amino acids of the alpha-isoform and the COOH-terminal
      196 amino acids of the beta-isoform displayed activity similar to that of the
      alpha-isoform. Site-selected mutagenesis of this 3alpha/beta-hydroxysteroid
      sulfotransferase chimera involving the 12 amino acid differences that exist
      between the two isoforms within the 91 amino acid NH(2)-terminal region revealed
      that the amino acid residue at position 51 plays a fundamental role in
      determining the stereospecificity exhibited by the alpha- and beta-isoforms, i.e.
      if residue 51 is an asparagine, alpha activity predominates, whereas if an
      isoleucine is in that position, beta activity prevails.

PMID- 10419462
TI  - HHV8-encoded vMIP-I selectively engages chemokine receptor CCR8. Agonist and
      antagonist profiles of viral chemokines.
AB  - Uncertainty regarding viral chemokine function is mirrored by an incomplete
      knowledge of host chemokine receptor usage by the virally encoded proteins. One
      such molecule is vMIP-I, a C-C type chemokine of undefined function and binding
      specificity, encoded by the Kaposi's sarcoma herpesvirus HHV-8. We report here
      that vMIP-I binds to and induces cytosolic [Ca(2+)] signals in human T cells
      selectively through CCR8, a CC chemokine receptor associated with Th2
      lymphocytes. Furthermore, using a panel of 65 different human, viral, and rodent
      chemokines, we have established a comprehensive ligand binding "fingerprint" for
      CCR8. The receptor exhibits marked "high" affinity (K(d) < 15 nM) only for four
      chemokines, three of them of viral origin: vMIP-I, vMIP-II, vMCC-I, and human I
      309. A previously unreported second class of lower affinity ligands includes MCP
      3 and possibly two other viral chemokines. vMIP-I and I-309 appear to act as CCR8
      agonists: binding to and inducing cytosolic [Ca(2+)] elevation through the
      receptor. By contrast, vMIP-II and vMCC-I act as potent antagonists: binding
      without inducing signaling, and blocking the effects of I-309 and vMIP-I. These
      results suggest a ligand hierarchy for CCR8, identifying vMIP-I as a selective
      viral chemokine agonist. CCR8 may thus engage a specific subset of chemokines
      with the potential to regulate each other during viral infection and immune
      regulation.

PMID- 10419463
TI  - Transient kinetic analysis of the 130-kDa myosin I (MYR-1 gene product) from rat
      liver. A myosin I designed for maintenance of tension?
AB  - The 130-kDa myosin I (MI(130)), product of the myr-1 gene, is one member of the
      mammalian class I myosins, a group of small, calmodulin-binding mechanochemical
      molecules of the myosin superfamily that translocate actin filaments. Roles for
      MI(130) are unknown. Our hypothesis is that, as with all myosins, MI(130) is
      designed for a particular function and hence possesses specific biochemical
      attributes. To test this hypothesis we have characterized the enzymatic
      properties of MI(130) using steady-state and stopped-flow kinetic analyses. Our
      results indicate that: (i) the Mg(2+)-ATPase activity is activated in proportion
      to actin concentration in the absence of Ca(2+); (ii) the ATP-induced
      dissociation of actin-MI(130) is much slower for MI(130) than has been observed
      for other myosins (-Ca(2+), second order rate constant of ATP binding, 1.7 x
      10(4) M(-1) s(-1); maximal rate constant, 32 s(-1)); (iii) ADP binds to actin
      MI(130) with an affinity of approximately 10 microM and competes with ATP-induced
      dissociation of actin-MI(130); the rate constant of ADP release from actin
      MI(130) is 2 s(-1); (iv) the rates of the ATP-induced dissociation of actin-MI
      and ADP release are 2-3 times greater in the presence of CaCl(2), indicating a
      sensitivity of motor activity to Ca(2+); and (v) the affinity of MI(130) for
      actin (15 nM) is typical of that observed for other myosins. Together, these
      results indicate that although MI(130) shares some characteristics with other
      myosins, it is well adapted for maintenance of cortical tension.

PMID- 10419464
TI  - Analysis of engineered multifunctional peptide synthetases. Enzymatic
      characterization of surfactin synthetase domains in hybrid bimodular systems.
AB  - The combinatorial reorganization of distinct modules of multimodular peptide
      synthetases is of increasing interest for the generation of new peptides with
      optimized bioactive properties. Each module is at least composed of enzymatic
      domains responsible for the adenylation, thioester formation, and condensation of
      an amino acid residue of the final peptide product. We analyzed various possible
      fusion sites for the recombination of peptide synthetases and evaluated the
      impact of different recombination strategies on the amino acid adenylation and
      acyl-thioester formation activities of peptide synthetase modules. Hybrid
      bimodular peptide synthetases were generated by recombination of the
      corresponding reading frames encoding for L-glutamic acid- and L-leucine-specific
      modules of surfactin synthetase SrfA-A at presumed inner- and intradomainic
      regions. We demonstrate that fusions at a previously postulated hinge region,
      dividing the amino acid adenylating domains of peptide synthetase modules into
      two subdomains, and at the highly conserved 4'-phosphopantetheine binding motif
      in acyl-thioester forming domains resulted in enzymatically active hybrid
      domains. By contrast, most manipulations in condensation domains like deletions,
      the complete exchange or the construction of chimeric domains considerably
      reduced or completely abolished the amino acid adenylation and thioester
      formation activity of the hybrid module.

PMID- 10419465
TI  - PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5
      phosphoinositides. Effect of insulin.
AB  - One or more free hydroxyls of the phosphatidylinositol (PtdIns) head group
      undergo enzymatic phosphorylation, yielding phosphoinositides (PIs) with key
      functions in eukaryotic cellular regulation. Two such species, PtdIns 5-P and
      PtdIns 3,5-P(2), have now been identified in mammalian cells, but their
      biosynthesis remains unclear. We have isolated a novel mammalian PI kinase, p235,
      whose exact substrate specificity remained to be determined (Shisheva, A.,
      Sbrissa, D., and Ikonomov, O. (1999) Mol. Cell. Biol. 19, 623-634). Here we
      report that recombinant p235 expressed in COS cells, like the authentic p235 in
      adipocytes, displays striking specificity for PtdIns over PI substrates and
      generates two products identified as PtdIns 5-P and PtdIns 3,5-P(2) by HPLC
      analyses. Synthetic PtdIns 3-P substrates were also converted to PtdIns 3,5-P(2)
      but to a substantially lesser extent than PtdIns isolated from natural sources.
      Important properties of the p235 PI 5-kinase include high sensitivity to nonionic
      detergents and relative resistance to wortmannin and adenosine. By analyzing
      deletion mutants in a heterologous cell system, we determined that in addition to
      the predicted catalytic domain other regions of the molecule are critical for the
      p235 enzymatic activity. HPLC resolution of monophosphoinositide products,
      generated by p235 immune complexes derived from lysates of 3T3-L1 adipocytes
      acutely stimulated with insulin, revealed essentially the same PtdIns 5-P levels
      as the corresponding p235 immune complexes of resting cells. However, the acute
      insulin action resulted in an increase of a wortmannin-sensitive PtdIns 3-P peak,
      suggestive of a plausible recruitment of wortmannin-sensitive PI 3-kinase(s) to
      p235. In conclusion, mouse p235 (renamed here PIKfyve) displays a strong in vitro
      activity for PtdIns 5-P and PtdIns 3,5-P(2) generation, implying PIKfyve has a
      key role in their biosynthesis.

PMID- 10419467
TI  - Essential requirement of cytosolic phospholipase A(2) for activation of the H(+)
      channel in phagocyte-like cells.
AB  - The NADPH oxidase-producing superoxide is the major mechanism by which phagocytes
      kill invading pathogens. We previously established a model of cytosolic
      phospholipase A(2) (cPLA(2))-deficient differentiated PLB-985 cells (PLB-D cells)
      and demonstrated that cPLA(2)-generated arachidonic acid (AA) is essential for
      NADPH oxidase activation (Dana, R., Leto, T., Malech, H., and Levy, R. (1998) J.
      Biol. Chem. 273, 441-445). In the present study, we used this model to determine
      the physiological role of cPLA(2) in the regulation of both the H(+) channel and
      the Na(+)/H(+) antiporter and to study whether NADPH oxidase activation is
      regulated by either of these transporters. PLB-D cells and two controls: parent
      PLB-985 cells and PLB-985 cells transfected with the vector only (PLB cells) were
      differentiated using 1.25% Me(2)SO or 5 x 10(-8) M 1, 25-dihydroxyvitamin D(3).
      Activation of differentiated PLB cells resulted in a Zn(2+)-sensitive
      alkalization, indicating H(+) channel activity. In contrast, differentiated PLB-D
      cells failed to activate the H(+) channel, but the addition of exogenous AA fully
      restored this activity, indicating the role of cPLA(2) in H(+) channel
      activation. The presence of the H(+) channel inhibitor Zn(2+) caused significant
      inhibition of NADPH oxidase activity, suggesting a role of the H(+) channel in
      regulating oxidase activity. Na(+)/H(+) antiporter activity was stimulated in
      differentiated PLB-D cells, indicating that cPLA(2) does not participate in the
      regulation of this antiporter. These results establish an essential and specific
      physiological requirement of cPLA(2)-generated AA for activation of the H(+)
      channel and suggest the participation of this channel in the regulation of NADPH
      oxidase activity.

PMID- 10419468
TI  - Mechanisms and consequences of affinity modulation of integrin alpha(V)beta(3)
      detected with a novel patch-engineered monovalent ligand.
AB  - Integrin alpha(V)beta(3) mediates diverse responses in vascular cells, ranging
      from cell adhesion, migration, and proliferation to uptake of adenoviruses.
      However, the extent to which alpha(V)beta(3) is regulated by changes in receptor
      conformation (affinity), receptor diffusion/clustering (avidity), or post
      receptor events is unknown. Affinity regulation of the related integrin,
      alpha(IIb)beta(3), has been established using a monovalent ligand-mimetic
      antibody, PAC1 Fab. To determine the role of affinity modulation of
      alpha(V)beta(3), a novel monovalent ligand-mimetic antibody (WOW-1) was created
      by replacing the heavy chain hypervariable region 3 of PAC1 Fab with a single
      alpha(V) integrin-binding domain from multivalent adenovirus penton base. Both
      WOW-1 Fab and penton base bound selectively to activated alpha(V)beta(3), but not
      to alpha(IIb)beta(3), in receptor and cell binding assays. alpha(V)beta(3)
      affinity varied with the cell type. Unstimulated B-lymphoblastoid cells bound WOW
      1 Fab poorly (apparent K(d) = 2.4 microM), but acute stimulation with phorbol 12
      myristate 13-acetate increased receptor affinity >30-fold (K(d) = 80 nM), with no
      change in receptor number. In contrast, alpha(V)beta(3) in melanoma cells was
      constitutively active, but ligand binding could be suppressed by overexpression
      of beta(3) cytoplasmic tails. Up-regulation of alpha(V)beta(3) affinity had
      functional consequences in that it increased cell adhesion and spreading and
      promoted adenovirus-mediated gene transfer. These studies establish that
      alpha(V)beta(3) is subject to rapid regulated changes in affinity that influence
      the biological functions of this integrin.

PMID- 10419466
TI  - The Caenorhabditis elegans homologue of thioredoxin reductase contains a
      selenocysteine insertion sequence (SECIS) element that differs from mammalian
      SECIS elements but directs selenocysteine incorporation.
AB  - Thioredoxin reductases (TRR) serve critical roles in maintaining cellular redox
      states. Two isoforms of TRR have been identified in mammals: both contain a
      penultimate selenocysteine residue that is essential for catalytic activity. A
      search of the genome of the invertebrate, Caenorhabditis elegans, reveals a gene
      highly homologous to mammalian TRR, with a TGA selenocysteine codon at the
      corresponding position. A selenocysteyl-tRNA was identified in this organism
      several years ago, but no selenoproteins have been identified experimentally.
      Herein we report the first identification of a C. elegans selenoprotein. By
      (75)Se labeling of C. elegans, one major band was identified, which migrated with
      the predicted mobility of the C. elegans TRR homologue. Western analysis with an
      antibody against human TRR provides strong evidence for identification of the C.
      elegans selenoprotein as a member of the TRR family. The 3'-untranslated region
      of this gene contains a selenocysteine insertion sequence (SECIS) element that
      deviates at one position from the previously invariant consensus "AUGA."
      Nonetheless, this element functions to direct selenocysteine incorporation in
      mammalian cells, suggesting conservation of the factors recognizing SECIS
      elements from worm to man.

PMID- 10419469
TI  - Mutation of the five conserved histidines in the endothelial nitric-oxide
      synthase hemoprotein domain. No evidence for a non-heme metal requirement for
      catalysis.
AB  - Five conserved histidine residues are found in the human endothelial nitric-oxide
      synthase (NOS) heme domain: His-420, His-421, and His-461 are close to the heme,
      whereas His-146 and His-214 are some distance away. To investigate whether the
      histidines form a non-heme iron-binding site, we have expressed the H146A, H214A,
      H420A, H421A, and H461A mutants. The H420A mutant could not be isolated, and the
      H146A and H421A mutants were inactive. The H214A mutant resembled the wild-type
      enzyme in all respects. The H461A mutant had a low-spin heme, but high
      concentrations of L-Arg and tetrahydrobiopterin led to partial recovery of
      activity. Laser atomic emission showed that the only significant metal in NOS
      other than calcium and iron is zinc. The activities of the NOS isoforms were not
      increased by incubation with Fe(2+), but were inhibited by high Fe(2+) or Zn(2+)
      concentrations. The histidine mutations altered the ability of the protein to
      dimerize and to bind heme. However, the protein metal content, the inability of
      exogenous Fe(2+) to increase catalytic activity, and the absence of evidence that
      the conserved histidines form a metal site provide no support for a catalytic
      role for a non-heme redox-active metal.

PMID- 10419470
TI  - Human cytoplasmic aconitase (Iron regulatory protein 1) is converted into its
      [3Fe-4S] form by hydrogen peroxide in vitro but is not activated for iron
      responsive element binding.
AB  - Iron regulatory protein 1 (IRP1) regulates the synthesis of proteins involved in
      iron homeostasis by binding to iron-responsive elements (IREs) of messenger RNA.
      IRP1 is a cytoplasmic aconitase when it contains a [4Fe-4S] cluster and an RNA
      binding protein after complete removal of the metal center by an unknown
      mechanism. Human IRP1, obtained as the pure recombinant [4Fe-4S] form, is an
      enzyme as efficient toward cis-aconitate as the homologous mitochondrial
      aconitase. The aconitase activity of IRP1 is rapidly lost by reaction with
      hydrogen peroxide as the [4Fe-4S] cluster is quantitatively converted into the
      [3Fe-4S] form with release of a single ferrous ion per molecule. The IRE binding
      capacity of IRP1 is not elicited with H(2)O(2). Ferrous sulfate (but not other
      more tightly coordinated ferrous ions, such as the complex with ethylenediamine
      tetraacetic acid) counteracts the inhibitory action of hydrogen peroxide on
      cytoplasmic aconitase, probably by replenishing iron at the active site. These
      results cast doubt on the ability of reactive oxygen species to directly increase
      IRP1 binding to IRE and support a signaling role for hydrogen peroxide in the
      posttranscriptional control of proteins involved in iron homeostasis in vivo.

PMID- 10419471
TI  - Transport of water and glycerol in aquaporin 3 is gated by H(+).
AB  - Aquaporins (AQPs) were expressed in Xenopus laevis oocytes in order to study the
      effects of external pH and solute structure on permeabilities. For AQP3 the
      osmotic water permeability, L(p), was abolished at acid pH values with a pK of
      6.4 and a Hill coefficient of 3. The L(p) values of AQP0, AQP1, AQP2, AQP4, and
      AQP5 were independent of pH. For AQP3 the glycerol permeability P(Gl), obtained
      from [(14)C]glycerol uptake, was abolished at acid pH values with a pK of 6.1 and
      a Hill coefficient of 6. Consequently, AQP3 acts as a glycerol and water channel
      at physiological pH, but predominantly as a glycerol channel at pH values around
      6.1. The pH effects were reversible. The interactions between fluxes of water and
      straight chain polyols were inferred from reflection coefficients (sigma). For
      AQP3, water and glycerol interacted by competing for titratable site(s):
      sigma(Gl) was 0.15 at neutral pH but doubled at pH 6.4. The sigma values were
      smaller for polyols in which the -OH groups were free to form hydrogen bonds. The
      activation energy for the transport processes was around 5 kcal mol(-1). We
      suggest that water and polyols permeate AQP3 by forming successive hydrogen bonds
      with titratable sites.

PMID- 10419472
TI  - DNA binding and aggregation properties of the vaccinia virus I3L gene product.
AB  - The vaccinia virus I3L gene encodes a single-stranded DNA-binding protein which
      may play a role in viral replication and genetic recombination. We have purified
      native and recombinant forms of gpI3L and characterized both the DNA-binding
      reaction and the structural properties of DNA-protein complexes. The purified
      proteins displayed anomalous electrophoretic properties in the presence of sodium
      dodecyl sulfate, behaving as if they were 4-kDa larger than the true mass.
      Agarose gel shift analysis was used to monitor the formation of complexes
      composed of single-stranded DNA plus gpI3L protein. These experiments detected
      two different DNA binding modes whose formation was dependent upon the protein
      density. The transition between the two binding modes occurred at a nucleotide to
      protein ratio of about 31 nucleotides per gpI3L monomer. S1 nuclease protection
      assay revealed that at saturating protein densities, each gpI3L monomer occludes
      9.5 +/- 2.5 nucleotides. In the presence of magnesium, gpI3L promoted the
      formation of large DNA aggregates from which double-stranded DNA was excluded.
      Electron microscopy showed that, in the absence of magnesium and at low protein
      densities, gpI3L forms beaded structures on DNA. At high protein density the
      complexes display a smoother and less compacted morphology. In the presence of
      magnesium the complexes contained long fibrous and tangled arrays. These results
      suggest that gpI3L can form octameric complexes on DNA much like those formed by
      Escherichia coli single-stranded DNA protein. Moreover, the capacity to aggregate
      DNA may provide an environment in which hybrid DNA formation could occur during
      DNA replication.

PMID- 10419473
TI  - Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein
      1 as a negative regulator of thioredoxin function and expression.
AB  - Recent works have shown the importance of reduction/oxidation (redox) regulation
      in various biological phenomena. Thioredoxin (TRX) is one of the major components
      of the thiol reducing system and plays multiple roles in cellular processes such
      as proliferation, apoptosis, and gene expression. To investigate the molecular
      mechanism of TRX action, we used a yeast two-hybrid system to identify TRX
      binding proteins. One of the candidates, designated as thioredoxin-binding
      protein-2 (TBP-2), was identical to vitamin D(3) up-regulated protein 1 (VDUP1).
      The association of TRX with TBP-2/VDUP1 was observed in vitro and in vivo. TBP
      2/VDUP1 bound to reduced TRX but not to oxidized TRX nor to mutant TRX, in which
      two redox active cysteine residues are substituted by serine. Thus, the catalytic
      center of TRX seems to be important for the interaction. Insulin reducing
      activity of TRX was inhibited by the addition of recombinant TBP-2/VDUP1 protein
      in vitro. In COS-7 and HEK293 cells transiently transfected with TBP-2/VDUP1
      expression vector, decrease of insulin reducing activity of TRX and diminishment
      of TRX expression was observed. These results suggested that TBP-2/VDUP1 serves
      as a negative regulator of the biological function and expression of TRX.
      Treatment of HL-60 cells with 1alpha, 25-dihydroxyvitamin D(3) caused an increase
      of TBP-2/VDUP1 expression and down-regulation of the expression and the reducing
      activity of TRX. Therefore, the TRX-TBP-2/VDUP1 interaction may be an important
      redox regulatory mechanism in cellular processes, including differentiation of
      myeloid and macrophage lineages.

PMID- 10419474
TI  - Regulation of AML2/CBFA3 in hematopoietic cells through the retinoic acid
      receptor alpha-dependent signaling pathway.
AB  - AML2 is a member of the acute myelogenous leukemia, AML family of transcription
      factors. The biologic functions of AML1 and AML3 have been well characterized;
      however, the functional role of AML2 remains unknown. In this study, we found
      that AML2 protein expressed predominantly in cells of hematopoietic origin is a
      nuclear serine phosphoprotein associated with the nuclear matrix, and its
      expression is not cell cycle-related. In HL-60 cells AML2 expression can be
      induced by all three natural retinoids, all-trans-retinoic acid (RA), 13-cis-RA,
      and 9-cis-RA in a dose-dependent manner. A synthetic retinoic acid derivative,
      4HPR, which neither activates RA receptor (RAR) alpha nor retinoic X receptor
      alpha was unable to induce the expression of AML2. A RAR-selective activator,
      TTNPB, induced AML2 expression similar to RA. Our study further showed that
      AGN193109, a potent RARalpha antagonist, suppressed AML2 expression induced by RA
      and that a retinoic X receptor pan agonist AGN194204 had no effect on its
      expression. Taken together, these studies conclusively demonstrated that the
      expression of AML2 in HL-60 cells is regulated through the RARalpha-specific
      signaling pathway. Our study further showed that after all-trans-retinoic acid
      priming, AML2 expression could be augmented by vitamin D(3). Based on these
      studies we hypothesize that AML2 expression is normally regulated by
      retinoid/vitamin D nuclear receptors mainly through the RARalpha-dependent
      signaling pathway and that it may play a role in hematopoietic cell
      differentiation.

PMID- 10419475
TI  - Dissociation of mismatch recognition and ATPase activity by hMSH2-hMSH3.
AB  - MSH2-MSH3 directs the repair of insertion/deletion loops of up to 13 nucleotides
      in vivo and in vitro. To examine the biochemical basis of this repair
      specificity, we characterized the mispair binding and ATPase activity of hMSH2
      hMSH3. The ATPase was found to be regulated by a mismatch-stimulated ADP --> ATP
      exchange, which induces a conformational transition by the protein complex. We
      demonstrated strong binding of hMSH2-hMSH3 to an insertion/deletion loop
      containing 24 nucleotides that is incapable of provoking ADP --> ATP exchange,
      suggesting that mismatch recognition appears to be necessary but not sufficient
      to induce the intrinsic ATPase. These studies support the idea that hMSH2-hMSH3
      functions as an adenosine nucleotide-regulated molecular switch that must be
      activated by mismatched nucleotides for classical mismatch repair to occur.

PMID- 10419476
TI  - Yeast and rat Coq3 and Escherichia coli UbiG polypeptides catalyze both O
      methyltransferase steps in coenzyme Q biosynthesis.
AB  - Ubiquinone (coenzyme Q or Q) is a lipid that functions in the electron transport
      chain in the inner mitochondrial membrane of eukaryotes and the plasma membrane
      of prokaryotes. Q-deficient mutants of Saccharomyces cerevisiae harbor defects in
      one of eight COQ genes (coq1-coq8) and are unable to grow on nonfermentable
      carbon sources. The biosynthesis of Q involves two separate O-methylation steps.
      In yeast, the first O-methylation utilizes 3, 4-dihydroxy-5-hexaprenylbenzoic
      acid as a substrate and is thought to be catalyzed by Coq3p, a 32.7-kDa protein
      that is 40% identical to the Escherichia coli O-methyltransferase, UbiG. In this
      study, farnesylated analogs corresponding to the second O-methylation step,
      demethyl-Q(3) and Q(3), have been chemically synthesized and used to study Q
      biosynthesis in yeast mitochondria in vitro. Both yeast and rat Coq3p recognize
      the demethyl-Q(3) precursor as a substrate. In addition, E. coli UbiGp was
      purified and found to catalyze both O-methylation steps. Futhermore, antibodies
      to yeast Coq3p were used to determine that the Coq3 polypeptide is peripherally
      associated with the matrix-side of the inner membrane of yeast mitochondria. The
      results indicate that one O-methyltransferase catalyzes both steps in Q
      biosynthesis in eukaryotes and prokaryotes and that Q biosynthesis is carried out
      within the matrix compartment of yeast mitochondria.

PMID- 10419477
TI  - Elevation of intracellular glucosylceramide levels results in an increase in
      endoplasmic reticulum density and in functional calcium stores in cultured
      neurons.
AB  - Gaucher disease is a glycosphingolipid storage disease caused by defects in the
      activity of the lysosomal hydrolase, glucocerebrosidase (GlcCerase), resulting in
      accumulation of glucocerebroside (glucosylceramide, GlcCer) in lysosomes. The
      acute neuronopathic type of the disease is characterized by severe loss of
      neurons in the central nervous system, suggesting that a neurotoxic agent might
      be responsible for cellular disruption and neuronal death. We now demonstrate
      that upon incubation with a chemical inhibitor of GlcCerase, conduritol-B-epoxide
      (CBE), cultured hippocampal neurons accumulate GlcCer. Surprisingly, increased
      levels of tubular endoplasmic reticulum elements, an increase in [Ca(2+)](i)
      response to glutamate, and a large increase in [Ca(2+)](i) release from the
      endoplasmic reticulum in response to caffeine were detected in these cells. There
      was a direct relationship between these effects and GlcCer accumulation since co
      incubation with CBE and an inhibitor of glycosphingolipid synthesis, fumonisin
      B(1), completely antagonized the effects of CBE. Similar effects on endoplasmic
      reticulum morphology and [Ca(2+)](i) stores were observed upon incubation with a
      short-acyl chain, nonhydrolyzable analogue of GlcCer, C(8)-glucosylthioceramide.
      Finally, neurons with elevated GlcCer levels were much more sensitive to the
      neurotoxic effects of high concentrations of glutamate than control cells;
      moreover, this enhanced toxicity was blocked by pre-incubation with ryanodine,
      suggesting that [Ca(2+)](i) release from ryanodine-sensitive intracellular stores
      can induce neuronal cell death, at least in neurons with elevated GlcCer levels.
      These results may provide a molecular mechanism to explain neuronal dysfunction
      and cell death in neuronopathic forms of Gaucher disease.

PMID- 10419478
TI  - DNA ligase III is recruited to DNA strand breaks by a zinc finger motif
      homologous to that of poly(ADP-ribose) polymerase. Identification of two
      functionally distinct DNA binding regions within DNA ligase III.
AB  - Mammalian DNA ligases are composed of a conserved catalytic domain flanked by
      unrelated sequences. At the C-terminal end of the catalytic domain, there is a 16
      amino acid sequence, known as the conserved peptide, whose role in the ligation
      reaction is unknown. Here we show that conserved positively charged residues at
      the C-terminal end of this motif are required for enzyme-AMP formation. These
      residues probably interact with the triphosphate tail of ATP, positioning it for
      nucleophilic attack by the active site lysine. Amino acid residues within the
      sequence RFPR, which is invariant in the conserved peptide of mammalian DNA
      ligases, play critical roles in the subsequent nucleotidyl transfer reaction that
      produces the DNA-adenylate intermediate. DNA binding by the N-terminal zinc
      finger of DNA ligase III, which is homologous with the two zinc fingers of
      poly(ADP-ribose) polymerase, is not required for DNA ligase activity in vitro or
      in vivo. However, this zinc finger enables DNA ligase III to interact with and
      ligate nicked DNA at physiological salt concentrations. We suggest that in vivo
      the DNA ligase III zinc finger may displace poly(ADP-ribose) polymerase from DNA
      strand breaks, allowing repair to occur.

PMID- 10419479
TI  - Catalysis of ATP hydrolysis by two NH(2)-terminal fragments of yeast DNA
      topoisomerase II.
AB  - Catalysis of ATP hydrolysis by two NH(2)-terminal fragments of yeast DNA
      topoisomerase II was studied in the absence and presence of DNA, and in the
      absence and presence of inhibitor ICRF-193. The results indicate that purified
      Top2-(1-409), a fragment containing the NH(2)-terminal 409 amino acids of the
      yeast enzyme, is predominantly monomeric, with a low level of ATPase owing to
      weak association of two monomers to form a catalytically active dimer. The ATPase
      activity of Top2-(1-409) is independent of DNA in a buffer containing 100 mM
      NaCl, in which intact yeast DNA topoisomerase II exhibits robust DNA-dependent
      ATPase and DNA transport activities. Purified Top2-(1-660), a fragment containing
      the NH(2)-terminal 660 amino acid of the yeast enzyme, appears to be dimeric in
      the absence or presence of DNA, and the ATPase activity of the protein is
      significantly stimulated by DNA. These results are consistent with a model in
      which binding of an intact DNA topoisomerase II to DNA places the various
      subfragments of the enzyme in a way that makes the intramolecular dimerization of
      the ATPase domains more favorable. We believe that this alignment of subfragments
      is mainly achieved through the binding of the enzyme to the DNA segment within
      which the enzyme makes transient breaks. The ATPase activity of Top2-(1-409) is
      inhibited by ICRF-193, suggesting that the bisdioxopiperazine class of DNA
      topoisomerase II inhibitors directly interacts with the paired ATPase domains of
      the enzyme.

PMID- 10419480
TI  - Rapid kinetics of tyrosyl radical formation and heme redox state changes in
      prostaglandin H synthase-1 and -2.
AB  - Hydroperoxide-induced tyrosyl radicals are putative intermediates in
      cyclooxygenase catalysis by prostaglandin H synthase (PGHS)-1 and -2. Rapid
      freeze EPR and stopped-flow were used to characterize tyrosyl radical kinetics in
      PGHS-1 and -2 reacted with ethyl hydrogen peroxide. In PGHS-1, a wide doublet
      tyrosyl radical (34-35 G) was formed by 4 ms, followed by transition to a wide
      singlet (33-34 G); changes in total radical intensity paralleled those of
      Intermediate II absorbance during both formation and decay phases. In PGHS-2,
      some wide doublet (30 G) was present at early time points, but transition to wide
      singlet (29 G) was complete by 50 ms. In contrast to PGHS-1, only the formation
      kinetics of the PGHS-2 tyrosyl radical matched the Intermediate II absorbance
      kinetics. Indomethacin-treated PGHS-1 and nimesulide-treated PGHS-2 rapidly
      formed narrow singlet EPR (25-26 G in PGHS-1; 21 G in PGHS-2), and the same line
      shapes persisted throughout the reactions. Radical intensity paralleled
      Intermediate II absorbance throughout the indomethacin-treated PGHS-1 reaction.
      For nimesulide-treated PGHS-2, radical formed in concert with Intermediate II,
      but later persisted while Intermediate II relaxed. These results substantiate the
      kinetic competence of a tyrosyl radical as the catalytic intermediate for both
      PGHS isoforms and also indicate that the heme redox state becomes uncoupled from
      the tyrosyl radical in PGHS-2.

PMID- 10419481
TI  - Muscarinic cholinergic receptors activate both inhibitory and stimulatory growth
      mechanisms in NIH3T3 cells.
AB  - Activation of G(q) protein-coupled receptors can either stimulate or inhibit cell
      growth. Previously, these opposite effects were explained by differences in the
      cell models. Here we show that activation of m3 muscarinic acetylcholine
      receptors ectopically expressed in NIH3T3 cells can cause stimulation and
      inhibition of growth in the same cell. A clonal cell line was selected from cells
      that formed foci agonist dependently (3T3/m3 cells). In quiescent 3T3/m3 cells,
      carbachol stimulated DNA synthesis. In contrast, when 3T3/m3 cells were growing,
      either due to the presence of serum or after transformation with oncogenic v-src,
      carbachol inhibited growth. This inhibition was not due to reduction of
      extracellular signal-regulated kinase activity because carbachol induced
      extracellular signal-regulated kinase phosphorylation in both quiescent and
      growing 3T3/m3 cells. Investigating the cell cycle mechanisms involved in growth
      inhibition, we found that carbachol treatment decreased cyclin D1 levels,
      increased p21(cip1) expression, and led to hypophosphorylation of the
      retinoblastoma gene product (Rb). Proteasome inhibitors blocked the carbachol
      induced degradation of cyclin D1. Effects on p21(cip1) were blocked by a protein
      kinase C inhibitor. Thus, m3 muscarinic acetylcholine receptors couple to both
      growth-stimulatory and -inhibitory signaling pathways in NIH3T3 cells, and the
      observed effects of receptor activation depend on the context of cellular growth.

PMID- 10419482
TI  - Nucleosomes bind to cell surface proteoglycans.
AB  - Material on the surface of activated T-cells was displaced following incubation
      with a sulfated polysaccharide, dextrin 2-sulfate (D2S), and purified by anion
      exchange chromatography. This revealed a complex comprising histones H2A, H2B,
      H3, and H4 and DNA fragmented into 180-base pair units characteristic of mono-,
      di-, tri, and polynucleosomes, a pattern of fragmentation similar to that found
      in apoptotic cells. An antibody raised against the purified nucleosome
      preparation bound to the plasma membrane of activated T-cells confirming the
      surface location of nucleosomes. The interaction of sulfated polysaccharides with
      nucleosomes was investigated using a biotinylated derivative of D2S. It was found
      that sulfated polysaccharides bound to nucleosomes via the N termini of histones,
      especially H2A and H2B. Treatment of T-cells with either heparinase or
      heparitinase abolished nucleosome binding to plasma membranes. This suggests that
      nucleosomes are anchored to the surface of T-cells by heparan sulfate
      proteoglycans through an ionic interaction with the basic N-terminal residues in
      the histones. Furthermore, nucleosomes bound to the cell surface in this manner
      are then able to bind other sulfated polysaccharides, such as D2S, heparin, or
      dextran sulfate, through unoccupied histone N termini forming a complex
      comprising cell surface heparan sulfate proteoglycans, nucleosomes, and sulfated
      polysaccharides.

PMID- 10419483
TI  - Human tumor necrosis factor-alpha gene 3' untranslated region confers inducible
      toxin responsiveness to homologous promoter in monocytic THP-1 cells.
AB  - To better define the role of 3' untranslated region (3'UTR) on transcriptional
      regulation of the human tumor necrosis factor (TNF)-alpha gene, monocytic human
      THP-1 cells were transfected with two TNF-alpha promoter constructs spanning base
      pairs -1897/-1 and -1214/-1, respectively, and linked to the rabbit beta-globin
      gene. Quantitative globin gene expression of chimerae was measured by reverse
      transcription-polymerase chain reaction. A construct linking the chicken beta
      actin promoter and a deleted portion of the beta-globin gene was cotransfected
      and used as internal standard. Unexpectedly, when THP-1 cells were stimulated
      with lipopolysaccharide or toxic shock syndrome toxin-1, gene regulation was
      hardly detected. In contrast, endogenous TNF-alpha gene regulation measured by
      the same reverse transcription-polymerase chain reaction procedure was vigorous.
      Remarkably, ligation of 3'UTR to chimeric constructs led to a drastic drop in the
      basal level of chimeric gene expression, resulting in a 15- to 40-fold induction
      of the reporter gene. Consistently, when the TNF-alpha promoter was replaced by
      the cytomegalovirus early immediate promoter, gene expression was also uniformly
      reduced but was no longer up-regulated upon stimulation with lipopolysaccharide
      and toxic shock syndrome toxin-1. These data provide the first line of evidence
      that, in addition to its role in TNF-alpha transcript stability and translation,
      human TNF-alpha 3'UTR also participates in modulating gene expression at the
      transcriptional level.

PMID- 10419484
TI  - Glycosaminoglycans mediate the coacervation of human tropoelastin through
      dominant charge interactions involving lysine side chains.
AB  - Following cellular secretion into the extracellular matrix, tropoelastin is
      transported, deposited, and cross-linked to make elastin. Assembly by
      coacervation was examined for an isoform of tropoelastin that lacks the
      hydrophilic domain encoded by exon 26A. It is equivalent to a naturally secreted
      form of tropoelastin and shows similar coacervation performance to its partner
      containing 26A, thereby generalizing the concept that splice form variants are
      able to coacervate under comparable conditions. This is optimal under
      physiological conditions of temperature, salt concentration, and pH. The proteins
      were examined for their ability to interact with extracellular matrix
      glycosaminoglycans. These negatively charged molecules interacted with positively
      charged lysine residues and promoted coacervation of tropoelastin in a
      temperature- and concentration-dependent manner. A testable model for elastin
      glycosaminoglycan interactions is proposed, where tropoelastin deposition during
      elastogenesis is encouraged by local exposure to matrix glycosaminoglycans.
      Unmodified proteins are retained at approximately 3 microM dissociation constant.
      Following lysyl oxidase modification of tropoelastin lysine residues, they are
      released from glycosaminoglycan interactions, thereby permitting those residues
      to contribute to elastin cross-links.

PMID- 10419485
TI  - Murine SHP-1 splice variants with altered Src homology 2 (SH2) domains.
      Implications for the SH2-mediated intramolecular regulation of SHP-1.
AB  - SHP-1 is a protein-tyrosine phosphatase with two Src homology 2 (SH2) domains.
      These SH2 domains determine which proteins SHP-1 associates with, but they also
      autoregulate the activity of the catalytic domain. In this report, we find that
      the murine SHP-1 transcript is processed to yield a series of alternatively
      spliced in-frame transcripts, the majority of which exclude exons encoding one or
      the other SH2 domain. We have examined the corresponding protein isoforms in
      several ways. First, our measurements of V(max) and K(m) under different
      conditions indicate that the SH2 variants have elevated activity because of
      lessened autoregulation. Second, to ascertain whether regulation by the SH2
      domains reflects intra- or intermolecular effects, we analyzed the state of SHP-1
      by high performance liquid chromatography and sucrose density gradient
      centrifugation. Our results showed that SHP-1 is a monomer and, thus, is
      regulated in an intramolecular manner. Third, our analyses detected shape
      differences between SHP-1 and the active splice variant protein deleted of the
      amino-terminal SH2 domain; i.e. SHP-1 was globular and resistant to proteolytic
      digestion, while the splice variant protein was "rod-shaped" and more susceptible
      to proteolytic digestion.

PMID- 10419486
TI  - The diadenosine hexaphosphate hydrolases from Schizosaccharomyces pombe and
      Saccharomyces cerevisiae are homologues of the human diphosphoinositol
      polyphosphate phosphohydrolase. Overlapping substrate specificities in a MutT
      type protein.
AB  - Aps1 from Schizosaccharomyces pombe (Ingram, S. W., Stratemann, S. A. , and
      Barnes, L. D. (1999) Biochemistry 38, 3649-3655) and YOR163w from Saccharomyces
      cerevisiae (Cartwright, J. L., and McLennan, A. G. (1999) J. Biol. Chem. 274,
      8604-8610) have both previously been characterized as MutT family hydrolases with
      high specificity for diadenosine hexa- and pentaphosphates (Ap(6)A and Ap(5)A).
      Using purified recombinant preparations of these enzymes, we have now discovered
      that they have an important additional function, namely, the efficient hydrolysis
      of diphosphorylated inositol polyphosphates. This overlapping specificity of an
      enzyme for two completely different classes of substrate is not only of
      enzymological significance, but in addition, this finding provides important new
      information pertinent to the structure, function, and evolution of the MutT
      motif. Moreover, we report that the human protein previously characterized as a
      diphosphorylated inositol phosphate phosphohydrolase represents the first
      example, in any animal, of an enzyme that degrades Ap(6)A and Ap(5)A, in
      preference to other diadenosine polyphosphates. The emergence of Ap(6)A and
      Ap(5)A as extracellular effectors and intracellular ion-channel ligands points
      not only to diphosphorylated inositol phosphate phosphohydrolase as a candidate
      for regulating signaling by diadenosine polyphosphates, but also suggests that
      diphosphorylated inositol phosphates may competitively inhibit this process.

PMID- 10419487
TI  - Starved Saccharomyces cerevisiae cells have the capacity to support internal
      initiation of translation.
AB  - Internal initiation of translation, whereby ribosomes are directed to internal
      AUG codon independently of the 5' end of the mRNA, has been observed rarely in
      higher eucaryotes and has not been demonstrated in living yeast. We report here
      that starved yeast cells are capable of initiating translation of a dicistronic
      message internally. The studied element that functions as an internal ribosome
      entry site (IRES) is hardly functional or not functional at all in
      logarithmically growing cells. Moreover, during the logarithmic growth phase,
      this element seems to inhibit translation reinitiation when placed as an
      intercistronic spacer or to inhibit translation when placed in the 5'
      untranslated region of a monocistronic message. Inhibition of translation is
      likely due to the putative strong secondary structure of the IRES that interferes
      with the cap-dependent scanning process. When cells exit the logarithmic growth
      phase, or when artificially starved for carbon source, translation of the IRES
      containing messages is substantially induced. Our findings imply that the
      capacity to translate internally is a characteristic of starved rather than
      vegetatively growing yeast cells.

PMID- 10419488
TI  - Characterization of a stable form of tryptophan hydroxylase from the human
      parasite Schistosoma mansoni.
AB  - A cDNA (Schistosoma mansoni tryptophan hydroxylase; SmTPH) encoding a protein
      homologous to tryptophan hydroxylase, the enzyme that catalyzes the rate-limiting
      step in the biosynthesis of serotonin, was cloned from the human parasite
      Schistosoma mansoni. Bacterial expression of SmTPH as a histidine fusion protein
      produced soluble active enzyme, which was purified to apparent homogeneity and a
      final specific activity of 0.17 micromol/min/mg of protein. The purified enzyme
      was found to be a tetramer of approximately 240 kDa with a subunit size of 58
      kDa. Several of the biochemical and kinetic properties of SmTPH were similar to
      those of mammalian tryptophan hydroxylase. Unlike the mammalian enzyme, however,
      SmTPH was found to be stable at 37 degrees C, its t((1)/(2)) being nearly 23
      times higher than that of a similarly expressed rabbit tryptophan hydroxylase. A
      semiquantitative reverse transcription polymerase chain reaction showed that the
      level of SmTPH mRNA in a larval stage of the parasite (cercaria) is 2.5 times
      higher than in adult S. mansoni, suggesting possible differences in the level of
      enzyme expression between the two developmental stages. This study demonstrates
      for the first time the presence of a functional tryptophan hydroxylase in a
      parasitic helminth and further suggests that the parasites are capable of
      synthesizing serotonin endogenously.

PMID- 10419489
TI  - Interaction of 7-hydroxy-8-(phenylazo)1,3-naphthalenedisulfonate with bovine
      plasma albumin. Spectroscopic studies.
AB  - Interaction of Orange G (OG) with bovine plasma albumin (BPA) has been
      investigated using NMR, UV-visible absorption, CD, and fluorescence techniques.
      The bound conformation of OG is a compact structure with N9-N10 bond in a non
      planar syn conformation. The binding causes a decrease in the 478-nm absorption
      band of OG. The analysis of the binding isotherm generated from UV-visible
      absorption measurements gives a dissociation constant of 10 microM and
      stoichiometry 1:1 for BPA.OG complex. Dissociation constant is invariant in the
      pH range 5.0-8.0 and is approximately 20 times higher at pH 4.0 than its value at
      pH 7.0. Near and far UV-CD studies indicate alterations in the helical content
      and in the tertiary structure of the protein on complexation. The binding induces
      (-) and (+) CD at 335 nm and 465 nm, respectively. The binding also results into
      an increase in the steady state fluorescence anisotropy of OG without affecting
      emission maximum and quantum yield. Fluorescence data indicate that quenching of
      Trp fluorescence by OG is static in nature and OG selectively binds near Trp-135.
      Observation of similar rotational correlation time for BPA and BPA.OG complex
      indicates that the overall globular structure of BPA remains unaltered on binding
      despite certain internal rearrangement in the protein structure.

PMID- 10419490
TI  - Repairing the sickle cell mutation. I. Specific covalent binding of a
      photoreactive third strand to the mutated base pair.
AB  - A DNA third strand with a 3'-psoralen substituent was designed to form a triplex
      with the sequence downstream of the T.A mutant base pair of the human sickle cell
      beta-globin gene. Triplex-mediated psoralen modification of the mutant T residue
      was sought as an approach to gene repair. The 24-nucleotide purine-rich target
      sequence switches from one strand to the other and has four pyrimidine
      interruptions. Therefore, a third strand sequence favorable to two triplex motifs
      was used, one parallel and the other antiparallel to it. To cope with the
      pyrimidine interruptions, which weaken third strand binding, 5-methylcytosine and
      5-propynyluracil were used in the third strand. Further, a six residue "hook"
      complementary to an overhang of a linear duplex target was added to the 5'-end of
      the third strand via a T(4) linker. In binding to the overhang by Watson-Crick
      pairing, the hook facilitates triplex formation. This third strand also binds
      specifically to the target within a supercoiled plasmid. The psoralen moiety at
      the 3'-end of the third strand forms photoadducts to the targeted T with high
      efficiency. Such monoadducts are known to preferentially trigger reversion of the
      mutation by DNA repair enzymes.

PMID- 10419491
TI  - The dihydrolipoamide S-acetyltransferase subunit of the mitochondrial pyruvate
      dehydrogenase complex from maize contains a single lipoyl domain.
AB  - The dihydrolipoamide S-acetyltransferase (E2) subunit of the maize mitochondrial
      pyruvate dehydrogenase complex (PDC) was postulated to contain a single lipoyl
      domain based upon molecular mass and N-terminal protein sequence (Thelen, J. J.,
      Miernyk, J. A., and Randall, D. D. (1998) Plant Physiol. 116, 1443-1450). This
      sequence was used to identify a cDNA from a maize expressed sequence tag data
      base. The deduced amino acid sequence of the full-length cDNA was greater than
      30% identical to other E2s and contained a single lipoyl domain. Mature maize E2
      was expressed in Escherichia coli and purified to a specific activity of 191
      units mg(-1). The purified recombinant protein had a native mass of approximately
      2.7 MDa and assembled into a 29-nm pentagonal dodecahedron as visualized by
      electron microscopy. Immunoanalysis of mitochondrial proteins from various
      plants, using a monoclonal antibody against the maize E2, revealed 50-54-kDa
      cross-reacting polypeptides in all samples. A larger protein (76 kDa) was also
      recognized in an enriched pea mitochondrial PDC preparation, indicating two
      distinct E2s. The presence of a single lipoyl-domain E2 in Arabidopsis thaliana
      was confirmed by identifying a gene encoding a hypothetical protein with 62%
      amino acid identity to the maize homologue. These data suggest that all plant
      mitochondrial PDCs contain an E2 with a single lipoyl domain. Additionally, A.
      thaliana and other dicots possess a second E2, which contains two lipoyl domains
      and is only 33% identical at the amino acid level to the smaller isoform. The
      reason two distinct E2s exist in dicotyledon plants is uncertain, although the
      variability between these isoforms, particularly within the subunit-binding
      domain, suggests different roles in assembly and/or function of the plant
      mitochondrial PDC.

PMID- 10419492
TI  - The aspartyl replacement of the active site histidine in histidine-containing
      protein, HPr, of the Escherichia coli Phosphoenolpyruvate:Sugar
      phosphotransferase system can accept and donate a phosphoryl group. Spontaneous
      dephosphorylation of acyl-phosphate autocatalyzes an internal cyclization.
AB  - The active site residue, His(15), in histidine-containing protein, HPr, can be
      replaced by aspartate and still act as a phosphoacceptor and phosphodonor with
      enzyme I and enzyme IIA(glucose), respectively. Other substitutions, including
      cysteine, glutamate, serine, threonine, and tyrosine, failed to show any
      activity. Enzyme I K(m) for His(15) --> Asp HPr is increased 10-fold and V(max)
      is decreased 1000-fold compared with wild type HPr. The phosphorylation of
      Asp(15) led to a spontaneous internal rearrangement involving the loss of the
      phosphoryl group and a water molecule, which was confirmed by mass spectrometry.
      The protein species formed had a higher pI than His(15) --> Asp HPr, which could
      arise from the formation of a succinimide or an isoimide. Hydrolysis of the
      isolated high pI form gave only aspartic acid at residue 15, and no isoaspartic
      acid was detected. This indicates that an isoimide rather than a succinimide is
      formed. In the absence of phosphorylation, no formation of the high pI form could
      be found, indicating that phosphorylation catalyzed the formation of the
      cyclization. The possible involvement of Asn(12) in an internal cyclization with
      Asp(15) was eliminated by the Asn(12) --> Ala mutation in His(15) --> AspHPr.
      Asn(12) substitutions of alanine, aspartate, serine, and threonine in wild type
      HPr indicated a general requirement for residues capable of forming a hydrogen
      bond with the Nepsilon(2) atom of His(15), but elimination of the hydrogen bond
      has only a 4-fold decrease in k(cat)/K(m).

PMID- 10419493
TI  - Antisense oligonucleotides with different backbones. Modification of splicing
      pathways and efficacy of uptake.
AB  - A novel, positive read-out assay that quantifies only sequence-specific nuclear
      activity of antisense oligonucleotides was used to evaluate morpholino and 2'-O
      methyl sugar-phosphate oligonucleotides. The assay is based on modification of
      the splicing pathway of human beta-globin pre-mRNA. In addition, scrape-loading
      of cells with oligonucleotides allows the separate assessment of intracellular
      antisense activity of the oligonucleotides and their ability to penetrate the
      cell membrane barrier. The results show that, with scrape-loading, the morpholino
      oligonucleotides were approximately 3-fold more effective in their intrinsic
      antisense activity than alternating phosphodiester/phosphorothioate 2'-O-methyl
      oligoribonucleotides and 6-9- and almost 200-fold more effective than the
      exclusively phosphorothioate and phosphodiester derivatives, respectively. The
      morpholino oligonucleotides were over 20-fold more effective than the
      phosphorothioate 2'-O-methyl-oligoribonucleotides in free uptake from the culture
      media. The antisense activity of the morpholino oligonucleotides was detectable
      not only in monolayer HeLa cells but also in suspension K562 cells. Time course
      experiments suggest that both the free uptake and efflux of morpholino
      oligonucleotides are slow.

PMID- 10419495
TI  - Characterization of PECI, a novel monofunctional Delta(3), Delta(2)-enoyl-CoA
      isomerase of mammalian peroxisomes.
AB  - We report here the identification and characterization of human and mouse PECI, a
      novel gene that encodes a monofunctional peroxisomal Delta(3),Delta(2)-enoyl-CoA
      isomerase. Human and mouse PECI were identified on the basis of their sequence
      similarity to Eci1p, a recently characterized peroxisomal Delta(3),Delta(2)-enoyl
      CoA isomerase from the yeast Saccharomyces cerevisiae. Cloning and sequencing of
      the human PECI cDNA revealed the presence of a 1077-base pair open reading frame
      predicted to encode a 359-amino acid protein with a mass of 39.6 kDa. The
      corresponding mouse cDNA contains a 1074-base pair open reading frame that
      encodes a 358-amino acid-long protein with a deduced mass of 39.4 kDa. Northern
      blot analysis demonstrated human PECI mRNA is expressed in all tissues. A
      bacterially expressed form of human PECI catalyzed the isomerization of 3-cis
      octenoyl-CoA to 2-trans-octenoyl-CoA with a specific activity of 27 units/mg of
      protein. The human and mouse PECI proteins contain type-1 peroxisomal targeting
      signals, and human PECI was localized to peroxisomes by both subcellular
      fractionation and immunofluorescence microscopy techniques. The potential roles
      for this monofunctional Delta(3),Delta(2)-enoyl-CoA isomerase in peroxisomal
      metabolism are discussed.

PMID- 10419494
TI  - Regulation of the protein kinase activity of Shaggy(Zeste-white3) by components
      of the wingless pathway in Drosophila cells and embryos.
AB  - The protein-serine kinase Shaggy(Zeste-white3) (Sgg(Zw3)) is the Drosophila
      homolog of mammalian glycogen synthase kinase-3 and has been genetically
      implicated in signal transduction pathways necessary for the establishment of
      patterning. Sgg(Zw3) is a putative component of the Wingless (Wg) pathway, and
      epistasis analyses suggest that Sgg(Zw3) function is repressed by Wg signaling.
      Here, we have investigated the biochemical consequences of Wg signaling with
      respect to the Sgg(Zw3) protein kinase in two types of Drosophila cell lines and
      in embryos. Our results demonstrate that Sgg(Zw3) activity is inhibited following
      exposure of cells to Wg protein and by expression of downstream components of Wg
      signaling, Drosophila frizzled 2 and dishevelled. Wg-dependent inactivation of
      Sgg(Zw3) is accompanied by serine phosphorylation. We also show that the level of
      Sgg(Zw3) activity regulates the stability of Armadillo protein and modulates the
      level of phosphorylation of D-Axin and Armadillo. Together, these results provide
      direct biochemical evidence in support of the genetic model of Wg signaling and
      provide a model for dissecting the molecular interactions between the signaling
      proteins.

PMID- 10419496
TI  - Interaction of an exchangeable apolipoprotein with phospholipid vesicles and
      lipoprotein particles. Role of leucines 32, 34, and 95 in Locusta migratoria
      apolipophorin III.
AB  - Apolipophorin III (apoLp-III) from Locusta migratoria is an exchangeable
      apolipoprotein that binds reversibly to lipid surfaces. In the lipid-free state
      this 164-residue protein exists as a bundle of five elongated amphipathic alpha
      helices. Upon lipid binding, apoLp-III undergoes a significant conformational
      change, resulting in exposure of its hydrophobic interior to the lipid
      environment. On the basis of x-ray crystallographic data (Breiter, D. R., Kanost,
      M. R., Benning, M. M., Wesenberg, G., Law, J. H., Wells, M. A., Rayment, I., and
      Holden, H. M. (1991) Biochemistry 30, 603-608), it was proposed that hydrophobic
      residues, present in loops that connect helices 1 and 2 (Leu-32 and Leu-34) and
      helices 3 and 4 (Leu-95), may function in initiation of lipid binding. To examine
      this hypothesis, mutant apoLp-IIIs were designed wherein the three Leu residues
      were replaced by Arg, individually or together. Circular dichroism spectroscopy
      and temperature and guanidine hydrochloride denaturation studies showed that the
      mutations did not cause major changes in secondary structure content or
      stability. In lipid binding assays, addition of apoLp-III to phospholipid
      vesicles caused a rapid clearance of vesicle turbidity due to transformation to
      discoidal complexes. L34R and L32R/L34R/L95R apoLp-IIIs displayed a much stronger
      interaction with lipid vesicles than wild-type apoLp-III. Furthermore, it was
      demonstrated that the mutant apoLp-IIIs retained their ability to bind to
      lipoprotein particles. However, in lipoprotein competition binding assays, the
      mutants displayed an impaired ability to initiate a binding interaction when
      compared with wild-type apoLp-III. The data indicate that the loops connecting
      helices 1 and 2 and helices 3 and 4 are critical regions in the protein,
      contributing to recognition of hydrophobic defects on lipoprotein surfaces by
      apoLp-III.

PMID- 10419497
TI  - Chlorophyll b to chlorophyll a conversion precedes chlorophyll degradation in
      Hordeum vulgare L.
AB  - This study reveals by in vivo deuterium labeling that in higher plants
      chlorophyll (Chl) b is converted to Chl a before degradation. For this purpose,
      de-greening of excised green primary leaves of barley (Hordeum vulgare) was
      induced by permanent darkness in the presence of heavy water (80 atom % (2)H).
      The resulting Chl a catabolite in the plant extract was subjected to chemical
      degradation by chromic acid. 3-(2-Hydroxyethyl)-4-methyl-maleimide, the key
      fragment that originates from the Chl catabolite, was isolated. High resolution
      (1)H-, (2)H-NMR and mass spectroscopy unequivocally demonstrates that a fraction
      of this maleimide fragment consists of a mono-deuterated methyl group. These
      results suggest that Chl b is converted into Chl a before degradation.
      Quantification proves that the initial ratio of Chl a:Chl b in the green plant is
      preserved to about 60-70% in the catabolite composition isolated from yellowing
      leaves. The incorporation of only one deuterium atom indicates the involvement of
      two distinguishable redox enzymes during the conversion.

PMID- 10419498
TI  - Bethlem myopathy and engineered collagen VI triple helical deletions prevent
      intracellular multimer assembly and protein secretion.
AB  - Mutations in the genes that code for collagen VI subunits, COL6A1, COL6A2, and
      COL6A3, are the cause of the autosomal dominant disorder, Bethlem myopathy.
      Although three different collagen VI structural mutations have previously been
      reported, the effect of these mutations on collagen VI assembly, structure, and
      function is currently unknown. We have characterized a new Bethlem myopathy
      mutation that results in skipping of COL6A1 exon 14 during pre-mRNA splicing and
      the deletion of 18 amino acids from the triple helical domain of the alpha1(VI)
      chain. Sequencing of genomic DNA identified a G to A transition in the +1
      position of the splice donor site of intron 14 in one allele. The mutant
      alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to
      form disulfide-bonded monomers, but further assembly into dimers and tetramers
      was prevented, and molecules containing the mutant chain were not secreted. This
      triple helical deletion thus resulted in production of half the normal amount of
      collagen VI. To further explore the biosynthetic consequences of collagen VI
      triple helical deletions, an alpha3(VI) cDNA expression construct containing a
      202-amino acid deletion within the triple helix was produced and stably expressed
      in SaOS-2 cells. The transfected mutant alpha3(VI) chains associated with
      endogenous alpha1(VI) and alpha2(VI) to form collagen VI monomers, but dimers and
      tetramers did not form and the mutant-containing molecules were not secreted.
      Thus, deletions within the triple helical region of both the alpha1(VI) and
      alpha3(VI) chains can prevent intracellular dimer and tetramer assembly and
      secretion. These results provide the first evidence of the biosynthetic
      consequences of structural collagen VI mutations and suggest that functional
      protein haploinsufficiency may be a common pathogenic mechanism in Bethlem
      myopathy.

PMID- 10419499
TI  - Pseudomonas aeruginosa exoenzyme S disrupts Ras-mediated signal transduction by
      inhibiting guanine nucleotide exchange factor-catalyzed nucleotide exchange.
AB  - Pseudomonas aeruginosa exoenzyme S double ADP-ribosylates Ras at Arg(41) and
      Arg(128). Since Arg(41) is adjacent to the switch 1 region of Ras, ADP
      ribosylation could interfere with Ras-mediated signal transduction via several
      mechanisms, including interaction with Raf, or guanine nucleotide exchange factor
      stimulated or intrinsic nucleotide exchange. Initial experiments showed that ADP
      ribosylated Ras (ADP-r-Ras) and unmodified Ras (Ras) interacted with Raf with
      equal efficiencies, indicating that ADP-ribosylation did not interfere with Ras
      Raf interactions. While ADP-r-Ras and Ras possessed equivalent intrinsic
      nucleotide exchange rates, guanine nucleotide exchange factor (Cdc25) stimulated
      the nucleotide exchange of ADP-r-Ras at a 3-fold slower rate than Ras. ADP-r-Ras
      did not affect the nucleotide exchange of Ras, indicating that the ADP
      ribosylation of Ras was not a dominant negative phenotype. Ras-R41K and ADP-r-Ras
      R41K possessed similar exchange rates as Ras, indicating that ADP-ribosylation at
      Arg(128) did not inhibit Cdc25-stimulated nucleotide exchange. Consistent with
      the slower nucleotide exchange rate of ADP-r-Ras as compared with Ras, ADP-r-Ras
      bound its guanine nucleotide exchange factor (Cdc25) less efficiently than Ras in
      direct binding experiments. Together, these data indicate that ADP-ribosylation
      of Ras at Arg(41) disrupts Ras-Cdc25 interactions, which inhibits the rate
      limiting step in Ras signal transduction, the activation of Ras by its guanine
      nucleotide exchange factor.

PMID- 10419500
TI  - Purification, cDNA cloning, and expression of GDP-L-Fuc:Asn-linked GlcNAc
      alpha1,3-fucosyltransferase from mung beans.
AB  - Substitution of the asparagine-linked GlcNAc by alpha1,3-linked fucose is a
      widespread feature of plant as well as of insect glycoproteins, which renders the
      N-glycan immunogenic. We have purified from mung bean seedlings the GDP-L-Fuc:Asn
      linked GlcNAc alpha1,3-fucosyltransferase (core alpha1,3-fucosyltransferase) that
      is responsible for the synthesis of this linkage. The major isoform had an
      apparent mass of 54 kDa and isoelectric points ranging from 6. 8 to 8.2. From
      that protein, four tryptic peptides were isolated and sequenced. Based on an
      approach involving reverse transcriptase-polymerase chain reaction with
      degenerate primers and rapid amplification of cDNA ends, core alpha1,3
      fucosyltransferase cDNA was cloned from mung bean mRNA. The 2200-base pair cDNA
      contained an open reading frame of 1530 base pairs that encoded a 510-amino acid
      protein with a predicted molecular mass of 56.8 kDa. Analysis of cDNA derived
      from genomic DNA revealed the presence of three introns within the open reading
      frame. Remarkably, from the four exons, only exon II exhibited significant
      homology to animal and bacterial alpha1,3/4-fucosyltransferases which, though,
      are responsible for the biosynthesis of Lewis determinants. The recombinant
      fucosyltransferase was expressed in Sf21 insect cells using a baculovirus vector.
      The enzyme acted on glycopeptides having the glycan structures GlcNAcbeta1
      2Manalpha1-3(GlcNAcbeta1-2Manalpha1- 6)Manbeta1-4GlcNAcbet a1-4GlcNAcbeta1-Asn,
      GlcNAcbeta1-2Manalpha1-3(GlcNAcbeta1-2Manalpha1- 6)Manbeta1-4GlcNAcbet a1
      4(Fucalpha1-6)GlcNAcbeta1-Asn, and GlcNAcbeta1-2Manalpha1-3[Manalpha1-3(Manalpha1
      6 )Manalpha1-6]Manbeta1 -4GlcNAcbeta1-4GlcNAcbeta1-Asn but not on, e.g. N
      acetyllactosamine. The structure of the core alpha1,3-fucosylated product was
      verified by high performance liquid chromatography of the pyridylaminated glycan
      and by its insensitivity to N-glycosidase F as revealed by matrix-assisted laser
      desorption/ionization time of flight mass spectrometry.

PMID- 10419502
TI  - Differential fMet-Leu-Phe- and platelet-activating factor-induced signaling
      toward Ral activation in primary human neutrophils.
AB  - We have measured the activation of the small GTPase Ral in human neutrophils
      after stimulation with fMet-Leu-Phe (fMLP), platelet activating factor (PAF), and
      granulocyte macrophage-colony stimulating factor and compared it with the
      activation of two other small GTPases, Ras and Rap1. We found that fMLP and PAF,
      but not granulocyte macrophage-colony stimulating factor, induce Ral activation.
      All three stimuli induce the activation of both Ras and Rap1. Utilizing specific
      inhibitors we demonstrate that fMLP-induced Ral activation is mediated by
      pertussis toxin-sensitive G-proteins and partially by Src-like kinases, whereas
      fMLP-induced Ras activation is independent of Src-like kinases. PAF-induced Ral
      activation is mediated by pertussis toxin-insensitive proteins, Src-like kinases
      and phosphatidylinositol 3-kinase. Phosphatidylinositol 3-kinase is not involved
      in PAF-induced Ras activation. The calcium ionophore ionomycin activates Ral, but
      calcium depletion partially inhibits fMLP- and PAF-induced Ral activation,
      whereas Ras activation was not affected. In addition, 12-O-tetradecanoylphorbol
      13-acetate-induced activation of Ral is completely abolished by inhibitors of
      protein kinase C, whereas 12-O-tetradecanoylphorbol-13-acetate-induced Ras
      activation is largely insensitive. We conclude that in neutrophils Ral activation
      is mediated by multiple pathways, and that fMLP and PAF induce Ral activation
      differently.

PMID- 10419503
TI  - The crystal structure of a penicilloyl-serine transferase of intermediate
      penicillin sensitivity. The DD-transpeptidase of streptomyces K15.
AB  - The serine DD-transpeptidase/penicillin-binding protein of Streptomyces K15
      catalyzes peptide bond formation in a way that mimics the penicillin-sensitive
      peptide cross-linking reaction involved in bacterial cell wall peptidoglycan
      assembly. The Streptomyces K15 enzyme is peculiar in that it can be considered as
      an intermediate between classical penicillin-binding proteins, for which
      benzylpenicillin is a very efficient inactivator, and the resistant penicillin
      binding proteins that have a low penicillin affinity. With its moderate
      penicillin sensitivity, the Streptomyces K15 DD-transpeptidase would be helpful
      in the understanding of the structure-activity relationship of this penicillin
      recognizing protein superfamily. The structure of the Streptomyces K15 enzyme has
      been determined by x-ray crystallography at 2.0-A resolution and refined to an R
      factor of 18.6%. The fold adopted by this 262-amino acid polypeptide generates a
      two-domain structure that is close to those of class A beta-lactamases. However,
      the Streptomyces K15 enzyme has two particular structural features. It lacks the
      amino-terminal alpha-helix found in the other penicilloyl-serine transferases,
      and it exhibits, at its surface, an additional four-stranded beta-sheet. These
      two characteristics might serve to anchor the enzyme in the plasma membrane. The
      overall topology of the catalytic pocket of the Streptomyces K15 enzyme is also
      comparable to that of the class A beta-lactamases, except that the Omega-loop,
      which bears the essential catalytic Glu(166) residue in the class A beta
      lactamases, is entirely modified. This loop adopts a conformation similar to
      those found in the Streptomyces R61 DD-carboxypeptidase and class C beta
      lactamases, with no equivalent acidic residue.

PMID- 10419501
TI  - Induction of tenascin-C in cardiac myocytes by mechanical deformation. Role of
      reactive oxygen species.
AB  - Mechanical overload may change cardiac structure through angiotensin II-dependent
      and angiotensin II-independent mechanisms. We investigated the effects of
      mechanical strain on the gene expression of tenascin-C, a prominent extracellular
      molecule in actively remodeling tissues, in neonatal rat cardiac myocytes.
      Mechanical strain induced tenascin-C mRNA (3.9 +/- 0.5-fold, p < 0.01, n = 13)
      and tenascin-C protein in an amplitude-dependent manner but did not induce
      secreted protein acidic and rich in cysteine nor fibronectin. RNase protection
      assay demonstrated that mechanical strain induced all three alternatively spliced
      isoforms of tenascin-C. An angiotensin II receptor type 1 antagonist inhibited
      mechanical induction of brain natriuretic peptide but not tenascin-C.
      Antioxidants such as N-acetyl-L-cysteine, catalase, and 1, 2-dihydroxy-benzene
      3,5-disulfonate significantly inhibited induction of tenascin-C. Truncated
      tenascin-C promoter-reporter assays using dominant negative mutants of
      IkappaBalpha and IkappaB kinase beta and electrophoretic mobility shift assays
      indicated that mechanical strain increases tenascin-C gene transcription by
      activating nuclear factor-kappaB through reactive oxygen species. Our findings
      demonstrate that mechanical strain induces tenascin-C in cardiac myocytes through
      a nuclear factor-kappaB-dependent and angiotensin II-independent mechanism. These
      data also suggest that reactive oxygen species may participate in mechanically
      induced left ventricular remodeling.

PMID- 10419504
TI  - Mutations in the leucine zipper motif and sterol-sensing domain inactivate the
      Niemann-Pick C1 glycoprotein.
AB  - Niemann-Pick type C (NPC) disease, characterized by accumulation of low density
      lipoprotein-derived free cholesterol in lysosomes, is caused by mutations in the
      NPC1 gene. We examined the ability of wild-type NPC1 and NPC1 mutants to correct
      the NPC sterol trafficking defect and their subcellular localization in CT60
      cells. Cells transfected with wild-type NPC1 expressed 170- and 190-kDa proteins.
      Tunicamycin treatment resulted in a 140-kDa protein, the deduced size of NPC1,
      suggesting that NPC1 is N-glycosylated. Mutation of all four asparagines in
      potential N-terminal N-glycosylation sites to glutamines resulted in a 20-kDa
      reduction of the expressed protein. Proteins with a single N-glycosylation site
      mutation localized to late endosome/lysosomal compartments, as did wild-type
      NPC1, and each corrected the cholesterol trafficking defect. However, mutation of
      all four potential N-glycosylation sites reduced ability to correct the NPC
      phenotype commensurate with reduced expression of the protein. Mutations in the
      putative sterol-sensing domain resulted in inactive proteins targeted to
      lysosomal membranes encircling cholesterol-laden cores. N-terminal leucine zipper
      motif mutants could not correct the NPC defect, although they accumulated in
      lysosomal membranes. We conclude that NPC1 is a glycoprotein that must have an
      intact sterol-sensing domain and leucine zipper motif for cholesterol-mobilizing
      activity.

PMID- 10419505
TI  - Chloroethylclonidine and 2-aminoethyl methanethiosulfonate recognize two
      different conformations of the human alpha(2A)-adrenergic receptor.
AB  - The substituted cysteine-accessibility method and two sulfhydryl-specific
      reagents, the methane-thiosulfonate derivative 2-aminoethyl methanethiosulfonate
      (MTSEA) and the alpha(2)-adrenergic receptor (alpha(2)-AR) agonist
      chloroethylclonidine (CEC), were used to determine the relative accessibility of
      engineered cysteines in the fifth transmembrane domain of the human alpha(2A)-AR
      (Halpha2A). The second-order rate constants for the reaction of the receptor with
      MTSEA and CEC were determined with the wild type Halpha2A (cysteine at position
      201) and receptor mutants containing accessible cysteines at other positions
      within the binding-site crevice (positions 197, 200, and 204). The rate of
      reaction of CEC was similar to that of MTSEA at residues Cys-197, Cys-201, and
      Cys-204. The rate of reaction of CEC with Cys-200, however, was more than 5 times
      that of MTSEA, suggesting that these compounds may interact with two different
      receptor conformations. MTSEA, having no recognition specificity for the
      receptor, likely reacts with the predominant inactive receptor conformation (R),
      whereas the agonist CEC may stabilize and react preferentially with the active
      receptor conformation (R*). This hypothesis was consistent with three-dimensional
      receptor-ligand models, which further suggest that alpha(2A)-AR activation may
      involve the clockwise rotation of transmembrane domain 5.

PMID- 10419506
TI  - C-terminal truncations destabilize the cystic fibrosis transmembrane conductance
      regulator without impairing its biogenesis. A novel class of mutation.
AB  - Defective cAMP-stimulated chloride conductance of the plasma membrane of
      epithelial cell is the hallmark of cystic fibrosis (CF) and results from
      mutations in the cystic fibrosis transmembrane conductance regulator, CFTR. In
      the majority of CF patients, mutations in the CFTR lead to its misfolding and
      premature degradation at the endoplasmic reticulum (ER). Other mutations impair
      the cAMP-dependent activation or the ion conductance of CFTR chloride channel. In
      the present work we identify a novel mechanism leading to reduced expression of
      CFTR at the cell surface, caused by C-terminal truncations. The phenotype of C
      terminally truncated CFTR, representing naturally occurring premature termination
      and frameshift mutations, were examined in transient and stable heterologous
      expression systems. Whereas the biosynthesis, processing, and macroscopic
      chloride channel function of truncated CFTRs are essentially normal, the
      degradation rate of the mature, complex-glycosylated form is 5- to 6-fold faster
      than the wild type CFTR. These experiments suggest that the C terminus has a
      central role in maintaining the metabolic stability of the complex-glycosylated
      CFTR following its exit from the ER and provide a plausible explanation for the
      severe phenotype of CF patients harboring C-terminal truncations.

PMID- 10419508
TI  - Structural conservation of the pores of calcium-activated and voltage-gated
      potassium channels determined by a sea anemone toxin.
AB  - The structurally defined sea anemone peptide toxins ShK and BgK potently block
      the intermediate conductance, Ca(2+)-activated potassium channel IKCa1, a well
      recognized therapeutic target present in erythrocytes, human T-lymphocytes, and
      the colon. The well characterized voltage-gated Kv1.3 channel in human T
      lymphocytes is also blocked by both peptides, although ShK has a approximately
      1,000-fold greater affinity for Kv1.3 than IKCa1. To gain insight into the
      architecture of the toxin receptor in IKCa1, we used alanine-scanning in
      combination with mutant cycle analyses to map the ShK-IKCa1 interface, and
      compared it with the ShK-Kv1.3 interaction surface. ShK uses the same five core
      residues, all clustered around the critical Lys(22), to interact with IKCa1 and
      Kv1.3, although it relies on a larger number of contacts to stabilize its weaker
      interactions with IKCa1 than with Kv1.3. The toxin binds to IKCa1 in a region
      corresponding to the external vestibule of Kv1.3, and the turret and outer pore
      of the structurally defined bacterial potassium channel, KcsA. Based on the NMR
      structure of ShK, we deduce the toxin receptor in IKCa1 to have x-y dimensions of
      approximately 22 A, a diameter of approximately 31 A, and a depth of
      approximately 8 A; we estimate that the ion selectivity lies approximately 13 A
      below the outer lip of the toxin receptor. These dimensions are in good agreement
      with those of the KcsA channel determined from its crystal structure, and the
      inferred structure of Kv1.3 based on mapping with scorpion toxins. Thus, these
      distantly related channels exhibit architectural similarities in the outer pore
      region. This information could facilitate development of specific and potent
      modulators of the therapeutically important IKCa1 channel.

PMID- 10419507
TI  - Engineering novel cell surface receptors for virus-mediated gene transfer.
AB  - The absence of viral receptors is a major barrier to efficient gene transfer in
      many cells. To overcome this barrier, we developed an artificial receptor based
      on expression of a novel sugar. We fed cells an unnatural monosaccharide, a
      modified mannosamine that replaced the acetyl group with a levulinate group
      (ManLev). ManLev was metabolized and incorporated into cell-surface
      glycoconjugates. The synthetic sugar decorated the cell surface with a unique
      ketone group that served as a foundation on which we built an adenovirus receptor
      by covalently binding biotin hydrazide to the ketone. The artificial receptor
      enhanced adenoviral vector binding and gene transfer to cells that are relatively
      resistant to adenovirus infection. These data are the first to suggest the
      feasibility of a strategy that improves the efficiency of gene transfer by using
      the biosynthetic machinery of the cell to engineer novel sugars on the cell
      surface.

PMID- 10419510
TI  - Interaction of mitogen-activated protein kinases with the kinase interaction
      motif of the tyrosine phosphatase PTP-SL provides substrate specificity and
      retains ERK2 in the cytoplasm.
AB  - ERK1 and ERK2 associate with the tyrosine phosphatase PTP-SL through a kinase
      interaction motif (KIM) located in the juxtamembrane region of PTP-SL. A
      glutathione S-transferase (GST)-PTP-SL fusion protein containing the KIM
      associated with ERK1 and ERK2 as well as with p38/HOG, but not with the related
      JNK1 kinase or with protein kinase A or C. Accordingly, ERK2 showed in vitro
      substrate specificity to phosphorylate GST-PTP-SL in comparison with GST-c-Jun.
      Furthermore, tyrosine dephosphorylation of ERK2 by the PTP-SLDeltaKIM mutant was
      impaired. The in vitro association of ERK1/2 with GST-PTP-SL was highly stable;
      however, low concentrations of nucleotides partially dissociated the ERK1/2.PTP
      SL complex. Partial deletions of the KIM abrogated the association of PTP-SL with
      ERK1/2, indicating that KIM integrity is required for interaction. Amino acid
      substitution analysis revealed that Arg and Leu residues within the KIM are
      essential for the interaction and suggested a regulatory role for Ser(231).
      Finally, coexpression of PTP-SL and ERK2 in COS-7 cells resulted in the retention
      of ERK2 in the cytoplasm in a KIM-dependent manner. Our results demonstrate that
      the noncatalytic region of PTP-SL associates with mitogen-activated protein
      kinases with high affinity and specificity, providing a mechanism for substrate
      specificity, and suggest a role for PTP-SL in the regulation of mitogen-activated
      protein kinase translocation to the nucleus upon activation.

PMID- 10419509
TI  - Antisense inhibition of hyaluronan synthase-2 in human articular chondrocytes
      inhibits proteoglycan retention and matrix assembly.
AB  - In order to define the role of cell-associated hyaluronan in cartilage matrix
      retention, human articular chondrocytes as well as cartilage slices were treated
      with phosphorothioate oligonucleotides comprised of sequence antisense to the
      mRNA of human HA synthase-2 (HAS-2). As a prerequisite for these studies, it was
      necessary to determine which HA synthase (HAS), of three separate human genes
      capable of synthesizing HA, designated HAS-1, HAS-2, or HAS-3, is primarily
      responsible for HA synthesis in human articular chondrocytes. The copy number of
      each HAS mRNA expressed in cultured human articular chondrocytes was determined
      using quantitative (competitive) reverse transcription-polymerase chain reaction
      (RT-PCR). Only HAS-2 and HAS-3 mRNA expression was detected. The level of HAS-2
      mRNA expression was 40-fold higher than that of HAS-3. Cultures of human
      articular chondrocytes and cartilage tissue slices were then transfected with HAS
      2-specific antisense oligonucleotides. This treatment resulted in time-dependent
      inhibition of HAS-2 mRNA expression, as measured by quantitative RT-PCR, and a
      significant loss of cell-associated HA staining. Sense and reverse HAS-2
      oligonucleotides showed no effect. The consequences of reduced HA levels (due to
      HAS-2 antisense inhibition) were a decrease in the diameter of the cell
      associated matrix and a decreased capacity to retain newly synthesized
      proteoglycan. These results suggest that HA synthesized by HAS-2 plays a crucial
      role in matrix assembly and retention by human articular chondrocytes.

PMID- 10419511
TI  - Calcineurin is required for skeletal muscle hypertrophy.
AB  - Molecular signaling pathways linking increases in skeletal muscle usage to
      alterations in muscle size have not been identified. In the present study, we
      tested the hypothesis that calcineurin, a calcium-regulated phosphatase recently
      implicated in the signaling of some forms of cardiomyopathic growth, is required
      to induce skeletal muscle hypertrophy and muscle fiber type conversions
      associated with functional overload in vivo. Administration of the specific
      calcineurin inhibitors cyclosporin (CsA) or FK506 to mice, for which the fast
      plantaris muscle was overloaded for 1-4 weeks, prevented the rapid doubling of
      mass and individual fiber size and the 4-20-fold increase in the number of slow
      fibers that characterize this condition. CsA treatment influenced the expression
      of muscle myofibrillar protein genes in a way reflective of fiber phenotype
      transformations but only in the long term of the overload condition, suggesting
      that the control of this growth response by calcineurin is not limited to the
      transcriptional activation of these muscle-specific genes. Clinically, these
      results provide insight to the post-surgical muscle wasting and weakness observed
      in recovering transplant recipients administered therapeutic dosages of these
      immunosuppressants.

PMID- 10419512
TI  - The II-III loop of the skeletal muscle dihydropyridine receptor is responsible
      for the Bi-directional coupling with the ryanodine receptor.
AB  - The dihydropyridine receptor (DHPR) in the skeletal muscle plasmalemma functions
      as both voltage-gated Ca(2+) channel and voltage sensor for excitation
      contraction (EC) coupling. As voltage sensor, the DHPR regulates intracellular
      Ca(2+) release via the skeletal isoform of the ryanodine receptor (RyR-1).
      Interaction with RyR-1 also feeds back to increase the Ca(2+) current mediated by
      the DHPR. To identify regions of the DHPR important for receiving this signal
      from RyR-1, we expressed in dysgenic myotubes a chimera (SkLC) having skeletal
      (Sk) DHPR sequence except for a cardiac (C) II-III loop (L). Tagging with green
      fluorescent protein (GFP) enabled identification of expressing myotubes. Dysgenic
      myotubes expressing GFP-SkLC or SkLC lacked EC coupling and had very small Ca(2+)
      currents. Introducing a short skeletal segment (alpha(1S) residues 720-765) into
      the cardiac II-III loop (replacing alpha(1C) residues 851-896) of GFP-SkLC
      restored both EC coupling and Ca(2+) current densities like those of the wild
      type skeletal DHPR. This 46-amino acid stretch of skeletal sequence was recently
      shown to be capable of transferring strong, skeletal-type EC coupling to an
      otherwise cardiac DHPR (Nakai, J., Tanabe, T., Konno, T., Adams, B., and Beam,
      K.G. (1998) J. Biol. Chem. 273, 24983-24986). Thus, this segment of the skeletal
      II-III loop contains a motif required for both skeletal-type EC coupling and RyR
      1-mediated enhancement of Ca(2+) current.

PMID- 10419513
TI  - Expression of peroxisome proliferator-activated receptor PPARdelta promotes
      induction of PPARgamma and adipocyte differentiation in 3T3C2 fibroblasts.
AB  - Nutritional long chain fatty acids control adipose tissue mass by regulating the
      number and the size of adipocytes. The molecular mechanisms implicated in this
      action of fatty acids remain poorly understood. It has been well established that
      peroxisome proliferator-activated receptor (PPAR) gamma, activated by specific
      prostanoids, plays a central role in the control of adipocyte gene expression and
      terminal differentiation. Thus far, the role of PPARdelta in the control of
      adipose tissue mass has remained unclear. Herein, we report the effects of
      ectopically expressed PPARdelta on the control of adipose-related gene expression
      and adipogenesis of 3T3C2 fibroblasts. Treatment of PPARdelta-expressing
      fibroblasts with fatty acids alone did not stimulate adipogenesis, whereas
      exposure of cells to a combination of fatty acids and PPARgamma activators
      promoted lipid accumulation and expression of a typical adipocyte program. At the
      molecular level, activation of PPARdelta by fatty acids induced transcription of
      the genes encoding fatty acid transporter, adipocyte lipid-binding protein, and
      PPARgamma. Subsequent activation of PPARgamma by specific agonists appeared to be
      required to promote terminal differentiation. These data demonstrate that
      PPARgamma gene expression is under the control of PPARdelta activated by fatty
      acids and could explain, at least partially, the adipogenic action of nutritional
      fatty acids.

PMID- 10419514
TI  - 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth
      muscle proliferation by preventing rho GTPase-induced down-regulation of
      p27(Kip1).
AB  - The mechanism by which platelet-derived growth factor (PDGF) regulates vascular
      smooth muscle cell (SMC) DNA synthesis is unknown, but may involve isoprenoid
      intermediates of the cholesterol biosynthetic pathway. Inhibition of isoprenoid
      synthesis with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor,
      simvastatin (Sim, 1-10 microM), inhibited PDGF-induced SMC DNA synthesis by >95%,
      retinoblastoma gene product hyperphosphorylation by 90%, and cyclin-dependent
      kinases (cdk)-2, -4, and -6 activity by 80 +/- 5, 50 +/- 3, and 48 +/- 3%,
      respectively. This correlated with a 20-fold increase in p27(Kip1) without
      changes in p16, p21(Waf1), or p53 levels compared with PDGF alone. Since Ras and
      Rho require isoprenoid modification for membrane localization and are implicated
      in cell cycle regulation, we investigated the effects of Sim on Ras and Rho. Up
      regulation of p27(Kip1) and inhibition of Rho but not Ras membrane translocation
      by Sim were reversed by geranylgeranylpyrophosphate, but not
      farnesylpyrophosphate. Indeed, inhibition of Rho by Clostridium botulinum C3
      transferase or overexpression of dominant-negative N19RhoA mutant increased
      p27(Kip1) and inhibited retinoblastoma hyperphosphorylation. In contrast,
      activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 decreased
      p27(Kip1) and increased SMC DNA synthesis. These findings indicate that the down
      regulation of p27(Kip1) by Rho GTPase mediates PDGF-induced SMC DNA synthesis and
      suggest a novel direct effect of 3-hydroxy-3-methylglutaryl-CoA reductase
      inhibitors on the vascular wall.

PMID- 10419515
TI  - Ion channel activity of the BH3 only Bcl-2 family member, BID.
AB  - BID is a member of the BH3-only subgroup of Bcl-2 family proteins that displays
      pro-apoptotic activity. The NH(2)-terminal region of BID contains a caspase-8
      (Casp-8) cleavage site and the cleaved form of BID translocates to mitochondrial
      membranes where it is a potent inducer of cytochrome c release. Secondary
      structure and fold predictions suggest that BID has a high degree of alpha
      helical content and structural similarity to Bcl-X(L), which itself is highly
      similar to bacterial pore-forming toxins. Moreover, circular dichroism analysis
      confirmed a high alpha-helical content of BID. Amino-terminal truncated BIDDelta1
      55, mimicking the Casp-8-cleaved molecule, formed channels in planar bilayers at
      neutral pH and in liposomes at acidic pH. In contrast, full-length BID displayed
      channel activity only at nonphysiological pH 4.0 (but not at neutral pH) in
      planar bilayers and failed to form channels in liposomes even under acidic
      conditions. On a single channel level, BIDDelta1-55 channels were voltage-gated
      and exhibited multiconductance behavior at neutral pH. When full-length BID was
      cleaved by Casp-8, it too demonstrated channel activity similar to that seen with
      BIDDelta1-55. Thus, BID appears to share structural and functional similarity
      with other Bcl-2 family proteins known to have channel-forming activity, but its
      activity exhibits a novel form of activation: proteolytic cleavage.

PMID- 10419516
TI  - Potent neuroprotective properties against the Alzheimer beta-amyloid by an
      endogenous melatonin-related indole structure, indole-3-propionic acid.
AB  - Widespread cerebral deposition of a 40-43-amino acid peptide called the amyloid
      beta-protein (Abeta) in the form of amyloid fibrils is one of the most prominent
      neuropathologic features of Alzheimer's disease. Numerous studies suggest that
      Abeta is toxic to neurons by free radical-mediated mechanisms. We have previously
      reported that melatonin prevents oxidative stress and death of neurons exposed to
      Abeta. In the process of screening indole compounds for neuroprotection against
      Abeta, potent neuroprotective properties were uncovered for an endogenous related
      species, indole-3-propionic acid (IPA). This compound has previously been
      identified in the plasma and cerebrospinal fluid of humans, but its functions are
      not known. IPA completely protected primary neurons and neuroblastoma cells
      against oxidative damage and death caused by exposure to Abeta, by inhibition of
      superoxide dismutase, or by treatment with hydrogen peroxide. In kinetic
      competition experiments using free radical-trapping agents, the capacity of IPA
      to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine
      considered to be the most potent naturally occurring scavenger of free radicals.
      In contrast with other antioxidants, IPA was not converted to reactive
      intermediates with pro-oxidant activity. These findings may have therapeutic
      applications in a broad range of clinical situations.

PMID- 10419517
TI  - Subcellular localization, stoichiometry, and protein levels of 26 S proteasome
      subunits in yeast.
AB  - The 26 S proteasome of eukaryotes is responsible for the degradation of proteins
      targeted for proteolysis by the ubiquitin system. Yeast has been an important
      model organism for understanding eukaryotic proteasome structure and function.
      Toward a quantitative characterization of the proteasome, we have determined the
      localization, cellular levels, and stoichiometry of proteasome subunits. The
      subcellular localization of two ATPase components of the regulatory complex of
      the proteasome, Sug2/Rpt4 and Sug1/Rpt6, and a subunit of the 20 S proteasome,
      Pre1, were determined by immunofluorescence. In contrast to findings in
      multicellular organisms, these proteins are localized almost exclusively to the
      nucleus throughout the cell cycle. We have also determined the cellular abundance
      and stoichiometry of these proteasome subunits. Sug1/Rpt6, Sug2/Rpt4, and Pre1
      are present in roughly equal stoichiometry with an abundance of 15,000-30,000
      molecules/cell, corresponding to a concentration of 13-26 microM in the nucleus.
      Also, in contrast to mammalian cells, we find no evidence of a p27-containing
      "modulator" of the proteasome in yeast. This information will be useful in
      comparing and contrasting the yeast and mammalian proteasomes and should
      contribute to a mechanistic understanding of how this complex functions.

PMID- 10419518
TI  - Caspase independent/dependent regulation of K(+), cell shrinkage, and
      mitochondrial membrane potential during lymphocyte apoptosis.
AB  - The loss of cell volume is a fundamental feature of apoptosis. We have previously
      shown that DNA degradation and caspase activity occur only in cells which have
      shrunken as a result of potassium and sodium efflux (Bortner, C. D., Hughes, F.
      M., Jr., and Cidlowski, J. A. (1997) J. Biol. Chem. 272, 32436-32442).
      Furthermore, maintaining a normal intracellular potassium concentration represses
      the cell death process by inhibiting the activity of apoptotic nucleases and
      suppressing the activation of effector caspases (Hughes, F. M., Jr., Bortner, C.
      D. Purdy, G. D., and Cidlowski, J. A. (1997) J. Biol. Chem. 272, 30567-30576). We
      have now investigated the relationship between cell shrinkage, ion efflux, and
      changes in the mitochondrial membrane potential, in addition to the role of
      caspases in these apoptotic events. Treatment of Jurkat cells with a series of
      inducers which act via distinct signal transduction pathways, resulted in all of
      the cell death characteristics including loss of cell viability, cell shrinkage,
      K(+) efflux, altered mitochondrial membrane potential, and DNA fragmentation.
      Interestingly, only cells which shrunk had a loss of mitochondrial membrane
      potential and the other apoptotic characteristics. Treatment of Jurkat cells with
      an anti-Fas antibody in the presence of the general caspase inhibitor z-VAD,
      abrogated these features. In contrast, when Jurkat cells were treated with either
      the calcium ionophore A23187 or thapsigargin, z-VAD failed to prevent cell
      shrinkage, K(+) efflux, or changes in the mitochondrial membrane potential, while
      effectively inhibiting DNA degradation. Treatment of Jurkat cells with various
      apoptotic agents in the presence of either the caspase-3 inhibitor DEVD, or the
      caspase-8 inhibitor IETD also blocked DNA degradation, but failed to prevent
      other characteristics of apoptosis. Together these data suggest that the cell
      shrinkage, K(+) efflux, and changes in the mitochondrial membrane potential are
      tightly coupled, but occur independent of DNA degradation, and can be largely
      caspase independent depending on the particular signal transduction pathway.

PMID- 10419519
TI  - 26 S proteasome-mediated production of an authentic major histocompatibility
      class I-restricted epitope from an intact protein substrate.
AB  - Peptides displayed on the cell surface by major histocompatibility class I
      molecules (MHC class I) are generated by proteolytic processing of protein
      antigens in the cytoplasm. Initially, antigens are degraded by the 26 S
      proteasome, most probably following ubiquitination. However, it is unclear
      whether this proteolysis results in the generation of MHC class I ligands or if
      further processing is required. To investigate the role of the 26 S proteasome in
      antigen presentation, we analyzed the processing of an intact antigen by purified
      26 S proteasome. A recombinant ornithine decarboxylase was produced harboring the
      H-2K(b)-restricted peptide epitope, derived from ovalbumin SIINFEKL (termed ODC
      ova). Utilizing recombinant antizyme to target the antigen to the 26 S
      proteasome, we found that proteolysis of ODC-ova by the 26 S proteasome resulted
      in the generation of the K(b)-ligand. Mass spectrometry analysis indicated that
      in addition to SIINFEKL, the N-terminally extended ligand, HSIINFEKL, was also
      generated. Production of SIINFEKL was linear with time and directly proportional
      to the rate of ODC-ova degradation. The overall yield of SIINFEKL was
      approximately 5% of the amount of ODC-ova degraded. The addition of PA28, the 20
      S, or the 20 S-PA28 complex to the 26 S proteasome did not significantly affect
      the yield of the antigenic peptide. These findings demonstrate that the 26 S
      proteasome can efficiently digest an intact physiological substrate and generate
      an authentic MHC class I-restricted epitope.

PMID- 10419520
TI  - Membrane topology of S2P, a protein required for intramembranous cleavage of
      sterol regulatory element-binding proteins.
AB  - In sterol-depleted mammalian cells, a two-step proteolytic process releases the
      NH(2)-terminal domains of sterol regulatory element-binding proteins (SREBPs)
      from membranes of the endoplasmic reticulum (ER). These domains translocate into
      the nucleus, where they activate genes of cholesterol and fatty acid
      biosynthesis. The SREBPs are oriented in the membrane in a hairpin fashion, with
      the NH(2)- and COOH-terminal domains facing the cytosol and a single hydrophilic
      loop projecting into the lumen. The first cleavage occurs at Site-1 within the ER
      lumen to generate an intermediate that is subsequently released from the membrane
      by cleavage at Site-2, which lies within the first transmembrane domain. A
      membrane protein, designated S2P, a putative zinc metalloprotease, is required
      for this cleavage. Here, we use protease protection and glycosylation site
      mapping to define the topology of S2P in ER membranes. Both the NH(2) and COOH
      termini of S2P face the cytosol. Most of S2P is hydrophobic and appears to be
      buried in the membrane. All three of the long hydrophilic sequences of S2P can be
      glycosylated, indicating that they all project into the lumen. The HEIGH sequence
      of S2P, which contains two potential zinc-coordinating residues, is contained
      within a long hydrophobic segment. Aspartic acid 467, located approximately 300
      residues away from the HEIGH sequence, appears to provide the third coordinating
      residue for the active site zinc. This residue, too, is located in a hydrophobic
      sequence. The hydrophobicity of these sequences suggests that the active site of
      S2P is located within the membrane in an ideal position to cleave its target, a
      Leu-Cys bond in the first transmembrane helix of SREBPs.

PMID- 10419521
TI  - Cloning and characterization of the EAP30 subunit of the ELL complex that confers
      derepression of transcription by RNA polymerase II.
AB  - The product of the human oncogene ELL encodes an RNA polymerase II transcription
      factor that undergoes frequent translocation in acute myeloid leukemia (AML). In
      addition to its elongation activity, ELL contains a novel type of RNA polymerase
      II interaction domain that is capable of repressing polymerase activity in
      promoter-specific transcription. Remarkably, the ELL translocation that is found
      in patients with AML results in the deletion of exactly this functional domain.
      Here we report that the EAP30 subunit of the ELL complex has sequence homology to
      the Saccharomyces cerevisiae SNF8, whose genetic analysis suggests its
      involvement in the derepression of gene expression. Remarkably, EAP30 can
      interact with ELL and derepress ELL's inhibitory activity in vitro. This finding
      may reveal a key role for EAP30 in the pathogenesis of human leukemia.

PMID- 10419522
TI  - Sequence selectivity of c-Myb in vivo. Resolution of a DNA target specificity
      paradox.
AB  - We have investigated the basis for the striking difference between the broad DNA
      sequence selectivity of the c-Myb transcription factor minimal DNA-binding domain
      R(2)R(3) in vitro and the more restricted preference of a R(2)R(3)VP16 protein
      for Myb-specific recognition elements (MREs) in a Saccharomyces cerevisiae
      transactivation system. We show that sequence discrimination in yeast is highly
      dependent on the expression level of Myb effector protein. Full-length c-Myb and
      a C-terminally truncated protein (residues 1-360) were also included in the
      study. All of the tested Myb proteins displayed very similar DNA binding
      properties in electrophoretic mobility shift assays. Only minor differences
      between full-length c-Myb and truncated c-Myb(1-360) were observed. In
      transactivation studies in CV-1 cells, the MRE selectivity was highest at low
      expression levels of Myb effector proteins. However, the discrimination between
      MRE variants was rapidly lost with high input levels of effector plasmid. In c
      Myb-expressing K-562 cells, the high degree of MRE selectivity was retained,
      thereby confirming the relevance of the results obtained in the yeast system.
      These data suggest that the MRE selectivity of c-Myb is an intrinsic property of
      only the R(2)R(3) domain itself and that the transactivation response of a
      specific MRE in vivo may be highly dependent on the expression level of the Myb
      protein in the cell.

PMID- 10419523
TI  - Activation of phospholipase C delta1 through C2 domain by a Ca(2+)-enzyme
      phosphatidylserine ternary complex.
AB  - The concentration of free Ca(2+) and the composition of nonsubstrate
      phospholipids profoundly affect the activity of phospholipase C delta1
      (PLCdelta1). The rate of PLCdelta1 hydrolysis of phosphatidylinositol 4,5
      bisphosphate was stimulated 20-fold by phosphatidylserine (PS), 4-fold by
      phosphatidic acid (PA), and not at all by phosphatidylethanolamine or
      phosphatidylcholine (PC). PS reduced the Ca(2+) concentration required for half
      maximal activation of PLCdelta1 from 5.4 to 0.5 microM. In the presence of
      Ca(2+), PLCdelta1 specifically bound to PS/PC but not to PA/PC vesicles in a dose
      dependent and saturable manner. Ca(2+) also bound to PLCdelta1 and required the
      presence of PS/PC vesicles but not PA/PC vesicles. The free Ca(2+) concentration
      required for half-maximal Ca(2+) binding was estimated to be 8 microM. Surface
      dilution kinetic analysis revealed that the K(m) was reduced 20-fold by the
      presence of 25 mol % PS, whereas V(max) and K(d) were unaffected. Deletion of
      amino acid residues 646-654 from the C2 domain of PLCdelta1 impaired Ca(2+)
      binding and reduced its stimulation and binding by PS. Taken together, the
      results suggest that the formation of an enzyme-Ca(2+)-PS ternary complex through
      the C2 domain increases the affinity for substrate and consequently leads to
      enzyme activation.

PMID- 10419524
TI  - Marked instability of the sigma(32) heat shock transcription factor at high
      temperature. Implications for heat shock regulation.
AB  - The heat shock response in Escherichia coli depends on a transient increase in
      the intracellular level of sigma(32) that results from both increased synthesis
      and transient stabilization of normally unstable sigma(32). Although the membrane
      bound ATP-dependent protease FtsH (HflB) plays an important role in degradation
      of sigma(32), our previous results suggested that several cytosolic ATP-dependent
      proteases including HslVU (ClpQY) are also involved in sigma(32) degradation
      (Kanemori, M., Nishihara, K., Yanagi, H., and Yura, T. (1997) J. Bacteriol. 179,
      7219-7225). We now report on the ATP-dependent proteolysis of sigma(32) by
      purified HslVU protease and its unusual dependence on high temperature: sigma(32)
      was rapidly degraded at 44 degrees C, but with much slower rates ( approximately
      15-fold) at 35 degrees C. FtsH-dependent degradation of sigma(32) also gave
      similar results. In agreement with these results in vitro, the turnover of
      sigma(32) in normally growing cells at high temperature (42 degrees C) was much
      faster than at low temperature (30 degrees C). Taken together with other
      evidence, these results suggest that the sigma(32) level during normal growth is
      primarily determined by the stability (susceptibility to proteases) and synthesis
      rate of sigma(32) set by ambient temperature, whereas fine adjustment such as
      transient stabilization of sigma(32) observed upon heat shock is brought about
      through monitoring changes in the cellular state of protein folding.

PMID- 10419526
TI  - Retinoic acid promotes ubiquitination and proteolysis of cyclin D1 during induced
      tumor cell differentiation.
AB  - Mechanisms by which differentiation programs engage the cell cycle are poorly
      understood. This study demonstrates that retinoids promote ubiquitination and
      degradation of cyclin D1 during retinoid-induced differentiation of human
      embryonal carcinoma cells. In response to all-trans-retinoic acid (RA) treatment,
      the human embryonal carcinoma cell line NT2/D1 exhibits a progressive decline in
      cyclin D1 expression beginning when the cells are committed to differentiate, but
      before onset of terminal neuronal differentiation. The decrease in cyclin D1
      protein is tightly associated with the accumulation of hypophosphorylated forms
      of the retinoblastoma protein and G(1) arrest. In contrast, retinoic acid
      receptor gamma-deficient NT2/D1-R1 cells do not growth-arrest or accumulate in
      G(1) and have persistent cyclin D1 overexpression despite RA treatment. Notably,
      stable transfection of retinoic acid receptor gamma restores RA-mediated growth
      suppression and differentiation to NT2/D1-R1 cells and restores the decline of
      cyclin D1. The proteasome inhibitor LLnL blocks this RA-mediated decline in
      cyclin D1. RA treatment markedly accelerates ubiquitination of wild-type cyclin
      D1, but not a cyclin D1 (T286A) mutant. Transient expression of cyclin D1 (T286A)
      in NT2/D1 cells blocks RA-mediated transcriptional decline of a differentiation
      sensitive reporter plasmid and represses induction of immunophenotypic neuronal
      markers. Taken together, these findings strongly implicate RA-mediated
      degradation of cyclin D1 as a means of coupling induced differentiation and cell
      cycle control of human embryonal carcinoma cells.

PMID- 10419525
TI  - Functional analysis of the N-terminal CXXC metal-binding motifs in the human
      Menkes copper-transporting P-type ATPase expressed in cultured mammalian cells.
AB  - The Menkes protein (MNK) is a copper-transporting P-type ATPase, which has six
      highly conserved metal-binding sites, GMTCXXC, at the N terminus. The metal
      binding sites may be involved in MNK trafficking and/or copper-translocating
      activity. In this study, we report the detailed functional analysis in mammalian
      cells of recombinant human MNK and its mutants with various metal-binding sites
      altered by site-directed mutagenesis. The results of the study, both in vitro and
      in vivo, provide evidence that the metal-binding sites of MNK are not essential
      for the ATP-dependent copper-translocating activity of MNK. Moreover, metal
      binding site mutations, which resulted in a loss of ability of MNK to traffick to
      the plasma membrane, produced a copper hyperaccumulating phenotype. Using an in
      vitro vesicle assay, we demonstrated that the apparent K(m) and V(max) values for
      the wild type MNK and its mutants were not significantly different. The results
      of this study suggest that copper-translocating activity of MNK and its copper
      induced relocalization to the plasma membrane represent a well coordinated copper
      homeostasis system. It is proposed that mutations in MNK which alter either its
      catalytic activity or/and ability to traffick can be the cause of Menkes disease.

PMID- 10419527
TI  - p85/p110-type phosphatidylinositol kinase phosphorylates not only the D-3, but
      also the D-4 position of the inositol ring.
AB  - Activation of p85/p110-type phosphatidylinositol (PI) kinase has been implicated
      in various cellular activities. This PI kinase phosphorylates the D-4 position
      with a similar or higher efficiency than the D-3 position when trichloroacetic
      acid-treated cell membrane is used as a substrate, although it phosphorylates
      almost exclusively the D-3 position of the inositol ring in phosphoinositides
      when purified PI is used as a substrate. Furthermore, the lipid kinase activities
      of p110 for both the D-3 and D-4 positions were completely abolished by
      introducing kinase-dead point mutations in their lipid kinase domains
      (DeltaKinalpha and DeltaKinbeta, respectively). In addition, both PI 3- and PI 4
      kinase activities of p110alpha and p110beta immunoprecipitates were similarly
      inhibited by either wortmannin or LY294002, specific inhibitors of p110. Insulin
      induced phosphorylation of not only the D-3 position, but also the D-4 position.
      Indeed, overexpression of p110 in Sf9 or 3T3-L1 cells induced marked
      phosphorylation of the D-4 position to a level comparable to or much greater than
      that of D-3, whereas inhibition of endogenous p85/p110-type PI kinase via
      overexpression of dominant-negative p85alpha (Deltap85alpha) in 3T3-L1 adipocytes
      abolished insulin-induced synthesis of both. Thus, p85/p110-type PI kinase
      phosphorylates the D-4 position of phosphoinositides more efficiently than the D
      3 position in vivo, and each of the D-3- or D-4-phosphorylated phosphoinositides
      may transmit signals downstream.

PMID- 10419529
TI  - Multiple ras effector pathways contribute to G(1) cell cycle progression.
AB  - The involvement of Ras in the activation of multiple early signaling pathways is
      well understood, but it is less clear how the various Ras effectors interact with
      the cell cycle machinery to cause G(1) progression. Ras-mediated activation of
      extracellular-regulated kinase/mitogen-activated protein kinase has been
      implicated in cyclin D(1) up-regulation, but there is little extracellular
      regulated kinase activity during the later stages of G(1), when cyclin D(1)
      expression becomes maximal, implying that other effector pathways may also be
      important in cyclin D(1) induction. We have addressed the involvement of Ras
      effectors from the phosphatidylinositol (PI) 3-kinase and Ral-GDS families in
      G(1) progression and compared it to that of the Raf/mitogen-activated protein
      kinase pathway. PI 3-kinase activity is required for the expression of endogenous
      cyclin D(1) and for S phase entry following serum stimulation of quiescent NIH
      3T3 fibroblasts. Activated PI 3-kinase induces cyclin D(1) transcription and E2F
      activity, at least in part mediated by the serine/threonine kinase Akt/PKB, and
      to a lesser extent the Rho family GTPase Rac. In addition, both activated Ral-GDS
      like factor and Raf stimulate cyclin D(1) transcription and E2F activity and act
      in synergy with PI 3-kinase. Therefore, multiple cooperating pathways mediate the
      effects of Ras on progression through the cell cycle.

PMID- 10419528
TI  - Nuclear import of plasmid DNA in digitonin-permeabilized cells requires both
      cytoplasmic factors and specific DNA sequences.
AB  - Although much is known about the mechanisms of signal-mediated protein and RNA
      nuclear import and export, little is understood concerning the nuclear import of
      plasmid DNA. Plasmids between 4.2 and 14.4 kilobases were specifically labeled
      using a fluorescein-conjugated peptide nucleic acid clamp. The resulting
      substrates were capable of gene expression and nuclear localization in
      microinjected cells in the absence of cell division. To elucidate the
      requirements for plasmid nuclear import, a digitonin-permeabilized cell system
      was adapted to follow the nuclear localization of plasmids. Nuclear import of
      labeled plasmid was time- and energy-dependent, was inhibited by the lectin wheat
      germ agglutinin, and showed an absolute requirement for cytoplasmic extract.
      Addition of nuclear extract alone did not support plasmid nuclear import but in
      combination with cytoplasm stimulated plasmid nuclear localization. Whereas
      addition of purified importin alpha, importin beta, and RAN was sufficient to
      support protein nuclear import, plasmid nuclear import also required the addition
      of nuclear extract. Finally, nuclear import of plasmid DNA was sequence-specific,
      requiring a region of the SV40 early promoter and enhancer. Taken together, these
      results confirm and extend our findings in microinjected cells and support a
      protein-mediated mechanism for plasmid nuclear import.

PMID- 10419530
TI  - Melatonin promotes osteoblast differentiation and bone formation.
AB  - Prior studies have demonstrated that the pineal hormone, melatonin, can stimulate
      chloramphenicol acetyltransferase activity in Drosophila SL-3 cells transfected
      with a chloramphenicol acetyltransferase reporter construct containing the
      response element of rat bone sialoprotein (BSP). Based on these findings, studies
      were performed to determine whether melatonin could similarly modulate the
      expression of BSP in two cell lines, the MC3T3-E1(MC3T3) pre-osteoblast and rat
      osteoblast-like osteosarcoma 17/2.8 cell. Initial studies demonstrated that MC3T3
      cells grown in the presence of 50 nM melatonin underwent cell differentiation and
      mineralization by day 12 instead of the 21-day period normally required for cells
      grown in untreated media. Melatonin increased gene expression of BSP and the
      other bone marker proteins, including alkaline phosphatase (ALP); osteopontin;
      secreted protein, acidic and rich in cysteine; and osteocalcin in MC3T3 cells in
      a concentration-dependent manner. Levels of melatonin as low as 10 nM were
      capable of stimulating transcription of these genes when cells were grown in the
      presence of beta-glycerophosphate and ascorbic acid. Under these conditions,
      melatonin induced gene expression of the bone marker proteins; however, this does
      not occur until the 5th day after seeding the culture dishes. Thereafter, MC3T3
      cells responded to melatonin within 2 h of treatment. The fully differentiated
      rat osteoblast-like osteosarcoma 17/2.8 cells responded rapidly to melatonin and
      displayed an increase in the expression of BSP, ALP, and osteocalcin genes within
      1 h of exposure to the hormone. To determine whether melatonin-induced osteoblast
      differentiation and bone formation are mediated via the transmembrane receptor,
      MC3T3 cells were treated in the presence and absence of melatonin with either
      luzindole, a competitive inhibitor of the binding of melatonin to the
      transmembrane receptors, or pertussis toxin, an uncoupler of G(i) from adenylate
      cyclase. Both luzindole and pertussis toxin were shown to reduce melatonin
      induced expression of BSP and ALP. These results demonstrate, for the first time,
      that the pineal hormone, melatonin, is capable of promoting osteoblast
      differentiation and mineralization of matrix in culture and suggest that this
      hormone may play an essential role in regulating bone growth.

PMID- 10419531
TI  - G(i) protein-mediated functional compartmentalization of cardiac beta(2)
      adrenergic signaling.
AB  - In contrast to beta(1)-adrenoreceptor (beta(1)-AR) signaling, beta(2)-AR
      stimulation in cardiomyocytes augments L-type Ca(2+) current in a cAMP-dependent
      protein kinase (PKA)-dependent manner but fails to phosphorylate phospholamban,
      indicating that the beta(2)-AR-induced cAMP/PKA signaling is highly localized.
      Here we show that inhibition of G(i) proteins with pertussis toxin (PTX) permits
      a full phospholamban phosphorylation and a de novo relaxant effect following
      beta(2)-AR stimulation, converting the localized beta(2)-AR signaling to a global
      signaling mode similar to that of beta(1)-AR. Thus, beta(2)-AR-mediated G(i)
      activation constricts the cAMP signaling to the sarcolemma. PTX treatment did not
      significantly affect the beta(2)-AR-stimulated PKA activation. Similar to G(i)
      inhibition, a protein phosphatase inhibitor, calyculin A (3 x 10(-8) M),
      selectively enhanced the beta(2)-AR but not beta(1)-AR-mediated contractile
      response. Furthermore, PTX and calyculin A treatment had a non-additive
      potentiating effect on the beta(2)-AR-mediated positive inotropic response. These
      results suggest that the interaction of the beta(2)-AR-coupled G(i) and G(s)
      signaling affects the local balance of protein kinase and phosphatase activities.
      Thus, the additional coupling of beta(2)-AR to G(i) proteins is a key factor
      causing the compartmentalization of beta(2)-AR-induced cAMP signaling.

PMID- 10419532
TI  - Structural variation of type XII collagen at its carboxyl-terminal NC1 domain
      generated by tissue-specific alternative splicing.
AB  - This paper reports the identification of two structural variations in the NC1
      domain of rat and mouse type XII collagen. The long NC1 domain encoding 74 amino
      acids showed homology to chicken type XII and XIV collagens. The short NC1 domain
      was composed of 19 amino acids. Through genomic DNA analyses, two alternative
      exons were identified, each of which contained the variable NC1 sequence. With
      the amino-terminal NC3 splicing alternatives, we propose here a new descriptive
      nomenclature: types XIIA-1 and XIIB-1 which include a long NC1 sequence encoded
      by exon 1 (from the 3'-end), and types XIIA-2 and XIIB-2 which include a short
      NC1 sequence encoded by exon 2. Types XIIA-1 and XIIB-1, the predominant
      transcripts in 15-day old mouse embryos, showed decreased expression in 17-day
      old embryos when type XIIB-2 expression was sustained at constant levels. In
      adult mice, type XIIB-1 associates with ligament and tendon, whereas type XIIB-2
      is expressed in various other tissues. The long NC1 domain contains an extended
      acidic region (pI = 3.4) followed by a terminal basic region (pI = 13.8). Because
      the short NC1 domain lacks these features, structural variations in the type XII
      collagen NC1 domain suggests different functional roles in a tissue-specific
      fashion.

PMID- 10419533
TI  - Roles of replication protein A and DNA-dependent protein kinase in the regulation
      of DNA replication following DNA damage.
AB  - Exposure of mammalian cells to DNA damage-inducing agents (DDIA) inhibits ongoing
      DNA replication. The molecular mechanism of this inhibition remains to be
      elucidated. We employed a simian virus 40 (SV40) based in vitro DNA replication
      assay to study biochemical aspects of this inhibition. We report here that the
      reduced DNA replication activity in extracts of DDIA-treated cells is partly
      caused by a reduction in the amount of replication protein A (RPA). We also
      report that the dominant inhibitory effect is caused by the DNA-dependent protein
      kinase (DNA-PK) which inactivates SV40 T antigen (TAg) by phosphorylation. The
      results demonstrate that RPA and DNA-PK are involved in the regulation of viral
      DNA replication after DNA damage and suggest that analogous processes regulate
      cellular DNA replication with the DNA-PK targeting the functional homologues of
      TAg.

PMID- 10419534
TI  - Characterization of a Rac1 signaling pathway to cyclin D(1) expression in airway
      smooth muscle cells.
AB  - We examined the importance of the Rho family GTPase Rac1 for cyclin D(1) promoter
      transcriptional activation in bovine tracheal myocytes. Overexpression of active
      Rac1 induced transcription from the cyclin D(1) promoter, whereas platelet
      derived growth factor (PDGF)-induced transcription was inhibited by a dominant
      negative allele of Rac1, suggesting that Rac1 functions as an upstream activator
      of cyclin D(1) in this system. Rac1 forms part of the NADPH oxidase complex that
      generates reactive oxygen species such as H(2)O(2). PDGF stimulated a substantial
      increase in intracellular reactive oxygen species, as measured by the
      fluorescence of dichlorofluorescein-loaded cells, and this was blocked by the
      glutathione peroxidase mimetic ebselen. Pretreatment with ebselen, catalase, and
      the flavoprotein inhibitor diphenylene iodonium each attenuated PDGF- and Rac1
      mediated cyclin D(1) promoter activation, while having no effect on the induction
      of cyclin D(1) by mitogen-activated protein kinase/extracellular signal-regulated
      kinase (ERK) kinase-1 (MEK1), the upstream activator of ERKs. Antioxidant
      treatment also inhibited PDGF-induced cyclin D(1) protein expression and DNA
      synthesis. Overexpression of an N-terminal fragment of p67(phox), a component of
      NADPH oxidase which interacts with Rac1, attenuated PDGF-induced cyclin D(1)
      promoter activity, whereas overexpression of the wild-type p67 did not. Finally,
      Rac1 was neither required nor sufficient for ERK activation. Taken together,
      these data suggest a model by which two distinct signaling pathways, the ERK and
      Rac1 pathways, positively regulate cyclin D(1) and smooth muscle growth.

PMID- 10419535
TI  - Cell volume-dependent regulation of L-selectin shedding in neutrophils. A role
      for p38 mitogen-activated protein kinase.
AB  - Neutrophil-mediated organ damage is a common feature of many disease states. We
      previously demonstrated that resuscitation with hypertonic salt solutions
      prevented the endotoxin-induced leukosequestration and consequent lung injury,
      and this effect was partially attributed to an altered surface expression of
      adhesion molecules, CD11b and L-selectin. In this study we investigated the
      mechanisms whereby osmotic stress evokes L-selectin shedding. The metalloprotease
      inhibitor RO 31-9790 prevented the osmotic down-regulation of L-selectin,
      indicating that this process was catalyzed by the same "sheddase" responsible for
      L-selectin cleavage induced by diverse inflammatory stimuli. The trigger for
      hypertonic shedding was cell shrinkage and not increased osmolarity, ionic
      strength, or intracellular pH. Volume reduction caused robust tyrosine
      phosphorylation and its inhibition by genistein and erbstatin abrogated shedding.
      Shrinkage stimulated tyrosine kinases Hck, Syk, and Pyk2, but prevention of their
      activation by the Src-family inhibitor PP1 failed to affect the L-selectin
      response. Hypertonicity elicited the Src family-independent activation of p38,
      and the inhibition of this kinase by SB203580 strongly reduced shedding. p38 was
      also essential for the N-formyl-methionyl-leucyl-phenylalanine- and
      lipopolysaccharide-induced shedding but not the phorbol ester-induced shedding.
      Thus, cell volume regulates L-selectin surface expression in a p38-mediated,
      metalloprotease-dependent manner. Moreover, p38 has a central role in shedding
      induced by many inflammatory mediators.

PMID- 10419536
TI  - Calmodulin binding to G protein-coupling domain of opioid receptors.
AB  - The ubiquitous intracellular Ca(2+) sensor calmodulin (CaM) regulates numerous
      proteins involved in cellular signaling of G protein-coupled receptors, but most
      known interactions between GPCRs and CaM occur downstream of the receptor. Using
      a sequence-based motif search, we have identified the third intracellular loop of
      the opioid receptor family as a possible direct contact point for interaction
      with CaM, in addition to its established role in G protein activation. Peptides
      derived from the third intracellular loop of the mu-opioid (OP(3)) receptor
      strongly bound CaM and were able to reduce binding interactions observed between
      CaM and immunopurified OP(3) receptor. Functionally, CaM reduced basal and
      agonist-stimulated (35)S-labeled guanosine 5'-3-O-(thio)triphosphate
      incorporation, a measure of G protein activation, in membranes containing
      recombinant OP(3) receptor. Changes in CaM membrane levels as a result of
      overexpression or antisense CaM suppression inversely affected basal and agonist
      induced G protein activation. The ability of CaM to abolish high affinity binding
      sites of an agonist at OP(3) further supports the hypothesis of a direct
      interaction between CaM and opioid receptors. An OP(3) receptor mutant with a
      Lys(273) --> Ala substitution (K273A-OP(3)), an amino acid predicted to play a
      critical role in CaM binding based on motif structure, was found to be unaffected
      by changes in CaM levels but coupled more efficiently to G proteins than the wild
      type receptor. Stimulation of both the OP(1) (delta-opioid) and OP(3) wild-type
      receptors, but not the K273A-OP(3) mutant, induced release of CaM from the plasma
      membrane. These results suggest that CaM directly competes with G proteins for
      binding to opioid receptors and that CaM may itself serve as an independent
      second messenger molecule that is released upon receptor stimulation.

PMID- 10419537
TI  - Overactivation of phospholipase C-gamma1 renders platelet-derived growth factor
      beta-receptor-expressing cells independent of the phosphatidylinositol 3-kinase
      pathway for chemotaxis.
AB  - We have previously shown that porcine aortic endothelial cells expressing the
      Y934F platelet-derived growth factor (PDGF) beta-receptor mutant respond to PDGF
      BB in a chemotaxis assay at about 100-fold lower concentration than do wild-type
      PDGF beta-receptor-expressing cells (Hansen, K., Johnell, M., Siegbahn, A. ,
      Rorsman, C., Engstrom, U., Wernstedt, C., Heldin, C.-H., and Ronnstrand, L.
      (1996) EMBO J. 15, 5299-5313). Here we show that the increased chemotaxis
      correlates with increased activation of phospholipase C-gamma1 (PLC-gamma1),
      measured as inositol-1,4, 5-trisphosphate release. By two-dimensional
      phosphopeptide mapping, the increase in phosphorylation of PLC-gamma1 was shown
      not to be selective for any site, rather a general increase in phosphorylation of
      PLC-gamma1 was seen. Specific inhibitors of protein kinase C, bisindolylmaleimide
      (GF109203X), and phosphatidylinositol 3-kinase (PI3-kinase), LY294002, did not
      affect the activation of PLC-gamma1. To assess whether increased activation of
      PLC-gamma1 is the cause of the hyperchemotactic behavior of the Y934F mutant cell
      line, we constructed cell lines expressing either wild-type or a catalytically
      compromised version of PLC-gamma1 under a tetracycline-inducible promoter.
      Overexpression and concomitant increased activation of wild-type PLC-gamma1 in
      response to PDGF-BB led to a hyperchemotactic behavior of the cells, while the
      catalytically compromised PLC-gamma1 mutant had no effect on PDGF-BB-induced
      chemotaxis. Furthermore, in cells expressing normal levels of PLC-gamma1,
      chemotaxis was inhibited by LY294002. In contrast, the increase in chemotactic
      response seen upon overexpression of PLC-gamma1 was not inhibited by the PI3
      kinase inhibitor LY294002. These observations suggest the existence of two
      different pathways which mediate PDGF-induced chemotaxis; depending on the
      cellular context, the PI3-kinase pathway or the PLC-gamma1 pathway may dominate.

PMID- 10419539
TI  - Yersinia enterocolitica type III secretion. On the role of SycE in targeting YopE
      into HeLa cells.
AB  - Yersinia enterocolitica inject toxic proteins (effector Yops) into the cytosol of
      eukaryotic cells by a mechanism requiring the type III machinery. Previous work
      mapped a signal sufficient for the targeting of fused reporter proteins to amino
      acids 1-100 of YopE. Targeting requires the binding of SycE to YopE residues 15
      100 in the bacterial cytoplasm. We asked whether SycE functions only to stabilize
      YopE in the bacterial cytoplasm, or whether the secretion chaperone itself
      contributes to substrate recognition by the type III machinery. Fusions of
      glutathione S-transferase to either the N or C terminus of SycE resulted in
      hybrid proteins that bound YopE but prevented targeting of the export substrate
      into HeLa cells. As compared with wild-type SycE, glutathione S-transferase-SycE
      bound and stabilized YopE in the bacterial cytoplasm but failed to release the
      polypeptide for export by the type III machinery. Thus, it appears that SycE
      functions to deliver YopE to the type III secretion machinery. A model is
      presented that accounts for substrate recognition of effector Yops, a group of
      proteins that do not share amino acid sequence or physical similarities.

PMID- 10419538
TI  - Cloning and characterization of human polyamine-modulated factor-1, a
      transcriptional cofactor that regulates the transcription of the
      spermidine/spermine N(1)-acetyltransferase gene.
AB  - The increased transcription and ultimate superinduction of the
      spermidine/spermine N(1)-acetyltransferase (SSAT) gene has been associated with
      the antineoplastic activity of several new antitumor polyamine analogues. In
      sensitive tumor cell types, the transcriptional induction appears to be regulated
      by the constitutive association of the transcription factor Nrf-2 with the
      recently discovered polyamine-responsive element. Using the yeast two-hybrid
      system, a new transcriptional cofactor, polyamine-modulated factor-1 (PMF-1), has
      been identified as a partner protein of Nrf-2 that, in combination with Nrf-2,
      regulates the polyamine analogue-induced transcription of SSAT. The human PMF-1
      gene, located on chromosome 1 near the 1q12/1q21 border, yields an mRNA
      transcript of approximately 1.2 kilobases that codes for a 165-amino acid protein
      with a predicted molecular mass of approximately 20 kDa. The PMF-1 mRNA appears
      to increase in response to analogue exposure only in analogue-responsive cells.
      In addition to the transcriptional regulation of SSAT, PMF-1 or similar factors
      should be considered in the regulation of other polyamine-dependent genes.

PMID- 10419540
TI  - Mutational analysis of the Shab-encoded delayed rectifier K(+) channels in
      Drosophila.
AB  - K(+) currents in Drosophila muscles have been resolved into two voltage-activated
      currents (I(A) and I(K)) and two Ca(2+)-activated currents (I(CF) and I(CS)).
      Mutations that affect I(A) (Shaker) and I(CF) (slowpoke) have helped greatly in
      the analysis of these currents and their role in membrane excitability. Lack of
      mutations that specifically affect channels for the delayed rectifier current
      (I(K)) has made their genetic and functional identity difficult to elucidate.
      With the help of mutations in the Shab K(+) channel gene, we show that this gene
      encodes the delayed rectifier K(+) channels in Drosophila. Three mutant alleles
      with a temperature-sensitive paralytic phenotype were analyzed. Analysis of the
      ionic currents from mutant larval body wall muscles showed a specific effect on
      delayed rectifier K(+) current (I(K)). Two of the mutant alleles contain missense
      mutations, one in the amino-terminal region of the channel protein and the other
      in the pore region of the channel. The third allele contains two deletions in the
      amino-terminal region and is a null allele. These observations identity the
      channels that carry the delayed rectifier current and provide an in vivo
      physiological role for the Shab-encoded K(+) channels in Drosophila. The
      availability of mutations that affect I(K) opens up possibilities for studying
      I(K) and its role in larval muscle excitability.

PMID- 10419541
TI  - Plant riboflavin biosynthesis. Cloning, chloroplast localization, expression,
      purification, and partial characterization of spinach lumazine synthase.
AB  - Lumazine synthase, which catalyzes the penultimate step of riboflavin
      biosynthesis, has been cloned from three higher plants (spinach, tobacco, and
      arabidopsis) through functional complementation of an Escherichia coli auxotroph.
      Whereas the three plant proteins exhibit some structural similarities to known
      microbial homologs, they uniquely possess N-terminal polypeptide extensions that
      resemble typical chloroplast transit peptides. In vitro protein import assays
      with intact chloroplasts and immunolocalization experiments verify that higher
      plant lumazine synthase is synthesized in the cytosol as a larger molecular
      weight precursor protein, which is post-translationally imported into
      chloroplasts where it is proteolytically cleaved to its mature size. The
      authentic spinach enzyme is estimated to constitute <0.02% of the total
      chloroplast protein. Recombinant "mature" spinach lumazine synthase is expressed
      in E. coli at levels exceeding 30% of the total soluble protein and is readily
      purified to homogeneity using a simple two-step procedure. Apparent V(max) and
      K(m) values obtained with the purified plant protein are similar to those
      reported for microbial lumazine synthases. Electron microscopy and hydrodynamic
      studies reveal that native plant lumazine synthase is a hollow capsid-like
      structure comprised of 60 identical 16.5-kDa subunits, resembling its icosahedral
      counterparts in E. coli and Bacillus subtilis.

PMID- 10419543
TI  - Intrastriatal dopamine injection induces apoptosis through oxidation-involved
      activation of transcription factors AP-1 and NF-kappaB in rats.
AB  - ABSTRACT More and more evidence suggests that increases in dopamine (DA) in
      striata may participate in neurodegenerative processes during acute ischemia,
      hypoxia, and excitotoxicity. With a rat model of intrastriatal DA injection, we
      studied the molecular events involved in DA toxicity. Intrastriatal injections of
      DA in amounts from 1 to 2 micromol result in apoptotic cell death, as indicated
      by terminal deoxynucleotidyl transferase labeling of DNA strand breaks and Klenow
      polymerase-catalyzed [(32)P]deoxycytidine triphosphate-labeled DNA laddering.
      Injections of DA produce a strong and prolonged activated protein 1 (AP-1)
      activity that contains c-fos, c-jun, and phosphorylated c-jun protein. DA
      injections also stimulate the activity of nuclear factor-kappaB (NF-kappaB), an
      oxidative stress-responsive transcription factor. Injection of curcumin at a dose
      that selectively inhibits AP-1 activation without affecting NF-kappaB activity
      attenuates DNA laddering induced by DA. Preinjection with SN50, a specific
      permeable recombinant NF-kappaB translocation inhibitor peptide, reduces DA
      induced NF-kappaB activation and apoptosis. Moreover, preinjection of the
      antioxidant GSH significantly inhibits both DA-induced activation of
      transcription factors AP-1 and NF-kappaB and subsequent apoptosis. Thus, our data
      suggest that DA-oxidative stress-induced apoptosis in vivo is mediated by
      activation of transcription factors AP-1 and NF-kappaB.

PMID- 10419542
TI  - The soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1
      one is a nonselective heme protein inhibitor of nitric oxide synthase and other
      cytochrome P-450 enzymes involved in nitric oxide donor bioactivation.
AB  - Soluble guanylyl cyclase (sGC) is an important effector for nitric oxide (NO). It
      acts by increasing intracellular cyclic GMP (cGMP) levels to mediate numerous
      biological functions. Recently, 1H-[1,2, 4]oxadiazolo[4,3,-a]quinoxalin-1-one
      (ODQ) was identified as a novel and selective inhibitor of this enzyme.
      Therefore, ODQ may represent an important pharmacological tool for
      differentiating cGMP-mediated from cGMP-independent effects of NO. In the present
      study, we examined the inhibitory action of ODQ both functionally and
      biochemically. In phenylephrine-preconstricted, endothelium-intact, isolated
      aortic rings from the rat, ODQ, in a concentration-dependent manner, increased
      contractile tone and inhibited relaxations to authentic NO with maximal effects
      at 3 microM. Pretreatment of vascular rings with ODQ induced a parallel, 2-log
      order shift to the right of the concentration-response curves (CRCs) to
      histamine, ATP, NO, the NO-donors S-nitrosoglutathione, S-nitroso-N-acetyl-D,L
      penicillamine, and spermine NONOate [N-[4-[1-(3-amino propyl)-2-hydroxy-2-nitroso
      hydrazino]butyl]-1, 3-propane diamine], and the direct sGC-stimulant [3-(5'
      hydroxymethyl-2'furyl)-1-benzyl indazole] YC-1 but did not affect relaxations
      induced by papaverine and atriopeptin II. Moreover, the rightward shift of the
      CRCs to Angeli's salt, peroxynitrite, and linsidomine was similar to that of NO.
      These results suggested that ODQ is specific for sGC. Furthermore, they indicate
      that NO can cause vasorelaxation independent of cGMP. Three interesting
      exceptions were observed to the otherwise rather uniform inhibitory effect of
      ODQ: the responses to acetylcholine, glycerol trinitrate, and sodium
      nitroprusside. The latter two agents are known to require metabolic activation,
      possibly by cytochrome P-450-type proteins. The 3- to 5-log-order rightward shift
      of their CRCs suggests that, in addition to sGC, ODQ may interfere with heme
      proteins involved in the bioactivation of these NO donors and the mechanism of
      vasorelaxation mediated by acetylcholine. In support of this notion, ODQ
      inhibited hepatic microsomal NO production from both glycerol trinitrate and
      sodium nitroprusside as well as NO synthase activity in aortic homogenates. The
      latter effect seemed to require biotransformation of ODQ. Collectively, these
      data reveal that ODQ interferes with various heme protein-dependent processes in
      vascular and hepatic tissue and lacks specificity for sGC.

PMID- 10419544
TI  - Protein kinase C-promoted inhibition of Galpha(11)-stimulated phospholipase C
      beta activity.
AB  - The effects of protein kinase C (PKC) activation on inositol lipid signaling were
      examined. Using the turkey erythrocyte model of receptor-regulated
      phosphoinositide hydrolysis, we developed a membrane reconstitution assay to
      study directly the effects of activation of PKC on the activities of Galpha(11),
      independent of potential effects on the receptor or on PLC-beta. Membranes
      isolated from erythrocytes pretreated with 4beta-phorbol-12beta-myristate-13alpha
      acetate (PMA) exhibited a decreased capacity for Galpha(11)-mediated activation
      of purified, reconstituted PLC-beta1. This inhibitory effect was dependent on
      both the time and concentration of PMA incubation and occurred as a decrease in
      the efficacy of GTPgammaS for activation of PLC-beta1, both in the presence and
      absence of agonist; no change in the apparent affinity for the guanine nucleotide
      occurred. Similar inhibitory effects were observed after treatment with the PKC
      activator phorbol-12,13-dibutyrate but not after treatment with an inactive
      phorbol ester. The inhibitory effects of PMA were prevented by coaddition of the
      PKC inhibitor bisindolylmaleimide. Although the effects of PKC could be localized
      to the membrane, no phosphorylation of Galpha(11) occurred either in vitro in the
      presence of purified PKC or in intact erythrocytes after PMA treatment. These
      results support the hypothesis that a signaling protein other than Galpha(11) is
      the target for PKC and that PKC-promoted phosphorylation of this protein results
      in a phosphorylation-dependent suppression of Galpha(11)-mediated PLC-beta1
      activation.

PMID- 10419545
TI  - Molecular characterization of binding of substrates and inhibitors to DT
      diaphorase: combined approach involving site-directed mutagenesis, inhibitor
      binding analysis, and computer modeling.
AB  - The molecular basis of the interaction of DT-diaphorase with a cytotoxic
      nitrobenzamide CB1954 [5-(aziridin-1-yl)-2, 4-dinitrobenzamide] and five
      inhibitors was investigated with wild-type DT-diaphorase (human and rat) and five
      mutants [three rat mutants (rY128D, rG150V, rH194D) and two human mutants
      (hY155F, hH161Q)]. hY155F and hH161Q were generated to evaluate a hypothesis that
      Tyr155 and His161 participate in the obligatory two-electron transfer reaction of
      the enzyme. The catalytic properties of hY155F and hH161Q were compared with a
      naturally occurring mutant, hP187S. Pro187 to Ser mutation disturbs the structure
      of the central parallel beta-sheet, resulting in a reduction of the binding
      affinity of the flavin-adenine dinucleotide prosthetic group. With NADH as the
      electron donor and menadione as the electron acceptor, the k(cat) values for the
      wild-type human DT-diaphorase, hY155F, hH161Q, and hP187S were measured as 66 +/-
      1, 23 +/- 0, 5 +/- 0 and 8 +/- 2 x 10(3) min(-1), respectively. Because hY155F
      still has significant catalytic activity, the hydroxyl group on Tyr155 may not be
      as important as proposed. Interestingly, hY155F was found to be 3. 3 times more
      active than the human wild-type DT-diaphorase in the reduction of CB1954.
      Computer modeling based on our results suggests that CB1954 is situated in the
      active site, with the aziridinyl group pointing toward Tyr155 and the amide group
      placed near a hydrophobic pocket next to Tyr128. Dicoumarol, Cibacron blue,
      chrysin, 7,8-dihydroxyflavone, and phenindone are competitive inhibitors of the
      enzyme with respect to nicotinamide coenzymes. The binding orientations of
      dicoumarol, flavones, and phenindone in the active site of DT-diaphorase were
      predicted by results from our inhibitor-binding studies and computer modeling
      based on published X-ray structures. Our studies generated results that explain
      why dicoumarol is a potent inhibitor and binds differently from flavones and
      phenindone in the active site of DT-diaphorase.

PMID- 10419546
TI  - Inducible cyclic AMP early repressor protein in rat pinealocytes: a highly
      sensitive natural reporter for regulated gene transcription.
AB  - Rhythmic activity of arylalkylamine N-acetyltransferase (AANAT) determines
      melatonin synthesis in rat pineal gland. The transcriptional regulation of AANAT
      involves the activating and inhibiting transcription factors of the cyclic AMP
      (cAMP)-signaling pathway, cAMP response element-binding protein and inducible
      cAMP early repressor (ICER), respectively. Activation of this pathway is centered
      around norepinephrine, stimulating beta(1)-adrenergic receptors, but various
      other transmitters can modulate melatonin biosynthesis. To compare the
      transcriptional impact of norepinephrine with that of other neurotransmitters on
      melatonin synthesis, we determined ICER protein levels in pinealocytes and, in
      parallel, hormone secretion. The dose-dependent inductions of ICER protein by
      norepinephrine, the beta(1)-adrenergic receptor agonist isoproterenol, vasoactive
      intestinal peptide, pituitary adenylate cyclase-activating polypeptide, and
      adenosine are correlated to regulatory dynamics in melatonin production.
      Importantly, ICER protein induction required lower ligand concentrations than the
      induction of melatonin biosynthesis. Although neuropeptide Y, glutamate, and
      vasopressin altered norepinephrine-stimulated hormone production without
      affecting ICER levels, the activation of voltage-gated cation channels increased
      ICER without affecting hormone synthesis. Sensitivity and versatility of ICER
      induction in pinealocytes make these neuroendocrine cells a valuable model system
      in which to study molecular interactions determining a regulated gene expression.

PMID- 10419547
TI  - Photoaffinity labeling the torpedo nicotinic acetylcholine receptor with
      [(3)H]tetracaine, a nondesensitizing noncompetitive antagonist.
AB  - Tetracaine (N,N-dimethylaminoethyl-4-butylaminobenzoate) and related N,N
      dialkylaminoethyl substituted benzoic acid esters have been used to characterize
      the high-affinity binding site for aromatic amine noncompetitive antagonists in
      the Torpedo nicotinic acetylcholine receptor (nAChR). [(3)H]Tetracaine binds at
      equilibrium to a single site with a K(eq) value of 0.5 microM in the absence of
      agonist or presence of alpha-bungarotoxin and with a K(eq) value of 30 microM in
      the presence of agonist (i.e., for nAChR in the desensitized state). Preferential
      binding to nAChR in the absence of agonist is also seen for N,N-DEAE and N,N
      diethylaminopropyl esters, both binding with 10-fold higher affinity in the
      absence of agonist than in the presence, and for the 4-ethoxybenzoic acid ester
      of N, N-diethylaminoethanol, but not for the 4-amino benzoate ester (procaine).
      Irradiation at 302 nm of nAChR-rich membranes equilibrated with [(3)H]tetracaine
      resulted in covalent incorporation with similar efficiency into nAChR alpha,
      beta, gamma, and delta subunits. The pharmacological specificity of nAChR subunit
      photolabeling as well as its dependence on [(3)H]tetracaine concentration
      establish that the observed photolabeling is at the high-affinity
      [(3)H]tetracaine-binding site. Within alpha subunit, >/=95% of specific
      photolabeling was contained within a 20-kilodalton proteolytic fragment beginning
      at Ser(173) that contains the M1 to M3 hydrophobic segments. With all four
      subunits contributing to [(3)H]tetracaine site, the site in the closed channel
      state of the nAChR is most likely within the central ion channel domain.

PMID- 10419548
TI  - Identification of amino acids of the torpedo nicotinic acetylcholine receptor
      contributing to the binding site for the noncompetitive antagonist
      [(3)H]tetracaine.
AB  - [(3)H]Tetracaine is a noncompetitive antagonist of the Torpedo nicotinic
      acetylcholine receptor (nAChR) that binds with high affinity in the absence of
      cholinergic agonist (K(eq) = 0.5 microM) and weakly (K(eq) = 30 microM) in the
      presence of agonist (i.e., to nAChR in the desensitized state). In the absence of
      agonist, irradiation at 302 nm of nAChR-rich membranes equilibrated with
      [(3)H]tetracaine results in specific photoincorporation of [(3)H]tetracaine into
      each nAChR subunit. In this report, we identify the amino acids of each nAChR
      subunit specifically photolabeled by [(3)H]tetracaine that contribute to the high
      affinity binding site. Subunits isolated from nAChR-rich membranes photolabeled
      with [(3)H]tetracaine were subjected to enzymatic digestion, and peptides
      containing (3)H were purified by SDS-polyacrylamide gel electrophoresis followed
      by reversed phase HPLC. N-terminal sequence analysis of the isolated peptides
      demonstrated that [(3)H]tetracaine specifically labeled two sets of homologous
      hydrophobic residues (alphaLeu(251), betaLeu(257), gammaLeu(260), and
      deltaLeu(265); alphaVal(255) and deltaVal(269)) as well as alphaIle(247) and
      deltaAla(268) within the M2 hydrophobic segments of each subunit. The labeling of
      these residues establishes that the high-affinity [(3)H]tetracaine-binding site
      is located within the lumen of the closed ion channel and provides a definition
      of the surface of the M2 helices facing the channel lumen.

PMID- 10419549
TI  - A transmembrane domain of the sulfonylurea receptor mediates activation of ATP
      sensitive K(+) channels by K(+) channel openers.
AB  - ATP-sensitive K(+) (K(ATP)) channels are a complex of an ATP-binding cassette
      transporter, the sulfonylurea receptor (SUR), and an inward rectifier K(+)
      channel subunit, Kir6.2. The diverse pharmacological responsiveness of K(ATP)
      channels from various tissues are thought to arise from distinct SUR isoforms.
      Thus, when assembled with Kir6. 2, the pancreatic beta cell isoform SUR1 is
      activated by the hyperglycemic drug diazoxide but not by hypotensive drugs like
      cromakalim, whereas the cardiac muscle isoform SUR2A is activated by cromakalim
      and not by diazoxide. We exploited these differences between SUR1 and SUR2A to
      pursue a chimeric approach designed to identify the structural determinants of
      SUR involved in the pharmacological activation of K(ATP) channels. Wild-type and
      chimeric SUR were coexpressed with Kir6.2 in Xenopus oocytes, and we studied the
      resulting channels with the patch-clamp technique in the excised inside-out
      configuration. The third transmembrane domain of SUR is found to be an important
      determinant of the response to cromakalim, which possibly harbors at least part
      of its binding site. Contrary to expectations, diazoxide sensitivity could not be
      linked specifically to the carboxyl-terminal end (nucleotide-binding domain 2) of
      SUR but appeared to involve complex allosteric interactions between transmembrane
      and nucleotide-binding domains. In addition to providing direct evidence for the
      structure-function relationship governing K(ATP) channel activation by potassium
      channel-opening drugs, a family of drugs of the highest therapeutic interest,
      these findings delineate the determinants of ligand specificity within the
      modular ATP-binding cassette-transporter architecture of SUR.

PMID- 10419550
TI  - Selective regulation of G protein-coupled receptor-mediated signaling by G
      protein-coupled receptor kinase 2 in FRTL-5 cells: analysis of thyrotropin,
      alpha(1B)-adrenergic, and A(1) adenosine receptor-mediated responses.
AB  - G protein-coupled receptor kinases (GRKs) play a key role in the process of
      receptor homologous desensitization. In the present study, we address the
      question of whether a variety of receptors coupled to different G protein
      subtypes and naturally expressed on the same cell are selectively regulated by
      GRK2. The signaling stimulated by thyrotropin (TSH), alpha(1B)-adrenergic, and
      A(1) adenosine receptors was studied in FRTL-5 cells permanently transfected to
      overexpress GRK2 and GRK2-K220R, a kinase dead GRK dominant negative mutant. In
      FRTL-5 overexpressing GRK2, TSH-induced cyclic AMP response was attenuated,
      indicating that TSH receptor is desensitized by this kinase. Consistently, FRTL-5
      cells overexpressing GRK2-K220R show increased TSH-induced cyclic AMP response,
      demonstrating that this receptor is under tonic control by GRK. Unlike TSH
      receptor, alpha(1B)-adrenergic receptor response was unaffected in FRTL-5
      overexpressing GRK2 and GRK2-K220R. When A(1) adenosine receptors were
      stimulated, G(ialpha)-mediated cyclic AMP inhibition was totally unaffected by
      overexpression of either GRK2 or GRK2-K220R. By contrast, G(betagamma)-mediated
      response (activation of mitogen-activated protein kinases) was efficiently
      desensitized by GRK2 but was unaffected by GRK2-K220R overexpression. The present
      study documents that overexpression of GRK2 results in a selective regulation of
      different G protein-coupled receptors expressed on the same cell and that this
      kinase can regulate preferentially only one of the different pathways activated
      by the same receptor. The preferential regulation of the A(1) adenosine receptor
      stimulated mitogen-activated protein kinases by GRK2 indicates that this kinase
      can have additional regulatory effects on G(betagamma)-stimulated pathways,
      possibly through direct binding and regulation of the receptor-G(betagamma)
      complex.

PMID- 10419551
TI  - Autoregulation of bradykinin receptors: agonists in the presence of interleukin
      1beta shift the repertoire of receptor subtypes from B2 to B1 in human lung
      fibroblasts.
AB  - Elevated formation of bradykinin (BK) and Lys-BK or kallidin (KD) and their
      carboxypeptidase metabolites desArg(9)BK and desArg(10)KD is evident at sites of
      inflammation. Moreover, B2 receptors (B2R), which mediate the action of BK and
      KD, participates in the acute stage of the inflammatory and pain response,
      whereas B1 receptors (B1R), through which desArg(9)BK and desArg(10)KD act,
      partake in the chronic stage. We hypothesized that kinins autoregulate B2R and
      B1R expression in favor of B1R. Incubation of IMR-90 cells with BK (100 nM) led
      to a loss (89%) of B2R with a half-life (T(1/2)) of 7.0 min. Concomitantly, BK
      increased B1R (2- to 3-fold) with a T(1/2) of 120 min. DesArg(10)KD (100 nM) had
      no effect on B2R but increased B1R (3- to 4-fold) with the same rate as BK.
      Interleukin-1beta (IL-1beta; 500 pg/ml) also increased B1R (4- to 6-fold).
      Although both desArg(10)KD and BK increased the level of IL-1beta mRNA, IL-1beta
      receptor antagonist inhibited the increase in B1R only in response to BK.
      DesArg(10)KD and BK synergistically increased B1R (9-fold), which was further
      increased by inclusion of IL-1beta (36-fold). Therefore, kinin metabolism and
      kinin-stimulated production of cytokines may play a pivotal role in shifting the
      repertoire of kinin receptor subtypes in favor of B1R during inflammation.

PMID- 10419552
TI  - Agonistic effect of buprenorphine in a nociceptin/OFQ receptor-triggered reporter
      gene assay.
AB  - The role of the opioid-like receptor 1 (ORL1) and its endogenous ligand,
      nociceptin/orphanin FQ (N/OFQ), in nociception, anxiety, and learning remains to
      be defined. To allow the rapid identification of agonists and antagonists, a
      reporter gene assay has been established in which the ORL1 receptor is
      functionally linked to the cyclic AMP-dependent expression of luciferase. N/OFQ
      and N/OFQ(1-13)NH(2) inhibited the forskolin-induced luciferase gene expression
      with IC(50) values of 0.81 +/- 0.5 and 0.87 +/- 0.16 nM, respectively.
      Buprenorphine was identified as a full agonist at the ORL1 receptor with an
      IC(50) value of 8.4 +/- 2.8 nM. Fentanyl and 7-benzylidenenaltrexone displayed a
      weak agonistic activity. The ORL1 antagonist [Phe(1)Psi(CH(2)-NH)Gly(2)]N/OFQ((1
      13))NH(2) clearly behaved as an agonist in this assay with an IC(50) value of 85
      +/- 47 nM. Thus, there is still a need for antagonistic tool compounds that might
      help to elucidate the neurophysiological role of N/OFQ.

PMID- 10419553
TI  - Regulation of nerve growth factor release by nitric oxide through cyclic GMP
      pathway in cortical glial cells.
AB  - In the present study, we found that S-nitroso-N-acetyl-DL-penicillamine, a
      spontaneous nitric oxide (NO) generator, dose-dependently inhibited basal nerve
      growth factor (NGF) release from mixed glial cells. To elucidate the function of
      endogenous NO in the regulation of NGF release, the mixed glial cells were
      stimulated with lipopolysaccharide (LPS) or LPS plus interferon-gamma (IFNgamma).
      The results showed that LPS alone induced NGF release and moderate NO production.
      However, costimulation with LPS plus IFNgamma greatly enhanced NO production but
      significantly suppressed LPS-induced NGF release. When N(G)-monomethyl-L
      arginine, an NOS inhibitor, was added to the culture, the suppression of NGF
      release by IFNgamma was significantly reduced. Quantitative reverse transcription
      polymerase chain reaction demonstrated S-nitroso-N-acetyl-DL-penicillamine was
      also able to inhibit the LPS-induced NGF mRNA expression. To understand the
      different contributions of astroglia and microglia to this phenomenon, both cell
      types were purified. We found purified astroglia produced high amounts of NGF but
      low amounts of NO. However, purified microglia produced a large amount of NO but
      very low amounts of NGF after stimulation with LPS or LPS plus IFNgamma. Our data
      also indicated the second messenger cyclic GMP, but not cyclic AMP, was able to
      inhibit basal NGF release. In vivo experiments confirmed that NGF protein level
      was significantly enhanced in rats treated with L-N(omega)-nitro-arginine methyl
      ester and in endothelial NO synthase mutant mice. Taken together, we conclude NO
      derived mainly from microglia down-regulates NGF release from astroglia at the
      transcriptional level by stimulating cyclic GMP pathway.

PMID- 10419554
TI  - Effects of guanine, inosine, and xanthine nucleotides on beta(2)-adrenergic
      receptor/G(s) interactions: evidence for multiple receptor conformations.
AB  - The aim of our study was to examine the effects of different purine nucleotides
      [GTP, ITP, and xanthosine 5'-triphosphate (XTP)] on receptor/G protein coupling.
      As a model system, we used a fusion protein of the beta(2)-adrenergic receptor
      and the alpha subunit of the G protein G(s). GTP was more potent and efficient
      than ITP and XTP at inhibiting ternary complex formation and supporting adenylyl
      cyclase (AC) activation. We also studied the effects of several beta(2)
      adrenergic receptor ligands on nucleotide hydrolysis and on AC activity in the
      presence of GTP, ITP, and XTP. The efficacy of agonists at promoting GTP
      hydrolysis correlated well with the efficacy of agonists for stimulating AC in
      the presence of GTP. This was, however, not the case for ITP hydrolysis and AC
      activity in the presence of ITP. The efficacy of ligands at stimulating AC in the
      presence of XTP differed considerably from the efficacies of ligands in the
      presence of GTP and ITP, and there was no evidence for receptor-regulated XTP
      hydrolysis. Our findings support the concept of multiple ligand-specific receptor
      conformations and demonstrate the usefulness of purine nucleotides as tools to
      study conformational states of receptors.

PMID- 10419555
TI  - Selective killing of cancer cells based on loss of heterozygosity and normal
      variation in the human genome: a new paradigm for anticancer drug therapy.
AB  - Most drugs for cancer therapy are targeted to relative differences in the
      biological characteristics of cancer cells and normal cells. The therapeutic
      index of such drugs is theoretically limited by the magnitude of such
      differences, and most anticancer drugs have considerable toxicity to normal
      cells. Here we describe a new approach for developing anticancer drugs. This
      approach, termed variagenic targeting, exploits the absolute difference in the
      genotype of normal cells and cancer cells arising from normal gene sequence
      variation in essential genes and loss of heterozygosity (LOH) occurring during
      oncogenesis. The technology involves identifying genes that are: 1) essential for
      cell survival; 2) are expressed as multiple alleles in the normal population
      because of the presence of one or more nucleotide polymorphisms; and 3) are
      frequently subject to LOH in several common cancers. An allele-specific drug
      inhibiting the essential gene remaining in cancer cells would be lethal to the
      malignant cell and would have minimal toxicity to the normal heterozygous cell
      that retains the drug-insensitive allele. With antisense oligonucleotides
      designed to target two alternative alleles of replication protein A, 70-kDa
      subunit (RPA70) we demonstrate in vitro selective killing of cancer cells that
      contain only the sensitive allele of the target gene without killing cells
      expressing the alternative RPA70 allele. Additionally, we identify several other
      candidate genes for variagenic targeting. This technology represents a new
      approach for the discovery of agents with high therapeutics indices for treating
      cancer and other proliferative disorders.

PMID- 10419557
TI  - Differential and selective inhibition of protein kinase A and protein kinase C in
      intact cells by balanol congeners.
AB  - The fungal metabolite balanol is a potent inhibitor of protein kinase A (PKA) and
      protein kinase C (PKC) in vitro that acts by competing with ATP for binding (K(i)
      approximately 4 nM); congeners of balanol show specificity for PKA over PKC. We
      have characterized the effects of balanol and 10"-deoxybalanol in intact cells to
      determine whether these compounds cross the cell membrane and whether the potency
      and specificity noted in vitro are preserved in vivo. In neonatal rat myocytes
      and cultured A431 cells transiently transfected with a cyclic AMP response
      element-luciferase reporter construct, balanol inhibits the induction of
      luciferase activity by isoproterenol, indicating inhibition of PKA. Western
      analysis shows that both balanol and 10"-deoxybalanol reduce phosphorylation of
      cAMP response element-binding protein in isoproterenol-stimulated A431 cells;
      inhibition is concentration dependent with an IC(50) value of approximately 3
      microM. Balanol, but not 10"-deoxybalanol, inhibits phosphorylation of the
      myristoylated alanine-rich C kinase substrate protein, a PKC substrate, in
      phorbol ester-stimulated A431 cells (IC(50) approximately 7 microM). Our data
      demonstrate that balanol is a potent inhibitor of PKA and PKC in several whole
      cell systems and causes no obvious toxicity. In addition, balanol congeners
      inhibit PKA and PKC with the specificity and potency predicted by in vitro
      experiments.

PMID- 10419556
TI  - Inhibition of protein kinases by balanol: specificity within the serine/threonine
      protein kinase subfamily.
AB  - Balanol is a potent inhibitor of cyclic AMP-dependent protein kinase and protein
      kinase C, acting competitively with ATP with an affinity 3000 times that of ATP.
      We tested the capacity of balanol to inhibit representative serine- and threonine
      specific protein kinases from the protein kinase subfamily that shares a common
      conserved catalytic core with cyclic AMP-dependent protein kinase. Balanol's
      pattern of interactions indicates considerable diversity of the ATP/balanol
      binding sites of protein kinases within familial groups and even among isoforms
      of the same kinase. We propose that balanol is a protean structure that may be
      modified to produce selective, high-affinity inhibitors and probes of the ATP
      binding sites of serine/threonine protein kinases.

PMID- 10419558
TI  - Interactions of HIV protease inhibitors with ATP-dependent drug export proteins.
AB  - We used renal proximal tubules from a teleost fish (killifish; Fundulus
      heteroclitus), fluorescent substrates and confocal microscopy to study the
      interactions between human immunodeficiency virus protease inhibitors and drug
      transporting ATPases. Both saquinavir and ritonavir inhibited luminal
      accumulation of a fluorescent cyclosporin A derivative (a substrate for P
      glycoprotein) and of fluorescein methotrexate [a substrate for multidrug
      resistance-associated protein 2 (Mrp2)]. Of the two protease inhibitors,
      ritonavir was the more potent inhibitor of transport by a factor of at least 20.
      Ritonavir was at least as good an inhibitor of P-glycoprotein- and Mrp2-mediated
      transport as cyclosporin A and leukotriene C4, respectively. Inhibition of P
      glycoprotein- and Mrp2-mediated transport was not due to toxicity or impaired
      metabolism, because neither saquinavir nor ritonavir inhibited transport of
      fluorescein on the renal organic anion system. Experiments with a fluorescent
      saquinavir derivative showed strong secretion into the tubular lumen that was
      inhibited by verapamil, leukotriene C4, saquinavir, and ritonavir. Together, the
      data demonstrate that saquinavir, and especially ritonavir, are potent inhibitors
      of P-glycoprotein- and Mrp2-mediated transport. The experiments with the
      fluorescent saquinavir derivative suggest that these protease inhibitors may also
      be substrates for both P-glycoprotein and Mrp2.

PMID- 10419559
TI  - Effect of loss of DNA mismatch repair on development of topotecan-, gemcitabine-,
      and paclitaxel-resistant variants after exposure to cisplatin.
AB  - Loss of DNA mismatch repair (MMR) causes genomic instability by markedly
      increasing the frequency of sporadic mutations in both coding and noncoding
      sequences. Little is known about how loss of MMR affects sensitivity to the
      mutagenic effect of chemotherapeutic agents. We wanted to determine how loss of
      MMR affects the ability of cisplatin, a known mutagen, to generate human tumor
      cell variants resistant to other drugs with which cisplatin is commonly combined
      in treatment regimens. We compared the ability of cisplatin to produce variants
      resistant to topotecan, gemcitabine, and paclitaxel in two pairs of MMR
      proficient and -deficient cells that included sublines of the human colon
      carcinoma cell line HCT-116 and sublines of the human endometrial adenocarcinoma
      cell line HEC59. Cells were exposed to increasing concentrations of cisplatin for
      1 h, and the surviving population was tested for the frequency of variants
      resistant to these single molecular target drugs 10 days later. The frequency of
      variants increased linearly with cisplatin concentration for all three drugs.
      Cisplatin was 2.6 +/- 0.3- (S.D.), 3.6 +/- 0.9-, and 2.3 +/- 0.1-fold more potent
      at producing topotecan-, gemcitabine-, and paclitaxel-resistant variants in the
      MMR-deficient than in the MMR-proficient HCT116 cells (P <.05 for all). Cisplatin
      was 1.4 +/- 0.3- and 1.4 +/- 0.4-fold more potent at generating topotecan- and
      gemcitabine-resistant variants in MMR-deficient HEC59 cells than in MMR
      proficient HEC59+ch2 cells. Cisplatin was not more potent in generating
      paclitaxel-resistant variants in the MMR-deficient HEC59 cells. Spontaneous rates
      of generation of cells resistant to these three drugs were also measured in the
      HCT116 sublines. MMR-deficient HCT116 cells exhibited rates of generation of
      resistant variants that were 1.94- and 1.51-fold higher (P <.05) than those in
      the MMR-proficient cells for topotecan and gemcitabine, respectively; loss of MMR
      had no effect on the rate of generation of variants resistant to paclitaxel. We
      conclude that the loss of MMR increases the ability of cisplatin to generate
      variants resistant to topotecan, gemcitabine, and possibly paclitaxel and that
      MMR also plays a role in controlling the spontaneous rate of generation of
      variants resistant to topotecan and gemcitabine.

PMID- 10419560
TI  - Identification and characterization of three new alternatively spliced mu-opioid
      receptor isoforms.
AB  - We have identified four new mu-opiod receptor (MOR)-1 exons, indicating that the
      gene now contains at least nine exons spanning more than 200 kilobases.
      Replacement of exon 4 by combinations of the new exons yields three new
      receptors. When expressed in Chinese hamster ovary cells, all three variants
      displayed high affinity for mu-opioid ligands, but kappa and delta drugs were
      inactive. However, there were subtle, but significant, differences in the binding
      profiles of the three variants among themselves and from MOR-1.
      Immunohistochemically, the major variant, MOR-1C, displayed a regional
      distribution quite distinct from that of MOR-1. Region-specific processing also
      was seen at the mRNA level. Antisense mapping revealed that the four new exons
      were all involved in morphine analgesia. Together with two other variants
      generated from alternative splicing of exon 4, there are now six distinct MOR-1
      receptors.

PMID- 10419561
TI  - Point mutations at N434 in D1-S6 of mu1 Na(+) channels modulate binding affinity
      and stereoselectivity of local anesthetic enantiomers.
AB  - Voltage-gated Na(+) channels are the primary targets of local anesthetics (LAs).
      Amino acid residues in domain 4, transmembrane segment 6 (D4-S6) form part of the
      LA binding site. LAs inhibit binding of the neurotoxin batrachotoxin (BTX). Parts
      of the BTX binding site are located in D1-S6 and D4-S6. The affinity of BTX
      resistant Na(+) channels mutated in D1-S6 (mu1-N434K, mu1-N437K) toward several
      LAs is significantly decreased. We have studied how residue mu1-N434 influences
      LA binding. By using site-directed mutagenesis, we created mutations at mu1-N434
      that vary the hydrophobicity, aromaticity, polarity, and charge and investigated
      their influence on state-dependent binding and stereoselectivity of bupivacaine.
      Wild-type and mutant channels were transiently expressed in human embryonic
      kidney 293t cells and investigated under whole-cell voltage-clamp. For resting
      channels, bupivacaine enantiomers showed a higher potency in all mutant channels
      compared with wild-type channels. These changes were not well correlated with the
      physical properties of the substituted residues. Stereoselectivity was small and
      almost unchanged. In inactivated channels, the potency of bupivacaine was
      increased in mutations containing a quadrupole of an aromatic group (mu1-N434F,
      mu1-N434W, mu1-N434Y), a polar group (mu1-N434C), or a negative charge (mu1
      N434D) and was decreased in a mutation containing a positive charge (mu1-N434K).
      In mutation mu1-N434R, containing the positively charged arginine, the potency of
      S(-)-bupivacaine was selectively decreased, resulting in a stereoselectivity
      (stereopotency ratio) of 3. Similar results were observed with cocaine but not
      with RAC 109 enantiomers. We propose that in inactivated channels, residue mu1
      N434 interacts directly with the positively charged moiety of LAs and that D1-S6
      and D4-S6 form a domain-interface site for binding of BTX and LAs in close
      proximity.

PMID- 10419562
TI  - Steric hindrance is not required for n-alkanol cutoff in soluble proteins.
AB  - A loss of potency as one ascends a homologous series of compounds (cutoff effect)
      is often used to map the dimensions of binding sites on a protein target. The
      implicit assumption of steric hindrance is rarely confirmed with direct binding
      measurements, yet other mechanisms for cutoff exist. We studied the binding and
      effect of a series of n-alkanols up to hexadecanol (C16) on two model proteins,
      BSA and myoglobin (MGB), using hydrogen-tritium exchange and light scattering.
      BSA binds the n-alkanols specifically and, at 1 mM total concentration, is
      stabilized with increasing potency up to decanol (C10), where a loss in
      stabilizing potency occurs. Cutoff in stabilizing potency is concentration
      dependent and occurs at progressively longer n-alkanols at progressively lower
      total n-alkanol concentrations. Light scattering measurements of n-alkanol/BSA
      solutions show a smooth decline in binding stoichiometry with increasing chain
      length until C14-16, where it levels off at approximately 2:1 (alkanol:BSA). MGB
      does not bind the n-alkanols specifically and is destabilized by them with
      increasing potency until C10, where a loss in destabilizing potency occurs. Like
      BSA, MGB demonstrates a concentration-dependent cutoff point for the n-alkanols.
      Derivation of the number of methylenes bound at K(D) and the free energy
      contribution per bound methylene showed that no discontinuity existed to explain
      cutoff, rendering steric hindrance unlikely. The data also allow an energetic
      explanation for the variance of the cutoff point in various reductionist systems.
      Finally, these results render cutoff an untenable approach for mapping binding
      site sterics in the absence of complementary binding measurements, and a poor
      discriminator of target relevance to general anesthesia.

PMID- 10419563
TI  - Agonist-induced phosphorylation by G protein-coupled receptor kinases of the EP4
      receptor carboxyl-terminal domain in an EP3/EP4 prostaglandin E(2) receptor
      hybrid.
AB  - Prostaglandin E(2) receptors (EP-Rs) belong to the family of heterotrimeric G
      protein-coupled ectoreceptors with seven transmembrane domains. They can be
      subdivided into four subtypes according to their ligand-binding and G protein
      coupling specificity: EP1 couple to G(q), EP2 and EP4 to G(s), and EP3 to G(i).
      The EP4-R, in contrast to the EP3beta-R, shows rapid agonist-induced
      desensitization. The agonist-induced desensitization depends on the presence of
      the EP4-R carboxyl-terminal domain, which also confers desensitization in a G(i)
      coupled rEP3hEP4 carboxyl-terminal domain receptor hybrid (rEP3hEP4-Ct-R). To
      elucidate the possible mechanism of this desensitization, in vivo phosphorylation
      stimulated by activators of second messenger kinases, by prostaglandin E(2), or
      by the EP3-R agonist M&B28767 was investigated in COS-7 cells expressing FLAG
      epitope-tagged rat EP3beta-R (rEP3beta-R), hEP4-R, or rEP3hEP4-Ct-R. Stimulation
      of protein kinase C with phorbol-12-myristate-13-acetate led to a slight
      phosphorylation of the FLAG-rEP3beta-R but to a strong phosphorylation of the
      FLAG-hEP4-R and the FLAG-rEP3hEP4-Ct-R, which was suppressed by the protein
      kinase A and protein kinase C inhibitor staurosporine. Prostaglandin E(2)
      stimulated phosphorylation of the FLAG-hEP4-R in its carboxyl-terminal receptor
      domain. The EP3-R agonist M&B28767 induced a time- and dose-dependent
      phosphorylation of the FLAG-rEP3hEP4-Ct-R but not of the FLAG-rEP3beta-R. Agonist
      induced phosphorylation of the FLAG-hEP4-R and the FLAG-rEP3hEP4-Ct-R were not
      inhibited by staurosporine, which implies a role of G protein-coupled receptor
      kinases (GRKs) in agonist-induced receptor phosphorylation. Overexpression of
      GRKs in FLAG-rEP3hEP4-Ct-R-expressing COS-7 cells augmented the M&B28767-induced
      receptor phosphorylation and receptor sequestration. These findings indicate that
      phosphorylation of the carboxyl-terminal hEP4-R domain possibly by GRKs but not
      by second messenger kinases may be involved in rapid agonist-induced
      desensitization of the hEP4-R and the rEP3hEP4-Ct-R.

PMID- 10419564
TI  - Kainate receptors coupled to G(i)/G(o) proteins in the rat hippocampus.
AB  - Kainate receptors are a subtype of ionotropic glutamate receptors, permeable to
      cations and thus expected to have an excitatory depolarizing action on neurons.
      However, kainate receptor activation inhibits gamma-aminobutyric acid release in
      the hippocampus through activation of protein kinase C in a pertussis toxin
      dependent manner, suggesting a coupling of kainate receptors to G proteins. Thus,
      we directly investigated the G protein coupling of kainate receptors in the rat
      hippocampus by using a selective kainate receptor agonist, [(3)H](2S,4R)-4
      methylglutamate ([(3)H]MGA). [(3)H]MGA bound to a single site to hippocampal
      membranes with a K(D) value of 32 nM and a B(max) value of 1024 fmol/mg protein.
      This binding likely represents kainate receptors because it was displaced by
      domoate (K(i) = 4 nM), kainate (K(i) = 11 nM), and 6-cyano-7-nitroquinoxaline-2,3
      dione (K(i) = 1.4 microM), but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazole
      propionate (K(i) > 10 microM), (RS)-alpha-methyl-4-phosphonophenylglycine (K(i) >
      10 microM), or (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (K(i) > 10
      microM). Guanylylimidodiphosphate (30 microM), which uncouples all G protein
      coupled receptors, shifted to the right the saturation curve of [(3)H]MGA (K(D) =
      133 nM). This effect was mimicked by pretreatment of hippocampal membranes with
      modifiers of G(i)/G(o) proteins [30 microM N-ethylmaleimide (K(D) = 98 nM) or 25
      microgram/ml pertussis toxin (K(D) = 95 nM)] but not by a modifier of G(s)
      proteins [50 microgram/ml cholera toxin (K(D) = 32 nM)]. Treatment of solubilized
      hippocampal membranes with pertussis toxin (25 microgram/ml) decreased [(3)H]MGA
      affinity (K(D) = 105-113 nM), which was recovered by reconstitution of these
      pretreated solubilized hippocampal membranes with G(i)/G(o) proteins (K(D) = 41
      76 nM). These results indicate that hippocampal kainate receptors are coupled to
      G(i)/G(o) proteins.

PMID- 10419565
TI  - Dopamine transporter: transmembrane phenylalanine mutations can selectively
      influence dopamine uptake and cocaine analog recognition.
AB  - Cocaine blocks the normal role of the dopamine transporter (DAT) in terminating
      dopamine signaling through molecular interactions that are only partially
      understood. Cocaine analog structure-activity studies have suggested roles for
      both cationic and aromatic interactions among DAT, dopamine, and cocaine. We
      hypothesized that phenylalanine residues lying in putative DAT transmembrane (TM)
      domains were good candidates to contribute to aromatic and/or cationic
      interactions among DAT, dopamine, and cocaine. To test this idea, we
      characterized the influences of alanine substitution for each of 29 phenylalanine
      residues lying in or near a putative DAT TM domain. Cells express 22 mutants at
      near wild-type levels, manifest by DAT immunohistochemistry and binding of the
      radiolabeled cocaine analog [(3)H](-)-2-beta-carbomethoxy-3-beta-(4
      fluorophenyl)tropane (CFT). Seven mutants fail to express at normal levels. Four
      mutations selectively reduce cocaine analog affinities. Alanine substitutions at
      Phe(76), Phe(98), Phe(390), and Phe(361) located in TM domains 1 and 2, the
      fourth extracellular loop near TM 4 and in TM 7, displayed normal affinities for
      dopamine but 3- to 8-fold reductions in affinities for CFT. One TM 3 mutation,
      F(155)A, selectively decreased dopamine affinity to less than 3% of wild-type
      levels while reducing CFT affinity less than 3-fold. In a current DAT structural
      model, each of the residues at which alanine substitution selectively reduces
      cocaine analog or dopamine affinities faces a central transporter cavity, whereas
      mutations that influence expression levels are more likely to lie at potential
      helix/helix interfaces. Specific, overlapping sets of phenylalanine residues
      contribute selectively to DAT recognition of dopamine and cocaine.

PMID- 10419566
TI  - The N-terminal domain of gamma-aminobutyric Acid(B) receptors is sufficient to
      specify agonist and antagonist binding.
AB  - The recently identified gamma-aminobutyric acid type B receptors (GABA(B)Rs)
      share low sequence similarity with the metabotropic glutamate (mGlu) receptors.
      Like the mGlu receptors, the N-terminal extracellular domain (NTED) of GABA(B)Rs
      is proposed to be related to bacterial periplasmic binding proteins (PBPs).
      However, in contrast to the mGlu receptors, the GABA(B)Rs lack a cysteine-rich
      region that links the PBP-like domain to the first transmembrane domain. This
      cysteine-rich region is necessary for the PBP-like domain of mGlu receptors to
      bind glutamate. To delimit the ligand-binding domain of GABA(B)Rs, we constructed
      a series of chimeric GABA(B)R1/mGluR1 and truncated GABA(B)R1 receptor mutants.
      We provide evidence that despite the lack of a cysteine-rich region, the NTED of
      GABA(B)Rs contains all of the structural information that is necessary and
      sufficient for ligand binding. Moreover, a soluble protein corresponding to the
      NTED of GABA(B)Rs reproduces the binding pharmacology of wild-type receptors.
      This demonstrates that the ligand-binding domain of the GABA(B)Rs can correctly
      fold when dissociated from the transmembrane domains.

PMID- 10419567
TI  - Pathology of cerebral vascular malformations.
AB  - The gross and microscopic features of cerebral arteriovenous malformations,
      cavernous malformations, capillary telangiectases, and venous malformations are
      compared and contrasted. The pathogenesis of these lesions and possible
      interrelationships suggested by transitional lesions are also reviewed.

PMID- 10419568
TI  - The natural history of cavernous malformations.
AB  - This article reviews general information about cavernous malformations, including
      histology, radiology, epidemiology, and symptomatology. Rates of hemorrhage as
      reported in the literature are presented. Familial cavernous malformations and
      their genetic basis are discussed. Finally, the variations in the biological
      behavior of cavernous malformations in different regions of the central nervous
      system are discussed and outcomes are assessed.

PMID- 10419569
TI  - Diagnostic imaging of angiographically occult vascular malformations.
AB  - Occult vascular malformations of the central nervous system include cavernous
      malformations, capillary telangiectasis, and developmental venous anomalies
      (DVAs). Cavernous malformations are prone to multiple small hemorrhages and may
      enlarge with time. They have a heterogeneous appearance on CT and MR imaging with
      areas of hemorrhage in various states of evolution and sometimes calcifications.
      Developmental venous anomalies and capillary telangiectasis are usually
      incidental findings on imaging studies. They usually are not the cause of
      pathology by themselves, although DVAs can be associated with cavernous
      malformations in 8% to 33% of cases.

PMID- 10419570
TI  - Microsurgical treatment of supratentorial cavernous malformations.
AB  - The indications for the surgical management of supratentorial cavernous
      malformations are outlined and the results following operation are presented in
      this article. Surgery is indicated for most patients who present with seizures,
      neurologic deficit, or headache. The surgical approaches to lesions in the
      cerebrum are described. The operative morbidity and mortality are low. Over 95%
      of all patients have excellent or good results and return to their previous level
      of activity.

PMID- 10419571
TI  - Microsurgical treatment of infratentorial malformations.
AB  - The brain stem has long lost the designation of "no-man's land." Armed with a
      detailed knowledge of skull base and parenchymal neuroanatomy, coupled with the
      advances in intraoperative mapping and monitoring, most intrinsic brain stem
      cavernous malformations can be resected microsurgically. Success continues to
      depend on proper patient selection, optimal timing, thorough planning, meticulous
      technique, and completeness of the resection.

PMID- 10419573
TI  - Microarteriovenous malformations.
AB  - Microarteriovenous malformations (micro-AVMs) are a subgroup of brain AVM with a
      nidus diameter of less than 1 cm. Although many micro-AVMs may appear
      angiographically occult on cursory review, careful analysis will often reveal a
      subtle diagnostic feature. Micro-AVMs present with intracranial hemorrhages that
      are generally large and associated with significant neurologic impairment. An
      awareness of these lesions as a possible source of hemorrhage in a young person
      is critical. In general, micro-AVMs are eminently resectable lesions and patient
      outcome is determined primarily by the hemorrhage that brings them to medical
      attention.

PMID- 10419572
TI  - Overall surgical results of occult vascular malformations.
AB  - Surgical experience with angiographically occult vascular malformations,
      specifically cavernous malformations (CMs), has increased substantially over
      recent years. CMs are generally well-circumscribed, low-pressure vascular lesions
      amenable to resection. Overall, results obtained with operative management have
      been favorable; however, the location of the lesion impacts significantly on the
      outcome and morbidity of surgery, with those located within deep and brain stem
      regions carrying a higher incidence of persistent neurologic complications. As
      knowledge emerges regarding the long-term natural history of these lesions, the
      role of operative intervention in cases where surgical morbidity is high will
      become better defined.

PMID- 10419574
TI  - Stereotactic radiosurgery for management of deep brain cavernous malformations.
AB  - The indications for stereotactic radiosurgery for patients with cavernous
      malformations of the brain are discussed. Specific reference is made to technique
      and dose selection and to the results and potential complications of this
      approach. Radiosurgery is an alternative to microsurgical resection for some
      patients with malformations in high-risk brain locations.

PMID- 10419575
TI  - Management of cavernous malformations in the pediatric population.
AB  - The management of cavernous malformations (CMs) in a child is similar in many
      ways to that of CMs in an adult. There are specific general principles that need
      to be considered when approaching these lesions in children, however. The long
      life span anticipated in the pediatric patient may favor an aggressive surgical
      approach for single, small asymptomatic cavernous malformations or for certain
      symptomatic lesions in eloquent locations. The observed history of a given
      malformation may be the best guide to determine its treatment. The authors
      discuss some of these principles and review their experience with a series of
      children who have presented for management of cerebral CM.

PMID- 10419576
TI  - Venous anomalies and associated lesions.
AB  - Developmental venous anomalies (DVAs) of the central nervous system are an
      exaggeration of the normal venous collector system, not a vascular lesion. They
      may be associated with many vascular and nonvascular processes with the nervous
      system including tumors, demyelinating lesions, arteriovenous malformations
      (AVMs), dural AVMs, cavernous malformations, and vascular lesions of the head,
      face, and eye. The instigating factors involved are not completely understood.
      The primary clinical significance of DVAs is that planned or inadvertent
      occlusion during treatment of associated lesions frequently leads to venous
      infarction of the surrounding normal brain.

PMID- 10419577
TI  - Occult vascular malformations and seizures.
AB  - Occult vascular malformations are frequently associated with intractable seizures
      and are a common cause of lesional epilepsy. MR imaging can identify and
      characterize these lesions with accuracy. The presurgical evaluation must be
      tailored to the individual patient's presentation and circumstances. Surgical
      results following lesionectomy plus corticectomy may be slightly superior to
      lesionectomy alone, but the overall prognosis is excellent.

PMID- 10419578
TI  - Normal human sleep.
AB  - Human sleep is an integral part of the basic rest-activity cycle that is found in
      all life forms. Comprised of cycling episodes of non-REM (NREM) and REM sleep,
      sleep can be measured and quantified by electrophysiologic, physiologic, and
      behavioral indices. Physiologic homeostasis changes markedly between wakefulness,
      NREM sleep, and REM sleep; moreover, many interacting factors determine sleep
      organization and sleep quality in a given individual. For the health
      practitioner, basic knowledge of sleep physiology and sleep modifiers is
      essential for the treatment of many clinical problems that are directly or
      indirectly related to phenomena occurring during sleep.

PMID- 10419579
TI  - Diagnosis and treatment of insomnia.
AB  - Insomnia is an extremely common complaint. Frequently, it occurs secondary to a
      number of medical and psychiatric conditions that directly affect the ability to
      initiate or maintain sleep. Insomnia can also occur secondary to behavioral
      factors, such as shift work, whereby patients either do not follow or control the
      dictates of their internal circadian rhythm or develop inappropriate conditioned
      responses to their sleep surroundings. Insomnia can be a primary and even
      lifelong complaint. Patients with primary insomnia probably have a physiologic
      problem that has not been clearly identified as the basis for their subjective
      complaint.

PMID- 10419580
TI  - Clinical and laboratory evaluations of excessive daytime sleepiness.
AB  - Sleepiness is common, dangerous, and difficult to quantitate. Sleepiness normally
      occurs if one tries to be awake during the circadian sleepiness phase or if one
      obtains insufficient sleep. Certain subjective tests of sleepiness can help the
      clinician to quantitate historical sleepiness. Objective tests of sleepiness are
      validated but imperfect predictors of future sleepiness. In spite of the
      difficulty in measuring sleepiness, a careful clinical evaluation of patients who
      complain of sleepiness is possible and usually reveals the correct diagnosis.

PMID- 10419581
TI  - The spectrum of sleep-disordered breathing.
AB  - The term sleep-disordered breathing has been used synonymously with the term
      obstructive sleep apnea syndrome (OSAS). In a broader sense, however, the
      disorders of breathing during sleep exist along a spectrum of severity. The
      mildest form of sleep-related breathing disorder is intermittent snoring, which
      is primarily a nuisance without significant health sequelae. The most severe form
      of disordered breathing is the obesity-hypoventilation syndrome, which is
      associated with severe morbidity and very high mortality. In between these two
      extremes are disorders of gradually increasing impact on morbidity and mortality:
      persistent snoring, upper airway resistance syndrome, and OSAS.

PMID- 10419582
TI  - Treatment of obstructive sleep apnea.
AB  - Options for the treatment of obstructive sleep apnea are varied and ever
      expanding. This article reviews the currently available treatment modalities in
      an evidence-based format. Focus is placed on the efficacy and limitations of each
      particular therapy.

PMID- 10419583
TI  - Sleep-disordered breathing in infants and children.
AB  - Sleep-disordered breathing (SDB) is underdiagnosed in infants and children. In
      addition to causing physical ailments that range from failure to thrive to cor
      pulmonale, SDB is often an unrecognized cause of failure in school or of
      behavioral disorders. Diagnosis of SDB requires a careful and detailed history
      and physical examination. Polysomnography is required to determine the nature of
      the problems, the magnitude of the physiologic disturbance, and, ultimately, the
      significance of the problem for the child. Earlier recognition, accurate
      diagnosis, and appropriate treatment should alleviate much of the childhood
      morbidity associated with these conditions.

PMID- 10419584
TI  - Narcolepsy and other causes of excessive daytime sleepiness.
AB  - Narcolepsy is a chronic disorder characterized by excessive daytime sleepiness,
      cataplexy, and other auxiliary symptoms. An interview can ascertain specific
      symptomatology, whereas a polysomnogram can reveal distinct clinical features.
      The clinical and laboratory evaluation together enable an accurate diagnosis of
      narcolepsy. This diagnosis includes a wide spectrum of symptom combinations.
      Treatment of narcolepsy should include the empathic guidance of a sleep
      clinician, an emphasis on sleep hygiene, and in many cases pharmacotherapy.

PMID- 10419585
TI  - Sleep in patients with respiratory disease.
AB  - Recent studies have emphasized the high prevalence and significant consequences
      of sleep abnormalities in patients who have underlying respiratory disease. Such
      abnormalities include the nocturnal increase in airway resistance in patients who
      have asthma, the impaired sleep quality and nocturnal desaturation (particularly
      during REM sleep) in patients who have chronic obstructive pulmonary disease, and
      the sleep-related hypoventilation and hypoxemia in patients who have various
      restrictive respiratory disorders. This article discusses the salient features,
      underlying pathophysiologic mechanisms, and treatment of these abnormalities of
      sleep in patients who have respiratory disease.

PMID- 10419586
TI  - Sleep in the elderly.
AB  - Older adults frequently experience difficulties with sleep that can be caused by
      specific sleep disorders (such as sleep-disordered breathing or periodic limb
      movements in sleep) and circadian rhythm disturbances. These all can be
      effectively treated. Medical illnesses and medications also can have a negative
      affect on sleep and effective management of these can significantly improve sleep
      in older adults. Sleep in institutionalized older adults is even more disturbed
      than sleep of community-dwelling older people and special considerations can be
      made to improve the quality of sleep in institutional settings.

PMID- 10419587
TI  - Oestrogen receptor and its potential role in breast cancer development.
AB  - The first studies of oestrogen receptor (ER) focused on measurements of levels in
      breast cancers and relationship to hormonal response, but the introduction of
      antibodies which can be used on fixed tissue has meant that ER can be studied in
      detail in normal and precancerous tissue. Cloning and sequencing of ER has
      resulted in more detailed understanding of structure and function, with the
      identification of variant forms in both tumours and normal, followed by the
      discovery that ER has two forms, the classical ER-alpha and ER-beta. Analyses of
      both forms in normal and preneoplastic breast will be important for our
      understanding of the role of ER in the development of breast cancer and its
      possible prevention.

PMID- 10419588
TI  - Human leukocyte antigens and cancer: is it in our genes?
AB  - Human leukocyte antigens (HLAs) are widely expressed cell surface molecules which
      present antigenic peptides to T-lymphocytes, thus modulating the immune response.
      The efficiency of peptide presentation by HLAs is dependent on the extreme
      polymorphism in the HLA-encoding loci within the major histocompatibility complex
      (MHC). HLA polymorphism is known to alter disease susceptibility and progression
      in a range of predominantly inflammatory conditions, many of which are T
      lymphocyte-mediated. More recently, the importance of alterations in HLA
      expression and polymorphisms within HLA-encoding loci has emerged in the
      development of malignancy. This review concentrates on the role of HLA
      polymorphism in malignant disease, with discussion of the major cancers in which
      HLA associations have become clear, as well as the potential mechanisms by which
      HLA polymorphisms may act as important factors, or cofactors, in the pathogenesis
      of malignant disease. In addition, the role of certain non-HLA genes within the
      MHC in the pathogenesis of malignancy is also considered briefly.

PMID- 10419589
TI  - Oestrogen receptor expression in the normal and pre-cancerous breast.
AB  - As oestrogen is associated with most of the epidemiological risk factors for
      breast cancer, the number and distribution of oestrogen receptor positive (ER+)
      cells could have a bearing on the development of the disease. ER+ cells were thus
      studied in the normal breast and in the spectrum of in situ proliferations which
      range from non-atypical hyperplasia to in situ carcinoma and are associated with
      different levels of risk for developing breast cancer. In the normal pre
      menopausal breast, ER+ cells comprised the minority and were distributed singly,
      being surrounded by oestrogen receptor negative (ER-) cells. ER+ cells showed a
      statistically significant increase with age, reaching a plateau after the
      menopause, and the increase was associated with a tendency for positive cells to
      become contiguous in patches of variable size. A small proportion of lobules
      showing involutional change comprised over 90 per cent ER+ cells. The
      significance of this feature is not clear but no evidence was found that it was
      pre-cancerous. The percentage of ER+ cells was slightly increased in hyperplasia
      of usual type (non-atypical hyperplasia, HUT) and the relationship to age was
      maintained. The staining pattern was variable; in some lesions ER+ cells were
      surrounded by ER- cells whereas in others there were contiguous groups of
      positive cells sometimes accounting for more than 90 per cent of cells in the
      lesion. In contrast, all cases of atypical ductal hyperplasia (ADH), lobular in
      situ neoplasia (LIN) and ductal carcinoma in situ (DCIS) exhibited positivity of
      contiguous cells accounting for the majority in the lesions. Furthermore, the
      relationship between ER+ cell numbers and age was lost in these lesions,
      indicating autonomy of ER expression or of proliferation of cells expressing the
      receptor. It is hypothesized that this dysregulation of receptor expression or of
      ER+ cell numbers at the ADH stage may be the precursor of abnormal expression of
      cyclins and other cell cycle control proteins which have been shown first to
      appear in DCIS.

PMID- 10419590
TI  - Different proliferative patterns characterize different preinvasive breast
      lesions.
AB  - The study of cell-cycle associated proteins Ki-67/MIB-1, bcl-2 and p53 could
      clarify some features regarding the early phases of neoplastic progression in the
      breast. An extensive immunohistochemical study was carried out of the expression
      of these markers in all kinds of preinvasive breast lesions and their collateral
      normal parenchyma, a type of analysis not previously reported. The specimens were
      35 florid ductal hyperplasias (FDHs), 8 atypical ductal hyperplasias (ADHs), 12
      well-differentiated intraductal carcinomas (WDICs), 20 intermediately
      differentiated intraductal carcinomas (IDICs), 14 poorly differentiated
      intraductal carcinomas (PDICs), 12 atypical lobular hyperplasias (ALHs), 12 type
      A lobular carcinomas in situ (LCIS), 150 normal small-size ducts and 365 lobules.
      All FDHs, ADHs, WDICs, and lobular lesions showed low proliferation (Ki-67/MIB
      1), bcl-2 positivity, and p53 negativity; all PDICs expressed high proliferation,
      while 85 per cent and 7 per cent were p53 and bcl-2 positive respectively; IDICs
      showed high proliferation (50 per cent), bcl-2 expression (70 per cent), and p53
      positivity (30 per cent), but no correlation between the expression of these
      markers was observed. Independent of the type of collateral lesion and age of the
      patient, 90 per cent and 10 per cent of small ducts/lobules showed low and high
      proliferation and diffuse and low bcl-2 expression respectively; no p53
      positivity was observed. The modulation of cell proliferation and apoptosis
      control in ductal lesions could be the expression of a progression from
      hyperplasia/WDIC to PDIC, in which IDICs represent the link, owing to their
      immunoprofile. An alternative purely speculative hypothesis is that the different
      immunoprofile of the preinvasive lesions reflects their different origin in
      normal breast parenchyma. Low proliferative or bcl-2 positive lobules could be
      the site of origin of the lesions maintaining this phenotype, namely FDHs, ADHs,
      WDICs and lobular lesions, while highly proliferative or bcl-2 negative lobules
      could be the site in which PDICs develop. Consequently, preinvasive breast
      lesions could express a different regulation of apoptosis control and
      proliferative activity from the very beginning, rather than a modulation during
      neoplastic progression.

PMID- 10419591
TI  - BAT-26 identifies sporadic colorectal cancers with mutator phenotype: a
      correlative study with clinico-pathological features and mutations in mismatch
      repair genes.
AB  - Microsatellite instability (MSI) is present in most colorectal cancers (CRC)
      associated with hereditary nonpolyposis colorectal cancer (HNPCC). MSI testing in
      so-called sporadic forms of CRC may become a useful tool in identifying new HNPCC
      kindred. The aim of this study was to analyse the utility of BAT-26 as a marker
      to identify CRCs with MSI and to investigate whether sporadic CRCs with MSI have
      a phenotypic expression similar to HNPCC cases. MSI was detected using two
      methods, an association of 7 poly(CA) repeats and a poly(A) repeat alone, BAT-26,
      in a series of 62 patients with apparently sporadic forms of CRC. Germ-line and
      somatic mutations in the hMSH2, hMLH1, and hMSH6 genes were analysed in patients
      with MSI+ tumours. Patients with MSI+ at poly(CA) loci and at BAT-26 were younger
      (p=0.024 and p=0.002), had tumours more frequently right sided (p=0.017 and
      p=0.0001) and more often mucinous (p=0.037 and p=0.005, respectively) than
      patients with MSI negative tumours. Mutation analysis allowed the identification
      of two patients carrying germ-line mutations in the hMLH1 gene (both were BAT
      26+) and two other patients who had somatic mutation in the hMSH2 and in hMLH1
      genes. In conclusion, the detection of MSI using poly(CA) repeats or BAT-26 alone
      allowed the identification of a subset of patients with clinico-pathological
      characteristics similar to those associated to HNPCC. BAT-26 has the advantage of
      being a simple and less expensive method that might be used as a screening
      procedure before mutation analysis.

PMID- 10419592
TI  - Comparison of losses of heterozygosity and replication errors in primary
      colorectal carcinomas and corresponding liver metastases.
AB  - In order to investigate genetic alterations specific to liver metastases of
      colorectal carcinomas, losses of heterozygosity and replication errors have been
      compared in 15 cases of primary colorectal carcinoma and in the corresponding
      metastatic liver tumours. Fifteen microsatellite markers located on 13 different
      chromosomal arms were used in the study. The LOH patterns of the primary and the
      metastatic tumours were identical in eight cases and showed differences in seven
      cases. Areas of deletion predominantly or completely common to the colorectal and
      the metastatic tumour were detected on chromosomes 5q, 8p, 17p, 18q, and 22q.
      Preferential loss in metastatic tumours was observed on chromosomal arm 3p.
      Replication errors were found in four primary tumours and in three of the
      corresponding secondaries. A replication error phenotype specific to a metastasis
      was not observed.

PMID- 10419593
TI  - Clonal analysis of a case of multifocal oesophageal (Barrett's) adenocarcinoma by
      comparative genomic hybridization.
AB  - Oesophageal adenocarcinomas arising in Barrett's epithelium occasionally present
      as multiple lesions. This could be due to either a multifocal presentation of the
      same tumour, or different neoplasms arising simultaneously in a dysplastic
      Barrett's oesophagus ('field cancerization'). This is a report of the genetic
      analysis of multiple neoplastic sites in a Barrett's oesophagus with an extensive
      area of dysplasia. In addition, the dysplastic Barrett's epithelium was
      evaluated. For the genetic screening, comparative genomic hybridization (CGH)
      allowed evaluation of the whole genome of each specimen. Five cancerous regions
      were selected and subsequently dissected from paraffin-embedded tissue blocks.
      The use of archival materials enabled a targeted collection of representative
      tumour locations. Multiple genetic aberrations were detected by CGH in all cancer
      sites. Losses on 3p, 4, 7q, 18q, and Y, as well as gains on 8q, 9q, 12p, 13q,
      17q, 20p and X, were found in each specimen. In four out of the five lesions,
      simultaneous losses on 9p, 15q, and 16q, with concomitant gains on 5p, 7q, and
      10p, were disclosed by CGH. Adjacent high-grade dysplastic Barrett's mucosa
      shared the losses on 3p, 4, 7q, 9p, 18, and Y, as well as the gains on 5p, 7q,
      13q, 17q, and X, thereby confirming its precursor status. Within this single and
      rare case of multifocal Barrett's adenocarcinoma, a monoclonal genotype was
      present. This must have been caused by an extensive outgrowth of a single tumour.

PMID- 10419594
TI  - Gene rearrangements in T-cell lymphoblastic lymphoma.
AB  - This study presents an examination of the Ig heavy chain (IgH) and T-cell
      receptor gamma (TCRgamma) genes in a series of 39 CD3-positive T-cell acute
      lymphoblastic leukaemia (ALL) cases with and without co-expression of CD79a;
      30/39 cases had a rearrangement of the TCRgamma genes and two of these 30 cases
      also demonstrated an IgH rearrangement. No cases had solely an IgH rearrangement.
      The conclusion of the study is that lymphoblastic lymphoma cases that are
      positive for CD3 are of T-cell lineage, regardless of CD79a expression.

PMID- 10419595
TI  - Molecular analysis of multifocal prostate cancer lesions.
AB  - To analyse the origin of multifocal prostate cancer lesions, radical
      prostatectomy specimens from 17 patients were examined. As a marker of genetic
      lineage, the allelotype based on 33 microsatellite loci was compared between the
      different tumours present in a given case. Some results provide evidence
      suggestive of a clonal origin of multiple tumours in a subset of the prostates.
      In five cases, for example, comparison of multifocal tumour lesions within a
      given case revealed at least two concordant changes in allelic imbalance (AI)
      sequence dosages at different loci. In addition, considerable heterogeneity of
      allelotype was found within and among tumour foci of a given case. In five of the
      six tumours analysed for intratumour heterogeneity, for example, more than five
      discordant AI changes were found in one tumour region but not in the other.
      Conclusions regarding the clonality of such heterogeneous lesions are difficult
      to draw. A high frequency of AI changes in four lesions exhibiting prostatic
      intraepithelial neoplasia (mean 6.5 changes per lesion, range 3-6) was found,
      compared with eight primary tumours present in the same cases (mean 5.8 changes
      per lesion, range 3-6). The interpretation of AI associated with clinically
      detected prostate cancer remains a highly complex issue. The fact that no clear
      evidence was obtained for either a clonal or a non-clonal origin of multiple
      lesions in a given prostate indicates that several different mechanisms are
      likely to operate in establishing the allelotype and that additional evidence
      from unique mutations or selective gene inactivation may be necessary to obtain
      definitive results.

PMID- 10419596
TI  - Correlation of the osteoblastic phenotype with prostate-specific antigen
      expression in metastatic prostate cancer: implications for paracrine growth.
AB  - The characteristic sclerotic appearance of bone metastases from prostate cancer
      is unexplained but could involve excess peritumoural activity of osteoblast
      mitogens such as the insulin-like growth factors (IGFs). Since prostatic
      metastases are distinguished by androgen-dependent secretion of prostate-specific
      antigen (PSA), a serine protease which cleaves extracellular IGF-binding proteins
      and thereby enhances the bioavailability of IGFs, the relationship was examined
      between tumour PSA expression and the osteoblastic phenotype. To this end, a
      cohort of 27 prostate cancer patients was evaluated to determine the relationship
      between serum PSA and radiographic bone lesion density at first presentation with
      metastatic disease. No linear correlation between absolute PSA levels and
      metastatic osteosclerosis was apparent. However, non-parametric statistical
      analysis revealed a highly significant link between low-PSA (<20 ng/ml)
      metastatic prostate cancer and osteolytic bone lesions (p<0.0001, chi(2)=21.5).
      This finding raises the possibility that the osteoblastic phenotype of prostate
      cancer derives in part from PSA-dependent proteolysis of IGF-binding proteins
      within bone matrix.

PMID- 10419597
TI  - Genetic aberrations in oligodendroglial tumours: an analysis using comparative
      genomic hybridization (CGH).
AB  - Four low-grade oligodendrogliomas, nine anaplastic oligodendrogliomas and two
      mixed oligoastrocytomas were investigated for chromosomal aberrations by
      comparative genomic hybridization on formalin-fixed, paraffin-embedded tissue
      samples. The most frequent losses observed involved 1p, 9p, 10pq, 14q, 16p, 19q,
      while the most frequent gains were seen on 7pq, 11pq, 17p, 19pq, and Xp. In one
      oligodendroglioma, a highly specific amplification of 1q32.1 was seen. The
      frequent losses of 14q have not been reported previously. In the two cases of
      mixed oligoastrocytomas multiple gains and losses were found that did not show a
      clear overlap with the alterations found in the pure oligodendrogliomas.

PMID- 10419598
TI  - Cyclin D1 expression in astrocytomas is associated with cell proliferation
      activity and patient prognosis.
AB  - An important positive regulator of the cell cycle, cyclin D1, is often amplified
      and overexpressed in malignancies. Cyclin D1 aberrations were analysed in grade
      II-IV astrocytomas by fluorescence in situ hybridization (FISH), mRNA in situ
      hybridization and immunohistochemistry. Proliferation activity was determined by
      Ki-67(MIB-1) immunolabelling and mitotic counting. High cyclin D1 expression was
      observed in grade IV astrocytomas (grades II-III versus grade IV; mRNA
      expression: p<0.001; immunoexpression: p=0.013), and correlated with poor patient
      survival (p<0.001, n=46). Upregulated cyclin D1 expression was also closely
      associated with poor patient prognosis in grade II-III astrocytomas (p<0.001,
      n=30). Cyclin D1 gene was not found to be amplified (n=7). Cell proliferation
      activity was significantly increased in tumours exhibiting high cyclin D1 mRNA
      levels (Ki-67(MIB-1): p<0.001; mitotic count: p<0.001) and high cyclin D1 protein
      expression (Ki-67(MIB-1): p=0.002; mitotic count: p=0.012). These results
      indicate that increased production of cyclin D1 is closely associated with high
      cell proliferation activity and aggressive behaviour in diffusely infiltrating
      astrocytomas.

PMID- 10419599
TI  - Effect of ovarian steroid deficiency on oestrogen receptor alpha expression in
      bone.
AB  - The mechanism by which oestrogen and hormone replacement therapy (HRT) maintain
      bone mass in women is still unclear. It has previously been shown that cells of
      osteoblast lineage in vivo, particularly osteocytes, express oestrogen receptor
      alpha (ERalpha). Nevertheless, it is still debatable whether oestrogen and the
      ovarian steroids have a direct affect on osteocytes. If they could regulate
      osteocyte ERalpha expression, this would be strong evidence for the involvement
      of these cells in the hormonal regulation of bone mass. This study therefore
      aimed to compare bone biopsies from women who were replete with ovarian steroids
      (pre-ovariectomy or post-HRT) with those from the same women when hormone
      deficient (post-ovariectomy or pre-HRT) for cellular localization of ERalpha
      protein or mRNA expression by indirect immunofluorescence, or by in situ
      hybridization combined with reverse transcriptase-polymerase chain reaction (IS
      RT-PCR) respectively. Image analysis showed that proportions of osteocytes
      positive for immunodetectable ERalpha were higher in hormone-replete than in
      hormone-deficient women (25+/-SEM 3 per cent, 12+/-SEM 4 per cent, respectively;
      n=5), with similar but non-statistically significant changes in osteoblasts. This
      was observed even when HRT was commenced 18 years after menopause. In contrast,
      grain volume/unit cell area of osteoblast mRNA signal was markedly higher when
      hormone-deficient (0.055+/-0.01) than when hormone-replete (0.016+/-0.004), with
      similar but non-significant differences in osteocytes. This preliminary study
      indicates up-regulation of osteocyte ERalpha protein by ovarian steroids in these
      patients, which is accompanied by decreased osteoblast ERalpha mRNA expression,
      providing further evidence for the involvement of osteocytes in the regulation of
      skeletal structure by ovarian steroids.

PMID- 10419600
TI  - Defective post-transcriptional processing of MUC2 mucin in ulcerative colitis and
      in Crohn's disease increases detectability of the MUC2 protein core.
AB  - Ulcerative colitis (UC) and, to a lesser extent, Crohn's disease (CD) are
      associated with a reduction of the protective mucus layer in the large intestine;
      the role of this alteration in the pathogenesis of either disease is, however,
      not clear. To learn more about the molecular mechanism of the alteration of the
      mucus layer, the expression of the main intestinal mucin, MUC2, was investigated
      in relation to inflammation and dysplasia. Formalin-fixed, paraffin-embedded
      biopsies from 70 patients with UC and 16 patients with CD, and 13 biopsies from
      normal colonic mucosa, were used for detection of MUC2 mRNA by in situ
      hybridization with the SMUC41 probe, and MUC2 protein by immunohistochemistry
      with the antibody CCP58. The steady-state concentration of MUC2 mRNA was not
      affected by UC or CD. By contrast, the amount of the detectable MUC2 protein,
      assessed as the immunoreactive score (IRS), was significantly (p<0. 0001)
      increased in UC (IRS=8.0+/-3.8) and CD (8.0+/-3.7), compared with the normal
      colonic mucosa (IRS=2.0+/-1.5). This alteration occurred in the inactive phase of
      inflammation and persisted in the active phase of the disease. It was also
      observed during bacterial or protozoal inflammation (n=7). The IRS values did not
      correlate with the grade of inflammation or dysplasia. Simultaneous
      histochemistry with high iron diamine and immunohistochemistry indicated that the
      increase of detectable MUC2 is concomitant with low mucin sulphation in the same
      cells. These data indicate that the strong MUC2 protein staining in colonic
      mucosa of patients with UC or CD is due to a long-term alteration of the post
      transcriptional modification of the MUC2 molecule, leading to its better
      detectability by the anti-MUC2 antibody CCP58. This alteration, induced by the
      inflammatory process, may affect the gel thickness and may contribute to a
      protracted autoimmune response.

PMID- 10419601
TI  - The trefoil peptide TFF1 inhibits the growth of the human gastric adenocarcinoma
      cell line AGS.
AB  - TFF1 is a 60-amino acid peptide produced in normal gastric mucosa which forms
      dimers spontaneously. Tumours of patients with gastric cancer usually have
      reduced TFF1 levels and disruption of the TFF1 gene causes animals to develop
      gastric adenomas and carcinomas. The effect of normal sequence human recombinant
      TFF1 and an analogue (Cys(58)-->Ser(58)), which is unable to dimerize, on the
      proliferation and morphology of the human gastric adenocarcinoma cell line AGS
      was therefore investigated. Proliferation, assessed by total cell number and
      [methyl-(3)H]thymidine incorporation, was reduced by dimeric TFF1 in a dose
      dependent manner. Monomeric TFF1 also reduced proliferation but was less potent
      than the dimeric form. It is concluded that TFF1 may be an important controller
      of gastric cell proliferation, that dimerization of TFF1 is important in this
      effect, and that the reduced levels of TFF1 seen in gastric cancer may be of
      clinical relevance.

PMID- 10419602
TI  - PCR analysis in the pathological diagnosis of Whipple's disease: emphasis on
      extraintestinal involvement or atypical morphological features.
AB  - PCR analysis of species-specific bacterial 16S rRNA gene of Tropheryma whippelii
      was performed in biopsies from 10 cases of Whipple's disease (WD). In seven
      patients showing the typical clinical picture of WD, PCR was performed on the
      diagnostic intestinal biopsy. In the remaining three cases (an autopsy case of
      disseminated WD and two patients showing lymphadenopathy as the initial clinical
      presentation), PCR was done on lymph node specimens. In one of the lymph node
      biopsies, an unusual sarcoidlike granulomatous reaction had led to the diagnosis
      of sarcoidosis. The specific bacterial DNA was detected in all cases, both in
      intestinal biopsies and in lymph node specimens. Follow-up biopsies after
      antibiotic therapy were evaluated in two patients. The two follow-up biopsies
      were negative, although in both of them scattered nests of PAS-positive
      macrophages remained. The results of this study suggest that PCR analysis of
      species-specific sequences of the 16S rRNA of Tropheryma whippelii is a very
      useful tool for the pathological diagnosis of WD. It confirms the diagnosis of WD
      in intestinal biopsies as well as in extraintestinal sites, even when the
      morphological appearance is not typical. It is also the most precise technique
      for monitoring therapeutic effects.

PMID- 10419603
TI  - Loss of one but not two mdm2 null alleles alters the tumour spectrum in p53 null
      mice.
AB  - The transcriptional activity of the p53 tumour suppressor is inhibited by binding
      to MDM2. The in vivo significance of this interaction was established in mdm2
      null mice. Embryonic lethality due to loss of mdm2 is completely rescued by
      deletion of p53, indicating that the lethality is due to inability to down
      modulate p53 function. The production of mice null for both p53 and mdm2 led to
      an assessment of the role of MDM2 in tumour development. Tumour latency and
      spectrum in p53 null mice were monitored in the presence or absence of mdm2. Two
      unusual findings resulted: tumour latency in p53 null/mdm2 heterozygous mice was
      longer than in p53/mdm2 double-null mice; and the incidence of sarcomas was
      higher in p53 null/mdm2 heterozygous mice than in p53 null or p53/mdm2 double
      null mice. These data raise the possibility that heterozygosity at the mdm2 locus
      in the absence of p53 affects the development of tumours of mesenchymal origin.

PMID- 10419604
TI  - Denaturation of type II collagen in articular cartilage in experimental murine
      arthritis. Evidence for collagen degradation in both reversible and irreversible
      cartilage damage.
AB  - Degradation of type II collagen is thought to be a key step in the destruction of
      articular cartilage in patients with rheumatoid arthritis or osteoarthritis. The
      aim of this study was to investigate whether type II collagen degradation is
      associated with cartilage destruction. Type II collagen degradation was studied
      in two murine arthritis models, zymosan-induced arthritis (ZIA), which develops
      reversible articular cartilage damage based on proteoglycan analysis, and antigen
      induced arthritis (AIA), in which there is irreversible damage to the cartilage.
      Type II collagen degradation was assayed immunohistochemically using the COL2
      3/4m antibody which recognizes denatured type II collagen, such as is produced by
      collagenase cleavage. In both models, degradation of type II collagen was
      observed in the non-calcified articular cartilage of arthritic but not of control
      knees. In the patella-femoral compartment, collagen denaturation started to
      increase on day 3 (ZIA) and day 7 (AIA) and remained high on day 14. In contrast,
      in the tibia-femoral compartment, type II collagen breakdown was not increased
      before 14 days in either model. By 28 days, collagen denaturation was strongly
      reduced in the patella-femoral compartment in the ZIA model, but persisted in the
      tibia-femoral compartment in both models. In conclusion, increased type II
      collagen degradation was found in articular cartilage of both ZIA and AIA
      animals. Since ZIA does not develop irreversible cartilage destruction, this
      indicates that cartilage may have the ability to withstand a limited degree of
      type II collagen degradation without developing irreversible damage.

PMID- 10419605
TI  - Cytogenetic study of spontaneous abortions by transabdominal villus sampling and
      direct analysis of villi.
AB  - We report our experience in a cytogenetic study of 93 spontaneous abortions.
      Specimens were obtained by transabdominal chorionic villus sampling (TACVS) in
      women requesting prenatal diagnosis by chorionic villus sampling (CVS) but in
      whom an arrested pregnancy had been diagnosed during the ultrasound examination.
      Our success rate, i.e. the percentage of cases where we obtained results, was 91.
      4 per cent, and the rate of abnormalities-mostly aneuploidies and polyploidies
      was 62.3 per cent. In normal cases, masculine:feminine ratio was 1:1. These
      results confirm those obtained by other groups earlier this decade and allow us
      to conclude that, for the cytogenetic study of spontaneous abortions, CVS is a
      better approach than the culture of the products of conception after evacuation,
      because the success rate is higher and because it provides certainty that the
      specimens obtained are of fetal origin.

PMID- 10419606
TI  - The risk of cystic fibrosis with prenatally detected echogenic bowel in an
      ethnically and racially diverse North American population.
AB  - Fetal echogenic bowel has been reported as a normal variant in the second
      trimester, and has also been associated with an adverse fetal outcome, including
      cystic fibrosis (CF), an autosomal recessive genetic disease. Previous studies
      have reported that 3.3 to 13.3 per cent of fetuses with echogenic bowel
      discovered during the second trimester were affected with CF. Between 1994 and
      1998 our laboratory tested 159 cases with echogenic bowel detected during a
      routine ultrasound examination. The ethnic/racial background of cases included
      Caucasian, African-American, Middle Eastern, Hispanic, Ashkenazi Jewish and
      Asian. We identified two CF fetuses (1.3 per cent) and eight fetuses with a
      single identifiable CF mutation (5 per cent) within this diverse population.
      These data indicated that the risk of CF in a fetus with echogenic bowel in this
      population was less than the 3.3 to 13.3 per cent prior risk currently used in
      most Bayesian calculations. Furthermore, the results suggested that specific
      risks for couples should be calculated using data specific for their ethnic or
      racial background. Based on our results, we recommend either amniocentesis for
      fetal CF studies or CF carrier screening of both parents when fetal echogenic
      bowel is detected as a 1.3 per cent risk of CF is considered high enough to
      warrant further testing.

PMID- 10419608
TI  - Prenatal sonographic chest and lung measurements for predicting severe pulmonary
      hypoplasia.
AB  - Pulmonary hypoplasia was diagnosed sonographically in 32 fetuses from 20 to 33
      weeks of gestation. In addition to standard biometry, transverse thoracic
      diameter (TTD), sagittal thoracic diameter (TSD), thoracic circumference (TC) and
      lung diameter (LD) were measured in all cases and compared with known nomograms.
      The fetuses were divided into five groups according to the main sonographic
      findings: group 1-skeletal dysplasia; group 2-renal agenesis; group 3
      diaphragmatic hernia; group 4-hydrothorax; and group 5-others. Severe pulmonary
      hypoplasia (PH) was diagnosed prenatally in all cases on the basis of LD
      measurements. In 17 (53.1 per cent) out of 32 cases TTD was below the 5th
      percentile while lower TSD measurements were recorded in 15 (46.8 per cent)
      fetuses. A thorax circumference below the 5th percentile for the respective
      gestational age was found in 15 cases (46.8 per cent) and a decreased LD/TC ratio
      in 25 cases (78.1 per cent). In 13 out of 32 fetuses pulmonary hypoplasia was
      diagnosed before, and in 19 cases after 24 weeks of gestation. Pulmonary
      hypoplasia was confirmed by autopsy in all cases. CONCLUSION: pulmonary
      hypoplasia can be sonographically detected before 24 weeks of gestation. In cases
      of skeletal dysplasia and renal agenesis pulmonary hypoplasia can be diagnosed by
      chest and lung measurements, whereas in diaphragmatic hernia and hydrothorax
      diagnosis of pulmonary hypoplasia is possible only by lung measurement.

PMID- 10419607
TI  - Tuberous sclerosis with intracardiac rhabdomyoma in a fetus with trisomy 21: case
      report and review of literature.
AB  - A large cardiac rhabdomyoma protruding into the left ventricle was diagnosed in a
      fetus at 21+2 weeks of gestation by grey-scale echocardiography. Obstruction to
      left ventricular outflow was ruled out by colour and spectral Doppler
      echocardiography. No other abnormalities were noted and karyotyping by
      cordocentesis revealed trisomy 21 (47,XY,+21). Post-mortem examination after
      termination of pregnancy confirmed the prenatal diagnosis of cardiac rhabdomyoma
      and in addition revealed fetal tuberous sclerosis. Demonstration of cardiac
      rhabdomyoma by prenatal ultrasound should raise suspicion of the presence of
      fetal tuberous sclerosis. Despite the incidental association with aneuploidy,
      fetal karyotyping is suggested for optimal counselling of parents.

PMID- 10419609
TI  - Cytogenetic aspects of the Canadian early and mid-trimester amniotic fluid trial
      (CEMAT).
AB  - Cytogenetic results from a large multicentre randomized controlled study of 2108
      amniotic fluids obtained at 11+0-12+6 weeks (EA) and 1999 fluids at 15+0-16+6
      weeks (MA) were compared. There was no statistically significant difference in
      the rate of chromosome abnormalities (EA =1.9 per cent; MA=1.7 per cent) or level
      III mosaicism (EA=0.2 per cent; MA= 0.2 per cent) between the groups. Level I and
      Level II mosaicism occurred more frequently in MA. Maternal cell contamination
      was not significantly different between the groups, but maternal cells only were
      analysed from one bloody EA fluid. The number of repeat amniocenteses because of
      cytogenetic problems was 2.2 per cent in the EA group compared with only 0.3 per
      cent in the MA group. On average, culture of EA fluids required one day more than
      MA fluids. Although both culture success (97.7 per cent) and accuracy (99.8 per
      cent) were high for patients randomized to the EA group, routine amniocentesis
      prior to 13 weeks' gestation is not recommended for clinical reasons including an
      increased risk of fetal loss and talipes equinovarus.

PMID- 10419610
TI  - Identification of fetal nucleated red cells in co-cultures from fetal and adult
      peripheral blood: differential effects of serum on fetal and adult
      erythropoiesis.
AB  - Seeking to optimize a novel method of isolating rare fetal erythroid cells in
      cultures from maternal blood, we have explored the effects of serum supplement on
      fetal and adult erythropoiesis. We used flow cytometry and sorting after
      labelling with antibodies to fetal haemoglobin (HbF) and adult haemoglobin (HbA).
      In adult blood-derived cultures, most nucleated red cells accumulated either only
      adult haemoglobin (F-A+) or a combination of fetal and adult haemoglobin (F+A+).
      Only a few were F+A-. Serum affected the proportions of adult cells expressing
      fetal haemoglobin (both F+A- and F+A+), which were minimized, but not eliminated
      altogether, with the use of charcoal-treated sera at low concentrations. In
      contrast, the expansion of fetal red cells, which made only fetal haemoglobin
      (F+A-) during at least one week of culture, was strongly increased with the use
      of charcoal treated sera, due to the removal of a charcoal-absorbable inhibitor.
      In co-cultures of fetal and adult erythroid cells, fetal cells could be enriched
      in the order of 200-fold by flow sorting with the F+A- criterion. However, since
      adult F+A- cells could not be suppressed completely, the purity of sorted fetal
      cells still depended on the relative numbers of fetal and maternal erythroid
      clonogenic cells in the blood sample. Thus, we demonstrate a method by which
      fetal nucleated red cells potentially present in maternal blood cultures can be
      identified and isolated from the vast majority of maternal erythroid cells, based
      on their correlated contents of fetal and adult haemoglobin.

PMID- 10419611
TI  - Ultrasound evaluation of fetal spine length between 14 and 24 weeks of gestation.
AB  - The objective of our study was to establish a nomogram of fetal spine length in
      the second trimester of pregnancy by using two and three-dimensional ultrasound.
      Fetal spine length was measured prospectively by means of transabdominal
      ultrasonography in 114 normal singleton pregnancies between 14 and 24 weeks of
      gestation. Regression analyses were performed on spine length, gestational age,
      biparietal diameter and femur length. Supplementary three-dimensional ultrasound
      to assess fetal spine length was performed in 75 cases. Fetal spine length, as a
      function of gestational age, was expressed by the following regression equation:
      spine length (mm) = -47.2 + 7.16 x gestational age (weeks), with a Pearson
      correlation coefficient of R(2)=0.956. The results of the measurements revealed
      no difference between two and three-dimensional ultrasound. Our study defines the
      normal limits of fetal spinal length in the second trimester of pregnancy and
      demonstrates a high correlation between spinal length, gestational age,
      biparietal diameter and femur length. However, there are still too few prenatal
      research data to say whether and to what extent an assessment of fetal spine
      length at this stage of pregnancy can be used for prenatal diagnosis of
      congenital syndromes, which, among other manifestations, are marked by fetal
      spine lengthening or shortening.

PMID- 10419612
TI  - Prenatal features of Noonan syndrome.
AB  - We report six cases of Noonan syndrome which presented prenatally with
      sonographic abnormalities. These included increased nuchal fluid, short femora,
      pleural effusions, hydrops, cardiac and renal abnormalities. A review of all
      cases of Noonan syndrome seen at two regional genetics centres confirms the
      association with these sonographic abnormalities. These cases demonstrate the
      diversity of prenatal presentation of Noonan syndrome and highlight the need to
      consider this diagnosis, particularly when faced with a fetus with a normal
      karyotype and varying degrees of oedema or hydrops, with a short femur length.

PMID- 10419613
TI  - Enrichment, identification and analysis of fetal cells from maternal blood:
      evaluation of a prenatal diagnosis system.
AB  - In this study we evaluated the performance of a system for the enrichment,
      identification and analysis of fetal cells in maternal peripheral blood. Blood
      samples were collected from women after chorionic villus sampling and enriched
      for the presence of nucleated erythrocytes using a three-step procedure, namely:
      (a) centrifugation to separate nucleated red blood cells (NRBCs) from the
      majority of red blood cells (RBCs) and white blood cells (WBCs); (b) selective
      lysis of the remaining maternal RBCs; (c) separating the NRBCs from the remaining
      WBCs in a three-layer density gradient. Fetal cells were identified by using a
      monoclonal antibody against the gamma-chain of fetal haemoglobin (anti-HbF) and a
      nuclear stain (DAPI). Additionally, to further increase the specificity of the
      identification, and to eliminate some of the undesired staining by maternal
      leukocytes, a fluorescent antibody (CD45) was added. The sex chromosome
      complement of the cells was determined by fluorescence in situ hybridization
      (FISH) with X and Y-specific probes and the results were compared with the
      karyotypes obtained after analysis of chorionic villi. Using the described
      method, in all cases where the woman was carrying a male fetus (n=18) at least
      one XY cell was found, while no male cells were found in women carrying a female
      fetus. However, in the majority of cases with a male fetus (n=11) female HbF
      positive cells were found indicating the presence of maternal nucleated
      erythrocytes. The study demonstrates that the combination of anti-HbF and CD45 is
      a useful, but not fully specific, marker for fetal NRBCs and that additional
      markers are needed.

PMID- 10419614
TI  - Prenatal diagnosis of JAK3 deficient SCID.
AB  - The JAK3 gene, encoding a tyrosine kinase functionally coupled to cytokine
      receptors which share the common gamma chain, has been identified as the
      defective gene for autosomal recessive severe combined immunodeficiency (SCID).
      Thus, specific mutational diagnosis has become possible. We screened all exons
      with a combined single strand conformational polymorphism and hetero-duplex
      formation assay followed by sequence analysis to identify specific mutations in
      two families. This assay was used on chorionic villus sampling derived DNA in two
      fetuses from two unrelated families, where we found mutations in both parents. We
      were able to exclude the mutations in both fetuses by the 12th week of gestation.
      The described method for first-trimester prenatal diagnosis of autosomal
      recessive T-B+SCID provides a valid tool to aid in genetic counselling and
      possibly prenatal therapy in this disease.

PMID- 10419615
TI  - Prenatal prediction of spinal muscular atrophy in Chinese.
AB  - We used linkage analysis, non-isotope SSCP (single-strand conformation
      polymorphism) and PCR-RFLP (polymerase chain reaction-restriction fragment length
      polymorphism) for prenatal diagnosis of spinal muscular atrophy (SMA). A total of
      26 cases from 20 SMA families (16, type 1 and 4) were evaluated. 5 out of 26
      fetuses were affected and, following genetic counselling, the parents decided to
      terminate the pregnancies. Aborted fetal tissues were examined and the diagnosis
      was confirmed in each case. The 21 unaffected cases were either normals (12
      cases) or carriers (9 cases). These children have been followed for six months to
      two and a half years. No false-negative or false-positive results on prenatal
      testing were found. We conclude that prenatal diagnosis of SMA is reliable and
      accurate.

PMID- 10419616
TI  - Congenital anterior abdominal wall defects in the north of England, 1986-1996:
      occurrence and outcome.
AB  - The aim was to describe trends in prevalence, maternal age-specific prevalence,
      associated anomalies, clinical outcomes and the sensitivity of antenatal
      diagnosis of congenital anterior abdominal wall defects (in particular
      gastroschisis and exomphalos). Data were identified from a population-based
      register of major congenital abnormalities in the Northern health region of
      England, the Northern Congenital Abnormality Survey (NorCAS), between 1986 and
      1996. 296 cases were notified; there were 133 cases of gastroschisis, 98
      exomphalos, 30 limb-body wall defects and 23 other anterior abdominal wall
      defects. 12 cases could not be classified. In 19 (6 per cent) the initial
      diagnosis was changed following case review. 30 (30.6 per cent) cases of
      exomphalos were associated with a chromosomal anomaly compared with 1 (0.8 per
      cent) case of gastroschisis. The total prevalence for the 11 years was 6.33 (95
      per cent CI=5.57-7.08) per 10 000 live births, still births and terminations of
      pregnancy, and the overall birth prevalence was 4.30 (95 per cent CI=3.68-4.93)
      per 10 000 live births and still births. For gastroschisis, there was a
      significant increase over the study period in both the total prevalence (1.48 in
      1986 to 5.29 per 10 000 in 1996; chi(2)=8.41, p=0.00433) and the birth prevalence
      (1.48 in 1986 to 4.72 per 10 000 in 1996; chi(2)=7.42, p=0.00644), but there was
      no such significant increase for exomphalos (total prevalence chi(2)=2.29,
      p=0.13055; birth prevalence chi(2)=0.16, p=0.69348). The maternal age-specific
      prevalence was highest in the 11-19 year age group for gastroschisis but in the
      35-39 year age group for exomphalos. Fewer pregnancies with gastroschisis
      resulted in a termination and a greater proportion of cases were alive at one
      year compared with exomphalos. The sensitivity of abnormality detection by
      ultrasonography was 75 per cent and 77.3 per cent for gastroschisis and
      exomphalos, respectively. Antenatal diagnosis improved from 47.4 per cent during
      1986-91 to 80 per cent between 1992-96 for gastroschisis (chi(2)=5.7, p=0.00169),
      and from 55.6 per cent to 68.8 per cent for isolated exomphalos, although this
      increase was not significant. Total and birth prevalence of gastroschisis
      increased in the Northern region between 1986 and 1996. For exomphalos, there was
      a trend towards an increase in total prevalence and towards a decrease in birth
      prevalence. This decreasing trend has been accompanied by improvements in
      antenatal detection and subsequent termination of cases of exomphalos associated
      with other anomalies.

PMID- 10419617
TI  - Prenatal diagnosis of Canavan disease.

PMID- 10419618
TI  - Biochemical examination of mother's urine is useful for prenatal diagnosis of
      Bartter syndrome.
AB  - Bartter syndrome is characterized by renal potassium and chloride loss,
      hypokalaemia, hypochloraemic metabolic alkalosis and increased plasma renin
      activity along with elevated angiotensin II and hyperaldosteronism. For diagnosis
      we conducted biochemical examinations of both amniotic fluid and the mother's
      urine. Except for potassium, amniotic fluid electrolytes in a mother with a fetus
      with Bartter syndrome were high. Urinary chloride, sodium and calcium were very
      low. Thus, the latter parameters may allow prediction of fetal Bartter syndrome
      during the prenatal period.

PMID- 10419619
TI  - Maternal serum prostate-specific antigen and Down syndrome in the first and
      second trimesters of pregnancy. International Prenatal Screening Research Group.
AB  - It has been suggested that high levels of maternal serum prostate-specific (PSA)
      may be associated with fetal Down syndrome. We retrieved stored blood samples
      from 102 singleton Down syndrome pregnancies at 8-14 weeks' gestation and 99 at
      15-22 weeks' gestation, together with samples from five unaffected singleton
      control pregnancies matched for gestational age. PSA was measured using an
      ultrasensitive assay. Contrary to earlier reports, PSA levels were similar in
      affected and unaffected pregnancies in both the first and second trimester of
      pregnancy; 1.1 and 0.9 multiple of the normal median, respectively, in affected
      pregnancies. There was no indication that PSA would be a useful screening marker.

PMID- 10419620
TI  - Prenatal diagnosis of long QT syndrome using fetal magnetocardiography.
AB  - We describe the detection of congenital long QT syndrome in a fetus at 37 weeks'
      gestation using magnetocardiography (MCG). The prenatal diagnosis was confirmed
      by standard electrocardiography (ECG) performed after birth. This is the first
      case report of fetal long QT syndrome detected by MCG. Fetal MCG may be useful in
      the prenatal diagnosis of congenital cardiac disease with abnormal ECG findings.

PMID- 10419621
TI  - Maternal uniparental isodisomy for chromosome 14 detected prenatally.
AB  - Maternal uniparental disomy (UPD) for chromosome 14 (upd(14)mat) has been
      associated with a distinct phenotype. We describe the first case of maternal
      uniparental isodisomy for chromosome 14 detected prenatally, in a pregnancy with
      mosaicism for trisomy 14 observed in both a chorionic villus sample (CVS) and in
      amniocytes. Detailed analysis of polymorphic microsatellites showed that the
      fetus was essentially isodisomic for one of the mother's chromosomes 14 and that
      recombination had introduced a mid-long arm region of heterodisomy. The fetus,
      which died in utero at 18 weeks, showed no apparent pathological features. The
      case demonstrates for the first time a maternal meiosis II non-disjunction of
      chromosome 14 leading to a trisomic conception which has been incompletely
      corrected by 'rescue' in the early embryo.

PMID- 10419622
TI  - Prenatal diagnosis of variant late infantile neuronal ceroid lipofuscinosis
      (vLINCL[Finnish]; CLN5).
AB  - The first prenatal diagnosis of variant late infantile neuronal ceroid
      lipofuscinosis (vLINCL[Finnish]; CLN5) is reported. The disease belongs to the
      group of progressive encephalopathies in children with psycho-motor
      deterioration, visual failure and premature death. Neurons and several
      extraneural cells harbour lysosomal inclusions showing accumulation of material
      with histochemical characteristics of ceroid and lipofuscin. A Finnish woman with
      a daughter with vLINCL came for genetic counselling for her current pregnancy.
      Electron microscopy of a chorionic villus sample (CVS) at the 11th week of
      gestation did not reveal inclusions characteristic for NCL. DNA analysis showed
      that the fetus had inherited the major mutation, a 2 bp deletion of the CLN5 gene
      from the mother, and the same paternal (and maternal) haplotypes for COLAC1 and
      AC224 as the affected daughter. The pregnancy was terminated. Electron microscopy
      of the CVS of the aborted fetus at the 14th week of pregnancy showed lysosomal
      electron dense inclusions with straight and curved lamellar profiles consistent
      with vLINCL. Prenatal diagnosis of NCL-disorders (CLN1, CLN2, CLN3) can be made
      from CVS by demonstrating the mutations of the affected genes or by haplotype
      analysis using the closely linked markers in most cases. In various clinical
      settings the DNA diagnostics may not be possible. Demonstration of the
      characteristic inclusions of the placenta and fetal tissues remains a helpful
      adjunct in such cases.

PMID- 10419623
TI  - Trisomy 17 mosaicism in a four-year seven-month-old white girl: follow-up report.

PMID- 10419624
TI  - Incidence of abdominal wall defects.

PMID- 10419625
TI  - Maternal serum alpha-fetoprotein and anal atresia.

PMID- 10419626
TI  - Studies of peptide binding to allyl amine and vinyl acetic acid-modified polymers
      using matrix-assisted laser desorption/ionization mass spectrometry.
AB  - Previous studies have shown that increases in surface-peptide binding affinity
      result in decreases in peptide matrix-assisted laser desorption/ionization
      (MALDI) mass spectrometry (MS) ion signals. The present work demonstrates that,
      with appropriate corrections for peptide ionization efficiency under MALDI
      conditions, relative surface-peptide binding affinities can be assayed using the
      MALDI MS methodology. Peptides with a range of pI values are allowed to interact
      with amine-modified and carboxylic acid-modified polymer surfaces (produced by
      pulsed radio-frequency plasma polymerization of allyl amine and vinyl acetic
      acid) in buffered solutions of neutral pH. Because of the net positive and
      negative charges associated with the peptides and surfaces in solution, both
      electrostatic and hydrophilic interactions play a role in the surface-peptide
      interaction. Consistent with expectations, the peptide MALDI ion signals for
      peptides with net negative charges in solution are smaller than those for
      peptides with net positive charges in solution when the peptides are allowed to
      interact with positively charged surfaces. A reversal of the relative peptide
      MALDI ion signal intensities is observed when the same peptides are allowed to
      interact with negatively charged surfaces. Cumulatively, the results demonstrate
      that even modest changes in surface-peptide interactions can be comparatively
      probed by MALDI mass spectrometry.

PMID- 10419627
TI  - The use of beta, gamma-methyleneadenosine 5'-triphosphate to determine ATP
      competition in a scintillation proximity kinase assay.
AB  - A novel method for characterizing the kinetics of protein kinase inhibitors is
      described. This method uses glycogen synthase kinase beta as the model protein
      kinase and looks at the shift in IC50 of inhibitors using the nonhydrolyzable ATP
      analog, beta, gamma-methyleneadenosine 5'-triphosphate, also known as AMP-PCP.
      Due to its inability to be hydrolyzed, AMP-PCP is being used to characterize
      known glycogen synthase kinase inhibitors by determining the shift in IC50 at
      concentrations above its calculated Ki of 490 microM. The assay format for the
      detection of inhibition is a scintillation proximity assay which is robust and
      reproducible at very low levels of [gamma-33P]ATP. The use of AMP-PCP coupled
      with the use of the scintillation proximity assay allows this characterization of
      inhibition without increasing [gamma-33P]ATP and without significantly diluting
      the overall assay signal. We have used this method in kinetic analyses to
      demonstrate that we can detect a significant shift in IC50 with the known ATP
      competitive inhibitors, staurosporine, Ro 31-8220, and olomoucine. The IC50 for
      glycogen synthase peptide and lithium chloride, which has been reported to be
      uncompetitive, remains unchanged.

PMID- 10419628
TI  - Development of a carbon dioxide-capture assay in microtiter plate for aspartyl
      beta-hydroxylase.
AB  - CO2-capture methods have been used for assaying many decarboxylating enzymes
      including hydroxylation-coupled decarboxylation reactions. The traditional CO2
      capture method involves performing the reaction in capped tubes and radiometric
      measurement of trapped 14CO2 by scintillation counting. In this report, a 14CO2
      capture method in a 96-well microtiter plate format has been developed and a
      phosphor imaging system has been employed for sample measurement. The new assay
      method has been used successfully to assay aspartyl-beta-hydroxylase activity in
      microtiter plate format. The results obtained here compare favorably with those
      obtained from the traditional tube method. The method is sensitive, suitable for
      high throughput, and generally applicable to many CO2-releasing enzyme assays.

PMID- 10419630
TI  - Disposable microbore high-pressure liquid chromatography columns for protein and
      peptide separations.
AB  - A range of high-performance liquid chromatography (HPLC) columns with internal
      diameters of 0.25 to 1.8 mm have been constructed by securing glass or plastic
      tubing into standard HPLC fittings. These were packed with chromatographic
      materials chosen for operation at moderate pressures with high flow rates. These
      columns were shown to be effective in a conventional HPLC instrument for peptide
      and protein separations in reverse-phase mode and for proteins in ion-exchange
      and size-exclusion modes. The simple construction and low cost of these microbore
      columns allow them to be considered as disposable. Using only small amounts of
      any type of packing material, they have the flexibility to be adapted to a wide
      range of analytical and micropreparative separations.

PMID- 10419629
TI  - A homogeneous and multiplexed immunoassay for high-throughput screening using
      fluorometric microvolume assay technology.
AB  - We have developed a simple, homogeneous bead-based immunoassay for use with
      fluorometric microvolume assay technology (FMAT). The FLISA (fluorescence-linked
      immunosorbent assay) can be easily adapted from existing immunoassays, is
      comparable to traditional ELISAs with respect to linear dynamic range and
      sensitivity, and can be readily performed in 96- and 384-well plates.
      Additionally, the FLISA utilizes 100-fold less primary antibody than the
      conventional immunoassay. The scanner uses a helium/neon laser to image and
      measure bead-bound fluorescence while the background fluorescence is ignored.
      Consequently, no wash steps are required to remove unbound antibody, ligand, and
      fluorophore. Furthermore, the instrument is capable of detecting two different
      fluorescent dyes, allowing for multiplexed assays based on color. Fluorescent
      bead-based immunoassays were developed for the cytokines IL-6 and IL-8, and their
      use in both one-color and two-color FLISAs is demonstrated. Although no wash
      steps were employed, the FLISA was able to accurately measure the concentrations
      of IL-6 and IL-8 in the growth media of cytokine-stimulated HUVEC cells. In
      addition, a simulated high-throughput two-color FLISA positively identified those
      wells in a 384-well plate that contained different amounts of IL-6 and/or IL-8
      peptide. The homogeneous, multiplex and multiplate format of the FLISA reduces
      hands-on time and reagent usage, and is therefore ideally suited for high
      throughput screening.

PMID- 10419631
TI  - A bifunctional luminogenic substrate for two luminescent enzymes: firefly
      luciferase and horseradish peroxidase.
AB  - Horseradish peroxidase (HRP) catalyzes the oxidative chemiluminescent reaction of
      luminol, and firefly luciferase catalyzes the oxidation of firefly D-luciferin.
      Here we report a novel substrate, 5-(5'-azoluciferinyl)-2,3-dihydro-1,4
      phthalazinedione (ALPDO), that can trigger the activity of HRP and firefly
      luciferase in solution because it contains both luminol and luciferin
      functionalities. It is synthesized by diazotization of luminol and its subsequent
      azo coupling with firefly luciferin. NMR spectral data show that the C5' of
      benzothiazole in luciferin connects the diazophthalahydrazide. The electronic
      absorption and fluorescence properties of ALPDO are different from those of its
      precursor molecules. The chemiluminescence emission spectra of the conjugate
      substrate display biphotonic emission characteristic of azophthalatedianion and
      oxyluciferin. It has an optimum pH of 8.0 for maximum activity with respect to
      HRP as well as luciferase. At pH 8.0 the bifunctional substrate has 12 times the
      activity of luminol but has 7 times less activity than the firefly luciferin
      luciferase system. The specific enhancement of light emission from the cyclic
      hydrazide part of ALPDO helped in the sensitive assay of HRP down to 2.0 x 10(
      13) M and of ATP to 1.0 x 10(-14) mol. Addition of enhancers such as firefly
      luciferin and p-iodophenol (PIP) to the HRP-ALPDO-H2O2 system enhanced the light
      output.

PMID- 10419632
TI  - Homogeneous bioluminescence assay for galactosuria: interference and kinetic
      analysis.
AB  - Elevated galactose concentration in urine is an important clinical symptom of
      galactosemia and other metabolic disorders. A quantitative assay for galactose
      using firefly luciferase bioluminescence is presented. The assay couples the
      galactokinase and firefly luciferase reactions. A higher concentration of
      galactose present in the sample produces a faster decrease in ATP concentration,
      which is monitored by firefly luciferase bioluminescence. The kinetic assay is
      modeled and analyzed. The interference between the two reactions, the
      interference of certain sugars and other components in the urine, the
      specificity, and the optimal pH for galactokinase were studied. Calibration
      curves were constructed and compared with a conventional spectrophotometric assay
      for galactose. The bioluminescence assay is relatively fast and specific for
      galactose with a linear range from 1 to 20 mM galactose. The effect of other
      galactose metabolites (galactonate and galactitol) has also been studied.

PMID- 10419633
TI  - Liposome dehydration on nitrocellulose and its application in a biotin
      immunoassay.
AB  - The feasibility of utilizing dehydrated liposomes in the development of a simple
      immunoassay device for point-of-care diagnostics or field assays was
      demonstrated. The recovery of liposomes after a cycle of dehydration and
      rehydration was studied using biotin-tagged, dye-loaded liposomes with antibiotin
      antibodies immobilized in a defined zone on nitrocellulose strips. Liposomes were
      vacuum-dehydrated on the strip at a location below the antibiotin zone. The strip
      was placed in a tube containing a carrier solution and capillary action brought
      the solution to the dehydrated liposomes, rehydrated them, and caused them to
      migrate to the antibody zone where intact liposomes were captured and measured
      optically. High concentrations of either trehalose or sucrose external to the
      liposomes and both polyvinylpyrrolidone and gelatin in the membrane blocking
      reagent were essential for preservation of the dehydrated/rehydrated liposomes on
      nitrocellulose. Between 70 and 80% of the liposomes were recovered on the
      nitrocellulose strips after a cycle of dehydration and rehydration. The
      dehydrated liposomes on the strips were stable for at least 1 year when stored in
      vacuum-sealed plastic bags at 4 degrees C. The technique was successfully applied
      to the development of a rapid one-step strip immunoassay for biotin.

PMID- 10419635
TI  - Secreted human placental alkaline phosphatase as a reporter gene for in vivo gene
      transfer.

PMID- 10419634
TI  - Rapid staining of lipids on thin-layer chromatograms with amido black 10B and
      other water-soluble stains.

PMID- 10419636
TI  - Analysis of reduced and oxidized forms of cytochrome c by capillary
      electrophoresis and capillary electrophoresis-mass spectrometry.

PMID- 10419637
TI  - Assay of nucleoside 2-deoxyribosyltransferase activity with pyruvate
      kinase/lactate dehydrogenase coupling system.

PMID- 10419638
TI  - Primer design strategies for the targeted amplification of alternatively spliced
      molecules.

PMID- 10419639
TI  - Quantitative protein precipitation from guanidine hydrochloride-containing
      solutions by sodium deoxycholate/trichloroacetic acid.

PMID- 10419640
TI  - "In-gel" assay for identifying alternative nucleotide substrates for protein
      kinases.

PMID- 10419641
TI  - Optimizing expression of a rare codon-rich viral protein in Escherichia coli
      using the IMPACT system.

PMID- 10419643
TI  - The inheritance of desired characteristics: Children's view of the role of
      intention in parent-offspring resemblance.
AB  - Two studies examined children's beliefs about maternal intention as a mechanism
      for trait inheritance. In Study 1, 42 preschool-aged (4 to 5 years old) children
      and 81 adults were shown pictures of adult women (mothers) and were asked to
      identify their daughters. In the critical condition participants were asked to
      choose between a girl who shared an attribute with the mother and a girl who had
      the attribute desired by the mother. Trait types included physically heritable
      traits, nonheritable traits, and beliefs. Results from this study suggest that
      preschoolers do believe that maternal intention plays a role in the inheritance
      of physical traits. Study 2 was designed to determine whether preschoolers
      recognize limits on both the efficacy and the timing of maternal intention.
      Results suggest that children see some properties as outside of maternal control.
      Further, they do seem to see maternal intentions as operating prior to birth. One
      finding of these studies is that preschoolers may not have strong intuitions that
      offspring will resemble their parents. In addition, children seem to have
      different intuitions about the mechanisms of inheritance than do adults.

PMID- 10419642
TI  - Identification of unique fragments in overlapping large-insert clones by
      subtraction through representational difference analysis.

PMID- 10419644
TI  - Remembering specific episodes of a scripted event.
AB  - Children's memory for a specific episode of a repeated event was investigated in
      2 experiments. In Experiment 1, eighty 4- and 7-year-olds experienced a standard
      novel event 1, 2, or 4 times, followed by an episodic event for those children
      who had multiple standard event experiences. The episodic event involved the
      addition of both schema-typical and schema-atypical activities to the standard
      event. Following a 1-week delay, children were asked to recall both event types.
      Four-year-olds were more confused than older children regarding when the new
      activities had been experienced, although experience improved memory for the
      schema-atypical activities. In contrast, 7-year-olds were able to establish more
      accurate memories for both the schema-typical and the schema-atypical changes.
      Experiment 2 demonstrated that 4-year-olds could, however, establish distinct
      memories for both types of changes when the standard event was simplified. The
      results are discussed in terms of the development of the relation between script
      memory and memory for a specific instance of an event.

PMID- 10419645
TI  - When days are numbered: calendar structure and the development of calendar
      processing in English and Chinese.
AB  - Unlike English, Chinese uses a numerical system for naming months and days. This
      study explored whether this difference in naming affects the development of
      simple calendar calculation. Eight- and 10-year-old children as well as
      undergraduates in China and the United States were asked to name the day or month
      that comes a specified time before or after a given day or month. In each age
      group Chinese speakers primarily used calculation based on calendar names to
      solve these tasks, while English speakers primarily resorted to reciting the
      names. The magnitude of these differences was substantial; on difficult tasks
      Chinese fourth graders performed at speeds comparable to those of English
      speaking adults. Implications for models of how linguistic structure affects
      cognition are discussed.

PMID- 10419646
TI  - Involvement of both the tyrosine kinase and the phosphatidylinositol-3' kinase
      signal transduction pathways in the regulation of lipoprotein lipase expression
      in J774.2 macrophages by cytokines and lipopolysaccharide.
AB  - The regulation of macrophage lipoprotein lipase (LPL) by cytokines and
      lipopolysaccharide (LPS) is of potentially crucial importance in the pathogenesis
      of atherosclerosis and in the responses to endotoxin challenge. We show here that
      the reduction of LPL activity in J774.2 macrophages observed in the presence of
      interleukin (IL-1) and IL-11 was sensitive to herbimycin A, with the effect of
      LPS, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) on
      LPL activity being sensitive to both herbimycin A and wortmannin. The action of
      the inhibitors on the IFN-gamma-dependent reduction of LPL activity was mediated
      at the level of LPL mRNA metabolism, with translational and/or post-translational
      levels of regulation being involved in the action of all the other mediators
      tested. These observations suggest that both the tyrosine kinase and the
      phosphatidylinositol-3'-kinase signalling pathways are involved in the
      suppression of macrophage LPL expression by LPS and cytokines.

PMID- 10419647
TI  - IP-10 mRNA expression in cultured keratinocytes is suppressed by inhibition of
      protein kinase-C and tyrosine kinase and elevation of cAMP.
AB  - IFN-gamma-inducible protein-10 (IP-10) is a chemokine, which plays an important
      role in mediating inflammation by attracting activated T cells, and it has been
      demonstrated in inflammatory skin diseases and cutaneous T cell lymphomas.
      Keratinocytes can abundantly produce IP-10 mRNA after IFN-gamma treatment. In
      this study we explored possibilities to downregulate IP-10 expression using human
      cultured keratinocytes as a model system. Decreased IP-10 mRNA levels were found
      using specific inhibitors of protein kinase (PK)-C (H-7 and Calphostin C).
      Moreover, depletion of PK-C by pretreatment of the cells with phorbol myristate
      (PMA) also down-regulated IP-10 mRNA expression. In addition, elevated cAMP
      levels were shown to inhibit IP-10 mRNA expression as could be concluded from
      experiments with forskolin and W-7, substances which, directly or indirectly,
      raise the intracellular cAMP level. With Genistein, an inhibitor of tyrosine
      kinase, the IFN-gamma-induced IP-10 mRNA expression was also found to be
      diminished. These data suggest that inhibitors of the IP-10 mRNA expression in
      cultured keratinocytes may be potentially of clinical relevance to suppress
      inflammatory processes in the skin.

PMID- 10419648
TI  - CD27 signals through PKC in human B cell lymphomas.
AB  - Tumour necrosis factor receptor (TNFR) superfamily members play critical roles in
      the regulation of cell proliferation and death. One member of the TNFR
      superfamily, CD27, is unique because it is the only covalently linked homodimer
      in the family. CD27 and its cellular ligand, CD70, have been implicated in the
      regulation of T cell and B cell interactions that lead to cellular activation and
      regulation of immunoglobulin expression. Due to the unique nature of CD27, we
      chose to screen a number of B cell lymphoma cell lines for CD27 and CD70
      expression and evaluate CD27 activation by antibody cross-linking. Two cell
      lines, HT and SU-4, showed greater cellular proliferation when CD27 was cross
      lined and this correlated with increased PKC activation. Additionally, in the HT
      cell line cell surface expression of IgG was increased by CD27 cross-linking.
      Thus we have identified cellular systems for the study of CD27 signal
      transduction that will allow definition of the CD27 signal cascade of some B cell
      lymphomas.

PMID- 10419649
TI  - Differential effects of human erythroid burst stimulating activity (HuEBSA) on
      human cord blood burst forming units-erythroid (BFU-Es) as a function of their
      differentiation state.
AB  - An erythroid stimulating activity which promotes the growth of small bursts
      probably arising from mature burst forming units-erythroid (BFU-Es) of adult
      human bone marrow cells and called human erythroid burst stimulating activity
      (HuEBSA), was previously found in media conditioned by a fetal human kidney cell
      line. In the present work we report that adding HuEBSA to cultures did not
      increase the burst number but increased the size of bursts from cord blood (CB)
      cells. A similar observation was made using stem cell factor (SCF). However, a
      synergistic effect on the burst number was noted when both HuEBSA and SCF were
      introduced to cultures. We also noticed that CB erythroid progenitors pre
      cultured with 5637-Conditioned Medium [as a source of burst promoting activity
      (BPA)] and erythopoietin (Epo) for 3 days could be stimulated by HuEBSA but not
      by SCF. Similar results were obtained when interleukin 3 (IL-3) was introduced
      with Epo to the pre-cultures. These results suggest that two different
      populations of erythroid progenitors coexist in cord blood, one is Epo- and IL-3
      sensitive, the other solely Epo-sensitive. It also seems probable that HuEBSA
      acts on erythroid progenitors arising from the more immature erythroid
      population, since its stimulating activity was evident after a 3-day pre-culture
      of cord blood cells in Epo and IL-3.

PMID- 10419651
TI  - Interleukin 1beta mediates the effect of high D-glucose on the secretion of TNF
      alpha by mouse uterine epithelial cells.
AB  - Previous observations have shown that tumour necrosis factor alpha (TNF-alpha)
      synthesis is increased in the uterus of diabetic rats and that the epithelial
      layer lining the uterine lumen is the major site of TNF-alpha over-production. In
      the present study, TNF-alpha secretion was found to be stimulated by high D
      glucose levels in primary cultures of mouse uterine luminal cells but not in
      cultures of the mouse uterine epithelial WEG-1 cell line. Experiments were
      performed to investigate the possibility that non-epithelial cells may mediate
      the influence of high D-glucose on TNF-alpha production by uterine epithelial
      cells. Immunocytochemical analysis revealed the reproducible presence of a small
      proportion of macrophages in primary cultures. Macrophages of the RAW 264.7 cell
      line were found to secrete more interleukin (IL)-1beta (but not TNF-alpha) when
      cultured in high D-glucose. TNF-alpha production in WEG-1 cells was increased
      upon exposure to IL-1beta and both protein kinase-C and tyrosine kinase pathways
      appeared to be involved in TNF-alpha stimulation. Addition of IL-1 receptor
      antagonist to primary cultures partially abrogated the effect of high D-glucose.
      Since WEG-1 cells do not produce IL-1beta, the data lend support to the
      hypothesis that uterine epithelial cells synthesize high levels of TNF-alpha in
      response to hyperglycaemia via an increase in IL-1beta secretion by stromal
      macrophages.

PMID- 10419650
TI  - Ingested interferon alpha induces Mx mRNA.
AB  - We have demonstrated that ingested murine interferon alpha (IFN-alpha) suppressed
      clinical relapse in chronic relapsing experimental autoimmune encephalomyelitis
      (CR-EAE), decreased inflammation and suppressed the adoptive transfer of EAE, and
      is a biological response modifier in patients with multiple sclerosis. We
      examined the relative levels of the Mx mRNA signal using semiquantitative reverse
      transcription-polymerase chain reaction analysis on splenocytes from mice and
      peripheral blood mononuclear cells from man after IFN-alpha ingestion. Both mice
      and man demonstrated inducible levels of Mx mRNA after ingesting IFN-alpha.
      Murine spleen T cells and CD8(+)T cells also demonstrated upregulation of Mx
      mRNA. Murine whole splenocytes demonstrated upregulation of Mx mRNA after IFN
      alpha ingestion of 10 and 100 U, but not after 0, 1000, 5000 U. Ingested IFN
      alpha acts via established pathways of type 1 IFN signalling.

PMID- 10419652
TI  - The kinetics and stimulant dependence of cytokine production by blood and
      bronchoalveolar lavage T cells evaluated at the single cell level.
AB  - We have previously shown that bronchoalveolar lavage (BAL) T cells from human
      airways predominantly produce interferon gamma (IFN-gamma) and interleukin 2 (IL
      2) when stimulated ex vivo. The kinetics of TH1 and TH2 cell cytokine production
      by T cells from both blood and BAL were studied to establish the optimal time
      after stimulation either with pharbol myristate (PMA) and ionomycin or with the
      more physiological stimulus of anti-CD3 for intracellular cytokine detection of
      IFN-gamma, IL-2, IL-4 and IL-5 in both blood and BAL T cells. The optimal time
      for positive identification of IL-2 in both blood and BAL was 5 h after
      PMA/ionomycin stimulation, whereas the first peak for IFN-gamma was found after 5
      h in blood but after only 3 h in BAL. T cells from different biological
      compartments responded differently to each of the stimuli. Whilst anti-CD3
      stimulation did not induce TH1 cytokine production in blood T cells, it readily
      induced both IFN-gamma and IL-2 production in BAL T cells. The kinetics of
      cytokine production were found to be stimulus dependent. Whilst IL-2 production
      showed similar kinetics with both stimuli, the kinetics of IFN-gamma production
      differed between stimuli. We have also examined the effect of five different
      stimuli on cytokine production by T cells to determine whether different forms of
      stimulation may selectively stimulate or inhibit different cytokines. Not
      surprisingly, PMA/ionomycin induced a greater percentage of BAL T cells to
      produce TH1 cytokines. However, other than modest amounts of the TH2 cytokines IL
      4 and IL-5 were not induced by any of the five stimuli.

PMID- 10419653
TI  - Interleukin 5 release into asthmatic airways 4 and 24 hours after endobronchial
      allergen challenge: its relationship with eosinophil recruitment.
AB  - Interleukin 5 (IL-5), a cytokine with a range of activities on eosinophils, has
      been implicated in the allergic asthmatic reaction. We have investigated the
      kinetics of release of this cytokine into asthmatic airways as well as its
      relationship to eosinophil recruitment following allergen challenge. Twelve
      asthmatic patients underwent endobronchial allergen challenge and bronchoalveolar
      lavage (BAL) fluid was obtained either 4 h (n=6) or 24 h (n=6) after challenge.
      Four hours after challenge, levels of IL-5 were significantly increased in BAL
      fluid (10-fold concentration obtained from the allergen-challenge site compared
      with the saline control (median 2.67 pg/ml, range 1.0-7.4 pg/ml vs 1.0 pg/ml <1.0
      2.4 pg/ml, P<0.05). At 24 h levels of IL-5 increased further at the allergen site
      but not at the saline control lavage (31.1 pg/ml, range 3.6-59. 0 pg/ml vs 1.5
      pg/ml, range <1.5-4.9 pg/ml, respectively P<0.02). At 4h there was almost a three
      fold increase in IL-5 level, whereas at 24 h IL-5 levels were 20-fold greater.
      Differential cell counts showed that eosinophil numbers obtained 4 and 24 h after
      allergen challenge were 7 and 32 times higher than numbers after saline
      challenge. The parallel increase of eosinophil numbers and IL-5 concentrations in
      BAL fluid suggests that this cytokine may contribute to the eosinophil
      recruitment observed into asthmatic airways after allergen challenge.

PMID- 10419654
TI  - Sustained high-level production of murine chemokine C10 during chronic
      inflammation.
AB  - The murine CC chemokine C10, a macrophage chemoattractant, has been shown to have
      an unusually restricted expression pattern in cultured cells (LPS non-responsive,
      IL-4 inducible). Its occurrence in vivo has not been characterized. Here the
      authors employ immunocytochemistry to demonstrate that C10 is expressed in
      inflammatory macrophages during irritant peritonitis. In addition, C10 was found
      to be a constitutive component of eosinophils. Peritoneal inflammation led to the
      accumulation of sufficient C10 (> 10 nM) to permit detection in exudate fluid.
      This accumulation did not begin until 24h after challenge, and was sustained
      through at least day 10 of the inflammation. In contrast, MIP-1alpha gene
      expression was earlier and transient. These kinetic features are consistent with
      earlier in vitro findings, suggesting that C10 is not a "first-wave" chemokine
      and may play a role related to chronic stages of host defence reactions.

PMID- 10419655
TI  - Abundant expression of chemokines in malignant and infective human
      lymphadenopathies.
AB  - Lymph nodes can be the primary target of infection or malignant transformation
      and may exhibit characteristic patterns of leukocyte infiltration analogous to
      those seen in inflammation of other tissues. Leukocyte migration to lymph nodes
      in vivo is a highly regulated, multi-step process that depends upon adhesion
      molecules and as yet, uncharacterized chemotactic signals. Chemokines are a key
      part of the orchestrated code of signals that directs leukocyte subsets to sites
      of inflammation or immune response. The potential role of these chemoattractants
      in selective trafficking of leukocyte subsets into lymph nodes was assessed by
      determining the expression of chemokines on a range of pathological and normal
      human lymph nodes and by evaluating the cellular composition of each lymph node.
      In situ hybridization using chemokine riboprobes and immunohistochemistry using
      specific antibodies were performed in order to correlate the mRNA and protein
      expression of the chemokines. The cellular source(s) of each chemokine was
      assessed by immunohistochemical staining of adjacent sections using antibodies
      directed against distinctive cellular markers. Substantial, but varied,
      expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, RANTES,
      macrophage chemotactic protein (MCP)-1, eotaxin, and interleukin 8 (IL-8) were
      detected in the pathological lymph nodes by diverse cell types. Control lymph
      nodes showed expression only of RANTES, mainly by high endothelial venules. In
      all lymph nodes, except the nodes infiltrated with breast cancer, chemokine mRNA
      expression was highly concordant with the corresponding protein. In contrast with
      in vitro studies that have suggested discrete target cell specificity of
      chemokines, this study showed that with the possible exception of the neutrophil
      chemoattractant, IL-8, no chemokine appeared to be uniquely associated with the
      accumulation of a specific leukocyte subset. These data implicate chemokines in
      the recruitment of leukocytes to lymph nodes affected by diverse disease states.

PMID- 10419656
TI  - Phase Behavior and Salt Partitioning in Two- and Three-Phase Anionic Surfactant
      Microemulsion Systems: Part I, Phase Behavior as a Function of Temperature.
AB  - Microemulsion phase behavior was studied as a function of salinity and
      temperature. The objectives were to investigate the influence of different
      electrolytes on optimal salinity and solubilization, and to relate the efficiency
      of each cation to change in microemulsion phase behavior. Two five-component
      microemulsion systems using anionic surfactants were studied as a function of
      type of cations (Na, K, Mg, Ca) and ionic strength. The phase behavior studies
      were performed at three different temperatures in the region [20 degrees C, 90
      degrees C], and at different surfactant concentrations. The optimal salinity,
      defined as equal water and oil solubilization in the microemulsion phase, was
      used to quantify changes in phase behavior. Consistently, the divalent ions
      reached optimal salinity at lower salt concentrations than did monovalent ions.
      The effect of the different electrolytes on phase behavior was quantified by
      introducing an efficiency parameter. Knowledge of the efficiency relation between
      different cations in a microemulsion system provided a tool for predicting
      optimal salinity for salt mixtures. The microemulsion phase behavior was more
      sensitive to temperature in monovalent electrolyte solutions compared to divalent
      ions. At lower surfactant concentration the divalent cations had an even stronger
      influence on phase behavior compared to monovalent cation electrolytes. Copyright
      1999 Academic Press.

PMID- 10419657
TI  - Phase Behavior and Salt Partitioning in Two- and Three-Phase Anionic Surfactant
      Microemulsion Systems: Part II, Partitioning of Salt.
AB  - The partitioning of salt (chlorides of Na, K, Ca, Mg) between an excess water
      phase and a microemulsion phase were studied for two five-component anionic
      microemulsion systems at 20 degrees C. Three-phase microemulsions contain two
      phases that include inorganic salts, that is, excess brine and the microemulsion
      phase. The aim of the investigation was to describe the partitioning of Na(+),
      K(+), Ca(++), Mg(++), and Cl(-) between water in the microemulsion phase and
      water in the excess water phase. Both surfactant systems were anionic with Na(+)
      as counterion. It was found that Na(+) and Cl(-) partitioned more strongly toward
      the excess water phase while K(+), Ca(++), and Mg(++) show more preference for
      the microemulsion phase. The validity of considering (NaCl + water) as pseudo
      component brine has been examined. Including a chloride depleted region, caused
      by electrostatic repulsion from the negatively charged surfactant layer, in the
      surfactant pseudo-component, is found to describe the NaCl partitioning. When
      discussing partitioning of K(+), Ca(++), and Mg(++) between the microemulsion
      phase and the excess water phase in these systems, it is important to consider
      that there are two cations in the solutions, Na(+) as counterion for the
      surfactant and either K(+), Ca(++), or Mg(++) for the electrolyte. The
      preferential partitioning toward the microemulsion phase for K(+), Ca(++), and
      Mg(++) seems to be caused by an ion exchange of Na(+) in the surfactant layer.
      Copyright 1999 Academic Press.

PMID- 10419658
TI  - Microstructure Evolution in Polymer Latex Coatings for Whole-Cell Biocatalyst
      Application.
AB  - The microstructure evolution of two poly(vinyl acetate-co-acrylic acid) latex
      coatings was elucidated by cryogenic scanning electron microscopy (cryo-SEM) and
      atomic force microscopy. The stages documented are particle suspension,
      consolidation, deformation, partial coalescence into a coherent film, and
      rehydration of the latter. Of particular interest is formation of a porous
      polymeric matrix of desired porosity and permeability of remnant interstices
      between deformed and partially coalesced particles; the application is to
      biocatalytic coatings in which viable bacteria are imprisoned in porous latex
      coatings. Effects of drying condition and time, rehydration behavior of latex,
      and the presence of glycerol on the microstructure of latex coatings were
      revealed by time-sectioning and cryofracture techniques of cryo-SEM. Results
      showed that porosity and permeability can be controlled by choice of drying and
      rehydration protocols. Evidence showed that glycerol retarded particle
      deformation, compaction, and coalescence and that substantial amounts of glycerol
      were expelled to the surface of the coating as drying proceeded. Implications for
      design of bacteria-laden and bacteria-free coating layers are discussed.
      Copyright 1999 Academic Press.

PMID- 10419659
TI  - Microstructure of a Biocatalytic Latex Coating Containing Viable Escherichia coli
      Cells.
AB  - Cryogenic scanning electron microscopy (cryo-SEM) was employed to visualize the
      microstructure of latex coatings in which viable Escherichia coli cells were
      entrapped for use as biocatalysts. Cryo-SEM examination of surfaces and fracture
      cross sections of dry and hydrated coatings cast with or without glycerol
      revealed two different porosities in the films: a macroporosity in which the
      bacterial cells reside and a microporosity made up of the interstitial voids
      between partially coalesced latex polymer particles. Polymer particle
      consolidation and coalescence in the cell-laden coatings were at an earlier stage
      than in cell-free latex coatings detailed in a companion paper. Coatings cast
      with glycerol showed a lesser degree of latex particle consolidation and
      coalescence than those cast without glycerol. However, the effect of glycerol was
      not as pronounced as in cell-free coatings. We conclude that part of the added
      glycerol is sequestered inside the bacterial cells and the portion remaining
      outside the cells retards the latex film formation process and enhances
      microporosity. Two commercial acrylic acid/vinyl acetate copolymer latexes were
      examined. Coatings made with the polydisperse latex showed less microporosity and
      a greater degree of particle welding than those made with the nearly monodisperse
      latex. Copyright 1999 Academic Press.

PMID- 10419660
TI  - Dynamic Surface Tension Measurement with a Dynamic Wilhelmy Plate Technique.
AB  - An experimental method called dynamic Wilhelmy plate technique (DWPT) for
      studying dynamic surface tension was designed in this study. A diffusion
      controlled model corresponding to the initial and boundary conditions of this
      method was proposed. Dynamic surface tension of Triton X-100 and SDS was measured
      with this technique and analyzed with the proposed model. The calculated
      diffusion coefficients for the short- and long-time approximations are 3.7 x 10(
      6) and 0.97 x 10(-6) cm(2)/s for Triton X-100 and 4.6 x 10(-6) and 0.79 x 10(-6)
      cm(2)/s for SDS, respectively. The predicted dynamic surface tension with these
      diffusion coefficients for the simultaneously generated aqueous/air interfaces is
      in good agreement with the drop mass technique. Another diffusion controlled
      model that considers the energy barrier at the aqueous/air interface was also
      proposed in this study. The calculated energy barriers are in the range of 4.1
      5.7 RT for Triton X-100 and 6.5-8.0 RT for SDS. Copyright 1999 Academic Press.

PMID- 10419661
TI  - Role of Silicone Surfactant in Flexible Polyurethane Foam.
AB  - Grafted copolymers which consist of a polydimethylsiloxane backbone and
      polyethylene oxide-co-propylene oxide pendant groups are used as surfactants to
      stabilize the foam cells in the flexible polyurethane foaming process. The
      mechanical properties of the cured polyurethane foam such as air permeability and
      foam cell size are affected significantly by the structure of the silicone
      surfactant used in the formulation. It is shown that silicone surfactant has an
      important impact on both the bubble generation and the cell window stabilization
      stage. A series of silicone surfactants with different structures was tested.
      Surfactants with higher silicone content will provide lower surface tension and
      thus help increase the number of air bubbles introduced during mixing. These air
      bubbles serve as the starting point for foam cell growth. As a result, the cured
      polyurethane foam made with higher silicone content surfactant has a smaller
      bubble size. It is also shown that silicone surfactant can reduce the cell window
      drainage rate due to the surface tension gradient along the cell window. The
      Gibbs film elasticity, the dynamic film elasticity, and the film drainage rate
      were measured for the first time versus surfactant composition. Surfactants with
      longer siloxane backbones are shown to give higher film elasticity. Using the
      vertical film drainage and foam column tests, it is shown that surfactants with
      higher film elasticity will yield slower drainage rate and better foam cell
      stability. Copyright 1999 Academic Press.

PMID- 10419662
TI  - Solid State Transitions of Asymmetric Catanionic Surfactants.
AB  - A series of asymmetric surfactants were prepared from cationic surfactant,
      hexadecyltrimethylammonium bromide, and anionic surfactant, sodium alkyl sulfate
      (the number of carbon atoms per chain being 10, 12, or 14). The influence of the
      alkyl chain asymmetry on the thermal properties of formed
      hexadecyltrimethylammonium alkyl sulfates was investigated by means of polarizing
      microscopy, differential scanning calorimetry, and X-ray diffraction. Asymmetric
      catanionic surfactants exhibited a complex polymorphism and thermotropic
      mesomorphism from the stable crystalline form to the isotropic phase. On heating,
      successive phase transitions (several solid crystalline-solid crystalline, solid
      crystalline-liquid crystalline, and liquid crystalline-isotropic liquid) were
      observed. The number of polymorphs, in all of the bilayered structure, depended
      on the asymmetry between the lengths of surfactant tails. The basic lamellar
      thickness varied linearly with the increase of alkyl sulfate chain length. An
      increase of the basic lamellar thickness with temperature was determined.
      Polarizing microscopy revealed a characteristic texture of the smectic phase. On
      cooling, all compounds underwent reversibly the isotropic liquid-liquid
      crystalline transitions, while crystallization from melted samples was
      kinetically controlled. Copyright 1999 Academic Press.

PMID- 10419663
TI  - Influence of Component Ratio on Adsorption of Polymer Mixtures under Phase
      Separation of Solutions.
AB  - The influence of the component ratio on polymer mixture adsorption in the two
      phase condition is estimated. Transition toward the two-phase condition was
      attained by increasing the solution concentration up to phase separation. For
      solutions that have separated into two phases with increasing component
      concentration, the adsorption from each phase has been studied separately and the
      total adsorption from two phases has been calculated. The polystyrene-poly(butyl
      methacrylate)-CCl(4) system was investigated using fumed silica as adsorbent.
      Simultaneously, the fraction of segments of each type that were immobilized by
      the surface was determined from NMR spectra. In all cases, poly(butyl
      methacrylate) is characterized by preferential adsorption. The main features of
      adsorption are similar in both one-phase and two-phase states; however, the
      values for adsorption and fraction of immobilized segments are different in the
      case of adsorption from two separated phases because of the difference between
      the phases in the ratio of components and their concentration in each phase. The
      distinctions between adsorption from one-phase solutions before phase separation
      and from solutions modeling separated phases are connected with the
      redistribution of components between upper and lower phases. As a result, their
      ratio does not correspond to the initial ratio, and therefore the thermodynamic
      conditions of solutions, responsible for adsorption, are changed. Because of
      this, the shape of isotherms of adsorption and the adsorption values are
      determined by the different levels of aggregation in solutions with various
      ratios of components. Copyright 1999 Academic Press.

PMID- 10419664
TI  - A New Straightforward Approach to Generate Si-H Groups on Silica.
AB  - In this paper it is demonstrated unequivocally by solid-state nuclear magnetic
      resonance and diffuse reflectance infrared Fourier transform spectroscopies that,
      at high temperature, hydrogen reacts directly with pyrogenic silica to form
      stable hydride Si-H groups. Such modified silicas should exhibit specific
      properties far from those of silicas having only surface silanol groups. The
      interest for hydride-modified silicas arises from the possibility of using their
      Si-H groups as reducing agents or as active sites for the synthesis of new
      chromatographic phases. Copyright 1999 Academic Press.

PMID- 10419665
TI  - Numerical Model of Electrokinetic Flow for Capillary Electrophoresis.
AB  - A numerical study is presented for the steady electrokinetic flow in intersecting
      channels in a T-shaped configuration. The electric potential and space charge
      density distribution along the capillary are obtained numerically by solving the
      nonlinear Poisson-Boltzmann equation for arbitrary electrokinetic radius and
      arbitrary surface potential. The velocity and pressure profiles are obtained by
      solving a modified Navier-Stokes equation using a primitive variable algorithm. A
      systematic study of flow in T-shaped intersecting channels showed that the
      hydrodynamic effect is an important factor that influences fluid leakage out of a
      channel where the electric potential is left floating. It was found that the flow
      in each channel can be controlled by applying a potential at each reservoir
      connected to the end of a channel. Copyright 1999 Academic Press.

PMID- 10419666
TI  - Modeling the Adsorption of Mercury(II) on (Hydr)oxides II: alpha-FeOOH (Goethite)
      and Amorphous Silica.
AB  - The surface complexation model is used to describe sorption experiments of
      inorganic mercury(II) in the presence of an amorphous silica, Aerosil 200, or an
      iron (hydr)oxide, the goethite alpha-FeOOH (Bayferrox 910). In the simulations,
      one assumes the formation of a monodentate surface complex &tbond;S&bond;OHg(+)
      and of ternary surface complexes with OH(-) surface groups, &tbond;S&bond;OHgOH
      and &tbond;S&bond;OHgCl, when chlorides are present in solution. Participation of
      the complex &tbond;S&bond;OHgCl has been especially evidenced. The mercury(II)
      surface complexation on oxides can be described by the following equilibria
      (298.15 K, I = 0): with log 5.8 and 8.0 for amorphous silica and goethite,
      respectively. Comparisons with other data from the literature have been made to
      investigate the influence of the nature of the oxide on the mechanism of
      mercury(II) adsorption. X-ray photoelectron spectroscopy was used to characterize
      the surface of the (hydr)oxides prior to adsorption and to observe when possible
      the mercury surface compounds. Copyright 1999 Academic Press.

PMID- 10419667
TI  - Protein Denaturation in Foam.
AB  - The aim of this study was to elucidate the mechanism by which protein molecules
      become denatured in foam. It was found that damage to the protein is mainly due
      to surface denaturation at the gas-liquid interface. A fraction of the molecules
      adsorbed do not refold to their native state when they desorb. The degree of
      denaturation was found to correlate directly with the interfacial exposure,
      which, for mobile or partially mobile interfaces, is increased by drainage.
      Experiments with two different proteins showed that, under the conditions of the
      tests, around 10% of BSA molecules which had adsorbed at the surface remained
      denatured when they desorbed. For pepsin the figure was around 75%. Oxidation,
      which was previously thought to be a major cause of protein damage in foam, was
      found to be minimal. Neither do the high shear stresses in the liquid bulk
      encountered during bubble bursting cause denaturation, because energy is
      dissipated at a much greater length scale than that of the protein molecule.
      Copyright 1999 Academic Press.

PMID- 10419668
TI  - Protein Denaturation in Foam.
AB  - As part of a study of protein denaturation in foam we have measured the surface
      tension and the changes in protein structure occurring at the interface for
      lysozyme, pepsin, BSA, YADH, IgG, and catalase. The apparent CMC values were
      found to be dependent on the size and rigidity of the molecule. The variability
      of protein damage at a gas-liquid interface in foam was assessed using these
      proteins. The foams were produced under controlled conditions in a bubble column
      and were found to induce conformational changes in the protein molecules, but no
      fragmentation or disassociation of subunits occurred. Tertiary structural changes
      were detected in all the proteins studied, with some proteins forming aggregates.
      For pepsin, the secondary structure was also found to be altered. Enzyme
      solutions were used to determine the degree of biological activity retained after
      foaming for proteins with different structural characteristics. The more rigid
      proteins were found to display a low surface activity and a low degree of damage
      in foam. Pepsin suffered the highest rate of damage, which is thought to be a
      result of its inability to refold following denaturation. Copyright 1999 Academic
      Press.

PMID- 10419669
TI  - The Effect of Thermal and Mechanical Treatments on Kaolinite: Characterization by
      XPS and IEP Measurements.
AB  - The surface transformations induced on kaolinite by different thermal and
      mechanical treatments have been investigated by means of X-ray photoelectron
      spectroscopy (XPS), Bremsstrahlung induced Auger spectroscopy, and isoelectric
      point (IEP) measurements. Heating the kaolinite at temperatures between 500 and
      750 degrees C results in the change of a substantial fraction of surface Al from
      octahedral to tetrahedral coordination, which we associate with the
      dehydroxylation of kaolinite. Heating at 900 and 980 degrees C brings about the
      development of an octahedral Al fraction which is associated with the formation
      of gamma-Al(2)O(3). The development of an Al tetrahedral component in the Al KLL
      spectra of the mechanically treated (ground) samples has been also observed. The
      Si/Al atomic ratio obtained by XPS in the thermally treated samples is the same
      as that shown by the original kaolinite. However, the XPS data show a clear
      reduction of the Si/Al atomic ratio in the mechanically treated samples, which
      suggests that the mechanical treatment has induced an Al enrichment of the
      kaolinite surface. The IEP values indicated a thermal transformation to
      metakaolinite and mullite with the increase of temperature (750 to 980 degrees
      C). The IEP change for the milled samples can be only explained by assuming a 30%
      kaolinite coating by the Al oxide neoformed by grinding. Copyright 1999 Academic
      Press.

PMID- 10419670
TI  - Kinetics of Nucleation at Increasing Supersaturation.
AB  - The kinetics of homogeneous nucleation-growth processes under increasing
      supersaturation is investigated. The increase of the supersaturation is hereby
      caused by an appropriate variation of external parameters such as pressure and
      temperature. Analytic expressions are formulated for the dependence of the number
      of supercritical clusters both on the rate of change of the supersaturation and
      on time. In generalization of previous studies, both thermal and athermal
      nucleation are taken into consideration. It turns out that in dependence on the
      rate of change of the external parameters, either thermal (for moderate rates) or
      athermal (for higher rates) nucleation, dominates the process. It is shown
      further that, in the range where thermal nucleation dominates, the onset of
      nucleation-growth processes, i.e., the minimum value of the supersaturation
      required for intensive nucleation, depends weakly (logarithmically) on the rate
      of increase of the supersaturation. Criteria are formulated under which
      conditions the commonly employed assumption-independence of the nucleation-growth
      process on the way the initial unstable state is established-is applicable. As
      shown, quite generally these criteria are not fulfilled. In a further step of the
      analysis, simultaneously to external variations of the thermodynamic parameters,
      internally generated changes of the state of the system (depletion effects) are
      accounted for. For segregation processes in solutions (bubble formation), which
      are analyzed here as an example, such effects result from a decrease of the
      supersaturation due to the consumption of solute particles by the clusters of the
      newly formed phase. Basic characteristics of the nucleation-growth process, such
      as the maximum number of clusters formed in the system, are determined in
      dependence on both externally (rate of change of the external parameters) and
      internally (depletion effects) induced changes of the thermodynamic state of the
      system. It is shown, in particular, that the interplay of both factors is, in
      general, of comparable importance for the outcome of the nucleation-growth
      process. Copyright 1999 Academic Press.

PMID- 10419671
TI  - Association of Blood Clotting Factors I and VII with Phospholipid Monolayers at
      the Air-Water Interface.
AB  - Phospholipid monolayers adsorbed at the air-water interface are useful model
      membranes and have been employed to study the interactions between phospholipids
      and blood clotting factors I and VII. Factor I is a non-membrane-binding protein
      and was found to penetrate both distearoylphosphatidylcholine (DSPC) and
      dipalmitoylphosphatidylcholine (DPPC) monolayers at low lipid pressures. At high
      lipid pressures, the protein was crowded out of the interface. Factor I
      penetration of phospholipid monolayers was independent of hydrocarbon chain
      length, while penetration was maximized with electrolytes in the subphase. Factor
      VII is a membrane binding protein and was found to penetrate a DPPC monolayer
      only when electrolytes were added to the subphase. Factor VII penetrated DSPC
      monolayers regardless of electrolyte addition in the subphase, and its
      interactions with DSPC films are attributed to protein-lipid hydrophobic
      interactions. Copyright 1999 Academic Press.

PMID- 10419672
TI  - Preparation, Characterization, and Catalytic Properties of Ultrafine Mixed Fe-Mo
      Oxide Particles.
AB  - Ultrafine mixed Fe-Mo oxide particles are prepared by the sol-gel technique using
      citric acid as a complex agent. The formation process of the ultrafine oxides is
      studied by using XRD, DTA-TG, FT-IR, TEM, and BET surface area measurement. It is
      found that the morphology and structure of the oxide particles are significantly
      dependent on the process parameters such as thermal treatment temperature (T), pH
      of the starting solution, and the molar ratio of citric acid to metallic ions
      (L/M). The formation temperature of crystalline Fe(2)(MoO(4))(3) by the sol-gel
      process is much lower than that by the coprecipitation method. The catalytic
      properties of ultrafine Fe-Mo oxide particles are tested and compared with those
      of large oxide particles having the same composition. It is shown that for
      selective oxidation of toluene to benzaldehyde the ultrafine Fe-Mo oxide
      particles exhibit higher benzaldehyde selectivity and toluene conversion than the
      large oxide particles. The unique catalytic properties of ultrafine Fe-Mo oxide
      particles may be correlated to the higher mobility of lattice oxygen species in
      the ultrafine oxide particles and their higher BET surface area. Copyright 1999
      Academic Press.

PMID- 10419673
TI  - Adhesion of Colloidal Hematite onto Mercury in Water-Ethanol Media.
AB  - The adherence of hematite (alpha-Fe(2)O(3)) particles onto mercury electrodes in
      water-ethanol mixtures has been studied by counting on optical microscope images,
      obtaining also the effective charge by electrophoretic measurements. The number
      of attached particles, when the ethanol content is small, decreases as the
      ethanol concentration increases. At an ethanol mole fraction near 0.2, the number
      of particles goes through a minimum and then increases with ethanol
      concentration. When the electrode potential is modified, curves of the number of
      particles vs ethanol mole fraction with the same shape are found, but they cross
      each other. The experimental behavior can be explained based on the dependence of
      particle/solution, metal/solution, and metal/particle interaction energies on the
      solvent composition. Copyright 1999 Academic Press.

PMID- 10419674
TI  - Hydrodynamic Instability of Liquid Films on Moving Fibers.
AB  - The stability of liquid films on moving fibers is studied with a focus on effects
      caused by film-solid adhesion interactions and hydrodynamic interactions between
      the film and the surrounding gas. We show that at high fiber velocities (large
      Reynolds numbers) the film-gas hydrodynamic interactions induce instability in
      films, which would, otherwise, be stabilized by the adhesion interactions at
      static conditions. Two types of unstable modes caused by hydrodynamic factors are
      found: the first corresponds to the Kelvin-Helmholtz waves induced by inertia
      effects; the second, induced by viscosity effects, is observed at smaller (yet
      still large) Reynolds numbers when the Kelvin-Helmholtz instability is
      suppressed. Linear stability analysis of the system of coupled hydrodynamic
      equations of film and gas flow is performed by the method of normal modes. We
      derive the general dispersion relation as an implicit equation with respect to
      the mode frequency. In the limit of vanishing fiber velocities, the obtained
      equation provides the dispersion equation for motionless fibers. The conditions
      of film stability and unstable modes are analyzed in terms of two dimensionless
      parameters, the adhesion factor, which quantifies the intensity of film-fiber
      interactions, and the Weber number, which quantifies the intensity of film-gas
      interactions. The Reynolds number determines the regions of validity of the
      inviscid and viscous regimes of film instability. The results are illustrated by
      estimates of the stability conditions for moving fibers in terms of the stability
      diagram, the critical film thickness, the fastest unstable mode, and the
      corresponding characteristic break-up time. Although the methods developed are
      applicable for any type of liquid-solid interaction, the estimates were made for
      the long-range van der Waals interactions. Practical applications include various
      technologies related to fabrication and chemical modifications of fibers and
      fiber products, e.g., spin finishing and lubrication. Copyright 1999 Academic
      Press.

PMID- 10419675
TI  - An Analysis of Electrophoresis of Concentrated Suspensions of Colloidal
      Particles.
AB  - An analysis of the electrophoretic motion of charged colloidal particles in a
      concentrated suspension is developed to predict the electrophoretic mobility of
      the particles and the electrical conductivity of the suspension. The analysis is
      based on a unit cell model that takes into account particle-particle hydrodynamic
      interactions and includes relatively thick electric double layers. The fluid
      motion in the unit cell is treated by writing the relevant Navier-Stokes equation
      in terms of the stream function and vorticity. The governing equations were then
      solved by a finite-difference method. The calculated electrophoretic mobilities
      are in agreement with prior analytical solutions for moderately concentrated
      suspensions, and the theory reduces to the result of O'Brien and White for low to
      moderate zeta potentials and dilute suspensions and to the classical result of
      Smoluchowski for thin double layers and dilute suspensions. A parametric study
      shows that the electrical conductivity of the suspension relative to a free
      electrolyte solution is affected by the counterion to co-ion diffusivity ratio,
      the double-layer thickness, and the volume fraction of particles. For a
      dispersion of moderately charged particles (moderate zeta potentials) with thick
      double layers, the numerical model predicts the electrical conductivity in
      agreement with experimental values reported in the literature. Copyright 1999
      Academic Press.

PMID- 10419677
TI  - Adsorption Behavior of Amphiphilic Polymers.
AB  - The work reported here involves a study of the adsorption behavior of some
      amphiphilic polymers containing alternating copolymers of stearyl methacrylate,
      mono-n-octylitaconate, styrene, and 1-octadecene with maleic anhydride. We have
      employed chromatographic and thermogravimetric measurements in order to
      characterize the adsorption process. Silica gel was the stationary phase in the
      case of the polar column, and a mixture of THF/toluene or chloroform/toluene as
      the mobile phase. Toluene content in the mobile phase affects the capacity to
      desorb the polymer from the interface. The adsorption of the polymers onto silica
      substrates from toluene between other solvents has been measured also with static
      experiments. The results are discussed in terms of the incorporation of
      hydrophilic groups as maleic-anhydride or hydrophobic groups as stearyl and n
      octyl chains. The solvent effect was also considered. Comparison of the
      adsorption isotherms for PA-18 onto hydrophilic substrate (Aerosil 200) from two
      different solvents shows strong competition of THF with the surface functionality
      of the substrate by the PA-18. Copyright 1999 Academic Press.

PMID- 10419676
TI  - Monolayers of Some Poly(oxyethylene)-Based Surfactants at the Air-Water
      Interface: The Effect of Structural Variations and Salt Concentration.
AB  - The Langmuir surface balance technique has been used to study the interfacial
      behavior of six structurally different poly(oxyethylene) (POE)-based polymer
      surfactants at the air-water interface. On a pure water subphase the surfactants
      have collapse surface pressures dependent on the POE chain length. The surfactant
      monolayers collapse at well-determined surface pressures, and the lower POE chain
      length surfactants collapse at higher pressures than those with high POE content.
      This difference vanishes as increasing amounts of salt are added to the subphase.
      The PiA-isotherms are smooth, which is normal for polymeric surfactants. A closer
      analysis of the isotherms reveals characteristic behavior that can be attributed
      to structural differences. Similarities in thermodynamic behavior suggest that
      the molecular orientation is the same despite the structural differences. A new
      expression for the compressibility factor is developed to explain the
      relationship between this parameter and surface pressure for polymeric
      monolayers. Copyright 1999 Academic Press.

PMID- 10419678
TI  - Unusual Contact-Line Dynamics of Thick Films and Drops.
AB  - We report several novel phenomena in contact-line and fingering dynamics of
      macroscopic spinning drops and gravity-driven films with dimensions larger than
      the capillary length. It is shown through experimental and theoretical analysis
      that such macroscopic films can exhibit various interfacial shapes, including
      multi valued ones, near the contact line due to a balance between the external
      body forces with capillarity. This rich variety of front shapes couples with the
      usual capillary, viscous, and intermolecular forces at the contact line to
      produce a rich and unexpected spectrum of contact-line dynamics. A single finger
      develops when part of the front becomes multivalued on a partially wetting
      macroscopic spinning drop in contrast to a different mechanism for microscopic
      drops of completely wetting fluids. Contrary to general expectation, we observe
      that, at high viscosity and low frequencies of rotation, the speed of a glycerine
      finger increases with increasing viscosity. Completely wetting Dow Corning 200
      Fluid spreads faster over a dry inclined plane than a prewetted one. The presence
      of a thin prewetted film suppresses fingering both for gravity-driven flow and
      for spin coating. We analyze some of these unique phenomena in detail and offer
      qualitative physical explanations for the others. Copyright 1999 Academic Press.

PMID- 10419679
TI  - Temperature Dependence of Bubble Nucleation Limits for Aqueous Solutions of
      Carbon Dioxide, Hydrogen, and Oxygen.
AB  - We report the temperature variation of critical supersaturation for carbon
      dioxide, hydrogen, and oxygen in water at 1 atm pressure. The measurements were
      made by generating solutions of the gases chemically. Between 273 and 323 K, the
      bubble nucleation limit for carbon dioxide decreases from 0.4 to 0.2 M. For
      oxygen the limit decreases from 0.15 to 0.10 M in the range 283-298 K. The limit
      for hydrogen increases from 0.03 M at 290 K to 0.08 M at 308 K. The trends
      correlate with the Lennard-Jones interaction energies of the molecules, in
      agreement with recently published bubble nucleation models based on density
      functional calculations. Copyright 1999 Academic Press.

PMID- 10419680
TI  - Effects of Salinity on Expression Dewatering of Waste Activated Sludge.
AB  - This work evaluates filtration followed by consolidation characteristics of
      sodium chloride containing activated sludge. Experimental results indicate that
      contact time and salinity level affect the dewatering efficiency. Considering the
      consolidation stage, a critical salinity level (around 1-2% (w/w)) is observed at
      which the contribution of secondary consolidation stage reaches its minimum.
      Meanwhile the creeping among constituent aggregates becomes much easier than in
      the original sludge. In addition, double-layer compression/hydrophobic
      interactions and ion exchange partially account for the experimental results.
      Copyright 1999 Academic Press.

PMID- 10419681
TI  - Impaired mammary gland development in Cyl-1(-/-) mice during pregnancy and
      lactation is epithelial cell autonomous.
AB  - A specific defect of mice lacking cyclin D1 (Cyl-1(-/-)) is impaired development
      of the mammary gland during pregnancy. Here we show that when tissue from Cyl-1(
      /-) mammary gland was transplanted into empty mammary fat pad of wild-type mice,
      the abnormal phenotype was maintained, indicating that it is epithelial cell
      autonomous. Nevertheless, in pregnancy the early proliferative response, which is
      characterized by extensive side branching, still occurs in the absence of cyclin
      D1. However, the response is atypical due to a marked reduction in the formation
      of accompanying alveoli. This reduction and delay in alveolar development
      persists throughout pregnancy. Moreover, although prolactin synthesis and release
      appear to be normal, lactogenesis is severely compromised. Consistent with the
      appearance of numerous side branches, progesterone receptor expression was
      readily detected in the mammary tissue of pregnant Cyl-1(-/-) mice, although
      there was a significant change in the ratio of the two (A and B) receptor
      isoforms. In Cyl-1(-/-) mammary glands during late pregnancy there was a decrease
      in the abundance of total and phosphorylated Stat5a, as well as delayed onset and
      substantial diminution of milk protein expression. The biochemical analysis
      suggests that there is a cumulative delay in growth and differentiation of the
      mammary gland during pregnancy that results in a severely compromised gland when,
      at parturition, further development is curtailed by the abrupt change in hormonal
      milieu.

PMID- 10419682
TI  - Competence and commitment of Caenorhabditis elegans vulval precursor cells.
AB  - Multipotent Caenorhabditis elegans vulval precursor cells (VPCs) choose among
      three fates (1 degrees, 2 degrees, and 3 degrees ) in response to two
      intercellular signals: the EGF family growth factor LIN-3 induces 1 degrees fates
      at high levels and 2 degrees fates at low levels; and a signal via the receptor
      LIN-12 induces 2 degrees fates. If the level of LIN-3 signal is reduced by a lin
      3 hypomorphic mutation, the daughters of the VPC closest to the anchor cell (AC),
      P6.p, are induced by the AC. By expressing LIN-3 as a function of time in LIN-3
      deficient animals, we find that both VPCs and the daughters of VPCs are competent
      to respond to LIN-3, and VPC daughters lose competence after fusing with the
      hypodermis. We also demonstrate that the daughters of VPCs specified to be 2
      degrees can respond to LIN-3, indicating that 2 degrees VPCs are not irreversibly
      committed. We propose that maintenance of VPC competence after the first cell
      cycle and the prioritization of the 1 degrees fate help ensure that P6.p will
      become 1 degrees. This mechanism of competence regulation might have been
      maintained from ancestral nematode species that used induction both before and
      after VPC division and serves to maximize the probability that a functional vulva
      is formed.

PMID- 10419683
TI  - Animal-vegetal asymmetries influence the earliest steps in retina fate commitment
      in Xenopus.
AB  - An individual retina descends from a restricted and invariant group of nine
      animal blastomeres at the 32-cell stage. We tested which molecular signaling
      pathways are responsible for the competence of animal blastomeres to contribute
      to the retina. Inactivation of activin/Vg1 or fibroblast growth factor (FGF)
      signaling by expression of dominant-negative receptors does not prevent an animal
      blastomere from contributing to the retina. However, increasing bone
      morphogenetic protein (BMP) signaling in the retina-producing blastomeres
      significantly reduces their contribution. Conversely, reducing BMP signaling by
      expression of a dominant-negative BMP receptor or Noggin allows other animal
      blastomeres to contribute to the retina. Thus, the initial step in the retinal
      lineage is regulated by position within the BMP/Noggin field of epidermal versus
      neural induction. Vegetal tier blastomeres, in contrast, cannot contribute to the
      retina even when given access to the appropriate position and signaling fields by
      transplantation to the dorsal animal pole. We tested whether expression of
      molecules within the mesoderm inducing (activin, FGF), mesoderm-modifying (Wnt),
      or neural-inducing (BMP, Noggin) pathways impart a retinal fate on vegetal cell
      descendants. None of these, several of which induce secondary head structures,
      caused vegetal cells to contribute to retina. This was true even if the injected
      blastomeres were transplanted to the dorsal animal pole. Two pathways that
      specifically induce head tissues also were investigated. The simultaneous
      blockade of Wnt and BMP signaling, which results in the formation of a complete
      secondary axis with head and eyes, did not cause the vegetal clone to give rise
      to retina. However, Cerberus, a secreted protein that also induces an ectopic
      head with eyes, redirected vegetal progeny into the retina. These experiments
      indicate that vegetal blastomere incompetence to express a retinal fate is not
      due to a lack of components of known signaling pathways, but relies on a specific
      pathway of head induction.

PMID- 10419684
TI  - Collapsin-1/semaphorin D is a repellent for chick ganglion of Remak axons.
AB  - Chick collapsin-1/human semaphorin III/mouse semaphorin D is believed to guide
      the extension of specific axons by a repellent mechanism. Here we examine its
      role in the guidance of axons of the ganglion of Remak (Remak) in the developing
      chick intestine. Early in embryogenesis Remak axons extend parallel to, but do
      not enter, the intestine when collapsin-1 is expressed in the adjacent rectal
      wall. Remak axons later penetrate the peripheral portions of the rectal wall when
      collapsin-1 expression retreats from the outer muscle layer to the more internal
      submucosal and mucosal layers of the rectum. Extension of Remak neurites is
      repelled in vitro by rectum explants and also by 293T cells expressing collapsin
      1. The rectal chemorepellent activity is blocked by anti-collapsin-1 antibodies.
      Our results suggest that collapsin-1 may help prevent Remak axons from projecting
      into the intestinal wall at early developmental times and later restricts Remak
      axon trajectories to the outer part of the intestinal muscle layer.

PMID- 10419686
TI  - Characterization of GDF-10 expression patterns and null mice.
AB  - Growth/differentiation factor-10 (GDF-10) is a TGF-beta family member highly
      related to bone morphogenetic protein-3. In order to determine the biological
      function of GDF-10, we carried out a detailed analysis of the expression pattern
      of GDF-10 and characterized GDF-10-null mice that we generated by gene targeting.
      During embryogenesis GDF-10 is expressed prominently in developing skeletal
      structures both in the craniofacial region and in the vertebral column. In adult
      animals, GDF-10 is expressed at high levels in the brain, where GDF-10 is
      localized primarily to cells in the Purkinje cell layer of the cerebellum, and in
      the uterus, where the expression levels of GDF-10 are regulated both during the
      menstrual cycle and during pregnancy. Despite the high levels of GDF-10
      expression in these tissues, we found no obvious abnormalities in GDF-10-knockout
      mice with respect to the development of these tissues. These findings suggest
      either that GDF-10 plays no regulatory role in these tissues or that its function
      is redundant with that of other growth factor-like molecules.

PMID- 10419685
TI  - Ectopic expression of the nude gene induces hyperproliferation and defects in
      differentiation: implications for the self-renewal of cutaneous epithelia.
AB  - Nude mice are characterized by the absence of visible hair, epidermal defects,
      and the failure to develop a thymus. This phenotype results from loss-of-function
      mutations in Whn (Hfh11), a winged-helix transcription factor. In murine
      epidermis and hair follicles, endogenous whn expression is induced as epithelial
      cells initiate terminal differentiation. Using the promoter for the
      differentiation marker involucrin, transgenic mice that ectopically express whn
      in stratified squamous epithelia, hair follicles, and the transitional epithelium
      of the urinary tract were generated. Transgenic epidermis and hair follicles
      displayed impaired terminal differentiation and a subset of hair defects, such as
      delayed growth, a waved coat, and curly whiskers, correlated with decreased
      transforming growth factor (TGF)-alpha expression. The exogenous Whn protein also
      stimulated epithelial cell multiplication. In the epidermis, basal keratinocytes
      exhibited hyperproliferation, though transgene expression was restricted to
      suprabasal, postmitotic cells. Hair follicles failed to enter telogen (a resting
      period) and remained continuously in an abnormal anagen (the growth phase of the
      hair cycle). Ureter epithelium developed severe hyperplasia, leading to the
      obstruction of urine outflow and death from hydronephrosis. Though an immune
      infiltrate was present occasionally in transgenic skin, the infiltrate was not
      the primary cause of the epithelial hyperproliferation, as the immune reaction
      was not observed in all affected transgenics, and the transgene induced identical
      skin and urinary tract abnormalities in immunodeficient Rag1-null mice. Given the
      effects of the transgene on cell proliferation and TGFalpha expression, the
      results suggest that Whn modulates growth factor production by differentiating
      epithelial cells, thereby regulating the balance between proliferative and
      postmitotic populations in self-renewing epithelia.

PMID- 10419687
TI  - Neurofibromin deficiency in mice causes exencephaly and is a modifier for Splotch
      neural tube defects.
AB  - Neural tube defects are common and serious human congenital anomalies. These
      malformations have a multifactorial etiology and can be reproduced in mouse
      models by mutations of numerous individual genes and by perturbation of multiple
      environmental factors. The identification of specific genetic interactions
      affecting neural tube closure will facilitate our understanding of molecular
      pathways regulating normal neural development and will enhance our ability to
      predict and modify the incidence of spina bifida and other neural tube defects.
      Here, we report a genetic interaction between Nf1, encoding the intracellular
      signal transduction protein neurofibromin, and Pax3, a transcription factor gene
      mutated in the Splotch mouse. Both Pax3 and Nf1 are important for the development
      of neural crest-derived structures and the central nervous system. Splotch is an
      established model of folate-sensitive neural tube defects, and homozygous mutant
      embryos develop spina bifida and sometimes exencephaly. Neural development is
      grossly normal in heterozygotes and neural tube defects are not seen. In
      contrast, we found a low incidence of neural tube defects in heterozygous Splotch
      mice that also harbored a mutation in one Nf1 allele. All compound homozygotes
      had severe neural tube defects and died earlier in embryogenesis than either Nf1(
      /-) or Sp(-/-) embryos. We also report occasional exencephaly in Nf1(-/-) mice
      and identify more subtle CNS abnormalities in normal-appearing Nf1(-/-) embryos.
      Though other genetic loci and environmental factors affect the incidence of
      neural tube defects in Splotch mice, these results establish Nf1 as the first
      known gene to act as a modifier of neural tube defects in Splotch.

PMID- 10419688
TI  - TGFbeta-like signaling and spicule development in Caenorhabditis elegans.
AB  - A TGFbeta-like signal is required for spicule development in Caenorhabditis
      elegans males. This signal appears to originate in the male-specific musculature
      and is required for the migrations of cells within the proctodeum. The migrations
      of these cells form cellular molds, the spicule traces, in which the cuticle of
      the spicules is secreted. Mutations in daf-4, sma-2, sma-3, and sma-4, which
      disrupt TGFbeta-like signaling, result in aberrant migrations and morphologically
      abnormal spicules. daf-4, and hence the TGFbeta-like signal, is required prior to
      or during cell migrations. Therefore, the TGFbeta-like signal may act to prime
      the migrating cells or as a guidance cue. Mutations in lin-31 result in identical
      cell migration and spicule morphology defects. Thus, lin-31, which encodes a
      "winged helix" protein (Miller et al., Genes Dev. 7, 933-947, 1993), may be a
      component of this TGFbeta-like signaling pathway.

PMID- 10419689
TI  - Ultrastructural features of the adult hermaphrodite gonad of Caenorhabditis
      elegans: relations between the germ line and soma.
AB  - Genetic and embryological experiments have established the Caenorhabditis elegans
      adult hermaphrodite gonad as a paradigm for studying the control of germline
      development and the role of soma-germline interactions. We describe
      ultrastructural features relating to essential germline events and the soma
      germline interactions upon which they depend, as revealed by electron and
      fluorescence microscopy. Gap junctions were observed between oocytes and proximal
      gonadal sheath cells that contract to ovulate the oocyte. These gap junctions
      must be evanescent since individual oocytes lose contact with sheath cells when
      they are ovulated. In addition, proximal sheath cells are coupled to each other
      by gap junctions. Within proximal sheath cells, actin/myosin bundles are anchored
      to the plasma membrane at plaque-like structures we have termed hemi-adherens
      junctions, which in turn are closely associated with the gonadal basal lamina.
      Gap junctions and hemi-adherens junctions are likely to function in the
      coordinated series of contractions required to ovulate the mature oocyte.
      Proximal sheath cells are fenestrated with multiple small pores forming conduits
      from the gonadal basal lamina to the surface of the oocyte, passing through the
      sheath cell. In most instances where pores occur, extracellular yolk particles
      penetrate the gonadal basal lamina to directly touch the underlying oocytes.
      Membrane-bounded yolk granules were generally not found in the sheath cytoplasm
      by either electron microscopy or fluorescence microscopy. Electron microscopic
      immunocytochemistry was used to confirm and characterize the appearance of yolk
      protein in cytoplasmic organelles within the oocyte and in free particles in the
      pseudocoelom. The primary route of yolk transport apparently proceeds from the
      intestine into the pseudocoelom, then through sheath pores to the surface of the
      oocyte, where endocytosis occurs. Scanning electron microscopy was used to
      directly visualize the distal tip cell which extends tentacle-like processes that
      directly contact distal germ cells. These distal tip cell processes are likely to
      play a critical role in promoting germline mitosis. Scanning electron microscopy
      also revealed thin filopodia extending from the distal sheath cells. Distal
      sheath filopodia were also visualized using a green fluorescent protein reporter
      gene fusion and confocal microscopy. Distal sheath filopodia may function to
      stretch the sheath over the distal arm.

PMID- 10419690
TI  - PDGFB regulates the development of the labyrinthine layer of the mouse fetal
      placenta.
AB  - PDGFB is a growth factor which is vital for the completion of normal prenatal
      development. In this study, we report the phenotypic analysis of placentas from
      mouse conceptuses that lack a functional PDGFB or PDGFRbeta gene. Placentas of
      both types of mutant exhibit changes in the labyrinthine layer, including dilated
      embryonic blood vessels and reduced numbers of both pericytes and trophoblasts.
      These changes are seen from embryonic day (E) 13.5, which coincides with the
      upregulation of PDGFB mRNA levels in normal placentas. By E17, modifications in
      shape, size, and number of the fetal blood vessels in the mutant placentas cause
      an abnormal ratio of the surface areas between the fetal and the maternal blood
      vessels in the labyrinthine layer. Our data suggest that PDGFB acts locally to
      contribute to the development of the labyrinthine layer of the fetal placenta and
      the formation of a proper nutrient-waste exchange system during fetal
      development. We point out that the roles of PDGFB/Rbeta signaling in the placenta
      may be analogous to those in the developing kidney, by controlling pericytes in
      the labyrinthine layer and mesangial cells in the kidney.

PMID- 10419691
TI  - Constitutive activation of sonic hedgehog signaling in the chicken mutant
      talpid(2): Shh-independent outgrowth and polarizing activity.
AB  - We have examined the developmental properties of the polydactylous chicken
      mutant, talpid(2). Ptc, Gli1, Bmp2, Hoxd13, and Fgf4 are expressed throughout the
      anteroposterior axis of the mutant limb bud, despite normal Shh expression. The
      expression of Gli3, Ihh, and Dhh appears to be normal, suggesting that the Shh
      signaling pathway is constitutively active in talpid(2) mutants. We show that
      preaxial talpid(2) limb bud mesoderm has polarizing activity in the absence of
      detectable Shh mRNA. When the postaxial talpid(2) limb bud (including all Shh
      expressing cells) is removed, the preaxial cells reform a normal-shaped talpid(2)
      limb bud (regulate). However, a Shh-expressing region (zone of polarizing
      activity) does not reform; nevertheless Fgf4 expression in the apical ectodermal
      ridge is maintained. Such reformed talpid(2) limb buds develop complete talpid(2)
      limbs. After similar treatment, normal limb buds downregulate Fgf4, the preaxial
      cells do not regulate, and a truncated anteroposterior deficient limb forms. In
      talpid(2) limbs, distal outgrowth is independent of Shh and correlates with Fgf4,
      but not Fgf8, expression by the apical ectodermal ridge. We propose a model for
      talpid(2) in which leaky activation of the Shh signaling pathway occurs in the
      absence of Shh ligand.

PMID- 10419692
TI  - Molecular subdivision of the cortex of dividing Tetrahymena is coupled with the
      formation of the fission zone.
AB  - In contrast to a mitotic-spindle-associated bipolar cytokinesis, the cytokinesis
      of polarized ciliates is preceded by a reorganization of the cortex into dual
      metameric patterns for prospective daughter cells and then separated by a
      transverse fission line. This study concerns relations between the generation of
      cortical metamery and the formation of the fission line in an amicronuclear
      (i.e., without mitotic spindle) ciliate, Tetrahymena pyriformis. The fission line
      appears in the division of T. pyriformis as a transverse line formed by
      equatorial gaps in the meridional ciliary rows, with the second oral structure
      (OA2) formed posterior to it. It was found that the metamery of cortical
      morphogenesis is expressed by the appearance of increased MPM2 antibody binding
      in dividing cells in an apical area and posterior to the fission line gaps,
      including patterned changes of this binding in both oral apparatuses (OA1 and
      OA2), and by a reciprocal decrease of binding of an anti-epiplasm antibody. These
      tested antigens are localized to different cortical structures, but in
      predividing cells both uniformly show formation of the fission line contrast of
      labeling. A serine/threonine kinase inhibitor, 6-dimethylaminopurine (6-DMAP),
      was applied to dividing T. pyriformis at specific stages: (1) if 6-DMAP was added
      to early dividing cells, it prevented cells from initiating cytokinesis. (2) If 6
      DMAP was added to cells at stages close to the physiological transition point of
      cell division, it yielded either (i) a partial formation of the fission line on
      the ventral side, combined with modified growth of undivided cortex adjacent to
      the fission line, with abnormal cytokinesis, or (ii) variable anterior
      displacement of the complete fission line, which contracted slowly but uniformly.
      (3) If 6-DMAP was applied during cytokinesis, it did not delay cell division, but
      daughter cells become abnormal and underwent an incomplete oral reorganization.
      These results suggest that the generation of metamerism in the cortex of T.
      pyriformis involves differentiation of the asymmetric fission zone. At least four
      stage-dependent 6-DMAP-sensitive effects jointly control the progress of cell
      division and the mutual spatial relations between the generation of metamery and
      the appearance, completeness, and position of the fission zone in the cortex of
      polarized T. pyriformis.

PMID- 10419693
TI  - Neurestin: putative transmembrane molecule implicated in neuronal development.
AB  - We have cloned a novel cDNA encoding a putative transmembrane protein, neurestin,
      from the rat olfactory bulb. Neurestin was identified based on a sequence similar
      to that of the second extracellular loops of odorant receptors in the cysteine
      rich CC box located immediately after EGF-like motifs. Neurestin shows homology
      to a neuregulin gene product, human gamma-heregulin, a Drosophila receptor-type
      pair-rule gene product, Odd Oz (Odz) / Ten(m), and Ten(a), suggesting a possible
      function in synapse formation and morphogenesis. Recently, a mouse neurestin
      homolog has independently been cloned as DOC4 from the NIH-3T3 cell line.
      Northern blot analysis showed that neurestin is highly expressed in the brain and
      also in other tissues at much lower levels. In situ hybridization studies showed
      that neurestin is expressed in many types of neurons, including pyramidal cells
      in the cerebral cortex and tufted cells in the olfactory bulb during development.
      In adults, neurestin is mainly expressed in olfactory and hippocampal granule
      cells, which are known to be generated throughout adulthood. Nonetheless, in
      adults the expression of neurestin was experimentally induced in external tufted
      cells during regeneration of olfactory sensory neurons. These results suggest a
      role for neurestin in neuronal development and regeneration in the central
      nervous system.

PMID- 10419694
TI  - Fingerprinting of adenylyl cyclase activities during Dictyostelium development
      indicates a dominant role for adenylyl cyclase B in terminal differentiation.
AB  - Activation of cAMP-dependent protein kinase (PKA) triggers terminal
      differentiation in Dictyostelium, without an obvious requirement for the G
      protein-coupled adenylyl cyclase, ACA, or the osmosensory adenylyl cyclase, ACG.
      A third adenylyl cyclase, ACB, was recently detected in rapidly developing
      mutants. The specific characteristics of ACA, ACG, and ACB were used to determine
      their respective activities during development of wild-type cells. ACA was highly
      active during aggregation, with negligible activity in the slug stage. ACG
      activity was not present at significant levels until mature spores had formed.
      ACB activity increased strongly after slugs had formed with optimal activity at
      early fruiting body formation. The same high activity was observed in slugs of
      ACG null mutants and ACA null mutants that overexpress PKA (acaA/PKA), indicating
      that it was not due to either ACA or ACG. The detection of high adenylyl cyclase
      activity in acaA/PKA null mutants contradicts earlier conclusions (B. Wang and A.
      Kuspa, Science 277, 251-254, 1997) that these mutants can develop into fruiting
      bodies in the complete absence of cAMP. In contrast to slugs of null mutants for
      the intracellular cAMP-phosphodiesterase REGA, where both intact cells and
      lysates show ACB activity, wild-type slugs only show activity in lysates. This
      indicates that cAMP accumulation by ACB in living cells is controlled by REGA.
      Both REGA inhibition and PKA overexpression cause precocious terminal
      differentiation. The developmental regulation of ACB and its relationship to REGA
      suggest that ACB activates PKA and induces terminal differentiation.

PMID- 10419695
TI  - A novel transgenic technique that allows specific marking of the neural crest
      cell lineage in mice.
AB  - Neural crest cells are embryonic, multipotent stem cells that give rise to
      various cell/tissue types and thus serve as a good model system for the study of
      cell specification and mechanisms of cell differentiation. For analysis of neural
      crest cell lineage, an efficient method has been devised for manipulating the
      mouse genome through the Cre-loxP system. We generated transgenic mice harboring
      a Cre gene driven by a promoter of protein 0 (P0). To detect the Cre-mediated DNA
      recombination, we crossed P0-Cre transgenic mice with CAG-CAT-Z indicator
      transgenic mice. The CAG-CAT-Z Tg line carries a lacZ gene downstream of a
      chicken beta-actin promoter and a "stuffer" fragment flanked by two loxP
      sequences, so that lacZ is expressed only when the stuffer is removed by the
      action of Cre recombinase. In three different P0-Cre lines crossed with CAG-CAT-Z
      Tg, embryos carrying both transgenes showed lacZ expression in tissues derived
      from neural crest cells, such as spinal dorsal root ganglia, sympathetic nervous
      system, enteric nervous system, and ventral craniofacial mesenchyme at stages
      later than 9.0 dpc. These findings give some insights into neural crest cell
      differentiation in mammals. We believe that P0-Cre transgenic mice will
      facilitate many interesting experiments, including lineage analysis,
      purification, and genetic manipulation of the mammalian neural crest cells.

PMID- 10419697
TI  - Activation of a UBC4-dependent pathway of ubiquitin conjugation during postnatal
      development of the rat testis.
AB  - During spermatogenesis, germ cells undergo mitotic and meiotic divisions to form
      haploid round spermatids which mature to functional elongated spermatozoa. During
      this process there occurs remodeling of cell structure and loss of most of the
      cytoplasm and a large fraction of cellular proteins. To evaluate the role of the
      ubiquitin proteolytic system in this protein loss, we measured levels of
      ubiquitinated proteins and rates of ubiquitin conjugation in extracts of testes
      from rats of different ages. Endogenous ubiquitin-protein conjugates increased
      till day 30 and then reached a plateau. In parallel, there was a progressive
      increase in the rate of conjugation of ubiquitin to proteins in testis extracts
      from these animals. To test the importance of two major ubiquitin conjugating
      enzyme families in the conjugation, immunoprecipitation of UBC2 or UBC4 from 10-
      and 30-day-old testis extracts was carried out and the remaining conjugation
      activity in supernatants was assayed. Depletion of either enzyme family resulted
      in decreased conjugation. However, most of the conjugation activity and, more
      importantly, the increased conjugation during development were UBC4-dependent.
      Immunocytochemistry demonstrated a marked increase in expression of UBC4 in
      spermatids, consistent with the UBC4-dependent activation of conjugation seen in
      vitro. In situ hybridization studies evaluated the contribution of various UBC4
      isoforms to this induction. UBC4-1 mRNA was expressed in most cells. UBC4-2 mRNA
      was restricted to germ cells with high levels of expression in round and
      elongated spermatids. UBC4-testis had previously been shown to be expressed only
      in spermatids. Our data suggest that induction of various UBC4 isoforms activates
      overall conjugation and plays an important role in the cellular remodeling and
      protein loss occurring during spermatogenesis.

PMID- 10419698
TI  - Cloning of rat fibrillin-2 cDNA and its role in branching morphogenesis of
      embryonic lung.
AB  - Fibrillin-2 is an extracellular matrix protein. It is associated with elastic
      fibers in several tissues and is believed to serve as a ligand for alphavbeta3
      integrin, the latter being a known morphogen. In this study, the role of
      fibrillin-2 in lung development was investigated. Also, rat fibrillin-2 cDNA was
      isolated and sequenced and its spatiotemporal expression determined. It had
      approximately 88% homology with human fibrillin-2 and had Ca(2+) binding
      epidermal growth factor-like domains, transforming growth factor-beta binding
      protein motifs, and two RGD binding sites. Northern blot analysis revealed an
      approximately 10-kb transcript, and fibrillin-2 expression was developmentally
      regulated, and it paralleled that of tropoelastin. At day 13 of gestation,
      fibrillin-2 was expressed in the mesenchyme and at the epithelial:mesenchymal
      interface. From day 13 to 19 of gestation, its expression intensified and was
      confined around the tracheobronchial airways, while it lessened during the
      postnatal period. Immunoprecipitation revealed an approximately 350-kDa band by
      SDS-PAGE. Treatment with fibrillin-2 antisense oligodeoxynucleotide induced
      dysmorphogenesis of the lung explants. They were smaller and had rudimentary lung
      bud branches, collapsed conducting airways, and loose expanded mesenchyme.
      Concomitantly, fibrillin-2 mRNA, antibody reactivity in the explants, and
      fibrillin-2-specific radioincorporation were reduced. Anti-alphav and -laminin
      antibody reactivity and their respective incorporated specific radioactivities
      were unaltered. These data indicate that fibrillin-2 modulates organogenesis of
      the lung in the context of epithelial:mesenchymal interactions. Conceivably, the
      collapse of the conducting airways may also be related to the perturbed biology
      of the fibrillin-2 interacting protein, i.e., elastin, the latter being critical
      for the normal biophysiology of the lungs.

PMID- 10419699
TI  - Slug is a mediator of epithelial-mesenchymal cell transformation in the
      developing chicken heart.
AB  - An epithelial-mesenchymal cell transformation occurs during the development of
      the endocardial cushions in the atrioventricular (AV) canal of the heart. We
      hypothesized that the transcription factor Slug is required for this epithelial
      mesenchymal cell transformation since Slug is required for similar
      transformations during gastrulation and neural crest differentiation in chicken
      embryos. We found by RT-PCR and immunostaining that the temporal and spatial
      localization of Slug in the embryonic chicken heart is consistent with a role for
      Slug in endocardial cushion formation. Moreover, we found that Slug expression by
      AV canal endothelial cells is induced by a signal provided by AV canal
      myocardium. Slug appears to be required for epithelial-mesenchymal cell
      transformation in the chicken heart since treatment of AV canal explants with
      antisense Slug oligodeoxynucleotides inhibited mesenchymal cell formation in
      vitro. Antisense Slug oligodeoxynucleotides prevented endothelial cell-cell
      separation, suggesting that Slug acts early in the transformation pathway.

PMID- 10419696
TI  - DHR3 is required for the prepupal-pupal transition and differentiation of adult
      structures during Drosophila metamorphosis.
AB  - Pulses of the steroid hormone ecdysone activate genetic regulatory hierarchies
      that coordinate the developmental changes associated with Drosophila
      metamorphosis. A high-titer ecdysone pulse at the end of larval development
      triggers puparium formation and induces expression of the DHR3 orphan nuclear
      receptor. Here we use both a heat-inducible DHR3 rescue construct and clonal
      analysis to define DHR3 functions during metamorphosis. Clonal analysis reveals
      requirements for DHR3 in the development of adult bristles, wings, and cuticle,
      and no apparent function in eye or leg development. DHR3 mutants rescued to the
      third larval instar also reveal essential functions during the onset of
      metamorphosis, leading to lethality during prepupal and early pupal stages. The
      phenotypes associated with these lethal phases are consistent with the effects of
      DHR3 mutations on ecdysone-regulated gene expression. Although DHR3 has been
      shown to be sufficient for early gene repression at puparium formation, it is not
      necessary for this response, indicating that other negative regulators may
      contribute to this pathway. In contrast, DHR3 is required for maximal expression
      of the midprepupal regulatory genes, EcR, E74B, and betaFTZ-1. Reductions in EcR
      and betaFTZ-F1 expression, in turn, lead to submaximal early gene induction in
      response to the prepupal ecdysone pulse and corresponding defects in adult head
      eversion and salivary gland cell death. These studies demonstrate that DHR3 is an
      essential regulator of the betaFTZ-F1 midprepupal competence factor, providing a
      functional link between the late larval and prepupal responses to ecdysone.
      Induction of DHR3 in early prepupae ensures that responses to the prepupal
      ecdysone pulse will be distinct from responses to the late larval pulse and thus
      that the animal progresses in an appropriate manner through the early stages of
      metamorphosis.

PMID- 10419700
TI  - A prognostic table to guide practitioners advising patients on adjuvant systemic
      therapy in early breast cancer.

PMID- 10419701
TI  - Patient evaluation of cosmetic outcome after conserving surgery for treatment of
      primary breast cancer.
AB  - AIMS: To investigate patient self-assessment of and satisfaction with cosmetic
      outcome following breast-conserving treatment. METHODS: A total of 254 patients
      with primary breast cancer who had been treated by wide local excision (WLE) were
      assessed objectively for cosmesis. Patients then self-rated their own cosmetic
      outcome and satisfaction via a questionnaire. RESULTS: Seventy-two per cent of
      the patients stated that there was little or no difference between the treated
      and untreated breast. Patient satisfaction was high with 90.5% being
      <<moderately>> or <<very satisfied>> with their cosmetic result. There were very
      good correlations between the objective assessment and the patient self
      assessment of the cosmetic result (chi(2)=77.98 P<0.001) and between the patient
      satisfaction and the patient self-assessment (chi(2)=122.65 P<0.001). CONCLUSION:
      This study shows very good cosmetic outcome with high patient satisfaction. These
      cosmetic results combined with a low local recurrence rate following wide local
      excision validate the operative method used.

PMID- 10419702
TI  - In search of the true sentinel node by different injection techniques in breast
      cancer patients.
AB  - AIMS: To evaluate two different injection techniques (peri-tumourally and
      intradermally) used in search for the sentinel node(s) in patients with breast
      cancer. METHODS: Ninety-nine patients were peri-tumourally injected with 2 ml 60
      MBq 99m-Tc-Nanocoll and underwent lymphoscintigraphy about 18 h later to detect
      focal accumulations. Next, they were injected intradermally with 0.2 ml 15 MBq
      99m-Tc-Nanocoll either in the skin overlying the tumour or para-areolarly in the
      quadrant of the tumour. Dynamic and static images were taken to visualize the
      (intradermal) lymphatic spread and accumulations. Special attention was paid to
      match or mismatch of hot spots visualized by both techniques. RESULTS: Ninety
      four patients had positive peri-tumoural and/or intradermal accumulations which
      could be compared. In 30 patients only peri-tumoural, and in nine only
      intradermal, identification was successful. Of the remaining 55 patients, in 52
      there was complete concordance of the axillary hot spots. However, there was a so
      called <<regional mismatch>> in nine of these patients concerning the internal
      mammary nodes. In the three remaining patients there was a sequential mismatch in
      the axilla: before draining lymph to the peri-tumourally visualized hot spot, an
      interposed node was encountered first after the intradermal injection technique.
      CONCLUSIONS: Intradermal injection is complementary to peri-tumoural injection
      for visualization of focal accumulations in patients with breast cancer. The two
      different injection techniques have a small number of sequential mismatches for
      hot spots in the axillary region. This means that it may be unclear which
      separate route leads to the true sentinel node. Internal mammary nodes visualized
      after peri-tumoural injection are not visualized by the intradermal technique.
      Para-areolar intradermal injection of Nanocoll for detection of sentinel nodes in
      patients with breast cancer needs further evaluation, because it seems to be a
      more practical procedure.

PMID- 10419703
TI  - Telomerase activity in phyllodes tumours.
AB  - AIMS: To investigate telomerase, a ribonucleoprotein that synthesizes telomeres.
      Recent evidence suggests that telomerase reactivation is associated with the
      acquisition of immortalization and malignancy. METHODS: Using a sensitive PCR
      based assay (the TRAP assay), we examined telomerase activity in two recurrent
      phyllodes tumours in two patients. RESULTS: Both tumours expressed telomerase
      activity. Histological examination of the lesions, according to the criteria
      proposed by Azzopardi and Salvadori, revealed a malignant phyllodes tumour in one
      patient and a benign phyllodes tumour in the other patient. CONCLUSIONS: Our
      findings suggest that telomerase activity may have a potential role as a
      prognostic marker in predicting the clinical behaviour of these rare tumours.

PMID- 10419704
TI  - The utility of mitotic index, oestrogen receptor and Ki-67 measurements in the
      creation of novel prognostic indices for node-negative breast cancer.
AB  - INTRODUCTION: Prognostic factors can be useful to identify node-negative patients
      at increased risk of relapse who should receive adjuvant treatment. In the past,
      oestrogen receptor status and mitotic index have been shown to be significant
      predictors of prognosis. Different techniques for the measurement of these
      prognostic factors are available. METHODS: Paraffin-embedded tumour specimens
      from 441 pre-menopausal patients with node-negative breast cancer who were
      previously randomized onto a trial comparing peri-operative chemotherapy with no
      further therapy were studied. Oestrogen receptor status was determined by the
      classical biochemical assay and by immunohistochemistry (ER-IA). Mitotic index
      was assessed by counting the number of mitoses and by calculating the percentage
      of tumour cells positively staining for the antibody Ki-67. RESULTS: There was a
      good correlation between ER-IA and the biochemical ER-assay (P<0.01), and the
      percentage of Ki-67 positive tumour cells and mitotic counts (P<0.01)
      respectively. However, ER-IA significantly predicted disease-free survival
      (RR=2.67, 95% CI: 1.60-4.44, P<0.01) whereas the biochemical assay was only
      borderline significant (RR=1.54, 95% CI: 1.00-2.36, P=0.05). Similarly, Ki-67 was
      a stronger indicator of prognosis (RR=2.84, 95% CI: 1.80-4.48, P<0.01) than
      mitotic counts (RR=1.56, 95% CI: 1.22-2. 00, P<0.01). CONCLUSIONS: We conclude
      that ER-IA performs better in predicting prognosis than the classical biochemical
      oestrogen receptor assay. Ki-67 is a more accurate marker for tumour cell
      proliferation and predicts prognosis of patients with breast cancer better than
      do mitotic counts.

PMID- 10419706
TI  - Improved survival and local control after total mesorectal excision or D3
      lymphadenectomy in the treatment of primary rectal cancer: an international
      analysis of 1411 patients.
AB  - AIMS: Improved local control and survival in the treatment of rectal cancer have
      been reported after total mesorectal excision and after extended lymphadenectomy.
      Comparison of published results is difficult because of differences in patient
      populations and definitions. We compared three series of patients who underwent
      standardized surgery [i.e. total mesorectal excision (TME) or D3 lymphadenectomy]
      with patients who underwent conventional surgery, using actual patient data and
      uniform definitions. METHODS: TME was performed at Memorial Sloan-Kettering
      Cancer Center, New York, USA (n=254) and the North Hampshire Hospital,
      Basingstoke, UK (n=204). D3 lymphadenectomy was performed at the National Cancer
      Center, Tokyo (n=233). Conventional surgery was used in hospitals in Norway
      (n=366) and in hospitals of the Comprehensive Cancer Center West, The Netherlands
      (n=354). Only patients with a curatively resected primary TNM Stage II or Stage
      III rectal cancer within 12 cm from the anal verge were included. RESULTS: Five
      year overall survival and cancer-specific survival were 62-75% and 75-80%,
      respectively, in the standardized surgery groups and 42-44% and 52%,
      respectively, in the conventional surgery groups. Local recurrence rates ranged
      from 4 to 9% in the standardized surgery groups and 32-35% in the conventional
      surgery groups. CONCLUSIONS: A 30% survival difference and 25% local recurrence
      difference is not likely to be caused by the shortcomings which are inherent in a
      non-randomized study: selection bias, assessment variability or stage migration.
      This study suggests that standardized surgery gives superior survival and local
      control when compared to conventional surgery.

PMID- 10419705
TI  - Amplification of cyclin D1 and MDM-2 in oesophageal carcinoma.
AB  - AIMS: This study investigated amplification of the cyclin D1 and MDM-2 genes, and
      overexpression of the cyclin D1 gene product, in oesophageal carcinoma. METHODS:
      Paired tumour and normal DNA samples from 26 oesophageal adenocarcinomas and 19
      squamous cell carcinomas were analysed by Southern blotting with specific DNA
      probes for cyclin D1 and MDM-2, and for a control gene (alpha-lactalbumin). The
      cyclin D1 and MDM-2 gene copy numbers were calculated for each tumour. Expression
      of the cyclin D1 gene was assessed by immunohistochemical analysis of its protein
      product. RESULTS: Cyclin D1 gene amplification (by a factor of between two and
      six) was identified in seven tumours (16%). MDM-2 gene amplification (by a factor
      of between two and 11) was identified in 10 tumours (22%). Overexpression of
      cyclin D1 protein was identified in eight tumours and was significantly
      associated with gene amplification (P=0.04; Fisher's exact test), and with early
      T stage (P=0.01; Fisher's exact test). CONCLUSIONS: Cyclin D1 and MDM-2
      amplification and cyclin D1 overexpression occur, although infrequently, in the
      development of oesophageal carcinoma. Cyclin D1 overexpression may influence
      tumour behaviour, causing the disease to present at an earlier T stage. The
      mechanism for this effect is unclear, and warrants further investigation.

PMID- 10419707
TI  - Peripheral cholangiocarcinoma: presentation, diagnosis, pathology and management.
AB  - AIMS: To report the clinical presentation, diagnosis and results of aggressive
      surgical management in patients with intrahepatic cholangiocarcinoma. METHODS:
      From February 1988 to June 1998, 21 patients underwent laparotomy with a 90%
      resectability rate (19 resections). The 19 liver resections included right
      trisegmentectomy in six patients, right lobectomy in five, wedge resection in
      four, left lobectomy in two, left trisegmentectomy in one and a lateral
      segmentectomy in one. Resection of the biliary confluence with reconstruction by
      a Roux en Y hepaticojejunostomy was performed in three patients. RESULTS: Mild
      abdominal pain, weight loss and gastrointestinal disturbances were the most
      frequent clinical signs. Jaundice was present in only four patients. Pre
      operative radiological investigations (abdominal ultrasound, computed tomography,
      arteriography) correlated with pathological findings in only 60% of cases. Pre
      operative histological findings (fine-needle cytology, liver biopsy), available
      for 19 patients, did not always provide an accurate diagnosis. The mortality and
      morbidity rates were 5 and 47%, respectively. The median survival of resected
      patients was 18 months. Overall patient and tumour-free survival rates were 83
      and 31% at 1 year, 33 and 16.5% at 2 years and 16.5 and 16.5% at 3 years in the
      resected group. Lymph-node spread, vascular invasion, positive margins and
      bilobar distribution were associated with a high recurrence rate and poor
      prognosis. CONCLUSION: Despite the advanced stage of these tumours at
      presentation, patient survival can be improved by aggressive surgical resection.
      As intrahepatic cholangiocarcinoma usually develops in a non-cirrhotic liver,
      major hepatic resections to obtain disease-free margins can be performed with low
      mortality.

PMID- 10419708
TI  - Downstaging by regional chemotherapy of non-resectable isolated colorectal liver
      metastases.
AB  - AIMS: To improve the course of isolated non-resectable colorectal liver
      metastases (CRLM) by hepatic arterial infusion treatment. Patients with CRLM have
      a worse prognosis than those whose liver metastases are resectable. Systemic
      (i.v.) chemotherapy for CRLM/colorectal metastases with 5-fluorouracil+folinic
      acid (5-FU+FA) i.v. may result in median survival times of 6.4-14.3 months.
      Hepatic artery infusion (HAI) with 5-fluorodeoxyuridine (5-FUDR) has been
      demonstrated in a meta-analysis of randomized trials to be superior to i.v.
      treatment/palliative care (median survival 15 vs. 10 months). The benefit of HAI
      with 5-FUDR, although recommended as treatment for CRLM, is severely compromised
      by the 5-FUDR induced hepatotoxicity, leading eventually to sclerosing
      cholangitis (SC)/liver cirrhosis. We have developed a stepwise protocol for HAI
      in CRLM, which is superior to HAI with 5-FUDR and to systemic chemotherapy.
      METHODS: Between 1982 and 1997, 168 CRLM patients were treated within the
      following protocols. In protocol A, 48 CRLM patients received HAI with 5-FUDR. In
      protocol B, 46 patients received 5-FUDR i.a. (HAI)+i.v. In protocol C 5-FU+FA
      were delivered via HAI in 24 patients with CRLM. In protocol D, based on in vitro
      phase II studies and the results of protocol C, mitoxantrone and mitomycin C were
      added to 5-FU+FA (MFFM). Fifty (50) CRLM patients received HAI with HFFM.
      RESULTS: The response rates, median survival time, systemic toxicity and SC rate
      were: 42%, 20.8 months, 0-19% and 38% for protocol A; 46%, 20.8 months, 0-20% and
      41% for protocol B; 45%, 19.8 months, 4-25% and 0% for protocol C; and 66%, 27.4
      months, 2-26% and 0% for protocol D. The surgically placed ports for HAI in
      protocols C and D functioned in 90%, 82% and 76% of patients, 6, 9, and 11 months
      after beginning HAI. Quality of life in protocol D was high. Nine patients from
      protocols C and D with either partial (PR, seven patients) or complete (CR, two
      patients) remissions received a secondary liver resection without hospital
      mortality, and seven of nine patients are alive 2-58 months after liver
      resection. The other two died 11 and 22 months after resection. CONCLUSIONS:
      Optimal treatment of CRLM was found to be protocol D: HAI with MFFM. The results
      of this protocol, including high remission rate, long median survival time, good
      port function, good quality of life and, interestingly, the possibility of
      downstaging and resecting primarily non-resectable metastases, seem to be
      superior to HAI with 5-FUDR or 5-FU+FA and to systemic chemotherapy with 5-FU+FA.
      This hypothesis is currently being examined in a phase III study (HAI with MFFM
      vs. 5-FU+FA i.v.).

PMID- 10419709
TI  - Surgical aspects of iliopsoas compartment tumours.
AB  - AIM: To demonstrate the pathological variety and highlight the surgical
      principles involved in the management of tumours of the iliopsoas compartment
      (IPC). METHODS: Review of four clinical cases. RESULTS: Adequate surgical
      resection or palliation was achieved in each case. CONCLUSION: Resection of IPC
      tumours is feasible but access to the most superior part of the muscle may be
      impossible. An extraperitoneal approach is advocated.

PMID- 10419710
TI  - Revision surgery in dermatofibrosarcoma protuberans of the trunk and extremities.
AB  - AIMS: Dermatofibrosarcoma protuberans is a rare condition which is frequently
      misdiagnosed at presentation, resulting in a high incidence of local recurrence
      due to inadequate resection. The archives of the Department of Orthopaedics at
      the University of Florida were analysed to investigate the natural history and
      results of treatment for this tumour. METHODS: Between 1975 and 1996, 35 cases of
      DFSP were treated at the University of Florida. Of these, one was treated
      primarily, five were treated for local recurrence, 17 had tumour bed excisions
      following inadequate primary excisions elsewhere and 12 had tumour bed excisions
      following inadequate resection of local recurrences elsewhere. The data were
      analysed to assess the impact of age, gender, duration of symptoms, tumour site
      and size, surgical margin, number of operations and adjuvant treatments on
      survival and local recurrence outcomes. RESULTS: Complete follow-up was available
      for 34 patients. Mean follow-up was 58 months (range 12-144 months). Thirty-three
      patients remain alive and disease-free. One patient died of unrelated causes. The
      margins obtained were wide in 28 patients, marginal in six and intralesional in
      one. Of the seven patients with inadequate surgical margins, four received
      adjuvant radiation therapy and remain disease-free. No patient with an adequate
      margin developed a local recurrence, but there were three local recurrences in
      the patients with an inadequate margin who did not receive adjuvant radiation
      therapy (local recurrence rate: 8%). No patient developed lymphatic or distant
      metastasis. Local recurrences were more likely to be classified Stage IB (17/17)
      than primary tumours (1/18) (P<0.001). Local recurrence was more likely where the
      surgical margin was less than 2.5 cm from the lesion. CONCLUSIONS:
      Dermatofibrosarcoma protuberans is a low-grade tumour that has a high potential
      for local recurrence unless it can be completely excised. The overall rate of
      local recurrence in referred patients in this series was 20/35 cases (57%). All
      occurred after inadequate margins at previous surgery in other institutions.
      Revision surgery in these patients showed a local recurrence rate of 8%. To avoid
      extensive surgery for recurrences, initial treatment should be by wide excision
      incorporating the underlying deep fascia and a cuff of 2.5-3 cm of normal skin
      tissue. Radiation therapy provides a useful adjunct where adequate margins cannot
      be obtained.

PMID- 10419711
TI  - Desmoid tumours of the anterior abdominal wall.
AB  - AIMS: To review the surgical management and outcomes for large desmoid tumours of
      the abdominal wall. METHODS: Seven patients with large desmoid tumours of the
      anterior abdominal wall were treated by wide local excision and reconstruction
      with two layers of Marlex V mesh (Bard, Galway, Ireland). RESULTS: No patient
      having initial surgery at this hospital has either a significant residual
      functional deficit or developed a recurrence. CONCLUSIONS: Large desmoid tumours
      of the abdominal wall are safely and adequately managed with abdominal wall
      resection followed by mesh reconstruction.

PMID- 10419712
TI  - Carcinoma of the ethmoid: results of treatment with conventional surgery and post
      operative radiotherapy.
AB  - AIMS: A retrospective study was carried out of 50 patients with carcinoma of the
      ethmoid, treated over a period of 20 years. METHODS: The treatment used was
      surgery, followed by post-operative external beam radiotherapy and when possible
      supplemented by brachytherapy. RESULTS: Although the nature of surgery in the
      majority of cases was conventional, the 63% 5-year overall survival, except in
      adenocarcinomas, was slightly better than that achieved by more aggressive
      surgery. There was no mortality and morbidity was minimal. CONCLUSIONS:
      Conventional surgery in combination with radiotherapy and brachytherapy gives
      satisfactory and comparable results.

PMID- 10419713
TI  - Adenoid cystic carcinoma of Bartholin's gland: what is the optimal approach?
AB  - AIMS AND METHODS: We report the case of a locally advanced adenoid cystic
      carcinoma of Bartholin's gland which required posterior pelvic exenteration,
      radical vulvectomy and ablation of the ischiorectal fossa in order to obtain
      tumour clearance with negative margins. Including this case, only three
      pelvectomies have been performed for this disease. This is the first reported
      case in which a controlateral unsuspected intravulvar metastasis was found on
      histology. RESULTS AND CONCLUSIONS: No consensus exists on the adequate surgical
      management of this particular disease. Nevertheless, a review of the literature
      and this reported case suggest that radical vulvectomy with negative margins
      should be preferred to wide local excision as the primary surgical procedure. It
      also suggests that inguinofemoral lymph-node dissection should only be performed
      when suspect lymph nodes are found at clinical examination.

PMID- 10419714
TI  - Part III. Progress in the 19th century.

PMID- 10419715
TI  - Fillet of finger flap for hand resurfacing after tumour excision.

PMID- 10419716
TI  - Intraoperative celiac plexus block in the surgical palliation for unresectable
      pancreatic cancer.

PMID- 10419717
TI  - Oophorectomy in women with colorectal cancer.

PMID- 10419718
TI  - Late onset of tonsillar metastasis from breast cancer.
AB  - A 71-year-old woman non-smoker referred for repeated haemoptysis showed a tumoral
      lesion of the left tonsil. Pathological analysis of the biopsy showed
      characteristics compatible with a breast carcinoma metastasis, in which oestrogen
      and progesterone receptors were present. The patient had undergone mastectomy and
      had received adjuvant radiotherapy 24 years previously for a breast cancer with
      no complaints or signs of recurrence since. Investigations showed disseminated
      bone metastases but no other soft-tissue deposits. Anti-oestrogen therapy was
      applied. Only seven similar cases of tonsillar metastasis from breast cancer have
      been reported.

PMID- 10419719
TI  - An unusual case of breast metastasis from an anorectal melanoma.
AB  - An unusual case of solitary breast metastasis from a primary anorectal melanoma
      in a 59-year-old post-menopausal woman is reported. The course and management of
      melanotic breast metastases is discussed.

PMID- 10419720
TI  - Sentinel node biopsy in male breast cancer.

PMID- 10419721
TI  - Sentinel-node guided lymph-node dissection for merkel cell carcinoma.
AB  - Merkel cell carcinoma is an aggressive neuroendocrine skin tumour. Treatment is
      still debatable. Merkel cell carcinoma resembles malignant melanoma in its
      cutaneous presentation and its embryonic origin; both have unpredictable
      biological behaviour, early regional lymph node involvement, early distant
      metastases and a high recurrence rate. In light of these common features, we used
      pre-operative lymphoscintigraphy, intraoperative lymph-node mapping and sentinel
      node biopsy-a well-described technique for the treatment of melanoma-in a 60-year
      old man with Merkel cell carcinoma in the right buttock. Following frozen section
      identification of a metastatic first-order sentinel node, radical right groin
      dissection was performed. All the other lymph nodes in this basin proved to be
      disease-free, including the second-order sentinel node and Cloquet node. The
      patient is now being treated with adjuvant chemotherapy and radiotherapy. This
      case shows that sentinel-node guided dissection is applicable to Merkel cell
      carcinoma.

PMID- 10419722
TI  - Leiomyoblastoma of the colon presenting as pseudo-Meigs' syndrome.
AB  - Leiomyoblastomas are rare smooth-muscle tumours, most commonly arising from the
      stomach wall. We describe a case of leiomyoblastoma of the colon presenting with
      the pseudo-Meigs>> syndrome.

PMID- 10419723
TI  - Malignant fibrous histiocytoma of the rectum.
AB  - Malignant fibrous histiocytoma (MFH) of the gastrointestinal tract is a rare
      occurrence. We report a case of MFH of the rectum in a 55-year-old man.
      Ultrasound examination revealed thickening of the rectal wall and the biopsy
      study indicated MFH. The patient underwent abdominoperineal resection and
      chemoradiation and is doing well after 46 months. A high index of suspicion for
      colorectal MFH should be taken into account in order to avoid histological
      misdiagnosis.

PMID- 10419724
TI  - Laparoscopy, laparotomy and abdominal wall implants: small is worse.

PMID- 10419725
TI  - Gynecologic oncology-on the eve of the new millennium.

PMID- 10419726
TI  - Stage IA cancer of the cervix: finally some resolution of definition and
      treatment?

PMID- 10419727
TI  - Assessment of the revised International Federation of Gynecology and obstetrics
      staging for early invasive squamous cervical cancer.
AB  - OBJECTIVE: The aim of this study was to investigate the value of the
      International Federation of Obstetrics and Gynecology (FIGO) classification
      (1995) for early invasive cervical cancer. Methods. Clinico-pathological analysis
      was performed in 402 patients with invasive squamous cervical cancer in whom the
      depth of stromal invasion was 5 mm or less. RESULTS: The incidence of lymph node
      metastasis was 1.2% (1/82) in patients with 3 mm or less depth of invasion; the
      node-positive patient was in stage IA1. The incidence of lymph node metastasis
      was 6.8% (5/73) in patients with 3-5 mm depth of invasion; this increased with
      increasing horizontal spread from 3.4% for 7 mm or less to 9.1% for more than 7
      mm. None of the patients in this series had metastasis to the parametrial
      tissues. Of 4 patients with recurrence, 3 had horizontal spread of more than 7 mm
      and the remaining patient was in stage IA2. CONCLUSION: The FIGO definition of
      early squamous cervical cancer is generally acceptable in its present form.

PMID- 10419728
TI  - Antitumor effect of GnRH agonist in epithelial ovarian cancer.
AB  - OBJECTIVE: The effects of the gonadotropin releasing hormone (GnRH) agonist (D
      Trp(6)) were examined in two human ovarian cancer cell lines and in severe
      combined immune deficiency (SCID) mice to evaluate its potential as a cytocidal,
      cytostatic, or differentiating antitumor agent. METHODS: We treated the human
      ovarian cancer cell lines OVCAR-3 and SKOV-3 for 5 or 7 days and sex-matched SCID
      mice with GnRH agonist for 29 days. The antitumor effect of GnRH agonist were
      studied in various aspects. To confirm the antiproliferative effect, we used 3
      (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide colorimetric assay,
      in vitro, and a serial measurement of tumor growth in vivo. The disturbances of
      progression in the cell cycle and the changes of cyclin-dependent kinase 1
      following treatment with GnRH agonist were evaluated with flow cytometric
      analysis in vitro. The induction of apoptosis following treatment with GnRH
      agonist was studied using in situ terminal deoxyribonucleotidyl transferase (Tdt)
      and further quantitated with ELISA in vitro. The presence of telomerase activity
      following treatment with GnRH agonist was measured by PCR-based telomeric repeat
      amplification protocol and ELISA detection in cell lines and xenografts in vitro
      and in vivo. RESULTS: Continuous exposure of cell lines and xenografts to GnRH
      agonist resulted in growth inhibition of cancer cells in a dose- and time
      dependent manner. In cultured cells, the GnRH agonist blocked cell cycle
      progression in G0/G1 phase and thus reduced the number of cells in S and G2/M
      phases. The phenomenon of apoptosis was documented in cultured cells treated with
      GnRH agonist by in situ Tdt assay. The frequency of apoptotic cells in the in
      situ Tdt assay was 5-6% compared with control, 4-5%. Apoptosis quantified by
      ELISA revealed a high incidence in cultured cells treated with GnRH agonist. The
      activities of telomerase in cell lines and xenografts were not decreased by GnRH
      agonist. There were not any significant changes of expression of CA-125 by flow
      cytometry and of the cellular morphology observed with light microscopy.
      CONCLUSIONS: Our results indicate that the antiproliferative effect of GnRH
      agonist in epithelial ovarian cancer cells may be mainly attributed to cytostatic
      activities resulting in blocking of cell cycle progression in the G0/G1 phase and
      minimally related to the induction of apoptosis.

PMID- 10419729
TI  - Modulation of proliferation and chemosensitivity by procathepsin D and its
      peptides in ovarian cancer.
AB  - Since the presence of precursors (pro-forms) of the aspartyl endoprotease,
      cathepsin D, appears to be linked with tumor progression, their presence was
      examined in sera and tumor tissues of ovarian cancer patients. The role of
      cathepsin D pro-forms was further assessed in the dysregulated proliferation and
      chemoresistance observed in advanced ovarian cancer. Cathepsin D was isolated
      from sera of ovarian cancer patients (n = 20) and normal volunteers (n = 11), as
      well as from solubilized normal ovarian epithelium (n = 8) and ovarian epithelial
      tumor tissue (n = 12). The specific molecular forms of cathepsin D were analyzed
      in these samples by Western immunoblot. Multiple circulating molecular weight
      forms of cathepsin D were identified in ovarian cancer patients ranging from 24
      to 60 kDa, while in normal controls, a major band was observed at 34 kDa in all
      samples and minor bands corresponding to 27 and 48 kDa were detected in
      approximately half of the controls. To assess its consequences on ovarian cancer,
      the 52-kDa protein was immunoprecipitated from culture medium of an exponentially
      growing ovarian tumor cell line and was further purified by reverse-phase high
      pressure liquid chromatography. Its effect on proliferation was assayed by
      determining cell doubling times and their chemosensitivity was measured in a
      standard cytotoxicity assay using cisplatin. In addition, decapeptides
      corresponding to the pro-portion of cathepsin D were analyzed in parallel.
      Procathepsin D and one decapeptide, peptide 2, as well as IGF-II (as a known
      positive) increased cell proliferation, with doubling times of 28.4, 28.8, and
      30.3 h, respectively, versus untreated UL-1 cells (36.4 h). Procathepsin D
      treatment of UL-1 tumor cells significantly increased the cisplatin LD(50) (74.9
      microgram/ml) over untreated (33.9 microgram/ml) as well as IGF-II-treated (38.8
      microgram/ml) cells. Peptide 2 also showed a significant increase in LD(50) (69.5
      microgram/ml) compared to untreated and peptide 1-treated cells (37.1
      microgram/ml). There are several unique forms of cathepsin D expressed and
      accumulated by ovarian tumors and these forms are detectable in the sera of those
      with ovarian cancer. The presence of these procathepsin D can increase the
      proliferation of these tumor cells, while decreasing their sensitivity to
      chemotherapeutic agents. While procathepsin D and IGF-II both enhance
      proliferation, only procathepsin D (and peptide 2) appears to modulate
      chemosensitivity, suggesting a separate receptor or pathway for this consequence.

PMID- 10419730
TI  - Presence of an eosinophilic infiltrate in cervical squamous carcinoma results
      from a type 2 immune response.
AB  - OBJECTIVES: The presence of an eosinophilic infiltrate in patients with cervical
      squamous carcinoma has been shown to correlate with a worse overall survival,
      suggesting a less effective immune response in these cases. Since type 2
      cytokines such as IL-4 and IL-5 are known to attract eosinophilic granulocytes,
      an immunohistochemical study was performed to gain further insight as to whether
      a type 1 or type 2 immune response is involved in eliciting an eosinophilic
      infiltrate. MATERIAL AND METHODS: Frozen tissue sections of 9 normal cervical
      tissues, 23 premalignant cervical lesions, and 23 cervical squamous carcinomas
      were stained by immunohistochemistry with monoclonal antibodies directed against
      IFN-gamma and IL-4 as representatives of a type 1 or a type 2 response,
      respectively. RESULTS: Normal tissues and premalignant lesions of the cervix did
      not contain eosinophilic granulocytes and showed very few IL-4- and IFN-gamma
      positive cells. In cervical carcinoma the presence of IL-4 on tumor infiltrating
      cells correlated with the presence of eosinophilic granulocytes in the tumor (P
      value <0.01) and stroma (P value <0.05). IFN-gamma-positive cells did not show
      any such correlation. In addition, colocalization was observed of CD3- and IL-4
      positive T lymphocytes indicating that IL-4 production is mediated by T
      lymphocytes. CONCLUSION: The relative increase of IL-4-positive cells in the
      presence of an eosinophilic infiltrate might thus reflect an imbalance between a
      type 1 and type 2 response, in favor of the latter. Since a type 1 response
      stimulates an adequate cellular response which is negatively regulated by type 2
      cytokines, these findings might explain the worse clinical outcome seen in
      cervical cancer patients with an eosinophilic tumor infiltrate. These results may
      have implications when developing immunotherapeutical strategies for cervical
      cancer.

PMID- 10419731
TI  - Leiomyosarcoma of the uterus: a clinicopathologic multicenter study of 71 cases.
AB  - OBJECTIVE: The aim of this study was to evaluate the behavior of uterine
      leiomyosarcomas in relation to their clinical and pathologic features and to
      identify possible prognostic factors. METHODS: Seventy-one patients with
      histologically proven uterine leiomyosarcoma were included in the analysis.
      Leiomyosarcomas were defined as uterine smooth-muscle tumors with five or more
      mitoses per 10 high-power fields and cytologic atypia. Cox proportional hazards
      regression model was used to identify independent prognostic factors. RESULTS:
      The median follow-up time was 108 months; 5-year overall survival rate was 65%.
      Evaluating the correlation between several clinicopathologic parameters, tumors
      with vascular space involvement had a statistically significantly higher stage
      than tumors without vasular space involvement (P = 0.015). In a univariate Cox
      model early tumor stage (P < 0.0001), age <50 years (P < 0.0001), low mitotic
      count (P = 0.05), and the absence of vascular space involvement (P < 0.0005) were
      associated with good prognosis. In a multivariate analysis age (P = 0.002), tumor
      stage (P = 0.004), vascular space involvement (P = 0.003), and mitotic count in
      stage I tumors (P = 0.002) were found to be independent parameters for good
      prognosis in patients with uterine leiomyosarcoma. CONCLUSION: Early tumor stage,
      age <50 years, and absence of vascular space involvement were independently
      associated with good prognosis. Mitotic count was detected to be a strong
      prognostic parameter in early tumor stage, but failed to act as an independent
      prognostic parameter in patients with tumor stage II-IV disease.

PMID- 10419732
TI  - Colony-stimulating factor-1 and its receptor do not have a role in the
      pathogenesis of uterine sarcomas.
AB  - OBJECTIVE: Several studies have demonstrated overexpression of the mononuclear
      phagocytic growth factor colony-stimulating factor-1 (CSF-1) and its receptor
      (CSF-1R) in breast, ovarian, and endometrial adenocarcinomas, and their
      expression in each of these cancers is strongly correlated with poor prognosis.
      In addition to adenocarcinomas, sarcomas that are highly malignant arise at much
      lower frequency in the uterus. Given the common organ of origin and hormonal
      environment of the adenocarcinomas, we evaluated the potential role of CSF-1 and
      CSF-1R in the genesis of these tumors using immunohistochemical methods. RESULTS:
      Immunohistochemical analysis was performed on 19 archival uterine sarcoma
      samples. Affinity-purified rabbit anti-CSF-1 antiserum (R52) and human cross
      reactive murine anti-c-fms antibody were used. In the 19 cases evaluated for CSF
      1 immunoreactivity, 42.1% had staining in less than 25% of the tumor, 36.9% had
      staining in 25-50% of the tumor, and only 21% had staining in greater than 50% of
      the tumor. When present, the majority of the CSF-1 immunostaining was associated
      with the extracellular matrix. There was variable intensity in CSF-1 expression:
      52.6% had negative to mild staining, and 47.4% had moderate to strong staining.
      Immunostaining for the CSF-1R revealed that 52.6% of tumors had expression in
      less than 25% of cells, 21.0% had expression in 25-50% of the tumor, and 26.4%
      had staining in greater than 50% of the tumor. There was variable intensity of
      CSF-1R staining. Slight staining was found in 31.6% of the cases, moderate
      staining was found in 47.4% of the tumors, and 21.0% of the cases had strong
      expression. There was no statistically significant correlation between CSF-1 and
      CSF-1R expression and stage, estrogen/progesterone receptor status, number of
      mitoses per 10 high-power fields, or disease outcome. In addition, overall
      expression and intensity of CSF-1 and CSF-1R did not predict tumor virulence or
      disease outcome. CONCLUSION: In contradistinction to endometrial adenocarcinomas,
      in which CSF-1/CSF-1R is strongly correlated with tumor progression, CSF-1 and
      CSF-1R overexpression does not appear to play a role in the growth and
      differentiation of uterine sarcomas.

PMID- 10419733
TI  - Cost-effectiveness of treatment of early stage endometrial cancer.
AB  - OBJECTIVE: The purpose of this study was to determine the average life-years
      gained and cost per life-year gained in treatment of early endometrial cancer.
      METHODS: We performed a decision analysis using statistical models for survival
      after treatment for Stage I endometrial cancer. Estimates for survival
      probabilities without treatment, with surgery alone, and with surgery and
      radiation were derived from the literature. Charges and costs of treatment were
      estimated based on data from our institution. We calculated the average number of
      life-years gained and the cost per life-year gained of various treatment options
      based on these estimates. Sensitivity analyses were performed to determine the
      effect of uncertainty about parameter estimates on the results derived from our
      model. RESULTS: Based on the assumptions of our model, most of the life-years
      gained in treatment of early endometrial cancer are attributable to hysterectomy,
      with a very low associated cost. For the "average" woman with endometrial cancer,
      about 10 life-years are gained from hysterectomy at a cost of $1000 per life-year
      gained, whereas adjuvant radiation yields on average 1 year of life gained at
      $4000 per life-year gained. Both life-years gained and cost are dramatically
      affected by age at diagnosis and to a lesser extent by histologic grade and
      comorbid medical conditions. CONCLUSIONS: This analysis suggests that the use of
      hysterectomy and adjuvant radiation in treatment of early endometrial cancer is a
      worthwhile use of health care resources. More sophisticated models may help
      determine the cost-effectiveness of various treatment strategies in specific
      subgroups of patients.

PMID- 10419734
TI  - Androgenetic complete mole coexistent with a twin live fetus.
AB  - OBJECTIVE: The aim of this study was to evaluate the clinical course and the
      management policy of complete mole coexistent with a twin live fetus confirmed
      with DNA polymorphism in a single hospital. METHODS: From 1981 to 1995, six
      patients with androgenetic complete hydatidiform mole coexistent with a twin live
      fetus were diagnosed by DNA polymorphism analysis. The clinical course of these
      six patients was analyzed. RESULTS: Two patients chose to terminate pregnancies
      and four patients desired to continue the pregnancy. However, the pregnancy had
      to be interrupted in two patients because of severe preeclampsia and sudden
      intrauterine fetal death. In two patients, fetuses were growing unremarkably and
      normal babies were delivered at term. The development of persistent trophoblastic
      tumor (PTT) in these rare pregnancies was higher (50.0%: 3/6) than that of single
      complete mole. In three patients, serum hCG titers during pregnancy were
      monitored. Although serum hCG levels progressively decreased during pregnancy in
      one patient without PTT, hCG levels initially decreased, but subsequently
      increased or showed a plateau with advancing gestational age in two patients with
      PTT. CONCLUSIONS: In patients with complete mole coexistent with a live fetus,
      the pregnancy may be allowed to continue when the fetal karyotype and development
      are normal and serum hCG titers are constantly falling with advancing gestational
      age.

PMID- 10419735
TI  - Long-term transvaginal ultrasonographic endometrial follow-up in postmenopausal
      breast cancer patients with tamoxifen treatment.
AB  - OBJECTIVE: The aim of this study was to evaluate changes in transvaginal
      ultrasonographic endometrial thickness with increased duration of tamoxifen
      treatment in postmenopausal breast cancer patients. MATERIAL AND METHODS: In this
      prospective study we evaluated the changes (mean +/- SD) of endometrial thickness
      measured by transvaginal ultrasonography in 181 postmenopausal breast cancer
      patients, according to the duration of tamoxifen treatment. According to our
      protocol, the ultrasonographic evaluations were performed every 6 months for the
      first 2 years of the follow-up and every 12 months thereafter. Two such
      subsequent ultrasonographic evaluations were performed in 181 patients following
      35.1 +/- 41.7 months of tamoxifen treatment, three studies in 127 patients
      following 44.7 +/- 47.98 months of treatment, four studies in 75 following 54.2
      +/- 61.7 months of treatment, five studies in 51 patients following 65.3 +/- 74.4
      months of treatment, and six studies in 27 patients following 79.5 +/- 98.8
      months of treatment. RESULTS: The measured endometrial thickness detected varied
      from 8.84 +/- 4.66 to 10.61 +/- 12.35 mm. There were no significant changes in
      mean +/- SD of endometrial thickness following various durations of tamoxifen
      treatment. CONCLUSIONS: Extension of duration of tamoxifen treatment in
      postmenopausal breast cancer patients up to 79.48 +/- 98.79 consecutive months
      does not cause a significant increase in transvaginal ultrasonographic
      endometrial thickness.

PMID- 10419737
TI  - Serum vascular endothelial growth factor in epithelial ovarian neoplasms:
      correlation with patient survival.
AB  - OBJECTIVE: To investigate the relationship between serum vascular endothelial
      growth factor (VEGF) and clinicopathological factors and to determine whether
      VEGF is an independent prognostic factor of ovarian cancer patients. METHODS:
      Fifty-six women with International Federation of Gynecology and Obstetrics stages
      I to IV epithelial ovarian cancer undergoing surgery were enrolled. Clinical and
      pathologic items were recorded. Pretreatment VEGF serum samples of the 56 women
      were measured by an enzyme-linked immunosorbent assay. The results were
      correlated to clinical data. The histopathologic items and serum VEGF influencing
      clinical outcome were evaluated comparatively. RESULTS: The median VEGF serum
      level in ovarian cancer patients was 458.7 pg/mL. The 75% quatile was defined as
      the cutoff level. Elevated vascular endothelial growth factor serum levels before
      therapy correlated significantly with poorer disease-free survival (DFS) (log
      rank test, P = 0.001) and overall survival (OS) (log rank test, P < 0.001) on all
      of the 56 patients. Besides, significantly reduced DFS (log rank test, P = 0.001)
      and OR (log rank test, P = 0.006) were also observed on 40 patients with residual
      disease less than 2 cm. High histologic grade (RR = 2.24 for DFS; RR = 2.38 for
      OS) and elevated serum VEGF levels (RR = 3.34 for DFS; RR = 4.47 for OS) are the
      prognostic factors on the 56 ovarian carcinoma patients by multivariate analyses.
      The advanced surgical staging (RR = 3.28 for DFS; RR = 3.84 for OS), high
      histologic grade (RR = 2.55 for DFS; RR = 2.44 for OS), and elevated serum VEGF
      levels (RR = 5.62 for DFS; RR = 5.37 for OS) are the prognostic factors for 40
      ovarian carcinoma patients with residual disease less than 2 cm by multivariate
      analyses. CONCLUSIONS: Pretreatment VEGF serum levels might be regarded as an
      additional factor in predicting the outcome of ovarian cancer patients. It also
      could provide prognostic information in clinically relevant subsets, such as
      those of residual disease less than 2 cm. Anti-angiogenic therapy, if is
      available, might be a new treatment modality for ovarian cancer patients with
      poor prognosis predicted by VEGF and other clinical parameters.

PMID- 10419736
TI  - An advanced generation of adenoviral vectors selectively enhances gene transfer
      for ovarian cancer gene therapy approaches.
AB  - OBJECTIVE: We hypothesized that incorporation of an integrin binding Arg-Gly-Asp
      (RGD)-containing peptide to the HI loop of the adenovirus fiber knob would allow
      enhanced, coxsackie-adenovirus receptor-independent gene transfer by modified Ad
      vector in the context of ovarian cancer. METHODS: Ovarian cancer cell lines,
      primary ovarian cancer cells, primary tumor explants, and mesothelial tissue were
      transfected with luciferase encoding adenovirus (AdCMVLuc) or a genetically
      modified adenovirus (Ad5lucRGD) which contained an RGD motif within the HI loop
      of the knob. The luciferase activity was measured and the transduction
      efficiencies of both viruses were compared. RESULTS: In all established ovarian
      cell lines and primary tumor cell samples there was dramatically augmented gene
      transfer observed with the Ad5lucRGD compared to AdCMVLuc. The enhanced gene
      transfer in ovarian cancer cell lines ranged from 2.5- to 471.6-fold, in ascites
      samples from 26.1- to 64.0-fold, and in tumor explants from 1.6- to 11.1-fold.
      Although gene transfer to normal mesothelial tissue was slightly augmented by RGD
      retargeting, the level of gene transfer was much lower than that seen in ovarian
      cancer cells. CONCLUSION: This study demonstrates that genetically altered
      adenoviruses with modified tropism are capable of more efficient gene transfer in
      the context of ovarian cancer. The higher level of transfer with respect to
      peritoneal mesothelium can be exploited to enhance the therapeutic index of
      interventions using adenoviral vectors. Studies are warranted, therefore, to
      determine the in vivo utility of this targeted vector approach in the context of
      gene therapeutic strategies for cancer of the ovary.

PMID- 10419738
TI  - Modified radical hysterectomy for early Ib cervical cancer.
AB  - A total of 39 patients with selected early Ib cervical cancer were treated with
      modified radical hysterectomy (MRH) and compared with 102 patients with nonbulky
      Ib cervical cancer treated with radical hysterectomy (RH). Postoperative voiding
      difficulty (15.4 vs 46%) and constipation (43.6 vs 74.5%) were significantly less
      after MRH than after RH. All patients with MRH were followed uneventfully and the
      3-year survival rate is 100%. No recurrence or persistence of disease was noted.
      It is suggested that patients with exophytic squamous cell carcinoma of the
      cervix less than 2 cm in diameter and invading less than 10 mm, as diagnosed by
      conization, may be effectively treated with MRH, resulting in less morbidity.

PMID- 10419739
TI  - Tumor size, depth of invasion, and grading of the invasive tumor front are the
      main prognostic factors in early squamous cell cervical carcinoma.
AB  - OBJECTIVE: The objective of this study was to evaluate the prognostic
      significance of clinical and histopathologic factors, including a new grading
      system focusing on the invasive tumor front. METHOD: A retrospective analysis of
      125 surgically treated patients with squamous cell cervical carcinoma FIGO stage
      IB was conducted. For each tumor, the degree of keratinization, nuclear
      polymorphism, pattern of invasion, and degree of lymphoid infiltration at the
      invasive tumor front were graded and given scores between 1 and 4. RESULTS:
      Clinical tumor size, depth of invasion, and grading of the invasive front had
      prognostic significance in multivariate analysis, while lymph vascular space
      involvement, lymph node status, and grade of differentiation did not. Based on
      clinical tumor size, depth of invasion, and grading of the invasive tumor front,
      patients could be separated into three groups: One group with minimal risk of
      recurrence (5-year disease-free survival (DFS) of 100%) consisting of 24% of the
      patients, an intermediate group with a fairly low risk of recurrence (5-year DFS
      of about 92%), and a high risk group with a 5-year DFS of 45%. This latter group
      contained 26% of the patients with 78% of all relapses occurring in the total
      group of patients. The invasive tumor front grading was reliably reproducible,
      with inter- and intraobserver agreement of 79 to 87% and kappa values of 0.47 to
      0.66. CONCLUSION: Clinical tumor size, depth of invasion, and grading of the
      invasive tumor front were the main predictors of prognosis in patients with stage
      IB squamous cell cancer of the cervix.

PMID- 10419740
TI  - Clinically apparent early stage invasive epithelial ovarian carcinoma: should all
      be treated similarly?
AB  - OBJECTIVES: The role of adjuvant therapy in patients with early stage ovarian
      carcinoma has not been clearly defined. Most randomized trials examining this
      issue have not used the vigorous staging exploration accepted as today's
      standard. This report examines the natural history of patients after surgically
      documented stage 1 ovarian carcinoma followed expectantly. METHODS: A
      retrospective chart review was carried out using strict criteria to include only
      patients who had an adequate staging procedure performed by gynecologic
      oncologists following a fixed protocol from 1987 to 1997. Patients' demographic
      data as well as current disease status were abstracted and analyzed. RESULTS: A
      total of 80 comprehensive surgical staging procedures were carried out over a 10
      year period for apparent stage 1 ovarian cancer at the time of exploratory
      laparotomy. Fifty cases were true surgicopathological stage 1. It was found that
      serous and anaplastic tumors were more likely than other subtypes to be upstaged
      by the procedure. Further follow-up confirmed the excellent prognosis of early
      stage serous, endometrioid, and mucinous tumor with only one recurrence noted in
      an extraabdominal location in a patient with serous histology with no
      postoperative adjuvant therapy. Clear cell histology stands out as a significant
      recurrence risk (33%) despite an initially negative surgical assessment.
      CONCLUSION: Careful surgical exploration can identify a group of patients with
      early stage epithelial ovarian carcinoma who will benefit little from further
      adjuvant therapy. Patients with clear cell histology prove to be at a high risk
      for recurrence even at an early stage such that chemotherapy should be
      considered.

PMID- 10419742
TI  - Carbogen inhalation in cervical cancer: assessment of oxygenation change.
AB  - OBJECTIVE: Our objectives were (1) to examine tumor oxygenation measured with an
      Eppendorf pO(2) histograph, prior to and during carbogen (95% oxygen, 5% carbon
      dioxide) breathing in patients with primary cervical cancer; and (2) to assess
      the feasibility of delivering external beam radiation therapy and concurrent
      carbogen to patients treated for cervical cancer. METHODS: Pretreatment tumoral
      pO(2) measurements were obtained using an Eppendorf pO(2) histograph in patients
      with primary cervical cancers while breathing room air and after 4 min of
      carbogen breathing. Patients able to tolerate the carbogen inhalation were asked
      to inhale it for 4 min prior to and during all external beam radiation therapy.
      RESULTS: Two sets of pO(2) measurements were obtained from 25 patients. The
      average median pO(2) increased from 8 mm Hg when breathing room air to 96 mm Hg
      after carbogen breathing. Twenty-four of 25 patients tolerated the carbogen; they
      inhaled carbogen during their daily external beam radiation therapy. All 24
      patients completed their planned course of external beam radiation therapy and
      daily concurrent carbogen without significant difficulty. CONCLUSION: (1)
      Carbogen inhalation increased the average median pO(2) value 10-fold and
      decreased the percentage of values </=2.5 and 5 mm Hg. (2) Carbogen inhalation is
      feasible during external beam pelvic radiation.

PMID- 10419741
TI  - Ovarian metastasis in stage IB and II cervical adenocarcinoma.
AB  - We performed the present study to identify those patients with adenocarcinoma of
      the cervix in whom ovarian preservation might be acceptable. Between January 1971
      and December 1996, 82 patients with International Federation of Gynecology and
      Obstetrics stage IB and II cervical adenocarcinoma and adenosquamous carcinoma,
      treated by radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic node
      dissection, were identified. The mean age of the patients was 44.6 years (range
      27-72). The incidence of ovarian metastasis was more frequent in stage II (19.0%)
      than in stage IB disease (2.5%), in which only 1 patient with apparent
      extrauterine disease at laparotomy had an ovarian metastasis. No patients with up
      to inner two-thirds of stromal invasion had ovarian metastasis; however, 5 of 24
      patients with outer one-third stromal invasion (20.8%) and 4 of 20 with
      parametrial invasion (20.0%) had ovarian metastasis. A significantly higher
      incidence of ovarian metastasis was also observed in 5 of 20 cases with lymph
      node metastasis (25.0%) than in 4 of 62 patients without lymph node metastasis
      (6.5%). Multivariate analysis, however, found only deep stromal invasion to be an
      independent risk factor for ovarian metastasis. Although it would be reasonable
      to conserve normal-appearing ovaries in young women undergoing radical
      hysterectomy for treatment of stage IB cervical adenocarcinoma and adenosquamous
      carcinoma, gross intraoperative inspection of the radical hysterectomy specimen
      may identify deep cervical invasion or extrauterine spread in those who are at
      increased risk of ovarian metastases.

PMID- 10419743
TI  - Primary ovarian cancer cultures are resistant to Fas-mediated apoptosis.
AB  - OBJECTIVES: Fas, a primary mediator of cellular apoptosis, is expressed by the
      normal ovarian epithelium. We analyzed the levels of Fas and soluble Fas (sFas)
      expression in ovarian cancer tissue and determined the susceptibility of primary
      ovarian cancer cell (CSOC) cultures to Fas-mediated apoptosis. METHODS: Fas mRNA
      levels were detected by RT-PCR, and Fas protein levels were determined by
      immunohistochemistry and Western blot analysis. Secreted sFas levels were
      measured by ELISA. Localization of Fas to the cell surface was demonstrated by
      flow cytometry. The effect of Fas on cell proliferation was measured by MTT
      assay. RESULTS: Intense Fas staining was detected on the cell surface and in the
      cytoplasm of ovarian carcinoma specimens. We also found that mean levels of sFas,
      which can function as a Fas agonist, were significantly increased in 18 sera from
      cancer patients (0.98 ng/ml) compared to those of 8 healthy individuals (0.61
      ng/ml, P = 0.004). Fas mRNA and protein were expressed in all primary ovarian
      cancer cell cultures. Despite abundant Fas expression, CSOC cultures were
      significantly less sensitive to Fas-mediated apoptosis (11.3%) than primary
      cultures of normal ovarian epithelial cells (HOSE) (50.0%) (P = 0.00001). The
      sFas level in CSOC-conditioned medium was minimal (0.07 ng/ml) and not
      significantly different from that of HOSE-conditioned medium (0. 09 ng/ml). The
      small amount of sFas secreted by CSOC does not likely account for the observed
      resistance to Fas-mediated apoptosis. CONCLUSION: Decreased sensitivity to Fas
      mediated apoptosis could contribute to ovarian tumorigenesis through resistance
      to cytotoxic T lymphocyte-mediated cytotoxicity and may play a role in ovarian
      tumorigenesis.

PMID- 10419744
TI  - The use of paclitaxel and platinum-based chemotherapy in uterine papillary serous
      carcinoma.
AB  - OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is an aggressive malignancy
      with a histologic appearance and pattern of spread that resembles that of
      papillary serous adenocarcinoma of the ovary. The current standard therapy for
      advanced ovarian cancer, cisplatin or carboplatin plus paclitaxel, results in
      high objective response rates for that tumor. This regimen has thus far not been
      evaluated in UPSC. METHODS: Twenty-four patients with UPSC treated with platinum
      based chemotherapy and paclitaxel were retrospectively evaluated. Eighteen
      patients received these agents in the adjuvant setting (n = 9) or for disease
      persistent after initial surgical management (n = 9). Eleven patients received
      one or more courses of this drug combination for recurrent disease, 5 of whom had
      prior exposure in the initial setting. RESULTS: Mean follow-up was 35 months
      (range 6-72+). A median progression-free interval (PFI) of 30 months (range 8
      61+) was seen in patients treated in the adjuvant setting. Objective response,
      indicated by normalization of an elevated prechemotherapy CA125 level, was seen
      in 8 of 9 patients treated for residual disease after initial surgery (median PFI
      of 13 months, range 5-38+). Objective response of both measurable and/or
      evaluable disease was seen in 7 of 11 patients treated for recurrent disease
      (median PFI of 9 months, range 4-18). Six patients had retreatment with one or
      both agents and 4 responded a second time. Overall, the regimen was well
      tolerated. CONCLUSION: Paclitaxel and platinum-based chemotherapy has
      demonstrated activity in UPSC with acceptable toxicity. These results merit
      further investigation of the possible role of these agents in patients with this
      aggressive histologic subtype.

PMID- 10419745
TI  - A case of thrombopoietin-producing ovarian carcinoma confirmed by
      immunohistochemistry.
AB  - A case of ovarian carcinoma with thrombopoietin production is reported. A 49-year
      old Japanese woman had serous cystadenocarcinoma of the right ovary with
      peritoneal spread. The platelet count was elevated to 432 x 10(9)/L. Enzyme
      linked immunosorbent assay of the serum demonstrated remarkably high levels of
      thrombopoietin (2.96 fmol/ml). Immunohistochemical examination using an antibody
      specific for thrombopoietin revealed positive staining in the carcinoma cells,
      confirming thrombopoietin production.

PMID- 10419746
TI  - Intra-abdominal embryonal rhabdomyosarcoma in an adult.
AB  - Rhabdomyosarcoma is an uncommon neoplasm in the adult population. Sporadic cases
      of primary rhabdomyosarcoma arising in the abdomen have been reported, but these
      cases are limited almost exclusively to the pediatric population. We report a
      well-documented case of primary intra-abdominal rhabdomyosarcoma in a 57-year-old
      woman. The patient presented with a pelvic mass and an elevated serum CA 125 and
      was referred to gynecologic oncologists at our institution for a presumed primary
      gynecologic malignancy. Intraoperatively, amorphous gelatinous tumor comprised a
      large portion of the peritoneal cavity. Surgical exploration of the abdomen
      failed to implicate any specific organ as the site of origin of the tumor. The
      overall histologic pattern of the resected tumor was most consistent with
      embryonal type rhabdomyosarcoma. To our knowledge this is the first well
      documented case report of non-hepatobiliary, adult, intra-abdominal embryonal
      rhabdomyosarcoma in the English language literature. The presentation of a rare
      adult sarcoma mimicking a gynecologic malignancy was an unusual feature that
      complicated the diagnosis in this case.

PMID- 10419747
TI  - First case of pregnancy after radical trachelectomy and pelvic irradiation.
AB  - BACKGROUND: Invasive carcinoma of the cervix above stage IA1 is usually treated
      by radical hysterectomy and/or radiotherapy, leading to definitive sterility.
      CASE REPORT: We report the case of a young patient with stage IB1 carcinoma of
      the cervix treated in June 1995 by radical trachelectomy (according to the
      technique described by Dargent) and adjuvant brachy + teletherapy. A hormonal
      replacement of "menopause" was prescribed. One year later, she became pregnant
      and at 27 weeks gestation gave birth to a healthy child by cesarean section.
      CONCLUSION: Radical trachelectomy is one of the most recent therapeutic steps
      forward in the treatment of early stage invasive cervical carcinoma, which can
      surely be treated in some cases preserving child-bearing potential.

PMID- 10419748
TI  - Primary malignant schwannoma of the uterine cervix: a case report and literature
      review.
AB  - Primary malignant schwannomas are a very rare neural sheath tumor. A case of
      primary epithelioid-type malignant schwannoma of the uterine cervix in a 65-year
      old woman is presented. This tumor is the first epithelioid malignant schwannoma
      documented within gynecologic tissues. Only two other cases of primary malignant
      schwannoma of the uterine cervix have been reported, and these cases are
      reviewed.

PMID- 10419749
TI  - Primary squamous cell carcinoma in a patient with vaginal agenesis.
AB  - BACKGROUND: The development of a carcinoma in a neovagina constructed in patients
      with congenital vaginal agenesis is rare. CASE: To our knowledge, this is the
      first report of a squamous cell carcinoma developing in a neovagina that had been
      constructed by a simple cleavage technique without tissue transplantation. The
      latency period between reconstruction and tumor diagnosis was 20 years, during
      which the patient regularly used a prosthesis. The most important observation
      during this time was the repeated formation of granulation tissue and chronic
      inflammatory pseudopolyps in the neovagina, which were removed by cauterization.
      Despite pre- and intraoperative irradiation and radical surgery followed by
      chemotherapy, the prognosis is poor. CONCLUSION: Patients with neovaginas,
      whatever the construction technique, need to be followed up regularly, as
      mechanical irritation from a prosthesis can add to other cancer risk factors,
      such as viral infection. Furthermore, the absence of transplanted tissue does not
      seem to protect from the risk.

PMID- 10419750
TI  - Cloacogenic adenocarcinoma of the vulva.
AB  - Primary adenocarcinoma of the vulva is rare, and cloagocenic adenocarcinoma of
      the vulva is extremely rare. Here we report a vulvar tumor characterized by
      columnar cells with prominent brush border and the presence of goblet cells and
      endocrine cells, presenting the tubulovillous pattern and mucin histochemistry of
      enteric adenocarcinoma. Electron microscopy verified a colon-like pattern. We
      suggest that cloacogenic carcinoma of the vulva arises from embryonic tissue,
      normally present in the vulvar introital area. In our case, a wide local excision
      was sufficient for radical cure.

PMID- 10419751
TI  - Following metastatic placental site trophoblastic tumor with urine beta-core
      fragment.
AB  - OBJECTIVE: We document a case with metastatic placental site trophoblastic tumor
      in a 47-year-old postmenopausal women. METHODS: beta-core fragment was measured
      in urine using the Triton UGP kit. hCG was also measured using the Bayer Immuno
      1hCG assay (at Memorial Sloan-Kettering Cancer Center). RESULTS: Over 2 years the
      patient underwent two courses of chemotherapy and two debulking operations.
      During this time, hCG levels decreased from 227 to 4.1 mIU/ml. hCG levels were
      close to the limit of detection (<3 mIU/ml), indicating complete or near-complete
      regression of disease. At this point urine beta-core fragment levels were
      determined. High levels were detected 7.9 fmol/ml, consistent with the continued
      existence of tumor (>1.9 fmol/ml). High-dose chemotherapy (CEM) was started with
      stem cell harvesting. In the following weeks hCG levels failed to identify the
      tumor (4.1 to <3 mIU/ml). In the first week (during therapy) beta-core fragment
      levels increased (12 fmol/ml), and in the following weeks (after therapy) levels
      regressed to 1.2 fmol/ml. CONCLUSION: Urine beta-core fragment may be a useful
      tumor maker when serum hCG levels are near to or below the limit of detection.

PMID- 10419753
TI  - Primary leiomyosarcoma arising from the greater omentum in a 15-year-old girl.
AB  - We present here a case of primary leiomyosarcoma of the greater omentum in a 15
      year-old girl. A laparotomy revealed a huge abdominal mass arising from the
      greater omentum. The tumor accompanied intra-abdominal dissemination, but had not
      invaded the muscle layer of the gastrointestinal tracts. An almost complete
      omentectomy and reduction of many disseminated tumors of abdominal wall and
      mesentery were performed for the case. The tumor was diagnosed as a
      leiomyoscarcoma by histological and immunohistochemical examinations. After the
      surgery, combination chemotherapy with cisplatin, ifosfamide, and pirarubicin was
      carried out. Leiomyosarcoma of the greater omentum in a young girl is extremely
      rare.

PMID- 10419752
TI  - Metastatic trophoblastic disease following partial hydatidiform mole: case report
      and literature review.
AB  - A patient with a triploid partial hydatidiform who had lung metastasis is
      presented. Complete response was achieved with methotrexate chemotherapy. A
      review of the literature revealed only 11 previously reported cases. In many of
      them clinical data are missing. All had lung metastasis and 1 had in addition a
      metastasis in the vagina. Only 1 of these patients died of disease. The others
      responded well to chemotherapy. Metastatic trophoblastic disease following
      partial mole is very rare but the exact prevalence is not known. Since risk
      factors for developing metastatic trophoblastic disease subsequent to partial
      mole are not known, all patients should be followed.

PMID- 10419754
TI  - Neoadjuvant chemotherapy for advanced ovarian cancer.

PMID- 10419755
TI  - Reply 

PMID- 10419756
TI  - On sex, mate selection and the red queen.
AB  - The widespread occurrence of sexual reproduction despite the two-fold
      disadvantage of producing males, is still an unsolved mystery in evolutionary
      biology. One explanatory theory, called the "Red Queen" hypothesis, states that
      sex is an adaptation to escape from parasites. A more recent hypothesis, the mate
      selection hypothesis, assumes that non-random mating, possible only with sex,
      accelerates the evolution of beneficial traits. This paper tests these two
      hypotheses, using an agent-based or "micro-analytic" evolutionary algorithm where
      host-parasite interaction is simulated adhering to biological reality. While
      previous simpler models testing the "Red Queen" hypothesis considered mainly
      haploid hosts, stable population density, random mating and simplified expression
      of fitness, our more realistic model allows diploidy, mate selection, live
      history constraints and variable population densities. Results suggest that the
      Red Queen hypothesis is not valid for more realistic evolutionary scenarios and
      that each of the two hypotheses tested seem to explain partially but not
      exhaustively the adaptive value of sex. Based on the results we suggest that
      sexual populations in nature should avoid both, maximizing outbreeding or
      maximizing inbreeding and should acquire mate selection strategies which favour
      optimal ranges of genetic mixing in accordance with environmental challenges.

PMID- 10419757
TI  - The application of a linear algebra to the analysis of mutation rates.
AB  - Cells and bacteria growing in culture are subject to mutation, and as this
      mutation is the ultimate substrate for selection and evolution, the factors
      controlling the mutation rate are of some interest. The mutational event is not
      observed directly, but is inferred from the phenotype of the original mutant or
      of its descendants; the rate of mutation is inferred from the number of such
      mutant phenotypes. Such inference presumes a knowledge of the probability
      distribution for the size of a clone arising from a single mutation. We develop a
      mathematical formulation that assists in the design and analysis of experiments
      which investigate mutation rates and mutant clone size distribution, and we use
      it to analyse data for which the classical Luria-Delbruck clone-size distribution
      must be rejected.

PMID- 10419758
TI  - Hemoglobin/O2 systems: using short-lived intermediates for mechanistic
      discrimination.
AB  - The kinetics of the reaction of hemoglobin with molecular oxygen, in which rapid
      mixing is followed by a very fast temperature jump, is numerically simulated.
      Four different mechanisms are considered. In two of them, oxygen reacts with the
      alpha-chains first, in the other two with the beta-chains first. Furthermore,
      either the third or the fourth measured (Adair) dissociation constant is composed
      of the product of a local dissociation constant and an allosteric interconversion
      constant. We explore whether these alternative mechanisms may be distinguished
      experimentally. We show that reaction steps not resolvable by rapid mixing can be
      resolved by chemical relaxation at appropriate points in time. Discrimination
      under experimental conditions is possible at higher oxygen concentrations (above
      100 microM), but high resolution in time and concentration amplitude are
      required.

PMID- 10419759
TI  - Optimal stoichiometric designs of ATP-producing systems as determined by an
      evolutionary algorithm.
AB  - The design of metabolic pathways is thought to be the result of an optimization
      process such that the structure of contemporary metabolic routes maximizes a
      particular objective function. Recently, it has been shown that some essential
      stoichiometric properties of glycolysis can be explained on the basis of the
      requirement for a high ATP production rate. Because the number of
      stoichiometrically feasible designs increases strongly with the number of
      reactions involved, a systematic analysis of all the possibilities turns out to
      be inaccessible beyond a certain system size. We present, therefore, an
      alternative approach to compute in a more efficient way the optimal design of
      glycolysis interacting with an external ATP-consuming reaction. The algorithm is
      based on the laws of evolution by natural selection, and may be viewed as a
      particular version of evolutionary algorithms. The following conclusions are
      derived: (a) evolutionary algorithms are very useful search strategies in
      determining optimal stoichiometries of metabolic pathways. (b) Essential
      topological features of the glycolytic network may be explained on the basis of
      flux optimization. (c) There is a strong interrelation between the optimal
      stoichiometries and the thermodynamic and kinetic properties of the participating
      reactions. (d) Some subsequences of reactions in optimal pathways are strongly
      conserved at variation of system parameters, which may be understood by applying
      principles of metabolic control analysis.

PMID- 10419760
TI  - Lethal toxins in non-preferred foods: how plant chemical defences can drive
      microtine cycles 
AB  - We hypothesize that periodic lethal toxin production by non-preferred food
      species can explain the precipitous decline phase of vole cycles in arctic and
      alpine tundra regions. For plants that cannot respond to grazing damage by
      compensatory shoot growth, periodic production of toxins can have an adaptive
      advantage at the individual level. Several plants in the diet of cyclical small
      mammals do produce lethal toxins and some production is known to be cyclical.
      Despite the wealth of indirect and anecdotal observation in support of the
      hypothesis, there remains a lacuna in the hard core of evidence: periodic
      production of lethal toxins and toxin-related deaths in microtines. We argue that
      this is only because it has not been sought among likely plants or has been
      sought at the wrong place or time. Strong candidate species are non-preferred
      foods with circumpolar distributions such as Empetrum nigrum or Vaccinium
      uliginosum. The right place to expect lethal toxin production is the high
      altitude or latitude epicentres of population crashes, in regions where recovery
      is by immigration as well as births; the right time is at the cusp of the crash.
      We propose an experimental design to test the hypothesis. Copyright 1999 Academic
      Press.

PMID- 10419761
TI  - The kinetics of epithelial cell generation: its relevance to cancer and ageing.
AB  - A hierarchical model of epithelial cell generation is proposed, in which even in
      extreme old age mature epithelial cells in humans are only a limited number of
      cell divisions from the zygote (60-120). This contrasts with conventional models
      in which regularly cycling stem cells can be several thousands of cell divisions
      from the zygote. The hierarchical model is supported by data on the rate of
      telomere shortening both in vivo and in vitro, and by data on the rate of
      synonymous substitutions in Y-linked, X-linked and autosomal genes in rodents.
      Limiting the number of cell generations leads to a vast reduction in the risk of
      cancer and reduces the rate of ageing. It is suggested that longer-lived animals
      need stricter control of the hierarchy than do shorter-lived animals and this
      difference has implications for theories of ageing.

PMID- 10419762
TI  - A novel parameter to estimate the minimum number of bound ligands needed to
      activate an ion channel.
AB  - We consider the Hill coefficient obtained from concentration-response curves and
      we stress the differences between the use of binding and the use of current for
      the response. We first show that in order to estimate the cooperativity of
      binding sites one must use the coefficient obtained from the binding curves and
      not that obtained from the current curves. For what concerns the estimation of
      the minimum number of bound ligands needed to activate the channel, while the
      coefficient obtained from the binding is simply not applicable, we show that the
      coefficient obtained from the current is not appropriate. We finally introduce a
      novel parameter that predicts the number of ligand molecules required to open the
      channel from current measurements at very low ligand concentration. The above
      considerations are exemplified by a few theoretical models.

PMID- 10419763
TI  - A thermodynamic optimization analysis of a possible relation between the
      parameters that determine the energetics of muscle contraction in steady state.
AB  - Given the phenomenological relations for muscle's steady-state contraction and
      proper definitions of power p and efficiency eta, the behavior of these
      quantities is analysed in terms of the parameters that determine the energetics
      of the muscle, here denoted by s(o)and alpha. s(o)is proportional to the so
      called maintenance heat, while alpha is the parameter that determines the
      curvature of the Hill's force-velocity curve. The dependence of the muscle's
      power and efficiency, averaged over the whole range of force the muscle can
      exert, on the parameters s(o)and alpha is studied. The average power p(avg)is a
      function only of alpha, and is a growing function that approaches 1/6
      asymptotically as alpha goes to infinity. The average efficiency eta(avg)is a
      function of both alpha and s(o). With the value of s(o)fixed, the graph of the
      function eta(avg)(s(o), alpha) is a convex curve with a single maximum. The value
      and the position of this maximum point both depend on s(o). In the limit alpha-
      >0, s(o)-->0, eta(avg)tends to 1. The points (s(o), alpha(m)(s(o))), with
      alpha(m)(s(o)) the value of alpha that maximizes eta(avg)for a given s(o), are
      fitted by the curve alpha=s(o 1/2). This relation was experimentally found by
      A.V. Hill in his early studies of muscle energetics. Other experimental data are
      found to qualitatively satisfy the same relation. Although some dynamical
      microscopic models for muscle contraction, based upon Huxley's cross-bridge
      model, show that the same kinetic parameters control both the maintenance heat
      (s(o)) and the muscle's power output (alpha), we suggest that the exact relation
      between them has been reached due to the evolutive stresses that made individuals
      with equally powerful and more efficient muscles more suitable to reproduce.

PMID- 10419764
TI  - A simple individual-based model of insoluble polysaccharide hydrolysis: the
      potential for autosynergism with dual-activity glycosidases.

PMID- 10419765
TI  - Preliminary results of simulations with an improved mathematical model of drug
      tolerance.

PMID- 10419766
TI  - Foreword 

PMID- 10419767
TI  - Sites of action for future therapy: an adenosine-dependent mechanism by which
      aspirin retains its antiinflammatory activity in cyclooxygenase-2 and NFkappaB
      knockout mice.
AB  - The antiinflammatory action of aspirin is generally attributed to inhibition of
      cyclooxygenases 1 and 2, but additional mechanisms are at work. These include
      inhibition of NFkappaB translocation to the nucleus and the capacity of aspirin
      to promote accumulation of adenosine, a potent antiinflammatory autocoid. We
      tested these hypotheses in the murine air pouch model of acute inflammation in
      wild type mice and in cyclooxygenase 2 or NFkappaB knockouts. The
      antiinflammatory effects of aspirin, sodium salicylate and indomethacin did not
      correlate with inhibition of cyclooxygenase in either group. Indeed, aspirin
      retained its antiinflammatory properties even in COX-2 knockouts. Similarly,
      aspirin was no less antiinflammatory in mice rendered deficient for NFkappaB
      (p105) than in wild type controls. In contrast, dexamethasone lost its
      antiinflammatory capacity in NFkappaB knockouts. Aspirin and sodium salicylate
      dramatically increased concentrations of adenosine in exudates, a property shared
      with methotrexate and sulfasalazine. Removal of adenosine by adenosine deaminase
      or specific antagonism of adenosine at A(2)receptors completely reversed the
      antiinflammatory effects of aspirin and sodium salicylate, but not those of
      dexamethasone. This adenosine-dependent, antiinflammatory effect of aspirin
      points to another target of drug development.

PMID- 10419768
TI  - Heritable osteoarthritis. Diagnosis and possible modes of cell and gene therapy.

PMID- 10419769
TI  - Interactions between the inducible cyclooxygenase (COX-2) and nitric oxide
      synthase (iNOS) pathways: implications for therapeutic intervention in
      osteoarthritis.

PMID- 10419770
TI  - Pathophysiology of osteoarthritis.

PMID- 10419771
TI  - The influence of tissue cross-talking on OA progression: role of nonsteroidal
      antiinflammatory drugs.
AB  - Osteoarthritis is increasingly recognized as a complex illness in which
      interrelationships between the different tissues of the joint are important. We
      are still some way from a complete understanding of the pathophysiologic and
      temporal relationships between bone, synovial tissue and cartilage. Recent
      evidence points to a significant role for cytokines and growth factors in
      osteoarthritis that leads to a preponderance of catabolic processes in the joint.
      In-vitro culture of human cartilage has been used as a model to measure the
      effects of drugs used in the treatment of osteoarthritis on anabolic and
      catabolic processes. On this basis, the nonsteroidal antiinflammatory drugs can
      be categorized into one of three classes depending on whether they are inhibitory
      (e.g., indomethacin and naproxen), neutral (e.g., diclofenac, aspirin and
      piroxicam) or stimulatory (e.g., aceclofenac, tenidap and tolmetin) of
      glycosaminoglycan synthesis in chondrocytes. The marked differences between these
      nonsteroidal antiinflammatory drugs suggest that a mechanism other than
      cyclooxygenase inhibition is involved in their effects on glycosaminoglycan
      synthesis. Inhibition of IL-1beta and the stimulation of growth factors are
      suggested as possible mechanisms. Although the significance of these properties
      of nonsteroidal antiinflammatory drugs awaits confirmation in in-vivo and
      clinical situations, they do provide the clinician with a new parameter with
      which to choose therapy in osteoarthritis.

PMID- 10419772
TI  - Nitric oxide in osteoarthritis.
AB  - Activated articular chondrocytes produce large amounts of nitric oxide (NO), and
      there is increasing evidence that this is involved in the etiopathogenesis of
      osteoarthritis (OA). Because of its short half-life, the biological effects of
      endogenously produced NO are likely to occur locally within the cartilage. We
      have observed that inhibitors of NO synthases relieve the inhibition of matrix
      synthesis that otherwise occurs in response to IL-1. To avoid the use of
      inhibitors, we have recently transduced chondrocytes with the iNOS (NOS-2) gene
      and confirmed the ability of the endogenously produced NO to inhibit matrix
      synthesis. Despite the high levels of NO made by these cells, there was no
      evidence of apoptosis or other forms of cell death. NO was also shown to inhibit
      the production of TGF-beta(1)by cells treated with IL-1, as well as to decrease
      matrix production in response to IGF-1. The hypothesis that NO inhibits matrix
      production by interfering with important autocrine and paracrine factors should
      be entertained.

PMID- 10419773
TI  - The role of COX-2 produced by cartilage in arthritis.
AB  - The development of selective COX-2 inhibitors has renewed interest in the
      treatment of osteoarthritis with prostaglandin synthesis inhibitors. The
      therapeutic effects of COX inhibitors in OA may be due to their analgesic
      properties. However, it is now apparent that stable prostaglandins are produced
      by chondrocytes in OA cartilage where they may act to alter matrix synthesis and
      degradation. In vitro, PGEs activate metalloproteinases, but also enhance
      proteoglycan and type II collagen synthesis. Their net effect on matrix
      homeostasis in vivo remains to be determined.

PMID- 10419775
TI  - Human chondrocyte culture models for studying cyclooxygenase expression and
      prostaglandin regulation of collagen gene expression.
AB  - Objective Since articular chondrocytes and synovial fibroblasts are particularly
      responsive to interleukin-1 (IL-1) with respect to stimulation of prostaglandin
      E(2)(PGE(2)) biosynthesis, we have used them as models to examine feedback
      modulatory effects of PGE(2), which blocks or attenuates the direct effects of IL
      1beta on cell-specific collagen gene expression. Methods Immortalized human
      chondrocytes were developed for studying responses to cytokines and
      prostaglandins. Regulatory sequences of the type II collagen gene (COL2A1) in
      reporter gene constructs were analyzed in transient transfection experiments.
      Endogenous expression of COL2A1 mRNA, as well as aggrecan, biglycan, and decorin
      mRNAs, and IL-1-inducible cyclooxygenase (COX-2), phospholipase A2 (PLA2), and
      inducible nitric oxide synthetase (iNOS) mRNAs were analyzed by RT-PCR. Results
      Previous work has shown that IL-1beta inhibits, while prostaglandins stimulate
      COL2A1 expression. In different immortalized chondrocyte cell lines, the ability
      to respond to IL-1beta with increased levels of COX-2, PLA2, and iNOS mRNAs
      depends upon expression of the differentiated chrondrocyte phenotype. Conclusions
      Our studies suggest that some IL-1-induced responses in chondrocytes may require
      differentiation-specific transcription factors that could serve as therapeutic
      targets for arthritis.

PMID- 10419774
TI  - Modulation of IL-1 effects on cartilage by NO synthase inhibitors:
      pharmacological studies in rats.
AB  - Objective To compare the ability of L-arginine (L-arg) analog nitric oxide
      synthase (NOS) inhibitors and isothioureas to restore the interleukin-1 (IL-1)
      induced inhibition of proteoglycan (PG) synthesis in rat.Methods Chondrocytes
      beads and patellae were challenged with IL-1betain vitro and monitored for NO
      production and proteoglycan synthesis. Rats injected with IL-1beta in knee joints
      were monitored for NO(2)( - )+NO(3)( - )levels in joint tissues and ex-vivo(35)S
      sulfate incorporation in patellae. NOS inhibitors were either added to culture
      medium or injected concomittantly to IL-1beta. Results Ability of NOS inhibitors
      to reduce NO(2)( - )levels decreased from chondrocytes beads to patellae. Partial
      restoration of PG synthesis was restricted to L-arg analogs in patellae. After IL
      1 injection, NO was produced from patella and synovium. L-arg analogs restored
      partly PG synthesis when decreasing significantly NO(2)( - )+NO(3)( - )levels in
      synovial fluid. Isothioureas were ineffective. Conclusions NO accounts
      importantly for IL-1 induced inhibition of cartilage anabolism in rat. L-arg
      analog NOS inhibitors are more effective than isothioureas in restoring PG
      synthesis and have chondroprotective potency when administered locally in
      diseased joint.

PMID- 10419777
TI  - Regulation of tumor necrosis factor-alpha and tumor necrosis factor converting
      enzyme in human osteoarthritis.
AB  - A snake venom-like protease isolated by a differential display screen between
      normal and osteoarthritis (OA)-affected cartilage (designated as cSVP) has a cDNA
      sequence identical to tumor necrosis factor (TNF)alpha convertase enzyme (TACE)
      and belongs to the adamalysin group of proteases. It has unique structural
      properties and when expressed in baculovirus, cleaves preferentially proTNFalpha
      to TNFalpha. The OA-affected cartilage has upregulated mRNA for TNFalpha and TACE
      as compared to normal cartilage. TNFalpha and TACE regulate inflammatory
      mediators in OA-affected cartilage which can be inhibited by both soluble
      TNFalpha receptors and inhibitors of TACE. These experiments demonstrate a
      functional paracrine/autocrine role of TNFalpha in OA-affected cartilage that is
      modulated by upregulated levels of chondrocyte-derived TACE.

PMID- 10419776
TI  - Mechanisms of chondrocyte apoptosis.
AB  - This study addresses the occurrence and significance of chondrocyte apoptosis in
      the pathogenesis of cartilage destruction. Chondrocyte apoptosis can be induced
      in vitro by nitric oxide donors, but not by pro-inflammatory cytokines, such as
      IL-1 or TNF. A subset of chondrocytes, located in the superficial zone of
      cartilage, expresses the Fas antigen. Activation of the Fas receptor triggers
      apoptosis in these cells. In human and experimental osteoarthritis (OA) induced
      in rabbits by anterior cruciate ligament transection increased numbers of
      chondrocytes were undergoing apoptosis. Cartilage areas that contained apoptotic
      cells showed proteoglycan depletion and the number of apoptotic cells was
      significantly correlated with the levels of nitric oxide production and with the
      severity of OA. Articular cartilage is not vascularized and does not contain
      mononuclear phagocytes. There is, thus, no apparent mechanism for the clearance
      of apoptotic bodies. Chondrocyte-derived apoptotic bodies produced pyrophosphate
      and precipitated calcium. These results suggest that chondrocyte-derived
      apoptotic bodies express functional properties that may contribute to the
      pathologic cartilage degradation and calcification. Inhibition of chondrocyte
      apoptosis may be of therapeutic value after cartilage injury and in arthritis.

PMID- 10419778
TI  - Suppression of tumor necrosis factor (TNF-alpha) gene expression by prostaglandin
      E(2). Role Of early growth response protein-1 (Egr-1).
AB  - We examined the mechanism by which PGE(2)suppresses the expression of TNF-alpha
      in human macrophages and synovial fibroblasts. Prostaglandin E(2)increased, in a
      time and dose-dependent (EC(50)75+/-15ng/ml, mean+/-SD) fashion, the expression
      and synthesis of Egr-1/Krox24 as judged by Northern blotting and electrophoretic
      mobility gel-shift analysis, respectively. In human macrophagic THP-1 cells, rhIL
      17 increased promoter activity by 7. 6+/-0.35-fold over controls, an effect that
      was abrogated in a dose-dependent fashion by coincubations with PGE(2)(IC(50)25+/
      4ng/ml). An intact Egr-1/Krox-24 enhancer sequence in the TNF-alpha promoter
      region was essential for the latter PGE(2)-dependent inhibitory effect as double
      base substitutions (GC-->TT) in the sequence curtailed promoter response to
      PGE(2). Overexpression of two dominant negative Egr-1/Krox-24 constructs in THP-1
      cells considerably diminished the inhibitory effects of PGE(2)on rhIL-17-induced
      TNF-alpha mRNA expression. We conclude that PGE(2)inhibits induced TNF-alpha
      expression in target cells through an Egr-1/Krox-24 mediated signaling process.

PMID- 10419780
TI  - T-cell mediated inflammatory pathway in osteoarthritis.
AB  - Osteoarthritis (OA) is not caused by a simple consequence of aging and cartilage
      degradation. Based on the conventional paradigm, OA has been considered a
      degenerative joint disorder. However, the dominant clinical symptom has been
      characterized by a non-infectious chronic inflammatory condition with
      infiltration of inflammatory cells in the synovial tissue or synovial fluid,
      especially in the early stage of the disease. The inflammatory process appeared
      to develop degeneration of chondrocytes and/or formation of osteophytes.
      Immunohistochemical staining of synovial tissue with OA in the early stage,
      suggests the presence of T-cell infiltration in the perivascular area, some of
      which were CD4 positive T cells. Among the T cells, we identified the clonality
      of restricted TCR usage of Vbeta chain by single strand conformation polymorphism
      (SSCP) method on T-cell repertoire. Therefore we address the immune response in
      primary OA.

PMID- 10419779
TI  - Nitric oxide alters chondrocyte function by disrupting cytoskeletal signaling
      complexes.
AB  - Components of osteoarthritis include increases in pericellular fibronectin and in
      chondrocyte beta1 integrin expression. Events which follow ligation of
      fibronectin to its chondrocyte-receptor, the integrin alpha5beta1 include an
      assembly of a subplasmalemmal actin/rho A/focal adhesion kinase signaling
      complex. In addition, nitric oxide (NO), a potential mediator of cartilage
      pathophysiology disrupts the cytoskeletal signaling complex associated with
      integrin signaling. In these studies, we examined the relationship among integrin
      signaling, biosynthesis of S-35 sulfate containing proteoglycans and release of
      YKL-40 (a secretory glycoprotein) by comparing cell responses using cells plated
      on a fibronectin-coated or polyHEME coated surfaces. We report that the release
      of proteoglycan and glycoprotein require anchorage dependent signals by integrin
      costimulation. NO which disrupts the integrin signaling complex attenuates both
      cell responses. Taken together NO may serve as a nonspecific 'brake' to prevent
      anabolic and catabolic injury responses.

PMID- 10419781
TI  - Role of nitric oxide in the angiogenesis of avascular tissue.
AB  - A number of independent lines of evidence converge indicating a role for nitric
      oxide (NO) in angiogenesis. Our data support the existence of an autocrine loop
      exerted by microvascular endothelium in angiogenesis which involves NO
      production, cyclic GMP elevation and fibroblast growth factor-2 (FGF-2)
      expression. Our results indicate that NO production significantly contributes to
      the growth-promoting effect of vasodilating peptides and vascular endothelial
      growth factor (VEGF), but not for that of FGF-2. On these basis, the nitric oxide
      pathway appears to be a promising target to be considered in pro- and anti
      angiogenic therapeutic strategies.

PMID- 10419782
TI  - COX-2 in synovial tissues.
AB  - Prostaglandins (PGs) are important mediators of acute and chronic inflammation.
      The production of PGs in synovial tissues is catalyzed by an enzyme cascade that
      includes phospholipase A(2)s (PLA(2)s), cyclooxygenases (COXs), and terminal PG
      synthases. There are two isoforms of COX expressed in synovial tissues. COX-1 is
      constitutively expressed in synovia, particularly in synovial lining cells. COX
      2, on the other hand, is localized most strikingly to the vascular endothelial
      cells, mononucler inflammatory cells, and subsynovial fibroblasts. There are no
      significant differences in immunostaining of COX-1 in vivo in inflammatory
      compared with non-inflammatory arthritis. COX-2 expression is increased in
      inflammatory arthritis. In-vitro, COX-2 expression in synovial cells is
      dramatically increased by proinflammatory cytokines, phorbol ester, and
      stimulation of certain cell surface receptors. A number of different
      transcription factors are likely to be involved in the up-regulation of COX-2 in
      synovial tissues. Expression of COX-2 is inhibited by glucocorticoids in synovial
      cells as in other cell types. Taken together, these data suggest that COX-2 is
      likely to be responsible for increased local PG production during inflammation of
      synovial tissues.

PMID- 10419783
TI  - Phosphocitrate blocks nitric oxide-induced calcification of cartilage and
      chondrocyte-derived apoptotic bodies.
AB  - OBJECTIVE: To examine whether phosphocitrate (PC) will block nitric oxide-induced
      calcification of cartilage or chondrocyte-derived apoptotic bodies. DESIGN:
      Articular cartilage vesicles (ACV) or apoptotic bodies (AB) were isolated from
      untreated or 1mM sodium nitroprusside (SNP) treated porcine cartilage slices.
      Mineralization of ACV, AB, control untreated and SNP-treated cartilage were done
      in the presence or absence of PC (1mM)+/-ATP (1mM). RESULTS: PC [1mM] blocked
      both the ATP-dependent and -independent mineralization in ACV and AB, untreated
      and SNP treated cartilage. Moreover, PC had no effect on NTPPPH activity in
      either ACV or AB fraction in the presence or absence of ATP suggesting that PC
      did not block the mineralization through the inhibition of NTPPPH activity.
      CONCLUSIONS: PC inhibits nitric oxide-induced calcification of cartilage and
      cartilage-derived apoptotic bodies.

PMID- 10419784
TI  - Animal models of arthritis in NOS2-deficient mice.
AB  - OBJECTIVE: To study the role of nitric oxide (NO) in cartilage destruction in
      murine models of arthritis and osteoarthritis. METHODS: Joint inflammation was
      induced in the knee joint by intraarticular injection of Zymosan. Osteoarthritis
      was induced by local injection of bacterial collagenase, causing joint
      instability. The effect of NO deficiency was studied by comparing the effects in
      normal mice and mice with genetically disrupted NOS2 (inducible NO synthase).
      Impact on articular cartilage was evaluated by histology and measurement of
      chondrocyte 35S-proteoglycan synthesis. RESULTS: NOS2 deficiency prevented
      chondrocyte proteoglycan synthesis inhibition in the arthritic cartilage and
      restored normal responsiveness to IGF-1. Net cartilage proteoglycan depletion was
      markedly reduced in the absence of NOS2, although inflammation was hardly
      affected. Osteoarthritic joint pathology was also significantly reduced,
      including diminished cartilage lesions and osteophyte formation. CONCLUSION: NO
      plays a major role in cartilage damage in both arthritic and osteoarthritic
      conditions.

PMID- 10419785
TI  - Reduction in the structural changes of experimental osteoarthritis by a nitric
      oxide inhibitor.
AB  - OBJECTIVE: To evaluate the in-vivo therapeutic efficacy of N -iminoethyl-L-Lysine
      (L-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS) in a
      dose response study, on the progression of lesions in the experimental
      osteoarthritic (OA) dog model. DESIGN: The sectioning of the anterior cruciate
      ligament of the right stifle joint of mongrel dogs was done by a stab wound. Dogs
      were separated into experimental groups: Group 1 received no treatment, Groups 2,
      3, and 4 received oral L-NIL (0.3, 1 or 10mg/kg/day, respectively) starting
      immediately after surgery. The OA dogs were killed at 12 weeks after surgery.
      RESULTS: Macroscopically, L-NIL decreased the size of the cartilage lesions on
      condyles and plateaus. The histologic severity of the cartilage lesions was
      decreased in the L-NIL-treated dogs. This effect was more pronounced at the
      highest dosage tested (3 and 10mg/kg/day). CONCLUSIONS: This study confirms the
      effectiveness of L-NIL, a selective inhibitor of iNOS, in attenuating the
      progression of experimental OA. It also clearly shows that the effect is dose
      dependent.

PMID- 10419786
TI  - Prostaglandins and bone: physiology and pathophysiology.
AB  - Prostaglandins (PGs) are potent stimulators of bone formation and resorption and
      are produced by bone cells. PGs also have inhibitory effects on fully
      differentiated osteoblasts and osteoclasts. This complex, multifunctional
      regulation is probably mediated by different PG receptors. Endogenous PGs in bone
      are produced largely by induction of COX-2, which is highly regulated by hormones
      and local factors. The development of specific agonists and antagonists for PG
      receptors and for COX-2 should allow us to define the physiologic and
      pathophysiologic roles of PGs more precisely and develop new therapeutic
      approaches to metabolic and inflammatory disorders of the skeleton.

PMID- 10419787
TI  - The role of prostaglandins and nitric oxide in the response of bone to mechanical
      forces.
AB  - We have developed an experimental model whereby bone is exposed to a brief
      episode of mechanical stimulation, which is followed by bone formation. The
      earliest response is in osteocytes, which express c-fos and insulin-like growth
      factor (IGF-1) within 30-60min. Thirty-six to 72h after loading bone matrix gene
      expression occurs on bone surfaces. The osteogenic response can be suppressed by
      a single dose of nitric oxide synthase (NOS) or prostaglandin (PG) synthase
      inhibitors, if these are administered just before mechanical stimulation: similar
      doses after stimulation have no effect. There is a later phase of indomethacin
      sensitivity associated with COX-2 expression in bone at 6h. Thus, mechanically
      induced osteogenesis involves early expression of c-fos and IGF-1 by osteocytes,
      which are believed to be the strain-sensitive cells in bone. Both NOS and PG
      synthase, either in parallel or in sequence, are crucial to the initial
      transduction of the mechanical stimulus into an osteogenic response.

PMID- 10419788
TI  - Clinical trials design: structure modifying agents for osteoarthritis. Future
      guidelines: areas for development.
AB  - Clinical trials guidelines should offer evidence-based recommendations, and,
      where evidence is lacking or absent, should reflect the considered opinion of
      experts in the field. Recent OsteoArthritis Research Society International
      (OARSI) guidelines encompass these principles and are the result of a Task Force
      Workshop involving representatives from academia, regulatory authorities and
      industry. Areas for continued development for trials of Structure Modifying
      Osteoarthritis Drugs (STMOAD) include patient selection, study duration, sample
      size estimation, outcome assessment, imaging, response definition and
      pharmoeconomics. As developments occur in these and related areas, guideline
      documents will require revision to reflect this evolution. Notwithstanding these
      issues, there is opportunity to identify STMOAD class agents using current
      methodologies.

PMID- 10419789
TI  - Radiographic assessment. Introduction: existing methodology.
AB  - Plain radiograph is the most accepted imaging technique to assess structural
      changes of osteoarthritis and it is proposed as 'surrogate' of outcome of the
      disease process. The existing radiographic methodology is well standardized with
      respect to its technique for investigation of hip, knee and hand joints,
      including advice on the most appropriate views, patient positioning, X-ray beam
      alignment, quality control. Quantitation of joint space narrowing is currently
      proposed as the primary variable in studies of disease progression for hip and
      knee, while semi-quantitation of this same parameter or of bone changes by
      published atlases have to be intended as secondary variables, or outcomes in hand
      studies. Unfortunately, the review of studies that evaluated the longitudinal
      rate of joint space narrowing indicates that the yearly change may be very small
      (<0.1mm/year) and of doubtful clinical significance. This underlines the need for
      further refinement in the definition of the radiographic outcome in prospective
      clinical trials.

PMID- 10419790
TI  - Radiographic assessment of osteoarthritis: comparison between existing
      methodologies.
AB  - Radiographic sensitivity for quantifying the rate of change in joint space width
      (JSW) for DMOAD trials, is influenced by the following, which vary between
      methodologies for imaging hip, knee and hand. Radio-anatomical plane of
      measurement JSW measurement precision is improve when the (i) joint is in a
      normal functional position, (ii) X-ray beam is centred on the joint space and
      (iii) plane of measurement is orthogonal to the beam and articular surfaces, and
      parallel to the film. Measuring instrument Manual methods, e.g. callipers with
      graduated magnifying lens or digitisation tablets, suffer from observer
      variability but are practical and can reliably measure JSW. Computer-based
      techniques provide precise and accurate JSW measurements. Site of measurement
      Minimum JSW may lie within the joint's load transmitting region. JSW area and
      mean area assess the entire JS width. Radiographic magnification This effect is
      present in hip and knee radiographs and when not corrected, requires increased
      study numbers. Type of X-ray unit Microfocal radiography's improved spatial
      resolution increases measurement precision and can decrease study numbers.

PMID- 10419791
TI  - Radiographic assessment of hip and knee osteoarthritis. Recommendations:
      recommended guidelines.
AB  - Pathological lesions of osteoarthritis, demonstrated by conventional radiography,
      can be assessed by scoring systems and/or measurement with a quite acceptable
      reproducibility. Scores are recommended for a rough staging of osteoarthritis and
      of bone changes. Measurement is recommended for assessment of joint space
      narrowing progression. A good assessment of progression implicates a perfect
      reproducibility of the radiographic image of the joint. Accuracy of standard
      radiograph is improved by some views such as the hip profile and the schuss view.

PMID- 10419793
TI  - Page for patients

PMID- 10419792
TI  - Educational differences in excessive alcohol consumption: the role of
      psychosocial and material stressors.
AB  - BACKGROUND: Socioeconomic differences in health are determined mainly by
      socioeconomic differences in unhealthy behavior. Little is known, however, about
      the mechanisms that account for socioeconomic differences in unhealthy behavior,
      such as excessive alcohol consumption. In this paper we examined educational
      differences in excessive alcohol consumption in The Netherlands and whether these
      may be explained by educational differences in experienced stress and stress
      moderating factors. METHODS: Data were obtained from the baseline survey of the
      Longitudinal Study on Socio Economic Health Differences in 1991. Excessive
      drinking was defined as drinking more than six glasses on 3 or more days a week
      or more than four glasses on 5 or more days a week. Socioeconomic status was
      indicated by educational level. Stressors were divided into psychosocial and
      material factors. Analyses were performed for women (n = 756) and men (n = 1,006)
      separately, among drinkers only. RESULTS: Excessive alcohol consumption was more
      common among lower educational groups. Material stressors, such as financial
      problems, deprivation, and income, were related to part of the educational
      gradient in excessive alcohol consumption. Differences in stress-moderating
      factors were not related to the educational gradient in excessive drinking.
      CONCLUSIONS: Our results suggest that improvement of material conditions among
      the lower educational groups could result in a reduction of socioeconomic
      differences in excessive alcohol consumption.

PMID- 10419794
TI  - Counseling youth in tobacco-use prevention: determinants of clinician compliance.
AB  - OBJECTIVE: The rate and determinants of tobacco prevention and cessation
      counseling to youth were examined for orthodontists participating in a controlled
      trial to decrease the incidence of tobacco use among adolescents. METHODS: A
      cross-sectional interview design in private practice offices throughout Southern
      California was used. The survey was completed with 126 (82%) orthodontists.
      Clinicians randomly assigned to the experimental group (N = 77) received a 1.5 h
      workshop, anti-tobacco materials, reimbursement for provision of anti-tobacco
      prescriptions, and quarterly checkup visits. Control group clinicians (N = 77)
      did not receive training, materials, or visits. RESULTS: Experimental group
      clinicians talked to more adolescent nonsmokers about never beginning tobacco use
      than did control group clinicians (P < 0.05). Experimental group clinicians
      talked to more adolescent tobacco users than did control group clinicians;
      however, the difference was not statistically significant. Content and
      determinants of counseling were affected by participation in the intervention.
      CONCLUSIONS: Though training and support increased prevention and cessation
      counseling, absolute rates remained less than optimal. Social learning factors
      were associated with prevention and cessation counseling.

PMID- 10419795
TI  - Satisfaction of women attending the Manitoba breast screening program.
AB  - BACKGROUND: This study evaluated the satisfaction of women who attended the
      Manitoba Breast Screening Program (MBSP) during the first 17 months of operation
      and examined differences in satisfaction by screening location and screening
      result. The setting was the province of Manitoba, Canada. METHODS: A breast
      screening program satisfaction questionnaire comprising six subscales was mailed
      to 1,331 randomly chosen women in five different categories who attended the
      MBSP. Four categories were based on location of screen (city of Brandon vs city
      of Winnipeg) and screen result (normal vs abnormal) and one category comprised
      women who were screened at a mobile unit. Eighty-eight percent of all
      questionnaires were returned. Data analyses included analyses of variance to
      examine the effect of location and result on satisfaction scores and logistic
      regression to explore the variables associated with reported satisfied and not
      satisfied responses to each satisfaction subscale. RESULTS: All satisfaction
      scores were above 80 of 100, indicating high levels of satisfaction. A
      significant difference in satisfaction scores between women in Winnipeg and women
      in Brandon was found for the convenience and accessibility (P = 0.0153) and the
      information transfer subscales (P = 0.0150). A significant difference was found
      between women with abnormal and women with normal screen results for all
      subscales (P < 0.01). Women were 4.5 times more likely to be dissatisfied on the
      general satisfaction subscale if they had an abnormal screen result (95% CI
      1.9,10.4). CONCLUSIONS: High levels of satisfaction were reported for all aspects
      of screening at the MBSP. However, women were less likely to be satisfied with
      program convenience and accessibility. Women with an abnormal result reported
      lower levels of satisfaction on all subscales. Some women with an abnormal
      screening result were confused about what their results meant and why they were
      sent for additional diagnostic tests. As a result of these findings, numerous
      changes were made to the MBSP.

PMID- 10419796
TI  - Successful postexposure rabies prophylaxis after erroneous starting treatment.
AB  - BACKGROUND: Postexposure prophylaxis, adequately applied after exposure to a
      rabid animal, is highly effective in prevention of human disease. Deviations from
      the recommended vaccination postexposure treatment protocol have been associated
      with vaccination failure and human mortality. We investigated an incident in
      which seven Israel Defense Forces soldiers were bitten by a rabid fox and
      initially treated not in accordance with the recommended vaccination protocol.
      METHODS: The soldiers received modified anti-rabies postexposure prophylaxis,
      including a higher dosage of both the active and the passive vaccines. The
      humoral antibody response was monitored subsequently. RESULTS: All soldiers
      showed a satisfactory increase (above 0.5 UE/ml by ELISA) in serum anti-rabies
      antibody titers. None developed the disease more than a year after follow-up.
      CONCLUSIONS: Strict adherence to the treatment guidelines following an injury by
      a rabid animal is of utmost importance. We suggest possible compensatory
      management after a potentially lethal deviation from protocol.

PMID- 10419797
TI  - Consequences of removing iron fortification of flour on iron status among Danish
      adults: some longitudinal observations between 1987 and 1994.
AB  - BACKGROUND: Health authorities recommend that populations consume a diet
      providing sufficient iron, and in order to prevent iron deficiency, a number of
      countries have fortified certain foods with iron. In Denmark, flour was fortified
      with iron from 1954 until 1987, at which time the mandatory fortification was
      stopped. This study examines the effect of iron fortification on iron status by
      comparing the intake of iron with serum ferritin over time and in relation to the
      removal of flour fortification. METHODS: In a cohort of 238 Danish men and women,
      at baseline ages 35-65 years, dietary intake and serum ferritin were measured,
      first in 1987/1988 and again in 1993/1994. RESULTS: In 1987/1988 the
      fortification may have supplied up to 25% of total iron intake, and without this
      enrichment some 35% of the men and 73% of the women may have had iron intakes
      lower than 10 mg/day. Assuming that no flour was enriched, iron intake was
      constant during the 6-year study period. Despite this, after flour fortification
      was stopped in 1987, serum ferritin increased among both men and postmenopausal
      women. CONCLUSIONS: Considering that mandatory iron fortification of flour
      affects the entire population, including subjects who are at risk for chronic
      diseases because of too-high iron stores, the decision to stop the mandatory
      fortification in Denmark seems to have been well-founded.

PMID- 10419798
TI  - Predicting children's sunscreen use: application of the theories of reasoned
      action and planned behavior.
AB  - BACKGROUND: Skin cancer remains the most common form of cancer in the United
      States despite the fact that most cases can be prevented by limiting sun
      exposure. Childhood and adolescence are periods of life during which prolonged
      sun exposure is particularly common. Accordingly, promoting sun-protective
      behaviors during these formative years can be of critical importance in
      preventing skin cancer. The present study applied the theories of reasoned action
      and planned behavior to the understanding of children's sunscreen use. Based on
      these theories, it was hypothesized that attitudes, subjective norms, and
      perceived behavioral control would be related to intentions to use sunscreen,
      which, in turn, would be related to actual sunscreen use. METHODS: Questionnaires
      measuring sun-related attitudes, beliefs, perceived control, and intentions were
      administered to 199 fourth graders (ages 9 to 13, mean = 10.3) attending public
      schools in Florida. Self-report measures of sun-related behavior were
      administered to the same subjects 1 month later. RESULTS: Results of
      correlational analyses were consistent with study hypotheses. Higher rates of
      sunscreen use at follow-up were predicted by stronger intentions to use sunscreen
      assessed 1 month previously. In addition, stronger intentions to use sunscreen
      were found to be related to more favorable attitudes toward sunscreen use,
      stronger beliefs that peers and parents favored sunscreen use, and greater
      perceptions of personal control in using sunscreen. Path and multiple regression
      analyses identified direct and indirect relationships among study variables that
      partially confirmed those predicted by the theories and provided support for the
      use of an expanded model that included perceived behavioral control. CONCLUSIONS:
      The present study confirmed hypotheses derived from the theories of reasoned
      action and planned behavior regarding the relation of attitudes, subjective
      norms, and perceived behavioral control to sunscreen use among fourth graders. In
      addition to their theoretical significance, these findings suggest ways to
      intervene at the individual, classroom, and family levels to promote greater
      sunscreen use in this age group.

PMID- 10419799
TI  - Direct measurement of sun protection in primary schools.
AB  - BACKGROUND: "Kidskin" is an intervention study involving children at 33 primary
      schools in Perth, Western Australia. This study includes measurement of changes
      in implementation of schools' sun protection policies. This paper reports on
      measurement of observable aspects of sun protection. METHODS: Hat use was
      assessed from videos of children in the playground. Shade use was measured using
      UVR-sensitive polysulfone badges worn by a random sample of children. Shade
      provision was measured from aerial photographs of the schools. Principals were
      surveyed about school policies and practices. RESULTS: Eighty-seven percent of
      children wore a hat during lunch time at school, although only 14% wore the most
      protective styles of hats. The mean proportion of ambient UVR exposure received
      by Year 1 children was 15.5%; children spent less time in the sun on sunnier
      days. On average, 14.5% of the playground was shaded; this was not associated
      with children's sun exposure. Correlations between these results and the
      principals' estimates were poor. CONCLUSIONS: Children should be encouraged to
      wear more protective styles of hats and to avoid sun exposure, even on less sunny
      days during spring and summer. Principals' estimates of shade provision and
      children's sun protection behavior at school are of little value.

PMID- 10419800
TI  - Perceptions of the effect of an impending restaurant smoking ban on dining-out
      experience.
AB  - BACKGROUND: The introduction of bans on smoking in restaurants is frequently
      marred by claims that they will lead to a loss of business. METHODS: A
      representative sample of 3,019 South Australians age 15+ years were asked
      questions about dining-out frequency and perceived effects of the ban on their
      dining-out enjoyment and restaurant patronage. RESULTS: Sixty-one percent thought
      the ban would make dining out more enjoyable, 5% thought it would be less
      enjoyable, and 34% thought it would make no difference. Overall, 82% thought the
      ban would make no difference to their likelihood of dining out, 14% would be more
      likely to dine out, and 4% would be less likely. CONCLUSIONS: These data suggest
      that the public expects bans on smoking in restaurants to result in both
      increased enjoyment and increased patronage of restaurants.

PMID- 10419802
TI  - Partial moles: from postnatal to prenatal diagnosis.
AB  - The partial hydatidiform mole is a histopathologic entity characterized by focal
      trophoblastic hyperplasia with villous hydrops together with identifiable fetal
      tissue which was first described by Szulman and Surti in 1978. Since then major
      advances in molecular biology have shown that more than 90 per cent of partial
      moles are secondary to diandric triploidy and that this condition accounts for
      most cases of persistent trophoblastic disease after partial mole. Case series
      describing the prenatal diagnosis of triploid partial mole were reviewed and
      outcomes were analysed for all pregnancies, and compared to those of non-molar
      triploidy using the chi-square test. In more than 90 per cent of both types of
      triploidy, the fetus shows growth restriction and multiple structural anomalies.
      Oligohydramnios and abnormal placental Doppler indices are common in both types.
      In triploid partial mole, 82.1 per cent of fetuses present with symmetrical
      growth restriction, the maternal serum human chorionic gonadotropin (MShCG) level
      is increased in 80.8 per cent of the cases and 41.9 per cent of the women are at
      risk of pre-eclampsia. The triploid partial mole is a lethal fetal condition
      which is linked with gestational trophoblastic disorders. The typical placental
      molar features are not always pathognomonic of triploid partial mole and are less
      likely to be apparent on ultrasound in early pregnancy. The perinatal diagnosis
      of this condition relies upon mainly on MShCG level and cytogenetic results which
      have to be correlated with the histopathologic diagnosis. Women with this
      pregnancy complication should be offered immediate termination and a specific
      follow-up.

PMID- 10419801
TI  - Gender and determinants of smoking cessation: a longitudinal study.
AB  - BACKGROUND: The less favorable trend in smoking prevalence in women compared to
      men may be due to lower cessation rates. We analyzed determinants of spontaneous
      smoking cessation with particular reference to gender differences. METHODS: Data
      on smoking were collected by questionnaire in three samples of the adult
      population, examined for the first time at intervals between 1976 and 1984. In
      total 11,802 (59%) subjects were smokers, and 9085 of them attended a
      reexamination after 5 years. Ten to 16 years later 6053 were examined once again.
      Logistic regression was performed to study the relation of determinants to having
      quit after 5 and 10-16 years. RESULTS: The prevalence of quitting was 12 and 22%
      at first and second follow-up, respectively. At both reexaminations, quitting
      smoking was positively associated with male sex and cigar smoking and negatively
      associated with the amount of tobacco smoked, inhalation, and alcohol
      consumption. Furthermore, in women, smoking cessation was positively associated
      with level of education and body mass index (BMI). Smoking cessation was not
      affected by cohabitation status, leisure activity, or bronchitis symptoms.
      CONCLUSIONS: Smoking cessation initiatives should be targeted at heavy cigarette
      smokers, and at women, in particular the lean and poorly educated.

PMID- 10419803
TI  - Uterine Doppler velocimetry and placental hypoxic-ischemic lesion in pregnancies
      with fetal intrauterine growth restriction.
AB  - We tested the hypothesis that Doppler velocimetry of the ascending uterine
      arteries (Ut.DV) in cases of fetal intrauterine growth restriction (IUGR) can
      reflect the presence of hypoxic-ischaemic lesions of the placenta, and whether
      this prediction is affected by the maternal blood pressure status.Ut.DV was
      obtained within 7 days of delivery in 90 consecutive pregnancies with IUGR and in
      37 uneventful control pregnancies. Abnormal Ut.DV was defined as an average of a
      (left and right systolic)/diastolic ratio >2.6 and diastolic notching. After
      delivery, pathological studies were performed with attention paid to macroscopic
      and microscopic evidence of hypoxic or ischaemic placental lesions related to
      uteroplacental vascular pathological features. In patients with IUGR, the total
      rate of placental lesions was significantly higher in the presence of abnormal
      Ut.DV compared to the presence of normal Ut.DV (relative risk, 6.35; 95 per cent
      confidence interval=5.2-7.3). The rate and the severity of these lesions was not
      significantly different between normotensive and hypertensive pregnancies (87
      versus 93 per cent;P =0.2). When Ut.DV was normal, the rate of placental lesions
      was similar between IUGR cases and control pregnancies (14 versus 8 per cent;P
      =0.69). The perinatal outcome was not significantly different in any of the
      normotensive and the hypertensive pregnancies with growth-restricted fetuses and
      abnormal Ut.DV.The presence of abnormal Doppler velocimetry of the uterine
      arteries in pregnancies with fetal intrauterine growth restriction is may be in
      fact an important indicator of hypoxic or ischaemic placental lesions. This
      abnormal Doppler velocimetry is independent of the maternal blood pressure
      status.

PMID- 10419804
TI  - Villitis of known origin: varicella and toxoplasma.
AB  - Chronic villitis is a common condition in human placentae. In some cases an
      infectious cause can be demonstrated, such as infection with cytomegalovirus and
      rubella virus. Most often it is of unknown aetiology, the so-called VUE (villitis
      of unknown aetiology). We describe two cases with identification of specific
      infectious agents, each demonstrating previously unreported findings, i.e.
      persistent varicella antigen in the villi in case 1, and presence of toxoplasma
      cysts in Wharton's jelly in case 2. The identification of the pathogens,
      varicella virus and toxoplasma, would easily have been overlooked in routine
      study of the placenta and were possible because of clinical suspicion.

PMID- 10419805
TI  - Expression patterns of the cell-cycle inhibitor p27 and the cell-cycle promoter
      cyclin E in the human placenta throughout gestation: implications for the control
      of proliferation.
AB  - The rapid development of the placenta necessitates a high proliferative potential
      and cell-division rate. This, coupled with a high capacity for invasion, could
      confer on the placental tissue a tumour-like character. To exclude this, tight
      mechanisms of control are necessary for both proliferation and invasiveness.
      Despite their importance, very little is known about the molecular basis of these
      mechanisms. The present study was thus designed to investigate the molecular
      mechanisms implicated in the control of proliferation in the human placenta. We
      used immunohistochemistry to study the expression of two cell-cycle controlling
      molecules with opposing effects: the cell-cycle inhibitor, p27, which belongs to
      the Kip/Cip family of CDK inhibitors and can mediate G1 arrest, and cyclin E, a
      G1-cyclin esential for G1/S progression. Expression was studied throughout
      pregnancy in a total of 41 normal human placental samples. In addition,
      immunohistochemistry for Ki-67 was performed as a control for proliferation. The
      cell-cycle inhibitor p27 was expressed in the differentiated, non-dividing
      syncytiotrophoblast, while expression of cell-cycle promoter cyclin E was
      localized to the nuclei of the cytotrophoblast and correlated well with
      expression of Ki-67. No cyclin E expression was observed in the
      syncytiotrophoblast. In conclusion, strong expression of the cell-cycle inhibitor
      p27 and absence of expression of cyclin E in the syncytiotrophoblast might
      represent an important control mechanism in placental proliferation. This
      differentiates it from the proliferation of malignant tumours, where p27 has been
      shown to be frequently downregulated while cell cycle promoters are
      overexpressed.

PMID- 10419806
TI  - Proliferation, differentiation and apoptosis in villous trophoblast at 13-41
      weeks of gestation (including observations on annulate lamellae and nuclear pore
      complexes).
AB  - Ultrastructural, immunochemical, fluorescence and stereological studies were
      undertaken on human villous trophoblast from 13 weeks of gestation to term. The
      aim was to describe and quantify morphological changes during proliferation,
      differentiation and apoptosis in cytotrophoblast and syncytial regions of non
      aggregated and aggregated nuclei. Numbers of trophoblast nuclei increased
      continuously from 13 weeks. In term placentae, intrasyncytial differentiation was
      characterized ultrastructurally by gradual decreases in nuclear size and packing
      density accompanied by nucleolar regression, and increasing
      heterochromatinization, envelope convolution and packing density of nuclear pore
      complexes. In densely packed areas, nuclear profiles resembled interlocking
      jigsaw pieces. Occasionally, these 'pre-apoptotic' nuclei were associated with
      annulate lamellae. Rarely, nuclear changes terminated in apoptosis with a
      characteristic pattern of condensed peripheral chromatin, a central island of
      euchromatin, no nucleoli and no discernible nuclear pores. Apoptotic nuclei were
      seen singly and within dense nuclear aggregations. Similar spatial patterns of
      nuclei and chromatin were seen in propidium iodide-stained sections at 13-41
      weeks. Whilst the relative incidence of intensely fluorescent nuclei remained
      constant, absolute numbers increased linearly during gestation and correlated
      positively with the volume of syncytial knots. Nuclei labelled for DNA
      fragmentation occurred very infrequently and were also found in nuclear clusters
      as well as singly. We suggest that nuclear differentiation in syncytium has two
      phases: on entering syncytium, nuclei become committed to a long programmed pre
      apoptotic phase which leads to a short apoptotic execution phase. We propose
      further that clustered nuclei (pre-apoptotic and apoptotic) in syncytial knots
      probably represent the extrusion component of normal continuous epithelial
      turnover.

PMID- 10419807
TI  - The role of Bcl-2 expression in EGF inhibition of TNF-alpha/IFN-gamma-induced
      villous trophoblast apoptosis.
AB  - The inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and immune
      interferon gamma (IFN-gamma) stimulate villous cytotrophoblast apoptosis while
      epidermal growth factor (EGF) protects. We hypothesize that TNF-alpha, IFN-gamma
      and EGF regulate apoptosis in part by modulating cellular expression levels of
      the anti-death gene bcl-2. While Bcl-2 is reported to be strongly expressed in
      villous syncytiotrophoblasts, it is not known whether the protein is expressed in
      cultured villous cytotrophoblasts (CT) and, if so, whether it is functional. We
      show by Northern blot analysis that bcl-2 mRNA is expressed in cultured CT and by
      immunoblot analysis that the protein is strongly expressed in highly purified
      first trimester and term villous cytotrophoblasts. The expression levels of Bcl-2
      protein were the same in first trimester and term cytotrophoblasts. Culture with
      TNF-alpha/IFN-gamma and EGF did not alter expression of either Bcl-2 protein or
      of the pro-apoptotic Bcl-2 family member Bak. Double label flow cytometric
      analysis that measured apoptosis and Bcl-2 content simultaneously showed that
      cells expressing low levels of Bcl-2 underwent TNF-alpha/IFN-gamma-induced
      apoptosis at a higher frequency than cells expressing lower levels. We conclude
      that Bcl-2 is expressed in cytotrophoblasts, that its expression is constitutive
      and that modulation of its expression levels does not mediate cytokine and growth
      factor regulation of apoptosis in these cells.

PMID- 10419808
TI  - Susceptibility of MHC class I expressing extravillous trophoblast cell lines to
      killing by natural killer cells.
AB  - Purified human first trimester extravillous trophoblast (EVT) cell lines HTR-8
      and HT-116 were examined for susceptibility to natural killer (NK) cell-mediated
      lysis. Based upon nucleic acid sequencing of an amplified fragment of cDNA,
      Western blot analysis and immunostaining of fixed and live cells, it was shown
      that both EVT cell lines expressed HLA-G mRNA and protein within the cytoplasm
      when cultured on laminin-coated plates. Very weak HLA-G expression was detectable
      on the cell surface under these conditions. However, strong cell surface
      expression of a classical MHC class I molecule (most likely HLA-C) was exhibited
      by these EVT cell lines when grown on laminin, as indicated by W6/32 FACS
      analysis (Ab recognizing pan MHC class I), and Western immunoblotting with HC10
      (Ab recognizing HLA-B/C). When these EVT cells, cultured on laminin, were used as
      targets for peripheral blood natural killer (NK) cells in a standard chromium
      release assay, both HTR-8 and HT-116 cells were lysed by NK cells in a dose
      dependent manner. The respective percentage specific lysis at an effector to
      target (E/T) ratio of 100 was 28+/-7, and 48+/-14. The choriocarcinoma cell lines
      JAR and JEG-3 which were respectively MHC class I negative and HLA-G positive
      were resistant to NK cell lysis. Thus, there was no clear relationship between
      the MHC class I expression and NK cell resistance or susceptibility among the EVT
      cell lines and choriocarcinoma cells. These findings raise the possibility that
      NK cells may take part in the surveillance of the invasive EVT cells during
      normal placentation.

PMID- 10419809
TI  - Immune competence involving the natural killer cell lineage promotes placental
      growth.
AB  - Very small placentae and absence of uterine natural killer (uNK) cells are
      amongst the reproductive deficits found in the natural killer (NK) cell and
      thymus-derived (T) cell immunodeficient mouse tgepsilon26. These defects can be
      reversed by grafting of adult tgepsilon26 females with bone marrow from T and B
      cell immunodeficient scid/scid donors. We report here that a second protocol,
      grafting of neonatal tgepsilon26 females with immunocompetent bone marrow
      pretreated with antibody to Thy-1, successfully established the uNK cell lineage
      and ameliorated the phenotype. Further, comparisons of mid-gestation (days 10-16)
      placental area measurements from tgepsilon26 and seven other immunodeficient
      strains to time-matched tissues from four strains of immunocompetent mice
      indicate that lymphocytes of the NK but not the T or B cell lineages are able to
      influence placental size during normal gestation and that this action is
      independent of interleukin 2. Area measurements of placentae produced in
      manipulated tgepsilon26 pregnancies (maternal bone marrow engraftment,
      outcrossing to immunocompetent males and reciprocal embryo transfers with an
      immunocompetent strain) suggest that NK cell competence is required in each of
      the maternal and fetal compartments to optimize placental growth.

PMID- 10419810
TI  - DNA content and ploidy level of bovine placentomal trophoblast giant cells.
AB  - Cytophotometric measurement of the DNA content of Feulgen-stained nuclei in touch
      preparations of bovine placentomes (n =5) revealed that 8C nuclei occurred in
      all, 16C nuclei in two, and 32C nuclei in one specimen. The determination of
      ploidy level by in situ hybridization with a Y-chromosome specific DNA probe
      showed that the majority of the fetal nuclei in touch preparations of placentomes
      from male fetuses (n =5) are tetraploid. Generally two tetraploid nuclei lie
      close together. These findings indicate that polyploidization is a normal feature
      in the development of the mostly binucleate trophoblast giant cells (TGCs). A new
      model for the development of these cells is proposed: a primary acytokinetic
      mitosis leads to a binucleate cell with two diploid nuclei. This cell enters a
      second acytokinetic mitosis during which the chromosomes of both nuclei form a
      common metaphase plate. The resulting cell with two tetraploid nuclei undergoes
      an additional S-phase but does not enter a renewed mitosis. The functional
      significance of this genome multiplication may be an increased synthetic capacity
      of bovine TGCs, caused by an increased number of gene copies available for
      transcription. Since genome multiplication is a property of invasive trophoblast
      cells of different species, it may be advantageous for trophoblast invasion.

PMID- 10419811
TI  - Retinoid binding proteins-expression patterns in the human placenta.
AB  - The present study examined the expression and occurrence of different retinoid
      binding proteins in human first trimester and term placenta. At both stages,
      messenger RNA for the serum transport vehicle for retinol, retinol-binding
      protein (RBP), was detected only in decidual cells of the basal plate. In
      contrast, immunoreactive RBP (irRBP) was present in syncytiotrophoblast, core
      mesenchyme and lumen of vessels in placental villi and in mesenchyme and decidual
      cells of the basal plate. In villi of term placentae, however, staining for irRBP
      was lost in syncytiotrophoblasts and villous core mesenchyme. A putative
      placental RBP-receptor, approx 60-65kDa, was detected in the villous
      syncytiotrophoblast of both stages investigated. Immunoreactivity for the
      cellular retinol binding protein type I (CRBP I), was found in villous stromal
      cells and in decidual cells of the basal plate in sections of first trimester and
      term placenta. These results may suggest that maternal RBP-retinol is transferred
      across the chorionic villi to the fetal/villous circulation and that villous
      absorption of the complex is mediated via a placental RBP-receptor. Moreover,
      binding and possibly also metabolism of retinol may occur in the CRBP I positive
      villous stromal cells and decidual cells of the basal plate. In the latter,
      release of placental RBP-retinol may also be anticipated.

PMID- 10419812
TI  - The localization and expression of the renin-angiotensin system in the human
      placenta throughout pregnancy.
AB  - All the components of the renin-angiotensin system (RAS), including the
      AT(1)receptor, have previously been shown to be present in the human term
      placenta. However, the presence of the RAS components has not been fully
      investigated in the human placenta throughout pregnancy. The aim of this study
      was to examine the localization of the angiotensin receptors AT(1)and AT(2)using
      immunocytochemistry and the expression of prorenin, angiotensinogen and the
      AT(1)and AT(2)receptor mRNA using RT-PCR in the human placenta in the first,
      second and third trimesters of pregnancy. Localization of the AT(1)receptor was
      shown throughout gestation in the syncytiotrophoblast, cytotrophoblast, Hofbauer
      cells and the fetal vascular endothelium. Expression of mRNA for prorenin,
      angiotensinogen and the AT(1)receptor was shown in the placenta throughout
      gestation. However, localization or mRNA expression of the AT(2)receptor was not
      detected in any of the placental samples studied. These results clearly show the
      expression of a majority of the components of the RAS in the placenta from early
      gestation onwards. Therefore, these results suggest that the RAS may have a role
      in the human placenta throughout gestation.

PMID- 10419813
TI  - A novel ATP-diphosphohydrolase from human term placental mitochondria.
AB  - This report describes an ATP-diphosphohydrolase activity associated with the
      inner membrane of human term placental mitochondria. An enriched fraction
      containing 30 per cent of the total protein and 80 per cent of the total ATP
      diphosphohydrolase activity was obtained from submitochondrial particles. ATP
      diphosphohydrolase activity was characterized in this fraction. The enzyme had a
      pH optimum of 8 and catalysed the hydrolysis of triphospho- and
      diphosphonucleosides other than ATP or ADP. Pyrophosphate was also hydrolysed,
      but AMP or other monoester phosphates were not. The activity of ATP
      diphosphohydrolase was dependent on Mg(2 + ), Ca(2 + )or Mn(2 + )and the enzyme
      substrate was the cation-nucleotide complex. An excess of free cation produced
      inhibition.ATP-diphosphohydrolase activity was stimulated at micromolar
      concentrations of calcium or magnesium in the presence of La-PPi. Negative
      cooperativity kinetics was observed with all substrates tested. The V(max)ranged
      from 150 to 300nmol of Pi released/mg/min. The [S](0.5)for nucleotides was 1-10m
      m and 182m m for PPi. The enzyme was inhibited by orthovanadate, but not by l 
      phenylalanine, oligomycin, sodium azide, P(1),P(5)-di(adenosine-5')pentaphosphate
      or sodium fluoride.The experimental evidence showing absence of inhibition by
      sodium azide and sodium fluoride, hydrolysis of pyrophosphate but not of
      monoester phosphates, and negative cooperativity suggested that this enzyme was a
      novel ATP-diphosphohydrolase.

PMID- 10419814
TI  - Properties of volume-activated taurine and iodide efflux from term human
      placental tissue.
AB  - The effect of cell swelling, induced by a hyposmotic challenge, upon the efflux
      of radiolabelled taurine and iodide from term human placental tissue explants has
      been studied. A hyposmotic shock markedly increased the unidirectional efflux of
      taurine in a manner which was fully reversible. It took approximately 6-8 min for
      taurine efflux to reach a maximum response following a hyposmotic challenge
      whereas it took about 16 min for taurine efflux to return to a basal level. This
      suggests that factors other than, or in addition to, membrane stretch are
      involved in the signal transduction process. A prolonged hyposmotic challenge
      appeared to inactivate volume-sensitive taurine release. Volume-activated taurine
      efflux was dependent upon the extent of cell swelling: the effect was greatest
      when the decrease in the osmolality was greater than 27 per cent. Cell swelling
      induced taurine efflux was markedly inhibited by diiodosalicylate and to a lesser
      extent by bumetanide and quinine. A hyposmotic challenge also increased the
      efflux of iodide via a pathway which was sensitive to niflumic acid. This is
      consistent with the presence of volume-activated Cl(-)channels. Volume-activated
      amino acid and anion (Cl(-)) efflux may act in parallel with K(+)efflux to
      regulate placental cell volume following swelling.

PMID- 10419815
TI  - Sites of mRNA expression of the cystic fibrosis (CF) and multidrug resistance
      (MDR1) genes in the human placenta of early pregnancy: No evidence for
      complementary expression.
AB  - The aims of this study were to establish the sites of mRNA expression of both the
      cystic fibrosis (CF) and multidrug resistance (MDR1) genes in human placental
      sections from early pregnancy (first, early and mid-second trimesters).
      Riboprobes specific for each of these two genes were generated and used for in
      situ hybridization experiments. The results show parallel mRNA expression for the
      CF and MDR1 genes, with the signal detected in the syncytiotrophoblast and
      cytotrophoblast cells of the placental villi. Other cell types within the villous
      core were negative. Similar results were obtained at all stages of pregnancy
      studied.

PMID- 10419816
TI  - Purification and crystallization of rhizopuspepsin: the use of nickel chelation
      chromatography to select for catalytically active species.
AB  - A new method to obtain pure zymogen-derived peptidases is presented. The key
      strategy is to install a polyhistidine peptide tag on the N-terminus of the
      propeptide sequence of a zymogen. After expression, purification, and folding of
      the protein, autocatalytic posttranslational cleavage and filtration through a
      nickel affinity column gives pure, functional peptidase. This method takes
      advantage of the nickel affinity chromatography system that removes both zymogen
      peptide and nonfunctional folded peptidase without the need to use external
      enzymes to remove, often incompletely, the resulting fusion peptide. This
      technique was used to prepare the aspartic peptidase rhizopuspepsin. His-tagged
      rhizopuspepsinogen was expressed, and the desired protein was isolated as
      inclusion bodies and refolded. The proenzyme was purified by normal methods and
      then the relatively pure proenzyme was activated via intramolecular proteolysis
      at low pH. The propeptide and any inactive rhizopuspepsinogen were removed via
      affinity chromatography. This procedure yields a highly active rhizopuspepsin in
      99% purity, which was demonstrated by PAGE, protein sequencing, and X-ray
      crystallography (1.5 A) of the isolated peptidase. A new fluorescent assay system
      is introduced for rhizopuspepsin, utilizing the substrate KPVSY(4-NO(3)-F)RL. The
      kinetics constants were K(m) = 3.4 microM +/- 0.31 and k(cat) = 55 +/- 1.0 s(-1).

PMID- 10419817
TI  - Purification of human chorionic gonadotrophin from urine by membrane filtration
      affinity chromatography with a positively charged membrane.
AB  - A new method of affinity chromatography, termed membrane filtration affinity
      chromatography (MFAC), has been developed and applied to purify HCG from urine.
      By filtrating urine through ZBM (HCG in urine would bind to the antibody on ZBM)
      and by dissociating the HCG from the antibody on ZBM in purified form, we
      developed the MFAC and purified HCG from urine of pregnant women by MFAC. The
      purified HCG showed a single band in polyacrylamide gel electrophoresis. ZBM (1
      cm(2)) could harvest 90.3 microg HCG, which showed immunoactivity of 8554 IU/mg.
      The rate of recovery was 87%. CONCLUSION: MFAC with ZBM is an effective method,
      which is much easier and cheaper than conventional affinity chromatography for
      purification of proteins from solution, especially from highly diluted solution.

PMID- 10419819
TI  - Purification of xyloglucan endotransglycosylase based on affinity sorption of the
      active glycosyl-enzyme intermediate complex to cellulose.
AB  - Xyloglucan endotransglycosylase (XET) catalyzes the cleavage of xyloglucan (XG)
      molecules by a transglycosylation mechanism involving two steps: (a) endocleavage
      of the beta-(1,4)-linked polyglucosyl backbone of the xyloglucan molecule with
      formation of a glycosyl-enzyme intermediate; (b) transfer of the glycosyl residue
      from the intermediate to the C-4 position of the nonreducing end glucosyl unit of
      another molecule of XG or an XG-derived oligosaccharide with liberation of the
      enzyme (Z. Sulova et al., 1998, Biochem. J. 330, 1475-1480). The formation of a
      relatively stable active complex of XET with XG and the tendency of xyloglucan to
      bind tightly via hydrogen bonds to cellulose were exploited in the present method
      of purification of XET. Crude extracts from nasturtium (Tropaeolum majus)
      cotyledons and other plant sources containing the enzyme were mixed with XG in
      order to form the XET:XG complex, which was applied onto cellulose. Unadsorbed
      proteins were removed by washing and the XET was released from the adsorbed
      XET:XG complex by transglycosylation of its glycosyl moiety to added XG-derived
      oligosaccharides. The described procedure resulted in an over 100-fold increase
      in specific activity of XET in a single step. Further purification of the enzyme
      to homogeneity was achieved by gel-permeation chromatography on Bio-Gel P30.
      Similar procedure could be used for purification of XET from other plant sources,
      such as lentil (Lens culinaris) seeds, pea (Pisum sativum) epicotyls, and
      supernatant of suspension-cultured Catharanthus roseus cells.

PMID- 10419818
TI  - Functional characterization of apolipoprotein E isoforms overexpressed in
      Escherichia coli.
AB  - Apolipoprotein (apo) E plays an important role in lipid metabolism, and the major
      isoforms of apoE (apoE2, apoE3, and apoE4) have significantly different metabolic
      effects. Apolipoprotein E4 is associated with a higher risk of both heart disease
      and Alzheimer's disease (AD). Patients homozygous for apolipoprotein E2 are
      predisposed to type III hyperlipoproteinemia, and apoE2 may be protective against
      AD. Structure/function studies have proved to be a useful tool in understanding
      how the different apoE isoforms result in different pathological consequences. As
      these studies continue, it is essential to have a reliable method to produce
      large quantities of apoE and mutants of apoE. We describe here a method of apoE
      production in Escherichia coli strain BL21(DE3). The cDNA from apoE isoforms was
      inserted into a pET32a vector with a T7 promoter and a fusion partner
      (thioredoxin). The T7 promoter results in high expression of an easily purified
      His-tagged fusion protein. A thrombin recognition site was positioned in the
      expression vector so that only two novel amino acids (Gly-Ser) are added to the
      amino terminus of apoE following the removal of thioredoxin. Approximately 20 mg
      of apoE is obtained from a 1-liter culture. The major isoforms of apoE produced
      with this system were extensively characterized for their ability to bind the low
      density lipoprotein (LDL) receptor, for their characteristic lipid association
      preferences, and for their stability as measured by guanidine denaturation. The
      recombinant proteins behaved identically to plasma-derived apoE isoforms.

PMID- 10419820
TI  - Purification, characterization, and crystallization of the distal BRCT domain of
      the human XRCC1 DNA repair protein.
AB  - The XRCC1 DNA repair protein contains two regions of approximately 100 amino
      acids each that share homology with the BRCT (BRCA1 carboxyl terminus) domain
      superfamily. These two regions of XRCC1 have been shown to interact independently
      with DNA ligase III and poly(ADP-ribose)polymerase as part of a mechanism
      involved in the repair of DNA single-strand breaks. To understand how these BRCT
      regions specify protein-protein interactions and contribute to DNA repair
      function, we have overexpressed and purified the distal BRCT domain of XRCC1 with
      the goal of structure determination. The cDNA encoding this BRCT region (X1BRCTb)
      was inserted into the pET29 bacterial expression vector; the polypeptide was
      expressed in mostly soluble form and then purified by anion-exchange and gel
      filtration chromatography. Crystallization screening with the purified material
      resulted in the formation of large bipyramidal crystals. Crystals formed within
      several hours at room temperature from salt solutions of ammonium sulfate.
      Crystals diffract to approximately 2.85 A and were found to be in space group
      P4(1)2(1)2 (or its enantiomorph P4(3)2(1)2) with unit cell dimensions a = 100.43
      A, c = 105.62 A. Crystals of similar character have also been obtained after
      incorporation of selenomethionine during expression of the protein. Efforts are
      now under way to determine the molecular structure of the X1BRCTb domain. These
      studies are likely to give insight into the interaction between XRCC1 and DNA
      ligase III and into general structural features of BRCT domains that exist in
      many other proteins.

PMID- 10419821
TI  - Expression and characterization of human salivary statherin from Escherichia coli
      using two different fusion constructs.
AB  - Saliva is a supersaturated solution with respect to hydroxyapatite, the main
      inorganic component of tooth enamel. Several acidic phosphoproteins are present
      in saliva which allow the supersaturated state to be maintained without random
      crystallization occurring. Statherin is the only salivary protein currently known
      to inhibit both the primary and secondary precipitation of hydroxyapatite in the
      supersaturated environment of saliva. To identify the residues of statherin that
      are necessary to control biomineralization, a recombinant form of human statherin
      was produced from Escherichia coli using a yeast intein fusion construct. The
      primary structure of the recombinant statherin was characterized by SDS-PAGE, N
      terminus sequencing, MALDI mass spectrometry, and amino acid analysis and found
      to have the expected values relative to human-derived statherin. The secondary
      structure of the recombinant statherin was investigated by circular dichroism
      spectroscopy, which revealed the predominant presence of random coil in phosphate
      buffered saline solution, with a higher propensity toward alpha helicity in 100%
      TFE. This increase in helicity in 100% TFE was also found in statherin that was
      synthesized by solid-phase synthesis. These results demonstrate that human
      statherin can be produced in a recombinant form which behaves comparably to the
      natural form.

PMID- 10419822
TI  - Heterologously expressed polypeptide from the yeast meiotic gene HOP1 binds
      preferentially to yeast DNA.
AB  - HOP1 protein, present in sporulating cells of Saccharomyces cerevisiae and
      believed to be a component of the synaptonemal complex, has been expressed in
      Escherichia coli fused to a biotinylated tag protein. Once solubilized from
      bacterial inclusion bodies, the HOP1 fusion protein was purified by using a
      combination of avidin-affinity chromatography and gel filtration FPLC and
      refolded. Sequence comparisons indicate that the HOP1 gene product contains a
      zinc finger motif, which may confer DNA binding properties, and the recombinant
      polypeptide was used to assess the putative DNA binding properties of the product
      of native HOP1 protein using a gel-shift assay. Protein and protein-DNA complexes
      were detected by exploiting the affinity of streptavidin-alkaline phosphatase for
      the biotinylated tag protein after Western blotting. The HOP1 fusion protein
      bound unambiguously to digested genomic yeast DNA. This binding possessed some
      degree of specificity, was maintained under a wide range of salt concentrations,
      and was unaffected by the presence of high concentrations of competitor DNA
      (synthetic poly[dI-dC].poly[dI-dC]). In contrast, no shift was detected when the
      fusion protein was incubated with digested genomic DNA from Arabidopsis, or with
      lambda/HindIII DNA. Incubation with digested genomic DNA from Lilium produced a
      small change in the mobility of the protein. The biotinylated tag protein failed
      to show any DNA binding activity. Scatchard analysis indicated an apparent yeast
      genomic DNA:HOP1 fusion protein dissociation constant of K(d) = 5 x 10(-7) M.

PMID- 10419823
TI  - Effect of accessible immobilized NAD(+) concentration on the bioaffinity
      chromatographic behavior of NAD(+)-dependent dehydrogenases using the kinetic
      locking-on strategy.
AB  - In preparation for studies aimed at establishing the relationship between
      immobilized NAD(+) concentration and the concentration of soluble locking-on
      ligand required to promote biospecific adsorption of NAD(+)-dependent
      dehydrogenases to immobilized NAD(+) derivatives (the "locking-on" strategy), two
      approaches were evaluated for varying substitution levels: (i) suitable dilution
      of the affinity matrix with unsubstituted Sepharose 4B and (ii) direct coupling
      of the required ligand concentration to the inert matrix. The latter approach was
      found to be the preferable strategy for evaluation of the locking-on tactic
      because it produced a more homogeneous distribution of immobilized NAD(+)
      concentration. Affinity chromatographic studies using S(6)-linked NAD(+)
      derivatives synthesized to various substitution levels showed that the total
      accessible immobilized NAD(+) concentration has a direct effect on the locking-on
      behavior of pyridine nucleotide-dependent dehydrogenases. The one-chromatographic
      step bioaffinity purification of l-lactate dehydrogenase (L-LDH, EC 1.1.1.27)
      from bovine heart illustrates the potential of the locking-on strategy for
      protein purification applications.

PMID- 10419824
TI  - The kinetic locking-on strategy for bioaffinity purification: further studies
      with bovine liver glutamate dehydrogenase.
AB  - The locking-on strategy uses soluble analogues of the enzymes specific substrate
      to produce biospecific adsorption of individual NAD(P)(+)-dependent
      dehydrogenases on immobilized NAD(P)(+) derivatives, which is so selective that a
      single enzyme activity can be purified from crude cellular extracts in a single
      chromatographic step with yields approaching 100%. However, attempts to further
      develop and apply this strategy to the biospecific chromatographic purification
      of a range of NAD(P)(+)-dependent dehydrogenases revealed some anomalous
      chromatographic behavior and certain unexplained phenomenon. Much of this can be
      attributed to nonbiospecific interference effects. Identification and elimination
      of this interference is discussed in the present study focusing on bovine liver
      glutamate dehydrogenase (GDH; EC 1.4.1.3) as the "test" enzyme. Results further
      confirm the potential of the locking-on strategy for the rapid purification of
      NAD(P)(+)-dependent dehydrogenases and provide further insight into the
      parameters which should be considered during the development of a truly
      biospecific affinity chromatographic system based on the locking-on strategy. The
      kinetic mechanism of bovine liver GDH has been the topic of much controversy with
      some reports advocating a sequential ordered mechanism of substrate binding and
      others reporting a sequential random mechanism. Since the kinetic locking-on
      strategy is dependent on the target NAD(P)(+)-dependent dehydrogenase having an
      ordered sequential mechanism of substrate binding, the bioaffinity
      chromatographic behavior of bovine liver GDH using the locking-on tactic suggests
      that this enzyme has an ordered sequential mechanism of substrate binding under a
      variety of experimental conditions when NAD(+) is used as cofactor.

PMID- 10419825
TI  - Expression and purification of recombinant human zona pellucida proteins.
AB  - Recombinant human zona pellucida (rhZP) proteins (minus the N-terminal leader and
      the C-terminal transmembrane-like domain) were expressed in four different
      expression systems: bacteria, yeast, insect cells, and Chinese Hamster Ovary
      (CHO) cells. The recombinant proteins in each system were engineered with a C
      terminal six histidine (His6) segment that was used to purify the proteins by
      metal affinity [either nickel (Ni) or cobalt (Co)] column chromatography. Each of
      the rhZP proteins was a candidate antigen as an immunocontraceptive vaccine.
      However, the rhZP proteins produced in bacteria, yeast and insect cell culture
      could only be purified after being solubilized by strong denaturants. After
      purification the final products of each of these expression systems required 6 M
      urea to maintain solubility. However, the rhZP proteins expressed by CHO cells
      were secreted into the media, and the soluble proteins could be purified to near
      homogeneity. In this report the expression and purification procedures used to
      produce and isolate these secreted proteins are described.

PMID- 10419826
TI  - Versatile copurification procedure for rapid isolation of homogeneous RAR-RXR
      heterodimers.
AB  - RAR-RXR heterodimeric complexes (RARalphaDeltaAB-RXRalphaDeltaAB) bound to
      cognate DR5 DNA response elements were purified to apparent structural and
      functional homogeneity using a novel versatile immobilized metal affinity
      chromatography (IMAC) copurification procedure. Dynamic light scattering studies
      indicated that the complexes were more than 85% monodisperse. By electron
      microscopy the negatively stained RAR-RXR-DNA complexes appeared homogeneous and
      corresponded to a dimeric arrangement of the molecules. Using heterodimers
      purified according to this procedure we demonstrate ligand binding of RXR in the
      context of the RAR-RXR heterodimer-DNA complex. The present copurification
      procedure is rapid and has yielded high quality heterodimer-DNA complexes
      suitable for both structural and biochemical studies.

PMID- 10419827
TI  - Use of the green fluorescent protein variant (YFP) to monitor MetArg human
      proinsulin production in Escherichia coli.
AB  - Green fluorescent protein (GFP), a relatively new reporter gene, is making an
      impact on many aspects of science. The attributes of GFP could also be applied to
      the area of recombinant protein production. The work described here represents
      the first experiments using GFP as a tool to monitor recombinant protein
      production in real time in the fermentation process. We have constructed plasmids
      containing an operon fusion of the gene encoding MetArg-human proinsulin and
      reporter gene GFP (GFP, BFP, and YFP variants). The MetArg-proinsulin and GFP
      variant reporter protein were overexpressed in Escherichia coli BL21(DE3) after
      isopropyl beta-d-thiogalactoside induction. The MetArg-proinsulin to YFP protein
      ratio did not change in the cells during the bioprocess. Since there is a
      quantitative relationship between the level of MetArg-proinsulin concentration
      and YFP fluorescence, it is possible to measure only YFP fluorescence in order to
      monitor the production of MetArg-proinsulin during the bioprocess. The expression
      level of MetArg-proinsulin could reach 20-25%. Some 140 mg recombinant MetArg
      human proinsulin could be obtained easily from 1 liter of fermentation medium.
      The MetArg-proinsulin could simply be changed into human insulin by trypsin and
      carboxypeptidase B treatment in later steps. These experiments provide
      possibilities for using the YFP reporter gene as a convenient tool to monitor
      protein expression in biotechnological processes. The proposed technique could
      reduce the time- and labor-intensive analysis of protein production and would
      improve the efficiency of process development.

PMID- 10419828
TI  - Expression of human gelatinase B in Pichia pastoris.
AB  - Full-length human gelatinase B (FLGelB) and its C-terminal truncated form (dGelB)
      were expressed in Pichia pastoris strain GS115, using the Saccharomyces
      cerevisiae Mat alpha signal peptide. In both cases, a high level of the secreted
      protein could be detected by SDS-PAGE. The truncated gene was also expressed
      using the human gelatinase B native signal peptide. Secretion using the Mat alpha
      signal peptide was significantly greater than that from the native signal
      peptide. The recombinant products were purified and characterized biochemically.
      The recombinant proteins, FLGelB and dGelB, were found to have similar
      biochemical properties and activity to that of the human gelatinase B native
      protein.

PMID- 10419829
TI  - Penicillin-binding protein 2a of Streptococcus pneumoniae: expression in
      Escherichia coli and purification and refolding of inclusion bodies into a
      soluble and enzymatically active enzyme.
AB  - Penicillin-binding proteins (PBPs), targets of beta-lactam antibiotics, are
      membrane-bound enzymes essential for the biosynthesis of the bacterial cell wall.
      PBPs possess transpeptidase and transglycosylase activities responsible for the
      final steps of the bacterial cell wall cross-linking and polymerization,
      respectively. To facilitate our structural studies of PBPs, we constructed a 5'
      truncated version (lacking bp from 1 to 231 encoding the N-terminal part of the
      protein including the transmembrane domain) of the pbp2a gene of Streptococcus
      pneumoniae and expressed the truncated gene product as a GST fusion protein in
      Escherichia coli. This GST fusion form of PBP2a, designated GST-PBP2a*, was
      expressed almost exclusively as inclusion bodies. Using a combination of high-
      and low-speed centrifugation, large amounts of purified inclusion bodies were
      obtained. These purified inclusion bodies were refolded into a soluble and
      enzymatically active enzyme using a single-step refolding method consisting of
      solubilization of the inclusion bodies with urea and direct dialysis of the
      solubilized preparations. Using these purification and refolding methods,
      approximately 37 mg of soluble GST-PBP2a* protein was obtained from 1 liter of
      culture. The identity of this refolded PBP2a* protein was confirmed by N-terminal
      sequencing. The refolded PBP2a*, with or without the GST-tag, was found to bind
      to BOCILLIN FL, a beta-lactam, and to hydrolyze S2d, an analog of the bacterial
      cell wall stem peptides. The S2d hydrolysis activity of PBP2a* was inhibited by
      penicillin G. In conclusion, using this expression system, and the purification
      and refolding methods, large amounts of the soluble GST-PBP2a* protein were
      obtained and shown to be enzymatically active.

PMID- 10419830
TI  - Purification of granulin-like polypeptide from the blood-sucking leech, Hirudo
      nipponia.
AB  - A cysteine-rich (approximately 20%), low molecular weight (MW 6 kDa) polypeptide
      has been isolated from the Korean blood-sucking leech, Hirudo nipponia. From its
      amino acid composition and N-terminal amino acid sequence analysis, the new
      protein is similar to granulin (or epithelin), and so it has been named leech
      granulin. The leech granulin behaved as a thrombin inhibitor in the purification
      steps of size-exclusion, ion-exchange, chromatofocusing, and reverse-phase high
      performance liquid chromatography. The leech granulin is an acidic peptide (pI
      3.75) containing high cysteine residues with a unique sequence similar to
      granulins or epithelins isolated from other organisms. For the first time, a
      granulin-like polypeptide having thrombin inhibitory activity has been isolated
      from a leech species.

PMID- 10419831
TI  - Production of chemokines CTAPIII and NAP/2 by digestion of recombinant ubiquitin
      CTAPIII with yeast ubiquitin C-terminal hydrolase and human immunodeficiency
      virus protease.
AB  - Recombinant yeast ubiquitin C-terminal hydrolase (YUH1), which has an N-terminal
      (His)(6) tag, and an autolysis-resistant mutant of the human immunodeficiency
      virus-1 protease (HIV-1 Pr) have been used as specific proteases to yield
      peptides from a ubiquitin conjugate. In the present example, connective tissue
      activating peptide (CTAPIII) and neutrophil-activating peptide 2 (NAP/2) were
      generated by digestion of a ubiquitin-CTAPIII conjugate with YUH1 and HIV Pr,
      respectively, as indicated below: [see text] YUH1 cleaved at the peptide bond
      formed by the C-terminal Gly(76) of ubiquitin (Ub) and the N-terminal Asn(1) of
      the 85-residue peptide CTAPIII. The HIV-1 Pr cleaved between Tyr(15) and Ala(16),
      the N-terminal Ala of the 70-residue peptide NAP/2. Both enzymes produced
      authentic peptides from the Ub fusion protein, with a nearly 100% yield. The
      liberated CTAPIII and NAP/2 were separated from (His)(6)-Ub, the trace amounts of
      unreacted (His)(6)-Ub-CTAPIII, HIV-1 Pr, and the (His)(6)-YUH1 by passage over a
      nickel-chelate column; the final yield was about 10 mg of peptide/liter of cell
      culture. (His)(6)-YUH1, the HIV Pr mutant, and the (His)(6)-Ub-CTAPIII substrate
      were all expressed individually in Escherichia coli. (His)(6)-YUH1 and (His)(6)
      Ub-CTAPIII were highly expressed in a soluble form, but about 75% of the total
      (His)(6)-YUH1 was also found in inclusion bodies. Both proteins from the soluble
      fractions were easily purified in a single step by immobilized metal ion affinity
      chromatography with a yield of about 27 mg of (His)(6)-Ub-CTAPIII and 13.6 mg of
      (His)(6)-YUH1 protein/liter of cell culture. Chemotactic factor activity, as
      assessed by the neutrophil shape change assay, was observed for NAP/2, but not
      for CTAPIII. This strategy, which employs YUH1 and the HIV-1 Pr as tools for the
      highly selective cleavage of the chimeric substrate, should be applicable to the
      large-scale production of a variety of peptides.

PMID- 10419832
TI  - A modified procedure for fast purification of T7 RNA polymerase.
AB  - The in vitro T7 transcription system allows one to synthesize biochemical amounts
      of RNA molecules functionally equivalent or similar to those transcripts normally
      existing at extremely low levels in vivo. In this study we described a modified
      method for efficient large-scale preparation of pure T7 RNA polymerase free of
      RNase activity from the recombinant Escherichia coli strain BL21/pAR1219 (4). The
      procedure, which used preparative column chromatography on DEAE-Sepharose CL-6B
      and Blue 3GA, was shown to be simple, rapid, and cost effective in comparison
      with other methods reported previously.

PMID- 10419833
TI  - High-level expression and purification of biologically active recombinant
      pokeweed antiviral protein.
AB  - Pokeweed antiviral protein (PAP) from the leaves of the pokeweed plant,
      Phytolacca americana, is a naturally occurring single-chain ribosome-inactivating
      protein, which catalytically inactivates both prokaryotic and eukaryotic
      ribosomes. The therapeutic potential of PAP has gained considerable interest in
      recent years due to the clinical use of native PAP as the active moiety of
      immunoconjugates against cancer and AIDS. The clinical use of native PAP is
      limited due to inherent difficulties in obtaining sufficient quantities of a
      homogenously pure and active PAP preparation with minimal batch to batch
      variability from its natural source. Previous methods for expression of
      recombinant PAP in yeast, transgenic plants and Escherichia coli have resulted in
      either unacceptably low yields or were too toxic to the host system. Here, we
      report a successful strategy which allows high level expression of PAP as
      inclusion bodies in E. coli. Purification of refolded recombinant protein from
      solubilized inclusion bodies by size-exclusion chromatography yielded
      biologically active recombinant PAP (final yield: 10 to 12 mg/L). The ribosome
      depurinating in vitro N-glycosidase activity and cellular anti-HIV activity of
      recombinant PAP were comparable to those of the native PAP. This expression and
      purification system makes it possible to obtain sufficient quantities of
      biologically active and homogenous recombinant PAP sufficient to carry out
      advanced clinical trials. To our knowledge, this is the first large-scale
      expression and purification of biologically active recombinant PAP from E. coli.

PMID- 10419835
TI  - Hepatocyte growth factor inhibits amiloride-sensitive Na(+) channel function in
      cystic fibrosis airway epithelium in vitro.
AB  - Cystic fibrosis (CF) airway epithelial cells have a reduced cAMP-dependent Cl(
      )conductance channel (CFTR) function but an increased level of amiloride
      sensitive Na(+)channel (ENaC) activity. Recently, expression of the alpha 
      subunit of the ENaC protein complex was shown to be down-regulated by activation
      of the extracellular signal-regulated protein kinase (ERK) pathway. In the
      present study we have examined the actions of a potent regulator of the ERK
      pathway, recombinant human hepatocyte growth factor (rhHGF), on the function of
      ENaC in confluent, polarized monolayers of both primary cultures of CF airway
      cells and an SV40-transformed CF nasal epithelial cell line (JME CF/15).
      Treatment of JME/CF 15 cells with rhHGF at concentrations of 100 ng/ml and above
      was found to dramatically decrease the activity of amiloride-sensitive
      Na(+)transport. This effect required basolateral exposure of the cytokine.
      Addition of 100 ng/ml rhHGF to JME/CF 15 cells decreased I(eq)with a t(1/2)of;18
      h, with a maximal inhibition of;90% by 36 h. By 48 h, stimulation with rhHGF
      induced a down-regulation of its receptor, c-met, expressed in these cells. The
      decrease in I(eq)of JME/CF 15 monolayers was not immediately reversed upon
      removal of rhHGF. Treatment with rhHGF did not appear to affect monolayer
      resistances nor Cl(-)currents induced by mediators such as isoproterenol,
      histamine or bradykinin. Studies with primary cultures of CF airway cell sheets
      demonstrated comparable sensitivity and time-course properties for the inhibition
      of amiloride-sensitive currents following rhHGF addition. These observations are
      consistent with the possible application of an extracellular signalling molecule,
      such as the cytokine HGF, to reduce the abnormally high activity of amiloride
      sensitive Na(+)ion channels observed in CF airway cells.

PMID- 10419834
TI  - Leukotoxins and the lung.

PMID- 10419836
TI  - Comparative effects of betamethasone, cyclosporin and nedocromil sodium in acute
      pulmonary inflammation and metalloproteinase activities in bronchoalveolar lavage
      fluid from mice exposed to lipopolysaccharide.
AB  - Matrix metalloproteinases (MMPs) are particularly potent in degrading basement
      membrane collagen associated with lung injury in inflammatory processes. We have
      investigated the effects of betamethasone, cyclosporin, and nedocromil on MMP2
      and MMP9 activities, on TNF-alpha and IL-10 release, as well as on the
      recruitment of inflammatory cells in the bronchoalveolar lavage (BAL) fluid after
      aerosol administration of lipopolysaccharide (LPS) in mice. When mice were
      pretreated with betamethasone (5 mg/kg, po), MMP2 and MMP9 activities, TNF-alpha
      in BAL fluids, and the enhanced neutrophil number of LPS-exposed mice were
      reduced, whereas the level of IL-10 was increased. Pretreatment of mice with
      cyclosporin (10 mg/kg, po) did not significantly reduce MMP activities, but
      cyclosporin inhibited neutrophil recruitment, inhibited increase TNF- alpha and
      inhibited IL-10 decrease. Nedocromil sodium (30 mg/kg, ip) had no influence on
      the LPS-induced MMP activities, on neutrophil recruitment, or on IL-10 level, but
      this drug elicited a significant inhibition of TNF- alpha level. These results
      showed that treatment with the antiinflammatory drugs cyclosporin and nedocromil
      sodium did not lead to reduction of MMP release. However, since betamethasone
      reduced the LPS-induced pulmonary inflammation and production of MMPs, these
      results suggest that corticosteroids may decrease tissue remodelling associated
      with acute lung injury.

PMID- 10419837
TI  - Repeat measurement of respiratory mechanics using the forced oscillation
      technique in non-paralysed rats.
AB  - The present study has established a method for obtaining low-frequency forced
      oscillation measurements of lung mechanics in the absence of neuromuscular
      blockade in the rat. Increasing the ventilation rate of the animals inhibited the
      spontaneous breathing of the animals for a short period of time; enough to make
      the low-frequency forced oscillation measurements of lung mechanics without the
      need for paralysis of the animals. Using this technique, it was possible to show
      that neuromuscular blockade with pancuronium bromide (0.4 mg/kg iv) resulted in a
      significant inhibition of methacholine responses in the parenchymal, but not the
      airway components of the rat lung. In studies where the animals were examined in
      a repeated manner, there was no significant difference in methacholine responses
      on day 3 compared with those obtained on day 1. Similarly, in animals that were
      both challenged with methacholine and lavaged, there was no significant
      difference in the methacholine responses or in the total and differential cell
      numbers obtained from the bronchoalveolar lavage fluid. Thus, this study presents
      a technique for obtaining low-frequency forced oscillation estimates of lung
      mechanics in non-paralysed rats and allows for repeated measures to be made in
      the same animals. In addition, this study has demonstrated that neuromuscular
      blockade has differential effects on methacholine responses in different parts of
      the lung.

PMID- 10419838
TI  - Pharmacokinetic/pharmacodynamic modelling of the eosinopenic and hypokalemic
      effects of formoterol and theophylline combination in healthy men.
AB  - Interactions of formoterol and theophylline were evaluated with the use of
      pharmacokinetic-pharmacodynamic (PK/PD) modelling. Oral doses of 144 microg of
      formoterol and 375 mg of theophylline were given separately or combined to
      healthy subjects. As effect parameters, plasma eosinophil and potassium
      concentrations were used. Kinetic interactions between formoterol and
      theophylline were not found. Plasma drug concentrations were linked to the
      observed effects via an effect compartment model with a sigmoid E max model. The
      E max values+/-SD for the hypokalemic effects were 2.29+/-0.78 mmol/l for
      formoterol and 1.64+/-1.16 mmol/l for theophylline (P>0.05). The E max values for
      the eosinopenic effects were fixed at zero. The EC 50 values of the eosinopenic
      and hypokalemic effects were respectively 91.4+/-38.2 pg/ml and 128.4+/-52.9
      pg/ml for formoterol, and 11. 9+/-4.6 microg/ml and 15.5+/-4.8 microg/ml for
      theophylline. Effects of both drugs combined were described with a non
      competitive interaction model. The correlation coefficients of the fits of the
      eosinopenic and hypokalemic effects were respectively 0.9520+/-0. 0311 and
      0.9371+/-0.0227, supporting our hypothesis of non-competitive interaction.

PMID- 10419839
TI  - Effects of early treatment with rSP-C surfactant on oxygenation and histology in
      rats with acute lung injury.
AB  - Surfactant treatment in patients with acute respiratory distress syndrome (ARDS)
      may be a promising treatment strategy. The aim of this study was to investigate
      whether addition of a recombinant surfactant protein C (rSP-C) to a plain
      phospholipid (PL) surfactant (PL surfactant) can result in activity comparable to
      commercially available surfactant preparations (Alveofact and bLES) which contain
      surfactant protein B and C. In this investigation dose-response comparisons of
      four surfactants were performed in an animal model of ARDS induced by total lung
      lavage. The surfactants were given shortly (;10 min) after the last lavage. The
      effects of surfactant treatment were compared with respect to improve oxygenation
      and to prevent histopathological changes, such as hyaline membrane formation. The
      surfactants were compared to lavaged, untreated controls. The surfactants were
      administered at doses of 25, 50 and 100 mg total amount of phospholipids/kg body
      weight. At 120 min after early treatment, all three doses of rSP-C surfactant
      showed statistically significant higher improvements in oxygenation than PL
      surfactant. This improvement was comparable to bLES and superior to Alveofact.
      The rSP-C surfactant showed the most prominent effect on preventing hyaline
      membrane formation. It was again superior to PL surfactant and comparable to
      bLES. It is concluded that addition of rSP-C enhances the activity of a pure PL
      surfactant. The rSP-C surfactant showed comparable or even superior activity to
      bovine-derived surfactant preparations containing both, SP-B and SP-C.

PMID- 10419840
TI  - The effect of chronic hypoxia on endothelin receptor subtype-mediated responses
      in rat isolated airways.
AB  - Contractile responses to endothelin-1 (ET-1) were investigated in isolated
      trachea from rats previously exposed to chronic hypoxia (10% O(2)) or room air
      for 14 days. Concentration-response curves were constructed to ET-1 (10(-11)
      3x10(-7)m ) in the presence and absence of the ET(A)receptor antagonist FR 139317
      (10(-8), 10(-7)and 10(-6)m ), the ET(B)receptor antagonist BQ 788 (10(-6)and
      3x10(-6)m ), the non-selective ET receptor antagonist SB 209670 (10(-7)and 10(
      6)m ) and a combination of FR 139317 (10(-6)m ) and BQ 788 (10(-6)m ).
      Concentration-response curves were also conducted to the ET(B)receptor agonist
      sarafotoxin S6c (10(-11)-3x10(-7)m ). In addition, responses to ET-1 (10(-11)
      3x10(-7)m ) were examined in the presence and absence of the nitric oxide
      synthase inhibitor, L-NAME. In control rat trachea, both FR 139317 and BQ 788
      failed to inhibit ET-1-induced contractions and, indeed, FR 139317 (10(-8)m ) and
      BQ 788 actually potentiated responses. In trachea from chronic hypoxic rats, FR
      139317 did not alter ET-1 responses whereas BQ 788 again potentiated ET-1-induced
      contractions. The non-selective ET receptor antagonist SB 209670 attenuated ET-1
      evoked contractions in trachea from control and chronically hypoxic rats. A
      combination of FR 139317 (10(-6)m ) and BQ 788 (10(-6)m ) also attenuated ET-1
      responses in control rat trachea, but not trachea from chronically hypoxic rats.
      In trachea from both control and chronically hypoxic rats, L-NAME significantly
      potentiated responses to ET-1. To investigate ET receptor-mediated relaxation,
      tissues were preconstricted with methacholine and concentration-response curves
      were conducted to ET-1 (10(-13)-10(-8)m ) in the presence and absence of BQ 788
      (10(-6)m ) and to the ET(B)receptor agonist sarafotoxin S6c (10(-13)-10(-8)m ).
      In trachea from control and chronic hypoxic rats, ET-1 and sarafotoxin S6c evoked
      only very small, non-reproducible relaxatory responses.

PMID- 10419841
TI  - Apoptosis: a potential target for discovering novel therapies for cardiovascular
      diseases.
AB  - The realization that apoptosis is genetically programmed raises the exciting
      prospect that modulating apoptosis may provide novel approaches for treatment of
      cardiovascular diseases in which apoptosis has been demonstrated. Low molecular
      weight inhibitors of caspases and mitogen-activated protein kinases have been
      evaluated, with promising results in a variety of cardiovascular apoptotic
      models.

PMID- 10419842
TI  - Cannabinoids, endogenous ligands and synthetic analogs.
AB  - The investigation of natural and synthetic cannabinoid ligands, including (-)
      Delta(9)-tetrahydrocannabinol, cannabinol, cannabidiol, HU-210, HU-211, CT3, CP
      55, 940, WIN 55, 212-2, SR 14, 1716A, anandamide, 2-arachidonoylglycerol, and
      numerous novel analogs, has led to important findings that have contributed to a
      better understanding of the role of these compounds in physiological processes.
      Their potential use for medicinal purposes is also better understood as a result.

PMID- 10419843
TI  - Pharmacokinetics and metabolism in early drug discovery.
AB  - The need for high-throughput approaches in absorption, distribution, metabolism
      and excretion studies is driven by the impact of high-speed chemistry and
      pharmacological screening. Perhaps an even greater impact is that these studies
      will, in the future, provide large data sets that can be used to predict
      biological events related to absorption, bioavailability and metabolism of drugs.
      Through linking of in silico and in vitro methods, considerable progress has
      recently been made towards this future perspective. Despite this progress, these
      approaches do not yet replace in vivo methods.

PMID- 10419844
TI  - The development and therapeutic potential of protein kinase inhibitors.
AB  - A number of small cell-permeant protein kinase inhibitors have been developed
      that have the potential for treating a variety of diseases. The basis for the
      specificity of several of these drugs has been elucidated and a number are
      undergoing human clinical trials.

PMID- 10419845
TI  - Nonpeptidic ligands for peptide and protein receptors.
AB  - The first potent nonpeptidic ligands for somatostatin, luteinizing hormone
      releasing hormone, glucagon and bradykinin receptors have been reported.
      Nonpeptidic clinical candidates have been identified or are currently under study
      for substance P, bradykinin, endothelin, growth hormone secretagogue,
      angiotensin, vasopressin, motilin and cholecystokinin. Design, screening,
      combinatorial chemistry and classical medicinal chemistry all played important
      roles in these advances.

PMID- 10419846
TI  - Chemoinformatics--a new name for an old problem?
AB  - Library chemistry and high-throughput screening require greater use of
      chemoinformatics to increase their effectiveness. Recent advances in
      chemoinformatics include new molecular descriptors and pharmacophore techniques,
      statistical tools and their applications. Visualisation methods and hardware
      development are also opening new opportunities. The advent of a chemically aware
      web language and cross-platform working is ensuring that chemoinformatics methods
      are becoming available to all chemists in a more appropriate manner. Much time
      will continue to be wasted with incompatible file types without internationally
      agreed standards.

PMID- 10419847
TI  - Hormone replacement therapy.
AB  - Hormone replacement therapy is increasingly being used for purposes unrelated to
      the alleviation of menopausal symptoms, such as the prevention of osteoporosis
      and cardiovascular disease. Clinical trials, however, suggest that the one
      drug/many purposes concept may be too optimistic. The availability of new
      estrogen-like compounds and the discovery of a second estrogen receptor have
      opened new possibilities for more specific drug development.

PMID- 10419848
TI  - Metabotropic G-protein-coupled glutamate receptors as therapeutic targets.
AB  - Metabotropic glutamate receptors have received considerable attention over the
      past decade in view of their relevance in multiple aspects of glutamatergic
      transmission. Recent advances in the molecular biology, pharmacology and
      medicinal chemistry of this family of G-protein-coupled receptors have led to
      therapeutic opportunities for subtype-selective modulators in brain disorders and
      diseases such as ischemia and schizophrenia.

PMID- 10419849
TI  - Novel strategies for pharmacotherapy of depression.
AB  - Modulating monoamine activity as a therapeutic strategy continues to dominate
      antidepressant research, with a recent emphasis on agents with multiple targets,
      including combined serotonin/noradrenaline re-uptake inhibitors and numerous
      serotonin receptor ligands. An important new development has been the emergence
      of potential novel mechanisms of action, notably modulation of the activity of
      neuropeptides substance P and corticotrophin-releasing factor, and the
      intracellular messenger cyclic adenosine monophosphate. Efforts in this area have
      recently been rewarded by the demonstration of antidepressant efficacy of the
      substance P receptor antagonist MK-0869.

PMID- 10419850
TI  - New targets for anti-inflammatory drugs.
AB  - Inflammatory and autoimmune diseases, including rheumatoid arthritis,
      inflammatory bowel diseases, multiple sclerosis, psoriasis and asthma, provide
      drug discoverers with a tremendous challenge. The precise causes of these
      diseases are not known, but our understanding of the molecular and cellular
      mechanisms associated with inflammatory diseases has increased dramatically. As a
      consequence, a wide array of gene targets have emerged that control cell influx
      and activation, inflammatory mediator release and activity, and tissue
      proliferation and degradation. Since multiple gene products have been identified
      at the sites of inflammation, there has been a surge of interest in identifying
      intracellular signaling targets, including transcription factors that control
      inflammatory gene expression and which are amenable to drug discovery.

PMID- 10419851
TI  - Pharmacology of voltage-gated and calcium-activated potassium channels.
AB  - Several important new findings have furthered the development of voltage-gated
      and calcium-activated potassium channel pharmacology. The molecular constituents
      of several members of these large ion channel families were identified. Small
      molecule modulators of some of these channels were reported, including
      correolide, the first potent, small-molecule, natural product inhibitor of the
      Shaker family of voltage-gated potassium channels to be disclosed. The initial
      crystal structure of a bacterial potassium channel was determined; this work
      gives a physical basis for understanding the mechanisms of ion selectivity and
      ion conduction. With the recent molecular characterization of a potassium channel
      structure and the discovery of new templates for channel modulatory agents, the
      ability to rationally identify and develop potassium channel agonists and
      antagonists may become a reality in the near future.

PMID- 10419852
TI  - Muscarinic receptor ligands and their therapeutic potential.
AB  - Over the past year, the introduction of novel ligands has accelerated the
      classification of muscarinic receptor subtypes and has led to a better
      understanding of their physiological role. Important in this respect is the
      recent recognition of the exquisite selectivity of a series of snake toxins,
      enabling better definition of the muscarinic subtype 4 receptor. Moreover,
      several compounds, both agonists and antagonists, are progressing in advanced
      clinical trials for the treatment of several conditions, including Alzheimer's
      disease, pain, urinary incontinence and chronic obstructive pulmonary disease.

PMID- 10419853
TI  - Interfering with chemokine networks--the hope for new therapeutics.
AB  - Chemokines are a large family of cytokines with a wide variety of biological
      actions. Originally, they were identified as controllers of the routine
      trafficking of immune cells, and directed migration of cells during inflammatory
      response - from which they get their name, a contraction of chemotactic
      cytokines. They are now also known to be active in angiogenesis, embryonic
      development and infection by viruses such as HIV-1. Studies with antibodies,
      modified chemokine and transgenic mice suggest that chemokine receptor
      antagonists may be selective anti-inflammatory, antiviral or immunomodulatory
      agents. Small-molecule antagonists of seven of the receptors have been reported,
      some with potency in the low nanomolar range. These compounds are shown to be
      active in cell biology assays; the next step will be to determine their efficacy
      in animal models of disease.

PMID- 10419854
TI  - Novel anticancer drug discovery.
AB  - There is at present, much optimism about the possibility of finding selective
      anticancer drugs that will eliminate the cytotoxic side effects associated with
      conventional cancer chemotherapy. This hope is based on uncovering many novel
      molecular targets that are 'cancer-specific', which will allow the targeting of
      cancer cells while normal cells are spared. Thus far, encouraging results have
      been obtained with several of these novel agents at the preclinical level, and
      clinical trials have begun. These targets are involved at one level or more in
      tumor biology, including tumor cell proliferation, angiogenesis and metastasis.
      Novel targets for which advances are being made include the following: growth
      factor receptor tyrosine kinases such as the epidermal growth factor receptor and
      HER-2/neu (proliferation); the vascular endothelial growth factor receptor and
      the basic fibroblast growth factor receptor (angiogenesis); the oncogenic GTP
      binding protein Ras (especially agents targeting Ras farnesylation,
      farnesyltransferase inhibitors) (proliferation); protein kinase C (proliferation
      and drug resistance); cyclin-dependent kinases (proliferation); and matrix
      metalloproteinases and angiogenin (angiogenesis and metastasis). Less explored,
      but potentially useful targets include the receptor tyrosine kinase platelet
      derived growth factor receptor, mitogen-activated protein kinase cascade
      oncogenes such as Raf-1 and mitogen-activated protein kinase kinase, cell
      adhesion molecules such as integrins, anti-apoptosis proteins such as Bcl-2, MDM2
      and survivin, and the cell life-span target telomerase.

PMID- 10419855
TI  - Positron emission tomography neuroreceptor imaging as a tool in drug discovery,
      research and development.
AB  - Improved communication and cooperation between research-driven drug companies and
      academic positron emission tomography (PET) centers, coupled with improvements in
      PET camera resolution, the availability of small animal PET cameras and a growing
      list of neuroreceptor-specific PET tracers, have all contributed to a substantial
      increase in the use and value of PET as a tool in central nervous system drug
      discovery and development.

PMID- 10419856
TI  - Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents.
AB  - Preclinical and clinical studies of phosphodiesterase 4 inhibitors have shown
      that these agents may find utility in a wide range of inflammatory disorders,
      including asthma, chronic obstructive pulmonary disease, atopic dermatitis,
      rheumatoid arthritis, multiple sclerosis and various neurological disorders. The
      future of this class of drugs will depend upon the ability to demonstrate a
      reasonable safety margin against emesis and other typical phosphodieserase (PDE4)
      side effects, as well as in identification of the inflammatory disorder(s) most
      relevant to PDE4 inhibition.

PMID- 10419857
TI  - Ionotropic glutamate receptors.
AB  - The glutamate-binding sites of ionotropic glutamate receptors are formed from two
      extracellular domains of a single subunit. Conformational changes induced by
      agonist binding produce mechanical processes that are translated into ion gating
      and receptor desensitization. The interactions between macromolecular assemblies
      of synaptic proteins and ionotropic glutamate receptors, and their subsequent
      roles in receptor clustering and specificity are being elucidated. Kainate
      receptor pharmacology is finally revealing its secrets as a result of the
      availability of selective pharmacological agents.

PMID- 10419858
TI  - Recognizing molecules with drug-like properties.
AB  - A variety of successful approaches to the problem of recognizing 'drug-like'
      molecules have been employed. These range from simple counting schemes such as
      the Lipinski 'rule of five' to the analysis of the multidimensional 'chemistry
      space' occupied by drugs, to neural network learning systems. With this variety
      of tools, it now appears possible to design libraries that are enriched in
      compounds which have desirable or 'drug-like' properties. Verifying the
      robustness of these methods, and extending them, will form the basis of research
      in this field during the next few years.

PMID- 10419860
TI  - Chemical biology 

PMID- 10419859
TI  - Next generation therapeutics.

PMID- 10419861
TI  - Next generation therapeutics 

PMID- 10419863
TI  - Polymyalgia and low back pain: a common cause not to be missed.

PMID- 10419862
TI  - Mechanisms of viral pathogenesis in rheumatic disease.

PMID- 10419865
TI  - Pregnancy and early onset pauciarticular juvenile chronic arthritis.
AB  - OBJECTIVES: To study interaction of early onset pauciarticular juvenile chronic
      arthritis (EOP-JCA) and pregnancy in the Polish population, in particular to
      confirm the ameliorating effect of pregnancy on disease activity reported by
      others and to analyse the factors that govern the occurrence of postpartum flare,
      with emphasis on the potential role of breast feeding. METHODS: The reproductive
      outcome and disease status in 39 adult women with history of EOP- JCA was
      examined by means of a questionnaire and an interview. In all patients the
      disease onset occurred before the 6th birthday, 19 had persistent pauciarticular
      JCA (PeEOP-JCA) and 20 had extended pauciarticular JCA (ExEOP-JCA). RESULTS: 23
      women had at least one successful pregnancy, seven had unsuccessful pregnancies
      but all of them had also one or more successful pregnancies. Among those who have
      never been pregnant (n=16) there was a higher frequency of eye disease and ExEOP
      JCA compared with the rest of the group. In almost all cases pregnancy was
      associated with remission of disease activity, however a postpartum flare
      appeared after 22 pregnancies (52%). The flares were more frequent in women who
      had an active disease before pregnancy, had a flare after a previous pregnancy
      and/or were breast feeding. CONCLUSIONS: In EOP-JCA patients pregnancy generally
      has a good outcome and induces amelioration of disease activity. After delivery,
      however, a flare of disease often appears, especially in women who were breast
      feeding, had a postparum flare previously or had an active disease before
      pregnancy. The pattern of interaction between disease and pregnancy found in EOP
      JCA makes EOP-JCA similar in this respect to RA, but different from systemic
      lupus erythematosus and ankylosing spondylitis.

PMID- 10419864
TI  - Treatment of oral dryness related complaints (xerostomia) in Sjogren's syndrome.

PMID- 10419866
TI  - Abnormal autonomic cardiovascular control in ankylosing spondylitis.
AB  - OBJECTIVE: This study was aimed at assessing the contribution of the autonomic
      nervous system to adjustments of cardiovascular function in patients with
      ankylosing spondylitis (AS). METHODS: In 18 AS patients (mean age: 34.9; mean
      disease duration: 6.4 years) and 13 healthy controls (mean age: 31.7) the changes
      of heart rate (HR) with deep breathing (E/I ratio) and standing up (30/15 ratio)
      were recorded. The slope of cardiac baroreflex, the times series of blood
      pressure and HR values upon lying and standing, and venous plasma concentrations
      of catecholamines were also analysed. Erythrocyte sedimentation rate (ESR),
      plasma C reactive protein (CRP) concentration and a clinical index (BASDAI score)
      were used to assess the degree of disease activity in patients. RESULTS: In the
      standing patients, blood pressure was found to decrease progressively (p< 0.001).
      Furthermore, the patients with a BASDAI score > 5 had a higher heart rate than
      patients with a BASDAI score < 5 (p<0.02), and there was a trend for a similar
      difference when patients were classified according to their ESR and CRP. Plasma
      catecholamine concentrations and the E/I ratio were not different in patients
      from controls. The 30/15 ratio and the slope of the spontaneous baroreflex during
      standing were both lower in AS patients than controls (p< 0.01). CONCLUSIONS:
      This study demonstrated a change in autonomic nervous system function of AS
      patients, with a decreased parasympathetic activity, as evidenced by higher HR
      and lower baroreflex slope. As these significant deviances were mainly observed
      in patients with more active (or more inflammatory) disease, the autonomic
      nervous system involvement could be related to the inflammatory process. This
      autonomic strain may be related to the cardiac involvement in AS patients.

PMID- 10419868
TI  - Quantitative analysis of synovial membrane inflammation: a comparison between
      automated and conventional microscopic measurements.
AB  - OBJECTIVE: The objective of this study was to quantify selected features of
      chronic synovial tissue inflammation by computerised image analysis and to
      validate the results by comparison with conventional microscopic measurements.
      METHODS: Synovial biopsy samples were obtained from the knee joints of patients
      with chronic arthritis and prepared for immunohistochemical analysis using
      standard techniques. Following the development of special software, four
      parameters of chronic synovial inflammation were evaluated: intimal layer
      thickness, CD3+ cell infiltration, CD8+ cell infiltration and vascularity.
      Intimal layer thickness was expressed in microns. The intensity of CD3+ and CD8+
      cell infiltration was expressed as the percentage area of the tissue section
      occupied by positively stained cells. Vascularity was expressed as the percentage
      area occupied by blood vessels. Conventional quantitative microscopic analysis
      was also undertaken and the results from both methods compared. RESULTS: Seventy
      eight tissue sections were selected for study. Measurements of intimal layer
      thickness by both techniques correlated strongly: r = 0.85, p = 0.0006.
      Measurements of CD8+ cell infiltration, usually widely dispersed, also correlated
      well: r = 0.64, p = 0.005. Measurements of CD3+ cell infiltration, often densely
      aggregated, correlated less well: r = 0.55, p = 0.02. Measurements of vascularity
      demonstrated no statistically significant correlation: r = 0.41, p = 0.07.
      Proficiency in the use of computerised image analysis was readily acquired.
      CONCLUSION: Computerised image analysis was successfully applied to the
      measurement of some features of synovial tissue inflammation. Further software
      development is required to validate measurement of blood vessels of variable
      size.

PMID- 10419867
TI  - Soluble urokinase plasminogen activator receptor in plasma of patients with
      inflammatory rheumatic disorders: increased concentrations in rheumatoid
      arthritis.
AB  - OBJECTIVE: Urokinase type plasminogen activator (uPA) catalyses the formation of
      the proteolytic enzyme plasmin, which is involved in matrix degradation in the
      processes of tissue remodelling. Because of a surface bound uPA receptor (uPAR),
      expressed by some cell types (for example, macrophages, malignant cells and
      inflammatory activated synoviocytes), the action of uPA can be localised and
      intensified. uPAR seems to have a role in the mechanisms leading to invasive
      growth of malignant tissue and the rheumatoid pannus. uPAR may become cleaved at
      its cell surface anchor, thus forming a free soluble receptor (suPAR). suPAR is
      detectable in low but constant values in plasma of healthy people, while
      increased concentrations are found in patients with disseminated malignant
      disease, so that suPAR may be an indicator of invasive growth and tissue
      remodelling. suPAR concentrations in plasma have not previously been measured in
      rheumatic patients. A controlled cross sectional measurement was performed of
      suPAR in plasma of patients with various inflammatory rheumatic disorders with
      special reference to rheumatoid arthritis (RA). METHODS: suPAR in plasma was
      measured by ELISA technique in patients with RA (n=51), reactive arthritis (ReA)
      (n=23), primary Sjogren's syndrome (PSS) (n=42) and sex and age matched healthy
      controls (n=53). RESULTS: In the control group suPAR (median) was 0. 91 (range
      0.56-1.94) microg/l. Median suPAR value in RA was 1.47 (range 0.65-6.62)
      microgram/l; in ReA 0.68 microgram/l (range 0.52-1.48) and in PSS 1.12
      microgram/l (range 0.76-1.92); p versus controls <0.001 in all patient groups.
      suPAR values in RA were also significantly increased compared with ReA (p<0.001)
      and PSS (p=0.004) groups. suPAR in RA was positively correlated to C reactive
      protein (CRP) (p<0.01) and erythrocyte sedimentation rate (p<0.05) and number of
      swollen joints (p<0.05). The ReA group had the highest CRP values of all groups,
      but at the same time the lowest suPAR concentrations in plasma. CONCLUSIONS:
      Increased suPAR concentrations were found in plasma in RA, and to a smaller
      extent also in PSS, but not in ReA. In RA suPAR is related to disease activity.
      suPAR seems though not merely to be an acute phase reactant like CRP. Increased
      suPAR values might reflect erosive activity in RA.

PMID- 10419869
TI  - Polymorphic CAG repeats of the androgen receptor gene and rheumatoid arthritis.
AB  - OBJECTIVE: In view of the possible role of androgens in the pathogenesis of
      rheumatoid arthritis (RA), this study investigated the association between repeat
      lengths of CAG microsatellites of the androgen receptor (AR) gene and RA.
      METHODS: The number of CAG repeats in exon 1 of the AR gene was determined in 90
      men and 276 women with RA, as well as in 305 male and 332 female controls.
      RESULTS: The male RA patients tended to have shorter repeats than the male
      controls (22.5 versus 23.1, p=0.07), whereas the female RA patients had similar
      repeats to the female controls (22.7 versus 22.9, p=0.17). Patients of both sexes
      were divided into younger and older age at onset groups, and compared with
      younger and older controls. Younger onset male RA patients had significantly
      shorter CAG repeat lengths than the younger male controls (21.8 versus 23.2,
      p=0.007) or the older onset male RA patients (21.8 versus 23.2, p=0.04). Older
      onset male RA and both younger and older onset female RA patients had similar CAG
      repeat lengths when compared with their controls. Neither seropositivity nor
      rheumatoid nodule positivity had a significant relation with CAG repeat lengths.
      CONCLUSION: Shorter CAG repeats of the AR gene, presenting high levels of
      transactivation activity, are related to younger age onset male RA, suggesting
      the possible role of androgens as a modulating factor.

PMID- 10419870
TI  - Influence of long term silicone implantation on type II collagen induced
      arthritis in mice.
AB  - OBJECTIVES: The use of silicone implants in cosmetic and reconstructive surgery
      has been implicated in the development of autoimmune connective tissue diseases.
      Previous investigation of the influence of short-term silicone implantation using
      an experimental model of rheumatoid arthritis revealed no adverse influence upon
      disease despite the generation of autoantibodies against silicone bound proteins.
      This study was designed to examine the influence of long term implantation of
      different forms of silicone in collagen induced arthritis. METHODS: DBA/1 mice
      were surgically implanted with silicone elastomers, gel or oil nine months before
      immunisation with type II collagen emulsified in Freund's incomplete adjuvant.
      The incidence and severity of arthritis, antibodies to type II collagen, and
      serum cytokines were assessed and compared with sham implanted mice. Silicone
      implants were recovered, and autoantibodies to silicone bound proteins evaluated
      in arthritic and non-arthritic mice. RESULTS: Immunisation with CII/FIA resulted
      in a 30% arthritis incidence in sham implanted DBA/1 mice. Long term silicone
      implantation resulted in an increased incidence of arthritis, with a significant
      increase of 90% arthritis in animals implanted with silicone elastomers. Animals
      implanted with silicone elastomer also developed foreign body sarcomas during the
      study. Serum concentrations of interleukin 10 were increased in mice implanted
      with elastomers and immunised with CII/FIA, while interleukin 5 concentrations
      were significantly diminished in these mice. The production of autoantibodies to
      autologous silicone bound proteins, including anti-type I collagen antibody, was
      also attributed to the implantation of either silicone gel or silicone elastomer
      in type II collagen immunised animals. CONCLUSIONS: These data suggest that long
      term silicone implantation results in both the production of autoantibodies to
      connective tissue antigens and increased susceptibility to an experimental model
      of autoimmune disease.

PMID- 10419871
TI  - Early referral, diagnosis, and treatment of rheumatoid arthritis: evidence for
      changing medical practice.
AB  - OBJECTIVES: To study the delay in starting disease modifying anti-rheumatic drugs
      (DMARDs) in patients with rheumatoid arthritis (RA), and any changes in medical
      practice between 1980 and 1997. METHODS: 198 consecutive RA patients attending
      the rheumatology clinics at a teaching hospital, for routine review, had their
      case sheet reviewed. The dates of symptom onset, general practitioner (GP)
      referral, first clinic appointment and first use of DMARD were recorded. Data
      were collected on the erythrocyte sedimentation rate, C reactive protein,
      rheumatoid factor, and the presence/absence of erosions at the first clinic
      assessment. Patients were split into four groups according to the date of their
      first clinic assessment-before 1986, 1987-9, 1990-3, and 1994-7. RESULTS: There
      was a sharp drop in the delay between symptom onset and GP referral (before 1986,
      21 months; 1987-89, 23 months; 1990-3, 7 months; 1994-7, 4 months, p<0.03), and
      in the delay between first assessment at the rheumatology clinic and the start of
      DMARD treatment (before 1986, 32 months; 1987-89, 21 months; 1990-1993, 8 months;
      1994-7, 1 month, p<0.001). The number of patients given DMARD treatment within
      six months of symptom onset increased from 5% (before 1994) to 44% (1994-7).
      Seventy three per cent of patients waiting more than a year from symptom onset to
      first clinic appointment already had erosive change, compared with 34% of
      patients seen within a year. CONCLUSIONS: Patients are being referred earlier in
      their disease, and DMARDs are prescribed sooner in the disease course. There has
      been a substantial increase in the proportion of patients treated with a DMARD
      within six months of symptom onset.

PMID- 10419872
TI  - Increased level of apolipoprotein B/apolipoprotein A1 ratio as a potential risk
      for osteonecrosis.
AB  - OBJECTIVE: This study was performed to investigate whether a high ratio of
      apolipoprotein B to apolipoprotein A1 (apo B/apo A1 ratio) is significantly
      associated with the risk of developing non-traumatic osteonecrosis of the femoral
      head (ON). METHODS: Fifty consecutive non-traumatic ON cases were compared with
      50 age and sex matched controls, using both univariate and stepwise discriminant
      analyses, regarding the factors of corticosteroid, alcohol, cigarettes,
      cholesterol, triglyceride, and apo B/apo A1 ratio. To eliminate the possibility
      that ON or osteoarthritic change itself can increase the apo B/apo A1 ratio, a
      further 32 consecutive cases comprising nine traumatic ON and 23 osteoarthritis
      (OA) patients were analysed using Scheffe's test. RESULTS: There was a
      significant association between a high apo B/apo A1 ratio and the development of
      non-traumatic ON with both univariate (p=0.0001) and stepwise discriminant
      analyses (partial r(2)=0.1239, p=0.0004). The apo B/apo A1 ratio in the non
      traumatic ON group was significantly higher than that in the traumatic ON
      (p<0.01), control (p<0.001), or the OA groups (p<0.001). CONCLUSION: A high apo
      B/apo A1 ratio is significantly associated with the risk of developing ON. This
      ratio may be useful for assessing the potential risk of developing osteonecrosis.

PMID- 10419873
TI  - Serial analysis of gene expression in human monocytes and macrophages.
AB  - Monocytes/macrophages serve as sentinels involved in chronic inflammation and the
      eradication of various pathogens. To define molecularly the differentiation of
      blood monocytes into macrophages, we conducted serial analysis of gene expression
      (SAGE) in human blood monocytes/macrophages induced by granulocyte-macrophage
      colony-stimulating factor (GM-CSF) or M-CSF. SAGE analysis of 57,560, 57,463, and
      55,856 tags from monocytes, GM-CSF-, and M-CSF-induced macrophages, respectively,
      allowed identification of 35,037 different transcripts. Interestingly, the genes
      with the highest expression during differentiation from monocytes into
      macrophages were genes involved in lipid metabolism. Both CSF-induced macrophages
      expressed similar sets of genes except for several genes such as monocyte-derived
      chemokine (MDC), legumain, prostaglandin D synthetase, and lysosomal
      sialoglycoprotein. The identification of specific gene expression in human
      monocytes, GM-CSF-, or M-CSF-induced macrophages provides novel methods to define
      macrophage subsets and the maturation and activation stage of cells of macrophage
      lineage and, possibly, to diagnose diseases in which macrophages play a major
      role. This study represents the first extensive serial analysis of gene
      expression for any type of human hematopoietic cells.

PMID- 10419874
TI  - Serial analysis of gene expression in human monocyte-derived dendritic cells.
AB  - Dendritic cells (DCs) are professional antigen-presenting cells in the immune
      system and can be generated in vitro from hematopoietic progenitor cells in the
      bone marrow, CD34(+) cord blood cells, precursor cells in the peripheral blood,
      and blood monocytes by culturing with granulocyte-macrophage colony-stimulating
      factor (GM-CSF), interleukin-4, and tumor necrosis factor-alpha. We have
      performed serial analysis of gene expression (SAGE) in DCs derived from human
      blood monocytes. A total of 58,540 tag sequences from a DC complementary DNA
      (cDNA) library represented more than 17,000 different genes, and these data were
      compared with SAGE analysis of tags from monocytes (Mo) and GM-CSF-induced
      macrophages (M open diamond). Many of the genes that were differentially
      expressed in DCs were identified as genes encoding proteins related to cell
      structure and cell motility. Interestingly, the highly expressed genes in DCs
      encode chemokines such as TARC, MDC, and MCP-4, which preferentially chemoattract
      Th2-type lymphocytes. Although DCs have been considered to be very heterogeneous,
      the identification of specific genes expressed in human Mo-derived DCs should
      provide candidate genes to define subsets of, the function of, and the maturation
      stage of DCs and possibly also to diagnose diseases in which DCs play a
      significant role, such as autoimmune diseases and neoplasms. This study
      represents the first extensive gene expression analysis in any type of DCs.

PMID- 10419875
TI  - Requirement of activation of JNK and p38 for environmental stress-induced
      erythroid differentiation and apoptosis and of inhibition of ERK for apoptosis.
AB  - C-Jun amino terminal kinase/stress-activated protein kinases (JNK/SAPK) and p38
      subgroups of mitogen-activated protein kinases have been suggested to play a
      critical role in apoptosis, cell growth, and/or differentiation. We found that a
      short exposure of SKT6 cells, which respond to erythropoietin (Epo) and induce
      erythroid differentiation, to osmotic or heat shock induced transient activation
      of JNK/SAPK and p38 and inactivation of ERK and resulted in erythroid
      differentiation without Epo, whereas long exposure of the cells to these stresses
      induced prolonged activation/inactivation of the same kinases and caused
      apoptosis. Inhibition of JNK/SAPK and p38 resulted in inhibition of stress
      induced erythroid differentiation and apoptosis. Inhibition of ERK had no effect
      on stress-induced erythroid differentiation, but stimulated apoptosis. Activation
      of p38 and/or JNK/SAPK for a short time caused erythroid differentiation without
      Epo, although its prolonged activation induced apoptosis. Activation of ERK
      suppressed stress-induced apoptosis. These results indicate that short cellular
      stresses, inducing transient activation of JNK/SAPK and p38, lead to cell
      differentiation rather than apoptosis. Furthermore, activation of JNK/SAPK and
      p38 is required for both cell differentiation and apoptosis, and the duration of
      their activation may determine the cell fate, cell differentiation, and
      apoptosis. In contrast, inactivation of ERK is required for stress-induced
      apoptosis but not cell differentiation.

PMID- 10419877
TI  - Loss of CCR2 expression and functional response to monocyte chemotactic protein
      (MCP-1) during the differentiation of human monocytes: role of secreted MCP-1 in
      the regulation of the chemotactic response.
AB  - Human peripheral blood monocytes differentiate into macrophages when cultured in
      vitro for a few days. In the present study, we investigated the expression of C-C
      chemokine and CXCR4 receptors in monocytes at different stages of
      differentiation. Culturing of monocytes for 7 days resulted in a progressive
      decrease of the mRNA that encodes for CCR2 and CCR3, whereas the expression of
      mRNA for other chemokine receptors (CCR1, CCR4, CCR5, and CXCR4) was not
      substantially affected. The loss of CCR2 mRNA expression in 7-day-cultured
      macrophages was associated with a strong reduction in the receptor expression at
      the plasma membrane, as well as in the monocyte chemotactic protein (MCP-1)
      binding, as compared with freshly isolated monocytes. Furthermore, the biologic
      response to MCP-1, as measured by intracellular calcium ions increase and
      chemotactic response, was lost in 7-day-cultured macrophages. Differentiation of
      monocytes into macrophages also resulted in an increased secretion of MCP-1 that,
      at least in part, was responsible for the downmodulation of its receptor (CCR2).
      The loss of CCR2 expression and the parallel increase of MCP-1 secretion
      triggered by differentiation may represent a feedback mechanism in the regulation
      of the chemotactic response of monocytes/macrophages.

PMID- 10419879
TI  - Extensive venous and arterial thrombosis associated with an inhibitor to
      activated protein C.
AB  - Activated protein C resistance (APCR) in the absence of alterations in the factor
      V gene has been observed during pregnancy, in patients on oral contraceptives, in
      the presence of antiphospholipid antibodies, and in patients with ischemic
      stroke. We report a 49-year-old woman with recurrent major venous and arterial
      thromboses who displayed pronounced APCR, yet no changes in the activated protein
      C (APC) cleavage sites of factor V. The APCR values determined by four different
      assays were similar to those obtained in plasma from a homozygote for factor V
      Q506. Addition of IgG isolated from the patient's serum to normal plasma lowered
      the APCR ratio from 2.4 to 1.6. Incubation of patient's IgG with normal APC
      resulted in a profound change in the mobility of APC in crossed
      immunoelectrophoresis. APC was also shown to bind to patient's IgG immobilized on
      a protein A agarose column. Factor Va inactivation by APC was inhibited by
      patient's IgG, but not by control IgG in the presence or absence of either
      phospholipids or protein S. These results provide evidence for the existence of
      an acquired antibody against APC in the patient's plasma, which gave rise to the
      APCR phenotype and was probably responsible for the major thrombotic events. We
      suggest that acquired APCR due to anti-APC antibodies be considered a potential
      cause for severe venous and arterial thromboses.

PMID- 10419878
TI  - Loss of endothelial surface expression of E-selectin in a patient with recurrent
      infections.
AB  - Neutrophil accumulation at sites of inflammation is mediated by specific groups
      of cell adhesion molecules including the beta2 (CD18) integrins on leukocytes and
      the selectins (P- and E-selectin on the endothelium and L-selectin on the
      leukocyte). This is supported by studies of patients with leukocyte adhesion
      deficiency syndromes whose leukocytes are genetically deficient in the expression
      of beta2 integrins or selectin carbohydrate ligands (eg, sialyl-Lewis(x)).
      However, inherited deficiency or dysfunction of endothelial cell adhesion
      molecules involved in leukocyte recruitment has not been previously described. In
      this report we describe a child with recurrent infections and clinical evidence
      of impaired pus formation reminiscent of a leukocyte adhesion deficiency
      syndrome, but whose neutrophils were functionally normal and expressed normal
      levels of CD18, L-selectin, and sialyl-Lewis(x). In contrast, immunohistochemical
      staining of inflamed tissue from the patient showed the absence of E-selectin
      from the endothelium, although E-selectin mRNA was present. However, E-selectin
      protein was expressed as significantly elevated levels of circulating soluble E
      selectin were detected, the molecular size of which was consistent with a
      proteolytically cleaved form of E-selectin. Gene sequencing failed to show
      evidence of a secreted mutant variant. These data represent, to our knowledge,
      the first description of a potentially inherited dysfunction of an endothelial
      cell adhesion molecule involved in leukocyte recruitment and provide additional
      human evidence of the importance of endothelial selectins in the inflammatory
      response.

PMID- 10419876
TI  - Adeno-associated virus vectors and hematology.

PMID- 10419880
TI  - Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and
      cytotoxic T-cell responses.
AB  - Progression of cutaneous T-cell lymphoma (CTCL) is associated with profound
      defects in cell-mediated immunity and depressed production of cytokines, which
      support cell-mediated immunity. Because we have observed marked defects in
      interleukin-12 (IL-12) production in CTCL and because IL-12 is critical for
      antitumor cytotoxic T-cell responses, we initiated a phase I dose escalation
      trial with recombinant human IL-12 (rhIL-12) where patients received either 50,
      100, or 300 ng/kg rhIL-12 twice weekly subcutaneously or intralesionally for up
      to 24 weeks. Ten patients were entered: 5 with extensive plaque, 3 with Sezary
      syndrome, and 2 with extensive tumors with large cell transformation. One patient
      with Sezary syndrome dropped out after 1 week for personal reasons. Subcutaneous
      dosing resulted in complete responses (CR) in 2 of 5 plaque and partial responses
      (PR) in 2 of 5 plaque, and 1 of 2 Sezary syndrome (overall response rate CR+PR 5
      of 9, 56%). A minor response also occurred in 1 of 5 plaque patients.
      Intralesional dosing resulted in individual tumor regression in 2 of 2 patients.
      Biopsy of regressing lesions showed a significant decrease in the density of the
      infiltrate in all cases and complete resolution of the infiltrate among those
      with clinical lesion resolution. An increase in numbers of CD8-positive and/or
      TIA-1-positive T cells were observed on immunohistochemical analysis of skin
      biopsy specimens obtained from regressing skin lesions. Adverse effects of rhIL
      12 on this regimen were minor and limited and included low-grade fever and
      headache. One patient discontinued rhIL-12 at week 6 because of depression. These
      results suggest that rhIL-12 may augment antitumor cytotoxic T-cell responses and
      may represent a potent and well-tolerated therapeutic agent for CTCL.

PMID- 10419881
TI  - The incidence of idiopathic thrombocytopenic purpura in adults increases with
      age.
AB  - With the aim of determining the incidence of idiopathic thrombocytopenic purpura
      (ITP) in adults, we searched all adult ITP patients diagnosed from April 1, 1973
      to December 31, 1995 in the County of Funen in Denmark. This county comprises 9%
      of the total Danish adult population. A total of 221 patients fulfilled the
      inclusion criteria, yielding an annual standardized incidence rate of 2.68 per
      100,000. The median age of the patient population was 56 years, and the female to
      male ratio was 1.7. Changing the platelet count cut-off point from 100 x 10(9)/L
      to 50 x 10(9)/L changed the incidence rate to 2.25 per 100,000. Comparing
      patients less and more than 60 years old, the incidence rate more than doubled
      and the sex difference was eliminated in the older age group. These two age
      groups were almost identical regarding platelet count at diagnosis and number of
      asymptomatic cases. The incidence rate increased in the study period. This
      increase in particular involved asymptomatic patients and old males who were both
      symptomatic or not symptomatic. Including additional patients identified by a
      questionnaire study of the contribution from the primary care physicians and the
      practicing specialists in the second half of the study period, a reliable
      estimate of the annual ITP incidence in Danish adults, using a platelet
      concentration cut-off point of 50 x 10(9)/L, is 3.2 per 100, 000 persons.

PMID- 10419882
TI  - Long-term correction of phagocyte NADPH oxidase activity by retroviral-mediated
      gene transfer in murine X-linked chronic granulomatous disease.
AB  - Chronic granulomatous disease (CGD) is an inherited deficiency of the superoxide
      generating phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase,
      resulting in recurrent, severe bacterial and fungal infections. The X-linked form
      of this disorder (X-CGD) results from mutations in the X-linked gene for
      gp91(phox), the larger subunit of the oxidase flavocytochrome b(558). In this
      study, we used a murine model of X-CGD to examine the long-term function of
      retroviral vectors for expression of gp91(phox) based on the murine stem cell
      virus (MSCV) backbone. NADPH oxidase activity was reconstituted in neutrophils
      and macrophages for up to 18 to 24 months posttransplantation of transduced X-CGD
      bone marrow into lethally irradiated syngeneic X-CGD mice. Southern blot analysis
      and secondary transplant data showed proviral integration in multilineage
      repopulating cells. Although relatively small amounts of recombinant gp91(phox)
      (approximately 5% to 10% of wild-type levels) were detected in neutrophils after
      retroviral-mediated gene transfer, superoxide-generating activity was
      approximately 20% to 25% of wild-type mouse neutrophils. Expression of gp91(phox)
      is normally restricted to mature phagocytes. No obvious toxicity was observed in
      other hematopoietic lineages in transplant recipients, and provirus-marked cells
      were capable of reconstituting secondary transplant recipients, who also
      exhibited NADPH oxidase-positive neutrophils. MSCV-based vectors for long-term
      expression of gp91(phox) may be useful for gene therapy of human CGD targeted at
      hematopoietic stem cells.

PMID- 10419883
TI  - The soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro
      maintenance and proliferation of human CD34(+)CD38(-/low) cells capable of
      repopulating severe combined immunodeficiency mice.
AB  - In vitro maintenance and proliferation of human hematopoietic stem cells is
      crucial for many clinical applications. Early hematopoietic cells express low
      levels of FLT-3 and c-kit receptors, as well as the interleukin-6 (IL-6) receptor
      signal transducing element, gp130, but do not express IL-6 receptor itself.
      Therefore, we have attempted to maintain human cord blood or bone marrow CD34(+)
      cells ex vivo in serum-free cultures containing stem cell factor (SCF) and FLT-3
      ligand (FL) alone or together with a new recombinant molecule of soluble IL-6
      receptor fused to IL-6 (IL6RIL6 chimera). The effect of IL6RIL6 chimera on the
      proliferation and differentiation of CD34(+) cells was compared with that of each
      chimera component added separately. The engraftment potential of in vitro
      cultured cells was determined using our recently established functional in vivo
      assay for primitive human severe combined immunodeficiency (SCID)-repopulating
      cells (SRC). We report here that IL6RIL6 chimera induced significantly higher
      levels of progenitors and SRC compared with SCF + FL alone or together with IL-6
      and soluble IL-6 receptor. IL6RIL6 chimera prolonged in vitro maintenance of SRC
      for up to 14 days. Stimulation of CD34(+)CD38(-/low) enriched cells with IL6RIL6
      chimera maintained the early CD34(+)CD38(-/low) cell subpopulation, which could
      be detected in vitro for up to 14 days. Moreover, IL6RIL6 chimera preferentially
      stimulated the growth of early CD34(+)38(-/low) cells, resulting in significantly
      higher levels of progenitors compared with more mature CD34(+)38(+) cells. Taken
      together, these findings demonstrate the importance of IL6RIL6 chimera in
      stimulating the proliferation of early CD34(+). CD38(-)gp130(+)IL-6R(-) cells in
      vitro and extended maintenance of progenitors and SRC.

PMID- 10419884
TI  - Dysregulated myelopoiesis in mice lacking Jak3.
AB  - Jak3 is a cytoplasmic tyrosine kinase that associates with the common chain of
      the interleukin-2 (IL-2) receptor and is involved in the function of the
      receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Mice deficient in Jak3 have few
      T and B cells, and no natural killer cells. Herein we show that the myeloid
      lineages in these mice are also affected by the loss of Jak3. Mice lacking Jak3
      exhibit splenomegaly by 4 months of age. Peripheral blood smears show an increase
      in the number of neutrophils and cells of the monocytic lineage. Flow cytometry
      of splenocytes and peripheral blood show a significant increase in
      FcgammaRII/III(FcgammaR)/Mac-1, FcgammaR/Gr-1, and FcgammaR/F4/80 double-positive
      cells in -/- and +/- mice compared to wild-type mice, consistent with an
      expansion of cells of the myeloid lineages. In addition, as the mice age, F4/80
      and CD3 positive mononuclear cells infiltrate the kidneys, lungs, and liver of
      these mice. When Jak3-/- mice are crossed with a transgenic mouse expressing Jak3
      in the T and NK cell compartments, the splenomegaly and myeloid expansion are
      accentuated. These data correlate with the constitutive activation of T cells in
      the periphery as the transgenic cells lose their expression of Jak3 with age.
      However, when Jak3-/- mice are crossed with RAG-1-deficient animals, no
      splenomegaly or myeloid expansion is apparent. These results indicate that the
      loss of Jak3 in the T-cell compartment drives the expansion of the myeloid
      lineages.

PMID- 10419885
TI  - Hyaluronate-enhanced hematopoiesis: two different receptors trigger the release
      of interleukin-1beta and interleukin-6 from bone marrow macrophages.
AB  - The glycosaminoglycan hyaluronate (HA) is part of the extracellular environment
      in bone marrow. We show here that HA activates signal transduction cascades
      important for hemopoiesis. In myeloid and lymphoid long-term bone marrow cultures
      (LTBMC), treatment with hyaluronidase (HA'ase) results in reduced production of
      both progenitor and mature cells. Exogeneous HA added to LTBMC had the opposite
      effect: it enhanced hematopoiesis. The effect of HA is mediated through two
      different HA receptors on bone marrow macrophage-like cells, one of which is CD44
      while the other is unknown. HA induces bone marrow macrophages to secrete IL
      1beta (CD44-dependent) and IL-6 (CD44-independent). The two receptors address
      different signal transduction pathways: CD44 links to a pathway activating p38
      protein kinase while the other yet unknown receptor induces Erk activity. There
      was no difference of the effect of HA and HA'ase on hematopoiesis in LTBMC and on
      cytokine production by macrophages in CD44-deficient mice compared with wild-type
      mice, indicating that the CD44 hyaluronate receptor and its signal transduction
      can be compensated for. Our data suggest a regulatory role for the extracellular
      matrix component HA in hematopoiesis and show the induction of signal
      transduction by HA receptors.

PMID- 10419886
TI  - Differential effects of human granulocyte colony-stimulating factor (hG-CSF) and
      thrombopoietin on megakaryopoiesis and platelet function in hG-CSF receptor
      transgenic mice.
AB  - Granulocyte-colony stimulating factor (G-CSF) has been found to act on the
      neutrophilic lineage. We recently showed that human G-CSF (hG-CSF) has effects
      similar to early-acting cytokines such as interleukin-3 (IL-3) in the development
      of multipotential hematopoietic progenitors in transgenic (Tg) mice expressing
      receptors (R) for hG-CSF. In the present study, we examined the effects of hG-CSF
      on more mature hematopoietic cells committed to megakaryocytic lineage in these
      Tg mice. The administration of hG-CSF to the Tg mice increased the numbers of
      both platelets in peripheral blood and megakaryocytes in the spleen, indicating
      that hG-CSF stimulates megakaryopoiesis in the Tg mice in vivo. The stimulatory
      effect of hG-CSF was also supported by the results of studies in vitro. hG-CSF
      supported megakaryocyte colony formation in a dose-dependent fashion in clonal
      cultures of bone marrow cells derived from the Tg mice. Direct effects of hG-CSF
      on megakaryocytic progenitors in the Tg mice were confirmed by culture of single
      cell sorted from bone marrow cells. hG-CSF showed a stronger effect on maturation
      of megakaryocytes in the Tg mice than that of IL-3 alone, but weaker than that of
      TPO alone. In addition, hG-CSF induced phosphorylation of STAT3 but not Jak2 or
      STAT5, while TPO induced phosphorylation of both. In contrast to TPO, hG-CSF did
      not enhance ADP-induced aggregation. Thus, hG-CSF has a wide variety of functions
      in megakaryopoiesis of hG-CSFR-Tg mice, as compared with other megakaryopoietic
      cytokines, but the activity of hG-CSF in megakaryocytes and platelets does not
      stand up to a comparison with that of TPO. Specific signals may be required for
      the full maturation and activation of platelets.

PMID- 10419887
TI  - Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to
      specific changes in gene expression in human vascular endothelial cells.
AB  - Alterations in the cellular redox potential by homocysteine promote endothelial
      cell (EC) dysfunction, an early event in the progression of atherothrombotic
      disease. In this study, we demonstrate that homocysteine causes endoplasmic
      reticulum (ER) stress and growth arrest in human umbilical vein endothelial cells
      (HUVEC). To determine if these effects reflect specific changes in gene
      expression, cDNA microarrays were screened using radiolabeled cDNA probes
      generated from mRNA derived from HUVEC, cultured in the absence or presence of
      homocysteine. Good correlation was observed between expression profiles
      determined by this method and by Northern blotting. Consistent with its adverse
      effects on the ER, homocysteine alters the expression of genes sensitive to ER
      stress (ie, GADD45, GADD153, ATF-4, YY1). Several other genes observed to be
      differentially expressed by homocysteine are known to mediate cell growth and
      differentiation (ie, GADD45, GADD153, Id-1, cyclin D1, FRA-2), a finding that
      supports the observation that homocysteine causes a dose-dependent decrease in
      DNA synthesis in HUVEC. Additional gene profiles also show that homocysteine
      decreases cellular antioxidant potential (glutathione peroxidase, NKEF-B PAG,
      superoxide dismutase, clusterin), which could potentially enhance the cytotoxic
      effects of agents or conditions known to cause oxidative damage. These results
      successfully demonstrate the use of cDNA microarrays in identifying homocysteine
      respondent genes and indicate that homocysteine-induced ER stress and growth
      arrest reflect specific changes in gene expression in human vascular EC.

PMID- 10419888
TI  - Real-time analysis of mural thrombus formation in various platelet aggregation
      disorders: distinct shear-dependent roles of platelet receptors and adhesive
      proteins under flow.
AB  - We evaluated real-time processes of platelet thrombus formation on a collagen
      surface in a flow chamber with whole blood from patients with various platelet
      aggregation disorders, such as Bernard-Soulier syndrome (BSS), Glanzmann's
      thrombasthenia (GTA), type 3 von Willebrand disease (vWD), and congenital
      afibrinogenemia (Af), who lack platelet glycoprotein (GP) Ib-IX complex, GP IIb
      IIIa, von Willebrand factor (vWF), and fibrinogen, respectively. Blood from GTA
      patients showed impaired thrombus growth but significant initial platelet-surface
      interaction under all shear conditions tested (50 to 1,500 s(-1)). By contrast,
      blood from patients with BSS or type 3 vWD showed no platelet-surface interaction
      under high shear (>/=1, 210 s(-1)) but normal thrombus formation under low shear
      (</=340 s(-1)). When shear rate was increased stepwise to 1,500 s(-1) during
      perfusion, the thrombus growth observed in type 3 vWD or BSS under low shear was
      arrested, whereas that in control blood was sharply accelerated as a function of
      shear rate. Overall thrombus formation in Af appeared indistinguishable from that
      of a control under shear rates between 50 and 1,500 s(-1). However, Af thrombi
      formed under such conditions collapsed immediately when shear rate was further
      increased to 4,500 s(-1), whereas thrombi of type 3 vWD or BSS formed under low
      shear were stable even when shear rate was elevated to 9,000 s(-1) during
      perfusion. These findings suggest that distinct molecular mechanisms underlie the
      pathologic bleeding in these diseases and point to the distinct roles of two
      major adhesive proteins, vWF and fibrinogen. In mural thrombus formation under
      flow conditions, vWF, perhaps mainly through its interaction with GP Ib-IX, acts
      as an "initiator and promoter," whereas fibrinogen, via its binding to GP IIb
      IIIa, acts as a "stabilizer" against heightened shear forces that could lead to
      peeling off of platelets from the surface.

PMID- 10419889
TI  - Cyclophilin B binding to platelets supports calcium-dependent adhesion to
      collagen.
AB  - We have recently reported that cyclophilin B (CyPB), a secreted cyclosporine
      binding protein, could bind to T lymphocytes through interactions with two types
      of binding sites. The first ones, referred to as type I, involve interactions
      with the conserved domain of CyPB and promote the endocytosis of surface-bound
      ligand, while the second type of binding sites, termed type II, are represented
      by glycosaminoglycans (GAG). Here, we further investigated the interactions of
      CyPB with blood cell populations. In addition to lymphocytes, CyPB was found to
      interact mainly with platelets. The binding is specific, with a dissociation
      constant (kd) of 9 +/- 3 nmol/L and the number of sites estimated at 960 +/- 60
      per cell. Platelet glycosaminoglycans are not required for the interactions, but
      the binding is dramatically reduced by active cyclosporine derivatives. We then
      analyzed the biologic effects of CyPB and found a significant increase in
      platelet adhesion to collagen. Concurrently, CyPB initiates a transmembranous
      influx of Ca(2+) and induces the phosphorylation of the P-20 light chains of
      myosin. Taken together, the present results demonstrate for the first time that
      extracellular CyPB specifically interacts with platelets through a functional
      receptor related to the lymphocyte type I binding sites and might act by
      regulating the activity of a receptor-operated membrane Ca(2+) channel.

PMID- 10419890
TI  - Inhibition of in vitro angiogenesis by platelet factor-4-derived peptides and
      mechanism of action.
AB  - In this study, we examined in detail the interaction of platelet factor-4 (PF-4)
      with fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor
      (VEGF) and the effect of PF-4-derived synthetic peptides. We show that a peptide
      between amino acids 47 and 70 that contains the heparin-binding lysine-rich site
      inhibits FGF-2 or VEGF function. This is based on the following observations: PF
      4 peptide 47-70 inhibited FGF-2 or VEGF binding to endothelial cells; it
      inhibited FGF-2 or VEGF binding to FGFRs or VEGFRs in heparan sulfate-deficient
      CHO cells transfected with FGFR1 (CHOFGFR1) or VEGFR2 (CHOmVEGFR2) cDNA; it
      blocked proliferation or tube formation in three-dimensional angiogenesis assays;
      and, finally, it competed with the direct association of (125)I-PF-4 with FGF-2
      or VEGF, respectively, and inhibited heparin-induced FGF-2 dimerization. A
      shorter C-terminal peptide (peptide 58-70), which still contained the heparin
      binding lysin-rich site, had no effect. Peptide 17-58, which is located in the
      central part of the molecule, although it does not inhibit FGF-2 or VEGF binding
      or biologic activity in endothelial cells, inhibited heparin-dependent binding of
      (125)I-FGF-2 or (125)I-VEGF to CHOmFGFR1 or CHOmVEGFR2 cells, respectively.
      Shorter peptides (peptides 34-58 and 47-58) did not show any of these effects.

PMID- 10419891
TI  - T-cell receptor-independent activation of clonal Th2 cells associated with
      chronic hypereosinophilia.
AB  - We recently observed a clonal expansion of CD3(-)CD4(+) T cells secreting Th2
      type cytokines in patients presenting chronic hypereosinophilia. As clonal T
      cells isolated from such patients did not spontaneously secrete cytokines in
      vitro, we reasoned that costimulatory signals delivered by antigen-presenting
      cells might be required to induce their full activation. To address this
      question, we investigated in two such patients the responses of CD3(-)CD4(+) T
      cells to dendritic cells (DC). DC elicited proliferation and production of
      interleukin-5 (IL-5) and IL-13 by clonal cells from patient 1 and upregulated
      their expression of CD25 (IL-2R-alpha). These effects were abolished when
      blocking monoclonal antibodies (MoAbs) against IL-2R-alpha and IL-2 were added to
      cocultures, indicating critical involvement of an autocrine IL-2/IL-2R pathway.
      Cells from patient 2 were stimulated by DC to produce Th2 cytokines only when rIL
      2 or rIL-15 was added to cocultures. In both patients, addition of inhibitory
      MoAbs against B7-1/B7-2 or CD2 to cocultures resulted in dramatic reduction of
      cytokine production and inhibited CD25 upregulation. Thus, TCR/CD3-independent
      activation of clonal Th2 cells by DC is an IL-2-dependent process, which requires
      signaling through CD2 and CD28.

PMID- 10419892
TI  - The interleukin-12-mediated pathway of immune events is dysfunctional in human
      immunodeficiency virus-infected individuals.
AB  - Interleukin-12 (IL-12) is a potentially critical factor in the immune response
      against human immunodeficiency virus (HIV) because it is important for regulating
      proliferation and interferon-gamma (IFN-gamma) production by T cells and natural
      killer (NK) cells, antigen presentation and accessory cell function by
      macrophages and dendritic cells, and cytolytic activities of cytotoxic T
      lymphocyte cells and NK cells, which are all functions known to be dysfunctional
      in patients with acquired immune deficiency syndrome. Peripheral blood
      mononuclear cells (PBMC) from HIV-infected patients have been previously shown to
      be deficient in the ability to produce IL-12 in response to the bacterial
      pathogen Staphylococcus aureus Cowan. In this study, impaired IL-12 production in
      cells from PBMC of HIV-infected patients compared with healthy donors was
      observed across a broad panel of stimuli derived from infectious pathogens with
      or without priming with cytokines such as IFN-gamma and IL-4, which amplify the
      IL-12 induction signal. Analysis of p40 and p35 mRNA accumulation showed that
      reductions in both subunits contribute to the lower IL-12 secretion of cells from
      HIV-infected individuals. PBMC from HIV-infected donors also failed to upregulate
      the IL-12 receptor beta2 chain (IL-12Rbeta2) in response to mitogenic stimuli.
      The expression of the IL-12Rbeta2 gene could, however, be restored by in vitro
      exposure to rIL-12. Thus, it is possible that a primary IL-12 defect may lead to
      secondary deficiencies in expression of the genes for IL-12Rbeta2 and IFN-gamma,
      thus amplifying immune deficiency during HIV infection.

PMID- 10419893
TI  - Surface molecule loss and bleb formation by human germinal center B cells
      undergoing apoptosis: role of apoptotic blebs in monocyte chemotaxis.
AB  - Human tonsil germinal center (GC) B cells rapidly undergo apoptosis in culture.
      Annexin-V binding shows an early event in this process. In the present study,
      this method has been used to label apoptotic GC B cells and to analyze additional
      surface molecules. The expression of all of the molecules studied was reduced in
      apoptotic (annexin-V(+)) GC B cells, and the reduction was more marked for CD11a,
      CD21, CD22, CD49d, and CD54, molecules that participate in survival interaction
      for GC B cells. The analysis of CD54, one of the molecules that was more
      drastically reduced, showed that GC, but not mantle zone, B cells actively
      secrete CD54 to the culture supernatant (SN). The secreted CD54 was partly
      released from the GC B cells in a particulate form as demonstrated by
      centrifugation. Further experiments using filtration, fluorescence microscopy,
      electron microscopy, and flow cytometry analysis showed that GC B cells released
      to the culture SN a population of spherical membranous vesicles of about 0.18
      micrometers in size, similar to the blebs described in other apoptosis systems.
      Bleb formation depended on active metabolism, Ca(2+), and, in part, on
      microfilament integrity. GC B-cell-derived blebs were clearly associated with
      apoptosis, as antiapoptotic stimuli prevented their formation. In addition, GC B
      cell-derived blebs contained the adhesion molecules previously studied.
      Consequently, bleb formation might contribute to the surface molecule loss
      occurring in apoptotic GC B cells. Finally, a chemotaxis assay showed that GC B
      cell blebs were chemotactic for human monocytes, suggesting that this mechanism
      might operate in vivo.

PMID- 10419894
TI  - Human immunodeficiency virus type 1 protease inhibitor modulates activation of
      peripheral blood CD4(+) T cells and decreases their susceptibility to apoptosis
      in vitro and in vivo.
AB  - CD4(+) T cells from patients with human immunodeficiency virus (HIV) infection
      undergo apoptosis at an increased rate, which leads to their depletion during
      disease progression. Both the Fas-Receptor (Fas-R) and interleukin-1beta (IL
      1beta)-converting enzyme (ICE; caspase 1) appear to play a role in the mechanism
      of apoptosis of CD4(+) lymphocytes. Although Fas-R is upregulated on both CD4(+)
      and CD8(+) cells in HIV-infected patients, results from our laboratory and others
      indicate that, in patients with advanced disease, CD4(+) cells preferentially
      express ICE. Protease inhibitors have successfully halted the progression of HIV
      disease and increased CD4(+) T counts. In this study, we examined the effect of
      protease inhibitors on Fas-R (CD95), ICE (caspase 1) expression, apoptosis, and
      cell death in CD4(+) T cells of (1) HIV-infected patients who were receiving
      protease inhibitors, and (2) normal and patient CD4(+) T cells cultured with a
      protease inhibitor in vitro. Fifteen patients with advanced HIV disease on
      treatment showed dramatically decreased CD4(+) T-cell ICE expression, diminished
      apoptosis, and increased numbers of CD4(+) cells within 6 weeks of institution of
      protease inhibitor therapy, and before down-modulation of Fas-R (CD95) expression
      was evident. To determine the role of HIV infection, we studied the effect of
      ritonavir, a protease inhibitor, on normal and patient cells in vitro. Stimulated
      and unstimulated normal CD4(+) T cells, cultured with protease inhibitor,
      demonstrated markedly decreased apoptosis and ICE expression (P =. 01). While Fas
      R expression was not significantly altered during short-term culture by such
      treatment, Fas-Ligand (Fas-L) membrane expression of phytohemagglutinin (PHA)
      stimulated blood lymphocytes was decreased by protease inhibitor. In the presence
      of ritonavir, CD4(+) T cells from HIV-infected patients showed similar changes in
      ICE intracellular levels without alteration of Fas expression. In conclusion,
      protease inhibitors appear to decrease CD4(+) T-cell ICE expression and apoptosis
      before they affect Fas-R expression in HIV-infected patients. This action was
      independent of HIV infection, as similar effects were seen in CD4(+) T cells from
      normal controls. Some of the benefit of protease inhibitors may be related to
      modification of programmed cell death, which increases CD4(+) T-cell number.
      Whether this is due to directly to the changes effected in the caspase system
      remains to be determined.

PMID- 10419895
TI  - Nitric oxide mediation of active immunosuppression associated with graft-versus
      host reaction.
AB  - In the immunosuppression accompanying the lethal systemic graft-versus-host
      reaction (GVHR) directed against minor histocompatibility antigens in irradiated
      adult mice, we previously determined that non-T, non-B, L-leucine methyl ester
      (LME)-sensitive cells were implicated via two different mechanisms: one, which is
      interferon-gamma (IFN-gamma)-dependent and affects both T-cell proliferative
      responses and thymus-independent antibody production by CD5(+) B cells; and a
      second, which is IFN-gamma-independent and affects B-cell proliferative
      responses. Because IFN-gamma induces the production of nitric oxide (NO), a
      potent immunosuppressive molecule, we investigated the involvement of NO in the
      suppression mediated by the LME-sensitive cells. Inducible NO synthase (iNOS)
      mRNA, iNOS protein, and the stable end products of iNOS pathway, L-citrulline and
      nitrite, were detected early in GVHR in LME-sensitive spleen cells taken ex vivo
      and could be amplified in vitro by T and B mitogens. Inhibition of NO production
      with arginine analogs (aminoguanidine, N(G)-monomethyl-L-arginine [LMMA]), like
      anti-IFN-gamma antibodies, reversed suppression of both T-cell responses to
      concanavalin A and CD5(+) B-cell responses, but not of B-cell response to
      lipopolysaccharides (LPS). The GVHR-associated, IFN-gamma-dependent
      immunosuppression of T-cell proliferation and of antibody synthesis by CD5(+) B
      cells is the consequence of NO production by LME-sensitive cells.
      Immunohistochemical analyses indicate that these cells belong to the macrophage
      lineage.

PMID- 10419896
TI  - A BCR-ABL oncoprotein p210b2a2 fusion region sequence is recognized by HLA-DR2a
      restricted cytotoxic T lymphocytes and presented by HLA-DR matched cells
      transfected with an Ii(b2a2) construct.
AB  - Peptides corresponding to the fusion site in 210 kD BCR-ABL protein b3a2
      (p210b3a2) were previously shown to bind to several HLA class I and II alleles.
      We have found that b3a2 peptide-specific CD4-positive T-helper cells were able to
      recognize p210b3a2-positive chronic myelogenous leukemia (CML) blasts in a DR4
      restricted manner. Until now, there were no reports of b2a2 breakpoint-specific
      human T-cell responses. Here we show that repetitive stimulation of T lymphocytes
      with a 17mer peptide covering the fusion region in p210b2a2 also leads to
      specific T-cell responses. CD4 and CD4/CD8 double-positive clones obtained from a
      b2a2 peptide-specific cell line were cytotoxic and proliferative in an HLA-DR2a
      (DRB5*0101) restricted fashion. Autologous Epstein-Barr virus (EBV) transformed
      cells, expressing BCR-ABL(b2a2) on transfection, and allogeneic HLA-DR matched
      p210b2a2-positive cells from CML patients were, however, not lysed. BCR-ABL
      peptide-specific T-cell clones did respond to autologous EBV cells transfected
      with invariant chain (li) cDNA in which the HLA class II-associated invariant
      chain peptide (CLIP) was replaced by a BCR-ABL b2a2 fusion oligonucleotide
      sequence, illustrating the potential of these T cells to recognize an endogenous
      BCR-ABL(b2a2) ligand.

PMID- 10419897
TI  - Simultaneous activity of MRP1 and Pgp is correlated with in vitro resistance to
      daunorubicin and with in vivo resistance in adult acute myeloid leukemia.
AB  - In adult acute myeloid leukemia (AML), the weight of the contribution of the
      combined activity of Pgp and MRP1 to drug resistance is not known. To address
      this question, we compared the activity of these proteins to the in vitro
      resistance to daunorubicin (DNR), etoposide, and cytosine arabinoside (Ara-C),
      using the calcein-AM uptake and the 3-[4, 5-di-methyl-thiazol-2, 5-diphenyl]
      tetrazolium bromide (MTT) assay in 80 adult AML patients. We found no correlation
      or only a weak correlation between the in vitro drug resistance to DNR and
      etoposide and MRP1 or Pgp expression or function when tested separately. However,
      a strong correlation was observed between the simultaneous activity of MRP1 and
      Pgp (quantified as the modulation of calcein-AM uptake by cyclosporin A and
      probenecid) and the LC50 of DNR (r =.77, P <.0001). This emphasized the role of
      these two proteins, not separately, but together in the resistance to DNR. In
      contrast, Mvp/LRP expression did not correlate with the LC50 of DNR. A high level
      of simultaneous activity of Pgp and MRP1 was predictive of a poor treatment
      outcome (for achievement of CR [P =.008], duration of relapse-free survival [RFS;
      P =.01], and duration of overall survival [OS; P =.02]). In addition, high LC50
      of DNR and high LC50 of etoposide together were also predictive of a poor
      treatment outcome (for duration of RFS [P =.02] and duration of OS [P =.02]). The
      unfavorable cytogenetic category was more closely associated with the combined
      activity of both MRP1 and Pgp (P =.002) than with the activity of Pgp or MRP1
      separately. This could explain the poor prognosis and the in vitro resistance to
      daunorubicin in this group of patients. These data suggest that treatment outcome
      may be improved when cellular DNR and etoposide resistance can be circumvented or
      modulated. Modulation of not only Pgp but also MRP1 could be essential to attain
      this aim in adult AML.

PMID- 10419898
TI  - Protracted and variable latency of acute lymphoblastic leukemia after TEL-AML1
      gene fusion in utero.
AB  - We report a pair of identical twins with concordant acute lymphoblastic leukemia
      (ALL). Unusually, their diagnoses were spaced 9 years apart at ages 5 and 14.
      Leukemic cells in both twins had a TEL-AML1 rearrangement, which was
      characterized at the DNA level by an adaptation of a long distance polymerase
      chain reaction (PCR) method. The genomic fusion sequence was identical in the two
      leukemias, indicative of a single cell origin in one fetus, in utero. At the time
      twin 1 was diagnosed (aged 5 years), the bone marrow of twin 2 was
      hematologically normal. However, retrospective scrutiny of the DNA from an
      archived slide with clonotypic TEL-AML1 primers showed that the presumptive
      preleukemic clone was present and disseminated 9 years before a clinical
      diagnosis. These data provide novel insight into the natural history of childhood
      leukemia and suggest that consequent to a prenatal initiation of a leukemic
      clone, most probably by TEL-AML fusion itself, the latency of ALL can be both
      extremely variable and protracted. This, in turn, is likely to reflect the timing
      of critical secondary events.

PMID- 10419899
TI  - Oligoclonal TCRBV gene usage in B-cell chronic lymphocytic leukemia: major
      perturbations are preferentially seen within the CD4 T-cell subset.
AB  - TCRBV (T-cell receptor B variable) gene usage and CDR3 size distribution were
      analyzed using reverse transcription polymerase chain reaction (RT-PCR) to assess
      the T-cell repertoire of 10 patients with B-cell chronic lymphocytic leukemia (B
      CLL) and in nine age-matched healthy control donors. When the usage of each TCRBV
      gene within the CD8(+) T cells of the patients was compared with that of the
      controls, no statistically significant difference was noted except for BV 6S1-3.
      In contrast, within the CD4(+) T cells of the CLL patients, a statistically
      significant overexpression for four BV families (2, 3, 5S1, 6S1-3) was seen while
      an underrepresentation was noted for five BV families (10, 11, 15, 16, 19). Based
      on the criterion that a value of any BV higher than the mean + 3 standard
      deviation (SD) of healthy controls indicated an overexpression, individual
      patients were shown to overexpress several TCRBV genes compared with the
      controls. Analyses of the CDR3 length polymorphism showed a significantly higher
      degree of restriction within CD4(+) and CD8(+) T cells of the patients, as
      compared with the corresponding control T-cell population. There was a
      significant difference in the CDR3 size distribution pattern with a more
      polymorphic CDR3 length pattern in the age-matched controls as compared with CLL
      patients, suggesting different mechanisms driving the T cells towards a
      clonal/oligoclonal TCRBV usage in patients and controls, respectively. The
      results show major perturbations of T cells in CLL patients, more frequently seen
      in the CD4(+) T-cell subset, indicating that nonmalignant CD4(+) T cells may be
      involved in the pathogenesis of CLL, but also CD8(+) T cells.

PMID- 10419900
TI  - V(H) gene analysis of IgM-secreting myeloma indicates an origin from a memory
      cell undergoing isotype switch events.
AB  - IgM-secreting plasma cell tumors are rare variants of typical isotype-switched
      multiple myeloma with a similar disease outcome. To probe the origin and clonal
      history of these tumors, we have analyzed V(H) gene sequences in 6 cases.
      Potentially functional tumor-derived V(H) genes were all derived from V(H)3, with
      the V(3-7) gene segment being used by 4 of 6. All were somatically mutated, with
      a mean deviation from germline sequence of 5.2% (range, 3.1% to 7.1%). The
      distribution of replacement mutations was consistent with antigen selection in 4
      of 6 cases, and no intraclonal heterogeneity was observed. Clonally related
      switched isotype transcripts were sought in 4 cases, and Cgamma transcripts with
      tumor-derived CDR3 sequence were identified in 2 of 4. These findings indicate
      that IgM-secreting myelomas are arrested at a postfollicular stage at which
      somatic mutation has been silenced. Isotype switch variants show the cell of
      origin to be at the IgM to IgG switch point. These features indicate that the
      final neoplastic event has occurred at a stage immediately before that of typical
      isotype-switched myeloma. One possibility is that IgM myeloma involves the
      previously identified precursor cell of typical myeloma.

PMID- 10419901
TI  - Basic fibroblast growth factor is expressed by CD19/CD11c-positive cells in hairy
      cell leukemia.
AB  - Several features are characteristic for hairy cell leukemia (HCL). Among those
      are pancytopenia, bone marrow fibrosis, and the appearance of a defined tumor
      cell phenotype in peripheral blood (PB), bone marrow (BM), and spleen. Hairy
      cells (HC) coexpress antigens specific for B lymphocytes and
      monocytes/macrophages and thus the malignant cell does not seem to be restricted
      to a defined lineage. When serum or bone marrow aspirate was screened by enzyme
      linked immunosorbent assay (ELISA) for basic fibroblast growth factor (bFGF),
      specimen derived from HCL (serum: mean value, 29 pg/mL; BM aspirate: mean value,
      641 pg/mL) contained significantly higher levels than those from healthy
      subjects. To study whether peripheral blood mononuclear cells (PBMC) derived from
      patients suffering from HCL and healthy donors (HD) were capable of producing
      bFGF, culture supernatant (conditioned medium, [CM]) was tested for the presence
      of this cytokine. While bFGF was not detectable in cell cultures from HD, HCL
      derived CM contained relatively high levels of bFGF. CM was successfully used for
      stimulation of mesenchymal cell proliferation, which could be inhibited by a
      neutralizing anti-bFGF antibody. Cellular activation by pokeweed mitogen (PWM) or
      the combination of 12-o-tetradecanoyl-phorbol-13-acetate (TPA) plus calcium
      ionophore (Ca-Ip) led to an enhanced mRNA expression. Results of Western blot
      experiments showed that HC synthesize at least three isoforms (approximately 18,
      23, and 25 kD), but only the 23-kD isoform is exported. To assess the nature of
      the producer cell, double immunofluorescence analysis using a bFGF-specific and
      an anti-CD11c monoclonal antibody (MoAb) was undertaken. The majority of cells
      scoring positive for CD11c were also reactive with the anti-bFGF MoAb.
      Furthermore, enrichment of CD19/CD11c-positive cells correlated with enhanced
      bFGF levels, thereby supporting the argument for HC being the producer cells of
      bFGF. A biological function of bFGF in HCL might be mediation of chemoresistance,
      as 2-chlorodeoxyadenosine (2-CdA)-induced inhibition of cell proliferation can be
      reversed by bFGF. Endogenous bFGF production by HC is not affected by this purine
      analogue and 2-CdA-induced apoptosis is diminished in bFGF-producing HC as
      compared with normal PBMC. Therefore, bFGF expression by HC might be important
      for resistance to chemotherapy and survival of the malignant cells.

PMID- 10419902
TI  - Frequency and clinical significance of the expression of the multidrug resistance
      proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a
      Southwest Oncology Group Study.
AB  - Therapeutic resistance is a major obstacle in the treatment of acute myeloid
      leukemia (AML). Such resistance has been associated with rapid drug efflux
      mediated by the multidrug resistance gene 1 (MDR1; encoding P-glycoprotein) and
      more recently with expression of other novel proteins conferring multidrug
      resistance such as MRP1 (multidrug resistance-associated protein 1) and LRP (lung
      resistance protein). To determine the frequency and clinical significance of
      MDR1, MRP1, and LRP in younger AML patients, we developed multiparameter flow
      cytometric assays to quantify expression of these proteins in pretreatment
      leukemic blasts from 352 newly diagnosed AML patients (median age, 44 years)
      registered to a single clinical trial (SWOG 8600). Protein expression was further
      correlated with functional efflux by leukemic blasts [assessed using two
      substrates: Di(OC)(2) and Rhodamine 123] and with the ability of MDR-reversing
      agents to inhibit efflux in vitro. MDR1/P-glycoprotein expression, which was
      highly correlated with cyclosporine-inhibited efflux, was noted in only 35% of
      these younger AML patients, distinctly lower than the frequency of 71% we
      previously reported in AML in the elderly (Blood 89:3323, 1997). Interestingly,
      MDR1 expression and functional drug efflux increased with patient age, from a
      frequency of only 17% in patients less than 35 years old to 39% in patients aged
      50 years (P =.010). In contrast, MRP1 was expressed in only 10% of cases and
      decreased with patient age (P =. 024). LRP was detected in 43% of cases and
      increased significantly with increasing white blood cell counts (P =.0015). LRP
      was also marginally associated with favorable cytogenetics (P =.012) and French
      American-British (FAB) AML FAB subtypes (P =.013), being particularly frequent in
      M4/M5 cases. Only MDR1/P-glycoprotein expression and cyclosporine-inhibited
      efflux were significantly associated with complete remission (CR) rate (P(MDR1)
      =.012; P(efflux) =.039) and resistant disease (RD; P(MDR1) =.0007; P(efflux)
      =.0092). No such correlations were observed for MRP1 (P(CR) =.93; P(RD) =.55) or
      LRP (P(CR) =.50; P(RD) =.53). None of these parameters were associated with
      overall or relapse-free survival. Unexpectedly, a distinct and nonoverlapping
      phenotype was detected in 18% of these cases: cyclosporine-resistant efflux not
      associated with MDR1, MRP1, or LRP expression, implying the existence of other as
      yet undefined efflux mechanisms in AML. In summary, MDR1 is less frequent in
      younger AML patients, which may in part explain their better response to therapy.
      Neither MRP1 nor LRP are significant predictors of outcome in this patient group.
      Thus, inclusion of MDR1-modulators alone may benefit younger AML patients with
      MDR1(+) disease.

PMID- 10419903
TI  - Expression of the death gene Bik/Nbk promotes sensitivity to drug-induced
      apoptosis in corticosteroid-resistant T-cell lymphoma and prevents tumor growth
      in severe combined immunodeficient mice.
AB  - Members of the Bcl-2 gene family have been implicated in the regulation of cell
      death induced by cytostatic drugs. In some malignancies such as B-cell lymphoma,
      there is evidence that high expression of Bcl-2 is an independent negative
      prognostic marker and the overexpression of Bcl-2 has been shown to confer
      resistance to cytotoxic drugs by preventing drug-induced apoptosis. This function
      of Bcl-2 can be antagonized by apoptosis-promoting members of the Bcl-2 family.
      We previously showed that overexpression of Bax restores the chemosensitivity of
      Bax-deficient breast cancer cell lines. Therefore, we investigated whether the
      death-promoting Bcl-2 homologue Bik/Nbk can enhance cytostatic drug-induced
      apoptosis. As a model, we used the T-cell leukemia H9 (CD3(+) and CD4(+)CD8(-)),
      which is resistant to corticosteroid-induced cell death and does not express
      endogenous Bik/Nbk. Sensitivity for drug-induced apoptosis was increased 10- to
      39-fold in cells transfected with the full-length coding sequence of Bik/Nbk. In
      addition, apoptosis induced via CD95/Fas or heat shock was increased to a similar
      extent. These data show that Bik/Nbk, which, unlike Bax, carries only a BH3 but
      no BH1 or BH2 domain may be a target to enhance chemosensitivity. The complete
      suppression of tumor growth in a severe combined immunodeficient mouse
      xenotransplant model suggests that, in analogy to Bax, Bik/Nbk may function as a
      tumor suppressor gene.

PMID- 10419904
TI  - STAT5 activation by BCR-Abl contributes to transformation of K562 leukemia cells.
AB  - Signal transducers and activators of transcription (STATs) belong to a family of
      transcription factors that were originally identified as mediators of cytokine
      induced gene expression. Recent evidence, however, has shown that certain members
      of the STAT family, including STAT3, are also involved in cellular
      transformation. Here we show that STAT5 also plays a role in cellular
      transformation by the BCR-Abl oncogene. In BCR-Abl transformed K562 cells, STAT5A
      and 5B are constitutively phosphorylated on tyrosine and are transcriptionally
      active. Moreover, expression of a dominant negative form of STAT5 shows that
      active STAT5 is necessary for the growth in soft agar of these cells. These
      results show that besides STAT3, STAT5 can also be involved in cellular
      transformation.

PMID- 10419905
TI  - Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation.
AB  - The p73 gene, a member of the p53 family, is a new candidate tumor suppressor
      gene. To investigate the possibility of genetic alteration of p73 in leukemia and
      lymphoma, we examined 55 cell lines and 39 patient samples together with 17
      nonhematopoietic cancer cell lines. Gene expression of p73 was detected by
      reverse transcriptase-polymerase chain reaction (RT-PCR) in cell lines (5 of 7
      pre B/B-acute lymphoblastic leukemia [ALL], 13 of 21 T-ALL/lymphoblastic
      lymphomas [LBL], 9 of 10 B-non-Hodgkin's lymphomas [B-NHL], 8 of 9 acute
      myelogenous leukemias [AML], 2 of 2 T-NHL, 3 of 3 multiple myeloma), and in
      patient samples (16 of 23 pre B-ALL, 5 of 8 T-ALL/LBL, 5 of 8 B-NHL). PCR-single
      strand conformation polymorphism (SSCP) of cDNAs showed no mutation in 43 p73
      expressing cell lines within the regions that corresponded to the 5 mutational
      hotspots of the p53 gene. Neither homologous deletion nor rearrangement of the
      p73 gene were found by Southern blot analysis in any of the cell lines that lack
      expression of p73. In contrast to prior published data, analysis of a polymorphic
      site showed that the p73 gene was expressed biallelically in cell lines and
      normal peripheral blood. Notably, the p73-negative cell lines were
      hypermethylated at a CpG island in the 5' untranslated region of the p73 mRNA,
      and treatment of these cell lines with 5-azacytidine (5-AC), a demethylation
      reagent, induced p73 expression. Taken together, we found that a sizable
      proportion (32%) of ALL/B-NHL cell lines and primary tumors had negligible or
      limited expression of the p73 gene associated with hypermethylation of the gene.
      These findings suggest that silencing of the p73 gene by hypermethylation may
      contribute to development and/or progression of lymphoid neoplasms.

PMID- 10419906
TI  - Regulation of p21rac activation in human neutrophils.
AB  - The small guanosine triphosphate (GTPase) p21rac is highly expressed in human
      neutrophils where it is thought to play a role in cytoskeletal reorganization and
      superoxide production. Using the p21rac binding domain of PAK (PAK-RBD) as an
      activation-specific probe, we have investigated agonist-stimulated activation of
      p21rac. Stimulation of neutrophils with the chemoattractants fMet-Leu-Phe (fMLP)
      or platelet-activating factor (PAF) induced an extremely rapid and transient
      p21rac activation, being optimal within 5 seconds. This activation correlates
      with the rapid changes of intracellular free Ca(2+) ([Ca(2+)](i)) stimulated by
      fMLP; however, changes in [Ca(2+)](i) were neither sufficient nor required for
      p21rac activation. Furthermore, fMLP-induced p21rac activation was not inhibited
      by broad tyrosine kinase inhibitors or specific inhibitors of ERK, p38 mitogen
      activated protein kinase, Src, or phosphatidylinositol 3-kinases. Surprisingly,
      the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor
      necrosis factor-alpha did not cause p21rac activation or modulate fMLP-induced
      p21rac activation. AlF(-), a potent activator of heterotrimeric G-protein alpha
      subunits, however, was found to activate p21rac. Stimulation of neutrophils with
      phorbol myristate acetate (PMA) strongly activated the respiratory burst, but did
      not induce p21rac activation, suggesting that superoxide production per se can
      occur independently of p21rac activation. These data suggest that in human
      granulocytes, G-protein coupled receptors, but not cytokine receptors, activate
      p21rac via a rapid, novel exchange-mechanism independently of changes in
      [Ca(2+)](i), tyrosine phosphorylation, or PI3K.

PMID- 10419907
TI  - Stable mixed hematopoietic chimerism in dog leukocyte antigen-identical
      littermate dogs given lymph node irradiation before and pharmacologic
      immunosuppression after marrow transplantation.
AB  - Stable mixed donor/host hematopoietic chimerism can be accomplished in dog
      leukocyte antigen (DLA)-identical littermate dogs given sublethal (200 cGy) total
      body irradiation (TBI) before and immunosuppression with mycophenolate mofetil
      (MMF) and cyclosporine (CSP) after transplant (Blood 89:3048, 1997). Studies were
      based on the hypothesis that drugs that prevent graft-versus-host disease (GVHD)
      after transplant also suppress host-versus-graft (HVG) reactions and thereby
      enhance engraftment. Here, we asked whether pretransplant TBI provided marrow
      space for the graft to home or caused host immunosuppression. To address the
      questions, recipients were given pretransplant irradiation to cervical, thoracic,
      and abdominal lymph nodes (except pelvis), DLA-identical littermate marrow
      grafts, and MMF/CSP posttransplant. Six dogs that received 450 cGy irradiation
      showed initial engraftment. Two rejected their grafts after 8 and 18 weeks, 1
      died with GVHD and engraftment, and 3 are alive as mixed chimeras after 57 to 97
      weeks. Four dogs given 200 cGy irradiation also showed initial engraftment, but
      rejected their grafts after 10 to 18 weeks. Mixed chimerism was present in
      nonirradiated marrow and lymph node spaces and involved granulocytes, T cells,
      and monocytes. While other explanations are possible, results seem consistent
      with the hypothesis that pretransplant radiation provides host immunosuppression,
      and grafts can create their own marrow space. These data set the stage for the
      development of novel transplant regimens that substitute immunosuppressive for
      cytotoxic agents.

PMID- 10419908
TI  - Striking up the match.

PMID- 10419909
TI  - Duration of exposure to gluten and risk for autoimmune disorders in patients with
      celiac disease. SIGEP Study Group for Autoimmune Disorders in Celiac Disease.
AB  - BACKGROUND & AIMS: The relationship between celiac disease and many autoimmune
      disorders has been explained by the sharing of a common genetic factor. In a
      multicenter national study, we examined the relationship between the prevalence
      of autoimmune disorders in celiac disease and the duration of exposure to gluten.
      METHODS: Over a 6-month period, 909 patients with celiac disease (group A; mean
      age, 16.1 +/- 3.8 years; grouped according to age at diagnosis into three
      subgroups [group A1, <2 years; group A2, 2-10 years; and group A3, >10 years]),
      1268 healthy controls (group B; mean age, 20.8 +/- 4.5 years), and 163 patients
      with Crohn's disease (group C; mean age, 28.8 +/- 10 years) were evaluated for
      the presence of autoimmune disorders. RESULTS: Prevalence of autoimmune disorders
      in group A was significantly higher than in group B (14% vs. 2.8%; P < 0.000001)
      but not higher than in group C (12.9%). Prevalence of autoimmune disorders in
      celiac disease increased with increasing age at diagnosis: 5.1% in group A1, 17%
      in group A2, and 23.6% in group A3 (P = 0.000001). In group A3, the prevalence of
      autoimmune disorders was significantly higher than in group C. In a logistic
      regression model, age at diagnosis was the only significant predictor variable of
      the odds of developing an autoimmune disorder (r = 0.3; P < 0.000001).
      CONCLUSIONS: Our data show for the first time that the prevalence of autoimmune
      disorders in celiac disease is related to the duration of exposure to gluten.

PMID- 10419910
TI  - Implementation of on-site screening sigmoidoscopy positively influences
      utilization by primary care providers.
AB  - BACKGROUND & AIMS: Sigmoidoscopy is an effective screening strategy for
      colorectal cancer that is not widely used by primary care providers. The aim of
      this study was to assess the impact of "academic detailing" in the form of an
      outreach educational seminar combined with implementation of on-site
      sigmoidoscopy services performed by university-based gastroenterologists on
      provider compliance. METHODS: A controlled trial was initiated at 9 urban
      neighborhood health centers, including 4 intervention and 5 comparison sites.
      Baseline data on provider attitudes and practice patterns were collected using a
      validated questionnaire. Outcome measures included a year 1 follow-up survey of
      provider attitudes and quarterly review of screening sigmoidoscopy referrals
      using appointment logs to assess utilization. RESULTS: Overall self-reported
      compliance rates for screening sigmoidoscopy increased by 36% (baseline, 24%;
      year 1, 60%) for the intervention group vs. only 7% (baseline, 19%; year 1, 26%)
      for the comparison group (P = 0. 001). When stratified by site, compliance rates
      increased at each intervention site (range, 7%-92%) but at only 2 control sites.
      Use of screening sigmoidoscopy was also significantly greater at the intervention
      sites (47% vs. 4%; P </= 0.001). CONCLUSIONS: An outreach educational seminar
      combined with implementation of on-site sigmoidoscopy services is an effective
      strategy for enhancing provider utilization of screening sigmoidoscopy.

PMID- 10419911
TI  - Accuracy of polyp detection by gastroenterologists and nurse endoscopists during
      flexible sigmoidoscopy: a randomized trial.
AB  - BACKGROUND & AIMS: The use of nurse endoscopists to perform flexible
      sigmoidoscopy is expanding, increasing the availability of colorectal cancer
      screening. However, the effectiveness of this practice has not been studied in
      randomized trials. The aim of this trial was to examine the miss rate of polyps,
      the depth of sigmoidoscope insertion, and the incidence of complications during
      flexible sigmoidoscopy performed by nurse endoscopists and by
      gastroenterologists. METHODS: Three hundred twenty-eight patients were randomized
      to undergo screening flexible sigmoidoscopy performed by a nurse endoscopist or
      by a gastroenterologist. Frequency of missed polyps was determined by repeat
      sigmoidoscopy, performed by a gastroenterologist blinded to the identity of the
      first endoscopist. Multiple logistic regression analysis identified
      characteristics associated with missed polyps. RESULTS: Gastroenterologists and
      nurse endoscopists had equivalent miss rates for adenomatous polyps (20% vs. 21%,
      respectively; P = 0.91). No complications occurred in any patient.
      Gastroenterologists inserted the sigmoidoscope further than nurse endoscopists
      (61 vs. 55 cm, respectively; P < 0.00001). Polyp location in the descending colon
      (odds ratio, 4.1; 95% confidence interval, 1.7-10.3) was highly associated with
      missed polyps. CONCLUSIONS: No differences in detection of adenomatous polyps or
      frequency of complications were found. These data suggest that experienced nurse
      endoscopists may perform screening flexible sigmoidoscopy as safely and as
      effectively as gastroenterologists.

PMID- 10419912
TI  - Lack of effect of acid suppression therapy on gastric atrophy. Nordic Gerd Study
      Group.
AB  - BACKGROUND & AIMS: A hypothesis suggesting that profound acid inhibition therapy
      facilitates and hastens the development of gastric glandular atrophy in patients
      infected with Helicobacter pylori was investigated in this randomized study
      comparing omeprazole therapy with antireflux surgery (ARS) for chronic
      gastroesophageal reflux disease (GERD). METHODS: Patients with esophagitis and/or
      chronic GERD were enrolled; 155 patients were randomized to ARS and 155 to long
      term omeprazole therapy. Baseline data were obtained and repeated after 3 years
      in 131 ARS patients and in 139 omeprazole-treated patients. Histopathologic
      status of the oxyntic mucosa was assessed according to the Sydney system.
      RESULTS: Forty omeprazole-treated patients were infected with H. pylori compared
      with 53 in the ARS group. Basal gastrin levels were significantly higher in H.
      pylori-infected patients, particularly in the omeprazole group. No further
      increases in serum gastrin levels were observed during 3 years. Despite 3 years
      of therapy, only slight changes were found in the prevalence of inflammation in
      the corpus mucosa of H. pylori-infected subjects. A slow progression of gastric
      glandular atrophy was observed in these patients irrespective of therapy with no
      obvious difference between treatment regimens. Intestinal metaplasia (all of type
      I) was only exceptionally observed with no difference between the treatment arms.
      CONCLUSIONS: Acid-suppressive therapy in the form of omeprazole maintained for 3
      years facilitates neither the development of gastric glandular atrophy of the
      corpus mucosa nor the occurrence of intestinal metaplasia in H. pylori-infected
      GERD patients.

PMID- 10419913
TI  - Differentiation and proliferation in Barrett's esophagus and the effects of acid
      suppression.
AB  - BACKGROUND & AIMS: Maintenance of normal epithelial differentiation and
      proliferation is an important goal in cancer chemoprevention. Because acid has a
      dynamic effect on cell proliferation/differentiation of Barrett's esophagus (BE)
      ex vivo, we investigated the relationship between differentiation, proliferation,
      and dysplasia in BE biopsy specimens and explored the role of normalization of
      intraesophageal pH in altering the BE phenotype. METHODS: Endoscopic biopsy
      specimens of BE (with or without dysplasia) were analyzed for (1) villin, a
      differentiation marker, by immunoblotting; (2) proliferating cell nuclear antigen
      (PCNA), a proliferation marker, by immunohistochemistry; and (3) dysplasia by
      histology before and after 6 months of normalization of intraesophageal pH
      (confirmed by 24-hour pH monitoring) with lansoprazole. RESULTS: At baseline,
      there was a negative correlation (r = -0.79) between villin and PCNA expression.
      Six months later, PCNA expression decreased and villin expression increased (P <
      0.001) in 24 patients whose intraesophageal pH normalized. Fifteen patients had
      persistently pathological intraesophageal acid reflux and no change in villin or
      PCNA expression. There were no differences in the occurrence of dysplasia after 6
      months in either group. CONCLUSIONS: In BE, there is an inverse relationship
      between villin and PCNA. In turn, dysplasia is unrelated to villin expression and
      well correlated with PCNA expression. Complete symptom eradication with
      lansoprazole does not guarantee normalization of intraesophageal pH profile in BE
      patients. Effective intraesophageal acid suppression favors differentiation and
      decreases proliferation. The intriguing possibility that acid suppression can be
      used to prevent dysplasia remains to be explored.

PMID- 10419914
TI  - Low rates of Helicobacter pylori reinfection in children.
AB  - BACKGROUND & AIMS: Reinfection after treatment for Helicobacter pylori is
      uncommon in adults. It is more likely to occur in children because they acquire
      primary infection. The aim of this study was to determine whether children are
      likely to become reinfected with H. pylori and if there are any risk factors for
      reinfection. METHODS: A prospective study of children who had documented evidence
      of successful treatment for H. pylori infection was performed. Sixty children
      were eligible for inclusion; results for 52 are presented. Children, parents, and
      siblings underwent [(13)C]urea breath tests. Details of family size and
      socioeconomic status were documented. Cox logistic regression analysis was used
      to determine the risk factors for reinfection. RESULTS: The duration of follow-up
      was 103.8 patient-years (mean +/- SD, 24 +/-14.0 months). Forty-six (88.5%) of
      the index children remained clear of infection, and 6 (11.5%) children were
      reinfected. The mean age of those who became reinfected was 5.8 +/- 5.6 years
      compared with 12.3 +/- 3.0 years for those who remained clear of infection (P =
      0.00001). Only 2 of 46 (4.3%) children older than 5 years of age were reinfected,
      although 80.8% had 1 infected parent and 65% of siblings were infected.
      Reinfection rate was 2.0% per person per year in children older than 5 years.
      Living with infected parents and siblings and low socioeconomic status were not
      risk factors for reinfection. In logistic regression analysis, age was the only
      risk factor for reinfection. CONCLUSIONS: Reinfection with H. pylori occurs
      rarely in children older than 5 years of age regardless of socioeconomic group or
      number of infected family members. These findings also indicate that it is not
      necessary to treat all family members to achieve long-term eradication of H.
      pylori.

PMID- 10419915
TI  - Relationship between the cagA 3' repeat region of Helicobacter pylori, gastric
      histology, and susceptibility to low pH.
AB  - BACKGROUND & AIMS: The variation in size of Helicobacter pylori CagA is related
      to repeat sequences in the 3' region of the cagA gene. We investigated whether
      structural subtypes of the cagA 3' region are associated with presentation of the
      infection or to susceptibility to acid. METHODS: We examined 319 cagA-positive H.
      pylori isolates: 84 isolates from Bogota, Colombia; 83 from Houston, Texas; 24
      from Siena, Italy; and 128 from Seoul, Korea. The cagA 3' region was amplified by
      polymerase chain reaction. Gastric histology and susceptibility to pH 3 were
      evaluated in relation to the number of cagA repeat regions. RESULTS: Strains with
      more than three repeat regions were associated with significantly higher scores
      for gastric mucosal atrophy and intestinal metaplasia than those with fewer
      repeat regions. H. pylori strains with three repeat regions were also
      significantly more susceptible to pH 3 than isolates with fewer repeat regions.
      CONCLUSIONS: H. pylori strains with more than three repeat regions in the 3'
      region of the cagA gene are associated with enhanced histological injury and with
      reduced survival in acidic conditions. It is hypothesized that these variants
      arise within the stomach.

PMID- 10419916
TI  - Reduced expression of cyclooxygenase 2 proteins in hereditary nonpolyposis
      colorectal cancers relative to sporadic cancers.
AB  - BACKGROUND & AIMS: Cyclooxygenase (COX) enzymes catalyze the conversion of
      arachidonic acid to prostaglandins. Evidence suggests that nonsteroidal anti
      inflammatory drugs reduce the risk of colorectal cancer (CRC) and that this
      effect is mediated through COX inhibition. We analyzed and compared expression of
      the inducible COX-2 isoform in colorectal neoplasms from patients with hereditary
      nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), and
      sporadic CRC. Given that COX-2 is induced by transforming growth factor (TGF)
      beta and that TGF-beta type II receptor (RII) mutations are found in HNPCCs, we
      determined the relationship between RII status and COX-2 expression. METHODS: COX
      2 protein expression was determined in colorectal epithelia using
      immunohistochemistry and Western blotting. Patients with HNPCC had known
      mutations in hMLH1 or hMSH2 genes and/or met the Amsterdam criteria. In CRCs from
      HNPCC cases, mutations were sought in the coding region of the RII gene using the
      polymerase chain reaction. RESULTS: COX-2 was detected in adenomas from 2 of 3
      HNPCC, 6 of 7 FAP, and 5 of 8 sporadic cases. In CRCs, COX-2 staining was found
      in 16 of 24 (67%) HNPCC vs. 24 of 26 (92%) sporadic cases (P = 0.035) and in 2 of
      2 FAP cases. Staining intensity was reduced in HNPCCs compared with sporadic CRCs
      (P = 0.035). Staining localized to the cytoplasm of neoplastic cells; normal
      epithelial cells were negative for COX-2. Overexpression of COX-2 in CRCs
      relative to normal mucosa was confirmed by Western blotting. TGF-beta RII
      mutations were detected in 12 of 14 HNPCCs examined, including 3 of 4 COX-2
      negative and 9 of 10 COX-2-positive cancers. CONCLUSIONS: The frequency and
      intensity of COX-2 expression was significantly reduced in HNPCCs relative to
      sporadic CRCs, and was not a consequence of RII mutations. Given that many HNPCCs
      express COX-2, inhibition of this enzyme may be an important strategy to prevent
      CRC in these patients.

PMID- 10419917
TI  - Chemokine receptor expression by human intestinal epithelial cells.
AB  - BACKGROUND & AIMS: Intestinal epithelial cells produce an array of
      proinflammatory chemokines that can provide signals to mucosal immune and
      inflammatory cells. To determine if chemokines can also signal epithelial cells,
      we characterized the expression of chemokine receptors on human colon epithelial
      cells in vitro and in vivo. METHODS: Expression of chemokine receptor messenger
      RNAs (mRNAs) by the human colon epithelial cell lines HT-29, HT-29.18.C1, Caco-2,
      T84, HCA-7, and LS174T was assessed by reverse-transcription polymerase chain
      reaction. Chemokine receptors on intestinal epithelial cells in vitro were
      determined by flow cytometry, and expression in vivo was determined by
      immunostaining of human colon. Interleukin (IL)-8 and growth-related (GRO) alpha
      secretion were assayed by enzyme-linked immunosorbent assay. RESULTS: Human colon
      epithelial cells constitutively expressed mRNAs for an array of CC and CXC
      chemokine receptors, including CCR1-8 and CXCR4, but little if any CXCR1 or
      CXCR2. Further studies focused on CXCR4 and CCR5 because mRNA for those chemokine
      receptors was abundantly expressed by each of the colon epithelial cell lines,
      and these receptors were present on the cell surface. Analogous to their
      localization on polarized cell lines, CXCR4 and CCR5 had a predominant apical
      and, to a lesser extent, basolateral distribution on human enterocytes, as
      demonstrated by immunostaining of human colon. Human colon epithelial cells
      stimulated with stromal cell-derived factor 1alpha and macrophage inflammatory
      protein (MIP)- 1alpha or MIP-1beta, which are the chemokine ligands for CXCR4 or
      CCR5, up-regulated production of the CXC chemokines IL-8 and GROalpha.
      CONCLUSIONS: Human colon epithelial cells express chemokine receptors. Human
      colonocytes have the potential to serve as targets for chemokine signaling.

PMID- 10419918
TI  - Modulation of intestinal epithelial wound healing in vitro and in vivo by
      lysophosphatidic acid.
AB  - BACKGROUND & AIMS: Lysophosphatidic acid (LPA) is assumed to play an important
      role in the modulation of injury and tissue repair in nonepithelial tissues. The
      effects of LPA on intestinal epithelial wound repair in vitro and in vivo were
      characterized. METHODS: Effects of LPA on intestinal epithelial restitution and
      proliferation were assessed by using an in vitro wounding model with confluent
      intestinal epithelial cell line 6 (IEC-6) monolayers and colorimetric thiazolyl
      blue (MTT) assays. In addition, LPA signaling pathways were characterized.
      Effects of LPA on intestinal wound healing in vivo were studied by using the
      trinitrobenzene model of colitis in rats. RESULTS: LPA significantly enhanced
      migration and inhibited cell proliferation of IEC-6 cells in vitro. The effects
      on intestinal epithelial cell migration and proliferation were mediated through
      transforming growth factor beta (TGF-beta)-independent pathways and binding to a
      G-protein receptor. In addition, LPA significantly ameliorated intestinal
      epithelial injury in the trinitrobenzene model of colitis in rats. CONCLUSIONS:
      These findings suggest that LPA enhances intestinal epithelial wound healing by
      modulation of intestinal epithelial cell migration and proliferation through TGF
      beta-independent pathways. Thus, exogenous administration of LPA may provide a
      new approach for modulating intestinal injury in vivo.

PMID- 10419919
TI  - Surgically induced leukocytic infiltrates within the rat intestinal muscularis
      mediate postoperative ileus.
AB  - BACKGROUND & AIMS: Postoperative ileus is a poorly understood and common problem.
      We previously demonstrated an association between a suppression in jejunal
      circular muscle activity and a massive extravasation of leukocytes into the
      muscularis after surgical manipulation of the small bowel. This study was pursued
      to establish a direct causal link between these events. METHODS: Reverse
      transcription polymerase chain reaction and immunohistochemistry were used to
      detect and localize expression of adhesion molecules: P-selectin, intercellular
      adhesion molecule 1 (ICAM-1), and lymphocyte function-associated antigen 1 (LFA
      1). Leukocyte infiltration and in vitro jejunal circular muscle function were
      quantified in controls and manipulated animals with and without antibody
      treatment (1A29, WT.1, and WT.3). RESULTS: Surgical manipulation caused a
      significant up-regulation within the muscularis of ICAM-1 and P-selectin
      messenger RNA. ICAM-1 and P-selectin protein expression was increased within the
      muscularis microvasculature, and ICAM-1 and LFA-1 were expressed on infiltrating
      cells. Administration of adhesion molecule antibodies prevented the recruitment
      of monocytes and neutrophils into the muscularis and also averted jejunal
      circular muscle dysfunction. CONCLUSIONS: The data demonstrate that adhesion
      molecule antibodies prevent surgically induced suppression of intestinal muscle
      contractions and therefore suggests that late postoperative ileus is mediated
      through a leukocytic inflammatory response within the intestinal muscularis
      externa.

PMID- 10419920
TI  - Kappa opioid receptor agonists differentially inhibit two classes of rat spinal
      neurons excited by colorectal distention.
AB  - BACKGROUND & AIMS: Quantitative neurophysiological studies have identified the
      presence of at least 2 spinal neuronal populations (abrupt and sustained) that
      are excited by the noxious visceral stimulus colorectal distention. This study
      examined the effects of the kappa opioid receptor agonists fedotozine and U50488H
      on the activity of these neurons. METHODS: In decerebrate, cervical spinal cord
      transected male rats, the lumbosacral spinal cord was exposed by a laminectomy.
      Dorsal horn neurons showing excitatory responses to colorectal distention (80 mm
      Hg, 20 seconds) were identified using microelectrodes. Cumulative doses of
      fedotozine and U50488H were administered intravenously or intrathecally, and
      antagonists were used. RESULTS: Intravenous fedotozine and U50488H dose
      dependently inhibited the evoked activity of sustained neurons. This inhibition
      was partially reversed by the kappa opioid antagonist norbinaltorphimine. The
      same agents had insignificant effects on the evoked activity of abrupt neurons.
      Fedotozine inhibited spontaneous activity of both abrupt and sustained neurons.
      Intrathecally administered U50488H had no effect on abrupt or sustained neurons,
      but intrathecally administered fedotozine inhibited the evoked and spontaneous
      activity of both groups. CONCLUSIONS: Kappa opioid receptor agonists acting
      peripherally had differential effects on 2 spinal neuronal populations responsive
      to colorectal distention. Fedotozine had additional inhibitory effects acting
      within the spinal cord.

PMID- 10419921
TI  - Methotrexate improves biochemical tests in patients with primary biliary
      cirrhosis who respond incompletely to ursodiol.
AB  - BACKGROUND & AIMS: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver
      disease of presumed autoimmune etiology. Ursodeoxycholic acid (UDCA),
      methotrexate, and colchicine each have shown promise in its treatment. The value
      of combining 2 or 3 of these drugs is uncertain. The aim of this study was to
      determine whether addition of methotrexate to the treatment regimen improves
      results of liver biochemical tests in patients with antimitochondrial antibody
      positive PBC who responded incompletely to treatment with UDCA and colchicine.
      METHODS: Methotrexate was added to the treatment regimen of 10 consecutive
      patients with antimitochondrial antibody-positive PBC who had an incomplete
      response to therapy with UDCA alone or in combination with colchicine. The
      primary end point was biochemical response. Symptoms and histological changes
      were also recorded. RESULTS: Addition of methotrexate to the UDCA plus colchicine
      regimen was associated with a significant reduction in serum alkaline phosphatase
      (ALP) levels beyond those found with UDCA and colchicine alone or in combination.
      Median ALP concentration was 389 IU (range, 247-1013 IU) at baseline, 300 IU
      (range, 155-467 IU) after treatment with UDCA plus colchicine, and 120 IU (range,
      66-351 IU) after treatment with methotrexate. CONCLUSIONS: Addition of
      methotrexate to a regimen of UDCA and colchicine may be beneficial for patients
      with PBC who respond incompletely to treatment with UDCA and colchicine.

PMID- 10419922
TI  - Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term
      results of a placebo-controlled trial.
AB  - BACKGROUND & AIMS: New treatments for primary biliary cirrhosis (PBC) need to be
      evaluated. We conducted a single-center double-blind, randomized trial of
      methotrexate, 7.5 mg/wk (n = 30), vs. placebo (n = 30) for up to 6 years in PBC.
      METHODS: Methods included three monthly symptom assessment and liver function
      tests and liver biopsy and gastroscopy at baseline, after 2 years, and after 4-6
      years. RESULTS: Patients randomized to methotrexate had, compared with patients
      randomized to placebo, (1) significantly lower on-treatment serum alkaline
      phosphatase, gamma-glutamyltransferase, immunoglobulin (Ig) M, IgG, and (after 24
      months) aspartate aminotransferase and alanine aminotransferase levels (P < 0.02
      0.001 by analysis of covariance to adjust for baseline differences); (2) a
      nonsignificant trend toward lower on-treatment pruritus scores; (3) similar on
      treatment Knodell inflammatory scores but nonsignificant trends toward lower
      Knodell fibrosis score and less ductopenia; (4) a trend toward greater increases
      in serum bilirubin level and Mayo score with time (both significant after 5 years
      of follow-up); and (5) a 2.9-fold (95% confidence interval, 0.85-10.25-fold)
      increase the rate of death or liver transplantation as a result of liver disease
      during or after the trial (P = 0.09) in a Cox multivariate regression analysis
      compared with patients randomized to placebo. CONCLUSIONS: These results do not
      support the clinical use of low-dose methotrexate in PBC.

PMID- 10419924
TI  - Risk of a first community-acquired spontaneous bacterial peritonitis in
      cirrhotics with low ascitic fluid protein levels.
AB  - BACKGROUND & AIMS: Long-term primary antibiotic prophylaxis of spontaneous
      bacterial peritonitis has been suggested to be useful in cirrhotic patients with
      low ascitic fluid protein levels. However, it is unlikely that all such patients
      need prophylactic treatment. The aim of this study was to identify the group of
      cirrhotic patients with low ascitic fluid protein levels at high risk of
      developing a first episode of spontaneous bacterial peritonitis during outpatient
      follow-up. METHODS: One hundred nine cirrhotic patients with low ascitic fluid
      protein levels and without previous episodes of spontaneous bacterial peritonitis
      were followed up in an outpatient clinic. RESULTS: Twenty-eight patients
      developed a first spontaneous bacterial peritonitis episode. In the multivariate
      analysis, serum bilirubin level (>3.2 mg /dL) and platelet count (<98.000/mm(3))
      independently correlated with the risk of developing the first spontaneous
      bacterial peritonitis (P < 0.01 and P < 0.05, respectively). According to the
      median relative risk coefficient, a low-risk group (relative risk <1.09) and a
      high-risk group (relative risk >1.09) were established. The probability of
      developing a first spontaneous bacterial peritonitis episode at 1-year follow-up
      was significantly higher in the high risk-group (low-risk group, 23.6%; high-risk
      group, 55%; P < 0.01) as a consequence of a higher probability of the first
      community-acquired episode (13.7% vs. 47.6%, respectively, P < 0.01). One-year
      probability of survival was significantly lower in the high-risk group (low-risk
      group, 57.6%; high-risk group, 38%, P < 0.05). CONCLUSIONS: Cirrhotic patients
      with low ascitic fluid protein levels (</=1 g /dL) and high bilirubin level
      and/or low platelet count are at high risk of developing a first episode of
      spontaneous bacterial peritonitis during long-term follow-up.

PMID- 10419923
TI  - Interferon-ribavirin for chronic hepatitis C with and without cirrhosis: analysis
      of individual patient data of six controlled trials. Eurohep Study Group for
      Viral Hepatitis.
AB  - BACKGROUND & AIMS: The aim of this study was to compare interferon (IFN)
      ribavirin combination therapy with IFN monotherapy in chronic hepatitis C with
      particular focus on its efficacy in cirrhosis. METHODS: A multivariate analysis
      of individual patient data of all randomized controlled trials using an IFN
      ribavirin arm, reported between 1991 and March 1998, was performed. Centers
      included 1 Asian and 5 European university-based referral centers for liver
      disease. A total of 197 patients with chronic hepatitis C received IFN-alpha (3
      MU three times weekly) and ribavirin (1-1.2 g daily) for 6 months, and 147
      patients received IFN-alpha (3 MU three times weekly) for 6 months. Patients were
      characterized according to previous IFN therapy, presence of cirrhosis, and
      genotype 1. Efficacy of therapy was evaluated by assessing the sustained response
      rate by logistic regression analysis. RESULTS: Patients without cirrhosis treated
      with IFN-ribavirin had a significantly higher sustained response rate than those
      treated with IFN, approximately 3-fold for previously untreated patients (IFN
      ribavirin: genotype 1, 33%; genotype 2/3, 65%; IFN: genotype 1, 8%; genotype 2/3,
      24%). In cirrhosis, sustained response rates with IFN-ribavirin (previously
      untreated: genotype 1, 7%; genotype 2/3, 24%) were also significantly higher than
      those with IFN (previously untreated: genotype 1, 1%; genotype 2/3, 5%). Clinical
      relevant superiority of combination therapy over IFN monotherapy was also
      observed for relapse; the same trend was observed for nonresponders. Tolerance
      for IFN-ribavirin was similar for patients with or without cirrhosis.
      CONCLUSIONS: Combination with ribavirin significantly enhances the sustained
      response rate of IFN therapy in major patient types (cirrhosis, genotype 1) with
      chronic hepatitis C. Thus, IFN-ribavirin combination is likely to become the
      antiviral therapy of choice for cirrhosis caused by hepatitis C.

PMID- 10419925
TI  - Vasoactive intestinal polypeptide is a potent regulator of bile secretion from
      rat cholangiocytes.
AB  - BACKGROUND & AIMS: Vasoactive intestinal polypeptide (VIP) is a neuropeptide with
      diverse biological functions including stimulatory effects on bile secretion. The
      effects of VIP on bile secretion and its site of action were examined. METHODS:
      Choleretic effects of VIP were examined using isolated perfused livers,
      hepatocyte couplets, isolated bile duct units, and cholangiocytes from rat liver.
      RESULTS: VIP (100 nmol/L) produced a small increase in bile flow and bile salt
      output in taurocholate-supplemented isolated perfused livers but had no
      significant effect on bile flow in the absence of bile salt supplements or on
      fluid secretion in isolated hepatocyte couplets. In addition, VIP significantly
      increased bile pH, bicarbonate concentration, and output in the isolated perfused
      livers from both normal and 2 week bile duct-ligated rats, although bile flow
      increased only in the bile duct-ligated model. VIP also produced a dose-dependent
      increase in fluid secretion in isolated bile duct units, which was inhibited
      significantly by VIP antagonist, a specific VIP receptor inhibitor. This VIP
      stimulated secretory response in isolated bile duct units was more potent than
      those produced by bombesin or secretin. Neither somatostatin nor substance P
      inhibited the VIP response in isolated bile duct units. In contrast to secretin,
      VIP had no significant effect on adenosine 3', 5'-cyclic monophosphate (cAMP)
      levels in isolated cholangiocytes. CONCLUSIONS: VIP is a potent stimulant of
      fluid and bicarbonate secretion from cholangiocytes via cAMP-independent
      pathways, suggesting that this neuropeptide plays a major regulatory role in
      biliary transport and secretion.

PMID- 10419926
TI  - Successful management of Crohn's disease of the ileoanal pouch with infliximab.
AB  - This study reports the clinical benefit and safety of the murine chimeric anti
      tumor necrosis factor (TNF)-alpha monoclonal antibody, infliximab, in the
      treatment of patients who developed findings compatible with Crohn's disease
      after undergoing colectomy with ileal-pouch anal anastomosis (IPAA) for an
      original diagnosis of ulcerative colitis. Medical records of 7 patients with
      Crohn's disease and an IPAA treated with infliximab were reviewed. Clinical
      response was classified as complete response, partial response, and no response.
      Concurrent treatment with immune modifier agents and/or antibiotics was recorded.
      Seven patients with active inflammatory or fistulizing Crohn's disease and an
      IPAA performed for diagnosis of ulcerative colitis were treated with infliximab
      after they had no response to conventional therapies. Patients received 1-4
      infliximab infusions at a dose of 5 mg/kg. All patients improved clinically. Six
      patients had a complete response, and 1 had a partial response. Four of the 5
      patients with complex perianal and fistulizing disease had closure of all fistula
      tracts, and 1 patient improved temporarily. Six of the 7 patients underwent
      concurrent treatment with immune modifier drugs. One patient had myalgias and
      malaise after the first infliximab infusion and flu-like symptoms after the
      second one. No other adverse effects were observed. This case series demonstrates
      that the murine chimeric anti-TNF-alpha monoclonal antibody, infliximab, can be
      used successfully to treat patients with Crohn's disease involving an IPAA who
      are refractory to conventional therapies.

PMID- 10419927
TI  - Signal transduction and hepatocellular bile acid transport: cross talk between
      bile acids and second messengers.

PMID- 10419929
TI  - List of available training programs 

PMID- 10419928
TI  - Pitfalls in the analysis of electrogastrographic recordings.
AB  - Electrogastrography (EGG) is a noninvasive method to study gastric myoelectrical
      activity in humans. Because frequency characteristics are the most reliable
      parameters and visual analysis of the EGG recordings is notoriously difficult,
      automated frequency analysis, especially running spectrum analysis, is often
      used. However, EGG frequency spectra can be misinterpreted easily. Movement
      artifacts and noise from various sources can result in abnormal frequency spectra
      with significant power in the low-frequency and high-frequency range, or even
      make the EGG completely uninterpretable. Signals that differ from a sinusoid
      waveform have harmonics in the high-frequency range of the spectrum and may be
      interpreted as abnormal. Visual inspection of raw signals and frequency spectra
      remains essential in the analysis of EGG signals. The value of computerized
      analysis should not be overrated. EGG is an important research tool, but a
      clinical role still needs to be established.

PMID- 10419930
TI  - Screening flexible sigmoidoscopy: effectiveness is not enough.

PMID- 10419931
TI  - Deflating postoperative ileus.

PMID- 10419932
TI  - Methotrexate in the treatment of primary biliary cirrhosis: the hype and the
      hope.

PMID- 10419933
TI  - Identifying new risk factors for spontaneous bacterial peritonitis: how important
      is it?

PMID- 10419934
TI  - Transforming growth factor beta and tumor-suppressing pathways: it doesn't matter
      how you get there, as long as you get there.

PMID- 10419935
TI  - Transplantation for hepatitis C: good news and bad news.

PMID- 10419937
TI  - Viral hepatitis 

PMID- 10419936
TI  - Floating the molecular machinery for t-cell activation.

PMID- 10419938
TI  - Iron acquisition and metabolism by mycobacteria.

PMID- 10419939
TI  - Evidence for a holin-like protein gene fully embedded out of frame in the
      endolysin gene of Staphylococcus aureus bacteriophage 187.
AB  - We have cloned, sequenced, and characterized the genes encoding the lytic system
      of the unique Staphylococcus aureus phage 187. The endolysin gene ply187 encodes
      a large cell wall-lytic enzyme (71.6 kDa). The catalytic site, responsible for
      the hydrolysis of staphylococcal peptidoglycan, was mapped to the N-terminal
      domain of the protein by the expression of defined ply187 domains. This
      enzymatically active N terminus showed convincing amino acid sequence homology to
      an N-acetylmuramoyl-L-alanine amidase, whereas the C-terminal part, whose
      function is unknown, revealed striking relatedness to major staphylococcal
      autolysins. An additional reading frame was identified entirely embedded out of
      frame (+1) within the 5' region of ply187 and was shown to encode a small,
      hydrophobic protein of holin-like function. The hol187 gene features a dual-start
      motif, possibly enabling the synthesis of two products of different lengths (57
      and 55 amino acids, respectively). Overproduction of Hol187 in Escherichia coli
      resulted in growth retardation, leakiness of the cytoplasmic membrane, and loss
      of de novo ATP synthesis. Compared to other holins identified to date, Hol187
      completely lacks the highly charged C terminus. The secondary structure of the
      polypeptide is predicted to consist of two small, antiparallel, hydrophobic,
      transmembrane helices. These are supposed to be essential for integration into
      the membrane, since site-specific introduction of negatively charged amino acids
      into the first transmembrane domain (V7D G8D) completely abolished the function
      of the Hol187 polypeptide. With antibodies raised against a synthetic 18-mer
      peptide representing a central part of the protein, it was possible to detect
      Hol187 in the cytoplasmic membrane of phage-infected S. aureus cells. An
      important indication that the protein actually functions as a holin in vivo was
      that the gene (but not the V7D G8D mutation) was able to complement a phage
      lambda Sam mutation in a nonsuppressing E. coli HB101 background. Plaque
      formation by lambdagt11::hol187 indicated that both phage genes have analogous
      functions. The data presented here indicate that a putative holin is encoded on a
      different reading frame within the enzymatically active domain of ply187 and that
      the holin is synthesized during the late stage of phage infection and found in
      the cytoplasmic membrane, where it causes membrane lesions which are thought to
      enable access of Ply187 to the peptidoglycan of phage-infected Staphylococcus
      cells.

PMID- 10419940
TI  - Isolation and properties of the complex between the enhancer binding protein NIFA
      and the sensor NIFL.
AB  - In Azotobacter vinelandii, activation of nif gene expression by the
      transcriptional regulatory enhancer binding protein NIFA is controlled by the
      sensor protein NIFL in response to changes in levels of oxygen and fixed nitrogen
      in vivo. NIFL is a novel redox-sensing flavoprotein which is also responsive to
      adenosine nucleotides in vitro. Inhibition of NIFA activity by NIFL requires
      stoichiometric amounts of the two proteins, implying that the mechanism of
      inhibition is by direct protein-protein interaction rather than by catalytic
      modification of the NIFA protein. The formation of the inhibitory complex between
      NIFL and NIFA may be regulated by the intracellular ATP/ADP ratio. We show that
      adenosine nucleotides promote complex formation between purified NIFA and NIFL in
      vitro, allowing isolation of the NIFL-NIFA complex. The complex can also be
      isolated from cell extracts containing coexpressed NIFL and NIFA in the presence
      of MgADP. Removal of the nucleotide causes dissociation of the complex.
      Experiments with truncated proteins demonstrate that the amino-terminal domain of
      NIFA and the C-terminal region of NIFL potentiate the ADP-dependent stimulation
      of NIFL-NIFA complex formation.

PMID- 10419941
TI  - Genomic relatedness of Chlamydia isolates determined by amplified fragment length
      polymorphism analysis.
AB  - The genomic relatedness of 19 Chlamydia pneumoniae isolates (17 from respiratory
      origin and 2 from atherosclerotic origin), 21 Chlamydia trachomatis isolates (all
      serovars from the human biovar, an isolate from the mouse biovar, and a porcine
      isolate), 6 Chlamydia psittaci isolates (5 avian isolates and 1 feline isolate),
      and 1 Chlamydia pecorum isolate was studied by analyzing genomic amplified
      fragment length polymorphism (AFLP) fingerprints. The AFLP procedure was adapted
      from a previously developed method for characterization of clinical C.
      trachomatis isolates. The fingerprints of all C. pneumoniae isolates were nearly
      identical, clustering together at a Dice similarity of 92.6% (+/- 1.6% standard
      deviation). The fingerprints of the C. trachomatis isolates of human, mouse, and
      swine origin were clearly distinct from each other. The fingerprints of the
      isolates from the human biovar could be divided into at least 12 different types
      when the presence or absence of specific bands was taken into account. The C.
      psittaci fingerprints could be divided into a parakeet, a pigeon, and a feline
      type. The fingerprint of C. pecorum was clearly distinct from all others. Cluster
      analysis of selected isolates from all species revealed groups other than those
      based on sequence data from single genes (in particular, omp1 and rRNA genes) but
      was in agreement with available DNA-DNA hybridization data. In conclusion,
      cluster analysis of AFLP fingerprints of representatives of all species provided
      suggestions for a grouping of chlamydiae based on the analysis of the whole
      genome. Furthermore, genomic AFLP analysis showed that the genome of C.
      pneumoniae is highly conserved and that no differences exist between isolates of
      respiratory and atherosclerotic origins.

PMID- 10419942
TI  - Role of TolR N-terminal, central, and C-terminal domains in dimerization and
      interaction with TolA and tolQ.
AB  - The Tol-PAL system of Escherichia coli is a multiprotein system involved in
      maintaining the cell envelope integrity and is necessary for the import of some
      colicins and phage DNA into the bacterium. It is organized into two complexes,
      one near the outer membrane between TolB and PAL and one in the cytoplasmic
      membrane between TolA, TolQ, and TolR. In the cytoplasmic membrane, all of the
      Tol proteins have been shown to interact with each other. Cross-linking
      experiments have shown that the TolA transmembrane domain interacts with TolQ and
      TolR. Suppressor mutant analyses have localized the TolQ-TolA interaction to the
      first transmembrane domain of TolQ and have shown that the third transmembrane
      domain of TolQ interacts with the transmembrane domain of TolR. To get insights
      on the composition of the cytoplasmic membrane complex and its possible contacts
      with the outer membrane complex, we focused our attention on TolR. Cross-linking
      and immunoprecipitation experiments allowed the identification of Tol proteins
      interacting with TolR. The interactions of TolR with TolA and TolQ were
      confirmed, TolR was shown to dimerize, and the resulting dimer was shown to
      interact with TolQ. Deletion mutants of TolR were constructed, and they allowed
      us to determine the TolR domains involved in each interaction. The TolR
      transmembrane domain was shown to be involved in the TolA-TolR and TolQ-TolR
      interactions, while TolR central and C-terminal domains appeared to be involved
      in TolR dimerization. The role of the TolR C-terminal domain in the TolA-TolR
      interaction and its association with the membranes was also demonstrated.
      Furthermore, phenotypic studies clearly showed that the three TolR domains (N
      terminal, central, and C terminal) and the level of TolR production are important
      for colicin A import and for the maintenance of cell envelope integrity.

PMID- 10419943
TI  - Autogenous regulation of the Bacillus anthracis pag operon.
AB  - Protective antigen (PA) is an important component of the edema and lethal toxins
      produced by Bacillus anthracis. PA is essential for binding the toxins to the
      target cell receptor and for facilitating translocation of the enzymatic toxin
      components, edema factor and lethal factor, across the target cell membrane. The
      structural gene for PA, pagA (previously known as pag), is located on the 182-kb
      virulence plasmid pXO1 at a locus distinct from the edema factor and lethal
      factor genes. Here we show that a 300-bp gene located downstream of pagA is
      cotranscribed with pagA and represses expression of the operon. We have
      designated this gene pagR (for protective antigen repressor). Two pagA mRNA
      transcripts were detected in cells producing PA: a short, 2.7-kb transcript
      corresponding to the pagA gene, and a longer, 4.2-kb transcript representing a
      bicistronic message derived from pagA and pagR. The 3' end of the short
      transcript mapped adjacent to an inverted repeat sequence, suggesting that the
      sequence can act as a transcription terminator. Attenuation of termination at
      this site results in transcription of pagR. A pagR mutant exhibited increased
      steady-state levels of pagA mRNA, indicating that pagR negatively controls
      expression of the operon. Autogenous control of the operon may involve atxA, a
      trans-acting positive regulator of pagA. The steady-state level of atxA mRNA was
      also increased in the pagR mutant. The mutant phenotype was complemented by
      addition of pagR in trans on a multicopy plasmid.

PMID- 10419944
TI  - Outer membrane changes in a toluene-sensitive mutant of toluene-tolerant
      Pseudomonas putida IH-2000.
AB  - We isolated a toluene-sensitive mutant, named mutant No. 32, which showed
      unchanged antibiotic resistance levels, from toluene-tolerant Pseudomonas putida
      IH-2000 by transposon mutagenesis with Tn5. The gene disrupted by insertion of
      Tn5 was identified as cyoC, which is one of the subunits of cytochrome o. The
      membrane protein, phospholipid, and lipopolysaccharide (LPS) of IH-2000 and that
      of mutant No. 32 were examined and compared. Some of the outer membrane proteins
      showed a decrease in mutant No. 32. The fatty acid components of LPS were found
      to be dodecanoic acid, 2-hydroxydodecanoic acid, 3-hydroxydodecanoic acid, and 3
      hydroxydecanoic acid in both IH-2000 and No. 32; however, the relative
      proportions of these components differed in the two strains. Furthermore, cell
      surface hydrophobicity was increased in No. 32. These data suggest that mutation
      of cyoC caused the decrease in outer membrane proteins and the changing fatty
      acid composition of LPS. These changes in the outer membrane would cause an
      increase in cell surface hydrophobicity, and mutant No. 32 is considered to be
      sensitive to toluene.

PMID- 10419945
TI  - Escherichia coli open reading frame 696 is idi, a nonessential gene encoding
      isopentenyl diphosphate isomerase.
AB  - Isopentenyl diphosphate isomerase catalyzes the interconversion of isopentenyl
      diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). In eukaryotes,
      archaebacteria, and some bacteria, IPP is synthesized from acetyl coenzyme A by
      the mevalonate pathway. The subsequent isomerization of IPP to DMAPP activates
      the five-carbon isoprene unit for subsequent prenyl transfer reactions. In
      Escherichia coli, the isoprene unit is synthesized from pyruvate and
      glyceraldehyde-3-phosphate by the recently discovered nonmevalonate pathway. An
      open reading frame (ORF696) encoding a putative IPP isomerase was identified in
      the E. coli chromosome at 65.3 min. ORF696 was cloned into an expression vector;
      the 20.5 kDa recombinant protein was purified in three steps, and its identity as
      an IPP isomerase was established biochemically. The gene for IPP isomerase, idi,
      is not clustered with other known genes for enzymes in the isoprenoid pathway. E.
      coli FH12 was constructed by disruption of the chromosomal idi gene with the
      aminoglycoside 3'-phosphotransferase gene and complemented by the wild-type idi
      gene on plasmid pFMH33 with a temperature-sensitive origin of replication.
      FH12/pFMH33 was able to grow at the restrictive temperature of 44 degrees C and
      FH12 lacking the plasmid grew on minimal medium, thereby establishing that idi is
      a nonessential gene. Although the V(max) of the bacterial protein was 20-fold
      lower than that of its yeast counterpart, the catalytic efficiencies of the two
      enzymes were similar through a counterbalance in K(m)s. The E. coli protein
      requires Mg(2+) or Mn(2+) for activity. The enzyme contains conserved cysteine
      and glutamate active-site residues found in other IPP isomerases.

PMID- 10419946
TI  - Isolation of additional bacteriophages with genomes of segmented double-stranded
      RNA.
AB  - Eight different bacteriophages were isolated from leaves of Pisum sativum,
      Phaseolus vulgaris, Lycopersicon esculentum, Daucus carota sativum, Raphanus
      sativum, and Ocimum basilicum. All contain three segments of double-stranded RNA
      and have genomic-segment sizes that are similar but not identical to those of
      previously described bacteriophage phi6. All appear to have lipid-containing
      membranes. The base sequences of some of the viruses are very similar but not
      identical to those of phi6. Three of the viruses have little or no base sequence
      identity to phi6. Two of the viruses, phi8 and phi12, contain proteins with a
      size distribution very different from that of phi6 and do not package genomic
      segments of phi6. Whereas phi6 attaches to host cells by means of a pilus,
      several of the new isolates attach directly to the outer membrane. Although the
      normal hosts of these viruses seem to be pseudomonads, those viruses that attach
      directly to the outer membrane can establish carrier states in Escherichia coli
      or Salmonella typhimurium. One of the isolates, phi8, can form plaques on
      heptoseless strains of S. typhimurium.

PMID- 10419947
TI  - Characterization of an atypical superoxide dismutase from Sinorhizobium meliloti.
AB  - Sinorhizobium meliloti Rm5000 is an aerobic bacterium that can live free in the
      soil or in symbiosis with the roots of leguminous plants. A single detectable
      superoxide dismutase (SOD) was found in free-living growth conditions. The
      corresponding gene was isolated from a genomic library by using a sod fragment
      amplified by PCR from degenerate primers as a probe. The sodA gene was located in
      the chromosome. It is transcribed monocistronically and encodes a 200-amino-acid
      protein with a theoretical M(r) of 22,430 and pI of 5. 8. S. meliloti SOD
      complemented a deficient E. coli mutant, restoring aerobic growth of a sodA sodB
      recA strain, when the gene was expressed from the synthetic tac promoter but not
      from its own promoter. Amino acid sequence alignment showed great similarity with
      Fe-containing SODs (FeSODs), but the enzyme was not inactivated by H(2)O(2). The
      native enzyme was purified and found to be a dimeric protein, with a specific
      activity of 4,000 U/mg. Despite its Fe-type sequence, atomic absorption
      spectroscopy showed manganese to be the cofactor (0.75 mol of manganese and 0.24
      mol of iron per mol of monomer). The apoenzyme was prepared from crude extracts
      of S. meliloti. Activity was restored by dialysis against either MnCl(2) or
      Fe(NH(4))(2)(SO(4))(2), demonstrating the cambialistic nature of the S. meliloti
      SOD. The recovered activity with manganese was sevenfold higher than with iron.
      Both reconstituted enzymes were resistant to H(2)O(2). Sequence comparison with
      70 FeSODs and MnSODs indicates that S. meliloti SOD contains several atypical
      residues at specific sites that might account for the activation by manganese and
      resistance to H(2)O(2) of this unusual Fe-type SOD.

PMID- 10419948
TI  - Citromicrobium bathyomarinum, a novel aerobic bacterium isolated from deep-sea
      hydrothermal vent plume waters that contains photosynthetic pigment-protein
      complexes.
AB  - We have taxonomically and phylogenetically characterized a new aerobic bacterial
      strain (JF-1) that contains photosynthetic pigment-protein complexes and which
      was recently isolated from black smoker plume waters of the Juan de Fuca Ridge.
      Strain JF-1 is a gram-negative, yellow-pigmented, motile bacterium that is salt-,
      pH-, and thermotolerant. These properties are consistent with an oligotrophic
      adaptation to varied environmental conditions thought to exist around deep-sea
      hydrothermal vents. The analysis of 16S rDNA sequences revealed that strain JF-1
      forms a separate phylogenetic branch between the genus Erythromonas and the
      Erythromicrobium-Porphyrobacter-Erythrobacter cluster within the alpha subclass
      of the Proteobacteria. The taxonomic name Citromicrobium bathyomarinum (gen.
      nov., sp. nov.) is proposed for strain JF-1.

PMID- 10419949
TI  - Cloning, sequence, and transcriptional regulation of the operon encoding a
      putative N-acetylmannosamine-6-phosphate epimerase (nanE) and sialic acid lyase
      (nanA) in Clostridium perfringens.
AB  - Clostridium perfringens can obtain sialic acid from host tissues by the activity
      of sialidase enzymes on sialoglycoconjugates. After sialic acid is transported
      into the cell, sialic acid lyase (NanA) then catalyzes the hydrolysis of sialic
      acid into pyruvate and N-acetylmannosamine. The latter is converted for use as a
      biosynthetic intermediate or carbohydrate source in a pathway including an
      epimerase (NanE) that converts N-acetylmannosamine-6-phosphate to N
      acetylglucosamine-6-phosphate. A 4.0-kb DNA fragment from C. perfringens NCTC
      8798 that contains the nanE and nanA genes has been cloned. The identification of
      the nanA gene product as sialic acid lyase was confirmed by overexpressing the
      gene and measuring sialic acid lyase activity in a nanA Escherichia coli strain,
      EV78. The nanA gene product was also shown to restore growth to EV78 in minimal
      medium with sialic acid as the sole carbon source. By using Northern blot
      experiments, it was demonstrated that the nanE and nanA genes comprise an operon
      and that transcription of the operon in C. perfringens is inducible by the
      addition of sialic acid to the growth medium. The Northern blot experiments also
      showed that there is no catabolite repression of nanE-nanA transcription by
      glucose. With a plasmid construct containing a promoterless cpe-gusA gene fusion,
      in which beta-glucuronidase activity indicated that the gusA gene acted as a
      reporter for transcription, a promoter was localized to the region upstream of
      the nanE gene. Primer extension experiments then allowed us to identify a sialic
      acid-inducible promoter located 30 bp upstream of the nanE coding sequence.

PMID- 10419951
TI  - Mutational analysis and membrane topology of ComP, a quorum-sensing histidine
      kinase of Bacillus subtilis controlling competence development.
AB  - ComP is a sensor histidine kinase of Bacillus subtilis required for the signal
      transduction pathway that initiates the development of competence for genetic
      transformation. It is believed that ComP senses the presence of ComX, a modified
      extracellular peptide pheromone, and donates a phosphate to ComA, thereby
      activating this transcription factor for binding to the srfA promoter. In the
      present study, fusions to the Escherichia coli proteins PhoA and LacZ and
      analysis of its susceptibility to the protease kallikrein were used to probe the
      membrane topology of ComP. These data suggest that ComP contains six or eight
      membrane-spanning segments and two large extracytoplasmic loops in its N-terminal
      membrane-associated domain. Deletions were introduced involving the large
      extracellular loops to explore the role of the N-terminal domain of ComP in
      signal transduction. The absence of the second loop conferred a phenotype in
      which ComP was active in the absence of ComX. The implications of these data are
      discussed.

PMID- 10419952
TI  - Illegitimate recombination induced by overproduction of DnaB helicase in
      Escherichia coli.
AB  - Illegitimate recombination that usually takes place at a low frequency is greatly
      enhanced by treatment with DNA-damaging agents. It is thought that DNA double
      strand breaks induced by this DNA damage are important for initiation of
      illegitimate recombination. Here we show that illegitimate recombination is
      enhanced by overexpression of the DnaB protein in Escherichia coli. The
      recombination enhanced by DnaB overexpression occurred between short regions of
      homology. We propose a model for the initiation of illegitimate recombination in
      which DnaB overexpression may excessively unwind DNA at replication forks and
      induce double-strand breaks, resulting in illegitimate recombination. The defect
      in RecQ has a synergistic effect on the increased illegitimate recombination in
      cells containing the overproduced DnaB protein, implying that DnaB works in the
      same pathway as RecQ does but that they work at different steps.

PMID- 10419950
TI  - Transcriptional activation of Agrobacterium tumefaciens virulence gene promoters
      in Escherichia coli requires the A. tumefaciens RpoA gene, encoding the alpha
      subunit of RNA polymerase.
AB  - The two-component regulatory system, composed of virA and virG, is indispensable
      for transcription of virulence genes within Agrobacterium tumefaciens. However,
      virA and virG are insufficient to activate transcription from virulence gene
      promoters within Escherichia coli cells, indicating a requirement for additional
      A. tumefaciens genes. In a search for these additional genes, we have identified
      the rpoA gene, encoding the alpha subunit of RNA polymerase (RNAP), which confers
      significant expression of a virB promoter (virBp)::lacZ fusion in E. coli in the
      presence of an active transcriptional regulator virG gene. We conducted in vitro
      transcription assays using either reconstituted E. coli RNAP or hybrid RNAP in
      which the alpha subunit was derived from A. tumefaciens. The two forms of RNAP
      were equally efficient in transcription from a sigma(70)-dependent E. coli galP1
      promoter; however, only the hybrid RNAP was able to transcribe virBp in a virG
      dependent manner. In addition, we provide evidence that the alpha subunit from A.
      tumefaciens, but not from E. coli, is able to interact with the VirG protein.
      These data suggest that transcription of virulence genes requires specific
      interaction between VirG and the alpha subunit of A. tumefaciens and that the
      alpha subunit from E. coli is unable to effectively interact with the VirG
      protein. This work provides the basis for future studies designed to examine vir
      gene expression as well as the T-DNA transfer process in E. coli.

PMID- 10419953
TI  - Ni(2+) transport and accumulation in Rhodospirillum rubrum.
AB  - The cooCTJ gene products are coexpressed with CO-dehydrogenase (CODH) and
      facilitate in vivo nickel insertion into CODH. A Ni(2+) transport assay was used
      to monitor uptake and accumulation of (63)Ni(2+) into R. rubrum and to observe
      the effect of mutations in the cooC, cooT, and cooJ genes on (63)Ni(2+) transport
      and accumulation. Cells grown either in the presence or absence of CO transported
      Ni(2+) with a K(m) of 19 +/- 4 microM and a V(max) of 310 +/- 22 pmol of
      Ni/min/mg of total protein. Insertional mutations disrupting the reading frame of
      the cooCTJ genes, either individually or all three genes simultaneously,
      transported Ni(2+) the same as wild-type cells. The nickel specificity for
      transport was tested by conducting the transport assay in the presence of other
      divalent metal ions. At a 17-fold excess Mn(2+), Mg(2+), Ca(2+), and Zn(2+)
      showed no inhibition of (63)Ni(2+) transport but Co(2+), Cd(2+), and Cu(2+)
      inhibited transport 35, 58, and 66%, respectively. Nickel transport was inhibited
      by cold (50% at 4 degrees C), by protonophores (carbonyl cyanide m
      chlorophenylhydrazone, 44%, and 2,4-dinitrophenol, 26%), by sodium azide (25%),
      and hydroxyl amine (33%). Inhibitors of ATP synthase (N, N'
      dicyclohexylcarbodiimide and oligomycin) and incubation of cells in the dark
      stimulated Ni(2+) transport. (63)Ni accumulation after 2 h was four times greater
      in CO-induced cells than in cells not exposed to CO. The CO-stimulated (63)Ni(2+)
      accumulation coincided with the appearance of CODH activity in the culture,
      suggesting that the (63)Ni(2+) was accumulating in CODH. The cooC, cooT, and cooJ
      genes are required for the increased (63)Ni(2+) accumulation observed upon CO
      exposure because cells containing mutations disrupting any or all of these genes
      accumulated (63)Ni(2+) like cells unexposed to CO.

PMID- 10419954
TI  - The structure of multiple polypeptide domains determines the signal recognition
      particle targeting requirement of Escherichia coli inner membrane proteins.
AB  - The signal recognition particle (SRP) targeting pathway is required for the
      efficient insertion of many polytopic inner membrane proteins (IMPs) into the
      Escherichia coli inner membrane, but in the absence of SRP protein export
      proceeds normally. To define the properties of IMPs that impose SRP dependence,
      we analyzed the targeting requirements of bitopic IMPs that are structurally
      intermediate between exported proteins and polytopic IMPs. We found that
      disruption of the SRP pathway inhibited the insertion of only a subset of bitopic
      IMPs. Studies on a model bitopic AcrB-alkaline phosphatase fusion protein (AcrB
      265-AP) showed that the SRP requirement for efficient insertion correlated with
      the presence of a large periplasmic domain (P1). As previously reported,
      perturbation of the SRP pathway also affected the insertion of a polytopic AcrB
      AP fusion. Even exhaustive SRP depletion, however, failed to block the insertion
      of any AcrB derivative by more than 50%. Taken together, these data suggest that
      many proteins that are normally targeted by SRP can utilize alternative targeting
      pathways and that the structure of both hydrophilic and membrane-spanning domains
      determines the degree to which the biogenesis of a protein is SRP dependent.

PMID- 10419955
TI  - areABC genes determine the catabolism of aryl esters in Acinetobacter sp. Strain
      ADP1.
AB  - Acinetobacter sp. strain ADP1 is able to grow on a range of esters of aromatic
      alcohols, converting them to the corresponding aromatic carboxylic acids by the
      sequential action of three inducible enzymes: an areA-encoded esterase, an areB
      encoded benzyl alcohol dehydrogenase, and an areC-encoded benzaldehyde
      dehydrogenase. The are genes, adjacent to each other on the chromosome and
      transcribed in the order areCBA, were located 3.5 kbp upstream of benK. benK,
      encoding a permease implicated in benzoate uptake, is at one end of the ben-cat
      supraoperonic cluster for benzoate catabolism by the beta-ketoadipate pathway.
      Two open reading frames which may encode a transcriptional regulator, areR, and a
      porin, benP, separate benK from areC. Each are gene was individually expressed to
      high specific activity in Escherichia coli. The relative activities against
      different substrates of the cloned enzymes were, within experimental error,
      identical to that of wild-type Acinetobacter sp. strain ADP1 grown on either
      benzyl acetate, benzyl alcohol, or 4-hydroxybenzyl alcohol as the carbon source.
      The substrate preferences of all three enzymes were broad, encompassing a range
      of substituted aromatic compounds and in the case of the AreA esterase, different
      carboxylic acids. The areA, areB, and areC genes were individually disrupted on
      the chromosome by insertion of a kanamycin resistance cassette, and the rates at
      which the resultant strains utilized substrates of the aryl ester catabolic
      pathway were severely reduced as determined by growth competitions between the
      mutant and wild-type strains.

PMID- 10419956
TI  - Cloning, sequencing, and characterization of the cgmB gene of Sinorhizobium
      meliloti involved in cyclic beta-glucan biosynthesis.
AB  - Periplasmic cyclic beta-glucans of Rhizobium species provide important functions
      during plant infection and hypo-osmotic adaptation. In Sinorhizobium meliloti
      (also known as Rhizobium meliloti), these molecules are highly modified with
      phosphoglycerol and succinyl substituents. We have previously identified an S.
      meliloti Tn5 insertion mutant, S9, which is specifically impaired in its ability
      to transfer phosphoglycerol substituents to the cyclic beta-glucan backbone (M.
      W. Breedveld, J. A. Hadley, and K. J. Miller, J. Bacteriol. 177:6346-6351, 1995).
      In the present study, we have cloned, sequenced, and characterized this mutation
      at the molecular level. By using the Tn5 flanking sequences (amplified by inverse
      PCR) as a probe, an S. meliloti genomic library was screened, and two overlapping
      cosmid clones which functionally complement S9 were isolated. A 3.1-kb HindIII
      EcoRI fragment found in both cosmids was shown to fully complement mutant S9.
      Furthermore, when a plasmid containing this 3.1-kb fragment was used to transform
      Rhizobium leguminosarum bv. trifolii TA-1JH, a strain which normally synthesizes
      only neutral cyclic beta-glucans, anionic glucans containing phosphoglycerol
      substituents were produced, consistent with the functional expression of an S.
      meliloti phosphoglycerol transferase gene. Sequence analysis revealed the
      presence of two major, overlapping open reading frames within the 3.1-kb
      fragment. Primer extension analysis revealed that one of these open reading
      frames, ORF1, was transcribed and its transcription was osmotically regulated.
      This novel locus of S. meliloti is designated the cgm (cyclic glucan
      modification) locus, and the product encoded by ORF1 is referred to as CgmB.

PMID- 10419957
TI  - The Bacillus subtilis yaaH gene is transcribed by SigE RNA polymerase during
      sporulation, and its product is involved in germination of spores.
AB  - The expression of 21 novel genes located in the region from dnaA to abrB of the
      Bacillus subtilis chromosome was analyzed. One of the genes, yaaH, had a
      predicted promoter sequence conserved among SigE-dependent genes. Northern blot
      analysis revealed that yaaH mRNA was first detected from 2 h after the cessation
      of logarithmic growth (T(2)) of sporulation in wild-type cells and in spoIIIG
      (SigG(-)) and spoIVCB (SigK(-)) mutants but not in spoIIAC (SigF(-)) and spoIIGAB
      (SigE(-)) mutants. The transcription start point was determined by primer
      extension analysis; the -10 and -35 regions are very similar to the consensus
      sequences recognized by SigE-containing RNA polymerase. A YaaH-His tag fusion
      encoded by a plasmid with a predicted promoter for the yaaH gene was produced
      from T(2) of sporulation in a B. subtilis transformant and extracted from mature
      spores, indicating that the yaaH gene product is a spore protein. Inactivation of
      the yaaH gene by insertion of an erythromycin resistance gene did not affect
      vegetative growth or spore resistance to heat, chloroform, and lysozyme. The
      germination of yaaH mutant spores in a mixture of L-asparagine, D-glucose, D
      fructose, and potassium chloride was almost the same as that of wild-type spores,
      but the mutant spores were defective in L-alanine-stimulated germination. These
      results suggest that yaaH is a novel gene encoding a spore protein produced in
      the mother cell compartment from T(2) of sporulation and that it is required for
      the L-alanine-stimulated germination pathway.

PMID- 10419958
TI  - Genetic characterization of a cell envelope-associated proteinase from
      Lactobacillus helveticus CNRZ32.
AB  - A cell envelope-associated proteinase gene (prtH) was identified in Lactobacillus
      helveticus CNRZ32. The prtH gene encodes a protein of 1,849 amino acids and with
      a predicted molecular mass of 204 kDa. The deduced amino acid sequence of the
      prtH product has significant identity (45%) to that of the lactococcal PrtP
      proteinases. Southern blot analysis indicates that prtH is not broadly
      distributed within L. helveticus. A prtH deletion mutant of CNRZ32 was
      constructed to evaluate the physiological role of PrtH. PrtH is not required for
      rapid growth or fast acid production in milk by CNRZ32. Cell surface proteinase
      activity and specificity were determined by hydrolysis of alpha(s1)-casein
      fragment 1-23 by whole cells. A comparison of CNRZ32 and its prtH deletion mutant
      indicates that CNRZ32 has at least two cell surface proteinases that differ in
      substrate specificity.

PMID- 10419959
TI  - A Zymomonas mobilis mutant with delayed growth on high glucose concentrations.
AB  - Exponentially growing cells of Zymomonas mobilis normally exhibit a lag period of
      up to 3 h when transferred from 0.11 M (2%) to 0.55 M (10%) glucose liquid
      medium. A mutant of Z. mobilis (CU1Rif2), fortuitously isolated, showed more than
      a 20-h lag period when grown under the same conditions, whereas on 0.55 M glucose
      solid medium, it failed to grow. The growth of CU1Rif2 on elevated concentrations
      of other fermentable (0.55 M sucrose or fructose) or nonfermentable (0.11 M
      glucose plus 0.44 M maltose or xylose) sugars appeared to be normal.
      Surprisingly, CU1Rif2 cells grew without any delay on 0.55 M glucose on which
      wild-type cells had been incubated for 3 h and removed at the beginning of their
      exponential phase. This apparent preconditioning was not observed with medium
      obtained from wild-type cells grown on 0.11 M glucose and supplemented to 0.55 M
      after removal of the wild-type cells. Undelayed growth of CU1Rif2 on 0.55 M
      glucose previously conditioned by the wild type was impaired by heating or
      protease treatment. It is suggested that in Z. mobilis, a diffusible
      proteinaceous heat-labile factor, transitionally not present in 0.55 M glucose
      CU1Rif2 cultures, triggers growth on 0.55 M glucose. Biochemical analysis of
      glucose uptake and glycolytic enzymes implied that glucose assimilation was not
      directly involved in the phenomenon. By use of a wild-type Z. mobilis genomic
      library, a 4.5-kb DNA fragment which complemented in low copy number the glucose
      defective phenotype as well as glucokinase and glucose uptake of CU1Rif2 was
      isolated. This fragment carries a gene cluster consisting of four putative coding
      regions, encoding 167, 167, 145, and 220 amino acids with typical Z. mobilis
      codon usage, -35 and -10 promoter elements, and individual Shine-Dalgarno
      consensus sites. However, strong homologies were not detected in a BLAST2 (EMBL
      Heidelberg) computer search with known protein sequences.

PMID- 10419960
TI  - Immunocytochemical localization of a calmodulinlike protein in Bacillus subtilis
      cells.
AB  - To determine possible functions of the calmodulinlike protein of Bacillus
      subtilis, the time course of its expression during sporulation and its cellular
      localization were studied. The protein was expressed in a constitutive manner
      from the end of logarithmic growth through 8 h of sporulation as determined by
      antibody cross-reactivity immunoblots and enzyme-linked immunosorbent assays
      (ELISAs). In partially purified extracts, the immunopositive protein comigrated
      upon electrophoresis with a protein which selectively bound [(45)Ca]CaCl(2),
      ruthenium red, and Stains-all. Previous studies showed increased extractability
      of the calmodulinlike protein from B. subtilis cells when urea and 2
      mercaptoethanol were used in breakage buffers, implying that the protein might be
      partially associated with the membrane fraction. This was confirmed by
      demonstrating that isolated membrane vesicles of B. subtilis also gave positive
      immunological tests with Western blotting and ELISAs. To more precisely locate
      the protein in cells, thin sections of late-log-phase cells, sporulating cells,
      and free spores were reacted first with bovine brain anticalmodulin specific
      antibodies and then with gold-conjugated secondary antibodies; the thin sections
      were examined by transmission electron microscopy. The calmodulinlike protein was
      found almost exclusively associated with the cell envelope of these fixed,
      sectioned cells. A possible function of the calmodulinlike protein in sensing
      calcium ions or regulating calcium ion transport is suggested.

PMID- 10419961
TI  - Functional analysis of the carbohydrate-binding domains of Erwinia chrysanthemi
      Cel5 (Endoglucanase Z) and an Escherichia coli putative chitinase.
AB  - The Cel5 cellulase (formerly known as endoglucanase Z) from Erwinia chrysanthemi
      is a multidomain enzyme consisting of a catalytic domain, a linker region, and a
      cellulose binding domain (CBD). A three-dimensional structure of the CBD(Cel5)
      has previously been obtained by nuclear magnetic resonance. In order to define
      the role of individual residues in cellulose binding, site-directed mutagenesis
      was performed. The role of three aromatic residues (Trp18, Trp43, and Tyr44) in
      cellulose binding was demonstrated. The exposed potential hydrogen bond donors,
      residues Gln22 and Glu27, appeared not to play a role in cellulose binding,
      whereas residue Asp17 was found to be important for the stability of Cel5. A
      deletion mutant lacking the residues Asp17 to Pro23 bound only weakly to
      cellulose. The sequence of CBD(Cel5) exhibits homology to a series of five
      repeating domains of a putative large protein, referred to as Yheb, from
      Escherichia coli. One of the repeating domains (Yheb1), consisting of 67 amino
      acids, was cloned from the E. coli chromosome and purified by metal chelating
      chromatography. While CBD(Cel5) bound to both cellulose and chitin, Yheb1 bound
      well to chitin, but only very poorly to cellulose. The Yheb protein contains a
      region that exhibits sequence homology with the catalytic domain of a chitinase,
      which is consistent with the hypothesis that the Yheb protein is a chitinase.

PMID- 10419962
TI  - Effects of growth conditions on expression of mycobacterial murA and tyrS genes
      and contributions of their transcripts to precursor rRNA synthesis.
AB  - All mycobacteria studied to date have an rRNA operon, designated rrnA, located
      downstream from a single copy of the murA gene, which encodes an enzyme (EC
      2.5.1.7) important for peptidoglycan synthesis. The rrnA operon has a promoter,
      P1(A), located within the coding region of murA, near the 3' end. Samples of RNA
      were isolated from Mycobacterium tuberculosis at different stages of the growth
      cycle and from Mycobacterium smegmatis grown under different conditions. RNase
      protection assays were used to investigate transcripts of both murA and rrnA.
      Transcription of murA was found to continue into the 16S rRNA gene, as if murA
      and rrnA form a hybrid (protein coding-rRNA coding) operon. During the growth of
      M. tuberculosis, the hybrid operon contributed approximately 2% to total pre
      rRNA. Analysis of M. smegmatis RNA revealed that the level of murA RNA depended
      on the growth rate and that the patterns of expression during the growth cycle
      were different for murA and rrnA. M. smegmatis has a second rRNA operon, rrnB,
      located downstream from a single copy of the tyrS gene, encoding tyrosyl-tRNA
      synthetase. Transcription of tyrS was found to continue into the 16S rRNA gene
      rrnB. The hybrid tyrS-rrnB operon contributed 0.2 to 0.6% to rrnB transcripts.
      The pattern of tyrS expression during the growth cycle matched the pattern of
      rrnB expression, reflecting the essential role of TyrS and rRNA in protein
      biosynthesis.

PMID- 10419963
TI  - MgATP binding and hydrolysis determinants of NtrC, a bacterial enhancer-binding
      protein.
AB  - When phosphorylated, the dimeric form of nitrogen regulatory protein C (NtrC) of
      Salmonella typhimurium forms a larger oligomer(s) that can hydrolyze ATP and
      hence activate transcription by the sigma(54)-holoenzyme form of RNA polymerase.
      Studies of Mg-nucleoside triphosphate binding using a filter-binding assay
      indicated that phosphorylation is not required for nucleotide binding but
      probably controls nucleotide hydrolysis per se. Studies of binding by isothermal
      titration calorimetry indicated that the apparent K(d) of unphosphorylated NtrC
      for MgATPgammaS is 100 microM at 25 degrees C, and studies by filter binding
      indicated that the concentration of MgATP required for half-maximal binding is
      130 microM at 37 degrees C. Filter-binding studies with mutant forms of NtrC
      defective in ATP hydrolysis implicated two regions of its central domain directly
      in nucleotide binding and three additional regions in hydrolysis. All five are
      highly conserved among activators of sigma(54)-holoenzyme. Regions implicated in
      binding are the Walker A motif and the region around residues G355 to R358, which
      may interact with the nucleotide base. Regions implicated in nucleotide
      hydrolysis are residues S207 and E208, which have been proposed to lie in a
      region analogous to the switch I effector region of p21(ras) and other purine
      nucleotide-binding proteins; residue R294, which may be a catalytic residue; and
      residue D239, which is the conserved aspartate in the putative Walker B motif.
      D239 appears to play a role in binding the divalent cation essential for
      nucleotide hydrolysis. Electron paramagnetic resonance analysis of Mn(2+) binding
      indicated that the central domain of NtrC does not bind divalent cation strongly
      in the absence of nucleotide.

PMID- 10419964
TI  - OxyR and SoxRS regulation of fur.
AB  - The cytotoxic effects of reactive oxygen species are largely mediated by iron.
      Hydrogen peroxide reacts with iron to form the extremely reactive and damaging
      hydroxyl radical via the Fenton reaction. Superoxide anion accelerates this
      reaction because the dismutation of superoxide leads to increased levels of
      hydrogen peroxide and because superoxide elevates the intracellular concentration
      of iron by attacking iron-sulfur proteins. We found that regulators of the
      Escherichia coli responses to oxidative stress, OxyR and SoxRS, activate the
      expression of Fur, the global repressor of ferric ion uptake. A transcript
      encoding Fur was induced by hydrogen peroxide in a wild-type strain but not in a
      DeltaoxyR strain, and DNase I footprinting assays showed that OxyR binds to the
      fur promoter. In cells treated with the superoxide-generating compound paraquat,
      we observed the induction of a longer transcript encompassing both fur and its
      immediate upstream gene fldA, which encodes a flavodoxin. This polycistronic mRNA
      is induced by paraquat in a wild-type strain but not in a DeltasoxRS strain, and
      SoxS was shown to bind to the fldA promoter. These results demonstrate that iron
      metabolism is coordinately regulated with the oxidative stress defenses.

PMID- 10419965
TI  - The Saccharomyces cerevisiae weak-acid-inducible ABC transporter Pdr12 transports
      fluorescein and preservative anions from the cytosol by an energy-dependent
      mechanism.
AB  - Growth of Saccharomyces cerevisiae in the presence of the weak-acid preservative
      sorbic acid results in the induction of the ATP-binding cassette (ABC)
      transporter Pdr12 in the plasma membrane (P. Piper, Y. Mahe, S. Thompson, R.
      Pandjaitan, C. Holyoak, R. Egner, M. Muhlbauer, P. Coote, and K. Kuchler, EMBO J.
      17:4257-4265, 1998). Pdr12 appears to mediate resistance to water-soluble,
      monocarboxylic acids with chain lengths of from C(1) to C(7). Exposure to acids
      with aliphatic chain lengths greater than C(7) resulted in no observable
      sensitivity of Deltapdr12 mutant cells compared to the parent. Parent and
      Deltapdr12 mutant cells were grown in the presence of sorbic acid and
      subsequently loaded with fluorescein. Upon addition of an energy source in the
      form of glucose, parent cells immediately effluxed fluorescein from the cytosol
      into the surrounding medium. In contrast, under the same conditions, cells of the
      Deltapdr12 mutant were unable to efflux any of the dye. When both parent and
      Deltapdr12 mutant cells were grown without sorbic acid and subsequently loaded
      with fluorescein, upon the addition of glucose no efflux of fluorescein was
      detected from either strain. Thus, we have shown that Pdr12 catalyzes the energy
      dependent extrusion of fluorescein from the cytosol. Lineweaver-Burk analysis
      revealed that sorbic and benzoic acids competitively inhibited ATP-dependent
      fluorescein efflux. Thus, these data provide strong evidence that sorbate and
      benzoate anions compete with fluorescein for a putative monocarboxylate binding
      site on the Pdr12 transporter.

PMID- 10419966
TI  - Obg, an essential GTP binding protein of Bacillus subtilis, is necessary for
      stress activation of transcription factor sigma(B).
AB  - sigma(B), the general stress response sigma factor of Bacillus subtilis, is
      activated when intracellular ATP levels fall or the bacterium experiences
      environmental stress. Stress activates sigma(B) by means of a collection of
      regulatory kinases and phosphatases (the Rsb proteins), which catalyze the
      release of sigma(B) from an anti-sigma factor inhibitor. By using the yeast
      dihybrid selection system to identify B. subtilis proteins that could interact
      with Rsb proteins and act as mediators of stress signaling, we isolated the GTP
      binding protein, Obg, as an interactor with several of these regulators (RsbT,
      RsbW, and RsbX). B. subtilis depleted of Obg no longer activated sigma(B) in
      response to environmental stress, but it retained the ability to activate
      sigma(B) by the ATP responsive pathway. Stress pathway components activated
      sigma(B) in the absence of Obg if the pathway's most upstream effector (RsbT) was
      synthesized in excess to the inhibitor (RsbS) from which it is normally released
      after stress. Thus, the Rsb proteins can function in the absence of Obg but fail
      to be triggered by stress. The data demonstrate that Obg, or a process under its
      control, is necessary to induce the stress-dependent activation of sigma(B) and
      suggest that Obg may directly communicate with one or more sigma(B) regulators.

PMID- 10419967
TI  - Molecular characterization of genetic loci required for secretion of exoproducts
      in Burkholderia pseudomallei.
AB  - Previous studies have demonstrated that Burkholderia pseudomallei secretes
      protease, lipase, and phospholipase C (PLC) into the extracellular milieu, but
      their mechanisms of secretion and roles in pathogenesis have not been elucidated.
      In this study, we isolated and characterized 29 transposon mutants unable to
      secrete protease, lipase, and PLC.

PMID- 10419968
TI  - The thermophilic yeast Hansenula polymorpha does not require trehalose synthesis
      for growth at high temperatures but does for normal acquisition of
      thermotolerance.
AB  - The TPS1 gene from Hansenula polymorpha, which encodes trehalose-6-phosphate
      (Tre6P) synthase, has been isolated and characterized. The deletion of TPS1
      rendered H. polymorpha cells incapable of trehalose synthesis under conditions
      where wild-type cells normally accumulate high levels of trehalose.
      Interestingly, the loss of Tre6P synthase did not cause any obvious growth
      defects on a glucose-containing medium, even at high temperatures, but seriously
      compromised the cells' ability to acquire thermotolerance.

PMID- 10419969
TI  - Alteration of the repressor activity of MarR, the negative regulator of the
      Escherichia coli marRAB locus, by multiple chemicals in vitro.
AB  - MarR negatively regulates expression of the multiple antibiotic resistance operon
      (marRAB) in Escherichia coli. In this study, it was demonstrated that sodium
      salicylate, plumbagin, 2, 4-dinitrophenol, and menadione-inducers of the marRAB
      operon in whole cells-all interfered with the repressor activity of MarR in
      vitro. It is proposed that these compounds can interact directly with MarR to
      affect its repressor activity.

PMID- 10419970
TI  - Growth and glucose repression are controlled by glucose transport in
      Saccharomyces cerevisiae cells containing only one glucose transporter.
AB  - A set of Saccharomyces cerevisiae strains with variable expression of only the
      high-affinity Hxt7 glucose transporter was constructed by partial deletion of the
      HXT7 promoter in vitro and integration of the gene at various copy numbers into
      the genome of an hxt1-7 gal2 deletion strain. The glucose transport capacity
      increased in strains with higher levels of HXT7 expression. The consequences for
      various physiological properties of varying the glucose transport capacity were
      examined. The control coefficient of glucose transport with respect to growth
      rate was 0.54. At high extracellular glucose concentrations, both invertase
      activity and the rate of oxidative glucose metabolism increased manyfold with
      decreasing glucose transport capacity, which is indicative of release from
      glucose repression. These results suggest that the intracellular glucose
      concentration produces the signal for glucose repression.

PMID- 10419971
TI  - Succinate dehydrogenase (Sdh) from Bradyrhizobium japonicum is closely related to
      mitochondrial Sdh.
AB  - The sdhCDAB operon, encoding succinate dehydrogenase, was cloned from the soybean
      symbiont Bradyrhizobium japonicum. Sdh from B. japonicum is phylogenetically
      related to Sdh from mitochondria. This is the first example of a mitochondrion
      like Sdh functionally expressed in Escherichia coli.

PMID- 10419972
TI  - Complementation of conjugation functions of Streptomyces lividans plasmid pIJ101
      by the related Streptomyces plasmid pSB24.2.
AB  - A database search revealed extensive sequence similarity between Streptomyces
      lividans plasmid pIJ101 and Streptomyces plasmid pSB24. 2, which is a deletion
      derivative of Streptomyces cyanogenus plasmid pSB24.1. The high degree of
      relatedness between the two plasmids allowed the construction of a genetic map of
      pSB24.2, consisting of putative transfer and replication loci. Two pSB24.2 loci,
      namely, the cis-acting locus for transfer (clt) and the transfer-associated korB
      gene, were shown to be capable of complementing the pIJ101 clt and korB
      functions, respectively, a result that is consistent with the notion that pIJ101
      and the parental plasmid pSB24.1 encode highly similar, if not identical,
      conjugation systems.

PMID- 10419973
TI  - Amino acid residues involved in the functional integrity of Escherichia coli
      methionine aminopeptidase.
AB  - Amino acid residues in the metal-binding and putative substrate-binding sites of
      Escherichia coli methionine aminopeptidase (MAP) were mutated, and their effects
      on the function of the enzyme were investigated. Substitution of any amino acid
      residue at the metal-binding site resulted in complete loss of the two cobalt
      ions bound to the protein and diminished the enzyme activity. However, only Cys70
      and Trp221 at the putative substrate-binding site are involved in the catalytic
      activity of MAP. Changing either of them caused partial loss of enzyme activity,
      while mutations at both positions abolished MAP function. Both residues are found
      to be conserved in type I but not type II MAPs.

PMID- 10419974
TI  - The Streptomyces peucetius dpsC gene determines the choice of starter unit in
      biosynthesis of the daunorubicin polyketide.
AB  - The starter unit used in the biosynthesis of daunorubicin is propionyl coenzyme A
      (CoA) rather than acetyl-CoA, which is used in the production of most of the
      bacterial aromatic polyketides studied to date. In the daunorubicin biosynthesis
      gene cluster of Streptomyces peucetius, directly downstream of the genes encoding
      the beta-ketoacyl:acyl carrier protein synthase subunits, are two genes, dpsC and
      dpsD, encoding proteins that are believed to function as the starter unit
      specifying enzymes. Recombinant strains containing plasmids carrying dpsC and
      dpsD, in addition to other daunorubicin polyketide synthase (PKS) genes,
      incorporate the correct starter unit into polyketides made by these genes,
      suggesting that, contrary to earlier reports, the enzymes encoded by dpsC and
      dpsD play a crucial role in starter unit specification. Additionally, the results
      of a cell-free synthesis of 21-carbon polyketides from propionyl-CoA and malonyl
      CoA that used the protein extracts of recombinant strains carrying other
      daunorubicin PKS genes to which purified DpsC was added suggest that this enzyme
      has the primary role in starter unit discrimination for daunorubicin
      biosynthesis.

PMID- 10419975
TI  - Molecular cloning, sequence analysis, and characterization of a penicillin
      resistant DD-carboxypeptidase of Myxococcus xanthus.
AB  - We have cloned a gene, pdcA, from the genomic library of Myxococcus xanthus with
      an oligonucleotide probe representing conserved regions of penicillin-resistant
      DD-carboxypeptidases. The amino- and carboxy-terminal halves of the predicted
      pdcA gene product showed significant sequence similarity to N-acetylmuramoyl-L
      alanine amidase and penicillin-resistant DD-carboxypeptidase, respectively. The
      pdcA gene was expressed in Escherichia coli, and the characteristics of the gene
      product were similar to those of DD-carboxypeptidase (VanY) of vancomycin
      resistant enterococci. No apparent changes in cell growth, sporulation, or
      germination were observed in pdcA deletion mutants.

PMID- 10419976
TI  - Three distinct phases of isoprene formation during growth and sporulation of
      Bacillus subtilis.
AB  - During growth on a glucose-tryptone medium, Bacillus subtilis 6051 (Marburg
      strain) exhibited three phases of isoprene (2-methyl-1, 3-butadiene) formation,
      corresponding to (i) glucose catabolism and secretion of acetoin, (ii) catabolism
      of acetoin, and (iii) the early stages of sporulation. These results establish an
      experimental system for studying the biological role of isoprene formation.

PMID- 10419977
TI  - Involvement of the RNA polymerase alpha-subunit C-terminal domain in LuxR
      dependent activation of the Vibrio fischeri luminescence genes.
AB  - LuxR is a sigma(70) RNA polymerase (RNAP)-dependent transcriptional activator
      that controls expression of the Vibrio fischeri lux operon in response to an
      acylhomoserine lactone-cell density signal. We have investigated whether the
      alpha-subunit C-terminal domain (alphaCTD) of RNAP is required for LuxR activity.
      A purified signal-independent, LuxR C-terminal domain-containing polypeptide
      (LuxRDeltaN) was used to study the activation of transcription from the luxI
      promoter in vitro. Initiation of lux operon transcription was observed in the
      presence of LuxRDeltaN and wild-type RNAP but not in the presence of LuxRDeltaN
      and RNAPs with truncated alphaCTDs. We also studied the in vivo role of the RNAP
      alphaCTD in activation of lux transcription in Escherichia coli. This enabled a
      comparison of results obtained with full-length LuxR to those obtained with
      LuxRDeltaN. These in vivo studies indicated that both LuxR and LuxRDeltaN require
      the RNAP alphaCTD for activity. The results of DNase I protection studies showed
      that LuxRDeltaN-RNAP complexes can bind and protect the luxI promoter, but with
      less efficacy when the alphaCTD is truncated in comparison to the wild type.
      Thus, both in vitro and in vivo experiments demonstrated that LuxR-dependent
      transcriptional activation of the lux operon involves the RNAP alphaCTD and
      suggest that alphaCTD-LuxR interactions may play a role in recruitment of RNAP to
      the luxI promoter.

PMID- 10419978
TI  - Gene organization of the dnaA region of Wolbachia.
AB  - The dnaA region of Wolbachia, an intracellular bacterial parasite of insects, is
      unique. A glnA cognate was found upstream of the dnaA gene, while neither of the
      two open reading frames detected downstream of dnaA has any homologue in the
      database. This unusual gene arrangement may reflect requirements associated with
      the unique ecological niche this agent occupies.

PMID- 10419979
TI  - Serotype 1a O-antigen modification: molecular characterization of the genes
      involved and their novel organization in the Shigella flexneri chromosome.
AB  - The factors responsible for serotype 1a O-antigen modification in Shigella
      flexneri were localized to a 5.8-kb chromosomal HindIII fragment of serotype 1a
      strain Y53. The entire 5.8-kb fragment and regions up- and downstream of it (10.6
      kb total) were sequenced. A putative three-gene operon, which showed homology
      with other serotype conversion genes, was identified and shown to confer serotype
      1a O-antigen modification. The serotype conversion genes were flanked on either
      side by phage DNA. Multiple insertion sequence (IS) elements were located within
      and upstream of the phage DNA in a composite transposon-like structure. Host DNA
      homologous to the dsdC and the thrW proA genes was located upstream of the IS
      elements and downstream of the phage DNA, respectively. The sequence analysis
      indicates that the organization of the 10.6-kb region of the Y53 chromosome is
      unique and suggests that the serotype conversion genes were originally brought
      into the host by a bacteriophage. Several features of this region are also
      characteristic of pathogenicity islands.

PMID- 10419982
TI  - Lemuel dary wright (March 1, 1913-May 12, 1995) 

PMID- 10419981
TI  - The role of apolipoprotein A-IV in food intake regulation.
AB  - Apolipoprotein (apo) A-IV is a glycoprotein synthesized by the human intestine.
      In rodents, both the small intestine and the liver secrete apo A-IV; the small
      intestine, however, is by far the major organ responsible for the circulating apo
      A-IV. Intestinal apo A-IV synthesis is markedly stimulated by fat absorption and
      appears not to be mediated by the uptake or reesterification of fatty acids to
      form triglycerides. Rather, it is the formation of chylomicrons that acts as a
      signal for the induction of intestinal apo A-IV synthesis. Intestinal apo A-IV
      synthesis is also enhanced by a factor from the ileum and that factor is probably
      peptide tyrosine-tyrosine (PYY). The inhibition of food intake by apo A-IV is
      probably mediated centrally. The stimulation of intestinal synthesis and
      secretion of apo A-IV by lipid absorption are rapid; thus, apo A-IV likely plays
      a role in the short-term regulation of food intake. Other evidence suggests that
      apo A-IV may also be involved in the long-term regulation of food intake and body
      weight. Chronic ingestion of a high fat diet blunts the intestinal apo A-IV
      response to lipid feeding and may explain why the chronic ingestion of a high fat
      diet predisposes both animals and humans to obesity.

PMID- 10419980
TI  - Glucose metabolism in gcr mutants of Saccharomyces cerevisiae.
AB  - A gcr2 null mutant of Saccharomyces cerevisiae grows well on glucose in spite of
      its lower level of glycolytic enzymes between triose phosphates and pyruvate. A
      quantitative analysis shows that these levels are adequate to the flux but
      glycerate phosphates are elevated.

PMID- 10419983
TI  - Chronic marginal vitamin A status reduces natural killer cell number and function
      in aging Lewis rats.
AB  - Natural killer (NK) cells function in the regulation of immune responses and in
      the surveillance of malignant or other abnormal cells. Little is known of the
      effects of chronic marginal vitamin A (VA) status or VA supplementation, or their
      interaction with age, on NK cell number and cytolytic activity. We have conducted
      a two-factor (diet, age) study in which male Lewis rats were fed AIN-93M diet,
      modified to contain either 0.3 (designated marginal), 4.0 (control) or 50
      (supplemented) mg retinol equivalents (RE)/kg diet, from the time of weaning
      until the ages of 2.5 mo (young), 8-10 mo (middle-aged) or 18-20 mo (old).
      Natural killer cells were identified and quantified in peripheral blood
      mononuclear cells (PBMC) and spleen with the use of flow cytometry, and NK cell
      cytotoxicity was assayed. The number and percentage of PBMC NK cells increased
      with age (P < 0.0001 by two-way ANOVA). For all age groups, values were lowest in
      rats with marginal VA status (P < 0.0001 vs. controls). NK cell lytic activity
      also declined with age (P = 0. 0003). As a result, NK cell lytic efficiency
      (lytic activity per NK cell) decreased markedly with age (P < 0.0001). Regardless
      of the donor's age or VA status, PBMC NK cell cytotoxicity doubled (100 +/- 25%
      increase) after exposure to interferon-alpha (5 x 10(5) U/L for 1 h before
      assay), indicating that IFN-stimulated lytic activity was related directly to
      basal NK cell activity. If the relationships observed in this animal model can be
      applied to humans, these data suggest that elderly people consuming diets
      chronically low in VA may be at increased risk for infectious or neoplastic
      diseases.

PMID- 10419984
TI  - Cardiac (n-3) non-esterified fatty acids are selectively increased in fish oil
      fed pigs following myocardial ischemia.
AB  - The effect of fish oil supplementation on the nonesterified fatty acid (NEFA)
      concentration and composition in the normoxic and hypoxic myocardium of pigs was
      examined. Two groups of female pigs (n = 7) were fed a diet supplemented with
      either 5 g beef tallow/kg (as control) or 5 g fish oil/kg (MaxEPA) rich in (n-3)
      fatty acids. After 6 wk of supplementation, the pigs were anesthetized, hearts
      exposed by thoracotomy followed by occlusion of the left anterior descending
      artery. Normoxic and hypoxic regions of the heart were examined for NEFA
      concentration and composition by using a combination of thin layer and gas
      chromatography. Nonesterified (n-6) and (n-3) fatty acid concentration and
      composition differed significantly between the two groups in both the normoxic
      and hypoxic areas of the heart. Eicosapentaenoic and docosahexaenoic acid
      concentration in the NEFA fraction of the normoxic myocardium were higher in the
      fish oil group than in the beef tallow group (P < 0.001). In the fish oil-fed
      pigs, the (n-3) NEFA concentration was significantly higher in the hypoxic
      compared to the normoxic region of the heart. The fish oil-fed group had lower
      levels of arachidonic acid in the NEFA fraction compared to the beef tallow-fed
      group, whereas the hypoxic myocardium had higher levels of arachidonic acid,
      regardless of the dietary fat supplementation. Despite large differences in the
      proportions of saturated fatty acids in the experimental diets, there was little
      or no difference in the saturated fatty acid content of cardiac phospholipid and
      NEFA fractions. Following myocardial ischemia, (n-3) fatty acids in the NEFA
      fractions were selectively increased in the fish oil-fed pigs, implicating the
      possible role of nonesterified (n-3) polyunsaturated fatty acids in the
      prevention of arrhythmias.

PMID- 10419985
TI  - Dietary glutamine enhances murine T-lymphocyte responsiveness.
AB  - To examine the effects of dietary glutamine on lymphocyte function, male mice
      aged 6 wk were fed for 2 wk one of three isonitrogenous, isocaloric diets, which
      varied in glutamine concentration. The control diet included 200 g casein/kg,
      providing 19.6 g glutamine/kg; the glutamine-enriched diet provided 54.8 g
      glutamine/kg partly at the expense of casein; and the alanine + glycine-enriched
      diet provided 13.3 g glutamine/kg. The plasma concentrations of a number of amino
      acids varied because of the diet fed. The plasma glycine concentration was
      greater in mice fed the alanine + glycine-enriched diet (380 +/- 22 micromol/L)
      than in mice fed the control (177 +/- 17 micromol/L) or the glutamine-enriched
      (115 +/- 18 micromol/L) diets. The plasma glutamine concentration was greater in
      mice fed the glutamine-enriched diet (945 +/- 117 micromol/L) than in those fed
      the diet enriched with alanine + glycine (561 +/- 127 micromol/L), but was not
      different from that in mice fed the control diet (791 +/- 35 micromol/L). There
      was a significant linear relationship between the amount of glutamine in the diet
      and plasma glutamine concentration (r = 0.655, P = 0.015). Plasma alanine
      concentration was unaffected by diet. The reason for the lack of effect of
      increasing the amount of alanine in the diet upon its concentration in the
      circulation may relate to its use by the liver. Thymidine incorporation (56 +/-
      18 kBq/well versus <10 kBq/well), expression of the alpha-subunit of the
      interleukin-2 receptor (62 versus 30% receptor positive cells) and interleukin-2
      production [189 +/- 28 versus 106 +/- 5 (control) or 61 +/- 13 (alanine + glycine
      enriched) ng/L] were greater for concanavalin A-stimulated spleen lymphocytes
      from mice fed the glutamine-enriched diet compared to those from mice fed the
      other two diets. Thus, increasing the amount of glutamine in the murine diet
      enhances the ability of T lymphocytes to respond to mitogenic stimulation. Taken
      together, these observations suggest that increasing the oral availability of
      glutamine could promote the T-cell driven, cell-mediated immune response.

PMID- 10419986
TI  - Expression of the growth arrest genes (GAS and GADD) changes during organogenesis
      in the rat fetus.
AB  - Mammalian cells mount an active response to nutrient limitation by overexpressing
      the growth arrest specific (GAS) and the growth arrest and DNA damage (GADD)
      genes. During embryogenesis in rats, there are quantitative and temporal
      differences in GAS and GADD gene expression during the development of the
      placenta, heart and kidney. Genes associated with the inhibition of DNA synthesis
      (p53 and GAS1) were predominantly expressed during the early stages of
      development, whereas those genes associated with inhibition of protein synthesis
      [GADD153 (also known as CHOP-10 or Ddit3) and C/EBP-beta] were more highly
      expressed during the later stages. The GADD45 gene was expressed throughout
      development. There were distinct periods of GAS3 and GAS6 gene expression during
      the development of the placenta, heart and kidneys, which is consistent with the
      proposed roles of these genes in cell interactions. These results show that there
      is a change in the expression of genes associated with the negative regulation of
      growth as the fetus develops.

PMID- 10419987
TI  - A minimally invasive tracer protocol is effective for assessing the response of
      leucine kinetics and oxidation to vaccination in chronically energy-deficient
      adult males and children.
AB  - In disadvantaged populations, recurrent infections lead to a loss of body
      nitrogen and worsen nutritional status. The resulting malnutrition, in its turn,
      produces a greater susceptibility to infection. This study aimed to examine the
      ability of a new minimally invasive tracer protocol to measure leucine oxidation,
      and then to use it to quantify the effect of vaccination on leucine kinetics and
      oxidation. Undernourished men (n = 5; body mass index 16.3 +/- 0.9 kg/m(2)) and
      children (n = 9; age 4.1 +/- 0.6 y; weight-for-age Z-score -2.3 +/- 0.7)
      underwent metabolic studies 6 d before and 1 d after vaccination with diphtheria,
      pertussis and tetanus (DPT). The tracer protocol was performed in the fed state
      and involved two 3-h sequential periods of frequent (20 min) oral doses of
      NaH(13)CO(3) or [1-(13)C] leucine. Frequent breath samples and urine collections
      were made. Blood samples were obtained from the men and used for the
      determination of the isotopic enrichment of alpha-ketoisocaproic acid. The
      prevaccination oxidation of leucine (percentage of dose +/- SD) was 18.1 +/- 2.3
      (men) and 16.7 +/- 3.8 (children). One day after vaccination, these values had
      risen to 19. 9 +/- 1.9 (P < 0.05) in the men and to 19.5 +/- 4.6 (P < 0.01) in
      the children. In the adults, vaccination was associated with a rise in whole-body
      protein breakdown [mg protein/(kg.h)] from 200 +/- 40 to 240 +/- 10 (P < 0.05). A
      minor simulated infection increases leucine catabolism in undernourished humans
      and this new, minimally invasive protocol is sufficiently sensitive to measure
      these changes.

PMID- 10419988
TI  - Weight loss due to energy restriction suppresses cholesterol biosynthesis in
      overweight, mildly hypercholesterolemic men.
AB  - Mechanisms explaining the decrease in circulatory cholesterol levels after weight
      loss remain ill defined. The objective was to examine effects of weight loss as
      achieved through energy restriction upon human in vivo cholesterol biosynthesis.
      Six subjects (64-77 y, body mass index, 30.3 +/- 3.8 kg/m(2)) were recruited into
      a two-phase prospective clinical trial. In the first phase, subjects complied
      with American Heart Association (AHA) Step I diets for 3 mo with no change in
      their usual energy intake. After this weight-stable phase, subjects consumed an
      AHA Step I diet with a targeted reduction in energy intake of approximately 1000
      kJ/d for 6 mo to achieve negative energy balance leading to weight loss. The
      incorporation rate of deuterium from body water into erythrocyte membrane free
      cholesterol over 24 h was utilized as an index of cholesterogenesis at the end of
      both phases. Subjects' mean weights decreased (P < 0.05) from 89.3 +/- 12.5 kg to
      83.2 +/- 11.5 kg (6.8 +/- 2.6% of initial body weight) across phases. Circulating
      concentrations of total and LDL-cholesterol, and triglycerides also decreased (P
      < 0. 05) across phases. HDL-cholesterol concentrations were unchanged (P > 0.05).
      Cholesterol fractional synthetic rate (FSR) after phase 2 (3.04 +/- 1.90%/d) was
      lower (P < 0.05) than that after phase 1 (8. 42 +/- 3.90%/d). Absolute synthesis
      rate (ASR) after phase 2 [0.59 +/- 0.38 g/(kg. d)] also was lower (P < 0.05) than
      that after phase 1 [1.66 +/- 0.84 g/(kg. d)]. These data suggest that, in obese
      men, energy restriction resulting in even modest weight loss suppresses
      endogenous cholesterol synthesis, which contributes to a decline in circulating
      lipid concentrations.

PMID- 10419989
TI  - Children's consumption of dark green, leafy vegetables with added fat enhances
      serum retinol.
AB  - A randomized, double-blind, controlled study was conducted to determine whether
      the consumption of leafy vegetables by preschool children would enhance their
      serum vitamin A concentration to acceptable levels. Preschool children (n = 519;
      2.5-6 y) in Saboba, northern Ghana, were randomly assigned to five feeding
      groups, differing essentially in the amount of fat and beta-carotene, fed once
      per d, 7 d per wk, for 3 mo. Serum retinol levels, anthropometric measurements,
      hemoglobin, rapid turnover proteins (pre-albumin and retinol-binding protein),
      worm infestation (stool examinations) and level of acute and chronic infection
      (serum C-reactive protein and acid glycoprotein) were determined before and after
      study. Relative to the baseline serum retinol values, consumption of dark green,
      leafy vegetables (Manihot sp. and Ceiba sp.) with fat (10 g/100 g) significantly
      (P < 0.05) enhanced serum retinol; consequently, the percentage of children with
      adequate retinol status increased from 28.2-48.2% after feeding (P < 0.05). There
      were no significant differences among groups, ages or pre- versus post
      anthropometric measurements, hemoglobin concentration, or levels of worm
      infestation. The importance of these findings in alleviating and/or controlling
      vitamin A deficiency in developing countries is discussed.

PMID- 10419990
TI  - Severity and timing of stunting in the first two years of life affect performance
      on cognitive tests in late childhood.
AB  - Undernutrition in infancy and early childhood is thought to adversely affect
      cognitive development, although evidence of lasting effects is not well
      established. With the use of data from the Cebu Longitudinal Health and Nutrition
      Study, we assesshere the relationship between stunting in the first 2 y of life
      and later cognitive development, focusing on the significance of severity, timing
      and persistence of early stunting. The sample included > 2000 Filipino children
      administered a cognitive ability test at ages 8 and 11 y. Stunting status was
      determined on the basis of anthropometric data collected prospectively between
      birth and age 2 y. Children stunted between birth and age 2 y had significantly
      lower test scores than nonstunted children, especially when stunting was severe.
      The shortfall in test scores among children stunted in the first 2 y was strongly
      related to reduced schooling, which was the result of a substantial delay in
      initial enrollment as well as higher absenteeism and repetition of school years
      among stunted children. Interactions between stunting and schooling were not
      significant, indicating that stunted and nonstunted children benefitted similarly
      from additional schooling. After multivariate adjustment, severe stunting at age
      2 y remained significantly associated with later deficits in cognitive ability.
      The timing of stunting was also related to test performance, largely because
      children stunted very early also tended to be severely stunted (chi(2) P =
      0.000). Deficits in children's scores were smaller at age 11 y than at age 8 y,
      suggesting that adverse effects may decline over time. Results emphasize the need
      to prevent early stunting and to provide adequate schooling to disadvantaged
      children.

PMID- 10419991
TI  - Maternal zinc supplementation does not affect size at birth or pregnancy duration
      in Peru.
AB  - To estimate the effect of maternal zinc deficiency on pregnancy outcomes, we
      conducted a zinc supplementation trial in an urban shantytown in Lima, Peru, a
      population with habitual low zinc intakes. Beginning at 10-24 wk gestation, 1295
      mothers were randomly assigned to receive prenatal supplements containing 60 mg
      iron and 250 (g folate, with or without 15 mg zinc. Women were followed up
      monthly during pregnancy. At birth, newborn weight was recorded, and crownheel
      length, head circumference and other circumferences and skinfold thicknesses were
      assessed on d 1. At delivery, 1016 remained in the study; duration of pregnancy
      was known for all women, and birth weight information was available for 957
      newborns. No differences were noted in duration of pregnancy (39.4 +/- 2.2 vs.
      39. 5 +/- 2.0 wk) or birth weight (3267 +/- 461 vs. 3300 +/- 498 g) by prenatal
      supplement type (iron + folate + zinc vs. iron + folate; P > 0.05), and there
      were no differences in the rates of preterm (<37 wk) or post-term (>42 wk)
      delivery, low birth weight (<2500 g) or high birth weight (>4000 g). Finally,
      there were no differences by prenatal supplement type in newborn head
      circumference, crownheel length, chest circumference, mid-upper arm
      circumference, calf circumference or skinfold thickness at any of three sites.
      Adjustment for covariates and confounding factors did not alter these results.
      Adding zinc to prenatal iron and folate tablets did not affect duration of
      pregnancy or size at birth in this population.

PMID- 10419992
TI  - Vitamin A administered with measles vaccine to nine-month-old infants does not
      reduce vaccine immunogenicity.
AB  - After a report of reduced seroconversion to measles in infants, aged 6 mo, given
      vitamin A with their measles vaccination, serious concerns were raised regarding
      the safety of the WHO's recommendation that infants be supplemented with vitamin
      A at the time of measles immunization. To determine the impact of coadministered
      vitamin A on the antibody response to measles vaccine given to infants aged 9 mo,
      the more common age for immunization in developing countries, we conducted a
      randomized, double-blind, placebo-controlled trial in an urban slum community in
      Delhi. Infants (618) were randomly allocated to receive 30 mg vitamin A or a
      placebo with the measles immunization. Antibodies to measles were measured by
      ELISA in serum samples obtained at before (baseline) and 12 wk after
      immunization. Overall, the seroconversion rates did not differ between vitamin A
      (89.5%) and placebo (87.6%) groups. There were no significant differences in the
      geometric mean titers in the two groups (ratio of geometric means, 1.19; 95%
      confidence interval, 0.97-1.46). Among malnourished infants, the geometric mean
      titer was significantly greater in the vitamin A group compared to the placebo
      group (ratio of geometric means, 1.57; 95% confidence interval, 1. 18-2.0), but
      seroconversion rates did not differ. There were no differences in seroconversion
      rates and geometric mean titers in the two study groups among the well-nourished
      children. These results indicate that 30 mg vitamin A does not reduce the immune
      response to the coadministered vaccine and, therefore, can be continued to be
      given safely in public health programs.

PMID- 10419993
TI  - A high dietary lipid intake during pregnancy and lactation enhances mammary gland
      lipid uptake and lipoprotein lipase activity in rats.
AB  - Rats fed a diet with high fat concentration produce larger amounts of milk with a
      higher lipid concentration than rats fed a lower fat diet. This investigation was
      designed to study the relationship between dietary fat intake, mammary gland
      lipid uptake and lipogenesis in rat dams fed, during pregnancy and lactation, one
      of two purified diets, with equal energy density, containing 2.5 (LL) or 20 g
      fat/100 g diet (HL). Milk lipid concentration and fatty acid composition were
      determined at d 14 of lactation. Mammary gland lipogenesis, lipoprotein lipase
      (LPL) activity and the uptake of [1-(14)C]triolein by the mammary gland and its
      transfer to the pups was measured. The intestinal absorption of oral (14)C-lipid,
      (14)CO(2) production and the amount of (14)C-lipid transferred to the pups (milk
      clot + pups carcass) were significantly higher in the HL group than in the LL
      group (P < 0.05). Mammary gland lipogenesis was 75% lower and LPL activity was
      30% higher in the HL group (P < 0.05). Medium-chain fatty acids (C6-C14)
      excretion was 46% lower and that of long-chain fatty acids was 142% (P < 0.001)
      higher in the HL group than in the LL group. The higher milk lipid excretion in
      the rats fed a high-fat diet resulted from a larger uptake of dietary lipid by
      the mammary gland, indicated by a larger transfer of (14)C-lipid to the pups and
      by a higher LPL activity in the mammary gland.

PMID- 10419994
TI  - Conjugated linoleic acids alter milk fatty acid composition and inhibit milk fat
      secretion in dairy cows.
AB  - Conjugated linoleic acids (CLA) have positive health effects in experimental
      models. Our objective was to determine the effect of CLA supplementation on milk
      of dairy cows. A commercial source of CLA was infused abomasally to by-pass rumen
      fermentation. The supplement contained 61.2% CLA; the major CLA isomers were
      cis/trans 8,10, cis/trans 9,11, cis/trans 10,12 and cis/trans 11,13. Four
      Holstein cows were used in a 4 x 4 Latin square design. Treatments were 5-d
      infusions of 0, 50, 100 and 150 g/d of CLA supplement. Infusion increased milk
      fat content of CLA from 6.8 mg/g fat (zero dose) to 63.6 mg/g fat (highest dose).
      All of the major CLA isomers in the supplement were transferred to milk fat in a
      dose-dependent manner. Apparent efficiency of transfer to milk fat was 22.5,
      22.5, 10.2 and 26.3% for cis/trans 8,10, cis/trans 9,11, cis/trans 10,12 and
      cis/trans 11,13, respectively. CLA infusion had no effect on milk protein and
      little effect on milk yield (21.5, 20.4, 20.9 and 18.3 kg/d for 0, 50, 100 and
      150 g/d CLA supplement, respectively). However, CLA infusion dramatically reduced
      milk fat. On average, the content and yield of milk fat were reduced by 52 and
      55%, respectively. The role of specific CLA isomers and mechanism(s) for the
      reduction in milk fat have not been established, although the pattern of milk
      fatty acids demonstrated effects were most pronounced on de novo fatty acid
      synthesis and the desaturation process. Overall, dietary supplemention of CLA
      increased milk fat content of CLA, altered milk fatty acid composition and
      markedly reduced the content and yield of milk fat.

PMID- 10419995
TI  - Intact dietary soy protein, but not adding an isoflavone-rich soy extract to
      casein, improves plasma lipids in ovariectomized cynomolgus monkeys.
AB  - The dietary consumption of soy protein has been linked to a reduction in coronary
      heart disease and improvements in a number of related risk factors. Recent
      investigations have focused on isoflavone components of soy protein. The purpose
      of this study was to examine plasma lipids and lipoproteins, particularly LDL,
      with the intake of intact soy protein or casein-lactalbumin diets with and
      without a semipurified extract of soy, rich in isoflavones. Sixty ovariectomized
      cynomolgus monkeys were assigned to one of three groups fed diets containing the
      following: 1) casein-lactalbumin as the protein source (CAS; n = 20); 2) CAS plus
      a semipurified extract of soy, rich in isoflavones (ISO; n = 20); or 3) intact
      soy protein (SOY; n = 20) for 12 wk. Lipoproteins were fractionated by combined
      ultracentrifugation and HPLC. Isolated LDL particles were further subfractionated
      by dividing the LDL peak into three fractions for compositional analyses. The SOY
      group had significantly lower plasma total cholesterol, VLDL plus IDL cholesterol
      and LDL cholesterol, and significantly less HDL cholesterol than the CAS group.
      LDL particles from the SOY group had a significantly less cholesteryl ester than
      the CAS group. The semipurified extract of soy, rich in isoflavones, added to
      casein-lactalbumin protein did not have the same effects as intact soy protein on
      plasma lipids and lipoproteins. Other components of soy protein, either alone or
      in combination with isoflavones, may be involved in the effects seen in this
      study.

PMID- 10419996
TI  - Energy intake and utilization vary during development in rats.
AB  - Energy intake, utilization, and partitioning were determined in male Wistar rats
      from 25 to 180 d of age. Serum free triiodothyronine, leptin, and free fatty acid
      concentrations were also measured. Energy balance measurements allowed us to
      identify a period from 25 to 90 d, characterized by a rapid body growth rate and
      another from 90 to 180 d, during which body growth rate slowed. From 25 to 180 d,
      we found decreases in daily energy intake and expenditure, which were faster
      before 90 d. The first period was characterized by storage of lipid and protein.
      In the second period, protein deposition approached zero and the excess of
      ingested energy was entirely stored as fat, so that age-associated obesity began
      to develop. The inability of rats to maintain a stable body weight after the
      cessation of growth of lean body mass is not due to decreased resting metabolism
      but rather to a partial leptin resistance.

PMID- 10419998
TI  - Essential amino acid deficiency enhances long-term intake but not short-term
      licking of the required nutrient.
AB  - Rats can adjust their nutrient intake in response to nutritional deficiency. This
      phenomenon has been described extensively for sodium deficiency, whereas other
      nutrient deficiencies have not been explored thoroughly. Essential amino acid
      (EAA) deficiency represents a relevant model to describe adaptive changes in
      behavior resulting from deficiency. The purpose of these experiments was to
      examine more closely the behavioral responses that occur as a result of lysine
      (LYS) and threonine (THR) deficiency. Licking to LYS, THR, glycine and distilled
      water during 10-s trials was measured in control (CON) and EAA-deficient rats.
      Licking tests were conducted both before and after 23-h intake tests. Although
      EAA-deficient rats did not show increased licking to the deficient EAA in any of
      the brief-access tests, in all cases, they did initiate significantly more
      overall trials than did CON. The EAA-deficient rats also had elevated intake of
      the deficient EAA in long-duration tests. These findings suggest that LYS or THR
      deficiency does not emulate the behavioral properties of sodium deficiency in
      that it does not result in enhanced immediate licking responses to the limiting
      EAA in brief-access tests. Nevertheless, an appetite is expressed to the relevant
      EAA in a long-term intake test.

PMID- 10419997
TI  - Expression of the insecticidal bean alpha-amylase inhibitor transgene has minimal
      detrimental effect on the nutritional value of peas fed to rats at 30% of the
      diet.
AB  - The effect of expression of bean alpha-amylase inhibitor (alpha-AI) transgene on
      the nutritional value of peas has been evaluated by pair-feeding rats diets
      containing transgenic or parent peas at 300 and 650 g/kg, respectively, and at
      150 g protein/kg diet, supplemented with essential amino acids to target
      requirements. The results were also compared with the effects of diets containing
      lactalbumin with or without 0.9 or 2.0 mg bean alpha-AI, levels equivalent to
      those in transgenic pea diets. When 300 and 650 g peas/kg diet were fed, the
      daily intake of alpha-AI was 11.5 or 26.3 mg alpha-AI, respectively. At the 300
      g/kg level, the nutritional value of the transgenic and parent line peas was not
      significantly different. The weight gain and tissue weights of rats fed either of
      the two pea diets were not significantly different from each other or from those
      of rats given the lactalbumin diet even when this was supplemented with 0.9 g
      alpha-AI/kg. The digestibilities of protein and dry matter of the pea diets were
      slightly but significantly lower than those of the lactalbumin diet, probably due
      to the presence of naturally occurring antinutrients in peas. The nutritional
      value of diets containing peas at the higher (650 g) inclusion level was less
      than that of the lactalbumin diet. However, the differences between transgenic
      and parent pea lines were small, possibly because neither the purified
      recombinant alpha-AI nor that in transgenic peas inhibited starch digestion in
      the rat small intestine in vivo to the same extent as did bean alpha-AI. This was
      the case even though both forms of alpha-AI equally inhibited alpha-amylase in
      vitro. Thus, this short-term study indicated that transgenic peas expressing bean
      alpha-AI gene could be used in rat diets at 300 g/kg level without major harmful
      effects on their growth, metabolism and health, raising the possibility that
      transgenic peas may also be used at this level in the diet of farm animals.

PMID- 10419999
TI  - A low-protein isocaloric diet during gestation affects brain development and
      alters permanently cerebral cortex blood vessels in rat offspring.
AB  - In humans, low birth weight is associated with nonfatal stroke, cardiovascular
      disease and diabetes at adulthood. The aim of this study was to investigate in
      rats the effect of early protein restriction, inducing low birth weight, on brain
      and endocrine pancreas vascularization at birth and to study if such alterations
      lasted until adulthood. Pregnant rats were fed either 20 or 8% protein isocaloric
      diets. Control newborns were nursed by their dams fed the 20% protein diet and
      low protein (LP) pups by dams fed either the 8 or 20% protein diet. The diets
      given during lactation were maintained until adulthood. The blood vessel density
      of cerebral cortex analyzed by morphometry in 3-d-old pups from dams fed the 8%
      protein diet was lower than in control (C). It remained lower at adulthood
      whether a LP or a C diet was given postnatally. Reduction of vascularization at
      adulthood induced by the LP diet limited to fetal life seems characteristic for
      the brain since vascularization of islets of Langerhans was reduced in neonates
      but normalized at adulthood by a C diet postnatally. Body and brain weights were
      lower in LP pups and adults. DNA concentration was lower in forebrain and higher
      in cerebellum in LP pups. In brain of LP adults, DNA, protein, cholesterol and
      phospholipid concentrations were lower and were restored at adulthood by a normal
      diet after birth. In conclusion, cerebral cortex of offspring exposed to a LP
      isocaloric diet during fetal development showed reduced vascularization which
      remained throughout life.

PMID- 10420000
TI  - Frequency tuning of cochlear hair cells by differential splicing of BK channel
      transcripts.

PMID- 10420001
TI  - Inactivation of N-type Ca2+ channels: Ca2+ vs. voltage.

PMID- 10420002
TI  - Phenotype of a recombinant store-operated channel: highly selective permeation of
      Ca2+.
AB  - 1. Genes related to trp (transient receptor potential) are proposed to encode
      store-operated channels. We examined the ionic permeation of recombinant channels
      formed by stable and transient expression of the TRP homologue bCCE1 in Chinese
      hamster ovary (CHO) cells (CHO(CCE1)) and rat basophilic leukaemia (RBL) cells,
      respectively. 2. Store-operated currents were activated in CHO(CCE1) cells by
      internal dialysis of IP3 under strong buffering of intracellular Ca2+. The action
      of IP3 was mimicked by thapsigargin but not by IP4. 3. With extracellular Ca2+,
      Na+ and Mg2+, the store-operated currents of CHO(CCE1) rectified inwardly in the
      presence of internal Cs+. Outward currents were not detected below +80 mV.
      Identical currents were recorded with external Ba2+ and also with no external Na+
      and Mg2+. In the absence of external Mg2+, the inward currents showed an
      anomalous mole fraction behaviour between Ca2+ and Na+. Half-maximal inhibition
      of Na+ currents was observed with approximately 100 nM and full block with 2-5
      microM external Ca2+. 4. In the parental CHO(-) cells, IP3 dialysis evoked inward
      currents that also displayed anomalous mole fraction behaviour between Ca2+ and
      Na+. However, half-maximal block of Na+ currents required 5 times higher Ca2+
      concentrations in CHO(-) cells. Additionally, the density of Ca2+ and Na+
      currents at -80 mV was 5 and 2 times larger in CHO(CCE1) cells, respectively. 5.
      In RBL cells, dialysis of IP3 evoked store-operated currents that showed 1.4-fold
      larger densities at -80 mV in cells expressing bCCE1. 6. The enhanced density of
      store-operated currents in CHO(CCE1) cells and in bCCE1-transfected RBL cells
      probably reflects the phenotype of CCE1. These results suggest a highly selective
      permeation of Ca2+ through recombinant channels formed by CCE1 either alone or in
      combination with endogenous channel proteins.

PMID- 10420003
TI  - Single-channel properties of BK-type calcium-activated potassium channels at a
      cholinergic presynaptic nerve terminal.
AB  - 1. A high-conductance calcium-activated potassium channel (BK KCa) was
      characterized at a cholinergic presynaptic nerve terminal using the calyx synapse
      isolated from the chick ciliary ganglion. 2. The channel had a conductance of 210
      pS in a 150 mM:150 mM K+ gradient, was highly selective for K+ over Na+, and was
      sensitive to block by external charybdotoxin or tetraethylammonium (TEA) and by
      internal Ba2+. At +60 mV it was activated by cytoplasmic calcium [Ca2+]i with a
      Kd of approximately 0.5 microM and a Hill coefficient of approximately 2.0. At 10
      microM [Ca2+]i the channel was 50 % activated (V) at -8.0 mV with a voltage
      dependence (Boltzmann slope-factor) of 32.7 mV. The V values hyperpolarized with
      an increase in [Ca2+]i while the slope factors decreased. There were no overt
      differences in conductance or [Ca2+]i sensitivity between BK channels from the
      transmitter release face and the non-release face. 3. Open and closed times were
      fitted by two and three exponentials, respectively. The slow time constants were
      strongly affected by both [Ca2+]i and membrane potential changes. 4. In cell
      attached patch recordings BK channel opening was enhanced by a prepulse
      permissive for calcium influx through the patch, suggesting that the channel can
      be activated by calcium ion influx through neighbouring calcium channels. 5. The
      properties of the presynaptic BK channel are well suited for rapid activation
      during the presynaptic depolarization and Ca2+ influx that are associated with
      transmitter release. This channel may play an important role in terminating
      release by rapid repolarization of the action potential.

PMID- 10420004
TI  - The role of Ca2+-activated K+ channel spliced variants in the tonotopic
      organization of the turtle cochlea.
AB  - 1. Turtle auditory hair cells contain multiple isoforms of the pore-forming alpha
      subunit of the large-conductance Ca2+-activated K+ (KCa) channel due to
      alternative splicing at two sites. Six splice variants were studied by expression
      in Xenopus oocytes. 2. The isoforms possessed differences in apparent Ca2+
      sensitivity and kinetics. The lowest Ca2+ sensitivity was observed in a novel
      variant resulting from a 26 amino acid deletion around one of the splice sites.
      3. Co-expression of a bovine beta-subunit slowed the current relaxation 10-fold
      compared with channels formed from alpha-subunits alone but preserved the
      original order of kinetic differences. The beta-subunit also increased the Ca2+
      sensitivity of isoforms to bring them nearer the range of sensitivity of the
      native KCa channels of the hair cell. 4. With channels formed from alpha-subunits
      or alpha + beta-subunits, the half-activation voltage in a fixed Ca2+
      concentration, and the time constant of the current relaxation, varied linearly
      with the combined size of the insertions/deletions at the splice sites. 5.
      Experiments in which the beta/alpha concentration ratio was varied indicated that
      the beta-subunit exerts an all-or-none effect on the Ca2+ sensitivity and
      kinetics of the channel. 6. Co-expression of an avian beta2-subunit had effects
      on kinetics and Ca2+ sensitivity of several alpha-isoforms which were
      qualitatively similar to those produced by the bovine beta-subunit. 7. We
      conclude that differential expression of alternatively spliced alpha-subunit
      variants and a non-uniform distribution of a beta-subunit can produce a range of
      KCa channel properties needed to explain the tonotopic organization of the turtle
      cochlea.

PMID- 10420006
TI  - Human axons contain at least five types of voltage-dependent potassium channel.
AB  - 1. We investigated voltage-gated potassium channels in human peripheral
      myelinated axons; apart from the I, S and F channels already described in
      amphibian and rat axons, we identified at least two other channel types. 2. The I
      channel activated between -70 and -40 mV, and inactivated very slowly (time
      constant 13.1 s at -40 mV). It had two gating modes: the dominant ('noisy') mode
      had a conductance of 30 pS (inward current, symmetrical 155 mM K+) and a
      deactivation time constant (tau) of 25 ms (-80 mV); it accounted for most (
      approximately 50-75 %) of the macroscopic K+ current in large patches. The
      secondary ('flickery') gating mode had a conductance of 22 pS, and showed bi
      exponential deactivation (tau = 16 and 102 ms -80 11 mV); it contributed part of
      the slow macroscopic K+ current. 3. The I channel current was blocked by 1 microM
      alpha-dendrotoxin (DTX); we also observed two other DTX-sensitive K+ channel
      types (40 pS and 25 pS). The S and F channels were not blocked by 1 microM DTX.
      4. The conductance of the S channel was 7-10 pS, and it activated at slightly
      more negative potentials than the I channel; its deactivation was slow (tau =
      41.7 ms at -100 mV). It contributed a second component of the slow macroscopic K+
      current. 5. The F channel had a conductance of 50 pS; it activated at potentials
      between -40 and +40 V, deactivated very rapidly (tau = 1.4 ms at -100 mV), and
      inactivated rapidly (tau = 62 ms at +80 mV). It accounted for the fast
      deactivating macroscopic K+ current and partly for fast K+ current inactivation.
      6. We conclude that human and rat axonal K+ channels are closely similar, but
      that the correspondence between K+ channel types and the macroscopic currents
      usually attributed to them is only partial. At least five channel types exist,
      and their characteristics overlap to a considerable extent.

PMID- 10420005
TI  - AMPA-preferring glutamate receptors in cochlear physiology of adult guinea-pig.
AB  - 1. The present study was designed to determine which glutamate (Glu) receptors
      are involved in excitatory neurotransmission at the first auditory synapse
      between the inner hair cells and the spiral ganglion neurons. 2. The Glu
      receptors present at the membrane level were investigated on isolated spiral
      ganglion neuron somata from guinea-pigs by whole-cell voltage-clamp measurements.
      Glu and AMPA induced a fast onset inward current that was rapidly desensitized,
      while kainate induced only a non-desensitizing, steady-state current. NMDA
      induced no detectable current. 3. To further discriminate between the AMPA and
      kainate receptors present, we used the receptor-specific desensitization
      blockers, cyclothiazide and concanavalin A. While no effect was observed with
      concanavalin A, cyclothiazide greatly enhanced the Glu-, AMPA- and kainate
      induced steady-state currents and potentiated Glu-induced membrane
      depolarization. 4. To extrapolate the results obtained from the somata to the
      events occurring in situ at the dendrites, the effects of these drugs were
      evaluated in vivo. Cyclothiazide reversibly increased spontaneous activity of
      single auditory nerve fibres, while concanavalin A had no effect, suggesting that
      the functional Glu receptors on the somata may be the same as those at the
      dendrites. 5. The combination of a moderate-level sound together with
      cyclothiazide increased and subsequently abolished the spontaneous and the sound
      evoked activity of the auditory nerve fibres. Histological examination revealed
      destruction of the dendrites, suggesting that cyclothiazide potentiates sound
      induced Glu excitotoxicity via AMPA receptors. 6. Our results reveal that fast
      synaptic transmission in the cochlea is mainly mediated by desensitizing AMPA
      receptors.

PMID- 10420007
TI  - Interaction between permeant ions and voltage sensor during inactivation of N
      type Ca2+ channels.
AB  - 1. Inactivation of neuronal N-type Ca2+ channels transiently expressed in human
      kidney tSA-201 cells was studied at the level of whole-cell Ca2+ current and
      intramembrane charge movement. 2. Prolonged (5 s) depolarization to 40 mV shifted
      the voltage distribution of intramembrane charge movement from a transition
      potential (mid-point voltage) of 9.5 +/- 3.8 mV to -55.4 +/- 8.2 mV. Because of
      the large negative shift, it was possible to record intramembrane charge movement
      from unblocked inactivated channels and determine the effect of Ca2+ influx on
      inactivation of intramembrane charge movement. 3. In unblocked channels, the rate
      of inactivation of charge movement (21 +/- 3 s-1 at 0 mV) was close to that of
      Ca2+ current decay during the conditioning pulse. However, in blocked channels
      inactivation was significantly slower (4 +/- 1 s-1 at 0 mV). In unblocked
      channels, the availability of Ca2+ current was minimal and charge movement from
      inactivated channels was maximal after conditioning to about 10 mV. After the
      block of ionic current, inactivation of charge movement gradually increased with
      voltage. 4. Although the rate of Ca2+ current run-down was not affected by 10-15
      microM free Ca2+ in the pipette solution, inactivation of Ca2+ currents during
      depolarization was about two times faster in high intracellular Ca2+. 5. The
      present results favour the current-dependent mechanism of inactivation of N-type
      channels. They also suggest that Ca2+ acting in the permeation pathway and
      transmembrane voltage are the proximate causes of the same inactivation
      transitions of voltage sensing moieties in these channels.

PMID- 10420008
TI  - Biophysical and pharmacological diversity of high-voltage-activated calcium
      currents in layer II neurones of guinea-pig piriform cortex.
AB  - 1. High-voltage-activated calcium currents were studied with the whole-cell,
      patch-clamp technique in acutely dissociated pyramidal neurones from guinea-pig
      piriform cortex layer II. Barium ions were used as charge carriers. 2. Barium
      currents (IBa) displayed a remarkable kinetic diversity in different neurones.
      The ratio between the current amplitude at the end of the test pulses and the
      peak amplitude (Re/p) showed two frequency-distribution peaks at approximately
      0.4 and 0.8. The index of current activation speed (rise time 10-90 %) directly
      correlated with the index of current persistence, Re/p. 3. The half-activation
      potential (V ) of total IBas positively correlated with the Re/p of the
      corresponding currents. This implied that the high-decay IBas also had a more
      negative voltage range of activation than the more persistent ones. 4. The L- and
      N-type channel blockers nifedipine (10 microM) and omega-conotoxin GVIA (omega
      CTx GVIA, 0.5-1 microM) additively blocked 20 and 25 % of the total IBa,
      respectively. The P/Q-type calcium channel blockers omega-agatoxin IVA (100 nM),
      omega-conotoxin MVIIC (1 microM) and 3.3 funnel toxin (1 microM), had little
      effect on IBa. 5. The nifedipine- and omega-CTx GVIA-sensitive current had a Re/p
      > 0.55 and their voltage dependence of activation was of the high-voltage
      activated type (V approximately 0 mV). 6. High-, intermediate- and low-decay
      blocker-resistant currents were observed in different neurones. Their Re/p values
      highly correlated with those of the corresponding total IBas and with the voltage
      dependence of activation of the underlying conductances. Exponential fittings of
      the inactivation phase of blocker-resistant currents returned very fast time
      constants (lower than 30 ms) for high-decay currents (Re/p < 0.25). The
      intermediate-decay currents (Re/p approximately 0.55) could not derive from
      variable combinations of high- and low-decay current components. 7. Our data
      demonstrate a remarkable variety in voltage-activated calcium currents expressed
      by piriform cortex neurones, that include currents resistant to high-voltage
      activated calcium-channel blockers.

PMID- 10420009
TI  - A study of the voltage dependence of capsaicin-activated membrane currents in rat
      sensory neurones before and after acute desensitization.
AB  - 1. Responses to capsaicin in isolated sensory neurones have been shown to
      desensitize in a Ca2+- and voltage-dependent manner. We have studied
      desensitization of capsaicin-activated currents in cultured adult rat dorsal root
      ganglion (DRG) neurones over a range of membrane potentials using whole-cell
      patch-clamp techniques. 2. Acute desensitization of responses to capsaicin (0.5
      microM) was significantly less when the holding potential (Vh) was +40 mV rather
      than -60 mV. This was not due only to reduced Ca2+ entry as the response to
      capsaicin was desensitized by the same amount whether prior exposure to capsaicin
      was at -60 or +40 mV. The I-V relationship for capsaicin-induced current,
      determined using a voltage step protocol, was outwardly rectifying and during the
      acute phase of desensitization the degree of outward rectification increased. 3.
      Acute desensitization and the increase in outward rectification that accompanied
      desensitization were inhibited when cells were dialysed with the rapid Ca2+
      chelator BAPTA. Addition of a pseudosubstrate inhibitor of the Ca2+-calmodulin
      dependent enzyme calcineurin (CI, 100 microM) prevented the increase in outward
      rectification although it did not cause a significant decrease of acute
      desensitization. 4. Removal of external Ca2+ or Mg2+ did not reverse the increase
      in outward rectification of capsaicin-activated current after Ca2+-dependent
      desensitization had occurred. This indicates that a voltage-dependent block of
      the capsaicin-activated ion channel by Ca2+ or Mg2+ was not responsible for the
      observed changes in the properties of the capsaicin-activated conductance.

PMID- 10420010
TI  - Influence of inorganic phosphate and pH on sarcoplasmic reticular ATPase in
      skinned muscle fibres of Xenopus laevis.
AB  - 1. The influence of 30 mM inorganic phosphate (Pi) and pH (6.2-7.4) on the rate
      of ATP utilization was determined in mechanically skinned bundles of myofibrils
      from the iliofibularis muscle of Xenopus laevis at approximately 5 C. 2. BDM (2,3
      butanedione monoxime; 10 mM) depressed isometric force production and actomyosin
      (AM) ATPase activity equally. Therefore sarcoplasmic reticular (SR) ATPase
      activity could be determined by extrapolation of the total ATPase activity to
      zero force. 3. The SR ATPase activity without added Pi at pH 7.1 was 42 +/- 2 %
      of the total ATPase activity. Addition of 30 mM Pi reduced SR ATPase activity
      slightly, by 9 +/- 5 %, and depressed force by 62 +/- 2 % and AM ATPase activity
      by 21 +/- 6 %. 4. At pH 6.2, force, SR ATPase activity and AM ATPase activity
      were reduced by 21 +/- 5, 61 +/- 5 and 10 +/- 4 % of their respective values at
      pH 7.1. 5. The SR ATPase activity at 30 mM Pi and pH 6.2 was reduced markedly to
      20 +/- 6 % of the value under control conditions, suggesting that the maximum
      rate of Ca2+ uptake during muscle fatigue was strongly depressed. This reduction
      was larger than expected on the basis of the effects of Pi and pH alone.

PMID- 10420011
TI  - CaM kinase II-dependent mobilization of secretory granules underlies
      acetylcholine-induced stimulation of exocytosis in mouse pancreatic B-cells.
AB  - 1. Measurements of cell capacitance were used to investigate the mechanisms by
      which acetylcholine (ACh) stimulates Ca2+-induced exocytosis in single insulin
      secreting mouse pancreatic B-cells. 2. ACh (250 microM) increased exocytotic
      responses elicited by voltage-clamp depolarizations 2.3-fold. This effect was
      mediated by activation of muscarinic receptors and dependent on elevation of the
      cytoplasmic Ca2+ concentration ([Ca2+]i) attributable to mobilization of Ca2+
      from intracellular stores. The latter action involved interference with the
      buffering of [Ca2+]i and the time constant (tau) for the recovery of [Ca2+]i
      following a voltage-clamp depolarization increased 5-fold. As a result, Ca2+ was
      present at concentrations sufficient to promote the replenishment of the readily
      releasable pool of granules (RRP; > 0.2 microM) for much longer periods in the
      presence than in the absence of the agonist. 3. The effect of Ca2+ on exocytosis
      was mediated by activation of CaM kinase II, but not protein kinase C, and
      involved both an increased size of the RRP from 40 to 140 granules and a decrease
      in tau for the refilling of the RRP from 31 to 19 s. 4. Collectively, the effects
      of ACh on the RRP and tau result in a > 10-fold stimulation of the rate at which
      granules are supplied for release.

PMID- 10420012
TI  - The effect of muscle contraction on the regulation of adenosine formation in rat
      skeletal muscle cells.
AB  - 1. The present study examined the effect of muscle contraction on the rate of
      extracellular adenosine formation and on the distribution of 5' nucleotidase in
      primary rat skeletal muscle cells in culture. Experiments were also performed to
      determine whether the muscle cells release a metabolite upon contraction which
      may influence the extracellular production of adenosine. 2. Muscle contraction,
      induced by electrical stimulation, increased (P < 0.05) the rate of adenosine
      formation in the presence of physiological concentrations (2 and 5 microM) of
      adenosine monophosphate (AMP). Muscle contraction also led to an increase (P <
      0.05) in the maximal rate of extracellular adenosine formation from 4.09 +/- 0.19
      to 7.04 +/- 0.27 micromol (g protein)-1 min-1. Similarly, homogenates of
      contracted muscle cells had a higher (by 19.5 +/- 10.5 %; P < 0.05) AMP 5'
      nucleotidase activity than homogenates of control cells. 3. Addition of buffer
      from contracted cells to control cells induced an elevation (18.4 +/- 5.3 %; P <
      0.05) in the rate of adenosine formation. The rate of adenosine formation was
      also increased with decreased intracellular adenylate charge (P < 0.05). 4. Cell
      homogenates treated with detergent had a higher (by 58.0 +/- 16.3 %; P < 0.05)
      AMP 5' nucleotidase activity than untreated homogenates, suggesting the existence
      of an enclosed pool of 5' nucleotidase within the muscle cells. The rate of
      adenosine formation in the detergent-treated homogenates was similar for
      electrically stimulated and non-electrically stimulated cells. 5. The present
      data show that muscle contraction induces an enhanced extracellular adenosine
      production via an increase in the activity of ecto AMP 5' nucleotidase. The
      activity of 5' nucleotidase can be elevated via a compound released by muscle
      cells during contraction and by alteration in intracellular adenylate charge. It
      is furthermore proposed that the extracellular adenosine formation is increased
      by translocation of 5' nucleotidase from an enclosed intracellular pool to the
      muscle membrane.

PMID- 10420013
TI  - Voltage-gated K+ currents in freshly isolated myocytes of the pregnant human
      myometrium.
AB  - 1. Voltage-gated K+ currents in human myometrium are not well characterized, and
      were therefore investigated, using the whole-cell patch clamp technique, in
      freshly isolated myometrial smooth muscle cells from pregnant women at term. 2.
      Three types of voltage-gated K+ currents were identified. IK1 was a 4
      aminopyridine-insensitive current with a negative half-inactivation (V0.5 = -61
      to -67 mV) and negative activation characteristics (threshold between -60 and -40
      mV) and slow kinetics. IK2 was a 4-aminopyridine-sensitive current (half-maximal
      block at approximately 1 mM) with relatively positive half-inactivation (V0.5 = 
      30 mV) and activation characteristics (threshold between -40 and -30 mV) and
      faster kinetics. IK,A was a 4-aminopyridine-sensitive current with a negative
      inactivation and very fast inactivation kinetics. 3. Both IK1 and IK2 were
      sensitive to high concentrations of tetraethylammonium (half-maximal block at
      approximately 3 mM) and low concentrations of clofilium (half-maximal block by 3
      10 microM). 4. IK1 and IK2 were unevenly distributed between myometrial cells,
      most cells possessing either IK1 (30 cells) or IK2 (24 cells) as the predominant
      current. 5. The characteristics of these currents suggest a possible function in
      the control of membrane potentials and smooth muscle quiescence in the pregnant
      human myometrium.

PMID- 10420014
TI  - In vivo pH and metabolite changes during a single contraction in rat uterine
      smooth muscle.
AB  - 1. We have used 31P NMR spectroscopy to measure metabolites and pHi at three
      periods during a phasic contraction of the uterus, in vivo, to determine whether
      they change as a consequence of contraction. The regular uterine contractions
      were recorded via a balloon catheter in the uterine lumen. Each phasic
      contraction was divided into three parts: the period between contractions (rest),
      the development of force (up) and the relaxation of force (down). The NMR data
      were summed separately from each of these three periods over 20-40 successive
      contractions. 2. Significant changes in ATP, phosphocreatine (PCr) and inorganic
      phosphate (Pi) occurred during the contraction. [ATP] fell from 2.0 to 1.6 mM and
      [PCr] from 2.6 to 2.0 mM during the up period, while [Pi] increased from 2.2 to
      2.8 mM. Recovery of ATP and PCr occurred during the relaxation part of the
      contraction, whereas Pi did not fully recover until the contraction was complete.
      3. Significant acidification from pH 7.28 +/- 0.02 at rest to 7.16 +/- 0.02,
      occurred with contraction. This acidification is greater than that previously
      reported for in vitro uterine preparations. Measurements of uterine blood flow
      show that it decreased with contraction. Therefore, ischaemia, in addition to the
      metabolic consequences of contraction, may account for the larger acidification
      observed in vivo. 4. Lowering pHi in an in vitro uterine preparation by a similar
      level to that found in vivo produced a significant reduction of the phasic
      contractions. Thus we propose that these changes, especially the fall in pHi
      during force development, feed back negatively on the contraction to limit its
      strength, and may help prevent uterine ischaemia and fetal hypoxia during labour.

PMID- 10420015
TI  - Bombesin-like peptides depolarize rat hippocampal interneurones through
      interaction with subtype 2 bombesin receptors.
AB  - 1. Whole-cell patch-clamp recordings were made from visually identified
      hippocampal interneurones in slices of rat brain tissue in vitro. Bath
      application of the bombesin-like neuropeptides gastrin-releasing peptide (GRP) or
      neuromedin B (NMB) produced a large membrane depolarization that was blocked by
      pre-incubation with the subtype 2 bombesin (BB2) receptor antagonist [D-Phe6, Des
      Met14]bombesin-(6-14)ethyl amide. 2. The inward current elicited by NMB or GRP
      was unaffected by K+ channel blockade with external Ba2+ or by replacement of
      potassium gluconate in the electrode solution with caesium acetate. 3.
      Replacement of external NaCl with Tris-HCl significantly reduced the magnitude of
      the GRP-induced current at -60 mV. In contrast, replacement of external NaCl with
      LiCl had no effect on the magnitude of this current. 4. Photorelease of caged
      GTPgammaS inside neurones irreversibly potentiated the GRP-induced current at -60
      mV. Similarly, bath application of the phospholipase C (PLC) inhibitor U-73122
      significantly reduced the size of the inward current induced by GRP. 5. Reverse
      transcription followed by the polymerase chain reaction using cytoplasm from
      single hippocampal interneurones demonstrated the expression of BB2 receptor mRNA
      together with glutamate decarboxylase (GAD67). 6. Although bath application of
      GRP or NMB had little or no effect on the resting membrane properties of CA1
      pyramidal cells per se, these neuropeptides produced a dramatic increase in the
      number and amplitude of miniature inhibitory postsynaptic currents in these cells
      in a TTX-sensitive manner.

PMID- 10420016
TI  - Actions of opioids on excitatory and inhibitory transmission in substantia
      gelatinosa of adult rat spinal cord.
AB  - 1. The actions of opioid receptor agonists on synaptic transmission in substantia
      gelatinosa (SG) neurones in adult (6- to 10-week-old) rat spinal cord slices were
      examined by use of the blind whole-cell patch-clamp technique. 2. Both the mu
      receptor agonist DAMGO (1 microM) and the delta-receptor agonist DPDPE (1 microM)
      reduced the amplitude of glutamatergic excitatory postsynaptic currents (EPSCs)
      which were monosynaptically evoked by stimulating Adelta afferent fibres. Both
      also decreased the frequency of miniature EPSCs without affecting their
      amplitude. 3. In contrast, the kappa-receptor agonist U-69593 (1 microM) had
      little effect on the evoked and miniature EPSCs. 4. The effects of DAMGO and
      DPDPE were not seen in the presence of the mu-receptor antagonist CTAP (1 microM)
      and the delta-receptor antagonist naltrindole (1 microM), respectively. 5.
      Neither DAMGO nor DPDPE at 1 microM affected the responses of SG neurones to bath
      applied AMPA (10 microM). 6. Evoked and miniature inhibitory postsynaptic
      currents (IPSCs), mediated by either the GABAA or the glycine receptor, were
      unaffected by the mu-, delta- and kappa-receptor agonists. Similar results were
      also obtained in SG neurones in young adult (3- to 4-week-old) rat spinal cord
      slices. 7. These results indicate that opioids suppress excitatory but not
      inhibitory synaptic transmission, possibly through the activation of mu- and
      delta- but not kappa-receptors in adult rat spinal cord SG neurones; these
      actions are presynaptic in origin. Such an action of opioids may be a possible
      mechanism for the antinociception produced by their intrathecal administration.

PMID- 10420018
TI  - Monosynaptic Ia pathways at the cat shoulder.
AB  - 1. The study aimed to describe in cat forelimb and shoulder motoneurones the
      convergence and projection patterns from large muscle spindle afferents (Ia). In
      11 chloralose-anaesthetized cats maximum Ia EPSPs evoked by electrical
      stimulation of ipsilateral forelimb nerves were obtained in 309 intracellularly
      recorded alpha-motoneurones. 2. Groups of motor nuclei displayed similar Ia
      patterns. As in the distal forelimb they were often interconnected by
      bidirectional pathways, which were used to combine Ia synergistic groups. Three
      such groups are described at the shoulder. 3. The first group was composed of the
      main flexors of the scapulo-humeral joint. Regular disto-proximal Ia excitation
      from elbow extensors (and median afferents) indicates a coupling of flexion in
      the scapulo-humeral joint to the angular position of the elbow. 4. The second
      group comprised the outward rotators of the humerus with differentiated Ia
      convergence onto the different group members. The patterns of Ia excitation
      received and sent by the group members demonstrate that the outward rotators are
      incorporated in versatile synergisms and may occupy a central position in
      steering forelimb movements. 5. The third group was formed by the spinatus muscle
      and the subscapularis. This arrangement is suggested by the common convergence
      onto them from the elbow extensors and flexors. The pattern may serve to guide
      and keep the humeral head in the joint capsule. 6. The Ia synergistic groups
      receive Ia convergence from muscles acting at distant joints and also project to
      distant muscles. This is discussed as part of an extended pattern of Ia
      connections along the forelimb. In this way the shoulder muscles would be
      incorporated in flexor and extensor oriented synergisms which are needed to co
      ordinate the muscular activation along the multijoint forelimb during locomotion.
      When the shoulder Ia pathways are compared with those in the distal forelimb,
      organization of the Ia system apparently follows a few basic principles which
      have adapted to the mechanical situation at the particular joints and their
      mechanical interaction.

PMID- 10420017
TI  - Local and cellular Ca2+ transients in smooth muscle of pressurized rat resistance
      arteries during myogenic and agonist stimulation.
AB  - 1. Confocal laser scanning microscopy was used to visualize Ca2+ transients in
      the vascular smooth muscle cells (VSMC) of intact, pressurized rat mesenteric
      resistance arteries loaded with fluorescent calcium indicators. Vasoconstriction
      was assessed by measuring inner arterial diameter. All arteries were studied at
      70 mmHg intralumenal pressure and 37 C. 2. In the control condition of myogenic
      tone the arteries were constricted to 62 % (n = 10) of their passive diameter
      (p.d.). The [Ca2+]i in most VSMC of these arteries was constant over time. In a
      small percentage (< 10 %) of cells in each artery, [Ca2+]i oscillated regularly.
      Local calcium transients (Ca2+ sparks) were observed in five arteries studied
      with confocal linescan imaging. 3. Activation of alpha-adrenoceptors by
      phenylephrine (PE, 1.0 microM) induced further vasoconstriction of pressurized
      arteries (to 27 % of p.d.). In this condition, [Ca2+]i oscillations were
      prominent in a large percentage (83 %) of the VSMC. The Ca2+ oscillations ranged
      in frequency from 4 to 22 min-1, and were usually asynchronous between cells. 4.
      High [KCl]o (65 mM) induced nearly comparable vasoconstriction to PE (37 % of
      p.d.) but [Ca2+]i oscillated in only about 13 % of cells in each artery. 5. Block
      of L-type Ca2+ channels (with nifedipine) in arteries activated by PE caused
      nearly full vasodilatation, but did not abolish the Ca2+ oscillations. Subsequent
      block of the sarcoplasmic reticulum Ca2+ pump (with cyclopiazonic acid) abolished
      Ca2+ oscillations in all cells. 6. We conclude that Ca2+ entering VSMC via L-type
      Ca2+ channels has an obligatory role in force development, both in myogenic tone
      and during alpha1-adrenoceptor activation. The oscillatory pattern of [Ca2+]i
      that persists in the absence of Ca2+ entry via L-type Ca2+ channels is
      ineffective in activating contraction.

PMID- 10420019
TI  - Regulation of baseline cholinergic tone in guinea-pig airway smooth muscle.
AB  - 1. We quantified baseline cholinergic tone in the trachealis of mechanically
      ventilated guinea-pigs and determined the influence of vagal afferent nerve
      activity on this parasympathetic tone. 2. There was a substantial amount of
      baseline cholinergic tone in the guinea-pig trachea, eliciting contractions of
      the trachealis that averaged 24.6 +/- 3.5 % (mean +/- s.e.m.) of the maximum
      attainable contraction. This tone was essentially abolished by vagotomy or
      ganglionic blockade, suggesting that it was dependent upon on-going pre
      ganglionic input arising from the central nervous system. 3. Cholinergic tone in
      the trachealis could be markedly and rapidly altered (either increased or
      decreased) by changes in ventilation (e. g. cessation of ventilation; hyperpnoea;
      slow, deep breathing) and by lung distention (via positive end-expiratory
      pressure). These effects were not accompanied by marked alterations in blood
      gases and were abolished by vagotomy or atropine. By contrast, tachykinin
      receptor antagonists, which abolished capsaicin-induced bronchospasm, were
      without effect on baseline cholinergic tone. This and other evidence suggests
      that capsaicin-sensitive nerves have little if any influence on baseline
      parasympathetic tone. Likewise, while activation of afferent nerves innervating
      the larynx can alter airway parasympathetic nerve activity, transection of the
      superior laryngeal nerves was without effect on baseline cholinergic tone. 4.
      Cutting the vagus nerves caudal to the recurrent laryngeal nerves, thus leaving
      the preganglionic parasympathetic innervation of the trachealis intact but
      disrupting all afferent nerves innervating the lungs and intrapulmonary airways,
      abolished baseline cholinergic tone in the trachea. Sham vagotomy or cutting the
      vagi caudal to the lungs did not reduce baseline cholinergic tone. 5. The results
      indicate that baseline airway cholinergic nerve activity is necessarily dependent
      upon afferent nerve activity arising from the intrapulmonary airways and lungs.
      More specifically, the data are consistent with the hypothesis that on-going
      activity arising from the nerve terminals of intrapulmonary rapidly adapting
      receptors determines the level of baseline airway cholinergic tone.

PMID- 10420020
TI  - Role of protons in activation of cardiac sympathetic C-fibre afferents during
      ischaemia in cats.
AB  - 1. Chest pain caused by myocardial ischaemia is mediated by cardiac sympathetic
      afferents. The mechanisms of activation of cardiac afferents during ischaemia
      remain poorly understood. Increased lactic acid production is associated closely
      with myocardial ischaemia. The present study examined the role of protons
      generated during ischaemia in activation of cardiac sympathetic C-fibre
      afferents. 2. Single-unit activity of cardiac afferents innervating both
      ventricles was recorded from the left sympathetic chain in anaesthetized cats.
      Epicardial tissue pH was measured within 1-1.5 mm of the surface by a pH
      sensitive needle electrode. Responses of cardiac afferents to myocardial
      ischaemia, lactic acid, sodium lactate, acidic phosphate buffer and hypercapnia
      were determined. 3. Occlusion of the coronary artery for 5 min decreased
      epicardial tissue pH from 7.35 +/- 0.21 to 6.98 +/- 0.22 (P < 0.05). Epicardial
      placement of isotonic neutral phosphate buffer, but not saline, prevented the
      ischaemia-induced decrease in epicardial pH. This manoeuvre significantly
      attenuated the response of 16 afferents to 5 min of ischaemia (1.56 +/- 0.23 pre
      treatment vs. 0.67 +/- 0.18 impulses s-1). Topical application of 10-100 microg
      ml-1 of lactic acid, but not sodium lactate, concentration-dependently stimulated
      18 cardiac afferents. Inhalation with high-CO2 gas failed to activate 12 separate
      cardiac afferents. Furthermore, lactic acid stimulated cardiac afferents to a
      greater extent than acidic phosphate buffer solution, applied at a similar pH to
      the same afferents. 4. Collectively, this study provides important in vivo
      evidence that protons contribute to activation/sensitization of cardiac
      sympathetic C-fibre afferents during myocardial ischaemia.

PMID- 10420021
TI  - The effect of firing on the excitability of a model motoneurone and its
      implications for cortical stimulation.
AB  - 1. To help clarify the use of measurements of 'excitability', a simple model
      motoneurone receiving noisy tonic background excitation was tested with brief
      stimuli. Its response was determined from its PSTH (post-stimulus time
      histogram). The tonic background was varied from well below to well above the
      threshold for tonic firing. The conclusions should apply to many other neurones.
      2. The response of the model to a stimulus depended upon a number of factors,
      including stimulus strength, synaptic membrane noise and especially whether or
      not the background drive elicited tonic firing. With the onset of firing, the
      shape of the stimulus-response curve changed drastically and the model then
      responded to the smallest stimulus without a threshold. When the drive was
      subthreshold, increasing the background excitation always increased the response
      to a given stimulus. However, what happened when the tonic drive exceeded the
      threshold for tonic firing depended upon the stimulus strength. With weak
      stimuli, the response increased with the drive to reach a plateau level where it
      was independent of the background firing rate; this occurred for stimuli
      comparable in size to the synaptic noise. With stronger stimuli, the response
      rose to a maximum for very low firing rates, but then decreased by up to 50 % to
      a plateau for high firing rates. Increasing the membrane noise reduced or
      abolished the maximum. 3. The model was also used to simulate a monosynaptic
      conditioning-testing paradigm. The effect of a given conditioning stimulus was
      then found to change with the onset of firing, including when the strength of the
      testing stimulus was adjusted to make the size of the test response the same in
      the presence and absence of firing. 4. The behaviour of real motoneurones can be
      expected to be at least as complex with the transition from silence to firing, so
      H reflex and other tests of 'excitability' must then be treated with caution. In
      particular, as has been observed experimentally, the response of a unit may
      decrease with increasing background excitation, as well as with inhibition. 5.
      Transferring the findings to corticospinal neurones makes it unlikely that the
      magnitude of the descending volley elicited by a given cortical stimulus
      ('excitability') will always increase with the initial level of cortical
      activity. In addition, the appreciable threshold for transcranial magnetic
      stimulation during voluntary contraction suggests that it first excites axons
      rather than the neural pacemakers.

PMID- 10420022
TI  - Evidence for strong synaptic coupling between single tactile afferents and
      motoneurones supplying the human hand.
AB  - 1. Electrical stimulation of digital nerves elicits short-latency excitatory and
      inhibitory spinal reflex responses in ongoing EMG in muscles acting on the
      fingers and thumb. Similar responses are elicited by stimulating a population of
      muscle spindles but not when a single muscle spindle is activated. The current
      study investigated whether short-latency EMG responses could be evoked from the
      discharge of a single cutaneous afferent. 2. Thirty-three tactile afferents were
      recorded via tungsten microelectrodes in the median nerve of awake humans. Spike
      triggered averaging revealed EMG events time-locked to the afferent discharge.
      The afferents were activated by an external probe and the EMG was elicited by a
      weak voluntary contraction. 3. Eleven cutaneous afferents (33 %) showed a short
      latency response in the ongoing EMG. Overt increases or decreases in EMG were
      observed for seven afferents (onset latency 20.0-41.1 ms). For four slowly
      adapting (SA) type II afferents, EMG showed a periodicity that was correlated to
      the afferent interspike interval (r = 0.99). 4. The EMG associated with two
      rapidly adapting (FA) type I afferents (29 %) showed a short-latency excitation
      while five showed neither excitation nor inhibition. Seven SA II afferents (39 %)
      showed excitation and 11 no response; and none of the six SA I afferents showed
      any response. 5. We conclude that, unlike muscle spindle afferents, the input
      from a single cutaneous afferent is strong enough to drive, via interneurones,
      motoneurones supplying muscles acting on the digits. The potent short-latency
      response we found supports the important role of cutaneous mechanoreceptors in
      fine motor control of the human hand.

PMID- 10420023
TI  - Dissociation of the pathways mediating ipsilateral and contralateral motor-evoked
      potentials in human hand and arm muscles.
AB  - 1. Growing evidence points toward involvement of the human motor cortex in the
      control of the ipsilateral hand. We used focal transcranial magnetic stimulation
      (TMS) to examine the pathways of these ipsilateral motor effects. 2. Ipsilateral
      motor-evoked potentials (MEPs) were obtained in hand and arm muscles of all 10
      healthy adult subjects tested. They occurred in the finger and wrist extensors
      and the biceps, but no response or inhibitory responses were observed in the
      opponens pollicis, finger and wrist flexors and the triceps. 3. The production of
      ipsilateral MEPs required contraction of the target muscle. The threshold TMS
      intensity for ipsilateral MEPs was on average 1.8 times higher, and the onset was
      5.7 ms later (in the wrist extensor muscles) compared with size-matched
      contralateral MEPs. 4. The corticofugal pathways of ipsilateral and contralateral
      MEPs could be dissociated through differences in cortical map location and
      preferred stimulating current direction. 5. Both ipsi- and contralateral MEPs in
      the wrist extensors increased with lateral head rotation toward, and decreased
      with head rotation away from, the side of the TMS, suggesting a privileged input
      of the asymmetrical tonic neck reflex to the pathway of the ipsilateral MEP. 6.
      Large ipsilateral MEPs were obtained in a patient with complete agenesis of the
      corpus callosum. 7. The dissociation of the pathways for ipsilateral and
      contralateral MEPs indicates that corticofugal motor fibres other than the fast
      conducting crossed corticomotoneuronal system can be activated by TMS. Our data
      suggest an ipsilateral oligosynaptic pathway, such as a corticoreticulospinal or
      a corticopropriospinal projection as the route for the ipsilateral MEP. Other
      pathways, such as branching of corticomotoneuronal axons, a transcallosal
      projection or a slow-conducting monosynaptic ipsilateral pathway are very
      unlikely or can be excluded.

PMID- 10420024
TI  - Discharge properties and recruitment of human diaphragmatic motor units during
      voluntary inspiratory tasks.
AB  - 1. The behaviour of inspiratory motoneurones is poorly understood in humans and
      even for limb muscles there are few studies of motoneurone behaviour under
      concentric conditions. The current study assessed the discharge properties of the
      human phrenic motoneurones during a range of non-isometric voluntary
      contractions. 2. We recorded activity from 60 motor units in the costal diaphragm
      of four subjects using an intramuscular electrode while subjects performed a set
      of voluntary inspiratory contractions. These included a range of inspiratory
      efforts above and below the usual tidal range: breaths of different sizes (5-40 %
      vital capacity, VC) at a constant inspiratory flow (5 % VC s-1) and breaths of a
      constant size (20 % VC) at different inspiratory flows (2.5-20 % VC s-1). 3. For
      all the voluntary tasks, motor units were recruited throughout inspiration. For
      the various tasks, half-way through inspiration, 61-87 % of the sampled motor
      units had been recruited. 4. When the inspiratory task was deliberately altered,
      most single motor units began their discharge at a particular volume even when
      the rate of contraction had altered. 5. The initial firing frequency (median, 6.5
      Hz) was consistent for tasks with a constant flow regardless of the size of the
      breath. However, for breaths of a constant size the initial firing frequencies
      increased as the inspiratory flow increased (range across tasks, 4.8-9.3 Hz). The
      'final' firing frequency at the end of inspiration increased significantly above
      the initial frequency for each task (by 0.8-5.2 Hz) and was higher for those
      tasks with higher final lung volumes and higher inspiratory flows (range across
      tasks, 7.8-11.0 Hz). 6. There was no correlation within a task between the time
      of recruitment and the initial or final firing frequency for each motor unit.
      However, for each inspiratory task, initial and final firing frequencies were
      positively correlated. 7. Because the discharge of three to four units could be
      recorded simultaneously in a range of tasks, a quantitative 'shuffle' index was
      developed to describe changes in their recruitment order. Recruitment order was
      invariant in the task with the slowest inspiratory flow, but varied slightly, but
      significantly, in tasks with higher inspiratory flows. 8. The discharge rates of
      single motor units were compared for targeted voluntary breaths and non-targeted
      involuntary breaths which were matched for size. There were no significant
      differences in the initial or final firing frequencies, but recruitment order was
      not always the same in the two types of breath.

PMID- 10420025
TI  - Is there a conflict between minimizing effort and energy expenditure with
      increasing velocities of muscle contraction in humans?
AB  - 1. The present study examined the possibility that minimizing effort conflicts
      with minimizing energy expenditure at different velocities of muscle contraction
      during cycling. 2. Six normal subjects underwent incremental exercise on an
      electrically stabilized cycle ergometer. Power output increased by 45 W every 3
      min to exhaustion at pedalling frequencies of 40, 60, 80 and 100 r.p.m. on
      separate days. Energy expenditure (oxygen uptake), leg effort and dyspnoea (Borg
      0-10 scale) were measured in parallel at the end of each minute. 3. All six
      subjects completed 10 min of exercise achieving 180 W for all four pedalling
      frequencies. Two-way analysis of variance indicated that oxygen uptake (P <
      0.0001), leg effort (P < 0.0001) and dyspnoea (P < 0.0001) increased with
      duration of exercise and power output; oxygen uptake (P < 0.0001) and leg effort
      (P < 0.05) were significantly different between pedalling frequencies; the
      interactions were not significant. Oxygen uptake was minimal at 60 r.p.m., and
      increased at both higher and lower pedalling frequencies. Both leg effort and
      dyspnoea were minimal at 80 r.p.m.; leg effort intensified at higher and lower
      pedalling frequencies; and dyspnoea was most intense at 100 r.p.m. 4. There was a
      conflict between minimization of energy expenditure and leg effort at power
      outputs less than 180 W. Minimizing effort occurred at the expense of an increase
      in energy expenditure.

PMID- 10420026
TI  - Neuromodulation by implant for treating lower urinary tract symptoms and
      dysfunction.
AB  - OBJECTIVE: Patients with irritative micturition complaints, pelvic pain,
      involuntary urine loss or urinary retention are sometimes difficult to treat. The
      advent of direct sacral nerve stimulation offers a therapeutic alternative if
      conservative measures fail and surgery is considered. This paper reviews
      therapeutic neuromodulation by implant for treating lower urinary tract symptoms
      and dysfunction. METHODS: The international literature is reviewed on topics such
      as the physiological basis of neuromodulation, techniques of acute testing and
      chronic implantation, and clinical results. Future developments and ways for
      possible improvement are discussed. RESULTS: The mode of action of
      neuromodulation is probably through restoring the correct balance between
      excitatory and inhibitory impulses from and to the pelvic organs at a sacral and
      supra-sacral level. Depending on the predefined success criteria, average success
      rates of definitive implants vary from 50 to 70%. From the data it seems that
      patients with urge incontinence and urinary retention are the best candidates for
      neuromodulation. In the literature the lack of standardisation of selection
      criteria, stimulation parameters and definitions of success is striking.
      CONCLUSIONS: Neuromodulation by implant is a useful therapeutic alternative. It
      should at least be considered in patients with therapy-resistant urge
      incontinence and urinary retention before proceeding to surgery. Issues such as
      underlying physiology, methodological standardisation, technical improvements,
      and patient selection must be addressed in future research.

PMID- 10420027
TI  - Quality of life changes following KTP/Nd:YAG laser treatment of the prostate and
      TURP.
AB  - OBJECTIVE: To compare health-related quality of life (HRQL) changes in patients
      receiving hybrid KTP/Nd:YAG laser treatment of the prostate with TURP. PATIENTS
      AND METHODS: Patients complaining of symptomatic benign prostatic enlargement
      were studied. Their symptoms (IPSS), disease-specific (BPH Impact Index (BPHII))
      and generic HRQL (Short Form-36 (SF-36)) was evaluated before and at 6 weeks, 6
      months and 1 year following treatment. RESULTS: 204 patients were randomized into
      the study. Patients in both groups reported an improvement in IPSS and BPHII at
      each postoperative assessment, but there were significant differences between the
      two groups at the 6-week stage in favor of the TURP group. At 6 weeks, patients
      in the laser group reported significantly worse scores in the SF-36 domains of
      bodily pain, social function and role emotional when compared to the TURP group.
      These differences disappeared at both the 6-month and 1-year follow-up
      assessments. CONCLUSIONS: Although hybrid KTP/Nd:YAG laser treatment and TURP
      differed in the way they affected patients in the early postoperative period, at
      1 year, patients reported similar improvements in symptoms and enjoyed a similar
      disease-specific and generic HRQL.

PMID- 10420028
TI  - Sorbitol-mannitol solution for urological electrosurgical resection-- a safer
      fluid than glycine 1.5%.
AB  - OBJECTIVE: To evaluate the safety and suitability of sorbitol-mannitol solution
      (Purisole((R)), Fresenius, Germany) as a fluid for irrigation during
      electrosurgical resection of prostate (TURP). PATIENTS AND METHODS: 120
      sequential patients undergoing TURP were studied. Serum electrolytes were
      measured before and the day after surgery. Time and weight of resection were
      recorded. Use of blood transfusion was recorded. RESULTS: There were no adverse
      effects attributable to the use of the irrigant. There were no technical,
      electrical or instrument problems. None of the surgeons had any difficulties with
      clarity of view during resection when bleeding was light. There was no
      significant change in any of the serum electrolytes between pre-operative and
      postoperative values. No patient developed significant postoperative
      hyponatraemia or the 'TUR syndrome'. CONCLUSIONS: Purisole (sorbitol-mannitol)
      solution is entirely satisfactory as an irrigant for electrosurgical resection
      and in the present study there were no measurable changes in patients'
      electrolytes around the time of surgery. What small changes occurred indicate
      there is an overall mild dehydration effect through the process of surgery, which
      may be in part attributable to irrigant, but this change was small and does not
      reach either clinical or statistical significance. Purisole offers theoretical
      advantages over glycine solution and there are no obvious disadvantages. The
      authors would thereby recommend it in preference to glycine.

PMID- 10420029
TI  - No evidence of fluid absorption during continuous low-pressure transurethral
      resection of the prostate: assessment by measuring expiratory breath ethanol
      concentrations.
AB  - OBJECTIVE: Measurement of the ethanol concentration in expired breath during
      transurethral resection of the prostate (TURP). METHODS: TURP is a noninvasive
      method to estimate the amount of irrigant absorbed. The expiratory breath ethanol
      concentrations (EBEC) were measured with a standard alcohol breath analyzer in 35
      patients in the course of TURP. All interventions were performed with a 27-french
      continuous flow resectoscope using a solution of 1. 5% glycine + 1% ethanol as
      irrigating fluid. Serum sodium and osmolality were measured pre- and
      postoperatively. No patient developed signs of transurethral resection syndrome;
      no significant changes in serum sodium, osmolality and EBEC were found throughout
      the operation. CONCLUSION: Absorption of irrigant fluid during TURP with
      continuous low-pressure irrigation seems to be extremely slight (if not absent)
      as measured by expired breath ethanol method.

PMID- 10420030
TI  - Improving bladder neck division in radical retropubic prostatectomy by prior
      dissection of the seminal vesicles and vasa deferentia.
AB  - OBJECTIVE: To develop a convenient technique for dividing the bladder neck during
      radical retropubic prostatectomy. METHOD: Before opening the bladder, we created
      a plane that separates the anterior surface of the seminal vesicles from the
      posterior wall of the bladder and ran an umbilical tape through the plane. The
      posterior bladder neck wall was later divided using this tape as a guide mark.
      RESULTS AND CONCLUSION: The posterior bladder neck was divided in a single, easy,
      and swift maneuver (less than 2 min) in 350 patients with no subsequent
      complications.

PMID- 10420032
TI  - Tissue prostate-specific antigen and androgen receptor immunoreactivity in
      prostate cancer biopsies before, during and after neo-adjuvant androgen
      deprivation followed by radiotherapy.
AB  - OBJECTIVE: The purpose of the study was to examine the immunohistochemical
      stainability of prostate-specific antigen (PSA) and androgen receptor (AR) in
      biopsies from localised prostate cancers before treatment, after androgen
      deprivation and after radiation therapy. PATIENTS AND METHODS: Biopsies were
      taken from 16 men with prostate cancer (T1-3,Nx,M0) before the start (START) of
      androgen deprivation with LHRH analogue, during the following pelvic lymph node
      dissection (PLND), and twice after radiotherapy (POSTRAD and FINAL). RESULTS:
      Malignant cells were observed in all START, PLND and POSTRAD biopsies and in 6 of
      7 FINAL specimens. During androgen suppression and subsequent radiotherapy a
      gradual reduction in tissue immunoreactivity for PSA and AR was observed
      paralleled by a reduction in serum PSA. The most striking observation was the
      complete lack of AR stainability after combined LHRH/radiation therapy. Of the 7
      patients who had a long-term follow-up after radiotherapy, 1 patient was cancer
      negative on biopsy and without AR and PSA stainability. Six patients with cancer
      positive FINAL biopsies had regained AR stainability. Five of these latter
      biopsies also stained for PSA. Five of the six patients had no elevation in serum
      PSA. CONCLUSION: After combined hormone/radiotherapy serum PSA is a relatively
      unreliable marker for the demonstration of residual cancer. This combination
      therapy leads to transient loss of immunohistochemically stained tissue PSA and
      AR in the residual cancer.

PMID- 10420033
TI  - Cavernospongious shunts: anatomical study of intrapenile vascular pathways.
AB  - OBJECTIVES: The reality of cavernospongious shunts has never been confirmed and
      their role in penile erection remains undetermined. We aim to describe the
      intrapenile vascular anatomy as the precise nature of the connections between the
      corpus spongiosum, the glans and the corpora cavernosa remains unknown. METHODS:
      Ten human penises were removed from adult male cadavers 8 days after arterial
      casting with latex. In four specimens coloured latex was injected into the corpus
      spongiosum. Ex situ microdissection was performed to analyse the origin and
      distribution of the penile arteries. The anastomotic arterial pathways were
      dissected. RESULTS: In all the specimens, 6-10 anastomoses were found between the
      cavernous arteries (a. profundae penis) and the spongious arterial network. These
      arteries arose at regular intervals from the cavernous arteries and perforated
      the tunica albuginea vertically to anastomose with urethral arteries (a.
      urethralis). No arteriovenous shunts were found between the corpus spongiosum and
      the corpora cavernosa, nor was there any venous drainage from the corpus
      spongiosum entering the corpora cavernosa. CONCLUSION: These shunts are arteries
      connecting the urethral and cavernous arteries. Cavernospongious arterial
      anastomoses were found in all the cadavers dissected. Further studies are needed
      to determine their role in penile erection.

PMID- 10420031
TI  - Intraindividual variations of total and percent free serum prostatic-specific
      antigen levels in patients with normal digital rectal examination.
AB  - PURPOSE: To analyze intraindividual variations of total and percent free serum
      prostate-specific antigen (PSA) in patients with normal digital rectal
      examination. MATERIAL AND METHODS: Total and free serum PSA were determined in
      two blood samples corresponding to 107 nonconsecutive patients. The period
      between both determinations ranged from 23 to 60 days. Prostatic biopsy was done
      after both determinations in all except 17 patients because the two serum PSA
      concentrations were <4 ng/ml. Total and free PSA were determined using double
      monoclonal antibody immunoassay Tandem and Tandem free (Hybritech Inc.). The
      diagnosis was benign prostatic hyperplasia (BPH) in 63 patients and prostate
      cancer (PCA) in 44. RESULTS: The variations of PSA ranged between -6.8 and +3.2
      ng/ml in BPH patients and between -2.8 and +9.0 in patients with PCA. The median
      coefficients of variation were 15.4 and 15.7% respectively. The variations in the
      percent free PSA were between -30.7 and +40.9 in the BPH group and between -17.9
      and +15.8 in the PCA group. The median coefficients of variation were 32.2 and
      32.3% respectively. If prostatic biopsy had been indicated when percent free PSA
      had been </=25 in the PSA range of 4.1-10 ng/ml, we would have found
      discrepancies in 15% of all the patients. The sensitivity for the first
      determination would have been 100 and 94.4% for the second. The rate of negative
      biopsies would have been reduced by 16.6 and 19. 4% respectively. CONCLUSIONS:
      Intraindividual variations in serum PSA concentration and percent free PSA could
      have clinical implications in the decision to perform prostatic biopsy.

PMID- 10420034
TI  - Penile implants in erectile impotence. The importance of clinical experience on
      outcome.
AB  - PURPOSE: We assessed maximum patient and partner acceptance and satisfaction by
      informed preoperative prosthesis selection. MATERIALS AND METHODS: Six months to
      5 years after penile prosthesis implantation, 71 men and partners were
      interviewed personally. Evaluation was focused on delineating not only the
      etiologic factors but also factors most likely to affect prosthesis
      recommendation and contribute to prognosis. RESULTS: Overall, 94% of the patients
      and 95% of the partners were satisfied, and 90% of these believed that they had
      equal erections to previously without the implant, and 81% reported an
      improvement in nonsexual relations with their partners after the device was
      implanted. 83 and 17% of the patients said they had increased or had no change in
      sexual desire, respectively. No one had a decrease in sexual desire. 86% of all
      the patients believed that their orgasm was improved. 89% of the patients were
      completely satisfied with the fit of their clothes after prosthesis implantation.
      93% of the patients reported good to excellent emotional adjustment to the
      prosthesis and the prosthesis produced a positive change in self-esteem in 94% of
      all the patients. CONCLUSIONS: A detailed assessment of patient-partner
      expectations is essential in order to be able to predict more accurately which
      patients will be best suited to the implant and which may need either concurrent
      counseling or preimplant education. A team was formed in which urologists and
      psychologists worked together, provided comprehensive information on several
      personality variables of interest in treatment planning and postoperative
      satisfaction. Our results clearly demonstrate that not only patient preference
      but also clinical data are important factors in enhancing patient and partner
      satisfaction.

PMID- 10420035
TI  - Effects of a 'common sense diet' on urinary composition and supersaturation in
      patients with idiopathic calcium urolithiasis.
AB  - OBJECTIVES: To test whether dietary advice as the only treatment is able to
      reduce urinary supersaturation in patients with idiopathic calcium urolithiasis.
      METHODS: By means of EQUIL 2, we calculated relative supersaturations of calcium
      oxalate (RS(CaOx)), brushite (RS(Brushite)), apatite (RS(Apatite)) and uric acid
      (RS(UA)) of 24-hour urine samples of 68 healthy male controls as well as of 47
      male idiopathic calcium stone formers (ICSF) before and after individualized
      dietary advice (DA). Main goals of DA were (1) to keep urine volume > 2,000
      ml/day, and (2) to reduce meat protein intake to 1 g/kg body weight per day.
      Compliance was judged from changes in urine volume and U(Urea)xV. RESULTS: In the
      whole group of ICSF, DA did not alter supersaturations. Only in those 9 ICSF
      (19%) with good compliance (increase in volume and decrease in U(Urea)xV),
      RS(CaOx) and RS(UA) fell by 26 and 49%, respectively. Besides poor compliance,
      these findings can be explained by positive correlations between changes in
      volume and U(Urea)xV in ICSF (r = 0. 319, p = 0.037) or U(Na)xV (r = 0.342, p =
      0.019). For instance, ICSF with volumes >/= 2,000 ml/day had evidence of elevated
      protein and salt intake; thus, DA mainly focused on protein and salt intake, but
      not on volume. This resulted in decreases in U(Urea)xV and U(Na)xV, but also in
      volume; thus, RS(CaOx) remained unaltered. CONCLUSIONS: DA is able to
      significantly lower RS(CaOx); however, because intakes of fluid and protein are
      directly and positively linked to each other, this only can be achieved if high
      fluid and lower meat protein intake are equally stressed in all ICSF.

PMID- 10420036
TI  - Impact of congenital narrowing of the bulbar urethra (Cobb's collar) and its
      transurethral incision in children.
AB  - OBJECTIVES: We described the clinical manifestation and outcome after
      transurethral incision (TUI) of a congenital narrowing of the bulbar urethra
      (Cobb's collar). MATERIALS AND METHODS: Over a period of 11 years a total of 74
      boys, from 3 months to 16 years old with a mean age of 5 years, were subjected to
      TUI. A febrile urinary tract infection (UTI) was the most common symptom in 40
      cases, enuresis in 15, urinary incontinence in 11, hematuria in 9, antenatally
      diagnosed dilated urinary tract in 4 and others in 9. Concurrent bladder
      instability was detected by cystometry in 27/31 boys older than 3 years with
      suspicious bladder urgency. When the bulbar narrowing was detected by
      cystourethroscopy under 8 Fr, the lesion was simultaneously incised by using an
      infantile resectoscope (Olympus 10 Fr with a knife electrode or Storz 10 F with a
      cold knife). RESULTS: Vesicoureteral refluxes (VURs) occurred in 39 cases (53%)
      and it was diminished in 11 and improved in 25 after TUI. Of the 40 cases, 38
      (95%) were free from UTI after TUI. For enuresis and urinary incontinence, 14/15
      and all 11, respectively, thrived after TUI and the anticholinergic supplement.
      Although 61 cases were primarily cured with no complications, insufficient
      cutting and recurrence of the stricture required an additional TUI in 13 cases
      for whom the knife electrode was mostly used. Overall clinical improvement was
      obtained in 71/74 (93%) cases after TUI. CONCLUSION: Meticulous cystourethroscopy
      is indispensable for detecting a clinically significant bulbar narrowing. TUI of
      the lesion is useful as a primary treatment in the majority of cases even with
      concurrent VUR and unstable bladder. A cold knife is preferable to electrocautery
      in incising this fine anterior urethral lesion.

PMID- 10420037
TI  - Ureteropelvic junction: A study of its anatomical structure and function.
      Ureteropelvic junction sphincter?
AB  - PURPOSE: To study the anatomy of the normal ureteropelvic junction (UPJ) and
      investigate its pressure response to distension, aiming at elucidation of its
      function in the light of its anatomical structure. METHOD: The UPJ of 25
      cadaveric specimens (15 male, 10 female; 15 adults, mean age 33.6 +/- 8.4 years;
      10 fully mature neonatal deaths) was studied morphologically and microscopically
      after staining with hematoxylin and eosin and Masson's trichrome. Furthermore,
      the length of the UPJ as well as the UPJ pressure response to UPJ distension were
      assessed in 13 subjects (8 men, 5 women, age 48.8 +/- 10.3 years). The response
      of the anesthetized UPJ to distension was reported in 7/13 subjects and of the
      saline-injected UPJ in the remaining 6/13. The UPJ had been anesthetized by
      injecting 1% xylocaine into its wall. RESULTS: Grossly, there were no features
      characteristic of the UPJ externally, although internally the mucosa was thrown
      into folds forming a 'mucosal rosette'. Microscopic examination showed the muscle
      fibers to be arranged in two well-formed layers: circular and longitudinal.
      Mucosal folding and structured muscle fiber arrangement were lacking in the
      adjacent renal pelvic and ureteral walls. The mean UPJ length in adults as
      measured manometrically by the pull-through technique was 6.9 +/- 1.5 mm. UPJ
      distension led to an elevated UPJ pressure; the latter increased with increase of
      the volume of distension. There was no UPJ pressure response to distension of the
      UPJ locally anesthetized by injecting xylocaine into its tissue, but there was
      response when saline was injected into the tissue of the UPJ. CONCLUSION: The UPJ
      might be identifiable by the presence of the mucosal rosette. The reaction of the
      UPJ to distension probably indicates that the UPJ possesses a motile activity.
      This, as well as the presence of a structured muscle coat at the UPJ would
      suggest the presence of a 'sphincter' at the UPJ.

PMID- 10420038
TI  - Collagen and elastic fibers in the penis of human fetuses at 28 weeks
      postconception.
AB  - OBJECTIVES: The extracellular matrix is a key element in penile function and
      pathology, yet little is known of its development. Herein we investigated the
      morphological organization of collagen and elastin in the corpora cavernosa and
      tunica albuginea of human fetuses. MATERIAL AND METHODS: The penises from 5 fresh
      human fetuses at 28 weeks postconception (WPC) were routinely fixed and embedded,
      and all staining procedures were carried out on paraffin sections. Collagen was
      evidenced by staining with: (1) Gomori's trichrome; (2) sirius red, followed by
      observation under polarized light, and (3) an antihuman collagen type-III
      antibody. Elastin and the whole elastic system were revealed using an antihuman
      elastin antibody and Weigert's resorcin fucsin, respectively. RESULTS: At this
      stage of fetal development, the albuginea is formed predominantly by dense
      bundles of collagen. Near the corpora cavernosa, the presence of type-III
      collagen was also observed. Weigert staining showed numerous fibers of the
      elastic system in the albuginea. Type-III collagen was found to be strongly
      positive in the cavernous trabeculae and in the connective sheath surrounding the
      central artery. Using Weigert staining and an immunolabeling method with primary
      antibody against human elastin, we found an important quantity of elastic system
      fibers in the trabeculae of the corpora cavernosa. CONCLUSION: In fetuses at 28
      WPC the albuginea is formed predominantly by dense bundles of collagen. The
      trabecular structures of the corpora cavernosa present a significant quantity of
      type-III collagen and elastic system fibers.

PMID- 10420039
TI  - Rapid prenatal diagnosis of aneuploidies in uncultured amniocytes by fluorescence
      in situ hybridization. Evaluation of >3,000 cases.
AB  - OBJECTIVE: A new method in prenatal diagnostics allows to demonstrate certain
      numeric chromosomal aneuploidies in amniotic cells within 24 h in contrast to
      conventional methods which take 1-3 weeks. MATERIALS: The experience with this
      rapid fluorescence in situ hybridization (FISH) method is compared to standard
      karyotyping and its clinical relevance is described in a large clinical pilot
      study. FISH on uncultured amniocytes has been performed from 12 weeks of
      gestation to the third trimester using commercially available chromosome-specific
      DNA probes for chromosomes 13, 18, 21, X and Y. RESULTS: FISH was performed
      successfully in 3,150 prenatal cases. All trisomies 13, 18 and 21 and all cases
      with gonosomal aberrations were detected by FISH analysis. Neither false-positive
      nor false-negative results were obtained using FISH. For all analyzable disorders
      the FISH results were in complete agreement with standard cytogenetics.
      CONCLUSIONS: In our experience, FISH is a valuable and reliable method for rapid
      diagnosis of numeric chromosomal aneuploidies.

PMID- 10420040
TI  - Ontogeny of recurrent hydrocephalus: presentation in three fetuses in one
      consanguineous family.
AB  - A consanguineous couple had 3 pregnancies in which prenatally diagnosed
      hydrocephalus was observed (in 1 female and 2 male fetuses). This case appears to
      represent an autosomal recessive form of hydrocephalus, given the consanguinity,
      affected sibs of both genders, and no evidence for intrauterine infection,
      chromosome abnormality, or neural tube defect.

PMID- 10420041
TI  - Predictive value of uterine artery velocimetry at midgestation in low- and high
      risk populations: a new perspective.
AB  - OBJECTIVE: The aim of this study was to assess the value of uterine artery
      Doppler velocimetry performed at 18-20 and 22-24 weeks of gestation in predicting
      preeclampsia and adverse pregnancy outcome in low- and high-risk patients.
      METHODS: 865 pregnant women were evaluated: 335 and 530 pregnant women
      represented the high- and low-risk groups, respectively. Doppler ultrasound
      examination of the uterine arteries was performed at 18-20 weeks of gestation in
      385 patients and at 22-24 weeks of gestation in 659 patients. Pregnancy outcome
      was evaluated in terms of: onset of preeclampsia; birth weight <2,500 g; birth
      weight <1,750 g; delivery before 36 weeks, and delivery before 32 weeks. RESULTS:
      At 18-20 weeks of gestation the sensitivity for the prediction of preeclampsia
      was 100 and 94% in low- and high-risk groups, respectively. Excellent negative
      predictive values towards birth weight <1,750 g (97% in low-risk and 93% in high
      risk groups) and delivery prior to 32 weeks of gestation (99% in low-risk and 95%
      in high-risk groups) were obtained. At 22-24 weeks of gestation the sensitivity
      for the prediction of preeclampsia was 100 and 97% in low- and high-risk groups,
      respectively. Negative predictive values towards birth weight <1,750 g were 97%
      in low-risk and 94% in high-risk groups, whereas towards delivery prior to 32
      weeks of gestation they were 98% in low-risk and 94% in high-risk groups.
      CONCLUSION: Doppler evaluation of the uterine artery at 18-20 and 22-24 weeks of
      gestation represents a useful predictive test in high-risk pregnancy and can also
      be used in prenatal surveillance of a low-risk population.

PMID- 10420042
TI  - Impact of demographic factors on prenatal diagnosis and elective pregnancy
      termination because of abdominal wall defects, Hawaii, 1986-1997.
AB  - OBJECTIVE: The intent of this study was to investigate the impact of various
      demographic factors on the antenatal diagnosis and elective termination of
      abdominal wall defect pregnancies. METHOD: Data were obtained from a birth
      defects registry in Hawaii between 1986 and 1997. RESULTS: The antenatal
      diagnosis rate was higher for gastroschisis than for omphalocele (76 vs. 60%).
      However, gastroschisis pregnancies were substantially less frequently electively
      terminated than omphalocele pregnancies (8 vs. 29%). Factors such as year of
      diagnosis and delivery, maternal age, race/ethnicity, residence, and maternal
      serum alpha-fetoprotein screening affected the prenatal diagnosis and/or elective
      termination of both omphalocele and gastroschisis pregnancies, but frequently in
      different ways. CONCLUSION: This investigation determined that antenatal
      diagnosis and elective termination varied with the type of abdominal wall defect
      and selected demographic factors.

PMID- 10420043
TI  - Prenatal diagnosis of a benign facial tumor.
AB  - We report a case of prenatal diagnosis of a benign fetal skin tumor on the chin
      made at 27 weeks of pregnancy by ultrasound scan. We report this case given the
      uncommon diagnosis and the unique fetal facial profile seen on ultrasound,
      resembling the image of an ancient Egyptian pharaoh which made us call it
      'Ramses' sign' as a future mnemonic aid to sonographers.

PMID- 10420044
TI  - Low neonatal risk of thrombocytopenia in pregnancy associated with immune
      thrombocytopenic purpura.
AB  - OBJECTIVE: To estimate the risk of neonatal thrombocytopenia in infants born to
      mothers with immune thrombocytopenic purpura (ITP). METHODS: During the years
      1993-1997, there were 6,082 deliveries. There were 32 infants born to 31 mothers
      with ITP. Cordocentesis was performed between 34 and 41 weeks of gestation in 16
      mothers with ITP. The cord blood platelet count was checked in all cases at
      delivery. RESULTS: In mothers with ITP, 5 neonates (15.6%) had mild
      thrombocytopenia and 7 neonates (21.9%) moderate thrombocytopenia. Severe
      thrombocytopenia was not observed in any neonate born to mothers with ITP.
      CONCLUSIONS: The means of delivery in pregnant women with ITP can be determined
      solely on the basis of obstetric indications because the incidence of severe
      fetal and neonatal thrombocytopenia is very rare, neonatal intracranial
      hemorrhage is unlikely to be related to the mode of delivery and percutaneous
      umbilical blood sampling is technically difficult with a risk of fetal death.

PMID- 10420045
TI  - Prenatal sonographic imaging of an immature intracranial teratoma.
AB  - This article describes the prenatal sonographic diagnosis of a rare case of
      intracranial immature teratoma in a fetus at the 35th week of gestation which
      looked normal at previous examinations. At sonography a markedly enlarged fetal
      head containing a complex irregular mass and hydrocephalus was detected. Color
      Doppler examination of the mass showed intense vascularization with low
      resistance flows.

PMID- 10420046
TI  - Influence of antenatal ultrasound on the management of fetal exomphalos.
AB  - OBJECTIVE: To determine the influence of antenatal ultrasound on the management
      of exomphalos. METHODS: Retrospective case note review of 23 fetuses and infants
      referred to our institution with either a pre- or postnatal diagnosis of
      exomphalos over a 7-year period. RESULTS: There were 21 cases of exomphalos of
      which 18 were correctly diagnosed on antenatal ultrasound by 18 weeks' gestation.
      There were 2 false-positives and 3 false-negatives, including 1 case of amniotic
      band syndrome with an abdominal wall defect and 1 morphologically normal fetus.
      Associated anomalies were correctly identified in 12 but incorrectly reported in
      8. Maternal serum alpha-fetoprotein levels were abnormal in 61% of cases of
      abdominal wall defects in this series. Amniocentesis was performed in 12 and
      cordocentesis in 1. There were 13 terminations, including 2 trisomy 18s and 1
      trisomy 13. Two fetal deaths followed amniocentesis. Of the 10 live births, 9 had
      their exomphalos repaired with a 1-year survival rate of 89%. Prenatal diagnosis
      did not appear to influence outcome. CONCLUSIONS: Antenatal ultrasound diagnosed
      86% of cases of exomphalos and correctly reported 67% of associated anomalies.
      Amniocentesis may have led to the death of 1 morphologically normal fetus.

PMID- 10420047
TI  - Improvement of fetal cell recovery from maternal blood: suitable density gradient
      for FACS separation.
AB  - OBJECTIVE: To improve the recovery of fetal nucleated erythrocytes (NRBCs) from
      maternal blood for noninvasive prenatal genetic diagnosis. METHODS: Blood samples
      were obtained from 10 women at 8-22 weeks of gestation. Samples were split and
      mononuclear cells were isolated using 1.083 and 1.090 g/ml of Percoll solution.
      Flow sorting with antibody to fetal hemoglobin and fluorescence in situ
      hybridization (FISH) analysis were used to evaluate the number of fetal cells
      recovered. RESULTS: In samples separated with the 1.090 density gradient, the
      yield of true gamma-hemoglobin-positive cells (median 21.0, range 2.2-303.8) was
      1.9 times higher than that in the 1.083 density (median 11.1, range 1.1-87.5),
      although it took 2. 1-fold longer time to flow sort the gamma-hemoglobin-positive
      cells. In 7 out of 10 cases, the number of gamma-hemoglobin-positive cells
      recovered from the 1.090 density gradient was 3 times or greater than that from
      1.083 gradient. After FISH analysis, we detected a median of 13.3 (range 2.2
      98.8) fetal NRBCs per 10-ml maternal blood in the 1.090 density gradient, whereas
      a median of 11.0 fetal NRBCs were detected in the 1.083 gradient (range 1.1
      35.0). The number of fetal NRBCs in the 1.090 density was significantly higher
      than that in the 1.083. CONCLUSION: Increased Percoll density results in improved
      fetal cell recovery in fresh posttermination maternal samples. The increased
      yield of fetal cells using this gradient may permit better noninvasive detection
      of fetal chromosome as well as DNA abnormalities in maternal blood.

PMID- 10420048
TI  - Utilization of the nuchal translucency image-scoring method during training of
      new examiners.
AB  - Training of new examiners, utilizing 1st-trimester nuchal translucency ultrasound
      screening, is mandatory for obtaining reproducible measurements. This study
      examined the contribution of the nuchal translucency image-scoring method to the
      process of training and its utilization as an objective tool of image evaluation
      and a tool for approving qualification. The study included an evaluation of the
      performance of two new examiners (examiners A and B) before and after
      intervention, using the image-scoring method. The preintervention period included
      75 images evaluated by two reviewers using general evaluation and the scoring
      method. The report of the scoring method was submitted to the examiners and was
      applied to 55 images performed afterwards. The agreement between two reviewers in
      classifying the first 75 images as 'accepted' or 'rejected' was tested using
      general evaluation versus the scoring method. The effect of the intervention was
      examined by comparing the quality of the images between the two time periods. A
      chart indicating final scores of 80 successive images analyzed by examiner A was
      used to set criteria for assessing qualification. Using general evaluation, the
      reviewers disagreed on 19 (25%) of the images, whereas using the scoring method
      they disagreed on only 5 (7%, p < 0.01). Comparison before and after application
      of the intervention demonstrated significant improvement expressed by the
      increased rate of better quality groups (p < 0.001) and improved mean scores from
      4.31 +/- 0.31 to 6.15 +/- 0.32 (p < 0. 001). Enhanced improvement of examiner's A
      performance could be attributed to the intervention rather than to his learning
      curve. Improvement was demonstrated in all the criteria examined; however, it was
      significant only for images size (from 33 to 98%), amnion demonstration (from 13
      to 42%), and caliper placement (from 49 to 71%). Examiner's A chart enabled us to
      set standards for assessing competence, based on the scoring method. These
      included a minimum of 40 scans, followed by more than ten sequential images of
      acceptable quality. The scoring method contributed to the process of training, as
      it made possible to objectively evaluate the images, pointed out specific errors,
      served as an efficient tool of intervention, and might be used for ascertaining
      competence. We recommend to consider its utilization in centers running 1st
      trimester ultrasound screening during training new examiners.

PMID- 10420049
TI  - Effects of fetal endotoxin administration on plasma prostaglandin f(2alpha) and
      cortisol levels in late-gestation fetal goats.
AB  - OBJECTIVE: Fetal plasma prostaglandin F(2alpha) (PGF(2alpha)) and cortisol
      responses to fetal endotoxin administration were evaluated in late-gestation
      goats (n = 9). METHODS: After endotoxin (Escherichia coli, O111:B4
      lipopolysaccharide) administration, fetal plasma PGF(2alpha) and cortisol levels,
      fetal blood gases and pH were measured periodically. RESULTS: After endotoxin
      administration, fetal plasma cortisol levels increased to 9.8 +/- 1.4 and 9.4 +/-
      1. 2 ng/ml after 1 and 3 h, respectively (p < 0.05) and PGF(2alpha) levels did
      not change throughout the study. CONCLUSIONS: These results suggest that absent
      PGF(2alpha) and attenuated cortisol responses to fetal endotoxin administration,
      relative to the adult, may be a self-protective mechanism which diminishes the
      likelihood of premature delivery.

PMID- 10420050
TI  - Preterm premature rupture of membranes in a patient with the hypermobility type
      of the Ehlers-Danlos syndrome. A case report.
AB  - OBJECTIVES: This report wants to focus on the risk of severe prematurity in
      patients with the hypermobility type of the Ehlers-Danlos syndrome (EDS), a
      heritable disorder of connective tissue. Although various obstetrical
      complications have been reported in patients with EDS, most reports specifically
      comment on the severe complications in patients with the vascular type of EDS,
      including uterine and arterial rupture. Pregnancy outcome in patients presenting
      the hypermobility type of EDS is poorly documented. CASE: A 33-year-old nullipara
      was referred for preconceptual genetic counseling with a history of easy
      bruising, generalized joint hypermobility and chronic arthralgia and myalgia. The
      diagnosis of the hypermobility type of EDS was confirmed on clinical examination.
      During her first pregnancy, she underwent a prophylactic McDonald cerclage at 14
      weeks' gestation. Premature rupture of membranes occurred at 23 weeks' gestation.
      A female infant was delivered at 26 weeks and died 3 h after birth. Electron
      microscopic examination showed collagen fibre abnormalities in the fetus' skin,
      which were compatible with the diagnosis of EDS. CONCLUSIONS: Patients with the
      hypermobility type of EDS can have an increased risk for pregnancy complications,
      including prematurity due to cervical incompetence and to premature rupture of
      membranes. We therefore demand the clinician's alertness for possible signs of
      this underdiagnosed type of EDS and recommend the collaboration between the
      obstetrician and the medical geneticist in the obstetrical management of these
      patients.

PMID- 10420051
TI  - Fetal hydrocephalus secondary to intraventricular hemorrhage diagnosed by
      ultrasonography and in utero fast magnetic resonance imaging. A case report.
AB  - Although fetal hydrocephalus is commonly detected by prenatal ultrasonographic
      examination, posthemorrhagic hydrocephalus has rarely been observed in the fetus.
      We report a case of hydrocephalus secondary to intraventricular hemorrhage (IVH)
      diagnosed by in utero magnetic resonance imaging (MRI) at 37 + 1 weeks of
      gestation. Ultrasonography revealed enlargement of the bilateral ventricles and
      an irregular mass measuring 20 x 12 x 10 mm in the right lateral ventricle. T1
      weighted images with two-dimensional fast low-angle shot (2D-FLASH) and T2
      weighted images with half-Fourier single-shot turbo spin echo (HASTE)
      demonstrated that an old hemorrhagic clot existed in the right lateral ventricle
      of the fetus. Hydrocephalus secondary to IVH was confirmed by postnatal MRI and
      ventriculoscopy. Fast MRI is especially useful for prenatal diagnosis of fetal
      brain abnormalities because it minimizes the artifact of fetal movement.

PMID- 10420053
TI  - [Chemotherapy of endometrial cancer revisited].
AB  - The current status and future directions of chemotherapy in the management of
      endometrial cancer are reviewed. For patients with advanced or recurrent
      endometrial carcinoma the most active single drugs are doxorubicin, epirubicin,
      cisplatin, carboplatin, paclitaxel, ifosfamide, 5-fluorouracil and vincristine
      with response rates ranging from 18 to 36%. Data at the present time support the
      conclusion that if chemotherapy is indicated a combination of doxorubicin +
      cisplatin is the standard chemotherapy for patients with advanced or recurrent
      endometrial carcinoma and yields a response rate of 47-60%. A first trial using a
      combination of these drugs with paclitaxel promises an increase in response rate
      to 73%, but data regarding prolongation of survival are not yet available. Up to
      now the benefit of neither chemotherapy nor endocrine therapy could be
      established in the adjuvant setting.

PMID- 10420052
TI  - Sectio parva for fetal preservation.
AB  - Selective abdominal delivery, or sectio parva, is cesarean delivery of one of
      multiple fetuses, but not the other(s). Eleven cases have been reported for the
      purpose of aborting one twin, and this is the second report of an attempt to
      improve the outcome of both twins. Perinatal outcomes have ranged from almost
      immediate delivery of the second twin because of placental abruption, to elective
      delivery of the survivor at term.

PMID- 10420055
TI  - [LSD and cannabis abuse in early pregnancy with good perinatal outcome. Case
      report and review of the literature].
AB  - This is a case report of a 27-year-old patient who had smoked a joint (cannabis)
      and 20 cigarettes (tobacco) daily up to the time of a positive pregnancy test at
      7 4/7 weeks (p.c.). On day 20 p.c. she had an LSD minitrip. There are reports of
      chromosome aberrations in in vitro animal studies with LSD. In humans the main
      consequences are malformations of the fetal extremities and dysplasias of the
      eye. In both animals and humans cannabis causes changes in dopaminergic activity.
      Our recommendation was to continue the pregnancy, but to monitor it closely. The
      patient had a spontaneous term delivery-a lively boy with weight between the 5th
      and the 50th percentile, length between the 50th and the 90th percentile, normal
      umbilical arterial and venous pH values, and Apgar scores 7/9/10. There were no
      visible abnormalities, and behaviour was normal. If it is suspected that a
      pregnant patient consumes LSD, dysplasias of the fetal skeleton and eye should be
      checked for. With respect to LSD and to cannabis, too, the intellectual
      development of the child should be closely followed.

PMID- 10420054
TI  - [Congenital skull depression. Case report and review of the literature].
AB  - A 40-week gestational age infant was delivered by cesarean section because of
      intense contractions and pathological fetal heart rate pattern. The umbilical
      artery pH was 7.03, Apgar scores were 1/4/7 at 1, 5 and 10 min of age. The 3,250
      gram infant had a skull depression of 5 x 7 cm in the left temporal-parietal
      region with a depth of 1.5 cm. There were no edemas or hematomas in this area;
      neurological examination was normal. A CT scan did not show a fracture, but the
      cortex below the depression appeared slightly compressed. At the age of 11 days,
      the depressed part of the parietal squama was surgically elevated. The child was
      discharged in good condition 8 days later and remained well at a 6-month follow
      up examination.

PMID- 10420056
TI  - [Urogynecology guidelines of the Urogynecology Work Group of the German Society
      of Gynecology and Obstetrics].

PMID- 10420057
TI  - [Guidelines for estrogen and gestagen replacement in the climacteric and
      postmenopause. The 21st work meeting of the Zurich Discussion Group, November,
      1998].

PMID- 10420059
TI  - The new epidemic: frequency of dementia in the Rotterdam Study.
AB  - Dementia is one of the most frequent and devastating disorders in the elderly.
      Due to the increased longevity and the increasing number of elderly people in our
      society, it is emerging more and more as a major health problem. We quantified
      the frequency and lifetime risk of dementia, and of subtypes of dementia, in the
      Rotterdam Study, a population-based prospective cohort study among 7, 983
      subjects over the age of 55 years. The overall prevalence was 6. 4% and the
      overall incidence 1 per 100 person-years. Both prevalence and incidence increased
      strongly with age. Typical incidence estimates for age 65, 75 and 95 are 1 per
      1,000, 1 per 100 and 1 per 10 person-years. One in 6 men, and almost 1 in 3
      women, will suffer at least some of their lifetime from dementia.

PMID- 10420058
TI  - [New data concerning breast carcinoma. A report on the 34th Meeting of the
      American Society of Clinical Oncology, Los Angeles, Calif., USA, May 16-19,
      1998].

PMID- 10420060
TI  - Epidemiology of post-stroke dementia.
AB  - Twenty to 25% of stroke patients are demented after stroke, which makes stroke an
      important risk factor for dementia. However, the diagnosis of dementia is
      difficult and depends heavily on methodology. In this review, we describe
      pitfalls of diagnosis, the prevalence and incidence of dementia after stroke
      based on data from prospectively studied stroke cohorts, and the risk factors for
      post-stroke dementia that emerged from these studies. Finally, the course and
      prognosis of post-stroke dementia are described.

PMID- 10420061
TI  - Epidemiology of vascular dementia.
AB  - Although epidemiological studies are limited by diagnostic uncertainties, they
      suggest that stroke increases the risk of dementia. The mortality rate is higher
      in vascular dementia (VaD) than in Alzheimer's disease (AD). Community-based
      studies have provided several consistent findings: (i) age dependence with
      prevalence rates doubling every 5 years, (ii) a higher frequency in men and (iii)
      nation-to-nation differences. The prevalence of VaD ranges from 2.2% in 70- to 79
      year-old women, to 16.3% in men >80 years. One sixth of acute stroke patients
      have preexisting dementia. The incidence of VaD has been studied much less
      extensively than that of AD, and substantial variations in the incidence rates
      have been observed: annual incidence rates (per 100,000) range from 20 to 40
      between 60 and 69 years of age and from 200 to 700 over 80. The incidence rate of
      VaD declined over the last 2 decades, probably as a consequence of effective
      stroke prevention. It is generally assumed that risk factors for VaD are those of
      stroke, with arterial hypertension as leading factor, followed by atherosclerotic
      disease, low education level, alcohol abuse and heart disease. Stroke
      characteristics, such as lacunar infarction and left-sided hemispheric lesions,
      are major determinants of VaD. The cerebrovascular lesions are likely to be the
      only cause of dementia in strategic infarcts, in lacunar state, in hereditary
      cystatin C amyloid angiopathy and in CADASIL. However, white matter changes, and
      associated Alzheimer pathology, which are both frequent in this age category, may
      also contribute to the cognitive decline.

PMID- 10420062
TI  - Diagnostic criteria for vascular dementia.
AB  - The term vascular dementia implies the presence of a clinical syndrome (dementia)
      caused by, or at least assumed to be caused by, a specific disorder
      (cerebrovascular disease). In this review, the various sets of criteria used to
      define vascular dementia are outlined. The various sets of criteria are judged
      whether they contain criteria for both dementia and vascular disease as well as
      for the relationship between the two. We conclude that only the criteria of the
      State of California Alzheimer's Disease Diagnostic and Treatment Centers and of
      NINDS-AIREN provide sufficient operational criteria for dementia suitable for use
      in patients with vascular disease as well as for the diagnosis of cerebrovascular
      disease and for the establishment of a relationship between dementia and vascular
      disease. The latter criteria include also specific recommendations to the use of
      CT and MRI. However, the interpretation of the neuroimaging findings in the
      context of mixed vascular and degenerative dementia demands further study. Given
      the heterogeneous pathophysiology and pathology of vascular dementia and the
      modest reliability of the criteria, it seems plausible that the diagnosis of
      vascular dementia will become more reliable when specific diagnostic tests for
      the various degenerative diseases, from which vascular dementia has to be
      differentiated, become available.

PMID- 10420063
TI  - Value of screening instruments in the diagnosis of post-stroke dementia.
AB  - Brief dementia screening instruments, or mental status tests are frequently used
      to screen for cognitive impairment. We discuss the strengths and weaknesses of
      existing mental status tests in dementia screening in general. Most screening
      instruments that are used in clinical practice are developed to detect dementia
      compatible with Alzheimer's disease, and their value in detecting dementia after
      stroke is less well known. A stroke may cause both cortical and subcortical
      deficits, and the clinical expression of post-stroke dementia is different from
      that of Alzheimer's disease. Existing brief mental status tests have limited
      value in this patient group because they tend to ignore specific problems which
      may occur in stroke patients. Some expanded screening instruments, like the
      CAMCOG, are more useful and have additional diagnostic value. With the growing
      interest in research for vascular factors in dementia over the past years,
      however, a specific screening instrument for post-stroke dementia would be a
      valuable contribution.

PMID- 10420064
TI  - Risk factors for vascular disease and dementia.
AB  - There is increasing evidence that risk factors for vascular disease and stroke
      are associated with cognitive impairment and Alzheimer's disease. This paper
      reviews current knowledge on the relationship between risk factors for stroke and
      Alzheimer's disease. The focus will be on 'classical' risk factors, including age
      and gender, socioeconomic status, diabetes, cholesterol, prior cardiovascular
      disease, atrial fibrillation, cigarette smoking and alcohol use; as well as on
      factors that more recently have been recognized as putative risk factors,
      including APOE genotype, serum homocysteine concentration, relative abnormalities
      in the hemostatic and thrombotic systems, and inflammation.

PMID- 10420065
TI  - Possible link between lipid metabolism and cerebral amyloid angiopathy in
      Alzheimer's disease: A role for high-density lipoproteins?
AB  - Although apolipoprotein E4 (ApoE4) is a well-established risk factor for the
      development of Alzheimer's disease (AD), it is unclear how ApoE affects the
      progression of the disease. beta-amyloid (Abeta) is a major constituent of
      cerebrovascular amyloid deposits in brains of subjects with Alzheimer's disease.
      In cerebrospinal fluid and in plasma, Abeta is normally present in association
      with high density lipoproteins (HDL). These lipoproteins may play a role in the
      removal of excess cholesterol from the brain through interaction with ApoE and
      heparan sulphate proteoglycans (HSPG) in the subendothelial space of cerebral
      microvessels. At the same time, HDL may have a role in maintaining Abeta soluble
      and in mediating its clearance. Therefore, similar factors, e.g. HDL, ApoE and
      HSPG, may be involved in the regulation of reverse cholesterol transport in the
      brain and in the processing of Abeta. Alterations in the process of cholesterol
      secretion from the brain may contribute to the deposition of Abeta in the
      vascular wall.

PMID- 10420066
TI  - Role of APOE in dementia: A critical reappraisal.
AB  - The apolipoprotein E (APOE) gene is strongly associated to the risk of
      Alzheimer's disease (AD). More specifically, it seems undisputed that the APOE*4
      allele plays an important role in the pathogenesis of AD. However, does this
      imply that it is ApoE4 which causes the increased susceptibility for AD?
      Empirical findings in non-Caucasians leave space for at least one alternative
      hypothesis: not the ApoE4 polymorphism but other defects in, or close to the APOE
      gene, could be responsible. We discuss this hypothesis, based on population and
      evolutionary genetic evidence.

PMID- 10420067
TI  - Role of platelet activation in dementia.
AB  - Platelets play an important role in atherosclerosis, and increased platelet
      activation is associated with stroke. Stroke is an important risk factor for
      dementia, as approximately 25% of the patients are demented after stroke. In this
      review, we describe platelet activation studies in patients with stroke and with
      dementia. In addition, we review the few studies that have investigated the
      effect of antiplatelet medication such as aspirin and non-steroidal anti
      inflammatory drugs on cognitive function and the occurrence of dementia. We
      conclude that further studies are needed to characterize the mechanisms and
      determinants of platelet activation in relation to the development of dementia.
      Furthermore, the efficacy and safety of antiplatelet intervention will have to be
      assessed in properly designed randomized trials.

PMID- 10420068
TI  - Response to activated protein C in subjects with and without dementia. The Dutch
      Vascular Factors in Dementia Study.
AB  - We performed a cross-sectional case-control study among 295 subjects with
      dementia and 406 control subjects drawn from participants of the Rotterdam Study,
      a population-based cohort study among subjects aged 55 years or over, and from
      participants of the Rotterdam Stroke Databank, a hospital-based stroke registry,
      to evaluate the association of the factor V Leiden mutation and activated protein
      C (APC) response with dementia and its subtypes. The risk of dementia was 2.11
      fold increased among carriers of factor V Leiden mutation relative to subjects
      lacking factor V Leiden mutation (95% confidence interval, CI, 0.93-4.77). The
      increased risks of vascular dementia and of Alzheimer's disease were 4.28 (95% CI
      1.26-14.5) and 2.15 (95% CI 0.82-5.63), respectively. No association was found
      for APC response. We showed a nonsignificant twofold increased risk of dementia
      among subjects with factor V Leiden. The association appeared to be stronger for
      vascular dementia.

PMID- 10420069
TI  - Coagulation and fibrinolysis markers and risk of dementia. The Dutch Vascular
      Factors in Dementia Study.
AB  - We performed a cross-sectional case-control study among 277 subjects with
      dementia and 298 control subjects drawn from participants of the Rotterdam Study,
      a population-based cohort study among subjects aged 55 years or over, and from
      participants of the Rotterdam Stroke Databank, a hospital-based stroke registry,
      with the objective to evaluate the association of indicators of coagulability,
      fibrinogen, prothrombin fragments 1+2, thrombin-antithrombin complex (TAT), and
      indicators of fibrinolysis, plasmin-inhibitor complex, D-dimer and tissue-type
      plasminogen activator (t-PA) with dementia. Increased levels of TAT, D-dimer and
      t-PA activity were associated with an increased risk of dementia. Additional
      stratified analyses indicated that an increased TAT level was the primary factor
      related to dementia. The present study provides evidence that predominantly
      increased thrombin generation is associated with dementia.

PMID- 10420070
TI  - Specificity of haemostasis abnormalities for vascular phenotypes.
AB  - Atherothrombosis is a systemic disease, hence it is difficult to prove the
      specificity of haemostasis abnormality for any single vascular phenotype.
      Associations between haemostatic variables and any given phenotype, e.g.
      (vascular) dementia, should be interpreted with caution, given the overlaps of
      vascular disease phenotypes, risk factors, and haemostatic variables.

PMID- 10420071
TI  - Efficacy of unfractionated heparin, low molecular weight heparin and both
      combined for releasing total and free tissue factor pathway inhibitor.
AB  - Unfractionated heparin (UFH) exerts its anticoagulant properties by increasing
      the inactivation of thrombin and activated factor X by antithrombin III. Apart
      from this main action release of tissue factor pathway inhibitor (TFPI) from
      endothelial cells could also be important for the antithrombotic activity of
      heparins. Four different heparin preparations were injected subcutaneously into 5
      healthy volunteers 1 week apart: (1) UFH 2,500 IU fix dose (FixUFH), (2) 1 mg/kg
      body weight of low molecular weight heparin (LMWH), (3) the combined LMWH
      adjusted dose plus UFH 2,500 IU fix dose (ComHep) and (4) UFH 2,500 IU/10 kg body
      weight (UFHvar). Plasma samples were drawn before and 1, 2, 4, 6, 12 and 24 h
      afterwards. FixUFH did not affect the concentration of total and free TFPI. Total
      TFPI increased in the 1st hour after LMWH injection from 74 to 124 ng/ml (p <
      0.01), after ComHep from 82 to 144 ng/ml (p < 0.01), and after UFHvar from 91 to
      113 ng/ml (p < 0.05). All observed elevations were significant at the peak value
      (+/- 2 h, p < 0.01 compared with baselines). The increase of free TFPI produced
      by UFHvar (74.5 and 70.5 ng/ml) was significantly higher than with LMWH (42.8 and
      38.0 ng/ml) at 2 and 4 h (p < 0.001 and p < 0.01, respectively). UFHvar and
      ComHep but not LMWH produced a statistically significant increase of free TFPI
      compared with FixUFH at 2, 4 and 6 h (p < 0. 01). We concluded that at comparable
      therapeutic doses, subcutaneous UFHvar released more free TFPI than LMWH and
      ComHep. A synergism between LMWH and low dose of UFH was found in 4-, 6- and 12
      hour blood samples.

PMID- 10420072
TI  - Secondary prevention of venous thromboembolism: A role for low-molecular-weight
      heparin.
AB  - BACKGROUND: After a short initial course of heparin therapy, patients with venous
      thrombo-embolism (VTE) require continuing anticoagulant therapy for several
      months after hospital discharge. At present, two small-scale studies have
      compared the efficacy and safety of low-molecular-weight heparin (LMWH) with
      warfarin in the secondary prevention of VTE. PATIENTS AND METHODS: We studied 654
      consecutive patients, 202 with pulmonary embolism (PE) and 452 patients with deep
      vein thrombosis (DVT) of the lower limbs. 220/654 patients (34%) were considered
      to have some contraindications to coumarin, and were discharged on LMWH
      (dalteparin, Fragmin((R)), 10, 000 IU s.c. once daily). The remaining 434/654
      patients were asked to choose between either coumarin or LMWH: 190 patients
      preferred LMWH and 244 coumarin. Patients were followed up for a 3-month (DVT
      patients) or 6-month (PE patients) period. RESULTS: 14/654 patients (2%)
      developed recurrent VTE while on anticoagulant therapy. One in every three
      recurrent episodes was PE (which was fatal in 2/5 patients), and half of the
      recurrent DVT were located in the contralateral leg. We failed to find any
      differences between patients receiving LMWH and those on coumarin therapy, but
      recurrences were more common in patients with cancer (hazard ratio: 17.15; 95%
      CI: 4.0-73.5; p < 0.001). 21 patients (3.3%) bled (major bleeding 5 patients;
      minor bleeding 16). Bleeding was more common in patients on coumarin therapy
      (hazard ratio: 3.14; 95% CI: 1.20-8.22; p = 0.02). CONCLUSIONS: Long-term LMWH
      therapy proved to be both effective and safe in the long-term treatment of VTE.
      Thus, we suggest long-term LMWH therapy should be considered for patients with
      contraindications to coumarin, or those with difficulties in coming to laboratory
      control.

PMID- 10420073
TI  - Antibodies against factor VIII in patients with solid tumors: successful
      treatment of cancer may suppress inhibitor formation.
AB  - Between 1995 and 1998, we treated 5 patients with anti-factor VIII antibodies and
      spontaneous bleeding. All patients had underlying malignant conditions. Initial
      control of the bleeding episodes and reduction in inhibitor titer was achieved in
      all patients. Disappearance of factor VIII inhibitor occurred in 3 patients after
      either resection of the tumor or chemotherapy. Immunosuppression therapy failed
      to eradicate the antibody in 2 patients with metastatic disease. Antibodies
      against factor VIII appearing in certain patients may be directly associated with
      the underlying malignancy, rather than a coincidental finding. Attempts to reduce
      the titer or eradicate the inhibitor may fail if recognition of the underlying
      condition is not sought, or an appropriate treatment of cancer is not offered.

PMID- 10420074
TI  - Massive intracranial bleeding requiring emergency splenectomy in a patient with
      CMV-associated thrombocytopenia.
AB  - We describe a previously healthy male patient, with severe immune
      thrombocytopenic purpura (ITP) following CMV infection which was refractory to
      steroids and intravenous immunoglobulin, who developed massive intracranial
      bleeding. Despite an extremely low platelet count (2x10(9)/liter) which was
      refractory to platelet transfusions, successful emergency splenectomy was
      performed, with rapid resolution of the thrombocytopenia. Bleeding complications
      are extremely rare in viral-associated ITP. Emergency splenectomy should be
      considered in the presence of life-threatening bleeding when other modalities
      fail to produce a rise in the platelet count. Infection with CMV should be ruled
      out in cases of severe, treatment-resistant ITP.

PMID- 10420075
TI  - High-dose dexamethasone for splenectomy in patients with idiopathic
      thrombocytopenic purpura.
AB  - High-dose intravenous immune globulin (IV IgG) is currently the treatment of
      choice for patients with idiopathic thrombocytopenic purpura (ITP) who undergo
      splenectomy; however, this treatment is extremely expensive. We report on 13 ITP
      patients with severe thrombocytopenia (<20 x 10(9)/l) who were prepared for
      laparoscopic splenectomy with a 4-day oral course of high-dose (40 mg/day)
      dexamethasone (DEX). Four patients had an excellent response with platelet counts
      that increased to above 150 x 10(9)/l. Seven patients had a good response with a
      platelet count that increased to between 50 and 150 x 10(9)/l (median 121 x
      10(9)/l). Two patients were resistant both to DEX and IV IgG. The operation was
      uneventful in all the patients, including the 2 who had resistant ITP and were
      operated on while their platelet count was very low (5 x 10(9)/l). Thus, high
      dose DEX, which is an easy, effective and inexpensive treatment, is recommended
      for the preparation of ITP patients prior to splenectomy.

PMID- 10420076
TI  - Adenosine 5'-diphosphate-induced platelet aggregation in uremia shows resistance
      to inhibition by the novel nitric oxide donor GEA 3175 but not by S-nitroso-N
      acetylpenicillamine.
AB  - Both bleeding and thrombosis are complications of uremia in patients on regular
      hemodialysis. An excessive endogenous formation of the vasodilator and platelet
      inhibitor nitric oxide (NO) has been proposed to contribute to the bleeding
      defect. Since exposure to pharmacological donors of NO, nitrovasodilators, can
      cause tolerance to NO, we investigated whether platelets from uremic patients on
      regular hemodialysis are influenced differently by NO donors than platelets from
      healthy subjects. A frequently used S-nitrosothiol, S-nitroso-N
      acetylpenicillamine (SNAP), was compared to a recently synthezised mesoionic
      oxatriazole derivate, GEA 3175, regarding its capacity to inhibit adenosine 5'
      diphosphate (ADP)-induced platelet aggregation in vitro. The final products of NO
      production, nitrite + nitrate, were found to be significantly increased in uremic
      patients. The capacity to inhibit platelet aggregation by SNAP was only slightly
      different between the groups. However, GEA 3175 showed a significantly marked and
      reduced capacity to inhibit aggregation of uremic platelets compared to controls.
      Interactions of erythropoietin (EPO) with NO have earlier been reported. Addition
      of EPO to platelets from healthy donors in vitro did not significantly influence
      the NO donor capacity to inhibit platelet aggregation, but showed a tendency to
      enhance the effect of SNAP while the effect of GEA 3175 was inhibited. These
      results suggest compound-specific resistance to NO donors in uremic platelet
      activation.

PMID- 10420077
TI  - Relation between carotid intima-media thickness, platelet surface activation and
      endothelial cell markers.
AB  - BACKGROUND: The role of platelet activation and endothelial cell damage in the
      pathogenesis of atherosclerosis was investigated. METHODS: Flow-cytometric
      detection of platelet activity was accomplished by measuring the surface
      expression of activated platelet glycoprotein IIb/IIIa (activated CD41) and the
      lysosomal integral membrane protein (CD63). Levels of thrombomodulin (TM) and von
      Willebrand factor (vWF) were estimated by the ELISA technique as markers of
      endothelial cell damage. These procedures were performed in healthy male subjects
      without obvious signs of atherosclerosis. Also, the intima-media thickness of the
      carotid artery was measured with high-resolution B- mode ultrasound to quantitate
      the presence and/or the extent of carotid atherosclerosis. RESULTS: According to
      ultrasound findings patients were divided into those with apparent evidence of
      atherosclerosis (AS+) with intima-media thickness >1.1 mm (n = 19) and those
      without such evidence (AS-) with intima-media thickness <1.1 mm (n = 17). The
      percentages of activated CD41 and CD63 surface antigen expression were
      significantly increased in the AS+ compared to AS- subjects. TM levels were
      elevated in the former group compared to the latter, while vWF levels were not
      different in the two groups. Multivariate analysis indicated the independent
      association of carotid atherosclerosis with each of the expression of activated
      CD41, CD63 as well as TM levels after adjustment of other risk factors.
      CONCLUSION: This study demonstrates that platelets circulate in an enhanced
      activation state in asymptomatic atherosclerosis, which is closely related to the
      degree of endothelial cell damage as expressed by increased plasma levels of TM.
      The detection of platelet activation can be used as a potential marker for
      oncoming atherosclerosis.

PMID- 10420078
TI  - Prevalence of Arg306 mutation of the factor V gene in Korean patients with
      thrombosis.

PMID- 10420079
TI  - GB virus-C/hepatitis G virus infection in Taiwan: a virus that fails to cause a
      disease?
AB  - Recently, an RNA virus designated GB virus-C or hepatitis G virus (GBV-C/HGV) was
      identified; however, its clinical significance remains uncertain. This discovery
      prompted us to investigate the virological, epidemiological and clinical
      implications of GBV-C/HGV infection in Taiwan where chronic liver diseases and
      liver cancer are endemic. Our results showed that genetic heterogeneity of GBV
      C/HGV isolates exists, and primers from the highly conserved 5' untranslated
      region of viral genome can efficiently detect GBV-C/HGV RNA. Epidemiological
      surveys showed that GBV-C/HGV infection is common in high-risk groups in Taiwan,
      and its coinfection does not aggravate the course of chronic hepatitis B or C. A
      prospective study of transfusion-transmitted GBV-C/HGV infection also showed GBV
      C/HGV does not cause classic hepatitis in most patients. In addition, GBV-C/HGV
      plays a minimal role in causing fulminant hepatitis. Like hepatitis C virus,
      sexual transmission of GBV-C/HGV exists. The risk increases with prolonged
      duration of exposure. In addition, high-titered maternal viremia and mode of
      delivery are associated with the mother-to-infant transmission of GBV-C/HGV.
      Interestingly, we found that GBV-C/HGV exerts no suppression on levels of chronic
      hepatitis B or hepatitis C viremia, and GBV-C/HGV responds to interferon;
      however, ribavirin plus interferon does not induce a higher sustained response.
      As to the replication sites of GBV-C/HGV, our preliminary results showed liver
      and peripheral blood mononuclear cells are not the major sites for GBV-C/HGV
      replication, and thus GBV-C/HGV is not a primary hepatotropic virus. In
      conclusion, transfusion and exchange of body fluids indeed can transmit GBV
      C/HGV; however, current lines of evidence suggest that GBV-C/HGV fails to cause a
      disease.

PMID- 10420081
TI  - Anticancer drug design based on plant-derived natural products.
AB  - This review article focuses on recent research in my laboratory on various
      classes of compounds that possess potent antitumor activity. These compounds were
      obtained by bioactivity- and mechanism of action-directed isolation and
      characterization coupled with rational drug design-based modification and analog
      synthesis. Structural modification, structure-activity relationship, and
      mechanism of action studies will be discussed.

PMID- 10420080
TI  - The isoprostanes: novel prostaglandin-like products of the free radical-catalyzed
      peroxidation of arachidonic acid.
AB  - The isoprostanes (IsoPs) are a unique series of prostaglandin-like compounds
      formed in vivo from the free radical-catalyzed peroxidation of arachidonic acid.
      This review summarizes our current knowledge regarding these compounds. Novel
      aspects of the biochemistry and bioactivity of IsoPs are detailed and methods by
      which these compounds are analyzed are discussed. A considerable portion of this
      review deals with the utility of measuring IsoPs as markers of oxidant injury in
      human diseases particularly in association with risk factors that predispose to
      atherosclerosis, a condition in which excessive oxidative stress has been
      causally implicated.

PMID- 10420082
TI  - Sensitivity of the slow component of the delayed rectifier potassium current
      (IKs) to potassium channel blockers: implications for clinical reverse use
      dependent effects.
AB  - The slow delayed rectifier potassium current (I(Ks)) is unique in its slow
      activation and deactivation kinetics. It is important during cardiac
      repolarization, especially when the heart rate is fast. We compared the effects
      of quinidine, procainamide, sotalol, and amiodarone on I(Ks) and correlated the
      findings with the clinical reverse use-dependent effects of potassium channel
      blockers. Human minK RNA was obtained by reverse transcription-polymerase chain
      reaction using explanted human heart. The RNA was injected into Xenopus oocytes
      for heterologous expression of I(Ks). A two-electrode voltage clamp technique was
      performed to investigate the I(Ks). We demonstrated that quinidine, sotalol and
      procainamide had no effects on I(Ks) up to a concentration of 300 microM while
      amiodarone inhibited I(Ks) in a concentration-dependent manner starting from 10
      microM. The inhibition by amiodarone was state-dependent with gradual unblocking
      after depolarization. The degree of inhibition was 53% immediately after
      depolarization and 19% at the end of a 5-second depolarization. I(Ks) is 30 times
      more sensitive to amiodarone than to quinidine, sotalol, and procainamide.
      Quinidine, sotalol and procainamide have reverse use-dependent effects while
      amiodarone does not. This is compatible with the hypothesis that no inhibition of
      I(Ks) at clinical concentrations contributes to the clinical reverse use
      dependent effects.

PMID- 10420083
TI  - The various effects of fractionated oxidized low density lipoproteins on the
      growth of smooth muscle cells in culture.
AB  - The effects of fractionated oxidized low density lipoproteins (oxidized LDL) on
      the growth of vascular smooth muscle cells (VSMC) and their relationship to the
      formation of lysophosphatidylcholine (lyso-PC) as well as the activation of
      protein kinase C (PKC) were studied. VSMC were isolated from porcine aorta by
      explant culture. LDL was isolated from porcine blood by sequential
      ultracentrifugation and oxidized LDL was obtained by incubating LDL with 5 microM
      CuSO(4) at 37 degrees C for various lengths of time. Our results showed that LDL
      oxidized for 12 h and eluted from fast protein liquid chromatography at 43 min
      inhibited the growth of VSMC, and that LDL oxidized for longer than 48 h and
      eluted at 48 min stimulated the growth of VSMC. The formation of lyso-PC in the
      oxidized LDL correlated well with its stimulatory effect, suggesting that lyso-PC
      is responsible for the mitogenic effect of oxidized LDL. This stimulatory effect
      of oxidized LDL was inhibited by staurosporine, a PKC inhibitor. Treatment with
      oxidized LDL increased the activity of membrane PKC, but it decreased that of
      cytosolic PKC, suggesting the translocation of PKC from cytosol to the membrane
      in the presence of oxidized LDL. These results suggested that the oxidized LDL
      stimulated VSMC growth was mediated by the formation of lyso-PC and the
      activation of PKC.

PMID- 10420084
TI  - Modulation of cytokine responses of murine CD8+ alphabeta intestinal
      intraepithelial lymphocytes by IL-4 and IL-12.
AB  - The immune responses of the intestine mucosa feature the noninflammatory type,
      such as IgA production and oral tolerance. Th2 type cytokines have been
      implicated in the induction of these noninflammatory responses. In the present
      study, cytokine responses of CD8+ and CD4+ TCRalphabeta+ intestinal
      intraepithelial lymphocyte (alphabeta iIEL) subsets to TCR stimulation under the
      influence of IL-12, IL-4, or CD28 costimulation were examined. IL-12 enhanced
      production of IL-10 and IFN-gamma by the CD8alphabeta+ alphabeta iIEL
      significantly but only marginally affected the CD8alphaalpha+ subset, whereas IL
      4 induced IL-4, IL-5, and IL-10 production and augmented TGF-beta production by
      both subsets. CD28 costimulation induced production of Th2 cytokines by CD4+ iIEL
      in the absence of exogenous IL-4. Unlike lymph node CD4+ cells, the CD28
      costimulation-induced Th2 differentiation of CD4+ iIEL was not inhibited by IFN
      gamma. These results demonstrate active cytokine production by CD4+,
      CD8alphabeta+, as well as CD8alphaalpha+ alphabeta iIEL. The Th2- skewed cytokine
      profile of CD8alphaalpha+ alphabeta iIEL and the IFN-gamma-resistance of Th2
      differentiation of the CD4+ alphabeta iIEL suggest that both iIEL subsets
      contribute to the induction of noninflammatory mucosal immune responses.

PMID- 10420085
TI  - Probing surface structure of sarcin domain on ribosomes of Escherichia coli by
      complementary oligo DNAs and ribosome-inactivating protein.
AB  - The regional structure of the sarcin domain of 23S rRNA of Escherichia coli
      ribosomes was determined by a combinatory approach of oligo DNA probes and the
      action of alpha-sarcin. The sarcin domain is protected by a reactive
      complementary oligo DNA probe against the hydrolytic action of alpha-sarcin. This
      protective effect is dependent upon the length and the complementary sequence of
      oligo DNA probes that react to ribosomes. Under UV irradiation and using of the
      primer extension, nucleotides that contacted by reactive oligo DNA probes were
      determined. Nucleotides at the 3' side of the domain (positions from G2659 to
      C2676) were targeted by oligo DNA probes that have their sequences to complement
      the domain, indicating that the 3' side region was exposed on the surface of
      ribosomes, whereas nucleotides at the 5' side of stem and extented to two bases
      at the loop (positions from C2646 to A2654) were not accessible to any oligo DNA
      probes, implying that the region could be buried in ribosomes. This study also
      provided evidence that the conformation of the sarcin domain is subjected to
      alteration if the exposed 3' side of domain is targeted by the reactive DNA
      probe. The importance of the topological arrangement of the sarcin domain that
      engages in the translocation event during translation is discussed.

PMID- 10420086
TI  - The tumor suppressor p53 can reduce stable transfection in the presence of
      irradiation.
AB  - The tumor suppressor p53 is believed to play an essential role in maintaining
      genome stability. Although it is currently unknown how p53 is involved in this
      important biological safeguard, several previous publications indicate that p53
      can help to maintain genome integrity through the recombination-mediated DNA
      repair process. The integration of linearized plasmid DNA into the host
      chromosome utilizes the same repair process, and the frequency can be measured by
      clonogenic assays in which cells that were stably transfected by plasmid
      integration can be scored by their colony-forming abilities. To gain insight into
      whether p53 has a direct role in plasmid integration into the host chromosome, we
      determined the frequency of stable transfection with CHO cells expressing either
      wild-type or mutant p53 in the presence and absence of irradiation. We found that
      low-dose irradiation ( approximately 50 to 100 cGy) increased stable transfection
      frequencies in CHO cells regardless of their p53 status. However, the increase of
      transfection frequency was significantly lower in CHO cells expressing wild-type
      p53. Our data thus suggest that wild-type p53 can suppress plasmid DNA
      integration into the host genome. This p53 function may play a direct and
      significant role in maintaining genome stability.

PMID- 10420087
TI  - The role of protein kinase C in thromboxane A2-induced pulmonary artery
      vasoconstriction.
AB  - In order to determine if protein kinase C (PKC) plays a significant role in the
      stimulant action of thromboxane A2 (TxA2) on pulmonary vascular smooth muscle,
      TxA(2)-induced contractile responses were measured following inhibition of PKC.
      Rabbits were sacrificed and segments of the main trunk of the pulmonary artery
      were removed and placed within a temperature-controlled (37 degrees C) organ
      bath. Contractile responses that were evoked by a TxA2 mimetic (U46,619, 0.5
      microM) decreased by 27 and 35% following treatment with the PKC inhibitors,
      calphostin C (2 microM) and staurosporine (200 nM), respectively. These results
      account for the effect of the vehicle, DMSO, which was also found to have a
      concentration-dependent inhibitory effect on the U46,619-induced contractions.
      The effects of DMSO alone was subsequently subtracted from the previously
      measured responses to PKC inhibitors that were dissolved in DMSO to obtain
      effects attributable to the PKC inhibitor alone. It can therefore be concluded
      that inhibition of PKC results in partial attenuation of U46,619-induced
      responses supporting the hypothesis that activation of PKC plays a partial role
      in TxA2-induced contraction of pulmonary arterial smooth muscle.

PMID- 10420089
TI  - Cold stress and corticotropin-releasing hormone induced changes in messenger
      ribonucleic acid for the alpha(1)-subunit of the L-type Ca(2+) channel in the rat
      anterior pituitary and enriched populations of corticotropes.
AB  - In response to stress, adrenocorticotropin (ACTH) is secreted from anterior
      pituitary corticotropes. Corticotropin-releasing hormone (CRH) is a potent
      stimulator of ACTH secretion. The CRH stimulation of secretion is mediated by
      cAMP and is largely dependent on Ca(2+) influx through voltage-gated L-type
      Ca(2+) channels. This study was designed to investigate whether the expression of
      L-type Ca(2+) channels in the rat anterior pituitary and in corticotropes is
      regulated by acute stress and CRH. RNase protection assays were used to quantify
      alpha(1C) mRNA of the L-type Ca(2+) channel. The alpha(1C) mRNA levels from
      stressed rats increased by 31% in anterior pituitaries of rats after 30 min of
      exposure to cold stress. Neither 60 min cold stress nor 30 min restraint stress
      had an effect on alpha(1C) mRNA levels. When alpha(1C) mRNA was detected by in
      situ hybridization in a population of corticotropes enriched to 90%, 0.5 nM CRH
      (3 h) stimulated a 36% increase in the average area of label/cell and a 10%
      increase in the average density of label. Our results suggest that (1) the
      expression of alpha(1C) subunit mRNA of L-type Ca(2+) channels is increased in
      the rat anterior pituitary with a stress-specific response that might reflect an
      increase both in thyrotropes and corticotropes (both are known to be stimulated
      by cold stress), and (2) the CRH-mediated increase in alpha(1C) mRNA expression
      in individual rat corticotropes, in vitro, supports the hypothesis that some of
      the increase in vivo is due to changes in corticotropes.

PMID- 10420088
TI  - Expression of the L-type Ca(2+) channel in AtT-20 cells is regulated by cyclic
      AMP.
AB  - Activation of adenylyl cyclase by corticotropin-releasing hormone (CRH)
      stimulates secretion of adrenocorticotropin (ACTH) in rat anterior pituitary
      corticotropes and in the murine AtT-20 cell line. The stimulation of secretion is
      mediated by cAMP and is largely dependent on Ca(2+) influx through voltage-gated
      L-type Ca(2+) channels. To investigate whether CRH and cAMP also increase
      expression of the L-type Ca(2+) channel in AtT-20 cells, an RNase protection
      assay was used to measure the alpha(1C) mRNA that encodes the pore-forming
      subunit of the L-type Ca(2+) channel. The alpha(1C) mRNA level was measured by
      autoradiographic densitometry and normalized to the beta-actin mRNA level in the
      same sample. The alpha(1C) mRNA was not changed by 24-hour treatment with CRH (10
      500 nM). A 24-hour treatment with 1 mM 8Br-cAMP significantly increased the
      alpha(1C) mRNA by 40% over its control. The stimulatory effect was blocked by 2
      microM actinomycin D and was, therefore, dependent on gene transcription. The
      measured half-life of the alpha(1C) mRNA, after inhibition of transcription, was
      4.7 +/- 0.3 h in control and 5.2 +/- 0.6 h in the presence of 8Br-cAMP. Thus the
      8Br-cAMP- induced increase in alpha(1C) mRNA could be due to an increase in
      alpha(1C) gene transcription or to a transcriptionally regulated increase in a
      protein that helps to stabilize alpha(1C) mRNA. Finally, to determine if the
      increased mRNA was followed by an increase in production of L-type Ca(2+)
      channels, the binding of [(3)H]PN200-110 to Ca(2+) channel proteins was assayed
      in AtT-20 membrane fragments. 8Br-cAMP increased [(3)H]PN200-110 binding sites by
      32% (B(max) 36.0 +/- 1.2 fmol/mg protein in control vs. 47.4 +/- 3.2 fmol/mg
      protein in 8Br-cAMP-treated cells) but did not change the K(d). These studies
      show that both alpha(1C) mRNA and L-type Ca(2+) channel protein are increased in
      AtT-20 cells by cAMP.

PMID- 10420090
TI  - Potentiation of prolactin secretion following lactotrope escape from dopamine
      action. I. Dopamine withdrawal augments l-type calcium current.
AB  - Hypothalamic dopamine (DA) tonically inhibits prolactin (PRL) release from the
      anterior pituitary gland. Transient escapes from this DA tone elicit a pronounced
      potentiation of the PRL-releasing action of secretagogues such as thyrotropin
      releasing hormone (TRH). Previous evidence has suggested that modulation of
      Ca(2+) channels can be involved in this potentiation. With a lactotropic cell
      line (GH(4)C(1)) expressing human D(2)-DA receptors, we tested the hypothesis
      that a brief escape from the tonic inhibitory action of DA triggers a
      facilitation of Ca(2+) influx through Ca(2+) channels. We initially found that in
      these cells, DA effectively and reversibly inhibited PRL secretion, and
      reversibly enhanced an inwardly rectifying K(+) current. The effects of DA
      administration and withdrawal on Ca(2+) currents were examined using the patch
      clamp technique in the whole-cell configuration and Ba(2+) as a divalent charge
      carrier through Ca(2+) channels. Macroscopic Ba(2+) currents were significantly
      decreased by short term (1-10 min) applications of DA (500 nM), which further
      declined following 24 h of constant exposure to DA. After DA removal, a biphasic
      facilitation of the density of Ba(2+) currents was observed. An initial 2-fold
      enhancement of conductance was detected between 10 and 40 min, followed by a
      second facilitation of the same magnitude observed 24 h after DA withdrawal. The
      present results directly demonstrate that dissociation of DA from D(2)-receptors
      expressed in GH(4)C(1) lactotrope cells causes an increase of high-voltage
      activated Ca(2+) channel function, which may play an important role in the cross
      talking amplification of endocrine cascades such as that involved in the TRH
      induced PRL-release potentiating action of DA withdrawal.

PMID- 10420091
TI  - Potentiation of prolactin secretion following lactotrope escape from dopamine
      action. II. Phosphorylation of the alpha(1) subunit of L-type, voltage-dependent
      calcium channels.
AB  - Modulation of Ca(2+) channels has been shown to alter cellular functions. It can
      play an important role in the amplification of signals in the endocrine system,
      including the pleiotropically regulated pituitary lactotropes. Prolactin (PRL)
      secretion is tonically inhibited by dopamine (DA), the escape from which triggers
      acute episodes of hormone secretion. The magnitude of these episodes is explained
      by a potentiation of the PRL-releasing action of secretagogues such as
      thyrotropin-releasing hormone (TRH). While the mechanisms of this potentiation
      are not fully understood, it is known to be mimicked by the dihydropyridine, L
      type Ca(2+) channel agonist Bay K 8644 and blocked by nifedipine and
      methoxyverapamil. The potentiation is also blocked by inhibitors of cyclic AMP
      dependent protein kinase and protein kinase C. We recently described that the
      escape from tonic actions of DA results in increased macroscopic Ca(2+) currents
      in GH(4)C(1) lactotropic clonal cells transfected with a cDNA encoding the long
      form of the human D(2)-DA receptor. Here we show that the withdrawal from DA
      potentiates the PRL-releasing action of TRH in GH(4)C(1)/D(2)-DAR cells to the
      same extent as in enriched lactotropes in primary culture. In both experimental
      models a low density of dihydropyridine receptors was shown by (+)-[(3)H]PN200
      110 binding. Photoaffinity labelling with the dihydropyridine [(3)H]azidopine
      revealed a protein consistent with the alpha(1) subunit of L-type Ca(2+) channels
      of 165-170 kDa. In both experimental models, the facilitation of TRH action
      triggered by the escape from DA was correlated with an enhanced rate of
      phosphorylation of this putative alpha(1) subunit, the nature of which was
      further supported by immunoprecipitation with selective antibodies directed
      against the alpha(1C) and alpha(1D) subunit of voltage-gated calcium channels. We
      propose that PKA- and PKC-dependent phosphorylation of the alpha(1) subunit of
      high voltage activated, L-type Ca(2+) channels is responsible for the
      facilitation of Ca(2+) currents in lactotropes, and hence for the potentiation of
      secretagogue-mediated PRL secretion. Thus, phosphorylation of Ca(2+) channels in
      endocrine cells may be a mechanism for the regulation of various functions
      including amplification of hormone secretion.

PMID- 10420092
TI  - Cloning of proopiomelanocortin from the brain of the african lungfish,
      Protopterus annectens, and the brain of the western spadefoot toad, Spea
      multiplicatus.
AB  - A degenerate primer, specific for the opioid core sequence YGGFM, was used to
      clone and sequence proopiomelanocortin (POMC) cDNAs from the brain of the African
      lungfish, Protopterus annectens, and from the brain of the western spadefoot
      toad, Spea multiplicatus. In addition, the opioid-specific primer was used to
      clone and sequence a 3'RACE product corresponding to a portion of the open
      reading frame of S. multiplicatus proenkephalin. For both species, cDNA was made
      from a single brain and a degenerate opioid-specific primer provided a reliable
      probe for detecting opioid-related cDNAs. The African lungfish POMC cDNA was
      1,168 nucleotides in length, and contained regions that are similar to tetrapod
      POMCs and fish POMCs. The African lungfish POMC encodes a tetrapod-like gamma-MSH
      sequence that is flanked by sets of paired basic amino acid proteolytic cleavage
      sites. The gamma-MSH region in ray-finned fish POMCs either has degenerate
      cleavage sites or is totally absent in some species. However, the African
      lungfish gamma-MSH sequence does contain a deletion which has not been observed
      in tetrapod gamma-MSH sequences. The beta-endorphin region of lungfish POMC has
      the di-amino acid sequence tryptophan-aspartic acid in the N-terminal region and
      an additional glutamic acid residue in the C-terminal region of beta-endorphin -
      features found in fish beta-endorphin, but not tetrapod beta-endorphins. The
      western spadefoot toad POMC was 1,186 nucleotides in length, and exhibited an
      organizational scheme typical for tetrapod POMCs. However, the toad POMC did lack
      a paired basic amino acid proteolytic cleavage site N-terminal to the beta-MSH
      sequence. Thus, like rat POMC, it is doubtful that beta-MSH is an end product in
      either the toad brain or intermediate pituitary. At the amino acid level, the
      toad POMC had 76% sequence identity with Xenopus laevis POMC and 68% sequence
      identity with Rana ribidunda POMC. The use of these POMC sequences to assess
      phylogenetic relationships within anuran amphibians will be discussed. With
      respect to the fragment of S. multiplicatus proenkephalin cDNA, two metenkephalin
      sequences and the metenkephalin-RF sequence were found encoded in this fragment.
      As seen for X. laevis and R. ridibunda proenkephalin, a leuenkephalin sequence
      was not detected in the C-terminal region of the S. multiplicatus proenkephalin.
      The absence of a leuenkephalin sequence may be a common feature of anuran
      amphibian proenkephalins.

PMID- 10420093
TI  - Differential effects of pregnancy on mineralocorticoid and glucocorticoid
      receptor availability and immunoreactivity in cortisol feedback sites.
AB  - The suppression of plasma adrenocorticotropic hormone by very low levels of
      cortisol is reduced in pregnant adrenalectomized ewes, suggesting that pregnancy
      reduces the efficacy of the high-affinity corticosteroid receptor. This study was
      designed to determine the effects of pregnancy on the availability,
      immunoreactivity, and affinity of both corticosteroid receptors: the high
      affinity mineralocorticoid receptor (MR) and the lower-affinity glucocorticoid
      receptor (GR). Availability was measured in the hypothalamus, pituitary,
      hippocampus and kidney using a saturation point radioligand binding assay. GR
      availability was significantly decreased in hippocampal cytosols obtained from
      pregnant ewes, but did not significantly change in other tissues. This finding is
      consistent with increased GR activation due to elevated circulating
      concentrations of cortisol. MR availability significantly increased from
      undetectable levels in hippocampal cytosols obtained from nonpregnant ewes to 2.8
      +/- 1.6 fmol/mg protein in pregnant ewes, suggesting a reduced MR activation in
      the hippocampus during pregnancy. MR availability tended to be greater in other
      tissues during pregnancy, but these differences were not significant. The amount
      of immunoreactive MR (iMR) and GR (iGR) protein was estimated by quantifying
      Western blots. iGR significantly increased in the pituitary, but did not
      significantly change in other tissues. In contrast, iMR was significantly
      increased during pregnancy in all tissues assayed, suggesting that an increased
      cytosolic MR protein amount contributes to the observed increase in MR
      availability. Since studies suggest that progesterone is a potent
      anticorticosteroid, we tested for evidence of endogenous inhibition of binding to
      MR and/or GR during pregnancy by determining MR and GR affinity in pituitary
      cytosols obtained from nonpregnant and pregnant ewes. Although there was a
      tendency towards a decreased affinity of the MR in pregnant ewes, there was no
      significant change in the K(D) of the pituitary MR or GR during pregnancy. We
      hypothesize that an alteration in activation and/or autoregulation of the MR
      during pregnancy, particularly in the hippocampus, may contribute to the observed
      changes in receptor availability and immunoreactivity and increase basal plasma
      cortisol levels during pregnancy.

PMID- 10420094
TI  - Brain potentials and attention after acute and subchronic intranasal
      administration ofACTH 4-10 and desacetyl-alpha-MSH in humans.
AB  - Neuropeptides related to adrenocorticotropin (ACTH) are potent regulators of
      neurobehavioral functions. In humans, ACTH and its behaviorally active fragment
      ACTH 4-10 have been consistently found to diminish event-related brain potential
      (ERP) signs of focussing attention. This study aimed at (1) evaluating effects of
      ACTH 4-10 on ERP indicators of attention in healthy controls after intranasal
      administration of the peptide. This route of administration has been proposed to
      provide a more direct access to the brain than the intravenous administration of
      the peptide, (2) comparing acute effects and effects of a subchronic treatment
      with ACTH 4-10, and (3) comparing effects of ACTH 4-10 with those of desacetyl
      alpha-MSH (corresponding to ACTH 1-13 amide) which like ACTH 4-10 binds to
      subgroups of the melanocortin receptor family. Double-blind placebo-controlled
      experiments were completed in 54 healthy young subjects. ERPs were recorded while
      the subject performed an auditory selective attention task. Moreover, a modified
      Stroop interference test including motivational (food, sex) and nonmotivational
      words was performed. Acute intranasal administration of ACTH 4-10 (1 mg) reduced
      the processing negativity (PN) of the ERP over frontal and central cortical areas
      (p < 0.05) indicating diminished focussing of attention. Moreover, on this
      condition subjects were more prone to interference on the Stroop task especially
      with motivational words (p < 0.05). Subchronic administration of ACTH 4-10 (1
      mg/day over 6 weeks) did not affect PN and Stroop performance. Acute intranasal
      administration of desacetyl-alpha-MSH at equimolar doses (1.68 mg) also remained
      ineffective. However, some measures of Stroop performance appeared to improve
      after subchronic desacetyl-alpha-MSH treatment. Results confirm an acute decrease
      in focussing of attention after ACTH 4-10. These effects of intranasal
      administration are likely to reflect a direct action of the peptide on respective
      brain functions. Moreover, they were specific to ACTH 4-10 and were not obtained
      after equimolar doses of desacetyl-alpha-MSH, thus excluding a mediation via the
      known melanocortin receptors.

PMID- 10420095
TI  - PACAP gene expression in neurons of the rat hypothalamo-pituitary-adrenocortical
      axis is induced by endotoxin and interleukin-1beta.
AB  - Inflammatory stress due to infection by various micro-organisms is known to
      activate the hypothalamo-pituitary-adrenocortical (HPA) axis through inflammatory
      mediators. Recently, pituitary-adenylate-cyclase-activating polypeptide (PACAP)
      was shown to be located in corticotropin-releasing factor containing neurons of
      the medial parvocellular part of the hypothalamic paraventricular nucleus
      (mpPVN). In the present study, we demonstrate that PACAP gene expression is
      induced in neurons of the mpPVN after intraperitoneal administration of bacterial
      lipopolysaccharide (LPS) which was accompanied by a marked increase in PACAP
      immunoreactivity in the external zone of the median eminence. As determined by
      quantitative in situ hybridization, PACAP gene expression was rapidly induced
      after 4 h and was elevated for 48 h, declining to normal levels after 72 h. A
      significant increase in PACAP mRNA was also observed following intraperitoneal
      injection of interleukin-1beta. PACAP gene expression was not induced by LPS in
      vagotomized animals, suggesting that the increase in PACAP mRNA following immune
      activation by LPS is mediated via the vagus nerve. The findings suggest that
      PACAP may function as a hypothalamo-pituitary-releasing factor during acute
      inflammation.

PMID- 10420096
TI  - Disturbances of corticogenesis in schizophrenia: morphological findings provide
      new evidence for the maldevelopmental hypothesis.
AB  - A comprehensive neuropathology of schizophrenic psychoses has not yet been
      established. According to the findings of clinical investigations,
      neurohistological studies mainly focused on limbic structures, the prefrontal
      cortex and the anterior cingulate cortex. The results of morphometric and
      stereological studies based on the classical neuropathological techniques are
      controversial and point to the necessity for a differentiated characterization of
      the morphological features of neurons. Therefore, methods of neurobiological
      fundamental research are employed for the detailed demonstration of the different
      neuron types that constitute cortical circuits. Using these techniques, the
      schizophrenic cortex is shown to contain a variety of characteristic alterations
      which are discussed in the light of hypotheses favoring a maldevelopmental
      pathogenesis of schizophrenic psychoses which can be looked upon as neuronal
      system disorders.

PMID- 10420097
TI  - Relationship of mismatch negativity to background EEG and morphological findings
      in schizophrenia.
AB  - The present study assessed relationships of mismatch negativity (MMN) of
      schizophrenics with other markers; quantitative EEG (QEEG), computed tomography
      (CT) and psychopathological ratings. Patients were divided into two groups before
      treatment; group A consisted of patients with greater MMN amplitudes while
      patients with lower ones were assigned to group B. In QEEG, group A showed no
      significant differences compared to controls, except for fast beta in the frontal
      region. The finding of well-preserved QEEG in group A indicates their function is
      less distorted than in group B, who showed greater powers in slow waves, slow
      alpha and fast beta bands. The greater slow-wave power of group B may be related
      to the cognitive impairment reflected by attenuated MMN, which corresponded to
      greater dilation in lateral ventricles and Sylvian fissures of group B on CT.
      Conclusively, MMN have crucial relationships to other biological markers
      representing the psychopathology of schizophrenia.

PMID- 10420098
TI  - Schizophrenia - A disturbance of signal interaction between the entorhinal cortex
      and the dentate gyrus? The contribution of experimental dibenamine psychosis to
      the pathogenesis of schizophrenia: A hypothesis.
AB  - In addition to the existence of complex memory (similar to the implicit
      nondeclarative memory of Squire), the existence of a phylogenetically old
      apparatus of a memory of situations (SMA) is supposed, which is to some extent
      comparable with the declarative memory of Squire. During actual sensory
      information the SMA generates a general frame and forms a general 'mark',
      indicating whether a given information has its origin inside or outside the body,
      and whether it is new or known. The procedure of this marking process can be
      explained as the time-depending arrest of a copy of the actual original
      information-transporting signal 'shower'; this copy must last until the feedback
      from thalamocortical centers indicates the termination of the processing of the
      original signal showers. The arrest of the shower copies is the performance of
      neuronal networks of the entorhinal cortex (EC) and the gyrus dentatus (GD). The
      psychopathological and biochemical analyses of experimental dibenamine psychosis
      show a different effect of dibenamine on the noradrenaline (NA) receptors of the
      EC and GD, respectively: these effects are responsible for the repeated
      perception cycles of a single situation. N,N-Dibencylamine blocks the
      postsynaptic alpha(1)-receptors of the EC without influencing the beta-receptors
      of the GD. Thus the interaction between EC and GD is changed: instead of new
      scenes, perceptions that have just been experienced get repeated presence and the
      quality of familiarity. The prolonged arrest of shower copies simultaneously
      blocks the entrance of new signal showers from the EC to the GD. No information
      transporting signal showers can come in as long as the arrest lasts. In case of a
      disturbance in NA-dependent actions within the EC and the GD, the duration of
      arrest of information-transporting signal showers is shortened. Thus the formal
      frame of experience receives the quality of novelty instead of familiarity, and
      in addition the qualities of uncertainty, vagueness, and alienity. These very
      changes in perception and experience represent the basic disturbance of
      schizophrenia. All the symptoms of schizophrenia may be explained by this basic
      disturbance. The analysis of biochemical aspects turns attention to the energetic
      situation of NA and N-methyl-D-aspartate systems. These considerations suggest a
      genetic background of the basic disturbance of schizophrenia: transmitter effects
      on membranes of neurons and possibly also on glial cells, and energy supply of
      these effects may be predetermined genetically. It may be assumed that the
      compensation of such membrane-dependent disturbances will be possible within wide
      areas of the neural network, except for the 'bottleneck' of the overlapping
      region of the iso- and allocortex.

PMID- 10420099
TI  - Impairment of the correlation between urinary contents of alpha-1-microglobulin
      and ulinastatin is induced by intracerebroventricularly administered interleukin
      6 in mice.
AB  - We have found previously that the correlation between urinary contents of alpha-1
      microglobulin (alpha1M) and ulinastatin (UT) depends on the type of
      neuropsychiatric disease. Since interleukin (IL)-1beta and IL-6 are closely
      involved in pathophysiological aspects of various neuropsychiatric diseases,
      effects of intracerebroventricularly (i.c.v.) administered IL-1beta and IL-6 on
      the correlation between urinary contents of these two glycoproteins were examined
      in mice, a species in which alpha1M and UT and also the correlation between the
      urinary contents thereof are expressed similarly to humans. Indices (volume,
      contents of creatinine, alpha1M and UT, and alpha1M/UT ratio) in urine collected
      after i.c.v. administrations of 2 and 20 ng of either IL-1beta or IL-6 were not
      statistically different from those of the vehicle-treated (control) groups.
      Neither IL-1beta (2 and 20 ng) nor the lower dose of IL-6 (2 ng) affected the
      positive correlation between urinary contents of alpha1M and UT. However, a
      higher dose of IL-6 (20 ng) nullified the positive correlation for 2 days after
      administration. Recovery to a positive correlation was thereafter displayed.
      These findings suggest that central IL-6 plays an important role in correlating
      urinary contents of alpha1M and UT without affecting the renal functions.

PMID- 10420100
TI  - Receptor test (pupillary dilatation after application of 0.01% tropicamide
      solution) and determination of central nervous activation (Fourier analysis of
      pupillary oscillations) in patients with Alzheimer's disease.
AB  - Memory loss and severe cognitive deficits in Alzheimer patients are supposed to
      be related to a reduction of acetylcholine as well as to central nervous
      deactivation. For the investigation of cholinergic deficits and deactivation, we
      used computer-assisted pupillometry. Cholinergic deficits caused by a
      particularly severe loss of cholinergic neurons may be responsible for cognitive
      and mnemonic performance deficits. The control of the pupillary diameter
      represents a balance between cholinergic and adrenergic innervation and is
      influenced directly or indirectly by central and autonomic nervous system inputs.
      Either of these systems could be affected in Alzheimer patients. A reduced
      innervation of the target muscle through neuronal cell death, axon retraction,
      reduced release, increased reuptake of altered amounts or function of
      neurotransmitter receptors seems to affect the pupillary response to cholinergic
      antagonists in Alzheimer patients. There is, however, no relationship between
      pupillary diameter and central deactivation, but between central nervous
      activation and pupillary oscillations which reflect the physiological
      corticodiencephalic activity, a relationship has to be assumed. Frequencies and
      amplitudes of pupillary oscillations measured by means of Fourier analysis are
      modulated corticodiencephalically. Therefore, Alzheimer patients were compared to
      healthy controls with respect to their pupillary diameters and responses to an
      acetylcholine antagonist. Twenty-nine patients, aged between 55 and 85 years,
      suffering from mild to moderate Alzheimer's disease (AD) and 29 normal controls
      of similar age (56-85 years) participated in the study. The cholinergic receptors
      of the pupil were blocked by the acetylcholine antagonist tropicamide. It could
      be assumed that the larger the pupillary dilatation, the larger the extent of
      cognitive deficits. Alzheimer patients show abnormal acetylcholine
      neurotransmission. Changes of pupillary diameter after instillation of 1 drop of
      0.01% tropicamide solution were measured and Fourier analysis of pupillary
      oscillations was performed. Times of measurement were: 0 (baseline), 20, 40, 60,
      80, and 100 min. After 4 min tropicamide was instilled. Forty min after the
      instillation of tropicamide into the left eye, the Alzheimer patients showed a
      pronounced dilatation of 41.57%. The dilatation in normal controls was 28.5%.
      Fourier analysis of pupillary oscillations (sum of frequency bands = power)
      demonstrated a marked deactivation (low amplitudes in low-frequency bands, but in
      contrast to our expectations no higher amplitudes in the higher frequency bands)
      in patients with AD which remained constant at all times of measurement. By means
      of discriminant analysis of pupillary diameter and pupillary oscillations
      (frequency band 0.00-1 Hz), 89. 7% were correctly predicted to be Alzheimer
      patients, 89% to be normal controls.

PMID- 10420101
TI  - Effects of cholinergic drugs on neocortical EEG and flash-visual evoked
      potentials in the mouse.
AB  - The effects of single intraperitoneal injection of two cholinesterase inhibitors,
      physostigmine (PHY; 0.01, 0.025, 0.05, 0. 1, 0.2 mg/kg) and heptylphysostigmine
      (HEP; 0.5, 2, 6 mg/kg) on electroencephalographic (EEG) activity and flash visual
      evoked potentials (f-VEP) in the occipital cortex were compared in DBA/2 mice.
      EEG spectral analysis of awake periods showed that PHY at all doses and HEP at 2
      mg/kg induced an increase of power in the 4.25- to 7-Hz frequency band.
      Furthermore, PHY at the higher doses and HEP at all doses induced a decrease of
      power in the 7.25- to 12-Hz frequency band, while the lower doses of PHY (0.01,
      0.025 mg/kg) produced an increase of this band. EEG effects elicited by the two
      drugs were similar, when doses displaying analogous biochemical effects
      (acetylcholinesterase inhibition) were used (i.e. 0.01 and 0. 025 mg/kg of PHY
      versus 0.5 and 2 mg/kg of HEP). PHY and HEP induced similar changes in f-VEPs.
      Amplitudes of early and late components (P1N1, N1P2, P4N4 and particularly N1P3)
      were enhanced, while amplitudes of middle components were depressed after all
      doses. The peak latency measures were generally delayed, even though, after the
      lower doses, a trend to a latency reduction was evident in late components. This
      finding might indicate a possible effect on stimulus speed diffusion by 'low
      therapeutic' doses, analogous to the ones used in men. Our data show that both
      drugs are effective in modifying EEG and f-VEP parameters connected with brain
      cholinergic function, although in a very narrow dose range.

PMID- 10420102
TI  - Confocal microscopy in posterior polymorphous corneal dystrophy.
AB  - PURPOSE: To report the distinguishing characteristics of posterior polymorphous
      corneal dystrophy (PPMD) using confocal microscopy. MATERIAL AND METHODS: Two
      consecutive patients with PPMD were prospectively examined using a white-light
      tandem scanning confocal microscope with a 24x/0.60 contact objective. RESULTS:
      At the level of Descement's membrane, roundish hyporeflective images were found
      in 1 patient. In the other patient, hyporeflective bands were detected. In both
      patients, patchy hyperreflective areas were identified. CONCLUSION: Confocal
      microscopy may allow diagnosis of PPMD by demonstrating the alterations in
      Descement's membrane. This technique is especially valuable in cases of
      endothelial decompensation, where slit-lamp and specular microscopy may fail to
      demonstrate changes in Descement's membrane.

PMID- 10420103
TI  - Effects of frequency-doubled Nd:YAG laser trabeculoplasty on diurnal intraocular
      pressure variations in primary open-angle glaucoma.
AB  - In order to investigate the effects of laser trabeculoplasty (LT) on diurnal
      intraocular pressure (IOP) variations in 36 eyes of 30 cases with primary open
      angle glaucoma (POAG) in which medical treatment was terminated, the IOP curves,
      recorded 24 h before as well as 24 h and 12 weeks after LT were compared. Twelve
      weeks after LT, significant IOP decreases were observed: 36.42% in the mean IOP,
      29. 77% in the mean peak IOP and 50.04% in the mean pressure range. LT might
      therefore have beneficial effects on the diurnal IOP variations in cases with
      POAG.

PMID- 10420104
TI  - Asymmetry in intraocular pressure and retinal nerve fiber layer thickness in
      normal-tension glaucoma.
AB  - The etiology of glaucoma is most probably multifactorial. This study intended to
      investigate the asymmetry in intraocular pressure (IOP) and that in retinal nerve
      fiber layer (RNFL) thickness in normal-tension glaucoma patients. Two diurnal
      tension curves, obtained within 3 months and counting at least five IOP readings
      each, including an early morning IOP measurement upon awaking, were obtained in
      15 normal-tension glaucoma patients. None of the patients received IOP-lowering
      therapy. IOP asymmetry was present in at least three readings and was always in
      the same direction. The optic nerve was imaged in both eyes in each patient by
      means of confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph).
      The interocular difference in RNFL thickness and the RNFL cross-sectional area
      were correlated with the interocular difference in IOP by means of Spearman's
      rank correlation factor. Nine female and 6 male normal-tension glaucoma patients
      (mean +/- SD age was 62. 4 +/- 16.9 years) were included in this study.
      Interocular IOP asymmetry varied between 0.30 and 4 mm Hg. Strong negative
      correlations were found between interocular asymmetry in IOP and interocular
      asymmetry in RNFL thickness asymmetry (R = -0.652, p = 0. 0083) and interocular
      asymmetry in RNFL cross-sectional area (R = -0. 702, p = 0.0034). The present
      results demonstrate for the first time a more marked thinning of the neuroretinal
      nerve fiber layer in the eye with the higher IOP in normal-tension glaucoma
      patients.

PMID- 10420105
TI  - Comparison of halothane/thiopental and propofol anesthesia for strabismus
      surgery.
AB  - Day case surgery has become a widely accepted practice for many ophthalmological
      procedures including strabismus surgery. Prompt recovery from anesthesia and
      minimal postoperative morbidity are especially requested to the anesthesiologists
      to deal with the high day case surgery burden. The purpose of this study was to
      compare two anesthesia techniques, halothane/thiopental anesthesia and propofol
      anesthesia, for patients undergoing monocular strabismus surgery. We studied the
      level of postoperative consciousness, nausea and vomiting, ocular pain, starting
      oral intake and activity in 43 patients, ranging from 7 to 41 years of age. A
      scoring system was used to assess these parameters in the first postoperative 48
      h. Although there was not a significant difference in the level of ocular pain,
      the propofol group had less morbidity in terms of having a better level of
      consciousness and appetite, less nausea and vomiting and enhanced activity than
      the halothane/thiopental group. We conclude that propofol anesthesia has
      significant advantages over halothane/thiopental anesthesia on an outpatient
      basis for strabismus surgery.

PMID- 10420106
TI  - The short-term effect of adding brimonidine 0.2% to timolol treatment in patients
      with open-angle glaucoma.
AB  - Brimonidine, a highly selective alpha(2)-adrenoceptor agonist, was studied to
      determine its ocular hypotensive effect and side effects in patients with
      elevated intraocular pressure (IOP) while on continuing therapy with timolol.
      This was a prospective, randomized, placebo-controlled study in 15 patients with
      primary open-angle or pseudoexfoliation glaucoma on therapy receiving timolol
      0.5% twice daily, with IOP greater than or equal to 22 mm Hg in one eye. IOP
      measurements, blood pressure and pulse rate were assessed on 2 days at a baseline
      and 1, 2, 4, 6 and 8 h later. A single drop of brimonidine 0.2% or placebo was
      added to treatment with timolol. The reductions in IOP at all time intervals
      observed with brimonidine + timolol were significantly greater than those with
      timolol + placebo. The maximum mean net decrease in IOP was 19.23 +/- 10.60% at 4
      h. Statistically significant decreases in systemic blood pressure and pulse rate
      without clinical symptoms were observed in the group receiving brimonidine +
      timolol. This study suggests that a combination of brimonidine and timolol may
      have potential in the treatment of glaucoma. Further clinical trials with
      brimonidine are indicated to assess its further role as adjunctive agent.

PMID- 10420107
TI  - A major review of antimetabolites in glaucoma therapy.
AB  - Antimetabolites have been used in combination with filtering surgery to improve
      surgical results for more than 10 years. Based on research published since the
      introduction of antimetabolites right up to date, we discuss the various forms of
      antimetabolites that have been used, including drugs and irradiation. Among the
      drugs used, mitomycin C and 5-fluorouracil are the most prominent. We discuss the
      background of these agents, the progress in the use of antimetabolites and the
      research done on these drugs. These agents have been used both intra-operatively
      and perioperatively. We discuss the indications for their use, their mode of
      action, the techniques of usage, their variations as well as the complications
      and the treatment of complications.

PMID- 10420108
TI  - Corneal wound healing after superficial foreign body injury: vitamin A and
      dexpanthenol versus a calf blood extract. A randomized double-blind study.
AB  - A prospective randomized double-blind clinical study was performed to investigate
      corneal wound healing after treatment either with an eye gel containing calf
      blood extract or an eye ointment containing vitamin A and dexpanthenol. A total
      of 54 outpatients were included in this study, all treated for corneal foreign
      body injury. The size of the corneal lesions was measured by planimetry on days
      0, 1, and on the following days until complete epithelial healing occurred.
      Results showed the calf blood extract eye gel to be statistically more effective
      in promoting corneal wound healing, especially in patients with wound areas
      larger than 6 mm(2).

PMID- 10420110
TI  - Corneal endothelium evaluation in type I and type II diabetes mellitus.
AB  - BACKGROUND: The purpose of this study is to evaluate the corneal endothelium in
      type I and type II diabetic patients. METHODS: Seventy-five diabetics divided
      into type I and type II groups and 62 healthy volunteers took part in the study.
      The mean endothelial cell density and morphology, and the central corneal
      thickness were evaluated and statistical analysis was done. RESULTS: All
      evaluated parameters were found to be significantly different in both diabetic
      groups with reduction of the mean cell density of 5% in type II and of 11% in
      type I diabetes with respect to the normal age-matched control group. Important
      alterations of endothelial morphology were observed. The central corneal
      pachymetry was significantly higher in diabetics, with p < 0.01 in the type I
      group and p < 0.05 in the type II group. CONCLUSION: It is concluded that corneal
      endothelium in diabetics should still be considered as a tissue under continuous
      metabolic stress with consequent high vulnerability, especially in case of any
      external insult such as a surgical procedure.

PMID- 10420109
TI  - Topical lomefloxacin 0.3% twice daily versus tobramycin 0.3% in acute bacterial
      conjunctivitis: A multicenter double-blind phase III study.
AB  - AIMS/BACKGROUND: To evaluate in a double-masked comparative, prospective,
      randomized multicenter trial the efficacy of lomefloxacin 0.3% eye drops twice
      daily and of tobramycin eye drops 4 times daily in patients with acute bacterial
      conjunctivitis. METHODS: Ninety-nine subjects were enrolled: 50 were treated with
      lomefloxacin 0.3% eye drops twice daily and 49 with tobramycin 0.3% eye drops 4
      times daily. In all patients, conjunctival swabbing and assessment of objective
      signs and of subjective symptoms were performed. RESULTS: There was no
      statistical difference for any individual sign or symptom or for the sum score of
      either key or other signs and symptoms at any of the examination days. The sum
      score of both key and other signs and symptoms decreased in both groups at day 3
      4 as compared to baseline values (p < 0.0001). The decrease in both these scores
      continued significantly from day 3-4 to day 7-8 (p < 0.05) and was similar in the
      two treatment groups (p > 0.4). The lowest resistance rate was seen in
      lomefloxacin (3.5%) and in neomycin (7.0%), while tobramycin showed resistance in
      10 out of 88 resistance strains (11.4%). CONCLUSION: Both lomefloxacin 0.3% twice
      daily and tobramycin 0.3% administered 4 times daily were well tolerated and
      showed a high degree of clinical and microbiological efficacy in the treatment of
      acute bacterial conjunctivitis. Lomefloxacin caused less resistance than other
      antibiotics evaluated.

PMID- 10420111
TI  - Optic nerve blindness due to paranasal sinus disease.
AB  - Patients with total blindness caused by paranasal sinus disease have rarely been
      reported. We retrospectively studied the prognosis of patients who had optic
      nerve blindness due to paranasal sinus disease. During the past 10 years, we
      identified 17 patients with optic nerve disease and posterior paranasal sinus
      disease. Seven of the 17 patients with optic nerve disease and paranasal sinus
      disease had no light perception. Five of these 7 patients with paranasal sinus
      disease had a final visual acuity of 20/200 or better. Two patients showed
      dramatic visual improvement after endonasal surgery. Because immediate surgery to
      correct paranasal sinus disease is required in affected patients, computed
      tomography should be done at the patient's first visit.

PMID- 10420112
TI  - In vitro viability of external eye microbial flora in hydroxy-propyl
      methylcellulose.
AB  - The aim of this study was to verify the in vitro influence of various dilutions
      of a viscoelastic substance containing 2% hydroxy-propyl-methylcellulose (HPMC)
      on the viability of some microbial strains representative of the normal flora of
      the external eye. Pure reference strain cultures of Candida albicans, Pseudomonas
      aeruginosa, Propionibacterium acnes, Staphylococcus aureus, Staphylococcus
      epidermidis and a fresh clinical isolate of Proteus mirabilis were selected for
      this study. Serial twofold dilutions of 2% HPMC, prepared so as to obtain a final
      concentration ranging from 50 to 0.78% of the product in sterile saline solution
      (0.85% NaCl), were taken out with a pipette that delivered 1.0 ml per tube. One
      hundred microliters of the abovementioned microbial inocula, used for the
      evaluation of the positive control of the test organism, were dispensed into each
      tube. After 24 h of incubation, 100 microl of samples were taken from each tube
      and plated into the specific medium for the growth of the test organism. After 24
      48 h of incubation, these agar plates were examined and the colony-forming-unit
      count of each test organism was compared to the corresponding total colony count,
      acting as a positive control, in order to determine the quantitative variation of
      the test organism grown in the presence of the viscoelastic compounds. C.
      albicans and P. aeruginosa showed a statistically significant increase in growth
      with HPMC dilutions varying from 1:2 to 1:16. P. acnes and P. mirabilis growth
      was significantly reduced by all dilutions except for the 1:128 one. S.
      epidermidis growth was also significantly reduced in the presence of HPMC
      dilutions varying from 1:2 to 1:64. S. aureus growth was not significantly
      influenced. The viability of P. aeruginosa in HPMC dilutions needs to be
      carefully considered because of the ability of this organism to induce
      endophthalmitis, and the possibility that during cataract surgery, a small amount
      of HPMC may be left in the eye, trapped behind the intraocular lens optic.

PMID- 10420113
TI  - Benign pleomorphic adenoma arising from the palpebral lobe of the lacrimal gland
      associated with elevated intraocular pressure.
AB  - A 46-year-old man complained of a painless mass in the left upper eyelid. At age
      51 years, the patient complained of dull pain in the left eye and diplopia. His
      left intraocular pressure had increased to 33 mm Hg. No proptosis was noted. The
      nontender mass in the eyelid was palpable. Computed tomography showed a mass
      anterior to the orbital rim compressing the globe. The lesion was removed en bloc
      by a transconjunctival approach. Histopathologic examination of the excised mass
      showed myxomatous stroma and highly cellular epithelial areas. Postoperatively,
      the left intraocular pressure normalized. To our knowledge, benign pleomorphic
      adenomas arising from the palpebral lobe of the lacrimal gland associated with
      elevated intraocular pressure, as demonstrated in our patient, may be rare.

PMID- 10420114
TI  - Unilateral glaucomatous damage in a patient with hemifacial spasm.
AB  - We report a patient with hemifacial spasm of the right hemiface and ipsilateral
      glaucomatous optic neuropathy. No risk factors were found to explain the
      unilateral glaucoma. Ocular pressure readings were always within normal range.

PMID- 10420115
TI  - Usefulness of visual field norms.

PMID- 10420116
TI  - Cataract development in 12-month-old rats fed a 25% galactose diet and its
      relation to osmotic stress and oxidative damage.
AB  - We attempted to clarify the pattern of cataract development in 12-month-old rats
      fed a 25% galactose diet and to assess the relation of cataract development with
      osmotic stress and oxidative damage. In lenses of 12-month-old male Wistar rats
      fed a 25% galactose diet over an 8-month period, suture accentuation appeared at
      6 months of galactose feeding and then opacities developed from the anterior
      subcapsular cortex toward the posterior subcapsular cortex, reaching the nuclear
      region at 8 months of galactose feeding. Increases in lens galactitol and lipid
      peroxide contents and a decrease in lens reduced glutathione content occurred at
      4, 6 and 8 months of galactose feeding. The increase in lens lipid peroxide
      content and the decrease in lens reduced glutathione content were accelerated
      with an increase in feeding period, while the increase in lens galactitol content
      was decelerated. An increase in lens water content and a decrease in lens protein
      content occurred at 6 and 8 months of galactose feeding. The lens vitamin E
      content increased at 6 months of galactose feeding and this increase was
      concomitant with increases in serum vitamin E and total cholesterol
      concentrations. The serum lipid peroxide concentration increased at 4 and 6
      months of galactose feeding. The present results indicate that in lenses of 12
      month-old rats fed a 25% galactose diet, suture accentuation appears initially
      and then opacities develop from the anterior subcapsular cortex toward the
      posterior subcapsular cortex, finally reaching the nuclear region. These results
      also suggest that in the galactosemic aged rats, osmotic stress would mainly
      contribute to cataract formation, while oxidative damage could be linked to both
      cataract formation and progression, although an increase in lens vitamin E
      content occurs during the cataract development.

PMID- 10420117
TI  - Nickel, chromium, manganese, iron and aluminum levels in human cataractous and
      normal lenses.
AB  - Atomic absorption spectrophotometry was used to detect lenticular nickel,
      chromium, manganese, iron and aluminum levels in 37 senile cataractous and 9
      normal human lenses. The nuclear parts of the lenses were used for the study in
      both groups. It was found that the concentrations of nickel and iron were
      significantly higher, and those of chromium, manganese and aluminum were
      significantly lower in human cataractous lenses than those in normal human
      lenses. None of the elements showed a significant difference according to sex in
      both groups. As remarkable differences in chromium, manganese, iron, aluminum and
      nickel levels exist in cataractous lenses, all the five elements may play some
      roles in cataractogenesis.

PMID- 10420118
TI  - Effects of age, sex, cataract, and cataract surgery on serum gamma-crystallin
      concentration.
AB  - PURPOSE: To determine if measurement of lens protein in serum is a feasible means
      to gain information on the physiologic status of the lens in human subjects.
      METHODS: The gamma-crystallin concentration was measured by a sandwich
      radioimmunoassay in the sera of 280 subjects aged 25-94 years. Medical records
      were reviewed for diagnoses of cataract and aphakia. RESULTS: There was no effect
      of age or sex on the serum gamma-crystallin concentration. There were 57 subjects
      with cataract and 27 with aphakia. gamma-Crystallin was higher in all cataract
      groups and lower in aphakia. The mean gamma-crystallin concentrations for
      selected subject groups were as follows: clear lens 301 pg/ml; pure nuclear
      cataract 344 pg/ml; pure cortical cataract 439 pg/ml and aphakia 255 pg/ml.
      CONCLUSIONS: This is the first published report to show that lens protein is
      measurable in serum and to demonstrate the feasibility of using serum assays of
      lens proteins to gain information on the physiological status of the lens. Our
      results confirm the hypothesis that molecular and cellular events leading to
      cataract cause increased leakiness of lens cell membranes with release of lens
      proteins appearing in the blood. It is conceivable that measurement of lens
      proteins in serum might find future use in the evaluation of cataract risk,
      potentially cataractogenic and anticataractogenic agents, retained lens fragments
      after phacoemulsification, secondary cataract, phacolytic glaucoma, anaphylactic
      endophthalmitis, eye injuries, and other eye diseases.

PMID- 10420119
TI  - Superoxide dismutase, catalase, glutathione peroxidase and xanthine oxidase in
      diabetic rat lenses.
AB  - The activities of the protective enzymes, superoxide dismutase, catalase,
      glutathione peroxidase and of xanthine oxidase, an enzyme acting as a source of
      O(-)(2), were measured in the lenses of alloxan-induced diabetic and control
      rats. Superoxide dismutase and glutathione peroxidase activities were found to be
      significantly decreased, while catalase and xanthine oxidase activities were
      increased. This means that the ratio of the oxidant/antioxidant enzymes increases
      in the diabetic rat lens, suggesting an increased oxidative stress. This
      imbalance is possibly an important contributing factor in the pathogenesis of
      diabetic cataract.

PMID- 10420120
TI  - Ocular volume change per minute with ocular pneumoplethysmography.
AB  - Ocular pneumoplethysmography was performed before and after 1,737 carotid
      endarterectomies, 82% of which were performed for carotid lesions of hemodynamic
      consequence. Preoperative ocular hypoperfusion without ischemia was associated
      with at least transient postoperative ocular hyperemia. A difference in ocular
      volume change per minute of 14.0%, female greater than male, was explained by sex
      differences in heart rate, brachial pulse pressure and eye size. These
      observations may have a direct application in the management of diabetic
      retinopathy with panretinal photocoagulation.

PMID- 10420121
TI  - Retinal capillary changes in Otsuka Long-Evans Tokushima fatty rats
      (spontaneously diabetic strain). Electron-microscopic study.
AB  - The Otsuka Long-Evans Tokushima fatty (OLETF) rat is a spontaneously diabetic
      strain with polyuria, polydipsia and mild obesity. The pathological features of
      OLETF rats closely resemble those of patients with non-insulin-dependent diabetes
      mellitus. The purpose of this study is to investigate the retinal capillary
      changes in the OLETF rat and to confirm the valuability of the OLETF rat as the
      model of diabetic retinal disease. One-month-old male OLETF rats and age- and sex
      matched Long-Evans Tokushima Otsuka (LETO) controls were supplied by Otsuka
      Pharmaceutical Co. Ltd. (Tokushima, Japan). Body weight and blood sugar levels
      were measured monthly. Their eyes were enucleated 14 months after birth.
      Ultrathin sections were made and examined with a transmission electron
      microscope. According to their location, two kinds of retinal capillaries were
      differentiated: those in the nerve fiber layer (NFL) and those in the outer
      plexiform layer (OPL). The image of each capillary was transferred to a computed
      image analyzer, and basement membrane thickness and the ratio of the pericyte
      area to total capillary cross-section area were determined. Corrosion casts of
      retinal vessels were made and examined with scanning electron microscopy (SEM).
      OLETF rats gained more weight than LETO rats from the beginning, and the
      difference increased gradually with age. The blood sugar level of OLETF rats was
      higher than that of LETO rats after 5 months of age. In the retinal capillaries
      of 14-month-old OLETF rats, basement membranes were significantly thicker (OLETF:
      209 +/- 51 nm in NFL, 132 +/- 23 nm in OPL; LETO: 118 +/- 28 nm in NFL, 79 +/- 14
      nm in OPL), and the ratio of pericyte area to the capillary cross-section area
      was significantly lower than that of the controls (OLETF: 0.131 +/- 0.92 in NFL,
      0.111 +/- 0.102 in OPL; LETO: 0.288 +/- 0.142 in NFL, 0.198 +/- 0.136 in OPL).
      The endothelial cell cytoplasm had degenerated. SEM examination of the vascular
      corrosion cast of a 14-month-old OLETF rat showed caliber irregularity,
      narrowing, tortuosity and loop formations of capillaries. The morphological
      changes in the retinal capillaries of OLETF rats were similar to those seen in
      diabetic patients. The OLETF rat may be a useful animal model for the study of
      ocular diabetic complications in humans.

PMID- 10420122
TI  - Vascular architecture of degenerated retina in WBN/Kob rats: corrosion cast and
      electron microscopic study.
AB  - The purpose of the present study is to determine the changes of vascular
      architecture in the degenerated retina. We used mainly corrosion casts of the
      retinal vasculature and scanning electron microscopy to obtain a wide three
      dimensional view. WBN/Kob rats (a spontaneously diabetic strain) were used
      because their outer retinas degenerate and become very thin with age. In 15-month
      old rats, localized constriction and irregular caliber of the capillaries were
      evident in the vascular casts. Two layers of capillary network in the retina were
      maintained, but the capillaries were decreased in number. Numerous loop
      formations were present in the superficial capillary networks. Neither
      microaneurysms nor arteriovenous shunts were seen in young and old rats.
      Transmission electron microscopy revealed that capillary pericytes in the inner
      and outer plexiform layers had thickened basement membranes and that endothelial
      cells had many vesicles in their cytoplasm. Thus the retinal capillary changes in
      WBN/Kob rats are nondiabetic but due to hereditary retinal degeneration, although
      the systemic and pancreatic abnormalities in this rat strain are diabetic. Even
      when the retina becomes very thin, two layer capillary networks remain.

PMID- 10420123
TI  - Three-dimensional arrangement of collagen fibrils in human ciliary body.
AB  - The purpose of this study is to visualize the three-dimensional arrangement of
      collagen fibrils in aged human ciliary body and discuss their significance. The
      ciliary bodies obtained from two human eyes were treated with a NaOH cell
      maceration method for 7 days, then prepared conventionally for light and scanning
      electron microscopy. The general morphology of the collagen tissue in the ciliary
      body appeared almost the same as that normally observed. Cellular elements were
      completely removed, but collagen fibrils were well preserved. In the stroma of
      the ciliary body, collagen fibrils were arranged irregularly. In the areas of the
      radial and circular ciliary muscles, considerable numbers of collagen fiber
      bundles were observed running in a circular direction. A honeycomb structure was
      seen in the pars plana, the walls and base of which were formed by interweaving
      collagen fibrils. The results suggested that collagen fibrils in the aged human
      ciliary body may be largely involved in the presbyopia.

PMID- 10420124
TI  - Cervical spine evaluation in obtunded or comatose pediatric trauma patients: A
      pilot study.
AB  - A uniformly accepted protocol for evaluation and clearance of the cervical spine
      of pediatric trauma patients with altered mental status does not currently exist.
      We sought to detect cervical spine injuries in this group with minimal risk.
      Patients were evaluated with standard three-view cervical spine radiographs and
      CT when necessary. Those patients without radiographic abnormality and altered
      mental status underwent flexion-extension of the cervical spine using fluoroscopy
      with somatosensory evoked potential (SSEP) monitoring. Those with abnormal
      movement by fluoroscopy or changes in SSEP underwent MRI. Fifteen patients were
      evaluated with this protocol. Two patients had movement on flexion-extension of
      the cervical spine and 5 had SSEP changes. Three patients had an MRI with only 1
      showing injury. Five patients had residual hemiparesis. Evaluation of the
      cervical spine in obtunded or comatose pediatric trauma patients can be done
      safely with flexion-extension under fluoroscopy and SSEP monitoring. Further
      prospective studies are required to determine the efficacy of SSEP monitoring for
      cervical spine clearance in this select population.

PMID- 10420125
TI  - Filum terminale fusion and dural sac termination: study in 27 cadavers.
AB  - The standard approach for sectioning of the filum terminale for a tethered spinal
      cord can be achieved via a limited S(1) exposure. This is performed with the
      commonly believed idea that the filum fuses with the dura at S(2). We dissected
      27 cadavers to exclusively look at the level at which the filum pierces/fuses
      with the dura and also the level at which the dural sac ends. Most of the fila
      fused at S(2) with a range from L(5) to S(3). The majority of dural sacs ended at
      S(2) with a range from S(1) to S(3). However, 15% of the fila (4 of 27) fused
      above the S(1) level. In addition, 11% of the fila (3 of 27) fused off the
      midline. We hope that this anatomical information may be useful for neurosurgeons
      when standard approaches fail to identify the filum at its usual level and
      location.

PMID- 10420126
TI  - Endoscopic-guided proximal catheter placement in treatment of posterior fossa
      cysts.
AB  - PURPOSE: Treatment of posterior fossa cysts by cystoperitoneal shunting may be
      complicated by a malpositioned proximal catheter located within the brainstem or
      cerebellum causing acute shunt malfunction or neurological deficits. We propose
      that proximal catheter placement from a posterior fossa approach aided by a
      malleable endoscope may prevent malposition and its complications. METHODS: We
      present 4 procedures we performed on 3 patients with posterior fossa cysts using
      a posterior fossa approach. In each case, the proximal catheter was molded along
      with a malleable endoscope to place the catheter parallel to the long axis of the
      fourth ventricle. Direct visualization during catheter placement insured an
      intracavitary position. RESULTS: Ultimately, the procedure was successful in all
      3 patients as judged by intracavitary catheter position and decrease in cyst size
      on postoperative imaging. In 1 patient, revision using the same technique was
      required based upon suboptimal catheter position within one of numerous cystic
      compartments within the posterior fossa. There were no complications related to
      direct or indirect brainstem injury. CONCLUSIONS: Many posterior fossa cysts can
      be treated effectively and safely via a posterior fossa approach with the aid of
      a malleable endoscope. Direct visualization facilitates intracavitary catheter
      placement and orientation of the catheter in the long axis of the cyst, thereby
      decreasing the risk of injury to surrounding structures.

PMID- 10420127
TI  - A prospective analysis of the use of octylcyanoacrylate tissue adhesive for wound
      closure in pediatric neurosurgery.
AB  - OBJECTIVE: Cyanoacrylate monomers have been developed for use as skin adhesives.
      Previous studies have demonstrated that using this skin adhesive for the closure
      of traumatic lacerations results in excellent cosmesis, decreased procedure
      related pain and timesavings. SURGICAL TECHNIQUE: Octylcyanoacrylate skin
      adhesive is applied after the placement of deep fascial sutures with close
      approximation of the skin edges. The adhesive is applied in liquid form and
      polymerizes rapidly to solid form. Multiple layers are applied forming a hard
      impenetrable barrier. RESULTS: This technique was prospectively evaluated in the
      closure of 102 elective neurosurgical operations with 142 incisions:
      ventriculoperitoneal shunt insertion/revision (53%) and craniotomy for tumors
      (10%) were the commonest procedures. There were a total of 83 scalp, 36
      abdominal, 8 neck, 6 chest and 6 lumbar incisions. The mean incision length was
      5.1 cm (range 0.25-50 cm). Fifty-nine percent of the wounds had previous areas of
      operative incisions. Complications included 1 poor cosmetic result and 4
      cerebrospinal fluid (CSF) leaks. Of the 4 patients with CSF leaks, 2 required
      operative wound revision, and 1 required ventriculoperitoneal shunting for
      hydrocephalus. CONCLUSION: Cyanoacrylate skin adhesive is a viable means of
      obtaining cosmetic wound closure. Its use requires attention to proper skin
      approximation and hemostasis. In our experience, propensity for CSF leakage
      especially in reoperative procedures is a relative contraindication.

PMID- 10420128
TI  - Cervical cord tethering mimicking focal muscular atrophy.
AB  - Spinal cord tethering rarely occurs in the cervical region. In adults, it usually
      results from previous operations. However, congenital origin is always diagnosed
      and treated early in the infant period. We report a 12-year-old boy with cervical
      spinal dysraphism which was erroneously diagnosed as focal muscular atrophy, a
      benign form of motor neuron disease. The patient was brought to our hospital
      because of rapid deterioration of symptoms. Careful evaluation disclosed a hairy
      dimple at the nuchal area, which led to the correct diagnosis. X-ray of the
      cervical spine showed spina bifida from C(4) to C(6) levels and fusion of the
      laminae of C(4) and C(5). Spine MRI studies disclosed that the cervical cord was
      tethered caudally and dorsally, and the ventral nerve roots were markedly
      stretched, especially over the left side. Surgical intervention was undertaken
      and the patient's muscle power improved after untethering. The purpose of this
      report is to acquaint the reader with a surgically treatable condition that may
      appear to be benign focal amyotrophy. Skin lesion at the nuchal area should be
      carefully looked for.

PMID- 10420129
TI  - Cranial growth unrestricted during treatment of deformational plagiocephaly.
AB  - OBJECTIVES: The Dynamic Orthotic Cranioplasty (DOC) Band(TM) is a cranial
      orthosis used to treat deformational plagiocephaly. The ability of this device to
      redirect growth and thus, improve craniofacial asymmetry has raised concerns
      regarding the potential restriction of cranial growth. The purpose of this study
      was to evaluate the growth of the head during correction of plagiocephaly.
      METHODS: The study sample consisted of 190 children: 81 females (42. 6%) and 109
      males (57.4%) All patients had been diagnosed with nonsynostotic plagiocephaly,
      did not have other significant medical conditions, were compliant with DOC
      protocol, and had complete anthropometric measurements at entrance and exit from
      treatment. Growth of the head was evaluated using head circumference, maximum
      cranial width and maximum cranial length. Correction of plagiocephaly was
      evaluated by documenting the reduction of craniofacial asymmetry of the cranial
      vault, skull base and face. Paired t tests were used to assess the significance
      of changes in these anthropometric measurements. Differences were considered
      significant if p < 0.05. RESULTS: Average entrance age was 6.5 months with a mean
      treatment time of 4.1 months. Statistical analysis demonstrated highly
      significant reductions in asymmetry in all three regions (p < 0.001). More
      importantly, these corrections were achieved with synchronous growth of the skull
      as demonstrated by highly significant increases (p < 0.001) in head
      circumference, maximum cranial width and maximum cranial length. CONCLUSIONS:
      These findings document statistically significant increases in cranial growth in
      association with concomitant reductions of the cranial asymmetries associated
      with deformational plagiocephaly.

PMID- 10420130
TI  - Intra-fourth-ventricle teratoma.
AB  - The computed tomographic (CT) scanning characteristics of a case of intra-fourth
      ventricle mature teratoma in a 15-month-old child are described and correlated
      with intraoperative findings.

PMID- 10420131
TI  - MR artifact mimicking a temporal lobe lesion in an epilepsy patient.
AB  - A ten-year-old healthy child presented with a right upper extremity focal seizure
      which secondarily generalized. Magnetic resonance imaging (MR) revealed a 1-cm
      area of abnormal signal intensity in the left posterior temporal lobe at the gray
      white junction. This did not appear on all imaging sequences, raising the
      suspicion of an artifact. Repeat MR revealed no intracranial or extracranial
      pathology. This case illustrates MR 'wrap around' artifact that mimicked a
      temporal lobe abnormality in an epilepsy patient. The physics of MR are reviewed
      as they pertain to this artifact.

PMID- 10420132
TI  - Symptomatic moyamoya disease and aortic coarctation in a patient with Noonan's
      syndrome: strategies for management.
AB  - Noonan's syndrome is a multiple congenital anomaly syndrome with characteristic
      facial features, short stature, congenital heart defects and a recently reported
      association with moyamoya disease. We report a case of symptomatic moyamoya
      disease and aortic coarctation in a patient with Noonan's syndrome. The case
      illustrates the need for a rational, coordinated treatment plan for dealing with
      the cardiac and neurologic syndromic anomalies to help avoid undesirable
      outcomes.

PMID- 10420133
TI  - A 10-year-old boy, HIV positive, develops progressive weakness.

PMID- 10420134
TI  - Image of the month: Joubert syndrome.

PMID- 10420135
TI  - A simple and safe technique for endoscopic third ventriculocisternostomy.
AB  - A simple and safe technique for performing an endoscopic third
      ventriculocisternostomy is described using a small-diameter semirigid
      neuroendoscope in conjunction with a perforated ventricular catheter to bluntly
      fenestrate the floor of the third ventricle. All previous descriptions involve
      the initial use of an introducer sheath that in our experience lends to loss of
      cerebrospinal fluid, consequently distorting the anatomic landmarks of the third
      ventricle as well as compromising the crucial concave shape of its floor. Our
      technique limits the loss of cerebrospinal fluid volume, therefore, reducing the
      chance of basilar artery complex perforation as a consequence of distortion of
      third ventricular landmarks and loss of third ventricular floor concavity.

PMID- 10420136
TI  - Topical retinoyl beta-glucuronide is an effective treatment of mild to moderate
      acne vulgaris in Asian-Indian patients.
AB  - Topical retinoyl beta-glucuronide (RBG) is beneficial in the treatment of mild to
      moderate acne (acne vulgaris) in patients largely of North-European origin in the
      US. Because the skin types of people in India are different from those in the US,
      we investigated the effectiveness and toxicity of topical RBG in acne patients in
      India. Each day, 27 acne patients were treated topically with the vehicle, and 39
      acne patients were treated topically with 0. 16% RBG cream for 18 weeks in a
      double-blind study. A significant reduction (p < 0.001) in total lesions,
      inflammatory lesions and noninflammatory lesions in patients treated with RBG as
      compared with the vehicle only (86.8, 80.2 and 94.6% vs. 40.1, 34.3 and 50%,
      respectively) was observed. No side effects were associated with topical RBG
      treatment. Thus, topical 0.16% RBG is a rapid, effective and nontoxic treatment
      for mild to moderate acne in Asian-Indian patients.

PMID- 10420139
TI  - Effects of prolonged occlusion on stratum corneum barrier function and water
      holding capacity.
AB  - PURPOSE OF THE STUDY: We aimed to evaluate whether prolonged occlusion can induce
      stratum corneum barrier damage, alterations in stratum corneum hydration or water
      holding capacity (WHC) lasting longer than the occlusion time. MATERIALS AND
      METHODS: 12 subjects were occluded on the forearm for 24, 48, 72 and 96 h. Two
      hours after occlusion removal, transepidermal water loss (TEWL) and skin
      hydration were measured and a sorption-desorption test performed. RESULTS: TEWL
      showed an increase reaching a plateau on day 2. Hydration and WHC did not show
      significant changes. Hygroscopicity showed the highest level on day 1, decreasing
      during the following days. A highly significant correlation between capacitance
      values and the WHC could be detected (p < 0.0001, r = 0.8206). No correlation
      could be detected between hygroscopicity and TEWL. CONCLUSIONS: Prolonged
      occlusion induces barrier damage without skin dryness. Occlusion also induces an
      increased hygroscopicity. A correlation between these two findings could not be
      proven.

PMID- 10420138
TI  - Characterisation and assay of five enzymatic activities in the stratum corneum
      using tape-strippings.
AB  - The report describes a method for the assay of five enzymatic activities involved
      in establishing the stratum corneum permeability barrier: beta
      glucocerebrosidase, acid phosphatase, phospholipase A(2) (PLA(2)) and two serine
      proteases: chymotrypsin and its activator in the stratum corneum, trypsin. The
      specific activities of these different enzymes have been determined along with
      their pH profiles and sensivities to specific inhibitors. It can be noted that
      only two presented a pH optimum similar to the pH of the stratum corneum. This
      could suggest that their activities are regulated by local variations in pH. The
      method was applied to a pathological situation, that of a non-eczematous dry
      atopic dermatitis. Atopic skin had significantly reduced trypsin activity,
      increased acid phosphatase and no change in the activities of three other studied
      enzymes. Understanding these activities can provide a tool for the
      characterization of skin pathologies and for the development of a certain number
      of applications in cosmetology and therapeutics.

PMID- 10420140
TI  - Postural skin colour changes during the corticosteroid blanching assay.
AB  - OBJECTIVE: To assess the effect of the position of a limb (dependency) on the
      cutaneous vasoconstrictor (blanching) assay (VCA) using topical corticosteroid
      preparations. METHOD: Two studies were performed on the forearms of healthy
      volunteers using tristimulus reflectance colorimetric assessments. The first one
      conducted in 60 normal adults aimed at quantifying the range of variation in the
      skin chromaticity a* when the arm was successively positioned horizontally and
      vertically, either in the upward or downward direction. In the second study, 16
      volunteers were selected according to a weak spontaneous postural dependency of
      the limb in a* (<2 units). The blanching effect of 0.1% mometasone furoate, 0.1%
      betamethasone valerate and petrolatum were compared to the colour of an untreated
      site. Chromaticity a* and the colorimetric variable (DeltatL*(2) +
      Deltata*(2))(0.5) were measured in time following a 2-hour application. RESULTS:
      The postural variations in skin colour varied among subjects. The majority of
      them (80%) presented a difference in a* higher than 2 units between the upright
      and downward arm positions. The upright position appeared to be the most
      sensitive to show significant differences in the VCA. Mometasone furoate
      exhibited the most prominent effect, significantly higher than betamethasone
      valerate and controls. CONCLUSION: The corticosteroid VCA is influenced by the
      position of the limb. The upright position increases the sensitivity of the test.
      Mometasone furoate is more potent than betamethasone valerate.

PMID- 10420137
TI  - Influence of tacalcitol on cell cycle kinetics of human keratinocytes following
      standardized injury.
AB  - In the last few years, tacalcitol (1alpha,24-dihydroxy vitamin D(3), TV-02) has
      become widely available for the topical treatment of psoriasis. Several studies
      documented its effect on epidermal differentiation, inflammation and
      proliferation. Especially the effect on epidermal proliferation has shown to be
      most substantial. This finding strongly suggests that the antipsoriatic effect of
      tacalcitol may be mediated by the normalization of epidermal cell cycle kinetics.
      Aim of the present study was to investigate the effect of tacalcitol ointment (4
      microg/g) compared with the ointment base on epidermal proliferation following
      tape stripping. In particular, we addressed the question to what extent
      tacalcitol influences the recruitment of G(0) cells after standardized injury. In
      15 healthy volunteers, Sellotape(TM) stripping of the epidermis was performed at
      two places on the lower back. Then, tacalcitol ointment (4 microg/g) and the
      ointment base were applied on the lesions and covered by a semiocclusive
      dressing. Punch biopsies of the lesions were obtained at 24, 32, 38, 44, 50, and
      56 h after tape stripping. Using a flow cytometric staining procedure with
      parameters for epidermal proliferation (DNA content), differentiation (keratin 10
      expression) and nonmesenchymal cells (vimentin expression), quantitative data
      were obtained. There was a statistically significant difference between the time
      intervals for tacalcitol and placebo with respect to the percentage of recruited
      basal cells in S phase: The peak of recruited basal cells in S phase was seen at
      38 h for the placebo-treated lesions, whereas this peak was seen at 50 h for the
      tacalcitol-treated lesions. There was no significant difference in the total
      number of recruited cells between tacalcitol and placebo. The influence of
      tacalcitol on epidermal keratinization and on the percentage of nonkeratinocytes
      did not show any significance compared to placebo. We concluded that the mode of
      action of tacalcitol on proliferation is mainly through an extension of the cell
      cycle time of keratinocytes and/or an extension of the duration of the
      recruitment process of cycling cells, whereas the ability to suppress recruitment
      of resting keratinocytes is not different from placebo. Moreover, because of the
      limited effect of tacalcitol on epidermal keratinization, combination treatments
      with agents which interfere with keratinization and/or inflammation may be
      attractive.

PMID- 10420141
TI  - Neurogenic modifications induced by substance P in an organ culture of human
      skin.
AB  - Neurogenic inflammation of the skin observed after topical application of an
      irritant substance or environmental stimulation induces vascular changes and the
      production of inflammatory mediators. Substance P (SP) is one of the main
      neuropeptides which trigger an inflammatory response in the skin. So, with the
      aim to develop an alternative method to study neurogenic inflammation of the
      skin, we used an organ culture of human skin. SP was added onto epidermis or
      directly to culture medium in an attempt to reproduce ex vivo the effects
      described in vivo. Even disconnected from systemic blood circulation, in skin
      fragments in culture, we observed dose-dependent edema, vasodilation and
      extravasation of lymphocytes and mast cells through the microvascular wall.
      Moreover, the release of proinflammatory mediators interleukin 1alpha and tumor
      necrosis factor alpha was evidenced.

PMID- 10420143
TI  - Nicotine-enhanced epithelial differentiation in reconstructed human oral mucosa
      in vitro.
AB  - Oral mucosal keratinocytes represent the cells that first encounter tobacco
      components. Therefore, tobacco-induced abnormal alteration of the mucosal
      keratinocytes may contribute to the development of oral white lesions. Nicotine
      is an ingredient of all tobacco products and pharmacologically the most active
      component of tobacco smoke. To clarify the effects of nicotine on the
      keratinization of oral mucosal and epidermal keratinocytes, we reconstructed
      artificial buccal mucosal and skin equivalents using keratinocytes and
      fibroblasts from noncornifying buccal mucosa and adult foreskin, respectively.
      The effect of nicotine on keratinization was assessed with morphology,
      immunohistochemistry and immunoblotting. Long-term treatment with nicotine for 2
      weeks enhanced in a dose-dependent manner the expression of differentiation
      specific proteins of oral mucosal keratinocytes on living oral mucosal equivalent
      and epidermal keratinocytes on living skin equivalent, respectively. The effect
      of nicotine on the cell viability was measured by the 3-(4, 5-dimethylthiazol-2
      yl)-2,5-diphenyl tetrazolium bromide assay. Oral mucosal keratinocytes showed a
      higher resistance to nicotine toxicity than epidermal keratinocytes. Our results
      suggest that nicotine stimulates differentiation of both mucosal and epidermal
      keratinocytes, and this nicotine-induced abnormal differentiation may be
      associated with the development of oral white lesions.

PMID- 10420144
TI  - Anatomical targeting in functional neurosurgery by the simultaneous use of
      multiple Schaltenbrand-Wahren brain atlas microseries.
AB  - This paper presents a novel approach for the use of the Atlas for Stereotaxy of
      the Human Brain by Schaltenbrand and Wahren [Stuttgart, Thieme, 1977] for
      anatomical targeting in functional neurosurgery. We propose to use simultaneously
      all three electronic axial, coronal and sagittal mutually coregistered
      Schaltenbrand-Wahren brain atlas microseries. The printed atlas microseries are
      digitized, extended to cover both hemispheres, contoured, labeled, organized into
      atlas volumes, and mutually coregistered. The electronic atlas is interactively
      registered with the data by using the three-dimensional Talairach proportional
      grid system transformation, followed up by local warping in the region of
      interest based on any clearly visible landmarks. The detailed targeting steps for
      pallidotomy, thalamotomy and subthalamotomy are formulated. The potential of this
      approach is to increase the accuracy of target definition, to decrease the time
      of the procedure by reducing the number of microelectrode tracts, and to give an
      extra degree of confidence to the neurosurgeon. The advantages of the approach
      and the limitations of the Schaltenbrand-Wahren atlas are discussed.

PMID- 10420142
TI  - Iontophoretic transdermal delivery of salicylic acid dissolved in ethanol-water
      mixture in rats.
AB  - The usefulness of iontophoresis is restricted to highly water-soluble compounds,
      since drugs are generally applied as an aqueous solution in a drug electrode. In
      the present study, salicylic acid (SA) dissolved in ethanol-water mixture was
      loaded in a drug electrode, and the effect of ethanol on the iontophoretic
      transdermal delivery of SA was evaluated. Ethanol at a concentration of 10 or 30%
      showed no significant effect on the iontophoretic transdermal delivery of SA
      compared to that in the absence of ethanol, but 40 or 70% ethanol increased it
      significantly. The current density passing through in vivo during iontophoretic
      treatment decreased with increase in ethanol concentrations. These results
      suggested that the enhanced transdermal absorption of SA iontophoretically by the
      presence of ethanol in a drug solution is not due to the increased current
      density in vivo, but probably due to the direct action of ethanol on the stratum
      corneum. In conclusion, addition of ethanol to a drug solution at an appropriate
      concentration was proved to enhance the iontophoretic transdermal delivery of SA.
      A mixture of ethanol and water can dissolve many poorly water-soluble drugs, and
      therefore it would be able to expand the application of iontophoresis to include
      many drugs that are poorly soluble in water.

PMID- 10420145
TI  - Comparison between stereotactic CT and MRI coordinates of pallidal and thalamic
      targets using the Laitinen noninvasive stereoadapter.
AB  - The coordinates of one and the same target were compared between stereotactic CT
      and MRI studies, using the original Laitinen noninvasive Stereoadapter, and a
      slightly modified stereoadapter in 34 patients scheduled for pallidotomy or
      thalamotomy. The differences between CT and MRI coordinates were significant for
      the anteroposterior y (p < 0.001) and the vertical z (p < 0.01) coordinates. When
      the targets were analyzed separately for the coordinates in the right and left
      hemispheres, only those of the left-sided targets were significantly different
      between CT and MRI measurements. In patients where a vertex support was added to
      the Stereoadapter, there were no differences between CT and MRI target
      coordinates, regardless of the side of the target. However, in all patient
      groups, the three-dimensional vectorial difference between CT and MRI coordinates
      showed that the MRI-defined targets lay anterior and dorsal, that is, rostral, to
      the CT-defined targets, with a 95% confidence interval of the differences ranging
      from 1.8 to 2.4 mm. This rostral shift in target coordinates on MRI versus CT
      happens to coincide with the usual approach of the probe towards the target
      during surgery. It is concluded that the differences in target coordinates in our
      study are due partly to MRI distortion and partly to repositioning error of the
      Stereoadapter on the head. The relatively low magnitude of these differences does
      not preclude the use of the Stereoadapter for MRI-guided functional stereotactic
      surgery, provided careful impedance monitoring and macrostimulation of the target
      area prior to lesioning.

PMID- 10420147
TI  - Stereotactic cyst wall disruption and aspiration of colloid cysts of the third
      ventricle.
AB  - BACKGROUND: Current strategies of surgical therapy for colloid cysts have been
      associated with low rates of initial success and high rates of morbidity,
      mortality and recurrence of cysts. Cyst recurrence following simple stereotactic
      aspiration has been hypothesized to be due to regrowth of the epithelium
      composing the cyst wall. METHODS: We propose a procedure involving stereotactic
      disruption of the colloid cyst wall with the removal of a portion of the cyst
      wall followed by aspiration of cyst contents as a surgical therapy for colloid
      cysts. RESULTS: This procedure was performed in 2 female and 3 male patients who
      were followed for an average of 49 months with all patients demonstrating
      immediate improvement of symptoms and resolution of the cyst verified with repeat
      computerized tomography (CT) scans. There was one incidence of recurrence in an
      asymptomatic patient at 75 months postoperatively. CONCLUSION: We propose that
      stereotactic partial cyst wall disruption and content aspiration may limit
      recurrence of colloid cysts, thus offering an advantage over simple stereotactic
      aspiration alone.

PMID- 10420146
TI  - Comparative magnetic resonance image-based evaluation of thalamotomy and
      pallidotomy lesion volumes.
AB  - Acute thalamotomy and pallidotomy lesion volumes based on magnetic resonance (MR)
      images were measured in 22 patients (11 thalamotomy and 11 pallidotomy patients).
      Thalamotomy inner lesion volumes (0.06 +/- 0.04 ml; thermocoagulative zone) were
      smaller than pallidotomy inner lesion volumes (0.14 +/- 0.08 ml) as determined
      using T(1)-weighted 3D-MPRAGE (1.5-mm slice spacing). Similar results were found
      using T(1)-weighted (6-mm slice spacing) image sets (0.09 +/- 0.05 ml,
      thalamotomy; 0.13 +/- 0.05 ml, pallidotomy). No differences were found when
      comparing thalamic or pallidal inner lesion volumes when the comparison was based
      on T(2) weighted images. Thalamotomy total lesion volumes (thermocoagulative and
      surrounding edematous zones) were less than pallidotomy total lesion volumes
      independent of the MR protocol. The difference in thalamotomy and pallidotomy
      lesion volumes is most likely based on the distance between each discrete lesion
      placed along the lesioning tracts. In 7 of 11 thalamotomies, this distance was 1
      mm with the remaining having 2 mm between each discrete lesion. All pallidotomy
      discrete lesions were 2 mm apart. More overlap between discrete lesioning sites
      for thalamotomies is likely to produce reduced lesion volumes.

PMID- 10420148
TI  - Cross talk between melatonin and TGFbeta1 in human benign prostate epithelial
      cells.
AB  - BACKGROUND: Epithelial cells from the human benign prostate express melatonin
      receptors which effect transient suppression of DNA synthesis and sustained
      attenuation of growth. The role of transforming growth factor-beta1 (TGFbeta1),
      which is produced in prostate epithelial cells and inhibits their growth, was
      examined in the action of melatonin. METHODS: The effects of melatonin and
      TGFbeta1 and their combination on (3)H-thymidine incorporation were assessed. The
      possibility that melatonin effected TGFbeta1 release from cells was studied.
      RESULTS: Incubation of the cells with TGFbeta1 resulted in a time- and dose
      dependent inhibition of (3)H-thymidine incorporation into cells. Melatonin (10
      500 pM) inhibited (3)H-thymidine incorporation, and its effects were attenuated
      at higher (1-10 nM) concentrations. In the presence of submaximal doses of
      TGFbeta1, the inhibitory effect of melatonin was maintained over the entire
      concentration range tested (10 pM-10 nM). The inhibition of (3)H-thymidine
      incorporation by TGFbeta1 was more pronounced in the absence of
      dihydrotestosterone (DHT) than in its presence, and melatonin had no further
      effect. Melatonin enhanced the release of proteins from cells, among them
      proteins recognized by specific TGFbeta1 antisera. The TGFbeta1-neutralizing
      antisera prevented the inhibitory action of melatonin on (3)H-thymidine
      incorporation into cells. CONCLUSIONS: These data indicate a role for TGFbeta1 in
      the melatonin-mediated attenuation of benign prostate epithelial cell growth.

PMID- 10420149
TI  - Exploratory analysis on the effect of race on clinical outcome in patients with
      advanced prostate cancer receiving bicalutamide or flutamide, each in combination
      with LHRH analogues. The Casodex Combination Study Group.
AB  - BACKGROUND: Black race has been associated with a significantly increased risk of
      prostate cancer mortality. This exploratory analysis investigated the effect of
      race on the clinical outcome of combined androgen blockade (CAB). METHODS: Data
      for analysis were obtained from a double-blind, randomized, multicenter trial
      comparing CAB in the form of bicalutamide (50 mg once daily) or flutamide (250 mg
      three times daily) plus luteinizing hormone-releasing hormone analogs (LHRHa;
      goserelin acetate 3.6 mg, or leuprolide acetate 7.5 mg) in 813 patients with
      stage D(2) prostate cancer (median follow-up, 160 weeks). Patients were analyzed
      according to race (African American [AA], white, or other). The primary clinical
      events were disease progression and survival. RESULTS: Four hundred and four
      patients received bicalutamide/LHRHa and 409 received flutamide/LHRHa. Although
      treatment with bicalutamide/LHRHa resulted in slightly longer time to progression
      and survival time in white and AA males than treatment with flutamide/LHRHa, the
      differences between the treatment groups were not statistically significant.
      CONCLUSIONS: No marked effect of race on clinical outcome was observed regardless
      of antiandrogen, suggesting that similar treatment benefits are to be expected in
      either race.

PMID- 10420150
TI  - Expression and mutational analysis of the MADR2/Smad2 gene in human prostate
      cancer.
AB  - BACKGROUND: Loss of heterozygosity (LOH) on chromosome arm 18q is common in
      sporadic prostate cancer and may be involved in cancer development through
      inactivation of tumor-suppressor genes (TSG). Recent identification, at 18q21.1,
      of MADR2/Smad2, a key component in transforming growth factor beta (TGFbeta)
      family signaling pathways, led us to investigate the role of this gene in
      prostate tumorigenesis. METHODS: Sporadic primary prostate tumors from 25
      patients with clinically localized tumors and 7 with metastatic forms were
      examined for MADR2/Smad2 mutations by using polymerase chain reaction-single
      strand conformational polymorphism (PCR-SSCP) analysis of cDNA, and for gene
      expression by quantitative reverse transcription-polymerase chain reaction (RT
      PCR). RESULTS: We detected no mutation in MADR2/Smad2 and no abnormal mRNA
      expression. CONCLUSIONS: Despite recent evidence indicating that MADR2/Smad2 acts
      as a tumor-suppressor gene, our findings suggest a limited role of this gene in
      prostate tumorigenesis, at least in the early stages. Another key tumor
      suppressor gene may therefore be the main target of the observed LOH at 18q21.1.

PMID- 10420151
TI  - Serenoa repens (Permixon): a 5alpha-reductase types I and II inhibitor-new
      evidence in a coculture model of BPH.
AB  - BACKGROUND: The aim of this study was to determine the effect of the
      phytotherapeutic agent, Permixon, on a novel coculture model of benign prostatic
      hyperplasia (BPH) in an effort to better understand the mode of action of the
      drug in vivo. METHODS: The effect of Permixon, at the calculated therapeutic
      concentration, on the activity of 5alpha-reductase isoenzymes was evaluated
      utilizing a pH-specific assay. Prostate-specific antigen (PSA) secretions into
      the medium were measured in the presence and absence of Permixon and quantified
      by an ELISA assay. The morphological patterns before and following Permixon
      treatment were also examined by electron microscopy. All results were compared to
      controls. RESULTS: Permixon at a concentration of 10 micrograms/ml (calculated
      plasma concentration in patient receiving recommended therapeutic dosage) was
      shown to be an effective inhibitor of both 5alpha-reductase types I and II
      isoenzymes without influencing the secretion of PSA by the epithelial cells, even
      after stimulation with testosterone. The morphology of Permixon-treated cells was
      found to be markedly different from that of untreated controls. Cells which had
      been treated with the drug demonstrated extensive accumulation of lipids in the
      cytoplasm and widespread damage of intracellular membranes, including
      mitochondrial and nuclear membranes. CONCLUSIONS: Permixon is an effective dual
      inhibitor of 5alpha-reductase isoenzyme activities in the prostate. Unlike other
      5alpha-reductase inhibitors, Permixon induces this effect without interfering
      with the cells' capacity to secrete PSA, thus permitting the continued use of PSA
      measurements for prostate cancer screening.

PMID- 10420152
TI  - Elastin gene expression in benign prostatic hyperplasia.
AB  - BACKGROUND: Benign prostatic hyperplasia (BPH) is mainly a stromal process,
      showing an increased ratio of stromal to epithelial elements, a collagen type III
      downregulation, and a collagen types I and IV upregulation. Little is known about
      elastin gene expression in BPH tissues due to difficulties related to extensive
      alternative splicing of the elastin gene. Therefore, we analyzed and quantified
      elastin gene expression in BPH. METHODS: A competitive reverse transcriptase
      polymerase chain reaction (competitive RT-PCR) quantitative technique was used,
      and a quantitative elastin mRNA analysis with normal (n = 10) and BPH (n = 12)
      tissues was performed with two newly designed elastin primers. Small tissue
      samples (4-8 mg) were homogenized and sonicated, and cDNA was synthesized from
      mRNA using a RT reaction. Various target (wild-type) elastin cDNAs with unknown
      concentrations were competitively coamplified with known serial dilutions of the
      control mutant template, differing from the target cDNA by a short deletion. Gel
      fractions and computerized densitometry, were performed and cDNA concentration
      was calculated by linear regression. RESULTS: The primers identified in our study
      (BOB-1 and BOB-2) accurately amplified a consistent length of the elastin cDNA,
      avoiding areas of alternative splicing. The average elastin mRNA concentration in
      BPH tissues was 53 attomole/mg +/- 11.6 vs. 140.6 attomole/mg +/- 19.6 in normal
      prostatic tissue (P = 0.019). The variation within every sample was less than
      10%. CONCLUSIONS: Our observations suggest a significant downregulation (70%) of
      the elastin mRNA gene in the transition zone of BPH patients.

PMID- 10420153
TI  - Growth factors in expressed prostatic fluid from men with prostate cancer, BPH,
      and clinically normal prostates.
AB  - BACKGROUND: Although growth factors such as epidermal growth factor (EGF),
      transforming growth factor (TGF)-alpha, and TGF-beta are important regulators of
      prostate cell growth in vitro and in animal models, evidence to support their
      role in human prostate cancer development remains sparse. We previously showed
      that men without prostate cancer have concentrations of EGF and TGF-alpha in
      expressed prostatic fluid (EPF) that are individually distinct and stable over
      time. This study addressed whether growth factor levels in EPF are associated
      with the presence or progression of prostate cancer. METHODS: We measured levels
      of immunoreactive EGF, TGF-alpha, and TGF-beta1 in stored EPF samples from three
      age-matched groups: 19 men with untreated, histologically diagnosed prostate
      cancer (CaP), 38 with benign prostate hyperplasia (BPH), and 19 with normal
      prostate glands (NPD). RESULTS: Median TGF-alpha was lower in the BPH group (0.45
      ng/ml) than in either CaP (0.63 ng/ml) or NPD (0.58 ng/ml) groups (P = 0.03 and
      0.12, respectively). For EGF, the median was lowest in the CaP group and highest
      in the NPD group (92.5 ng/ml vs. 175.5 ng/ml, P = 0.006). For TGF-beta1, the
      median level in CaP was 2.7 times higher than the median level among all controls
      (6.65 ng/ml vs. 2.46 ng/ml, P = 0.002). Growth factor levels were not associated
      with tumor stage or Gleason score. However, the single case with distant
      metastases had TGF-beta1 levels 23-fold higher than the CaP median. CONCLUSIONS:
      The results suggest that at the time of CaP diagnosis, EGF levels in EPF are
      significantly lower, and TGF-beta1 levels significantly higher, than normal.
      Marked overexpression of TGF-beta1 in advanced CaP might be reflected in
      extremely high EPF levels.

PMID- 10420154
TI  - Relationship of p21(WAF1) expression with disease-free survival and biochemical
      recurrence in prostate adenocarcinomas (PCa).
AB  - BACKGROUND: The p21(WAF1) gene is considered to be one of the major regulators of
      the cell cycle. Its level of expression has been shown to correlate with
      pathologic stage and Gleason score in prostatic cancer. However, its relationship
      to clinical outcome is not yet well-characterized. METHODS: Immunohistochemical
      staining for p21(WAF1) protein expression was performed in 62 consecutive radical
      prostatectomy specimens from our institution. The results were correlated with
      the disease-free survival and biochemical recurrence of the patients. RESULTS:
      Thirty-four of the 62 patients were Caucasian and 28 were African American. There
      was a significant correlation between p21(WAF1) expression and biochemical
      recurrence after radical prostatectomy (P < 0.0095). However, while p21(WAF1)
      staining in prostate cancer was a prognostic indicator of disease-free survival
      in Caucasians (P < 0.0001), it appeared not to be a factor in African-American
      men (P = 0.908). CONCLUSIONS: This study suggests that p21(WAF1) may have a role
      in the pathogenesis and progression of prostate carcinoma, and may serve as a
      predictor of biochemical recurrence of this tumor. The differences in the values
      of p21(WAF1) as a prognostic marker of disease-free survival in Caucasians vs.
      African Americans suggest that progression of prostate cancer may have different
      mechanisms in different ethnic groups.

PMID- 10420155
TI  - Future prospects in prostate cancer.
AB  - BACKGROUND: Prostate cancer has displayed an increase in incidence unparalleled
      by any other tumor in the last two decades, with a steady, more gradual increase
      in mortality rate. Current curative strategies are focused on the detection and
      treatment of early-stage (T1-2 N0 M0), clinically significant tumors. METHODS: To
      this aim, refinement of surgical approaches, with appropriate adjuvant therapies,
      will ensure more complete cancer control, while minimizing associated morbidity.
      New delivery systems for radiotherapy, as well as other energy sources, are
      evolving, while a number of promising pharmacological agents, including
      angiogenesis inhibitors and drugs which alter signal transduction pathways, are
      currently under investigation. Early detection is also being facilitated by a
      more widespread implementation of screening programs. Advances in tumor markers,
      and imaging and biopsy techniques, will allow more accurate preoperative staging.
      These, coupled with improvements in prognostic markers, aid the physician and
      patient alike in deciding on the suitability of treatment options with better
      estimation of outcome. Perhaps the most exciting developments in prostate cancer
      will come from knowledge of the molecular mechanisms underlying carcinogenesis.
      The potential for the development of diagnostic and therapeutic tools is immense.
      The efficacy of treatment can be studied at a molecular level, and strategies for
      preventing or slowing the development of malignancy can be formulated. RESULTS
      AND CONCLUSIONS Application of this knowledge in the form of gene and cellular
      therapy and in the development of novel systemic agents is beginning to enter the
      realm of clinical practice, and it may be in this field that means for cure and
      prevention of prostate cancer will eventually be found.

PMID- 10420156
TI  - Caveolin expression is decreased following androgen deprivation in human prostate
      cancer cell lines.
AB  - BACKGROUND: Increased expression of caveolin has been associated with prostate
      cancer progression. In a mouse reconstitution model of prostate cancer,
      expression of caveolin was inversely related to androgen sensitivity: androgen
      independent clones had high caveolin expression; low caveolin expression was
      associated with sensitivity to androgen withdrawal. In contrast, several
      independent observations support the hypothesis that caveolin functions as a
      tumor suppressor. METHODS: Caveolin expression was studied by Western blot
      analysis and/or immunohistochemistry in three androgen-sensitive human prostate
      cancer cell lines LNCaP, LAPC-4 and LAPC-9, and following acute and chronic
      androgen deprivation, and in benign prostate epithelial cells. Expression of
      caveolin, androgen receptor (AR) and prostate specific antigen (PSA) was also
      examined after reintroduction of androgen. RESULTS: LNCaP grown continuously
      under androgen-depleted conditions for 6 to 42 months produced several androgen
      independent and tumorigenic clones: tumors formed in 13/15 castrate and 7/15
      intact male athymic nu/nu mice, but no tumors formed in wildtype LNCaP-bearing
      animals. Caveolin expression was decreased in every androgen-deprived LNCaP clone
      and following 150 days of androgen deprivation in LAPC-4. Caveolin expression by
      LAPC-9 was very low. Following exposure to dihydrotestosterone in vitro, caveolin
      and PSA expression increased within three days in the androgen-deprived clones of
      LNCaP. Benign prostate epithelial cells have high caveolin expression.
      CONCLUSIONS: Unlike the mouse reconstitution model of prostate cancer, the
      pattern of caveolin expression in benign prostatic epithelium and androgen
      sensitive human prostate cancer is consistent with tumor suppressive activity.

PMID- 10420157
TI  - Morphological analysis of the pharyngeal jaws in two populations of Lebias
      fasciata Valenciennes, 1821 (Teleostei: Cyprinodontidae).
AB  - The study of the pharyngeal jaws in two geographically isolated Italian
      populations of Lebias fasciata indicated the presence of two phenotypes: the
      Adriatic phenotype with a large ceratobranchial V and upper and lower pharyngeal
      jaws bearing few large teeth and the Sicilian phenotype with a smaller
      ceratobranchial V and pharyngeal jaws with smaller and more numerous teeth. The
      morphological variations of pharyngeal jaws should be interpreted as a result of
      the geographical isolation of these two populations.

PMID- 10420158
TI  - Skull allometry in the marine toad, Bufo marinus.
AB  - Scaling predictions pioneered by A.V. Hill state that isometric changes in
      kinematics result from isometric changes in size. These predictions have been
      difficult to support because few animals display truly isometric growth. An
      exception to this rule is said to be the toads in the genus Bufo, which can grow
      over three orders of magnitude. To determine whether skull shape increases
      isometrically, I used linear measurements and geometric morphometrics to quantify
      shape variation in a size series of 69 skulls from the marine toad, B. marinus.
      Toads ranged in body mass from 1.8 gm to a calculated 1, 558.9 gm. Of all linear
      measurements (S/V length, skull width, skull length, levator mass, depressor
      mass, adductor foramen area), only the area of the adductor foramen increased
      faster than body mass; the remaining variables increased more slowly. In
      addition, modeling the lower jaw as a lever-arm system showed that the lengths of
      the closing in- and out-levers scaled isometrically with body mass despite the
      fact that the skull itself is changing allometrically. Geometric morphometrics
      discerned areas of greatest variability with increasing body mass at the rear of
      the skull in the area of the squamosal bone and the adductor foramen. This
      increase in area of the adductor foramen may allow more muscle to move the
      relatively greater mass of the lower jaw in larger toads, although adductor mass
      scales with body mass. If B. marinus feeds in a similar manner to other Bufo,
      these results imply that morphological allometry may still result in kinematic
      isometry.

PMID- 10420159
TI  - Pneumatic processes in the temporal bone of chimpanzee (Pan troglodytes) and
      gorilla (Gorilla gorilla).
AB  - The ontogeny of human temporal bone pneumatization has been well studied from
      both comparative and clinical perspectives. While a difference in the extent of
      air cell distribution has been noted in our closest living relatives, chimpanzees
      and gorillas, the processes responsible have been relatively unexplored. To
      examine these processes, a large, age-graded series of hominoid skulls was
      radiographed and the progress of pneumatization recorded. Additionally, a
      subsample of 30 chimpanzees and 12 gorillas was subjected to high-resolution CT
      scanning. Neonatal specimens show a well-developed mastoid antrum, as well as a
      capacious hypotympanum extending into the petrous apex. In African apes, as in
      humans, the mastoid antrum serves as the focus for air cell expansion into the
      mastoid and immediately adjacent areas. In chimpanzees and gorillas, however, a
      pronounced lateral structure, described as the squamous antrum, serves as the
      focus of pneumatization for anterior structures such as the squamous and
      zygomatic. The diminution of this structure in Homo sapiens explains the
      difference in air cell distribution in these regions.

PMID- 10420160
TI  - Epidermal differentiation in the developing scales of embryos of the Australian
      scincid lizard Lampropholis guichenoti.
AB  - Formation of the first epidermal layers in the embryonic scales of the lizard
      Lampropholis guichenoti was studied by optical and electron microscopy.
      Morphogenesis of embryonic scales is similar to the general process in lizards,
      with well-developed overlapping scales being differentiated before hatching. The
      narrow outer peridermis is torn and partially lost during scale morphogenesis. A
      second layer, probably homologous to the inner peridermis of other lizard
      species, but specialized to produce lipid-like material, develops beneath the
      outer peridermis. Two or three lipogenic layers of this type develop in the
      forming outer surface of scales near to the hinge region. These layers form a
      structure here termed "sebaceous-like secretory cells." These cells secrete lipid
      like material into the interscale space so that the whole epidermis is eventually
      coated with it. This lipid-like material may help to reduce friction and to
      reduce accumulation of dirt between adjacent extremely overlapping scales. At the
      end of their differentiation, the modified inner periderm turns into extremely
      thin cornified cells. The layer beneath the inner peridermis is granulated due to
      the accumulation of keratohyalin-like granules, and forms a shedding complex with
      the oberhautchen, which develops beneath. Typically tilted spinulae of the
      oberhautchen are formed by the aggregation of tonofilaments into
      characteristically pointed cytoplasmic outgrowths. Initially, there is little
      accumulation of beta-keratin packets in these cells. During differentiation, the
      oberhautchen layer merges with cells of the beta-keratin layer produced
      underneath, so that a typical syncytial beta-keratin layer is eventually formed
      before hatching. Between one-fourth distal and the scale tip, the dermis under
      epidermal cells is scarce or absent so that the mature scale tip is made of a
      solid rod of beta-keratinized cells. At the time of hatching, differentiation of
      a mesos layer is well advanced, and the epidermal histology of scales corresponds
      to Stage 5 of an adult shedding cycle. The present study confirms that the
      embryonic sequence of epidermal stratification observed in other species is
      basically maintained in L. guichenoti.

PMID- 10420161
TI  - Morphological variation of hypaxial musculature in salamanders (Lissamphibia:
      caudata).
AB  - Despite the acknowledged importance of the locomotory and respiratory functions
      associated with hypaxial musculature in salamanders, variation in gross
      morphology of this musculature has not been documented or evaluated within a
      phylogenetic or ecological context. In this study, we characterize and quantify
      the morphological variation of lateral hypaxial muscles using phylogenetically
      and ecologically diverse salamander species from eight families: Ambystomatidae
      (Ambystoma tigrinum), Amphiumidae (Amphiuma tridactylum), Cryptobranchidae
      (Cryptobranchus alleganiensis), Dicamptodontidae (Dicamptodon sp.),
      Plethodontidae (Gyrinophilus porphyriticus), Proteidae (Necturus maculosus),
      Salamandridae (Pachytriton sp.), and Sirenidae (Siren lacertina). For the lateral
      hypaxial musculature, we document 1) the presence or absence of muscle layers, 2)
      the muscle fiber angles of layers at mid-trunk, and 3) the relative dorsoventral
      positions and cross-sectional areas of muscle layers. Combinations of two, three,
      or four layers are observed. However, all species retain at least two layers with
      opposing fiber angles. The number of layers and the presence or absence of layers
      vary within species (Necturus maculosus and Siren lacertina), within genera
      (e.g., Triturus), and within families. No phylogenetic pattern in the number of
      layers can be detected with a family-level phylogeny. Fiber angle variation of
      hypaxial muscles is considerable: fiber angles of the M. obliquus externus range
      from 20-80 degrees; M. obliquus internus, 14-34 degrees; M. transversus
      abdominis, 58-80 degrees (acute angles measured relative to the horizontal
      septum). Hypaxial musculature comprises 17-37% of total trunk cross-sectional
      area. Aquatic salamanders show relatively larger total cross-sectional hypaxial
      area than salamanders that are primarily terrestrial.

PMID- 10420162
TI  - Ultrastructure of neuro-spirocyte synapses in the sea anemone Aiptasia pallida
      (Cnidaria, Anthozoa, Zoantharia).
AB  - Using transmission electron microscopy of serially sectioned tentacles from the
      sea anemone Aiptasia pallida, we located and characterized two types of neuro
      spirocyte synapses. Clear vesicles were observed at 10 synapses and dense-cored
      vesicles at five synapses. The diameters of vesicles at each neuro-spirocyte
      synapse were averaged; clear vesicles ranged from 49-89 nm in diameter, whereas
      the dense-cored vesicles ranged from 97-120 nm in diameter. One sequential pair
      of synapses included a neuro-spirocyte synapse with clear vesicles (81 nm) and a
      neuro-neuronal synapse with dense-cored vesicles (168 nm). A second synapse on
      the same cell had dense-cored vesicles (103 nm). An Antho-RFamide-labeled
      ganglion cell and three different neurites were observed adjacent to spirocytes,
      but no neuro-spirocyte synapses were present. Many of the spirocytes also were
      immunoreactive to Antho-RFamide. The presence of sequential neuro-neuro-spirocyte
      synapses suggests that synaptic modulation may be involved in the neural control
      of spirocyst discharge. The occurrence of either dense-cored or clear vesicles at
      neuro-spirocyte synapses suggests that at least two types of neurotransmitter
      substances control the discharge of spirocysts in sea anemones.

PMID- 10420163
TI  - Historical and biomechanical analysis of integration and dissociation in
      molluscan feeding, with special emphasis on the true limpets (Patellogastropoda:
      Gastropoda).
AB  - Modifications of the molluscan feeding apparatus have long been recognized as a
      crucial feature in molluscan diversification, related to the important process of
      gathering energy from the environment. An ecologically and evolutionarily
      significant dichotomy in molluscan feeding kinematics is whether radular teeth
      flex laterally (flexoglossate) or do not (stereoglossate). In this study, we use
      a combination of phylogenetic inference and biomechanical modeling to understand
      the transformational and causal basis for flexure or lack thereof. We also
      determine whether structural subsystems making up the feeding system are
      structurally, functionally, and evolutionarily integrated or dissociated.
      Regarding evolutionary dissociation, statistical analysis of state changes
      revealed by the phylogenetic analysis shows that radular and cartilage subsystems
      evolved independently. Regarding kinematics, the phylogenetic analysis shows that
      flexure arose at the base of the Mollusca and lack of flexure is a derived
      condition in one gastropod clade, the Patellogastropoda. Significantly, radular
      morphology shows no change at the node where kinematics become stereoglossate.
      However, acquisition of stereoglossy in the Patellogastropoda is correlated with
      the structural dissociation of the subradular membrane and underlying cartilages.
      Correlation is not causality, so we present a biomechanical model explaining the
      structural conditions necessary for the plesiomorphic kinematic state
      (flexoglossy). Our model suggests that plesiomorphically the radular teeth must
      flex laterally as they pass over the bending plane as a result of the mechanical
      restrictions in the flexible but inelastic subradular membrane and close
      association between subradular membrane and cartilages. Relating this model to
      the specific character states of the clades, we conclude that lack of flexure in
      patellogastropods is caused by the dissociation of the subradular membrane and
      cartilage supports.

PMID- 10420164
TI  - CART peptide analysis by Western blotting.
AB  - CART peptides have been implicated in leptin-regulated feeding, reward and
      reinforcement, neurotropism, and other processes. In this Western blotting study,
      at least six different CART peptides varying from 4 to 14 kD were found in rat
      brain, pituitary, gut, and adrenal gland. The peptides may be processed
      differently in different tissues and one species found in the rat was not found
      in human hypothalamus. The higher molecular weight species are likely to include
      preproCART and proCART, while lower molecular weight peptides may be CART 55-102
      and 62-102, physiologically active fragments.

PMID- 10420165
TI  - Glutamatergic synaptic responses and long-term potentiation are impaired in the
      CA1 hippocampal area of calbindin D(28k)-deficient mice.
AB  - The contribution of the cytosolic calcium binding protein calbindin D(28K) (CaBP)
      to glutamatergic neurotransmission and synaptic plasticity was investigated in
      hippocampal CA1 area of wild-type and antisense transgenic CaBP-deficient mice,
      with the use of extracellular recordings in the ex vivo slice preparation. The
      amplitude of non-N-methyl-D-aspartate receptor (non-NMDAr)-mediated extracellular
      field excitatory postsynaptic potentials (fEPSPs) recorded in control medium was
      significantly greater in CaBP-deficient mice, whereas the afferent fiber volley
      was not affected. In contrast, the amplitude of NMDAr-mediated fEPSPs isolated in
      a magnesium-free medium after blockade of non-NMDAr and GABAergic receptors was
      significantly depressed in these animals. No alteration in the magnitude of
      paired-pulse facilitation was found, indicating that the presynaptic calcium
      mechanisms controlling glutamate release were not altered in CaBP-deficient mice.
      The magnitude and time course of the short-term potentiation (STP) of fEPSPs
      induced by a 30 Hz conditioning stimulation, which was blocked by the NMDAr
      antagonist 2-amino-5-phosphonovalerate acid (2-APV), was not impaired in the
      transgenic mice, whereas long-term potentiation (LTP) induced by a 100 Hz tetanus
      was not maintained. The long-term depression (LTD) induced by low-frequency
      stimulation (1 Hz, 15 min) in the presence of the GABA antagonist bicuculline was
      not altered. These results argue for a contribution of CaBP to the mechanisms
      responsible for the maintenance of long-term synaptic potentiation, at least in
      part by modulating the activation of NMDA receptors.

PMID- 10420166
TI  - Analysis of cannabinoid receptor binding and mRNA expression and endogenous
      cannabinoid contents in the developing rat brain during late gestation and early
      postnatal period.
AB  - Cannabinoid CB(1) receptors emerge early in the rat brain during prenatal
      development, supporting their potential participation in events related to neural
      development. In the present investigation, we completed earlier studies,
      analyzing CB(1) receptor binding and mRNA expression by using autoradiography and
      in situ hybridization, respectively, in the brain of rat fetuses at gestational
      day (GD) 21 and of newborns at postnatal days (PND) 1 and 5, in comparison with
      the adult brain. These analyses were paralleled by quantitation of levels of
      anandamide and its precursor, N-arachidonoyl-phosphatidylethanolamine (NAPE), and
      of 2-arachidonoyl-glycerol (2-AG), carried out by using gas chromatography / mass
      spectrometry of the tri-methyl-sylyl-ether derivatives. As expected, CB(1)
      receptor binding was detected at GD21 in a variety of brain structures. In most
      of them, such as the hippocampus, cerebral cortex, cerebellum, basal ganglia, and
      limbic nuclei, there were no marked differences in the density of CB(1) receptors
      in animals at GD21 as compared to early newborns (PND1 and 5), although it
      markedly increased in these regions in adulthood. However, with the exception of
      the cerebellum and, in part, the caudate-putamen, the pattern observed for
      binding in these regions was clearly different from that observed for mRNA
      expression of the CB(1) receptor, which currently exhibited the highest levels at
      PND1 and the lowest in the adult brain. This was also seen in the basolateral
      amygdaloid nucleus, ventromedial hypothalamic nucleus, medial habenula, and other
      structures. In the caudate-putamen and, particularly, in the cerebellum, mRNA
      expression was higher in the adult brain as compared with other ages. As
      previously reported, specific binding for CB(1) receptors was also detected at
      GD21 in white matter areas, such as the corpus callosum, anterior commissure,
      fornix, fimbria, stria medullaris, stria terminalis, and fasciculus retroflexum.
      With the exception of the anterior commissure and the fimbria, specific binding
      progressively decreased at PND1 and PND5 until disappearing in the adult brain.
      In the fimbria, the highest values of binding were seen at PND1, but binding also
      completely disappeared in the adult brain, whereas in the anterior commissure,
      specific binding at PND1 and PND5 was lesser than that observed at GD21 and,
      particularly, in adulthood. CB(1) receptor mRNA expression was not detected in
      these white matter areas, thus dismissing the possible presence of these
      receptors in glial cells rather than in neuronal axons. However, mRNA expression
      was detected in the brainstem, an area also rich in white matter, and it mostly
      correlated with receptor binding, exhibiting a progressive decrease from GD21 up
      to adulthood. CB(1) receptor mRNA expression was also detected at GD21 in
      atypical areas where binding was not detected. These areas are proliferative
      regions, such as the subventricular zones of the neocortex, striatum, and nucleus
      accumbens. This atypical location only persisted at PND1 and PND5 in the striatal
      subventricular zone, but disappeared in the adult brain. We also found measurable
      levels of different endogenous cannabinoids in the developing brain. High levels
      of 2-AG, comparable to those found in the adult brain, were measured at GD21,
      whereas significantly lower levels were measured for anandamide and NAPE at this
      fetal age compared with the levels found in the adult brain. Levels of anandamide
      and NAPE increased during the early postnatal period until reaching the maximum
      in the adult brain. By contrast, 2-AG levels peaked at PND1, with values
      approximately twofold higher than those found at the other ages. In summary, all
      these data demonstrate that the endogenous cannabinoid system, constituted by
      endogenous ligands and receptor signaling pathways, is present in the developing
      brain, which suggests a possible specific role of this system in key processes of
      neural development. (c) 1999 Wiley-Liss, Inc.

PMID- 10420167
TI  - Glycine-immunoreactive synaptic terminals in the nucleus tractus solitarii of the
      cat: ultrastructure and relationship to GABA-immunoreactive terminals.
AB  - Postembedding immunogold labeling methods applied to ultrathin and semithin
      sections of cat dorsomedial medulla showed that neuronal perikarya, dendrites,
      myelinated and nonmyelinated axons, and axon terminals in the nucleus tractus
      solitarii contain glycine immunoreactivity. Light microscopic observations on
      semithin sections revealed that these immunoreactive structures were unevenly
      distributed throughout the entire nucleus. At the electron microscopic level,
      synaptic terminals with high levels of glycine-immunoreactivity, assumed to
      represent those releasing glycine as a neurotransmitter, were discriminated from
      terminals containing low, probably metabolic levels of glycine-immunoreactivity,
      by a quantitative analysis method. This compared the immunolabeling of randomly
      sampled terminals with a reference level of labeling derived from sampling the
      perikarya of dorsal vagal neurones. The vast majority of these "glycinergic"
      terminals contained pleomorphic vesicles, formed symmetrical synaptic active
      zones, and targeted dendrites. They appeared to be more numerous in areas of the
      nucleus tractus solitarii adjoining the tractus solitarius, but rather scarce
      caudally, medially, ventrally, and in the dorsal motor vagal nucleus. In a random
      analysis of the entire nucleus tractus solitarii, 26.2% of sampled terminals were
      found to qualify as glycine-immunoreactive. In contrast, boutons immunoreactive
      for gamma-aminobutyric acid (GABA) were more evenly distributed throughout the
      dorsal vagal complex and accounted for 33.7% of the synaptic terminals sampled. A
      comparison of serial ultrathin sections suggested three subpopulations of
      synaptic terminals: one containing high levels of both GABA- and glycine
      immunoreactivities (21% of all terminals sampled), one containing only GABA
      immunoreactivity (12.7%), and relatively few terminals (5.2%) that were
      immunoreactive for glycine alone. These results were confirmed by dual labeling
      of sections using gold particles of different sizes. This study reports the first
      analysis of the ultrastructure of glycinergic nerve terminals in the cat dorsal
      vagal complex, and the pattern of coexistence of glycine and GABA observed
      provides an anatomical explanation for our previously reported inhibitory effects
      of glycine and GABA on neurones with cardiovascular and respiratory functions in
      the nucleus tractus solitarii.

PMID- 10420168
TI  - Effects of antihistamines on 3, 4-methylenedioxymethamphetamine-induced depletion
      of serotonin in rats.
AB  - This study investigated the effects of chlorpheniramine (CPA, 10-25 mg/kg),
      diphenhydramine (DIPH, 20 mg/kg), tripelennamine (TRIP, 20 mg/kg), and pyrilamine
      (PYRI, 20 mg/kg) on 3, 4-methylenedioxymethamphetamine (MDMA, 20 mg/kg x 2)
      induced hyperthermia and depletion of indoles in rat brains, on the uptake of
      serotonin and dopamine into rat synaptosomes, on the binding affinity of CPA for
      biogenic amine transporters in the synaptosomes of rat brain, and on the
      scavenging hydroxyl free radicals activity. Rats were treated with two injections
      of MDMA, CPA, DIPH, TRIP, PYRI, and saline, alone or in combination of MDMA with
      one of the antihistamines, 6 h apart and sacrificed 5 days later. Rectal
      temperature was measured prior to and hourly following the drug injections for 13
      h. As compared to saline controls, MDMA increased body temperature and decreased
      levels of indoles, measured by HPLC, in several brain regions of rats. CPA
      attenuated and DIPH had no effect on MDMA-induced hyperthermia, yet both
      attenuated the depletion of indoles, whereas PYRI and TRIP potentiated these
      effects. CPA inhibited the binding of [(3)H]paroxetine and [(3)H]nisoxetine to
      the synaptosomes of cerebral cortex and of [(3)H]win 35,428 to the synaptosomes
      of striatum. CPA, DIPH, TRIP, and PYRI inhibited [(3)H]serotonin uptake. CPA,
      PYRI, and TRIP, but not DIPH, scavenge hydroxyl radicals. Possible mechanisms of
      the different effects of the antihistamines on MDMA-induced hyperthermia and
      depletion of serotonin are discussed. Published 1999 Wiley-Liss, Inc.

PMID- 10420169
TI  - Afferents from rat temporal cortex synapse on lateral amygdala neurons that
      express NMDA and AMPA receptors.
AB  - The lateral nucleus of the amygdala (LA) is a critical component of the circuitry
      through which environmental stimuli are endowed with emotional meaning through
      association with painful or threatening events. Individual cells in LA receive
      convergent input from auditory processing areas in the thalamus and cortex, and
      the excitatory amino-acid L-glutamate (Glu) participates in synaptic transmission
      in both pathways. Previously, we characterized the ultrastructure of pre- and
      postsynaptic processes in the thalamo-amygdala pathway, and showed the relation
      of presynaptic inputs to N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydoxy-5
      methyl-4-isoxazole propionic acid (AMPA) receptor subunits. In the present study,
      we examined the nature of cortico-amygdala synaptic interactions with Glu
      receptors in LA and determined whether they are similar or different from those
      in the thalamo-amygdala pathway. Cortical afferents to the LA were identified by
      anterograde transport of biotinylated-dextran amine (BDA) and postsynaptic sites
      were labeled immunocytochemically using antisera directed against the R1 subunit
      the NMDA receptor, and the R1 and R2/3 subunits of the AMPA receptor. Electron
      microscopy revealed that the vast majority of cortical afferents (99%) synapse
      onto distal dendritic processes and most of these processes (62%) contained at
      least one glutamate receptor subtype. Cortical afferents synapsed on
      approximately the same proportion of immunoreactive targets for each glutamate
      receptor subtype examined. These data provide morphological evidence that
      cortical afferents form direct synaptic contacts with LA neurons that express
      both NMDA and AMPA receptors and are consistent with recent physiological studies
      demonstrating the participation of NMDA and AMPA receptors in cortico-amygdala
      transmission. These results are nearly identical to those obtained in the studies
      of the thalamo-amygdala pathway.

PMID- 10420170
TI  - Multisubtrate mechanism for the inward transport of dopamine by the human
      dopamine transporter expressed in HEK cells and its inhibition by cocaine.
AB  - Rotating disk electrode voltammetry was used to measure the time-resolved inward
      transport of dopamine into human embryonic kidney cells expressing the human
      transporter for dopamine and a kinetic mechanism of transport is hypothesized.
      Dopamine transport in this preparation was highly concentrative, with a 10(6)
      10(7) inward bias, first order in dopamine and the K(m) and V(max) were found to
      be 1.6 microM and 18 pmol/sec x 10(6) cells), respectively. The hDAT turnover was
      estimated to be approximately 18 s(-1) and the second order rate constant of
      association of dopamine with hDAT was approximately 10(7) M(-1)s(-1). Dopamine
      transport was found to have a second order dependence on Na(+) (K(Na)
      approximately 100 mM) and a first order dependence on Cl(-) (K(Cl) approximately
      12 mM). Multisubstrate analyses suggested that hDAT operates with an ordered
      kinetic mechanism in which Na(+) binds first to the transporter protein, dopamine
      second, and Cl(-) last before translocation of dopamine into or across the
      membrane. Cocaine competitively inhibited dopamine transport (reaction order of
      unity and K(i) approximately 0.34 microM) with no discernible effect at the Na(+)
      and Cl(-) binding sites. These results differ from those of previous studies
      conducted in preparations of the striatum and nucleus accumbens. Comparisons of
      the variant results are made and an analysis of the differing apparent kinetic
      mechanisms is presented.

PMID- 10420171
TI  - Discovery of novel peptidic dopamine transporter ligands by screening a
      positional scanning combinatorial hexapeptide library.
AB  - The acute reinforcing effects of cocaine are thought by some to result from
      cocaine binding to the dopamine (DA) transporter, which inhibits DA uptake and
      increases synaptic DA levels in the mesolimbic system. Other data suggest that
      neurotransmitters other than DA contribute to cocaine reinforcement and
      addiction. These considerations illustrate the need to have additional research
      tools with which to test the "DA hypothesis." One strategy is to identify drugs
      which bind to the DA transporter (DAT ligands) but which do not inhibit DA uptake
      as effectively as cocaine. The purpose of the present study was to identify
      members of a novel structural class of DAT ligands and to characterize their
      interactions at the DA transporter. A positional scanning hexapeptide D-amino
      acid library was screened for inhibition of [(125)I]RTI-55 binding to rat caudate
      DA transporters. Based on the results, 12 peptides were synthesized. All 12
      peptides inhibited [(125)I]RTI-55 binding to DA transporters with IC(50) values,
      which ranged from 1.8 microM to 12 microM. The two most potent peptides (TPI-669
      1 and TPI-669-4) were prepared in larger quantities and were characterized
      further for activity at the DAT and 5-HT transporter. Both peptides inhibited DA
      and 5-HT uptake and transporter binding with IC(50)/K(i) values in the low
      micromolar range. In vivo microdialysis studies demonstrated that both peptides
      increase extracellular DA and 5-HT in the nucleus accumbens of rats. These data
      demonstrate that peptides can function as inhibitors of biogenic amine transport.
      Future work will focus on developing more potent and selective peptides.
      Published 1999 Wiley-Liss, Inc.

PMID- 10420172
TI  - Measurement of crystal thickness and crystal tilt from HRTEM images and a way to
      correct for their effects.
AB  - The effects of thickness and tilt angle are studied numerically on experimental
      high-resolution transmission electron microscope (HRTEM) images of a wedge-shaped
      metal oxide crystal. For sufficiently thin and well-aligned crystals, the
      amplitudes and phases of the Fourier transforms of the HRTEM images are
      essentially the same as the crystallographic structure factors. For tilted
      crystals, the changes of amplitudes and phases as a function of increased
      thickness and tilt angle can be described by a simple model. A method is
      presented by which the local thickness can be determined from one HRTEM image and
      one convergent-beam electron diffraction pattern from the same crystal. It is
      also shown how the projected potential can be reconstructed from HRTEM images of
      tilted crystals, disclosing the crystal structure, even from quite thick (>20 nm)
      samples.

PMID- 10420173
TI  - Electron crystallography in surface structure analysis.
AB  - Surface structure analysis is an important area of research, and in recent years
      notable advances have been made in this field, both in improved techniques for
      studying surfaces and in methods of analyzing them. This review aims to summarize
      the techniques available, particularly those relating to electron microscopy, and
      also to outline one of the newest areas of development, the application of direct
      methods to surface structure analysis.

PMID- 10420174
TI  - Electron crystallography and non-linear optics.
AB  - Electron crystallography can be used to obtain specific information about
      molecular parameters such as the polarisability, dipole moment, and
      hyperpolarisability. In this, work we show how a combination of quantum mechanics
      and simulation methods can be used to solve several unknown organic structures
      and how the calculated molecular parameters can be used to predict the
      corresponding physical properties of the crystals.

PMID- 10420175
TI  - On the phase problem in electron microscopy: the relationship between structure
      factors, exit waves, and HREM images.
AB  - In electron microscopy, the word phase is used for different physical phenomena,
      including crystallographic structure-factor phases and the electron wave phases.
      This has resulted in great confusion, as to whether the phase information is
      present or lost when an image is recorded. The aim of this paper is to solve this
      phase confusion problem by studying the relationships between structure factors,
      exit waves, and high-resolution electron microscopy (HREM) images. Three
      approaches are taken. First phases at different stages of the imaging processes
      are compared analytically for a crystal that can be considered a weak phase
      object (WPO). Then these different phases are calculated by the multi-slice
      method based on dynamical diffraction theory, and their numerical values are
      compared. Finally, the validity of the theoretical description is checked by
      comparison with experimental data on a real crystal, Ti(2)S. It is demonstrated
      that it is possible to obtain accurate structure factor-phases directly from HREM
      images by crystallographic image processing. The two major methods for structure
      determination from HREM images-exit wave reconstruction and crystallographic
      image processing-are compared. It is shown that the information utilised by the
      two methods as well as the results are essentially the same.

PMID- 10420176
TI  - Accurate structure refinement and measurement of crystal charge distribution
      using convergent beam electron diffraction.
AB  - The method for accurate structure refinement from energy-filtered convergent-beam
      electron diffraction (CBED) patterns is described with emphasis on recent
      progress in using imaging filters and 2-D detectors. Details are given about the
      underlying theoretical model and the statistical analysis of experimental data.
      The relationship between crystal potential and charge density is also derived for
      crystals at thermal equilibrium. The method is applied to the refinement of Si
      (111) and (222) structure factors using various goodness-of-fit (GOF) criteria.
      Results show that the refinement method is robust and highly accurate. The
      importance of the experimentally measured structure factors is illustrated
      through the study of the charge density in MgO. With the measured structure
      factors, it is possible to obtain details about the charge redistribution due to
      crystal bonding.

PMID- 10420177
TI  - Cryoprecipitate: An autologous substrate for human fetal retinal pigment
      epithelium.
AB  - PURPOSE: To harvest thin membranes from cryoprecipitates isolated from human
      blood donors and utilize them as substrates for the adhesion of human fetal
      retinal pigment epithelial (HFRPE) cells. METHODS: Frozen human cryoprecipitates
      from anonymous blood donors were obtained from the blood bank. Thin cryo
      membranes were harvested by their mixture with riboflavin-5-phosphate (R5P) and
      overnight exposure to ultra-violet light. Sheets of retinal pigment epithelium
      (RPE) were isolated from fetal eyes at 17-22 weeks gestational age. The sheets
      were subsequently attached to cryo-membranes. The morphology of the cells was
      examined with phase contrast and electron microscope. Cell proliferation was
      evaluated by their incorporation of 5-bromo-2'-deoxyuridine (BrdU). Functional
      viability was assessed by rod outer segment (ROS) phagocytosis. RESULTS: Thin
      membrane films were made from isolated human cryoprecipitates. Isolated sheets of
      pure HFRPE cells were attached to the membranes. The cells maintained their
      cuboidal morphology and did not dedifferentiate. The cells subsequently
      proliferated and migrated onto the culture plate, forming cellular monolayers.
      The cultured cells phagocytized isolated ROS. CONCLUSIONS: Cryoprecipitate
      membranes may provide an ideal source for the adhesion, cultivation, and transfer
      of HFRPE cells. Their autologous isolation from the recipient's blood grants an
      additional advantage for their application as a carrier for HFRPE transplantation
      into the subretinal space.

PMID- 10420178
TI  - Ultrastructural evidence of mucus in human conjunctival epithelial cultures.
AB  - PURPOSE: To demonstrate by ultrastructural techniques that human conjunctival
      epithelium cells in vitro can produce mucin-like secretion. METHODS: Primary
      cultures of human conjunctival epithelial cells were grown in different culture
      media. Cultures were allowed to grow and were processed after 5 days and 1, 2, 3,
      4, or 5 weeks for transmission and scanning electron microscopy, according to the
      method of Nichols et al. modified in our laboratory. RESULTS: Marked differences
      were seen between primary cultures grown with or without hydrocortisone. A thick
      tannic acid-stained layer was observed when hydrocortisone was present in the
      culture medium; however, that layer was virtually absent in cultures grown with
      hydrocortisone-free media. Scanning electron microscopy revealed a dense deposit
      showing a network-like structure. Moreover, the age of the cultures clearly
      influenced the thickness of the tannic acid-stained deposit, which thickened as
      the cultures aged. CONCLUSIONS: These results strongly suggest that the layer
      growing in the presence of hydrocortisone is mucus. The fact that this material
      became more abundant as the cultures aged indicates that mucus is actively
      produced and secreted by conjunctival epithelial cells in vitro. This study might
      contribute to the knowledge of mucus-deficient pathologies of the ocular surface.

PMID- 10420179
TI  - Human corneal epithelial cell adhesion to laminins.
AB  - PURPOSE: To analyze alpha-integrin mediated adhesion of human corneal epithelial
      cells to placental and EHS laminin isoforms. METHODS: Western blot analysis was
      used to partially characterize commercially available preparations of laminin
      isolated from the mouse EHS sarcoma and from human placenta. Using the human
      corneal epithelial cell line HCE-T, adhesion to laminin isoforms and fibronectin
      was determined using a colorimetric adhesion assay. alpha-integrin sub-unit
      modulation of corneal epithelial cell interaction with laminin isoforms was
      analyzed using immunofluorescence microscopy and adhesion assays incorporating
      functional blocking antibodies. RESULTS: In short-term adhesion assays, the
      preferred substrate for HCE-T attachment is placental laminin. Immunofluorescence
      microscopy reveals that alpha-integrin protein localization patterns are not
      significantly different in HCE-T interacting with EHS or placental laminin.
      However, in short-term assays alpha3 integrin plays a major role, and alpha2
      integrin a minor role, in mediating HCE-T adhesion to laminin. alpha6 integrin
      does not appear to mediate adhesion to either substrate. CONCLUSIONS: These
      studies demonstrate that human corneal epithelial cells are capable of rapid
      adhesion to, and enhanced spreading on, laminin isoforms not characteristically
      resident in the adult corneal basement membrane. This characteristic of human
      corneal epithelium may explain, at least in part, why amniotic membrane
      transplantation is proving to be clinically useful for human ocular surface
      reconstruction.

PMID- 10420180
TI  - Heme oxygenase-1 gene expression as a stress index to ocular irritation.
AB  - PURPOSE: Predicting the toxic potential of compounds to the ocular surface has
      depended on the Draize test for the past half century. Alternatives to Draize
      testing have recently been sought for a number of reasons. Stress gene expression
      has emerged as a means of quantifying cellular reaction and, thus, the toxic
      potential of the compound in question. This study examines the expression of the
      major stress response gene heme oxygenase-1 (HO-1) in a human corneal epithelial
      cell line (HCE-T) following challenges with a number of known ocular irritants.
      METHODS: HCE-T was used to investigate the effect of ocular irritants on cell
      viability and HO-1 expression. Irritants tested included hydrogen peroxide,
      isopropyl alcohol, sodium hydroxide and trichloroacetic acid. HCE-T cells were
      grown to 80% confluency and treated with the listed irritants at a concentration
      range of 10-100 microM. Cell viability and northern blot analysis were performed
      following a 24 and 48 hr incubation period. RESULTS: HCE-T cells expressed HO-1
      mRNA and HO activity similar to other human cell lines. Northern blot analysis
      demonstrated that levels of HO-1 mRNA transcripts increased regularly after
      exposure to the irritants in a concentration-dependent manner. Studies on the
      effect of various inhibitors and inducers of HO-1 on cell viability showed that
      inhibition of HO-1 potentiates the cytotoxic effect of ocular irritants. In
      contrast, pre-induction of HO-1 in HCE-T decreases the effect of various
      irritants on cell viability. CONCLUSIONS: These results are consistent with the
      idea that HO-1 mRNA levels may be used as an indicator of toxicity resulting from
      ocular irritants and that HCE-T cells respond to stress in a fashion similar to
      other human cell lines. This strategy for testing may be important in the
      development of an alternative to Draize testing. The results of this study also
      suggest that HO-1 may constitute a part of the protective defense mechanism
      against chemical injury.

PMID- 10420181
TI  - The influence of retinal detachment surgery on perioperative blood fibrinolysis.
AB  - PURPOSE: To evaluate perioperative changes in fibrinolysis in patients undergoing
      retinal detachment surgery. MATERIAL: Prospective study of 56 patients (30 male,
      26 female), aged from 19 to 82 (mean: 53, SD = 16.8) years, subjected to retinal
      detachment surgery (encirclement with scleral buckling) performed under general
      anaesthesia. Excluded were patients with vein or arterial disease and with other
      factors which could change evaluated parameters. METHOD: Blood was sampled from
      cubital vein one day before surgery, immediately after induction of anaesthesia
      but before surgery, immediately after the completion of the operation but before
      the termination of anaesthesia and after operation (on the 1(st) and 4(th) day).
      In the citrate plasma of patients studied, tissue plasminogen activator (t-PA),
      plasminogen activator inhibitor type 1 (PAI-1), plasmin-alpha(2)-antiplasmin
      (PAP) complexes, fibrin-fibrinogen degradation products (FDP) and euglobulin
      lysis time (ELT) were measured. RESULTS: In the group studied intraoperative
      values of t-PA Ag, PAP and FDP were significantly higher, PAI-1 Ag concentration
      decreased and ELT was reduced. These results indicate a significant activation of
      fibrinolysis during the retinal detachment surgery. On the first postoperative
      day the fibrinolytic activity was reduced (decrease in t-PA Ag and FDP
      concentration and prolongation of ELT). CONCLUSION: During retinal detachment
      surgery the patients reveal activation of fibrinolysis in systemic circulation.

PMID- 10420182
TI  - Sugars including erythronic and threonic acids in human aqueous humour.
AB  - PURPOSE: Sugars in the aqueous humour of the eye serve both as a source of
      nutrients to the lens and other anterior ocular tissues, and potentially as an
      indicator of waste products from these tissues. In this work we intended to
      measure the levels of sugars in human blood and aqueous humour from cataract
      patients with and without diabetes. After initial results we decided to identify
      an unknown sugar component. METHODS: Sugars were measured by hplc. The unknown
      sugar peak was identified by gas chromatography/mass spectrometry RESULTS: Very
      little fructose and sorbitol were found. Glucose levels were higher in both blood
      and aqueous from diabetic patients. During these analyses we found a major
      component that did not correspond to any sugar reported previously in aqueous
      humour. This was identified as a mixture of threonic and erythronic acids.
      CONCLUSIONS: Glucose levels increase in human aqueous humour in diabetes without
      markedly raised levels of sorbitol or fructose. Erythronic and threonic acids are
      normal components of aqueous humour and blood. They may be derived from glycated
      proteins or from degradation of ascorbic acid.

PMID- 10420183
TI  - Pre-enrichment of modified low density lipoproteins with alpha-tocopherol
      mitigates adverse effects on cultured retinal capillary cells.
AB  - PURPOSE: We determined whether pre-enrichment of low density lipoproteins (LDL)
      with alpha-tocopherol mitigates their adverse effects, following in vitro
      glycation, oxidation or glycoxidation, towards cultured bovine retinal capillary
      endothelial cells (RCEC) and pericytes. METHODS: LDL, while still in plasma
      obtained and pooled from non-diabetic humans, was supplemented in vitro with
      alpha-tocopherol. It was then isolated and modified in vitro by glycation,
      minimal oxidation, and glycoxidation. Bovine RCEC and pericytes were exposed to
      LDL (100mg protein/ ml) for three days. Cell count was determined by cell
      counting, supernatant levels of plasminogen activator inhibitor-1 (PAI-1) and
      endothelin-1 (ET-1) by ELISA, and nitrite levels by spectroscopic colorimetric
      assay. RESULTS: While pre-enrichment of LDL with alpha-tocopherol did not reduce
      the measured extent of lipoprotein modification, it abolished the reduction in
      cell count observed with glycated, oxidized and glycoxidized LDL v. normal LDL.
      Pre-enrichment of LDL with alpha-tocopherol also reduced RCEC supernatant PAI-1
      and ET-1 (corrected for cell counts) and increased RCEC and pericyte-associated
      supernatant nitrite levels: such effects of alpha-tocopherol may inhibit clot
      formation and favor vasodilatation. CONCLUSIONS: Enrichment of LDL with alpha
      tocopherol abolishes adverse effects of glycated, mildly oxidized, and
      glycoxidized LDL on cultured retinal cell count, and mitigates adverse effects on
      modulators of fibrinolysis and vascular tone. Direct evidence is required before
      Vitamin E supplementation is recommended for people with diabetes.

PMID- 10420184
TI  - Glycosaminoglycans in components of the rabbit eye: synthesis and
      characterization.
AB  - PURPOSE: To trace the eye components involved in proteoglycan synthesis and to
      characterize the sulfated glycosaminoglycans which are associated to these
      macromolecules. METHODS: Sodium [(35)S]-sulfate was injected intravitreally and
      the rabbits were killed at different time intervals after the injection. The
      glycosaminoglycans of choroid, ciliary body, cornea, iris, lens capsule, retina
      and sclera were extracted and processed for estimations of their specific
      activities, and for electrophoresis plus autoradiography with or without previous
      treatment with specific enzymes. In addition, methacrylate sections of the eyes
      were analysed by autoradiography. RESULTS: The peak of specific activities of the
      glycosaminoglycans of all eye components occurred at 2 days after the
      intravitreal injection of [( 35)S]-sulfate. The autoradiography of the agarose
      gels revealed three types of glycosaminoglycans, namely, heparan-, chondroitin-
      and dermatan sulfate, only in the retina. The other eye components contained
      heparan sulfate and either chondroitin or dermatan sulfate. Tissue
      autoradiography together with the biochemical techniques contributed to unravel
      the origin of the glycosaminoglycans in the eye components. CONCLUSIONS: The
      results of the present investigation have shown that heparan sulfate, contrasting
      to chondroitin sulfate and dermatan sulfate, is synthesized in all eye components
      studied and that the glycosaminoglycan composition differs according to the
      tissue of origin.

PMID- 10420185
TI  - Differential expression and regulation of TGF-beta1, TGF-beta2, TGF-beta3, TGF
      betaRI, TGF-betaRII and TGF-betaRIII in cultured human corneal, limbal, and
      conjunctival fibroblasts.
AB  - PURPOSE: We have reported that three patterns of cytokine expression are
      potentially involved between epithelia and fibroblasts of the human ocular
      surface. The TGF-beta family is a prototypical fibrogenic cytokine responsible
      for fibroblast activation in wound healing. We investigated how the TGF-beta
      family is differentially expressed and regulated in cultured human corneal,
      limbal and conjunctival fibroblasts. METHODS: Human corneal (HCF), limbal (HLF)
      and conjunctival fibroblast (HJF) were cultured in DMEM-10% FBS until confluence
      and switched to serum-free DMEM-ITS for 48 h before adding 10 ng/ml of each of
      eight cytokines for 4 h in three separate experiments. Total RNA was isolated and
      subjected to Northern hybridization with GAPDH as a control. ELISA was used to
      determine TGF-beta1 and TGF-beta2 proteins in the media. RESULTS: All three
      isoforms of TGF-beta and three types of TGF-betaR were expressed by HCF, HLF and
      HJF. Expression of TGF-beta1 mRNA was strongest and upregulated by the three TGF
      betas in all three types of fibroblast. PDGF-BB and TGF-alpha slightly increased
      TGF-beta1 mRNA. TGF-betas also upregulated TGF-beta3 mRNA in HJF. TGF-betaRI mRNA
      was the only receptor upregulated by TGF-betas. TGF-betaRII and TGF-betaRIII mRNA
      were not regulated by all cytokines tested. CONCLUSIONS: TGF-betas auto-induction
      is the major mechanism upregulating TGF-beta1 expression. Promotion of TGF-beta3
      by the TGF-betas may have a special role in HJF. Differential expression and
      regulation of TGF-betas and TGF-betaRs suggest that each TGF-beta isoform may
      have specific functions in different ocular surface fibroblasts. No cytokine
      tested can downregulate TGF-beta1 and the TGF-betaRs.

PMID- 10420186
TI  - Glucose-mediated regulation of transforming growth factor-beta (TGF-beta) and TGF
      beta receptors in human retinal endothelial cells.
AB  - PURPOSE: Diabetic retinopathy is a micro-angiopathy affecting predominantly small
      vessels of the retina. Clinical trials have demonstrated a strong association
      between tight glucose control and a reduction in the incidence and the severity
      of diabetic retinopathy. Transforming growth factor beta (TGF-beta) is involved
      in the control of endothelial cell proliferation, adhesion, and deposition of
      extracellular matrix, thus TGF-beta may play a role in the control of endothelial
      cell proliferation seen in the disease. We wished to investigate the regulation
      of transforming growth factor beta and its receptors (type I and II) in human
      retinal endothelial cells exposed to a range of glucose concentrations. METHODS:
      Human retinal endothelial cells were isolated from donor eyes, cultured in vitro
      and exposed to a range of glucose concentrations (0-25 mmol/l). TGF-beta protein
      and mRNA levels were determined by ELISA and Northern analysis, respectively. The
      binding affinities and TGF-beta receptor numbers were defined using a binding
      assay. RESULTS: Northern hybridisation and ELISA showed that after 8 hours, the
      level of TGF-beta mRNA and protein was significantly higher at 15mmol/l compared
      to 5, 20 or 25mmol/ l. Binding assays showed that for high glucose (25 mmol/l),
      human retinal endothelial cells express a population of TGF-beta receptors with
      higher affinity for its ligand than at 5 or 15 mmol/l. CONCLUSIONS: These results
      demonstrate that glucose regulates TGF-beta mRNA and protein production and also
      TGF-beta receptor expression in human retinal endothelial cells. Thus, the
      glucose-mediated changes that occur in diabetic patients may expose human retinal
      endothelial cells to potential angiogenic factors which may influence disease
      progression.

PMID- 10420187
TI  - The application of in vivo confocal microscopy and tear LDH measurement in
      assessing corneal response to contact lens and contact lens solutions.
AB  - PURPOSE: To evaluate differences in corneal response to daily wear (DW) of soft
      contact lens (CL) wear with different CL solutions and to assess the ability of
      in vivo confocal microscopy (CM) and tear lactate dehydrogenase (LDH) measurement
      to detect such differences in NZW rabbits. METHODS: Daily treatment of lenses
      consisted of a rub and rinse cleaning, then overnight soak in one of five
      solutions: Sauflon All in One (ALL), Compound A (CoA), OPTI-FREE((R) )Rinsing,
      Disinfecting, and Storage Solution (OPT), ReNu((R)) <?Pub Caret>Multipurpose
      Solution (REN), and UNISOL( (R)) Saline Solution (UNI). Rabbits (4/test group)
      wore 71% H( 2)O/type4 soft lenses approximately 7 hours daily. On days 0, 1, 3
      and 7, slit lamp examination, tear LDH measurement, and in vivo CM were performed
      after removal of lenses. Using in vivo CM, epithelial thickness, epithelial cell
      area, and stromal thickness were measured, both centrally and peripherally.
      RESULTS: Epithelial thickness in ALL, CoA, and UNI-treated eyes showed a
      significant decrease of 15.6%, 13. 3%, and 10.6% (p < 0.05 in all groups),
      centrally, while CoA, OPT, and UNI showed a significant decrease of 9.3%, 7.1%,
      and 4.4% (p < 0. 05 in all groups), peripherally. ALL showed a significant 9.5%
      (p < 0.05) decrease of central cell area, while CoA showed a significant 21.5% (p
      < 0.01) decrease peripherally. UNI demonstrated a significant 3.2% (p < 0.05)
      decrease in central stromal thickness. ALL, CoA, and UNI showed a significant
      increase in LDH level of 152. 1%, 192.1%, and 308.2% (p < 0.05 in all groups) at
      day 3, respectively, but values declined at day 7. Significant changes in basal
      epithelial morphology were also observed with CoA on day 7 on in vivo CM.
      CONCLUSIONS: Overall, lens care solutions in combination with CL wear may
      interact to cause increased epithelial desquamation leading to decreased surface
      cell area and epithelial thickness. The clinical significance of these changes
      will require further investigation. In vivo CM combined with tear LDH assay is a
      quantitative, objective, non-invasive method of assessing CL wear and CL
      disinfecting solution effects on the cornea, and is able to detect differences in
      corneal response to different CL solutions.

PMID- 10420188
TI  - Role of endothelium-derived vasodilators and K(+) channels in ischemic
      vasodilation of guinea-pig choroidal arterioles.
AB  - PURPOSE: To assess the roles of endothelium-derived vasodilators and K(+)
      channels on metabolic ischemia-induced vasodilation from diameter changes in
      choroidal arterioles of the guinea-pig. METHODS: The choroid was isolated from
      the guinea-pig eye-ball, pinned flat on a silicone rubber plate, and superfused
      with oxygenated warmed (35 degrees C) Krebs solution. Diameters of choroidal
      arterioles were measured using video microscopy and a computer program for
      analysis. Vasodilatory effects were examined after the choroid was exposed to
      glucose-free/NaCN solutions for 10 minutes. The effects of Nomega-nitro-L
      arginine (nitroarginine), indomethacin, and K(+)<?Pub Caret> channel inhibitors
      (glibenclamide [Glib] and charybdotoxin [ChTX]) on ischemic vasodilation were
      assessed. RESULTS: Reversible vasodilation was observed when the choroid was
      exposed to glucose-free/NaCN (10(-3) M) solutions. Nitroarginine (10( -4) M),
      Glib (2x10(-5) M) and ChTX (10(-7) M) significantly inhibited glucose-free/NaCN
      (10(-3) M)-induced vasodilation by 47%, 62%, and 24%, respectively. No
      significant inhibitory effect was observed with indomethacin (10(-5) M).
      Simultaneous application of Glib and ChTX reduced vasodilation by 77%. When Glib
      and ChTX were added together to nitroarginine, dilation was reduced by 86%. With
      high K(+) ([K]o = 47.2 mM) Krebs solution, ischemia caused a slight vasodilation
      (11%), which was significantly inhibited by nitroarginine. CONCLUSIONS: In guinea
      pig choroidal arterioles, glucose-free/ NaCN-induced ischemic vasodilation was
      mainly mediated by NO and K(ATP) channels. A part of NO-mediated vasodilation was
      induced independent of the opening of K(+) channels.

PMID- 10420189
TI  - Photoreceptor cell damage by light in young Royal College of Surgeons rats.
AB  - PURPOSE: To determine the effects of genetic background and light rearing
      conditions on intense-light-mediated retinal degeneration in young RCS rats.
      MATERIALS AND METHODS: Albino rats, homozygous or heterozygous for the rdy gene
      were bred and born in dim cyclic light. At P7 they were moved to a dark
      environment, and maintained there until exposure to intense visible (green) light
      at P18 or P25. Other rats remained in the dim cyclic light environment. At
      various times between P11 and P40 rats were killed for determinations of
      rhodopsin and photoreceptor cell DNA levels, western transblot analysis of
      retinal S-antigen (arrestin) and alpha-transducin, or northern slot blot analysis
      of their respective mRNA levels. RESULTS: At P18, unexposed dark maintained
      homozygous RCS rats and their phenotypically normal heterozygous counterparts
      have nearly equivalent rhodopsin levels and photoreceptor cell DNA. Intense light
      exposure at this age, to 8 hours of continuous light or 3 hours of intermittent
      light, did not lead to a loss of either rhodopsin or retinal DNA when compared
      with their respective unexposed controls. At P25 rhodopsin levels were higher
      than at P18, while photoreceptor cell DNA was essentially the same as in the
      younger rats. However, intense light exposure at P25 resulted in substantial
      losses of rhodopsin and photorecptor cell DNA and the losses were greater in
      homozygous rats than in heterozygous animals. Light damage of P25 rats maintained
      in dim cyclic light was essentially the same as in dark maintained homozygous
      rats, but no damage was found in the heterozygous animals. By western analysis,
      alpha-transducin levels in the retina increased with time in darkness, while
      retinal S-antigen levels either remained the same or decreased during the period
      P15-P35. For rats in the cyclic light environment S-antigen expression was
      greater than alpha-transducin at all ages. Slot blot analysis of mRNAs for the
      two proteins generally followed the patterns seen by western analysis. S-antigen
      mRNA was expressed at an earlier age and at higher levels than alpha-transducin
      in both types of rats from both light rearing conditions. Peak expression of S
      antigen most often occurred at P18 in both the heterozygous and homozygous rats.
      CONCLUSIONS: The relative expressions of S-antigen and alpha-transducin in P18
      and P25 rats correlates with their relative resistance to retinal light damage at
      P18 and their enhanced susceptibility at P25. Rats homozygous for the rdy gene
      also exhibit more damage than heterozygous animals when photoreceptor cell DNA is
      used to estimate the extent of retinal light damage.

PMID- 10420190
TI  - Effects of subconjunctival injection of mitomycin-C on iridial circulation in
      rabbits.
AB  - PURPOSE: To determine the effects of a subconjunctival injection of mitomycin-C
      (MMC) on iridial circulation in rabbits. METHODS: Dutch rabbits anesthetized with
      pentobarbital received a 0.2-ml subconjunctival injection of 0.4 mg/ml or 0.1
      mg/ml MMC; the contralateral eye received 0.2 ml physiological saline.
      Intraocular pressure (IOP) and NB( iris), a quantitative index of iridial tissue
      blood velocity, were measured up to 24 hours after treatment. RESULTS: At a
      dosage of 0.4 mg/ml MMC, NB iris obtained from the iridial area adjacent to the
      injection site decreased significantly by 13.6% and 18.6% at 1 and 2 hours (P =
      0.03, 0.01, respectively) after treatment; NB iris obtained on the contralateral
      side of the injection showed no significant change. In eyes treated with 0.1
      mg/ml MMC, NB iris did not change significantly. The mean IOP was significantly
      lower by 3.1, 3.0, and 1.8 mm Hg at 6, 12, and 24 hours after the 0.4 mg/ml
      injection of MMC compared with the fellow eyes (P = 0.03, 0.01, and 0.03,
      respectively), the IOP decreased by 1.7 mm Hg at 4 hours in the eyes treated with
      0.1 mg/ml MMC (P = 0. 04). CONCLUSIONS: Subconjunctival injections of 0.2 ml of
      0.4 mg/ ml MMC caused not only a significant decrease of IOP but also a transient
      but significant effect on iridial circulation.

PMID- 10420191
TI  - Clinical and genetic studies of an autosomal dominant cone-rod dystrophy with
      features of Stargardt disease.
AB  - Cone-rod dystrophy (CORD) and Stargardt disease (STGD) are two hereditary retinal
      dystrophies with similarities to age-related macular degeneration. Cone-rod
      dystrophies are a group of degenerative disorders resulting in decreased visual
      acuity and color vision, attenuated electroretinographic (ERG) responses, and
      atrophic macular lesions. Autosomal dominant, autosomal recessive, and X-linked
      forms of cone-rod dystrophy have been reported. Stargardt disease is
      characterized by reduced visual acuity, atrophic macular changes, prominent
      'flavimaculatus flecks' in the pigment epithelium of the posterior retina, and a
      virtually pathognomic 'dark choroid' pattern on fluorescein angiography.
      Stargardt disease is classically inherited as an autosomal recessive trait,
      although numerous families have been described in which features of Stargardt
      disease are transmitted in an autosomal dominant manner. We have identified a new
      kindred with autosomal dominant cone-rod dystrophy with features of Stargardt
      like disease. Detailed clinical evaluation, genotype analysis, and linkage
      analysis were performed. Fluorescein angiography revealed a 'dark choroid'
      pattern in three affected subjects. Electroretinography disclosed markedly
      reduced scotopic and photopic responses in three affected individuals. Genetic
      analysis revealed linkage to known loci for cone-rod dystrophy (CORD7) and
      Stargardt-like disease (STGD3) on chromosome 6q14. A peak lod score of 3.3 was
      obtained with the marker D6S280 at straight theta =0.010. A physical map was
      constructed by screening a YAC library with short tandem repeat markers in the
      region. Screening of a candidate gene, the rho1 subunit of the GABA receptor,
      failed to reveal any mutations.

PMID- 10420192
TI  - Histopathology and molecular basis of iridogoniodysgenesis syndrome.
AB  - Iridogoniodysgenesis is an autosomal dominant disorder in which there are
      abnormalities in the development of the iris stroma and trabecular meshwork
      tissues commonly resulting in glaucoma. The unoperated eye from an affected
      member of a family with iridogoniodysgenesis syndrome (IGDS) was removed shortly
      after death. Histopathological studies showed an incomplete, normally positioned
      line of Schwalbe and iris stromal hypoplasia. The molecular basis underlying the
      disorder is a missense mutation in the RIEG gene at 4q25, mutations of which have
      been previously shown to cause Axenfeld-Rieger syndrome (ARS). Coupled with
      another report of a missense mutation of the RIEG gene in a family with IGDS, we
      suggest that these mutations may interfere less with gene function and thereby
      may be responsible for a milder phenotype than occurs in the more characteristic
      ARS.

PMID- 10420193
TI  - No missense mutation in choroideremia patients analyzed to date.
AB  - PURPOSE: To elucidate the status of a previously described missense mutation
      (1442A>T) reported in the Rab Escort Protein 1 gene of a patient with
      choroideremia. METHODS: The base substitution previously described by Donnelly et
      al. (Hum Mol Genet 1994;3:1017) was first confirmed by direct genomic DNA
      sequencing. The REP-1 cDNA region encompassing exons 10-14 was then specifically
      amplified from lymphocyte-derived mRNA. The effect on mRNA splicing of the
      mutation was analyzed by RT-PCR and cDNA sequencing. RESULTS: The 1442A>T change
      located at the penultimate nucleotide of exon 11 causes complete skipping of this
      exon during the processing of REP-1 mRNA. Loss of exon 11 leads to the
      translation of a premature termination codon within exon 12. CONCLUSION: RT-PCR
      analyses demonstrated that the 1442A>T transversion previously described as a
      possible causative missense mutation does act as a splice-site error and gives
      rise to a truncated REP-1 protein. The virtual absence of any missense mutation
      found to be responsible for choroideremia makes the RT-PCR-based protein
      truncation test the most relevant genotypic diagnostic procedure for identifying
      mutations in the CHM gene.

PMID- 10420194
TI  - EEM syndrome: report of a family and results of a ten-year follow-up.
AB  - We report on a Brazilian kindred in which two sibs presented with the complete
      form of EEM (ectodermal dysplasia, ectrodactyly, and macular dystrophy) syndrome
      with hypotrichosis, dental anomalies, syndactyly, and retinal changes with
      prominent pigmentation in the posterior pole of the retina. In this family, we
      also observed another sib with syndactyly, as well as a first cousin with
      ectrodactyly. A 10-year follow-up demonstrated gradually decreasing visual acuity
      and progression of retinal degenerative anomalies.

PMID- 10420195
TI  - Presence of bilateral limbal dermoids and choroidal osteomas in a family with
      inherited limbal dermoids.
AB  - We report a case of bilateral limbal dermoids and bilateral choroidal osteomas in
      a 14-year-old girl with no extraocular anomalies. Histopathological examination
      of a limbal lesion confirmed the clinical diagnosis of dermoid. Computerized
      tomography and ultrasonography were compatible with a diagnosis of choroidal
      osteoma. Limbal dermoids were present in the patient's mother, in a brother with
      Down syndrome, and in an aunt with no choroidal osteoma. The present pedigree is
      compatible with autosomal dominant inheritance of bilateral limbal dermoids. The
      same gene may be involved in the pathogenesis of ocular choristomas in same
      patients.

PMID- 10420196
TI  - Visual impairment and REP-1 gene mutations in Japanese choroideremia patients.
AB  - Choroideremia (CHM), an X-linked recessive hereditary disease, is an intractable
      chorioretinal dystrophy. The rate of disease progression of CHM reportedly shows
      considerable variability. A number of mutations involving the gene that codes for
      Rab escort protein-1 (REP-1) have been detected in CHM patients. We have analyzed
      REP-1 gene mutations of Japanese CHM patients. The present study was designed to
      investigate the clinical variability and the genotype to phenotype relationship
      in 15 Japanese CHM patients referred to the Department of Ophthalmology of
      Juntendo University Hospital. The clinical investigation of visual acuity, visual
      field, color vision and refraction revealed inter-individual variability.
      Mutation analyses of the REP-1 gene revealed 10 types of mutations in 13 patients
      from 11 families, including an insertion, small deletions, nonsense mutations and
      an A to CC mutation. In 13 CHM patients with detectable REP-1 gene mutations, no
      relationship of genotype to phenotype was detected. At present, we consider the
      REP-1 genotype to be an unreliable prognostic factor for counseling of CHM
      patients. In two patients from one family, no mutations were detected in coding
      regions of the REP-1 gene. These patients may have intron mutations of the REP-1
      gene, not detectable by the techniques employed in this study, or other causative
      genes. Both were observed to have somewhat slower disease progression than the
      other 13 patients. More advanced analyses are necessary to answer questions
      regarding the genotype-phenotype relationship in CHM patients.

PMID- 10420197
TI  - 1147 del A mutation in the arrestin gene in Japanese patients with Oguchi
      disease.
AB  - We examined the sequence of the arrestin gene in two unrelated patients with
      Oguchi disease. A 35-year-old woman and a 72-year-old man underwent a complete
      ophthalmological examination, including evaluation of visual acuity and color
      vision, fundus examination, and electroretinography. A golden-yellow
      discoloration was observed in their fundi. After 30 minutes of dark adaptation,
      the discoloration in the fundus disappeared. A deletion of an adenine in codon
      309 of exon 11 of the arrestin gene was identified in both patients. Mutations in
      the arrestin are common in Japanese patients with Oguchi disease.

PMID- 10420198
TI  - Retinal degeneration associated with ectopia lentis.
AB  - Two brothers had retinal degeneration, lens subluxation, and myopia since early
      life. There was no evidence of Marfan syndrome, homocystinuria, or other systemic
      disease. They had nystagmus, myopia, inferior dislocation of the lens, and
      posterior subcapsular opacities in both eyes. Fundus examination showed
      attenuated retinal vessels, macular atrophy with occasional pigment accumulation
      as clumps, and perivascular sleeves. Electroretinography revealed decreased
      photopic and scotopic responses. The visual fields were constricted. We believe
      this to be the first report of retinal degeneration with bilateral lens
      subluxation in a family. It appears to be inherited in an autosomal recessive
      fashion.

PMID- 10420199
TI  - Retinitis pigmentosa, mental retardation, marked short stature, and brachydactyly
      in two sibs.
AB  - We present two siblings with retinitis pigmentosa, mental retardation, markedly
      short stature, and brachydactyly. This association of clinical findings appears
      to be distinct from previously described syndromes and seems to represent the
      pleiotropic effects of a single autosomal recessive gene.

PMID- 10420200
TI  - Tear secretory IgA: evaluation of usefulness as a diagnostic marker in herpetic
      keratitis.
AB  - In a South Indian study, an 'in-house' enzyme-linked immunosorbent assay (ELISA)
      was developed to evaluate the potential of herpes simplex virus (HSV)-specific
      tear secretory IgA (sIgA) in the diagnosis of herpes simplex keratitis (HSK). The
      presence of HSV-specific tear sIgA was found to be diagnostic in 20.28% of cases.
      The usefulness of the sIgA ELISA system was evaluated against HSV isolation,
      which is the 'gold standard' and HSV antigen detection, a more sensitive,
      commonly employed method. Analysis of HSV-specific IgG and IgM results showed
      their failure as reliable indicators of active or ongoing infection. Comparison
      of sIgA ELISA with culture as 'gold standard' showed its sensitivity,
      specificity, and positive and negative predictive values to be 60% (95% CI 36.4
      80), 93.2% (95% CI 86.7-96.8), 60% (95% CI 36.4-80), and 93.2% (95% CI 86.7-96.
      8), respectively. This study is the first report on the complete evaluation of
      the usefulness of tear anti-HSV sIgA in the laboratory diagnosis of HSK, taking
      into account both epithelial and stromal keratitis cases.

PMID- 10420201
TI  - Behcet's disease and antibody titers to various heat-shock protein 60s.
AB  - It has been suggested that the 65 kDa heat-shock protein (HSP) of Streptococcus
      in recurrent aphthae within the oral cavity may be involved in the uveoretinitis
      of Behcet's disease, possibly through sensitization of the immune system. To
      investigate this possibility, we examined serum antibody titers for various
      members of the 60 kDa family of HSPs and their implications with regard to a role
      for HSP60s in Behcet's disease. We isolated HSP60 of Streptococcus pyogenes from
      the margin of oral aphthae in one Behcet's disease patient with severe
      uveoretinitis and the HSP60s of Yersinia enterocolitica, retinoblastoma cell line
      clone Y79, and bovine retinal extract and investigated the reaction of each of
      these HSP60s with 100-fold diluted serum samples from 20 Behcet's disease
      patients using anti-HSP60 antibody titers determined by ELISA. The anti-
      Streptococcus HSP60 antibody and anti-retinal HSP60 antibody titers of the 100
      fold diluted serum samples from the Behcet's disease patients were both
      significantly higher than those of similarly diluted serum samples from healthy
      donors. The results of the ELISA antibody titer assay showed that, although the
      various HSP60s share a common basic antigenicity, they differed in reactivity to
      the anti-HSP60 antibodies in the sera of the Behcet's disease patients. The
      results indicate that subtle but significant differences exist in the
      antigenicity of the various HSP60s tested, all of which share a common basic
      antigenicity and are of approximately the same molecular weight, and suggest that
      an immuno-cross-reaction between retinal and streptococcal HSPs and a related
      autoimmune response may be involved in the development of Behcet's disease.

PMID- 10420202
TI  - Interleukin 6 and its soluble receptor are elevated in aqueous humor of patients
      with uveitis.
AB  - PURPOSE: To determine the levels of interleukin 6 (IL-6) and its soluble receptor
      (sIL-6R) in the aqueous humor (AH) of patients with different uveitis entities.
      PATIENTS AND METHODS: AH and serum samples were collected from 35 patients (39
      eyes) who underwent surgery for uveitis complications and from 10 controls
      (senile cataract). In the studied group, seven patients had HLA-B27(+) anterior
      uveitis, two had Fuchs' heterochromic iridocyclitis, 12 had chronic anterior
      uveitis of unknown etiology, and in the remaining 14 the causative agent was
      exogenous. The cytokine and receptor levels were measured by enzyme-linked
      immunosorbent assay (ELISA). RESULTS: In controls, the median IL-6 level in AH
      was higher than that in corresponding sera (40.4 pg/ml and 5.2 pg/ml,
      respectively). In contrast, sIL-6R showed an inverse relation: there were less
      sIL-6R in control AH than in control sera (378.9 pg/ml and 52749.0 pg/ml,
      respectively). The same qualitative relationship was observed in patients with
      uveitis. Quantitatively, in comparison to controls, elevated levels of IL-6 and
      sIL-6R were found in AH of patients with uveitis. As expected, the maximal IL-6
      and sIL-6R values were observed in the patients with uveitis of exogenous
      etiology (1558.3 and 1326.2 pg/ml, respectively). sIL-6R was also significantly
      elevated in AH of patients with HLA-B27( +) anterior uveitis (p<0. 01). In all
      individuals under study, sIL-6R levels in AH samples were 2-10 times higher than
      IL-6 levels. In serum samples, sIL-6R level were 10000 times higher than
      corresponding IL-6 values. CONCLUSION: The results confirmed the role of IL-6 in
      intraocular inflammation and gave new information regarding the presence of its
      sR in normal and inflamed eyes. Low levels of sIL-6R in AH compared to those
      found in serum suggest the presence of active local regulatory mechanisms that
      require further investigation.

PMID- 10420203
TI  - Posterior segment inflammation in HLA-B27+ acute anterior uveitis: clinical
      characteristics.
AB  - PURPOSE: To examine clinical characteristics of patients who have posterior
      segment manifestations in HLA-B27-associated acute anterior uveitis. METHODS:
      Medical records of 114 HLA-B27-positive patients with acute anterior uveitis were
      reviewed in a retrospective fashion. Criteria for inclusion were the presence of
      acute anterior uveitis, a positive HLA-B27 antigen, and one of the following
      findings: vitreous cells >/=+2; cystoid macular edema; papillitis; vasculitis; or
      pars plana exudates. Twenty-four patients met the inclusion criteria. RESULTS:
      Posterior segment manifestations were found in 24 (21.05%) of 114 patients with
      HLA-B27+ acute anterior uveitis. Eighteen patients had diffuse vitritis (75%),
      seven had cystoid macular edema (29.1%), and two had papillitis (8.3%). Three
      patients had more than one finding. The prevalence of associated systemic disease
      (15 of 24 patients, 62.5%) and hypopyon (6 of 24 patients, 25%) in patients with
      posterior segment involvement was significantly higher than in the group of
      patients without posterior segment involvement (systemic disease, 33 of 90,
      36.7%, p=0.04, exact chi-quare test; hypopyon, 4 of 90, 4.4%, p=0.006, exact chi
      square test). The mean visual acuity at the last visit was 20/30 (range 20/20
      20/100). Immunosuppressive therapy (other than corticosteroids) and surgical
      intervention were not required in the treatment of patients with posterior
      segment manifestations. CONCLUSION<?Pub Caret>: HLA-B27+ anterior uveitis is
      associated with posterior segment manifestations. Patients with posterior segment
      involvement have a significantly higher incidence of associated systemic diseases
      and hypopyon.

PMID- 10420204
TI  - Punctate outer retinal toxoplasmosis in an HIV-positive child.
AB  - PURPOSE: To discover whether the outer layer of the retina can be the site for
      toxoplasmosis in AIDS patients. METHODS: An HIV-positive child, who previously
      had a normal ocular examination, was reexamined three months later. This
      examination showed outer retinal lesions compatible with toxoplasmosis and
      positive IgM and IgG titers specific for that organism, despite the small drop in
      the CD4 count. RESULTS: During the first examination, the antibodies for
      toxoplasmosis were negative. At the three-months follow-up, the anti
      toxoplasmosis antibodies were positive and the rest of the workup was negative,
      suggesting a strong correlation with the patient's fundus pattern. CONCLUSION: We
      describe a case of punctate outer retinal toxoplasmosis uveitis, which has been
      previously associated with immunocompetent hosts. We, however, believe that it
      can be seen in immunocompromised patients as well.

PMID- 10420206
TI  - Does trabeculectomy influence the course of uveitis?
AB  - It was our clinical impression that patients with uveitis who had undergone
      trabeculectomy had an improvement in their intraocular inflammation following
      surgery. We undertook a retrospective review of the notes of all patients who
      underwent unaugmented trabeculectomy for uncontrolled intraocular pressure
      secondary to uveitis between September 1990-July 1994, at the Uveitis Service of
      the Birmingham and Midland Eye Centre, UK. The severity of the inflammation and
      the number of relapses post-trabeculectomy were compared to those during the pre
      trabeculectomy period. A total of 32 eyes of 20 patients with various types of
      uveitis were included in the study. Mean age was 40 years (SD+/-2.5), range: 14
      67 years, median follow-up of 53 months (SE+/-1.8), range: 33-84 months. An
      improvement in the pattern of uveitis post-trabeculectomy, defined as reduction
      in the severity of the inflammation and the number of relapses, was seen in 23
      out of 32 (71.9%) eyes. Furthermore, five out of 15 patients in this group had
      either their systemic treatment stopped or the number of systemic agents reduced.
      Another five eyes (15.6%) showed no change in the pattern of uveitis. The
      remaining four eyes (12.5%) suffered an increase in the number of relapses or
      increased severity of inflammation requiring additional treatment. It appears
      that trabeculectomy may have a beneficial effect on the course of uveitis. The
      mechanism for this is not clear.

PMID- 10420205
TI  - Progressive changes in the fluorescein and indocyanine green angiogram in acute
      idiopathic maculopathy.
AB  - AIMS/BACKGROUND: To report progressive changes in the fluorescein and indocyanine
      green angiograms of a patient with acute idiopathic maculopathy (AIM). METHODS:
      Over a two-year period, the patient underwent repeated ophthalmoscopic
      examinations and fluorescein (FA) and indocyanine green (ICG) angiography.
      RESULTS: The patient presented with subretinal neovascularization in his right
      eye. He developed recurrences after laser photocoagulation and surgical removal
      of the neovascular complex. One year later, he experienced a sudden loss of
      vision in his left eye with a maculopathy consistent with AIM. The maculopathy
      resolved after two weeks with poor vision. During the acute stage, FA showed
      lobular hyperfluorescence in the early phase and pooling in the late phase of the
      angiogram. In the resolved stage of the disease, FA showed irregular window
      defects and blockage. ICG revealed late hyperfluorescence of the macula in the
      acute stage. In the resolved stage of the disease, early hypofluorescence was
      noted in the ICG, which persisted throughout the late phase. CONCLUSION: This
      patient had poor vision in his right eye as a result of subretinal retinal
      neovascularization and poor vision in his left eye from a severe form of AIM. FA
      and ICG differed markedly during the acute and resolved stages of AIM. All cases
      of idiopathic subretinal neovascularization should be carefully evaluated to
      exclude AIM as the primary disease.

PMID- 10420207
TI  - Leptospirosis.
AB  - Leptospirosis, a waterborne spirochetal illness, is common in tropical climates.
      Rodents and wild animals are the most common reservoirs for this widespread
      zoonosis. Human disease is acquired by contact with urine or tissues of an
      infected animal or through contaminated water and soil. Systemic leptospirosis is
      characterized by its multisystem involvement, protean manifestation, and varying
      severity. The clinical presentation ranges from occult infection to fatal
      complications like hepatorenal failure. Early diagnosis is important to halt the
      fulminate course. The microagglutination test is considered the gold standard
      serological test for leptospirosis, although molecular techniques are now under
      study. Treatment of systemic leptospirosis includes penicillin or tetracycline in
      addition to supportive treatment. Ocular involvement occurs during the
      immunological phase of the disease. One or both eyes may be involved, typically
      with a panuveitis often accompanied by retinal periphlebitis and hypopyon. In
      general, leptospiral uveitis has a good prognosis and the patient recovers full
      vision in spite of severe panuveal inflammation. Awareness of this infectious
      uveitic entity is essential not only in order to differentiate it from other
      severe autoimmune uveitides, but also to reduce the percentage of idiopathic
      uveitis in endemic areas.

PMID- 10420208
TI  - Epidemiology of eye injuries in rural Tanzania.
AB  - In the developing world, ocular trauma is an important cause of monocular
      blindness. However, little is known about the epidemiology of eye injuries in
      rural Africa. This study presents five- year data on hospitalized ocular injuries
      in a rural region in Tanzania. Data were collected from Mvumi Hospital, a
      tertiary hospital serving rural Dodoma, and the only hospital during this time
      period able to care for serious trauma. All in-patient charts from January 1,
      1985 to December 31, 1989 were reviewed for cases of ocular trauma who presented
      within 30 days of injury. Data on demographics, cause of injury, visual acuity,
      and current diagnosis were abstracted. A total of 157 cases were recorded, of
      whom 69% were male. A third of the injuries occurred in those less than age 20.
      Injury with a stick was the most common cause, accounting for 67% of the cases. A
      third of the cases presented to the hospital 8 or more days after the injury, and
      most had poor visual acuity in the affected eye. In those age 20 or younger, 82%
      of females and 67% of males presented with visual acuity <3/60. Ruptured globe
      and uveitis were the most common diagnosis made at presentation. Preventive
      ophthalmology efforts in this area should focus on decreasing stick-related
      ocular injuries and improving rapid access to appropriate care when injuries
      occur.

PMID- 10420209
TI  - Prevalence and incidence of age-related cataract in a population sample from
      Priverno, Italy.
AB  - PURPOSE: To study the prevalence and incidence of age-related cataract in a
      random population sample from the town of Priverno in the Lazio Region, Italy.
      METHODS: In 1987, 860 people between the ages of 45 and 69 years, already
      participating in a study on cardiovascular risk factors, underwent an
      ophthalmological examination. Patients with lens opacities, assessed by a
      clinical biomicroscopy and a best-corrected VA equal to or worse than 0.2 LogMar
      (20/30), were defined as age-related cataract cases. Of the 828 patients without
      age-related cataract at the baseline, 602 were re-examined in 1994. The 7-year
      Cumulative Incidence was calculated in three ways, as follows: - referring to the
      baseline sample without age-related cataract; - referring to the follow-up sample
      without age-related cataract at baseline; and - adjusted for non-response to the
      follow-up. RESULTS: In the baseline sample, the prevalence of age-related
      cataract was 3.7% (2.7%-5.2%, 95% C.I.). Cumulative Incidence referring to the
      baseline sample was 6.5% (4. 8%-8.2%, 95% C.I.); Cumulative Incidence referring
      to the follow-up sample was 9.0% (6.7%-11.3%, 95% C.I.). Adjusted Cumulative
      Incidence of age-related cataract was 7.6% (5.6%-9.5%, 95% C.I.). CONCLUSIONS:
      The study suggests that, in the Priverno sample, aging, but not gender, is a very
      important risk factor for cataract. The authors conclude that more information is
      needed on incidence of age-related cataract needing surgical rehabilitation and
      on risk factors causing both progression of lens opacities and visual loss.

PMID- 10420210
TI  - The role of past intake of vitamin E in early cataract changes.
AB  - PURPOSE: We examined the association between prior supplementation of vitamin E
      and early cataract changes in volunteers currently enrolled in the cross
      sectional VECAT study. The Vitamin E and Cataract Prevention Study (VECAT) is a
      clinical trial currently in progress, designed to assess the affect of vitamin E
      supplementation on the development and progression of cataract and age-related
      macular degeneration. METHODS: A history of vitamin E supplementation was
      ascertained through a self-administered questionnaire that was mailed to each of
      the 1,111 participants who were enrolled at the time in the prospective VECAT
      Study. RESULTS: With a 99% response rate, we found that 26% of participants
      reported prior supplementation of vitamin E. Only 8.8% of these participants took
      supplementation greater than the recommended daily intake (RDI) of 10 mg/day. Of
      these 26%, 57% took supplementation in the form of multivitamins as opposed to a
      vitamin E supplement on its own. The range of supplement intake ranged from as
      little as 0.1 mg/day to a maximum of 55 mg/day. A statistically significant
      association was found between prior supplementation and the absence of cortical
      opacity (OR = 0.47, 95%CI = 0.28-0.83), after adjusting for age. The levels of
      nuclear opacity (NO) were not statistically different between those who reported
      intake and those with no prior vitamin E supplementation. CONCLUSION: Prior
      vitamin E supplementation may protect VECAT participants from developing at least
      early cortical cataracts. No apparent protective role in terms of nuclear
      opacities and nuclear color was found regardless of the level, regularity or
      duration of intake.

PMID- 10420211
TI  - Optimization of a university cataract-patient care service in Campinas, Brazil.
AB  - PURPOSE: To show the results of operational research techniques applied to the
      cataract service of a public university hospital in Brazil. METHODS: Using a
      heuristic approach for operational research, a study was designed to evaluate,
      develop solutions, and validate the implemented modifications to optimize service
      performance. RESULTS: Following implementation of the solutions and
      modifications, 24.9% more patients were examined and 39.9% more cataract surgery
      was performed than during a similar period prior to implementation. Solutions
      were provided by group discussion among service professionals and based on common
      sense, possibility of prompt implementation, and the use of available resources
      and fixed costs. CONCLUSION: The results of this study show the importance of
      operational research to a public cataract service wishing to improve its
      performance with simple and efficient solutions.

PMID- 10420212
TI  - Do age-related macular degeneration and cardiovascular disease share common
      antecedents?
AB  - Age-related macular degeneration (AMD) is the leading cause of irreversible
      vision loss and blindness in elderly Americans. The etiology of this condition
      remains unknown and treatment options are limited. Some epidemiological findings
      point to a cardiovascular risk profile among persons with AMD. Documented risk
      factors for cardiovascular disease (such as age, smoking, hypertension,
      hypercholesterolemia, post-menopausal estrogen use, diabetes, and dietary intake
      of fats, alcohol and antioxidants) have also been associated with AMD in some
      studies. This raises the possibility that the causal pathways for cardiovascular
      disease and AMD may share similar risk factors. Future research on this
      hypothesis could lead to important insights into etiologic factors for AMD.
      Research could also identify modifiable risk factors and suggest new treatment
      options which could prevent AMD, slow its progression, or reduce visual loss.
      Susceptible individuals could then be targeted for improved health promotion and
      disease prevention measures for this disabling and highly prevalent disorder.

PMID- 10420213
TI  - Assessment of contrast sensitivity in children aged 3 years 9 months - 6 years
      with normal vision, visual impairment due to ocular disease and strabismic
      amblyopia.
AB  - The contrast sensitivity function was assessed in children and adults with normal
      vision, visual impairment due to ocular disease, and strabismic amblyopia. The
      methods used were: the LH contrast vision test and the ability to detect raisins,
      puffed rice and white and black sugar strands against a white and black
      background. The aim of the study was to see whether any of the tests could be
      used in the detection of subnormal vision, and to compare the results between the
      different groups of patients. The following parameters of contrast sensitivity
      function (CSF) were measured with the LH-test: the maximum contrast sensitivity,
      the total area of CSF, and the area of 8 spatial frequency bands. Difficulty in
      detecting an object with low versus high contrast was measured with the sugar
      strands. Subjects with subnormal vision due to ocular disease and strabismic
      amblyopia had lower contrast sensitivity than subjects with normal vision
      measured as the total area of the CSF or the area of a specific frequency band.
      However, the maximum contrast sensitivity value that could be measured with the
      test was not significantly different between the groups. No subject had
      difficulties in the detection of raisins and puffed rice on a white and black
      background. Difficulties in detecting sugar strands on a white background were
      not seen in the normal children, but approximately 65% of the children with
      visual impairment had difficulties, as did approximately 25% of the children and
      adults with strabismus. Most of these subjects also had low visual acuity, but
      there was no correlation between the level of reduction of visual acuity and the
      difficulty in detecting sugar strands.

PMID- 10420214
TI  - Infantile esotropia in very low birth weight (VLBW) children.
AB  - VLBW children are known to have a high frequency of early onset strabismus, which
      is related to the high prevalence of pre- and perinatal cerebral disturbances
      reported in these children. It is unknown if the early onset strabismus in VLBW
      children has the characteristics of infantile esotropia. If so, then (acquired)
      cerebral damage may play an important role in the origin of this type of
      strabismus. For this reason, the charts of 265 VLBW children were retrospectively
      reviewed. Strabismus was present in 55 (20.7%) children. Mean follow-up was 75
      weeks, with 29.8% of the children having a follow-up of less then 6 months. Only
      5 children (1.9%) with characteristics of infantile esotropia could be
      identified. Another 8 children (3.0%) possibly had infantile esotropia, but
      follow-up had been too infrequent during the first year of life to determine the
      time of onset of strabismus precisely. The other 42 children with strabismus all
      had ophthalmological disorders (i.e. ROP, optic nerve atrophy, cortical
      blindness) explaining early disruption of binocular visual development.
      Therefore, VLBW children are at risk for early onset strabismus. However,
      infantile esotropia is not typical for VLBW children and may be an indication
      that early acquired cerebral damage does not play an important role in the
      pathogenesis of infantile esotropia.

PMID- 10420215
TI  - Botulinum toxin in childhood strabismus.
AB  - The use of botulinum toxin A (BTXA) in childhood strabismus is still a matter of
      debate. This study investigates the indications for and outcome of BTXA therapy
      in children at our institution. From 1985 to 1995, 237 children up to and
      including 16 years of age were treated with BTXA for strabismus. We undertook a
      retrospective study of 163 (69%) children from this group. Factors considered
      were age; anaesthesia; number of, indication for and outcome of injections;
      complications and follow-up. There were three major indications for the use of
      BTXA in children: firstly to improve binocular function, secondly as a post
      operative diplopia test or for cosmetic reasons, and thirdly in the investigation
      or treatment of paralytic and restrictive strabismus. In the first group (54
      children), BTXA produced improved binocular function in 54% of all patients
      treated and in 49% of those with a minimum follow-up of 12 months. In the second
      group (82 children), 88% showed informative post-operative diplopia tests and 44%
      had more than one injection to maintain improved cosmetic alignment. The third
      group comprised 27 children with a range of diagnoses, including 1 third nerve
      paresis, 12 unilateral or bilateral sixth nerve pareses, 7 unilateral or
      bilateral Duane's syndromes, 5 lost or fibrosed muscles and 2 others. This group
      had a range of outcomes which are discussed in the text. BTXA is useful in the
      treatment of a select group of children with strabismus. If there is evidence of
      threatened or recently lost binocularity, or risk of creating or worsening
      diplopia after surgery, it is a useful therapeutic tool. In children with
      strabismus of unusual cause it has diagnostic value.

PMID- 10420216
TI  - Electronic monitoring of treatment compliance in patching for amblyopia.
AB  - We developed a coinsized occlusion dose monitor (ODM) to measure compliance with
      patch-wearing during the treatment of amblyopia objectively. It measures the
      temperature difference between the front and back of the ODM every 2-5 minutes by
      means of two thermistors. The data is stored in EEPROM memory and read out after
      recording for a week by connecting it to a PC. The ODM measures 35x23x4 mm and
      weighs 6 g. The back of the ODM is glued to the front of the amblyopia patch with
      double-sided Scotch tape. When the patch with the ODM is on the eye, the
      temperature at the back of the ODM is higher than at the front. Compliance is
      being studied in children taking part in a large amblyopia cohort study. The
      parents were instructed during home visits every three months to put the ODM on
      the patch. After a week, the ODM was collected and read out. Although the parents
      knew that a recording was being made, compliance was mediocre in many cases.
      Children were patched infrequently, for 5 minutes only, for long periods on the
      last days of the recording, at night, etc. Diaries detailing patch time were
      unreliable.

PMID- 10420217
TI  - A portrait in history: The extraordinary international career of Dr Brown
      Sequard.

PMID- 10420218
TI  - The role of transfusion medicine physicians. A vanishing breed?
AB  - Physicians with interest or expertise in transfusion medicine must apply their
      clinical consultation and laboratory management skills to be accorded support for
      their activities. To establish credibility, efforts must initially be directed
      where patient benefit and financial gain can be documented. Focusing efforts on
      practice improvements and sharing the results of those efforts with physician
      colleagues and administrators can help ensure continued support. Transfusion
      medicine continues to play an important role in health care, particularly in an
      era of managed care and reduced resources. Investment in the activities of this
      discipline will pay off for patients, clinicians, and hospitals.

PMID- 10420219
TI  - The changing relationships in transfusion medicine.
AB  - Maintaining quality in provision of transfusion services in the face of mergers,
      acquisitions, affiliations, and risk-sharing relationships between organizations
      that formerly conducted business in a traditional vendor-purchaser model is the
      ultimate challenge. Publications, both lay and professional, highlight the speed
      and nature of the impetus for change, especially in the United States, where
      managed care philosophies are driving a bottom-line mentality. Blood collection
      and transfusion organizations are developing new relationships, including entry
      of for-profit entities into a formerly virtually exclusively not-for-profit
      environment, provision of transfusion services by formerly exclusive blood
      collection entities and vice versa, outsourcing of selected portions, and other
      innovative relationships, with significantly more competitive marketing
      strategies. Measures of quality of transfusion services should benchmark current
      practices, if possible, before entering into new relationships to ensure that the
      quality of patient care remains high. Concerns about the fiscal viability of
      organizations should not minimize safety and availability of blood for
      transfusion when needed.

PMID- 10420220
TI  - Impact of innovations on transfusion medicine.
AB  - The final decade of the last century of the second millennium ad has seen
      dramatic changes in all aspects of science and health care. In transfusion
      medicine, the blood supply is the safest it has ever been. Newer refinements and
      innovations are continuously being researched and implemented to achieve and
      further enhance safety. Advances in blood conservation, pharmacologic
      manipulation, engineered blood derivatives, and recombinant growth factors can
      now provide safer and more effective alternatives to blood transfusions for many
      patients. This overview highlights selective innovations in transfusion medicine
      and emphasizes some significant advances that have occurred in blood donor
      screening, blood component collections and therapy, and laboratory testing. Newer
      technologies are anticipated that will further enhance the safety of blood and
      transfusions and potentially augment annually the blood supply on a worldwide
      basis.

PMID- 10420221
TI  - Managed care organizations' assessment of reimbursement for new technology,
      procedures, and drugs.
AB  - Managed care organizations must establish formal processes for the evaluation of
      new technology, procedures, and drugs to enhance the quality of health care
      delivered and to support coverage and utilization decision making. Evidence-based
      research and the results of controlled clinical trials are the preferred sources
      of outcomes data to support the safety and effectiveness of the technology,
      procedure, or drug under review. In addition to extensive literature review, the
      opinion of experts in the field and acceptance by the medical community are
      considered. Assessments of new technology and drugs are available for purchase
      from several vendors, and managed care organizations can adopt or modify such
      evaluations to develop medical coverage policies. The research community can
      assist third-party payers by conducting studies on practices that might lead to
      substantial, rather than marginal, improvement in health, pay particular
      attention to study design when randomized controlled studies are not possible,
      and include functional and behavioral measures in analysis of outcomes.

PMID- 10420222
TI  - College of American Pathologists Conference XXXIII on transfusion medicine
      performance improvement.

PMID- 10420223
TI  - Gynecologic cytology turnaround time. A College of American Pathologists Q-Probes
      Study of 371 laboratories.
AB  - OBJECTIVES: To determine the turnaround time for gynecologic cytology in a large
      sample of laboratories and to identify laboratory and specimen characteristics
      associated with better and worse performance. DESIGN AND SETTING: Prospective
      evaluation of gynecologic cytology turnaround times in 371 laboratories. MAIN
      OUTCOME MEASURE: Gynecologic cytology case turnaround time. RESULTS: Three
      hundred seventy-one laboratories submitted information regarding laboratory
      characteristics and processes, and turnaround times of 66 042 gynecologic
      cytology cases. Half of the participating laboratories had mean turnaround times
      of 6 calendar days or less and were able to complete 90% of their cases within 8
      calendar days. Ten percent of participants had mean turnaround times greater than
      13 days and required 19 or more days to report 90% of their cases. Longer
      turnaround times were associated with the use of reference laboratories for all
      or part of the evaluation; contacting the physician's office for additional
      information; using cytotechnology students, residents, or fellows in the
      evaluation; and providing service on the weekend. CONCLUSION: Practice patterns
      contribute to the long turnaround times for gynecologic cytology found in some
      laboratories and may be improved by local site-specific process analysis.

PMID- 10420224
TI  - Diagnostic uncertainty expressed in prostate needle biopsies. A College of
      American Pathologists Q-probes Study of 15,753 prostate needle biopsies in 332
      institutions.
AB  - OBJECTIVE: To determine the rate of diagnostic uncertainty in rendering diagnoses
      on prostate needle biopsies and to examine pathology practice variables that
      influence that rate. DESIGN: Anatomic pathology departments participating in the
      College of American Pathologists Q-Probes laboratory quality improvement program
      retrospectively reviewed their last 50 consecutive prostate needle biopsy
      diagnoses. For each diagnosis, participants provided information concerning
      patients' prostate-specific antigen levels; number, locations, and laterality of
      biopsy specimens; number of tissue levels examined; performance of high-molecular
      weight cytokeratin immunoperoxidase staining; and acquisition of consultations
      from general pathologists or experts in prostate pathology. Characteristics of
      pathology practices included yearly surgical and prostate needle biopsy
      caseloads, number of pathologists rendering biopsy diagnoses, use of standard
      descriptive checklists, access to patients' prostate-specific antigen and digital
      rectal examination results, percentages of prostate needle biopsies routinely
      submitted for internal consultations, and presence of departmental experts in
      prostate pathology. SETTING AND PARTICIPANTS: Three hundred thirty-two public and
      private institutions located in the United States (n = 318), Canada (n = 6),
      Australia (n = 5), United Kingdom (n = 2), and Guam (n = 1). MAIN OUTCOME
      MEASURE: The rate of diagnostic uncertainty in prostate needle biopsy diagnoses.
      RESULTS: Participants submitted diagnoses on a total of 15 753 prostate needle
      biopsy cases, of which 33.4% were adenocarcinoma; 55.5% were benign; 3.9% were
      carcinoma in situ, prostatic intraepithelial neoplasia, or both; and 7.1% were
      diagnostically uncertain. The median rate of diagnostic uncertainty was 6%,
      ranging from 0 at the 10th percentile to 14% at the 90th percentile of all
      participating laboratories. Performing high-molecular-weight cytokeratin
      immunoperoxidase staining resolved diagnostic uncertainty in 68% of cases in
      which it was performed, and obtaining intradepartmental and extradepartmental
      consultations resolved diagnostic uncertainty in 70% to 87% of cases for which
      they were obtained. Knowledge of patients' prostate-specific antigen results and
      examining multiple biopsy cores had marginal effects on the rate of uncertainty.
      Thoroughness of prostate gland sampling and examination of multiple tissue block
      levels were not associated with the aggregate rate of diagnostic uncertainty. We
      found no particular pathology departmental practices or institutional demographic
      characteristics associated with institutional rates of diagnostic uncertainty.
      CONCLUSIONS: Use of high-molecular-weight cytokeratin immunoperoxidase staining
      and obtaining intradepartmental and extradepartmental consultations may be
      effective in reducing diagnostic uncertainty in prostate biopsies.

PMID- 10420225
TI  - Evaluation and implementation of the gel test for indirect antiglobulin testing
      in a community hospital laboratory.
AB  - BACKGROUND: The gel test, developed by Lapierre in 1984, was designed to
      standardize antiglobulin testing while improving sensitivity and specificity of
      the method. PRINCIPLE: Anti-human serum immunoglobulin G (IgG) mixed with
      Sephadex G100 (gel phase) in a microtube traps red cell-IgG agglutination
      complexes during migration through the gel in a centrifugation step.
      Agglutination complexes are visibly detectable at various levels in the microtube
      as an inverse function of antibody coated on red cells. Unsensitized red cells
      form a cell pellet at the base of the microtube. OBJECTIVE: To determine if
      indirect anti-human globulin testing could be standardized and simplified by
      replacing the tube test with the gel test without compromising quality or
      increasing costs. SETTING: A medium-sized community hospital. RESULTS: In a
      blinded retrospective study, we used patient sera (n = 40), which included 10
      positive specimens containing 18 known antibodies. Sixteen antibodies were
      detected and identified with the tube method (1 anti-D and 1 anti-C not
      detected). By the gel test, 18 antibodies were detected and identified. All
      negative samples showed 100% concordance. Favorable results were obtained in a
      nonblinded prospective correlation study (n = 121). Our technologists found the
      gel test easier to read and more reproducible and reliable than the tube method;
      they also found increased sensitivity for detecting weakly reacting antibodies.
      We successfully introduced the gel test into our laboratory as the standard
      method for indirect antiglobulin testing. Following implementation, improved
      personnel management was achieved. CONCLUSIONS: The gel test is a reliable and
      advantageous method and is appropriate for routine use for detection and
      identification of alloantibodies in a community hospital transfusion service
      laboratory.

PMID- 10420226
TI  - Hybrid carcinomas of salivary glands. Report of 4 cases and review of the
      literature.
AB  - OBJECTIVE: To report 4 cases of hybrid carcinoma and to review the literature on
      these rare neoplasms of the salivary gland. METHODS: Hematoxylin-eosin-stained,
      formalin-fixed, paraffin-embedded tissue sections from 3 parotid tumors and 1
      palate tumor were examined. RESULTS: The cases were classified as adenoid cystic
      and mucoepidermoid carcinoma, adenoid cystic and epithelial-myoepithelial
      carcinoma, epithelial-myoepithelial and salivary duct carcinoma, and adenoid
      cystic and salivary duct carcinoma. All patients were men, 28 to 71 years old; 3
      patients presented with parotid mass, and 1 patient presented with palatal mass.
      One patient presented with facial nerve paralysis and pain. The soft palatal
      tumor was a slowly growing mass with maxillary sinus involvement at the time of
      the diagnosis. All patients were treated with surgery and radiotherapy.
      CONCLUSIONS: Correct identification of 2 or more neoplastic entities will help
      assess the aggressiveness and metastatic potential of the tumor and influence the
      clinical course and treatment.

PMID- 10420227
TI  - Tumor-to-tumor metastasis to follicular variant of papillary carcinoma of
      thyroid.
AB  - OBJECTIVE: To describe and document tumor-to-tumor metastases in the thyroid
      gland. METHODS AND RESULTS: In this series we describe 3 cases of tumor-to-tumor
      metastasis in which the recipient tumor was a follicular variant of papillary
      thyroid carcinoma. The donor tumors and sites were small cell carcinoma of the
      lung, neuroendocrine carcinoma probably of pancreatic origin with initial
      presentation as liver metastasis, and clear cell carcinoma of the kidney with
      metastasis to liver and pancreas. The donor tumor cells infiltrated the substance
      of the follicular variant of papillary thyroid carcinoma, the nontumorous thyroid
      parenchyma, and the lymphovascular spaces. Small cell carcinoma and
      neuroendocrine carcinoma showed positive reactivity for neuroendocrine markers
      and were negative for thyroglobulin and calcitonin. The follicular variant of
      papillary thyroid carcinoma showed positivity with thyroglobulin and cytokeratin
      19. CONCLUSIONS: Although tumor-to-tumor metastases in thyroid gland are
      exceedingly rare, one should be aware of this phenomenon as the metastatic lesion
      may simulate a thyroid primary. History of a previous tumor and
      immunohistochemical stains can be helpful in distinguishing between primary and
      metastatic thyroid neoplasms.

PMID- 10420228
TI  - Carcinoma in jejunal pancreatic heterotopia.
AB  - BACKGROUND: Although heterotopic pancreas in the gastrointestinal tract is not
      uncommon, jejunal pancreatic heterotopia is a rare finding, and malignant
      transformation in such a location is very unusual. METHODS: We encountered a case
      of jejunal carcinoma in pancreatic heterotopia and because of its rarity, we
      reviewed the Armed Forces Institute of Pathology experience as well as the
      literature. The clinical, histopathologic, and immunohistochemical features were
      studied. RESULTS: In 109 patients diagnosed as having pancreatic heterotopia in
      the gastrointestinal tract between 1970 and 1997 at the Armed Forces Institute of
      Pathology, 67 cases (62%) occurred in the stomach, 42 (38%) in the small
      intestine, and none in the large intestine. We found 2 patients with
      adenocarcinoma arising in pancreatic heterotopia. The 2 cases arose in the
      jejunum. One was of the ductal type, while the other was an acinar cell carcinoma
      with focal ductular differentiation. In both cases the nontumoral pancreatic
      tissue contained ducts, acini, and islets. Review of the literature yielded 26
      reports of 28 cases of carcinoma arising in heterotopic pancreas; of these, 18
      were well documented. Only 1 occurred in the jejunum, and none was of the acinar
      type. CONCLUSIONS: Carcinoma in pancreatic heterotopia is rare, and acinar cell
      carcinoma in pancreatic heterotopia is extremely rare. Recognition of carcinoma
      in pancreatic heterotopia is important to prevent its misinterpretation as a
      metastatic tumor.

PMID- 10420229
TI  - Diagnostic accuracy and clinical utility of endoscopic bile duct brushing in the
      evaluation of biliary strictures.
AB  - Pathologic evidence of malignancy in biliary strictures is useful in the
      preoperative setting because it helps define therapeutic planning and prognosis.
      The purpose of this study was to assess the diagnostic accuracy and clinical
      utility of endoscopic bile duct brushings in the evaluation of bile duct
      strictures. We retrospectively evaluated 34 endoscopic biliary brushings derived
      from 31 patients with bile duct strictures. Relevant clinical and follow-up data
      were collected. Histologic specimens were reviewed in patients undergoing
      subsequent biopsies. Patients included 18 men and 13 women with an age range of
      25 to 79 years (mean, 52 years). All patients had histologic and/or clinical
      follow-up. Cytologic diagnosis included cholangiocarcinoma (14.7%), suspicious
      for cholangiocarcinoma (5.9%), atypical hyperplasia (17.6%), and negative for
      malignancy (61.7%). All positive diagnoses were confirmed by histologic testing
      (false-positive rate, 0%). The cases that were suspicious for cholangiocarcinoma
      and the 5 atypical hyperplasia cases were also subsequently diagnosed as
      cholangiocarcinoma by biopsy. One atypical case was diagnosed as pancreatic
      carcinoma. All 21 negative cases were confirmed by biopsies (15) and clinical
      follow-up (6) (false-negative rate, 20%). Endoscopic bile duct brushing is
      diagnostically accurate and hence clinically useful in the management of patients
      with bile duct strictures. Atypical hyperplasias may contribute to diagnostic
      pitfalls leading to false-positive and false-negative diagnoses.

PMID- 10420230
TI  - Primary hepatic B-cell lymphoma of mucosa-associated lymphoid tissue.
AB  - Mucosa-associated lymphoid tissue (MALT) lymphomas are low-grade B-cell lymphomas
      that occur in a variety of extranodal sites but rarely as a primary hepatic
      lymphoma. We describe the histological findings, immunophenotype, and
      immunohistochemistry of one such lymphoma found incidentally in a 69-year-old
      woman. The lymphoid infiltrate invaded the liver in a serpiginous configuration
      with entrapment of nodules of normal liver. Reactive follicles were surrounded by
      intermediate-sized lymphoid cells with slightly irregular nuclei and pale
      cytoplasm. Only a few scattered lymphoepithelial lesions were identified since
      most of the bile ducts were destroyed. The immunophenotype determined by flow
      cytometry identified the lymphoid cells as being CD19, CD20 positive and
      exhibiting lambda light chain restriction. CD5, CD10, and CD23 were negative.
      Immunohistochemistry showed the neoplastic cells to be positive for CD20 (L-26)
      and bcl-2. The reactive follicles were negative for bcl-2. CD3 showed only a few
      scattered T cells. Cyclin D1 did not stain the neoplastic cells. Cytokeratin
      (AE1/AE3) highlighted the lymphoepithelial lesions and residual bile ducts. MALT
      lymphomas need to be recognized and distinguished from other B-cell lymphomas,
      particularly mantle cell lymphomas, because of the difference in behavior and
      treatment.

PMID- 10420231
TI  - Lymphoepithelioma-like carcinoma of the colon in a patient with hereditary
      nonpolyposis colorectal cancer.
AB  - Tumors with features similar to those of nasopharyngeal carcinoma, so-called
      lymphoepithelioma-like carcinomas, have been described in several organs but are
      extremely rare in the colon. We describe a patient with a family history
      consistent with hereditary nonpolyposis colorectal cancer who had 3 malignant
      lesions in the right colon, namely, a mucinous cancer, a lymphoepithelioma-like
      carcinoma, and a well-differentiated adenocarcinoma with prominent lymphoid
      stroma. To the best of our knowledge, lymphoepithelioma-like carcinoma has not
      been described previously in hereditary nonpolyposis colorectal cancer.

PMID- 10420232
TI  - Immunohistochemical detection of parathyroid hormone-related protein in a
      cutaneous squamous cell carcinoma causing humoral hypercalcemia of malignancy.
AB  - Humoral hypercalcemia of malignancy is a cancer-related hypercalcemia caused by
      production of humoral factors by malignant cells in patients without bone
      metastases. Squamous cell carcinomas are the tumors most frequently associated
      with humoral hypercalcemia of malignancy, and parathyroid hormone-related protein
      is the main humoral factor implicated. In spite of the fact that normal
      keratinocytes produce parathyroid hormone-related protein, it is highly unusual
      for patients with squamous cell carcinomas of the skin to present with humoral
      hypercalcemia of malignancy. We present a well-documented case of cutaneous
      squamous cell carcinoma complicated by hypercalcemia in a patient with high
      levels of plasma parathyroid hormone-related protein and immunohistochemical
      evidence of high parathyroid hormone-related protein production by the tumoral
      cells.

PMID- 10420233
TI  - Diagnosis of primary fibrosarcoma of the lung by fine-needle aspiration and core
      biopsy.
AB  - Primary pulmonary sarcomas are uncommon neoplasms. Primary fibrosarcoma of the
      lung is extremely rare, and only 53 cases have been documented in the literature
      to date. To our knowledge, the diagnosis of primary lung fibrosarcoma by fine
      needle aspiration cytology has never been reported. We report a case of pulmonary
      fibrosarcoma diagnosed by fine-needle aspiration cytology and core biopsy. The
      neoplasm consisted of interweaving fascicles of minimally atypical spindle cells
      with slender nuclei and scant cytoplasm. Positive immunohistochemistry for
      vimentin along with nonreactivity of tumor cells for keratin, S100 protein,
      desmin, alpha-smooth muscle actin, and CD34 supported the the diagnosis. The
      diagnosis was later confirmed by histologic and ultrastructural findings
      following lobectomy. A meticulous clinical search for a possible primary neoplasm
      elsewhere was unsuccessful, and lung was established as the primary site. Fine
      needle aspiration cytology and core biopsy are reliable methods for establishing
      a diagnosis of fibrosarcoma.

PMID- 10420234
TI  - Munchausen syndrome presenting as pulmonary talcosis.
AB  - We describe a patient with self-induced inhalational pulmonary talcosis
      originally diagnosed as asthma. A 35-year-old female respiratory technologist
      developed severe asthma that was refractory to steroids and methotrexate. An open
      lung biopsy specimen showed scattered aggregates of refractile golden crystals
      within membranous and respiratory bronchioles. The particles ranged in size from
      30 to 100 microm and were birefringent when viewed with polarized light.
      Following review of the lung biopsy specimen, the patient admitted to regularly
      inhaling large amounts of hospital baby powder. Analysis of the lung biopsy
      specimen and a sample of the hospital baby powder by x-ray energy dispersion
      showed identical spectroscopic peaks, including elemental peaks for magnesium
      silicate. Many patients with self-induced illness lack the picturesque
      symptomatology classically attributed to Munchausen syndrome. Awareness of these
      more subtle and varied patterns of presentation may aid in earlier recognition.

PMID- 10420235
TI  - Adenosquamous carcinoma of the small intestine. Report of a case and review of
      the literature.
AB  - Primary adenosquamous carcinomas of the intestine are rare tumors, particularly
      those occurring in the small bowel. We report the third case of an adenosquamous
      carcinoma of the ileum in a 55-year-old-man. Histologically, the tumor consisted
      of malignant glandular and squamous elements. A review of the literature is
      presented.

PMID- 10420236
TI  - Pathologic quiz case. Pathologic diagnosis: Intravascular lymphomatosis
      (angiotropic lymphoma).

PMID- 10420237
TI  - Acute lymphoblastic leukemia in sickle cell disease.

PMID- 10420239
TI  - Orthodontic products update. Molar band sizes.

PMID- 10420240
TI  - The William Houston Gold Medal 1997.

PMID- 10420241
TI  - Elastic activator for treatment of open bite.
AB  - This article presents a modified activator for treatment of open bite cases. The
      intermaxillary acrylic of the lateral occlusal zones is replaced by elastic
      rubber tubes. By stimulating orthopaedic gymnastics (chewing gum effect), the
      elastic activator intrudes upper and lower posterior teeth. A noticeable
      counterclockwise rotation of the mandible was accomplished by a decrease of the
      gonial angle. Besides the simple fabrication of the device and uncomplicated
      replacement of the elastic rubber tubes, treatment can be started even in mixed
      dentition when affixing plates may be difficult.

PMID- 10420242
TI  - Gingivitis artefacta--a case report of a patient undergoing orthodontic
      treatment.

PMID- 10420243
TI  - The influence of maxillary incisor inclination on arch length.
AB  - This ex vivo study was designed to investigate Andrews' hypothesis that there is
      a space implication when incisors are torqued correctly. A working model was
      constructed to allow acrylic typodont incisors of varying known values of
      inclination to be substituted into the model. The arch lengths of the various
      'set-ups' were measured using a reflex microscope linked to a PC. In order to
      quantify the space requirement of clinical relevance for adequate incisor torque,
      the method was repeated by substituting replicas of patients' 'natural' incisors.
      For both acrylic and natural incisors it was found that, as the inclination of
      the teeth increased, there was an increase in all arch lengths, this being
      greater for the natural incisors. This larger increase for the natural incisors
      was related not only to their increased size, but was also dependent on the
      morphology of the incisor. Those incisors which were parallel-sided showed the
      greatest increase in arch length, whereas the incisors that were relatively
      triangular in shape showed the smallest increase. When the inclination of an
      'average' set of 21/12 is increased by 5 degrees, an increase in the arch length
      of approximately 1 mm may be expected.

PMID- 10420244
TI  - The heritability of malocclusion: Part 1--Genetics, principles and terminology.
AB  - The relative contribution of genes and the environment to the aetiology of
      malocclusion has been a matter of controversy throughout the twentieth century.
      Genetic mechanisms are clearly predominant during embryonic craniofacial
      morphogenesis, but environment is also thought to influence dentofacial
      morphology postnatally, particularly during facial growth. Orthodontic and
      orthopaedic techniques are used in the treatment of malocclusion and other
      dentofacial deformities, but with limited effectiveness. The key to the
      determination of the aetiology of malocclusion, and its treatability lies in the
      ability to differentiate the effect of genes and environment on the craniofacial
      skeleton in a particular individual. Our ability to do this is limited by our
      lack of knowledge on the genetic mechanisms that control facial growth and lack
      of scientific evidence for the influence of environmental factors on human
      craniofacial morphogenesis.

PMID- 10420245
TI  - The role of folic acid in oral clefting.
AB  - The objective of this study is to describe the role of periconceptional folic
      acid supplementation and assess it's potential in the prevention of foetal
      abnormalities, and consists of a review of the literature undertaken using an
      electronic and hand search. This includes research trials and methodology
      associated with folic acid supplementation. It is recommended that all women
      planning to conceive should supplement their diet with folic acid in order to
      prevent abnormalities in neural tube development, particularly if there is a
      history of a previously affected pregnancy. There is increasing evidence that
      folic acid supplementation may, in addition, reduce the incidence of oral facial
      clefting. Further research with multi-disciplinary approaches in biochemistry,
      genetics, gene/environment interactions, and embryology are indicated.

PMID- 10420246
TI  - The incidence of cleft lip and palate deformities in the south-east of Scotland
      (1971-1990).
AB  - This retrospective study reports the incidence of infants born with the cleft lip
      and palate anomaly within the Edinburgh Cleft Units catchment area, between 1
      January, 1971, and 31 December, 1990. The importance of accurate data collection
      for local, regional, and national data bases is discussed with reference to the
      recent CSAG report on cleft lip and palate services in the UK. Five-hundred-and
      two cleft lip and palate patients were identified (291 males, 211 females). The
      incidence is reported as 1.4 per 1000 live births (1 in 711). Twenty-five per
      cent of clefts affected the primary palate, 45 per cent affected the secondary
      palate, and the remaining 30 per cent were clefts of both the primary and
      secondary palate. Overall, a higher percentage of males were affected (58 per
      cent males to 42 per cent females). Clefts of the secondary palate, however, were
      more common in females (56 per cent females to 44 per cent males). Data presented
      in this study is similar to that previously reported from UK centres. It is
      suggested the accuracy of the UK cleft lip and palate data collection needs to be
      improved. Prospective data collection in a standardized format carried out on a
      national basis has to be a priority as recommended by the CSAG report.

PMID- 10420247
TI  - Skeletal and dental changes following the use of the Frankel functional
      regulator.
AB  - The purpose of this study was to assess the relative contributions of skeletal
      and dental components in correction of Class II division 1 malocclusions when
      treated with Frankel's functional regulator (FR). This was a retrospective study
      involving analyses of pre- and post-treatment cephalograms of 63 Class II
      division 1 patients treated with the FR to demonstrate the relative maxillary,
      mandibular, incisor, and molar movements during treatment compared with normal
      growth within a control group of untreated 39 Class II division 1 cases drawn
      from the same demographic population. All cephalograms were digitized and
      subjected to a Pitchfork analysis, which measured individual anteroposterior
      skeletal and dental changes during the period of study. It was shown that the FR
      was effective in treating Class II division 1 cases with the studied group being
      corrected to a clinically acceptable overjet and overbite of 2-3 mm. The majority
      of the correction came from dental movements, the most significant being the
      retroclination of the upper incisor teeth (mean 4.1 mm, 95 per cent CI +/- 0.44)
      and proclination of the lowers (mean 2.2 mm 95 per cent CI +/- 0.57). As regards
      skeletal correction, the most significant contribution was the restraint of
      normal maxillary forward growth (mean -0.2 mm, 95 per cent CI +/- 0.62) with
      forward mandibular growth not being a significant factor.

PMID- 10420248
TI  - Distortion of metallic orthodontic brackets after clinical use and debond by two
      methods.
AB  - The objective of this paper was to compare distortion of the tie wings and bases
      of metallic orthodontic brackets following clinical use and after debond by
      either of two methods, and took the form of a prospective random control trial.
      Five-hundred-and-seven brackets were debonded using either bracket removing
      pliers or a lift off debonding instrument (LODI). By a system of random
      allocation contralateral opposing quadrants were debonded with a 0.019 x 0.025
      inch archwire either in place or removed. After debond brackets were tested for
      slot closure by the fit of rectangular test wires from 0.016 x 0.022 to 0.021 x
      0.025 inch in size. The LODI produced few slot closures sufficient to affect the
      fit of all but the largest test wire. Bracket removing pliers used after removal
      of the archwire produced significantly greater numbers of distorted brackets in
      response to testing with all but the largest wire. With the 0.021 x 0.025 inch
      wire in place the presence or absence of the archwire at the time of debond made
      no difference to the number of slot closures. Ten per cent of the brackets
      debonded using bracket removing pliers had distorted bases, no base damage was
      produced by the LODI. The use of bracket removing pliers at debond caused
      significantly more slot closures than use of the LODI. When bracket removing
      pliers are used the archwire should be left in place at the time of debond since
      this reduces the number of distortions.

PMID- 10420249
TI  - A laboratory investigation to compare enamel preparation by sandblasting or acid
      etching prior to bracket bonding.
AB  - A laboratory investigation to compare the mean shear debonding force and mode of
      bond failure of metallic brackets bonded to sandblasted and acid-etched enamel is
      described. The buccal surfaces of 30 extracted human premolars were sandblasted
      for 5 seconds with 50 mu alumina and the buccal surfaces of a further 30 human
      premolars were etched with 37 per cent phosphoric acid for 15 seconds. Following
      storage for 24 hours at 37 degrees C in distilled water, shear debonding force
      was measured using an Instron Universal Testing Machine with a cross-head speed
      of 10 mm/minute. Mean shear debonding force was significantly lower for brackets
      bonded to sandblasted enamel compared to acid etched enamel (P < 0.001). Weibull
      analysis showed that at a given stress the probability of failure was
      significantly greater for brackets bonded to sandblasted enamel. Brackets bonded
      to etched enamel showed a mixed mode of bond failure whereas following
      sandblasting, failure was adhesive at the enamel/composite interface (P < 0.01).

PMID- 10420250
TI  - The British Orthodontic Society Foundation.

PMID- 10420251
TI  - Prophylactic removal of impacted third molars: is it justified?

PMID- 10420252
TI  - Do you care? A national register for cleft lip and palate patients.
AB  - The Cleft Palate Index and, more recently, the Craniofacial Anomalies Register-
      CARE--have been in operation since 1982. This paper summarizes its development
      and plans for the future. CARE is a multidisciplinary committee involving all
      specialties involved in the treatment of this group of patients therefore it
      should and can be well placed to co-ordinate the cleft data arising from these
      patients.

PMID- 10420254
TI  - Re: A case report: to find surgical needle in the oropharyngeal region during
      screening of orthodontic radiographs is it strange?

PMID- 10420253
TI  - Re: Guest editorial--in pursuit of improvement before excellence.

PMID- 10420255
TI  - [Photodissociation of oxygenated forms of native hemoglobin HbA and its isolated
      alpha- and beta-subunits, and kinetics of rebinding of molecular oxygen].

PMID- 10420257
TI  - [Local cell interaction and control of cell growth].

PMID- 10420256
TI  - [Genetic variability of Mycoplasma during interaction with host: vertical
      transfer and rearrangement in genes of surface antigenic determinants].

PMID- 10420258
TI  - [Dynamics of gas bubbles in tissues with heterogeneous structure and diffusion
      permeability during decompression].

PMID- 10420259
TI  - [Molecular structure of super-unstable mutations in Drosophila melanogaster].

PMID- 10420260
TI  - [The role of tremor and drift in the visual signal formation].

PMID- 10420261
TI  - [Morphofunctional characteristics of myocardial hypertrophy in rabbits with
      vasorenal arterial hypertension during pharmacological blockade of angiotensin
      II].

PMID- 10420262
TI  - [Karyologic differentiation in the common shrew Sorex araneus L. from the upper
      and middle Volga river basin (Insectivora, mammalia)].

PMID- 10420263
TI  - [Insulator can suppress the nonisolated enhancer activity].

PMID- 10420265
TI  - [Environmental stress and genetic variation in animal populations].
AB  - The impact of environmental stress factors on genetic variation in animal
      populations is considered. It is tentatively concluded that genetical variability
      of populations generally increases in stressful environments. The exposure to
      stressful factors result in an increase of recombination and mutation rates. In
      quantitative traits, on which the review is focused, stress often leads to an
      increase in the genetic component of variation. Experiments on Drosophila
      demonstrated that the effect of stress on genetic variation is stress- and trait
      specific. The possible role of stress factors in adaptation and evolution of
      populations is discussed.

PMID- 10420266
TI  - [Role of the "enhancer of yellow" genes in the regulation of expression of the
      "yellow" gene in Drosophila melanogaster].
AB  - The e(y)1/TAFII40, e(y)2 and e(y)3 genes encode general transcription factors in
      Drosophila melanogaster. Weak mutations in e(y)1u1, e(y)2u1 and e(y)3u1 regulate
      enhancer-dependent transcription of the yellow gene in bristles similarly, even
      if it is activated by a non-yellow specific enhancer element. At the same time,
      these mutations do not affect yellow expression in the body and wings. We found
      genetic data indicating that the e(y) proteins support the promoter/bristle
      enhancer interaction. Futhermore, the su(Hw) insulator properties change in the
      presence of e(y)1u1, e(y)2u1 and e(y)3u1 mutations. When introduced at +2490 from
      the transcription initiation site, the su(Hw) insulator becomes able to block
      interactions between the bristle enhancer and yellow promoter, not separating
      them from each other.

PMID- 10420264
TI  - [Molecular origin of the phenotypic diversity of superunstable mutations in
      Drosophila melanogaster].

PMID- 10420267
TI  - [Constitutive inhibition of DNA degradation due to the enzyme RecBCD in the
      radiation-resistant Escherichia coli K-12 mutant Gam(r)444].
AB  - Exonucleolytic degradation of [3]H-labeled DNA was examined in partially purified
      fractions of lysates obtained from nonirradiated RecBCD enzyme-containing cells
      of Escherichia coli and in the radiation-resistant mutant Gamr444. The
      degradative activity was shown to be lowered in these cells to the same extent as
      in the recBC mutant. The efficiency of plating of the mutant phage T4 2-, DNA of
      which can be degraded by exonuclease V, was 400-fold higher on the strain Gamr444
      than on the wild-type strain AB1157. This value was shown to be only twice as low
      as that on the recB mutant or on the strain AB1157 carrying plasmid pGam26 with a
      radiation-resistance allele gam26 cloned from mutant Gamr444. The data obtained
      confirmed the hypothesis that the Gamr444 mutant contains a constitutive
      inhibitor of exonucleolytic activity of the RecBCD enzyme in nonirradiated cells.
      This inhibitor was shown to be encoded by the gam26 allele that had previously
      been mapped at 56.8 min of the E. coli chromosome. A possible mechanism of the
      involvement of this inhibitor in enhanced radiation resistance of the mutant
      Gamr444 is considered.

PMID- 10420268
TI  - [Expression and functions of adaptive response genes in Escherichia coli treated
      with mono- and bifunctional alkylating agents. Interference with SOS response].
AB  - The expression of genes belonging to the Ada regulon of Escherichia coli under
      the action of mono- and bifunctional alkylating agents--high-efficiency antitumor
      HMM, ACNU, and BCNU preparations--was studied. The functional specificity of the
      alkA, alkB, and aidB1 genes concerning both the structure and volume of DNA
      alkylation and the specificity of cell preadaptation was revealed. Additional
      experimental evidence for the role of the aidB1 gene as a unique "hazard gene", a
      component of the E. coli ada operon, was obtained. A phenomenon of positive
      interference between alternative SOS and Ada responses was observed for the first
      time upon gene expression.

PMID- 10420269
TI  - [Formation of the heterozygous tandem duplication in the process of conjugation
      recombination in Escherichia coli: study of the effect of mutations for the recQ,
      uvrD, and recJ genes].
AB  - Stable tandem duplications were shown to originate from conjugational
      recombination between Escherichia coli HfrH strains carrying mutations for the
      deo operon. The duplications deoC deoD/deoA deoB::Tn5 usually constitute
      approximately 5% of the Deo+ offspring. The effect of mutations for the recQ,
      uvrD, and recJ genes on the frequency of duplications was studied. The CM1563
      strain carrying the recQ mutation was shown to give, as a recipient, 20% of
      duplications in the Deo+ offspring. However, this property of CM1563 seems to
      depend on the presence of a spontaneous mutation of unknown nature, which also
      increased UV sensitivity of bacteria. The recQ mutation itself increased the
      frequency of duplications by less than 50%. The recJ mutation did not virtually
      affect the frequency of duplications. The uvrD mutation possessing the
      recombinogenic effect was shown to increase the frequency of deo+ recombinants
      and simultaneously decrease the frequency of duplications. Tandem duplications
      are assumed to be normal intermediates of multi-stage conjugational recombination
      initiated by the integration of the proximal region of the Hfr chromosome into
      different nonhomologous regions of the recipient chromosome.

PMID- 10420270
TI  - [Chromosome rearrangement: two ways of influencing crossing over in Drosophila].
AB  - Insertion of the Y-material into the 34A Is(Y;2L)419 region diminished
      recombinational length of the left arm of chromosome 2 (2L) from 49.1 to 15.0 cM.
      This decrease was compensated by the increase of recombinational length in the
      other chromosomal arms due to interchromosomal effect. The increase in the X
      chromosome was 11.4 cM; it was 2.0 cM in chromosome 2R; and 17.3 cM in chromosome
      3. The insertion-induced decrease of the 2L recombinational length could be
      eliminated by evoking interchromosomal effects from other chromosomes. The
      presence of the inversion in the X chromosome increased the 2L recombinational
      length from 15.0 to 30.2 cM, while its association with the In(3LR)D inversion
      increased this length to 45.6 cM. The interchromosomal effects in the inductor
      chromosome were induced by distortion of pairing rather than by the low
      recombinational length of this chromosome. For example, the interchromosomal
      effect of the insertion on the X chromosome was higher in the Is(Y;2L)/+;
      In(3LR)/+ females than in the Is(Y;2L)/+; +/+ females (15.4 versus 11.5 cM),
      though the 2L recombinational length in the females with the former genotype
      (30.2 cM) was twofold higher than in females with the latter genotype (15.0 cM).
      It is suggested that chromosomal rearrangement hampers the development of local
      contacts in the homologues. This delay affects crossing over in the given pair of
      homologues in two ways: directly via diminishing the number of exchange sites,
      and indirectly through regulatory delay of crossing over determination in the
      meiocyte. The effects of the insertion on crossing over in nonhomologous
      chromosomes are implemented by through the second way.

PMID- 10420271
TI  - [Genetic differentiation of voles of the tribe Arvicolini (Cricetidae, Rodentia)
      using taxonprint analysis and polymerase chain reaction with random primers].
AB  - The variability of the genomes of ten vole species was analyzed by means of
      taxonomic DNA fingerprinting and polymerase chain reaction using random primers
      (RAPD-PCR). The dendrograms of genetic similarity between the representatives of
      the tribe Arvicolinae (Gray, 1821) were constructed, based on the data obtained
      by means of both methods. The topology of the genetic similarity dendrogram that
      is based on the RAPD-PCR data generally correlates with the genetic distances
      estimated from biochemical and karyological data. The results did not confirm the
      genus status of Terricola. On the other hand, the data from taxonprint analysis
      suggest the recognition of Lasiopodomys as a separate genus.

PMID- 10420272
TI  - [Chromosomal localization of 10 genes on the cytogenetic map of the common shrew
      Sorex araneus L].
AB  - Using a panel of hybrid clones (common shrew--Chinese hamster and common shrew-
      mouse), the syntheny and localization of the following genes was determined:
      genes for alpha-galactosidase (GLA), acid phosphatase (ACP1), and
      phosphoglycerate kinase (PGK1) on chromosome de; adenosine kinase (ADK) and
      glucuronidase 2 (GUS2) on chromosome ik; glutamic-oxaloacetic transaminase 2
      (GOT2) and peptidase D (PEPD) on chromosome hn; and glyoxalase 1 (GLO1) and
      phosphoglucomutase 2 (PGM2) on chromosome go. Gene for beta-galactosidase (GLB1)
      was assigned to arm p of chromosome mp. Thus, including previously mapped genes,
      the cytogenetic map of the common shrew contains 39 genes. They form seven
      syntheny groups and mark eight out of ten chromosomes.

PMID- 10420273
TI  - [Associations between the coat color and the blood-group system D antigens in
      horses].
AB  - The study of the association between the coat-color variants and the blood-group
      system D antigens in the populations of two related trotter breeds (Orlov Trotter
      and Russian Trotter) showed the presence of three associations between these
      characters in the Orlov Trotter breed. In the populations of Russian trotters,
      these associations were not detected. Possible reasons for the formation and
      maintenance of these associations and the role of the selection for coat color in
      the differentiation of breeds by the frequencies of some system D antigens are
      discussed.

PMID- 10420274
TI  - [Frequency distribution patterns of HLA antigens, genes, and haplotypesin the
      migrant population of northwestern Russia in relation to time of residence in the
      region and sex differentiation].
AB  - Frequency distribution patterns of the HLA antigens, genes, and haplotypes at
      subloci A, B, and Cw were examined in 664 female and 765 male Slavs in dependence
      to the duration of their residence in the extreme conditions of the Magadan
      region. In the groups studied, no statistically significant differences in the
      frequencies of the corresponding genes and antigens were found. Analysis of
      gamete associations showed that positive and negative associations revealed in
      some cases were typical of the population of the region on the whole. However,
      sex-dependent association, as well as that dependent on the duration of residence
      in extreme conditions were also established.

PMID- 10420276
TI  - [Genetic-epidemiologic study of adenoma and cancer of the large intestine].
AB  - A clinical/genealogical study of colorectal adenomas (CRA) and cancer (CRC), and
      multiple primary malignant tumors (MPMT) was performed. The CRA prevalence in the
      population was 4.7 +/- 1.4% (single CRA--6.3% and multiple CRA--3.0%). The
      frequencies of malignant adenomas, 0.7% CRC, and MPMT were 0.7, 0.17 +/- 0.07%,
      and 0.004 +/- 0.003%, respectively. The prevalence of cancer of the female
      reproductive organs was also estimated (cancer of uterine body, 0.2 +/- 0.1%;
      cancer of ovaries, 0.08 +/- 0.1%; cancer of uterine cervix, 0.55 +/- 0.1%; cancer
      of mammary gland 0.57 +/- 0.1%). The main parameters of the familial inheritance
      of adenomas, CRC, and MPMT were also studied in general and at various clinical
      variants of these pathologies. Among the first-degree relatives of patients with
      solitary and multiple adenomas, the adenoma frequencies were 5.9 +/- 0.6 and 3.7
      +/- 0.5%, respectively. The CRC frequency among the first-degree relatives of
      patients with adenoma was 3.0 +/- 0.6% and the frequency of MPMT was 5.8 +/-
      0.6%. On the basis of the data obtained on frequencies of malignant tumors in
      various groups of relatives, the following conclusions were made: (1) in families
      of each proband group, specific pathology was accumulated; (2) the familial
      frequency of malignant tumors increased with an increase in proliferative
      processes and the severity of a pathology in probands.

PMID- 10420275
TI  - [Analysis of DNA polymorphism in populations of the Volga-Ural region using
      genome fingerprinting with phage M13 DNA].
AB  - The hyperpolymorphism of minisatellite DNA hybridizing with DNA of bacteriophage
      M13 was analyzed in seven Turkic and Finno-Ugric populations from the Volga-Urals
      region. In total, hybridization revealed 80 BspRI genomic DNA fragments ranging
      in size from 1.7 to 10 kb; the average frequency of an individual fragment was
      0.299 +/- 0.020. The average number of hybridization fragments per pattern
      (varying from 14 to 20 in different populations) and frequencies of individual
      fragments showed significant interpopulation differences. Parameters of this
      polymorphic system were assumed to reflect phenotypic diversity of populations.
      Genome fingerprinting with the use of phage M13 can be employed in the studies of
      population genetic structure and differentiation and in forensic medicine, for
      more accurate personal identification.

PMID- 10420278
TI  - [Inheritance of quantitative traits in hybrid pedigrees: mixed models].
AB  - Mixed models have been extended to make them applicable to description of
      inheritance of quantitative traits in pedigrees obtained via interbreed or
      interpopulation hybridization. Additional assumptions specify definite
      relationships between the parameters that characterize the inheritance of the
      trait in two parental populations. It is assumed that (1) parental populations
      differ from each other only in the allelic frequencies in the major gene locus
      and polygenic loci and (2) the patterns of phenotype formation based on an
      individual genotype and the transmission of genes to the next generation are the
      same in both parental populations, as well as in their hybrids. Based on these
      assumptions, the likelihood function for a hybrid pedigree is derived, and the
      heterosis effect is formalized. The results of this study offer new possibilities
      for estimating the contribution of the major gene effect to interpopulation and
      interbreed differences in the expression of quantitative traits.

PMID- 10420277
TI  - [Segregation and genetic-dispersion analysis of predisposition to adenoma and
      cancer of the large intestine].
AB  - Segregation analysis of inheritance of adenomas, colorectal cancer (CRC), and
      multiple primary malignant tumors (MPMT) revealed their low penetrance: from 3.2
      to 29% for homozygotes and from 2.0 to 14.4% for heterozygotes. This cast a doubt
      on the monogenic type of their inheritance, although it formally corresponded to
      the quasidominant type, i.e., only a fraction of heterozygotes was expressed.
      Therefore, the multifactorial model of inheritance was tested, which seemed more
      adequate because genetic heterogeneity of adenomas, CRC, and MPMT was suggested
      from the data on genetic correlations between various clinical forms.
      Predisposition to various clinical forms of adenomas, CRC, and MPMT was shown to
      be specific, i.e., the ratio between genetic and environmental predisposition
      determining factors reflected pathogenetic differences between these diseases.
      However, analysis of variance which revealed genetic (pathogenetic) distinctions
      between adenomas, CRC, and MPMT is insufficient to confirm complete nosologic
      identity of each of these clinical forms.

PMID- 10420279
TI  - [Methodologic aspects of genomic fingerprinting in population studies].
AB  - Use of DNA fingerprinting in population studies is complicated by a number of
      methodical problems caused by the necessity to work with a large amount of
      experimental data and insufficient reproducibility of the results. In this work,
      possible approaches to overcome methodical difficulties faced by the authors
      during elaboration of the experimental technique are discussed.

PMID- 10420280
TI  - [Analysis of deletions in the dystrophin gene in patients with Duchenne muscular
      dystrophy in the Bashkir Republic].
AB  - The deletion spectrum and distribution of deletion breakpoints (DBs) in 36
      patients with Duchenne muscular dystrophy (DMD) from 33 families and in three
      patients with Becker muscular dystrophy (BMD) from one family from Bashkortostan
      were studied by amplifying 20 exons of the dystrophin gene by multiplex
      polymerase chain reaction (mPCR). Eight out of 34 unrelated DMD (BMD) patients
      (23.2%) were shown to carry a deletion varying in size from one to seven exons.
      Most DBs (15 out of 16, 93.7%) were in the distal region of the gene, commonly
      between exons 44-45, 45-47, and 50-52. Thus, high-polymorphic intergenic markers
      located in introns 44 (STR 44), 45 (STR 45), 49 (STR 49), and 50 (STR 50) can be
      used for indirect or direct carrier detection among women closely related to DMD
      patients that carry a deletion with DB located between exons 44-45, 45-47, and 50
      52. Prenatal diagnosis of DMD is also possible in these families.

PMID- 10420281
TI  - [Characterization of a novel wild-type t(wMPI) haplotype of the house mouse (Mus
      domesticus L.) from Peru].
AB  - Data on molecular genetic analysis of the novel wild-type twMP1 haplotype found
      in a population of Mus domesticus from Peru are presented. Complementation
      attribution of the novel haplotype as well as fertility of heterozygotes and
      transmission ratio distortion (TRD) of the t-carrying chromosome in the progeny
      of the heterozygous males were studied. Molecular analysis was carried out by
      means of blot hybridization with the four t-specific probes (Tu48, Tu66, Tu119,
      and Tu122). Comparison of the results obtained with the data on the structure and
      properties of the t complexes permitted conclusion on the complete lethality of
      the haplotype described.

PMID- 10420282
TI  - [The DASH(Disability of Arm-Shoulder-Hand) Questionnaire--a new instrument for
      evaluating upper extremity treatment outcome].
AB  - The paper presents the translation of a new measurement tool, the DASH
      Questionnaire. The DASH (Disability of Arm--Shoulder--Hand) is an outcomes data
      collection instrument which has been developed by the "American Academy of
      Orthopaedic Surgeons", the Council of the "Musculoskeletal Specialty Societies",
      and the "Institute for Work and Health", in order to assess outcomes among
      patient groups with musculoskeletal disorders. Using a self-report system,
      patients attribute scores of 1 to 5 on 30 items relating to functional activities
      and symptoms; a further optional module contains four items relating to
      disability levels among musicians and athletes. The raw score is then transformed
      to a 0 to 100 scale, whereby 0 reflects minimum and 100 maximum disability. The
      subjective nature of this instrument makes it suitable for both postal or in situ
      clinical surveys. The instrument is in the process of validation for use with a
      German population.

PMID- 10420283
TI  - [Evaluation protocol for assessment of the wrist joint].

PMID- 10420284
TI  - [Comparison of various evaluation measures for assessment of treatment success
      after scaphoid injuries].
AB  - Different evaluation scores have been developed in order to assess treatment
      outcome of carpal injuries. The available scores are not comparable and differ in
      type and number of parameters. This is a retrospective study of 100 patients who
      presented with a fracture or a pseudarthrosis of the scaphoid from 1983 to 1997.
      The Cooney and the Meine scores were compared with our own score. While the
      Cooney score and the newly developed score show an equal distribution of results
      in all categories, the score of Meine led to an overall better outcome
      assessment. The comparative evaluation of the different scores shows that the
      combination of only a few well defined parameters is sufficient for assessing the
      treatment outcome of carpal injuries.

PMID- 10420285
TI  - [Long-term outcome of partial prosthesis management of proximal scaphoid
      pseudarthroses with a comparison of different follow-up protocols].
AB  - Replacement of the proximal scaphoid pole with a silicone implant is a possible
      surgical treatment in cases of avascular necrosis of the proximal pole after
      scaphoid nonunion despite the possible development of silicone induced
      synovialitis. Based on six scores, the results of this procedure are discussed
      and scoring systems compared. After an average follow-up of 6.5 years, eleven
      patients with proximal scaphoid silicone implant were evaluated personally. The
      results were excellent in three patients, good in two and satisfactory in six
      patients. There were no poor results. In the six scores results were good or
      satisfactory. Mostly, satisfied patients with poor radiological results were
      seen. Number and weighting of the different criteria influence the results. We
      conclude that scaphoid silicone arthroplasty is an useful procedure for avascular
      necrosis of the proximal scaphoid pole. Patients may have a painless wrist and
      good range of motion for years. In some patients, silicone synovialitis is found.
      Before arthrodesis becomes inavoidable, some years of better mobility can be
      gained.

PMID- 10420287
TI  - [Proximal scaphoid pseudarthrosis--reconstruction by dorsal bone screw and
      spongiosa transplantation].
AB  - Stable fixation of small proximal pole nonunions of the scaphoid by conventional
      techniques of bone grafting remains difficult. Because of this, long-lasting
      immobilisation is necessary. Treatment by retrograde Herbert-screw fixation
      offers the possibility of stable osteosynthesis resulting in shorter
      immobilisation. Even in case of avascular proximal fragments, it allows healing
      of the nonunion. We report on the 29 months follow-up of 23 patients treated in
      this manner showing bony consolidation in 17 cases (74%). Four patients
      demonstrated fibrous nonunion with minor symptoms, and in two patients persistent
      nonunion with slight impairment was seen. Evaluation with the DASH-questionnaire
      revealed slight disability with an average score of ten points. The availability
      of the mini-Herbert-screw has improved this treatment concept.

PMID- 10420286
TI  - Proximal scaphoid nonunion-osteosynthesis.
AB  - Proximal pole fractures of the scaphoid have a high incidence of nonunion and
      avascular necrosis. Because of their poor prognosis, the treatment of these
      fractures remains controversial. 102 patients with symptomatic nonunion of the
      proximal pole were treated by simple osteosynthesis, using retrograde screw
      fixation through a direct dorsal approach to the scaphoid. Fracture preparation
      and bone grafting were kept to a minimum, in order to preserve as much bone stock
      as possible, and to avoid damage to the already compromised vascularity of the
      proximal fragment. No postoperative splinting was used and most patients were
      able to return to their normal work within a few weeks of surgery. 69 patients
      were followed-up at an average of 34 months. 59 (85%) were asymptomatic, and had
      regained excellent wrist function, in spite of the fact that sound radiological
      union was present in only 50% of these. Union was often slow (3 to 36 months) and
      appeared to be related to the vascularity of the bone fragments. However, even
      when bone union was incomplete, the fracture remained stable, with no loss of
      fixation. The ten patients with unsatisfactory results had all developed late
      avascular necrosis of the proximal pole, requiring salvage surgery. Stable
      internal fixation of proximal pole nonunion leads to rapid symptomatic
      improvement in the majority of cases and sets the scene for revascularisation and
      healing. Even when union is incomplete the scaphoid remains intact, thus
      preserving excellent wrist function and, at the same time, offering the best
      possible long term prognosis.

PMID- 10420289
TI  - [Long-term outcome of reconstruction of proximal scaphoid pseudarthroses with
      Matti-Russe-plasty].
AB  - Thirty-two patients who were treated with Matti-Russe grafts between 1985 and
      1995 after a fracture of the proximal scaphoid pole were examined in a
      retrospective study. The purpose of the study was the evaluation of the long-term
      results of functional outcome, radiological results, and postoperative quality of
      life. Main object of the study was to clarify whether the development of carpal
      collapse is inevitable or if it is correlated to the persistence of bony
      nonunion. Measured parameters were: grip strength and range of motion, pain was
      evaluated with a visual analog scale from 0 to 100 (VAS). The analysis of the X
      rays was carried out with a special wrist-score that was developed for the 1997
      meeting of the German Speaking Society for Surgery of the Hand (DAH). The
      functional outcome was evaluated with the DASH-questionnaire. Twenty-nine
      patients were male, three were female. In 22 patients the right hand was
      involved, in ten patients the operation was performed on the left hand. The
      average follow-up period was 66 months. Bony union was achieved in 26 cases, six
      patients still demonstrated a persistent nonunion. The mean postoperative pain
      score was 1.8 (non-stress) and 42.5 (stress) in patients with scaphoid union.
      Active range of motion and grip strength were 90% compared to the contralateral
      side, the DASH-score reached 12.73. Only in persistent nonunion an advanced
      carpal collapse could be detected. The results show the reliability of the Matti
      Russe graft in nonunion of fractures of the proximal pole of the scaphoid.
      Alternative treatment options have no advantages in bony union. The disadvantage
      of the Matti-Russe graft is the long period of immobilisation.

PMID- 10420288
TI  - [Scaphoid pseudarthrosis of the proximal third--results of treatment with the
      Herbert screw].
AB  - Purpose of this study was to assess the value of the Herbert screw used with
      iliac crest cancellous bone graft for treatment of scaphoid nonunion in the
      proximal third. From 1986 to 1996, 75 patients underwent this procedure. We
      followed-up on 67 of them using the Martini score, which covers pain, grip
      strength and social activities, range of motion, X-ray results, individual,
      clinical and overall assessment. We found 57 patients (85.1%) with a good to
      excellent outcome, eight patients (11.9%) with satisfactory results and two
      patients with a poor result. We conclude that the Herbert screw with or without
      cancellous bone graft should be the first choice for surgical treatment of non
      union located in the proximal third of the scaphoid bone.

PMID- 10420290
TI  - [Persistent scaphoid pseudarthrosis after surgical treatment: results of repeated
      bone transplantation].
AB  - From 1984 to 1993, 30 patients with persistent scaphoid non-union despite bone
      grafting procedures underwent additional reconstructive surgery. Twenty-five
      patients were followed-up between one and eleven years after revision with a mean
      follow-up time of 4.8 years. Fifteen patients had bone graft procedures alone,
      ten patients had additional internal fixation with the Herbert screw or Ender
      plate. At follow-up, scaphoid union was achieved in 16 patients (64%), 19
      patients had arthritic changes of the radiocarpal joint. Only patients with
      scaphoid union showed satisfactory functional results. Five patients with failed
      revision surgery needed further operations for chronic wrist pain, including
      three wrist arthrodeses.

PMID- 10420291
TI  - [Proximal scaphoid pseudarthrosis with avascular pol fragment: long-term outcome
      after reconstruction with microvascular pedicled iliac crest bone graft].
AB  - 56 patients suffering from scaphoid nonunion with avascular necrosis of the
      proximal pole were treated by a free vascularized iliac bone graft. Follow-up
      examination of 27 patients at 8.8 years included evaluation of scaphoid nonunion,
      progression of arthrosis and clinical parameters. Union was achieved in 85% of
      the patients (Group A). Arthrosis remained unchanged in 75%. No carpal collapse
      occurred. 81% of the patients were painfree. Grip strength was 95% and range of
      motion 75% compared to the noninvolved wrist. Nonunion persisted in 15% (Group
      B). In all these patients carpal collapse had established. 66% of the patients
      showed mild pain. Grip strength was 71% and range of motion 65% of normal.
      Transplantation of a free vascularized iliac bone graft resulted in union of a
      scaphoid pseudarthrosis with avascular proximal pole in 85%. When union occurred,
      progression of degenerative arthrosis could be arrested and good clinical late
      results could be achieved.

PMID- 10420292
TI  - [Long-term outcome of partial alloplastic replacement of the scaphoid bone].
AB  - The operative treatment of scaphoid nonunion with a small, sclerotic, or
      avascular proximal fragment and with accompanying radioscaphoid arthrosis is
      difficult and often disappointing. Excision of the proximal fragment,
      styloidectomy, partial replacement of the scaphoid, and insertion of a silicone
      rubber lunate prosthesis has been recommended in these cases. From 1980 to 1984,
      eleven patients (all male, average age 42 [25 to 59] years) with conditions
      described above were treated by partial replacement of the scaphoid. In one
      patient, the prosthesis dislocated dorsally and was removed five months later. In
      another patient, increasing pain at the wrist necessitated a wrist fusion five
      years after implant replacement arthroplasty. Nine patients remained for
      evaluation with an average follow-up of 14 years, ranging from 12 to 16 years.
      Clinical and radiographic studies were performed according to the score proposed
      by Martini (see p. 153 of this issue). The overall results were satisfactory. The
      outcome was good in one case, satisfactory in six cases and poor in two cases.
      The best results could be observed in "subjective estimation" and in "work and
      sports". The worst results were found in the "X-ray" and "motility" evaluation.
      In all patients, radiographic and clinical symptoms of silicone synovialitis
      appeared approximately two years after surgery. This developed adjacent to the
      implant and later spread throughout the wrist. Simultaneously, carpal collapse
      and secondary arthrosis of the wrist developed. Only two patients complained of
      moderate wrist pain at the time of examination. None of the patients desired
      further treatment. This study shows that in advanced scaphoid nonunion partial
      replacement of the proximal fragment of the scaphoid with a silicone implant
      provides long-lasting pain relief and satisfactory hand function. However,
      progressive carpal collapse (SNAC) and radiocarpal arthrosis developing within
      four to five years cannot be prevented. Furthermore, severe silicone synovialitis
      was detected in all patients. Therefore, the procedure was abandoned after 1984.

PMID- 10420293
TI  - [Relation of necrosis to outcome and site of fracture in scaphoid
      pseudarthrosis].
AB  - Usually, untreated scaphoid fractures lead to non-union and partial or complete
      avascular necrosis. The purpose of our study was to examine the influence of
      location and fracture line on the pattern of necrosis. Therefore, 85 patients
      with scaphoid non-union were examined by enhanced highfield MRI. Fractures were
      classified by location and fracture line. A staging system based on signal
      intensity in T1-weighted spin-echo sequences in enhanced MRI was used to evaluate
      extent and location of avascular necrosis, which was found in 81% of our
      patients. In our patients, viability of the scaphoid was independent of the
      fracture line without dominance of vertical oblique fractures (2%). Based on our
      staging system, signal intensity as a sign of fragment viability was reduced in
      the proximal fragment in 46 patients, whereas in eight patients the distal
      fragment showed reduced viability. In 26 patients, no difference was found
      between proximal and distal fragments. Fractures proximal to the transition of
      middle to distal third showed less viability of the proximal fragment, not
      dependent of how proximal the fracture was seen. In triple fractures (6%) signal
      intensity of scaphoid bone was more reduced in enhanced MRI.

PMID- 10420294
TI  - [Correction of malalignment of the ring finger after Kirschner wire infection of
      the phalangeal-interphalangeal joint].
AB  - After a tractus-intermedius rupture of the extensor aponeurosis of the ring
      finger, a Kirschner wire infection developed following an initially uncomplicated
      course after surgical care and PIP-joint transfixation. In spite of adequate
      therapy, destruction of the PIP-joint subsequently developed with an ulnar
      dislocation of the distal ring finger. With an unicondylar corrective osteotomy
      it was possible to achieve a normal position and an improvement in mobility.

PMID- 10420296
TI  - The reality behind suffering.

PMID- 10420297
TI  - Saving John Worthy.

PMID- 10420295
TI  - Gatekeepers.

PMID- 10420298
TI  - "Don't die of ignorance".

PMID- 10420299
TI  - Toward a broader view of values in cost-effectiveness analysis of health.

PMID- 10420300
TI  - Policy as product. Morality and metaphor in health policy discourse.

PMID- 10420301
TI  - The patient, the physician, and the truth.

PMID- 10420302
TI  - Science in the courtroom. A new approach.

PMID- 10420303
TI  - Pedestrian vs. train.

PMID- 10420304
TI  - Physician-assisted suicide. Promoting autonomy--or medicalizing suicide?

PMID- 10420305
TI  - The Oregon report. Don't ask, don't tell.

PMID- 10420306
TI  - Arthroscopic irrigation/distention systems.
AB  - Arthroscopic irrigation/distention systems (AI/DSs) are used during endoscopic
      orthopedic procedures to keep the cavity of a joint (such as the knee or
      shoulder) filled with pressurized distention solution. This expands the joint,
      thereby improving visualization. Controlled release of this solution from the
      joint is used to flush out debris. For this study, we evaluated units that use a
      motorized pump to propel fluid into the joint. We based our judgment primarily on
      how well the units sustained safe pressures inside the joint. We tested seven
      units from six suppliers, finding three of them Acceptable: the Karl Storz
      Arthropump 283300 20, the Richard Wolf Arthro Pump 2202, and the W.O.M. Arthro
      Surgimat. We found a fourth unit Conditionally Acceptable: the Linvatec APEX
      Universal C7100A. We recommend against purchasing any of the other three units
      because of problems or limitations in their performance. In addition to our
      testing and results, this Evaluation includes an overview of AI/DS technology. We
      also discuss how AI/DSs can contribute to extravasation of distention solution
      into a joint and note the pressure levels that are considered safe. In addition,
      we outline the primary factors a facility should consider when selecting an AI/DS
      -including whether a pump-type AI/DS is the best choice for every facility.

PMID- 10420307
TI  - Hazard report. Falling InfiMed X-ray monitors.

PMID- 10420309
TI  - [Psychological and social etiology of drug dependence].

PMID- 10420308
TI  - [Diagnosis and therapy of addictive diseases].

PMID- 10420311
TI  - [Diagnosis of drug dependence].

PMID- 10420310
TI  - [Psychiatric definition of addiction. Habituation, abuse and dependence].

PMID- 10420312
TI  - [Detection of drugs of abuse].

PMID- 10420314
TI  - [Drug-related emergencies with opiates].

PMID- 10420313
TI  - [Pharmacology of drugs of abuse].

PMID- 10420315
TI  - [Poisoning with amphetamines and designer drugs].

PMID- 10420316
TI  - [Drug withdrawal therapies].

PMID- 10420317
TI  - [Principles of ambulatory drug withdrawal treatment].

PMID- 10420318
TI  - [Principles of withdrawal from illicit drugs during inpatient therapy].

PMID- 10420319
TI  - [Drug substitution from the legal viewpoint].

PMID- 10420320
TI  - [Drug substitution in heroin dependence with methadone].

PMID- 10420322
TI  - [Hemostaseology--rational diagnosis].

PMID- 10420321
TI  - [Heroin-assisted treatment of opiate dependent patients. Experiences from Swiss
      trials for medical prescription of narcotics (PROVE)].

PMID- 10420324
TI  - [Father and son with muscle pain and loss of muscle strength. Acute trichinosis].

PMID- 10420325
TI  - [Combination therapy with ACE inhibitors and angiotensin receptor antagonists].

PMID- 10420323
TI  - [56-year-old patient with segmental florid colitis and colonic amyloidosis].

PMID- 10420326
TI  - [Beta-blockers. Value in cardiovascular diseases].

PMID- 10420328
TI  - Antibacterial activity of liposome-encapsulated antibiotics against Pseudomonas
      aeruginosa attached to the matrix of human dermis.
AB  - The present studies were undertaken to compare the antibacterial activity of
      liposome vesicles containing amikacin, ciprofloxacin or polymyxin B in the
      removal of P. aeruginosa organisms from microcolonies growing on sections of the
      matrix of human dermis. Encapsulation efficiency of antimicrobials inside
      cationic liposomes was 30% for amikacin, 50% for ciprofloxacin, and 100% for
      polymyxin B. The sections of dermis were colonized for 72 h with P. aeruginosa
      strains isolated from burn wounds. After that time, an intense growth of
      microorganisms on the dermis surface was observed. The sessile organisms were
      treated (with mild shaking) with solutions of either liposomal or free amikacin,
      ciprofloxacin, and polymyxin B for 1 h, and also with a mixture of liposomal or
      free ciprofloxacin and polymyxin B (1:1) for 20 min. After treatment with
      liposomal antimicrobials, the mean per cent of viable cells attached to the
      dermis was 48.7% for liposomal amikacin, 17.4% for liposomal ciprofloxacin, 19.1%
      for liposomal polymyxin B, and 3.6% for a mixture of liposomal ciprofloxacin and
      liposomal polymyxin B. Removal of P. aeruginosa from microcolonies growing on the
      dermal matrix was more effective when liposomal formulations were used compared
      to the free antibiotics. Therefore, cleansing of the contaminated matrix of human
      dermis with liposomal ciprofloxacin, liposomal polymyxin B or with the mixture of
      both liposomal antibiotics seems to increase the efficacy at the removal of
      attached bacterial cells.

PMID- 10420327
TI  - Effect of production variables on the physical characteristics of ibuprofen
      loaded polystyrene microparticles.
AB  - Ibuprofen-loaded polystyrene microparticles were prepared by the emulsion-solvent
      evaporation method from an aqueous system containing methylcellulose as the
      emulsion stabilizer. The effect of production variables on the formation and the
      physical characteristics of the microparticles were studied. While an increase in
      stirring speed, concentration of emulsion stabilizer up to a critical value and
      disperse phase volume decreased the mean diameter of the particles, increase in
      drug loading and concentrations of emulsion stabilizer beyond the critical value
      tended to increase in size. The microparticles, except those prepared at higher
      stirring speeds, and with higher disperse phase volumes and drug-loads, were
      found to be spherical.

PMID- 10420329
TI  - Microspheres of chitosan/poly(vinylalcohol) incorporating tetrasulphonated copper
      (II) phthalocyanine: preparation and characterization.
AB  - Tetrasulphonated copper (II) phthalocyanine (TCP), in the salt form, was
      incorporated into a blend of chitosan (CTS)/poly(vinylalcohol) (PVA) and
      microspheres were produced using the method of salt coacervation with
      (approximately 20% w/v) sodium sulphate. Spectroscopic analysis, DSC and TGA were
      carried out to characterize the form in which the macro-complex was immobilized
      in the blend. Alkaline treatment of the coagulating medium produces species which
      are more stable, but with a different morphology observed by scanning electronic
      microscopy (SEM). Microspheres coagulated in sodium sulphate and also in an
      alkaline salt medium (0.5 and 2.0 M NaOH) were exposed to a solution of the dye,
      methylene blue, at an initial concentration of 7 mg/l and maintained in contact
      for 14 h at 26 +/- 1 degrees C. The kinetic data revealed a decrease in the
      capacity of sorption of the microspheres that had received the alkaline
      treatment. It is proposed that the new morphology attributed to these species
      blocks some sites for complex formation, making them inaccessible to the dye.

PMID- 10420330
TI  - Polymers for sustained release formulations of dipyridamole-alginate microspheres
      and tabletted microspheres.
AB  - The preparation of dipyridamole (DIP) alginate (alg) microspheres by different
      methods or the incorporation of tragacanth (trgh), pectin or Eudragit L-100 55
      (Eud) in alg microsphere formulations did not provide a prolonged release of DIP
      at pH 1.2. Tabletted microsphere formulations containing alg, trgh, pectin,
      sodium carboxymethyl cellulose (CMC), sodium starch glycolate (SSG), carrageenan
      (carrg) or Eud as diluents in different ratios, produced tablets with good
      physical properties which did prolong DIP release. The type, viscosity and the
      ratio of the diluent polymer, microsphere size and the compression pressure were
      found to be important factors to produce tablets with desired properties. No
      advantage of the tablets containing alg microspheres and granulated diluents was
      observed over the tablets containing powdered diluents.

PMID- 10420332
TI  - Effect of formulation variables on in vitro drug release and micromeritic
      properties of modified release ibuprofen microspheres.
AB  - Modified release microspheres of the non-steroidal anti-inflammatory drug,
      ibuprofen, were formulated and prepared using the emulsion solvent diffusion
      technique. The contribution of various dispersed phase and continuous phase
      formulation factors on in vitro drug release and micromeritic characteristics of
      microspheres was examined. The results demonstrated that the use of Eudragit RS
      100 and Eudragit RL 100 as embedding polymers modified the drug release
      properties as a function of polymer type and concentration. Eudragit RS 100
      retarded ibuprofen release from the microspheres to a greater extent than
      Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced
      the particle size and drug release properties of the formed microspheres. It was
      found that the presence of emulsifier was essential for microsphere formation.
      Increasing the concentration of emulsifier, sucrose fatty acid ester F-70,
      decreased the particle size which contributed to increased drug release
      properties. Scanning electron microscopy revealed profound distortion in both the
      shape and surface morphology of the microspheres with the use of magnesium
      stearate as added emulsifier. The application of an additional Eudragit RS 100
      coat onto formed microspheres using fluid bed technology was successful and
      modulated the drug release properties of the coated microspheres.

PMID- 10420331
TI  - Solvent influence on spray-dried biodegradable microspheres.
AB  - Microspheres of fixed poly(D,L-lactic acid) (PDLLA) composition--Resomer
      R104:R202H (30:70)--containing 20% w/w rifampicin have been spray-dried from a
      range of acetonic, halogenated, and solvent mixtures thereof under constant
      process conditions to examine the influence of solvent selection on microsphere
      characteristics. Solubility of the polymer composite in the studied solvents
      determined the kinetics of polymer deposition during drying. Viscosity studies
      provided an indirect index of solvent power in ascending order: acetone (ACT) <
      dichloromethane (DCM) < chloroform (CFM) < halothane (HAL). Accordingly, poorer
      acetonic solvents produced a more open, porous matrix of increased mean diameter,
      whereas DCM, CFM and HAL generated more coherent matrices of greater density and
      elevated glass transition temperature, which significantly retarded drug release.
      Yield generally increased in parallel with solvent strength and microsphere
      density consistent with the proposed generalized particle formation mechanism.
      Residual solvent also increased with particle density, both parameters being
      interrelated and dictated by the inherent affinity of the polymer composite for
      individual solvents. In turn, the position of glass transition temperature (Tg)
      and the quantity of associated polymer stress-relaxation were a direct function
      of amount and persistence of organic residue. The magnitude of these changes
      determined the relative rates and extents of microsphere ageing, as measured by
      drug release studies. In general, rate of drug release increased with Tg, after
      corrections were made for specific surface area (r2 = 0.963). Overall, solvent
      choice for spray-drying has a remarkable influence on microsphere characteristics
      and, accordingly, technological as well as toxicological considerations should be
      paid during selection of same.

PMID- 10420333
TI  - Physical properties and heavy metal uptake of encapsulated Escherichia coli
      expressing a metal binding gene (NCP).
AB  - A recombinant Escherichia coli expressing the Neurospora crassa metallothionein
      gene (NCP) has previously been shown to remove low levels of Cd and other metals
      from solution. For further development as a biosorbent, the encapsulation of the
      NCP is investigated by various matrices. The NCP was encapsulated in alginate,
      chitosan-alginate or kappa-carrageenan, and its physical properties
      characterized. Results indicated that encapsulation in alginate resulted in
      fragile beads, whereas encapsulation in kappa-carrageenan or chitosan-alginate
      provided more physical and chemical integrity to the beads. Maximal heavy metal
      removal by cells encapsulated in carrageenan occurred within 3 h, while a gradual
      increase in removal was observed up to 24 h for cells encapsulated in chitosan
      alginate. Metal removal by cells encapsulated in alginate beads was lower than
      those encapsulated in carrageenan or chitosan-alginate.

PMID- 10420335
TI  - A novel method to prepare liposomes containing amikacin.
AB  - This work describes a novel method to prepare liposomal amikacin composed of
      soyabean lecithin and cholesterol; these were also prepared using two other
      methods (cast film method and proliposome method). Encapsulation efficiency was
      evaluated. Liposomes prepared by the new method, which combines the method of
      preparing proliposomes with freeze-drying, had the highest encapsulation
      efficiency. The influence of drug to lipid ratio on the encapsulation efficiency
      was investigated. The in vitro efflux of amikacin from liposomes with different
      lecithin: cholesterol ratios was also investigated.

PMID- 10420334
TI  - Effect of ultrasonication on the stability of oligonucleotides adsorbed on
      nanoparticles and liposomes.
AB  - In the present study, oligonucleotides were adsorbed onto the surface of cationic
      liposomes and nanoparticles at different ratios. As a result, the surface charges
      of the colloidal carriers were decreased with increasing oligonucleotide
      concentration. At a certain oligonucleotide concentration, complete charge
      neutralization led to the aggregation of the carrier systems. Further increasing
      oligonucleotide concentrations reversed the surface charge of liposomes and
      nanoparticles to a negative one. Ultrasonication was investigated as a possible
      means for the homogenization of the formed aggregates. However, the use of
      ultrasonication led to a time-dependent damage of oligonucleotides adsorbed onto
      AH-Chol liposomes and MMAEMC-nanoparticles, as well as of unbound
      oligonucleotides. Nearly 60% of the oligonucleotides adsorbed to MMAEMC
      nanoparticles and 65% of ODNs adsorbed to the liposomes were degraded by the
      effect of cavitation produced by ultrasonication within 10 min. In contrast, the
      oligonucleotides were protected from degradation when DEAE-stabilized PHCA
      nanoparticles were employed as ODN carriers. More than 80% of the
      oligonucleotides entangled in the surface matrix of these nanoparticles remained
      intact.

PMID- 10420336
TI  - Microencapsulation of the water-soluble pesticide Monocrotophos by an oil in oil
      interfacial polyaddition method.

PMID- 10420337
TI  - A new stabilizer used in microencapsulation.
AB  - In this communication, a new microencapsulation method is reported to entrap
      solid drug powder in an aqueous system. A hydrophobically modified, random
      polyacrylamide derivative was used as a stabilizer: with a hydrophilic back bone
      and hydrophobic side chain, it showed good dispersing and stabilizing effects in
      the preparation of microcapsules. The preparation of streptomycin microcapsules,
      using poly(lactide) and poly(caprolactone), showed the successful entrapment of
      streptomycin powder which is readily soluble in water (solubility larger than 20
      mg/ml). In addition, a low concentration of stabilizer (0.25%) is used and a
      short preparation process is also an advantage of the method.

PMID- 10420338
TI  - And there we shall wallow...

PMID- 10420339
TI  - Battlefield First Aid: a simple, systematic approach for every soldier.
AB  - First aid training for the trained soldier has been modified to incorporate the
      best available current clinical evidence and clinical experience. This annual
      training requirement will be achieved in one day and is introduced as Individual
      Training Directive (Army) 3 (ITD(A) 3) on 1 April 1999. With the exception of a
      short introductory video, the course is entirely taught and assessed on practical
      models. ITD(A) 3 teaches a systematic approach to every incident and to each
      injured soldier. This is presented in a robust, waterproof pocket aide memoire of
      Battlefield First Aid Drills, which is an individual issue item. The soldier must
      start with the MASTER DRILL to control the incident, and will then follow the
      INJURED SOLDIER DRILL to identify and treat life-threatening injuries. The best
      available clinical experience has resulted in the replacement of the three-sided
      dressing with the Asherman Chest Seal for open pneumothorax, and the introduction
      of a simple physiology based triage system. The best available clinical evidence
      has led to the removal of basic life support in the context of a soldier with no
      vital signs on the battlefield. It is retained as an 'add on' package for peace
      and peace-keeping environments.

PMID- 10420340
TI  - A unified emergency care system for the early management of emergencies in
      medicine.
AB  - Emergency medicine is increasingly compartmentalised. The Unified Emergency Care
      System (UECS) requires the user to consider every option for emergency care for
      each patient, in a logical manner that transcends these artificial compartments
      and recognises the relative priority of concomitant medical, surgical,
      environmental and toxicological problems. The system is presented as a series of
      icons, allowing considerations to be made at a glance. Drop shadows refer the
      user to detailed management protocols for specific conditions. The system follows
      the logical sequence of quick history, quick look, primary survey with
      resuscitation and secondary survey. Established management principles of airway
      breathing-circulation-disability (ABCD) are incorporated. The complexity of the
      management algorithms increases from first aider through medic, paramedic, and
      primary care physician to emergency physician. The stepwise care facilitates
      seamless immediate medical care between providers, teamwork, and the development
      of a structured series of training programmes.

PMID- 10420341
TI  - Conservative management of splenic trauma.
AB  - conservative approach to splenic trauma has been practised in many countries.
      Haemodynamically stable patients who have been carefully assessed clinically and
      radiographically may safely be treated non-operatively. In those patients who
      require surgery the spleen may be preserved by splenorrhaphy or partial
      splenectomy. This approach has been practised at our hospital and we present our
      experience over seven years to show that expectant treatment of splenic injury
      following trauma is safe.

PMID- 10420342
TI  - The CompPAC and PortaPAC portable ventilators bench tests and field experience.
AB  - The military and some civilian rescue agencies have a requirement for portable
      ventilators in the anaesthetic, resuscitation and pre-hospital environment. This
      paper describes two new portable ventilators specifically designed to satisfy the
      military requirement for lightweight, robust and versatile equipment which can
      also be used in a contaminated environment.

PMID- 10420343
TI  - Use of tissue glue in field situations.
AB  - Tissue glues are in widespread use in Accident & Emergency departments, and are
      simple to use. Results of closure of uncomplicated wounds using glue are
      comparable to traditional methods such as suture, 'sterile strips'. There are
      certain times in the field situation where evacuation of a casualty with a simple
      laceration could be impossible. These circumstances could be suitable for an
      individual suitably trained to effect wound closure using a tissue glue. This
      study simply set out to establish whether it was possible to train an infantry
      soldier how and when to close a wound using a tissue glue. A short period of
      instruction was followed by a practical session using wound simulators. It was
      found that the theoretical concepts and practical skills required to successfully
      glue a simulated wound were readily acquired by infantry soldiers, irrespective
      of their previous level of first aid training. The authors suggest that this
      concept should be pursued with the aim of field trials of cyanoacrylate tissue
      adhesives being carried out.

PMID- 10420344
TI  - Options for future military health surveillance systems.
AB  - This paper examines the requirement for health surveillance systems for military
      forces. Military health surveillance is the routine systematic collection,
      analysis, interpretation, and reporting of standardised, population based data
      for the purpose of characterising and countering threats to the military
      population's health, well-being and performance. The components of a health
      surveillance system should enable concurrent or retrospective analysis of health
      effects in military personnel using a cohort study design. Military hazards
      include trauma, infection, toxic effects, radiation, psychological stress and
      ergonomic stress. Variations in distribution of the hazard, distribution of the
      population, fragility of the cohort, and the variation in the duration and
      magnitude of exposure complicate definition of the exposed cohort. The
      measurement of biological effect is complicated by limits in knowledge about the
      relationship between exposure to the hazard and effect. A biological model that
      explains detection, causality, pathological process and health effect should
      support this knowledge. Lastly the definition of health effect needs to consider
      the difference between clinical activity rates and true measures of health
      outcome. The UK has a number of health surveillance systems including sentinel
      reporting, a population-based primary care reporting system and measures of
      medical discharge and death. The US Army is developing IT-based surveillance
      systems to link hazard, personnel and medical databases. The paper suggests a
      conceptual model for such a system in the UK military.

PMID- 10420345
TI  - The requirement for hepatitis A vaccine in Gurkha soldiers.
AB  - This Hepatitis A seroprevalence study aimed to determine the cost effectiveness
      of Hepatitis A vaccination for Gurkha soldiers. One hundred and sixty Gurkha
      recruits had serum analysed for Hepatitis A IgG. One hundred and fifty nine
      (99.4%) were IgG positive. Continuing to vaccinate Gurkha soldiers against
      Hepatitis A will confer little benefit and is not cost effective.

PMID- 10420346
TI  - Handsearching the Journal of the Royal Army Medical Corps for trials.
AB  - As part of the Cochrane Collaboration's international research endeavour, the
      authors carried out a handsearch of the RAMC Journal from 1948 to 1998, searching
      for randomised controlled trials (RCTs) and controlled clinical trials (CCTs).
      Ten trials were identified, of which 6 were RCTs and 4 were CCTs. The first trial
      was published in 1967. Four of the 10 identified trials were in the field of
      respiratory medicine, and 2 were in obstetrics and gynaecology. Of the 10 trials,
      only 3 had been found through a rigorous interrogation of Medline. The 7 newly
      identified trials were reported to the UK Cochrane Centre, and summary details of
      these trials were entered into Medline for use by clinicians and investigators in
      the future.

PMID- 10420347
TI  - Anterior knee pain syndrome. A review of current concepts and controversies.
AB  - Anterior knee pain syndrome is a common condition in the military population.
      Current management is moving away from surgery as the most effective treatment,
      towards prolonged specific physiotherapy to recondition the extensor mechanism,
      especially the Vastus Medialis Obliquus (VMO) component of the quadriceps.

PMID- 10420348
TI  - Travellers' diarrhoea: a military problem?
AB  - One hundred years ago, apart from the treatment of war injuries, the prevention
      and treatment of diarrhoea was the dominant preoccupation of the deployed
      military doctor. Since, then our understanding of the pathogenesis and
      pathophysiology of enteric disease has developed exponentially and our
      armamentarium for the treatment of enteric diseases has expanded considerably.
      However, diarrhoea continues to be the dominant military medical concern in
      deployed units. Here, we examine the evidence for this, discuss the reasons why
      and critically evaluate current modes of prevention and treatment that are now
      available to the military medical officer.

PMID- 10420349
TI  - Emergency medical conference South Africa, October 1998--a report on proceedings
      and clinical visits.
AB  - The South Africans are keen to adopt the Major Incident Medical Management and
      Support course, developed in the UK. South Africa can provide an excellent
      training ground for military personnel in the triage, resuscitation and surgical
      management of the patient with penetrating trauma. Johannesburg General Hospital
      has a high quality training system under the direction of Dr Ken Boffard. The
      nearby Baragwaneth Hospital is the closest to military surgical practice one can
      probably get in a civilian setting. There is an unprecedented opportunity for
      clinical skills training, and a wealth of research opportunities.

PMID- 10420350
TI  - World Health Organization "Roll Back Malaria" Campaign--report on a visit to the
      Central Drug Research Institute, Lucknow, India.

PMID- 10420351
TI  - Synchronous genital tract neoplasms.
AB  - Synchronous genital tract neoplasms constitute a more common clinical problem
      than would be generally expected. This case focuses on mixed mullerian tumours
      and postulates a mechanism for an increased incidence found associated with
      synchronous genital tract neoplasms.

PMID- 10420352
TI  - The history of colonic surgery in war.
AB  - The history of laparotomy for penetrating abdominal wounds is reviewed from its
      origins in the sixteenth century to the large series from World War II. It is
      shown that the mass casualties of World War I allowed the management of organ
      specific injuries to be studied. This review concentrates upon one of the most
      contentious topics in war surgery-the management of colonic wounds, and suggests
      that post-war surgical practice may have been influenced too strongly by
      experiences from the pre-Penicillin era.

PMID- 10420353
TI  - Trauma related symptoms following a tour in Fry.

PMID- 10420355
TI  - Mental health and Gurkhas.

PMID- 10420354
TI  - Malaria in the army.

PMID- 10420356
TI  - [The ophthalmologist, family physician for the eye?].

PMID- 10420357
TI  - [Results of a survey of current therapy of primary angle block glaucoma].

PMID- 10420358
TI  - [Asteroid hyalosis--development and disappearance of asteroid bodies of the
      vitreous body].

PMID- 10420359
TI  - [Effect of naftidrofuryl (praxilene) on optic nerve head blood flow in the
      patient with glaucoma].
AB  - PURPOSE: To evaluate the effects of an S2 specific antiserotonine agent
      (Naftidrofuryl) on the optic nerve head blood flow in glaucomatous patient.
      PATIENTS AND METHOD: 11 glaucomatous subjects were enrolled in the study. After
      administration of 200 mg naftidrofuryl twice daily for 7 days: values of optic
      nerve head blood flow (Fonh), velocity and volume were recorded in the temporal
      rim and cup of the optic nerve head. Blood flow measurements were performed by
      laser doppler flow-metry at day 0 and day 7 before and one and two hours after
      drug administration. RESULTS: Our study showed a significant improvement of
      perfusion pressure (p = 0.02) at day 7 and an increase of mean ophthalmique
      artery pressure (p = 0.03). DISCUSSION: Our preliminary results on a small number
      of patients and a short follow-up indicate that the use of naftidrofuryl may
      enhance optic nerve head blood flow in glaucomatous patients. Further studies may
      confirm these results.

PMID- 10420360
TI  - [Membrane-bound carbonic anhydrase (CA IV) in human corneal epithelium and
      endothelium].
AB  - PURPOSE: Active HCO3- transport through the corneal endothelial cell layer causes
      a dehydration of the corneal stroma and is thought to be driven by Na/K- and
      HCO3(-)-dependent ATPase as well as an electro-genic Na/HCO3- cotransport.
      Transmembrane bicarbonate transport has also been associated with the recently
      characterised membrane-anchored isoform of carbonic anhydrase (CA IV) in various
      tissues. We investigated the localisation of CA IV in human fresh and cultured
      epi- and endothelium at the light- (LM) and electron-microscopic (EM) level.
      METHODS: Postmortem corneas were obtained within 12 hours of death, stored in
      formaldehyde and sectioned in paraffin. LM immunohisto-chemistry was performed
      using the purified gamma-globulin fraction of a polyclonal chicken antibody
      against CA IV isolated from human kidneys. Epi- and endothelial cell cultures
      were grown in uncoated flasks under standard conditions and processed both for LM
      and EM immunohistochemistry using the same antibody. RESULTS: Lightmicroscopy of
      fresh tissue showed membrane staining for CA IV in the whole circumference of the
      endothelium. Little staining was also observed in some cells of the basal cell
      layer of the epithelium. Immunohistochemical staining at the EM level was
      confined to the cell surface of confluent cultures of both epi- and endothelial
      cells. CONCLUSION: The localisation of CA IV to the cell surface of fresh and
      cultured corneal endothelium suggests the presence of a membrane-bound ion
      exchange mechanism which may be important for HCO3- transport and corneal
      hydration. Compromising this mechanism by treatment with local carbonicanhydrase
      inhibitors may be of clinical importance in selected endothelial disease.

PMID- 10420362
TI  - [Titration of intraoperative anesthesia and postoperative analgesia].
AB  - PURPOSE: To evaluate a temporary retrobulbar catheter for local anesthesia in
      intraocular surgery and for postoperative analgesia after intraocular surgery.
      PATIENTS AND METHODS: The study included 40 patients undergoing pars-plana
      vitrectomy (n = 24) or cyclocryocoagulation (n = 16). After a retrobulbar
      injection through a 23 G needle, a commercially available 28 G flexible catheter
      was inserted through the needle. As soon as the patients complained about pain
      during or up to 24 hours after surgery, local anesthetics were injected through
      the catheter. RESULTS: Repetitive injections of anesthetics were necessary in 13
      patients during pars plana vitrectomy. Starting about 2 hours after surgery, 13
      patients after pars-plana vitrectomy and all patients who had undergone
      cyclocryocoagulation received up to 6 re-injections (every 1.5-5 hours). After
      all re-injections, the patients became pain-free within two minutes. The catheter
      was removed after 24 hours. CONCLUSIONS: The results suggest that a temporary
      insertion of a catheter into the retrobulbar space allows repetitive application
      of local anesthetics thus leading to a titrable local anesthesia and
      postoperative analgesia in intraocular surgery.

PMID- 10420361
TI  - [Color and form changes in the iris].
AB  - BACKGROUND: The high variability of iris structures can be used for diagnostic
      purposes. METHODS: An overview of the numerous changes visible at the slit lamp
      and possible diagnosis. RESULTS: Short description of possible irispathology with
      hints on pathology and treatment.

PMID- 10420363
TI  - [Mechanical model of ocular pulsatile flow for evaluating the ocular blood flow
      device with known pressure pulsations].
AB  - BACKGROUND: Ocular perfusion consists of steady-state and pulsatile components of
      flow. The latter can be measured clinically by means of the 'Ocular Blood Flow'
      (OBF)-device (O.B.F. Ltd, Crowshearst, GB). METHODS: 1) Mechanical 'eye': To
      mechanically simulate the effect of pulsatile flow in the eye, a mechanical 'eye'
      model was built: A brass chamber (9 cm3) was machined and fitted with in- and
      outflow connections. The front opening was covered with a taughtly fixed rubber
      membrane (COSANO, no. 5203.106, Migros AG, Zurich) which, as mechanical 'cornea',
      pulsated with changes in pressure within the mechanical chamber. 2) Mechanical
      'heart': To mechanically simulate pulsatile flow (i.e. pulsations in pressure
      like those within the human eye), two reservoirs were constructed of acrylic
      plastic and mounted on an upright optical bench with a millimeter scale. The
      reservoirs were constantly filled to overflowing with perfusate (tap water) and
      were connected by rubber tubing to the 'eye'-chamber. A computer-guided valve
      alternated between the 'systolic' and 'diastolic' columns of different,
      independently adjustable elevation. Frequency and duration of each pressure phase
      could also be independently adjusted via dialog with the computer. Input pressure
      levels were measured just outside the input using a transducer. The OBF-device
      measured the chamber pressure at the center of the rubber 'cornea'. RESULTS: Even
      the slightest alterations in the parameters (frequency, amplitude, and pressure)
      were precisely detected by the OBF-device, both graphically and numerically.
      CONCLUSIONS: Challenged by the mechanical model, the OBF-device demonstrated high
      sensitivity and fidelity of reproduction of any and all pulsations in intra-
      "ocular" -pressure.

PMID- 10420364
TI  - [The mechanical fundus perfusion model: blood flow velocity determined by ICG
      angiography and Heidelberg retina flowmetry].
AB  - BACKGROUND: Heidelberg Retina Flowmetry (HRF) is now popularly, perhaps even
      indiscriminately applied in eye research, without apparent concern for the fact
      that the results are given numerically, but without physical units. METHODS: 1)
      HRF: To challenge the HRF-device with known values of blood-flow velocity, a
      perfusion chamber with input and output connections was constructed of acrylic
      plastic. Three serial segments were milled to provide cross-sectional areas (1.93
      mm2, 3.33 mm2, and 5.08 mm2) and accordingly decreasing, true, clinically
      representative flow-velocity values. Under a constant perfusion setting of a
      calibrated clinical infusion pump (Perfusor Secura FT, B. Braun Medical AG,
      Sempach, CH), heparinized human blood (P. H.) was pumped through the chamber, and
      the HRF-parameter, "VELOCITY" was measured within one image encompassing the
      three chamber segments, using a 20 degrees x 5 degrees-field and a 20 x 20-pixel
      measuring "window". 2) HRA: Immediately thereafter, our perfusion model was
      placed in front of the Heidelberg Retina Angiography device, the infusion pump
      started at the same constant level, and a 1 cc bolus of ICG dye was added to the
      blood. Digital ICG-angiography was then conducted, and the images analyzed on
      screen. RESULTS: In the three segments of the perfusion chamber, flow velocities
      determined ICG-angiographically were 11.5 mm/s, 6.7 mm/s, and 4.4 mm/s,
      respectively. The corresponding values for HRF- "VELOCITY" were 5.3, 4.2, and
      3.4, respectively (no units). CONCLUSIONS: Under identical perfusion conditions,
      the phenomenologically (ICG-angiographically) determined values of flow velocity
      in the 3 perfusion chamber segments ran similar to (but not numerically
      coincidental with) those determined for HRF-parameter "VELOCITY". Extrapolation
      of HRF-values to true physical units is, thus, feasible.

PMID- 10420365
TI  - [Secondary complications in surgery of epiretinal membranes].
AB  - MATERIAL AND METHODS: Preoperative findings, intraoperative and postoperative
      complications as final results of 70 consecutive cases of idiopathic or secondary
      ERM operated by the same retina surgeon were analyzed. RESULTS: In all cases the
      ERMs were successfully removed from the fovea. The mean v.a. increased from 0.34
      +/- 0.2. to 0.54 +/- 0.31, (p < 0.05) postoperatively. Idiopathic and secondary
      ERMs both showed significant improvement after surgery. Complications included
      intraoperative hemorrhage and retinal tears. Postoperative progressive nuclear
      sclerosis, retinal tears causing detachments, macular edema and retinal
      pigmentary epitheliopathy. CONCLUSIONS: Performing surgery for ERMs is worthwhile
      on eyes with major decreased v.a. and on eyes with metamorphopsia but only
      moderately reduced vision. Postoperative complications are frequent but can
      usually be managed successfully. Of them only retinal detachment is of some worse
      prognosis on the final functional outcome.

PMID- 10420366
TI  - [Nitric oxide donors and retinal vein occlusion].
AB  - PURPOSE: The development of extended territories of nonperfused capillaries after
      branch vein occlusion (b.v.o.) is correlated to the secondary constriction of the
      arteriole crossing the occluded territory. Local NO release is impaired soon
      after b.v.o. and accounts for the secondary arteriolar constriction. In this
      report we present evidences showing that administration of an NO donor can
      reverse the secondary arteriolar vasoconstriction observed after b.v.o. MATERIAL
      AND METHODS: Simultaneous preretinal NO profiles and arteriolar diameter
      measurements were performed in miniature pigs after experimental b.v.o. The
      effect of preretinal microinjections of the NO-donor Sodium Nitroprusside on the
      arteriolar diameter was studied. RESULTS: A significant arteriolar
      vasoconstriction occurring in parallel with a preretinal [NO] decrease was
      observed 4 hours after b.v.o. Microinjection of the NO-donor SNP caused a
      segmental, reversible arteriolar dilatation. CONCLUSION: The present results,
      suggest that local NO supply in the first hours following b.v.o. may contribute
      to protect the retina against ischemic injury.

PMID- 10420367
TI  - [Results and complications of surgery for idiopathic macular holes].
AB  - AIM OF THE STUDY: We conducted a retrospective study in order to evaluate the
      anatomical and functional outcomes of eyes with constituted idiopathic macular
      holes as well as the rate of peri and postoperative complications when patients
      are operated on by conventional surgery. MATERIAL AND METHODS: Twenty-nine
      consecutive eyes (26 patients) presenting idiopathic macular holes (stage II or
      III) were included in the study. Conventional vitreous surgery with a three-port
      system and a careful peeling of the internal limiting membrane and/or an
      epiretinal membrane was performed. History, preoperative eye examination,
      operative findings, postoperative course and final examination were reviewed.
      RESULTS: Anatomical closure was obtained in 76% of the cases after one operation
      and in 93% following additional operation. Cataract was the most frequent
      complication (71%). Peripheral iatrogenic, retinal tears were found in 14% of the
      cases perioperatively, and retinal pigment epithelial anomalies in 24% of the
      cases postoperatively. DISCUSSION: Conventional surgery of the idiopathic macular
      holes with careful peeling of the internal limiting membrane and/or an epiretinal
      membrane is successful for the anatomic closure of the hole in most of the cases.
      Complications are without major incidence in the visual function.

PMID- 10420368
TI  - [Measuring choroid blood flow with a new confocal laser Doppler device].
AB  - A new instrument for the measurement of choroidal blood flow in the fovea is
      presented. It is based on the laser Doppler method and a confocal optical system
      with an indirect detection of the Doppler shifted light. METHOD: The intensity of
      the laser beam (785 nm) at the cornea is 90 microW. Measurements were obtained
      from a normal population of 21 subjects under resting conditions without dilating
      the pupil. RESULTS: The reproducibility of the choroidal blood flow, based on 5
      measurements of 10 s each in 5 randomly selected subjects, is 9%. The minimum
      detectable change for a statistical significance of p < or = 0.05, based on a
      population of 21 subjects and 10 s measurements, is 9%. CONCLUSION: This new
      compact instrument appears to be suitable for the investigation of the physiology
      and pharmacology of choroidal blood flow and the effect of age-related macular
      degeneration.

PMID- 10420369
TI  - [The electroretinogram (ERG) of the mouse: normal values, optimal stimulation and
      recording].
AB  - PURPOSE: The electroretinogram (ERG) is an appropriate method to evaluate the
      retinal function in a variety of animal models. In this study we present suitable
      conditions of stimulation and recording in the dark-adapted mouse. METHODS: Mice
      (n = 15) were dark-adapted during 14 hours and anesthetized with a single
      intraperitoneal injection of xylazine/ketamine. Pupils were dilated and a d.c.
      silk-silver electrode or a AgCl-contact-lens electrode was placed on the cornea.
      The electroretinogram (ERG) was obtained by Ganzfeld stimulation over a range of
      6 log units of intensity (8 x 10(-2) - 8 x 104 cd/m2). Intensity, duration and
      the interval of the light stimuli were varied separately. RESULTS: Reproducible
      values of the intensity-response functions are obtained for the a-, b- and c
      waves of the ERG under well controlled adaptation- and stimulus-conditions. C
      wave amplitudes are best evaluated using d.c.-recording and a stimulus duration
      of 4 seconds. The position of the d.c.-silk-silver electrode on the cornea can
      affect the ERG-amplitudes. Using a contact-lens electrode, the recorded b-wave
      amplitudes are on average 20% below those recorded with a centrally positioned
      d.c.-silk-silver electrode. Stimulus-intervals of at least 60 seconds are
      recommended at high intensities. CONCLUSIONS: An unequivocal assessment of
      retinal function requires reproducible ERG-values over a wide range of
      intensities. To obtain these, well controlled and standardized experimental
      conditions are required.

PMID- 10420370
TI  - [Central corneal diseases].
AB  - BACKGROUND: Central corneal pathologies can lead to an irreversible decrease of
      best corrected visual acuity if not diagnosed and treated appropriately. This
      article reviews the differential diagnosis of central corneal opacities in the
      newborn, of central infectious corneal ulcers, and the therapy of sterile,
      central keratolysis. MATERIAL AND METHODS: Authors' personal experience and
      review of the literature. RESULTS: Flow charts for diagnosis and treatment
      strategy have been elaborated. CONCLUSIONS: Corneal opacities in newborns create
      an emergency situation. In order to treat successfully and avoid or diminish
      amblyopia, it is imperative to rule out congenital glaucoma. The aetiology of
      central corneal ulcers should always be confirmed by positive cultures to be able
      to treat specifically. When the standard topic therapy fails, one has to consider
      rare bacteria, parasites, virus, or patients' compliance. The treatment of
      central sterile keratolysis in rheumatoid arthritis must be intensive and
      immunosuppression has to be performed early enough in the course of prevent the
      formation of a descemetocoele or spontaneous corneal perforation.

PMID- 10420371
TI  - [Study of the optic papilla and nerve fiber layer in glaucoma].
AB  - BACKGROUND: For diagnosis and follow-up of glaucoma an exact evaluation of the
      optic nerve disc and the nerve fiber layer is necessary. METHODS: The slit-lamp
      evaluation of the optic nerve disc and nerve fiber layer is presented as well as
      the evaluation with the Nerve Fiber Analyzer and the Heidelberg Retina Tomograph.
      RESULTS: Signs of a glaucomatous optic disc include a difference of more than 0.2
      in the vertical cup to disc (CD) ratio between the eyes, a vertical CD ratio
      exceeding more than 0.1 the horizontal, larger CD ratios in small optic discs,
      notching of the neuroretinal rim, an enlarged zone beta of parapapillary
      chorioretinal atrophy, and peripapillary hemorrhages. Atrophy of the nerve fiber
      layer may be localized or diffuse. Both types of atrophy may be present at the
      same time. CONCLUSIONS: Knowledge of all signs of the glaucomatous optic disc and
      forms of nerve fiber layer atrophy allows an earlier diagnosis of glaucoma and an
      earlier recognition of progression.

PMID- 10420372
TI  - [Exit of the retinal central vascular trunk and extent of para-papillary
      atrophy].
AB  - PURPOSE: To evaluate whether the position of the central retinal vessel trunk
      exit on the lamina cribrosa spatially correlates with the location of
      parapapillary atrophy in glaucoma. METHODS: Color stereo optic disc photographs
      of 79 patients with primary or secondary open-angle glaucoma and 53 normal
      subjects were morphometrically evaluated. We determined the position of the
      central retinal vessel trunk exit on the lamina cribrosa surface and measured the
      area of parapapillary atrophy in four 90 degrees quadrants. RESULTS: After
      correction for normal values, the beta zone area of parapapillary atrophy in the
      glaucoma eyes was significantly larger, when measured in the disc quadrant most
      distant to the central retinal vessel trunk exit than as if measured in the
      quadrant containing the vessel trunk exit. CONCLUSIONS: Position of the central
      retinal vessel trunk exit on the lamina cribrosa influences the location of
      parapapillary atrophy in glaucoma. The longer the distance to the central retinal
      vessel trunk exit, the more enlarged is parapapillary atrophy.

PMID- 10420373
TI  - [Effect of decreased ocular perfusion pressure on iris blood flow measured by
      laser Doppler flowmetry].
AB  - PURPOSE: To determine whether iris blood flow (IBF) is regulated in response to
      an acute decrease in mean ocular perfusion pressure (PPm = MOAP-IOP, MOAP = mean
      ophthalmic arterial pressure) induced by increasing the intraocular pressure
      (IOP). METHODS: Iris blood flow was measured using a slit lamp incorporating a
      laser Doppler flowmetry (LDF) module. The study was conducted on 12 normal
      volunteers (14 to 59 years old). IOP was raised using a scleral suction cup. In
      Exp. #1, the suction pressure was successively raised in steps of 50 to 100 mm
      Hg, each lasting about 10 sec, until IOP reached the MOAP level. In Exp. #2, the
      suction was raised to 200 mm Hg in 4 successive steps of 2 min duration. RESULTS:
      In Exp. #1, no significant change of IBF was observed for small decreases of PPm
      (< 23%); greater decreases of PPm resulted in a linear IBF decrease (p < 0.01).
      In Exp. #2, such a IBF versus PPm decrease was also observed (p < 0.001).
      Immediately after release of suction, a significant, transient IBF increase of
      79% above baseline level was observed. CONCLUSION: These results suggest that
      some IBF regulation occurs for small PPm decreases (< 23%); no IBF compensatory
      mechanism appears to operate for further decreases of PPm (> 23%).

PMID- 10420374
TI  - [Diseases of the vitreo-macular interface].
AB  - BACKGROUND: A pathological vitreomacular adhesion is a common pathogenetic
      mechanism of various clinical entities such as idiopathic epimacular membrane,
      vitreomacular traction syndrome, and macular hole. Vitrectomy is recommended for
      these disorders. Anatomical and functional results in 207 operated eyes are
      discussed. PATIENTS AND METHODS: The results of a vitrectomy in 3 groups of
      patients were compared: idiopathic epimacular membrane (group 1, n = 52),
      vitreomacular traction syndrome (group 2, n = 48); macular hole (group 3, n =
      107; 33 eyes without and 74 eyes with retinal detachment). After excision of the
      vitreous gel, a thin layer of epimacular vitreous cortex was identified and
      excised by gentle aspiration under continuous air infusion. In 50 of the 107 eyes
      of group 3, the vitrectomy was combined with the application of a drop of
      autologous blood to the macular hole. RESULTS: A vitreomacular adhesion existed
      in 56% of group 1, 74% of group 2, and 84% of group 3. The visual acuity improved
      in 54%, 62% and 50% of eyes of the 3 groups, respectively. More eyes with an
      initial visual acuity of at least 40/200 achieved final vision of 80/200 or
      better (57%, 65% and 48% of group 1 to 3, respectively) than eyes with acuities
      of less than 80/200. A postoperative cataract was the main reason for reduced
      visual results in all cases. In group 3-eyes with retinal detachment and/or
      myopia, a significant postoperative visual improvement was achieved only after
      application of autologous blood to the macular hole. CONCLUSION: A pathological
      vitreomacular adhesion was identified in the majority of patients with idiopathic
      epimacular membranes, vitreomacular traction syndrome, and macular hole,
      respectively. Vitreoretinal surgery for syndromes with vitreomacular traction is
      indicated as it warrants a significant improvement of visual function and relief
      of metamorphopsia.

PMID- 10420375
TI  - [Macular edema: from symptom to diagnosis].
AB  - BACKGROUND: In this study, the "Macular edema" syndrome is examined in detail
      from the symptoms right through to the diagnosis. The 9 most important
      differential diagnoses are also listed, as well as a summary of the currently
      applicable therapy recommendations. MATERIAL AND METHODS: This overview is based
      on existing literature as well as own case studies. RESULTS: The symptoms of
      macular edema consist of visual acuity deterioration, micropsy, metamorphopsy,
      reduced colour perception, as well as central or paracentral scotoma.
      Ophthalmologist checks should include a case history (age, diabetes, hypertonia,
      allergies, cataract surgery?), a detailed examination of the fundus, if possible
      with a slit-lamp and a contact or non-contact lens, whereby one must pay
      attention here to the swelling of the retina as well as the presence of hard
      exsudates in the macular region. It is important to use fluorescence angiography
      in this case, to achieve a correct differential diagnosis, and eventually for
      treatment. This angiography may equally reveal a capillary leakage, a cystoid
      macular edema, a leaking point or a choroidal neovascularization. The
      differential diagnosis can be divided into the following commonly-occurring
      groups: age-related macular degeneration/macular edema after a branch or central
      retinal vein thrombosis/central serous chorioretinopathy/Irvine-Gass syndrome
      after cataract operation/uveitis/epiretinal fibroplasia/juxtafoveal retinal
      teleangiectasis and tumors (choroidal melanoma, metastasis and hemangioma).
      TREATMENT: Apart from the seldomly applicable causal therapy, the following
      treatments can be used: laser photocoagulation, anti-inflammatory and rinse
      medication, and in some cases vitrectomy as well as a low dosage of radiation
      therapy. CONCLUSIONS: In the case of macular edema the ophthalmologist's
      responsibility is to perform a differential diagnosis and recommend appropriate
      and sensible methods or treatment.

PMID- 10420376
TI  - [Examination of the posterior eye segment during HIV infection: what is new?].
AB  - AIM: A patient was till now considered at high risk of developing a
      cytomegalovirus retinitis when the CD4+ cells were under 100/mm3. The risk was
      major when the CD4+ were under 50/mm3. With the onset of a Highly Active
      Antiretroviral Therapy (HAART) the follow-up of AIDS patients has changed. The
      introduction of a HAART is associated with an increase in CD4+ cells. The aim of
      the study was to highlight clinical modifications of classical AIDS associated
      ocular diseases. MATERIALS AND METHODS: Clinical observations will be correlated
      to recent data published in literature. RESULTS: An immune response can be
      present against opportunitic infections. Cytomegalovirus retinitis can present an
      atypical pattern: The host immune response can be responsible for an increase of
      ocular inflammation, a hypopyon can even be seen. An intense vitritis can be
      present and frosted angiitis syndrome can be observed. A severe macular edema can
      be present and has to be treated with posterior sub-Tenon's steroid injections.
      CONCLUSION: With the restoration of an immune response under HAART therapy,
      clinical manifestation of AIDS associated ocular diseases has changed and the
      differential diagnosis of ocular lesions must include endogenous uveitis.

PMID- 10420377
TI  - [Entoptic phenomena and potential visual acuity].
AB  - REVIEW OF PREOPERATIVE EVALUATION OF VISUAL FUNCTION: In the presence of media
      opacities, the prevision of the potential postoperative visual acuity constitutes
      often a complicate diagnostic problem. Its solution requires the experience of
      the ophthalmologist, who should take into account various elements from the
      patient's visual aggravation progress, the dissociation between far and near
      vision under mesopic and scotopic conditions, the actual grating acuity and the
      eventual hand movement and light-perception, as well as, elements from the
      patient's objective examination, i.e., from the biomicroscopy with direct and
      indirect illumination through the still transparent media and from the binocular
      ophthalmoscopy of the fundus. METHODS REVIEWED: Purkinje figure and luminous
      darting points visualization. POSSIBLE PREDICTIONS: Light induced entoptic
      imagery, as Purkinje figure and luminous darting points, visualization, helps as
      a supplementary diagnostic procedure, for the prevision of a low, but socially
      useful postoperative visual acuity.

PMID- 10420378
TI  - [Visual hallucinations and illusions, symptoms frequently misdiagnosed by the
      practitioner].
AB  - INTRODUCTION: Visual hallucinations or illusions are not a rare symptom. However,
      they are often unrecognized. Unawareness of the meaning of these symptoms often
      mislead both the patient and his physician. PURPOSE: To define and describe the
      types of visual illusions and hallucinations which can be commonly encountered in
      neuro-ophthalmological practice. METHODS: Overview article. RESULTS:
      Hallucinations are a perception not based on sensory input, whereas illusions are
      a misinterpretation of a correct sensory input. Both phenomenon can be due to
      medication or drug, or to an altered mental status. Visual hallucinations can be
      formed (objects, people) or unformed (light, geometric figures). They can be
      generated either by a lesion on the antechiasmatic pathway, by a seizure
      phenomenon, by a migrainous phenomenon, or by a release phenomenon secondary to
      visual differentiation. Investigations will be directed towards a retinopathy, an
      optic neuropathy, a chiasmal or retrochiasmal lesion, or a bilateral antechiasmal
      lesion (Charles Bonnet syndrome). Visual illusions include meta-morphopsias,
      micro- macropsias, polyopia, palinopsia (visual perseveration), achromatopsia,
      Pulfrich phenomenon, or subjective vertical deviation. Illusions can be due to
      lesions of the retina, the optic nerve, the visual cortex (primary or
      associative), or the graviceptive pathways. CONCLUSIONS: As most patients do not
      spontaneously mention their symptoms, history taking is essential. The first step
      is to rule out medication or an altered mental status as the possible cause of
      these symptoms. Then, careful visual function examination should provide a good
      insight in the location of the lesion.

PMID- 10420379
TI  - [From the symptom to electroretinography diagnosis].
AB  - Retinal function can be documented noninvasively and objectively by
      electroretinography, complementing clinical examinations. Symptoms of
      nightblindness and of dayblindness with photoaversion, nystagmus, poor vision in
      infants or unclear visual field defects are meaningful indications for ERG
      testing. We use standardized (ISCEV) full-field single flash ERGs to evaluate the
      function of the rod- and of the cone-system. In infants, general anesthesia is
      useful to combine an abbreviated ERG protocol with ophthalmoscopy and fundus
      photography. ERG testing facilitates to distinguish between functional deficits
      in the rod- and cone-system, between congenital-stationary retinal dysfunction
      and progressive retinal heredo-degenerations. Frequently a functional deficit of
      the retina without ophthalmoscopic changes can be assessed. These entities
      include achromatopsia, congenital stationary night blindness, early stages of
      retinitis pigmentosa (RP) or progressive cone dystrophy, as well as toxic retinal
      changes. Congenital amaurosis Leber (LCA), infantile RP, Usher's syndrome and
      retinal involvement in other neuropediatric or metabolic syndromes can be
      diagnosed or excluded by ERG recording early-on. Synoptic evaluation of the full
      field ERG, pattern-ERG and VEP completes neuro-ophthalmological screening.

PMID- 10420381
TI  - [Ophthalmologic examination of the infant].
AB  - BACKGROUND: The examination of the infant needs patience, special knowledge and
      skills to get to a reliable judgment of the visual functions of the child. For
      the practitioner it is important to rely on clinical methods without the
      apparatus reserved to ophthalmologic institutions. METHODS: Based on the
      literature and personal experience the clinical examination techniques for
      infants are presented and the results are discussed with respect to the possible
      diagnosis. CONCLUSION: Simple clinical tests reveal most symptoms in the infant.
      Electrophysiological tests and imaging procedures are sometimes necessary.

PMID- 10420380
TI  - [Leukokoria in a child: emergency and challenge].
AB  - PURPOSE: To heighten the awareness of the medical world to the importance of
      correct and rapid diagnosis in the presence of leukocoria in the child. METHODS:
      Starting with the presenting symptom, the authors present the guide lines to
      follow in a practical manner in order to reach a diagnosis in the principal
      retinal diseases causing leukocoria. RESULTS: A white pupil is due to
      retinoblastoma in almost half of all cases. Other possible causes, in order of
      frequency, are: persistent hyperplastic primary vitreous, Coats' disease, ocular
      toxocariasis, retinopathy of prematurity, retinal hamartomas. Diagnosis can
      usually readily be made by ophthalmoscopy, but may be problematic when the
      clinical presentation is atypical or in the presence of late complications. Age,
      sex, laterality, heredity, and in particular the presence or absence of
      calcifications and the size of the globe, are the main criteria for diagnosis.
      Ultrasonography plays a major role in this essential quest for correct diagnosis,
      quest which may ultimately lead to enucleation. CONCLUSION: Leukocoria in the
      child is a danger signal demanding certain diagnosis within the shortest possible
      time.

PMID- 10420382
TI  - [Concomitant strabismus: of strabismus in strabismus syndromes].
AB  - PURPOSE: To show how to progress from the deviation of the visual axis (provided
      the diagnosis of concomitant strabismus is certain) to the classification of the
      squint in one out of the different squint syndromes and consequently to adopt the
      appropriate therapeutic strategy. METHOD: Every sign correlated with the
      deviation contributes to progress step by step to the diagnosis of a given squint
      syndrome. The age on onset of strabismus, either convergent or divergent, and its
      characteristic, intermittent or constant, allow in a first step to evaluate the
      potential binocularity, as well in early as late (acquired) strabismus. The first
      group of early strabismus includes manifest infantile strabismus and
      microstrabismus. Both have abnormal binocularity. The possibility of functional
      amblyopia, angle variability and additional incomitances have to be investigated.
      Early intermittent strabismus keeping a potential normal binocularity are seldom.
      In the second group of late onset strabismus, retinal correspondence has to be
      investigated by correspondence tests and prism or bifocus compensation to
      distinguish between the two possible types (including the accommodative forms of
      strabismus), i.e. decompensated microstrabismus with abnormal binocularity or
      normosensorial strabismus with potential normal binocularity. In some cases
      potential binocularity may be initially uncertain and/or remain later on
      subnormal. RESULTS: As the result of this systematic approach, every cases of
      squint can be classified in one out of the different squint syndromes. Based on
      the precise diagnosis, the appropriate treatment can be carried out. The goals of
      treatment which can be reached in every syndrome are indicated. DISCUSSION: For
      an overall view of the squint syndromes a classification with two entrances are
      necessary, on the one hand early or late onset, on the other hand normal or
      abnormal binocular conditions. CONCLUSION: This approach of concomitant
      strabismus should serve as guide lines for clinical practice.

PMID- 10420383
TI  - [Diplopia: from symptom to diagnosis].
AB  - BACKGROUND: This overview gives a rough frame how to proceed to a quick diagnosis
      and possible differential diagnosis in patients with diplopia. METHOD: A thorough
      interview concerning the onset of symptoms, invariability, and subjective
      perception is mandatory. The first step before examining ocular motility is to
      verify monocular or binocular double vision. When the reported diplopia is
      binocular, the examiner can carry out the red-glass test to determine the site of
      the double image. In a next step monocular range of movement in the 9 directions
      of gaze is evaluated to search for incomitance. RESULTS: The main causes of
      diplopia are palsies of the oculomotor nerves, mechanical restriction-
      posttraumatic or inflammatory--, supranuclear lesions and disturbed neuromuscular
      junction. CONCLUSION: With a simple and clear diagnostic diagram ist is easy to
      work out the underlying cause of diplopia.

PMID- 10420384
TI  - [60 years Alfred Vogt Foundation. The prize winners and their work].
AB  - BACKGROUND: The Alfred Vogt-Prize is the highest award in Switzerland for
      scientific research in ophthalmology and related fields of research. The Alfred
      Vogt institution was founded 60 years ago in Zurich, where Alfred Vogt was
      working as the head of the department of Ophthalmology of the University
      Hospital. For this reason the activity of the foundation was recognized on the
      occasion of the annual meeting of the Swiss Ophthalmology Society in Zurich 1998.
      METHOD AND RESULTS: The biographical notes of Alfred Vogt were compiled. The
      winners of the prize and their distinguished papers are listed below. During the
      60 years since the establishment of the foundation the prize was rewarded to 53
      researchers or research teams. The awards were divided among several researchers
      in those years when many outstanding papers were submitted. On the other hand in
      many years no award was given due to lack of award worthing research papers. 7
      researchers received the prize more than once. CONCLUSION: The list of the
      winners of the Alfred Vogt-Prize reflects the history of the Swiss Ophthalmology.
      To a number of researchers the awards allowed them further research, which let to
      excellent contributions to international Ophthalmology.

PMID- 10420385
TI  - Immunohistochemical detection of cytokines and cell adhesion molecules in the
      synovial membrane.
AB  - This paper describes the immunohistochemical techniques which can be used to
      detect cytokines and cell adhesion molecules in synovial membrane tissue,
      including a list of reagents and possible problems in each technique. It also
      describes three methods of quantitation of the resultant immunohistochemical
      detection, including the recent innovation computer-assisted digital video image
      analysis, and lists the advantages and disadvantages of each quantitation
      technique. This information will be a useful summary for any scientist interested
      in applying such techniques to the detection of cytokines and cell adhesion
      molecules in human tissue sections.

PMID- 10420386
TI  - Further studies of the effects of diamide and hydrogen peroxide on calcium
      signaling in the human platelet.
AB  - Intracellular calcium levels were measured in Fura-2/AM loaded human platelets.
      Diamide (30 microM) reduced the Ca2+ response to serotonin (1 microM), but not to
      4-bromo-A23187 (1 microM). The small reduction in the maximum fluorescence
      produced by diamide was not mirrored by a change in the sensitivity of Fura-2
      pentapotassium salt to Ca2+. Changes in the spectral properties of Fura-2 thus
      cannot wholly explain the reduced serotonin response following diamide treatment.
      Hydrogen peroxide (500 microM) produced a steady increase in the observed
      fluorescence ratio that was partially inhibited by the phospholipase C inhibitor
      U-73122 (1.5 microM). In the absence of platelets, H2O2 reduced the Ca(2+)
      sensitivity of Fura-2 pentapotassium salt, although it is not clear the extent to
      which this effect contributes to the reduction in the Ca2+ response to serotonin
      seen after H2O2. It is concluded that some caution may be warranted in the
      interpretation of the effects of H2O2 upon receptor-mediated Ca2+ signaling as
      measured using Fura-2.

PMID- 10420388
TI  - Effects of Cerebrolysin on in vitro primary microglial and astrocyte rat cell
      cultures.
AB  - In recent years the potential use of neurotrophic factors in the prevention
      and/or treatment of neurodegenerative diseases has received much attention. To
      determine whether Cerebrolysin, a porcine brain-derived peptide preparation, was
      able to modulate in vitro lipopolysaccharide (LPS)-induced microglial activation
      and to test the direct effect of Cerebrolysin on astrocyte morphology, survival
      and proliferation, rat glial and astrocyte cell culture experiments were carried
      out. The morphology of microglia, ameboid/activated and flat/resting, was
      examined under contrast microscopy and cell counts obtained. In addition, the
      release of interleukin (IL)-1 beta and brain-derived neurotrophic factor (BDNF)
      was measured from cell culture supernatant using an enzyme-linked-immunoassay
      (ELISA). The results obtained in this study clearly suggest a protective effect
      of Cerebrolysin as revealed by downregulation of microglial activation after LPS
      treatment as well as by the control of IL-1 beta expression. No significant
      differences were observed on astrocyte morphology, survival or the production
      and/or release of BDNF. In conclusion, these in vitro studies indicate that
      Cerebrolysin might exert a neuroimmunotrophic function which can in turn reduce
      the extent of inflammation and accelerate neuronal death under pathological
      conditions such as human neurodegenerative disorders.

PMID- 10420387
TI  - Effects of saiboku-to on the survival of human eosinophils.
AB  - In recent years, bronchial asthma has come to be regarded as a chronic
      inflammatory disease of the respiratory tract, with mast cells, lymphocytes and
      eosinophils playing important roles in its pathogenesis. Proteins contained in
      eosinophil granules, especially major basic protein (MBP), eosinophil cationic
      protein (ECP), eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase
      (EPO), can cause tissue injury. When stimulated, eosinophils release mediators
      such as leukotriene C4 (LTC4) and platelet activating factors (PAF). Thus, they
      are recognized as effector cells that are actively involved in the development of
      allergic inflammation. In this study, eosinophils from healthy volunteers were
      used to investigate the effects of Saiboku-to on eosinophils whose survival had
      been prolonged through stimulation with eosinophil-activating cytokines such as
      interleukin (IL)-3, IL-5 and granulocyte macrophage colony stimulating factors
      (GM-CSF). As a result, the cytokine-enhanced survival of eosinophils was
      significantly shortened by the addition of Saiboku-to. These findings suggest
      that Saiboku-to has the potential to inhibit allergic responses by directly
      affecting eosinophils which are related to allergic inflammation.

PMID- 10420389
TI  - Influence of a protein hydrolysate from green algae on the activity of some
      ATPase systems in frog skeletal muscle.
AB  - The present study investigated the effect of a protein hydrolysate from green
      algae cultured in the Bulgarian region of Rupy, on the enzyme activity of frog
      skeletal muscle. The activity of pure Mg(2+)-ATPase, Mg2+,Ca(2+)-ATPase, NaHCO3
      stimulated Mg(2+)-ATPase and the latter in the presence of the inhibitors NaSCN
      and NaN3 in mitochondrial (B-3) and membrane (B-12) fractions were determined
      before and after treatment with the protein hydrolysate from green algae (30 and
      300 micrograms/ml). The differences between ATPase activity of mitochondrial and
      membrane fractions were described and it was established that in the B-3
      fraction, the activity of the NaHCO3-stimulated Mg(2+)-ATPase and Ca(2+)
      dependent Mg(2+)-ATPase were accelerated by increasing concentrations of the
      algae protein hydrolysate. Irrespective of the different (equal or inverse) dose
      dependent effects, the protein hydrolysate stimulated Mg(2+)-ATPase and that
      inhibited by NaSCN an NaN3 bicarbonate-stimulated Mg(2+)-ATPase activity. In most
      of the probes, the protein hydrolysate produced some increase in enzyme activity
      of NaHCO3-stimulated Mg(2+)-ATPase and Ca(2+)-dependent Mg(2+)-ATPase in B-12
      fractions. The observed properties of the algae protein hydrolysate suggest that
      it is capable of stimulating enzyme processes in addition to having some
      antitoxic effect in skeletal muscle.

PMID- 10420390
TI  - Nociceptin/orphanin FQ: effects on thermoregulation in rats.
AB  - Nociceptin/orphanin FQ is a 17 amino acid peptide which acts as a potent
      endogenous agonist of the opioid receptor-like 1 (ORL1) receptor. ORL1 receptor
      is a G protein-coupled unique member of the cloned opioid receptor family. We
      have investigated the effects of nociceptin (1, 10 and 100 nM) on the temperature
      sensitivity of neurons from the preoptic area of the anterior hypothalamus
      (PO/AH) in rat brain slices. The body temperature of male Wistar rats was
      measured after intrahypothalamic application of nociceptin (1 nM) via cannulas in
      the PO/AH. Low dose nociceptin (1 nM) significantly increased (p < 0.05)
      temperature sensitivity (TC) of warm-sensitive PO/AH neurons, while the high
      concentration (100 nM) decreased TC in both warm-sensitive and temperature
      insensitive neurons. Similar agonistic activity was obtained after addition of
      [Phe1 psi (CH2-NH) Gly2]-nociceptin-(1-13)-NH2 (1, 10 and 100 nM), recently
      proposed to be a selective antagonist of the nociceptin receptor. Neither
      antagonism nor additive synergism were observed when nociceptin and [Phe1 psi
      (CH2-NH) Gly2]-nociceptin-(1-13)-NH2 were applied simultaneously in equimolar
      concentrations. The selective opioid OP3 receptor antagonist CTOP, the selective
      opioid OP2 receptor antagonist nor-binaltorphimine and selective opioid OP1
      receptor antagonist naltrindol had no influence on the effects of nociceptin on
      temperature sensitivity in PO/AH neurons. In vivo experiments showed that
      nociceptin (1 nM; 1 microliter/rat) significantly decreased body temperature (p <
      0.05) between 30 and 60 min after intrahypothalamic application. These data are
      in agreement with the hypothesis that the specific action of endogeous substances
      on body temperature appears to be closely related to a specific change in the
      temperature sensitivity of warm-sensitive PO/AH neurons.

PMID- 10420392
TI  - Decrease in serum LDL cholesterol with microcrystalline chitosan.
AB  - Peroral microcrystalline chitosan (MCCh; 3 capsules, each 400 mg b.i.d.) or
      placebo was given for 8 weeks in a double-blind manner to 51 healthy obese women
      just before routine hospital and home meals. Weight records, serum lipids (total,
      LDL and HDL cholesterol, triglycerides) and safety laboratory parameters were
      monitored before the trial and at 4, 6 and 8 weeks of treatment. In a subgroup of
      subjects with a body mass index > or = 30 who had not changed their eating
      habits, serum LDL cholesterol decreased 0.57 +/- 0.72 mmol/l (n = ll) at 4 weeks
      in the MCCh group and 0.10 +/- 0.60 mmol/l (n = 14) in the placebo group (p <
      0.05). At 8 weeks, LDL cholesterol reduction was 0.48 +/- 0.91 mmol/l in the MCCh
      group and 0.26 +/- 0.57 mmol/l in the placebo group (p > 0.1). In all subjects,
      the reduction in LDL cholesterol at 4 weeks was 0.48 +/- 0.72 mmol/l (n = 24) in
      MCCh subjects and 0.18 +/- 0.58 mmol/l (n = 27) in placebo subjects (p = 0.057),
      and 0.52 +/- 0.69 mmol/l and 0.31 +/- 0.63 mmol/l, respectively, at 8 weeks (p >
      0.1). MCCh did not significantly alter serum total and HDL cholesterol (p > 0.1),
      but slightly increased serum triglycerides compared to placebo (p = 0.015-0.06).
      No reductions in weight were observed in any treatment group. Chitosan was well
      tolerated and no serious adverse events or changes in safety laboratory
      parameters were noted including serum fat-soluble vitamins A and E, and serum
      Fe++ and transferrin.

PMID- 10420391
TI  - Effects of fujibitol, a remedy for nasal symptoms of immediate and delayed type
      allergic reactions.
AB  - The effects of Fujibitol, a remedy for the nasal symptoms of immediate and
      delayed type allergic reactions were studied. Fujibitol inhibited active systemic
      anaphylaxis in mice, heterologous passive cutaneous anaphylaxis (PCA) in rats,
      Masugi's nephritis in rats and delayed type hypersensitivity induced by picryl
      chloride in mice, but did not affect homologous PCA or immune complex-induced
      glomerulonephritis in rats. These results suggested that Fujibitol is effective
      for treatment of allergy-induced inflammation since IgG and type IV allergic
      reactions were inhibited.

PMID- 10420393
TI  - Antagonism of the renin-angiotensin system, hypertrophy and gene expression in
      cardiac myocytes.
AB  - In response to humoral and mechanical stimuli, the myocardium adapts to increased
      work load through hypertrophy of individual muscle cells. Myocardial hypertrophy
      is characterized by an increase in cell size in the absence of cell division and
      is accompanied by changes in gene expression. Angiotensin II (Ang II), the
      effector peptide of the renin-angiotensin system (RAS), regulates volume and
      electrolyte homeostasis and is involved in cardiac and vascular growth in rats.
      In this review, the role of RAS in myocyte protein synthesis (myocyte
      hypertrophy) and in induction of gene expression will be discussed in rat
      cardiomyocytes in culture. Traditional RAS can be considered as a system in which
      circulating Ang II is delivered to target tissues or cells. However, a local RAS
      has also been described in cardiac cells and evidence has been accumulated for
      autocrine and/or paracrine pathways by which biological actions of Ang II can be
      mediated. These actions of Ang II are primarily mediated through Ang II receptors
      subtype I (AT1-R). When evaluating the effects of Ang II in situ, both changes in
      circulating levels and local production have to be taken into account.
      Contrasting results have been found concerning the in vitro effect of Ang II on
      the protein synthesis in cardiac myocytes and can be at least partly be
      attributed to methodological problems such as assay of de novo protein synthesis
      and isolation and separation procedure of cardiac myocytes. The Ang II-induced
      hypertrophic effect also depends on the existence of nonmyocytes in a cardiocyte
      culture. In rat cardiocytes, AngII also causes induction of many immediately
      early genes (c-fos, c-jun, jun-B, Egr-1 and c-myc) and induces also late markers
      of cardiac hypertrophy (skeletal alpha-actin and atrial natriuretic peptide
      expression) and growth factors (TGF-beta 1 gene expression). In vivo AngII via
      AT1-R, causes not only ventricular hypertrophy but also a shift to the fetal
      phenotype of the myocardium. Angiotensin-converting enzyme inhibitors and AngII
      receptor antagonists of the subtype I not only induce the regression but also
      prevent the development of cardiac hypertrophy in experimental rat models.

PMID- 10420394
TI  - Discovery of new CCK2 receptor antagonists. A review of pharmacological studies.
      Part I: Development of potential therapeutic tools for gastrin-related
      gastrointestinal diseases.

PMID- 10420395
TI  - [FMN-reductase from Escherichia coli and its effect on the activity of luciferase
      from marine bacterium Vibrio fischeri].
AB  - Interactions of luciferases isolated from Vibrio fischeri 6 and Escherichia coli
      JM109(pF3) (bearing cloned V. fischeri luxAB genes) with FMN reductase isolated
      from E. coli JM109 were studied. FMN reductase formed a stable complex with
      luciferase, suggesting similar properties of the FMN reductases in the
      taxonomically close families Vibrionaceae and Enterobacteriaceae.

PMID- 10420396
TI  - [Changes in the trophic organization of mitotic cycle of Candida utilis after
      exposure to RNAse from Bacillus intermedius].
AB  - The effect of the RNase from Bacillus intermedius on the growth and trophic cycle
      of Candida utilis was studied. The RNase at concentrations of 0.001-0.01
      microgram/ml stimulated yeast growth by 30-40% as compared to the control,
      reduced the mitotic cycle of the yeast by shortening its G1 phase, and decreased
      the number of exotrophic cells in the G1 phase to a minimum. It was suggested
      that RNase is involved in the regulation of the transition of cells from the exo-
      to endotrophic state.

PMID- 10420397
TI  - [Effect of conditions od Trichosporon pullulans culturing on the synthesis of
      immunomodulating glycoprotein].
AB  - An extracellular glycoprotein (GP) exhibiting immunomodulating activity produced
      by the yeast Trichosporon pullulans grown in a defined ethanol-containing medium
      differed substantially in its composition from that of the yeast cell walls:
      therefore, it cannot be considered a structural component of the cell walls. In
      batch culture, the greatest GP production (40 mg/l) occurred in the exponential
      phase of the yeast growth. Under continuous cultivation, in both chemostat and pH
      auxostat regimes, the specific rate of GP synthesis (qGP) increased with the
      increasing specific growth rate (mu) and reached 1.55 mg/(g h) at mumax. Under
      limitation of the yeast growth by zinc qGP was three times lower than under
      nitrogen or iron limitation. The rate of GP production depended inversely on the
      oxygen concentration.

PMID- 10420398
TI  - [Effect of arsenite on the physiological and cytological properties of
      Pseudomonas putida strains capable of degrading polycyclic aromatic
      hydrocarbons].
AB  - Some physiological and cytological properties of Pseudomonas putida strains
      resistant to arsenite and capable of degrading polycyclic aromatic hydrocarbons
      were studied. The resistance of P. putida BS202 (NPL-1) to arsenite proved to be
      determined by chromosomal genes, while the arsenite resistance of P. putida BS238
      (pBS2; pBS3031) was by plasmid-borne genes. Arsenite affected the pattern and
      rate of growth of strain BS202 (NPL-1) in media with naphthalene or salicylate as
      carbon sources; particularly, it lengthened the lag phase. Electron-microscope
      analysis of the strains studied did not reveal any arsenite-induced destructive
      changes in the cell envelope. At the same time, arsenite in the growth medium
      induced some alterations in the structure of the outer membrane of strain BS202
      (NPL-1) and the cytoplasmic membrane of strain BS238 (pBS2; pBS3031) and, in both
      strains, led to an increase in the density of intramembrane particles on the EF
      face of the freeze-fractured cytoplasmic membrane. Arsenite resistance probably
      evidently protects cells of both strains from greater damage. Physiological and
      cytological data suggest that the mechanisms of arsenite resistance in the
      strains studied are different.

PMID- 10420399
TI  - [Effect of carbon, nitrogen, and phosphorus sources of nutrition on the growth of
      R-, S- and M-dissociants of Pseudomonas aeruginosa].
AB  - The effect of glucose, nitrate, and phosphate on the stationary-phase growth
      parameters of the R, S, and M dissociants of the hydrocarbon-oxidizing bacterium
      Pseudomonas aeruginosa K-2 was studied. The data obtained were analyzed in terms
      of the Mitscherlich equation. S dissociant required less glucose than other
      dissociants, whereas M dissociant required less nitrogen and phosphorus. These
      findings were confirmed by the results of investigation of the combined action of
      glucose, nitrate, and phosphate in a 3 x 3 x 3 factor experiment. It is
      anticipated that M dissociant must prevail under conditions of nitrogen and
      phosphorus deficiency, and S dissociant must be dominant in the case of optimally
      chosen proportions between the biogenic elements studied.

PMID- 10420400
TI  - [Characteristics of carbohydrate metabolism of R-, S- i M-dissociants of
      Pseudomonas aeruginosa].
AB  - R and S dissociants of the hydrocarbon-oxidizing strain Pseudomonas aeruginosa K
      2 differed but little in their growth in a minimal defined medium with glucose as
      the source of carbon and energy. At the same time, the number of cells of M
      dissociant in the late exponential phase was five orders of magnitude less than
      that of R and S dissociants. The growth of M dissociant was accompanied by the
      accumulation of formate in the culture liquid and a concurrent decrease in pH.
      All three dissociants contained the key enzymes of the Entner-Doudoroff pathway
      of glucose oxidation; however, the activities of these enzymes, especially 6
      phosphogluconate dehydrogenase, were low in M dissociant. Conversely, the
      activity of formate dehydrogenase in cells of M dissociant was higher than in
      other dissociants. The activity of 6-phosphogluconate dehydrogenase, a key enzyme
      of the pentosephosphate pathway of glucose oxidation, was detected only in S
      dissociant. The peculiarities of the carbohydrate metabolism of M dissociant are
      probably responsible for its poor growth on glucose and determine the more
      pronounced anaerobic type of its metabolism.

PMID- 10420401
TI  - [Neuroembryologic considerations on the so-called malformative syringomyelia].
AB  - Modern neuroradiological techniques can evidence the presence of liquid-filled
      spaces within the spinal cord, called syringomyelia. These lesions may be
      associated with numerous causes, the most frequent of which is an abnormality of
      the shape of the posterior fossa. Neuropathological analysis of these cavities
      demonstrates whether they are completely lined by ependymal cells or not.
      Comparing neuropathological and embryological data suggests that syringomyelia is
      a secondary deformation affecting a normally-formed spinal cord. The unique case
      in which such a cavity is really a primary malformation is the so-called
      myelocytocele. The most frequently encountered lesion associated with
      syringomyelia is the Chiari abnormality (either type I or II). In this case, the
      size of the posterior fossa is too small whereas neural elements are normal.
      Since Chiari abnormality may be familial, some genes are likely to be involved
      for its generation. In experimental animals, it has been shown that genes
      belonging to the Hox family or the Mhox gene control the development of the final
      shape of the occipital bone. Syringomyelia is thus a secondary event affecting
      the spinal cord and due to a distant cause.

PMID- 10420402
TI  - [Syringomyelia and Chiari abnormality in the adult. Analysis of the results of a
      cooperative series of 285 cases].
AB  - This chapter discusses the retrospective data found in 285 patients with
      syringomyelia associated with Chiari abnormality and collected from 18
      neurosurgical departments. A pre and postoperative MRI study and a minimum follow
      up of at least 2 years were required. A scale of severity was fixed and tested
      before and after treatment. The size of the cyst, the degree of the foraminal
      obstruction were analyzed. The mean age at diagnosis was about 39 years and the
      duration of symptoms about 6.7 years. Sensory disorders were present in 91% of
      cases, pain in 66% and motor deficit in about 60%. According to our functional
      classification, the majority of our patients were moderately disabled and only
      10.8% showed a severe impotence. Results of the two major surgical procedures,
      foramen magnum decompression (FMD) (88% of cases) and cyst shunting procedures
      (SP) (32% of cases) were evaluated with a mean follow-up period of 6.7 years
      (ranged from 2 to 14 years). Better clinical and morphological results (87% of
      stabilization or improvement for FMD versus 71% for SP) were obtained by FMD
      procedure comparing to SP, with the same rate of complications.

PMID- 10420403
TI  - [Syringomyelia in children].
AB  - From 1985 to 1997, 442 children were treated for syringomyelia. One hundred and
      eighty eight had syringomyelia in association with Chiari I malformation. In 65%
      of the case scoliosis was the initial symptom. All these children were treated by
      posterior fossa decompression, 95% were clinically improved or stabilized. The
      scoliosis remained unchanged or improved in only 44% of the cases. Many other
      causes of craniovertebral junction anomalies have been found (Chiari II,
      achondroplasia, mucopolysaccharidosis, craniosynostosis, Dandy-Walker
      malformation, posterior fossa cysts, birth injuries, or other causes of raised
      intracranial pressure). All these children were treated by posterior fossa
      decompression or when possible treatment of the cause. Features and results are
      presented. Spinal causes (diastematomyelias, lumbar lipomas, ventricule
      terminalis, spinal tumors ...) are presented. Whe discuss the treatment of
      scoliosis with specific attention to scoliosis associated to isolated
      syringomyelia.

PMID- 10420404
TI  - [Post-traumatic syringomyelia].
AB  - Clinical and neuroradiological data were recorded in a series of 73 spinal cord
      injured patients (33 in Nantes, 40 in Paris-Bicetre) in whom a post traumatic
      syringomyelia (PTS) developed. These findings and a review of the literature
      allow to point out some of the main characteristics in such a pathology. Clinical
      symptoms are frequent, the commonest of them are pain and sensory loss but any
      alteration of the neurological status after spinal cord injury has to be
      considered. Magnetic resonance imaging (MRI), sagittal and axial T1 and T2
      weighted images, confirms the diagnosis of syrinx (area with the same signal
      intensity as CSF extending beyond the site of the initial lesion at least on 2
      vertebral segments). MRI allows the diagnosis when it is performed in the follow
      up of asymptomatic patients. So PTS is not infrequent in spinal cord injured
      patients, for some of them in the first year after the trauma. The highest
      incidence is found in patients with complete thoracic lesions. Pathophysiology
      and surgical management have to take into account post traumatic residual
      stenosis of the vertebral canal.

PMID- 10420405
TI  - [Non-traumatic arachnoiditis and syringomyelia. A series of 32 cases].
AB  - We conducted a retrospective study of 32 patients treated for syringomyelia
      associated with non-traumatic arachnoid scarring. We selected the cases with
      documented history of arachnoiditis with pre and post-operative clinical
      evaluation of the neurological status and anatomical study on MRI with a minimal
      follow-up of one year. Extensive arachnoid scarring (Group I) was noted in 18
      cases, after spinal meningitis in 15 cases (tuberculosis in 9 cases, listeria in
      3 cases, pyogenic meningitis in 3 cases), subarachnoid hemorrhage in 3 cases.
      Focal arachnoid scarring (Group II) occurred in 10 cases, related to spinal
      surgery in 5 cases (meningiomas: 2, neurinomas: 2, thoracic discectomy: 1), to
      peridural anesthesia in 1 case, thoracic disc herniation in 1 case, Pott's
      disease in 1 case, no obvious cause in 2 cases. Basal arachnoid scarring without
      hindbrain herniation (Group III) was associated with birth injuries in 4 cases.
      Shunting of the syrinx to the subarachnoid or peritoneal cavity was associated
      with a recurrence rate of 60% whereas microsurgical dissection of the arachnoid
      scar and decompression of the subarachnoid space with a recurrence rate of 33%,
      with a mean follow-up period of 28 months. Successful long-term management of the
      syrinx was associated with basal or focal spinal arachnoid scarring, no history
      of spinal meningitis, microsurgical dissection of the arachnoid scar and
      decompression of the subarachnoid space.

PMID- 10420406
TI  - [Characterization of sensation disorders and neuropathic pain related to
      syringomyelia. A prospective study].
AB  - The present prospective study aimed to perform quantitative sensory testing (QST)
      in patients with painful or painless syringomyelia before and after surgical
      treatment of their syrinx (at 3 and 9 months). Eighteen consecutive patients with
      cervical or dorso-lumbar syringomyelia completed the study and 9 underwent
      surgery. Twelve patients had central neuropathic pain (of whom 6 were followed
      up). Spontaneous pain and brush-evoked allodynia were assessed. Von Frey hairs,
      vibrameter and a thermotest device were used to determine the mechanical-,
      vibratory-, thermal-detection thresholds, and the mechanical and thermal pain
      thresholds. Results showed evidence of deficits in temperature and pain
      sensibility in 17 cases, often associated with deficits in vibration and touch
      sensitivity (11 cases). Magnetic resonance scan, including axial images,
      demonstrated good correlation between paramedian extension of the syrinx and the
      laterality of thermal deficits. Somatosensory evoked potentials (11 patients)
      were abnormal in 9 cases at level, and showed good correlation with deficits in
      vibration. The magnitude of the thermal and tactile deficit was similar between
      areas of spontaneous pain and adjacent non painful areas. Surgery induced a
      significant decrease of tactile deficits, and to a lesser extent, of thermal
      deficits. Effects on neuropathic pain were positive in 3 patients (total
      disappearance of pain) and negligible or negative in 3 patients, despite collapse
      of the syrinx (in 2 cases). These results confirm that QST are useful in clinical
      practice to quantify the clinical results of surgery in patients with
      syringomyelia, and allow some hypotheses about the mechanisms of neuropathic pain
      in these patients.

PMID- 10420408
TI  - [Imaging of syringomyelia].
AB  - MRI is the best imaging method to evaluate syringomyelia. It is important to
      study from the posterior cranial fossa to the sacro-lumbar region and also the
      supra-tentorial structures. This complete analysis is essential to classify the
      syringomyelia and to investigate other associated malformations. Radiographs and
      CT scan are useful to analyze bone structures. For MRI, the new sequences with
      phased-array coils are also very important to study the entire spinal cord and
      the posterior fossa. It is essential to study the spinal cord with sagittal and
      axial spin echo T1 and fast spin echo T2 weighted images with sometimes coronal
      view, particularly when the patient presents a scoliosis, to have a correct
      morphological and functional evaluation. MRI gives an excellent study of the
      spinal cord with an excellent analysis of a primitive or foraminal syringomyelia,
      but also traumatic, infectious or post arachnoiditis syringomyelia. Spin echo T1
      weighted images with injection of gadolinium can be used if an intra-medullary
      tumor is suspected. MRI is also useful for the post-operative follow up to
      evaluate the persistence of the medullary cyst and the enlargement of the foramen
      magnum.

PMID- 10420407
TI  - [Evoked motor and sensory potentials in syringomyelia].
AB  - Seventy nine patients were admitted for syringomyelia. Fifty-nine had a
      malformative syringomyelia, 15 a post-traumatic syrinx and 5 a syringomyelia
      related to a meningitis. For all the patients, the diagnosis of syringomyelia was
      performed by MRI with measures of syrinx extension and transverse diameter.
      Posterior tibial somato sensory evoked potentials (PT SEP), median (M SEP),
      trigeminal (V3 SEP), brain stem auditory evoked potentials (BEAP), cortical and
      cervical motor evoked potentials (MEP) were correlated with clinical and
      radiological findings. SEP abnormalities were not correlated with the duration of
      symptoms. PT SEP proved to be more sensitive than M SEP, MEP abnormalities were
      very frequent (72% of the cases), even without clinical motor deficit. Trigeminal
      SEP were more sensitive than BAEP which were not related to the presence of
      associated cranio vertebral abnormalities. No significant relationship between
      clinical and radiological results was observed. There was a positive relationship
      between electrophysiological and radiological results. Nevertheless, a good
      correlation was observed between lateral clinical, MRI and electrophysiological
      results. Abnormal trigeminal SEP were detected in 46.6% of the patients with high
      cervical syringomyelia. In all cases, trigeminal SEP and MEP should be done in
      association with M and PT SEP as both of them detect subclinical evidence of
      spinal cord dysfunction in syringomyelia.

PMID- 10420410
TI  - [Treatment of syringomyelia].
AB  - Treatment of syringomyelia utilizes two operative approaches: posterior fossa
      decompression and syrinx shunting (including subarachnoid, pleural and peritoneal
      shunting). MRI study is nowadays the indispensable tool for the evaluation of
      patients with syringomyelia and allows to choose the best therapeutic option.
      Posterior fossa decompression is regarded as the procedure of choice for
      syringomyelia with Chiari. After intradural exploration, additional steps may be
      necessary as excision of the cerebellar tonsils. Other therapeutic alternatives
      are associated with higher complication rates. Patients with persistent focal
      syrinxes after PFD respond best to syringoperitoneal shunts. For the management
      of post-traumatic syringomyelia, a large decompressive laminectomy at the
      fracture site is recommended; the use of a drain does not offer any long-term
      therapeutic advantage. Syringoperitoneal shunting is the treatment of post
      infection syringomyelia but good long-term result is rare in this type of syrinx.

PMID- 10420409
TI  - [Dynamic MRI in the evaluation of syringomyelic cysts].
AB  - We report the results of a MR velocity study of the cerebrospinal fluid including
      36 patients with syringomyelic cysts (25 with a foraminal syringomyelia, 7 with a
      post-traumatic cyst, 2 with a tumoral spinal cord cyst, 2 with a spinal
      arachnoiditis). Velocity measurements were performed in the cysts and in the
      pericystic subarachnoid spaces and compared with clinical data, evolutive pattern
      of the disease, cyst volume, degree of stenosis of the cranio-cervical junction
      (in patients with Chiari I) or of the spinal canal (in post-traumatic cases), and
      with the extension of the cyst (post-traumatic cases). Cyst velocities correlated
      in the pre operative course with the clinical status of the patients and with the
      volume of the cyst. Correlation with the degree of foraminal stenosis was
      uncertain and no correlation was found with the duration of the disease course.
      In the post-operative course cyst velocity decreased and velocity of the
      subarachnoid spaces increased. Onset of the systolic peak occurred sooner in the
      cyst than in the subarachnoid spaces. We believe that this point may be important
      in the pathogenesis of the disease. We consider that systolic and diastolic cyst
      velocities respectively greater than 2.3 cm/s and 1.5 cm/s in the post-operative
      course may characterize aggressive cysts. In the future comparison of velocity
      measurements in patients with Chiari I without syrinx and patients with Chiari I
      related syringomyelia may be helpful for a better understanding of the natural
      history of the syringomyelia.

PMID- 10420411
TI  - [History, controversy and pathogenesis].
AB  - In this paper, we discuss the historical and pathophysiological aspects of
      syringomyelia. Defined as fluid cavities extending beyond several segments within
      the spinal cord this pathological entity is a condition with many possible
      causes. Hindbrain herniation is the commonest foramen magnum abnormality
      associated with the so called "hindbrain related syringomyelia". A history of
      birth injury, a small posterior fossa, an arachnoid scarring of the basal
      cisterna, a segmentation abnormality of the superior cervical vertebrae, a
      hydrocephalus or arachnoid cyst of the posterior fossa are often present in this
      context. Previous theories of the origin and the mechanism of syringomyelia
      progression have been controversly proposed. Gardner and colleagues postulated
      that the primary event is the incomplete embryonic opening of the outlets of the
      fourth ventricle. The fluid arrived in the syrinx along the embryologically
      natural route down the central canal. Their hydrodynamic theory states that with
      each arterial pulse, the outflow of CSF is transmitted from the fourth ventricle
      down to the syrinx via the central canal. Most patients have patent fourth
      ventricle foramina and evidence of communication between the ventricle and the
      syrinx is rare. Williams then proposed his "cranio-spinal pressure dissociation
      theory". Significant pressure differential occur daily during activities that
      increase intrathoracic pressure such as sneezing, coughing and could be
      transmitted to the spinal fluid from the epidural spinal veins. The progression
      of the cavity is better understood and analyzed with dynamic MR imaging and
      quantitative analysis. The CSF flow from the cranial to the spinal subarachnoid
      space results from the expansile motion of the brain during the cardiac cycle.
      The progression of the cavity is based on pressure acting on the surface of the
      cord and does not require any communication of the fourth ventricle with the
      central canal and the syrinx. The origin of fluid cavity remain questionable.
      Aboulker but also Ball and Dayan pointed out the role of the perivascular spaces
      and the DREZ which are involved in the communication between the perimedullar
      CSF, the spinal cord extracellular spaces and the central canal. Other causes of
      syringomylia include acquired conditions which could be grouped under the heading
      of "non-hindbrain related syringomyelia". Arachnoid scarring is related in many
      case to spinal trauma or occurs after spinal meningitis, spinal intradural
      surgery, peridural anesthesia, subarachnoid hemorrhage. Rarely an extra medullary
      compression is discussed. The mechanism involved is here again an alteration of
      the CSF flow at the spinal level.

PMID- 10420412
TI  - Integrating advanced practice nurses into inpatient care.

PMID- 10420414
TI  - On the "path" to improving patient care and increasing satisfaction: a positive
      outcome of managed care.

PMID- 10420413
TI  - A model for comprehensive care in bone marrow transplantation.

PMID- 10420415
TI  - Coming together to improve cancer care.

PMID- 10420416
TI  - A graft versus host disease prevention and management tool: a mechanism for
      improving continuity of care.

PMID- 10420417
TI  - Surviving the cancer, surviving the treatment: acute cardiac and pulmonary
      toxicity.
AB  - Even though acute cardiopulmonary toxicities occur infrequently, nurses must be
      aware of the quick responses that are needed to manage these occurrences. Narrow
      therapeutic index of cancer treatment is well recognized and attributable to the
      relative inability of cancer treatment to discriminate effectively between normal
      and cancer tissues. As a consequence, a broad range of cardiopulmonary toxicities
      is encountered in clinical practice that not only has an impact on a patient's
      quality of life and ability to accept potentially effective treatment but also
      may have serious life-threatening consequences. Because of the amount of time
      spent directly with the patient receiving cancer treatment, the nurse is the one
      who recognizes subtle changes in the patient's status that indicate acute
      complications. Subsequently, measures must be taken to minimize acute
      complications when they occur.

PMID- 10420418
TI  - Breast cancer and African American women: moving beyond fear, fatalism, and
      silence.

PMID- 10420419
TI  - Surviving and thriving: the nurse scientist in the clinical setting.

PMID- 10420420
TI  - Does emotional expression make a difference in reactions to breast cancer?
AB  - PURPOSE/OBJECTIVES: To examine the feasibility of using an emotional expression
      intervention with patients with cancer and test the hypothesis that emotional
      expression improves psychosocial adjustment. DESIGN: Sequentially randomized
      pretest/post-test design with repeated measures. SETTING: Two radiation therapy
      (RT) facilities. SAMPLE: Women completing RT for stage I or II breast cancer, who
      spoke and read English, were independent in self-care, and provided written
      consent. Subjects (N = 44) were middle-aged (mean = 53.6 years), Caucasian,
      married, and well educated. METHODS: Following a baseline interview, subjects
      were sequentially randomized to an attentional control group, a single dose, or a
      three-dose emotional expression writing group. Interventions were administered at
      the time of completion of RT. Follow-up telephone interviews were completed at 1,
      4-6, 16, and 28 weeks post-RT. MAIN RESEARCH VARIABLES: Positive and negative
      affect, intrusiveness of thoughts, use of avoidant coping, side effect severity,
      trait negative affectivity, content of written essay, and themes derived from
      content analysis. FINDINGS: A high level of acceptance and completion of
      emotional expression existed, but no effect of the intervention on psychosocial
      adjustment was evident. Process measures in the three-dose group changed as
      expected. No relationship existed between content changes and outcome measures.
      CONCLUSIONS: Emotional expression is feasible for patients with cancer, but the
      efficacy of the intervention in improving mood and decreasing cognitive intrusion
      and avoidance was not supported. Emotional expression processes were consistent
      with those seen in other samples and may influence outcomes that were not
      addressed in this study. IMPLICATIONS FOR NURSING PRACTICE: More extensive
      testing is needed, including additional outcome variables. Essays reveal concerns
      around communication, recurrence, and health behavior changes that should be
      considered in practice.

PMID- 10420421
TI  - Chemotherapy medication errors: descriptions, severity, and contributing factors.
AB  - PURPOSE/OBJECTIVES: To expand the limited body of knowledge of medication errors
      involving chemotherapy. DESIGN: Exploratory, descriptive. SAMPLE: 160 (26%) of
      620 randomly selected Oncology Nursing Society members employed in direct patient
      care positions and 26 nonmembers with chemotherapy administration
      responsibilities employed in different settings. METHODS: Mailed investigator
      developed questionnaire containing 24 demographic and open-ended questions. MAIN
      RESEARCH VARIABLES: Nurses' descriptions of the nature and severity of
      chemotherapy medication errors. FINDINGS: Chemotherapy medication errors were
      reported to have occurred in the workplace of 63% of the respondents, and 140
      errors were described. Errors included under- and overdosing, schedule and timing
      errors, wrong drugs, infusion-rate errors, omission of drugs or hydration,
      improper preparation of drugs, and chemotherapy given to the wrong patients.
      Stress, understaffing, lack of experience, and unclear orders were cited as
      factors believed to contribute to the occurrence of the errors. Most of the
      errors were reported internally, but only 3% were known to be reported to
      national reporting databases or drug manufacturers. CONCLUSIONS: Chemotherapy
      medication errors are not uncommon and infrequently are reported externally to
      databases or manufacturers. IMPLICATIONS FOR NURSING PRACTICE: Risk management
      strategies to promote safe chemotherapy administration include comprehensive
      chemotherapy administration training, adherence to basic principles of medication
      administration, and adequate staffing. Oncology nurses need to know how and when
      to report chemotherapy medication errors to national databases and drug
      manufacturers.

PMID- 10420422
TI  - Lymphedema prevention and management knowledge in women treated for breast
      cancer.
AB  - PURPOSE/OBJECTIVES: To describe what women treated for breast cancer know about
      upper extremity lymphedema, what they recall being told to help prevent
      lymphedema, what preventive strategies they used, and, if lymphedema occurred,
      factors related to its occurrence and strategies they used to manage it. DESIGN:
      Descriptive, correlational survey. SETTING: Survivor-established Breast Cancer
      Resource Center. SAMPLE: 72 women with breast cancer who returned a mailed
      questionnaire that was enclosed with a quarterly newsletter. METHODS: A survey
      instrument, the Lymphedema Knowledge Scale, developed from National-Lymphedema
      Network guidelines to prevent upper extremity lymphedema. Data that was analyzed
      using descriptive statistics, chi square, and t-tests. MAIN RESEARCH VARIABLES:
      Lymphedema knowledge, lymphedema occurrence, and lymphedema prevention and
      management strategies. FINDINGS: Although many respondents were aware of their
      risk for lymphedema, their knowledge and use of prevention strategies were poor.
      Most knowledge was obtained from surgeons, reading materials, and breast cancer
      survivors. Occurrence of lymphedema was significantly associated only with
      radiation therapy to breast and axilla and use of any prevention strategy. The 27
      women experiencing lymphedema used several management strategies to control the
      condition. CONCLUSIONS: The few women who had knowledge of most of the
      recommended guidelines for lymphedema prevention and management did not recall
      nurses as resources. Research in a larger sample is needed to better examine the
      association between preventive practices and lymphedema occurrence. IMPLICATIONS
      FOR NURSING PRACTICE: Nurses could do more to inform patients before and during
      breast cancer treatment about their risk for lymphedema and the need for prompt
      diagnosis and treatment of the condition. Until strategies for lymphedema
      prevention are researched further, nurses should be cautious in counseling about
      lymphedema prevention.

PMID- 10420423
TI  - Staging of malignant cutaneous wounds: a pilot study.
AB  - PURPOSE/OBJECTIVES: To determine the color, size, hydration, and general
      appearance of malignant cutaneous wounds (MCWs); the effectiveness of using
      digital imagery to quantify wound characteristics; and the feasibility of an MCW
      staging system. DESIGN: Descriptive pilot study. SETTING: A university
      affiliated, comprehensive cancer center. METHODS: Assessment of each subject's
      wound (N = 13) using the Hopkins Wound Assessment Tool (HWAT) and digital
      analysis of photographs. Development of an MCW staging system from grouping and
      classifying the assessment data. A panel of experts used the assessment data and
      MCW staging system to determine each subject's wound stage and the feasibility of
      a staging system. Visual HWAT data and digital photographic assessment data were
      compared for consistency in size, color, and hydration status. MAIN RESEARCH
      VARIABLES: Characteristics and stages of MCW; digital imagery. FINDINGS:
      Investigators identified four stages of MCW using the wound characteristics.
      Digitally assessed wound measurements of size, color, and hydration status were
      consistent, reflecting the ability of this method to accurately capture malignant
      wound characteristics. CONCLUSIONS: An MCW staging system is feasible. Wound
      color, hydration status, the absence or presence of nodules, drainage, pain,
      odor, and tunneling indicate the stage of malignant wound progression. The two
      stages identified are distinctly different from pressure or diabetic wound
      progression. Stage 1N is characterized by fibrous desmoplasia (hard fibrous
      nodule) of cancer metastasis, and stage 4 is characterized by destruction of the
      basement membrane. Data comparisons indicate that digital assessment has
      potential for more accurately recording wound assessment indices. IMPLICATIONS
      FOR NURSING PRACTICE: Nurses can improve their assessment and management of a
      patient's MCW by understanding the wounds' stages and using a digital imaging
      protocol. Further research is needed to establish the reliability and validity of
      the MCW staging system and the digital assessment and quantification protocol.

PMID- 10420424
TI  - Reducing burnout: development of an oncology staff bereavement program.
AB  - PURPOSE/OBJECTIVES: To understand the necessity of providing a mechanism for
      staff bereavement that promotes stress reduction and enhances job longevity in
      the oncology nursing work environment and to describe the implementation of one
      such program. DATA SOURCES: Journal articles and on-site resources. DATA
      SYNTHESIS: Personnel conflicts, job dissatisfaction, and workplace burnout caused
      by constant patient loss are common in oncology nursing. The work setting must
      offer support for staff to deal with these conflicts to prevent burnout and
      decrease dissatisfaction. This can foster a sense of understanding among
      colleagues and provide support mechanisms for closure and acceptance of perpetual
      patient loss. CONCLUSION: Conflicts, dissatisfaction, and other sources of
      burnout must be contained so that oncology nurses remain in their vital roles.
      The potential for long-term professional fulfillment and improved quality of
      nursing care for patients and their families is increased by implementation of
      support mechanisms. IMPLICATIONS FOR NURSING PRACTICE: Educating colleagues about
      the multifaceted role of the oncology nurse can increase the staff's awareness of
      the need for support. Implementation of a program to reduce the stressors that
      oncology nurses encounter will encourage improved care delivery.

PMID- 10420425
TI  - Preliminary research on plasma oxytocin in normal cycling women: investigating
      emotion and interpersonal distress.
AB  - The neurohormone oxytocin is responsible for initiating childbirth and the let
      down reflex in lactating women and is released during sexual orgasm. Oxytocin has
      been thought of as an affiliation hormone because research on nonhuman mammals
      has demonstrated that it plays a key role in the initiation of maternal behavior
      and the formation of adult pair bonds. It has been speculated that social stimuli
      may induce oxytocin release and that oxytocin may make positive social contact
      more rewarding. Data are presented from an initial study to examine change in
      plasma oxytocin in response to a standard imagery task that elicits emotion
      related to attachment. Twenty-five normal cycling, healthy women underwent
      imagery tasks and completed questionnaires on attachment and interpersonal
      problems. Blood draws (5 ml) were bone via an indwelling catheter before, during,
      and after three interventions (massage, positive emotion, and negative emotion)
      and to establish baselines. Overall, the data showed a tendency for oxytocin
      levels to be elevated in response to relaxation massage and decreased in response
      to sad emotion. There were individual differences in response to the
      interventions. Those who showed evidence of increased oxytocin levels for
      positive emotion and massage and who maintained oxytocin levels during negative
      emotion were less likely to report interpersonal problems associated with
      intrusiveness. Maintaining oxytocin levels during sadness was also correlated
      with lower anxiety in close relationships. Women who were in a couple
      relationship had greater increases in oxytocin in response to positive emotion.
      In contrast, higher basal levels of oxytocin were associated with greater
      interpersonal distress. These data suggest that peripheral secretion of oxytocin
      in response to emotional stimuli is associated with the individual's
      interpersonal characteristics.

PMID- 10420427
TI  - Describing traumatic responses and distress of community residents directly and
      indirectly exposed to an aircraft crash.
AB  - This study described the traumatic responses and the extent of psychological
      distress among residents who had been exposed directly or indirectly to an
      aircraft crash in Coventry, U.K. The direct exposure group consisted of 62
      residents who were on the housing estate at the time of the accident and 20 who
      were not. They were interviewed on their subjective responses to the crash and
      then asked to fill in two distress measures: the Impact of Event Scale (IES) and
      the General Health Questionnaire (GHQ). The results showed a contrast between the
      responses of the two groups at the time of the crash. They also showed that the
      direct exposure group had a significantly higher score in the IES item of
      avoidance, the IES total, the GHQ items of somatization, social dysfunction, and
      the total score than the indirect exposure group had. Associations were then made
      between subjective responses and distress measures. Stepwise multiple regression
      analyses showed that for the direct exposure residents, the IES total was
      predicted by "whether they received professional help" and "whether they were
      worried about their safety after the crash." The GHQ total of the direct exposure
      residents was predicted by "anger about what had happened to them." For the
      indirect exposure residents, the IES total was predicted by "their present
      feelings when they heard planes flying over." There were no predictions found
      between responses and the GHQ total.

PMID- 10420426
TI  - The cascade model: an alternative to comorbidity in the pathogenesis of
      posttraumatic stress disorder.
AB  - Comorbidity has been used extensively to explain the numerous co-occurring
      psychiatric syndromes accompanying chronic posttraumatic stress disorder (PTSD).
      A cascade model is proposed as an alternative to comorbidity for the pathogenesis
      and clinical course of the condition. This model allows for a dynamic, integrated
      conceptualization of disease progression in PTSD. Findings in the clinical,
      epidemiological, neurobiological, and psychosocial literature which might support
      this model are described. Conceptual and heuristic difficulties and/or potential
      objections to the model are also examined. Finally, diagnostic and treatment
      implications as well as potential research applications of the model are
      discussed.

PMID- 10420428
TI  - Frontal lobe psychopathology: mania, depression, confabulation, catatonia,
      perseveration, obsessive compulsions, and schizophrenia.
AB  - The frontal lobes can be subdivided into major functional neuroanatomical
      domains, which, when injured, surgically destroyed, or reduced in activity or
      volume, give rise to signature pathological and psychiatric symptomology. A
      review of case reports and over 50 years of research, including magnetic
      resonance imaging, positron emission tomography, and single photon emission
      computed tomography scans, indicates that apathy, "blunted" schizophrenia, major
      depression, and aphasic-perseverative disturbance of speech and thought are
      associated with left lateral as well as bilateral frontal (and striatal)
      abnormalities. Impulsiveness, confabulatory verbosity, grandiosity, increased
      sexuality, and mania are associated with right frontal (as well as bilateral)
      disturbances. Gegenhalten, catatonia, and disturbances of "will" are indicative
      of medial frontal injuries. Disinhibitory states and obsessive-compulsive
      perseverative abnormalities are more frequently observed with orbital frontal
      lobe dysfunction, including frontal-striatal disturbances. These associations,
      however, are not always clear-cut as patients with the same diagnosis may
      demonstrate different symptoms that may be due to an additional abnormality in a
      different region of the brain. Moreover, as the frontal subdivisions are richly
      interconnected, and as frontal lobe abnormalities are not always discrete or well
      localized, a wide array of seemingly divergent waxing and waning symptoms may be
      manifest, sometimes simultaneously, including manic depression and what has been
      referred to as the "frontal lobe personality."

PMID- 10420429
TI  - The constitution of community: how individuals diagnosed with schizophrenia and
      their friends achieved community.
AB  - This article describes a qualitative research project, based on a grounded theory
      design, that addressed the processes involved in how individuals with
      schizophrenia were able to use their own abilities to form a self-authored
      community. The article offers a perspective on community integration that takes
      into account the importance of relationships, and in the case of individuals with
      schizophrenia, the importance of day-to-day relationships. The assumption is that
      the constitution of community is an outcome of the processes involved in learning
      and practicing being social (Cohen 1985, p. 15). These relationships do not
      necessarily have to be strong or numerous in order for community integration to
      be realized. In this article it is argued that an element in the establishment of
      such relationships for individuals with schizophrenia is the ready availability
      of others on a day-to-day basis. Relationships and friendships grew for
      individuals diagnosed with schizophrenia when such access occurred in a place
      where the context of what was likely to happen in an interaction was relatively
      well understood.

PMID- 10420430
TI  - Gender in homosexual boys: some developmental and clinical considerations.
AB  - Each of the homosexual men I have worked with has described gender-discordant
      traits during childhood that made him feel "different." In this article I
      illustrate that early parental admonitions and interventions to curb or replace
      these traits with more typically male behaviors may be harmful to the child's
      development, particularly to his emotional resilience. As a result, some gay
      adults have lost their capacity to recognize and express a variety of affects,
      and some attempt to avoid intimate relationships that evoke these and other
      repudiated "feminine" traits.

PMID- 10420431
TI  - Circadian clocks--from genes to complex behaviour.
AB  - Circadian clocks control temporal structure in practically all organisms and on
      all levels of biology, from gene expression to complex behaviour and cognition.
      Over the last decades, research has begun to unravel the physiological and, more
      recently, molecular mechanisms that underlie this endogenous temporal programme.
      The generation of circadian rhythms can be explained, at the molecular level, by
      a model based upon a set of genes and their products which form an autoregulating
      negative feedback loop. The elements contributing to this transcriptional
      feedback appear to be conserved from insects to mammals. Here, we summarize the
      process of the genetic and molecular research that led to 'closing the molecular
      loop'. Now that the reductionist approach has led to the description of a
      detailed clock model at the molecular level, further insights into the circadian
      system can be provided by combining the extensive knowledge gained from decades
      of physiological research with molecular tools, thereby reconstructing the clock
      within the organism and its environment. We describe experiments combining old
      and new tools and show that they constitute a powerful approach to understanding
      the mechanisms that lead to temporal structure in complex behaviour.

PMID- 10420432
TI  - Effects of light on human circadian rhythms.
AB  - Blind subjects with defective retinal processing provide a good model to study
      the effects of light (or absence of light) on the human circadian system. The
      circadian rhythms (melatonin, cortisol, timing of sleep/wake) of individuals with
      different degrees of light perception (n = 67) have been studied. Blind subjects
      with some degree of light perception (LP) mainly have normally entrained
      circadian rhythms, whereas subjects with no conscious light perception (NPL) are
      more likely to exhibit disturbed circadian rhythms. All subjects who were
      bilaterally enucleated showed free running melatonin and cortisol rhythms.
      Studies assessing the light-induced suppression of melatonin show the response to
      be intensity and wavelength dependent. In contrast to ocular light exposure,
      extraocular light failed to suppress night-time melatonin. Thus, ocular light
      appears to be the predominant time cue and major determinant of circadian rhythm
      type. Optimisation of the light for entrainment (intensity, duration, wavelength,
      time of administration) requires further study.

PMID- 10420433
TI  - Cholinergic signal transduction cascades in rat pinealocytes: functional and
      ontogenetic aspects.
AB  - In adult rat pinealocytes, acetylcholine activates nicotinic receptors whose
      stimulation causes a depolarization of the cells, opening of voltage-gated cation
      channels of the L-type and subsequent increase in the intracellular calcium ion
      concentration. These events trigger a release of glutamate that, by its action on
      metabotropic glutamate type 3 receptors, activates an inhibitory cyclic AMP
      cascade and suppresses norepinephrine-induced melatonin biosynthesis. The
      nicotinic response is fully developed in the third postnatal week. Prior to this
      timepoint, rat pinealocytes possess functional muscarinic receptors whose
      activation causes a rise in the intracellular calcium ion concentration through a
      calcium release from thapsigargin-sensitive intracellular calcium stores and an
      opening of store-operated calcium channels. This cascade may influence tissue
      differentiation and maturation of the melatonin pathway. The demonstration of
      functional cholinoreceptors and the ontogenetic switch from muscarinic to
      nicotinic signalling in rat pinealocytes supports the concept that pineal
      functions in mammals are influenced by neuronal inputs other than the sympathetic
      innervation which serves as the major regulatory system.

PMID- 10420434
TI  - Polymorphism and signalling of melatonin receptors.
AB  - Melatonin receptors belong to the superfamily of G protein-coupled receptors.
      Cloning of Mel1c receptors expressed in Xenopus skin revealed the existence of a
      polymorphism for these receptors. Heterologous expression of the two allelic
      isoforms, called Mel1c(alpha) and Mel1c(beta), indicated functional differences
      in their signalling properties. Both isoforms are coupled to the cAMP and cGMP
      pathways. However, the alpha isoform is preferentially coupled to the cAMP
      pathway, whereas the beta isoform couples preferentially to the cGMP pathway.
      Coupling differences may be explained by the fact that five of the six amino acid
      substitutions between the two isoforms are localized within intracellular
      receptor regions potentially involved in G protein coupling. Allelic isoforms
      were also observed for Mel1a receptors expressed in ovine pars tuberalis,
      suggesting that polymorphism is a general feature of the melatonin receptor
      family. We also evaluated the potential of the two human melatonin receptor
      subtypes, Mel1a and Mel1b, to modulate the cGMP pathway. Melatonin inhibited
      intracellular cGMP levels in a dose-dependent manner in HEK293 cells transfected
      with the human Mel1b receptor. This was not the case for HEK293 cells transfected
      with the human Mel1a receptor. In conclusion, our results indicate that the
      expression of receptor subtypes and isoforms may permit differential signalling
      between melatonin receptors.

PMID- 10420435
TI  - Melatonin synthesis pathway: circadian regulation of the genes encoding the key
      enzymes in the chicken pineal gland and retina.
AB  - The mRNAs encoding three enzymes of the melatonin synthesis pathway (tryptophan
      hydroxylase (TPH), arylalkylamine-N-acetyltransferase (AANAT) and hydroxyindole-O
      methyl-transferase (HIOMT)) are expressed with a day/night rhythm in the chicken
      pineal gland and retina. TPH and AANAT mRNA levels reach their peak at night.
      HIOMT mRNA levels peak at night in the retina, but during the day in the pineal
      gland. In this tissue, the rhythm of TPH, AANAT and HIOMT mRNA levels persisted
      in constant darkness (DD), both in vivo and in vitro, indicating that the three
      genes are controlled by the circadian oscillator of the chicken pineal. In the
      retina, the rhythms of TPH and AANAT mRNA levels also persisted in DD in vivo,
      suggesting that they are driven by a circadian oscillator. In contrast, the
      rhythm of HIOMT mRNA in the retina appeared to be controlled only by light. The
      clones of chicken AANAT and HIOMT genes that we have isolated should help us to
      understand the molecular mechanisms of: 1) their transcriptional regulation by
      circadian oscillators and by light; 2) their tissue-specific expression in the
      pineal gland and the retina.

PMID- 10420436
TI  - Design of subtype selective melatonin receptor agonists and antagonists.
AB  - Studies of the physiological actions of melatonin have been hindered by the lack
      of specific, potent and subtype selective agonists and antagonists. In the
      present study, we describe the utility of a melanophore cell line from Xenopus
      laevis for exploring structure-activity relationships among novel melatonin
      analogues and report a novel MT2-selective agonist (IIK7) and MT2-selective
      receptor antagonist (K185). IIK7 is a potent melatonin receptor agonist in the
      melanophore model, and in NIH3T3 cells expressing human mt1 and MT2 receptor
      subtypes. In radioligand binding experiments IIK7 is 90-fold selective for the
      MT2 subtype. K185 is devoid of agonist activity, but acts as a competitive
      melatonin antagonist in melanophores. A low concentration (10(-9) M) antagonizes
      melatonin inhibition of forskolin stimulation of cyclic AMP in NIH3T3 cells
      expressing human MT2 receptors, but has no effect in cells expressing mt1
      receptors. In binding assays, K185 is 140-fold selective for the MT2 subtype.

PMID- 10420437
TI  - Innervation of the rat pineal gland by nerve fibres originating in the
      sphenopalatine, otic and trigeminal ganglia. A retrograde in vivo neuronal
      tracing study.
AB  - The innervation of the rat pineal gland from the sphenopalatine, otic, superior
      cervical and trigeminal ganglia was investigated in animals by use of in vivo
      retrograde tracings. A solution of 2% Fluorogold was iontophoretically injected
      into the superficial pineal gland in a series of Wistar rats. After a survival
      time of 4-10 days, the animals were fixed by perfusion and the brains,
      sphenopalatine, otic, superior cervical and trigeminal ganglia were investigated
      with a fluorescence microscope. Many retrogradely labelled perikarya were found
      in the superior cervical ganglia, but a smaller number of neurones were also
      labelled in the sphenopalatine, otic and trigeminal ganglia. Injections of the
      tracer into the subarachnoidal space were used as the control for unspecific
      uptake and transport of the tracer. The input to the pineal gland from the
      parasympathetic sphenopalatine and otic ganglia might be involved in the
      regulation of the annual rhythms of the pineal gland. The projections from the
      sensory trigeminal ganglion could be involved in the control of the blood flow of
      the gland.

PMID- 10420438
TI  - Melatonin and the seasonal control of reproduction.
AB  - Many mammalian species from temperate latitudes exhibit seasonal variations in
      breeding activity which are controlled by the annual photoperiodic cycle.
      Photoperiodic information is conveyed through several neural relays from the
      retina to the pineal gland where the light signal is translated into a daily
      cycle of melatonin secretion: high at night, low in the day. The length of the
      nocturnal secretion of melatonin reflects the duration of the night and it
      regulates the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from
      the hypothalamus. Changes in GnRH release induce corresponding changes in
      luteinising hormone secretion which are responsible for the alternating presence
      or absence of ovulation in the female, and varying sperm production in the male.
      It is not yet known where and how this pineal indoleamine acts to exert this
      effect. Although melatonin binding sites are preferentially localised in the pars
      tuberalis (PT) of the adenohypophysis, the hypothalamus contains the
      physiological target sites of melatonin for its action on reproduction. Melatonin
      does not seem to act directly on GnRH neurons; rather it appears to involve a
      complex neural circuit of interneurons that includes at least dopaminergic,
      serotoninergic and excitatory aminoacidergic neurons.

PMID- 10420439
TI  - Melatonin and clinical application.
AB  - A review of the different publications dealing with melatonin in humans shows
      that this field has been very active in the last few years. Normative melatonin
      values have been defined. Various relationships between melatonin and other
      traits have been studied, such as sleep, circadian rhythm, surgical stress and
      anaesthesia. Age-related melatonin studies and melatonin during depression and
      other psychiatric disorders have been reviewed. Finally, some studies have been
      performed to use melatonin as a medication for sleep disturbance in depression,
      for jet-lag and as a skin protector for ultraviolet light.

PMID- 10420440
TI  - Melatonin mediates seasonal adjustments in immune function.
AB  - In addition to seasonal changes in reproductive function, seasonal changes in
      immune function are mediated by the pineal hormone, melatonin. Melatonin affects
      immune function both indirectly, acting through other hormones, and directly by
      acting on components of the immune system. Melatonin also affects tumorigenesis
      and tumor development. We hypothesize that many of the indirect effects of
      melatonin on immune function are mediated through glucocorticoids, and appear to
      be part of an integrated series of adaptations to manage energy. Direct effects
      of melatonin on immune function appear to be mediated by melatonin receptors on
      lymphatic tissue or on immune cells in circulation. Winter is energetically
      demanding and stressful; thermoregulatory demands typically increase when food
      availability decreases. Individuals would enjoy a survival advantage if
      seasonally recurring stressors could be anticipated and countered by bolstering
      immune function. To summarize, melatonin may be part of an integrative system to
      coordinate reproductive, immunologic and other physiological processes to cope
      successfully with energetic stressors during winter.

PMID- 10420441
TI  - Melatonin and 5-methoxytryptamine in non-metazoans.
AB  - Melatonin seems to be an almost ubiquitous substance, which has been detected not
      only in metazoans, but also in all major non-metazoan taxa investigated,
      including bacteria, dinoflagellates, euglenoids, trypanosomids, fungi,
      rhodophyceans, pheophyceans, chlorophyceans and angiosperms. Despite its vast
      abundance, little is known to date about its functions. Its presence is not
      necessarily associated with circadian rhythmicity, which is evident in yeast.
      Circadian rhythms of melatonin have been reported in non-metazoans only for
      several unicellular organisms and in one angiosperm. In dinoflagellates, which
      have been studied in the most detail, the effects on enzyme activities and on
      phase shifting are known, but the most spectacular actions concerning the
      stimulation of bioluminescence, changes in cytoplasmic pH and induction of
      resting stages, can be related to a metabolite of melatonin, the 5
      methoxytryptamine; therefore, melatonin should also be considered as a source of
      other agonists.

PMID- 10420442
TI  - [Diagnosis of vitamin B12 deficiency: only apparently child's play].
AB  - We performed a systematic literature search for diagnostic criteria in
      establishing cobalamin deficiency. The diagnostic procedure is particularly
      uncertain in elderly patients with neurological symptoms and in cases with
      borderline cobalamin values. In any patient with suspected cobalamin deficiency
      we recommend analysing a full blood count and determining cobalamin concentration
      in a serum sample. Particularly in elderly patients and cases with neurological
      symptoms presenting borderline cobalamin values and no abnormalities in the blood
      count, we recommend further investigation with methylmalonic acid, homocystein
      and Schilling test. These additional tests should make it possible to decide
      whether to recommend lifelong substitution with cobalamin. Various cobalamin
      assays, Schilling test, food cobalamin test, gastroscopic evaluation and the
      problems surrounding these assays in the elderly are discussed. Our own
      experience with methylmalonic acid, homocystein determination and food cobalamin
      test did not reveal a simple diagnostic procedure in such cases. We conclude that
      there is still no "gold standard" for diagnostic procedure in the special cases
      mentioned.

PMID- 10420443
TI  - [A normal thyroid gland upon autopsy: a relatively uncommon finding].
AB  - In a series of 420 autopsies the thyroid glands have been weighed, serial
      sections made and examined histologically with at least one specimen per lobe.
      There is an age-dependent increase in mean thyroid weight. In the 7th decade the
      mean weight exceeds 29 g and weights above this are regarded as goitre. Between
      the 4th and 8th decade the incidence of goitre is 20-30%, after which the
      incidence rises steadily to 64% in the 10th decade. The commonest thyroid
      pathology is hyperplastic nodules, which are found in 39% of patients (49.4% of
      males and 33.4% of females). 2.4% of all patients have adenomas, 1.9% primary
      carcinomas and 2.8% thyroid metastases. Inflammatory infiltrates are observed in
      6.6% of cases (9.4% of females and 4.4 of males). To establish the incidence of
      normal thyroid glands we have studied 840 serial autopsies. Only 25% of thyroids
      are normal (19% of females and 30% of males). The incidence of normal thyroid
      glands tends to decrease with age and in no decade does it reach 50%.

PMID- 10420444
TI  - [From Hashimoto thyroiditis to B-cell lymphoma of the thyroid gland].
AB  - Lymphoma of the thyroid gland is an uncommon condition occurring primarily in
      older women. Most patients have a short history of an enlarging thyroid or a neck
      mass causing tracheal compression. There is also a strong association between
      thyroid lymphoma and Hashimoto's thyroiditis. The diagnosis is established by
      biopsy. The conventional approach to treatment is combination of radiation
      therapy with multi-agent chemotherapy, while there is no significant role for
      extirpative surgery in the management of thyroid lymphoma. The prognosis of
      localised tumours (stage IE, Ann Arbor classification) is excellent.
      Extrathyroidal involvement (stage IIE-IVE) reduces the 5-year survival rate to
      about 70%, provided that current therapy regimens are respected. In this case
      report, the different stages of development from Hashimoto's thyroiditis to
      thyroid lymphoma are demonstrated by histology. In a review of the literature we
      discuss the diagnostic procedure and the current approach to treatment.

PMID- 10420445
TI  - [Cushing syndrome due to ectopic ACTH secretion: an uncommon case presentation,
      diagnosis and therapy].
AB  - Ectopic ACTH secretion due to malignant tumours is the most frequently
      underdiagnosed form of Cushing's syndrome. The majority of neoplasms causing
      ectopic ACTH syndrome are small-cell cancers of the lung or carcinoids. Other
      well-documented cases include adenocarcinoma of the lung, medullary thyroid
      carcinoma, pancreatic islet tumours and malignant thymoma. We report a rare case
      of metastatic colonic adenocarcinoma with ectopic ACTH syndrome. Clinical
      features such as proximal muscle weakness, peripheral oedema, hypertension or
      hirsutism in women, or the presence of unexplained hyperglycaemia, hypokalaemia
      or metabolic alkalosis in patients with known malignancy strongly suggest ectopic
      ACTH syndrome. Removal of the source of ACTH is the treatment of first choice,
      but often not feasible. Most often, treatment modalities are only palliative,
      with drugs directed against hypercortisolism such as aminoglutethimide,
      metyrapone, ketoconazole or mifepristone.

PMID- 10420446
TI  - [Acromegaly].

PMID- 10420447
TI  - [Celebrating the 70th birth anniversary of Evgenii Ivanovich Chazov: some facts
      from life].

PMID- 10420448
TI  - [Place and role of high technologies in cardiological practice].

PMID- 10420449
TI  - [Renal effects of non-narcotic analgesics and non-steroidal anti-inflammatory
      drugs].

PMID- 10420450
TI  - [Development of arterial hypertension in urate tubulointerstitial renal damage].

PMID- 10420451
TI  - [Prediction of accelerated progression of chronic glomerulonephritis basing on
      clinical and histomorphological data].
AB  - AIM: To find out predictive value of three factors in progression of chronic
      glomerulonephritis (CGN): unfavorable clinical course, unfavorable morphological
      type and tubulointerstitial changes. MATERIALS AND METHODS: 150 CGN patients
      entered the trial. Frequency of onset of chronic renal failure (CRF) within 7
      years after the diagnosis was chosen as a criterium of accelerated progression of
      CGN (AP CGN). Chi-square criterium was used for testing relationships between AP
      CGN and the parameters under study. RESULTS: The findings support previously
      published data on statistically more frequent occurrence of AP CGN in unfavorable
      clinical types (active nephritic and nephrotically-hypertensive), in unfavorable
      morphological types (mesangiocapillary CGN and focal-segmental
      hyalinosis/sclerosis and tubulointerstitial lesions). In unfavorable clinical
      types there was a significantly more frequent occurrence of AP CGN irrespective
      of unfavorable morphological changes. In contrast, both in unfavorable and
      favorable clinical types, frequency of AP CGN in unfavorable morphological types
      of CGN and tubulointerstitial changes was the same. CONCLUSION: Clinical type of
      CGN is a valuable prognostic criterium for AP CGN.

PMID- 10420452
TI  - [Polymorphism studies of angiotensin converting enzyme gene in chronic
      glomerulonephritis].
AB  - AIM: To investigate the relationship between polymorphism of angiotensin
      converting enzyme (ACE) gene and predisposition to chronic glomerulonephritis
      (CGN) as well as antihypertensive and anti proteinuric response to ACE inhibitors
      (ACEI) treatment, therapy with angiotensin II receptor antagonists. MATERIALS AND
      METHODS: Genotype was determined in 57 CGN patients and 113 subjects free of
      chronic diseases. Effects of ACE gene polymorphism on antihypertensive and
      antiproteinuric efficiency of ACEI and cozaar were studied in 35 CGN patients on
      monotherapy. 24-h proteinuria, levels of creatinine, potassium in the serum,
      arterial pressure, glomerular filtration rate were measured in all the patients.
      RESULTS: No significant differences were found between incidence of ACE gene
      genotypes and alleles in patients with CGN and controls. Maximal antihypertensive
      response to therapy was observed after a month treatment in patients with
      genotypes II and ID. Lowering of arterial pressure in patients with genotype DD
      was observed on month 6-12 of continuous therapy. Proteinuria diminished on the
      treatment month 1-3 in patients with genotypes II and ID, in genotype DD
      proteinuria rose for the same period of time. Proteinuria dropped similarly in
      all the groups by month 6-12. CONCLUSION: Relations between ACE gene polymorphism
      and genetic predisposition to CGN were not found. Patients with genotype II were
      most sensitive to IACE and cosaar treatment. Lack of an early anti proteinuric
      response in homozygotes DD does not determine effectiveness of long-term IACE
      treatment and should not be a reason for the above drug discontinuation.

PMID- 10420453
TI  - [Urinary fibronectin as an indicator of kidney fibrosis in nephritis].
AB  - AIM: To investigate clinicomorphological relationships between elevated urinary
      excretion of fibronectin (FN) and development of fibrosis in the kidney in
      patients with lupus nephritis (LN) and chronic glomerulonephritis (CGN).
      MATERIALS AND METHODS: Urinary FN excretion was measured at radial
      immunodiffusion in 54 LN patients. Of them, 15 patients had inactive LN, 39
      patients had active LN varying in clinical forms. Urinary FN was also measured by
      passive hemagglutination in 36 CGN patients (11 inactive CGN and 25 active CGN
      cases). Biopsy specimens were obtained from 49 patients with active nephritis (43
      with CGN and 6 with LN). FN deposits were studied immunohistochemically and
      morphometrically with determination of relative fibrosis area. RESULTS: Urinary
      FN excretion in patients with nephritis was higher than in healthy controls. In
      active CGN and LN the levels of FN were significantly higher than in inactive CGN
      and LN. The highest FN urinary concentrations were registered in patients with
      severe CGN and LN, especially in the presence of renal failure and arterial
      hypertension. Among them, the highest individual values were observed in patients
      with rapidly progressive nephritis. No positive correlations were found between
      the degree of the urinary FN excretion increment and degree of proteinuria. This
      suggests local-renal origin of most urinary FN. Morphologically, FN deposits were
      revealed in 73% of the biopsies. In most of the patients with severe nephritis
      both in CGN and LN there was a diffuse distribution of FN in the glomerules and
      interstitium. A correlation with a morphological nephritis type was absent, but
      existed between FN presence in the renal biopsies and relative area of
      interstitium (fibrosis). CONCLUSION: FN excreted in high amounts with urine in
      nephritis originates from the kidneys and reflects severity of fibrogenesis in
      the kidney.

PMID- 10420454
TI  - [Informative value of immunomembrane indicator of glomerulonephritis activity and
      effectiveness of membranostabiliser dimephosphon].
AB  - AIM: Study of effectiveness of dimephosphone with regard of the kind and degree
      of membrane disorders in various clinicomorphological forms of active
      glomerulonephritis (GN). MATERIALS AND METHODS: 170 patients with nephrotic,
      nephritic GN have undergone a complete nephrological examination. Informative
      value of immunological, morphological and membrane (phospholipids, lipid
      peroxidation) indicators of GN and lupus nephritis (LN) activity was analysed.
      RESULTS: Membrane destabilisation and GN activity were correlated. Membrane
      destabilization was also associated with dislipid- and disproteinemia,
      disturbances of renal function. This can be used for diagnosis of GN activity and
      its rapid progression. Dimephosphone monotherapy was found effective in
      correction of immunomembrane disturbances in minimally active GN and hormone
      resistant forms irrespectively of the activity forms. Combination of
      dimephosphone with prednisolone and/or cytostatics proved more effective than
      dimephsphone monotherapy or conventional treatment with glucocorticoids and/or
      cytostatics without dimephosphone in respect of frequency of remission and early
      remission achievement in various types of activity and clinicomorphological forms
      of GN. CONCLUSION: Combination of dimephosphone with glucocorticoids and/or
      cytostatics is more effective than monotherapy or combined treatment with
      glucocorticoids and cytostatics in the treatment of GN of different
      clinicomorphological forms, hormone-resistant among them, and types of activity.

PMID- 10420455
TI  - [Platelet dysfunction and pregnancy in gestational exacerbation of chronic
      glomerulonephritis].
AB  - AIM: To evaluate platelet dysfunctions and pregnancy outcomes in females with
      gestational exacerbation of chronic glomerulonephritis (CGN) and the disease
      remission. MATERIALS AND METHODS: Platelet metabolism was studied by activity of
      intraplatelet LDG, platelet secretory activity by plasm beta-TG and ADP
      aggregation in 75 gravidae. Of them 16 had exacerbation of CGN, 40 females were
      in remission of CGN and 19 healthy pregnant women served control. RESULTS:
      Enhanced LDG activity and intensity of maximal ADP aggregation, high beta-TG
      levels compared to control were recorded in gravidae with CGN both in
      exacerbation and remission. The frequency of preterm deliveries, intrauterine
      growth retardation, neonatal hypotrophy was greater in women with gestational
      exacerbation of nephritis compared to pregnant women with stable nephritis.
      CONCLUSION: Metabolic and functional platelet hyperactivity with platelet
      intravascular activation in pregnancy in aggravated CGN suggest contribution of
      platelets to onset of the disease gestational exacerbation. Pregnancy-induced
      overactivation of platelets in CGN exacerbation stimulates intravascular
      coagulation in placental circulation with resultant microthrombi in placental
      vessels responsible for high rate of unfavorable pregnancy outcomes in relevant
      patients.

PMID- 10420456
TI  - [Diabetic nephropathy: risk factors of rapid progression of renal failure].
AB  - AIM: To reveal factors accelerating development of chronic renal failure (CRF) in
      patients with insulin-dependent diabetes mellitus type I (DM-I). MATERIALS AND
      METHODS: A retrospective analysis of case histories was made for 40 patients with
      DM-I exhibiting progression of proteinuric stage of diabetic nephropathy prior to
      CRF stage. Clinical-laboratory indices were compared for patients with slow
      (group 1, n = 17) and fast (group 2, n = 23) development of CRF. RESULTS:
      Patients of group 2 had significantly higher levels of glycosylated hemoglobin,
      total cholesterol, triglycerides in the blood, urine protein excretion, systolic
      and diastolic blood pressure than patients of group 1. Also, patients of group 2
      had not taken antihypertensive drugs regularly. CONCLUSION: Factors of risk of
      CRF early development of DM-I patients comprise unsatisfactory compensation of
      carbohydrate metabolism, hyperlipidemia, high proteinuria, arterial hypertension
      and inadequate antihypertensive therapy.

PMID- 10420457
TI  - [Effects of sodium ethamsylate on anticoagulant and anti-aggregation activity of
      vascular endothelium in hemorrhagic fever patients with renal syndrome].
AB  - AIM: To elucidate effects of sodium ethamsylate (SE) on anticoagulant and
      antiaggregation activity of vascular endothelium in patients suffering from
      hemorrhagic fever with renal syndrome (HFRS). MATERIALS AND METHODS: A trial of
      SE enrolled 70 HFRS patients (58 males, 12 females aged under 30 years)
      compatible by the disease severity. They were divided into two groups. 42
      patients of the control group received standard therapy, 28 patients of the study
      group received adjuvant 12% solution of SE in daily dose 1500-2000 mg in the
      course of HFRS oliguria period. Hemostatic parameters were measured before and
      after the cuff test to investigate the condition of vascular wall with
      calculation of the athrombogenicity index (the ratio of the relevant indices
      before and after the cuff test). SE effects on vascular endothelium was assessed
      by a blind method. RESULTS: In oliguria, both groups had baseline antiaggregation
      indices significantly higher than in the control. After the cuff test, control
      patients' indices tended to an increase while in the study group there was a
      marked decrease. The trend in anticoagulant activity of microvascular endothelium
      did not differ much with the groups. This picture persisted also in polyuria. In
      convalescence hemostasis was similar in both groups. CONCLUSION: SE enhances
      antiaggregant activity of vascular endothelium in oliguria period of HFRS without
      affecting its anticoagulant properties. This is explained by a direct effect of
      SE on vascular endothelium.

PMID- 10420459
TI  - [Detection of urate tubulointerstitial nephritis: contribution of diagnostic
      questionnaire].
AB  - AIM: To develop a diagnostic questionnaire to identify individuals with uric acid
      hyperproduction and risk of urate tubulointerstitial nephritis (UTIN). MATERIALS
      AND METHODS: Clinical symptoms of 650 patients with verified hyperuricemia or
      hyperuricosemia have been summarized to design a special questionnaire which will
      be able to identify subjects to whom test for uricemia and uricosuria may be
      recommended to prevent onset and/or progression of UTIN. RESULTS: The
      questionnaire has been compiled which has rather high sensitivity and specificity
      in identification of persons with hyperuricemia and/or hyperuricosuria at risk to
      develop UTIN. CONCLUSION: The designed questionnaire allows to select subjects
      with existing UTIN or at UTIN risk both in population and individual studies.

PMID- 10420458
TI  - [Urate affection of kidneys and metabolic disturbances in hypertensive patients].
AB  - AIM: To detect urate renal affection and correlations between purine metabolism,
      hyperinsulinemia, obesity, dyslipidemia in patients with arterial hypertension
      (AH). MATERIALS AND METHODS: 78 patients with mild, moderate and severe
      hypertension have undergone 24-h monitoring of arterial pressure and
      microalbuminuria test. RESULTS: Hyperuricemia was diagnosed in 21 of 78,
      hyperuricosuria in 27 patients. 13 patients had combination of hyperinsulinemia
      with obesity, dyslipidemia, arterial hypertension. Renal symptoms occurred in
      almost half of the patients with hyperuricemia. Disturbed 24-h rhythm and
      variability of arterial pressure were encountered more frequently in patients
      with hyperuricemia and hyperinsulinemia than in patients with normal purin
      metabolism and no other metabolic shifts. CONCLUSION: Renal abnormalities were
      found more frequently in hypertensive patients with hyperuricemia and those free
      of urate disturbances and metabolic changes. A positive correlation exists
      between body mass index and insulinemia (r = 0.58, p < 0.01), body mass index and
      uricemia (r = 0.37, p < 0.01), insulinemia and uricemia (r = 0.32, p < 0.01).

PMID- 10420460
TI  - [Low doses of recombinant erythropoietin in the treatment of renal anemia in
      patients on chronic hemodialysis and ambulatory peritoneal dialysis].
AB  - AIM: A comparative study of efficiency and safety of low-dose erythropoietin (EP)
      in two groups of patients with chronic renal failure (CRF): patients on chronic
      hemodialysis (CHD) and patients on continuous ambulatory hemodialysis (CAHD).
      MATERIALS AND METHODS: 51 CRF adult patients with renal anemia on hemodialysis
      entered the trial: 34 CHD and 17 CAHD patients. EP compounds were injected s.c.
      in a dose 1000-2000 U 2-3 times a week. RESULTS: EP treatment provided a rapid
      correction of renal anemia in the majority of patients. After 3-month EP therapy
      a mean increment of Hct (Hct delta) was much greater (p < 0.05) in CAHD than CHD
      patients (12.2 +/- 6.0 and 9.0 +/- 5.1%, respectively), though EP dose were the
      same in both the groups. CONCLUSION: Low doses of recombinant human EP injected
      subcutaneously were effective and safe for correction of anemia in both CHD and
      CAHD. In CAHD patients EP effectiveness was much higher than in CHD patients.

PMID- 10420461
TI  - [Role of renin-angiotensin-aldosterone system in pathogenesis of arterial
      hypertension in chronic renal failure].
AB  - AIM: To characterize status of renin-angiotensin-aldosterone system (RAAS) in
      patients with chronic and terminal renal failure (CRF, TRF) and its role in
      pathogenesis of arterial hypertension (AH). MATERIALS AND METHODS: RAAS was
      studied in 90 patients with TRF on chronic hemodialysis (CHD) and 17 CRF patients
      with AH on conservative therapy. Plasma renin activity (PRA) and the level of
      plasma aldosterone (PA) were measured with radioimmunoassay. RESULTS: PRA with
      moderate CHD-controlled hypertension (1.16 ng/ml/h) was not higher than in
      control group (1.33 ng/ml/h), while in severe hypertension PRA was increased 4.6
      fold (6.09, p < 0.05). In CRF with severe AH PRA was higher 3.6 times (4.8
      ng/ml/h, p < 0.05). PA was in CRF and TRF patients 4-5 times higher than in
      healthy controls. A positive correlation was found between PRA and mean dynamic
      AP (r = 0.448, p < 0.01) and PRA with PA (r = 0.31, p < 0.05). CONCLUSION: A
      leading role of RAAS is shown in pathogenesis of AH in patients with hemodialysis
      uncontrolled hypertension and, partially, in patients with CRF and severe AH.

PMID- 10420462
TI  - [Betaxolol treatment of hypertension in postmenopausal women].
AB  - AIM: The study of hypotensive efficacy of high-cardioselective beta-blocker
      betaxolol, its effects on lipid and carbohydrate metabolism, menopausal syndrome
      in females with mild and moderate arterial hypertension. MATERIALS AND METHODS:
      20 postmenopausal 45-59-year-old women entered the trial of betaxolol. They had
      diastolic blood pressure 90-114 mm Hg. Beta-blockers were not contraindicated.
      Arterial pressure, heart rate, body mass, blood lipid spectrum, glucose and
      insulin levels were evaluated before the treatment, 1, 3 and 6 months after it.
      RESULTS: Betaxolol safely and effectively lowered blood pressure. Blood lipid
      spectrum remained unchanged. A transitory rise in fasting insulin levels did not
      worsen glucose tolerance despite a small gain in body mass. Menopausal syndrome
      relieved due to good effect of betaxolol on vasomotor disorders. CONCLUSION:
      Betaxolol has a good hypotensive effect in the absence of adverse effects on
      lipid and carbohydrate metabolism. A reduction of menopausal syndrome was also
      achieved.

PMID- 10420463
TI  - [Case of early pronounced anemia and its effective treatment with human
      recombinant erythropoietin in a female patient with polycystic kidney in a
      conservative stage of chronic renal failure].

PMID- 10420464
TI  - [Case of renal anomalies in Marfan's disease].

PMID- 10420465
TI  - [A case of chronic glomerulonephritis nephrotic form remission complicated by
      nephrotic crisis and sepsis].

PMID- 10420466
TI  - [Acute renal failure induced by antitubercular antibiotics reversible after
      steroid pulse therapy].

PMID- 10420467
TI  - [Effect of human immunoglobulin preparation in resistance to immunosuppressive
      therapy in a male patient with nephrotic syndrome].

PMID- 10420468
TI  - [Clinical features of focal-segmental glomerular sclerosis (review of literature
      and personal findings)].

PMID- 10420469
TI  - [Spatial organization of polytene chromosomes in ovarian trophocyte nuclei of the
      malaria mosquito Anopheles labranchiae Fall].
AB  - Spatial arrangement of polytene chromosomes in the ovarian trophocyte nuclei was
      studied in Anopheles labranchiae Fall. The system of chromosome attachment to the
      nuclear envelope in this species was found to differ from those in other species
      of the A. maculipennis complex. These results confirm that the spatial
      organization of nurse ovarian cell chromosomes is species-specific.

PMID- 10420470
TI  - [An information system for automated cytogenetic image processing: analysis of
      interphase chromatin of nerve cells of embryonic brain of rats with varying
      nervous system excitability].
AB  - To reveal a relationship between the genetically determined excitability of rats
      and the structural-functional chromosome organization in their neurone nuclei a
      computer information system has been developed to classify the neurone nuclei
      according to their specific DNA image cytometry features. The nuclear features,
      such as size, shape, and DNA content, are calculated, along with features
      describing characteristics of chromatin with the nucleus. The neural and glial
      cells are separated according to the rule based expert system approach with the
      use of a nuclear feature vector. The DNA image processing is performed and a
      feature vector consisting of normalized measures of the neurone nucleus chromatin
      region descriptors is extracted. The results indicate a relationship between the
      peculiarities of the nervous system and the structural-functional state of the
      chromosomal apparatus.

PMID- 10420471
TI  - [Effect of bemithyl (bemactor) on the bronchial epithelium regeneration and the
      main protector mechanisms of the respiratory system in chronic inflammation].
AB  - To improve the efficiency of the therapy of respiratory diseases, the influence
      of a drug belonging to the group of actoprotectors--bemithyl (bemactor) on the
      main protector mechanisms of respiratory organs was evaluated, using functional
      morphological studies of mucocilliary apparatus and local bronchial immunity.
      Bemithyl was found to produce no direct influence on these mechanisms, but the
      use of bemithyl by special technology is perspective for these purposes.

PMID- 10420472
TI  - [Pituitary adenylate cyclase activating peptide (PACAP)--its polyfunctionality in
      the mechanisms of brain protection].
AB  - Modern data of molecular and biological properties and physiological role of new
      pituitary adenylate cyclase activating polypeptide--PACAP--review. PACAP play key
      role in the embryogenesis of brain, in the protection of brain nerve cells from
      ischemia-induced death, injuring and apoptosis. New data are discussed concerned
      with molecular cloning and tissue distribution of receptors for PACAP, gene
      proPACAP expression in gastrointestinal tract, reproductive organs and nervous
      system. PACAP increase cytosolic free calcium and modifies the calcium-sensitive
      K(+)-channels, PACAP protects cultures cortical and hippocampal neurons from
      glutamate-induced cytotoxicity. The sleep modulation and modification of seizures
      activity of brain through the secretion of vasopressin or/and through NMDA
      receptors directly should be include in the program of PACAP "physiological
      continuum" of functions.

PMID- 10420473
TI  - [The dynamics of neocortical modifications: the dependence on motivational and
      emotiogenic systems].
AB  - A concept is advanced according to which for complete and successive development
      of membrane and synaptic modifications in the neocortex during the conditioned
      reflex (CR) elaboration the differentiated changes in impulse flow structure of
      the motivation and emotion systems of the hypothalamus and reciprocal character
      of excitatory and inhibitory interactions between them are necessary. Motivation
      excitation coordinated with repeated activation of synaptic inputs by pairing
      stimuli contributes to temporary (lasting about hour) increase in somatodendritic
      electroexcitability of neocortical neurons. It is necessary for maintaining cells
      in the state of readiness for summation of polymodal excitations during the CR
      generalization stage. Emotion excitation contributes to long-lasting (about
      twenty-four hours) increase in synaptic efficacy of excitatory and inhibitory
      connections which determine a conditioned act during the stage of specialization.
      Hetero- and homosynaptic facilitation of synaptic transmission lead to global and
      local character of spatial synchronization of slow activity during these stages.
      These processes are mainly determined cooperative interaction glutamatergic
      system with modulator cholin- and monoaminergic (noradren- and serotonin-)
      systems activating during motivational and emotional behavior components,
      respectively.

PMID- 10420474
TI  - [The participation of the nontraditional neuromediator nitric oxide in the
      mechanisms of adaptation to extreme conditions].
AB  - The investigation was performed on the medial (MMS) and lateral (LMS)
      magnocellular subdivisions of the hypothalamic paraventricular nuclei (HPN). The
      histochemical activity NO synthesizing enzyme nitric oxide synthase or NOS whose
      histochemical marker is NADPH-diaphorase (NADPH-D), immunocytochemical content of
      oxytocin (OXY), vasopressin (VP) and nucleoli sizes (squares) were studied in the
      mature male rats under experimental reconstruction of the both micro- and
      macrogravity, which are factors of the gravity field changes acting to the body
      during the space flight. Two experimental effects were used: B--tail suspending
      (imitation of the microgravity effects), C--centrifugation at 2 G (imitation of
      the macrogravity effects). The effect durations were designed as a time period
      when body is mostly affected by (1 day) and adapted (15 days) to the stress.
      There were 6 animal groups. 1--B(15 days), 2--B(15 days) succeeded by C(1 day), 3
      -B(15 days) succeeded by C(15 days), 4--C(1 day), 5--C(15 days), 6--intact
      animals. The histochemically and immuno-cytochemically stained neurons developing
      the high, moderate and small reaction intensity were counted in serial HPN
      sections under the light microscope and the results obtained were transformed to
      percent neuron contents. The nucleoli squares were examined by using the TV
      analyser. The histochemical staining intensity of NADPH-D in MMS is enhanced in
      the animals of the groups 1-4; the number of NADPH-D staining neurons with high
      enzyme activity was increased in 8-14 times. In the animals of group 5 the NADPH
      D activity did not differ from the intact animals. The number of MMS neurons with
      high OXY immunoreactivities was increased up to 1.5-1.7 times in groups 1-5 if
      compared to those of intact controls. VP-positive neurons of LMS developed the
      similar increase in number of the high staining neurons in experimental animals
      as well as OXY-positive neurons of MMS. The nucleoli enlargement was observed in
      MMS (in 1.3-1.5 times) of groups 1-5 (insignificantly in group 5) and in the most
      magnocellular neurons LMS (in 1.5-1.7 times) of group 2-5 except group 1 where
      nucleoli were insignificantly decreased. The nucleoli sizes of group 4 were more
      than group 5. So the hypothalamo-neurohypophyseal system was activated in the
      animals subjected of the earthly correlates of micro- and macrogravity. The data
      obtained suggest involvement both the nonconventional neurotransmitter NO and
      stress-related peptides OXY and VP in the mechanisms subserving adaptation to the
      extreme factors by what a human has to be faced with during the space flight.

PMID- 10420475
TI  - [Human adaptive phenotypes in physiology and medicine].
AB  - The study of pathological and physiological features associated with genetic
      syndromes has gained increasing momentum over the past two decades. In this
      paper, the definition of adaptive phenotypes is presented and the complexities
      and obstacles to progress in this field are summarized. This is a problem of
      general biology and is related to genetic specificity of every organism. The
      concept of individual norm of man's responses is to a certain extent associated
      with the doctrine of constitutions. From the practical point of view it is
      suggested to use in medicine and physiology an individual-constitutional approach
      and the term adaptophenotype (adaptive phenotype) which means a stable complex of
      genetic and phenotypical characteristics. It can be determined using clinical,
      physiological, genealogical, and dermatoglyphic methods, methods of genetic
      markers, phenotypical analysis, etc. A variety of developmental and physiological
      characteristics can form the "adaptophenotype" is used in general application, it
      is used to refer to a broad range of human functioning including pathological
      characteristics (somatic disorders), psychopathology (mental disorders),
      physiological and behavior problems. Genetic approaches help reveal not only
      individual hereditary parameters which manifest as signs but also latent
      pathological and physiological characteristics that may be used for professional
      selection. The delineation of adaptive phenotypes is a difficult enterprise, not
      that should not dissuade clinicians and researchers from undertaking it.

PMID- 10420476
TI  - [Visual suppression during eye movements (a brief review on the problem of the
      mechanisms and their role in visual perception). I. A brief review and the
      mechanisms].
AB  - A problem of visual suppression during eye movements is discussed. The short
      critical review of the main published papers is adduced. A comparative analysis
      of the literary and author's data has been considered. These data provide
      evidence for the existence of three but not two (how is maintained) mechanisms of
      visual suppression: a retinal, efferent copy, and proprioceptive (from
      extraocular muscles) signals. The proprioceptive mechanism is more powerful than
      efferent copy. Both retinal and extraretinal mechanisms of visual suppression are
      discussed in detail. The sources and the passage's pathways of the extraretinal
      signals are considered thoroughly. It is shown that the retino-geniculate system
      provide mainly retinal mechanisms vs the tecto-thalamic system provide
      extraretinal mechanisms.

PMID- 10420477
TI  - [The functional activity of the ATP-dependent K+ channels of normal pancreatic
      beta cells and in pathology].
AB  - The paper deals with the analysis of the status of ATP-dependent K+ channels of
      pancreatic beta cell functional by attenuated under the effect of streptozotocin
      and simultaneous assessment of their reaction to sulfonylamide agents
      glybenclamide, glipizil and glyclazid. Highly specific response of the tested
      ionic channels showed under the effect of both glucose and sulfonylurea agents.
      Analysis of the time course of electrophysiological processes coursing in them,
      showed appreciable changes in the time of the channel closing, which led to
      deceleration of insulin secretin starting from the moment of exposure to glucose
      or sulfonylurea agents till exocytosis of insulin quantum. Glybenclamide proved
      to be the most active of the tested agents as regards their secretogenic
      properties.

PMID- 10420478
TI  - [Peptides as inhibitors of thrombin coagulation activity and of thrombocyte
      aggregation].
AB  - The analysis of literature and our own data of regulatory peptides influence on
      the blood coagulation system is presenting. Various natural and synthetic
      peptides inhibit the activity of thrombin and platelet aggregation. Direct
      specific inhibitors of thrombin are peptides developed on the base of D-Phe-Pro
      Arg sequence. Strong specific inhibitors of the prothrombinase complex factor Xa
      were isolated from tissues and saliva of the blood-sucking organisms. These
      inhibitors decrease thrombin generation at the early stage of blood coagulation
      cascade Anticoagulating peptides from the tick Ornithodoros moubata tissue (TAP),
      the recombinant rTAP from the saliva glands of tick Ornithodoros savignyi and
      peptide with even greater anticoagulating activity from saliva glands of fly
      Glossina morsitans morsitans were isolated and characterised. For complete and
      reliable suppression of thrombus formation simultaneous administration of
      thrombin and platelet aggregation inhibitors is necessary. Main terminal stage of
      platelet aggregation is the interaction of receptor GP IIb/IIIa with adhesive
      fibrinogen sequence Arg-Pro-Asp (RGD). Peptides derived on the base of this
      sequence compete with fibrinogen in reaction with platelet receptors. A lot of
      corresponding peptidomimetics were synthesised, e.g. MK-852, RO-44 and
      particularly effective compound integrelin. Many direct platelet aggregation
      inhibitors were found in snake venoms. Recombinant peptide TAP mentioned above
      exerts both antithrombin and antiaggregation activity. Peptides and peptide
      mimetics of this type rapidly and irreversibly bound with receptor GP IIb/IIIa.
      They have short half life time in the blood plasma. Their preference in
      comparison with other drugs is particularly rapid and strong action. In our
      experiments it was demonstrated, that simple proline-containing peptides Pro-Gly,
      Trp-Pro, Pro-Gly-Pro (putative fragments of collagen and elastin) possesses
      significant antithrombotic and anticoagulant potential in vitro and in in vivo.
      Perhaps these peptides are members on intrinsic complex of haemostasis
      regulators.

PMID- 10420481
TI  - Call for reduced use of antimicrobials.

PMID- 10420482
TI  - Effect on young calves of a one-hour feeding stop during a 19-hour road journey.
AB  - This study examined the effects of transporting calves less than four weeks of
      age on a journey at the limit of the maximum time laid down by recent EU
      legislation. In both summer and winter, 45 calves were transported by road for 19
      hours. The journey included a one-hour break on the lorry in which the calves
      were given either a glucose/electrolyte solution, water, or nothing at all.
      Control groups of 15 calves remained on farm and were fed normally. The effects
      of the journey were greater during winter when liveweight loss was greater and
      more prolonged, and the calves suffered a depression in body temperature. Mid
      journey feeding was of minimal benefit. Feeding electrolytes reduced the extent
      of dehydration as measured by changes in plasma total protein and albumin
      concentrations, but there was some indication that giving water alone was
      detrimental. Most of the variables which changed during the journey had recovered
      in line with the values in the control animals within 24 hours of the end of the
      journey, but the calves' liveweight and plasma creatine kinase activity took up
      to seven days to stabilise. The study highlighted the problem that young calves
      have in maintaining body temperature during transport, especially during colder
      weather.

PMID- 10420483
TI  - Mass screening of Irish wolfhound puppies for portosystemic shunts by the dynamic
      bile acid test.
AB  - Five hundred and sixty-six Irish wolfhound puppies aged six to 15 weeks were
      tested for congenital portosystemic shunts by the dynamic bile acid method.
      Plasma ammonia concentration was also measured in 165 of the puppies both fasting
      and postprandially. Nineteen puppies (3.4 per cent), nine males and 10 females,
      had portosystemic shunts. Smaller litters appeared to be more likely to contain
      affected puppies. The postprandial bile acid concentration was a reliable
      predictor of the presence of a shunt, with the highest concentration in a normal
      puppy being 38 mumol/litre and the lowest in an affected puppy being 43
      mumol/litre. In contrast, fasting bile acid concentrations were normal in the
      majority of the affected puppies. There was considerable overlap in fasting
      plasma ammonia concentrations between normal and affected puppies (26 puppies,
      15.8 per cent of those tested). Postprandial ammonia concentration appeared to
      give better separation between the two groups, apart from two individuals which
      produced bizarre results. It was concluded that the postprandial or dynamic bile
      acid test is an appropriate test for the mass screening of Irish wolfhound
      puppies for portosystemic shunts, and guidelines are proposed for the
      interpretation and follow-up of the test.

PMID- 10420484
TI  - Comparison of cyclosporin A and dexamethasone in the treatment of canine
      nictitans plasmacytic conjunctivitis.
AB  - Thirteen dogs with nictitans plasmocytic conjunctivitis were treated with 2.0 per
      cent cyclosporin drops in the right eye and with 0.1 per cent dexamethasone
      ointment in the left eye. The response to both therapies was monitored for six
      weeks, repeat biopsy specimens were taken, and the time for the clinical signs to
      recur recorded. Conjunctival cultures were taken before and after both therapies.
      There were no significant differences between the treatments in the remission of
      clinical signs, the reduction of inflammatory infiltrate in the biopsy specimens,
      or the time to recurrence of the condition or its subsequent severity. However,
      the eyes treated with 0.1 per cent dexamethasone tended to recover more rapidly
      than the eyes treated with 2.0 per cent cyclosporin, and the eyes treated with
      2.0 per cent cyclosporin tended to be protected from a recurrence for longer than
      the eyes treated with 0.1 per cent dexamethasone.

PMID- 10420485
TI  - Effect of flunixin meglumine on placental expulsion in dairy cattle after a
      caesarean.

PMID- 10420486
TI  - Cost-effectiveness of bovine spongiform encephalopathy screening.

PMID- 10420487
TI  - The farming crisis.

PMID- 10420489
TI  - Controlling sheep dip pollution.

PMID- 10420488
TI  - Excretion of VTEC O157 by cattle.

PMID- 10420490
TI  - NLF coliforms in milk samples.

PMID- 10420491
TI  - Host-pathogen relationship: evasion from control.

PMID- 10420492
TI  - Dynamics of immune escape in HIV infection.
AB  - The dynamics between pathogens and the immune system involve complicated
      interactions of many different components and this makes the use of mathematical
      models necessary to provide a correct interpretation of empirical results as well
      as to generate new insights and hypotheses. We demonstrate this approach by
      discussing mathematical models describing the dynamics between HIV and the immune
      response. Specifically, we show that viral evolution towards increased antigenic
      diversity may be the driving force underlying HIV disease progression and the
      reason for the eventual breakdown of the immune system upon development of AIDS.
      Such insights have important implications for designing efficient treatment
      regimes for HIV-infected patients.

PMID- 10420493
TI  - [Development of insulinoma cells as therapy in insulin-dependent diabetes
      mellitus].
AB  - In healthy persons insulin secreting beta-cells of the pancreas regulate blood
      glucose levels within a narrow physiological range. Since the detection of
      insulin in 1922 by Banting and Best, subcutaneous insulin replacement has
      remained the sole treatment modality for insulin-dependent diabetes mellitus
      (IDDM). However, even trained patients undergoing intensive insulin therapy fail
      to achieve normal function of the pancreatic beta-cells. One approach to solve
      this problem is pancreas and islet cell transplantation. Because of technical
      problems, limited number of transplantable organs and toxicity of
      immunosuppressive therapy, both are still in an experimental state. An
      alternative approach is the development of genetically modified insulin secreting
      cell lines for replacement of islet cells. So far, experiments support the
      expectation to develop genetically manipulated cell lines who imitate the
      function of islet beta-cells and are protected from the immune response. The
      ultimate goal is the development of an engineered human beta-cell line and, after
      animal experiments, to use it for treatment of patients with IDDM.

PMID- 10420494
TI  - [Analysis of referral diagnoses of patients with normal coronary angiogram].
AB  - BACKGROUND AND AIMS: Angiography permits an evaluation of the morphology of the
      coronary artery, stratification of risk and optimal therapeutic management in
      patients with suspected coronary artery disease (CAD). The sophisticated
      apparatus, cost and invasiveness of the procedure necessitate well-considered
      application of this method. In spite of an exact documentation of the patient's
      medical history and careful establishment of the indication, the results of
      angiography are often normal. Therefore, it appears important to analyse the
      referral diagnoses in patients with normal coronary angiograms. PATIENTS AND
      METHODS: We studied 1000 consecutive patients (625 men, 375 women, mean age 63.1
      years) who underwent coronary angiography at our institution from January to May
      1998. All patients were included in the retrospective analysis of the referral
      diagnoses. RESULTS: 875 patients (554 men, 321 women) were referred due to
      suspected CAD; 173 of these had normal angiographic findings (20%; 73 men, 100
      women; mean age 58.4 years). The referral diagnoses were as follows: unstable
      angina in 62 patients (36%), stable angina in 40 patients (23%), chest pain and
      pathological findings of non-invasive testing in 32 patients (19%), atypical
      chest pain in 25 patients (14%), previous myocardial infarction and multiple risk
      factors in 7 patients each (4% each). Gender-related differences were remarkable.
      Only 73 of the 554 referred men (13%) had normal angiographic findings, whereas
      in women the rate of normal results was more than twofold higher, i.e. 100 of the
      321 referred women (31%) had normal angiographic findings (p < 0.01).
      CONCLUSIONS: Among 875 patients referred to our catheter laboratory for coronary
      angiography due to suspected CAD, normal angiographic results were documented in
      20%. The high frequency of the referral diagnosis 'unstable angina' and
      'pathological result of noninvasive testing' was as remarkable as the high
      proportion of women among patients with normal findings.

PMID- 10420495
TI  - Efficacy of fluoxetine in Austrian patients with obsessive-compulsive disorder.
AB  - In an 8-week double-blind placebo-controlled trial we studied the efficacy of
      fluoxetine (FLX) in 53 Austrian patients with obsessive compulsive disorder (OCD)
      diagnosed according to DSM-III-R. The dosage of FLX was fixed at either 20, 40,
      or 60 mg per day. Response was prospectively defined as an at least 25% reduction
      on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and an improvement on
      Clinical Global Impression (CGI) rating to at least "much improved" at the
      endpoint. Patients treated with at least 40 mg FLX per day showed significantly
      higher response rates than did those receiving either placebo or FLX 20 mg/day.
      Compulsions were more reduced than obsessions and we also observed a strong
      placebo effect which is largely attributable to an improvement in the Y-BOCS
      compulsion subscore.

PMID- 10420496
TI  - Inhalation devices for the treatment of asthma--how much do paediatricians know
      about their correct use?
AB  - The present study was undertaken to assess the practical and theoretical
      knowledge of paediatricians in regard of inhalation devices for the treatment of
      childhood asthma. Forty-one paediatricians (39 from different parts of Austria
      and 2 from Switzerland), all of them running hospital-based chest clinics, were
      tested in regard of 4 items (Diskhaler, Metered dose inhaler (MDI) with
      Aerochamber, cleaning of an Aerochamber and a Pari Junior jet nebuliser).
      Practical performance and theoretical knowledge were assessed. Scoring was done
      by one consultant using a score of 1-5, with 1 point being given for the poorest
      performance and 5 points for the best. Overall performance was acceptable with a
      median of 13 points (the maximum achievable score was 20), but there were some
      deficits in the practical use of special devices. Better training on the use of
      different devices for inhalation therapy of asthmatic children is desirable.

PMID- 10420497
TI  - Septicaemia and endomyocarditis caused by Aerococcus urinae.
AB  - Aerococcus urinae, an uncommon urinary tract pathogen, was recently shown to
      cause septicaemia and endocarditis in a few patients in Denmark and the
      Netherlands. In Austria this is the first report of a fatal course of
      endomyocarditis by Aerococcus urinae, associated with multiple septic infarcts.

PMID- 10420498
TI  - [Are there still indications for albumin?].

PMID- 10420499
TI  - [Are there still indications for albumin?].

PMID- 10420500
TI  - [Are there still indications for albumin?].

PMID- 10420503
TI  - [Were we right? Personal choice of schools in higher education].

PMID- 10420502
TI  - [Are there still indications for albumin?].

PMID- 10420501
TI  - [Are there still indications for albumin?].

PMID- 10420504
TI  - The hepatitis alphabet--hepatitis A-G and TTV.
AB  - During the past three decades the number of viruses known to be capable to
      inducing liver inflammation has been considerably expanded. This short review
      gives a quick overview of the virologic characteristics, clinical manifestations,
      diagnosis, and treatment options. Newer hepatitis viruses such as hepatitis E
      virus (HEV), hepatitis GB-virus C/hepatitis G virus (GBV-C/HGV), and transfusion
      transmitted virus (TTV) are discussed and data concerning their disease-inducing
      capacity reviewed.

PMID- 10420505
TI  - Clinical symptoms in psychogenic seizures.
AB  - PURPOSE: To develop a classification system of psychogenic seizures based on
      characteristic clinical symptom clusters and sequences in order to facilitate the
      correct differential diagnosis of epileptic seizures. METHODS: We analysed the
      symptoms: clonic movements, hypermotor movements, trembling and tonic posturing
      of the upper/lower extremities, pelvic thrusting, stiffening of the body,
      version, side-to-side-head movements, non-versive head-turning and falling to the
      floor. We did this in a series of 16 patients with psychogenic seizures
      documented with prolonged video EEG monitoring. Nine patients (7 with frontal
      lobe epilepsy and 2 with primary generalised epilepsy with tonic, clonic
      seizures) served as a control group. RESULTS: We classified psychogenic seizures
      into 3 groups, namely (1) atonic psychogenic seizures, (2) psychogenic motor
      seizures and (3) psychogenic hypermotor seizures characterised by (1) falling to
      the ground, (2) trembling in the upper/lower extremities and (3) pelvic thrusting
      in combination with beating and kicking. While version exclusively occurred in
      epileptic seizures (incidence = 20%) and side-to-side head movements were only
      observed during psychogenic seizures (incidence = 8%), all other analysed
      symptoms were observed in both psychogenic and epileptic seizures. CONCLUSION:
      Our classification scheme should be useful in terms of permitting a more
      comprehensive clinical assessment of psychogenic seizures and their underlying
      psychiatric disorders. Furthermore, the differential diagnosis of psychogenic
      seizures should be considerably improved.

PMID- 10420506
TI  - [Skeletal muscle strength following orthotopic heart transplantation].
AB  - AIM OF THE STUDY: Strength measurement of thigh muscles of patients after
      orthotopic heart transplantation (HTX) with a sedentary lifestyle, entering a
      cardiac rehabilitation program. DESIGN: Cross-sectional study; values are
      compared to patients with chronic heart failure (CHF) and healthy controls.
      METHODS: Isometric and isokinetic peak torque of knee extensor and flexor muscles
      measured on a Cybex 6000. Twenty minutes' muscle fatigue test of knee extensor
      muscles. Test of motor tasks of daily living. RESULTS: HTX group: n = 18, age 59
      +/- 7 years, body mass index (BMI) 29 +/- 5, months after HTX 46 +/- 36 months;
      CHI group: n = 24, age 55 +/- 8 years, BMI 25 +/- 4, months after CHF 19 +/- 16
      months; control group: n = 10, age 55 +/- 6 years, BMI 26 +/- 5. The HTX group
      differed significantly (p < 0.05) from the CHI group. Peak torque of knee
      extensor muscles: HTX: 120.3 +/- 8.4; CHI: 127.8 +/- 8.0 Nm; controls: 158.3 +/-
      5.5 (ANOVA p < 0.05); peak torque of knee flexor muscles: HTX 65.6 +/- 5.9 Nm;
      CHI 70.1 +/- 6.2 Nm; controls 84.4 +/- 3.1 Nm(ANOVA p < 0.01). Peak torque of
      knee extensor muscles related to body weight: HTX: 137.4 +/- 10.0 Nm%, CHI: 162.6
      +/- 9.3 Nm%, control group 202.8 +/- 5.7 Nm% (ANOVA p < 0.01). Muscle fatigue
      test of knee extensor muscles: isometric maximal strength (maximal voluntary
      contraction, MCV; HTX vs. CHI): 331.6 +/- 14.7 N vs. 335.5 +/- 18.6 N (n.s.), MVC
      after 5 minutes 296.3 +/- 15.7 N vs. 288.4 +/- 16.7 N; MVC after 10 minutes:
      283.5 +/- 15.7 N vs. 282.5 +/- 17.7 N; MVC after 15 minutes 275.7 +/- 13.7 N vs.
      280.6 +/- 21.6 N. No significant differences between groups were observed. All
      values were significantly lower than those of healthy controls (406.2 N; 385.9 N;
      373.7 N and 369.6 N). There was a significant decline in MVC after 5 minutes
      compared to initial values (p < 0.01), in both patients groups but not in the
      control group. No further decline in MVC was observed beyond the 5th minute of
      the fatigue test (p > 0.05). CONCLUSION: Peak torque related to body weight and
      muscle endurance of knee extensor muscles of sedentary patients after orthotopic
      HTX do not significantly differ from those of comparable patients with CHF but do
      differ from those of healthy controls. Specific training of muscle strength is
      needed for patients even several years after orthotopic heart transplantation.

PMID- 10420507
TI  - Severe forms of tick-borne encephalitis in children.
AB  - Records of patients aged 0 to 15 years, hospitalised between 1993 and 1998 at the
      intensive care unit (ICU) of the Department of Infectious Diseases, Ljubljana,
      Slovenia, suffering from a severe attack of tick-borne encephalitis (TBE), were
      reviewed. Of 133 children hospitalised due to TBE virus infection during the
      observation period, 7 (5.2%) were treated in the ICU. All patients were male,
      aged 6 to 14 (mean, 11.1) years. In six cases, focal encephalitis was diagnosed,
      and in one case it was suspected. All patients survived. After a mean follow-up
      period of 7.9 (range, 1.5 to 17) months, one patient was found to have severe
      neurologic sequelae and two patients had moderate sequelae. In conclusion, the
      results of our retrospective study of severe forms of TBE in children demonstrate
      that this disease can run a severe course and may lead to permanent sequelae,
      most often in boys of school-going age who present with focal encephalitis.
      Therefore, immunisation of school children against TBE in endemic areas is
      strongly recommended.

PMID- 10420508
TI  - [Mementos of the Berlin-Jewish ophthalmologist Oskar Fehr (1871-1959)].
AB  - Anti-Semitism and National Socialism destroyed the existence of many individuals.
      Their names and biographies disappeared into oblivion. The bequest of ophthalmo-
      historical papers by Ms. Jutta Lauber, daughter of the Austrian ophthalmologist
      Hans Lauber (1876-1952), allowed us to trace the fate of the Jewish
      ophthalmologist Oskar Fehr (1871-1959). In the first decades of the 20th century
      Oskar Fehr was an internationally renowned ophthalmic surgeon and pathologist.
      Disregarding political adversities and ignoring personal losses and hardships he
      dedicated his life to the service of human health.

PMID- 10420509
TI  - [The sources of the travel illness "jet lag" are still not clear].

PMID- 10420510
TI  - [The so-called 'Science Citation Index' -- miscellaneous, rankings for 1995 (E.
      Saling and A. Uphoff) and the Zeitschrift f"ur Geburtshilfe und Neonatologie
      (ZGN)].

PMID- 10420512
TI  - [Sialic acid, steroids and proteohormones in maternal, cord and retroplacental
      blood].
AB  - BACKGROUND: To study the storage of sialic acid in newborns reference
      concentrations for sialic acid were measured in maternal, retroplacental and cord
      blood and compared with the concentration of human placental lactogen (hPL) and
      estriol (E3). High serum concentrations of hPL and E3 in retroplacental blood
      indicate the synthesis of these products in the fetoplacental unit. The
      comparison of the serum concentrations give first informations for a possible
      role of the placenta as a place of production and storage of the investigated
      products. METHODS: The concentrations of sialic acid, hPL and unconjugated E3
      were determined in maternal and retroplacental blood samples of 126 pregnant
      women (16-42 years old) between 28 and 42 weeks of gestation. 84 of these
      pregnant women had uncomplicated pregnancy with birth after 37 gestational weeks.
      Measurements of E3 and hPL were performed by solid phase radioimmunoassays.
      Concentrations of sialic acid were determined by HPLC (high performance liquid
      chromatography). RESULTS: Means and medians of the three parameters for both
      groups differentiate hardly. The retroplacental serum concentrations of hPL and
      E3 are increased significantly compared with maternal blood. The same trend was
      found for sialic acid without significance. The highest concentrations of E3 were
      found in the cord blood (298.2 +/- 138.0 ng/ml) (p < 0.01). On the other hand the
      lowest concentrations of sialic acid (36.1 +/- 19.6 mg/l) (p < 0.01) were
      estimated in cord blood samples. It was estimated a significant correlation
      between fetal and retroplacental concentrations of E3. Significant correlations
      (p < 0.01) were found for sialic acid between maternal and retroplacental blood
      on the one side and maternal and the cord blood on the other side. Significant
      increased mean sialic acid concentrations in retroplacental blood (x = 102.67
      mg/l) were found in female newborns in comparison with male newborns (x = 80.58
      mg/l). There were not significant differences between prematurity and term
      delivery. CONCLUSION: Increased sialic acid concentrations in retroplacental
      blood samples are a sign of sialic acid accumulation in the fetomaternal area
      aiming to induce the tolerance of fetal allotransplantat. There are no evidence
      for a take up of free sialic acid by fetus.

PMID- 10420511
TI  - [Parasitic infections in pregnancy and congenital protozoan infections. Part I.:
      Protozoan infections].
AB  - Intestinal protozoan disease diagnosed in pregnancy is mostly controlled by
      symptomatic treatment. Specific therapy can be delayed until after delivery. Only
      severe cases, i.e. continued diarrhea leading to malnutrition of either mother or
      fetus, require an immediate specific drug therapy, which might be harmful to the
      fetus due to toxic and teratogenic potentials. Vertical transmission of
      intestinal protozoa has not been described. Invasive protozoan infections can be
      lethal to the mother making immediate drug therapy mandatory, even if the
      potentials of fetotoxicity or teratogenicity are known. Vertical transmission
      occurs independent of maternal symptoms, causing clinical disease in the child
      either directly after birth or during the first months of life. The knowledge of
      endemic regions and of the maternal travel history is essential for early
      diagnosis and treatment of protozoan disease in pregnancy and of congenital
      protozoan infections.

PMID- 10420514
TI  - [Theoretical and experimental models of sonographic diagnosis of umbilical cord
      knot and their application in practice].
AB  - Modern sonographic technique allows the detection of cord complication as neck
      cord entanglement. Far more difficult is the detection of a real cord knot. This
      article describes a theoretical model for detection of a cord knot and proves it
      in an in-vitro model.

PMID- 10420513
TI  - [Acoustically evoked brain magnetic activity in normal and growth retarded
      fetuses during the third trimester of pregnancy].
AB  - The fetal magnetoencephalogram with a 31 chanal biomagnetometer made by Philips
      was measured in a fetal 1F-phase in 20 normotroph unimpaired and in 14 growth
      retarded fetuses with a birth weight < 5 percentile after completed 36th
      gestational week. Trough defined acoustic stimulations, which were applied over
      the maternal abdominal wall, it was possible to measure acoustic evoked
      cerebromagnetic field changes using a special computer programs. The registrated
      evoked cerebromagnetic field changes had a latence time of 112.8 +/- 18.4 ms in
      normotroph fetuses and 130.9 +/- 18.5 ms in hypotroph fetuses. The difference was
      significant (p < 0.01). The presented results lead to the conclusions that the
      fetal magnetoencephalography makes a differentiation between normal and disturbed
      fetal cerebral integrity possible.

PMID- 10420515
TI  - [Fiberoptic measurement of arterial oxygen saturation in premature and term
      neonates].
AB  - BACKGROUND: Non-invasive oxygen monitoring with pulse oximetry or transcutaneous
      monitoring has gained widespread use in neonatology. Different factors like
      arterial hypotension, peripheral vasoconstriction and edema adversely affect the
      accuracy of both methods. To ensure reliable monitoring of oxygen saturation in
      critically ill patients we measured oxygen saturation with a fiberoptic catheter
      via umbilical artery. METHODS: In ventilated premature infants (FiO2 > 0.4) a 4F
      fiberoptic catheter (Oximetrix)-3, Abbott) was inserted to the descending aorta
      (Th 6-8). Simultaneously pulse oximetry (SaPO2) was performed with the Ohmeda
      Biox 3700. To compare the reliability of both methods, blood was analysed for
      arterial partial oxygen pressure (PaO2), fetal hemoglobin (HbF) and arterial
      oxygen saturation (SaO2) by complete co-oximetry (Radiometer Copenhagen OSM3) as
      reference. RESULTS: In 10 premature infants (median gestational age 30.5 weeks;
      median birth weight 1360 g) oxygen saturation was measured with the fiberoptic
      catheter (SaFO2) over a total period of 935 hours. In all, 137 blood samples were
      analysed for arterial saturation (SaO2) by co-oximetry. The mean difference
      between the SaO2 and SaFO2 was -1.89% (+/- 1.53); the mean difference between
      SaO2 and the values obtained by pulse oximetry (SaPO2) was -3.09% (+/- 2.33). The
      SaFO2 results correlated closely with the co-oximetry values (r = 0.97; p <
      0.0001). CONCLUSION: In critically ill patients, if non-invasive oxygen
      monitoring fails, a fiberoptic catheter offers the possibility of continuous and
      reliable measurement of oxygen saturation.

PMID- 10420516
TI  - [Iodine concentration in the breast milk of mothers of premature infants].
AB  - In this prospective study the longitudinal iodine concentration was compared in
      breast milk of preterm infants mothers, with and without iodine supplementation.
      195 samples of breast milk from 60 mothers were analyzed by HPLC longitudinally.
      RESULTS: Mothers who take additional iodine (200 micrograms/d) had significant
      higher mean iodine concentrations in breast milk (mean: 7.6 +/- 6.3
      micrograms/dl) than mothers without additional iodine supply (mean: 5.5 +/- 5.8
      micrograms/dl/p < 0.02). Nontreated mothers showed significantly more breast milk
      iodine concentrations below the recommended minimum concentration of 5
      micrograms/dl (64%, n = 84) than treated mothers (40%, n = 25/p = 0.0016). Mean
      iodine intake in preterm infants of treated mothers was higher (11.9 micrograms
      l/kg) than in preterm infants of nontreated mothers (7.9 micrograms l/kg).
      DISCUSSION: The measured iodine concentrations in breast milk of preterm infants
      mothers markedly varied inter- and intraindividual. The variations might be
      explained by irregular daily iodine intake and a dilution effect by increasing
      breast milk volumes. CONCLUSIONS: Iodine supplementation of lactating mothers
      leads to elevated iodine content of their breast milk. The recommended intake of
      iodine for both newborns (15 micrograms l/kg) and preterm infants (30 micrograms
      l/kg) was not reached in the breast fed preterm infants in both groups of our
      study.

PMID- 10420517
TI  - [Unusual course of an advanced extra-uterine pregnancy].
AB  - We report about the course of an advanced ectopic pregnancy in case of uterine
      leiomyomata, which was diagnosed after surgery. A vaginal bleeding appeared in
      the first trimester. Vaginal ultrascan was missing in those early time of
      pregnancy. Finally prenatal diagnosis in a center of perinatal medicine led to a
      suspicious fetal morphology and gave the indication for medical abortion. The
      induction of abortion with Gemeprost remained without success. Meanwhile
      abdominal pain increased and a laparoscopic exploration was carried out and
      showed a big vital ectopic pregnancy. This indicated laparotomy. This case showed
      the difficulties in diagnosis of ectopic pregnancy in the second trimester and
      discusses possibilities of the therapeutic procedures.

PMID- 10420520
TI  - [Optimizing therapy of tumors of the gastrointestinal tract].

PMID- 10420518
TI  - [Epilepsy and pregnancy].
AB  - One out of 200 pregnant women suffers from epilepsy. Pregnancy and epileptic
      disease or its medical treatment, respectively, do interfere, as on the one hand
      serum concentration of antiepileptic drugs can severely be altered during
      pregnancy. On the other hand these drugs cause a fetal malformation rate 2-3
      times higher than in an average population. These facts demand an
      interdisciplinary cooperation between neurologists, pediatricians and
      obstetricians. Preconceptional advice should lead to a preventive folic acid
      medication and information about the higher risk for preterm delivery,
      intrauterine growth retardation or fetal death as sequelae of epileptic attacks.
      In antepartal investigations the emphasis should be on the sonographic diagnosis
      of fetal malformations and on regular control of serum concentration of
      antiepileptic drugs. During labor a tight fetal monitoring is obligatory. There
      is no indication for a primary cesarean section. The risk of neonatal hemorrhage
      due to a lack of vitamin K is reduced by prophylactic medication. Under optimal
      conditions about 90% of pregnancies and deliveries will be uncomplicated. During
      puerperium serum levels of antiepileptics should be controlled again.
      Breastfeeding is possible.

PMID- 10420521
TI  - [Stomach carcinoma. Optimizing therapy by extended lymph node dissection].
AB  - BACKGROUND: The prognosis for surgically treated gastric cancer patients remains
      poor in most Western countries compared with reports of Japanese investigators
      over the last three decades. The aim of the study was to prove whether D2, D3
      lymphadenectomy is able to improve long-term survival in a Western gastric cancer
      patients collective as well. METHODS: A radical surgical procedure using D2, D3
      lymphadenectomy on principle as defined by the Japanese Research Society for
      Gastric Cancer was done prospectively since January 1984. Out of 626 patients
      with gastric cancer, 433 were surgically treated for potential cure between
      January 1st, 1984 and December 31st, 1996. Postoperative complications and long
      term survival were evaluated. RESULTS: For curatively operated patients five- and
      ten-year tumor specific survival rates were 57.7% and 44.3%, the median survival
      time was 96 months. Postoperative hospital mortality was 4.8% for R0 resected
      patients and 10.4% for palliative procedures. CONCLUSION: Radical D2, D3
      lymphadenectomy yielded survival rates similar to those in Japanese
      investigations without negative effect on low postoperative mortality. These
      results reaffirm the value of radical lymph node dissection with wide resection
      margins.

PMID- 10420519
TI  - [Readers ask--experts answer. Cholelithiasis in the 2nd and 3rd trimesters
      treated with laparoscopic surgery. Effects of pneumoperitoneum on the pregnancy].

PMID- 10420522
TI  - [Stomach carcinoma. Optimizing therapy by stomach replacement or subtotal
      resection?].
AB  - The extent of surgical resection in the treatment of gastric carcinoma depends on
      the tumor site as well as on the histomorphological type according to Lauren
      taking into account the margins of clearance at the oral resection line.
      Following subtotal distal gastrectomy functional long-term results might be
      generally better in comparison to total gastrectomy. Among the large variety of
      operative methods of reconstruction after total gastrectomy the Roux-en-Y
      procedure is preferred by the majority of surgeons. Nevertheless, according to
      experimental and clinical trials jejunal interposition technique seems to allow a
      more physiological gastric replacement with improved postoperative function and
      quality of life. Furthermore, jejunal interposition can influence the motility of
      the entire intestinal tract resulting in a better functional outcome. The
      importance of pouches for gastric substitute with positive impact on the long
      term nutritional status must be clarified in further clinical trials. In
      conclusion, the question of ideal mode of reconstruction of the upper
      gastrointestinal tract is still open and continues to be found out.

PMID- 10420523
TI  - [Stomach carcinoma. Optimizing therapy by neoadjuvant or adjuvant therapy?].
AB  - Despite the decreasing frequency of gastric cancer in most Western countries
      prognosis could not be improved by surgery alone in the past. Advanced tumor
      stage due to late diagnosis is one of the reasons for this observation. Contrary
      to breast and colorectal cancer, postoperative chemotherapy failed to improve
      prognosis in gastric cancer. Small number of patients in Western studies,
      insufficient surgical procedures and the high frequency of locoregional relapse
      may be attributed for this observation. Intraperitoneal, adjuvant chemotherapy
      showed a positive impact on survival in Asian studies only, but was also used
      successfully as a part of a multimodality approach in Western phase II trials.
      Since neoadjuvant therapy proved to create downstaging of tumor size in some
      patients with advanced gastric cancer some working groups tried to influence
      prognosis of potentially resectable tumors by preoperative chemotherapy, surgical
      resection and postoperative, adjuvant therapy in the recent past. However, the
      efficacy of this therapeutic approach has to be reconfirmed in a controlled,
      phase III fashion.

PMID- 10420524
TI  - [Optimizing palliative therapy in pancreatic carcinoma].
AB  - Only an interdisciplinary approach between surgeon, medical oncologist and
      radiologist may allow the optimisation of palliative treatment for pancreatic
      carcinoma. If imaging diagnostics do not allow to decide about the resectability
      of a tumour, an explorative laparotomy should be performed, unless this is
      precluded by comorbidity. Due to similar morbidity and mortality, but better long
      term results, a choloedocho-jejunostomy should be performed for intra-operatively
      unresectable tumors in favour of a cholecysto-jejunostomy. In selected patients a
      gastro-enterostomy may be indicated. However, this is not justified
      prophylactically. If imaging diagnostics show definite signs of unresectability
      in the absence of a gastric outlet obstruction, the treatment depends on the
      general condition of the patient: Insertion of a pigtail-catheter is sufficient
      for patients in poor general condition and a short life expectancy; metal
      wallstents should be preferred for patients in good general condition and a life
      expectancy in excess of six months, due to better results regarding quality of
      life. Chemoablation of the celiac plexus is an useful method to control the sever
      pain, which is common in these patients; radiotherapy or analgesic therapy may be
      used alternatively.

PMID- 10420525
TI  - [Pancreatic carcinoma. Optimizing therapy by adjuvant and neoadjuvant therapy?].
AB  - Increasing resection rates for pancreatic tumors and decreasing postoperative
      mortality rates in specialised centres let arise the question of an additional
      benefit of adjuvant therapy. Despite of extended and radical surgery the
      recurrence rates after resection of pancreatic cancer remain high. Several
      studies have indicated some chemo- and radiosensitivity of these tumors. Whether
      a (combination-)chemotherapy alone or a combined radiochemotherapy should be
      recommended can actually not be answered yet. However, adjuvant radiotherapy
      alone seems to be inferior to combined radiochemotherapy. Intraoperative
      radiotherapy as well as preoperative radiotherapy are not superior to
      postoperative percutaneous radiotherapy regarding recurrence rate and survival.
      Preoperative radiotherapy, preferably in combination with chemotherapy, should be
      considered in patients with non resectable or borderline resectable pancreatic
      tumors with the aim of downstaging and secondary resection. The preliminary
      results of regional adjuvant chemotherapy are impressing, but need to be
      confirmed in further, randomised studies. Overall, the availability of a good or
      even optimal adjuvant therapy for pancreatic cancer still seems to be far away.
      Therefore, all surgeons need to be encouraged to include their patients with
      resected pancreatic carcinoma in a current study protocol of adjuvant treatment,
      since only tenacious and multicentric research can lead to progress in this
      severe disease.

PMID- 10420526
TI  - [Histopathologic examination of rectal carcinoma].
AB  - In patients with rectal carcinoma, the histopathological evaluation of the
      surgical specimen provides pivotal prognostic and therapeutic information.
      Important parameters are tumor site, depth of invasion, histological type and
      grade, pattern of invasion (diffusely infiltrating versus expanding margin),
      degree of peritumoral lymphocytic infiltration, and tumor involvement of surgical
      margins and lymph nodes. Evaluation of the circumferential (deep, lateral) margin
      is of utmost importance. It should be labeled with ink in the gross specimen and
      should be examined histologically using several tissue blocks. The number of
      lymph node metastases and the total number of lymph nodes examined should be
      reported. A histological evaluation of the distal mesorectum in its entirety is
      recommended to detect discontinuous distal mesorectal tumor spread. The
      histopathological findings should be summarized using the TNM-classification.

PMID- 10420527
TI  - [Rectal carcinoma. Optimizing therapy by knowledge of anatomy with special
      reference to the mesorectum].
AB  - The connective tissue spaces of the pelvis and pelvic floor originate from an
      urogenital and perirectal mesenchymal cell complex, which can be clearly
      discerned. In the adult, the final compartments, which arise from these distinct
      tissue complexes, are still functionally separated. The perirectal tissue gives
      rise to the rectal fascia or rectal adventitia, also known as mesorectum. The
      connective tissue space between rectal and parietal pelvic fascia can be
      dissected as a plane free of vessels and nerves. Surgical dissection along this
      plane with complete mesorectum excision results in reliable excision of all
      relevant lymphatic pathways with extensive preservation of continence and sexual
      function.

PMID- 10420528
TI  - [Rectal carcinoma--optimizing therapy by improved preoperative staging? Is
      endosonography required?].
AB  - Endosonography is superior to other imaging modalities (CT, MRI) and has to be
      considered as the most useful and accurate method in staging rectal carcinoma
      inclusive the invasion of the sphincter apparatus. Selection of patients for
      sphincter saving operation, local excision and in case of preoperative adjuvant
      therapy is greatly supported by endosonography and has to be considered as
      inevitable in the preoperative management.

PMID- 10420529
TI  - [Rectum carcinoma. Optimizing therapy by deep resection or excision].
AB  - Abdominoperineal excision of the rectum has been the surgical treatment of choice
      for rectal cancer of the middle and lower third for decades. However, subsequent
      to technical developments, particularly stapling instruments, sphincter saving
      procedures such as low anterior or intersphincteric resection superseded
      abdominoperineal excision in the majority of tumors of the middle and even lower
      third of the rectum. Within the last seven years (1990-1997), 253 patients with
      distal rectal cancer underwent surgery--in 204 patients surgery was carried out
      for the cure of malignancy, whereas in 49 patients surgery was performed for
      palliation. In the meantime, the rate of abdominoperineal excision with permanent
      stoma was steadily decreased from 25% (1990-1993) to 9% (1994-1997). Concerning
      oncologic quality, sphincter saving resections showed evidence that cure rates (3
      and 5-year survival) were not compromised by these techniques; conversely,
      sphincter saving resections offered oncologic cure rates superior to
      abdominoperineal excision of the rectum. Complete lymphadenectomy with high
      ligation of the inferior mesenteric artery and total mesorectal excision (TME)
      are fundamental components of this approach. Moreover, the adverse effects of a
      permanent colostomy and the consecutively diminished quality of life following
      abdominoperineal excision can be avoided in approximately 80% of cases. In
      conclusion, at present 80-85% of rectal carcinomas of the middle or lower third
      can be surgically treated by sphincter saving low resections without compromising
      oncologic radicality.

PMID- 10420530
TI  - [Rectal carcinoma. Optimizing therapy by partial or total mesorectum removal].
AB  - The role of total mesorectal excision for rectal cancer treatment is one of the
      most exciting findings in surgical oncology of the recent years. The patient's
      prognosis largely depends on the surgical quality of rectal resection. The
      excision of the cancer bearing rectum has to follow very precisely along the
      mesorectal fascia by sharp dissection without damaging the mesorectum itself.
      This technique reduces the local recurrence rate to below 10% and allows long
      term survival in two thirds of all patients. Rectal cancers of the middle and
      lower third of the rectum need to be treated by total mesorectal excision down to
      the muscular pelvic floor, the ones of the upper third and the sigmoideo-rectal
      junction are appropriately treated by partial mesorectal excision down to 5 cm
      below the tumor. No additional survival benefit may be expected when pelvic
      lymphadenectomy has been performed. The direct tumor spread along the bowel wall
      and the lymphatic tumor spread in a caudal direction are uncommon and late
      findings in rectal cancer disease. Low and ultralow rectal carcinomas may
      therefore be treated by a sphincter preserving procedure respecting a safety
      margin of at least 1 to 2 cm. Thus, continence preserving surgery may be
      performed in over 80% of patients suffering from rectal cancer without
      compromising long-term outcome.

PMID- 10420531
TI  - [Rectal carcinoma. Optimizing therapy by local excision].
AB  - The results of local excision and radical surgery in patients with T1-carcinomas
      of the rectum were compared. In a retrospective study (1.1.1985-1.7.1997) the
      results obtained in 107 patients with T1-rectal carcinoma ("low risk" T1: n = 83,
      "high risk" T1: n = 24) undergoing local excision or radical surgical therapy
      were compared. The complication rate in patients undergoing local excision was
      3.3% (2/60) and ranged at 19% (9/47) in the group treated with radical surgery.
      Two out of 47 patients (4.2%) died after radical resection; there were no deaths
      after local excision. With regard to the actuarial 5-year survival rate, in the
      group with "low risk" T1 carcinoma no difference was observed between patients
      treated with local excision (79%) or radical resection (81%) (p = 0.72). In
      patients with "high risk" T1 carcinoma lymph node metastases were identified in 4
      out of 11 patients undergoing radical resection (36%). 4 out of 13 patients with
      "high risk" T1 carcinoma treated by local excision developed recurrences, while
      none of the patients undergoing primary radical surgery had a recurrence. This
      underlines the necessity of radical surgery in "high risk" T1-carcinomas. Local
      excision for the treatment of "low risk" T1-carcinoma is associated with a
      significantly lower complication rate than the performance of a radical surgical
      therapy. There is no difference in five-year-survival between local and radical
      surgical therapy in patients with "low risk" T1 carcinoma.

PMID- 10420532
TI  - [Rectal carcinoma. Optimizing treatment by neoadjuvant and adjuvant therapy?].
AB  - Despite of improvement of results in rectum cancer treatment after systematical
      introduction of total mesorectal excision as a standard procedure to control the
      compartment disease, surgical radicality may be limited in cases with large
      tumours in ventral position because of eccentric location of the rectum in the
      perirectal fat. In these cases (neo)adjuvant treatment with a 45-54 Gy dose
      radiotherapy and 5 FU-based chemotherapy seems to be useful to minimize local
      recurrence and distant metastases and also to provide a better outcome.

PMID- 10420533
TI  - [Rectal carcinoma. Optimizing the procedures in an emergency].
AB  - Emergency conditions in rectal cancer can happen pre-, intra-, and
      postoperatively. Preoperative emergencies are perforation and obstipation.
      Spontaneous intraperitoneal perforations have a mortality of 17 to 33% and a five
      year survival of only 7 to 10%. The site of the perforation is not identical with
      the the site of the tumor. Due to fecal peritonitis a defunctioning stoma and
      planned repeat laparotomies are indicated. Initial fecal diversion is followed by
      tumor resection with anastomosis when the peritonitis has subsided. Iatrogenic
      perforations from endoscopy or barium enema examination are rare (0.09 to
      0.004%). Tumor obstruction occurs in 15% of colorectal cancers. Immediate
      resection with primary anastomosis is deemed to be feasible if preceded by on
      table colonic lavage. Immediate resection has a lower mortality (13.6%) than two
      staged fecal diversion and resection (35.5%). Intraoperative emergency conditions
      are bleeding and tumor cell spillage. Bleeding from the presacral veins will be
      controlled with the hemorrhage occluder pin. Inadvertent perforation of the tumor
      leads to dissemination of tumor cells. In case of spillage local recurrence was
      seen in 39% of resections within five years. Multivisceral resection and precise
      preparation with respect to anatomical planes may prevent damage of the rectum.
      The leading postoperative emergency condition is anastomotic leak. The incidence
      of clinical leaks is 6%. In diffuse peritonitis the anastomosis should be taken
      down and planned repeat laparotomy should be performed. This concept reduces the
      mortality down to 18.7%.

PMID- 10420536
TI  - [Surgical procedures of the neck (1)].

PMID- 10420535
TI  - [Comments on the contributions by Seiler ChA, Brugger L, Maurer CA, Renzulli P,
      Buchler MW. Peritonitis in diverticulitis: the Bern concept. Gertsch P, Al-Muaid
      J, Pelloni A, Bogen M. Surgical therapy of complicated sigmoid diverticulitis:
      single or multi-stage therapy?].

PMID- 10420534
TI  - [Laparoscopic gastric banding in morbid obesity].
AB  - Laparoscopic "Gastric Banding" is a modern, minimally invasive technique to
      induce significant weight loss in morbidly obese individuals. If performed
      according to the established principles of elective surgery, the procedure has to
      be classified as a serious offer to a specific group of patients, who have, as
      yet, been confronted with the option of futile conservative therapies or
      irreversible interventions in the gastrointestine. The technique comprises the
      laparoscopic placement of a silicone band below the cardia, connected to a port
      system. By the hourglass-like segmentation of the stomach a "pouch" and an
      artificial "stoma" (outlet) is created, with the effect of decreasing food intake
      and--psychologically intended--inducing an early feeling of satiety. The
      complexity of the pathogenetic impulses leading to severe nutritional obesity
      requires a serious risk/benefit appreciation with multidisciplinary responder
      analyse. Apart from the main indications like overweight, patient history and
      obesity-associated disorders it is indispensable to include the psychological
      status of the patient and his capability of compliance into the decision-finding.
      With the inflatable inner surface of the band connected to the access port, the
      system is designed to permit postoperative regulation of the therapeutic outcome
      by percutaneous stoma size adjustment without further surgery. The placement of
      the band as well as the specific anatomical conditions of extremely obese
      patients involve severe risks such as primary organ lesions, post-operative pouch
      dilatation or "slippage" by herniation of the gastric wall. Therefore the
      technical performance of the implantation demands a high level of experience and
      practical knowledge of abdominal laparoscopic procedures. It is to assume, that
      prospective validation to establish operation standards will have a critical look
      to the modification of the surgical procedure, the size of the implant, the pouch
      and the stoma.

PMID- 10420537
TI  - [The current neurosurgical resources on the Internet].
AB  - Progress of information and telecommunication technologies, rapid development of
      local computer networks and their incorporation into the global computer network
      Internet are of great importance for the development of modern civilization.
      Internet presents all spheres of human activities, including medicine,
      neurosurgery in particular. It is the most available resource that has an
      unlimited amount of information, expands and is supplemented in geometric
      progression. A great deal of specialized neurosurgical information has been
      accumulated in the network that may be available to any neurosurgeon irrespective
      of the geographical region. There has come a time when information can be
      obtained through progress in telecommunication technologies that accelerate this
      process by hundreds of times, there has come a time when colleagues can actively
      contact with each other by transmitting not only verbal and textual information,
      but also graphic and video information. The present paper presents a review of
      currently available Internet neurosurgical resources by showing the benefits of
      this information source and the possibilities of its use in neurosurgery for both
      educational and scientific purposes.

PMID- 10420538
TI  - [The selective phlebography of the large tributaries of the vena cava system in
      the diagnosis of venous circulatory disorders in the spinal complex].
AB  - As any other organ, the spinal cord also suffers in chronic congestion. Since the
      epidural venous system drains into the vena cava system and participates in
      collateral circulation, there is increased inflow with impaired blood flow along
      its large tributaries in the vertebral canal along with poor outflow, resulting
      in intracanal hypertension and chronic congestion. Venous hemodynamic disorders
      are found beyond the vertebral canal and detected by selective phlebography of
      the large tributaries of the vena cava system. The technique was used to examine
      46 patients with spastic paraparesis or tetraparesis of unclear etiology, which
      provides evidence for the fact that vena cava stenoses, compressions, atresia,
      and thromboses can be responsible for impaired venous hemodynamics in the
      vertebral apparatus and its surgical correction is possible.

PMID- 10420539
TI  - [Posttraumatic spinal instability and the methods for its surgical correction].
AB  - The paper deals with the outcomes of 982 patients with thoracic and lumbar spinal
      lesions and the data of biomechanical testing (298 studies on 103 specimens from
      the cervical, thoracic, and lumbar spine). Major types of acute posttraumatic
      spinal instability (such as axial instability, threatening fractured fragment
      instability, and threatening segmental instability) are defined and the
      stabilizing capacities of routine surgical techniques are assessed. The current
      systems for stabilizing the spine (transpedicular designs and plates for anterior
      spinal fixation is shown to be effective.

PMID- 10420540
TI  - [A clinico-immunological study in recurrent mild craniocerebral trauma in the
      acute period].
AB  - Comparative clinical (X-ray study, computed tomography, echoencephalography,
      electroencephalography, electrocardiography, examination of the fundus of the
      eye, lumbar puncture) and immunological (examination of cellular and humoral
      immunities, neurosensitization) studies were conducted in 98 patients with the
      first mild brain injury and 92 with repeated injury. Clinical and immunological
      parameters became worse in patients with repeated brain injury at week 3, which
      shows the development of autoimmune autoaggressive reactions in the sensitized
      body. These patients should be referred to as a risk group of disease progression
      and they should be given immunomodulating therapy.

PMID- 10420541
TI  - [A combination of a meningioma of the base of the skull and an arteriovenous
      micromalformation of the brain stem].
AB  - The paper describes a rare combination of atypical meningioma of the base of the
      skull, which was greatly extended, with a life-time unrecognized small vascular
      malformation of the brain stem at the level of the pons. Intraoperative
      hemorrhage into the stem from the micromalformation was a cause of the female
      patient's death. A detailed account of the operation and the postoperative period
      and a review of literature on the main aspects of the problem in the diagnosis of
      cerebral micromalformations are given.

PMID- 10420543
TI  - [An arteriovenous malformation of the cervical spinal cord with drainage into the
      cranial cavity combined with thymus hyperplasia].

PMID- 10420542
TI  - [Plastic repair of a defect in the base of the skull with soft tissues from the
      orbit after the removal of an extensive esthesioneuroepithelioma].
AB  - The paper describes a clinical observation of closure of sphenoidal sinus defect
      and plastic repair of dura mater by using orbital tissues after removal of a
      tumor from the medial portions of the middle cranial fossa, which spread into the
      orbit and sphenoidal sinus, in complete irreversible loss of visual function,
      ophthalmoplegia and ptosis in a patient with skull soft tissue hypotrophy due to
      multiple operations and radiation therapy and hence unsuitable for displacement
      and closure. This observation shows it possible to use orbital soft tissue for
      repair of the base of the skull, in cases when integumentary cranial tissues are
      impossible to use as a plastic material due to their hypotrophicity. At the same
      time severe dysfunctions, such as blindness and ophthalmoplegia enable orbital
      tissues to be employed without significantly deteriorating any functional and
      cosmetic effect.

PMID- 10420544
TI  - [A combination of an aneurysm of the bifurcation of the internal carotid artery
      with agenesis of its trunk].
AB  - A case of agenesis of the internal carotid artery with ipsilateral aneurysm of
      the anterior middle cerebral artery is first described in the literature. This is
      a 23-year-old male with seizures in whom computed tomography and magnetic
      resonance imaging (MRI) revealed a large left paracellular calcified formation.
      MRI showed no ipsilateral aneurysms of the internal carotid artery and carotid
      canal. Agenesis was confirmed by intraoperative data at removal of thrombotic
      aneurysm. The paper provides a brief account of the outcome of surgery and a
      review of literature on agenesis of the internal carotid artery concurrent with
      cerebral aneurysms.

PMID- 10420545
TI  - [A cryptococcal granuloma of the midbrain].
AB  - The paper describes the most infrequent case of cryptococcal granuloma of the
      midbrain in a HIV-negative female patient aged 41 years. The patient with
      midbrain lesion without signs of meningitis was found to have a bulky midbrain
      opercular formation that was regarded as a nodal glioma. The diagnosis of
      cryptococcal granuloma was established after removal of the formation (via
      occipito-transtentorial access with dissection of the lamina tecti) and
      pathomorphological examination. Microbiological studies verified the diagnosis.
      Despite the initiation of specific treatment with amphotericin B, the patient
      died on day 12 following surgery for cryptococcal meningoencephalitis.

PMID- 10420546
TI  - [The excessive cerebrospinal fluid drainage syndrome as a complication of the
      surgical treatment of hydrocephalus].
AB  - The paper presents a clinical case of severe excess cerebrospinal spinal fluid
      drain syndrome with hematomas of the cerebral hemispheres being formed in a 18
      year-old young man undergone ventriculoatriostomy with mean-pressure pump
      implantation. A complication occurred 6 months after surgery and ran
      progressively. Closed external drainage of hematomas greatly reduced their
      volumes, but deteriorated the patient's condition due to the development of
      excess drain syndrome. Replacement of the mean-pressure pump by a high-pressure
      one rapidly normalized the patient's status.

PMID- 10420547
TI  - [The pterional approach].

PMID- 10420548
TI  - [The dependence of the results of the surgical treatment of patients with primary
      intracranial tumors on the volume of the surgical activities of a neurosurgical
      department (exemplified by Saint Petersburg)].

PMID- 10420549
TI  - [The use of dissociated learning in the study of the mechanisms of memory].
AB  - The review is dedicated to description of the phenomenon of dissociated learning.
      The distinct criteria which discriminate this phenomenon from those similar in
      appearance are presented. The experimental procedure is described: habituation of
      an animal, a device for dissociated learning, and the mode of determination of
      the necessary dose of a drug and injection time. Different versions of
      dissociated learning which can be gained using the same device, as well as
      methodical recommendations for researchers in the field of studying this
      phenomenon. Analysis of the author's data shows that the use of dissociated
      learning can be promising for studying mechanisms of learning and memory.

PMID- 10420550
TI  - [The typological characteristics of higher nervous activity in dogs and the
      maxima of the cross-correlation function between the electrical activities of the
      frontal cortex and the brain limbic systems].
AB  - Electrical activity of the frontal cortex, dorsal hippocampus, basolateral
      amygdala and lateral hypothalamus was recorded in eight dogs with chronically
      implanted electrodes. Mean values of the maxima of crosscorrelation function
      (MCCF) between electrical potentials in the theta, alpha and beta-2 ranges were
      used as a basis for assessment of conditions for interaction between these
      structures. Typological features of the higher nervous activity were assessed by
      the animal performance under conditions of free choice of the reinforcement mode
      of a conditioned stimulus: either high probable but of low alimentary quality or
      with low probability but more valuable. The mean MCCF values in the theta range
      were higher than in the other ranges. The brain structure which had the high MCCF
      in the theta-range, at least, with two of the structures under study was
      considered as "dominant". It was shown that hippocampus was the dominant
      structure for melancholic dogs, the frontal cortex was in phlegmatics. The
      hypothalamus was shown to be the "dominant structure" in both sanguine and
      choleric animals, but, for the most part, its activity was correlated with
      different structures. Thus, conditions for interaction between the frontal
      cortex, hippocampus, amygdala and hypothalamus seem to be an important factor,
      which determines typological features of the higher nervous activity of dogs.

PMID- 10420551
TI  - [The neuronal reactions of the cat motor cortex to electrical stimulation of the
      ventral tegmental area as a conditioned signal for the reflex of placing the
      forelimb on a support].
AB  - Electrical stimulation (50-100 pulses, 100-500 Hz) of the ventral tegmental area
      (VTA) in the vicinity of the n. interpeduncularis in the frontal plane AP2-AP4,
      L1-L2 caused a cat to grab food placed near its mouth. The conditioned forepaw
      placing reaction was elaborated using food reinforcement and VTA stimulation as a
      conditioned stimulus. The conditioned reflex, being once established, was
      repeatedly performed without extinction in the course of up to 250 trials without
      food reinforcement. Short (5-10 pulses) conditioned VTA stimulation evoked a
      prolonged (up to 1000 ms or longer) activation of neurons of the motor cortex and
      caused a substitution of the inhibitory phase of response to stimulation of the
      parietal cortex in poststimulus interval in 50-200 ms for the late secondary
      excitatory response.

PMID- 10420552
TI  - [Sexual and interhemispheric differences in the involvement of serotonin from the
      hippocampus and amygdaloid body in the processing of new and repeatedly presented
      information in rats].
AB  - Effects of novel or relevant (a single exposure to experimental chamber) and
      irrelevant (20 exposures to experimental chamber) stimuli on the levels of
      serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the
      left and right hippocamp and amygdala were studied in male and female rats. It
      was found that hemispheric specificity of 5-HT metabolism in hippocampus and
      amygdala depended on sex and novelty of information. In male rats, the
      hippocampal level of 5-HT in response to the novel stimulus increased in the left
      hemisphere, and the 5-HIAA hippocampal level increased bilaterally in response to
      irrelevant stimulus. In females, an increase in 5-HT and/or 5-HIAA levels was
      observed only in the left hippocampus in response both to relevant and irrelevant
      stimuli. In the amygdala, a hemispheric asymmetry of the 5-HT involvement, due to
      right-hemispheric changes in 5-HT metabolism, was observed only in male rats. In
      females, an increase in 5-HT level was found in the left and right amygdalas in
      response to irrelevant stimulus. These data suggest that serotonergic
      neurotransmitter mechanisms are an important factor which determines hemispheric
      and sex differences in selective attention.

PMID- 10420553
TI  - [The adaptive classification of the dynamic spectral patterns in the human EEG].
AB  - The classification technique of single spectra based on a matrix of
      intercorrelation between these spectra and the fixed set of standard spectral
      patterns (SP) has been put forward. Including in the classification technique a
      special procedure for automatic adaptation of the standard SP to given EEG
      records makes it possible to reduce the number of unclassified single spectra to
      a minimum (6-10%), which we can ignore during comparative analysis of the EEG
      classification profiles. Using the universal set of standard SP makes it possible
      to compare the results of classification of different EEG records. The results of
      the analysis of classification profiles of human multichannel EEG during
      performance of the memory task on perception of visual images are described in
      the paper. It has been shown that both the total EEG reorganization associated
      with the alpha rhythm blockade during eyes opening and less noticeable EEG shifts
      accompanying changes in the stages of cognitive activity are underlain by a
      rather differentiated transformations of relative contributions of each type of
      the SP into the total power spectrum. It has been revealed that a relatively
      small part (15-20%) of the elementary EEG segments participates in the
      reorganization of the EEG classification profile.

PMID- 10420554
TI  - [The EEG correlates of the erroneous identification of noise-masked visual
      stimuli].
AB  - Specific features of EEG coherence of a man-operator were revealed before the
      erroneous actions ("false alarm" and "signal omission") in the process of
      training to recognize masked visual stimuli. In persons with expressed alpha
      rhythm at rest the "false alarms" were associated with the highest level of beta
      frequency correlation in the frontal areas. Errors of the "signal omission" type
      were observed against the background of increased alpha-coherence in the frontal
      and occipital derivations. These features were more pronounced in the right brain
      hemisphere. The results suggest that the erroneous actions are predetermined by a
      specific state of the frontal brain regions, which participate in decision
      making, and are probably related with inadequate information transmission from
      the caudal regions to the frontal ones.

PMID- 10420555
TI  - [The learning characteristics of rats under free-choice conditions].
AB  - The ability to organize a four-link operant food-procuring habit in a multiple
      alternative maze using the free-choice method was studied in albino rats. Three
      types of animals were observed which were different in the character of learning.
      The learning curve of 20% of rats had of exponential character (type I). Some
      animals (37%) acquired the skill through "insight" and the process of learning in
      these cases could be described by a logistic regression function (type II). The
      remaining rats (43%) refused from solving the intricate task and were able to
      acquire only the simplest form of a response, i.e., running to feeders. It is
      suggested that learning differences between the I and II types of animals may be
      associated with different strategies of problem solving: "procedural"
      (algorithmic) and "conceptual" (semantic).

PMID- 10420556
TI  - [The analytical characteristics of the dynamics of interneuronal functional
      connections during conditioned-reflex activity].
AB  - The dynamics of functional relations between neurons was studied in the frontal
      cortex of dogs performing reversal conditioning task. To reveal the functionally
      relevant relationships between the temporal patterns of correlated firing and
      behavioral events, we developed an original processing technique. The technique
      included the following procedures: a) isolation of the "coupled spikes" (CS) from
      simultaneously recorded impulse trains: b) search for the temporal patterns of
      correlated firings and their classification by clustering single trials with
      similar temporal distribution of CS; c) assessment of behavioral significance of
      the identified patterns by evaluation of the probabilities of coincidence of
      behavioral events and different CS patterns. Significant correlations between
      impulse trains were revealed in 38 neuronal pairs of 456 analyzed. The effects of
      change in behavioral context on the CS dynamics during the task performance were
      found in 87% of neuronal pairs with correlated activity. In 17 pairs the
      behavioral conditions were identified, under which potentially connected neurons
      fired independently during all the periods of the behavioral task. The
      potentialities of the advanced processing technique are discussed. We suggest
      that this analysis can provide useful information about the temporal distribution
      of correlated firings under conditions of nonstereotyped behavior, when an animal
      reacts in the dynamically organized experimental context.

PMID- 10420557
TI  - [The modulation of the pulse activity of neocortical neurons during a conditioned
      reflex].
AB  - Spontaneous and evoked activity of neurons in the sensorimotor cortex was
      recorded in cats with learned conditioned placing reaction before, during, and
      after the iontophoretic application of synaptically active substances. It was
      shown that apart from direct excitatory effect on the cortical neurons during its
      application, glutamate (Glu) exerted some modulatory influence on unit activity
      in subsequent 20 min. Noradrenaline suppressed the background and evoked activity
      through beta 1 adrenoreceptors. Activation of beta 2 adrenoreceptors by
      metaproterenol was accompanied by facilitation of the background and evoked
      activity during application and 10-20 min after. The joint application of Glu and
      metaproterenol improved facilitation of neuronal responses evoked by conditioned
      stimuli. Application of levodopa, like Glu, increased the background and evoked
      activity of many sensorimotor cortical neurons. The joint effect of Glu and
      levodopa was not substantially more intensive than the changes produced by the
      isolated application of any of these substances. A nonselective blocker of DA1
      and DA2 receptors haloperidol either increased or did not change the background
      and evoked activity of some cortical neurons. In contrast to isolated application
      of Glu, simultaneous application of Glu and haloperidol to neocortex suppressed
      the neuronal responses associated with conditioned movements. The results suggest
      that the Glu-induced potentiation is substantially realized through molecular
      mechanisms common for Glu and dopamine, probably, through Gi-proteins. The
      conclusion is drawn that the adrenergic and dopaminergic inputs to neocortical
      neurons are involved in the Glu-mediated plastic changes in the cortex during
      conditioning.

PMID- 10420558
TI  - [The behavioral changes and the EEG of the rat brain induced by hyperactivation
      of the amygdaloid body under noradrenergic deficiency].
AB  - The brain NA deficit was produced by bilateral injection of 6-OHDA into the locus
      coeruleus. Three weeks later amygdala hyperactivation was initiated by local
      penicillin injection (1% solution, 0.5 mcl). Saline in the same volume was used
      in control groups in both cases. It was shown that the decrease in NA level
      facilitated the development of epileptiform activity in rat brain and appearance
      of immobility-related high-voltage spindles during waking. The amygdala
      hyperactivation after NA deprivation resulted in a decrease in exploratory
      activity and disruption of the reaction to novelty. The delta component of the
      EEG power spectrum increased. The alterations appeared 1-2 weeks after the
      experimental procedure and became more pronounced towards the end of the third
      week.

PMID- 10420559
TI  - [The characteristics of motor asymmetry in rats with genetic epilepsy (the
      WAG/Rij strain)].
AB  - Motor asymmetry was studied in two groups of WAG/Rij rats with genetic absence
      epilepsy. A rat had to get food from the horizontal tube with preferable
      forelimb. The asymmetry coefficient Cas was calculated for the first 10, 50, and
      100 trials. In the first group ("pure" absence epilepsy, n = 34) the percent of
      "left-handers", "right-handers", and ambidextrous calculated for the first 10
      trials, was 56, 26, and 18, respectively. In the second group (mixed form of
      epilepsy, n = 27) this ratio was 19, 40, and 41%, respectively. The percent of
      ambidextrous, calculated for 50 and 100 trials, substantially decreased in both
      groups, and the above mentioned ratio became 62, 32, and 6% in the first group
      and 30, 63, and 7% in the second one. A possible association of pathogenesis of
      different forms of epilepsy with forelimb preference is discussed.

PMID- 10420560
TI  - [The behavioral effects of a single adverse exposure in a number of rat
      generations: the role of maternal glucocorticoids].
AB  - The ionizing irradiation of rat fetuses during the last third of intrauterine
      development increased blood corticosterone level adulthood and decreased the open
      field locomotion of their adult offsprings of the next first nonirradiated
      generation. Treatment of the pregnant rats with glucocorticoids also decreased
      the offspring locomotion. Irradiation of fetuses in the middle of embryogenesis
      decreased blood corticosterone level in adulthood and shortened the open-field
      freezing reaction of their adult offsprings of the next first nonirradiated
      generation. Adrenalectomy of females before mating decreasing the blood
      corticosterone level had a similar effect on freezing duration of their adult
      offsprings. Irradiation of the ancestors within the last third of their
      intrauterine development had no effect on blood corticosterone level of their
      adult offsprings of the first generation and produced no behavioral alterations
      in their descendants of the next second nonirradiated generation. Irradiation of
      the ancestors in the middle of their embryogenesis decreased the stress-induced
      corticosterone response in their adult offsprings of the first generation and
      increased rearings and locomotion in their descendants of the next second
      nonirradiated generation. The data suggest that a single noxious treatment may
      have behavioral effects throughout two consequent generations of rats. Mother's
      glucocorticoid hormones may be one of the factors which transmit the effect.

PMID- 10420561
TI  - [The morphogenesis of Wulst neurons in the pied flycatcher under conditions of
      limited afferent inflow].
AB  - Golgi preparations of the pied flycatcher Wulst region (the structure analogous
      to the mammalian visual cortex) were analyzed using the method of computerized
      morphometry, to study the influence of visual deprivation on the development of
      different types of neurons selected previously. Deprivation was accomplished by
      covering the young's eye with nontransparent caps. The experiments were carried
      out in 10-day-old nestlings (the onset of patterned vision) and 13-day-old
      nestlings (functioning patterned vision). In 10-day-old nestlings, the
      deprivation produced constructive changes in dendritic apparatus of projective
      stellate cells (among them, the most pronounced was more than three-fold increase
      in the number of foci of maximal branching) practically not affecting the small
      stellate-like cells. In 13-day-old nestlings, cells belonging to all selected
      cell types underwent destructive changes: their quantitative characteristics were
      decreased as compared to those in control nestlings. A large number of tree-like
      neurons were revealed in the Wulst in the deprived 10-day-old nestlings while in
      the control age-matched nestlings they were virtually never found. This
      phenomenon may be explained by the increased affinity to impregnation evoked by
      deprivation-induced biochemical changes in the tree-like neurons or to increase
      in their number. In the latter case, the phenomenon may be considered as
      compensatory, directed at the establishing of contacts with nonvisual afferents.

PMID- 10420562
TI  - [The effect of the limitation of afferent inflow in early ontogeny on the evoked
      activity of projective neurons depends on the degree of the maturity of the
      sensory inputs].
AB  - The study is focused on the influence of a partial limitation of the sensory
      inflow in rat pups on the development of the sensory systems, which mature
      earlier and later. In accordance with the ontogenetic rule of proximal-distal
      maturation, the sensory inflow from the forelimbs matures faster than that from
      the hindlimbs. Fourteen Wistar rat pups (from 28) were deafferented on the 13th
      day of postnatal ontogeny (a small portion of the median nerve was unilaterally
      dissected). The background and evoked activity of single neurons was recorded in
      26-47-day-old pups in the somatosensory cortex (in the projection areas of the
      intact n. medianus, which matures earlier, and n. ischiadicus, which matures
      later). The changes in firing activity produced by deafferentation were observed.
      In the projection area of the intact forelimb of the denervated rats, the
      incidence of inhibitory responses significantly increased, whereas the incidence
      of completes responses significantly decreased. In the hindlimb projection area
      of the denervated animals the background firing rate was significantly lower and
      the incidence of activation responses was increased.

PMID- 10420563
TI  - [The nature of the relationships between the dynamics of local interneuronal
      connections and of the total bioelectrical activity of the frontal cortex in the
      dog].
AB  - Temporal patterns of correlated firings were studied in small groups of neurons
      simultaneously recorded in the frontal cortex of a behaving dog. To identify the
      character of relations between the patterns of interneuronal connections in local
      ensembles and event-related potentials (ERP), the following procedure was
      applied. At the first step, single trials of behavioral task were classified by
      clustering temporal distribution of correlated firings in pairs of units. Then
      the surface ERP were averaged separately for each cluster and parameters of the
      ERP components were compared between the clusters. The analysis revealed 3 of 7
      recording sites, where significant differences were observed between the ERP
      sampled from the clusters with different structures of the local interneuronal
      connections. The results suggest that temporal modulation of interactions between
      neurons in local ensembles reflects a large-scale reorganization of cortical
      networks.

PMID- 10420564
TI  - [The acceleration of the acquisition of a conditioned reflex to time in rats with
      destruction of the suprachiasmatic nuclei of the hypothalamus].
AB  - In male rats sound conditioned reflex with water reinforcement was gradually
      (within 14-16 daily training sessions) was replaced by a conditioned reflex to
      time. After the bilateral lesions of the suprachiasmatic nuclei of hypothalamus,
      the necessary level of timing performance was reached sooner than in the animals
      with a partial destruction of the nuclei.

PMID- 10420566
TI  - Intrinsic membrane properties and dynamics of medial vestibular neurons: a
      simulation.
AB  - The vestibulo-ocular and vestibulo-spinal network provides the ability to hold
      gaze fixed on an object during passive head movement. Within that network, most
      of the second-order neurons of the medial vestibular nucleus (MVNn) compute
      internal representations of head movement velocity in the horizontal plane. Our
      previous in vitro studies of the MVNn membrane properties indicated that they may
      play a major role in determining the dynamic properties of these neurons
      independently of their connectivity. The present study investigated that
      hypothesis at a theoretical level. Biophysical models of type A and B MVNn were
      developed. Two factors were found to be important in modeling tonic and phasic
      firing activity: the activation of the delayed potassium current and the rate of
      calcium flux. In addition, the model showed that the strength of the delayed
      potassium current may determine the different forms of action potentials observed
      experimentally. These two models (type A and B cells) were examined using
      depolarizing stimulation, random noise, step, ramp and sinusoidal inputs. For
      random noise, type A cells showed stable (regular) firing frequencies, while type
      B cells exhibited irregular activity. With step stimulation, the models exhibited
      tonic and phasic firing responses, respectively. Using ramp stimulations,
      frequency versus current curves showed a linear response for the type B neuron
      model. Finally, with sinusoidal stimulation of increasing frequencies, the type A
      model demonstrated a decrease in sensitivity, while the type B model exhibited an
      increase in sensitivity. These theoretical results support the hypothesis that
      MVNn intrinsic membrane properties specify various types of dynamic properties
      amongst these cells and therefore contribute to the wide range of dynamic
      responses which characterize the vestibulo-ocular and vestibulo-spinal network.

PMID- 10420565
TI  - [A decreased frequency of peeking out from the dark compartment--the only
      constant index of the effect of anxiogens on the behavior of mice in a "light
      darkness" chamber].
AB  - Special measurements of the effects of anxiolytics and anxiogens on the commonly
      used parameters of behavior of mice in a dark-light chamber (the rate of
      transitions and time spent in a dark and light compartments) demonstrated their
      low reproducibility in consecutive experiments. Therefore, these indices are not
      reliable (Lapin, 1992). One more parameter was tested in the present study. A
      decrease in the rate of leanings out of the dark compartment appeared to be a
      constant effect of standard anxiety-inducing drugs: caffeine, pentylenetetrazole,
      yohimbine, and a putative endogenous anxiogen phenylethylamine. Increase in the
      rate of leanings out, like increase in the rate of transitions and shortening of
      the time spent in a dark compartment produced by anxiolytics diazepam,
      chlordiazepoxide, hydroxyzine, phenibut and baclofen were not significant in the
      majority of experiments. That is why these effects of anxiolytics are not
      reliable for measuring the activity of anxiolytics in a dark-light chamber.

PMID- 10420567
TI  - A model of induced coupled movements in the human body: a case study.
AB  - We present a case study of involuntary motion in one part of the body induced by
      a voluntary motion in another part. The case investigated was that of a steady
      state motion of the fingers at various frequencies, which induced a similar kind
      of motion in the legs. These phenomena were observed in a subject practicing
      sphincter gymnastics, a physical therapy method in which repetitive motion of
      different muscles is exercised, and is known to induce motions in other muscles
      of the body. We show that a linear model, for which we give an experimental
      transfer function and demonstrate its validity, can describe the generation of
      the induced periodic motions by the voluntary motions. We compare the results of
      the transfer function with those of Von Holst's statistical analysis.

PMID- 10420568
TI  - Directional coding of three-dimensional movements by the vestibular semicircular
      canals.
AB  - A morphologically descriptive mathematical model was developed to study the role
      of labyrinthine geometry in determining sensitivities of each semicircular canal
      to angular motion stimuli in three-dimensional (3D) space. For this, equations
      describing viscous flow of the endolymph and poro-elastic response of the cupulae
      were coupled together and solved within a 3D reconstructed geometry. Results
      predict the existence of prime rotational directions about which the labyrinth
      resolves 3D angular movements into separate vectorial components. The components
      are predicted to be transmitted to the brain separately, one coded by each canal
      nerve. Prime directions predicted by the model are non-orthogonal, distinct from
      the anatomical canal planes, and distinct from the directions of rotation which
      elicit maximal responses of individual canal nerves. They occur for each canal
      along the intersection of the two null planes defined by its sister canals.
      Hence, rotation about a prime direction excites only one canal nerve. This
      contrasts the situation for rotations about anatomical canal planes, or about
      maximal response directions, where the model predicts activation of multiple
      canal nerves. The prime directions are sensitive to labyrinthine morphology and,
      hence, are predicted to vary between species and, to a lesser extent, vary
      between individual animals. Prime directions were estimated in the present work
      using a mathematical model, but could be determined experimentally based on the
      directional sensitivities of individual canal nerves. The model also predicts the
      existence of dominant eigenmodes and time constants associated with rotation in
      each of the prime directions. Results may have implications regarding the central
      representation of angular head movements in space as well as the neuronal
      mappings between three-canal afferent inputs and motor outputs.

PMID- 10420569
TI  - Translation-invariant pattern recognition based on Synfire chains.
AB  - Most of current neural network architectures are not suited to recognize a
      pattern at various displaced positions. This lack seems due to the prevailing
      neuron model which reduces a neuron's information transmission to its firing
      rate. With this information code, a neuronal assembly cannot distinguish between
      different combinations of its entities and therefore fails to represent the fine
      structure within a pattern. In our approach, the main idea of the correlation
      theory is accepted that spatial relationships in a pattern should be coded by
      temporal relations in the timing of action potentials. However, we do not assume
      that synchronized spikes are a sign for strong synapses between the neurons
      concerned. Instead, the synchronization of Synfire chains can be exploited to
      produce the relevant timing relationships between the neuronal signals.
      Therefore, we do not require fast synaptic plasticity to account for the precise
      timing of action potentials. In order to illustrate this claim, we propose a
      model for translation-invariant pattern recognition which does not depend on any
      changes in synaptic efficacies.

PMID- 10420570
TI  - Three-dimensional kinematic analysis of influence of hand orientation and joint
      limits on the control of arm postures and movements.
AB  - The problems related to kinematic redundancy in both task and joint space were
      investigated for arm prehension movements in this paper. After a detailed
      analysis of kinematic redundancy of the arm, it is shown that the redundancy
      problem is ill posed only for the control of hand orientation. An experiment was
      then designed to investigate the influence of hand orientation on the control of
      arm movements. Since movements must be made within the limits of the joints, the
      influence of these limits was also analyzed quantitatively. The results of the
      experiment confirm that the increase of movement time because of the change of
      object orientation is due to the lengthening of the deceleration phase
      disproportionately to the rest of the movement. The variation of hand path due to
      the change of object orientation was observed as being surprisingly small for
      some subjects as opposed to the large range of object orientation, implying that
      hand path and hand orientation could be controlled separately, thus simplifying
      the computational problem of inverse kinematics. Moreover, the observations from
      the present experiment strongly suggest that a functional segmentation of the
      proximal and distal joints exists and that the control of wrist motion is
      dissociated from the rest of joint motions. The contribution of each joint in the
      control of arm movements could be determined through the principle of minimum
      energy and minimum discomfort under the constraints of the joint limits. A
      simplified inverse kinematics model was tested. It shows that these hypotheses
      can be easily implemented in a geometric algorithm and be used to predict arm
      prehension postures reasonably well under the constraints of joint limits.

PMID- 10420571
TI  - Evaluation of genotoxic and immunotoxic activities of potential glucose biosensor
      components: ferrocenes.
AB  - Three ferrocenes used in glucose biosensor construction were tested in the aspect
      of genotoxic and immunotoxic activities. All three ferrocenes were not mutagenic
      in the standard bacterial Ames test. Equally in the Sister Chromatid Exchanges
      test in human lymphocyte cultures, the genotoxic action of tested ferrocenes
      could be excluded. However, all three significantly decreased the rate of
      lymphocyte proliferation and especially diminished the numbers of B-lymphocytes
      and NK-cells after 72 hours of in vitro culture. Marked differences between the
      ferrocenes in their immunotoxic activities were noticed, and we were able to
      select those which would be relatively safe and those which should be avoided in
      further investigation of the glucose biosensor construction. Our results indicate
      the necessity to estimate immunotoxic effects as well as genotoxic effects,
      especially in biosensor components potentially used in vivo.

PMID- 10420572
TI  - Redox and specific effects of vanadium ions on respiratory enzymes.
AB  - The effects of vanadium ions on the activities of enzymes of aerobic and
      anaerobic respiratory chains were investigated in vitro and in situ employing 1H
      , 14N-, 31P- and 51V- nuclear magnetic resonance spectroscopy, electron
      paramagnetic resonance spectroscopy and spectrophotometry. Vanadate and vanadyl
      ions produced either non-specific redox or specific activation or inhibition of
      respiratory enzymes. The oxidants molybdate and chromate and the reductant
      dithiothreitol were used to distinguish between non-specific and specific effects
      of vanadium ions on enzyme activities. The results suggested that components of
      anaerobic respiratory chains were more susceptible to vanadium ions than those of
      the aerobic respiratory chain.

PMID- 10420573
TI  - Influence of metal ions and temperature on the conformation of Escherichia coli
      K1 capsular polysaccharide.
AB  - Escherichia coli K1 secretes a homopolymer capsular polysaccharide (CPS)
      consisting of alpha 2, 8 linked N-acetylneuraminic acid (poly alpha 2,8NeuNAc).
      Typically poly alpha 2,8NeuNAc is arranged in low and high order alpha helices
      with carboxyl and hydroxyl groups extending from the helices. Several properties
      of CPS such as antigenicity and metal binding can be influenced by its structural
      conformation. We examined the influences of metal ions and temperature on the
      secondary structure of poly alpha 2,8NeuNAc. Conformation alteration was detected
      by ultraviolet (UV) spectroscopy and circular dichroism (CD). The majority of
      metal ions tested had no detectable influence on poly alpha 2,8NeuNAc structure.
      In contrast, Yb3+, Hg2+, and Cu2+ ions greatly altered the UV and CD spectra,
      which suggests that these ions had disrupted the alpha helical structure of poly
      alpha 2,8NeuNAc. These changes were influenced by the metal ion concentration.
      When poly alpha 2,8NeuNAc was incubated at temperatures ranging from 20-60
      degrees C, alterations in its UV absorption spectra were also seen. The most
      significant change occurred between 35 and 40 degrees C. In summary, this study
      suggests that the higher order structure and function of bacterial CPS may be
      influenced by environmental factors.

PMID- 10420575
TI  - Physico-chemical characterization of meglumine antimoniate.
AB  - The leishmanicidal drug, meglumine antimoniate (MA), has been synthesized by the
      reaction of antimony oxyhydrated and N-methyl glucamine. Infrared and solid state
      NMR 13C analysis of MA and the ligand strongly suggests that antimony binds to N
      methyl glucamine through the oxygen of C-3 carbon. Potentiometric titration
      indicated that, between pH 4.5 and 7.5, MA exists in the zwitterionic form.

PMID- 10420574
TI  - The ferric-reducing activity of duodenal brush-border membrane vesicles is
      associated with a b-type haem.
AB  - Rabbit brush-border membrane vesicles possess ferricyanide reducing activity.
      This activity is preferentially dependent on NADH as reductant, and can be
      stimulated by the addition of FMN. The latency of activity observed following
      vesicle solubilisation suggests that the responsible component is
      transmembranous, and partially sequestered on the inner-face of the vesicles
      prior to full solubilisation. Subsequent increases in detergent concentration (>
      0.3% w/v lauryl maltoside) were found to be inhibitory. Ferricyanide reducing
      activity was effectively inhibited by the sulphydryl modifying reagents N-ethyl
      malemide and p-chloromercuribenzoate, but not by the flavin analogue diphenylene
      iodonium. The ferric-reducing activity co-purified with a b-type haem when
      applied to Sephacryl S-200 columns. The putative cytochrome was found to be
      immunologically distinct from neutrophil cytochrome b558.

PMID- 10420576
TI  - Magnetic analysis of human brain tissue.
AB  - Fourteen samples of human hippocampal tissue were resected during amygdalo
      hippocampectomies performed on patients suffering from Mesial Temporal Lobe
      Epilepsy (MTLE). In addition, eight tissue samples from the hippocampus, cortex
      basalganglia, cerebellum and leptomeninges were resected from cadavers during
      routine autopsy and were not chemically fixed. All samples were preserved in
      liquid nitrogen and magnetic properties were measured at 77K and 273K.
      Measurements indicate that there are no systematic variations in magnetic
      particle concentrations or magnetic properties between MTLE patients and non
      pathologic tissue from the cadavers. The presence of superparamagnetic particles
      can be inferred due to differences in the saturation remanence acquired at 77K
      and 273K. This is a further indication that biogenic magnetite and/or maghemite
      present in the human brain likely is not primarily associated with geomagnetic
      field sensing as it is known to occur in other organisms.

PMID- 10420577
TI  - Magnetic iron biomineralization in rat brains: effects of iron loading.
AB  - Isothermal remanent magnetization was measured in 14 Wistar and five Porton rat
      brains. Results indicate that magnetic iron biominerals are present in most of
      the samples and the formation of these minerals in the rat brain is influenced by
      transfusion and dietary iron loading when compared to control samples. The high
      level of consistency in the concentrations and the lack of magnetic material in
      several of the measured samples indicates that a genetic mechanism may be
      responsible for magnetic iron biomineralization in the rat brain. Comparison with
      human studies indicates that extrapolation of the results of rat studies of
      electromagnetic field bioeffects may not be accurately extrapolated to humans in
      all cases.

PMID- 10420578
TI  - Purification of catechol siderophores by boronate affinity chromatography:
      identification of chrysobactin from Erwinia carotovora subsp. carotovora.
AB  - Catechols are co-planar cis-diols known to form stable, isolable complexes with
      borate under weakly basic conditions. We exploited this chemistry and developed a
      boronate affinity chromatography for isolating catechol siderophores. The method
      was applied to the isolation of chrysobactin, enterobactin, and an unknown
      catechol siderophore produce by Erwinia carotovora subsp. carotovora W3C105.
      Yields of chrysobactin and enterobactin purified by boronate affinity
      chromatography were at least two-fold greater than those achieved through
      alternate methods. The unknown catechol produced by E. carotovora subsp.
      carotovora W3C105 was isolated by boronate affinity chromatography and shown to
      be identical to chrysobactin. Boronate affinity chromatography enabled separation
      of catechol from its rust-colored decomposition products, and simultaneous
      isolation of catechol and hydroxamate siderophores. Boronate affinity
      chromatography is a rapid and efficient method for purifying catechol
      siderophores from bacterial culture supernatants.

PMID- 10420579
TI  - Parenteral immunization with a glycoconjugate vaccine containing the O157 antigen
      of Escherichia coli O157:H7 elicits a systemic humoral immune response in mice,
      but fails to prevent colonization by the pathogen.
AB  - The results of the present study show that whereas both BALB/c and C57BL/6 mice
      parenterally inoculated with a horse serum albumin-Escherichia coli O157 antigen
      conjugate vaccine develop systemic, specific antibodies to the carrier protein,
      only the former mice routinely develop antibodies to the carbohydrate O157
      moiety. However, little convincing evidence was found to show that these
      antibodies transuded into the intestinal tract either naturally or in response to
      an oral inoculum of the pathogen. Moreover, this vaccination procedure failed to
      protect mice against intestinal colonization following oral challenge with the
      pathogen. Thus, the results of this study suggest that parenteral vaccination
      might be an unsuitable strategy for combatting E. coli O157:H7 organisms located
      in the gut.

PMID- 10420580
TI  - Diversification of Pseudomonas corrugata 2140 produces new phenotypes altered in
      GC-FAME, BIOLOG, and in vitro inhibition profiles and taxonomic identification.
AB  - Bacteria are known to rapidly produce new phenotypes, but it is unclear how
      phenotype "plasticity" relates to studies on the population ecology of bacteria
      in complex environments. We characterised a collection of 14 spontaneous
      phenotype variants, derived from in vitro and in vivo cultures (wheat roots) of
      Pseudomonas corrugata 2140, using fatty acid methyl ester profiles (GC-FAME),
      carbon substrate utilisation (BIOLOG), and in vitro inhibition against seven soil
      microorganisms. All three phenotype profiles indicated marked differences between
      some variants and the parent isolate. Some variant types were classified
      taxonomically by GC-FAME as different species to their wild-type parent, and up
      to a Euclidian distance of 11 from their parent. Taxonomic identification by the
      BIOLOG assay was more consistent; however, use of 22 carbon sources were altered
      (lost or gained) in one or more variants. All variant types had a reduced ability
      to inhibit one or more test organisms, depending on the variant and test
      organism. Hierarchical cluster analysis of variants using GC-FAME, BIOLOG, and
      inhibition profiles produced different groupings. The ability of variants to
      cross taxonomic boundaries specified by the GC-FAME and BIOLOG libraries at the
      species level has implications for both taxonomy and the ecological study of
      bacterial communities.

PMID- 10420581
TI  - Construction of a genomic map of Moraxella (Branhamella) catarrhalis ATCC 25238
      and physical mapping of virulence-associated genes.
AB  - A physical genome map of the Moraxella catarrhalis type strain (ATCC 25238) has
      been constructed using pulsed field gel electrophoresis. Macrorestriction
      analyses of the genome of M. catarrhalis were performed by digestion with the
      restriction enzymes SmaI, NotI, and RsrII, which cleave the single circular
      chromosome into 9, 10, and 6 fragments, respectively. The chromosomal fragments
      generated by pulsed field gel electrophoresis were converted to a linkage map
      utilizing a combination of partial digestions, and cross-hybridizations.
      Moraxella catarrhalis, like a number of other respiratory pathogens, has a
      relatively small genome estimated at 1750 kilobase pairs or about 40% of the size
      of the Escherichia coli genome. The locations of the four ribosomal RNA operons
      (rrnLS) were determined by Southern hybridization and by digestion with I-CeuI
      endonuclease. A number of genes involved in virulence have been placed onto the
      physical map by Southern hybridization including those encoding the predominant
      outer-membrane proteins and the chromosomal gene encoding beta-lactamase.

PMID- 10420582
TI  - The inorganic ion content of native aquatic bacteria.
AB  - In this study we have quantified the ionic content and volume of native aquatic,
      and two cultured bacteria, by X-ray microanalysis (XRMA) in the transmission
      electron microscope (TEM). The cellular concentrations of magnesium (means of 630
      and 710 mM) were more than an order of a magnitude higher than the outside
      concentrations. The internal concentrations of sodium were on average 50-180 mM,
      and the [K+]/[Na+] ratios were in the range of 0.1-0.5; lowest for apparently
      nonactive bacteria. Magnesium and chloride probably act as the major components
      of cell turgor, since no other inorganic ions were present in comparable amounts.
      Our carbon and nitrogen measurements indicated that organic solutes are not
      likely to be present at significant concentrations. The estimated charge of
      inorganic ions (Na, Mg, P, Cl, K, and Ca) gave a positive net internal charge for
      most cells. However, in cultures of Vibrio natriegens, the high internal chloride
      concentration made the net inorganic charge negative in these cells. Our results
      suggest that growing marine bacterioplankton have an internal environment in
      which magnesium is the dominating cation. These results suggest that actively
      growing marine bacteria are physiologically adapted to high internal
      concentrations of both magnesium and chloride.

PMID- 10420583
TI  - Identification of genes unique to Mo-independent nitrogenase systems in diverse
      diazotrophs.
AB  - A number of nitrogen-fixing bacteria were screened using PCR for genes (vnfG and
      anfG) unique to the V-containing nitrogenase (vnf) and the Fe-only nitrogenase
      (anf) systems. Products with sequences similar to that of vnfG were obtained from
      Azotobacter paspali and Azotobacter salinestris genomic DNAs, and products with
      sequences similar to that of anfG were obtained from Azomonas macrocytogenes,
      Rhodospirillum rubrum, and Azotobacter paspali DNAs. Phylogenetic analysis of the
      deduced amino acid sequences of anfG and vnfG genes shows that each gene product
      forms a distinct cluster. Furthermore, amplification of an internal 839-bp region
      in anfD and vnfD yielded a product similar to anfD from Heliobacterium gestii and
      a product similar to vnfD from Azotobacter paspali and Azotobacter salinestris.
      Phylogenetic analysis of NifD, VnfD, and AnfD amino acid sequences indicates that
      AnfD and VnfD sequences are more closely related to each other than either is to
      NifD. The results of this study suggest that Azotobacter salinestris possesses
      the potential to express the vanadium (V)-containing nitrogenase (nitrogenase 2)
      and that R. rubrum, Azomonas macrocytogenes, and H. gestii possess the potential
      to express the Fe-only nitrogenase (nitrogenase 3). Like Azotobacter vinelandii,
      Azotobacter paspali appears to have the potential to express both the V
      containing nitrogenase and the Fe-only nitrogenase.

PMID- 10420585
TI  - Sequence analysis of the Gluconobacter oxydans RecA protein and construction of a
      recA-deficient mutant.
AB  - The deduced amino acid sequence of Gluconobacter oxydans RecA protein shows 75.2,
      69.4, and 66.2% homology with those from Aquaspirillum magnetotacticum,
      Escherichia coli, and Pseudomonas aeruginosa, respectively. The amino acid
      residues essential for function of the recombinase, protease, and ATPase in E.
      coli recA protein are conserved in G. oxydans. Of 24 amino acid residues believed
      to be the ATP binding domain of E. coli RecA, 17 are found to be identical in G.
      oxydans RecA. Interestingly, nucleotide sequence alignment between the SOS box of
      G. orphans recA gene and those from different microorganisms revealed that all
      the DNA sequences examined have dyad symmetry that can form a stem-loop
      structure. A G. oxydans recA-deficient mutant (LCC96) was created by allelic
      exchange using the cloned recA gene that had been insertionally inactivated by a
      kanamycin-resistance cassette. Such replacement of the wild-type recA with a
      kanamycin resistance gene in the chromosome was further verified by Southern
      hybridization. Phenotypically, the recA-deficient mutant is significantly more
      sensitive to UV irradiation than the wild-type strain, suggesting that the recA
      gene of G. oxydans ATCC9324 plays a role in repairing DNA damage caused by UV
      irradiation. Moreover, the mutant strain is much more plasmid transformable than
      its parent strain, illustrating that G. oxydans LCC96 could be used as a host to
      take up the recombinant plasmid for gene manipulation.

PMID- 10420584
TI  - Characterization of the bacterial community of a zinc-polluted soil.
AB  - The bacterial community of a zinc-contaminated soil (Maatheide soil in Lommel,
      Belgium) was studied using cultivation as well as cultivation-independent
      techniques. Colony-forming units (CFU) were determined by plating on media with
      or without metals. Dominant isolates were characterized by fatty acid methyl
      ester analysis (FAME analysis) and PCR fingerprinting using repetitive extragenic
      palindromic sequences as primers. DNA was directly extracted from soil samples
      and used as a template for the PCR amplification of the 16S rDNA (8-1511) or a
      16S rDNA fragment (968-1401). Clones resulting from cloning the 16S rDNA from
      soil DNA were sequenced. Temperature gradient gel electrophoresis (TGGE analysis)
      was performed for 16S rDNA fragments (968-1401) amplified from the dominant
      isolates, the clones, and the total soil DNA extracted according to two protocols
      differing in strength of lysis. Total CFU ranged from 10(4) to 10(5)/g soil. The
      majority of the isolates were identified by FAME analysis as Arthrobacter spp.
      (18 out of 23). None of the isolates were identified as a Ralstonia eutropha like
      strain (formerly Alcaligenes eutrophus). Metalloresistant Rastomia eutropha like
      strains were previously shown to be dominant in the analyzed biotope. Most of the
      isolates were zinc tolerant but only seven could be considered zinc resistant.
      Sequences of the 16S rDNA clones obtained from total soil DNA were affiliated
      with genes of different bacteria such as alpha-proteobacteria, beta
      proteobacteria, and the Cytophaga-Flexibacter-Bacteroides group. None of the
      sequenced clones aligned with the Ralstonia eutropha 16S rRNA gene. TGGE analysis
      of the 16S rDNA fragments (968-1401) amplified from the dominant strains, the
      clones, and the total soil DNA showed that isolates and clones represented only a
      part of the bands present in the TGGE pattern from total DNA. The 968-1401
      fragment amplified from all Arthrobacter strains had a similar electrophoretic
      mobility. This band was seen as a major band in the pattern of DNA extracted from
      soil using a harsh cell lysis, whereas it did not appear, or appeared only as a
      weak band, in patterns obtained from soil DNA extracted using gentle lysis. The
      previously reported predominance of a Ralstonia eutropha like strain in this soil
      was no longer observed. This may suggest a population replacement by less
      resistant bacteria, concomitant with a progressive decrease of the zinc toxicity
      in the Maatheide soil.

PMID- 10420586
TI  - Ganglioside GD1 alpha analogues as high-affinity ligands for myelin-associated
      glycoprotein (MAG).
AB  - The first systematic synthesis of ganglioside GD1 alpha analogues carrying N
      acetyldeoxyneuraminic acids linked to C-6 of the GalNAc residue was accomplished.
      The suitably protected GM1b pentasaccharide derivative was regioselectively
      glycosylated with the phenyl 2-thioglycosides of 7-deoxy, 8-deoxy, and 9-deoxy-N
      acetylneuraminic acid promoted by N-iodosuccinimide (NIS)
      trifluoromethanesulfonic acid (TfOH) in acetonitrile, and the resulting
      hexasaccharides were converted to the target GD1 alpha analogues. All of the
      analogues retained excellent efficiency in supporting the adhesion to myelin
      associated glycoprotein (MAG), raising the possibility that the internal sialic
      acid linked to the GalNAc residue may be replaced by other anionic substituents,
      in contrast to the terminal sialic acid, which is essential for MAG binding.

PMID- 10420587
TI  - Synthesis and antitumor activity of 7-O-[2,6-dideoxy-2-fluoro-5-C
      (trifluoromethyl)-alpha-L-talopyranosyl]- daunomycinone and -adriamycinone.
AB  - 7-O-[2,6-Dideoxy-2-fluoro-5-C-(trifluoromethyl)-alpha-L-talopyranosyl]-
      daunomycinone and -adriamycinone have been prepared by the coupling of 3,4-di-O
      acetyl-2,6-dideoxy-2-fluoro-5-C-(trifluoromethyl)-alpha-L- talopyranosyl iodide
      with daunomycinone. The key steps in this synthesis are the regioselective
      fluorination of methyl alpha-D-lyxopyranoside to give the 4-deoxy-4-fluoro-beta-L
      ribopyranoside and the C-trifluoromethylation of the aldehydo-L-ribose derivative
      to give the 1,1,1-trifluoro-5-monofluoro-L-altritol derivative. Antitumor
      activities of the synthetic products were compared with those for the 2'-deoxy-2'
      fluoro and 2',6'-dideoxy-5'-C-trifluoromethyl analogs.

PMID- 10420588
TI  - Synthetic studies on glycosphingolipids from the parasite Echinococcus
      multilocularis.
AB  - Novel neutral glycosphingolipids isolated from the metacestodes of Echinococcus
      multilocularis by Persat, may be expected to be involved in host-parasite
      interactions. We have synthesized these glycosphingolipid analogues containing 2
      branched fatty alkyl residues in place of ceramide. The glycosylation of
      galactosyl donors 4 and 5 with each of the acceptors 2 and 11 in the presence of
      N-iodosuccinimide (NIS)/TfOH, and the glycosylation of fucosyl donor 13 with
      acceptors 12 and 20 in the presence of dimethyl(methylthio)sulfonium triflate
      (DMTST) gave the desired oligosaccharide derivatives at good yield. The fully per
      O-acylated 2-(trimethylsilyl)ethyl glycosides 6, 15, 21, and 26 were converted to
      glycosylimidates 7, 16, 22, and 27, which were condensed with 2
      (tetradecyl)hexadecanol and subsequently deacylated give four target
      glycosphingolipid analogues.

PMID- 10420589
TI  - Alkylating agents from sugars. Alkyl hexopyranoside derivatives as carrier
      systems for chlorambucil.
AB  - Chlorambucil derivatives involving alkyl 2-aminodeoxy sugars have been
      synthesized in good yield by coupling the chlorambucil moiety to positions C-2 or
      C-3 of the sugar, directly or via a spacer. The starting material was easily
      available from 2-acetamido-2-deoxy-D-glucose. The final compounds were tested for
      cytotoxicity, and some of those that presented the best results were studied for
      inhibition of cell proliferation.

PMID- 10420590
TI  - Synthesis of the 3-methyl ether and 4-deoxy derivatives of 4-cyanophenyl 1,5
      dithio-beta-D-xylopyranoside (Beciparcil).
AB  - Treatment of the 2,3-isopropylidene acetal of the title dithioxyloside with 2,4,5
      triiodoimidazole-PPh3 caused replacement of the 4-hydroxyl group by iodine to
      afford 82% of the 4-axial iodide 6, converted by base into 4-cyanophenyl 2,3-O
      isopropylidene-1,5-dithio-beta-D-glycero-pent-3-enopyranoside++ + (8). Acid
      treatment of 8 gave 87% of the deacetonated glycos-3-ulose, borohydride reduction
      of which afforded 63% of 4-cyanophenyl 4-deoxy-1,5-dithio-alpha-L-threo
      pentopyranoside (3), together with 27% of the 3-axial epimer. The 3-methyl ether
      of the title dithioxyloside was satisfactorily prepared via 2,4-protection as the
      cyclic phenylboronate, methylation, and deprotection; alternative strategy via
      the 2,4-bis(triisopropylsilyl) ether was complicated because of silyl-group
      migration under methylation conditions.

PMID- 10420591
TI  - Synthesis of lacto-N-neotetraose and lacto-N-tetraose using the dimethylmaleoyl
      group as amino protective group.
AB  - The disaccharide donor O-[2,3,4,6-tetra-O-acetyl-beta-D- galactopyranosyl)-(1-
      >4)-3,6-di-O-benzyl-2-deoxy-2-dimethylmaleimido - alpha,beta-D-glucopyranosyl]
      trichloroacetimidate (7) was prepared by reacting O-(2,3,4,6-tetra-O-acetyl-
      alpha-D-galactopyranosyl) trichloroacetimidate with tert-butyldimethylsilyl 3,6
      di-O-benzyl-2-deoxy-2- dimethylmaleoylamido-glucopyranoside to give the
      corresponding disaccharide 5. Deprotection of the anomeric center and then
      reaction with trichloroacetonitrile afforded 7. Reaction of 7 with 3'-O
      unprotected benzyl (2,4,6-tri-O-benzyl-beta-D-galactopyranosyl)- (1-->4)-2,3,6
      tri-O-benzyl-beta-D-glucopyranoside (8) as acceptor afforded the desired
      tetrasaccharide benzyl (2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-(1-->4)
      (3,6-di-O- benzyl-2-deoxy-2-dimethylmaleimido-beta-D-glucopyranosyl)-(1-->3)-
      (2,4,6- tri-O-benzyl-beta-D-galactopyranosyl)-(1-->4)-2,3,6-tri-O-benzyl-beta-D-
      glucopyranoside. Replacement of the N-dimethylmaleoyl group by the acetyl group,
      O-debenzylation and finally O-deacetylation gave lacto-N-neotetraose. Similarly,
      reaction of O-[(2,3,4,6-tetra-O-acetyl-beta- D-galactopyranosyl)-(1-->3)-4,6-O
      benzylidene-2-deoxy-2-dimethylmalei mido- alpha,beta-D-glycopyranosyl]
      trichloroacetimidate as donor with 8 as acceptor afforded the desired
      tetrasaccharide benzyl (2,3,4,6-tetra-O-acetyl-beta-D- galactopyranosyl)-(1-->3)
      (4,6-benzylidene-2-deoxy-2-dimethylmaleimid o- beta-D-glucopyranosyl)-(1-->3)
      (2,4,6-tri-O-benzyl-beta-D-galactopyranos yl)- (1-->4)-2,3,6-tri-O-benzyl-beta-D
      glucopyranoside. Removal of the benzylidene group, replacement of the N
      dimethylmaleoyl group by the acetyl group and then O-acetylation afforded
      tetrasaccharide intermediate 15, which carries only O-benzyl and O-acetyl
      protective groups. O-Debenzylation and O-deacetylation gave lacto-N-tetraose (1).
      Additionally, known tertbutyldimethylsilyl (2,3,4,6-tetra-O-acetyl-beta-D
      galactopyranosyl)-(1-->3)-4,6-O-benzylide ne- 2-deoxy-2-dimethylmaleimido-beta-D
      glucopyranoside was transformed into O-[2,3,4,6-tetra-O-acetyl-beta-D
      galactopyranosyl)- (1-->3)-4,6-di-O-acetyl-2-deoxy-2-dimethylmaleimido-alpha,beta
      D- glucopyranosyl] trichloroacetimidate as glycosyl donor, to afford with 8 as
      acceptor the corresponding tetrasaccharide 22, which is transformed into 15, thus
      giving an alternative approach to 1.

PMID- 10420592
TI  - Enzymatic modification of hydroxyethylcellulose by transgalactosylation with beta
      galactosidases.
AB  - beta-galactosidases from A. oryzae and a thermophilic CLONEZYME glycosidase
      library were used to catalyze the transfer of the beta-D-galactopyranosyl moiety
      from lactose to the hydroxyl groups of hydroxyethylcellulose (HEC) in sodium
      acetate buffer. The degree of substitution was quantified by using galactose
      oxidase enzymatic assays. Depolymerization was also observed in the course of the
      transglycosylation reactions.

PMID- 10420593
TI  - Extracellular polysaccharide of Erwinia chrysanthemi CU643.
AB  - Erwinia chrysanthemi are gram-negative bacterial phytopathogens causing soft rots
      in a number of plants. The structure of the extracellular polysaccharide (EPS)
      produced by E. chrysanthemi strain CU643, pathogenic to Philodendron, has been
      determined using a combination of chemical and physical techniques including
      methylation analysis, high- and low-pressure gel-filtration and anion-exchange
      chromatography, high-pH anion-exchange chromatography, partial acid hydrolysis,
      mass spectrometry, and 1- and 2-D NMR spectroscopy. In contrast to the structures
      of the EPS reported for other strains of E. chrysanthemi, the EPS from strain
      CU643 is a linear polysaccharide containing L-Rhap, D-Galp, and D-GlcAp in the
      ratio 4:1:1. Evidence is presented for the following hexasaccharide repeat unit: 
      ->3)-beta-D-Galp-(1-->2)-alpha-L-Rhap-(1-->4)-beta-D-GlcAp- (1-->2)-alpha-L- Rhap
      (1-->2)-alpha-L-Rhap-(1-->2)-alpha-L-Rhap-(1-->(1 ).

PMID- 10420594
TI  - Structure of an antigenic teichoic acid shared by clinical isolates of
      Enterococcus faecalis and vancomycin-resistant Enterococcus faecium.
AB  - A shared antigenic teichoic acid, previously found to be a surface capsule-like
      polysaccharide, was isolated from clinical isolates of Enterococcus faecalis and
      vancomycin-resistant E. faecium. It was composed of glucose, glycerol, and
      phosphate as determined by chemical and GC-MS analysis. The repeating-unit
      structure was elucidated by a series of 1H, 13C, and 31P NMR spectroscopy to be
      the following: [formula: see text]

PMID- 10420595
TI  - Solubilization of yeast cell-wall beta-(1-->3)-D-glucan by sodium hypochlorite
      oxidation and dimethyl sulfoxide extraction.
AB  - The limulus test is a well-established method for the diagnosis of both Gram
      negative sepsis and invasive fungal infection. To diagnose fungal infections, a
      beta-(1-->3)-D-glucan-specific chromogenic kit (Fungitec G test MK) has been
      developed and applied clinically. We are concentrating our main efforts on
      developing a better standard to improve the precision of this method. To this
      end, we have successfully developed a protocol to obtain a soluble Candida spp.
      beta-(1-->3)-D-glucan (CSBG) by sodium hypochlorite (NaClO) oxidation and
      subsequent dimethyl sulfoxide (Me2SO) extraction (yield of 9.6 +/- 4.1%) of
      acetone-dried whole-cell preparations. The beta-glucan fraction is free from the
      cell-wall mannan, gives a symmetrical peak by gel filtration, and is soluble in
      dilute NaOH. The product is composed mainly of beta-(1-->3)- and beta-(1-->6)-D
      glucosidic linkages. The specific activity of the beta-glucan is comparable with
      pachyman when combined with the Fungitec G test as the standard glucan and
      reacted as low as 10(-11) g/mL.

PMID- 10420597
TI  - Liquid chromatographic study of the enzymatic degradation of endomorphins, with
      identification by electrospray ionization mass spectrometry.
AB  - The recently discovered native endomorphins play an important role in opioid
      analgesia, but their metabolic fate in the organism remains relatively little
      known. This paper describes the application of high-performance liquid
      chromatography combined with electrospray ionization mass spectrometry to
      identify the degradation products resulting from the incubation of endomorphins
      with proteolytic enzymes. The native endomorphin-1, H-Tyr-Pro-Trp-Phe-NH2 (1),
      and endomorphin-2, H-Tyr-Pro-Phe-Phe-NH2 (2), and an analog of endomorphin-2, H
      Tyr-Pro-Phe-Phe-OH (3), were synthetized, and the levels of their resistance
      against carboxypeptidase A, carboxypeptidase Y, aminopeptidase M and proteinase A
      were determined. The patterns of peptide metabolites identified by this method
      indicated that carboxypeptidase Y first hydrolyzes the C-terminal amide group to
      a carboxy group, and then splits the peptides at the Trp3-Phe4 or Phe3-Phe4 bond.
      The remaining fragment peptides are stable against the enzymes investigated.
      Carboxypeptidase A degrades only analog 3 at the Phe3-Phe4 bond. Aminopeptidase M
      cleaves the peptides at the Pro2-Trp3 or Pro2-Phe3 bond. The C-terminal fragments
      hydrolyze further, giving amino acids and Phe-NH2-s while the N-terminal part
      displays a resistance to further aminopeptidase M digestion. Proteinase A
      exhibits a similar effect to carboxypeptidase Y: the C-terminal amide group is
      first converted to a carboxy group, and one amino acid is then split off from the
      C-terminal side.

PMID- 10420596
TI  - Large-scale production of N-acetyllactosamine through bacterial coupling.
AB  - A large-scale production system of N-acetyllactosamine, a core structure of
      various oligosaccharides, was established by a whole-cell reaction through the
      combination of recombinant Escherichia coli strains and Corynebacterium
      ammoniagenes. Two recombinant E. coli strains over-expressed the UDP-Gal
      biosynthetic genes and the beta-(1-->4)-galactosyltransferase gene of Neisseria
      gonorrhoeae, respectively. C. ammoniagenes contributed the production of UTP from
      orotic acid. N-Acetyllactosamine was accumulated at 279 mM (107 g L-1) after a 38
      h reaction (2.5 L in volume) starting from orotic acid, D-galactose, and 2
      acetamido-2-deoxy-D-glucose.

PMID- 10420598
TI  - High-performance liquid chromatography-mass spectrometry of an osteocalcin
      derivative.
AB  - High-performance liquid chromatography (HPLC) was combined on-line with
      electrospray ionization mass spectrometry (ESI-MS) for structural analysis of a
      synthetic osteocalcin derivative and its degradation products. Initial
      determination of amino acid sequence of the synthetic peptide was performed after
      tryptic degradation. Hydrolytic degradation of the osteocalcin derivative was
      studied under different pH conditions: pH 2, pH 7 and pH 10 at 60 degrees C up to
      20 h. According the HPLC-ESI-MS results, the chemical stability was dependent on
      pH. Two major degradation products and a number of other fragments were obtained
      in acidic solution, whereas the osteocalcin molecule was rather stable in neutral
      and alkaline conditions.

PMID- 10420599
TI  - Analytical strategy for the assessment of the protein glycation status in uremic
      patients by high-performance liquid chromatography.
AB  - We propose a newly integrated procedure for the analysis of furosine (early
      glycation product) and pentosidine (glycoxidation end-product) in plasma proteins
      and the simultaneous assessment of advanced glycation end-product (AGE) peptides
      and free pentosidine in plasma. In order to determine furosine and protein-linked
      pentosidine, plasma proteins were hydrolyzed in 8 M HCl and each analyte was
      purified by solid-phase extraction. Furosine was determined by ion-pair RP-HPLC
      methodology with isocratic elution and spectrophotometric detection at 280 nm and
      pentosidine by ion-pair RP-HPLC by using gradient elution and fluorimetric
      detection at 335/385 nm. To assess free pentosidine concentration and
      simultaneously evaluate the AGE peptides, an aliquot of plasma sample was diluted
      and ultrafiltered by using Centricon 10 M(r) < or = 10,000) ultrafiltration
      membranes. Free pentosidine and AGE peptides were analysed by ion-pair RP-HPLC,
      by using gradient elution and fluorimetric detection at 385 nm upon excitation at
      335 nm. The HPLC methodology has been successfully used for the determination of
      glycation and glycoxidation protein status in uremic patients.

PMID- 10420601
TI  - Automated high-performance liquid chromatographic method for the determination of
      homocysteine in plasma samples.
AB  - Plasma homocysteine determination is essential for the diagnosis of inborn errors
      of metabolism of sulfur amino acids and is achieving considerable importance as a
      possible risk marker in vascular occlusive pathology. The aim of this study was
      therefore to develop a fast and sensitive method to assay total and free
      homocysteine and total and free cysteine in plasma samples, using an automated
      precolumn sample pretreatment including reduction with 2-mercaptoethanol,
      carboxymethylation of free thiols and derivation with o-phthalaldehyde. The
      chromatographic separation was accomplished in 7 min, the within-run and between
      run R.S.D.s were all less than 4.3%, the response was linear in the range 0.4-150
      microM for homocysteine and 4-1000 microM for cysteine and the mean recoveries
      were higher than 96%. Moreover, with minimal modification, the method allowed the
      evaluation of methionine, another important marker of transsulfuration and
      remethylation defects. The method was applied to the diagnosis of inborn errors
      involving sulfur amino acids metabolism and to detect mild hyperhomocysteinemia.

PMID- 10420600
TI  - High-performance liquid chromatographic separation of novel atropic alpha,alpha
      disubstituted-beta-amino acids, either on different beta-cyclodextrin-bonded
      phases or as their 1-fluoro-2,4-dinitrophenyl-5-L-alanine amide derivatives.
AB  - The high-performance liquid chromatographic enantioresolution of free and N-
      and/or C-protected derivatives of (R,S)-2',1':1,2;1",2":3,4-dinaphthcyclohepta
      1,3-diene-6-aminometh yl-6- carboxylic acid (beta 2-Bin) by direct and indirect
      methods is reported. The direct separation was carried out on native and
      different derivatized beta-cyclodextrin-bonded phases. The indirect resolution
      was achieved by applying pre-column derivatization with 1-fluoro-2,4
      dinitrophenyl-5-L-alanine amide. The effects of different parameters such as the
      mobile phase composition and the structures of the compounds on the enantiomeric
      resolution are discussed.

PMID- 10420604
TI  - Simultaneous determination of Pseudomonas aeruginosa elastase, human leukocyte
      elastase and cathepsin G activities by micellar electrokinetic chromatography.
AB  - Micellar electrokinetic chromatography (MEKC) is a new method for analysing
      proteolytic activities simultaneously present in incubation mixtures. Here we
      demonstrate that MEKC differentiates between the enzymatic activities of
      Pseudomonas aeruginosa elastase (PsE) and human leukocyte elastase (HLE) or
      cathepsin G (Cat G) in assays using the chromogenic peptide substrates Suc-Ala
      Ala-Ala-NA or Suc-Ala-Ala-Pro-Phe-NA, respectively (where Suc = succinyl and NA =
      4-nitroaniline/u-nitroanilide). When PsE and Cat G were incubated at equimolar
      ratio with Suc-Ala-Ala-Pro-Phe-NA, the PsE-specific cleavage products PheNA and
      Suc-Ala-Ala-Pro were detected whereas inhibition of the metalloproteinase PsE
      with EDTA resulted in detection of NA and Suc-Ala-Ala-Pro-Phe only. Similarly,
      when PsE and HLE were incubated at equimolar ratio with Suc-Ala-Ala-Ala-NA, the
      PsE-specific cleavage products Suc-Ala and Ala-Ala-NA were detected whereas at an
      PsE-HLE ratio 1:50, both the PsE-specific and the HLE-specific cleavage products
      NA and Suc-Ala-Ala-Ala were separated. MEKC also allowed determination of the
      kinetic constants for the interactions of PsE, Cat G and HLE with the substrates
      considered.

PMID- 10420605
TI  - Determination of cows' milk in goats' milk and cheese by capillary
      electrophoresis of the whey protein fractions.
AB  - The use of capillary zone electrophoresis to determine the adulteration of cows'
      milk in goats' milk products is described. The detection and quantification of
      cows' milk was based on the presence of the specific whey proteins: the relative
      calibration curve is reported. The peaks of interest were well resolved by using
      sodium borate at pH 9.2 as background electrolyte in methyl-silanized
      capillaries. The minimum amount detectable of cows' milk was 2% in milk mixtures
      and 4% in cheeses. Restrictions due to genetic variability and possible heat
      treatments, on only one of the two types of milk employed, are taken into
      account. Qualitative analysis of goat-ewe-cow and goat-ewe samples are also
      reported.

PMID- 10420606
TI  - Characterization of the isoforms of PIXY321, a granulocyte-macrophage-colony
      stimulating factor-interleukin-3 fusion protein, separated by preparative
      isoelectric focusing on immobilized pH gradients.
AB  - We present here the purification and the characterization of the isoforms of
      PIXY321, a genetically engineered fusion of granulocyte-macrophage-colony
      stimulating factor and interleukin-3 expressed in yeast. The isoforms of PIXY321
      were isolated using preparative isoelectric focusing (IEF) on immobilized pH
      gradients. Analysis of the collected fractions on analytical IEF gels showed that
      PIXY321 was resolved into four discrete isoforms of isoelectric point (pI) 5.0,
      5.1, 5.2 and 5.3 with excellent yields. Subsequent analysis of purified isoforms
      of PIXY321 by peptide mapping and mass spectrometry linked the microheterogeneity
      of the original molecule to three parameters, the presence of deamidated
      residues, charged glycans and the pattern of O-linked glycosylation along the
      peptide sequence. This last parameter emphasizes the role of conformational
      aspects as key factors influencing the apparent isoelectric point of protein
      isoforms.

PMID- 10420607
TI  - Determination of 2,3-benzodiazepine derivatives in rat plasma by high-performance
      liquid chromatography.
AB  - A simple high-performance liquid chromatographic method with ultraviolet
      detection at 240 nm for determination of a novel AMPA/kainate antagonist 1-(4'
      aminophenyl)-3,5-dihydro-7,8-dimethoxy-2,3-benzodiazepine (2,3-BZ 6), and its
      derivatives in rat plasma is described. The procedure involves a fast extraction
      of the drugs from the plasma spiked with an internal standard. The samples are
      applied to a pre-packed glass column and drugs are eluted using ethyl acetate. A
      linear response was observed over the examined concentration range. The lower
      limit of detection of 2,3-BZ 6 was 5.5 ng/ml. The assay has been used to
      determine the time course of plasma levels of the 2,3-benzodiazepine derivatives
      in Sprague-Dawley rats.

PMID- 10420608
TI  - Sensitive method for the determination of baclofen in plasma by means of solid
      phase extraction and liquid chromatography-tandem mass spectrometry.
AB  - A simple and sensitive method for the determination of baclofen in plasma is
      described. Baclofen and the internal standard, KM 08205, were isolated from
      plasma by solid-phase extraction using C18 material. After separation by reversed
      phase liquid chromatography, the analytes were detected with tandem mass
      spectrometry. The extraction procedure was optimised regarding the solid-phase
      extraction material, the pH in the conditioning solution and the washing volume.
      The method was proven to be selective and sensitive with an absolute recovery of
      about 95%, a relative standard deviation below 5% and a limit of quantification
      of 10 nmol/1.

PMID- 10420609
TI  - Determination of trovafloxacin in human body fluids by high-performance liquid
      chromatography.
AB  - For the quantitative determination of trovafloxacin (a new naphthyridinone
      antibacterial agent) in serum and urine a simple isocratic HPLC method with
      fluorimetric detection is described. Serum was deproteinised with a mixture of
      acetonitrile and perchloric acid. The protein-free extract was separated on a
      reversed-phase column (Nucleosil 100-5 C18) and quantified by means of
      fluorescence (excitation 275 nm, emission 405 nm). The mobile phase consisted of
      a mixture of 250 ml acetonitrile and 750 ml distilled water containing 10 mmol/l
      tetrabutylammonium phosphate. Urine was diluted with 0.25 mol/l phosphoric acid
      1:20 (v/v) which was adjusted to pH 3.6 with sodium hydroxide solution. Diluted
      urine samples were separated on a cation-exchange column (Nucleosil 100-5 SA) and
      also detected by means of fluorescence. Trovafloxacin was sufficiently separated
      from endogenous compounds. Results of validation are given. The method was
      applied successfully to a study of healthy volunteers.

PMID- 10420610
TI  - Microcolumn high-performance liquid chromatographic assay for doxycycline in
      isolated alveolar macrophages.
AB  - A procedure for the isolation of doxycycline from the alveolar macrophages is
      described. Due to the minimal amount of the sample, it was necessary to employ
      microcolumn HPLC. A great advantage of the methodology developed in the present
      paper consists in the direct injection of an aqueous supernatant over
      disintegrated macrophages without the use of liquid-liquid or solid-liquid
      extraction. Another advantage of the method is the fact that the injection of an
      aqueous solution on a microcolumn with a lipophilic stationary phase makes the
      analyzed substances concentrate, which increases the sensitivity of assay.
      Separation was performed on a Separon SGX C18 microcolumn, 150 x 1 mm, detection
      at 254 nm by UV, 1 microliter flow cell. Rabbits were treated intravenously with
      Vibramycin inj. sic. in a dose of 13 mg/kg body weight doxycycline. A procedure
      for washing macrophages from rabbit lungs was developed. Dry matter of
      macrophages ranged from 5.9 to 11.4 mg. In the samples of three rabbits the
      levels of doxycycline ranged from 110 to 270 ng per 1 mg of macrophages dry
      matter.

PMID- 10420611
TI  - Determination of ramoplanin in human urine by high-performance liquid
      chromatography with automated column switching.
AB  - Ramoplanin is a novel glycolipodepsipeptide antibiotic, currently undergoing
      clinical trials. This method describes the determination of ramoplanin by direct
      injection of human urine into a coupled-column liquid chromatographic system. An
      internal-surface reversed-phase column has been used for on-line sample clean-up
      and enrichment. Analytical separation of ramoplanin and MDL 62,456 used as
      internal standard, has been achieved on a ABZ+ reversed-phase column with
      ammonium acetate buffer-acetonitrile-methanol according to a gradient profile.
      Analytes were detected by their UV absorbance at 270 nm. The limit of
      quantitation was 0.1 microgram/ml urine and the limit of detection was found to
      be 0.035 microgram/ml, corresponding to 13.7 pmol/ml. Linearity was determined in
      the range 0.1-2 micrograms/ml. Precision (relative standard deviation) ranged
      from 0.71 to 8.75% and the accuracy from -9.9 to 11.6%. Different human sources
      were tested and no interference between analytes and urine constituents was
      observed. The method is simple and rapid, requiring a total analysis time of 35
      min per sample and reaching greater selectivity and accuracy than microbiological
      assays.

PMID- 10420613
TI  - Sensitive method for the determination of the antiarrhythmic drug detajmium in
      serum by solid-phase extraction and high-performance liquid chromatography with
      fluorimetric detection.
AB  - The objective of this study was to develop a very sensitive and selective method
      for the determination of detajmium (4-3-diethylamino-2-hydroxypropyl-ajmaline), a
      sodium-channel-blocking drug with antiarrhythmic properties, in serum. A high
      performance liquid chromatography (HPLC) method with solid-phase extraction and
      fluorimetric detection has been applied. Serum samples were diluted with
      phosphate buffer (pH 3.5) and the extraction of detajmium and ajmaline, which was
      used as an internal standard, was carried out with Oasis cartridges (Waters). The
      chromatographic separation was performed on a RP18 column. The limit of
      quantification for serum samples of detajmium was 1 ng/ml with good
      reproducibility (R.S.D. < 15%) and a linear response from 1 to 200 ng/ml. The
      described method is highly sensitive and specific for the determination of
      detajmium in serum of patients and volunteers.

PMID- 10420612
TI  - Piroxicam quantitation in human plasma by high-performance liquid chromatography
      with on- and off-line solid-phase extraction.
AB  - A comparative study of two analytical methodologies for piroxicam quantitation in
      plasma by off-line and on-line solid-phase extraction (SPE) and high-performance
      liquid chromatography (HPLC) is described. The SPE cartridges contained C8 for
      both extraction methods. The analytes piroxicam and tenoxican (internal standard)
      were separated on a C18 column with a mobile phase consisting of acetonitrile:20
      mM phosphate buffer pH 3.1 (50:50, v/v) followed by UV detection at 360 nm. The
      validation of the methods demonstrated good recoveries (over 90%), sensitivity
      (limits of quantification of 0.05 microgram/ml with on-line SPE and 0.1
      microgram/ml with off-line SPE, based on a 100 microliters and 200 microliters
      sample volume, respectively), accuracy and precision (better than 9.5%). Both
      methodologies have been used for bioequivalence studies.

PMID- 10420614
TI  - Simultaneous stereoselective analysis by capillary electrophoresis of tramadol
      enantiomers and their main phase I metabolites in urine.
AB  - Capillary zone electrophoresis was successfully applied to the enantiomeric
      resolution of racemic tramadol and its six phase I metabolites using
      carboxymethylated beta-cyclodextrin (CMB) added to the background electrolyte
      (BGE). Baseline resolution of tramadol and its metabolites was obtained in less
      than 30 min using a 50 mM phosphate buffer (pH 2.5) containing 5 mM of CMB.
      Chiral determinations of tramadol and its main three metabolites, O
      demethyltramadol (M1), N-demethyltramadol (M2) and O-demethyl-N-demethyltramadol
      (M5), were performed in urine after a simple double liquid-liquid extraction of
      200 microliters of biological material. In the tested concentration range (0.5-20
      micrograms/ml, except for M2: 0.5-10 micrograms/ml) coefficients of correlation
      superior than 0.994 were obtained. Within-day variation determined on three
      different concentrations for each enantiomers showed accuracies ranging from
      95.4% to 103.2%. The relative standard deviation (RSD) of these assays was
      determined to be less than 10.0%. Day-to-day variation presented accuracies
      ranging from 96.3% to 106.5% with a RSD less than 9.0%. After oral administration
      of 100 mg of tramadol hydrochloride to an healthy volunteer, the urinary
      excretion was monitored during 30 h. About 15% of the dose was excreted as
      unchanged tramadol. The enantiomeric ratios of all the excreted analytes, T, M1,
      M2 and M5, were found to be very different to 1.0, showing that a stereoselective
      metabolism of tramadol clearly occurred.

PMID- 10420615
TI  - Trace analysis of haloperidol and its chiral metabolite in plasma by capillary
      electrophoresis.
AB  - Capillary zone electrophoresis was developed for the simultaneous determination
      of haloperidol (HP) and its chiral metabolites [(+)- and (-)- reduced
      haloperidol, (+)- and (-)-RHP] in human plasma. The method involved the presence
      of an internal standard and liquid-liquid extraction from plasma. After
      concentration, the residue from the organic extract was dissolved in aqueous acid
      for capillary electrophoretic analysis. The background electrolyte was Tris
      phosphate buffer with dimethyl-beta-cyclodextrin and PEG 6000. In spiked plasma
      the quantitative ranges were 40-400 nM for HP and 50-500 nM for (+)-RHP or (-)
      RHP. The intra-day and inter-day relative standard deviations (n = 3) were all <
      20% for each substance. The detection limits were found to be 15 ng/ml for HP and
      30 ng/ml for both enantiomers of RHP (S/N = 3, injection 20 s). All recoveries
      were > 70%. We investigated the in vivo metabolism of HP in Chinese schizophrenia
      patients. The results show that (-)-RHP seems to be the only chiral metabolite
      from these two HP-dosed patients.

PMID- 10420616
TI  - Distribution of n-alkanes, polynuclear aromatic hydrocarbons and nitrated
      polynuclear aromatic hydrocarbons between the fine and coarse fractions of
      inhalable atmospheric particulates.
AB  - The distribution ratios of n-alkanes, polynuclear aromatic hydrocarbons (PAHs)
      and nitrated PAH components between fine and coarse fractions of soot has been
      investigated in downtown Rome through three field campaigns carried out at
      different times of the year. The preferential accumulation of almost all species
      investigated onto fine particles has been observed in all field experiments
      performed. Moreover, nitrated PAHs had varied distributions, according to the
      origin of their occurrence in the atmosphere; in fact, congeners of photochemical
      origin accumulated more in fine particles than those released by primary sources.

PMID- 10420617
TI  - Selective on-line immunoextraction coupled to liquid chromatography for the trace
      determination of benzidine, congeners and related azo dyes in surface water and
      industrial effluents.
AB  - A new extraction immunosorbent involving antigen-antibody interactions was
      coupled on-line to liquid chromatography for the selective extraction in aqueous
      samples of benzidine and congeners, widely used as intermediate compounds in the
      manufacturing of dyes and pigments. Due to the cross-reactivity of the antibodies
      for analytes with chemical structures closely related to that of the analyte used
      for immunization, the immunoextraction sorbent was shown to be able to extract
      aminoazobenzene and related azo dyes with good recoveries. The on-line coupling
      was optimized for the trace determination of benzidine, dichlorobenzidine,
      aminoazobenzene and some azo dyes with detection limits in the range 0.1 to 1
      microgram/l. The high selectivity of the immunoextraction was shown by comparing
      the analysis of an industrial textile effluent obtained using precolumns packed
      either with a non-selective polymeric sorbent or with the anti-benzidine
      immunosorbent. In such complex samples, extraction and clean-up are achieved in
      the same step.

PMID- 10420618
TI  - Determination of bentazon residues in water by high-performance liquid
      chromatography. Validation of the method.
AB  - A method for determination of bentazon residues in water has been developed. The
      method involves solid-phase extraction with C18 extraction tubes and high
      performance liquid chromatographic analysis. A C18 column and guard column were
      used with UV detection at 230 nm, a mobile phase of methanol-water (60:40, v/v)
      at pH 4.6 (phosphoric acid) and a flow-rate of 0.8 ml/min. After optimization of
      the extraction and separation conditions, the method was validated. The method
      developed can be used for determination of bentazon in water, within the
      international limits of 0.1 microgram/l, with a 500-fold pre-concentration.

PMID- 10420620
TI  - Modeling of an electrohydraulic lithotripter with the KZK equation.
AB  - The acoustic pressure field of an electrohydraulic extracorporeal shock wave
      lithotripter is modeled with a nonlinear parabolic wave equation (the KZK
      equation). The model accounts for diffraction, nonlinearity, and thermoviscous
      absorption. A numerical algorithm for solving the KZK equation in the time domain
      is used to model sound propagation from the mouth of the ellipsoidal reflector of
      the lithotripter. Propagation within the reflector is modeled with geometrical
      acoustics. It is shown that nonlinear distortion within the ellipsoidal reflector
      can play an important role for certain parameters. Calculated waveforms are
      compared with waveforms measured in a clinical lithotripter and good agreement is
      found. It is shown that the spatial location of the maximum negative pressure
      occurs pre-focally which suggests that the strongest cavitation activity will
      also be in front of the focus. Propagation of shock waves from a lithotripter
      with a pressure release reflector is considered and because of nonlinear
      propagation the focal waveform is not the inverse of the rigid reflector. Results
      from propagation through tissue are presented; waveforms are similar to those
      predicted in water except that the higher absorption in the tissue decreases the
      peak amplitude and lengthens the rise time of the shock.

PMID- 10420619
TI  - Quantitative determination of Closantel residues in milk by high-performance
      liquid chromatography with fluorescence detection.
AB  - A HPLC method with fluorescence detection for quantitative determination of
      Closantel residues in milk has been developed and validated. The proposed
      cleaning procedure with acetonitrile and acetone extraction, and solid-phase
      clean-up with Florisil enables concentrations of Closantel below 50 micrograms/l
      to be determined. The method was shown to be sufficient, precise, accurate,
      selective and rugged. The method was applied in the regular monitoring of
      Closantel residues in milk and of the pharmacokinetic behavior of Closantel in
      sheep.

PMID- 10420621
TI  - Wideband reflectance tympanometry in normal adults.
AB  - Acoustic impedance/reflectance measurements were made at various ear-canal
      pressures in 20 subjects with a clinical acoustic immittance instrument and an
      experimental impedance/reflectance system. Measurements were made over a
      frequency range of 226-2000 Hz with the clinical system and 125-11,310 Hz with
      the experimental system. For frequencies < or = 2.0 kHz, tympanograms obtained
      with the two systems are similar, with patterns that progress through the same
      orderly sequence with increasing frequency. Eardrum impedance measurements were
      also similar. There are small gender differences in middle-ear impedance.
      Reflectance patterns (reflectance versus frequency) at ambient ear-canal air
      pressure are characterized by high reflectance at low frequencies, two district
      minima at 1.2 and 3.5 kHz, increasing reflectance to 8.0 kHz, and decreasing
      reflectance above that frequency. Ear-canal pressure increases reflectance at low
      frequencies, decreases reflectance in the region of the minimum, and increases
      reflectance slightly at high frequencies. Reflectance tympanograms (reflectance
      versus ear-canal pressure) progress through a sequence of three patterns. At low
      frequencies, reflectance tympanograms are "V" shaped, indicating that pressure
      increases reflectance. At frequencies near the minimum reflectance, the pattern
      inverts, indicating that pressure decreases reflectance. At high frequencies, the
      patterns are flat, indicating that ear-canal pressure has little effect. Results
      presented for one patient suggest that reflectance tympanometry may be useful for
      detecting middle-ear pathology.

PMID- 10420622
TI  - Localization by interaural time difference (ITD): effects of interaural frequency
      mismatch.
AB  - A commonly accepted physiological model for lateralization of low-frequency
      sounds by interaural time delay (ITD) stipulates that binaural comparison neurons
      receive input from frequency-matched channels from each ear. Here, the effects of
      hypothetical interaural frequency mismatches on this model are reported. For this
      study, the cat's auditory system peripheral to the binaural comparison neurons
      was represented by a neurophysiologically derived model, and binaural comparison
      neurons were represented by cross-correlators. The results of the study indicate
      that, for binaural comparison neurons receiving input from one cochlear channel
      from each ear, interaural CF mismatches may serve to either augment or diminish
      the effective difference in ipsilateral and contralateral axonal time delays from
      the periphery to the binaural comparison neuron. The magnitude of this increase
      or decrease in the effective time delay difference can be up to 400 microseconds
      for CF mismatches of 0.2 octaves or less for binaural neurons with CFs between
      250 Hz and 2.5 kHz. For binaural comparison neurons with nominal CFs near 500 Hz,
      the 25-microsecond effective time delay difference caused by a 0.012-octave CF
      mismatch is equal to the ITD previously shown to be behaviorally sufficient for
      the cat to lateralize a low-frequency sound source.

PMID- 10420623
TI  - Near-field responses from the round window, inferior colliculus, and auditory
      cortex of the unanesthetized chinchilla: manipulations of noiseburst level and
      rate.
AB  - Few studies have compared the response properties of near-field potentials from
      multiple levels of the auditory nervous system of unanesthetized animals. The
      purpose of this study was to investigate the effects of brief-duration
      noisebursts on neural responses recorded from electrodes chronically implanted at
      the round window, inferior colliculus and auditory cortex of chinchillas.
      Responses were obtained from seven unanesthetized chinchillas to a noiseburst
      level and noiseburst-rate series. For the noiseburst-rate series, a 70 dB pSPL
      noiseburst was varied in rate from 10 to 100 Hz using conventional averaging
      procedures, and from 100 to 500 Hz using pseudorandom pulse trains called maximum
      length sequences (MLSs). Response thresholds were similar for the compound action
      potential (CAP), inferior colliculus potential (ICP) and auditory cortex
      potential (ACP). With decreasing noiseburst level, there were decreases in the
      amplitudes and increases in the latencies of the CAP, ICP and ACP. The shapes of
      the mean normalized amplitude input/output (I/O) functions were similar for the
      ICP and ACP, while the normalized I/O functions for the first positive peak (P1)
      and first negative peak (N1) of the CAP differed from each other and from the ICP
      and ACP. The slopes of the latency/intensity functions were shallowest for the
      CAP, intermediate for the ICP, and steepest for the ACP. With increasing rate,
      the latency shift was least for the CAP, intermediate for the ICP and greatest
      for the ACP. The amplitude of P1 of the CAP varied little with rate. All other
      potentials showed a pronounced decrease in amplitude at high stimulation rates.
      Excluding CAP P1, proportional amplitude decrease with rate was greatest for the
      ACP, intermediate for N1 of the CAP and least for the ICP. Responses were present
      in most animals at all recording sites, even for the highest rate (500 Hz) used
      in this study. For all potentials, the MLS procedure allowed the collection of a
      response at rates well above those where sequential responses would have
      overlapped using conventional averaging procedures.

PMID- 10420624
TI  - Detection of time- and bandlimited increments and decrements in a random-level
      noise.
AB  - The purpose of this study was to compare detection of increments and decrements
      occurring over limited regions of time and frequency within a 500-ms broadband (0
      6000 Hz) noise. Three listeners tracked detection thresholds adaptively in a two
      interval, two-alternative forced-choice task. Thresholds were measured for both
      increments and decrements in level [delta L = 10 log10(1 + delta N0/N0) dB, where
      N0 is the spectral power density of the noise] as a function of signal duration
      (T = 30-500 ms) for a range of signal bandwidths (W = 62-6000 Hz) that were
      logarithmically centered around 2500 Hz. Listeners were forced to rely on
      temporal- and spectral-profile cues for detection due to randomization of overall
      presentation level from interval to interval, which rendered overall energy an
      inconsistent cue. Increments were detectable for all combinations of W and T,
      whereas decrements were not consistently detectable for W < 500 Hz. Narrow-band
      decrements were not detectable due to spread of excitation from the spectral
      edges of the noise into the decrements. Increment and decrement thresholds were
      similar for W > or = 1000 Hz. Temporal- and spectral-integration effects were
      observed for both increments and decrements. The exceptions were for random-level
      conditions in which the signal matched the bandwidth or duration of the standard.
      A multicue decision process is described qualitatively to explain how the
      combination of temporal- and spectral-profile cues can produce temporal- and
      spectral-integration effects in the absence of overall-energy cues.

PMID- 10420625
TI  - Vowel-specific effects in concurrent vowel identification.
AB  - An experiment investigated the effects of amplitude ratio (-35 to 35 dB in 10-dB
      steps) and fundamental frequency difference (0%, 3%, 6%, and 12%) on the
      identification of pairs of concurrent synthetic vowels. Vowels as weak as -25 dB
      relative to their competitor were easier to identify in the presence of a
      fundamental frequency difference (delta F0). Vowels as weak as -35 dB were not.
      Identification was generally the same at delta F0 = 3%, 6%, and 12% for all
      amplitude ratios: unfavorable amplitude ratios could not be compensated by larger
      delta F0's. Data for each vowel pair and each amplitude ratio, at delta F0 = 0%,
      were compared to the spectral envelope of the stimulus at the same ratio, in
      order to determine which spectral cues determined identification. This
      information was then used to interpret the pattern of improvement with delta F0
      for each vowel pair, to better understand mechanisms of F0-guided segregation.
      Identification of a vowel was possible in the presence of strong cues belonging
      to its competitor, as long as cues to its own formants F1 and F2 were prominent.
      delta F0 enhanced the prominence of a target vowel's cues, even when the spectrum
      of the target was up to 10 dB below that of its competitor at all frequencies.
      The results are incompatible with models of segregation based on harmonic
      enhancement, beats, or channel selection.

PMID- 10420626
TI  - Growth of simultaneous masking for fm < fs: effects of overall frequency and
      level.
AB  - Growth-of-masking (GOM) functions were obtained in three groups of normal-hearing
      subjects using a simultaneous-masking paradigm. In all cases, the signal
      frequency (fs) was higher than the masker frequency (fm), either by a certain
      ratio (1.44) or by a certain distance [3 equivalent rectangular bandwidths
      (ERBs)]. The purpose was to evaluate the effect of overall frequency on the slope
      of the steep portion of the GOM function, and to evaluate the change in slope
      that can occur at high levels. Signal frequency ranged from 400 to 5000 Hz, and
      masker level ranged from 40 to 95 dB SPL. On average, the slope of the steep
      portion of the GOM function was about 1.4 for signal frequencies from 400 to 750
      Hz, and 2.0 for signal frequencies from 1944 to 5000 Hz. This is consistent with
      the possibility that the cochlea may behave more linearly at the apical (low
      frequency) region than at the basal (high-frequency) region. In addition, for
      signal frequencies at and above 750 Hz, the slope of the masking function changed
      from a value much greater than 1.0 to a value of 1.0 at high levels. The change
      in slope was better correlated with signal sensation level (i.e., amount of
      masking) than with either signal or masker SPL: the lack of a change at the lower
      signal frequencies may reflect the smaller amounts of masking there. The change
      to a linear growth of masking may represent a change in the response to the
      signal from compressive to linear at high levels.

PMID- 10420627
TI  - Discrimination of frequency steps linked by glides of various durations.
AB  - Thresholds were measured for detecting steps in frequency linked by glides of
      various durations. The goals were to assess the relative importance of place and
      temporal information for this task, and to determine whether there is a mechanism
      for detecting dynamic frequency changes per se, as opposed to comparing the
      initial and final frequencies of the stimuli. Subjects discriminated a 500-ms
      sinusoid of constant frequency from a sinusoid with three parts: an initial part
      with constant frequency, a downward frequency glide, and a final part with
      constant frequency. The overall duration was 500 ms, and the glide duration was
      varied from 5 to 500 ms. In one special case, the portion of the stimuli when a
      glide might occur was replaced by a brief silent interval. The center frequency
      was fixed at 0.5, 1, 2, 4, or 6 kHz (condition 1), or varied randomly from one
      stimulus to the next over a 4-ERB range around the nominal center frequency
      (condition 2). The randomization impaired performance, but thresholds remained
      lower than the best that could be achieved by monitoring either the initial or
      final frequency of the stimuli. Condition 3 was like condition 2, but for each
      stimulus a glide in level was added at the time when a frequency glide might
      occur, so the initial and final levels differed; the glides in level varied
      randomly in extent and direction from one stimulus to the next over the range +/-
      20 dB. This impaired performance, but thresholds remained lower than the best
      that could be achieved by monitoring changes in excitation level on only one side
      of the excitation pattern. Excitation-pattern models of frequency discrimination
      predict that thresholds should not vary across center frequency when expressed as
      the change in ERB number, delta E. For all conditions, delta E values increased
      at 6 kHz, suggesting a role for temporal information at lower frequencies. The
      increase was smallest for the longest glide duration, consistent with a greater
      relative role of place information when there was no steady state portion.
      Performance was better when a brief glide was present than when no glide was
      present, but worsened with increasing glide duration. The results were fitted
      well by a model based on the assumption that information from the steady parts of
      the stimuli (perhaps extracted mainly using temporal information) was combined
      with information from the glides (perhaps extracted mainly using place
      information).

PMID- 10420628
TI  - Gap detection thresholds as a function of tonal duration for younger and older
      listeners.
AB  - Twenty normal hearing younger and twenty older adults in the early stages of
      presbycusis, but with relatively normal hearing at 2 kHz, were asked to
      discriminate between the presence versus absence of a gap between two equal
      duration tonal markers. The duration of each marker was constant within a block
      of trials but varied between 0.83 and 500 ms across blocks. Notched-noise,
      centered at 2 kHz, was used to mask on- and off-transients. Gap detection
      thresholds of older adults were markedly higher than those of younger adults for
      marker durations of less than 250 ms but converged on those of younger adults at
      500 ms. For both age groups, gap detection thresholds were independent of
      audiometric thresholds. These results indicate that older adults have more
      difficulty detecting a gap than younger adults when short marker durations (i.e.,
      durations characteristic of speech sounds) are employed. It is shown that these
      results cannot be explained by linear models of temporal processing but are
      consistent with differential adaptation effects in younger and older adults.

PMID- 10420630
TI  - A comparison of intergestural patterns in deaf and hearing adult speakers:
      implications from an acoustic analysis of disyllables.
AB  - Coarticulation studies in speech of deaf individuals have so far focused on
      intrasyllabic patterning of various consonant-vowel sequences. In this study,
      both inter- and intrasyllabic patterning were examined in disyllables /symbol see
      text #CVC/ and the effects of phonetic context, speaking rate, and segment type
      were explored. Systematic observation of F2 and durational measurements in
      disyllables minimally contrasting in vocalic ([i], [u,][a]) and in consonant
      ([b], [d]) context, respectively, was made at selected locations in the
      disyllable, in order to relate inferences about articulatory adjustments with
      their temporal coordinates. Results indicated that intervocalic coarticulation
      across hearing and deaf speakers varied as a function of the phonetic composition
      of disyllables (b_b or d_d). The deaf speakers showed reduced intervocalic
      coarticulation for bilabial but not for alveolar disyllables compared to the
      hearing speakers. Furthermore, they showed less marked consonant influences on
      the schwa and stressed vowel of disyllables compared to the hearing controls.
      Rate effects were minimal and did not alter the coarticulatory patterns observed
      across hearing status. The above findings modify the conclusions drawn from
      previous studies and suggest that the speech of deaf and hearing speakers is
      guided by different gestural organization.

PMID- 10420629
TI  - Compensation strategies for the perturbation of French [u] using a lip tube. II.
      Perceptual analysis.
AB  - A perceptual analysis of the French vowel [u] produced by 10 speakers under
      normal and perturbed conditions (Savariaux et al., 1995) is presented which aims
      at characterizing in the perceptual domain the task of a speaker for this vowel,
      and, then, at understanding the strategies developed by the speakers to deal with
      the lip perturbation. Identification and rating tests showed that the French [u]
      is perceptually fairly well described in the [F1, (F2-F0)] plane, and that the
      parameter (((F2-F0) + F1)/2) (all frequencies in bark) provides a good overall
      correlate of the "grave" feature classically used to describe the vowel [u] in
      all languages. This permitted reanalysis of the behavior of the speakers during
      the perturbation experiment. Three of them succeed in producing a good [u] in
      spite of the lip tube, thanks to a combination of limited changes on F1 and (F2
      F0), but without producing the strong backward movement of the tongue, which
      would be necessary to keep the [F1,F2] pattern close to the one measured in
      normal speech. The only speaker who strongly moved his tongue back and maintained
      F1 and F2 at low values did not produce a perceptually well-rated [u], but
      additional tests demonstrate that this gesture allowed him to preserve the most
      important phonetic features of the French [u], which is primarily a back and
      rounded vowel. It is concluded that speech production is clearly guided by
      perceptual requirements, and that the speakers have a good representation of
      them, even if they are not all able to meet them in perturbed conditions.

PMID- 10420631
TI  - Effect of vocal effort on spectral properties of vowels.
AB  - The effects of variations in vocal effort corresponding to common conversation
      situations on spectral properties of vowels were investigated. A database in
      which three degrees of vocal effort were suggested to the speakers by varying the
      distance to their interlocutor in three steps (close--0.4 m, normal--1.5 m, and
      far--6 m) was recorded. The speech materials consisted of isolated French vowels,
      uttered by ten naive speakers in a quiet furnished room. Manual measurements of
      fundamental frequency F0, frequencies, and amplitudes of the first three formants
      (F1, F2, F3, A1, A2, and A3), and on total amplitude were carried out. The speech
      materials were perceptually validated in three respects: identity of the vowel,
      gender of the speaker, and vocal effort. Results indicated that the speech
      materials were appropriate for the study. Acoustic analysis showed that F0 and F1
      were highly correlated with vocal effort and varied at rates close to 5 Hz/dB for
      F0 and 3.5 Hz/dB for F1. Statistically F2 and F3 did not vary significantly with
      vocal effort. Formant amplitudes A1, A2, and A3 increased significantly; The
      amplitudes in the high-frequency range increased more than those in the lower
      part of the spectrum, revealing a change in spectral tilt. On the average, when
      the overall amplitude is increased by 10 dB, A1, A2, and A3 are increased by 11,
      12.4, and 13 dB, respectively. Using "auditory" dimensions, such as the F1-F0
      difference, and a "spectral center of gravity" between adjacent formants for
      representing vowel features did not reveal a better constancy of these parameters
      with respect to the variations of vocal effort and speaker. Thus a global view is
      evoked, in which all of the aspects of the signal should be processed
      simultaneously.

PMID- 10420632
TI  - Analysis and perception of spectral 1/f characteristics of amplitude and period
      fluctuations in normal sustained vowels.
AB  - Two kinds of fluctuations are always observed in the steady parts of normal
      sustained vowels. One is amplitude fluctuation, defined as the cyclic changes of
      maximum peak amplitudes. The other is period fluctuation, defined as the cyclic
      changes of pitch periods. The primary purpose of this paper is to present
      quantitative descriptions of amplitude and period sequences obtained from normal
      sustained vowels. These fluctuation sequences consisted of maximum peak
      amplitudes or pitch periods extracted successively from 512 consecutive pitch
      periods in the steady part. Results of the frequency analysis indicated that
      their frequency characteristics seemed to be subject to the spectral 1/f power
      law. In order to investigate the possibility that the frequency characteristics
      of the fluctuation sequences influence the voice quality of sustained vowels,
      psychoacoustic experiments were conducted. Amplitude and period sequences
      evaluated in the experiments were spectral 1/f0 (white noise), 1/f, 1/f2, and
      1/f3 sequences, respectively. The experimental results indicated that the
      subjective voice quality of synthesized sustained vowels could reflect the
      differences in the frequency characteristics of the fluctuation sequences.

PMID- 10420633
TI  - The role of F1 in the perception of voice onset time and voice offset time.
AB  - An important speech cue is that of voice onset time (VOT), a cue for the
      perception of voicing and aspiration in word-initial stops. Preaspiration, an [h]
      like sound between a vowel and the following stop, can be cued by voice offset
      time, a cue which in most respects mirrors VOT. In Icelandic VOffT is much more
      sensitive to the duration of the preceding vowel than is VOT to the duration of
      the following vowel. This has been explained by noting that preaspiration can
      only follow a phonemically short vowel. Lengthening of the vowel, either by
      changing its duration or by moving the spectrum towards that appropriate for a
      long vowel, will thus demand a longer VOffT to cue preaspiration. An experiment
      is reported showing that this greater effect that vowel quantity has on the
      perception of VOffT than on the perception of VOT cannot be explained by the
      effect of F1 frequency at vowel offset.

PMID- 10420634
TI  - Context-independent dynamic information for the perception of coarticulated
      vowels.
AB  - Most investigators agree that the acoustic information for American English
      vowels includes dynamic (time-varying) parameters as well as static "target"
      information contained in a single cross section of the syllable. Using the silent
      center (SC) paradigm, the present experiment examined the case in which the
      initial and final portions of stop consonant-vowel-stop consonant (CVC) syllables
      containing the same vowel but different consonants were recombined into mixed
      consonant SC syllables and presented to listeners for vowel identification. Ten
      vowels were spoken in six different syllables, /b Vb, bVd, bVt, dVb, dVd, dVt/,
      embedded in a carrier sentence. Initial and final transitional portions of these
      syllables were cross-matched in: (1) silent-center syllables with original
      syllable durations (silences) preserved (mixed-consonant SC condition) and (2)
      mixed-consonant SC syllables with syllable duration equated across the ten vowels
      (fixed duration mixed-consonant SC condition). Vowel-identification accuracy in
      these two mixed consonant SC conditions was compared with performance on the
      original SC and fixed duration SC stimuli, and in initial and final control
      conditions in which initial and final transitional portions were each presented
      alone. Vowels were identified highly accurately in both mixed-consonant SC and
      original syllable SC conditions (only 7%-8% overall errors). Neutralizing
      duration information led to small, but significant, increases in identification
      errors in both mixed-consonant and original fixed-duration SC conditions (14%-15%
      errors), but performance was still much more accurate than for initial and finals
      control conditions (35% and 52% errors, respectively). Acoustical analysis
      confirmed that direction and extent of formant change from initial to final
      portions of mixed-consonant stimuli differed from that of original syllables,
      arguing against a target + offglide explanation of the perceptual results.
      Results do support the hypothesis that temporal trajectories specifying "style of
      movement" provide information for the differentiation of American English tense
      and lax vowels, and that this information is invariant over the place of
      articulation and voicing of the surrounding stop consonants.

PMID- 10420635
TI  - Functional neuroimaging of speech perception in six normal and two aphasic
      subjects.
AB  - This positron emission tomography study used a correlational design to
      investigate neural activity during speech perception in six normal subjects and
      two aphasic patients. The normal subjects listened either to speech or to signal
      correlated noise equivalents; the latter were nonspeech stimuli, similar to
      speech in complexity but not perceived as speechlike. Regions common to the
      auditory processing of both types of stimuli were dissociated from those specific
      to spoken words. Increasing rates of presentation of both speech and nonspeech
      correlated with cerebral activity in bilateral transverse gyri and adjacent
      superior temporal cortex. Correlations specific to speech stimuli were located
      more anteriorly in both superior temporal sulci. The only asymmetry in normal
      subjects was a left lateralized response to speech in the posterior superior
      temporal sulcus, corresponding closely to structural asymmetry on the subjects'
      magnetic resonance images. Two patients, who had left temporal infarction but
      performed well on single word comprehension tasks, were also scanned while
      listening to speech. These cases showed right superior temporal activity
      correlating with increasing rates of hearing speech, but no significant left
      temporal activation. These findings together suggest that the dorsolateral
      temporal cortex of both hemispheres can be involved in prelexical processing of
      speech.

PMID- 10420636
TI  - Acoustic evidence for dynamic formant trajectories in Australian English vowels.
AB  - The extent to which it is necessary to model the dynamic behavior of vowel
      formants to enable vowel separation has been the subject of debate in recent
      years. To investigate this issue, a study has been made on the vowels of 132
      Australian English speakers (male and female). The degree of vowel separation
      from the formant values at the target was contrasted to that from modeling the
      formant contour with discrete cosine transform coefficients. The findings are
      that, although it is necessary to model the formant contour to separate out the
      diphthongs, the formant values at the target, plus vowel duration are sufficient
      to separate out the monophthongs. However, further analysis revealed that there
      are formant contour differences which benefit the within-class separation of the
      tense/lax monophthong pairs.

PMID- 10420637
TI  - A microcosm of musical expression. III. Contributions of timing and dynamics to
      the aesthetic impression of pianists' performances of the initial measures of
      Chopin's Etude in E major.
AB  - Four judges repeatedly assessed the overall aesthetic quality of more than 100
      recorded performances of the opening of Chopin's Etude in E major on a 10-point
      scale. The judgments, which exhibited reasonable reliability and modest
      intercorrelations, were entered into regression analyses with 16 independent
      variables derived from earlier objective analyses of the expressive timing and
      dynamics of the performances [Repp, J. Acoust. Soc. Am. 104, 1085-1100 (1998);
      105, 1972-1988 (1999)]. Only between 9% and 18% of the variance in the judges'
      ratings was accounted for. By contrast, timing variables accounted for 53% of the
      variance in one judge's ratings of synthesized performances that varied in timing
      only and mimicked the timing patterns of the original performances. These results
      indicate, first, that the aesthetic impression of the original recordings rested
      primarily on aspects other than those measured (such as texture, tone, or aspects
      of timing and dynamics that eluded the earlier analyses) and, second, that very
      different patterns of timing and dynamics are aesthetically acceptable for the
      same music, provided that other, aesthetically more crucial performance aspects
      are present.

PMID- 10420638
TI  - Cortical representation of spatiotemporal pattern of firing evoked by
      echolocation signals: population encoding of target features in real time.
AB  - Target perception in echolocating bats entails the generation of an acoustic
      image of the target in the auditory cortex. By integrating information conveyed
      in the sequence of acoustic echoes, the population of cortical neurons in
      hypothesized to encode different target features based on its spatiotemporal
      pattern of neural-spike firing during the course of echolocation. A biologically
      plausible approach to the cortical representation of target features is employed
      by using electrophysiological data recorded from the auditory cortex of the FM
      bat, Myotis lucifugus. A single-neuron model of delay-sensitive neurons is first
      approximated by the formulation of a Gaussian function with different variables
      to represent the delay-tuning properties of individual cortical neurons. A
      cortical region consisting of delay-sensitive neurons organized topographically
      according to best frequency (i.e., tontopically organized) is then modeled with
      multiple layers of the single-neuron model. A mechanism is developed to represent
      and encode the responses of these neurons based on time-dependent, incoming echo
      signals. The time-varying responses of the population of neurons are mapped
      spatially on the auditory-cortical surface as a cortical response map (CORMAP).
      The model is tested using phantom targets with single and multiple glints. These
      simulation results provide further validation of the current auditory framework
      as a biomimetic mechanism for capturing time-varying, acoustic stimuli impinging
      in the bat's ears, and the neural representation of acoustic stimulus features by
      saptiotemporal-firing patterns in the cortical population.

PMID- 10420639
TI  - Vocal production mechanisms in the budgerigar (Melopsittacus undulatus): the
      presence and implications of amplitude modulation.
AB  - In this paper acoustic evidence is presented for the presence of amplitude
      modulation in budgerigar (Melopsittacus undulatus) contact calls and learned
      English vocalizations. Previously, acoustic analyses of budgerigar vocalizations
      have consisted solely of visual inspection of spectrograms or power spectra
      (derived from Fourier transformation). Such analyses have led researchers to
      conclude that budgerigar vocalizations are primarily frequency-modulated,
      harmonic vocalizations. Although budgerigar calls have been shown to contain
      regions that are modulated in amplitude, the implications of this fact have been
      largely ignored. Amplitude modulation, the nonlinear interaction between two
      separate signals that results in the creation of new, heterodyne (sum and
      difference) frequencies, can produce a very complex Fourier spectrum that may
      resemble that produced by a harmonic vocalization. In this paper, the acoustic
      principles necessary for identifying amplitude modulation present in signals are
      outlined, and followed by data demonstrating that amplitude modulation is a
      prominent feature not only of natural budgerigar contact calls, but also of their
      learned English vocalizations. It is illustrated how analyzing a vocalization
      that contains amplitude modulation as if it were harmonic can result in
      misinterpretations of the acoustic and physical properties of the sound and sound
      source. The implications of amplitude modulation for studies of the ontogenetic,
      physical, and neural basis of budgerigar vocalizations are discussed, and a
      potential model for how the budgerigar syrinx may function to produce amplitude
      modulation is proposed.

PMID- 10420640
TI  - Acoustic detections of singing humpback whales (Megaptera novaeangliae) in the
      eastern North Pacific during their northbound migration.
AB  - Numerous (84) acoustic detections of singing humpback whales were made during a
      spring (08 March-09 June 1997) research cruise to study sperm whales in the
      central and eastern North Pacific. Over 15,000 km of track-line was surveyed
      acoustically using a towed hydrophone array. Additionally, 83 sonobuoys were
      deployed throughout the study area. Detection rates were greatest in late March,
      near the Hawaiian Islands, and in early April, northeast of the islands. Only one
      detection was made after April. Detection rates for sonobuoys were unequal in
      three equally divided longitudinal regions of the study area. Two high density
      clusters of detections occurred approximately 1200-2000 km northeast of the
      Hawaiian Islands and were attributed to a large aggregation of migrating animals.
      The distribution of these detections corroborates findings of previous studies.
      It is possible that these animals were maintaining acoustic contact during
      migration. Two unexpected clusters of singing whales were detected approximately
      900 to 1000 km west of central and southern California. The location of these
      detections may indicate a previously undocumented migration route between an
      offshore breeding area, such as the Revillagigedo Islands, Mexico, and possible
      feeding areas in the western North Pacific or Bering Sea.

PMID- 10420641
TI  - Stoichiometric analysis of protein- and nucleic acid-based structures in the cell
      nucleus.
AB  - We describe a method to image selectively the protein-based architecture in the
      eukaryotic cell nucleus using nitrogen and phosphorus mapping. In addition, we
      describe a method to determine total mass as well as stoichiometric relationships
      between protein and RNA. This method is illustrated using particulate structures
      in the nucleus called interchromatin granules. In so doing, we demonstrate that
      these granules contain heterogeneous nuclear RNA, and have an average protein and
      RNA content of 3.094 and 1.672 MDa, respectively. We also tested the sensitivity
      of phosphorus detection by exogenously applying purified duplex DNA to the
      surfaces of thin sections, and have shown that structures as small as single
      molecules of duplex DNA can be detected in situ using these electron
      spectroscopic imaging techniques.

PMID- 10420642
TI  - Microfabrication techniques using focused ion beams and emergent applications.
AB  - The application of focused ion beam (FIB) machining in several technologies aimed
      at microstructure fabrication is presented. These emergent applications include
      the production of micromilling tools for machining of metals and the production
      of microsurgical tools. An example of the use of microsurgical manipulators in a
      circulatory system measurement is presented. The steps needed to transform the
      laboratory fabrication of these tools and manipulators into a routine FIB
      production process are discussed. The ion milling of three-dimensional cavities
      by the exact solution of a mathematical model of the FIB deflection is
      demonstrated. A good agreement between the model calculation and the ion beam
      control has been obtained for parabolic and cosine cross-section features with
      planes of symmetry.

PMID- 10420643
TI  - A new D-type cyclin of Arabidopsis thaliana expressed during lateral root
      primordia formation.
AB  - D-type cyclins are believed to regulate the onset of cell division upon mitogenic
      signaling. Here, the isolation is reported of a new D-type cyclin gene (CYCD4;1)
      of Arabidopsis thaliana (L.) Heynh. during a two-hybrid screen using the cyclin
      dependent kinase CDC2aAt as bait. Transcription of CYCD4;1 can be induced by
      sucrose. The co-regulated expression of CYCD4;1 and CDC2aAt in starved suspension
      cultures upon mitogenic stimulation indicates that the formation of a complex
      between these two partners is important for the resumption of cell division
      activity. By in-situ hybridizations CYCD4;1 was shown to be expressed during
      vascular tissue development, embryogenesis, and formation of lateral root
      primordia. Expression during the latter process suggests that the induced
      expression of D-type cyclins by mitogenic stimuli might be one of the rate
      limiting events for the initiation of lateral roots.

PMID- 10420644
TI  - Structure and regulation of the Arabidopsis thaliana allene oxide synthase gene.
AB  - Allene oxide synthase (AOS) is encoded by a single intronless gene in Arabidopsis
      thaliana (L.) Heynh. The promoter region of the AOS gene exhibits, in addition to
      the clements of a minimal promoter and the presence of general enhancers, cis
      elements that, in other promoters, are responsible for stress- and
      ethyleneresponsiveness. Arabidopsis thaliana and Nicotiana tabacum L. were
      transformed with a chimaeric gene consisting of a 1.9-kb 5'-upstream sequence and
      the first 95 nucleotides of the AOS coding sequence translationally fused to uidA
      encoding beta-glucuronidase (GUS). Using histochemistry, GUS activity was seen in
      older leaves, in the bases of petioles and in stipules, during the early stages
      of carpel development, in maturing pollen grains and at the base of elongated
      filaments, as well as in abscission-zone scars. A role for jasmonates in floral
      organ abscission is suggested by these findings. Furthermore, the AOS promoter
      was activated both locally as well as systemically upon wounding. Jasmonic acid,
      12-oxophytodienoic acid and coronatine strongly induced GUS activity. This
      induction remained confined to the treated leaf when agonists were applied
      locally to a leaf, suggesting that neither jasmonic acid nor 12-oxophytodienoic
      acid are physiologically relevant components of the systemic wound signal
      complex. Rather, the data show that jasmonates behave as local response
      regulators produced at or around the sites of action in response to appropriate
      triggers of their synthesis.

PMID- 10420646
TI  - Cloning and functional analysis of a cDNA encoding a starch synthase from potato
      (Solanum tuberosum L.) that is predominantly expressed in leaf tissue.
AB  - Three isoforms of starch synthase (SS) were shown to be present in soluble potato
      tuber extracts by activity staining after native gel electrophoresis. A cDNA
      encoding SSI from rice was used as a probe to clone a corresponding cDNA from
      potato. The deduced amino acid sequence identified the protein as an SS from
      potato with an M(r) of 70.6 kDa for the immature enzyme including its transit
      peptide. This novel isoform was designated SSI. An analysis of the expression
      pattern of the gene indicated that SSI is predominantly expressed in sink and
      source leaves, and, to a lower extent in tubers. In several independent
      transgenic potato lines, where the expression of SSI was repressed using the
      antisense approach, the activity of a specific SS isoform was reduced to non
      detectable levels as determined through activity staining after native gel
      electrophoresis. The reduction in the amount of this isoform of SS did not lead
      to any detectable changes in starch structure, probably due to the fact that this
      isoform only represents a minor activity in potato tubers.

PMID- 10420650
TI  - Cloning and expression of an arginine decarboxylase cDNA from Vitis vinifera L.
      cell-suspension cultures.
AB  - Arginine decarboxylase (ADC; EC 4.1.1.19) is a key enzyme in one of the two
      pathways to putrescine. We present the first ADC cDNA from a woody perennial
      plant species, the grapevine (Vitis vinifera L.), which exhibits 70-80% homology
      with other dicot ADCs. The effects of ammonium, nitrate, and putrescine on ADC
      specific activity, soluble polyamine levels, ADC-mRNA, endogeneous arginine and
      ornithine, and arginase specific activity were investigated in suspension
      cultures of grapevine cells. The addition of NH4+ to cells cultured in NH4(+)
      free medium, resulted in a 4-fold increase in ADC activity and concomitantly in a
      4-fold increase in putrescine and a 3-fold decrease in arginine. During this
      period ornithine increased and arginase activity followed a reverse pattern of
      changes compared with ADC. In contrast, the addition of NO3- did not markedly
      affect ADC activity, putrescine, arginine and ornithine, but transiently
      increased arginase activity. The addition of putrescine caused a 4-fold decrease
      in ADC activity and increased arginine, ornithine and arginase activity. The
      changes in ADC specific activity were not accompanied by analogous changes in the
      ADC transcript levels. These results further support the view that ADC regulation
      is not exhibited, at least for the factors considered in this work, at the
      transcriptional level.

PMID- 10420651
TI  - Composition and role of tapetal lipid bodies in the biogenesis of the pollen coat
      of Brassica napus.
AB  - The composition of the two major lipidic organelles of the tapetum of Brassica
      napus L. has been determined. Elaioplasts contained numerous small (0.2-0.6
      micron) lipid bodies that were largely made up of sterol esters and
      triacylglycerols, with monogalactosyldiacylglycerol as the major polar lipid.
      This is the first report in any species of the presence of non-cytosolic, sterol
      ester-rich, lipid bodies. The elaioplast lipid bodies also contained 34- and 36
      kDa proteins which were shown by N-terminal sequencing to be homologous to
      fibrillin and other plastid lipid-associated proteins. Tapetosomes contained
      mainly polyunsaturated triacylglycerols and associated phospholipids plus a
      diverse class of oleosin-like proteins. The pollen coat, which is derived from
      tapetosomes and elaioplasts, was largely made up of sterol esters and the C
      terminal domains of the oleosin-like proteins, but contained virtually no
      galactolipids, triacylglycerols or plastid lipid-associated proteins. The sterol
      compositions of the elaioplast and pollen coat were almost identical, consisting
      of stigmasterol > campestdienol > campesterol > sitosterol >> cholesterol, which
      is consistent with the majority of the pollen coat lipids being derived from
      elaioplasts. These data demonstrate that there is substantial remodelling of both
      the lipid and protein components of elaioplasts and tapetosomes following their
      release into the anther locule from lysed tapetal cells, and that components of
      both organelles contribute to the formation of the lipidic coating of mature
      pollen grains.

PMID- 10420652
TI  - Stress-induced expression of cyclophilins in proembryonic masses of Digitalis
      lanata does not protect against freezing/thawing stress.
AB  - Using proembryonic masses (PEMs) of Digitalis lanata Erh., it was demonstrated
      that cold, hormonal or osmotic stress, which increased freezing tolerance during
      cryopreservation, induced an increasing level of two peptidyl-prolyl
      cis/transisomerases (PPIases). The difference in pI (9.2 +/- 0.2 and 9.5 +/- 0.2,
      +/- SD; n = 3) allowed the separation of the two enzymes by free-flow
      isoelectrophoresis. Both were inhibited by cyclosporin A and thus belong to the
      cyclophilin family of PPIases. The enzymes differed slightly in their substrate
      specificity and their relative molecular masses of 18038 +/- 4 Da (D.
      lanataCyp18.0) and 18132 +/- 3 Da (D. lanataCyp18.1). Both cyclophilins were
      blocked N-terminally. Partial internal amino acid sequences from the two
      cyclophilins, with a length of 34 amino acids, displayed 82% sequence identity to
      each other. Pretreatment of PEMs with abscisic acid, sorbitol or a combination of
      both substances led to a 270 +/- 30% elevation of the total cytosolic cyclophilin
      concentration determined with a cyclophylin affinity sensor. During the first 4 d
      of pretreatment, the total PPIase activity was enhanced up to 230 +/- SD%
      compared with the control culture. The lag phase between maximal PPIase
      concentration after 4 d of pretreatment and maximal effect of freezing tolerance
      after 10 d of pretreatment indicated that increasing levels of cytosolic PPIases
      may be necessary to overcome the stress induced by hormones and osmotica during
      pretreatment but not to protect against freezing/thawing stress.

PMID- 10420654
TI  - Characterization of the Bacillus macerans cyclodextrin glucanotransferase
      overexpressed in Escherichia coli.
AB  - Cyclodextrin glucanotransferase (CGTase, EC 2. 4. 1. 19) converts starch and
      related alpha-1,4-glucans to cyclodextrin (CD). Our previous studies of the
      enzyme have suggested that E344 on the polypeptide is crucial to the enzyme
      activity. Mutational analysis of CGTase was performed to confirm this idea. Three
      mutant CGTases containing either E344D, E344K or E344L substitution were
      overexpressed in Escherichia coli. However, only the wild-type and E344D CGTases
      became soluble when expressed at 20 degrees C. These two enzymes were purified to
      homogeniety from E. coli cells after beta-CD and Ni-NTA affinity
      chromatographies. The Km values of the authentic Bacillus macerans CGTase (2.10
      mM), and of the wild-type (0.58 mM) and E344D (1.05 mM) CGTases purified from E.
      coli were different. The kcat values of the three CGTases were 99.8, 26.5 and
      90.7 s-1, respectively. The percentage of alpha-CD production was 18.4% for the
      authentic CGTase, 24.9% for the wild-type and 14.5% for the E344D CGTases
      purified from E. coli. The changes of both the coupling and cyclization
      activities of CGTase caused by E344D suggest that E344 is important to the
      catalytic function of CGTase.

PMID- 10420655
TI  - Characterization of a putative Pseudomonas UDPglucose pyrophosphorylase.
AB  - A UDP-glucose pyrophosphorylase encoding gene was identified through functional
      complementation screening by using an Escherichia coli galU mutant. Sequence
      analysis of the gene indicated that it is most likely derived from a Pseud monas
      sp. The gene is located immediately upstream and transcribed in the same
      direction of the gor (glutathione reductase) gene and is capable of encoding a
      protein 30,943 daltons in size. The gene product synthesized in Escherichia coli
      was purified and its biochemical properties characterized. The recombinant UDP
      glucose pyrophosphorylase exhibited a molecular weight of 130 kDa, suggesting a
      tetrameric organization of the gene product. Two mutant forms of the enzyme were
      identified. The activity of the mutant enzyme with a tyrosine to histidine (Y26
      1H) substitution was found to be greatly reduced. On the other hand, the tyrosine
      to cysteine (Y84C) substitution resulted in an enzyme that functions normally at
      37 degrees C but rather poorly at temperatures lower than 30 degrees C.

PMID- 10420656
TI  - An appreciation.

PMID- 10420658
TI  - The power of one: self-advocacy. How do you eat an elephant? One bite at a time.

PMID- 10420657
TI  - Assistive technology for dyslexia.

PMID- 10420660
TI  - Getting what you're worth: valuable lessons.

PMID- 10420661
TI  - Weaving research into your clinical speech-language pathology practice.
AB  - A myth exists that the fabric of practicing clinicians in audiology and speech
      language pathology rarely intertwines with that of the researcher. In fact, there
      are many instances where the fabrics overlap and are dependent upon each other.
      The opportunities that exist for weaving these two different (but similar) cloths
      together are immense. The benefits to professional development, scientific
      discovery, and ultimately, effective patient care are too numerous to mention in
      this short text (so numerous, in fact, that this article will deal only with
      speech-language pathology; look to a future Asha for a discussion of the
      interdependence of clinical audiology and research.

PMID- 10420659
TI  - Interpreting a living will after stroke.
AB  - Mr. Duffy is 83 years old and is admitted to rehabilitation 4 weeks after a right
      thalamic cerebral vascular accident (CVA). He has dysphagia, dysarthria, left
      hemiplegia, and is moderately-severely confused. He pulls out his nasogastric
      feeding tube and his physician decides not to reinsert it because of significant
      nasal tissue necrosis. The team recommends a gastrostomy tube for nutrition
      because of Mr. Duffy's lack of alertness and high risk for aspiration. Mr. Duffy
      has a Living Will that states he does not wish to have his life sustained with a
      feeding tube. He does not have a formal Durable Power of Attorney for Health
      Care. His wife has dementia and their daughters are making decisions for both
      parents. They are not sure about his wishes in this particular circumstance, but
      report that he said of a relative who died of cancer, "things went on too long
      because of that feeding tube." After 3 days, Mr. Duffy is more alert, and during
      a discussion about tube feedings he says, "I'll go for the works." His
      fluctuating alertness level prevents him from responding to this question again.
      His daughters feel he would not want the tube and suggest waiting to see if his
      swallowing improves in the next week before making a decision.

PMID- 10420662
TI  - National Institutes of Health, Warren Grant Magnuson Clinical Center.

PMID- 10420663
TI  - The concept of a minimal competence core shows assessment promise.

PMID- 10420664
TI  - Inclusive practices and service delivery models for preschool children with
      speech and language disorders.

PMID- 10420677
TI  - Free/total prostate specific antigen ratio: a new hope.

PMID- 10420678
TI  - Clinical, morphological, immunological correlation of kidney biopsies and
      prognostication.
AB  - Twenty seven ANA and dsDNA positive cases were selected from surgical files from
      years 1986 to 1997. Clinical, biochemical, morphological and immunofluorescence
      findings were correlated. Routine Haematoxylin and Eosin, Per iodic-Acid-Schiff
      and Methaneamine-Silver stains were used for all cases. Direct immunofluorescence
      was done whenever possible. Morphologically cases were grouped as per WHO
      criteria. Morphologically cases were quantified into Austin's chronicity and
      activity indices. Twenty one to thirty years was common age group. M:F:: 1:4.4.
      Anemia, skin rash and arthralgia were common extra-renal manifestations. There
      were 1,5,7,10 and three cases as per WHO class I to V respectively. All cases of
      class IV had active urine sediments and proteinuria. Four cases had high BUN and
      Serum creatinine levels. All (12) cases of immunofluorescence revealed group
      specific patterns. Five cases died. Infection was common cause of death. Twenty
      to thirty years, males, High BUN and Creatinine levels and high activity and
      chronicity indices were associated with poor prognosis.

PMID- 10420679
TI  - Diagnostic utility of ELISA test using antigen A60 in suspected cases of
      tuberculous meningitis in paediatric age group.
AB  - The aim of the study was evaluation of the utility of ELISA test using antigen
      A60 for rapid diagnosis of tuberculous menigitis (TBM) in paediatric age group.
      ELISA test based on mycrobacterial antigen A60 (Anda biological, France) was used
      to estimate specific IgM and IgG antibodies in the sera and CSF of 20 suspected
      cases of TBM which were selected on the basis of numerous parameters and were
      smear negative on concentrated smear of CSF. Sera of 20 Montoux negative healthy
      children was taken as control by detecting IgM and IgG antibodies to A60 antigen.
      Response to anti-tubercular treatment was observed in all the suspected cases of
      TBM. This study showed that specificity for diagnosis of TBM by detecting IgM and
      IgG antibodies in sera was 90% and 80% respectively. Sensitivity of the test by
      detecting IgM and IgG antibodies in sera was 85% and 80% respectively with
      positive predictive value of 89.47% for IgM antibody and 80% for IgG antibody. In
      CSF IgM and IgG antibodies were found in 75% and 60% cases respectively. Both
      were positive only in 60% of cases. It is concluded from this study that 80-85%
      cases of TBM in paediatric age group have eigher IgM or IgG antibodies in sera
      whereas 60-75% have antibodies in CSF.

PMID- 10420680
TI  - T cell rich B cell lymphoma (TCRBCL): study of sixteen cases with review of
      literature.
AB  - T cell rich B cell lymphoma (TCRBCL) is a recently described variant of diffuse
      non Hodgkin's lymphoma (NHL), the acronym of which has gained wide acceptance
      among hematopathologists in a relatively shorter period of time. The recognition
      of this entity requires immunohistochemical facilities especially on paraffin
      embedded tissues. TCRBCL is one of the many examples in the diagnostic anatomic
      pathology which emphasizes the need of immunocytochemistry and availability of
      this technique at least in referral laboratories. One of the differential
      diagnosis in this case includes lymphocyte predominance Hodgkin's disease (LPHD)
      which is the most favorable prognostic histologic subtype of Hodgkin's disease
      (HD) while TCRBCL is an aggressive B Cell NHL and should be treated as high grade
      large cell lymphoma. The other close differential includes peripheral T cell non
      Hodgkin's lymphoma (PTCL). We reported sixteen (16) cases of TcRBCL diagnosed
      during a period of two and a half years (January 1995 to June 1997). HD and PTCL
      were the main differential diagnoses in most of these cases. The median age at
      diagnosis was 39 years and male to female ratio was equal. TCRBCL was nodal in
      location in 15 cases and a single case in extranodal site presenting as spinal
      tumor. The mean neoplastic B cell population was 12%, while that of reactive T
      cells was 82%. A significant polymorphous inflammatory cellular background was
      noted in 5 cases. Reed-Stenberg like cells were observed in 3 cases.
      Immunoglobulin light chain restriction studies were performed in fourteen cases
      and revealed lambda light chains in ten cases while in four cases kappa light
      chains were present.

PMID- 10420682
TI  - Platelet auto-antibodies in septicaemic patients.
AB  - Thrombocytopenia associated with acute Septicaemia has been reported which may be
      due to Disseminated Intravasscular Coagulation (DIC), but has also been reported
      even without any evidence of it. An immunological cause has been suggested to
      explain this observation. The present study involved the investigation of 50
      patients with clinical and bacteriological evidence of Septicaemia. By Direct
      Platelet Suspension Immunofluorescence Test (PSIFT) antiplatelet antibodies were
      detected in 54% patients with septicaemia and 67.5% with those having
      thrombocytopenia. The septicaemic patients were treated with antibiotics (mean 14
      days). After successful treatment, i.e., when there was no bacteriological
      evidence of septicaemia, there was in increase in the platelet count (> 150 x
      10(9)/L) with a corresponding fall in "PSIFT" positivity in 17 cases (P < 0.001).
      Hence an immunological process is considered to play a significant role in the
      pathogenesis of thrombocytopenia in these patients with septicaemia.

PMID- 10420681
TI  - Polymicrobial etiology of dental caries.
AB  - The present study was carried out to establish the normal bacterial oral flora
      and the aerobic and anaerobic bacterial flora from deep seated dental caries, and
      to determine the antimicrobial sensitivity of the clinical isolates so obtained
      Streptococcus mutans (48%) and Streptococcus sanguis (20%) were the main aerobic
      isolates whereas Lactobacillus spp. (52%), Veillonella spp. (24%) and Actinomyces
      spp. (12%) were the major anaerobic isolates. Hundred percent of the samples from
      dental caries yielded polymicrobial isolates while in two samples from healthy
      individuals S. mutans was the sole isolate. As the flora changed from healthy
      tooth to dental caries it changed from one predominated by anaerobic gram
      positive cocci to anaerobic gram-positive bacilli. All the anaerobes isolated
      were sensitive to metronidazole and cefotaxime, whereas all the isolated
      streptococci were sensitive to penicillin, erythromycin and clindamycin.
      Incorporation of the antibiotics in baseline restoration, if technically
      feasible, has been advocated.

PMID- 10420683
TI  - Immunological assessment of infertility by estimation of antisperm antibodies in
      infertile couples.
AB  - 160 clinical samples were collected from 40 infertile couples with unexplained
      infertility. The samples collected included serum and seminal plasma of the male
      partners and serum and cervical mucus samples of the female partners. 25 fertile
      healthy couples were investigated as controls. All the samples collected were
      then tested for class-specific antisperm antibodies by an Enzyme linked
      immunosorbent assay (ELISA). Antisperm antibodies were detected in 30% of the
      infertile couples which included 25% female and 10% male partners. Amongst the
      cases positive for antisperm antibodies, antibodies were detected most frequently
      in female sera 58.4% followed by male sera 33% and 25% in cervical mucus. The
      isotyping of antisperm antibodies in various samples showed IgG to be the most
      frequent type specific antibody followed by IgM & IgA types of antibodies. ELISA
      has provided a relatively simple, reliable and highly reproducible method of
      detection of antisperm antibodies. Thus application of antisperm antibody testing
      especially in cervical mucus should become an integral part of the investigation
      of immunologic infertility.

PMID- 10420684
TI  - Renal lesions in AIDS: a biopsy and autopsy study.
AB  - We studied renal lesions at biopsy (20 cases) and at autopsy (21 cases) among
      patients with the acquired immune deficiency syndrome (AIDS). Nephrotic syndrome
      with concomitant renal insufficiency was most common indication for biopsy. 85
      percent of biopsies showed features of HIV associated nephropathy (HIVAN) which
      include: Focal segmental glomerulosclerosis (FSGS), glomerular collapse and
      mesangial hyperplasia. These glomerular changes were always accompanied by
      tubular microcysts and ultrastructurally, tubuloreticular inclusions (TRI) within
      the glomerular endothelium were often noted. Changes of HIVAN were also seen in
      two cases who were HIV negative at the time of biopsy but were positive on repeat
      testing. Minimal change disease, mesangiocapillary glomerulonephritis and diffuse
      proliferative lupus nephritis were other biopsy lesions. Autopsy findings were
      HIVAN (33 percent), tubular necrosis and opportunistic infections. We conclude
      that HIVAN is a distinct clinicopathologic entity that may sometimes be the first
      manifestation of the underlying disease state.

PMID- 10420685
TI  - Red cell indices and discriminant functions in the detection of beta-thalassaemia
      trait in a population with high prevalence of iron deficiency anaemia.
AB  - Red cell indices and discriminant functions were studied in 463 heterozygous beta
      thalassaemics (337 without iron deficiency, 126 with iron deficiency) and 195
      patients of iron deficiency anaemia (IDA) to ascertain their utility in the
      detection of betathalassaemia trait (BTT). Majority of traits in both groups had
      an elevated RBC count (> or = 5.0 x 10(12)/L). The counts were significantly
      higher than of patients with IDA, only 4.6% of whom had this degree of
      erythrocytosis. Mean Hb concentration was significantly higher in traits as
      compared to iron deficient subjects (p < 0.0001). Mean MCV and MCH were
      significantly (p < 0.0001) lower in traits more so in those with ID as compared
      to patients of IDA. MCV < 80 fl and MCH < 27 pg were found to be sensitive
      markers in the detection of traits even in the presence of ID. Of the four
      discriminant functions studied MCSQ was found to be most sensitive in detection
      of BTT and it identified 97.9% traits. DF of England and Fraser was most specific
      for BTT being < 8.4 in only 6.2% patients with IDA. Detection of erythrocytosis
      especially in the presence of mild anaemia and calculation of discriminant
      functions derived from red cell indices were found to play an important role in
      screening for BTT even in the presence of ID and helped identify those patients
      who required further laboratory evaluation.

PMID- 10420686
TI  - Renal lesions associated with AIDS--an autopsy study.
AB  - Kidneys from 55 cases (20 with HIV infection and 35 with AIDS) were studied by
      routine Haematoxylin and Eosin stains and special stains (PAS, PASM GMS, ZN,
      Mucicarmine and Congo red) to evaluate, glomerular, interstitial and vascular
      pathology. Twenty-four of the 35 (68.6%) cases of AIDS showed infective aetiology
      which included 17 cases (48.5%) of tuberculosis, 5 cases (14.4%) of fungal
      infection (3 cryptococcus neoformans and 2 candida species) and 2 cases (5.7%) of
      CMV infection. Other lesions noted were amyloidosis and tubular calcinosis. HIV
      associated nephropathy (HIVAN) was not detected in any of the cases. Intravenous
      drug abuse was not a risk factor in our cases which probably explains the absence
      of HIV associated nephropathy in the present study.

PMID- 10420687
TI  - Cytomorphological spectrum of cysticercosis--a review of 132 cases.
AB  - A retrospective analysis of fine needle aspirates of 132 cases of cysticercosis
      presenting as palpable nodule is presented. In 98 cases, larval parts, detached
      hooklets and scolex established the diagnosis; in another 34 cases, the
      background inflammatory pattern was helpful in suggesting the diagnosis of a
      parastic lesion.

PMID- 10420688
TI  - Study of gastric carcinomas with special reference to intestinal metaplasia.
AB  - An attempt was made to classify 61 cases of gastric carcinomas according to
      Lauren's classification from the period January 1992-December 1993. All the
      gastrectomy specimens resected for carcinoma of stomach were included in the
      study. Of 61 cases, 57 were classifiable according to Lauren's criteria. 38
      (62.3%) were of intestinal type and 19 (31.1%) were of diffuse type. 4 cases
      could not be classified into either group. There were significant correlation of
      type III intestinal metaplasia with intestinal type gastric carcinoma.

PMID- 10420689
TI  - A study of mycotic keratitis in Mumbai.
AB  - A total of 1010 clinically suspected cases of mycotic keratitis were studied from
      1988 to 1996 for evidence of fungal infection and for identification of the
      aetiologic agents of keratitis in Mumbai. Of these 367 cases were reported
      positive by microscopy and culture. Seventy nine percent of the cases were
      between the ages 21 and 50 years. Male patients were more often affected than
      females. Eighty eight percent of patients were farmers or construction workers
      and 89.92% of cases gave a definite history of antecedent corneal trauma. A
      single fungal isolate was obtained in 307 cases and multiple isolates in 20
      cases. Mixed isolates of bacteria and fungi were grown in 40 cases. The
      predominant isolate was Aspergillus species in 219 cases, followed by Candida
      species (36), Fusarium species (33) and Penicillium species (34). Filamentous
      fungal isolates from 22 cases remained unidentified. Mycotic keratitis should be
      suspected in every patient with a corneal lesion and should be ruled out before
      commencing steroids and antiboitics.

PMID- 10420691
TI  - Secretory carcinoma of breast in an elderly female.
AB  - Secretory carcinoma is the currently preferred designation for a unique neoplasm
      earlier thought to be exclusive to the adolescent/pre-menarchal breast. The
      neoplasm has a predilection for juveniles and young adults (< 30 years of age),
      becoming progressively less common with advancing age. This report is of one such
      instance in a 52 year old female, a rare occurrence in the elderly (> 50 years of
      age), with only five earlier cases on record in the English literature.

PMID- 10420690
TI  - Xanthogranulomatous oophoritis--a case report.
AB  - This is a case of a 25 year old unmarried women who presented with intermittent
      fever and lower abdominal pain. Laparotomy revealed a large cystic left sided
      tuboovarian mass adherent to surrounding structures and containing foul smelling
      fluid. Microscopy showed extensive replacement of the ovary by a chronic
      inflammatory exudate composed predominantly of foamy macrophages.

PMID- 10420692
TI  - Sclerosing stromal tumour of the ovary--a case report.
AB  - Sclerosing stromal tumour (SST) of the ovary is a rare, benign tumour of the
      ovary, distinct from thecoma-fibroma group of tumours because of predominant
      occurrence below 30 years of age, lack of hormonal manifestations and histologic
      heterogenity. A case of 17-year-old female patient is described in the present
      article. The differential diagnosis is also discussed.

PMID- 10420693
TI  - Phlegmonous inflammation of gastrointestinal tract autopsy study of three cases.
AB  - Three cases of Phlegmonous inflammation of gastrointestinal tract detected at
      necropsy are described. Predisposing factors were seen in all three cases. These
      were chronic alcoholism with submissive hepatic necrosis (HbsAg and HbcAg
      positive) in Case 1, Indian Childhood cirrhosis in Case 2 and acute on chronic
      Budd Chiari syndrome in Case 3. In case 1 and 3 the inflammation was limited to
      the large intestine where as in Case 2 it was seen both in the stomach and large
      intestine. In two of the three cases blood culture grew Staphylococcus aureus
      (Case 1) and gram negative organisms (Case 2).

PMID- 10420694
TI  - Spectrum of cystic variants of Wilm's tumour: cystic nephroma (multilocular cyst)
      and cystic partially differentiated nephroma--a report of four cases.
AB  - Two cases of cystic nephroma (multilocular cyst of the kidney), and one case each
      of cystic partially differentiated nephroblastoma (CPDN) and rhabdomyomatous
      Wilms' tumour are described. All were male and in the pediatric age group.
      Grossly tumours were unilateral, unicentric and multiloculated. The need for
      proper designation of these lesions is highlighted because of difference in the
      treatment and prognosis of these tumours.

PMID- 10420695
TI  - Cytological diagnosis of adenoid cystic carcinoma breast--a case report.
AB  - The cytologic features of a case of adenoid cystic carcinoma of breast diagnosed
      on fine needle aspiration cytology (FNAC) in a 52 years old female are described.
      FNAC was carried out on outer quadrant of breast. The characteristic cytological
      features were numerous single to branching small round to Avoid cells at places
      forming microacini. Numerous pink hyaline globules of variable sizes were seen
      along with finger like projections containing basement membrane material.

PMID- 10420696
TI  - Exploring the scientific basis of surgery: transmyocardial revascularization.
AB  - Transmyocardial revascularization (TMR) is a new surgical procedure aimed at
      increasing blood flow to the ischemic myocardium. It has been used for treatment
      of patients with end-stage coronary artery disease who are not candidates for
      conventional measures such as medication, percutaneous transluminal coronary
      angioplasty, and coronary artery bypass grafting. TMR involves creating
      transmural channels in the myocardium using lasers, in areas shown to be ischemic
      during preoperative testing. This procedure has shown promising results in
      clinical trials, but the mechanism of its efficacy remains largely unknown. TMR
      was originally developed as a means of supplying blood to the ventricular
      myocardium, directly through channels made in the wall of the ventricle. This was
      in an attempt to recreate the situation that exists in the reptilian heart, in
      which the myocardium is perfused directly from the ventricular chamber through a
      rich network of sinusoids that bathe the myocardial cells. However, the existence
      of a significant sinusoidal network in the human heart is doubtful. Whether the
      myocardium can be perfused directly via the TMR channels is controversial; it is
      becoming clear that other mechanisms such as angiogenesis are also at work. This
      review will use TMR as an example to illustrate how surgical practice and
      thinking can be based on theories that have little or no sound experimental
      evidence to support them. The importance of elucidating the valid scientific
      basis of surgical procedures in this modern era of evidence-based medicine will
      be emphasized.

PMID- 10420697
TI  - Implications of an early reversal pattern of body surface potential maps in
      coronary artery disease.
AB  - During early ventricular depolarization, the normal body surface potential map
      (BSPM) has a maximal potential that is greater than the absolute value of the
      minimal potential; this reverses in late depolarization, so that the absolute
      value of the minimal potential is greater. Nevertheless, an abnormal "early
      reversal" BSPM pattern has been observed in some patients with cardiovascular
      disease. To investigate the implications of this abnormal pattern, BSPMs were
      studied in 100 patients with angiographically proven coronary artery disease
      (CAD). There were 57 patients (57%; group A) with an abnormal early reversal
      pattern and 43 (43%; group B) without this early reversal pattern. A significant
      (> 70% narrowing) CAD lesion was observed in a significantly higher proportion of
      group A (97%) than group B (77%) patients, although the number of involved
      coronary arteries was not significantly different between the two groups. The
      maximal extent of the abnormal negative potential was significantly greater in
      group A (21.2 +/- 9.6 cm2) than in group B (12.2 +/- 7.5 cm2). The abnormal
      negative potential lasted significantly longer in group A (22.1 +/- 12.1 msec)
      than in group B (14.4 +/- 9.2 msec). Similarly, the minimal potential lasted
      significantly longer in group A (20.1 +/- 11.3 msec) than in group B (11.8 +/-
      7.1 msec). These findings suggest that the abnormal early reversal BSPM pattern
      is a valuable indicator of extensive myocardial lesions and the severity of CAD.

PMID- 10420698
TI  - Treatment, outcomes, and prognostic factors of ear cancer.
AB  - Cancer of the ear is rare and a consensus has not been reached as to the most
      appropriate treatment. In this retrospective study, we examined the treatment
      modalities, prognostic factors, and outcomes of patients treated for ear cancer
      at the National Taiwan University Hospital during a 15-year period. The disease
      free survival rates of patients with three different disease grades were compared
      using the log-rank test. The effects of prognostic factors on survival were
      examined with Cox's proportional hazard model. Of the 61 ear cancer patients
      treated from January 1982 through October 1996, 47 (36 men, 11 women; mean age,
      54.6 yr) had complete records and were included in this study. The tumor
      originated from the middle ear in 29 (62%) patients and from the external ear
      canal in 18 (38%). A total of 37 patients underwent radical mastoidectomy to
      remove the gross tumor, while six underwent wide excision of the tumor.
      Concomitant parotidectomy or neck dissection was performed in seven patients.
      Thirty-eight patients received postoperative radiation therapy and five patients
      received chemotherapy for palliative treatment of recurrent or inoperable tumors.
      All but four (9%) of 43 patients developed facial nerve palsy postoperatively.
      There were no deaths directly related to surgery or other major complications,
      including cerebrospinal fluid leakage, meningitis, or hemiparesis. The 5-year
      disease-free survival rate was 53% overall (n = 47), but differed significantly
      among patients with different grades of disease (p = 0.038): 66% for grade I (n =
      27), 44% for grade II (n = 17), and 0% for grade III (n = 3). Multivariate
      analysis revealed that cervical lymph node metastasis was a poor prognostic
      factor (relative hazard, 16.4; p < 0.001). These results suggest that
      mastoidectomy with postoperative radiation therapy can yield satisfactory
      outcomes, even in some cases of advanced (grade II) disease.

PMID- 10420699
TI  - Prevalence of antimicrobial resistance among clinical isolates of Haemophilus
      influenzae in Taiwan.
AB  - The purpose of this study was to determine the prevalence of resistance to
      various antimicrobial drugs among Haemophilus influenzae isolates in Taiwan. Two
      hundred and ninety-six clinical isolates of H. influenzae were prospectively
      obtained from nine teaching hospitals throughout Taiwan, from June 1994 to April
      1995. All isolates were examined for the presence of type b encapsulation and
      beta-lactamase production. Antibiotic susceptibility was determined by means of
      standard broth microdilution procedures. Twenty-three isolates (7.8%) were type
      b, and the overall rate of beta-lactamase production was 58.1% (172/296). The
      rates of resistance to antibiotics were 58.1% for ampicillin, 33.8% for
      trimethoprim-sulfamethoxazole, 20.6% for chloramphenicol, 27% for tetracycline,
      6.7% for azithromycin, 3.4% for cefaclor, and 0.3% for cefuroxime. Cefixime,
      ceftriaxone, and ciprofloxacin were active against all H. influenzae isolates.
      Thirty (10.1%) of the 296 isolates were resistant to three drugs (ampicillin,
      chloramphenicol, and tetracycline), 16 of which (5.4%) were resistant to four
      drugs (ampicillin, chloramphenicol, tetracycline, and trimethoprim
      sulfamethoxazole). There was a marked increase in the rates of ampicillin
      resistance and beta-lactamase production among H. influenzae isolates compared
      with a previous survey in Taiwan conducted 9 years ago. In addition, isolates
      with multiple drug resistance were also identified. Continued efforts are needed
      to monitor antibiotic resistance patterns of H. influenzae in the region.

PMID- 10420701
TI  - Effectiveness of psoralen photochemotherapy for vitiligo.
AB  - To evaluate the response to oral psoralen ultraviolet-A (PUVA) photochemotherapy
      in patients with vitiligo in Taiwan, we retrospectively reviewed the clinical
      data of 21 vitiligo patients treated from 1990 to 1998. Diagnosis included
      generalized vitiligo in 16 patients, focal vitiligo in three, and acrofacial
      vitiligo in two. All patients were treated two to three times per week over a
      period of 3 to 19 months with 0.2 to 0.4 mg/kg of trioxsalen 2 hours before
      exposure to long-wave ultraviolet light irradiation. The results for PUVA therapy
      showed 10 patients (48%) had an excellent response (75-100% repigmentation), four
      (19%) had a good response (50-75% repigmentation), one had a moderate response
      (25-50% repigmentation), and six (29%) had a poor response (0-25%
      repigmentation). Despite the high rate of satisfactory outcomes, the response to
      PUVA therapy with respect to specific localization revealed poor response in
      eight out of 10 patients with vitiligo on the hands and feet. Acute adverse
      effects of PUVA included pruritus in eight patients xerosis in one patient, and
      burning with blistering in four patients. Long-term adverse effects such as
      actinic keratosis and skin cancer were not found within the follow-up period,
      which ranged from 2 months to 7 years. Our findings indicate that long-term oral
      PUVA with trioxsalen is an effective treatment for vitiligo in Taiwanese
      patients.

PMID- 10420700
TI  - Molecular epidemiologic study of mitochondrial DNA mutations in patients with
      mitochondrial diseases in Taiwan.
AB  - We report an 8-year molecular study of mitochondrial DNA (mtDNA) mutations in
      patients with mitochondrial diseases in Taiwan. One hundred and seventy-seven
      patients met the diagnostic criteria of mitochondrial disease and were recruited
      into the study. The results showed that 32 patients, including 25 with
      mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
      (MELAS) syndrome, one with Kearns-Sayre syndrome (KSS), one with diabetes
      mellitus and deafness, and five with chronic progressive external ophthalmoplegia
      (CPEO), harbored the A3243G mtDNA mutation. The A8344G mutation was found in nine
      patients, all of whom suffered from myoclonic epilepsy and ragged-red fibers
      (MERRF) syndrome. The G11778A mtDNA mutation was found in 18 of 22 patients with
      Leber's hereditary optic neuropathy. The T8993C and T8993G mutations were found,
      respectively, in one and two patients with Leigh syndrome. Large-scale deletions
      of mtDNA were found in 17 patients with CPEO, one with KSS, one with MELAS, and
      two with MERRF syndrome. The mtDNA mutations in patients with each of the
      mitochondrial diseases found in Taiwan were restricted mainly to a single site,
      while those reported for the same diseases in other ethnic groups occurred in
      many sites. Furthermore, significant levels of additional mtDNA mutations
      occurred in some patients with mitochondrial encephalomyopathies. We suggest that
      these additional (or secondary) mtDNA mutations are generated as a consequence of
      the preexisting primary mtDNA mutations and may contribute to the age-dependent
      progressive deterioration characteristic of mitochondrial diseases.

PMID- 10420702
TI  - Effects of norepinephrine on renal function in chronically hypoxic rats.
AB  - The sympathetic nervous system is activated in response to altitude hypoxia and
      activation of renal sympathetic nerves may cause vasoconstriction and fluid
      retention. However, renal excretion does not differ significantly between rats
      exposed to high altitude hypoxia and control rats. We hypothesize that renal
      response to norepinephrine (NE) is altered after chronic hypoxia. Female Wistar
      rats weighing 200 to 220 g were exposed to hypoxia in an altitude chamber (5,500
      m, 380 torr) 15 hours/day for 4 weeks (HA, high altitude). Our findings showed
      that systemic infusion of NE (300 micrograms.kg-1.hr-1) produced less
      diuresis/natriuresis in HA rats that in sea level (SL) controls. With mechanical
      elevation of arterial blood pressure, both SL and HA rats showed no significant
      difference in their response to pressure diuresis. Direct intrarenal arterial NE
      (10 micrograms.kg-1.hr-1) administration reduced renal function more in HA rats
      than in SL rats. Intrarenal arterial administration of L-arginine (100
      micrograms.kg-1.hr-1) did not alter the renal action of NE in HA rats. However,
      with intrarenal arterial infusion of phosphoramidon (100 micrograms.kg-1.hr-1),
      NE increased renal response in HA rats to almost the same level as that in SL
      rats. These results suggest that HA rats may have either an excess renal action
      of antidiuretic and antinatriuretic factors or an insufficient renal action of
      diuretic and natriuretic factors during NE administration.

PMID- 10420703
TI  - Diagnosis of herniated intervertebral disc assisted by 3-dimensional, multiaxial,
      magnetic resonance imaging.
AB  - Magnetic resonance (MR) imaging with multiaxial cross sections has been used to
      improve the resolution of small, fine, and slender spinal roots to more precisely
      diagnose herniated intervertebral disc (HIVD), especially in cases of far lateral
      disc (FLD) herniation. However, false-negative results remain a problem because
      of the unsatisfactory resolution of these methods. We report the use of a volume
      visualization technique to generate three-dimensional (3D) images from multiaxial
      sections. In our study, 10 patients with FLD herniation each underwent MR imaging
      (method 1), 3D MR image reconstruction with single-axis cross-sections (method
      2), and 3D MR image reconstruction with multiaxial cross sections (method 3).
      Final diagnoses were confirmed at surgery. The preoperative diagnosis matched the
      operative findings in five patients using method 1, six patients using method 2,
      and nine patients using method 3. In addition, the software developed for this
      application includes functions which simulate decompression of the spinal cord
      and roots. Therefore, this computer-aided diagnosis system using multiaxial cross
      sections is a useful tool for diagnosing HIVD and for training medical residents
      and students. This technique has three main advantages over conventional imaging
      modalities: 1) resolution of small, fine, or slender anatomic structures, which
      reduces the possibility of false-positive and false-negative image findings; 2)
      segmentation (disarticulation) of images; and 3) simulation of surgery.

PMID- 10420704
TI  - Clones of Lactobacillus casei and Torulopsis glabrata associated with recurrent
      abdominal wall abscess.
AB  - Infectious disease caused by Lactobacillus sp has not been previously reported in
      Taiwan. We present a case of recurrent abdominal wall abscess in a chronically
      ill 36-year-old woman, and review the literature on Lactobacillus infection. Five
      isolates of L. casei were recovered from blood and pus samples, and two isolates
      of Torulopsis glabrata were isolated from two blood specimens 3 months apart. Two
      clones of L. casei and T. glabrata were identified by means of antibiotyping with
      the E test and molecular methods. The abscess was surgically removed because of
      poor response to 7 months of antimicrobial therapy for the second infectious
      episode. Recurrent Lactobacillus infection can occur in chronically ill or
      immunosuppressed patients. Treatment of these infections may require a longer
      duration of antibiotic therapy, or surgical intervention.

PMID- 10420705
TI  - Isolated leptomeningeal tuberculoma.
AB  - Intracranial leptomeningeal tuberculoma without evidence of systemic tuberculosis
      is rarely encountered and is often difficult to diagnose because there are no
      specific signs or symptoms. A 49-year-old woman, without any past history of
      tuberculosis, presented with weakness and focal seizures in the right hand.
      Cranial magnetic resonance imaging revealed a leptomeningeal lesion in the left
      frontoparietal region. All conventional examinations demonstrated no evidence of
      tuberculous infection. The patient underwent biopsy, and histopathologic
      examination showed caseating granulomas compatible with tuberculomas. The culture
      of the surgical specimen grew Mycobacterium tuberculosis 4 weeks later. The
      patient was then actively treated with antituberculous agents for 1 year.
      Subsequent clinical features and image studies showed the intracranial lesion in
      resolution. The findings of this case argue in favor of surgical biopsy when
      intracranial tuberculosis is clinically suspected, even without evidence of
      systemic tuberculous infection.

PMID- 10420706
TI  - Brain tumors with hemorrhage.
AB  - Various types of brain tumors may cause hemorrhage. The purpose of the study was
      to examine the clinical relevance of tumor hemorrhage and the hemorrhagic
      mechanism from the pathologic viewpoint. We retrospectively reviewed 761
      consecutive brain tumor cases according to clinical, operative, and pathologic
      records. Pituitary adenomas and recurrent tumors were excluded. Twenty-seven
      patients (17 men and 10 women, mean age, 50 years) with brain tumor hemorrhage
      were identified, resulting in an incidence of 3.5%. In 632 cases of primary brain
      tumors, there were 15 cases with hemorrhage, resulting in an incidence of 2.4%.
      There were 12 cases of brain tumor hemorrhage in 129 patients with metastatic
      tumors, for an incidence of 9.3% Among hemorrhagic cases, 63.0% of patients
      presented with acute onset of clinical deterioration. In 72.7% of gliomas with
      hemorrhage, hematoma appeared within the tumor, and 75% of metastatic brain
      tumors with hemorrhage were intracerebral hemorrhages around the borders of the
      tumors. The highest hemorrhage rate for primary brain tumors occurred in
      pilocytic astrocytomas, while the highest hemorrhage rates in secondary tumors
      occurred in metastatic thyroid papillary carcinomas and hepatocellular
      carcinomas. In our pathology study, increasing intratumor vascularization with
      dilated, thin-walled vessels and tumor necrosis were the most important
      mechanisms of hemorrhage.

PMID- 10420707
TI  - Small cell lung carcinoma associated with paraneoplastic limbic encephalitis.
AB  - Limbic encephalitis is an unusual presentation of paraneoplastic syndrome. We
      report a case of small cell lung carcinoma associated with limbic encephalitis. A
      67-year-old man presented with convulsions, memory impairment, and
      neuropsychiatric disturbances as initial symptoms. Subsequently, small cell lung
      carcinoma was diagnosed by bronchoscopic biopsy. The cerebrospinal fluid studies,
      electroencephalography, and magnetic resonance imaging findings had distinctive
      features compatible with paraneoplastic limbic encephalitis. The neuropsychiatric
      symptoms improved significantly after six cycles of systemic chemotherapy and
      adjuvant radiotherapy, resulting in partial remission of the tumor. A follow-up
      computed tomography scan of the head showed no evidence of intracranial
      metastasis 7 months after the diagnosis of cancer. Limbic encephalitis may be an
      initial manifestation of lung cancer. Greater awareness for diagnosis and early
      treatment of the primary tumor offers the best chance for improvement in patients
      with lung cancer presenting with limbic encephalitis.

PMID- 10420708
TI  - [Present status and tasks of occupational regulations for radiofrequency of
      electromagnetic fields].
AB  - Intensive use of various emitters of radiofrequency electromagnetic fields is a
      potential health hazard both for workers and general population. Thus, improved
      hygienic regulation and control of nonionizing electromagnetic radiation becomes
      very important for prophylactics. Hygienic regulation of radiofrequency
      electromagnetic fields is based on elimination of their influence on human
      health. Incomplete knowledge of biologic mechanisms underlying influence of low
      intensity radiofrequency electromagnetic fields is a serious obstacle to further
      improvement of hygienic regulation. Special attention should be paid on clinical,
      physiologic and epidemiologic research aimed to study long-term effects and
      influence of the stated fields on general morbidity.

PMID- 10420709
TI  - [Analysis of electromagnetic absorption in biologic objects with industrial high
      frequency heating of dielectric materials].
AB  - The article deals with analysis of electromagnetic safety for individuals who
      operate high-frequency devices heating dielectrics. The authors suggest a surface
      integral equation, present calculations of the electric field intensity and
      specific absorption rate for electromagnetic energy by biologic objects and
      analyze various floor covering materials for industrial compartments. The results
      are compared with those obtained by finite-difference time domain method.

PMID- 10420710
TI  - [Physiological-occupational assessment of acoustic load with equal energy but
      different time and informational characteristics].
AB  - The article deals with results of experimental study comparing effects of 4 types
      of acoustic load--noise (constant and impulse) and music (electronic symphonic
      one and rap)--on hearing sensitivity, processes in nervous system and subjective
      evaluation. All types of acoustic load were equal in energy (on evaluation
      according to equivalent level during the experiment). The study included 2 levels
      of load--90 and 95 dB. The differences revealed demonstrate importance of impulse
      parameters of noise and musical load for reactions of acoustic analyzer and
      central nervous system. The experiments show that evaluation of harm caused by
      temporary and impulse noises should be based not only on assessment of specific
      (hearing) function, but also on parameters of central nervous system state. The
      authors found that music of certain acoustic and informational parameters may
      harm hearing function.

PMID- 10420711
TI  - [Clinical endoscopic and pathomorphologic study of the stomach in vibration
      disease].
AB  - The authors present results of manifold evaluation of stomach in 109 patients
      with vibration disease caused by various vibration characteristics. The
      evaluation covered clinical signs, laboratory studies, endoscopic and
      pathomorphologic methods with light and electronic microscopy, in vitro
      radioautography and morphostereologic analysis. Features of gastric disease in
      vibration disease are asymptomatic course, depressed gastric secretion, prevalent
      atrophic changes of mucosa on endoscopy. Morphologic analysis of gastric biopsies
      revealed marked dystrophy and atrophy of the lining, glandular atrophy, diffuse
      stromal sclerosis and in most cases no signs of gastritis. The findings are
      termed vibration gastropathy.

PMID- 10420712
TI  - [Changes in occupational cochlear neuritis and its incidence in Moscow].
AB  - The authors analyze completeness and reliability of State statistics exemplified
      by occupational deafness. Cochlear neuritis morbidity appears to change
      unfavorably. For calculation of the necessary parameters, the authors suggest a
      rational method considering only number of those working in noisy conditions, but
      not the total number. The results appear more objective, that is essential for
      adequate evaluation of occupational deafness risk for main industries and
      occupations exposed to noise, in order to manage this risks effectively.

PMID- 10420713
TI  - [Aspects of healthy humans' response to hyperthermia].
AB  - Single-shot hyperthermia of healthy young men in climate chamber up to rectal
      temperature of 39.5 degrees C over 75-110 minutes revealed variable heat
      resistance. Individuals with prevalent sympathetic vegetative regulation were
      more resistant to overheating, if compared to those with prevalent
      parasympathetic one. Endocrine group peculiarities were observed, the examinees
      with prevalent parasympathetic vegetative regulation demonstrated more drastic
      changes of some biochemical parameters.

PMID- 10420714
TI  - [On the role of technogenic rotating electrical fields in inner and outer
      ecologic relations (literature review)].

PMID- 10420715
TI  - [Occupational assessment of computer placement in school areas].
AB  - The study included measurements of electromagnetic radiation emitted by MACINTOSH
      PC placed in public schools, functional state examination of schoolchildren
      sitting in rows in front of PCs. Electromagnetic radiation emitted by PCs
      appeared to harm higher nervous activity of the schoolchildren. With
      consideration of the studies conducted the recommendation is not to set
      workplaces in rows. The workplaces could be set perimetrically, with at least 1.0
      m between the lateral borders of neighboring monitors. Angle-wise set workplaces
      should stay at least 2.0 m apart.

PMID- 10420716
TI  - [Single number index of vibratory and force load during hand-arm vibration].
AB  - Having analyzed the data from literature, the authors suggested a single-number
      index for integral assessment of combined vibratory and force load during work
      with vibrating manually held device. The index considers the acceleration value
      and combination of grip and feed forces. The authors calculated average values of
      these forces and the resultant coupling force for various device weights. If the
      coupling force is considered, the risk of vibration disease varies in accordance
      with forecast model and demonstrates 1.06-1.1 up to 1.6-2.6 times increase
      depending on device weight. The index could be useful for hygienic certification
      of manually held devices.

PMID- 10420717
TI  - [Local ventilation in the use of heat and moist releasing equipment].
AB  - The authors suggest a new technologic type of local exhauster for devices
      releasing heat and moist. The novelty considers convection and radiating heat:
      The article contains formulae to calculate quantities of the air removed as well
      as sanitary, hygienic and economic results of the novelty.

PMID- 10420718
TI  - [Combined effect of noise and electromagnetic fields of industrial frequency
      (experimental study)].

PMID- 10420719
TI  - [On radiation safety of medical personnel and patients during X-ray studies in
      stomatology].

PMID- 10420720
TI  - [Labor conditions and occupational diseases among workers at ferro-concrete ware
      plants in Armenia].

PMID- 10420721
TI  - [What is the value of determining walking distance in peripheral arterial
      occlusive disease on the treadmill and in daily life? Prospective correlation
      study].
AB  - AIM: To investigate the question whether and how walking distances measured under
      standardized conditions on the treadmill and on the level correlate with the
      patients walking ability under everyday conditions. PATIENTS AND METHOD: In 49
      patients (33 men, 16 women, age 34 to 84 years) with Fontaine Stage II peripheral
      arterial occlusive disease the pain-free and absolute walking distance on the
      treadmill were measured under standardized conditions, as also the walking
      distance on the level at freely selected speed. RESULT: It was found that the
      pain-free walking distance under everyday conditions was about 2 to 3 times
      longer than that measured under standardized conditions on the treadmill.

PMID- 10420722
TI  - [The German Cardiovascular Disease Prevention Study: social gradient in use of
      drugs with a potentially addictive nature. An analysis of selected indications
      groups].
AB  - BACKGROUND: Not only prescription but also turnover of medicines are well
      established by documentary evidence. However, there is a lack of information
      regarding the usage of drugs in different social classes. MATERIALS AND METHODS:
      Within the scope of the German Cardiovascular Prevention Study (GCP), a cross
      sectional community-based multicenter intervention study, (t0 = 1984/5, t1 = 1988
      und t2 = 1991/2) the usage of drugs was examined. Four groups of drugs with a
      potentially addictive character (analgesics, sedatives, sleeping drugs,
      psychotropics) were analyzed with regard to socioeconomic differences in
      consumption. RESULTS: A gradient was found for all analyzed groups of drugs. The
      data analysis of the 3 pooled surveys (t0, t1, t2) regarding analgesics yields an
      OR of 1.67 (95%-CI: 1.41 to 1.98) for the middle class (mc) and 2.33 (95%-CI:
      1.95 to 2.80) for the lower class (lc) (reference being the upper class). For
      psychotropics the values are OR = 1.40 (95%-CI: 1.12 to 1.75) (mc) and OR = 2.01
      (95%-CI: 1.58 to 2.55) (lc), for sleeping drugs OR = 1.31 (95%-CI: 1.05 to 1.65)
      (mc) and OR = 1.54 (95%-CI: 1.37 to 1.96) (lc) and for sedatives OR = 1.40 (95%
      CI: 1.19 to 1.64) (mc) and OR = 1.94 (95%-CI: 1.63 to 2.30) (lc). CONCLUSION:
      Considering possible indicators of different drug utilization (age, sex,
      occupation, individual health, last medical care, mental distress) the gradient
      was diminished but--especially for the lower class--remained at significant OR's
      between 1.37 and 1.65.

PMID- 10420723
TI  - [Hepatic porphyrias and alcohol].
AB  - Alcohol has an porphyrinogenic action and can cause a disturbance of porphyrin
      metabolism in healthy people as well as lead to a biochemical and clinical
      manifestation of acute and chronic hepatic porphyrias, especially acute
      intermittent porphyria and porphyria cutanea tarda. After excessive consumption
      of alcohol a temporary, clinically asymptomatic secondary hepatic
      coproporphyrinuria in man can be observed, which can become persistent in cases
      of alcohol-induced liver damage. Nowadays alcohol-liver-porphyrinuria syndrome is
      the first to be mentioned in secondary hepatic disturbances of porphyrin
      metabolism. In people with a genetic lack of uroporphyrinogen-decarboxylase
      alcohol is able to transform an asymptomatic coproporphyrinuria into a chronic
      hepatic porphyria or porphyria cutanea tarda. From experimental and clinical
      studies the conclusion can be drawn that alcohol inhibits the enzymes delta
      aminolevulinic-acid-dehydratase (synonym: porphobilinogen-synthase),
      uroporphyrinogen-decarboxylase and coproporphyrinogen-oxidase and induces delta
      aminolevulinic-acid-synthase in the liver. Abstinence of alcohol is a
      therapeutically and prophylactically important measurement in all types of
      hepatic porphyrias. For clinical experience follows that in cases with chronic
      consumption of alcohol, fatty liver, alcohol induced hepatitis and liver
      cirrhosis porphyrin studies in urine should be made to notice a hepatic porphyria
      in the latent phase very early. When dealing with abdominal and cutaneous
      symptoms in clinical context with consumption of alcohol one has to exclude
      hepatic porphyria differential diagnostically.

PMID- 10420724
TI  - [Gastrointestinal complications of diabetes mellitus].
AB  - BACKGROUND: Diabetes mellitus leads to a broad spectrum of symptoms and
      manifestations in the field of gastroenterology. BASIS: This article reviews the
      pathophysiology, differential diagnoses and secondary diseases of the
      gastrointestinal tract in diabetic patients. CLINICAL APPEARANCE: Motility
      disorders, infectious complications, secondary diseases of the stomach, liver,
      pancreas, gall bladder, small and large bowel are considered and discussed.
      Diagnostic and therapeutic approaches for the management of diabetic enteropathy
      are presented. CONCLUSION: The new strategies in diagnosis and therapy for a
      successful prevention or treatment of gastrointestinal complications due to
      diabetes mellitus need good cooperation of clinical specialties.

PMID- 10420725
TI  - [Gastrointestinal hemorrhage in a 22-year-old patient].

PMID- 10420726
TI  - [Hereditary angioedema. Diagnostic and treatment errors as systemic lupus
      erythematosus].
AB  - BACKGROUND: Symptoms of hereditary angioedema are intermittent edema of
      subcutaneous tissues, abdominal organs, upper airways, and brain. Because of
      spontaneous mutation, in 20% of patients a familial history is lacking.
      Serological hallmarks are diminished complement factor 4 and C1-esterase
      inhibitor. The heterogenicity of the clinical symptoms frequently leads to false
      or delayed diagnosis. CASE REPORT: We report on a 50-year-old male patient with
      intermittent joint swellings, abdominal complaints, pleural effusions, ascites
      and headaches with disturbances of consciousness since early adulthood. Diagnosis
      was systemic lupus erythematosus. Immunosuppressive therapy was ineffective over
      months. Careful re-evaluation of the patient's clinical history and further
      laboratory examinations led to the diagnosis of an hereditary angioedema.
      Anamnestic and laboratory exploration of family members disclosed four other
      cases. Two of them also were symptomatic for decades without adequate diagnosis.
      CONCLUSION: In case of intermittent swellings, abdominal complaints, laryngeal
      edema, pleural effusions or ascites, differential diagnosis should involve
      hereditary angioedema. With early diagnosis and adequate treatment, prognosis is
      good. Since ACE inhibitors can aggravate the disease they are contraindicated.
      Diagnosis, pathogenesis, and treatment are discussed by reviewing the literature.

PMID- 10420728
TI  - [Adrenal cortex insufficiency: diagnosis and therapy].

PMID- 10420727
TI  - [Intestinal lymphoma. A long diagnostic path].
AB  - CASE REPORT: We describe the case of a 43-year-old patient with a Burkitt
      lymphoma in the small intestine, who initially presented with abdominal
      discomfort, weight loss, constipation and neurological symptoms. DIAGNOSIS: In
      terms of differential diagnosis other inflammatory and tumorous diseases had to
      be considered. Non-Hodgkin lymphomas are common malignant afflictions of the GI
      tract. The total body tumor burden is the principal determinant of prognosis.
      Serum lactate dehydrogenase (LDH) level is one parameter that reflects the tumor
      burden. On the other hand abdominal mass, bone marrow and central nervous system
      involvement are negative prognostic factors. Lymphomas can invade in the CNS at
      any time during the course of disease. This is generally associated with a poor
      prognosis if not treated immediately. TREATMENT: High doses of cyclophosphamid
      and MTX have been shown successful in the treatment of Burkitt lymphoma. Almost
      all relapses occur on therapy or shortly after termination of treatment.
      Therefore, criteria are needed to select patients of higher and lesser risk to
      protect the latter from the further intensification of therapy.

PMID- 10420729
TI  - [Social change necessitates a reform of the medical profession. A contribution to
      the public health policy discussion regarding the future of health care in
      Germany].

PMID- 10420730
TI  - [The duality of medical progress. On the contribution by Arnold M. The Janus head
      of medical technical progress].

PMID- 10420731
TI  - [Acutely progressive tuberculosis: a new category of patients in the present-day
      tuberculosis treatment].

PMID- 10420732
TI  - [Several features of present-day clinical aspects of acute caseous pneumonia].

PMID- 10420733
TI  - [Course of destructive pulmonary tuberculosis under present-day conditions].

PMID- 10420734
TI  - [Defensive systems of blood in patients with caseous pneumonia].

PMID- 10420735
TI  - [Progressive forms of pulmonary tuberculosis].

PMID- 10420736
TI  - [Clinical and diagnostic aspects of meningeal tuberculosis in children].

PMID- 10420737
TI  - [Combined x-ray and endoscopic diagnosis of lung lesions in bronchial stenosis].

PMID- 10420738
TI  - [Statistics of tuberculosis in the Republic of Sakha (Yakutia)].

PMID- 10420739
TI  - [Main ways of optimizing the epidemiological surveillance of tuberculous
      infection].

PMID- 10420740
TI  - [Experience in the cooperation of IK-33 and the mission "Physicians without
      Borders" (Belgium) in tuberculosis control].

PMID- 10420741
TI  - [Effects of the zones of adverse ecological conditions on the course of an
      infectious process].

PMID- 10420742
TI  - [Present-day clinical and social characteristics of newly diagnosed patients with
      pulmonary tuberculosis].
AB  - The present clinical and social characteristics of new cases with pulmonary
      tuberculosis show some features. The clinical characteristics of patients in 1995
      to 1997 indicate an increased number of patients with disseminated, frequently
      bilateral processes and acute tuberculosis which is largely associated with the
      decline in preventive fluorographic surveys of the population including those who
      have contacted bacteria-isolating patients. There were 61.3% with pulmonary
      symptoms among those who visit physicians and 62.1% among those from the foci of
      tuberculous infection. Social aspects of the study demonstrate that there is a
      great number of young patients (56.4% of those under 39-49 years) and a high
      proportion (81.1%) of able-bodied patients among both males and females. There
      was an increase in the proportion of patients having higher education (43.7%) and
      a decrease in laboring patients (21.4%). This is most likely to be associated
      with the fact that many patients did not work by the profession they had been
      trained. There was a higher proportion (43.0%) of the patients having different
      poor working conditions and patterns. In these years, the patients' financial
      position deteriorated. It was slightly better in the employed than in the
      unemployed. However, in both groups the bulk of the patients had income per head
      in the family at the subsistence level or lower (56.2 and 21.6% in the unemployed
      and employed, respectively. These data were assessed by the guidelines made by
      the State Statistics Committee of the Russian Federation and the RF Ministry of
      Labour. It should be noted that the nutritional quality did not correspond to the
      optimal composition ratio of dietary foods and it was characterized by the high
      content of less valuable foods, carbohydrates, low levels of protein and
      vitamins. Poor social aspects in characteristics of patients were undoubtedly to
      be associated with a greater number of patients with severe, frequently
      progressive forms of tuberculosis although they had received specific
      chemotherapy.

PMID- 10420743
TI  - [Reasons for hospital readmission of infants and preschool children with
      tuberculosis].
AB  - As high as 12.4% of children suffering from tuberculosis are readmitted, rural
      children are more frequently readmitted (18.0 versus 7.2%, p < 0.01), children
      having tuberculosis (10.9%) and nonspecific pathology (1.5%). Among the children
      readmitted for tuberculosis, 75.9% had exacerbations which provoke infectious
      diseases in 18.2%. In 72.7% of cases, the cause of readmission was premature
      discharge due to their parents' noncompliance.

PMID- 10420744
TI  - [Clinical aspects and treatment of tuberculosis of respiratory organs in
      adolescents under present epidemiological conditions].
AB  - The paper summarizes the results of clinical observations of 55 teenagers
      suffering from active respiratory tuberculosis. It defines risk factors for this
      disease in adolescents. Emphasis is laid on the current pathomorphology and a
      great variety of clinical types of tuberculosis. Treatment of tuberculosis is
      ascertained to be preferred by using the short-term intensive chemotherapy
      regimen recommended by the World Health Organization, which is intended to cure
      most patients in the shortest period as compared with existing routine regimens.

PMID- 10420745
TI  - [Treatment of patients with pulmonary tuberculosis with regard to their
      personality traits and attitude to disease].
AB  - Experimental psychological examination was made in 149 patients with pulmonary
      tuberculosis. Most patients with tuberculosis were ascertained to have mental
      disorders which increase in chronic alcoholism or progress to chronic destructive
      tuberculosis. As high as 21.2% were found to show a harmonic attitude towards the
      disease. The other patients had inadequate disease responses in combination with
      a low sanitary education. Psychotherapy makes it possible to eliminate mental
      disorders, to form an adequate disease attitude and to keep to the necessary
      treatment duration. This enhances the efficiency of tuberculosis treatment.

PMID- 10420747
TI  - [Experience in the work of the unit of surgical diagnosis of respiratory organ
      diseases].
AB  - From 1986 to 1997, the Unit made 2637 diagnostic operations: 1687 thoracoscopies,
      49 telethoracoscopies, 232 mediastinoscopies, 171, diagnostic thoracotomies, 108
      open pleural biopsies, 390 peripheral nodal biopsies. The diseases detected were
      arranged as follows: tuberculosis (33.8%), nonspecific (32.5%), malignant
      (16.3%), sarcoidosis (9.9%), alveolitis (2.5%). Verification was 95.3%.

PMID- 10420746
TI  - [Ramipril treatment of heart failure in disseminated forms of pulmonary
      tuberculosis].
AB  - A total of 108 patients with heart failure-complicated disseminated pulmonary
      tuberculosis were followed up. Fifty eight patients received combined therapy
      including the angiotensin-converting enzyme inhibitor ramipril in a daily dose of
      0.25-0.50 mg for 1.5-2 months. Fifty ramipril-untreated patients comprised a
      control group. Examinations revealed the benefits of the agent in decompensatory
      chronic cor pulmonale as improved right ventricular systolic and diastolic
      functions and health in the patients.

PMID- 10420748
TI  - [Comparative effects of acute tests using ventolin, ventodisk and intal plus in
      the ambulatory pulmonological practice].
AB  - In the outpatient setting, 108 patients with obstructive respiratory diseases
      were examined. They were divided into 3 equal groups which underwent acute
      ventolin, ventodisk, and intal plus tests. There were no differences in the
      frequency and magnitude of effects of the three agents as evidenced by the forced
      expiration flow-volume curve. At the same time albuterol insufflation through a
      disk-haler (ventodisk) caused powder irritation in some cases, those occurred
      less frequently with intal plus inhalations. It is concluded that ventolin or
      intal plus may be the drugs of choice in acute attacks of bronchospasm.

PMID- 10420749
TI  - [Secondary immunodeficiency syndrome in patients with chronic bronchitis].
AB  - To identify secondary immunodeficiency, the author examined 510 patients with
      various types of chronic bronchitis (CB) and revealed that 82.5% of the examinees
      had secondary immunodeficiency syndrome which was characterized by immunological
      alterations: decreased T lymphocyte counts which was most common in patients with
      obstructive CB, differences in lymphocytic proliferation in response to PGA,
      which indicates reductions in the functional activity of T cells and in effector
      links of the immunity system, an increase in the blood levels of circulating
      immune complexes, imbalance in the ratio of Ig classes. The leading clinical
      manifestation of patients with secondary immunodeficiency was an infectious
      process: frequent, advanced or chronic infections. On exacerbation, H. influenza
      played a great role in the infectious process due to the high activity of an
      inflammatory process caused by Pneumococcus and due to the impairments of the
      function and pattern of the mucociliary apparatus of the bronchial tree.

PMID- 10420750
TI  - [Detection and characteristics of rpoB gene mutations in rifampicin-resistant
      clinical strains of M. tuberculosis].
AB  - The resistance of M. tuberculosis to rifampicin, one of the key agents used in
      the treatment of tuberculosis is due to point mutations in the rpoB gene encoding
      for the B-subunit of PNA polymerase. Based on the detection of such mutations,
      genotypic determinations of rifampicin resistance is a serous alternative to
      routine microbiological assays that take much more time. Nevertheless, the
      efficiency of genotypic methods largely depends how completely the resistance
      associated mutations are studied and characterized. It is shown that the types
      and detection rates of certain rpoB mutations can greatly vary in the
      Mycobacterium strains spread in different geographical regions. By applying the
      approach based on the direct sequencing of PCR with rpoB gene fragments, the
      present paper analyzed 48 rifampicin-sensitive and 52 rifampicin-resistant
      clinical M. tuberculosis strains provided by Moscow tuberculous control
      facilities. Mutations responsible for rifampicin resistance were detected in 51
      (98%) of the 52 resistant strains. The mutations involving codons 531 (46%), 526
      (23%), and 516 (23%) of the rpoB gene were proved to be dominant. An unusual
      double mutation combining the replacement of F by L in codon 514 and previously
      uncharacterized methionine deletion in the position 515 was detected in the
      single investigated strain. The efficiency of the employed approach for rapid
      diagnosis of rifampicin-resistant M. tuberculosis strains is discussed.

PMID- 10420751
TI  - [Distribution of transplantation HLA antigens in children and adolescents with
      meningitis of various etiology].
AB  - An interaction between HLA antigens and predisposition to meningitis of specific
      and nonspecific etiology was studied in children and adolescents from an
      Azerbaijan population. The distribution of HLA antigens was found to be
      heterogeneous in the patients with meningitis of various etiology. Tuberculous
      meningitis was characterized by a significant rise in the detection rate of HLA
      DR3 antigen, by a considerable frequency of B14 and DR2 antigens; patients with
      purulent meningitis much more significantly showed HLA-B12 antigen; in terms of
      locus A, there was an increase in the detection rates of HLA-A19 antigen in
      serous meningitis.

PMID- 10420752
TI  - [Biological properties of laboratory strains and clinical isolates of
      mycobacteria multiresistant to antitubercular preparations].
AB  - Multiresistant M. tuberculosis strains show varying drug resistance, virulence
      and growth rates. The count of cells of some multiresistant strains in the guinea
      pig parenchymatous organs after intracardiac inoculation was comparable with that
      of after inoculation with clinical isolates. Furthermore, some multiresistant
      strains were not inferior to sensitive clinical isolates. The findings lead to
      the conclusion that there is a wide range in the virulence of multiresistant
      strains and hence they can present an epidemiological hazard.

PMID- 10420753
TI  - [2 case reports of multiple pulmonary echinococcosis].

PMID- 10420754
TI  - [Cystic teratoma of the mediastinum].

PMID- 10420755
TI  - [Current problems of tuberculosis in the north-wester region of Russia].
AB  - Tuberculosis remains a social challenge. There has been a drastic aggravation of
      the tuberculosis situation since the early 1990s. This has been caused by
      diminished state infection control, sharply changed human and poor socioeconomic
      living conditions, the causative agent's resistance and aggressiveness.
      Unfavourable economic trends are maintained by latent infection sources whose
      size has increased under the crisis of the system of active tuberculosis
      detection in the population. This requires the introduction of new treatment
      modalities which will provide as high as 80-95% final efficiency by abacillation
      and closure of decay cavities. Tuberculous infection must be daily and actively
      managed. Today's main goal is to achieve only stabilization and to prevent the
      disease from its further spread.

PMID- 10420756
TI  - [Organization of antituberculous work with homeless in Saint Petersburg].
AB  - The paper deals with organizational measures for detection and treatment of
      homeless persons with tuberculosis in Saint Petersburg. A total of 1653 homeless
      tuberculosis patients were followed up in 1991-1997. There was high incidence of
      tuberculosis in homeless persons (30 detected per 1000 examinees. All agencies,
      facilities, and services should participate in detecting and treating
      tuberculosis among homeless subjects. Large-scale solution of this problems
      requires a package of measures by providing additional funds stipulated by a
      regional goal-oriented tuberculosis control programme.

PMID- 10420757
TI  - [Multilevel automatic monitoring system for epidemiological tuberculous process
      in the north-western region, project and implementation].
AB  - The paper proposes a variant how to solve the problem of complex automation of
      the work of antituberculous service by using the concept of building up a
      multilevel automatic informational and analytical system of antituberculous
      service at the regional level developed at the regional level. The programme
      product "statistical phthisiologist AMP" for the lower level of the area (urban)
      antituberculous dispensary which has been developed within this project is given.

PMID- 10420758
TI  - [Clinical and X-ray characteristics of progressive tuberculosis in teenagers].
AB  - The causes of progressive destructive pulmonary tuberculosis are analyzed in 22
      adolescents. The main causes of progressive pulmonary tuberculosis is its late
      detection, the polyresistance of Mycobacteria tuberculosis, negative blood
      bacterial activity, the body's diminished responsiveness. Complex
      etiopathogenetic therapy resulted in positive changes in the specific process in
      over two thirds of patients.

PMID- 10420759
TI  - [External respiratory function and pulmonary capillary blood flow in patients
      with postoperative recurrent pulmonary tuberculosis].
AB  - To clarify criteria for functional operability, external respiratory function
      (ERF) and pulmonary capillary blood flow (PCBF) were studied in 116 patients with
      postoperative recurrent pulmonary tuberculosis who had been admitted to the
      resurgery unit. Moderate ERF impairments (stages I and II) were identified in 65%
      of cases, 23% had stage III ventilation disorders (VD), and 11% were found to
      have stages IV and V VD. In focal recurrences, overall PCBF ranged 19 to 36% of
      the total pulmonary blood flow with is decrease from 11 to 0.3% in the total
      number of recurrences. Preoperative preparation improved ERF in 54% of patients.
      Contraindications for surgery were found in 9% due their low functional reserves.
      A total of 105 patients were operated on, postoperative mortality was 11.4%.
      Cardiopulmonary insufficiency was a cause of death in 4 cases, of them 3 patients
      underwent repeated resection of the lung as pneumonectomy in baseline stage III
      VD, which allows these patients to refer to as a high surgical risk group.

PMID- 10420760
TI  - [Magnetic resonance imaging in the complex radiation diagnosis of tuberculous
      spondylitis in adults].
AB  - The paper analyzes X-ray study and MR imaging of 36 adult patients with
      tuberculosis spondylosis having an active process developed in maturity (n = 20)
      and sequelae of childhood spondylitis (n = 16). X-ray study is shown to retain
      its basic value in the diagnosis of spondylitis. MRI is the optimum technique for
      early diagnosis of inflammatory changes in the spine and soft tissues, the method
      of choice in neurological disorders.

PMID- 10420761
TI  - [Surgical treatment of patients with cervicothoracic and upper thoracic spinal
      abnormalities].
AB  - The authors have developed an approach to cervicothoracic and upper thoracic
      spine for surgical treatment of patients with tuberculous spondylitis complicated
      by severe kyphotic deformity, which allows one to make the entire scope of
      reparative surgical intervention under visual guidance from the fifth cervical
      vertebra to the ninth thoracic one with the minimum traumaticity and preserved
      muscle integrity. This is performed through the periscapular triangle by
      diverting the scapula cranially without dissecting its fixing muscles, the
      musculus latissimus dorsa caudally. The third or fourth rib is resected in
      relation to the site of a pathological process.

PMID- 10420762
TI  - [Correction of kyphosis in tuberculous spondylitis in children].
AB  - Various modifications of radical reparative surgery were made in 145 children
      with tuberculous spondylitis were comparatively analyzed. Greatest correction of
      kyphosis was achieved by combining anterior spinal repair with posterior plunged
      contractors, in additional resection of the apical vertebral arch in particular.
      There is a direct correlation between the degree of compression of the dural sac
      and the severity of neurological disorders. Anterior decompression of the spinal
      cord is an obligatory surgical component in tuberculous spondylitis, eliminates
      central stenosis of the spinal canal; however, it is insufficient to eliminate
      neurological disorders caused by myelic ischemia.

PMID- 10420763
TI  - [Stepwise motor rehabilitation of children with neurologic complications of
      tuberculous spondylitis].
AB  - The proposed protocol for postoperative motor rehabilitation of children with
      tuberculous spondylitis complicated by severe neurological disorders is based on
      the procedures developed by the authors to induce spinal locomotor activity. The
      developed algorithm of motor rehabilitation of spinal patients involves separate
      restoration of gait components (rhythmic stereotypic walking (spinal locomotion),
      maintenance of a standing posture and voluntary control over the movements
      ensuring gait. The stages of motor rehabilitation were defined by taking into
      account these factors and a child's neurological status. The use of the algorithm
      in the treatment of 11 children with tuberculosis and 13 children with other
      spinal diseases resulted in the restoration of normal compensatory gait or in its
      formation in the vast majority of patients.

PMID- 10420765
TI  - [Specific features of tuberculous uveitis pathomorphology].
AB  - There have been great changes in the clinical picture and course of ocular
      tuberculosis in the 90s versus the 70-80s. There has been a upward trend in the
      incidence of ocular tuberculosis in the population, in children and teenagers in
      particular. Patients with tuberculous uveitis involving the posterior eye makes
      up over 70%. A specific eye tissue inflammatory process is mainly exudative and
      infiltrative with rapid development of the complications masking a tuberculous
      focus, which hampers treatment and causes a significant decrease in visual
      functions.

PMID- 10420764
TI  - [Efficiency of plastic surgery for osteoarticular tuberculosis by using
      revascularization of osseous tissue bed and graft].
AB  - The paper provides the results of using original procedures for revascularization
      of the osseous bed and free bony grafts by transplanting osteovascular complexes
      in patients with tuberculosis of the hip joint and spine. A total of 20 patients
      with tuberculous coxitis and 14 with spondylitis were operated on. These
      interventions were found to have advantages over plastic surgery with bony grafts
      and mobilizing operations without plasty in similar skeletal lesions, appeared as
      a great scope of movements in the operated joints is achieved, less time for
      grafts to adhere with the bed and bony block of vertebrae, and enhanced
      accumulation of a radioopaque agent in the area to be replaced.

PMID- 10420766
TI  - [Laparoscopy in the complex diagnosis abdominal and genital tuberculosis].
AB  - Laparoscopy may detect pathognomonic signs of rashes on the visceral peritoneum,
      enlarged mesenteric lymph nodes, a profound commissural process in the small
      pelvis and Douglas space to identify abdominal and genital tuberculosis. The
      examinees were also found to have a prior tuberculosis of other sites or a
      contact with bacillary patients. Laparoscopy shows a 19.7% increases in the
      diagnostic potentialities by morphologically verifying the diagnosis based on
      biopsy specimens.

PMID- 10420767
TI  - [Genetic marking of polyresistant mycobacterium tuberculosis strains isolated in
      the north-west of Russia].
AB  - RFLP analysis using a IS6110 probe was used to genetically marked polyresistant
      Mycobacterium tuberculosis strains isolated from patients with pulmonary
      tuberculosis in the north-west of Russia in 1996-1997. Two groups of genetically
      closely related, but epidemiologically unrelated strains of different territorial
      origin were identified. The epidemiological value of and the origin of
      genetically identified and related strains are discussed. The significance and
      prospects of the use of RFLP-based genome dactyloscopy are shown for follow-ups
      of the circulation of epidemic strains in order to improve the system of
      tuberculosis epidemiological surveillance and treatment efficiency control.

PMID- 10420768
TI  - [Diagnostic value of some cytological parameters of alveolar lavage fluid in
      restrictive lung diseases].
AB  - The time course of cytological parameters of alveolar lavage fluid in restrictive
      lung disease of tuberculous or other genesis during tuberculin provocative test
      was studied. A focal response as higher levels of alveolar macrophages, plasma
      and epithelioid cells was noted in 62.5% of patients with tuberculosis. The
      method promotes greater diagnostic efficiency for pulmonary tuberculosis.

PMID- 10420769
TI  - [Design and study of new agents having antitubercular activity: the original
      compound perchlosone as a potent agent of etiotropic therapy for tuberculosis].
AB  - Studies dealing with the design of new antituberculous agents based on goal
      oriented synthesis have provided the agent Perchlosone which is similar to
      isoniazid and rifampicin, produces in tuberculostatic activity against sensitive
      laboratory cultured mycobacteria, produces an inhibitory action on polyresistant
      clinical strains. Experiments on animals (mice, rabbits) with experimental
      tuberculosis have established that Perchlosone and isoniazid have equal
      therapeutical properties, and the former shows a synergist interaction with
      rifampicin, has neither mutagenic activity nor negative effects on immunity and
      the surfactant system of the lung.

PMID- 10420770
TI  - [Type UUKM-4d carbonic carbon and porous titanium in plastic repair of bone
      defects: experimental studies].
AB  - The experimental laboratory of the Saint Petersburg Research Institute of
      Pharmacology studied the potentialities of replacing bony defects and cavities by
      type UUKM-4d high-porous carbonic carbon. It was found that in orthotopic
      implantation, the more intensively bony osseous tissue was grown into the pores
      of an implant made of carbonic carbon, the more prolonged a postsurgical interval
      was; just at month 1 after orthotopic implantation, carbonic carbon implant was
      tightly fixed in the bony bed. Porous titanium is also fixed in the osseous
      defect without producing negative reactions of a patient's osseous tissue.

PMID- 10420771
TI  - [Training of high-skilled researchers at the Saint-Petersburg Research Institute
      of Phtisiopulmonology in 1994-1998].
AB  - The paper presents the Institute's activities in qualification rating of its
      staff from January 1994 to September 1998. It analyzes theses prepared and
      defended by the Institute's researchers and competitors. The activities of the
      dissertation council are briefly characterized.

PMID- 10420772
TI  - Ultrasonic investigation of blood flow.
AB  - Ultrasound and the Doppler effect are used to measure blood velocity non
      invasively in order to diagnose blood vessel disease. Intrusive lesions on
      arterial walls give rise to an alteration of the time-varying blood velocity
      waveform and local blood flow disturbance which are detected and measured using
      the envelope and width of the Doppler signal spectrogram respectively. Flow may
      also be imaged in colour superimposed on a grey-scale anatomical image allowing
      vessel narrowing and the accompanying flow disturbance to be visualized.
      Developments in three-dimensional imaging, angle tolerant velocity measurements
      and increased sensitivity using second harmonic backscatter from encapsulated
      bubble contrast media ensure increasing use of this modality.

PMID- 10420773
TI  - Measurement of tissue motion.
AB  - A number of ultrasonic methods are available for the detection of tissue motion
      as it occurs physiologically in the body. The detection of echoes from within the
      body in less than 1 ms after the initial transmission of ultrasound and the
      Doppler effect have enabled a range of instrumentation to be developed. The
      subject owes a great deal to advances in transducer design, electronics and
      computer technology. Over many years fast B-mode imaging and M-mode traces of
      boundary position versus time have been the main clinical tools. Currently new
      sophisticated detection and imaging techniques are being produced based on the
      Doppler effect and on tracking motion in tissue images. The measurement of
      several velocity components is permitting velocity vectors to be determined more
      completely, adding to accuracy. Not surprisingly, cardiology is the main field of
      application but there are other areas of interest, e.g. vascular, musculo
      skeletal and foetal function studies.

PMID- 10420776
TI  - Elastography: ultrasonic estimation and imaging of the elastic properties of
      tissues.
AB  - The basic principles of using sonographic techniques for imaging the elastic
      properties of tissues are described, with particular emphasis on elastography.
      After some preliminaries that describe some basic tissue stiffness measurements
      and some contrast transfer limitations of strain images are presented, four types
      of elastograms are described, which include axial strain, lateral strain, modulus
      and Poisson's ratio elastograms. The strain filter formalism and its utility in
      understanding the noise performance of the elastographic process is then given,
      as well as its use for various image improvements. After discussing some main
      classes of elastographic artefacts, the paper concludes with recent results of
      tissue elastography in vitro and in vivo.

PMID- 10420777
TI  - Three-dimensional morphometry in ultrasound.
AB  - The clinical use of three-dimensional (3D) ultrasound has rapidly spread to many
      specialities over the last ten years. The reason is easy to see, namely that
      single two-dimensional (2D) scans are often difficult to interpret and the mental
      correlation of multiple 2D scans to form a 3D image of anatomical morphology is
      taxing and uncertain. The rapid development of techniques for the realtime
      tracking of the spatial position and orientation of ultrasound probes and the
      development of computer graphics techniques for the presentation of anatomical
      images have made 3D ultrasound a realistic diagnostic tool. The authors describe
      the range of methods of data acquisition and display and provide illustrations of
      some current clinical applications.

PMID- 10420778
TI  - Measurements of organ volume by ultrasonography.
AB  - In a clinical context, measurements of organ volume are often performed in the
      diagnosis and follow-up of patients with a variety of diseases. Ultrasonography
      is a cheap, widely available and non-hazardous imaging modality to use for
      estimation of volumes, and a range of two- and three-dimensional methods have
      emerged to accomplish this task. This paper reviews some of the ultrasound
      methods available in cardiology, gastroenterology, nephrology/urology and
      gynaecology/obstetrics. Using two-dimensional (2D) ultrasound, the simplest
      method of calculating the volume of an organ is based on the multiplication of
      three diameters perpendicular to each other. These 2D methods are often based on
      geometrical assumptions which may introduce significant errors in volume
      estimation. Therefore, volume estimation based on three-dimensional (3D)
      ultrasound has been developed to increase accuracy and precision. At present, the
      process of making 3D images based on ultrasonography is divided into five steps:
      data acquisition, data digitization, data storage, data processing and data
      display. In conclusion, ultrasonography is a useful and reliable tool to
      calculate volumes of organs. In particular, 3D ultrasonography seems promising in
      this respect and appears to be superior to 2D ultrasonography in accuracy and
      precision in volume measurements.

PMID- 10420779
TI  - Acoustic and ultrasonic tissue characterization--assessment of osteoporosis.
AB  - Osteoporosis, often termed the 'silent epidemic', has been defined as 'a decrease
      in bone mass and architectural deterioration of bone tissue, leading to enhanced
      bone fragility and consequent increase in fracture risk'. In the United Kingdom
      alone, the annual health costs are in excess of 750 million Pounds, with 60,000
      patients suffering a hip fracture each year. A quarter of these will die within
      12 months of their fracture, half of the remainder will never regain independent
      living. The established procedure for assessing the risk of osteoporotic fracture
      is via bone mineral density (BMD) assessment using dual-energy X-ray
      absorptiometry (DXA). However, DXA is an expensive technique and is not widely
      available. Within the past 15 years, ultrasound assessment of bone has rapidly
      advanced in scientific understanding, technical development and clinical utility.
      Measurements of cancellous bone (particularly at the calcaneus) are generally
      performed in preference to those of cortical bone (tibial cortex). There are
      currently 15 commercial systems available and over 3500 systems are in use world
      wide. The low cost and portability offered by ultrasound systems should enable an
      integrated community-based screening programme to be established in the near
      future. Ultrasound measurements of bone are generally obtained using transmission
      rather than pulse-echo techniques owing to its highly attenuating nature.
      Ultrasound velocity and attenuation measurements are utilized. For velocity,
      there are well-defined fundamental relationships describing the dependence upon
      the elasticity and density of bone.

PMID- 10420780
TI  - The use of low-frequency vibration measurement in orthopaedics.
AB  - This paper reviews the literature regarding the use of applying conventional low
      frequency vibration analysis as a possible diagnostic tool in the orthopaedic
      field. Although a considerable number of investigations have been carried out,
      including the effects of soft tissue, the technique has not been widely accepted
      clinically. The application of ultrasound appears to be a more realistic
      alternative.

PMID- 10420781
TI  - [Comments on the editorial about the scientific statute of epidemiology].

PMID- 10420783
TI  - [A third opinion on the prevalence of domestic violence en the city of Durango].

PMID- 10420782
TI  - [Comments on the article about prevalence of domestic violence in the city of
      Durango].

PMID- 10420784
TI  - [Development and appearance of a new epidemiologic profile].

PMID- 10420785
TI  - [Development and evaluation of food supplements for the education, health, and
      nutrition program].
AB  - OBJECTIVE: To develop and evaluate nutritional supplements destined to a program
      of social assistance. MATERIAL AND METHODS: In the design of the nutritional
      supplements a series of criteria were considered including nutrient composition,
      physicochemical properties and feasibility of production and utilization. Final
      products were initially evaluated to determine the level of acceptance in 40
      children, 52 pregnant women and 62 lactating women in Mexico City. A community
      trial was also carried out to determine acceptance and consumption in 108
      children and 128 women from a rural community in the state of Morelos. RESULTS:
      The specific formulation and technical processes of production of the nutritional
      supplements are presented. Products proved to be widely accepted, with average
      scores of 4.11-4.29 for the children's beverage, and 3.98-4.15 for a more viscous
      pap (range of scores was 1 to 5). Products for women received average scores from
      4.75 to 5.70 in pregnant and from 4.8 to 5.4 in lactating women (range of scores
      from 1 to 7). In the community trial, supplements were very well accepted.
      Average consumption was > 75% among children and > 98% among women. Mean energy
      intake from supplements was 244 Kcal/day for women, and for children, 168
      Kcal/day with the pap and 147 Kcal/day with the beverage. Consumption was
      consistent in all cases along the study. CONCLUSIONS: Nine nutritional
      supplements were developed and evaluated which comply with the necessary
      nutritional, physicochemical and hygienic characteristics for the target
      population, besides being relatively simple to prepare, and widely well accepted
      and consumed.

PMID- 10420786
TI  - [Acceptability of food supplements in pregnant or lactating women and children
      under 5 years of age].
AB  - OBJECTIVE: The present study explores the acceptance and consumption of
      nutritional supplements that form part of a governmental program to support
      nutritionally vulnerable groups. MATERIAL AND METHODS: Pregnant and lactating
      women, and mothers of malnourished toddlers, infants and children were
      interviewed. Data were collected, after introduction with an interview guide with
      an open-ended format, through face-to-face interviews conducted at home.
      Interviews were taped with previous informed consent. Analysis included topics
      and subtopics approached by the interviewed women. RESULTS: The studied
      population showed good acceptance to the supplement when offered as a drink. When
      considering benefits, pregnant women thought first of their baby's health than of
      their own and associated the possible advantages of the supplement to its
      "vitamin" contents. Acceptance of the flavors was largely influenced by previous
      contact to specific flavors. Children under 1 year of age preferred the liquid
      consistency and elderly children favored the puree. Most mothers considered that
      the offered amount was enough and there was the general impression that, as the
      time of the intervention elapsed, children showed greater appetite. The diet was
      not substituted by the supplement. CONCLUSIONS: Acceptance of the supplement may
      be improved by messages focusing on the well-being and health of the child and
      insisting on the benefits for the pregnant mother. Community health providers
      should be involved in supporting the program, recommending consumption and
      acceptance of the supplement. The identification by mothers of "vitamins" as part
      of the supplement may be used to reinforce the concept of beneficial effects
      associated to micronutrient supplementation. Qualitative evaluations should be
      performed as part of the assessment of community-based programs.

PMID- 10420787
TI  - [Age-period-cohort analysis of mortality caused by traffic accidents in Spain].
AB  - OBJECTIVE: To study the evolution of traffic accidents mortality in Spain and its
      possible application to an age-period-cohort analysis, as well as the effect of
      selected road safety measures. MATERIAL AND METHODS: Road accidents rates of
      mortality were obtained, and five-year interval age rates for each sex, which
      allows the study of specific rates of age by birth cohorts. To determine the
      association between the selected road safety measures and mortality. Poisson
      regression models were adjusted. RESULTS: Two waves emerge in the evolution of
      traffic accidents. There was no clear effect with respect to age, nor was there a
      cohort effect for men or women. As to the road safety measures, we discuss the
      consistency between the selected models and graphic results. The compulsory use
      of helmet and of crossing lights is significantly associated to a reduction in
      mortality (RR 0.73, p < 0.05). CONCLUSIONS: Road accidents mortality shows a
      slight increase in the studies period. This rate performance cannot be
      sufficiently explained by age effects, diagnostic period nor birth cohort,
      however, road safety measures are considered positive.

PMID- 10420788
TI  - [Gender differences in alcohol consumption in Mexico City].
AB  - OBJECTIVE: The objectives of the present study were: 1) To corroborate the
      increase in alcohol consumption in the female population registered by results
      from the National Surveys on Addictions (ENA), 1988 and 1993; and 2) to determine
      affected age groups, and obtain basic information on age of onset, amount
      consumed per event and drunkenness frequency in the adult population of Mexico
      City, as indicators to orient preventive measures. MATERIAL AND METHODS: A multi
      stage, stratified household survey was applied. A total of 1,932 interviews was
      completed, subjects were between 18 and 65 years of age, with a response rate of
      60.4%. The instrument was a modified version of the Composite International
      Psychiatric Interview (CIDI), which is a highly structured instrument, applicable
      by non-specialized personnel, although limited training is necessary. The alcohol
      section included questions on the age of the first drink, the frequency and
      amount consumed during each event and the drunkenness frequency during the last
      12 months, among other variables. Median and percentage were obtained by sex and
      among age-cohorts. RESULTS: Of the total, 96.5% of men and 18.1% of women have
      consumed at least one drink in their lives. In average, age of onset is 16 years
      for men, and 18 years for women. Age group comparisons show a clear tendency to
      begin drinking at an earlier age, particularly in women. The growing trend
      indicated by ENA with respect to alcohol consumption in the feminine population
      and at a younger age was corroborated. Results indicated that, in average, 5
      years after the age of onset, both men and women reach their highest quantities
      of alcohol consumption, which tend to be excessive. Additionally, high-risk
      drinking among women (five or more drinks per event) increased to be four times
      higher in a period of seven years, and with an apparent tendency to rise. Sixty
      percent of the drinking population reduced alcohol consumption before the age of
      30, however, the remaining 40% continued to drink at the same rate, or even
      increased consumption, particularly among women. CONCLUSIONS: The age of onset of
      alcohol consumption has diminished, especially in women, showing tendencies
      towards abuse. Preventive programs should predominantly focus on young age groups
      with emphasis on the feminine population.

PMID- 10420789
TI  - Depression in late life: a hidden public health problem for Mexico?
AB  - Depression is one of the most important causes of disability in the world, causes
      considerable suffering, and problems associated with depression are extremely
      costly to society. Depression is one of the most common and debilitating
      illnesses of older people that is frequently overlooked. The most recent
      epidemiological study in Mexico estimated the lifetime prevalence of major
      depressive episodes among people 18 to 54 years old to be 7.8%, only second to
      alcohol dependence (8.2%). A previous study found that older adults tend to have
      higher levels of depression than younger adults. There are important gaps of
      information about depression among the elderly. Along with refined measurement
      approaches, further research is needed on risk and protective factors for
      depression as these factors might highlight the areas that need to be targeted.
      Addressing depression among the elderly can significantly contribute in reduced
      health care costs, lowered disability, morbidity and mortality. This could yield
      important savings, freeing resources that might become available for the
      attention of important health care needs.

PMID- 10420790
TI  - [Evolution of air pollution and impact on control programs in 3 megacities in
      Latin America].
AB  - The present work discusses the problems of atmospheric pollution of three
      Megacities of Latin America (Mexico City, Sao Paulo and Santiago). The
      environmental pollution control programs implemented by the Government are
      revised and the evolution of pollution levels during the period of 1988-1995 at
      Santiago de Chile and Sao Paulo, but until 1997 at Mexico City, in order to
      evaluate the impact of these programs. During this period, a decreasing trend is
      observed in the three cities in the levels of PTS, PM10, SO2, NO2, CO and O3,
      although most of these contaminants still exceed the air quality standards. It
      must be emphasized that the largest impact has been on the levels of SO2. We
      recommend the development of sustainable transport policies; in this context,
      various strategies were proposed by the Organization for Economic Cooperation and
      Development (OECD) in the European Conference of Ministers of Transport.
      Additionally, public participation is important when decisions are taken on
      transport policies.

PMID- 10420791
TI  - [Acceptance and use of medicinal plants in family medicine].
AB  - OBJECTIVE: To explore the degree of usage of therapeutic medical plants among the
      patients, physicians and health workers in a local Family Medical Care Unit of
      the Mexican Institute of Social Security (IMSS)). MATERIAL AND METHODS: A
      transversal descriptive study was performed. A questionnaire focusing on two
      variables was designed and validated. It was applied to 60 family physicians, a
      randomized sample of 130 health workers and another of 264 patients of the Family
      Mediccal Care Unit. Response percentage was 78%. RESULTS: The study found that
      83% of family physicians accept the therapeutic use of herbal medicine; moreover,
      75% use it as a therapeutic resource. Among health workers, acceptance and use
      was 100%, while in patients the level of acceptance was of 92% and of use it was
      90%. Differences between groups are significant (p < 0.05). The more frequently
      used plants are Gordolobo (Gnaphalium sp.), Eucalyptus (Eucalyptus sp., probably
      E. globulus), spearmint (Mentha sp.), camomile (Matricaria chamomilla) and
      prickly pear cladodes (the vegetative parts of the prickly pear, Opuntia sp.
      Probably Opuntia ficus indica). CONCLUSIONS: This information agrees with
      previous reports about Mexico, however, in this case, data were gathered in urban
      areas where physicians have been trained in the biomedical paradigm of medicine.

PMID- 10420792
TI  - [The shamanic cure: a psychosocial interpretation].
AB  - The present paper is basically a theoretical analysis of the shamanic cure, which
      proposes communication as the basis of the healing process. This process is
      described as a communicative act focusing on the interpretation of symbolic
      elements. The context is the social dimension in which the process is inscribed,
      the linguistic mode employed, and the type of relationship established between
      the shaman, the patient and the people. We also recount the way in which a shared
      symbolic reality is built, and how the shaman's world view has important effects
      on people. The interpretative framework is the psychosocial focus and an
      explanation is offered in terms of the establishment of a communicative act as a
      scenario in which the symbolic reality is constructed, and in itself constitutes
      the cure into which the patient enters every session. The magical vision of
      shamanism is analyzed and its influence on the health-illness process.

PMID- 10420793
TI  - The philosophy of nursing.
AB  - The purpose of this article is to provide an overview of the philosophy of
      nursing. First, the ontological, epistemological, and ethical issues that
      comprise the field of inquiry are identified. Second, we discuss how some of
      these issues are being addressed as demonstrated by the articles in this issue of
      Scholarly Inquiry for Nursing Practice. Finally, suggestions are made for the
      further development of the philosophy of nursing in the 21st century.

PMID- 10420794
TI  - A philosophical interpretation of nursing.
AB  - The authors discuss their interpretation of nursing as the practice of caring.
      Through interpretive phenomenology, they lift out the essential meaning of
      nursing as practiced, and through generative interpretation of philosophical
      treatments of relationships, practice, and caring, they enlighten nursing
      practice. They discuss the implications of interpreting nursing as the practice
      of caring for nursing scholarship, education, and ethics.

PMID- 10420795
TI  - Theorizing the knowledge that nurses use in the conduct of their work.
AB  - The authors propose a classification of knowledge that they call case, patient,
      and person and that reflects the content of the knowledge necessary to the
      conduct of nursing work. This classification represents an attempt to theorize
      from their respective empirical research data. Case knowledge is general
      knowledge of pathophysiology, disease processes, pharmacology, and other
      therapeutic protocols. Patient knowledge is that knowledge that defines the
      individual within the health care system, the knowledge expressed in the
      individual's response to therapeutics, and the knowledge that enables nurses to
      move the recipient of care through the health care system and along the illness
      trajectory. Person knowledge is knowledge of the individual as a subject with a
      personal biography who occupies a certain social space and who acts with his or
      her own desires and intentions for reasons that make sense to him or her. Two
      types of social knowledge serve as relational knowledge, or a bridge that links
      case knowledge to patient knowledge and patient knowledge to person knowledge.
      Each type of knowledge is accessed differently and the extent to which each is
      attained and used is determined by the circumstances of the patient's illness and
      his or her location in the health care system. The authors make a case for why
      this classification might be useful to the discipline.

PMID- 10420796
TI  - Practical nursing judgment: a moderate realist conception.
AB  - Under the influence of idealist mainstream thinking that reality is mind
      dependent, many nurses are dismissing the possibility of attaining objectively
      true judgments. A worrisome trend that has emerged from such thinking is to
      recommend that nursing practice decisions ultimately be based solely on
      subjective judgments. We present a conception of practical nursing judgment based
      on the common-sense philosophy of moderate realism, which has the potential to
      help offset the trend. It allows for nursing decision making in which nursing
      principles and rules are modified in light of the contingent circumstances of a
      nursing situation, resulting in decisions which have both a subjective and an
      objective aspect to them. This feature, plus the fact that the nursing principles
      are grounded in common natural needs, rights, and obligations, provides nurses
      with a basis for nursing care which is individualized, just, benevolent, and
      sensible, a means requisite to making our lives good.

PMID- 10420797
TI  - Relational narrative: the postmodern turn in nursing ethics.
AB  - A philosophy of nursing requires an ethical cornerstone. I describe three
      dialectical layers of an ethical cornerstone: subjective immersion, objective
      detachment, and relational narrative. Dialectically, the move from immersion to
      detachment is the turn from communitarian to rational ethics, replacing
      traditions with universal principles. The move from universalism to engagement is
      the turn from rational to relational ethics, replacing detached reason with
      engagement between particular selves. Conceptually, the three layers correspond
      to premodern, modern, and postmodern ethics. I propose that the layers be viewed
      not as stages, but as elements that coexist in an ethically vital profession, and
      I conclude with an illustration of their coexistence in a clinical situation.

PMID- 10420798
TI  - [Measles, mumps and rubella: vaccination rate and seroprevalence in 8th grade
      students of 8 different sites in Switzerland 1995/96].
AB  - In 1987, the Swiss Federal Health Office (BAG) and the Swiss cantons launched the
      MMR-vaccination campaign. Within the frame of the SCARPOL Study, the vaccination
      status of 649, 8th class students was registered and serum samples were
      collected. The measles, mumps and rubella specific antibody levels were
      determined. The vaccination rate was 84% for measles, 74% for mumps, and 62% for
      rubella, 55% of these children had been vaccinated with the combined vaccine MMR.
      The vaccination rate for the different study areas varied from 70% to 95% for
      measles, 42% to 94% for mumps and 18% to 89% for rubella, 92% of the children
      tested seropositive for measles specific antibodies, 87% for mumps and 84% for
      rubella. The seroprevalence for measles, mumps and rubella was significantly
      higher for vaccinated than for unvaccinated children. Non-Swiss children had,
      without exception, a higher seroprevalence rate than Swiss children. Undergoing
      the disease did not influence the seroprevalence for measles, but it did so for
      mumps and rubella, for vaccinated and unvaccinated children alike. By analysis
      according to study site, we observed that sites with higher vaccination rates
      (e.g. Grabs in Rheintal) sometimes showed a lower seroprevalence than sites with
      lower vaccination rates (e.g. Langnau). This was the case for all three vaccines.
      This, together with other observations, shows that a booster is necessary for an
      adequate immunisation--as a wild virus infection or as a second vaccination.

PMID- 10420799
TI  - [Some aspects of prebyphonia].
AB  - Vocal disorders are a common dysfunction associated with aging that can have a
      significant effect on the quality of life. Advancing age produces physiologic
      changes that may alter voice. Some of these changes are inevitable; others may be
      avoidable or reversible. An appreciation for the causes of vocal dysfunction in
      the elderly is a first step to providing better care for the geriatric patient
      with complaints about voice dysfunction.

PMID- 10420800
TI  - [Breast carcinoma: ever smaller lumps--even less surgery?].

PMID- 10420801
TI  - ["Everything hurts me"].

PMID- 10420802
TI  - [Hirsutism. Polycystic ovaries with suspected metabolic syndrome].

PMID- 10420803
TI  - [Stomach pain and loss of appetite. Non-ulcer dyspepsia with gastroesophageal
      reflux].

PMID- 10420804
TI  - [Beta blockers after myocardial infarct: patients with low and high risk factors
      benefit equally].

PMID- 10420805
TI  - [Expensive long-term care with virustatic drugs frequently reduces herpes
      genitalis episodes].

PMID- 10420806
TI  - [Malignant melanoma].

PMID- 10420807
TI  - [Enjoying the sun well protected].
AB  - According to the annual figures, skin cancer is the fastest growing type of
      cancer: one child in every hundred is currently at risk of developing a melanoma,
      the most malignant form of skin cancer. Surveys show that people are changing
      their behaviour when it comes to dealing with the sun. But only in small steps.
      That's why the Cancer League launches a sun protection campaign every year.
      Simple rules for protection from the sun: Between 11.00 a.m. and 3.00 p.m.
      (summer time), people should remain in the shade. A head covering and light,
      loose clothing should be worn in the sun. Tightly-woven, strong-coloured fabric
      offers better UV protection than coarsely-woven natural fibres. Sunglasses
      protect the eyes. The choice of sun screen depends on the skin type, the desired
      level of protection and the intended activity in the sun. The sun cream should be
      applied liberally half an hour before exposure to the sun. Depending on the
      particular preparation, it may need to be reapplied after bathing or showering to
      ensure that sun protection is maintained. Where reflective surfaces are present,
      e.g. sand, snow, cement and water, it is advisable to use sun protection creams
      even in the shade. Babies up to one year of age should be kept in the shade and
      sun protection agents should not be used on them. Like other chemical products,
      these may irritate the sensitive skin of babies and trigger allergies. Sunscreens
      used in older children should be waterproof, contain no alcohol and possess a
      high sun protection factor (at least SPF 15). Baby oil should not be used since
      it makes the child's skin even more sensitive to light. Parents should set an
      example to children in the way they protect themselves from the sun. Artificial
      UV light from sunbeds should be avoided, particularly by children and persons
      with an increased risk of developing a melanoma.

PMID- 10420808
TI  - [Secondary prevention of malignant melanoma].
AB  - Secondary prevention of melanoma covers early recognition of malignant melanoma
      and precursors. The aims of secondary prevention are: decrease of tumor thickness
      at the time of first detection and first therapy. decrease of melanoma mortality.
      Screening of high-risk-persons for melanoma is a fair strategy for Switzerland:
      easy to perform and also efficient.

PMID- 10420809
TI  - [From epidemiology of melanoma to prevention--facts and references].
AB  - Melanoma incidence rates in Switzerland are very high for European standards.
      Incidence is increasing like in other white populations; melanoma mortality has
      stopped its secular increase and is decreasing in people under the age of 65. The
      reasons for the high melanoma rates in Switzerland can only be guessed:
      Switzerland is a rich country (melanoma is more prevalent among the rich); the
      Swiss are known to spend their vacations in Southern countries, exposing
      themselves to the sun. The paradox of increasing incidence and decreasing
      mortality rates is discussed, also from the view of the histopathologist.
      Melanoma patients are at increased risk for subsequent skin carcinoma
      (basalioma/spinalioma) and vice versa. This may be explained by the common risk
      factor: sun exposure. The importance of primary prevention is stressed; the Swiss
      Cancer League is organising annual education campaigns among youngsters.
      Secondary prevention should focus on high risk groups: families prone to
      melanoma; older men.

PMID- 10420810
TI  - [Risk factors for the development of malignant melanomas].
AB  - There are numerous risk factors for the development of malignant melanomas.
      Genetic and environmental aspects have to be considered. The most important
      genetic risk factor is a mutation in the CDKN2A gene, which is a turmorsuppressor
      gene which regulates the cell cycle. In addition, the familial dysplastic nevus
      syndrome shows a marked risk for the development of malignant melanoma. Patients
      with xeroderma pigmentosum have an inability to repair UV-induced DNA defects.
      This constellation leads to early development of epitheliomas and malignant
      melanomas. Constitutional risk factors are fair-red hair and blue eyes with a
      high tendency for sunburns. The most important environmental factor is UV
      exposition. Sunburns before the age of 15 and the total cumulative UV-dosage are
      high impact risk factors. The most important preventive measures are to check the
      whole skin at a regular base in a patient with the familal dysplastic nevus
      syndrome and in addition all persons should wear a hat, trousers, shirt and
      glasses. Furthermore direct sun exposure should be avoided during noon time.

PMID- 10420811
TI  - [Clinical aspects and pathology of melanoma].
AB  - The annual incidence of melanoma is continually increasing. Melanomas can easily
      be diagnosed because they are readily visible on the skin. The prognosis is
      excellent for melanoma when it is diagnosed in an early stage. The clinical
      diagnosis of melanomas is made by the simple A-B-C-D-E-rule. Clinically, we
      distinguish the following melanoma types by the order of frequency: the melanoma
      of the superficial spreading type (SSM), the melanoma with nodular type (NM), the
      lentigo maligna melanoma (LMM) and the acro-lentiginous melanoma (ALM). Other
      clinical subtypes of melanoma are congenital giant nevus and melanoma of the
      mucous membranes. With help of histogenesis, we can distinguish similar forms for
      melanoma of the SSM-type, melanoma of the NM-type, the lentigo maligna melanoma
      (LMM) and the melanoma of the ALM-type. In this case, it is preferable to use the
      terminology acanthotic-lentiginous melanoma since acro-lentiginous is the
      clinical expression and not a histopathological one. Further subtypes can be
      distinguished histopathologically such as the desmoplasic melanoma which has been
      recently described as melanoma from a dysplasic nevus as well as melanoma of the
      lichen cleanness type. Furthermore, due to histopathology other particular forms
      can be distinguished such as the melanoma of the nevus Spitz type and melanoma
      originating from a blue nevus. Most important for the histopathological report is
      the thickness of the melanoma in millimeters related to the Breslow index as well
      as the invasion level in the skin by the Clark classification since the melanoma
      thickness is the most important risk factor for the melanoma patient.

PMID- 10420812
TI  - [Cytogenetic aspects of malignant melanoma].
AB  - In analogy to colon carcinoma, where a stepwise accumulation of genetic changes
      have been described during tumor progression, a sequence of genetic events may be
      responsible for the transformation of melanocytes to dysplastic nevi and melanoma
      with horizontal and vertical growth phases and finally the formation of distant
      metastases. The current literature supporting this concept as well as own
      contributions are presented.

PMID- 10420813
TI  - [Clinical differential diagnosis of pigmented skin changes and contribution of
      epiluminescence microscopy].
AB  - The differential diagnosis of skin pigmented lesions is an everyday challenge for
      the physician. The main goal is the early diagnosis of malignant melanoma because
      its prognosis is directly correlated with its thickness at the time of the
      excision. Identification criterion of invasive melanoma have been recognized in
      the past, like bleeding or ulceration. More subtle clinical criterion have been
      identified and are summarized in the ABCDE rule (Asymmetry, irregular Border,
      variegation in Colour, Dimension and Enlargement). A knowledge of the various
      kind of skin pigmented lesions should help the physician to differentiate benign
      lesions from suspicious or frankly malignant ones, in order to set up the
      indication for an histological procedure or for a subsequent follow-up of the
      patient. More recently, skin surface biomicroscopy, or dermoscopy, has revealed
      invisible structures to naked eye, allowing to enhance the clinical diagnosis of
      skin pigmented lesions, but a specific education is needed.

PMID- 10420814
TI  - [Surgical treatment of malignant melanoma].
AB  - Early diagnosis and total tumor excision are fundamental to assure a favorable
      outcome in the treatment of the malignant melanoma. Previously a large local
      excision up to 5 cm was recommended. In the past two decades some prospective
      studies showed the same survival rate when using narrower margins of excision (1
      3 cm). The elective lymphadenectomy increases the survival rate only in a small
      group of patients and has a high rate of complications. The concept of lymphatic
      mapping can greatly help in finding the lymph node ("sentinel lymph node") which
      is the first one to receive lymphatic drainage from the affected area. This node
      has the highest probability of containing a metastasis and is excised. With this
      procedure the number of patients requiring lymphadenectomy can be limited to
      those who have documented lymph node metastases. The sentinel biopsy technique
      can provide new insight into the tumor biology of melanoma and helps in
      determining adjuvant therapy. In order to evaluate the influence of sentinel node
      biopsy on survival rate of melanoma patients clinical trials have been designed.
      Systemic melanoma metastases carry a poor prognosis. Surgical resection of
      isolated metastases may provide good palliation, in combination with other
      therapies.

PMID- 10420815
TI  - [Adjuvant therapy of malignant melanoma].
AB  - The goal of adjuvant therapy after routine surgery of malignant melanoma is the
      effective suppression of progression of disease caused by clinically inapparent
      micrometastases. While individual small and mostly retrospective clinical studies
      comparing adjuvant chemotherapy with untreated historical controls suggested a
      possible benefit for treated patients, large and multicenter prospective,
      randomized studies failed to clearly demonstrate a benefit for treated patients
      in regard to improvement of disease free or overall survival. Therefore, adjuvant
      chemotherapy can no longer be recommended for patients with malignant melanoma
      outside of controlled clinical studies. Current promising candidates for
      successful adjuvant therapy of patients with malignant melanoma are recombinant
      biological response modifiers, in particular interferons. Three randomized
      studies consistently reported a benefit in regard to relapse free survival for
      patients treated with interferon-alpha compared to untreated controls. However,
      the impact, on extension of overall survival ('cure') remains unclear.
      Furthermore, to date, no definitive data on the optimal dose and duration of
      interferon-alpha-therapy are available. Thus, patients with high risk of tumor
      progression should be enrolled in national and international prospective,
      randomized clinical trials, which may lead to valid data and clear
      recommendations about optimal adjuvant therapy.

PMID- 10420816
TI  - [Systemic therapy of metastatic melanoma].
AB  - Therapy of metastatic melanoma still remains difficult. All therapeutic
      strategies have to consider the individual patient's condition and number and
      localisation of the metastases. Solitary metastases in lung, CNS, soft tissues
      and lymph nodes have to be removed by surgery. Multiple metastases are treated
      with a systemic chemoimmunotherpy. Promising approaches use interleukin-2,
      interferons, DTIC, temozolamide, vindesine and cisplatin. Radiotherapy is the
      treatment of first choice for bone and CNS metastases. These therapeutic
      strategies have improved the prognosis of metastatic melanoma. Additional multi
      center trials and experimental approaches will help to reach the goal of a
      curative systemic therapy for metastatic melanoma.

PMID- 10420817
TI  - [Vaccination therapy of malignant melanoma].
AB  - There is no cure for advanced melanoma. Chemo- or chemo-immunotherapy may lead to
      tumor regression in a minority of patients. New perspectives for treatment derive
      from recent efforts to develop vaccination strategies for melanoma. Insights into
      the immunobiology of this disease combined with the characterization of tumor
      specific peptide epitopes as well as appreciation of the crucial role of
      dendritic cells for the induction of anti-tumor immunity are beginning to be
      translated into the every day clinical practice.

PMID- 10420818
TI  - [Therapy of CNS metastases].
AB  - Brain metastases occur in 20-30% of patients with systemic cancer and represent
      one of the most unfavourable prognostic parameters. In the majority of cases
      brain metastases are multiple and are usually treated with whole brain
      irradiation. The treatment of single brain metastases often includes surgery,
      followed by whole brain radiotherapy. Although the goal of treatment of both
      single and brain metastases is almost always palliation and not cure, it is
      important that several modes of treatment are carefully compared. In comparing
      different treatment regimens it should be emphasised that not only duration of
      survival time and time until tumour recurrence are used as outcome parameters but
      also the quality of life. The only way in which the results of different
      therapies can be compared is by means of randomised trials. As long as high
      quality studies are not available, any definitive assessment of the relative
      effectiveness of radiosurgery to standard treatment for brain cannot be defined.
      Radiosurgery can be used to treat patients, whose metastases recur after
      traditional therapies. As with other definitive therapies for patients with brain
      metastases, highly functional patients with well-controlled systemic cancers
      derive the greatest benefit from treatment with radiosurgery.

PMID- 10420819
TI  - [Psychosocial aspects of malignant melanoma].
AB  - Psychosocial aspects play a role in every stage of malignant melanoma: they are
      significant in terms of sun exposure habits (primary prevention) and have an
      important influence on the time lapse between the onset of malignant melanoma and
      its diagnosis (secondary prevention). Knowledge about psychosocial aspects is
      also necessary during the course of illness following primary treatment as during
      this phase patients make critical efforts in understanding and adapting to their
      illness. These efforts in turn interact with treatment measures and the course of
      the illness (tertiary prevention). Effective psychosocial interventions are
      available that can have an important impact on patients' quality of life. Stage
      appropriate disease management requires knowledge of relevant psychosocial
      aspects during the course of cancer and has practical consequences not only for
      future prevention measures, but also for individual patients, physician-patient
      relationship and interdisciplinary patient care.

PMID- 10420820
TI  - [Fractures of the proximal humerus].

PMID- 10420821
TI  - [Fractures of the proximal humerus].
AB  - Proximal humeral fractures are common particularly in the elderly. The decision
      of the optimal treatment is dependent on many factors. On the one hand the
      biological age of the patient and the bone structure plays a key-role, on the
      other hand the living conditions and individual needs are of importance. Most
      fractures with minimal displacement respond satisfactorily to simple conservative
      treatment including short sling immobilisation and functional aftertreatment
      under supervision of the physiotherapist. Most recently there is a trend towards
      more aggressive surgical intervention with percutaneous insertion of cannulated
      screws also in the slightly displaced fracture situation. This protocol allows
      for earlier functional and less painful aftertreatment, less risk of displacement
      of the fracture fragments and better outcome. In severely unstable fractures with
      marked displacement of the fragments an operative stabilisation is advocated by
      most surgeons. Again there is a trend from plating towards cannulated screw
      fixation combined with tension absorbing (resorbable) sutures. In special cases
      which are described in detail a minimal invasive percutaneous screw technique
      with less stripping of bone and therefore preservation of the crucial blood
      supply of the humeral head is recommended. Instead of percutaneous pinning using
      K-wires only, cannulated screws are inserted today. Plating of proximal humerus
      joint fractures is the exception in our days, only the subcapital unstable
      fracture of the elderly would be an indication. LC-condylar plating seems to
      yield better stability than the conventional T-plate-system. In the most severe
      fractures of the proximal humerus (4-segment-fractures and dislocation fractures
      according to Neer, respectively C-2- and C-3-fractures according to the AO
      classification) there is still controversy on the best management. Most authors
      prefer hemiarthroplasty in this situation whereas the other group of orthopaedic
      surgeons try open reduction and internal fixation particularly in the younger
      individuals. This stabilisation provides the orthopaedic surgeons with a
      formidable challenge and requires a lot of experience in this field. Also the
      understanding of the fracture morphology is needed for optimal results. In spite
      of good stabilisation techniques often partial or total humeral head necrosis
      occurs in the most severe fractures. Surprisingly enough results with reasonable
      function can be obtained even with partial avascular necrosis of the humeral
      head. A crucial part of the management is team work with the physiotherapist and
      an individual program for each fracture situation, depending on the stability of
      the fixation. Close contact between these two professions is of utmost
      importance. Finally it can be stated that the management of proximal humeral
      fractures is fairly standardised but it is always dependent on the experience and
      resources of the attending surgeon and must be tailored to the individual needs
      of the patient.

PMID- 10420822
TI  - [Fractures of the foot region of car drivers and passengers. Occurrence, causes
      and long-term results].
AB  - During 1973 and 1989, 6,378 car accidents with 8,931 injured persons were
      evaluated in the area of Hannover. 3,267 car drivers and passengers sustained
      fractures overall and 148 (4.5%) fractures of the foot. A major role in the
      etiology of the foot fractures evolves from the deformation of the foot room.
      Driver and front seat passenger showed similar injuries. Among the 286 single
      fractures, the forefoot was affected most often (45%), followed by ankle (38%),
      midfoot (11%) and hindfoot (6%). 5% were open fractures. The long term results
      were estimated upon the limitation of working ability caused by the foot injury
      in relation to the entire working ability. The evaluation concludes that the foot
      fractures especially in combination with other injuries were frequently not
      recognized within the primary examination and therefore underestimated. The long
      term outcome leaded to a high degree of impairment due to foot fractures.

PMID- 10420823
TI  - [Clinical and radiological results after arthroscopic partial medial
      meniscectomy. Are there risk factors?].
AB  - In a retrospective study 100 patients underwent a clinical and radiological
      follow-up 7 years and 7 months after an arthroscopic partial medial meniscectomy.
      None of these patients had associated intraarticular lesions apart a minor
      chondral damage of the medial compartment. The follow-up showed excellent
      clinical results in 96% of patients according to the modified Marshall Score. The
      radiological results demonstrated a deterioration or development of
      osteoarthritis of the operated knee joint in 33% of patients, with a statistical
      significance between radiological and clinical results (p < 0.05). The age of the
      patients at time of operation and any angular deformity of the knee joint had no
      statistical significant influence on the radiological results. Women had a
      statistically significant higher risk to deteriorate or develop gonarthrosis
      after partial medial meniscectomy than men (p < 0.05). The arthroscopic partial
      medial meniscectomy leads to excellent subjective and functional results, but it
      could not totally prevent the increase or development of degenerative changes in
      the medial knee compartment.

PMID- 10420824
TI  - [The effect of soft care mattresses on subcutaneous tissue pressure and pO2 over
      the os sacrum].
AB  - In this study the influence of soft-care systems on subcutaneous tissue pressure
      and pO2 has been examined. In 14 volunteers 3 probes were implanted over the os
      sacrum for measurement during the 20-minute periods. Then the probands were asked
      to lie on a standard mattress, on 8 static beds of various kind and on 3 dynamic
      soft-care systems. The clinical mattress pressure values amounted to 25.5 mm Hg
      (+/- 5.2; n = 14). The gell-cushion showed increased values (26.9 +/- 9.5 mm Hg;
      n = 5). Compared to the standard mattress the other systems showed reductions in
      pressure from 32.7% to 83.1%. The lowest pressure was recorded with an air
      supported mattress (8.3 +/- 2.3 mm Hg; n = 5). The pO2 initial values before
      lying down varied greatly from individual to individual (26.9-71.3 mm Hg). In the
      course of the 20-minute periods the pO2 value sometimes remained constant,
      sometimes increased and at other times it decreased. Under extreme conditions
      (with 8 probands asked to lie on the floor) a correlation (r = -0.787) between
      pressure and pO2 was observed (pressure values between 20.6 and 192.9 mm Hg). The
      results indicate the use of modern soft-care systems depending on the individual
      risk of pressure sores.

PMID- 10420826
TI  - [Allogeneic vascularized transplantation in cases of bone and joint defects].
AB  - This paper presents preliminary results of allogeneic vascularized
      transplantations of three femoral diaphyses and four total human knee joints.
      Grafts were harvested from multi-organ-donors and immediately transplanted.
      Osteosyntheses were performed employing intramedullary nails. Vascular pedicles
      of the grafts were anastomosed in end-to-side technique. Immunosuppression mainly
      based on Cyclosporine and Azathioprine. Grafts' perfusion was demonstrated by DSA
      and Duplex-sonograms, bone metabolism by SPECT-scintigraphy. Five months
      following transplantation osteotomies demonstrated consolidation in conventional
      X-rays. Biopsies of the grafted bone revealed intact osteocytes and arthroscopy
      demonstrated intact synovial, chondral and ligamentous structures. From the
      technical aspect vascularized transplantation of the femoral diaphyses and total
      knee joints is feasible. The main problems are of immunologic nature.
      Transplantations were performed respecting the ABO-compatibility but with a large
      HLA-mismatch. Acute and chronic rejection crises may damage the grafts. At least
      in synovial joints live-long immunosuppression of the recipients seems to be
      unavoidable.

PMID- 10420825
TI  - [Functional treatment of acute Achilles tendon rupture. A histological,
      immunohistological and ultrasonographic analysis of the animal model].
AB  - In 105 rabbits the course of healing was examined at 1, 2, 4, 8 and 12 weeks (21
      rabbits per group) after an experimental Achilles tendon rupture. The following
      treatment modalities were compared: a. operative functional treatment (resorbable
      suture, Kleinert technique) b. operative functional treatment with fibrin glue c.
      primary functional treatment. For the functional (after)-treatment a special
      orthosis was applied. A 7.5 MHz Ultrasound probe was used for the
      ultrasonographic evaluation. The histological specimens were stained after Masson
      Goldner with Azan. Collagen Type III was depicted immunohistologically with
      polyclonal antibodies. A semiquantitative fibrocytes count was performed. The
      histological results showed a smooth healing in the prim. functional treatment
      group reaching parallel orientation of collagen fibers at 12 weeks. In the fibrin
      glue-group the fibrin was resorbed after 4 weeks without essential influence to
      the course of healing. In the suture-group a secondary gapping of the tendon
      stumps was detectable. At 12 weeks the histological evaluation in all groups
      showed approximately normal tendon pattern. Immunohistochemically all groups
      showed cell-associated positive reactions for type III-collagen after 1 week with
      a maximum after 2 weeks. The semiquantitative fibrocyte count in the primary
      funct. group showed a maximal number after 1 week, in the fibrin glue- and suture
      groups the maximal number could be found after 2 weeks. Sonographically an
      increase in tendon thickness was detectable up to the 4th weeks in all groups.
      The secondary gapping of the tendon stumps in the suture group could be detected
      sonographically. The echogenicity of the tendon during the course of healing
      showed increasing homogeneity and parallelism in all groups. At 12 weeks the
      echogenicity was comparable in all groups. The experiment could prove the
      equivalence of the primary functional treatment to operative therapy in Achilles
      tendon rupture.

PMID- 10420827
TI  - [Technique of finger arthrodesis by dorsal thread tension band fixation.
      Comparing biomechanical investigations].
AB  - Dorsal tension band fixation is a wide-spread technique of finger arthrodesis.
      When using a resorbable PDS-suture as tension band fixation a costly implant
      removal is not needed. Aim of this study is the investigation of the primary
      stability of this technique in combination with the cup-in-cone-procedure. Freeze
      preserved fingers with thread tension band fixation using the PDS-material
      (series 1), the same fixating method on formaldehyde preserved fingers (series
      3), freeze-preserved fingers with a standard tension band fixating (wire loop,
      series 2) are load in a four-point-bending in the direction of palmarflexion.
      From 6 degrees onwards the wire-tension-system requires a higher torque for
      bending, but in case of higher torque frequently leads to fracture. The
      examination shows that the thread-tension-band method by PDS-loop for the
      stabilisation of finger joint arthrodesis has a sufficient initial stability
      against bending forces.

PMID- 10420828
TI  - [Intensive care for patients with multiple injuries].

PMID- 10420829
TI  - [Pseudarthrosis of an occult fracture in zone III of the sacrum].
AB  - Fractures in the midline of the sacrum are rare, a pseudarthrosis has not been
      described previously. We report about a 53-year-old woman with a midline fracture
      of the sacrum which has not been recognized, although there were indirect
      fracture signs on the native x-rays and a CT was performed. The surgical
      treatment with sacral compression bars was successful and pseudarthrosis healing
      resulted but the patient continued to have mild low back pain. The case reported
      here confirms that low back pain may caused by pathologic changes of the
      posterior part of the pelvis. The unusual fracture location could be caused by a
      bifid spinous process.

PMID- 10420831
TI  - [Surgical management of type III thoracic shotgun injury].
AB  - Reporting the case of a short-range severe thoracic shotgun injury the
      differentiated management of this trauma is discussed. Indication for operative
      exploration under emergency conditions is hemorrhagic shock, perforation of
      esophagus/stomach and pericardial tamponade. Even under a toxicological point of
      view there is no indication for emergency revisions.

PMID- 10420830
TI  - [Iatrogenic avulsion of the greater trochanter during prosthetic replacement of
      the hip].
AB  - An iatrogenic avulsion of the greater trochanter occurring during prosthetic hip
      replacement after a fracture of the neck of the femur is a rare complication. The
      need for maximum internal rotation of the limb during the operation imposes
      serious mechanical stress on the greater trochanter in patients who are often
      elderly and whose bones are osteoporotic. Two case reports illustrate that a
      conservative management--without internal fixation--combined with early
      mobilisation is successful. Our view is based on the current, international
      opinion that conservative management with early mobilisation is preferable for
      isolated traumatic avulsion of the greater trochanter, even if there is wide
      displacement.

PMID- 10420833
TI  - [Rehabilitation management as a new benefit of mandatory automobile driver and
      accident insurance].

PMID- 10420832
TI  - [Trauma surgery 2020. Development in the past, definition of future topics and
      programs. II. Research in trauma surgery 1998].
AB  - The field surgery has been structured into four specialties of equal importance
      that are Thoracic Surgery, Vascular Surgery, Visceral Surgery and last but not
      least Trauma Surgery. Each specialty defines its research tasks. Therefore it is
      necessary to evaluate the situation of research in trauma surgery and define
      future topics and programs. The aim of this survey was to cover the present
      research situation in Germany. Out of the 200 questionnaires 112 were available
      for evaluation. The major deficiencies were stated to be a lack of personnel,
      budget and coordination of topics and resources. Of general interest was to
      initiate activities of the German Society for Trauma Surgery (DGU) in view of
      coordination of research activities, setting up of new funds and integration of
      teaching hospitals into university research programs. The data, shown in this
      article, may serve to start a discussion aiming on the improvement of the
      financial and scientific environment.

PMID- 10420834
TI  - [Epidemiology, manifestations and complications of chronic polyarthritis].
AB  - Rheumatoid arthritis is an inflammatory systemic disease mainly affecting the
      joints. Frequent extra-articular manifestations are often recognized too late.
      Particularly the skin, the cardiovascular system, the kidneys, the eyes, the
      gastrointestinal tract, the liver, the nervous system and the blood may be
      involved. Examples of important complications affecting different organs are
      bacterial infections, AA-amyloidosis and hyperviscosity syndrome. Current data on
      the different disease manifestations and complications provide the basis for the
      assessment of the morbidity and mortality relevant for insurance purposes.

PMID- 10420835
TI  - [Long-term prognosis of conservative or surgical treatment of peripheral arterial
      occlusive disease--critical evaluation].
AB  - The spectrum of therapeutic measures for PAOD (peripheral arterial occlusive
      disease) has increased substantially. A combination of therapeutic measures is
      therefore applied more frequently. It makes sense to evaluate the patients
      individually. This is increasingly recommended. Some therapeutic guidelines are
      shown. It has to be stressed that there are no more clear-cut borders between
      conservative and operative measures. It is a fact, that the treatment of PAOD
      improves the quality of life and the morbidity.

PMID- 10420836
TI  - [Long-term prognosis after kidney transplantation].
AB  - In Germany, nearly 8,000 patients are living with a functioning renal
      transplantation. The average age of those undergoing transplantation is 43.5
      years. Without mismatch 70% of transplanted kidneys show normal function after
      five years. Other risk factors are important for the long term prognosis. The
      most important causes of death are cardiovascular diseases. The risk estimation
      factors are enumerated.

PMID- 10420837
TI  - [Psychotropic drugs and automobile driving ability of elderly patients].
AB  - Many elderly patients are prescribed psychotropic medication, many of them are
      car drivers. Driving ability may be impaired by the underlying psychiatric
      disease, the medication or the combination of both. Psychoactive medications do
      not all influence driving ability to the same extent. Cyclic antidepressants
      impair driving performance to a higher degree than selective serotonin reuptake
      inhibitors (SSRI) or MAO inhibitors. In cases of severe psychiatric diseases like
      major depression an appropriate psychoactive medication may improve driving
      performance. The influence of psychoactive drugs on driving ability is not always
      taken into account. There are no data available that allow a reliable assessment
      of these drugs in elderly patients. To meet the challenge of this problem,
      patients and doctors have to be aware of this problem; studies about the impact
      of psychoactive drugs on driving ability are necessary.

PMID- 10420838
TI  - [Knowledge and effectiveness of so-called foot sole reflex massage].
AB  - Plantar reflex massage is hardly of any importance to insurance medicine. It
      however helps to explain the affinity of patients for so-called alternative
      medicine and its methods. A proof of the effectiveness of the pretended radius of
      curative properties has never been aspired to nor is it scientifically
      conceivable. Various aspects combine to create the attraction of the method. Two
      of these result precisely from its unscientific nature. The effect is to be found
      in the improvement of the general feeling of well-being.

PMID- 10420839
TI  - [Insurance expert assessment of traumatic Achilles tendon rupture. A case
      report].
AB  - Achilles tendon ruptures are among of the most frequent tendon ruptures. Usually
      middle aged men with infrequent sports activity are involved. In most cases
      histopathology reveals degenerative changes within the tendon. Unusual rupture
      location and physical signs of trauma should lead one to consider a traumatic
      origin of the rupture. Traumatic origin can be confirmed by the accident history
      and physical signs as well as with the histopathology of the rupture site and
      possibly a tissue section far away the rupture site. This information can be
      helpful in insurance inquiries.

PMID- 10420840
TI  - [Odds ration and relative risk: confounded effects?].
AB  - This paper defines some epidemiological and arithmetrical terms. Three examples
      demonstrate confounded effects between age and exposure to risk factors. For
      prognostic purposes the cross-product ratios are not helpful.

PMID- 10420841
TI  - [Systematic treatment of depression].

PMID- 10420844
TI  - Potentiation of photodynamic therapy antitumor activity in mice by nitric oxide
      synthase inhibition is fluence rate dependent.
AB  - The effects of systemic administration of the nitric oxide synthase (NOS)
      inhibitor NG-nitro-L-arginine (L-NNA) in combination with photodynamic therapy
      (PDT) on tumor response, tumor oxygenation and tumor and normal skin perfusion
      were studied in C3H mice bearing subcutaneous radiation-induced fibrosarcoma
      tumors. Photodynamic therapy was carried out using the photosensitizer Photofrin
      (5 mg/kg) in conjunction with a low fluence rate (30 mW/cm2) and a high fluence
      rate (150 mW/cm2) protocol at a total fluence of 100 J/cm2. Low fluence rate PDT
      produced approximately 15% tumor cures, a response not significantly altered by
      administration of 20 mg/kg L-NNA either 5 min before or after PDT. In contrast,
      high fluence rate PDT produced no tumor cures by itself, but addition of L-NNA
      either pre- or post-PDT resulted in approximately 30% and approximately 10% tumor
      cures, respectively. The L-NNA by itself tended to decrease tumor pO2 levels and
      perfusion, but statistically significant differences were reached only at one
      time point (1 h) with one of the oxygenation parameters measured (% values < 2 mm
      Hg). Photodynamic therapy by itself decreased tumor oxygenation and perfusion
      more significantly. Addition of L-NNA before PDT further potentiated this effect.
      The L-NNA exerted its most striking effects on the PDT response of the normal
      skin microvasculature. Low fluence rate PDT caused severe and lasting shut-down
      of skin microvascular perfusion. With high fluence rate PDT, skin perfusion was
      initially decreased but recovered to persistent normal levels within 1 h of
      treatment. Administration of L-NNA reversed this response, converting it to
      complete and lasting vascular shut-down identical to that achieved with low
      fluence rate PDT. This effect was somewhat L-NNA dose dependent but was still
      marked at a dose of 1 mg/kg. It occurred whether L-NNA was given before or after
      PDT. The L-NNA did not alter the long-term vascular response of skin to low
      fluence rate PDT. The ability of L-NNA to correspondingly improve tumor response
      and severely limit skin vascular perfusion following high fluence rate PDT, while
      providing no benefit for the low fluence rate protocol, suggests that vascular
      changes in the tumor surrounding normal tissue contribute to the enhanced tumor
      curability with adjuvant L-NNA treatment.

PMID- 10420845
TI  - Immunosuppressive effects of silicon phthalocyanine photodynamic therapy.
AB  - The purpose of this study was to determine if silicon phthalocyanine 4 (Pc 4), a
      second-generation photosensitizer being evaluated for the photodynamic therapy
      (PDT) of solid tumors, was immunosuppressive. Mice treated with Pc 4 PDT 3 days
      before dinitrofluorobenzene sensitization showed significant suppression of their
      cell-mediated immune response when compared to mice that were not exposed to PDT.
      The response was dose dependent, required both Pc 4 and light and occurred at a
      skin site remote from that exposed to the laser. The immunosuppression could not
      be reversed by in vivo pre-treatment of mice with antibodies to tumor necrosis
      factor-alpha or interleukin-10. These results provide evidence that induction of
      cell-mediated immunity is suppressed after Pc 4 PDT. Strategies that prevent PDT
      mediated immunosuppression may therefore enhance the efficacy of this therapeutic
      modality.

PMID- 10420846
TI  - Involvement of heat-shock protein 70 and P53 proteins in attenuation of UVC
      induced apoptosis by thermal stress in hepatocellular carcinoma cells.
AB  - Induction of apoptosis is a function of external stimuli and cellular gene
      expression. Many cells respond to DNA damage by the induction of apoptosis, which
      depends on a functional p53 protein and is signaled by elevation of p53 levels.
      In this study, we found that a prior exposure to mild stress (42 degrees C) can
      protect HepG2 (p53+/+) cells from a subsequent UVC-induced apoptosis determined
      by DNA fragmentation and ratio of sub-G1 peak, but no heat-enhanced protection
      was found in Hep3B (p53-/-) cells. Although a similar inductive pattern of HSP70
      protein and mRNA was detected in the two cell lines under thermal stress, the
      effect of thermal stress on UVC-induced apoptosis in HepG2 and Hep3B cells was
      obviously different. Overexpression of HSP70 by transient transfection of HSP70
      expression vector in HepG2 cells significantly inhibited UVC-induced cell death;
      however, this inhibitory effect did not occur in transfected-Hep3B cells.
      Treatment of HepG2 cells with p53-specific antisense oligonucleotide could
      effectively block the antiapoptotic effect of thermal stress on UVC-induced
      apoptosis and increase of intracellular wild-type p53 protein by transfecting
      wtp53 expression plasmid into Hep3B cells yielded more resistance to UVC
      irradiation after prior thermal stress exposure. The results reveal an
      involvement of p53 in the antiapoptotic effect of thermal stress on UVC
      irradiation. Finally, a p53 protein increase was detected in UVC-treated HepG2
      cells and could be coimmunoprecipitated with HSP70 after a thermal stress
      treatment. Prolonged p53 binding activity and enhanced expression of p53
      controlled genes such as G1 arrest and DNA damage 45 and wild-type p53 activation
      factor 1/Cdk-interacting protein 1 by thermal stress are also observed in UVC
      irradiated HepG2 cells. Based on these results, we propose that the antiapoptotic
      effect of thermal stress is mediated by increasing HSP70 and modulating
      intracellular p53 function.

PMID- 10420847
TI  - Imaging of spontaneous canine mammary tumors using fluorescent contrast agents.
AB  - We present near-infrared frequency-domain photon migration imaging for the
      lifetime sensitive detection and localization of exogenous fluorescent contrast
      agents within tissue-simulating phantoms and actual tissues. We employ intensity
      modulated excitation light that is expanded and delivered to the surface of a
      tissue or tissue-simulating phantom. The intensity-modulated fluorescence
      generated from within the volume propagates to the surface and is collected using
      a gain-modulated image-intensified charge-coupled device camera. From the spatial
      values of modulation amplitude and phase of the detected fluorescent light,
      micromolar volumes of diethylthiatricarbocyanine iodide (tau = 1.17 ns) and
      indocyanine green (ICG) (tau = 0.58 ns) embedded 1.0 cm deep in a tissue phantom
      are localized and discriminated on the basis of their lifetime differences. To
      demonstrate the utility of frequency-domain fluorescent measurements for imaging
      disease, we image the fluorescence emitted from the surface of in vivo and ex
      vivo canine mammary gland tissues containing lesions with preferential uptake of
      ICG. Pathology confirms the ability to detect spontaneous mammary tumors and
      regional lymph nodes amidst normal mammary tissue and fat as deep as 1.5 cm from
      the tissue surface.

PMID- 10420848
TI  - Photomovement of the gliding cyanobacterium Synechocystis sp. PCC 6803.
AB  - Using a computerized videomicroscope motion analysis system, we investigated the
      photomovements of two Synechocystis sp. (PCC 6803 and ATCC 27184). Synechocystis
      sp. PCC 6803 displays a relatively slow gliding motion. The phototactic and
      photokinetic speeds of this cyanobacterium in liquid media were 5 microns/min and
      15.8 microns/min, respectively, at 3 mumol/m2/s of stimulant white light.
      Synechocystis sp. PCC 6803 senses light direction rather than intensity for
      phototaxis. Synechocystis sp. ATCC 27184 showed a weak photokinesis but no
      phototaxis. Analysis of Synechocystis sp. ATCC 27184 suggests that the loss of
      phototaxis results from spontaneous mutation during several years of subculture.
      When directional irradiation was applied, the cell population of Synechocystis
      sp. PCC 6803 began to deviate from random movement and reached maximum
      orientation at 5 min after the onset of stimulant white light. Synechocystis sp.
      PCC 6803 showed high sensitivity to the stimulant white light of fluence rates as
      low as 0.002 mumol/m2/s. Neither 1,3-dichlorophenyldimethyl urea nor cyanide
      affected phototactic orientation, whereas cyanide inhibited gliding speed. This
      result suggests that the phototaxis of Synechocystis sp. PCC 6803 is independent
      of photosynthetic phosphorylation and that its gliding movement is primarily
      powered by oxidative phosphorylation. In the visible wavelength region, 560 nm,
      660 nm and even 760 nm caused positive phototaxis. However, 360 nm light induced
      strikingly negative phototaxis. Therefore, at least two independent
      photoreceptors may exist to control phototaxis. The photoreceptor for positive
      phototaxis appears likely to be a phytochrome-like tetrapyrrole rather than
      chlorophyll a.

PMID- 10420849
TI  - Probing for the threshold energy for visual transduction: red-shifted visual
      pigment analogs from 3-methoxy-3-dehydroretinal and related compounds.
AB  - While azulenic retinal analogs failed to yield a red-shifted visual pigment
      analog, the 9-cis isomers of the push-pull polyenals 3-methoxy-3-dehydroretinal
      and 14F-3-methoxy-3-dehydroretinal yielded iodopsin pigment analogs with
      absorption maxima at, respectively, 663 and 720 nm. The former gave a relatively
      stable batho product (700 nm) and was able to activate transducin. A lower
      activity was observed for the latter. One possible explanation for the combined
      results is that the excitation energies of these red-shifted pigments are
      approaching the threshold energy for visual transduction (although at this time
      we cannot rigorously exclude a role of the added F-atom in reducing the
      transducin activity).

PMID- 10420851
TI  - Bringing health care to the homeless.

PMID- 10420850
TI  - Computational analysis of the oxygen addition at the C4a site of reduced flavin
      in the bacterial luciferase bioluminescence reaction.
AB  - The energetic characteristics of selected reaction steps in the bacterial
      luciferase-catalyzed luminescence reaction were examined by computation using the
      MNDO-PM3 method. Specifically, a three-step model was proposed to account for the
      reaction between oxygen and reduced riboflavin 5'-phosphate (1,5H2-FMN) to
      generate first the 5-hydroFMN-4a-peroxide (5H-FMN-4aOO-) and then the 5-hydro-4a
      hydroperoxyFMN (5H-FMN-4aOOH) intermediates. Lysine (Lys-H+) and aspartate (Asp-)
      were chosen as representative catalytic residues involved in the protonation and
      deprotonation processes. Results show that deprotonation at the N1 site of 1,5H2
      FMN by a basic amino acid residue at the luciferase active site would efficiently
      accelerate the reaction rate of O2 addition to form 5H-FMN-4aOO-. The most
      favored site of oxygen attack is at the flavin C4a. With the aid of a catalytic
      acid group, the 5H-FMN-4aOO- so formed tends to undergo a spontaneous protonation
      reaction to yield the 5H-FMN-4aOOH.

PMID- 10420852
TI  - Breast cancer treatment and older women.

PMID- 10420855
TI  - The real costs of screening mammography.

PMID- 10420856
TI  - The real costs of screening mammography.

PMID- 10420857
TI  - Euthanasia's never an answer.

PMID- 10420858
TI  - To screen: perchance to treat.

PMID- 10420859
TI  - Death in a hobble restraint.

PMID- 10420860
TI  - Systematic review of antihypertensive therapies: does the evidence assist in
      choosing a first-line drug?

PMID- 10420861
TI  - Use of hormone replacement therapy among cardiac patients at a Canadian academic
      centre.
AB  - BACKGROUND: Although hormone replacement therapy (HRT) is associated with a
      reduced risk of coronary artery disease (CAD), use of this treatment among post
      menopausal women is not widespread. The authors sought to determine the extent of
      HRT use in a select population of women at high risk for CAD. METHODS: A cross
      sectional survey was performed involving all consecutive post-menopausal women
      who attended a cardiology clinic in a Toronto teaching hospital between January
      1996 and August 1997. A chart review was followed by a telephone interview with
      the patients or their physicians. The utilization rate of HRT was obtained.
      Predictors of HRT use were identified using a multivariate logistic regression
      model. RESULTS: A total of 80 women with risk factors for CAD, symptoms
      suspicious of CAD or definite CAD diagnosed after cardiac investigations were
      included in the survey. Information on HRT use or nonuse was documented in 17
      (21%) of the charts. Of the 72 women for whom data on HRT were available 16 (22%)
      were currently using it, 41 (57%) were not, and 15 (21%) had used it in the past.
      Five women (7%) were receiving HRT but there was no chart documentation. On
      multivariate analysis, younger women were more likely than older women to use HRT
      (odds ratio 0.91, 95% confidence interval 0.22-0.96; p < 0.05). Coronary risk
      profile, CAD diagnosis and history of hysterectomy were not associated with HRT
      use. Of the 41 women who had never received HRT 10 (24%) had possible
      contraindications (e.g., breast cancer or deep vein thrombosis); the proportion
      was similar in the group of women who were current or past users of HRT (29%).
      INTERPRETATION: Documentation of HRT use in patient charts is lacking. Few women
      in the study who were at risk for CAD were currently using HRT. The data support
      the need for better adherence to optimal practices in the management of women at
      high risk for CAD.

PMID- 10420862
TI  - Effectiveness of an educational strategy to improve family physicians' detection
      and management of depression: a randomized controlled trial.
AB  - BACKGROUND: Depression, a common disorder often treated by family physicians, may
      be both underdiagnosed and undertreated. The objective of this study was to
      determine whether the diagnosis and treatment of depression by family physicians
      could be improved through an educational strategy. METHODS: In this study,
      conducted between July and December 1997, 42 family physicians in Newfoundland
      were randomly assigned to an intervention group (3-hour case-based educational
      session on clinical practice guidelines [CPGs] for depression and access to a
      psychiatrist for consultation) or to a control group (receipt of CPGs without
      educational session or access to the psychiatrist). Physicians were asked to keep
      a log of patients with newly diagnosed depression and to record information on
      severity of depression, medications and referrals to mental health professionals.
      Patients were asked to complete the Centre for Epidemiologic Studies Depression
      (CES-D) scale before treatment and after 6 months of follow-up. The primary
      outcome measure was the "gain" score (difference between first and last CES-D
      scores). RESULTS: During the study period physicians in the intervention group
      diagnosed 91 new cases of depression (mean 4.1 per physician) and those in the
      control group diagnosed 56 (mean 2.8 per physician); the difference was not
      significant. Most patients (91.2% in the intervention group and 89.3% in the
      control group received a prescription for an antidepressant on their first visit.
      Similar proportions (46.2% in the intervention group and 37.5% in the control
      group) took their medication for the full 6 months; however, significantly more
      patients in the intervention group were taking an antidepressant at the 6-month
      follow-up (56% v. 39.3%, p = 0.02). The mean number of visits per patient was
      similar in the 2 groups (7.7 in the intervention group and 7.6 in the control
      group). Physicians in the intervention group consulted the psychiatrist 9 times.
      The overall rate of referrals to psychiatrists and other mental health
      professionals was 10.9%; however, referrals were significantly higher in the
      intervention group (15.4% v. 3.5%, p = 0.05). After 6 months of follow-up, a
      significant difference in gain scores was detected between the intervention and
      control groups for both the patient's self-rated CES-D scores (mean gain score
      19.3 v. 15.5 respectively, p = 0.04) and the physicians' ratings of depression
      severity before treatment and at 6 months (mean gain 1.1 v. 0.7 respectively, p =
      0.02). INTERPRETATION: The educational strategy had a modest beneficial effect on
      the outcomes of patients with depression, but there are still concerns regarding
      the low rates of drug treatment and referral to mental health professionals by
      family physicians.

PMID- 10420863
TI  - E-biomed: scientific publishing's brave new world.

PMID- 10420864
TI  - Estrogen replacement for women with cardiovascular disease: why don't physicians
      and patients follow the guidelines?

PMID- 10420865
TI  - Power to the people: taking the assessment of physician performance outside the
      profession.

PMID- 10420866
TI  - Tuberculosis: 8. The disease in association with HIV infection.

PMID- 10420868
TI  - A novel formulary: collaboration between health care professionals, seniors,
      private sector and government in Nova Scotia.
AB  - A novel formulary has been developed in Nova Scotia with the objective of
      providing quality treatment with needed medications at affordable cost. Creation
      of the formulary has involved collaboration among health care professionals,
      seniors, the Department of Health and pharmaceutical companies. This is the first
      Canadian formulary to use the Anatomic, Therapeutic, Chemical system. Drug
      listing is comprehensive rather than exclusive. Colour-coded recommendations on
      use assist physicians with drug choice. Relative costs are indicated within each
      therapeutic grouping. Listings indicate drugs approved for reimbursement,
      interchangeable medications, maximum allowable cost, drug identification number
      and manufacturer code. Treatment summaries provide brief overviews of therapeutic
      advice. Updates on new products and new or modified treatment summaries are
      provided every 6 months. The formulary will be the focus of coordinated
      educational activities on treatment for seniors and health care professionals.

PMID- 10420867
TI  - Assessment of physician performance in Alberta: the physician achievement review.
AB  - The College of Physicians and Surgeons of Alberta, in collaboration with the
      Universities of Calgary and Alberta, has developed a program to routinely assess
      the performance of physicians, intended primarily for quality improvement in
      medical practice. The Physician Achievement Review (PAR) provides a
      multidimensional view of performance through structured feedback to physicians.
      The program will also provide a new mechanism for identifying physicians for whom
      more detailed assessment of practice performance or medical competence may be
      needed. Questionnaires were created to assess an array of performance attributes,
      and then appropriate assessors were designated--the physician himself or herself
      (self-evaluation), patients, medical peers, consultants and referring physicians,
      and non-physician coworkers. A pilot study with 308 physician volunteers was used
      to evaluate the psychometric and statistical properties of the questionnaires and
      to develop operating policies. The pilot surveys showed good statistical validity
      and technical reliability of the PAR questionnaires. For only 28 (9.1%) of the
      physicians were the PAR results more than one standard deviation from the peer
      group means for 3 or more of the 5 major domains of assessment (self, patients,
      peers, consultants and coworkers). In post-survey feedback, two-thirds of the
      physicians indicated that they were considering or had implemented changes to
      their medical practice on the basis of their PAR data. The estimated operating
      cost of the PAR program is approximately $200 per physician. In February 1999, on
      the basis of the operating experience and the results of the pilot survey, the
      College of Physicians and Surgeons of Alberta implemented this innovative
      program, in which all Alberta physicians will be required to participate every 5
      years.

PMID- 10420870
TI  - Does the body mass index get more attention than it deserves?

PMID- 10420869
TI  - A line in the sand.

PMID- 10420871
TI  - Coronary microvascular disease in humans.
AB  - Myocardial perfusion abnormalities occur in the absence of epicardial coronary
      artery disease in patients with a wide spectrum of cardiovascular disorders
      including microvascular angina, hypertension and left ventricular hypertrophy,
      coronary atherosclerosis, hypercholesterolemia, and non-ischemic left ventricular
      dysfunction. These patients have limited coronary microvascular dilator reserve
      which occasionally is associated with evidence of myocardial ischemia. Primary
      microvascular hyperconstriction (spasm) is also proposed to cause myocardial
      ischemia in a subset of patients with rest angina. There is ample evidence
      suggesting that endothelial dysfunction contributes to microvascular dysfunction,
      but the precise mechanism of endothelial dysfunction is not known. Nitric oxide
      is one of the key molecules which control microvascular tone and therefore
      coronary blood flow, and its decreased availability appears to be involved under
      certain conditions. This hypothesis has attracted considerable interest as a new
      therapeutic strategy for these patients having coronary microvascular
      derangements caused by divergent cardiovascular diseases.

PMID- 10420872
TI  - Morphological effects on in-stent restenosis assessed by intravascular ultrasound
      imaging.
AB  - The purpose of this study was to evaluate the rupture and dissection of the
      vessel wall immediately after balloon dilatation by intravascular ultrasound
      (IVUS) imaging and to predict restenosis in patients who underwent subsequent
      coronary stent implantation. Stent implantation improves the long-term results of
      coronary angioplasty by reducing lesion elastic recoil and arterial remodeling.
      However, several studies have suggested that neointimal hyperplasia is the cause
      of instant restenosis. We recruited 60 patients in whom IVUS studies were
      performed immediately after successful balloon dilatation and just before stent
      implantation. We compared IVUS parameters with 6-month follow-up quantitative
      coronary angiography. This was performed in 51 lesions of 51 patients (85%).
      Qualitative analysis included assessment of plaque composition, plaque
      eccentricity, plaque fracture and the presence of dissection. In addition,
      minimal luminal diameter, percent diameter stenosis, percent area stenosis and
      plaque burden were quantitatively analyzed. Two morphological patterns after
      balloon dilatation were classified by IVUS. Type I was defined as absence or
      partial tear of the plaque without disclosure of the media to lumen (22 lesions).
      Type II was defined as a split in the plaque or dissection of the vessel wall
      with disclosure of the media to the lumen (29 lesions). At 6 months follow-up,
      angiographic restenosis occurred in 17 of the 51 lesions (33%). Restenosis was
      significantly (p < 0.05) more likely to occur in type II (13/29: 45% incidence)
      than in type I (4/22: 18% incidence). The assessment of plaque morphology
      immediately after balloon dilatation and before stent implantation provides
      important therapeutic and prognostic implications.

PMID- 10420873
TI  - Dynamic changes of QT dispersion as a predictor of myocardial ischemia on
      exercise testing in patients with angina pectoris.
AB  - The difference between the maximum and minimum QT intervals on the standard 12
      lead ECG (QT dispersion) may be a significant predictor of serious arrhythmias.
      Dynamic changes in QTd were determined during exercise-induced ischemia in 15
      patients with effort angina (> or = 75% coronary stenosis) and 10 normal
      individuals. Treadmill exercise testing was performed according to Bruce's
      protocol and the rate-corrected QT dispersion (QTcd) was calculated using
      Bazett's formula. The resting QTcd before exercise was similar in the angina
      patients and the controls. After the first stage of exercise, QTcd was
      significantly increased in the angina patients (p = 0.035), while it remained
      near baseline in the controls. Five minutes after completing exercise, QTcd was
      significantly greater in the angina patients than in the controls (p = 0.011).
      Furthermore, QTcd values after the first stage of exercise were significantly
      correlated with the maximum ST depression observed on completing exercise in the
      angina patients (r = 0.714, p = 0.0028). Because QTd may represent the
      heterogeneity of ventricular repolarization, its significant exercise-induced
      increase in the angina patients suggests that myocardial ischemia caused
      repolarization disorders. The significant correlation between QTcd values after
      the first stage of exercise (before significant ST depression) and the maximum ST
      depression on completing exercise suggests that an increase in QTcd preceding
      ischemic ST depression may predict myocardial ischemia. In addition, even daily
      activities not causing significant ST changes may increase QTcd and the risk of
      serious arrhythmia in angina patients.

PMID- 10420875
TI  - Cyclic bursts of ventricular premature contractions of more than one minute
      intervals.
AB  - Ventricular premature contractions (VPCs) occasionally appear successively in the
      form of bigeminy, trigeminy or quadrigeminy associated with quiescent periods.
      However, details of these rhythmic VPC bursts have not been well documented. We
      analyzed the incidence, periodicity and interval of VPC bursts exhibiting
      bigeminy or trigeminy using ambulatory ECG monitoring and computer analysis. We
      defined VPC bursts as more than 5 successive groups of VPCs each containing more
      than 20 VPCs in the form of bigeminy or trigeminy that were interrupted by normal
      sinus rhythm lasting for more than 60 seconds. Bursts thus defined were observed
      transiently or continuously in 78 out of 500 consecutive patients showing > 3000
      VPCs a day. Their age ranged from 14 to 76 years (mean 48). Forty patients were
      men and 38 were women. We could discriminate between two types of bursts on the
      instantaneous heart rate tachograms. Dome type bursts (n = 48) showed gradual
      shortening of the VPC coupling intervals whereas horizontal type bursts (n = 30)
      demonstrated fixed coupling intervals during the bursts. Cycle length of the dome
      type burst was 185 +/- 40 seconds and regular, whereas it was 210 +/- 63 seconds
      and irregular in the horizontal type (NS). Duration of the VPC bursts was 101 +/-
      31 seconds in the dome type and 98 +/- 41 seconds in the horizontal type. Both
      burst types were associated with transient increases in sinus rate and
      abbreviated VPC-VPC intervals. We suspect ventricular parasystole to be the
      mechanism of these bursts especially in the dome type. Recognition of these two
      burst types from heart rate tachograms may be of value in the suppression of
      VPCs.

PMID- 10420874
TI  - Relationship between exercise capacity and ventilatory equivalent for carbon
      dioxide in patients with stable old myocardial infarction.
AB  - The aim of the present study was to evaluate the relationship between exercise
      capacity and ventilatory response in patients with stable old myocardial
      infarction. We performed cardiopulmonary exercise test in 61 patients with stable
      old myocardial infarction and in 30 healthy men. Each subject exercised on a
      bicycle ergometer until exhaustion. Patients who had anginal pain or
      electrocardiographic ischemic changes during exercise were excluded. The patients
      were classified into three groups according to peakVO2 achieved during exercise,
      using Weber's method: group A, peakVO2 > or = 21 ml/min/kg (n = 4); group B, 14 <
      or = peakVO2 < 21 ml/min/kg (n = 45); and group C, peakVO2 < 14 ml/min/kg (n =
      12). With progressive increases in VCO2, VE increased linearly below the
      anaerobic threshold (AT) level. The slope of the linear regression line between
      VCO2 and VE (SLOPE) was calculated in each subject. The mean SLOPE of the healthy
      men (group N) and groups A, B and C were 25.8 +/- 0.5, 25.1 +/- 0.5, 28.9 +/- 0.8
      and 37.1 +/- 1.7 (x 10(-3), respectively. Thus, the SLOPE was steeper in patients
      with lower peakVO2. It is difficult to perform a maximal exercise tolerance test
      on patients with chronic heart failure to evaluate their exercise capacity. We
      can assess exercise capacity by the slope of the linear regression line between
      VCO2 and VE (SLOPE) at the lower exercise level.

PMID- 10420876
TI  - Estimation of left ventricular function in right ventricular volume and pressure
      overload. Detection of early left ventricular dysfunction by Tei index.
AB  - Although the effects of right ventricular (RV) volume and pressure overload (RVVO
      and RVPO) on ventricular septal motion are different, the differential effect on
      left ventricular (LV) function is still controversial. The Doppler-derived index
      (Tei index) combining systolic and diastolic ventricular function, defined as the
      sum of isovolumetric contraction time (ICT) and isovolumetric relaxation time
      (IRT) divided by ejection time (ET), has been demonstrated to be a useful index
      to estimate LV function and to predict the prognosis of patients with congestive
      heart failure. This study was designed to evaluate the differential effects of
      RVVO and RVPO on LV function using the Tei index. Study patients consisted of 26
      age-matched normal subjects, 22 patients with atrial septal defect (ASD) with
      normal or borderline RV pressure and 25 with primary pulmonary hypertension
      (PPH). All subjects had normal LV ejection fractions measured with 2-dimensional
      echocardiogram using biplane Simpson's method (61 +/- 4 vs 61 +/- 4 vs 63 +/- 8%,
      normal vs ASD vs PPH). Tei index was easily obtained in all subjects from
      transthoracic Doppler echocardiogram of LV inflow and outflow. Patients with ASD
      had normal ICT, IRT and ET, resulting in normal Tei index, however, patients with
      PPH had significantly prolonged ICT and IRT with shortened ET, resulting in a
      significant increase in Tei index (0.38 +/- 0.04 vs 0.36 +/- 0.03 vs 0.61 +/-
      0.22, p < 0.001). Although RVVO due to ASD has no significant effects on LV
      function, RVPO due to PPH can adversely affect LV function. The Tei index is a
      simple and sensitive measure to assess LV function caused by RVVO or RVPO.

PMID- 10420877
TI  - Clinical and morphologic features of hypertrophic cardiomyopathy in elderly
      patients 85 years or older.
AB  - We studied the distinctive morphology of the left ventricle (LV) and attempted to
      relate advanced age and hypertension to this characteristic feature in elderly
      patients with hypertrophic cardiomyopathy (HC). Fourteen elderly patients > or =
      85 years old (mean age 90 +/- 5 years) with HC were compared with 45 young
      patients < or = 40 years (mean age 34 +/- 4 years) with this disease. More mild
      hypertension in the elderly (10/14, 71%) than in the young (0%), and more syncope
      in the young (10/45, 22%) than in the elderly (0%) were observed.
      Echocardiography showed that the elderly patients had relatively mild LV wall
      thickening, generally confined to the septum (elderly vs young: 18 +/- 4 vs 25 +/
      8 mm, p < 0.001), with more basal septal bulging (elderly vs young: 12/14, 86%
      vs 0%, p < 0.001) and anterior septal hypertrophy of LV (elderly vs young: 11/14,
      79% vs 0%, p < 0.001). Elderly patients with mild hypertension showed a
      predominantly basal septal bulging (10/10, 100%) and anterior septal hypertrophy
      of LV (9/10, 90%). HC in elderly patients > or = 85 years old has a striking LV
      morphology. Mild hypertension and advanced age may contribute to the distinctive
      geometry.

PMID- 10420878
TI  - A study to determine if basic fibroblast growth factor (bFGF) reduces myocardial
      infarct size in acute coronary arterial occlusion.
AB  - We investigated the angiogenic and myocardial salvage effects of bFGF. Twelve
      beagles with ligated left anterior descending coronary arteries were divided into
      two groups: a FGF group administered bFGF intravenously, and a Control group,
      after CAG immediately post-ligation. One week post-ligation, CAG was repeated.
      The heart was sliced along the short axis. For each section, the fluorescein Na
      staining deficit area (DA) and ratio of DA to total area (DAR), TTC staining of
      the infarct area (IA) and ratio of IA to total area (IAR), and Masson trichrome
      staining of the fibrosed area (MA) and ratio of MA to total area (MAR), were
      calculated. The increase in the number of collateral vessels, seen on CAG from
      post-ligation to 1 week later, was significantly greater in the FGF group. No
      significant differences in IAR or MAR were seen between the groups. However, DAR
      and DA/IA were significantly less in the FGF group. In conclusion, bFGF had no
      effect on infarct size, but stimulated the growth of collateral vessels and
      improved coronary blood flow in IA.

PMID- 10420879
TI  - Canine model of ventricular fibrillation using programmed stimuli and localized
      myocardial warming or cooling.
AB  - The purpose of this study was to establish an animal model in which ventricular
      fibrillation (VF) can be induced reproducibly and defibrillation can be
      accomplished repeatedly. The left anterior descending artery (LAD) was cannulated
      and perfused with blood from the carotid artery in eleven open-chest dogs.
      Electrodes of the internal defibrillator were inserted in the cavities of the
      left atrium and left ventricle via incisions in the left atrial appendage and
      left ventricular apex. The perfused blood temperature was modulated to produce
      regional myocardial warming (42 degrees C) or cooling (28 degrees C). In all
      dogs, VF was repeatedly induced by the combination of warming and left
      ventricular extrastimuli and by the combination of cooling and right ventricular
      extrastimuli. The VF was quickly defibrillated by use of the internal
      defibrillator. The mechanism of VF was found to be reentry by the analysis of
      activation sequences. This VF model may be useful when evaluating the efficacy of
      antiarrhythmic drugs because of the high reproducibility.

PMID- 10420880
TI  - Experimental ablation study using a new long linear probe in isolated porcine
      hearts.
AB  - We studied a new technique for creating long linear lesions in hearts using a
      custom-made linear probe. Radiofrequency (RF) energy applications using a 25-mm
      long stainless steel linear probe and a corresponding 500-kHz energy generator
      were tested, creating 90 lesions in isolated porcine hearts. The RF current was
      applied between the linear probe and a large patch electrode attached to the back
      of the specimen. Three parameters, comprising the power of the delivered energy,
      the pressure of contact between the probe and the specimen, and the duration of
      energy delivery were changed independently and the size of the resulting lesions
      was measured. All 90 lesions were transmural, well demarcated and created by a
      single stationary RF application. Lesion length and width increased with: 1)
      increasing power, when the other two parameters were maintained at constant
      levels, 2) increasing contact pressure, when the other two parameters were
      maintained at constant levels, and 3) increasing duration of energy delivery when
      the other two parameters were maintained at constant levels. The maximum width of
      the lesions was 3.7 mm. No overheating of any of the specimens was observed. In
      conclusion, the new original long linear probe used in this study was effective
      for creating transmural linear lesions, presenting the possibility of a
      worthwhile contribution to the maze surgical procedure applied to atrial
      fibrillation.

PMID- 10420881
TI  - A novel A-kinase anchoring protein in the heart interacts with G alpha 13.
AB  - A cDNA of a tentative A-kinase anchoring protein, presumably coupled with
      heterotrimeric GTP binding protein alpha 13 subunit (G alpha 13), was cloned from
      a human heart cDNA library. It was approximately 650 bases and its mRNA was
      expressed in the heart. Homology search of DNA sequences revealed that it was a
      novel cDNA with 84% homology with the partial sequence of rabbit cDNA of AKAP 120
      without a stop codon. 3'-Rapid Amplification of cDNA Ends (3'-RACE) and yeast
      functional assay were performed to determine the 3'-end of the cDNA and ribosomal
      frameshifting was suggested as a translational mechanism. Here we report that a
      protein encoded by the cDNA may be involved in intracellular signal transduction
      via the G alpha 13 and PKA in hearts.

PMID- 10420882
TI  - Relations of vascular calcium channels with blood pressure and endothelium in
      hypertension and with aging.
AB  - To investigate the relationships between the activity in potential operated Ca2+
      channels (POC), blood pressure, and endothelium in hypertension, we tested the
      contractile responses to a Ca2+ channel agonist Bay K 8644 (BAY K) in aorta from
      deoxycorticosterone-acetate-saline (DOCA-S) and reduced renal mass-saline (RRM-S)
      hypertensive rats. The effects of mechanical rubbing, N omega-Nitro-L-Arginine
      Methyl Ester (l-NAME) and indomethacin were also examined. Sensitivity to BAY K
      increased in experimental rats before they became hypertensive and contractile
      responses were enhanced as hypertension developed. Force development to BAY K was
      correlated with blood pressure levels. Endothelium removal enhanced the
      contractile response to BAY K. L-NAME, but not indomethacin, potentiated the
      response to BAY K. Contractile response to BAY K was negatively correlated with
      relaxation to acetylcholine. An enhanced contractile response to BAY K was
      observed also in aged rats. Enhanced activation of vascular POC in hypertension
      results from elevated blood pressure and partly from diminished inhibitory action
      of endothelium. Senescence also enhances vascular POC activity.

PMID- 10420884
TI  - Torsades de pointes in a case of hypertrophic cardiomyopathy with special
      reference to the pathologic findings of the heart including the conduction
      system.
AB  - A clinicopathologic study was performed in a 77-year-old female with hypertrophic
      cardiomyopathy who had experienced recurrent syncopal attacks due to Torsades de
      Pointes (TdP) following QT prolongation and atrioventricular block. She died
      suddenly two years later while eating dinner. Pathologic findings of the heart
      showed a dilated and hypertrophied left ventricle. The heart weighed 550 g. There
      were two foci of localized endocardial fibroelastosis (EFE) beneath the aortic
      valve, one with a size of 3.5 x 3.5 cm, and the other (2 x 1 cm) located on the
      upper ventricular septum. Histologic findings showed hypertrophy and disarray in
      the left ventricular myocardium. The conduction system using serial sectioning
      revealed remarkable bilateral bundle branch fibrosis and hypertrophied Purkinje
      fibers in the left bundle branch adjacent to the EFE on the ventricular septum.
      These findings were thought to be related to the occurrence of TdP.

PMID- 10420883
TI  - Infradian rhythm of paroxysmal atrial fibrillation. A case report.
AB  - To examine the circadian and infradian rhythms of paroxysmal atrial fibrillation,
      the time and date of 85 arrhythmic attacks occurring over a period of 4 years
      were analyzed in a patient with reliable symptoms. In the hourly analysis, a
      remarkable circadian rhythm similar to the reported population circadian rhythm
      was observed. On a day basis, the distribution of the intervals between 2
      successive episodes showed a significant departure from the exponential
      distribution, indicating the arrhythmia was not a simple probabilistic
      phenomenon. Spectrum analysis revealed a prominent peak occurring at about 0.3
      cycles/day, suggesting a possible circasemiseptan rhythm. Thus, in this patient,
      paroxysmal atrial fibrillation was not a random event when observed not only from
      an hour incremental perspective but also from a day incremental perspective,
      suggesting the circadian and infradian rhythms of this arrhythmia.

PMID- 10420886
TI  - [Bacterial concentration in the cerebrospinal fluid in childhood meningitis].
AB  - OBJECTIVES: The aim of this study was to analyze the epidemiological evolution of
      causal germs in meningitis in children aged 1 day to 15 years and determine the
      relationship between pretreatment concentrations of bacteria in cerebral spinal
      fluid (CSF), patient age, bacterial species and bacteriological eradication.
      PATIENTS AND METHODS: A quantitative analysis of germs was performed in 212
      children with bacterial meningitis (mean age 19.8 months). RESULTS: Bacterial
      counts ranged from 2.10(1) to 4.10(9) CFU/ml in CSF. Among the 212 patients, 52
      (24.5%) had counts 10(7)/ml. Infants had significantly higher counts than the
      other age groups. Mean counts for Hoemophilus influenzoe serotype B were not
      different from those for Streptococcus pneumoniae but were significantly higher
      than for Neisseria meningitidis. Compared with initial germ counts, 98.5% of the
      CSF specimens were sterile at 24 and 48 hours and 100% at 72 hours. CONCLUSION:
      Germ counts were higher in infants.

PMID- 10420885
TI  - Lower extremity hematoma as a complication of warfarinization in patients with
      artificial heart valves.
AB  - Four cases of lower extremity hematoma in patients undergoing anticoagulant
      therapy after heart valve replacement are herein reported, with special emphasis
      on the comparative diagnostic value of ultrasonography and computerized
      tomography. Although conservative management is sufficient for patients with no
      neurological impairment, needle aspiration after autolysis of the hematoma, which
      can be confirmed by CT study, is also recommended.

PMID- 10420887
TI  - [Neuro-endocrine tumors and von Hippel-Lindau disease. 3 cases].
AB  - BACKGROUND: Neuroendocrine tumors can occur in patients with hereditary syndromes
      predisposing to multiple endocrine neoplasia (MEN) and Von Hippel-Lindau disease
      (VHL). CASE REPORTS: We report the cases of three men with pheochromocytomas, one
      with an associated neuroendocrine tumor of the pancreas. In one case, diagnosis
      was suggested by the familial context of VHL in the patients father. In the two
      other cases, the bilateral character of the pheochromocytoma, and in one case the
      associated pancreatic neuroendocrine tumor led to the diagnosis of VHL.
      Systematic biological surveillance gave the diagnosis of contralateral
      pheochromocytoma in two cases. Search for associated tumoral lesions led to the
      diagnosis of hemangioblastoma of the cerebellum in two patients and pancreatic
      cyst in the third. No renal or retinal lesions were observed. Molecular study of
      the VHL gene evidenced point nonsense mutation of the gene in all three patients,
      involving codon 184 in two and codon 167 in the third (identical to the proband
      case). Systematic investigations in the families of the two other patients
      remains to be completed. CONCLUSION: The diagnosis of HVL disease should be
      suggested in case of familial pheochromocytoma and/or bilateral localizations,
      but also in case of neuroendocrine tumors of the pancreas associated with another
      cardinal lesion of the disease. Early screening and treatment of this potentially
      fatal disease is essential.

PMID- 10420888
TI  - [Basaloid cancer of the esophagus].
AB  - BACKGROUND: Basaloid cancer of the esophagus is exceptional. The tumor probably
      develops from epithelial basal cells. This histological type is generally
      observed in ENT or bronchial localizations. CASE REPORT: A 62-year-old man
      underwent total pharyngo-laryngo-esophagectomy for a double tumor localization of
      a basaloid carcinoma of the esophagus and a hypophyayngeal squamous cell
      carcinoma. DISCUSSION: Basaloid carcinoma has specific histological features
      difficult to recognize at the pathology examination. Because of the high risk of
      metastasis, it may be important to propose radiotherapy and/or chemotherapy after
      surgical excision.

PMID- 10420890
TI  - [Can the D-dimer assay predict the importance of pulmonary reperfusion in
      pulmonary embolism?].

PMID- 10420889
TI  - [Myopericarditis caused by Campylobacter jejuni].

PMID- 10420891
TI  - [Pancreatic cyto-steatonecrosis and pancreatic-pleural fistula: successful
      surgical management].

PMID- 10420892
TI  - [Beneficial effect of aspirin in diabetic coronary disease: facts to prove it].

PMID- 10420893
TI  - [Forgotten by the media: the so-called "tension headache"].

PMID- 10420894
TI  - [Comments on hepatitis B vaccination in France].
AB  - We recall the selective preventive measures which led to a significant reduction
      in the rate of acute hepatitis B cases detected in France prior to generalized
      vaccination. These measures, screening for HBs antigens in blood donors and
      pregnant women, vaccination of high risk groups, suggest the need to better
      define risk groups and to develop better epidemiology information on the
      evolution of hepatitis B incidence, both in at risk groups and in subjects
      outside these groups. The importance of serological screening among chronic
      carriers in at risk groups is underlined. For health carers who have already been
      vaccinated, we propose determining anti-HBs titer prior to booster vaccinations,
      whatever the age. Finally, an active surveillance system to register the
      secondary effects of vaccination (linked to the Regional Drug Monitoning Center)
      is needed. The issues of the content of anti-hepatitis B vaccine (dose, adjuvant,
      antigenic fraction, molecular mimetism) and injection route remain timely.

PMID- 10420896
TI  - [Psoriasis. Rheumatologic manifestations].
AB  - THE CONTEXT: Psoriasic arthritis lies somewhere between rhumatoid polyarthritis
      and spondyloathropathy. Its prevalence is about 0.1% with a 1/1 sex ratio. Mean
      age at onset of symptoms is 40 years. In 10 to 15% of the cases, rhumatological
      manifestations are observed before skin lesions. Ungueal involvement is
      particularly frequent. FIVE CLINICAL FORMS: Classically, five clinical forms are
      described: arthritis limited to the distal interphalangeal joints, mutilating
      arthritis, symmetrical polyarthritis, asymmetrical mono- or oligoarthritis, and
      spondylitis. Asymmetrical oligoarticular forms and polyarithrtis predominate.
      DISEASE SEVERITY: In general psoriasic arthritis is a benign condition. Severe
      forms have however been described with erosion and osteolysis involving the
      distal interphalangeal joints. Typical radiological may be observed. THERAPEUTIC
      OPTIONS: Non-steroidal antiinflammatory drugs help control disease progression in
      about one-third of the cases. In other patients, gold salts, D-penicillamine,
      methotrexate, or sulfasalazine may be required.

PMID- 10420897
TI  - [Psoriasis. Pathogenesis].
AB  - A MULTIFACTORIAL ORIGIN: Psoriasis is an inflammatory dermatosis resulting from
      abnormal epidermal homeostatis and characterized by hyperproliferation and
      abnormal keratinocyte differentiation as well as activation of the skinis immune
      system. This dermatosis is a prototype of multifactorial conditions implicating
      hereditary and environmental pathogenic mechanisms. TWO TYPES OF PSORISASIS:
      Familial psoriasis is observed early in life and is strongly associated with the
      major histocompatibility complex, particularly CW6, DR7, B1, and B57 molecules.
      The sporadic non-familial form develops later in life. ENVIRONMENTAL FACTORS: A
      large number of triggering or aggravating factors have been identified in
      subjects genetically predisposed to psoriasis. Bacterial (streptococci) and viral
      (HIV) infections have been studied in particular. DRUGS AND OTHER FACTORS: The
      aggravating role of certain drugs as well as stress, psychoaffective factors,
      alcoholism and smoking is well known. KERATOCYES OR IMMUNE SYSTEM: One of the
      most widely discussed theories proposes a keratinocytic origin. Epidermal
      keratinocytes would be activated by various stimuli, secondarily provoking their
      abnormal proliferation and differentiation leading to the inflammatory reaction.
      In any case, the most popular theory suggests that psoriasis is an autoimmune
      disease implicating T lymphocytes.

PMID- 10420895
TI  - [Psoriasis. Clinical cutaneous aspects].
AB  - PREDOMINANT FEATURES: Psoriasis is a frequent inflammatory dermatosis. All age
      groups are involved. The typical lesion is a well-limited erythemato-squamaous
      non-pruriginous lesion. All skin areas may be involved but each individual has
      preferential zones. CLINICAL COURSE: This chronic condition progresses by acute
      flare-ups which occur at variable frequency and with variable intensity.
      SEVERITY: Although psoriasis is a benign dermatosis, the psychosocial impact must
      not be overlooked. Life-threatening forms do occur (generalized or erythrodermic
      pustulous psoriasis). SPECIAL FORMS: HIV serology would be advisable if sudden
      aggravation occurs in a patient with no known triggering factor. Late onset
      psoriasis in a patient with no familial history or particular risk factors may
      also suggest possible HIV infection.

PMID- 10420898
TI  - [Psoriasis. Treatment].
AB  - FUNDAMENTALS: The aim of treatment in psoriasis is to reduce the degree of
      extension to a point compatible with the patients social, occupational and
      personal lifestyle. The patient should be informed that there is no curative
      treatment. A good patient-doctor relationship is required for the patient to
      understand that the proposed treatment can provide symptomatic relief but must
      take into account an optimal balance between treatment benefit and risk.
      Therapeutic abstention must be recognized as a possibility. In all cases, efforts
      must be made to recognize and eliminate if possible any favoring factors. A TWO
      PHASE TREATMENT: Initially, the aim of the treatment is to induce an involution
      of the active lesions. A second phase is aimed at avoiding subsequent fiare-ups.
      Local treatments: Local care should always be preferred in patients with limited
      lesions. Keratolytic agents, dermocorticoids and vitamin D3 derivatives can be
      used. Topical retinoids, particularly tazarotene are in the development stage.
      SYSTEMIC TREATMENTS: Systemic treatments should be reserved for extensive
      psoriasis and for failure after well-conducted local care. Photoherapy,
      particularly PUVA-therapy and more recently narrow-spectrum UVB-therapy play an
      important role. Systemic retinoids can be used alone or in combination with PUVA
      therapy. The risks of methrotrexate and cyclosporin impose their use exclusively
      in specialized centers. Several other treatments are still in the experimental
      stage, particularly promising highly selective immunotherapy.

PMID- 10420899
TI  - [Images in medicine: pharmacokinetic hazards].

PMID- 10420900
TI  - [Transvenous liver biopsy].
AB  - In patients with an indication for histological evaluation of diffuse liver
      disease a transvenous approach may be advisable if a percutaneous technique is
      contraindicated by severe coagulopathy or ascites. In general, the procedure may
      be performed as an aspiration core, or forceps biopsy technique using a
      transjugular approach. Alternatively, the forceps biopsy technique may be
      performed via a transfemoral access. Adequate specimens for histologic diagnosis
      may be obtained in 77-100% with either biopsy technique. Complications after
      transvenous liver biopsies occur in 0-20% with an overall mortality rate below
      0.5%. Although the transvenous liver biopsy techniques take more time and are
      more expensive than percutaneous biopsy techniques, they represent a safe and
      effective alternative for obtaining adequate liver samples for histological
      diagnosis in special clinical settings.

PMID- 10420901
TI  - [Combined use of MRI and MR cholangiopancreatography and contrast enhanced dual
      phase 3-D MR angiography in diagnosis of pancreatic tumors: initial clinical
      results].
AB  - PURPOSE: To evaluate the accuracy of a non-invasive "all-in-one" staging MR
      method in patients with pancreatic tumors. MATERIAL AND METHODS: 46 patients were
      prospectively evaluated by a combined MR imaging protocol including breath-hold
      T1- and T2-weighted pulse sequence, MRCP using a breath-hold 2D-RARE sequence,
      and breath-hold gadolinium-enhanced dual-phase 3D-MR angiography. RESULTS: All
      pancreatic tumors were detected by the combination of cross-sectional imaging and
      MRCP. In spite of the use of MRCP, definitive differentiation between pancreatic
      carcinoma and chronic pancreatitis was not possible in 3 (6.5%) out of 46 cases.
      High quality 3D-MR angiograms were obtained in 43 (93.5%) cases. In 6 (13%)
      patients 3D-MRA showed an aberrant right hepatic artery. The overall accuracy of
      MRI in assessing extrapancreatic tumor spread, lymph node metastases, liver
      metastases, and vascular involvement was 95.7%, 80.4%, 93.5%, and 89.1%,
      respectively. CONCLUSION: Due to its high accuracy, the "all-in-one" MR protocol
      may become the most important modality after clinical examination and ultrasound
      in the diagnostic work-up for most patients with suspicion of pancreatic tumors.

PMID- 10420902
TI  - [Comparison of left and right ventricular ejection and filling parameters of the
      heart using cine-MRI with breath holding technique. Clinical study of 42 patients
      with cardiomyopathy and coronary heart disease].
AB  - PURPOSE: Quantification of left and right ventricular filling and ejection of
      localized and diffuse heart diseases with fast cine MR imaging in breath-hold
      technique. METHODS: 42 patients (14 idiopathic dilated cardiomyopathies (DCM), 13
      hypertrophic cardiomyopathies (HCM) and 15 coronary artery diseases (CAD)) and 10
      healthy volunteers were examined. Time-volume-curves of three left ventricular
      and one right ventricular slices were evaluated and peak ejection and filling
      rates (PER, PFR end-diastolic volume (EDV)/s) time to PER and PFR (TPER, TPFR ms)
      and time of end-systole (TSYS in % RR-intervall) were calculated. RESULTS: There
      were significant regional and left-/right-sided differences of the filling and
      ejection of both ventricles within and between the different groups. In DCM the
      left ventricular PFR was reduced (DCM 3.1 EDV/s; volunteers 4.9 EDV/s) and Z-SYS
      prolonged (DCM 50.1%; volunteers 35.4%). In CAD there were localized decreased
      filling rates in comparison to the normal volunteer group (left ventricle: basal:
      2.9 and 6.3 EDV/s, apical: 4.4 and 6.3 EDV/s; right ventricle: 3.6 and 5.7
      EDV/s). HCM typically showed an isovolumetric lengthening of the endsystole.
      CONCLUSIONS: Cardiac MR imaging in breath-hold technique is suitable for
      measuring contraction and relaxation disturbances of localized and diffuse heart
      diseases by means of ejection and filling volume indices.

PMID- 10420903
TI  - [Evaluation of right heart load with spiral CT in patients with acute lung
      embolism].
AB  - PURPOSE: Purpose of this study was to evaluate whether spiral-CT allows judgment
      of right ventricular failure in patients with acute pulmonary embolism. MATERIALS
      AND METHODS: 61 patients underwent spiral-CT due to suspicion of acute pulmonary
      embolism. Patients with pulmonary embolism were divided into subpopulations
      according to the severity of pulmonary embolism in the CT scan. Cardiac
      measurements were performed on axial spiral-CT images and compared to those of
      patients without suspicion of pulmonary embolism or cardiac diseases. RESULTS: In
      30 patients spiral-CT revealed acute pulmonary embolism. Significant differences
      in cardiac measurements in patients with severe and less severe pulmonary
      embolism were found on comparing the following dimensions: left ventricular width
      (p = 0.0003), left (p = 0.008) and right (p = 0.009) ventricular cross-sectional
      area, proportion of right to left ventricular width (p = 0.0003) and proportion
      of right to left ventricular cross-sectional area (p = 0.0001). The proportion of
      the cross-sectional areas (r = 0.65) and the proportion of the width (r = 0.60)
      of both ventricles correlated well with the severity of central pulmonary
      embolism. CONCLUSION: Besides reliable assessment of pulmonary embolism spiral-CT
      allows the evaluation of cardiac dimensions for judgment of right ventricular
      failure.

PMID- 10420904
TI  - [Virtual endoscopy of the upper urinary tract based on contrast-enhanced MR
      urography data sets].
AB  - PURPOSE: To investigate the feasibility of reconstructing a virtual endoscopy
      from MR imaging data sets of the upper urinary tract. METHOD: The data obtained
      from 28 contrast-enhanced MR urographic examinations (5 normal; 23 pathologic)
      were post-processed to reconstruct a virtual ureterorenoscopy (VURS) using a
      threshold image segmentation. The visualization of the upper urinary tract was
      based on the acquisition of T1-weighted 3D gradient-echo sequences after
      intravenous administration of gadolinium-DTPA and a prior injection of low-dose
      furosemide. RESULTS: The employed MR urography technique created in all 28 cases
      a complete and strong contrast enhancement of the urinary tract. These 3D
      sequence data allowed the reconstruction of a VURS, even when the collecting
      system was not dilated. The best accuracy was provided by the MR urography
      sequences with the smallest voxel size. Moreover, the data acquisition based on a
      breath-hold technique has proved superior to that using a respiratory gating.
      Inside the renal pelvis, all calices could be assessed by turning the virtual
      endoscope in the appropriate direction. The visualization of the ureteral
      orifices in the bladder was also possible. All filling defects that were
      diagnosed by MR urography could be evaluated from the endoluminal view using the
      VURS. The exact characterization of the lesions based only on the assessment of
      the surface structure was difficult. CONCLUSION: A virtual endoscopy of the upper
      urinary tract can be successfully reconstructed using the data sets of high
      resolution 3D MR urography sequences.

PMID- 10420905
TI  - [Prostaglandin E1 for prevention of contrast medium-induced kidney dysfunction].
AB  - PURPOSE: Acute renal failure is a known complication of contrast media (CM)
      application in risk patients. Therefore an efficient prevention is highly
      desirable. The purpose of this pilot study was a) to demonstrate the efficacy and
      safety of prostaglandin E1 (PGE1 = alprostadil) in the prophylaxis against CM
      associated renal dysfunction in patients with renal disease, and b) to identify
      the adequate dose. METHODS: A total of 130 patients with renal dysfunction who
      were scheduled for intravascular CM administration were enrolled. They received
      PGE1 (10, 20, or 40 ng/kg/min) or placebo intravenously over a period of six
      hours (beginning one hour prior to exposure). Efficacy was determined by
      measuring serum creatinine and creatinine clearance. Safety was assessed by
      recording adverse experiences throughout the study and close monitoring of vital
      parameters especially during study drug administration. RESULTS: PGE1 proved to
      be superior to placebo in all doses. The dose of 20 ng/kg/min was most promising
      due to the lowest increase of serum creatinine 48 hours after CM administration.
      With respect to creatinine clearance, no relevant differences between study and
      control groups were observed. CONCLUSION: Our results suggest that intravenously
      administered PGE1 may be efficient in preventing CM-induced renal dysfunction in
      patients with renal impairment.

PMID- 10420906
TI  - [Panorama ultrasound of the spinal canal with determination of the level of the
      conus medullaris in newborn infants and infants].
AB  - PURPOSE: To evaluate the utility of panoramic ultrasound in visualizing the
      spinal canal and the conus medullaris level in neonates and young infants.
      METHOD: 30 children (aged 2 days to 5 months, 2058-6660 g, 41-57 cm) underwent
      examination of the spinal canal. The children were examined by a single,
      continuous 9.0 MHz transducer movement from the cervico thoracic spine to the
      coccyx. A dedicated computer processor produced an extended field of view image
      in realtime mode. RESULTS: With panoramic ultrasound coverage of the thoracic,
      lumbar and sacral spinal canal on one extended image was possible. Visualization
      of the spinal cord, the conus medullaris level, the subarachnoid space, the cauda
      equina and the tip of the dural sac was easily accomplished in each child. An
      average of four trials was necessary to obtain an image of sufficient diagnostic
      quality. The conus level ranged from L1 to L3, the tip of the dural sac was
      localized at S1 to S3. CONCLUSIONS: Panoramic ultrasound offers nearly complete
      visualization of the spinal canal in children on one single extended field of
      view image. The conus medullaris level and the tip of the dural sac can easily be
      localized.

PMID- 10420908
TI  - [Multi-rotation CT during continuous ventilation: comparison of different density
      areas in healthy lungs and in the ARDS lavage model].
AB  - PURPOSE: In this animal study, density ranges for CT-based quantification of
      ventilated lung area were determined. Healthy lungs and ARDS lungs were compared
      during artificial respiration. MATERIAL AND METHODS: CT-scans were performed in 5
      anesthetized pigs using a dynamic multiscan CT option on a predefined transverse
      slice (slice thickness 1 mm; effective temporal resolution, 250 ms). During
      continuous CT acquisition, airway pressure was increased or decreased in a
      stepwise manner. In all images, areas of defined HU ranges were determined
      planimetrically. The lower threshold was set to -910 HE in all images. The upper
      threshold was varied from -800 HE to -200 HE in steps of 100 HE. RESULTS: During
      inspiration in healthy lungs the HU-range of -910 to -700 HU showed the largest
      increase in area. During inspiration in ARDS lungs the HU range from -910 to -300
      HU allowed the most sensitive assessment of area changes. These findings can be
      explained by recruitment of atelectases (HU-range > -300 HU) and their transition
      to a HU range from -700 to -300 HU. CONCLUSION: Dynamic multiscan CT acquisitions
      are a useful method to determine changes of ventilated lung area during a
      respiratory cycle. Different HU-ranges are required to access volume changes in
      healthy lungs and in ARDS lungs.

PMID- 10420907
TI  - [Phosphorus-31-MR spectroscopy imaging in preoperative embolization treatment of
      meningioma].
AB  - PURPOSE: 31P MR spectroscopic imaging (31P SI) was evaluated in a clinical study
      as a method for monitoring presurgical devascularization of meningiomas. The aim
      was to assess noninvasively metabolic alterations in tumor and in healthy brain
      tissue before and after embolization. METHODS: Localized 31P MR spectra of the
      brain were obtained by means of 2D-SI (voxel size: 36 cm3) using a 1,5-T whole
      body MR tomograph. RESULTS: Eleven of 19 patients with intracranial meningiomas
      examined in this study underwent preoperative embolization therapy; eight
      patients were examined before and after treatment. After embolization,
      alterations of pH and of the concentrations of high-energy phosphates (nucleoside
      5' triphosphate = NTP, phosphocreatine = PCr), inorganic phosphate (Pi), and
      membrane constituents were observed in the tumors. A tendency of [Pi] increase
      and decrease of [NTP], [PCr], and pH predominated, which is explained by ischemic
      processes after tumor devascularization. CONCLUSION: 31P SI is applicable in
      clinical studies and detects alterations of phosphate metabolism in a meningioma
      after embolization.

PMID- 10420909
TI  - [MRI follow-up in multiple sclerosis. A guideline for quality assurance].
AB  - Magnetic resonance imaging (MRI) is highly sensitive to pathological tissue
      changes in multiple sclerosis (MS) patients. It demonstrates the frequently
      subclinical disease activity and follow-up examinations regularly show the
      accumulation of new lesions and the development of atrophy. The increasing
      importance of follow-up examinations in MS patients makes it necessary to provide
      comparable MRI data even over long observation periods. This review article
      focusses on critical variables in this regard and technical issues; practical
      guidelines for MRI protocols in MS patients are presented. The influence of field
      strength, MR systems from different manufacturers, and new software releases is
      described. Guidelines concerning the graphic planning of the examination,
      sequence protocols, documentation and reporting of cranial MR studies in MS
      patients are presented.

PMID- 10420911
TI  - [MRI in funicular myelosis].
AB  - The MRI morphology in combined subacute degeneration has only rarely been
      reported. We describe two patients suffering from subacute combined degeneration
      of the spinal cord on the basis of a deficiency of vitamin B12. In both patients
      characteristic hyperintense areas on T2-weighted images in the posterior columns
      of the cervical and thoracic cord without contrast enhancement were demonstrated
      by MRI.

PMID- 10420910
TI  - [Diagnostic imaging in hepatosplenic candidiasis].
AB  - Hepatosplenic candidiasis is a severe complication encountered in immuno
      compromised patients. Different imaging techniques can establish the diagnosis.
      After an introduction to the pathophysiological and clinical principles, the role
      of plain radiography, radionuclide scans, ultrasound, computed tomography and
      magnetic resonance imaging is discussed.

PMID- 10420912
TI  - [Tubular ectasia of the rete testis as cystic space-occupying lesion of the
      testis--magnetic resonance tomography aspects in 5 cases].

PMID- 10420913
TI  - [Metastases of renal cell carcinoma to the pancreas and gallbladder-
      possibilities and limits of MRI diagnosis].

PMID- 10420914
TI  - [Granulomatous spondylodiscitis of the lumbar spine in chronic brucellosis].

PMID- 10420915
TI  - [Angiomyolipoma of the kidney with tumor thrombus of the renal vein and inferior
      vena cava].

PMID- 10420917
TI  - Der Impact Faktor: Eine kritische Analyse. The impact factor: a critical
      analysis.

PMID- 10420916
TI  - [Aneurysm rupture of the ileocolic artery, multiple aneurysms, renal
      arteriovenous fistula and fatal aortic rupture in Ehlers-Danlos syndrome, subtype
      IV].

PMID- 10420918
TI  - [Human cloning].

PMID- 10420919
TI  - [Intensive chemotherapy in the treatment of patients with metastatic breast
      cancer].
AB  - PURPOSE: Phase II study with intensive chemotherapy and autologous stem cells
      support in patients with metastatic breast cancer. METHODS: Forty-nine patients
      were treated with high-doses of two cytotoxic drugs and support with stem cells
      obtained from several leukapheresis without movilitation. The cells were
      reinfused forty-eight hours after finishing the administration of chemotherapy.
      RESULTS: Twenty-one patients (47%, CI-95%: 32.4-63.3%) achieved a complete
      remission. The objective responses rate was 73% (CI-95%: 57.2-85%). Overall and
      progression-free survival up to 4 years were 31% and 20%, respectively. Ten
      patients remain progression-free among 17 and 46 months. The most frequent
      extramedullary toxicity was hepatic and renal. Three patients (6%) died during
      the procedure. CONCLUSIONS: Intensive chemotherapy with hematopoietic support
      yields, with a moderate toxicity, a high objective response and complete
      remission rate. A small group of patients achieves a long progression-free
      survival.

PMID- 10420921
TI  - [Breast cancer: value of various examinations in the diagnosis of the primary
      lesion].
AB  - Breast physical examination which is enormous help in clinical diagnosis of
      cancer of the breast is not useful in the diagnosis of early lesions. We analized
      in this study different complementary examinations we do for the diagnosis of the
      cancer of the breast. Mammography, though maintaining a 5-7% false negative
      results is the examination of choice of the breast. Not with standing its
      simplicity, its contribution with respect to breast and neoplastic biology makes
      it a useful investigation. The diagnosis obtained through mammography in non
      palpable tumors permit the use of conservative therapeutic techniques at the same
      time allowing improvement in curation and survival rates when we deal preferently
      with Stage I cancer. It is still necessary in our means an information
      sensibilization of the female population about breast autoexamination and the
      need for early specialized medical consultation. Any abnormal breast sign should
      alert us that more than 2.5 months delay would suppose a difference from a T1 to
      a T2 tumor.

PMID- 10420920
TI  - [Tuberous sclerosis. Apropos of 22 cases].
AB  - A retrospective study on twenty two cases with tuberous sclerosis, from 1972 to
      1994, is done. It is also reviewed national and international literature,
      emphasizing epidemiologic, clinical, radiological, genetic and therapeutic
      aspects, as well as diagnosis and prognosis.

PMID- 10420922
TI  - [Predictors of tobacco addiction in young adults].
AB  - To identify smoking dependence predictors, 150 active smokers were interviewed.
      To assess tobacco dependence Fagerstrom's test was used. The potential
      associations between smoking dependence and some variables related to life style
      were investigated. In a case-control study design an induction period > or = 2
      months was assumed. After estimating crude odds ratios, a logistic regression
      model was fitted. The dependent variable was dependence to tobacco smoking. In
      the multivariate analysis independent predictors, in addition to age, were: a) an
      earlier hour for starting smoking (OR: 6.08; 95% CI: 2.29-16.2), b) thinking that
      smoking avoids getting fat (OR: 4.36; 95% CI: 1.50-12.7) and c) not knowing any
      person with smoking-related pathology (OR: 3.75; 95% CI: 1.36-10.3). Exercise
      appeared to protect against smoking addiction (OR: 0.36; 95% CI: 0.13-0.98). The
      knowledge of these factors could help to avoid the development of smoking
      addiction.

PMID- 10420924
TI  - [Neurotrophins. II: therapeutic potential].
AB  - Neurodegenerative diseases are highly devastating disorders characterized by the
      damage and loss of discrete neuronal populations. Until recently, it was assumed
      that the ability of the central nervous system to recover from injury was
      extremely limited. However, many "in vitro" and "in vivo" studies have shown that
      neurotrophic factor are able to prevent or inhibit neuronal cell death induced by
      a variety of insults. Accordingly, trophic factors may represent a new tool for
      treating neuronal injury and death in a variety of neurodegenerative diseases. In
      his review, the therapeutic possibilities of neurotrophins in the treatment of
      Parkinson's disease, Alzheimer disease and amyotrophic lateral sclerosis are
      analysed.

PMID- 10420923
TI  - [Neurotrophins. I: Molecular features].
AB  - Neurotrophic factors are proteins necessary for neuronal development and
      survival. The first isolated and characterized neurotrophin was nerve growth
      factor (NGF). Other structurally related neurotrophins are brain-derived
      neurotrophic factor (BDNF) and the neurotrophins NT-3, NT-4/5 and NT-6. The
      neurotrophins bind to specific tyrosine-kinase (trk) receptors, which are
      transmembrane proteins with intrinsic phosphorylating activity. Three trk
      receptor subtypes are known at present, trk A, trk B and trk C, which
      preferentially bind NGF, BDNF and NT-3 respectively. All of the neurotrophins
      bind to another low-affinity receptor called p75. The neurotrophins are generally
      synthesized in target cells and, after receptor binding, are transported
      retrogradely from the nerve terminal to the nucleus where they regulate gene
      expression. The role of neurotrophins in development has been further
      characterized by means of gene disruption studies that show profound phenotype
      alterations in mice lacking any of the trk receptors.

PMID- 10420925
TI  - [Nutrition, energy balance, and obesity].
AB  - Energy supply from foods and drinks depends upon carbohydrate, protein, lipid and
      alcohol content. Cells obtain the energy through a complex and integrated system
      of physico-chemical processes. The energy value of foods is applied for ATP
      formation, but also for nutrient utilization and turnover. Net energy from foods
      is expended for basal metabolism, thermic effect of food and physical activity.
      Total energy expenditure for human beings is displayed in different lists
      developed by national and international organisms and institutions. Energy
      balance and body weight are narrowly interrelated as well as body composition,
      which depends also of age, sex, exercise and neuroendocrine status. Obesity, is
      known as an excessive deposition of fat for height, and it is associated with
      cancer, dislipemias, endocrine abnormalities, diabetes, etc. Recent advances
      suggest that genetic and neuroendocrine factors are more involved in obesity
      rather than gluttony or sloth as previously reported.

PMID- 10420926
TI  - [Losartan].

PMID- 10420927
TI  - [Information network handling of some bioethics-related topics].

PMID- 10420928
TI  - [Cardiovascular disease research].

PMID- 10420930
TI  - [Surgical treatment of vertebral metastasis].
AB  - Spinal metastases may cause pain and neurologic dysfunction secondary to bone
      destruction and spinal cord compression. The new oncology therapy have prolonged
      life expectancy of many patients with different primary tumors. The treatment of
      metastases is frequently necessary to enhance quality of life. We reviewed 121
      patients with spinal metastases of different primary tumors operated between 1982
      and 1995. We employed different approach and instrumentation depending on
      particular case, metastases location and life expectancy. We analysed primary
      tumor location, spinal pain, neurologic function, pre and post surgical
      treatment, complications and development. Spinal stabilization and cord
      decompression gives excellent results for pain relief, neurological improvement
      and quality of life, always helping to medical treatment of a patient with
      metastatic disease.

PMID- 10420929
TI  - [Intestinal bacteria overgrowth in chronic hepatopathies].
AB  - Intestinal bacterial overgrowth (IBD) is very frequent in patients with chronic
      hepatopathies. Causes of IBO, although not entirely known, principally are: the
      hepatopathy, the alcoholism and the alterations produced by these two factors,
      such as achylia (and above all hypochlorhydria), decrease in the secretion of
      IgA, and malnutrition. On the other hand, the IBO increases the severity of the
      hepatopathy and frequently produces a bacterial peritonitis. All these data
      suggest that the IBO play an important role increasing the hepatopathy severity
      and consequently is a factor to bear in mind.

PMID- 10420931
TI  - [Antiphospholipid syndrome].
AB  - Antiphospholipid syndrome is a well-defined clinical and serological entity
      characterized by arterial and/or venous thrombosis, recurrent abortion and
      thrombocytopenia. Anticardiolipin antibodies and lupus anticoagulant are
      autoantibodies directed against negatively charged phospholipids, which represent
      the serologic criteria for the diagnosis of the antiphospholipid syndrome. In
      this review the pathogenic mechanisms of anticardiolipin antibodies, their
      clinical findings and the current therapeutical strategies are discussed.

PMID- 10420932
TI  - [Pulmonary fibrosis caused by inhalation: silicosis].
AB  - Silicosis is an important disease not only for its prevalence and the degree of
      pulmonary insufficiency it entails but also because it provides a natural model
      of interstitial fibrotic disease in the lung which is of known origin. This can,
      in turn, help us understand the pathogenic nature of a great number of pulmonary
      fibroses whose cause is unknown. The fifty postmortem studies which we describe
      correspond to miners who had worked in underground mines in the mountainous
      region near Cartagena (SE Spain) for times ranging from 5 to 36 years. The
      autopsies showed that they had been exposed to dust containing abundant metallic
      particles, particularly iron oxide (mixed dust). Although the pathogenic action
      was related with silica, it was also clearly modified by the composition of the
      dust associated with it. The basic lesions which are produced in the lung after
      inhalation of silica (< 5 microns diameter) are coniosis, fibroconiosis and
      sclerohyalinosis. The sclerohyalino nodules are characterized by abundant
      collagenization and hyalinization, different types of which can be distinguished
      according to the disposition of the collagenous fibres. Nodular lesions gradually
      grow in size even when exposure to dust has ceased. As they grow they get nearer
      until they join to form conglomerate masses. When the diameter exceeds 3 cm this
      is called massive fibrosis. Pulmonary tuberculosis was found in 27% of cases.
      This took the form of lesions, which could be associated to or independent of
      silicotic lesions. Besides evolutive nodular lesions, a patient suffering from
      silicosis may show other unspecific lesions which must be correctly evaluated for
      a more correct clinical-pathological assessment, since, clinically, the
      respiratory function may be profoundly affected although such silicotic damage
      may be not very noticeable by radiological examination. Silicosis of the liver
      and spleen was not infrequent in the autopsies carried out, with basic lesions in
      all evolutive states being observed, the most evolved in the spleen. This means
      that silicosis should be considered as a systemic illness.

PMID- 10420933
TI  - [Levofloxacin].

PMID- 10420934
TI  - [A medical commentary on the approval of RU-486].

PMID- 10420935
TI  - [New perspectives in cancer treatment].

PMID- 10420936
TI  - [Color Doppler echography study of ocular blood flow velocity in patients with
      proliferative diabetic retinopathy after performance of retinal pan
      photocoagulation: 2 years' follow-up].
AB  - PURPOSE: Color Doppler imaging allows for simultaneous two-dimensional anatomical
      imaging and Doppler measurement of blood flow velocity. Because hemodynamic
      changes have been seen in diabetic patients after photocoagulation by other
      techniques, the authors compared 25 eyes with proliferative diabetic retinopathy
      before, 6 months, 1 year, and 2 years after panretinal photocoagulation with a
      matched control group of 30 healthy volunteers. METHODS: The ophthalmic artery,
      short posterior ciliary artery, central retinal vessels and vortex veins of all
      patients were examined, and the systolic, diastolic and mean arterial velocities
      were measured. Panretinal photocoagulation was performed with these parameters:
      800-1000 spots, 0.1s, 500 micron argon laser. RESULTS: Student's t test revealed
      that the perfusion velocity was significantly lower in diabetic patients than in
      normals (Vsystolic in the ophthalmic artery: 31.7 (6.7) cm/s vs 36.6 (7.0) cm/s,
      respectively, P = 0.03). After treatment, blood flow velocities were
      significantly lower than before photocoagulation (Vsystolic in the ophthalmic
      artery: 6 months after treatment 26.9 (7.2) cm/s, P = 0.018 and 1 year after
      photocoagulation 25.5 (7.0) cm/s, P = 0.009; and 2 years after photocoagulation,
      25.7 (6.8) cm/s, P = 0.01). No statistically significant differences were found
      between 6 months, 1 year, and 2 years after panretinal photocoagulation. No
      significant correlations were found between age and blood velocities in diabetics
      and healthy volunteers. CONCLUSIONS: Eyes with proliferative diabetic retinopathy
      showed lower ocular perfusion velocities than normals. Photocoagulation resulted
      in a reduction in ocular blood flow velocities; these values did not change
      during 2 years of follow-up.

PMID- 10420937
TI  - [Barrett's esophagus].
AB  - Barrett's esophagus (BE), a complication of gastroesophageal reflux disease, is
      the replacement of squamous tissue with specialized intestinal metaplasia. Other
      noxious factor, as biliary acids, may contribute to the induction of BE. It is a
      premalignant condition, and adenocarcinoma arises in some cases. An endoscopic
      surveillance with multiple biopsies is mandatory to detect different grades of
      dysplasia or intramucosal cancer and allow effective therapy. Since its
      prevalence is high, current surveillance protocols become expensive and patient's
      compliance is difficult. The main medical goals are: 1) To stratify individuals
      without dysplasia as either lower or higher risk, to screen less often those at
      lower risk. 2) To obtain complete remission or eliminate the risk of cancer and
      the need for surveillance. Current treatments have not demonstrate complete
      regression of metaplasia. Recently, new endoscopic approaches to therapy have
      been developed. Although they remain experimental and larger series are required,
      initial results are encouraging.

PMID- 10420938
TI  - [Practical approximation to the diagnosis of tachyarrhythmias].
AB  - Even though the 12-lead electrocardiogram is the most helpful tool in the
      diagnosis of tachycardia, a careful history and physical examination can be
      useful in both differentiating between ventricular and supraventricular
      tachycardia and elucidating the electrophysiological mechanism of
      supraventricular tachycardia. This article will focus on the most relevant
      clinical aspects of tachyarrhythmias as well as on the electrocardiographic
      differential diagnosis of regular broad complex tachycardia.

PMID- 10420939
TI  - [Irbesartan].

PMID- 10420940
TI  - [Roots of existential angst].

PMID- 10420941
TI  - [Stable isotopes in biomedicine].

PMID- 10420942
TI  - [Applications of stable isotopes in biomedical sciences].
AB  - The employment of stable isotopes technology allows to perform a wide range of
      studies in vivo avoiding the utilisation of radioactive isotopes. As stable
      isotopes naturally occur in nature, the technique detects the enrichment in
      breath air of the tracer administered. Stable isotopes technology is increasingly
      being used in biomedical investigation due to the security of its use and the
      development and availability of new substrates. Breath tests such 13C-urea in the
      detection of Helicobacter pylori and 13C-octanoic acid for gastric emptying are
      the most important clinical applications.

PMID- 10420943
TI  - [Studying intestinal maturation in newborn infants by means of stable isotopes].
AB  - Survival and subsequent quality of life in low birth weight infants are related
      to an adequate early nutrition. Premature children require parenteral nutrition
      support in the first days of life due to their intolerance enteral nutrition. In
      experimental studies, parenteral nutrition promotes intestinal abnormalities.
      Minimal enteral feeding has been proposed to minimise these adverse effects.
      Stable isotopes technology is an adequate tool to investigate metabolism in the
      perinatal period. The amino acid Leucine has been used by different authors for
      the study of protein turnover. The double tracer technology allows to follow the
      seizure of an amino acid administered enterally in splanchnic tissue. By
      continuous infusion and breath tests we can estimate protein synthesis in these
      children.

PMID- 10420944
TI  - [Studying of gastric emptying for solids and liquids by means of using stable
      isotopes].
AB  - The study of gastric emptying is usually performed by scintigraphy. Over the last
      years alternative non radioactive methods have been developed based on the stable
      isotopes technology. Such techniques use 13C-octanoic acid to measure gastric
      emptying of solids and sodium 13C-acetate to measure liquids emptying. The
      enrichment of 13C in breath air along the time reflects the velocity of gastric
      emptying. Kinetic parameters can be obtained from this enrichment to quantify
      gastric emptying. Samples can be obtained outside the processing laboratory. Due
      to the characteristics of the method, it is adequate and safe to evaluate
      pathologies related to gastric emptying and the efficiency of the therapy.

PMID- 10420945
TI  - [Lipid metabolism and lipogenesis: application of stable isotopes].
AB  - Fat metabolism is regulated by several neuroendocrine and nutritional factors,
      which affect equilibrium between lipogenesis and lipolysis. Lipid utilization and
      fate in the organism can be assessed by in vivo and in vitro methods by measuring
      the rate of the different metabolic pathways (dynamic aspects), but also the net
      balance which may lead to fat accumulation or loss (static aspects). The
      quantitation of synthesis and breakdown reactions can be performed by using
      different tracers such as radioactive and stable isotopes. Fatty acid synthesis
      can be independently measured by the intravenous infusion of 13C acetate and
      application of the MIDA technique. In brief, this method uses probability
      analysis to measure the synthesis of biological polymers. It is based on the
      mathematical principle that the labeling pattern of a polymer synthesized from a
      stable-isotopically labeled precursor will conform to a predicted binomial or
      multinomial expansion. Thus, the isotopic enrichment of the precursor pool is
      calculated from measurements on the product alone. In the case of fatty acid
      synthesis, the proportions of excess (above natural background abundance) of
      single-labeled and double labeled (EM1 and EM2 species respectively) are a
      function of the probability (p) that the precursor subunits were isotopically
      labeled. Using this value of P for the isotopic enrichment of the acetylCoA pool,
      the theoretical 13C enrichment in the fatty acid if 100% were newly formed from
      this acetate pool is calculated. The actual isotopic enrichment is measured by
      gas chromatography-mass spectrometry (GCMS). This value divided by the
      theoretical maximum value equals the fraction of the fatty acid that is newly
      formed (f). The value for f represents dilution of de novo synthesized fatty acid
      by non-de novo sources. This method requires that newly synthesized (labeled) and
      preformed (unlabeled) mix in the liver and communicate with plasma VLDL over the
      period of the isotope infusion. It also assumes that the major de novo fatty acid
      is only a single fatty acid, with minor elongation and/or desaturation processes.
      Finally, the infused isotopic acetate should have no physiologically important
      effect. This methodology can be applied to assess lipogenesis in very different
      nutritional and physiopathological conditions such as diabetes, AIDS, obesity,
      etc.

PMID- 10420946
TI  - "Mixed" triglyceride breath test: methodological problems and clinical
      applications.
AB  - Laboratory assessment of pancreatic function is unpleasant for the patient and
      time-consuming for the investigator since it requires duodenal intubation and
      measurement of maximal pancreatic enzyme output by means of perfusion techniques.
      Non-invasive indirect tests such as bentiromide test, pancreolauryl test and
      faecal fat measurement have been introduced in clinical practice but their
      results depend on the collaboration of the patient in collecting urine or stool.
      Moreover, faecal fat reflects fat malabsorption but it is neither sensitive nor
      specific to evaluate exocrine pancreatic function. With the aim to determine
      whether steatorrhea is due to pancreatic insufficiency, several 14C- (or 13C)
      breath tests have been developed in which triolein, trioctanoin, tripalmitin, and
      cholesteryl-octanoate are used as marker substances. In 1989, G. Vantrappen and
      its group in Leuven developed a breath test in which a new substrate was used:
      the [1,3-distearyl, 2[carboxyl-13C]octanoyl glycerol] or 13C-"mixed"-triglyceride
      (MT). The "mixed triglyceride breath test" (MTBT) was shown to be an excellent
      test of exocrine pancreatic insufficiency when compared with the maximal lipase
      output after CCK-pancreozymin stimulation. Aim of this paper is to review the
      methodology of the MTBT and its actual and future applications in clinical
      practice.

PMID- 10420947
TI  - Study of protein assimilation, using stable isotope techniques.
AB  - Information on the efficiency and kinetics of protein assimilation in humans is
      scanty and moreover controversial. This is mainly due to the lack of a reliable
      and non-invasive measuring technique. The recent availability of stable isotope
      labelled protein allowed to study protein assimilation using tracer techniques.
      Applying these techniques, we showed that protein digestibility depends both on
      characteristics of the ingested meal and on the digestive and absorptive capacity
      of the upper gastrointestinal tract. The latter is significantly impaired in
      pancreatic disease but is also compromised by some drugs often used in clinical
      practice. We moreover confirmed that a substantial amount of even easily
      digestible dietary protein escapes assimilation in the small intestine.

PMID- 10420948
TI  - [Donepezil : a new option in the treatment of Alzheimer's disease] ONEPA.

PMID- 10420949
TI  - [Sociopolitical issues in medical research].

PMID- 10420950
TI  - [Gene therapy and hepatology: a priority research area at the University of
      Navarre].

PMID- 10420951
TI  - [Follow-up of breast cancer: review of 750 cases after 5 years].
AB  - Recurrence of breast cancer can present in very small tumors even 20 years after
      initial treatment. Periodic revision of all the operated population during a long
      time will be necessary to detect all the recurrences. For this the cost-benefit
      relation of follow-up in breast cancer is a controversial topic. We present our
      results in 750 cases of breast cancer operated from 1980 and submitted to a
      follow-up protocol during five years. We analyzed the value of follow-up for the
      discovery of metastases, local recurrence after conservative treatment and after
      mastectomy. Finally we considered the usefulness of early diagnosis of familial
      breast cancer and cancer in the contralateral breast. Metastases was discovered
      in asymptomatic patients in 68%, which could improve the survival. Recurrence
      after mastectomy was seen in 1.3% of the patient and a half of these after
      treatment presented survival superior to 3 years. Follow-up favours early
      diagnosis and could have influence on survival.

PMID- 10420952
TI  - [Chlamydia pneumoniae pneumonia].
AB  - Chlamydia pneumoniae causes respiratory tract infections, and it is transmitted
      by air and fomites. It is probably more frequent than it is described, due to
      asymptomatic or mild symptomatic patients. They respond to macrolides,
      tetracyclines and quinolones, though patients may recover slowly. An increase of
      the incidence of pneumonia, caused by Chlamydia pneumoniae, is shown in recent
      multicenter surveys, being even more frequent than Streptococcus pneumoniae and
      Mycoplasma pneumoniae. Recently it has been demonstrated an association between
      coronary artery disease and atherosclerosis with Chlamydia pneumoniae infection.
      Special attention must be paid to the cardiovascular complications of Chlamydia
      pneumoniae. We describe six clinical cases of Chlamydia pneumoniae pneumonia in
      which two of them suffered from ischemic artery disease as a complication of the
      infection.

PMID- 10420953
TI  - [Effects of the chronic administration of midazolam on the rat hippocampus].
AB  - The effects of midazolam (MDZ) treatment during 120 days have been studied in 2
      groups of young and old Wistar rats: (50 animals two months, 50 aged 24 months).
      20 rats of both groups got 1 mg/kg of MDZ daily, 20 3 mg/kg, and finally 10,
      animals 1 ml saline all administered by gastric intubation. The general effects
      of MDZ (mortality, weight changes and memory of an aversive stimuli showed no
      significant differences with the controls either in young or old rats. In the
      hippocampus, the total count of neurons gave no significant differences compared
      to controls. However, in the group of old rats a higher number of dark and
      pycnotic cells, principally in those rats treated with 3 mg/kg of MDZ was
      observed. The global area of the CA1, CA4 fields and of the GD was significant
      reduced in comparison with the controls. These results favour the conclusion that
      the MDZ has a minimal neurotoxicity: only the group of old rats treated with 3
      mg/kg showed weak signs of hippocampal effects.

PMID- 10420955
TI  - [Radiofrequency ablation of supraventricular tachycardias].
AB  - Radiofrequency catheter ablation has been established as a non-surgical curative
      treatment modality for the management of patients with paroxismal
      supraventricular tachycardia. Success rates for atrioventricular node reentrant
      tachycardia and accessory pathway-mediated macroreentrant tachycardia exceed 95%.
      Results in patients with atrial flutter and atrial tachycardia are encouraging,
      with success rates exceeding 75%.

PMID- 10420954
TI  - [McArdle's disease. Apropos of a case].
AB  - McArdle's disease (glycogenosis type V) is a metabolic disorder of hydrocarbons,
      inherited with autosomic recessive pattern. Biochemically is defined by a
      myophosphorylase deficiency; clinically it is characterized by exercise
      intolerance, due to the impossibility of providing energetic substrate to the
      muscle, myalgias and stiffness. We present a case report of a patient with
      McArdle's disease and we comment the diagnostic procedures and current
      therapeutic options.

PMID- 10420956
TI  - [Age-related macular degeneration].
AB  - Age-related macular degeneration (ARMD) is the leading cause of blindness in the
      occidental world. Patients suffering this process have an important reduction on
      their quality of life being handicapped to read, to write, to recognise faces of
      their friends, or even to watch the television. One of the main problems of that
      disease is the absence of an effective treatment able to revert the process.
      Laser treatment is only useful in a limited number of patients, and even in these
      cases recurrent lesions are frequent. These facts and the progressive ageing of
      our society establish the ARMD as one of the biggest aim of medical
      investigations for the next century, and currently is focus of attention in the
      most industrialised countries. One of the most promising pieces of research is
      focused in the investigation of the risk factors associated with the age-related
      macular degeneration, in order to achieve a prophylactic treatment avoiding its
      appearance. Diet elements such as fat ingestion or reduced antioxidant intakes
      are being investigated as some of these factors, what open a new possibility for
      a prophylactic treatment. Finally, research is looking for new therapeutic
      modalities such as selective radiotherapy in order to improve or maintain the
      vision of these patients.

PMID- 10420957
TI  - [Atorvastatin . A new generation of hypolipemic agents?].

PMID- 10420958
TI  - [Technical advances and medical practice].

PMID- 10420959
TI  - [Age discrimination].

PMID- 10420960
TI  - [Carotid endarterectomy. Analysis of 193 consecutive cases].
AB  - In the last years, several randomized and multicenter trials have been performed
      to evaluate the benefit of carotid endarterectomy (CE) in the carotid stenosis.
      To determine whether CE could be performed safely at hospitals not included in
      international trials, the results of 193 consecutive CEs performed during a 10
      year period at a medical center of our environment were reviewed. A 65.8% of CEs
      were performed on symptomatic patients, 68.5% of whom had stenosis superiores to
      70%. Among asymptomatic patients, 89.4% had stenosis superiores to 70%. Three
      patients died. Besides there were five nonfatal neurologic complications (one
      reversible ischemic neurologic deficit, one minor stroke and three major
      strokes). The mortality rate was 1.5%, the rate of mayor neurologic morbidity and
      mortality was 3.1% and the rate of total neurologic morbidity and mortality was
      4.1%. These data demonstrate that CE can be performed with safety at Divisions of
      Vascular Surgery of our environment.

PMID- 10420961
TI  - [Utility of bronchoalveolar lavage in the diagnosis of respiratory infection in
      HIV patients].
AB  - From January 1, 1992, to December 31, 1995, we studied 52 bronchoalveolar lavages
      in 45 HIV-infected patients. All patients with pulmonary symptoms and/or new
      pulmonary infiltrates underwent bronchoalveolar lavage (BAL) when the results of
      blood cultures and mycobacterial smears of sputum and urine were negative. Lavage
      fluid was investigated for the presence of P. carinii, bacteria, mycobacteria,
      fungi and virus. BAL was diagnostic in 39 (75%) cases. The organisms more
      frequently isolated were P. carinii and M. tuberculosis. Only one pathogen was
      identified in 28 cases (54%); two in ten (19%); and three in one patient (2%).
      BAL was, generally, well tolerated by the patient and had a high diagnostic yield
      in the evaluation of patients with HIV infection and respiratory symptoms.

PMID- 10420963
TI  - [Surgical options in the treatment of polycystic ovary syndrome].
AB  - Since it was defined, SOP has been related to surgery. Before clomifero was
      introduced, ovarian wedge resection was the only way to stimulate ovulation and
      gestation in women with this syndrome. Surgical techniques were derelict in
      favour of less aggressive medical treatments. However, surgery has reduced its
      side effects due to the incorporation of laparoscopic techniques and other
      advances. Because of this fact, surgery is being reintroduced in the treatment of
      polycystic ovarian disease.

PMID- 10420964
TI  - [Health outcomes analysis and its applications].
AB  - The goal is to describe the applications of outcomes studies to improve health
      care. Health care has structure, process and outcomes (clinical, economic and
      humanistic). Pharmacoeconomic studies identifies, measures and compares the costs
      and consequences of pharmaceutical products and services. The main source of
      information in health-related quality of life is the patient's perspective. The
      patients' opinion are used to assess drug treatments and healthcare programs.
      Although there are still controversies about their standardisation,
      pharmacoeconomics studies are important tools for decision-making process. We
      should use the terminology property and know the methodologies in
      pharmacoeconomic studies for applying and interpreting these studies. Health
      outcomes' assessing permits to us improve quality and efficiency of our services
      that we offer to the society.

PMID- 10420962
TI  - [Familial fatal insomnia: a human prion disease which opens the door to a greater
      understanding of the thalamus].
AB  - In 1986, Lugaresi [1] described fatal familial insomnia (FFI), an inherited prion
      disease, characterised by untreatable insomnia and dysautonomia. The most severe
      neuropathological changes have been found in the mediodorsal (MD) and anterior
      (A) thalamic nuclei. The data lead to think that the thalamus could play an
      important role in the wake-sleep cycle and other vegetative and endocrine
      circadian activities, specially MD and A.

PMID- 10420965
TI  - [Differential features of SSRIs].
AB  - The goal of this study is to review the pharmacologic profiles of the selective
      serotonin reuptake inhibitors (SSRIs) presently available, with particular
      emphasis placed on therapeutically relevant distinctions.

PMID- 10420967
TI  - Epitope discovery using monoclonal antibodies and phage peptide libraries.
AB  - Phage display is a biological system which facilitates the cloning and rapid
      selection of peptides from large combinatorial libraries. In comparison to the
      chemical combinatorial approach, the advantages of phage display lie in its
      simplicity and replicability. While phage display has many diverse applications,
      this review will focus on the use of phage peptide libraries to discover epitopes
      recognised by monoclonal antibodies. As monoclonal antibodies are useful tools
      for the detection of proteins and for the investigation of molecular
      interactions, the identification of their epitopes will serve to elucidate the
      structure and function of proteins, as well as aid in the discovery of new drugs
      and the development of vaccines.

PMID- 10420966
TI  - [The homosexual, born or made?].

PMID- 10420968
TI  - Energetic dissection of specificity in serine proteases.
AB  - Serine proteases of the chymotrypsin family share a similar fold and
      architecture, but they differ widely in specificity. The molecular origin of this
      difference remains for the most part elusive. A detailed understanding of the
      molecular origin of their specificity is of fundamental importance for structure
      function and evolutionary studies. Current approaches put much emphasis on single
      site substitutions of ligand sequences or protein residues and neglect second-
      and higher-order coupling among residues leading to an incomplete and often
      misleading assessment of the underlying energetics. Information on how
      recognition sites interact is key to unveil structure-function links and to
      enable the development of more effective drugs for therapeutic purposes. A novel
      strategy has been recently developed for dissecting enzyme specificity using the
      principles of site-specific thermodynamics and is applied in the present work to
      thrombin, trypsin, tissue plasminogen activator. The results provide a much
      needed data base of information for computational studies of protease specificity
      and protein-ligand interaction. They suggest precise guidelines for the design of
      novel active-site inhibitors. Basic differences are also identified between
      thrombin, tPA, plasmin and trypsin in the energetic contribution of the
      specificity sites and the coupling between them.

PMID- 10420969
TI  - Isolation of fibroblast growth factor receptor binding sequences using evolved
      phage display libraries.
AB  - A fusion protein construct consisting of the short form of human fibroblast
      growth factor (FGFR) fused to the heavy chain of mouse IgG1 was used to screen
      four phage display libraries displaying 8, 13, 38 and 43 amino acids at the amino
      terminus of the bacteriophage M13 gene III minor coat protein. Phage with
      specific FGFR binding activity were isolated from the 13, 38 and 43 mer
      libraries. One of the highest affinity phage clones from the 13mer library was
      chosen to be further evolved by oligonucleotide saturation mutagenesis. We have
      isolated evolved sequences that have approximately 8 times the relative binding
      affinity of the parent sequence. The phage clones have a minimum consensus
      sequence of CR/SXLLXGAPFXXXXC, where X represents positions tolerant of several
      amino acids. A synthetic peptide based on this sequence specifically inhibits FGF
      from binding to its receptor in an in vitro ELISA.

PMID- 10420971
TI  - Phage displayed peptide libraries.
AB  - Peptide libraries may be constructed by grafting, in vitro, random DNA sequences
      into a carrier gene and then introducing the degenerate hybrid coding sequence
      into an expression organism. This review will focus on phage display, which was
      the first expression organism for peptide library expression to be described and
      which still maintains predominance in this area because of its simplicity,
      minimal cost, ease of manipulation, power and robustness. Using phage as the
      host, a repertoire of random peptides can be expressed that may be searched by a
      variety of screening or selection procedures. By physically associating each
      element of the peptide library with its coding sequence, selection for a property
      of a specific peptide results in the enrichment of the corresponding gene thus
      facilitating its cloning and amplification. This review focuses on the
      construction and screening of peptide libraries displayed on filamentous phage
      capsid and only briefly discusses the display of proteins and protein domains.

PMID- 10420970
TI  - Screening for xenobiotic electrophilic metabolites using pulsed ultrafiltration
      mass spectrometry.
AB  - A pulsed ultrafiltration-mass spectrometric screening assay has been developed to
      generate and identify electrophilic metabolites of xenobiotic compounds formed by
      hepatic cytochrome P450 enzymes. This assay would be suitable for the early
      identification of potentially toxic compounds during the initial phase of drug
      development. Rat liver microsomes were trapped by an ultrafiltration membrane in
      a stirred flow-through chamber, and substrates for microsomal cytochrome P450
      including hydroxychavicol, 3-methylindole, cyproheptadine and 2-tert-butyl-4,6
      dimethylphenol were flow-injected individually through the chamber along with the
      cofactors, NADPH and glutathione. Metabolites and glutathione conjugates were
      detected on-line using electrospray mass spectrometry. Alternatively, the
      ultrafiltrate was concentrated on a reversed phase HPLC column and analyzed using
      electrospray LC-MS or LC-MS-MS to separate and characterize isomeric metabolites
      and metabolites present at low concentration. Enzymatic activation of each
      xenobiotic substrate produced highly electrophilic metabolites such as quinones,
      quinone methides and imine methides that reacted with glutathione on-line to
      produce glutathione conjugates which were detected by using electrospray mass
      spectrometry. Although epoxides such as cyproheptadine epoxide were generated, it
      is likely that these compounds were insufficiently reactive to form glutathione
      conjugates in the absence of cytosolic glutathione S-transferases. Pulsed
      ultrafiltration-electrospray mass spectrometry offers an efficient method for in
      vitro formation and mass spectrometric characterization of activated microsomal
      drug metabolites and is suitable for use during the drug discovery process for
      the early identification and screening out of potentially toxic lead compounds.

PMID- 10420972
TI  - Phage display in proteolysis and signal transduction.
AB  - The power of the phage display technology relies on the coupling of the
      functional display of combinatorial peptide or protein libraries with the ability
      of each member in the library to self-replicate and, at the same time, to encode
      the primary structure of the displayed polypeptide in its genome. Phage display
      systems, therefore, reflect the principle of encoded combinatorial chemistry
      close to perfection. Phage display libraries have extensively been used for the
      selection of peptides, antibody combining sites or protein variants binding to
      given structures such as polypeptides, carbohydrates, nucleic acids or small
      molecular weight compounds. The use of peptide libraries in selecting molecular
      interaction partners was extensively described in numerous publications and was
      subject to a variety of review articles in the past. More recently, and in the
      focus of this review, combinatorial phage libraries have been employed to examine
      substrate recognition in catalysis and signal transduction. The sensitivity and
      versatility of phage display for probing molecular recognition and catalysis by
      enzymes was demonstrated inasmuch as discriminating peptide substrates could be
      identified for even closely related proteases or tyrosine kinases. Furthermore,
      the modification of whole phage libraries by tyrosine kinases led to the
      identification of phosphopeptides specific for Src-homology-2 (SH2)- and
      phosphotyrosine-binding (PTB) domains, which are both structural and functional
      modules facilitating substrate recognition by protein kinases, phosphatases or
      adapter molecules involved in signal transduction.

PMID- 10420973
TI  - A novel cleavage protocol for use with Rf-encoded split pool synthesis
      technology: product cleavage and collection in standard 96 well format.
AB  - A novel protocol which employs commercially available, standard tools and
      hardware has been developed. This protocol allows for cleavage and collection of
      IRORI Microkan products in 96 well plate format. Typically, 640 compounds can be
      cleaved in a 4 hour time period using approximately 3 square feet of space. This
      protocol has been used successfully for the liberation of thousands of individual
      compounds, in single compound per well format from the solid phase. Additionally,
      this protocol is the first example of making IRORI Microkan technology directly
      compatible with standard 96 position deep well blocks.

PMID- 10420974
TI  - A solid phase approach to substituted pyrimidines and their conversion into
      condensed heterocycles for potential use in combinatorial chemistry.
AB  - A novel general synthesis of substituted pyrimidine 3 has been carried out on
      solid support. The C-atoms carring the cyano, amino, carboxamido, as well as
      anchoring site have exploited to generate libraries of compounds 6-8, 10, 13, 15,
      17, 19, 21, 23, 25 and 27. A novel strategy to cleave the resin to resin-site
      unsubstituted system has been developed and it provides 5,6-disubstituted
      pyrimidines 6-8. In addition, synthesis of 2,5,6-trisubstituted pyrimidines of
      prototype 10 were carried out by nucleophilic displacement of the anchor by
      various amines. Further investigations were directed toward the solid phase
      synthesis of pyrimido[4,5-d]pyrimidines 12, 16, 20 and 24 in which C-atoms
      carring the oxo, thio, amino, anchoring site as well as NH could be introduced as
      center of diversity to generate libraries of compounds for potential use. 4
      Aminopyrimido[4,5-d]pyrimidines 13 and 17 were obtained from fusion of 3a with
      urea or thiourea followed by cleavage of support while 3-phenylpyrimido[4,5
      d]pyrimidines 21 and 27 were synthesized from cyclisation of 4 with phenyl
      isocyanate or isothiocyanate followed by release of resin. 7-substituted
      pyrimido[4,5-d]pyrimidines 15, 19, 23 and 27 were obtained by oxidation of 12,
      16, 20 and 24 followed by aminolytic cleavage of support.

PMID- 10420975
TI  - High throughput liquid chromatography-mass spectrometry assessment of the
      metabolic activity of commercially available hepatocytes from 96-well plates.
AB  - We have assessed the metabolic activity of freshly isolated and commercially
      preserved rat, monkey, and human primary hepatocytes in a 96 well plate format
      utilizing eight beta-adrenolytic drugs as model compounds. Sample introduction
      from 96 well plates, HPLC solvent delivery, mass spectrometric (MS) detection,
      and/or UV detection were fully integrated and operated unattended. After drugs
      were incubated with hepatocytes for three or six hr, LC-MS analyses were carried
      out to determine the amount of drug which was not metabolized. Two LC-MS methods
      were used which had a sample throughput of 4 samples/hr and 12 samples/hr. Under
      optimal conditions, this hepatic assay could screen 300 samples/week or 1200
      samples/month. Although freshly isolated hepatocytes were more active,
      commercially available rat, monkey, and human primary isolated hepatocytes
      metabolized drug substrates in similar relative rank orders. This drug-hepatocyte
      assay provides useful information for prioritizing pharmaceutical leads in
      relative rank orders or in a high/low manner according to their resistance toward
      liver metabolism.

PMID- 10420976
TI  - Selective enrichment and high-throughput screening of phage surface-displayed
      cDNA libraries from complex allergenic systems.
AB  - Phage surface display technology, first described in 1985, enables the
      construction of large combinatorial peptide and antibody libraries. The basic
      concept of linking the phenotype, expressed as gene product displayed on the
      phage surface, to its genetic information integrated into the phage genome,
      allows the survey of large libraries for the presence of specific clones using
      the discriminative power of affinity purification. The selection procedure
      involves the enrichment of phage by binding to an immobilized target molecule. As
      a consequence of the physical linkage between genotype and phenotype, sequencing
      the DNA of the integrated section of the phage genome can readily elucidate the
      amino acid sequence of a displayed gene product. Phage surface display technology
      has revolutionized our ability to select agonist and antagonist peptides,
      antibodies with desired specificities, and DNA-binding molecules. We have
      extended phage surface display to access cDNA libraries with this powerful
      screening technology based on affinity selection of desired clones. Here we
      discuss construction of cDNA libraries displayed on the phage surface, selective
      enrichment of clones and robotics-based high-throughput screening of enriched
      libraries.

PMID- 10420977
TI  - Combinatorial strategies for the discovery of novel protease specificities.
AB  - This article discusses proven and possible ways to generate novel cleavage
      specificities in serine proteases using combinatorial mutagenesis, compares the
      different ways of screening or selecting for desirable mutants, and examines the
      ways in which combinatorial substrate libraries can be used to gain a more
      comprehensive insight into protease cleavage preferences. The use of
      bacteriophage to display both combinatorial protease libraries and combinatorial
      substrate libraries will be discussed.

PMID- 10420978
TI  - Computational ligand design.
AB  - A variety of computational tools that are used to assist drug design are
      reviewed. Particular emphasis is given to the limitations and merits of different
      methodologies. Recently, a number of general methods have been proposed for
      clustering compounds in classes of drug-like and non-drug-like molecules. The
      usefulness of this classification for drug design is discussed. The estimation of
      (relative) binding affinities is from a theoretical point of view the most
      challenging part of ligand design. We review three methods for the estimation of
      binding energies. Firstly, quantitative structure-activity relationships (QSAR)
      are presented. These have gained significantly from recent developments of
      experimental techniques for combinatorial synthesis and high-throughput screening
      as well as the use of powerful computational procedures like genetic algorithms
      and neural networks for the derivation of models. Secondly, empirical energy
      functions are shown to lead to more general models than standard QSAR, since they
      are fitted to a variety of complexes. They have been used recently with
      considerable success. Thirdly, we briefly outline free energy calculations based
      on molecular dynamics simulations, the method with the most sound theoretical
      foundation. Recent developments are reestablishing the interest in this approach.
      In the last part of this review structure-based ligand design programs are
      described. These are closely related to docking, with the difference that in
      design, unlike in most docking procedures, ligands are built on a fragment-by
      fragment basis. Finally, a short description of our approach to computational
      combinatorial ligand design is given.

PMID- 10420979
TI  - Combinatorial libraries by portioning and mixing.
AB  - Combinatorial chemistry--due to its radically new synthetic methods--can be
      considered a forerunner of chemistry in the next century. One of the most
      important methods is the portioning-mixing (split-mix) synthesis which embodies
      the combinatorial principle. It is easily realized. Both manual and automatic
      devices have been described. Some features that contribute to its popularity
      include: it produces all possible structural combinations of the monomers, it has
      outstanding productivity, it leads to the formation of individual compounds in
      nearly equimolar quantities (affected by statistics and incomplete reactions),
      and it can be applied to all classes of organic compounds. Since an enormously
      large number of compounds can be produced in principle in a relatively short
      time, some practical considerations are discussed that can be useful in library
      design. Encoding organic libraries by peptide or nucleotide sequences or with
      binary tags are also described together with methods for tagging macroscopic
      support units with electronic chips, two dimensional bar codes or colored resin
      and capsule caps. Among the deconvolution strategies, the iteration method,
      positional scanning, omission libraries, the Selectide and the Pharmacopeia
      methods are mentioned. A collection of libraries prepared by portioning-mixing is
      also included in graphical format.

PMID- 10420980
TI  - Cellular proteinases trigger the infectivity of the influenza A and Sendai
      viruses.
AB  - It has been proposed that the pathogenicity of the influenza and Sendai virus is
      primarily determined by host cellular proteases that activate viral infectivity.
      We isolated trypsin-type serine proteases from rat lungs, candidates for the
      processing proteases of viral envelope glycoproteins, such as tryptase Clara
      localized in the Clara cells of the bronchial epithelium and mini-plasmin. These
      enzymes specifically cleave the precursor of fusion glycoprotein HA of influenza
      virus at Arg325, and the F0 of Sendai virus at Arg116 in the consensus cleavage
      motif, Gln(Glu)-X-Arg, resulting in the induction of infectivity of these
      viruses. Proteolytic activation of viruses by these enzymes occurs
      extracellularly, probably on the surface and/or in the lumen of the respiratory
      tract. On the other hand, we isolated two compounds from human bronchial lavage,
      which inhibit the activity of tryptase Clara. One was a mucus protease inhibitor
      and the other was a pulmonary surfactant. These compounds inhibited multiple
      cycles of virus replication in vitro and in vivo, but did not themselves affect
      the hemagglutination and the infectivity of the virus. Administration of these
      compounds in the airway may be useful for preventing and treating infection with
      influenza virus and Sendai virus.

PMID- 10420981
TI  - mRNA expression of netrin-1, an axon guidance protein in chick and rat embryos.
AB  - The guidance of axons to their targets in developing neurons is believed to be
      mediated by diffusible chemotropic factors secreted by target cells. In
      vertebrates, commissural axons pioneer a circumferential pathway to the floor
      plate at the ventral midline of the embryonic spinal cord. Floor plate cells
      secrete a diffusible factor called 'netrin', that promotes the outgrowth of axons
      in the embryonic chick brain. The cloning of cDNAs encoding netrin showed that it
      is homologous to UNC-6, a laminin-related protein which is required for the
      circumferential migration of cells and axons in Caenorhabditis elegans. The
      differential expression of the netrin-1 gene was examined by slot blot analysis
      in various chick embryonic tissues, especially in the embryonic brain at various
      developmental stages. The netrin-1 transcript was most strongly expressed in the
      brain at the early developmental stages of E3 to E7 that corresponds to the time
      of emergence and full generation of commissural axons in the chick brain. In
      order to study whether netrin-1 can act as a global cue to guide all
      circumferentially migrating axons in the CNS, the localization of netrin-1 mRNA
      expression in the rat embryos was examined by in situ hybridization. Netrin-1
      mRNA was detected in the neuroepithelial cells of the ventral midline along the
      entire rostrocaudal axis of the E18 rat embryo. These results suggest that netrin
      1 functions as a global guidance cue for ventrally directed circumferential
      migrations toward the midline at all axial levels where the floor plate is found.

PMID- 10420983
TI  - Analysis of cDNAs expressed during first cell division of petunia petal
      protoplast cultures using expressed sequence tags.
AB  - A large-scale sequence analysis of randomly selected cDNA clones was performed to
      isolate numerous genes in petunia petal protoplast cultures. We have partially
      sequenced 1158 randomly selected genes of the cDNA library constructed from 2-6 d
      cultured petal protoplasts. Three hundred and sixty-five different genes were
      identified, 25% of which showed significant similarity to existing sequences in
      the petunia, and an array of other organisms. In this report, 90 independent
      genes are analyzed in detail. A functional categorization of the database-matched
      expressed sequence tags (ESTs) showed that defense- or stress-related genes, as
      well as genes involved in the primary metabolic pathways and in the
      transcriptional or translational apparatus are abundantly represented. In
      particular, ESTs were identified with apparent homologies to the cyclin-dependent
      kinase, histone, actin-depolymerizing factor, proteasome, and ubiquitin which are
      expected to be related to cell division or to cell cycle control.

PMID- 10420982
TI  - ermSF, a ribosomal RNA adenine N6-methyltransferase gene from Streptomyces
      fradiae, confers MLS (macrolide-lincosamide-streptogramin B) resistance to E.
      coli when it is expressed.
AB  - The Erm family of methyltransferases confers the MLS antibiotic resistance to
      pathogenic microorganism through the mono- or dimethylation of a single adenine
      residue in 23S rRNA, which is known as the target site for modification. One of
      the erm genes, ermSF was cloned from Streptomyces fradiae NRRL 2702 by PCR and
      overexpressed in E. coli BL21(DE3) as both a soluble protein and insoluble
      aggregate (inclusion body) using the T7 promoter driven expression vector,
      pET23b. Even though most of the overexpressed protein existed as an inclusion
      body, E. coli cells showed resistance to erythromycin. The lowering of incubation
      temperature from 37 degrees C to 22 degrees C facilitated the purification of the
      protein by increasing the fraction of soluble protein. The soluble protein was
      purified using immobilized metal ion (Ni2+) affinity chromatography in a one-step
      manner to the apparent homogeneity. The 23S rRNA of E. coli was found to be a
      good substrate for the purified ErmSF.

PMID- 10420984
TI  - Selection of RAPD marker for growth of seedlings at low temperature in rice.
AB  - We have developed a polymerase chain reaction (PCR)-based assay that could
      effectively reduce the time period required to screen and select the cold
      tolerance gene of rice seedlings under field conditions. The two specific random
      amplified polymorphic DNA (RAPD) fragments for the assay were identified on the
      basis of quantitative trait loci (QTL) analysis which were found to be tightly
      linked to cold sensitivity. The two RAPD fragments, OPT8(600) in the cold
      sensitivity rice cultivar 'Dular (indica)' and OPU20(1200) in the resistance rice
      cultivar 'Toyohatamochi (japonica)', were identified after screening 11 RAPD
      fragments using 2 random primers on the genomic DNAs of 'Dular' and
      'Toyohatamochi'. These primers, when used in a multiplexed PCR, specifically
      amplified a 0.6 kb and a 1.2 kb fragment in the sensitive and resistant rice
      cultivars, respectively. When this assay was performed on the genomic DNAs of 16
      japonica, 3 Tongil (indica/ japonica), and 2 indica rice cultivars, the primers
      amplified a 0.6 kb fragment in all of the cold sensitivity rice cultivars or 1.2
      kb fragment in all of the resistance ones. These markers can be of potential use
      in the marker-assisted selection (MAS) for cold tolerance in rice seedling. As
      screening for resistance can now be conducted independent of the availability of
      low temperature, the breeding of cold tolerance cultivars can be hastened.

PMID- 10420986
TI  - Activation of the thymidine kinase promoter by herpes simplex virus type 1
      immediate early proteins.
AB  - The herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) gene promoter
      contains binding sites for the cellular transcription factors such as Spl, CTF,
      and TFIID, each of which affects basal level expression of the TK gene. The
      transcription of the TK gene was induced by viral immediate early proteins, ICP0
      and ICP4 in an additive manner, but was repressed by ICP22 and ICP27. To gain
      further insights into the role of ICP0 and ICP4 for expression of the TK gene
      during virus infection, several mutants with deletions or point mutations in each
      of the transcriptional regulatory elements were generated starting at -109 and
      progressing toward +1. According to the CAT assay involving these mutants, the
      cellular transcription factor (CTF) binding site was necessary for efficient
      expression in the presence of transfected ICP0 and ICP4 or during virus
      infection, whereas the Sp1 binding site had a minor effect on ICP0-mediated TK
      expression. These results indicate that the immediate early proteins of HSV-1
      regulate expression of the TK gene during virus infection by modulating
      activities of cellular transcription factors such as CTF.

PMID- 10420985
TI  - cDNA cloning of the CEPUS, a secreted type of neural glycoprotein belonging to
      the immunoglobulin-like opioid binding cell adhesion molecule (OBCAM) subfamily.
AB  - GP55 is a family of glycoproteins distributed predominantly in the nervous
      system, and its previously characterized members, including the GP55A (EMBL
      Y08170) and E19S (EMBL Y08171) reveal a typical glycosyl phosphatidyl inositol
      (GPI)-anchored pattern for membrane proteins. CEPUS identified in this study
      appeared to represent the third member of GP55. This 3.2 kb long complete cDNA
      clone from the chicken brain exhibited 3 Ig-like domains. The open reading frame
      of CEPUS contains 313 amino acids, which can encode a 31.7 kDa core protein (pI
      5.75) for the mature form. The signal peptide cleavage site was predicted at
      Gln25. The structural features of the CEPUS cDNA sequence represented a soluble
      counterpart to the recently identified cerebellar Purkinje cell specific antigen,
      CEPU-1. The sequence difference between CEPU-1 and CEPUS was only found in the C
      terminus in which the CEPUS lacked the GPI-anchored binding site. It displays
      significant sequence homology to GP55-related molecules, including OBCAM, GP55A,
      E19S/LAMP, neurotrimin, and CEPU-1, which are all membrane attached types. The
      absence of the hydrophobic tail sequence in CEPUS may, therefore, suggest that
      CEPUS would represent the first identified secreted member in this group of
      genes. We defined that this molecule forms the opioid-binding cell adhesion
      molecule (OBCAM) subfamily in the molecular phylogeny. Structurally, these
      molecules represent acidic proteins (pI 5.47-6.09). Six cysteins, as well as 5
      Asn-linked potential glycosylation sites were evolutionary-conserved, suggesting
      that this OBCAM subfamily resembles immunoglobulin-like and highly glycosylated
      molecules. The presence of CEPUS would probably suggest to us that the
      spatial/local expression of the CEPU gene may provide a favorable route for
      migrating CEPU-positive population of neurons to generate a neuron-specific
      guidance in developing neurons in vivo.

PMID- 10420988
TI  - Downregulation of telomerase in rat during the aging process.
AB  - Telomerase is an RNA-dependent DNA polymerase that maintains the tandem arrays of
      telomeric repeats at the eukaryotic chromosome ends. Because of its ability to
      replenish lost telomeric sequences, telomerase is thought to be required for cell
      proliferation. At present, very little information on the role of telomerase in
      aging is available. In the present study, we tested the telomerase activity of
      Fischer 344 rat testis and liver at 6, 12, 18 and 24 months of age. As the testis
      is an androgen-dependent tissue, we also investigated the changes of testosterone
      and mRNA levels of androgen receptor in this tissue. Our results show that the
      telomerase activity of Fischer 344 rat testis significantly reduced at 24 months
      of age compared to 6 months of age, and that the mRNA level of telomerase protein
      component 1 (TLP-1) show a corresponding decrease with the telomerase activity.
      Interestingly, this down-regulation was not observed in the liver. The
      testosterone level in testis increased until 18 months of age, but reduced by 50%
      at 24 months of age. Our conclusions are that the telomerase activity is age
      dependent and its change is a tissue-specific phenomenon.

PMID- 10420987
TI  - The cytoplasmic domain of HIV-1 gp41 interacts with the carboxyl-terminal region
      of alpha-catenin.
AB  - To know the cellular protein interactions with the viral protein can give an
      insight into the molecular mechanisms of the virus life cycle. As the function of
      the cytoplasmic domain of human immunodeficiency virus type 1 (HIV-1) gp41 is not
      known clearly, we searched for a cellular protein that interacts with the
      cytoplasmic domain of the HIV-1 gp41 using the yeast two-hybrid assay system.
      Screening of HeLa cell cDNA library yielded alpha-catenin cDNA. The cytoplasmic
      domain of the HIV-1 gp41 and the simian immunodeficiency virus (SIV) gp41 were
      able to interact with the carboxyl-terminal region of alpha-catenin specifically.
      Mapping of the interaction sites revealed that the interaction between the domain
      containing the second helix structure from the carboxyl-terminus of HIV-1 gp41
      and the carboxyl-terminal region of alpha-catenin was stronger than other domains
      of gp41.

PMID- 10420989
TI  - Lysophosphatidic acid increases intracellular H2O2 by phospholipase D and RhoA in
      rat-2 fibroblasts.
AB  - We have investigated the possible roles of phospholipase D (PLD) and RhoA in the
      production of intracellular H2O2 and actin polymerization in response to
      lysophosphatidic acid (LPA) in Rat-2 fibroblasts. LPA increased intracellular
      H2O2, with a maximal increase at 30 min, which was blocked by the catalase from
      Aspergillus niger. The LPA-stimulated production of H2O2 was inhibited by 1
      butanol or PKC-downregulation, but not by 2-butanol. Purified phosphatidic acid
      (PA) also increased intracellular H2O2 and the increase was inhibited by the
      catalase. The role of RhoA was studied by the scrape-loading of C3 transferase
      into the cells. The C3 toxin, which inhibited stress fiber formation stimulated
      by LPA, blocked the H2O2 production in response to LPA or PA, but had no
      inhibitory effect on the activation of PLD by LPA. Exogenous H2O2 increased F
      actin content by stress fiber formation. In addition, catalase inhibited actin
      polymerization activated by LPA, PA, or H2O2, indicated the role of H2O2 in actin
      polymerization. These results suggest that LPA increased intracellular H2O2 by
      the activation of PLD and RhoA, and that intracellular H2O2 was required for the
      LPA-stimulated stress fiber formation.

PMID- 10420990
TI  - Analysis of Corynebacterium glutamicum methionine biosynthetic pathway: isolation
      and analysis of metB encoding cystathionine gamma-synthase.
AB  - The metB gene encoding cystathionine y-synthase, the second enzyme of methionine
      biosynthetic pathway, was isolated from a pSL109-based Corynebacterium glutamicum
      gene library via complementation of an Escherichia coli metB mutant. A DNA
      sequence analysis of the cloned DNA identified an open-reading frame of 1161 bp
      which encodes a protein with the molecular weight of 41,655 comprising of 386
      amino acids. The putative protein product showed good amino acid-sequence
      homology to its counterpart in other organisms. Introduction of a plasmid
      carrying the cloned metB into the C. glutamicum resulted in a 10-fold increase in
      cystathionine gamma-synthase activities, demonstrating the identity of the cloned
      gene. The C. glutamicum metB mutant which was generated by the site-specific
      integration of the cloned DNA into its chromosome did not lose the ability to
      grow on glucose minimal medium lacking supplemental methionine. The growth rate
      of the mutant strain was also comparable to that of the parental strain. These
      data indicate that, in addition to the transsulfuration pathway, other methionine
      biosynthetic pathways may be present in C. glutamicum.

PMID- 10420991
TI  - Localisation of DNA topoisomerase IIalpha in mouse erythroleukemia cells.
AB  - The presence of DNA topoisomerase IIalpha was investigated in interphase and
      metaphase mouse erythroleukemia (MEL) Friend-S cells, and in extracted with 25 mM
      lithium diiodosalicylate buffer (Lis) nuclei using indirect immunofluorescence.
      The results showed that DNA topoisomerase IIalpha is localised in the nuclei. In
      the metaphase cells, we found high concentrations of this enzyme in the mitotic
      chromosomes. Our results support the idea of the accumulation of DNA
      topoisomerase IIalpha at the end of the cell cycle. The extractions of nuclei
      with 25 mM Lis led to the complete depletion of DNA topoisomerase IIalpha from
      the residual nuclear matrix. Using a high dilution of the first antibody, we
      established that the high level of heterochromatin compactisation in the
      interphase nuclei is caused by the high concentration of DNA topoisomerase
      IIalpha.

PMID- 10420992
TI  - Drug concentration-dependent expression of multidrug resistance-associated
      protein and P-glycoprotein in the doxorubicin-resistant acute myelogenous
      leukemia sublines.
AB  - The multidrug resistance of cancer cells can be mediated by an overexpression of
      the human MDR1 and MRP genes, which encode the transmembrane efflux pumps, the
      170 kDa P-glycoprotein (Pgp) and the 190 kDa multidrug resistance-associated
      protein (MRP), respectively. In this study, we investigate which protein is
      preferentially overexpressed in the function of doxorubicin concentrations in the
      acute myelogenous leukemia cell line (OCI/AML-2). Multidrug-resistant AML-2
      sublines were isolated in doxorubicin concentrations of 20, 100, 250, and 500
      ng/ml. MRP was at first expressed at low concentrations of less than 5 x IC50
      (100 ng/ml) of doxorubicin followed by the overexpression of Pgp with
      concentrations of more than 12.5 x IC50 (250 ng/ml) of doxorubicin. In addition,
      it appeared that increased amounts of MRP and its mRNA in AML-2/DX20 and /DX100
      decreased gradually in both AML-2/DX250 and /DX500 overexpressing Pgp. In
      conclusion, it is thought that the overexpression of MRP or Pgp is dependent upon
      drug concentrations. It could be implicated that the overexpression of MRP might
      be negatively related to that of Pgp.

PMID- 10420993
TI  - Molecular cloning of a catalase cDNA from Nicotiana glutinosa L. and its
      repression by tobacco mosaic virus infection.
AB  - Recent reports revealed that catalase has a role in the plant defense mechanism
      against a broad range of pathogens through being inhibited by salicylic acid
      (SA). During an effort to clone disease resistance-responsive genes, a cDNA
      encoding catalase (Ngcat1; Nicotiana glutinosa cat1) was isolated from a tobacco
      cDNA library. In N. glutinosa, catalase is encoded by a small gene family. The
      deduced amino acid sequence of the Ngcat1 cDNA has 98% homology with the cat1
      gene of N. plumbaginifolia. The Ngcat1 expression is controlled by the circadian
      clock, and its mRNA level is the most abundant in leaves. Both the expression of
      Ngcat1 mRNA and its enzyme activity in the tobacco plant undergoing a
      hypersensitive response (HR) to TMV infection were repressed. The repression of
      the mRNA level was also observed following treatment with SA. These results imply
      that SA may act as an inhibitor of catalase transcription during the HR of
      tobacco. Cloning and expression of the Ngcat1 in tobacco following pathogen
      infection and SA treatment are presented.

PMID- 10420994
TI  - Calcium influx factor (CIF) as a diffusible messenger for the activation of
      capacitative calcium entry in Xenopus oocytes.
AB  - Acid extracts of thapsigargin-treated Xenopus oocytes revealed Ca2(+)-dependent
      Cl- currents by microinjection into Xenopus oocytes. These currents were detected
      in highly purified fractions by carrying out a sequence of purification steps
      including gel filtration chromatography and high performance thin layer
      chromatography. The nature of the membrane currents evoked by the highly purified
      fractions were carried by chloride ions as blockade by the selective chloride
      channel blocker 1 mM niflumic acid. Injection of the Ca2+ chelator 1,2-bis(2
      aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) eradicated the current
      activities, indicating that the current responses are completely Ca2(+)
      dependent. Moreover, the currents were sensitive to the removal of extracellular
      calcium, indicating the dependence on calcium entry through plasma membrane
      calcium entry channels. These results elucidate that the highly purified
      fractions aquired by thapsigargin-stimulated oocytes is an authentic calcium
      influx factor (CIF). Thus, the detection of increased CIF production from
      thapsigargin treatment in Xenopus oocytes would give strong support for the
      existence of CIF as a diffusible messenger for the activation of capacitative
      calcium entry pathways in Xenopus oocytes.

PMID- 10420996
TI  - Nucleotide sequence analysis of the 3'-terminal region of two Korean isolates of
      lily symptomless Carlavirus and expression of the coat protein in E. coli.
AB  - The 3'-terminal regions of the genomic RNAs of two Korean isolates of the lily
      symptomless Carlavirus (LSV), LSV-Ko and LSV-KII, were cloned and their
      nucleotide sequences were determined. The nucleotide sequence analysis and
      protein analysis by the Western blot revealed that E. coli expressed a 32-kDa
      protein that is the viral coat protein (CP) for the LSV. The two Korean strains
      share 98.4% and 98.3% sequence identities at the nucleotide and amino acid
      levels, respectively. The CP gene of LSV-Ko showed 99.1% and 87.0% nucleotide
      sequence identities, and 99.0% and 96.6% amino acid sequence identities with
      those of the Netherlands and the Japanese LSV strains, respectively. A pairwise
      amino acid sequence comparison revealed a sequence similarity of 29.6% to 69.8%
      between LSV-Ko and other species of the carlavirus. The 16 kDa protein of LSV-Ko
      shares 17.6% to 42.7% amino acid similarity with those of 8 other the
      carlaviruses, and they are variable in the N-terminal region. The Cys repeated
      zinc finger nucleic acid binding domain was found in the 16 kDa protein for all
      of the LSV strains. Sequence comparisons of the 7 kDa protein of LSV in the
      strain level showed significant identities from 100.0% to 98.4%. LSV-Ko shares
      21.9% to 42.2% amino acid similarity with those of 8 other carlaviruses, 4
      members of the potexviruses, and a closterovirus. LSV is closely related to
      blueberry scorch virus (BISV) based upon the phylogenetic tree analyses of the
      three proteins, indicating LSV to be a quite distinct member of the genus
      Carlavirus.

PMID- 10420995
TI  - Cloning of the argF gene encoding the ornithine carbamoyltransferase from
      Corynebacterium glutamicum.
AB  - The argF gene encoding ornithine carbamoyl-transferase (OTCase; EC2.1.3.3) has
      been cloned from Corynebacterium glutamicum by transforming the Escherichia coli
      arginine auxotroph with the genomic DNA library. The cloned DNA also complements
      the E. coli argG mutant, suggesting a clustered organization of the genes in the
      genome. We have determined the DNA sequence of the minimal fragment complementing
      the E. coli argF mutant. The coding region of the cloned gene is 957 nucleotides
      long with a deduced molecular mass of about 35 kDa polypeptide. The enzyme
      activity and size of the expressed protein in the E. coli auxotroph carrying the
      argF gene revealed that the cloned gene indeed codes for OTCase. Analysis of the
      amino acid sequence of the predicted protein revealed a strong similarity to the
      corresponding protein of other bacteria.

PMID- 10420997
TI  - Wisconsin Card Sorting Test performance following head injury: dorsolateral
      fronto-striatal circuit activity predicts perseveration.
AB  - The Wisconsin Card Sorting Test (WCST) has been argued to be a sensitive
      indicator of frontal lobe function. However, several recent studies have failed
      to find a consistent relationship between structural damage to this cortical area
      and perseveration on the test. In the present study, positron emission tomography
      (PET) imaging with 18F-fluorodeoxyglucose was used to examine the relationship of
      regional brain metabolism to perseverative responding on the WCST in patients
      with a history of closed-head injury. An inverse relationship was found between
      perseverative responses and metabolism in the right, but not the left,
      dorsolateral prefrontal cortex and caudate nucleus. Perseverative responding was
      not related to metabolism in several other regions of the frontal lobes and basal
      ganglia, including the putamen and the frontal poles bilaterally. These data
      suggest that the functional integrity of the right dorsolateral frontal
      subcortical circuit is critical for WCST performance.

PMID- 10420998
TI  - Is there a sex difference in human laterality? III. An exhaustive survey of
      tactile laterality studies from six neuropsychology journals.
AB  - The contents of six neuropsychology journals (161 volumes, 612 issues) were
      screened to identify tactile laterality experiments. Of 73 experiments
      identified, 40% provided information about sex differences. Seventeen experiments
      yielded a total of 18 sex differences, of which 4 could be interpreted in terms
      of the hypothesis that functional cerebral lateralization is more pronounced in
      males. All 4 interpretable outcomes (constituting 5.5% of the population of
      experiments and 13.8% of the informative experiments) were found to be consistent
      with the differential lateralization hypothesis. The results, in isolation, do
      not justify rejecting the null hypothesis. However, when considered in
      conjunction with findings for auditory and visual laterality studies, the present
      results are compatible with a weak population-level sex difference.

PMID- 10420999
TI  - Screening for dementia: comparison of three commonly used instruments.
AB  - The sensitivity and specificity of three cognitive screening measures - the Mini
      Mental State Exam (MMSE), Mattis Dementia Rating Scale (MDRS), and
      Neurobehavioral Cognitive Status Examination (NCSE) - were compared in a cohort
      of subjects with dementia as well as normal elderly individuals. Twenty-two
      patients met criteria for probable Alzheimer' s disease (AD), 19 for vascular
      dementia (VaD), and 12 were normal control subjects. The use of standard
      cutpoints resulted in poor to good classification accuracy for the three
      measures, but measurable improvement in sensitivity was obtained by adjusting the
      cutpoints for each measure. Discriminatory power was maximized with an MMSE
      cutpoint of < or = 26, an MDRS cutpoint of < or = 134, and requiring one or more
      NCSE subtests to be in the impaired range. Use of age and education adjusted
      norms resulted in good to excellent classification accuracy for the MMSE and
      MDRS. The NCSE subtest score pattern failed to differentiate between AD and VaD.

PMID- 10421000
TI  - Image vividness as a psychophysiological regulator in Posttraumatic Stress
      Disorder.
AB  - This study examined the relationship between image vividness and
      psychophysiological responses to trauma-related stimuli in participants with
      Posttraumatic Stress Disorder (PTSD). An auditory stimulus related to a shared
      trauma was presented to participants with and without PTSD and physiological
      parameters (heart rate and blood pressure) were measured concurrently. A negative
      correlation was noted in the PTSD group between image vividness and the level of
      physiological response. When the PTSD group was divided into high and low
      vividness, the physiological response was higher than that of the non-PTSD
      controls only when image vividness was low. The results are discussed in the
      context of Lang' s theoretical model, emphasizing the role of image vividness in
      the mediation and regulation of psychophysiology.

PMID- 10421001
TI  - Performance of individuals with severe long-term traumatic brain injury on time-,
      event-, and activity-based prospective memory tasks.
AB  - This study investigated the effect of traumatic brain injury (TBI) on time-,
      event-, and activity-based prospective memory using a laboratory paradigm
      developed in the literature on ageing (Einstein, McDaniel, Richardson, Guynn, &
      Cunfer, 1995). The participants were 12 individuals with severe long-term TBI and
      12 community controls. Participants were asked to answer general-knowledge
      questions on a computer for two sessions. The time- and event-based tasks were
      embedded in this filler activity. Participants were also required to carry out
      activity-based actions at the end of the two sessions. Participants with TBI
      performed significantly worse than did controls on all three prospective-memory
      tasks, indicating that TBI affects not only retrospective but also prospective
      memory. Implications of these results for the assessment and rehabilitation of
      memory problems in individuals with TBI are discussed.

PMID- 10421003
TI  - Concussion in contact sports: reliable change indices of impairment and recovery.
AB  - This paper reports a follow-up study to an article on the sensitivity of three
      tests of speed of information processing to impairment after concussion (Hinton
      Bayre, Geffen, & McFarland, 1997). Group analyses showed that practice effects
      can obscure the effects of concussion on information processing, thereby making
      the assessment of functional impairment and recovery after injury unreliable. A
      Reliable Change Index (RCI) was used to assess individual variations following
      concussion. It was found that 16 of the 20 concussed professional rugby league
      players were impaired 1-3 days following injury. It was also demonstrated that 7
      players still displayed cognitive deficits at 1-2 weeks, before returning to
      preseason levels at 3-5 weeks. The RCI permits comparisons between different
      tests, players, and repeated assessments, thereby providing a quantitative basis
      for decisions regarding return to play.

PMID- 10421004
TI  - Confirmatory factor analysis of the Wechsler Memory Scale-III.
AB  - The latent structure of the Wechsler Memory Scale-III was analyzed by
      confirmatory factor analysis using the covariance matrix based on the 11 primary
      subtests from the standardization sample. Omnibus fit indexes and individual
      parameter estimates were examined. Of the five models evaluated, a three-factor
      model (working memory, auditory memory, and visual memory) provided the best fit
      for the standardization sample (NNFI = .98, RMSEA = .05, GFI = .98, BIC =
      429.42). Models that proposed separate immediate and delayed memory constructs
      were hampered by inadmissible parameter estimates that signaled model
      specification errors. R2 values for the Faces subtests were uniformly low for all
      five models that suggested that this subtest has insufficient commonality with
      the visual memory construct.

PMID- 10421002
TI  - Detecting the faking of amnesia: a comparison of the effectiveness of three
      different techniques for distinguishing simulators from patients with amnesia.
AB  - This paper compared the effectiveness of three different procedures that have
      been put forward as possible ways of distinguishing patients with genuine memory
      problems from those who are attempting to simulate amnesia. The performance of 20
      patients with amnesia was compared with the performance of 20 normal control
      individuals and 20 normal individuals who had been asked to simulate amnesia on
      the distraction/no distraction test (Baker, Hanley, Kimmance, & Slade, 1993), the
      coin-in-the-hand test (Kapur, 1994) and word fragment completion (Horton, Smith,
      Barghout, & Connolly, 1992). The distraction/no distraction test and the coin-in
      the-hand test both proved successful in distinguishing patients with amnesia from
      simulators (p < .01). Excellent performance by virtually all patients with
      amnesia coupled with chance or below chance performance by 19/20 simulators on
      the coin-in-the-hand test was particularly striking. Consistent with the results
      of Horton et al. ( 1992), the word fragment completion test successfully
      discriminated between the performance of simulators and controls (p < .01).
      However, the fragment completion test proved incapable of distinguishing between
      the performance of patients with amnesia and simulators (p > .05). It is argued
      that there may be problems inherent in the use of tests designed to investigate
      implicit memory in attempts to detect malingering.

PMID- 10421005
TI  - Visual search and visual target detection in patients with infarctions of the
      left or right posterior or the right middle brain artery.
AB  - We compared visual target detection and search performance of patient groups with
      infarctions of (1) the right middle brain artery (R-MBA) and with neglect; (2)
      the left posterior artery (L-PBA), (3) the right posterior artery (R-PBA), the
      latter two groups had contralesional hemianopias, or (4) with right hemisphere
      lesions without hemianopia or neglect. We found that: (1) The first three groups
      differed from the fourth (control) group in omissions. (2) The first three groups
      differed only in horizontal search but not in target detection. (3) No vertical
      search deficit was present for either group. (4) R-MBA patients found
      increasingly more targets in visual search from left to right, R-PBA patients had
      problems with the outermost contralesional column, L-PBA patients showed a
      generally slowed and more variable search pattern. Infarctions of left and R-PBA
      therefore resulted in different visual search patterns. The behavior of the
      patients with R-MBA is consistent with Kinsbourne's (1992) interactive inhibition
      theory of neglect.

PMID- 10421006
TI  - Neuropsychological performance and cognitive olfactory event-related brain
      potentials in young and elderly adults.
AB  - The P3 event-related brain potential (ERP) reflects neuroelectric activity
      related to the speed of cognitive processing and allocation of attentional
      resources. The objective of the present study was to assess the relationship
      between the P3 and Slow Wave components of the olfactory event-related potential
      (OERP) with neuropsychological performance in young (n = 16) and elderly (n = 16)
      adults. OERPs were recorded monopolarly from midline electrode sites while
      subjects estimated the odor magnitude of each stimulus, eliciting highly
      reproducible P3s. Results showed that the late cognitive components (P3
      amplitude, P3 latency and Slow Wave area) decline with age and that this
      decreased neuronal efficiency is associated with reductions in the
      neuropsychological performance indexed by the Trail Making Test and the
      California Verbal Learning Test.

PMID- 10421007
TI  - Normative data on the Korean version of the Boston Naming Test.
AB  - The purpose of this study is to introduce the Korean version of the Boston Naming
      Test (K-BNT) and to present the normative data. The K-BNT contains the same
      number of test items and uses the identical general administration method as the
      original Boston Naming Test (BNT). However, most of the items had to be altered
      due to the linguistic and cultural differences between Korean and English
      speakers. We administered 60 line-drawing pictures to six hundred normal
      participants in eight age groups (15-19, 20-24, 25-34, 35-44, 45-54, 55-64, 65
      74, and 75 years and older), five educational levels (0, 1-6, 7-9, 10-12, and 13
      years and more), and gender. Since the K-BNT scores were not affected by gender
      and found not to be significantly different among some age groups, we finalized
      each cell based on four age groups (15-44, 45-54, 55-74, and 75 years and older)
      and five education levels (0, 1-6, 7-9, 10-12, and 13 years and more). The
      highest score was achieved by the 15-44 age group with 13 and more years of
      education (M = 53.93, SD = 3.06), and the lowest by those of 75 years and older
      with no education (M = 27.42, SD = 8.22).

PMID- 10421008
TI  - Towards an analytic framework for the visuospatial domain: spatial reference
      frames, cognitive operations, and neural systems.
AB  - This article addresses the confusion in neuropsychological literature on
      visuospatial function and then proposes an analytic framework towards resolution
      in the visuospatial domain. Three bodies of literature on visuospatial processing
      are summarized, and from each is derived an analytic dimension for visuospatial
      investigation. They are: (1) the frame of space (e.g., egocentric), (2) the
      definition of spatial operations in cognitive terms, and (3) spatial processing
      in terms of neural hierarchy and respective neural centers. It is proposed that
      these dimensions can constitute a working model to clarify the complexity of
      visuospatial function.

PMID- 10421009
TI  - Colonic esophagopharyngoplasty in combined chemical esophageal and pharyngeal
      strictures.
AB  - The treatment of patients with combined chemical strictures located in the upper
      gastrointestinal tract presents a difficult task. A complicated mechanism of
      swallowing-breathing can be broken by the development of a cicatricial process in
      the pharynx or laryngo-oropharynx. The surgical interference is aimed not only at
      construction of an artificial esophagus but restoration of the normal swallowing
      and adequate feeding of a patient. The article presents the experience of 47
      colonic esophagopharyngoplasties. Preference is given to one-stage procedures.
      The graft in the majority of cases was constructed from the left colon. The
      mortality rate was 2.1%, and pharyngeal anastomotic leak occurred in 5 (10.6%)
      patients. Pharyngeal anastomotic cicatricial stricture developed in 4 (8.5%)
      patients and 2 of them required of reconstructive surgery. Long-term results have
      shown that the majority of patients are using the artificial esophagus. Only in 2
      patients is swallowing still impaired and they continue to feed via a
      gastrostomy. The results obtained show that a one-stage colonic
      esophagopharyngoplasty is the method of choice in combined chemical
      pharyngoesophageal strictures. Nevertheless, such procedures should only be
      carried out in specialized divisions with experience in reconstructive esophageal
      surgery.

PMID- 10421011
TI  - Lymph node metastasis with adenocarcinoma of the gastric cardia:
      clinicopathological analysis and indication for D1 dissection.
AB  - PURPOSE: To establish the indications for proximal resection with dissection of
      perigastric lymph nodes in order to treat adenocarcinoma of the gastric cardia.
      METHODS: We analyzed the clinicopathological features of 110 resected
      adenocarcinomas of the gastric cardia with respect to the appropriate operative
      method and extent of lymphadenectomy for treatment. RESULTS: Of the 110 patients,
      93 underwent curative resection. The D2 group (total gastrectomy with dissection
      of extended regional lymph nodes) revealed higher morbidity and mortality rates
      compared to the D1 group (proximal resection with dissection of perigastric lymph
      nodes). The risk of lymph node metastasis was determined by depth of invasion,
      size of tumors, and gross findings of tumors. CONCLUSION: The appropriate
      operative method for adenocarcinoma of the gastric cardia requires: (i) tumor
      size less than 4 cm; and (ii) gross findings indicating a superficial type of
      lesion, which are recommended for proximal resection with dissection of
      perigastric lymph nodes.

PMID- 10421010
TI  - Gastric cancer with invasion limited to the muscularis propria.
AB  - The clinicopathological features of 84 muscularis propria (mp) gastric cancers,
      defined as gastric cancer invading the muscularis propria of the stomach, were
      reviewed retrospectively, and compared with 267 early gastric cancers (m/sm
      cancer) and 333 gastric cancers invading beyond the subserosal layer (ss-si
      cancer). There were statistical differences in tumor size, histological growth
      pattern, cancer-stromal relationship, lymph node metastasis, lymphatic invasion,
      vascular permeation and operative procedure between mp gastric cancer and early
      gastric cancer or ss-si gastric cancer. The mp tumors were significantly larger
      than the early cancer tumors but significantly smaller than the ss-si tumors (P <
      0.0001), and mp cancer had more frequent lymph node metastasis (50%) than did
      early gastric cancer (10%) but less frequent lymph node metastasis than did ss-si
      cancer (84%; P < 0.0001). Histologically, infiltrative and scirrhous types were
      more common in the mp cancer group than in the early cancer group. The frequency
      of vascular permeation in the mp cancer group was almost the same as that in the
      early cancer group. Univariate analysis revealed that the significant prognostic
      factors were nodal involvement (P = 0.0213) and lymphatic invasion (P = 0.0364).
      Multivariate analysis of the mp-invaded cancer cases, however, revealed that
      lymph node metastasis was not a significant prognostic factor, although it was
      more important than was lymphatic invasion. Multivariate analysis also revealed
      that the prognosis of our mp gastric cancer patients was affected most by
      vascular permeation, followed by tumor size.

PMID- 10421012
TI  - Surgical results of pancreaticoduodenectomy for carcinoma of the distal third of
      the stomach.
AB  - Pancreaticoduodenectomy (PD) was performed as a radical operation on 10 patients
      who had stage III or IV carcinoma of the distal third of the stomach which
      invaded the pancreas head (T4) or had level 3 lymph node metastasis. The surgical
      results of the PD were compared with those of 69 patients treated with subtotal
      gastrectomy (SG). Although the postoperative morbidity was higher (70%) in the PD
      group than in the SG group (32%), no hospital death occurred. The overall
      postoperative survival provided by PD was as good as that provided by SG for 43
      patients who had stage III or IV tumors (the 5-year survival rates, 40 versus
      45%). Regarding the T4 tumors invading the pancreas, the survival of the 9
      patients with PD was better than that of the 12 patients with SG (median survival
      time, 19 versus 9 months). Thus, PD might improve the postoperative survival of
      patients with carcinoma of the distal stomach invading the pancreas.

PMID- 10421013
TI  - Prevalence of gallstones in a Brazilian population.
AB  - The objective of the present study was to determine the prevalence of gallstones
      in the population of Curitiba, Brazil. A total of 1000 persons was randomly
      recruited among individuals who were visiting two shopping centers of the city in
      order to represent the Brazilian population in relation to age and sex. The
      selected people underwent ultrasonographic examination of the upper abdomen
      immediately after a medical interview. Of the 1000 persons evaluated, 93 (9.3%)
      had gallstones (64 persons) or had been subjected to cholecystectomy due to
      cholelithiasis. The gallstone prevalence increased from 2.4% in persons of 20-29
      years of age to 27.5% in persons of more than 70 years (chi2 = 37.29; P <0.001).
      The prevalence was 2.4 greater in females (12.9%) than in males (5.4%) (chi2 =
      16.34; P <0.001). The prevalence increased with the number of pregnancies from 4%
      in nulliparous women, to 34.6% in persons with a history of six or more
      pregnancies (chi2 = 200.1; P <0,001). The prevalence also increased according to
      the body weight (chi2 = 30.08; P <0.001). There was no difference in the
      prevalence between individuals with diabetes mellitus and controls. It is
      concluded from this study that the prevalence of gallstones in the city of
      Curitiba is elevated.

PMID- 10421014
TI  - Alternative surgical treatment for complex enterocutaneous fistula.
AB  - A retrospective analysis on the clinical-surgical handling of patients with
      enterocutaneous fistula (ECF) was performed, where an alternative surgical
      technique was discussed: intestinal bypass. Fistula with draining over 500 ml/24
      h, which were present in 13 patients, were classified as high debit. We defined
      as complex, the fistula with multiple orifices, high defect of the abdominal wall
      or through the mesh. The population studied consisted of 25 patients, 11 male, in
      a total of 34 ECF and mean age of 41.9 years. At clinical treatment with TPN for
      high debit ECF, 2 patients (16.6%) were cured, another 2 died and 8 (66.8%)
      needed surgical treatment. The surgery cured 7 patients (77.7%) with high debit
      ECF but 2 (22.3%) died. In the patients with low debit ECF, TPN cured 2 patients
      (40%) but failed in another 3 (60%). All patients with low debit ECF resolved
      with surgical treatment.

PMID- 10421015
TI  - The ideal treatment of the typhoid enteric perforation - resection anastomosis.
AB  - Eighty-one cases of typhoid enteric perforation were studied prospectively after
      separating them into four groups. Group A patients were treated with resection
      anastomosis, group B by debridement of margins of the perforation/wedge excision
      and simple closure, group C by simple closure and group D by ileostomy of
      perforated ileum or simple peritoneal drainage. A copious lavage of the
      peritoneal cavity with normal saline was performed in all four groups. The
      complication and mortality rates for group A patients were 37.50% and 21.47%,
      respectively, very much less than that observed in the other three groups. The
      ideal treatment for typhoid enteric perforation was found to be resection
      anastomosis with copious peritoneal lavage.

PMID- 10421016
TI  - Acute abdomen caused by inflammatory colonic non-parasitic pathology: staging by
      CT.
AB  - A staging classification is proposed by CT findings in 27 patients with acute
      abdomen, caused by inflammatory colonic non-parasitic pathology. Of the 17
      patients with diverticular disease, 4 were stage A (edema/ischemia on thickness
      of the abdominal wall), 2 were stage B (partial intramural infarction on the
      abdominal wall) and 3 were stage C (abscess/peritonitis and obstruction/vascular
      strangulation). None of the patients in the series were stage D
      (ischemia/infarction of the colonic wall with dilatation). Of the 4 patients with
      ulcerative colitis, 3 were stage A and 1 in stage C. Of the 3 patients with
      Crohn's disease, 2 were stage A and 1 was in stage C. Classified as stage D were
      1 pseudomembranous colitis, 1 volvulus and 1 idiopathic megacolon. Clinical
      severity was in parallel with CT stages that gave better information on the
      progression of the pathology. Staging by CT in acute abdomen caused by
      inflammatory colonic non-parasitic pathology could be useful in therapeutics.

PMID- 10421017
TI  - Seldom found acute abdomen: perforated diverticulum in the transverse colon.
AB  - The authors report a recently examined rare case of isolated perforated
      diverticulum of the transverse colon. At surgery, a perforated omentum-sealed
      diverticulum was found in the third distal wall of the transverse colon. A
      diverticulectomy was performed. The postoperative course was excellent.

PMID- 10421018
TI  - Mini-invasive surgery for sigmoid volvulus.
AB  - Sigmoid volvulus is a pathology which can be treated with beneficial effect using
      the fully laparoscopic or laparoscopic-assisted approach. We describe a technique
      which, although it does not qualify as a true laparoscopic operation, it also
      does not require advanced laparoscopic skills or prolonged operating time.

PMID- 10421019
TI  - Long-term follow-up of the Indiana pouch: efficacy of the pouch construction
      using the absorbable gastrointestinal staples.
AB  - The Indiana pouch procedure was used on 34 bladder cancer patients. The Heinecke
      Mikulicz reconfiguration was carried out, involving the conventional hand-sewn
      and the absorbable GIA stapled methods with the continence mechanism of a staple
      tapered efferent limb. The tunnelled tenial anti-refluxing implantation of
      ureters was performed. The stapled pouch construction saved approximately 1 h of
      operating time and reduced by 18% the overall loss of blood. There were 3
      complications (wound infection/dehiscence in two, leakage from the enteric
      anastomosis in one, and acute renal failure in one) within 30 days
      postoperatively. As a late complication, ureter implantation stricture was
      experienced in two and pouch stone formation in five. No significant difference
      in the incidence of stone formation was evident between the hand-sewn and the
      stapled pouches, nor was any difference of pouch volume and catheterization
      interval. All patients had acceptable continence. These data demonstrated that
      the Indiana pouch is a reliable procedure with an acceptable complication rate.
      The pouch construction using the stapled method, which simplified the procedure,
      is more convenient than the one using the hand-sewn technique.

PMID- 10421020
TI  - Mesh plug migration into scrotum: a new complication of hernia repair.
AB  - Hernia repair is one of the most frequent operative procedures performed
      throughout the world. The technique has continued to evolve and we now are
      performing these repairs utilizing mesh as a patch and also as a plug. The mesh
      plug concept has been advocated by Rutkow and others. With this change in
      technique, we have seen a new complication of hernia repair - the migration of
      the mesh plug from the original hernia repair site into the scrotum. It presented
      as a large tender mass in the scrotum of a 45-year-old male who had had previous
      recurrent surgery. In addition, he again had a recurrent incarcerated hernia.
      Correction of the hernia and resection of the migrated mesh plug from the scrotum
      were carried out. It is recommended that both the patch and the plug be into
      position to avoid or reduce the risk of such a recurrence and plug migration.

PMID- 10421021
TI  - Chemohyperthermic peritoneal perfusion for peritoneal dissemination in various
      intra-abdominal malignancies.
AB  - A total of 25 patients with severe peritoneal dissemination underwent
      chemohyperthermic peritoneal perfusion (CHPP). The primary tumors in these
      patients comprised colorectal cancer (n = 14), ovarian cancer (n = 6), cervical
      cancer, (n = 1), small bowel cancer (n = 1), pseudomyxoma retroperitonei (n = 1),
      cystoadenocarcinoma of liver (n = 1), and pancreas cancer (n = 1). The
      intraperitoneal perfusion was carried out with a magnet pump for 60 min. The
      heated perfusate contained anticancer drugs to act synergistically with the
      hyperthermia. The intraperitoneal temperature was maintained at 42.0-42.5 degrees
      C. Eight of 25 patients showed CR, four PR, ten NC, and three PD, and the
      percentage (CR+PR) representing the overall efficacy rate was 48.0%. The
      morbidity rate was 8% (2/25) and there was no treatment-associated mortality. The
      percentage (CR+PR) of the patients with colorectal cancer was 57%; ovarian
      cancer, 50%; and other malignancies, 20%. The 1 year-and 3 year-survival rates of
      all the patients were 55% and 26%, respectively. The median survival periods of
      the CR, PR, NC, and PD groups were 4.0, 1.0, 1.0, and 0.7 years, respectively.
      The survival curve of the CR group was the best of all the groups (P = 0.02).
      These results indicated that CHPP was a feasible therapy and exerted a direct
      anticancer effect on peritoneal dissemination especially in the case of ovarian
      cancer, and the prognosis of complete responders was improved.

PMID- 10421023
TI  - Vertebral arteriovenous fistula as a result of Swan-Ganz catheter insertion:
      surgical correction in a symptomatic patient.
AB  - A case of a vertebral arteriovenous fistula is reported after being caused by
      insertion of a Swan-Ganz catheter into the vertebral artery prior to cardiac
      surgery. The patient's clinical symptoms which precipitated re-admission
      consisted of multiple episodes of diaphoresis and dizziness. A right carotid
      bruit was detected in the neck. Four vessel cerebral arteriograms could not
      accurately identify the origin of the fistula. The proximal carotid artery was
      considered by several radiologists to be the arterial source of the fistula.
      During the surgical procedure, a tortuous right vertebral artery was found to be
      the source of the fistula. Surgical correction of the fistula was successful with
      preservation of the vertebral artery. Recommendations from a review of the
      literature are made for the current treatment of this rare complication from an
      insertion of a Swan-Ganz catheter.

PMID- 10421022
TI  - Radical surgery after neoadjuvant intra-arterial chemotherapy in stage IIIb
      squamous cell carcinoma of the cervix.
AB  - We examined the efficacy and safety of neoadjuvant intra-arterial chemotherapy
      (NAC) followed by radical hysterectomy and/or radiotherapy in patients with stage
      IIIb cervical cancer. Treatment consisted of bilateral internal iliac artery
      infusion of cisplatin or carboplatin and peplomycin every 21 days for two
      courses. Patients who responded to NAC underwent radical surgery. Patients who
      did not respond to NAC were treated with pelvic radiotherapy. Complete response
      was achieved in 2 (7.1%) of 28 patients, while a partial response was observed in
      17 (60.7%) and stable disease in 9 (32.1%) patients. Sixteen patients (57.2%)
      were able to undergo surgery. The median blood loss (674 ml) and operating time
      (232 min) for radical surgery in patients with stage IIIb disease was similar to
      that in patients with stages Ib to IIb disease. No intra-operative or immediate
      postoperative complications were observed. The 5-year disease-free survival (DFS)
      for patients who underwent surgery (81.3%) was higher than for patients who
      underwent radiotherapy after NAC (31.3%). Radical surgery after NAC for stage
      IIIb disease was safe, and a survival benefit followed by surgery with or without
      radiotherapy.

PMID- 10421024
TI  - Successful surgical treatment of the brachial plexus paresis in leiomyosarcoma of
      the subclavian artery.
AB  - Described here is a unique case of surgical treatment of brachial plexus paresis
      in a 63-year-old female patient. The paretic condition was considerably improved
      by excision of a tumor in the upper mediastinum, growing from the left subclavian
      artery, and classified as leiomyosarcoma.

PMID- 10421025
TI  - Surgical treatment of HIV-related immune thrombocytopenia.
AB  - Immune related thrombocytopenia has been described extensively in patients
      infected with the human immunodeficiency virus (HIV). The efficacy and safety of
      splenectomy performed in 21 patients affected with HIV-related immune
      thrombocytopenia (platelet count less than 50,000/mm3), between 1992 and 1996,
      were evaluated. All the patients were symptomatic and had failed medical therapy.
      Nine of them were affected with acquired immune deficiency syndrome (AIDS),
      whereas 12 were HIV-positive (non-AIDS). In all the patients, a pre-operative
      bone marrow biopsy revealed increased megakaryocytes. Follow-up ranged from 5-16
      months. The response rate to splenectomy (platelet count greater than
      100,000/mm3) in the AIDS group was 83%, as opposed to 100% in the HIV-positive
      (non-AIDS) group. During the follow-up period, 19 of the 21 patients maintained
      platelet counts greater than 98,000/mm3; of the two non-responders, one patient
      expired 3 weeks after surgery, and a second patient had never responded. None of
      the HIV-positive (non-AIDS) patients developed AIDS during the follow-up period.
      All the complications observed (24%) were treated without sequelae. Based on
      these data, splenectomy can be considered safe and effective in treating patients
      with symptomatic HIV-related thrombocytopenia, when medical therapy has failed.
      Moreover, splenectomy did not appear to adversely affect the rate of conversion
      from the HIV-positive to the AIDS status, nor did it accelerate the progression
      of the disease in patients already diagnosed with AIDS.

PMID- 10421026
TI  - Post-laparoscopic cholecystectomy bile leak secondary to an accessory duct of
      Luschka.
AB  - Intraperitoneal bile collection following laparoscopic cholecystectomy has been
      reported to occur in 0.2-2% of cases and appears to be slightly higher than when
      the open technique is used. When the injuries of the common bile duct, technical
      problems with the cystic duct, diathermic injuries to the biliary tree, and
      iatrogenic interruption of congenital anomalous of the biliary tree are excluded,
      the iatrogenic transaction of the cholecystohepatic ducts commonly known as the
      'Ducts of Luschka' should be considered as the cause of the biliary leak. This
      article reports a case of bile leakage due to an unrecognized division of a large
      duct of Luschka within the gall bladder fossa during laparoscopic cholecystectomy
      and reviews clinical diagnosis, radiological confirmation, and the appropriate
      treatment for this uncommon complication of laparoscopic cholecystectomy.

PMID- 10421027
TI  - Primary posterior chest wall echinococcosis.
AB  - Hydatid cyst is not mentioned among the chest wall tumours in areas not known to
      harbour echinococcosis. One of the uncommon sites for echinococcosis even in
      endemic countries is the chest wall. The striking resemblance between neoplasm
      and hydatid cysts forms a diagnostic dilemma and makes the correct diagnosis
      essential before surgery.

PMID- 10421029
TI  - Terbutaline increases open channel density of epithelial sodium channel (ENaC) in
      distal lung.
AB  - Neonatal and adult vertebrate respiration is facilitated by alveolar fluid and
      sodium (Na+) absorption driven by apical sodium channels (ENaC). ENaC are
      characterized in Xenopus laevis lung (XLL) epithelia using voltage clamping and
      fluctuation analysis to non-invasively examine macroscopic transepithelial
      current and resistance (I(SC), R(T)), single channel current (i(Na)) and total
      channel density (N(T)) responses to a beta adrenergic agonist (Terbutaline).
      Terbutaline addition to the basolateral bath of XLL increased Na entry to > 200%
      of control reflecting a doubling of open channel density (N(o). These data are
      consistent with the notion that XLL can serve as a useful model for investigation
      of distal lung ENaC response to agents of physiological interest.

PMID- 10421028
TI  - Thoracic epidural pain control for chest trauma patient.
AB  - Epidural pain control is used widely in different fields, such as after surgery,
      during labour, and for the patients with terminal cancer. It can also be used in
      patients with severe pain due to chest trauma to improve the pulmonary condition
      and shorten the period of hospitalization.

PMID- 10421030
TI  - Respiratory-related pharyngeal constrictor muscle activity in awake goats.
AB  - Respiratory-related electromyogram (EMG) activities of the middle (MPC) and
      inferior (IPC) pharyngeal constrictor (PC) muscles were determined simultaneously
      with up to six additional upper airway abductor and adductor muscles in awake
      adult goats. Phasic PC activation began in late inspiration and persisted
      throughout expiration with a steady, an augmenting or a biphasic pattern of
      activity. Considerable differences were noted in the EMG responses of the MPC and
      IPC muscles to respiratory-related stimuli. During hypoxia and hypercapnia,
      phasic MPC activity decreased or was not recruited whereas phasic IPC activity
      was augmented with increased chemical drive. During spontaneous augmented breaths
      and peripheral chemoreceptor stimulation with sodium cyanide, the pattern of
      activation of the MPC was similar to that of the thyroarytenoid muscle (TA), a
      laryngeal adductor whereas IPC activity was strikingly similar to activity of the
      laryngeal and pharyngeal dilators. The expiratory portion of an augmented breath
      was associated with increased phasic MPC and TA but not IPC activities. Dopamine
      induced apneas resulted in tonic activation of the MPC and TA at a level equal to
      or greater than control activity but no recruitment of IPC activity. The marked
      differences in MPC and IPC responses to respiratory-related stimuli suggests that
      these muscles may have different mechanical effects on pharyngeal airway caliber
      in the goat. The results suggest that the MPC may help brake expiratory flow thus
      helping to control expiratory timing and lung volume. In contrast, the IPC may
      promote pharyngeal airway patency by stiffening or dilating the pharyngeal
      airway. The results demonstrate that a variety of stimuli can influence
      respiratory-related PC activity and suggest that the PC muscles are important in
      the regulation of breathing and upper airway patency.

PMID- 10421031
TI  - Interaction between somatic and vagal afferent inputs in control of ventilation
      in 2-week-old rabbits.
AB  - Effects of saphenous nerve stimulation (SNS) on the Hering-Breuer expiratory
      promoting reflex evoked by a positive tracheal pressure (PTR; 5 cmH2O) and on the
      diaphragmatic EMG (EMG(DI)), inspiratory (TI) and expiratory (TE) time, were
      studied in 16 urethane-anesthetized (1.2-1.6 g/kg, i.p.) spontaneously breathing
      2-week-old rabbits. Positive P(TR) applied at the end of T(I) increased the
      subsequent TE to 255+/-29% (+/-S.E.; P < 0.0001) of control. SNS (1 sec train, 2
      msec pulse, 6 Hz) applied at the onset of TE, shortened this TE by 42+/-3% (P <
      0.0001). When SNS preceded positive PTR or positive PTR preceded SNS, the TE
      increased to 163+/-20 and 184+/-21% of control, respectively. These responses
      were not different, and smaller than that provoked by the PTR test alone (P <
      0.003 and 0.05, respectively). The results show that in newborns somatic afferent
      stimulation attenuates the vagally mediated respiratory inhibition, whether
      immediately before or during the vagal stimulation.

PMID- 10421032
TI  - Reduced inspiratory drive following laryngeal chemoreflex apnea during hypoxia.
AB  - Respiratory inhibition following laryngeal water administration was investigated
      by breath-by-breath analysis of inspiratory ventilation (VI) and central
      inspiratory drive (P0.1) in 15 unanesthetized lambs studied in 0.21 FIO2 (PaO2:
      82-92 torr, PaCO2 41-43 torr) and in 0.1 FIO2 (Pao2 30-34 torr, PaCO2 32-33
      torr). During the 30 sec period after stimulation, VI decreased significantly
      compared to prestimulation levels both in 0.21 FIO2 (-22, -21 and -18%) and in
      0.1 FI(O2), (-16, -23 and -19%) at 5, 16 and 29 days, respectively. In contrast,
      P0.1 remained at prestimulation levels during normoxia in all age groups (1, 10
      and 9%, NS), but decreased significantly during hypoxia (-11 and -13%, P < 0.05)
      at 16 and 29 days, respectively. Poststimulation apnea duration was significantly
      related to the decrease in VI (P < 0.001) but not to the change in P0.1.
      Laryngeal stimulation during hypoxemia/hypocapnia induces a prolonged decrease of
      central inspiratory drive in postneonatal lambs, a finding of potential
      significance for the mechanisms of sudden infant death syndrome.

PMID- 10421033
TI  - Rostral medullary respiratory neuronal activities of decerebrate cats in eupnea,
      apneusis and gasping.
AB  - Eupnea is generated by mechanisms within the pons and medulla. Following removal
      of pons or exposure to anoxia, gasping is elicited. Eupnea and gasping are
      markedly different ventilatory patterns. The genesis of gasping is dependent upon
      rostral medullary neuronal activities. To generate the gasp, these activities
      should commence before the phrenic burst. In decerebrate, vagotomized, paralyzed
      and ventilated cats, eupnea was altered to gasping in anoxia. Rostral medullary
      neuronal activities had inspiratory, expiratory and phase-spanning patterns in
      eupnea. During gasping, some inspiratory neuronal activities commenced before the
      phrenic gasp; these same neurons had commenced activities after the onset of the
      eupneic phrenic burst. Expiratory and phase-spanning neurons did not discharge.
      Neuronal activities which are consonant with a role in the neurogenesis of
      gasping had very different discharge patterns in eupnea. Results support the
      concept that medullary mechanisms for gasping are incorporated in the ponto
      medullary circuit responsible for the neurogenesis and expression of eupnea.

PMID- 10421034
TI  - Assessment of the dynamic relationship between external diameter and lumen flow
      in isolated bronchi.
AB  - Histologic studies of large airways suggest that outer airway wall area increases
      during bronchoconstriction, which could influence the relationship between
      external diameter and lumen flow. Using isolated bronchi from pigs we
      simultaneously recorded external diameter using sonomicrometry, and lumen flow of
      liquid using an electromagnetic flowmeter to determine the relationship between
      the two. External diameter fell from 4.13+/-0.19 to 3.65+/-0.19 mm (11+/-3%, n =
      5) during maximal electrical field stimulation (EFS), and flow decreased by 67+/
      9%. External diameter plotted against lumen flow showed hysteresis between
      contraction and relaxation. External narrowing ceased towards the end of a
      stimulation period, but flow continued to decrease. This differed from
      predictions based on an assumption that the wall area does not change during
      contraction. Histologic sections of bronchi fixed after acetylcholine (ACh)
      challenge showed an increase in total wall area. These results illustrate dynamic
      wall movement during bronchoconstriction induced by EFS or acetylcholine.

PMID- 10421035
TI  - Carbon isotope fractionation between blood and expired CO2 at rest and exercise.
AB  - Carbon isotope fractionation occurs between bicarbonates and gaseous CO2.
      Accordingly, expired CO2 could be impoverished in 13C vs. blood CO2
      (approximately 90% bicarbonates). The ratio 13C/12C in expired and blood CO2 was
      measured in six healthy subjects at rest and at the end of exercise (90 min; 65+/
      5% VO2max), with ingestion of water (300 ml) without or with glucose (30 g)
      naturally or artificially enriched in 13C, in order to study a range of 13C/12C
      in blood (-17.5+/-0.3 to 3.4+/-0.6% delta 13C PDB-1). At rest, 13C/12C in expired
      CO2 was 4.7+/-0.2% delta 13C PDB-1 lower than in blood CO2. This difference was
      not modified in response to exercise with ingestion of water or 13C-glucose
      (average difference 4.6+/-0.4 % delta 13C PDB-1). Carbon isotope fractionation
      across the lung was approximately 30% lower than predicted from the fractionation
      factor between bicarbonates and gaseous CO2 (1.00674 at 37 degrees C, or a
      approximately 6.6% delta 13C PDB-1 difference). This is consistent with the fact
      that approximately 40% of expired CO2 is released from carbamates and dissolved
      CO2. From a methodological point of view, these results indicate that 13C/12C in
      expired CO2 adequately tracks 13C/12C in blood CO2 with a constant approximately
      4.6 % delta 13C PDB-1 difference.

PMID- 10421036
TI  - Radiotelemetry system for apnea study in lambs.
AB  - Neonatal apneas are being studied in the laboratory using polysomnographic
      recordings in lambs. Standard equipment, requiring animal restraint, disrupts
      sleep and prevents development of spontaneous apneas. The aim of the current work
      was to develop and validate a wireless recording equipment to study freely moving
      lambs. Firstly, a radiotelemetry equipment composed of a multichannel FM
      transmitter and a receiver was developed. Secondly, to test the telemetry
      equipment, each biopotential - [electroencephalogram (EEG), electrooculogram
      (EOG), electrocardiogram (ECG), electromyograms (EMGs), nasal airflow] - was
      recorded simultaneously by standard equipment and by telemetry (5 lambs). The
      results indicated an excellent concordance between signals obtained by both
      systems. Finally, the 8-channel telemetry prototype was tested for
      polysomnographic recordings (16 lambs). Results obtained confirmed the
      possibility of recording frequent REM sleep periods and spontaneous apneas. In
      conclusion, this radiotelemetry polysomnographic equipment brings new
      possibilities for research on neonatal apneas.

PMID- 10421037
TI  - Epidemiology of bacterial infection during management of open leg fractures.
AB  - In a randomised double-blind trial conducted between 1990 and 1994, 616 patients
      from 43 centres, pefloxacin (group P, 316 patients) and a cefazolin-oxacillin
      combination (group C, 300 patients) were compared in the prophylaxis of bone
      infection after grade 1 and 2 open leg fractures. Samples were obtained at
      emergency, before and during surgery, and from drain aspirates. Antimicrobial
      susceptibility, slime production and adherence properties of the bacteria were
      tested. Cultures at emergency and before surgery showed similar distributions of
      gram-positive and gram-negative bacteria in both groups, while wound closure and
      infecting isolates showed prevailing gram-positive bacteria in group P and gram
      negative bacteria in group C. Positive cultures at each stage were correlated
      with the occurrence of infection but were not predictive of the infecting
      species, which were nosocomial bacteria in most cases. Positive cultures at wound
      closure warn of a higher infection risk. Twenty-one of 316 (6.6%) patients in
      group P and 24 of 300 (8%) in group C were considered infected within 3 months.
      The difference is not significant (chi-square test = 0.42; P = 0.51). Infecting
      strains were isolated from 38 patients (group P, 18; group C, 20). Infecting
      species, although not predictable, appear to be those escaping the spectrum of
      the prescribed antimicrobial prophylaxis.

PMID- 10421038
TI  - Etiology, clinical features and outcome of splenic microabscesses in HIV-infected
      patients with prolonged fever.
AB  - A prospective study was conducted to determine the etiology, clinical features,
      and outcome in a series of 32 consecutively enrolled HIV-infected patients with
      prolonged fever in whom high resolution (7.5 Mhz) sonography revealed multiple
      splenic microabscesses. Conventional (3.5 Mhz) sonography showed no splenic
      abnormalities in any patients. The diagnoses were: tuberculosis (14), visceral
      leishmaniasis (7), disseminated Mycobacterium avium complex infection (5),
      Salmonella spp. bacteremia (2), lymphoma (2), disseminated Rhodococcus equi
      infection (1), disseminated Candida krusei infection (1) and Pneumocystis carinii
      pneumonia (1). Twenty-eight patients were followed up for six months and four
      were lost to follow-up. In 16 patients with a clinical cure and microbiological
      eradication, the findings on follow-up high resolution sonography were normal,
      and in two patients the microabscesses persisted; ten patients died. In
      conclusion, the findings suggest splenic microabscesses may be a frequent
      condition in HIV-infected patients with prolonged fever, being an unspecific
      manifestation of the opportunistic diseases causing fever of unknown origin in
      this population. They cannot be detected by conventional abdominal sonography,
      whereas high resolution sonography is a useful technique for their detection and
      follow-up.

PMID- 10421039
TI  - Home intravenous antibiotic therapy for patients with infective endocarditis.
AB  - Although home intravenous antibiotic therapy (HIAT) is increasingly being used
      for various infectious diseases, outpatient treatment of infective endocarditis
      (IE) is still uncommon. Recently, the American Heart Association recommended
      outpatient treatment of endocarditis only for infections with streptococci that
      are highly susceptible to penicillin. Herein, the experience with HIAT in
      patients with IE due to a diversity of pathogens is presented. During a 3-year
      period, 37 patients with IE who were in a stable condition and were cooperative
      were enrolled in a service for HIAT after completion of diagnostic procedures. Of
      the 37 patients, 21 were male; mean age was 64.3 years (range 20-87 years); in
      most cases (26/37), IE involved a native valve. Causative organisms were
      Streptococcus spp. (20), Staphylococcus spp. (10), Enterococcus spp. (2),
      Enterobacter spp. (1), and Erysipelothrix rhusiopathiae (1), while three were
      unknown. The most common antibiotics used were ceftriaxone and vancomycin. Almost
      three-quarters of the intravenous lines were peripheral. The mean duration of
      HIAT was 26.2 +/- 8.5 days, with 92% of the patients cured by it. Most
      complications were minor. Six patients were rehospitalised and two of them
      required valve replacement. In half of the rehospitalised patients, the
      complication was unrelated to HIAT. Surprisingly, almost all of the complications
      necessitating rehospitalisation occurred in patients with streptococcal IE and
      most involved native valves. HIAT may be suitable for IE due to a diversity of
      pathogens and involving prosthetic as well as native heart valves, provided there
      are proper patient and antibiotic selections, good follow-up, and vigilant
      monitoring of complications.

PMID- 10421040
TI  - Epidemiological analysis of methicillin-resistant Staphylococcus aureus in a
      Zagreb Trauma Hospital using a randomly amplified polymorphic DNA-typing method.
AB  - During a 1-month period in 1996, all inpatients and staff in the Zagreb Trauma
      Hospital were screened for methicillin-resistant Staphylococcus aureus (MRSA)
      carriage in order to control MRSA spread within the hospital. During the study
      period, 663 patients were admitted to the hospital, and screening prior to
      discharge revealed that 42 were colonised or infected with MRSA. Twenty-three
      (55%) of these would not have been detected if active screening had not been
      performed. Amongst 205 staff members, MRSA carriage was only found in one (0.5%)
      nurse. The prevalence and incidence of MRSA carriage varied significantly amongst
      the wards and was related to the length of hospital stay. One-third of the
      patients colonised or infected with MRSA had a history of previous admission to
      another hospital, and one-third were transferred to another institution after
      discharge. Thirty-nine of 42 MRSA isolates shared the same antibiotic sensitivity
      pattern, suggesting endemic spread of MRSA. However, randomly amplified
      polymorphic DNA molecular typing revealed four profiles, the most common
      involving 15 of 36 tested strains. There was no obvious clustering of
      epidemiological types by ward, except for the appearance of a single type on the
      burns unit, and it was likely that different strains had been introduced into the
      hospital by patient transfers from elsewhere. The results of this study indicate
      that a substantial proportion of MRSA carriers escape infection control measures
      if active screening is not performed. Based on the results of this study, steps
      have been taken to improve interhospital communication about the transfer of
      patients colonised with MRSA. Randomly amplified polymorphic DNA typing proved to
      be a useful aid to epidemiological investigations of MRSA.

PMID- 10421041
TI  - Evaluation of a single-sample serological technique for diagnosing pertussis in
      unvaccinated children.
AB  - This study was performed to evaluate the sensitivity of immunoglobulin (Ig)G and
      IgA antibodies to pertussis toxin and filamentous hemagglutinin in diagnosing
      pertussis from a single serum sample. The pertussis group was defined according
      to the World Health Organization pertussis case definition. The control group
      coughed for 21 days or more but had no microbiological or serological evidence of
      Bordetella infection. Both cohorts were divided into infants (< 12 months of
      age), toddlers (1-4 years) and school children (5-10 years). There were 525
      subjects in the pertussis group and 321 in the control group, with an even
      distribution of genders. IgG and IgA antibodies to pertussis toxin and
      filamentous hemagglutinin were measured in a standardized enzyme immunoassay.
      Antibody levels beyond the 95 percentile of the control cohort were regarded as
      indicative of recent contact, setting the specificity level at 0.95. Acute serum
      samples drawn between 1 week and 3 weeks after the onset of coughing showed a low
      sensitivity (2-19%) for diagnosing pertussis. In convalescent samples taken 5-10
      weeks after the onset of symptoms, detection of IgG anti-pertussis toxin was the
      best single test, with a sensitivity of 61%, 65%, and 74% in infants, toddlers
      and school children, respectively. A combination of IgG anti-pertussis toxin and
      IgA anti-filamentous hemagglutinin using age-specific reference values had a
      sensitivity of 81-89% in diagnosing pertussis from a single serum sample taken 5
      10 weeks after the beginning of symptoms.

PMID- 10421042
TI  - Early identification of Mycobacterium tuberculosis and Mycobacterium avium using
      the polymerase chain reaction on samples positive by a rapid commercial culture
      system.
AB  - A combination of two methods -- a rapid culture method [Mycobacteria Growth
      Indicator Tube (MGIT); Becton-Dickinson, USA] and a double polymerase chain
      reaction (PCR) assay -- was assessed for the detection and identification of
      Mycobacterium tuberculosis and Mycobacterium avium from clinical samples. The aim
      of the study was to evaluate the ability of the system to offer rapid and
      accurate diagnosis of mycobacterial infections. After decontamination, clinical
      samples (n = 554) were stained and cultured in parallel on solid media and in
      MGITs following standard procedures. The performance of the two culture systems
      was compared. Positive MGITs were tested for the presence of Mycobacterium
      tuberculosis and Mycobacterium avium by PCR of IS6110 (Mycobacterium
      tuberculosis) and the 16S rRNA gene (Mycobacterium avium). A total of 41
      mycobacteria -- 27 Mycobacterium tuberculosis isolates, eight Mycobacterium avium
      isolates, and six other species of mycobacteria -- were isolated by one or both
      culture media. The MGIT system recovered 36 (87.8%) mycobacteria and the solid
      media 33 (80.4%). The mean time to detection by the two culture systems did not
      differ overall, but the mean time to detection of Mycobacterium avium from smear
      positive specimens was shorter in MGITs than in solid media (5.25 days vs. 16.25
      days, P < 0.05). The double PCR assay performed on the 36 positive MGITs
      correctly identified all 24 Mycobacterium tuberculosis-positive MGITs and all six
      Mycobacterium avium-positive vials. Therefore, application of the PCR assay to
      positive MGITs may mean that Mycobacterium tuberculosis and Mycobacterium avium
      can be identified at an earlier stage than with current methods.

PMID- 10421043
TI  - Use of oligoprobes on amplified DNA in the diagnosis of bacterial meningitis.
AB  - An approach based on the 16 S rDNA polymerase chain reaction (16S PCR) and
      oligoprobe hybridization was applied to 77 cerebrospinal fluid samples submitted
      to the clinical microbiology laboratory for culture. Broad-range 16S rDNA primers
      were selected in conserved regions of the gene. Oligoprobes specific for
      Neisseria meningitidis, Haemophilus influenzae, Streptococcus spp., and
      Mycobacterium tuberculosis were selected in specific variable regions of the
      amplified 600 base pairs (bp) in the 16S rDNA. None of the oligoprobes cross
      hybridized with DNA from the other bacteria or from common contaminants. There
      were no false-negative results in culture-positive cerebrospinal fluid samples.
      Ten cases of meningitis caused by bacteria other than the four probes were not
      identified by any of the four probes. In culture-negative cerebrospinal fluid
      samples with some abnormal chemical parameters, there were 14 amplicons -- one of
      Haemophilus influenzae, three of Streptococcus spp., six of Mycobacterium
      tuberculosis, and four not identified -- while in normal cerebrospinal fluid
      samples there were no amplicons.

PMID- 10421045
TI  - Invasive group B streptococcal disease in nonpregnant adults.
AB  - Forty episodes of invasive group B streptococcal infections in nonpregnant adults
      at Chris Hani Baragwanath Hospital, Soweto, South Africa, were retrospectively
      reviewed. The mean age of the patients was 45.6 years. Twenty (50%) patients were
      bacteraemic. Common predisposing conditions included diabetes mellitus (27.5%),
      trauma (25%), and HIV infection (12.5%). Soft tissue abscesses and pneumonia
      accounted for 70% of the presentations. Ten (25%) patients had acquired the
      infection nosocomially. Death occurred in 14 (35%) patients and was significantly
      associated with bacteraemia (P = 0.0009) and pneumonia (P = 0.0012). Trauma is an
      important predisposing condition, and HIV infection may have played a role in the
      setting described; both factors probably accounted for the relatively young age
      of the patients.

PMID- 10421044
TI  - Six-year prospective study of risk and prognostic factors in patients with
      nosocomial sepsis caused by Acinetobacter baumannii.
AB  - In this prospective study, the risk factors associated with nosocomial sepsis
      Caused by Acinetobacter baumannii or Pseudomonas aeruginosa were compared. Prior
      use of broad-spectrum antibiotics, urinary tract catheter, prior surgery, and
      mechanical ventilation were significantly associated with nosocomial sepsis
      caused by Acinetobacter baumannii. The mean prognostic factors significantly
      associated with mortality were known focus of infection, multiresistant
      Acinetobacter baumannii, and inappropriate antibiotic treatment. Adequate
      knowledge of these findings is important to ensure appropriate management of
      patients and rational use of antibiotics.

PMID- 10421046
TI  - Bacteremia complicated by vertebral osteomyelitis due to Streptococcus bovis.
AB  - The diagnosis of vertebral osteomyelitis is easily missed, especially in the
      elderly in whom clinical signs of bacteremia might not be manifest. Spontaneously
      occurring disc-space infection in adults often has an insidious presentation. The
      infecting microorganism can be difficult to identify. Although discitis due to
      Streptococcus bovis is occasionally found, it is often difficult to fully confirm
      the diagnosis. Here, a case of vertebral osteomyelitis due to this microorganism
      is reported.

PMID- 10421047
TI  - Three cases of serious infection caused by Aerococcus urinae.
AB  - Three cases of serious infection caused by Aerococcus urinae are presented: a
      patient with endocarditis and two patients with soft-tissue infection (phlegmon
      and balanitis respectively). The literature on Aerococcus urinae infections is
      reviewed and the antibiotic therapy discussed. Aerococcus urinae is a pathogen
      isolated primarily from urine specimens of elderly patients with local or
      systemic predisposing conditions. Most infections are mild, but serious
      infections such as endocarditis and septicemia/urosepsis have been described.
      Penicillin or ampicillin in combination with an aminoglycoside and close
      monitoring of the patient's clinical status and laboratory results would seem to
      be the best strategy for management of cases of serious infection.

PMID- 10421048
TI  - Multiple drug resistance genotype causing failure of antiretroviral treatment in
      an HIV-infected patient heavily exposed to nucleoside analogues.
AB  - A 37-year-old homosexual man began antiretroviral combination therapy with
      didanosine (ddI), lamivudine (3TC) and indinavir (IDV) after being exposed
      previously to zidovudine (ZDV), ddI and 3TC in different sequential regimens. The
      patient's viral load did not fall below a detectable level despite his adherence
      to drug therapy, which was considered optimal. Stavudine (d4T) was prescribed in
      the third month of treatment instead of ddI without any evident improvement in
      the treatment response. A point mutation nested PCR assay showed that the patient
      carried a virus with a codon Q151M mutation, which confers multiple drug
      resistance to nucleoside analogues. Genetic sequence analysis showed that,
      despite none of the classically associated mutations to Q151M being present at
      the beginning of treatment, continuous genetic evolution under selective drug
      pressure allowed the virus to accumulate mutations at codons 62, 74 and 116 over
      time. As expected, the CD4+ cell count declined during the study period, and the
      viral load remained detectable.

PMID- 10421049
TI  - Resistance patterns of Streptococcus pneumoniae from children in central Italy.
AB  - Nasopharyngeal swabs were collected from children aged 3-5 years in central Italy
      who were attending day-care centres or hospital outpatient clinics. One hundred
      and twenty-one strains of Streptococcus pneumoniae isolated were tested for
      susceptibility to penicillin, cefotaxime, erythromycin, clindamycin,
      tetracycline, chloramphenicol and cotrimoxazole. A high prevalence of penicillin
      resistant (14%), erythromycin-resistant (60%) and multiply resistant strains
      (53%) were found. An unusual finding was that 49 of the 64 (76.6%) multiply
      resistant strains were penicillin-susceptible, 28 serogroup 6 strains also being
      resistant to the other antibiotics tested. Such strains have not previously been
      reported from Italy but have the same features as strains recently found in child
      carriers in the eastern Mediterranean area.

PMID- 10421050
TI  - Simple procedure for drug susceptibility testing of Mycobacterium tuberculosis
      using a commercial colorimetic assay.
AB  - The aim of this study was to evaluate a simple method using a commercial
      colorimetric assay (Alamar Blue Oxidation-Reduction Indicator; Accumed, USA) in a
      microtiter format for testing the susceptibility of 94 strains of Mycobacterium
      tuberculosis to isoniazid, rifampicin, ethambutol and streptomycin. The method
      makes use of one critical concentration of each drug, and the results are
      available within 8-10 days. Overall, 97.1% agreement with the proportion method
      was obtained. Full agreement was obtained for isoniazid and rifampicin. The
      method is simple to perform, permits visual reading of results, and is
      practicable for laboratories with limited resources.

PMID- 10421051
TI  - A further case of acute human granulocytic ehrlichiosis in Slovenia.

PMID- 10421053
TI  - Fatal native valve endocarditis due to Scedosporium apiospermum (Pseudallescheria
      boydii) following trauma.

PMID- 10421052
TI  - Acute renal failure caused by indinavir in a patient with a single functioning
      kidney.

PMID- 10421054
TI  - CCR5 genotype and human immunodeficiency virus type 1 infection in perinatally
      exposed infants.

PMID- 10421055
TI  - Genotypic, phenotypic and functional analysis of CD4+CD7+ and CD4+CD7- T
      lymphocyte subsets in Sezary syndrome.
AB  - The expansion of CD4+CD7- T cells in the peripheral blood of Sezary syndrome (SS)
      is well known. It remains unclear whether this population contains the dominant T
      cell clone. Peripheral blood mononuclear cells (PBMC) of five SS patients were
      sorted by fluorescence-activated cell sorting into CD4+CD7- and CD4+CD7+
      populations. These populations were analysed separately for clonality of the T
      cell receptor gamma chain (TCR-gamma) by PCR-DGGE. The cytokine profile of both
      populations was investigated by RT-PCR ELISA for IFN-gamma, IL-2, IL-4, IL-5, IL
      10, IL-13 and IL-15. In three other patients with known Vbeta-usage, the dominant
      T cell clones were phenotypically characterized by double staining. PCR-DGGE of
      TCR-gamma demonstrated that all patients had a clonal population in their blood
      and that this population was present in CD4+CD7- and CD4+CD7+ populations.
      Concerning mRNA cytokine transcription, the two populations did not show any
      consistent differences. In three patients with identified clones (Vbeta 3.1, 5.3
      and 6.7), double staining revealed positivity for CD2, CD3, CD4, CD5, CD45RO and
      CD7 in a significant proportion (at least 35%). We conclude that the CD4+CD7-
      population does not represent the dominant T cell clone in patients with SS. An
      increase in this population of PBMC in SS might account for deviations in the T
      cell functions of the patients.

PMID- 10421056
TI  - Posttranslational regulation of neurofibromin content in melanocytes of
      neurofibromatosis type 1 patients.
AB  - Neurofibromatosis type 1 (NF1) is a common autosomal dominantly inherited
      disorder characterized by neurofibromas and cafe-au-lait macules. Most of the NF1
      gene germline mutations result in a reduction in the level of neurofibromin. As
      shown recently, the neurofibromin level can be regulated posttranslationally
      through alteration of the protein half-life. This raises the question as to
      whether this type of regulation is also operating in cultured melanocytes of NF1
      patients especially in melanocytes derived from cafe-au-lait macules. In
      melanocytes cultured without phorbol 12-myristate 13-acetate (PMA) the
      neurofibromin half-lives were 24 h (healthy controls, MC), 26 h (apparently
      healthy skin of NF1 patients, MNFS) and 25 h (cafe-au-lait macules of NF1
      patients, MNFC). In PMA-stimulated cells the neurofibromin half-lives were 68 h
      (MC) and 73 h (MNFS) whereas it was 45 h in melanocytes derived from NF1 cafe-au
      lait macules. The amount of NF1 mRNA was not altered under these culture
      conditions as shown by competitive RT-PCR. We speculate that this regulation is
      involved in the formation of some NF1 symptoms, for instance in the formation of
      cafe-au-lait macules.

PMID- 10421057
TI  - Local injection of recombinant human stem cell factor promotes human skin mast
      cell survival and neurofibroma cell proliferation in the transplanted
      neurofibroma in nude mice.
AB  - We studied the effects of stem cell factor (SCF) on human skin mast cell (HSMC)
      survival and the proliferation of neurofibroma (NF) cells in transplanted NF in
      nude mice. Small pieces of cutaneous NF from a patient with von Recklinghausen's
      disease were transplanted subcutaneously into nude mice. Recombinant human SCF
      (10 or 100 ng) was injected six or seven times around the NF transplantation
      sites over 11 days (i.e. every other day). The number of HSMCs was reduced in
      vehicle-injected NF compared to the amount present before transplantation. In
      contrast, NF-transplanted animals that were injected with SCF (10 or 100 ng)
      showed preservation of mast cell numbers in the tissue. Using computerized image
      analysis, mast cell size in SCF-treated NF transplants was significantly altered
      (larger at the 10 ng dose, and smaller at the 100 ng dose) compared with the size
      before transplantation or in vehicle-injected tissue. Furthermore, at the higher
      SCF dose (100 ng) PCNA-positive NF cells showed a significant increase. These
      results indicate that HSMCs in transplanted NF tissue retain their capacity to
      respond to SCF in vivo, and that SCF contributes to the regulation of both HSMC
      survival and size in cutaneous NF. In addition, activated HSMCs induced by SCF
      may be involved in the growth of cutaneous NF in von Recklinghausen's disease.
      Thus, this experimental model may be useful in the study of the cellular
      interactions between HSMCs and other stromal cells in cutaneous NF.

PMID- 10421058
TI  - Human melanocytes grown in epidermal equivalents transfer their melanin to
      follicular outer root sheath keratinocytes.
AB  - Because outer root sheath (ORS) cells are valuable substitutes for
      interfollicular epidermal keratinocytes, we wanted to determine whether epidermal
      equivalents generated from ORS cells and containing cultured melanocytes can
      serve as an in vitro model for skin pigmentation. In such epidermal equivalents
      prepared with ORS cells and melanocytes from donors of phototypes II, III and VI,
      a stratified epithelium resembling normal epidermis developed within 14 days, as
      documented by histological, ultrastructural (e.g. basement membrane-like
      structure, keratohyalin granules, keratinosomes) and immunohistochemical (e.g.
      keratins, integrins, gp80, involucrin, filaggrin) criteria. The melanocytes were
      localized in the basal layer and accounted for 10% of the total cell number.
      Heavily pigmented melanocytes from black donors contained regular melanosomes in
      all stages of maturation, whereas melanocytes derived from white donors contained
      predominantly melanosomes of stages I and II. Melanosome-laden dendrites were
      readily detected extending from the heavily pigmented melanocytes, while they
      were less conspicuous in melanocytes from white donors. The extent of melanosome
      transfer was independent of the racial origin of the ORS cells. Melanosomes could
      also be transferred "through racial barriers". Melanosomes, mainly of stages III
      and IV, were detected in the ORS cells, being distributed either as single or
      compound melanosomes, again irrespective of the racial origin of the ORS cells.
      In conclusion, pigmented epidermal equivalents generated from ORS cells offer
      practical advantages over other in vitro pigmentation models: (1) the ORS cells
      are easily and repeatedly available from any donor regardless of age; (2) primary
      cultures of ORS cells are free of contaminating melanocytes, a bias if using
      interfollicular epidermal keratinocytes; (3) a high degree of epidermal
      differentiation is maintained for 3 weeks in fully defined medium, enabling
      labelling and stimulation experiments to be performed and compounds interfering
      with melanin pigmentation to be tested.

PMID- 10421059
TI  - Effect of 12-O-tetradecanoyl-phorbol ester and incisional wounding on neuropsin
      mRNA and its protein expression in murine skin.
AB  - The expression of neuropsin mRNA in vivo in mouse skin was examined by in situ
      hybridization and Northern blotting under stimulated conditions. Two kinds of
      epidermal stimuli, a topical application of a chemical tumor promoter and
      incisional wounding, were used. A single topical application of 12-O
      tetradecanoyl-phorbol 13-acetate induced epidermal hyperplasia and simultaneously
      induced an extensive increase in neuropsin mRNA in the suprabasal cells. A full
      thickness skin incision also induced a profound increase in neuropsin mRNA in the
      suprabasal cells surrounding the wound but not in actively proliferating basal
      cells. The increases in neuropsin mRNA occurred rather late and were limited to
      the site of drug application or around the incision. Interestingly, neuropsin
      mRNA was not expressed in the epithelial tongue migrating toward the wound during
      re-epithelialization. Thus, neuropsin might participate in accelerated epidermal
      differentiation rather than in the proliferation or migration of keratinocytes in
      the wound.

PMID- 10421061
TI  - The loss of desmosomes after retinoic acid treatment results in an apparent
      inhibition of HaCaT keratinocyte differentiation.
AB  - Epithelial tissue cohesion is based on various types of intercellular adhering
      junctions of which the desmosomes are particularly abundant in stratified
      epithelia. The desmogleins (dsg) and desmocollins are their transmembrane
      components. One or more of the three isoforms of these desmosomal cadherins are
      co-expressed and specific subtypes prevail at different stages of epidermal
      differentiation. In HaCaT keratinocytes, desmosomal cadherin expression increased
      with ongoing differentiation, apart from dsg2. Continuous treatment with retinoic
      acid (RA) inhibits the differentiation of HaCaT keratinocyte cultures. RA
      strongly increased the shedding of cells into the culture medium where they
      quickly underwent cellular death. Electron microscopy showed a marked reduction
      of desmosomes with nearly complete absence of their structural components,
      suggesting that RA inhibits their synthesis. RA indeed downregulated the
      transcript levels of all HaCaT desmosomal cadherins, except dsg2. Immunostaining
      revealed that desmosomal protein contents corresponded to alterations in
      transcription rates. Our findings indicate that the RA-induced inhibition of
      differentiation of keratinocyte cultures results from removal of cells committed
      to differentiation. In vivo, less adhering but still differentiating cells cannot
      be removed as easily as they can be in a culture system. The consequence is a
      sticky and fragile skin.

PMID- 10421060
TI  - The vitamin A metabolism and expression of retinoid-binding proteins differ in
      HaCaT cells and normal human keratinocytes.
AB  - HaCaT keratinocytes differ from normal human epidermal keratinocytes (HEK) by
      constitutive expression of differentiation markers which are normally suppressed
      by vitamin A. In search of an explanation for this discrepancy we compared the
      vitamin A content, the expression of retinoid-binding proteins, and the vitamin A
      metabolism in the two cell types. The concentrations of retinol and 3,4
      didehydroretinol in cultured HaCaT cells were less than one-fifth those in HEK,
      and the content of fatty acyl esters was even lower. Similarly, the
      concentrations of cellular retinol-binding protein and cellular retinoic acid
      binding protein (CRBPI and CRABPII, respectively) were 10-30 times lower in HaCaT
      cells than in HEK corresponding to a reduced mRNA expression of these proteins.
      Unexpectedly, HaCaT cells expressed RARbeta in addition to RARalpha, RARgamma and
      RXRalpha, which are nuclear receptors normally found in HEK. Radioactive retinol
      added to the culture medium appeared only transiently in HaCaT cells, and pulse
      labeling confirmed a defective cellular retention of retinyl esters. After 24 h
      of incubation with [3H]retinol, cell-associated radioactivity corresponding to
      retinol, 3,4-didehydroretinol, all-trans-retinoic acid and 3,4-didehydroretinoic
      acid was found in both HaCaT cells and HEK. [3H]Retinoic acid showed a more rapid
      metabolism to 4-hydroxy/4-keto-retinoic acid in HaCaT cells than in HEK, which
      could be explained by a higher expression of cytochrome p450RAI in the former
      cells. In conclusion, the abnormal uptake of vitamin A and low levels of retinoid
      binding proteins in HaCaT cells, linked with an aberrant metabolism of retinol,
      may help to explain why these cells differentiate also in the presence of
      retinoids.

PMID- 10421062
TI  - Increased serum interleukin-15 levels in bullous skin diseases: correlation with
      disease intensity.

PMID- 10421063
TI  - Langerhans cell migration in mice requires intact type I interleukin 1 receptor
      (IL-1RI) function.

PMID- 10421064
TI  - Allelic loss at the p73 locus (1p36.33) is infrequent in malignant melanoma.

PMID- 10421066
TI  - Copper/zinc superoxide dismutase, nuclear DNA content, and progression in human
      gliomas.
AB  - To our knowledge, there have been no previous reports regarding the
      immunohistochemistry and image cytometry to demonstrate elevated Copper/zinc
      superoxide dismutase (Cu/Zn SOD) expression and numbers of the clonal cells in
      human gliomas. In 30 well-studied patients with gliomas, immunoreactivity for
      Cu/Zn SOD and cytometric evidence of DNA ploidy in the G2M cell cycle phase were
      evaluated from routinely prepared tissue blocks. Cu/Zn SOD positive tumor cells
      were shown in 8 of 13 glioblastomas (mean quantitative immunoreactivity SOD
      score; 1), 3 of 8 anaplastic gliomas (score; 0.6), and none of 9 low-grade
      gliomas. The differences in SOD score was not significant. In hypertetraploid
      glioblastomas, time to progression was shorter than for hypertetraploid of
      anaplastic gliomas, while SOD scores were not significantly different. The same
      relationship held for tetraploid specimens. Considering variables in combination,
      hypertetraploid gliomas with high SOD immunoreactivity showed a significantly
      short time to progression (p < 0.05) (1-5 months after radiotherapy and
      chemotherapy) compared with hypertetraploid, low-SOD immunoreactivity gliomas or
      tetraploid, low-SOD immunoreactivity gliomas. The tumor cells with high SOD
      activity also tended to be resistant for radiotherapy and anticancer drugs. Those
      results were suggested that the high grade glioma with a single clone and low SOD
      activity were effective for radiotherapy associated with oxidative stress, and
      that the high grade gliomas with more than two clones and high SOD activity were
      very less effective for same therapy. Cu/Zn SOD activity and the degree of the
      clonality in human gliomas should be very important factors influencing a choice
      of oxidative cytotoxic treatment.

PMID- 10421065
TI  - Cisplatin resistant glioblastoma cells may have increased concentration of
      urokinase plasminogen activator and plasminogen activator inhibitor type 1.
AB  - Gliomas are the most common form of intrinsic primary brain tumors, that
      extensively invade the surrounding normal brain tissue. The failure of
      chemotherapy treatment of these tumors is chiefly attributed to drug-resistance.
      From human glioblastoma we developed two cell sublines resistant to cisplatin due
      to acute (AT cells) or continuous (CT cells) treatment with clinically relevant
      doses of cisplatin. We examined their sensitivity to different cytostatics by
      colorimetric MTT assay. The concentrations of urokinase plasminogen activator
      (uPA) and plasminogen activator inhibitor type 1 (PAI-1) were determined by the
      ELISA assay. The results reveal that both AT and CT cells became resistant to
      cisplatin and vincristine; AT cells became resistant also to etoposide. Both AT
      and CT cells did not significantly change their sensitivity to doxorubicin, 5
      fluorouracil and chlorambucil. Concentrations of uPA and PAI-1 were increased in
      CT cells, with no change in AT cells. In the conditioned medium of both, AT and
      CT cells, the level of uPA were increased. No differences in concentrations of
      PAI-1 in the conditioned medium of these cells were found. Thus, our results show
      that drug-resistance of glioblastoma cells may be accompanied with the increased
      levels of markers for tumor invasion.

PMID- 10421067
TI  - Expression of estrogen receptors alpha and beta in human meningiomas.
AB  - The predominance of meningiomas in females, their accelerated growth during the
      luteal phase of the menstrual cycle and during pregnancy; and the association
      between meningiomas and breast cancer has led to a number of studies examining
      the potential role of steroids on the growth of meningiomas. It is generally
      agreed that the majority of meningiomas possess the progesterone and androgen
      receptor. There are numerous discrepancies in the literature among the results
      for estrogen receptor (ER). The aim of this study was to examine the expression
      of ER-alpha mRNA and the recently described novel ER, ER-beta in meningiomas.
      Using reverse transcription and polymerase chain reaction (RT-PCR) Southern blot
      analysis thirty-four meningiomas were examined for the presence of ER-alpha and
      ER-beta. Forty-four percent of meningiomas showed a strong band for ER-beta mRNA
      and sixty-eight percent of meningiomas showed a strong band for ER-alpha mRNA.
      The involvement of ER-beta in meningioma biology should be examined further,
      given the differences in the ER-alpha and ER-beta gene products.

PMID- 10421068
TI  - The accumulation of topotecan in 9L glioma and in brain parenchyma with and
      without dexamethasone administration.
AB  - The accumulation of the topoisomerase I inhibitor topotecan in brain tumor as
      well as in brain around tumor (BAT) and normal brain following an intravenous
      bolus of topotecan of 0.5 mg/kg was investigated in rats bearing a 9L glioma.
      Also the influence of dexamethasone (Dex) on the uptake of topotecan was
      examined. Tumor, BAT and brain tissue as well as whole blood were collected at 1
      h after an i.v. bolus of topotecan. Concentrations of total topotecan in tumor,
      BAT and brain were quantified with high-performance liquid chromatography (HPLC)
      and compared with concentrations in plasma of total topotecan. In brain tumor
      tissue the mean total topotecan concentration was 96 +/- 33 ng/g which was 20
      fold higher than the accumulation of topotecan in normal brain tissue. In BAT
      intermediate concentrations of 13 +/- 4.9 ng/g were reached. Mean total topotecan
      concentration in plasma was 100 +/- 25 ng/ml. We did not find an influence of Dex
      on the uptake of topotecan in either tissue. We conclude that high tissue
      concentrations of topotecan can be reached in experimental brain tumors in rats.
      This observation may be useful in the design of clinical studies with topotecan.

PMID- 10421069
TI  - Enhanced uptake of [3H] spermidine by 9L rat brain tumors after direct
      intratumoral infusion of inhibitors of enzymes of the polyamine biosynthetic
      pathway.
AB  - We have been exploring the feasibility of delivering ionizing radiation to brain
      tumor cells by using tritium labeled polyamines. Polyamines are taken up
      preferentially by dividing cells and form noncovalent bonds with DNA. Their
      uptake can be enhanced by drugs which deplete endogenous polyamines. To test this
      in vivo, 9L cells were implanted in the striatal region of the brain in male
      Fisher 344 rats. Osmotic pumps containing trace amounts of [3H] spermidine or
      [3H] putrescine with either difluoromethylornithine or combinations of 3
      inhibitors of enzymes of the polyamine biosynthetic pathway were implanted
      subcutaneously and were connected to intratumoral cannulas. After 14-16 days the
      brains were removed and sliced in the coronal plane. The diameters of the tumors
      were measured and tumor tissue was dissected from each slice, weighed and lysed
      for scintillation counting. It was found that difluoromethylornithine enhanced
      the uptake of [3H] putrescine while a combination of inhibitors of enzymes of the
      polyamine biosynthetic pathway enhanced the uptake of [3H] putrescine and [3H]
      spermidine producing a localized region of radioactivity in the 9L tumor. It is
      estimated that if the [3H] polyamines were at higher specific activity
      (commercially available), instead of the trace dose given here, the [3H]
      polyamine uptake would be sufficient to kill 9L tumor cells within a 2 to 3 week
      period.

PMID- 10421070
TI  - PAR 1-type thrombin receptors are involved in thrombin-induced calcium signaling
      in human meningioma cells.
AB  - Thrombin is known to play a role as regulator in tumor spreading and tumor
      growth. Proteinase-activated receptor 1 (PAR 1)-type thrombin receptors were
      identified in different cancer cells including human glioblastoma cells. Thus a
      function of PAR 1 in brain tumors may be suggested. In this study, the presence
      of PAR 1-type thrombin receptors was investigated in primary cell cultures
      established from operated human meningiomas from two 59- and 79-year-old women.
      Characterization of PAR 1 on binding level was performed using immunofluorescence
      studies with the monoclonal anti-PAR 1 antibody Mab 61-1 directed against a
      domain in the NH2-terminus of PAR 1. These binding sites constitute functional
      thrombin receptors that are involved in thrombin-induced signaling in human
      meningioma cells as demonstrated by investigation of alpha-thrombin- and PAR 1
      activating hexapeptide (TRAP-6)-induced [Ca2+]i mobilization. To our knowledge,
      this is the first report demonstrating thrombin-induced intracellular signaling
      in human meningioma cells mediated by the PAR 1-type thrombin receptor.

PMID- 10421071
TI  - A simple mouse model for leptomeningeal metastases and repeated intrathecal
      therapy.
AB  - Leptomeningeal metastases occur in 0.8-8% of cancer patients. Despite recent
      developments in cancer therapy, survival of these patients is usually less than
      six months. Here, we describe an easy and reproducible mouse model of
      leptomeningeal metastases through intracisternal injection of B16F-10 murine
      melanoma cells, with histological characteristics comparable with human
      leptomeningeal metastases. After intracisternal injection of a recombinant
      adenoviral vector containing the LacZ gene, we found transfected cells in
      ependymal and subependymal cells throughout the brain, but not in parenchymal
      cells. Intracisternal injection of adenoviral vector, preceded by daily
      intracisternal injections with saline, did not result in a decreased vector
      delivery. After a single intracisternal injection, gene expression persisted for
      at least a month in immunodeficient mice, without apparent toxicity or decrease
      in intensity. The results of this study show the facility of a mouse model for
      leptomeningeal metastases as well as repeated intrathecal drug delivery.

PMID- 10421072
TI  - Proliferative activity as measured by MIB-1 labeling index and long-term outcome
      of visual pathway astrocytomas in children.
AB  - Although most visual pathway tumors are low-grade gliomas their biologic behavior
      is highly unpredictable. In order to determine whether assessment of
      proliferative activity can assist in predicting tumor behavior, we studied the
      MIB-1 labeling indices (MIB-1 LIs) in surgical specimens and monitored tumor
      growth in 31 consecutive children operated on between 1978 and 1997. The MIB-1
      LIs at diagnosis varied from 0-10.6% (mean +/- SD, 3.27 +/- 2.49%). Tumor
      progression occurred in 19 patients leading to death in seven, three of whom had
      neurofibromatosis type 1 (NF1). No association between MIB-1 LI at initial
      diagnosis and both progression free and overall survival was apparent. However,
      the MIB-1 LIs increased to 15.2% and 18% in two patients with NF1 who developed
      highly malignant gliomas 6 and 6.5 years after irradiation. In the remaining
      patients the MIB-1 LIs did not change significantly over time in a total of 17
      repeat surgeries. Three patients with LIs of 6.8%, 10.6% and 8.8% are stable
      after 6, 4.5 and 3.5 years with partial resection, biopsy and subtotal resection,
      respectively, and no further therapy in the first two and chemotherapy in the
      latter. Three patients (10%) with LIs of 6.4%, 4.8% and 2.2% either presented
      with or developed leptomeningeal spread during follow-up. While MIB-1 LI does not
      appear to assist in clinical decision making patient numbers were too small to
      find out whether response to chemotherapy varies with proliferative potential.

PMID- 10421073
TI  - Spontaneous remission of primary central nervous system lymphoma: report of 3
      cases and discussion of pathophysiology.
AB  - Primary central nervous system lymphoma (PCNSL) is a relatively uncommon disease
      in which spontaneous remission is exceedingly rare. We are reporting three cases
      of primary CNS lymphoma with spontaneous regression in two to eight weeks, from
      the time of the initial diagnosis. The remission lasted for four years in the
      first case, two years in the second, and one year in the third case. Tissue
      diagnosis was made in the first two cases after relapse, and in the third case a
      biopsy was done at the initial presentation. The literature and the possible
      pathophysiological mechanisms of this interesting phenomenon are discussed.

PMID- 10421075
TI  - Prognostic factor analysis for multiple brain metastases after gamma knife
      radiosurgery: results in 97 patients.
AB  - Stereotactic radiosurgery (SR) is being used with increasing frequency in the
      treatment of brain metastases. This study provides data from a clinical
      experience with radiosurgery in the treatment of cases with multiple metastases
      and identifies parameters that may be useful in the proper selection and therapy
      of these patients. From January 1993 to April 1997, 97 patients (43 women and 54
      men; median age 58 years) suffering from multiple brain metastases (median 3;
      range 2-4) in MRI scans, received SR with the Gamma Knife. The median dose at the
      tumor margin was 20 Gy (range 17-30 Gy). Median tumor volume was 3900 cmm (range
      100-10,000). Different forms of hemiparesis, focal and generalized seizures,
      cognitive deficit, headache, dizziness and ataxia had been the predominant
      neurological symptoms. Major histologies included lung carcinoma (44%), breast
      cancer (21%), renal cell carcinoma (10%), colorectal cancer (8%), and melanoma
      (7%). The median survival time was 6 months after SR. The actual one-year
      survival rate was 26%. In univariate and multivariate analysis, a higher
      Karnofsky performance rating and absence of extracranial metastases had a
      significantly positive effect on survival. Local tumor control was achieved in
      94% of the patients. Complications included the onset of peritumoral edema (n =
      5) and necrosis (n = 1). SR induces a significant tumor remission accompanied by
      neurological improvement and, therefore, provides the opportunity for prolonged
      high quality survival. We conclude that radiosurgical treatment of multiple brain
      metastases leads to an equivalent rate of survival when compared to the historic
      experience of patients treated with whole brain radiotherapy. Patients presenting
      initially with a higher Karnofsky performance rating and without extracranial
      metastases had a median survival time of nine months. Each such case should
      therefore be evaluated based on these factors to determine an optimal treatment
      regimen.

PMID- 10421074
TI  - Systemic chemotherapy with vincristine, cyclophosphamide, doxorubicin and
      prednisolone following radiotherapy for primary central nervous system lymphoma:
      a phase II study.
AB  - We treated 23 patients with primary central nervous system lymphoma with a
      protocol of conventional radiation up to 55 +/- 5 Gy followed by 4 to 6 cycles of
      intravenous doxorubicin (30 mg/m2), vincristine (1 mg/m2) and cyclophosphamide
      (350 mg/m2), and oral prednisolone (8-30 mg/m2) (VEPA chemotherapy) repeated at 2
      week intervals. The median age of the 23 patients was 59 years, and the median
      World Health Organization performance status score was 2. Seventeen patients
      received 4 or more courses of the chemotherapy, but 6 received only 1 or 2
      courses for various reasons. The median survival time for all 23 patients was
      25.5 months and their 5-year survival rate was 23%. These values were 34 months
      and 32%, respectively, for the 17 patients who received 4-6 courses of
      chemotherapy. After treatment, decline in performance status unaccompanied with
      tumor recurrence was observed in 44% of the patients; the incidence was
      apparently higher in older than in younger patients. The survival results
      obtained with this combined radiochemotherapy regimen appear to be better than
      those reported in most previous studies of patients treated with radiation alone.
      Post-irradiation VEPA chemotherapy appears to be worthy of further evaluation.

PMID- 10421077
TI  - Postoperative radiotherapy for supratentorial malignant gliomas.
AB  - From January 1988 to December 1996, sixty-five patients with histologically
      confirmed supratentorial malignant gliomas were treated with postoperative
      radiation therapy in our department. They were subjected to this analysis
      according to different clinical and pathologic parameters. The overall 1-year, 2
      year survival rate was 57% and 23%, respectively. With univariate analysis, age,
      postoperative Karnofsky performance status, duration of symptoms, multiplicity of
      lesions and the extent of surgery were identified as significant prognostic
      factors. With multivariate analysis, postoperative Karnofsky performance status
      and the extent of surgery continued to show independent prognostic significance
      on overall survival.

PMID- 10421076
TI  - A phase II study of KRN8602(MX2), a novel morpholino anthracycline derivative, in
      patients with recurrent malignant glioma.
AB  - KRN8602(MX2) is a newly developed morpholino-anthracycline that has been found to
      cross the blood-brain barrier and be distributed in brain tissue after
      intravenous administration and to be effective against human glioma cells and the
      intracerebrally transplanted tumors in vivo. In order to confirm these promising
      preclinical observations clinically, we performed a phase II trial of KRN8602 in
      patients with recurrent malignant glioma. The 44 patients enrolled received at
      least 2 cycles of KRN8602 35 mg/m2/day at 3-4 week intervals by intravenous
      bolus. Of the 44 patients, 37 could be evaluated for response, and 39 for
      toxicity. One patient with anaplastic astrocytoma had a complete response (1/37,
      3%), and 2 patients with anaplastic astrocytoma and 1 with brain stem glioma had
      a partial response (3/37, 8%). The overall response rate was 11% (4/37). All
      patients who responded had received prior chemotherapy that included
      nitrosoureas. No response was observed in the patients with glioblastoma.
      Myelosuppression was moderately severe, with 72% of patients developing grade 3
      or 4 leukopenia. Severe nausea/vomiting was observed in 31% of the patients. No
      severe cardiotoxicity was observed. The results indicate that KRN8602 has modest
      activity against recurrent malignant glioma with relatively severe, but
      manageable toxicity. It seems to be worthwhile to further assess the efficacy and
      toxicity of KRN8602 against malignant glioma, which is generally less sensitive
      to chemotherapy.

PMID- 10421078
TI  - Racial/ethnic disparities in health: the interplay between discrimination and
      socioeconomic status.
AB  - In the past decade, racial/ethnic discrepancy in health status has drawn
      increased attention from academicians, policy makers and planners, service
      providers, and community advocates. While the field has witnessed a growth in
      research projects and intervention programs, the gap in health status among
      racial/ethnic groups persists, which suggests that future research should
      incorporate a focus on one neglected area, ie, the health implications of
      discrimination. Using the National Survey of Functional Health (N=1,659), a
      nationally representative sample of English-speaking persons 18 years of age and
      older living in non-institutional arrangements within the United States, we
      analyzed how self-perceived unfairness (discrimination due to racial identity or
      to low socioeconomic status [SES]) was linked to self-assessed health status. The
      study found that racial and class discrimination were rather pervasive in the
      United States. Experiences of discrimination tended to have a strong negative
      association with health and accounted for some racial/ethnic differences in
      health status. The study also revealed a complex relationship between experiences
      of discrimination and social class, suggesting that future research should focus
      on specifying the social distribution of discrimination and assessing its
      subsequent association with health.

PMID- 10421079
TI  - The association between acculturation and health practices among middle-aged and
      elderly Latinas.
AB  - OBJECTIVES: To examine the relationship between acculturation and five health
      practices, including cigarette smoking, alcohol consumption, exercise, obesity,
      and sleeping habits. METHODS: The study sample consisted of 573 Latinas, aged 46
      to 92 years. Participants were recruited from 17 publicly subsidized housing
      projects in Los Angeles, Calif. Health practices information was obtained through
      an interview. RESULTS: Regression analyses showed an interaction between age and
      acculturation: the effects of acculturation on health practices were stronger
      among Latinas aged 64 years and under than among their 65 to 74 year-old
      counterparts. Level of acculturation did not affect the likelihood of engaging in
      healthy practices for elderly women (aged 75 and over). CONCLUSIONS: The data
      indicate that acculturation negatively affects the health practices of middle
      aged Latinas, who are at a particularly critical age during which chronic
      diseases emerge. Intervention programs are needed to encourage adoption of
      healthy practices, particularly exercise and weight control, at an earlier stage
      in life.

PMID- 10421080
TI  - Secular trend of earlier onset of menarche with increasing obesity in black and
      white girls: the Bogalusa Heart Study.
AB  - Secular trends in onset of menarche and obesity were examined 14 years apart in
      two biracial (black-white) cohorts of girls aged 8 to 17 under study for
      cardiovascular risk. The first cohort (N=1,190, 64% white) was examined in 1978
      1979, the second (N=1,164, 57% white) in 1992-1994. The second cohort was heavier
      in terms of body weight and Rohrer index (weight/height3) than the first
      (P<0.001), except among black girls aged 12 to 13 years. Subscapular skinfold
      thickness increased in the second cohort of all ages (P<0.0001), while increases
      in triceps skinfold were less marked. The onset of menarche occurred at an
      earlier age in the second cohort compared with the first cohort (P<0.0001), both
      in black girls (11.4+/-1.3 vs 12.3+/-1.4 years) and white girls (11.5+/-1.3 vs
      12.3+/-1.3 years). Furthermore, twice as many girls in the second cohort had
      reached menarche by ages younger than 12 years (P<0.001). All of these obesity
      measures were significantly associated with the age of menarche in both cohorts
      (P<0.001) adjusting for height, race and age at examination. These results
      suggest that this secular trend toward increasing frequency of early onset of
      menarche may be the result of increasing obesity noted in girls of both races.
      Since increases in body fatness and related early onset of menarche are risk
      factors for disorders in adult life including cardiovascular disease and breast
      cancer, the secular trend in the increasing incidence of obesity throughout the
      United States is becoming a major public health problem.

PMID- 10421082
TI  - Cancer knowledge and misconceptions: a survey of immigrant Salvadorean women.
AB  - This study assessed cancer knowledge, beliefs, and awareness of signs, symptoms,
      and early detection methods in immigrant Salvadorean women in the Washington,
      D.C. metropolitan area (DCMA). A face-to-face survey sampled 843 females aged 20
      and above. Descriptive statistics were used to compute frequency of response for
      sociodemographic characteristics, beliefs, and awareness of signs, symptoms, and
      early detection methods. The sample's mean age was 34.5 years; 10% had no
      schooling, and 7.4% had more than a high school education. Sixty-six percent of
      the women worked full- or part-time; 16% had an annual income of $20,000 or more;
      and 26% reported having medical insurance. Thirty percent of the sample lacked
      knowledge of the etiology and spread of cancer. The statement, "Bumps on your
      body can cause cancer" was endorsed by 61.6%. Beliefs that "destiny cannot be
      changed" or "just about anything can cause cancer" were prevalent among 18.5%.
      "Cancer is a punishment from God" was believed by 10.9%. A general physical
      examination was the most frequent (82%) early detection method mentioned. The Pap
      test was identified by 24.2%, and mammography by 14%; 5.6% mentioned breast self
      examination. Similar to other Hispanics, immigrant Salvadorean women in DCMA
      demonstrated a lack of knowledge of cancer's signs and symptoms, and early
      detection methods of and beliefs about cancer. Educational programs designed
      specifically for immigrant Salvadorean women to increase their knowledge of
      cancer and prevention methods are essential.

PMID- 10421081
TI  - Prevalence of diabetes and impaired glucose tolerance in Nigerians, Jamaicans and
      US blacks.
AB  - The prevalence of type 2 diabetes, impaired glucose tolerance and associated risk
      factors were compared in sample surveys in Africa and the Caribbean with the
      Third National Health and Nutrition Survey (NHANES-III) from the United States. A
      total of 856 Nigerians, 1286 Jamaicans, and 1827 US blacks were included in the
      study. Body mass index (BMI) increased in a stepwise fashion across the three
      populations groups, ie, 23 kg/m2 in Nigerians, 26 kg/m2 in Jamaicans, and 28
      kg/m2 in US blacks. The corresponding age-adjusted prevalences of type 2 diabetes
      among persons aged 25-74, were 1%, 12%, 13%. Jamaican women were found to have
      the same prevalence of type 2 diabetes as US women (14 vs 13%, respectively);
      mean BMI was likewise very similar (28 kg/m2 in Jamaican and 29 kg/m2 in US
      women). BMI and waist-to-hip ratio were both associated with type 2 diabetes
      prevalence. Findings of this study confirm the marked gradient in type 2 diabetes
      risk among these genetically related populations and suggest that the blacks in
      the island nations of the Caribbean and the United States are at particularly
      high risk. Nigerians exhibited remarkably well-preserved glucose tolerance.
      Understanding the factors that limit the risk of type 2 diabetes in West Africa,
      beyond relative absence of obesity, would have considerable public health
      significance.

PMID- 10421083
TI  - Physical and psychosocial consequences of stroke in elderly Mexican Americans.
AB  - OBJECTIVE: The current study examines the psychosocial and physical predictors
      and consequences of stroke among elderly non-institutionalized Mexican Americans.
      DESIGN: A cross-sectional cohort study design was used. SETTING: The sampling
      frame included the Southwestern United States (Arizona, California, Colorado, New
      Mexico and Texas) where subjects were interviewed in their homes. PARTICIPANTS: A
      probability sample consisted of 3,050 Mexican Americans aged 65 or older. MAIN
      OUTCOME MEASURE: The main outcome measure was self-report of being diagnosed by a
      physician as having a stroke that required hospitalization. RESULTS: Those who
      ever had a stroke (N=159) were less likely to be able to perform activities of
      daily living than persons who never had a stroke (N=2,869). Rates of disability
      and prevalence of stroke appear to be higher in elderly Mexican Americans than in
      the general elderly population. Greater education and language acculturation were
      risk factors for having a stroke. CONCLUSIONS: The finding that Mexican Americans
      who are less acculturated are more healthy suggests that acculturation may
      increase morbidity and, potentially, mortality from stroke.

PMID- 10421084
TI  - The relation of central adiposity to components of the insulin resistance
      syndrome in a biracial US population sample.
AB  - The higher rates of type 2 diabetes mellitus, hypertension, and many others
      factors of the insulin resistant syndrome (IRS) often seen in African Americans
      compared to whites do not seem to be explained by differences in central obesity.
      Reasons for this may be due, in part, to the validity of the commonly used
      anthropometric surrogate of central adiposity. Recent findings have shown that
      waist circumference is a better surrogate of total body and visceral adipose
      tissue and is better correlated with CVD than the traditionally used
      anthropometric indexes of the body mass index or waist/hip ratios. In this study,
      waist circumference was employed to determine the association between central
      adiposity and components of the insulin resistance syndrome in blacks (N=1963)
      and whites (N=4894) from the US national population-based samples. Sex-specific
      correlation coefficients were used to estimate the association between waist
      circumference and factors of the IRS. Multiple linear regression analyses were
      used to determine racial differences in waist circumference and the independent
      association of waist circumference to some known factors of IRS adjusting for
      age, BMI, alcohol use, and smoking. Waist circumference was positively correlated
      with plasma glucose, DBP, SBP, LDL cholesterol, fasting insulin, serum
      triglyceride, total cholesterol and total cholesterol/HDL ratio in black and
      white men and women (P<0.01). In both biracial groups, waist circumference was
      significantly associated with increases in glucose, DBP, LDL cholesterol, total
      cholesterol, triglyceride and fasting insulin levels controlling for age, BMI,
      and behavioral risk factors, such as alcohol use and smoking (P<0.05). Our data
      shows that central adiposity assessed with waist girth did not wholly explain the
      higher prevalence of IRS components often seen among blacks. The results of this
      study reinforce the need to encourage the use of waist measure as a public health
      tool in screening for CVD risks.

PMID- 10421086
TI  - Risk for alcohol and drug abuse among ethnically diverse female recipients of
      public assistance.
AB  - OBJECTIVE: The present pilot study was conducted to examine the importance of
      hypothesized psychosocial risk factors in explaining substance abuse among female
      welfare recipients. DESIGN: The study consisted of a cross-sectional design where
      participants completed a self-report questionnaire consisting of psychometrically
      appropriate measures. PARTICIPANTS: The sample consisted of an ethnically diverse
      group of 150 adult female recipients of public assistance. The average age of
      participants was 33 years. Overall, participants were Hawaiian/Part-Hawaiian or
      Caucasian, unmarried mothers with one or two children, unemployed with an annual
      family income of less than $5000. RESULTS: Increased alcohol and other drug (AOD)
      use and related problems were associated significantly with five predictors:
      mental health problems, aggressiveness, history of AOD problems in family, family
      cohesion, and lack of social support. CONCLUSIONS: The findings of this study
      generated a greater understanding of factors associated with increased AOD use
      and related problems that may be used to assist in the prevention and treatment
      of substance abuse problems among women living in poverty.

PMID- 10421085
TI  - Rubella outbreaks among Hispanics in North Carolina: lessons learned from a field
      investigation.
AB  - OBJECTIVE: To describe the epidemiology and the lessons learned from two
      simultaneous, but unrelated, outbreaks of rubella in North Carolina affecting
      mostly Hispanic immigrants of Mexican origin. METHODS: A case and contact
      investigation was conducted at industrial work sites and Hispanic communities
      between March 26 and June 15, 1996, using both structured and informal
      interviews. Active surveillance was conducted at hospitals, clinical
      laboratories, primary care physicians' offices, local health departments, and
      migrant health centers to identify additional cases. Rubella specific IgM testing
      was performed by the North Carolina State Laboratory to confirm cases.
      Vaccination clinics were conducted in communities and at work sites with a large
      Hispanic population in affected counties to reduce the number of susceptible
      persons. RESULTS: Eighty-three confirmed cases of rubella were reported: 75 cases
      from the first outbreak and 8 from the second. The mean age of cases from both
      outbreaks was 24 and 20 years, respectively. Only three cases occurred among
      children under five years of age, two in the first outbreak and one in the
      second. Seventy-one (95%) cases in the first outbreak and all 8 cases in the
      second outbreak were Hispanics; 21 (28%) cases from the first and 3 (37%) from
      the second outbreak were females, and a total of 65 (78%) cases from both
      outbreaks were industrial workers. Six women with confirmed cases in the first
      outbreak were pregnant at the time of exposure. No females cases were pregnant in
      the second outbreak. CONCLUSIONS: The outbreaks in North Carolina confirmed the
      persistent susceptibility to rubella in Hispanics and persons migrating from
      countries where the rubella vaccine is not used for routine childhood
      vaccination. The ultimate goal of rubella vaccination programs is to prevent
      fetal infection and congenital rubella syndrome (CRS). Thus, to eliminate rubella
      from the United States, efforts should focus on understanding new emerging
      patterns of disease transmission and vaccinating susceptible adults in settings
      where they congregate.

PMID- 10421087
TI  - Comparison of the prevalence of cardiovascular risk factors between Quebec and
      other Canadian provinces: the Canadian heart health surveys.
AB  - OBJECTIVE: To compare the prevalence of different cardiovascular (CVD) risk
      factors between Quebec, a Canadian Province with a population of mainly French
      descendants, and other Canadian provinces. DESIGN: Cross-sectional surveys in the
      ten Canadian provinces using stratified, two-stage, replicated probability
      samples from health insurance registries. PARTICIPANTS: A total of 2,353 Quebec
      residents and 20,776 other Canadians aged 18 to 74 years were surveyed.
      INTERVENTION: Standardized interviews and measurement of CVD risk factors.
      RESULTS: Compared with other provinces, Quebec had a higher prevalence of
      smoking, (32% vs 25%), dyslipidemia (48% vs 43%), a similarly sedentary lifestyle
      (37% vs 38%), a lower prevalence of hypertension (19% vs 23%) and body mass index
      > or =27 (28% vs 33%). Prevalence of two of the above risk factors was greater in
      Quebec (29%) than in the other provinces (25%). The difference in the prevalence
      of dyslipidemia between Quebec and the other provinces remained after
      stratification by body mass index and smoking status. Combination of risk factors
      differed between Quebec and the other provinces. CONCLUSIONS: Different genetic
      backgrounds, cultural influences occurring at different times among different age
      groups, as well as different trends in CVD risk factors and their interaction may
      explain why cross-sectional surveys cannot fully explain the differences in CVD
      mortality between ethnic groups. Given these differences in CVD risk factors
      between Quebec and other provinces, the relatively high level of all risk factors
      in Canada justifies increased focus on the Canadian Heart Health Initiative and
      attention to regional and ethnic differences when addressing CVD risk factors.

PMID- 10421088
TI  - Blood pressure and hypertension in rural and urban Sierra Leoneans.
AB  - OBJECTIVE: To determine the prevalence and awareness of hypertension and
      determinants of blood pressure in rural and urban Sierra Leoneans. METHOD: 598
      subjects from Freetown and 606 subjects from three villages in the northern
      province of Sierra Leone were selected for this study using multi-stage sampling.
      All were adults aged 15 years and over. Single blood pressure measurements were
      made after a minimum rest period of 10 minutes using a mercury sphygmomanometer.
      Korotkoffs phases I and V were used for systolic and diastolic blood pressures,
      respectively. Standard anthropometric measurements were made and a questionnaire
      used to collect information on demographic, dietary, and social factors,
      including consumption of tobacco products, alcohol, salt, palm oil, and kola
      nuts. Hypertension was diagnosed if systolic blood pressure(SBP) was equal or
      greater than 160 mm Hg and/or if diastolic blood pressure(DBP) was equal or
      greater than 95 mm Hg and/or there was a history of hypertensive therapy.
      RESULTS: The age-adjusted prevalence of hypertension in the Freetown and Port
      Loko subjects was 23.4% and 14.7%, respectively (P=0.006). Females had a higher
      prevalence in both populations. The most significant determinants of blood
      pressure were age, body mass index (BMI) and a low level of education. When
      adjusted for BMI and age, no significant difference in prevalence was observed
      between the two populations. The level of awareness was low, particularly in the
      rural areas. CONCLUSION: This survey confirms a high prevalence, and low level of
      awareness, of hypertension in rural and urban Sierra Leoneans.

PMID- 10421089
TI  - Cardiovascular reactivity in Zimbabwe.
AB  - OBJECTIVE: In this study, we examined the effects of residency and gender on
      cardiovascular reactivity to a speech stressor in 50 rural Zimbabweans (24 males,
      26 females) and 47 urban Zimbabweans (25 males and 22 females). METHODS:
      Participants were engaged in 4 periods: pre-task rest period, speech preparatory
      period, speaking task period, and the final recovery period. During each period,
      systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate
      (HR) were assessed. RESULTS: There was a significant interaction between area of
      residence and period for SBP and HR. Urban residents exhibited greater SBP and HR
      during the speaking phase of the speech task than did rural residents. However,
      rural residents displayed more exaggerated HR reactivity during the speech
      preparatory phase as compared to the urban residents. No gender differences were
      observed on blood pressure or heart rate reactivity. CONCLUSION: In conclusion,
      the more exaggerated SBP and HR reactivity to the speaking phase among urban
      residents as compared to rural residents may be influenced by factors associated
      with urbanization.

PMID- 10421090
TI  - Diet, diabetes, hypertension and blacks.
AB  - The prevalence of non insulin dependent diabetes mellitus (NIDDM) is increasing
      in all populations. This increment has been correlated with changes in lifestyle,
      particularly in eating behavior. Migration studies strongly suggest that NIDDM
      becomes more common when lifestyle factors interact with genetic susceptibility.
      Blacks have a higher prevalence of NIDDM than whites. In this study, it is
      suggested that persistent hyperglycemia mediated through the main carbohydrate of
      the Western diet-wheat, as white flour and whole wheat-in combination with
      partial or complete glucose 6-phosphate dehydrogenase deficiency are possible
      factors for the higher prevalence of NIDDM in blacks.

PMID- 10421091
TI  - Is being Hispanic a risk factor for non-insulin dependent diabetes mellitus
      (NIDDM)?
AB  - The objective of this paper is to critically assess the basis of the hypothesis
      that the ethnicity of Hispanics is by itself a risk factor of NIDDM. Showing that
      the definition of the term Hispanics has both operational and methodological
      problems, it is argued that in the United States, a group identified by this term
      is genetically, as well as culturally, heterogeneous. Further, the actual risk
      factors of NIDDM may simply co-vary with the ethnicity of Hispanics, so that the
      notion that this ethnicity is a stand-alone independent risk factor of NIDDM may
      be too simplistic.

PMID- 10421092
TI  - Obesity and other risk factors in children.
AB  - The prevalence of obesity has increased over the past three decades, in children
      as well as in adults. When obesity develops in the childhood years, excess
      adiposity generally continues into adult years, and adult obesity with childhood
      onset is frequently more severe. The health consequences of obesity in adults are
      well established, including greater rates of hypertension, non-insulin dependent
      diabetes mellitus, and heart disease. This paper will discuss the risk factors
      for these adult disorders that are detectable in obese children. Compared to
      normal weight children, obese children have higher blood pressure, higher plasma
      insulin levels, and a more atherogenic lipid pattern. Thus, the characteristic
      features of Syndrome X, or the insulin resistant syndrome, can be detected in
      obese children and adolescents. The vascular consequences of exposure to these
      metabolic risk factors beginning in childhood have yet to be completely
      determined. However, it is very likely that childhood obesity does contribute
      significantly to cardiovascular disease. For these reasons, greater efforts
      should be mounted to reduce the currently rising rates.

PMID- 10421093
TI  - Detection of viral antigen in placenta and fetus of cattle acutely infected with
      bovine viral diarrhea virus.
AB  - The reproductive organs and fetuses of seven Norwegian Red heifers were
      investigated for the presence of bovine viral diarrhea virus (BVDV) antigen
      during the time of initial transplacental transmission of the virus. The heifers
      were inoculated with a noncytopathogenic BVDV at day 85/86 of gestation and were
      slaughtered at day 7, 10, 14, 18, or 22 postinoculation (pi). Cryostat sections
      of uterus, ovaries, placentomes, intercotyledonary fetal membranes, and fetal
      organs were examined using immunohistochemical techniques. A double
      immunofluorescence technique was used to identify cells that showed staining with
      antibodies against the leukocyte common antigen CD45 or the intermediate filament
      vimentin and BVDV antigens. The earliest stage of infection at which BVDV antigen
      could be detected in the fetuses was 14 days pi. At this stage, BVDV antigen was
      detected in cells of mesenchymal origin in the lungs and in large cells that
      morphologically resembled immature megakaryocytes in the liver. In the
      intercotyledonary fetal membranes and in the placentomes, BVDV antigen was not
      detected until 18 and 22 days pi, respectively. BVDV antigen was not detected in
      maternal tissue from any of the heifers. The present results indicate that fetal
      infection with BVDV can take place without preceding or simultaneous high
      concentrations of BVDV in uterus or placenta of acutely infected heifers.

PMID- 10421094
TI  - The hamster model of intraperitoneal Burkholderia mallei (glanders).
AB  - Thirty-one female Syrian hamsters (Mesocricetus auratus) were inoculated
      intraperitoneally with a lethal dose of Burkholderia mallei (Budapest strain).
      Hamsters were killed postinoculation on days 0 through 6. Lesions were first
      noted in the spleens on postinoculation day 1, and in mediastinal and mesenteric
      lymph nodes, mediastinum, liver, and bone marrow on day 2. Lesions were present
      in the lung and submandibular lymph nodes on day 3, and in the brain on day 5.
      The characteristic histopathologic change was necrotizing pyogranulomatous
      inflammation, often with hemorrhage. Lesions indicative of impaired vascular
      perfusion, such as ischemia and infarction, were evident at the later time
      points. Pathologic changes generally increased in severity and distribution with
      time, and almost all tissues were ultimately affected. Our findings suggest that
      intraperitoneal bacteria were rapidly transported to mediastinal lymph nodes by
      transdiaphragmatic lymphatics and ultimately seeded other tissues hematogenously.
      The results of the study indicate that the Syrian hamster is a useful small
      animal model for glanders.

PMID- 10421095
TI  - Prognostic factors for treated canine malignant lymphoma.
AB  - The aim of this study was to investigate the prognostic importance of different
      clinical, immunohistologic and tumor proliferation characteristics in dogs with
      malignant lymphoma treated with chemotherapy. From 74 dogs with malignant
      lymphoma at least one enlarged peripheral lymph node was taken for biopsy before
      chemotherapy following a standardized protocol (vincristine, cyclophosphamide,
      prednisolone, doxorubicin, and L-asparaginase). The variables evaluated as
      prognostic factors were age, sex, and tumor stage, as well as histomorphologic
      grade (Kiel classification, Working Formulation), immunophenotype (using markers
      for CD3 and CD79a), and cell proliferation (Ki-67, proliferation cell nuclear
      antigen, mitotic index, and argyrophil nucleolar organizer regions [AgNORs]) in
      extirpated lymph nodes. All markers were used on routinely formalin-fixed,
      paraffin-embedded tissues. The AgNORs were assessed qualitatively, based on the
      AgNOR pattern distribution, and quantitatively using image analysis and routine
      counting. In both univariate and multivariate survival analyses, AgNORs were a
      valuable prognostic marker for the treatment of canine malignant lymphomas. Based
      on the results of the multivariate analysis longer survival time correlated with
      a B-cell type, a larger mean AgNOR area, a larger total AgNOR area, a shorter
      distance between two AgNORs, and a smaller AgNOR area to nucleus ratio. Longer
      disease-free survival time correlated with a smaller number of AgNORs per
      nucleus, a larger mean AgNOR area, a larger maximal AgNOR area, and a larger
      total AgNOR area. This study clearly demonstrates the additional benefit of the
      use of AgNORs in predicting treatment outcome in dogs with malignant lymphoma.

PMID- 10421096
TI  - Detection of an autoantibody from Pug dogs with necrotizing encephalitis (Pug dog
      encephalitis).
AB  - An autoantibody against canine brain tissue was detected in the cerebrospinal
      fluid (CSF) and serum of two Pug dogs (Nos. 1 and 2) by indirect
      immunofluorescence assay (IFA). Dog No. 1, a 2-year-old male, exhibited severe
      depression, ataxia, and generalized seizures and died 2 months after the onset of
      symptoms. Dog No. 2, a 9-month-old male, exhibited severe generalized seizures
      and died 17 months after the onset of symptoms. Histopathologic examination
      revealed a moderate to severe multifocal accumulation of lymphocytes, plasma
      cells, and a few neutrophils in both the gray and white matter of the cerebrum in
      dog No. 1. In dog No. 2, the cellular infiltrates were mild, but there was a
      severe, diffuse, and multifocal necrosis in the cerebral cortex with prominent
      astrocytosis. With the aid of IFA using fluorescein isothiocyanate-labeled
      antidog IgG goat serum and a confocal imaging system, specific reactions for
      glial cells were detected in the CSF of these Pug dogs but not in six canine
      control CSF samples. Double-labeling IFA using CSF from these Pug dogs and a
      rabbit antiserum against glial fibrillary acidic protein (GFAP) revealed that the
      autoantibody recognized GFAP-positive astrocytes and their cytoplasmic
      projections. By immunoblot analysis, the autoantibody from CSF of these Pug dogs
      recognized two common positive bands at 58 and 54 kd, which corresponded to the
      molecular mass of human GFAP. The role of this autoantibody for astrocytes is not
      yet clear. However, if the presence of the autoantibody is a specific feature of
      Pug dog encephalitis, it will be a useful clinical diagnostic marker and a key to
      the pathogenesis of this unique canine neurologic disease.

PMID- 10421097
TI  - Detection and localization of Mycoplasma hyopneumoniae DNA in lungs from
      naturally infected pigs by in situ hybridization using a digoxigenin-labeled
      probe.
AB  - Mycoplasma hyopneumoniae DNA was detected in 20 naturally infected pigs by in
      situ hybridization using a nonradioactive digoxigenin-labeled DNA probe. A 520
      base-pair DNA probe targeting a reiterative sequence of the M. hyopneumoniae
      genome was generated by the polymerase chain reaction. All 20 pigs infected with
      M. hyopneumoniae had distinct and positive hybridization signals without
      background staining. A strong hybridization signal was detected mainly in the
      luminal surface of bronchial and bronchiolar lining epithelial cells, whereas no
      hybridization signal was seen in the cytoplasm of bronchial and bronchiolar
      lining epithelial cells. When hybridization signal was detected in the luminal
      surface of bronchial and bronchiolar lining epithelial cells, a given bronchus or
      bronchiole had peribronchiolar lymphoid hyperplastic tissues. Hybridization
      signals were not seen in the peribronchiolar lymphoid hyperplastic tissues. A
      less intense signal was detected in the interstitial and alveolar macrophages
      randomly scattered in the thickened alveolar septa and spaces. Hybridization
      signal was rarely detected in the type I pneumocytes. The in situ hybridization
      technique developed in this study was useful for detection of M. hyopneumoniae
      nucleic acids in tissues taken from naturally infected piglets and may be a
      valuable technique for studying the pathogenesis of M. hyopneumoniae infection.

PMID- 10421098
TI  - Electron microscopic and immunohistochemical localization of Marek's disease (MD)
      herpesvirus particles in MD skin lymphomas.
AB  - Skin lymphomas induced in 11 specific-pathogen-free chickens by inoculation at 1
      day of age with Marek's disease virus (MDV) were biopsied weekly and examined by
      electron microscopy and immunohistochemistry. In the sequentially biopsied
      lymphomas, immature MDV particles (abortive replication) were found only in the
      nuclei of necrotic lymphoblasts within necrotizing neoplasms. The necrotizing
      lymphomas were observed in two of the 11 experimental birds and were associated
      with prominent vascular endothelial cell injury, including fibrinoid necrosis of
      blood vessels. Nonnecrotizing lymphomas biopsied sequentially from the 11
      experimental birds did not contain virus particles of any kind in the
      lymphoblasts and had no distinct vascular lesions. Immunohistochemically, MDV
      early antigen (pp38), but not late antigens (glycoproteins B and C), was detected
      only in the necrotizing lymphomas. These findings indicate that abortive MDV
      replication mainly occurred in necrotic lymphoblasts, which might have been
      induced by ischemia.

PMID- 10421099
TI  - Pathological and immunological findings of athymic nude and congenic wild type
      BALB/c mice experimentally infected with Neospora caninum.
AB  - Neospora is a cyst-forming coccidian parasite that causes abortions and
      neuromuscular disorders in a wide variety of mammals. Japanese bovine isolate
      JPA1 was inoculated intraperitoneally into BALB/c nu/ nu (athymic nude) and
      BALB/c (congenic wild type) female mice to examine the distribution of parasites
      and resistance mechanisms to Neospora infection. All the athymic nude mice died
      within 28 days after intraperitoneal injection of 2 x 10(5) JPA1 tachyzoites,
      whereas all the congenic wild type mice survived without exhibiting any clinical
      signs. Tachyzoites were identified in the uterus and pancreas and later spread to
      many other organs. Most tachyzoites identified in the necrotic foci were
      localized in the epithelium of the venules and capillaries. Nude mice developed
      high level of serum interferon-gamma and interleukin-6 as infection proceeded.
      Inflammatory response to Neospora infection might be mediated by Th1-type
      dependent cellular immunity.

PMID- 10421100
TI  - Novel feline autoimmune blistering disease resembling bullous pemphigoid in
      humans: IgG autoantibodies target the NC16A ectodomain of type XVII collagen
      (BP180/BPAG2).
AB  - In humans and dogs, bullous pemphigoid (BP) is an autoimmune blistering disease
      associated with the production of basement membrane autoantibodies that target
      the 180-kd type XVII collagen (BP180, BPAG2) and/or the 230-kd plakin epidermal
      isoform BPAG1e (BP230). In two adult cats, an acquired dermatosis and stomatitis
      was diagnosed as BP subsequent to the fulfillment of the following criteria: 1)
      presence of cutaneous vesicles, erosions, and ulcers; 2) histologic demonstration
      of subepidermal vesiculation with inflammatory cells, including eosinophils; 3)
      in vivo deposition of IgG autoantibodies at the epidermal basement membrane zone;
      and 4) serum IgG autoantibodies targeting a 180-kd epidermal protein identified
      as type XVII collagen. In both cats, the antigenic epitopes targeted by IgG
      autoantibodies were shown to be situated in the NC16A ectodomain of type XVII
      collagen, a situation similar to that of humans and dogs with BP. Feline BP
      therefore can be considered a clinical, histopathologic, and immunologic
      homologue of BP in humans and dogs.

PMID- 10421102
TI  - Double aortic arch in a Siamese cat.
AB  - A double aortic arch is described in an 8-week-old female Siamese cat. In this
      case a vascular ring anomaly consistent with a double aortic arch is described in
      a cat. Stridor and dysphagia were noted in the cat. Radiography showed an
      esophageal dilation, with constriction at the fifth intercostal space. At
      necropsy, the esophagus and trachea were constricted at the base of the heart.
      The cause of the constriction of both the esophagus and trachea was a vascular
      ring formed by well-developed right and left aortic arches. The ascending aorta
      divided into two asymmetrical arches. The right aortic arch was larger than the
      left. The origin of the major arteries from the aortic arches were anomalous.

PMID- 10421101
TI  - Disseminated Rhodococcus equi infection in two goats.
AB  - Rhodococcus equi infection was diagnosed in two goats from the same herd. At
      necropsy, numerous caseating granulomas were disseminated throughout the liver,
      lungs, abdominal lymph nodes, medulla of right humerus, and the right fifth rib
      of goat No. 1, and the liver of goat No. 2. Histopathologic examination confirmed
      the presence of multiple caseating granulomas in these organs. Numerous gram
      positive and Giemsa-positive coccobacilli were identified within the cytoplasm of
      macrophages. Aerobic bacterial cultures of the liver and lung from both goats
      yielded a pure growth of R. equi. R. equi antigens were immunohistochemically
      identified in caseating granulomas from both goats. However, the 15- to 17-kd
      virulence antigens of R. equi were not detected, suggesting possible infection by
      an avirulent strain of this organism.

PMID- 10421103
TI  - Thyroid C-cell carcinoma with amyloid in a red fox (Vulpes vulpes schrenchki).
AB  - An amyloid-producing medullary thyroid carcinoma (MTC) in a red fox (Vulpes
      vulpes schrenchki) bred in a zoo was examined using histopathologic and
      immunohistochemical techniques. The neoplastic cells had an ill-defined
      cytoplasmic membrane and abundant, finely granular eosinophilic cytoplasm,
      containing numerous argyrophilic granules. The neoplastic tissues were divided
      into various sizes by a vascular connective stroma, which was partly
      fibrovascular with broad areas of hyalinization containing varied amounts of
      amyloid. Immunohistochemically, neoplastic cells showed reactivity to anti
      calcitonin, neuron-specific enolase, somatostatin, and keratin antibodies.
      However, amyloid in the stroma did not show immunoreactivity to the antibodies
      used. Histologic and immunohistochemical features of MTC in the present animal
      were analogous to those of the C-cell carcinoma derived from thyroid C cells
      (parafollicular cells) reported in humans and dogs.

PMID- 10421104
TI  - Nocardia nova causing pulmonary nocardiosis of black crakes (Limnocorax
      flavirostra).
AB  - Natural nocardial infection has been reported in many different species including
      mammals and fish, but reports in birds remain uncommon. Eight juvenile Black
      Crakes (Limnocoraxflavirostra) died unexpectedly at the Basle Zoo. Necropsy
      revealed disseminated white, firm nodules, 1-3 mm in diameter, throughout the
      lung parenchyma. Histologically, the lungs contained multiple, often confluent
      granulomas with central necrosis. Delicate, gram-positive, 0.5- to 1.0-microm
      wide, branching, occasionally beaded, filamentous organisms were visible in
      necrotic centers. These organisms were acid fast when stained with Fite-Faraco.
      No histologic lesions were seen in other organs. Nocardia nova was isolated from
      liver, spleen, kidney, and lung. Granulomatous and necrotizing nocardial
      pneumonia with agonal septicemia was diagnosed, suggesting an aerogenous
      infection. To our knowledge, this is the first reported epizootic outbreak of
      nocardiosis in birds, which is additionally unusual because it was caused by N.
      nova.

PMID- 10421105
TI  - Necrotizing mycotic vasculitis with cerebral infarction caused by Aspergillus
      niger in a horse with acute typholocolitis.
AB  - An 18-year-old Morgan mare was presented to the Veterinary Medical Teaching
      Hospital, University of Illinois, with a 10-day history of watery diarrhea,
      depression, and dysphagia. On admission, the animal was severely dehydrated,
      depressed, and unable to swallow and had no clinical signs of diarrhea. The
      respiratory and heart rate and body temperature were within normal limits.
      Following fluid therapy, the mare developed severe watery diarrhea and continued
      to be depressed, incoordinated, and dysphagic. The animal died on the fourth day
      after admission and was sent to the Laboratories of Veterinary Diagnostic
      Medicine for necropsy. Gross postmortem findings were consistent with an acute
      cerebral infarction in the right cerebral hemisphere, an acute necrotizing
      typhlocolitis, multifocal petechial and ecchymotic hemorrhages, enlarged and
      congested pars intermedia of the pituitary gland, and marked bilateral
      adrenocortical hyperplasia with multifocal areas of necrosis and hemorrhage.
      Histologic evaluation of the affected brain demonstrated an area of coagulative
      necrosis of the gray matter, with hemorrhage, vasculitis, and thrombosis. There
      were many fungal hyphae 3.5-6.0 microm, pale basophilic, septate, and
      occasionally branching at 45 degrees present in the arterial walls and throughout
      the necrotic tissue. Immunohistochemical analysis revealed Aspergillus niger as
      the etiologic agent responsible for the mycotic vasculitis and infarction in the
      brain. Bacteria culture and immunohistochemical staining of the colon and cecum
      failed to demonstrate specific pathogens.

PMID- 10421106
TI  - Thoracic surgical clinical trials: Y2K and beyond.

PMID- 10421107
TI  - Intermittent perfusion protects the brain during deep hypothermic circulatory
      arrest.
AB  - BACKGROUND: Deep hypothermic circulatory arrest (DHCA) has been shown to cause
      impairment in recovery of cerebral blood flow (CBF) and cerebral metabolism
      (CMRO2) proportional to the duration of the DHCA period. This effect on CMRO2 may
      be a marker for brain injury, because CMRO2 recovers normally after
      cardiopulmonary bypass (CPB) when DHCA is not used. The aim of this study was to
      investigate the effects of intermittent perfusion during DHCA on the recovery of
      CMRO2 after CPB and to correlate these findings with electron microscopy (EM) of
      the cerebral microcirculatory bed. METHODS: Fifteen neonatal piglets were placed
      on CPB and cooled to 18 degrees C. Each animal then underwent either: (1) 60
      minute continuous CPB (control), (2) 60 minute uninterrupted DHCA (UI-DHCA), or
      (3) 60 minute DHCA with intermittent perfusion (1 minute every 15 minutes) (I
      DHCA). All animals were then rewarmed and weaned from CPB. Measurements of CBF
      and CMRO2 were taken before and after CPB. A further 9 animals underwent CPB
      without DHCA (2 animals) or with DHCA (7 animals), under various conditions of
      arterial blood gas management, intermittent perfusion, and reperfusion time.
      RESULTS: UI-DHCA resulted in significant impairment to recovery of CMRO2 after
      CPB (p < 0.05). Regardless of the blood gas strategy used, the EM after UI-DHCA
      revealed extensive damage characterized by perivascular intracellular and
      organelle edema, and vascular collapse. I-DHCA, on the other hand, produced a
      pattern of normal CMRO2 recovery identical to controls, and the EM was normal for
      both these groups. CONCLUSIONS: Intermittent perfusion during DHCA is clinically
      practical and results in normal cerebral metabolic and ultrastructural recovery.
      Furthermore, the correlation between brain structure and CMRO2 suggests that
      monitoring CMRO2 during the operation may be an outstanding way to investigate
      new strategies for neuroprotection designed to reduce cerebral damage in children
      undergoing correction of congenital cardiac defects.

PMID- 10421108
TI  - Coronary bypass and carotid endarterectomy: does a combined approach increase
      risk? A metaanalysis.
AB  - BACKGROUND: Patients with concomitant carotid and coronary artery disease present
      a surgical dilemma. We compared the stroke and mortality rates for combined
      coronary artery bypass grafting and carotid endarterectomy in which both
      procedures were performed under a single anesthetic, versus a staged approach, in
      which coronary artery bypass grafting and carotid endarterectomy were performed
      separately. METHODS: A computerized MEDLINE search supplemented with a manual
      bibliographic review was performed for all peer-reviewed English language
      publications that contained both combined and staged coronary artery bypass
      grafting/carotid endarterectomy patient cohorts. Outcomes of interest were
      stroke, death, and stroke or death; aggregation of outcome rates was performed
      with the Mantel-Haenszel method. RESULTS: Sixteen studies were identified with a
      total of 844 combined patients and 920 staged patients. None of the studies was
      completely randomized. The combined surgical group had a higher prevalence of
      unstable angina; the two groups had a similar prevalence of symptomatic carotid
      disease and severe carotid stenosis. Meta-analysis revealed a significantly
      increased risk of the composite end point, stroke or death, for patients
      undergoing combined procedures (relative risk 1.49; 95% confidence interval 1.03
      2.15; p = 0.034). There was also a trend toward increased risk during combined
      procedures for the end points of stroke (relative risk 1.50; 95% confidence
      interval 0.97-2.32; p = 0.068) and death (relative risk 1.55; 95% confidence
      interval 0.94-2.53; p = 0.084) considered separately. The crude event rates for
      stroke were 6.0% versus 3.2% for combined versus staged procedure, 4.7% versus
      2.9% for death, and 9.5% versus 5.7% for stroke or death. Two of the 16
      individual studies showed a statistically significant increase in the risk of
      stroke or death for combined procedure (p < 0.05). CONCLUSIONS: Combined coronary
      artery bypass grafting and carotid endarterectomy may be associated with a higher
      risk of stroke or death than staged procedures. A randomized trial needs to be
      performed to determine the optimal management of patients with concomitant
      carotid and coronary artery disease.

PMID- 10421110
TI  - Hemodynamic effects of carbon dioxide insufflation under single-lung ventilation
      during thoracoscopy.
AB  - BACKGROUND: The hemodynamic effects of carbon dioxide insufflation under single
      lung ventilation were studied in 22 consecutive thoracoscopic harvests of the
      left internal mammary artery, which was used for minimally invasive coronary
      artery bypass grafting. METHODS: An electrocardiograph, arterial catheter, Swan
      Ganz catheter, and transesophageal echocardiograph were used to monitor seven
      hemodynamic variables. Baseline data were obtained during ventilation of both
      lungs and the measurements were repeated after the left lung was collapsed and at
      5 and 30 minutes after hemithorax insufflation with low-flow (2 to 3 L/minute)
      carbon dioxide gas was begun. The intrapleural pressure was maintained at 8 to 10
      mm Hg. RESULTS: Thoracoscopic harvest of the internal mammary artery was
      completed in all cases with a mean insufflation time of 44+/-12 minutes. There
      were no significant changes in the mean arterial pressure, heart rate, cardiac
      index, and left ventricular ejection fraction throughout the procedure, whereas
      the central venous pressure, mean pulmonary arterial pressure, and pulmonary
      capillary wedge pressure (p < 0.05 for each variable) during insufflation.
      CONCLUSIONS: Low-flow carbon dioxide insufflation into the left hemithorax with
      an intrapleural pressure of 8 to 10 mm Hg under selective right-lung ventilation
      does not compromise the human heart with normal to moderately depressed function
      and can be an efficacious adjunct in specific thoracoscopic procedures.

PMID- 10421109
TI  - Hyperdynamic circulation of arteriovenous fistula preconditions the heart and
      limits infarct size.
AB  - BACKGROUND: Chronic arteriovenous fistulae (AVF) create sustained hyperdynamic
      circulation. It is not known whether hyperdynamic circulation alters myocardial
      sensitivity to ischemia and reperfusion injury. We tested the hypothesis that AVF
      activate molecular responses that increase tolerance to infarction in dogs.
      METHODS: Twelve dogs were divided into two groups: 1) AVF group, where an AVF in
      the femoral region was done; and 2) sham-operated group (each n = 6). After 8
      weeks, left ventricular performance was determined from stroke work/end-diastolic
      length relationship. Myocardial biopsy was obtained to determine heat-shock
      protein 70 and adenosine triphosphate (ATP) pool. Left anterior descending
      coronary artery was occluded for 90 minutes at 37 degrees C, followed by 4 hours
      of reperfusion. Coronary blood flow was determined using different colored
      microspheres. RESULTS: The fistula group showed improvement of left ventricular
      performance (p = 0.03). The infarct size was significantly lower in the fistula
      group; it was 9.2+/-2.0% in the fistula group versus 28.4+/-5.2% in the sham
      group (p < 0.05). ATP depletion during ischemia was less in the fistula group (p
      = 0.02). Regional myocardial blood flow was significantly higher in the fistula
      group (p = 0.03). CONCLUSIONS: Peripheral AVF improve the left ventricular
      performance, and decrease infarct size and ATP depletion. This protective effect
      is caused by the development of collaterals in the coronary circulation without
      expression of heat-shock protein 70.

PMID- 10421111
TI  - Effects of hypothermic and normothermic cardiopulmonary bypass on brain
      oxygenation.
AB  - BACKGROUND: In this study, we assessed the effects of normothermia and
      hypothermia during cardiopulmonary bypass (CPB) both on internal jugular venous
      oxygen saturation (SjvO2) and the regional cerebral oxygenation state (rSO2)
      estimated by near infrared spectroscopy (NIRS). METHODS: Thirty patients
      scheduled for elective coronary artery bypass graft surgery (CABG) were randomly
      divided into two groups. Group 1 (n = 15) underwent surgery for normothermic (>
      35 degrees C) CPB, and group 2 (n = 15) underwent surgery for hypothermic (30
      degrees C) CPB, and alpha-stat regulation was applied. A 4.0-French fiberoptic
      oximetry oxygen saturation catheter was inserted into the right jugular bulb to
      continuously monitor the SjvO2 value. To estimate the rSO2 state, a
      spectrophotometer probe was attached to the mid-forehead. SjvO2 and rSO2 values
      were then collected simultaneously using a computer. RESULTS: Neither the
      cerebral desaturation time (duration during SjvO2 value below 50%), nor the ratio
      of the cerebral desaturation time to the total CPB time significantly differed
      (normothermic group: 18+/-6 min, 15+/-6%; hypothermic group: 17+/-6 min, 13+/-6%,
      respectively). The rSO2 value in the normothermic group decreased during the CPB
      period compared with the pre-CPB period. The rSO2 value in the hypothermic group
      did not change throughout the perioperative period. CONCLUSIONS: These findings
      suggest that near infrared spectroscopy might be sensitive enough to detect
      subtle changes in regional cerebral oxygenation.

PMID- 10421112
TI  - "I" ministernotomy for aortic valve replacement.
AB  - BACKGROUND: Minimally invasive surgical approaches have been applied recently in
      the management of valvular heart disease. In this report, we reviewed our
      preliminary experience of minimally invasive aortic valve replacement. METHODS:
      Eighteen patients were operated on by means of an "I" ministernotomy, and 16
      patients were operated on by means of a full median sternotomy during the same
      period. There was no difference between these two groups in term of age, sex, and
      preoperative left ventricular ejection fraction. In patients of the
      ministernotomy group, the operations were approached through an "I" median
      sternal split, from the second to the fifth intercostal space, 8 to 10 cm in
      length, with transverse division. Cardiopulmonary bypass was established through
      aorto-right atrial cannulation with aortic cross-clamping and antegrade or
      retrograde delivery of blood cardioplegia. RESULTS: Under direct vision, aortic
      valve replacement was performed successfully in patients of both groups. The
      duration of cardiopulmonary bypass time and aortic cross-clamp time was
      significantly longer in the ministernotomy group than in the full sternotomy
      group. However, the length of incision, duration of endotracheal intubation,
      intensive care unit stay, pain score, postoperative length of stay, and return to
      normal activity interval were significantly shorter and lower in patients of the
      ministernotomy group than in those of the full sternotomy group. All patients
      recovered from the operation rapidly. Follow-up was complete in all patients with
      no late complications. Echocardiographic examination showed good function of
      aortic prostheses. CONCLUSIONS: Our experience demonstrates that the "I"
      ministernotomy provides good exposure, reduced wound pain, enhanced recovery,
      shortened hospital stay, and good cosmetic healing. It may be a good alternative
      for surgical correction of aortic valve lesions.

PMID- 10421113
TI  - Cardiomyoplasty: the benefits of electrical prestimulation of the latissimus
      dorsi muscle in situ.
AB  - BACKGROUND: Ischemic damage in the latissimus dorsi muscle may limit the success
      of cardiomyoplasty. Electrical prestimulation of the muscle in situ is known to
      enhance thoracodorsal perfusion to the distal latissimus dorsi muscle immediately
      after grafting. In this study we asked whether prestimulation was also beneficial
      under typical postoperative conditions. METHODS: Ten sheep were randomly assigned
      to two equal groups. In one group the latissimus dorsi muscle was stimulated
      continuously in situ at 2 Hz for 2 weeks; in the other group the muscle was not
      stimulated. Regional blood flows in the muscle were determined sequentially (1)
      under baseline conditions, (2) immediately after surgical mobilization, handling,
      and reattachment at 80% of the resting length, and (3) after 5 days. RESULTS:
      Manipulation of the unstimulated muscle resulted in an acute global reduction in
      blood flow with no improvement after 5 days. The distal region was most severely
      affected (26.2%+/-4.2% of baseline blood flow). Electrical prestimulation
      significantly reduced regional blood flow under baseline conditions but rendered
      the whole muscle more resistant to the surgical manipulations; blood flow was
      significantly better-preserved immediately afterwards, and there was complete
      recovery to baseline levels after 5 days. CONCLUSIONS: Electrical prestimulation
      of the latissimus dorsi muscle in situ reduces the acute distal ischemia caused
      by surgical manipulations, and promotes subsequent recovery of blood flow to
      baseline levels after a few days. Use of a prestimulated graft may therefore
      improve the outcome of skeletal muscle cardiac assistance.

PMID- 10421114
TI  - Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and
      myocardial injury.
AB  - BACKGROUND: Proinflammatory cytokines play a key role in the inflammatory cascade
      after cardiopulmonary bypass and may induce cardiac dysfunction. We compared the
      production of cytokines and the degree of postoperative myocardial injury in
      patients with multivessel coronary artery disease undergoing coronary artery
      bypass grafting through median sternotomy with or without cardiopulmonary bypass.
      METHODS: Forty-four consecutive patients were studied. Patients were selected for
      off-pump coronary artery bypass grafting whenever complete revascularization was
      technically feasible. There were no differences between the two groups with
      respect to age, sex, symptoms, or functional class. Plasma levels of tumor
      necrosis factor-alpha, interleukin (IL)-6, IL-8, and IL-10 were measured before
      the operation, at the end of the procedure, and 2, 4, 8, 24, and 48 hours
      thereafter. Levels of the MB isoenzyme of creatine kinase and cardiac troponin-I
      were also measured after the operation. RESULTS: The number of grafts was 2+/-0.7
      in the off-pump group (n = 18) and 3+/-0.8 in the cardiopulmonary bypass group (n
      = 26). There were no deaths or major complications in either group. Levels of
      tumor necrosis factor-alpha were low in both groups. No significant intergroup
      differences were noted regarding serial IL-6 measurements. However, IL-8 and IL
      10 levels after the operation were lower in the off-pump group (IL-8, 4+/-1
      versus 38+/-12 pg/mL, p < 0.01; IL-10, 5+/-2 versus 191+/-33 pg/mL, p < 0.001).
      Whereas postoperative creatine kinase-MB values were similar in the two groups,
      cardiac troponin-I levels were significantly lower in the off-pump group (8
      hours, p < 0.005; 24 hours, p < 0.02, respectively). Moreover, cardiac troponin-I
      values 24 hours after operation correlated strongly with IL-8 levels (r = 0.61, p
      < 0.005), indicating that the degree of myocardial injury may be related to IL-8
      production. CONCLUSIONS: Compared with conventional coronary artery bypass
      grafting, coronary revascularization without cardiopulmonary bypass is associated
      with reduced cytokine responses and less myocardial injury.

PMID- 10421115
TI  - Influence of different autotransfusion devices on the quality of salvaged blood.
AB  - BACKGROUND: Cardiopulmonary bypass causes a systemic inflammatory response and
      impaired hemostasis. We investigated whether intraoperative blood salvage with
      the cardiotomy suction contributes to these alterations. Furthermore, an
      alternative autotransfusion device (Haemonetics cell-saving device) was examined.
      METHODS: In 10 patients, interleukin-6, interleukin-8, tumor necrosis factor
      alpha, thrombin-antithrombin complex, plasmin-antiplasmin complex, free
      hemoglobin, and the percentage of CD62+ thrombocytes were determined in the
      systemic circulation during cardiopulmonary bypass, in the cardiotomy suction
      tube, and in the blood from the cell-saving device. Additionally, bacterial
      contamination was examined. RESULTS: Median levels of interleukin-6 (52 versus 10
      microg/L; p = 0.005), interleukin-8 (26 versus 20 microg/L; p = 0.017), tumor
      necrosis factor-alpha (24 versus 1 microg/L; p = 0.005), thrombin-antithrombin
      complex (113 versus 43 microg/L; p = 0.005), plasmin-antiplasmin complex (566
      versus 489 microg/L; p = 0.022), and free hemoglobin (61 versus 30 mg/dL; p =
      0.005) were higher in the cardiotomy suction tube compared with the systemic
      circulation. After processing the blood from the cell-saving device, interleukin
      8, thrombin-antithrombin complex, and free hemoglobin remained above reference
      range, and in 90% of the cases bacterial contamination was observed. CONCLUSIONS:
      Cardiotomy suction additionally contributes to the release of proinflammatory
      cytokines, activation of coagulation, and hemolysis. Because blood salvage with a
      Haemonetics cell-saving device led to normalization of some, but not all,
      parameters and bacterial contamination was common, the alternative use seems at
      least questionable.

PMID- 10421116
TI  - Midterm results of mitral valve repair with homemade annuloplasty rings.
AB  - BACKGROUND: There are many kinds of prosthetic mitral annuloplasty rings. We
      report results of our homemade annuloplasty rings. METHODS: Between January 1991
      and January 1998, 107 patients with mitral insufficiency underwent mitral valve
      repair with homemade annuloplasty rings. Mitral insufficiency was due to
      rheumatic disease in 71 patients, degenerative disease in 29, endocarditis in 3,
      and congenital heart disease in 4 patients. A total of 67 patients were in New
      York Heart Association functional class III or IV preoperatively. Midterm follow
      up was available in 106 patients from 1 month to 6.6 years (average, 2.4 years).
      RESULTS: Operative mortality was 0.9%. At 5 years, survival and event-free
      survival rates were 92% and 80%, and freedom from thromboembolic complications
      and reoperation were 95% and 93%, respectively. Ninety-three patients (97%) were
      in New York Heart Association functional class I, 3 patients (3%) were in class
      II. Echocardiography at follow-up showed satisfactory mitral valve function.
      CONCLUSIONS: Midterm results of homemade annuloplasty rings are comparable to
      commercial ones.

PMID- 10421117
TI  - Potassium-channel opener cardioplegia is superior to St. Thomas' solution in the
      intact animal.
AB  - BACKGROUND: In isolated hearts, the potassium-channel opener pinacidil is an
      effective cardioplegic agent. This study tested the hypothesis that pinacidil is
      superior to St. Thomas' solution in the more clinically relevant intact animal.
      METHODS: Sixteen pigs were placed on full cardiopulmonary bypass. Hearts
      underwent 2 hours of global ischemia (10 degrees to 15 degrees C). Either St.
      Thomas' or 100 micromol/L pinacidil was administered every 20 minutes (10 mL/kg).
      Preischemic and postreperfusion slopes of the preload-recruitable stroke work
      relationship were determined. Changes in myocardial adenine nucleotide levels and
      cellular ultrastructure were analyzed. RESULTS: Pinacidil cardioplegia resulted
      in an insignificant change in the slope of the preload-recruitable stroke work
      relationship (40.6+/-2.1 mm Hg/mm before ischemia and 36.5+/-3.7 mm Hg/mm after
      ischemia; p = 0.466). In contrast, St. Thomas' solution resulted in a significant
      decrease in the slope after reperfusion (34.3+/-5.5 mm Hg/mm and 13.5+/-2.3 mm
      Hg/mm; p = 0.003). Adenine nucleotide levels, myocardial tissue water, and
      ultrastructural changes were similar between groups. CONCLUSIONS: Pinacidil
      ameliorated myocardial stunning associated with traditional hyperkalemic
      cardioplegia without causing significant differences in cellular metabolism.

PMID- 10421119
TI  - Reduction of intimal and medial thickening in sheathed vein grafts.
AB  - BACKGROUND: Arterial pressures are described as an important factor in the
      development of graft degeneration and in reduced patency rate in vein bypass
      grafts. Sheathing of the graft with a pressure resistant mesh tubing might slow
      down this development. METHODS: Saphenous vein grafts were implanted into the
      carotid arteries of five pigs in order to evaluate the influence on myointimal
      hyperplasia of a compliant Phynox mesh tubing (a wrought Cobalt-Chromium-Nickel
      Molybdenum-Iron Alloy), which surrounded autologous vein grafts that were exposed
      to arterial pressure. Each pig was operated on using a sheathed vein graft
      (biocompound-graft, a hybrid vascular prosthesis) on one side and an untreated
      saphenous vein on the other. RESULTS: After 4 weeks intimal hyperplastic changes
      were found in all histological sections. The wall thickness (medial and intimal
      layer) varied from 351 microm to 432 microm in the biocompound-graft and from 391
      microm to 1196 microm in the native vein grafts (p < 0.05, n = 5). Severe
      myocytial and fibroblast proliferation was only found in the control grafts.
      Cellularity of the medial layer differed at sites of maximal cellular density and
      ranged from 11 to 12 cells in the biocompound-graft and from 17 to 18 cells per
      counting field in the native vein grafts (p < 0.05, n = 5). CONCLUSIONS: External
      support of vein grafts reduces intimal and medial layer proliferation. The
      findings of this study are in accordance with the results reported by other
      research groups.

PMID- 10421118
TI  - Incidence of atrial flutter/fibrillation in adults with atrial septal defect
      before and after surgery.
AB  - BACKGROUND: There is controversy about the benefit of surgical repair for atrial
      septal defect in adults, especially its effect on the incidence of
      supraventricular dysrhythmias, atrial flutter and fibrillation. We studied their
      incidence before and after operation. METHODS: We examined surface and 24-hour
      Holter electrocardiograms before, early (between 3 and 7 days), and late (more
      than 6 months) after operation, performed at age 42.2 years (range, 18.5 to 74.9
      years), in 211 adults with atrial septal defect. Patients were arbitrarily
      divided into three groups: age 18 to 40 years (n = 101), age 40 to 60 years (n =
      83), and age more than 60 years (n = 27). All consecutive patients operated on
      between January 1988 and December 1996 and having a pulmonary to systemic flow
      ratio of 1.5:1 or greater were included in this study. RESULTS: The age of
      patients without arrhythmias before or after atrial septal defect closure (39+/
      13 years) was significantly lower than that of patients with flutter (54+/-12
      years) or fibrillation (59+/-8 years). The incidence of atrial flutter was
      influenced by surgical repair as atrial flutter converted to sinus rhythm late
      after operation in 10 of 18 patients. However, there was no change in the
      incidence of atrial fibrillation before (n = 28) and after (n = 21) operation.
      CONCLUSIONS: Our data show that surgical correction of atrial septal defect leads
      to regression of the incidence of atrial flutter but not fibrillation. Thus,
      surgical repair of atrial septal defect to abolish supraventricular
      tachyarrhythmias in adults is warranted, but in patients with fibrillation, it
      may have to be combined with a Maze operation in the future.

PMID- 10421120
TI  - Inhibitory effect of methylene blue-induced photooxidation on intimal thickening
      of vein graft.
AB  - BACKGROUND: We have previously speculated that methylene blue-induced
      photooxidation of adventitial surface for 5 minutes can completely inhibit the
      intimal and medial growth of surgically prepared saphenous vein in vitro. In this
      study, inhibitory effect of methylene blue-induced photooxidation on intimal
      thickening of vein graft in vivo was investigated. METHODS: Jugular vein grafts
      were photooxidized in 0.01% methylene blue solution for 5 minutes, and interposed
      into arterial circulation for 4 weeks in rabbits. Vein grafts were studied by
      morphometry and immunohistochemistry. RESULTS: The intimal thickening of
      photooxidized vein grafts were suppressed significantly compared with those in
      the nonphotooxidized group. Proliferated cell nuclear antigen (PCNA) index (total
      PCNA-positive cells/total cell count x 100%) of vein graft was significantly
      higher in the nonphotooxidized group than those in the photooxidized group.
      CONCLUSIONS: Methylene blue-induced photooxidation is effective in the inhibition
      of intimal thickening of vein graft interposed in the arterial circulation for 4
      weeks in vivo.

PMID- 10421121
TI  - Cerebral microemboli during cardiopulmonary bypass: increased emboli during
      perfusionist interventions.
AB  - BACKGROUND: Microemboli to the cerebral circulation occur during cardiopulmonary
      bypass (CPB) and can contribute to postoperative neurologic dysfunction. Cerebral
      microemboli are known to occur during specific surgical interventions, but the
      source of a large proportion of emboli remains unexplained. We investigated
      whether interventions by the perfusionist could account for the appearance of
      cerebral microemboli. METHODS: Transcranial Doppler ultrasonography was used to
      continuously monitor the middle cerebral artery of 18 patients undergoing
      coronary artery bypass grafting. The CPB circuit consisted of a softshell venous
      reservoir, a hollow-fiber membrane oxygenator, and a 32-microm arterial filter.
      The mean embolic rate was calculated for three time periods: (1) during surgical
      interventions (aortic cannulation and decannulation, cross-clamp application and
      removal, CPB start and end, and start of cardiac ejection); (2) during
      perfusionist interventions (blood sampling and drug administration into the
      venous reservoir); and (3) during baseline (all other time periods during CPB).
      RESULTS: Microemboli were detected in all patients (mean +/- standard deviation,
      207+/-142 per patient, median, 132). The number of emboli per minute was
      significantly (p < 0.001) higher during perfusionist interventions (6.9+/-4.5)
      than during surgical interventions (1.5+/-1.5) or during baseline (0.4+/-0.5).
      Drug administration resulted in a higher embolic rate than blood sampling.
      CONCLUSIONS: Interventions by the perfusionist account for a large proportion of
      previously unexplained cerebral microemboli during CPB. These emboli likely
      represent air bubbles that are not eliminated by the arterial line filter.
      Although further studies of additional types of CPB circuits are required, we
      believe that air in the venous reservoir should be avoided whenever possible to
      minimize the risk of neurologic injury.

PMID- 10421122
TI  - Off-pump revascularization of the circumflex artery: technical aspect and short
      term results.
AB  - BACKGROUND: Beating heart surgery is a technique currently used for
      revascularization of the anterior and inferior territory. However,
      revascularization of the circumflex artery is more problematic. With a specific
      apparatus and surgical technique, we have extended the use of beating heart
      surgery to more than 90% of patients with multivessel disease, including those
      necessitating circumflex artery revascularization. METHODS: Between October 1996
      and November 1997, 140 patients underwent beating heart surgery by the same
      surgeon (R.C.). Among these patients, 111 required reconstruction of the
      circumflex artery territory and were followed up prospectively. They represent
      the cohort of patients presented in this study. There were 90 men and 21 women
      averaging 64+/-9.9 years of age. Mean left ventricular ejection fraction was
      55%+/-13.7%, and a significant left main coronary artery disease was present in
      27% of the patients. Five patients had prior coronary revascularization. RESULTS:
      An average of 3.1+/-0.1 grafts/patient were performed. Complete revascularization
      was achieved in 95%. Only 1 patient needed conversion to cardiopulmonary bypass
      because of spontaneous ascending aortic dissection. Perioperative and
      postoperative bleeding were 446+/-245 mL and 644+/-442 mL, respectively.
      Homologous transfusions were required in 40% of the patients. Myocardial
      infarction occurred in 2.7% and operative mortality in 0.7% (1 patient). Average
      hospital stay was 6.6+/-3.1 days, and no patient exhibited early recurrence of
      angina. Early coronary angiograms (first 8 patients) demonstrated a 100% patency
      with 95% freedom from significant stenosis. CONCLUSIONS: Complete coronary artery
      revascularization is feasible on the beating heart without the assistance of
      cardiopulmonary bypass with a low morbidity and mortality and excellent early
      angiographic results. Long-term follow-ups are needed to substantiate the
      potential long-term benefits of this technique.

PMID- 10421123
TI  - Fixed left ventricular outflow tract obstruction in presumed hypertrophic
      obstructive cardiomyopathy: implications for therapy.
AB  - BACKGROUND: A subset of patients presenting with a presumed diagnosis of
      hypertrophic obstructive cardiomyopathy (HOCM) have a fixed left ventricular
      outflow tract (LVOT) obstruction. Recognition of this pathophysiologic
      abnormality is important in choosing therapy. METHODS: Of patients referred for
      treatment of HOCM, 4 had fixed LVOT obstruction. Clinical and echocardiographic
      data and surgical findings were reviewed. RESULTS: In the 4 patients with
      clinical features consistent with HOCM or HOCM-like conditions, echocardiography
      showed fixed LVOT obstruction with an early-peaking LVOT Doppler signal or
      absence of severe systolic anterior motion of the mitral valve. The causes of
      fixed obstruction included accessory mitral tissue with associated fibrous ring
      (1 patient), fixed subaortic tunnel stenosis (2 patients), and a discreet
      subaortic ridge (1 patient). After surgical relief of the fixed LVOT obstruction,
      all patients had relief of the ventricular outflow tract gradient. CONCLUSIONS:
      Not all patients with a presumed diagnosis of HOCM have isolated dynamic LVOT
      obstruction but may have isolated or additional fixed obstruction. Careful two
      dimensional and Doppler echocardiography are needed to identify this subset of
      patients who are best treated surgically.

PMID- 10421124
TI  - The spectrum of aortic complications after heart transplantation.
AB  - BACKGROUND: The connection between the donor and the recipient aorta is a
      potential source of early and late complications as a result of infection,
      compliance mismatch, and technical and hemodynamic factors. Moreover, the abrupt
      change in systolic pressure after heart transplantation involves the entire
      thoracic aorta in the risk of aneurysm formation. The aim of this study was to
      analyze the types of aortic complications encountered in our heart
      transplantation series and to discuss etiology, diagnostic approach, and modes of
      treatment. METHODS: Of the 442 patients having orthotopic heart transplantation
      and the 11 patients having heterotopic heart transplantation at our center, 9
      (2%) sustained complications involving the thoracic aorta. These 9 patients were
      divided into four groups according to the aortic disease: acute aortic rupture (2
      patients); infective pseudoaneurysm (3 patients); true aneurysm and dissection of
      native aorta (2 patients); and aortic dissection after heterotopic heart
      transplantation (2 patients). Surgical intervention was undertaken in 8. RESULTS:
      Five (83%) of 6 patients who underwent surgical treatment for noninfective
      complications survived the operation, and 4 are long-term survivors. One patient
      who underwent a Bentall procedure 71/2 years after heterotopic heart
      transplantation died in the perioperative period of low-output syndrome secondary
      to underestimated chronic rejection of the graft. One patient with pseudoaneurysm
      survives without surgical treatment but died several years later of cardiac
      arrest due to chronic rejection. Both patients operated on for evolving infective
      pseudoaneurysm died in the perioperative period. CONCLUSIONS: Infective
      pseudoaneurysms of the aortic anastomosis are associated with a significant
      mortality. In noninfective complications, an aggressive surgical approach offers
      good long-term results. The possibility of retransplantation in spite of complex
      surgical repair should be considered in the late follow-up after heart
      transplantation, due to the increasing incidence of chronic rejection.

PMID- 10421125
TI  - Recovery of LV contractility in man is enhanced by preischemic administration of
      enflurane.
AB  - BACKGROUND: Volatile anesthetics enhance postischemic functional recovery in
      animal models; this effect has not been investigated in man. METHODS: Twenty-two
      patients undergoing coronary surgery were randomized to enflurane administration
      (0.5% to 2%) for 5 minutes to reduce systolic blood pressure by 20% to 25%
      immediately before cardioplegic arrest. Left ventricular contractility was
      assessed by pressure-area relations using echocardiographic automated border
      detection during inflow occlusion before and after cardiopulmonary bypass. Linear
      regression analysis in 16 patients with paired data sets assessed changes in
      contractility. RESULTS: The relation was highly linear (r = 0.95+/-0.02). A
      change of slope versus the change in x intercept was detected in controls (mean
      difference, 16.1 mm Hg/cm2, 95% confidence limits, 5.9 to 26.3; 2.2 cm2, 95%
      confidence limits, -1.1 to 5.5; p = 0.007), which was different from those of
      treated patients (mean difference, 0.7 mm Hg/cm2, 95% confidence limits, -2.2 to
      3.7; -0.06 cm2, 95% confidence limits, -1.6 to 1.5; p > 0.2). Analysis of
      covariance in the overall group confirmed a significant effect of treatment (p =
      0.002). CONCLUSIONS: Enflurane enhances postischemic functional recovery,
      possibly through pharmacologic preconditioning of myocardium.

PMID- 10421126
TI  - Pressure delivery of AS-ICAM-1 ODN with LFA-1 mAb reduces reperfusion injury in
      cardiac allografts.
AB  - BACKGROUND: The goal of this study is to determine the effects of ex vivo
      hyperbaric pressure administration of AS-ICAM-1 ODN and systemic anti-LFA-1 mAb
      treatment on reperfusion injury in the rat cardiac allograft model. METHODS: A
      PVG to ACI functional heterotopic rat heart model was used. Donor hearts were
      treated with either saline or AS-ICAM-1 ODN and 5 atm of hyperbaric pressure for
      45 minutes. Anti-LFA-1 mAb was administered systemically prior to reperfusion of
      the allograft. Allografts were procured 24 hours after transplantation for
      assessment of reperfusion injury or 72 hours to determine ICAM-1 protein
      expression. RESULTS: Ex vivo administration of AS-ICAM-1 ODN led to decreases in
      percentage wet weight (77.1+/-0.83% vs 78.7+/-1.0%, p < 0.05), myeloperoxidase
      activity (3.14+/-0.72 vs 4.07+/-0.59, p < 0.05), contraction band necrosis (6.4+/
      6.47% vs 21.1+/-7.43%, p < 0.01), and ICAM-1 protein expression determined by
      immunohistochemistry compared to saline controls. Treatment with anti-LFA-1 mAb
      resulted in decreases in wet weight ratio (76.7+/-0.63%, p < 0.05 vs saline),
      myeloperoxidase activity (3.58+/-0.39, p < 0.05 vs saline) and contraction band
      necrosis (11.8+/-3.56%, p < 0.05 vs saline). Combination of pressure
      administration of AS-ICAM-1 ODN and anti-LFA-1 mAb decreased wet weight ratios
      (77.1+/-0.93%, p < 0.05 vs saline), myeloperoxidase activity (2.88+/-0.44, p <
      0.01 vs saline), and contraction band necrosis (6.75+/-5.67%, p < 0.05 vs
      saline). CONCLUSIONS: Ex vivo pressure mediated delivery of AS-ICAM-1 ODN
      decreases ICAM-1 protein expression, reduces reperfusion injury in rodent cardiac
      allografts, and is more effective than anti-LFA-1 mAb treatment alone.

PMID- 10421127
TI  - Are there vascular density gradients along myocardial laser channels?
AB  - BACKGROUND: Clinical studies suggest that transmyocardial laser revascularization
      may improve regional blood flow of the subendocardial layer. The vascular growth
      pattern of laser channels was analyzed. METHODS: Twenty pigs were randomized to
      undergo ligation of left marginal arteries (n = 5), to undergo transmyocardial
      laser revascularization of the left lateral wall (n = 5), to undergo both
      procedures (n = 5) or to a control group (n = 5). All the animals were sacrificed
      after 1 month. Computed morphometric analysis of vascular density of the involved
      area was expressed as number of vascular structures per square millimeter (+/-1
      standard deviation). RESULTS: The vascular density of the scar tissue of the
      laser channel was significantly increased in comparison with myocardial
      infarction alone: 49.6+/-12.8/mm2 versus 25.5+/-8.6/mm2 (p < 0.0001). The
      vascular densities of subendocardial and subepicardial channel areas were
      similar: 52.9+/-16.8/mm2 versus 46.3+/-13.6/mm2 (p = 0.41). The area immediately
      adjacent to the channels showed a vascular density similar to that of normal
      tissue: 6.02+/-1.7/mm2 versus 5.2+/-1.9/mm2 (p = 0.08). In the infarction +
      transmyocardial laser revascularization group, the channels were
      indistinguishable from infarction scar. CONCLUSIONS: Scars of transmyocardial
      laser revascularization channels exhibit an increased vascular density in
      comparison with scar tissue of myocardial infarction, which does not extend into
      their immediate vicinity. There was no vascular density gradient along the
      longitudinal axis of the channels.

PMID- 10421128
TI  - Multiple minimally invasive direct coronary artery bypass grafting for the
      complete revascularization of the left ventricle.
AB  - BACKGROUND: Single-vessel coronary artery bypass grafting of the left internal
      mammary artery to the left anterior descending coronary artery using a
      minithoracotomy has been shown to produce excellent results with a very low
      mortality rate. However, this procedure cannot be used in patients with double-
      or triple-vessel disease. Our goal was to develop a minimally invasive direct
      coronary artery bypass grafting without cardiopulmonary bypass for total
      revascularization of the left ventricle using multiple arterial grafts. METHODS:
      Limited lateral thoracotomy was performed in the fourth or fifth intercostal
      spaces, exposing the left anterior descending coronary artery and left circumflex
      coronary artery. Two or three arterial grafts were harvested. Revascularization
      of the left anterior descending coronary artery and the left circumflex coronary
      artery were performed in 20 patients without cardiopulmonary bypass through the
      limited lateral thoracotomy using complex performed arterial grafts. In 4
      patients, triple- and quadruple-vessel grafting was performed. RESULTS: The mean
      coronary cross-clamp time was 14.5+/-4.0 minutes for the left anterior descending
      coronary artery and 16.8+/-5.1 minutes for the left circumflex coronary artery.
      No early deaths or postoperative complications occurred. There were no late
      deaths or angina during the mean follow-up of 7.0 months (range, 2 to 22 months).
      Postoperative coronary angiography demonstrated widely patent grafts in all
      patients. CONCLUSIONS: Minimally invasive approach through a limited thoracotomy
      in multiple coronary artery bypass graftings are technically feasible and may be
      an alternative approach in the complete revascularization of the left ventricle.
      Mechanical immobilization of the coronary artery enhances early graft patency and
      is an essential part of this procedure.

PMID- 10421129
TI  - Increased incidence of antiphospholipid antibodies in left ventricular assist
      system recipients.
AB  - BACKGROUND: Antiphospholipid antibodies are associated with thrombosis. Because
      thromboembolic complications are often observed in recipients of a left
      ventricular assist system, we questioned if antiphospholipid antibodies were
      present in these patients. We report results from 10 patients who received a
      Novacor left ventricular assist system. METHODS: Serum samples were collected
      before left ventricular assist system placement and weekly thereafter until
      discharge after cardiac transplantation. Samples were tested for IgG, IgA, and
      IgM antiphosphatidylserine, anticardiolipin, and antiphosphatidylethanolamine
      using an enzyme-linked immunosorbent assay. RESULTS: Development of phospholipid
      binding plasma protein-dependent antiphospholipid antibodies was observed in 9 of
      the 10 patients. Before placement of the assist system, 3 patients had IgG
      antiphospholipid antibodies, and 9 were positive after placement. None had IgA
      antiphospholipid antibodies before placement, whereas 5 seroconverted for IgA
      after placement. One patient had IgM antiphospholipid antibodies before
      placement, and 1 additional patient became positive after placement. In patients
      with a preexisting antibody, increased titers and additional specificities
      developed subsequent to placement. CONCLUSIONS: All but 1 patient showed
      development of phospholipid-binding plasma protein-dependent antiphospholipid
      antibodies after left ventricular assist system placement.

PMID- 10421130
TI  - Morphology and histology of human and canine internal thoracic arteries.
AB  - BACKGROUND: We evaluated human and canine internal thoracic arteries (ITAs) to
      determine whether the latter is valid for studies relevant to clinical use.
      METHODS: We studied 19 human ITAs obtained from 1 female and 14 male victims of
      recent fatal accidents who had no evidence of cardiovascular disease (mean age =
      39+/-19 years; range = 15 to 79 years), and ITAs of 21 randomly-selected mongrel
      dogs of both sexes, weighing 18-40 kg (average = 24.3+/-5.7 kg). Specimens were
      fixed in formalin at a controlled pressure of 120 mm Hg, before extensive
      assessment that included intimal thickening, condition of the internal elastic
      lamina, and number of medial elastic lamellae and vasa vasorum. RESULTS: The
      canine morphology and histology were similar to the human ITAs, but there was no
      intimal hyperplasia, and the media and adventitia were thinner (ITAs of humans
      older than 40 years had significant increases in medial thickness, as well as in
      overall length). Morphologically and histologically, the left and right canine
      ITAs were almost completely the same. CONCLUSIONS: Canine ITAs are valid for
      bilateral comparative studies and are a useful tissue source and model for
      clinically-relevant experimental studies.

PMID- 10421131
TI  - Perventricular [correction of Periventricular] closure of ventricular septal
      defects without cardiopulmonary bypass.
AB  - BACKGROUND: Minimally invasive techniques are currently in use to close atrial
      and ventricular septal defects (VSD). Cardiopulmonary bypass (CPB) is instituted
      via the femoral vessels, which may cause injury to these vessels, especially in
      younger patients. The objectives of this study were to demonstrate the
      feasibility of perventricular [corrected] closure of muscular VSD (MVSD) and
      paramembranous VSD (PVSD) without CPB, using the Amplatz VSD device. METHODS:
      Five Yucatan pigs with naturally occurring PVSD (3- to 7-mm diameter) and 5 dogs
      with surgically created MVSD (6- to 14-mm diameter) were subjects of this study.
      The VSDs were closed intraoperatively with a 7-French delivery sheath inserted
      through the free wall of the right (n = 5) or left ventricle (n = 5), under
      epicardial echocardiogram guidance. The animals were followed for 3 months.
      RESULTS: There was no operative mortality. All MVSD closed after placement of the
      device. Closure rate of PVSD was 4 of 5 after placement and 3 of 5 after 3
      months. One pig developed aortic incompetence at the last follow-up. CONCLUSIONS:
      Perventricular closure of MVSD and PVSD is feasible. Avoidance of CPB can
      decrease recovery time, its complications, and trauma to the femoral vessels.

PMID- 10421133
TI  - Peritoneal dialysis after infant open heart surgery: observations in 27 patients.
AB  - BACKGROUND: The role of peritoneal dialysis (PD) in the management of infants
      after heart operation is under discussion. The aim of this study was to
      investigate the effect of PD on fluid balance and outcome. METHODS: Twenty-seven
      (33%) of 81 consecutive infants who underwent heart operation required PD. In 22
      patients (81%), PD was started prophylactically at the end of the operation. We
      recorded hemodynamic data and fluid balance. Patients experiencing acute renal
      failure (ARF) were compared with the remaining infants. RESULTS: Eleven of 81
      patients (14%) experienced ARF; 3 of them died (4% of all patients undergoing
      operation, 27% of those with ARF). Complications of PD, present in 33%, were
      transitory and of minor significance. Patients with ARF had decreased cardiac
      function compared with those without ARF but similar fluid balance. CONCLUSIONS:
      Peritoneal dialysis is an effective and safe method for the treatment of ARF in
      infants after open heart operation. As PD is helpful in modulating postoperative
      fluid balance, prophylactic use of PD can be recommended for selected patients
      who are at risk for low cardiac output syndrome.

PMID- 10421132
TI  - Repair of total anomalous pulmonary venous connection in infancy: experience from
      a developing country.
AB  - BACKGROUND: Corrective surgery for total anomalous pulmonary venous connection in
      infancy still carries high morbidity and mortality rates in developing countries.
      The present study evaluates the factors responsible for it. METHODS: Seventy
      three infants were operated on for total anomalous pulmonary venous connection
      from January 1987 through October 1997. Age ranged from 5 days to 12 months
      (mean, 3.9+/-0.24 months), with 10 (13.7%) patients younger than 1 month old.
      Patient weight varied from 2.0 to 5.2 kg (mean, 3.7+/-0.27 kg). Most (90.5%)
      patients were small for their ages (< 50th percentile). Anomalous connection was
      supracardiac in 42 (57.5%), cardiac in 18 (24.7%), infracardiac in 4 (5.5%), and
      mixed in 9 (12.3%) patients. Thirty-five patients had obstructed drainage.
      Preoperatively, 30 patients received antibiotic therapy for respiratory tract
      infection, 3 patients had balloon atrial septostomy, and 4 patients required
      mechanical ventilation. Fifteen patients (20.5%) were operated on as an emergency
      procedure. For supracardiac and infracardiac connections, a posterior approach
      was used for anastomosis. In cardiac type, coronary sinus was unroofed and the
      resultant defect along with atrial septal defect was closed with a single patch.
      RESULTS: The operative mortality rate was 23.3% (17 of 73). Pulmonary
      hypertensive crisis was the cause of death in 10 patients. Emergency operation
      and weight less than the 25th percentile were the important risk factors for
      operative mortality. Young age (< 1 month) and type of drainage did not affect
      the mortality. Follow-up ranged from 1 to 108 months (mean, 56.4+/-26.0 months).
      There were two late deaths. The actuarial survival (Kaplan Meier) at 9 years was
      72.87%+/-5.39%. CONCLUSION: Failure of early recognition, and thus delayed
      referral, accounted for onset of cardiac cachexia, respiratory tract infection,
      and severe pulmonary hypertension, which had a major effect on unfavorable
      outcome.

PMID- 10421134
TI  - Pulmonary vein stenosis with normal connection: associated cardiac abnormalities
      and variable outcome.
AB  - BACKGROUND: Pulmonary vein (PV) stenosis with anatomically normal connection is
      considered rare, unresponsive to treatment, progressive, and usually fatal.
      METHODS: We reviewed the records of 13 children with this diagnosis at our center
      since 1990. RESULTS: The number of stenosed PVs ranged from all PVs (n = 5);
      three PVs (n = 1); two PVs (n = 5); and one PV (n = 2). All patients had
      associated congenital cardiac abnormalities. Operation on PV stenosis was
      attempted in 7 patients (54%), 2 of whom have done well and 5 of whom have not.
      Two patients underwent heart transplantation for inoperable associated cardiac
      lesions. Significantly more patients with three or four stenosed PVs died (83%)
      compared with patients with one or two stenosed PVs (0%). CONCLUSIONS: (1)
      Pulmonary vein stenosis with anatomically normal connection is associated with
      other congenital cardiac abnormalities, (2) presentation and outcome are
      contingent on the number of stenosed PVs, (3) surgical palliation may be helpful
      in some patients, and (4) heart transplantation for inoperable associated cardiac
      abnormalities may be an option in patients with only one or two stenosed PVs.

PMID- 10421136
TI  - Placement of a permanent epicardial pacemaker in children using a subcostal
      approach.
AB  - BACKGROUND: Previously described techniques for epicardial pacemakers in children
      have generally included either a left thoracotomy approach or a subxiphoid
      incision. METHODS: We have recently used a single left subcostal incision for
      placement of both the epicardial electrodes and the pacemaker generator. We
      report our initial experience with this technique in 8 patients. The mean age was
      4 years (range, 4 months to 12 years). The smallest patient weighed 4,100 g.
      RESULTS: The subcostal approach was successful in 7 patients. One patient with a
      narrow costal margin operated on early in our experience required conversion to a
      thoracotomy. The pacing thresholds were uniformly excellent in all patients.
      There have been no associated complications. CONCLUSIONS: Placement of epicardial
      leads using a left subcostal incision avoids a thoracotomy, is simpler than a
      subxiphoid approach, and results in acceptable thresholds with minimal morbidity.

PMID- 10421135
TI  - Time course of endothelin-1 and adrenomedullin after the Fontan procedure.
AB  - BACKGROUND: The endothelium-derived vasoconstrictor endothelin (ET)-1 might
      contribute to the physiology of blood flow regulation and play a role in
      cardiovascular disease. Adrenomedullin (AM) is a potent vasodilator peptide that
      has major effects on cardiovascular function and has multiple biologic effects
      involved in cardiovascular homeostasis. Although pulmonary vascular resistance is
      known to be one of the most important factors to determine the indications for a
      Fontan procedure, the time course of the plasma cytokine before and after the
      Fontan procedure is not known. METHODS: Sixteen patients were divided into two
      groups, 8 patients (1 to 14 years) who had the Fontan procedure (atriopulmonary
      connection) and 8 age-matched controls who had biventricular repair with normal
      central venous pressure. Plasma ET-1 and adrenomedullin levels were measured in
      both groups immediately before cardiopulmonary bypass, immediately after
      cardiopulmonary bypass, and 6 and 24 hours after cardiopulmonary bypass. A
      thermodilution catheter was inserted during the operation, and mean pulmonary
      arterial pressure, pulmonary wedge pressure, and cardiac output were measured,
      and pulmonary vascular resistance was calculated at the same time points.
      Correlation between the plasma ET-1 levels and pulmonary vascular resistance data
      were obtained in the Fontan group. RESULTS: Plasma ET-1 levels in the Fontan
      group were elevated after operation and were higher than the control group at 6
      and 24 hours after cardiopulmonary bypass. Plasma adrenomedullin in the Fontan
      group was lower than in the control group at 6 and 24 hours after cardiopulmonary
      bypass. A significant positive correlation was obtained between the plasma ET-1
      and pulmonary vascular resistance data (r = 0.475). CONCLUSIONS: Imbalance
      between increased ET-1 and relatively decreased adrenomedullin after
      cardiopulmonary bypass in the Fontan procedure could contribute to dominant
      effects of ET-1, which might induce vasoconstriction after the Fontan procedure.
      ET-1 might play an important role in maintaining vasoconstriction after the
      Fontan procedure.

PMID- 10421137
TI  - Rejection with heart failure after pediatric cardiac transplantation.
AB  - BACKGROUND: Rejection associated with heart failure or death occurs after
      pediatric cardiac transplantation but has had limited analysis. METHODS: We
      analyzed the records of 96 consecutive pediatric cardiac transplant recipients
      who survived to hospital discharge. RESULTS: Eighteen patients (19%) experienced
      23 episodes of heart failure or death associated with rejection. Univariate
      analysis demonstrated black race (p = 0.041), transplantation after 12 months of
      age (p = 0.032), later time after transplantation (p = 0.037), rejection episode
      in the first year after transplantation (p = 0.001), and history of two or more
      rejection episodes (p < 0.001) were significantly associated with rejection seen
      with heart failure. A multivariate regression analysis identified two or more
      rejection episodes to be the only independent risk factor for the development of
      rejection with heart failure (odds ratio 20; 95% confidence limits, 4-104; p <
      0.0001). CONCLUSIONS: This study identified pediatric heart transplant recipients
      with a history of previous rejection episodes to be at a higher risk for
      symptomatic or fatal rejection. Further studies are needed to determine if
      intensification of maintenance immunosuppression, long-term rejection
      surveillance, or both in patients with multiple rejection episodes could reduce
      morbidity and mortality from rejection.

PMID- 10421138
TI  - Percutaneous extracorporeal arteriovenous CO2 removal for severe respiratory
      failure.
AB  - BACKGROUND: In previous animal studies, arteriovenous CO2 removal (AVCO2R)
      achieved significant reduction in ventilator pressures and improvement in the
      Pao2 to fraction of inspired oxygen ratio during severe respiratory failure. For
      our initial clinical experience, 5 patients were approved for treatment of severe
      respiratory failure and CO2 retention to evaluate the feasibility and safety of
      percutaneous AVCO2R. METHODS: Patients were anticoagulated with heparin
      (activated clotting time, 260 to 300 seconds), underwent percutaneous femoral
      cannulation (10F to 12F arterial and 12F to 15F venous catheters), and then were
      connected to a low-resistance, 2.5-m2 hollow-fiber oxygenator for 72 hours.
      RESULTS: Mean AVCO2R flow at 24, 48, and 72 hours was 837.4+/-73.9, 873+/-83.6,
      and 750+/-104.5 mL/min, respectively, with no vascular complications and no
      significant change in heart rate or mean arterial pressure. Removal of CO2
      plateaued at an AVCO2R flow of 1086 mL/min with 208 mL/min CO2 removed. Average
      CO2 transfer at 24 and 48 hours was 142+/-17 and 129+/-16 mL/min. Use of AVCO2R
      allowed a significant decrease in minute ventilation from 7.2+/-2.3 L/min at
      baseline to 3.4+/-0.8 L/min at 24 hours. CONCLUSIONS: All patients survived the
      experimental period without adverse sequelae. Percutaneous AVCO2R can achieve
      approximately 70% CO2 removal in adults with severe respiratory failure and CO2
      retention without hemodynamic compromise or instability.

PMID- 10421140
TI  - Minimally invasive lobectomy directed toward frail and high-risk patients: a case
      control study.
AB  - BACKGROUND: To compare minimally invasive video-assisted thoracic surgery (VATS)
      with thoracotomy, cases were matched from a pool of pulmonary lobectomies
      performed by one surgeon who offered VATS for patients with unfavorable risk
      factors. METHODS: A thoracotomy case was paired to each of 19 VATS cases by age,
      sex, lobe, side, and forced expiratory volume in 1 second. Eleven VATS and 5
      thoracotomy patients with severe activity impairments or reduced forced
      expiratory volume in 1 second (< 1.5 L or 50% predicted) were classified as
      higher risk than the others. RESULTS: Despite more high-risk cases, VATS yielded
      shorter hospitalizations (5.3+/-3.7 versus 12.2+/-11.1 days, p = 0.02), chest
      tube durations (4.0+/-2.8 versus 8.3+/-8.9 days, p = 0.06), and earlier returns
      to full preoperative activities (2.2+/-1.0 versus 3.6+/-1.0 months, p < 0.01).
      The VATS operations had no intraoperative complications and lasted 229+/-59
      minutes. Pain 3 weeks later was dramatically better for the VATS group (none or
      mild, 63% versus 6%; severe, 6% versus 63%; p < 0.01). Six complications or
      deaths occurred in each group and were related to forced expiratory volume in 1
      second, steroid usage, age, active smoking, and upper lobe resection (p < 0.01).
      Three VATS deaths occurred only in elderly, performance status 3 patients, with
      two caused by gastrointestinal-related problems masked by steroid use.
      CONCLUSIONS: A VATS lobectomy is less painful and may offer faster recovery for
      the frail or high-risk patient. Further study, particularly of its safety in
      severely activity-impaired patients, is warranted.

PMID- 10421139
TI  - Extent of chest wall invasion and survival in patients with lung cancer.
AB  - BACKGROUND: The long-term survival after operation of patients with lung cancer
      involving the chest wall is known to be related to regional nodal involvement and
      completeness of resection, but it is not known whether the depth of chest wall
      involvement or the type of resection (extrapleural or en bloc) affects either the
      rate of local recurrence or survival. METHODS: We retrospectively reviewed the
      Memorial Sloan-Kettering Cancer Center experience between 1974 and 1993 of 334
      patients undergoing surgical exploration for lung cancer involving the chest wall
      or parietal pleura. RESULTS: Of 334 patients who underwent exploration, 175 had
      apparently complete (R0) resections, 94 had incomplete (R1 or R2) resections, and
      65 underwent exploration without resection. The overall 5-year survival of R0
      patients was 32%, of R1 or R2 patients 4%, and of patients undergoing exploration
      without resection 0%. In the patients undergoing R0 resections, the extent of
      chest wall involvement was limited to the parietal pleura in 80 patients, and
      extended into the ribs or soft tissues in 95. The 5-year survival of R0 patients
      with T3 N0 M0 disease was 49%, T3 N1 M0 disease 27%, and T3 N2 M0 disease 15% (p
      < 0.0003). Independent of lymph node involvement, a survival advantage was
      observed in R0 patients if the chest wall involvement was limited to parietal
      pleura only, rather than invading into the chest wall musculature or ribs.
      CONCLUSIONS: Survival of patients with lung cancer invading the chest wall after
      resection with curative intent is highly dependent on the extent of nodal
      involvement and the completeness of resection, and much less so on the depth of
      chest wall invasion.

PMID- 10421141
TI  - Lung cancer staging and treatment in multidisciplinary trials: Cancer and
      Leukemia Group B cooperative group approach. Thoracic Surgeons of CALGB.
AB  - BACKGROUND: Aggressive routine surgical staging is necessary to evaluate patients
      to be treated on cooperative oncology protocols. Less than 1% of lung cancer
      patients in the United States are currently being treated in a clinical trial.
      Only with results from large, prospective trials can the questions of neoadjuvant
      and adjuvant therapy be answered. METHODS: An outline describing the schema of
      preoperative patient evaluation, surgical staging, and the definition of surgical
      staging and resection procedures appropriate for patients considered for
      cooperative group protocol is presented. Current Cancer and Leukemia Group B
      (CALGB) protocols are used in the discussion as examples of this systematic
      approach. CONCLUSIONS: Over the next few years, it will be important to enter the
      maximum number of patients into combined modality studies to identify the role of
      neoadjuvant treatment in lung cancer. Entry of patients into protocols will also
      make their pathological specimens and clinical information available for basic
      science research related to treatment results. Adherence to a logical sequence of
      patient evaluation as outlined above will optimize patient care, as well as
      accrual to cooperative group studies.

PMID- 10421142
TI  - Preoperative microbiologic screening and antibiotic prophylaxis in pulmonary
      resection operations.
AB  - BACKGROUND: Pulmonary resection is associated with considerable risk of
      infection, so antibiotic prophylaxis has become routine practice in pulmonary
      operations. We studied two standard flash antibiotic prophylaxis regimens and
      matched them to preoperatively acquired microorganisms. METHODS: In 120 patients
      scheduled for elective pulmonary resection, aspirates were taken separately from
      the left and the right lung using a double-lumen tube. Then the patients received
      either 1.5 g of sulbactam plus ampicillin (n = 60; group 1) or 2 g of cefazolin
      (n = 60; group 2) intravenously as a single-shot antibiotic prophylaxis according
      to a prospective randomized sequence. When bacteria were found in the aspirates,
      both antibiotics were tested for susceptibility. The patients were monitored for
      the first 3 postoperative days with regard to bronchopulmonary infections.
      RESULTS: Fifty-eight pathogens were isolated from the 120 patients. The cultured
      bacteria did not differ significantly between the two groups. In group 1 all
      found bacteria were susceptible to the used antibiotic prophylaxis, whereas in
      group 2 eight of the 25 found bacteria were not susceptible to antibiotic
      prophylaxis. Postoperatively, group 2 showed significantly more signs of
      bronchopulmonary infections than the group 1 and subsequently needed additional
      antibiotics more often. Intensive care unit stay was longer in patients of group
      2 and costs were higher for these patients. CONCLUSIONS: Preoperative
      microbiologic examination could be helpful to evaluate efficacy of the antibiotic
      prophylaxis regimen. Sulbactam plus ampicillin was significantly more effective
      than cefazolin.

PMID- 10421143
TI  - Management of descending necrotizing mediastinitis: an aggressive treatment for
      an aggressive disease.
AB  - BACKGROUND: Descending necrotizing mediastinitis represent a virulent form of
      mediastinal infection requiring prompt diagnosis and treatment to reduce the high
      mortality associated with this disease. Surgical management and a particularly
      optimal form of mediastinal drainage remain controversial. METHODS: Over a 10
      year period, 12 patients were treated at our institution. Surgical treatment
      consisted of 1 or several cervical drainages, associated with drainage of the
      mediastinum through a thoracic approach in 11 patients. Thoracic procedures
      included radical surgical debridement of the mediastinum with complete excision
      of the tissue necrosis, decortication, and pleural drainage with adequate
      placement of chest tubes for mediastinopleural irrigation. Transcervical
      mediastinal drainage was performed in only 1 patient. RESULTS: The outcome was
      favorable in 10 patients, 9 of whom had mediastinal drainage through thoracotomy.
      Two patients were initially drained through a minor thoracic approach; the first
      died of tracheal fistula and the second required new drainage through a
      thoracotomy. The patient who had transcervical mediastinal drainage without a
      thoracic approach presented an abscess limited to the anterior and superior
      mediastinum. In 3 patients, ongoing mediastinal sepsis required a second
      thoracotomy. CONCLUSION: A stepwise approach with transcervical mediastinal
      drainage is first justified in patients with very limited disease to the upper
      mediastinum. However, ongoing mediastinal sepsis requires new drainage, through a
      major thoracic approach, without delay. Extensive mediastinitis can not be
      adequately treated without mediastinal drainage including a thoracotomy. This
      aggressive surgical policy has allowed us to maintain a low mortality rate
      (16.5%) in a series of 12 patients with this highly lethal disease.

PMID- 10421144
TI  - Intraoperative ultrasound during thoracoscopic procedures for solitary pulmonary
      nodules.
AB  - BACKGROUND: Traditional nonoperative diagnostic approaches to the solitary
      pulmonary nodule (bronchoscopy and percutaneous needle biopsy) can be
      inconclusive. Video-assisted thoracic surgery (VATS) provides a minimally
      invasive way to diagnose and treat these nodules. We evaluated the use of a
      dedicated intraoperative ultrasound probe as an aid in localization of small
      pulmonary nodules during VATS. METHODS: An intraoperative ultrasound examination
      during a thoracoscopic procedure was performed on 18 patients to localize deep
      pulmonary nodules less than 20 mm in diameter without a definitive diagnosis by
      preoperative imaging techniques. RESULTS: In the 18 patients, all nodules were
      successfully identified by intraoperative ultrasound. A definitive pathologic
      diagnosis was obtained from thoracoscopic biopsy or resection. The final
      diagnoses were primary lung cancer in 5 patients, metastatic lesions in 4
      patients, hamartoma or chondroma in 4, granuloma in 3, and interstitial fibrosis
      in 2 patients. CONCLUSIONS: In our experience, intraoperative ultrasound can
      safely and effectively localize invisible or nonpalpable pulmonary nodules at the
      time of thoracoscopy. This may help surgeons perform minimally invasive lung
      resections with clear surgical margins.

PMID- 10421145
TI  - Mediastinoscopy in superior vena cava obstruction: analysis of 80 consecutive
      patients.
AB  - BACKGROUND: Prejudices against mediastinoscopy in superior vena cava obstruction
      still remain. Hereby we analyze risk/benefit balance in a large series of
      patients. METHODS: Eighty consecutive patients underwent cervical mediastinoscopy
      for caval obstruction, 51 after uncertain diagnosis obtained by lesser
      techniques, 17 after ineffective chemotherapy (n = 9) or radiotherapy (n = 8). In
      12 patients we immediately performed mediastinoscopy as an urgent procedure. In
      addition the examination was combined with left anterior mediastinotomy (n = 7)
      for staging purposes. RESULTS: No perioperative mortality was recorded. Five
      patients had significant bleeding, but only one required sternotomy. Definitive
      diagnosis was obtained in all patients: 50 lung cancer, 17 lymphoma, 7 invasive
      thymoma, 3 postradiation fibrosis, 2 metastatic lymph nodes from renal carcinoma,
      and 1 fibrosing mediastinitis. Specific therapy had excellent effects in 71
      patients, negligible in 7, and adverse in 2. Postmediastinoscopy brachial venous
      pressure had a mean significant decrease (p < 0.0001). Lung cancer was the sole
      variable significantly associated with unfavorable outcome (p < 0.0004).
      CONCLUSIONS: Mediastinoscopy should be routinely included after less invasive
      procedures in the diagnostic program because it is simple, low risk, and
      effective.

PMID- 10421146
TI  - Prognostic factors and results after surgical treatment of primary sarcomas of
      the lung.
AB  - BACKGROUND: Primary sarcoma of the lung is a rare tumor. Our purpose was to study
      survival after resection and prognostic factors, which have been rarely reported.
      METHODS: In a 24-year period, we performed 20 complete resections and three
      exploratory thoracotomies only for primary lung sarcomas. One patient declined
      operation. Mean diameter of resected tumors was 9 cm (range, 4 to 18 cm). There
      were eight stage IB, eight stage IIB, one stage IIIA, and three stage IIIB. Sixty
      percent of patients with resected tumors received adjuvant therapy. Age, sex,
      resectability, tumor size, histologic cell type, stage, and adjuvant therapy were
      analyzed as predictors of survival. RESULTS: No postoperative deaths occurred.
      All 4 patients who had no resection died within 15 months. The 5- and 10-year
      actuarial survival after complete resection was 48%. The 5- and 10-year actuarial
      survival in stage IB was 83%, whereas the 4-year actuarial survival in stage IIB
      was 30% (p < 0.05). Complete resection and stage of disease were the sole
      significant prognostic factors. CONCLUSIONS: Complete resection of primary
      sarcoma of the lung, when feasible, can achieve prolonged survival, although
      almost half of the patients died of metastasis within 2 years of operation.
      Adjuvant therapy needs to be investigated.

PMID- 10421147
TI  - Hepatic vein to the azygous vein anastomosis for pulmonary arteriovenous
      fistulae.
AB  - Pulmonary arteriovenous fistulae after a cavopulmonary anastomosis have been
      reported to resolve after hepatic venous return is included in the pulmonary
      circulation. We report a case in which the hepatic veins were redirected to the
      pulmonary circulation by connecting them directly to the azygous continuation of
      the inferior vena cava that had previously been connected to the right pulmonary
      artery. The patient's arterial saturation of 71% increased to 92% after 6 months.

PMID- 10421148
TI  - Minimally invasive direct coronary artery bypass using H graft for pleural
      symphysis.
AB  - In November 1995, video-assisted minimally invasive direct coronary artery bypass
      procedure, which is defined as a combination of the thoracoscopic internal
      mammary artery (IMA) harvest and direct coronary bypass grafting, was introduced
      for patients who need minimally invasive direct coronary artery bypass (MIDCAB)
      using IMA. In the thoracoscopic IMA harvest, the pleural adhesions or symphysis
      present an obstacle. We present a case where a redo patient who had complete
      pleural symphysis of left chest cavity precluded the thoracoscopic IMA harvest,
      and MIDCAB with the H graft procedure was performed.

PMID- 10421149
TI  - Bronchial obstruction after upper lobectomy: kinked bronchus relieved by
      stenting.
AB  - Post resectional kinking of the lower lobe bronchus caused obstructive symptoms
      in 2 patients following upper lobectomy. Exaggerated upward displacement of the
      remaining lower lobe seemed to be causative. Intrabronchial stenting relieved the
      obstruction in each case with satisfactory intermediate term results.

PMID- 10421150
TI  - Rapid onset of pulmonary arteriovenous malformations after cavopulmonary
      anastomosis.
AB  - The reported incidence of pulmonary arteriovenous malformations after superior
      cavopulmonary anastamosis in patients with heterotaxia syndrome is 18%-21%. The
      manifestation is usually in young children and the onset is gradual. We report an
      unusual case of pulmonary arteriovenous malformations developing within 72 hours
      of bilateral superior cavopulmonary anastamosis (Kawashima procedure) in an
      adolescent with heterotaxia syndrome.

PMID- 10421151
TI  - Pulmonary homograft repair of a mycotic aortic aneurysm in an infant.
AB  - Thoracic aortic aneurysms are rare in children and even more unusual in infants.
      The vast majority are mycotic. Frequently, those with mycotic thoracic aortic
      aneurysm do not survive and the diagnosis is made at autopsy. We present the case
      of an asymptomatic infant found to have a mycotic thoracic aortic aneurysm. The
      clinical course, diagnosis, and surgical repair of the aneurysm with pulmonary
      homograft are discussed.

PMID- 10421152
TI  - Pulmonary venous aneurysm presenting as a mediastinal mass in ischemic
      cardiomyopathy.
AB  - True aneurysm of the pulmonary vein is a rare lesion and may present as a
      mediastinal mass. Acquired aneurysm of the right superior pulmonary vein
      presenting as a middle mediastinal mass in a patient with ischemic cardiomyopathy
      associated with severe mitral regurgitation and dilated left atrium is described.
      Though the natural history of this lesion is uncertain, it may progressively
      enlarge and become symptomatic. Presence of this lesion in this patient with
      cardiomyopathy may require a modification of surgical technique at cardiac
      transplantation or surgical resection of an aneurysm without cardiopulmonary
      bypass.

PMID- 10421153
TI  - Noninvasive methods of diagnosing thoracic splenosis.
AB  - Thoracic splenosis is a rare condition resulting from concomitant rupture of the
      spleen and left hemidiaphragm, with autotransplantation of splenic tissue into
      the left hemithorax. It is usually an incidental finding on chest plain film or
      computed tomogram and is rarely diagnosed without biopsy or operation. A history
      of old splenic trauma and findings of left-sided, pleural-based nodules should
      indicate the diagnosis, which can be confirmed with nuclear medicine studies.

PMID- 10421154
TI  - Supraarterial decompression myotomy for myocardial bridging in a child.
AB  - A 10-year-old boy presented with a history of exertional chest pain. An
      electrocardiogram demonstrated an inferior apical myocardial infarction. Cardiac
      catheterization revealed myocardial bridging of the left anterior descending
      coronary artery with evidence of intramyocardial obstruction during systole. The
      patient underwent successful treatment with supraarterial decompression myotomy
      and remains symptom free at 1 year.

PMID- 10421155
TI  - Septal branch right ventricular fistula: a complication in coronary artery
      snaring.
AB  - We report a septal branch right ventricular fistula complicated after coronary
      snaring in coronary artery bypass surgery without aortic cross-clamping. The tip
      of the needle of the snaring suture is made blunt in order to decrease the risk
      of mechanical injury, but trauma to the septal branch is possible. This rare
      complication of snaring should be taken into consideration in performing aortic
      nonclamping coronary artery bypass surgery.

PMID- 10421156
TI  - Ascending aortic aneurysm associated with aortic insufficiency due to Takayasu's
      arteritis.
AB  - We report the case of a child with an ascending aortic aneurysm associated with
      aortic insufficiency. Histopathological examination of the ascending aorta and
      aortic valve showed findings in favor of Takayasu's arteritis, and subsequent
      evaluation of the entire aorta demonstrated the presence of multiple steno
      occlusive lesions. This unusual clinical problem in the young population is
      discussed with regard to other eventual pathologies that should be taken into
      account in the differential diagnosis.

PMID- 10421157
TI  - Pleural incarceration of the gastric graft after trans-hiatal esophagectomy.
AB  - We report on a 73-year-old man who underwent a transhiatal esophagectomy for a
      T2N1M0 adenocarcinoma of the distal esophagus and developed an incarcerated
      herniation of the gastric graft through a defect in the right mediastinal pleura.
      The patient experienced delayed gastric emptying postoperatively, which was
      initially suggested by barium swallow. The gastric herniation was unidentified by
      early postoperative swallowing studies and endoscopies. After diagnosis by a
      later computed tomographic scan and barium study, the herniation was reduced by
      incising the mediastinal pleura from the diaphragm to the apex of the chest and
      by plication of the stomach longitudinally in order to reduce its intrathoracic
      diameter.

PMID- 10421158
TI  - Repeat syncopal attacks due to postsurgical right ventricular pseudoaneurysm.
AB  - Pseudoaneurysm of the right ventricular outflow tract is a rare lesion caused by
      disruption of the ventricular wall that allows the blood to leak into the
      surrounding space. It often complicates surgery involving right ventriculotomy
      and progressively increases in size, therefore causing airway compression,
      pulmonary perfusion asymmetry, thromboembolism, and rupture. We report on a
      patient who developed right ventricular pseudoaneurysm early after surgery for
      atrio-ventricular septal defect with tetralogy of Fallot and needed emergency
      surgical repair due to low cardiac output and repeat syncopal attacks.

PMID- 10421159
TI  - Cholelithoptysis and pleural empyema.
AB  - We report a case of delayed cholelithoptysis and pleural empyema caused by
      gallstone spillage at the time of laparoscopic cholecystecomy. An occult
      subphrenic abscess developed, and the patient became symptomatic only after trans
      diaphragmatic penetration occurred. This resulted in expectoration of bile,
      gallstones, and pus. Spontaneous decompression of the empyema occurred because of
      a peritoneo-pleuro-bronchial fistula. This is the first case of such managed
      nonoperatively and provides support for the importance of intraoperative
      retrieval of spilled gallstones at the time of laparoscopic cholecystectomy.

PMID- 10421160
TI  - Left ventricular outflow tract obstruction with mitral mechanical prosthesis.
AB  - Left ventricular outflow tract obstruction after mitral valve replacement may
      occur when the native mitral apparatus is preserved intact. Although it has
      usually been reported using bioprostheses, we present one case using a low
      profile mechanical prosthesis. The reduction of left ventricular dimensions and
      valvular redundancy contributed to this complication. We obtained definitive
      relief of left ventricular outflow tract obstruction by transaortic exposure and
      partial resection of the obstructing tissue with the help of video-assisted
      cardioscopy.

PMID- 10421161
TI  - Early valve failure after aortic valve-sparing root reconstruction.
AB  - Aortic valve-sparing root reconstructive surgery has been widely adopted to
      improve the patient's quality of life. We experienced a patient who required
      reoperation for progressive aortic regurgitation 17 months after the initial
      operation of valve-sparing root reconstruction with the reimplantation method in
      acute aortic dissection. In this study, we were concerned with valve durability
      because of the absence of sinuses of Valsalva in the new aortic root and the need
      for careful follow-up after this procedure.

PMID- 10421162
TI  - Use of the anterior mitral leaflet to reinforce the posterior mitral annulus
      after debridement of calcium.
AB  - In mitral valve surgery, preservation of continuity between the papillary
      muscles, chordae, and annulus is associated with preservation of left ventricular
      function and reduced risk of postoperative left ventricular rupture. However, at
      mitral valve replacement, extensive annulus and leaflet calcification can
      necessitate resection of the posterior mitral leaflet. We describe a technique in
      which the anterior mitral leaflet and its subvalvular apparatus are used to
      reinforce the posterior mitral annulus after extensive debridement of calcium
      along the same annulus.

PMID- 10421163
TI  - Intraoperative detection of embedded coronary arteries in MIDCAB using a color
      Doppler microprobe.
AB  - Intraoperative detection of deeply embedded coronary arteries is difficult,
      especially in minimally invasive coronary artery bypass grafts. This report
      describes an effective method to identify embedded coronary arteries by using a
      color Doppler microprobe. Five embedded left anterior descending coronary
      arteries were successfully identified by intraoperative ultrasonography. We
      believe that the color Doppler microprobe is helpful for surgeons in this
      difficult situation.

PMID- 10421164
TI  - Technique for heterotopic pig heart xenotransplantation in primates.
AB  - The primate is a commonly utilized model for the human immune response after
      heart transplantation. This report describes our experience with heterotopic
      abdominal transplantation of porcine hearts into primate recipients. Abdominal
      graft placement was surprisingly well tolerated, and we found this approach to be
      particularly useful in the setting of significant donor-recipient size mismatch.
      Continuous monitoring with an implantable monitoring system facilitated
      assessment of graft viability in awake recipients; progressive graft bradycardia
      and decreasing QRS amplitude were predictive of ensuing graft failure.

PMID- 10421165
TI  - Remnant omental transfer for the mediastinitis after coronary bypass surgery with
      right gastroepiploic artery.
AB  - A one-stage procedure for the treatment of mediastinitis after coronary bypass
      surgery utilizing the right gastroepiploic artery is described. This procedure
      consists of thorough debridement of mediastinal pus and necrotic tissue, excision
      of infected sternal bone, mediastinal irrigation, and immediate transfer of the
      "remnant" omental pedicle based on the "left" gastroepiploic artery without
      postoperative drainage or irrigation. Recently, this procedure was applied to our
      patients followed by excellent results.

PMID- 10421166
TI  - Fenestrated felt facilitates anastomotic stability and safety in "off-pump"
      coronary bypass.
AB  - Metal stabilizing devices used in beating heart surgery, although largely
      effective, occasionally slip or cause lacerations of epicardial veins or
      myocardium, resulting in blood loss that requires time-consuming corrective
      maneuvers. The use of a fenestrated felt as a cushion in conjunction with the
      stabilizers eliminates slipping and/or trauma, thus facilitating coronary
      anastomoses on the beating heart.

PMID- 10421167
TI  - A special adapted retractor for the mini-sternotomy approach.
AB  - Minimally invasive cardiac operations are now possible through different
      approaches. To provide the best exposure and sufficient space to manipulate the
      heart, a special adapted thoracic retractor has been developed for the
      ministernotomy approach. It is universally adjustable and provides excellent and
      consistent exposure especially below the incision edges. The retractor has the
      further advantage of a very low profile on the surgeon's side and at the cephalic
      and caudal extremes of the operative field, which permits the greatest possible
      access through a limited access. We have successfully used this retractor in more
      than 180 patients. A less invasive median sternotomy through a 6-9-cm incision
      has been our original approach.

PMID- 10421169
TI  - Pulmonary metastasectomy.

PMID- 10421168
TI  - Aprotinin in deep hypothermic circulatory arrest.
AB  - Early experience with aprotinin in deep hypothermic circulatory arrest (DHCA)
      raised alarm about hazards associated with its use. Based on what little is known
      about possible mechanistic interactions between hypothermia, stasis, and
      aprotinin, there is no evidence that aprotinin becomes unusually hazardous in
      DHCA. Excessive mortality and complication rates have only been reported in
      clinical series in which the adequacy of heparinization is questionable. Benefits
      associated with use of aprotinin in DHCA have been inconsistently demonstrated.
      The only prospective, randomized series showed significant reduction in blood
      loss and transfusion requirements. Use of aprotinin in DHCA should be based on
      the same considerations applied in other cardiothoracic procedures.

PMID- 10421170
TI  - As originally published in 1992: Aortic allografts: reconstruction of right
      ventricle-pulmonary artery continuity. Updated in 1999.

PMID- 10421171
TI  - Foreign bodies in the heart: surgical or medical therapy?

PMID- 10421173
TI  - Right-sided partial sternotomy for adult congenital heart disease.

PMID- 10421172
TI  - Anomalous origin of the right coronary artery from the pulmonary artery.

PMID- 10421174
TI  - Left superior vena cava in a distal arch aneurysm: could it be of any advantage?

PMID- 10421175
TI  - Lymphatic angiogenesis induced by transmyocardial laser revascularization.

PMID- 10421176
TI  - On the therapeutic value of patience.

PMID- 10421177
TI  - Coexistent coronary and cerebrovascular disease: a place for carotid stenting.

PMID- 10421178
TI  - Cardiopulmonary resuscitation in pediatric trauma patients: survival and
      functional outcome.
AB  - BACKGROUND: Although injury is the leading cause of cardiac arrests in children
      older than 1 year, few studies have examined the survival and functional outcome
      of cardiopulmonary resuscitation (CPR) in pediatric trauma patients. METHODS: A
      historical cohort of 957 trauma patients younger than 15 years who received CPR
      at the scene of injury or at the admitting hospital was constructed on the basis
      of the National Pediatric Trauma Registry. The rate of survival to discharge and
      factors related to survival were examined. Functional impairments were documented
      for surviving patients. RESULTS: The overall survival rate was 23.5%. With
      adjustment for the Injury Severity Score, the risk of fatality after CPR
      increased for children with systolic blood pressure below 60 mm Hg at admission
      (odds ratio [OR] 24.5, 95% confidence interval [CI] 8.6-69.3), for those who were
      comatose at admission (OR, 4.7; 95% CI, 1.9-11.6), for those with penetrating
      injury (OR, 4.4; 95% CI, 1.5-13.3), and for those with CPR initiated at the
      hospital (OR, 2.4; 95% CI, 1.5-3.9). Surviving patients stayed in hospitals for
      an average of 24.3 days; at discharge, 64% had at least one impairment in the
      functional activities of daily living. CONCLUSIONS: Survival outcome of CPR in
      pediatric trauma patients appears to be comparable to that reported in adults of
      mixed arrest causes. Future research needs to identify factors underlying the
      excess mortality associated with penetrating trauma.

PMID- 10421180
TI  - Incidence and impact of childhood and adolescent injuries: a population-based
      study.
AB  - BACKGROUND: The study of disabilities, use of health services, and absenteeism of
      parents among 0- to 17-year-old residents of Jerusalem (n = 432) hospitalized for
      unintentional injuries. METHODS: Telephone interviews with parents, 6 months
      after hospitalization. Disabilities among 4 to 17 year olds were measured by a 25
      item scale derived from the International Classification of Impairments,
      Disabilities, and Handicaps and by limitations of activities. RESULTS: Six months
      after the injury, limitations ranged from 8.3% (daily activities) to 19.4% (sport
      activities). About one in three presented at least one disability in the 25-item
      scale. All disabilities were present in higher proportions among adolescents. The
      more severe injuries whether to the head or other parts of the body presented
      higher percentages of disabilities. Burns and traffic crashes were associated
      with higher proportions of disabilities than other causes and with more frequent
      work absenteeism by their parents. CONCLUSION: A relatively large proportion of
      children remain with long-term disabilities irrespective of cause and body part
      injured. Because the sequelae of injuries is multifaceted, rehabilitation should
      include coordination between health and other services.

PMID- 10421179
TI  - Predictors of mortality in adult patients with blunt injuries in New York State:
      a comparison of the Trauma and Injury Severity Score (TRISS) and the
      International Classification of Disease, Ninth Revision-based Injury Severity
      Score (ICISS).
AB  - BACKGROUND: The purpose of this study was to determine the statistical model that
      best predicted mortality from blunt trauma using a contemporary population-based
      database. METHODS: 1994-1995 New York State Trauma Registry data for patients
      with blunt injuries were used to predict mortality using three statistical
      models: (1) the original Trauma and Injury Severity Score (TRISS) model based on
      Major Trauma Outcome Study data, (2) a new TRISS model whose coefficients were
      derived using New York data, and (3) the International Classification of Disease,
      Ninth Revision-based Injury Severity Score (ICISS) with predicted survival values
      obtained from the Agency for Health Care Policy and Research's Health Care
      Utilization Project. The models were compared with respect to discrimination
      (using the C statistic) and calibration (using the Hosmer-Lemeshow [H-L]
      statistic). In addition, the models were tested to see how well they predicted
      outcomes for each of the three mechanisms of blunt injury. RESULTS: The ICISS
      model had a significantly higher C statistic (0.878) and a better H-L statistic
      (29.38) for predicting mortality for all adult patients with blunt injuries. The
      original TRISS model had very poor calibration (H-L = 687.38). None of the three
      models predicted mortality accurately for victims of motor vehicle crashes or
      victims of low falls. When separate models were developed for all motor vehicle
      crashes, low falls, and other blunt injuries, the ICISS and New York TRISS models
      both fit well, although the calibration was marginal in most cases. The ICISS
      model had a statistically significantly higher C statistic for other blunt
      injuries and for motor vehicle crashes. The New York TRISS model had better
      calibration for low falls. CONCLUSIONS: The ICISS has promise as an alternative
      to TRISS, but many more comparative studies need to be undertaken using updated
      TRISS coefficients. Models should also be developed for mechanisms of injury, not
      just for blunt and penetrating injuries.

PMID- 10421181
TI  - Sphincteroplasty as an adjunct in penetrating duodenal trauma.

PMID- 10421182
TI  - Calf-thigh sequential pneumatic compression compared with plantar venous
      pneumatic compression to prevent deep-vein thrombosis after non-lower extremity
      trauma.
AB  - OBJECTIVE: To compare the effectiveness of calf-thigh sequential pneumatic
      compression devices with the effectiveness of plantar venous intermittent
      pneumatic compression devices in prevention of venous thrombosis after major
      trauma. SUBJECTS AND METHODS: We evaluated 181 consecutive patients after major
      trauma without lower extremity injuries that precluded the use of pneumatic
      compression devices. We randomly assigned 149 patients to either calf-thigh
      sequential pneumatic compression or plantar venous pneumatic compression. After
      blinding the observers to the method of prophylaxis against deep-vein thrombosis,
      we performed bilateral compression ultrasonography on or before day 8 after
      randomization. RESULTS: Among 149 randomized patients, 62 who received calf-thigh
      sequential pneumatic compression and 62 who received plantar venous intermittent
      pneumatic compression devices completed the trial. Thirteen patients randomized
      to plantar venous intermittent pneumatic compression (21.0%) and 4 patients
      randomized to calf-thigh sequential pneumatic compression (6.5%) had deep-vein
      thrombosis (p = 0.009). Seven of 13 patients with deep-vein thrombosis after
      prophylaxis with plantar venous intermittent pneumatic compression had bilateral
      deep-vein thromboses, whereas all 4 patients with deep-vein thrombosis after
      prophylaxis with calf-thigh sequential pneumatic compression had unilateral deep
      vein thrombosis. CONCLUSION: Calf-thigh sequential pneumatic compression prevents
      deep-vein thrombosis more effectively than plantar venous intermittent pneumatic
      compression after major trauma without lower extremity injuries.

PMID- 10421183
TI  - Severe head injury in children: impact of risk factors on outcome.
AB  - BACKGROUND: Outcome after severe head injury has been shown in some studies to be
      more favorable in children than in adults. Mortality rates reported range between
      20% and 40% for children. Only contradicting data are available regarding the
      impact of trauma modalities on long-term outcome, or the relative influence of
      head fractures, intracranial hemorrhages, and brain edema on survival or
      neurologic sequelae in children. METHODS: A retrospective study in a tertiary
      care facility of long-term outcome of children after severe head injury, and
      analysis of risk factors for poor outcome. All children up to 16 years of age
      with severe head injury (Glasgow Coma Scale [GCS] score < or = 8), which have
      been treated in the pediatric intensive care unit from 1977 until 1994 in a
      single institution. RESULTS: A total of 150 children with severe head injury (GCS
      score < or = 8) were treated, 92 of them (61.3%) had traffic-related injuries.
      The median age was 6.6 years (SD +/- 3.6). There were 96 boys (64%) and 54 girls
      (36%). Sixty-five children (43.3%) had skull fractures, 87 patients (58.0%)
      developed an intracranial hemorrhage, and 79 patients (52.7%) developed a diffuse
      brain swelling/edema visible in computed tomographic scans within 72 hours after
      trauma. Of 150 children treated, 33 died (22%). In most cases, death was related
      to the development of secondary brain edema. Fifty-nine children (39.3%) had
      severe neurologic impairments at the time of discharge. The most significant risk
      factors for adverse outcome, shown by multivariate analysis, were primary
      areflexia and secondary brain edema. The risk for development of brain edema and
      poor prognosis was well predicted by the GCS score. CONCLUSION: The overall death
      rate in this study of children with severe head injury was low (22%) compared
      with other studies. However, the incidence of severe neurologic impairment at
      discharge remained high. The major risks for death or neurologic impairment were
      primary areflexia and the development of secondary brain swelling/edema,
      indicated by a low GCS score.

PMID- 10421184
TI  - Surgical outcome of traumatic intracranial hematoma at a regional hospital in
      Taiwan.
AB  - BACKGROUND: To report the experience in the management of 489 consecutive
      patients with traumatic intracranial hematoma and determine the prognostic
      factors. METHODS: All patients were classified into three groups based on the
      number of operations for each case. A total of 538 operations were performed for
      evacuation of 720 intracranial hematomas. RESULTS: The most common cause of
      injury was motor vehicular traffic crashes (68.7%) and most victims were
      motorcyclists (40.1%). The most common type of lesion was acute epidural hematoma
      (31.0%). The overall mortality rate was 9.6%, and the complication rate was
      11.2%. Follow-up assessment of 480 patients revealed that 270 (56.2%) patients
      made a good recovery, 99 (20.6%) were moderately disabled, 32 (6.7%) were
      severely disabled, 21 (4.4%) were vegetative, and 58 (12.1%) had died.
      CONCLUSION: The surgical outcome was significantly correlated with the score of
      the Glasgow Coma Scale, pupillary reactivity, number of operations, and type of
      lesion.

PMID- 10421185
TI  - Comparative use of magnetic resonance imaging and electrophysiologic
      investigation for the prognosis of head injury.
AB  - BACKGROUND: To compare magnetic resonance imaging (MRI) and electrophysiologic
      investigation as prognostic methods in acute head injury. METHODS: Fifty-seven
      patients suffering moderate to mild (Glasgow Coma Scale score > 8) or severe
      (Glasgow Coma Scale score < 8) head injury were included. Both groups were
      analyzed as a total and separately for outcome as assessed by Glasgow Outcome
      Score. Two outcome groups were separated (Glasgow Outcome Score 1-3: unfavorable
      vs. Glasgow Outcome Score 4-5: favorable). MRI scans (T1-, T2-, T2*-sequences;
      transverse, coronal, and sagittal slices) were obtained 1 to 39 days after trauma
      (mean, 14 days). Electrophysiologic investigations consisted of median nerve
      evoked somatosensory responses to assess corticosubcortical function and brain
      stem auditory-evoked potentials and brain stem reflexes for brain stem function.
      Recordings were performed 24 to 72 hours after trauma and repeated every 3 to 5
      days. RESULTS: Evaluation of all patients revealed a prognostic significance of
      MRI lesions within the corpus callosum, the basal ganglia, the hippocampus, the
      midbrain, and the pons. In the severe head injury subgroup, significance was
      limited to lesions within the corpus callosum, the basal ganglia, and the
      midbrain. Among the electrophysiologic findings, dysfunction of the
      corticosubcortical region as well as of the midbrain were linked to an
      unfavorable outcome. In severe head injury, prognostic significance was
      restricted to bilateral corticosubcortical dysfunction. A statistical test for
      diagnostic convergence of both methods indicated a distinct convergence only for
      lesions of the midbrain and the pons. CONCLUSION: MRI scans performed early after
      head injury provide several indicators for unfavorable outcome.
      Electrophysiologic investigations add to this prognostic evidence. Both methods
      have comparably high specificity. However, because of the higher density of
      prognostic information obtained, MRI seems superior to electrophysiologic
      testing.

PMID- 10421186
TI  - Differential profile of facial injuries among mountainbikers compared with
      bicyclists.
AB  - BACKGROUND: Bicyclists and mountainbikers are prone to facial trauma. In the
      current study, we present a large series of cycling-related sports trauma to the
      face in an effort to identify the injury pattern among mountainbikers compared
      with bicyclists. METHODS: The medical records of a single pediatric and adult
      Level I trauma center were evaluated from January 1, 1991, through October 31,
      1996. All admissions with injuries caused by cycling-related sports were
      reviewed, analyzed, and compared according to age and sex distributions, causes
      of accidents, injury types, frequency, and localization of fractures and
      associated injuries. The injury types were divided into three categories:
      fractures, dentoalveolar trauma, and soft-tissue injuries. RESULTS: Five hundred
      sixty-two injured bicyclists (10.3% of all trauma patients) were registered at
      the Department of Oral and Maxillofacial Surgery, University of Innsbruck,
      Austria, during the study period, accounting for 31% of all sports-related or
      48.4% of all traffic collisions, respectively. The review of the patient records
      revealed especially more severe injury profiles in 60 mountainbikers, with 55%
      facial bone fractures, 22% dentoalveolar trauma, and 23% soft-tissue injuries,
      compared with 502 street cyclists showing 50.8% dentoalveolar trauma, 34.5%
      facial bone fractures, and 14% soft-tissue lesions. The dominant fracture site in
      bicyclists was the zygoma (30.8%), whereas mountainbikers sustained an impressive
      15.2% Le Fort I, II, and III fractures. Condyle fractures were more common in
      bicyclists, with 18.8% opposing 10.8% in mountainbikers. CONCLUSION: Appropriate
      design of helmets with faceguards will reduce the incidence of facial injuries
      caused by cycling-related accidents and incentives are needed for making helmet
      use compulsory for all cyclists, particularly for mountainbikers.

PMID- 10421187
TI  - The static rotator cuff does not affect inferior translation of the humerus at
      the glenohumeral joint.
AB  - BACKGROUND: The static contribution of the rotator cuff to the inferior stability
      of the shoulder is poorly understood. The purpose of this study was to determine
      the effect of static rotator cuff muscles on the inferior stability of the
      glenohumeral joint. METHODS: The humeral head positions relative to the glenoid
      were obtained in 12 shoulder specimens under the following conditions: with and
      without a 1.5-kg load; with the humerus adducted and abducted 90 degrees; and in
      three stages of dissection: (1) before release of any of the rotator cuff
      muscles, (2) after release of the supraspinatus or the cuff muscles other than
      the supraspinatus, and (3) after release of all of the cuff muscles. The order of
      release was changed in two ways: release of the supraspinatus followed by the
      release of other muscles in one group, and the opposite order in the other group.
      RESULTS: In both adduction and abduction, there were no significant differences
      in the positions of the humeral head either among the three stages of release or
      between the two different orders of release. CONCLUSION: The static contribution
      of the cuff muscles to the inferior stability of the shoulder is insignificant.

PMID- 10421188
TI  - Severity of injuries associated with traumatic hip dislocation as a result of
      motor vehicle collisions.
AB  - BACKGROUND: Previous reports have shown a high rate of associated injuries in
      patients who sustain traumatic hip dislocation. Since these earlier reports
      appeared, improvements have been made in passenger safety systems and the rate of
      restraint usage has increased. The purpose of this study was to review the
      associated injuries present in a current series of patients who sustained
      traumatic hip dislocation as a result of motor vehicle collisions. METHODS: We
      retrospectively reviewed our trauma registry and identified 66 patients who
      sustained traumatic hip dislocation as a result of motor vehicle collisions.
      Thirty patients (45%) were restrained and 36 (55%) were unrestrained. Airbags
      were known to have deployed in 14 cases. RESULTS: The incidence of associated
      injuries was 95% (63 patients). Orthopedic injuries alone were seen in 22
      patients (33%), whereas associated injuries were seen in 44 patients (67%).
      Abdominal injuries were present in 10 patients (15%), thoracic injuries were
      present in 14 patients (21%), closed head injuries were present in 16 patients
      (24%), and craniofacial injuries were present in 14 patients (21%). Acetabular
      fractures were seen in 46 patients (70%), femoral head fractures were identified
      in 9 patients (14%), and other extremity fractures occurred in 26 patients (39%).
      The average Injury Severity Score for all patients was 17.4 (range, 9-59). The
      average Injury Severity Score of the restrained patients was not statistically
      different from that of the unrestrained patients (p = 0.491). CONCLUSION:
      Although improvements in automotive safety features and restraint usage have
      occurred since previous reports appeared, there continues to be a high rate of
      severe injuries associated with traumatic hip dislocation that occur in motor
      vehicle collisions. We believe that all patients who sustain traumatic hip
      dislocation warrant a general surgery trauma evaluation to rule out any potential
      associated injuries.

PMID- 10421189
TI  - Temporary arterial shunts to maintain limb perfusion after arterial injury: an
      animal study.
AB  - BACKGROUND: Temporary shunt placement can quickly restore perfusion after
      extremity arterial injury. This study examined the adequacy of limb blood flow
      with shunt use, non-heparin-bonded shunt patency over prolonged periods, and the
      safety of this technique. METHODS: Common iliac arteries were divided and 4.0-mm
      Silastic Sundt shunts placed in 16 anesthetized pigs. Eight (group I) had shunts
      placed immediately; eight others (group II) were shunted after an hour of limb
      ischemia and hemorrhagic shock. Physiologic parameters and femoral artery blood
      flow in both hindlimbs were continuously monitored. Limb lactic acid generation,
      oxygen utilization, and hematologic and metabolic effects were serially evaluated
      for 24 hours. RESULTS: Shunts remained patent in 13 of 16 pigs. Shunts thrombosed
      in two group I animals because of technical errors, but functioned well after
      thrombectomy and repositioning. Patency could not be maintained in one animal
      that died from shock. Flow in group I shunted limbs was 57 (+/-11 SD) % of
      control. For group II animals in shock, shunted limb flow initially averaged 46
      +/- 15% of control, but 4 hours after shunt placement, the mean limb blood flow
      was the same as in group I. Increased oxygen extraction compensated for the lower
      flow. Lactic acid production was not increased in comparison to control limbs.
      CONCLUSION: Shunts provided adequate flow in this model of extremity trauma.
      Correctly placed shunts stayed patent for 24 hours, without anticoagulation, if
      shunt placement followed resuscitation.

PMID- 10421190
TI  - Selective use of temporary intravascular shunts in coincident vascular and
      orthopedic upper and lower limb trauma.
AB  - BACKGROUND: Combined vascular and skeletal injuries are associated with a high
      limb loss rate. One of the major factors resulting in amputation is frequently
      because the allowable warm ischemia time for skeletal muscle is exceeded before
      adequate revascularization. METHODS: Temporary vascular shunting has been used in
      selected patients with complete ischemia to minimize the ischemic time of the
      injured limb, allowing identification of vital structures, thorough debridement,
      and rigid internal fixation before definitive vascular repair. RESULTS: Five male
      and two female patients with a median age of 46 years (range, 27-76 years)
      admitted with combined orthopedic and vascular injuries of the upper limbs in
      four and the lower limbs in three patients underwent primary vascular shunting.
      The median ischemic time for all patients was 180 minutes (range, 120-210
      minutes). Shunt insertion was accomplished in all cases within 30 minutes. Median
      dwell time for the shunt was 185 minutes (range, 90-390 minutes). No shunt
      related complications or limb loss occurred. During follow-up ranging from 2 to
      24 months, all vascular repairs remained patent. All fractures healed primarily,
      except for one patient in whom a necrosis of the humeral head occurred. Five
      patients had an excellent and two patients a good result. CONCLUSION: Initial
      temporary vascular shunting in selected patients with combined skeletal and
      vascular injury of the upper or lower limb may reduce the complications resulting
      from prolonged ischemia and permits an unhurried and reasonable sequence of
      treatment.

PMID- 10421192
TI  - Reconstruction of ankle and heel defects by a modified wide-base reverse sural
      flap.
AB  - BACKGROUND: Flap reconstruction around the ankle and heel is a technically
      demanding procedure. Some patients have contraindications for microsurgery,
      however, limiting the options for local tissue transfer. In this study, we
      describe our experience with a new flap technique for ankle and heel coverage.
      METHODS: We designed a modified wide-base reverse sural flap and applied it to 20
      patients with lower leg trauma from 1994 to 1997. All patients sustained Gustilo
      type IIIb,c open fractures with soft-tissue defects around the ankle and heel.
      Six cases had chronic osteomyelitis. Most of our patients had contraindications
      for microsurgery such as old age, poor medical condition, or heavy smoker status.
      The average age was 69.5 years old, and the average follow-up time was 18.5
      months. RESULTS: All 20 patients underwent successful modified reverse sural flap
      reconstruction. There were no deep infections, no soft-tissue necrosis, or
      pressure ulcers. The nonunion rate was 5%. The average time for flap elevation
      and rotation was 29.3 minutes. No blood transfusion was required. An unsightly
      scar was the major complaint (60%) from our patients. Seventeen cases (85%)
      achieved good functional outcomes. CONCLUSION: This report demonstrates that our
      design of this modified wide-base reverse sural flap is suitable for flap
      reconstruction around the ankle and heel; especially for patients who have
      difficulty in receiving microsurgery. The surgical procedure is simple, and the
      results are satisfactory.

PMID- 10421191
TI  - Fracture and dislocation of snowboarder's elbow.
AB  - BACKGROUND: This study focuses on the analysis of snowboarding versus skiing
      injuries, especially fracture, dislocation, or both, of the elbow, based on 7
      years of medical records and roentgenograms of patients injured at a ski
      snowboard area, Mt. Zao National Park, and demonstrates the precise
      characteristics of snowboard injury in the elbow region. METHODS: A retrospective
      study of 1,445 injured snowboarders and 10,152 injured skiers was undertaken to
      assess both snowboarding and skiing injuries. Sixty-four cases of snowboarding
      injuries and 152 cases of skiing injuries were available for precise analysis of
      fracture, dislocation, or both, in the elbow region. RESULTS: Fractures,
      dislocations, or both, in the elbow were more frequently observed for
      snowboarders (30 of 64 cases, 46.9%) when compared with that for skiers (26 of
      152 cases, 17.1%) (p < 0.001). The rate of dislocation with or without fracture
      of the elbow was also significantly higher for snowboarders (17 of 64 cases,
      26.6%) than for skiers (8 of 152 cases, 5.3%, p < 0.001). Seventeen cases of
      elbow dislocation in snowboarding were all of the posterior type, which
      accompanied two coronoid process fractures and two radial neck fractures.
      Fractures of the coronoid process (five cases), radial head (one case), radial
      neck (five cases), olecranon (one case), proximal ulnar shaft (one case), and
      extension-type fracture of distal humerus (four cases) were the fracture types
      observed in the analysis. CONCLUSION: Posterior dislocation; fractures of
      coronoid process, radial neck, and radial head; and extension-type fracture of
      the distal humerus characterize the particular and frequent injury mechanism
      responsible for snowboarding trauma in the elbow region. Thus, snowboarding
      injury of the elbow is recognized as a severe injury and is characterized by a
      frequent risk of posterior dislocation, fracture, or both. The severity of elbow
      injuries in snowboarding mainly seems to be due to direct mechanical force on the
      elbow, receiving the full impact of falling down, combined with an outstretched
      hand and elbow extension, or with an outstretched hand and longitudinal thrust
      force, to the proximal radius and ulna and distal humerus.

PMID- 10421193
TI  - Combined ischemic preconditioning and laser Doppler measurement for early
      division of pedicled groin flap.
AB  - OBJECTIVES: The main disadvantage of the pedicled groin flap for hand
      reconstruction is the long period of immobilization required. Early division of
      the pedicled groin flap is desirable for both patients and surgeons. The aims of
      this study were to investigate whether ischemic preconditioning can effectively
      accelerate the neovascularization of the junction between the donor and recipient
      sites in the pedicled flap, and the most objective method of judging the timing
      of early division of the pedicled groin flap. This report is the first
      prospective study to use ischemic preconditioning for early division of pedicled
      cutaneous flap combined with laser Doppler measurement. METHODS: The severe hand
      injuries of 12 patients were reconstructed by using the pedicled groin flap
      method. The ischemic preconditioning program was prospectively performed as
      scheduled for 5 to 7 days postoperatively. The pedicled groin flap was monitored
      with laser Doppler when the flap was elevated, inset, with clamping and
      nonclamping postoperatively. RESULTS: Eleven of the 12 pedicled groin flaps were
      divided safely and survived completely. Only one pedicled groin flap with a
      simultaneous harvest of iliac bone graft had partial flap loss, giving a success
      rate of 90.1%. CONCLUSION: With ischemic preconditioning, the pedicled groin flap
      can be safely divided postoperatively at a mean period of 8.4 days according to
      the laser Doppler measurement, especially when the perfusion unit ratio of
      clamping over nonclamping reaches more than 36.6%.

PMID- 10421194
TI  - Blast injury from explosive munitions.
AB  - OBJECTIVE: To evaluate the effect of blast in common war injuries. METHODS: One
      thousand three hundred and three patients injured by explosive munitions and
      demonstrating extremity wounds without other penetrating injuries were admitted
      to the Military Medical Academy in Belgrade between 1991 and 1994. Of these, 665
      patients (51%) had symptoms and physical signs that were compatible with the
      clinical diagnosis of primary blast injury, whereas the remaining 658 patients
      did not. RESULTS: Random sampling of 65 patients in the blast group during the
      early posttraumatic period showed statistically significant elevations in blood
      thromboxane A2 (TxA2), prostacyclin (PGI2), and sulfidopeptide leukotrienes
      compared with the random sample of 62 patients in the nonblast group. This
      difference could not be accounted for by differing injury severity between the
      groups, because the severity of wounds as measured by both the Injury Severity
      Score and the Red Cross Wound Classification was similar in both groups. Amongst
      blast patients, 200 patients (30%) had long-term (1 year) symptoms and signs
      reflecting central nervous system disorders. These symptoms and signs were only
      sporadically found in 4% of the nonblast patients. These findings indicate that
      primary blast injury is more common in war injuries than previously thought and
      that of those affected by blast, a surprisingly high proportion retain long-term
      neurologic disability. The elevation in eicosanoids could be used to confirm and
      monitor blast injury. CONCLUSION: In relation to the immediate management of
      patients injured by explosive weapons, it follows that particular attention
      should be paid to the presence and/or development of blast injury. Our findings
      indicate that blast is more common in war injuries than previously thought.
      Eicosanoid changes after blast injury suggest that blast injury causes a major
      physiologic stress. A variety of effects on the central nervous system suggest
      that blast injury could be responsible for some aspects of what is now considered
      to be the posttraumatic stress disorder.

PMID- 10421195
TI  - Shock after blast wave injury is caused by a vagally mediated reflex.
AB  - OBJECTIVE: Bomb blast survivors occasionally suffer from profound shock and
      hypoxemia without signs of external injury. We hypothesize that a vagally
      mediated reflex such as the pulmonary defensive reflex is the cause of shock from
      blast wave injury. This study was a prospectively randomized, controlled animal
      study. METHODS: By using a previously described model of blast wave injury, we
      randomized rats to one of four groups: control, blast-only, bilateral cervical
      vagotomy plus atropine 200 microg/kg i.p. only, and bilateral cervical vagotomy
      plus atropine 200 microg/kg i.p. before blast injury. Cardiopulmonary parameters
      were recorded for 90 minutes after the blast or until death. RESULTS:
      Bradycardia, hypotension, and absence of compensatory peripheral
      vasoconstriction, typically seen in animals subjected to a blast pressure injury,
      were prevented by bilateral cervical vagotomy and intraperitoneal injection of
      atropine methyl-bromide. Hypoxia and lung injury were not statistically
      significant between the blasted groups, suggesting equivalent injury. CONCLUSION:
      Our data implicate a vagally mediated reflex such as the pulmonary defensive
      reflex as the cause of shock seen immediately after a blast pressure wave injury.

PMID- 10421196
TI  - Triolein-induced pulmonary embolization and increased microvascular permeability
      in isolated perfused rat lungs.
AB  - BACKGROUND: The pathophysiologic mechanism of the fat embolism syndrome is poorly
      understood. This study was designed to determine the effects of fat emboli on
      pulmonary vasculature. METHOD: Triolein was infused into isolated rat lungs
      perfused with Krebs-Henseleit buffer. Pulmonary arterial pressure and
      microvascular permeability (Kf) were measured at baseline and 20 minutes after
      the triolein infusion. RESULT: The 99% triolein produced dose-dependent increases
      in both pulmonary arterial pressure and Kf. The 65% triolein, containing free
      fatty acid, resulted in a greater increase in Kf. Pretreatment with indomethacin
      attenuated the increase in Kf after 65% triolein but not after 99% triolein.
      CONCLUSION: Pure triolein induced mainly embolization in the pulmonary
      vasculature, and 65% triolein caused embolization and subsequently increased
      vascular permeability, which are, at least in part, mediated by the action of
      cyclooxygenase products. Free fatty acids might induce permeability edema by
      means of a cyclooxygenase-dependent mechanism. We conclude that triolein-induced
      increases in pulmonary arterial pressure and Kf in isolated rat lungs provides a
      useful model of acute lung injury by fat embolism.

PMID- 10421197
TI  - Humoral versus neural pathways for fever production in rats after administration
      of lipopolysaccharide.
AB  - BACKGROUND: These studies address the question of the relative roles of humoral
      and neural pathways in the genesis and control of the fever component of the
      acute phase response. METHODS: Two experiments were performed to examine the
      effect of vagotomy (VagX) on the febrile response to intraperitoneal (i.p.) and
      intra-arterial (i.a.) lipopolysaccharide (LPS), and plasma cytokine and LPS
      concentrations after intravenous (i.v.) or i.p. injections of LPS. In experiment
      1, body temperature (T(B)) was obtained from unperturbed animals by using radio
      transmitters and telemetry after injection of LPS i.a. or i.p. In the second
      study, serial blood samples were obtained for cytokine and LPS assay after
      injection of LPS either i.v. or i.p. Colonic temperatures (T(C)) were obtained
      from indwelling thermistors. RESULTS: The maximal increments in T(B) for animals
      receiving LPS i.a. and i.p. with or without VagX were not different from one
      another: sham vagotomy (Sham-VagX) + LPS i.a., 1.20 +/- 0.26 degrees C; VagX +
      LPS i.a., 1.23 +/- 0.64 degrees C; Sham-VagX + LPS i.p., 1.45 +/- 0.27 degrees C;
      VagX + LPS i.p., 1.50 +/- 0.35 degrees C (F = 1.12, p = 0.36). Neither were the
      four resulting response curves for T(B) different from one another. Plasma levels
      of LPS, tumor necrosis factor-alpha, and interleukin-6 were significantly
      elevated at 45 minutes after LPS injection by either the i.v. or i.p. routes,
      preceding any increments in T(B), and were not effected by VagX. CONCLUSION:
      Fever development for animals receiving LPS in experiment 1 demonstrates a
      temporal relationship -- with increments in plasma levels of LPS and pyrogenic
      cytokines obtained in experiment 2 after administration of LPS either i.p. or
      i.v. Vagotomy had no discernible effect on the responses regardless of the route
      of administration of LPS.

PMID- 10421198
TI  - Inhibition of alpha-smooth muscle actin expression in an in vitro wound healing
      model by certain antibiotics.
AB  - OBJECTIVE: This study assesses the effects of antimicrobials on wound healing in
      an in vitro model of chicken flexor tendons in a collagen gel matrix. Two
      equidistant tendons were bathed in a culture medium for 28 days as fibroblasts
      (fb) grew from the tendon ends into the collagen gel and migrated toward each
      other until gap closure. Five groups of 10 paired tendons each included the
      control and the study groups, which received oxacillin (Ox), clindamycin (Cl),
      chloramphenicol (Chl), or tetracycline (Tet) in the culture medium to assess
      their effects on gap closure rate, fb migration, and myofibroblast alpha-smooth
      muscle (alpha-SM) actin expression. RESULTS: Gap closure, by day 27, was 98.5% in
      the controls compared with 97%, 92%, 89.5%, 21.75% in the Tet, Cl, Ox, and Chl
      groups. Chl retarded gap closure (p < 0.05). Fb migration was similar for all
      groups. In the control and Ox groups, myofibroblast expressed actin at day 5. By
      day 7, fb cells were clearly visible in the control, Ox, and Cl groups, whereas,
      only light actin was present in the Chl and Tet groups. Actin band densities for
      the Cl, Ox, Tet, and Chl groups were 78.4%, 62.5%, 61.7% and 26.1%, respectively,
      of the control group. CONCLUSION: These studies suggest that one reason certain
      antimicrobials impair wound healing, is due to myofibroblast inhibition of alpha
      SM actin.

PMID- 10421199
TI  - In vitro elution of antibiotic from antibiotic-impregnated biodegradable calcium
      alginate wound dressing.
AB  - OBJECTIVE: The authors investigated the calcium alginate dressing as a drug
      delivery system for the treatment of various surgical infections. METHODS:
      Cytotoxicity of the calcium alginate dressing to fibroblasts and HeLa cells was
      evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide
      (MITT) colorimetric assay. The calcium alginate dressing was mixed with
      vancomycin, and lyophilized or not lyophilized to form two types of antibiotic
      dressings. The antibiotic dressings were placed in 2 mL of phosphate buffered
      saline (PBS) or in PBS containing 0.01% calcium ions, and incubated at 37 degrees
      C. The PBS was changed daily, and the removed solutions were stored at -70
      degrees C until the antibiotic concentration in each sample was determined by
      high performance liquid chromatography assay. RESULTS: The results suggested that
      the antibiotic dressings present no obvious toxic risk to their use as a drug
      delivery system. The concentration of vancomycin in each sample was well above
      the breakpoint sensitivity concentration (the antibiotic concentration at the
      transition point between bacterial kill. ing and resistance to the antibiotic)
      for more than 14 days. The release was most marked during the first 48 hours. The
      concentration of calcium ions in PBS and the lyophilization of the manufacture
      process of antibiotic dressings prolonged the antibiotic diffusion duration. The
      diameter of the sample inhibition zone ranged from 10 to 11 mm, and the relative
      activity of vancomycin ranged from 62.88% to 92.18%. CONCLUSION: All antibiotic
      dressings released bactericidal concentrations of the antibiotics in vitro for
      the period of time needed to treat surgical infections. This study offers a
      convenient method to meet the specific antibiotic requirement for different
      patients.

PMID- 10421200
TI  - Dilatational percutaneous tracheostomy: modification of technique.
AB  - BACKGROUND: Major inherent risks associated with percutaneous dilatational
      tracheostomy include loss of airway during endotracheal tube manipulation,
      inability to cannulate the trachea below the endotracheal tube, and difficulties
      related to neck anatomy. METHOD: Percutaneous dilatational tracheostomy technique
      was modified to make the incision in the suprasternal area, and the use of air
      leak technique confirmed tracheal penetration below the endotracheal cuff.
      Bronchoscopy was not used. RESULTS: One hundred patients underwent percutaneous
      dilatational tracheostomy using the modification mentioned above. Although three
      patients had minor bleeding complications, there was no loss of airway; nor were
      there other complications. CONCLUSION: This technique provides improved safety
      from loss of airway and illuminates the need for concomitant bronchoscopy.

PMID- 10421201
TI  - Handgun safety features: a review for physicians.
AB  - OBJECTIVE: Handguns are a ubiquitous consumer product in the United States, which
      annually cause significant morbidity and mortality. Handgun safety devices are
      often proposed as potential solutions to this problem. Their effectiveness at
      reducing handgun injuries and deaths is intensely debated. However, to
      effectively analyze the potential utility of handgun safety devices, physicians
      need to be aware of the safety devices available in the consumer market and how
      they operate. METHODS: A wide variety of safety devices are available in the
      consumer market, which vary in terms of their ease of operation, cost, and the
      types of injuries they may prevent. We reviewed several types of handgun safety
      devices, including loaded chamber indicators, manual thumb safeties, grip
      safeties, magazine disconnectors, drop safeties, built-in locks, trigger locks,
      lockboxes, and personalized handguns. Each device is described within the context
      of reducing unintended discharge and unauthorized use. RESULTS: This review is
      not exhaustive. There are other types of safety devices that limit access to
      handguns. Many of these devices, such as barrel locks and chamber locks, work in
      a similar manner as trigger locks and have the same limitations. The user of any
      type of safety device should think about the types of injuries the device is
      designed to prevent and be aware of its limitations. CONCLUSION: Physicians have
      the potential to reduce the risk of firearm injuries with their patients and
      communities. Providing accurate information on firearm safety devices and their
      limitations is important, just as it is for other aspects of health care advice.
      Armed with accurate information, physicians can hopefully be effective in firearm
      injury prevention.

PMID- 10421202
TI  - Civil war head injury and twentieth-century treatment.

PMID- 10421203
TI  - Traumatic lumbar hernia due to seat belt injury: case report.

PMID- 10421204
TI  - Intussusception caused by blunt abdominal trauma.

PMID- 10421205
TI  - Delayed diagnosis of an intra-articular gunshot injury of the knee: a case
      report.

PMID- 10421206
TI  - Sternal fracture with mediastinal hematoma: delayed cardiopulmonary sequelae.

PMID- 10421207
TI  - Acute traumatic mitral valve insufficiency.

PMID- 10421208
TI  - Treatment of posttraumatic dissection of the renal artery with endoprosthesis in
      a 15-year-old girl.

PMID- 10421209
TI  - Traumatic splenic arteriovenous fistula: splenic conservation by embolization.

PMID- 10421210
TI  - Brachial artery transection following closed elbow dislocation.

PMID- 10421211
TI  - Intraoral blunt carotid injury in an adult: case report and review of the
      literature.

PMID- 10421212
TI  - Erectile dysfunction induced by orthopedic trauma managed with a fracture table:
      a case report and review of the literature.

PMID- 10421213
TI  - Blunt ureteropelvic junction disruption.

PMID- 10421214
TI  - Pulmonary and systemic fat embolization after medullary canal pressurization: a
      hemodynamic and histologic investigation in the dog.

PMID- 10421215
TI  - Temporary abdominal closure.

PMID- 10421217
TI  - State laws on tobacco control--United States, 1998.
AB  - PROBLEM/CONDITION: State laws addressing tobacco use, the leading preventable
      cause of death in the United States, are summarized. Laws address smoke-free
      indoor air, minors' access to tobacco products, advertising of tobacco products,
      and excise taxes on tobacco products. REPORTING PERIOD COVERED: Legislation
      effective through December 31, 1998. DESCRIPTION OF SYSTEM: CDC identified laws
      addressing tobacco control by using an on-line legal research database. CDC's
      findings were verified with the National Cancer Institute's State Cancer
      Legislative Database. RESULTS: Since a previous surveillance summary on state
      tobacco-control laws published in November 1995 (covering legislation effective
      through June 30, 1995), several states have enacted new restrictions or
      strengthened existing legislation that addresses smoke-free indoor air, minors'
      access to tobacco, tobacco advertising, and tobacco taxes. Five states
      strengthened their smoke-free indoor air legislation. All states and Washington,
      D.C., continued to prohibit the sale and distribution of tobacco products to
      minors; however, 21 states expanded minors' access laws by designating
      enforcement authorities, adding license suspension or revocation for sale to
      minors, or requiring signage. Since the 1995 report, eight additional states (a
      total of 19 states and Washington, D.C.) now ban vending machines from areas
      accessible to minors. Thirteen states restrict advertising of tobacco products,
      an increase of four states since the 1995 report. Although the number of states
      that tax cigarettes and smokeless tobacco did not change, 13 states increased
      excise taxes on cigarettes, and five states increased excise taxes on smokeless
      tobacco products. The average state excise tax on cigarettes is 38.9 cents per
      pack, an increase of 7.4 cents compared with the average tax in the 1995 report.
      INTERPRETATION: State laws addressing tobacco control vary in relation to
      restrictiveness, enforcement and penalties, preemptions, and exceptions. ACTIONS
      TAKEN: The data summarizing state tobacco-control laws are available through
      CDC's State Tobacco Activities Tracking and Evaluation (STATE) System; the laws
      are collected and updated every quarter. The STATE System also contains state
      specific data on the prevalence of tobacco use, tobacco-related deaths, and the
      costs of tobacco use. Information from the STATE System is available for use by
      policy makers at the state and local levels to plan and implement initiatives to
      prevent and reduce tobacco use. In addition, CDC is using this information to
      assess the ongoing impact of tobacco-control programs and policies on tobacco
      use.

PMID- 10421216
TI  - Surveillance of work-related asthma in selected U.S. states using surveillance
      guidelines for state health departments--California, Massachusetts, Michigan, and
      New Jersey, 1993-1995.
AB  - PROBLEM/CONDITION: Cases of work-related asthma (WRA) are sentinel health events
      that indicate the need for preventive intervention. WRA includes new-onset asthma
      caused by workplace exposure to sensitizers or irritants and preexisting asthma
      exacerbated by workplace exposures. REPORTING PERIOD: This report reviews cases
      of WRA identified by state health departments from January 1, 1993, through
      December 31, 1995, as well as follow-up investigations of cases and associated
      workplaces conducted through June 30, 1998. DESCRIPTION OF THE SYSTEMS: State
      based surveillance and intervention programs for WRA are conducted in California,
      Massachusetts, Michigan, and New Jersey as part of the Sentinel Event
      Notification Systems for Occupational Risks (SENSOR) cooperative agreement
      program, initiated by CDC's National Institute for Occupational Safety and Health
      (NIOSH). RESULTS: From 1993 through 1995, a total of 1,101 cases of WRA were
      identified by SENSOR surveillance staff members in California, Massachusetts,
      Michigan, and New Jersey. Of these 1,101 cases, 19.1% were classified as work
      aggravated asthma, and 80.9% were classified as new-onset asthma. Objective
      evidence substantiating asthma work-relatedness was documented in the medical
      records of 3.4% of WRA cases identified in the two states (Michigan and New
      Jersey) where medical records are routinely reviewed for this information. Indoor
      air pollutants, dusts, cleaning materials, lubricants (e.g., metalworking
      fluids), and diisocyanates were among the most frequently reported causes of WRA.
      In addition, a well-recognized cause of occupational asthma - natural rubber
      latex - was identified in a new setting, the healthcare industry. The most common
      industries associated with WRA cases included transportation equipment
      manufacturing (19.3%), health services (14.2%), and educational services (8.7%).
      Air sampling for agents known to induce occupational asthma was performed in
      Michigan for comparison with established federal time-weighted average exposure
      limits. Sixteen (13.4%) of 119 workplaces tested had airborne concentrations
      exceeding NIOSH recommended exposure limits (RELs); 11 (9.1%) of 121 workplaces
      had concentrations exceeding permissible exposure limits (PELs) of the Michigan
      Occupational Safety and Health Act (MIOSHA) program. INTERPRETATION: The
      surveillance data findings confirm well-recognized causes of asthma and have
      identified new putative causes (e.g., cleaning materials and metalworking
      fluids). Because the surveillance program depends on physicians' recognizing
      asthma work-relatedness and reporting diagnosed cases, the data are considered an
      underestimate of the magnitude of the WRA problem. The data also indicate that
      physicians are not commonly performing objective physiologic tests to
      substantiate a WRA diagnosis. Workplace findings suggest a need to evaluate
      existing exposure standards for specific agents known to induce occupational
      asthma (e.g., diisocyanates). Case-based surveillance can help improve the
      recognition, control, and prevention of WRA. The SENSOR model also provides a
      mechanism for workers and physicians to request workplace investigations aimed at
      primary prevention for other workers. PUBLIC HEALTH ACTION: NIOSH and state
      health department representatives are working to establish a long-term agenda for
      state-based surveillance of work-related conditions and hazards. The results from
      the SENSOR WRA programs described in this report support inclusion of WRA as a
      priority condition warranting surveillance at the state level.

PMID- 10421218
TI  - Alterations in the activity of several glycohydrolases in red blood cell membrane
      from type 2 diabetes mellitus patients.
AB  - The erythrocyte membrane in 71 patients with type 2 diabetes mellitus was
      assessed for glycohydrolase activity: N-acetyl-beta-D-glucosaminidase, beta-D
      glucuronidase, alpha- and beta-D-galactosidase, alpha- and beta-D-glucosidase,
      alpha-D-mannosidase, and alpha-L-fucosidase. Only beta-D-glucuronidase, alpha-D
      glucosidase, and beta-D-glucosidase showed markedly elevated levels with respect
      to the controls regardless of the presence of complications. Among the examined
      patients, those with good metabolic control (not yet submitted to any therapy)
      showed the same enzyme levels as the reference subjects, while the levels in
      patients with unsatisfactory metabolic control (treated with oral hypoglycemic
      and/or insulin) significantly differed from the control levels. For alpha-D
      glucosidase and beta-glucosidase, a correlation with glycemia and the parameters
      of metabolic control was also evidenced. Alterations of beta-D-glucuronidase,
      alpha-D-glucosidase, and beta-D-glucosidase were also ascertained in the plasma
      of the same diabetic patients according to the literature; each enzyme correlated
      with the other, either in plasma or in the erythrocyte membrane. This study shows
      a correlation between plasma and erythrocyte membrane levels for these three
      enzymes. The strict parallelism of the glycohydrolases in the two different
      compartments provides a profile of these enzymes in the pathology of diabetes.

PMID- 10421219
TI  - Lipoprotein response to a National Cholesterol Education Program step II diet
      with and without energy restriction.
AB  - This study examined the efficacy of a National Cholesterol Education Program
      (NCEP) step II diet (25% fat with < 7% saturated fat [SFA]) with and without
      moderate energy restriction. We tested the hypothesis that moderate energy
      restriction would improve the lipid profile resulting from an isoweight NCEP step
      II diet. Twenty hypercholesterolemic subjets (10 men and 10 postmenopausal women)
      consumed the following three controlled diets, each of 4 weeks' duration, as
      outpatients: (1) high-fat, high-saturated-fat diet to establish baseline lipids
      and isoweight energy requirements, (2) NCEP step II diet at isoweight energy, and
      (3) NCEP step II diet with an energy level 15% less than isoweight. The NCEP step
      II diet at isoweight energy reduced total cholesterol (TC) by 4% (P = .015), high
      density lipoprotein cholesterol (HDL-c) by 13% (P < .0001), and HDL2-c by 40% (P
      < .0001). The TC:HDL-c ratio increased from 4.9 to 5.5 (P < .0001) and was
      increased in 19 of 20 subjects. Apolipoprotein B (apo B)-containing lipoproteins
      changed reciprocally: low-density lipoprotein cholesterol (LDL-c) decreased 4% (P
      = .008) and very-low-density lipoprotein cholesterol (VLDL-c) increased 29% (P <
      .0001). Apo B levels did not change. Compared with the NCEP isoweight diet the
      NCEP hypocaloric diet significantly reduced VLDL-c (-9%, P = .014) and apo B (
      5%, P = .015). There was an additional reduction in TC (-4%, P = .073) and LDL-c
      (-4%, P = .126) with no change in HDL-c (P = .807). These data indicate that a
      NCEP step II diet with energy restriction produces a more desirable lipoprotein
      response than a NCEP step II isoweight diet. Neither NCEP step II diet improved
      the TC:HDL-c ratio.

PMID- 10421220
TI  - 2-Chloroadenosine reverses hyperglycemia-induced inhibition of phosphoinositide
      synthesis in cultured human retinal pigment epithelial cells and prevents reduced
      nerve conduction velocity in diabetic rats.
AB  - The effect of the adenosine (AD) analog 2-chloroadenosine (C-AD) on glucose
      induced inhibition of phosphoinositide synthesis was studied in human retinal
      pigment epithelial (RPE) cells by monitoring the level of the
      phosphatidylinositol (PI) synthase substrate, cytidine diphosphate diglyceride
      (CDP-DG). In high-aldose reductase (AR)-expressing RPE 91 cells, C-AD decreased
      CDP-DG at 5 mmol/L glucose and reversed the increase by 20 mmol/L glucose. AD
      deaminase (ADA), which inactivates endogenously released AD, potentiated the
      hyperglycemia-induced increase in CDP-DG. Theophylline, an AD-A1 and AD-A2
      receptor antagonist, caused an increase in CDP-DG at 20 mmol/L glucose. C-AD did
      not alter CDP-DG in low-AR-expressing RPE 45 cells, but did decrease CDP-DG after
      cells were conditioned in 300 mmol/L glucose for 1 week (which induces AR). The
      mechanism by which AD regulates PI synthase in cells with high AR activity is
      unknown, but it is independent of Gi or Gs proteins, adenylate cyclase and
      phospholipase C (PLC) activation, myo-inositol (MI) uptake, or MI efflux.
      Administration of C-AD to streptozotocin-induced diabetic rats prevented the
      slowing of motor nerve conduction velocity (MNCV). Thus, AD derivatives, which
      reverse a glucose-induced deficit in phosphoinositide metabolism, might serve as
      a useful pharmacological tool to intervene in hyperglycemia-induced diabetic
      complications.

PMID- 10421221
TI  - Impact of different low-density lipoprotein (LDL) receptor mutations on the
      ability of LDL to support lymphocyte proliferation.
AB  - Based on the demand for cholesterol for membrane formation, we determined the
      ability of low-density lipoprotein (LDL) to support proliferation in lymphocytes
      bearing different LDL receptor mutations, which were treated "in vitro" with
      lovastatin to inhibit endogenous cholesterol synthesis. Peripheral lymphocytes
      were isolated from two patients with homozygous familial hypercholesterolemia
      (FH), one homozygote for the mutation N804K (FH(Colmenar)) in exon 17, herein
      described for the first time, and a compound heterozygote carrying the mutations
      D280G and G528V, which determine a transport-defective biochemical phenotype.
      Flow cytometric analysis with 1,1'-dioctadecyl-3,3,3,3'
      tetramethylindocarbocyanineperchlorate (Dil)-LDL showed normal LDL binding but
      defective internalization in lymphocytes from case 1, whereas in lymphocytes from
      case 2 both LDL binding and internalization were affected. Studies with mitogen
      stimulated lymphocytes demonstrated that despite the different phenotype, the
      ability of LDL to support proliferation was impaired in both cases to a similar
      extent. These results indicate that internalization of the LDL particle is
      required for expression of the mitogenic effect of LDL.

PMID- 10421222
TI  - Relationship between serum leptin and the insulin-like growth factor-I system in
      humans.
AB  - The growth hormone (GH)/insulin-like growth factor-I (IGF-I) system and leptin
      both play an important role in the regulation of body composition. Although the
      regulation of these two hormonal systems by insulin has been under intense
      investigation, the physiologic interactions between leptin and the GH/IGF-I
      system remain unknown. In this study, we examined the relationships among
      circulating leptin and key elements of the IGF-I system in 60 subjects (27
      nondiabetic lean, 21 nondiabetic obese, and 12 type 1 diabetic subjects) with a
      wide range of insulin secretory capacity. Leptin, glucose, insulin, free IGF-I,
      total IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 levels were measured in
      the basal state after an overnight fast, and the acute insulin response to
      glucose (AIRG) was determined after intravenous glucose injection. AIRG was
      significantly higher (P < .01) in the obese (3,365+/-562 pmol/L x min) versus
      lean subjects (1,624+/-155 pmol/L x min). In simple regression analysis, the
      serum leptin concentration was positively correlated with the body mass index
      ([BMI] men, r = .51, P = .005; women, r = .71, P < .001), IGFBP-3 (men, r = .20,
      P = nonsignificant; women, r = .41, P < .025), and AIRG (men, r = .73, P < .001;
      women, r = .62, P < .01). There was a nonlinear correlation between leptin and
      IGFBP-1, but there was no correlation between leptin and free or total IGF-I. In
      multiple regression analysis with leptin as the dependent variable, gender, BMI,
      and IGFBP-3 entered the equations at a statistically significant level. The
      correlation of leptin with IGFBP-3 was independent of obesity and persisted after
      correction for AIRG, suggesting a link between leptin and GH action.

PMID- 10421223
TI  - Production of endothelin by cultured human endothelial cells following exposure
      to nicotine or caffeine.
AB  - This study evaluated endothelin production by endothelial cells after exposure to
      nicotine or caffeine. Vasoconstrictive properties have been attributed to both
      nicotine and caffeine. The presence of endothelin, a potent vasoconstrictor
      itself, was determined using a radioimmunoassay. The optimal stimulatory doses
      for nicotine and caffeine were determined to be 1.0 micromol/L and 1.0 mmol/L,
      respectively. When endothelin production was evaluated over time after exposure
      to the optimal dose of each agent, it was determined that nicotine stimulated
      maximum endothelin production within 5 minutes. Caffeine failed to cause a
      distinct peak of endothelin production within 20 minutes. These results suggest
      that nicotine may have a possible acute and short-lived effect on the
      vasoconstrictive response associated with endothelin, while caffeine-induced
      endothelin release may require more long-term exposure.

PMID- 10421224
TI  - Evaluation of phenylalanine and tyrosine metabolism in late human pregnancy.
AB  - The [2H5]-phenylalanine method for measurement of protein metabolism requires the
      phenylalanine hydroxylation to tyrosine to be calculated from the tyrosine flux.
      Although this can be estimated, for pregnancy, we made a direct measurement of
      the molar ratio of the fluxes of tyrosine and phenylalanine from protein
      breakdown (Pt/Pp) using [2H2]-tyrosine infusion. Six normal pregnant women were
      studied at 37 weeks' gestation. While fasting, they were administered a 3-hour
      primed-constant infusion with [13C]-leucine, [2H5]-phenylalanine, and [2H2]
      tyrosine. Leucine (alpha-ketoisocaproic acid [KIC]) flux was 136.2+/-15.1
      micromol/kg/h (mean +/- SD), phenylalanine flux 41.2+/-5.6, and tyrosine flux
      25.0+/-6.0, and phenylalanine hydroxylation was 3.3+/-2.1 micromol/kg/h. The mean
      tyrosine to phenylalanine molar flux ratio (Pt/Pp) was 0.52+/-0.10, lower than
      the ratio of 0.65 to 0.85 reported in normal nonpregnant subjects and 0.73
      estimated from animal studies. We studied protein metabolism in six additional
      pregnant women and six nonpregnant women using [13C]-leucine and [2H5]
      phenylalanine infusions only and applied the lower Pt/Pp ratio to the former
      group. Tyrosine flux (42.0+/-7.2 micromol/kg/h) and phenylalanine hydroxylation
      (9.2+/-4.2 micromol/kg/h) were significantly higher in nonpregnant subjects than
      in both groups of pregnant subjects. The percent contribution of phenylalanine
      hydroxylation to total tyrosine flux was reduced from 20% to 14%. When using
      [2H5]-phenylalanine to study whole-body protein metabolism in pregnancy and
      tyrosine flux is not measured directly by infusion of [2H2]-tyrosine, the lower
      Pt/Pp ratio is required. The phenylalanine model shows that tyrosine flux derived
      from protein breakdown and phenylalanine hydroxylation are both reduced in
      pregnancy.

PMID- 10421225
TI  - The codon 64 polymorphism of the beta3-adrenergic receptor gene is not associated
      with coronary heart disease or insulin resistance in nondiabetic subjects and non
      insulin-dependent diabetic patients.
AB  - Hyperinsulinemia has been shown to predict coronary heart disease (CHD) events in
      both nondiabetic subjects and patients with non-insulin-dependent diabetes
      mellitus (NIDDM). Therefore, defects in genes that regulate insulin action could
      be responsible for an increased risk of CHD. The Trp64Arg polymorphism of the
      beta3-adrenergic receptor gene has been linked with abdominal obesity, insulin
      resistance, and early-onset NIDDM. Therefore, we screened for this polymorphism
      among 185 unrelated nondiabetic subjects (101 men and 84 women; age, 56+/-1 years
      [mean +/- SEM]; body mass index [BMI], 27.8+/-0.3 kg/m2) with angiographically
      confirmed CHD (stenosis > 50% in > or = two coronary arteries), among 119
      unrelated patients with NIDDM (90 men and 29 women; age, 62+/-1 years; BMI,
      28.7+/-0.4 kg/m2; 95 had CHD by the same criteria and 24 had definite myocardial
      infarction [MI]), and among 82 healthy men (age, 54+/-1 years; BMI, 26.3+/-0.4
      kg/m2) from our previous study. The frequency of the Trp64Arg allele of the beta3
      adrenergic receptor gene was similar in nondiabetic patients with CHD (8%), NIDDM
      patients with CHD (7%), and nondiabetic subjects without CHD (7%). No association
      was found between cardiovascular risk factors and the codon 64 polymorphism of
      the beta3-adrenergic receptor gene in patients with CHD. Similarly, this
      polymorphism was not significantly related to insulin resistance in nondiabetic
      and NIDDM subjects with CHD evaluated by the euglycemic clamp technique. These
      results indicate that the Trp64Arg allele of the beta3-adrenergic receptor gene
      does not contribute to the risk of CHD in nondiabetic subjects and NIDDM
      patients.

PMID- 10421226
TI  - Basal insulin hypersecretion in insulin-resistant Zucker diabetic and Zucker
      fatty rats: role of enhanced fuel metabolism.
AB  - The biochemical mechanisms responsible for basal hyperinsulinemia in insulin
      resistant states have not been fully defined. We therefore studied pancreatic
      beta-cell function in vitro to characterize the relative importance of fuel
      metabolism or secretion via a constitutive pathway in the maintenance of high
      basal insulin secretion in Zucker diabetic fatty (ZDF) and Zucker fatty (ZF)
      rats. Insulin secretion from ZF (10+/-1.8 v 5+/-0.6 pmol/ng DNA/h) and ZDF (30+/
      4 v 7+/-0.8 pmol/ng DNA/h) islets at 2.8 mmol/L glucose was two to four times
      greater than secretion from islets of lean littermate control rats. In response
      to a decreasing glucose concentration (from 12 to 0 mmol/L), a paradoxical
      increase in insulin secretion was observed in perfused ZDF rat pancreas. Insulin
      secretion at 2.8 mmol/L glucose was suppressed approximately 70% to 80% in islets
      from ZDF and ZF rats following exposure to diazoxide, a K+-adenosine triphosphate
      (K(ATP)) channel opener that inhibits membrane depolarization, or rotenone and
      oligomycin, agents that inhibit ATP production, or by incubation at 23 degrees C.
      Inhibition of glycolysis with mannoheptulose, 2-deoxyglucose, and iodoacetate or
      fatty acid oxidation with a carnitine palmitoyltransferase I inhibitor also
      significantly inhibited basal insulin secretion in islets of ZDF and ZF rats but
      not their lean littermates. Furthermore, the glycolytic flux at 2.8 mmol/L
      glucose was significantly higher in ZDF islets versus ZDF lean littermate (ZLC)
      islets (2.2+/-0.1 v 3.7+/-0.3 pmol/ng DNA/2 h, P < .01) and was suppressed by
      mannoheptulose. In ZDF and ZF islets, high basal insulin secretion was maintained
      despite a 50% reduction in the rate of proinsulin/insulin biosynthesis at 2.8
      mmol/L glucose. The rate of proinsulin to insulin conversion and the ratio of
      proinsulin to insulin secretion by islets of ZDF rats were similar to the values
      in the lean littermates. Thus, basal hypersecretion in these two insulin
      resistant models appears to be related to enhanced fuel metabolism rather than
      the contribution of a constitutive pathway of secretion.

PMID- 10421227
TI  - Insulin activation of pyruvate dehydrogenase complex is enhanced by exercise
      training.
AB  - We studied the effects of exercise training on the activity of the pyruvate
      dehydrogenase (PDH) complex in rat gastrocnemius muscle (experiment 1) and the
      response of the complex to glucose and insulin infusion (euglycemic clamp) in
      trained and sedentary rats (experiment 2). In experiment 1, half of the rats were
      randomly allocated as sedentary animals and the other half were trained by
      voluntary running exercise for 8 weeks. The total activity of the PDH complex was
      not affected by exercise training, and the activity state (proportion of the
      active form) of the PDH complex was decreased from 15.0%+/-2.4% to 7.5%+/-1.1% by
      exercise training. The activity of 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase
      ([3-HADH] an enzyme in beta-oxidation) was significantly higher in trained versus
      sedentary rats. In experiment 2, sedentary and trained rats were starved for 24
      hours before performing the euglycemic clamp. Glucose and insulin infusion was
      performed by a euglycemic clamp (insulin infusion rate, 6 mU/kg/min) for 90
      minutes. The PDH complex was inactivated to less than 1% in both sedentary and
      trained rats after 24 hours of starvation. The glucose infusion rate (GIR) during
      the euglycemic clamp was higher in trained versus sedentary rats. The euglycemic
      clamp resulted in activation of the PDH complex in both sedentary and trained
      rats, but the response of the PDH complex to the euglycemic clamp was
      significantly higher in trained rats (5.8%+/-0.5%) than in sedentary rats (2.9%+/
      0.5%). These results suggest that exercise training promotes fatty acid oxidation
      in association with suppression of glucose oxidation in skeletal muscle under
      resting conditions, but increases the rate of carbohydrate oxidation when glucose
      flux into muscle cells is stimulated by insulin.

PMID- 10421228
TI  - A high-trans fatty acid diet and insulin sensitivity in young healthy women.
AB  - Epidemiological and experimental studies suggest that a diet rich in saturated
      fat affects insulin sensitivity. Monoenes and dienes that have an usaturated bond
      with the trans configuration (trans fatty acids) resemble saturated fatty acids
      with respect to structure, but no published data are available on the effect of
      trans fatty acids on insulin sensitivity. Therefore, the effects of diets high in
      trans fatty acids (TFA diet) and oleic acid (monounsaturated fat [MUFA] diet) on
      glucose and lipid metabolism were studied in 14 healthy women. Subjects consumed
      both experimental diets for 4 weeks according to a randomized crossover study
      design. Both experimental diet periods were preceded by consumption of a
      standardized baseline diet for 2 weeks. The diets provided 36.6% to 37.9% of
      energy (E%) as fat. In the TFA diet, there was 5.1 E% trans fatty acids, and in
      the MUFA diet, 5.2 E% oleic acid, substituted for saturated fatty acids in the
      baseline diet. A frequently sampled intravenous glucose tolerance test (FSIGT)
      was performed at the end of the experimental diet periods. Glucose effectiveness
      (S(G)) and the insulin sensitivity index (S(I)) did not differ after the two
      experimental diet periods. There was also no difference in the acute insulin
      response between the diets. The total cholesterol to high-density lipoprotein
      (HDL) cholesterol ratio and serum total triglyceride, HDL, and low-density
      lipoprotein (LDL) triglyceride and apolipoprotein B (apoB) concentrations were
      higher (P < .05) after the TFA diet. In conclusion, in young healthy women, the
      TFA diet resulted in a higher total/HDL cholesterol ratio and an elevation in
      triglyceride and apo B concentrations but had no effect on glucose and insulin
      metabolism compared with the MUFA diet.

PMID- 10421229
TI  - GLUT3 protein and mRNA in autopsy muscle specimens.
AB  - GLUT3 is expressed in rat muscle, but this glucose transporter protein has not
      been identified previously in adult human skeletal muscle. We quantified the
      rapidity of disappearance of mRNA and protein from human skeletal muscle at room
      temperature and at 4 degrees C. Fifty percent of the immunologically detectable
      GLUT3 protein disappeared by 1 hour at 20 degrees C and by 2 hours at 4 degrees
      C. mRNA for GLUT3 was decreased 50% by 2.2 hours at 20 degrees C and by 24 hours
      at 4 degrees C. Half of the measurable mRNAs for GLUT4, glyceraldehyde 3
      phosphate dehydrogenase (GAPDH), alpha-actin, and beta-myosin disappeared by 0.8
      to 2.1 hours at 20 degrees C and by 5.0 to 16.6 hours at 4 degrees C. Previous
      conclusions that GLUT3 is not expressed in human muscle were likely drawn because
      of artifacts related to degradation of GLUT3 protein in the specimens prior to
      study. Because of the rapid degradation of protein and mRNA, autopsy specimens of
      muscle must be obtained within 6 hours of death, and even then, protein and mRNA
      data will likely dramatically underestimate their expression in fresh muscle.
      Some previously published conclusions and recommendations regarding autopsy
      specimens are not stringent enough to consistently yield useful protein and mRNA.

PMID- 10421230
TI  - Low-density lipoprotein (LDL) oxidizability before and after LDL apheresis.
AB  - Oxidation of low-density lipoprotein (LDL) plays a major role in the development
      of atherosclerosis. Hypercholesterolemia has been associated with enhanced in
      vitro oxidation of LDL, and lipid-lowering therapy reduces LDL oxidizability. In
      the present study, we investigated whether LDL apheresis performed with different
      techniques affects in vitro diene formation (lag phase) and modification of
      apolipoprotein B-100 (apoB). Baseline and posttreatment diene formation was
      correlated with the baseline pattern of plasma total fatty acids. We then
      performed a computer-simulation study to test the hypothesis that LDL apheresis
      induced changes in LDL oxidizability are related to changes in the mass ratio
      between freshly produced and older LDL. In 19 patients aged 49+/-7 years with
      heterozygous familial hypercholesterolemia (FH) regularly treated with either
      immunoadsorption, heparin-induced LDL precipitation (HELP), or dextran sulfate
      (DS) adsorption, we determined lipoprotein levels, the lag phase, apoB
      modification, and the fatty acid pattern in plasma samples drawn at the onset and
      termination of one LDL apheresis. LDL apheresis significantly decreased total
      cholesterol, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, and
      triglycerides by 50.4%, 14.9%, 62.6%, and 33.6%, respectively. The lag phase
      increased by a significant mean of 9.8%; the charge of apoB was not altered. The
      lag phase before treatment positively correlated with the baseline concentration
      of plasma total palmitic, myristic, and oleic acid. The increase in the lag phase
      during treatment correlated with a high pretreatment concentration of lauric,
      linoleic, and docosahexanoic acid. The simulation study indicates that a
      temporary imbalance between two LDL compartments, one representing freshly
      secreted LDL and the other representing older LDL, could explain the observed
      increase in the lag phase after LDL apheresis. In conclusion, in patients with
      heterozygous FH, LDL apheresis performed with different techniques decreases the
      susceptibility of LDL to oxidation. This decrease may be related to a temporary
      mass imbalance between freshly produced and older LDL particles. Furthermore, the
      baseline fatty acid pattern influences pretreatment and posttreatment
      susceptibility to oxidation.

PMID- 10421232
TI  - Evidence of a state of increased insulin resistance in preeclampsia.
AB  - Similarities in certain biochemical variables between preeclampsia and the
      insulin resistance syndrome imply a possible link between insulin resistance and
      preeclampsia. We measured insulin sensitivity by the minimal model technique
      between 29 and 39 weeks of gestation in 22 preeclamptic and 16 control women,
      whose glucose tolerance was first confirmed as normal by an oral glucose
      tolerance test. In addition, we measured the fasting levels of serum C-peptide,
      uric acid, lipids, and lipoproteins. Preeclamptic women showed a higher insulin
      response (P = .001) during the oral glucose tolerance test than the controls.
      Insulin sensitivity in preeclamptic women (1.11+/-0.15 x 10(-4) x min(-1) x
      microU/mL) was 37% lower (P = .009) than in control women (1.77+/-0.19 x 10(-4) x
      min(-1) x microU/mL). The free fatty acid (FFA) concentration in preeclamptic
      women (0.17+/-0.01 g/L, P = .0004) was 70% higher than in control women (0.10+/
      0.01 g/L). Also, baseline serum levels of C-peptide, uric acid, and triglyceride
      were higher in preeclamptic women. Insulin sensitivity increased fourfold to
      fivefold within the first 3 postpartum months, but insulin sensitivity in
      preeclamptic women was still 26% lower (P = .04) than in control women.
      Preeclampsia is a state of increased insulin resistance, and it persists for at
      least 3 months after pregnancy. This may be a pathogenetic factor in preeclampsia
      and may contribute to the excess cardiovascular morbidity among women with prior
      preeclampsia.

PMID- 10421231
TI  - Effects of acute euglycemic hyperinsulinemia on urinary nitrite/nitrate excretion
      and plasma endothelin-1 levels in men with essential hypertension and
      normotensive controls.
AB  - Insulin stimulates the production of endothelin-1 (ET-1) and nitric oxide (NO) by
      isolated endothelial cells. Additionally, insulin-dependent glucose transport and
      insulin-mediated NO production partially share common elements in signal
      transduction. There are discordant data on plasma ET-1 levels during acute
      euglycemic systemic hyperinsulinemia in normotensive men and men with essential
      hypertension (EH) (known to be insulin-resistant), as well as on the relations
      between insulin sensitivity and vascular function. Our aim was to assess the
      response of approximate measures of whole-body generation of NO and ET-1 to acute
      euglycemic hyperinsulinemia in EH patients and controls. We studied 17 newly
      diagnosed untreated men with uncomplicated EH and 10 normotensive controls.
      Plasma ET-1 and urinary excretion of nitrite plus nitrate, stable NO metabolites
      (Uno(x)), were measured before and during a 3-hour hyperinsulinemic-euglycemic
      clamp. Both in hypertensives and normotensives, plasma ET-1 levels were reduced
      after 2 hours of the clamp (EH: baseline, 3.1+/-1.9 pg/mL; 2 hours, 1.9+/-1.2
      pg/mL, P = .04 v baseline; controls: baseline, 4.2+/-2.6 pg/mL; 2 hours, 2.8+/
      1.4 pg/mL, P = .04 v baseline). No significant changes in Uno(x) during the clamp
      were observed. Changes in Uno(x) during the clamp (deltaUno(x)) and differences
      in plasma ET-1 measured before the end and before the beginning of the clamp
      (deltaET-1) were correlated in the controls (r = .75, P = .01) but not in EH (r =
      -.01, P = .97). No parameter of glucose metabolism correlated with basal Uno(x),
      basal plasma ET-1, deltaUno(x), and deltaET-1, whether absolute or percent
      values, in either group. Thus, acute euglycemic hyperinsulinemia produces a
      decrease in plasma ET-1 in both EH patients and controls. The lack of correlation
      between deltaUno(x) and deltaET-1 under these conditions in EH may suggest an
      impairment of systems governing interactions between the NO-dependent pathway and
      ET-1. In addition, insulin actions on glucose metabolism and on the endothelial
      mediators appear dissociated.

PMID- 10421233
TI  - Effects of gliclazide versus metformin on the clinical profile and lipid
      peroxidation markers in type 2 diabetes.
AB  - The sulfonylurea gliclazide and the biguanide metformin have different mechanisms
      to reduce glycemia. We performed a randomized study to compare these two agents
      with respect to glycemic control and effects on lipid peroxidation markers in 36
      adult patients with type 2 diabetes. Both agents significantly decreased
      glycosylated hemoglobin ([HbA1c] P < .05), fructosamine (P < .05), and the
      glucose-excursion curve during the oral glucose tolerance test ([OGTT] P < .01).
      With regard to the insulin curve during this test, no significant change was
      observed with metformin and a significant increase was measured with gliclazide
      (P < .05). Considering the small number of events, no significant difference was
      detected in the number of hypoglycemic episodes between the two agents. More
      upper-gastrointestinal (GI) symptoms were observed with metformin compared with
      gliclazide (P < .05). Even with no change in the standard lipid profile, both
      agents increased serum vitamin E (P < .01 for gliclazide and P < .05 for
      metformin) and decreased the level of lipid peroxidation markers in low-density
      lipoprotein (LDL) and high-density lipoprotein (HDL) particles (P < .05). Despite
      different mechanisms of action, gliclazide and metformin demonstrated comparable
      levels of efficacy and complementary effects on lipid peroxidation markers.

PMID- 10421235
TI  - Impact of acute epinephrine removal on hepatic glucose metabolism during stress
      hormone infusion.
AB  - We examined the effect of acute discontinuation of an epinephrine (EPI) infusion
      on hepatic glucose metabolism during stress hormone infusion (SHI). Glucose
      metabolism was assessed in 11 conscious, 20-hour fasted dogs using tracer and
      arteriovenous techniques after a 3-day exposure to SHI. SHI increased EPI,
      norepinephrine, cortisol, and glucagon levels (approximately sixfold to 10-fold),
      which led to marked hyperglycemia, hyperinsulinemia, and accelerated glucose
      metabolism. On day 3, EPI infusion was acutely discontinued for 180 minutes in
      five dogs while infusion of the other hormones was continued (SHI - EPI). In the
      remaining six dogs, all hormones were continued for the duration of the study
      (SHI + EPI). In SHI - EPI, EPI levels decreased from 1,678+/-191 to 161+/-47
      pg/mL. Isoglycemia (183+/-10 to 185+/-15 mg/dL) was maintained with an exogenous
      glucose infusion. Arterial insulin levels increased from 41+/-8 to 64+/-8
      microU/mL. Whole-body glucose utilization increased from 3.5+/-0.5 to 9.4+/-1.9
      mg/kg/min. Nonesterified fatty acids ([NEFAs] 763+/-292 to 147+/-32 micromol/L)
      decreased. Net hepatic glucose output decreased (2.6+/-0.6 to 0.1+/-0.3
      mg/kg/min). In SHI + EPI, hepatic glucose metabolism remained unaltered. In
      summary, EPI plays a pivotal role during SHI by stimulating glucose production
      and inhibiting glucose utilization. In part, these effects are mediated by
      restraining pancreatic insulin secretion.

PMID- 10421234
TI  - Protective effect of an aldose reductase inhibitor against bone loss in galactose
      fed rats: possible involvement of the polyol pathway in bone metabolism.
AB  - Many patients with diabetes mellitus show a moderate reduction in bone mass. Our
      recent in vitro studies showed that sustained exposure of osteoblast-like MG-63
      cells to high glucose by itself impairs their functions partly via the polyol
      pathway. To investigate the role of hyperglycemia in the etiology of diabetic
      osteopenia in vivo separately from insulin deficiency, we determined whether
      epalrestat, an aldose reductase (AR) inhibitor (ARI), lessens the abnormalities
      in calcium (Ca) metabolism in galactose-fed rats. Weight gain was impaired in the
      rats, which was not altered by epalrestat. Galactose feeding temporarily enhanced
      bone resorption as reflected by increased biochemical markers for bone resorption
      (urinary excretion of pyridinoline [PYR] and deoxypyridinoline [DPYR]) at 1 to 3
      months, which were significantly decreased by epalrestat. Epalrestat also
      restored the positive correlation between a bone-formation marker (serum
      osteocalcin [OC]) and a bone-resorption marker (urinary DPYR excretion) at 6.5
      months. Histomorphometric analysis of bone performed 6.5 months after galactose
      feeding showed that both the bone volume and osteoblast numbers in the tibia,
      which were significantly suppressed by galactose feeding, were partly restored to
      a significant extent by the simultaneous administration of epalrestat. In
      summary, epalrestat partially protected against the development of osteoblast
      dysfunction and reduced the temporary increase in biochemical markers for bone
      resorption induced by galactose feeding, with a resultant increase in bone
      volume, suggesting that the polyol pathway may be intimately involved in the
      development of abnormal bone metabolism in galactose-fed rats.

PMID- 10421236
TI  - Splanchnic utilization of enteral alanine in humans.
AB  - The splanchnic bed extracts the majority of the enteral nonessential amino acids
      glutamine and glutamate, while extracting a much smaller proportion of essential
      amino acids such as leucine and phenylalanine. Alanine is an abundant
      nonessential amino acid that plays an important role in hepatic gluconeogenesis
      and ureagenesis. However, its enteral fate has not been studied. Twelve normal
      healthy postabsorptive adults received a 7-hour infusion of [1-13C]alanine, 3.5
      hours intravenously (IV) and 3.5 hours via a nasogastric tube (NG). The order of
      infusion was randomized among subjects. Alanine kinetics were calculated from the
      enrichments of plasma alanine 13C and expired 13CO2. The alanine appearance rate
      (Ra), measured during the IV tracer infusion, was 279+/-17 micromol/kg/h; 92%+/
      2% of the IV-infused and 86%+/-2% of the NG-infused [1-13C]alanine tracer was
      recovered as 13CO2. From the difference in plasma alanine 13C enrichment between
      IV-infused and NG-infused tracers, we determined that the splanchnic bed
      extracted 69%+/-1% of the enterally delivered alanine tracer on the first pass
      during absorption. Only one third of the enteral alanine passed intact through
      the splanchnic bed and was made available to systemic tissues. Of the enteral
      alanine extracted, 83%+/-3% of the carboxyl-carbon label was recovered as CO2,
      leaving only 17% of the sequestered alanine available for use in splanchnic
      protein synthesis. Thus, the splanchnic bed, presumably the liver, extracts and
      metabolizes most of the enterally delivered alanine.

PMID- 10421237
TI  - The value of combined radionuclide and magnetic resonance imaging in the
      diagnosis and conservative management of minimal or localized osteomyelitis of
      the foot in diabetic patients.
AB  - Early diagnosis of osteomyelitis is helpful for a successful conservative
      treatment. The value of bone scanning combined with granulocytes labeled with
      hexamethylpropylene amine oxime (HMPAO) granulocyte-Tc99m (GN) radionuclide
      imaging (combined [RI]) with magnetic resonance imaging (MRI) for the diagnosis
      of osteomyelitis was assessed in 24 diabetic patients with foot ulcers. Evidence
      of osteomyelitis was based on the presence of at least one of the following
      criteria: (1) clinical bone involvement, (2) radiological bone involvement, (3)
      both positive combined RI and MRI, and (4) evidence of clinical bone involvement
      during the follow-up period. Thirteen patients had osteomyelitis. Seven patients
      had clinical bone involvement (sensitivity, 54%), five had radiological bone
      involvement (sensitivity, 38%), and 10 had positive combined RI for osteomyelitis
      (sensitivity, 77%). MRI demonstrated a higher sensitivity (100%). The specificity
      for combined RI and MRI was 82%. These results lead to a new diagnostic strategy
      for the early detection of minimal or localized osteomyelitis to avoid
      amputations. MRI is most appropriate following a negative x-ray in determining
      whether to treat osteomyelitis, since a negative MRI result rules out
      osteomyelitis. Antibiotic therapy should be used in the case of a positive MRI
      result, but Charcot joint disease can lead to false-positive MRI results. In this
      case, combined RI should be performed.

PMID- 10421238
TI  - Temporal association between obesity and hyperinsulinemia in children,
      adolescents, and young adults: the Bogalusa Heart Study.
AB  - Obesity is generally associated with hyperinsulinemia. However, whether obesity
      precedes or follows hyperinsulinemia is not clear. The present study examined the
      temporal nature of the association between obesity and hyperinsulinemia in a
      biracial (black-white) community-based population enrolled in the Bogalusa Heart
      Study. Three longitudinal cohorts of children (n = 427; baseline age, 5 to 7
      years), adolescents (n = 674; baseline age, 12 to 14 years), and young adults (n
      = 396; baseline age, 20 to 24 years) were selected retrospectively, with a follow
      up period of approximately 3 years. In general, longitudinal changes in the mean
      body mass index (kilograms per meter squared), an indicator of adiposity, and
      fasting insulin level did not parallel each other. In a bivariate analysis,
      baseline insulin levels correlated significantly with the follow-up body mass
      index in adolescents and adults, but not in children. On the other hand, the
      baseline body mass index correlated significantly with follow-up insulin levels
      in all cases. Logistic regression analysis showed that the proportion of subjects
      who developed obesity (body mass index > 75th percentile, specific for age, race,
      gender, and survey year) at follow-up study increased significantly across
      baseline quintiles (specific for age, race, gender, and survey year) of insulin
      only among adolescents, irrespective of race and gender. This relationship
      disappeared after adjusting for the baseline body mass index. By contrast, a
      significant positive trend between baseline quintiles of the body mass index and
      incidence of hyperinsulinemia (> 75th percentile) at follow-up study was noted
      among all age groups independent of race, gender, and baseline insulin levels.
      Further, in a multiple stepwise regression model, the best predictor of the
      follow-up insulin level was the baseline body mass index in children and adults
      and the baseline insulin in adolescents. The baseline body mass index was the
      best predictor of the follow-up body mass index in all three age groups. These
      results, by showing the temporal nature of the relation between obesity and
      hyperinsulinemia beginning in childhood, support the role of obesity in the
      development of hyperinsulinemia.

PMID- 10421239
TI  - The amylin analog pramlintide improves glycemic control and reduces postprandial
      glucagon concentrations in patients with type 1 diabetes mellitus.
AB  - To explore further the effects of the human amylin analog pramlintide on overall
      glycemic control and postprandial responses of circulating glucose, glucagon, and
      metabolic intermediates in type 1 diabetes mellitus, 14 male type 1 diabetic
      patients were examined in a double-blind, placebo-controlled, crossover study.
      Pramlintide (30 microg four times daily) or placebo were administered for 4
      weeks, after which a daytime blood profile (8:30 AM to 4:30 PM) was performed.
      Serum fructosamine was decreased after pramlintide (314+/-14 micromol/L) compared
      with placebo (350+/-14 micromol/L, P = .008). On the profile day, the mean plasma
      glucose (8.3+/-0.7 v 10.2+/-0.8 mmol/L, P = .04) and postprandial concentrations
      (incremental areas under the curve [AUCs] from 0 to 120 minutes) were
      significantly decreased during pramlintide administration (P < .01 for both)
      despite comparable circulating insulin levels (359+/-41 v 340+/-35 pmol/L). Mean
      blood glycerol values were reduced (0.029+/-0.004 v 0.040+/-0.004 mmol/L, P =
      .01) and blood alanine levels were elevated (0.274+/-0.012 v 0.246+/-0.008
      mmol/L, P = .03) after pramlintide versus placebo. Blood lactate concentrations
      did not differ during the two regimens. During pramlintide administration, the
      AUC (0 to 120 minutes) for plasma glucagon after breakfast was diminished (P =
      .02), and a similar trend was observed following lunch. In addition, peak plasma
      glucagon concentrations 60 minutes after breakfast (45.8+/-7.3 v 72.4+/-8.0 ng/L,
      P = .005) and lunch (47.6+/-9.0 v 60.9+/-8.2 ng/L, P = .02) were both decreased
      following pramlintide. These data indicate that pramlintide (30 microg four times
      daily) is capable of improving metabolic control in type 1 diabetics. This may
      relate, in part, to suppression of glucagon concentrations. Longer-term studies
      are required to ascertain whether these findings are sustained over time.

PMID- 10421240
TI  - Role of beta-chemokines in HIV-1 infection of dendritic cells maturing from CD34+
      stem cells.
AB  - OBJECTIVES: To study the susceptibility to infection by different strains of HIV
      1 viruses and the roles of chemokines (macrophage inflammatory protein-1alpha
      [MIP-1alpha], MIP-1beta, and regulated-on-activation-T-expressed-and-secreted
      [RANTES]) in CD34+ stem cells maturing into dendritic cells (DC). DESIGN: It has
      been controversial whether CD34+ stem cells are susceptible to HIV-1 infection
      and whether high levels of beta-chemokines are beneficial for suppressing HIV-1
      infection during DC maturation. These questions were addressed using different
      strains of HIV-1 and CD34+ stem cells taken from cord blood and cultured with
      granulocyte-macrophage colony stimulating factor (GM-CSF) and tumor necrosis
      factor-alpha (TNF-alpha) to generate mature DC. METHODS: CD34+ stem cells were
      exposed with M-tropic virus Ba-L or T-tropic viruses IIIB or Rut at day 1. Beta
      chemokines were added to some cells before the virus and kept throughout the
      culture. Virus replication was measured throughout the maturation of these cells
      into CD1a+ DC and CD1a- CD14+ cells using enzyme-linked immunosorbent assay
      (ELISA) for p24, nested polymerase chain reaction (PCR) for env and intracellular
      p24 detection by flow cytometry. RESULTS: First, CD34+ stem cells acquired or
      were infected by live virus because maturing cells showed infection by both M-
      and T-tropic viruses. Second, the viruses replicated actively during the
      maturation of CD34+ stem cells toward CD1a+ DC and CD1a- CD14+ cells. Third, beta
      chemokines suppressed infection by M-tropic virus Ba-L. And finally, beta
      chemokines enhanced infection by T-tropic viruses IIIB and Rut. CONCLUSIONS: In
      addition to the initial anti-M-tropic virus effect by beta-chemokines, selective
      pressure on viruses may also result because of an increase in susceptibility to T
      tropic virus. Caution should be taken when evaluating the effect of beta
      chemokine receptor agonists in AIDS therapy.

PMID- 10421241
TI  - CCR5 genotype and resistance to vertical transmission of HIV-1.
AB  - A human gene has been identified that affects susceptibility to HIV-1 infection.
      The gene codes for CCR5, the coreceptor for macrophage-tropic strains of HIV-1.
      Individuals who are homozygous for a deleted, mutant form of the gene, delta32,
      display a high degree of natural resistance to sexual and parenteral transmission
      of HIV-1. To investigate whether delta32 plays a role in vertical transmission,
      we determined the CCR5 genotype of 552 children born to infected mothers in the
      United States and correlated the genotypes with HIV-1 infection status. Of these
      children, 13% were white, 30% Latino, and 56% African American, reflecting the
      ethnic makeup of infected women in the United States. The delta32 gene frequency
      varied among these groups, ranging from 0.08 in whites to 0.02 in both Latinos
      and African Americans. Approximately 27% of the children in each ethnic group
      were infected. Four children were identified as delta32 homozygotes, two
      uninfected whites (3.77%) and two uninfected Latinos (1.68%). None of the
      infected children displayed the delta32 homozygous genotype. Among Latinos and
      whites, the number of uninfected children who carried the homozygous delta32
      mutation was significantly greater than that predicted by the Hardy-Weinberg
      equilibrium (p < .001 for Latinos, p = .044 for whites). This association was
      noted in Latino and white children whose mothers were either treated or untreated
      with zidovudine. These data document the occurrence of the homozygous delta32
      genotype among children of HIV-1-infected mothers and suggest that this mutant
      genotype may confer protection from mother-to-child transmission of HIV-1. They
      also suggest that sexual, parenteral, and vertical transmission all involve
      processes that use CCR5 as a coreceptor for primary HIV-1 infection. Therefore,
      blocking the CCR5 receptor may provide an additional strategy to prevent HIV-1
      vertical transmission.

PMID- 10421242
TI  - Bacterial vaginosis-associated microflora isolated from the female genital tract
      activates HIV-1 expression.
AB  - Alteration of cervicovaginal microbial flora can lead to vaginosis, which is
      associated with an increased risk of HIV-1 transmission. We recently
      characterized a soluble HIV-inducing factor (HIF) from the cervicovaginal lavage
      (CVL) samples of women. The goals of this study were to determine the effect of
      cervicovaginal microflora on HIV-1 expression and to elucidate the relationship
      between HIF activity and microflora. Physiologically relevant microorganisms,
      Mycoplasma, diphtheroid-like bacteria, Gardnerella vaginalis, Streptococcus
      agalactiae, and Streptococcus constellatus, cultured from the CVL of a
      representative woman with a clinical condition of bacterial vaginosis and
      possessing HIF activity, induced HIV-1 expression. The magnitude of virus
      induction varied widely with the greatest stimulation induced by diphtheroid-like
      bacteria and Mycoplasma. The transcriptional induction by Mycoplasma was mediated
      by activation of the KB enhancer, an activation mechanism shared with HIF. Also
      as with HIF, Mycoplasma induced AP-1 dependent transcription. Polymerase chain
      reaction (PCR)-based speciation showed that the isolate was M. hominis. Our data
      indicate that bacterial vaginosis-associated microflora can enhance HIV-1
      transcription and replication and identify M. hominis as a potential source for
      HIF activity. The virus-enhancing activities associated with the microflora and
      HIF may increase genital tract viral load, potentially contributing to HIV
      transmission.

PMID- 10421243
TI  - Development and significance of the HIV-1 reverse transcriptase M184V mutation
      during combination therapy with lamivudine, zidovudine, and protease inhibitors.
AB  - To analyze the emergence and role of the lamivudine (3TC)-selected HIV-1 reverse
      transcriptase (RT) M184V mutation under triple therapy, we performed a
      retrospective study of 40 nucleoside RT inhibitor-pretreated and 16 drug-naive
      patients who were switched to combined treatment with zidovudine (ZDV) plus 3TC
      plus a protease inhibitor (PI). Plasma viral load and pol genotype were analyzed
      at baseline and after 24 and 48 weeks of combination therapy. Emergence of the
      M184V RT mutation at week 48 was detected in 3 of 16 (18.7%) initially drug-naive
      subjects as opposed to 21 of 40 (52.5%) ZDV-pretreated patients. Multivariate
      logistic analysis detected HIV-1 RNA load at week 24 as the best predictor of
      subsequent selection of the M184V mutant (p = .0121). Among ZDV-resistant study
      subjects at week 24 (n = 17), those with mutant RT M184V codon had a more
      favorable HIV-1 RNA slope than those with wild-type RT 184M codon (p = .0551).
      This trend was observed, although in a less evident manner, even in pretreated
      ZDV-sensitive patients. These findings suggest that development of the 3TC
      resistance M184V mutation under triple therapy with 3TC, ZDV, and a PI may have
      unexpected beneficial effects in vivo in addition to those associated with
      resensitization of ZDV-resistant virus to ZDV.

PMID- 10421245
TI  - Prevention of mother-to-child transmission of HIV in Thailand: physicians'
      attitudes on zidovudine use, pregnancy termination, and willingness to provide
      care.
AB  - We administered a survey to Thai physicians, using regular mail, on their
      attitudes and practices regarding zidovudine (ZDV) use and pregnancy termination
      in HIV-infected pregnant women. We surveyed their willingness to care for these
      patients as well. In 1997, 79.5% of 480 respondents reported that they did not
      routinely use perinatal ZDV prophylaxis. Predictors of failure to use ZDV found
      to be significant in our logistic regression model included practice outside of
      Bangkok (odds ratio [OR] = 2.0), belief that ZDV is not cost effective (OR =
      2.5), unfamiliarity with AIDS Clinical Trials Group (ACTG) 076 results (OR =
      2.5), and failure to screen for HIV routinely (OR = 4.9). Elective abortion for
      HIV-infected women was advocated by 45.3% of respondents. Factors associated in
      multivariable analysis with this preference included specialty training in
      obstetrics/gynecology (OR = 1.8), practice inside Bangkok (OR = 2.0), male gender
      (OR = 1.9), and treatment of < or =2 HIV-infected patients yearly (OR = 1.8). A
      significant proportion of respondents described themselves as unwilling to
      perform pelvic examinations (19.2%), vaginal deliveries (30.7%), or cesarean
      deliveries (39.5%) on women who were known to be infected with HIV. We conclude
      that many Thai obstetric providers are reluctant to care for HIV-infected women,
      do not routinely use perinatal ZDV prophylaxis, and prefer to terminate
      pregnancies among HIV-infected patients. Physician education concerning the value
      of HIV screening and antiretroviral therapy in HIV-infected pregnant women is
      needed urgently in Thailand.

PMID- 10421246
TI  - Adequacy of prenatal care and prescription of zidovudine to prevent perinatal HIV
      transmission.
AB  - In 1994, data were published on the effectiveness of zidovudine in preventing
      perinatal transmission of HIV infection. Using data from surveillance projects in
      San Antonio, Dallas, and Houston, Texas, U.S.A., we linked records of children
      born from 1987 through 1996 with records of their HIV-infected mothers. Prenatal
      care was measured by Kotelchuck's Adequacy of Prenatal Care Utilization (APNCU)
      Index. We examined the association between adequacy of prenatal care and four
      measures of zidovudine prescription: prenatal, intrapartum, neonatal, and the
      complete regimen. Inclusion criteria was that the mother's HIV infection was
      diagnosed before a live birth; 221 mother-infant pairs were included in the
      analysis. Overall, 68% received inadequate or no prenatal care. Over time, the
      proportion of mother-infant pairs with adequate prenatal care doubled (24%-48%;
      relative risk [RR], 2.0; 95% confidence interval [CI], 1.3-3.0), and the
      proportion prescribed prenatal zidovudine tripled (20%-67%; RR, 3.4; 95% CI, 2.4
      4.9). In logistic regression, APNCU (adjusted odds ratio [aOR], 2.6; 95% CI, 1.1
      6.2) and time period (aOR, 19.9; 95% CI, 8.1-48.7) were associated with prenatal
      prescription of zidovudine. The benefits of prenatal care, including HIV testing
      and zidovudine treatment, underscore the urgent need to improve access to and use
      of prenatal care services.

PMID- 10421244
TI  - Insulin resistance in HIV protease inhibitor-associated diabetes.
AB  - BACKGROUND: Fasting hyperglycemia has been associated with HIV protease inhibitor
      (PI) therapy. OBJECTIVE: To determine whether absolute insulin deficiency or
      insulin resistance with relative insulin deficiency and an elevated body mass
      index (BMI) contribute to HIV PI-associated diabetes. DESIGN: Cross-sectional
      evaluation. PATIENTS: 8 healthy seronegative men, 10 nondiabetic HIV-positive
      patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26
      kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8
      HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients
      on PI received indinavir. MEASUREMENTS: Fasting concentrations of glucoregulatory
      hormones. Direct effects of indinavir (20 microM) on rat pancreatic beta-cell
      function in vitro. RESULTS: In hyperglycemic HIV-positive subjects, circulating
      concentrations of insulin, C-peptide, proinsulin, glucagon, and the
      proinsulin/insulin ratio were increased when compared with those of the other 4
      groups (p < .05). Morning fasting serum cortisol concentrations were not
      different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers
      were uncommon in all groups. High BMI was not always associated with diabetes. In
      vitro, indinavir did not inhibit proinsulin to insulin conversion or impair
      glucose-induced secretion of insulin and C-peptide from rat beta-cells.
      CONCLUSIONS: The pathogenesis of HIV PI-associated diabetes involves peripheral
      insulin resistance with insulin deficiency relative to hyperglucagonemia and a
      high BMI. Pancreatic beta-cell function was not impaired by indinavir. HIV PI
      associated diabetes mirrors that of non-insulin-dependent diabetes mellitus and
      impaired insulin action in the periphery.

PMID- 10421247
TI  - Adherence to guidelines for antiretroviral therapy and for preventing
      opportunistic infections in HIV-infected adults and adolescents in Ryan White
      funded facilities in the United States.
AB  - To determine adherence by health care providers to guidelines for antiretroviral
      therapy and for prevention of opportunistic infections (OIs) in adults with HIV
      infection in federally funded facilities in the United States, we reviewed
      records of HIV-infected adults (>13 years) in 11 Ryan White Title III facilities
      in four states for information on eight standard-of-care recommendations during
      November 1996 through September 1997. Eligibility required a visit to the
      facility within 6 months before record abstraction and a lowest CD4+ lymphocyte
      count <500 cells/microl. Reviews were completed for 148 patients in Maryland, 355
      in New York, 370 in Georgia, and 538 in Illinois. Adherence to prevention
      measures by health care providers was >85% for HIV plasma RNA testing,
      prescription of antiretroviral therapy, Pneumocystis carinii pneumonia (PCP)
      prophylaxis, anti-Toxoplasma antibody testing, and obtaining Papanicolaou (Pap)
      smears but lower (69%-80%) for Mycobacterium avium complex (MAC) prophylaxis,
      tuberculin skin testing (TST), and pneumococcal vaccination. Adherence was
      similar by patient age, gender, racial/ethnic group, urban versus rural, and
      hospital versus clinic setting but was generally lower for injecting drug users
      (IDUs) than for patients with other HIV exposures (p < .05 by multivariate
      analysis for TST, anti-Toxoplasma antibody testing, Pap smear, and measurement of
      HIV plasma RNA). Adherence by health care providers to guidelines for preventing
      OIs in these federally funded facilities is generally high but could be improved
      for some prevention measures, for instance, MAC prophylaxis, TST, and
      pneumococcal vaccination, especially for IDUs.

PMID- 10421248
TI  - Effect of receptive oral sex and smoking on the incidence of hairy leukoplakia in
      HIV-positive gay men.
AB  - We sought to determine whether hairy leukoplakia (HL), an Epstein-Barr virus
      related oral lesion, is associated with receptive oral sex activity and cigarette
      smoking among HIV-positive gay men. Oral examinations were conducted every 6
      months among San Francisco Men's Health Study participants over a 6-year period.
      We fitted time-to-lesion regression models to compare the incidence of HL among
      men who had mouth-to-penis contact with various numbers of partners, while
      controlling for cigarette smoking and CD4 count. The 6-year incidence of HL was
      32% among 291 HIV-positive men. We found no significant increase in the hazard of
      developing HL for each additional insertive-oral-sex male partner in the past 6
      months (relative hazard = 1.01; 95% confidence interval [CI], 0.99, 1.02), and a
      similar lack of association when number of sex partners was categorized. However,
      the hazard of developing HL doubled with any 300-unit decrease in CD4 count (95%
      CI, 1.4, 2.7), or if men smoked > or =20 cigarettes/day compared with nonsmokers
      (95% CI, 1.2, 3.9). This finding, which may suggest one effect that smoking
      produces on the oral mucosa's local immune response, merits further
      investigation.

PMID- 10421250
TI  - Supplemental vitamin B and progression to AIDS and death in black South African
      patients infected with HIV.

PMID- 10421249
TI  - Willingness of injection drug users to participate in an HIV vaccine efficacy
      trial in Bangkok, Thailand.
AB  - We assessed willingness to participate in an HIV recombinant gp120 bivalent
      subtypes B/E candidate vaccine efficacy trial among 193 injection drug users
      (IDUs) attending drug treatment clinics in Bangkok, Thailand. IDUs previously
      enrolled in a prospective cohort study were invited to group sessions describing
      a potential trial, then completed questionnaires assessing comprehension and
      willingness to participate. A week later, they completed a follow-up
      questionnaire that again assessed comprehension and willingness to participate,
      as well as barriers to and positive motives for participation, with whom (if
      anyone) they talked about the information, and whether others thought
      participation was a good, bad, or neutral idea. At baseline, 51% were definitely
      willing to participate, and at follow-up 54%; only 3% were not willing to
      participate at either time. Comprehension was high at baseline and improved at
      follow-up. Participants who viewed altruism, regular HIV tests, and family
      support for participation as important were more willing to volunteer. Frequency
      of incarceration and concerns about the length of the trial, possible vaccine
      induced accelerated disease progression, and lack of family support were
      negatively associated with willingness. Overall, IDUs comprehended the
      information needed to make a fully informed decision about participating in an
      rgp120 vaccine efficacy trial and expressed a high level of willingness to
      participate in such a trial.

PMID- 10421251
TI  - Decreased peripheral circulation of HIV-infected cells in a subset of long-term
      nonprogressors. The French ALT Study Group.

PMID- 10421252
TI  - Evidence for a local synthesis of beta-chemokines within the genital tract of
      both HIV-1-infected and uninfected women.

PMID- 10421253
TI  - The role of postoperative radiotherapy for patients with completely resected
      nonsmall cell lung carcinoma: seeking to optimize local control and survival
      while minimizing toxicity.

PMID- 10421254
TI  - The development of new brain tumor therapy utilizing the local and sustained
      delivery of chemotherapeutic agents from biodegradable polymers.

PMID- 10421255
TI  - Relation between lymphatic vessel diameter and clinicopathologic parameters in
      squamous cell carcinomas of the oral region.
AB  - BACKGROUND: In an attempt to determine the mechanism of cervical lymph node
      metastases, the authors studied the relation between lymphatic vessels in or
      around tumor tissue and lymph node metastases in patients with primary squamous
      cell carcinoma (SCC) of the oral region by enzyme histochemistry using
      5'nucleotidase-alkaline phosphatase. METHODS: The subjects were 23 patients who
      had biopsy proven oral SCC. After enzyme histochemical staining, the cross
      sectional dimension (referred to as diameter) of the lymphatic vessels were
      measured and analyzed in relation to the T classification of the tumor, degree of
      tumor differentiation, and mode of invasion. RESULTS: The average diameter of the
      lymphatic vessels in or around tumor tissue was significantly greater than that
      in tumor free tissue (P < 0.01). The mode of invasion correlated significantly
      with the lymphatic vessel diameter (P < 0.01). The diameter did not correlate
      significantly with the T classification (P range, 0.135-0.254) or tumor
      differentiation (P = 0.274). The following relation was found between the
      incidence of cervical lymph node metastases and the mode of invasion: 40.0% of
      Grade 2 tumors were positive for metastases, 71.4% of Grade 3 tumors were
      positive, and 75.0% of Grade 4 tumors were positive (grading was according to
      Jakobsson's classification). CONCLUSIONS: Of the factors evaluated in this study,
      only the mode of invasion correlated significantly with the diameter of the
      lymphatic vessels. Although other studies have shown that tumor thickness and
      perhaps even perineural and blood vessel invasion may be equally important, the
      findings of the current study suggest that both lymphatic vessel diameter and the
      mode of invasion may be important factors in the prediction of cervical lymph
      node metastases.

PMID- 10421256
TI  - Polymorphous low grade adenocarcinoma: a clinicopathologic study of 164 cases.
AB  - BACKGROUND: Polymorphous low grade adenocarcinomas (PLGA) are minor salivary
      gland neoplasms with a predilection for intraoral sites. METHODS: One hundred
      sixty-four cases of PLGA diagnosed between 1970-1994 were retrieved from the
      files of the Armed Forces Institute of Pathology, Washington, DC. Histologic
      features were reviewed, immunohistochemical studies and prognostic markers were
      performed, and patient follow-up was obtained. The data were analyzed
      statistically. RESULTS: The patients included 109 women and 55 men, ages 23-94
      years (average, 57.6 years). The patients usually presented clinically with a
      palatal mass that ranged in size from 0.4-6 cm (average, 2.2 cm). The tumors were
      infiltrative and characterized by a polymorphous growth pattern, with individual
      tumors demonstrating multiple patterns, including solid, ductotubular,
      cribriform, trabecular, and single file growth. Neurotropism was identified
      frequently. The neoplastic cells were isomorphic with vesicular nuclei. Mitotic
      activity was inconspicuous. At an average of 115.4 months after presentation,
      approximately 97.6% of all patients were either alive or had died without
      evidence of recurrent disease after treatment with surgical excision only. Four
      patients had evidence of disease at last follow-up; three had died with evidence
      of tumor, and one patient was alive with tumor. CONCLUSIONS: PLGA is a neoplasm
      of minor salivary gland origin that must be separated from adenoid cystic
      carcinoma and benign mixed tumor for therapeutic and prognostic considerations.
      Conservative but complete surgical excision is the treatment of choice for these
      slow-growing tumors with a low proliferation index; adjuvant therapy does not
      appear to alter the prognosis.

PMID- 10421257
TI  - External beam radiation therapy with or without high-dose-rate intraluminal
      brachytherapy for patients with superficial esophageal carcinoma.
AB  - BACKGROUND: Clinical results of external beam radiation therapy (RT) with or
      without intraluminal brachytherapy (IBT) for patients with superficial esophageal
      carcinoma were evaluated retrospectively. METHODS: Between 1985 and 1996, 21
      patients with superficial esophageal squamous cell carcinoma were treated by
      external beam RT, with or without high dose rate IBT, with curative intent. There
      were 18 males and 3 females; their median age was 67 years (range, 51-85 years).
      Eight patients were treated by external beam RT alone (60-69 gray [Gy]), whereas
      the remaining 13 patients were treated by IBT after external beam RT. Most
      patients in the IBT group received 2 or 3 fractions of IBT of 4 Gy after external
      beam RT of 50-56 Gy. RESULTS: All of the 21 tumors showed complete regression at
      the end of RT. Local recurrence was noted in 4 patients in the group that
      received external beam RT alone and in 2 patients in the IBT group. Salvage
      therapy was successful for 4 patients. Local control probability and cause
      specific survival probability for the IBT group were significantly higher than
      those for the group that received external beam RT alone (P < 0.05 for both). The
      3-year local control and cause specific survival rates for the IBT group were 85%
      and 100%, respectively, whereas those for the external beam RT group were 45% and
      67%, respectively. Transient esophageal ulcers were noted in two patients in the
      IBT group. CONCLUSIONS: External beam RT and IBT is a safe and effective
      treatment modality for patients with superficial esophageal carcinoma.

PMID- 10421258
TI  - Evaluation of chest computed tomography in the staging of patients with
      potentially resectable liver metastases from colorectal carcinoma.
AB  - BACKGROUND: Chest computed tomography (CT) often is used to rule out lung
      metastases in patients with potentially resectable liver metastases from
      colorectal carcinoma. In the current study the authors evaluated whether CT of
      the chest was necessary in patients with a negative chest radiograph. METHODS:
      The authors performed a retrospective analysis of 202 patients with negative
      initial chest X-rays who were undergoing evaluation for potentially resectable
      liver metastases from colorectal carcinoma. Patients with highly suspicious
      pulmonary lesions on the initial chest CT scan underwent a thoracoscopy and
      biopsy. All patients were monitored for the development of pulmonary metastases.
      RESULTS: Sixty patients (30%) had a positive initial chest CT scan. Two patients
      were found to have metastases by comparison with prior CT scans. Seventeen
      patients had highly suspicious lesions that were biopsied, but only 2 were found
      to have pulmonary metastases; the other lesions were benign. An additional 13 of
      these 60 patients developed lung metastases during follow-up, 6 of whom were
      diagnosed in retrospect. Of the 142 patients with a negative initial CT scan, 33
      (23%) developed pulmonary metastases. The rate of pulmonary metastases in both
      groups was not significantly different, regardless of whether the CT scans were
      positive or negative. CONCLUSIONS: During routine preoperative workup for liver
      resection, the majority of lesions appearing on chest CT scans of patients with
      negative chest radiographs were not malignant. The positive yield of CT-guided
      workup was only 10 of 202 patients (5%). Based on this review the authors
      question the use of chest CT scans in this setting.

PMID- 10421259
TI  - Three different intraoperative radiation modalities (electron beam, high-dose
      rate brachytherapy, and iodine-125 brachytherapy) in the adjuvant treatment of
      patients with recurrent colorectal adenocarcinoma.
AB  - BACKGROUND: Intraoperative electron beam radiation therapy (IOERT) has been used
      in the treatment of patients with recurrent colorectal adenocarcinoma for the
      last 2 decades. Other intraoperative radiation modalities, such as intraoperative
      high-dose-rate brachytherapy (IOHDR) and intraoperative iodine-125 (125I)
      brachytherapy, present theoretic advantages for selected patients with recurrent
      colorectal adenocarcinoma. The experience of a single-institution series in which
      these three intraoperative radiation modalities were used in a nonrandomized
      manner is discussed in this report. METHODS: Between September 1989 and January
      1997, 80 patients with colorectal adenocarcinoma recurrent in the pelvis or in
      the paraaortic lymph nodes were treated with IOERT (28 patients), IOHDR (23
      patients), or 125I brachytherapy (29 patients). RESULTS: The overall 5-year local
      control rate was 26% (median = 12 months; 95% confidence interval [95%CI], 6-17).
      Tumors in paraaortic sites had significantly better local control than those in
      the pelvis (P = 0.03). The 5-year overall survival rate was 4% (median = 20
      months; 95% CI, 17-23). Patients with microscopic residual disease (P = 0.02) and
      those treated with postoperative external beam irradiation (EBRT) (P = 0.0007)
      had statistically significant longer survival. Forty-one percent of the treated
      patients experienced complications: These were severe (Radiation Therapy Oncology
      Group Grade 4-5) in 19% of patients. CONCLUSIONS: Intraoperative radiation can
      locally control recurrent colorectal adenocarcinoma in a select group of
      patients. Patients with localized relapses, microscopic residual tumor, and no
      distant metastases and those receiving additional EBRT are most likely to benefit
      from intraoperative irradiation. The authors now routinely recommend EBRT to all
      patients for whom it is suitable (including those who have had prior EBRT) and
      consider the combination of the intraoperative modalities whenever feasible.

PMID- 10421260
TI  - Postoperative prediction of and strategy for metastatic recurrent hepatocellular
      carcinoma according to histologic activity of hepatitis.
AB  - BACKGROUND: The hepatitis activity index (HAI) score describes the histologic
      status of accompanying chronic hepatitis and was established by pathologists. The
      aim of this study was twofold: 1) to investigate the correlation between
      intrahepatic metastatic recurrence (IM) and the HAI score of the noncancerous
      region of the liver and 2) to estimate the usefulness of postoperative preventive
      chemotherapy in patients with hepatocellular carcinoma (HCC). METHODS: The study
      included 158 consecutive patients who underwent curative resection for HCC and
      had been observed for > 1 year. Based on the HAI scores of the noncancerous
      region the patients were classified into 3 groups: those with mild hepatitis (n =
      33) (i.e., with HAI scores of 0-5), those with moderate hepatitis (n = 77) (with
      HAI scores of 6-9), and those with severe hepatitis (n = 48) (those with HAI
      scores of > or = 10). In addition, a prospective randomized trial of
      postoperative adjuvant chemotherapy was performed for 21 patients with moderate
      hepatitis. RESULTS: The patients in the moderate hepatitis group were found to be
      at higher risk for IM recurrence within 2 years after HCC resection compared with
      those patients in the mild (P = 0.05) and severe (P < 0.01) hepatitis groups. The
      incidences of more than two tumors and portal vein involvement in patients with
      moderate hepatitis were much higher than in those patients with mild or severe
      hepatitis. Multivariate analysis showed that intraoperative bleeding volume, the
      number of nodules, portal vein involvement, and moderate hepatitis were
      independent predictive factors for IM recurrence free survival. Ten patients with
      moderate hepatitis had received postoperative intrahepatic arterial chemotherapy
      (2-3 courses with a maximum dose of 80 mg of cisplatin and 10 mg of mitomycin C
      at 1-month intervals) for the last 3 years. Although the number of patients was
      small, the therapy improved the disease free survival rate significantly compared
      with 11 patients who received no therapy. CONCLUSIONS: The patients with moderate
      hepatitis (HAI score of 6-9) had the highest rate of IM recurrence among the
      three HAI groups. Postoperative hepatic arterial chemotherapy may be useful in
      improving the rate of disease free survival after surgery among these patients.

PMID- 10421261
TI  - ras gene mutations in ethmoid sinus adenocarcinoma: prognostic implications.
AB  - BACKGROUND: The presence of mutations of the 3 ras proto-oncogenes in 31 cases of
      ethmoid sinus adenocarcinoma, an uncommon tumor type epidemiologically related to
      professional exposure to wood dust, was studied. METHODS: The authors studied 31
      patients with ethmoid sinus adenocarcinoma. The polymerase chain reaction was
      used to amplify ras specific sequences of DNA isolated from paraffin embedded
      tumor samples. ras point mutations were subsequently detected with mutation
      specific oligonucleotide probes. RESULTS: H-ras was found to be mutated in 5
      cases (16%). It is noteworthy that all of these mutations were identical and
      consisted of a G-for-T transversion at the second base of codon 12. H-ras
      mutations were related to a worse prognosis, with shorter tumor free survival (P
      = 0.04) and overall survival (P = 0.008). T classification was a significant
      clinical factor related to survival (P = 0.01 for disease free survival and P =
      0.006 for overall survival). The prognostic value of H-ras mutation was
      consistent after adjustment for T classification. H-ras mutations showed no
      association with patients' previous exposure to wood dust. K-ras was found to be
      transformed in a single case; this was the only patient in the series to develop
      lymph node metastases. In this case, both the nasal tumor and the lymph nodes
      showed the GAT-for-GGT mutation at codon 12 of K-ras. No activation of the N-ras
      gene was detected. CONCLUSIONS: The presence of H-ras point mutations defines a
      subgroup of patients with ethmoid sinus adenocarcinomas for whom the prognosis is
      very poor. The finding that all of these mutations are identical emphasizes the
      peculiarity of this type of tumor.

PMID- 10421262
TI  - A controlled study of postoperative radiotherapy for patients with completely
      resected nonsmall cell lung carcinoma. Groupe d'Etude et de Traitement des
      Cancers Bronchiques.
AB  - BACKGROUND: Postoperative radiotherapy is commonly used to treat patients with
      completely resected nonsmall cell lung carcinoma, but its effect on overall
      survival has not been established. METHODS: After undergoing complete surgical
      resection, 728 patients with non-small cell lung carcinoma (221 Stage I, 180
      Stage II, and 327 Stage III) were randomized to receive either postoperative
      radiotherapy at a total dose of 60 gray or observation only . The main end point
      was overall survival. RESULTS: At the reference date, 218 of 355 patients in the
      control group had died and 262 of 373 in the radiotherapy group had died. Five
      year overall survival was 43% for the control group and 30% for the radiotherapy
      group (P = 0.002, log rank test; relative risk [RR]: 1.33; 95% confidence
      interval [CI]: 1.11-1.59). This result was not modified by adjustment for
      potential prognostic factors. The excess mortality rate for the radiotherapy
      group was due to an excess of intercurrent deaths (P = 0.0001; RR: 3.47; the 5
      year intercurrent death rate was 8% for the control group and 31% for the
      radiotherapy group). Radiotherapy had no significant effect on local recurrence
      (RR: 0.85; 95% CI: 0.64-1.14) and no effect on metastasis (RR: 1.06; 95% CI: 0.85
      1.31). The rate of non-cancer-related death increased with the dose per fraction
      delivered.

PMID- 10421263
TI  - Frequent false-positive results of Aspergillus latex agglutination test:
      transient Aspergillus antigenemia during neutropenia.
AB  - BACKGROUND: Two serologic assays, Aspergillus latex agglutination testing (LA)
      and plasma (1-->3)-beta-D-glucan (BDG) measurement, are used when invasive
      pulmonary aspergillosis (IPA) is suspected. Despite the high specificity of these
      assays, false-positive results are frequent for neutropenic patients. This study
      was conducted to evaluate the efficacy of LA and BDG and to investigate the cause
      of the false-positive results. METHODS: Eighty-eight consecutive patients with
      hematologic malignancies who underwent intensive chemotherapy were tested weekly
      with LA and BDG. RESULTS: Sixteen of 88 patients were diagnosed as having IPA.
      The sensitivity, specificity, and positive predictive values were 23%, 98%, and
      64% for LA and 27%, 88%, and 52% for BDG, respectively. Of 11 patients who became
      positive for LA only during neutropenic periods, 2 patients developed IPA. In
      contrast, six of eight patients who became positive for LA during nonneutropenic
      periods developed IPA. Transient Aspergillus antigenemia was more frequently
      encountered during neutropenia (2.9%) than during nonneutropenic periods (0.2%).
      The plasma BDG concentration increased at the nadir of neutropenia in 36 of 45
      patients who had no signs of IPA, and it exceeded the level of 20 pg/mL in 2
      patients. CONCLUSIONS: Both BDG and LA have a low sensitivity and a high
      specificity for IPA. However, the false-positive rate of LA increases during
      neutropenic periods. Caution should be exercised in interpreting the results of
      these blood tests, especially when patients are neutropenic.

PMID- 10421264
TI  - Mucosal oncogenic human papillomaviruses and extragenital Bowen disease.
AB  - BACKGROUND: Genital Bowen disease is known to have a strong association with
      human papillomavirus (HPV) type 16. On the other hand, previous studies of
      extragenital Bowen disease (EBD) that have used different hybridization
      techniques have produced discordant results in the detection of mucosal oncogenic
      HPV. METHODS: Ninety-four samples of EBD from 78 patients were investigated
      clinicopathologically. DNA extracted from fixed and embedded tissues was analyzed
      for the presence of the main mucosal oncogenic HPV types 16, 18, 31, and 33 using
      polymerase chain reaction (PCR) with specific primers described in 1996 by Baay
      et al., which are particularly well adapted to fixed tissues and give small
      amplimers. Moreover, 11 EBD of the hands were investigated by in situ
      hybridization (ISH). RESULTS: Of the 94 extragenital BD obtained from 78
      patients, HPV DNA type 16 was detected in 78 cases (83%) from 65 patients (83.3%)
      by PCR. Nine patients with EBD of the hands (90%) had HPV type 16, and ISH
      displayed a diffuse hybridization pattern that corresponded to the episomal viral
      form of HPV DNA. CONCLUSIONS: The current retrospective study of 94 samples
      clearly demonstrates the high prevalence of HPV type 16 infection in EBD,
      especially in EBD of the hands. In this study, no specific clinical, topographic,
      or histopathologic features of any lesions were found to be indicative of the
      presence or absence of HPV.

PMID- 10421265
TI  - Classification of cutaneous malignant melanoma: a reassessment of histopathologic
      criteria for the distinction of different types.
AB  - BACKGROUND: Human cutaneous malignant melanoma currently is classified into four
      principle types: nodular, superficial spreading, lentigo maligna, and acral
      lentiginous. The criteria for the histopathologic diagnosis of these types are
      not applied consistently. Nevertheless, the classification has become the
      foundation of many clinical, histopathologic, epidemiologic, and molecular
      studies. The results of those studies can have validity only if the
      classification itself is valid. For this reason, the authors reassessed
      histopathologic criteria advocated for the distinction of the different types of
      melanoma and searched for other repeatable constellations of findings that may
      serve to define distinct subsets of the neoplasm. METHODS: Nine hundred fifteen
      melanomas were examined with regard to 72 parameters that are considered to be
      important for histopathologic diagnosis. The results were analyzed statistically
      with special attention to findings that have been reported to be characteristic
      of the four principle types of melanoma. RESULTS: The histopathologic criteria
      advocated for the distinction of different types of melanoma were found not to
      correlate with one another. A logistic regression analysis did not detect any
      other repeatable constellation of morphologic findings that may reflect a
      distinct biologic subgroup. CONCLUSIONS: The validity of the current
      classification of cutaneous malignant melanoma into four principle types could
      not be substantiated. Malignant melanoma may present with many different forms,
      but these forms appear to be part of a continuous spectrum rather than examples
      of distinct biologic entities.

PMID- 10421266
TI  - Multidrug resistance modulators and doxorubicin synergize to elevate ceramide
      levels and elicit apoptosis in drug-resistant cancer cells.
AB  - BACKGROUND: To provide insight for the development of more effective clinical
      agents, the authors attempted to elucidate the mechanisms of action of multidrug
      resistance (MDR) modulators. Previously, the authors found that MDR modulators
      blocked the conversion of ceramide to glucosylceramide in MDR cells, thereby
      enhancing cytotoxicity. Because ceramide is a critical component of the apoptosis
      signaling cascade, the current study examined the impact of therapy using agents
      that elicit ceramide formation combined with agents that block ceramide
      glycosylation. METHODS: Doxorubicin-resistant human breast carcinoma cells (MCF-7
      AdrR) were treated with either doxorubicin, tamoxifen, cyclosporine A, or the
      cyclosporine A analog SDZ PSC 833 (PSC 833) or with combinations thereof, and
      ceramide and glucosylceramide metabolisms were measured by cell radiolabeling.
      Cell viability was quantitated spectrophotometrically and apoptosis was evaluated
      analyzing DNA integrity by gel electrophoresis. RESULTS: Whereas cyclosporine A
      blocked the generation of glucosylceramide in MCF-7-AdrR cells, a chemical
      cousin, PSC 833, elicited a 3-fold increase in glucosylceramide and a 5-fold
      increase in ceramide levels at 24 hours. The PSC 833 response was time
      dependent(as early as 30 minutes) and dose-dependent (as low as 0.1 microM). The
      appearance of ceramide foreran the generation of glucosylceramide. Sphingomyelin
      levels were not decreased in response to PSC 833; however, Fumonisin B1, a
      ceramide synthase inhibitor, blocked PSC 833-induced ceramide generation. Adding
      tamoxifen, which blocks ceramide glycosylation, to the PSC 833 regimen boosted
      ceramide levels 11-fold over controls and caused DNA fragmentation. A 3-component
      regimen comprised of tamoxifen, doxorubicin, and PSC 833 increased ceramide
      levels 26-fold and brought cell viability to zero. CONCLUSIONS: These results
      demonstrate that MDR modulators can be used separately, in combination, or in
      conjunction with chemotherapy at clinically relevant concentrations to manipulate
      cellular ceramide levels and restore sensitivity in the drug resistant setting.
      As such, this represents a new direction in the treatment of cancer.

PMID- 10421267
TI  - Serum testosterone and sex hormone-binding globulin concentrations and the risk
      of prostate carcinoma: a longitudinal study.
AB  - BACKGROUND: It has been hypothesized that high androgen levels are determinants
      of prostate carcinoma. METHODS: Serum concentrations of testosterone, sex hormone
      binding globulin (SHBG), and androstenedione were analyzed to determine their
      role as predictors of prostate carcinoma in a longitudinal, population-based,
      nested case-control study. The serum concentrations of testosterone, SHBG, and
      androstenedione were determined from serum samples collected by the Finnish
      Mobile Clinic Health Examination Survey between 1968-1972 and stored at -20
      degrees C. During a follow-up period of 24 years, a total of 166 prostate
      carcinoma cases occurred among men who originally were cancer free. Two controls
      (matched for age and municipality) were chosen. RESULTS: There was no association
      between serum testosterone, SHBG, or androstenedione concentrations and the
      occurrence of subsequent prostate carcinoma in the total study population or in
      subgroups determined based on age or body mass index. The association was not
      strengthened by simultaneous adjustment for the hormonal variables. CONCLUSIONS:
      The results of the current study do not appear to corroborate the hypothesis that
      serum testosterone, SHBG, or androstenedione are determinants of the subsequent
      occurrence of prostate carcinoma.

PMID- 10421268
TI  - Increased angiogenin expression in the tumor tissue and serum of urothelial
      carcinoma patients is related to disease progression and recurrence.
AB  - BACKGROUND: The progression of solid tumors is at least partly dependent on
      angiogenesis, the induction of which is mediated by several angiogenic factors,
      including angiogenin (ANG). The authors evaluated the expression of ANG in the
      tumor tissue and serum of patients with urothelial carcinoma. METHODS: The
      expression of ANG in 5 human bladder carcinoma cell lines and 24 urothelial
      carcinomas (10 superficial carcinomas and 14 invasive carcinomas) and in
      corresponding normal urothelial tissues was investigated by reverse transcriptase
      polymerase chain reaction and Northern blot analysis. Serum levels of ANG in 52
      healthy volunteers and in 135 patients with urothelial carcinomas (81 superficial
      carcinomas and 54 invasive carcinomas) were measured by using a sandwich enzyme
      immunoassay. RESULTS: ANG mRNA transcripts were detected in all of the bladder
      carcinoma cell lines, urothelial carcinomas, and normal tissues. The mean level
      of ANG expression in invasive urothelial carcinomas was 4-fold higher than in
      superficial carcinomas and 5-fold higher than in normal tissues. The mean serum
      ANG concentration for invasive urothelial carcinoma patients (514.6+/-211.1
      ng/mL) was significantly higher than for superficial urothelial carcinoma
      patients (381.7+/-169.3 ng/mL) and healthy volunteers (337.5+/-71.4 ng/mL). The
      overall survival rate of patients with elevated serum levels of ANG was
      significantly lower than that of patients with normal levels. Moreover, among the
      47 patients with advanced urothelial carcinoma who underwent complete resection,
      the disease free survival rate of patients with elevated serum levels of ANG was
      significantly lower than that of patients with normal levels. CONCLUSIONS: These
      results indicate that ANG is strongly expressed in the tumor tissue and is
      present in high levels in the serum of patients with invasive urothelial
      carcinoma compared with superficial carcinoma patients and that elevation of
      serum ANG level could be used as a novel predictor of the prognoses of patients
      with urothelial carcinoma.

PMID- 10421269
TI  - Local and sustained delivery of 5-fluorouracil from biodegradable microspheres
      for the radiosensitization of glioblastoma: a pilot study.
AB  - BACKGROUND: The authors have developed a new method of drug delivery into the
      brain using implantable biodegradable microspheres. In this study, this method
      was used to provide localized and sustained delivery of 5-fluorouracil (5-FU)
      after the surgical resection of glioblastoma. This antimetabolite and
      radiosensitizing drug was selected in an attempt to decrease the rate of local
      recurrence of the tumor. METHODS: Eight patients with newly diagnosed
      glioblastoma were included in the study and 2 increasing amounts of 5-FU were
      studied (70 mg and 132 mg). After surgical resection of the tumor, poly(D-L
      lactide-co-glycolide) 5-FU-loaded microspheres with an average dimension of 45
      microm were implanted in the wall of the surgical bed. External beam radiation
      (59.4 grays) was initiated before the seventh postsurgical day. Patients were
      followed by clinical examination, magnetic resonance imaging, and 5-FU assays in
      the blood and cerebrospinal fluid (CSF). RESULTS: 5-FU assays confirmed sustained
      concentrations in the CSF for at least 1 month. Concentrations of 5-FU in the
      blood were lower and transitory. Systemic tolerance to the treatment was good;
      one case of recurrent brain swelling was observed at the higher dose studied. At
      the time of last follow-up the overall median survival time was 98 weeks from the
      time of implantation and 2 patients had achieved disease remission at 139 and 153
      weeks, respectively. CONCLUSIONS: This study demonstrates that biodegradable
      microspheres are efficient systems for drug delivery into the brain and may have
      future application in the treatment of brain tumors. Further studies are needed
      to confirm the potential of 5-FU-loaded microspheres for the radiosensitization
      of glioblastoma. [Please see editorial on pages 197-9, this issue].

PMID- 10421270
TI  - Comparative genomic hybridization in patients with supratentorial and
      infratentorial primitive neuroectodermal tumors.
AB  - BACKGROUND: Intracranial primitive neuroectodermal tumors (PNETs) occur in the
      supratentorial and infratentorial regions of the brain. Although histologically
      similar, the natural history of the tumor at each site differs. The study goal
      was to determine whether there was evidence of a genetic difference between
      supratentorial and infratentorial PNETs. METHODS: Using comparative genomic
      hybridization (CGH), 53 PNETs were analyzed to determine copy number aberrations.
      Forty-three tumors were located in the cerebellum (IPNETs), and ten were
      supratentorial PNETs (SPNETs). All samples were reviewed to confirm the
      diagnosis. Each specimen had at least 50% tumor. RESULTS: Six of the 43 cases of
      IPNET had no copy number aberrations. In contrast, each case of SPNET had copy
      number aberrations detected by CGH. Statistically significant differences in copy
      number aberrations of chromosomes 14, 17, and 19 were detected in the two groups.
      The most common copy number aberration in the IPNETs was gain of chromosome 17q,
      which was observed in 16 of 43 cases (37%). However, no case of SPNET had gain of
      17q. Loss of 14q was detected in four of ten SPNETs but was not detected in any
      of the IPNET cases. Loss of 19q was detected in 4 of 10 SPNETs and in only 1 of
      43 IPNETs. CONCLUSIONS: These results indicate that the genetic aberrations of
      IPNETs differ from the genetic aberrations of SPNETs. Although they are similar
      histologically, SPNETs and IPNETs appear to be biologically distinct entities.

PMID- 10421271
TI  - Additive effects of infection and neutropenia on the induction of
      granulocytopoietic activity in vivo.
AB  - BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is a potent stimulator
      of granulocytopoiesis and granulocyte function. It has been used in the treatment
      of children with neutropenic infection; in this context, it was expected to
      shorten aplasia and limit the severity of infection. Clinical trials, however,
      have demonstrated conflicting results as to whether these aims can be met.
      Recently, the use of other, less lineage specific growth factors, such as
      interleukin (IL)-11 and stem cell factor (SCF), has also been discussed. The
      dynamics of growth factors and growth factor-regulating proteins during
      neutropenic infection, particularly in youngsters, are not well understood.
      METHODS: Serial blood samples from children and adolescents with infection during
      chemotherapy-induced neutropenia were assayed for C-reactive protein, white blood
      cell count, IL-11, SCF, G-CSF, IL-10, IL-4, IL-lalpha, and IL-1beta. RESULTS:
      Although no correlation could be demonstrated between endogenous IL-11 or SCF
      levels, infection, and leukocyte counts, endogenous G-CSF levels were increased
      during both aplasia and infection. However, only the additive effects of
      infection and neutropenia led to maximally stimulated endogenous G-CSF levels.
      CONCLUSIONS: The elevated G-CSF levels in a majority of patients during severe
      neutropenic infection may explain why a therapeutic benefit of G-CSF treatment
      cannot be demonstrated in all cases. There remains, however, a subgroup of
      patients in whom infection and cytopenia do not yield a good G-CSF response. This
      latter group should be identified, because they might derive some benefit from
      adjuvant growth factor therapy. The authors predict that the efficacy of G-CSF in
      the treatment of patients with neutropenic fever might depend on each
      individual's ability to initiate the necessary cytokine production.

PMID- 10421272
TI  - Terminology and morphologic criteria of neuroblastic tumors: recommendations by
      the International Neuroblastoma Pathology Committee.
AB  - BACKGROUND: As part of the international cooperative effort to develop a complete
      set of International Neuroblastoma Risk Groups, the International Neuroblastoma
      Pathology Committee (INPC) initiated activities in 1994 to devise a morphologic
      classification of neuroblastic tumors (NTs; neuroblastoma, ganglioneuroblastoma,
      and ganglioneuroma). METHODS: Six member pathologists (H.S., I.M.A., L.P.D.,
      J.H., V.V.J., and B.R.) discussed and defined morphologically based
      classifications (Shimada classification; risk group and modified risk group
      proposed by Joshi et al.) on the basis of a review of 227 cases, using various
      pathologic characteristics of the NTs. The classification-grading system was
      evaluated for prognostic significance and biologic relevance. RESULTS: The INPC
      has adopted a prognostic system modeled on one proposed by Shimada et al. It is
      an age-linked classification dependent on the differentiation grade of the
      neuroblasts, their cellular turnover index, and the presence or absence of
      Schwannian stromal development. Based on morphologic criteria defined in this
      article, NTs were classified into four categories and their subtypes: 1)
      neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated,
      and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma
      rich); 3) ganglioneuroma (Schwannian stroma-dominant), maturing and mature; and
      4) ganglioneuroblastoma, nodular (composite Schwannian stroma-richlstroma
      dominant and stroma-poor). Specific features, such as the mitosis-karyorrhexis
      index, the mitotic rate, and calcification, were also included to allow the
      prognostic significance of the classification to be tested. Recommendations are
      made regarding the surgical materials to use for an optimal pathobiologic
      assessment and the practical handling of samples. CONCLUSIONS: The current
      article covers the essentials and important points regarding the histopathologic
      evaluation of NTs. Using the morphologic criteria described herein, the INPC is
      proposing the International Neuroblastoma Pathology Classification. It is
      reported in a companion article in this issue (Cancer 1999;86:363-71).

PMID- 10421273
TI  - The International Neuroblastoma Pathology Classification (the Shimada system).
AB  - BACKGROUND: The International Neuroblastoma Pathology Committee, which is
      comprised of six member pathologists, was convened with the objective of
      proposing a prognostically significant and biologically relevant classification
      based on morphologic features of neuroblastic tumors (NTs) (i.e., neuroblastoma,
      ganglioneuroblastoma, and ganglioneuroma). METHODS: A total of 227 cases were
      reviewed. Consensus diagnoses from morphologic features (criteria described
      separately) based on five of six or six of six agreements by the reviewer
      pathologists were used for prognostic analysis. Prognostic effects of morphology,
      both individual and in combination, taken in conjunction with age (Shimada
      classification, histologic grade, and risk group), were analyzed. RESULTS:
      Approximately 99% of cases (224 of 227) had consensus diagnoses for
      categorization: neuroblastoma (Schwannian stroma-poor), 190 cases;
      ganglioneuroblastoma, intermixed (Schwannian stroma-rich), 5 cases;
      ganglioneuroma (Schwannian stroma-dominant) maturing, 1 case;
      ganglioneuroblastoma, nodular (composite Schwannian stroma-rich/stroma-dominant
      and stroma-poor), 19 cases; and NT-unclassifiable, 9 cases. For the NTs, subtype
      (93% consensus: undifferentiated, 6 cases; poorly differentiated, 155 cases; and
      differentiated, 15 cases), mitosis-karyorrhexis index (90% consensus: low, 94
      cases; intermediate, 40 cases; and high, 37 cases), mitotic rate (75% consensus:
      low, 89 cases; high, 50 cases; and not determined, 4 cases), and calcification
      (100% consensus: yes, 110 cases and no, 80 cases) were recorded. Statistical
      analysis demonstrated that the Shimada classification system (90% consensus; 3
      year event free survival: 85% for the group with favorable histology and 41% for
      the group with unfavorable histology; P = 0.31 x 10(-9)) had a significantly
      stronger prognostic effect than individual features and other combinations.
      CONCLUSIONS: The International Neuroblastoma Pathology Classification, a system
      based on a framework of the Shimada classification with minor modifications, is
      proposed for international use in assessing NTs.

PMID- 10421274
TI  - Freud's physician-assisted death.

PMID- 10421275
TI  - Genetic testing for cystic fibrosis. National Institutes of Health Consensus
      Development Conference Statement on genetic testing for cystic fibrosis.
AB  - OBJECTIVE: To provide health care providers, patients, and the general public
      with a responsible assessment of the optimal practices for genetic testing for
      cystic fibrosis (CF). PARTICIPANTS: A nonfederal, nonadvocate, 14-member panel
      representing the fields of genetics, obstetrics, internal medicine, nursing,
      social work, epidemiology, pediatrics, psychiatry, genetic counseling, bioethics,
      health economics, health services research, law, and the public. In addition, 21
      experts from these same fields presented data to the panel and a conference
      audience of 500. EVIDENCE: The literature was searched through MEDLINE, and an
      extensive bibliography of references was provided to the panel and the conference
      audience. Experts prepared abstracts with relevant citations from the literature.
      Scientific evidence was given precedence over clinical anecdotal experience.
      CONSENSUS PROCESS: The panel, answering predefined questions, developed its
      conclusions based on the scientific evidence presented in open forum and the
      scientific literature. The panel composed a draft statement that was read in its
      entirety and circulated to the experts and the audience for comment. Thereafter,
      the panel resolved conflicting recommendations and released a revised statement
      at the end of the conference. The panel finalized the revisions within a few
      weeks after the conference. CONCLUSIONS: Genetic testing for CF should be offered
      to adults with a positive family history of CF, to partners of people with CF, to
      couples currently planning a pregnancy, and to couples seeking prenatal care. The
      panel does not recommend offering CF genetic testing to the general population or
      newborns. The panel advocates active research to develop improved treatments for
      people with CF and continued investigation into the understanding of the
      pathophysiology of the disease. Comprehensive educational programs targeted to
      health care professionals and the public should be developed using input from
      people living with CF and their families and from people from diverse racial and
      ethnic groups. Additionally, genetic counseling services must be accurate and
      provide balanced information to afford individuals the opportunity to make
      autonomous decisions. Every attempt should be made to protect individual rights,
      genetic and medical privacy rights, and to prevent discrimination and
      stigmatization. It is essential that the offering of CF carrier testing be phased
      in over a period to ensure that adequate education and appropriate genetic
      testing and counseling services are available to all persons being tested.

PMID- 10421276
TI  - Iron, atherosclerosis, and ischemic heart disease.
AB  - OBJECTIVE: To review the epidemiological and experimental data concerning iron
      and the development of atherosclerosis and ischemic heart disease. DATA SOURCES:
      The English-language literature was searched from 1981 through 1998 manually and
      using MEDLINE and Current Contents. Important references in the articles that
      were found were also included in this review. RESULTS: There is growing
      epidemiological evidence for a relationship between iron levels and
      cardiovascular disease. Some experimental data support the role of iron in the
      process of lipid peroxidation, the first step in the formation of atherosclerotic
      lesions. Macrophages and endothelial cells are involved in this process, but the
      exact mechanism and the sites of the interactions between these cells, iron, and
      low-density lipoprotein are still unknown. CONCLUSIONS: Strong epidemiological
      evidence is available that iron is an important factor in the process of
      atherosclerosis. Epidemiological studies, eg, prospective follow-up studies in
      blood donors, may clarify the cardiovascular benefits of iron depletion.
      Knowledge of the molecular mechanism of iron-related cardiovascular disease is
      still limited. We speculate that catalytically active iron species modify low
      density lipoprotein levels to interact with the macrophage oxidized low-density
      lipoprotein receptor. Both nontransferrin-bound plasma iron and hemoglobin are
      candidates for such interactions.

PMID- 10421277
TI  - Prognosis after community-acquired pneumonia in the elderly: a population-based
      12-year follow-up study.
AB  - BACKGROUND: Only a few studies have investigated the long-term effects of
      community-acquired pneumonia (CAP). These studies have focused on cases treated
      in the hospital, and, to our knowledge, no long-term survival studies that
      include all cases of CAP are available. METHODS: A prospective observational
      study on the survival rates in a population-based cohort of elderly inhabitants
      aged 60 years or older at baseline in 1 township in eastern Finland in 1983. A
      total of 4167 (99% of the total elderly population), 122 of whom survived CAP
      during a prospective pneumonia surveillance period from 1983 to 1985, were
      followed up for mortality from 1983 to 1994 for a median of 9.2 years. The
      relative risk (RR) of death in patients who survived CAP was compared with that
      in elderly inhabitants without CAP by Cox multivariate regression analysis. Data
      on causes of death were obtained from a central register based on death
      certificates. RESULTS: The long-term survival rate was significantly lower in
      persons who had survived CAP or pneumococcal CAP (PCAP) than in the rest of the
      study population. The RR of pneumonia-related mortality was 2.1 (95% confidence
      interval [CI], 1.3-3.4; P = .004) in all patients with CAP and 2.8 (95% CI, 1.5
      5.3; P = .001) in patients with PCAP. The respective numbers for total mortality
      were 1.5 (95% CI, 1.2-1.9; P = .001) in all patients with CAP and 1.6 (95% CI,
      1.1-2.2; P= .01) in those with PCAP. Also the risk of cardiovascular mortality
      was increased in persons with CAP (RR, 1.4; 95% CI, 1.0-1.9; P = .02) and in
      those with PCAP (RR, 1.6; 95% CI, 1.0-2.4; P= .04). CONCLUSIONS: The present
      results indicate that elderly patients treated for CAP are at high risk of
      subsequent mortality for several years. Based on the high incidence and negative
      long-term effects of pneumonia, it can be concluded that there is a clear need
      for prevention, eg, by influenza and pneumococcal immunization.

PMID- 10421278
TI  - Effectiveness of Helicobacter pylori therapies in a clinical practice setting.
AB  - BACKGROUND: Whether eradication rates for Helicobacter pylori treatment regimens
      obtained in controlled clinical trials (efficacy) can also be obtained in
      clinical practice (effectiveness) is unknown because no such trials have been
      reported in the United States. OBJECTIVES: To determine the eradication rates of
      H pylori in a community practice setting and the effects of practice variation in
      the choice of treatment regimen on patient outcome (H pylori infection cure) and
      cost. METHODS: Between February 1 and December 30, 1996, 38 community-based
      gastroenterologists in the Portland, Ore, metropolitan area enrolled a total of
      250 patients infected with H pylori, as determined by endoscopic or noninvasive
      methods. Various therapeutic regimens aimed at eradicating H pylori were used by
      the gastroenterologists, and a posttreatment urea breath test was used to
      determine H pylori infection cure. Compliance and incidental effects were also
      measured and decision analysis was used to estimate the cost of treatment.
      RESULTS: The regimens used varied considerably. Patients receiving a 2- or 3
      times-a-day treatment regimen were significantly more compliant (P=.01) than
      those receiving a 4-times-a-day regimen. Proton pump inhibitor-based triple
      therapy regimens were significantly more effective than all other treatment
      regimens combined (87% vs 70%; P = .001) in eradicating H pylori. These proton
      pump inhibitor-based triple-therapy regimens were also more cost-effective by
      decision analysis for a hypothetical cohort of patients with duodenal ulcer
      disease. CONCLUSIONS: The considerable variation in the choice of treatment
      regimens affects the clinical and economic outcomes of patients undergoing
      therapy for H pylori infection. Whether these data reflect the outcome in other
      communities is unknown but should be determined. It will be necessary to
      determine if the dissemination of these data results in a reduction of practice
      variation and improvement in clinical and economic outcomes of patients being
      treated for H pylori infection in clinical practice.

PMID- 10421279
TI  - Normal D-dimer levels in patients with pulmonary embolism.
AB  - BACKGROUND: Pulmonary embolism (PE) is frequently evaluated in acute care
      settings. Despite this, the clinical diagnosis of PE is difficult. Results of
      ventilation-perfusion (V/Q) scans may be inconclusive, and pulmonary angiograms
      (PAGs) are cumbersome, involve risk, and are often unavailable. Using PAG as the
      standard criterion, we evaluated the relationship between PE, V/Q scans, and
      semiquantitative latex agglutination (LA) D-dimer levels. METHODS: Ninety-eight
      patients who underwent V/Q scanning for suspected PE were enrolled; based on the
      results of the scans, the patients were scheduled for PAG. Blood samples were
      drawn for LA D-dimer assays during the PAGs at Saint Joseph Hospital, Denver,
      Colo, from January 1, 1996, to February 1, 1997. A detailed medical record review
      was performed for all enrollees. RESULTS: The mean+/-SEM patient age was 56.6+/
      1.9 years; 52 (53%) were men, 13 (13%) had cancer, 23 (23%) had undergone surgery
      within 30 days of their PAG, and 13 (13%) were receiving warfarin sodium. There
      were no differences in warfarin therapy, hypercoaguable state, or cancer
      prevalence between patients with negative and positive PAGs (P = .53).
      Ventilation-perfusion scan results were available for all study patients. Eight
      (27%) of 30 patients who had positive angiogram results had LA D-dimer levels
      less than 250 ng/mL. Patients with positive PAGs (n = 30) had the following V/Q
      scan results: normal, 0; low probability, 7; intermediate or indeterminate
      probability, 22; and high probability, 1. In patients with low-probability V/Q
      scan results (n = 34), a positive D-dimer result for PE (>250 ng/mL) had a
      sensitivity of 71.4% (95% confidence interval, 0.29-0.97) and a negative
      predictive value of 87.5% (95% confidence interval, 0.62-0.98). We found a
      significant difference in D-dimer levels in patients with an abnormal angiogram
      result (mean, 750 ng/mL) compared with patients with a normal angiogram result
      (mean, 250 ng/mL) (P= .01, chi2 test). CONCLUSIONS: Eight patients had normal D
      dimer levels with angiographic evidence of PE. Algorithms in acute care settings
      have been proposed; they exclude PE with normal D-dimer levels using the enzyme
      linked immunosorbent assay technique. These cannot be extrapolated to the more
      widely used LA assays. A normal LA D-dimer level alone or with V/Q scan results
      is not recommended to preclude the treatment of PE.

PMID- 10421280
TI  - Temporal trends in the use of anticoagulants among older adults with atrial
      fibrillation.
AB  - BACKGROUND: Several recent randomized clinical trials have demonstrated that
      warfarin sodium treatment, and to a lesser extent aspirin, reduces risk of stroke
      and death compared with placebo in persons with atrial fibrillation. Insufficient
      documentation exists on the extent to which the use of these therapies following
      trial publications has continued to increase in the elderly with atrial
      fibrillation. METHODS: We used data from the Cardiovascular Health Study, a study
      of 5888 community-dwelling adults aged 65 years or older, to determine the
      prevalence of warfarin and aspirin use in persons with electrocardiogram
      identified atrial fibrillation. Electrocardiogram examinations were conducted at
      baseline from 1989 through 1990, and at 6 subsequent annual examinations through
      1995-1996. Medication data were collected by inventory methods at each
      examination. Temporal change in use of anticoagulants was analyzed by comparing
      percentage use in 1990 to use in each year through 1996. RESULTS: The use of
      warfarin increased 4-fold from 13% in 1990 to 50% in 1996 among participants with
      prevalent atrial fibrillation (P<.001). Daily use of aspirin did not increase
      over time. Participants younger than 80 years were 4 times more likely to use
      warfarin in 1996 (P<.001) than those 80 years and older. Use of aspirin did not
      vary significantly with age. CONCLUSIONS: Warfarin use in community-dwelling
      elderly persons with electrocardiogram-documented atrial fibrillation increased
      steadily following the first publication of its treatment benefit, reaching 50%
      by 1996. In contrast, use of aspirin was unchanged during this same period.
      Continued efforts to promote appropriate anticoagulation therapy to physicians
      and their patients may still be needed.

PMID- 10421281
TI  - The siesta in the elderly: risk factor for mortality?
AB  - BACKGROUND: During the siesta, blood pressure declines like it does during night
      sleep. Because cardiovascular and cerebrovascular events cluster during the
      morning hours, when hemodynamic changes from nocturnal baseline are maximal, we
      hypothesized that an additional sleep period during the day (the siesta) may
      increase cardiovascular and cerebrovascular events, and thus mortality. METHODS:
      A prospective population-based cohort study of 455 70-year-old residents of
      Jerusalem, Israel, using self-reported siesta at baseline and 6 1/2 years of
      total mortality data. RESULTS: The prevalence of the practice of the siesta was
      60.7%. It was more prevalent among men than women (68% vs 51%, P<.001) and in
      survivors of previous myocardial infarction than in those without previous
      myocardial infarction (78% vs 58%, P = .009). After 6 1/2 years of follow-up
      (1990-1996), 75 subjects died. For those who practiced the siesta, total
      mortality was 20% vs 11% for those who did not (P = .01; risk odds ratio, 2.0;
      95% confidence interval, 1.1-3.4). In a multiple logistic regression model that
      included several lifestyle descriptors, risk factors, and diseases, the siesta
      remained predictive of mortality (P = .03; risk odds ratio, 2.1; 95% confidence
      interval, 1.1-3.9).

PMID- 10421282
TI  - Heartburn risk factors, knowledge, and prevention strategies: a population-based
      survey of individuals with heartburn.
AB  - BACKGROUND: Twenty-five million adults experience heartburn daily. To target
      individuals for prevention programs, characteristics of persons with heartburn
      and the associated causes of this condition must first be identified. METHODS: We
      conducted a population-based telephone survey of 2000 individuals with heartburn
      to describe the cause of the disease, knowledge of risk factors, and prevention
      strategies. RESULTS: Lifestyle and work habits, and certain food and beverage
      consumption, were associated with heartburn. Women reported the onset of
      heartburn about 5 years later than men. Survey respondents were unaware of the
      risk factors for heartburn, and sex-dependent differences in knowledge were
      apparent. Logistic regression modeling identified increasing age, female sex,
      higher level of education, and frequent vs infrequent heartburn as significant
      (P<.02) predictors of whether patients told a physician about their heartburn
      symptoms. Increasing age, higher body mass index, and reduced level of education
      were significant (P<.02) predictors of frequent vs infrequent heartburn in this
      study population. CONCLUSION: The findings of this study provide a framework for
      the development of a heartburn prevention program based on lifestyle
      modification.

PMID- 10421283
TI  - Furosemide withdrawal improves postprandial hypotension in elderly patients with
      heart failure and preserved left ventricular systolic function.
AB  - OBJECTIVE: To assess the effects of furosemide withdrawal on postprandial blood
      pressure (BP) in elderly patients with heart failure and preserved left
      ventricular systolic function. METHODS: Noninvasive measurement of blood pressure
      (BP) and heart rate, computation of stroke volume and cardiac output (after a
      1247-kJ (297-kcal) meal, and Doppler echocardiography before and 3 months after
      placebo-controlled withdrawal of furosemide therapy. RESULTS: Of 20 patients with
      heart failure (mean+/-SEM age, 75+/-1 years; left ventricular ejection fraction,
      61%+/-3%), 13 were successfully able to discontinue furosemide therapy. At
      baseline, 11 (55%) of the 20 patients (had maximum postprandial systolic BP
      declines of 20 mm Hg or more. In the withdrawal group, the maximum systolic BP
      decline lessened from -25+/-4 to -11+/-2 mm Hg (P<.001) and the maximum diastolic
      BP from -18+/-3 to -9+/-1 mm Hg (P= .01), compared with no changes in the
      continuation group. In the withdrawal group, maximum postprandial declines in
      stroke volume and cardiac output decreased from -9+/-1 to -4+/-2 mL (P =.01) and
      from -0.6+/-0.2 to -0.2+/-0.1 L/min) (P = .04), respectively. The baseline
      maximum postprandial systolic BP decrease was correlated with the ratio of early
      to late flow (n = 20; Spearman rank correlation coefficient, 0.58; P = .007). For
      patients in the withdrawal group, the changes in postprandial systolic BP
      response were independently related to changes in peak velocity of early flow (n
      = 13; r2= 0.61; P = .003). CONCLUSIONS: Postprandial hypotension is common in
      elderly patients with heart failure and preserved left ventricular systolic
      function. The withdrawal of furosemide therapy ameliorates postprandial BP
      homeostasis in these patients, possibly by improving left ventricular diastolic
      filling.

PMID- 10421284
TI  - Maternal size at birth and the development of hypertension during pregnancy: a
      test of the Barker hypothesis.
AB  - BACKGROUND: Whether individuals who were small at birth are at increased risk of
      developing cardiovascular disease (the Barker hypothesis) is a topic of great
      controversy. Although an increased risk has been suggested by several reports,
      the reports have been criticized for being based on ill-defined populations, for
      the large numbers of subjects who were unavailable for follow-up, and for
      inadequate control of socioeconomic status. OBJECTIVE: To determine whether a
      woman's weight and gestational age at birth predict the development of
      hypertension during her subsequent pregnancies. DESIGN: Prospective observational
      study. SUBJECTS: Women born in Copenhagen, Denmark, as subjects in the Danish
      Perinatal Study (1959-1961) were traced through the Danish Population Register.
      Information was obtained on their pregnancies from 1974 to 1989. MAIN OUTCOME
      MEASURES: Onset of hypertension in pregnancy, defined by the presence of a
      systolic blood pressure of 140 mm Hg or greater or a diastolic blood pressure of
      90 mm Hg or greater on 2 visits at or after 140 days' gestation. RESULTS:
      Hypertension developed in 11.3% of the pregnant women who were small for
      gestational age at birth, compared with 7.2% of the pregnant women who were not
      small for gestational age at birth (odds ratio [OR], 1.7; 95% confidence interval
      [CI], 1.1-2.6), and in 9.4% of the pregnancies in women who were preterm at
      birth, compared with 7.6% of pregnancies in women who were not preterm at birth
      (OR, 1.3; 95% CI, 0.8-2.0). After adjustment for adult body mass index, smoking,
      birth order, and hypertension in the subjects' own mothers, the ORs for small-for
      gestational-age women and preterm women to develop hypertension during pregnancy
      were 1.8 (95% CI, 1.1-2.8) and 1.5 (95% CI, 0.96-2.5), respectively. CONCLUSION:
      These results support the Barker hypothesis, while addressing many of the
      methodological criticisms of previous investigations.

PMID- 10421285
TI  - Factors influencing knowledge of and adherence to self-care among patients with
      heart failure.
AB  - BACKGROUND: Patient education has been shown to be a key component in
      comprehensive heart failure management. Few data, however, are available
      regarding patients' knowledge of and adherence to self-care recommendations for
      the disease. OBJECTIVES: To assess the knowledge level of and adherence to self
      care among patients with heart failure and to determine associated factors.
      METHODS: We conducted a needs-assessment survey among new patients visiting a
      heart failure clinic from April 1997 through June 1998. Multiple linear
      regression analysis was used to assess the factors predictive of patients'
      knowledge level and adherence behaviors. RESULTS: Of the 113 patients surveyed,
      77% were referred by cardiologists and 60% had New York Heart Association class
      III or IV status. Two thirds of the patients reported receiving information or
      advice about self-care from health care providers. When asked how much they knew
      about congestive heart failure, however, 37% said "a little or nothing," 49% said
      "some," and only 14% said "a lot." Approximately 40% of the patients did not
      recognize the importance of weighing themselves daily and 27% weighed themselves
      twice a month or less often. Although 80% of the patients knew they should limit
      their salt intake, only one third always avoided salty foods. Additionally, 25%
      of the patients did not appreciate the risk of alcohol use and 36% believed they
      should drink a lot of fluids. The multiple linear regression analysis indicated
      that a higher knowledge score was associated with being married, prior
      hospitalization, and having received both advice and information about self-care
      from physicians or nurses. A poor adherence behavior score was associated with
      being unmarried, lower perceived self-efficacy, a lack of knowledge about self
      care, and no prior hospitalization. CONCLUSIONS: We observed a gap between
      patients receiving and absorbing or retaining information on self-care for
      congestive heart failure supplied by health care providers. Self-care education
      needs to be directed to outpatients in addition to inpatients.

PMID- 10421286
TI  - Antihypertensive therapy in the elderly: evidence-based guidelines and reality.

PMID- 10421287
TI  - Evidence-based evaluation of preoperative vs postoperative use of low-molecular
      weight heparin in preventing deep vein thrombosis in elective hip surgery.

PMID- 10421288
TI  - Chromobacterium violaceum sepsis accompanied by bacteria-associated
      hemophagocytic syndrome in a Japanese man.

PMID- 10421289
TI  - Thrombotic thrombocytopenic purpura associated with ticlopidine use.

PMID- 10421291
TI  - Coke adds life, but cannot always explain it.

PMID- 10421290
TI  - Comparing 5-mg and 10-mg warfarin loading doses: are the groups similar?

PMID- 10421292
TI  - Extended-wear contact lenses, microbial keratitis, and public health.

PMID- 10421293
TI  - Inguinal herniorrhaphy: for surgical specialists only?

PMID- 10421294
TI  - Rehabilitation therapy after stroke.

PMID- 10421295
TI  - Quitting smoking and lungs.

PMID- 10421296
TI  - Implantable insulin pumps.

PMID- 10421297
TI  - What test for hypothalamic-pituitary-adrenocortical insufficiency?

PMID- 10421298
TI  - Incidence of contact-lens-associated microbial keratitis and its related
      morbidity.
AB  - BACKGROUND: The incidence of contact-lens-associated microbial keratitis is
      uncertain and its related morbidity in the general population of contact-lens
      wearers is not known. We examined these issues in a prospective epidemiological
      study. METHODS: We surveyed all practising ophthalmologists in the Netherlands to
      identify all new cases of microbial keratitis reported during a 3-month period in
      1996. Follow-up telephone calls were made to examine ocular morbidity. We
      undertook annual nationwide telephone surveys between 1994 and 1997 to estimate
      the prevalence of contact-lens wear. FINDINGS: Of 440 ophthalmologists contacted,
      379 provided information. There were 92 cases of microbial keratitis; 17 used
      daily-wear rigid gas-permeable lenses, 63 daily-wear soft lenses, and 12 extended
      wear soft lenses. The estimated annualised incidence of microbial keratitis was
      1.1 per 10,000 (95% CI 0.6-1.7) users of daily-wear rigid gas-permeable lenses,
      3.5 per 10,000 (2.7-4.5) users of daily-wear soft lenses, and 20.0 per 10,000
      (10.3-35.0) users of extended-wear soft lenses (p<0.00001 for comparison between
      all groups), Five of the 92 patients achieved a final visual acuity of 20/70 or
      less. Pseudomonas and Serratia spp were the organisms most commonly isolated.
      Pseudomonas keratitis accounted for the largest mean diameter of corneal ulcers,
      the highest mean number of days in hospital, the greatest number of mean
      outpatients visits, and the poorest visual acuity outcome. INTERPRETATION: The
      incidence of microbial keratitis among users of extended-wear soft contact lenses
      in the Netherlands is similar to that reported in the USA during 1989. Awareness
      of risk factors and improvement in contact-lens materials have not led to a
      decrease in incidence. Overnight wear should be strongly discouraged.

PMID- 10421299
TI  - Laparoscopic versus open repair of groin hernia: a randomised comparison. The MRC
      Laparoscopic Groin Hernia Trial Group.
AB  - BACKGROUND: Repair of a groin hernia is one of the most common elective
      operations performed in general surgery. Our aim was to compare laparoscopic
      repair with open repair of groin hernia. METHODS: 928 patients with groin hernia,
      from 26 hospitals in the UK and Ireland, were randomly assigned to laparoscopic
      repair (n=468) or to open hernia repair (n=460, of which 433 were tension-free
      mesh repairs). Patients were clinically assessed at 1 week and 1 year after
      surgery, and were sent questionnaires at 3 months and 1 year. The primary
      endpoints were: complications; return to usual activities of social life (as the
      most generally applicable example of return to usual activities); hernia
      recurrence; groin pain that persisted at 1 year; and costs to the health
      services. All analyses were by intention to treat. FINDINGS: At 1 week, at least
      one complication was found in 108 (29.9%) patients allocated to laparoscopic
      repair and in 155 (43.5%) patients allocated to open repair (95% CI for
      difference -20.6% to -6.6%, p<0.001). There were three serious surgical
      complications all of which occurred in the laparoscopic group. Patients in the
      laparoscopic group returned to the usual activities of social life sooner than
      the patients in the open repair group (10 [IQR 7-21] vs 14 [7-28] days, p=0.004).
      At 1 year after the operation, the laparoscopic group had a lower rate of
      persistent groin pain than those who had open repair (28.7% vs 36.7% [95% CI for
      difference -14.7% to -1.4%], p=0.018). However, all seven hernia recurrences
      occurred in the laparoscopic group and not in the open repair group (1.9% vs 0.0%
      [95% CI for difference 0.5% to 3.4%], p=0.017). INTERPRETATION: Although
      laparoscopic hernia repair has advantages for patients, concerns about safety
      indicate that open repair is the more appropriate option for the general surgeon.
      Our findings lend support to the move towards laparoscopic hernia surgery
      becoming part of the domain of specialist surgeons.

PMID- 10421300
TI  - Intensity of leg and arm training after primary middle-cerebral-artery stroke: a
      randomised trial.
AB  - BACKGROUND: We investigated the effects of different intensities of arm and leg
      rehabilitation training on the functional recovery of activities of daily living
      (ADL), walking ability, and dexterity of the paretic arm, in a single-blind
      randomised controlled trial. METHODS: Within 14 days after stroke onset, 101
      severely disabled patients with a primary middle-cerebral-artery stroke were
      randomly assigned to: a rehabilitation programme with emphasis on arm training; a
      rehabilitation programme with emphasis on leg training; or a control programme in
      which the arm and leg were immobilised with an inflatable pressure splint. Each
      treatment regimen was applied for 30 min, 5 days a week during the first 20 weeks
      after stroke. In addition, all patients underwent a basic rehabilitation
      programme. The main outcome measures were ability in ADL (Barthel index), walking
      ability (functional ambulation categories), and dexterity of the paretic arm
      (Action Research arm test) at 6, 12, 20, and 26 weeks. Analyses were by intention
      to treat. FINDINGS: At week 20, the leg-training group (n=31) had higher scores
      than the control group (n=37) for ADL ability (median 19 [IQR 16-20] vs 16 [10
      19], p<0.05), walking ability (4 [3-5] vs 3 [1-4], p<0.05), and dexterity (2 [0
      56] vs 0 [0-2], p<0.01). The arm-training group (n=33) differed significantly
      from the control group only in dexterity (9 [0-39] vs 0 [0-2], p<0.01). There
      were no significant differences in these endpoints at 20 weeks between the arm
      training and leg-training groups. INTERPRETATION: Greater intensity of leg
      rehabilitation improves functional recovery and health-related functional status,
      whereas greater intensity of arm rehabilitation results in small improvements in
      dexterity, providing further evidence that exercise therapy primarily induces
      treatment effects on the abilities at which training is specifically aimed.

PMID- 10421301
TI  - Outcome of primary-breast-cancer patients with micrometastases: a long-term
      follow-up study.
AB  - BACKGROUND: Bone-marrow micrometastases have been found in patients with primary
      breast cancer. We report long-term follow-up of women with primary breast cancer,
      diagnosed between 1981 and 1986, who had multiple aspirates taken at the time of
      initial surgery. METHODS: 350 women with primary breast cancer were examined
      immunocytochemically with antibody to epithelial membrane antigen. We
      investigated associations with various prognostic factors as well as the effect
      of micrometastases on relapse-free survival and overall survival. FINDINGS: At
      median follow-up of 12.5 years, 151 patients had metastatic disease and 136
      patients had died from breast cancer. 10-year relapse-free and overall survival
      were 43.9% (95% CI 33.4-54.7) and 44.9% (34.2-55.9) in patients with
      micrometastases, and 62.7% (56.5-68.6) and 65.7% (59.4-71.5) in patients without
      micrometastases at presentation (p<0.001). For relapse-free survival and overall
      survival, allowing for tumour size, lymph-node status, and vascular invasion, the
      effect of micrometastases decreased and was no longer significant, with a hazard
      ratio of 1.09 (0.74-1.61) for relapse-free survival and 1.21 (0.84-1.75) for
      overall survival. INTERPRETATION: The presence of bone-marrow micrometastases in
      patients with primary breast cancer is associated with a shorter relapse-free
      survival and overall survival, but is not an independent prognostic factor. This
      immunocytochemical technique may be of value in patients for whom pathological
      tumour size and lymph-node status are unavailable (ie, patients receiving primary
      medical treatment).

PMID- 10421303
TI  - Prescription of transdermal nicotine patches for smoking cessation in general
      practice: evaluation of cost-effectiveness.
AB  - BACKGROUND: The 1998 UK government White Paper Smoking Kills emphasises that
      normal practice should be for general practitioners (GPs), practice nurses, and
      others to offer advice and support to smokers in their efforts to stop. However,
      GPs are not allowed to write NHS prescriptions for nicotine-replacement therapy,
      even though this is the only effective pharmaceutical treatment available in the
      UK. We estimated the cost-effectiveness, for the NHS, of allowing GPs to
      prescribe transdermal nicotine patches for up to 12 weeks. METHODS: We used data
      from a randomised, placebo-controlled efficacy trial of nicotine patches and a
      survey of associated resource use in 30 GP surgeries in 15 English counties. We
      calculated the health benefit of nicotine-patch treatment in number of life years
      that would be saved by stopping smoking at various ages, and used an abstinence
      contingent treatment model to calculate the incremental cost per life year saved
      by GP counselling with nicotine-patch treatment over GP counselling alone. Cost
      effectiveness was assessed on the basis that GPs would provide repeat NHS
      prescriptions for up to 12 weeks if the treatment was proving successful.
      FINDINGS: If GPs were allowed to prescribe transdermal nicotine patches on the
      NHS, for up to 12 weeks, the incremental cost per life year saved would be: Pound
      Sterling 398 per person younger than 35 years; Pound Sterling 345 for those aged
      35-44 years; Pound Sterling 432 for those aged 45-54 years; and Pound Sterling
      785 for those aged 55-65 years. INTERPRETATION: The low cost per life year saved
      would make GP intervention against smoking a cost-effective life-saving
      treatment. The priniciples of the government White Paper could be cost
      effectively extended into general practice to reduce smoking and smoking-related
      illnesses.

PMID- 10421302
TI  - Effect of vitamin A supplementation on morbidity due to Plasmodium falciparum in
      young children in Papua New Guinea: a randomised trial.
AB  - BACKGROUND: Many individuals at risk of malaria also have micronutrient
      deficiencies that may hamper protective immunity. Vitamin A is central to normal
      immune function, and supplementation has been shown to lower the morbidity of
      some infectious diseases. We investigated the effect of vitamin A supplementation
      on malaria morbidity. METHODS: This randomised double-blind placebo-controlled
      trial of vitamin A supplementation took place in a P. falciparum endemic area of
      Papua New Guinea. Of 520 potentially eligible children aged 6-60 months, 480 were
      randomly assigned high-dose vitamin A (n=239) or placebo (n=241), every 3 months
      for 13 months. Malaria morbidity was assessed through weekly community-based case
      detection and surveillance of patients who self-reported to the health centre.
      Cross-sectional surveys were also done at the beginning, middle, and end of the
      study to assess malariometric indicators. Analyses were by intention to treat.
      FINDINGS: The number of P. falciparum febrile episodes (temperature > or = 37.5
      degrees C with a parasite count of at least 8000/microL) was 30% lower in the
      vitamin A group than in the placebo group (178 vs 249 episodes; relative risk
      0.70 [95% CI 0.57-0.87], p=0.0013). At the end of the study P. falciparum
      geometric mean density was lower in the vitamin A than the placebo group (1300
      [907-1863] vs 2039 [1408-2951]) as was the proportion with spleen enlargement
      (125/196 [64%] vs 148/207 [71%]); neither difference was significant (p=0.093 and
      p=0.075). Children aged 12-36 months benefited most, having 35% fewer febrile
      episodes (89 vs 141; relative risk 0.65 [14-50], p=0.0023), 26% fewer enlarged
      spleens (46/79 [58%] vs 67/90 [74%], p=0.0045), and a 68% lower parasite density
      (1160 [95% CI 665-2022] vs 3569 [2080-6124], p=0.0054). Vitamin A had no
      consistent effect on cross-sectional indices of proportion infected or with
      anaemia. INTERPRETATION: Vitamin A supplementation may be an effective low-cost
      strategy to lower morbidity due to P. falciparum in young children. The findings
      suggest that clinical episodes, spleen enlargement, and parasite density are
      influenced by different immunological mechanisms from infection and anaemia.

PMID- 10421304
TI  - Erythrocytosis and a fibroid.

PMID- 10421305
TI  - Reduced movement of median nerve in carpal tunnel during wrist flexion in
      patients with non-specific arm pain.
AB  - Magnetic resonance scans on patients with non-specific arm pain (repetitive
      strain injury) show reduced median-nerve movement in the carpal tunnel,
      suggesting that this common condition may involve nerve entrapment.

PMID- 10421307
TI  - Serum homocysteine increases after therapy with fenofibrate or bezafibrate.
AB  - A 44% and 17.5% increase of homocysteine occurred in patients treated either with
      fenofibrate or bezafibrate. The increase was not explained by changes in vitamin
      concentrations but may be related to renal function.

PMID- 10421306
TI  - Codon 72 polymorphism of p53 and its association with cervical cancer.
AB  - Swedish and Italian women with HPV 16-positive cervical disease were checked for
      codon 72 polymorphisms of p53. In both groups, arginine homozygotes were enriched
      in cancer compared with controls and precursor lesions.

PMID- 10421308
TI  - Microchimerism in Japanese women patients with systemic sclerosis.
AB  - To examine whether microchimerism occurs in Japanese women patients with systemic
      sclerosis, we analysed the Y-chromosome in DNA by PCR. There was no significant
      difference between patients and healthy people, suggesting that microchimerism
      may not be the sole pathogenesis in Japanese women with systemic sclerosis.

PMID- 10421309
TI  - Detection of risk of falling and hip fracture in women referred for bone
      densitometry.
AB  - In an assessment of the practicality of measurement of fall-related risk factors
      for bone fracture, assessment was easy and the frequency of fractures was high
      enough to justify routine measurement.

PMID- 10421310
TI  - Haemochromatosis gene C282Y homozygotes in an elderly male population.
AB  - We found that C282Y homozygosity was not under-represented in an elderly male
      population. This suggests that life-threatening, haemochromatosis-related disease
      may not occur in many C282Y homozygotes.

PMID- 10421311
TI  - Prevalence of coeliac disease in idiopathic dilated cardiomyopathy.
AB  - We examined 52 patients with idiopathic cardiomyopathy (IDCM) for coeliac
      disease. Three of them had coeliac disease, suggesting that prevalence of coeliac
      disease in IDCM patients is increased.

PMID- 10421312
TI  - NHS attitudes to good medical practice.
AB  - Perceptions of good medical practice among senior NHS staff were collected
      through a survey. There are differences between the perceived seriousness of poor
      communication skills and poor technical skills.

PMID- 10421313
TI  - Oestrogen and age estimations of perimenopausal women.
AB  - We estimated the age of perimenopausal women at a first visit and measured the
      concentrations of oestradiol in serum. The accuracy of estimation of age strongly
      correlated with oestradiol concentrations: age was overestimated when oestradiol
      was low and underestimated when oestradiol was high.

PMID- 10421314
TI  - Alleged unlicensed gene-therapy trial comes to light.

PMID- 10421315
TI  - Viewing the mind's maladies through Darwin's eyes.

PMID- 10421316
TI  - Media coverage of first transplantations fuels public distrust in Japan.

PMID- 10421317
TI  - Tobacco industry giants scorched in Florida lawsuit.

PMID- 10421318
TI  - Psychopharmacotherapy in children and adults with intellectual disability.
AB  - The prevalence of psychiatric disorders is increased in children and adults with
      intellectual disability. Brain damage or dysfunction interact with social and
      family factors to increase susceptibility to mental illness. Psychiatric
      disorders in the context of genetic syndromes are commonly overlooked, and there
      is substantial underdiagnosis of mental disorders because of the atypical and non
      specific clinical presentations, and the frequent assumption that psychiatric
      symptoms are an inherent part of the underlying intellectual disability. There is
      a strong need for evidence-based practice in the prescribing and monitoring of
      drugs in this population, especially since many of the drugs are unlicensed for
      use in children. There is an urgent need to understand and establish the
      pharmacokinetics, pharmacodynamics, and side-effect profiles of psychotropic
      medication in this population. Positive trends in pharmacotherapy include the use
      of atypical antipsychotics instead of the classic antipsychotics, serotonin
      specific reuptake inhibitors (SSRIs) rather than tricyclic antidepressants, and
      newer antiepileptic drugs. Another welcome trend is the use of SSRIs instead of
      antipsychotics in the long-term management of challenging behaviour in this
      population.

PMID- 10421319
TI  - Stories at work: reflective writing for practitioners.

PMID- 10421321
TI  - Pancreatic enzymes and fibrosing colonopathy.

PMID- 10421320
TI  - What does the human embryo look like, and does it matter?

PMID- 10421322
TI  - Pancreatic enzymes and fibrosing colonopathy.

PMID- 10421323
TI  - Pancreatic enzymes and fibrosing colonopathy.

PMID- 10421324
TI  - Pancreatic enzymes and fibrosing colonopathy.

PMID- 10421325
TI  - Pancreatic enzymes and fibrosing colonopathy.

PMID- 10421326
TI  - Home blood-glucose monitoring.

PMID- 10421328
TI  - Hepatocellular carcinoma.

PMID- 10421327
TI  - High-dose chemotherapy for breast cancer in USA.

PMID- 10421329
TI  - Hepatocellular carcinoma.

PMID- 10421330
TI  - Hepatocellular carcinoma.

PMID- 10421331
TI  - Eflornithine for African sleeping sickness.

PMID- 10421332
TI  - Drug-induced headaches.

PMID- 10421333
TI  - Effects of somatic cloning.

PMID- 10421334
TI  - Antenatal betamethasone and fetoplacental blood flow.

PMID- 10421335
TI  - Antenatal betamethasone and fetoplacental blood flow.

PMID- 10421336
TI  - Hormone replacement therapy and heart-rate variability.

PMID- 10421337
TI  - Harmonisation of availability of drugs for Alzheimer's disease.

PMID- 10421338
TI  - Randomised controlled trials in surgery.

PMID- 10421339
TI  - Averting a malaria disaster.

PMID- 10421340
TI  - Nobel chronicle: Fleming and Gratia.

PMID- 10421341
TI  - What's amiss with web search engines?

PMID- 10421342
TI  - Depression, physical illness, and the faces of Rembrandt.

PMID- 10421343
TI  - The Nobel chronicles. 1963: Sir Alan Lloyd Hodgkin (1914-98), Sir Andrew Fielding
      Huxley (b 1917), and Sir John Carew Eccles (1903-97).

PMID- 10421344
TI  - Legal bid could extend US animal welfare law to cover lab rodents.

PMID- 10421346
TI  - Five young life scientists win $1m no-strings grants.

PMID- 10421345
TI  - UK spotlight on alternatives to using animals.

PMID- 10421347
TI  - UK biotech industry aims to clean up its act.

PMID- 10421348
TI  - France losing genome race, says report...as government announces creation of
      genome research consortium.

PMID- 10421349
TI  - Bumpy ride for 'core e-journals' project.

PMID- 10421350
TI  - Critics query financing of proposed 'E-Biomed'.

PMID- 10421351
TI  - Covert trade in toxic vetch continues.

PMID- 10421352
TI  - Global e-journal must take radical approach.

PMID- 10421353
TI  - Behavioural ecology. Electrifying diversity.

PMID- 10421354
TI  - Signal transduction. Neither straight nor narrow.

PMID- 10421355
TI  - Neurobiology. Monkeys play the odds.

PMID- 10421356
TI  - Physiology. Crossing over to the dark side.

PMID- 10421357
TI  - Human evolution. We are what we ate.

PMID- 10421358
TI  - Biophysics. Relating dynamics to function.

PMID- 10421359
TI  - Too good to be true.

PMID- 10421361
TI  - Breast-cancer diagnosis using hair.

PMID- 10421360
TI  - Prions prevent neuronal cell-line death.

PMID- 10421362
TI  - Evolution of cooperation between individuals.

PMID- 10421363
TI  - Higher fullerenes in the Allende meteorite.

PMID- 10421364
TI  - Neural correlates of decision variables in parietal cortex.
AB  - Decision theory proposes that humans and animals decide what to do in a given
      situation by assessing the relative value of each possible response. This
      assessment can be computed, in part, from the probability that each action will
      result in a gain and the magnitude of the gain expected. Here we show that the
      gain (or reward) a monkey can expect to realize from an eye-movement response
      modulates the activity of neurons in the lateral intraparietal area, an area of
      primate cortex that is thought to transform visual signals into eye-movement
      commands. We also show that the activity of these neurons is sensitive to the
      probability that a particular response will result in a gain. When animals can
      choose freely between two alternative responses, the choices subjects make and
      neuronal activation in this area are both correlated with the relative amount of
      gain that the animal can expect from each response. Our data indicate that a
      decision-theoretic model may provide a powerful new framework for studying the
      neural processes that intervene between sensation and action.

PMID- 10421365
TI  - Predation enhances complexity in the evolution of electric fish signals.
AB  - Theories of sexual selection assume that predation is a restrictive, simplifying
      force in the evolution of animal display characters and many empirical studies
      have shown that predation opposes excessive elaboration of sexually selected
      traits. In an unexpected turnaround, I show here that predation pressure on
      neotropical, weakly electric fish (order Gymnotiformes) seems to have selected
      for greater signal complexity, by favouring characters that have enabled further
      signal elaboration by sexual selection. Most gymnotiform fish demonstrate
      adaptations that lower detectability of their electrolocation/communication
      signals by key predators. A second wave phase added to the ancestral monophasic
      signal shifts the emitted spectrum above the most sensitive frequencies of
      electroreceptive predators. By using playback trials with the predatory electric
      eel (Electrophorus electricus), I show that these biphasic signals are less
      detectable than the primitive monophasic signals. But sexually mature males of
      many species in the family Hypopomidae extend the duration of the second phase of
      their electric signal pulses and further amplify this sexual dimorphism nightly
      during the peak hours of reproduction. Thus a signal element that evolved for
      crypsis has itself been modified by sexual selection.

PMID- 10421366
TI  - 'Green revolution' genes encode mutant gibberellin response modulators.
AB  - World wheat grain yields increased substantially in the 1960s and 1970s because
      farmers rapidly adopted the new varieties and cultivation methods of the so
      called 'green revolution'. The new varieties are shorter, increase grain yield at
      the expense of straw biomass, and are more resistant to damage by wind and rain.
      These wheats are short because they respond abnormally to the plant growth
      hormone gibberellin. This reduced response to gibberellin is conferred by mutant
      dwarfing alleles at one of two Reduced height-1 (Rht-B1 and Rht-D1) loci. Here we
      show that Rht-B1/Rht-D1 and maize dwarf-8 (d8) are orthologues of the Arabidopsis
      Gibberellin Insensitive (GAI) gene. These genes encode proteins that resemble
      nuclear transcription factors and contain an SH2-like domain, indicating that
      phosphotyrosine may participate in gibberellin signalling. Six different
      orthologous dwarfing mutant alleles encode proteins that are altered in a
      conserved amino-terminal gibberellin signalling domain. Transgenic rice plants
      containing a mutant GAI allele give reduced responses to gibberellin and are
      dwarfed, indicating that mutant GAI orthologues could be used to increase yield
      in a wide range of crop species.

PMID- 10421368
TI  - Molecular characterization of the melanin-concentrating-hormone receptor.
AB  - Orphan G-protein-coupled receptors (GPCRs) are cloned proteins with structural
      characteristics common to the GPCRs but that bind unidentified ligands. Orphan
      GPCRs have been used as targets to identify novel transmitter molecules. Here we
      describe the isolation from brain extracts and the characterization of the
      natural ligand of a particular orphan GPCR (SLC-1) that is sequentially
      homologous to the somatostatin receptors. We show that the natural ligand of this
      receptor is the neuropeptide melanin-concentrating hormone (MCH). MCH is a cyclic
      peptide that regulates a variety of functions in the mammalian brain, in
      particular feeding behaviour. We demonstrate that nanomolar concentrations of MCH
      strongly activate SLC-1-related pathways through G(alpha)i and/or G(alpha)q
      proteins. We have analysed the tissue localization of the MCH receptor and find
      that it is expressed in several brain regions, in particular those involved in
      olfactory learning and reinforcement mechanisms, indicating that therapies
      targeting the MCH receptor should act on the neuronal regulation of food
      consumption.

PMID- 10421367
TI  - Melanin-concentrating hormone is the cognate ligand for the orphan G-protein
      coupled receptor SLC-1.
AB  - The underlying causes of obesity are poorly understood but probably involve
      complex interactions between many neurotransmitter and neuropeptide systems
      involved in the regulation of food intake and energy balance. Three pieces of
      evidence indicate that the neuropeptide melanin-concentrating hormone (MCH) is an
      important component of this system. First, MCH stimulates feeding when injected
      directly into rat brains; second, the messenger RNA for the MCH precursor is
      upregulated in the hypothalamus of genetically obese mice and in fasted animals;
      and third, mice lacking MCH eat less and are lean. MCH antagonists might,
      therefore, provide a treatment for obesity. However, the development of such
      molecules has been hampered because the identity of the MCH receptor has been
      unknown until now. Here we show that the 353-amino-acid human orphan G-protein
      coupled receptor SLC-1 expressed in HEK293 cells binds MCH with sub-nanomolar
      affinity, and is stimulated by MCH to mobilize intracellular Ca2+ and reduce
      forskolin-elevated cyclic AMP levels. We also show that SLC-1 messenger RNA and
      protein is expressed in the ventromedial and dorsomedial nuclei of the
      hypothalamus, consistent with a role for SLC-1 in mediating the effects of MCH on
      feeding.

PMID- 10421369
TI  - Therapy of tuberculosis in mice by DNA vaccination.
AB  - Mycobacterium tuberculosis continues to kill about 3 million people every year,
      more than any other single infectious agent. This is attributed primarily to an
      inadequate immune response towards infecting bacteria, which suffer growth
      inhibition rather than death and subsequently multiply catastrophically. Although
      the bacillus Calmette-Guerin (BCG) vaccine is widely used, it has major
      limitations as a preventative measure. In addition, effective treatment requires
      that patients take large doses of antibacterial drug combinations for at least 6
      months after diagnosis, which is difficult to achieve in many parts of the world
      and is further restricted by the emergence of multidrug-resistant strains of M.
      tuberculosis. In these circumstances, immunotherapy to boost the efficiency of
      the immune system in infected patients could be a valuable adjunct to
      antibacterial chemotherapy. Here we show in mice that DNA vaccines, initially
      designed to prevent infection, can also have a pronounced therapeutic action. In
      heavily infected mice, DNA vaccinations can switch the immune response from one
      that is relatively inefficient and gives bacterial stasis to one that kills
      bacteria. Application of such immunotherapy in conjunction with conventional
      chemotherapeutic antibacterial drugs might result in faster or more certain cure
      of the disease in humans.

PMID- 10421370
TI  - ovo/svb integrates Wingless and DER pathways to control epidermis
      differentiation.
AB  - In Drosophila, as in mammals, epidermal differentiation is controlled by
      signalling cascades that include Wnt proteins and the ovo/shavenbaby (svb) family
      of zinc-finger transcription factors. Ovo/svb is a complex gene with two genetic
      functions corresponding to separate control regions: ovo is required for female
      germline development and svb for epidermal morphogenesis. In the Drosophila
      embryo, the ventral epidermis consists of the segmental alternance of two major
      cell types that produce either naked cuticle or cytoplasmic extrusions known as
      denticles. Wingless signalling specifies smooth cells that produce naked cuticle,
      whereas the activation of the Drosophila epidermal growth factor (EGF) receptor
      (DER) leads to the production of denticles. Here we show that expression of the
      ovo/svb gene controls the choice between these cell fates. We find that svb is a
      key selector gene that, cell autonomously, directs cytoskeletal modifications
      producing the denticle. The DER pathway promotes denticle formation by activating
      svb expression. Conversely, Wingless promotes the smooth cell fate through the
      transcriptional repression of svb by the bipartite nuclear factor Armadillo/dTcf.
      Our data indicate that transcriptional regulation of svb integrates inputs from
      the Wingless and DER pathways and controls epidermal differentiation.

PMID- 10421371
TI  - The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila.
AB  - Wingless (Wg) is a member of the Wnt family of growth factors, secreted proteins
      that control proliferation and differentiation during development. Studies in
      Drosophila have shown that responses to Wg require cell-surface heparan sulphate,
      a glycosaminoglycan component of proteoglycans. These findings suggest that a
      cell-surface proteoglycan is a component of a Wg/Wnt receptor complex. We
      demonstrate here that the protein encoded by the division abnormally delayed
      (dally) gene is a cell-surface, heparan-sulphate-modified proteoglycan. dally
      partial loss-of-function mutations compromise Wg-directed events, and disruption
      of dally function with RNA interference produces phenotypes comparable to those
      found with RNA interference of wg or frizzled (fz)/Dfz2. Ectopic expression of
      Dally potentiates Wg signalling without altering levels of Wg and can rescue a wg
      partial loss-of-function mutant. We also show that dally, a regulator of
      Decapentaplegic (Dpp) signalling during post-embryonic development, has tissue
      specific effects on Wg and Dpp signalling. Dally can therefore differentially
      influence signalling mediated by two growth factors, and may form a regulatory
      component of both Wg and Dpp receptor complexes.

PMID- 10421372
TI  - Dally cooperates with Drosophila Frizzled 2 to transduce Wingless signalling.
AB  - The Drosophila wingless gene (wg) encodes a protein of the Wnt family and is a
      critical regulator in many developmental processes. Biochemical studies have
      indicated that heparan sulphate proteoglycans, consisting of a protein core to
      which heparan sulphate glycosaminoglycans are attached, are important for Wg
      function. Here we show that, consistent with these findings, the Drosophila gene
      sulfateless (sfl), which encodes a homologue of vertebrate heparan sulphate N
      deacetylase/N-sulphotransferase (an enzyme needed for the modification of heparan
      sulphate) is essential for Wg signalling. We have identified the product of
      division abnormally delayed (dally), a glycosyl-phosphatidyl inositol (GPI)
      linked glypican, as a heparan sulphate proteoglycan molecule involved in Wg
      signalling. Our results indicate that Dally may act as a co-receptor for Wg, and
      that Dally, together with Drosophila Frizzled 2, modulates both short- and long
      range activities of Wg.

PMID- 10421373
TI  - The chromatin-specific transcription elongation factor FACT comprises human SPT16
      and SSRP1 proteins.
AB  - The regulation of gene expression depends critically upon chromatin structure.
      Transcription of protein-coding genes can be reconstituted on naked DNA with only
      the general transcription factors and RNA polymerase II. This minimal system
      cannot transcribe DNA packaged into chromatin, indicating that accessory factors
      may facilitate access to DNA. Two classes of accessory factor, ATP-dependent
      chromatin-remodelling enzymes and histone acetyltransferases, facilitate
      transcription initiation from chromatin templates. FACT (for facilitates
      chromatin transcription) is a chromatin-specific elongation factor required for
      transcription of chromatin templates in vitro. Here we show that FACT comprises a
      new human homologue of the Saccharomyces cerevisiae Spt16/Cdc68 protein and the
      high-mobility group-1-like protein structure-specific recognition protein-1.
      Yeast SPT16/CDC68 is an essential gene that has been implicated in transcription
      and cell-cycle regulation. Consistent with our biochemical analysis of FACT, we
      provide evidence that Spt16/Cdc68 is involved in transcript elongation in vivo.
      Moreover, FACT specifically interacts with nucleosomes and histone H2A/H2B
      dimers, indicating that it may work by promoting nucleosome disassembly upon
      transcription. In support of this model, we show that FACT activity is abrogated
      by covalently crosslinking nucleosomal histones.

PMID- 10421374
TI  - Millisecond-timescale motions contribute to the function of the bacterial
      response regulator protein Spo0F.
AB  - Protein backbones and side chains display varying degrees of flexibility, which
      allows many slightly different but related conformational substates to occur.
      Such fluctuations are known to differ in both timescale and magnitude, from
      rotation of methyl groups (nanoseconds) to the flipping of buried tyrosine rings
      (seconds). Because many mechanisms for protein function require conformational
      change, it has been proposed that some of these ground-state fluctuations are
      related to protein function. But exactly which aspects of motion are functionally
      relevant remains to be determined. Only a few examples so far exist where
      function can be correlated to structural fluctuations with known magnitude and
      timescale. As part of an investigation of the mechanism of action of the Bacillus
      subtilis response regulator SpoOF, we have explored the relationship between the
      motional characteristics and protein-protein interactions. Here we use a set of
      nuclear magnetic resonance 15N relaxation measurements to determine the relative
      timescales of SpoOF backbone fluctuations on the picosecond-to-millisecond
      timescale. We show that regions having motion on the millisecond timescale
      correlate with residues and surfaces that are known to be critical for protein
      protein interactions.

PMID- 10421375
TI  - Protein binding to simple repetitive sequences depends on DNA secondary
      structure(s).
AB  - Simple repetitive DNA sequences are ubiquitous constituents of eukaryotic
      chromosomes. The properties of simple repeats generate increased interest as
      expansions of certain trinucleotide blocks cause human diseases. We studied
      protein binding and structural features of (gaa x ttc)n tracts e.g. in the
      polymorphic frataxin intron 1 and (gt)n(ga)m stretches from different HLA-DRB1
      alleles in their original genomic environments. Electrophoretic mobility shift
      assays revealed that HeLa nuclear proteins bind to DNA fragments containing these
      simple repeat blocks. The major retarded protein/DNA complexes comprise, in both
      cases, zinc-dependent proteins present in nuclear extracts from different cell
      types. Competition experiments using various simple repeats differing in length
      and flanking regions demonstrate specific interactions. DNase I footprinting
      shows protein-binding sites located either within the repeats alone or within the
      repeats as well as their flanking regions, often with preference for one strand.
      Comparing different (gt)n(ga)m alleles, a regular pattern of footprints was not
      detectable in the (gt)n part indicating that the zinc-dependent protein
      recognizes structural rather than sequence-specific features. OsO4 and DEPC
      modifications followed by electrophoretic and electron microscopical analyses
      demonstrate that the homopurine blocks often form different types of
      intramolecular triple helices. A similar situation was evident using (gaa x ttc)n
      blocks of different lengths within frataxin intron 1 as targets. These data have
      functional implications for non-coding (gaa x ttc)n and (gt)n(ga)m tracts with
      regard to gene expression in vivo.

PMID- 10421376
TI  - Chromosome painting in marsupials: genome conservation in the kangaroo family.
AB  - In order to deduce the ancestral genome arrangement in the karyotypically diverse
      marsupial family Macropodidae, and to assess chromosome change in this family,
      chromosome-specific paints from the tammar wallaby (2n = 16) were hybridized to
      metaphase spreads from the two species proposed to represent the 2n = 22
      ancestral karyotype, as well as species with derived 2n = 20 and 2n = 14
      karyotypes. Identical patterns were observed in the two 2n = 22 species, from
      which the rearrangements to form the three derived karyotypes may be easily
      deduced to be 1, 3 and 4 different fusions, respectively. The identical Thylogale
      and Dorcopsis genomes may both be used to represent the pleisiomorphic macropodid
      chromosome complement. Variation in the X chromosome was also investigated by
      hybridizing an X-Y shared tammar wallaby 12-kb repeat element to chromosomes from
      the other four macropodid species, finding that it hybridized only to the most
      closely related species, and therefore is of recent origin.

PMID- 10421377
TI  - Localization of HTLV-1 and HIV-1 proviral sequences in chromosomes of
      persistently infected cells.
AB  - Integration sites for HTLV-1 and HIV-1proviruses were detected by FISH on the
      chromosomes of HTHIV27 cells persistently infected by HIV-1 (strain IIIB). HTLV-1
      signals were found on 9 loci of chromosomes 4, 6, 9, 15 and 16. Integration sites
      of GC-rich HTLV-1 provirus are located in GC-rich isochores, confirming an
      'isopycnic' integration, namely an integration in which the GC level of the host
      sequences around the integration site match the GC level of the provirus. This
      conclusion is not only derived from the compositional map of human chromosomes,
      but also from HTLV-1 hybridization on compositional fractions of human DNA.
      Integration of GC-poor HIV-1 provirus was found on 4 loci of chromosomes 2, 7, 17
      and 19. One copy of a complete HIV-1 provirus, which is active, was integrated in
      H1 isochores, whereas other defective copies were located in GC-poor L isochores.
      These results are discussed in terms of regional integration of retroviral
      sequences.

PMID- 10421378
TI  - Sister chromatid differentiation with biotin-dUTP.
AB  - The method of choice to differentiate sister chromatids is to incorporate BrdU in
      replicating DNA. The disadvantage of BrdU is that its spontaneous or induced
      radicalization may itself lead to sister chromatid exchanges. Biotin-labelled
      dUTP is a widely used thymidine analogon for labelling isolated DNA. Its chemical
      structure suggests that, in contrast to BrdU, it does not give rise to radical
      formation. We electroporated proliferating Chinese hamster ovary (CHO) cells in
      the presence of biotin-dUTP which was subsequently detected in metaphase cells
      with TRITC-conjugated avidin. Microscopic analysis of second mitoses after
      labelling revealed a clear differential staining of sister chromatids. Thus
      substitution of thymidine with biotin-dUTP is another method to analyse SCE.

PMID- 10421379
TI  - Multiple causes of size variation in the diploid megabase chromosomes of African
      tyrpanosomes.
AB  - The chromosomes of many protozoans are polymorphic in size, but African
      trypanosomes contain diploid homologues which are exceptionally size-polymorphic.
      We present the first complete analysis of the structure of a Trypanosoma brucei
      megabase chromosome which reveals the concentration of repetitive sequence, non
      random distribution of transposon-like elements, and a hemizygous variant surface
      glycoprotein gene expression site. Subsequent comparative analyses of size
      polymorphic homologues show that the repetitive regions are highly polymorphic,
      as demonstrated in studies on the chromosomes of other protozoan parasites. We
      show that a large number of the transposon-like elements are located in these
      regions. However, although we have shown elsewhere that synteny is maintained in
      coding regions, homologous chromosomes may vary along their entire length. Thus,
      the variable chromosomal location of variant surface glycoprotein expression gene
      sites, the expansion and contraction of repetitive DNA, the number of putative
      transposons, sequence polymorphism at chromosome ends, and expansion and
      contraction within or between coding regions all contribute to huge chromosomal
      size polymorphisms in T brucei.

PMID- 10421380
TI  - Rye chromosome variability in wheat-rye addition and substitution lines.
AB  - In a study of polymorphism and stability in rye chromosomes, three rye varieties
      and the sets of wheat-rye addition and substitution lines were compared using two
      non-homologous highly repetitive DNA families, pSc200 and pSc250. The rye
      varieties, Petkus, Imperial and Onohoiskaya, showed polymorphism for the presence
      and the size of the pSc200 in-situ hybridization signals on chromosome pairs, 2R,
      4R and 7R, and the pSc250 signals on chromosomes, 5R, 6R and 7R. Chromosome 1R
      was heteromorphic within the Onohoiskaya variety. Differences in the distribution
      of chromosome polymorphisms imply that intervarietal changes to these highly
      repetitive DNA families occurred independently, despite their juxtaposition or
      even overlapping locations in subtelomeric heterochromatic regions. In the set of
      Saratovskaya 29 wheat/Onohoiskaya substitution lines, only chromosome 2R was
      altered relative to its counterpart in the parental rye variety due to
      amplification of the pSc250 signal on the long arm, although this did not exceed
      intervarietal polymorphism. In the set of Chinese Spring wheat/Imperial addition
      lines, only two Imperial chromosomes, 4R and 6R, were unchanged. We detected the
      loss of one or both rye homologous chromosomes, the loss of one arm, and the
      deletion of subtelomeric heterochromatin accompanied by the loss of the pSc200
      signal. The results show that Saratovskaya 29/Onohoiskaya chromosome substitution
      lines possess increased chromosome stability compared with Chinese
      Spring/Imperial addition lines.

PMID- 10421381
TI  - Comparative karyotype of rat and mouse using bidirectional chromosome painting.
AB  - A comparative karyotype of rat (Rattus norvegicus) and mouse (Mus musculus) based
      on chromosome G-banding morphology, heterologous chromosome painting results and
      available gene mapping data is proposed. Whole chromosome painting probes from
      both species were generated by PARM-PCR amplification of flow sorted chromosomes.
      Bidirectional chromosome painting identifies 36 segments of syntenic homology and
      allows us to propose a nearly complete comparative karyotype of mouse and rat
      (except for RNO 13 p and RNO 19 p12-13). Seven segments completely covered the
      RNO chromosomes 3, 5, 8, 11, 12, 15 and 18. Eight segments completely covered the
      MMU chromosomes 3, 4, 6, 7, 9, 12, 18 and 19. The RNO chromosomes 5, 8, 18 show
      complete homology with the MMU chromosomes 4, 9 and 18, respectively.
      Bidirectional hybridization results clearly assign 16 segments to subchromosomal
      regions in both species. Interpretation of the results allows subchromosomal
      assignment of all the remaining segments apart from seven distributed on
      chromosomes MMU 15, MMU 10 B2-D3 and MMU 17 E3-E5. The proposed comparative
      karyotype shows overall agreement with available comparative mapping data. The
      proposed repartition of syntenic homologous segments between the two species
      provides useful data for gene-mapping studies. In addition, these results will
      enable the reconstruction of the karyotype of the Cricetidae and Muridae common
      ancestor and the definition of the precise rearrangements which have occurred in
      both mouse and rat lineages during evolution.

PMID- 10421383
TI  - Telomeric (TTAGGG)n sequences are associated with nucleolus organizer regions
      (NORs) in the wood lemming.
AB  - The distribution of the (TTAGGG)n telomeric sequence was studied in chromosomes
      of the wood lemming, Myopus schisticolor, by fluorescence in-situ hybridization.
      As expected, the hybridization signals were observed at telomeres of all
      chromosomes. However, quite a number of interstitial telomeric sites were present
      in the pericentric heterochromatic regions. Consistent strong hybridization
      signals were also seen at one terminus of chromosomes 5, 7 and 12--15. By post
      hybridization G-banding and silver-staining, the large blocks of the telomeric
      sequences on chromosomes 5 and 12 were localized to nucleolus organizer regions
      (NORs).

PMID- 10421384
TI  - Simultaneous fluorescence in-situ hybridization (FISH) an R-banding by primed in
      situ labelling (PRINS).

PMID- 10421382
TI  - Localization and characterization of nucleotide sequences from the canine Y
      chromosome.
AB  - We previously reported the identification of a male-specific 658-bp DNA sequence
      in dogs. We used a specific primer pair designed for PCR amplification of this
      fragment with DNA samples from 238 dogs, 6 dingoes and 12 wolves. All 133 male
      samples amplified the 658-bp sequence, whereas all female samples did not. The
      sequence was not amplified from male DNA samples representing other wild canids
      (jackals, coyotes, foxes). A lambda phage was isolated from a canine male genomic
      library that contained an insert of approximately 15 kb of canine genomic DNA,
      including the male-specific 658-bp sequence. This lambda phage was used in
      fluorescence in-situ hybridization experiments. It hybridized to the canine Y
      chromosome together with a lambda clone containing a segment of the SRY gene and
      a cosmid clone containing a portion of the pseudoautosomal region. The male
      specific 658-bp sequence was located at the end opposite to the pseudoautosomal
      region while the SRY gene sequence hybridized near the centromere. Additionally,
      two (CA)-repeat sequences were identified in the lambda clone that contained the
      658-bp sequence. Specific primer pairs were designed to amplify each of the
      repeats. Primer pair MS34 amplified three different alleles from 13 unrelated
      canine male DNA samples with a PIC value of 0.40. Primer pair MS41 amplified five
      alleles with a PIC value of 0.71. These microsatellites are the first reported
      polymorphic sequences in the dog located in the non-recombining portion of the Y
      chromosome.

PMID- 10421385
TI  - Human GALR1 galanin receptor (GALNR1). Map position 18q23.

PMID- 10421386
TI  - 1999 Jonathan E. Rhoads lecture. Isotopic metaprobes, nutrition, and the roads
      ahead.
AB  - The 1999 Jonathan E. Rhoads lecture, delivered by Vernon R. Young at the annual
      meeting of American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.),
      San Diego, February 2, 1999, with the printed version coauthored with Alfred M.
      Ajami, is concerned with the application of isotopic probes and how, in
      particular, they may be used as diagnostic tools to enhance the role of nutrition
      in the comprehensive medical management of the patient. Following a brief review
      of the early uses of stable isotopes in metabolic research we consider the
      present and possible future application of stable isotope probes. The concept of
      a "gateway" enzyme in a discrete biochemical pathway and how the flow of
      substrate through this step might be assessed by giving a "metaprobe" is
      developed. The specific and desirable structural requirements of the metaprobe
      are considered. A number of examples are given that further exploit the concepts
      of "underground" metabolism and of metabolic "hijackers." It is our view that we
      are on the verge of a new era where, for the many pragmatic and exciting reasons
      discussed, stable isotope probes will find and increasing use in the practice of
      clinical medicine and in the preventive and public health areas.

PMID- 10421387
TI  - Nutrition support: ethical or expedient, and who will choose?

PMID- 10421388
TI  - Differences in cholecystokinin release and gallbladder contraction between
      emulsified and nonemulsified long-chain triglycerides.
AB  - BACKGROUND: Fat is a potent stimulus of cholecystokinin (CCK) release. Apart from
      lipolysis, fatty acid chain length, and saturation, emulsification may also
      determine the magnitude of CCK release. METHODS: We have studied the effect of
      emulsification of soybean oil on CCK and pancreatic polypeptide (PP) release
      (radioimmunoassay [RIA]) and gallbladder motility (ultrasonography). Six healthy
      subjects were studied on three separate occasions in random order during (1)
      intraduodenal administration of emulsified long-chain triglycerides (LCT) (6
      mmol/h for 120 minutes); (2) equimolar amounts of nonemulsified LCT with addition
      of emulsifier; and (3) saline with emulsifier (control). RESULTS: Intraduodenal
      administration of both nonemulsified LCT and emulsified LCT induced significant
      (p < .05) increases in plasma CCK and PP levels and reductions in gallbladder
      volume. However, compared with nonemulsified LCT, emulsified LCT resulted in a
      readier and significantly stronger CCK release (212+/-62 pmol/L per 120 minutes
      vs 36+/-7 pmol/L per 120 minutes; p < .05); PP release (2034+/-461 pmol/L per 120
      minutes vs 671+/-106 pmol/L per 120 minutes; p < .05); and gallbladder
      contraction (77%+/-2% vs 41%+/-7%; p < .05). No significant alterations were
      observed in plasma CCK or PP levels and gallbladder volume during administration
      of saline with emulsifier. CONCLUSIONS: Intraduodenal administration of a low
      dose emulsified LCT more potently stimulates CCK and PP release and gallbladder
      contraction in comparison to equimolar amounts of nonemulsified LCT. These
      findings point to an important role for solubilization of LCT in determining the
      magnitude of CCK release from the intestine.

PMID- 10421389
TI  - Whole-protein-based enteral formula stimulates intestinal ornithine decarboxylase
      activity more than single amino acids but does not affect mucosal adenosine
      triphosphate content in early postsurgical refeeding.
AB  - BACKGROUND: To restore intestinal integrity after starvation and trauma, luminal
      nutrients are essential. Specific nutrients such as glutamine support mucosal
      proliferation and energy metabolism. The aim of this study was to compare effects
      of enteral formula vs specific amino acids on ornithine decarboxylase (ODC)
      activity and adenine nucleotide metabolism in jejunal mucosa. METHODS: Male
      Wistar rats (240 to 280 g) were starved for 48 hours and subjected to intestinal
      transection, gastrotomy, and jejunal instillation of 5mL nutrient solution. In
      the first experiment, standard enteral formula (EF) was compared with
      isonitrogenous formula supplemented with the glutamine precursor, alpha
      ketoglutarate (alpha-KG). In a second experiment, 2% glutamine was compared with
      isonitrogenous ornithine alpha-KG, arginine alpha-KG, glycine and diluted
      standard enteral formula (EF), or saline. The ODC activity, adenosine
      triphosphates (ATP), and RNA and protein in the jejunal mucosa were analyzed 2
      hours after surgery. RESULTS: The ODC peak in jejunal mucosa in animals treated
      with EF was higher than when supplemented with alpha-KG (p < .05). Compared with
      specific amino compounds, EF resulted in a significantly higher ODC peak and no
      differences were seen between the different specific amino acids. Differences
      seen in ATP or energy charge between the groups were not significant.
      CONCLUSIONS: Immediate postoperative enteral feeding by standard EF results in
      rapid increase of ODC activity. This response was attenuated when the enteral
      nutrition was supplemented with alpha-KG and was absent when isonitrogenous
      single amino acids were administered. We found no significant effects on ATP
      content in the small bowel mucosa by supplementing the diet with alpha-KG.

PMID- 10421390
TI  - Chronic infusion of interleukin 1 induces hyperlactatemia and altered regulation
      of lactate metabolism in skeletal muscle.
AB  - BACKGROUND: Hyperlactatemia is observed commonly in patients with severe
      inflammation syndrome or sepsis. Elevated plasma lactate concentrations may be
      caused by cytokine-mediated alterations in specific organ systems responsible for
      lactate homeostasis. The role of interleukin 1 (IL-1) in inducing hyperlactatemia
      and derangements in skeletal muscle and hepatic lactate metabolism was
      investigated by examining the consequences of infusing IL-1 continuously into
      normal rats. METHODS: Male Sprague-Dawley rats were anesthetized, and catheters
      were placed in the jugular vein. Rats were allowed to recover for 48 hours and
      were infused subsequently with either saline (control) or human recombinant IL
      1alpha (20 microg/kg/d) for 6 days. On day 6, plasma, liver, and muscle samples
      were extracted and assayed for lactate and pyruvate dehydrogenase (PDH) activity.
      RESULTS: Plasma glucose concentrations were not different in the two groups. IL-1
      infusion resulted in a twofold (p < .05) increase in the plasma lactate
      concentration compared with controls. IL-1 infusion also resulted in an elevated
      lactate content in skeletal muscle (p < .05) but not in liver. The proportion of
      PDH in the active form (PDHa) was reduced significantly (p < .05) in the skeletal
      muscle of animals infused with IL-1 compared with controls. In contrast to
      muscle, hepatic PDHa did not differ between the two groups. Total PDH complex
      activity was not affected in either liver or skeletal muscle. CONCLUSIONS: IL-1
      infusion results in hyperlactatemia, increased skeletal muscle lactate, and a
      reduced PDHa in skeletal muscle. We conclude that IL-1 is a potential mediator of
      the derangements in lactate metabolism in skeletal muscle but not in liver.

PMID- 10421391
TI  - Assessment of drug-related problems in clinical nutrition patients.
AB  - BACKGROUND: Medication use in clinical nutrition patients is affected by
      concomitant disease states and alterations in medication administration and
      delivery. The purpose of this evaluation was to document the number and type of
      drug-related problems that occurred and to evaluate the effect pharmacists had on
      the care of nutrition patients. METHODS: Patients were evaluated by a pharmacist
      who was part of the clinical nutrition team. Drug-related problems were
      identified and recommendations were made to resolve them. Acceptance of the
      recommendations and patient outcomes were documented. RESULTS: After the
      evaluation of 440 patients, 220 pharmacist interventions were made. Interventions
      included 35 drug information requests and 185 recommendations made to solve
      identified drug-related problems in 126 patients. The most frequent drug-related
      problems were drug interactions (33/185) and untreated indications (24/185). Of
      185 recommendations, 166 were accepted, and 19 were accepted with a modification.
      A total of 132 of 155 recommendations that were accepted or accepted with
      modification had a positive outcome: 45 patients responded, and 87 patients
      developed no complications. Six patients did not respond to the recommendation,
      and in 17 patients the outcome was unknown. Fifty-eight recommendations avoided
      potential adverse drug events. CONCLUSIONS: Pharmacist intervention identified
      drug-related problems in almost 30% of clinical nutrition patients. The
      identification and resolution of the problems had a positive effect on patient
      care, as indicated by patient outcome and the avoidance of adverse drug events.
      The drug-related problem approach identified areas in which pharmacists can
      educate the health care team and ensure proper medication use in this patient
      population.

PMID- 10421392
TI  - Trace element contamination of total parenteral nutrition. 1. Contribution of
      component solutions.
AB  - BACKGROUND: Trace elements have been shown to contaminate total parenteral
      nutrition (TPN) solutions. METHODS: This study used the multi-elemental
      technology of inductively coupled plasma-mass spectrometry to demonstrate the
      extent to which trace elements were present in amounts above (ie, as
      contaminants) or below expected levels in eight TPN component solutions. RESULTS:
      Of the 66 trace elements scanned, there were 12 trace element contaminants in
      amounts >1 microg/L (zinc, copper, manganese, chromium, selenium, boron,
      aluminum, titanium, barium, vanadium, arsenic, and strontium) in the eight
      component solutions studied. Trace element contaminants were present in all
      solutions, and different trace elements contaminated the solutions at various
      concentrations. Component solutions of amino acid, potassium chloride, calcium
      gluconate, and sodium chloride contained the greatest numbers of trace element
      contaminants, whereas the lowest numbers were present in sterile water and
      magnesium sulfate. Interlot and intermanufacturer variations were apparent.
      Measured concentrations of trace elements in the multi-trace element additive
      solution also were higher than the labeled values. A comparison of the amounts of
      contaminated trace elements delivered by a typical TPN mixture relative to the
      amounts typically absorbed by the gastrointestinal tract indicates that the
      inadvertent delivery of trace elements from contaminated TPN solutions may be
      substantial. CONCLUSIONS: All eight components tested were contaminated with
      trace elements not intended to be present in the product, and similarly, the
      multi-trace element component contained trace elements either above or below that
      which the label claimed.

PMID- 10421393
TI  - Trace element contamination of total parenteral nutrition. 2. Effect of storage
      duration and temperature.
AB  - BACKGROUND: Patients who receive home total parenteral nutrition (TPN) frequently
      are supplied with solutions up to 30 days in advance of anticipated use. The
      purpose of this study was to determine the stability of trace elements relative
      to time and temperature conditions, in a typical adult TPN solution stored in a
      usual home environment by examining variations in delivery of intended trace
      elements and inadvertent trace element contamination. METHODS: Trace element
      concentrations were determined using inductively coupled plasma-mass spectrometry
      technology. The effect of the delivery apparatus, storage duration (36 hours or
      30 days) after compounding, and storage temperature (4 degrees C or 20 degrees C)
      were examined. RESULTS: The delivery apparatus contaminated the delivered TPN
      solution with cobalt but did not alter trace elements formulated into the TPN
      solution. Storage duration and temperature significantly decreased three (Zn, Cu,
      and Mn) of the six trace elements formulated into the TPN solution. Higher
      temperatures and longer duration of storage accelerated this decrease. Boron, Al,
      V, Ti, Ba, Sr, and CO were the trace elements that appeared as contaminants
      during storage. Boron, Al, V, and Ti contamination decreased with higher
      temperatures and longer duration of storage. CONCLUSIONS: Longer storage duration
      and higher storage temperature progressively reduced the deliverable
      concentrations of trace elements specifically formulated into the TPN solution
      and also of those trace elements that were not formulated into the TPN solution
      but that appeared as contaminants.

PMID- 10421394
TI  - Effects of Pseudomonas colonization on body composition and resting energy
      expenditure in children with cystic fibrosis.
AB  - BACKGROUND: To determine the extent and effects of increased metabolic demand
      represented by Pseudomonas colonization on body composition and resting energy
      expenditure in children with cystic fibrosis (CF). METHODS: The study comprised
      18 stable children with CF, of whom 10 (6 male/4 female) were colonized with
      Pseudomonas species and 8 (4 male/4 female) were not. The groups were of similar
      age range and genotype. Measured resting energy expenditure (REE) was performed
      by open circuit indirect calorimetry and compared with predicted REE calculated
      from standard equations. Body composition was determined by dual-energy x-ray
      absorptiometry, including lean body mass (LBM), fat mass (FM), bone mineral
      density (BMD), and anterior-posterior spine density (APS); these were compared
      using z-scores. Routine pulmonary function testing assessed forced vital
      capacity, forced expiratory volume in 1 second (FEV1), and forced expiratory flow
      over middle half of vital capacity (FEF25% to 75%); these were compared as
      percent predicted. RESULTS: As expected, results of pulmonary function testing
      showed significant deterioration among the children colonized with Pseudomonas
      species when compared with the children who were not, while standard
      anthropometry showed no differences in weight, height, or weight-for-height
      percentile and respective z-scores. Although a trend of lower LBM was noted among
      the children colonized with Pseudomonas species, no significant differences were
      found between these children and children who were not colonized with Pseudomonas
      species when z-scores for LBM, FM, BMD, or APS were compared during body
      composition analysis. In addition, neither REE as kilocalories per day (kcal/d)
      nor REE expressed as a percent predicted by standard equations discriminated
      between subgroups of children colonized with Pseudomonas species and children who
      were not. However, metabolic demand, expressed as resting energy expenditure in
      kilocalories per kilogram (kcal/kg) of LBM (REE/LBM), revealed significant
      differences between children colonized with Pseudomonas species and children who
      were not (75.4+/-4.4 vs 58.6+/-2.9 kcal/kg, p < .05). CONCLUSIONS: The effect of
      Pseudomonas colonization on metabolic demand in children with CF can be
      accurately assessed by expressing resting energy expenditure as kilocalorie per
      kilogram of LBM, the active metabolic component of the body. The 50% increase in
      REE/LBM seen in the children colonized with Pseudomonas species represents the
      metabolic demand from the inflammatory burden and work of breathing resulting
      from the effects of the Pseudomonas colonization. The trend of a lower LBM in the
      children colonized with Pseudomonas species makes this finding even more
      dramatic.

PMID- 10421396
TI  - Hepatitis A among health workers in Paris hospitals. Occupational Health
      Physicians of Paris Hospital (AP-HP).
AB  - To design a vaccination strategy against hepatitis A among hospital employees, we
      carried out a serological survey of hepatitis A virus (HAV) infection in 10
      university hospitals in the Paris area. Subjects under 60 years of age were
      consecutively enrolled by occupational health services and tested for IgG to HAV
      by ELISA. Of the 1,516 subjects recruited, 926 were health workers (HW), 322
      clerks, and 268 cooks or kitchen employees. Among HW and clerks the HAV
      seroprevalence was 53.8% (95% CI: 44.0-65.6), increasing with age and being
      higher among employees of African or Caribbean origin than those from Europe
      (83.6% vs 45.6%, P < .001). Age correlated closely with the duration of hospital
      work, so only age was taken into account for further analysis. The HAV
      seroprevalences among HW and clerks originating from Europe were close (46.8% vs
      42.6%) and remained so after adjustment for age. HAV seroprevalences in HW caring
      for adults and those caring for children were also similar (45.2% vs 40.1%).
      Seroprevalence was higher in assistant nurses than in nurses (51.3% vs. 39.8%, P
      < .02). Among cooks and kitchen employees, 53.4% were HAV-seropositive. This
      study shows that hospital employees need not routinely be vaccinated against HAV;
      the decision should be taken by the occupational physician according to the type
      of work, but should be routine for cooks and kitchen employees. The need for
      prevaccinal screening for anti-HAV should be assessed in the light of employees'
      geographical origin and age.

PMID- 10421395
TI  - Effects of parenteral nutrition support and chemotherapy on the phasic
      composition of tumor cells in gastrointestinal cancer.
AB  - BACKGROUND: Some clinical studies report the effects of parenteral nutrition in
      malnourished cancer patients, but few discuss the tumor response to parenteral
      nutrition plus chemotherapy. If used in combination, the antitumor activity of
      chemotherapeutic agents may compensate for the tumor stimulation of parenteral
      nutrition. METHODS: Ninety-two patients with operable gastrointestinal cancer and
      malnutrition were randomly assigned to four interventions that were administered
      for 7 days preoperatively: parenteral nutrition alone, parenteral nutrition plus
      chemotherapy, chemotherapy alone, or no treatment (control). The preintervention
      and postintervention DNA content, DNA index, percentage of cells in S phase, and
      tumor cell sensitivity to chemotherapy were measured using image cytometry.
      RESULTS: Parenteral nutrition resulted in a significant proliferation of tumor
      cells and a significant increase in the sensitivity of tumor cells to
      chemotherapy; these effects were not seen in tumors of patients receiving
      parenteral nutrition plus chemotherapy. There was, however, a nonsignificant
      increase in tumor cell proliferation and sensitivity to chemotherapy in the
      tumors of subjects receiving combined therapy compared with those of subjects who
      received chemotherapy alone. The postintervention nutritional status of both the
      parenteral nutrition group and the parenteral nutrition plus chemotherapy group
      were significantly better than that of the control group and the chemotherapy
      group. The short-term, postoperative clinical outcomes in the chemotherapy group
      were significantly worse than those in the other three groups. CONCLUSIONS: These
      results indicate that combining chemotherapy and nutrition support preoperatively
      for malnourished patients with gastrointestinal cancer improves short-term
      nutritional status without increasing the proliferation of tumor cells and
      prevents the postoperative complications that occur when such patients are given
      chemotherapy without nutrition support. The results also suggest--but do not
      prove--that parenteral nutrition may increase the effectiveness of chemotherapy
      in malnourished patients.

PMID- 10421397
TI  - Quantitative DNA analysis of low-level hepatitis B viremia in two patients with
      serologically negative chronic hepatitis B.
AB  - Low-level viremia due to hepatitis B virus (HBV) was demonstrated in the sera of
      two patients diagnosed previously as having non-B, non-C chronic hepatitis. Both
      patients had a "silent" HBV infection, because they were negative for both
      hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antibody. The
      TaqMan chemistry polymerase chain reaction (PCR) amplified the HBV DNA, enabling
      quantitation of the virus in their sera. Their serum HBV DNA concentrations were
      low: the amount of each HBV S or X gene amplified showed there were approximately
      10(3) copies/ml and HBV DNA was detected occasionally during clinical follow-up.
      Positive HBsAg staining in liver tissues was demonstrated by an immunoperoxidase
      technique. Vertical transmission of silent HBV from one patient to her daughter
      was confirmed. Direct nucleotide sequencing of the amplified HBV X region
      revealed several mutations, suggesting reduced viral replication. One patient had
      a T-to-C mutation at the extreme 5'-terminus of the direct repeat 2 region and
      the other exhibited a coexisting X region with a 155-nucleotide deletion. These
      findings suggest that HBV replication is suppressed considerably in patients with
      silent hepatitis B.

PMID- 10421398
TI  - Low level wild-type and pre-core mutant hepatitis B viruses and HBeAg negative
      reactivation of chronic hepatitis B.
AB  - A qualitative and a quantitative mutation-site specific polymerase chain reaction
      assay (MSSA) was used to detect low level wild-type and pre-core mutant hepatitis
      B virus (HBV)-DNA. Serum samples from 11 anti-hepatitis B e (anti-HBe)-positive
      asymptomatic HBV carriers (Group A) and 10 anti-HBe-positive chronic hepatitis B
      patients who achieved alanine transaminase (ALT) normalization after antiviral
      therapy (Group B) were tested. Eleven patients had both wild-type and pre-core
      mutant HBV-DNA (52%, 4 from Group A and 7 from Group B), whereas 3 patients had
      only pre-core mutant HBV-DNA (14%, 2 from Group A and 1 from Group B) by
      qualitative MSSA assay. During a 3-year follow-up period, relapses were observed
      in 3 patients from Group B and intermittent ALT elevation was observed in 4
      patients from Group A and 3 patients from Group B. The wild-type HBV-DNA
      concentration in the patients with reactivation was 10(2.06+/-2.62) copies/ml,
      whereas that in all patients without reactivation was below 10(2) copies/ml (P <
      .05). The pre-core mutant HBV-DNA concentration in the patients with reactivation
      was also significantly higher than that in the patients without reactivation
      (10(3.94+/-2.25) vs. 10(0.65+/-1.45) copies/ml, P < .001). All patients with both
      HBV-DNA concentrations below 10(2) copies/ml did not exhibit reactivation. Our
      result suggest that a high prevalence of coexistence of low level wild-type and
      pre-core mutant HBV-DNA has the potential for reactivation in anti-HBe-positive
      patients. Furthermore, quantification of wild-type and pre-core mutant HBV-DNA
      was useful to predict the prognosis of anti-HBe-positive infection and evaluate
      the efficacy of antiviral therapy.

PMID- 10421399
TI  - Bacterial expression of a human recombinant monoclonal antibody fab fragment
      against hepatitis B surface antigen.
AB  - The Fab fragment was cloned from the monoclonal cell line TAPC301-CL4, which was
      produced using the Epstein-Barr virus (EBV) transformation method. This cell line
      produces a human monoclonal antibody (CL4MAb) against the hepatitis B surface
      antigen (HBsAg). This MAb was shown to have hepatitis B virus (HBV) neutralizing
      activity in chimpanzees. The Fab fragment was produced by subjecting the heavy
      and light chain antibody genes of the TAPC301-CL4 cell line to reverse
      transcription-polymerase chain reaction, cloning the products in the plasmid
      vector pFab1-His2 and introducing the plasmid into bacteria. Sequence analyses of
      the CL4Fab fragment revealed that the light and heavy chains belong to the Vk3a
      and VH3 groups of the immunoglobulin (Ig) family, respectively. An enzyme-linked
      immunosorbent assay confirmed that specificity of the recombinant CL4Fab antibody
      against HBsAg was the same as that of the parental MAb. Flow cytometric analysis
      using PLC/PRF/5 (Alexander) cells, which express HBsAg, showed the reactivities
      of the CL4MAb and CL4Fab antibody were the same. These results suggest that the
      recombinant CL4Fab antibody produced by Escherichia coli using the new vector
      primer system developed for human IgG Fab fragments has a very high affinity for
      the HBsAg and may be useful clinically. A source for generation of human MAb for
      human therapy with very stable and specific expression was thus produced by
      isolating antibodies from EBV-transformed cell lines.

PMID- 10421400
TI  - A hepatitis B virus variant found in the sera of immunised children induces a
      conformational change in the HBsAg "a" determinant.
AB  - The emergence of variants in the outer envelope proteins of hepatitis B virus
      (HBV) are found among individuals vaccinated against HBV and asymptomatic
      carriers of the infection. For example, children in The Gambia vaccinated against
      hepatitis B may show serological evidence of breakthrough infections,
      particularly if anti-HBs antibodies induced by the vaccine are low in titre. A
      single-point mutation at nucleotide 421 of the S gene is associated with such
      breakthrough infections. In the present study, the antigenicity of variant HBV S
      protein expressed as HBsAg particles in a vaccinia virus expression system has
      been characterised using a panel of monoclonal antibodies directed against linear
      and conformational determinations of the S protein. A cellular ELISA procedure
      using expressed antigen in Vero cells revealed differences in reactivity using
      four of the six antibodies that had been raised against the adw subtype of HBV
      and recognise conformational epitopes in the a determinant. In two instances, an
      enhanced reactivity for the variant antigen was found, confirming that point
      mutations in the a determinant of the S protein between residues 139 and 147 may
      result in significant changes in conformation. These findings also demonstrate
      that there are distinct antigenic differences between the vaccine strains of
      HBsAg/ adw subtype and the predominant HBsAg subtype circulating in West Africa.
      The implications of this work are that serodiagnosis of HBV infections may be
      unreliable in populations where there is a possibility of variant HBV infections
      emerging in the face of increasing herd immunity to HBV as a result of
      vaccination, particularly using monoclonal antibody-based diagnostic tests. Such
      variants may play a role in the maintenance of HBV infections in endemic regions.

PMID- 10421401
TI  - Mutations in the NS5A region do not predict interferon-responsiveness in american
      patients infected with genotype 1b hepatitis C virus.
AB  - A striking association has been demonstrated recently between mutations in amino
      acid residues 2209-2248 of the nonstructural protein 5a (NS5a) region of
      hepatitis C virus (HCV) and sustained responses to interferon in Japanese
      patients infected with genotype 1b. Therefore, analysis of this sequence has been
      suggested as a predictor of treatment response. We sought to determine whether
      mutations in this region predict outcome in U.S. patients infected with genotype
      1b hepatitis C virus (HCV-1b). We analyzed stored pretreatment sera
      retrospectively from 22 patients with HCV-1b infection who had received
      interferon alpha-2b (IFNalpha-2b) as part of a controlled trial. Two patients
      were sustained responders (SR), 7 were transient responders (TR), and 13 were
      nonresponders (NR). We performed nested reverse transcription-polymerase chain
      reaction (RT-PCR) on extracted RNA using primers flanking HCV amino acids 2209
      2248 and sequenced the PCR products directly. The deduced amino acid sequences
      were compared with the prototype HCV-J. Isolates with four or more deviations
      from the prototype were defined as "mutant" type, those with one to three
      substitutions as "intermediate" type, and those matching the prototype as
      "wildtype." Of the 22 HCV-1b isolates, 6 were wildtype, 11 intermediate type, and
      5 mutant type. Both of the SRs were intermediate type. The 20 TRs and NRs were
      distributed among mutant (5), intermediate (9), and wildtype (6). Of the five
      patients with mutant virus, four were NR and one a TR. Variation in NS5a(2209
      2248) fails to predict interferon responsiveness in this cohort of American
      patients infected with HCV-1b. Thus, the utility of this sequence as a predictor
      of interferon responsiveness appears to be specific to Japanese patients and may
      reflect differences between patient groups in treatment regimens, host genetic
      background, or alterations in the interferon signaling pathway induced by
      surrounding sequences within or outside NS5a. Overall, NS5a is not as integral a
      determinant of interferon responsiveness as previously suggested.

PMID- 10421402
TI  - Expression of interferon receptor genes in the liver as a predictor of interferon
      response in patients with chronic hepatitis C.
AB  - Interferon (IFN) receptor mRNA expression patterns in the liver have been shown
      to correlate with the effectiveness of IFN therapy in patients with hepatitis C
      virus (HCV) infection. However, it is not clear to what extent this factor
      contributes to the short (primary)- and long (sustained)-term results of IFN
      treatment with respect to biochemical and virological remission. Eighty-two
      patients who subsequently received lymphoblastoid IFN-alpha therapy underwent
      liver biopsies before IFN therapy. Possible factors that might correlate with IFN
      response were chosen and analyzed. The primary biochemical and virological
      responses at the end to treatment (24 weeks) were 63% and 43% vs. 46% and 32% for
      sustained biochemical and virological remission at the end of follow-up (48
      weeks), respectively. In univariate analysis, the absence of HCV genotype 1b, a
      low titer of HCV RNA, and the expression of IFN receptor mRNA were significantly
      correlated with sustained biochemical and virological responses to IFN therapy.
      Multiple logistic regression analysis showed that IFN receptor mRNA expression
      and the absence of genotype 1b were significant predictors of the sustained
      biochemical and virological effectiveness of IFN therapy. IFN receptor mRNA
      expression predicted a sustained virological response to IFN therapy with a
      positive predictive value of 100% with genotype non-1b and had a negative
      predictive value of 97% with genotype 1b. It is concluded that expression of IFN
      receptor genes in the liver is a useful index for predicting the short- and long
      term efficacy of IFN therapy in patients with chronic HCV infection.

PMID- 10421403
TI  - Hepatitis delta virus genotype IIb predominates in an endemic area, Okinawa,
      Japan.
AB  - Hepatitis delta virus (HDV) infection is relatively common in the Miyako Islands,
      Okinawa, Japan, where the infection has been reported to be associated with low
      pathogenicity. HDV RNA extracted from each of 6 patients with HDV-related chronic
      liver disease living in the islands was amplified by reverse transcription
      polymerase chain reaction and examined genetically to determine the HDV genotype.
      All isolates from the 6 patients were classified as genotype II by the neighbor
      joining method. However, these isolates had relatively low homology (75-81%) to
      the HDV genotype II isolate reported from Japan, and showed relatively high
      identity (83-95%) to the novel genotype II isolate (HDV genotype IIb) recently
      reported from Taiwan. Phylogenetic analysis showed that the 6 isolates form a
      novel group within HDV genotype II. Furthermore, there was notable variation in
      sequence among the 6 isolates compared with the relatively close clustering of
      HDV isolates within limited areas (e.g., United States, Archangelos, Turkey,
      Albania, Peru). HDV genotype II in the Miyako Islands is therefore unique, and
      HDV infection may have been introduced at a relatively early time in this area.

PMID- 10421404
TI  - Prevalence of GBV-C/hepatitis G virus RNA and E2 antibody among subjects infected
      with human immunodeficiency virus type 1 after parenteral or sexual exposure.
AB  - GB virus C (GBV-C) or hepatitis G virus (HGV) is transmitted by the parenteral
      route but the importance of sexual transmission needs to be ascertained. GBV
      C/HGV infections were investigated using RNA and E2-antibody detection methods in
      80 subjects infected by the human immunodeficiency virus type 1 (HIV-1) divided
      into 4 groups of 20 individuals each according to their main risk factor for HIV
      1 infection: blood product recipients (group 1), intravenous drug users (group
      2), homosexuals (group 3), or heterosexual exposure (group 4). The overall
      prevalence of GBV-C/HGV infection was 66.3%. No significant difference was
      observed in GBV-C/ HGV prevalence among the four groups: 75, 75, 55, and 60% in
      groups 1, 2, 3, and 4, respectively. Hepatitis C virus (HCV) antibodies, used as
      a control for parenteral exposure, were found in 70% and 90% of the subjects in
      groups 1 and 2 versus only 15% and 20% of the subjects in groups 3 and 4,
      respectively (P< .001). Similarly, coinfections with GBV-C/HGV and HCV were
      significantly associated with the parenteral route (P <.001). These data
      emphasized the usefulness of combining the detection of RNA and the E2 antibody
      to determine the actual prevalence of GBV-C/HGV infection. The high prevalence of
      the GBV-C/HGV markers among the HIV-1-infected subjects, especially those with
      sexual exposure, provides additional evidence that this route of transmission
      plays a key role in the epidemiology of GBV-C/HGV. The potential influence of GBV
      C/HGV infection on the course of HIV-1 disease needs further evaluation.

PMID- 10421405
TI  - Human papillomavirus genotype spectrum in Czech women: correlation of HPV DNA
      presence with antibodies against HPV-16, 18, and 33 virus-like particles.
AB  - Because the biological spectrum of human papillomavirus (HPV) genotypes present
      in cervical cancer lesions varies according to the geographical region studied,
      and because little genotype information is available for Central and Eastern
      European countries, we studied the endemic HPV-genotype spectrum in cervical
      samples collected from women visiting gynaecological departments of selected
      hospitals in the Czech Republic. In a series of 389 samples, 171 (44.0%) were
      positive for HPV DNA using a consensus-primer polymerase chain reaction (PCR).
      Genotyping of the HPV PCR products was done using dot-blot hybridisation with
      type-specific oligonucleotide probes and thermocycle DNA sequencing. Twenty-two
      different HPV types were detected, HPV-16 being the most prevalent type
      irrespective of severity of the lesions (55.0%). Multiple HPV types were found in
      16.4% of our HPV-DNA-positive samples. The prevalence of HPV infection was 23.0%
      in women with normal findings and 59.4% in patients with cervical neoplasia, and
      increased significantly with the severity of the disease: 52.9% in low-grade
      lesions, 58.0% in high-grade lesions, and 73.5% in cervical carcinomas (P for
      trend < .00001). In the sera of 191 subjects, 89 with normal findings and 102
      with different forms of cervical neoplasia, the prevalence of HPV-specific IgG
      antibodies was tested by an enzyme-linked immunosorbent assay (ELISA) using virus
      like particles (VLPs) of HPV-16, -18, and -33. Antibodies were significantly more
      prevalent in HPV-DNA-positive than in HPV-DNA-negative women and there was no
      association with age. In agreement with the results of HPV genotyping, antibodies
      reactive with HPV-16 VLPs were the most frequent and, moreover, their prevalence
      increased with the cervical lesion severity. About half of the subjects with
      smears in which either HPV-16 or HPV-33 DNA had been detected possessed
      antibodies reactive with homotypic VLPs. With HPV-18-DNA-positive subjects,
      however, fewer than 25% displayed homotypic antibodies. In general, subjects
      older than 30 years of age had antibodies reactive to HPV-specific VLPs more
      often than subjects younger than 30 years of age. In women with benign findings,
      the seropositivity to HPV-16, -18, and -33 VLPs increased with age, whereas in
      women with cervical neoplasia the seropositivity decreased with age.

PMID- 10421406
TI  - Nucleotide sequence of thymidine kinase gene of sequential acyclovir-resistant
      herpes simplex virus type 1 isolates recovered from a child with Wiskott-Aldrich
      syndrome: evidence for reactivation of acyclovir-resistant herpes simplex virus.
AB  - Recurrent acyclovir (ACV)-resistant (ACV-r) herpes simplex virus type 1 (HSV-1)
      infections occurred in a patient with Wiskott-Aldrich syndrome, an X-linked
      recessive immunodeficiency syndrome composed of three clinical characteristics of
      immunodeficiency, thrombocytopenia, and an eczematous dermatitis. The patient had
      severe and recurrent ACV-r herpes simplex and was treated with vidarabine in a
      satisfactory manner from 1993 to 1997. During the 4-year observation period, two
      ACV-sensitive (ACV-s) HSV-1 isolates and five ACV-r HSV-1 isolates were
      recovered. The nucleotide sequence of the thymidine kinase (TK) gene from these
      sequential ACV-r isolates was compared with the ACV-s isolates. A single
      nucleotide deletion of cytosine (C) from homopolymer stretch of four C residues
      between nucleotide 1061 and 1064 of the open reading frame was found in all ACV-r
      isolates. No other differences were observed in the TK nucleotide sequence
      between ACV-s and ACV-r isolates. The TK nucleotide sequences of the two ACV-s
      isolates were identical to each other and those of the five ACV-r isolates were
      identical to one another. These results suggest that the ACV-r HSV-1 might have
      derived from the ACV-s strain in the patient body and that TK-associated ACV-r
      HSV-1 can reactivate from latency.

PMID- 10421407
TI  - Establishing and characterizing a CD30-positive cell line harboring HHV-8 from a
      primary effusion lymphoma.
AB  - Primary effusion lymphoma (PEL, or body-cavity-based lymphoma [BCBL]) is a new
      subtype of non-Hodgkin's lymphoma in which tumor cells locate in the body cavity
      exclusively. PEL/BCBL is widely accepted as one of the neoplastic complications
      of AIDS, associated mostly with human herpesvirus 8 (HHV-8/Kaposi's sarcoma
      associated herpesvirus [KSHV]) and Epstein-Barr virus (EBV). We established and
      characterized a PEL cell line named TY-1 from a 47-year-old patient with AIDS. TY
      1 exhibits indeterminate immunophenotype, expressing CD45 and CD30 cell surface
      antigens but not expressing B- or T-cell markers. Cytogenetic analysis revealed
      the representative karyotype of 50,XYq-,+7,+8,+11,+15. Southern blot analysis
      demonstrated HHV-8 and EBV genomes in the original tumor cells obtained from the
      pericardial effusion, while HHV-8 but not EBV was detected in TY-1 using PCR or
      Southern blot analysis. Tetradecanylphorbol acetate treatment induced some TY-1
      cells to proceed to the reproductive phase. This cell line may be an useful tool
      for research on PEL and HHV-8.

PMID- 10421408
TI  - Quantitative changes in cytomegalovirus DNAemia and genetic analysis of the UL97
      and UL54 genes in AIDS patients receiving cidofovir following ganciclovir
      therapy.
AB  - Five AIDS patients with cytomegalovirus (CMV) retinitis who had received
      ganciclovir (GCV) therapy were followed with serial blood sampling to
      detectchanges both in CMV load and in the genetic composition of genes UL97 and
      UL54 whilst receiving cidofovir (CDV) therapy. CDV neither reduced CMV load in
      blood nor prevented its quantitative resurgence during therapy. These effects
      were not explained by the initial presence or development of CDV-associated drug
      resistance mutations in UL54. In two patients, UL97 genotypic resistance to GCV
      involving either a L595S mutation or a deletion of amino acids 590-603 were
      present at the initiation of CDV and, in both patients, repopulation of CMV
      strains with wild-type UL97 sequences occurred during CDV therapy. These data are
      consistent with GCV-resistant strains containing UL97 mutations being less fit
      than their wild-type counterparts and so being able to persist only with the
      selective pressure of GCV.

PMID- 10421409
TI  - Genome type analysis of Brazilian adenovirus strains of serotypes 1,2,3,5, and 7
      collected between 1976 and 1995.
AB  - A collection of 92 epidemiologically unrelated isolates of Ad1 (n = 14), Ad2 (n =
      29), Ad3 (n = 19), Ad5 (n = 16), and Ad7 (n = 14) collected in the cities of
      Belem do Para (1 degree S 48 degrees W) and Rio de Janeiro (23 degrees S 43
      degrees W) between 1976 and 1995 from patients with respiratory disease and
      conjunctivitis were characterized by restriction enzyme analysis of genomic DNA.
      Among the strains of subgenus B, two different genome types of serotype 7, 7b and
      7e, were identified. The analysis of their temporal distribution throughout the
      study period suggested an alternating appearance of these two DNA variants. Only
      one genome type of Ad3, 3p, was detected during the sampling period. Further
      analysis with Xba I, Bcl I, and Hpa I indicated that it is a p1-like genome type.
      Both previously described and new genomic variants were identified among subgenus
      C strains. Genome types D1, D7, D10, and one not previously described were
      identified among the 14 Ad1 strains analyzed. Genome types D2, D5, D25, and 13
      new DNA variants were identified among the 29 Ad2 isolates. Genome type D38 and 5
      new variants were found among the 16 strains of Ad5. In spite of the relatively
      small size of the sample analyzed, the results of this study confirm the
      important genetic variability previously observed for members of subgenus C by
      other authors.

PMID- 10421410
TI  - Identification of a new control region in the genome of the DDP strain of BK
      virus isolated from PBMC.
AB  - The various strains of human polyomavirus BK (BKV) show a marked heterogeneity in
      the non-coding control region (NCCR), which includes the origin of replication
      and the regulatory region for early and late transcription. A new BKV strain
      (DDP, U91605) was identified by direct detection and sequencing of PCR products
      of BKV-NCCR DNA obtained from PBMC samples of HIV-positive or -negative subjects.
      The DDP strain NCCR sequence showed an organisation not described previously in
      vivo with the maximum homology with the archetypal strain (WW) (M34048), as
      compared with those collected in GenBank. Structurally, P68, Q39, and S68 boxes
      were perfectly conserved, whereas the R63 box was completely deleted. This
      deletion involves the loss of sequences able to bind cellular factors essential
      for the DNA transcription, such as NF1 binding sites, normally present twice in
      the R box and the modification of SP1. It is possible that these rearrangements
      represent a cause of the loss of the VP1 region observed in 9/22 PBMC samples and
      never observed in urine isolates, which are similar to the WW strain.

PMID- 10421411
TI  - Detection of influenza virus RNA by reverse transcription-PCR and proinflammatory
      cytokines in influenza-virus-associated encephalopathy.
AB  - Eleven children with acute encephalopathy associated with an influenza virus
      infection were treated during the 1997-1998 influenza season. Reverse
      transcription-polymerase chain reaction (RT-PCR) assay was used to detect the
      viral genome in peripheral blood and cerebrospinal fluid (CSF) samples. The
      results were compared with those of control influenza patients without
      neurological complications. Viral RNA was detected only in the peripheral blood
      mononuclear cells of one patient with influenza-virus-associated encephalopathy
      (1 of 9; 11%) and in the CSF of another patient (1 of 11;9%). RT-PCR was negative
      in the blood of all the controls, but the percentage of RT-PCR-positive samples
      in the two groups was not significantly different. Cytokines and soluble cytokine
      receptors in plasma and CSF were then quantified using an enzyme-linked
      immunosorbent assay. The CSF concentrations of soluble tumor necrosis factor
      receptor-1 were elevated in two patients and interleukin-6 (IL-6) was elevated in
      one patient with influenza-virus-associated encephalopathy. On the other hand,
      the plasma concentrations of IL-6 were elevated in four of nine patients. The
      number of encephalopathy patients who had elevated plasma concentrations of IL-6
      100 pg/ml was significantly higher than that of controls (P= .01). In conclusion,
      the infrequent detection of the viral genome in the CSF and blood showed that
      direct invasion of the virus into the central nervous system was an uncommon
      event. Proinflammatory cytokines and soluble cytokine receptors may mediate the
      disease. The high plasma concentration of IL-6 could be an indicator of the
      progression to encephalopathy.

PMID- 10421412
TI  - Genomic diversity of "Norwalk like viruses" (NLVs): pediatric infections in a
      Brazilian shantytown.
AB  - "Norwalk-like viruses" (NLVs) are a common cause of epidemic gastroenteritis in
      adults and children in developed countries. However, little is known about the
      role of NLVs in endemic pediatric gastroenteritis in developing countries. We
      sequenced Genogroup I and II NLV reverse transcription-polymerase chain reaction
      (RT-PCR) products from an 81-nucleotide region of the viral RNA polymerase gene
      to examine the molecular epidemiology of NLV infection in children younger than 5
      years of age in Forteleza, Ceara, Brazil. NLV-positive PCR products were obtained
      from stool specimens collected over a 16-month period (1990-1991) from diarrhea
      cases and controls in a cohort of 120 children in an urban shantytown and from a
      study in the same city of hospitalized children with persistent diarrhea. Eight
      unique strains were detected in 15 specimens from 10 cohort children and in two
      hospital specimens. Nucleotide identity between the strains (5 Genogroup I, 3
      Genogroup II) ranged from 63% to 88%. We designated these strains BraV1-8, for
      Brazil virus 1-8. The degree of genomic diversity of NLV strains we identified in
      this cohort during a short time period suggests multiple foci of infection within
      the community. Furthermore, sequence analysis of strains from two children with
      multiple symptomatic NLV infections indicates that infection with one strain was
      not protective against subsequent infection with a different strain in the same
      genogroup. These findings have implications for vaccine development and the
      prevention of pediatric gastroenteritis in developing countries.

PMID- 10421413
TI  - Characterization of cell surface lectin-binding patterns of human airway
      epithelium.
AB  - Glycosylated structures on the cell surface have a role in cell adhesion,
      migration, and proliferation. Repair of the airway epithelium after injury
      requires each of these processes, but the normal cell surface glycosylation of
      non-mucin producing airway epithelial cells is unknown. We examined cell surface
      glycosylation in human airway epithelial cells in tissue sections and in human
      airway epithelial cell lines in culture. Thirty-eight lectin probes were used to
      determine specific carbohydrate residues by lectin-histochemistry. Galactose or
      galactosamine-specific lectins labeled basal epithelial cells, lectins specific
      for several different carbohydrate structures bound columnar epithelial cells,
      and fucose-specific lectins labeled all airway epithelial cells. The epithelial
      cell lines 1HAEo- and 16HBE14o- bound lectins that were specific to basal
      epithelial cells. Flow cytometry of these cell lines with selected lectins
      demonstrated that lectin binding was to cell surface carbohydrates, and revealed
      possible hidden tissue antigens on dispersed cultured cells. We demonstrate
      specific lectin-binding patterns on the surface of normal human airway epithelial
      cells. The expression of specific carbohydrate residues may be useful to type
      epithelial cells and as a tool to examine cell events involved in epithelial
      repair.

PMID- 10421414
TI  - Effect of inflammatory stimuli on the silver staining pattern of the rat carotid
      endothelium.
AB  - Silver nitrate stains the intercellular junctions of the endothelium and other
      cytoplasmic or membrane components. Two protocols are described for the silver
      staining of rat carotid endothelium that exclude the use of pressurized fixatives
      and simplify the technique previously described for rat aorta. The entire surface
      of the carotid endothelium was examined and several parameters (stigmata,
      granularity, clustering of anionic sites, transversal lines, weakening of silver
      lines and leukocyte adhesion) were evaluated. We studied the pattern of silver
      staining in two situations: (1) endothelial activation and (2) neurogenic
      inflammation. Endothelial activation was produced by the intravenous
      administration of a proinflammatory albumin or polyinosinic acid. Both products
      cause a marked increase in leukocyte adhesion concomitant with a decrease in
      argyrophilia and a weakness or loss of silver lines. Neurogenic inflammation,
      which is mediated by substances released from sensory nerves, was induced by the
      intravenous administration of substance P or capsaicin. Both stimuli produced an
      increase in argyrophilia and weakness or loss of silver lines. Substance P caused
      a clustering of anionic sites, whereas this phenomenon was more discrete with
      capsaicin. Nearly 80% of all examined rats (controls and inflammatory stimuli
      treated) showed endothelial membrane disruptions formed by clusters of cells
      often in the shape of streaks aligned with the long axis of the vessel. The
      detection of these discontinuities is important, as loss of endothelial integrity
      is central in the initiation of pathological events.

PMID- 10421415
TI  - Uneven distribution and size of rabbit lens capsule proteoglycans.
AB  - To document the ultrastructural distribution of lens capsule proteoglycans,
      rabbit lens capsules were fixed and stained overnight in 50 mM sodium acetate, pH
      5.6, containing 2.5% glutaraldehyde, 0.2% Cuprolinic Blue and 0.2 M MgCl2. They
      were rinsed, stained with 1% aqueous sodium tungstate, embedded in Epon,
      sectioned (60 nm), and examined with an electron microscope at 60 kV.
      Proteoglycan-Cuprolinic Blue complexes mainly appeared as networks of small
      electron-dense filaments throughout the posterior and anterior capsules. The
      posterior capsule was a single layer with a network of small proteoglycan
      filaments gradually decreasing in size from the humoral side (90 x 10 nm) to the
      lenticular side (30 x 8 nm). The humoral side of the anterior capsule had a thin
      lamina (400 nm) containing large (180 x 40 nm), very electron-dense proteoglycan
      Cuprolinic Blue complexes plus small proteoglycans. Below this lamina, the
      complexes were only seen as filaments slightly smaller than those in the
      corresponding area of the posterior capsule. Cuprolinic Blue binding of the
      anterior and posterior lens capsules revealed differences in the size and
      distribution of their sulphated proteoglycans which do not correspond to the
      patterns of their immunoreactivity with anti-heparan sulphate proteoglycan. The
      humoral lamina in the anterior capsules, with large proteoglycan structures,
      might be a distinct structural and functional compartment.

PMID- 10421416
TI  - Peptide transporter in the rat small intestine: ultrastructural localization and
      the effect of starvation and administration of amino acids.
AB  - Peptide transporter-1 is a H+/peptide cotransporter responsible for the uptake of
      small peptides and peptide-like drugs, and is present in the absorptive
      epithelial cells of the villi in the small intestine (duodenum, jejunum, and
      ileum). It has been localized to the apical microvillous plasma membrane of the
      absorptive epithelial cells of the rat small intestine using the immunogold
      electron microscopic technique. Digital image analysis of the jejunum revealed
      that the transporter protein was abundant at the tip of the villus and that the
      amount decreased from the tip of the villus to its base. The effect of dietary
      administration of amino acids and starvation on the expression of PepT1 in the
      jejunum was examined by immunoblotting and image analysis of immunofluorescence.
      Starvation markedly increased the amount of peptide transporter present, whereas
      dietary administration of amino acids reduced it. The gradient of the transporter
      protein along the crypt-villus axis was maintained under either condition. These
      observations show that it is specific to the microvillous plasma membrane and
      that its expression is regulated by the nutritional condition.

PMID- 10421417
TI  - Effect of follicular cells on calcitonin gene expression in thyroid
      parafollicular cells in cell culture.
AB  - Expression of calcitonin (CT) gene in thyroid parafollicular cells involves
      alternate formation of CT mRNA or CGRP mRNA. High amounts of CT mRNA are formed
      only in thyroid gland and formation of CGRP mRNA dominates in the remaining
      organs. Apart from paracrine and endocrine factors, mRNA formation on the CT gene
      seems to be affected also by direct contacts with other cells present in the
      thyroid gland, in which parafollicular cells are located next to follicular
      cells. The present study aimed at examining whether thyroid follicular cells
      affect formation of mRNAs for CT and CGRP in parafollicular cells. The studies
      were performed in cell cultures. A parafollicular cell line (TT cells) and a
      follicular cell line (F6BTY cells) served as the experimental model. For
      comparison, co-cultures with fibroblasts, 3T3 cells, and malignant melanoma, MM
      cells, were also examined. CT gene expression was examined at the level of mRNAs
      (in situ hybridization and morphometric studies) and at the level of hormones
      (immunocytochemistry, morphometric studies and radioimmunological estimation of
      hormone levels in the medium). The immunocytochemical and hybridocytochemical
      studies, in line with morphometry studies, demonstrated that F6BTY and 3T3 cells
      were capable of affecting mRNA production for CT and CGRP and that they changed
      the ratio of CGRP/CT secretion by TT cells, as a sequel of contact between the
      two cell types and due to mediation of secreted substances. On the other hand,
      the malignant melanoma MM cells showed no effect on the secretion ratio. Our
      study seems to indicate that control of mRNA formation from CT gene may involve
      not only humoral factors but also direct contacts with other cells, which may
      explain differences in expression of the gene between cells localized in
      different organs.

PMID- 10421418
TI  - Detection of oxidant producing-sites in glutaraldehyde-fixed human neutrophils
      and eosinophils stimulated with phorbol myristate acetate.
AB  - The aim of the present study was to detect oxidant-producing sites, and to
      elucidate their dynamic reorganization in human polymorphonuclear leukocytes
      (PMNs) fixed with glutaraldehyde which preserves cell structure. In biochemical
      analyses, the detectable O2- generation in unfixed PMNs upon stimulation with
      phorbol 12-myristate 13-acetate (PMA) in the presence of cytochalasin B was
      characterized by a lag period of approximately 10 sec followed by O2- production.
      The maximal rate reached was 3.18+/-0.07 nmol/min/l x 10(6) cells (mean+/-S.D.; n
      = 4) after 30 sec of stimulation. PMNs exposed to PMA and cytochalasin B followed
      by fixation with glutaraldehyde generated O2- without a lag period at a rate of
      0.35+/-0.05 n mol/min/l x 10(6) cells (mean+/-S.D.) by the addition of NADPH as
      substrate to the cell suspension. In the cytochemical assays, we employed both
      cells exposed to PMA and cytochalasin B, and then fixed with glutaraldehyde
      followed by incubation in the cytochemical reaction medium (pre-fixed cells) and
      cells incubated in the medium containing PMA and cytochalasin B followed by
      fixation with glutaraldehyde (post-fixed cells). Oxidant reaction in the pre
      fixed cells was detected by the addition of NADPH and FAD to the reaction medium.
      No oxidant-reaction product was seen in pre-fixed cells stimulated for 10 sec
      whereas the oxidant reaction was visualized in intracellular compartments of pre
      fixed PMNs stimulated for 20 sec. The fact that the pre-fixed PMNs stimulated for
      30 sec showed increased numbers of oxidant-producing structures compared to those
      seen in the pre-fixed cells stimulated for 20 sec, demonstrates that the amount
      of the reaction product and the number of oxidant-producing intracellular
      compartments increases between 20 and 30 sec after start of stimulation with PMA.
      These cytochemical results using the pre-fixed cells coincided with the findings
      obtained from the biochemical assays in the pre-fixed cells exposed to PMA and
      cytochalasin B. The oxidant reaction was observed in elongated tubular structures
      that were arranged in a radial fashion, and were associated with the plasma
      membrane in the pre-fixed PMNs, whereas post-fixed PMNs exhibited slender
      spherical or rod-shaped structures of various lengths. The present results
      indicate that the pre-fixed PMNs can be employed for elucidating the dynamic
      reorganization of oxidant-producing sites in human PMNs.

PMID- 10421419
TI  - Concentration dependent and adverse effects in immunohistochemistry using the
      tyramine amplification technique.
AB  - Although the tyramine amplification technique to enhance sensitivity in
      immunohistochemistry has been described in numerous methodological papers, it has
      not yet gained access to diagnostic immunohistochemistry. This is mainly due to
      problems and pitfalls occurring in adaptation of this method to routine
      application. In this study a monoclonal antibody and a polyclonal antiserum (pan
      cytokeratin and anti-myoglobin) were tested in tissues with different amounts of
      epitopes, using a checkerboard table and testing a total of 133 different
      dilution combinations of both the tyramide solution and the primary antibodies.
      The specific tissue investigated, i.e. the amount of accessible epitope to be
      detected and the applied concentration of the tyramide solution mainly influenced
      the staining reaction. Several pitfalls such as an uneven distribution of the
      staining or dramatic overstaining (paradoxical overstaining) must be considered
      to achieve optimal results. In conclusion, our data confirm methodological
      studies that the tyramine amplification technique is a powerful method to enhance
      immunohistochemical sensitivity. However, for reliable daily practice several
      pitfalls of the technique have to be circumvented.

PMID- 10421420
TI  - Microscopical and spectroscopic studies on the fluorescence of a daunomycin
      aluminum complex.
AB  - In this study, the spectroscopic features and microscopical applications of the
      fluorescent daunomycin-Al3+ complex have been analyzed. In the presence of Al3+,
      the absorption spectrum of daunomycin showed a deep bathochromic shift and new
      peaks at 529 and 566 nm, whereas the fluorescence emission was considerably
      modified. The emission of daunomycin alone (peak at 560 nm under optimal
      excitation at 470 nm) decreased continuously from 0.5 to 24h after addition of
      Al3+ ions, and a new emission peak appeared at 580 nm (optimal excitation at 530
      nm). Under the fluorescence microscope using green exciting light, nuclei from
      chicken blood smears and paraffin sections of rat embryos stained with daunomycin
      showed a weak emission, which greatly increased after treatment with Al3+ ions.
      The bright and stable fluorescence of chromatin DNA induced by daunomycin-Al3+
      could be a valuable labelling method in fluorescence microscopy and DNA
      cytochemistry.

PMID- 10421421
TI  - Flavonoids: old and new aspects of a class of natural therapeutic drugs.
AB  - Flavonoids are natural products widely distributed in the vegetable kingdom and
      currently consumed in large amounts in the daily diet. Flavonoids are capable of
      modulating the activity of enzymes and affect the behaviour of many cell systems,
      suggesting that the compounds may possess significant antihepatotoxic,
      antiallergic, anti-inflammatory, antiosteoporotic and even antitumor activities.
      This review summarizes available data on these beneficial effects of flavonoids.

PMID- 10421422
TI  - Reducing the immunogenicity and improving the in vivo activity of trichosanthin
      by site-directed pegylation.
AB  - PEG modification (PEGylation) has been shown to reduce immunogenicity and prolong
      circulating half-life of proteins. In the present study, site-directed PEGylation
      was used to reduce immunogenicity and prolong plasma half-life of trichosanthin
      (TCS). Four TCS mutants, i.e. S7C, Q219C, K173C and [K173C,Q219C] (KQ), were
      constructed by site-directed mutagenesis. PEG modifications were done by reacting
      PEG5k-maleimide or PEG20k-maleimide reagent with the newly introduced cysteine
      residue of the mutants. The plasma clearance rate of PEGylated TCS mutants
      decreased up to 100-fold and the decrease was inversely proportional to the
      effective molecular size. The in vitro activities such as ribosome-inactivating
      activity and cytotoxicity were also decreased. However, the in vivo abortifacient
      activity was, slightly decreased, unchanged, or even enhanced in some
      preparations. PEG5k modification had little effect on immunogenicity. However,
      PEG20k modification significantly reduced immunogenicity. All PEG20k modified TCS
      mutants induced lower level IgG and IgE antibodies. In particular, PEG20k-KQ and
      PEG20k-K173C induced weaker systemic anaphylaxis reaction in guinea pigs. In
      conclusion, the present results suggest that PEG20k is better than PEG5k for
      reducing immunogenicity and prolonging plasma half-life. The conjugate can become
      a better therapeutic agent.

PMID- 10421423
TI  - Augmentation of the inotropic response to insulin in diabetic rat hearts.
AB  - Insulin participates in the modulation of myocardial function, but its inotropic
      action in diabetes mellitus is not fully clear. In the present study, we examined
      contractile responses to insulin in left-ventricular papillary muscles and
      ventricular myocytes isolated from hearts of normal or short-term (5-7 days)
      streptozotocin-induced (65 mg/kg) diabetic rats. Mechanical properties of
      papillary muscles and ventricular myocytes were evaluated using a force
      transducer and an edge-detector, respectively. Contractile properties of
      papillary muscles or cardiac myocytes, electrically stimulated at 0.5 Hz, were
      analyzed in terms of peak tension development (PTD) or peak twitch amplitude
      (PTA), time-to-peak contraction (TPT) and time-to-90% relaxation (RT90).
      Intracellular Ca2+ transients were measured as fura-2 fluorescence intensity
      change (deltaFFI). Insulin (1-500 nM) had no effect on PTD in normal myocardium,
      whereas it produced a positive inotropic response in preparations from diabetic
      animals, with a maximal increase of 11%. Insulin did not modify TPT or RT90 in
      either group. Further studies revealed that insulin enhanced cell shortening in
      diabetic but not normal myocytes, with a maximal increase of 21%. Consistent with
      its action on the mechanical properties of papillary muscles and cardiac
      myocytes, insulin also induced a dose-dependent increase in the intracellular
      Ca2+ transient in diabetic but not normal myocytes. Collectively, these data
      suggest that the myocardial contractile response to insulin may be altered in
      diabetes.

PMID- 10421424
TI  - Suppression of oncogenic transformation by hypothemycin associated with
      accelerated cyclin D1 degradation through ubiquitin-proteasome pathway.
AB  - Hypothemycin was originally isolated as an antifungal metabolite of Hypomyces
      trichothecoides. Here we report that treatment on v-K-ras-transformed NIH3T3
      cells (DT cells) with hypothemycin caused drastic decrease in amount of cyclin D1
      protein with concomitant prolongation of G1 phase in their cell cycle. Analysis
      using hypothemycin-resistant mutant of Schizosaccharomyces pombe (S. pombe) was
      carried out to show that S. pombe rhp6+ (homologue of Saccharomyces cerevisiae
      RAD6) and mammalian ubiquitin-conjugating enzyme 2 (ubc2) are the targets of
      hypothemycin or its downstream molecules in ubiquitin-conjugation process.
      Furthermore, in the presence of lactacystin, a specific inhibitor for proteasome,
      hypothemycin greatly enhanced the accumulation of multi-ubiquitinated form of
      cyclin D1 in DT cells. Therefore, it is indicated that hypothemycin facilitates
      ubiquitinating process of cyclin D1. In terms of malignant phenotype,
      hypothemycin inhibited anchorage-independent growth and reverted the morphology
      of DT cells. On the contrary, their morphology still remained transformed in the
      additional presence of lactacystin. Our results suggest that cyclin D1 is a key
      molecule working downstream in ras-signaling and that the transformation can be
      inhibited by the compound which can activate ubiquitin-proteasome pathway
      including degradation of cyclin D1.

PMID- 10421425
TI  - Paradoxical effects of intracerebroventricular low-dose opioid antagonists in SHR
      with chronic pain.
AB  - The aim of our study was to investigate the effect of intracerebroventricular
      (i.c.v.) administration of very low doses of opioid antagonists on the pain
      threshold, arterial blood pressure and body temperature of spontaneously
      hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v.
      administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4
      microg) produce paradoxical hypoalgesia. Similar results were not observed
      following i.c.v. administration of nor-binaltorphimine (0.6 microg). A
      paradoxical increase in the severity of hypertension followed i.c.v. opioid
      antagonist administration. This suggests an involvement of the opioid system in
      the mechanisms of blood pressure control. The paradoxical results obtained both
      for pain threshold and blood pressure after low doses of some opioid antagonists
      seem to confirm the role played by opioid autoreceptors in these effects.
      Existence of autoreceptors is suggested. Results obtained following i.c.v.
      administration of nor-binaltorphimine also suggest a role for the kappa
      autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.

PMID- 10421426
TI  - Alpha2 adrenergic and high affinity serotonergic receptor changes in the brain
      stem of streptozotocin-induced diabetic rats.
AB  - The brain stems (BS) of streptozotocin (STZ)-diabetic rats were studied to see
      the changes in neurotransmitter content and their receptor regulation. The
      norepinephrine (NE) content determined in the diabetic brain stems did not show
      an increase, while epinephrine (EPI) content increased significantly compared
      with control. The NE to EPI turnover showed a significant increase. The alpha2
      adrenergic receptor kinetics revealed that the receptor affinity was
      significantly reduced during diabetes. In insulin treated rats the NE content
      decreased while EPI content remained increased as in the diabetic state. Insulin
      treatment increased the Bmax for alpha2 adrenergic receptors significantly while
      the increase in Kd reversed to normal. Unlabelled clonidine inhibited [3H]NE
      binding in BS of control diabetic and insulin treated diabetic rats showed that
      alpha2 adrenergic receptors consisted of two populations of binding sites with
      Hill slopes significantly away from unity. In diabetic animals the ligand bound
      weaker to the low affinity site than in controls. Insulin treatment reversed this
      alteration to control levels. The displacement analysis using (-)-epinephrine
      against [3H]yohimbine in control and diabetic animals revealed two populations of
      receptor affinity states. In control animals, when GTP analogue added with
      epinephrine, the curve fitted for a single affinity model; but in the diabetic BS
      this effect was not observed. In both the diabetic and control BS the effects of
      monovalent cations on affinity alterations were intact. Our data thus show that
      alpha2 adrenergic receptors have a reduced affinity due to an altered post
      receptor affinity regulation The serotonin (5-HT) content in the brain stem
      increased. Its precursor (5-hydroxy) tryptophan (5-HTP) showed an increase and
      its breakdown metabolite (5-hydroxy) indoleacetic acid (5-HIAA) showed a
      significant decrease. This showed that in serotonergic nerves there is a
      disturbance in both synthetic and breakdown pathways which lead to an increased 5
      HT. The high affinity serotonin receptor numbers remained unaltered with a
      decrease in the receptor affinity. The insulin treatment reversed these altered
      serotonergic receptor kinetic parameters to control level. Thus our study shows a
      decreased serotonergic receptor function. These changes in adrenergic and
      serotonergic receptor function were suggested to be important in insulin function
      during STZ diabetes.

PMID- 10421427
TI  - Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells
      in vitro.
AB  - The aim of the present work was to study whether melatonin, at physiological
      concentrations, exerts its antiproliferative effects on MCF-7 human breast cancer
      cells by inducing the expression of some of the proteins involved in the control
      of the cell cycle. MCF-7 cells were cultured for 48 h in DMEM media containing
      either melatonin (1 nM) or the diluent (0.001% ethanol). At this concentration,
      after 48 hours of incubation, melatonin reduced the number of viable cells in
      relation to controls. The decreased cell proliferation was coincident with a
      significant increase in the expression of p53 as well as p21WAF1 proteins. These
      results demonstrate that melatonin inhibits MCF-7 cell proliferation by inducing
      an arrest of cell cycle dependent on an increased expression of p21WAF1 protein,
      which is mediated by the p53 pathway.

PMID- 10421428
TI  - Acteoside inhibits apoptosis in D-galactosamine and lipopolysaccharide-induced
      liver injury.
AB  - We assessed the effect of acteoside, a naturally occurring antioxidative
      phenylethanoid, on hepatic apoptosis and the subsequent liver failure induced by
      D-Galactosamine (D-GalN) and lipopolysaccharide (LPS). A co-administration of D
      GalN (700 mg/kg) and LPS (35 microg/kg) to mice evoked typical hepatic apoptosis
      characterized by DNA fragmentation and apoptotic body formation, resulting in
      fulminant hepatitis and lethality of mice. Pre-administration of acteoside at 10
      or 50 mg/kg subcutaneously at 12 and 1 h prior to D-GalN/LPS intoxication
      significantly inhibited hepatic apoptosis, hepatitis and lethality. Tumor
      necrosis factor-alpha (TNF-alpha) secreted from LPS-stimulated macrophages is an
      important mediator of apoptosis in this model. Acteoside showed no apparent
      effect on the marked elevation of serum TNF-alpha, but it partially prevented in
      vitro TNF-alpha (100 ng/ml)-induced cell death in D-GalN (0.5 mM)-sensitized
      hepatocytes at the concentrations of 50, 100 and 200 microM. These results
      indicated that D-GalN/LPS-induced hepatic apoptosis can be blocked by an
      exogenous antioxidant, suggesting the involvement of reactive oxygen
      intermediates (ROIs) in TNF-alpha-dependent hepatic apoptosis.

PMID- 10421429
TI  - Effects of dehydroepiandrosterone on mitogen-activated protein kinase in human
      aortic smooth muscle cells.
AB  - The objective of the present study was to determine whether
      dehydroepiandrosterone (DHEA) modifies growth factor-induced mitogen-activated
      protein kinase (MAPK) activation, based on our previous study demonstrating that
      DHEA attenuates fetal calf serum-induced proliferation in human male aortic
      smooth muscle cells (human male aortic SMCs). Human male aortic SMCs were used
      for this study. Platelet-derived growth factor-BB (PDGF-BB), epidermal growth
      factor (EGF), and basic fibroblast growth factor (bFGF), but not insulin-like
      growth factor-1 (IGF-1), stimulated MAPK activity. Only MAPK activation induced
      by PDGF-BB was reduced by pretreatment with DHEA, although DHEA did not affect
      the MAPK activation induced by EGF or bFGF. The basal and PDGF-stimulated MAPK
      activity were decreased by two types of cyclic AMP (cAMP) elevating agents and
      increased by cAMP-dependent protein kinase (PKA) inhibitor in human male aortic
      SMCs, suggesting that cAMP regulates MAPK negatively. The intracellular cAMP was
      increased by PDGF-BB. The increase of cAMP by PDGF-BB was augmented by
      pretreatment with DHEA, although DHEA alone did not affect cAMP. Neither EGF nor
      bFGF affected cAMP with and without DHEA pretreatment. Secretion of PGE2 induced
      by PDGF was augmented by pretreatment with DHEA. Stimulatory effects of DHEA on
      the production of PGE2 and cAMP were partially canceled by aromatase inhibitor
      and completely canceled by indomethacin or selective inhibitor of cyclooxygenase
      2. These results suggest that DHEA inhibited MAPK activation induced by PDGF-BB
      via PGE2 overproduction and subsequent cAMP-dependent pathway in human male
      aortic SMCs.

PMID- 10421430
TI  - Characterization of monoamine oxidase isoforms in human islets of Langerhans.
AB  - In this paper, we describe the characterization of the expression of monoamine
      oxidase (MAO) in whole pancreas and in isolated islets of Langerhans from human.
      Classical monamine oxidase activity assays reveal that both isoforms A & B are
      present in human pancreas. Two complementary approaches indicated that both MAO A
      and B are expressed in isolated islet: RT-PCR using specific primers revealed
      amplification products with the expected size for MAO-A and MAO-B: two peptides
      corresponding to MAO A (approximately 61 kDa) and B (approximately 55 kDa) were
      detected using a polyclonal anti MAO-A/MAO-B antiserum. Western blotting and
      subsequent densitometric analysis indicate that whole and endocrine pancreas
      express the two isoforms with different relative proportions. Islets appear to
      express almost twice as much MAO protein as whole pancreas, in near equal
      proportions of the two isoforms, whereas whole pancreas expresses more MAO-A than
      the B isoform. The expression of MAO A and B in islets could be the first step
      toward the characterization of the functional properties of these enzymes in the
      endocrine pancreas.

PMID- 10421431
TI  - Stimulant effect of nitric oxide generator and roxatidine on mucin biosynthesis
      of rat gastric oxyntic mucosa.
AB  - Although the involvement of nitric oxide (NO) in an increasing gastric mucus
      metabolism has been reported, information on whether or not its activation is
      limited to the specific mucus-producing cells is lacking. In this paper, we
      report the effect of the exogenous NO-donor, isosorbide dinitrate (ISDN), and
      second-generation histamine H2 receptor antagonist roxatidine (2-acetoxy-N-(3-[m
      (1-piperidinylmethyl)phenoxy]propyl)acetamide hydrochloride) which is
      demonstrated to accelerate the mucin metabolism mediated by endogenous NO, on the
      mucin biosynthesis in distinct sites and layers of the rat gastric mucosa using
      an organ culture technique. Radiolabeled mucin was obtained from the tissue of
      full-thickness and the deep corpus layer, and the antrum of the rat stomach
      incubated for 5 hr with [3H]glucosamine(GlcN) in vitro. With the addition of ISDN
      to the culture medium, 3H-labeled mucin in the full-thickness corpus mucosa
      increased to 124-145% of the control (p<0.05), but not in the antrum. This
      stimulation of the mucin synthesis disappeared by the removal treatment of the
      surface mucous cell layer which has immunoreactivity of neuronal NO synthase.
      Similarly, roxatidine stimulated the mucin biosynthesis in the full-thickness
      corpus mucosa, but not in the gland mucous cell layer. These results suggest that
      the stimulation of the mucin biosynthesis mediated by NO is restricted to the
      surface mucous cells of the rat gastric oxyntic mucosa.

PMID- 10421432
TI  - Differential regulation of vasopressin gene expression in the hypothalamus of
      endotoxin-treated 14-day-old rat.
AB  - The E. coli endotoxin 0111 B4, a lipopolysaccharide (LPS), in a dose of 200 ng/kg
      body weight/50 microl artificial cerebrospinal fluid (CSF) was given
      intracisternally to 14-day-old rats. Four hours later CSF, blood and urine were
      sampled, and consecutive brain sections from the hypothalamic area of the brain
      were prepared for in situ hybridization. The LPS treatment resulted in a
      significant (p<0.001) pleocytosis and an elevation of the protein content of the
      CSF. There were no changes observed in the chemical parameters of the CSF,
      plasma, blood or urine, i.e. vasopressin (VP) levels, osmolality, Na+ and K+
      concentrations, glucose level, pH, bicarbonate or PaCO2, PaO2 values. LPS
      injection, however, resulted in a significantly (p<0.01) increased VP mRNA level
      (121% of the control value) in the supraoptic nuclei (SON), but not in the
      paraventricular nuclei (PVN), as compared to controls. Our findings suggest an
      early effect of LPS on VP gene expression selectively in the SON of 14-days-old
      rats. This animal model might be suitable for studying the regulation of VP gene
      expression and the role of this peptide in the pathogenesis of bacterial
      meningitis in pediatric patients.

PMID- 10421433
TI  - Chronic administration of the non-peptide CRH type 1 receptor antagonist
      antalarmin does not blunt hypothalamic-pituitary-adrenal axis responses to acute
      immobilization stress.
AB  - Antalarmin is a pyrrolopyrimidine compound that antagonizes corticotropin
      releasing hormone (CRH) type 1 receptors (CRHR1). In order to assess the effects
      of antalarmin treatment on hypothalamic-pituitary-adrenal (HPA) function we
      measured the plasma concentrations of adrenocorticotropic hormone (ACTH) and
      corticosterone in animals treated with either antalarmin or vehicle for 1 week or
      for 8 weeks. We found that antalarmin treatment for 1 week did not affect basal
      concentrations of ACTH or corticosterone. In contrast, treatment for 8 weeks
      significantly lowered basal ACTH and corticosterone concentrations and also
      significantly decreased the basal corticosterone to ACTH ratio, indicating
      decreased basal adrenocortical responsiveness to ACTH. However, immobilization
      stress resulted in ACTH and corticosterone concentrations that were the same in
      animals treated with vehicle or antalarmin for either 1 or 8 weeks. We conclude
      that even though 8-week antagonism of CRHR1 by the non-peptide antalarmin blunts
      basal concentrations of ACTH and corticosterone, and affects the adrenal
      responsiveness to ACTH, it does not blunt the HPA response to acute stress, and
      it does not appear to cause stress-induced adrenal insufficiency.

PMID- 10421434
TI  - Analysis of cholinesterase inactivation and reactivation by systematic structural
      modification and enantiomeric selectivity.
AB  - We show here with a congeneric series of Rp- and Sp-alkoxymethyl
      phosphonothiolates of known absolute stereochemistry that chiral selectivity in
      their reaction with acetylcholinesterase can be described in terms of discrete
      orientational and steric requirements. Stereoselectivity depends on acyl pocket
      dimensions, which govern leaving group orientation and a productive association
      of the phosphonyl oxygen in the oxyanion hole. Overall geometry is consistent
      with a pentavalent intermediate where the attacking serine and leaving group are
      at apical positions. Oxime reactivation of the phosphonylated enzyme occurs
      through a similar associative intermediate presumably forming an oxime
      phosphonate. The oximes of differing structure show distinct angles of attacking
      the phosphate where the attack angles and access to the phosphorus are
      constrained in the sterically impacted gorge. Hence, efficacy of oxime
      reactivation is dependent on both oxime and conjugated phosphonate structures.

PMID- 10421435
TI  - Structural and hydration changes in the active site gorge of phosporhylated
      butyrylcholinesterase accompanying the aging process.
AB  - Wild-type (wt) butyrylcholinesterase (BuChE) and the E197D and D70G mutants were
      inhibited by diisopropylfluorophosphate (DFP) or soman under standard conditions
      of pH, temperature and pressure. The effect of hydrostatic and osmotic pressures
      on the aging process of DFP-phosphorylated enzymes (diisopropylphosphoryl-BuChE
      (DIP-BuChE)) was investigated. Hydrostatic pressure strongly increased the rate
      of aging of wt enzyme. The activation volumes (deltaV*) for the dealkylation
      reaction was -150 ml/mol for DIP-wtBuChE. On the other hand, pressure had little
      effect on the aging of the DIP-E197D mutant and no effect on the DIP-D70G mutant,
      indicating that the transition state of the aging reaction (dealkylation of an
      isoproxy chain) was associated with an extended conformation/hydration change in
      wtBuChE but not in mutants. The rate of aging decreased with osmotic pressure,
      supporting the idea that water is important for stabilizing the transition state.
      Molecular dynamics simulations were performed on the wtDIP adduct to relate the
      kinetic data to hydration changes in the enzyme active site gorge. The pH
      dependence of the melting temperature (Tm) of native and soman-wtBuChE, as
      determined by differential scanning calorimetry (DSC), indicated that the
      stabilization energy of aged BuChE is mainly due to the salt bridge between
      protonated H438 and PO-, with pK(H438) = 8.3. Electrophoresis under high pressure
      up to 2.5 kbar showed that aged wtBuChE did not undergo pressure-induced molten
      globule transition unlike the native enzyme. This transition was not seen for the
      mutant enzymes, indicating that mutants are resistant to the penetration of water
      into their structure. Our results support the conclusion that D70 and E197 are
      major residues for the water/H-bond network dynamics in the active site gorge of
      BuChE, both residues acting like valves. In mutant enzymes, mutated residues
      function like check valves: forced penetration of water in the gorge is
      difficult, release of water is facilitated.

PMID- 10421436
TI  - The polymorphism of acetylcholinesterase: post-translational processing,
      quaternary associations and localization.
AB  - The molecular forms of acetylcholinesterase (AChE) correspond to various
      quaternary structures and modes of anchoring of the enzyme. In vertebrates, these
      molecules are generated from a single gene: the catalytic domain may be
      associated with several types of C-terminal peptides, that define distinct types
      of catalytic subunits (AChE(S), AChE(H), AChE(T)) and determine their post
      translational maturation. AChE(S) generates soluble monomers, in the venom of
      Elapid snakes. AChE(H) generates GPI-anchored dimers, in Torpedo muscles and on
      mammalian blood cells. AChE(T) is the only type of catalytic subunit that exists
      in all vertebrate cholinesterases; it produces the major forms in adult brain and
      muscle. AChE(T) generates multiple structures, ranging from monomers and dimers
      to collagen-tailed and hydrophobic-tailed forms, in which catalytic tetramers are
      associated with anchoring proteins that attach them to the basal lamina or to
      cell membranes. In the collagen-tailed forms, AChE(T) subunits are associated
      with a specific collagen, ColQ, which is encoded by a single gene in mammals.
      ColQ contains a short peptidic motif, the proline-rich attachment domain (PRAD),
      that triggers the formation of AChE(T) tetramers, from monomers and dimers. The
      critical feature of this motif is the presence of a string of prolines, and in
      fact synthetic polyproline shows a similar capacity to organize AChE(T)
      tetramers. Although the COLQ gene produces multiple transcripts, it does not
      generate the hydrophobic tail. P, which anchors AChE in mammalian brain
      membranes. The coordinated expression of AChE(T) subunits and anchoring proteins
      determines the pattern of molecular forms and therefore the localization and
      functionality of the enzyme.

PMID- 10421437
TI  - A preliminary comparison of structural models for catalytic intermediates of
      acetylcholinesterase.
AB  - Determination of the three dimensional structure of Torpedo Californica
      acetylcholinesterase (TcAChE) provided an experimental tool for directly
      visualizing interaction of AChE with cholinesterase inhibitors of fundamental,
      pharmacological and toxicological interest. The structure revealed that the
      active site is located near the bottom of a deep and narrow gorge lined with 14
      conserved aromatic amino acids. The structure of a complex of TcAChE with the
      powerful 'transition state analog' inhibitor, TMTFA, suggested that its
      orientation in the experimentally determined structure was very similar to that
      proposed for the natural substrate, acetylcholine, by manual docking. The array
      of enzyme-ligand interactions visualized in the TMFTA complex also are expected
      to envelope the unstable TI that forms with acetylcholine during acylation, and
      to sequester it from solvent. In our most recent studies, the crystal structures
      of several 'aged' conjugates of TcAChE obtained with OP nerve agents have been
      solved and compared with that of the native enzyme. The methylphosphonylated
      enzyme obtained by reaction with soman provides a useful structural analog for
      the TI that forms during deacylation after the reaction of TcAChE with
      acetylcholine. By comparing these structures, we conclude that the same 'oxyanion
      hole' residues, as well as the aromatic side chains constituting the 'acyl
      pocket', participate in acylation (TMTFA-AChE) and deacylation (OP-AChE), and
      that AChE can accommodate both TIs at the bottom of the gorge without major
      conformational movements.

PMID- 10421438
TI  - Association of tetramers of human butyrylcholinesterase is mediated by conserved
      aromatic residues of the carboxy terminus.
AB  - Human butyrylcholinesterase (BChE) is composed predominantly of tetramers. Our
      laboratory has shown that up to 40 carboxy terminal residues of each subunit
      contribute to the stabilization of tetramers (R.M. Blong, E. Bedows, O.
      Lockridge, The tetramerization domain of butyrylcholinesterase is at the carboxy
      terminus, Biochem. J. 327 (1997) 747-757). To better define the residues which
      participate in tetramer stabilization, the in vivo interaction of the BChE C
      terminus 46 residue peptide was quantitated for wild type and mutant BChE using
      the yeast two-hybrid system. The wild type C-terminal peptides interacted with
      one another in this system. The K-variant (A539T) and C571A peptides showed
      interaction similar to that of the wild type. However, only 11.7% of the
      interaction seen with the wild type peptide was observed with the mutant in which
      seven conserved aromatic residues (Trp 543, Phe 547, Trp 550, Tyr 553, Trp 557,
      Phe 561, and Tyr 564) had been altered to alanines (aromatics off mutant). When
      these seven mutations were incorporated into the complete BChE molecule and
      expressed in 293T cells, only monomers and dimers were observed. The addition of
      poly-L-proline to the medium of 293T cells expressing wild type BChE resulted in
      the increase of the tetrameric form, similar to that observed by Bon et al. (S.
      Bon, F. Coussen, J. Massoulie, Quaternary associations of acetylcholinesterase
      II. The polyproline attachment domain of the collagen tail, J. Biol. Chem. 272
      (1997) 3016-3021) for acetylcholinesterase expressed in COS cells. However, no
      increase in tetramers was observed with poly-L-proline addition to the medium of
      293T cells expressing the aromatics off BChE mutant. These observations suggest
      that the stabilization of BChE tetramers is mediated through the interaction of
      the seven conserved aromatic residues, Trp 543, Phe 547, Trp 550, Tyr 553, Trp
      557, Phe 561, and Tyr 564, and that the poly-L-proline induced increase in
      tetrameric BChE is mediated through these seven aromatic residues.

PMID- 10421440
TI  - Human serum paraoxonase (PON1): identification of essential amino acid residues
      by group-selective labelling and site-directed mutagenesis.
AB  - Human serum paraoxonase/arylesterase (PON1, EC 3.1.8.1.) is a calcium-dependent
      enzyme which hydrolyzes a wide variety of organophosphates, including paraoxon,
      DFP, sarin and soman. Although the 3-D structure of PON has not yet been
      determined and its sequence shows no similarity with any other crystallized
      proteins, we undertook to identify some of its essential amino acid residues by
      two complementary approaches: group-specific labelling and site-directed
      mutagenesis. Group-specific labelling studies, performed on the purified native
      enzyme, indicated that one or more Trp, His and Asp/Glu are potentially important
      residues for PON activity. Based on these results, we identified some of these
      residues, conserved in the sequenced mammalian PON1, by site-directed
      mutagenesis. PON1 mutants were transiently expressed in 293T cells. The catalytic
      constants k(cat) and Km (relative to k(cat) and Km of the wild-type) determined
      with four different substrates (phenylacetate, paraoxon, diazoxon, chlorpyrifos
      oxon), were not significantly changed for the following mutants: W193A, W201A,
      W253A, H160N, H245N, H250N, H347N, E32A, E48A, D88A, D107A, D121A, D273A. By
      contrast, k(cat) was less than 1% for eight mutants: W280A, H114N, H133N, H154N,
      H242N, H284N, E52A and D53A. The essential amino acid residues identified in this
      work could be part of the PON1 active site, acting either as calcium ligands (E52
      and D53?) or as substrate binding (W280?) or nucleophilic (His residues?) sites.
      However, we cannot rule out that the effects of mutations on catalytic properties
      resulted from a remote conformational change and/or misfolding of mutant
      proteins.

PMID- 10421439
TI  - Differences in active-site gorge dimensions of cholinesterases revealed by
      binding of inhibitors to human butyrylcholinesterase.
AB  - We examined the role of A328(F330) in the binding of various inhibitors to
      cholinesterases (ChEs) using human butyrylcholinesterase (BChE) mutants to
      determine if the conclusions drawn from studies with acetylcholinesterase (AChE)
      mutants could be extended to BChE. For huperzine A and edrophonium, the results
      obtained with AChE mutants could be directly correlated with those obtained with
      native ChEs and site-specific mutants of human BChE. Inhibition studies of
      ethopropazine with BChE mutants, where A328 was modified to either F or Y,
      suggested that A328 was not solely responsible for the selectivity of
      ethopropazine. Volume calculations for the active-site gorge showed that the poor
      inhibitory activity of ethopropazine towards AChE was due to the smaller
      dimension of the active-site gorge. The volume of the BChE active-site gorge is
      approximately 200 A3 larger than that of the AChE gorge, which allows the
      accommodation of ethopropazine in two different orientations as demonstrated by
      rigid-body refinement and molecular dynamics calculations. These results suggest
      that, although the overall scaffolding of the two enzymes may be highly similar,
      the dimensions and the micro-environment of the gorge play a significant role in
      determining the selectivity of substrate and inhibitors for ChEs.

PMID- 10421441
TI  - Tryptophan residue(s) as major components of the human serum paraoxonase active
      site.
AB  - Serum paraoxonase (PON1, EC 3.1.8.1.) is a high density lipid- (HDL)-associated,
      calcium-dependent enzyme whose 3D structure, active site residues and
      physiological substrates are not known. The kinetic parameters k(cat) and Km
      (relative to k(cat) and Km of the wild-type), determined with four substrates
      (phenylacetate, paraoxon, diazoxon and chlorpyrifosoxon) were less than 1, and
      more than 100% for the W280A and W280F mutant enzymes, respectively. These
      results indicated that the aromatic/hydrophobic character of the amino acid in
      position 280 is essential for PON1 activity. In this study, we investigated
      whether this aromatic residue is in the PON1 active site. Group-specific
      labelling studies with N-bromosuccinimide, an oxidative agent of tryptophan,
      strongly suggested that one or several Trp could be in the active site of PON1
      but we could not conclude either on the specificity of the labelling reaction or
      on the number of oxidized Trp. However, although PON activity was not altered by
      the hydrophilic tryptophan-modifying reagent 2-hydroxy-5-nitrobenzyl chloride
      (NBC), it was significantly reduced by the p-nitrophenylacetate analog 2-acetoxy
      5-nitrobenzyl chloride (ANBC), whose hydrolysis by PON1 generated NBC in the
      active site. Moreover, since at least one calcium ion is present in the PON
      catalytic site, we attempted to probe the metal local environment using the
      calcium analog terbium. The luminescence spectrum of the PON terbium complex
      exhibited an emission peak at 545 nm characteristic of an aromatic residue (Trp
      and/or Tyr)-terbium interaction. In conclusion, both the results obtained with
      the mechanism-based inhibitor of PON1 (ANBC) and the calcium-binding site
      luminescent probe terbium support the hypothesis of the presence of at least one
      Trp residue in the PON1 active site. Trp residue(s) may be involved in the
      binding of aromatic substrates.

PMID- 10421442
TI  - A steric blockade model for inhibition of acetylcholinesterase by peripheral site
      ligands and substrate.
AB  - The active site gorge of acetylcholinesterase (AChE) contains two sites of ligand
      binding, an acylation site near the base of the gorge and a peripheral site at
      its mouth. We recently introduced a steric blockade model which demonstrated that
      small peripheral site ligands like propidium can inhibit substrate hydrolysis
      simply by decreasing the substrate association and dissociation rate constants
      without altering the equilibrium constant for substrate binding to the acylation
      site. We now employ our nonequilibrium kinetic analysis to extend this model to
      include blockade of the dissociation of substrate hydrolysis products by bound
      peripheral site ligand. We also report here that acetylthiocholine can bind to
      the AChE peripheral site with an equilibrium dissociation constant K(S) of about
      1 mM. This value was determined from the effect of the acetylthiocholine
      concentration on the rate at which fasciculin associates with the peripheral
      site. When substrate binding to the peripheral site is incorporated into our
      steric blockade model, hydrolysis rates at low substrate concentration appear to
      be accelerated while substrate inhibition of hydrolysis occurs at high substrate
      concentration. The model predicts that hydrolysis rates for substrates which
      equilibrate with the acylation site prior to the acylation step should not be
      inhibited by bound peripheral site ligand. Organophosphates equilibrate with AChE
      prior to phosphorylating the active site serine residue, and as predicted
      propidium had little effect on the phosphorylation rate constants for the
      fluorogenic organophosphate ethylmethyl-phosphonylcoumarin (EMPC). The 2nd-order
      phosphorylation rate constant kOP/K(OP) was decreased 3-fold by a high
      concentration of propidium and the 1st-order rate constant kOP increased
      somewhat. In contrast to propidium, when the neurotoxin fasciculin bound to the
      AChE peripheral site both a steric blockade and a conformational change in the
      acylation site appeared to occur. With saturating fasciculin, kOP/K(OP) decreased
      by a factor of more than 750 and kOP decreased 300-fold. These data suggest that
      new peripheral site ligands may be designed to have selective effects on AChE
      phosphorylation.

PMID- 10421443
TI  - Theoretical and experimental investigations of electrostatic effects on
      acetylcholinesterase catalysis and inhibition.
AB  - The role of electrostatics in the function of acetylcholinesterase (AChE) has
      been investigated by both theoretical and experimental approaches. Second-order
      rate constants (kE = k(cat)/Km) for acetylthiocholine (ATCh) turnover have been
      measured as a function of ionic strength of the reaction medium for wild-type and
      mutant AChEs. Also, binding and dissociation rate constants have been measured as
      a function of ionic strength for the respective charged and neutral transition
      state analog inhibitors m-(N,N,N-trimethylammonio)trifluoroacetophenone (TMTFA)
      and m-(t-butyl)trifluoroacetophenone (TBTFA). Linear free-energy correlations
      between catalytic rate constants and inhibition constants indicate that kE for
      ATCh turnover is rate limited by terminal binding events. Comparison of binding
      rate constants for TMTFA and TBTFA attests to the sizable electrostatic
      discrimination of AChE. Free energy profiles for cationic ligand release from the
      active sites of wild-type and mutant AChEs have been calculated via a model that
      utilizes the structure of T. californica AChE, a spherical ligand, and energy
      terms that account for electrostatic and van der Waals interactions and chemical
      potential. These calculations indicate that EA and EI complexes are not bound
      with respect to electrostatic interactions, which obviates the need for a 'back
      door' for cationic ligand release. Moreover, the computed energy barriers for
      ligand release give linear free-energy correlations with log(kE) for substrate
      turnover, which supports the general correctness of the computational model.

PMID- 10421444
TI  - The influence of peripheral site ligands on the reaction of symmetric and chiral
      organophosphates with wildtype and mutant acetylcholinesterases.
AB  - The rates of inhibition of mouse acetylcholinesterase (AChE) (EC 3.1.1.7) by
      paraoxon, haloxon, DDVP, and enantiomers of neutral alkyl methylphosphonyl
      thioates and cationic alkyl methylphosphonyl thiocholines were measured in the
      presence and absence of AChE peripheral site inhibitors: gallamine, D
      tubocurarine, propidium, atropine and derivatives of coumarin. All ligands,
      except the coumarins, at submillimolar concentrations enhanced the rates of
      inhibition by neutral organophosphorus compounds (OPs) while inhibition rates by
      cationic OPs were slowed down. When peripheral site ligand concentrations
      extended to millimolar, the extent of the enhancement decreased creating a bell
      shaped activation profile. Analysis of inhibition by DDVP and haloxon revealed
      that peripheral site inhibitors increased the second order reaction rates by
      increasing maximal rates of phosphylation.

PMID- 10421446
TI  - Role of edrophonium in prevention of the re-inhibition of acetylcholinesterase by
      phosphorylated oxime.
AB  - We examined the role of edrophonium in the acceleration phenomenon using mouse
      wild-type and mutant D74N AChE inhibited with 7-(O,O-diethyl-phosphinyloxy)-1
      methylquinolinium methylsulfate (DEPQ). With DEPQ-inhibited wild-type mouse
      acetylcholinesterase (AChE), the reactivation kinetic profile demonstrated one
      phase exponential association only when 2-[hydroxyimino methyl]-1
      methylpyridinium chloride (2-PAM) and 1-(2-hydroxy-iminomethyl-1-pyridinium)-1-(4
      carboxy-aminopyridi nium)-dimethyl ether hydrochloride (HI-6) were used as
      reactivators. When 1,1[oxybis-methylene)bis[4-(hydroxyimino)methyl] pyridinium
      dichloride (LuH6) and 1,1-trimethylene bis(4-hydroxyimino methyl) pyridinium
      dichloride (TMB4) were used, the reactivation kinetic profile was biphasic in
      nature. Edrophonium had no effect on reactivation by 2-PAM and HI-6, but
      significantly accelerated LuH6- and TMB4-induced reactivation of DEPQ-inhibited
      wild-type mouse AChE. Comparison of the initial and overall reactivation rate
      constants with five oximes indicated that acceleration by edrophonium may be due
      to the prevention of re-inhibition of the reactivated enzyme by the
      phosphorylated oxime (POX) produced during the reactivation. With LuH6 and TMB4,
      about 2.5-fold increase in the reactivation rate constants was observed in the
      presence of edrophonium, but little or no effect was observed with the other
      three oximes. The initial reactivation rate constants were 5.4- and 4.2-fold of
      the overall rate constants with LuH6 and TMB4 as reactivators respectively,
      however, very little change was found between the initial and overall rate
      constants with the other three oximes. In experiments with D74N AChE, for which
      the inhibition potency of charged organophosphate (OP) was two to three orders
      less than wild-type enzyme, edrophonium had no effect on the reactivation by LuH6
      and TMB4 and the time courses of reactivation were monophasic. The data from
      mutant enzyme substantiate the involvement of edrophonium in protecting POX re
      inhibition of reactivated enzyme formed during the reactivation of OP-inhibited
      AChE.

PMID- 10421445
TI  - Reversible inhibition of acetylcholinesterase and butyrylcholinesterase by 4,4'
      bipyridine and by a coumarin derivative.
AB  - Inhibition of recombinant mouse wild type AChE (EC 3.1.1.7) and BChE (EC
      3.1.1.8), and AChE peripheral site-directed mutants and human serum BChE variants
      by 4,4'-bipyridine (4,4'-BP) and the coumarin derivative 3-chloro-7-hydroxy-4
      methylcoumarin (CHMC) was studied. The enzyme activity was measured with
      acetylthiocholine as substrate. Enzyme-inhibitor dissociation constants for the
      catalytic and peripheral sites were evaluated from the apparent dissociation
      constants as a function of the substrate concentration. Inhibition by 4,4'-BP of
      AChE, BChE and the AChE mutant Y72N/Y124Q/W286A, was consistent with inhibitor
      binding to both catalytic and peripheral sites. The dissociation constants for
      the peripheral site were about 3.5-times higher than for the catalytic site. The
      competition between CHMC and substrate displayed two binding sites on the AChE
      mutants Y72N, Y124Q, W286A and W286R, and on the atypical and fluoride-resistant
      BChE variants. The dissociation constants for the peripheral site were on average
      two-times higher than for the catalytic site. CHMC displayed binding only to the
      catalytic site of Y72N/Y124Q/W286A mutant and only to the peripheral site of w.t.
      AChE and the human usual BChE. Modelling of the 4,4'-BP and CHMC binding to wild
      type mouse AChE substantiated the difference between the inhibitors in their mode
      of binding which was revealed in the kinetic studies.

PMID- 10421447
TI  - Effect of tetramethylammonium, choline and edrophonium on insect
      acetylcholinesterase: test of a kinetic model.
AB  - Cholinesterases display a non-Michaelian behaviour with respect to substrate
      concentration. With the insect enzyme, there is an activation at low substrate
      concentrations and an inhibition at high concentrations. Previous studies allow
      us to propose a kinetic model involving a secondary non-productive binding site
      for the substrate. Unexpectedly, this secondary site has a very high affinity for
      the substrate when the enzyme is free. On the contrary, when the catalytic site
      of the enzyme is occupied a strong decrease of this affinity was observed.
      Moreover, a substrate molecule bound to the peripheral site results in a global
      decrease of the acylation and/or the deacylation step. Kinetic studies with three
      reversible inhibitors, tetramethylammonium, edrophonium and choline supported the
      kinetic model and enable its further refinement.

PMID- 10421448
TI  - Inhibition of Drosophila acetylcholinesterase by 7-(methylethoxyphosphinyloxy)1
      methyl-quinolinium iodide.
AB  - The kinetic behaviour of Drosophila melanogaster acetylcholinesterase toward its
      substrate shows, in comparison with classic Michaelis-Menten kinetics, an
      apparent homotropic cooperative double activation-inhibition pattern. In order to
      construct an appropriate kinetic model and obtain further information on the
      mechanism of the catalytic action of this enzyme, the hydrolysis of
      acetylthiocholine in the absence and presence of different concentrations of
      synthetic quaternary methylphosphonate, 7-(methylethoxyphosphinyloxy)1-methyl
      quinolinium iodide (MEPQ), was followed on a stopped-flow apparatus. The reaction
      at low substrate concentrations was followed until the change of the absorbance
      became negligible and at high concentrations only initial parts were recorded. A
      simultaneous analysis of the progress curves using numerical integration showed
      that the powerful organophosphonate inhibitor binds and compete with the
      substrate for the same binding sites. The results are also in accordance with the
      hypothesis that virtually every substrate or quasi-substrate molecule that enters
      into the gorge of active site is hydrolysed.

PMID- 10421449
TI  - An explanation for the different inhibitory characteristics of human serum
      butyrylcholinesterase phenotypes deriving from inhibition of atypical
      heterozygotes.
AB  - The time course of inhibition of butyrylcholinesterase (EC 3.1.1.8) by the
      dimethylcarbamate Ro 02-0683 in sera taken from patients heterozygous for the
      usual (U), atypical (A), K or J variants was followed using propionylthiocholine
      as substrate. Data obtained were used to determine rate constants of inhibition
      together with the contribution made by each variant to total enzyme activity. The
      findings substantiate earlier reports that J and K mutations lead to quantitative
      changes in the concentration of usual enzyme in contrast to the qualitative
      changes of the atypical variant. The contribution of the atypical enzyme to the
      total activity in serum from UA, AK and AJ heterozygotes was respectively 17-20,
      24-31 and 34-53%. The altered ratios of atypical to usual, K or J enzyme in UA,
      AK and AJ together with the constants on the usual enzyme alone, explain the
      differences in observed inhibitor numbers which enable these heterozygotes to be
      identified.

PMID- 10421450
TI  - Catalytic parameters for the hydrolysis of butyrylthiocholine by human serum
      butyrylcholinesterase variants.
AB  - Catalysed hydrolysis of butyrylthiocholine (BTCh) by the usual (UU), fluoride
      resistant (FS), AK, AJ and atypical (AA) human serum butyrylcholinesterase (EC
      3.1.1.8) variants was measured in phosphate buffer pH 7.4 at 25 degrees C. pS
      curves for all phenotypes were S-shaped; the activities rose to a plateau with
      increasing substrate concentration except at 100 mM where there was a small
      decrease. To obtain the catalytic constants, three equations were applied:
      Michaelis-Menten equation (Eq. 1), Hill equation (Eq. 2) and an equation which
      assumes simultaneous binding of the substrate to the catalytic site and to a
      peripheral site on the enzyme (Eq. 3). Over a range from 0.01 to 50 mM BTCh, the
      activity versus substrate concentration relationship deviated from Michaelis
      Menten kinetics (Eq. 1) while data fitted well with Eqs. 2 and 3. The Michaelis
      Menten equation was applied separately to two BTCh concentration ranges: the
      corresponding Km constants for the UU, FS, AK, AJ and AA phenotypes ranged from
      0.1 to 0.2 mM (at 0.01-1.0 mM BTCh) and from 0.3 to 2.0 mM (at 1.0-50 mM BTCh).
      Hill coefficients (nH) calculated from Eq. 2 were similar for all phenotypes (nH
      approximately 0.5). The dissociation constants K1 and K2 calculated from Eq. 3
      for two sites on the enzyme fell between 0.02 and 0.12 mM (K1) and 0.89 and 4.9
      mM (K2) for the five phenotypes. Experimental data support the assumption that
      the phenotypes studied have two substrate binding sites.

PMID- 10421452
TI  - Organophosphate inhibition of human heart muscle cholinesterase isoenzymes.
AB  - The rate of acetylcholine hydrolysis of mammalian heart muscle influences cardiac
      responses to vagal innervation. We characterized cholinesterases of human left
      ventricular heart muscle with respect to both substrate specificity and
      irreversible inhibition kinetics with the organophosphorus inhibitor N,N'-di
      isopropylphosphorodiamidic fluoride (mipafox). Specimens were obtained postmortem
      from three men and four women (61 +/- 5 years) with no history of cardiovascular
      disease. Myocardial choline ester hydrolyzing activity was determined with
      acetylthiocholine (ASCh; 1.25 mM), acetyl-beta-methylthiocholine (AbetaMSCh; 2.0
      mM), and butyrylthiocholine (BSCh; 30 mM). After irreversible and covalent
      inhibition (60 min; 25 degrees C) with a wide range of mipafox concentrations (50
      nM-5 mM), residual choline ester hydrolyzing activities were fitted to a sum of
      up to five exponentials using weighted least-squares non-linear curve fitting. In
      each ease, quality of curve fitting reached its optimum on the basis of a four
      component model. Final classification of heart muscle cholinesterases was
      achieved according to substrate hydrolysis patterns (nmol/min per g wet weight)
      and to second-order organophosphate inhibition rate constants k2 (1/mol per min);
      one choline ester hydrolyzing enzyme was identified as acetylcholinesterase
      (AChE; k2/mipafox = 6.1 (+/- 0.8) x 10(2)), and one as butyrylcholinesterase
      (BChE; k2/mipafox = 5.3 (+/- 1.1) x 10(3)). An enzyme exhibiting both ChE-like
      substrate specificity and relative resistance to mipafox inhibition (k2/mipafox =
      5.2 (+/- 1.0) x 10(-1)) was classified as atypical cholinesterase.

PMID- 10421451
TI  - 3-Hydroxyquinuclidinium derivatives: synthesis of compounds and inhibition of
      acetylcholinesterase.
AB  - Four compounds were prepared: 3-hydroxy-1-methylquinuclidinium iodide (I), 3-(N,N
      dimethylcarbamoyloxy)-1-methylquinuclidinum iodide (II), and two conjugates of I
      and II with 2-hydroxyiminomethyl-3-methylimidazole in which two parts of the
      molecule were linked by -CH2-O-CH2- (III and IV). III and IV are new compounds
      and their synthesis and physical data were given. All compounds were tested as
      inhibitors of human erythrocyte acetylcholinesterase (EC 3.1.1.7, AChE). The
      enzyme activity was measured in 0.1 M phosphate buffer (pH 7.4) at 10 and 37
      degrees C with acetylthiocholine (ATCh) as the substrate. The obtained
      enzyme/inhibitor dissociation constants were between 0.05 and 0.5 mM at 10
      degrees C and between 0.2 and 0.6 mM at 37 degrees C. At both temperatures
      compounds III and IV had higher affinities for the enzyme than compounds I and II
      and this difference was more pronounced at 10 than at 37 degrees C. The
      carbamates II and IV were also progressive AChE inhibitors. For compound II the
      rate constants of inhibition were 6300 and 2020 M(-1) min(-1) at 37 and 10
      degrees C, respectively. Compound IV was a very weak carbamoylating agent with
      rate constants of inhibition of 100 and 63 M(-1) min(-1) at 37 and 10 degrees C,
      respectively. The oxime group in compounds III and IV hydrolyzed ATCh at rates of
      23 and 3.2 M(-1) min(-1) at 37 and 10 degrees C, respectively.

PMID- 10421453
TI  - Biological variations of human serum butyrylcholinesterase activity in a
      population from Zagreb, Croatia.
AB  - Biological variations of total butyrylcholinesterase activity (EC 3.1.1.8) in
      sera were determined in 993 healthy school children (age 8-19 years) and 2246
      healthy adults (20-70 years) in a population from Zagreb, Croatia. Physiological
      variations corresponding to age and sex and genetically determined changes were
      studied as the important factors affecting biological variation in total
      butyrylcholinesterase activity. Based on biological variability, using a non
      parametric statistical method, reference intervals for total
      butyrylcholinesterase activity were produced in order to provide medically
      reliable evaluation of laboratory results by pediatricians and clinicians in our
      country.

PMID- 10421454
TI  - Distribution profiles of paraoxonase and cholinesterase phenotypes in a Spanish
      population.
AB  - The paraoxonase/arylesterase phenotype was measured in a Spanish population as
      previous studies have reported that the polymorphic variation in serum
      paraoxonase activity may affect the metabolism of organophosphates in individuals
      at risk of chronic intoxication. The prevalence of congenital deficiency in serum
      cholinesterase was also established in order to ascertain whether individuals
      with a congenital defect would be at a higher risk against a potential
      organophosphate exposure. We consider it useful to incorporate these two
      biomarkers into the health programme of agricultural workers with the purpose of
      monitoring workers who spray organophosphate pesticides, as they provide reliable
      indications of early-stage effects related to biochemical alterations that might
      precede overt clinical pictures.

PMID- 10421455
TI  - Rational design of organophosphorus hydrolase for altered substrate
      specificities.
AB  - Organophosphorus hydrolase (OPH) is a bacterial enzyme that hydrolyzes a broad
      variety of OP neurotoxins, including chemical warfare agents and many widely used
      pesticides. OPH has extremely high hydrolytic efficiency with different
      phosphotriester and phophothiolester pesticides (k(cat) = 50-15,000 s(-1)) as
      well as phosphorofluorates such as DFP and the chemical warfare agents sarin and
      soman (k(cat) = 50-11,000 s(-1)). In contrast, the enzyme has much lower
      catalytic capabilities for phosphonothioate neurotoxins such as acephate or the
      chemical warfare agent VX [O-ethyl S-(2-diisopropyl aminoethyl)
      methylphosphonothioate] (k(cat) = 0.3-20 s(-1)). Different metal-associated forms
      of the enzyme have demonstrated varying hydrolytic capabilities for each of the
      OP neurotoxins, and the activity of OPH (Co2+) is consistently higher than that
      of OPH (Zn2+) by five- to 20-fold. Protein engineering strategies have exploited
      these metal-induced catalytic differences, and other slight modifications to the
      opd gene have resulted in significant enhancement of the rates of detoxification
      of the thioate pesticides and chemical warfare agents. In order to develop
      practical applications of OPH, other experiments have focused on improvement of
      enzyme production, localization, stability, and shelf-life, as well as efficient
      catalysis of substrates of interest.

PMID- 10421456
TI  - Stereochemical preferences for chiral substrates by the bacterial
      phosphotriesterase.
AB  - The bacterial phosphotriesterase from Pseudomonas diminuta catalyzes the
      hydrolysis of organophosphate nerve agents such as paraoxon (diethyl p
      nitrophenyl phosphate) with a turnover number of approximately 10(4) s(-1). The
      active site of the enzyme has been shown to be composed of a binuclear Zn2+
      complex with a bridging hydroxide. The utilization of chiral phosphotriesters has
      demonstrated that the overall hydrolytic reaction occurs with net inversion of
      stereochemistry at the phosphorus center. The stereochemical constraints of the
      active site have been probed by the synthesis and characterization of paraoxon
      analogs. One or both of the two ethoxy substituents of paraoxon have been
      replaced with various combinations of methyl, isopropyl, or phenyl groups.
      Racemic mixtures and individual enantiomers were tested as substrates for the
      phosphotriesterase. In general, the kinetic constants (k(cat) and k(cat)/Km) for
      the (-)-enantiomers were one to two orders of magnitude greater than the (+)
      enantiomer. Conversely, acetylcholinesterase was more rapidly inactivated by the
      (+)-enantiomers than the (-)-enantiomers. These results were examined in the
      context of the three-dimensional structure of the bacterial phosphotriesterase.

PMID- 10421457
TI  - Evidence that several conserved histidine residues are required for hydrolytic
      activity of human paraoxonase/arylesterase.
AB  - Recent evidence has been acquired that implicates an important role for several
      histidine residues in the hydrolytic mechanisms of human paraoxonase/arylesterase
      (PON1). Following titration with diethylpyrocarbonate (DEPC), both human serum
      and recombinant human type Q PON1 were inhibited in respect to their hydrolytic
      activity in a dose-responsive manner. Human PON1 treated with varying
      concentrations lost hydrolytic activity, and with each histidine modified, there
      was an exponential drop in hydrolytic activity. The reaction was followed
      spectrophotometrically at 244 nm. Recombinant wild-type and C283A PON1 enzymes
      inhibited with DEPC and subsequently treated with hydroxylamine had partial
      restoration of activity. The C283A mutant lacks a free sulfhydryl group,
      indicating that its inactivation is due to histidine specific modification. The
      dose response and time course of inactivation as well as the extent of
      reactivation by hydroxylamine were similar for both the wild-type and mutant
      recombinant enzymes. Mutants of PON1 containing an asparagine substituted for
      each of several conserved histidine residues lost hydrolytic activity for each
      single substitution. The mutants of PON1 constructed and assayed for arylesterase
      activity were H114N, H133N, and H284N. Each single aminoacid substitution
      rendered the enzyme catalytically inactive. These two pieces of evidence
      implicate an important role for several histidine residues in the hydrolytic
      mechanism of PON1. Although it is unusual for a calcium dependent enzyme to
      require histidines for its catalytic activity, acquired data suggest such a
      circumstance.

PMID- 10421459
TI  - Characterization of a soluble mouse liver enzyme capable of hydrolyzing
      diisopropyl phosphorofluoridate.
AB  - A novel mouse liver soluble fraction DFPase which has organophosphatase
      activities with sarin, soman and tabun, was purified and characterized. However,
      it lacks paraoxonase and arylesterase activities with paraoxon and phenyl
      acetate, respectively. This DFPase closely resembles and may be identical with
      the one purified by Little et al. in 1989 from the soluble fraction of rat liver,
      based on its substrate specificity, size (approximately 39 kDa) and its
      stimulation by several metal ions, namely magnesium, manganese and cobalt.
      Sequencing of our purified mouse liver DFPase showed it to be identical in its
      amino acid sequence with the recently identified senescence marker protein-30
      (SMP-30) by Fujita et al. in 1996. Other senescence marker proteins possessing
      high structural homology with the mouse SMP-30 have also been found and sequenced
      from human and rat livers. There is no structural homology between the senescence
      marker protein family and the group of mammalian paraoxonases. Thus, it is clear
      that there are at least two distinct, unrelated families of mammalian liver
      enzymes that share DFPase activity.

PMID- 10421458
TI  - Properties of the retained N-terminal hydrophobic leader sequence in human serum
      paraoxonase/arylesterase.
AB  - Human serum paraoxonase/arylesterase (PON1) is HDL-associated and appears to
      protect low density lipoproteins (LDL) from oxidation. Mature PON1 retains its N
      terminal hydrophobic signal sequence, which may be needed for binding to HDL. By
      site-directed mutagenesis, we created a mutant PON1 (A19A20) with a cleavable N
      terminus to determine if this peptide mediated binding to lipoproteins. As a
      model system, we studied binding of mutant and wild type PON1s to lipoproteins in
      fetal bovine serum-containing expression medium and found that the wild type
      recombinant enzyme associated with lipoproteins whereas the A19A20 mutant did
      not. These results show that the N-terminus is required for binding to either
      apolipoproteins or phospholipids. Furthermore, we showed that wild type enzyme
      can bind to phospholipids directly without apolipoproteins. To determine if lipid
      binding is a requirement for PON1's protection against LDL oxidation, we used a
      copper ion-induced oxidation system and found that the wild type enzyme and
      A19A20 mutant showed similar reductions in both peroxide and aldehyde formation.
      We conclude that PON1 depends upon its N-terminal hydrophobic peptide for its
      association with serum lipoproteins.

PMID- 10421460
TI  - Dichlorophenyl phosphoramidates as substrates for avian and mammalian liver
      phosphotriesterases: activity levels, calcium dependence and stereospecificity.
AB  - The present study shows the existence of both Ca2+-dependent and EDTA-resistant
      hydrolysing activities against HDCP and paraoxon in the particulate and soluble
      fractions of hen, rat and rabbit liver. HDCP was more extensively hydrolysed than
      paraoxon in both subcellular fractions and each of three individuals of the three
      animal species under study in spite of wide interindividual variations. However
      the ratio of HDCP versus paraoxon hydrolysing activity (HDCPase/paraoxonase),
      although within the same order of magnitude, cannot be considered as constant as
      it ranges one- to seven-fold between individuals of the same species. Also there
      is no constant ratio of Ca2+-dependent/EDTA-resistant activities. Rabbit liver
      showed the highest rates of Ca2+-dependent hydrolysis for both organophosphorus
      compounds whereas the hen paraoxonase activity was not inhibited by EDTA. The
      stereospecific hydrolysis of HDCP was mostly a Ca2+-dependent one, the S-HDCP
      isomer being hydrolysed faster than the R-HDCP one. The suggestion is made that
      HDCP could be conveniently used to measure PTE activity in the liver.

PMID- 10421461
TI  - Identification of two rat liver proteins with paraoxonase activity: biochemical
      evidence for the identity of paraoxonase and arylesterase.
AB  - The existence of two or more enzyme forms with paraoxonase activity has been
      reported in sheep, rabbit, human and rat serum and recently in mouse and rat
      liver. In this study we describe the presence of two peaks with paraoxonase
      activity (M1 and M2) after non-specific affinity chromatography of rat liver
      microsomes on Cibacron Blue 3GA. The first peak (M1) was obtained during the
      washing of the column and coeluted with albumin. The second active peak (M2) was
      eluted with 1 M NaCl. The characterization of each peak was determined by
      SDS/PAGE electrophoresis and Western-blotting. A comparison of both active
      fractions on the basis of kinetic parameters, heat inactivation and pH stability,
      calcium requirement and inhibition by EDTA and several metals was performed. Our
      results support the fact that two proteins capable of hydrolyzing paraoxon are
      present in rat liver microsomes. Furthermore, during the purification to
      homogeneity of rat liver paraoxonase we have performed a study of its hydrolytic
      ability against three different substrates: paraoxon, phenylacetate and phenyl
      thioacetate (Paraoxonase (PON), Arylesterase (ArE), Phenyl thioacetate esterase
      (PTase)). The elution profile in different chromatographic steps, as well as the
      activity ratios from the crude extract throughout the purification process, heat
      inactivation and effect of inhibitors were used as identity criteria for the
      three hydrolytic activities. Our results show evidence for the hydrolysis of
      paraoxon and phenylacetate by the same protein from rat liver (paraoxonase).

PMID- 10421463
TI  - Paraoxonase polymorphism in rabbits.
AB  - Paraoxonase in serum and liver of rabbits and cattle was investigated. In serum
      the two substrates paraoxon and phenylacetate are exclusively hydrolyzed by alpha
      lipoprotein-bound paraoxonase. In rabbit liver paraoxon is hydrolyzed only by
      paraoxonase, while phenylacetate is hydrolyzed by paraoxonase (20%) and
      additionally by an organophosphate sensitive carboxylesterase (B-Esterase), which
      is responsible for 80% of total liver phenylacetate hydrolysis. Phenyl acetate
      hydrolysis by B-Esterase of rabbit liver was shown to be inhibited by paraoxon
      and by mipafox covalently in a time and concentration dependent manner. Rabbit
      serum exhibits by far the highest serum paraoxonase activity (2.6 +/- 0.66 U/ml)
      of all vertebrate species tested up to now, while rabbit liver contains only 0.5
      +/- 0.2 U/g fresh weight. In cattle extremely high paraoxonase activity is found
      in liver (2.8 U/g), while bovine serum contains only 0.2 U/g. The paraoxonase
      activity ratio (hydrolysis rate paraoxon: phenylacetate x 1000) in cattle does
      not show interindividual variation (activity ratio 4.0 +/- 0.4, correlation
      coefficient 0.996, P < 0.001). In contrast, the paraoxon/phenylacetate hydrolysis
      ratio of rabbit paraoxonase in serum as well as in liver does vary considerably
      between individuals. In cross-bred rabbits paraoxonase activity ratios from three
      to ten are found. In a strain of pure-bred New Zealand White rabbits three
      polymorphic serum paraoxonase phenotypes could be clearly differentiated by the
      activity ratio. By analogy with the human paraoxonase polymorphism, the rabbit
      paraoxonase isotypes were classified as paraoxonase A (activity ratio 3.8-4.3),
      AB (ratio 5.5-6.0) and B (ratio 7.3-8.6). The corresponding frequencies of the
      three isotypes were 40, 35 and 25%.

PMID- 10421462
TI  - In vitro sequestration of two organophosphorus homologs by the rat liver.
AB  - Bromophos (Bp) and ethylbromophos (EBp) are two structurally homologous
      organophosphorus insecticides (OP) which show a 24-fold difference in their
      toxicity to the laboratory rat (LD50--2215 and 91 mg/kg b.w., respectively). The
      role of rat liver in the sequestration of the OP oxons was studied based on
      carboxylesterase (CaE) inhibition in vitro. Bromoxon (Bo) and ethylbromoxon (EBo)
      were greater inhibitors of rat hepatic CaE than brain acetylcholinesterase (AChE)
      with IC50 values at nanomolar and picomolar levels, respectively. The capacity of
      the liver to sequester OPs was determined by measuring AChE inhibition pre
      incubated with or without liver homogenate. AChE inhibition by Bo decreased with
      increasing concentration of liver tissue, whereas it was unaffected in the case
      of EBo. The results imply that liver tissue contains binding sites, which
      sequester Bo thereby reducing the number of OP molecules available to inhibit
      AChE. Although CaE inhibition leads to sequestration, other binding sites in the
      liver may have a significant role in determining the toxicity of OPs.
      Differential sequestration of the OPs by hepatic tissue, therefore, could be
      important in understanding the role of differential saturation of the target
      molecules, which has a bearing on differential toxicity.

PMID- 10421465
TI  - Acetylcholinesterase in the neuromuscular junction.
AB  - New findings regarding acetylcholinesterase (AChE) in the neuromuscular junction
      (NMJ), obtained in the last decade, are briefly reviewed. AChE is highly
      concentrated in the NMJs of vertebrates. Its location remains stable after
      denervation in mature rat muscles but not in early postnatal muscles. Agrin in
      the synaptic basal lamina is able to induce sarcolemmal differentiations
      accumulating AChE even in the absence of a nerve ending. Asymmetric A12 AChE form
      is the major molecular form of AChE in vertebrate NMJs. Extrajunctional
      suppression of this form is a developmental phenomenon. Motor nerve is able to
      reinduce expression of the A12 AChE form in the ectopic NMJs even in muscles with
      complete extrajunctional suppression of this form. The 'tail' of the A12 AChE
      form is made of collagen Q. It contains domains for binding AChE to basal lamina
      with ionic and covalent interactions. Muscle activity is required for normal AChE
      expression in muscles and its accumulation in the NMJs. In addition, the pattern
      of muscle activation also regulates AChE activity in the NMJs, demonstrating that
      the pattern of synaptic transmission is able to modulate one of the key synaptic
      components.

PMID- 10421466
TI  - Control levels of acetylcholinesterase expression in the mammalian skeletal
      muscle.
AB  - Protein expression can be controled at different levels. Understanding
      acetylcholinesterase (EC. 3.1.1.7, AChE) expression in the living organisms
      therefore necessitates: (1) determination and mapping of control levels of AChE
      metabolism; (2) identification of the regulatory factors acting at these levels;
      and (3) detailed insight into the mechanisms of action of these factors. Here we
      summarize the results of our studies on the regulation of AChE expression in the
      mammalian skeletal muscle. Three experimental models were employed: in vitro
      innervated human muscle, mechanically denervated adult fast rat muscle, and the
      glucocorticoid treated fast rat muscle. In situ hybridization of AChE mRNA,
      combined with AChE histochemistry, revealed that different distribution patterns
      of AChE, observed during in vitro ontogenesis and synaptogenesis of human
      skeletal muscle, reflect alterations in the distribution of AChE mRNA (Z. Grubic,
      R. Komel, W.F. Walker, A.F. Miranda, Myoblast fusion and innervation with rat
      motor nerve alter the distribution of acetylcholinesterase and its mRNA in human
      muscle cultures, Neuron 14 (1995) 317-327). To study the mechanisms of AChE mRNA
      loss in denervated adult rat skeletal muscle, we exposed deproteinated AChE mRNA
      to various subcellular fractions in vitro. Fractions were isolated from the
      normal and denervated rat sternomastoideus muscle. We found significantly
      increased, but non-specific AChE mRNA degradation capacities in the three
      fractions studied, suggesting that increased susceptibility of muscle mRNA to
      degradation might be at least partly responsible for the decreased AChE mRNA
      observed under such conditions (K. Zajc-Kreft, S. Kreft, Z. Grubic, Degradation
      of AChE mRNA in the normal and denervated rat skeletal muscle, Book of Abstracts,
      The Sixth International Meeting on Cholinesterases, La Jolla, CA, March 20-24,
      1998, p. A3.). In adult fast rat muscle, treated chronically with
      glucocorticoids, we found the fraction of early synthesized AChE molecular forms
      to be reduced and AChE mRNA unchanged. This observation is consistent with the
      explanation that translation and/or early post-translational processes are
      impaired under such conditions (M. Brank, K. Zajc-Kreft, S. Kreft, R. Komel, Z.
      Grubic, Biogenesis of acetylcholinesterase is impaired, although its mRNA level
      remains normal, in the glucocorticoid-treated rat skeletal muscle, Eur. J.
      Biochem. 251 (1998) 374-381). The AChE mRNA level is therefore important but not
      the only control level of AChE expression in the mammalian skeletal muscle.

PMID- 10421464
TI  - Knockout of one acetylcholinesterase allele in the mouse.
AB  - One allele of the AChE gene (ACHE) was knocked out in embryonic stem (ES) cells
      by homologous recombination. The targeting vector contained 2 kb of a TK gene
      cassette for negative selection, 884 bp of ACHE including exon 1, 1.6 kb of a
      Neo(r) gene cassette for positive selection, 5.2 kb of the ACHE Bam HI fragment
      including exon 6, and 3 kb of Bluescript. The use of this vector deleted exons 2
      5, which removed 93% of the ACHE coding sequence including the signal peptide,
      the active site serine, and the histidine and glutamic acid of the catalytic
      triad. The gene targeting vector was transfected into ES cells by
      electroporation. Colonies resistant to G418 and gancyclovir were screened for
      homologous recombination by Southern blotting. Out of 200 colonies, four were
      found to have undergone homologous recombination. These four ACHE (+/-) ES cell
      lines were expanded to provide cells for microinjection into C57Bl/6 mouse
      blastocysts. The injected blastocysts were implanted into pseudopregnant CD/l
      white mice. More than 200 injected blastocysts were transferred into 20 mice.
      More than 65 mice were born, of which 11 were chimeras. Chimeras were identified
      by their black and agouti coat color. Littermates were all black. Thus far, seven
      male chimeras have been bred with more than 130 C57Bl/6 females to generate 26
      agouti mice out of 199 living offspring. This demonstrated that the ACHE (+/-) ES
      cells contributed to the germline. Offspring with agouti coat color have a 50%
      chance of carrying the knockout allele. The 26 agouti offspring were screened for
      an ACHE (+/-) genotype by tail biopsy PCR. Ten out of 26 agouti mice are
      heterozygous ACHE knockout mice, and they are healthy and alive at 29 days of
      age. We expect a phenotype to appear in nullizygous animals.

PMID- 10421467
TI  - Morphometric characteristics of myonuclear distribution in the normal and
      denervated fast rat muscle fiber.
AB  - Unlike the majority of mammalian tissues, which have mononuclear cells as a basic
      unit of the tissue composition, skeletal muscle fiber is a polynuclear syncytium.
      Polynuclear organization offers an additional possibility for the regulation of
      protein expression: it can also be controlled at the level of myonuclear
      distribution and specialization. Distribution of myonuclei can be considered as
      the distribution of genes. Variability in gene concentration may have important
      impact on the regional differentiation of the muscle fiber, since it leads to
      different regional concentrations of various gene products including factors
      controlling their expression. The aim of the present study was: 1) to provide
      morphometrical data on the myonuclear distribution in the junctional and
      extrajunctional regions of the normal fast rat muscle fiber, and 2) to analyze,
      whether morphometrical parameters of nuclear distribution change after mechanical
      denervation of this muscle. Single muscle fibers were isolated from the normal
      and denervated fast rat m. sternomastoideus. Their neuromuscular junctions were
      stained by thiocholine histochemical procedure and myonuclei were fluorescently
      labeled by Hoechst 33342. Myonuclear distribution in each individual muscle fiber
      was morphometrically analyzed on the image analyzer. Synaptic concentrations of
      myonuclei were found to exceed extrasynaptic concentrations by a factor of 17.
      The number of myonuclei accumulated at the endplates did not change after one or
      two weeks of denervation, neither did the morphometric parameters of these
      nuclei. A higher concentration of myonuclei due to muscle atrophy was observed in
      the extrasynaptic region and the longitudinal axis of these nuclei also became
      significantly shorter. Unchanged morphometric parameters of the junctional
      myonuclei after denervation are indicative of either irreversibility of the nerve
      induced formation of nuclear clusters in this region or persistence of the
      factors responsible for their formation and maintenance.

PMID- 10421468
TI  - Localization of cells expressing AChE mRNA in rat striatum using nonradioactive
      in situ hybridization.
AB  - A better understanding of the role of AChE in mammalian brain requires knowledge
      of the distribution of AChE synthesizing cells in this tissue. The aim of the
      present study is to test a nonradioactive approach for the localization of AChE
      mRNA positive cells in rat striatum. Nonradioactive in situ hybridization has not
      been used before for the localization of this mRNA in mammalian brain. In order
      to find optimal conditions for localization, we employed both RNA and
      oligonucleotide probes. We also examined various prehybridization protocols and
      approaches. The total number of cells in brain sections was determined by
      subsequent fluorescent staining of the nuclei. Optimal AChE mRNA localization was
      obtained with a digoxigenine-labeled RNA probe. We were not able to localize AChE
      mRNA with nonradioactively 3' end-labeled oligonucleotides. An acetylation step
      prior to hybridization was found to be essential for optimal signal/background
      ratios; high nonspecific staining was observed, if this step was omitted. In
      accordance with reports of other authors, who used radioactive in situ
      hybridization, we found very low percentages of AChE mRNA-positive cells in
      striatum, although this area exhibits very high AChE staining. In comparison to
      radioactive techniques, the nonradioactive approach avoids the risks of
      radioactivity, and is much less time consuming. In our experiments AChE mRNA
      localization in striatum was practically the same as that demonstrated previously
      by radioactive approaches.

PMID- 10421469
TI  - Combined effects of glucocorticoids and electromechanical activity on the
      acetylcholinesterase expression in the fast rat muscle.
AB  - Protein synthesis is impaired in the glucocorticoid (GC)-treated fast mammalian
      muscle. Electromechanical activity was reported to alleviate this effect.
      Acetylcholinesterase (AChE; EC 3.1.1.7) synthesis in the skeletal muscle is
      regulated by both, GCs and electromechanical activity. In light of the above
      reports, one would expect that electrical stimulation will prevent GC-mediated
      fall of AChE synthesis in the muscle. On the other hand, a substantial body of
      evidence suggests that electromechanical activity exerts its effect at the AChE
      mRNA level, while GCs most probably act at the translational or early
      posttranslational level. Different levels of action would be more consistent with
      the independent and therefore additive influences of the two regulatory factors.
      In order to ascertain whether glucocorticoid and electromechanical effects
      interact in the control of AChE activity, we compared the effects of GCs on
      normal, nonstimulated fast rat skeletal muscle, with those of GC-treated and
      simultaneously electrically stimulated (tonic pattern, 10 Hz) muscle. Untreated
      and stimulated-only muscles were used as respective controls. The effects on the
      fast extensor digitorum longus muscle and slow soleus muscle, treated similarly
      were compared. As expected, chronic GC treatment and electrical stimulation of
      fast rat muscles with slow activity patterns both downregulated AChE activity.
      However, no additional decrease in AChE activity was observed, if stimulated fast
      muscle was simultaneously treated with GCs, suggesting that slow pattern of
      electromechanical activity prevents GC-mediated downregulation of AChE. The most
      plausible explanation of this observation is, that muscle activity blocks
      expression of some generally acting factors, which are induced by GCs and are
      responsible for the impaired synthesis of several proteins including AChE.

PMID- 10421470
TI  - Glucocorticoids differentially control synthesis of acetylcholinesterase and
      butyrylcholinesterase in rat liver and brain.
AB  - Mammalian organisms possess two cholinesterases: acetylcholinesterase (AChE, EC
      3.1.1.7.) and butyrylcholinesterase (BuChE, EC 3.1.1.8.). A clear explanation for
      this dual expression of acetylcholine-hydrolyzing enzymes is still missing.
      Better knowledge on how these two enzymes respond to various physiological or
      pharmacological factors would importantly contribute to the understanding of
      their function. The aim of the present study is to elucidate glucocorticoid (GC)
      influences on the synthesis of AChE and BuChE in rat liver and brain. Female
      Wistar rats were treated with dexamethasone until body weight loss was greater
      than 15%, signaling full expression of a GC response. At this stage, liver and
      brain were isolated and AChE and BuChE activities were determined in their
      homogenates. A new approach, based on precise radiometric measurements of AChE
      and BuChE activities in the polysomal fractions, prepared under non-denaturing
      conditions, was used to study GC influences on the early stages of biosynthesis
      of both enzymes. We found a differential GC influence on AChE and BuChE. In
      brain, only BuChE activity was affected (-30%), while AChE remained practically
      unchanged. In liver, BuChE activity fell by 60%, while AChE lost only 18% of its
      control activity. In case of BuChE, decreased activities in the whole homogenates
      correlated with decreased activities in the polysomal fractions, suggesting that
      early stages of enzyme biosynthesis were primarily affected. On the other hand,
      decreased AChE activity in liver homogenates was not paralleled by a significant
      change at the level of polysomal AChE activity in this organ, suggesting that
      higher AChE turn-over is primarily responsible for the decreased activity in
      homogenate. These results, together with the GC-mediated elimination of the
      correlation between brain and liver BuChE activities, strongly support the
      proposal of Edwards and Brimijoin (J.A. Edwards, S. Brimijoin, Effects of
      hypophysectomy on acetylcholinesterase and butyrylcholinesterase in the rat,
      Biochem. Pharmacol. 32 (1983) 1183-1189) that BuChE is regulated by systemically
      acting factors, including various hormones, while regulation of AChE is primarily
      tissue-specific.

PMID- 10421471
TI  - Anticholinesterases induce multigenic transcriptional feedback response
      suppressing cholinergic neurotransmission.
AB  - Cholinesterase inhibitors (anti-ChEs) include a wide range of therapeutic,
      agricultural and warfare agents all aimed to inhibit the catalytic activity of
      the acetylcholine (ACh) hydrolysing enzyme acetylcholinesterase (AChE). In
      addition to promoting immediate excitation of cholinergic neurotransmission
      through transient elevation of synaptic ACh levels, anti-ChEs exposure is
      associated with long-term effects reminiscent of post-traumatic stress disorder.
      This suggested that exposure to anti-ChEs leads to persistent changes in brain
      proteins and called for exploring the mechanism(s) through which such changes
      could occur. For this purpose, we established an in vitro system of perfused,
      sagittal mouse brain slices which sustains authentic transcriptional responses
      for over 10 h and enables the study of gene regulation under controlled exposure
      to anti-ChEs. Slices were exposed to either organophosphate or cabamate anti
      ChEs, both of which induced within 10 min excessive overexpression of the mRNA
      encoding the immediate early response transcription factor c-Fos. Twenty minutes
      later we noted 8-fold increases over control levels in AChE mRNA, accompanied by
      a 3-fold decrease in the mRNAs encoding for the ACh synthesizing enzyme choline
      acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT). No changes
      were detected in synaptophysin mRNA levels. These modulations in gene expression
      paralleled those taking place under in vivo exposure. Of particular concern is
      the possibility that feedback processes leading to elevated levels of brain AChE
      may be similarly associated with low-level exposure to common organophosphorous
      anti-cholinesterases, and lead to long-term deleterious changes in cognitive
      functions.

PMID- 10421472
TI  - Grafting of genetically modified human fetal fibroblasts to produce human
      butyrylcholinesterase in mice.
AB  - Human diploid fibroblast cultures were established from fetal skin tissue.
      Enzymic dissociation yielded cultures of higher growth capacity of fibroblasts
      than those prepared by mechanical dissociation followed by spontaneous outgrowth
      of cells. Transfer of recombinant human butyrylcholinesterase (BChE, EC 3.1.1.8)
      gene into primary human fibroblasts was achieved successfully using lipofection
      and retrovirus-mediated transfection. The analysis of drug-resistant colonies
      suggested the presence of the transcripted BChE mRNA in the cytoplasm of
      transfected cells. The secreted BChE protein in culture medium was assayed for
      enzyme activity using butyrylthiocholine as substrate. The genetically modified
      fibroblasts were mixed with rat tail collagen and transplanted subcutaneously and
      intraperitoneally to mice. Immunoreactive human BChE appeared in the plasma from
      the transplanted mice. reaching the top level at day 13. It was not present any
      longer in most of the mice 20 days later.

PMID- 10421473
TI  - Effects of organophosphates on cholinesterase activity and neurite regeneration
      in Aplysia.
AB  - In Aplysia, a marine mollusc, acetylcholinesterase (AChE) is present in
      cholinergic and non-cholinergic neurons and in hemolymph. Aplysia hemolymph has a
      very high level of AChE which promotes neurite growth in primary cultures of
      dopaminergic neurons via a non-catalytic mechanism. In contrast, AChE is known to
      facilitate neurite growth in cholinoceptive neurons by hydrolyzing ACh which
      inhibits neurite growth. In order to test whether AChE's site-specific
      neurotrophic action varies with the neuronal phenotype, we investigated the
      effects of active-site inhibited hemolymph AChE on neurite growth of cholinergic
      neurons of Aplysia in primary culture. Organophosphates being long-acting active
      site inhibitors of AChE were chosen for this study. The effects of active site
      inhibited hemolymph AChE was tested on large cholinergic neurons, R2 (abdominal
      ganglion) and LPL1 (left pleural ganglion) as well as small cholinergic neurons
      (buccal ganglion) of Aplysia, maintained in culture. Partially purified hemolymph
      AChE was inhibited by either 10 microM of echothiophate or 5 microM of paraoxon.
      Neurons were maintained in (1) L15 (defined medium) alone; (2) L15 +
      echothiophate; (3) L-15 + paraoxon; (4) L-15 + hemolymph AChE; (5) L15 +
      hemolymph AChE + echothiophate; and (6) L-15 + hemolymph AChE + paraoxon.
      Addition of uninhibited hemolymph AChE significantly increased neurite growth of
      cultured neurons compared to L15 alone. In the presence of echothiophate
      inhibited or praoxon-inhibited AChE, neurite growth was significantly reduced
      when compared to L15 + uninhibited AChE. While the presence of echothiophate by
      itself did not reduce survival or neurite growth when compared to L-15 alone, the
      presence of paraoxon by itself markedly reduced survival and neurite growth of
      cultured neurons. The results show that AChE's catalytic action contributes to
      enhance neurite growth in cholinergic neurons and the effects of paraoxon appears
      to differ from that of echothiophate on cholinergic neurons of Aplysia.

PMID- 10421474
TI  - On the physiological role(s) of the paraoxonases.
AB  - In recent years several lines of evidence have indicated that serum paraoxonase
      (PON1), and perhaps other mammalian paraoxonases, act as important guardians
      against cellular damage from toxic agents, such as organophosphates, oxidized
      lipids in the plasma low density lipoproteins (LDL), and against bacterial
      endotoxins. For some of these protective activities but not all, PON1 requires
      calcium ion. The catalyzed chemical reactions generally seem to be hydrolytic,
      but for some types of protection this may not be so. Several other metals have
      very high affinity for PON1 and may displace calcium. Replacement or substitution
      of calcium by other metals could extend the range of catalytic properties and the
      substrate specificity of the paraoxonases, as it does for the mammalian DFPases.
      Although this Third International Meeting on Esterases Reacting with
      Organophosphorus Compounds focuses on the organophosphatase activities of
      paraoxonase and related enzymes, it is important to also briefly review some of
      the current directions in several laboratories searching for additional functions
      of the paraoxonases to extend our understanding of the properties of this family
      of enzymes which now seem to have both physiological and toxicological
      importance.

PMID- 10421475
TI  - Low serum paraoxonase: a risk factor for atherosclerotic disease?
AB  - Serum paraoxonase (PON1) hydrolyses organophosphate (OP) insecticides and nerve
      gases and is responsible for determining the selective toxicity of these
      compounds in mammals. PON1 has two genetic polymorphisms giving rise to amino
      acid substitutions at position 55 and 192. The 192 polymorphism is the major
      determinant of the PON1 activity polymorphism towards organophosphates. However,
      the 55 polymorphism also modulates activity. PON1 also may be a determinant of
      resistance to the development of atherosclerosis by protecting lipoproteins
      against oxidative modification perhaps by hydrolysing phospholipid
      hydroperoxides. The PON1 polymorphisms are important in determining the capacity
      of high-density lipoprotein (HDL) to protect low-density lipoprotein (LDL)
      against oxidative modification in vitro and this may explain the relationship
      between the PON1 alleles and coronary heart disease in case-control studies.

PMID- 10421476
TI  - Organophosphorus acid anhydrolase in slime mold, duckweed and mung bean: a
      continuing search for a physiological role and a natural substrate.
AB  - Recently, and for the first time, a diisopropylphosphorofluoridate (DFP)
      hydrolyzing enzyme, i.e. an organophosphorus acid anhydrolase (OPAA), has been
      reported in a plant-source. Based on this and other suggestive evidence, the
      ability of three plant sources and a protist to hydrolyze DFP and 1,2,2
      trimethylpropyl methylphosphonofluoridate (Soman) were tested, and the effects of
      Mn2+ and ethylenediamine tetraacetate (EDTA) on this activity. The plants are
      duckweed (Lemna minor), giant duckweed (Spirodela oligorhiza), and germinated
      mung bean (Vigna radiata); the protist is a slime mold (Dictyostelium
      discoidium). The tests are based on a crude classification of OPAAs as 'squid
      type' (DFP hydrolyzed more rapidly than Soman) and all of the others termed by
      us, with questionable justification, as 'Mazur type' (Soman hydrolyzed more
      rapidly than DFP). Of the two duckweeds, Spirodela oligorhiza hydrolyzes Soman
      but not DFP, and Lemna minor does not hydrolyze either substrate. In contrast to
      the report of Yu and Sakurai, mung bean does not hydrolyze DFP and hydrolyzes
      Soman with a 5-fold stimulation by Mn2+ and a marked inhibition by EDTA. The
      slime mold hydrolyzes Soman more rapidly than DFP (but does hydrolyze DFP) and
      the hydrolysis is Mn2+ stimulated. The failure of these plant sources to
      hydrolyze DFP is similar to the behavior of OPAA from Bacillus
      stearothermophilus.

PMID- 10421477
TI  - Paraoxonase and arylesterase activities in the serum of two hyperlipoproteinaemic
      patients after repeated extracorporal lipid precipitation.
AB  - The effect of heparin-induced extracorporal lipid precipitation (HELP) on the
      activities of paraoxonase (EC 3.1.8.1) and arylesterase (EC 3.1.1.2) was studied
      in serum of a patient with hyperlipoproteinaemia (A) and of a patient with non
      insulin dependent diabetes mellitus and hyperlipoproteinaemia (B). The enzyme
      activities were measured spectrophotometrically (Tris-HCl buffer, pH 7.4, 37
      degrees C) with paraoxon and phenylacetate as substrates of paraoxonase and
      arylesterase, respectively. Both patients underwent HELP applications once a week
      over a period of 7 weeks. Over that period no overall change was observed either
      in enzyme activities or in the lipid and protein content of the sera. However,
      each HELP session caused an immediate decrease of EDTA-insensitive arylesterase
      activity (on average 56% in A and 42% in B), while EDTA-sensitive arylesterase
      remained almost unaltered. Paraoxonase remained unchanged in A, but decreased in
      B (approximately 60%). Of the atherogenic lipoprotein parameters, the most
      pronounced decrease was found in VLDL-cholesterol and in triglycerides (on
      average 45% in A and 32% in B), while the anti-atherogenic HDL-cholesterol
      decreased < 10%. Possible implications of the effect of HELP on the enzyme
      activities studied remain to be explained.

PMID- 10421478
TI  - Protein engineering of a human enzyme that hydrolyzes V and G nerve agents:
      design, construction and characterization.
AB  - Because of deficiencies in the present treatments for organophosphorus
      anticholinesterase poisoning, we are attempting to develop a catalytic scavenger
      that can be administered as prophylactic protection. Currently known enzymes are
      inadequate for this purpose because they have weak binding and slow turnover, so
      we are trying to make an appropriate enzyme by protein engineering techniques.
      One butyrylcholinesterase mutant, G117H, has the desired type of activity but
      reacts much too slowly. This communication describes an attempt to determine the
      reason for the slow reaction so that a more efficient enzyme might be designed.
      The results indicate that the mutation at residue 117 has resulted in a
      distortion of the transition state of the reaction of organophosphorus compounds
      with the active site serine. This information will be used to develop other
      mutants that avoid transition state stabilization sites.

PMID- 10421479
TI  - Improvements in scavenger protection against organophosphorus agents by
      modification of cholinesterases.
AB  - The ability of stoichiometric scavengers, such as ChEs, to protect against a
      variety of OP agents has been demonstrated in several in vivo models. To improve
      the detoxification of OP agents by ChEs, several approaches have been recently
      used to increase the stoichiometry, stability, and in vivo effectiveness of ChEs
      as OP scavengers. For example, the in vitro stoichiometric neutralization of
      sarin by AChE was increased from 1:1 to 3200:1 by the addition of the oxime HI-6,
      while the in vivo stoichiometry was increased to 57:1 in mice by HI-6. The aging
      rate of soman-inhibited mouse AChE was reduced 12-fold in a mutant AChE (E202Q)
      which resulted in a two-fold increase in oxime-assisted detoxification of soman.
      To improve the duration of scavenger protection provided by ChEs, the mean
      residence times of five tissue-derived and two recombinant ChEs injected i.v. in
      mice were compared with their oligosaccharide profiles. The mean residence times
      of these ChEs were found to increase with molecular weight and with the levels of
      oligosaccharide sialylation. The stability of AChE in non-physiological
      environments was improved by immobilizing it in a polyurethane foam matrix that
      allowed AChE to retain enzymatic activity at high temperature (75 degrees C)
      where soluble enzyme denatured. These developments in scavenger technology have
      improved the in vivo protection provided by OP scavengers and extended their
      applicability to provide external decontamination of chemical agents and
      pesticides.

PMID- 10421480
TI  - The role of paraoxonase (PON1) in the detoxication of organophosphates and its
      human polymorphism.
AB  - In human populations, serum paraoxonase (PON1) exhibits a substrate dependent
      polymorphism. The Arg192 isoform hydrolyzes paraoxon rapidly but diazoxon, soman
      and especially sarin slowly. On the other hand, the Gln192 isoform hydrolyzes
      paraoxon slowly, but diazoxon, soman and sarin more rapidly than the Arg192
      isoform. Our experiments with a mouse model system have convincingly shown that
      PON1 plays a major role in the detoxication of organophosphate (OP) compounds
      processed through the P450/PON1 pathway. Recent studies have also shown that PON1
      plays an important role in the metabolism of oxidized lipid compounds. Currently,
      there is an effort underway to identify genes and polymorphisms that play an
      important role in 'environmental susceptibility'. The PON1 polymorphism has been
      cited as a prime example of such a genetic polymorphism. The advent of the
      polymerase chain reaction (PCR) for DNA amplification with improvements,
      modifications and automation has provided a very convenient way to do individual
      genotyping. It is tempting to set up large scale PCR analyses of populations to
      determine individuals at risk for environmental exposures affected by the PON1
      polymorphism. In fact, a number of such studies have already been carried out in
      examining the relationship of the PON1 polymorphism to vascular disease. We
      advocate the use of a high throughput two-dimensional enzyme assay that provides
      both PON1 genotype and phenotype (PON1 status). The high level of variation of
      gene expression within each genetic class in humans, together with our animal
      model studies indicate that it is very important to determine PON status as
      opposed to PON1 genotype alone. Experiments in rats and mice have shown that
      injection of PON1 purified from rabbit serum by the i.v., i.p. or i.m. route,
      significantly increases PON1 activities in rodents' plasma. Under these
      conditions, the acute toxicity (assessed by the degree of acetylcholinesterase
      inhibition) of paraoxon and chlorpyrifos oxon is significantly decreased,
      compared to control animals. Protection is maximal when PON1 is administered
      before the OPs, but still occurs when PON1 is utilized as a post-exposure
      treatment. Furthermore, protection by PON1 is also provided toward the parent
      compound chlorpyrifos. Pon1-knockout mice display a much greater sensitivity to
      chlorpyrifos oxon toxicity than wild mice. However, the acute toxicity of
      guthion, which is not a substrate for PON1, does not differ between knockout and
      wild mice. These observations underline the importance of considering both
      genetic variability of enzyme isoform as well as enzyme level (PON1 status) and
      the developmental time course of appearance of PON1 in developing risk assessment
      models.

PMID- 10421481
TI  - Degradation of nerve gases by CLECS and cells: kinetics of heterogenous systems.
AB  - We have reported the enzymatic hydrolysis of phosphoro- and phosphonofluoridates
      and phosphoro- and phosphonothiolates and -thionates by an organophosphorus
      hydrolase (OPH) from Pseudomonas diminuta. In screening for other microbial
      sources of nerve gas hydrolyzing enzymes, it would be convenient, indeed
      essential, to be able to determine such hydrolyses on intact cells. As a
      preliminary step to such screening we have measured the hydrolysis of O,O
      diisopropyl S-(2-diisopropylaminoethyl) phosphorothiolate (Tetriso) and O,O
      diethyl S-(2-ethylthioethyl) phosphorothiolate (Demeton-S; formerly Isosystox) by
      intact cells and sonicates. The purified OPH has also been cross-linked to itself
      (CLEC = cross-linked enzyme crystals) and this has also been tested for its
      ability to hydrolyze Tetriso and Demeton-S. The testing of such heterogenous
      systems by a spectrophotometric assay (Ellman) has required novel modifications.
      Our findings are that both Tetriso and Demeton-S are subject to intact-cell
      assay, that both are readily hydrolyzed by the CLEC-ed OPH without marked change
      in kinetics, but that at any given substrate concentration Tetriso is hydrolyzed
      much more rapidly. However, since Demeton-S is commercially available, this
      appears to be the substrate most suitable for screening for our final goal in a
      search for sources of enzymes to detoxify O-ethyl S-(2-diisopropylaminoethyl)
      methylphosphonothiolate (VX).

PMID- 10421482
TI  - Different role of carboxylesterases in toxicity and tolerance to paraoxon and
      DFP.
AB  - The contribution of carboxylesterase (CarbE) to toxicity and tolerance to the
      organophosphorus anticholinesterases (OP-antiChE) paraoxon (diethyl p-nitrophenyl
      phosphate) and DFP (diisopropylphosphorofluoridate) was investigated in rats.
      Daily injections (20 days) of paraoxon (0.33 micromol/kg) or DFP (2.72
      micromol/kg) reduced AChE activity in brain to 29 or 16% and in diaphragm to 58
      or 54%, respectively. The animals tolerated an accumulated 6-fold LD50 dose and
      survived an LD90 dose of carbachol, indicating tolerance to this cholinergic
      agonist. A single dose of paraoxon or DFP significantly reduced CarbE activity of
      plasma, lung and liver. After paraoxon, rapid recovery was seen of plasma and
      liver CarbE while recovery after DFP was much slower. Daily pretreatment with the
      CarbE inhibitors CBDP (2-[o-cresyl]-4H-1,2,3-benzodioxa- phosphorin-2-oxide)
      (7.22 micromol/kg, s.c.) or iso-OMPA (tetraisopropylpyrophosphoramide) (8.76
      micromol/kg, i.p.), followed by paraoxon (0.33 micromol/kg, s.c.) 30 min later,
      prevented the development of tolerance to paraoxon and potentiated its toxicity.
      Rats died on day four of the combined treatment. The CarbE inhibitors neither
      potentiated the DFP toxicity, nor prevented tolerance development to DFP. We
      conclude that rat plasma CarbE provides a significant protection against paraoxon
      toxicity because its rapid reactivation can reduce the toxicity of repeated
      paraoxon applications and thus contribute to tolerance development. This same
      mechanism does not apply to DFP toxicity, as inhibition of CarbE of plasma, liver
      and lung neither potentiated its toxicity, nor prevented tolerance development.
      These findings confirm previous observations that CarbE detoxification is of
      greater importance for highly toxic OP-antiChEs such as nerve agents and paraoxon
      than for less toxic ones such as DFP.

PMID- 10421483
TI  - Alteromonas prolidase for organophosphorus G-agent decontamination.
AB  - Enzymes catalyzing the hydrolysis of highly toxic organophosphorus compounds
      (OPs) are classified as organophosphorus acid anhydrolases (OPAA; EC 3.1.8.2).
      Recently, the genes encoding OPAA from two species of Alteromonas were cloned and
      sequenced. Sequence and biochemical analyses of the cloned genes and enzymes have
      established Alteromonas OPAAs to be prolidases (E.C. 3.4.13.9), a type of
      dipeptidase hydrolyzing dipeptides with a prolyl residue in the carboxyl-terminal
      position (X-Pro). Alteromonas prolidases hydrolyze a broad range of G-type
      chemical warfare (CW) nerve agents. Efforts to over-produce a prolidase from A.
      sp.JD6.5 with the goal of developing strategies for long-term storage and
      decontamination have been successfully achieved. Large-scale production of this G
      agent degrading enzyme is now feasible with the availability of an over-producing
      recombinant cell line. Use of this enzyme for development of a safe and non
      corrosive decontamination system is discussed.

PMID- 10421484
TI  - Organophosphate skin decontamination using immobilized enzymes.
AB  - We previously demonstrated that a combination of cholinesterase (ChE) pre
      treatment with an oxime is an effective measure against soman and sarin. We
      describe here a novel approach for the preparation of covalently linked ChEs
      which are immobilized to a polyurethane matrix. Such preparation of ChE-sponges
      enhances the stability and usefulness of the enzymes in non-physiological
      environments. The ChE-sponges, which can be molded to any form, can effectively
      be used to remove and decontaminate organophosphates (OPs) from surfaces,
      biological (skin or wounds) or otherwise (clothing or sensitive medical
      equipment), or the environment. The ChE-sponges retained their catalytic activity
      under conditions of temperature, time, and drying where the native soluble enzyme
      would rapidly denature, and can be reused in conjunction with oximes many times.
      The ChE-sponge in the presence of oxime repeatedly detoxified OPs such as DFP or
      MEPQ. These developments in ChE technology have extended the applicability of OP
      scavengers from in vivo protection, to a variety of external detoxification and
      decontamination schemes. In addition to treatment of OP-contaminated soldiers,
      the ChE-sponge could protect medical personnel from secondary contamination while
      attending chemical casualties, and civilians exposed to pesticides or highly
      toxic nerve agents such as sarin.

PMID- 10421485
TI  - Toxicological significance in the cleavage of esterase-beta-glucuronidase complex
      in liver microsomes by organophosphorus compounds.
AB  - Egasyn is an accessory protein of beta-glucuronidase (beta-G) in the liver
      microsomes. Liver microsomal beta-G is stabilized within the luminal site of the
      microsomal vesicles by complexation with egasyn which is one of the
      carboxylesterase isozymes. We investigated the effects of organophosphorus
      compounds (OPs) such as insecticides on the dissociation of egasyn-beta
      glucuronidase (EG) complex. The EG complex was easily dissociated by
      administration of OPs, i.e. fenitrothion, EPN, phenthionate, and bis-beta
      nitrophenyl phosphate (BNPP), and resulting beta-G dissociated was released into
      blood, leading to the rapid and transient increase of plasma beta-G level with a
      concomitant decrease of liver microsomal beta-G level. In a case of phenthionate
      treatment, less increase in plasma beta-G level was observed, as compared with
      those of other OPs. This may be explained by the fact that phenthionate was
      easily hydrolyzed by carboxylesterase. Similarly, carbamate insecticides such as
      carbaryl caused rapid increase of plasma beta-G level. In contrast, no
      significant increase of plasma beta-G level was observed when pyrethroid
      insecticides were administered to rats. This is due to the fact that pyrethroids
      such as phenthrin and allethrin were easily hydrolyzed by A-esterase as well as
      carboxylesterase. On the other hand, addition of OPs to the incubation mixture
      containing liver microsomes caused the release of beta-G from microsomes to the
      medium. From these in vivo and in vitro data, it is concluded that increase of
      the plasma beta-G level after OP administration is much more sensitive biomarker
      than cholinesterase inhibition to acute intoxication of OPs and carbamates.

PMID- 10421486
TI  - Dimethylphosphorus metabolites in serum and urine of persons poisoned by
      malathion or thiometon.
AB  - The urinary excretion rates of dimethyl-phosphate, -phosphorothioate and 
      phosphorodithioate were studied in six persons of whom four had ingested a
      concentrated solution of malathion and two of thiometon. The concentration
      decrease of single and total dimethylphosphorus metabolites was biphased, with a
      fast initial rate and a slow later rate. The excretion rate of total metabolites
      in the faster phase depended on the initial concentration in urine. At
      concentrations higher than 100 nmol/mg creatinine, the excretion half-times
      ranged from 7.5 to 15.4 h and at concentrations between 52 and 95 nmol/mg
      creatinine from 34.7 to 55.4 h. Non-metabolized malathion was detected only in
      one urine sample collected from one person immediately after hospitalization. Two
      persons poisoned with malathion were taken blood serum samples for the analysis
      of the parent pesticide and its metabolites on a daily basis after
      hospitalization. The parent pesticide was detectable in the serum only one day
      after the poisoning. The concentration of total malathion dimethylphosphorus
      metabolites in serum decreased very quickly within 1.5 days after
      hospitalization. The total metabolite elimination half-times were 4.1 and 4.7 h
      in the initial phase, and 53.3 and 69.3 days in the later slower elimination
      phase. There was no correlation between maximum concentrations of total
      metabolites measured in serum and/or urine on the day of admission to hospital
      and the initial depression of serum cholinesterase (BChE, EC 3.1.1.8) and
      erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7).

PMID- 10421487
TI  - Intravenous paraoxon (POX) exposure: coagulation studies in mini pigs.
AB  - The in vivo effects of the organophosphorus compound (OPC) paraoxon (POX) on
      blood coagulation of mini pigs were assessed by measuring the partial
      thromboplastin time (PTT), prothrombin time (PT), fibrinogen, factor V, factor
      VII, factor VIII, antithrombin III, protein C, and platelet count. The mini pigs
      were randomly assigned to a POX-treatment group (n = 9) receiving 54 mg POX kg(
      1) BW(-1) or the control group (n = 9). Measurements were carried out over a
      period of 150 min after poisoning. The exposure to POX did not have any influence
      on measurements of PT, factor VIII, factor VII, factor V, antithrombin III,
      protein C, or fibrinogen compared to the control group evaluated by rank order
      test (ROT) during the time of observation (150 min). Changes seen in the
      intrinsic coagulation followed a biphasic pattern corresponding to an early
      sympathomimetic phase with PTT-shortening and a decrease of the platelet count,
      and a late vagal phase, with PTT-prolongation. The hypercoagulability seen in the
      sympathomimetic phase is probably due to a massive release of catecholamines from
      the adrenals. Previous studies showed in vitro no coagulation activating effect
      of POX. The hypocoagulability in the vagal phase shown by the PTT-protongation is
      probably due to POX influencing platelet function or its inhibition of clotting
      factors, which are serine proteases, or a combination of the two.

PMID- 10421488
TI  - Phospholipase A2 (PLA2) activity in mini pigs after acute high dose i.v.-paraoxon
      (POX) intoxication.
AB  - The purpose of the present study was to establish in the mini pig model the
      effects of paraoxon (POX) on PLA2 activity. Six anesthetized and mechanically
      ventilated mini pigs were infused over 50 min with 0.3, 1, 3, 9, 27 and 81 mg POX
      kg(-1) BW(-1) dissolved in ethanol, respectively. The control animal received no
      POX but the ethanol amount corresponding to the highest POX dose. PLA2 activity
      measurements were carried out immediately after POX application. Data were
      analysed with the Mann Whitney-Wilcoxon rank order test. Statistical significance
      was assumed for P < or = 0.05. Exposure to POX inhibited PLA2 activity to 50.5 +/
      8.9% of baseline activity. The changes seen were not dose-dependent. The dose
      dependency previously demonstrated in vitro was not reproducible in vivo. This is
      most probably due to the massive endogenous catecholamine release leading to PLA2
      activation. An additional masking effect is due to the (co)administration of
      drugs needed for anesthesia and cardiovascular support, especially Mg2+. These
      substances also influence the PLA2 activity.

PMID- 10421489
TI  - Novel protein targets for organophosphorus compounds.
AB  - Inhibition of tritiated di-isopropyl phosphorofluoridate labelling by a range of
      organophopshorus compounds was used to screen for novel OP-reactive targets in
      rat-brain homogenates. Analysis of target proteins was conducted by SDS/PAGE and
      detection of tritiated proteins using a thin layer chromatography (TLC) linear
      analyser. Two major sites of 3H-DFP labelling were found with relative molecular
      masses of 30 and 85 kDa. Rates of reaction of these labelling sites with a range
      of OP compounds were compared to that of acetylcholinesterase. The 30 kDa band
      was found to be more sensitive to paraoxon, dichlorvos and diazoxon than
      acetylcholinesterase. The 85 kDa band was found to be more sensitive to
      dichlorvos and diazoxon than acetylcholinesterase. Neither labelling band reacted
      with chlorfenvinphos or demeton-s-methyl at significant rates.

PMID- 10421490
TI  - Molecular cloning of neuropathy target esterase (NTE).
AB  - Covalent modification of NTE, a neuronal protein with serine esterase activity,
      by certain organophosphates (OP) initiates degeneration of long axons in the
      peripheral and central nervous system. Simple inhibition of NTE esterase activity
      does not initiate neuropathy; the latter requires aging of the OP bound to the
      catalytic serine residue so that a negatively-charged species is left attached to
      the active site. This may indicate that a non-esterase function of NTE is
      important for axonal maintenance. We have recently cloned NTE and shown that it
      is unrelated to any known serine hydrolases but contains a novel C-terminal
      domain which is conserved from bacteria to man. Furthermore, the catalytic serine
      is located within this domain at the centre of a helical hydrophobic segment of
      the polypeptide's secondary structure. The integrity of NTE would be severely
      compromised by the presence of a negatively-charged organophosphate moiety at
      this site. Implications for possible higher-order structures and functions for
      NTE are discussed.

PMID- 10421491
TI  - Promotion of organophosphate induced delayed polyneuropathy by certain esterase
      inhibitors.
AB  - Certain esterase inhibitors elicit or intensify the clinical expression of
      various insults to axons. This phenomenon was called promotion of axonopathies
      because these chemicals are not additive neurotoxicants nor do they interfere
      with the pharmacokinetics. Characterization of promotion was carried out by using
      organophosphate induced delayed polyneuropathy (OPIDP) as a model. The search for
      a physiological explanation of promotion has the following background: (1)
      Promotion expresses clinically the biochemical lesions which are otherwise well
      compensated (such as 30/40% neuropathy target esterase (NTE) inhibition by
      neuropathic organophosphates). (2) Promotion is not specific because axonopathies
      of different origin are affected. (3) Promoters are effective when given several
      days before the neuropathic insult. (4) Promotion is less effective in young
      animals as compared with adults. (5) Promotion occurs when axons, but not
      necessarily the cell body, are targeted by promoters. (6) Repeated dosing with a
      promoter failed to produce axonopathy. Based on this evidence it is suggested
      that promotion might interfere with a mechanism(s) of compensation and/or repair
      of long axons. The target of promotion of axonopathies is thought to be similar
      or linked to NTE which is defined as the phenyl valerate esterase activity (PVE)
      in nervous tissues resistant to paraoxon and sensitive to mipafox (40 and 50
      microM, pH 8.0, 20 min, respectively). Mipafox (50 microM) resistant PVEs include
      some activity sensitive to the promoter phenylmethane sulfonylfluoride (PMSF) but
      no correlation was found between its inhibition and promotion. A complete
      titration curve of paraoxon-resistant PVEs by mipafox (0-1 mM) dissected, besides
      NTE (I50 about 10 microM), another PVE with an I50 of approximately 200 microM.
      This enzyme was present in hen brain, spinal cord and peripheral nerve,
      corresponding to about 10, 20 and 30% of NTE activity, respectively, and was
      sensitive both in vitro and in vivo to promoters and much less so to neuropathic
      NTE inhibitors. By means of chromatography, other workers have identified in
      soluble extracts of peripheral nerves two forms of mipafox-sensitive PVEs with
      different molecular weights and different sensitivity to mipafox. These might
      correspond to NTE and to the other enzyme. Inhibition in vivo of the latter also
      correlated with promotion.

PMID- 10421492
TI  - NTE soluble isoforms: new perspectives for targets of neuropathy inducers and
      promoters.
AB  - Neural carboxylesterases can be discriminated by differential inhibition assays
      with organophosphorus compounds (OPs), paraoxon (O,O'-diethyl p-nitrophenyl
      phosphate) and mipafox (N,N'-diisopropyl phosphorodiamidofluoridate) being the
      ones used to discriminate esterases that should be either irrelevant or
      candidates as targets of the mechanism of induction of the organophosphorus
      induced delayed polyneuropathy (OPIDP). The brain membrane-bound phenyl valerate
      esterase (PVase) defined by Dr Johnson in 1969 as neuropathy target esterase
      (NTE) and recently cloned by Dr Glynn and coworkers is termed here as particulate
      NTE due to its association to the membrane particulate fraction. It is considered
      as the target of OPIDP and is the activity measured in standard NTE assays and
      toxicity tests. Following the same operational criteria in the soluble fraction
      of sciatic nerve a paraoxon-resistant but mipafox-sensitive PVase activity was
      described and termed as S-NTE, with an apparent lower sensitivity to some
      inhibitors than particulate NTE. Two isoforms (S-NTE1 and S-NTE2) were
      subsequently separated by gel filtration chromatography. In a partly purified S
      NTE2 preparation polypeptides were identified in western blots by labelling with
      S9B [1-(saligenin cyclic phospho)-9-biotinyldiaminononane], the same biotinylated
      OP used to label and isolate particulate NTE, but not with anti-particulate NTE
      antibodies. From sequential inhibition protocols, inhibitor washing-out and time
      course inhibition studies it is deduced that reversibility of inhibition is a new
      factor introducing a higher complexity in the identification of the esterases
      that could be candidates as targets of the mechanisms of induction and/or
      promotion of neuropathy. We have evidences that in sciatic nerve soluble fraction
      a high proportion (about 70%) of the activity that is inhibited by paraoxon in
      the usual concurrent assay is quickly reactivated after removing paraoxon and it
      is permanently inhibited by mipafox. Under this improved sequential
      paraoxon/mipafox inhibition procedure S-NTE represents about 50% of total PVases
      while in the usual concurrent assay it was only apparently about 1-2%. Moreover
      with such criteria, S-NTE2 isoform(s) represents about 97-99% of total S-NTE, and
      S-NTE1 is only a marginal amount probably resulting of a partial solubilization
      from particulate NTE. Fixed time inhibiton curves with variable mipafox
      concentration failed to discriminate more than one component. However kinetic
      behaviour of the time progressive inhibition cannot be explained by a simple
      model with a single exponential mathematical component, indicating that either
      the possibility of more than one component or a more complex mechanistic model
      should be considered. Consequently both particulate NTE and S-NTE assay protocols
      and their role in induction and promotion of neuropathies will need to be
      reviewed. Data published by Drs Lotti, Moretto and coworkers suggest that
      particulate NTE cannot be the target of promotion of axonopathies. The proposal
      that S-NTE2 could be such a target is suggestive and under collaborative
      biochemical and toxicological studies.

PMID- 10421493
TI  - Peripheral nerve soluble esterases are spontaneously reactivated after inhibition
      by paraoxon: implications for a new definition of neuropathy target esterase.
AB  - Soluble extracts of chicken peripheral nerve contain detectable amounts of phenyl
      valerate esterase (PVase) activity (about 2000 nmol/min per g of fresh tissue).
      More than 95% of this activity is inhibited in assays where substrate has been
      added to a preincubated mixture of tissue with the non-neuropathic
      organophosphorus compound (OP) paraoxon (O,O'-diethyl p-nitrophenyl phosphate):
      residual activity includes soluble neuropathy target esterase (S-NTE) which, by
      definition, is considered resistant to long-term progressive (covalent)
      inhibition by paraoxon. However we have previously shown that paraoxon strongly
      interacts with S-NTE so interfering with its sensitivity to other inhibitors. We
      now show that, surprisingly, removal of paraoxon by ultrafiltration ('P' tissue)
      in order to avoid such an interference results in the reappearance of about 65%
      of total original soluble PVase activity which is inhibited in the presence of
      this OP. Although a purely reversible non-progressive inhibition might be
      suspected, kinetic analysis data show a time-progressive inhibition which
      suggests that such PVase(s) covalently bind paraoxon. Also a time-dependent
      recovery due to spontaneous reactivation of the PVase activity was observed after
      dilution of the inhibitor. Gel filtration chromatography of 'P' tissue in
      Sephacryl S-300 shows that the reactivated activity is associated with proteins
      of about 100-kDa mass which include S-NTE and an, as yet, unknown number of other
      PVases. The implications of these findings in the definition of NTE in a target
      tissue for the so-called organophosphorus-induced delayed polyneuropathy (OPIDP)
      are discussed.

PMID- 10421494
TI  - A stable preparation of hen brain neuropathy target esterase for rapid
      biochemical assessment of neurotoxic potential of organophosphates.
AB  - Neuropathy target esterase (NTE) is a molecular target for organophosphate
      induced delayed neurotoxicity (OPIDN). This enzyme has proved to be an excellent
      tool for the assessment of neuropathic potential of organophosphates (OP), in
      particular by comparison of an OP inhibitory activity in vitro against NTE and
      acetylcholinesterase. A large-scale OP screening for delayed neurotoxicity was
      largely prevented by the lack of an available stable preparation of NTE. To
      obtain a stable NTE preparation the influence of intensive freezing and
      subsequent lyophilization of paraoxon-preinhibited (P2 + P3) hen brain membrane
      fraction on NTE properties has been studied using two neuropathic OP: mipafox and
      O,O-dipropyldichlorovinyl phosphate (PrDChVP). It was shown that lyophilization
      preserved a high NTE specific activity and did not alter the inhibitor
      characteristics of the enzyme. A long-term storage study showed that lyophilized
      NTE preparation exhibited inhibitory features actually identical to those of the
      native enzyme during 1 year and retained rather high specific activity; in this
      case some loss of NTE specific activity has been observed. Comparative studies of
      inhibition of the native and lyophilized NTE preparations by a model series of
      phenyl phosphonates RO(C6H5)P(O)ON=CClCH3 (R = alkyl), demonstrated a good
      correlation between the values pI50 obtained with both enzyme preparations as
      well as identical structure-activity relationships for the lyophilized and native
      enzymes. The results allow the conclusion that the obtained NTE preparation can
      be used as a standard, stable and readily available source of NTE for assessing
      the anti-NTE activity of OP.

PMID- 10421495
TI  - A new approach for determination of neuropathy target esterase activity.
AB  - Neuropathy target esterase (NTE) was shown to be an excellent biochemical marker
      for screening of organophosphates (OPs) with respect to their ability to result
      in organophosphate induced delayed neurotoxicity (OPIDN). This paper describes a
      new biosensor approach to the analysis of NTE and its inhibitors. The method is
      based on the combination of NTE enzymatic hydrolysis of phenyl valerate (PV) with
      phenol detection by the Clark-type oxygen electrode modified by immobilized
      tyrosinase. The validity of this biosensor method is confirmed by the facts that
      the calibration curves for NTE obtained by colorimetric and flow-through
      electrochemical methods were nearly identical and the titration of NTE by test
      inhibitor mipafox was shown to yield the same pI50 values. The developed
      electrochemical methods can be considered as a promising approach both for serial
      express NTE analysis and for kinetic characteristics of NTE.

PMID- 10421496
TI  - Kinetic parameters of cholinesterase interactions with organophosphates:
      retrieval and comparison tools available through ESTHER database: ESTerases,
      alpha/beta Hydrolase Enzymes and Relatives.
AB  - Cholinesterases are targets for organophosphorus compounds which are used as
      insecticides, chemical warfare agents and drugs for the treatment of disease such
      as glaucoma, or parasitic infections. The widespread use of these chemicals
      explains the growing of this area of research and the ever increasing number of
      sequences, structures, or biochemical data available. Future advances will depend
      upon effective management of existing information as well as upon creation of new
      knowledge. The ESTHER database goal is to facilitate retrieval and comparison of
      data about structure and function of proteins presenting the alpha/beta hydrolase
      fold. Protein engineering and in vitro production of enzymes allow direct
      comparison of biochemical parameters. Kinetic parameters of enzymatic reactions
      are now included in the database. These parameters can be searched and compared
      with a table construction tool. ESTHER can be reached through internet
      (http://www.ensam.inra.fr/cholinesterase). The full database or the specialised X
      window Client-server system can be downloaded from our ftp server
      (ftp://ftp.toulouse.inra.fr./pub/esther). Forms can be used to send updates or
      corrections directly from the web.

PMID- 10421497
TI  - Estimation of inhibitory organophosphates with purified pig liver
      carboxylesterase.
AB  - Organophosphates that inhibit acetylcholinesterase normally also inhibit pig
      liver carboxylesterase irreversibly. Since this liver esterase is well
      characterized and easily accessible in large amounts, we propose the use of this
      enzyme for the quantitation of low concentrations of such organophosphates. The
      principle of two estimation methods is described. Both methods involve the
      addition of an unknown amount of organophosphate to an assay mixture of purified
      esterase, buffer and a low affinity esterase substrate. In the first of these
      methods, the inhibitor concentration is calculated from the esterase activities
      before and after the addition of the inhibitor. In the second method, the amounts
      of inhibitor or of enzyme are changed in several assays, until equimolar
      conditions can be detected from the observed reaction kinetics. The theoretical
      background of these methods is discussed and practical examples for the
      estimation of paraoxon (order of 0.1 nmoles) are given.

PMID- 10421498
TI  - Isoesterases related to cell differentiation in plant tissue culture.
AB  - Normal, habituated and transformed in vitro tissue lines of sugar beet (Beta
      vulgaris L.), horseradish (Armoracia lapathifolia Gilib.) and potato (Solanum
      tuberosum L.) were studied with regard to isoesterase patterns. Isoenzymes were
      separated in gradient gels (5-12%) of polyacrylamide and by isoelectric focussing
      in pH range 4-9. 1- and 2-naphtylacetate were used as substrates of broad
      spectrum which cover also esterases (arylesterases and carboxylesterases)
      reacting with organophosphorous compounds. Distinct isoesterase patterns were
      noticed in sugar beet normal, habituated and crown gall tumour tissues.
      Horseradish tumour and teratoma, on the contrary, differed only in one anodic
      isoenzyme. Even the malformed shoots and unorganised tissue of teratoma had the
      same patterns. In potato tuber tissue, change in isoesterase pattern,
      characterised by disappearance of a dominant dark area, was observed during
      tumour development. The gradient gels gave more stable and reproducible isoenzyme
      patterns than isoelectric focussing.

PMID- 10421499
TI  - Molecular biological characterization of phosphodiesterase 3A from human corpus
      cavernosum.
AB  - The hydrolysis of the second messenger cyclic AMP (cAMP) by phosphodiesterase 3
      (PDE3) is known to play an important regulatory role in the context of relaxation
      of cavernous smooth muscle of the penis. Thus, we investigated the PDE3A isoform
      from penile cavernous tissues of male patients with and without symptoms of
      erectile dysfunction at the molecular biological level. As revealed by reverse
      transcriptase polymerase chain reaction, of all tissues of the urogenital tract
      analyzed the expression of the PDE3A gene was highest in the corpus cavernosum.
      However, significant differences in the levels of gene expression were not found
      between the two subgroups of patients. Also, the determined nucleotide sequences
      of the cloned penile PDE3A cDNAs of all patients were absolutely identical.
      Surprisingly, some deviations could be detected in the cDNA sequences of PDE3A
      from human myocard and platelets. The data obtained indicate that neither the
      expression levels nor the sequence deviations of PDE3A are the main reasons for
      erectile dysfunction in men.

PMID- 10421500
TI  - Recommended nomenclature system for the paraoxonases.

PMID- 10421501
TI  - Breast cancer and organochlorines: a marker for susceptibility?
AB  - The incidence of breast cancer is increasing and despite extensive research
      efforts, the etiology of this disease is largely unknown. Most women exhibit no
      known risk factors except for their age and sex. It has recently been postulated
      that the increased breast cancer incidence might be attributed to exposure to
      environmental carcinogens such as the organochlorine compounds. In this article,
      the scientific literature with respect to this possibility is reviewed and
      alternative hypotheses, which may in part explain the possible role of
      organochlorine compounds in the etiology of breast cancer, are presented.

PMID- 10421502
TI  - Malignant pleural mesothelioma: a problematic review.
AB  - Malignant pleural mesothelioma is a rare tumor that has been difficult to study.
      Because of disappointing treatment results, malignant pleural mesothelioma has
      remained an area of active research and development. A clinicopathologic review
      is performed in light of several problematic issues involving diagnosis, staging,
      natural history, and treatment. Multimodality treatment with surgery followed by
      adjuvant local and systemic therapy remains the most optimal therapy. Many
      controversial issues still exist in the treatment of malignant pleural
      mesothelioma. In the ensuing years newer staging systems, better preoperative
      staging, newer experimental therapies, and the localization of patients at expert
      centers will undoubtedly have an impact on disease management.

PMID- 10421503
TI  - Reconstructive rectal surgery.
AB  - Rectal cancer causes approximately 6000 deaths in the UK each year. The role of
      the surgeon in rectal cancer is to control local disease and minimise the risk of
      recurrence. Reconstructive rectal surgery for cancer aims to combine a safe
      oncological procedure with the maximum quality of life possible. An improved
      understanding of rectal cancer pathology allied to modern surgical techniques
      such as intestinal stapling guns, endoanal anastomoses and the colonic pouch has
      led to an increased number of sphincter saving operations being performed. We
      have reviewed the background, technical advances and looked at the future of
      reconstructive rectal surgery for rectal cancer. Firstly we discuss the work
      which led to low anterior resection being accepted as an oncologically safe
      operation. followed by an overview of surgical techniques that have facilitated
      low anterior resection for rectal cancer with good functional results for the
      patient. Lastly, we look at the role of radiotherapy and the neosphincter in
      reducing the need for a permanent stoma.

PMID- 10421504
TI  - Staging and surgery for non-small cell lung cancer (NSCLC).
AB  - Despite current advances in diagnosis, staging, and treatment, carcinoma of the
      lung remains the leading cause of death from cancer in both men and women. Non
      small cell lung cancer represents approximately 80% of all new lung cancer cases;
      however, only one-third of these cases will undergo surgical resection for tumor
      control. This article reviews the evaluation, latest revisions in staging, and
      surgical management of non-small cell lung cancer.

PMID- 10421505
TI  - Carcinoma of the breast during pregnancy: a review and update on treatment
      options.
AB  - Gestational breast cancer is occurring with increasing incidence because more
      women are delaying childbirth into their thirties and forties. Although breast
      cancer during pregnancy or within the first year postpartum is occurring more
      often, there is still some confusion regarding its treatment. Although breast
      conservation therapy has evolved as the major treatment in breast cancer, it has
      been thought that pregnancy was a contraindication for this type of breast cancer
      therapy due to risks imposed on the fetus by chemotherapy and radiation. However,
      recent studies have shown that the use of chemotherapeutics during the second and
      third trimesters is possible. Also, if chemotherapy is initiated after a
      lumpectomy, radiation can be withheld until after the birth of the baby when the
      cancer is detected in the second or third trimester.

PMID- 10421507
TI  - Isolated lung perfusion for the treatment of pulmonary metastases.
AB  - Today, pulmonary metastasectomy is the treatment of choice for many patients with
      lung metastases from various solid tumors. Prognostic factors for a better
      survival are patients with germ cell tumors, long disease-free intervals and
      single metastases. Nevertheless, 5-year survival after surgical resection is low
      due to relative insensitivity to currently available chemotherapy. Isolated lung
      perfusion as a regional therapy proved to be a technique that can deliver a
      higher drug level within the tumor mass without apparent systemic toxicity. In
      addition, isolated lung perfusion in animal models proved to be more effective
      compared to intravenous therapy. In this way, isolated lung perfusion seems very
      promising although optimal regimens in patients are still unknown.

PMID- 10421506
TI  - Lymphatic mapping and sentinel lymph node biopsy in the staging of melanoma.
AB  - In recent months, we have witnessed a 'paradigm shift' in the management of
      intermediate-thickness melanoma. The collective experience of the recent past
      confirms the validity of the 'sentinel' lymph node as being the initial draining
      site from a specific area of skin. Furthermore, the sentinel lymph node has been
      confirmed as the most likely site in the regional lymph node basin to harbor
      occult metastatic disease. Identification of sentinel lymph nodes by visual
      inspection and intraoperative gamma probe detection after the peritumoral
      injection of Lymphazurin blue dye and technetium sulfur colloid is a reliable new
      technique. Staging accuracy also has improved, allowing the precise
      identification of patients who benefit from avoiding the morbidity of radical
      lymphadenectomy. The importance of accurate staging has been heightened by data
      demonstrating effective adjuvant therapy with recombinant interferon-alpha 2B.
      Precisely defining patient subsets who benefit from adjuvant high-dose interferon
      alpha 2B is the current focus of clinical trials designed to maximize the
      enhanced staging accuracy of the novel approach of sentinel lymph node biopsy.

PMID- 10421508
TI  - Reconstruction following total gastrectomy: a review and summary of the
      randomized prospective clinical trials.
AB  - Reconstruction of gastrointestinal tract continuity following total gastrectomy
      can be achieved using a variety of operations. Worldwide, Roux-en-Y esophago
      jejunostomy with or without a pouch reservoir, is the most frequently performed
      operation after total gastrectomy. Others have advocated the preservation of the
      duodenal food passage, employing an interposed segment of bowel between the
      esophageal remnant and duodenum as a more physiologic operation. Several methods
      for either approach are described. In recent years, six randomized prospective
      clinical trials assessing various operations for gastrointestinal reconstruction
      have been reported. While there is a general consensus for the indications and
      patient selection criteria in order to proceed with total gastrectomy, a defined
      optimal procedure has not been clearly established. In the present work, these
      recent clinical studies addressing gastrointestinal reconstruction following
      total gastrectomy are reviewed and summarized.

PMID- 10421509
TI  - Prognostic factors: guidelines for investigation design and state of the art
      analytical methods.
AB  - The proliferation of putative prognostic factors, derived prognostic indices and
      computerised prediction of outcome in surgical oncology has led to some confusion
      over the exact methods available for deriving clinically significant prognostic
      factors. The realisation that the interaction between factors is often complex
      and non-linear has led to the development of new statistical techniques. The aim
      of this article is to review the currently available methods of analysis. A
      review of the relevant literature available from statistical, medical and
      computer science sources was performed. Information has been conveyed at a level
      aimed at producing a practical understanding of the techniques involved rather
      than their underlying mathematical basis. There are now clear guidelines for the
      investigation of putative prognostic factors (Table 1). The established role of
      linear statistical models and prognostic indices remains vitally important for
      the majority of diseases with many derived prognostic indices having been
      validated in a prospective fashion. However, in order to improve the delineation
      of prognostic factors other more complex methods of analysis are now being
      utilised. Furthermore, the recognition of complex dynamic non-linearity within
      biological systems has led to the increasing use of non-linear statistical
      techniques and artificial intelligence. As such it is incumbent upon the modern
      clinician to be able to understand the basic assumptions required for
      multivariate analysis and also to realise when alternative statistical techniques
      should be employed.

PMID- 10421510
TI  - Retroperitoneal sarcoma--the continued challenge for surgery and oncology.
AB  - Retroperitoneal sarcomas (RS) are rare malignant tumours with an incidence rate
      of about 1-2 cases per million per year. Therefore only a few centres are able to
      acquire more experience in this field. Tumours are usually of large size, due to
      slow growth and uncommon symptoms. Different histologic types, grades and rare
      incidence make any comparison difficult. Radical excision including adjacent
      organs, called "en-block" resection, is the treatment of choice, however it is
      very often difficult to obtain adequate free margins around the tumour. Complete
      tumour excision remains a challenge even for an experienced surgeon. In the
      published series, resectability ranges from 38 to 100% with radicality rate
      between 8 and 95%. Local recurrence is very common (33-86%), with rare distant
      metastases (max. 33%), so local failure is usually the cause of death. It is well
      known that histological grading and completeness of surgery determine the chance
      of survival. Five-year survival rates after radical excision ranged from 62-92%
      in well-differentiated tumours, compared with 16-48% in nondifferentiated
      sarcomas. There is no evidence that adjuvant or neoadjuvant treatment affects the
      prognosis. Only the development of an international registry of retroperitoneal
      sarcoma and co-operative intergroup studies can help in evaluating treatment and
      in applying innovative multimodal therapies to these neoplasms.

PMID- 10421511
TI  - The treatment of malignancy by hyperthermia.
AB  - The use of hyperthermia for the selective destruction of tumours may be applied
      by a whole body, surgical perfusion or interstitial techniques. The main
      determinant of selectivity is tumour blood flow. The effects of hyperthermia may
      be augmented by step-down heating, manipulating pH changes and sensitisation by
      chemotherapy or specific pharmacological agents.

PMID- 10421513
TI  - Andreas Vesalius (1514-1567).

PMID- 10421512
TI  - Conservative neck surgery in squamous cell carcinoma.
AB  - Squamous cell carcinoma of the upper aerodigestive tract metastasises to lymph
      nodes in the upper-deep cervical group. Control of these metastases is the single
      most important prognostic factor in the management of this disease.
      Traditionally, surgical control was achieved by the radical neck dissection, a
      mutilating procedure with significant morbidity. Contemporary research has led to
      an improved understanding of the patterns of nodal metastases. This has led to
      the evolution of more conservative techniques that still produce comparable
      results of control. This paper describes this evolutionary process, and the
      current management thinking.

PMID- 10421514
TI  - Diamond-like carbon coating and plasma or glow discharge treatment of mechanical
      heart valves.
AB  - All mechanical heart valves (MHV) are thrombogenic. Application of surface
      modification technology to reduce the incidence of thrombus formation on MHV is a
      novel undertaking. This requires collaboration within the bioengineering and
      cardiothoracic surgery fields. From reviewing results of recent and past
      investigations, and our own preliminary study with diamond-like carbon coating
      (DLC) and plasma or glow discharge treatment (GDT) of MHV, we identify and
      discuss several potentially beneficial effects that may reduce the extent of
      valve-related thrombogenesis by surface modification. DLC and GDT may affect the
      surfaces of MHV in many ways, including cleaning of organic and inorganic debris,
      generating reactive and functional groups on the surface layers without affecting
      their bulk properties, and making the surfaces more adherent to endothelial cells
      and albumin and less adherent to platelets. These different effects of surface
      modification, separately or in combination, may transform the surfaces of MHV to
      be more thromboresistant in the vascular system.

PMID- 10421515
TI  - Effect of different barriers of oxidized regenerated cellulose (ORC) on cecal and
      sidewall adhesions in the presence and absence of bleeding.
AB  - Adhesion formation after bowel surgery is a significant problem. The objective of
      this study was to evaluate two adhesion barriers composed of oxidized regenerated
      cellulose (ORC) in a model of bowel surgery, with and without bleeding. Ceca of
      female New Zealand White rabbits were abraded with gauze and a 3 x 5 cm patch of
      peritoneum and underlying muscle was excised from the right sidewall. Animals
      were randomized to receive no treatment, INTERCEED Barrier (Ethicon, Inc.), or
      neutralized INTERCEED (nTC7). ORC fabrics were applied to the excision site.
      Seven days later the percentage of the site and length of cecum with adhesions
      were estimated. The study was replicated in the presence of blood by nicking
      small vessels near the site sufficient to saturate the fabrics with blood. With
      hemostasis, the percentage of the sidewall with adhesions was reduced (p < .01)
      from 63.2 +/- 14.7% in controls (n = 6) to 4 +/- 2.7% with INTERCEED Barrier (n =
      6) and 3 +/- 1.2% (n = 5) with nTC7. With bleeding, however, control (n = 5)
      levels of adhesions (67 +/- 17.5%) were reduced significantly with nTC7 (5.5 +/-
      4%, n = 4; p < .01), but not INTERCEED Barrier (34.2 +/- 18.4%, n = 4). Similar
      trends were observed when the extent of adherent cecum was examined, since the
      cecum was the main site of adherence to the sidewall. However in the presence of
      blood, there was no effect of INTERCEED Barrier on cecal adhesions. We conclude
      that with hemostasis, both absorbable fabrics of ORC reduced adhesion formation
      between the injured cecum and abdominal sidewall. The effectiveness of INTERCEED
      Barrier, but not nTC7, was reduced but not eliminated in the presence of
      bleeding. This confirms similar observations in models of gynecologic surgery.

PMID- 10421516
TI  - Postsurgical adhesion formation in germfree and ex-germfree rats--a study using
      three scoring scales.
AB  - Postsurgical adhesions occur commonly after surgical procedures and are the
      source of substantial postoperative morbidity. No preventive or prophylactic
      regimen against adhesions has proven successful in all circumstances. The reasons
      for this are not clear. The basic mechanisms causing adhesion formation have not
      been elucidated fully, and furthermore, lack of accurate methods of measuring
      adhesions may be a contributing factor. Postoperative adhesions may occur in all
      kinds of surgery but are especially prominent in the abdomen, where the bowel
      flora may be a compromising factor. This study was undertaken to study the
      influence of the gastrointestinal microflora on adhesion formation. Germfree and
      ex-germfree DA rats were subjected to a cecal crush model, and adhesions were
      evaluated after 7 days using 3 different scoring scales. Germfree rats formed
      significantly fewer adhesions than their ex-germfree (conventionalized)
      counterparts. The differences were so great that all three scoring scales
      achieved significance (p < .005). This study corroborates that the endogenous
      bowel flora per se is involved in adhesion formation without causing frank
      infection.

PMID- 10421517
TI  - Detection of perivenous inflammation in a rat model of venous thrombosis using
      MRV.
AB  - Venous thrombosis is associated with a significant inflammatory response in the
      vein wall, which can be imaged noninvasively with gadolinium (Gd)-enhanced
      magnetic resonance venography (MRV). Interleukin-10 (IL-10), a naturally
      occurring anti-inflammatory cytokine, has been found to decrease the inflammatory
      response at the proper dosage and timing of administration. The present study
      determines if MRV with Gd is useful in a rat model of stasis-induced venous
      thrombosis to document the anti-inflammatory effects of rIL-10. Rats underwent
      laparotomy and ligation of the inferior vena cava (IVC). Animals were infused
      with rIL-10 at 2.5 microg (n = 6), rIL-10 at 10 microg (n = 6), or rIL-10 at 40
      microg (n = 6). Six animals without IVC ligation or drug infusion served as
      controls. Two days after thrombosis induction, the rats underwent MRV with both
      time-of-flight imaging and pre/post-Gd T1-weighted imaging. Inflammation was
      analyzed by measuring the area of Gd enhancement at the point of IVC thrombosis.
      Enhancement area was also measured in the distal IVC where flow persisted. All
      animals with IVC ligation developed thrombosis, and all control rats were free of
      thrombus. In areas where flow remained, the area of enhancement was 1.8 +/- 0.4
      mm2, while controls demonstrated 3.8 +/- 1.0 mm2 enhancement. Enhancement was
      significantly greater in all groups at the level of thrombus compared to the area
      of distal IVC flow and control IVCs (p < .001). Animals receiving rIL-10 at 40
      microg revealed the most enhancement, 32.7 +/- 6.2 mm2, while the least
      enhancement was noted with 2.5 microg, 14.7 +/- 1.5 mm2 (p < .05). In conclusion,
      Gd-enhanced MRV was found useful in this rat model of stasis-induced venous
      thrombosis to document inflammation noninvasively and to evaluate the effects of
      anti-inflammatory interventions during stasis-induced IVC venous thrombosis.

PMID- 10421518
TI  - Videoendoscopy: an effective and efficient way to perform multiple visceral
      biopsies in small animals.
AB  - Because major surgery is usually required to obtain biopsies of abdominal organs,
      regulations tend to limit the number of procedures on individual animals to one.
      This study was conducted to develop a more humane, minor, comparatively cost
      effective, minimally invasive surgical procedure, which reduces surgical trauma
      and the number of animals used. Biopsy techniques were developed in two
      nonsurvival rabbit surgeries. Safety and efficacy of multiple procedures were
      assessed in survival studies on four rabbits. Anesthesia was induced with
      ketamine/xylazine and maintained with isoflurane. Initial carbon dioxide
      insufflation (6 mmHg) was achieved through a Veress needle. A triangulated 5-mm
      port technique allowed introduction of pediatric 3.5- to 5.0-mm laparoscopic
      instruments. Biopsies of liver, spleen, kidney, and full-thickness bowel were
      obtained and evaluated for suitability (size) for polymerase chain reaction, in
      situ hybridization, and histopathology studies. Animals in survival studies were
      assessed for infection, pain, bleeding, adhesion development, bowel function, and
      intestinal stenosis. All had normal appetite and stools within 48 h
      postoperatively. Biopsies obtained from either a Tru-Cut Biopsy Needle, 3.5- to
      5.0-mm biopsy cups, or with the aid ofa pre-tied loop were adequate for all
      studies. There was no postoperative bowel obstruction, wound infection, or
      bleeding. Mean hematocrit decrease at 24 h postoperative was 3.4% +/- 6.7%.
      Adhesions formed at 9/52 (17%) evaluable sites. Multiple visceral organ biopsy
      under videoendoscopic guidance constitutes a minor procedure and is a promising
      means for longitudinal studies in animals. Utility for ill animals remains to be
      determined.

PMID- 10421519
TI  - A new model for improved gastrectomy drainage.
AB  - Slow waves in isolated jejunal segments have been shown, in at least two studies,
      to have an increased percentage of neither prograde nor retrograde progression.
      Instead the pattern has been characterized as "nonpropagating" by Johnson and
      Sarna et al., and "chaotic" by others. We compared gastric drainage produced by a
      Roux-Y created with a single transection, with gastric drainage produced by a
      Roux-Y created in a jejunal segment isolated between two transections.
      Theoretically, this avoids the retrograde slow waves produced by a single
      transection. Ten dogs of either gender were divided into two groups of five. One
      group was given a truncal vagotomy, hemigastrectomy, and a standard Roux-Y
      drainage with a single jejunal transection; the other five were given the same
      operation with a distal jejunal transection and anastomosis 25 cm beyond the
      jejunojejunostomy (thus creating the Roux-Y in an isolated segment). In the
      approximate 50-day follow-up, 3 of 5 animals with standard preparations developed
      considerable difficulty in maintaining nutrition and developed hugely dilated
      stomachs. Animals with stomachs drained by the isolated jejunal segment Roux-Y
      had less difficulty maintaining nutrition and experienced minimal gastric
      dilatation. These findings were confirmed by upper gastrointestinal series at 2
      weeks and at autopsy. In conclusion, this study shows that gastric drainage
      following truncal vagotomy and hemigastrectomy is enhanced by a Roux-Y created in
      an isolated jejunal segment.

PMID- 10421520
TI  - Lattice simulations of aggregation funnels for protein folding.
AB  - A computer model of protein aggregation competing with productive folding is
      proposed. Our model adapts techniques from lattice Monte Carlo studies of protein
      folding to the problem of aggregation. However, rather than starting with a
      single string of residues, we allow independently folding strings to undergo
      collisions and consider their interactions in different orientations. We first
      present some background into the nature and significance of protein aggregation
      and the use of lattice Monte Carlo simulations in understanding other aspects of
      protein folding. The results of a series of simulation experiments involving
      simple versions of the model illustrate the importance of considering aggregation
      in simulations of protein folding and provide some preliminary understanding of
      the characteristics of the model. Finally, we discuss the value of the model in
      general and of our particular design decisions and experiments. We conclude that
      computer simulation techniques developed to study protein folding can provide
      insights into protein aggregation, and that a better understanding of aggregation
      may in turn provide new insights into and constraints on the more general protein
      folding problem.

PMID- 10421521
TI  - AMASS: a structured pattern matching approach to shotgun sequence assembly.
AB  - In this paper, we propose an efficient, reliable shotgun sequence assembly
      algorithm based on a fingerprinting scheme that is robust to both noise and
      repetitive sequences in the data, two primary roadblocks to effective whole
      genome shotgun sequencing. Our algorithm uses exact matches of short patterns
      randomly selected from fragment data to identify fragment overlaps, construct an
      overlap map, and deliver a consensus sequence. We show how statistical clues made
      explicit in our approach can easily be exploited to correctly assemble results
      even in the presence of extensive repetitive sequences. Our approach is both
      accurate and exceptionally fast in practice: e.g., we have correctly assembled
      the whole Mycoplasma genitalium genome (approximately 580 kbp) is roughly 8
      minutes of 64MB 200MHz Pentium Pro CPU time from real shotgun data, where most
      existing algorithms can be expected to run for several hours to a day on the same
      data. Moreover, experiments with artificially-shotgunned data prepared from real
      DNA sequences from a wide range of organisms (including human DNA) and containing
      complex repeating regions demonstrate our algorithm's robustness to input noise
      and the presence of repetitive sequences. For example, we have correctly
      assembled a 238-kbp human DNA sequence in less than 3 min of 64-MB 200-MHz
      Pentium Pro CPU time.

PMID- 10421523
TI  - New techniques for DNA sequence classification.
AB  - DNA sequence classification is the activity of determining whether or not an
      unlabeled sequence S belongs to an existing class C. This paper proposes two new
      techniques for DNA sequence classification. The first technique works by
      comparing the unlabeled sequence S with a group of active motifs discovered from
      the elements of C and by distinction with elements outside of C. The second
      technique generates and matches gapped fingerprints of S with elements of C.
      Experimental results obtained by running these algorithms on long and well
      conserved Alu sequences demonstrate the good performance of the presented methods
      compared with FASTA. When applied to less conserved and relatively short
      functional sites such as splice-junctions, a variation of the second technique
      combining fingerprinting with consensus sequence analysis gives better results
      than the current classifiers employing text compression and machine learning
      algorithms.

PMID- 10421522
TI  - An algorithmic approach to multiple complete digest mapping.
AB  - Multiple Complete Digest (MCD) mapping is a method of determining the locations
      of restriction sites along a target DNA molecule. The resulting restriction map
      has many potential applications in DNA sequencing and genetics. In this work, we
      present a heuristic algorithm for fragment identification, a key step in the
      process of constructing an MCD map. Given measurements of the restriction
      fragment sizes from one or more complete digestions of each clone in a clone
      library covering the molecule to be mapped, the algorithm identifies groups of
      restriction fragments on different clones that correspond to the same region of
      the target DNA. Once these groups are correctly determined the desired map can be
      constructed by solving a system of simple linear inequalities. We demonstrate the
      effectiveness of our algorithm on real data provided by the Genome Center at the
      University of Washington.

PMID- 10421524
TI  - Minimal-risk scoring matrices for sequence analysis.
AB  - We introduce a minimal-risk method for estimating the frequencies of amino acids
      at conserved positions in a protein family. Our method, called minimal-risk
      estimation, finds the optimal weighting between a set of observed amino acid
      counts and a set of pseudofrequencies, which represent prior information about
      the frequencies. We compute the optimal weighting by minimizing the expected
      distance between the estimated frequencies and the true population frequencies,
      measured by either a squared-error or a relative-entropy metric. Our method
      accounts for the source of the pseudofrequencies, which arise either from the
      background distribution of amino acids or from applying a substitution matrix to
      the observed data. Our frequency estimates therefore depend on the size and
      composition of the observed data as well as the source of the pseudofrequencies.
      We convert our frequency estimates into minimal-risk scoring matrices for
      sequence analysis. A large-scale cross-validation study, involving 48 variants of
      seven methods, shows that the best performing method is minimal-risk estimation
      using the squared-error metric. Our method is implemented in the package EMATRIX,
      which is available on the Internet at http://motif.stanford.edu/ematrix.

PMID- 10421525
TI  - Construction of physical maps from oligonucleotide fingerprints data.
AB  - A new algorithm for the construction of physical maps from hybridization
      fingerprints of short oligonucleotide probes has been developed. Extensive
      simulations in high-noise scenarios show that the algorithm produces an
      essentially completely correct map in over 95% of trials. Tests for the influence
      of specific experimental parameters demonstrate that the algorithm is robust to
      both false positive and false negative experimental errors. The algorithm was
      also tested in simulations using real DNA sequences of C. elegans, E. coli, S.
      cerevisiae, and H. sapiens. To overcome the non-randomness of probe frequencies
      in these sequences, probes were preselected based on sequence statistics and a
      screening process of the hybridization data was developed. With these
      modifications, the algorithm produced very encouraging results.

PMID- 10421526
TI  - Positional statistical significance in sequence alignment.
AB  - Beginning with the concept of near-optimal sequence alignments, we can assign a
      probability that each element in one sequence is paired in an alignment with each
      element in another sequence. This involves a sum over the set of all possible
      pairwise alignments. The method employs a designed hidden Markov model (HMM) and
      the rigorous forward and forward-backward algorithms of Rabiner. The approach can
      use any standard sequence-element-to-element probabilistic similarity measures
      and affine gap penalty functions. This allows the positional alignment
      statistical significance to be obtained as a function of such variables. A
      measure of the probabilistic relationship between any single sequence and a set
      of sequences can be directly obtained. In addition, the employed HMM with the
      Viterbi algorithm provides a simple link to the standard dynamic programming
      optimal alignment algorithms.

PMID- 10421527
TI  - Bayesian restoration of a hidden Markov chain with applications to DNA
      sequencing.
AB  - Hidden Markov models (HMMs) are a class of stochastic models that have proven to
      be powerful tools for the analysis of molecular sequence data. A hidden Markov
      model can be viewed as a black box that generates sequences of observations. The
      unobservable internal state of the box is stochastic and is determined by a
      finite state Markov chain. The observable output is stochastic with distribution
      determined by the state of the hidden Markov chain. We present a Bayesian
      solution to the problem of restoring the sequence of states visited by the hidden
      Markov chain from a given sequence of observed outputs. Our approach is based on
      a Monte Carlo Markov chain algorithm that allows us to draw samples from the full
      posterior distribution of the hidden Markov chain paths. The problem of
      estimating the probability of individual paths and the associated Monte Carlo
      error of these estimates is addressed. The method is illustrated by considering a
      problem of DNA sequence multiple alignment. The special structure for the hidden
      Markov model used in the sequence alignment problem is considered in detail. In
      conclusion, we discuss certain interesting aspects of biological sequence
      alignments that become accessible through the Bayesian approach to HMM
      restoration.

PMID- 10421528
TI  - Collagen vascular diseases and radiation therapy: a critical review.
AB  - PURPOSE: Although many oncologists have the impression that patients with
      collagen vascular disease tolerate radiotherapy less well than other patients,
      until now this was never described in a review article. METHODS AND RESULTS: The
      principal objective was to determine whether patients with collagen vascular
      diseases have a greater risk of severe radiation therapy complications, than
      those without a collagen vascular disease. However, most of the publications
      found on this topic are short anecdotal case reports of patients with increased
      toxicity after radiation. Consequently, the true incidence of these side effects
      is unknown. CONCLUSIONS: Unless further studies on this subject are reported,
      each radiation oncologist should be cautious in treating these patients.

PMID- 10421529
TI  - Sequence analysis of the ATM gene in 20 patients with RTOG grade 3 or 4 acute
      and/or late tissue radiation side effects.
AB  - PURPOSE: Patients with ataxia-telangiectasia (A-T) show greatly increased
      radiation sensitivity and cancer predisposition. Family studies imply that the
      otherwise clinically silent heterozygotes of this autosomal recessive disease run
      a 3.5 to 3.8 higher risk of developing cancer. In vitro studies suggest
      moderately increased cellular radiation sensitivity of A-T carriers. They may
      also show elevated clinical radiosensitivity. We retrospectively examined
      patients who presented with severe adverse reactions during or after standard
      radiation treatment for mutations in the gene responsible for A-T, ATM,
      considering a potential means of future identification of radiosensitive
      individuals prospectively to adjust dosage schedules. MATERIAL AND METHODS: We
      selected 20 cancer patients (breast, 11; rectum, 2; ENT, 2; bladder, 1; prostate,
      1; anus, 1; astrocytoma, 1; Hodgkins lymphoma, 1) with Grade 3 to 4 (RTOG) acute
      and/or late tissue radiation side effects by reaction severity. DNA from the
      peripheral blood of patients was isolated. All 66 exons and adjacent intron
      regions of the ATM gene were PCR-amplified and examined for mutations by a
      combination of agarose gel electrophoresis, single-stranded conformational
      polymorphism (SSCP) analysis, and exon-scanning direct sequencing. RESULTS: Only
      2 of the patients revealed altogether four heteroallelic sequence variants. The
      latter included two single-base deletions in different introns, a single-base
      change causing an amino acid substitution in an exon, and a large insertion in
      another intron. Both the single-base deletions and the single-base change
      represent known polymorphisms. The large insertion was an Alu repeat, shown not
      to give rise to altered gene product. CONCLUSIONS: Despite high technical
      efforts, no unequivocal ATM mutation was detected. Nevertheless, extension of
      similar studies to larger and differently composed cohorts of patients suffering
      severe adverse effects of radiotherapy, and application of new technologies for
      mutation detection may be worthwhile to assess the definite prevalence of
      significant ATM mutations within the group of radiotherapy patients with adverse
      reactions. To date, it must be recognized that our present results do not suggest
      that heterozygous ATM mutations are involved in clinically observed
      radiosensitivity but, rather, invoke different genetic predisposition or so far
      unknown exogenous factors.

PMID- 10421530
TI  - Consensus Statement on postmastectomy radiation therapy.

PMID- 10421532
TI  - Internal mammary nodal irradiation in conservatively-managed breast cancer
      patients: is there a benefit?
AB  - PURPOSE: Recent randomized trials have demonstrated a significant benefit to
      postmastectomy radiation in node-positive breast cancer patients. The
      contribution of internal mammary nodal radiation (IMNR) to this benefit remains
      controversial, and in conservatively-treated patients (CS + RT), may compromise
      cosmesis and contribute to morbidity. The purpose of this retrospective analysis
      is to evaluate outcome as a function of IMNR in a cohort of breast cancer
      patients treated with CS + RT. PATIENTS AND METHODS: Between January 1970 and
      December 1990, 984 patients with invasive breast cancer were treated at our
      facility with CS + RT, and serve as the base for this study. Of these patients,
      399 patients had pathologically-negative lymph nodes, 167 (17%) had
      pathologically-involved lymph nodes, and 381 did not undergo lymph node
      dissection. The majority of node-positive patients received adjuvant systemic
      therapy (94%) and were treated with tangential fields matched to a separate
      supraclavicular field (95%) with or without IMNR. For this analysis, patients
      were divided into two groups: those treated by intentionally targeting the
      internal mammary nodes (IM-yes, n = 535) and without intentionally targeting the
      internal mammary nodes (IM-no, n = 411). In the IM-no group, the medial border
      was typically placed at midline. The decision not to use a separate internal
      mammary field was a result of a change in treatment policy over time, and
      generally not based on number of nodes or tumor location. RESULTS: As of August
      1998, with a median follow-up of 13 years, the overall survival at 10 years is
      76%, the distant disease-free survival is 81%, and the breast relapse-free
      survival is 88%. There were no significant differences between the IM-yes and IM
      no groups with respect to age, ER/PR status, or use of adjuvant chemotherapy or
      hormone therapy. There were more patients with T2 tumors, positive nodes, medial
      lesions, indeterminate margins, and slightly longer follow-up in the IM-yes group
      compared to the IM-no group. Although there was a trend toward better outcome in
      the IM-no group, there were no significant differences between the IM-yes and IM
      no groups with respect to overall survival (72% IM-yes vs. 84% IM-no, p = NS) or
      distant metastasis-free survival (64% IM-yes vs. 82% IM-no, p = NS). Subset
      analysis showed no benefit in the IM-yes group regardless of age, number of
      nodes, or location. CONCLUSION: In this retrospective analysis, no benefit could
      be attributed to IMNR in conservatively-treated breast cancer patients, even if
      node-positive or medial in location. Until results of an ongoing EORTC randomized
      trial addressing this issue are available, these data suggest that it is
      acceptable to continue to treat node-positive conservatively-managed patients to
      tangential fields usually matched to a supraclavicular field, but without a
      separate internal mammary field.

PMID- 10421531
TI  - Radiotherapy following mastectomy: indication and contraindication of chest wall
      irradiation.
AB  - PURPOSE: To determine in which cases radiotherapy of the chest wall following
      mastectomy is indicated, based on the local recurrent rate in patients with
      locally advanced breast cancer. METHODS AND MATERIALS: From 1984 until 1994, 105
      patients who had four or more histopathologically confirmed axillary nodes
      metastases, or T3-4Nany, were subjected to mastectomy and were administered
      radiotherapy postoperatively using the hockey-stick field, which included the
      ipsilateral supraclavicular fossa and internal mammary nodes, except the chest
      wall. Median age was 51 years old (range, 23 to 82 years old). Eighty-five
      patients underwent radical mastectomy, 18 modified radical mastectomy, and 2
      extended radical mastectomy. Fraction size was 2 Gy/day, the weekly fraction size
      was 10 Gy and the total dose ranged from 44 Gy to 54 Gy (median 50 Gy). Seventy
      four patients were administered adjuvant chemotherapy, and 61 patients were
      administered hormone therapy. RESULTS: The 5-year disease-free survival rates of
      the whole study population were 66%. The 5-year chest wall recurrence rates were
      10%. The 5-year chest wall recurrence rates of the patients who had no vascular
      invasion (n = 19) and the patients who had definite vascular invasion (n = 38)
      were 0% and 24%, respectively (p = 0.036). All the patients who presented chest
      wall recurrence had four or more axillary nodes metastases. Nine of the 10
      patients who presented chest wall recurrence had definite vascular invasion,
      while there was no information about vascular invasion for the remaining patient.
      Factors such as age, pathological subtypes, tumor location, estrogen receptors,
      extent of resection, chemotherapy, and hormone therapy did not influence the
      development of chest wall recurrence. CONCLUSION: Among patients with breast
      cancer who have four or more positive axillary nodes or T3-4Nany, those who have
      no vascular invasion or less than 4 axillary nodes metastases do not need to be
      subjected to chest wall irradiation after radical mastectomy.

PMID- 10421533
TI  - Patients with early stage invasive cancer with close or positive margins treated
      with conservative surgery and radiation have an increased risk of breast
      recurrence that is delayed by adjuvant systemic therapy.
AB  - PURPOSE: The association between a positive resection margin and the risk of
      ipsilateral breast tumor recurrence (IBTR) after conservative surgery and
      radiation is controversial. The width of the resection margin that minimizes the
      risk of IBTR is unknown. While adjuvant systemic therapy may decrease the risk of
      an IBTR in all patients, its impact on patients with positive or close margins is
      largely unknown. This study examines the interaction between margin status,
      margin width, and adjuvant systemic therapy on the 5- and 10-year risk of IBTR
      after conservative surgery and radiation. METHODS AND MATERIALS: A series of
      1,262 patients with clinical Stage I or II breast cancer were treated by breast
      conserving surgery, axillary node dissection, and radiation between March 1979
      and December 1992. The median follow-up was 6.3 years (range 0.1-15.6). The
      median age was 55 years (range 24-89). Clinical size was T1 in 66% and T2 in 34%.
      Seventy-three percent of patients were node-negative. Only 5 % of patients had
      tumors that were EIC-positive. Forty-one percent had a single excision, and 59%
      had a reexcision. The final margins were negative in 77%, positive in 12%, and
      close (< or = 2 mm) in 11%. The median total dose to the tumor bed was 60 Gy with
      negative margins, 64 Gy with close margins, and 66 Gy with positive margins.
      Chemotherapy +/- tamoxifen was used in 28%, tamoxifen alone in 20%, and no
      adjuvant systemic therapy in 52%. RESULTS: The 5-year cumulative incidence (CI)
      of IBTR was not significantly different between patients with negative (4%),
      positive (5%), or close (7%) margins. However, by 10 years, a significant
      difference in IBTR became apparent (negative 7%, positive 12%, close 14%, p =
      0.04). There was no significant difference in IBTR when a close or positive
      margin was involved by invasive tumor or DCIS. Reexcision diminished the IBTR
      rate to 7% at 10 years if the final margin was negative; however, the highest
      risk was observed in patients with persistently positive (13%) or close (21%) (p
      = 0.02) margins. The median interval to failure was 3.7 years after no adjuvant
      systemic therapy, 5.0 years after chemotherapy +/- tamoxifen, and 6.7 years after
      tamoxifen alone. This delay to IBTR was observed in patients with close or
      positive margins, with little impact on the time to failure in patients with
      negative margins. The 5-year CI of IBTR in patients with close or positive
      margins was 1% with adjuvant systemic therapy and 13% with no adjuvant therapy.
      However, by 10 years, the CI of IBTR was similar (18% vs. 14%) due to more late
      failures in the patients who received adjuvant systemic therapy. CONCLUSION: A
      negative margin (> 2 mm) identifies patients with a very low risk of IBTR (7% at
      10 years) after conservative surgery and radiation. Patients with a close margin
      (< or = 2 mm) are at an equal or greater risk of IBTR as with a positive margin,
      especially following a reexcision. A margin involved by DCIS or invasive tumor
      has the same increased risk of IBTR. A reexcision of an initially close or
      positive margin that results in a negative final margin reduces the risk of IBTR
      to that of an initially negative margin. A close or positive margin is associated
      with an increased risk of IBTR even in patients who are EIC-negative or receiving
      higher boost doses of radiation. The median time to IBTR is delayed; however, the
      CI is not significantly decreased by adjuvant systemic therapy in patients with
      close or positive margins-the 5 year results in these patients underestimate
      their ultimate risk of recurrence.

PMID- 10421534
TI  - Variability of the location of internal mammary vessels and glandular breast
      tissue in breast cancer patients undergoing routine CT-based treatment planning.
AB  - PURPOSE: To determine the variability of position of internal mammary vessels
      (IMV) and glandular breast tissue (GBT) in patients undergoing breast-conserving
      radiation therapy. To assess the frequency and magnitude of tangential field
      border shifts based on preradiation therapy (RT) computed tomography (CT) imaging
      in breast cancer patients. METHODS AND MATERIALS: Five hundred and ninety breast
      cancer patients irradiated between 9/94 and 3/98 underwent routine CT-based
      treatment planning. Two analyses were performed. First, the position of IMV and
      GBT, outlined on the central axis CT image, was determined relative to the
      midsternum in 111 patients irradiated during a 12-month period. In the second
      analysis, the difference between anticipated (pre-CT) and actual (CT-based)
      tangential field borders was assessed in 254 patients irradiated during a 2-year
      period. RESULTS: In the first analysis, the depth of the IMVs varied from 1 to 6
      cm (median 2.4 cm). The lateral distance from the midsternum also varied widely
      (range 1.7 to 3.7 cm, median 2.5 cm). Similar variability was found in the
      position of the GBT. In the second analysis, CT information led to changes of
      anticipated field borders in 65% of patients. The lateral border was shifted in
      56% of patients (anteriorly 18%, posteriorly 38%). When the patients were
      segregated based on internal mammary node (IMN) treatment, the medial border was
      shifted in 49% of patients when the IMNs were treated in the tangential fields
      and in 24% when the GBT only was treated. The frequency of lateral field border
      shifts was similar in both groups. CONCLUSIONS: The position of IMVs and GBT
      varies widely in breast cancer patients. Tangential field borders based on
      surface anatomy may not be ideal. Among 254 breast cancer patients, the field
      borders were shifted in 65% of patients when CT information was available. Thus,
      in most breast cancer patients, field borders are shifted when CT-based treatment
      planning is used.

PMID- 10421535
TI  - Tumor downstaging and sphincter preservation with preoperative chemoradiation in
      locally advanced rectal cancer: the M. D. Anderson Cancer Center experience.
AB  - PURPOSE: To evaluate the rates of tumor downstaging after preoperative
      chemoradiation for locally advanced rectal cancer. MATERIALS AND METHODS:
      Preoperative chemoradiotherapy (CTX/XRT) that delivered 45 Gy in 25 fractions
      over 5 weeks with continuous infusion 5-fluorouracil (300 mg/m2/day) was given to
      117 patients. The pretreatment stage distribution, as determined by endorectal
      ultrasound (u), included uT2N0 in 2%, uT3N0 in 47%, uT3N1 in 49%, and uT4N0 in 2%
      of cases; endorectal ultrasound was not performed in 13% of cases (15 patients).
      Approximately 6 weeks after completion of CTX/XRT, surgery was performed.
      RESULTS: The pathological tumor stages were Tis-2N0 in 26%, T2N1 in 5%, T3N0 in
      21%, T3N1 in 15%, T4N0 in 5%, and T4NI in 1%; a complete response (CR) to
      preoperative CTX/XRT was pathologically confirmed in 32 (27%) of patients. Tumor
      downstaging occurred in 72 (62%) cases. Only 3% of cases had pathologic evidence
      of progressive disease. Pretreatment tumor size (< 5 cm vs. > or = 5 cm) was the
      only factor predictive of tumor downstaging (p < 0.04). A decrease of > 1 T-stage
      level was accomplished in 45% of those downstaged. Overall, a sphincter-saving
      (SP) procedure was possible in 59% of patients and an abdominoperineal resection
      (APR) was required in 41 % of cases. Factors predictive of SP included
      downstaging (p < 0.03), age > 40 years (p < 0.007), pretreatment tumor distance,
      3 to 6 cm from the anal verge (p < 0.00001), tumor size <6 cm (p < 0.02),
      mobility (p < 0.004), tumor stage <T4 (p < 0.01), and uN negative (p < 0.008). SP
      was performed in 23 patients (72%) with a CR and in 48 (67%) of downstaged cases.
      Among the 69 tumors located < 6 cm from the anal verge, 29 (42%) were resected
      with a SP. The level of response was important for tumors located < 6 cm from the
      anal verge because a SP was performed in 9 of the 17 (53%) CRs in this group
      while only 20 of 52 patients (38%) had a SP when residual disease was present
      after CTX/XRT. For tumors located > 6 cm from the anal verge, SP was performed in
      14 of the 15 (93%) patients with a CR and 32 of 33 (97%) of patients with
      residual disease (p < 0.00004). CONCLUSIONS: Significant tumor downstaging
      results from preoperative chemoradiation allowing sphincter sparing surgery in
      over 40% of patients whose tumors were located < 6 cm from the anal verge and who
      otherwise would have required colostomy.

PMID- 10421536
TI  - Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma:
      survival results and observations regarding patterns of failure, radiotherapy
      dose and CA19-9 levels.
AB  - PURPOSE: Primary endpoints were 1. To determine if, in the context of
      postoperative adjuvant therapy of pancreatic and nonpancreatic periampullary
      adenocarcinoma, continuous infusion (C.I.) 5-fluorouracil (5-FU) and leucovorin
      (Lv), combined with continuous-course external-beam radiotherapy (EBRT) to liver
      (23.4-27.0 Gy), regional lymph nodes (50.4-54.0 Gy) and tumor bed (50.4-57.6 Gy),
      followed by 4 months of C.I. 5-FU/Lv without EBRT could be given with acceptable
      toxicity. 2. To determine an estimate of disease-free and overall survival (DFS,
      OS) with this treatment in this context. Secondary endpoints were 1. To observe
      the effects of therapy at two different dose levels of irradiation, and 2. To
      observe for correlations among DFS, OS and CA 19-9 levels during therapy.
      METHODS: Patients received C.I. 5-FU 200 mg/m2 and Lv 5 mg/m2 Monday through
      Friday during EBRT, and 4 cycles of the same chemotherapy without EBRT were
      planned for each 2 weeks of 4, beginning 1 month following the completion of
      EBRT. Therapy was to begin within 10 weeks of surgery and patients were monitored
      for disease recurrence, toxicity, and CA 19-9 levels before the start of EBRT/5
      FU/Lv, before each cycle of C.I. 5-FU/Lv, and periodically after the completion
      of therapy. There were two EBRT dosage groups: Low EBRT, 23.4 Gy to the whole
      liver, 50.4 Gy to regional nodes and 50.4 Gy to the tumor bed; High EBRT, 27.0 Gy
      to the whole liver, 54.0 Gy to regional nodes, and 57.6 Gy to the tumor bed.
      RESULTS: 29 patients were enrolled and treated (23 with pancreatic cancer, and 6
      with nonpancreatic periampullary cancer). Of these, 18 had tumor sizes > or = 3
      cm and 23 had at least one histologically involved lymph node; 6 had
      histologically positive resection margins. Mean time to start of EBRT/5-FU/Lv was
      53 +/- 2 days following surgery. The first 18 patients were in the Low EBRT Group
      and the last 11 in the High EBRT Group. Toxicity was moderate and manageable,
      including a possible case of late radiation hepatitis. Median DFS was 8.3 months
      (pancreatic cancer patients 8.5 months) and OS was 14.1 months (pancreatic cancer
      patients 15.9 months). Among patients with pancreatic cancer, results were
      similar for the Low and High EBRT Groups (DFS: 8.3 vs. 8.6 months; OS: 14.4 vs.
      16.9 months, respectively). With a mean follow up of 2.6 +/- 0.3 years for the
      surviving patients and a minimal follow-up of 2.5 years, 27 of 29 pts have
      relapsed and 25 pts have died. A rise in CA 19-9 levels preceded clinical relapse
      by 9.1 +/- 1.5 months. Time to first relapse by site showed inverse correlation
      with dose of radiotherapy to that site: peritoneal (5 +/- 1 month), hepatic (7 +/
      0.9 months), regional nodes/tumor bed (9.6 +/- 1.8 months). Mean postresection
      CA 19-9 level was 63.3 +/- 16.2 U/ml. Postresection CA 19-9 values did not
      correlate with survival, margin status, or with the identification of metastatic
      carcinoma in resected lymph nodes. However, among patients with histologically
      involved nodes in the resected specimen, postresection CA 19-9 values did
      correlate with the number of positive nodes identified (p = 0.05). CONCLUSIONS:
      Although toxicity was acceptable, survival results were not improved over those
      seen with standard adjuvant treatment. Most patients relapsed before the planned
      chemotherapy cycles were completed, or within 100 days thereof, suggesting
      disease resistance to C.I. 5-FU/Lv as used in this study. Although this regimen
      is not recommended for further study, the doses of EBRT utilized may be suitable
      for evaluation with other chemotherapy combinations. Postoperative CA 19-9 levels
      did not correlate with survival, but did correlate with the number of
      histologically involved lymph nodes found in the resected specimen among node
      positive patients. Moreover, rising CA 19-9 levels anticipated ultimate clinical
      failure by 9 months.

PMID- 10421537
TI  - Does race influence survival for esophageal cancer patients treated on the
      radiation and chemotherapy arm of RTOG #85-01?
AB  - PURPOSE: In reported retrospective non-randomized trials of treatment of
      esophageal carcinoma, blacks have a lower survival from esophageal cancer than
      whites. None of these studies has accounted for the extent of disease, or the
      methods and quality of treatment. We reviewed the data that included only
      patients treated on the chemoradiation arm of the RTOG-8501 esophageal carcinoma
      trial to see if there were differences in overall survival between black and
      white patients receiving the same standard of care. METHODS AND MATERIALS: One
      hundred-nineteen patients, 37 blacks and 82 whites were evaluated who met the
      criteria for receiving chemoradiation of 5000 cGy and four courses of Cisplatin
      (75 mg/m2) and Fluorouracil (1000 mg/m2 for 4 days). RESULTS: Blacks had squamous
      histology only, with 86% of blacks having weight loss of 10 lbs. or more compared
      to 56% of whites (p = 0.001). In addition, blacks had larger tumors and more
      difficulty eating (p = 0.010). Overall, there was no difference in the Kaplan
      Meier median survival estimate by race (p = 0.2757). Only when we limited the
      analysis to the "squamous histology" subgroup, stratified according to age >70
      vs. <70 years (p = 0.0002), and nodal status (p = 0.0177) in a Cox regression
      model analysis, did race appear to be a significant factor (p = 0.0012). However,
      using the entire database, the age effect was found to be a "bimodal" effect,
      wherein the "youngest" (< age 60 years) and "oldest" patients (age > 70 years)
      did poorly. Because of the dramatic differences in the age and histology
      distributions between blacks and whites, this issue could not be resolved in the
      subset of squamous only who received chemoradiation. CONCLUSIONS: The increasing
      incidence of adenocarcinoma among white patients without a corresponding increase
      of this histology in blacks reflects a difference in diet and or lifestyle
      compared to blacks that deserves additional study. When treated aggressively with
      chemoradiation, race did not appear to be a statistically significant factor for
      overall survival.

PMID- 10421538
TI  - Effectiveness of accelerated radiotherapy for patients with inoperable non-small
      cell lung cancer (NSCLC) and borderline prognostic factors without distant
      metastasis: a retrospective review.
AB  - PURPOSE: The standard treatment for patients with unresectable or medically
      inoperable non-small cell lung cancer (NSCLC) and good prognostic factors (e.g.,
      weight loss [WL] < or = 5% and Karnofsky performance status [KPS] > or = 70) is
      induction chemotherapy followed by definitive radiotherapy to the primary site at
      1.8-2.0 Gy per fraction with a total dose of 60-63 Gy to the target volume.
      Patients with poor prognostic factors usually receive radiotherapy alone, but the
      fractionation schedule and total dose have not been standardized. To attempt to
      optimize irradiation doses and schedule, we compared the effectiveness of
      accelerated radiotherapy (ACRT) alone to 45 Gy at 3 Gy per fraction with standard
      radiation therapy (STRT) of 60-66 Gy at 2 Gy per fraction in regard to tumor
      response, local control, distant metastasis, toxicity, and survival. METHODS AND
      MATERIALS: Fifty-five patients treated with radiation for NSCLC at The University
      of Texas M. D. Anderson Cancer Center between 1990 and 1994 were identified. All
      55 patients had node-positive, and no distant metastasis (N+, M0) of NSCLC. Two
      cohorts were identified. One cohort (26 patients) had borderline poor prognostic
      factors (KPS less than 70 but higher than 50, and/or WL of more than 5%) and was
      treated with radiotherapy alone to 45 Gy over 3 weeks at 3 Gy/fraction (ACRT).
      The second cohort (29 patients) had significantly better prognostic factors (KPS
      > or = 70 and WL < or = 5%) and was treated to 60-66 Gy over 6 to 6 1/2 weeks at
      2 Gy per fraction (STRT) during the same period. RESULTS: In the first cohort
      treated by ACRT, the distribution of patients by AJCC stage was IIB 8%, IIIA 19%,
      and IIIB 73%. Sixty-two percent had KPS <70, and 76% had a WL of >5%. The maximum
      response rate as determined by chest X-ray was 60% among 45 of 55 patients who
      were evaluable for response: combined complete responses (20%) and partial
      responses (40%). Overall survival in these patients was 13% at 2 and 5 years,
      with a locoregional control rate of 42% and a freedom from distant metastasis
      rate of 54%. The ACRT cohort treated with 3 Gy per fraction had significantly
      lower KPS scores (p = 0.003) and greater WL (p = 0.063) than the cohort STRT
      treated with 2 Gy per fraction. However, treatment results and toxicity were not
      significantly different between the two cohorts in spite of significantly better
      prognostic factors in the STRT cohort. CONCLUSIONS: Despite having worse
      prognostic factors, the cohort treated with radiotherapy alone to 45 Gy at 3 Gy
      per fraction over 3 weeks (ACRT) had response rates, locoregional control, and
      overall survival comparable to those in the cohort treated by a total dose of 60
      66 Gy at 2 Gy per fraction over 6 to 6 1/2 weeks (STRT). Given that accelerated
      treatment schedules decrease treatment time and cost less, these may, in the
      current health care environment, be important factors for health care providers
      to consider in treating patients who have locally advanced NSCLC and borderline
      poor prognostic factors.

PMID- 10421539
TI  - Intraoperative 125I brachytherapy for high-risk stage I non-small cell lung
      carcinoma.
AB  - PURPOSE: Preliminary assessment of feasibility, efficacy, acute and chronic side
      effects associated with permanent intraoperative placement of 125I vicryl mesh
      brachytherapy in a select group of high-risk Stage I NSCLC who have undergone
      video-assisted thoracoscopic resection (VATR). METHODS AND MATERIALS: From
      January 8, 1997 to March 16, 1998, 23 patients with Stage I NSCLC at high risk
      for conventional surgery due to cardiopulmonary compromise underwent combined
      VATR and intraoperative placement of 125I seeds embedded in vicryl mesh. Seeds
      embedded in vicryl suture were attached with surgical clips to a sheet of vicryl
      mesh, and thoracoscopically inserted over the target area (tumor bed and staple
      line) with nonabsorbable suture or surgical clips. A total dose of 100-120 Gy
      prescribed to the periphery of the target area (defined as the staple line and
      tumor bed with a 1-cm margin) was delivered. RESULTS: The mean target area
      covered was 48 cm2 (range 40-72) and mean total activity was 22 mCi (range 17.2
      28.2). The median length of postoperative stay was 7 days. The median follow-up
      was 11 months (range 2-20). Postoperative CT scans of the chest revealed no
      dislodgement of the seeds and no local recurrence in any patient. Three patients
      developed distant metastasis (1 died 6 months postoperatively; the other 2 are
      currently alive with disease). One patient developed an ipsilateral recurrence in
      the right lower lobe after having had a right upper lobe resection. There were 3
      postoperative deaths due to medical comorbid conditions or surgical complications
      (1 in the immediate postoperative period). Pulmonary function testing performed 3
      months after implantation revealed no significant difference between preoperative
      and postoperative values: mean preoperative FVC was 2.3 L (range 1.31-3.0) and
      postoperative FVC was 2.2 L (range 1.1-3.9), p = 0.42; mean preoperative FEV1 was
      1.2 L (range 0.71-2.2), and postoperative FEV1 was 1.5 L (range 0.8-2.9), p =
      0.28. CONCLUSION: Review of early data suggests that intraoperative 125I vicryl
      mesh brachytherapy in high-risk Stage I NSCLC is potentially effective and well
      tolerated, with no significant decline in measurable pulmonary function studies
      and no increase in postoperative complications. Longer follow-up is needed to
      determine ultimate local control and survival.

PMID- 10421540
TI  - Nodal radiation therapy for metastatic melanoma.
AB  - PURPOSE: The aim of this retrospective study was to review our experience of
      radiation therapy to regional nodes in patients with proven nodal metastases,
      with respect to regional control, late toxicity, and overall survival. METHODS
      AND MATERIALS: All patients with a histological diagnosis of malignant melanoma,
      with involvement of the regional nodes but without distant metastases, who
      commenced nodal irradiation between January 1985 and July 1995 at Peter MacCallum
      Cancer Institute were studied. The study population of 113 patients was divided
      into two categories: those with no residual macroscopic disease following nodal
      surgery (adjuvant group, 42 patients) and those who had no surgery (8) or had
      macroscopic residual disease following nodal surgery (63) (palliative group, 71
      patients). RESULTS: In the adjuvant group at 5 years following commencement of
      nodal irradiation 26% were estimated to be failure-free. Of the 74% who had
      experienced treatment failure by 5 years, an estimated 20% failed first with
      nodal relapse, 52% with distant metastases, and 2% with both nodal relapse and
      distant metastases. The estimated 5-year overall survival for this group was 33%.
      In the palliative group 16 patients (23%) had an objective complete response.
      Altogether 48 patients (68%) had a symptomatic response. At 5 years the overall
      survival in this group was 8% and an estimated 4% were failure-free. Of the 96%
      who had failed by 5 years, 68% failed first in the regional nodes, 25% had
      distant metastases as the first failure, and 3% had both nodal relapse and
      distant metastases. CONCLUSION: We recommend adjuvant postoperative radiation
      therapy for patients with proven nodal metastases and high risk of regional
      recurrence (multiple nodes, extracapsular extension, or recurrent nodal disease)
      in addition to adjuvant interferon.

PMID- 10421541
TI  - Consequences of voice impairment in daily life for patients following
      radiotherapy for early glottic cancer: voice quality, vocal function, and vocal
      performance.
AB  - PURPOSE: To assess consequences of voice impairment in daily life for patients
      following radiotherapy for early glottic cancer, by means of a multidimensional
      analysis protocol including voice quality, vocal function, and vocal performance
      measures. METHODS AND MATERIALS: A total of 60 men treated with radiotherapy (66
      Gy/33 fractions, 60 Gy/30 fractions, 60 Gy/25 fractions) for early T1 glottic
      cancer and 20 matched control speakers filled in questionnaires on vocal
      performance. Furthermore, perceptual analyses of voice quality and stroboscopic
      measures of vocal function were performed. There was a longitudinal group of 10
      patients from whom data were collected before, as well as 6 months and 2 years
      after, radiation. Furthermore, data were collected on 5 separate groups of 10
      patients each: before, 6 months after, 2 years after, 3-7 years after, and 7-10
      years after radiation. RESULTS: High correlations were found between self-ratings
      of vocal performance and several voice measures. Patients before radiotherapy
      experienced poor voice characteristics that improved 6 months to 10 years after
      treatment, and became comparable to vocal performance of control speakers in 50%
      of the patients. Following radiotherapy, deviant voice characteristics and
      consequences in daily life occurred significantly more often for patients in whom
      initial diagnosis consisted of stripping the vocal cord instead of biopsies and
      for patients who continued smoking after treatment. CONCLUSION: Voice
      characteristics of patients diagnosed with early glottic cancer improved after
      radiotherapy, and became normal in half of our patients. Stripping the vocal cord
      for initial diagnosis and continued smoking after treatment decreased deviant
      voice characteristics.

PMID- 10421542
TI  - Comparison of AJCC 1988 and 1997 classifications for nasopharyngeal carcinoma.
      American Joint Committee on Cancer.
AB  - PURPOSE: A comparison of American Joint Committee on Cancer (AJCC) 1988 and 1997
      nasopharyngeal carcinoma (NPC) classifications was made in terms of patient
      distribution and efficacy in predicting prognosis. METHODS AND MATERIALS: Between
      1993-1997, 90 patients (64 M, 26 F) with non-metastatic NPC were treated. The
      mean age was 42.02 (range: 9-82) years old. Histopathological diagnosis was WHO 2
      and 3 in 83 (92.2%) patients. All patients were prospectively staged using AJCC
      1988 and modified Ho's classifications (1989) and these data were stored in a
      computer database. Retrieval of this information enabled us to restage patients
      according to the AJCC 1997. Median follow-up was 38 months. RESULTS: According to
      the AJCC 1988 there were 2 (2.2%), 6 (6.7%), 13 (14.4%), and 69 (76.7%) patients
      in Stage I, II, III and IV, respectively. Same figures were 8 (8.8%), 21 (23.3%),
      26 (28.9%), and 35 (38.8%), according to AJCC 1997. Three year overall survival
      (OS) rates were 100%, 100%, 67%, and 62% for patients Stage I, II, III, and IV
      according to the AJCC 1988 and 100%, 72%, 65%, and 55%, (I vs. IV; p = 0.03, I
      vs. III; p = 0.05) respectively, according to the AJCC 1997. Three year loco
      regional relapse free survival (LRRFS) rates were 50%, 100%, 100%, and 83% (I vs.
      III; p = 0.03) for patients in Stage I, II, III, and IV according to the AJCC
      1988. Same figures were 88%, 90%, 89%, and 85% according to the AJCC 1997. Three
      year distant metastasis free survival (DMFS) rates were 100%, 100%, 82%, and 67%
      for patients in Stage I, II, III, and IV according to the AJCC 1988. Same figures
      were 100%, 74%, 80%, and 57% (I vs. IV; p = 0.03) according to the AJCC 1997. We
      did not observe any significant difference in LRRFS among T stages for both
      staging system and the N stage was the primary determinant for DMFS in both
      systems. CONCLUSIONS: We observed a better patient distribution with AJCC 1997
      comparing to AJCC 1988. The new classification also attained better statistical
      significances among stages in the OS and DMFS rates.

PMID- 10421543
TI  - Five year results of LINAC radiosurgery for arteriovenous malformations: outcome
      for large AVMS.
AB  - PURPOSE: For radiosurgery of large arteriovenous malformations (AVMs), the
      optimal relationship of dose and volume to obliteration, complications, and
      hemorrhage is not well defined. Multivariate analysis was performed to assess the
      relationship of multiple AVM and treatment factors to the outcome of AVMs
      significantly larger than previously reported in the literature. METHODS AND
      MATERIALS: 73 patients with intracranial AVMs underwent LINAC radiosurgery. Over
      50% of the AVMs were larger than 3 cm in diameter and the median and mean
      treatment volumes were 8.4 cc and 15.3 cc, respectively (range 0.4-143.4 cc).
      Minimum AVM treatment doses varied between 1000-2200 cGy (median: 1600 cGy).
      RESULTS: The obliteration rates for treatment volumes < 4 cc, 4-13.9 cc, and > or
      = 14 cc were 67%, 58%, and 23%, respectively. AVM obliteration was significantly
      associated with higher minimum treatment dose and negatively associated with a
      history of prior embolization with particulate materials. No AVM receiving < 1400
      cGy was obliterated. The incidence of post-radiosurgical imaging abnormalities
      and clinical complications rose with increasing treatment volume. For treatment
      volumes > 14 cc receiving > or = 1600 cGy, the incidence of post-radiosurgical
      MRI T2 abnormalities was 72% and the incidence of radiation necrosis requiring
      resection was 22%. The rate of post-radiosurgical hemorrhage was 2.7% per person
      year for AVMs with treatment volumes < 14 cc and 7.5% per person-year for AVMs >
      or = 14 cc. CONCLUSION: As AVM size increases, the dose-volume range for the
      optimal balance between successful obliteration and the risk of complications and
      post-radiosurgical hemorrhage narrows.

PMID- 10421544
TI  - The effect of androgen deprivation on the early changes in prostate volume
      following transperineal ultrasound guided interstitial therapy for localized
      carcinoma of the prostate.
AB  - PURPOSE: To determine the change in volume of the prostate as a result of
      neoadjuvant androgen deprivation prior to prostate implant and in the early
      postimplant period following transperineal ultrasound guided palladium-103
      brachytherapy for early-stage prostate cancer. METHODS AND MATERIALS: Sixty-nine
      men received 3 to 6 months of androgen deprivation therapy followed by treatment
      planning ultrasound followed 4 to 8 weeks later by palladium-103 implant of the
      prostate. All patients had clinical and radiographic stage T1c-T2b adenocarcinoma
      of the prostate. A second ultrasound study was carried out 11 to 13 days
      following the implant to determine the change in volume of the prostate as a
      result of the implant. The prehormonal and preimplant volumes were compared to
      the postimplant volume to determine the effect of hormones and brachytherapy on
      prostate volume. RESULTS: The median decrease in prostate volume as a result of
      androgen deprivation was 33% among the 54 patients with prostate volume
      determinations prior to hormonal therapy. The reduction in volume was greatest in
      the quartile of men with the largest initial gland volume (59%) and least in the
      quartile of men with smallest glands (10%). The median reduction in prostate
      volume between the treatment planning ultrasound and the follow-up study after
      implant was 3%, but 23 (33%) patients had an increase in prostate volume,
      including 16 (23%) who had an increase in volume >20%; 11 of these patients (16%)
      had an increase in volume >30%. The time course of development and resolution of
      this edema is not known. The severity of the edema was not related to initial or
      preimplant prostate volume or duration of hormonal therapy. CONCLUSIONS: Prostate
      edema may significantly affect the dose delivered to the prostate following
      transperineal ultrasound guided brachytherapy. The effect on the actual delivered
      dose will be greater when shorter lived isotopes are used. It remains to be
      observed whether this edema will affect outcome.

PMID- 10421545
TI  - The dependence of prostate postimplant dosimetric quality on CT volume
      determination.
AB  - PURPOSE: The postoperative evaluation of permanent prostate brachytherapy
      requires a subjective determination of the implant volume. This work investigates
      the magnitude of the effect that various methods of treatment volume delineation
      have on dosimetric quality parameters for a treatment planning philosophy that
      defines a target volume as the prostate with a periprostatic margin. METHODS AND
      MATERIALS: Eight consecutive prostate brachytherapy patients with a prescribed
      dose of 145 Gy from 125I as monotherapy comprised the study population. The
      prostate ultrasound volume was enlarged to a planning volume by an average factor
      of 1.8 to encompass probable extracapsular extension in the periprostatic region.
      For this cohort, the mean pretreatment parameters were 30.3 cm3 ultrasound
      volume, 51.8 cm3 planning volume, 131 seeds per patient, and 42.9 mCi total
      activity. On CT study sets obtained less than 2 hours postoperatively, target
      volumes were drawn using three methods: prostate plus a periprostatic margin,
      prostate only which excluded the puborectalis muscles, the periprostatic fat and
      the periprostatic venous plexus, and the preplanning ultrasound magnified to
      conform to the magnification factor of the postimplant CT scan. Three sets of 5
      dosimetric quality parameters corresponding to the different volumetric
      approaches were calculated: V100, V150, and V200 which are the fractions of the
      target volume covered by 100, 150, and 200% of the prescribed dose, and D90 and
      D100, which are the minimal doses covering 90 and 100% of the target volume.
      RESULTS: The postoperative CT volume utilizing the prostate plus margin technique
      was comparable to the initial planning volume (mean 55.5 cm3 vs. 51.8 cm3,
      respectively) whereas those determined via superimposing the preplan ultrasound
      resulted in volumes nearly identical to the initial ultrasound evaluation (mean
      32.4 cm3 vs. 30.3 cm3). The prostate only approach resulted in volumes
      approximately 25% larger than the ultrasound volume approach. Despite the volume
      determinations being markedly different, no significant differences between the
      approaches were appreciated for V100, V150, V200, and D90. Large variations seen
      in D100 were uncorrelated to any of the other parameters and make D100 unsuitable
      as a quality indicator. CONCLUSIONS: In terms of a logarithmic measure, the
      variation between volumetric approach for V100, V150, V200, and D90 was less than
      one-fifth the variation of the CT volumes. These results which indicate relative
      independence of postimplant CT volume determination and dosimetric quality are
      only valid for a planning philosophy that includes the prostate with a
      periprostatic margin as the target volume.

PMID- 10421546
TI  - Paclitaxel sensitivity correlates with p53 status and DNA fragmentation, but not
      G2/M accumulation.
AB  - PURPOSE: The antitumor agent paclitaxel (Taxol) has been shown to arrest cells in
      mitosis through microtubule stabilization and to induce apoptosis. The tumor
      suppressor gene p53 is implicated in the regulation of cell cycle checkpoints and
      can mediate apoptotic cell death. Although initial studies demonstrated that
      various DNA-damaging agents can induce p53, more recent studies have also shown
      p53 induction following nonDNA-damaging agents, including paclitaxel. We
      investigated the influence of p53 abrogation on paclitaxel-induced cell kill and
      correlated the extent of mitotic arrest and DNA fragmentation by paclitaxel with
      the drug's cytotoxic effect. MATERIALS AND METHODS: The parental human colorectal
      carcinoma cell line (RKO) with wild-type p53 alleles, and two transfected RKO
      cell lines with inactivated p53 (RKO.p53.13 with transfected mutant p53 and RC
      10.3 with HPV-16-derived E6 gene) were exposed to graded doses of paclitaxel (1
      100 nM) for 24-h intervals. The functional status of p53 in cells was assessed by
      thymidine and BrdU incorporation following exposure to ionizing radiation (4 Gy).
      Reproductive integrity following paclitaxel treatment was assessed by clonogenic
      assay. Immunolabeling and microscopic evaluation were used to assess mitotic
      accumulation and micronucleation. Apoptosis was assayed using DNA fragmentation
      analyses. RESULTS: A 4-fold increase in paclitaxel sensitivity was observed among
      RKO cells deficient in p53 function compared with wild-type RKO cells (IC 50: 4
      nM, 1 nM, 1nM for RKO, RKO.p53.13, RC 10.3, respectively). The increased
      cytotoxic effect in RKO cells with inactive p53 correlated with an increased
      propensity towards micronucleation and DNA fragmentation following paclitaxel
      treatment. However, no significant difference in peak mitotic accumulation was
      observed among RKO cells with functional or abrogated p53. CONCLUSIONS: RKO cells
      lacking functional p53 demonstrate significantly enhanced sensitivity to
      paclitaxel compared with that of wild-type RKO cells. This response corresponded
      with increased micronucleation and DNA fragmentation in cells deficient in p53
      function. Although previous published reports of enhanced paclitaxel sensitivity
      in p53-deficient cells correlated this finding with increased G2/M arrest, we did
      not observe any significant correlation between paclitaxel-induced cell kill and
      the degree of mitotic arrest. Our data suggest that apoptosis is the predominant
      mechanism of paclitaxel cytotoxicity in RKO cells and is likely mediated by a p53
      independent process.

PMID- 10421547
TI  - Maximizing therapeutic gain with gemcitabine and fractionated radiation.
AB  - PURPOSE/OBJECTIVE: The nucleoside analogue gemcitabine inhibits cellular repair
      and repopulation, induces apoptosis, causes tumor growth delay, and enhances
      radiation-induced growth delay. After single doses of drug and radiation, maximum
      enhancement of tumor response was obtained when gemcitabine preceded radiation by
      at least 24 h. Conversely, the cellular radioresponse of the normal
      gastrointestinal epithelium was slightly protected when gemcitabine and radiation
      were separated by 24 h. This differential response created a time frame within
      which therapeutic gain could be maximized. In our present investigation, we
      sought to define the most therapeutically beneficial scheme of gemcitabine
      administration when combined with fractionated radiotherapy. METHODS AND
      MATERIALS: C3Hf/Kam mice were given identical drug and radiation schedules of
      administration, and both normal tissue (jejunal mucosa) and tumor (Sa-NH)
      responses were measured. Irradiation was given once per day for 5 days in normal
      tissue and tumor growth delay studies and twice per day for the tumor cure
      endpoint. A total dose of 25 mg/kg gemcitabine was given i.p. in 1 of 3
      schedules: a single dose of 25 mg/kg 24 h before the start of fractionated
      irradiation, 12.5 mg/kg 24 h before the first and third radiation doses, or 24 h
      before each of 5 radiation doses. Groups of mice bearing 7- or 8-mm diameter
      tumors were treated with gemcitabine alone or in combination with fractionated
      irradiation under ambient or hypoxic conditions. The survival response of the
      jejunal mucosa was quantified by the microcolony assay and histologically by
      quantifying apoptosis, mitosis, S-phase fraction, and crypt cellularity. RESULTS:
      For tumor growth delay, dose-modifying factors (DMFs) were similar (1.34-1.46)
      for all 3 schedules of drug administration. In contrast, the response of the
      jejunum was strongly dependent on the schedule of gemcitabine administration. A
      single dose of gemcitabine before the start of fractionated radiotherapy resulted
      in slight radioprotection (DMF 0.96). Two doses and 5 daily doses of gemcitabine
      enhanced radiation response by factors of 1.09 and 1.23, respectively. Major
      factors affecting the response of the jejunal mucosa were apoptotic death of S
      phase cells exposed to gemcitabine and cell cycle synchrony of surviving cells.
      Tumor reoxygenation was found to be a major mechanism for tumor radioenhancement,
      in addition to those reported earlier. CONCLUSION: All 3 schedules of drug
      administration produced therapeutic gain; however, when gemcitabine was given
      more than once in a 5-fraction radiation treatment schedule, normal tissue
      toxicity increased. The highest therapeutic gain (1.4) was achieved by giving a
      single dose of gemcitabine (25 mg/kg) 24 h before the start of fractionated
      radiotherapy.

PMID- 10421548
TI  - A comparison in individual murine tumors of techniques for measuring oxygen
      levels.
AB  - PURPOSE: To investigate the relationship between different techniques for
      measuring oxygen levels in a murine tumor model. METHODS AND MATERIALS: Using the
      murine fibrosarcoma line KHT-C, five techniques of measuring oxygen levels-the
      Eppendorf pO2 Histograph, EF5 binding, the comet assay, a paired survival assay,
      and an in vivo growth delay assay-were assessed. In these experiments, three or
      more techniques were applied in different combinations to measure the oxygen
      levels in individual tumors. RESULTS: Statistically significant correlations were
      observed between the hypoxic proportions calculated from the paired survival
      assay with those from EF5 binding. The comet assay was found to have a
      statistically significant correlation with the paired survival analysis and the
      growth delay analysis. No statistically significant correlation was found between
      the Eppendorf pO2 Histograph measurements and those from the other techniques,
      although there were weak correlations with the paired survival assay and EF5
      binding. For technical reasons, a comparison was not made between EF5 binding and
      the growth delay assay. CONCLUSIONS: The correlations found between EF5 binding
      and the comet assay with the radiobiological assays suggest that these techniques
      have potential for predicting outcome following radiation treatment. The lack of
      correlation seen between the pO2 Histograph data and the radiobiological assays
      is in contrast to results from early clinical trials.

PMID- 10421549
TI  - Synchronizing dynamic multileaf collimators for producing two-dimensional
      intensity-modulated fields with minimum beam delivery time.
AB  - PURPOSE: Leaf motion synchronization of dynamic multileaf collimators (DMLC) for
      intensity-modulated radiotherapy (IMRT) is important in improving dose
      distribution and reducing "tongue-and-groove" effects for a prescribed intensity
      profile. Leaf synchronization could also be used in transforming a one
      dimensional leaf-setting algorithm into a two-dimensional leaf-setting algorithm.
      In this work, we aim to develop a generalized leaf synchronization method for
      delivering IMRT with the minimized beam delivery time and the optimized subfield
      variations for a leaf-setting sequence. METHODS AND MATERIALS: With the leaf
      synchronization procedure, all active MLC leaf pairs start and finish off a leaf
      sequence simultaneously. In this work, the MLC leaf pairs were synchronized under
      the condition that the resulting leaf sequence produces the desired intensity
      profile with the minimum beam delivery time. The parameter of the leaf
      synchronization function was determined through the least-square minimization of
      the area variations of all subfields within a leaf sequence. The leaf
      synchronization and optimization procedure were applied and analyzed for clinical
      relevant intensity profiles for treating the head-and-neck cancer patients using
      IMRT. RESULTS: The total monitor units and the optimized beam delivery time of
      generating a two-dimensional intensity profile was proven through this work to be
      the global minimum of all leaf-setting sequences including the unsynchronized
      leaf-setting sequences. The optimized parameter for subfield variations of the
      synchronized leaf trajectories was found to be dependent on individual intensity
      profiles. For all our studied cases, the unsynchronized leaf trajectories always
      have significantly larger subfield variations than the synchronized leaf
      trajectories. CONCLUSION: It is important and also feasible to synchronize and
      optimize dynamic MLC leaf motions while still keeping the total beam delivery
      time minimum for delivering arbitrary two-dimensional intensity-modulated fields.

PMID- 10421550
TI  - Intensity-modulated tangential beam irradiation of the intact breast.
AB  - PURPOSE: To evaluate the potential benefits of intensity modulated tangential
      beams in the irradiation of the intact breast. METHODS AND MATERIALS: Three
      dimensional treatment planning was performed on five left and five right breasts
      using standard wedged and intensity modulated (IM) tangential beams. Optimal beam
      parameters were chosen using beams-eye-view display. For the standard plans, the
      optimal wedge angles were chosen based on dose distributions in the central plane
      calculated without inhomogeneity corrections, according to our standard protocol.
      Intensity-modulated plans were generated using an inverse planning algorithm and
      a standard set of target and critical structure optimization criteria. Plans were
      compared using multiple dose distributions and dose volume histograms for the
      planning target volume (PTV), ipsilateral lung, coronary arteries, and
      contralateral breast. RESULTS: Significant improvements in the doses to critical
      structures were achieved using intensity modulation. Compared with a standard
      wedged plan prescribed to 46 Gy, the dose from the IM plan encompassing 20% of
      the coronary artery region decreased by 25% (from 36 to 27 Gy) for patients
      treated to the left breast; the mean dose to the contralateral breast decreased
      by 42% (from 1.2 to 0.7 Gy); the ipsilateral lung volume receiving more than 46
      Gy decreased by 30% (from 10% to 7%); the volume of surrounding soft tissue
      receiving more than 46 Gy decreased by 31% (from 48% to 33%). Dose homogeneity
      within the target volume improved greatest in the superior and inferior regions
      of the breast (approximately 8%), although some decrease in the medial and
      lateral high-dose regions (approximately 4%) was also observed. CONCLUSION:
      Intensity modulation with a standard tangential beam arrangement significantly
      reduces the dose to the coronary arteries, ipsilateral lung, contralateral
      breast, and surrounding soft tissues. Improvements in dose homogeneity throughout
      the target volume can also be achieved, particularly in the superior and inferior
      regions of the breast. It remains to be seen whether the dosimetric improvements
      achievable with IMRT will lead to significant clinical outcome improvements.

PMID- 10421551
TI  - Planning target volumes for radiotherapy: how much margin is needed?
AB  - PURPOSE: The radiotherapy planning target volume (PTV) encloses the clinical
      target volume (CTV) with anisotropic margins to account for possible
      uncertainties in beam alignment, patient positioning, organ motion, and organ
      deformation. Ideally, the CTV-PTV margin should be determined solely by the
      magnitudes of the uncertainties involved. In practice, the clinician usually also
      considers doses to abutting healthy tissues when deciding on the size of the CTV
      PTV margin. This study calculates the ideal size of the CTV-PTV margin when only
      physical position uncertainties are considered. METHODS AND MATERIALS: The
      position of the CTV for any treatment is assumed to be described by independent
      Gaussian distributions in each of the three Cartesian directions. Three
      strategies for choosing a CTV-PTV margin are analyzed. The CTV-PTV margin can be
      based on: 1. the probability that the CTV is completely enclosed by the PTV; 2.
      the probability that the projection of the CTV in the beam's eye view (BEV) is
      completely enclosed by the projection of the PTV in the BEV; and 3. the
      probability that a point on the edge of the CTV is within the PTV. Cumulative
      probability distributions are derived for each of the above strategies. RESULTS:
      Expansion of the CTV by 1 standard deviation (SD) in each direction results in
      the CTV being entirely enclosed within the PTV 24% of the time; the BEV
      projection of the CTV is enclosed within the BEV projection of the PTV 39% of the
      time; and a point on the edge of the CTV is within the PTV 84% of the time. To
      have the CTV enclosed entirely within the PTV 95% of the time requires a margin
      of 2.8 SD. For the BEV projection of the CTV to be within the BEV projection of
      the PTV 95% of the time requires a margin of 2.45 SD. To have any point on the
      surface of the CTV be within the PTV 95% of the time requires a margin of 1.65
      SD. CONCLUSION: In the first two strategies for selecting a margin, the
      probability of finding the CTV within the PTV is unrelated to dose variations in
      the CTV. In the third strategy, the specified confidence limit is correlated with
      the minimum target dose. We recommend that the PTV be calculated from the CTV
      using a margin of 1.65 SD in each direction. This gives a minimum CTV dose that
      is greater than 95% of the minimum PTV dose. Additional sparing of adjoining
      healthy structures should be accomplished by modifying beam portals, rather than
      adjusting the PTV. Then, the dose distributions more accurately reflect the
      clinical compromise between treating the tumor and sparing the patient.

PMID- 10421552
TI  - Optimization of planar high-dose-rate implants.
AB  - PURPOSE: Brachytherapy has long been used to deliver localized radiation to the
      breast and other cancer sites. For interstitial implants, proper source
      positioning is critical in obtaining satisfactory dose distributions. The present
      work examines techniques for optimizing source guide placement in high-dose-rate
      (HDR) biplanar implants, and examines the effects of suboptimal catheter
      placement. METHODS AND MATERIALS: Control of individual dwell times in HDR
      implants allows a high degree of dose uniformity in planes parallel to the
      implant planes. Biplanar HDR implants can be considered optimized when the dose
      at the implant center is equal to the dose at the symmetric target boundaries. It
      is shown that this optimal dose uniformity is achieved when the interplanar
      separation is related to the target thickness T through the direct
      proportionality, s = T/square root2. To quantify the significance of source
      positioning, the average dose and a related quantity, equivalent uniform dose
      (EUD), were calculated inside the treatment volume for two conditions of
      suboptimal catheter geometry. In one case, the interplanar spacing was varied
      from 1 cm up to the target thickness T, while a second study examined the effects
      of off-center placement of the implant planes. RESULTS: Both the average dose and
      EUD were minimized when the interplanar spacing satisfied the relationship s =
      T/square root2. EUD, however, was significantly smaller than the average dose,
      indicating a reduced relative cell killing in the high dose regions near the
      dwell points. It was also noted that in contrast to the average dose, the EUD is
      a relatively weak function of catheter misplacement, suggesting that the
      biological consequences of suboptimal implant geometry may be less significant
      than is indicated by the increase in average dose. CONCLUSION: A concise formula
      can be used to determine the interplanar separation needed for optimal dose
      uniformity in Manchester-type implants. Deviations from optimal source geometry
      result in an increase in the average dose inside the treatment volume, but the
      weaker dependence of the EUD suggests that the surviving fraction of cells may
      not be not strongly affected by suboptimal source geometry.

PMID- 10421553
TI  - Relative dose uniformity assessment in interstitial implants.
AB  - PURPOSE: Two new indices, the peak index (PI) and the new geometry index (NGI),
      that quantify implant dose uniformity and quality are presented. Their advantages
      include independence to absolute treatment dose and high sensitivity compared
      with other adopted dose-uniformity measures. The applicability of these indices
      were evaluated through computer simulations and several clinically executed
      implant cases. Target coverage is assumed to be properly observed and will not be
      discussed herein. METHODS AND MATERIALS: The natural volume-dose histogram serves
      as the basis of our investigation. The PI and NGI definitions are based on
      parameters derived from the histogram. Two computer-simulated implants and 12
      clinically executed implants, using high-dose rate remote afterloading
      techniques, are studied. Various indices that quantify the dose uniformity of the
      implant, namely the quality index (QI), geometry index, as well as the PI and
      NGI, are computed, and the results are compared. RESULTS: The PI demonstrated
      significantly increased sensitivity (up to 5 times) to dose-uniformity
      evaluation, compared with the QI. The deduced parameter NGI may thus offer a
      better measure of implant qualities, allowing a more meaningful assessment and
      correlation between implant qualities to the treatment results. The PI system
      also offers a guideline to the design of optimal implant geometry. CONCLUSION:
      The PI overcomes some of the shortcomings of the QI in that it provides more
      information about the peaking of the natural dose-volume histogram of a
      particular implant. The PI and NGI may offer better, more sensitive means to
      assess implant dose uniformity, independent of prescription dose, than other
      measures.

PMID- 10421554
TI  - Regarding Zhang, Gu, Yin, IJROBP 1998;42:928-934.

PMID- 10421555
TI  - Neoadjuvant chemotherapy should not be the standard of care for advanced
      nasopharynx cancer.

PMID- 10421556
TI  - Status epilepticus: an overview of the clinical problem.
AB  - Status epilepticus has been recognized since antiquity. The terms etat de mal and
      "status epilepticus" are derived from the slang used by epilepsy patients housed
      in Salpetriere and Bicetre hospitals in Paris during the 1800s. The definition of
      status epilepticus has been evolving, and is still not precise. In 1903-04 it was
      described as a development of epilepsy in which seizures are so frequent that
      "coma and exhaustion are continuous between seizures." In 1964 the International
      League Against Epilepsy adopted the definition "a seizure [that] persists for a
      sufficient length of time or is repeated frequently enough to produce a fixed and
      enduring epileptic condition." 30 min has been the most common specified duration
      of seizures for the diagnosis of status epilepticus, although a duration of 10 or
      20 min has been suggested as well. However, a new set of definitions for
      generalized, convulsive status epilepticus in adults has been proposed and
      includes an operational definition (specifying a seizure duration of a least 5
      min) and a mechanistic definition. In the future, laboratory tests will provide
      the means for detecting and defining the critical factors that distinguish a
      single epileptic seizure from status epilepticus. Recent epidemiological studies
      suggest status epilepticus occurs in 100,000 to 150,000 people in the US each
      year, and is associated with substantial morbidity and mortality. Etiology,
      duration of the seizures, and the patient's age seem to be important determinants
      of the outcome in status epilepticus.

PMID- 10421557
TI  - Acute cellular alterations in the hippocampus after status epilepticus.
AB  - The critical, fundamental mechanisms that determine the emergence of status
      epilepticus from a single seizure and the prolonged duration of status
      epilepticus are uncertain. However, several general concepts of the
      pathophysiology of status epilepticus have emerged: (a) the hippocampus is
      consistently activated during status epilepticus; (b) loss of GABA-mediated
      inhibitory synaptic transmission in the hippocampus is critical for emergence of
      status epilepticus; and, finally (c) glutamatergic excitatory synaptic
      transmission is important in sustaining status epilepticus. This review focuses
      on the alteration of GABAergic inhibition in the hippocampus that occurs during
      the prolonged seizures of status epilepticus. If reduction in GABAergic
      inhibition leads to development of status epilepticus, enhancement of GABAergic
      inhibition would be expected to interrupt status epilepticus. Benzodiazepines and
      barbiturates are both used in the treatment of status epilepticus and both drugs
      enhance GABA(A) receptor-mediated inhibition. However, patients often become
      refractory to benzodiazepines when seizures are prolonged, and barbiturates are
      often then used for these refractory cases of status epilepticus. Recent evidence
      suggests the presence of multiple GABA(A) receptor isoforms in the hippocampus
      with different sensitivity to benzodiazepines but similar sensitivity to
      barbiturates, thus explaining why the two drug classes might have different
      clinical effects. In addition, rapid functional plasticity of GABA(A) receptors
      has been demonstrated to occur during status epilepticus in rats. During status
      epilepticus, there was a substantial reduction of diazepam potency for
      termination of the seizures. The loss of sensitivity of the animals to diazepam
      during status epilepticus was accompanied by an alteration in the functional
      properties of hippocampal dentate granule cell GABA(A) receptors. Dentate granule
      cell GABA(A) receptor currents from rats undergoing status epilepticus had
      reduced sensitivity to diazepam and zinc but normal sensitivity to GABA and
      pentobarbital. Therefore, the prolonged seizures of status epilepticus rapidly
      altered the functional properties of hippocampal dentate granule cell GABA(A)
      receptors, possibly explaining why benzodiazepines and barbiturates may not be
      equally effective during treatment of the prolonged seizures of status
      epilepticus. A comprehensive understanding of the cellular and molecular events
      leading to the development, maintenance, and cytotoxicity of status epilepticus
      should permit development of more effective treatment strategies and reduction in
      the mortality and morbidity of status epilepticus.

PMID- 10421558
TI  - Chronic epileptogenic cellular alterations in the limbic system after status
      epilepticus.
AB  - Status epilepticus (SE) is associated with both acute and permanent pathological
      sequellae. One common long term consequence of SE is the subsequent development
      of a chronic epileptic condition, with seizures frequently originating from and
      involving the limbic system. Following SE, many studies have demonstrated
      selective loss of neurons within the hilar region of the dentate gyrus, CA1 and
      CA3 pyramidal neurons. Selective loss of distinct subpopulations of interneurons
      throughout the hippocampus is also frequently evident, although interneurons as a
      whole are selectively spared relative to principal cells. Accompanying this loss
      of neurons are circuit rearrangements, the most widely studied being the
      sprouting of dentate granule cell (DGC) axons back onto the inner molecular layer
      of the dentate gyrus, termed mossy fiber sprouting. Less studied are the receptor
      properties of the surviving neurons within the epileptic hippocampus following
      SE. DGCs in epileptic animals exhibit marked alterations in the functional and
      pharmacological properties of gamma-aminobutyric acid (GABA) receptors. DGCs have
      a significantly elevated density of GABA(A) receptors in chronically epileptic
      animals. In addition, the pharmacological properties of GABA(A) receptors in post
      SE epileptic animals are quite different compared to controls. In particular,
      GABA(A) receptors in DGCs from epileptic animals show an enhanced sensitivity to
      blockade by zinc, and a markedly altered sensitivity to modulation by
      benzodiazepines. These pharmacological differences may be due to a decreased
      expression of alpha1 subunits of the GABA(A) receptor relative to other alpha
      subunits in DGCs of post-SE epileptic animals. These GABA(A) receptor alterations
      precede the onset of spontaneous seizures in post-SE DGCs, and so are temporally
      positioned to contribute to the process of epileptogenesis in the limbic system.
      The presence of zinc sensitive GABA receptors combined with the presence of zinc
      containing "sprouted" mossy fiber terminals innervating the proximal dendrites of
      DGCs in the post-SE epileptic hippocampus prompted the development of the
      hypothesis that repetitive activation of the DG in the epileptic brain could
      result in the release of zine. This zinc in turn may diffuse to and block
      "epileptic" zinc-sensitive GABA(A) receptors in DGCs, leading to a catastrophic
      failure of inhibition and concomitant enhanced seizure propensity in the post-SE
      epileptic limbic system.

PMID- 10421559
TI  - Status epilepticus-induced neuronal injury and network reorganization.
AB  - It is now evident that prolonged febrile seizures in childhood, or an episode of
      status epilepticus at any age, can produce the highly characteristic pattern of
      hippocampal cell loss and shrinkage that is seen later in life, when patients
      develop temporal lobe epilepsy. Seizure-induced and presumably excitotoxic
      pathology includes neuronal loss, reactive gliosis, aberrant synaptic
      reorganization of surviving cells, and hippocampal tissue shrinkage that may
      alter extracellular space and affect ionic homeostasis. Whether any of these
      pathological effects of prolonged excitation play a causal role in the
      epileptogenic process that ultimately leads to spontaneous afebrile seizures
      remains a subject of intense interest. Two hypotheses have been suggested to
      explain how seizure-induced neuronal loss might initiate the epileptogenic
      process. One hypothesis suggests that normal inhibition and excitability is
      maintained by vulnerable non-principal cells, and that their loss deactivates
      inhibitory neurons, rendering principal cells disinhibited and hyperexcitable.
      The other hypothesis regards the initial loss as a stimulus for normally
      unconnected principal cells to form aberrant recurrent excitatory connections.
      Additional influences undoubtedly include a "kindling" process that gradually
      overcomes polysynaptic inhibition, and changes in extracellular space that may
      facilitate synaptic and ephaptic depolarization. Identification of the suspected
      substrates of epileptogenesis will serve as a stimulus for future progress and
      provide direction for new experimental designs.

PMID- 10421560
TI  - Acute and chronic effects of seizures in the developing brain: lessons from
      clinical experience.
AB  - Seizures in the neonate are often considered a form of status epilepticus (SE)
      because they are relatively prolonged, difficult to control with antiepileptic
      drugs (AEDs), and may be associated with significant morbidity and mortality.
      Despite their clinical importance, there is still no clear understanding of how
      seizures may affect the developing brain. Although both basic neuroscience and
      clinical research have addressed these issues, there are difficulties in the
      design and analysis of each type of investigation. Animal studies should reflect
      the human condition, the most relevant studies being those that consider
      neocortical rather than hippocampal seizures. Clinical investigations should be
      based on precise, age-specific definitions of seizures of epileptic origin and of
      SE. Treatment strategies should be standardized with defined rationale and end
      points. Outcome measures are best when defined and quantifiable. The relative
      effects of underlying CNS injuries that coexist with the onset of neonatal
      seizures may be difficult to differentiate from the effects of the seizures
      themselves or their treatment. Current clinical studies suggest that the
      overriding factors in determining the outcome of neonates with seizures are the
      cause, the degree, and the distribution of brain injury at the time of seizure
      occurrence. However, such studies have limitations and may not yet employ
      methodology sensitive enough to detect a full range of adverse effects of
      seizures themselves.

PMID- 10421561
TI  - Acute and chronic effects of seizures in the developing brain: experimental
      models.
AB  - Clinical experience suggests two major components to the relationship between
      brain development and epilepsy. First, the maturational state of the immature
      brain appears to generally decrease seizure threshold and contribute to a
      different seizure phenotype from the adult. Second, certain forms of seizures,
      when present during development, may modify brain maturation to result in chronic
      epilepsy and/or other neurocognitive deficits. Maturational studies in animals
      suggest there are numerous factors developmentally regulated in such a way as to
      increase excitability in immature neuronal networks in the forebrain. The
      developing brain appears to exhibit a transient overexpression of glutamate
      receptors, glutamate receptor subunit composition permissive of enhanced
      excitatory neurotransmission, a relative lack of GABAergic inhibitory
      transmission, and ion channel expression and homeostasis which enhance neuronal
      excitability. The increased excitatory "drive" that is likely to be critical for
      normal brain development may share common mechanisms with those responsible for
      rendering the immature brain more susceptible to seizures, seizure induced
      plasticity (epileptogenesis), and neuronal injury. Furthermore, the coincidence
      of seizures during early postnatal brain development may modify many of these
      parameters, which in turn may promote long term epilepsy.

PMID- 10421562
TI  - Management approaches to prolonged seizures and status epilepticus.
AB  - Status epilepticus (SE) treatment should proceed on four fronts: termination of
      SE, prevention of recurrence, management of potential precipitating causes, and
      management of SE complications and underlying conditions. The intensity of the
      treatment should reflect the risk to the patient from SE, and drugs likely to
      depress respiration and blood pressure should initially be avoided. The Veterans
      Administration cooperative trial showed that when treating overt SE, first-line
      treatment success rates were: lorazepam 64.9%; phenobarbital 58.2%;
      diazepam/phenytoin 55.8%; and phenytoin alone 43.6%. The aggregate response rate
      to second-line agents for patients who did not respond to first-line agents was
      7.0%, and it was 2.3% for third-line agents, raising the question of the efficacy
      of a second and third drug. The recommended treatment for generalized convulsive
      SE is to begin with lorazepam. As a second-line agent, phenytoin or fosphenytoin,
      is still recommended if SE control is not achieved within 5 to 7 min.
      Fosphenytoin achieves a free phenytoin level of about 2 micro/mL in 15 min, as
      opposed to 25 min with phenytoin itself. Moreover, fosphenytoin is safer and,
      despite higher cost, it may be cost-effective. High-dose barbiturates, high-dose
      benzodiazepines, and propofol are employed for major treatment for refractory SE.
      Patients at this stage should undergo continuous electroencephalogram monitoring.
      Once SE is controlled, prevention of seizure recurrence should be individualized
      to each patient. The major complications of generalized convulsive SE (GCSE),
      rhabdomyolysis and hyperthermia, should be watched for and treated.

PMID- 10421563
TI  - The role of surgery in lung metastases.
AB  - AIMS: To evaluate the efficacy of pulmonary metastasectomy in 93 patients with
      lung metastases (LM) operated on from 1983 to 1997. METHODS: We assessed:
      location and histological diagnosis of the primary tumour (PT); the extent of
      pulmonary resection; and disease-free interval (DFI). Survival analysis was
      undertaken using the Kaplan-Meier method. RESULTS: Surgical complications
      occurred in eight (9%) patients; two (3%) died in hospital; seven (8%) were
      operated again because of further LM. In the whole patient group the average
      survival after metastasectomy was 40 months (median 22 months). The actuarial
      survival was 44% at 3 years and 35% at 5 years. With metastasectomy we achieved
      an overall survival after treatment of PT of 87 months (median 58 months). The
      actuarial survival was 58% at 5 years and 38% at 10 years. The average time
      between the treatment of PT and metastasectomy DFI was 4 years (median 41
      months). Patients with a DFI of more than 2 years tended to live longer
      (P=0.086). There were 23 patients with non-epithelial and 70 patients with
      epithelial tumours. Their DFIs were similar (mean 47, median 34 months for non
      epithelial and mean 51, median 29 months for epithelial tumours). Of patients
      with non-epithelial tumours, 38% survived for 5 years and their survival curves
      were similar. In the group of tumours with the most frequent location, the
      results of metastasectomy did not differ considerably: 5 year survival rates of
      20% for patients with kidney tumours, 28% for colorectal cancer, 30% for soft
      tissue sarcoma, 28% for skin melanoma and 18% for breast cancer. CONCLUSIONS:
      Lung metastasectomy seems to be a safe and efficient method of treatment even for
      patients who show further metastases. According to our study it seems that,
      except for LM of breast carcinoma (which has a slightly worse prognosis), the
      results of surgical resection are not dependent on either the location or the
      histological pattern of the PT. For this reason patients indicated for operation
      can be selected according to similar criteria.

PMID- 10421564
TI  - Cell polarity: Versatile scaffolds keep things in place.
AB  - Protein scaffolds organize transmembrane and cytoplasmic proteins and serve to
      integrate both structure and signaling at the apical junctional complex of
      polarized epithelial cells. These scaffolds are important in coordinating local
      and global changes in cell organization.

PMID- 10421565
TI  - Endocytosis: Is dynamin a 'blue collar' or 'white collar' worker?
AB  - The GTPase dynamin clearly plays an important role in endocytosis, but precisely
      how has been controversial. Some recent results support the view that dynamin
      uses GTP hydrolysis physically to drive vesiculation; others support the view
      that dynamin acts as a classical G protein 'switch'. Perhaps both views are
      correct.

PMID- 10421566
TI  - Plant development: Genetic clues to petal evolution.
AB  - A recent study of the expression of floral organ identity genes in buttercups,
      poppies and their relatives has shed light on the evolutionary origin of petals.

PMID- 10421567
TI  - Genetic recombination: Helicases and topoisomerases link up.
AB  - RecQ helicases and topoisomerase III are both required for genome stability,
      particularly to prevent 'promiscuous' genetic recombination. A recent study
      demonstrates that, together, these enzymes can catalyse the interlinking of
      plasmid DNA, and suggests a novel mechanism for the control of recombination.

PMID- 10421568
TI  - Airway patterning: A paradigm for restricted signalling.
AB  - Intercellular signalling is limited by the range of cell responsiveness, often
      mediated by repressors. A recently identified repressor, Sprouty, inhibits MAP
      kinase signalling in flies, mice and humans and has a conserved function in
      patterning the airways of these divergent species.

PMID- 10421569
TI  - Autoimmunity: Another pathway towards arthritis.
AB  - A new pathway leading to arthritis has been revealed by the discovery that
      antibodies specific for a ubiquitously expressed antigen are able to transfer a
      severe arthritic phenotype in mice. This new model will be useful for further
      analyses of the different pathways involved in rheumatoid arthritis.

PMID- 10421570
TI  - Chromosome segregation: Samurai separation of Siamese sisters.
AB  - How do cells ensure that sister chromatids are precisely partitioned in mitosis?
      New studies on budding yeast have revealed that sister chromatid separation at
      anaphase requires endoproteolytic cleavage of a protein that maintains the
      association between sister chromatids.

PMID- 10421571
TI  - Kinase phosphorylation: Keeping it all in the family.
AB  - The identification of PDK1 as a kinase that phosphorylates the AGC family of
      kinases led to a hunt for 'PDK2', a hypothetical regulated kinase(s) that would
      be required for full activation of the AGC kinases. Recent findings suggest that
      the elusive PDK2 may actually be a familiar kinase with an atypical associate.

PMID- 10421572
TI  - Visual discrimination: Seeing the third quality of light.
AB  - Objects can differ in brightness and colour. At least that is what our own visual
      system tells us. It now seems that stomatopod shrimps, and possibly also
      cephalopod molluscs, can see the direction of the electric vector of light, in
      much the same way we see colour.

PMID- 10421574
TI  - The hydrophobic phosphorylation motif of conventional protein kinase C is
      regulated by autophosphorylation.
AB  - BACKGROUND: A growing number of kinases are now known to be controlled by two
      phosphorylation switches, one on a loop near the entrance to the active site and
      a second on the carboxyl terminus. For the protein kinase C (PKC) family of
      enzymes, phosphorylation at the activation loop is mediated by another kinase but
      the mechanism for carboxy-terminal phosphorylation is still unclear. The latter
      switch contains two phosphorylation sites - one on a 'turn' motif and the second
      on a conserved hydrophobic phosphorylation motif - that are found separately or
      together in a number of other kinases. RESULTS: Here, we investigated whether the
      carboxy-terminal phosphorylation sites of a conventional PKC are controlled by
      autophosphorylation or by another kinase. First, kinetic analyses revealed that a
      purified construct of the kinase domain of PKC betaII autophosphorylated on the
      Ser660 residue of the hydrophobic phosphorylation motif in an apparently
      concentration-independent manner. Second, kinase-inactive mutants of PKC did not
      incorporate phosphate at either of the carboxy-terminal sites, Thr641 or Ser660,
      when expressed in COS-7 cells. The inability to incorporate phosphate on the
      hydrophobic site was unrelated to the phosphorylation state of the other key
      phosphorylation sites: kinase-inactive mutants with negative charge at Thr641
      and/or the activation-loop position were also not phosphorylated in vivo.
      CONCLUSIONS: PKC betaII autophosphorylates at its conserved carboxy-terminal
      hydrophobic phosphorylation site by an apparently intramolecular mechanism.
      Expression studies with kinase-inactive mutants revealed that this mechanism is
      the only one responsible for phosphorylating this motif in vivo. Thus,
      conventional PKC autoregulates the carboxy-terminal phosphorylation switch
      following phosphorylation by another kinase at the activation loop switch.

PMID- 10421573
TI  - Presenilin-1 deficiency leads to loss of Cajal-Retzius neurons and cortical
      dysplasia similar to human type 2 lissencephaly.
AB  - BACKGROUND: Presenilin-1 (PS1) is a transmembrane protein that is located in the
      endoplasmic reticulum and the cis Golgi apparatus. Missense mutations of PS1 that
      modify gamma-secretase function, leading to a pathologic processing of amyloid
      precursor protein, are an important cause of familial Alzheimer's disease.
      Physiologically, the presenilins are involved in the Notch and Wnt-beta-catenin
      signaling pathways. RESULTS: PS1-deficient mice develop a cortical dysplasia
      resembling human type 2 lissencephaly, with leptomeningeal fibrosis and migration
      of cortical-plate neurons beyond their normal position into the marginal zone and
      subarachnoid space. This disorder of neuronal migration is associated with the
      disappearance of the majority of the cells of the marginal zone, notably most of
      the Cajal-Retzius pioneer neurons, between embryonic days E14 and E18, and is
      preceded and accompanied by disorganization of Notch-1 immunoreactivity on the
      neuronal cell membranes. The marginal zone also becomes depleted of the
      extracellular matrix protein reelin and chondroitin sulfate proteoglycans. At
      that stage PS1 is transiently expressed in leptomeningeal fibroblasts, which are
      mandatory for the trophic support of Cajal-Retzius neurons. CONCLUSIONS: In
      agreement with models in which neuronal migration disorders have been linked to a
      defect in Cajal-Retzius cells, the loss of most of these cells in PS1-deficient
      mice leads to cortical dysplasia. Because PS1 is normally expressed in the
      leptomeninges, and these become fibrotic in the PS1-knockout mice, we favor the
      hypothesis that the loss of Cajal-Retzius cells is caused by a defective trophic
      interaction with leptomeningeal cells, possibly involving disruption of Notch
      signaling.

PMID- 10421575
TI  - Depletion of syntaxins in the early Caenorhabditis elegans embryo reveals a role
      for membrane fusion events in cytokinesis.
AB  - BACKGROUND: During cytokinesis, the plasma membrane of the parent cell is
      resolved into the two plasma membranes of the daughter cells. Membrane fusion
      events mediated by the machinery that participates in intracellular vesicle
      trafficking might contribute to this process. Two classes of molecules that are
      required for membrane fusion are the t-SNAREs and the v-SNAREs. The t-SNAREs
      (syntaxins) comprise a multi-gene family that has been suggested to mediate, at
      least in part, selective membrane fusion events in the cell. RESULTS: We have
      analyzed the genome of Caenorhabditis elegans and identified eight syntaxin
      genes. RNA-mediated interference (RNAi) was used to produce embryos deficient in
      individual syntaxins and these embryos were phenotypically characterized. Embryos
      deficient in one syntaxin, Syn-4, became multinucleate because of defects in
      karyomere fusion and cytokinesis. Syn-4 localized both to ingressing cleavage
      furrows and to punctate structures surrounding nuclei as they reformed during
      interphase. CONCLUSIONS: Our analyses indicate that both cytokinesis and
      reformation of the nuclear envelope are dependent on SNARE-mediated membrane
      fusion.

PMID- 10421576
TI  - Do essential genes evolve slowly?
AB  - Approximately two thirds of all knockouts of individual mouse genes give rise to
      viable fertile mice. These genes have thus been termed 'non-essential' in
      contrast to 'essential' genes, the knockouts of which result in death or
      infertility. Although non-essential genes are likely to be under selection that
      favours sequence conservation [1], it is predicted that they are less subject to
      such stabilising selection than essential genes, and hence evolve faster [2]. We
      have addressed this issue by analysing the molecular evolution of 108 non
      essential and 67 essential genes that have been sequenced in both mouse and rat.
      On preliminary analysis, the non-essential genes appeared to be faster evolving
      than the essential ones. We found, however, that the non-essential class contains
      a disproportionate number of immune-system genes that may be under directional
      selection (that is, selection favouring change) because of host-parasite
      coevolution. After correction for this bias, we found that the rate at which
      genes evolve does not correlate with the severity of the knockout phenotype. This
      was corroborated by the finding that, whereas neuron-specific genes have
      significantly lower rates of change than other genes, essential and non-essential
      neuronal genes have comparable rates of evolution. Our findings most probably
      reflect strong selection acting against even very subtle deleterious phenotypes,
      and indicate that the putative involvement of directional selection in host
      parasite coevolution and gene expression within the nervous system explains much
      more of the variance in rates of gene evolution than does the knockout phenotype.

PMID- 10421577
TI  - Animal cell-death suppressors Bcl-x(L) and Ced-9 inhibit cell death in tobacco
      plants.
AB  - In plants, events similar to programmed cell death have been reported [1] [2],
      although little is known of their mechanisms at the molecular level. To
      investigate the mechanism(s) involved, we overexpressed bcl-x(L), which encodes a
      mammalian suppressor of programmed cell death, in tobacco plants, under the
      control of a strong promoter [3]. In plants expressing Bcl-x(L), cell death
      induced by UV-B irradiation, paraquat treatment or the hypersensitive reaction
      (HR) to tobacco mosaic virus (TMV) infection was suppressed. The extent of
      suppression of cell death depended on the amount of Bcl-x(L) protein expressed.
      Similar enhanced resistance to cell death was found in transgenic tobacco plants
      overexpressing the ced-9 gene, a Caenorhabditis elegans homolog of bcl-x(L) [4],
      indicating that Bcl-x(L) and Ced-9 can function to inhibit cell death in plants.

PMID- 10421578
TI  - The Arp2/3 complex is essential for the actin-based motility of Listeria
      monocytogenes.
AB  - Actin polymerisation is thought to drive the movement of eukaryotic cells and
      some intracellular pathogens such as Listeria monocytogenes. The Listeria surface
      protein ActA synergises with recruited host proteins to induce actin
      polymerisation, propelling the bacterium through the host cytoplasm [1]. The
      Arp2/3 complex is one recruited host factor [2] [3]; it is also believed to
      regulate actin dynamics in lamellipodia [4] [5]. The Arp2/3 complex promotes
      actin filament nucleation in vitro, which is further enhanced by ActA [6] [7].
      The Arp2/3 complex also interacts with members of the Wiskott-Aldrich syndrome
      protein (WASP) [8] family - Scar1 [9] [10] and WASP itself [11]. We interfered
      with the targeting of the Arp2/3 complex to Listeria by using carboxy-terminal
      fragments of Scar1 that bind the Arp2/3 complex [11]. These fragments completely
      blocked actin tail formation and motility of Listeria, both in mouse brain
      extract and in Ptk2 cells overexpressing Scar1 constructs. In both systems,
      Listeria could initiate actin cloud formation, but tail formation was blocked.
      Full motility in vitro was restored by adding purified Arp2/3 complex. We
      conclude that the Arp2/3 complex is a host-cell factor essential for the actin
      based motility of L. monocytogenes, suggesting that it plays a pivotal role in
      regulating the actin cytoskeleton.

PMID- 10421579
TI  - Nicotinic acid adenine dinucleotide phosphate triggers Ca2+ release from brain
      microsomes.
AB  - Mobilization of Ca2+ from intracellular stores is an important mechanism for
      generating cytoplasmic Ca2+ signals [1]. Two families of intracellular Ca(2+)
      release channels - the inositol-1,4, 5-trisphosphate (IP3) receptors and the
      ryanodine receptors (RyRs) - have been described in mammalian tissues [2].
      Recently, nicotinic acid adenine dinucleotide phosphate (NAADP), a molecule
      derived from NADP+, has been shown to trigger Ca2+ release from intracellular
      stores in invertebrate eggs [3] [4] [5] [6] and pancreatic acinar cells [7]. The
      nature of NAADP-induced Ca2+ release is unknown but it is clearly distinct from
      the IP3- and cyclic ADP ribose (cADPR)-sensitive mechanisms in eggs (reviewed in
      [8] [9]). Furthermore, mammalian cells can synthesize and degrade NAADP,
      suggesting that NAADP-induced Ca2+ release may be widespread and thus contribute
      to the complexity of Ca2+ signalling [10] [11]. Here, we show for the first time
      that NAADP evokes Ca2+ release from rat brain microsomes by a mechanism that is
      distinct from those sensitive to IP3 or cADPR, and has a remarkably similar
      pharmacology to the action of NAADP in sea urchin eggs [12]. Membranes prepared
      from the same rat brain tissues are able to support the synthesis and degradation
      of NAADP. We therefore suggest that NAADP-mediated Ca2+ signalling could play an
      important role in neuronal Ca2+ signalling.

PMID- 10421580
TI  - Behavioural evidence for polarisation vision in stomatopods reveals a potential
      channel for communication.
AB  - Polarisation sensitivity (PS) - the ability to detect the orientation of
      polarised light - occurs in a wide variety of invertebrates [1] [2] and
      vertebrates [3] [4] [5], many of which are marine species [1]. Of these, the
      crustacea are particularly well documented in terms of their structural [6] and
      neural [7] [8] adaptations for PS. The few behavioural studies conducted on
      crustaceans demonstrate orientation to, or local navigation with, polarised sky
      patterns [9]. Aside from this, the function of PS in crustaceans, and indeed in
      most animals, remains obscure. Where PS can be shown to allow perception of
      polarised light as a 'special sensory quality' [1], separate from intensity or
      colour, it has been termed polarisation vision (PV). Here, within the remarkable
      visual system of the stomatopod crustaceans (mantis shrimps) [10], we provide the
      first demonstration of PV in the crustacea and the first convincing evidence for
      learning the orientation of polarised light in any animal. Using new polarimetric
      [11] and photographic methods to examine stomatopods, we found striking patterns
      of polarisation on their antennae and telson, suggesting that one function of PV
      in stomatopods may be communication [12]. PV may also be used for tasks such as
      navigation [5] [9] [13], location of reflective water surfaces [14] and contrast
      enhancement [1] [15] [16] [17] [18]. It is possible that the stomatopod PV system
      also contributes to some of these functions.

PMID- 10421581
TI  - Evidence for cooperative interactions between the two motor domains of
      cytoplasmic dynein.
AB  - Cytoplasmic dynein is a force-transducing ATPase that powers the movement of
      cellular cargoes along microtubules. Two identical heavy chain polypeptides (>
      500 kDa) of the cytoplasmic dynein complex contain motor domains that possess the
      ATPase and microtubule-binding activities required for force production [1]. It
      is of great interest to determine whether both heavy chains (DHCs) in the dynein
      complex are required for progression of the mechanochemical cycle and motility,
      as observed for other dimeric motors. We have used transgenic constructs to
      investigate cooperative interactions between the two motor domains of the
      Drosophila cytoplasmic dynein complex. We show that 138 kDa and 180 kDa amino
      terminal fragments of DHC can assemble with full-length DHC to form heterodimeric
      complexes containing only a single motor domain. The single-headed dynein
      complexes can bind and hydrolyze ATP, yet do not show the ATP-induced detachment
      from microtubules that is characteristic of wild-type homodimeric dynein. These
      results suggest that cooperative interactions between the monomeric units of the
      dimer are required for efficient ATP-induced detachment of dynein and
      unidirectional movement along the microtubule.

PMID- 10421582
TI  - Role of yeast SIR genes and mating type in directing DNA double-strand breaks to
      homologous and non-homologous repair paths.
AB  - Eukaryotes have acquired many mechanisms to repair DNA double-strand breaks
      (DSBs) [1]. In the yeast Saccharomyces cerevisiae, this damage can be repaired
      either by homologous recombination, which depends on the Rad52 protein, or by non
      homologous end-joining (NHEJ), which depends on the proteins yKu70 and yKu80 [2]
      [3]. How do cells choose which repair pathway to use? Deletions of the SIR2, SIR3
      and SIR4 genes - which are involved in transcriptional silencing at telomeres and
      HM mating-type loci (HMLalpha and HMRa) in yeast [4] - have been reported to
      reduce NHEJ as severely as deletions of genes encoding Ku proteins [5]. Here, we
      report that the effect of deleting SIR genes is largely attributable to
      derepression of silent mating-type genes, although Sir proteins do play a minor
      role in end-joining. When DSBs were made on chromosomes in haploid cells that
      retain their mating type, sir Delta mutants reduced the frequency of NHEJ by
      twofold or threefold, although plasmid end-joining was not affected. In diploid
      cells, sir mutants showed a twofold reduction in the frequency of NHEJ in two
      assays. Mating type also regulated the efficiency of DSB-induced homologous
      recombination. In MATa/MATalpha diploid cells, a DSB induced by HO endonuclease
      was repaired 98% of the time by gene conversion with the homologous chromosome,
      whereas in diploid cells with an alpha mating type (matDelta/MATalpha) repair
      succeeded only 82% of the time. Mating-type regulation of genes specific to
      haploid or diploid cells plays a key role in determining which pathways are used
      to repair DSBs.

PMID- 10421583
TI  - Cardinal directions for visual optic flow.
AB  - As we move through our environment, the flow of deforming images on the retinae
      provides a rich source of information about the three-dimensional structure of
      the external world and how to navigate through it. Recent evidence from
      psychophysical [1] [2] [3] [4], electrophysiological [5] [6] [7] [8] [9] and
      imaging [10] [11] studies suggests that there are neurons in the primate visual
      system - in the medial superior temporal cortex - that are specialised to respond
      to this type of complex 'optic flow' motion. In principle, optic flow could be
      encoded by a small number of neural mechanisms tuned to 'cardinal directions',
      including radial and circular motion [12] [13]. There is little support for this
      idea at present, however, from either physiological [6] [7] or psychophysical
      [14] research. We have measured the sensitivity of human subjects for detection
      of motion and for discrimination of motion direction over a wide and densely
      sampled range of complex motions. Average sensitivity was higher for inward and
      outward radial movement and for both directions of rotation, consistent with the
      existence of detectors tuned to these four types of motion. Principle component
      analysis revealed two clear components, one for radial stimuli (outward and
      inward) and the other for circular stimuli (clockwise and counter-clock-wise).
      The results imply that the mechanisms that analyse optic flow in humans tend to
      be tuned to the cardinal axes of radial and rotational motion.

PMID- 10421584
TI  - The counterforce.

PMID- 10421585
TI  - Hydrogen bonding.

PMID- 10421586
TI  - The seven good byways of science...the rest.

PMID- 10421588
TI  - Circulation online only : july 27, 1999 

PMID- 10421587
TI  - Biology in pictures. Mantis shrimp display.

PMID- 10421589
TI  - 1999 Bristol-Myers Squibb cardiovascular metabolic research award. Earl Davie,
      PhD, defined the system of blood coagulation.

PMID- 10421590
TI  - Targeting the proteolytic arsenal of neutrophils. A promising approach for
      postpump syndrome and ARDS.

PMID- 10421591
TI  - Effects of oral folic acid supplementation on endothelial function in familial
      hypercholesterolemia. A randomized placebo-controlled trial.
AB  - BACKGROUND: Folates have been suggested to be of benefit in reducing
      cardiovascular risk. The present study was designed to examine whether oral folic
      acid supplementation could improve endothelial function as an intermediate end
      point for cardiovascular risk in patients with increased risk of atherosclerosis
      due to familial hypercholesterolemia (FH). METHODS AND RESULTS: In a prospective,
      randomized, double-blind, placebo-controlled study with crossover design, we
      evaluated the effects of 4 weeks of treatment with oral folic acid (5 mg PO) on
      endothelial function in FH. In 20 FH patients, forearm vascular function was
      assessed at baseline, after 4 weeks of folic acid treatment, and after 4 weeks of
      placebo treatment by venous occlusion plethysmography, with serotonin and sodium
      nitroprusside used as endothelium-dependent and -independent vasodilators. In
      addition, we examined the vasoconstrictor response to the NO synthase inhibitor
      N(G)-monomethyl-L-arginine to assess basal NO activity. In FH patients, folic
      acid supplementation restored the impaired endothelium-dependent vasodilation,
      whereas it did not significantly influence endothelium-independent vasodilation
      or basal forearm vasomotion. There was a trend toward improvement in basal NO
      activity. CONCLUSIONS: These data demonstrate that oral supplementation of folic
      acid can improve endothelial function in patients with increased risk of
      atherosclerotic disease due to hypercholesterolemia, without changes in plasma
      lipids.

PMID- 10421592
TI  - Can coronary blood flow velocity pattern after primary percutaneous transluminal
      coronary angioplasty [correction of angiography] predict recovery of regional
      left ventricular function in patients with acute myocardial infarction?
AB  - BACKGROUND: In the era of primary percutaneous transluminal coronary angioplasty
      (PTCA), it is important to judge whether myocardium within acute ischemic injury
      is viable. This study sought to investigate parameters derived from the coronary
      blood flow velocity spectrum immediately after primary PTCA in patients with
      acute myocardial infarction and to elucidate the clinical value of coronary blood
      flow measurement in predicting myocardial viability. METHODS AND RESULTS: Using a
      Doppler guidewire, we measured coronary blood flow velocity after successful
      completion of primary PTCA in 23 consecutive patients with acute anterior
      myocardial infarction. Regional wall motion was analyzed to estimate anterior
      wall motion score index (A-WMSI) by echocardiography before PTCA and 1 month
      after the onset of symptoms. Average systolic peak velocity (ASV) and
      deceleration time of diastolic flow velocity (DDT) significantly correlated to 1
      month A-WMSI (r=-0.54, P=0.007 and r=-0.62, P=0.002, respectively), and optimal
      cutoff values to predict viable myocardium (defined as 1-month A-WMSI </=2.0)
      were 6.5 cm/s for ASV and 600 ms for DDT (sensitivity=0.79, specificity=0.89 and
      sensitivity=0.86, specificity=0.89, respectively). ASV and DDT also correlated
      weakly to the change in A-WMSI (r=0.46, P=0.03 and r=0.49, P=0.02, respectively).
      CONCLUSIONS: Low ASV and rapid DDT of coronary blood flow spectrum immediately
      after primary PTCA reflects a greater degree of microvascular damage in the risk
      area. Analysis of coronary blood flow spectrum immediately after primary PTCA by
      use of a Doppler guidewire is useful in predicting recovery of regional left
      ventricular function.

PMID- 10421593
TI  - Effect of beta-blockers on free radical-induced cardiac contractile dysfunction.
AB  - BACKGROUND: We examined the effects of hydroxyl radicals (OH.) on human
      myocardial contractility and on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA)
      activity and the effects of the beta-receptor antagonists metoprolol, carvedilol,
      and its metabolite BM-910228. METHODS AND RESULTS: Isometric force of contraction
      was determined in isolated human myocardium. H(2)O(2) 1 mmol/L and Fe(3+)
      nitrilotriacetic acid (Fe(3+)-NTA) 0.1 mmol/L used for generation of OH. induced
      a decrease in basal force of contraction and an increase in diastolic tension in
      atrial and left ventricular myocardial preparations. After challenge with OH.,
      the maximum positive inotropic response to Ca(2+) 1.8 to 15 mmol/L was decreased
      by 60% and by 39%, respectively. The effects of OH. could be blocked by catalase.
      Carvedilol and its metabolite BM-910228 attenuated the OH.-induced impairment of
      the inotropic response to Ca(2+) in atrial myocardial preparations. Metoprolol
      had no significant effect. The stimulation frequency (0.5 to 3.0 Hz)-dependent
      increase in force of contraction and decrease in diastolic tension were abolished
      after exposure of atrial trabeculae to OH. In parallel, SERCA activity was
      decreased by OH. concentration-dependently, as determined in myocardial membrane
      preparations. BM-910228 partially restored the force-frequency relationship and
      preserved SERCA activity. CONCLUSIONS: OH. radicals induce an impairment of
      contraction and relaxation and an attenuation of the force-frequency relationship
      in human myocardium accompanied by an inhibition of SERCA. Carvedilol and BM
      910228 partly prevented OH.-induced contractile dysfunction. These observations
      could explain the improvement of ejection fraction in heart failure trials with
      carvedilol without a restoration of beta-adrenergic receptor density.

PMID- 10421594
TI  - Is pulse pressure useful in predicting risk for coronary heart Disease? The
      Framingham heart study.
AB  - BACKGROUND: Current definitions of hypertension are based on levels of systolic
      blood pressure (SBP) and diastolic blood pressure (DBP), but not on pulse
      pressure (PP). We examined whether PP adds useful information for predicting
      coronary heart disease (CHD) in the population-based Framingham Heart Study.
      METHODS AND RESULTS: We studied 1924 men and women between 50 and 79 years of age
      at baseline with no clinical evidence of CHD and not taking antihypertensive drug
      therapy. Cox regression, adjusted for age, sex, and other risk factors, was used
      to assess the relations between blood pressure components and CHD risk over a 20
      year follow-up. The association with CHD risk was positive for SBP, DBP, and PP,
      considering each pressure individually; of the 3, PP yielded the largest chi(2)
      statistic. When SBP and DBP were jointly entered into the multivariable model,
      the association with CHD risk was positive for SBP (HR, 1.22; 95% CI, 1.15 to
      1.30) and negative for DBP (HR, 0. 86; 95% CI, 0.75 to 0.98). Four subgroups were
      defined according to SBP levels (<120, 120 to 139, 140 to 159, and >/=160 mm Hg).
      Within each subgroup, the association with CHD risk was negative for DBP and
      positive for PP. A cross-classification of SBP-DBP levels confirmed these
      results. CONCLUSIONS: In the middle-aged and elderly, CHD risk increased with
      lower DBP at any level of SBP>/=120 mm Hg, suggesting that higher PP was an
      important component of risk. Neither SBP nor DBP was superior to PP in predicting
      CHD risk.

PMID- 10421596
TI  - Efficacy and safety of ibutilide fumarate for the conversion of atrial
      arrhythmias after cardiac surgery.
AB  - BACKGROUND: Atrial arrhythmias occur commonly after cardiac surgery and are a
      cause of significant morbidity and increased hospital costs, yet there is no well
      studied treatment strategy to deal with them expeditiously. The purpose of this
      study was to determine the efficacy and safety of ibutilide fumarate, an approved
      drug for the rapid conversion of atrial fibrillation and flutter, in patients
      after cardiac surgery. METHODS AND RESULTS: Patients with atrial fibrillation or
      flutter occurring 1 to 7 days after surgery and lasting 1 hour to 3 days were
      randomized to receive two 10-minute blinded infusions of placebo or 0.25, 0.5, or
      1.0 mg of ibutilide fumarate. Treatment was considered successful if sinus rhythm
      was restored for any period of time by hour 1.5. A total of 302 patients were
      randomized, 201 with fibrillation and 101 with flutter. Treatment with ibutilide
      resulted in significantly higher conversion rates than placebo, and efficacy was
      dose related (placebo 15%; ibutilide 0.25 mg 40%, 0.5 mg 47%, and 1.0 mg 57%).
      Conversion rates at all doses were higher for atrial flutter than for atrial
      fibrillation. Mean time to conversion decreased as the dose was increased.
      Polymorphic ventricular tachycardia was the most serious adverse effect and
      occurred in 1.8% of the ibutilide-treated patients compared with 1.2% of patients
      who received placebo. CONCLUSIONS: Ibutilide is a useful and safe treatment
      alternative for the atrial arrhythmias that occur after cardiac surgery.

PMID- 10421595
TI  - Alterations in the local myocardial motion pattern in patients suffering from
      pressure overload due to aortic stenosis.
AB  - BACKGROUND: MR tissue tagging allows the noninvasive assessment of the locally
      and temporally resolved motion pattern of the left ventricle. Alterations in
      cardiac torsion and diastolic relaxation of the left ventricle were studied in
      patients with aortic stenosis and were compared with those of healthy control
      subjects and championship rowers with physiological volume-overload hypertrophy.
      METHODS AND RESULTS: Twelve aortic stenosis patients, 11 healthy control subjects
      with normal left ventricular function, and 11 world-championship rowers were
      investigated for systolic and diastolic heart wall motion on a basal and an
      apical level of the myocardium. Systolic torsion and untwisting during diastole
      were examined by use of a novel tagging technique (CSPAMM) that provides access
      to systolic and diastolic motion data. In the healthy heart, the left ventricle
      performs a systolic wringing motion, with a counterclockwise rotation at the apex
      and a clockwise rotation at the base. Apical untwisting precedes diastolic
      filling. In the athlete's heart, torsion and untwisting remain unchanged compared
      with those of the control subjects. In aortic stenosis patients, torsion is
      significantly increased and diastolic apical untwisting is prolonged compared
      with those of control subjects or athletes. CONCLUSIONS: Torsional behavior as
      observed in pressure- and volume-overloaded hearts is consistent with current
      theoretical findings. A delayed diastolic untwisting in the pressure-overloaded
      hearts of the patients may contribute to a tendency toward diastolic dysfunction.

PMID- 10421597
TI  - Trandolapril reduces the incidence of atrial fibrillation after acute myocardial
      infarction in patients with left ventricular dysfunction.
AB  - BACKGROUND: Studies have suggested that ACE inhibitors have an antiarrhythmic
      effect on ventricular arrhythmias. Whether they have an effect on atrial
      fibrillation is unknown. METHODS AND RESULTS: We investigated the effect of ACE
      inhibition with trandolapril on the incidence of atrial fibrillation in patients
      with reduced left ventricular function secondary to acute myocardial infarction.
      The patients in this study were those who qualified for inclusion into the
      TRAndolapril Cardiac Evaluation (TRACE) study, a randomized double-blind placebo
      controlled study and who had sinus rhythm on the ECG obtained at randomization.
      Patients who fulfilled the criteria for inclusion were randomized to treatment
      with the ACE inhibitor trandolapril or placebo and were followed up for 2 to 4
      years. Development and time to occurrence of atrial fibrillation in one 12-lead
      ECG recorded at the outpatient visits was the primary end point of this
      investigation. Of the 1749 patients included in the TRACE study, 1577 had sinus
      rhythm on the ECG recorded at randomization. Of these patients, 790 were
      randomized to trandolapril treatment and 787 to placebo treatment. The groups
      differed only slightly with respect to baseline characteristics. A total of 64
      patients developed atrial fibrillation during the 2- to 4-year follow-up period.
      Significantly more patients developed atrial fibrillation in the placebo group
      than in the trandolapril group, 5.3% (n=42) versus 2.8% (n=22), respectively,
      P<0.05. Cox multivariable regression analysis, adjusting for important baseline
      characteristics, revealed that trandolapril treatment significantly reduced the
      risk of developing atrial fibrillation (RR, 0.45; 95% CI, 0.26 to 0.76; P<0.01).
      CONCLUSIONS: The results from the present study demonstrate that trandolapril
      treatment reduces the incidence of atrial fibrillation in patients with left
      ventricular dysfunction after acute myocardial infarction.

PMID- 10421599
TI  - Interactions between electronic article surveillance systems and implantable
      cardioverter-defibrillators.
AB  - BACKGROUND: In patients with implantable cardioverter-defibrillators (ICDs).
      inappropriate shocks have been reported with exposure to electronic article
      surveillance systems. The risk to patients with ICDs of walking through or
      lingering near surveillance systems requires further investigation. METHODS AND
      RESULTS: We evaluated the response in ICD function in 170 subjects during a 10-
      to 15-second midgate walk-through of and during extreme (2 minutes within 6 in of
      the gate) exposure to 3 common article surveillance systems. Complete testing was
      done in 169 subjects. During a 10- to 15-second (very slow) walk-through of the 3
      surveillance systems, no interactions were observed that would negatively affect
      ICD function. During extreme exposure (169 subjects) and during extreme exposure
      and pacing via the ICD (126 subjects), interactions between the ICD and the
      article surveillance systems were observed in 19 subjects. In 7 subjects, this
      interaction was clinically relevant and would have likely (3 subjects) and
      possibly (4 subjects) resulted in ICD shocks. In 12 subjects, the interaction was
      minor. CONCLUSIONS: It is safe for a patient with an ICD to walk through
      electronic article surveillance systems. Lingering in a surveillance system may
      result in an inappropriate ICD shock.

PMID- 10421598
TI  - Baroreflex gain predicts blood pressure recovery during simulated ventricular
      tachycardia in humans.
AB  - BACKGROUND: Despite similar degrees of left ventricular dysfunction and similar
      tachycardia or pacing rate, blood pressure (BP) response and symptoms vary
      greatly among patients. Sympathetic nerve activity (SNA) increases during
      sustained ventricular tachycardia (VT), and the magnitude of this
      sympathoexcitatory response appears to contribute to the net hemodynamic outcome.
      We hypothesize that the magnitude of sympathoexcitation and thus arterial
      baroreflex gain is an important determinant of the hemodynamic outcome of VT.
      METHODS AND RESULTS: We evaluated the relation between arterial baroreflex
      sympathetic gain and BP recovery during rapid ventricular pacing (VP) in patients
      referred for electrophysiological study. Efferent postganglionic muscle SNA, BP,
      and central venous pressure (CVP) were measured in 14 patients during
      nitroprusside infusion and during VP at 150 (n=12) or 120 (n=2) bpm. Arterial
      baroreflex gain was defined as the slope of the relationship of change in SNA to
      change in diastolic BP during nitroprusside infusion. Recovery of mean arterial
      pressure (MAP) during VP was measured as the increase in MAP from the nadir at
      the onset of pacing to the steady-state value during sustained VP. Arterial
      baroreflex gain correlated positively with recovery of MAP (r=0.57, P=0.034). No
      significant correlation between ejection fraction and baroreflex gain (r=0.48,
      P=0.08) or BP recovery (r=0.41, P=0.15) was found. When patients were separated
      into high versus low baroreflex gain, the recovery of MAP during simulated VT was
      significantly greater in patients with high gain. CONCLUSIONS: These data
      strongly suggest that arterial baroreflex gain contributes significantly to
      hemodynamic stability during simulated VT. Knowledge of baroreflex gain in
      individual patients may help the clinician tailor therapy directed toward
      sustained VT.

PMID- 10421600
TI  - Cardiac interbeat interval dynamics from childhood to senescence : comparison of
      conventional and new measures based on fractals and chaos theory.
AB  - BACKGROUND: New methods of R-R interval variability based on fractal scaling and
      nonlinear dynamics ("chaos theory") may give new insights into heart rate
      dynamics. The aims of this study were to (1) systematically characterize and
      quantify the effects of aging from early childhood to advanced age on 24-hour
      heart rate dynamics in healthy subjects; (2) compare age-related changes in
      conventional time- and frequency-domain measures with changes in newly derived
      measures based on fractal scaling and complexity (chaos) theory; and (3) further
      test the hypothesis that there is loss of complexity and altered fractal scaling
      of heart rate dynamics with advanced age. METHODS AND RESULTS: The relationship
      between age and cardiac interbeat (R-R) interval dynamics from childhood to
      senescence was studied in 114 healthy subjects (age range, 1 to 82 years) by
      measurement of the slope, beta, of the power-law regression line (log power-log
      frequency) of R-R interval variability (10(-4) to 10(-2) Hz), approximate entropy
      (ApEn), short-term (alpha(1)) and intermediate-term (alpha(2)) fractal scaling
      exponents obtained by detrended fluctuation analysis, and traditional time- and
      frequency-domain measures from 24-hour ECG recordings. Compared with young adults
      (<40 years old, n=29), children (<15 years old, n=27) showed similar complexity
      (ApEn) and fractal correlation properties (alpha(1), alpha(2), beta) of R-R
      interval dynamics despite lower spectral and time-domain measures. Progressive
      loss of complexity (decreased ApEn, r=-0.69, P<0.001) and alterations of long
      term fractal-like heart rate behavior (increased alpha(2), r=0.63, decreased
      beta, r=-0.60, P<0.001 for both) were observed thereafter from middle age (40 to
      60 years, n=29) to old age (>60 years, n=29). CONCLUSIONS: Cardiac interbeat
      interval dynamics change markedly from childhood to old age in healthy subjects.
      Children show complexity and fractal correlation properties of R-R interval time
      series comparable to those of young adults, despite lower overall heart rate
      variability. Healthy aging is associated with R-R interval dynamics showing
      higher regularity and altered fractal scaling consistent with a loss of complex
      variability.

PMID- 10421601
TI  - Matrix metalloproteinase inhibitor prevents acute lung injury after
      cardiopulmonary bypass.
AB  - BACKGROUND: Acute lung injury (ALI) after cardiopulmonary bypass (CPB) results
      from sequential priming and activation of neutrophils. Activated neutrophils
      release neutral serine, elastase, and matrix metalloproteinases (MMPs) and oxygen
      radical species, which damage alveolar-capillary basement membranes and the
      extracellular matrix, resulting in an ALI clinically defined as adult respiratory
      distress syndrome (ARDS). We hypothesized that treatment with a potent MMP and
      elastase inhibitor, a chemically modified tetracycline (CMT-3), would prevent ALI
      in our sequential insult model of ALI after CPB. METHODS AND RESULTS:
      Anesthetized Yorkshire pigs were randomized to 1 of 5 groups: control (n=3); CPB
      (n=5), femoral-femoral hypothermic bypass for 1 hour; LPS (n=7), sham bypass
      followed by infusion of low-dose Escherichia coli lipopolysaccharide (LPS; 1
      microgram/kg); CPB+LPS (n=6), both insults; and CPB+LPS+CMT-3 (n=5), both insults
      plus intravenous CMT-3 dosed to obtain a 25-micromol/L blood concentration.
      CPB+LPS caused severe lung injury, as demonstrated by a significant fall in
      PaO(2) and an increase in intrapulmonary shunt compared with all groups (P<0.05).
      These changes were associated with significant pulmonary infiltration of
      neutrophils and an increase in elastase and MMP-9 activity. CONCLUSIONS: All
      pathological changes typical of ALI after CPB were prevented by CMT-3. Prevention
      of lung dysfunction followed an attenuation of both elastase and MMP-2 activity.
      This study suggests that strategies to combat ARDS should target terminal
      neutrophil effectors.

PMID- 10421602
TI  - Neuregulin in cardiac hypertrophy in rats with aortic stenosis. Differential
      expression of erbB2 and erbB4 receptors.
AB  - BACKGROUND: Neuregulins are a family of peptide growth factors that promote cell
      growth and viability. The potential role of neuregulin-erbB signaling in
      hypertrophic growth and later failure in the adult heart in vivo is not known.
      METHODS AND RESULTS: We used ribonuclease protection assays to quantify mRNA
      levels of neuregulin, erbB2, and erbB4 in left ventricular (LV) tissue and
      myocytes of normal rats and rats with aortic stenosis with pressure-overload
      hypertrophy 6 and 22 weeks after banding. At both stages of hypertrophy, Northern
      blot analyses of mRNA from LV myocytes showed upregulation of atrial natriuretic
      peptide, a molecular marker of hypertrophy (P<0.05). LV tissue neuregulin message
      levels were similar in animals with aortic stenosis compared with controls (P=NS)
      and were not detectable in myocytes. LV erbB2 and erbB4 message levels in LV
      tissue and myocytes were maintained during early compensatory hypertrophy in 6
      week aortic stenosis animals compared with age-matched controls; in contrast,
      erbB2 and erbB4 message levels were depressed in 22-week aortic stenosis animals
      at the stage of early failure (both P<0.01 vs age-matched controls).
      Immunoblotting of erbB2 and erbB4 also showed normal protein levels in 6-week
      aortic stenosis animals compared with controls; however, erbB2 and erbB4 protein
      levels were depressed in 22-week aortic stenosis animals (48% decrease in erbB2,
      P<0.05, and 43% decrease in erbB4, P<0.01) relative to age-matched controls.
      CONCLUSIONS: The neuregulin receptors erbB2 and erbB4 are downregulated at both
      the message and protein levels at the stage of early failure in animals with
      chronic hypertrophy secondary to aortic stenosis. These data suggest a role for
      disabled erbB receptor signaling in the transition from compensatory hypertrophy
      to failure.

PMID- 10421603
TI  - Selective activation of the K(+)(ATP) channel is a mechanism by which sudden
      death is produced by low-energy chest-wall impact (Commotio cordis).
AB  - BACKGROUND: Sudden death due to relatively innocent chest-wall impact has been
      described in young individuals (commotio cordis). In our previously reported
      swine model of commotio cordis, ventricular fibrillation (with T-wave strikes)
      and ST-segment elevation (with QRS strikes) were produced by 30-mph baseball
      impacts to the precordium. Because activation of the K(+)(ATP) channel has been
      implicated in the pathogenesis of ST elevation and ventricular fibrillation in
      myocardial ischemia, we hypothesized that this channel could be responsible for
      the electrophysiologic findings in our experimental model and in victims of
      commotio cordis. METHODS AND RESULTS: In the initial experiment, 6 juvenile swine
      were given 0.5 mg/kg IV glibenclamide, a selective inhibitor of the K(+)(ATP)
      channel, and chest impact was given on the QRS. The results of these strikes were
      compared with animals in which no glibenclamide was given. In the second phase,
      20 swine were randomized to receive glibenclamide or a control vehicle (in a
      double-blind fashion), with chest impact delivered just before the T-wave peak.
      With QRS impacts, the maximal ST elevation was significantly less in those
      animals given glibenclamide (0.16+/-0.10 mV) than in controls (0.35+/-0.20 mV;
      P=0.004). With T-wave impacts, the animals that received glibenclamide had
      significantly fewer occurrences of ventricular fibrillation (1 episode in 27
      impacts; 4%) than controls (6 episodes in 18 impacts; 33%; P=0.01). CONCLUSIONS:
      In this experimental model of commotio cordis, blockade of the K(+)(ATP) channel
      reduced the incidence of ventricular fibrillation and the magnitude of ST-segment
      elevation. Therefore, selective K(+)(ATP) channel activation may be a pivotal
      mechanism in sudden death resulting from low-energy chest-wall trauma in young
      people during sporting activities.

PMID- 10421604
TI  - Atrial linear ablations in pigs. Chronic effects on atrial electrophysiology and
      pathology.
AB  - BACKGROUND: Generation of long and continuous linear ablations is required in a
      growing number of atrial arrhythmias. However, deployment and assessment of these
      lesions may be difficult, and there are few data regarding their short- and long
      term effects on atrial electrophysiology and pathology. METHODS AND RESULTS: A
      nonfluoroscopic mapping and navigation technique was used to generate 3
      dimensional (3D) electroanatomic maps of the right atrium in 8 pigs. The catheter
      was then used to deliver sequential radiofrequency (RF) applications (power
      output gradually increased until 80% reduction in the amplitude of the unipolar
      electrogram) to generate a continuous lesion between the superior and inferior
      venae cavae. The animals were remapped 4 weeks after ablation during septal
      pacing. Lesion continuity was confirmed in all cases by the following criteria:
      (1) activation maps indicating conduction block [significant disparities in
      activation times (52.0+/-16.0 ms) and opposite orientation of the activation wave
      front on opposing sides of the lesion], (2) evidence of double potentials
      (interspike time difference of 52.3+/-17.1 ms), and (3) low peak-to-peak
      amplitude of the bipolar electrograms (0.7+/-0.6 mV) along the lesion. At
      autopsy, all lesions were continuous and transmural, averaged 50.5+/-6.7 mm, and
      were characterized histologically by transmural fibrosis throughout the length of
      the lesion. CONCLUSIONS: Long linear atrial ablation, created by sequential RF
      applications (using unipolar amplitude attenuation as the end point for energy
      delivery), results in long-term continuous and transmural lesions. Lesion
      continuity is associated with evidence of conduction block in the 3D activation
      maps and the presence of double potentials and low electrogram amplitude along
      the lesion.

PMID- 10421606
TI  - Platelet glycoprotein IIb/IIIa antagonists. What are the relevant issues
      concerning their pharmacology and clinical use?
AB  - During the last decade, intensive efforts have been made to evaluate the role of
      the platelet glycoprotein (GP) IIb/IIIa complex in platelet-mediated thrombus
      formation. Significant efforts have also been made to design potent antagonists
      of this "final common pathway" of platelet aggregation to be used as novel
      therapeutic strategies to treat acute coronary syndromes. Although several
      different GP IIb/IIIa antagonists have convincingly demonstrated the usefulness
      of this platelet-directed therapeutic strategy, a number of lingering unsolved
      and sometimes misunderstood issues concerning the pharmacology and optimal
      clinical usefulness of these agents remain to be explored. This article reviews
      these issues, which include antagonist affinity, reversibility, and receptor
      specificity. Other issues are related to the effects of GP IIb/IIIa receptor
      availability, neoepitopes induced by antagonist binding with the potential to
      mediate thrombocytopenia, optimal methods of platelet monitoring and, perhaps
      ultimately, the potential therapeutic index of the oral class of GP IIb/IIIa
      antagonists. All of these specific issues are likely to be illuminated in the
      next several years, which will greatly determine the breadth of this therapeutic
      class.

PMID- 10421605
TI  - Left atrial relaxation and left ventricular systolic function determine left
      atrial reservoir function.
AB  - BACKGROUND: Determinants of left atrial (LA) reservoir function and its influence
      on left ventricular (LV) function have not been quantified. METHODS AND RESULTS:
      In an open-pericardium, paced (70 and 90 bpm) pig model of LV regional ischemia
      (left anterior descending coronary constriction), with high-fidelity LV, LA, and
      RV pressure recordings, we obtained the LA area with 2D automated border
      detection echocardiography, LA pressure-area loops, and Doppler transmitral flow.
      We calculated LV tau, LA relaxation (a-x pressure difference divided by time,
      normalized by a pressure), and stiffness (slope between x and v pressure points
      of v loop). Determinants of total LA reservoir (maximum-minimum area, cm(2)) were
      identified by multiple regression analysis. Different mean rates of LA area
      increase identified 2 consecutive (early rapid and late slow) reservoir phases.
      During ischemia, LV long-axis shortening (LAS, LV base systolic descent) and LA
      reservoir area change decreased (7.3+/-0.3 [SEM] versus 5.6+/-0.3 cm(2), P<0.001)
      and LA stiffness increased (1.6+/-0.3 versus 3.1+/-0.3 mm Hg/cm(2), P=0.009).
      Early reservoir area change depended on LA mean ejection rate (LA area at ECG P
      wave minus minimum area divided by time; multiple regression coefficient=0.9;
      P<0.001) and relaxation (coefficient=4.9 cm(2)xms/s; P<0.001). Late reservoir
      area change depended on LAS (coefficient=8 cm/s; P<0.001). Total reservoir
      filling depended on LA stiffness (coefficient=-0.31 cm(4)/mm Hg; P=0. 001) and
      cardiac output (coefficient=0.001 cm(2)xmin/L; P=0.002). The strongest predictor
      of cardiac output was LA reservoir filling (coefficient=301 L/minxcm(2);
      P<0.001). The v loop area was determined by cardiac output, LV ejection time,
      tau, and early transmitral flow. CONCLUSIONS: Two (early and late) reservoir
      phases are determined by LA contraction and relaxation and LV base descent. Acute
      LV regional ischemia increases LA stiffness and impairs LA reservoir function by
      reducing LV base descent.

PMID- 10421607
TI  - Chronic coronary artery dissection presenting as heart failure.

PMID- 10421608
TI  - Body iron stores, infection, and risk of acute myocardial infarction.

PMID- 10421609
TI  - Summary of a scientific conference on preventive nutrition: pediatrics to
      geriatrics.

PMID- 10421610
TI  - A double-peak phenomenon in the pharmacokinetics of alprazolam after oral
      administration.
AB  - The pharmacokinetics of alprazolam (ALP) after i.v. and p.o. administration in
      rats were characterized. ALP decayed biexponentially after the i.v. dose (1.25
      mg/kg), but the concentration-time profiles after the p.o. doses (7 and 12.5
      mg/kg) exhibited a double-peak phenomenon. The presence of two peaks was
      confirmed by statistical analysis of the serum concentration data of ALP, as well
      as by observed double peaks in the serum concentration-time profiles of the two
      active metabolites (alpha-hydroxyalprazolam and 4-hydroxyalprazolam). An
      absorption model incorporating a delay site is proposed to describe the data, and
      the absolute oral bioavailability is estimated to be about 30%. The two peaks
      were approximately 80 to 115 min apart, and there was a delay in the absorption
      of close to 80% of oral ALP, regardless of dose. We hypothesize that the
      mechanism underlying the double-peak phenomenon is due to reduction in gastric
      motility caused by the muscle relaxant effect of ALP. This hypothesis is
      supported by the observed longer delay in the appearance of the second peak at
      the higher p.o. dose. Enterohepatic recycling is precluded from being the
      underlying mechanism, because of the presence of double peaks after the p.o.
      doses but not after the i.v. dose. This is the first reported case of double
      peaks for oral ALP, and this phenomenon has not been reported for other
      benzodiazepines. The double-peak phenomenon caused by the hypothesized mechanism
      may have important therapeutic and drug interaction implications, especially
      because benzodiazepines are commonly coadministered with other drugs.

PMID- 10421611
TI  - Involvement of CYP2E1 as A low-affinity enzyme in phenacetin O-deethylation in
      human liver microsomes.
AB  - Phenacetin O-deethylation (POD) exhibits biphasic kinetics in human liver
      microsomes. Although cytochrome P-450 (CYP) 1A2 is responsible for the high
      affinity component of POD, the enzyme(s) that catalyzes the low-affinity reaction
      is still unknown. We examined the roles of human CYPs in POD by using human liver
      microsomes and recombinant CYPs from baculovirus-infected insect cells. Of the
      recombinant CYPs studied, CYP1A2 showed the highest POD activity. CYP1A1,
      CYP2C19, CYP2D6, CYP2E1, and CYP3A4 also showed POD activity at 500 microM
      phenacetin. K(M) values of recombinant CYP1A2 and CYP2E1 (28 +/- 2 microM and 785
      +/- 125 microM, respectively) were similar to those of the high- and low-affinity
      components of POD in pooled human liver microsomes (15 +/- 5 and 894 +/- 189
      microM, respectively). Fluvoxamine (10 microM) and anti-CYP1A2 antibodies
      potently inhibited POD activity at 500 microM phenacetin in pooled human liver
      microsomes to 22.8 and 34.2% of controls, respectively. CYP2E1 inhibitors
      diethyldithiocarbamate and aniline also reduced POD activity. The combination of
      fluvoxamine (10 microM) and aniline (1 mM) further inhibited the residual POD
      activity not inhibited by fluvoxamine alone. Microsomal POD activity in 12 human
      livers in the absence of fluvoxamine was correlated with immunoquantified CYP1A2
      levels (r = 0.961, p <.001) and, in the presence of 10 microM fluvoxamine, was
      correlated with immunoquantified CYP2E1 levels (r = 0.589, p <.01) or
      chlorzoxazone 6-hydroxylase activity (r = 0.823, p <.001). These results suggest
      that CYP2E1 is responsible for the low-affinity component of POD in human liver
      microsomes.

PMID- 10421613
TI  - Canalicular membrane transport is primarily responsible for the difference in
      hepatobiliary excretion of triethylmethylammonium and tributylmethylammonium in
      rats.
AB  - Two structurally similar quaternary ammonium compounds, triethylmethylammonium
      (TEMA, M(r) 116) and tributylmethylammonium (TBuMA, M(r) 200) were used as model
      compounds to identify the unit process of hepatobiliary excretion that is
      responsible for markedly different biliary excretion of organic cations (OCs).
      Cumulative biliary excretion (in percentage of dose; i.v., 12 micromol/kg) was
      0.17 for TEMA and 34.5 for TBuMA. In vivo uptake clearance into the liver was
      0.686 +/- 0.020 ml/min for TEMA and 0.421 +/- 0.028 ml/min for TBuMA. When the
      uptake clearance was examined in an isolated hepatocyte system, comparable
      clearance between TEMA and TBuMA was obtained, consistent with the in vivo
      result. These observations suggest that uptake into the liver is not the major
      determinant for the difference in biliary excretion of the OCs. Coadministration
      of colchicine, an inhibitor of microtubule formation, had no effect on biliary
      excretion of the model compounds, and the primary site of subcellular
      distribution of the OCs appears to be the cytosol, suggesting that intracellular
      movement does not play a major role in the markedly different biliary excretion
      of the OCs. In contrast, in vivo excretion clearance across the canalicular
      membrane for TBuMA was 180-fold greater than that for TEMA, and in vitro efflux
      clearance of TBuMA was smaller than that of TEMA (p <.01), indicative of
      involvement of these processes in the markedly different biliary excretion of the
      OCs. Therefore, these data indicate that canalicular transport is primarily
      responsible for the markedly different biliary excretion of TEMA and TBuMA.

PMID- 10421614
TI  - Flavin-containing monooxygenase-mediated metabolism of N-deacetyl ketoconazole by
      rat hepatic microsomes.
AB  - Although ketoconazole is extensively metabolized by hepatic microsomal enzymes,
      the route of formation and toxicity of suspected metabolites are largely unknown.
      Reports indicate that N-deacetyl ketoconazole (DAK) is a major initial metabolite
      in mice. DAK may be susceptible to successive oxidative attacks on the N-1
      position by flavin-containing monooxygenases (FMO) producing potentially toxic
      metabolites. Previous laboratory findings have demonstrated that postnatal rat
      hepatic microsomes metabolize DAK by NADPH-dependent monooxygenases to two
      metabolites as determined by HPLC. Our current investigation evaluated DAK's
      metabolism in adult male and female rats and identified metabolites that may be
      responsible for ketoconazole's hepatotoxicity. DAK was extensively metabolized by
      rat liver microsomal monooxygenases at pH 8.8 in pyrophosphate buffer containing
      the glucose 6-phosphate NADPH-generating system to three metabolites as
      determined by HPLC. The initial metabolite of DAK was a secondary hydroxylamine,
      N-deacetyl-N-hydroxyketoconazole, which was confirmed by liquid
      chromatography/mass spectrometry and NMR spectroscopy. Extensive metabolism of
      DAK occurred at pH 8.8 in pyrophosphate buffer (female 29% and male 53% at 0.25
      h; female 55% and male 57% at 0.5 h; and female 62% and male 66% at 1.0 h).
      Significantly less metabolism of DAK occurred at pH 7.4 in phosphate buffer
      (female 11%, male 17% at 0.25 h; female 20%, male 31% at 0.5 h; and female 27%,
      male 37% at 1 h). Heat inactivation of microsomal-FMO abolished the formation of
      these metabolites from DAK. SKF-525A did not inhibit this reaction. These results
      suggest that DAK appears to be extensively metabolized by adult FMO-mediated
      monooxygenation.

PMID- 10421612
TI  - OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of
      fexofenadine.
AB  - Fexofenadine, a nonsedating antihistamine, does not undergo significant metabolic
      biotransformation. Accordingly, it was hypothesized that uptake and efflux
      transporters could be importantly involved in the drug's disposition. Utilizing a
      recombinant vaccinia expression system, members of the organic anion transporting
      polypeptide family, such as the human organic anion transporting polypeptide
      (OATP) and rat organic anion transporting polypeptides 1 and 2 (Oatp1 and Oatp2),
      were found to mediate [(14)C]fexofenadine cellular uptake. On the other hand, the
      bile acid transporter human sodium taurocholate cotransporting polypeptide (NTCP)
      and the rat organic cation transporter rOCT1 did not exhibit such activity. P
      glycoprotein (P-gp) was identified as a fexofenadine efflux transporter, using
      the LLC-PK1 cell, a polarized epithelial cell line lacking P-gp, and the
      derivative cell line (L-MDR1), which overexpresses P-gp. In addition, oral and
      i.v. administration of [(14)C]fexofenadine to mice lacking mdr1a-encoded P-gp
      resulted in 5- and 9-fold increases in the drug's plasma and brain levels,
      respectively, compared with wild-type mice. Also, a number of drug inhibitors of
      P-gp were found to be effective inhibitors of OATP. Because OATP transporters and
      P-gp colocalize in organs of importance to drug disposition such as the liver,
      their activity provides an explanation for the heretofore unknown mechanism(s)
      responsible for fexofenadine's disposition and suggests potentially similar roles
      in the disposition of other xenobiotics.

PMID- 10421616
TI  - Disposition and biotransformation of the antiretroviral drug nevirapine in
      humans.
AB  - The pharmacokinetics and biotransformation of the antiretroviral agent nevirapine
      (NVP) after autoinduction were characterized in eight healthy male volunteers.
      Subjects received 200-mg NVP tablets once daily for 2 weeks, followed by 200 mg
      twice daily for 2 weeks. Then they received a single oral dose (solution) of 50
      mg containing 100 microCi of [(14)C]NVP. Biological fluids were analyzed for
      total radioactivity, parent compound (HPLC/UV), and metabolites (electrospray
      liquid chromatography/mass spectroscopy and liquid chromatography/tandem mass
      spectroscopy). Mean recovery of radioactivity was 91.4%, with 81.3% excreted in
      urine and 10.1% recovered in the feces over a period of 10 days. Circulating
      radioactivity was evenly distributed between whole blood and plasma. At maximum
      plasma concentration, parent compound accounted for approximately 75% of the
      circulating radioactivity. Mean plasma elimination half-lives for total
      radioactivity and NVP were 21.3 and 20.0 h, respectively. Several metabolites
      were identified in urine including 2-hydroxynevirapine glucuronide (18.6%), 3
      hydroxynevirapine glucuronide (25.7%), 12-hydroxynevirapine glucuronide (23.7%),
      8-hydroxynevirapine glucuronide (1.3%), 3-hydroxynevirapine (1.2%), 12
      hydroxynevirapine (0.6%), and 4-carboxynevirapine (2.4%). Greater than 80% of the
      radioactivity in urine was made up of glucuronidated conjugates of hydroxylated
      metabolites of NVP. Thus, cytochrome P-450 metabolism, glucuronide conjugation,
      and urinary excretion of glucuronidated metabolites represent the primary route
      of NVP biotransformation and elimination in humans. Only a small fraction of the
      dose (2.7%) was excreted in urine as parent compound.

PMID- 10421615
TI  - The use of human hepatocyte cultures to study the induction of cytochrome P-450.
AB  - We have previously reported that paclitaxel (Taxol) is a potent inducer of
      cytochrome P-450 (CYP) 3A protein and CYP3A mRNA in human hepatocyte cultures.
      Here we report that Taxol increased CYP3A-dependent testosterone 6beta
      hydroxylation in intact hepatocytes. This effect was concentration-dependent,
      with maximal increase in enzyme activity being observed at 10 microM Taxol.
      Treatment of hepatocyte cultures with concentrations of Taxol higher than 10
      microM caused a dose-dependent decrease in testosterone 6beta-hydroxylase
      activity, amount of CYP3A protein, and total protein synthesis. The maximal CYP3A
      activity detected after treatment with Taxol or rifampicin was similar in six
      separate human hepatocyte cultures, suggesting that the cultures have achieved a
      limit of maximally inducible CYP3A. The fold increase in enzyme activity,
      however, was different and was inversely related to the level of expression in
      untreated hepatocytes, with the greatest increases being observed in the
      hepatocytes that expressed the lowest basal level of CYP3A. Pretreatment of
      hepatocytes with triacetyloleandomycin resulted in a 90% inhibition of
      testosterone 6beta-hydroxylase activity. Our results demonstrate the use of human
      hepatocyte cultures to investigate the induction of cytochrome P-450 by
      xenobiotics in intact cells and stress the importance of large dose-response
      studies as well as the need to assess toxicity in these investigations. The
      response to inducers of CYP3A activity were very consistent among different
      hepatocyte donors. Absolute values of testosterone 6beta-hydroxylase activity did
      not vary more than 2- and 5-fold in induced and untreated hepatocytes,
      respectively.

PMID- 10421617
TI  - Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal
      metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug
      interaction.
AB  - ABT-378 is a potent in vitro inhibitor of the HIV protease and is currently being
      developed for coadministration with another HIV protease inhibitor, ritonavir, as
      an oral therapeutic treatment for HIV infection. In the present study, the effect
      of ritonavir, a potent inhibitor of cytochrome P-450 (CYP) 3A, on the in vitro
      metabolism of ABT-378 was examined. Furthermore, the effect of ABT-378-ritonavir
      combinations on several CYP-dependent monooxygenase activities in human liver
      microsomes was also examined. ABT-378 was found to undergo NADPH- and CYP3A4/5
      dependent metabolism to three major metabolites, M-1 (4-oxo) and M-3/M-4 (4
      hydroxy epimers), as well as several minor oxidative metabolites in human liver
      microsomes. The mean apparent K(m) and V(max) values for the metabolism of ABT
      378 by human liver microsomes were 6.8 +/- 3.6 microM and 9.4 +/- 5.5 nmol of ABT
      378 metabolized/mg protein/min, respectively. Ritonavir inhibited human liver
      microsomal metabolism of ABT-378 potently (K(i) = 0.013 microM). The combination
      of ABT-378 and ritonavir was much weaker in inhibiting CYP-mediated
      biotransformations than ritonavir alone, and the inhibitory effect appears to be
      primarily due to the ritonavir component of the combination. The ABT-378
      ritonavir combinations (at 3:1 and 29:1 ratios) inhibited CYP3A (IC(50) = 1.1 and
      4.6 microM), albeit less potently than ritonavir (IC(50) = 0.14 microM).
      Metabolic reactions mediated by CYP1A2, CYP2A6, and CYP2E1 were not affected by
      the ABT-378-ritonavir combinations. The inhibitory effects of ABT-378-ritonavir
      combinations on CYP2B6 (IC(50) = >30 microM), CYP2C9 (IC(50) = 13.7 and 23.0
      microM), CYP2C19 (IC(50) = 28.7 and 38.0 microM), and CYP2D6 (IC(50) = 13.5 and
      29.0 microM) were marginal and are not likely to produce clinically significant
      drug-drug interactions.

PMID- 10421618
TI  - Influence of extracellular matrix overlay and medium formulation on the induction
      of cytochrome P-450 2B enzymes in primary cultures of rat hepatocytes.
AB  - The effect of medium formulation, composition of extracellular matrix overlay,
      and culture dish material on liver microsomal cytochrome P-450 (CYP) 2B induction
      by phenobarbital (PB) was investigated in primary cultures of rat hepatocytes.
      When hepatocytes were maintained on Permanox dishes with an overlay of either
      collagen (type I) or Matrigel, Williams' E medium was superior to other medium
      formulations in terms of the magnitude of induction of CYP2B on a per milligram
      microsomal protein basis. Modified Chee's medium (MCM) and hepatocyte culture
      medium were intermediate in their capacity to sustain induction of CYP2B by PB,
      and Dulbecco's modified Eagle's medium was slightly less effective. The overall
      induction of CYP2B activity by PB was, on average, 50% lower in hepatocytes
      cultured on polystyrene dishes (LUX). Little or no difference was observed
      between hepatocytes overlaid with collagen and those overlaid with Matrigel. MCM
      was superior to Williams' E medium in terms of the yield of microsomal protein
      and the ultrastructural features of the hepatocyte monolayers. CYP2B induction by
      PB was optimal after 3 days of treatment in either medium. CYP1A, CYP3A, and
      CYP4A activities could be induced in vitro by prototypical inducing agents in
      hepatocytes cultured on Permanox dishes with MCM and a Matrigel overlay to
      comparable levels observed in vivo. The results of these studies show that medium
      formulation and culture vessel material, but not the type of extracellular matrix
      overlay, have significant effects on the induction of CYP enzymes in cultured rat
      hepatocytes maintained in a sandwich configuration.

PMID- 10421619
TI  - Metabolism and excretion of atorvastatin in rats and dogs.
AB  - Atorvastatin (AT) is a second-generation potent inhibitor of 3-hydroxy-3
      methylglutaryl-CoA reductase, clinically approved for lowering plasma
      cholesterol. Using a mixture of [D(5)/D(0)] AT and/or [(14)C]AT, the metabolic
      fate and excretion of AT were examined in rats and dogs following single and
      multiple oral doses. Limited biliary recycling was examined in one dog after a
      single dose of AT. AT-derived metabolites in bile samples were identified by
      metabolite screening of the [D(5)/D(0)] AT molecular clusters using tandem mass
      spectrometry. Bile was a major route of [(14)C] drug-derived excretion,
      accounting for 73 and 33% of the oral dose in the rat and dog, respectively. The
      remaining radioactivity was recovered in the feces; only trace amounts were
      excreted in urine. Radioactive components identified in rat and dog bile were the
      para- and ortho-hydroxy metabolites, a glucuronide conjugate of ortho-hydroxy AT,
      and unchanged AT. Two minor radioactive components were identified as beta
      oxidation products of AT with one confirmed as a beta-oxidized AT derivative. The
      reappearance of AT and major metabolites in bile from a dog administered a sample
      of its previously excreted bile indicated biliary recycling is an important
      component in AT metabolism. Multiple dose administration in rats did not alter
      biliary metabolic profiles. Rat and dog plasma profiles after multiple dose
      administration were similar and showed no additional metabolites not found in
      bile. Examination of rat and dog bile and plasma indicates that AT primarily
      undergoes oxidative metabolism.

PMID- 10421620
TI  - Characterization of cytochrome P-450 2D1 activity in rat brain: high-affinity
      kinetics for dextromethorphan.
AB  - We investigated the enzymatic function, stability, and regional distribution of
      rat brain cytochrome P-450 (CYP) 2D1 activity. CYP2D1 is the homolog of human
      CYP2D6, a genetically variable enzyme that activates or inactivates many clinical
      drugs acting on the central nervous system (e.g., antidepressants, monoamine
      oxidase inhibitors, serotonin uptake inhibitors, and neuroleptics), drugs of
      abuse (e.g., amphetamine and codeine), neurotoxins (e.g., 1-methyl-4-phenyl
      1,2,3,6-tetrahydropyridine, 1,2,3, 4-tetrahydroquinoline), and endogenous
      neurochemicals (e.g., tryptamine). The CYP2D family has been identified in
      rodent, canine, and primate brain. Conversion of dextromethorphan to dextrorphan
      by rat brain membranes was assayed by HPLC and was dependent on NADPH, protein
      concentration, and incubation time. Significant loss of activity was observed in
      some homogenizing buffers and after freezing of whole tissues or membrane
      preparations. Dextromethorphan (0.5-640 microM) metabolism was mediated by high-
      and low-affinity enzyme systems; K(m1) was 2.7 +/- 2.6 and K(m2) was 757 +/- 156
      microM (n = 3 rats, mean +/- S.E.). The enzyme activity was significantly (p
      <.01) and stereoselectively inhibited by CYP2D1 inhibitors quinine and quinidine
      (not by CYP2C or CYP3A inhibitors), and by anti-CYP2D6 peptide antiserum (not by
      anti-CYP2C, -CYP2B, or -CYP3A antibodies). The enzymatic activity demonstrated
      significant brain regional variation (n = 10 regions, p <.001). These data
      characterize CYP2D1-mediated dextromethorphan metabolism in rat brain and suggest
      that localized metabolism of other CYP2D1 substrates (drugs, neurotoxins, and
      possibly endogenous compounds) within the brain will occur. In humans, CYP2D6 is
      genetically polymorphic; the variable expression of brain CYP2D6 may result in
      interindividual differences in central drug and neurotoxin metabolism, possibly
      contributing to interindividual differences in drug effects and neurotoxicity.

PMID- 10421621
TI  - Inhibition of esterolysis of enalapril by paraoxon increases the urinary
      clearance in isolated perfused rat kidney.
AB  - The effect of competing elimination pathways on the metabolic and excretory
      clearance estimates was examined with tracer concentrations of [(3)H]enalapril,
      which was both metabolized and excreted by the rat kidney. Perturbation was
      achieved with use of the carboxylesterase inhibitor paraoxon, which inhibited
      [(3)H]enalapril metabolism to [(3)H]enalaprilat in rat renal S9 fraction. At 0.1,
      0.5, 1, and 10 microM paraoxon, esterolysis of enalapril was inhibited by 76 +/-
      7, 93 +/- 5, 96 +/- 5, and 93 +/- 6%, respectively. The lowest concentration (0.1
      microM) of paraoxon was chosen for single-pass isolated perfused kidney (IPK)
      studies because viability was least compromised, and the sodium and glucose
      reabsorptive functions of the IPK remained constant. After an equilibration
      period (15-20 min at constant pressure, 90-100 mm Hg), perfusion of the rat
      kidney with [(3)H]enalapril was carried out under constant flow (8 ml/min) for 30
      min in the absence and presence of paraoxon (0.1 microM). The metabolic (from
      1.83 +/- 0.52 to 1.48 +/- 0.47 ml/min/g) and total renal (from 1.87 +/- 0.46 to
      1. 57 +/- 0.41 ml/min/g) clearances of [(3)H]enalapril in the IPKs were decreased
      significantly (p <.05) in the presence of paraoxon when compared with controls.
      Concomitantly, the urinary clearance (from 0. 04 +/- 0.07 to 0.09 +/- 0.09
      ml/min/g) and the fractional excretion (from 0.23 +/- 0.18 to 0.52 +/- 0.25) of
      [(3)H]enalapril doubled (p <.05). The study illustrates that a reduction in
      cellular metabolism of the kidney brings forth a rise in the estimate of
      clearance of its complimentary pathway, estimate of the excretory (urinary)
      clearance.

PMID- 10421622
TI  - Modulation of multidrug resistance protein expression in porcine brain capillary
      endothelial cells in vitro.
AB  - Multidrug resistance-associated protein (MRP) is a transport system that is
      involved in the elimination of xenobiotics and biologically active endogenous
      substrates. Recently, the presence of MRP has been demonstrated in cultured brain
      capillary endothelial cells (BCECs). The time-dependent, functional expression of
      MRP in porcine BCECs was investigated to assess the value of this cell culture
      model for drug transport at the blood-brain barrier. Western blot analysis was
      used to investigate MRP expression in freshly isolated porcine BCECs and compared
      to MRP expression at days 8 and 10 in culture. Subcellular localization of MRP
      was investigated by immunocytochemistry with an MRP-specific monoclonal antibody,
      MRPr1. Functional activity of MRP was assessed by efflux studies with the
      fluorescent MRP substrate glutathione-methylfluorescein (GS-MF). No significant
      MRP expression was detected in freshly isolated endothelial cells. However, MRP
      expression is up-regulated in cell culture in a time-dependent manner.
      Immunostaining revealed predominantly perinuclear and, to a lesser degree, plasma
      membrane localization of MRP. At 10 degrees C GS-MF efflux was significantly
      decreased, indicating the involvement of an energy-dependent transport system.
      Efflux of GS-MF was apparently inhibited by MK571, a specific inhibitor for MRP.
      Porcine BCECs demonstrate up-regulation of functional MRP expression during
      culture, as observed in human tissue, and therefore might serve as a useful in
      vitro system for studying MRP-mediated blood-brain barrier transport.

PMID- 10421623
TI  - In vitro identification of the human cytochrome P-450 enzymes involved in the N
      demethylation of azelastine.
AB  - Azelastine hydrochloride [4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H
      azepin-4yl )-1-(2 H)-phthalazinone monohydrochloride], is a long-acting
      antiallergic and antiasthmatic drug. The human cytochrome P-450 (CYP) isoform
      responsible for azelastine N-demethylation, the major metabolic pathway for
      azelastine, has been examined. Eadie-Hofstee plots of azelastine N-demethylation
      in human liver microsomes were biphasic. In microsomes from baculovirus-infected
      insect cells, recombinant CYP3A4, 2D6, 1A2, and 2C19 exhibited high azelastine N
      demethylase activity. The K(m) values of the recombinant CYP2D6 (3.75 microM) and
      CYP3A4 (43.7 microM) were relatively close to that of high-affinity (14.1 microM)
      and low-affinity (54.7 microM) components in human liver microsomes,
      respectively. Azelastine N-demethylase activity was inhibited only by the anti
      CYP3A antibody, in contrast to antibodies for CYP1A, 2D6, and 2C. In addition,
      desmethylazelastine formation was significantly inhibited by ketoconazole and
      troleandomycin but only weakly by omeprazole, sulfaphenazole, and furafylline.
      These observations suggested that the N-demethylation of azelastine is most
      extensively catalyzed by the CYP2D6 and 3A4 isoforms in humans.

PMID- 10421625
TI  - Repeated oral rifampicin decreases the jejunal permeability of R/S-verapamil in
      rats.
AB  - The main purpose of this rat study was to investigate the effect of rifampicin on
      the effective permeability (P(eff)) of R/S-verapamil in the rat jejunum. In
      addition the effect on metabolism of R/S-verapamil to R/S-norverapamil was
      examined. In situ single-pass perfusions of the rat jejunum were performed in
      animals pretreated with oral rifampicin (250 mg/kg/day) or saline (control) over
      various time periods (1, 4, 7, and 14 days). The jejunal P(eff) of each of the
      enantiomers of verapamil and D-glucose was estimated. The appearance ratios of
      the CYP3A-formed metabolites R- and S-norverapamil were also estimated in the
      outlet jejunal perfusate. The jejunal P(eff) of both R- and S-verapamil decreased
      as an effect of the oral pretreatment with rifampicin. The appearance of R- and S
      norverapamil in the jejunum was also affected by the oral pretreatment with
      rifampicin, with increasing concentrations of R/S-norverapamil being evident
      after 14 days of rifampicin pretreatment. There was no stereoselectivity in
      either the P(eff) of R- and S-verapamil or the metabolic appearance of R- and S
      norverapamil. Treatment with oral rifampicin decreased the P(eff) of R/S
      verapamil, which is in accordance with an induction of P-glycoprotein activity in
      the apical enterocyte membrane. The increase in appearance of R/S-norverapamil in
      jejunum is in accordance with an induction of CYP3A metabolism in the rat.

PMID- 10421626
TI  - Infection and atherosclerosis: emerging mechanistic paradigms.
AB  - Although definitive proof of a causal role of infection contributing to
      atherogenesis is lacking, multiple investigations have demonstrated that
      infectious agents evoke cellular and molecular changes supportive of such a role.
      Moreover, both Chlamydia pneumoniae and cytomegalovirus exacerbate lesion
      development in animal models of atherosclerosis and restenosis. The fact that
      multiple pathogens have been associated with atherosclerosis implies that many
      "atherogenic" pathogens exist, and recent data suggest that the risk of
      atherosclerosis conveyed by infection relates to the number of atherogenic
      pathogens with which an individual is infected. It also is evident that
      variability in host susceptibility to the atherogenic effects of pathogens
      exists; this variability appears to be related at least in part to whether the
      host can generate an immune response that successfully controls pathogen
      inflammatory activity and in part to the specific pattern of immune response-
      humoral or cellular. The latter may relate to host capacity to control pathogen
      activity and to a pathogen-induced autoimmune component of the atherogenic
      process. Additional animal and human studies are necessary to further test the
      validity of the infection/atherosclerosis link and to provide more insight into
      the mechanisms by which infection may contribute to atherosclerosis, information
      critical for devising strategies to reduce or eliminate any contribution to
      atherosclerosis caused by infection.

PMID- 10421624
TI  - Disposition of cosalane, a novel anti-HIV agent, in isolated perfused rat livers.
AB  - Cosalane is a potent inhibitor of HIV replication with a broad range of activity.
      In this study, the hepatic disposition of cosalane was investigated with a
      noncirculating isolated perfused rat liver technique. When 6 microM cosalane was
      infused into livers from untreated rats, the drug was highly extracted by the
      liver (only 2. 5% of influent cosalane concentration appeared in the effluent
      perfusate). Pretreatment of rats with various inducers of cytochrome P-450 before
      perfusion neither altered the effluent cosalane concentration nor resulted in the
      appearance of detectable metabolites in the effluent perfusate or liver
      homogenates. Hepatic uptake of cosalane was negligible when the drug was infused
      in the presence of BSA, and infusion of albumin after cosalane resulted in a
      significant displacement of the drug into the effluent perfusate. Furthermore,
      permeabilization of perfused livers with digitonin significantly diminished
      effluent cosalane concentration while enhancing cosalane uptake by the liver.
      Based on our data, it appears that a significant proportion of cosalane does not
      penetrate the hepatocyte membrane and may accumulate in the lipid bilayer of the
      cell membrane. This finding supports the proposed mechanism explaining the
      antiviral effect of cosalane which stipulates that this compound appears to imbed
      perpendicularly in the lipid bilayer of the cell membrane and the viral envelope.
      Also, cosalane does not seem to be metabolized by the liver as evidenced by the
      lack of detectable metabolites in the effluent perfusate, liver homogenates, and
      liver microsomal incubations.

PMID- 10421627
TI  - Pulmonary arteriovenous malformation.

PMID- 10421628
TI  - A G-protein signaling network mediated by an RGS protein.

PMID- 10421629
TI  - Wnt-induced dephosphorylation of axin releases beta-catenin from the axin
      complex.
AB  - The stabilization of beta-catenin is a key regulatory step during cell fate
      changes and transformations to tumor cells. Several interacting proteins,
      including Axin, APC, and the protein kinase GSK-3beta are implicated in
      regulating beta-catenin phosphorylation and its subsequent degradation. Wnt
      signaling stabilizes beta-catenin, but it was not clear whether and how Wnt
      signaling regulates the beta-catenin complex. Here we show that Axin is
      dephosphorylated in response to Wnt signaling. The dephosphorylated Axin binds
      beta-catenin less efficiently than the phosphorylated form. Thus, Wnt signaling
      lowers Axin's affinity for beta-catenin, thereby disengaging beta-catenin from
      the degradation machinery.

PMID- 10421630
TI  - Transcription elongation factor hSPT5 stimulates mRNA capping.
AB  - RNA polymerase II nascent transcripts are capped during pausing before
      elongation. Here we report that hSPT5, the human homolog of yeast elongation
      factor SPT5, interacts directly with the capping enzyme. hSPT5 stimulated capping
      enzyme guanylylation and mRNA capping by severalfold. Although RNA 5'
      triphosphatase activity was unaffected, binding to this domain in the full-length
      enzyme is likely involved in the stimulation, as hSPT5 did not increase the
      activity of the guanylyltransferase fragment. Consistent with capping enzyme
      binding, TFIIH-phosphorylated CTD stimulated guanylylation, and this increase was
      not additive with hSPT5.

PMID- 10421632
TI  - Alternative olfactory neuron fates are specified by the LIM homeobox gene lim-4.
AB  - The Caenorhabditis elegans AWA, AWB, and AWC olfactory neurons are each required
      for the recognition of a specific subset of volatile odorants. lim-4 mutants
      express an AWC reporter gene inappropriately in the AWB olfactory neurons and
      fail to express an AWB reporter gene. The AWB cells are morphologically
      transformed toward an AWC fate in lim-4 mutants, adopting cilia and axon
      morphologies characteristic of AWC. AWB function is also transformed in these
      mutants: Rather than mediating the repulsive behavioral responses appropriate for
      AWB, the AWB neurons mediate attractive responses, like AWC. LIM-4 is a predicted
      LIM homeobox gene that is expressed in AWB and a few other head neurons. Ectopic
      expression of LIM-4 in the AWC neuron pair is sufficient to force those cells to
      adopt an AWB fate. The AWA nuclear hormone receptor ODR-7 described previously
      also represses AWC genes, as well as inducing AWA genes. We propose that the LIM
      4 and ODR-7 transcription factors function to diversify C. elegans olfactory
      neuron identities, driving them from an AWC-like state into alternative fates.

PMID- 10421631
TI  - Antagonism between G(o)alpha and G(q)alpha in Caenorhabditis elegans: the RGS
      protein EAT-16 is necessary for G(o)alpha signaling and regulates G(q)alpha
      activity.
AB  - To elucidate the cellular role of the heterotrimeric G protein G(o), we have
      taken a molecular genetic approach in Caenorhabditis elegans. We screened for
      suppressors of activated GOA-1 (G(o)alpha) that do not simply decrease its
      expression and found mutations in only two genes, sag-1 and eat-16. Animals
      defective in either gene display a hyperactive phenotype similar to that of goa-1
      loss-of-function mutants. Double-mutant analysis indicates that both sag-1 and
      eat-16 act downstream of, or parallel to, G(o)alpha and negatively regulate EGL
      30 (G(q)alpha) signaling. eat-16 encodes a regulator of G protein signaling (RGS)
      most similar to the mammalian RGS7 and RGS9 proteins and can inhibit endogenous
      mammalian G(q)/G(11) in COS-7 cells. Animals defective in both sag-1 and eat-16
      are inviable, but reducing function in egl-30 restores viability, indicating that
      the lethality of the eat-16; sag-1 double mutant is due to excessive G(q)alpha
      activity. Analysis of these mutations indicates that the G(o) and G(q) pathways
      function antagonistically in C. elegans, and that G(o)alpha negatively regulates
      the G(q) pathway, possibly via EAT-16 or SAG-1. We propose that a major cellular
      role of G(o) is to antagonize signaling by G(q).

PMID- 10421633
TI  - SNAP(c): a core promoter factor with a built-in DNA-binding damper that is
      deactivated by the Oct-1 POU domain.
AB  - snRNA gene transcription is activated in part by recruitment of SNAP(c) to the
      core promoter through protein-protein contacts with the POU domain of the
      enhancer-binding factor Oct-1. We show that a mini-SNAP(c) consisting of a subset
      of SNAP(c) subunits is capable of directing both RNA polymerase II (Pol II) and
      Pol III snRNA gene transcription. Mini-SNAP(c) cannot be recruited by Oct-1, but
      binds as efficiently to the promoter as SNAP(c) together with Oct-1 and directs
      activated RNA Pol III transcription. Thus, SNAP(c) represses its own binding to
      DNA, and repression is relieved by interactions with the Oct-1 POU domain that
      promote cooperative binding. We have shown previously that TBP also represses its
      own binding, and in that case repression is relieved by cooperative interactions
      with SNAP(c). This may represent a general mechanism to ensure that core promoter
      binding factors, which have strikingly slow off-rates, are recruited specifically
      to promoter sequences rather than to cryptic-binding sites in the genome.

PMID- 10421634
TI  - The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin
      protein ligase activity.
AB  - pVHL, the product of the VHL tumor suppressor gene, plays an important role in
      the regulation of cell growth and differentiation of human kidney cells, and
      inactivation of the VHL gene is the most frequent genetic event in human kidney
      cancer. The biochemical function of pVHL is unknown. Here we report that pVHL
      exists in vivo in a complex that displays ubiquitination-promoting activity in
      conjunction with the universally required components E1, E2, and ubiquitin. pVHL
      associated ubiquitination activity requires, at a minimum, pVHL to bind elongin C
      and Cul-2, relatives of core components of SCF (Skp1-Cdc53/Cul-1-F-box protein)
      E3 ligase complexes. Notably, certain tumor-derived mutants of pVHL demonstrate
      loss of associated ubiquitination promoting activity. These results identify pVHL
      as a component of a potential SCF-like E3 ubiquitin-protein ligase complex and
      suggest a direct link between pVHL tumor suppressor and the process of
      ubiquitination.

PMID- 10421636
TI  - A GATA-2/estrogen receptor chimera functions as a ligand-dependent negative
      regulator of self-renewal.
AB  - The transcription factor GATA-2 is expressed in hematopoietic stem and progenitor
      cells and is functionally implicated in their survival and proliferation. We have
      used estrogen and tamoxifen-inducible forms of GATA-2 to modulate the levels of
      GATA-2 in the IL-3-dependent multipotential hematopoietic progenitor cell model
      FDCP mix. Ligand-dependent induction of exogenous GATA-2 activity did not rescue
      cells deprived of IL-3 from apoptosis. However, induction of GATA-2 activity in
      cells cultured in IL-3 blocked factor-dependent self-renewal but not factor
      dependent survival: Cells undergo cell cycle arrest and cease proliferating but
      do not apoptose. This was accompanied by differentiation down the monocytic and
      granulocytic pathways. Differentiation occurred in the presence of IL-3 and did
      not require addition of exogenous differentiation growth factors such as G-CSF or
      GM-CSF normally required to induce granulomonocytic differentiation of FDCP-mix
      cells. Conversely, EPO-dependent erythroid differentiation was inhibited by GATA
      2 activation. These biological effects were obtained with levels of exogenous
      GATA-2 representing less than twofold increases over endogenous GATA-2 levels and
      were not observed in cells overexpressing GATA-1/ER. Similar effects on
      proliferation and differentiation were also observed in primary progenitor cells,
      freshly isolated from murine bone marrow and transduced with a GATA-2/ER
      containing retrovirus. Taken together, these data suggest that threshold
      activities of GATA-2 in hematopoietic progenitor cells are a critical determinant
      in influencing self-renewal versus differentiation outcomes.

PMID- 10421635
TI  - Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating
      mouse embryo.
AB  - Fgf8 and Fgf4 encode FGF family members that are coexpressed in the primitive
      streak of the gastrulating mouse embryo. We have analyzed the phenotype of Fgf8(
      /-) embryos and discovered that they fail to express Fgf4 in the streak. In the
      absence of both FGF8 and FGF4, epiblast cells move into the streak and undergo an
      epithelial-to-mesenchymal transition, but most cells then fail to move away from
      the streak. As a consequence, no embryonic mesoderm- or endoderm-derived tissues
      develop, although extraembryonic tissues form. Patterning of the prospective
      neuroectoderm is greatly perturbed in the mutant embryos. Anterior neuroectoderm
      markers are widely expressed, at least in part because the anterior visceral
      endoderm, which provides signals that regulate their expression, is not displaced
      proximally in the absence of definitive endoderm. Posterior neuroectoderm markers
      are not expressed, presumably because there is neither mesendoderm underlying the
      prospective neuroectoderm nor a morphologically normal node to provide the
      inductive signals necessary for their expression. This study identifies Fgf8 as a
      gene essential for gastrulation and shows that signaling via FGF8 and/or FGF4 is
      required for cell migration away from the primitive streak.

PMID- 10421637
TI  - Assembly of the Escherichia coli RuvABC resolvasome directs the orientation of
      holliday junction resolution.
AB  - Genetic recombination can lead to the formation of intermediates in which DNA
      molecules are linked by Holliday junctions. Movement of a junction along DNA, by
      a process known as branch migration, leads to heteroduplex formation, whereas
      resolution of a junction completes the recombination process. Holliday junctions
      can be resolved in either of two ways, yielding products in which there has, or
      has not, been an exchange of flanking markers. The ratio of these products is
      thought to be determined by the frequency with which the two isomeric forms
      (conformers) of the Holliday junction are cleaved. Recent studies with enzymes
      that process Holliday junctions in Escherichia coli, the RuvABC proteins,
      however, indicate that protein binding causes the junction to adopt an open
      square-planar configuration. Within such a structure, DNA isomerization can have
      little role in determining the orientation of resolution. To determine the role
      that junction-specific protein assembly has in determining resolution bias, a
      defined in vitro system was developed in which we were able to direct the
      assembly of the RuvABC resolvasome. We found that the bias toward resolution in
      one orientation or the other was determined simply by the way in which the Ruv
      proteins were positioned on the junction. Additionally, we provide evidence that
      supports current models on RuvABC action in which Holliday junction resolution
      occurs as the resolvasome promotes branch migration.

PMID- 10421638
TI  - Collisions between yeast chromosomal loci in vivo are governed by three layers of
      organization.
AB  - The relative probabilities that different pairs of chromosomal loci will collide
      with one another in vegetatively growing diploid yeast cells have been assessed
      using a genetic assay for Cre/loxP site-specific recombination. Recombination
      rates have been determined for 18 different pairs of loxP sites representing
      diverse pairs of positions within the genome. Overall, relative collision
      probabilities vary over an eightfold range. Within this range, a hierarchy
      comprising three levels of organization can be discerned. First, collisions
      between loci on nonhomologous chromosomes are governed by nonspecific centromere
      clustering. Second, a sequence is closer to allelic or nearby sequences on its
      homolog than to sequences on nonhomologous chromosomes, an effect most simply
      attributed to homolog pairing. Third, a sequence can be closer to other sequences
      nearby on the same chromosome than to sequences on other chromosomes. These
      findings provide a framework for assessing the role of chromosome disposition in
      cellular processes such as DNA repair and gene expression. Also the possibility
      is raised that genome-wide coalignment of homologs is not the fundamental raison
      d'etre of the somatic pairing process. We suggest instead that pairing may exist
      to promote juxtaposition of homologous regions within irregular genome
      complements.

PMID- 10421639
TI  - Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization
      directed by the AU-rich element.
AB  - AU-rich RNA-destabilizing elements (AREs) have become a paradigm for studying
      cytoplasmic mRNA turnover in mammalian cells. Though many RNA-binding proteins
      have been shown to bind to AREs in vitro, trans-acting factors that participate
      in the in vivo destabilization of cytoplasmic RNA by AREs remains unknown.
      Experiments were performed to investigate the cellular mechanisms and to identify
      potential trans-acting factors for ARE-directed mRNA decay. These experiments
      identified hnRNP D, a heterogeneous nuclear ribonucleoprotein (hnRNP) capable of
      shuttling between the nucleus and cytoplasm, as an RNA destabilizing protein in
      vivo in ARE-mediated rapid mRNA decay. Our results show that the ARE
      destabilizing function is dramatically impeded during hemin-induced erythroid
      differentiation and not in TPA-induced megakaryocytic differentiation of human
      erythroleukemic K562 cells. A sequestration of hnRNP D into a hemin-induced
      protein complex, termed hemin-regulated factor or HRF, correlates well with the
      loss of ARE-destabilizing function in the cytoplasm. Further experiments show
      that in hemin-treated cells, ectopic expression of hnRNP D restores the rapid
      decay directed by the ARE. The extent of destabilizing effect varies among the
      four isoforms of hnRNP D, with p37 and p42 displaying the most profound effect.
      These results demonstrate a specific cytoplasmic function for hnRNP D as an RNA
      destabilizing protein in ARE-mediated decay pathway. These in vivo findings
      support an emerging idea that shuttling hnRNP proteins have not only a nuclear
      but also a cytoplasmic function in mRNA metabolism. The data further imply that
      shuttling hnRNP proteins define, at least in part, the nuclear history of
      individual mRNAs and thereby influence their cytoplasmic fate.

PMID- 10421640
TI  - The immunobiology of bile and biliary epithelium.
AB  - Long thought to be just a simple pipe involved in the delivery of bile from
      hepatocytes to the gallbladder and intestine, bile ducts are now regarded as
      highly dynamic structures consisting of cell populations involved in formation,
      transport and modification of bile by both secretory and absorptive processes. In
      fact, both bile and biliary epithelium appear to have active immunologic roles in
      both innate and adaptive immune responses. These roles are becoming increasingly
      clear as techniques have been developed allowing for the study of bile and
      biliary epithelial cells (BECs) in mucosal immunity. Bile is actively involved in
      the transport of immunoglobulin to the intestine, while BECs secrete chemokines
      and cytokines and serve to localize the immune response by expressing critical
      cell adhesion molecules. Evidence suggests that BECs may also function as
      professional antigen-presenting cells (APC) and, in the process, contribute to
      the modulation of inflammatory reactions. Bile ducts and, in particular, BECs,
      are the primary site of damage in several immunologically mediated liver
      diseases. Progress in these important areas has been rapid and forms the basis of
      this review.

PMID- 10421641
TI  - Immortalized intrahepatic mouse biliary epithelial cells: immunologic
      characterization and immunogenicity.
AB  - Nonsuppurative destructive cholangitis (NSDC), a process of T-cell-mediated
      destruction of biliary epithelia observed in primary biliary cirrhosis (PBC),
      graft-versus-host disease (GVHD), and hepatic allograft rejection (HAR), also
      occurs in the B10. D2-->BALB/c model of GVHD. To advance studies of
      immunopathogenesis in this murine model, we immortalized 4 BALB/c intrahepatic
      biliary epithelial cell (BEC) lines as a reliable source of target cells. Freshly
      isolated BEC, as well as each cell line, expressed cytokeratin-19 (CK-19),
      epithelial cell adhesion molecule (EPCAM) and cystic fibrosis transmembrane
      conductance regulator (CFTR). None expressed albumin. Immortalized cells also
      expressed SV40 large T antigen. Class I major histocompatibility complex (MHC)
      was expressed by >97% of immortalized cells, while class II MHC and intercellular
      adhesion molecule-1 (ICAM-1) expression ranged from 0% to 13% and 14% to 74%,
      respectively. Interferon gamma (IFN-gamma) induced aberrant class II MHC
      expression and increased expression of ICAM-1. Variable proportions of
      immortalized cells expressed B7-1/B7-2 molecules and FAS. IFN-gamma significantly
      reduced B7-1 expression in some lines and significantly increased B7-2 expression
      in others. Allografts of freshly isolated and immortalized BEC injected into
      subscapular fat pads spontaneously formed duct-like structures. Inflammation was
      absent in BALB/c recipients. In contrast, inflammatory lesions in B10.D2
      recipients were reminiscent of NSDC. Our results indicate that BALB/c
      immortalized intrahepatic biliary cells: 1) retain the phenotype of mouse BEC; 2)
      can be induced to express aberrant class II MHC and increased ICAM-1; 3) express
      costimulatory B7-1/B7-2 molecules and FAS; and 4) spontaneously form duct-like
      structures after in vivo injection that are immunogenic in B10.D2 mice. These
      cell lines should facilitate future studies of the immunopathogenesis of NSDC in
      the B10. D2-->BALB/c murine model.

PMID- 10421642
TI  - Anomalous development of the hepatobiliary system in the Inv mouse.
AB  - Extrahepatic biliary atresia (BA) is a devastating disease of the neonate in
      which the hepatic and/or common bile duct is obliterated or interrupted. Infants
      and children with this diagnosis constitute 50% to 60% of the pediatric
      population that undergoes orthotopic liver transplantation. However, there is
      still very little known about the etiology and pathogenesis of BA. Several recent
      studies have demonstrated that anomalies of situs determination are more commonly
      associated with BA than previously recognized. In this study, we examined the
      pathogenesis of jaundice in the inv mouse, a transgenic mouse in which a
      recessive deletion of the inversin gene results in situs inversus and jaundice.
      The results show that these mice have cholestasis with conjugated
      hyperbilirubinemia, failure to excrete technetium-labeled mebrofenin from the
      liver into the small intestine, lack of continuity between the extrahepatic
      biliary tree and the small intestine as demonstrated by Trypan blue
      cholangiography, and a liver histological picture indicative of extrahepatic
      biliary obstruction with negligible inflammation/necrosis within the hepatic
      parenchyma. Lectin histochemical staining of biliary epithelial cells in serial
      sections suggests the presence of several different anomalies in the architecture
      of the extrahepatic biliary system. These results suggest that the inversin gene
      plays an essential role in the morphogenesis of the hepatobiliary system and
      raise the possibility that alterations in the human orthologue of inversin
      account for some of the cases of BA in which there are also anomalies of situs
      determination.

PMID- 10421644
TI  - Somatostatin alone or combined with emergency sclerotherapy in the treatment of
      acute esophageal variceal bleeding: a prospective randomized trial.
AB  - Recent trials have shown that somatostatin (SMT) is as effective as sclerotherapy
      in the treatment of acute variceal bleeding and that the combination of both
      treatments is more effective than sclerotherapy alone. To assess whether the
      addition of sclerotherapy improves the efficacy of SMT alone, all patients
      admitted to our unit with gastrointestinal bleeding and with suspected cirrhosis
      received a continuous infusion of SMT (250 micrograms/h). Endoscopy was performed
      between 1 and 5 hours later, and patients with esophageal variceal bleeding were
      randomized to receive or not to receive sclerotherapy. In both groups, SMT
      infusion was continued for 5 days. Fifty patient admissions were allocated to
      each group. Therapeutic failure occurred in 21 cases of the SMT group and in 7
      cases of the combined-therapy group (P =.002). Failure to control the acute
      episode occurred in 24% vs. 8% (P =.03) and early rebleeding in 24% vs. 7% (P
      =.03), respectively. Transfusional requirements were significantly higher in the
      SMT group, while the incidence of complications was lower (8% vs. 24%; P =.029).
      In the multivariate analysis, the presence of shock at admission and active
      bleeding during endoscopy were the variables that better predicted the failure of
      therapy with SMT alone. Mortality at 6 weeks was similar. These data demonstrate
      that the addition of sclerotherapy significantly improves the efficacy of SMT
      alone for the treatment of acute variceal bleeding, although it also increases
      the rate of complications. Patients with shock and those with active bleeding are
      more likely to benefit from this combined therapy.

PMID- 10421643
TI  - Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen
      carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite
      M1.
AB  - We followed 145 men with chronic hepatitis B virus (HBV) hepatitis for 10 years
      to determine whether exposure to aflatoxin, or concomitant exposure to hepatitis
      C virus (HCV), or family history of hepatocellular carcinoma (HCC) increased the
      risk of developing HCC. We collected 8 monthly urine samples before beginning
      follow-up and pooled them to detect aflatoxin metabolite M1 (AFM1). AFM1 was
      detected in 78 (54%) of the subjects. The risk of HCC was increased 3.3-fold
      (with a 95% confidence interval of 1.2-8.7) in those with detectable AFM1 (above
      3.6 ng/L). This relative risk was adjusted for age and for HCV status. The
      attributable risk from exposure to detectable AFM1 was 0.553 (0.087, 0.94). The
      relative risk of fatal cirrhosis for those with elevated AFM1 was 2.8 (0.6,
      14.3), and the odds of having a persistently elevated alanine transaminase (ALT)
      were 2.5-fold greater in those with detectable AFM1 (P =.007). Concomitant
      infection with HCV increased the risk of HCC 5.8-fold (2. 0-17), adjusted for age
      and AFM1 status. A family history of HCC increased the risk of HCC 5.6-fold,
      adjusted for age and AFM1. Four men with detectable AFM1 and HCC all had missense
      mutation in codon 249 of the p53 gene in cancer tissues. This study shows that
      exposure to AFM1 can account for a substantial part of the risk of HCC in men
      with chronic HBV hepatitis and adds importantly to the evidence that HCV and
      family history of HCC increase the risk of HCC in men with chronic HBV hepatitis.

PMID- 10421645
TI  - Primary biliary cirrhosis once rare, now common in the United Kingdom?
AB  - There is a widespread impression that the number of patients with the autoimmune
      liver disease primary biliary cirrhosis (PBC) is increasing, although its
      incidence and prevalence vary widely. Using thorough case-finding methods and
      rigorous definitions to assess changes in incidence and prevalence with time and
      to explore the symptomatology and mortality of the disease in a large group of
      unselected patients, we performed a descriptive epidemiological study of PBC in a
      well defined population over a fixed period of time using established diagnostic
      criteria and with clinical follow-up of all cases. In a population of 2.05
      million in northern England 770 definite or probable PBC cases were identified.
      Prevalence rose from 201.9 per 10(6) in the adult population and 541. 4 per 10(6)
      women over 40 in 1987 to 334.6 per 10(6) adults and 939. 8 per 10(6) women over
      40 in 1994. Incidence was 23 per 10(6) in 1987 and 32.2 per 10(6) in 1994. Three
      hundred patients died in median follow-up of 6.27 years (141 liver deaths); the
      standardized mortality ratio was 2.85. At presumed diagnosis, 60.9% had no
      symptoms of liver disease. By June 1994 62% of prevalent patients had liver
      symptoms. PBC is apparently increasing. It is still unclear whether this is
      because of a true increase, case finding, or increased disease awareness. The
      study draws attention to (1) high mortality from liver disease and non-liver
      related causes even in patients initially with no liver symptoms and (2)
      apparently poor diagnostic awareness of the disease.

PMID- 10421647
TI  - Endothelin-1 modulates intrahepatic resistance in a rat model of noncirrhotic
      portal hypertension.
AB  - Factors that increase resistance to blood flow through the hepatic sinusoids when
      portal hypertension occurs in the absence of significant hepatic fibrosis are not
      completely understood. Experiments were designed to test the hypothesis that
      endothelin-1 (ET-1) is one of the humoral factors that increases sinusoidal
      vascular resistance in a bile duct- ligated noncirrhotic portal hypertensive
      (BDL) rat. The effect of ET-1 and nitric oxide (NO) on contractility of rings of
      portal vein taken from BDL rats was tested. The effect of ET-1 and NO on
      intrahepatic resistance in an isolated perfused liver was studied, and
      localization of ET-1 in the liver was identified by immunohistochemistry. Portal
      vein rings in BDL rats showed increased maximal tension in response to ET-1, as
      well as a shift of the dose-response curve to the left as compared with sham
      operated animals. Removal of the endothelium further increased contractility. In
      isolated perfused liver studies, ET-1 increased portal resistance in both sham
      operated and BDL rats. The endothelin Type A receptor antagonist BQ 123 lowered
      the high portal resistance in BDL rats to levels comparable with sham operated
      animals. Infusion of L-arginine lowered resistance to a much smaller extent. In
      livers from BDL rats, ET-1 was localized in periportal and pericentral
      hepatocytes and hepatic sinusoidal cells. We conclude that in a BDL model of
      portal hypertension where distortion of hepatic architecture by fibrosis is
      minimal, increased resistance to portal blood flow may be mediated by ET-1.

PMID- 10421646
TI  - Hepatic retransplantation in cholestatic liver disease: impact of the interval to
      retransplantation on survival and resource utilization.
AB  - The aim of our study was to quantitatively assess the impact of hepatic
      retransplantation on patient and graft survival and resource utilization. We
      studied patients undergoing hepatic retransplantation among 447 transplant
      recipients with primary biliary cirrhosis (PBC) and primary sclerosing
      cholangitis (PSC) at 3 transplantation centers. Cox proportional hazards
      regression analysis was used for survival analysis. Measures of resource
      utilization included the duration of hospitalization, length of stay in the
      intensive care unit, and the duration of transplantation surgery. Forty-six
      (10.3%) patients received 2 or more grafts during the follow-up period (median,
      2.8 years). Patients who underwent retransplantation had a 3.8-fold increase in
      the risk of death compared with those without retransplantation (P <.01).
      Retransplantation after an interval of greater than 30 days from the primary
      graft was associated with a 6.7-fold increase in the risk of death (P <.01). The
      survival following retransplantations performed 30 days or earlier was similar to
      primary transplantations. Resource utilization was higher in patients who
      underwent multiple consecutive transplantations, even after adjustment for the
      number of grafts during the hospitalization. Among cholestatic liver disease
      patients, poor survival following hepatic retransplantation is attributed to late
      retransplantations, namely those performed more than 30 days after the initial
      transplantation. While efforts must be made to improve the outcome following
      retransplantation, a more critical evaluation may be warranted for late
      retransplantation candidates.

PMID- 10421648
TI  - Reduction of telomeric repeats as a possible predictor for development of
      hepatocellular carcinoma: convenient evaluation by slot-blot analysis.
AB  - Hepatocellular carcinoma (HCC) mainly arises from the liver with chronic
      inflammation. Because telomere reduction reflects replicative history in somatic
      cells, we analyzed the possibility that liver tissues surrounding HCC consist of
      the cells carrying substantial reduction of telomere. We studied 20 HCC and
      surrounding noncancerous liver tissues (SL) obtained by surgical resection, and
      10 laparoscopically obtained needle biopsy specimens of the liver with chronic
      inflammation including no overt HCC (CI). Five liver tissues without chronic
      liver diseases (ND) were also examined. Extracted genomic DNAs were blotted on a
      nylon membrane, and probed at first with radio-labeled d(TTAGGG)(3) and reprobed
      with radio-labeled d(CCT)(7). The intensity caused by d(TTAGGG)(3) was divided by
      that of d(CCT)(7). The ratio was defined as telomeric repeats content (TC).
      Dilution experiments reproducibly revealed almost the same TC. The reduction rate
      of telomere length through aging estimated by regression analysis of TC was 0.62%
      per year. Concomitant analyses of TC and average telomere length revealed that
      both values were significantly correlated (r =.45; P =.009). To compare TC in the
      liver with respect to chronic inflammation, the value was divided by TC in
      peripheral blood leukocytes (PBL) from the same donor. The ratio was defined as
      relative TC (RTC). There was a statistically significant decrease of RTC in CI
      compared with that in ND (P =.03). Furthermore, RTC in SL was significantly lower
      than that in CI (P =.0001). These observations suggest that RTC value in liver
      tissues may digitally indicate a replicative history of hepatocytes under chronic
      inflammation, and a risk of HCC development.

PMID- 10421649
TI  - The alteration of Fas receptor and ligand system in hepatocellular carcinomas:
      how do hepatoma cells escape from the host immune surveillance in vivo?
AB  - Escape from the immune surveillance may play an important role in tumor outgrowth
      and metastasis. Alteration of the Fas receptor (Fas)/ligand (FasL) system
      including soluble forms is regarded as one of the mechanisms preventing the
      immune system from rejecting the tumor cells. However, less attention has been
      paid to the role of Fas/FasL interaction in vivo. Therefore, we investigated the
      expression of Fas and FasL by immunohistochemistry and reverse-transcription
      polymerase chain reaction (RT-PCR) and measured the serum levels of soluble Fas
      (sFas) and FasL (sFasL) in 44 patients with hepatocellular carcinoma (HCC). In
      the noncancerous liver tissues, Fas expression was up-regulated in most cases,
      and FasL expression was detected in 6 cases. In Fas-positive HCC cases (n = 15),
      the intrahepatic metastatic foci was less (P =.037), apoptosis of tumor cells was
      more (P =.004), the disease-free survival rate was higher (P =.004), and p53
      positive cases were less (P =.003), compared with Fas-negative cases. The sFas
      and sFasL levels in HCC patients were significantly higher and lower than those
      in controls, respectively. RT-PCR and immunohistochemistry revealed generation of
      sFas in the hepatocytes and tumor-infiltrating mononuclear cells rather than in
      hepatoma cells. Accordingly, hepatoma cells may eliminate Fas expression on
      themselves and let the hepatocytes and infiltrating mononuclear cells generate
      sFas to escape from the immune system and to produce metastasis. FasL might
      contribute to malignant transformation in some circumstances, because hepatocytes
      in the pericancerous pseudolobules expressed FasL.

PMID- 10421650
TI  - B7-1 (CD80)-gene transfer combined with interleukin-12 administration elicits
      protective and therapeutic immunity against mouse hepatocellular carcinoma.
AB  - Human hepatocellular carcinoma (HCC) frequently recurs after primary therapy,
      resulting in poor prognosis. To try to find a way to prevent this, we examined
      the combined effectiveness of B7-1 (CD80)-gene transfer and interleukin-12 (IL
      12) on the induction of protective antitumor immunity against poorly immunogenic
      BNL1ME A.7R. 1 (BNL) mouse HCC cells. We introduced mouse B7-1 gene into BNL1ME
      A. 7R.1 cells. Overexpression of B7-1 on BNL1ME A.7R.1 cells resulted in
      significant inhibititon of subcutaneous tumor development in syngeneic BALB/c
      mice, but not in complete rejection, suggesting that strong expression of B7-1
      molecules may enhance the immunogenicity of BNL1ME A.7R.1 cells in
      immunocompetent mice. Lymphocyte study revealed that the cytolytic activity
      generated by immunization with B7-1 transfectants against BNL1ME A.7R.1 cells was
      mediated mainly by CD8(+) cytotoxic T lymphocytes (CTL). We examined the
      synergistic effect of IL-12 and immunization with B7-1 transfectants. The
      combination led to rejection of BNL1ME A.7R.1 cells in 6 of 10 tested mice and
      delayed tumor development in the remaining mice. Furthermore, the combined
      treatment against pre-established BNL1ME A.7R.1 tumors resulted in rejection in 3
      of 8 tested mice or in significant inhibition of tumor growth in the remaining
      mice. In vivo lymphocyte subset depletion study indicated that the combined
      antitumor effect was dependent on the presence of both CD8(+) and CD4(+) T cells.
      In conclusion, the combination of immunization of B7-1-transfected HCC cells and
      IL-12 could induce protective and therapeutic immunity against parental HCC
      cells, and this combination may be therapeutically useful for suppressing
      recurrence of HCC.

PMID- 10421651
TI  - Activation of mouse liver natural killer cells and NK1.1(+) T cells by bacterial
      superantigen-primed Kupffer cells.
AB  - Although bacterial superantigens have been well characterized as potent
      stimulators of T cells, their role in natural killer (NK)-type cells remains
      largely unknown. In the present study, we examined the effect of bacterial
      superantigens on mouse liver NK cells and NK1.1 Ag(+) (NK1(+)) T cells. C57BL/6
      mice were intravenously injected with staphylococcal enterotoxin B (SEB) or
      streptococcal pyrogenic exotoxin A (SPE-A), and mononuclear cells (MNC) of
      various organs were obtained from mice 4 hours after being injected with
      superantigen. MNC were cultured for 48 hours, and interferon gamma (IFN-gamma)
      levels of supernatants were measured. The antitumor cytotoxicities of the liver
      and spleen MNC were also evaluated 24 hours after the mice were injected with
      superantigen. Liver MNC produced more IFN-gamma than did splenocytes, and
      peripheral blood and lung MNC did not produce any detectable IFN-gamma. In
      addition, liver MNC acquired a potent antitumor cytotoxicity by the SEB
      injection, and both NK cells and NK1(+)T cells but not cluster of differentiation
      (CD)8(+) T cells were responsible for the cytotoxicity as demonstrated by either
      in vivo or in vitro cell depletion experiments, and the NK-type cells were partly
      responsible for the increased serum IFN-gamma. Activation of liver NK-type cells
      was also supported by the fact that liver NK cells proportionally increased and
      NK1(+) T cells augmented their CD11a expressions after SEB injection. The
      pretreatment of mice with anti-IFN-gamma Ab and/or with anti-interleukin-12 (IL
      12) Ab diminished the SEB-induced cytotoxicity of liver MNC. Furthermore, the in
      vivo depletion of Kupffer cells decreased the SEB-induced cytotoxicity of liver
      MNC. Consistent with these results, liver MNC stimulated with superantigens in
      the presence of Kupffer cells in vitro produced a greater amount of IFN-gamma
      than did the liver MNC without Kupffer cells or splenocytes. Our results suggest
      that bacterial superantigen-primed Kupffer cells produce IL-12 and other
      monokines, while also nonspecifically activating both NK cells and NK1(+) T cells
      to produce IFN-gamma.

PMID- 10421652
TI  - Inhibition of system A amino acid transport and hepatocyte proliferation
      following partial hepatectomy in the rat.
AB  - System A, the sodium-dependent neutral amino acid transport activity, has a 3
      fold increase in its initial uptake velocity into hepatocytes following partial
      hepatectomy (PH) in the rat. The purpose of this study was to examine the effect
      of inhibition of System A-mediated amino acid transport on hepatocyte
      proliferation and liver regeneration. We describe the in vivo competitive
      inhibition of System A activity following PH by the nonmetabolizable, System A
      specific substrate, alpha-(methylamino)isobutyric acid (MeAIB). Administration of
      MeAIB 60 minutes before PH decreased the incorporation of [(3)H]thymidine into
      DNA by 45% +/- 5% and 76% +/- 17% at 24 and 36 hours, respectively. The
      readministration of MeAIB every 12 hours further decreased DNA synthesis by 92%
      +/- 18% and 82% +/- 11% at 24 and 36 hours. The recovery of liver mass of rats
      receiving MeAIB was decreased by 46.4% +/- 5.1% at 24 hours after PH. In vitro, 5
      mmol/L MeAIB inhibited proliferation of primary hepatocytes by 56% +/- 4% and 61%
      +/- 12% 48 hours after incubation with 10% fetal calf serum or epidermal growth
      factor (5 ng/mL), respectively. Thus, MeAIB inhibition of System A transport
      activity decreased both in vivo and in vitro inducement of hepatocyte
      proliferation. Treatment with MeAIB did not significantly change the
      incorporation of [(3)H]leucine into total liver protein, but changes in serum
      amino acids and hepatocyte cell volume were observed, suggesting System A
      transport activity during hepatocyte proliferation functions primarily to provide
      amino acids to fuel liver-specific biochemical pathways and to increase cell
      volume.

PMID- 10421653
TI  - Impaired mesenteric leukocyte recruitment in experimental portal hypertension in
      the rat.
AB  - Increased incidence of septic complications in human and experimental portal
      hypertension has been documented. Because development of an inflammatory response
      is essential in defense against infectious agents, the aim of this study was to
      assess leukocyte-endothelial cell interactions in an experimental model of portal
      hypertension. Intravital microscopy studies showed that under baseline
      conditions, leukocyte rolling, adhesion, and emigration in mesenteric venules
      were similar in control, sham operated (SO), and partial portal vein ligated
      (PPVL) rats. Compared with either control or SO rats, PPVL animals exhibited a
      markedly reduced recruitment of rolling, adherent, and emigrated leukocytes in
      response to leukotriene B(4) (LTB(4)) stimulation. Similarly, platelet-activating
      factor (PAF) superfusion, which induced a large increment in leukocyte rolling
      and adherence in control and SO rats, was without any effect in PPVL animals.
      Endothelial P-selectin expression in control rats, as measured by the double
      radio-labeled monoclonal antibody (mAb) technique, was not modified by LTB(4),
      but significantly increased in response to PAF. PPVL rats had a significantly
      lower expression of P-selectin after stimulation with PAF. Neutrophils isolated
      from PPVL rats exhibited increased L-selectin shedding and CD11b up-regulation in
      response to PAF and LTB(4), compared with neutrophils isolated from SO rats.
      These observations indicate that portal hypertension is associated with a
      defective inflammatory response, which is manifested as a decreased recruitment
      of rolling leukocytes, and subsequently reduced adhesion/emigration. This defect
      appears to result from a reduced endothelial P-selectin up-regulation and
      increased L-selectin shedding.

PMID- 10421654
TI  - Increase by anaphylatoxin C5a of glucose output in perfused rat liver via
      prostanoids derived from nonparenchymal cells: direct action of prostaglandins
      and indirect action of thromboxane A(2) on hepatocytes.
AB  - In the perfused rat liver the anaphylatoxin C5a enhanced glucose output, reduced
      flow, and elevated prostanoid overflow. Because hepatocytes (HCs) do not express
      C5a receptors, the metabolic C5a actions must be indirect, mediated by e.g.
      prostanoids from Kupffer cells (KCs) and hepatic stellate cells (HSCs), which
      possess C5a receptors. Surprisingly, the metabolic C5a effects were not only
      impaired by the prostanoid synthesis inhibitor, indomethacin, but also by the
      thromboxane A(2) (TXA(2)) receptor antagonist, daltroban, even though HCs do not
      express TXA(2) receptors. TXA(2) did not induce prostaglandin (PG) or an unknown
      factor release from KCs or sinusoidal endothelial cells (SECs), which express
      TXA(2) receptors, because (1) daltroban did neither influence the C5a-induced
      release of prostanoids from cultured KCs nor the C5a-dependent activation of
      glycogen phosphorylase in KC/HC cocultures and because (2) the TXA(2) analog,
      U46619, failed to stimulate prostanoid release from cultured KCs or SECs or to
      activate glycogen phosphorylase in KC/HC or SEC/HC cocultures. In the perfused
      liver, Ca(2+)-deprivation inhibited not only flow reduction but also glucose
      output elicited by C5a to similar extents as daltroban. Similarly, in the absence
      of extracellular Ca(2+), flow reduction and glucose output induced by U46619 were
      almost completely prevented, whereas glucose output induced by the directly
      acting PGF(2alpha) was only slightly lowered. Thus, in the perfused rat liver PGs
      released after C5a-stimulation from KCs and HSCs directly activated glycogen
      phosphorylase in HCs, and TXA(2) enhanced glucose output indirectly mainly by
      causing hypoxia as a result of flow reduction.

PMID- 10421655
TI  - MMP2 activation by collagen I and concanavalin A in cultured human hepatic
      stellate cells.
AB  - Fibrosis occurs in most chronic liver injuries and results from changes in the
      balance between synthesis and degradation of extracellular matrix components. In
      fibrotic livers, there is a markedly increased activity of matrix
      metalloproteinase 2 (MMP2), a major enzyme involved in extracellular matrix
      remodeling. We have previously shown that hepatic stellate cells secrete latent
      MMP2 and that MMP2 activation occurs in coculture of hepatic stellate cells and
      hepatocytes concomitantly with matrix deposition. In the present work we
      investigated the effects of various extracellular matrix components and
      concanavalin A, an inducer of immune-mediated liver injuries, on MMP2 activation
      in cultured human hepatic stellate cells. Collagen I induced a dose-dependent
      MMP2 activation, which was not blocked by both actinomycin and cycloheximide.
      Collagen VI, laminin, and a reconstituted basement membrane (matrigel) were
      ineffective in inducing activation. Specific antibodies against the subunits of
      alpha2beta1 integrins, the major collagen I receptor, induced partial inhibition
      of MMP2 activation. Treatment of cells with concanavalin A resulted in a marked
      activation of MMP2 that correlated with the proteolytic processing of MT1-MMP,
      the MMP2 activator, from a Mr=60 kd toward a Mr=43 kd polypeptide. Actinomycin
      and cycloheximide inhibited the MMP2 activation induced by concanavalin A.
      Recombinant tissue inhibitor of metalloproteinase-2 and the MMP inhibitor BB
      3103, but not PMSF, blocked MMP2 activation induced by collagen I or concanavalin
      A, and MT1-MMP processing to its Mr-43 kd form. These results suggest that the
      accumulation of collagen I may specifically contribute to the remodeling of
      extracellular matrix in fibrotic livers by inducing MMP2 activation.

PMID- 10421656
TI  - Ischemia impairs liver regeneration after major tissue loss in rodents:
      protective effects of interleukin-6.
AB  - The effects of ischemia on the regenerative capacity of the liver after major
      tissue loss remain unclear. Interleukin-6 (IL-6) has been shown to confer
      protection in models of normothermic ischemia and reperfusion injury and to
      initiate hepatocyte proliferation after major hepatectomy. Therefore, we
      investigated the effects of ischemia on the regenerative capacity of the liver
      and evaluated the role of IL-6 in reducing reperfusion injury and enhancing
      hepatic proliferation in models combining ischemia and major hepatectomy. Rats
      subjected to 70% hepatectomy and 30 minutes of hepatic ischemia showed
      significantly reduced regenerative capacity (mitotic index, proliferating cell
      nuclear antigen, and regenerated liver weight) when compared with animals
      subjected to hepatectomy alone. Pretreatment of animals subjected to hepatectomy
      and ischemia with recombinant interleukin-6 (rIL-6) completely restored each
      parameter of regeneration to levels comparable with those of animals subjected to
      hepatectomy only. Similar results were obtained in IL-6 deficient (IL-6(-/-))
      mice. IL-6(-/-) mice exposed to ischemia and hepatectomy showed impaired hepatic
      regeneration when compared with wild-type mice subjected to the same experimental
      conditions. The use of rIL-6 completely corrected each parameter of regeneration
      showing the specificity of IL-6 in this type of injury. The impact of IL-6 on
      animal survival was studied in a model combining 45 minutes of ischemia and 68%
      hepatectomy. Five of 7 (71%) animals pretreated with rIL-6 survived permanently,
      whereas all control animals died within 3 days of surgery (P =.02, Fisher's exact
      test). In conclusion, the study shows that ischemia dramatically impairs the
      regenerative capacity of the liver. IL-6 appears to be a key protective molecule
      in reducing injury and promoting regeneration following combined ischemia and
      major tissue loss.

PMID- 10421658
TI  - Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human
      and rat multidrug resistance protein 2.
AB  - The secretion of bilirubin conjugates from hepatocytes into bile represents a
      decisive step in the prevention of hyperbilirubinemia. The bilirubin conjugates,
      monoglucuronosyl bilirubin (MGB) and bisglucuronosyl bilirubin (BGB), were
      previously suggested to be endogenous substrates for the apical multidrug
      resistance protein (MRP2), a member of the adenosine triphosphate (ATP)-binding
      cassette family of transporters (symbol ABCC2), also termed canalicular
      multispecific organic anion transporter. We have characterized this ATP-dependent
      transport using membrane vesicles from human embryonic kidney (HEK) cells
      expressing recombinant rat as well as human MRP2. MGB and BGB, (3)H-labeled in
      the glucuronosyl moiety, were synthesized enzymatically with recombinant UDP
      glucuronosyltransferase 1A1, and stabilized with ascorbate. Rates for ATP
      dependent transport of MGB and BGB (0.5 micromol/L each) by human MRP2 were 183
      and 104 pmol x mg protein(-1) x min(-1), respectively. K(m) values were 0.7 and
      0.9 micromol/L for human MRP2, and 0.8 and 0.5 micromol/L for rat MRP2, with MGB
      and BGB as substrates, respectively. Leukotriene C(4) and 17beta-glucuronosyl
      estradiol, which are both known high-affinity substrates for human MRP2,
      inhibited [(3)H]MGB transport with IC(50) values of 2.3 and 30 micromol/L,
      respectively. Cyclosporin A competitively inhibited human and rat MRP2-mediated
      transport of [(3)H]MGB, with K(i) values of 21 and 10 micromol/L, respectively.
      Our results provide direct evidence that recombinant MRP2, cloned from rat as
      well as human liver, mediates the primary-active ATP-dependent transport of the
      bilirubin conjugates MGB and BGB.

PMID- 10421659
TI  - Acyl-coenzyme A:cholesterol acyltransferase inhibitor, avasimibe, stimulates bile
      acid synthesis and cholesterol 7alpha-hydroxylase in cultured rat hepatocytes and
      in vivo in the rat.
AB  - Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors are currently in
      clinical development as potential lipid-lowering and antiatherosclerotic agents.
      We investigated the effect of avasimibe (Cl- 1011), a novel ACAT inhibitor, on
      bile acid synthesis and cholesterol 7alpha-hydroxylase in cultured rat
      hepatocytes and rats fed different diets. Avasimibe dose-dependently decreased
      ACAT activity in rat hepatocytes in the presence and absence of beta-migrating
      very low-density lipoproteins (betaVLDL) (by 93% and 75% at 10 micromol/L) and
      reduced intracellular storage of cholesteryl esters. Avasimibe (3 micromol/L)
      increased bile acid synthesis (2.9-fold) after preincubation with betaVLDL and
      cholesterol 7alpha-hydroxylase activity (1.7- and 2.6-fold, with or without
      betaVLDL), the latter paralleled by a similar induction of its messenger RNA
      (mRNA). Hepatocytes treated with avasimibe showed a shift from storage and
      secretion of cholesteryl esters to conversion of cholesterol into bile acids. In
      rats fed diets containing different amounts of cholesterol and cholate, avasimibe
      reduced plasma cholesterol (by 52% to 71%) and triglyceride levels (by 28% to
      62%). Avasimibe did not further increase cholesterol 7alpha-hydroxylase activity
      and mRNA in cholesterol-fed rats, but prevented down-regulation by cholate.
      Avasimibe did not affect sterol 27-hydroxylase and oxysterol 7alpha-hydroxylase,
      2 enzymes in the alternative pathway in bile acid synthesis. No increase in the
      ratio of biliary excreted cholesterol to bile acids was found, indicating that
      ACAT inhibition does not result in a more lithogenic bile. Avasimibe increases
      bile acid synthesis in cultured hepatocytes by enhancing the supply of free
      cholesterol both as substrate and inducer of cholesterol 7alpha-hydroxylase.
      These effects may partially explain the potent cholesterol-lowering effects of
      avasimibe in the rat.

PMID- 10421657
TI  - Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase
      UGT1A1 in liver and cultured primary hepatocytes: evidence for both genetic and
      environmental influences.
AB  - In Crigler-Najjar type II patients and, recently, in Crigler-Najjar type I
      patients treated with human hepatocyte cell therapy, phenobarbital has been used
      for reducing the serum bilirubin load. Its effect is attributed to induction of
      the enzyme required for hepatic bilirubin elimination, UDP
      glucuronosyltransferase, UGT1A1. This study investigated the expression and
      inducibility of UGT1A1 in human donor livers and their corresponding primary
      hepatocyte cultures. Immunoblot analysis using a specific antibody directed
      against the amino terminal of the human UGT1A1 isoform showed that 5 hepatocyte
      donors exhibited a >50-fold difference in UGT1A1 level. UGT1A1 protein level
      correlated strongly with both liver microsomal bilirubin UGT activity and liver
      UGT1A1 mRNA level (r(2) =.82 and.72, respectively). Of the 4 patients with the
      lowest UGT1A1 levels, 3 were homozygotes for the UGT1A1 promoter variant sequence
      associated with Gilbert's syndrome, and the fourth was a heterozygote. The 3
      donors with the highest levels had a history of phenytoin exposure. Hepatocytes
      isolated from the phenytoin-exposed donors exhibited marked declines in UGT1A1
      mRNA levels during culturing. Induction studies using hepatocytes treated for 48
      hours with phenobarbital (2 mmol/L), oltipraz (50 micromol/L), or 3
      methylcholanthrene (2.5 micromol/L) revealed UGT1A1-inducing effects of
      phenobarbital, oltipraz, and, in particular, 3-methylcholanthrene. Our data
      suggest that both genetic and environmental factors play an important role in the
      marked interindividual variability in UGT1A1 expression. An understanding of
      these mechanisms could lead to advances in the pharmacological therapy of life
      threatening unconjugated hyperbilirubinemia.

PMID- 10421660
TI  - Atrial natriuretic peptide antagonizes endothelin-induced calcium increase and
      cell contraction in cultured human hepatic stellate cells.
AB  - Hepatic stellate cells (HSCs) participate in the regulation of hepatic
      microcirculation and have receptors for many vasoconstrictor factors. It is
      unknown whether HSCs have receptors for circulating vasodilators such as atrial
      natriuretic peptide (ANP). This study investigated the presence of ANP receptors
      in human HSCs and whether ANP antagonizes the effects of endothelin-1 in these
      cells. ANP receptors were assessed by binding and cross-linking studies, reverse
      transcriptase polymerase chain reaction (PCR), and measuring intracellular cyclic
      guanosine monophosphate concentration. Intracellular calcium concentration
      ([Ca(2+)](i)) and cell contraction were measured in individual cells loaded with
      fura-2 using a morphometric method. Binding and cross-linking affinity
      experiments showed the existence of ANP receptors in human HSCs. PCR products
      with the expected length were obtained for guanylate cyclase A receptor, the
      physiological receptor of ANP, both in quiescent and activated human cells. ANP
      induced a dose-dependent increase in intracellular cyclic guanosine monophosphate
      concentration and blunted the increase in [Ca(2+)](i) elicited by endothelin-1.
      Most importantly, ANP markedly reduced cell contraction induced by endothelin-1.
      HSCs isolated from rats with carbon tetrachloride-induced cirrhosis showed a
      higher number of ANP receptors compared with HSCs isolated from normal rats,
      indicating that in vivo activation of HSCs is associated with an up-regulation of
      ANP receptors. These results indicate that human HSCs have receptors for ANP, the
      activation of which reduces the effects of endothelin-1 on [Ca(2+)](i) and cell
      contraction. ANP could participate in regulating the contractility of HSCs by
      antagonizing the effect of vasoconstrictors.

PMID- 10421661
TI  - Nonsteroidal anti-inflammatory drug metabolism potentiates interferon alfa
      signaling by increasing STAT1 phosphorylation.
AB  - A sustained response to standard interferon therapy for chronic hepatitis C has
      been demonstrated in no more than 25% of patients. To improve interferon alfa
      (IFN-alpha) antiviral effect, a number of combination therapies with IFNs plus
      other drugs have been proposed for both relapser and nonresponder hepatitis C
      virus (HCV)-infected patients. Although the causes of IFN resistance in subsets
      of HCV-infected patients are unknown, both viral and host factors have been
      involved, including defects in IFN signal transduction and IFN-alpha/beta
      receptor down-regulation. Here, we report that nonsteroidal anti-inflammatory
      drugs (NSAIDs), which have been proposed for IFN-alpha combination therapy in
      nonresponders, potentiate IFN-alpha signaling. We found that, in the hepatoma
      cell lines, CCL13/Chang and HepG2, indomethacin, a selective cyclo-oxygenase 1
      and 2 (COX-1 and COX-2) inhibitor, increases IFN-alpha stimulation of interferon
      stimulated response element (ISRE)-dependent transcription in a dose-dependent
      manner. Interestingly, maximal potentiation was observed with suboptimal IFN
      alpha concentrations. Indomethacin exerts its effects by synergizing with IFN
      alpha in inducing STAT1 activation by phosphorylation, without affecting
      concurrent Jak1 phosphorylation. Our data indicate that blockade of arachidonic
      acid (AA) metabolism by indomethacin activates a signaling pathway that converges
      on STAT1 activation to potentiate IFN-alpha-dependent gene activation.

PMID- 10421662
TI  - The pre-S region determines the intracellular localization and appearance of
      hepatitis B virus.
AB  - The functional role of the hepatitis B virus (HBV) pre-S region for assembly and
      appearance of the virus is not completely understood. In this study, 3 natural
      occurring mutants were investigated. Three mutants of the pre-S region-a point
      mutation in the CCAAT box (MUT1), a 6-bp deletion (MUT2) 3' of the CCAAT box, and
      a 153-bp deletion (MUT3) in the preS2 domain-were cloned alone or in combinations
      in replication-competent HBV plasmids and transfected in hepatoma cells. The
      impact on HBV assembly and appearance was studied by Northern Blot, primer
      extension analysis, immunofluorescence studies, enzyme-linked immunosorbent
      assay, and electron microscopy. An inversed ratio of pre-S/S mRNA transcripts
      compared with wild-type (wt) HBV was found when either MUT1 or -2 were included
      into the plasmid. Intracellular localization with both mutants showed retention
      of large S-protein in the endoplasmic reticulum and nuclear accumulation of core
      protein. The extracellular amount of S-protein was reduced with MUT1 and -2 or
      combinations in which 1 of the mutants was included. However, the extracellular
      appearance of viral products was comparable with wtHBV. In contrast, MUT3 showed
      major changes. Virion-like particles had a fried-egg, and filaments a screw-like
      appearance. The S-promoter mutations MUT1 and MUT2 correlated with viral
      retention. MUT3 leads to malformed viral particles. Therefore, different regions
      in the pre-S domain are essential to determine the intracellular localization and
      extracellular appearance of HBV, and might contribute to the prognosis of chronic
      HBV infection.

PMID- 10421663
TI  - Interleukin-10 promoter polymorphism predicts initial response of chronic
      hepatitis C to interferon alfa.
AB  - Serum levels of interleukin-10 (IL-10) are elevated in a proportion of patients
      with untreated chronic hepatitis C, and this may compromise the host immune
      response to the virus. The capacity for IL-10 production varies according to the
      genetic composition of the IL-10 locus. We examined the inheritance of 3
      biallelic polymorphisms in the IL-10 gene promoter in patients with chronic
      hepatitis C and their association with response to treatment with interferon alfa
      (IFN-alpha). After adjusting for potential confounding variables, a highly
      significant relationship was found between inheritance of the IL-10 promoter 
      592*A and -819*T alleles or the ATA haplotype and response to IFN-alpha therapy
      (P =.016). Response to treatment was also associated with viral genotype 3a, a
      low viral load, and less fibrosis on liver biopsy. Following in vitro stimulation
      of peripheral blood mononuclear cells, the IL-10 promoter haplotypes, GCC, ACC,
      and ATA, were associated with high, intermediate, and low IL-10 production,
      respectively. These findings indicate that heterogeneity in the promoter region
      of the IL-10 gene has a role in determining the initial response of chronic
      hepatitis C to IFN-alpha therapy. Patients who are genetically predisposed to
      high IL-10 production have a poor response to IFN-alpha and may benefit from
      additional treatment strategies designed to enhance a T-helper type 1 (Th1)
      response.

PMID- 10421664
TI  - A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with
      hepatitis B virus. The CY1899 T Cell Vaccine Study Group.
AB  - Clinical observations suggest that eradication of the hepatitis B virus (HBV) is
      immune-mediated. Vigorous cytotoxic T lymphocyte (CTL) activity directed at HLA
      class I-bound viral epitopes are detected during acute hepatitis B, but not in
      chronic hepatitis B carriers. A CTL epitope derived from the hepatitis B core
      protein amino acids 18-27 has been incorporated into a vaccine also comprised of
      a T-helper cell epitope and 2 palmitic acid residues (CY-1899). The aim of this
      study was to determine whether repeated doses of CY-1899 given to patients with
      chronic hepatitis B could initiate in vivo CTL activity and viral clearance.
      Patients with chronic hepatitis B received up to 4 doses (ranging from 0.05 mg to
      15 mg) 6 weeks apart. Following vaccination, patients were monitored for
      hepatitis B surface antigen and "e" status, HBV-DNA levels, liver biochemistry,
      CTL activity, and any adverse events. Ninety patients with chronic hepatitis B
      infection received CY-1899. Mean CTL responses were all low but were maximal
      following vaccination with 5 mg CY-1899. Peak CTL responses never exceeded 10
      lytic units (LU) regardless of vaccine dose, this value being well below that
      seen following resolution of acute hepatitis B. No significant changes in liver
      biochemistry or viral serology were observed during follow-up. No serious adverse
      events were noted. Administration of the single-epitope vaccine, CY-1899,
      initiated CTL activity, but of a magnitude lower than that observed during
      spontaneous HBV clearance. This low-level CTL activity was not associated with
      viral clearance.

PMID- 10421665
TI  - Antibody responses to hepatitis C virus hypervariable region 1: evidence for
      cross-reactivity and immune-mediated sequence variation.
AB  - Sequence heterogeneity of hepatitis C virus (HCV) is unevenly distributed along
      the genome, and maximal variation is confined to a short sequence of the HCV
      second envelope glycoprotein (E2), designated hypervariable region 1 (HVR1),
      whose biological function is still undefined. We prospectively studied
      serological responses to synthetic oligopeptides derived from HVR1 sequences of
      patients with acute and chronic HCV infection obtained at baseline and after a
      defined follow-up period. Extensive serological cross-reactivity for unrelated
      HVR1 peptides was observed in the majority of the patients. Antibody response was
      restricted to the IgG1 isotype and was focused on the carboxyterminal end of the
      HVR1 region. Cross-reactive antibodies could be readily elicited following
      immunization of mice with multiple antigenic peptides carrying HVR1 sequences
      derived from our patients. The vigor and heterogeneity of cross-reactive antibody
      responses were significantly higher in patients with chronic hepatitis compared
      with those with acute hepatitis and in patients infected with HCV type 2 compared
      with patients infected with other viral genotypes (predominantly type 1), which
      suggest that higher time-related HVR1 sequence diversification previously
      described for type 2 may result from immune selection. The finding of a
      statistically significant correlation between HVR1 sequence variation, and
      intensity, and cross-reactivity of humoral immune responses provided stronger
      evidence in support of the contention that HCV variant selection is driven by the
      host's immune pressure.

PMID- 10421667
TI  - Health-related quality of life in chronic hepatitis C: impact of disease and
      treatment response. The Interventional Therapy Group.
AB  - Hepatitis C infects nearly 4 million Americans. Most have chronic hepatitis C
      (CHC), which progresses to cirrhosis in about 20% of patients. Interferon
      treatment leads to transient responses in about 40% of patients and apparent
      eradication of infection in 7% to 40% of patients. In this report, we document
      the impact of CHC on health-related quality of life (HQL), and changes in HQL
      among treatment responders. Three hundred twenty-four CHC patients from 10
      countries who had relapsed after responding to interferon-alfa therapy were
      randomized to monotherapy (IFN alfa-2b + placebo) or combination therapy (IFN
      alfa-2b + ribavirin), treated for 24 weeks, and followed up for 24 weeks. HQL was
      assessed using the Hepatitis Quality of Life Questionnaire (HQLQ), containing the
      generic SF-36 Health Survey, three additional generic scales, and two hepatitis
      specific scales. Before treatment, CHC patients were impaired in 5 of 8 SF-36
      concepts (physical functioning, role-physical, general health, vitality, and
      social functioning) in comparison with matched population norms. Sustained
      virological response (SVR) to treatment yielded improvements on three generic
      scales (vitality, social functioning, and health distress) and the CHC-specific
      health distress scale. Overall response to treatment (SVR plus histological
      improvement) yielded the same pattern of improvements with additional gains in
      generic general health and CHC-specific limitations. Successful treatment of CHC
      improved HQL as measured by both CHC-specific and generic measures of functional
      health and well being.

PMID- 10421666
TI  - Lamivudine for chronic delta hepatitis.
AB  - Chronic delta hepatitis is a severe form of chronic liver disease caused by
      hepatitis delta virus (HDV) infection superimposed on chronic hepatitis B or the
      hepatitis B surface antigen (HBsAg) carrier state. Therapy of delta hepatitis is
      currently unsatisfactory. We have evaluated lamivudine (3-thiacytidine), an oral
      nucleoside analogue with marked effects against hepatitis B, as therapy in 5
      patients with chronic hepatitis D. Five men, ages 38 to 65 years, were treated.
      All had HBsAg, antibody to HDV, and HDV RNA in serum, as well as persistent
      elevations in alanine aminotransferase (ALT) levels and liver histology showing
      severe chronic hepatitis with fibrosis or cirrhosis. Lamivudine was given in a
      dose of 100 mg orally daily for 12 months. Patients were monitored carefully and
      tested for HBsAg, HBV-DNA and HDV-RNA levels serially during the year of
      treatment and for 6 months thereafter. Liver biopsies were performed before
      therapy and repeated after 1 year. Serum levels of HBV DNA fell rapidly in all 5
      patients, becoming undetectable even by polymerase chain reaction (PCR) in 4.
      However, all 5 patients remained HBsAg- and HDV-RNA-positive, and serum ALT
      levels and liver histology did not improve. All patients tolerated therapy well.
      When lamivudine was stopped, HBV-DNA levels returned to pretreatment values
      without a change in disease activity. Lamivudine is a potent inhibitor of HBV-DNA
      replication, but does not improve disease activity or lower HDV-RNA levels in
      patients with chronic delta hepatitis.

PMID- 10421668
TI  - Quasispecies of hepatitis C virus in serum and in three different parts of the
      liver of patients with chronic hepatitis.
AB  - Hepatitis C virus (HCV) has been known to infect hosts as a quasispecies. Several
      reports have shown this using serum samples, but there is little information
      about quasispecies in the liver. In this study, we evaluated quasispecies in
      serum and in 3 different parts of the liver in 8 patients with varying severity
      of chronic hepatitis C by calculating nucleotide diversity, entropy, type of
      substitution and by phylogenetic analysis. Nucleotide diversity of HCV was
      different in each sample and ranged from 0.37% +/- 0.31% to 4.10% +/- 1.06%.
      However, the degree of HCV diversity in serum correlated with that in the liver
      in each patient (P <.01). Common HCV clones were found both in serum and liver
      samples in all 6 noncirrhotic patients, but all serum clones were different from
      the clones from the 2 cirrhotic livers. Phylogenetic analysis showed that the
      degree of genetic diversity of HCV among the 3 liver samples was significantly
      high in the 4 patients with fibrosis. These genetic compartmentalizations of HCV
      did not depend on the type of substitution or the viral load of each liver
      sample. HCV quasispecies within the liver may be closely related to the viral
      life cycle and the pathogenesis of persistent infection of HCV.

PMID- 10421669
TI  - Chronic hepatitis C virus patients with breakthroughs during interferon treatment
      can successfully be retreated with consensus interferon. The Consensus Interferon
      Study Group.
AB  - Patients with chronic hepatitis C who have not had a sustained hepatitis C virus
      (HCV)-RNA response or serum alanine transaminase (ALT) response to a 6-month
      course of interferon (IFN) may respond to higher dose retreatment with consensus
      interferon (CIFN). Some nonresponders to initial IFN treatment have a transient
      response defined as undetectable HCV RNA or normalization of ALT during
      treatment, but subsequently have a "breakthrough" while still on treatment. The
      aim of this study was to determine if nonresponders who had breakthroughs
      responded differently to CIFN retreatment than nonresponders without
      breakthroughs using data from a large, multicenter trial. ALT and HCV RNA were
      monitored frequently during initial IFN therapy (either 9 mcg CIFN or 3 MU IFN
      alpha2b 3 times per week). HCV-RNA breakthroughs were observed in 86 of 467 (18%)
      of all treated patients, and ALT breakthroughs were observed in 90 of 467 (19%)
      of all treated patients. There was no association between breakthroughs and the
      presence of either binding or neutralizing anti-IFN antibodies. When the patients
      who were nonresponders to initial IFN treatment were retreated with CIFN (15 mcg)
      for 12 months, 27% of those with viral breakthroughs had a sustained viral
      response compared with 8% in prior nonresponders without breakthroughs (P =.102).
      Sustained ALT responses were observed in 39% with breakthroughs compared with 10%
      in those without breakthroughs (P =.014). The data suggest that prior
      nonresponders with breakthroughs have a greater chance of responding to
      retreatment than do nonresponders without breakthroughs. However, most
      breakthrough patients would be missed unless repeated HCV-RNA testing were
      conducted during therapy.

PMID- 10421670
TI  - Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif
      mutation during lamivudine therapy.
AB  - Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication, but its
      long-term use may be associated with HBV tyrosine-methionine-aspartate-aspartate
      (YMDD) motif mutation. To examine the clinical features and course after
      emergence of YMDD mutants, 55 patients who received lamivudine therapy over 104
      weeks at our unit were assayed for YMDD mutation(s). Thirty-two of them were
      found to have the YMDD mutation. They continued lamivudine therapy and were
      followed up weekly or biweekly if clinically indicated. Thirty (93.7%) of them
      showed elevation of alanine transaminase (ALT), and 13 (40.6%) experienced acute
      exacerbation at 4 to 94 weeks (median, 24 weeks) after emergence of the YMDD
      mutant. The incidence of exacerbation is much higher than 4.3% in patients
      without the YMDD mutation (P =.003). Compared with patients without exacerbation,
      patients with exacerbation had a significantly higher serum HBV-DNA level after
      emergence of the YMDD mutant (P <.005). Before exacerbation, serum HBV-DNA level
      was rising to its peak, followed by the peaking of ALT (247-2,010 U/L) 1 to 4
      weeks later. Three patients developed hepatic decompensation, but then in
      association with hepatitis B e antigen (HBeAg) seroconversion, recovered. Of the
      12 evaluable patients, 8 (75%) showed HBeAg seroconversion, and 3 showed mutant
      clearance within 1 to 5 months after exacerbation. In contrast, none of the
      patients without exacerbation showed HBeAg seroconversion (P <.001). These
      results indicate that acute exacerbations may occur after emergence of the YMDD
      mutation. The incidence, clinicopathological features, and subsequent course, and
      possibly the underlying immune mechanisms, are similar to those of wild-type HBV
      chronic infection. Because severe hepatitis may occur, patients should be
      followed carefully once the YMDD mutant emerges.

PMID- 10421671
TI  - Aflatoxin as a human carcinogen.

PMID- 10421672
TI  - Immune escape in hepatocellular cancer: is a good offense the best defense?

PMID- 10421674
TI  - Congenital hepatic fibrosis-is it really a matter of "a spoonful of sugar?".

PMID- 10421673
TI  - Hepatitis B therapy: the plot thickens.

PMID- 10421676
TI  - On the evolution of multicelluarity and eusociality.
AB  - In this article versions of the abstract NKC model are used to examine the
      conditions under which two significant evolutionary phenomena - multicellularity
      and eusociality - are likely to occur and why. First, comparisons in evolutionary
      performance are made between simulations of unicellular organisms and very simple
      multicellular-like organisms, under varying conditions. The results show that
      such multicellularity without differentiation appears selectively neutral, but
      that differentiation to soma (nonreproductives) proves beneficial as the amount
      of epistasis in the fitness landscape increases. This is explained by considering
      mutations in the generation of daughter cells and their subsequent effect on the
      propagule's fitness. This is interpreted as a simple example of the Baldwin
      effect. Second, the correspondences between multicellularity and eusociality are
      highlighted, particularly that both contain individuals who do not reproduce. The
      same process is then used to explain the emergence of eusocial colonies.

PMID- 10421677
TI  - Visualizing evolutionary activity of genotypes.
AB  - We introduce a method for visualizing evolutionary activity of genotypes.
      Following a proposal of Bedau and Packard [11], we define a genotype's
      evolutionary activity in terms of the history of its concentration in the
      evolving population. To visualize this evolutionary activity we graph the
      distribution of evolutionary activity in the population of genotypes as a
      function of time. Adaptively significant genotypes trace a salient line or "wave"
      in these graphs. The quality of these waves indicates a variety of neutral
      variation, and random genetic drift. We apply this method in an evolutionary
      model of self-replicating assembly language programs competing for room in a two
      dimensional space. Comparison with fitness graphs and with a nonadaptive analogue
      of this model shows how this method highlights adaptively significant events.

PMID- 10421678
TI  - The Creatures global digital ecosystem.
AB  - An artificial life entertainment software product called Creatures was released
      in Europe in late 1996 and in the United States and Japan in mid-1997. When
      installed on a domestic computer (PC or Macintosh), each Creatures CD-ROM creates
      a virtual world in which autonomous software agents exist. The agents, known as
      "norn," interact with the human user, with each other, and with objects in their
      virtual world. Each norn coordinates perception and action via its own modular
      recurrent neural network. Each network has Hebbian learning, plus diffuse
      modulation of activity via a "hormonal" system that is part of that norns
      "biochemistry." Details of each norns neural network and biochemistry are
      genetically specified, and norns can breed via sexual reproduction. In the
      reproduction process, genetic material may be mutated and may also be subjected
      to "gene duplications" that enable potentially unlimited increases in complexity
      of the norns' design. Over 500,000 Creatures CD-ROMS have now been sold. As each
      installed copy of Creatures can support 5 to 10 simultaneously existing
      individual norns, it seems reasonable to estimate that there are up to 5 million
      norns existing in the "cyberspace" provided by the global Creatures user
      community. Continued growth of the global norn population, to figures measured in
      tens of millions, is quite likely. Although a commercial product, the Creatures
      digital ecosystem should be of interest to artificial life scientists. There are
      obvious parallels with Yaeger's PolyWorld and Ray's NetTierra systems. This
      article provides a detailed discussion of the links between the artificial life
      literature and the technology used in Creatures and includes anecdotal discussion
      of the "digital naturalism" witnessed on the many independent websites maintained
      by Creatures enthusiasts.

PMID- 10421675
TI  - Inferences from pulmonary O2 uptake with respect to intramuscular
      [phosphocreatine] kinetics during moderate exercise in humans.
AB  - 1. In the non-steady state of moderate intensity exercise, pulmonary O2 uptake
      (Vp,O2) is temporally dissociated from muscle O2 consumption (Vm,O2) due to the
      influence of the intervening venous blood volume and the contribution of body O2
      stores to ATP synthesis. A monoexponential model of Vp,O2 without a delay term,
      therefore, implies an obligatory slowing of Vp,O2 kinetics in comparison to Vm,
      O2. 2. During moderate exercise, an association of Vm,O2 and [phosphocreatine]
      ([PCr]) kinetics is a necessary consequence of the control of muscular oxidative
      phosphorylation mediated by some function of [PCr]. It has also been suggested
      that the kinetics of Vp,O2 will be expressed with a time constant within 10 % of
      that of Vm,O2. 3. Vp,O2 and intramuscular [PCr] kinetics were investigated
      simultaneously during moderate exercise of a large muscle mass in a whole-body
      NMR spectrometer. Six healthy males performed prone constant-load quadriceps
      exercise. A transmit-receive coil under the right quadriceps allowed
      determination of intramuscular [PCr]; Vp,O2 was measured breath-by-breath, in
      concert with [PCr], using a turbine and a mass spectrometer system. 4.
      Intramuscular [PCr] decreased monoexponentially with no delay in response to
      exercise. The mean of the time constants (tauPCr) was 35 s (range, 20-64 s) for
      the six subjects. 5. Two temporal phases were evident in the Vp, O2 response.
      When the entire Vp,O2 response was modelled to be exponential with no delay, its
      time constant (tau'Vp,O2) was longer in all subjects (group mean = 62 s; range,
      52-92 s) than that of [PCr], reflecting the energy contribution of the O2 stores.
      6. Restricting the Vp,O2 model fit to phase II resulted in matching kinetics for
      Vp,O2 (group mean tauVp,O2 = 36 s; range, 20-68 s) and [PCr], for all subjects.
      7. We conclude that during moderate intensity exercise the phase II tauVp,O2
      provides a good estimate of tauPCr and by implication that of Vm,O2 (tauVm,O2).

PMID- 10421680
TI  - Effects of cyclic bending and physiological solution on plasma-sprayed
      hydroxylapatite coatings of varying crystallinity.
AB  - This study investigated the effects of cyclic bending stress levels and testing
      in simulated physiological solutions or air on the integrity of plasma-sprayed
      hydroxylapatite (HA) coatings of two different crystallinities. Hydroxylapatite
      coated commercially pure (CP) Ti rods were evaluated by immersion testing in
      Hank's Balanced Salt Solution (HBSS) and by rotating bending in air and HBSS.
      Static immersion testing of nonstressed specimens resulted in significant
      microcracking of coating surfaces after 42 days. Specimens cyclically tested at
      bending stresses above the yield strength of Ti experienced low cycle fatigue
      failure of the Ti substrates prior to spallation of the HA coatings. Coatings
      tested at 1 x 10(6) cycles with interface bending stresses of 180 MPa displayed
      increased surface microcracking, but no bulk coating spallation. Coatings cycled
      in HBSS displayed greater amounts of microcracking and surface alteration than
      samples cycled in air. There was no apparent relation between HA crystallinity
      and mechanical integrity under cyclic bending stresses.

PMID- 10421679
TI  - Mineralization processes in demineralized bone matrix grafts in human maxillary
      sinus floor elevations.
AB  - For reconstruction of the severely resorbed lateral maxilla for dental implant
      placement, one of the successful procedures is to elevate the maxillary sinus
      floor by implanting demineralized bone matrix (DBM). We studied bone formation in
      DBM grafts in the lateral maxilla in humans by means of histology and
      histomorphometry. Six months after grafting, at the time of dental implantation
      biopsies were taken from the grafted areas of seven patients. All biopsies
      contained mineralized matrix (MM) in the grafted area. At close inspection, three
      types of mineralization were found. First, lamellar biomineralization was seen in
      and near the maxillary host bone. Second, remineralization was observed in some
      particles that probably had not been completely demineralized. In the area
      connecting the graft and host bone, where woven bone was formed against DBM
      particles, a third mechanism was detected. In this case many dotlike foci of
      remineralization appeared close to the bone-DBM interface. The remineralized DBM
      and woven bone were both subsequently remodeled. Bone formation was most active
      in the area adjoining the maxillary host bone. We conclude that in human sinus
      floor elevation, allogenic DBM increases mineralized tissue volume by
      osteoconduction that is supported by the remineralization processes.
      Osteoinduction by this material seems questionable.

PMID- 10421681
TI  - Scanning electron microscopy observation of vascularization around hydroxyapatite
      using vascular corrosion casts.
AB  - An intimate relationship exists between the regenerative response of the vascular
      and osseous elements following hydroxyapatite (HA) implantation. In order to
      fully comprehend the 3-dimensional vascular architecture around HA, dense HA
      particles were implanted into the tibiae of dogs. Following healing periods of 2
      weeks, 1 month, and 3 months, the tibiae were prepared by the corrosion cast
      technique. Under scanning electron microscopy (SEM) observation, the
      characteristic vascular morphology of the HA-implanted cavity was successfully
      demonstrated. The initial vascularization began in the form of loose sinusoidal
      capillaries. Many sinusoids formed a complex network by anastomosing with each
      other. The newly formed vessels extended centripetally from the peripheral cavity
      wall and from the periosteal surface. Under greater magnification, the tapered
      vascular sprouting was shown to project into the space that was previously
      occupied by an HA particle. The presence of vascular sprouting is clearly an
      important indicator of angiogenesis. Increasing vascularization was demonstrated
      with time. The presence of vessels in the Haversian's canal indicated the more
      established vascularization. Almost full vascularization of the HA-implanted
      cavity was seen 3 months after implantation. The vascular organizational layout
      of the cavity was also clearly shown in the fractured transverse-sectioned
      sample. In the control without HA implantation, the central region of the cavity
      showed a hollow pattern in the initial stage. The vascularization looked like it
      was collapsing and not fully filling the cavity. However, remarkable differences
      of the final vascular pattern could not be found between the study and control
      group after 3-month implantation. The study provides the time-lapsed 3
      dimensional vascular changes of the HA-implanted cavity, as well as the value of
      the corrosion cast technique in examining the bony circulation.

PMID- 10421682
TI  - Disaggregated osteoclasts increase in resorption activity in response to
      roughness of bone surface.
AB  - The roughness of the bone matrix surface affects osteoblastic differentiation.
      However, the effect of the roughness of the matrix surface on osteoclastic bone
      resorption remains to be studied. We examined the latter effect using
      disaggregated osteoclasts from neonatal rats. The resorption pit number and the
      total pit area on the rough surface were not different from those on smooth
      surfaces after 1 day, but they were 2 or more times higher after 3 days. The
      number of osteoclasts was not different on bone slices with either smooth or
      rough surfaces at 3 days. The alkaline phosphatase (ALP)-positive osteoblasts
      were relatively rare in both types of slices at first, then the number and the
      diameter of the enzyme-positive cells and the clusters preferentially increased
      on the rough bone slices. When hydroxyurea was added to the culture in order to
      suppress the proliferation and the subsequent differentiation of osteoblastic
      cells on rough surfaces, the increase in resorption on the rough surfaces was
      effaced; however, this agent had little affect on resorption of the smooth
      surfaces. The addition of ALP-positive cells to disaggregated osteoclasts
      increased bone resorption on the smooth surface. The results suggest that
      osteoblast development and subsequently bone resorption by osteoclasts is
      enhanced by the roughness of matrix surfaces.

PMID- 10421683
TI  - Evaluating sol-gel ceramic thin films for metal implant applications: III. In
      vitro aging of sol-gel-derived zirconia films on Ti-6Al-4V.
AB  - Sol-gel-derived zirconia films were deposited onto polished Ti-6Al-4V substrates
      by dip-coating from an alkoxide precursor solution. No change in morphology of
      the zirconia film was observed after aging at 37 degrees C for 4-12 weeks in pH
      4.0 buffer solution or Hanks' balanced salt solution (HBSS), although a
      precipitate predominantly composed of calcium phosphate was formed on those films
      aged in HBSS. X-ray diffraction identified the phase of the zirconia film as
      either cubic or tetragonal, and revealed no degradation to the monoclinic phase
      after aging. By a substrate straining test, the fracture strain of the coating
      was revealed to be 1.5%, above the yield strain of the titanium alloy substrate.
      At this strain level, through-thickness cracks formed in the coating where slip
      bands emerged from the substrate. Qualitatively, the adhesion of the film was
      sufficient to prevent gross delamination of the film at high strain levels,
      although small regions of delamination were caused by compressive buckling of the
      film. This behavior indicates generally good adhesion. No change in this behavior
      was observed after aging.

PMID- 10421684
TI  - Proinflammatory mediator release in response to particle challenge: studies using
      the bone harvest chamber.
AB  - This study reports on the effects of phagocytosable particles on proinflammatory
      mediator release in an animal model. Bone harvest chambers (BHCs) were implanted
      bilaterally into mature rabbits; phagocytosable ultrahigh molecular weight
      polyethylene (UHMWPE) and polystyrene (PS) particles, and the carrier sodium
      hyaluronate (HE) were tested for their ability to stimulate proinflammatory
      mediator release. Tissues were harvested after 3, 4, or 6 weeks. Retrieved
      tissues were placed into culture medium. The release of the proinflammatory
      mediators interleukin-6 (IL-6), interleukin-1beta (IL-1beta), and tumor necrosis
      factor alpha (TNF-alpha) into the culture medium was assessed using bioassays.
      DNA content and dry weights were also measured. The maximal biological response
      to the PE particles with respect to TNF-alpha and IL-1beta was observed at three
      weeks with 11- and fivefold stimulations over controls, respectively. The maximal
      response to PE particles with respect to IL-6 was observed at 4 weeks with a
      twofold stimulation over controls. Similar patterns were seen with PS particles;
      however, PE particles stimulated higher cytokine release. PE particles stimulated
      the expression of IL-1beta, IL-6, and TNF-alpha in the BHC model. Cell culture
      and human retrieval studies also implicate these proinflammatory mediators in
      loosening and osteolysis of total joint replacements. Thus, the BHC is a useful
      in vivo model to document the effects of particles on the evolution of biological
      responses to particulate debris.

PMID- 10421685
TI  - Effect of metal surface topography on mechanical bonding at simulated total hip
      stem-cement interfaces.
AB  - Bonding and loosening mechanisms between bone cement and joint prostheses have
      not been well identified. In this study, the effects of simulated hip stem
      surface topography on the interfacial shear strength were examined. Six different
      surface topographies were used. They were described by several surface
      characterization parameters that may directly relate to the interfacial bonding
      strength: average surface roughness R(a), root mean square slope R(Deltaq),
      correlation length beta, and fluid retention index R(ri). The shear strengths
      between Palacos E bone cement and stainless steel rods were measured using an
      Instron materials testing machine. We found that cement can "flow" into the
      surface microtopography and establish good contact with the metal surface. The
      results show that the interfacial strength increases monotonically with the
      increase of R(Deltaq) instead of with R(a). The relationship between interfacial
      strength and surface parameters shows that a metal stem with an isotropic surface
      texture, higher R(Deltaq), and greater R(ri) gives a higher interfacial strength.

PMID- 10421686
TI  - Characterization of new acrylic bone cement based on methyl methacrylate/1
      hydroxypropyl methacrylate monomer.
AB  - New formulations of acrylic bone cement based on methyl methacrylate/1
      hydroxypropyl methacrylate (MMA/HPMA) monomers were developed with the purpose of
      obtaining more ductile materials with reduced polymerization shrinkage. In this
      way, the ductility of such materials increased, but the introduction of high
      percentages of the hydrophilic component produced an important decrease in
      Young's modulus and strength. To ascertain the reason for the deterioration of
      the tensile parameters, an analysis by scanning electron microscopy of these
      formulations was carried out; it revealed poor adhesion between the matrix and
      poly(MMA) beads. We also observed that the polymerization shrinkage increased as
      the amount of hydrophilic monomer in the formulation decreased, and the 50% (v/v)
      HPMA modified bone cement compensated for this volume reduction with its water
      uptake swelling. Measurements taken on the setting time and polymerization
      exotherm showed a decrease in the former and an increase in the latter, because
      of the introduction of a more reactive monomer in the bone cement formulation.

PMID- 10421688
TI  - Effect of protein lubrication on the wear properties of materials for prosthetic
      joints.
AB  - The effects of pre-dilution and other modifications of bovine serum lubricants on
      the wear properties of UHMW polyethylene acetabular cups were evaluated in a hip
      joint simulator. The wear rate increased, and a nonphysiological type of surface
      pitting occurred, when the serum was pre-diluted to 40% or lower concentration.
      During the wear test, the equilibrium temperature and the precipitation of
      proteins were substantially greater with zirconia balls than with cobalt
      chromium. Protein precipitation, a potential modulator of in vitro wear, was
      shown to be temperature, concentration, and time-dependent in water-bath tests,
      which indicated that ball-cup interface temperatures in the simulator must be
      above 60 degrees C, i.e., well above the bulk lubricant temperature, to account
      for wear test protein precipitation. Several modifications of serum that were, in
      part, intended to decrease the tendency for protein precipitation were found to
      markedly affect the wear properties of the two combinations of materials. In
      particular, modified serum, which lacked some of the higher molecular weight
      proteins, produced a much higher wear rate than a control serum with the same
      initial protein concentration. The results indicated directions for further
      research to clarify the lubricating properties of serum, and for developing a
      universal standard test lubricant.

PMID- 10421687
TI  - Potential thermal artifacts in hip joint wear simulators.
AB  - Frictional heat was monitored during wear tests of ultrahigh molecular weight
      polyethylene acetabular cups bearing against femoral balls of metal or ceramic in
      a hip simulator, using bovine serum as a lubricant. About 1 to 2 h of continuous
      cycling were required for the temperature in the zone of contact between the cup
      and ball to rise to its maximum steady value, and this equilibrium temperature
      was markedly higher with increased load and/or cycling rate. Frictional heating
      caused substantial precipitation of the proteins from the serum and, in some of
      the tests running at 1.5 or 2 Hz, an adherent proteinaceous layer was observed
      attached to the surface of the balls. The maximum temperature was also
      substantially higher in tests run with the cup mounted above the ball rather than
      below. Surprisingly, the tests running at higher frictional torque and
      temperature (i.e., those with the most protein precipitation and/or adherent
      layers) produced the least wear of the polyethylene. This might have been due to
      the solid proteins that formed a protective layer between the ball and cup.
      Because patients with hip prostheses typically do not walk for hours without
      rest, the maximum temperatures in vivo are likely to be much lower than those
      reached in the hip simulator. Therefore, the affects of protein precipitation on
      the resultant wear properties of the materials should be considered potential
      artifacts of the hip simulator tests. Increasing the volume of the lubricant bath
      reduced the maximum temperatures for tests running at 1.5 Hz but had little
      affect at 2 Hz. Reducing the cycling rate is an effective way to avoid
      overheating of the specimens, but this necessarily extends the time required to
      complete a test.

PMID- 10421689
TI  - Prevention of fatigue cracks in ultrahigh molecular weight polyethylene joint
      components by the addition of vitamin E.
AB  - Flaking-type wear, so-called delamination, is often observed in polyethylene
      joint components. This is thought to occur partly due to crack formation and
      propagation at grain boundaries. This study examined the effect of vitamin E on
      the crack formation and/or propagation in UHMWPE by using 2-dimensional sliding
      fatigue testing and micro indenter testing. An in vitro sliding fatigue test was
      performed under two simplified articulating movements, and the cracks produced
      were observed by scanning acoustic tomography (SAT). Gamma-irradiated ultrahigh
      molecular weight polyethylene (UHMWPE) specimens demonstrated a smaller area of
      accumulated cracks as compared to virgin specimens, when the loading movement was
      reciprocated on a single linear locus. However, four out of five gamma-irradiated
      UHMWPE specimens exhibited severe flaking-like destruction under the complicated
      sliding condition, suggesting that gamma irradiation accelerated crack
      propagation under multidirectional loading. All the gamma-irradiated vitamin-E
      containing specimens demonstrated no subsurface crack formation and no flaking
      like destruction. Results using micro indenter testing showed that the dynamic
      hardness at grain boundary was higher than that in grain, and was increased by
      gamma irradiation. This hardening at grain boundary was reduced by adding vitamin
      E. It is possible that the presence of vitamin E prevents crack propagation
      partly due to reduced hardness at grain boundaries. The gamma-irradiated vitamin
      E-containing UHMWPE is a promising material to prevent flaking-like destruction
      of polyethylene joint components.

PMID- 10421690
TI  - Enhancing knot security by heat treatment of knot ears.
AB  - Heat treatment of the ears of knotted sutures markedly enhances knot security.
      Using coated polyester sutures commonly used in arthroscopic surgery, heat
      treatment of the knot ears allows secure knot construction to be achieved with a
      two throw granny (1 x 1) or square (1 = 1) knot. A heat source is being designed
      for secure knot construction in arthroscopic surgery.

PMID- 10421691
TI  - In vivo characterization of indentation stiffness of articular cartilage in the
      normal human knee.
AB  - Previous laboratory measurements showed topographical variation in the properties
      of articular cartilage in several animal species and in humans. In this study we
      characterize for the first time the topographical variation of the stiffness of
      the human knee articular cartilage in vivo using a novel arthroscopic indentation
      instrument. The instrument indicates the stiffness in the form of force (Newtons)
      by which the tissue resists the constant deformation (300 microm) produced by the
      small (1-mm diameter) cylindrical indenter. Measurements were carried out at
      eight sites in the knee joint of 20 persons who had intact cartilage in the
      arthroscopic examination. The stiffest cartilage (5.6 +/- 1.2 N, mean +/- SD) was
      located in the lateral condyle of the femur, whereas the softest cartilage (2.4
      +/- 0.8 N) was in the medial plateau of the tibia. In general, the cartilage
      stiffness was higher in the femur than in the tibia (p < 0. 01) or in the patella
      (p < 0.01). In the femur, the condyles were stiffer than the patellar surface (p
      < 0.01). The stiffness variation was consistent with earlier biphasic indentation
      analyses of laboratory measurements with the knee joint cartilage of cadavers.
      This study provides baseline data for characterization of cartilage stiffness in
      pathological situations or follow-up of the cartilage quality after surgical
      interventions.

PMID- 10421692
TI  - Nickel release from orthodontic arch wires and cellular immune response to
      various nickel concentrations.
AB  - AIMS: Results from two previous clinical studies suggested that exposure to high
      nickel-containing orthodontic arch wires may induce hypersensitivity in certain
      individuals. The purpose of this study was to measure the amount of nickel
      released from three types of nickel-containing arch wires into a synthetic saliva
      in vitro, and determine if the concentrations were sufficient to elicit either
      cytotoxic (trypan blue exclusion test) or stimulatory (MTT test) responses in
      human peripheral blood mononuclear cells (PBMCs) derived from nickel-sensitive
      and nickel-nonsensitive individuals. PBMCs were exposed to five concentrations of
      nickel sulfate solutions ranging from 0-29 ppm, and results were compared,
      particularly at concentrations obtained from nickel release experiments.
      FINDINGS: The amount of nickel released into synthetic saliva ranged from 0.4-4.1
      ppb. Wires subjected to a combination of soaking and cyclic straining released
      significantly more nickel than those that were soaked only (p </= 0.05), and NiTi
      wires released significantly more nickel than did stainless steel or nitrogen
      implanted NiTi wires (p </= 0.05). For PBMCs, significant increased cell
      proliferation was not observed for any nickel concentration. PBMC cell death
      rates were highest at nickel concentrations of 29 ppm when the cells were
      cultured without a cell growth promoter (p </= 0.05), and MTT test values were
      significantly reduced at both 2.9 and 29 ppm when a growth promoter was included
      (p </= 0.05). CONCLUSION: The maximum amount of nickel released from all tested
      arch wires was 700 times lower than the concentrations necessary to elicit
      cytotoxic reactions in human PBMCs.

PMID- 10421693
TI  - Design, formulation, and evaluation of isocyanatoacrylate copolymer dental
      adhesives.
AB  - Experiments have recently been completed to explore the development of
      isocyanatoacrylate copolymers as new dental adhesives. A main goal of this work
      was to test the utility of solubility parameter differences between the candidate
      adhesives and etched dentin as a predictor of relative bond strength. All
      candidate adhesive mixtures contained 2-isocyanatoethyl methacrylate (IEM), a
      selected amount of tri-n-butylborane oxide (TBBO) initiator, and one of 13
      methacrylate comonomers. Reactivity ratios were computed for comonomer pairs as
      indicators of relative reactivity. The concentration of TBBO was optimized for
      each comonomer mixture to obtain working times of 2-6 min and setting times of 6
      10 min. The solubility parameter difference Deltadelta (J/cm(3))(1/2) was
      calculated for each test mixture with respect to an etched dentin substrate, as
      an approximation of wetting ability. Using standard techniques for shear bond
      strength evaluation, mean shear bond strength values ranging between 7-15.5 MPa
      were obtained for comonomer adhesives in bonding Z-100 composite to treated
      dentin. Shear bond strength values showed a good correlation (r = -0.612, P </=
      0.05) with solubility parameter differences. This study illustrates the
      usefulness of reactivity ratios and solubility parameters in the design and
      development of effective dentin bonding agents.

PMID- 10421695
TI  - Photocurable surgical tissue adhesive glues composed of photoreactive gelatin and
      poly(ethylene glycol) diacrylate.
AB  - This article presents a novel photochemically driven surgical tissue adhesive
      technology using photoreactive gelatins and a water-soluble difunctional macromer
      (poly(ethylene glycol) diacrylate: PEGDA).The gelatins were partially derivatized
      with photoreactive groups, such as ultraviolet light (UV)-reactive benzophenone
      and visible light-reactive xanthene dye (e.g., fluorescein sodium salt, eosin Y,
      and rose bengal). A series of the prepared photocurable tissue adhesive glues,
      consisting of the photoreactive gelatin, PEGDA, and a saline solution with or
      without ascorbic acid as a reducing agent, were viscous solutions under warming,
      and their effectiveness was evaluated as hemostasis- and anastomosis-aid in
      cardiovascular surgery. Regardless of the type of photoreactive groups, the
      irradiation of the photocurable tissue adhesive glues by UV or visible light
      within 1 min produced water-swollen gels, which had a high adhesive strength to
      wet collagen film. These were due to the synergistic action of photoreactive
      group-initiated photo-cross-linking and photograft polymerization. An increase in
      the irradiation time resulted in increased gel yield and reduced water
      swellability. A decrease in the molecular weight of PEGDA and an increase in
      concentration of both gelatin and PEGDA resulted in reduced water swellability
      and increased tensile and burst strengths of the resultant gels. In rats whose
      livers were injured with a trephine in laparotomy, the bleeding spots were coated
      with the photocurable adhesive glue and irradiated through an optical fiber. The
      coated solution was immediately converted to a swollen gel. The gel was tightly
      adhered to the liver tissue presumably by interpenetration, and concomitantly
      hemostasis was completed. The anastomosis treatment with the photocurable glue in
      the canine abdominal or thoracic aortas incised with a knife resulted in little
      bleeding under pulsatile flow after declamping. Histological examination showed
      that the glues photocured on rat liver surfaces were gradually degraded with time
      in vivo with infiltration of inflammatory cells and connective tissues without
      necrotic sign in surrounding tissue. In addition, in the laparoscopic surgery,
      percutaneous delivery of the glue and its in situ photogelation on rat liver
      surfaces were demonstrated using a specially designed fiberscope. These results
      indicate that the photocurable glues developed here may serve as a biodegradable
      tissue adhesive glue usable in cardiovascular surgery and endoscopic surgery.

PMID- 10421694
TI  - The development of an embedding technique for polylactide sponges.
AB  - The use of absorbable polymeric biomaterials is increasing in the field of tissue
      engineering. These polymeric scaffolds provide mechanical strength and shape as
      the engineered tissue forms. Histological analysis is an important part of the
      development of an appropriate polymeric construct, because it allows the analysis
      of the cell/material interaction. Unfortunately, routine paraffin processing
      often degrades these absorbable polymers, and routine staining can dissolve the
      remnants. This research sought to develop a histological procedure that would
      retain the polymer structure. Two processing procedures, paraffin and glycol
      methacrylate, were tested on three in vitro groups of poly-L-lactide sponges,
      high cell density seeding, low cell density seeding, and a control. The paraffin
      processing caused shrinkage and degradation of the polymer, and staining
      dissolved the remnants. The glycol methacrylate processing minimized damage to
      the polymer even after staining.

PMID- 10421697
TI  - Technical note: biomechanical analysis of two absorbable fracture fixation pins
      after long-term canine implantation.
AB  - The design requirements for bioabsorbable fracture fixation devices for specific
      applications are as yet unknown. Therefore, a range of initial mechanical
      properties and degradation kinetics may provide developers with additional
      choices for the design of absorbable fracture fixation devices. This study
      evaluated the changes in push-out strength, polymer mechanical properties, and
      bone mechanical properties of self-reinforced poly(glycolide) (SR-PGA) and
      poly(ortho ester) (POE) fracture fixation pins implanted into the canine femoral
      canal for 18 months. Mechanical testing indicated that SR-PGA pins had degraded
      to a pasty consistency by 3 months, showing complete loss of all mechanical
      properties. Meanwhile, POE pins showed a simultaneous linear decrease in both
      compressive strength and stiffness to almost zero by the end of the study period,
      suggesting that these devices were undergoing surface erosion. However, changes
      in specimen diameter, which would support this mechanism, were not apparent. The
      decrease in polymer density after 12 months suggests that there was an increase
      in bulk erosion for POE devices. This was further supported by the observation of
      internal polymer resorption noticed in specimen cross-sections after 18 months.
      This observation appears to be related to the method of polymer processing; hot
      compression molding of fine powdered polymer. The appearance of grain boundaries
      would provide a path for water to penetrate into the bulk polymer and cause
      autocatalysis in the interior of the implant.

PMID- 10421696
TI  - In vivo evaluation of a novel alginate dressing.
AB  - Alginate dressings are currently used in the management of epidermal and dermal
      wounds, and provide a moist environment that leads to rapid granulation and
      reepithelialization. However, a cytotoxic effect on proliferation of fibroblasts
      and residual material with inflammation in healing wounds have been reported
      recently. We have developed a new alginate dressing (AGA-100), which does not
      have an inhibitory effect on proliferation of fibroblasts. The purpose of this
      study was to evaluate the new alginate dressing with respect to wound healing in
      full- and partial-thickness pig wounds and with respect to biodegradation
      following implantation into rabbit muscle. Kaltostat and Sorbsan, both well
      established commercial dressings, were used as control. The closure rate of full
      thickness wounds treated with AGA-100 was significantly higher on day 15 compared
      with that with Kaltostat and Sorbsan. Reepithelialization rate of partial
      thickness wounds treated with Sorbsan was statistically significantly lower on
      day 3 than those with the other two dressings. As to dressing debris remained in
      the healing wound, a large amount of foreign debris was noted in all the full
      thickness wounds treated with Kaltostat or Sorbsan, while only about one-third of
      wounds treated with AGA-100 showed a little dressing debris. AGA-100 implanted
      into the muscle of rabbits was bioresorbed completely within 3 months. Therefore,
      dressing residue in AGA-100-treated full-thickness wounds might be fully absorbed
      in a few months. In conclusion, it is shown that our newly developed AGA-100
      possesses superior properties compared with typical alginate dressings.

PMID- 10421698
TI  - Failure mechanisms of polyester fiber anterior cruciate ligament implants: A
      human retrieval and laboratory study.
AB  - It has been hypothesized that ACL implant failure is often caused by bone
      impingement in knee extension following malplacement of the tibial tunnel. This
      study examined polyethylene terephtalate fiber ACL implants retrieved from a
      clinical study, and, to confirm the hypothesis, also set up a laboratory study
      intended to duplicate the failure mechanism. SEM and TEM examination of 25
      ruptured implants gave details of fiber failure morphology, with shearing into
      longitudinal fibrils, followed by rupture, when the fibrils burst apart. Cadaver
      joints were run in a knee simulator, with deliberately impinging ACL implants.
      SEM examination of implants abraded in the knee in vitro showed identical fiber
      damage patterns, thus confirming the impingement hypothesis.

PMID- 10421699
TI  - Evaluation of chemical and mechanical properties of dental composites.
AB  - Composite materials were aged in distilled, deionized water and a solution by
      volume of 50% distilled, deionized water and 50% ethanol for three mon at 37
      degrees C. Also investigated was the effect of aging dental glass filler powder
      in distilled, deionized water for one, three, six, and ten mon at 2 degrees C, 37
      degrees C, and 72 degrees C. Atomic absorption analysis was performed on the
      aqueous media in which the samples were aged in order to determine the extent of
      leaching of silicon and strontium. From the leaching rates at various aging
      temperatures, the activation energies for silicon (10.3-16.4 j/mol) and strontium
      (57.0-58.4 j/mol) were determined. Aging in the 50% distilled, deionized water
      and 50% ethanol solution greatly increased the leaching rate of both silicon and
      strontium, as compared to aging in distilled, deionized water. Glass powder
      leached far more than the composite materials, due to an increase in exposed
      surface area, as well as a lack of chemical bonding to a resin matrix or a linked
      glass network. Temperature greatly increased the leaching rate of both silicon
      and strontium. Only after ten mon did strontium leach substantially more than
      silicon. For the dental composites investigated after 3 mon aging, Mode I
      fracture toughness decreased 57-68% in ethanol and 37-43% in water, and mode II
      fracture toughness decreased 41-49% in ethanol and 6-11% in water.

PMID- 10421700
TI  - A new generation of polyurethane vascular prostheses: rara avis or ignis fatuus?
AB  - Three polyurethane (PU) vascular grafts with novel designs were investigated and
      compared in terms of the microporous structure, reinforcement technology, polymer
      chemistry, microphase separation, and mechanical properties. The Corvita graft,
      composed of a poly(carbonate urethane) polymer, displayed a helically wound
      filament structure with communicating inter-fiber spaces. The reinforced model
      contained an external PET mesh impregnated with a protein sealant, and displayed
      good microphase separation, the highest Young's modulus in the longitudinal
      direction, and the second highest in the radial direction. The Thoratec graft was
      made of a polyetherurethaneurea with an average micropore size of 15 microns.
      Silicone was observed on both surfaces of the graft. The Thoratec device
      displayed a low degree of hydrogen-bonding among the urethane groups and had no
      well-organized hard-segment domains. Its mechanical strength was superior to that
      of the Pulse-Tec graft. A solid PU layer underneath the luminal surface precluded
      any communication between the luminal and adventitial sides. The Pulse-Tec
      prosthesis was composed of polyetherurethane, with an average micropore size of
      28 microns. It offered the highest radial compliance, a high degree of hydrogen
      bonding, a narrow molecular weight distribution, and a certain degree of
      microphase separation. Its tensile strength and hysteresis loss were inferior to
      those of the other two grafts.

PMID- 10421701
TI  - Surface analysis of failed oral titanium implants.
AB  - The aim of the present study was to investigate the surface topography,
      composition, and oxide thickness of consecutively failed, oral Branemark implants
      in order to determine possible causes for failure. The failure criterion was lack
      of osseointegration manifested as implant mobility. Ten implants were retrieved
      before loading (early failures) and 12 during a period of function up to 8 years
      (late failures). At retrieval, early losses did not display any clinical sign of
      infection. All late failures were radiographically characterized by peri-implant
      radiolucency and did not show infectious signs with one exception. No implant
      seemed to be lost due to peri-implantitis (plaque-induced progressive marginal
      bone loss). Twelve implants were analyzed by scanning electron microscopy (SEM),
      Auger electron spectroscopy (AES), and depth profiling using a blind protocol.
      Two pristine fixtures, which underwent the same preparation as the failed
      implants, were used as controls. In the SEM, control samples were essentially
      free from macroscopic contamination, whereas failed implants contained varying
      amounts of tissue residues. AES showed that all surfaces consisted of Ti oxide
      and varying amounts of additional elements, with C dominating in most cases.
      Nitrogen and sometimes Na, Ca, P, Cl, S, and Si were detected. The Si
      contamination was most likely due to ion leaching from the glass vials used for
      storage. Depth profiles showed a typical oxide thickness of 5-8 nm for all
      samples. In conclusion, no significant changes in the oxide layer composition or
      thickness as a result of implantation were observed. The results do not indicate
      any material-related cause for the failures of these implants. Possible reasons
      for these failures were impaired healing, asymptomatic infection, and overload.

PMID- 10421702
TI  - The scientific basis of surgical glove selection in an in vitro fertilization
      laboratory.
AB  - Mouse embryos and human sperm are used as quality control bioassays in human in
      vitro fertilization (IVF) laboratories. These two models can reveal the
      cytotoxicty of items commonly used in IVF, such as surgical gloves. The
      literature published in this area points to the cytotoxicity of both glove
      powders and glove products.

PMID- 10421703
TI  - Biomechanical performance of examination gloves.
AB  - The purpose of this study was to compare the biomechanical performance of new
      powder-free commercially available synthetic examination gloves to that of
      commercially available powder-free latex examination gloves. The synthetic gloves
      were significantly thinner than the latex gloves. Despite the decreased
      thickness, all three nitrile gloves, as well as the polyvinyl chloride glove,
      exhibited a greater resistance to glove puncture. The glove donning forces varied
      considerably among all gloves, and wet donning forces were greater than dry
      donning forces. Under dry conditions, the donning forces for the synthetic gloves
      were less than or equal to the forces for the latex gloves. Because of their
      increased puncture resistance and similar donning forces, synthetic gloves are a
      safe alternative to latex examination gloves.

PMID- 10421704
TI  - Carboxymethyl benzylamide sulfonate dextrans (CMDBS), a family of biospecific
      polymers endowed with numerous biological properties: a review.
AB  - The functionalized dextrans termed carboxymethyl benzylamide sulfonate dextran
      (CMDBS) represent a family encompassing a wide range of polymers. These soluble
      macromolecular compounds, which are substituted with specific chemical functional
      groups, are designed to interact with living systems. By analogy with
      glycosaminoglycan heparin, a natural highly charged anionic polysaccharide that
      exerts a variety of biological effects, we postulated that CMDBS compounds also
      possess binding sites capable of specific interactions with biological
      constituents, depending on the overall composition of the polymer. The synthesis
      and heparin-like properties of these CMDBS have been extensively investigated.
      Thus, it appears that dextran derivatives can mimic the action of heparin in
      regard to its interactions with antithrombin and serine proteases involved in
      blood coagulation. Other derivatives interact with various components of the
      immune system or with adhesive proteins such as fibronectin in modulating the
      proliferation of Staphylococcus aureus. Because they are able to stimulate wound
      healing in various in vivo models, these polysaccharides may also constitute a
      family of tissue repair agents because of their protecting and potentiating
      effects with heparin binding growth factors. Moreover, dextran derivatives in
      contact with cells such as endothelial cells, smooth muscle cells, or tumoral
      cells can affect both cell proliferation and metabolism. It appears that these
      bioactive polymers are also efficient tools to investigate the precise mechanism
      of action of individual biological activities by contrasting their mode of action
      to that of heparin. In addition to their numerous biological properties and
      biospecificity, functionalized dextrans are relatively simple to manufacture and
      exempt of donor contaminant, which make them attractive in a variety of clinical
      applications.

PMID- 10421705
TI  - Cerebral 6-[(18)F]fluoro-L-DOPA (FDOPA) metabolism in pig studied by positron
      emission tomography.
AB  - We measured 6-[(18)F]fluoro-L-DOPA (FDOPA) uptake and metabolism in the brain of
      4-month-old female pigs (n = 8) using a high-resolution positron emission
      tomograph (PET) in 3D mode. The mean net blood-brain clearance of FDOPA (K(i)(D))
      to striatum was 0.011 ml g(-1) min(-1). Correcting for the elimination of
      decarboxylated metabolites from striatum (k(loss) = 0.004 min(-1)) increased the
      apparent magnitude of the estimate of K(i)(D) by 50%, at the expense of doubling
      the variance of the mean estimate. The mean decarboxylation rate of FDOPA in
      striatum relative to the cerebellum input (k(3)(s)) was 0.008 min(-1). For
      multicompartmental analyses, the FDOPA partition volume (V(e)(D)) was constrained
      to the individual value observed in cerebellum (mean = 0.53 ml g(-1)), with
      correction for the presence in brain of the plasma metabolite 3-O-methyl-FDOPA
      (OMFD). Using the first 60 min of the dynamic PET scans, the rate constant of
      FDOPA decarboxylation (k(3)(D)) was estimated to be 0.037 min(-1 )in striatum,
      but was not significantly different than zero in frontal cortex. Fitting of a
      compartmental model correcting for elimination of decarboxylated metabolites to
      the complete PET frame-sequence (120 min) increased the variance of the estimate
      of k(3)(D) in striatum. The magnitude of k(3)(D) in striatum of young pig was
      less than values estimated previously in neonatal piglet, adult monkey, and
      human. MRI-based simulations predicted that recovery of radioactivity from pig
      striatum was highly sensitive to the volume of interest. We conclude that the
      spatial resolution of our tomograph reduces the apparent magnitude of k(3)(D) in
      striatum. However, anaesthetised pigs are an appropriate experimental model for
      PET studies of DOPA decarboxylation in striatum.

PMID- 10421706
TI  - Subconvulsive dose of pentylenetetrazole increases the firing rate of substantia
      nigra pars reticulata neurons in dystonic but not in nondystonic hamsters.
AB  - Dystonic attacks, including twisting movements, can be initiated by mild stress
      in mutant (gene symbol dt(sz)) Syrian golden hamsters, an animal model of
      idiopathic paroxysmal dystonia. Previous studies suggested that dysfunctions in
      basal ganglia, which are not restricted to periods of attacks, are involved in
      the dystonic syndrome in mutant hamsters. Therefore, in the present study in
      anesthetized animals, we examined whether the spontaneous firing rate of
      extracellularly recorded neurons of the substantia nigra pars reticulata (SNr)
      differs between dt(sz) and age-matched nondystonic control hamsters. Furthermore,
      we investigated the responsiveness of these nondopaminergic, presumably GABAergic
      neurons to a subconvulsive dose (25mg/kg i.p.) of systemically applied
      pentylenetetrazole (PTZ), which exerts prodystonic effects in mutant hamsters.
      The mean basal (spontaneous) firing rate of SNr neurons was not altered in mutant
      hamsters. However, within 5 min after i.p. injection of PTZ, the mean firing rate
      of SNr neurons significantly increased to about 160% of predrug control values in
      dt(sz) but not in control hamsters. Although the present study failed to reveal
      changes in the basal firing rate of SNr neurons in mutant hamsters, the abnormal
      response to PTZ is in line with previous pharmacological and biochemical data
      indicating disturbed function of the GABAergic system.

PMID- 10421707
TI  - GBR12909 attenuates amphetamine-induced striatal dopamine release as measured by
      [(11)C]raclopride continuous infusion PET scans.
AB  - Major neurochemical effects of methamphetamine include release of dopamine (DA),
      serotonin (5-HT), and norepinephrine (NE) via a carrier-mediated exchange
      mechanism. Preclinical research supports the hypothesis that elevations of
      mesolimbic DA mediate the addictive and reinforcing effects of methamphetamine
      and amphetamine. This hypothesis has not been adequately tested in humans.
      Previous in vivo rodent microdialysis demonstrated that the high affinity DA
      uptake inhibitor, GBR12909, attenuates cocaine- and amphetamine-induced increases
      in mesolimbic DA. The present study determined the ability of GBR12909 to
      attenuate amphetamine-induced increases in striatal DA as measured by
      [(11)C]raclopride continuous infusion positron emission tomography (PET) scans in
      two Papio anubis baboons. [(11)C]Raclopride was given in a continuous infusion
      paradigm resulting in a flat volume of distribution vs. time for up to 45 min
      postinjection. At that time, a 1.5 mg/kg amphetamine i.v. bolus was administered
      which caused a significant (30.3%) reduction in the volume of distribution
      (V(3)"). The percent reduction in the volume of distribution and, hence, a
      measure of the intrasynaptic DA release ranged between 22-41%. GBR12909 (1 mg/kg,
      slow i.v. infusion) was administered 90 min before the administration of the
      radiotracer. The comparison of the volume of distribution before and after
      administration of GBR12909 showed that GBR12909 inhibited amphetamine-induced DA
      release by 74%. These experiments suggest that GBR12909 is an important
      prototypical medication to test the hypothesis that stimulant-induced euphoria is
      mediated by DA and, if the DA hypothesis is correct, a potential treatment agent
      for cocaine and methamphetamine abuse. Furthermore, this quantitative approach
      demonstrates a way of testing various treatment medications, including other
      forms of GBR12909 such as a decanoate derivative.

PMID- 10421708
TI  - Modulation of endogenous GABA release by an antagonistic adenosine A1/dopamineD1
      receptor interaction in rat brain limbic regions but not basal ganglia.
AB  - Behavioral and biochemical studies suggest that a negative interaction exists
      between adenosine A(1) and dopamine D(1) receptors in the brain and that this may
      contribute to the psychomotor effects of adenosine receptor agonists and
      antagonists. We examined the functional significance of A(1) and D(1) receptor
      subtypes in modulating electrically evoked endogenous GABA release from
      slices/punches of rat basal ganglia (striatum, globus pallidus, striatum
      containing globus pallidus, and substantia nigra reticulata) and limbic regions
      (ventral pallidum and nucleus accumbens). In basal ganglia, stimulation of A(1)
      receptors with the selective agonist R-PIA (1-100 nM) resulted in a concentration
      dependent decrease in GABA release. The selective A(1) antagonist DPCPX (10-100
      nM) increased GABA release, suggesting that endogenous adenosine tonically
      inhibits GABA release. However, in basal ganglia, consistent dopamine D(1)
      receptor modulation of GABA, release was not observed in response to either D(1)
      agonists or antagonists. Furthermore, the A(1) receptor-mediated inhibition of
      GABA release was not changed by concurrent activation of D(1) receptors, thus
      confirming the lack of D(1) receptor modulation under these conditions. In
      contrast, in ventral pallidum and nucleus accumbens, stimulation of D(1)
      receptors with SKF-82958 (1 microM) increased GABA release significantly. The
      D(1) receptor-mediated increase in GABA release was attenuated by concurrent
      activation of adenosine A(1) receptors. These results are consistent with the
      hypothesis that an antagonistic A(1)/D(1) receptor interaction may be important
      in modulating GABA release in limbic regions.

PMID- 10421709
TI  - Opiate receptor avidity is reduced bilaterally in rhesus monkeys unilaterally
      lesioned with MPTP.
AB  - Opiate receptor avidity (unoccupied receptor density / the receptor dissociation
      constant), was measured in four animals with unilateral parkinsonian symptoms
      following MPTP (1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine) infusions into the
      internal carotid of one side, and nine normal controls with positron emission
      tomography (PET) and 6-deoxy-6-beta-[(18)F]fluoronaltrexone (cyclofoxy, CF), a mu
      and kappa-opiate receptor antagonist. PET studies of 6-[(18)F]-L-fluoro-L-3,4
      dihydroxyphenylalanine ([(18)F]-DOPA) in these parkinsonian animals, although
      documenting the primarily unilateral nature of the lesion, also demonstrated a
      milder loss of dopaminergic on the side opposite the infusion. Opiate receptor
      avidity was found to be reduced by 20-34% in the caudate, anterior putamen,
      thalamus, and amygdala of these primarily unilaterally MPTP-exposed animals,
      bilaterally with no statistically significant differences between the two sides.
      The affected regions are the same as those previously demonstrated to have a 30
      35% loss in clinically recovered bilaterally MPTP-lesioned animals. These
      findings confirm that the opiate pathway can change in response to modest
      decreases in basal ganglia dopamine innervation. Thus, opiate pathway adaptation
      is likely to contribute to the dynamic changes in basal ganglia circuits that
      forestall the initial clinical manifestations of Parkinson's disease. In
      addition, opiate pathway(s) may contribute to the treatment responsiveness and
      progression of the disease either directly through effects on basal ganglia
      function or indirectly through effects on basal ganglia plasticity.

PMID- 10421710
TI  - Enhancement of N-methyl-D-aspartate (NMDA) immunoreactivity in residual dendritic
      spines in the caudate-putamen nucleus after chronic haloperidol administration.
AB  - Glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype in the caudate
      putamen nucleus (CPN) have been implicated in the adverse motor effects produced
      by chronic administration of the typical antipsychotic drug haloperidol. To
      determine the functionally relevant sites, we examined the electron microscopic
      immunocytochemical localization of the R1 receptor subunit (NMDAR1) in the
      dorsolateral CPN of rats receiving 4 months of biweekly depot intramuscular
      injections of either haloperidol or vehicle. In all animals, NMDAR1
      immunoreactivity was seen mainly in dendritic spines, but was also present in a
      few somata and dendrites of spiny neurons, axon terminals, and glia. In
      comparison with controls, the dissector stereological analysis showed a
      significant reduction in the numerical density of total NMDAR1-labeled and
      unlabeled dendritic spines in the dorsolateral CPN after haloperidol
      administration. When labeled spines were identified separately based exclusively
      on the presence of immunoreactivity within a single plane of section, there was,
      however, a significant increase in the numerical density of NMDAR1-containing
      spines in haloperidol vs. control animals. This increase was not seen using a
      classic dissector, suggesting that the enhancement was mainly attributed to more
      frequent detection of spines having higher levels of NMDA immunoreactivity. Our
      results are the first to identify dendritic spines in the dorsolateral CPN as
      preferential sites for the regulated expression of NMDA receptors following
      chronic administration of haloperidol.

PMID- 10421711
TI  - Discrete local application of corticotropin-releasing factor increases locus
      coeruleus discharge and extracellular norepinephrine in rat hippocampus.
AB  - The most prominent afferents impinging upon the noradrenergic neurons of the
      locus coeruleus (LC) utilize GABA and glutamate. However, peptide
      neurotransmitters such as galanin, neuropeptide Y, and corticotropin-releasing
      factor (CRF) have also been localized to LC afferents. The evidence for CRF
      modulation of LC activity was examined in the present studies. Specifically, the
      impact of local CRF administration on both LC-NE discharge characteristics and
      release of norepinephrine (NE) in hippocampus was determined. First, the ability
      of CRF microinfused into the LC area to increase NE efflux in the dorsal
      hippocampus was determined using in vivo microdialysis techniques in awake rats.
      CRF into the LC dose-dependently increased extracellular NE in the ipsilateral
      hippocampus. Second, a more detailed analysis was performed in halothane
      anesthetized rats by characterizing the electrophysiological activity of LC-NE
      neurons in response to local application of CRF. Changes in the firing rate and
      pattern of single LC-NE neurons were measured while simultaneously monitoring the
      extracellular level of NE in hippocampus. A dose of 30 ng CRF applied directly
      into LC via pressure ejection elicited an 88% increase in the discharge rate of
      LC-NE neurons and increased the incidence of burst firing from 14% to 33%. This
      manipulation simultaneously increased extracellular NE in hippocampus by 63%. The
      CRF-induced increases in discharge rate of LC-NE neurons and extracellular NE
      efflux in hippocampus were prevented by prior i.c.v. administration of the CRF
      antagonist, d-PheCRF(12-41 )(3 microg / 3 microl). The present findings
      demonstrate that CRF applied directly into the LC increases both the activity of
      LC-NE neurons and the release of NE in an LC terminal region. The shift in
      activity of LC-NE neurons to more burst-like firing in response to CRF may
      provide a means for enhanced release of NE in LC projection fields. This is the
      first report to demonstrate a dose-dependent increase in extracellular NE levels
      evoked by intra-LC infusion of CRF in unanesthetized animals.

PMID- 10421713
TI  - "Controversies in epidemiology", teaching causality in context at the University
      at Albany, School of Public Health.
AB  - Social inequalities relate not only to disparities in health but also are the
      social context for theories of disease causality being legitimized or denied. In
      the discipline of epidemiology, conventional discussions on whether or not a
      given exposure "causes" a specific disease are framed almost exclusively as
      debates of validity and whether there is sufficient accumulation of evidence to
      satisfy "Hill's Causal Criteria". However, the way in which the conceptualization
      of disease processes is restricted to conform to the current causal paradigm,
      which is based on socially determined ideas of individualism, reductionism,
      monocausality and the legitimacy of social inequalities, can be identified as a
      fundamental assumption underlying conventional epidemiological debates of
      causality. Any argument that social inequalities are an important determinant of
      poor public health must also explicitly critique the current causal paradigm,
      which disallows epidemiologists from conceptualizing social relationships as
      causal of poor health in populations.

PMID- 10421712
TI  - Indirect evidence for an association of 5-HT(1B) binding sites with retinal and
      geniculate axon terminals in the rat suprachiasmatic nucleus.
AB  - The purpose of the present study was to investigate the possible cellular
      location of 5-HT(1B) receptors on retinal and geniculate afferents in the rat
      suprachiasmatic nucleus (SCN). Biocular enucleation significantly decreased 5
      HT(1B) binding site labeling (35%), specifically in the ventral part of the SCN,
      while monocular enucleation produced a decrease of smaller magnitude (12%),
      limited to the ventral part of the contralateral SCN, these results being
      consistent with the known distribution of retinal afferents in the nucleus. By
      contrast, bilateral geniculate lesion did not induce any significant variation of
      5-HT(1B) binding site labeling in the SCN. Previously, we reported that serotonin
      (5-HT) synthesis inhibition by parachlorophenylalanine increases 5-HT(1B) binding
      site labeling in the SCN. Using saturation studies, we have now demonstrated that
      this upregulation reflected an increase in the total number of 5-HT(1B) binding
      sites (+41% in the dorsal and +67% in the ventral part of the SCN). Furthermore,
      we evaluated the effects of bilateral geniculate lesion after 5-HT stores
      depletion in order to overcome problems of technical resolution limits. The
      magnitude of upregulation was significantly decreased (27%) after bilateral
      geniculate lesion, suggesting that part of the 5-HT(1B) receptor population was
      located on geniculate axon terminals within the SCN. The possible involvement of
      5-HT(1B) receptors, according to their cellular locations evidenced in the
      present study, in photic and nonphotic entrainment of the circadian clock is
      discussed.

PMID- 10421714
TI  - Suicide mortality in Finland during an economic cycle, 1985-1995.
AB  - This is a study on associations between suicide mortality, unemployment, divorce
      rate and mean alcohol consumption during an economic cycle in Finland, from 1985
      to 1995. Data on annual suicide mortality, gross domestic product, unemployment,
      divorce rate and mean alcohol consumption were collected from official Finnish
      statistics. Regression analyses using a correction for serial autocorrelation
      were performed. Suicide mortality in both males and females increased during an
      economic upswing from 1985 to 1990 and decreased during an economic recession
      from 1990 to 1995. Suicide mortality was not associated with unemployment or
      divorce rate. These results are opposed to those of many previous studies.
      However, a significant association was found between male suicide mortality and
      mean alcohol consumption, in accord with other studies. In conclusion, the
      results suggest diversity in associations between suicide mortality,
      socioeconomic factors and alcohol consumption.

PMID- 10421715
TI  - Risk of low birthweight in social districts of Copenhagen.
AB  - The purpose of this survey was to investigate the small-area variations in low
      birthweight within social services districts in Copenhagen and the relation of
      such variations to the socioeconomic characteristics of the district. The study
      was based on register data and included all live-born single on births to women
      living in the city of Copenhagen from 1987-90. We found a statistically
      significant association between district and risk of newborns being small-for
      gestational age (SGA). This association was independent of adjustment for
      maternal age and parity. Only part of the association was explained, though this
      was still significant, using an index summarizing the socioeconomic living
      conditions in the district. Splitting up the index into its four constituent
      components, however, showed that the association between SGA and district was
      primarily due to housing conditions in the districts. Mapping the districts
      demonstrated a clear tendency of clustering of the high-risk areas with poor
      socioeconomic conditions.

PMID- 10421716
TI  - Health and re-employment in a five-year follow-up of long-term unemployed.
AB  - OBJECTIVES: To study health and re-employment in a five-year follow-up of a
      community sample of long-term unemployed people. METHODS: A random sample
      registered for more than 12 weeks at the labour offices in Grenland, Norway, were
      given medical check-ups in 1988 and 1990, and a postal questionnaire in 1993.
      RESULTS: Only 37% were employed five years after the first spell of long-term
      unemployment. Recovery after re-employment was demonstrated, indicating that
      unemployment causes poor mental health. Health-related selection to continuous
      unemployment was only found for medical diagnoses. The unemployed who might be
      selected to continuous unemployment because of poor health at the two-year follow
      up seemed to deteriorate most. CONCLUSION: The high morbidity of mental health
      problems among unemployed people is mostly explained by the causal hypothesis.
      This is a challenge to preventive medicine. Sick unemployed people should be
      given special attention.

PMID- 10421717
TI  - Socio-economic characteristics and quality of life in diabetes mellitus--relation
      to metabolic control.
AB  - Diabetes mellitus is a chronic metabolic disease with wide implications for well
      being and social life. The aim of this cross-sectional, observational study was
      to describe possible differences in clinical characteristics, socio-economic
      factors and quality of life between diabetes patients in poor and good/acceptable
      metabolic control, as defined by levels of glycated haemoglobin A1c. From a
      population-based register of diabetes patients at a clinical chemistry
      department, we selected 96 subjects in poor metabolic control (HbA1c > 10%), and
      96 subjects in good/acceptable (HbA1c 6.5-7.5%) metabolic control, matched for
      sex, age and duration of diabetes. Each participant was sent a self-administered
      questionnaire regarding medical history, family situation and socio-economic
      background, as well as self-rated health based on a validated instrument (SF-36).
      The diabetes patients in poor metabolic control reported more retinopathy,
      vascular complications and nervous problems than did the patients in acceptable
      metabolic control. Furthermore, the group in poor metabolic control was also
      characterized by a lower educational level, a higher number of sick leave days or
      disability pension and a lower degree of physical activity. Both of the diabetic
      groups reported lower scorings for physical functioning, general health, vitality
      and mental health, than did a comparable non-diabetic group from another study.
      In summary, diabetic patients in poor metabolic control have a lower educational
      level and report more complications, nervous problems, sick leave days and
      disability pensions than patients in good/acceptable metabolic control. The lower
      degree of physical activity adds to the problems of the first group and should be
      the target for intervention to achieve better metabolic control.

PMID- 10421718
TI  - Functional status and need of help among people aged 90 or over: a mailed survey
      with a total home-dwelling population.
AB  - The aims of this study were to test the feasibility of a mailed survey in a
      population aged 90 years and over and to establish whether self-reported
      indicators of functioning and need of help predict mortality and
      institutionalization. A self-administered survey was mailed to the total home
      dwelling people aged 90 years or over in the city of Tampere (n = 448). The
      response rate was 81%. Confirmation of place of residence was carried out after
      12 months and a mortality follow-up was conducted after 18 months. Seventy-one
      percent of the home-dwelling respondents lived alone, 49% went out of doors
      regularly and 32% received help on a daily basis. Mortality was higher among the
      institutionalized people than among those living at home. Being bed-ridden, not
      doing one's own shopping, not reading newspapers and regular need of help were
      significant predictors of mortality. Regular need of help also predicted
      institutionalization. We conclude that the population aged 90+ is very
      heterogeneous. In good conditions a mailed survey can be a feasible method of
      collecting data even among the oldest-old.

PMID- 10421719
TI  - Characteristics of injured skiers in Norway. A case-control study.
AB  - A case-control study investigating the characteristics of injured versus
      uninjured skiers was carried out. The study comprised patients (n = 67) who had
      received medical treatment for ski injuries at a hospital in Norway in 1993, and
      controls (n = 227) taken from the same population but who had not sustained any
      ski injuries. The results showed that the hospital cases skied more often, were
      more confident in their skiing ability, had a higher education but that the
      younger members of this group tended to be less safety conscious compared with
      the corresponding controls. A reduction in the risk of ski injury might be
      possible if younger persons could be encouraged to adopt the same level of safety
      behaviour as older persons.

PMID- 10421720
TI  - Impairment and work disability due to whiplash injury following traffic
      collisions. An analysis of insurance material from the Swedish Road Traffic
      Injury Commission.
AB  - A study was set up to determine the trends in medical impairment and work
      disability ratings for persons affected by whiplash associated disorders (WAD)
      and other injuries secondary to road traffic collisions, and into the influence
      of age, gender, professional status, and final medical impairment rating on final
      work disability. A cross-sectional study was carried out of insurance files of
      2,523 subjects in 1989 and 3,223 subjects in 1994 judged to have a permanent
      medical impairment of 10% or more and work disability due to road traffic injury.
      Files were obtained from the Swedish Road Traffic Injury Commission. The main
      outcome measures were the crude frequency and age-specific, standardized
      percentage of traffic injuries with a medical impairment of 10% or more for the
      years 1989 and 1994. Final work disability status was analysed with respect to
      age, gender, type of injury, degree of medical impairment, and professional
      status. The proportion of medical impairment due to WAD was found to have
      increased from 16% in 1989 to 28% in 1994, but the proportion of work disability
      was found to have remained the same. Age over 40 years, low professional status,
      and having a medical impairment judgement of 15% or more were independently
      associated with reduced or full work disability.

PMID- 10421722
TI  - Effects of maternal education on infant mortality and stillbirths in Denmark.
AB  - This study examined inequalities in infant mortality in Denmark in relation to
      maternal educational level, and compared the inequalities to those observed in a
      similar study 10 years earlier. It was a register-based study of all singleton
      births in Denmark 1991-92, a study population of 113,814 births. When adjusted
      for mother's age, parity, and smoking, the stillbirth rate was independent of
      mother's educational level, but a clear social gradient in infant mortality was
      observed. Compared with a similar study in 1982-83, infant mortality has
      decreased most in the highest educational group and has increased in the lowest
      educational group. In conclusion, social inequality in infant mortality in
      Denmark is pronounced and cannot be explained by differences in smoking habits.
      The social gap between different educational groups has widened during the last
      decade, but may partly be explained by the decreasing number of women in the
      lowest educational group.

PMID- 10421721
TI  - Variation in referring newborns to special care in Finland.
AB  - We studied the frequency of referring newborns to special care in Finland and its
      variation between hospitals. Data was obtained from the nationwide Finnish Birth
      Register for 1991 and 1994. Newborns who during their first week of life had been
      in special care, in another hospital, in a respirator, or who had received a
      blood exchange were defined as having been in special care. This applied to 7% of
      newborns in 1991 and to 8% in 1994. The proportions of newborns in special care
      varied notably between hospitals of the same level. The differences could be
      explained by varying patient mixtures and different thresholds for referral to
      care. The indications for referring newborns into special care, especially in
      hospitals with high rates of referral, requires scrutiny.

PMID- 10421723
TI  - Is old age necessarily connected with high hospital admission rates?
AB  - The proportion of old people in a population is often taken as an indicator of
      the perceived need for and utilization of health services. What is the relation
      between age and hospital admission rates, and has it changed over time? These
      questions are investigated by a study of hospital statistics. In 1930
      hospitalization rates were approximately the same for all age groups. In 1950
      there was an increase with increasing age for men, but not for women, who had
      experienced a general increase in all age groups. In 1979 there was a pronounced
      increase in hospitalization rates in the high age groups for both sexes; this
      increase has been even more marked in the decades since. The number of admissions
      per 1,000 inhabitants over 64 years of age increased from 296 in 1979 to 418 in
      1993. Changes in diagnoses and operation patterns for old patients during the
      last decade illustrate marginal changes in disease patterns and a slight increase
      in some types of surgery. An increase in readmission rates contributes
      substantially to the overall increase. The proportion of old people in a
      population tells us very little about perceived need for health services and
      cannot be used to predict hospital admission rates.

PMID- 10421724
TI  - Drinking problems load health centre hospitals in Finland.
AB  - This study examined the reasons for referral of patients from general practice to
      health centre hospitals in central and northern Finland during one week in 1994.
      Participants were 806 general practitioners (GPs) from public health centres.
      Outcome measures were reasons for referral by ICPC codes, with respect to
      characteristics of patients, GPs, and practices. A total of 723 patients (1.4%)
      were referred from 53,633 consultations. Most referrals (532, 74%) were from out
      of hours consultations. The most commonly reported reasons for referral in the
      age group under 65 years were alcohol abuse for males and vertigo for females.
      For patients aged 65 or over, angina pectoris was the most common reason for
      referral for both male and female patients. Our results will be useful in
      developing primary healthcare and the training of GPs. Future research should
      focus on alcohol-related diseases in those patients referred to health centre
      hospitals.

PMID- 10421725
TI  - Coding of occupation for the "young cohort" of the Danish twin register. A
      resource for future epidemiologic research.
AB  - OBJECTIVES: Information on health-related outcomes and exposures is available in
      user-friendly computerized format for the "young cohort" of the Danish Twin
      Register born 1953-82. We incorporated occupation information within the database
      to facilitate future job-related studies. METHODS: Occupation information for the
      29,430 twins responding to a mailed questionnaire in 1995 was coded according to
      DISCO-88. The subjects were classified in three ways depending on the information
      available: directly from the 2,196 job titles listed in the DISCO-88 handbook,
      according to a set of predetermined rules, or by consensus if ambiguous
      information was provided. Two percent (2%) of the sample was recoded
      independently by two investigators to demonstrate coding consistency. RESULTS:
      Occupation could be directly coded using job titles for 61% of the sample; 15%
      were coded according to a set of rules or by consensus; 24% could not be coded.
      The recoded sample was 99% in agreement with the original coding. CONCLUSION:
      Occupation information has been incorporated within the extensive health-related
      database for the "young cohort" of the Danish Twin Register. This resource is
      available to researchers for future studies concerning occupation, health, and
      heredity using (1) the existing data (2) via linkage to other Danish databases,
      or (3) by contacting selected subjects directly.

PMID- 10421726
TI  - Research ethics committees: a comparative study of assessment of ethical
      dilemmas.
AB  - Research ethics committees (REC) constitute an important instrument for the
      regulation of biomedical research involving human beings. The purposes of this
      work were to study the ethical reasoning in RECs and to ascertain whether the
      composition of RECs has any bearing on the decisions subsequently made by them.
      We used a postal questionnaire, containing authentic cases of research ethical
      dilemmas, sent to the ten RECs in Sweden (n = 124) and to comparison groups
      consisting of 200 randomly selected medical researchers, 200 randomly selected
      healthcare politicians and 200 randomly selected district nurses. The average
      response rate was 68%. A difference was found in how REC members assess a project
      in comparison with researchers, healthcare politicians and district nurses.
      Differences depended on the type of project assessed. The study indicates that
      membership in RECs may exert a normative influence on its members. It is proposed
      that this investigation should be followed up by a study with a qualitative
      design.

PMID- 10421728
TI  - Colloidal Stability of Polymer Colloids with Variable Surface Charge.
AB  - Colloidal stability of two latexes with variable charge surface groups has been
      studied at a range of pH. Experimental log W vs log[electrolyte] plots were
      fitted using the DLVO theory, and values for the diffuse potential, psi(d), and
      the Hamaker constant, A, were obtained. Reasonable tendency was found for the
      diffuse potential of both latexes, decreasing when the surface charge decreased.
      However, the Hamaker constant, which was expected to be constant over the range
      of pH covered, also showed a decreasing behavior with decreasing charge. Several
      theories for the electric repulsive potential have been used to try to explain
      this paradoxing trend, although none of them was successful. Finally, two
      explanations are proposed, one based on coion adsorption and the other on the
      hairy layer model, although the first one seems to be the most probable on the
      basis of thermodynamics considerations. Copyright 1999 Academic Press.

PMID- 10421727
TI  - Polyacrylamide at Solid/Liquid Interfaces.
AB  - In the literature, the term polyacrylamide refers to neutral, hydrolyzed, and
      chemically modified polyacrylamide and in this sense polyacrylic acid may
      likewise be considered to consist of hydrolyzed acrylamide groups. These
      hydrosoluble polymers are employed in wide range of applications where the
      polymer characteristics at solid-liquid interfaces play an important role. The
      interaction with solid adsorbents is very complex since electrostatic, hydration,
      van der Waals, and other forces operate simultaneously. As in most applications
      the polyacrylamide is brought into contact with oxides, clays or soils, synthetic
      alumino-silicates, and aluminum oxide may be used as model adsorbents. Thus, with
      reference to the two systems polyacrylamide/alumino-silicate and
      polyacrylamide/aluminum oxide, the author attempts to define some of the
      interfacial processes affecting the adsorbed macromolecules and to describe
      certain interfacial characteristics of these complex systems. The main results
      are as follows. -Neutral polyacrylamide. Hydrogen bonding between acrylamide and
      neutral aluminol groups is responsible for adsorption and the amount of polymer
      adsorbed parallels the surface density of aluminol sites. At ambient temperature,
      the kinetics of layer formation is governed initially by the random deposition of
      solution macromolecules and finally by tunneling. Thermodynamic and kinetic
      considerations lead to a model where the majority of the adsorbed macromolecule
      share identical dynamic characteristics under equilibrium conditions. Departure
      from equilibrium induced by changing the polymer concentration in the supernatant
      phase greatly modifies the dynamic features of the adsorbed macromolecules. 
      Hydrolyzed polyacrylamide. Charge-charge interactions superimpose on the
      persistent effects of hydrogen bonding to alter the amount of polymer adsorbed
      and the adsorption kinetics. The strong affinity of hydrolyzed polyacrylamide for
      positively charged surfaces induces interfacial spreading of the adsorbed
      macromolecules and in some instances desorption of part of this population
      (overshoots). -Complexed polyacrylamide. The presence of positively charged,
      negatively charged, and neutral chain segments confers amphoteric character on
      the polymer chain. Strongly complexed polymers display fast adsorption, while
      initially weakly complexed polymers show delayed adsorption. In addition, under
      certain circumstances, the presence of hydrophobic microdomains confers an
      amphiphilic character on the macromolecules, which profoundly modifies the nature
      of the interaction forces. The specific interaction typical of neutral
      polyacrylamide progressively disappears with increasing hydrolysis until for
      polyacrylic acid the surface coverage corresponds to nonselective interfacial
      deposition. Extremely slow displacement of hydrophilic and hydrophobic groups are
      found to occur within the adsorbed layer. Despite the promising use of
      macromolecules in environmental strategies, a consideration of the complexity of
      the underlying interfacial phenomena points to the difficulties which may arise
      at short or long terms in such applications. Copyright 1999 Academic Press.

PMID- 10421729
TI  - Preparation of Cu Nanoparticles from Water-in-Oil Microemulsions.
AB  - Spherical Cu nanoparticles were synthesized in sodium dodecyl sulfate
      (SDS)/isopentanol/cyclohexane/water microemulsions with sodium borohydride as a
      reducing agent. Nanoparticles formed in microemulsions were characterized by
      transmission electron microscopy (TEM), x-ray diffractometry (XRD), and small
      angle X-ray scattering (SAXS). The size and polydisperity of particles were
      greatly affected by the mole ratio of water to surfactant (w) and the
      concentration of precursor salt. The ideal size and monodispersity of
      nanoparticles can be obtained at the smaller w value and lower concentration of
      Cu(2+) solution. Copyright 1999 Academic Press.

PMID- 10421730
TI  - Hyperbranched Polymers and Aggregates: Distribution Kinetics of Dendrimer Growth.
AB  - We present an analytic solution for growth of branched aggregates or polymers
      with distributed cluster (dendrimer) size. Monomer addition to each branch
      follows first-order polymerization kinetics leading to a distribution of branch
      lengths. The rate constant for monomer addition is considered diffusion
      dependent. Deterministic branching occurs so that at prescribed times t(j) (j >/=
      1), p branches emanate from the tip of a branch that began to grow at t(j-1).
      When the ratio of average branch lengths is constant, L(j)/L(j-1) = a, the
      fractal dimension of branches is ln(p)/ ||ln(a) ||. Closed expressions for
      cluster mass moments show unbounded growth with time unless ap < 1. The number of
      clusters (zeroth moment) is constant during growth and equal to the number of
      initiating buds. Expressions for the number of branches and clusters, average
      cluster mass, volume, density, and viscosity in solution are functions of p and
      a. Density and molecular weight show features similar to observed behavior of
      dendrimers and hyperbranched polymers. Copyright 1999 Academic Press.

PMID- 10421731
TI  - Adsorption of a Cationic Surfactant on Na-Montmorillonite: Inspection of
      Adsorption Layer by X-Ray and Fluorescence Spectroscopies.
AB  - The adsorption of the cationic surfactant BDDAC on a hydrophilic smectite
      (montmorillonite) surface has been investigated, especially in the range of low
      coverage ratios where surfactant ions are adsorbed through cation-exchange with
      the counterions of the clay. The surfactant coions (Cl(-)) were found to be
      adsorbed simultaneously with the cationic part after a complete alkyl ammonium
      ion-exchange of montmorillonite (CEC). We observe that organoclay particles
      remain flocculated in aqueous medium in almost all the range of adsorption
      isotherms up to 1.38 CEC and afterward redisperse incompletely. The intercalation
      of surfactant in the interlamellar space was followed by X-ray measurements.
      Fluorescence spectroscopy was used to obtain information about the adsorption
      layer at the interface. A calculation from geometrical considerations and from
      adsorption isotherms shows that below 1.38 CEC, there is a flat double layer in
      the interlamellar space and after this amount of adsorbed surfactant, an
      interstratified clay-surfactant mixed system is formed. Copyright 1999 Academic
      Press.

PMID- 10421732
TI  - Ultrathin Polymer Films on Gold Surfaces through Activation of Si-H Bonds.
AB  - Several poly(siloxane)s and a poly(silazane) were bound to gold surfaces by
      activation of Si-H bonds with cis-[PtCl(2)(PhCH&dbond;CH(2))(2)]. Under the
      reaction conditions used here, adsorption of the poly(siloxane) is observed
      exclusively in presence of the platinum compound. The resulting ultrathin layers
      were studied with IR spectroscopy at grazing incidence reflection, X-ray
      photoelectron spectroscopy, contact angle measurements, and ellipsometry. The
      layer thicknesses (2.9-5.2 nm) are in the typical range of polymer monolayers
      adsorbed on gold. The wetting properties of the modified gold substrates
      correspond to those of the pure polymers, indicating that the gold is covered to
      a high extent or completely with polymer. The highest contact angles of water
      (115 degrees ) were observed with Si-H-terminated poly(dimethylsiloxane) and are
      among the highest reported for an ultrathin layer on gold. We assume that the
      activator cleaves Si-H bonds. The polymers might be bound to the surface by Au-Si
      bonds or via Pt-Si species. Copyright 1999 Academic Press.

PMID- 10421733
TI  - The Use of XAFS to Distinguish between Inner- and Outer-Sphere Lead Adsorption
      Complexes on Montmorillonite.
AB  - Adsorption mechanisms of Pb on montmorillonite were investigated by conducting
      equilibrium and X-ray absorption fine structure (XAFS) spectroscopy studies. Data
      from the batch equilibrium studies indicate that Pb could be adsorbing via two
      mechanisms, depending on ionic strength. At low ionic strength (I = 0.006 M) Pb
      adsorption is pH-independent: 97% of the available Pb was removed from solution
      at pH 4.42 and 100% at pH 8.0. This behavior is consistent with an outer-sphere
      complexation mechanism. At high ionic strength (I = 0.1 M) Pb adsorption is pH
      dependent, suggesting inner-sphere complexation as the adsorption mechanism: 43%
      of the available Pb was removed from the solution at pH 4.11 and 98.9% at pH
      7.83. X-ray absorption near edge structure (XANES) and extended X-ray absorption
      fine structure (EXAFS) spectroscopy results reveal that in the sample
      equilibrated at I = 0.006 M, pH 4.48-6.40 the local atomic structure (LAS)
      surrounding the adsorbed Pb is similar to the LAS surrounding Pb(2+) (aq),
      confirming that the adsorption mechanism is outer-sphere complexation. In the
      system equilibrated at I = 0.1 M, pH 6.77 the XANES and EXAFS results show that
      the LAS surrounding the adsorbed Pb atom is similar to the LAS surrounding
      reference compounds in which Pb is forming covalent bonds (Pb(4)(OH)(4+)(4) (aq)
      and a sample of gamma-Al(2)O(3) with Pb adsorbed via inner-sphere complexation).
      These similarities indicate that Pb is forming inner-sphere complexes on the
      montmorillonite at this ionic strength and pH. In samples equilibrated at I =
      0.006 M, pH 6.77 and I = 0.1 M, pH 6.31 the XAFS results suggest that Pb is
      forming both inner- and outer-sphere adsorption complexes. This observation could
      not be distinguished by making macroscopic observations only. Thus, the results
      of this study reveal important information on Pb sorption behavior on clays and
      also provides insights into the use of XAFS to determine sorption mechanisms.
      Copyright 1999 Academic Press.

PMID- 10421734
TI  - Influence of Molecular Structure on the Ideality of Mixing in Micelles Formed in
      Binary Mixtures of Surface-Active Drugs.
AB  - The influence of the structure of the hydrophobic group on the ideality of mixing
      in binary mixtures of surface active molecules has been investigated using
      combinations of amphiphilic penicillins. Critical concentrations (cc) of the
      binary mixtures of these anionic surfactants were determined by conductivity
      measurements as a function of the composition. The nonideality of mixing was
      evaluated using a regular solution approximation and expressed in terms of the
      interaction parameter, beta. Mixing in micelles formed in binary mixtures of the
      structurally similar penicillins cloxacillin, dicloxacillin, and flucloxacillin
      was ideal (beta = 0). In contrast, the combination of either cloxacillin or
      dicloxacillin with the penicillin nafcillin produced mixed micelles in which the
      mixing deviated from ideality (beta = +0.1 to +0.2). The positive values of beta
      for these systems indicated negative synergism between components of the mixtures
      that may be a consequence of the marked structural differences between the
      hydrophobic groups of these drugs. The composition of the mixed micelles was
      derived from the cc data by application of a theoretical treatment based on
      excess thermodynamic quantities. Copyright 1999 Academic Press.

PMID- 10421735
TI  - Physicochemical Properties of Ursodeoxycholic Acid Dispersed in Controlled Pore
      Glass.
AB  - The objective of this study was to reduce the crystallinity of ursodeoxycholic
      acid (UDCA) by solid dispersion with controlled pore glass (CPG). To evaluate the
      effect of pore diameter and pore volume of CPG on the crystalline properties of
      UDCA, we used powder X-ray diffractometry (PXRD) and differential scanning
      calorimetry (DSC). PXRD patterns and the DSC data indicated the presence of UDCA
      in a crystalline state in the physical mixtures. It was found that amorphous UDCA
      could be formed via solid dispersion with CPG obtained by a solvent method. The
      DSC thermograms of solid dispersions showed that there were two states of UDCA,
      amorphous and crystalline. The amount of crystalline fraction in the solid
      dispersions depended on the pore size, pore volume, and the specific surface area
      of CPG. When UDCA was mixed with different pore diameters of CPG, it was found
      that UDCA molecules preferentially interacted with pores of smaller size.
      Copyright 1999 Academic Press.

PMID- 10421736
TI  - Electrokinetic Phenomena in Homogeneous Cylindrical Pores.
AB  - The electrokinetic phenomena occurring in homogeneous cylindrical pores
      containing symmetric electrolytes are studied. The local relations for flow in
      the pores (Nernst-Planck and Navier-Stokes equations) are developed. The analysis
      includes a numerical solution of the nonlinear Poisson-Boltzmann equation. The
      integral expressions of the phenomenological coefficients coupling the solvent
      flow and the electrical current with the hydrostatic pressure and the electrical
      potential gradients are established and calculated numerically. The mobilities of
      anions and cations are individually specified and the electroviscous effects as
      well as the surface conductance are taken into account. Streaming potentials
      obtained from numerical calculations are compared with results given by classical
      relations in a range of zeta potentials and electrokinetic radii that may
      commonly occur in experimental investigation of micro- and ultrafiltration
      membranes. In this work, it is shown that classical approximated relations can
      give rise to very misleading conclusions and that the determination of the true
      zeta potential requires a full analysis (including numerical calculations) of the
      basic relations for flow and potential distribution in charged pores. Copyright
      1999 Academic Press.

PMID- 10421737
TI  - Microencapsulation of Organic Solvents in Polyelectrolyte Multilayer Micrometer
      Sized Shells.
AB  - Hollow-shell micrometer-sized particles were fabricated in aqueous media by
      stepwise deposition of oppositely charged polyelectrolytes onto melamine latex
      particles and biological cells with a dissolution of the core afterward. It is
      demonstrated that these shells can be suspended in various organic media, such as
      methanol, ethanol, pentanol, hexanol, octanol, octane, and decane, by a gradual
      solvent exchange. At this stage of the procedure the shells contain the
      respective organic solvent. Oil suspensions in water are then formed by
      transferring the particles from the organic media into water, without the use of
      any further surfactant addition. By an additional adsorption step employing
      phospholipids, it is possible to obtain a dispersion of shells in organic
      solvents containing an aqueous solution inside. AFM measurements are provided
      which show that the shells preserve their integrity in the different solvents.
      Confocal microscopy is employed to demonstrate encapsulation of solvents and the
      presence of lipids. Copyright 1999 Academic Press.

PMID- 10421738
TI  - Acoustic Spectroscopy for Characterizing Heptane/H(2)O/AOT Reverse
      Microemulsions.
AB  - Acoustic spectroscopy was used to monitor the droplet size distribution in a
      classic three component system of heptane, water, and aerosol-OT (AOT). The size
      of the reverse microemulsion drops was varied by changing the molar ratio of
      water to AOT surfactant. The acoustic results for this transparent microemulsion
      were found to be in close agreement with literature results obtained with small
      angle neutron scattering and small angle X-ray scattering. The system was
      investigated well into the turbid region where microemulsion changes to
      macroemulsion. The droplet size distribution was found to shift to a bimodal form
      due to this transition. Copyright 1999 Academic Press.

PMID- 10421739
TI  - Influence of Thermal, Hydrothermal, and Acid-Base Treatments on Structural
      Stability and Surface Properties of Macro-, Meso-, and Microporous Carbons.
AB  - Effects of thermal treatment (at 723 K), hydrothermal treatment [low-pressure
      steam vapor (34 Torr) at 723 and 923 K and water (at autogenous pressure) at 398
      and 473 K], and acid-base treatment (at 473 K) on the structural stability and
      physical properties of porous carbon samples prepared from both natural and
      synthetic sources have been studied. These thermally, hydrothermally, and acid
      base-treated carbons have been characterized using BET, thermogravimetric, and
      infrared techniques. Investigations of the treated carbon samples revealed that
      the thermal stability, pore structure, pore size distribution, and surface area
      are strongly affected by the thermal, hydrothermal, and acid-base treatments. The
      method of sample treatment influences the order of thermal stability and porosity
      and surface area (differences in surface area were attributed to differences in
      porosity, based on micropore and total pore volume). FTIR studies show that the
      carbon structures are significantly influenced by the hydrothermal and acid-base
      treatments. The surface and pore structure modifications of the microporous
      carbon have also been studied by controlled air decomposition and high
      temperature aliphatic and aromatic organic vapor deposition. Copyright 1999
      Academic Press.

PMID- 10421741
TI  - Interactions between Two Spherical Particles with Nonuniform Surface Potentials:
      The Linearized Poisson-Boltzmann Theory.
AB  - Using the linearized Poisson-Boltzmann theory, electrical double layer
      interactions are calculated between two nonuniform spherical colloidal particles
      with mean potential zero. Most results are for the case of surface potentials
      modeled by a single spherical harmonic and aligned relative to each other. As
      previously observed for flat surfaces, interactions decay more rapidly as a
      function of separation between spheres with such periodic, "single-mode"
      potentials than between spheres with uniform potentials. The Deryaguin
      approximation for single-mode spheres is tested and calculations are made of the
      force and torque that particles in a doublet exert on one another. Many of the
      concepts developed from models of flat plates with periodic aligned surface
      potentials are shown to be useful in this more general case. Attempts to explain
      recent differential electrophoresis experiments on the basis of nonuniform double
      layers fail in that the maximum restraining torques produced under plausible
      assumptions about the amplitude of nonuniformity are an order of magnitude
      smaller than those implied by the measurements. The main reason for this is that
      the torques are too small at the separations characteristic of a secondary
      minimum. The effect of misalignment of single-mode spheres is assessed by
      calculating the distribution of interaction energies over a set of relative
      orientations generated by quasi-random sampling. Finally, a method for generating
      spheres with "random" surface potentials is devised and potentials of mean force
      are calculated for pairs of spheres with such surface potentials. Comparison with
      the single-mode case is kept at a qualitative level, in the absence of detailed
      knowledge of how realistic such "random" surfaces are. Copyright 1999 Academic
      Press.

PMID- 10421740
TI  - Rheological Evidence for the Silica-Mediated Gelation of Xanthan Gum.
AB  - In the present study, the conformational effects of the adsorbed polyelectrolyte
      xanthan gum on the stability of colloidal silica suspensions were investigated by
      monitoring the rheological responses. The conformational transition of xanthan
      molecules was induced by changes in pH, added salts, and annealing temperature.
      The suspension stability was probed by examining the rheological behavior such as
      shear viscosity versus shear rate and shear moduli versus oscillatory frequency.
      The oscillatory shear measurements provided useful information on the structural
      change in the suspension. The results showed that the silica particles dispersed
      in the xanthan solution remained stable at pH 9 for a long period, whereas at pH
      2, the gel network structure formed within a few days. When the gel structure
      formed, the storage modulus was larger than the loss modulus over the entire
      frequency range considered here and exhibited a thixotropic behavior. The heat
      treatment temperature best for stabilizing the silica suspension was shown about
      60 degrees C and the silica sol treated at this temperature sustained its
      stability for more than 6 weeks. Copyright 1999 Academic Press.

PMID- 10421742
TI  - Chemical and Structural Properties of Jordanian Zeolitic Tuffs and Their
      Admixtures with Urea and Thiourea: Potential Scavengers for Phenolics in Aqueous
      Medium.
AB  - Native Jordanian zeolitic tuffs, rich in phillipsite, were treated with urea and
      thiourea. The chemical and structural properties of the tuffs and their urea and
      thiourea admixtures were studied using SEM, XRF, XRD, and FTIR techniques, and
      their adsorption capacities were estimated by the methylene blue method. The urea
      and thiourea treatment has not affected the mineral constitution of the tuffs.
      The results revealed that urea and thiourea were linked by hydrogen bonding
      through the NH(2) moiety to the zeolite substrate, with urea showing the
      strongest effect. Experiments were carried out to investigate the possible use of
      the prepared materials for the removal of phenol and chlorinated phenols from
      aqueous solutions. Although thiourea caused a reduction in the relative surface
      area, both urea and thiourea admixtures were more effective than the free
      zeolitic tuff in the removal of phenol and chlorinated phenols from water, with
      urea admixture displaying the largest removal capacity. Copyright 1999 Academic
      Press.

PMID- 10421743
TI  - Effect of pH and Surface Chemistry on the Mechanism of H(2)S Removal by Activated
      Carbons.
AB  - The performances of three wood-based activated carbons as adsorbents of hydrogen
      sulfide were evaluated by dynamic breakthrough testing. The subsequent products
      of H(2)S oxidation on the carbon surfaces were analyzed. The adsorbents were
      studied using sorption of nitrogen, thermal analysis, Boehm titration, FTIR, ion
      chromatography, and temperature programmed desorption. Based on the results, the
      effects of surface chemistry and structural features on the yield of water
      soluble products and on the regenerability of the exhausted carbons were
      evaluated. The results showed that the breakthrough capacity and the yield on
      regeneration depend on the average pH of the carbon surface related to the pH in
      local pore environment. When the surface is very acidic, the dissociation of
      H(2)S is suppressed resulting in a very small concentration of hydrogen sulfide
      ions and thus in the formation of highly dispersed sulfur. Such conditions are
      favorable for oxidation of sulfur to S(4+) and S(6+). When the surface is less
      acidic the degree of dissociation is higher and the creation of polymeric
      elemental sulfur species resistant to further oxidation is more favorable. A
      small increase in pH (half a unit) in the acidic range results in a 15-fold
      increase in hydrogen sulfide breakthrough capacity accompanied by only a one
      third decrease in the yield of sulfur oxides. Copyright 1999 Academic Press.

PMID- 10421744
TI  - The Electrostatic Interactions between Two Corrugated Charged Planes.
AB  - The surfaces of association colloids often undergo undulating motion due to
      thermal fluctuations. The electrostatic interactions between two charged planes
      of arbitrary corrugation are investigated on the basis of the Poisson-Boltzmann
      equation under the Debye-Huckle approximation. The surfaces are parallel and
      subject to the spatial periodicity of the amplitude A and wavelength q(-1). When
      the amplitude is small compared to the wavelength, i.e., (qA)(2) << 1, the
      electric field can be calculated by using the perturbation method. The
      interaction free energy is then obtained for surfaces associated with the
      condition of either constant surface potential or constant surface charge density
      during interactions. The effects of the amplitude and phase angle on the
      interaction energy are discussed and asymptotic expressions are obtained when the
      mean separation is large compared to the amplitude. At the same mean separation,
      the interaction energy for the corrugated surfaces is always higher than that for
      the planar surfaces. In other words, undulation enhances the electrostatic
      repulsion. The repulsive energy is minimum when the two surfaces are in-phase and
      maximum for the out-of-phase mode. Copyright 1999 Academic Press.

PMID- 10421745
TI  - Coagulation Kinetics and Mechanical Behavior of Wet Alumina Green Bodies Produced
      via DCC.
AB  - Ceramic green bodies can be produced by enzyme-catalyzed reactions from
      suspensions with high solids loading. There are two ways of destabilizing an
      electrostatically stabilized suspension: shifting the pH to the isoelectric point
      (IEP) or increasing the ionic strength. Both can be done via the urease-catalyzed
      decomposition of urea. The properties of wet green bodies produced by these two
      methods were compared using compressive strength measurements. Ionic-strength
      samples needed 24 h or more to achieve sufficient strength because the high urea
      concentrations required for these slurries inhibit the enzyme. Due to the long
      coagulation time and to the weak attractive forces formed, the particles can
      rearrange. This causes the wet green strength and the Young's modulus of these
      bodies to be considerably higher than those of the pH shift bodies. For the
      latter, coagulation needs only about one hour, and the interparticle attractive
      forces are strong. pH shift bodies are more or less insensitive to vibration,
      whereas ionic-strength bodies tend to flow under oscillatory stress. Copyright
      1999 Academic Press.

PMID- 10421746
TI  - Effects of Hydrophobizing Methods of Surfaces on the Interaction in Aqueous
      Solutions.
AB  - The hydrophobic interaction between the surfaces hydrophobized by the adsorption
      of STAC in a STAC solution (system I) and the interaction between the surfaces
      hydrophobized by the reaction with OTS in water (system II) were investigated
      using an atomic force microscope, and their difference was compared. Clear
      differences of the interaction between systems I and II were found with respect
      to the force curves and the morphology of the surfactants adsorbed on the
      surfaces. It is postulated that the hydrophobic interaction for system II is
      attributable to the cavity bridging between the surfaces, but that for system I
      it is originated from a different mechanism. It is also implied that the
      existence of the surfactants in the bulk will play an important role for the
      hydrophobic interaction. Copyright 1999 Academic Press.

PMID- 10421747
TI  - Adhesive Force between Hydrophilic Surfaces in Alcohol-Water Solutions.
AB  - The interaction and adhesive forces between a mica plate and SiO(2) surfaces in
      water-alcohol (ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol) mixtures
      were investigated on the molecular scale, using an atomic force microscope. The
      following results were obtained: (i) alcohols higher than 1-propanol adsorb
      standing on the hydrophilic surface vertically to form a structured monolayer,
      when the alcohol concentration is high enough; (ii) the adhesive force between
      surfaces depends on how closely two surfaces can be brought by breaking the
      adsorbed layers; (iii) the adhesive force between surfaces is maximized at
      w(w)/w(ws) approximately 0.25, independent of the kind of alcohol, where w(w) and
      w(ws) are the weight fractions of water and saturated water, respectively; and
      (iv) the adhesive force for a particle of rough surface is much smaller than the
      adhesive force predicted for a particle of smooth surface. It is hypothesized
      that this adhesive force much greater than the van der Waals attractive force
      originates from the water bridging between surfaces, and this hypothesis is
      confirmed by the predictions given by the Laplace equation and the Kelvin
      relation. Copyright 1999 Academic Press.